PMID- 21648461 TI - Microstructure-based modeling of aging mechanisms in catalyst layers of polymer electrolyte fuel cells. AB - This work is comprised of a versatile multiscale modeling of carbon corrosion processes in catalyst layers (CLs) of polymer electrolyte fuel cells (PEFCs). Slow rates of electrocatalytic processes in CLs and materials aging are the main sources of voltage loss in PEFCs under realistic operating conditions. We combined microstructure data obtained from coarse-grained molecular dynamics (CGMD) simulations with a detailed description of the nanoscale elementary kinetic processes and electrochemical double-layer effects at the catalyst/electrolyte and carbon/electrolyte interfaces. We exclusively focused on morphology and microstructure changes in the catalyst layer of PEFCs as a result of carbon corrosion. By employing extensive CGMD simulations, we analyzed the microstructure of CLs as a function of carbon loss and in view of ionomer and water morphology, water and ionomer coverage, and overall changes in carbon surface. These ingredients are integrated into a kinetic model, which allows capture of the impact of the structural changes on the PEFC performance decay. In principle, such multiscale simulation studies allow a relation of the aging of CLs to the selection of carbon particles (sizes and wettability), the catalyst loading, and the level of ionomer structural changes during the CL degradation process. PMID- 21648460 TI - Design, synthesis, and diversification of 3,5-substituted enone library. AB - This paper describes the synthesis of a 300 member library of 3,5-substituted enones. The synthesis starts with 6 different bromoenones that are accessed from the corresponding 1,3 diones. These bromides are then diversified by Suzuki coupling with a variety of aromatic and vinyl boronic acids. Additionally a small series of triazoles was synthesized by a Sonogashira coupling reaction dipolar cycloaddition sequence. The library was analyzed by principal component analysis to examine its diversity. PMID- 21648462 TI - Effects of Cu ions and explicit water molecules on the copper binding domain of amyloid precursor protein APP(131-189): a molecular dynamics study. AB - Amyloid precursor protein (APP) is a cell-surface trans-membrane glycoprotein that appears to play an important role in in vivo Cu ion homeostasis. This protein includes a copper-binding-domain (CuBD) fragment consisting of residues 124-189, of which His147, His151, Tyr168, and possibly Met170 comprise the explicit Cu-binding site (CuBS). Molecular dynamics (MD) simulations are carried out on Cu-free and Cu-bound APP models, based on crystal structures including residues 131-189 obtained from the Protein Data Bank, to confirm the site of Cu ion binding and to elucidate the effects of the oxidation state of the Cu ions (default GROMACS parameters modeled only the electrostatic binding to the Cu ions at the CuBS) and explicit water molecules on the conformational properties of the 131-189 residue portion of the CuBD. MD trajectory analysis demonstrated a conformational change of Met170. The sulfur atom of Met170 moves closer to the Cu(II) ion and away from Cu(I), and this change may play an important role in the reduction of Cu(II) and the release of Cu(I). Two explicit water molecules were included in the MD simulations. These water molecules that bind strongly to the Cu ions via their lone pair electrons result in a significant modification of the binding interactions with the other residues at the CuBS. PMID- 21648463 TI - Efficient three-step one-pot synthesis of a novel 2,3,5-substituted pyrazine library. AB - The partnership between rational synthesis design and mass-triggered preparative LCMS is a powerful one, capable of furnishing very large libraries in a selective manner in a very short space of time. Herein, we communicate one example of possibly a perfect marriage between the synthetic chemistry and the subsequent purification method employed, affording a ~1000-member library supplying 50 mg on average of final compound in less than a month. PMID- 21648465 TI - The electronically excited states of LH2 complexes from Rhodopseudomonas acidophila strain 10050 studied by time-resolved spectroscopy and dynamic Monte Carlo simulations. I. Isolated, non-interacting LH2 complexes. AB - We have employed time-resolved spectroscopy on the picosecond time scale in combination with dynamic Monte Carlo simulations to investigate the photophysical properties of light-harvesting 2 (LH2) complexes from the purple photosynthetic bacterium Rhodopseudomonas acidophila. The variations of the fluorescence transients were studied as a function of the excitation fluence, the repetition rate of the excitation and the sample preparation conditions. Here we present the results obtained on detergent solubilized LH2 complexes, i.e., avoiding intercomplex interactions, and show that a simple four-state model is sufficient to grasp the experimental observations quantitatively without the need for any free parameters. This approach allows us to obtain a quantitative measure for the singlet-triplet annihilation rate in isolated, noninteracting LH2 complexes. PMID- 21648464 TI - Enantioselective construction of all-carbon quaternary centers by branch selective Pd-catalyzed allyl-allyl cross-coupling. AB - The Pd-catalyzed cross-coupling of racemic tertiary allylic carbonates and allylboronates is described. This reaction generates all-carbon quaternary centers in a highly regioselective and enantioselective fashion. The outcome of these reactions is consistent with a process that proceeds by way of 3,3' reductive elimination of bis(eta(1)-allyl)palladium intermediates. Strategies for distinguishing the product alkenes and application to the synthesis of (+)-alpha cuparenone are also described. PMID- 21648466 TI - Electron-induced dissociation of CO2 on TiO2(110). AB - The electron-induced dissociation of CO(2) adsorbed at the oxygen vacancy defect on the TiO(2)(110) surface has been investigated at the single-molecular level using scanning tunneling microscopy (STM). Electron injection from the STM tip into the adsorbed CO(2) induces the dissociation of CO(2). The oxygen vacancy defect is found to be healed by the oxygen atom released during the dissociation process. Statistical analysis shows that the dissociation of CO(2) is one electron process. The bias-dependent dissociation yield reveals that the threshold energy for electron-induced dissociation of CO(2) is 1.4 eV above the conduction-band minimum of TiO(2). The formation of a transient negative ion by the injected electron is considered to be the key process in CO(2) dissociation. PMID- 21648467 TI - Facile synthesis of highly fluorescent Boranil complexes. AB - Complexation of a large variety of Anils (aniline-imines) with boron(III) precursors provides stable Boranils, some of which have been structurally characterized. Analysis of their optical properties reveals that the fluorescence stems from an intraligand charge transfer (ILCT) state with the best quantum yields reaching 90%. Chemistry on the Boranils allows grafting of photoactive modules acting as energy antennae for borondipyrromethene (Bodipy) and subphtalocyanine (SubPc) fluorophores. PMID- 21648468 TI - Enhanced capacitance of composite anodic ZrO2 films comprising high permittivity oxide nanocrystals and highly resistive amorphous oxide matrix. AB - Anodic oxide films with nanocrystalline tetragonal ZrO(2) precipitated in an amorphous oxide matrix were formed on Zr-Si and Zr-Al alloys and had significantly enhanced capacitance in comparison with those formed on zirconium metal. The capacitance enhancement was associated with the formation of a high temperature stable tetragonal ZrO(2) phase with high relative permittivity as well as increased ionic resistivity, which reduces the thickness of anodic oxide films at a certain formation voltage. However, there is a general empirical trend that single-phase materials with higher permittivity have lower ionic resistivity. This study presents a novel material design based on a nanocrystalline-amorphous composite anodic oxide film for capacitor applications. PMID- 21648469 TI - Investigation of ionic conductivity and long-term stability of a LiI and KI coupled diphenylamine quasi-solid-state dye-sensitized solar cell. AB - In this work, enhancement of ionic conductivity and long-term stability through the addition of diphenylamine (DPA) in poly(ethylene oxide) (PEO) is demonstrated. Potassium iodide (KI) is adopted as the crystal growth inhibitor, and DPA is used as a charge transport enhancer in the electrolyte. The modified electrolyte is used with titanium dioxide (TiO2) nanoparticles, which is systematically tuned to obtain high surface area. The dye-sensitized solar cell (DSSC) showed a photocurrent of 14 mAcm2 with a total conversion efficiency of 5.8% under one sun irradiation. DPA enhances the interaction of the TiO2 nanoparticle film and the I-/I3- electrolyte leading to high ionic conductivity (3.5 * 10-3 Scm-1), without compromising on the electrochemical and mechanical stability. Electrochemical impedance spectroscopy (EIS) studies show that electron transport and electron lifetime are enhanced in the DPA added electrolyte due to reduced sublimation of iodine. The most promising feature of the electrolyte is increased device stability with 89% of the overall efficiency preserved even after 40 days. PMID- 21648471 TI - Copper-glucosamine microcubes: synthesis, characterization, and C-reactive protein detection. AB - Cubelike microstructures of glucosamine-functionalized copper (GlcN-CuMC's) have been fabricated by the integration of injection pump and ultrasonochemistry. Although bulk microstructures and the nanostructure of metallic copper exhibit distinct applications, the amino sugar surface-functionalized copper is almost biocompatible and exhibits advanced features such as more crystallinity, high thermal stability, and electrochemical feasibility toward biomolecule (C-reactive protein, CRP) detection. An electrochemical test of this GlcN-CuMC's was demonstrated by immobilization on a conventional gold-PCB (Au-PCB) electrode. The combination of a biointerface membrane, from glucosamine functionalization, and electroactive sites of metallic copper provides a very efficient electrochemical response against various concentration of CRP. A perfect scaling of steady-state currents with r(2) values of 0.9862 (I(pa)) and 0.9972 (I(pc)) indicate the promise of this kind of biofunctionalized microstructure electrode for many surface and interface applications. PMID- 21648472 TI - Delayed fluorescence in perhydrotriphenylene-oligothiophene inclusion compounds: evidence for molecular oxygen-related excited States. AB - Delayed emission from alpha-terthiophene (3T) and alpha-quinquethiophene (5T) in a perhydrotriphenylene (PHTP) host is investigated. Delayed fluorescence for the lowest singlet excited state of 3T and 5T is detected at both low (80 K) and room temperatures. In addition, at low temperature, phosphorescence from 3T is observed with a lifetime of ~100 MUs. Comparison of the dependence of delayed fluorescence and phosphorescence on excitation intensity and time shows that delayed fluorescence does not originate from triplet--triplet annihilation. A dependence of the delayed fluorescence on atmospheric pressure indicates that it originates, at least partially, from complexes of photoexcited oligothiophene and molecular oxygen O(2). PMID- 21648473 TI - Thermodynamic behavior of the binaries 1-butylpyridinium tetrafluoroborate with water and alkanols: their interpretation using 1H NMR spectroscopy and quantum chemistry calculations. AB - Here we present experimental data of different properties for a set of binary mixtures composed of water or alkanols (methanol to butanol) with an ionic liquid (IL), butylpyridinium tetrafluoroborate [bpy][BF(4)]. Solubility data (x(IL),T) are presented for each of the mixtures, including water, which is found to have a small interval of compositions in IL, x(IL), with immiscibility. In each case, the upper critical solubility temperature (UCST) is determined and a correlation was observed between the UCST and the nature of the compounds in the mixtures. Miscibility curves establish the composition and temperature intervals where thermodynamic properties of the mixtures, such as enthalpies H(m)(E) and volumes V(m)(E), can be determined. Hence, at 298.15 and 318.15 K these can only be found with the first four alkanols. All mixing properties are correlated with a suitable equation xi (x(IL),T,Y(m)(E) = 0. An analysis on the influence of the temperature in the properties is shown, likewise a comparison between the results obtained here and those of analogous mixtures, discussing the position of the CH(3) group in the pyridinic ring. The (1)H NMR spectra are determined to analyze the molecular interactions present, especially those due to hydrogen bonds. Additional information about the molecular interactions and their influence on the mixing properties is obtained by quantum chemistry calculations. PMID- 21648474 TI - Mesoporous TiO2 core-shell spheres composed of nanocrystals with exposed high energy facets: facile synthesis and formation mechanism. AB - A facile new method that combines electrospray and hydrothermal treatment is used to prepare mesoporous core-shell TiO(2) spheres with high specific surface areas and high pore volumes. Interestingly, the resulting TiO(2) spheres are composed of anatase TiO(2) nanocrystals with exposed step-like {001} and smooth {010} facets. The percentage of exposed {001} facets can be adjusted by changing the experimental parameters used in the electrospray and hydrothermal treatment processes, such as the contents of poly(N-vinyl-2-pyrrolidone) and acetic acid. The combination of high specific surface area (>100 m(2) g(-1)), high pore volume (>0.30 cm(3) g(-1)), useful pore size (10-15 nm), spherical core-shell structure, and exposed high energy facets makes these TiO(2) spheres an important candidate for use in many photoelectrochemical applications. The formation mechanism of the mesoporous TiO(2) spheres is also studied. The great advantage of this method is that interesting and complicated mesoporous superstructures can be prepared using electrospray technology. PMID- 21648475 TI - Evaluation of different nonspecific binding blocking agents deposited inside poly(methyl methacrylate) microfluidic flow-cells. AB - Poly(methyl methacrylate) (PMMA) flow-cells containing microwells were deposited with different nonspecific binding blocking agents, namely, bovine serum albumin (BSA), cationic lipid (DOTAP:DOPE) and diethylene glycol dimethyl ether (DEGDME). Water contact angle (WCA) and atomic force microscope (AFM) measurements were carried out to confirm the successful depositions of BSA, DOTAP, and DEGDME onto the PMMA surfaces. Fluorescent intensity measurements were performed to evaluate the degree of nonspecific adsorption of Cy5-labeled anti-IgG proteins onto plain and oxygen plasma-treated (PT) PMMA flow-cells as well as PMMA flow-cells deposited with different above-mentioned blocking agents. We then employed a label-free detection method called total internal reflection ellipsometry (TIRE) to evaluate the stability of the deposited blocking agents inside the PMMA flow cells. It was found that, while DOTAP:DOPE was the best agent for blocking the nonspecific adsorption, it could be removed from the PMMA surfaces of the flow cells upon rinsing with phosphate buffered saline (PBS) and later deposited back onto the Au-coated glass sensing substrate of the TIRE. The removal of the blocking agents from PMMA surfaces and their deposition onto the sensing substrate were further manifested by measuring the kinetics and the amount of adsorbed anti-alpha-hCG proteins. Overall, the dry DEGDME coating by plasma enhanced chemical vapor deposition (PECVD) showed very good blocking and excellent stability for subsequent assay inside the microwells. Our results could be useful when one considers what blocking agents should be used for PMMA-based microfluidic immunosensor or biosensor devices by looking at both the blocking efficiency and the stability of the blocking agent. PMID- 21648476 TI - Determination of the hydrogen-bonding induced local viscosity enhancement in room temperature ionic liquids via femtosecond time-resolved depleted spontaneous emission. AB - The fluorescence depletion dynamics of Rhodamine 700 (R-700) molecules in room temperature ionic liquids (RTILs) 1-ethyl-3-methylimidazolium tetrafluoroborate ([emim][BF(4)]) and 1-hydroxyethyl-3-methylimidazolium tetrafluoroborate ([HOemim][BF(4)]) were investigated to determine the local viscosity of the microenvironment surrounding the fluorescent molecules, which is induced by strong hydrogen bonding interaction between cationic and anionic components in RTILs. The solvation and rotation dynamics of R-700 molecules in RTILs show slower time constants relative to that in conventional protic solvents with the same bulk viscosity, indicating that the probe molecule is facing a more viscous microenvironment in RTILs than in conventional solvents because of the strong hydrogen bonding interaction between cationic and anionic components. In addition, this effect is more pronounced in hydroxyl-functionalized ionic liquid than in the regular RTIL due to the presence of a hydroxyl group as a strong hydrogen bonding donor. The hydrogen-bonding-induced local viscosity enhancement effect related to the heterogeneity character of RTILs is confirmed by the nonexponential rotational relaxation of R-700 determined by time-correlated single photon counting (TCSPC). The geometry of hydrogen bonding complexes with different components and sizes are further optimized by density functional theory methods to show the possible hydrogen-bond networks. A model of the hydrogen bonding network in RTILs is further proposed to interpret the observed specific solvation and local viscosity enhancement effect in RTILs, where most of the fluoroprobes exist as the free nonbonding species in the RTIL solutions and are surrounded by the hydrogen-bonding network formed by the strong hydrogen-bonding between the cationic and anionic components in RTIL. The optimized geometry of hydrogen bonding complexes with different components and sizes by density functional theory methods confirms the local viscosity enhancement effect deduced from fluorescence depletion and TCSPC experiments. The calculated interaction energies reveal the existence of the stronger hydrogen bonding network in RTILs (especially in hydroxyl-functionalized ionic liquid) than that in conventional protic solvent, which leads to the enhancement effect of local microviscosity, and therefore leads to the slow solvation and rotation dynamics of probe molecules observed in RTILs. PMID- 21648477 TI - Total synthesis and absolute stereochemical assignment of kibdelone C. AB - Kibdelones are hexacyclic tetrahydroxanthones and potent anticancer agents isolated from an Australian microbe. Herein, we describe the synthesis of a chiral, nonracemic iodocyclohexene carboxylate EF ring fragment of the kibdelones employing an intramolecular iodo halo-Michael aldol reaction and its merger with an ABCD ring fragment to afford the congener kibdelone C. PMID- 21648478 TI - Enantioselective total synthesis of (-)-kibdelone C. AB - The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton. PMID- 21648479 TI - Semiempirical quantum mechanical method PM6-DH2X describes the geometry and energetics of CK2-inhibitor complexes involving halogen bonds well, while the empirical potential fails. AB - In the present study, we have investigated complexes of CK2 protein kinase with halogenated inhibitors by means of the advanced semiempirical quantum mechanical (SQM) PM6 method (called PM6-DH2X), which describes various types of noncovalent interactions including halogen bonding well. The PM6-DH2X method provides reliable geometries of those CK2 protein kinase-inhibitor complexes involving halogen bonds that agree well with the X-ray crystal structures. When the Amber empirical potential is applied, this agreement becomes considerably worse. Similarly, the binding free energies determined by the PM6-DH2X SQM method are much closer to the experimental inhibition constants than those based on the Amber empirical potential. PMID- 21648480 TI - Imaging carbon nanotube interactions, diffusion, and stability in nanopores. AB - We report optical microscopy measurements of three-dimensional trajectories of individual multiwalled carbon nanotubes (MWCNTs) in nanoscale silica slit pores. Trajectories are analyzed to nonintrusively measure MWCNT interactions, diffusion, and stability as a function of pH and ionic strength. Evanescent wave scattering is used to track MWCNT positions normal to pore walls with nanometer scale resolution, and video microscopy is used to track lateral positions with spatial resolution comparable to the diffraction limit. Analysis of MWCNT excursions normal to pore walls yields particle-wall potentials that agree with theoretical electrostatic and van der Waals potentials assuming a rotationally averaged potential of mean force. MWCNT lateral mean square displacements are used to quantify translational diffusivities, which are comparable to predictions based on the best available theories. Finally, measured MWCNT pH and ionic strength dependent stabilities are in excellent agreement with predictions. Our findings demonstrate novel measurement and modeling tools to understand the behavior of confined MWCNTs relevant to a broad range of applications. PMID- 21648481 TI - Spectroscopic and electronic structure studies of a dimethyl sulfoxide reductase catalytic intermediate: implications for electron- and atom-transfer reactivity. AB - The electronic structure of a genuine paramagnetic des-oxo Mo(V) catalytic intermediate in the reaction of dimethyl sulfoxide reductase (DMSOR) with (CH(3))(3)NO has been probed by electron paramagnetic resonance (EPR), electronic absorption, and magnetic circular dichroism (MCD) spectroscopies. EPR spectroscopy reveals rhombic g- and A-tensors that indicate a low-symmetry geometry for this intermediate and a singly occupied molecular orbital that is dominantly metal centered. The excited-state spectroscopic data were interpreted in the context of electronic structure calculations, and this has resulted in a full assignment of the observed MCD and electronic absorption bands, a detailed understanding of the metal-ligand bonding scheme, and an evaluation of the Mo(V) coordination geometry and Mo(V)-S(dithiolene) covalency as it pertains to the stability of the intermediate and electron-transfer regeneration. Finally, the relationship between des-oxo Mo(V) and des-oxo Mo(IV) geometric and electronic structures is discussed relative to the reaction coordinate in members of the DMSOR enzyme family. PMID- 21648482 TI - Water boiling inside carbon nanotubes: toward efficient drug release. AB - We show using molecular dynamics simulation that spatial confinement of water inside carbon nanotubes (CNTs) substantially increases its boiling temperature and that a small temperature growth above the boiling point dramatically raises the inside pressure. Capillary theory successfully predicts the boiling point elevation down to 2 nm, below which large deviations between the theory and atomistic simulation take place. Water behaves qualitatively different inside narrow CNTs, exhibiting transition into an unusual phase, where pressure is gas like and grows linearly with temperature, while the diffusion constant is temperature-independent. Precise control over boiling by CNT diameter, together with the rapid growth of inside pressure above the boiling point, suggests a novel drug delivery protocol. Polar drug molecules are packaged inside CNTs; the latter are delivered into living tissues and heated by laser. Solvent boiling facilitates drug release. PMID- 21648483 TI - Deiodination of thyroid hormones by iodothyronine deiodinase mimics: does an increase in the reactivity alter the regioselectivity? AB - Organoselenium compounds as functional mimics of iodothyronine deiodinase are described. The naphthyl-based compounds having two selenol groups are remarkably efficient in the inner-ring deiodination of thyroxine. The introduction of a basic amino group in close proximity to one of the selenol moieties enhances the deiodination. This study suggests that an increase in the nucleophilic reactivity of the conserved Cys residue at the active site of deiodinases is very important for effective deiodination. PMID- 21648484 TI - Insights on the role of (dis)order from protein-protein interaction linear free energy relationships. AB - Protein-protein interactions (PPIs) are remarkably diverse and form the basis for various cellular functions. PPIs can be classified as ordered or disordered; the disordered ones do not have a well-defined structure prior to association, which is an exception to the conventional structure-function relationship. The occurrence of disordered proteins in functional roles is not explained by the conventional structure-function paradigm, and at present there is no clear understanding of the differences between the natures of these two PPIs. In this work, we studied the relationship between the kinetics and thermodynamics in PPIs to provide insights into the latter, with possible implications for the former. Analyzing the experimental data for various protein complexes, we found linear free-energy behavior with a striking kinetic difference between these two types of interactions. Binding affinities of (dis)ordered proteins are correlated with their (association) dissociation rates. Our observation, combined with the correspondence between biological activity and affinity, suggests that selection pressure on the dissociation or association kinetics in a functional context necessitates the presence of (dis)order in the structure. PMID- 21648485 TI - High-performance electron-transporting polymers derived from a heteroaryl bis(trifluoroborate). AB - In this communication, we report that dipotassium aryl bis(trifluoroborate)s make stable and easy-to-purify yet reactive monomers under Suzuki polycondensation reactions. A bis(trifluoroborate) of 2-alkylbenzotriazole was prepared successfully and copolymerized with dibromobenzothiadiazole in the presence of a Pd catalyst and LiOH, yielding high molecular weight conjugated polymers. This polymer (P1) composed of all electron-accepting units shows excellent electron transport properties (MU(e) = 0.02 cm(2) V(-1) s(-1)), which proves the value of the aryl bis(trifluoroborate) monomers and suggests that many other types of semiconducting polymers that could not be accessed previously can be synthesized using this approach. PMID- 21648486 TI - Structural basis for the exceptional stability of bisaminoacylated nucleotides and transfer RNAs. AB - At least one bisaminoacyl-tRNA is synthesized in nature (by Thermus thermophilus phenylalanyl-tRNA synthetase), and many disubstituted tRNAs have been prepared in vitro. Such misacylated tRNAs are able to participate in protein synthesis, even though they lack the free 2'-OH group of the 3'-terminal adenosine moiety. Their ready participation in protein synthesis implies significant chemical reactivity. The basis for this reactivity has been documented previously. Surprisingly, the aminoacyl moieties of these tRNAs also exhibit exceptional chemical stability. In the present report, bisaminoacylated nucleotides are investigated computationally and experimentally to define the basis for the stability of such species. Molecular modeling of bisalanyl-AMP in the absence of solvent and in the presence of a limited number of water molecules revealed two common features among the low energy structures. The first was the presence of H-bonding interactions between the two aminoacyl moieties. The second was the presence of a H-bonding interaction between the 2'-O-alanyl moiety and the N-3 atom of the adenine nucleobase, typically mediated through a water molecule. The prediction of an interaction between an aminoacyl moiety and the adenine nucleobase was confirmed experimentally by comparing the behavior of bisalanyl-AMP and bisalanyl-UMP in the presence of model nucleophiles. This study suggests a possible role for the adenosine moiety at the 3'-end of aminoanyl-tRNAs in controlling the stability and reactivity of the aminoacyl moiety and has important implications for the reactivity and stability of normal aminoacyl-tRNAs. PMID- 21648489 TI - Other/miscellaneous. PMID- 21648487 TI - Exploring the folding free energy landscape of a beta-hairpin miniprotein, chignolin, using multiscale free energy landscape calculation method. AB - The folding process for a beta-hairpin miniprotein, chignolin, was investigated by free energy landscape (FEL) calculations using the recently proposed multiscale free energy landscape calculation method (MSFEL). First, coarse grained molecular dynamics simulations searched a broad conformational space, then multiple independent, all-atom molecular dynamics simulations with explicit solvent determined the detailed local FEL using massively distributed computing. The combination of the two models enabled efficient calculation of the free energy landscapes. The MSFEL analysis showed that chignolin has an intermediate state as well as a misfolded state. The folding process is initiated by the formation of a beta-hairpin turn, followed by the formation of contacts in the hydrophobic core between Tyr2 and Trp9. Furthermore, mutation of Tyr2 shifts the population to the misfolded conformation. The results indicate that the hydrophobic core plays an important role in stabilizing the native state of chignolin. PMID- 21648491 TI - Conflicts of interest. PMID- 21648490 TI - Other/miscellaneous. PMID- 21648503 TI - Research Watch: Nitrogen saturation in western U.S. ecosystems. PMID- 21648505 TI - EPA Watch: Landfill emissions rule has small impact. PMID- 21648504 TI - EPA Watch: Prevention incorporated into furniture-making MACT. PMID- 21648506 TI - EPA Watch: Superfund soil screening guidelines published. PMID- 21648507 TI - EPA Watch: More public comment on waste permits. PMID- 21648508 TI - EPA Watch: Costs of Great Lakes Guidance confirmed. PMID- 21648509 TI - EPA Watch: Low-VOC products could earn EPA "green label". PMID- 21648510 TI - News: EPA considers standard for airborne fine particles. PMID- 21648519 TI - News briefs: news briefs. PMID- 21648520 TI - Environment On-line: A Guide to Internet Resources. AB - The new medium is gradually establishing itself as an essential tool for environmental professionals. PMID- 21648521 TI - Peer reviewed: the u.s. Dioxin inventory: are there missing sources? AB - Some attempts to balance atmospheric emissions of dioxins with deposition have suggested "missing sources." But the evidence disappears in the uncertainties in deposition data. PMID- 21648528 TI - Other/miscellaneous. PMID- 21648524 TI - New products: new products. PMID- 21648529 TI - Other/miscellaneous. PMID- 21648535 TI - Research Watch: New model of alternative bioremediation methods. PMID- 21648530 TI - Preservation and wonder. PMID- 21648544 TI - EPA Watch: Regulatory delays. PMID- 21648543 TI - EPA Watch: Ambient air standards get Air Office priority. PMID- 21648545 TI - EPA Watch: Solid waste office focuses LDRs/combustion rule. PMID- 21648547 TI - EPA Watch: TRI deadline extended. PMID- 21648546 TI - EPA Watch: Drinking-water data collection rule delayed. PMID- 21648548 TI - EPA Watch: Acid rain rule lowers Nox emissions limits. PMID- 21648549 TI - EPA Watch: Almost 300 Superfund projects shut down. PMID- 21648550 TI - News: EPA continues to wrestle with budget cuts, short-term funding. PMID- 21648552 TI - News: Enforcement cuts hit by corporate attorney. PMID- 21648553 TI - News: Clinton releases "thematic" budget. PMID- 21648562 TI - News briefs: news briefs. PMID- 21648564 TI - Peer reviewed: understanding the water quality of pit lakes. AB - The increase in deep pit mining in western North America raises concerns about the environmental impact of mine closure. PMID- 21648567 TI - New products: new products. PMID- 21648565 TI - Supercritical carbon dioxide: the "greener" solvent. AB - It's not toxic and it doesn't harm the ozone layer, but can supercritical CO2 do the job in major industrial applications? PMID- 21648571 TI - Other/miscellaneous. PMID- 21648572 TI - Other/miscellaneous. PMID- 21648573 TI - We need solid peer review. PMID- 21648578 TI - Research Watch: Effects of load reduction on bioaccumulation. PMID- 21648584 TI - Research Watch: Tracking dioxins in an English pasture. PMID- 21648595 TI - EPA Watch: Office of Water introduces effluent trading program. PMID- 21648594 TI - EPA Watch: Interim policy issued on major source definition. PMID- 21648597 TI - EPA Watch: New wastewater method eliminates CFC use. PMID- 21648596 TI - EPA Watch: Second HWIR rule eases requirements on media. PMID- 21648598 TI - EPA Watch: SAB rejects written public disclosures. PMID- 21648599 TI - EPA Watch: New brownfield projects announced. PMID- 21648601 TI - News: Contractors look elsewhere as Superfund faces cuts, turmoil. PMID- 21648602 TI - News: Browner predicts damage to Superfund, environmental programs. PMID- 21648613 TI - News briefs: news briefs. PMID- 21648615 TI - Health of a continent. AB - A massive new report on the environmental condition of Europe is a feat of data analysis and a challenge to policy makers. PMID- 21648616 TI - Will our stolen future be another silent spring? AB - A new book sparks debate over endocrine disruptors and the regulation of synthetic chemicals and pesticides. PMID- 21648618 TI - Ecological risk assessment struggles to define itself. AB - Practitioners are debating how to turn this young field into a rigorous discipline. PMID- 21648619 TI - Ecological risk assessment struggles to define itself: ecological risk case study. PMID- 21648624 TI - Other/miscellaneous. PMID- 21648627 TI - Letters: Dioxin inventory. PMID- 21648626 TI - The rediscovery of public health microbiology. PMID- 21648628 TI - Letters: internet resources. PMID- 21648630 TI - Letters: internet resources. PMID- 21648629 TI - Letters: Authors' response. PMID- 21648636 TI - Research Watch: Measuring atmospheric reactions of smog-forming organics. PMID- 21648638 TI - Research Watch: Solid state speciation of lead. PMID- 21648646 TI - Correction: correction. PMID- 21648649 TI - EPA Watch: HWIR multipath analysis not scientifically defensible. PMID- 21648648 TI - EPA Watch: Increased speed limits will not trigger changes to SIPs. PMID- 21648651 TI - EPA Watch: Cryptosporidium may not be included in ICR. PMID- 21648650 TI - EPA Watch: Regional enforcement activities decrease. PMID- 21648652 TI - EPA Watch: Proposal steers EPA away from continuous monitoring. PMID- 21648653 TI - EPA Watch: Goals document sets expected results. PMID- 21648654 TI - News: States take on new role in setting their own environmental agenda. PMID- 21648655 TI - News: Wide range in federal environmental funds for states. PMID- 21648656 TI - News: Ruckelshaus panel to recommend new regulatory framework to reform EPA. PMID- 21648657 TI - News: One in three facilities violate Water Act. PMID- 21648667 TI - News briefs: news briefs. PMID- 21648669 TI - Air Quality Modeling's: Proposed Ozone Standard Challenges. PMID- 21648668 TI - Air Quality Modeling's Brave New World. AB - A new generation of software systems is set to tackle regional and multipollutant air quality issues. PMID- 21648671 TI - Pollution-fueled "biodeterioration" threatens historic stone. AB - Researchers are probing the role microorganisms play in the decay of buildings and artwork. PMID- 21648677 TI - New products: online resources. PMID- 21648673 TI - Estrogens may link pesticides, breast cancer. AB - A controversial hypothesis suggests that pesticides' impact on estrogen metabolism can trigger cancer. PMID- 21648682 TI - Other/miscellaneous. PMID- 21648684 TI - Other/miscellaneous. PMID- 21648686 TI - Chemicals don't kill people.... PMID- 21648692 TI - Research Watch: Characterizing colloids. PMID- 21648687 TI - Letters: Chlorine incineration. PMID- 21648701 TI - Research Watch: Modeling the behavior of humic substances. PMID- 21648704 TI - Research Watch: New pesticides method for water samples. PMID- 21648705 TI - EPA Watch: Agreement promotes risk-based UST cleanup. PMID- 21648706 TI - EPA Watch: MACT proposed for cement kilns, incinerators. PMID- 21648707 TI - EPA Watch: "Transitional" MACT set for new, rebuilt plants. PMID- 21648709 TI - EPA Watch: Agency proposes revoking pesticide uses. PMID- 21648710 TI - EPA Watch: ORD research grant funding increases. PMID- 21648711 TI - EPA Watch: EPA, Customs broaden border enforcement. PMID- 21648712 TI - News: Proposed cancer risk guidelines open door to use of new data. PMID- 21648722 TI - News briefs: news briefs. PMID- 21648723 TI - Peer reviewed: the challenge of remediating chromium-contaminated soil. AB - The complex chemistry of chromium compounds presents unique measurement and regulatory challenges. PMID- 21648724 TI - Peer Reviewed: New Instrument Brings PAH Analysis to the Field. AB - A field-portable scanning spectrofluorometer has completed site tests and is nearing commercialization. PMID- 21648726 TI - Peer reviewed: remote emissions testing hits the road. AB - On-road detectors have arrived, but are they more effective than stationary tests? PMID- 21648728 TI - New products: new products. PMID- 21648731 TI - Other/miscellaneous. PMID- 21648733 TI - Other/miscellaneous. PMID- 21648735 TI - Time to explore. PMID- 21648743 TI - Research Watch: Sampling colloids. PMID- 21648748 TI - EPA Watch: Lawsuit challenges PCB importation rule. PMID- 21648749 TI - EPA Watch: Chairman questions enforcement performance. PMID- 21648750 TI - EPA Watch: NAAQS revision addresses long-range pollution. PMID- 21648752 TI - EPA Watch: Sustainable development grants program set to grow. PMID- 21648751 TI - EPA Watch: Emissions from R&D facilities targeted for controls. PMID- 21648753 TI - EPA Watch: Reduced oversight of "capable" PRPs underway. PMID- 21648765 TI - News briefs: news briefs. PMID- 21648754 TI - News: Project XL founders in Minnesota; Critics call for national legislation. PMID- 21648766 TI - Risk-based Remediation Guidelines Take Hold. AB - ASTM's risk-based approach to petroleum cleanups will soon be applied to chemical contamination. PMID- 21648767 TI - Risk-Based Remediation Guidleines take Hold: How RBCA Works. PMID- 21648770 TI - Freshwater science: a discipline divided. AB - Without a central academic home or funding source, limnology is a fragmented and struggling field. PMID- 21648775 TI - Other/miscellaneous. PMID- 21648777 TI - Other/miscellaneous. PMID- 21648778 TI - Other/miscellaneous. PMID- 21648779 TI - The leadership vacuum. PMID- 21648780 TI - Letters: Ranking risks. PMID- 21648781 TI - Letters: response. PMID- 21648782 TI - Correction: correction. PMID- 21648787 TI - Research Watch: Pesticide metabolites contaminate groundwater. PMID- 21648796 TI - EPA Watch: Three petroleum wastes proposed as hazardous. PMID- 21648795 TI - Research Watch: Seeking zero-valent iron's reaction mechanism. PMID- 21648797 TI - EPA Watch: Concentration of hazardous waste to determine listing. PMID- 21648798 TI - EPA Watch: MACT rule may shut down smaller incinerators. PMID- 21648799 TI - EPA Watch: Partial delisting of NPL sites approved. PMID- 21648801 TI - EPA Watch: TRI reporting set out in federal contracts. PMID- 21648800 TI - EPA Watch: Proposal reduces VOCs through product changes. PMID- 21648803 TI - News: Risk assessment draft gives WTI incinerator clean slate. PMID- 21648814 TI - News briefs: news briefs. PMID- 21648816 TI - Special issue: special issue: the new environmental landscape. PMID- 21648818 TI - Special issue: features panels. PMID- 21648817 TI - Other/miscellaneous. PMID- 21648819 TI - Special issue: current conditions. AB - A survey of recent developments in science, technology, and policy reveals key strengths and weaknesses in our capability to advance the field and meet the environmental challenges of the future. PMID- 21648821 TI - Special issue: priority concerns. AB - Renewed efforts are needed to confront difficult scientific questions such as endocrine disruptors and ecosystem health and to adapt to a changing regulatory environment where federal influence is waning and local, site-specific solutions are required. PMID- 21648820 TI - Special issue: emerging frontiers. AB - Bioremediation, risk-based decision making, life cycle assessment, and the health impact of complex chemical mixtures are among the forefront fields that will shape the research and policy agenda. PMID- 21648822 TI - Special issue: managing the future. AB - As environmental issues and problems become more complex and resources with which to tackle them increasingly scarce, the environmental profession will need to turn to multidisciplinary collaborations, priority setting, and regulatory experimentation. PMID- 21648825 TI - ES&T Advisory Board: 1996 Advisory Board. PMID- 21648826 TI - Editorial policy. PMID- 21648828 TI - Current research. PMID- 21648827 TI - Peer review. PMID- 21648829 TI - Manuscript preparation: text and figures. PMID- 21648830 TI - Other/miscellaneous. PMID- 21648833 TI - Other/miscellaneous. PMID- 21648837 TI - Research Watch: Assessing the bioavailability of sedimentary contaminants. PMID- 21648835 TI - A Dead-end Energy Policy. PMID- 21648842 TI - Research Watch: Photodegrading furans in lake waters. PMID- 21648853 TI - EPA Watch: EPA-industry collaboration focuses on PM controls. PMID- 21648844 TI - Research Watch: Sediments used to monitor water quality. PMID- 21648855 TI - EPA Watch: ORD to establish peer review advisory panel. PMID- 21648854 TI - EPA Watch: EPA begins endocrine distrupter screening plan. PMID- 21648856 TI - EPA Watch: Large systems to monitor drinking water sources. PMID- 21648858 TI - EPA Watch: Hazardous spill report requirements changed. PMID- 21648857 TI - EPA Watch: Court backs TRI additions; groups file appeal. PMID- 21648860 TI - EPA Watch: Survey of 233 hazardous waste facilities planned. PMID- 21648859 TI - EPA Watch: Panel to address U.S.-Mexico air pollution. PMID- 21648862 TI - News: 104th Congress marks few environmental wins. PMID- 21648863 TI - News: Drinking Water reauthorization clears House, Senate. PMID- 21648865 TI - News: Endocrine disruption: Potent combinations. PMID- 21648876 TI - News briefs: news briefs. PMID- 21648878 TI - Integrating environmental data to meet multimedia challenges. AB - Agencies are pulling together their disparate data resources for better decision making. PMID- 21648877 TI - Environmental GIS: The World in a Computer. AB - Expanding data resources are spurring widespread use of geographic information systems in the environmental field. PMID- 21648882 TI - New products: new products. PMID- 21648889 TI - Other/miscellaneous. PMID- 21648888 TI - Other/miscellaneous. PMID- 21648891 TI - Other/miscellaneous. PMID- 21648893 TI - "Originality" of research and the internet. PMID- 21648897 TI - Research Watch: PCB accumulation by phytoplankton modeled. PMID- 21648903 TI - Research Watch: Elemental field analysis of soil samples. PMID- 21648912 TI - Research Watch: Simultaneous treatment of solvents and metals. PMID- 21648913 TI - EPA Watch: Hazardous waste MACT levels criticized. PMID- 21648914 TI - EPA Watch: Industry hits "credible evidence" proposal. PMID- 21648916 TI - EPA Watch: Medical waste rule delayed to consider new data. PMID- 21648915 TI - EPA Watch: Proposal waives need for most new source permits. PMID- 21648917 TI - EPA Watch: Cluster rule delays air controls for paper mills. PMID- 21648918 TI - EPA Watch: Agency dumps obsolete air regulations. PMID- 21648919 TI - News: Recent health studies find link. PMID- 21648920 TI - News: Particulate, ozone standards to be coupled, released late in year. PMID- 21648921 TI - News: Europe to target vehicle emissions in new air quality strategies. PMID- 21648922 TI - News: EPA research takes a hit in final 1996 budget appropriation. PMID- 21648934 TI - News briefs: news briefs. PMID- 21648936 TI - The "new science" of wetland restoration. AB - The intricate workings of natural wetlands are slowly yielding their secrets to scientists applying a number of experimental approaches. PMID- 21648938 TI - ISO 14000: A Step Toward Industry Self-Regulation. AB - New international environmental management standards are seen by industry as a means to reduce regulatory stringency, but U.S. regulators are still on the fence. PMID- 21648940 TI - Peer reviewed: the lead fingerprints of gasoline contamination. AB - Isotopic analysis of the lead additives in gasoline can improve estimates of the ages of leaks and spills. PMID- 21648944 TI - Other/miscellaneous. PMID- 21648946 TI - Bisaziridine tetracarboxylates as building blocks in the stereoselective synthesis of C60-fullerene diads and dumbbell-like bis-C60-fullerene triads. AB - The synthesis of alkoxycarbonyl-substituted bisaziridines with the two aziridine units connected by conjugated p-phenylene, partly conjugated 1,1'-biphenyl-4,4' diyl, and nonconjugated 4,4'-methylenediphenyl linkers was developed. The reaction of azomethine ylides derived from the bisaziridines with fullerene C(60) was optimized and used for the stereoselective preparation of both the monoadducts (C(60)-linker-aziridine dicarboxylate), and the dumbbell bisadducts (C(60)-linker-C(60)). The reasons for the observed selectivity of the azomethine ylide formation and cycloaddition were theoretically studied at the DFT B3LYP/6 31G(d) level or at the ONIOM B3LYP/6-31G(d):B3LYP/STO-3G level for fullerene containing molecules. PMID- 21648947 TI - Synthesis of allylic hydroperoxides and EPR spin-trapping studies on the formation of radicals in iron systems as potential initiators of the sensitizing pathway. AB - Many terpenes used as fragrance compounds autoxidize when exposed to air, forming allylic hydroperoxides that have the potential to be skin contact allergens. To trigger the immunotoxicity process that characterizes contact allergy, these hydroperoxides are supposed to bind covalently to proteins in the skin via radical pathways. We investigated the formation of reactive radical intermediates from 7-hydroperoxy-3,7-dimethylocta-1,5-dien-3-ol and 2-hydroperoxylimonene, responsible for the sensitizing potential acquired by autoxidized linalool and limonene. Both compounds were synthesized through new short and reproducible synthetic pathways. The hydroperoxide decomposition catalyzed by Fe(II)/Fe(III) redox systems, playing a key role in degradating peroxides in vivo, was examined by spin-trapping-EPR spectroscopy. Alkoxyl and carbon-centered free radicals derived from the hydroperoxides were successfully trapped by the spin-trap 5,5 dimethyl-1-pyrroline N-oxide, whereas peroxyl radicals were characterized by spin trapping studies with 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide. Using liquid chromatography combined with mass spectrometry, we demonstrated the formation of adducts, via radical mechanisms induced by Fe(II)/Fe(III), between the hydroperoxides and N-acetylhistidine methyl ester, a model amino acid that is prone to radical reactions. Free radicals derived from these hydroperoxides can thus induce amino acid chemical modifications via radical mechanisms. The study of these mechanisms will help to understand the sensitizing potential of hydroperoxides. PMID- 21648948 TI - Extension of a classic thin double layer polarization theory of colloidal suspensions to include the stagnant layer conductivity. AB - A rigorous extension of the classic Dukhin-Shilov thin double layer polarization theory including the stagnant layer conductivity is presented. Precisely the same assumptions and approximations made in the original theory are maintained, and the same adsorption isotherms are used as in most of the existing numerical calculations. The obtained analytical results improve upon existing approximate extensions, mainly for low surface conductivities and high surface potentials and for high surface conductivities and low surface potentials. Moreover, they avoid the assumption that all the adsorbed ions in the stagnant layer must have a single sign. Finally, they present a very good agreement with numerical calculations specifically made using the same system parameters. PMID- 21648949 TI - Low-temperature neutron diffraction structures of N-glycoprotein linkage models and analogues: structure refinement and trifurcated hydrogen bonds. AB - The biological addition of oligosaccharide moieties to asparagine residues of N glycoproteins influences the properties and bioactivities of these macromolecules. The low-temperature neutron crystal structures of three N glycoprotein linkage models and analogues provide accurate characterization of the three-dimensional structure of the conserved GlcNAc-Asn linkage. These first crystal structures of N-acetylated carbohydrates obtained by neutron diffraction provide high-resolution geometrical parameters that can be used for force-field parametrization and subsequent molecular dynamics simulation of N-glycoproteins. The correct localization of hydrogen atoms demonstrates the occurrence of trifurcated hydrogen bonds and hydrophobic contacts. PMID- 21648950 TI - Interaction of cholesterol-conjugated ionizable amino lipids with biomembranes: lipid polymorphism, structure-activity relationship, and implications for siRNA delivery. AB - Delivery of siRNA is a major obstacle to the advancement of RNAi as a novel therapeutic modality. Lipid nanoparticles (LNP) consisting of ionizable amino lipids are being developed as an important delivery platform for siRNAs, and significant efforts are being made to understand the structure-activity relationship (SAR) of the lipids. This article uses a combination of small-angle X-ray scattering (SAXS) and differential scanning calorimetry (DSC) to evaluate the interaction between cholesterol-conjugated ionizable amino lipids and biomembranes, focusing on an important area of lipid SAR--the ability of lipids to destabilize membrane bilayer structures and facilitate endosomal escape. In this study, cholesterol-conjugated amino lipids were found to be effective in increasing the order of biomembranes and also highly effective in inducing phase changes in biological membranes in vitro (i.e., the lamellar to inverted hexagonal phase transition). The phase transition temperatures, determined using SAXS and DSC, serve as an indicator for ranking the potency of lipids to destabilize endosomal membranes. It was found that the bilayer disruption ability of amino lipids depends strongly on the amino lipid concentration in membranes. Amino lipids with systematic variations in headgroups, the extent of ionization, tail length, the degree of unsaturation, and tail asymmetry were evaluated for their bilayer disruption ability to establish SAR. Overall, it was found that the impact of these lipid structure changes on their bilayer disruption ability agrees well with the results from a conceptual molecular "shape" analysis. Implications of the findings from this study for siRNA delivery are discussed. The methods reported here can be used to support the SAR screening of cationic lipids for siRNA delivery, and the information revealed through the study of the interaction between cationic lipids and biomembranes will contribute significantly to the design of more efficient siRNA delivery vehicles. PMID- 21648951 TI - Model for membrane organization and protein sorting in the cyanobacterium Synechocystis sp. PCC 6803 inferred from proteomics and multivariate sequence analyses. AB - Cyanobacteria are unique eubacteria with an organized subcellular compartmentalization of highly differentiated internal thylakoid membranes (TM), in addition to the outer and plasma membranes (PM). This leads to a complicated system for transport and sorting of proteins into the different membranes and compartments. By shotgun and gel-based proteomics of plasma and thylakoid membranes from the cyanobacterium Synechocystis sp. PCC 6803, a large number of membrane proteins were identified. Proteins localized uniquely in each membrane were used as a platform describing a model for cellular membrane organization and protein intermembrane sorting and were analyzed by multivariate sequence analyses to trace potential differences in sequence properties important for insertion and sorting to the correct membrane. Sequence traits in the C-terminal region, but not in the N-terminal nor in any individual transmembrane segments, were discriminatory between the TM and PM classes. The results are consistent with a contact zone between plasma and thylakoid membranes, which may contain short lived "hemifusion" protein traffic connection assemblies. Insertion of both integral and peripheral membrane proteins is suggested to occur through common translocons in these subdomains, followed by a potential translation arrest and structure-based sorting into the correct membrane compartment. PMID- 21648953 TI - Thermal decomposition of 1,5-dinitrobiuret (DNB): direct dynamics trajectory simulations and statistical modeling. AB - A large set of quasi-classical, direct dynamics trajectory simulations were performed for decomposition of 1,5-dinitrobiuret (DNB) over a temperature range from 4000 to 6000 K, aimed at providing insight into DNB decomposition mechanisms. The trajectories revealed various decomposition paths and reproduced the products (including HNCO, N(2)O, NO(2), NO, and water) observed in DNB pyrolysis experiments. Using trajectory results as a guide, structures of intermediate complexes and transition states that might be important for decomposition were determined using density functional theory calculations. Rice Ramsperger-Kassel-Marcus (RRKM) theory was then utilized to examine behaviors of the energized reactant and intermediates and to determine unimolecular rates for crossing various transition states. According to RRKM predictions, the dominant initial decomposition path of energized DNB corresponds to elimination of HNNO(2)H via a concerted mechanism where the molecular decomposition is accompanied with intramolecular H-atom transfer from the central nitrogen to the terminal nitro oxygen. Other important paths correspond to elimination of NO(2) and H(2)NNO(2). NO(2) elimination is a simple N-N bond scission process. Formation and elimination of nitramide is, however, dynamically complicated, requiring twisting a -NHNO(2) group out of the molecular plane, followed by an intramolecular reaction to form nitramide before its elimination. These two paths become significant at temperatures above 1500 K, accounting for >17% of DNB decomposition at 2000 K. This work demonstrates that quasi-classical trajectory simulations, in conjunction with electronic structure and RRKM calculations, are able to extract mechanisms, kinetics, dynamics and product branching ratios for the decomposition of complex energetic molecules and to predict how they vary with decomposition temperature. PMID- 21648954 TI - Superlocalization of single molecules and nanoparticles in high-fidelity optical imaging microfluidic devices. AB - Superlocalization of single molecules and nanoparticles with a precision of subnanometer to a few tens of nanometers is crucial for elucidating nanoscale structures and movements in biological and chemical systems. A novel design of ultraflat and ultrathin glass/polydimethylsiloxane (PDMS) hybrid microdevices is introduced to provide almost uncompromised optical imaging quality for on-chip superlocalization and super-resolution imaging of single molecules and nanoparticles under a variety of microscopy modes. The performance of the high fidelity (Hi-Fi) optical imaging microfluidic device was validated by precisely mapping micronecklaces made of fluorescent microtubules and 40 nm gold nanoparticles and by demonstrating the activation and excitation cycles of single Alexa Fluor 647 dyes for direct stochastic optical reconstruction microscopy in PDMS-based microchannels for the first time. Furthermore, the microdevice's feasibility for multimodality microscopy imaging was demonstrated by a vertical scan of live cells in epi-fluorescence and differential interference contrast (DIC) microscopy modes simultaneously. PMID- 21648952 TI - Major remodelling of the murine stem cell kinome following differentiation in the hematopoietic compartment. AB - The changes in signal transduction associated with the acquisition of specific cell fates remain poorly understood. We performed massive parallel assessment of kinase signatures of the radiations of the hematopoietic system, including long term repopulating hematopoietic stem cells (LT-HSC), short-term repopulating HSC (ST-HSC), immature natural killer (iNK) cells, NK cells, B cells, T cells, and myeloid cells. The LT-HSC kinome is characterized by noncanonical Wnt, Ca(2+) and classical protein kinase C (PKC)-driven signaling, which is lost upon the transition to ST-HSC, whose kinome signature prominently features receptor tyrosine kinase (RTK) activation of the Ras/MAPK signaling cassette. Further differentiation to iNK maintains signaling through this cassette but simultaneously leads to activation of a PI3K/PKB/Rac signaling, which becomes the dominant trait in the kinase signature following full differentiation toward NK cells. Differentiation along the myeloid and B cell lineages is accompanied by hyperactivation of both the Ras/MAPK and PI3K/PKB/Rac signaling cassette. T cells, however, deactivate signaling and only display residual G protein-coupled pathways. Thus, differentiation along the hematopoietic lineage is associated with major remodelling of cellular kinase signature. PMID- 21648955 TI - Templated techniques for the synthesis and assembly of plasmonic nanostructures. PMID- 21648956 TI - Localized surface plasmon resonance sensors. PMID- 21648957 TI - Quantitative fluorescence microscopy to determine molecular occupancy of phospholipid vesicles. AB - Encapsulation of molecules in phospholipid vesicles provides unique opportunities to study chemical reactions in small volumes as well as the behavior of individual proteins, enzymes, and ribozymes in a confined region without requiring a tether to immobilize the molecule to a surface. These experiments generally depend on generating a predictable loading of vesicles with small numbers of target molecules and thus raise a significant measurement challenge, namely, to quantify molecular occupancy of vesicles at the single-molecule level. In this work, we describe an imaging experiment to measure the time-dependent fluorescence from individual dye molecules encapsulated in ~130 nm vesicles that are adhered to a glass surface. For determining a fit of the molecular occupancy data to a Poisson model, it is critical to count empty vesicles in the population since these dominate the sample when the mean occupancy is small, lambda <= ~1. Counting empty vesicles was accomplished by subsequently labeling all the vesicles with a lipophilic dye and reimaging the sample. By counting both the empty vesicles and those containing fluors, and quantifying the number of fluors present, we demonstrate a self-consistent Poisson distribution of molecular occupancy for well-solvated molecules, as well as anomalies due to aggregation of dye, which can arise even at very low solution concentrations. By observation of many vesicles in parallel in an image, this approach provides quantitative information about the distribution of molecular occupancy in a population of vesicles. PMID- 21648959 TI - Other/miscellaneous. PMID- 21648960 TI - Other/miscellaneous. PMID- 21648965 TI - Analytical Currents: Viewing multilayered thin films. PMID- 21648963 TI - In AC Research: In AC Research. PMID- 21648966 TI - Analytical Currents: Single-molecule enzymatic dynamics. PMID- 21648967 TI - Analytical Currents: TNT in land mines. PMID- 21648968 TI - Analytical Currents: As the protein unfolds. PMID- 21648970 TI - Analytical Currents: DNA on the straight and narrow. PMID- 21648969 TI - Analytical Currents: Dual-pipet generation/collection. PMID- 21648971 TI - Analytical Currents: Androgen disrupters. PMID- 21648972 TI - Analytical Currents: RNA studies with MALDI-MS. PMID- 21648973 TI - Analytical Currents: Understanding electrospray. PMID- 21648975 TI - Analytical Currents: Resistance to dechlorination. PMID- 21648974 TI - Analytical Currents: Something old, something new. PMID- 21648976 TI - Science: Gas-phase separation of biomolecules. PMID- 21648977 TI - Government and Society: Big small-scale funds. PMID- 21648978 TI - Science: Combinatorial MIPs. PMID- 21648979 TI - Government and Society: Raman effect declared landmark. PMID- 21648980 TI - Government and Society: Regulating new drinking water contaminants. PMID- 21648981 TI - News from the Eastern Analytical Symposium: Epitope mapping. PMID- 21648982 TI - News from the Eastern Analytical Symposium: Chemometrics give NMR a boost. PMID- 21648983 TI - Laboratory Profile: Analytical research at Riken. PMID- 21648984 TI - Business: Online analytical complaints. PMID- 21648987 TI - Pittcon '99. PMID- 21648985 TI - Business: ANDI encounters delays. PMID- 21648988 TI - New products: new products. PMID- 21648989 TI - Instructions to authors: instructions to authors. PMID- 21648991 TI - Other/miscellaneous. PMID- 21648993 TI - Other/miscellaneous. PMID- 21648992 TI - Information express: information express. PMID- 21648995 TI - Mentoring--one of the most important acts. PMID- 21648994 TI - Other/miscellaneous. PMID- 21648997 TI - In AC Research: In AC Research. PMID- 21648998 TI - Analytical Currents: Low-affinity ligands. PMID- 21648999 TI - Analytical Currents: Guiding light. PMID- 21649001 TI - Analytical Currents: Hybrid mass spectrometer for electrospray. PMID- 21649000 TI - Analytical Currents: No laser required. PMID- 21649002 TI - Analytical Currents: Sweeping for enhanced sensitivity. PMID- 21649003 TI - Analytical Currents: In the clouds. PMID- 21649004 TI - Analytical Currents: Interfacing CE-ICPMS. PMID- 21649006 TI - Science: Modulated sensor. PMID- 21649005 TI - Science: Looking for mosquito attractants. PMID- 21649007 TI - Science: Rapid angle on wood stiffness. PMID- 21649008 TI - Business: Dionex acquires Softron. PMID- 21649009 TI - People: New Advisory Board and A-page Advisory Panel members appointed. PMID- 21649010 TI - People: therese m. Cotton (1939-1998). PMID- 21649011 TI - Business: Analect becomes part of Orbital. PMID- 21649014 TI - Product Review: Microplate fluorometers reach critical mass. AB - Whether you need an intensity reader or a multimode instrument, 96 wells or 1536, there's a microplate fluorometer for you. PMID- 21649015 TI - A: A tunnel too far: Virtual private networks. PMID- 21649018 TI - Meetings: HPCE '99. PMID- 21649019 TI - Meetings: conferences. PMID- 21649020 TI - Meetings: Short courses. PMID- 21649021 TI - Books and Software: Getting the basics of NMR. AB - A review of Acomplete Introduction to Modern NMR Spectroscopy. PMID- 21649022 TI - Books and Software: A tool for understanding GFAAS. AB - A review of A Practical Guide to Graphite Furnace Atomic Absorption Spectrometry. PMID- 21649024 TI - New products: new products. PMID- 21649025 TI - Instructions to authors: instructions to authors. PMID- 21649023 TI - Books and Software: New uses of MS. AB - A review of Mass Spectrometry of Biological Materials. PMID- 21649026 TI - Copyright status form: copyright status form. PMID- 21649027 TI - Other/miscellaneous. PMID- 21649028 TI - Information express: information express. PMID- 21649030 TI - Other/miscellaneous. PMID- 21649031 TI - Other/miscellaneous. PMID- 21649032 TI - The climbing syndrome (anthills). PMID- 21649036 TI - In AC Research: In AC Research. PMID- 21649040 TI - Analytical Currents: Vapor-sensing zeolite. PMID- 21649039 TI - Analytical Currents: Immunoaffinity-based SPE with GC. PMID- 21649041 TI - Analytical Currents: Shrinking traps. PMID- 21649042 TI - Analytical Currents: Entropic trapping of macromolecules. PMID- 21649043 TI - Analytical Currents: Monitoring protein unfolding. PMID- 21649045 TI - Analytical Currents: Sequencing "trouble" spots. PMID- 21649044 TI - Analytical Currents: Characterizing large proteins. PMID- 21649047 TI - Analytical Currents: Oligonucleotide fragmentation. PMID- 21649046 TI - Analytical Currents: Microelectrodes for mismatch detection. PMID- 21649048 TI - Analytical Currents: Single molecules by STM. PMID- 21649049 TI - Science: The eyes have it. PMID- 21649050 TI - Analytical Currents: Imaging particles. PMID- 21649051 TI - News from HPCE '99: Correlating enzymatic activity and cell cycle. PMID- 21649052 TI - News from HPCE '99: Coordination ionspray MS. PMID- 21649053 TI - Government and Society: NIST opens new research facility. PMID- 21649054 TI - Government and Society: Copyright competition. PMID- 21649055 TI - Business: Hip to split. PMID- 21649057 TI - People: year 2000 division of analytical chemistry awards. PMID- 21649056 TI - People: abraham savitzky. PMID- 21649059 TI - Peer Reviewed: MIPs as Chromatographic Stationary Phases for Molecular Recognition. AB - Molecular imprint polymers recognize specific compounds and show promise as separation media, especially for chiral molecules. PMID- 21649061 TI - Focus: The incredible shrinking mass spectrometers. AB - Miniaturization is on track to take MS into space and the doctor's office. PMID- 21649064 TI - Product Review: GC at a standstill. PMID- 21649066 TI - Books and Software: One-semester course on chemical analysis. PMID- 21649068 TI - New products: new products. PMID- 21649067 TI - Books and Software: Getting the complete view. PMID- 21649069 TI - Meetings: HPLC '99 in granada, Spain. PMID- 21649070 TI - Meetings: conferences. PMID- 21649071 TI - Meetings: Short courses. PMID- 21649073 TI - Information express: information express. PMID- 21649072 TI - Other/miscellaneous. PMID- 21649079 TI - In AC Research: In AC Research. PMID- 21649077 TI - A little history and some more changes. PMID- 21649082 TI - Analytical Currents: Photophysics of MEH-PPV. PMID- 21649083 TI - Analytical Currents: Carcinogenicity of PACs. PMID- 21649084 TI - Analytical Currents: Biotin coats for electrodes. PMID- 21649085 TI - Analytical Currents: Fluorescent microsphere labels. PMID- 21649086 TI - Analytical Currents: Ring in the elements. PMID- 21649087 TI - Analytical Currents: Sensing CO2. PMID- 21649089 TI - Science: Chiral analysis on microchips. PMID- 21649088 TI - Analytical Currents: Neural networks help CE. PMID- 21649090 TI - Analytical Currents: Toward FT-IR microscopy. PMID- 21649091 TI - Science: "Fairy dust" electrospray emitters. PMID- 21649092 TI - People: Heineman receives Bergen Medal. PMID- 21649096 TI - Peer reviewed: instrumental analysis at the University of Kansas: an experiment in problem-based learning. AB - Students work in groups to solve real-world problems. PMID- 21649093 TI - People: Near-IR travel award. PMID- 21649100 TI - Product Review: The many faces of thermal analysis. AB - Manufacturers broaden product lines to accommodate more applications. PMID- 21649101 TI - A: Does problem-based learning sacrifice content and fundamentals? PMID- 21649102 TI - Books and Software: Uncovering complex mixtures of anionic surfactants. AB - A review of Anionic Surfactants: Analytical Chemistry, Second Edition. PMID- 21649103 TI - Books and Software: Filling in the gaps. AB - A review of Impurities Evaluation of Pharmaceuticals. PMID- 21649104 TI - Meetings: EAS '99. PMID- 21649105 TI - Meetings: conferences. PMID- 21649107 TI - New products: new products. PMID- 21649110 TI - Information express: information express. PMID- 21649112 TI - Other/miscellaneous. PMID- 21649114 TI - Analytical chemistry--then and now. PMID- 21649113 TI - Other/miscellaneous. PMID- 21649116 TI - In AC Research: In AC Research. PMID- 21649118 TI - Analytical Currents: Back-flush micro-LC/MS. PMID- 21649119 TI - Analytical Currents: Natural channel meets cyclodextrin. PMID- 21649120 TI - Analytical Currents: Investigating on-column fluorescence lifetimes. PMID- 21649121 TI - Analytical Currents: Nanotube electrode. PMID- 21649122 TI - Analytical Currents: Imprinting proteins. PMID- 21649123 TI - Analytical Currents: Near-field IR imaging. PMID- 21649124 TI - Analytical Currents: Separating nanotubes. PMID- 21649125 TI - Analytical Currents: Catalyst screening. PMID- 21649126 TI - Analytical Currents: Blue and green LECs. PMID- 21649127 TI - Analytical Currents: Multibeam circular dichroism detector. PMID- 21649128 TI - Analytical Currents: Probing protein secondary structure. PMID- 21649129 TI - Analytical Currents: Laser desorption MS for biomolecules. PMID- 21649130 TI - Science: going to the maxam. PMID- 21649131 TI - Science: Diffractive optical sensor. PMID- 21649132 TI - Science: CE tackles protein complexes. PMID- 21649134 TI - Science: Near-IR imaging of peptide synthesis. PMID- 21649133 TI - Government and Society: Is winter coming for Eureka? PMID- 21649135 TI - People: Zare to receive Welch award. PMID- 21649136 TI - Government and Society: Uniting peers. PMID- 21649138 TI - Peer Reviewed: The New Time-of-Flight Mass Spectrometry. AB - Performance results have finally laid to rest TOF's reputation as a low resolution mass technique. PMID- 21649139 TI - Peer Reviewed: Orthogonal-Injection TOFMS for Analyzing Biomolecules. AB - Orthogonal injection provides a high- efficiency interface for transferring ions from a continuous beam to a pulsed mode and makes it easier to obtain high resolution. PMID- 21649140 TI - Focus: DNA microarrays in toxicology. AB - Gene expression analysis promises to change toxicology. PMID- 21649141 TI - Product Reviews: Ion chromatography. AB - Manufacturers continue to battle over suppression technology. PMID- 21649142 TI - Product Reviews: State-of-the-Art Mercury CEMs. AB - New technologies for continuous monitoring of mercury emissions from hazardous and mixed-waste incineration. PMID- 21649143 TI - A: Paradise lost and regained? PMID- 21649145 TI - Books and Software: Reference guide for GC/MS. AB - A review of Practical Introduction to GS-MC Analysis with Quadrupoles. PMID- 21649146 TI - Books and Software: Getting serious about ICPMS. AB - A review of Inductively Coupled Plasma Mass Spectrometry. PMID- 21649149 TI - Meetings: conferences. PMID- 21649151 TI - New products: new products. PMID- 21649153 TI - Other/miscellaneous. PMID- 21649154 TI - Information express: information express. PMID- 21649156 TI - Other/miscellaneous. PMID- 21649158 TI - Ce + HPLC = cec. PMID- 21649157 TI - Other/miscellaneous. PMID- 21649160 TI - In AC Research: In AC Research. PMID- 21649161 TI - Analytical Currents: Validating kinetic RT-PCR. PMID- 21649162 TI - Analytical Currents: Quicker than thieves. PMID- 21649164 TI - Analytical Currents: SIMS of cellular membranes. PMID- 21649163 TI - Analytical Currents: High power play. PMID- 21649165 TI - Analytical Currents: Pump-probe goes local. PMID- 21649167 TI - Analytical Currents: Toxins ring loud and clear. PMID- 21649166 TI - Analytical Currents: Combinatorial libraries by NMR. PMID- 21649168 TI - Analytical Currents: Diffusion NMR--be careful. PMID- 21649169 TI - News from the International Symposium on Environmental Analytical Chemistry: Detecting critters in food. PMID- 21649170 TI - Science: Optics and chips. PMID- 21649171 TI - News from the International Symposium on Environmental Analytical Chemistry: Selecting the selectors. PMID- 21649172 TI - ASMS: Amyloid beta peptide assay. PMID- 21649173 TI - News from HPLC '99: Putting a cloud in a test tube. PMID- 21649175 TI - ASMS: Bringing MALDI on-line. PMID- 21649174 TI - News from HPLC '99: Carotenoids in spinach. PMID- 21649176 TI - Government and Society: Bringing QA/QC to the fore. PMID- 21649177 TI - People: Division awards. PMID- 21649180 TI - Peer reviewed: the weakest link exercise. PMID- 21649182 TI - Product Review: CD begins to bloom. AB - Circular dichroism adapts itself to the pharmaceutical market and finally blossoms. PMID- 21649185 TI - Books and Software: A complete lesson on chromatography. AB - A review of Advances in Chromatography, Volume 39. PMID- 21649184 TI - Books and Software: Mixed bag of particles. PMID- 21649186 TI - Books and Software: Quantitative analysis made easy. AB - A review of Chemometric Techniques for Quantitative Analysis. PMID- 21649188 TI - Meetings: ACS in New Orleans. PMID- 21649189 TI - Meetings: ISPPP '99. PMID- 21649190 TI - Meetings: conferences. PMID- 21649191 TI - New products: new products. PMID- 21649193 TI - Other/miscellaneous. PMID- 21649194 TI - Information express: information express. PMID- 21649198 TI - University conflicts of interest: Manage rather than avoid. PMID- 21649200 TI - Letter to the Editor: Mercury CEMs. PMID- 21649202 TI - In AC Research: In AC Research. PMID- 21649204 TI - Analytical Currents: Hollow core fiber. PMID- 21649206 TI - Analytical Currents: Thermal analysis meets MS. PMID- 21649205 TI - Analytical Currents: Genome mapping goes light. PMID- 21649207 TI - Analytical Currents: Pesticide sorption equilibria. PMID- 21649208 TI - Analytical Currents: DNA condensate. PMID- 21649209 TI - Analytical Currents: Evanescent microwave microscopy. PMID- 21649210 TI - Analytical Currents: Two methods for quantitative proteome analysis. PMID- 21649211 TI - Analytical Currents: Combinatorial chemistry-based protein purification. PMID- 21649212 TI - Analytical Currents: Classifying coronary artery tissue. PMID- 21649214 TI - Analytical Currents: Characterizing a porous silicon optical biosensor. PMID- 21649213 TI - Science: "Mild" fragmentation of peptides. PMID- 21649215 TI - Science: Faster prototyping for ESI-MS chips. PMID- 21649216 TI - News from the Royal Society of Chemistry's Annual Meeting: GM check. PMID- 21649217 TI - News from the Royal Society of Chemistry's Annual Meeting: Folate assay fails. PMID- 21649218 TI - People: Armstrong receives Public Outreach Award. PMID- 21649219 TI - People: Tran to receive gold medal. PMID- 21649220 TI - Government and Society: Changes in NIH's review process. PMID- 21649221 TI - People: Ewing receives award. PMID- 21649222 TI - People: Niessner appointed associate editor. PMID- 21649224 TI - Business: First commercial lab-on-a-chip. PMID- 21649223 TI - Government and Society: New analytical chemistry forum. PMID- 21649225 TI - People: 1999-2000 DAC officers. PMID- 21649226 TI - People: dal Nagare award. PMID- 21649228 TI - Peer Reviewed: Understanding Reversed-Phase LC with solid-state NMR. AB - NMR techniques offer a variety of tools for studying bonded-phase structure, surface chemistry and stability, and dynamic behavior. PMID- 21649229 TI - Focus: Protecting wildlife. AB - The world's only forensic laboratory solely devoted to wildlife protection is developing new analytical methods and transferring that knowledge worldwide. PMID- 21649233 TI - A: New perspectives: Multimedia in analytical chemistry. PMID- 21649232 TI - Product Review: Going with the flow. AB - The gap between benchtop and floor-model flow cytometers narrows. PMID- 21649236 TI - Books and Software: MIPs made easy. AB - A review of Molecular and Ionic Recognition with Imprinted Polymers. PMID- 21649238 TI - Meetings: short course. PMID- 21649237 TI - Meetings: conferences. PMID- 21649240 TI - New products: new products. PMID- 21649241 TI - Other/miscellaneous. PMID- 21649243 TI - Information express: information express. PMID- 21649246 TI - Other/miscellaneous. PMID- 21649245 TI - Other/miscellaneous. PMID- 21649249 TI - In AC Research: In AC Research. PMID- 21649247 TI - A year 2000 celebration. PMID- 21649251 TI - Analytical Currents: Rapid breast cancer analysis. PMID- 21649252 TI - Analytical Currents: Soft landings. PMID- 21649253 TI - Analytical Currents: Toward well-characterized adenovirus products. PMID- 21649255 TI - Analytical Currents: Monolithic capillary columns for CEC. PMID- 21649254 TI - Analytical Currents: Laser-activated voltammetry. PMID- 21649257 TI - Analytical Currents: All-in-one synthesis and evaluation. PMID- 21649256 TI - Analytical Currents: As the film grows. PMID- 21649258 TI - News from the Joint Meeting of the Asia-Pacific Biosensors Group and the Australian Society for Biophysics.: All-in-one biosensing probe. AB - Alison Downard reports from Gold Coast, Queensland, Australia. PMID- 21649259 TI - News from the Joint Meeting of the Asia-Pacific Biosensors Group and the Australian Society for Biophysics.: Taking the O out of BOD. AB - Alison Downard reports from Gold Coast, Queensland, Australia. PMID- 21649260 TI - Analytical Currents: Ion-pair reagents enhance SERRS. PMID- 21649263 TI - Focus: GC in the fast lane. AB - It's a day at the races for PerkinElmer's Jedd Allebach and his gas chromatograph. PMID- 21649261 TI - News from the Autumn Meeting of the New Swiss Chemical Society: Laser MS reveals urban air pollution. AB - Veronika R. Meyer reports from Basel, Switzerland. PMID- 21649264 TI - Product Review: ICPMS--Beyond quadrupole. AB - New designs emerge to combat interferences and reduce costs. PMID- 21649267 TI - Meetings: pittcon 2000 in new orleans. PMID- 21649266 TI - A: The lecture as a learning device. AB - The challenge in college teaching is not covering the material, but uncovering it. PMID- 21649268 TI - Meetings: Well-Characterized Biotechnology Pharmaceuticals (WCBP 2000). PMID- 21649269 TI - Meetings: conferences. PMID- 21649270 TI - Books and Software: Oldie but (still a) goodie. AB - A review of Thin-Layer Chromatography, Fourth Edition. PMID- 21649272 TI - New products: new products. PMID- 21649277 TI - Other/miscellaneous. PMID- 21649278 TI - Information express: information express. PMID- 21649280 TI - Other/miscellaneous. PMID- 21649282 TI - Dealing with research growth. PMID- 21649284 TI - Letters: Authors' response. PMID- 21649285 TI - Letters: Soil cleanup goals. PMID- 21649286 TI - Research Watch: Colloid transport in pollutant migration. PMID- 21649295 TI - Research Watch: Mussels as bioindicators of water contamination. PMID- 21649299 TI - Research Watch: Residue transport into homes by shoes and feet. PMID- 21649305 TI - EPA Watch: NYC watershed pact settles longstanding feud. PMID- 21649306 TI - EPA Watch: New policy focuses on threats to children's health. PMID- 21649307 TI - EPA Watch: Ecological risk assessment guidance proposed. PMID- 21649308 TI - EPA Watch: Chemical industry air toxics rule modified. PMID- 21649309 TI - EPA Watch: $50 million in "hardship" wastewater grants. PMID- 21649310 TI - EPA Watch: Electronic data reporting project launched. PMID- 21649311 TI - News: EPA says chemical use reporting proposal due in early 1997. PMID- 21649312 TI - News: New pesticide law draws fire as supporters predict implementation delays. PMID- 21649327 TI - Peer reviewed: environmental biosensors: a status report. AB - New instruments and methods being developed show promise for continuous, in situ monitoring of toxic compounds. PMID- 21649325 TI - News briefs: news briefs. PMID- 21649328 TI - Rebuilding EPA science. AB - The agency pursues "sound science" despite falling budgets, stagnant staff levels, and turmoil in the labs. PMID- 21649329 TI - Rebuilding EPA Science: ORD Reorganization debate goes Public. PMID- 21649330 TI - Peer reviewed: the changing landscape of the chlorine debate. AB - Growing health concerns and emerging market forces have reshaped the terms of the chlorine debate. PMID- 21649333 TI - Other/miscellaneous. PMID- 21649335 TI - Other/miscellaneous. PMID- 21649337 TI - Restructure environmental R&D. PMID- 21649338 TI - Letters: Defending electric cars. PMID- 21649340 TI - Letters: authors' response. PMID- 21649339 TI - Letters: Defending electric cars. PMID- 21649341 TI - Letters: When EVs age. PMID- 21649345 TI - Research Watch: Global fractionation of PCBs in Arctic lakes. PMID- 21649348 TI - Research Watch: Microbial effects on aquifer denitrification. PMID- 21649352 TI - Research Watch: Detecting estrogenic compounds in river water. PMID- 21649355 TI - Research Watch: Redox processes in contaminated groundwater. PMID- 21649359 TI - Research Watch: A reactor for gas-phase VOC remediation. PMID- 21649361 TI - EPA Watch: NO2 standard remains as is despite regional concerns. PMID- 21649362 TI - EPA Watch: One-stop reporting inches forward. PMID- 21649363 TI - EPA Watch: Massive Superfund cleanup settled at New Jersey site. PMID- 21649364 TI - EPA Watch: Toxic releases from waste sites under investigation. PMID- 21649365 TI - EPA Watch: Agency peer review "uneven," says GAO. PMID- 21649366 TI - EPA Watch: Duluth lab begins to study causes of deformed frogs. PMID- 21649368 TI - News: Critics doubt Clinton's second term will advance reg reforms. PMID- 21649369 TI - News: Administration's environmental record "unparalleled," says Browner. PMID- 21649377 TI - News briefs: news briefs. PMID- 21649378 TI - New cryptosporidium testing methods. AB - Better methods for detecting waterborne microbes in drinking water advance as EPA begins nationwide data collection. PMID- 21649379 TI - A nickel-iron wall against contaminated groundwater. AB - New reactive-wall technology begins pilot study at Cape Cod military site. PMID- 21649381 TI - A testing deadline for endocrine disrupters: separating synthetic estrogens. PMID- 21649380 TI - A testing deadline for endocrine disrupters. AB - EPA scrambles to develop a screening program for these complex substances. PMID- 21649382 TI - A Testing Deadline for Endocrine Disrupters: Screening for other Estrogen Receptors. PMID- 21649385 TI - New products: new products. PMID- 21649383 TI - A Testing Deadline for Endocrine Disrupters: Testing for Fetal effects. PMID- 21649389 TI - Other/miscellaneous. PMID- 21649391 TI - Other/miscellaneous. PMID- 21649392 TI - Other/miscellaneous. PMID- 21649407 TI - EPA Watch: Proposal gives states control of top pesticides. PMID- 21649393 TI - A New "Home" for ES&T. PMID- 21649408 TI - EPA Watch: Major NOx reductions proposed for trucks, buses. PMID- 21649409 TI - EPA Watch: Health effects data sought on 21 air pollutants. PMID- 21649410 TI - EPA Watch: VOC proposal requires reformulated paints, coatings. PMID- 21649411 TI - EPA Watch: Cheaper dioxin controls considered for paper, pulp. PMID- 21649412 TI - EPA Watch: Agreement reached to clean up Lake Champlain. PMID- 21649414 TI - News: New pesticide law drops "zero-tolerance" standard, focuses on exposures to children. PMID- 21649415 TI - News: National "environmental indicators" issued by EPA to track health of U.S. waters. PMID- 21649420 TI - News: Monsanto awards pollution prevention research grant. PMID- 21649425 TI - News briefs: news briefs. PMID- 21649427 TI - Peer reviewed: tracking the distribution of persistent organic pollutants. AB - Control strategies for these contaminants will require a better understanding of how they move around the globe. PMID- 21649429 TI - Peer reviewed: in situ bioremediation: defining the limits. AB - New approaches to engineered and intrinsic bioremediation are being developed and field tested. PMID- 21649434 TI - Other/miscellaneous. PMID- 21649437 TI - Semiexperimental equilibrium structure for cis,trans-1,4-difluorobutadiene by the mixed estimation method. AB - The available experimental rotational constants of cis,trans-1,4 difluorobutadiene do not permit a determination of a complete structure. However, this problem, rather frequent in finding structures, may be solved by the mixed estimation method. The experimental ground state rotational constants are corrected for the rovibrational contribution calculated from an ab initio force field. These semiexperimental data are supplemented by structural parameters from ab initio calculations and a weighted least-squares fit allows us to obtain a reasonable structure. The accuracy of the fitted parameters is checked by optimizing a structure at the coupled cluster level. A good agreement is found between the two methods, validating our procedure. PMID- 21649438 TI - Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma. AB - This work describes an exploratory NMR metabonomic study of second trimester maternal urine and plasma, in an attempt to characterize the metabolic changes underlying prenatal disorders and identify possible early biomarkers. Fetal malformations have the strongest metabolic impact in both biofluids, suggesting effects due to hypoxia (leading to hypoxanthine increased excretion) and a need for enhanced gluconeogenesis, with higher ketone bodies (acetone and 3 hydroxybutyric acid) production and TCA cycle demand (suggested by glucogenic amino acids and cis-aconitate overproduction). Choline and nucleotide metabolisms also seem affected and a distinct plasma lipids profile is observed for mothers with fetuses affected by central nervous system malformations. Urine from women who subsequently develop gestational diabetes mellitus exhibits higher 3 hydroxyisovalerate and 2-hydroxyisobutyrate levels, probably due to altered biotin status and amino acid and/or gut metabolisms (the latter possibly related to higher BMI values). Other urinary changes suggest choline and nucleotide metabolic alterations, whereas lower plasma betaine and TMAO levels are found. Chromosomal disorders and pre-preterm delivery groups show urinary changes in choline and, in the latter case, in 2-hydroxyisobutyrate. These results show that NMR metabonomics of maternal biofluids enables the noninvasive detection of metabolic changes associated to prenatal disorders, thus unveiling potential disorder biomarkers. PMID- 21649439 TI - Emissions of halogenated compounds in East Asia determined from measurements at Jeju Island, Korea. AB - High-frequency in situ measurements at Gosan (Jeju Island, Korea) during November 2007 to December 2008 have been combined with interspecies correlation analysis to estimate national emissions of halogenated compounds (HCs) in East Asia, including the chlorofluorocarbons (CFCs), halons, hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs), perfluorocarbons (PFCs), sulfur hexafluoride (SF(6)), and other chlorinated and brominated compounds. Our results suggest that overall China is the dominant emitter of HCs in East Asia, however significant emissions are also found in South Korea, Japan and Taiwan for HFC-134a, HFC-143a, C(2)F(6), SF(6), CH(3)CCl(3), and HFC-365mfc. The combined emissions of CFCs, halon-1211, HCFCs, HFCs, PFCs, and SF(6) from all four countries in 2008 are 25.3, 1.6, 135, 42.6, 3.6, and 2.0 kt/a, respectively. They account for approximately 15%, 26%, 29%, 16%, 32%, and 26.5% of global emissions, respectively. Our results show signs that Japan has successfully phased out CFCs and HCFCs in compliance with the Montreal Protocol (MP), Korea has started transitioning from HCFCs to HFCs, while China still significantly consumes HCFCs. Taiwan, while not directly regulated under the MP, is shown to have adapted the use of HFCs. Combined analysis of emission rates and the interspecies correlation matrix presented in this study proves to be a powerful tool for monitoring and diagnosing changes in consumption of HCs in East Asia. PMID- 21649440 TI - Adsorption of tetracycline and sulfamethoxazole on crop residue-derived ashes: implication for the relative importance of black carbon to soil sorption. AB - The main objective of this study was to investigate the key factors and mechanisms of antibiotic adsorption on crop residue-derived black carbon, as well as the relative importance of black carbon to the overall sorption to soil. Batch sorption experiments were performed for two reference antibiotics (sulfamethoxazole and tetracycline) on wheat- and maize-residue-derived black carbon. After removal of the mineral fraction from the raw black carbon by acidification, tetracycline exhibited less enhanced adsorption than sulfamethoxazole, implying stronger complexation of tetracycline on the mineral components. The antibiotic adsorption on the demineralized black carbon was very strong (The measured K(d) was in the order of 10(3)-10(5) L/kg). The adsorbent surface area-normalized adsorption of sulfamethoxazole was higher on the demineralized black carbon than on nonporous graphite due to the micropore filling effect. The opposite trend observed for bulky tetracycline was attributed to the size-exclusion effect. Owing to the strong surface complexation and/or cation exchange reaction, sorption of tetracycline to Na(+)-exchanged montmorillonite, soil humic acids, and bulk soil was remarkably stronger than sulfamethoxazole. It was estimated that the contribution of black carbon to the overall sorption to bulk soil was important for sulfamethoxazole, but negligible for tetracycline. PMID- 21649441 TI - Cationic gel-phase liposomes with "decorated" anionic SPIO nanoparticles: morphology, colloidal, and bilayer properties. AB - The assembly and complexation of oppositely charged colloids are important phenomena in many natural and synthetic processes. Liposome-nanoparticle assemblies (LNAs) represent an interesting hybrid system that combines "soft" and "hard" colloidal materials. This work describes the formation and characterization of gel-phase LNAs formed by the binding of anionic superparamagnetic iron oxide (SPIO) nanoparticles to cationic dipalmitoylphosphatidylcholine (DPPC)/dipalmitoyltrimethylammonium propane (DPTAP) liposomes. Particles were examined with hydrodynamic diameters below (16 nm) and above (30 nm) the cutoff reported for supported lipid bilayer formation. LNA formation with 16 nm particles was entropically driven and particles bound individually to yield "decorated" structures. In this case, increasing nanoparticle concentration yielded colloidal LNA aggregates and eventual charge inversion. In contrast, LNA formation with 30 nm particles was enthalpically driven, and the nanoparticles aggregated at the bilayer interface. These aggregates led to significant LNA aggregation and large bilayer sheets due to liposome rupture despite minimal charge screening of the liposome surface. In this case SLBs were present, but these structures were not dominant. Differences in LNA structure were also revealed through the lipid phase transition behavior. This work infers size-dependent nanoparticle binding and LNA formation mechanisms that can be used to tailor colloidal and bilayer properties. Analogies are made to polyelectrolyte patch charge heterogeneities and DNA complexation with cationic liposomes. PMID- 21649442 TI - Application of hybrid life cycle approaches to emerging energy technologies--the case of wind power in the UK. AB - Future energy technologies will be key for a successful reduction of man-made greenhouse gas emissions. With demand for electricity projected to increase significantly in the future, climate policy goals of limiting the effects of global atmospheric warming can only be achieved if power generation processes are profoundly decarbonized. Energy models, however, have ignored the fact that upstream emissions are associated with any energy technology. In this work we explore methodological options for hybrid life cycle assessment (hybrid LCA) to account for the indirect greenhouse gas (GHG) emissions of energy technologies using wind power generation in the UK as a case study. We develop and compare two different approaches using a multiregion input-output modeling framework - Input Output-based Hybrid LCA and Integrated Hybrid LCA. The latter utilizes the full sized Ecoinvent process database. We discuss significance and reliability of the results and suggest ways to improve the accuracy of the calculations. The comparison of hybrid LCA methodologies provides valuable insight into the availability and robustness of approaches for informing energy and environmental policy. PMID- 21649443 TI - Z-selective homodimerization of terminal olefins with a ruthenium metathesis catalyst. AB - The cross-metathesis of terminal olefins using a novel ruthenium catalyst results in excellent selectivity for the Z-olefin homodimer. The reaction was found to tolerate a large number of functional groups, solvents, and temperatures while maintaining excellent Z-selectivity, even at high reaction conversions. PMID- 21649444 TI - Synthesis of amphiphilic alternating polyesters with oligo(ethylene glycol) side chains and potential use for sustained release drug delivery. AB - Novel amphiphilic alternating polyesters, poly((N-phthaloyl-l-glutamic anhydride) co-(2-(2-(2-methoxyethoxy)ethoxy)methyl)oxirane) (P(PGA-co-ME(2)MO)), were synthesized by alternating copolymerization of PGA and ME(2)MO. The structures of the synthesized polyesters were characterized by (1)H NMR, (13)C NMR, FT-IR, and GPC analyses. Because of the presence of oligo(ethylene glycol) (OEG) side chains, the polyesters could self-assemble into thermosensitive micelles. Dynamic light scattering (DLS) showed that these micelles underwent thermoinduced size decrease without intermicellar aggregation. In vitro methyl thiazolyl tetrazolium (MTT) assay demonstrated that the polyesters were biocompatible to Henrietta Lacks (HeLa) cells, rendering their potential for drug delivery applications. Two hydrophobic drugs, rifampin and doxorubicin (DOX), were loaded into the polyester micelles and observed to be released in a zero-order sustained manner. The sustained release could be accelerated in lower pH or in the presence of proteinase K, due to the degradation of the polyester under these conditions. Remarkably, in vitro cell experiments showed that the polyester micelles accomplished fast release of DOX inside cells and higher anticancer efficacy as compared with the free DOX. With enhanced stability during circulation condition and accelerated drug release at the target sites (e.g., low pH or enzyme presence), these novel polyesters with amphiphilic structures are promising to be used in sustained release drug delivery systems. PMID- 21649445 TI - Hydrogen-bond-directed giant unilamellar vesicles of guanosine derivative: preparation, properties, and fusion. AB - By mixing a small volume of THF containing guanosine derivative 1 and tetraethylenegrycol dodecyl ether (TEGDE) with water and subsequently removing TEGDE by gel permeation chromatography, micrometer-sized giant unilamellar vesicles (GUV) of 1 were successfully prepared. The vesicle membrane was a 2-D sheet assembly of thickness 2.5 nm, composed of a 2-D inter-guanine hydrogen-bond network. The GUV dispersion showed high stability because of a large negative zeta potential, which allowed repeated sedimentation and redispersion by centrifugation and subsequent gentle agitation. TEGDE-triggered fusion of GUVs took place within 350 ms, which proceeded by fusion of the vesicle membranes in contact. These unique static and dynamic properties of the GUV membrane assembled by the 2-D hydrogen-bond network are discussed. PMID- 21649446 TI - Pharmacotherapy for primary CNS lymphoma: progress beyond methotrexate? AB - Studies conducted in the 1990s have established that high-dose methotrexate-based chemotherapy added to whole-brain radiotherapy improves survival in primary CNS lymphoma (PCNSL). However, radiotherapy-related delayed neurotoxicity has emerged as a serious complication of chemo-radiotherapy, particularly in the elderly. Unfortunately, omitting radiotherapy results in decreased progression-free survival, and therefore establishing more effective chemotherapy regimens is necessary in order to improve the number of long-term remissions. Recent studies have suggested that a combination of drugs is superior to single-agent methotrexate, but the optimal chemotherapy combination and the role of alternative consolidation treatments such as reduced-dose radiotherapy and high dose chemotherapy with stem cell rescue remain to be defined. In this article, we review the multiple chemotherapy options reported in newly diagnosed and in progressive/refractory PCNSL, including recently reported and ongoing clinical trials, as well as future perspectives. PMID- 21649447 TI - Suicidal ideation during antidepressant treatment: do genetic predictors exist? AB - Suicidal thoughts during antidepressant treatment have recently been the focus of several candidate gene and genome-wide association studies. Although the clinical risk factors for such events are well known, unfortunately they do not help to predict who will have a suicidal event during antidepressant treatment and who will not. Pharmacogenomic studies have therefore attempted to use genetic variants to predict individual susceptibility to treatment-related suicidal ideation. In this perspective, several genetic predictors have been highlighted, the majority of which relate to common mechanisms of antidepressant action: genes involved in the neurotrophic and synaptic plasticity systems (CREB1, and BDNF and its receptor NTRK2), noradrenergic system (ADRA2A), glutamatergic system (GRIA3, GRIK2 and GDA), inflammatory and hypothalamic-pituitary-adrenal (HPA) axis systems (IL28RA and FKBP5) and in other brain functions (PAPLN, APOO, KCNIP4 and ELP3). Although some of these genes may be of interest in predicting antidepressant-induced suicidal ideation, they still need to be validated in better phenotypically designed samples. Several methodological factors are indeed responsible for the problems involved in implicating these findings in the causation of a clinically relevant phenotype. These include discrepancies between studies in defining phenotypes, with several different thresholds used to establish significant suicidal ideation; the use of scales not truly designed to measure suicidal ideation; and the paucity of true suicidal events (suicide attempts and/or completion) in pharmacogenomic studies. In conclusion, pharmacogenomic studies are far from fulfilling their promise. There is a need for future pharmacogenetic studies targeting events that are clinically significant in order to find associated variants that will help clinicians to improve their treatment strategies. While awaiting these genetic predictors, clinicians need to bear in mind that all studies in this field support a beneficial effect of antidepressants on suicidal ideation. This should therefore encourage them to prescribe antidepressant medication even in patients with suicidal ideation. PMID- 21649448 TI - Assessing QT interval prolongation and its associated risks with antipsychotics. AB - Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500 ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive. PMID- 21649450 TI - Lower IQ is associated with decreased clinical response to atomoxetine in children and adolescents with attention-deficit hyperactivity disorder. AB - OBJECTIVES: Atomoxetine is commonly used to treat attention-deficit hyperactivity disorder (ADHD) in children with a broad range of cognitive abilities. We examined the association between level of cognitive functioning as determined by IQ and clinical response during treatment with atomoxetine. METHODS: The records of all the children and adolescents treated with atomoxetine at a university clinic in Catania, Italy, over a 3-year period were examined. A total of 55 clinically referred children and adolescents (aged 5-15 years, 53 males) with ADHD were treated with atomoxetine (10-110 mg/day; mean: 1.28 mg/kg/day) for a period ranging from 2 to 168 weeks (mean: 57.3 +/- SD 39.4, median: 56). The IQ was assessed as part of the diagnostic evaluation prior to starting treatment. During treatment, clinical outcome was rated on the Clinical Global Impression Improvement (CGI-I) and CGI-Severity (CGI-S) scales. RESULTS: The IQ ranged from 43 to 117 (mean: 80.6 +/- SD 18.6, median: 84). The IQ and final CGI-I scores were negatively correlated (r = -0.68; p < 0.01). Children and adolescents with an IQ <85 were less likely to be responders (defined as a final CGI-I score of 1 or 2) than children and adolescents with an IQ >=85 (20.71% vs 76.9%; p < 0.001). None of the patients discontinued atomoxetine due to adverse effects, while treatment was discontinued in 20 subjects due to a lack of efficacy or ambivalence of parents about pharmacological treatment. CONCLUSIONS: Atomoxetine appears to be less effective in children and adolescents with an IQ <85 than in children and adolescents in the average range of cognitive functioning. This difference is not accounted for by differences in the severity of ADHD symptoms, co-morbidity or reduced tolerability to the medication. These findings suggest that, in order to be fully informative, clinical trials of medications for ADHD should also include children and adolescents functioning in the borderline and cognitive disability range. PMID- 21649449 TI - The mechanism of action of interferon-beta in relapsing multiple sclerosis. AB - Multiple sclerosis (MS) is characterized by autoimmune inflammation and subsequent neurodegeneration. It is believed that early in the disease course, proinflammatory T cells that are activated in the periphery by antigen presentation cross the blood-brain barrier (BBB) into the CNS directed by various chemotaxic agents. However, to date, there has been no formal demonstration of a specific precipitating antigen. Once inside the CNS, activated T cells including T helper-1 (T(h)1), T(h)17, gammadelta and CD8+ types are believed to secrete proinflammatory cytokines. Decreased levels of T(h)2 cells also correlate with relapses and disease progression in MS, since T(h)2-derived cytokines are predominantly anti-inflammatory. In healthy tissue, inflammatory effects are opposed by specific subsets of regulatory T cells (T(regs)) including CD4+, CD25+ and FoxP3+ cells that have the ability to downregulate the activity of proinflammatory T cells, allowing repair and recovery to generally follow inflammatory insult. Given their function, the pathogenesis of MS most likely involves deficits of T(reg) function, which allow autoimmune inflammation and resultant neurodegeneration to proceed relatively unchecked. Interferons (IFNs) are naturally occurring cytokines possessing a wide range of anti-inflammatory properties. Recombinant forms of IFNbeta are widely used as first-line treatment in relapsing forms of MS. The mechanism of action of IFNbeta is complex, involving effects at multiple levels of cellular function. IFNbeta appears to directly increase expression and concentration of anti-inflammatory agents while downregulating the expression of proinflammatory cytokines. IFNbeta treatment may reduce the trafficking of inflammatory cells across the BBB and increase nerve growth factor production, leading to a potential increase in neuronal survival and repair. IFNbeta can also increase the number of CD56bright natural killer cells in the peripheral blood. These cells are efficient producers of anti inflammatory mediators, and may have the ability to curb neuron inflammation. The mechanistic effects of IFNbeta manifest clinically as reduced MRI lesion activity, reduced brain atrophy, increased time to reach clinically definite MS after the onset of neurological symptoms, decreased relapse rate and reduced risk of sustained disability progression. The mechanism of action of IFNbeta in MS is multifactorial and incompletely understood. Ongoing and future studies will increase our understanding of the actions of IFNbeta on the immune system and the CNS, which will in turn aid advances in the management of MS. PMID- 21649451 TI - Fentanyl pectin nasal spray: in breakthrough pain in opioid-tolerant adults with cancer. AB - Fentanyl pectin nasal spray (PecFent(r)) uses a novel pectin-based delivery system that turns from an aqueous solution into a gel when applied to mucosal surfaces. Fentanyl is absorbed in a controlled manner from the pectin gel formed in the nasal cavity, and has a rapid onset of pain relief and duration of action that matches the time course of a typical episode of breakthrough pain in cancer (BTPc). Relative to administration as oral transmucosal fentanyl, fentanyl administered as fentanyl pectin nasal spray is more rapidly absorbed, reaches higher maximum plasma concentrations and has greater bioavailability. In the treatment of BTPc in two randomized, double-blind, crossover trials in opioid tolerant adults, fentanyl pectin nasal spray (100-800 MUg titrated doses) was significantly more effective than placebo in reducing pain intensity and provided a significantly faster onset of pain relief than oral immediate-release morphine. During long-term treatment of BTPc episodes, fentanyl pectin nasal spray consistently provided effective pain relief in an open-label, 16-week trial. Most patients were satisfied or very satisfied with the ease of use and convenience of the nasal spray. Fentanyl pectin nasal spray 100-800 MUg was generally well tolerated and was not associated with nasal tolerability problems. PMID- 21649452 TI - Oral paliperidone: a review of its use in the management of schizoaffective disorder. AB - Oral paliperidone extended or prolonged release (Invega(r)) is an atypical antipsychotic, and is the first agent approved for the treatment of schizoaffective disorder. Paliperidone (or 9-hydroxyrisperidone) is the major active metabolite of the well known atypical antipsychotic risperidone, and its mechanism of action is thought to be the antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors. The clinical efficacy of paliperidone was demonstrated in two 6-week, randomized, double-blind, placebo-controlled, multicentre trials in patients with schizoaffective disorder. One trial was flexible dose in design (3-12 mg/day) and the other was fixed dose in design (3-6 and 9-12 mg/day). Compared with placebo, the change from baseline at study end in the Positive and Negative Syndrome Scale (PANSS) total score (primary endpoint) was significantly greater with paliperidone 3-12 mg/day in one trial and with 9 12 mg/day (but not 3-6 mg/day) in the other trial. However, pooled analyses reported a significantly greater change in PANSS total score across all paliperidone dosages than with placebo. Paliperidone was generally well tolerated in the 6-week trials, and no unexpected adverse events were reported. The most commonly reported treatment-emergent adverse events were headache, tremor, dizziness, insomnia, nausea, akathisia, dyspepsia, hypertonia, somnolence and sedation. Although long-term efficacy and tolerability data and comparisons with other antipsychotics are needed, paliperidone appears to be a useful agent for the short-term management of patients with schizoaffective disorder. PMID- 21649453 TI - EDTA redistribution of lead and cadmium into the soft tissues in a human with a high lead burden - should DMSA always be used to follow EDTA in such cases? AB - Intravenous sodium calcium ethylene diamine tetra acetic acid (EDTA) and oral 2,3 dimercaptosuccinic acid (DMSA) have both been used to reduce the burden of lead in humans. Each of these agents enhances the mobilization of lead from different areas of the body - EDTA from the trabecular bone and DMSA from the soft tissue. A study of Korean battery workers revealed that EDTA appeared to increase the soft tissue burden of lead, resulting in increased levels of aminolevulinic acid and greater subsequent lead mobilization with DMSA. This case report discusses a patient with a higher-than-normal lead burden who exhibited increased tissue lead burden after intravenous EDTA. The elevated tissue burden of lead was still present, albeit lower, after five consecutive days of oral DMSA therapy. If this single case is representative of a typical human response to the use of intravenous (IV) EDTA for lead, then it suggests that all persons undergoing such treatment should be administered oral DMSA for a minimum of one week after EDTA treatment. PMID- 21649454 TI - Gastroesophageal reflux disease (GERD): a review of conventional and alternative treatments. AB - Gastroesophageal reflux disorder (GERD), a common disorder in the Western world, can lead to complications that include esophageal stricture and esophageal adenocarcinoma. Multiple challenges are associated with GERD treatment. First, lack of symptoms does not correlate with the absence of or the healing of esophageal lesions. Second, proton pump inhibitors, the current standard of care for GERD, are ineffective for the majority of GERD patients who have non-erosive disease. This article discusses these challenges, investigates the mechanisms of damage in GERD, and explores the existing data on unconventional forms of treatment, including melatonin, acupuncture, botanicals, and dietary interventions. PMID- 21649455 TI - Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/alternative approaches. AB - Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder with a range of symptoms that significantly affect quality of life for patients. The difficulty of differential diagnosis and its treatment may significantly delay initiation of optimal therapy. Hence, persons with IBS often self-treat symptoms with non-prescribed pharmacological regimens and/or complementary and alternative medicines (CAM) and by modifying diet and daily activities. In addition, most common pharmacological approaches target IBS symptom management rather than treatment, and prescribed medications often result in significant side effects. The purposes of this review article are to: (1) address current issues related to IBS, including symptom presentation, diagnosis, and current treatment options; (2) summarize benefits and side effects of currently available pharmacological regimens and other symptom management strategies, with an emphasis on commonly used CAM therapies and diet modification; and (3) outline recommendations and future directions of IBS management based on systematic reviews, meta-analyses, and research findings. PMID- 21649456 TI - Curcumin for inflammatory bowel disease: a review of human studies. AB - OBJECTIVE: To evaluate the use of curcumin in inflammatory bowel disease. DATA SOURCES: ALTMEDEX, Comprehensive Database of Natural Medicines, MEDLINE/PubMed were searched from January 1980 through May 2009 using the terms curcumin, turmeric, ulcerative colitis, Crohn's disease, Curcuma longa, Curcuma domestica, Indian saffron, inflammatory bowel disease. Data was limited to human trials. References of identified articles were reviewed. DATA SYNTHESIS: Data evaluating the use of curcumin in inflammatory bowel disease (including ulcerative colitis and Crohn's disease) is limited to two studies comprising data for only 99 patients. Curcumin in conjunction with mainstream therapy, consisting of sulfasalazine (SZ) or mesalamine (5-aminosalicylic acid [5-ASA] derivatives) or corticosteroids was shown to improve patient symptoms and allow for a decrease in the dosage of corticosteroids or 5-ASA derivatives. In one small study of 10 patients, some patients even stopped taking corticosteroids or 5-ASA. CONCLUSIONS: Although two small studies have shown promising results, all authors conclude that larger-scale, double-blind trials need to be conducted to establish a role for curcumin in the treatment of ulcerative colitis. In addition to improving results when used in conjunction with conventional medications for UC, curcumin may pose a less-expensive alternative. PMID- 21649457 TI - Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebo-controlled clinical trial. AB - BACKGROUND: Green tea is one of the most popular beverages in the world. It is believed to have beneficial effects in the prevention and treatment of many diseases, one of which is type 2 diabetes. The aim of the study is to examine the effect of a decaffeinated green tea extract (GTE) providing a daily dose of 856 mg of epigallocatechin gallate (EGCG) on obese individuals with type 2 diabetes. MATERIALS AND METHODS: The clinical trial was a randomized, double-blind, placebo controlled clinical trial conducted from December 2007 through November 2008. The subjects were randomly assigned to either receive 1,500 mg of a decaffeinated GTE or placebo daily for 16 weeks. Sixty-eight of 80 subjects, ages 20-65 years with BMI > 25 kg/m2 and type 2 diabetes for more than one year, completed this study. Homeostasis model assessment for insulin resistance (HOMA-IR) was used as the major outcome measurement. At baseline and after 16 weeks of treatment, anthropometric measurements, fasting glucose, hemoglobin A1C percent (HbA1C), hormone peptides, and plasma lipoproteins were measured from both groups. RESULTS: No statistically significant differences were detected between the decaffeinated GTE and placebo groups in any measured variable. A statistically significant within-group 0.4-percent reduction in HbA1C (from 8.4 to 8.0%) was observed after GTE treatment compared to baseline. Within-group comparison also revealed that the GTE group had significant reductions in waist circumference (WC), HOMA-IR index, and insulin level, and a significant increase in the level of ghrelin. Within-group comparison of those in the placebo group showed a significant increase in the level of ghrelin. CONCLUSIONS: This study found no statistical difference in any measured variable between the decaffeinated GTE and placebo groups; however, there were some statistically significant within-group changes detected. More research is required to determine whether a decaffeinated GTE standardized for EGCG content will provide any clinical benefits in obese individuals with type 2 diabetes. Clinical Trial Registration NO: NCT00567905. PMID- 21649458 TI - Conservative management of post-surgical urinary incontinence in an adolescent using applied kinesiology: a case report. AB - INTRODUCTION: This case report describes the successful treatment of an adolescent female suffering daily stress and occasional total urinary incontinence with applied kinesiology methods and chiropractic manipulative therapy. PATIENT PRESENTATION: A 13-year-old female developed unpredictable urinary incontinence and right hip pain immediately following emergency open appendectomy surgery. The patient was forced to wear an incontinence pad throughout the day and night for 10 months because of unpredictable urinary incontinence. ASSESSMENT AND INTERVENTION: Chiropractic and applied kinesiology (AK) methods - a multi-modal diagnostic technique that utilizes manual muscle tests (MMT) for the detection of musculoskeletal impairments and specific AK techniques for correction of identified issues - were utilized to diagnose and treat this patient for muscle impairments in the lumbar spine and pelvis. RESULTS: Patient experienced a rapid resolution of her urinary incontinence and hip pain. A six-year follow-up confirmed complete resolution of symptoms. DISCUSSION: In this case, utilization of MMT allowed for the identification of several inhibited muscles. Utilizing the appropriate corrective techniques improved the strength of these muscles and resulted in their being graded as facilitated. Symptoms of urinary incontinence and hip pain resolved with this diagnostic and treatment approach. CONCLUSION: AK methods were useful for the discovery of a number of apparent causative factors underlying this patient's urinary incontinence and hip pain. Treatment for these pelvic-floor muscle and joint abnormalities resulted in rapid, long-lasting resolution of her urinary incontinence and hip pain. PMID- 21649459 TI - Quercetin. Monograph. PMID- 21649460 TI - Patterns of transfer in labour and birth in rural New Zealand. AB - INTRODUCTION: For many women, and particularly rural women, birthing locally and within their own community is important for personal, social and/or cultural reasons. If concerns about the woman or her baby mean transfer to a secondary or tertiary facility is necessary, this can be disruptive and stressful, especially if road transfer is complicated by terrain, weather or distance, as is often the case in rural New Zealand. The objective of this study was to explore the number of and reason for transfers during labour and birth for well women, close to full term, from primary rural maternity facilities to specialist care in rural New Zealand. METHODS: This retrospective survey of 45 rural maternity units in the North and South Islands of New Zealand was conducted over a 2 year period ending on 30 June 2006. The participants were the 4678 women who began labour in a rural facility during this time period. RESULTS: The survey response rate was 66.6%. The data revealed that 16.6% of women who commenced labour in a rural unit were transferred in labour or within 6 hours of birth; 3% of babies born in rural units were transferred after birth and up to 7 days post-birth. The primary reason for maternal transfer was slow progress in labour (49.67%). Of the 123 babies transferred, this was most often due to respiratory problems (43%). Key features of the rural context (times and distances to be travelled, geological and climatic characteristics, types of transport systems and availability of local assistance) influenced the timeliness of the decision to transfer. CONCLUSIONS: Within New Zealand's regionalised perinatal system, midwives make cautious decisions about transfer, taking into account the local rural local circumstances, and also the topography as it impacts on transport. PMID- 21649461 TI - Inflammatory and genotoxic effects of nanoparticles designed for inclusion in paints and lacquers. AB - Manufactured nanomaterials are projected to be used on a large scale in paints and lacquers. We selected seven commercially interesting materials: Three titanium dioxide-based (two coated rutile; one uncoated anatase), one carbon black (Flamruss 101), one kaolinite clay, and two silica products, whereas carbon black, Printex 90, was used as reference material. DNA damaging activity and inflammogenicity (pulmonary cell composition and mRNAs) were determined 24 h after intratracheal instillation of a single dose of 54 MUg in mice. Greatest inflammation was induced by Printex 90 and uncoated titanium dioxide. The inflammatory potency correlated with instilled surface area (R(2) = 0.94) but not with material volume (R(2) = 0.17). The coated titanium dioxides induced DNA damage in lung lining fluid cells. The uncoated titanium dioxide was not DNA damaging by the comet assay 24 h after exposure despite being highly inflammogenic. This suggests that inflammation is not a prerequisite to DNA damage in titanium dioxide-based products. PMID- 21649462 TI - Prevalence of vanC vancomycin-resistant enterococci in the teaching hospitals of the University of Debrecen, Hungary. AB - Vancomycin-resistant enterococci (VRE) are common nosocomial pathogens; however, until now they have been rarely encountered in Hungary. In the present study, we investigated the prevalence of VRE in the teaching hospitals of the University of Debrecen. Of 7,271 Enterococcus-containing clinical samples collected between 2004 and 2009, we identified 16 VRE. Species-specific polymerase chain reaction was used to detect Enterococcus faecalis, Enterococcus faecium, Enterococcus casseliflavus, and Enterococcus gallinarum. Multiplex polymerase chain reaction was performed to identify the vancomycin resistance genes: vanA, vanB, vanC1/C2, vanD, vanE, and vanG. Restriction digestion with SalI and HindIII was introduced to differentiate the vanC1 and vanC2 genes from each other. Genetic relationships between the strains were investigated by pulsed-field gel electrophoresis. Overall, we identified the vanC1 resistance gene in 14 E. gallinarum and the vanC2 resistance gene in two E. casseliflavus strains. Except for two samples, the isolates had different pulsed-field gel electrophoresis types, suggesting sporadic emergence of the resistant bacteria. In addition, antibiotic resistance profile was determined by E-test. Three E. gallinarum strains proved to be resistant to gentamicin because of the presence of the aacA-aphD gene. Although the prevalence of VRE in Debrecen is rather low, the appearance of multiple resistances is of concern. PMID- 21649463 TI - Knockdown of beta-Catenin through shRNA cause a reversal of EMT and metastatic phenotypes induced by HIF-1alpha. AB - OBJECTIVE: Wnt/beta-catenin signaling pathway regulates pattern formation during embryogenesis as well as tumor progression. Numbers of studies suggest that this signaling pathway may play an important role in Epithelial-Mesenchymal transition (EMT), however, there was no evidence that Wnt/beta-catenin signaling pathway directly controlled the EMT occurrence. Our previous research has successfully proved that overexpression of hypoxia inducible factor-1alpha (HIF-1alpha) could induce EMT in LNCaP cells, but not in PC-3. Consistently, the expression of beta catenin protein increased in LNCaP/HIF-1alpha cells, but not in PC-3/HIF-1alpha. This study mainly aimed at exploring the essentiality and importance of Wnt/beta catenin signaling pathway in HIF-1alpha-induced EMT. METHODS: Human prostate cancer cells (LNCaP) were stably transfected by recombinant plasmid pcDNA3.1( )/HIF-1alpha. The positive clones were selected by G418 and confirmed through western blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), and indirect immunofluoesence. Then LNCaP/HIF-1alpha was transiently transfected with beta-catenin shRNA (shRNA1 and shRNA2) and negative shRNA (shRNA-scr). The epithelial markers, mesenchymal markers, and critical proteins in Wnt/beta catenin signaling pathway were separately detected by western blot analysis. Finally, the invasive potency of cells in different transfection group was examined by Matrgel transwell assay. RESULT: We successfully established prostate cancer cell line LNCaP/HIF-1alpha and LNCaP/HIF-1alpha/beta-catenin(-). LNCaP/HIF 1alpha displayed high expression of mesenchymal markers and low expression of epithelial markers. However, compared with LNCaP/HIF-1alpha, the epithelial marker E-cadherin was increased in LNCaP/HIF-1alpha/beta-catenin(-), whereas the expression of mesenchymal marker N-cadherin, vimentin, MMP-2 were significantly decreased. Inhibition of Wnt signal activity through beta-catenin shRNA cause a reversal of EMT induced by HIF-1alpha in human prostate cancer. CONCLUSION: Overexpression of HIF-1alpha stimulates the invasion potency of human prostate carcinoma cells through EMT pathway and Wnt/beta-catenin signaling pathway played a vital role in this process. Wnt/beta-catenin signaling pathway might be a necessary endogenous signal that directly controlled the EMT occurrence induced by HIF-1alpha. PMID- 21649465 TI - Potential role of P-gp for flavone-induced diminished apoptosis and increased adenoma size in the small intestine of APC(min/+) mice. AB - APC(min/+) mice, carrying a nonsense mutation in the adenomatous polyposis coli (APC) gene, appear as a perfect model to study development or therapy of intestinal neoplasia. We tested whether the flavonoid flavone is able to affect adenoma development in APC(min/+) mice. Tumor sizes were significantly increased by flavone selectively in small intestine. This was associated with reduced cell numbers displaying cleaved caspase-3 and enhanced expression of phosphoglycoprotein (P-gp). However, according to great variability in P-gp expression in all parts of mice intestines, an association between expression of P-gp and inhibition of apoptosis was demonstrated in human Caco-2 colorectal cancer cells. PMID- 21649464 TI - The Levels of H11/HspB8 DNA methylation in human melanoma tissues and xenografts are a critical molecular marker for 5-Aza-2'-deoxycytidine therapy. AB - H11/HspB8 is a functionally distinct small heat shock protein. It causes growth arrest in melanocytes, associated with the inhibition of Cyclin E/Cdk2 and beta catenin phosphorylation at the transcriptional activity site Ser(552) and is silenced through DNA methylation in 27/35 (77%) melanoma tissues/early cultures. 5-Aza-2'-deoxycytidine (Aza-C) induces melanoma cell death correlated with the levels of H11/HspB8 DNA methylation (p < .001). In line with low/moderate H11/HspB8 methylation, PI3-K inhibition increases Aza-C-induced cell death. Aza-C inhibits the growth of melanoma xenografts related to the levels of H11/HspB8 methylation, and a nonmethylated/non-TAK1 binding H11/HspB8 mutant confers Aza-C resistance. H11/HspB8 is a potential molecular marker for demethylation therapies. PMID- 21649466 TI - Clinical implications for girdin protein expression in breast cancer. AB - Girdin is highly expressed in breast carcinomas. Suppression of Girdin inhibited breast cancer cell migration. However, the clinical implications of Girdin as a marker are still unclear. Here we examined 80 breast cancer specimens using immunohistochemistry. Overall, positive Girdin staining was 41.25% in all of the cases. Girdin was strongly expressed in tumors of CerbB2-positive breast cancers (p < .05). Cases with both CerbB2- and Girdin-positive expression had a higher histological grade than the others. These findings indicated the closed relationship between breast cancer progression and Girdin expression. Girdin together with CerbB2 might be a new potential marker for breast cancers. PMID- 21649467 TI - Association of functionally important polymorphism of microsomal epoxide hydrolase gene (EPHX1) with lung cancer susceptibility. AB - Distribution and gene-environment interaction of EPHX1 polymorphism was evaluated in 175 lung cancer patients and 322 controls from north India. Two novel non synonymous, Lys117Arg and Leu263Phe, and twelve single nucleotide polymorphisms were identified in the present study. Binary logistic regression analysis showed association of polymorphism Tyr113His with increased risk of lung cancer (OR = 2.2, 95% CI = 1.2-4.0, p < .05). Gene-environment interaction revealed that patients with His113His and smoking habit had significantly greater risk of lung cancer (OR = 4.52, 95% CI = 0.93-43.05, p < .05). Present study provided evidence that EPHX1 polymorphism is associated with lung cancer susceptibility in Indian population. PMID- 21649469 TI - Waist circumference predicts increased cardiometabolic risk in normal weight adolescent males. AB - OBJECTIVE: The aims of the study were to establish waist circumference (WC) cut off points that identify clustering of obesity-related conditions and determine if the cut-off points identified an increased risk of disease when used within BMI categories. METHODS: This is a secondary analysis of the Centers for Disease Control NHANES III complex, multistage probability weighted data set collected between 1988 and 1994 from multiple locations in the United States. There were 2003 adolescents ages 12-19 years. Main outcome measures were low (<2 risk factors) or high (>=2 risk factors) risk for cardiometabolic disease based on the number of abnormal serum measurements for fasting glucose, high-density lipoprotein (HDL), triglycerides, and blood pressure. Receiver-operating characteristic curve analysis created the WC cut-off points and logistic regression determined if cut-off points predicted of within BMI categories. RESULTS: Analysis identified cut-off points of >=80.5 cm for males and >=81 cm for females. Cut-off points predicted abnormal values for all outcome variables except fasting serum glucose in females, p < 0.05. Males with a normal BMI and elevated waist circumference were more likely to be high risk (OR = 5.23, CI = 1.79, 15.24, p < 0.013) and have increased odds of abnormal serum triglycerides, HDL and blood pressure. Overweight females (BMI >= 85-94%) with elevated waist circumference were more likely to have elevated blood pressure (OR = 9.05, 95% CI: 1.44, 56.83). CONCLUSION: WC within BMI categories may identify those who have cardiometabolic disease risk factors despite having normal or overweight BMI. PMID- 21649468 TI - The numbers of FoxP3+ lymphocytes in sentinel lymph nodes of breast cancer patients correlate with primary tumor size but not nodal status. AB - Regulatory T cells, lymphocytes marked by expression of the transcription factor Forkhead Box Protein P3 (FoxP3), inhibit the activation of tumor-specific T cells in tumor-draining lymph nodes. Immunohistochemical analyses of sentinel lymph nodes (SLNs) from 104 breast cancer patients showed a significant association (p = .0028, Pearson correlation) between the number of FoxP3+ cells and the size of primary breast invasive ductal carcinoma. In contrast, there was no correlation between the number of FoxP3+ cells and the presence of SLN metastases, or other clinicopathological parameters. These results suggest the presence of an immune suppressive environment in SLNs of larger tumors. PMID- 21649470 TI - Differentiated thyroid cancer in two patients with resistance to thyroid hormone. AB - BACKGROUND: Resistance to thyroid hormone (RTH) is a genetic disease characterized by a reduced responsiveness of the pituitary and peripheral target tissues to TH. We describe two patients with RTH in whom differentiated thyroid cancer was diagnosed. PATIENT FINDINGS: In both patients, RTH was unequivocally diagnosed and both underwent thyroidectomy for multinodular goiter. In Patient 1, histology showed a papillary thyroid carcinoma pT2. Because serum thyrotropin (TSH) levels were elevated even while the patient was taking 150 MUg daily of levothyroxine (LT(4)), the patient was treated with (131)I 100 mCi for ablation of the thyroid remnant without discontinuing his LT(4) therapy. We obtained a clinically adequate response by administering LT(4) 175 MUg/day (2.18 MUg/kg), but the serum TSH was persistently elevated on this dose. The patient was considered "free of disease" after 8 years of follow-up. In Patient 2, histology revealed a papillary microcarcinoma (0.6 cm). Diagnostic whole-body scan was performed while the patient was taking 100 MUg/day LT(4), a time that his serum TSH was 38 MUU/mL. Only a small remnant was revealed, so (131)I remnant ablation was not performed. While taking LT(4) at a dose of 175 MUg/day (3 MUg/kg), the serum TSH was persistently high, serum TH levels were in the normal-high range, and he appeared to be clinically euthyroid. There has been no evidence of persistent or recurrent thyroid carcinoma in ultrasonography and thyroglobulin measurements that have been performed on a yearly basis for 3 years. CONCLUSION: Patients with thyroid carcinoma and RTH are a unique model of thyroid cancer in which follow-up likely occurs in the setting of constantly elevated serum TSH concentrations. The concern in these patients is that their persistent elevation of serum TSH may have an adverse effect on their thyroid cancer, and management choices in terms of the dose of LT(4) that provides the optimum lowering of serum TSH without toxicity are difficult, particularly in the situation wherein, as was the case with one of our patients, there is cardiac disease. PMID- 21649471 TI - An attempt to induce "Graves' disease of the gonads" by immunizing mice with the luteinizing hormone receptor provides insight into breaking tolerance to self antigens. AB - BACKGROUND: Gonadotropin receptors, unlike the thyrotropin receptor (TSHR), are not cleaved into disulfide-linked A- and B-subunits, nor do they shed A-subunits. Heavily glycosylated TSHR A-subunits initiate or amplify responses leading to stimulating TSHR-autoantibodies and Graves' hyperthyroidism. METHODS: To investigate the possibility that mice immunized with luteinizing hormone receptor (LHR) would develop functional antibodies, we constructed adenoviruses expressing the rat-LH holoreceptor (LHR-Ad) and an LHR A-subunit equivalent (LHR-289-Ad). Female BALB/c mice were immunized with high doses (10(11) particles) of LHR-Ad, LHR-289-Ad, or control (Con)-Ad. Sera were tested using LHR-expressing eukaryotic cells for antibody binding by flow cytometry and for bioactivity by measuring cyclic adenosine monophosphate (cAMP) stimulation. RESULTS: Elevated serum binding to LHR cells in some LHR-Ad and LHR-289-Ad immunized mice was not specific for LHR-expressing cells. Moreover, sera lacked bioactivity, consistent with unchanged serum estradiol and ovary histology. The difference between rat and mouse LHR-ectodomains is relatively small (3% at the amino-acid level). In contrast, despite amino-acid identity, immunization of mice with adenovirus expressing membrane-bound mouse thyroid peroxidase (TPO), but not soluble mouse TPO ectodomain, elicited strong TPO-specific antibodies. CONCLUSIONS: Our investigations provide insight into antibody responses to self-antigens. First, antibodies are induced to large self-antigens like mouse-TPO when membrane bound. Second, lesser amino acid homology between the immunogen and mouse protein (91% vs. 97% for the human-TSHR and rat-LHR, respectively) favors antibody induction. Finally, from previous studies demonstrating the immunogenicity of the highly glycosylated human TSHR A-subunit versus our present data for the nonimmunogenic less glycosylated rat LHR, we suggest that the extent of glycosylation contributes to breaking self-tolerance. PMID- 21649472 TI - Prognostic impact of serum thyroglobulin doubling-time under thyrotropin suppression in patients with papillary thyroid carcinoma who underwent total thyroidectomy. AB - BACKGROUND: Detectable serum thyroglobulin (Tg) in patients with papillary thyroid carcinoma (PTC) after total thyroidectomy implies unsuccessful surgery, indicating a high risk of recurrence. Serum Tg kinetics in such patients have not been extensively studied. We studied serum Tg kinetics in patients with suppressed serum thyrotropin levels and undetectable anti-Tg antibody to minimize the effects of these factors on Tg values, and evaluated the relationship of prognosis to the serum Tg doubling-time. METHODS: Between January 1998 and December 2004, 1515 patients with PTC underwent total thyroidectomy in Kuma Hospital. After excluding patients with other thyroid cancers and those positive tests for anti-Tg antibody, there were 426 patients with 4 or more serum Tg measurements at a time that serum thyrotropin concentrations were <0.1 mIU/L. These patients were selected for the present retrospective study. Tg doubling time was computed using Tg values measured during routine follow-up. Patients were followed for a mean of 88.1 months and a median of 86.7 months. RESULTS: Of the 426 patients, 137 patients had 4 or more measurements that revealed detectable Tg in serum Tg. The Tg doubling-time (DT), calculated using all available data, varied widely, and were grouped into those that were <1 year (17 patients), those that were 1-3 years (21 patients), and those that were >= 3 years (30 patients), as well as those with a negative value due to decrease in serum Tg (69 patients). There were also 88 patients who had three or fewer serum Tg measurements that showed detectable Tg levels, as well as 201 patients in whom serum Tg measurements were below the lower limit of detection. In the group of patients with a Tg-DT of <1 year the cause specific survival at 10 years was 50%, and in the group with a Tg-DT of 1-3 years it was 95%. In all other groups it was 100%. Many classical prognostic factors (TNM stage, age, and gender) as well as the Tg-DT were significant indicators of survival by univariate analysis, but Tg DT remained the only independent predictor by multivariate analysis. Tg-DT was also the only independent predictor of distant metastases and loco-regional recurrence on multivariate analysis. Tg-DT calculated using only the first four data [Tg-DT (first four data)] was also the only independent predictor of survival, distant metastases, and loco-regional recurrence on multivariate analysis. CONCLUSIONS: Tg-DT (all data or first four data) is a very strong prognostic predictor superior to the classical prognostic factors in patients with PTC. PMID- 21649473 TI - Evaluation of a cryopreservation procedure to set up a new bone marrow transplant unit using lymphocyte proliferation test. AB - A bone marrow transplant (BMT) is one kind of standard treatment modality in advanced hemato-oncology. In order to set up a BMT unit, one of the important steps before starting a clinical program is to evaluate the cryopreservation procedure for stem cell storage. Twenty one bags of buffy coat were used to be the testing specimens. They were processed and frozen according to cryopreservation protocol and kept in liquid nitrogen for 2 weeks. The evaluation process was carried out with a lymphocyte proliferation test together with trypan blue staining. By measuring the optical density of each lymphocyte containing well after stimulation, the lymphocyte proliferation value (LPV) could be obtained. When comparing them before and after cryopreservation, the LPV was 2.064 +/- 0.379 (mean +/- SD) and 1.913 +/- 0.546, (p = 0.314), respectively. At 2 weeks after cryopreservation, comparing between the frozen group and the unfrozen control, the LPV was 1.913 +/- 0.546 and 0.486 +/- 0.453, (p < 0.05), respectively. The LPV showed clear efficacy of the procedure, especially for preserving the cellular proliferation function. Our model of the cryopreservation procedure evaluation at pre-clinical phase by use of a buffy coat and lymphocyte proliferation test seems feasible for newly-established small BMT units. With these results, clinical transplantations can be performed with more confidence. PMID- 21649474 TI - Global epidemics of childhood obesity is hitting a 'less industrialized' corner in Asia: a case study in Macao. AB - Childhood obesity prevalence amongst children is rising virtually in all countries with rapid acceleration in major cities in China. A cross-sectional study was conducted amongst 2,015 primary and secondary students in Macao to investigate the nutritional status and analyzed for the relationship of overweight and other cardio-metabolic risk factors. Subjects were randomly selected in proportion to the gender and age of the population. A total of 26.4% of boys and 13.9% of girls were overweight or obese with the highest prevalence around 40% among boys aged 9-12 and girls aged 10 and 11. Some 18.1% of boys and 20.4% of girls were found to have borderline LDL levels; a further 9.3% and 10.4% were found to have high-risk, respectively. For those students with overweight and obesity, a significant higher proportion of them had cardio-metabolic risk factors. Based on this evidence, there is a concern that obesity and its associated co-morbidity could reach epidemic proportions in the 'less industrialized' cities of China. PMID- 21649475 TI - Soman-induced alterations of protein kinase C isozymes expression in five discrete areas of the rat brain. AB - Soman is a highly neurotoxic chemical warfare agent and inhibits the neural enzyme, acetylcholinesterase (AChE). Protein kinase C (PKC) isozymes regulate a wide range of cellular functions to a variety of extracellular stimuli. However, their exact role in nerve-agent poisoning is not well understood. In the present study, we investigated the effect of soman (80 MUg/kg-1, administered subcutaneously) on two PKC isozymes' immunoreactivity levels and activities of PKC and AChE in different rat-brain areas. Results showed a significant induction in PKC betaII and zeta isoenzyme expression levels from 2.5 hours to 14 days post soman exposure periods in the hippocampus, cerebellum, thalamus and cerebral cortex. The striatum showed reduced expression levels of both the isozymes from 1 to 3 days after soman exposure. PKC activity was increased in the cerebrum and cerebellum up to 7 days post-soman exposure. The toxicity target enzyme, AChE activity remained inhibited in plasma and brain up to 3 days post exposure and thereafter recovered to control levels. The results suggest a possible role of PKC isozymes in nerve-agent-induced neurotoxicity. PMID- 21649476 TI - A comparison of the neuroprotective efficacy of individual oxime (HI-6) and combinations of oximes (HI-6+trimedoxime, HI-6+K203) in soman-poisoned rats. AB - The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 MUg/kg intramuscularly, i.m.; 80% of LD50 value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime. PMID- 21649477 TI - Genotoxic assessment and toxicity evaluation of peginesatide in CByB6F1 hybrid mice. AB - Peginesatide is a PEGylated, investigational, peptide-based erythropoiesis stimulating agent (ESA) that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. Clinical use of peginesatide is anticipated to result in chronic dosing in chronic kidney disease (CKD) patients, and the nonclinical data to support development should include an evaluation of carcinogenic potential evaluation. Peginesatide was not mutagenic or clastogenic in a standard genotoxicity battery of tests. Doses for a rasH2 transgenic mouse carcinogenicity assay were defined in a 28-day study in the wild-type littermates of the rasH2 transgenic mouse strain, using intravenous doses of 1-25 mg/kg on days 1 and 22. The findings were consistent with exaggerated pharmacology, including polycythemia, with associated increases in hemoglobin level and extramedullary hematopoiesis and bone marrow hypercellularity. PMID- 21649478 TI - Effects of dipotassium trioxohydroxytetrafluorotriborate (K2[BO3F4OH]) on genetic material and inhibition of cell division in human cell cultures. AB - We have examined antiproliferative, cytotoxic, and genotoxic potential of a halogenated boroxine dipotassium trioxohydroxytetrafluorotriborate (K2[B3O3F4OH]). The impact on cell growth was evaluated by alamarBlue assay in basal cell carcinoma culture. Cytostatic, cytotoxic, and genotoxic potential were evaluated in lymphocytes culture, applying cytokinesis-block micronucleus cytome assay and chromosome aberrations analysis. Tested concentrations (0.05, 0.1, 0.2, and 0.4 mg/mL) were correlated with inhibition of cell growth in basal cell carcinoma culture and with the lymphocytes proliferation. Clastogenic activity has been confirmed, without evidences of aneugenic activity, in human lymphocytes. PMID- 21649479 TI - Investigation of oxidative stress in blood, brain, kidney, and liver after oxime antidote HI-6 application in a mouse experimental model. AB - Oxime reactivator HI-6 (asoxime, in some sources) is a potent antidote suitable for treatment of intoxication by nerve agents. Despite the fact that HI-6 is considered for practical application in emergency situations, the impact of HI-6 on patients' bodies has not been established yet. The present experiment was carried out in order to estimate whether HI-6 would be able to trigger or protect from oxidative stress in a BALB/c mice model. HI-6 was applied in doses ranging from 0.2 to 20% of LD50. Ferric-reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and glutathione reductase (GR) were assayed in the blood, liver, kidney, and brain of treated animals. It was found that HI-6 does not increase GR or TBARS. On the contrary, TBARS levels in the brain and liver were found to be significantly decreased in HI-6-treated animals. Pertinent antioxidant properties of HI-6 were excluded by the FRAP method. Endogenous antioxidants were unchanged, with the exception of the kidney. Low-molecular-weight antioxidants assayed by the FRAP method were significantly decreased in kidneys of animals treated with HI-6. However, GSH partially recovered the loss of the other low-molecular-weight antioxidants and was significantly increased in the kidney of HI-6-exposed mice. HI-6 potential to produce nephropathy is hypothesized. The achieved conclusions were quite surprising and showed a complex impact of HI-6 on the body. PMID- 21649480 TI - Vernolide-A, a sesquiterpene lactone from Vernonia cinerea, induces apoptosis in B16F-10 melanoma cells by modulating p53 and caspase-3 gene expressions and regulating NF-kappaB-mediated bcl-2 activation. AB - In this study, we investigated the effect of vernolide-A on the induction of apoptosis as well as its regulatory effect on the activation of transcription factors in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentrations of vernolide-A showed the presence of apoptotic bodies and induced DNA fragmentation in a dose-dependent manner. Cell-cycle analysis and TUNEL assays also confirmed the observation. The proapoptotic genes, p53, Bax, caspase 9, and caspase-3, were upregulated in vernolide-A-treated cells, whereas the antiapoptotic gene, Bcl-2, was downregulated. vernolide-A treatment also showed a downregulation of cyclin D1 expression and upregulated p21 and p27 gene expression in B16F-10 melanoma cells. The study also reveals that vernolide-A treatment could alter the production and expression of proinflammatory cytokines and could inhibit the activation and nuclear translocation of p65, p50, and c-Rel subunits of nuclear factor-kappaB and other transcription factors, such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response element-binding protein in B16F-10 melanoma cells. These results suggest that vernolide-A induces apoptosis via activation of p53-induced, caspase-3-mediated proapoptotic signaling and suppression of NF-kappaB-induced, bcl-2-mediated survival signaling. PMID- 21649481 TI - Antitumor activity of novel pyrrolo[2,3-d]pyrimidin-4-ones. AB - Pyrrolo[2,3-d]pyrimidine is known to have a broad spectrum of biological activities, including antitumor activity. The cytotoxic properties of six novel pyrrolo[2,3-d]pyrimidin-4-ones in vitro were investigated on four different human cancer cell lines. Meanwhile, the role of apoptosis was explored. Malignant cells were cultured in RPMI medium and incubated with different concentrations. Cell viability was quantitated by MTT assay. Apoptotic cells were determined using DAPI (4'-6-diamidino-2-phenylindole) and propidium iodide staining of DNA fragmentation by flow cytometry (sub-G1 peak). We have identified new analogs as a novel class of antiproliferative agents by a cell-based screening method. All compounds inhibited the growth of malignant cells in a dose-dependent manner. The IC50 of compounds 4 and 5 as the two most potent analogs was determined as 122.4 and 106.7 MUM in HeLa cells, respectively. Compounds 4 and 5 induced a sub-G1 peak in the flow-cytometry histogram of treated cells, compared to control, indicating that apoptotic cell death is involved in compound 4- and 5-induced toxicity. In conclusion, compounds 4 and 5 exert cytotoxic effects in different cancer cell lines in which apoptosis plays an important role. Thus, compounds 4 and 5 could be considered as potential chemotherapeutic agents. PMID- 21649482 TI - Cytotoxicity and genotoxicity of titanium dioxide nanoparticles in UVA-irradiated normal peripheral blood lymphocytes. AB - The phototoxicity of ultraviolet A irradiation (UVA) can be enhanced by photosensitizing agents, such as titanium dioxide nanoparticles (100 nm in diameter, "normal-TiO2"). Nano-TiO2 treatment in the absence of UVA caused a slight decrease in cell viability, but in the presence of UVA, it caused a significant decrease in cell viability. In the presence of UVA, nano-TiO2 also significantly increased the percentage of the cell population in the sub-G1 phase, induced activation of the proapoptotic proteins, caspase-9, caspase-3, and poly(ADP)ribose polymerase, significantly increased the production of reactive oxygen species (ROS), and induced the loss of the mitochondrial membrane potential (MMP), suggesting that UVA and nano-TiO2 synergistically promoted apoptosis via a mitochondrial pathway. In the presence of UVA, but not in its absence, nano-TiO2 treatment also caused a significant increase in DNA damage. Normal-TiO2 used at the same concentrations did not cause DNA damage, induce ROS generation, trigger mitochondrial membrane depolarization, or increase apoptotic cell death, regardless of UVA exposure. Taken together, these results suggest that nano-TiO2 and UVA synergistically promote rapid ROS generation and MMP collapse, triggering apoptosis. Additionally, they show that small TiO2 particles are more phototoxic than larger ones. PMID- 21649483 TI - Genetic toxicology and preliminary in vivo studies of nitric oxide donor tocopherol analogs as potential new class of antiatherogenic agents. AB - Nitric oxide donor tocopherol analogs were found to be incorporated in low density lipoprotein to release nitric oxide into the hydrophobic core of the lipoprotein, thus inhibiting lipid oxidation processes associated with atheroma plaque formation. Previously, we studied their cytotoxicity against human and murine macrophages as first selection for in vivo studies. Herein, we examined both the in vitro mutagenic and DNA-damage effects of selected compounds to further evaluate drug potential. While the compounds of interest were nongenotoxics in both experimental tests (Ames and alkaline comet), one of the potential blood metabolites exhibited genotoxicity (alkaline comet test), and the furazan derivative was mutagenic (Ames test). Two selected (nitrooxy and furoxan) compounds were studied in long- and short-term in vivo treatment, and in these conditions, animal toxicity was not evidenced, suggesting the possibility of these compounds as potential antiatherogenic drugs. PMID- 21649484 TI - Methylphenidate lacks genotoxic effects in mouse peripheral blood erythrocytes. AB - Methylphenidate (MPH; Ritalin(r); Novartis Pharmaceuticals, Inc., Basel, Switzerland) has been prescribed to treat attention deficit/hyperactivity disorder (ADHD) since its approval by the U.S. Food and Drug Administration over 50 years ago. Due to concerns that MPH might induce cytogenetic alterations in children, treatment with this drug has been a controversial issue. In the present study, we assessed the frequency of micronucleated erythrocytes (MNEs), micronucleated polychromatic erythrocytes (MNPCEs), and polychromatic erythrocytes (PCEs) in peripheral blood samples from mice treated with three different doses of MPH (30, 60, or 125 mg/kg). We found no evidence of increased MNEs or MNPCEs, nor did PCEs decline. These results add to the accumulating evidence that MPH does not induce genotoxic or cytotoxic damage. PMID- 21649485 TI - Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies. AB - 9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD(r) rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day. PMID- 21649486 TI - Prenatal developmental toxicity study of ethyl tertiary-butyl ether in rabbits. AB - Ethyl tertiary-butyl ether (ETBE) is commonly used as an oxygenated gasoline additive. In this study, the prenatal developmental toxicity of ETBE was determined in rabbits. New Zealand white rabbits were given ETBE by gavage at 100, 300, or 1,000 mg/kg/day on gestational days (GDs) 6-27, and the pregnancy outcome was determined on GD 28. Neither death nor abortion occurred in the pregnant rabbits at any dose. Slightly and significantly suppressed maternal body weight gain and transiently decreased maternal food consumption were found at 1,000 mg/kg/day during the administration period. At this dose, no changes in clinical or macroscopic finding were noted in dams. No treatment-related changes were observed in any dam treated at 300 mg/kg/day or less. There was no significant effect of ETBE on the numbers of corpora lutea, implantations, live fetuses, resorptions and dead fetuses, incidences of pre- and postimplantation loss, viability of fetuses, fetal body weight, sex ratio of fetuses, or weights of gravid uteri. No significant difference was detected in the incidences of fetuses with malformations or variations between the ETBE-treated and control groups. Also, no adverse effects on the progress of ossification were noted in fetuses of dams given ETBE. Based on these findings, it is concluded that the no observed adverse effect levels of ETBE were 300 mg/kg/day for dams and 1,000 mg/kg/day for fetuses in rabbits. PMID- 21649487 TI - Effect of oral coadministration of artesunate with ferrous sulfate on rat liver mitochondrial membrane permeability transition. AB - The recent resurgence of interest in the study of mitochondria has been fuelled in large part by the recognition that genetic and/or metabolic alterations in this organelle are causative or contributing factors in a variety of human diseases including cancer. This study hypothesizes that co-administration of artesunate and ferrous sulfate could induce apoptosis which can be targeted on cancerous cells in such a manner, thus providing a novel, viable and perhaps inexpensive way of dealing with the cancer scourge. Artesunate and Ferrous sulfate were co-administered to rats at various doses for seven days. At the end of the treatment, the rats were fasted overnight and sacrificed by cervical dislocation. Low ionic strength mitochondria were isolated from hepatic cells of the rats and assayed for protein content; changes in the absorbance of the liver mitochondria; and mitochondrial swelling. Co-administration of artesunate and ferrous sulfate resulted in a significant increase (P<0.05) in pore opening. The difference in pore opening was found to be statistically significant (P<0.05) when the artesunate and ferrous iron-treated groups were compared with the artesunate only treated group. Results from this study show that co administration of artesunate and ferrous sulfate can cause an opening in the mitochondrial membrane transition pore. A combined dose of ferrous sulfate and artesunate may prove to be a more potent therapy for targeting cancerous cells. PMID- 21649489 TI - Induction of apoptosis by sulforaphane in highly metastatic B16F-10 melanoma cells. AB - Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables, such as broccoli, cabbage, cauliflower, etc. SFN has received a great deal of attention because of its ability to inhibit cell proliferation and induce apoptosis in several tumor cell lines. Previously, we have demonstrated that SFN inhibits the metastasis of B16F-10 melanoma cells in both in vivo and in vitro models. Melanomas are among the aggressive tumor types because of their notorious resistance to treatment and their high tendency to metastasize. In this study, we investigated the influence of SFN on the induction of apoptosis in B16F-10 melanoma cells, which was evidenced by morphological changes such as membrane blebbing, presence of apoptotic bodies, DNA condensation, and also by nuclear DNA fragmentation. SFN-induced apoptosis was associated with the activation of caspases 3 and 9, Bax, and p53 and the downregulation of Bcl-2, caspase-8, Bid, and NF-kB. Caspase-3 is a most likely candidate to mediate SFN-induced apoptosis. In addition to the caspase-dependent pathway, our results also showed the involvement of proinflammatory cytokines, namely tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-1beta, IL-6, IL-12p40, and granulocyte-macrophage colony stimulating factor (GM-CSF), and the nuclear translocation of factors kappa B (NF kappaB) p65, NF-kappaB p50, NF-kappaB c-Rel, c-FOS, ATF-2, and CREB-1 in SFN induced apoptosis. These results raise the possibility that SFN may be a promising candidate for molecular-targeting chemotherapy against melanoma. PMID- 21649488 TI - Antidermatophytic activity of pyrazolo[3,4-c]isothiazoles: a preliminary approach on 4-chlorophenyl derivative for evaluation of mutagenic and clastogenic effects on bacteria and human chromosomes in vitro. AB - The antifungal activity of eight pyrazolo[3,4-c]isothiazole derivatives was evaluated on five dermatophytes: three were of an anthropophilic species (i.e., Epidermophyton floccosum, Trichophyton rubrum, and Trichophyton tonsurans) and two were of a geophilic species (i.e., Microsporum gypseum and Nannizzia cajetani). The new compounds proved to be unlikely effective in inhibiting the growth of the different strains. In general, the fungi parasitic on man were more sensitive than the geophilic species. This fact can be positive for a possible practical-therapeutic utilization of this class of compounds. To verify their possible use against fungi of medical interest, the most interesting substance at low doses, 6-(4-chlorophenyl)-4-methyl-6H-pyrazolo[3,4-c]isothiazol-3-amine, was chosen to perform in vitro genotoxicity tests using the following: Salmonella/microsome test (SAL), sister chromatid excange test (SCE), cytokinesis blocked micronucleus test (CBMN), and its improvement (Ara-C/CBMN). The compound showed no mutagenic activity at low doses, whereas at the highest dose (100 ug/mL), it caused a generalized cytotoxic effect. The high growth inhibition exerted on fungi at the lowest dose and the concomitant lack of genotoxicity, at least until the dose of 50 ug/mL, might suggest the compound as a safe candidate as an antidermatophytic substance. PMID- 21649490 TI - Free versus total ligand-binding assays: points to consider in biotherapeutic drug development. PMID- 21649491 TI - High-resolution mass spectrometry will dramatically change our drug-discovery bioanalysis procedures. PMID- 21649492 TI - Genetic information from archived blood spots. PMID- 21649494 TI - Pittcon Conference and Expo 2011. PMID- 21649495 TI - Biospectroscopy at the Manchester Interdisciplinary Biocentre. PMID- 21649496 TI - Richard A Scheltema. PMID- 21649497 TI - Challenges of developing a bioanalytical method for a macrolide immunosuppressant compound by LC-MS/MS. AB - The quantification of tacrolimus in human whole blood was developed by LC-MS/MS for a range of 50.0 to 50,000.0 pg/ml. Different challenges were faced during method development due to ion-suppression, lack of sensitivity and low recovery. The optimization of the extraction procedure played a crucial role as tacrolimus had to be isolated from red blood cells, to which it is strongly bound. Another particular challenge arose from the freeze-thaw stability where the extracted samples from fresh blood always showed a lower recovery. Finally, matrix effect was observed in some matrices over time, which resulted in a failed long-term stability in whole blood. In order to resolve the matrix effect issue, the sample procedure had to be improved. The final assay showed good recovery, low matrix effect, linearity, blood stability and good precision and accuracy. PMID- 21649498 TI - Direct analysis in real time coupled with dried spot sampling for bioanalysis in a drug-discovery setting. AB - BACKGROUND: Conventional mouse or rat pharmacokinetic/toxicokinetic (PK/TK) studies frequently require sacrifice or use of multiple animals for a full time course in order to obtain adequate blood volume. Currently accepted LC-MS/MS analyses require tedious sample preparation and large blood volume, therefore, a bioanalytical method with a simpler blood-sampling procedure using fewer animals, lower sample volume and no additional sample preparation is desirable. RESULTS: We have developed a method that combines the direct analysis in real time (DART) open-air ambient ionization source and MS/MS to directly analyze dried blood spots (DBS) on glass from low volume whole blood samples without additional sample preparation or manipulation of the spots. Single mouse serial bleeding was performed for sample collection for DART-MS/MS and the results were comparable to the conventional terminal bleeding method for LC-MS/MS. CONCLUSION: The DART MS/MS method was applied to DBS sampling for PK/TK studies and also for in vitro screening of absorption, distribution, metabolism and excretion properties. The results from the DART-MS/MS approach correlated well with the LC-MS/MS analyses for comparison. PMID- 21649499 TI - Automated micropipette tip-based SPE in quantitative bioanalysis. AB - BACKGROUND: Automated methodologies using silica-based, monolithic, micropipette tip-based SPE have been developed for the analysis of small molecules in support of both preclinical and first-in-human development studies using LC-MS/MS. The use of micropipette tip-based SPE with the Tomtec Quadra 96((r)) and the evaluation of prototype micropipette tips for use with the Hamilton Microlab((r)) Star robot is outlined. RESULTS: Mixed-mode cation exchange and C18 SPE methods have been developed using human and rat plasma for the extraction of lipophilic and polar analytes. These methods are advantageous as they use low plasma sample, washing and elution volumes and result in a method extraction cycle time of approximately 6.2 min for 96 samples. CONCLUSION: This significantly reduced extraction time, compared with 96-well plate format SPE, indicates that the sample preparation stage is no longer the rate-limiting stage in performing a selective extraction procedure. Robust and sensitive methods have been developed that have proven to be more cost effective than traditional 96-well plate format SPE methods. PMID- 21649500 TI - Implementing DBS methodology for the determination of Compound A in monkey blood: GLP method validation and investigation of the impact of blood spreading on performance. AB - BACKGROUND: This article describes validation work for analysis of an Abbott investigational drug (Compound A) in monkey whole blood with dried blood spots (DBS). The impact of DBS spotting volume on analyte concentration was investigated. RESULTS: The quantitation range was between 30.5 and 10,200 ng/ml. Accuracy and precision of quality controls, linearity of calibration curves, matrix effect, selectivity, dilution, recovery and multiple stabilities were evaluated in the validation, and all demonstrated acceptable results. Incurred sample reanalysis was performed with 57 out of 58 samples having a percentage difference (versus the mean value) less than 20%. A linear relationship between the spotting volume and the spot area was drawn. The influence of spotting volume on concentration was discussed. CONCLUSION: All validation results met good laboratory practice acceptance requirements. Radial spreading of blood on DBS cards can be a factor in DBS concentrations at smaller spotting volumes. PMID- 21649501 TI - Utilization of DBS within drug discovery: a simple 2D-LC-MS/MS system to minimize blood- and paper-based matrix effects from FTA eluteTM DBS. AB - BACKGROUND: Dried blood spot-based bioanalysis potentially introduces novel matrix effects that need to be eliminated or controlled. Within nonregulatory drug discovery these can be defined as <=20% and <=30% for nominal peak area, respectively. RESULTS: Controlling matrix effects for a panel of compounds by simple 1D-HPLC-MS/MS was not achievable and the optimization of 2D-HPLC-MS/MS is reported here. Simple inclusion of a 'trapping' stage was not sufficient to improve matrix effects and optimization of the reconstitution solvent, reconstitution volume and injection volume was required for a generic system to be developed. CONCLUSION: A generic 2D-LC-MS/MS system has been developed that eliminates paper-based matrix effects and eliminates or controls dried blood spot matrix effects for a panel of compounds extracted from FTA EluteTM with methanol. PMID- 21649502 TI - The absolute quantification of endogenous levels of brain neuropeptides in vivo using LC-MS/MS. AB - Neuropeptides seem to play an important role when the CNS is challenged. In order to obtain better insights into the central peptidergic effects, it is essential to monitor their concentration in the brain. Quantification of neuropeptides in dialysates is challenging due to their low extracellular concentrations (low pM range), their low microdialysis efficiencies, the need for acceptable temporal resolution, the small sample volumes, the complexity of the matrix and the tendency of peptides to stick to glass and polymeric materials. The quantification of neuropeptides in dialysates therefore necessitates the use of very sensitive nano-LC-MS/MS methods. A number of LC-MS/MS and microdialysis parameters need to be optimized to achieve maximal sensitivity. The optimized and validated methods can be used to investigate the in vivo neuropeptide release during pathological conditions, in this way initiating new and immense challenges for the development of new drugs. PMID- 21649503 TI - Application and interpretation of free and total drug measurements in the development of biologics. AB - Ligand-binding assays are used to determine concentration levels of biopharmaceuticals in biological matrices. The whole molecule does not serve as a basis for quantification, but subregions are captured and detected by specific binding critical reagents that have been produced for the sole purpose of bioanalysis. An assay can be designed to measure the free or the total analyte. Depending on the format of the assay, different observations and interpretations could be deemed. In the case studies presented in this article, the same serum samples were subjected to analysis in parallel by two different assay formats. In three out of the four cases presented, the results and the data interpretation were remarkably different. Therefore, it is essential for the bioanalyst to communicate to other stake-holders, such as toxicologists and pharmacokineticists, what the assay detects and measures for plausible data interpretation and implication. PMID- 21649505 TI - DNA interaction studies of ethylenediaminetetraaceticacid food additive and selenium effect in DNA cleavage-inhibition. AB - The interaction of native calf thymus DNA with ethylenediaminetetraaceticacid (EDTA) in Tris-HCl buffer at pH = 7.8 (at this pH EDTA forms a disodium salt) was investigated. EDTA is widely used in medicine, food technology, and the chemical industry. The DNA binding mode of EDTA was monitored by absorption spectrophotometry, circular dichrosim, viscometry, and gel electrophoresis. Ultraviolet spectra of DNA showed small hyperchromicity with increase in EDTA concentration. The circular dichrosim signals at 245 and 280 nm indicated structural changes in DNA structure, and no significant effect on DNA viscosity was observed in the presence of increasing amounts of EDTA. Results are indicative of an outside, nonintercalative binding mode of EDTA to DNA. Moreover, gel electrophoresis studies showed considerable oxidative cleavage of plasmid DNA by EDTA. Mechanistic aspects of the chemical nuclease reactions were investigated using the OH radical quencher dimethylsulfoxide. In the presence of selenium, DNA cleavage by EDTA was inhibited. PMID- 21649506 TI - Antitumor therapeutic and antimetastatic activity of electroporation-delivered human papillomavirus 16 E7 DNA vaccines: a possible mechanism for enhanced tumor control. AB - DNA vaccines are known to be lacking in immunogenicity in humans. Presently, electroporation (EP) is thought to overcome this limitation. Here, we investigate whether human papillomavirus 16 E7 DNA vaccines delivered by EP might elicit potent antitumor activity in animal cervical cancer models, with a focus on the underlying mechanism(s). Intramuscular (IM)-EP delivery of E7 DNA vaccines induced more potent antitumor therapeutic and antimetastatic activity compared with IM delivery. Moreover, the tumor-controlled animals by IM-EP possessed long term memory responses to parental tumor cells. This improved antitumor effect was concomitant with augmented Ag-specific CTL activities. IM-EP also induced IgG and Th-cell responses higher than IM delivery. Finally, IM-EP resulted in more antigen production in and more attraction of immune cells into the site of DNA injection, suggesting that these biological and immunological changes made by IM EP might be responsible for enhanced CTL activities and antitumor resistance. Thus, this study shows that IM-EP can induce more potent antitumor activity by augmenting CTL responses possibly through more antigen production in and more attraction of immune cells into the muscle sites. This study also suggests that IM-EP of E7 DNA vaccines might be a potential approach toward treating patients with cervical cancer. PMID- 21649507 TI - Does use of an intrauterine catheter during labor increase risk of infection? AB - OBJECTIVE: To determine whether the use of an intrauterine catheter during labor is related to the occurrence of infection in mother or newborn during labor and up to 3 weeks postpartum. METHODS: We performed a follow-up study of 1435 women who participated in a previously published multicentre randomized controlled trial in the Netherlands that assigned women in whom labor was induced or augmented with intravenous oxytocin to internal or external tocodynamometry. In the present post hoc analysis, we assessed the risk for infection, defined as a composite measure of any clinical sign of infection, treatment with antibiotics or sepsis during labor or in the postpartum period up to 3 weeks in mother or newborn. RESULTS: There were 64 cases with indication of infection in the intrauterine catheter group (8.8%) versus 74 cases in the external monitoring group (10.4%). Relative risk: 0.91, 95% confidence interval: 0.77-1.1, and p: 0.33. CONCLUSION: Use of an intrauterine catheter during labor does not increase the risk of infection. PMID- 21649508 TI - Maxillofacial characteristics affecting chin deviation between mandibular retrusion and prognathism patients. AB - OBJECTIVE: To examine and compare the maxillofacial characteristics affecting chin deviation three-dimensionally in facial asymmetry patients with mandibular retrusion and mandibular prognathism. MATERIALS AND METHODS: Maxillofacial computed tomography (CT) scan data were obtained from 48 orthognathic surgery patients (24 cases of mandibular retrusion and 24 cases of mandibular prognathism) with facial asymmetry. Although chin deviation was assessed on the basis of the ANS-to-menton line on frontal cephalograms, its contributing factors were evaluated on three-dimensional CT images. Maxillary height, ramus length, frontal ramal inclination, lateral ramal inclination, mandibular body length, and body height were defined on each side, and right-left differences were calculated and analyzed. RESULTS: In an assessment of chin deviation, subjects in this study showed predominantly left side deviation regardless of the group, and the degree of menton deviation did not reveal significant differences between groups. In a comparison of right-left differences in contributing factors, all values were noted to be greater in the retrusion group, except for body height, which showed no difference between chin-deviated and contralateral sides. In particular, ramus length presented a statistically significant difference between the two groups. CONCLUSION: Based on the same degree of chin deviation in mandibular prognathism and retrusion in this study, results of right-left differences in contributing factors indicate that chin deviations are expressed easily in mandibular prognathism, whereas they occur only with significant right-left differences in relevant maxillofacial structures in individuals with mandibular retrusion. PMID- 21649509 TI - Microbial volatile-induced accumulation of exceptionally high levels of starch in Arabidopsis leaves is a process involving NTRC and starch synthase classes III and IV. AB - Microbial volatiles promote the accumulation of exceptionally high levels of starch in leaves. Time-course analyses of starch accumulation in Arabidopsis leaves exposed to fungal volatiles (FV) emitted by Alternaria alternata revealed that a microbial volatile-induced starch accumulation process (MIVOISAP) is due to stimulation of starch biosynthesis during illumination. The increase of starch content in illuminated leaves of FV-treated hy1/cry1, hy1/cry2, and hy1/cry1/cry2 Arabidopsis mutants was many-fold lower than that of wild-type (WT) leaves, indicating that MIVOISAP is subjected to photoreceptor-mediated control. This phenomenon was inhibited by cordycepin and accompanied by drastic changes in the Arabidopsis transcriptome. MIVOISAP was also accompanied by enhancement of the total 3-phosphoglycerate/Pi ratio, and a two- to threefold increase of the levels of the reduced form of ADP-glucose pyrophosphorylase. Using different Arabidopsis knockout mutants, we investigated the impact in MIVOISAP of downregulation of genes directly or indirectly related to starch metabolism. These analyses revealed that the magnitude of the FV-induced starch accumulation was low in mutants impaired in starch synthase (SS) classes III and IV and plastidial NADP thioredoxin reductase C (NTRC). Thus, the overall data showed that Arabidopsis MIVOISAP involves a photocontrolled, transcriptionally and post-translationally regulated network wherein photoreceptor-, SSIII-, SSIV-, and NTRC-mediated changes in redox status of plastidial enzymes play important roles. PMID- 21649510 TI - Changes in carbohydrate metabolism in Plasmopara viticola-infected grapevine leaves. AB - The oomycete Plasmopara viticola is responsible for downy mildew, a severe grapevine disease. In infected grapevine leaves, we have observed an abnormal starch accumulation at the end of the dark period, suggesting modifications in starch metabolism. Therefore, several complementary approaches, including transcriptomic analyses, measurements of enzyme activities, and sugar quantification, were performed in order to investigate and to understand the effects of P. viticola infection on leaf starch and-to a larger extent carbohydrate metabolism. Our results indicate that starch accumulation is associated with an increase in ADP-glucose pyrophosphorylase (AGPase) activity and modifications in the starch degradation pathway, especially an increased alpha-amylase activity. Together with these alterations in starch metabolism, we have observed an accumulation of hexoses, an increase in invertase activity, and a reduction of photosynthesis, indicating a source-to-sink transition in infected leaf tissue. Additionally, we have measured an accumulation of the disaccharide trehalose correlated to an increased trehalase gene expression and enzyme activity. Altogether, these results highlight a dramatic alteration of carbohydrate metabolism correlated with later stages of P. viticola development in leaves. PMID- 21649511 TI - Induction of Pseudomonas syringae pv. tomato DC3000 MexAB-OprM multidrug efflux pump by flavonoids is mediated by the repressor PmeR. AB - In this study, we have analyzed the expression of the Pseudomonas syringae pv. tomato DC3000 mexAB-oprM efflux pump operon and of the regulatory gene pmeR, and we have investigated the role of the PmeR protein on transcription from both promoters. We demonstrate that mexAB-oprM and pmeR are expressed in vivo at a relatively high and moderate basal level, respectively, which, in both cases, increases in the presence of different flavonoids and other compounds, such as butyl and methylparaben. We show that PmeR is the local repressor of the mexAB oprM promoter and is able to regulate its own expression. The mechanism for this regulation includes binding to a pseudopalindromic operator site which overlaps both mexAB-oprM and pmeR promoters. We have also proven that flavonoids are able to interact with PmeR and induce a conformational change that interferes with the DNA binding ability of PmeR, thereby modulating mexAB-oprM and pmeR expression. Finally, we demonstrate by in vivo experiments that the PmeR/MexAB-OprM system contributes to the colonization of tomato plants. These results provide new insight into a transcriptional regulator and a transport system that play essential roles in the ability of P. syringae pv. tomato DC3000 to resist the action of flavonoids produced by the host. PMID- 21649512 TI - Cloning and characterization of r3b; members of the r3 superfamily of late blight resistance genes show sequence and functional divergence. AB - Massive resistance (R) gene stacking is considered to be one of the most promising approaches to provide durable resistance to potato late blight for both conventional and genetically modified breeding strategies. The R3 complex locus on chromosome XI in potato is an example of natural R gene stacking, because it contains two closely linked R genes (R3a and R3b) with distinct resistance specificities to Phytophthora infestans. Here, we report about the positional cloning of R3b. Both transient and stable transformations of susceptible tobacco and potato plants showed that R3b conferred full resistance to incompatible P. infestans isolates. R3b encodes a coiled-coil nucleotide-binding site leucine rich repeat protein and exhibits 82% nucleotide identity with R3a located in the same R3 cluster. The R3b gene specifically recognizes Avr3b, a newly identified avirulence factor from P. infestans. R3b does not recognize Avr3a, the corresponding avirulence gene for R3a, showing that, despite their high sequence similarity, R3b and R3a have clearly distinct recognition specificities. In addition to the Rpi-mcd1/Rpi-blb3 locus on chromosome IV, the R3 locus on chromosome XI is the second example of an R-gene cluster with multiple genes recognizing different races of P. infestans. PMID- 21649514 TI - Distinguishing between complementary and alternative medicine and integrative medicine delivery: the United Kingdom joins world leaders in professional integrative medicine education. PMID- 21649515 TI - Prameha in Ayurveda: correlation with obesity, metabolic syndrome, and diabetes mellitus. Part 1-etiology, classification, and pathogenesis. AB - BACKGROUND: Obesity, metabolic syndrome, and diabetes mellitus are increasing in epidemic proportions globally. Prameha is a syndrome described in the ancient Ayurvedic texts that includes clinical conditions involved in obesity, prediabetes, diabetes mellitus, and metabolic syndrome. MATERIALS AND METHODS: Integrating the theory and modalities of Ayurveda in the management of these disorders may prove to be beneficial. Even though Prameha is a Tridoshaja Vyadhi (a disease involving all three of the psychophysiologic principles known as Doshas [i.e., Vata, Pitta, and Kapha]), it is basically a disease with Kapha predominance. RESULTS: There are 20 subtypes of Prameha due to the interaction of the three Doshas and 10 Dushyas (disturbed functioning of the principles that support the various bodily tissues); several of these subtypes have sweet urine, whereas some of them have different coloration of the urine, highlighting the inflammatory conditions involved in the metabolic syndrome. This disease has close ties to Sthaulya (i.e., obesity). With regard to diabetes mellitus, Sahaja Prameha and Jatah Pramehi correlate with type 1 diabetes; Apathyanimittaja Prameha correlates with type 2 diabetes. Madhumeha is a subtype of Vataja Prameha (Prameha with Vata predominance) that can occur as the terminal stage of type 2 diabetes (in which insulin is required), or as type 1 diabetes beginning in early childhood. The latter is defined as Jatah Pramehi Madhumehino in Charaka Samhita, one of the classical Ayurvedic texts. CONCLUSIONS: Various dietary, lifestyle, and psychologic factors are involved in the etiology of Prameha, particularly in relation to disturbances in fat and carbohydrate metabolism. The ancient Ayurvedic knowledge regarding Prameha can be utilized to expand the current understanding of obesity, metabolic syndrome, and diabetes. PMID- 21649516 TI - Heat stimulation on the skin for medical treatment: can it be controlled? AB - OBJECTIVES: It has become increasingly important for evidence-based medicine to have a proper control for randomized-controlled trials. However, appropriately controlling manual therapies such as moxibustion has proved challenging. Our team designed a novel device based on sensory illusion, and tested its feasibility. DESIGN AND RESULTS: A sham moxibustion device was constructed to allow participants to feel moxibustion treatment without actually stimulating the corresponding acupoint. The device consisted of two pieces of aluminum, each shaped like a horseshoe, so that the center of the device would not touch the skin. Participants perceived two heat stimuli as one when the distances of two heat sources were within 15 mm on the forearm. The thermal stimulation of the sham device was adjusted to the lowest possible temperature, but enough to elicit a heat sensation (39 degrees C), while that of verum was set at around 44 degrees C. The subject blinding, tested in 30 healthy volunteers, was successful. With the exception of 1 subject, subjects in the sham group described the sensation as a warm solid circle, unable to differentiate between two-pieced sham moxibustion and verum moxibustion. CONCLUSIONS: This preliminary study indicates that this device may serve as an appropriate control for clinical studies of moxibustion, but more research is clearly needed. A validated sham moxibustion device based on sensory illusion may contribute in expanding knowledge of somatosensory studies. PMID- 21649517 TI - Risk of hemorrhage associated with co-prescriptions for Ginkgo biloba and antiplatelet or anticoagulant drugs. AB - OBJECTIVES: The aim of this study was to explore the risk of hemorrhage associated with co-prescriptions for Ginkgo biloba extract (GBE) and antiplatelet or anticoagulant agents, and evaluate the trends of co-prescriptions. METHODS: A retrospective population based study was performed by using claim data of the Taiwan National Health Insurance Research Database from 2000 to 2008. Prescriptions for GBE alone and in combination with antiplatelet/anticoagulant drugs were retrieved and the odds ratio for co-prescriptions after the first prescription of GBE was explored. RESULTS: The total number of prescriptions for GBE alone or in combination with antiplatelet or anticoagulant agents increased gradually from 1547 (0.08%) and 3575 (0.19%) in 2000 to 4676 (0.23%) and 15,297 (0.79%) in 2008, respectively. GBE was mostly prescribed to patients aged 60 years or older. The adjusted odds ratio for co-prescriptions associated with the risk of hemorrhage is 1.5 (95% confidence interval, 0.5-5.0). The risk of hemorrhage was associated with patients aged >=65 and male patients, who were prescribed GBE alone (adjusted odds ratio: 3.8 and 1.4; 95% confidence interval, 2.8-5.2 and 1.1-1.9). CONCLUSIONS: Although the combination of G. biloba extract with antiplatelet or anticoagulants showed insignificant correlation to the risk of hemorrhage, patients using ginkgo, particularly those with known bleeding risks and elderly, should take a particular attention to the possibility of increasing risk of bleeding. PMID- 21649518 TI - Lifestyle and self-care advice within traditional acupuncture consultations: a qualitative observational study nested in a co-operative inquiry. AB - OBJECTIVES: The study objective was to develop methodology for observational research within traditional acupuncture consultations in community-based practice, and to explore how traditional acupuncturists communicate with patients about lifestyle and self-care. DESIGN: This was a mixed-method qualitative study, using audio-recording of consultations followed by telephone interviews of patients. The study was nested within a cooperative inquiry. As co-researchers, group members participated in framing the research questions, deciding methods to be used, and discussing the emergent findings. SETTINGS: Four (4) experienced traditional acupuncture practitioners, registered with the British Acupuncture Council, contributed to the co-operative enquiry and recorded consultations in three clinics in Somerset. SUBJECTS: Subjects comprised a convenience sample of patients attending 21 consultations. A purposive subsample of patients was selected for interview. RESULTS: Audio-recording was challenging to some practitioners who felt that it might result in infrequent, but nevertheless worrying, withholding of personal information by patients. Patients, however, reported that they were generally positive about the audio-recording. Each consultation was analyzed as a trajectory in which eight categories of talk interwove with each other and with periods of physical examination, needling, and silence. Trajectories showed where talk about self-care ("self-care talk") appeared in the consultations, the content of such talk, and who initiated it. The data confirmed that self-care advice arises from, and is explained in terms of, each person's individual Chinese Medicine diagnosis. The identification of different types of talk and the way that "self-care talk" is interwoven throughout the consultation emphasized the integral nature of self-care support and advice in the practice of traditional acupuncture. Some patients had difficulty putting self-care advice into practice, even when they were intellectually committed to it, suggesting that practitioners may need to follow up more carefully on the advice they have given. CONCLUSIONS: Self-care in traditional acupuncture consultations is integral, interactive, and individualized. This study has mapped out a potential agenda for research into self-care in traditional acupuncture consultations and illustrates the exciting opportunities that open up when observational and interview data are combined. PMID- 21649519 TI - Complementary and alternative medicine used by children in military pediatric clinics. AB - OBJECTIVES: The objective of this study was to evaluate the prevalence, types, perceived effects, and factors that influence the use of complementary and alternative medicine (CAM) by military children. DESIGN: A parent survey was administered in two military general pediatric clinics from June to September 2009. Parents completed surveys about their children including the following items: demographic information, a list of specific CAM therapies, family CAM use, and child health status. RESULTS: Caregivers completed 278 surveys. The overall use of CAM was 23%. The most common type of CAM used was herbal therapy (34%). The CAM therapies most commonly reported to be very helpful were special diets (67%), melatonin (57%), vitamins and minerals used at doses higher than the recommended daily allowance (50%), and massage therapy (50%). The majority of users reported no side-effects (96%). Among CAM users, 53% had discussed their CAM use with a physician and 47% had seen a CAM practitioner. Factors associated with CAM use in multiple regression analysis included chronic conditions (p = 0.001), parent/sibling use of CAM (p < 0.001), and parent age over 30 years (p = 0.02). Primary sources of CAM information were friends and family (68%) and doctors (44%). Common reasons for using CAM were to promote general health (70%), to relieve symptoms (56%), and to improve quality of life (48%). Eighty percent (80%) of all respondents indicated they would use CAM if recommended by a physician. CONCLUSIONS: In this military population with access to universal health care, CAM use is higher than the U.S. national average and nearly double that of the 2007 National Health Interview Survey study. Patients with chronic conditions, family members using CAM, and parental age over 30 years are more likely to use CAM. CAM is perceived as helpful with minimal to no side-effects. Pediatricians should inquire about CAM use and be prepared to provide guidance on this topic. PMID- 21649521 TI - Ayurvedic concept of obesity, metabolic syndrome, and diabetes mellitus. AB - Obesity, metabolic syndrome, and diabetes mellitus are increasing to epidemic proportions globally. There are 400 million clinically obese adults worldwide and there are more than 220 million people who have diabetes. The global impact of these disorders is immense in terms of human suffering and economic burden. There is an urgent need for a more effective understanding of these disease processes and their management, including the use of natural strategies that are affordable and efficacious. The health care system known as Ayurveda has much to offer in this regard. Ayurveda describes a set of complex clinical disorders, collectively called Prameha, that are characterized by frequent abnormal micturition. The clinical conditions associated with Prameha correlate in many ways with obesity, metabolic syndrome, and diabetes mellitus. The etiology, classification, pathogenesis, and management of Prameha are discussed at length and in detail in the Ayurvedic texts. The theoretical background and comprehensive set of strategies Ayurveda utilizes to treat Prameha may be valuable in managing obesity, metabolic syndrome, and diabetes mellitus in an efficacious and cost effective manner. PMID- 21649520 TI - Efficacy of individualized Chinese herbal medication in osteoarthrosis of hip and knee: a double-blind, randomized-controlled clinical study. AB - OBJECTIVES: The objective of this study was to determine the efficacy of individually designed herbal formulas according to the rules of Traditional Chinese Medicine (TCM) in patients with osteoarthritis of the hip and knee. DESIGN: This was a randomized, controlled, double-blind study with two parallel groups. SETTINGS/LOCATION: This study was conducted at the University-centre in Gars am Kamp/Austria and was organized by the Institute of TCM and Complementary Medicine of the Danube University Krems /Austria. SUBJECTS: The study comprised female and male patients with osteoarthritis of hip or knee aged between 45 and 75 years. INTERVENTIONS: Patients were randomized into a treatment with individualized, water-based herbal decoctions prepared in a standardized cooking process (Verum group) or to a treatment with nonspecific presumably ineffective, water-based herbal decoctions (Control group). OUTCOME MEASURES: The primary outcome was the comparison of change between the intervention groups in the Western Ontario and McMaster Universities lower limb global index questionnaire (WOMAC global index) between baseline and week 20. Secondary outcomes included subscales of WOMAC for pain (A), stiffness (B), and functional impairment (C) and general quality of life in the form of the SF-36 questionnaire. RESULTS: Altogether, 102 patients were randomized in this trial. The demographic and medical baseline characteristics were comparable in the 2 groups. The change of the WOMAC global index and all three subscales was significant in both groups between week 20 and baseline (verum group, global WOMAC: at baseline 47 [SD +/- 11.8] and at week 20: 24 (SD +/- 18.3); change of mean 23; p > 0.001; control group; global WOMAC: at baseline: 48 (SD +/- 14.7) and at week 20: 25 (SD +/- 18.3); change of mean 23; p > 0.001). However, there was no significant difference (p = 0.783) between the treatment groups. There were significant changes in the subscales "physical functioning," "bodily pain," "vitality," "social-functioning," and "role-physical" of the SF-36 in both study groups between 20 weeks and baseline, but again no significant difference between the groups. There were no drug-related serious adverse events. CONCLUSIONS: While the individual prescription consisting of medicinal herbs according to TCM diagnosis investigated in this trial tend to improve the osteoarthritis, the same effect was also achieved with the nonspecific prescription. PMID- 21649522 TI - Prolonged effectiveness of bepotastine besilate ophthalmic solution for the treatment of ocular symptoms of allergic conjunctivitis. AB - PURPOSE: This clinical trial evaluated the safety and effectiveness of bepotastine besilate ophthalmic solutions 1.0% and 1.5% compared with placebo for the treatment of ocular itching and conjunctival hyperemia (redness) using the conjunctival allergen challenge (CAC) model of allergic conjunctivitis when dosed 16 h before a CAC test. METHODS: Subjects with a history of allergic conjunctivitis were assigned to receive placebo or bepotastine besilate ophthalmic solution 1.0% or 1.5% in a single-center, randomized, placebo controlled clinical trial. Eligible subjects (n=107) aged 10 years and older with a history of allergic conjunctivitis who had a reproducible positive reaction to a CAC were enrolled and dosed with test agent. The primary trial objectives included assessment of ocular itching and conjunctival redness at 16 h after instillation of test agent. Reductions in several CAC-induced secondary symptoms and signs of allergic conjunctivitis were also evaluated for tearing, ciliary and episcleral redness, eyelid swelling, chemosis, and mucous discharge. RESULTS: Bepotastine besilate ophthalmic solution 1.5% demonstrated clinical effectiveness and statistical significance in comparison to placebo for the reduction in CAC induced ocular itching 16 h after drug administration. Bepotastine besilate ophthalmic solution 1.0% also achieved statistical significance in comparison to placebo for reducing ocular itching at all time points 16 h after dosing. Statistically significant reduction (P<=0.05) was additionally seen in this CAC test for the secondary ocular efficacy variable of allergen-induced tearing for bepotastine besilate ophthalmic solution 1.5%. No clinical benefit was seen for reducing the coprimary efficacy variable of conjunctival redness with the CAC model of allergic conjunctivitis. CONCLUSIONS: Bepotastine besilate ophthalmic solution 1.5% produced predefined clinically meaningful reduction in CAC-induced ocular itching and tearing in a single-site trial and was more effective than bepotastine besilate ophthalmic solution 1.0% and placebo for reducing ocular itching in a CAC test 16 h after dosing. PMID- 21649523 TI - Atropine in ameliorating the progression of myopia in children with mild to moderate myopia: a meta-analysis of controlled clinical trials. AB - OBJECTIVES: Myopia is the most common ocular disorder associated with increasing risk for chorioretinal degeneration, retinal detachment, and other vision threatening abnormalities worldwide. Recently, atropine has been becoming a focus of attention due to its role in ameliorating the myopia progression in children. This meta-analysis was conducted to address the efficacy and safety of atropine on myopia in children and the dose-response relationship between atropine and annual rate of myopia progression. METHODS: Controlled clinical trials were retrospectively analyzed to compare atropine and placebo for the treatment of myopia. The primary outcome measure was annual rate of myopia progression after daily atropine application over 1 year. Data were extracted from 6 randomized clinical trials and analyzed using standard meta-analysis and meta-regression methods. RESULTS: Comparing with placebo, the effect size of atropine for retarding myopia progression was 0.773 diopters (D)/year [95% confidence interval (CI): 0.699-0.848]. Regression model, -0.728+1.281log (dose+1), revealed the dose response relationship between atropine and myopia progression. The estimate of effect for 0.05%, 0.1%, and 0.25% atropine was -0.665 (95% CI: -1.070 to -0.260), -0.606 (95% CI: -0.967 to -0.245), and -0.442 (95% CI: -0.701 to -0.183) D/year respectively, whereas that for 0.5% and 1% was -0.208 (95% CI: -0.435-0.018) and 0.160 (95% CI: -0.293-0.613), respectively, suggesting that myopia might deteriorate at low dose of atropine but not at 0.5% atropine and 1% atropine within the duration of 6-24 months. No serious adverse event was reported during the period of treatment. The major adverse reactions associated with 0.5% and 1% atropine were photophobia, glare, and recurrent allergic blepharitis. Photochromatic lenses or sunglasses with ultraviolet protection could be used to minimize the glare and photophobia. CONCLUSION: In summary, 0.5% and 1% atropine was demonstrated to be effective and safe to ameliorate myopia progression in childhood with low-to-moderate myopia. PMID- 21649525 TI - Reduced surface toll-like receptor-4 expression and absent interferon-gamma inducible protein-10 induction in cystic fibrosis airway cells. AB - ABSTRACT As part of the innate and adaptive immune system, airway epithelial cells secrete proinflammatory cytokines after activation of Toll-like receptors (TLRs) by pathogens. Nevertheless, cystic fibrosis (CF) airways are chronically infected with Pseudomonas aeruginosa, suggesting a modified immune response in CF. The authors have shown that in CF bronchial epithelial cells, a reduced surface expression of TLR-4 causes a diminished interleukin (IL)-8 and IL-6 response upon lipopolysaccharide (LPS) stimulation. However, there is no information regarding activation of the MyD88 (myeloid differentiation primary response gene 88)-independent TLR-4 signaling pathway by LPS, which results in the activation of adaptive immune responses by secretion of the T cell-recruiting chemokine interferon-gamma-inducible protein (IP)-10. Therefore, the authors investigated the induction of IP-10 in CF bronchial epithelial cell line CFBE41o- and its CFTR-corrected isotype under well-differentiating conditions. TLR-4 surface expression was significantly reduced in CFBE41o- by a factor of 2, compared to the CFTR-corrected cells. In CFTR-corrected cells, stimulation with LPS increased IP-10 secretion. Incubating cells with siRNA directed against TLR-4 inhibited the LPS stimulated increase of IP-10 in CFTR-corrected cells. The reduced TLR-4 surface expression in CF cells causes the loss of induction of IP 10 by LPS. This could compromise adaptive immune responses in CF due to a reduced T-cell recruitment. PMID- 21649526 TI - Comparison of genetic and epigenetic alterations at 11 tumor suppressor loci in pulmonary sclerosing hemangioma and adenocarcinoma. AB - Pulmonary sclerosing hemangioma (SH) is an unusual tumor of pneumocytic origin. Morphologically, SH can mimic pulmonary adenocarcinomas. Here, the authors compared genetic and epigenetic aberrations in SH with those in pulmonary adenocarcinoma. Clinicopathologic characteristics, microsatellite alterations, and CpG island methylation were analyzed in pulmonary SHs (n = 24) and adenocarcinomas (n = 34) to compare their patterns of molecular abnormalities. SHs were also analyzed immunohistochemically to characterize the expression status of proteins involved in basic biologic processes. The clinical presentation of SH cases was generally benign. Both cell types of SH stained positive for thyroid transcription factor 1 (TTF-1), epithelial membrane antigen (EMA), beta-catenin, E-cadherin, and vascular endothelial growth factor (VEGF). Allelic imbalances in D3S1283, D3S1234, D3S1300, D3S1285, TP53, D17S938, and D9S179 were less frequent in SH than in adenocarcinoma; rates of allelic imbalances in D20S170 and D21S1446 were not significantly different. In SH, CpG island methylation frequencies of p16(INK4a) (0.0%) and RASSF1A (12.5%) were significantly lower than those in adenocarcinoma (29.4% and 38.2%, respectively); the frequencies of HOX D9, D11, and D13 gene methylation in SH were 37.5%, 33.3%, and 33.3%, respectively. The results show that pulmonary SH and adenocarcinoma share similar genetic and epigenetic aberrations, but also exhibit significant differences, especially in tumor suppressor genes. PMID- 21649524 TI - Diverse injurious stimuli reduce protein tyrosine phosphatase-MU expression and enhance epidermal growth factor receptor signaling in human airway epithelia. AB - In response to injury, airway epithelia utilize an epidermal growth factor (EGF) receptor (EGFR) signaling program to institute repair and restitution. Protein tyrosine phosphatases (PTPs) counterregulate EGFR autophosphorylation and downstream signaling. PTPMU is highly expressed in lung epithelia and can be localized to intercellular junctions where its ectodomain homophilically interacts with PTPMU ectodomain expressed on neighboring cells. We asked whether PTPMU expression might be altered in response to epithelial injury and whether altered PTPMU expression might influence EGFR signaling. In A549 cells, diverse injurious stimuli dramatically reduced PTPMU protein expression. Under basal conditions, small interfering RNA (siRNA)-induced silencing of PTPMU increased EGFR Y992 and Y1068 phosphorylation. In the presence of EGF, PTPMU knockdown increased EGFR Y845, Y992, Y1045, Y1068, Y1086, and Y1173 but not Y1148 phosphorylation. Reduced PTPMU expression increased EGF-stimulated phosphorylation of Y992, a docking site for phospholipase C (PLC)gamma(1), activation of PLCgamma(1) itself, and increased cell migration in both wounding and chemotaxis assays. In contrast, overexpression of PTPMU decreased EGF stimulated EGFR Y992 and Y1068 phosphorylation. Therefore, airway epithelial injury profoundly reduces PTPMU expression, and PTPMU depletion selectively increases phosphorylation of specific EGFR tyrosine residues, PLCgamma(1) activation, and cell migration, providing a novel mechanism through which epithelial integrity may be restored. PMID- 21649527 TI - Exposure to neonatal cigarette smoke causes durable lung changes but does not potentiate cigarette smoke-induced chronic obstructive pulmonary disease in adult mice. AB - The impact of early childhood cigarette smoke (CS) exposure on CS-induced chronic obstructive pulmonary disease (COPD) is unknown. This study was performed to evaluate the individual and combined effects of neonatal and adult CS exposure on lung structure, function, and gene expression in adult mice. To model a childhood CS exposure, neonatal C57/B6 mice were exposed to 14 days of CS (Neo CS). At 10 weeks of age, Neo CS and control mice were exposed to 4 months of CS. Pulmonary function tests, bronchoalveolar lavage, and lung morphometry were measured and gene expression profiling was performed on lung tissue. Mean chord lengths and lung volumes were increased in neonatal and/or adult CS-exposed mice. Differences in immune, cornified envelope protein, muscle, and erythrocyte genes were found in CS-exposed lung. Neonatal CS exposure caused durable structural and functional changes in the adult lung but did not potentiate CS-induced COPD changes. Cornified envelope protein gene expression was decreased in all CS-exposed mice, whereas myosin and erythrocyte gene expression was increased in mice exposed to both neonatal and adult CS, suggesting an adaptive response. Additional studies may be warranted to determine the utility of these genes as biomarkers of respiratory outcomes. PMID- 21649528 TI - Switching therapy from variable-dose multiple pill to fixed-dose single-pill combinations of angiotensin II receptor blockers and thiazides for hypertension. AB - The efficacy and tolerability of switching therapy from free combinations of angiotensin II receptor blocker (ARB) and thiazide (A/T) to a fixed-dose of losartan and hydrochlorothiazide (L/H) has not been evaluated in Japan. We examined effects of switching therapy from variable-dose multiple-pill A/T to a fixed-dose L/H on blood pressure (BP) along with medication adherence and the degree of satisfaction in 91 hypertensive outpatients (mean age, 65.2 +/- 9.6 years). After 6 months, a significant BP reduction (132 +/- 9/76 +/- 10 vs. 126 +/- 12/72 +/- 11 mm Hg), along with an improvement of attaining target BP (44.0 vs. 61.5%) and that of adherence, were observed. The magnitude of BP reduction in the participants increased their degree of satisfaction more significantly than in the participants who worsened their degree of satisfaction. The estimated glomerular filtration rate and the serum uric acid (UA) level decreased slightly but significantly. The hemoglobin A1c of participants with diabetes mellitus increased slightly but significantly. In conclusion, a switch in therapy from variable-dose, multiple-pill A/T combinations to a fixed-dose, single-pill L/H was effective in decreasing BP and serum UA in Japanese clinical practice. Metabolic side effects of L/H in patients with diabetes mellitus remain to be investigated. PMID- 21649529 TI - Long-term MMP inhibition by doxycycline exerts divergent effect on ventricular extracellular matrix deposition and systolic performance in stroke-prone spontaneously hypertensive rats. AB - Pharmacologic inhibition of matrix metalloproteinases (MMP) by doxycycline is of therapeutic potential for a number of cardiovascular diseases characterized by excessive activation of MMP. So far, long-term administration of doxycycline in the treatment of hypertensive ventricular remodeling has not been systemically investigated. Seven-week-old stroke-prone spontaneously hypertensive rats (SHRSP) were fed with doxycycline (30 mgKg(-1) daily) for 26 weeks, when the mortality rate of the control group reached 50%. Stroke incidence was recognized by daily monitoring of stroke symptoms. Left ventricular (LV) performance was measured by in-vivo pressure-volume loop analysis and ex-vivo passive pressure-volume relationship at the time of sacrifice. Collagen deposition, gelatinases activity, protein abundance of gelatinases, and tissue inhibitor of matrix metalloproteinases (TIMP) -1, -2, and related mRNA levels in the heart were determined. MMP-9 expression was not detected in all groups. Excessive activation of MMP-2 in the heart could be partially suppressed by doxycycline. Left ventricular systolic function and ventricular size was partially ameliorated by doxycycline; however, elevated collagen deposition co-existed in the heart. Moreover, doxycycline could downregulate MMP-2 and TIMP-1 expression both at mRNA and protein levels, and TIMP-2 represented opposite expression pattern. These results demonstrate that long-term administration of doxycycline during the development of hypertension has no impact on stroke death, and could partially preserve LV systolic performance and restrain LV chamber dilation, but leads to increased LV extracellular matrix accumulation. Interrupted cardiac MMP-2/TIMP-2 balance by doxycycline may play a role in this process. PMID- 21649530 TI - Rare case of reninoma with double inferior vena cava. AB - A 16-year-old boy suffered from headaches and dizziness for 2 years. He was found to have remarkably elevated blood pressure (BP) of 180/110 mmHg. Laboratory findings showed a low level of serum potassium and markedly increased plasma renin activity. A solid mass at the periphery of the right kidney and double inferior vena cava (IVC) were detected by abdominal computer tomography (CT). Right partial nephrectomy via laparoscopy was performed on the patient. The histologic and electron microscopic findings comfirmed a diagnosis of juxtaglomerlar cell tumor. The patient had no headache or dizziness with normal BP after surgery. PMID- 21649531 TI - Prevalence and correlates of echocardiographic left atrial enlargement in hypertensive outpatients in clinical practice. AB - Prevalence of left atrial enlargement (LAE) in hypertension has been mostly assessed in population-based samples and selected hypertensive groups. A few data are available in clinical practice. We examined LAE prevalence and severity in a cohort of hypertensive patients referred by general practitioners to a routine echocardiographic examination. A total of 2170 hypertensive individuals (mean age 62 years, 53% men) referred by practitioners to 17 outpatient echocardiographic laboratories across Italy for detection of hypertensive cardiac disease were included in the study. LAE was defined as: A) absolute LA diameter >4.0 cm in men and >3.8 cm in women; B) LA diameter normalized to body surface area (BSA) >2.3 cm/m(2) in both sexes. Left atrial enlargement was graded as mild, moderate, and severe according to Lang's report. Patients with LAE were 38% by criterion A, and 20% by criterion B. A moderate/severe increase in LA size was present in 34% (A) and 32% (B) of patients with LAE. Severe LAE was 3.3-fold (A) and 2.6-fold (B) more frequent in women than in men. Left ventricular mass was the strongest correlate of absolute LA diameter as well as of normalized LA diameter, after age. Left atrial enlargement defined either by absolute or normalized LA diameter is a frequent cardiac phenotype in hypertensive patients referred to echo-labs in clinical practice. This cardiac parameter is closely related to LV mass and its severity is highly prevalent in women. PMID- 21649532 TI - Ile-Pro-Pro and Val-Pro-Pro tripeptide-containing milk product has acute blood pressure lowering effects in mildly hypertensive subjects. AB - Casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine proline-proline (Val-Pro-Pro) lower blood pressure (BP) in long-term clinical studies. Their acute effects on BP and vascular function, important for daily dosing scheme, were studied in a placebo-controlled double-blind crossover study using a single oral dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro as well as plant sterols. Twenty-five subjects with untreated mild hypertension received in random order 250 g of study product (25 mg peptides and 2 g plant sterols) or placebo. Ambulatory BP was monitored for 8 h post-dose and arterial stiffness measured by pulse wave analysis at 2, 4, and 8 h. Blood and urine samples were analyzed for markers of the renin-angiotensin system (RAS) and endothelial function. Baseline adjusted treatment effect for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial BP was -2.1 mmHg (95% CI: -4.1 to -0.1, p = 0.045), -1.6 mmHg (95% CI: -3.1 to -0.1, p = 0.03), and -1,9 mmHg (95% CI: -3-3 to -0.4, p = 0.0093), respectively, in favor of the active treatment for 8 h post- dose. No significant differences between the treatments were seen in brachial or aortic augmentation index, pulse wave velocity, or markers of RAS. Urinary excretion of cGMP, the second messenger of endothelial nitric oxide, was higher in the active group vs. placebo (p = 0.01). The results indicate that a single dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols acutely lowers brachial SBP and DBP in mildly hypertensive subjects. PMID- 21649533 TI - Associated factors of home versus ambulatory heart rate variability in the general population: the Ohasama study. AB - We previously demonstrated that heart rate (HR) variability obtained by daytime ambulatory monitoring and that of daily home measurement associated differently with cardiovascular mortality risk; cardiovascular mortality was linked with decreased daytime ambulatory HR variability and increased day-by-day home HR variability. The aim of this study was to identify factors contributing to each variability, clarifying possible reasons for their different predictive values. We obtained daytime ambulatory HR and home HR in 538 individuals of a general Japanese population aged >=55 years. Daytime ambulatory HR variability and day-by day home HR variability were estimated as a standard deviation measured every 30 min by daytime ambulatory monitoring and day-by-day home measurements once in the morning for 4 weeks, respectively. There was only weak correlation between daytime ambulatory HR variability and day-by-day home HR variability (r = 0.08~0.14). In a multiple regression model, daytime ambulatory HR variability was associated with daytime ambulatory HR (P < 0.0001), daytime ambulatory blood pressure (BP) variability (P < 0.0001), and male sex (P = 0.003), while negatively associated with daytime ambulatory systolic blood pressure (SBP) (P < 0.0001) and smoking (P = 0.038). Meanwhile, day-by-day home HR variability was positively associated with home HR (P < 0.0001), day-by-day home BP variability (P < 0.0001), and male sex (P = 0.018). Associated factors of daytime ambulatory HR variability and day-by-day home HR variability were different. Our findings suggest that HR variabilities by different intervals of measurements might be mediated by different mechanisms. PMID- 21649534 TI - Design and rationale of the study of assessment for kidney function by urinary microalbumin in randomized (SAKURA) trial. AB - Recently, it has been demonstrated that L-/N-type calcium channel blockers (CCBs), cilnidipine, but not L-type CCB, decreased urinary protein in renin angiotensin system (RAS), inhibitor-treated hypertensive patients with macroproteinuria. However, the antiproteinuric effect of cilnidipine was weaker in diabetic patients than in nondiabetic patients with macroproteinuria. This may be due to the fact that diabetic neuropathy was also developed in patients with advanced diabetic nephropathy because L-/N-type CCB has been considered to exert its renoprotetive effects through sympatholytic action. If so, the antiproteinuric effect of cilnidipine may be potent in patients with early stages of diabetic nephropathy. To elucidate our hypothesis, we designed a multi-center, open-labeled, randomized trial to compare the antialbuminuric effect between cilnidipine and amlodipine in RAS inhibitor-treated hypertensive (blood pressure [BP]: 130-180/80-110 mmHg) patients with type 2 diabetes and microalbuminuria (urinary albumin/creatinine [Cr] ratio: 30-300 mg/g). The primary study endpoint is the change in the urinary albumin/Cr ratio after a 1-year treatment. Enrollment began in April 2008 and was completed in March 2010. A total of 367 patients were randomly allocated to receive cilnidipine or amlodipine. At baseline, study subjects had 63.3+/- 8.5 years of age, 145.9 +/- 12.2/80.8 +/- 10.0 mmHg of BP, 101.0 +/- 111.6 mg/g of urinary albumin/Cr. The trial is expected to show whether cilnidipine can exert an antialbuminuric effect in RAS inhibitor-treated hypertensive patients with early stages of diabetic nephropathy. PMID- 21649535 TI - Ascorbic acid levels and neutrophil superoxide production in blood of pre-, early and late hypertensive stroke-prone spontaneously hypertensive rats. AB - We compared ascorbic acid (AA) levels in the blood and TPA- and fMLP-stimulated superoxide (O(2)(*-)) production in neutrophils of pre-, early, and late hypertensive stroke-prone spontaneously hypertensive rats (SHRSP) with those of age-matched Wistar Kyoto rats (WKY), or two other normotensive strains of rats. Plasma and lymphocyte AA levels were about two-fold higher in SHRSP as early as 4 weeks old compared to WKY, and also higher than those of Wistar and Sprague Dawley (SD) rats. Levels of AA were high in the liver and adrenal glands of SHRSP, indicating congenitally high AA levels. The production of O(2)(*-) in neutrophils was about two-fold higher in SHRSP than in WKY even at 4 weeks of age, and increased with age in both strains. Among SHRSP, AA levels in lymphocytes decreased at the late hypertensive stages with a decrease in hepatic l-gulono-gamma-lactone oxidase (GLO) activities. These data suggest that bi phasic AA levels in the blood of SHRSP comprise congenitally high levels and a decrease after persistent hypertension due to enhanced O(2)(*-) production and a decrease in de novo AA synthesis through GLO. PMID- 21649536 TI - Abatacept: a biologic immune modulator for rheumatoid arthritis. AB - INTRODUCTION: Abatacept is a biologic drug that belongs to the class of T-cell co stimulation modulators and is used for the treatment of rheumatoid arthritis (RA). AREAS COVERED: This article covers major randomized clinical trials and meta-analyses concerning abatacept in the treatment of RA, as identified in a Pubmed search. Scientific meeting abstracts describing long-term extension data of the identified trials are also included. Efficacy outcomes and the safety profile are the focus of this evaluation. EXPERT OPINION: Abatacept in combination with methotrexate (MTX) or other synthetic disease-modifying anti rheumatic drugs (DMARD) has been proven effective for the treatment of RA in different groups of patients: with early RA and no prior exposure to DMARD; with DMARD-resistant RA; and with RA not responding to TNF-alpha-blocking agents. Significant reductions of disease activity are achieved, with 1-year remission rates reaching up to 41% of DMARD-naive patients with early RA receiving a combination of abatacept plus MTX. Abatacept treatment has been shown to improve function and quality of life and to suppress radiographic progression. No major safety issues have emerged during clinical trials and long-term extensions. Therefore, abatacept is a drug with a favorable efficacy and safety profile, which may offer substantial benefits to RA patients. PMID- 21649537 TI - The relationship of body fatness indices and retinal vascular caliber in children. AB - OBJECTIVE: To examine the association between body fatness indices and retinal vascular calibre in Singapore Chinese children. METHODS: We recruited 136 Singapore Chinese children aged 6-16 years from the STARS (The Strabismus, Amblyopia and Refractive Error Study in Singaporean Chinese Preschoolers) Family study in 2008-2010. Anthropometric measurements including weight, height and triceps skinfold (TSF) and right eye retinal photographs were performed. TSF was measured with Holtain-Tanner calliper on the back of the arm and midway between the point of the acromoion and olecranon process while the arm was hanging relaxed. TSF and BMI threshold (cut-off points for overweight and obesity) were defined as 85th and above of age- and gender-specific TSF and BMI standard charts which were based on American representative survey data. RESULTS: The mean retinal arteriolar and venular calibres were 155.78 ? 15.02 ?m and 219.66 ? 21.88 ?m, respectively in the STARS Family study. Each standard deviation (SD) increase in TSF (4.49 mm) and BMI (3.52 kg/m(2)) was associated with a 2.94 ?m (p = 0.012) and a 3.40 ?m (p = 0.005) widening in retinal venular calibre, respectively. Compared with children with TSF and BMI below threshold, children with TSF and BMI above threshold had a 10.21 ?m (p = 0.001) and a 9.33 ?m (p = 0.021) increase in retinal venular calibre, respectively. CONCLUSIONS: Greater TSF and BMI are associated with wider retinal venular calibre in healthy children aged 6 years and above. These findings suggest a possible effect of abnormal body fatness indices on early retinal vascular changes that reflect microvasculature in children. PMID- 21649538 TI - Improvement of aerobic fitness in obese children: a meta-analysis. AB - The purpose of this meta-analysis was to assess the effectiveness of diverse interventions in aerobic fitness adjusted for weight in obese children. A computerized search of seven databases was carried out using keywords. Effect sizes and 95% confidence intervals were calculated, and the heterogeneity of the studies was assessed using Cochran's Q statistic applied to the effect size means. Nine studies were selected for review as satisfying the inclusion criteria (n patients = 311). The conclusions of the meta-analysis were: (i) the programs based on aerobic exercise have a moderate positive effect on aerobic fitness; (ii) the programs based on aerobic exercise lasting more than 12 weeks (3000 minutes total exercise time) in three sessions per week (more than 60 min per session) obtain better results; (iii) overall, combined programs fail to achieve improvements in aerobic fitness; and (iv) few randomized clinical trials have been conducted. PMID- 21649539 TI - Acute Budd-Chiari syndrome in pediatric acute promyelocytic leukemia. PMID- 21649541 TI - Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma. AB - This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB-IVB, or Sezary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with >=7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1-2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related. PMID- 21649542 TI - Ranimustine, ifosfamide, procarbazine, dexamethasone, and etoposide therapy for central nervous system recurrence of diffuse large B-cell lymphoma in patients with poor performance status: a pilot study. AB - The prognosis of patients with diffuse large B-cell lymphoma with central nervous system (CNS) involvement is still poor. We performed a pilot study to establish treatment for patients who had refractory or recurrent CNS involvement without employing high-dose chemotherapy or stem cell support. Eight patients with diffuse large B-cell lymphoma and CNS disease after first-line chemotherapy were enrolled. They were treated with MIND-E therapy (ranimustine, ifosfamide, procarbazine, dexamethasone, and etoposide) every 4 weeks. Three patients achieved complete remission, two patients achieved partial remission, and three patients did not respond. One patient received an autologous peripheral stem cell transplant after MIND-E therapy. Three patients are still alive. In conclusion, MIND-E therapy was effective for CNS disease in patients with B-cell lymphoma who were judged to be poor candidates for intensive chemotherapy. Its toxicity was tolerable. A prospective study should be done to confirm the efficacy of this regimen. PMID- 21649540 TI - Activation of CD44, a receptor for extracellular matrix components, protects chronic lymphocytic leukemia cells from spontaneous and drug induced apoptosis through MCL-1. AB - Survival of chronic lymphocytic leukemia (CLL) cells in vivo is supported by the tissue microenvironment, which includes components of the extracellular matrix. Interactions between tumor cells and the extracellular matrix are in part mediated by CD44, whose principal ligand is hyaluronic acid. Here, we show that CD44 is more highly expressed on CLL cells of the clinically more progressive immunglobulin heavy chain variable gene (IGHV)-unmutated subtype than on cells of the IGHV-mutated type. Engagement of CD44 activated the phosphatidylinositol 3 kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK)/ERK pathways and increased myeloid cell leukemia sequence 1 (MCL-1) protein expression. Consistent with the induction of these anti-apoptotic mechanisms, CD44 protected CLL cells from spontaneous and fludarabine-induced apoptosis. Obatoclax, an antagonist of MCL-1, blocked the pro-survival effect of CD44. In addition, obatoclax synergized with fludarabine to induce apoptosis of CLL cells. In conclusion, components of the extracellular matrix may provide survival signals to CLL cells through engagement of CD44. Inhibition of MCL-1 is a promising strategy to reduce the anti-apoptotic effect of the microenvironment on CLL cells. PMID- 21649543 TI - Clinical significance of productive immunoglobulin heavy chain gene rearrangements in childhood acute lymphoblastic leukemia. AB - We analyzed the CDR3 region of 80 children with B-cell acute lymphoblastic leukemia (B-ALL) using the ImMunoGeneTics Information System and JOINSOLVER. In total, 108 IGH@ rearrangements were analyzed. Most of them (75.3%) were non productive. IGHV@ segments proximal to IGHD-IGHJ@ were preferentially rearranged (45.3%). Increased utilization of IGHV3 segments IGHV3-13 (11.3%) and IGHV3-15 (9.3%), IGHD3 (30.5%), and IGHJ4 (34%) was noted. In pro-B ALL more frequent were IGHV3-11 (33.3%) and IGHV6-1 (33.3%), IGHD2-21 (50%), IGHJ4 (50%), and IGHJ6 (50%) segments. Shorter CDR3 length was observed in IGHV@6, IGHD7, and IGHJ1 segments, whereas increased CDR3 length was related to IGHV3, IGHD2, and IGHJ4 segments. Increased risk of relapse was found in patients with productive sequences. Specifically, the relapse-free survival rate at 5 years in patients with productive sequences at diagnosis was 75% (standard error [SE] +/-9%), whereas in patients with non-productive sequences it was 97% (SE +/-1.92%) (p value =0.0264). Monoclonality and oligoclonality were identified in 81.2% and 18.75% cases at diagnosis, respectively. Sequence analysis revealed IGHV@ to IGHDJ joining only in 6.6% cases with oligoclonality. The majority (75%) of relapsed patients had monoclonal IGH@ rearrangements. The preferential utilization of IGHV@ segments proximal to IGHDJ depended on their location on the IGHV@ locus. Molecular mechanisms occurring during IGH@ rearrangement might play an essential role in childhood ALL prognosis. In our study, the productivity of the rearranged sequences at diagnosis proved to be a significant prognostic factor. PMID- 21649544 TI - A case of benign natural killer cell proliferative disorder of the stomach (gastric manifestation of natural killer cell lymphomatoid gastroenteropathy) mimicking extranodal natural killer/T-cell lymphoma. PMID- 21649545 TI - Keratinocyte growth factor enhanced immune reconstitution in murine allogeneic umbilical cord blood cell transplant. AB - Umbilical cord blood (UCB) is used increasingly as a source of hematopoietic cells because of a lower risk of graft-versus-host disease (GVHD). Myeloablative conditioning before allogeneic umbilical cord blood transplant (allo-UCBT) results in thymic epithelial cell injury and T-cell immune deficiency. Full-term fetal blood cells were used as hematopoietic cells in a previous murine allo-UCBT model with a limited number of mice surviving the myeloablative conditioning. We designed a viable murine allo-UCBT protocol with platelet concentrate support. Keratinocyte growth factor (KGF) is a mitogen of thymic epithelial cells that promotes recovery of thymic epithelium when given before total body irradiation (TBI)-containing conditioning in experimental murine models. We hypothesized that KGF pre-administration would improve post-allo-UCBT thymopoiesis. To test this hypothesis, allo-UCBT recipient mice were given KGF or control saline prior to UCBT. Platelet concentrate support significantly improved the survival rate of murine allo-UCBT recipients. KGF administration significantly increased donor derived T and natural killer T (NKT) cells at day +35 in spleens of allo-UCBT recipients. KGF administration also improved thymic function after allo-UCBT, resulting in higher copies of signal joint T-cell receptor rearrangement excision circles (sjTRECs) in splenocytes. Finally, we found that KGF pre-administration could enhance the graft-versus-leukemia effect. In conclusion, KGF can be administered safely to recipients of allo-UCBT to enhance T-cell immune reconstitution. PMID- 21649546 TI - Current and future imaging modalities for multiple myeloma and its precursor states. AB - Traditionally, the skeletal survey has been the standard modality for the detection of osteolytic bone disease in multiple myeloma. In addition to its poor sensitivity for the detection of osteolytic lesions, this modality is not able to identify extramedullary lesions and focal bone marrow involvement, nor measure response to therapy. The application of novel imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and molecular imaging such as fluorine-18 fluorodeoxyglucose positron emission tomography CT ((18)F-FDG PET/CT) and fluorine-18 sodium fluoride positron emission tomography CT ((18)F-NaF PET/CT) has the potential to overcome these limitations as well as provide prognostic information in precursor states and multiple myeloma. Also promising is the use of dynamic contrast enhanced magnetic resonance imaging (DCE MRI) to measure vascular permeability, an important feature of myelomagenesis. This review summarizes the current status and possible future role of novel imaging modalities in multiple myeloma and its precursor states. PMID- 21649547 TI - miRNA expression profiles in myelodysplastic syndromes reveal Epstein-Barr virus miR-BART13 dysregulation. AB - Recently, the microRNA (miRNA) signature has been used for better characterization and understanding of the pathogenesis of different malignancies, including myelodysplastic syndromes (MDS). MDS are a heterogeneous group of stem cell disorders in which the genetic and molecular defects are not well defined. In the present study, we applied array based miRNA profiling to study 19 bone marrow cell samples of de novo MDS compared with eight healthy individuals. In addition, integration of the miRNA profiling data with our previous array comparative genomic hybridization data, from the same cohort of patients, was performed. We observed up-regulation of hsa-miR-720 and hsa-miR-21, and down regulation of hsa-miR-671-5p and one human virus miRNA (Epstein-Barr virus miR BART13) in MDS samples compared with normal samples. In our study, the copy number alteration harboring miRNA was not affecting miRNA expression, but a distinct microRNA expression pattern was observed, not only in MDS compared with controls, but also between MDS entities. PMID- 21649548 TI - Fatal disseminated infection due to Scedosporium prolificans in a patient with acute myeloid leukemia and posaconazole prophylaxis. PMID- 21649550 TI - Molecular markers in medicinal plant biotechnology: past and present. AB - Plant based medicines have gained popularity worldwide due to their almost negligible side effects. In India, the three traditional medicinal systems, namely homeopathy, Ayurveda and Siddha rely heavily on plants for medicinal formulations. To prevent the indiscriminate collection of these valuable medicinal plants and for their proper authentication and conservation, it is imperative to go for sustained efforts towards proper germplasm cataloguing and devising conservation strategies. For this purpose, molecular markers have a significant role, as they provide information ranging from diversity at nucleotide level (single nucleotide polymorphisms) to gene and allele frequencies (genotype information), the extent and distribution of genetic diversity, and population structure. Over the past twenty years, the molecular marker field has completely transformed the meaning of conservation genetics which has emerged from a theory-based field of population biology to a full-fledged pragmatic discipline. In this review, we have explored the transition and transformation of molecular marker technologies throughout these years. PMID- 21649549 TI - Management of patients with chronic lymphocytic leukemia with a high risk of adverse outcome: the Mayo Clinic approach. AB - Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) is usually an incidental diagnosis in patients with early-intermediate stage disease. However, most patients with a diagnosis of CLL will subsequently have significant morbidity and die from their disease and its complications. For these patients, CLL is not the 'good leukemia' with a predictably 'benign' outcome. Indeed, we can now identify a cohort of patients with high-risk CLL at diagnosis who will have rapid disease progression, poor response to treatment, and poor survival based on prognostic methods developed from an improved understanding of the biology of CLL. The concomitant development of improved treatments has led to risk-adjusted management approaches that could improve outcomes. We discuss the clinical and laboratory components of comprehensive risk evaluation of patients with CLL and our approach to the management of patients with a high to very high risk of disease progression and poor outcome. In addition, we review the challenges and prospects for improving prognostic precision and the development of new drugs to improve the treatment of patients with CLL with a high risk of adverse outcome. PMID- 21649551 TI - Effect of millimeter waves and cyclophosphamide on cytokine regulation. AB - We have reported previously that millimeter waves (MMWs) protect T-cell functions from the toxic side effects of cyclophosphamide (CPA), an anticancer drug. Since the effect of MMWs has been reported to be mediated by endogenous opioids, the present study was undertaken to investigate the role of endogenous opioids in protection of T-cell functions by MMWs. The effect of MMWs (42.2 GHz, incident power density = 38 mW/cm2) was studied on CPA-induced suppression of cytokine release by T cells in the presence of selective opioid receptor antagonists (ORA). Production of cytokines was measured in CD4 T cells isolated from splenocytes. Treatment of mice with CPA suppressed the formation of Th1 cytokines (TNF-alpha, IFN-gamma, and IL-2), shifting the overall balance toward Th2 (IL-4 and IL-5). MMW irradiation of CPA-treated groups up-regulated the production of Th1 cytokines suppressed by CPA. Treatment of the CPA+MMW group with selective kappa (kappa) ORA further potentiated this effect of MMWs on Th1 cytokine production, whereas treatment with MU or delta ORA increased the imbalance of cytokine production in the Th2 direction. These results provide further evidence that endogenous opioids are involved in immunomodulation by MMWs. PMID- 21649554 TI - A bias in quantitative RT-PCR limit of detection is induced by the use of cancer cell lines in the molecular detection of circulating tumor cells. PMID- 21649553 TI - Diagnostic value of pro-gastrin-releasing peptide for small cell lung cancer: a meta-analysis. AB - BACKGROUND: Lung cancer, of which 15%-20% is small cell lung cancer, is the leading cause of cancer mortality and shows a high incidence worldwide. While pro gastrin-releasing peptide (ProGRP) has been reported as a predictive diagnostic factor, it has not been widely accepted because of inconsistent conclusions. The aim of this study was to systematically evaluate ProGRP as the diagnostic standard for small cell lung cancer. METHODS: All published studies on ProGRP in the diagnosis of small cell lung cancer from January 1994 to April of 2010 were retrieved. By measuring methodological qualities, 11 papers were selected for this study. The overall diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate ProGRP as the diagnostic standard for small cell lung cancer using Meta DiSc statistical software. RESULTS: There were 5146 subjects included in this meta-analysis. The sensitivity and specificity (95% confidence interval) of ProGRP was 0.716 (0.688 0.743) and 0.921 (0.909-0.932), respectively. The area under the summary receiver operating characteristic curve of ProGRP was 0.9236. The index of Q* was 0.8575. CONCLUSIONS: ProGRP has better sensitivity and high specificity as an auxiliary indicator for the diagnosis of small cell lung cancer. PMID- 21649556 TI - Blood pressure in children in relation to relative body fat composition and cardio-respiratory fitness. AB - OBJECTIVE: To examine whether higher physical fitness is associated with lower levels of blood pressure independent of adiposity in an established cohort of children. We explored how the method used to adjust fitness for body size would influence the findings. METHODS AND RESULTS: Blood pressure, adiposity (DXA scan) and fitness (predicted work capacity at a heart rate of 170 bpm [PWC170]) were assessed in children aged 9 years (n = 3594). Separate regression analyses for boys and girls yielded strong linear relationships between blood pressure (dependent variable) and ratio of fat to lean + bone (independent variable; all P < 0.001). An independent effect of fitness was assessed by adding PWC170 to the above models. Blood pressure was strongly inversely related to PWC170 when the latter was first adjusted for size in the conventional way (division by weight; all P < 0.001), probably because of mathematical ?coupling? (via weight). PWC170 expressed as a residual from our own regression of PWC170 on weight showed no association with systolic blood pressure and a small negative association with diastolic blood pressure (girls P = 0.042; boys P < 0.001). Across the observed ranges of fitness, mean blood pressure differed by 1 [95% CI 0?3] mm Hg for boys and 3 [95% CI 2?4] mm Hg for girls. CONCLUSIONS: Fitness is not associated with systolic blood pressure independent of levels of adiposity but there is a small but independent association with diastolic blood pressure. PMID- 21649557 TI - The reality of in-line tablet coating. AB - The possibility of continuous processing in pharmaceutical tablet manufacturing is hampered by the viscoelastic recovery of tablets post-compaction. Compacted tablets are typically aged before coating to allow complete viscoelastic recovery so as to avoid subsequent coating defects. There has been little attempt to overcome tablet recovery in order to enable continuous processing and improve manufacturing efficiency. However, with the introduction of improved or newly developed types of tablet-coating equipment, there is renewed interest in the coating of tablets in-line. In-line tablet coating is defined as the coating of tablets immediately after compaction. It is a one-step highly integrated system that circumvents the delay in processing time typically given to allow viscoelastic recovery of tablets. This review aims to summarize the requirements of an in-line tablet-coating system. The possibility of carrying out in-line tablet coating in the near future will also be discussed. PMID- 21649558 TI - The mouse mammary microenvironment redirects mesoderm-derived bone marrow cells to a mammary epithelial progenitor cell fate. AB - Mammary stem cells reside in protected tissue locales (niches), where their reproductive potency remains essentially unchanged through life. Disruption of the tissue leads to a reduced capacity of dispersed epithelial cells to recapitulate complete functional mammary structures. Previous studies demonstrate that during the reformation of mammary stem cell niches by dispersed epithelial cells in the mammary stroma, nonmammary cells of ectodermal germ origin may be sequestered and reprogrammed to perform mammary epithelial cell (MEC) functions, including those ascribed to mammary stem/progenitor cells. To test whether tissue cells from organs derived from different germ layers could respond to mammary epithelial-specific signals, we utilized fluorescence-activated cell sorting purified Lin(-) and Lin(-)/cKit+adult male bone marrow cells to mix with MECs. Our evidence shows that the signals provided by the mammary microenvironment are capable of redirecting mesoderm-derived adult progenitor cells to produce functional MEC progeny. PMID- 21649559 TI - Enhanced production of neuroprogenitors, dopaminergic neurons, and identification of target genes by overexpression of sonic hedgehog in human embryonic stem cells. AB - Molecular and cellular signaling pathways are involved in the process of neural differentiation from human embryonic stem cells (hESC) to terminally differentiated neurons. The Sonic hedgehog (SHH) morphogen is required to direct the differentiation of hESC to several neural subtypes, for example, dopaminergic (DA) or motor neurons. However, the roles of SHH signaling and the pathway target genes that regulate the diversity of cellular responses arising from SHH activation during neurogenesis of hESC have yet to be elucidated. In this study, we report that overexpression of SHH in hESC promotes the derivation of neuroprogenitors (NP), increases proliferation of NP, and subsequently increases the yield of DA neurons. Next, gene expression changes resulting from the overexpression of SHH in hESC-derived NP were examined by genome-wide transcriptional profiling. Categorizing the differentially expressed genes according to the Gene Ontology biological processes showed that they are involved in numerous cellular processes, including neural development, NP proliferation, and neural specification. In silico GLI-binding sites analysis of the differentially expressed genes also identified a set of putative novel direct target genes of SHH in hESC-derived NP, which are involved in nervous system development. Electrophoretic mobility shift assays and promoter-luciferase assays confirmed that GLI1 binds to the promoter region and activates transcription of HEY2, a NOTCH signaling target gene. Taken together, our data provide evidence for the first time that there is cross-talk between the NOTCH and SHH signaling pathways in hESC-derived NP and also provide significant new insights into transcriptional targets in SHH-mediated neural differentiation of hESC. PMID- 21649560 TI - Pulmonary exposure to carbon black by inhalation or instillation in pregnant mice: effects on liver DNA strand breaks in dams and offspring. AB - Effects of maternal pulmonary exposure to carbon black (Printex 90) on gestation, lactation and DNA strand breaks were evaluated. Time-mated C57BL/6BomTac mice were exposed by inhalation to 42 mg/m(3) Printex 90 for 1 h/day on gestation days (GD) 8-18, or by four intratracheal instillations on GD 7, 10, 15 and 18, with total doses of 11, 54 and 268 MUg/animal. Dams were monitored until weaning and some offspring until adolescence. Inflammation was assessed in maternal bronchoalveolar lavage (BAL) 3-5 days after exposure, and at weaning. Levels of DNA strand breaks were assessed in maternal BAL cells and liver, and in offspring liver. Persistent lung inflammation was observed in exposed mothers. Inhalation exposure induced more DNA strand breaks in the liver of mothers and their offspring, whereas intratracheal instillation did not. Neither inhalation nor instillation affected gestation and lactation. Maternal inhalation exposure to Printex 90-induced liver DNA damage in the mothers and the in utero exposed offspring. PMID- 21649561 TI - PUMILIO-2 is involved in the positive regulation of cellular proliferation in human adipose-derived stem cells. AB - Stem cells can either differentiate into more specialized cells or undergo self renewal. Several lines of evidence from different organisms suggest that these processes depend on the post-transcriptional regulation of gene expression. The presence of the PUF [Pumilio/FBF (fem-3 binding factor)] domain defines a conserved family of RNA binding proteins involved in repressing gene expression. It has been suggested that a conserved function of PUF proteins is to repress differentiation and sustain the mitotic proliferation of stem cells. In humans, Pumilio-2 (PUM2) is expressed in embryonic stem cells and adult germ cells. Here we show that PUM2 is expressed in a subpopulation of adipose-derived stem cell (ASC) cultures, with a granular pattern of staining in the cytoplasm. Protein levels of PUM2 showed no changes during the differentiation of ASCs into adipocytes. Moreover, RNAi knockdown of pum2 did not alter the rate of adipogenic differentiation compared with wild-type control cells. A ribonomic approach was used to identify PUM2-associated mRNAs. Microarray analysis showed that PUM2 bound mRNAs are part of gene networks involved in cell proliferation and gene expression control. We studied pum2 expression in cell cultures with low or very high levels of proliferation and found that changes in pum2 production were dependent on the proliferation status of the cell. Transient knockdown of pum2 expression by RNAi impaired proliferation of ASCs in vitro. Our results suggest that PUM2 does not repress differentiation of ASCs but rather is involved in the positive control of ASCs division and proliferation. PMID- 21649562 TI - Evaluating steatosis in pancreatic transplant. AB - Pancreatic transplant remains the only treatment that cures insulin-dependent diabetes mellitus. It is recognized by transplant surgeons that donor pancreases with excessive fat infiltration have a poorer clinical outcome, resulting in significant recipient morbidity and mortality. However, no objective measure of pancreatic fat infiltration exists, and no study has been done that correlates the level of fat infiltration with clinical outcome. There have been significant radiologic advances that allow assessment of fat content of organs, and these could be used to accurately quantify the extent of pancreatic fat infiltration. We reviewed the literature regarding pancreatic steatosis, and examined ways in which the level of steatosis could be objectively measured before transplant, thereby improving clinical outcome. PMID- 21649563 TI - Outcome of a solitary kidney transplant into adult recipients from pediatric donors after controlled circulatory death. AB - OBJECTIVES: We sought to evaluate the outcomes of a single kidney transplant from pediatric donors into adult recipients after controlled circulatory death. MATERIALS AND METHODS: A retrospective, single-center review of all adult recipients who received a single pediatric kidney from controlled-cardiac deceased-donors (aged, < 9 years old) between January 2006 and March 2008 was performed. RESULTS: Eleven adult recipients (aged, 16-41 years) used single renal grafts from the controlled-cardiac deceased-donors (median donor age, 74 months; range, 49-106 months; median donor weight, 20.95 kg; range, 16.6-37.8 kg). The median recipient age was 27 years (range, 16-41 years; median recipient weight, 47 kg; range 39.5-53.6 kg). The patient's serum creatinine level gradually decreased, and the estimated glomerular filtration rate increased stably more than 2 times during follow-up. The graft length increased significantly the first week after transplant compared with that recorded immediately after reperfusion (P < .001) and grew slightly thereafter. Acute rejection occurred in 1 patient. Nine patients had high renal artery blood flow velocity index at 1 to 2 cm. Beside the anastomosis (167-321 cm/s), only 1 patient developed hypertension and slightly increased serum creatinine at 14 weeks after transplant. The 1-year patient/graft survival was 100%. CONCLUSIONS: Use of single kidneys from pediatric donors after controlled cardiac death could expand the donor pool without compromising recipient outcomes. PMID- 21649564 TI - Cyclosporine versus tacrolimus maintenance therapy in renal transplant. AB - OBJECTIVES: Several studies have shown comparable results in long-term graft and patient survival, comparing a tacrolimus-based therapy to cyclosporine, while other studies have shown that a tacrolimus-based regimen had a better renal function with fewer episodes of acute rejection. Most of these studies were in a white population. We describe our experiences comparing tacrolimus versus cyclosporine maintenance therapy in a Saudi population. MATERIALS AND METHODS: All patients from 2003 until 2008 in our transplant clinic were evaluated. A retrospective analysis was done comparing patient and graft survival, kidney function, and metabolic profile. RESULTS: There was no statistical difference in acute rejection rate between the cyclosporine group and the tacrolimus group (18.7% vs 20.9%; P = .756). Mean serum creatinine was not statistically different between the 2 groups. Patient and graft survival at 1 and 2 years also were similar. Although patient and graft survival were similar, the cyclosporine group had a higher level of cholesterol compared with the tacrolimus group (4.6 +/- 1.03 mmol/L vs 4.1 +/- 0.80 mmol/L; P = .010). CONCLUSIONS: There is no difference in 1- or 2-year patient and graft survival between patients maintained on cyclosporine compared with tacrolimus. However, patients on cyclosporine had a higher blood pressure and serum cholesterol level. PMID- 21649565 TI - Prospective study of posttransplant polyomavirus infection in renal transplant recipients. AB - OBJECTIVES: The BK virus is the most common pathogen in renal transplant recipients. Limited information is available regarding JC virus or Simian virus infections in renal transplant recipients. This prospective study sought to investigate the rate of BK virus, JC virus, and Simian virus 40 infections and their influence on allograft function in the early stages after surgery. MATERIALS AND METHODS: In total, 50 renal transplant recipients and 20 healthy blood donors were studied. The BK virus, the JC virus, and the Simian virus 40 were detected by nested qualitative polymerase chain reaction assays in urine and plasma. The difference of glomerular filtration rate among BK virus-infected, JC virus-infected, and uninfected patients was compared using the Kruskal-Wallis test. RESULTS: The polyomavirus viruria was detected in 46% of renal transplant recipients (4% of the BK virus and 42% of the JC virus viruria) and 10% of the healthy blood donors (5% for the BK virus and the JC virus viruria). No polyomavirus viremia was detected. No difference of glomerular filtration rate was found among the 3 groups (chi-square = 0.228; P = .892). CONCLUSIONS: Polyomavirus infections are not uncommon, and the incidence of JC virus infection is much higher in renal transplant recipients than it is in BK virus. Neither BK virus nor JC virus infections appeared to influence graft function in the early stages after surgery. PMID- 21649566 TI - Expanding the live kidney donor pool: ethical considerations regarding altruistic donors, paired and pooled programs. AB - In renal transplant, there is a well-known deficiency in organ supply relative to demand. Live donation provides superior results when compared with deceased donation including a better rate of graft success and fewer immunologic complications. This deficiency in organs leads to significant morbidity and mortality rates. Alternative avenues have been extensively explored that may expand the live donor pool. They include altruistic donation as well as paired and pooled exchange programs. Altruistic donation is a truly selfless act from a donor unknown to the recipient. Kidney paired donation involves 2 incompatible donor-recipient pairs swapping donors to produce compatibility. Pooled donation involves at least 2 pairs, and can take the form of domino chains in which altruistic input sets up a chain of transplants, in which each recipient's incompatible donor makes a donation for the next recipient. Despite application of these various methods, there lie extensive ethical issues surrounding them. Misconceptions frequently occur; for instance, the perceived benefit that donating an organ to a loved one is greater for a related donor than for an altruistic one. Additionally, it is frequently believed that immunologic incompatibility offers coerced donors liberation from surgery, and that overcoming these barriers by introducing exchange programs provides vulnerable donors less protection. This article explores these and other complex ethical issues surrounding the various methods of expanding the donor pool. The authors offer opinions that challenge the ethical issues and attempt to overcome those views that hinder progress in the field. PMID- 21649567 TI - Long-term results of incidental hepatocellular carcinoma after liver transplant. AB - OBJECTIVES: The incidence of detecting hepatocellular carcinoma in a removed recipient liver after a liver transplant is not rare. Here, we sought to evaluate incidental hepatocellular carcinoma at our center. MATERIALS AND METHODS: Among 296 patients who had undergone a liver transplant between September 2001 and November 2010, we retrospectively analyzed the outcomes of 6 patients with incidental hepatocellular carcinoma. The proportion of incidental hepatocellular carcinoma was 2%. The rate of incidental hepatocellular carcinoma among all hepatocellular carcinoma patients is 11.5%. There were 3 children and 3 adults (mean age, 28.3 +/- 26 years; age range, 1-57 years). Two of the 6 patients were 1 year old. Alpha-fetoprotein levels were mildly elevated in 3 patients. RESULTS: The results of preoperative imaging studies in all patients were normal, except for those that demonstrated regenerative or dysplastic nodules. One of the grafts was from a deceased donor, the remaining 5 were from living-related donors. We encountered no complications after the transplants. Pathology findings showed a mean tumor size of 0.8 +/- 0.3 cm (range, 0.5-1.2 cm) and multiplicity in 1 patient. One patient with multiple tumors had microvascular invasion. According to the Tumor Node Metastasis staging system, 5 patients had Stage I, and the remaining patient had Stage II carcinoma. There were no recurrences of hepatocellular carcinoma, and no deaths occurred during a mean follow-up of 63 +/ 16.5 months (range, 33-79 months). CONCLUSIONS: The incidence of hepatocellular carcinoma in patients with cirrhosis who have undergone a liver transplant at our hospital is similar to those reported in other studies. Incidentally found hepatocellular carcinomas showed less-invasive pathologic features and better prognoses than did preoperatively found hepatocellular carcinomas. PMID- 21649568 TI - Hepatic artery thrombosis after orthotopic liver transplant: a review of the same institute 5 years later. AB - OBJECTIVES: Summarize the experience of managing patients with hepatic artery thrombosis after orthotopic liver transplant in a single center. MATERIALS AND METHODS: A total of 726 adult patients who received a liver transplant at the Department of Organ Transplantation, the First Affiliated Hospital of Sun Yat-Sen University, between January 2004 and December 2009, were selected. Fourteen patients had hepatic artery thrombosis after the operation, and the clinical data of these patients were analyzed retrospectively. RESULTS: The incidence rate of hepatic artery thrombosis was 1.9% (14/726), and the mean time of onset was 10 days (range, 1-41 d) after surgery. Six patients had acute deterioration of liver function, 4 had bile leakage, 1 had hepatic abscess, and 3 had no symptoms. Three patients received urgent rearterialization, 2 received intra-arterial thrombolysis, 3 received combined urgent rearterialization and intra-arterial thrombolysis, and 6 patients received a retransplant. The mortality rate associated with hepatic artery thrombosis was 42.9% (6/14); 2 from biliary necrosis and secondary hepatic failure after urgent rearterialization; 1 from recurrent hepatic artery thrombosis and multiple organ failure after intra arterial thrombolysis; 1 from renal failure and severe infection after combined urgent rearterialization and intra-arterial thrombolysis, and 2 from severe infection after retransplant. The other patients recovered and were followed for 18 to 66 months. Their liver grafts all functioned well with a patent artery. Two died from tumor recurrence at 18 and 29 months after transplant. CONCLUSIONS: Hepatic artery thrombosis is a severe complication after liver transplant, which leads to graft loss and recipient death. Rearterialization as early as possible before irreversible biliary and liver parenchyma damage can avoid retransplant. PMID- 21649570 TI - Lepromatous leprosy in a kidney transplant recipient: a case report. AB - Leprosy is a chronic granulomatous disease of the skin and peripheral nerves caused by Mycobacterium leprae. Among mycobacterial infections, leprosy is rare in renal transplant recipients. Here, we report the manifestations of lepromatous leprosy in a 41-year-old renal transplant recipient. Before the renal transplant, the patient had recurrent bullous lesions on his extremities with no systemic complaints. He was on an immunosuppressive regimen that included prednisolone (1 mg/kg/d), cyclosporine (6 mg/kg), and mycophenolate mofetil (2000 mg/d), and had 2 serologically confirmed acute episodes of cytomegalovirus infection that responded favorably to intravenous ganciclovir. The density of his bullous skin lesions decreased after renal transplant. During his regular posttransplant visits, we noticed a decrease in his eyebrow hairs on their lateral margins bilaterally. Later, he developed generalized, symmetric, erythematous papules. With a positive acid-fast bacilli with Fite staining, the results of a skin biopsy showed diffuse foamy histiocyte infiltration in the dermis. These findings are compatible with lepromatous leprosy. After antileprosy therapy, no deterioration of renal allograft function or lepra reactions was noted in a 4 month follow-up. Clinicians should consider leprosy in the differential diagnosis of skin lesions in immunocompromised hosts, and in particular, solid organ transplant recipients in endemic areas. PMID- 21649569 TI - Limb salvage using intramuscular injection of unfractionated autologous bone marrow mononuclear cells in critical limb ischemia: a prospective pilot clinical trial. AB - OBJECTIVES: Despite advances in surgical and radiologic vascular techniques, many patients with critical limb ischemia are not eligible for revascularization procedures. Without pharmacologic therapy, the only option left is amputation. Bone marrow-derived progenitor cells represent a good revascularization option. This study sought to evaluate the therapeutic effectiveness of autologous unfractionated bone marrow mononuclear cell injection in revascularization of critical limb ischemia patients. MATERIALS AND METHODS: Twenty critical limb ischemia patients were not eligible for open or endo-vascular interventions. Bone marrow mononuclear cells were obtained by aspiration of 300 mL bone marrow, injected intramuscular in affected muscles. Patients were followed-up by walking distance, resting pain, skin condition, and ankle brachial index. RESULTS: Walking distance improved from a mean of 56 meters to a mean of 132 meters; rest pain improved markedly in 50% of patients, mildly in 5% of patients, and was unaffected in 45% of the patients. Fifty percent of patients showed improved skin condition, while ankle brachial index showed improvement in 40% of patients. No procedure-related complications were encountered. CONCLUSIONS: Autologous bone marrow mononuclear cell injection provides a safe and effective option for critical limb ischemia patients. PMID- 21649571 TI - Rare complication of a sigmoid colon perforation after a kidney transplant with an artificial vascular graft. AB - A 65-year-old man (blood type O) came to our hospital for transplant of an unrelated kidney (6/6 mismatch of HLA genotype) donated by his living 60-year-old wife (blood type B). The planned right donor nephrectomy was uneventful, with a warm ischemic time of 5 minutes, but her right renal vein was too fragile and weak to be repaired for vascular anastomosis. Therefore, we used an artificial vascular graft (polytetrafluoroethylene) interposed between the donor renal vein and the recipient's left external iliac vein. On the 11th day after surgery, infraphrenic free air (identified by a chest radiograph) made us do an emergent laparoscopic examination that showed a perforation of his sigmoid colon. A transient transverse colostomy was therefore prepared. The transient transverse colostomy was closed 8 months after the kidney transplant. Twelve months after the transplant, the patient is doing well with a serum creatinine level of 150.44 micromol/L (1.7 mg/dL). PMID- 21649572 TI - Spontaneous mycotic external iliac artery aneurysm rupture after perforated acute appendicitis in a renal allograft recipient. AB - Acute appendicitis is uncommon after renal transplant. Infection with Candida albicans can produce serious complications by compromising the vascular anastomosis. In such cases, the origin of Candida albicans is often in the gastrointestinal system. Here, we report 2 uncommon complications that occurred in the same patient. A 27-year-old female renal transplant patient with appendicitis presented to our institution with acute graft failure. The patient was treated with an appendectomy and a transplant nephrectomy. Subsequently, the patient had a mycotic pseudoaneurysm rupture of the external iliac artery secondary to Candida albicans infection that originated possibly in the gastrointestinal system. This complication was further treated with a cross femoral bypass. The occurrence of these 2 complications together is rare. PMID- 21649573 TI - Mucocele of the cystic duct remnant after orthotopic liver transplant: a problem revisited. AB - Mucocele of the cystic duct remnant is an uncommon hepatobiliary complication of a liver transplant. Current practice usually involves either excising the cystic duct, or incorporating the distal end of the transected cystic duct into the suture line of the biliary anastomosis to ensure drainage. We report a patient who developed cystic duct remnant mucocele after the latter approach was adopted. We believe that this is likely related to delayed anastomotic stricturing, which prevented draining from the remnant cystic duct. We also discuss the incidence, pathology, investigations, and treatment of this condition. PMID- 21649574 TI - Hemophagocytic lymphohistiocytosis after lung transplant: report of 2 cases and a literature review. AB - Hemophagocytic lymphohistiocytosis is a rare and often fatal disease that may occur in solid organ transplant recipients. Here, we describe 2 patients who developed hemophagocytic lymphohistiocytosis after having a lung transplant and present a review of all cases of hemophagocytic lymphohistiocytosis occurring in solid organ transplant recipients. Diagnosis of hemophagocytic lymphohistiocytosis relies on the association of clinical findings and the presence of hemophagocytosis. Clinical presentation is nonspecific and patients may present with unexplained sepsis or multiple organ failure. Management consists of treating the underlying process; but unfortunately, the prognosis is poor. PMID- 21649575 TI - SOD enzymes and their mimics in cancer: pro vs anti-odixative mode of action-part II. PMID- 21649576 TI - Phosphoinositide 3-kinase pathway inhibitors: pharmacology, metabolism & drug development. PMID- 21649577 TI - Present and future of PI3K pathway inhibition in cancer: perspectives and limitations. AB - Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival, motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over expression of PI3Ks and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I PI3Ks (alpha, beta, gamma, delta isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein, we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on potential side effects, caveats and limitations for PI3K blockade in patients. PMID- 21649579 TI - Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells. AB - Cancer stem cells (CSCs) comprise a subset of hierarchically organized, rare cancer cells with the ability to initiate cancer in xenografts of genetically modified murine models. CSCs are thought to be responsible for tumor onset, self renewal/maintenance, mutation accumulation, and metastasis. The existence of CSCs could explain the high frequency of neoplasia relapse and resistance to all of currently available therapies, including chemotherapy. The phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is a key regulator of physiological cell processes which include proliferation, differentiation, apoptosis, motility, metabolism, and autophagy. Nevertheless, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences prognosis. Several lines of evidence indicate that this signaling system plays a key role also in CSC biology. Of note, CSCs are more sensitive to pathway inhibition with small molecules when compared to healthy stem cells. This observation provides the proof-of-principle that functional differences in signaling transduction pathways between CSCs and healthy stem cells can be identified. Here, we review the evidence which links the signals deriving from the PI3K/Akt/mTOR network with CSC biology, both in hematological and solid tumors. We then highlight how therapeutic targeting of PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome, by eliminating CSCs. PMID- 21649578 TI - Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors. AB - The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer. PMID- 21649581 TI - mTOR inhibitors: facing new challenges ahead. AB - The enzyme mammalian target of rapamycin (mTOR) is a master kinase that regulates several critical intracellular processes. It is now well established that this enzyme has a key role in cancer and its inhibition as therapeutic anti-cancer strategy is well recognised. Several clinical trials using mTOR inhibitors have been and are currently being performed. A huge scientific literature exists not only reporting the results of these trials but also discussing the reasons for the limited efficacy of strategies used so far and the need for new strategies to overcome the problem of resistance. The aim of this review is mainly to reflect on how the complexity of the mTOR-dependent signalling pathway and our difficulty to untangle it can ultimately affect the development of proper strategies to fully exploit the potential benefits of mTOR inhibition as anti-cancer strategy. PMID- 21649582 TI - Serotonin receptors of type 6 (5-HT6): what can we expect from them? AB - The serotonin (5-HT) receptors of type 6 (5-HT6) are relatively new. They are quite different from all other 5-HT receptors, as they are characterized by a short third cytoplasmatic loop and a long C-terminal tail, and contain one intron located in the middle of the third cytoplasmatic loop. After some initial controversies, the available findings are now apparently more congruent. Nevertheless, discrepancies still exist, such as those in binding affinity, effects of 5-HT6 ligands on brain catecholamines and behavioral syndromes mediated by them. Much interest in 5-HT6 receptors was triggered by the evidence that some antipsychotics could bind to them. Subsequently, despite the lack of complete information on metabolic patterns of the various compounds, some of 5 HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic and anti-obese drugs. In any case, the available information on both the pharmacology of 5-HT6 receptors is still quite scant. Therefore, with the present paper we aimed at reporting a comprehensive review on the status of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists. PMID- 21649580 TI - Novel inhibitors of AKT: assessment of a different approach targeting the pleckstrin homology domain. AB - Protein kinase B/AKT plays a central role in cancer. The serine/threonine kinase is overexpressed or constitutively active in many cancers and has been validated as a therapeutic target for cancer treatment. However, targeting the kinase activity has revealed itself to be a challenge due to non-selectivity of the compounds towards other kinases. This review summarizes other approaches scientists have developed to inhibit the activity and function of AKT. They consist in targeting the pleckstrin homology (PH) domain of AKT. Indeed, upon the generation of 3-phosphorylated phosphatidylinositol phosphates (PI3Ps) by PI3 kinase (PI3K), AKT translocates from the cytosol to the plasma membrane and binds to the PI3Ps via its PH domain. Thus, several analogs of PI3Ps (PI Analogs or PIAs), alkylphospholipids (APLs), such as edelfosine or inositol phophates (IPs) have been described that inhibit the binding of the PH domain to PI3Ps. Recent allostertic inhibitors and small molecules that do not bind the kinase domain but affect the kinase activity of AKT, presumably by interacting with the PH domain, have been also identified. Finally, several drug screening studies spawned novel chemical scaffolds that bind the PH domain of AKT. Together, these approaches have been more or less sucessfull in vitro and to some extent translated in preclinical studies. Several of these new AKT PH domain inhibitors exhibit promising anti-tumor activity in mouse models and some of them show synergy with ionizing radiation and chemotherapy. Early clinical trials have started and results will attest to the validity and efficacy of such approaches in the near future. PMID- 21649583 TI - Adenosine in the inflamed gut: a Janus faced compound. AB - The purine ribonucleoside adenosine (Ado) has been recognized for its regulatory functions in situations of cellular stress like ischemia, hypoxia and inflammation. The importance of extracellular Ado as a modulator in the immune system is a theme of great appreciation and the focus of recent increasing interest in the field of gastrointestinal inflammation. In this review, the different aspects of Ado signaling during inflammatory responses in the gut are discussed, considering the contribution of the four known Ado receptors (ARs; A(1), A(2A), A(2B), and A(3)), their mechanisms and expression patterns. Activation of these receptors in epithelial cells as well as in immune cells recruited to the inflamed intestinal mucosa determines the overall effect, ranging from a protective, anti-inflammatory modulation to a strong pro inflammatory induction. Here we present the current advances in agonists and antagonists development and their potential therapeutic application studied in animal models of intestinal inflammation. In addition, alternative complementary approaches to manipulate such a complex signaling system are discussed, for example, the use of AR allosteric modulators or interference with Ado metabolism. Special features of the gut environment are taken into account: the contribution of diet components; the involvement of Ado in intestinal infections; the interactions with the gut microbiome, particularly, the recent exciting finding that an intestinal bacterium can directly produce extracellular Ado in response to host defense mechanisms in an inflammation scenario. Understanding each component of this dynamic system will broaden the possibilities for applying Ado signaling as a therapeutic target in gut inflammation. PMID- 21649585 TI - The molecular stoichiometric hydration model (SHM) as applied to tendon/collagen, globular proteins and cells. AB - This report describes and documents the presence of multiple water-of-hydration fractions on proteins and in cells. Initial studies of hydration fractions in g of water/g of DM (dry mass) for tendon/collagen led to the development of the molecular SHM (stoichiometric hydration model) and the development of methods for calculating the size of hydration fractions on a number of different proteins of known amino acid composition. The water fractions have differences in molecular motion and other physical properties due to electrostatic interactions of polar water molecules with electric fields generated by covalently bound pairs of opposite partial charge on the protein backbone. The methods allow calculation of the size of four hydration fractions: single water bridges, double water bridges, dielectric water clusters over polar-hydrophilic surfaces and water clusters over hydrophobic surfaces. These four fractions provide monolayer water coverage. The predicted SHM hydration fractions match closely measured hydration fraction values for collagen and for globular proteins. This report also presents water sorption findings that support the SHM. The SHM is applicable for cell systems where it has been studied. In seven cell systems studied, more than half of all of the cell water had properties unlike those of bulk water. The SHM predicts and explains the commonly cited and measured bound water fraction of 0.2-0.4 g of water/g of DM on proteins. The commonly accepted concept that water beyond this bound water fraction can be considered bulk-like water in its physical properties is unwarranted. PMID- 21649586 TI - Human mesenchymal stem cells protect neutrophils from serum-deprived cell death. AB - We have previously shown that human MSC (mesenchymal stem cells) inhibit the proliferation of most of the immune cells. However, there are innate immune cells such as neutrophils and other PMN (polymorphonuclear) cells that do not require an extensive proliferation prior to their effector function. In this study, the effect of MSC on neutrophils in the presence of complete and serum-deprived culture media was investigated. In the presence of MSC, the viability of neutrophils increase as measured in 24 h of incubation at various supplementation of serum concentration. We have utilized Annexin V and PI (propidium iodide) staining to confirm whether the enhancement of neutrophil's viability is due to a reduction in PCD (programmed cell death). MSC significantly rescue neutrophils from apoptosis at 1, 5 and 10% of FBS (fetal bovine serum) supplementation. The fractions of viable and dead cells were increased and decreased respectively in the presence of MSC. Our results indicate MSC rescue neutrophils from nutrient- or serum-deprived cell death. However, whether this effect is exerted through a specific signalling pathway or confining neutrophils in resting state by MSC requires further investigation. PMID- 21649584 TI - Suppression of TG-interacting factor sensitizes arsenic trioxide-induced apoptosis in human hepatocellular carcinoma cells. AB - HCC (hepatocellular carcinoma) is among the most common and lethal cancers worldwide with a poor prognosis mainly due to a high recurrence rate and chemotherapy resistance. ATO (arsenic trioxide) is a multi-target drug that has been effectively used as an anticancer drug in acute promyelocytic leukaemia. However, a Phase II trial involving patients with HCC indicates that the use of arsenic as a single agent is not effective against HCC. TGIF (TG-interacting factor) is a transcriptional co-repressor that interferes with TGF-beta (transforming growth factor-beta) signalling which plays a growth-inhibitory role in HCC. In the present study, we demonstrated that ATO induced hepatocellular apoptosis via TGF-beta/Smad signalling and led to downstream induction of p21(WAF1/CIP1) (p21). However, ATO could also induce TGIF expression via a post transcriptional regulation mechanism to antagonize this effect. Using a biotin labelled RNA probe pull-down assay and in vivo RNA immunoprecipitation analysis, we identified that HuR (human antigen R) bound to the TGIF mRNA 3'-UTR (3' untranslated region) and prevented it from degradation. ATO treatment increased the interaction between HuR and TGIF mRNA, and reduction of HuR expression inhibited ATO-induced TGIF expression. Moreover, the EGFR (epidermal growth factor receptor)/PI3K (phosphoinositide 3-kinase)/Akt pathway was shown to mediate the post-transcriptional regulation of TGIF in response to ATO. Finally, we also demonstrated that the down-regulation of TGIF could sensitize ATO-induced HepG2 cell apoptosis. Collectively, we propose that the EGFR/PI3K/Akt pathway may regulate the post-transcriptional regulation of TGIF expression to antagonize ATO induced apoptosis in HCC. Blockage of the PI3K/Akt pathway or TGIF expression combined with ATO treatment may be a promising strategy for HCC therapy. PMID- 21649587 TI - Altered signal transduction in Folr1-/- mouse embryo fibroblasts. AB - Mice lacking the gene for Folr1 (folic acid receptor 1) have an NTD (neural tube defect) that is rescued by maternal folate supplementation. Primary cultures of MEFs (mouse embryonic fibroblasts) were established from these embryos and the effect on various signalling pathways examined. TGFbeta1 (transforming growth factor beta1) inhibited the proliferation of wild-type and Folr1-/- MEFs, and folate restriction, either in growth medium or through folate uptake, led to further inhibition of growth. This effect may be Smad-independent because reporter assays using the Smad-dependent reporter, p3TP-lux, revealed attenuation of TGFbeta1/Smad signalling in Folr1-/- MEFs. Signalling through the canonical Wnt pathway, measured by Wnt-3a stimulated expression of the target gene, Axin2, demonstrated increased activity in Folr1-/- MEFs. Only minor changes in the expression of a panel of TGFbeta (transforming growth factor beta) and Wnt pathway-associated genes were revealed when Folr1-/- MEFs were compared with wild type cells. These results demonstrate that under conditions of reduced folate (Folr-/-) signalling, pathways crucial for proper development of the neural tube are significantly altered. PMID- 21649588 TI - Aberrant interaction of calmodulin with the ryanodine receptor develops hypertrophy in the neonatal cardiomyocyte. AB - We have shown previously that the inter-domain interaction between the two domains of RyR (ryanodine receptor), CaMBD [CaM (calmodulin)-binding domain] and CaMLD (CaM-like domain), activates the Ca(2+) channel, and this process is called activation-link formation [Gangopadhyay and Ikemoto (2008) Biochem. J. 411, 415 423]. Thus CaM that is bound to CaMBD is expected to interfere the activation link formation, thereby stabilizing the closed state of the channel under normal conditions. In the present paper, we report that, upon stimulation of neonatal cardiomyocytes with the pro-hypertrophy agonist ET-1 (endothelin-1), CaM dissociates from the RyR, which induces a series of intracellular events: increased frequency of Ca(2+) transients, translocation of the signalling molecules CaM, CaMKII (CaM kinase II) and the transcription factor NFAT (nuclear factor of activated T-cells) to the nucleus. These events then lead to the development of hypertrophy. Importantly, an anti-CaMBD antibody that interferes with activation-link formation prevented all of these intracellular events triggered by ET-1 and prevented the development of hypertrophy. These results indicate that the aberrant formation of the activation link between CaMBD and CaMLD of RyR is a key step in the development of hypertrophy in cultured cardiomyocytes. PMID- 21649589 TI - [Metabolic syndrome in families of patients with premature coronary heart disease: impact of 2009 Joint Interim Statement criteria]. AB - AIM: To assess effect of transition from metabolic syndrome (MS) definition of International Diabetic Federation (IDF, 2005) to definition of Joint Interim Statement (JIS, 2009) on proportion of persons with MS among patients with premature coronary heart disease (CHD) and members of their families. MATERIAL: We examined 817 members of 375 families: 353-probands with premature CHD (65.7% men, 77.6% after MI, age 23-67 years); their 212 consorts (18.9% men, 5.7% with CHD, age 28-67 years), and 252 their children (52.4% men, without overt CHD, age 16-46 years). Parameters analyzed included body mass index (BMI), waist circumference, systolic/diastolic BP, serum high density lipoprotein (HDL) cholesterol (CH), triglycerides (TG). Impaired fasting glucose (IFG) and diabetes mellitus (DM) we defined according to ADA criteria. High BP was defined as prehypertension or hypertension (NHBPEP 4 report on high BP in children/adolescents or JNC 7 criteria, depending on age). RESULTS: Portions of individuals with MS according to JIS and IDF definitions were in the whole population 335/817 (41.0%) and 305/817 (37.3%), among probands 62.9% and 56.1%, consorts 37.3% and 36.8%, adult children 13.5% and 11.5%, respectively. All 305 persons with IDF MS satisfied JIS definition but JIS criteria identified MS in 30 more persons (25 with CHD). They were predominantly men (22/30), not obese (BMI range 19.1-29.1; median 25.5 kg/m2), with 3-4 AHA/NHLBI (2005) MS components, most had low HDL-CH (27); high TG (26), high BP (24), 14 persons had IFG, 5 - DM. CONCLUSION: In this heterogeneous population the use of JIS definition resulted in diagnosis of MS in small additional portion (9%) of persons with obvious high risk already requiring interventions because of CHD and/or level of CHD risk factors. PMID- 21649590 TI - [Pleiotropic effects of nicotinic acid therapy in men with coronary heart disease and elevated lipoprotein(a) levels]. AB - PURPOSE: To assess effects of niacin on risk factors of atherosclerosis in men with coronary heart disease (CHD) and high lipoprotein(a) [Lp(a)] levels. MATERIAL AND METHODS: Sixty men (mean age 54+/-6 years) with angiographic evidence of CHD were randomized into two groups. Active group (n=30) received extended release nicotinic acid 1500 mg, control group consisted of remaining 30 patients. All patients received basic therapy with atorvastatin 10-40 mg qd. Blood samples were collected for total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), Lp(a), lipoprotein-associated phospholipase A2 (Lp-PL-2), high-sensitivity C-reactive protein (hsCRP), complex of tissue-type plasminogen activator with plasminogen activator inhibitor type 1 (tPA/PAI-1). Carotid intima media thickness (CIMT) was measured at baseline and after 6-months therapy. RESULTS: There was no statistically significant difference between the groups in the clinical and biochemical characteristics. During the study lipid profile data were within the target levels. In the active group median percent decrease of Lp(a) level was 23% (from 84+/-40 to 67+/-25 mg/dl after 6 weeks and up to 65+/-37 mg/dl after 6 months of treatment, p<0.01); LDL-C, TG, tPA/PAI-1, and Lp-PL-2 mass levels decreased by 25, 20, 25, and 32%, respectively; HDL-C increased by 16% (p<0.05 vs baseline, respectively). Nicotinic acid treatment produced statistically significant reduction nicotinic acid of the mean CIMT (right: 0.83+/-0.16 vs 0.77+/-0.17 mm, p<0.05; left: 0.88+/ 0.21 vs 0.82+/-0.17, p<0.05). In control group no changes of CIMT or blood tests were observed. CONCLUSION: In men with CHD and Lp(a) excess of addition to atorvastatin results in regression of CIMT on an average of 0.06 mm in 6 months. Such rapid and significant effect on the arterial wall structure can be attributed to the complex influence of nicotinic acid on Lp(a), lipids, Lp-PL-2 and thrombogenic factors. This is the first study providing the evidence of using Lp(a) as one of therapeutic targets in patients with high Lp(a) levels for achieving beneficial effect on a surrogate marker of atherosclerosis. PMID- 21649591 TI - [Polymorphism of connexin 40 gene-- a novel genetic marker of the sick sinus node syndrome]. AB - In this work we have demonstrated for the first time on the clinico-genetic material association between hereditary sick sinus node syndrome and connexin 40 gene polymorphism. We have revealed that heterozygous variant of connexin 40 gene variant is more frequent among patients with sick sinus node syndrome and their healthy relatives than in persons of control group. PMID- 21649592 TI - [Analysis of causes of development of anemia in patients with chronic heart failure]. AB - High prevalence of anemia and its direct relation with morbidity and mortality in congestive heart failure (CHF) has been shown in numerous studies. Among etiology factors of anemia are hemodilution, chronic kidney insufficiency, deficiency of iron, folate, and vitamin 12, high level of inflammatory cytokines. Aims of this study were elucidation of causes of anemia in patients with CHF and assessment of dependence of prognosis of these patients on etiology of anemia. We examined 317 patients hospitalized with diagnosis of NYHA class II-IVCHF and anemia (129, [40.7%] men and 188 [59.3%] women, mean age 74.4+/-1.75 years, duration of CHF 4.4+/-0.2 years; 46, 42, 12% with NYHA class IV, III and II, respectively). Causes of anemia were chronic kidney insufficiency, iron deficiency, vitamin B12 deficiency, hemodilution, and chronic diseases. Glomerular filtration rate (GFR) below 50 ml/min was found in 27 patients (8.5%), deficiency of iron with lowered ferritin concentration and/or saturation of transferrin was revealed in 104 (32.8 %), vitamin B12-deficiency in 4 (1.3%), hemodilution in 40 (12.6%) patients. In 142 patients (44.8%) anemia was associated with chronic diseases. Hospital mortality in the whole group was 18.3%. Death rates in patients with hemodilution, chronic kidney insufficiency, vitamin B12-deficiency, anemia due to chronic diseases, and iron deficiency anemia were 32.5, 25.9, 25, 16.2 and 13.5%. PMID- 21649593 TI - [The use of screening methods in diagnosis of disturbances of respiration during sleep in patients with cardiac pathology]. AB - Disturbances of respiration during sleep especially those of obstructive character are sufficiently widespread phenomena. In addition to worsening of the quality of sleep itself they facilitate formation and development of concomitant pathology of cardiovascular system, endocrine system, cognitive sphere. This results in lowering of quality of life and its duration. At present standard method of diagnosis of disturbances of respiration during sleep is polysomnographical examination. At the same time more accessible screening methods are also actively used with the aim of detection of subjects with high probability of respiratory disturbances during sleep. Among them cardiorespiratory monitoring, nocturnal pulsoximetry, registration of oro-nasal flow during sleep, are questionnaires most widely-spread. PMID- 21649594 TI - [Systematic analysis of molecular mechanisms of action of omega-3 polyunsaturated fatty acids on arrhythmia]. AB - Safe pharmacotherapy and prevention of arrhythmia is an urgent problem of modern cardiology. Essential micronutrients such as omega-3 polyunsaturated fatty acids (-3 PUF-) significantly contribute to the metabolic processes in cardiomyocytes and cardiac conduction system. This article presents a systematic analysis of anti-arrhythmic effects of omega-3 PUFA and of standardized ethyl esters of omega 3 PUFA. The currently available data indicate two fundamentally different molecular mechanisms of anti-arrhythmic effects: "slow" and "fast" types. Formulation of fundamental prospects of bioinformatic studies of molecular effects of anti-arrhythmic action of omega-3 PUF-s is presented. PMID- 21649595 TI - [Diagnosis, sudden death risk stratification, and treatment of main long QT syndrome molecular-genetic variants]. AB - Inherited long QT syndrome (LQTS) refers to the primary electrical diseases of the heart. It is characterized by QT prolongation on resting ECG and syncope due to life-threatening ventricular arrhythmias. This review focuses on diagnosis, differential diagnosis, risk stratification of sudden cardiac death, and treatment strategy of patients with most prevalent genetic fOrms of LQTS - LQT1, LQT2 and LQT3, which accounted for about 90% of all genetically confirmed cases. Recent advances in understanding of relationship between clinical, electrocardiographic features (on ECG, body surface mapping, stress test) and genetic variants of LQT presented. Characteristics of syncopal events and ECG features of LQTl, LQT2 and LQT3 in the majority of cases are helpful to make an appropriate choice for therapy, even before positive result of molecular genetic testing. Management has focused on the use of beta blockers as first-line treatment and exclusion of triggers of life-threatening arrhythmia which are specific for each molecular-genetic variant. Implantation of cardioverter defibrillator for secondary prevention of sudden death in the high-risk patients or patients with insufficient effect of antiarrhythmic therapy is required. PMID- 21649596 TI - [Drug prevention of pulmonary embolism in orthopedic practice: traditional and novel approaches]. AB - We consider in this review traditional and novel approaches to drug prevention of pulmonary embolism (PE) which in predominant number of cases is related to deep vein thrombosis of lower extremities. Risk of PE development is especially high in patients after orthopedic hip or knee surgery. Modern recommendations contemplate use of unfractionated and low molecular weight heparins, vitamin K antagonists (warfarin in the first place), fondaparinux. Oral direct anticoagulants related to selective inhibitors of blood coagulation factors IIa (thrombin) and Xa have appeared recently and proved their preventive efficacy and safety in randomized controlled studies. Preventive efficacy and safety of dabigatran among direct selective factor IIa (thrombin) inhibitors and of rivaroxaban, apixaban, and edoxaban among direct selective factor IIa inhibitors have been studied best. PMID- 21649597 TI - [Efficacy and safety of hormone replacement therapy with levothyroxine in patients with subclinical hypothyroidism and heart failure]. PMID- 21649598 TI - [The use of natural phytosterins for correction of abnormalities of lipid metabolism]. PMID- 21649599 TI - [Allegations that sartans cause cancerogenic effects in cardiological patients are unfounded]. PMID- 21649600 TI - [From results of BEAUTIFUL trial to results of SHIFT trial: BEAUTIFUL possibility to make a SHIFT in current guidelines]. AB - The article is devoted to results of randomized clinical trails BEAUTIFUL and SHIFT. Position of If-inhibitor ivabradine in current guidelines on management of patients with stable angina and heart failure is discussed. PMID- 21649601 TI - [Noncompaction myocardium]. PMID- 21649602 TI - Chronic inflammatory demyelinating polyneuropathy and ventilatory failure: report of seven new cases and review of the literature. AB - BACKGROUND: Ventilatory involvement is rarely reported in chronic inflammatory demyelinating polyneuropathy (CIDP), but small prospective studies showed frequent involvement of phrenic nerves, which is usually overshadowed by severe limb weakness. OBJECTIVES: To report the clinical features of CIDP associated with ventilatory failure. RESULTS: There were seven patients (43% women), with a mean age of 58.6 (range 38-82). The clinical courses were relapsing in five and progressive in two. Four patients had an initial event simulating Guillain-Barre syndrome (GBS). Ventilatory failure was recurrent in three patients. Five patients had full or nearly complete recoveries; one still requires nocturnal ventilation; and one died (14%) of myocardial infarction while still requiring mechanical ventilation. CONCLUSIONS: Clinical ventilatory dysfunction in CIDP is usually not an indicator of poor prognosis, and many patients recover without significant permanent disability. The mortality rate is similar to intubated patients with GBS. Patients with cardiopulmonary comorbidities and acute GBS-like onset of CIDP may be at higher risk of ventilatory failure which typically responds to 'standard' treatments of CIDP. Larger prospective studies are needed to define the prevalence, clinical spectrum and significance of ventilatory involvement in CIDP and to establish guidelines for evaluation and treatment. PMID- 21649603 TI - Multiple sclerosis in the Faroe Islands: a core context for neuroanthropology. PMID- 21649605 TI - Exploring sexual problems among patients with multiple sclerosis. PMID- 21649607 TI - White matter disorders with autosomal dominant heredity. PMID- 21649609 TI - The gender gap in stroke: a meta-analysis. AB - Several studies have indicated that gender differences might exist in stroke. OBJECTIVES AND METHODS: Our goal was to perform a comprehensive meta-analysis in order to evaluate and quantify stroke gender disparities through a systematic search of relevant articles published up to October 2009 and addressing gender related differences in ischemic stroke risk factors, stroke subtype and severity, diagnostic tests, and acute phase and secondary prevention treatments. RESULTS: Forty-five articles were included in the analysis, representing a total of 673,935 patients. Women were globally older than men (+5.2 years) and suffered more hypertension (P = 0.017) and atrial fibrillation (P < 0.001), although they were less likely to drink alcohol (P < 0.001), smoke cigarettes (P < 0.001), present hyperlipidemia (P = 0.033) or diabetes (P = 0.003) than men. Baseline stroke severity was not different between genders. Women suffered more cardioembolic strokes, while men had more atherothrombotic strokes. Moreover, women were less likely to receive stroke-related treatments, such as antiplatelets (P < 0.001), statins (P < 0.001), and tPA (P < 0.001) than men. Although meta-regression did not identify age or stroke etiology as sources of heterogeneity, caution should be taken as that analysis was possible only for gender differences in secondary prevention with antiplatelets because of limited data for other end points. CONCLUSIONS: Gender differences have been identified on the risk factors profile and diagnostic and therapeutic management of patients with ischemic stroke. Active measures should thus be taken to avoid bias in clinical practice. PMID- 21649610 TI - Effects of high-dose paracetamol on blood pressure in acute stroke. AB - BACKGROUND: Early administration of paracetamol may improve outcome of patients with acute stroke and a baseline body temperature of 37 degrees C or above by lowering body temperature and preventing fever. Besides its antipyretic effects, paracetamol may affect blood pressure through cyclooxygenase-2 inhibition. We therefore aimed to assess the effect of high-dose paracetamol on blood pressure in patients with acute stroke. METHODS: We analyzed data of 540 patients admitted within 24 h of stroke onset who were randomized to treatment with either paracetamol (6 g daily) or placebo. Blood pressures were measured at 12, 24, and 48 h from the start of treatment. Changes in blood pressure from baseline in the two treatment groups and corresponding 95% confidence intervals (CI) were calculated with linear regression analysis. Adjustments for potential confounders were made with a multiple linear regression model. RESULTS: Treatment with high dose paracetamol was associated with a significant reduction in systolic blood pressure of 4.5 mm Hg (95% CI 0.6-8.5) at 12 h from the start of treatment. This effect was no longer present after 24 and 48 h. CONCLUSION: High-dose paracetamol reduces not only body temperature but also systolic blood pressure in the first 12 h after start of treatment. Both effects may improve functional outcome after stroke, but this needs further study. PMID- 21649611 TI - Frequency and severity of headache is worsened by Interferon-beta therapy in patients with multiple sclerosis. AB - BACKGROUND: The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon-beta (IFNbeta) could induce or worsen HA. OBJECTIVE: To evaluate the impact of IFNbeta treatment on HA and the relationship between HA and the various commercial preparations of IFNbeta in mildly disabled patients with MS. METHODS: A specific questionnaire was administered to 357 relapsing-remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNbeta administration. RESULTS: One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNbeta-1a (Avonex((r))), 84 with subcutaneous injections of IFNbeta-1b (Betaferon((r))) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNbeta-1a (Rebif((r))) 22 mcg or IFNbeta-1a (Rebif((r))) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNbeta therapy; this was more frequently reported by patients treated with Avonex((r)) and Rebif((r)) 44. Ninety-five patients experienced new HA. CONCLUSION: IFNbeta treatment could worsen HA in patients with pre-existing HA or cause the appearance of new HA. Among different IFNbeta preparations, Rebif((r)) 44 and Avonex((r)) seemed to be more cephalalgic than the other drugs. PMID- 21649612 TI - Tetracycline treatment in patients with progressive external ophthalmoplegia. AB - BACKGROUND: Tetracyclines could have neuroprotective effects in neuromuscular and neurodegenerative disorders. AIMS OF THE STUDY AND METHODS: Objective of this double-blind randomized pilot study (followed by an adjunctive open-label phase) was to evaluate whether tetracycline (500 mg/day * 14 days/month * 3 months) could be useful in patients (n = 16) with progressive external ophthalmoplegia (PEO). RESULTS: Our results do not formally support any effect of tetracycline on eye motility in PEO. However, some possible protective effects could not be completely ruled out, i.e. a further analysis suggests a possible difference between the tetracycline group and the placebo group, significant at least for oblique motility, when comparing the ratio between the end of the double-blind phase and baseline. Tetracycline could modify some oxidative stress biomarkers in patients with PEO. CONCLUSIONS: Further studies are needed to confirm such effects of tetracycline in patients with PEO, if any, and to clarify the mechanisms of action for antioxidant effects of tetracyclines in mitochondrial disorders and other diseases. PMID- 21649613 TI - Apolipoprotein genotype for prediction of Alzheimer's disease in older Japanese: the Hisayama Study. AB - OBJECTIVES: To estimate the effects of the apolipoprotein E (APOE)-E4 allele on the development of dementia and to elucidate its usefulness in the risk prediction of dementia in Japanese. DESIGN: Prospective cohort study. SETTING: The Hisayama Study, in Japan. PARTICIPANTS: Five hundred twenty-three participants with deoxyribonucleic acid samples from a population of 1,073 community-dwelling participants without dementia aged 60 to 79. MEASUREMENTS: The risk estimates of the APOE-E4 allele on the development of all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). RESULTS: During 17 years of follow-up, 136 participants developed dementia, 81 of whom had AD and 39 VaD. After adjusting for age, sex, education, smoking, alcohol intake, systolic blood pressure, use of antihypertensive agents, glycosylated hemoglobin, serum total cholesterol, body mass index, and regular exercise, the risks of all-cause dementia and AD were significantly higher in APOE-E4 carriers than in noncarriers, but no such association was observed for VaD (all-cause dementia: hazard ratio (HR)=1.81, P=.004; AD: HR=3.42, P<.001; VaD: HR=1.08, P=.86). The area under the receiver operating characteristic curve was significantly greater when the APOE genotype was incorporated into a model with potential risk factors for AD (0.74 vs 0.68, P=.02). Other measures of model discrimination (net reclassification improvement: 0.18, P=.01; integrated discrimination improvement: 6.25, P<.001) also confirmed this improvement in AD risk assessment. CONCLUSION: The APOE-E4 allele is a risk factor for AD in the Japanese population. Information on APOE genotype improves AD risk assessment substantially beyond a model based on potential risk factors. PMID- 21649614 TI - Exposure to trauma and posttraumatic stress disorder symptoms in older veterans attending primary care: comorbid conditions and self-rated health status. AB - OBJECTIVES: Assess the prevalence of posttraumatic stress disorder (PTSD) symptomatology and its association with health characteristics in a geriatric primary care population. DESIGN: Cross-sectional screening assessments during a multisite trial for the treatment of depression, anxiety, and at-risk drinking. SETTING: Department of Veterans Affairs (VA)-based primary care clinics across the United States. PARTICIPANTS: Seventeen thousand two hundred five veterans aged 65 and older. MEASUREMENTS: Sociodemographic information, the General Health Questionnaire (GHQ-12), questions about death wishes and suicidal ideation, quantity and frequency of alcohol use, smoking, exposure to traumatic events, and PTSD symptom clusters. RESULTS: Twelve percent (2,041/17,205) of participants screened endorsed PTSD symptoms. Veterans with PTSD symptoms from some (partial PTSD) or each (PTSD all clusters) of the symptom clusters were significantly more likely to report poor general health, currently smoke, be divorced, report little or no social support, and have a higher prevalence of mental distress, death wishes, and suicidal ideation than those with no trauma history or those with trauma but no symptoms. Group differences were most pronounced for mental distress and least for at-risk drinking. Presence of PTSD all clusters was associated with poorer outcomes on all of the above-mentioned health characteristics than partial PTSD. CONCLUSION: PTSD symptoms are common in a substantial minority of older veterans in primary care, and careful inquiry about these symptoms is important for comprehensive assessment in geriatric populations. PMID- 21649615 TI - The nonlinear relationship between gait speed and falls: the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly of Boston Study. AB - OBJECTIVES: To examine the relationship between gait speed and falls risk. DESIGN: Longitudinal analysis of the association between gait speed and subsequent falls and analysis of gait speed decline as a predictor of future falls. SETTING: Population-based cohort study. PARTICIPANTS: Seven hundred sixty three community-dwelling older adults underwent baseline assessments and were followed for falls; 600 completed an 18-month follow-up assessment to determine change in gait speed and were followed for subsequent falls. MEASUREMENTS: Gait speed was measured during a 4-m walk, falls data were collected from monthly post card calendars, and covariates were collected from in-home and clinic visits. RESULTS: There was a U-shaped relationship between gait speed and falls, with participants with faster (>=1.3 m/s, incident rate ratio (IRR)=2.12, 95% confidence interval (CI)=1.48-3.04) and slower (<0.6 m/s, IRR=1.60, 95% CI=1.06 2.42) gait speeds at higher risk than those with normal gait speeds (1.0-<1.3 m/s). In adjusted analyses, slower gait speeds were associated with greater risk of indoor falls (<0.6 m/s, IRR=2.17, 95% CI=1.33-3.55; 0.6-<1.0 m/s, IRR=1.45, 95% CI=1.08-1.94), and faster gait speed was associated with greater risk of outdoor falls (IRR=2.11, 95% CI=1.40-3.16). A gait speed decline of more than 0.15 m/s per year predicted greater risk of all falls (IRR=1.86, 95% CI=1.15 3.01). CONCLUSION: There is a nonlinear relationship between gait speed and falls, with a greater risk of outdoor falls in fast walkers and a greater risk of indoor falls in slow walkers. PMID- 21649617 TI - Effect of dehydroepiandrosterone on muscle strength and physical function in older adults: a systematic review. AB - OBJECTIVES: To evaluate studies that have assessed the effect of dehydroepiandrosterone (DHEA) supplementation on body composition and physical performance in older adults. DESIGN: A systematic review of the medical literature identified from searches of databases, reference lists, and recent conference proceedings with qualitative assessment of the desired end points. SETTING: Not applicable. PARTICIPANTS: Adults aged 50 and older. INTERVENTIONS: Oral DHEA supplement with or without concomitant exercise. MEASUREMENTS: Muscle strength, physical function, and physical performance. RESULTS: Of the 155 eligible studies, eight (n=661 participants) met inclusion criteria. The studies differed in their included populations, duration of follow-up, and interventions (e.g., exercise). Seven studies examined measures of muscle strength. One study showed improvement in handgrip strength, one showed improvement in chest press, two showed improvement in leg press, and one showed improvement in knee extension and flexion. Nevertheless, similar numbers of studies had negative results for each of these endpoints. Five studies examined measures of physical function and performance. Only one study showed improvement in a composite score measuring physical performance; the rest reported no differences between DHEA and control for any end point. CONCLUSION: Overall, the benefit of DHEA on muscle strength and physical function in older adults remains inconclusive. Some measures of muscle strength may improve, although consensus was not reached. DHEA does not appear to routinely benefit measures of physical function or performance. Further large clinical trials are necessary to better identify the clinical role of DHEA supplementation in this population. PMID- 21649618 TI - Characterizing predictive models of mortality for older adults and their validation for use in clinical practice. AB - OBJECTIVES: To systematically identify and characterize prognostic models of mortality for older adults, their reported potential use, and the actual level of their (external) validity. DESIGN: The Scopus database until January 2010 was searched for articles that developed and validated new models or validated existing prognostic models of mortality or survival in older adults. SETTING: All domains of health care. PARTICIPANTS: Adults aged 50 and older. MEASUREMENTS: Study and model characteristics were summarized, including the model's development method and degree of validation, data types used, and outcomes. RESULTS: One hundred three articles describing 193 models in 10 domains and mostly originating from the United States were included. These domains were mostly secondary or tertiary care settings (54%) such as intensive care (7%) or geriatric units (8%). Half of the studies (50%) were not disease specific. Heart failure-related diseases (9%) and pneumonia (9%) constituted the major disease specific subgroups. Most studies (67%) reported support of clinical individual (treatment) decisions as use of prognostic models, but only 34% were externally validated, and only four models (2%) were validated in more than two studies. Most studies (68%) developed at least one new model, but they did not often go beyond addressing their apparent validation (49%). CONCLUSION: Although prognostic models are regularly developed to support clinical individual decisions and could be useful for this purpose, their use is premature. Because clinical credibility and evidence of external validity build trust in prognostic models, both require much more consideration to enhance model acceptance in the future. PMID- 21649616 TI - A clinical index to stratify hospitalized older adults according to risk for new onset disability. AB - BACKGROUND: Many older adults who are independent prior to hospitalization develop a new disability by hospital discharge. Early risk stratification for new onset disability may improve care. Thus, this study's objective was to develop and validate a clinical index to determine, at admission, risk for new-onset disability among older, hospitalized adults at discharge. DESIGN: Data analyses derived from two prospective studies. SETTING: Two teaching hospitals in Ohio. PARTICIPANTS: Eight hundred eighty-five patients aged 70 years and older were discharged from a general medical service at a tertiary care hospital (mean age 78, 59% female) and 753 patients discharged from a separate community teaching hospital (mean age 79, 63% female). All participants reported being independent in five activities of daily living (ADLs: bathing, dressing, transferring, toileting, and eating) 2 weeks before admission. MEASUREMENTS: New-onset disability, defined as a new need for personal assistance in one or more ADLs at discharge in participants who were independent 2 weeks before hospital admission. RESULTS: Seven independent risk factors known on admission were identified and weighted using logistic regression: age (80-89, 1 point; >=90, 2 points); dependence in three or more instrumental ADLs at baseline (2 points); impaired mobility at baseline (unable to run, 1 point; unable to climb stairs, 2 points); dependence in ADLs at admission (2-3 ADLs, 1 point; 4-5 ADLs, 3 points); acute stroke or metastatic cancer (2 points); severe cognitive impairment (1 point); and albumin less than 3.0 g/dL (2 points). New-onset disability occurred in 6%, 13%, 18%, 34%, 35%, 45%, 50%, and 87% of participants with 0, 1, 2, 3, 4, 5, 6, and 7 or more points, respectively, in the derivation cohort (area under the receiver operating characteristic curve (AUC)=0.784), and in 8%, 10%, 27%, 38%, 44%, 45%, 58%, and 83%, respectively, in the validation cohort (AUC=0.784). The risk score also predicted (P<.001) disability severity, nursing home placement, and long-term survival. CONCLUSION: This clinical index determines risk for new onset disability in hospitalized older adults and may inform clinical care. PMID- 21649619 TI - Agreement between older persons and their surrogate decision-makers regarding participation in advance care planning. AB - OBJECTIVES: To examine agreement between older persons and their surrogates regarding participation in advance care planning (ACP). DESIGN: Observational cohort study. SETTING: Community. PARTICIPANTS: Persons aged 65 and older and the individual they identified as most likely to make treatment decisions on their behalf. MEASUREMENTS: Older persons were asked about participation in four activities: completion of living will, completion of healthcare proxy, communication regarding views about life-sustaining treatment, and communication regarding views about quality versus quantity of life. Surrogates were asked whether they believed the older person had completed these activities. RESULTS: Of 216 pairs, 81% agreed about whether a living will had been completed (kappa=0.61, 95% confidence interval (CI) 0.51-0.72). Only 68% of pairs agreed about whether a healthcare proxy had been completed (kappa=0.39, 95% CI 0.29 0.50), 64% agreed about whether they had communicated regarding life-sustaining treatment (kappa=0.22, 95% CI 0.09-0.35), and 62% agreed about whether they had communicated regarding quality versus quantity of life (kappa=0.23, 95% CI 0.11 0.35). CONCLUSION: Although agreement between older persons and their surrogates regarding living will completion was good, agreement about participation in other aspects of ACP was fair to poor. Additional study is necessary to determine who is providing the most accurate report of objective ACP components and whether agreement regarding participation in ACP is associated with greater shared understanding of patient preferences. PMID- 21649620 TI - In-hospital use of continence aids and new-onset urinary incontinence in adults aged 70 and older. AB - OBJECTIVES: To describe the types of continence aids that older adults hospitalized in acute medical units use and to test the association between use of continence aids and development of new urinary incontinence (UI) at discharge. DESIGN: Prospective cohort study. SETTING: A 900-bed teaching hospital in Israel. PARTICIPANTS: Three hundred fifty-two acute medical patients aged 70 and older who were continent before admission. MEASUREMENTS: In-hospital use of continence aids was assessed according to participant self-report on use of urinary catheters (UCs) or adult diapers or of self-toileting. The development of new UI was defined as participant report of inability to control voiding at discharge. Multivariate analyses modeled the association between use of continence aids (vs self-toileting) and the development of new UI, controlling for baseline functional and cognitive status, disease severity, age, and length of stay. RESULTS: Of the 352 participants, 58 (16.5%) used adult diapers, and 27 (7.7%) had a UC during most of the hospital stay. Sixty (17.1%) participants developed new UI at discharge. The odds of developing new UI were 4.26 (95% confidence interval (CI)=1.53-11.83) times higher for UC users and 2.62 (95% CI=1.17-5.87) times higher for adult diaper users than for the self-toileting group, controlling for the above risk factors. CONCLUSION: The use of adult diapers and UCs during acute hospitalization is associated with the development of new UI at discharge. The management of continence in hospitalized older adults requires more diligence, and further investigation is needed to devise continence promotion methods in hospital settings. PMID- 21649621 TI - Advance directives for euthanasia in dementia: how do they affect resident care in Dutch nursing homes? Experiences of physicians and relatives. AB - OBJECTIVES: To gain insight into how advance directives for euthanasia affect resident care in Dutch nursing homes. DESIGN: Survey of elderly care physicians and additional qualitative interviews with a selection of elderly care physicians and relatives of people with dementia who had an advance directive for euthanasia. SETTING: Dutch nursing home practice. PARTICIPANTS: Four hundred thirty-four elderly care physicians completed the general part of the questionnaire; 110 physicians provided case histories. Interviews were conducted with 11 physicians and eight relatives. MEASUREMENTS: The questionnaire contained general questions about the incidence of advance directives for euthanasia in people with dementia. A second part involved questions about the most recent case of a person with dementia and an advance directive for euthanasia who had died. The interviews with elderly care physicians and relatives focused on further exploration of the decision-making process regarding adherence to the advance directive for euthanasia. RESULTS: Despite law-based possibilities, advance directives for euthanasia of people with dementia were rarely adhered to, although they seem to have a supportive role in setting limitations on life sustaining treatments. Elderly care physicians and relatives were found to be reluctant to adhere to advance directives for euthanasia. Not being able to engage in meaningful communication played a crucial role in this reluctance. CONCLUSION: Advance directives for euthanasia are never adhered to in the Netherlands in the case of people with advanced dementia, and their role in advance care planning and end-of-life care of people with advanced dementia is limited. Communication with the patient is essential for elderly care physicians to consider adherence to an advance directive for euthanasia of a person with dementia. PMID- 21649622 TI - Improving disposition outcomes for patients in a geriatric skilled nursing facility. AB - OBJECTIVES: To evaluate an intervention to improve discharge disposition from a skilled nursing unit (SNU). DESIGN: Historical control comparison of discharge disposition before and after implementation. SETTING: Fifty-bed SNU. PARTICIPANTS: All patients admitted from acute care hospitals to a SNU between June 2008 and May 2010. INTERVENTION: Physician admission procedures were standardized using a template, patients with three or more hospital admissions over the prior 6 months received palliative care consultations, and multidisciplinary root-cause analysis conferences for patients transferred back to the hospital acutely were conducted bimonthly to identify problems and improve processes of care. MEASUREMENTS: Patients' discharge disposition (i.e., acute care, long-term care, home, or death) before and after implementation were compared. RESULTS: Discharge dispositions were determined for all 1,725 patients admitted during the study; 862 patients before (June-May 2008) and 863 during (June 2009-May 2010) the intervention. Discharge dispositions were significantly differently distributed across the two periods (P=.03). Readmission to acute care declined (from 16.5% to 13.3%, a nearly 20% decline). Multivariable logistic regression, controlling for age, sex, and case-mix index and adjusting for clustering due to repeated admissions of individual patients, suggests that, during the intervention period, patients were more likely than during the baseline period to die on the unit in accordance with their wishes than to be transferred out to the hospital (odds ratio=2.45, 95% confidence interval=1.09 5.5). CONCLUSION: Interventions such as the ones implemented can lead to fewer hospital transfers for SNUs. PMID- 21649623 TI - Effect of a pharmacist-led multicomponent intervention focusing on the medication monitoring phase to prevent potential adverse drug events in nursing homes. AB - OBJECTIVES: To determine the extent to which the use of a clinical informatics tool that implements prospective monitoring plans reduces the incidence of potential delirium, falls, hospitalizations potentially due to adverse drug events, and mortality. DESIGN: Randomized cluster trial. SETTING: Twenty-five nursing homes serviced by two long-term care pharmacies. PARTICIPANTS: Residents living in nursing homes during 2003 (1,711 in 12 intervention; 1,491 in 13 usual care) and 2004 (1,769 in 12 intervention; 1,552 in 13 usual care). INTERVENTION: The pharmacy automatically generated Geriatric Risk Assessment MedGuide (GRAM) reports and automated monitoring plans for falls and delirium within 24 hours of admission or as part of the normal time frame of federally mandated drug regimen review. MEASUREMENTS: Incidence of potential delirium, falls, hospitalizations potentially due to adverse drug events, and mortality. RESULTS: GRAM triggered monitoring plans for 491 residents. Newly admitted residents in the intervention homes experienced a lower rate of potential delirium onset than those in usual care homes (adjusted hazard ratio (HR)=0.42, 95% confidence interval (CI)=0.35 0.52), overall hospitalization (adjusted HR=0.89, 95% CI=0.72-1.09), and mortality (adjusted HR=0.88, 95% CI=0.66-1.16). In longer stay residents, the effects of the intervention were attenuated, and all estimates included unity. CONCLUSION: Using health information technology in long-term care pharmacies to identify residents who might benefit from the implementation of prospective medication monitoring care plans when complex medication regimens carry potential risks for falls and delirium may reduce adverse effects associated with appropriate medication use. PMID- 21649624 TI - Does excess body fat maintained after the seventh decade decrease life expectancy? AB - OBJECTIVES: To determine whether the attenuation in risk of death due to excess body fat seen in most studies of older adults may be due to confounding, the relationship between adiposity and mortality was examined in adults who never smoked, were free of major chronic diseases, and maintained stable weight over long periods. DESIGN: Prospective cohort study. SETTING: The Adventist Health Study and Adventist Mortality Study in California. PARTICIPANTS: Six thousand thirty adults aged 25 to 82 who had never smoked and had no history of coronary heart disease, cancer, or stroke. MEASUREMENTS: During 29 years of follow-up, anthropometric data were collected at baseline and 17 years later, and mortality surveillance continued for 12 years thereafter. Data were analyzed using survival analysis with attained age as the time variable. RESULTS: Instantaneous hazard plots indicated that men with a body mass index (BMI) greater than 22.3 kg/m2 and women with a BMI greater than 27.4 kg/m2 had a greater mortality risk through the ninth decade than those with lower BMI. For men aged 75 to 99 who maintained stable body weight, a BMI greater than 22.3 kg/m2 was associated with a 3.7-year (95% confidence interval (CI)=1.1-6.3) shorter life expectancy and significantly greater mortality (hazard ratio (HR)=1.88, 95% CI=1.16-3.04, for BMI=22.3-27.3 kg/m2; HR=2.00, 95% CI=1.01-3.97 for BMI>27.3 kg/m2; reference, BMI<=22.3 kg/m2). For women aged 75 to 99 who maintained stable body weight, a BMI greater than 27.4 kg/m2 was associated with a 2.1-year (95% CI=0.5-3.8) shorter life expectancy and significantly greater mortality (HR=1.12, 95% CI=0.80-1.58 for BMI<20.6 kg/m2; HR=1.41, 95% CI=1.05-1.89 for BMI>27.4 kg/m2; reference, BMI 20.6 27.4 kg/m2). CONCLUSION: Excess body fat maintained after the seventh decade decreases life expectancy but appears to be less lethal in women. PMID- 21649625 TI - Racial and ethnic group variations in service use in a national sample of Medicare home health care patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus is known to affect adults in racial and ethnic minority groups disproportionately. When diabetes mellitus-related symptoms lead to the need for skilled care in the community-dwelling Medicare population, physicians can order the Medicare home health care (HHC) benefit, and Medicare-certified home health agencies can deliver it. Little is known about the extent to which racial and ethnic disparities exist in types and patterns of HHC services delivered to Medicare beneficiaries with diabetes mellitus when they are approved for the Medicare HHC benefit. This was examined by comparing racial and ethnic groups in terms of measures of HHC service use in a nationally representative sample of Medicare HHC beneficiaries with a primary diagnosis of type 2 diabetes mellitus. Uniform clinical data from the Outcome and Assessment Information Set were linked with Medicare HHC claims for beneficiaries who received a complete episode of HHC in 2002. In the study sample (n=9,838), 62% of participants self identified as white, 22% African American, 12% Hispanic, and 3% Asian. Nearly all (99%) participants in all racial and ethnic groups received skilled nursing services. Controlling for numerous sociodemographic and health-related covariates and geographic region of the country, African-American participants received fewer nurse visits per week and fewer visits per week from all clinical disciplines combined than whites (both P<.001), and Hispanic participants were less likely than whites to receive physical therapy (adjusted odds ratio (AOR)=0.640, 95% confidence interval (CI)=0.543-0.754, P<.001) or home health aide (AOR=0.716, 95% CI=0.582-0.880, P=.002) services. Lower use of skilled nursing and rehabilitation services by African Americans and of rehabilitation services by Hispanics warrant further clinical and research attention. PMID- 21649626 TI - Multidimensional risk assessment for tooth loss in a geriatric population with diverse medical and dental backgrounds. AB - OBJECTIVES: To introduce a multidimensional approach to assess risk of tooth loss for older adults with diverse medical and dental backgrounds. DESIGN: Retrospective longitudinal study. SETTING: Community-based geriatric dental clinic in Minnesota. PARTICIPANTS: Four hundred ninety-one older adults who presented to the studied clinic as new patients between October 1999 and December 2006, remained dentate after finishing the initial treatment plan, and returned for care at least once thereafter were selected as participants. INTERVENTION: All existing dental conditions were treated before enrollment. Comprehensive dental care was continually provided for all participants during follow-up. MEASUREMENTS: Demographic information, together with medical, dental, functional, and cognitive assessment at arrival, was abstracted from dental records. Logistic, Cox, Poisson, and negative-binomial regressions were developed to assess risk of tooth loss from four dimensions: likelihood of tooth loss, time to first tooth loss, and frequency and rate of tooth loss per person-year. RESULTS: Although the traditional single-dimensional risk assessment approach indicated that number of teeth being carious or retaining roots at arrival was the only contributing factor for tooth loss in older adults, the multidimensional approach found that risk factors of tooth loss differed when assessed from different perspectives. While likelihood of tooth loss and time to first tooth loss were associated only with dental factors, both dental and nondental factors were associated with frequency and rate of tooth loss. CONCLUSION: A single dimensional risk assessment approach focusing on likelihood of tooth loss alone fails to provide a comprehensive risk profile for older adults. A multidimensional approach should be considered during assessment and treatment planning. PMID- 21649627 TI - Simultaneously measuring gait and cognitive performance in cognitively healthy and cognitively impaired older adults: the Basel motor-cognition dual-task paradigm. AB - OBJECTIVES: To investigate dual-task performance of gait and cognition in cognitively healthy and cognitively impaired older adults using a motor-cognition dual-task paradigm. DESIGN: Cross-sectional retrospective study. SETTING: The Basel Memory Clinic and the Basel Study on the Elderly (Project BASEL). PARTICIPANTS: Seven hundred eleven older adults (mean age 77.2+/-6.2, 350 (49.2%) female and 361 (50.8%) male). MEASUREMENTS: Gait velocity and cognitive task performance using a working memory (counting backward from 50 by 2s) and a semantic memory (enumerating animal names) task were measured during single- and dual-task conditions. Gait was assessed using the GAITRite electronic walkway system. Cognitive impairment was defined as a score less than 25 on the Mini Mental State Examination. RESULTS: During dual tasks, participants reduced gait velocity (P<.001) and calculated fewer numbers (P=.03) but did not enumerate fewer animals and did not make more errors or repetitions (P>.10). Cognitively impaired individuals had lower baseline gait velocity and a greater reduction in gait velocity but not cognitive performance during dual tasks than cognitively healthy participants (P<.01). CONCLUSION: Gait velocity was lower during both dual tasks, whereas decrease in cognitive performance depended on the cognitive ability needed in the dual-task condition. Cognitively impaired individuals generally have poorer baseline performance and greater dual task-related gait velocity reduction than those who are cognitively healthy. Future research should include different conditions for gait to determine adaptive potentials of older adults. PMID- 21649628 TI - Medication administration errors in assisted living: scope, characteristics, and the importance of staff training. AB - OBJECTIVES: To compare rates of medication errors committed by assisted living staff with different training and to examine characteristics of errors. DESIGN: Observation of medication preparation and passes, chart review, interviews, and questionnaires. SETTING: Stratified random sample of 11 assisted living communities in South Carolina (which permits nonnurses to administer medications) and Tennessee (which does not). PARTICIPANTS: All staff who prepared or passed medications: nurses (one registered nurse and six licensed practical nurses (LPNs)); medication aides (n=10); and others (n=19), including those with more and less training. MEASUREMENTS: Rates of errors related to medication, dose and form, preparation, route, and timing. RESULTS: Medication preparation and administration were observed for 4,957 administrations during 83 passes for 301 residents. The error rate was 42% (20% when omitting timing errors). Of all administrations, 7% were errors with moderate or high potential for harm. The odds of such an error by a medication aide were no more likely than by a LPN, but the odds of one by staff with less training was more than two times as great (odds ratio=2.10, 95% confidence interval=1.27-3.49). A review of state regulations found that 20 states restrict nonnurses to assisting with self administration of medications. CONCLUSION: Medication aides do not commit more errors than LPNs, but other nonnurses who administered a significant number of medications and assisted with self-administration committed more errors. Consequently, all staff who handle medications should be trained to the level of a medication aide. PMID- 21649630 TI - Pressure-redistributing support surface use and pressure ulcer incidence in elderly hip fracture patients. AB - OBJECTIVES: To evaluate the association between pressure-redistributing support surface (PRSS) use and incident pressure ulcers in older adults with hip fracture. DESIGN: Secondary analysis of data from prospective cohort with assessments performed as soon as possible after hospital admission and on alternating days for 21 days. SETTING: Nine hospitals in the Baltimore Hip Studies network and 105 postacute facilities to which participants were discharged. PARTICIPANTS: Six hundred fifty-eight people aged 65 and older who underwent surgery for hip fracture. MEASUREMENTS: Full-body examination for pressure ulcers; bedbound status; and PRSS use, recorded as none, powered (alternating pressure mattresses, low-air-loss mattresses, and alternating pressure overlays), or nonpowered (high-density foam, static air, or gel-filled mattresses or pressure-redistributing overlays except for alternating pressure overlays). RESULTS: Incident pressure ulcers (IPUs), Stage 2 or higher, were observed at 4.2% (195/4,638) of visits after no PRSS use, 4.5% (28/623) of visits after powered PRSS use, and 3.6% (54/1,496) of visits after nonpowered PRSS use. The rate of IPU per person-day of follow-up did not differ significantly between participants using powered PRSSs and those not using PRSSs. The rate also did not differ significantly between participants using nonpowered PRSSs and those not using PRSSs, except in the subset of bedbound participants (incidence rate ratio=0.3, 95% confidence interval=0.1-0.7). CONCLUSION: PRSS use was not associated with a lower IPU rate. Clinical guidelines may need revision for the limited effect of PRSS use, and it may be appropriate to target PRSS use to bedbound patients at risk of pressure ulcers. PMID- 21649631 TI - Diagnosis and treatment of depression in older community-dwelling adults: 1992 2005. AB - OBJECTIVE: To examine evolving patterns of depression diagnosis and treatment in older U.S. adults in the era of newer-generation antidepressants. DESIGN: Trend analysis using data from the Medicare Current Beneficiary Survey, a nationally representative survey of Medicare enrollees, from 1992 to 2005. SETTING: Community, usual care. PARTICIPANTS: Older Medicare fee-for-service beneficiaries. MEASUREMENTS: Depression diagnoses and psychotherapy use identified from Medicare claims; antidepressant use identified from detailed medication inventories conducted by interviewers. RESULTS: The proportion of older adults who received a depression diagnosis doubled, from 3.2% to 6.3%, with rates increasing substantially across all demographic subgroups. Of those diagnosed, the proportion receiving antidepressants increased from 53.7% to 67.1%, whereas the proportion receiving psychotherapy declined from 26.1% to 14.8%. Adjusting for other characteristics, odds of antidepressant treatment in older adults diagnosed with depression were 86% greater for women, 53% greater for men, 89% greater for whites, 13% greater for African Americans, 84% greater for metropolitan-area residents, and 55% greater for nonmetropolitan-area residents. Odds of antidepressant treatment were 54% greater for those diagnosed with major depressive disorder (MDD) and 83% greater for those with other depression diagnoses, whereas the odds of receiving psychotherapy was 29% lower in those with MDD diagnoses and 74% lower in those with other depression diagnoses. CONCLUSION: Overall diagnosis and treatment rates increased over time. Antidepressants are assuming a more-prominent and psychotherapy a less-prominent role. These shifts are most pronounced in groups with less-severe depression, in whom evidence of efficacy of treatment with antidepressants alone is less clear. PMID- 21649629 TI - Hearing sensitivity in older adults: associations with cardiovascular risk factors in the health, aging and body composition study. AB - OBJECTIVES: To examine the association between cardiovascular disease (CVD) and its risk factors and age-associated hearing loss in a cohort of older black and white adults. DESIGN: Cross-sectional cohort study. SETTING: The Health, Aging, and Body Composition (Health ABC) Study, a community-based cohort study of older adults from Pittsburgh, Pennsylvania, and Memphis, Tennessee. PARTICIPANTS: Two thousand forty-nine well-functioning adults (mean age 77.5; 37% black). MEASUREMENTS: Pure-tone audiometry measurement and history of clinical CVD were obtained at the fourth annual follow-up visit. Pure-tone averages in decibels reflecting low (250, 500, and 1,000 Hz), middle (500, 1,000, and 2,000 Hz), and high (2,000, 4,000, and 8,000 Hz) frequencies were calculated for each ear. CVD risk factors, aortic pulse-wave velocity (PWV), and ankle-arm index (AAI) were obtained at study baseline. RESULTS: In sex-stratified models, after adjustment for age, race, study site, and occupational noise exposure, risk factors associated with poorer hearing sensitivity in men included high triglyceride levels, high resting heart rate, and history of smoking. In women, poor hearing sensitivity was associated with high body mass index, high resting heart rate, fast PWV, and low AAI. CONCLUSION: Modifiable risk factors for CVD may play a role in the development of age-related hearing loss. PMID- 21649632 TI - A roadmap of aging in Russia: the prevalence of frailty in community-dwelling older adults in the St. Petersburg district--the "Crystal" study. AB - OBJECTIVES: To categorize the health problems of older Russians and identify the number of frail older adults using different approaches. DESIGN: Cross-sectional study. SETTING: The Kolpino district of St. Petersburg. PARTICIPANTS: A random sample of 611 community-dwelling adults aged 65 and older was selected from a population-based register and stratified into two age groups (65-74, >=75). MEASUREMENTS: Anthropometry, medical history, nutritional status, Physical Performance Battery, activities of daily living, grip strength, spirometry, renal function, 15-item Geriatric Depression Scale, Mini-Mental State Examination, and sense of coherence. RESULTS: The female:male ratio was 2.5:1; 19% were malnourished or at risk for malnutrition, and 78.6% presented with one to three chronic pathologies, with no differences according to age or sex. Problems with hearing (60.7%), vision (89.5%), and incontinence (40.9%) were highly prevalent. Moreover, 25.9% of the younger group (65-74) and 42.5% of the older group (>=75) were found to be at risk for depression. Mild to severe cognitive impairment was found in 34.5% of the participants, and 14.4% of those aged 65 to 74 and 33.0% of those aged 75 and older reported dependence in daily living activities. The prevalence of frailty assessed using different models varied from 21.1% to 43.9%. The Fried model revealed the strongest associations with the frailty outcomes (dependence and performance). No significant differences between the sexes were found in either age group (P=.82), although the percentage of frail women increased with age (P=.001). CONCLUSION: The findings emphasize the need for attention and resources to be shifted from disease-oriented to functional approaches in the older Russian population. The population studied is consistent with the Fried model, in which one in five older adults can be labeled as frail. PMID- 21649633 TI - A randomized clinical trial of theory-based activities for the behavioral symptoms of dementia in nursing home residents. AB - OBJECTIVES: To test the main and interactive effects of activities derived from the Need-Driven Dementia-Compromised Behavior model for responding to behavioral symptoms in nursing home residents. DESIGN: Randomized double-blind clinical trial. SETTING: Nine community-based nursing homes. PARTICIPANTS: One hundred twenty-eight cognitively impaired residents randomly assigned to activities adjusted to functional level (FL) (n=32), personality style of interest (PSI) (n=33), functional level and personality style of interest (FL+PSI) (n=31), or active control (AC) (n=32). INTERVENTION: Three weeks of activities provided twice daily. MEASUREMENTS: Agitation, passivity, engagement, affect, and mood assessed from video recordings and real-time observations during baseline, intervention, random times outside of intervention, and 1 week after intervention. RESULTS: All treatments improved outcomes during intervention except mood, which worsened under AC. During intervention the PSI group demonstrated greater engagement, alertness, and attention than the other groups; the FL+PSI group demonstrated greater pleasure. During random times, engagement returned to baseline levels except in the FL group in which it decreased. There was also less agitation and passivity in groups with a component adjusted to PSI. One week after the intervention, mood, anxiety, and passivity improved over baseline; significantly less pleasure was displayed after withdrawal of treatment. CONCLUSION: The hypothesis that activities adjusted to FL+PSI would improve behavioral outcomes to a greater extent than partially adjusted or nonadjusted activities was partially supported. PSI is a critical component of individualized activity prescription. PMID- 21649635 TI - Predictors of extraordinary survival in the Iowa established populations for epidemiologic study of the elderly: cohort follow-up to "extinction". AB - OBJECTIVES: To identify predictors of extraordinary survival. DESIGN: Longitudinal study of a cohort of elderly people followed up until almost all have died. SETTING: Two counties in Iowa; a part of the Established Populations for Epidemiologic Study of the Elderly. PARTICIPANTS: Two thousand eight hundred ninety community-dwelling citizens aged 65 to 85 at baseline and surviving at least 3 years. MEASUREMENTS: Data relating to age, sex, birth order, parental longevity, marital status, education, family income, social support, self reported health, chronic diseases, blood pressure, body mass index, physical ability, exercise, life attitude and mental health were obtained. Extraordinary survivors (ESs) were defined to include approximately 10% of the longest survivors in their sex group. RESULTS: The 253 ESs were far more likely never to have smoked. In models adjusted for age, sex, and smoking, the earlier-life factors such as parental longevity, being earlier in the birth order (in women only), and body mass index at age 50 were associated with extraordinary survival. In similar models for predictors at age 65 to 85, extraordinary survival was associated with excellent self-reported health, fewer chronic diseases, better physical mobility and memory, and positive attitude toward life, but it was not associated with depression, anxiety, or sleep quality. In multivariable models, attitude toward life was not an independent predictor. Women in the top third of a cumulative score of independent predictors were 9.3 (95% confidence interval=4.4-19.6, P<.001) times as likely to reach extraordinary survival as those in the bottom third. CONCLUSION: ESs had fewer "classical" risk factors and were in better health than their contemporaneous controls. Possibly genetic factors such as parental longevity and birth order appear to be less predictive in men than in women. PMID- 21649636 TI - Salvianolic acid B suppresses maturation of human monocyte-derived dendritic cells by activating PPARgamma. AB - BACKGROUND AND PURPOSE: Salvianolic acid B (Sal B), a water-soluble antioxidant derived from a Chinese medicinal herb, is known to be effective in the prevention of atherosclerosis. Here, we tested the hypothesis that the anti-atherosclerotic effect of Sal B might be mediated by suppressing maturation of human monocyte derived dendritic cells (h-monDC). EXPERIMENTAL APPROACH: h-monDC were derived by incubating purified human monocytes with GM-CSF and IL-4. h-monDC were pre incubated with or without Sal B and stimulated by oxidized low-density lipoprotein (ox-LDL) in the presence or absence of PPARgamma siRNA. Expression of h-monDC membrane molecules (CD40, CD86, CD1a, HLA-DR) were analysed by FACS, cytokines were measured by elisa and the TLR4-associated signalling pathway was determined by Western blotting. KEY RESULTS: Ox-LDL promoted h-monDC maturation, stimulated CD40, CD86, CD1a, HLA-DR expression and IL-12, IL-10, TNF-alpha production; and up-regulated TLR4 signalling. These effects were inhibited by Sal B. Sal B also triggered PPARgamma activation and promoted PPARgamma nuclear translocation, attenuated ox-LDL-induced up-regulation of TLR4 and myeloid differentiation primary-response protein 88 and inhibited the downstream p38-MAPK signalling cascade. Knocking down PPARgamma with the corresponding siRNA blocked these effects of Sal B. CONCLUSIONS AND IMPLICATIONS: Our data suggested that Sal B effectively suppressed maturation of h-monDC induced by ox-LDL through PPARgamma activation. PMID- 21649634 TI - Dementia medications and risk of falls, syncope, and related adverse events: meta analysis of randomized controlled trials. AB - OBJECTIVES: To evaluate the effect of cholinesterase inhibitors (ChEIs) and memantine on the risk of falls, syncope, and related events, defined as fracture and accidental injury. DESIGN: Meta-analysis of randomized controlled trials that were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (no language restriction, through July 2009), and manual search. SETTING: Community and nursing homes. PARTICIPANTS: Participants in fifty-four placebo controlled randomized trials and extension studies of ChEIs and memantine that reported falls, syncope, and related events in cognitively impaired older adults. MEASUREMENTS: Falls, syncope, fracture, and accidental injury. RESULTS: ChEI use was associated with greater risk of syncope (odds ratio (OR)=1.53, 95% confidence interval (CI)=1.02-2.30) than placebo but not with other events (falls: OR=0.88, 95% CI=0.74-1.04; fracture: OR=1.39, 95% CI=0.75-2.56; accidental injury: OR=1.13, 95% CI=0.87-1.45). Memantine use was associated with fewer fractures (OR=0.21, 95% CI=0.05-0.85) but not with other events (falls: OR=0.92, 95% CI=0.72-1.18; syncope: OR=1.04, 95% CI=0.35-3.04; accidental injury: OR=0.80, 95% CI=0.56-1.12). There was no differential effect according to type and severity of cognitive impairment, residential status, or length of follow-up, although because of underreporting and small number of events, a potential benefit or risk cannot be excluded. CONCLUSION: ChEIs may increase the risk of syncope, with no effects on falls, fracture, or accidental injury in cognitively impaired older adults. Memantine may have a favorable effect on fracture, with no effects on other events. More research is needed to confirm the reduction in fractures observed for memantine. PMID- 21649637 TI - Cannabinoids and bone: endocannabinoids modulate human osteoclast function in vitro. AB - BACKGROUND AND PURPOSE: Both CB(1) and CB(2) cannabinoid receptors have been shown to play a role in bone metabolism. Crucially, previous studies have focussed on the effects of cannabinoid ligands in murine bone cells. This study aimed to investigate the effects of cannabinoids on human bone cells in vitro. EXPERIMENTAL APPROACH: Quantitative RT-PCR was used to determine expression of cannabinoid receptors and liquid chromatography-electrospray ionization tandem mass spectrometry was used to determine the presence of endocannabinoids in human bone cells. The effect of cannabinoids on human osteoclast formation, polarization and resorption was determined by assessing the number of cells expressing alpha(v) beta(3) or with F-actin rings, or measurement of resorption area. KEY RESULTS: Human osteoclasts express both CB(1) and CB(2) receptors. CB(2) expression was significantly higher in human monocytes compared to differentiated osteoclasts. Furthermore, the differentiation of human osteoclasts from monocytes was associated with a reduction in 2-AG levels and an increase in anandamide (AEA) levels. Treatment of osteoclasts with LPS significantly increased levels of AEA. Nanomolar concentrations of AEA and the synthetic agonists CP 55 940 and JWH015 stimulated human osteoclast polarization and resorption; these effects were attenuated in the presence of CB(1) and/or CB(2) antagonists. CONCLUSIONS: AND IMPLICATIONS Low concentrations of cannabinoids activate human osteoclasts in vitro. There is a dynamic regulation of the expression of the CB(2) receptor and the production of the endocannabinoids during the differentiation of human bone cells. These data suggest that small molecules modulating the endocannabinoid system could be important therapeutics in human bone disease. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21649638 TI - Involvement of the first transmembrane segment of human alpha(2) -adrenoceptors in the subtype-selective binding of chlorpromazine, spiperone and spiroxatrine. AB - BACKGROUND AND PURPOSE: Some large antagonist ligands (ARC239, chlorpromazine, prazosin, spiperone, spiroxatrine) bind to the human alpha(2A) -adrenoceptor with 10- to 100-fold lower affinity than to the alpha(2B)- and alpha(2C)-adrenoceptor subtypes. Previous mutagenesis studies have not explained this subtype selectivity. EXPERIMENTAL APPROACH: The possible involvement of the extracellular amino terminus and transmembrane domain 1 (TM1) in subtype selectivity was elucidated with eight chimaeric receptors: six where TM1 and the N-terminus were exchanged between the alpha(2)-adrenoceptor subtypes and two where only TM1 was exchanged. Receptors were expressed in CHO cells and tested for ligand binding with nine chemically diverse antagonist ligands. For purposes of interpretation, molecular models of the three human alpha(2)-adrenoceptors were constructed based on the beta(2)-adrenoceptor crystal structure. KEY RESULTS: The affinities of three antagonists (spiperone, spiroxatrine and chlorpromazine) were significantly improved by TM1 substitutions of the alpha(2A)-adrenoceptor, but reciprocal effects were not seen for chimaeric receptors based on alpha(2B)- and alpha(2C) adrenoceptors. Molecular docking of these ligands suggested that binding occurs in the orthosteric ligand binding pocket. CONCLUSIONS AND IMPLICATIONS: TM1 is involved in determining the low affinity of some antagonist ligands at the human alpha(2A)-adrenoceptor. The exact mechanism is not known, but the position of TM1 at a large distance from the binding pocket indicates that TM1 does not participate in specific side-chain interactions with amino acids within the binding pocket of the receptor or with ligands bound therein. Instead, molecular models suggest that TM1 has indirect conformational effects related to the charge distribution or overall shape of the binding pocket. PMID- 21649639 TI - Anti-tumour effects of small interfering RNA targeting anion exchanger 1 in experimental gastric cancer. AB - BACKGROUND AND PURPOSE: Anion exchanger 1 (AE1) is an integral membrane protein found in erythrocytes. Our previous studies have demonstrated that AE1 is expressed in human gastric cancer cells and may be involved in the carcinogenesis of cancer. In this study, we further investigated the role of AE1 in gastric carcinogenesis and the anti-tumour effects of AE1-targeted small interfering RNAs (siRNAs) in two experimental models of gastric cancer. EXPERIMENTAL APPROACH: Molecular and cellular experiments were performed to elucidate the role of AE1 in the malignant transformation of gastric epithelium and the effects of AE1 targeted siRNAs on gastric cancer cells. The anti-tumour effect of the siRNA was evaluated in vivo in two mouse models, nude mice implanted with human gastric cancer xenografts (Model I) and mice with gastric cancer induced by N-methyl-N nitrosourea (MNU) and Helicobacter pylori (Model II). KEY RESULTS: AE1 was found to increase gastric carcinogenesis by promoting cell proliferation. AE1-targeted siRNA significantly suppressed AE1 expression and hindered tumour growth. Furthermore, the siRNA markedly decreased the detection rate of gastric cancer, in parallel with an increase in atypical hyperplasia at the end of the experiment in Model II. CONCLUSIONS AND IMPLICATIONS: Knockdown of AE1 expression in gastric mucosa by administration of synthetic siRNAs significantly inhibits the growth of gastric cancer and decreases the detection rate of this tumour in experimental mice. These results suggest that AE1 is potentially a key therapeutic target and the silencing of AE1 expression in gastric mucosa could provide a new therapeutic approach for treating gastric cancer. PMID- 21649642 TI - Identification of five novel SPRED1 germline mutations in Legius syndrome. PMID- 21649641 TI - Effects of aldosterone and related steroids on LPS-induced increased expression of inducible NOS in rat aortic smooth muscle cells. AB - BACKGROUND AND PURPOSE: Expression of inducible NOS (iNOS) is important in certain inflammatory diseases. We determined if the hormone aldosterone, a mineralocorticoid receptor (MR) agonist, affects LPS activation of iNOS expression in rat aortic smooth muscle cells (RASMC). EXPERIMENTAL APPROACH: Cultured RASMC were treated with LPS, with or without agonists/antagonists of steroid receptors. iNOS expression was determined by nitrite assays on culture medium removed from treated cells and by immunoblotting of cell protein extracts. KEY RESULTS: LPS (1 ug.mL(-1) ) increased nitrite and iNOS protein above that in control (untreated) cells. These effects of LPS were reduced by aldosterone (0.1 10 uM). The MR antagonists, eplerenone (10 uM) and spironolactone (10 or 50 uM), did not inhibit these actions of 1 uM aldosterone, but the latter were prevented by 10 uM mifepristone, a glucocorticoid (GR) and progestogen receptor (PR) antagonist. Mifepristone also prevented the reduction of LPS-induced nitrite increase produced by 1 uM dexamethasone (GR agonist) and 10 uM progesterone (PR agonist). Spironolactone (10-50 uM) by itself decreased LPS-induced increases in nitrite and iNOS protein. Mifepristone (10 uM) partially reversed these effects of 10 uM spironolactone, but not those of 50 uM; the effects of 50 uM spironolactone were also unchanged when mifepristone was increased to 50 uM. CONCLUSIONS AND IMPLICATIONS: This pharmacological profile suggests that aldosterone, and possibly 10 uM spironolactone, use mechanisms that are dependent on PR and/or GR, but not MR, to inhibit iNOS induction in RASMC. With 50 uM spironolactone, other inhibitory mechanisms requiring further investigation may become predominant. PMID- 21649640 TI - Scoparone potentiates transactivation of the bile salt export pump gene and this effect is enhanced by cytochrome P450 metabolism but abolished by a PKC inhibitor. AB - BACKGROUND AND PURPOSE: Hyperbilirubinaemia and cholestasis are two major forms of liver abnormality. The Chinese herb Yin Chin has been used for thousands of years to treat liver dysfunctions. In mice, this herb and its principal ingredient scoparone were found to accelerate the clearance of bilirubin accompanied by the induction of uridine diphosphate-5'-glucuronosyltransferase 1A1 (UGT1A1), a bilirubin processing enzyme. The aim of this study was to determine whether scoparone induces the expression of human UGT1A1. In addition, the expression of the bile salt export pump (BSEP), a transporter of bile acids, was determined. EXPERIMENTAL APPROACH: Primary human hepatocytes and hepatoma line Huh7 were treated with scoparone, chenodeoxycholic acid (CDCA) or both. The expression of UGT1A1 and BSEP mRNA was determined. The activation of the human BSEP promoter reporter by scoparone was determined in Huh7 cells by transient transfection and in mice by bioluminescent imaging. The metabolism of scoparone was investigated by recombinant CYP enzymes and pooled human liver microsomes. KEY RESULTS: Scoparone did not enhance the expression of either human BSEP or, surprisingly, UGT1A1. However, scoparone significantly potentiated the expression of BSEP induced by CDCA. Consistent with this, scoparone potentiated the stimulant effect of CDCA on the human BSEP promoter. This potentiation was enhanced by co-transfection of cytochrome P4501A2 but abolished by the PKC inhibitor GF109203X. CONCLUSIONS AND IMPLICATIONS: Scoparone and Yin Chin normalize liver function primarily by enhancing the secretion of bile acids, and this effect probably varies depending on the metabolic rate of scoparone. PMID- 21649643 TI - Assessment of the prevalence of de novo mutations in the BRCA1 and BRCA2 genes. PMID- 21649644 TI - GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non emetic doses. AB - BACKGROUND AND PURPOSE: Strategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3-cyclopentyloxy-4-methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR-7b, on memory performance, nausea, hippocampal cAMP and amyloid beta (Abeta) levels. EXPERIMENTAL APPROACH: To measure memory performance, we performed object recognition tests on rats and mice treated with GEBR-7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Abeta peptides were measured in hippocampal tissues and cultured N2a cells by elisa. KEY RESULTS: GEBR-7b increased hippocampal cAMP, did not influence Abeta levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR-7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents. CONCLUSION AND IMPLICATIONS: Our results demonstrate that GEBR-7b enhances memory functions at doses that do not cause emesis-like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment. PMID- 21649646 TI - Erythropoietin enhances immunostimulatory properties of immature dendritic cells. AB - Dendritic cells (DCs) are the most potent antigen-presenting cells and play a crucial role by modulating the T cell immune response against infective agents, tumour antigens and alloantigens. The current study shows that differentiating bone marrow (BM)-derived DCs but not fully differentiated DCs are targets of erythropoietin (EPO). Indeed, DCs emerging from rat bone marrow, but not splenic DCs, express the EPO receptor (Epo-R) and respond to EPO stimulation displaying a more activated phenotype with increased CD86, CD40 and interleukin (IL)-12 expression levels and a higher allostimulatory capacity on T cells than untreated DCs. Moreover, results here presented show that EPO up-regulates Toll-like receptor (TLR)-4 in differentiating DCs rendering these cells more sensitive to stimulation by the TLR-4 ligand lipopolysaccharide (LPS). Indeed, DCs treated with EPO and then stimulated by LPS were strongly allostimulatory and expressed CCR7, CD86, CD40, IL-12 and IL-23 at higher levels than those observed in DCs stimulated with LPS alone. It is tempting to speculate that EPO could act as an additional danger signal in concert with TLR-4 engagement. Thus, EPO, beyond its erythropoietic and cytoprotective effects, turns out to be an immune modulator. PMID- 21649645 TI - Calcitonin and calcitonin receptor-like receptors: common themes with family B GPCRs? AB - The calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR) are two of the 15 human family B (or Secretin-like) GPCRs. CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins. They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with receptor activity-modifying proteins adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and recurring themes and how such findings relate to two unusual but important receptors, CTR and CLR. PMID- 21649647 TI - Small molecule CXCR3 antagonist NIBR2130 has only a limited impact on type 1 diabetes in a virus-induced mouse model. AB - CXCL10 is one of the key chemokines involved in trafficking of autoaggressive T cells to the islets of Langerhans during the autoimmune destruction of beta cells in type 1 diabetes (T1D). Blockade of CXCL10 or genetic deletion of its receptor CXCR3 results in a reduction of T1D in animal models. As an alternative to the use of neutralizing monoclonal antibodies to CXCL10 or CXCR3 we evaluated the small molecule CXCR3 antagonist NIBR2130 in a virus-induced mouse model for T1D. We found that the overall frequency of T1D was not reduced in mice administered with NIBR2130. An initial slight delay of diabetes onset was not stable over time, because the mice turned diabetic upon removal of the antagonist. Accordingly, no significant differences were found in the islet infiltration rate and the frequency and activity of islet antigen-specific T cells between protected mice administered with NIBR2130 and control mice. Our data indicate that in contrast to direct inhibition of CXCL10, blockade of CXCR3 with the small molecule antagonist NIBR2130 has no impact on trafficking and/or activation of autoaggressive T cells and is not sufficient to prevent T1D. PMID- 21649649 TI - Channels: exciting developments. PMID- 21649648 TI - Antibody fragments as tools in crystallography. AB - While antibody-based therapeutics have become firmly established as front-line drugs, the use of antibodies as research tools in small molecule drug discovery is still in its infancy. In this review we focus on the use of antibody fragments as crystallization chaperones to aid the structural determination of otherwise 'uncrystallizable' or 'undruggable' target proteins. We also highlight a potential application for this technology, in which antibody-mediated structures may be used to inform the design of new chemical entities. PMID- 21649650 TI - How does exercise benefit performance on cognitive tests in primary-school pupils? AB - AIM: We have previously demonstrated improved cognitive performance after a classroom-based exercise regime. In this study, we examined the reproducibility of this effect in a more socio-economically diverse sample and also investigated whether cognitive benefits of exercise were moderated by body mass index (BMI) or symptoms of attention-deficit-hyperactivity disorder (ADHD). METHOD: A crossover design trial (2 wks in duration) randomized 552 children (mean age 9 y 8 mo, SD 1 y 2 mo; range 8-12 y) by their school into two counterbalanced groups. Children were eligible to participate provided that they did not receive any additional support. One group received a classroom-based programme of physical exercise on week 1 and then no programme on week 2, and this order was reversed for the other group. Each week, all participants completed a cognitive test battery that was delivered in one part per day at the end of each school day. RESULTS: On the cognitive tests, a significant interaction between counterbalance group and exercise was observed (p<0.001). Benefits occurred only for participants who exercised during the second week (mean improvement mean 3.85, standard error 1.39). Although test scores were affected by age, sex, and level of ADHD symptoms, the effect of exercise was not moderated by either these factors or BMI. INTERPRETATION: Exercise interventions have a positive effect (with variable magnitude) on cognitive performance, possibly by facilitating practice effects. These effects are not moderated by sex, ADHD symptom level, or BMI. PMID- 21649651 TI - Milder phenotypes of glucose transporter type 1 deficiency syndrome. AB - Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non classical phenotypes with movement disorders and early-onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose<2.2 mmol/l) in the presence of normoglycaemia with a CSF/blood glucose ratio of less than 0.4. GLUT1DS is due to a mutation in the solute carrier family 2, member 1 gene (SLC2A1). We present five individuals (four males, one female), all of whom had a mild phenotype, highlighting the importance of considering this diagnosis in unexplained neurological disorders associated with mild learning difficulties, subtle motor delay, early-onset absence epilepsy, fluctuating gait disorders, and/or dystonia. The mean age at diagnosis was 8 years 8 months. This paper also shows phenotypical parallels between GLUT1DS and paroxysmal exertion-induced dyskinesia. PMID- 21649652 TI - Analysis of leukocytes in medication-overuse headache, chronic migraine, and episodic migraine. AB - OBJECTIVE: To evaluate the number of immune cells in the peripheral blood of medication-overuse headache (MOH), chronic migraine (CM), and migraine without aura (MWA) patients, as well as from controls. BACKGROUND: Migraine has been linked to immunologic disturbances, but the role of the immune system in chronic forms of headache that evolve from migraine has not been studied. Psychiatric co morbidity has been related to both headache chronification and immunologic alterations. METHODS: This cross-sectional study comprised 68 subjects divided in 4 groups: MOH, CM, MWA, control. Subjects were gender-matched, had no physical co morbidity, and were taking only acetaminophen. Clinical and psychological data were recorded in a standardized protocol. Samples of peripheral blood for hematological analysis were obtained in the morning during the ictal (MOH, CM, and MWA groups) and interictal periods (MWA group), as well from control group. RESULTS: A higher lymphocyte count was measured in MOH patients relative to the MWA patients (mean +/- standard deviation: 2448.7/mm3 +/- 775.8 vs. 1859.7/mm3 +/- 564.7; P = .027). The numbers of blood lymphocytes for CM and control subjects were 2086.1/mm3 +/- 540.5 and 1961.7/mm3 +/- 385.6, respectively. Multiple linear regression analysis demonstrated that only MOH and MWA groups remained associated with lymphocyte count (B = 540.7; CI 95%: 55.2-1026.1; P = .03; R2 = 19.2%). Analysis for linearity of variables in the spectrum control/MWA/CM/MOH resulted positive for body mass index (from 23.5 +/- 3.25 in controls to 26.5 +/- 4.49 in MOH patients; P = .034), scores on Beck Depression Inventory (from 3.29 +/- 3.05 to 14.65 +/- 11.21; P < 0.001) and Hamilton Anxiety Scale (from 4.29 +/- 3.93 to 23.24 +/- 11.01; P < 0.001), hemoglobin (from 13.7 +/- 0.79 to 14.6 +/- 1.31; P = .022), and lymphocyte count (from 1961.7 +/- 385.6 to 2448.7 +/- 775.8; P = .01), but negative for CD8+ T lymphocytes (from 34.0 +/- 8.82 to 30.0 +/- 6.64; P = .046). CONCLUSIONS: A higher lymphocyte count in the MOH group relative to the MWA group may indicate a chronic inflammatory state. Several clinical and laboratorial characteristics have a range along a spectrum extending from healthy subjects to patients suffering from chronic forms of migraine. PMID- 21649653 TI - Diagnostic accuracy of the ID Migraine: a systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this systematic review with meta-analysis is to determine the diagnostic accuracy of the identification of migraine (ID Migraine) as a decision rule for identifying patients with migraine. BACKGROUND: The ID Migraine screening tool is designed to identify patients with migraine in primary care settings. Several studies have validated the ID Migraine across various clinical settings, including primary care, neurology departments, headache clinics, dental clinics, ear, nose, and throat (ENT) and ophthalmology. METHODS: A systematic literature search was conducted to identify all studies validating the ID Migraine, with the International Headache Criteria as the reference standard. The methodological quality of selected studies was assessed using the Quality of Diagnostic Accuracy Studies tool. All selected studies were combined using a bivariate random effects model. A sensitivity analysis was also conducted, pooling only those studies using representative patient groups (primary care, neurology departments, and headache clinics) to determine the potential influence of spectrum bias on the results. RESULTS: Thirteen studies incorporating 5866 patients are included. The weighted prior probability of migraine across the 13 studies is 59%. The ID Migraine is shown to be useful for ruling out rather than ruling in migraine, with a greater pooled sensitivity estimate (0.84, 95% confidence interval 0.75-0.90) than specificity (0.76, 95% confidence interval 0.69-0.83). A negative ID Migraine score reduces the probability of migraine from 59% to 23%. The sensitivity analysis reveals similar results. CONCLUSIONS: This systematic review quantifies the diagnostic accuracy of the ID Migraine as a brief, practical, and easy to use diagnostic tool for Migraine. Application of the ID Migraine as a diagnostic tool is likely to improve appropriate diagnosis and management of migraine sufferers. PMID- 21649654 TI - Complementary and alternative medicine use among adults with migraines/severe headaches. AB - OBJECTIVE: Our objective was to determine patterns, reasons for, and correlates of complementary and alternative medicine (CAM) use by US adults with migraines/severe headaches. BACKGROUND: While many patients with chronic conditions use CAM, little is known about CAM use by adults with migraines/severe headaches. METHODS: We compared CAM use between adults with and without self reported migraines/severe headaches using the 2007 National Health Interview Survey (n=23,393), a national cross-sectional survey. RESULTS: Adults with migraines/severe headaches used CAM more frequently than those without (49.5% vs 33.9%, P< .0001); differences persisted after adjustment (adjusted odds ratio=1.29, 95% confidence interval [1.15, 1.45]). Mind-body therapies (eg, deep breathing exercises, meditation, yoga) were used most commonly. More than 50% of adults with migraines/severe headaches reporting CAM use had not discussed it with their health care provider. Nonetheless, those with migraines/severe headaches used CAM more often than those without because of provider recommendation and because conventional treatments were perceived as ineffective or too costly. Correlates of CAM use among adults with migraines/severe headaches included anxiety, joint or low back pain, alcohol use, higher education, and living in the western USA. Only 4.5% of adults with migraines/severe headaches reported using CAM to specifically treat their migraines/severe headaches. CONCLUSIONS: CAM is used more often among adults with migraines/severe headaches than those without. However, few report using CAM to specifically treat migraines/severe headaches. Mind-body therapies are used most frequently. Further research is needed to understand the effectiveness and mechanisms of CAM treatments in adults with migraines/severe headaches. PMID- 21649655 TI - Serotonin depletion leads to cortical hyperexcitability and trigeminal nociceptive facilitation via the nitric oxide pathway. AB - OBJECTIVE: To investigate the role of nitric oxide (NO) in the development of cortical hyperexcitability and trigeminal nociceptive facilitation induced by serotonin (5-HT) depletion. BACKGROUND: Nitric oxide and 5-HT are important in the pathogenesis of primary headaches. An increase in cortical excitability and trigeminal nociception has been demonstrated in animals with low 5-HT levels. Although the mechanism underlying this increase is unclear, an alteration of the NO system is one possible explanation. METHODS: Male Wistar rats were divided into control and 5-HT-depleted groups. 5-HT was depleted by i.p. injection of parachlorophenylalanine (100 mg/kg). Three days after injection, a microelectrode was inserted into the cerebral cortex for electrocorticograph recording and waves of cortical spreading depression (CSD) were triggered with KCl application. N nitro-L-arginine methyl ester (L-NAME; 10 mg/kg by i.v. injection) or saline was given after the second CSD wave. Following the experiment, the cerebral cortex and brain stem were removed for anti-neuronal nitric oxide synthase (nNOS) and anti-Fos immunohistochemistry. RESULTS: Relative to the control group, the 5-HT depleted group exhibited a higher frequency of CSD waves, more nNOS immunoreactive cells in both the cerebral cortex and brainstem and more Fos immunoreactive cells in the trigeminal nucleus caudalis (TNC). In the control group, L-NAME application led to fewer nNOS-immunoreactive cells in the cerebral cortex and TNC, and fewer Fos-immunoreactive cells in the TNC; however, L-NAME was without effect on the CSD pattern. By contrast, in addition to decreased nNOS and Fos expression, L-NAME significantly reduced the frequency of CSD events in the 5-HT-depleted group. CONCLUSIONS: Inhibition of NO production can counter both the cortical hyperexcitability and facilitation of trigeminal nociception that develop in the depleted 5-HT state. Therefore, NO is likely involved in the increase in both CSD events and CSD-evoked trigeminal nociception under decreased 5-HT conditions. PMID- 21649656 TI - Spinal manipulations for cervicogenic headaches: a systematic review of randomized clinical trials. AB - The objective of this systematic review was to assess the effectiveness of spinal manipulations as a treatment option for cervicogenic headaches. Seven databases were searched from their inception to February 2011. All randomized trials which investigated spinal manipulations performed by any type of healthcare professional for treating cervicogenic headaches in human subjects were considered. The selection of studies, data extraction, and validation were performed independently by 2 reviewers. Nine randomized clinical trials (RCTs) met the inclusion criteria. Their methodological quality was mostly poor. Six RCTs suggested that spinal manipulation is more effective than physical therapy, gentle massage, drug therapy, or no intervention. Three RCTs showed no differences in pain, duration, and frequency of headaches compared to placebo, manipulation, physical therapy, massage, or wait list controls. Adequate control for placebo effect was achieved in 1 RCT only, and this trial showed no benefit of spinal manipulations beyond a placebo effect. The majority of RCTs failed to provide details of adverse effects. There are few rigorous RCTs testing the effectiveness of spinal manipulations for treating cervicogenic headaches. The results are mixed and the only trial accounting for placebo effects fails to be positive. Therefore, the therapeutic value of this approach remains uncertain. PMID- 21649657 TI - Ophthalmoplegic migraine. PMID- 21649658 TI - Migraine and vestibular symptoms--identifying clinical features that predict "vestibular migraine". AB - BACKGROUND: Migraine and symptoms that may suggest a vestibular disorder (referred to herein broadly as vestibular symptoms-VS) often co-exist. In part due to a lack of standardized diagnostic criteria, this relationship remains unknown to many physicians. OBJECTIVE: To determine common clinical features that may be associated with "vestibular migraine" (VM). METHODS: We retrospectively reviewed charts of patients diagnosed with VM at a headache center. In this group we recorded certain demographic and clinical features related to their disorder, including the most common triggers of the VS and the specific characteristics of the symptoms that suggested VM. RESULTS: Our sample consisted of 147 patients (68% women, mean age = 45 years, 39% with aura). Migraine onset preceded the onset of VS by a mean of 8 years. A total of 62 patients (42%) had gradual onset of VS, while in 48 (33%) symptoms began suddenly. The most commonly reported symptoms that led to the diagnosis of VM were: unsteadiness (134; 91%), balance disturbance (120; 82%), "light-headedness" (113; 77%), and vertigo (84; 57%). VS and headache occurred concomitantly in 48% of patients. A total of 67 (47%) patients had VS that were chronic from onset, 29 (21%) had episodic symptoms, and in 46 (32%) the VS had evolved from episodic to chronic (with an average duration of 7.04 years required for this evolution to occur). CONCLUSIONS: Vestibular migraine is a heterogeneous condition with varying symptomatology. As with migraine itself, symptomatic expression varies along a spectrum that extends from episodic to chronic. As the histories of many of the patients we evaluated would not meet current International Classification of Headache Disorders criteria, we suggest that new criteria which account for the heterogeneity and natural history of the disorder may be required to adequately diagnose and treat those who suffer from VM. PMID- 21649660 TI - WSAVA Nutritional Assessment Guidelines. PMID- 21649659 TI - Identifying chronic conditions in Medicare claims data: evaluating the Chronic Condition Data Warehouse algorithm. AB - OBJECTIVE: To examine the strengths and limitations of the Center for Medicare and Medicaid Services' Chronic Condition Data Warehouse (CCW) algorithm for identifying chronic conditions in older persons from Medicare beneficiary data. DATA SOURCES: Records from participants of the NHANES I Epidemiologic Follow-up Study (NHEFS 1971-1992) linked to Medicare claims data from 1991 to 2000. STUDY DESIGN: We estimated the percent of preexisting cases of chronic conditions correctly identified by the CCW algorithm during its reference period and the number of years of claims data necessary to find a preexisting condition. PRINCIPAL FINDINGS: The CCW algorithm identified 69 percent of preexisting diabetes cases but only 17 percent of preexisting arthritis cases. Cases identified by the CCW are a mix of preexisting and newly diagnosed conditions. CONCLUSIONS: The prevalence of conditions needing less frequent health care utilization (e.g., arthritis) may be underestimated by the CCW algorithm. The CCW reference periods may not be sufficient for all analytic purposes. PMID- 21649661 TI - Modelling the size and composition of fruit, grain and seed by process-based simulation models. AB - Understanding what determines the size and composition of fruit, grain and seed in response to the environment and genotype is challenging, as these traits result from several linked processes controlled at different levels of organization, from the subcellular to the crop level, with subtle interactions occurring at or between the levels of organization. Process-based simulation models (PBSMs) implement algorithms to simulate metabolic and biophysical aspects of cell, tissue and organ behaviour. In this review, fruit, grain and seed PBSMs describing the main phases of growth, development and storage metabolism are discussed. From this concurrent work, it is possible to identify generic storage organ processes which can be modelled similarly for fruit, grain and seed. Spatial heterogeneity at the tissue and whole-plant level is found to be a key consideration in modelling the effects of the environment and genotype on fruit, grain and seed end-use value. In the future, PBSMs may well become the main link between studies at the molecular and whole-plant levels. To bridge this phenotype to-genotype gap, future models need to remain plastic without becoming overparameterized. PMID- 21649662 TI - Evolution of sexual systems, dispersal strategies and habitat selection in the liverwort genus Radula. AB - * Shifts in sexual systems are among the most common and important transitions in plants and are correlated with a suite of life-history traits. The evolution of sexual systems and their relationships to gametophyte size, sexual and asexual reproduction, and epiphytism are examined here in the liverwort genus Radula. * The sequence of trait acquisition and the phylogenetic correlations between those traits was investigated using comparative methods. * Shifts in sexual systems recurrently occurred from dioecy to monoecy within facultative epiphyte lineages. Production of specialized asexual gemmae was correlated to neither dioecy nor strict epiphytism. * The significant correlations among life-history traits related to sexual systems and habitat conditions suggest the existence of evolutionary trade-offs. Obligate epiphytes do not produce gemmae more frequently than facultative epiphytes and disperse by whole gametophyte fragments, presumably to avoid the sensitive protonemal stage in a habitat prone to rapid changes in moisture availability. As dispersal ranges correlate with diaspore size, this reinforces the notion that epiphytes experience strong dispersal limitations. Our results thus provide the evolutionary complement to metapopulation, metacommunity and experimental studies demonstrating trade-offs between dispersal distance, establishment ability, and life-history strategy, which may be central to the evolution of reproductive strategies in bryophytes. PMID- 21649663 TI - How do I audit hospital blood product utilization? PMID- 21649664 TI - Scan patterns when viewing natural scenes: emotion, complexity, and repetition. AB - Eye movements were monitored during picture viewing, and effects of hedonic content, perceptual composition, and repetition on scanning assessed. In Experiment 1, emotional and neutral pictures that were figure-ground compositions or more complex scenes were presented for a 6-s free viewing period. Viewing emotional pictures or complex scenes prompted more fixations and broader scanning of the visual array, compared to neutral pictures or simple figure-ground compositions. Effects of emotion and composition were independent, supporting the hypothesis that these oculomotor indices reflect enhanced information seeking. Experiment 2 tested an orienting hypothesis by repeatedly presenting the same pictures. Although repetition altered specific scan patterns, emotional, compared to neutral, picture viewing continued to prompt oculomotor differences, suggesting that motivationally relevant cues enhance information seeking in appetitive and defensive contexts. PMID- 21649665 TI - TGF-beta1, EGF and FGF4 synergistically induce differentiation of the seminoma cell line TCam-2 into a cell type resembling mixed non-seminoma. AB - Malignant germ-cell tumours arise from a neoplastic precursor, the carcinoma in situ, and develop into seminomas and/or non-seminomas (embryonal carcinomas, teratomas, yolk-sac tumours and choriocarcinomas). Based on histological and clinical findings, it has been postulated that seminomas can eventually transform into non-seminomas. Here, we used the cell line TCam-2 as model for seminomas and interrogated their differentiation potential. We demonstrate that TCam-2 cells are able to differentiate into mixed non-seminomatous lineages after supplementing the media with TGF-beta1, EGF and FGF4. On a molecular level, the differentiation is initiated by repression of BMP/SMAD signalling. As a consequence, BLIMP1, a molecule known to inhibit the differentiation of murine primordial germ cells, is down-regulated and differentiation-inhibiting histone modifications are lost. The appearance of multinucleated giant cells and the expression of marker genes indicate that cells differentiate predominantly into extra-embryonic choriocarcinoma-like cells. This is most likely due to the presence of components of the Hippo pathway, TEAD4 and YAP1. These molecules have been described to trigger extra-embryonic fate determination in the murine system. This study supports the model that seminomas indeed have an intrinsic ability to transform into a non-seminoma. In addition, the data suggest that the transformation does not require an additional mutation, but can be triggered by changes in the tumour microenvironment. PMID- 21649666 TI - Testing the social identity relative deprivation (SIRD) model of social change: the political rise of Scottish nationalism. AB - We tested a social-identity relative deprivation (SIRD) model predicting Scottish nationalist beliefs and intention to vote for the separatist Scottish Nationalist Party (SNP). Data were from a survey of a large and representative sample of Scottish teenagers administered in the late 1980s. The SIRD model distinguishes effects of group-based and personal relative deprivation, which should be independent of one another. Importantly, social change beliefs should mediate the effects of both collective relative deprivation and group identification on protest intentions (in this case intention to vote for the SNP). Egoistic relative deprivation should be the strongest predictor of feelings of depression. Using structural equation modelling, the results strongly support this model and replicate in two different cohorts. PMID- 21649667 TI - Local and regional network function in behaviorally relevant cortical circuits of adult mice following postnatal alcohol exposure. AB - BACKGROUND: Ethanol consumption during pregnancy can lead to fetal alcohol spectrum disorder (FASD), which consists of the complete spectrum of developmental deficits including neurological dysfunction. FASD is associated with a variety of neurobehavioral disturbances dependent on the age and duration of exposure. Ethanol exposure in neonatal rodents can also induce widespread apoptotic neurodegeneration and long-lasting behavioral abnormalities similar to FASD. The developmental stage of neonatal rodent brains that are at the peak of synaptogenesis is equivalent to the third trimester of human gestation. METHODS: Male and female C57BL/6By mice were injected with ethanol (20%, 2.5 g/kg, 2 s.c. injections) or an equal volume of saline (controls) on postnatal day 7 (P7). Animals were allowed to mature and at 3 months were tested on an olfactory habituation task known to be dependent on piriform cortex function, a hippocampal dependent object place memory task, and used for electrophysiological testing of spontaneous and odor-evoked local field potential (LFP) activity in the olfactory bulb, piriform cortex, and dorsal hippocampus. RESULTS: P7 ethanol induced widespread cell death within 1 day of exposure, with highest levels in the neocortex, intermediate levels in the dorsal hippocampus, and relatively low levels in the primary olfactory system. No impairment of odor investigation or odor habituation was detected in P7 ethanol-exposed 3-month-old mice compared to saline controls. However, hippocampal-dependent object place memory was significantly impaired in the P7 ethanol-treated adult mice. Odor-evoked LFP activity was enhanced throughout the olfacto-hippocampal pathway, primarily within the theta frequency band, although the hippocampus also showed elevated evoked delta frequency activity. In addition, functional coherence between the piriform cortex and olfactory bulb and between the piriform cortex and dorsal hippocampus was enhanced in the beta frequency range in P7 ethanol-treated adult mice compared to controls. CONCLUSIONS: P7 ethanol induces an immediate wave of regionally selective cell death followed by long-lasting changes in local circuit and regional network function that are accompanied by changes in neurobehavioral performance. The results suggest that both the activity of local neural circuits within a brain region and the flow of information between brain regions can be modified by early alcohol exposure, which may contribute to long-lasting behavioral abnormalities known to rely on those circuits. PMID- 21649669 TI - Narrow complex tachycardia with ventriculoatrial dissociation--what is the mechanism? PMID- 21649670 TI - Isoelectric atrioventricular interval during DDD pacing: what is the mechanism? PMID- 21649672 TI - A modest (real estate) proposal. PMID- 21649668 TI - Alteration of ethanol drinking in mice via modulation of the GABA(A) receptor with ganaxolone, finasteride, and gaboxadol. AB - BACKGROUND: Neurosteroids and other gamma-aminobutyric acid(A) (GABA(A) ) receptor-modulating compounds have been shown to affect ethanol intake, although their mechanism remains unclear. This study examined how patterns of 24-hour ethanol drinking in mice were altered with the synthetic GABAergic neurosteroid ganaxolone (GAN), with an inhibitor of neurosteroid synthesis (finasteride [FIN]), or a GABA(A) receptor agonist with some selectivity at extrasynaptic receptors (gaboxadol HCL [THIP]). METHODS: Male C57BL/6J mice had continuous access to a 10% v/v ethanol solution (10E) or water. Using lickometer chambers, drinking patterns were analyzed among mice treated in succession to GAN (0, 5, and 10 mg/kg), FIN (0 or 100 mg/kg), and THIP (0, 2, 4, 8, and 16 mg/kg). RESULTS: GAN shifted drinking in a similar but extended manner to previous reports using low doses of the neurosteroid allopregnanolone (ALLO); drinking was increased in hour 1, decreased in hours 2 and 3, and increased in hours 4 and 5 postinjection. THIP (8 mg/kg) and FIN both decreased 10E drinking during the first 5 hours postinjection by 30 and 53%, respectively, while having no effect on or increasing water drinking, respectively. All 3 drugs altered the initiation of drinking sessions in a dose-dependent fashion. FIN increased and GAN decreased time to first lick and first bout. THIP (8 mg/kg) decreased time to first lick but increased time to first bout and attenuated first bout size. CONCLUSIONS: The present findings support a role for the modulation of ethanol intake by neurosteroids and GABA(A) receptor-acting compounds and provide hints as to how drinking patterns are shifted. The ability of THIP to alter 10E drinking suggests that extrasynaptic GABA(A) receptors may be involved in the modulation of ethanol intake. Further, the consistent results with THIP to that seen previously with high doses of ALLO suggest that future studies should further examine the relationship between neurosteroids and extrasynaptic GABA(A) receptors, which could provide a better understanding of the mechanism by which neurosteroids influence ethanol intake. PMID- 21649673 TI - Commonalities. PMID- 21649674 TI - Changes in health professionals' knowledge, attitudes and practice following provision of educational resources about prevention of prenatal alcohol exposure and fetal alcohol spectrum disorder. AB - We provided health professionals in Western Australia (WA) with educational resources about prevention of prenatal alcohol exposure and fetal alcohol spectrum disorder and assessed changes in their knowledge, attitudes and practice concerning fetal alcohol syndrome (FAS) and alcohol consumption in pregnancy. Following our 2002 survey of health professionals in WA, we developed and distributed educational resources to 3348 health professionals in WA in 2007. Six months later we surveyed 1483 of these health professionals. Prevalence rate ratios [PRR] and 95% confidence intervals [CI] were calculated to compare 2007 results with results from the 2002 survey. Of the 1001 responding health professionals, 69.8% had seen the educational resources; of these 77.1% have used them and 48.5% said the resources had assisted them to change their practice or their intention to change their practice. Compared with 2002, there was an increase in the proportion who knew all the essential features of FAS from 11.7% to 15.8% [PRR 1.35; 95% CI 1.09, 1.67] and had diagnosed FAS, from 4.8% to 7.3% [PRR 1.52; 95% CI 1.08, 2.13]. In 2007, 98.1% of health professionals stated they would advise pregnant women to consider not drinking at all or advise them that no alcohol in pregnancy is the safest choice. Health professionals surveyed in 2007 have increased their knowledge, changed their attitudes and practice about FAS, and altered the advice they give to pregnant women about alcohol consumption since our survey in 2002. It is essential that we build on this change and continue to support health professionals' knowledge, attitudes and practice about the prevention of prenatal alcohol exposure and fetal alcohol spectrum disorder. The educational resources for health professionals may be ordered as hard copies and downloaded from the internet http://www.ichr.uwa.edu.au/alcoholandpregnancy. PMID- 21649675 TI - Patterns of alcohol consumption among pregnant African-American women in Washington, DC, USA. AB - The objective of this paper is to describe the patterns and associated behaviours related to alcohol consumption among a selected sample of pregnant women seeking prenatal care in inner city Washington DC. Women receiving prenatal care at one of nine sites completed an anonymous alcohol-screening questionnaire. Questions concerned the amount, type and pattern of alcohol consumption. Women were categorised as at no, low, moderate or high risk for alcohol consumption during pregnancy. For comparisons of risk levels of drinking, bivariate associations were examined using Fisher's exact test. Odds ratios (ORs) and 95% confidence intervals (CIs) were also computed. Although 31% of current/recent drinkers stated that they continued to drink during pregnancy, responses to quantity/frequency questions revealed that 42% continued to do so. Women who were at high compared with moderate risk acknowledged that others were worried about their consumption [OR=4.0, 95% CI 1.5, 10.6], that they drank upon rising [OR=6.7, 95% CI 1.8, 26.9], had a need to reduce drinking [OR=3.2, 95% CI 1.3, 8.1] and in the past 5 years had had fractures [OR=4.2, 95% CI 1.0, 17.8] or a road traffic injury [OR=3.4, 95% CI 1.0, 12.2]. Women in the high/moderate compared with low-risk group were more likely to have been injured in a fight or assault [OR=2.7, 95% CI 1.3, 5.6]. This study validated the usefulness of our questionnaire in identifying women who were at risk for alcohol consumption during pregnancy across a range of consumption levels. Using our screening tool, women were willing to disclose their drinking habits. This low-cost method identifies women appropriate for targeting of interventions. PMID- 21649676 TI - Maternal dietary glycaemic intake during pregnancy and the risk of birth defects. AB - High sugar intake has been linked to fetal anomalies in the presence and absence of insulin resistance. Using dietary data collected in the Boston University Slone Epidemiology Birth Defects Study, we examined whether high dietary glycaemic index (dGI) or load (dGL) increased the risk of birth defects. Non diabetic mothers of 1921 cases and 704 controls were interviewed within 6 months of delivery (1988-98) about pregnancy events and exposures, including a 99-item food frequency questionnaire. Case groups included amniotic bands, craniosynostosis, gastroschisis, hypospadias, small intestinal defects, anorectal defects, limb reductions, omphalocele, cleft lip and/or palate, renal agenesis, and tracheoesophageal fistula. Cubic splines were used to determine cut-point values for high dGI and dGL in relation to the risk of each birth defect. The cut points were used in logistic regression models to calculate odds ratios (OR) and 95% confidence intervals [CI]. Control mothers in the lowest quartile of glycaemic intake were more likely to be non-Hispanic White, >= 30 years of age, have higher family income, have a normal body mass index and reside in Boston. Findings were null for most case groups. The anorectal defect case group was found to have elevated risks for dGL [adjusted OR: 2.4; 95% CI: 1.1, 4.9], while estimates for dGI were elevated for the amniotic band case group [adjusted OR: 3.0; 95% CI: 1.1, 8.1]. Because this is the first paper (to our knowledge) to explore dGI and dGL in relation to a spectrum of birth defects, additional studies are needed. PMID- 21649677 TI - Neighbourhood socio-economic characteristics and the risk of preterm birth for migrant and non-migrant women: a study in a French district. AB - Neighbourhood-level deprivation is associated with preterm birth; preterm birth rates are also higher for some, but not all migrant groups. We studied the impact of neighbourhood characteristics (a deprivation score and the proportion of foreign-born residents) on singleton preterm birth in the French district of Seine-Saint-Denis for women born in France, North Africa, sub-Saharan Africa and other countries. Multilevel logistic regression models were adjusted for maternal demographic and health care characteristics. For women born in France, the preterm birth rate rose with neighbourhood deprivation quintile (3.8% in the first to 5.7% in the fifth, adjusted odds ratio: 1.40 [95% confidence interval 1.14, 1.72]) and with increasing proportions of foreign-born residents. Preterm birth rates were not higher in more deprived neighbourhoods for women born outside of France and were lower in neighbourhoods with more foreign-born residents; in multilevel models, the inverse association with deprivation remained significant for women from sub-Saharan Africa. Area-based deprivation measures should be used with caution in populations with large numbers of migrants. These results raise questions about the health benefits of clustering for migrant communities as well as the negative consequences of acculturation. PMID- 21649678 TI - Socioeconomic inequalities and infant mortality of 46,470 preterm infants born in Sweden between 1992 and 2006. AB - Studies on possible sociodemographic inequities in the survival of preterm infants are scarce. Individual and neighbourhood sociodemographic factors are related to preterm birth and to infant mortality in full-term infants. The aim here was to examine whether infant mortality in Swedish preterm infants is related to individual and neighbourhood sociodemographic factors, and to study whether the hypothesised association between neighbourhood deprivation and infant mortality persists after accounting for individual sociodemographic factors. The study included 46,470 infants with a gestational length of <37 weeks, born in Sweden between 1992 and 2006. Neighbourhood deprivation was assessed by an index (education, income, unemployment, welfare assistance) in small geographical units, and categorised into low, moderate and high deprivation. Adjusted odds ratios for infant mortality were examined in relation to individual and neighbourhood sociodemographic factors. After adjusting for maternal age, infant mortality was associated with the following sociodemographic variables: maternal non-married/non-cohabiting status, low family income, low maternal education and rural status. After full adjustment, the odds ratio [95% confidence interval] was 2.98 [2.42, 3.67] for low family income compared with high family income. An increase in infant mortality was also associated with high neighbourhood deprivation; however, this increased risk no longer remained statistically significant after adjusting for individual sociodemographic factors. In conclusion, this study showed an increased infant mortality in preterm infants born to women with a less favourable sociodemographic profile. PMID- 21649679 TI - The Modified Checklist for Autism in Toddlers in extremely low gestational age newborns: individual items associated with motor, cognitive, vision and hearing limitations. AB - The Modified Checklist for Autism in Toddlers (M-CHAT) has yielded elevated rates of screening failure for children born preterm or with low birthweight. We extended these findings with a detailed examination of M-CHAT items in a large sample of children born at extremely low gestational age. The sample was grouped according to children's current limitations and degree of impairment. The aim was to better understand how disabilities might influence M-CHAT scores. Fourteen participating institutions of the Extremely Low Gestational Age Newborns (ELGAN) Study prospectively collected information about 1086 infants who were born before the 28th week of gestation and had an assessment at age 24-months. The 24-month visit included a neurological assessment, the Bayley Scales of Infant Development, Second edition (BSID-II), M-CHAT and a medical history form. Outcome measures included the distribution of failed M-CHAT items among groups classified according to cerebral palsy diagnosis, gross motor function, BSID-II scores and vision or hearing impairments. M-CHAT items were failed more frequently by children with concurrently identified impairments (motor, cognitive, vision and hearing). In addition, the frequency of item failure increased with the severity of impairment. The failed M-CHAT items were often, but not consistently, related to children's specific impairments. Importantly, four of the six M-CHAT 'critical items' were commonly affected by presence and severity of concurrent impairments. The strong association between impaired sensory or motor function and M-CHAT results among extremely low gestational age children suggests that such impairments might give rise to false positive M-CHAT screening. PMID- 21649680 TI - Duration of gestation, size at birth and later childhood behaviour. AB - Although many previous studies have reported an association between preterm birth or small size at birth and later behaviour, multiple methodological limitations threaten the validity of causal inferences from reported associations. The authors have examined the association between gestational age and gestational age specific size at birth (weight, length and head circumference) and behaviour in a large sample of children born healthy at term. The data were from the 6.5-year follow-up of 13,889 Belarusian children who participated in the Promotion of Breastfeeding Intervention Trial, a cluster-randomised trial of a breast-feeding promotion intervention. Child behaviour was measured using the parent and teacher versions of the Strengths and Difficulties Questionnaire (SDQ). Differences in SDQ scores by gestational age and by birthweight, birth length and birth head circumference standardised for gestational age and sex (z-scores) were analysed after controlling for potentially confounding maternal and family factors. There was no association between gestational age and child behaviour after adjusting for potential confounding factors. Lower birthweight-for-gestational age was associated with higher scores in problem behaviours including total difficulties, conduct problems, hyperactivity, emotional symptoms and peer problems. Similar but smaller differences were observed with birth length and birth head circumference, but those differences were attenuated with adjustment for birthweight. The patterns of association were consistent in both parent and teacher assessments. Among school-age children born at term within normal range of birthweight, fetal growth, but not gestational age, was associated with behavioural problem scores. PMID- 21649681 TI - Seroepidemiology of varicella-zoster virus and reliability of varicella history in Turkish children, adolescents and adults. AB - This study aimed to assess the age specific varicella-zoster virus (VZV) seroprevalence in Izmir, Turkey and to determine the reliability of a history of varicella to detect susceptible children, adolescents and adults. A questionnaire, including previous history of varicella, was completed for each participant and, in 590 of them, VZV-specific IgG was measured using an ELISA test. Overall, 28.5% of individuals were seronegative for VZV. By 5 years of age, only 25.5% of children were seropositive for VZV. Among adolescents and young adults, 18.8% and 11.7% were seronegative, respectively. The negative predictive value was 57.8%, decreasing with age (81.9% in children, 34.5% in adolescents and 8.3% in adults). In conclusion, a negative history of varicella is not a reliable predictor of varicella antibody status in adolescents and young adults. Serological testing before immunisation will be logical, rather than presumptive vaccination, for adolescents and adults with negative history of varicella. PMID- 21649682 TI - Secular trends in age at menarche in women in the UK born 1908-93: results from the Breakthrough Generations Study. AB - Menarcheal age decreased over time in Western countries until cohorts born in the mid-20th century. It then stabilised, but limited data are available for recent cohorts. Menarche data were collected retrospectively by questionnaire in 2003-10 from 94,170 women who were participating in the Breakthrough Generations Study, aged 16-98 years, born 1908-93 and resident in the UK. Average menarcheal age declined from women born in 1908-19 (mean=13.5 years) to those born in 1945-49 (mean=12.6 years). It was then stable for several birth cohorts, but resumed its downward trend in recent cohorts (mean=12.3 years in 1990-93 cohort). Trends differed between socio-economic groups, but the recent decline was present in each group. In conclusion, menarcheal age appears to have decreased again in recent cohorts after a period of stabilisation. PMID- 21649683 TI - How should research in bioethics be assessed? PMID- 21649684 TI - Making principlism practical: a commentary on Gordon, Rauprich, and Vollmann. PMID- 21649685 TI - 'They say Islam has a solution for everything, so why are there no guidelines for this?' Ethical dilemmas associated with the births and deaths of infants with fatal abnormalities from a small sample of Pakistani Muslim couples in Britain. AB - This paper presents ethical dilemmas concerning the termination of pregnancy, the management of childbirth, and the withdrawal of life-support from infants in special care, for a small sample of British Pakistani Muslim parents of babies diagnosed with fatal abnormalities. Case studies illustrating these dilemmas are taken from a qualitative study of 66 families of Pakistani origin referred to a genetics clinic in Southern England. The paper shows how parents negotiated between the authoritative knowledge of their doctors, religious experts, and senior family members in response to the ethical dilemmas they faced. There was little knowledge or open discussion of the view that Islam permits the termination of pregnancy for serious or fatal abnormality within 120 days and there was considerable disquiet over the idea of ending a pregnancy. For some parents, whether their newborn baby would draw breath was a main worry, with implications for the baby's Muslim identity and for the recognition of loss the parents would receive from family and community. This concern sometimes conflicted with doctors' concerns to minimize risk to future pregnancies by not performing a Caesarean delivery if a baby is sure to die. The paper also identifies parents' concerns and feelings of wrong-doing regarding the withdrawal of artificial life-support from infants with multiple abnormalities. The conclusion considers some of the implications of these observations for the counselling and support of Muslim parents following the pre- or neo-natal diagnosis of fatal abnormalities in their children. PMID- 21649686 TI - Lateral epicondylalgia. A quantitative and qualitative analysis of interdisciplinary cooperation and treatment choice in the Swedish health care system. AB - OBJECTIVE AND AIM: Interdisciplinary cooperation is essential to develop a broad range of knowledge and skills. The aim of this study was to describe health care professionals' treatment choices, their cooperation with other professionals and their perceptions of potential risks regarding treatments of acute lateral epicondylalgia (LE). DESIGN: A quantitative descriptive study design with a summative approach to qualitative analysis. ETHICAL ISSUES: The ethical committee was asked verbally for approval but, as this study was performed to develop an organised way to treat LE, it did not require approval. The four ethical aspects information, consent, confidentiality and the use of the study materials were all addressed. SUBJECTS: All orthopaedic surgeons, general practitioners, physiotherapists and occupational therapists in a county. METHODS: Questionnaire with 18 dichotomous, multiple-response, multiple-choice questions and three open ended questions were analysed using quantitative cross-tab and qualitative content analysis with summative approach. RESULTS: The most common treatment choices were Non Steroidal Anti Inflammatory Drugs (NSAID), corticosteroid injections, training programmes, braces and ergonomics. Advantages from interdisciplinary cooperation were higher rated than disadvantages. The qualitative findings dealt with perceptions of interdisciplinary cooperation and resulted in three categories; right level of care, increased quality of care and decreased quality of care. Almost half of the physicians felt potential risks associated with their treatment methods. The qualitative findings dealt with perceptions of the potential risks and resulted in two categories: side effects and inadequate treatment. STUDY LIMITATIONS: The number of responses varied because some of the respondents did not answered all of the questions. CONCLUSION: Interdisciplinary cooperation in the treatment of patients with acute LE benefits the patients by shortening the rehabilitation period and provides health care professionals the opportunity for an improved learning and exchanging experiences. These basic conditions must be met to improve health care quality. PMID- 21649687 TI - Assessing the emerging oncogene protein kinase C epsilon as a candidate gene in families with Carney complex-2. PMID- 21649688 TI - New therapeutic options for metastatic malignant insulinomas. AB - Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded. PMID- 21649689 TI - Superficial Ewing's sarcoma family of tumors: a clinicopathological study with differential diagnoses. AB - BACKGROUND: Superficial/cutaneous Ewing's sarcoma family of tumors (ESFT) are rare and have a relatively favorable prognosis compared with deep-seated tumors. The aim of the present study is to describe the clinicopathological characteristics of six genetically confirmed ESFT presenting a superficial location. METHODS: Clinical data, radiology, histopathology, immunohistochemistry, molecular study [reverse transcriptase-polymerase chain reaction (RT-PCR)/fluorescence in situ hybridization], treatment and follow-up data were retrieved. RESULTS: Locations included fingers (2), back (1), neck (1), thigh (1) and subcutaneous breast (1). Two tumors showed conventional morphology, one consisted of primitive neuroectodermal tumor and three tumors showed atypical vascular morphology with hemosiderin deposition and pigmentation. All cases showed CD99, FLI-1, HNK-1 and CAV-1 positivity. RT-PCR revealed the EWS/Fli1 gene fusion in all cases. Treatment was by wide excision in all cases; one received chemotherapy (CT) and one CT and radiotherapy. Available follow-up revealed the following: two patients with metastasis and death at 5 months and 2 years and one local recurrence at 18 years. CONCLUSIONS: Superficial ESFT appears to have a relatively favorable prognosis but further studies with additional series, a larger number of cases and more extensive follow-up are necessary to confirm this statement. PMID- 21649690 TI - Verrucous hemangioma: a report of two cases and review of the literature. AB - Verrucous hemangioma represents a rare congenital vascular proliferation that may be mistaken for angiokeratoma. Histopathological examination of a deep biopsy is necessary to confirm the diagnosis of verrucous hemangioma based on its involvement of the deep dermis and subcutaneous tissue. We present two cases of verrucous hemangioma and discuss the clinicopathologic and immunohistochemical findings. PMID- 21649692 TI - Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents. AB - AIMS: To investigate atazanavir (ATV) population pharmacokinetics in children and adolescents, establish factors that influence ATV pharmacokinetics and investigate the ATV exposure after recommended doses. METHODS: Atazanavir concentrations were measured in 51 children/adolescents during a mean therapeutic monitoring follow up of 6.6 months. A total of 151 ATV plasma concentrations were obtained, and a population pharmacokinetic model was developed with NONMEM. Patients received ATV alone or boosted with ritonavir. RESULTS: Atazanavir pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The effect of bodyweight was added on both apparent elimination clearance (CL/F) and volume of distribution using allometric scaling. Atazanavir CL/F was reduced by ritonavir by 45%. Tenofovir disoproxil fumarate (TDF) co-medication (300 mg) increased significantly by 25% the atazanavir/ritonavir (ATV/r) CL/F. Mean ATV/r CL/F values with or without TDF were 8.9 and 7.1 L h(-1) (70 kg)(-1), respectively. With the recommended 250/100 mg and 300/100 mg ATV/r doses, the exposure was higher than the mean adult steady state exposure in the bodyweight range of 32-50 kg. CONCLUSIONS: To target the mean adult exposure, children should receive the following once-daily ATV/r dose: 200/100 mg from 25 to 39 kg, 250/100 mg from 39 to 50 kg and 300/100 mg above 50 kg. When 300 mg TDF is co-administered, children should receive (ATV/r) at 250/100 mg between 35 and 39 kg, then 300/100 mg over 39 kg. PMID- 21649691 TI - Anti-platelet therapy: phosphodiesterase inhibitors. AB - Inhibition of platelet aggregation can be achieved either by the blockade of membrane receptors or by interaction with intracellular signalling pathways. Cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5' monophosphate (cGMP) are two critical intracellular second messengers provided with strong inhibitory activity on fundamental platelet functions. Phosphodiesterases (PDEs), by catalysing the hydrolysis of cAMP and cGMP, limit the intracellular levels of cyclic nucleotides, thus regulating platelet function. The inhibition of PDEs may therefore exert a strong platelet inhibitory effect. Platelets possess three PDE isoforms (PDE2, PDE3 and PDE5), with different selectivity for cAMP and cGMP. Several nonselective or isoenzyme selective PDE inhibitors have been developed, and some of them have entered clinical use as antiplatelet agents. This review focuses on the effect of PDE2, PDE3 and PDE5 inhibitors on platelet function and on the evidence for an antithrombotic action of some of them, and in particular of dipyridamole and cilostazol. PMID- 21649694 TI - Curiosity: a best practice in education. PMID- 21649695 TI - Curiosity's curious influence on medical doctors. PMID- 21649696 TI - Ethics lie in the situation and in the response. PMID- 21649697 TI - Teaching in general practice: considering conceptual lenses. PMID- 21649698 TI - Curiosity and medical education. AB - CONTEXT: For doctors, curiosity is fundamental to understanding each patient's unique experience of illness, building respectful relationships with patients, deepening self-awareness, supporting clinical reasoning, avoiding premature closure and encouraging lifelong learning. Yet, curiosity has received limited attention in medical education and research, and studies from the fields of cognitive psychology and education suggest that common practices in medical education may inadvertently suppress curiosity. OBJECTIVES: This study aimed to identify common barriers to and facilitators of curiosity and related habits of mind in the education of doctors. METHODS: We conducted a theory-driven conceptual exploration and qualitative review of the literature. RESULTS: Curiosity is related to inquisitiveness, reflection and mindfulness. Instructional practices can suppress curiosity by confusing haste with efficiency, neglecting negative emotions, promoting overconfidence and using teaching approaches that encourage passive learning. Curiosity tends to flourish in educational environments that promote the student's responsibility for his or her own learning, multiple perspectives and mindful reflection on both the subject and the learning process. Specific educational strategies that can support curiosity in classroom and clinical settings include the mindful pacing of teaching, modelling effective management of emotions, confronting uncertainty and overconfidence, using inquiry-based learning, helping students see familiar situations as novel, simultaneously considering multiple perspectives, and maximising the value of small-group discussions. Instructor attributes that contribute to the development of student curiosity include patience, a habit of inquiry, emotional candour, intellectual humility, transparency and recognition of the benefits to be gained in learning from peers. CONCLUSIONS: Curiosity, inquisitiveness and related habits of mind can be supported in medical education through specific, evidence-based instructional approaches. Medical educators should balance the teaching of facts, techniques and protocols with approaches that help students cultivate and sustain curiosity and wonder in the context rich, often ambiguous world of clinical medicine. PMID- 21649699 TI - How post-call resident doctors perform, feel and are perceived in out-patient clinics. AB - CONTEXT: Recently, in the U.S.A., the Accreditation Council for Graduate Medical Education guidelines limited residents' consecutive duty to 24 hours. In Europe, the European Working Time Directive limits the average working week to 48 hours. OBJECTIVES: This study aimed to examine the performance of post-call residents in out-patient interviews using subjective and objective measures and to assess residents' subjective feelings. METHODS: We conducted a cross-sectional analysis of a systematic sample of 170 paediatric primary care consultations conducted during 117 clinic sessions served by 47 residents at a teaching hospital, including 34 consultations conducted during 23 sessions by 20 post-call residents. Interviews were audiotaped and quantitatively analysed using the Roter Interactional Analysis System (RIAS). Residents and patients' parents gave subjective appraisals of the visits using short questionnaires. Major covariates are resident gender and the timing of the clinic. RESULTS: Results did not show significant differences between post-call residents and their peers who had left the hospital on time in most components of the out-patient interview. Subtle yet probably important differences emerged with findings that post-call residents were significantly less likely to ask a parent to repeat what she had just said, and parents seeing post-call residents were more likely to request the resident to repeat what he or she had just said and to check if the resident understood what they had said. Post-call residents were rated by objective coders as having better attitudes than their left-on-time counterparts, yet subjectively felt less satisfied and more fatigued. Female post-call residents felt less competent, less productive and less energetic; male post-call residents felt more challenged, more demoralised and busier. CONCLUSIONS: The changes in activating and partnering talk that occur in post-call residents are consistent with findings concerning sleep deprivation and speech. Female and male residents tended to attribute their post-call performance to different factors. Setting limits on working hours might help to avoid potential negative impacts on post-call resident feelings, and the impact of working hours on resident performance warrants further exploration. PMID- 21649700 TI - Stress responses in medical students in ambulatory and in-hospital patient consultations. AB - CONTEXT: Little is known about health professionals' responses to acute stressors encountered in the clinical environment. The goal of this study was to measure the subjective and physiological stress responses of medical students to consultations in familiar (in-hospital) and unfamiliar (ambulatory) settings. We hypothesised that: (i) providing a consultation in an unfamiliar setting would result in increased stress responses in medical students, and (ii) some differences in stress responses according to gender might become apparent. METHODS: A quantitative cross-over study was conducted over a 6-month period. Participating students were invited to provide consultations to patients in an ambulatory setting. In order to provide a control condition, each student was required to conduct a similar consultation (without reporting back to the patient) with an in-hospital patient during his or her rotation in internal medicine. Pre- and post-consultation subjective and physiological responses were measured using a visual analogue scale (VAS), the State-Trait Anxiety Inventory (STAI), a cognitive appraisal scale and salivary cortisol levels. RESULTS: All of the subjective and physiological stress responses were greater in the ambulatory setting than the in-hospital setting. There was an effect of gender on the responses. Women showed greater pre-consultation subjective stress levels in the ambulatory setting, whereas men exhibited greater physiological stress levels in the ambulatory setting. No correlations were observed between subjective and cortisol responses. CONCLUSIONS: Ambulatory consultations are more stressful for medical students than consultations carried out in the more familiar in-hospital setting. Further studies should be conducted to investigate the nature of the stressors in this particular environment, to explore the possible explanations for a gender effect, and to explore the effects of these stress responses on students' diagnostic skills. PMID- 21649701 TI - The influence of medical students' self-explanations on diagnostic performance. AB - CONTEXT: Skill in clinical reasoning is a highly valued attribute of doctors, but instructional approaches to foster medical students' clinical reasoning skills remain scarce. Self-explanation is an instructional procedure, the positive effects of which on learning have been demonstrated in a variety of domains, but which remain largely unexplored in medical education. OBJECTIVES: The purpose of this study was to investigate the effects of self-explanation on students' learning of clinical reasoning during clerkships and to examine whether these effects are affected by topic familiarity. METHODS: An experimental study with a training phase and an assessment phase was conducted with 36 Year 3 medical students, randomly assigned to one of two groups. In the training phase, students solved 12 clinical cases (four cases on a less familiar topic; four on a more familiar topic; four on filler topics), either generating self-explanations (n = 18) or not (n = 18). The self-explanations were generated after minimal instructions and no feedback was provided to students. One week later, in the assessment phase, students were requested to diagnose 12 different, more difficult cases, similarly distributed among the same more familiar topic, less familiar topic and filler topics, and their diagnostic performance was assessed. RESULTS: In the training phase the performance of the two groups did not differ. However, in the assessment phase 1 week later, a significant interaction was found between self-explanation and case topic familiarity (F(1,34) = 6.18, p < 0.05). Students in the self-explanation condition, compared with those in the control condition, demonstrated better diagnostic performance on subsequent clinical cases, but this effect emerged only for cases concerning the less familiar topic. CONCLUSIONS: The present study shows the beneficial influence of generating self-explanations when dealing with less familiar clinical contexts. Generating self-explanations without feedback resulted in better diagnostic performance than in the control group at 1 week after the intervention. PMID- 21649702 TI - Do study strategies predict academic performance in medical school? AB - CONTEXT: Study strategies, such as time and study management techniques, seem to be consistently related to achievement even when aptitude is controlled for, but the picture is not entirely clear. As there is limited research in this area, we explored the relative strengths of academic aptitude, as measured by the Medical College Admission Test (MCAT), undergraduate grade point average (UGPA) and study strategies, as measured by the Learning and Study Strategies Inventory (LASSI), in predicting academic performance in 106 students in the first semester of an integrated curriculum. OBJECTIVES: Our purpose was to determine whether relationships could be identified between academic aptitude, study strategies and academic performance which would enable us to provide students with feedback in certain skill areas in order to maximise achievement. METHODS: Data analysis consisted of four multiple regression analyses. The criterion variables were: semester overall final average, semester written examination average, semester practical examination average, and percentage correct on a customised National Board of Medical Examiners (NBME) examination. The predictor variables in each regression were: MCAT score; UGPA; and subscores on the 10 LASSI subscales for Anxiety, Attitude, Motivation, Concentration, Information Processing, Self Testing, Selecting Main Idea, Study Aids, Time Management and Test-Taking Strategies. RESULTS: The results of three regressions indicated that two study skills, time management and self-testing, were generally stronger predictors of first-semester academic performance than aptitude. CONCLUSIONS: Improving the prioritisation and organisation of study time and teaching students to predict, compose and answer their own questions when studying may help to advance student performance regardless of student aptitude, especially on course-specific examinations. PMID- 21649703 TI - Ethical issues encountered by medical students during international health electives. AB - CONTEXT: Medical students increasingly wish to participate in international health electives (IHEs). The authors undertook to understand from the students' perspective the ethical challenges encountered on IHEs in low-resource settings and how students respond to these issues. METHODS: Semi-structured interviews were conducted with 12 medical students upon their return from an IHE. A purposive sampling strategy was used. Inductive data analysis using a constant comparative technique generated initial codes which were later organised into higher-order themes. RESULTS: Five themes relating to ethical issues were identified: (i) uncertainty about how best to help; (ii) perceptions of Western medical students as different; (iii) moving beyond one's scope of practice; (iv) navigating different cultures of medicine, and (v) unilateral capacity building. CONCLUSIONS: International health electives are associated with a range of ethical issues for students. Students would benefit from formal pre-departure training, which should include an evaluation of their expectations of and motivations for participating in an IHE, careful selection of the IHE from amongst the opportunities available, learning about the local context of the IHE prior to departure, and the exploration and discussion of ethical and professionalism issues. Other factors that would benefit students include having an invested onsite colleague or supervisor, maintaining an ongoing connection with the home institution, and formal debriefing on conclusion of the IHE. PMID- 21649704 TI - Everyday ethics in internal medicine resident clinic: an opportunity to teach. AB - OBJECTIVES: Being a good doctor requires competency in ethics. Accordingly, ethics education during residency training is important. We studied the everyday ethics-related issues (i.e. ordinary ethics issues commonly faced) that internal medical residents encounter in their out-patient clinic and determined whether teaching about these issues occurred during faculty preceptor-resident interactions. METHODS: This study involved a multi-method qualitative research design combining observation of preceptor-resident discussions with preceptor interviews. The study was conducted in two different internal medicine training programme clinics over a 2-week period in June 2007. Fifty-three residents and 19 preceptors were observed, and 10 preceptors were interviewed. Transcripts of observer field notes and faculty interviews were carefully analysed. The analysis identified several themes of everyday ethics issues and determined whether preceptors identified and taught about these issues. RESULTS: Everyday ethics content was considered present in 109 (81%) of the 135 observed case presentations. Three major thematic domains and associated sub-themes related to everyday ethics issues were identified, concerning: (i) the Doctor-Patient Interaction (relationships; communication; shared decision making); (ii) the Resident as Learner (developmental issues; challenges and conflicts associated with training; relationships with colleagues and mentors; interactions with the preceptor), and; (iii) the Doctor-System Interaction (financial issues; doctor system issues; external influences; doctor frustration related to system issues). Everyday ethics issues were explicitly identified by preceptors (without teaching) in 18 of 109 cases (17%); explicit identification and teaching occurred in only 13 cases (12%). CONCLUSIONS: In this study a variety of everyday ethics issues were frequently encountered as residents cared for patients. Yet, faculty preceptors infrequently explicitly identified or taught these issues during their interactions with residents. Ethics education is important and residents may regard teaching about the ethics-related issues they actually encounter to be highly relevant. A better understanding of the barriers to teaching is needed in order to promote education about everyday ethics in the out-patient setting. PMID- 21649705 TI - Rewards, costs and challenges: the general practitioner's experience of teaching medical students. AB - CONTEXT: Medical student attachments in general practices play an important role in undergraduate medical education internationally. The recruitment by universities of new teaching practices or an increase in the teaching commitment of existing practices will be necessary to address rising medical student numbers. General practitioners (GPs) are likely to weigh the perceived rewards of practice-based teaching against the perceived costs and challenges in deciding whether to accept a student placement and how to teach. These aspects of the 'lived experience' of the GP-teacher have not been adequately investigated. OBJECTIVES: This study aims to enhance understanding of the GP clinical teacher experience in order to inform strategies for the recruitment, retention, training and support of teaching general practices. METHODS: Sixty GP clinical teachers in Brisbane-based urban teaching general practices were interviewed individually face-to-face by the principal investigator, using a semi-structured interview plan. Representativeness was ensured through quota sampling. The interview data were analysed thematically by two of the investigators independently, following member checking of interview transcripts. RESULTS: The results demonstrate a number of key inter-related perceived rewards, costs and challenges of teaching, including intellectual stimulation, cognitive fatigue and student characteristics. CONCLUSIONS: The findings extend reports in the previous literature by offering a richer description of current GP-teacher experience. Participants identified teaching rewards in a manner largely consistent with previous research, with the exception of enhanced practice morale and teamwork. Findings confirm that reduced productivity and increased time pressures remain key perceived negative impacts of teaching, but also reveal a number of other important costs and challenges. They emphasise the diversity of GP experience and practice cultures, and the need for teaching to enhance both GP and patient perceptions of consultation quality without increasing the load on the GP teacher. Recruitment and retention strategies should promote the rewards of teaching, and teacher training should respond to the costs and challenges of practice-based teaching, and facilitate the growth of GPs in their role as clinical educators. PMID- 21649706 TI - Early clinical experience: do students learn what we expect? AB - CONTEXT: Early clinical experience is thought to contribute to the professional development of medical students, but little is known about the kind of learning processes that actually take place. Learning in practice is highly informal and may be difficult to direct by predefined learning outcomes. Learning in medical practice includes a socialisation process in which some learning outcomes may be valued, but others neglected or discouraged. OBJECTIVES: This study describes students' learning goals (prior to a Year 1 nursing attachment) and learning outcomes (after the attachment) in relation to institutional educational goals, and evaluates associations between learning outcomes, student characteristics and place of attachment. METHODS: A questionnaire containing open-ended questions about learning goals and learning outcomes was administered to all Year 1 medical students (n = 347) before and directly after a 4-week nursing attachment in either a hospital or a nursing home. Two confirmatory focus group interviews were conducted and data were analysed using qualitative and quantitative content analyses. RESULTS: Students' learning goals corresponded with educational goals with a main emphasis on communication and empathy. Other learning goals included gaining insight into the organisation of health care and learning to deal with emotions. Self-reported learning outcomes were the same, but students additionally mentioned reflection on professional behaviour and their own future development. Women and younger students mentioned communication and empathy more often than men and older students. Individual learning goals, with the exception of communicating and empathising with patients, did not predict learning outcomes. CONCLUSIONS: Students' learning goals closely match educational goals, which are adequately met in early nursing attachments in both hospitals and nursing homes. Learning to deal with emotions was under-represented as a learning goal and learning outcome, which may indicate that emotional aspects of medical students' professional development are neglected in the first year of medical education. PMID- 21649707 TI - A final clinical examination using a sequential design to improve cost effectiveness. AB - CONTEXT: Good examinations have a number of characteristics, including validity, reliable scores, educational impact, practicability and acceptability. Scores from the objective structured clinical examination (OSCE) are more reliable than the single long case examination, but concerns about its validity have led to modifications and the development of other models, such as the mini-clinical evaluation exercise (mini-CEX) and the objective structured long examination record (OSLER). These retain some of the characteristics of the long case, but feature repeated encounters and more structure. Nevertheless, the practical considerations and costs associated with mounting large-scale examinations remain significant. The lack of metrics handicaps progress. This paper reports a system whereby a sequential design concentrates limited resources where they are most needed in order to maintain the reliability of scores and practicability at the pass/fail interface. METHODS: We analysed data pertaining to the final examination administered in 2009. In the complete final examination, candidates see eight real patients (the OSLER) and encounter 12 OSCE stations. Candidates whose performance is judged as entirely satisfactory after the first four patients and six OSCE stations are not examined further. The others - about a third of candidates - see the remaining patients and stations and are judged on the complete examination. Reliability was calculated from the scores of all candidates on the first part of the examination using generalisability theory and practicability in terms of financial resources. The functioning of the sequential system was assessed by the ability of the first part of the examination to predict the final result for the cohort. RESULTS: Generalisability for the OSLER was 0.63 after four patients and 0.77 after eight patients. The OSCE was less reliable (0.38 after six stations and 0.55 after 12). There was only a weak correlation between the OSLER and the OSCE. The first stage was highly predictive of the results of the second stage. Savings facilitated by the sequential design amounted to approximately GBP 30,000. CONCLUSIONS: The overall utility of examinations involves compromise. The system described provides good perceived validity with reasonably reliable scores; a sequential design can concentrate resources where they are most needed and still allow wide sampling of tasks. PMID- 21649708 TI - Student views of research training programmes in medical schools. AB - CONTEXT: Research activity is not a mandatory component of medical education in many developing countries, including Brazil, although such experiences can have a positive impact on the quality of medical education. The interest and involvement of medical students in research and the barriers they face in accessing research training in developing countries have not been adequately addressed. OBJECTIVES: We sought to assess the availability of scientific training programmes in Brazilian medical schools, the degree of involvement of medical students in these programmes, the main barriers to student involvement in research and possible reasons for the lack of scientific training programmes. METHODS: This study examined 13 medical programmes conducted in six Brazilian states. A total of 1004 medical students were interviewed. We evaluated the availability of scientific training in the institutions attended by these students, the participation of the students in such activities and students' reasons for not joining such programmes based on student answers to our questionnaire. RESULTS: Although only 7% of the medical students expressed no interest in research, only 60% of them were involved in research training. Students regarded a lack of institutional incentive as the most significant barrier to their participation in research activities. Other significant barriers included defective infrastructure and insufficient time available for professors to mentor undergraduate students. According to the feedback from the students, eight of the 13 schools investigated featured structured programmes for scientific training. However, a mean of only 47% of students participated in scientific training programmes on their campuses and 13% of students were compelled to pursue such activities off-campus. CONCLUSIONS: Although scientific training during medical education in Brazil is still less frequent than expected, most of the students were interested in research activities. The barriers to undergraduate scientific training described in this paper may help the Brazilian government improve research training in medical schools. These issues might also be explored in other developing countries. PMID- 21649709 TI - Dramaturgy in medical education. PMID- 21649710 TI - Medical safety: using end objectives to drive learning. PMID- 21649711 TI - Nonseptic tenosynovitis of the digital flexor tendon sheath caused by longitudinal tears in the digital flexor tendons: a retrospective study of 135 tenoscopic procedures. AB - REASONS FOR PERFORMING STUDY: Longitudinal tears (LTs) of the digital flexor tendons are an important cause of chronic tenosynovitis of the digital flexor tendon sheath (DFTS). The origin of those marginal tears is not yet fully understood. The long-term outcome after medical and surgical treatment is guarded. OBJECTIVES: To determine the prevalence of LTs of the digital flexor tendons in a large population of horses undergoing diagnostic tenoscopy of the DFTS and to assess the outcome of surgical treatment and the factors influencing the outcome. METHODS: Medical records of 130 horses with chronic tenosynovitis of the DFTS that had tenoscopic surgery between 1999 and 2009 were evaluated. One hundred and thirty-five DFTSs were examined. LTs were diagnosed in 104 DFTSs in 101 horses and long-term follow-up was obtained. RESULTS: Seventy-eight percent of the horses with a nonseptic tenosynovitis of the DFTS had a LT. Preoperative ultrasonographic examination diagnosed tears in 76% of the cases. In showjumpers forelimbs were more frequently affected than hindlimbs (88 vs. 12%), with the right front having a higher incidence of injury than the left front (76 vs. 24%). Seventy-nine percent of the tears involved the deep digital flexor tendon (DDFT) and 87% were located on the lateral tendon border. Thirty-seven horses (38%) returned to an equal or higher level of work. The use of a radiofrequency probe (coblation) was associated with a lower level of performance and decreased the cosmetic end result. Persistence of marked post operative distension of the DFTS carried a poor prognosis for return to previous level of work. CONCLUSIONS AND POTENTIAL RELEVANCE: A guarded prognosis for future soundness should be given to horses presented for treatment of LTs of the digital flexor tendons. The use of coblation wands had a negative effect on the final outcome. PMID- 21649712 TI - Arthroscopic reattachment of osteochondritis dissecans cartilage flaps of the femoropatellar joint: long-term results. AB - REASONS FOR PERFORMING STUDY: Long-term efficacy of arthroscopic cartilage reattachment for the treatment of osteochondritis dissecans (OCD) lesions in the equine femoropatellar joint is unknown. OBJECTIVE: To evaluate radiographic outcome and long-term performance of horses undergoing OCD reattachment. HYPOTHESIS: Separated OCD cartilage flaps may be reincorporated into the joint surface by reattachment rather than flap removal. METHODS: Polydioxanone pins were utilised arthroscopically to reattach OCD lesions in 40 of 44 joints from 27 horses. Cartilage was reattached when it had persisting perimeter continuity, the surface was not deeply fissured or irregular, and the cartilage was not protuberant or extensively mineralised. Bone marrow aspirate concentrate was grafted to additional areas denuded of cartilage or alongside reattached cartilage. RESULTS: Breeds included Thoroughbred (n = 18), Quarter Horse (n = 4), Warmblood (n = 3), Standardbred (n = 1) and Arabian (n = 1). Mean age was 9.7 months. Radiographic lesion length was 1.5-6.3 cm. Reattachment alone was used in 32 of 44 affected joints, a combination of debridement and reattachment in 8 joints and debridement alone in 4 joints. One horse was destroyed due to tendon laceration. Of the remaining 26 horses, mean duration of follow-up was 15.6 months (range 2 months-12 years). Radiographic resolution of OCD lesions treated with reattachment was significantly improved at 6 months. Twenty horses had long term performance data, of which 19 were sound and had reached intended athletic potential. One horse remained lame, and an additional 6 were sound but remained unbroken or were convalescing. Thus, an overall success rate based upon continued soundness in performing horses was 95% (19/20). CONCLUSION: Cartilage flap reattachment can salvage OCD cartilage by integration with the underlying bone. POTENTIAL RELEVANCE: Extensive OCD cartilage flaps may be salvaged by reattachment which can result in normal radiographic subchondral bone contour and long-term athletic performance. PMID- 21649713 TI - A nationwide surveillance scheme for equine grass sickness in Great Britain: results for the period 2000-2009. AB - REASONS FOR PERFORMING STUDY: Equine grass sickness (EGS) remains a frequently fatal disease of equids in Great Britain (GB). The first nationwide surveillance scheme for EGS was developed to obtain information on the occurrence of EGS and to help facilitate future proposed intervention studies, such as vaccine trials. OBJECTIVES: To collect both retrospective and prospective data on cases of EGS occurring in GB since 2000 and to assess potential risk factors for categories of EGS and survival after chronic EGS. METHODS: Prospective data were collected using a nationwide surveillance scheme for EGS that was developed and initiated in 2007. Data were collected by means of postal and online questionnaires documenting both retrospective premises-level and prospective case-level information. Data on outcomes of EGS category and survival after chronic grass sickness (CGS) were analysed using univariable logistic regression. RESULTS: Descriptive data for 1410 EGS cases occurring in GB in the decade between the beginning of 2000 and the end of 2009 are presented. Univariable logistic regression analyses identified that CGS cases in Scotland were significantly more likely to survive than those occurring elsewhere in GB. There was no relationship between case details and the category of EGS or the outcome among CGS cases. CONCLUSIONS: EGS affected equids throughout England, Scotland and Wales. Although an overall average of 141 cases were reported to the nationwide surveillance scheme annually, this number of cases was not consistent between years. Around 50% of CGS cases survived, although regional differences in survival rates existed, probably due to variation in expertise of care and/or disease severity. POTENTIAL RELEVANCE: This study provides information on the spatiotemporal occurrence of EGS in GB during the last decade. Data from the nationwide surveillance scheme can be used in developing protocols for future intervention studies such as Clostridium botulinum vaccine trials. PMID- 21649714 TI - Magnetic resonance imaging and histological findings in the proximal aspect of the suspensory ligament of forelimbs in nonlame horses. AB - REASONS FOR PERFORMING STUDY: Detailed magnetic resonance imaging (MRI) and histological appearances of the proximal aspect of the suspensory ligament (PSL) in the forelimb of nonlame horses have not been previously documented. OBJECTIVES: 1) to describe detailed anatomy of the PSL, 2) describe high- and low field MRI and histological appearances of the PSL and surrounding structures in the forelimb of horses with no carpal or proximal metacarpal pain, 3) assess the relationship between age, breed, gender, height, bodyweight and MRI findings and 4) describe the histological appearance of the PSL and compare this with MRI findings. METHODS: High- and low-field MR images of the PSL and related structures from 30 cadaver limbs of nonlame horses were analysed subjectively and objectively. Univariable and multivariable linear regression analyses were used to assess the association of age, breed, gender, height and bodyweight with MRI findings. Histological and MRI findings of the PSL of 9 limbs were compared subjectively. RESULTS: The collagenous tissue of the PSL had low to intermediate signal intensity depending on the pulse sequence. There was a large variation among horses in the amount, shape and signal intensity of the muscle and adipose tissue within the PSL. Comparison of MR images with histological slides revealed that the high signal intensity areas corresponded to adipose tissue and intermediate signal intensity areas to muscle tissue. The medial lobe of the PSL had a smaller cross sectional area (CSA) than the lateral lobe; there was a positive association between CSA of the PSL and both horse height and bodyweight (P<0.001). CONCLUSIONS AND POTENTIAL RELEVANCE: The large variability in the MRI appearance of the PSL in nonlame horses should be borne in mind when interpreting MR images of lame horses. PMID- 21649715 TI - The arthroscopic and ultrasonographic boundaries of the equine femorotibial joints. AB - REASONS FOR PERFORMING STUDY: While descriptions of the visible soft tissues of the femorotibial joints exist for both arthroscopy and ultrasonography, there are few examples in the literature that discuss in detail the combined findings of these modalities. OBJECTIVES: To further elucidate the ultrasonographic and arthroscopic boundaries of the normal equine femorotibial joints and improve the understanding of the benefits and limitations of each individual modality. METHODS: Simultaneous arthroscopy and ultrasonography were performed in 10 equine cadaver stifles as well as bilateral stifles on a horse that underwent nonrecovery surgery. The arthroscopic probe was visualised ultrasonographically and concurrent video and still images acquired. RESULTS: Arthroscopy provided good visualisation of the cranial meniscal ligaments, the distal portion of the cranial cruciate ligament, proximal portion of the medial collateral ligament within the fibrous tissue of the joint capsule and a limited view of the abaxial border of meniscus. Ultrasonography allowed for almost complete visualisation of the menisci, collateral ligaments and cranial meniscal ligaments and a portion of the cranial cruciate ligament. CONCLUSIONS: By comparing the ultrasonographically and arthroscopically visible structures, this study allowed for a more complete understanding of the advantages and limitations of each modality. The ability of ultrasonography to resolve mild pathological changes should be further explored. POTENTIAL RELEVANCE: When used together, these modalities can provide a more global image of the femorotibial joints. PMID- 21649716 TI - Exercise in Thoroughbred yearlings during sales preparation: a cohort study. AB - REASONS FOR PERFORMING STUDY: There is increasing evidence suggesting that early exercise in Thoroughbred racehorses may be beneficial to the development of the musculoskeletal system. At present, information on the exercise programmes and health problems of individual yearlings during a sales preparation is scant. OBJECTIVES: To describe the exercise and health problems of Thoroughbred yearlings during preparation for sales, and to identify variations in exercise between and within farms. METHODS: A prospective cohort study was used to collect exercise and health information from 18 farms across New Zealand. Daily exercise records for individual horses were recorded during the studfarms' preparation for the annual national yearling sales in January 2009. RESULTS: Data were collected from 319 yearlings, of which 283 (88.7%) were exercised (hand walking, mechanical walker and lungeing) during their preparations. Sales preparation lasted a median of 69 days (interquartile range 61-78) and differed significantly between farms (P<0.001). The median exercise time performed differed significantly by gender (P<0.001), farm (P<0.001) and month of the preparation (P<0.001), but not by type of sale (P = 0.14) or category of sales price (P = 0.12). Within certain farms, daily exercise differed between horses as did total exercise by gender and the number of days spent in the sales preparation. Lameness was the most common condition affecting yearlings and the overall incidence rate of lameness was 0.08 per 100 horse days (95% confidence interval 0.05-0.13). Incidence rates of lameness varied significantly between farms (P = 0.02), but not by age (P = 0.77), sales type (P = 0.58) or month of the preparation (P = 0.53). CONCLUSIONS AND POTENTIAL RELEVANCE: Yearling exercise programmes varied between and within farms. Since exercise is already being tailored for each individual horse, there may be an opportunity to allow for modifications to sales preparation with the future career in mind. PMID- 21649717 TI - Mechanism of osteoporosis in adolescent idiopathic scoliosis: experimental scoliosis in pinealectomized chickens. AB - To clarify the mechanism of osteoporosis in adolescent idiopathic scoliosis (AIS), we investigated radiological and histological changes in the cervical vertebrae of a chicken thoracic scoliosis model. Forty newly hatched broiler chicks were randomly divided into four equal groups: sham-operated chickens serving as control (CON), pinealectomized chickens (PNX), sham-operated (CON + MLT) and pinealectomized chickens (PNX + MLT) that received intraperitoneal administration of melatonin. Pinealectomy was performed at the age of 3 days, and the chickens were killed at 2 months of age. Postmortem X-rays were examined for the presence of scoliosis, and micro-computed tomography (micro-CT) images were taken to evaluate the microstructure of the cervical vertebrae. Histological specimens of the scanned cervical vertebra were prepared, and a midsagittal section was stained with hematoxylin and eosin and tartrate-resistant acid phosphatase to evaluate the numbers of osteoblasts and osteoclasts, respectively. Scoliosis developed at the thoracic spine in all chickens of the PNX and in two of the PNX + MLT group. Micro-CT data revealed that chickens in the PNX group had a greater degree of generalized osteoporosis compared with the other birds. The number of osteoblasts was significantly decreased in the PNX group, while no significant difference was observed among chickens in the numbers of osteoclasts. Our results suggest that melatonin deficiency reduces osteoblast proliferation and leads to the development of scoliosis and osteoporosis. The restoration of melatonin prevented the development of scoliosis and osteoporosis, indicating that melatonin levels may be crucial to the development of deformity and osteoporosis in AIS. PMID- 21649718 TI - Melatonin, and to a lesser extent growth hormone, restores colonic smooth muscle physiology in old rats. AB - There is increasing evidence that aging is associated with oxidative damage, inflammation, and apoptosis in different cell types. However, there is limited information regarding aging mechanisms in colon smooth muscle. Old male Wistar rats (22 months) were treated for 10 wks with melatonin or growth hormone (GH). Animals were sacrificed at 24 months of age by decapitation. The colon was dissected and the smooth muscle homogenized. H(2)O(2) and malonyl dialdehyde (MDA) content and catalase and glutathione peroxidase (GPX) activities were determined using colorimetric kits. Expression of nuclear factor kappa B (NF kappaB), cyclooxygenase 2 (COX-2), caspase-3, and caspase-9 were determined by Western blot. Aging of colon smooth muscle correlated with an increase in H(2)O(2) and MDA levels when compared with young animals in both proximal and distal segments; these changes were associated with a decrease in the catalase activity in the distal colon. Oxidative stress correlated with an increase in COX 2 and NF-kappaB expression, which were accompanied by an enhanced expression of the pro-apoptotic enzyme caspase-3 and its upstream enzyme, caspase-9. Melatonin treatment normalized the oxidative, inflammatory, and apoptotic patterns, whereas GH replacement, although effective in reducing oxidative stress in distal colon, did not reverse the age-related inflammation or apoptosis. These results suggest that melatonin should be the treatment of choice to most effectively recover physiological functions in aged colonic smooth muscle. PMID- 21649719 TI - Body composition measured by dual-energy X-ray absorptiometry half-body scans in obese children. AB - AIM: To perform a methods comparison of a left or right half-body scan versus whole-body scan for measuring body composition in a sample of obese children. METHODS: A group of obese children (n = 58; >= 95th BMI percentile; 8-18 years) were required to undergo a dual-energy X-ray absorptiometry (DXA) body composition measurement as part of an ongoing cohort study; 34 fit within the imaging field of the DXA scanner and were eligible for inclusion in the present analysis. Percent fat, total mass, fat mass, lean mass and bone mineral content (BMC) were estimated from half-body scans and compared with the whole-body results. Assessment was completed using GE enCORE 11.40 software. RESULTS: In comparing left- and right-side scans to whole-body scans, there was significant correlation for all body composition variables (p <= 0.005, R(2) = 0.996-1.0). Bland Altman analyses also showed high levels of agreement between half-body estimates and whole-body measurements. CONCLUSION: This study supports using a half-body scan methodology for percent fat, total mass, fat mass, lean mass, and BMC as a valid alternative to full-body analysis in obese children and youth. PMID- 21649720 TI - Factors that influence cecal intubation rate during colonoscopy in deeply sedated patients. AB - BACKGROUND AND AIM: The technical performance of colonoscopy performed in deeply sedated patients differs from that performed without sedation or under minimal to moderate sedation. The aim of this study is to evaluate the factors affecting cecal intubation during colonoscopy performed under deep sedation. METHODS: A total of 5352 consecutive subjects who underwent a screening colonoscopy as part of a health check-up between January 2008 and December 2008 at an academic hospital were reviewed. All endoscopies were performed with deep sedation using combination propofol or propofol alone. Data collected included characteristics of the patients (age, gender, body mass index, bowel habits, history of abdominal or pelvic surgery, quality of bowel preparation, and presence/absence of colonic diverticula) and characteristics of the colonoscopists (experience level, colonoscopy procedure volume, and instrument handling method). These factors were analyzed to evaluate their impact on cecal intubation rates. RESULTS: The crude cecal intubation rate was 98% and the adjusted cecal intubation rate was 98.3%. The mean cecal intubation time was 5.6 +/- 3.2 min. Multivariate logistic regression analysis demonstrated that patient age greater than 60 years, constipation, poor colon preparation and a two-person colonoscopy procedure were independently associated with lower cecal intubation rates. CONCLUSIONS: Colonoscopy performed under deep sedation by experienced colonoscopists results in high cecal intubation rates. Among the significant patient-related predictors influencing the cecal intubation, the quality of the bowel preparation was the only modifiable factor. When performed by experienced hands, the one-person method was associated with higher cecal intubation rates than the two-person method. PMID- 21649721 TI - Identification of two portal vein tumor thrombosis associated proteins in hepatocellular carcinoma: protein disulfide-isomerase A6 and apolipoprotein A-I. AB - BACKGROUND AND AIM: Portal vein tumor thrombus (PVTT) is one of the factors that can affect prognosis and survival of hepatocellular carcinoma (HCC). In the present study, we aimed to find out some biomarkers associated with vascular invasion features of HCC with the method of comparative proteomic analysis. METHODS: The proteins were extracted from a pair of HCC tissues with PVTT and without PVTT, and then separated by two-dimensional polyacrylamide gel electrophoresis. Differentially expressed protein spots were identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Further analysis of two proteins were completed using real-time fluorescence quantitative polymerase chain reaction and western-blot in 40 HCC tissues with PVTT (n = 20) and without PVTT (n = 20). RESULTS: Among 465 protein spots displayed on the gels, 33 unique proteins (> twofold change, P < 0.01) were identified, including 24 upregulated in HCC tissue without PVTT and nine upregulated in HCC tissue with PVTT. The real-time fluorescence quantitative PCR showed no statistically significant difference between HCC tissues with PVTT and without PVTT for mRNA expressions of protein disulfide-isomerase, A6 (PDI A6) (P = 0.137) and apolipoprotein A-I (Apo A-I) (P = 0.718). However, compared with HCC tissues without PVTT, protein expression of PDI A6 was higher in HCC tissues with PVTT (P < 0.001), while protein expression of Apo A-I was lower in HCC tissues with PVTT (P = 0.012). CONCLUSIONS: PDI A6 and Apo A-I are closely related to vascular invasion feature of HCC. PMID- 21649722 TI - Frequent somatic mutations of mitochondrial DNA in traditional serrated adenomas but not in sessile serrated adenomas of the colorectum. AB - BACKGROUND AND AIM: Serrated adenomas (SAs), recently subdivided into traditional SAs (TSAs) and sessile SAs (SSAs), are recognized as a distinct form of neoplasia of the colorectum. One of the characteristics of SAs is hypermaturation of the gland epithelium due to the low extent of cell loss by apoptosis. Mutations of mitochondrial DNA (mtDNA) are closely associated with abnormality in apoptosis. We therefore examined mtDNA mutations in colorectal lesions including hyperplastic polyps (HPs), SSAs, TSAs, and carcinomas. METHODS: Examined were 25 HPs, 32 SSAs, 19 TSAs, and 138 carcinomas. The D310 region of the mtDNAs was examined by microsatellite assay. RESULTS: mtDNA mutations were detected in none of 25 (0%) HPs, one of 32 (3%) SSAs, six of 19 (32%) TSAs, and eleven of 133 (8%) carcinomas (five of the 138 carcinomas were not informative). The frequency of mtDNA mutations in the TSAs was significantly higher than that in the HPs, SSAs, and carcinomas (P = 0.004, P = 0.008, and P = 0.009, respectively). The frequency of mtDNA mutations in carcinomas was not significantly higher than that in HPs and SSAs (P = 0.14 and P = 0.28, respectively). CONCLUSION: Our data suggest that mtDNA mutations may play an important role in the development of TSAs and could be used as a genetic marker to aid in the diagnosis of colorectal lesions. PMID- 21649723 TI - Efficacy of adipose tissue-derived mesenchymal stem cells for fulminant hepatitis in mice induced by concanavalin A. AB - BACKGROUND AND AIM: Fulminant hepatitis is mainly caused by excessive immune response-mediated liver injury and its definitive therapy is liver transplantation. Mesenchymal stem cells, one of the adult stem cells, have an immunomodulatory effect on immune cells and reside in various tissues. The aim of this study was to investigate a therapeutic effect of adipose tissue-derived mesenchymal stem cells (ASCs) on fulminant hepatitis induced by concanavalin A (ConA). METHODS: The ASCs were isolated from adipose tissues of BALB/c mice and confirmed by detection of cell surface markers and induction of multi-lineage differentiation. BALB/c mice were injected with ConA and treated with ASCs, phosphate buffered saline (PBS) or splenocytes (SPLCs). Survival rates, levels of serum liver enzymes, titers of serum cytokines, histopathology and localization of ASCs were investigated. RESULT: The survival rate of ASC-injected mice significantly increased compared to PBS or SPLC-injected mice. This effect was dependent on doses and timing of ASCs injected. Improvement of liver enzyme levels, histopathological changes and suppression of inflammatory cytokine production were observed in ASC-injected mice. Fluorescent stained ASCs were detected in inflammatory liver, but not in normal liver. CONCLUSION: These results suggest that ASC treatment has a high potential to be an innovative therapy for fulminant hepatitis. PMID- 21649724 TI - Variation in human genetic polymorphisms, their association with Helicobacter pylori acquisition and gastric cancer in a multi-ethnic country. AB - BACKGROUND AND AIM: The contribution of human genetic polymorphisms to Helicobacter pylori infection and gastric cancer (GC) development remains unclear due to geographic variation in the association between specific host genetic polymorphisms and GC. In the current study we investigated the association between polymorphisms related to immune and cancer-related pathways and H. pylori infection among the major ethnicities, Chinese, Malay and Indian, resident in Singapore and Malaysia as well as the association between these polymorphisms and GC development in ethnic Chinese patients. METHODS: Thirty-four polymorphisms in 26 genes were typed by mass spectrometry in 422 patients undergoing endoscopy (162 Chinese, 113 Indian and 87 Malay controls and 60 Chinese GC cases). Patients were assessed for evidence of H. pylori infection. Odds ratios (OR) and confidence intervals (CI) were obtained using logistic regression models. RESULT: The prevalence of 16 polymorphisms varied significantly among the ethnicities. In the Chinese subgroup, nominally significant associations were shown between (i) EBBR2+1963G (rs1801200) and H. pylori infection (per-allele OR: 0.48, 95% CI 0.23, 0.98, P = 0.04), (ii) PTGS2-1195G (rs689466) and an increased risk of GC on adjusting for H. pylori status (OR: 1.53, 95% CI 0.99, 2.37, P = 0.05), and (iii) IL1B-1473C (rs1143623) and a decreased risk of GC (OR: 0.64, 95% CI 0.41, 0.99, P = 0.05). Borderline significant associations were seen between IL2-330G (rs2069762) (OR 1.45, 95% CI 0.95, 2.15, P = 0.06) and IL13-1111T (rs1800925) (OR 0.65, 95% CI 0.42, 1.01, P = 0.06) and H. pylori infection. CONCLUSION: These findings contribute to the understanding of the genetic variation between ethnicities, which may influence H. pylori susceptibility and the outcome of infection. PMID- 21649725 TI - Endosonography-guided fine needle aspiration cytology of intra-abdominal lymph nodes with unknown primary in a tuberculosis endemic region. AB - BACKGROUND AND AIM: Intra-abdominal lymphadenopathy poses a diagnostic and management challenge in highly endemic regions for tuberculosis. Opting for empirical anti-tuberculosis treatment raises the risk of wrong or delayed treatment. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the procedure of choice for tissue acquisition from peri-luminal lymph nodes. We studied the utility of EUS-FNA in evaluating intra-abdominal lymph nodes of unknown etiology, in the setting of high endemicity of tuberculosis. METHODS: Consecutive patients with intra-abdominal lymph nodes of unknown etiology underwent EUS-FNA using a 22-gauge needle. Final diagnosis was made on surgical histology or on 6-months follow-up. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic yield were calculated. RESULTS: Sixty-six patients were included. Final diagnoses were tuberculosis, 35 (53%); metastatic adenocarcinoma, 11 (16.7%); lymphoma, three (4.5%); carcinoid, one (1.5%) and reactive nodes, 16 (24.2%). EUS-FNA provided a diagnosis in 61 patients (92.4%). Sensitivity, specificity, PPV and NPV for diagnosing tuberculosis via EUS-FNA were 97.1%, 100%, 100% and 96.9%, respectively. In 10 (15.2%) patients receiving empirical anti-tuberculosis treatment, the final diagnoses were metastatic adenocarcinoma (5), lymphoma (2), carcinoid (1) and reactive adenopathy (2). CONCLUSION: Despite being in a highly endemic area, almost half of the patients studied have a non-tuberculosis etiology. EUS-FNA is a safe and accurate procedure for establishing the diagnosis of unexplained intra-abdominal lymphadenopathy. PMID- 21649726 TI - Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. AB - BACKGROUND AND AIMS: Although hepatic steatosis (HS) has an association with hepatitis C virus (HCV) infection, an association with hepatitis B virus (HBV) is controversial. We performed a meta-analysis to evaluate HS prevalence and risk factors, in HBV infection. METHODS: Standard guidelines for performance of meta analyses were followed. Studies with HS assessed by histology were included. Pooled odd ratios (OR) and standardized mean differences (SMD) were obtained with the random-effects model and DerSimonian-Laid method. RESULTS: Seventeen out of 21 studies were included, comprising 4100 HBV infected patients. Overall HS prevalence was 29.6%. Eight studies also included 945 HCV infected patients, showing decreased risk of HS in HBV versus HCV patients (OR 0.55, 95%CI [0.45 0.67], P < 0.001). In HBV, HS positively associated with male gender (OR 1.74, 95%CI [1.28-2.38], P < 0.001), body mass index (SMD 2.17, 95%CI [1.23, 3.11], P < 0.001), obesity (OR 6.59, 95%CI [3.51-12.257], P = 0.003), diabetes (OR 2.62, 95%CI [1.37-4.00], P = 0.004), glycemia (SMD 0.84, 95%CI [0.00, 1.67], P = 0.049), triglycerides (SMD 1.18, 95%CI [0.48, 1.89], P = 0.001), cholesterol (SMD 0.88, 95%CI [0.31, 1.45], P = 0.003), moderate alcohol consumption (OR 1.54, 95%CI [1.10-2.15], P = 0.011) and negatively with HBV DNA (SMD -74.12, 95%CI [ 82.93, -65.31], P < 0.001). HS had no association with aminotransferases, HBeAg, genotype or hepatic histology, necroinflammation or fibrosis. CONCLUSION: HS in HBV seems to be as frequent as in the general population, and lower than in HCV infected patients, relating to metabolic factors but not with hepatic histology severity. A puzzling strong negative association between viral load and HS, may even suggest a protective effect of the virus on HS. PMID- 21649728 TI - One-step percutaneous transhepatic insertion of a balloon-expanding metallic stent for obstructive jaundice. AB - BACKGROUND AND AIM: The aim of this study was to evaluate the efficacy and safety of one-step percutaneous transhepatic insertion of the Express LD stent, a balloon-expanding stainless steel stent used for the management of distal artery stenosis in the treatment of obstructive jaundice caused by various inoperable malignancies. METHODS: Seventy-one consecutive patients with unresectable malignant biliary obstruction who underwent Express LD stent placement between 2007 and 2010 at our institute were reviewed. RESULTS: Mean stent patency was 165 +/- 144 days and mean patient survival was 180 +/- 156 days, while the cumulative stent patency rate and patient survival rate at 6 and 12 months were 79% and 65%, and 38% and 16%, respectively. Stents were successfully placed in all cases without any stent migration or misplacement. Stent failure occurred in 14 patients (20%), and 16 complications were observed, including 12 cholangitis (17%), two cholecysitis (3%), and two pancreatitis (3%). Y-configuration stenting for hilar bile duct obstruction was the only independent prognostic factor for stent failure. CONCLUSIONS: One-step percutaneous transhepatic insertion of the Express LD stent is effective and safe for the management of obstructive jaundice caused by inoperable malignancies. PMID- 21649727 TI - Optimal follow-up time to determine the sustained virological response in patients with chronic hepatitis C receiving pegylated-interferon and ribavirin. AB - BACKGROUND AND AIM: This study evaluated whether the assessment of hepatitis C virus (HCV)-RNA at 12 weeks (FW+12) post-treatment follow-up was as applicable as FW+24 to evaluate sustained virological response (SVR) using the highly sensitive real-time polymerase chain reaction (PCR) HCV assay. METHODS AND RESULTS: Two hundred and twenty-two patients with chronic hepatitis C were included in this study. Pegylated interferon (Peg-IFN) and ribavirin were administered for 24-72 weeks based on the genotype and viral load. Serum HCV-RNA was measured using real time PCR at pretreatment, the end of treatment, FW+4, FW+8, FW+12, FW+16, FW+20 and FW+24. Two hundred patients had a virological response at the end of treatment. One hundred and forty-eight of 200 (74.0%) patients with a virological response at the end of treatment had an SVR at the FW+24. The positive predictive value (PPV) to identify patients with SVR at FW+4, FW+8, FW+12 was 87.1, 96.1, 98.0%, respectively. The viral load showed a reversion to the basal level as early as 8 weeks in relapse patients. There were only three patients who relapsed after FW+12 and all three of these patients were females with genotype Ib and a high viral load. CONCLUSION: The assessment of serum HCV-RNA FW+12, using the highly sensitive real-time PCR assay, is almost as effective as FW+24 to predict SVR. However, there are false negatives in female patients with a high viral load of genotype Ib when the SVR is predicted by FW+12. The current standard with FW+24 is reasonable, but the assessment of serum HCV-RNA FW+12 may be effective in most patients. PMID- 21649729 TI - Preoperative evaluation of the longitudinal extent of borderline resectable hilar cholangiocarcinoma by intraductal ultrasonography. AB - BACKGROUND AND AIM: In patients with hilar cholangiocarcinoma (HC), longitudinal tumor extent is important for curative resection. The purpose of this study was to evaluate the longitudinal extents of HC using transpapillary intraductal ultrasonography (IDUS) for optimal surgical planning. METHODS: From July 2006 to April 2010, a total of 42 patients with borderline resectable HC were enrolled at Samsung Medical Center, a tertiary referral hospital in Seoul, Korea. All patients were evaluated using multi-detector computed tomography (MDCT), endoscopic retrograde cholangiopancreatography (ERCP) and IDUS. The new modified Bismuth Type (MBT) classification, in which the traditional Bismuth type IV stage is divided into stages IVa and IVb, was used to determine whether the tumor invaded the left lateral section. Among the subtypes of HC, the periductal infiltrative type (PDI) and intraductal papillary neoplasm of the bile duct (IPN B) were compared. The accuracies of CT, ERCP, and IDUS were assessed through comparison with the postoperative histology findings. RESULTS: A total of 42 patients were prospectively enrolled, and the tumor extent could be assessed histologically in 30 patients. The accuracies of CT, ERCP, and IDUS were 66.6%, 60%, and 90%, respectively. The accuracy of IDUS was 85.7% in 21 patients with PDI and 100% in nine patients with IPN-B. CONCLUSIONS: Hilar cholangiocarcinoma staging based on IDUS findings was highly accurate. We therefore highly recommend using IDUS for optimal surgical planning in patients with borderline resectable HC. PMID- 21649730 TI - Functional characterization of genetic variants in the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). AB - BACKGROUND AND AIM: The major transporter responsible for bile acid uptake from the intestinal lumen is the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). Analysis of the SLC10A2 gene has identified a variety of sequence variants including coding region single nucleotide polymorphisms (SNPs) that may influence bile acid homeostasis/intestinal function. In this study, we systematically characterized the effect of coding SNPs on SLC10A2 protein expression and bile acid transport activity. METHODS: Single nucleotide polymorphisms in SLC10A2 from genomic DNA of ethnically-defined healthy individuals were identified using a polymerase chain reaction (PCR)-based temperature gradient capillary electrophoresis (TGCE) system. A heterologous gene expression system was used to assess transport activity of SLC10A2 nonsynonymous variants and missense mutations. Total and cell surface protein expression of wild-type and variant ASBT was assessed by Western blot analysis and immunofluorescence confocal microscopy. Expression of ASBT mRNA and protein was also measured in human intestinal samples. RESULTS: The studies revealed two nonsynonymous SNPs, 292G>A and 431G>A, with partially impaired in vitro taurocholate transport. A novel variant, 790A>G, was also shown to exhibit near complete loss of taurocholate transport, similar to the previously identified ASBT missense mutations. Examination of ASBT protein expression revealed no significant differences in expression or trafficking to the cell surface among variants versus wild-type ASBT. Analysis of ASBT mRNA and protein expression in human intestinal samples revealed modest intersubject variability. CONCLUSIONS: Genome sequencing and in vitro studies reveal the presence of multiple functionally relevant variants in SLC10A2 that may influence bile acid homeostasis and physiology. PMID- 21649731 TI - Validation study of the Leeds Dyspepsia Questionnaire in a multi-ethnic Asian population. AB - BACKGROUND AND AIM: Outcome measures for clinical trials in dyspepsia require an assessment of symptom response. There is a lack of validated instruments assessing dyspepsia symptoms in the Asian region. We aimed to translate and validate the Leeds Dyspepsia Questionnaire (LDQ) in a multi-ethnic Asian population. METHODS: A Malay and culturally adapted English version of the LDQ were developed according to established protocols. Psychometric evaluation was performed by assessing the validity, internal consistency, test-retest reliability and responsiveness of the instruments in both primary and secondary care patients. RESULTS: Between April and September 2010, both Malay (n=166) and Malaysian English (n=154) versions were assessed in primary and secondary care patients. Both language versions were found to be reliable (internal consistency was 0.80 and 0.74 (Cronbach's alpha) for Malay and English, respectively; spearman's correlation coefficient for test-retest reliability was 0.98 for both versions), valid (area under receiver operating curve for accuracy of diagnosing dyspepsia was 0.71 and 0.77 for Malay and English versions, respectively), discriminative (median LDQ score discriminated between primary and secondary care patients in Malay (11.0 vs 20.0, P<0.0001) and English (10.0 vs 14.0, P=0.001), and responsive (median LDQ score reduced after treatment in Malay (17.0 to 14.0, P=0.08) and English (18.0 to 11.0, P=0.008) to dyspepsia. CONCLUSIONS: The Malaysian versions of the LDQ are valid, reliable and responsive instruments for assessing symptoms in a multi-ethnic Asian population with dyspepsia. PMID- 21649732 TI - Susceptibility of rat non-alcoholic fatty liver to the acute toxic effect of acetaminophen. AB - BACKGROUND AND AIM: Acetaminophen overdose is the most frequent cause of acute liver failure. Non-alcoholic fatty liver disease is the most common chronic condition of the liver. The aim was to assess whether non-alcoholic steatosis sensitizes rat liver to acute toxic effect of acetaminophen. METHODS: Male Sprague-Dawley rats were fed a standard diet (ST-1, 10% kcal fat) and high-fat gelled diet (HFGD, 71% kcal fat) for 6 weeks and then acetaminophen was applied in a single dose (1 g/kg body weight). Animals were killed 24, 48 and 72 h after acetaminophen administration. Serum biochemistry, activities of mitochondrial complexes, hepatic malondialdehyde, reduced and oxidized glutathione, triacylglycerol and cholesterol contents, and concentrations of serum and liver cytokines (TNF-alpha, TGF-beta1) were measured and histopathological samples were prepared. RESULTS: The degree of liver inflammation and hepatocellular necrosis were significantly higher in HFGD fed animals after acetaminophen administration. Serum markers of liver injury were elevated only in acetaminophen treated HFGD fed animals. Concentration of hepatic reduced glutathione and ratio of reduced/oxidized glutathione were decreased in both ST-1 and HFGD groups at 24 h after acetaminophen application. Mild oxidative stress induced by acetaminophen was confirmed by measurement of malondialdehyde. Liver content of TNF-alpha was not significantly altered, but hepatic TGF-beta1 was elevated in acetaminophen treated HFGD rats. We did not observe acetaminophen-induced changes in activities of respiratory complexes I, II, and IV and activity of caspase-3. CONCLUSION: Liver from rats fed HFGD is more susceptible to acute toxic effect of acetaminophen, compared to non-steatotic liver. PMID- 21649733 TI - Helicobacter pylori induces promoter hypermethylation and downregulates gene expression of IRX1 transcription factor on human gastric mucosa. AB - BACKGROUND AND AIM: Gene silence of IRX1 tumor suppressor by promoter CpG methylation combined with loss of heterozygosity (LOH) has been identified in human gastric cancer. This study investigated the association between methylation of IRX1 and Helicobacter pylori infection in gastric mucosa tissues and cell line. METHODS: IRX1 methylation was studied by methylation specific polymerase chain reaction (MSP) and bisulfate sequencing polymerase chain reaction (BSP) methods in gastric mucosa tissues from H. pylori-positive chronic gastritis patients or H. pylori-negative chronic gastritis patients. Promoter activity, methylation status and gene expressing level of IRX1 were evaluated by persistent infecting H. pylori on human gastric cells GES-1 in vitro. Electron microscopy was used to observe the effect of H. pylori infection on GES-1 gastric mucosa cells. RESULTS: The methylation level of IRX1 promoter in H. pylori positive chronic gastritis and H. pylori negative chronic gastritis was 55.30%+/-13.17 versus 5.20%+/-6.31, respectively (P<0.01). H. pylori infection stimulated increased microvillus, and mucous secretion on GES-1 cells. Infection of H. pylori induced IRX1 promoter methylation and downregulation of the promoter activity as well as gene expression significantly. CONCLUSIONS: This study firstly demonstrated that H. pylori infection contributes to IRX1 promoter methylation on gastric mucosa. PMID- 21649734 TI - Percutaneous treatment of congenital coronary arteriovenous fistulas. AB - BACKGROUND: Congenital coronary arteriovenous fistulas (CAVF), although rare, can present as significant hemodynamic lesions necessitating intervention. METHODS AND RESULTS: Six patients (two males) with congenital coronary arteriovenous fistulas (CAVF) underwent percutaneous transcatheter occlusion. The ages ranged from 4 years to 49 years (mean 20.1 years). The fistulas had their origins from the right coronary artery (two), the left anterior descending coronary artery (two), and the left circumflex coronary artery (two). One of the fistulas drained to the right ventricle, four drained to the right atrium, and the remaining one to the left ventricle (LV). The fistulas were closed using the arterial approach with CookTM coils in two patients and with nitinol ductal occluders (NDOs) using the venous approach in four patients. One patient developed dissection of the wall of the fistula during attempted closure and had spontaneous occlusion of the fistula. Complete occlusion of the fistulas were achieved in all patients. Complications consisted of migration and embolization of the coils in one patient (later closed successfully with NDO) and myocardial infarction occurring two weeks following successful closure in another patient. At mean follow-up of 39.6 +/- 22.9 months, all patients were asymptomatic and echo-Doppler evaluation revealed no residual fistulae. CONCLUSIONS: CAVF are very well amenable to percutaneous closure with acceptable morbidity and high success rates. PMID- 21649736 TI - DNA hypermethylation as an epigenetic mark for oral cancer diagnosis. AB - Oral cancer is the largest group of cancers which fall into the head and neck category. While genetic alterations in oral cancer have long been documented, the effect of epigenetic changes is more recent. The recent explosion in science of how chromatin organization modulates the gene expression has highlighted the epigenetic mechanism of oral cancer pathogenesis. DNA methylation, which is an important epigenetic marker, is perhaps the best characterized chemical modification of mammalian DNA and provides a stable, heritable, and critical component of epigenetic regulation. This review attempts to decipher the epigenetic aspects of oral cancer by evaluating the DNA methylation status through its various stages from normal to potentially malignant to malignant states. In doing so, we emphasize DNA methylation as a novel biomarker in oral cancer research, thus opening newer avenues in oral cancer research. PMID- 21649737 TI - Alteration of stratum corneum ceramide profiles in spontaneous canine model of atopic dermatitis. AB - Ceramides (CERs) in the stratum corneum (SC) are thought to play a key role in cutaneous barrier function. It has been reported that human SC contains 11 free CER classes and that their profiles are altered in humans with atopic dermatitis (AD). Although decreased proportions of free CERs or quantities of protein-bound CERs in the SC have been reported in dogs with AD, the overall profile of CERs in the canine SC has not been fully elucidated. The aim of this study was thus to investigate the profile of free CERs in the canine SC and to identify alterations in the CER profiles in dogs with AD. Normal-phase liquid chromatography electrospray ionization-mass spectrometry indicated 11 clusters of peaks for free CER classes, similar to those recognized in the human SC. The fractions of free SC CER in dogs with AD and in breed- and age-matched healthy dogs were quantitatively compared using high-performance thin-layer chromatography. CER[EOS], CER[EOP] and CER[NP], which are known to be decreased in the skin of humans with AD, were also decreased in the skin of dogs with AD. These findings highlight canine AD as a spontaneous animal model for investigating the disruption of CER-associated cutaneous barrier functions in the corresponding human disease. PMID- 21649738 TI - Different patterns of fibronectin and tenascin-C splice variants expression in primary and metastatic melanoma lesions. AB - We have investigated the staining patterns of primary and metastatic melanoma lesions using F8, L19 and F16. These three clinical-stage antibodies are currently being studied in clinical trials for the pharmacodelivery of cytokines or therapeutic radionuclides to neoplastic sites in patients with cancer. Frozen sections of 24 primary and 29 metastatic melanoma lesions were stained, using immunofluorescence procedures, with biotinylated preparations of the F8, L19 and F16 antibodies, which are specific to the alternatively spliced extra domain A and extra domain B domains of fibronectin and A1 domain of tenascin-C, respectively. Blood vessels were costained using von Willebrand factor-specific antibodies. In primary cutaneous melanoma lesions, F16 and F8 (but not L19) strongly stained the basal lamina at the interface between epidermis and dermis, with a strikingly complementary pattern. By contrast, metastatic melanoma lesions displayed a strong and diffuse pattern of immunoreactivity with all three antibodies. It was found that the extracellular matrix in melanoma undergoes extensive remodelling during the transition from primary to metastatic lesions. The intense staining of metastatic melanoma lesions by the F8, L19 and F16 antibodies provides a strong rationale for the use of these antibodies and their derivatives for the treatment of melanoma patients and possibly for the personalized choice of the best performing antibody in individual patients. PMID- 21649735 TI - Response of iron overload to deferasirox in rare transfusion-dependent anaemias: equivalent effects on serum ferritin and labile plasma iron for haemolytic or production anaemias. AB - OBJECTIVES: It is widely assumed that, at matched transfusional iron-loading rates, responses to chelation therapy are similar, irrespective of the underlying condition. However, data are limited for rare transfusion-dependent anaemias, and it remains to be elucidated if response differs, depending on whether the anaemia has a primary haemolytic or production mechanism. METHODS: The efficacy and safety of deferasirox (Exjade(r)) in rare transfusion-dependent anaemias were evaluated over 1 yr, with change in serum ferritin as the primary efficacy endpoint. Initial deferasirox doses were 10-30 mg/kg/d, depending on transfusion requirements; 34 patients had production anaemias, and 23 had haemolytic anaemias. RESULTS: Patients with production anaemias or haemolytic anaemias had comparable transfusional iron-loading rates (0.31 vs. 0.30 mL red blood cells/kg/d), mean deferasirox dosing (19.3 vs. 19.0 mg/kg/d) and baseline median serum ferritin (2926 vs. 2682 ng/mL). Baseline labile plasma iron (LPI) levels correlated significantly with the transfusional iron-loading rates and with serum ferritin levels in both cohorts. Reductions in median serum ferritin levels were initially faster in the production than the haemolytic anaemias, but at 1 yr, similar significant reductions of 940 and 617 ng/mL were attained, respectively ( 26.0% overall). Mean LPI decreased significantly in patients with production (P < 0.0001) and haemolytic (P = 0.037) anaemias after the first dose and was maintained at normal mean levels (< 0.4 MUm) subsequently. The most common drug related, investigator-assessed adverse events were diarrhoea (n = 16) and nausea (n = 12). CONCLUSIONS: At matched transfusional iron-loading rates, the responses of rare transfusion-dependent anaemias to deferasirox are similar at 1 yr, irrespective of the underlying pathogenic mechanism. PMID- 21649739 TI - Editorial comment to prostatic abscess caused by community-acquired methicillin resistant Staphylococcus aureus. PMID- 21649740 TI - Does the temporary porto-caval shunt have any beneficial impact in orthotopic liver transplantation? PMID- 21649741 TI - Implications for the usage of the left lateral liver graft for infants <=10 kg, irrespective of a large-for-size situation--are monosegmental grafts redundant? AB - Organ donor shortage for infant liver transplant recipients has lead to an increase in splitting and living donation. For cases in which even transplantation of the left lateral graft (Couinaud's segments II + III) results in a "large for size situation" with an estimated graft body weight ratio (GBWR) of >4%, monosegmental liver transplantation was developed. This, however, bears complications because of greater parenchymal surface and suboptimal vascular flow. We exclusively use the left lateral graft from living donors or split grafts. Temporary abdominal closure is attempted in cases of increased pressure. We report of 41 pediatric transplants in 38 children <=10 kg. Within this group, there were 23 cases with a GBWR of >=4, and 15 cases with a GBWR <4. There was no statistical difference in vascular or biliary complications. Despite a more frequent rate of temporary abdominal closure, we did not find a higher rate of intra-abdominal infections. Overall, patient and graft survival was excellent in both groups (one death, three re-transplants). We noticed, however, that the ventro-dorsal diameter of the graft appears to be more relevant to potential graft necrosis than the actual graft size. In conclusion, the usage of monosegmental grafts seems unnecessary if transplantation of left lateral grafts is performed by an experienced multidisciplinary team, and temporary abdominal closure is favored in cases of increased abdominal pressure. PMID- 21649743 TI - Hepatic encephalopathy and post-transplant hyponatremia predict early calcineurin inhibitor-induced neurotoxicity after liver transplantation. AB - Early calcineurin inhibitor-induced neurotoxicity (ECIIN) is considered when neurological symptoms occur within 4 weeks after liver transplantation (LT). Risk factors and clinical outcome of ECIIN remain largely unknown. We sought to estimate the incidence, risk factors, and outcome of ECIIN after LT. We retrospectively evaluated 158 patients that underwent LT in a 2-year period and received immunosuppression with calcineurin inhibitors (CNI) and prednisone. ECIIN was considered when moderate/severe neurological events (after excluding other etiologies) occurred within 4 weeks after LT and improved after modification of CNI. Demographic and clinical variables were analyzed as risk factors. Twenty-eight (18%) patients developed ECIIN and the remaining 130 patients were analyzed as controls. History of pre-LT hepatic encephalopathy (OR 3.16, 95% CI 1.29-7.75, P = 0.012), post-LT hyponatremia (OR 3.34, 95% CI 1.38 9.85, P = 0.028), and surgical time >7 h (OR 2.62, 95% CI 1.07-6.41, P = 0.035) were independent factors for ECIIN. Acute graft rejection and infections were more frequent in the ECIIN group. In addition, length of stay was longer in ECIIN patients. In conclusion, pre-LT hepatic encephalopathy, surgical time >7 h, and post-LT hyponatremia are risk factors for ECIIN. Clinical complications and a longer hospital stay are associated with ECIIN development. PMID- 21649744 TI - Ureteroperitoneostomy--a rare complication after kidney transplantation. PMID- 21649746 TI - Validity and reliability of a short questionnaire for assessing the impact of cooking skills interventions. AB - BACKGROUND: Food skills programmes are widely used as a means to improve confidence in food preparation, the use of basic food skills and food selections amongst low income communities. However, the impact of such interventions are rarely evaluated as a result of a lack of validated assessment tools appropriate for use within this target group. METHODS: A two-page questionnaire utilising a closed-question format was designed based on key domains known to be influenced by cooking skills programmes. Content validity was assessed by a panel of public health experts and face validity by individuals, typical of those who may attend cooking skills classes. Internal and repeat reliability were assessed with groups of adults attending community-based classes. The feasibility of using the tool in community settings was also assessed. RESULTS: The draft questionnaire was amended as appropriate subsequent to content and face validity testing. Cronbach's alpha for confidence and knowledge sections was 0.86 and 0.84, respectively, indicating good internal consistency. Spearman correlation coefficients for repeat reliability testing between time 1 and time 2 for each item were in the range 0.46-0.91 (all significant at P < 0.001), indicating that the questionnaire elicited stable responses for repeated use. Feasibility testing highlighted the need for detailed instructions for course tutors on how to distribute and check questionnaires for completion. CONCLUSIONS: This tool provides a standardised method of evaluating cooking skills interventions that could be utilised in the development and evaluation of multicentre cooking skills interventions. PMID- 21649745 TI - Different experiences and perspectives between head and neck cancer patients and their care-givers on their daily impact of a gastrostomy tube. AB - BACKGROUND: Gastrostomy feeding in head and neck cancer patients is recognised standard practice in some cancer centres with beneficial effects on outcomes for appropriately selected patients. However, the impact on patients and care-givers needs consideration. The present study aimed to understand the daily impact of gastrostomy feeding on head and neck cancer patients and their care-givers to identify improvements to services. METHODS: Twenty-one adult patients were randomly selected from the Head and Neck centre at University College London Hospital. Six head and neck cancer patients and three care-givers participated in focus groups. The sessions were recorded, fully transcribed and qualitatively thematically analysed, and the resulting data were tabulated. RESULTS: Patients and care-givers expressed opposite experiences within knowledge and understanding of why the tube was necessary; their personal perceptions and objectives of nutritional support. Themes expressing similar experiences included: developing positive coping strategies; preventing nutritional decline; tube dependency; dentures; finance; active care; and psychological support. Furthermore, both groups expressed the benefits of retaining a support network for rehabilitation with the hospital-based specialist team. Also patients and carers recognised that the gastrostomy tube helped patient survival and, with timely dietetic management, helped them wean off the tube reliance with more confidence. CONCLUSIONS: It is essential that patients and care-givers attend pretreatment clinics to discuss nutritional support via the artificial route; their quality of life can be enhanced if guided through a specialist support pathway based at the clinical site where they initiated their care, with links to key agencies. PMID- 21649748 TI - The hippocratic oath. PMID- 21649747 TI - Body mass, frequency of eating and breakfast consumption in 9-13-year-olds. AB - BACKGROUND: Unhealthy eating patterns in childhood can lead to adverse health conditions, particularly obesity. However, debate remains around the precise eating behaviours that lead to these conditions. The present study aimed to address this lack of evidence by reporting on the eating frequency, breakfast consumption and body mass index (BMI, kg m(-2) ) of youth in the UK. METHODS: A total of 264 (133 boys and 131 girls) participants, aged 10-13years, completed self-report measures of dietary intake via 3-day food/drink diaries (Friday to Sunday). Trained researchers recorded height and weight to calculate the BMI. Diaries were analysed using dietplan 6 nutritional analysis software (Forestfield Software, Horsham, UK) and multivariate linear regression was used to examine any association between breakfast consumption, frequency of eating and BMI. RESULTS: No relationship existed between BMI Z-score, eating frequency and breakfast consumption. However, frequent breakfast consumers had significantly lower mean (SD) BMI Z-scores [0.18(1.06) versus 0.57(1.23)] and higher intakes of iron, calcium and vitamin E than those who did not eat breakfast regularly. Those aged >=11years consumed breakfast less frequently [0.92(0.20)] and were less likely to eat regularly [4.6(1.4)] than those aged <=10years. CONCLUSIONS: Older boys were the least likely to eat regularly and the least likely to consume breakfast. Promoting the importance of regular eating, particularly breakfast consumption to these boys, may be essential to ensure healthier, long-term eating patterns. Furthermore, the lower breakfast intakes in 11-13-year-olds and higher BMI Z scores of those who did not eat breakfast regularly should be monitored. PMID- 21649749 TI - Parental attitudes to digital recording: A paediatric hospital survey. AB - AIM: Digital recording is ubiquitous in the community. Its objectivity, permanence and utility in medical education have led to increasing use in health care settings. As participants in this process, the perspectives of families are important to inform practice. We surveyed family members of hospitalized children to evaluate their opinions. METHODS: A survey was administered to adults in emergency, operating room or ICU waiting areas at a university-affiliated paediatric hospital in Toronto. Respondents rated the frequency of digital recording in the community and hospital environments, the acceptability of five clinical indications and of consent discussions. RESULTS: Participants completed 154 surveys (response rate 83%) with median (interquartile range) of 2 (1-2) children. Community use of recording >4 times in the week prior was reported by 47 (31%); 42 (28%) reported no recording. The respondents rated the following indications for digital recording acceptable in the health care research 142 (94%), medical education 140 (93%), quality improvement 140 (92%), patient safety 147 (97%), and clinical care (96%). Within healthcare, consent discussions at different times were rated as acceptable before recording by 99%; after recording by 41%; and with no consent by 17%. CONCLUSION: We performed the first post privacy legislation survey of digital recording in Canadian health care. There is widespread acceptance of digital recording in public spaces and health care; however, respondents preferred to provide consent before recording. Balancing these preferences with the demonstrated advantages of video recording in health care presents challenges for optimal health policy creation. This study provides contemporary data to inform discussions. PMID- 21649751 TI - Intravenous immunoglobulin in the treatment of childhood Stevens Johnson syndrome. PMID- 21649752 TI - Multiple asymptomatic umbilicated papules on abdomen. PMID- 21649753 TI - Should ADHD broaden diagnostic classification to include oppositional defiant disorder? PMID- 21649754 TI - Uthoff phenomenon - a rare manifestation of a rare disease. PMID- 21649755 TI - When biopsy of the tumour is necessary to diagnose tuberculosis. PMID- 21649756 TI - Unilateral total lung sequestration: a rare condition. PMID- 21649758 TI - Intensive language training and attention modulate the involvement of fronto parietal regions during a non-verbal auditory discrimination task. AB - This event-related functional magnetic resonance imaging (fMRI) study was designed in such a manner so as to contribute to the present debate on behavioural and functional transfer effects associated with intensive language training. To address this novel issue, we measured professional simultaneous interpreters and control subjects while they performed a non-verbal auditory discrimination task that primarily relies on attention and categorization functions. The fMRI results revealed that the discrimination of the target stimuli was associated with differential blood oxygen level-dependent responses in fronto-parietal regions between the two groups, even though in-scanner behavioural results did not show significant group differences. These findings are in line with previous observations showing the contribution of fronto parietal regions to auditory attention and categorization functions. Our results imply that language training modulates brain activity in regions involved in the top-down regulation of auditory functions. PMID- 21649759 TI - Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. AB - Cellular stress increases progressively with aging in mammalian tissues. Chronic stress triggers several signaling cascades that can induce a condition called cellular senescence. Recent studies have demonstrated that senescent cells express a senescence-associated secretory phenotype (SASP). Emerging evidence indicates that the number of cells expressing biomarkers of cellular senescence increases in tissues with aging, which implies that cellular senescence is an important player in organismal aging. In the brain, the aging process is associated with degenerative changes, e.g. synaptic loss and white matter atrophy, which lead to progressive cognitive impairment. There is substantial evidence for the presence of oxidative, proteotoxic and metabolic stresses in aging brain. A low-level, chronic inflammatory process is also present in brain during aging. Astrocytes demonstrate age-related changes that resemble those of the SASP: (i) increased level of intermediate glial fibrillary acidic protein and vimentin filaments, (ii) increased expression of several cytokines and (iii) increased accumulation of proteotoxic aggregates. In addition, in vitro stress evokes a typical senescent phenotype in cultured astrocytes and, moreover, isolated astrocytes from aged brain display the proinflammatory phenotype. All of these observations indicate that astrocytes are capable of triggering the SASP and the astrocytes in aging brain display typical characteristics of cellular senescence. Bearing in mind the many functions of astrocytes, it is evident that the age-related senescence of astrocytes enhances the decline in functional capacity of the brain. We will review the astroglial changes occurring during aging and emphasize that senescent astrocytes can have an important role in age related neuroinflammation and neuronal degeneration. PMID- 21649761 TI - Marijuana-induced recurrent acute coronary syndrome with normal coronary angiograms. AB - We report a case of a man in his 40s presented to the emergency department twice, 1 month apart, with severe ischaemic sounding chest pain within 1 h of smoking marijuana on both occasions. He had elevated serial biomarkers and ischaemic electrocardiogram changes. His coronary angiograms on both episodes were entirely normal along with normal echocardiogram. This potentially suggests a coronary vasospasm as an underlying mechanism for these non-ST elevation myocardial infarctions. This should alert clinicians and the public alike to this potential risk of cannabis use. PMID- 21649760 TI - Differential involvement of phosphoinositide 3-kinase in gonadotrophin-releasing hormone actions in gonadotrophs and somatotrophs of goldfish, Carassius auratus. AB - In goldfish, two endogenous gonadotrophin-releasing hormones (GnRHs) [salmon (s)GnRH and chicken (c)GnRH-II] control maturational gonadotrophin-II [lutenising hormone (LH)] and growth hormone (GH) secretion via Ca(2+)-dependent intracellular signalling pathways. We investigated the involvement of phosphoinositide 3-kinase (PI3K) in GnRH-evoked LH and GH release and associated intracellular Ca(2+) increases ([Ca(2+)](i) ) in goldfish gonadotrophs and somatotrophs. Immunoreactive PI3K p85alpha, the predominant regulatory subunit for class IA PI3Ks, was detected in goldfish pituitary tissue extracts and both endogenous GnRH isoforms increased phosphorylation of PI3K p85alpha in excised pituitary fragments. sGnRH- and cGnRH-II-elicited LH release responses from primary cultures of pituitary cells and [Ca(2+)](i) increases in identified gonadotrophs were significantly reduced in the presence of PI3K inhibitors wortmannin (100 nm) and LY294002 (10 MUm). Unexpectedly, wortmannin and LY294002 inhibited GnRH-evoked GH release but only attenuated the [Ca(2+)](i) response in identified somatotrophs to cGnRH-II, and not sGnRH. On the other hand, Ca(2+) ionophore-evoked LH and GH secretion remained unaltered in the presence of the PI3K inhibitors, suggesting that general decreases in the releasable hormone pool or sensitivity to [Ca(2+)](i) changes did not underlie the ability of wortmannin and LY294002 to reduce the actions of GnRH. These results provide the first evidence for the presence and involvement of PI3K in GnRH-induced LH and GH release in any primary pituitary cell system. In gonadotrophs, the inhibitory action of PI3K on both sGnRH and cGnRH-II involves the attenuation of their evoked [Ca(2+)](i); in contrast, GnRH isoform-specific effects occur in somatotrophs. PMID- 21649762 TI - A NAC domain protein family contributing to the regulation of wood formation in poplar. AB - Wood harvested from trees is one of the most widely utilized natural materials on our planet. Recent environmental issues have prompted an increase in the demand for wood, especially as a cost-effective and renewable resource for industry and energy, so it is important to understand the process of wood formation. In the present study, we focused on poplar (Populus trichocarpa) NAC domain protein genes which are homologous to well-known Arabidopsis transcription factors regulating the differentiation of xylem vessels and fiber cells. From phylogenetic analysis, we isolated 16 poplar NAC domain protein genes, and named them PtVNS (VND-, NST/SND- and SMB-related proteins) genes. Expression analysis revealed that 12 PtVNS (also called PtrWND) genes including both VND and NST groups were expressed in developing xylem tissue and phloem fiber, whereas in primary xylem vessels, only PtVNS/PtrWND genes of the VND group were expressed. By using the post-translational induction system of Arabidopsis VND7, a master regulator of xylem vessel element differentiation, many poplar genes functioning in xylem vessel differentiation downstream from NAC domain protein genes were identified. Transient expression assays showed the variation in PtVNS/PtrWND transactivation activity toward downstream genes, even between duplicate gene pairs. Furthermore, overexpression of PtVNS/PtrWND genes induced ectopic secondary wall thickening in poplar leaves as well as in Arabidopsis seedlings with different levels of induction efficiency according to the gene. These results suggest that wood formation in poplar is regulated by cooperative functions of the NAC domain proteins. PMID- 21649763 TI - The effectiveness of an early parenting intervention for mothers with infants with sleep and settling concerns: a prospective non-equivalent before-after design. AB - AIM: The study aim was to compare changes in maternal confidence, competence, depression, anxiety and settling behaviours and children's sleep and settling behaviours for mothers and infants (4-6 months of age) attending a Day Stay intervention at an early parenting centre in Western Australia and a community group. BACKGROUND: Infant difficulties in getting to sleep and frequent night waking are concerns for parents. Techniques are available to assist parents with infants exhibiting behavioural sleep problems; however, parents often lack confidence to consistently initiate sleep interventions. DESIGN: The study incorporated a prospective non-equivalent before-after design. METHOD: The conceptual framework guiding this intervention emphasised the development of parental confidence and competence through connection with practitioners to promote change. Both groups provided baseline data (time 1) and four weeks postbaseline (time 2). Recruitment occurred between July 2007-July 2009. RESULTS: The Ngala group (n = 93) and community group (n = 85) were not equivalent for infant age and maternal parity; there were more multiparous mothers in the community group, with infants on average one week older. The Ngala group, the majority of which were primiparous women, had significantly higher levels of competence and confidence four weeks following their Day Stay visit. There were no significant differences between groups at time 2 for time to settle the infant at night, infant night waking and maternal depression and anxiety scores. CONCLUSIONS: Although both groups demonstrated an improvement in depression and anxiety scores, with decreased sleep and settling concerns, the results indicate parental inconsistency in settling approaches. Given links between inconsistent infant settling approaches and infants' difficulty with sleep self-initiation, further exploration is warranted. RELEVANCE TO CLINICAL PRACTICE: The conceptual framework guiding the Ngala practitioners was effective in developing confidence and competence for the sample. PMID- 21649764 TI - Crickets detect the genetic similarity of mating partners via cuticular hydrocarbons. AB - Animals should decipher information about the genetic make-up of conspecifics in order to enhance the fitness benefits associated with mate choice. Although there is increasing evidence to suggest that animals make genetically informed decisions about their mating partners, we understand relatively little about the sensory mechanisms informing these decisions. Here, we investigate whether cuticular hydrocarbons, chemical compounds found on the cuticle of most terrestrial arthropods, provide a means of discerning genetic similarity during mate choice in the cricket, Teleogryllus oceanicus. We found that individuals preferentially mated with partners who share more dissimilar cuticular hydrocarbon profiles and that similarity in cuticular hydrocarbon profiles between mating pairs correlated with their genetic similarity. Our results provide good evidence that cuticular hydrocarbon profiles offer a means of assessing genetic compatibility in T. oceanicus, enabling individuals to choose their most genetically suitable mate. PMID- 21649765 TI - Quantitative genetic inheritance of morphological divergence in a lake-stream stickleback ecotype pair: implications for reproductive isolation. AB - Ecological selection against hybrids between populations occupying different habitats might be an important component of reproductive isolation during the initial stages of speciation. The strength and directionality of this barrier to gene flow depends on the genetic architecture underlying divergence in ecologically relevant phenotypes. We here present line cross analyses of inheritance for two key foraging-related morphological traits involved in adaptive divergence between stickleback ecotypes residing parapatrically in lake and stream habitats within the Misty Lake watershed (Vancouver Island, Canada). One main finding is the striking genetic dominance of the lake phenotype for body depth. Selection associated with this phenotype against first- and later generation hybrids should therefore be asymmetric, hindering introgression from the lake to the stream population but not vice versa. Another main finding is that divergence in gill raker number is inherited additively and should therefore contribute symmetrically to reproductive isolation. Our study suggests that traits involved in adaptation might contribute to reproductive isolation qualitatively differently, depending on their mode of inheritance. PMID- 21649766 TI - Does maternal care evolve through egg recognition or directed territoriality? AB - The mechanism that facilitates the evolution of maternal care is ambiguous in egg laying terrestrial vertebrates: does the ability of mothers to recognize their own eggs lead them under some circumstances to begin providing care or can maternal care evolve from simply being in close proximity to the eggs (e.g. through territorial behaviour)? This question is difficult to answer because in most species, parental care is either absent altogether or present; in only a few species we have the opportunity to observe intraspecific variation in the expression of parental care. We studied a population of long-tailed skinks (Eutropis longicaudata) in which females have recently evolved maternal care from a noncaring state. Females on Orchid Island, Taiwan, remain with their eggs during incubation and when doing so, actively deter egg predation by egg-eating snakes (Oligodon formosanus); in all other populations, females lack post ovipositional maternal care. Nest-guarding females on Orchid Island (i) showed antipredator behaviours only in the original nest site in which they laid eggs, even after we removed all of the eggs or substituted them with those of a conspecific; (ii) protect any eggs present inside the original nest site (even when the eggs belong to a conspecific); and (iii) develop this behaviour while gravid (i.e. prior to laying eggs). This supports the hypothesis that long-tailed skinks cannot recognize their own eggs, suggesting that maternal care is a directed form of territoriality only expressed towards egg-eating snakes and only during reproduction. Nest guarding is among the most primitive forms of parental care, and the recent evolution of this behaviour in a single population provides insight into one of the mechanisms by which parental care can originate in terrestrial vertebrates. PMID- 21649767 TI - A history of phenotypic plasticity accelerates adaptation to a new environment. AB - Can a history of phenotypic plasticity increase the rate of adaptation to a new environment? Theory suggests it can be through two different mechanisms. Phenotypically plastic organisms can adapt rapidly to new environments through genetic assimilation, or the fluctuating environments that result in phenotypic plasticity can produce evolvable genetic architectures. In this article, I studied a model of a gene regulatory network that determined a phenotypic character in one population selected for phenotypic plasticity and a second population in a constant environment. A history of phenotypic plasticity increased the rate of adaptation in a new environment, but the amount of this increase was dependent on the strength of selection in the original environment. Phenotypic variance in the original environment predicted the adaptive capacity of the trait within, but not between, plastic and nonplastic populations. These results have implications for invasive species and ecological studies of rapid adaptation. PMID- 21649768 TI - Probiotics for prevention of antibiotic-associated diarrhea and Clostridium difficile-associated disease in hospitalized adults--a meta-analysis. AB - PURPOSE: A serious complication associated with the use of most antibiotics is antibiotic-associated diarrhea (AAD). The purpose of this article is to report findings from a meta-analysis of available studies on adult hospitalized populations to evaluate efficacy of probiotics for prevention of AAD and Clostridium difficile-associated disease (CDAD). DATA SOURCES: A comprehensive, systematic search was conducted to identify all relevant studies on probiotic efficacy for prevention of AAD and CDAD. Data synthesis was done using MAStARI software from the Joanna Briggs Institute (University of Adelaide, Australia). CONCLUSIONS: AAD affects one in five people on antibiotics. Risk factors for the development of AAD include the use of broad-spectrum antibiotics and host factors such as age, health status, hospitalization status, and exposure to nosocomial pathogens. About a third of AAD cases have CDAD. Meta-analysis showed that administration of probiotics led to a statistically significant relative risk reduction of 44% for AAD and 71% for CDAD. IMPLICATIONS FOR PRACTICE: Extended hospital stays, readmissions, and higher hospital costs are just some of the consequences of ADD and CDAD. Strategies currently used include discontinuing or changing the inciting antibiotic, restricting high-risk antibiotics, and encouraging the use of antibiotics based on sensitivity reports. Healthcare spending, morbidity, and mortality can potentially be reduced considerably by reducing the occurrence of ADD and CDAD by administering prophylaxis with probiotics concurrently with antibiotics. PMID- 21649769 TI - Black-spot poison ivy: a rare phenomenon. AB - PURPOSE: To provide an overview of the clinical presentation, diagnosis, management, and treatment with advanced practice nursing implications of black spot poison ivy phenomenon. DATA SOURCES: Case presentation and comprehensive literature review on black-spot poison ivy. CONCLUSIONS: Black-spot poison ivy is a rare phenomenon and usually poses a diagnostic challenge. It usually presents after exposure to a higher concentration of uroshiol on Toxicodendron plants. Patients present with black-spot deposits on the epidermis with underlying poison ivy dermatitis. The black deposits cannot be washed off the skin and are followed by itchy blisters. They eventually peel off and the skin heals without scarring. IMPLICATIONS FOR PRACTICE: An understanding of the pathophysiology, clinical presentation, treatment, and management of this rare phenomenon is important for the nurse practitioner (NP) to be able to make an accurate diagnosis and initiate appropriate treatment without delay. The NP's recognition and differentiation of it from other skin disorders including melanoma is paramount. PMID- 21649770 TI - How can primary care providers manage pediatric obesity in the real world? AB - PURPOSE: To provide information regarding evidence-based interventions and clinical practice guidelines as a basis for a clinical toolkit utilizing a step management approach for the primary care provider in managing childhood obesity. DATA SOURCES: Evidence-based literature including original clinical trials, literature reviews, and clinical practice guidelines. CONCLUSIONS: Interventions can be stratified based on initial screening of children and adolescents so that selection of treatment options is optimized. For all treatments, lifestyle modifications include attention to diet and activity level. Levels of initial success, as well as maintenance of target body mass index, may be related to the intensity and duration of interventions; involvement of family may increase success rates. For failed lifestyle interventions, or for patients with extreme obesity and/or certain comorbidities, pharmacologic or surgical options should be considered. IMPLICATIONS FOR PRACTICE: Many intensive programs have shown success, but the resources required for these approaches may be unavailable to the typical community provider and family. However, using current guidelines, the primary care provider can initiate and manage ongoing interventions in pediatric obesity. A toolkit for primary care implementation and maintenance interventions is provided. PMID- 21649771 TI - The Game of Health(c): an innovative lifestyle change program implemented in a family practice. AB - PURPOSE: The purpose of this clinical pilot project was to evaluate the effectiveness of a 12 week lifestyle change program targeted to patients with chronic disease. DATA SOURCES: Data were collected weekly from participants using individual and group feedback and body composition analysis. CONCLUSIONS: The Game of Health was well received by patients and was effective in modifying behaviors to achieve a healthier lifestyle and to improve body composition. Primary care providers need to consider how to make lifestyle change programs available to their patients to complement clinical interventions. PMID- 21649772 TI - Community-based participatory research and American Indian/Alaska Native nurse practitioners: a partnership to promote adolescent health. AB - PURPOSE: To make recommendations for American Indian/Alaska Native (AI/AN) nurse practitioners (NPs) and university partners who are partnering on community-based participatory (CBPR) research projects. An example of a CBPR study using focus groups to assess an important adolescent health problem is used to illustrate opportunities and challenges for AI/AN NPs. DATA SOURCES: Thirteen focus groups were held with 95 participants on the reservation where the AI/AN NP was a member and working. Results indicated that a majority of the community represented in the focus groups were concerned about substance abuse among its youth. CONCLUSIONS: The NP faced several challenges, including remembering emotional events recounted during focus groups differently than participants. This necessitated debriefing and a recommendation to carefully form policies and procedures before collecting data to anticipate such events. By far, the benefit of the NP's involvement was her ability to identify key members for focus groups, to assist in tribal council meetings, and to schedule meetings. IMPLICATIONS FOR PRACTICE: CBPR research partnerships are enhanced by NPs that are members of the community. CBPR partnerships present opportunities for NPs and university faculty to work on relevant community problems together. PMID- 21649773 TI - Hypertension among the uninsured: tensions and challenges. AB - PURPOSE: To explore the experience of living with hypertension (HTN) in uninsured Southern, Appalachian adults who receive care in a nurse practitioner-run clinic. DATA SOURCES: Focus groups with 16 clients. CONCLUSIONS: Living with hypertension encompassed living with many tensions and challenges. It was described by five organizing themes, each of which involved two basic themes held in tension. The organizing themes were: (a) centrality of HTN; (b) controllability of HTN; (c) visibility of HTN, (d) accessibility and quality of health care; and (e) existential reality. IMPLICATIONS FOR PRACTICE: Interventions are needed to help clients deal with the tensions and challenges; these include a greater focus on partnering with clients, individual and group educational activities, and developing community partnerships. PMID- 21649774 TI - The evolution of specialists in women's health care across the lifespan: women's health nurse practitioners. AB - PURPOSE: In this article, we will trace the beginnings of this nurse practitioner specialist, illustrating with the stories of women's health nurse practitioners who were some of the pioneers in developing the role and models of care to meet the unique needs of women across their lifespan. DATA SOURCES: Oral history interviews with pioneers in the role who graduated from both certificate and master's programs preparing nurse practitioners informed and shaped the story. Additional data came from the literature on the evolution of advanced practice nurse roles and education and documents from early educational programs and the legal and regulatory literature affecting the roles and practices of advanced practice nurses. CONCLUSIONS: Women's health nurse practitioners have evolved to fill an important role in healthcare delivery, caring for women across generations often within the same families. IMPLICATIONS FOR PRACTICE: Women's health nurse practitioners, as do all nurse practitioners, offer a unique approach to care. To paraphrase the words of one participant, I think we address a major healthcare need because if women are educated about themselves and what they need to do to take care of themselves, the result is a better community. PMID- 21649775 TI - Optimizing treatment outcomes with phosphodiesterase type 5 inhibitors for erectile dysfunction: opening windows to enhanced sexual function and overall health. AB - PURPOSE: Phosphodiesterase type 5 (PDE5) inhibitors have proved to be efficacious, safe, and well tolerated, in clinical trials and practice, for men with erectile dysfunction (ED). However, many patients are not satisfied with treatment and discontinue it prematurely. This review discusses evidence-based strategies that nurse practitioners (NPs) can use to improve diagnosis of ED, optimize patient outcomes, and identify opportunities to detect other potentially serious comorbid conditions. DATA SOURCES: This article was based on a previously published review, which involved a PubMed-MEDLINE search of the clinical literature from January 1, 1998 (year of sildenafil's approval in many markets), through August 30, 2008 (date of search). CONCLUSIONS: Strategies to optimize responses to PDE5 therapy are summarized by the mnemonic "EPOCH": Evaluating and educating to ensure realistic expectations of therapy; Prescribing a treatment individualized to the couple's needs and preferences; Optimizing drug dose/regimen and revisiting key educational messages at follow-up visits; Controlling comorbidities via lifestyle counseling, medications, and/or referrals; and Helping patients and their partners to seek other forms of therapy if they have decided not to use a PDE5 inhibitor. IMPLICATIONS FOR PRACTICE: The "EPOCH" mnemonic may remind NPs of steps to optimize treatment outcomes with PDE5 inhibitors. PMID- 21649776 TI - Retraction notice. Critical care nurse practitioners and clinical nurse specialists interface patterns with computer-based decision support systems by Scott Weber. PMID- 21649777 TI - Towards a safer approach to epicardial ablation. PMID- 21649778 TI - AV nodal ablation-induced Gerbode defect (LV-RA Shunt). AB - A Gerbode defect that comprises a left ventricular to right atrial shunt is usually a congenital cardiac condition. Rarely, acquired Gerbode defects secondary to aortic or tricuspid valve endocarditis have been reported. We present a case of a Gerbode defect caused by catheter ablation of the AV node in a patient with a severely dilated cardiomyopathy and refractory atrial fibrillation. PMID- 21649779 TI - Completion of mitral isthmus ablation using a steerable sheath: prospective randomized comparison with a nonsteerable sheath. AB - BACKGROUND: Although mitral isthmus (MI) ablation in atrial fibrillation (AF) patients has been shown to be an effective ablative strategy, the establishment of the bidirectional conduction block of the MI is technically challenging. We investigated the usefulness of a steerable sheath for MI ablation in patients with persistent AF and its impact on the clinical outcome of persistent AF ablation. METHODS: A total of 80 consecutive patients undergoing MI ablation were randomized to 1 of the following 2 groups: group S (using a steerable long sheath) or group NS (using a nonsteerable long sheath). MI ablation was performed by using an open-irrigated ablation catheter with the guidance of a 3-dimensional mapping system. The endpoint of the MI ablation was the achievement of a bidirectional block. RESULTS: Bidirectional block through the MI was achieved in 87.5% (70/80) of patients with 14.0 +/- 6.7 minutes of radiofrequency application. The bidirectional block was more frequently achieved in patients in group S compared to group NS (97.5% (39/40) vs 77.5% (31/40), P = 0.02). Additionally, epicardial ablation within the coronary sinus was less frequently required in group S compared to group NS (12.5% (5/40) vs 72.5% (29/40), P < 0.0001). Atrial tachycardia after the procedure more frequently occurred in the patients in whom MI block had not been achieved during the initial procedure (40.0% (4/10) vs 10.0% (7/70), P = 0.04). CONCLUSIONS: The MI block could be achieved in the majority of patients by using a steerable sheath. An incomplete MI block increased the risk of AT following persistent AF ablation. PMID- 21649780 TI - Morphology and small subunit (SSU) rRNA gene sequence of the new brackish water ciliate Neobakuella flava n. g., n. sp. (Ciliophora, Spirotricha, Bakuellidae) and SSU rRNA gene sequences of six additional hypotrichs from Korea. AB - The morphology and the small subunit (SSU) rRNA gene sequence of the hypotrich Neobakuella flava n. g., n. sp. from the estuary of the Taehwagang River (Ulsan, South Korea) were investigated. The three frontal cirri, the composition of the midventral complex of cirral pairs and rows, and the simple dorsal kinety pattern of three bipolar kineties assign it to the urostyloid taxon Bakuellidae. The increased number of buccal and parabuccal cirri, the presence of transverse cirri, and more than one left marginal row, as well as the lack of caudal cirri separate Neobakuella n. g. from the other bakuellids. Neobakuella flava n. sp. has many 0.3 MUm sized green and/or yellow usually dark-green cortical granules and some sparsely distributed, 2 * 1 MUm sized grass green with yellowish shimmer granules. The gene sequence data indicate a close relationship with Diaxonella and a distinct separation from the bakuellid Metaurostylopsis and parabirojimid Parabirojimia. The SSU rRNA gene sequences of four further urostyloids (i.e. Diaxonella pseudorubra, Anteholosticha monilata, Metaurostylopsis struederkypkeae, Pseudourostyla cristata) and two stylonychines (i.e. Sterkiella cavicola, Sterkiella histriomuscorum) from Korea were analyzed. Anteholosticha monilata, type of the genus, is clearly separated from the Holosticha clade, supporting the morphological separation from Holosticha. Sterkiella cavicola, type of Sterkiella, clusters within the stylonychines and is obviously closely related with S. histriomuscorum. PMID- 21649781 TI - High mortality in patients with chronic wounds. PMID- 21649782 TI - Indirect effects of oral tolerance improve wound healing in skin. AB - Tissue injury in adult mammalian skin frequently results in scarring while fetal mammalian skin heals with complete regeneration. Inflammatory reactions are among the factors thought to impair regeneration. Previous studies have shown that the injection of an immunologically tolerated protein blocks immune responses to unrelated antigens and is also able to inhibit inflammation in mice. This phenomenon, which we refer to as the indirect effects of oral tolerance, does not require the simultaneous injection of the tolerated antigen and the second antigen, and also occurs when the two antigens are given by separate routes of immunization. Herein, we investigated whether the i.p. injection of an orally tolerated antigen (ovalbumin, OVA) would inhibit inflammatory reactions at an incisional lesion and influence healing of adult mouse skin. In OVA-tolerant mice, the injection of OVA minutes before wounding altered inflammation: it reduced the numbers of mast cells, neutrophils, and lymphocytes but increased the number of macrophages around the lesion area. Tolerant mice also showed fewer myofibroblasts and reduced scar area. Furthermore, tolerant mice displayed a pattern of extracellular matrix deposition similar to that observed in intact skin, plus characteristics of regeneration, such as an increased deposition of fibronectin and tenascin-C. These observations suggest that the indirect effects of oral tolerance can alter the process of wound healing in skin and reduce scar formation. PMID- 21649783 TI - Noncontact low-frequency ultrasound therapy in the treatment of chronic wounds: a meta-analysis. AB - Our objective was to summarize and quantify the effects of a noncontact low frequency ultrasound (NLFU) therapy on healing of chronic wounds. We performed a meta-analysis of eight published studies reporting effects of NLFU on wound size and healing rate of chronic wounds in 444 NLFU-treated patients. A search of the PubMed database was conducted in January 2010 and updated in October 2010. We used random-effects linear regression models to estimate the proportional reductions in wound area and volume and the proportion of wounds healed from baseline to last follow-up. In four studies (N=188) reporting change in wound area from baseline, NLFU was associated with 85.2% area reduction (95% CI 64.7% 97.6%) over a mean 7 weeks. In four studies (N=278) reporting reduction in wound volume, NLFU was associated with 79.7% volume reduction (95% CI 46.1%-98.8%) over a mean 12 weeks. In seven studies (N=429) reporting proportion of wounds healing by study end (mean time to healing 8.2 weeks; median 6.8 weeks), meta-analyzed healing rates over time suggest 32.7% of wounds healed on average by 6 weeks (95% CI 23.3%-42.1%) and 41.7% by 12 weeks. NLFU for treatment of chronic wounds was associated with consistent and substantial wound size reductions, as well as favorable rates of healing. PMID- 21649784 TI - Rapid healing of chronic venous stasis leg ulcers treated by the application of a novel serum-free cultured autologous epidermis. AB - The efficacy and durability of wound closure was examined in a prospective randomized unbalanced clinical trial using the application of a living serum-free cultured epidermal autograft in conjunction with wound-area debridement and a four-layer compression wrap (N=10) compared with wound-area debridement and a four-layer compression wrap in patients with hard-to-heal leg ulcers arising from confirmed venous stasis (N=5). All 15 patients who presented with full-thickness venous ulceration were treated weekly for 8 weeks, with a 12-week final evaluation. The average time to wound closure for the grafted wounds was 4.1 weeks for 80% (8/10) of the cases that closed in 12 weeks compared with 12 weeks for the one closed in the control case. All of the grafted wounds remained closed at 12-month follow-up and one more healed at 30 weeks postenrollment. In the control group, one additional wound healed at 21 weeks postenrollment after the placement of an autograft. No serious adverse events were reported and subjective pain assessment was substantially reduced immediately after graft application. The graft treatment significantly improved outcome and provided durable wound closure. The data suggest that this adaption of this procedure may reduce the management costs of these wound types. PMID- 21649785 TI - Zucker diabetic fatty rat: a new model of impaired cutaneous wound repair with type II diabetes mellitus and obesity. AB - Impaired diabetic wound healing is an important current medical issue, mainly concerning patients recovering from complicated operations or patients with ulcers on their feet. The obese Zucker diabetic fatty rat, with a mutation in leptin receptors, may be a good choice for studying impaired wound healing. Male and female rats were fed a diabetogenic high-fat diet. Wound size changes of air exposed excisional 2 cm circular wounds were measured until Day 10. Wound tissue was analyzed morphologically, histologically, and immunohistochemically. The hydroxyproline content in the granulation tissue (GT) was determined. mRNA expression was assayed by DNA-array analysis and real-time reverse transcription polymerase chain reaction. Wound-size changes were retarded in diabetic rats and differed between the sexes. Diabetic wounds were characterized by impaired contraction, abundant crust production, increased inflammation, and pus formation. On Day 10, the GT contained a significantly increased amount of intercalated fat tissue and showed an irregular arrangement of GT and collagen fibers. Interestingly, the length of new epithelium was increased in diabetic wounds. The concentration of hydroxyproline in the GT of diabetic animals was significantly decreased to about one half when compared with the nondiabetic controls. The expression of interleukin-6, myeloperoxidase, stromelysin-1, and collagenase-3 was increased in the GT of diabetic rats on Day 10, while the expression of type I collagen and elastin was decreased. Taken together, Zucker diabetic fatty rats exhibited impairments in wound-size reduction, inflammatory response, tissue organization, and connective tissue turnover and are thus proposed as a new model for studying impaired repair. PMID- 21649786 TI - Heparan sulfate glycosaminoglycan mimetic improves pressure ulcer healing in a rat model of cutaneous ischemia-reperfusion injury. AB - Pressure ulcers are a major clinical problem, with a large burden on healthcare resources. This study evaluated the effects of the heparan sulfate glycosaminoglycan mimetic, OTR4120, on pressure ulceration and healing. Ischemia reperfusion (I-R) was evoked to induce pressure ulcers by external clamping and then removal of a pair of magnet disks on rat dorsal skin for a single ischemic period of 16 hours. Immediately after magnet removal, rats received an intramuscular injection of OTR4120 weekly for up to 1 month. During the ischemic period, normal skin perfusion was reduced by at least 60% and at least 20-45% reperfused into the ischemic region after compression release. This model caused sustained skin incomplete necrosis for up to 14 days and led to grade 2-3 ulcers. OTR4120 treatment decreased the area of skin incomplete necrosis and degree of ulceration. OTR4120 treatment also reduced inflammation and increased angiogenesis. In OTR4120-treated ulcers, the contents of vascular endothelial growth factor, platelet-derived growth factor, and transforming growth factor beta-1 were increased. Moreover, OTR4120 treatment promoted early expression of alpha-smooth muscle actin and increased collagen biosynthesis. Long-term restoration of wounded tissue biomechanical strength was significantly enhanced after OTR4120 treatment. Taken together, we conclude that OTR4120 treatment reduces pressure ulcer formation and potentiates the internal healing bioavailability. PMID- 21649787 TI - Enhancement of flap survival and changes in angiogenic gene expression after AAV2 mediated VEGF gene transfer to rat ischemic flaps. AB - Necrosis of surgically transferred flaps due to ischemia is a serious wound problem. We evaluated the improvement of flap survival and changes in angiogenic gene expression profiles after transfer of the VEGF gene by means of adeno associated virus type 2 (AAV2) vector to rat ischemic flaps. Thirty rats were divided into one experimental group, one AAV2-GFP group, and one saline group. AAV2-VEGF or AAV2-GFP were injected intradermally into the rat dorsum in the AAV2 VEGF or AAV2-GFP group. The saline group received saline injection. A 3 * 10 cm flap was raised in each rat two weeks post-injection. One week after surgery, flap viability was evaluated. Angiogenesis real-time PCR array was performed to analyze the expression of angiogenesis-associated genes. The AAV2-VEGF treatment significantly improved flap survival (p<0.05). Immunohistochemical staining showed increased VEGF expression in AAV2-VEGF treated flaps. The PCR array identified remarkable changes in 6 out of the 84 angiogenesis-associated genes in AAV2-VEGF treated flaps. Particularly, EGF, PDGF-A and VEGF-B genes were up regulated in these flaps. In contrast, FGF2 gene expression was down-regulated. In conclusion, AAV2-VEGF improves flap survival and affects the expression of a series of endogenous growth factor genes, which likely play critical roles in the enhancement of ischemic flap survival. PMID- 21649788 TI - Immunohistological evaluation of skin responses after treatment using a fractional ultrapulse carbon dioxide laser on back skin. AB - BACKGROUND AND OBJECTIVE: Fractional photothermolysis (FP) lasers have been widely used in treating photo-aged skin, acne scars, and other skin conditions. Although plenty of clinical data have demonstrated the efficacy of the FP laser, only limited histologic studies have been available to observe serial short- to long-term skin responses. METHODS: Seven healthy Chinese women received one pass of fractional carbon dioxide laser treatment on the left upper back. Biopsies were taken at the baseline and 4 hours, 1 day, 5 days, 1 month, 3 months, 6 months, and 1 year after the procedure for hematoxylin and eosin stains, immunohistochemical evaluation (for heat shock proteins and elastin), and Verhoeff-iron-hematoxylin stains (for collagen and elastic fiber). RESULTS: Remarkably greater expression of heat shock protein (HSP)70 could be observed 4 hours after the procedure, which diminished significantly by 3 months, 6 months, and 1 year after the procedure. HSP47 reached its peak expression 1 month after the procedure, especially around microscopic thermal zones, and maintained its high level of expression 3 and 6 months after the procedure. Distinct new formation and remodeling of collagen and elastic fibers could be observed 3 and 6 months after procedure. CONCLUSION: FP-induced HSP expression and new formation of collagen and elastic fibers lasted as long as 6 months, longer than the previously acknowledged 3 months. PMID- 21649789 TI - Verrucous carcinoma of the lip: an unusual kissing type. PMID- 21649790 TI - A two-phase, retrospective analysis evaluating efficacy of and patient satisfaction with abobotulinumtoxina used to treat dynamic facial rhytides. AB - BACKGROUND: Numerous studies on cosmetic uses of the two major forms of botulinum type A toxin-onabotulinumtoxinA and abobotulinumtoxinA--have been reported, but there is a lack of published, non-industry-funded data regarding efficacy and patient satisfaction with abobotulinumtoxinA. OBJECTIVES To evaluate the efficacy of and patient satisfaction with abobotulinumtoxinA injections. METHODS: Retrospective, two-phase study of 185 patients treated with abobotulinumtoxinA for dynamic facial rhytid reduction over an 8-month period. Data were gathered using chart review and patient follow-up. RESULTS: The average total amount of abobotulinumtoxinA injected per visit was similar in each phase (93.7 U in phase I, which used a ratio of 2.5 abobotulinumtoxinA units to 1 onabotulinumtoxinA unit, and 99.6 U in phase II, which used a ratio of 3:1). Of patients with a history of onabotulinumtoxinA injections (89.1% in phase I and 91% in phase II), the majority preferred onabotulinumtoxinA. A similar percentage in each group reported overall satisfaction with abobotulinumtoxinA (70.9% in phase I and 68% in phase II). CONCLUSION: Although generally satisfied with abobotulinumtoxinA, when given a choice between abobotulinumtoxinA and onabotulinumtoxinA, the majority of patients favored the latter. This preference remained even after the dilution of abobotulinumtoxinA was decreased. PMID- 21649791 TI - Microcystic adnexal carcinoma associated with multiple benign syringomatous proliferations: a report of two cases. PMID- 21649792 TI - Serum osteoprotegerin measurement for early diagnosis of chronic kidney disease mineral and bone disorder. AB - AIM: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been proposed to be the replacement of renal osteodystrophy by the Organization of Kidney Disease: Improving Global Outcomes since 2005 because the mineral disorder is not confined to the skeleton in CKD. Accordingly, laboratory and imaging tests have been emphasized for the clinical assessment of patients with CKD besides renal biopsy. The objective of the current study was to investigate whether osteoprotegerin (OPG) could be made a useful biomarker for early diagnosis of CKD MBD. METHODS: Sixty pre-dialysis patients with CKD 1-5 were enrolled in this study. The serum calcium, phosphorus, blood urea nitrogen, creatinine, alkaline phosphatase, Osteocalcin, Calcitonin, intact parathyroid hormone and OPG were measured. Bone mineral densities of the lumbar spine (L2-L4), femoral neck, Ward's triangle and trochanter were measured by dual-energy X-ray absorptiometry. RESULTS: Among all measured serum bone metabolism indexes, the changing of serum OPG level happened at the earliest time (CKD 3) and its correlation coefficient with estimated glomerular filtration rate (eGFR) was also the highest (r = 0.601, P = 0.001). In the multivariable analysis that included sex, age and eGFR as controlling factors, the serum OPG correlated with the bone mineral density (BMD) of Ward's triangle (r = -0.390, P = 0.041). CONCLUSION: Serum OPG may be a useful biomarker for early diagnosis of CKD-MBD. PMID- 21649793 TI - Impact of non-traditional phosphate binders and cinacalcet on haemodialysis patient biochemistry, pill burden and cost. AB - AIM: The Australian Pharmaceutical Benefits Scheme (PBS) commenced cost subsidization for haemodialysis patients of sevelamer in December 2007, cinacalcet in July 2008 and lanthanum in May 2009. To determine the impact of PBS listing of these medications, we performed a single centre cross-sectional, longitudinal study. METHODS: Dialysis parameters and biochemistry were prospectively collected at 6 monthly intervals for all prevalent haemodialysis patients from October 2007 to April 2010. Medications prescribed to manage chronic kidney disease mineral and bone disorder were recorded. Univariate regression analysis was undertaken for each variable against time. RESULTS: Patient numbers ranged from 87 to 114 in each period. At baseline, mean age was 68.8 +/- 14.3 years, 71% male, 15.1 +/- 3.5 haemodialysis hours/week and urea reduction ratio 71.9 +/- 9.8%. These variables were unchanged over time. The use of sevelamer, cinacalcet and lanthanum increased (P < 0.001). There was a decrease in the use of aluminium- and calcium-based phosphate binders (P < 0.001) but no change in the use of magnesium based phosphate binders (P = 0.09) or calcitriol (P = 0.11). Serum phosphate (P = 0.13) and parathyroid hormone (PTH) (P = 0.87) were unchanged. Mean 'bone pill' burden fell from 60.3/week to 51.9/week (P = 0.02). Mean pill cost increased from Australian dollars (AUD) 12.85/patient per week to AUD 59.85/patient per week (P < 0.001). CONCLUSION: The PBS subsidization of sevelamer, cinacalcet and lanthanum has changed prescribing patterns, although serum phosphate and PTH remain unchanged. These changes have been at an additional cost of AUD 2444/patient per year. Data to address clinical end-points of mortality and hospitalization is needed to determine if the cost of these newer agents is warranted. PMID- 21649794 TI - Incidence and features of dual anti-GBM-positive and ANCA-positive patients. AB - AIMS: Goodpasture's syndrome, glomerulonephritis and pulmonary haemorrhage, may be due to a variety of causes. Rarely, patients with Goodpasture's syndrome present with both anti-glomerular basement membrane (GBM) and antineutrophil cytoplasmic antibody (ANCA). The aim of this report was to determine the incidence, clinical features, management and outcomes of patients presenting with concurrent ANCA and anti-GBM disease in Auckland. METHODS: Potential patients were identified by an electronic search of serology for ANCA and anti-GBM antibody, diagnostic renal biopsy, or in-hospital admissions using ICD9 and ICD10 codes between 1998 and 2008. A retrospective case-note review of all potential cases was performed. RESULTS: Six cases were identified: two women and four men. The incidence was estimated at 0.47 cases per million people per year. The mean age of presentation was 59 years (range 25-85 years). One patient was a smoker and two patients were ex-smokers. All subjects were anaemic, had haemoptysis and an abnormal chest X-ray at presentation. The mean creatinine at presentation was 225 umol/L (range 126-406 umol/L); all patients had haematuria and proteinuria. All patients received corticosteroids and cyclophosphamide. Two patients were not plasma exchanged and died. Four patients received plasma exchange and are alive. One patient had a clinical relapse 6 years after their initial presentation and is on renal replacement therapy. CONCLUSION: Concurrent ANCA and anti-GBM disease is rare. The mortality rate is high. Aggressive immunosuppression with steroids, cyclophosphamide and plasma exchange can induce remission and preserve renal function. Long-term monitoring for relapses should occur. PMID- 21649796 TI - Molecular analysis of severe factor XI deficiency in three Italian patients. PMID- 21649795 TI - Haemophilia management: time to get personal? AB - The possibility of alloimmunization in patients receiving protein replacement therapy depends on (at least) three risk factors, which are necessary concomitantly but insufficient alone. The first is the degree of structural difference between the therapeutic protein and the patient's own endogenous protein, if expressed. Such differences depend on the nature of the disease mutation and the pre-mutation endogenous protein structure as well as on post translational changes and sequence-engineered alterations in the therapeutic protein. Genetic variations in the recipients' immune systems comprise the second set of risk determinants for deleterious immune responses. For example, the limited repertoire of MHC class II isomers encoded by a given person's collection of HLA genes may or may not be able to present a 'foreign' peptide(s) produced from the therapeutic protein - following its internalization and proteolytic processing - on the surface of their antigen-presenting cells (APCs). The third (and least characterized) variable is the presence or absence of immunologic 'danger signals' during the display of foreign-peptide/MHC-complexes on APCs. A choice between existing therapeutic products or the manufacture of new proteins, which may be less immunogenic in some patients or patient populations, may require prior definition of the first two of these variables. This leads then to the possibility of developing personalized therapies for disorders due to genetic deficiencies in endogenous proteins, such as haemophilia A and B. [Correction made after online publication 11 July 2011: several critical corrections have been made to the abstract]. PMID- 21649797 TI - Immune tolerance induction with a factor VIII concentrate containing von Willebrand factor (Haemoctin SDH(r)) in 14 patients with severe haemophilia A. PMID- 21649798 TI - Predictors of treatment difficulties and satisfaction with haemophilia therapy in adult patients. AB - Adherence is a complex and multifaceted behaviour. The study of factors influencing adherence behaviour, including difficulties with treatment and treatment satisfaction (TS), are still needed. This research report describes different questions related to treatment adherence, focusing on perceived barriers and difficulties with treatment, satisfaction with treatment and risk factors that help explain the experience of difficulties and low TS. A cross sectional study assessing 121 Spanish adult patients (range 17-70) collected information about the characteristics of treatment, perceived barriers to treatment, difficulties and satisfaction with treatment and negative affect. The results show differences in difficulties and satisfaction with treatment depending on haemophilia severity level and describe an association of negative affect with the greater experience of treatment difficulties and lower TS. In conclusion, perceived barriers, level of skills related to self-treatment, haemophilia severity level and affective state are important predictors of treatment difficulties and satisfaction with treatment and these should be taken into account in strategies for improving compliance and maintaining quality of life. PMID- 21649799 TI - Clinical outcomes and patient satisfaction following total joint replacement in haemophilia--23-year experience in knees, hips and elbows. AB - Joint replacement surgery is an available option for end-stage haemophilic arthropathy. However, reports with long-term follow-up are limited. Moreover, patient satisfaction in this setting has never been measured. We share our institution's experience with joint arthroplasty in haemophilic arthropathy and report on clinical outcomes and patient satisfaction. Between 1985 and 2007, 65 consecutive joints in 45 patients (mean age: 48.6; range: 22-83) underwent joint replacement surgery. Of these, 40 total knee replacements in 31 patients, 18 total hip replacements in 16 patients and 6 total elbow replacements in 3 patients were included. Average follow-up was 10.7 years (2.4-24.3). Charts were reviewed retrospectively and patients were asked to return for clinical assessment and completion of questionnaires. According to the Knee Society clinical score, postoperative results were good to excellent in 83% of knees. According to the Harris Hip Score, results were good to excellent in 31% of hips. According to the Mayo Elbow Performance Score, results were good to excellent in 83% of elbows. Complication rates are higher than in the non-haemophilic population, while prosthesis survival rates are lower. Patient satisfaction with pain relief is higher than satisfaction with functional improvement. For 88% of joints, patients are willing to have the same operation again. This study confirms previous knowledge on the role of total joint arthroplasty in haemophilic arthropathy. Despite high complication rates and modest functional outcomes, the operations are valuable for achieving pain relief. In general, patients find that risks are outweighed by the benefits. PMID- 21649800 TI - A survey of the outcome of prophylaxis, on-demand or combined treatment in 20-35 year old men with severe haemophilia in four European countries. PMID- 21649801 TI - A study of variations in the reported haemophilia B prevalence around the world. AB - The objectives of this article were to study the reported prevalence of haemophilia B (HB) on a country-by-country basis and to analyse whether the prevalence of HB varied by national economy. The prevalence of HB is the proportion of diagnosed, reported cases of HB in a population at a specific point of time. We collected data on the HB prevalence for 105 countries from the World Federation of Hemophilia annual global surveys. Our results showed that the HB prevalence varied considerably among countries, even among the wealthiest of countries. The HB prevalence (per 100 000 males) for the highest income countries was 2.69 +/- 1.61 (mean +/- SD), whereas the prevalence for the rest of the world was 1.20 +/- 1.33 (mean +/- SD). Ireland had the highest reported HB prevalence of 8.07 per 100 000 males. There was a strong trend of increasing HB prevalence (per 100 000 males) over time. Prevalence data reported from the WFH compared well with prevalence data from the literature. The WFH annual global surveys have some limitations, but they are the best available source of worldwide haemophilia data. Prevalence data are extremely valuable information for the planning efforts of national healthcare agencies in setting priorities and allocating resources for the treatment of HB. PMID- 21649802 TI - Economical comparison of APCC vs. rFVIIa for mild-to-moderate bleeding episodes in haemophilia patients with inhibitors. AB - To construct a cost-minimization model comparing activated prothrombin complex concentrates (APCC) vs. recombinant factor VIIa (rFVIIa) in haemophilia patients with inhibitors from a US third party payer perspective. A literature-based decision model was used to model inhibitor treatment costs and outcomes. As existing clinical trials fail to demonstrate differences in the relative efficacy or safety of APCC vs. rFVIIa, we assumed the same efficacy for both products in the base-case. Regimens of APCC (75 IU kg-1 * 2 doses) and rFVIIa (90 MUg kg-1* 3 doses) were assumed according to manufacturer recommendations. If the first-line treatment failed, patients chose to continue the current treatment or switch to another drug. All costs were adjusted to 2009 US dollars. Sensitivity analyses on the infusion frequency, efficacy, unit price, switch rate, re-bleed rate and body weight were performed to assess model robustness. In the base-case, the total medical cost to treat a bleed with APCC or rFVIIa as first-line medication was US$25,969 and US$35,838, respectively. One-way sensitivity analyses showed that results were insensitive to the efficacy of rFVIIa, unit price of APCC or rFVIIa, switch rate, re-bleed rate or body weight. The rFVIIa will reach cost neutrality when the efficacy of APCC is as low as 60%, or rFVIIa is infused only twice for each line, or APCC is infused three times for each line. Two-way sensitivity analyses showed that results were quite sensitive to the assumed infusion frequency for both products. First-line APCC compared with rFVIIa can be a cost saving alternative for home treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors. PMID- 21649803 TI - Analysis of five polymorphic DNA markers for indirect genetic diagnosis of haemophilia A in the Brazilian population. AB - Hemophilia A is an X-linked, inherited, bleeding disorder caused by the partial or total inactivity of the coagulation factor VIII (FVIII). Due to difficulties in the direct recognition of the disease-associated mutation in the F8 gene, indirect diagnosis using polymorphic markers located inside or close to the gene is used as an alternative for determining the segregation of the mutant gene within families and thus for detecting carrier individuals and/or assisting in prenatal diagnosis. This study characterizes the allelic and haplotype frequencies, genetic diversity, population differentiation and linkage disequilibrium of five microsatellites (F8Int1, F8Int13, F8Int22, F8Int25.3 and IKBKG) in samples of healthy individuals from Sao Paulo, Rio Grande do Sul and Pernambuco and of patients from Sao Paulo with haemophilia A to determine the degree of informativeness of these microsatellites for diagnostic purposes. The interpopulational diversity parameters highlight the differences among the analyzed population samples. Regional differences in allelic frequencies must be taken into account when conducting indirect diagnosis of haemophilia A. With the exception of IKBKG, all of the microsatellites presented high heterozygosity levels. Using the markers described, diagnosis was possible in 10 of 11 families. The F8Int22, F8Int1, F8Int13, F8Int25.3 and IKBKG microsatellites were informative in seven, six, five and two of the cases, respectively, demonstrating the effectiveness of using these microsatellites in prenatal diagnosis and in carrier identification in the Brazilian population. PMID- 21649804 TI - A whole water catchment approach to investigating the origin and distribution of Cryptosporidium species. AB - AIMS: Investigating the distribution and origin of Cryptosporidium species in a water catchment affected by destocking and restocking of livestock as a result of a foot and mouth disease epidemic. METHODS AND RESULTS: Surface water, livestock and wildlife samples were screened for Cryptosporidium and oocysts characterised by sequencing SSU rRNA and COWP loci, and fragment analysis of ML1, ML2 and GP60 microsatellite loci. Oocyst concentrations in water samples (0-20.29 per 10 l) were related to rainfall events, amount of rainfall and topography. There was no detectable impact from catchment restocking. Cryptosporidium spp. found in water were indicative of livestock (Cryptosporidium andersoni and Cryptosporidium parvum) and wildlife (novel genotypes) sources. However, C. andersoni was not found in any animals sampled. Calf infections were age related; C. parvum was significantly more common in younger animals (<4 weeks old). Older calves shared Cryptosporidium bovis, Cryptosporidium ryanae and C. parvum. Wildlife shed C. parvum, Cryptosporidium ubiquitum, muskrat genotype II and deer genotype. CONCLUSIONS: Several factors affect the occurrence of Cryptosporidium within a catchment. In addition to farmed and wild animal hosts, topography and rainfall patterns are particularly important. SIGNIFICANCE AND IMPACT OF THE STUDY: These factors must be considered when undertaking risk-based water safety plans. PMID- 21649805 TI - A role of the sulfonylurea receptor 1 in endocytic trafficking of ATP-sensitive potassium channels. AB - The ATP-sensitive potassium (K(ATP) ) channel consisting of sulfonylurea receptor 1 (SUR1) and inward-rectifier potassium channel 6.2 (Kir6.2) has a well established role in insulin secretion. Mutations in either subunit can lead to disease due to aberrant channel gating, altered channel density at the cell surface or a combination of both. Endocytic trafficking of channels at the plasma membrane is one way to influence surface channel numbers. It has been previously reported that channel endocytosis is dependent on a tyrosine-based motif in Kir6.2, while SUR1 alone is unable to internalize. In this study, we followed endocytic trafficking of surface channels in real time by live-cell imaging of channel subunits tagged with an extracellular minimal alpha-bungarotoxin-binding peptide labeled with a fluorescent dye. We show that SUR1 undergoes endocytosis independent of Kir6.2. Moreover, mutations in the putative endocytosis motif of Kir6.2, Y330C, Y330A and F333I are unable to prevent channel endocytosis. These findings challenge the notion that Kir6.2 bears the sole endocytic signal for K(ATP) channels and support a role of SUR1 in this trafficking process. PMID- 21649806 TI - Vacuolar import of phosphatidylcholine requires the ATP-binding cassette transporter Ybt1. AB - ATP-binding cassette (ABC) transporters are well known for their roles as multidrug resistance determinants but also play important roles in regulation of lipid levels. In the yeast Saccharomyces cerevisiae, the plasma membrane ABC transporter proteins Pdr5 and Yor1 are required for normal rates of transport of phosphatidyethanolamine to the surface of the cell. Loss of these ABC transporters causes a defect in phospholipid asymmetry across the plasma membrane and has been linked with slowed rates of trafficking of other membrane proteins. Four ABC transporter proteins are found on the limiting membrane of the yeast vacuole and loss of one of these vacuolar ABC transporters, Ybt1, caused a major defect in the normal delivery of the phosphatidylcholine (PC) analog NBD-PC (7 nitro-2,1,3-benzoxadiazol-PC) to the lumen of the vacuole. NBD-PC accumulates on cytosolic membranes in an ybt1Delta strain. We demonstrated that Ybt1 is required to import NBD-PC into vacuoles in the presence of ATP in vitro. Loss of Ybt1 prevented vacuolar remodeling of PC analogs. Turnover of Ybt1 was reduced under conditions in which function of this vacuolar remodeling pathway was required. Our data describe a novel vacuolar route for lipid remodeling and reutilization in addition to previously described enzymatic avenues in the cytoplasm. PMID- 21649807 TI - Is experience enough? PMID- 21649808 TI - Eyes are the window to the soul. PMID- 21649809 TI - Screening for uncorrected refractive error in secondary school-age students in Fiji. AB - BACKGROUND: To estimate the rate of uncorrected refractive error and the associations with gender, age, ethnicity and place of residence. DESIGN: Population-based study. PARTICIPANTS: Secondary school students in the Central Division of Fiji. METHODS: All 58 secondary schools in the Central Division of Fiji were invited to participate and one class per year level at each participating school was randomly selected for screening. Visual acuity was tested using a logMAR chart and pinhole. Outcomes of screening included normal vision, corrected refractive error, uncorrected refractive error (VA <6/12 and improvement to >= 6/12 with pinhole (myopia) or hyperopia (tested with +2.00-D lens) and low vision (corrected VA <6/18). MAIN OUTCOME MEASURE: Prevalence of uncorrected refractive error. RESULTS: The participation rate of schools was 91% with 8201 students aged 12-20 years; 8021 students had normal vision; 180 had impaired vision (166 refractive error and 14 low vision). The rate of refractive error was 2.0% (95% CI: 1.7-2.3). Indian students were nearly 6 times more likely (OR: 5.89; 95% CI: 4.17-8.34; P < 0.001) to have refractive error than Fijians. The rate of uncorrected refractive error was 0.9% (95% CI: 0.7-1.1) in Fijian students (OR: 2.89; 95% CI: 1.37-6.10; P = 0.01) and those living in rural areas (OR: 3.28; 95% CI: 1.32-8.16; P = 0.01) were more likely to have uncorrected refractive error. The rate decreased by 20% (95% CI: 4.0-33.0) with each year of increasing age. CONCLUSION: The prevalence of uncorrected refractive error in children is relatively low in Fiji with higher rates in Fijian and rural children. PMID- 21649811 TI - Robotic cosmetic dermatology. PMID- 21649812 TI - Effects of lavender olfactory input on cosmetic procedures. AB - OBJECTIVES: To evaluate the effects of the aroma of essential oil of lavender against placebo on subjects' pain perceptions and levels of anxiety when undergoing elective cosmetic facial injections of botulinum toxin type A (BOTOX((r)) COSMETIC) for the correction of glabellar wrinkles. METHODS: Subjects (N=30) who had not previously received any cosmetic facial injections were randomized to essential oil of lavender aroma exposure or to placebo during elective cosmetic facial injections of BOTOX((r)) (12 U) for the correction of glabellar wrinkles. Evaluations of subjects' pain perceptions and levels of anxiety assessed by the Spielberger State-Trait Anxiety Inventory, heart rate (HR), and blood pressure (BP) measurements were taken at baseline, before, and after injections. RESULTS: Subjects exposed to essential lavender oil showed a significant reduction in HR after the injection as compared to the pre-injection HR. Subjects exposed to the placebo did not show any significant difference in BP or HR between pre-injection and postinjection. CONCLUSIONS: Although essential oil of lavender did not have an effect on the subjects' perception of pain during a facial injection, subjects showed significant increases in parasympathetic activity when exposed to the lavender aroma. Lavender aromatherapy has the potential to ease anxiety in patients undergoing minimally invasive facial cosmetic procedures. PMID- 21649813 TI - Efficacy and safety of a new hyaluronic acid dermal filler in the treatment of severe nasolabial lines - 6-month interim results of a randomized, evaluator blinded, intra-individual comparison study. AB - BACKGROUND: Hyaluronic acid (HA) fillers are frequently used for the correction of facial soft tissue defects. AIM: To compare the efficacy and safety of a novel HA filler, HA(E) (Emervel Deep), with those of HA(P) (Restylane Perlane) in the treatment of severe nasolabial folds (NLF). PATIENTS/METHODS: A split-face, randomized and evaluator-blinded comparison study. Subjects were randomized to receive injection of HA(E) or HA(P) on their left or right NLF. Efficacy was evaluated based on the change in Wrinkle Severity Rating Scale (WSRS) from baseline. Local tolerability was assessed based on subject diary during the first 3 weeks after injection. Adverse events were also evaluated. RESULTS: At both weeks 12 and 24, the mean improvement in WSRS from baseline was significantly greater for HA(E) than for HA(P) (1.58+/-0.89 vs. 1.33+/-0.82 at week 24; P=0.002). Similar volume of both products was injected at baseline and touch-up. Both fillers were well tolerated, with similar worst score distribution and mean score for erythema, edema/swelling, bruising, and pruritus. Significantly less severe pain/tenderness was reported with HA(E) than with HA(P) (P<0.05). CONCLUSIONS: The new HA filler HA(E) provides better efficacy and similar local tolerability compared with HA(P) 6 months after the treatment of severe NLF. PMID- 21649814 TI - Eyebrow bleaching among females: a cross-sectional study. AB - BACKGROUND: Eyebrow bleaching is a common practice among women with dark hair that allows for alterations in the eyebrows' shape without the use of hair removal. A literature search on this topic failed to reveal any extant studies. OBJECTIVE: To explore the prevalence, associated motives, and side effects of eyebrow bleaching among women. Methods A questionnaire about eyebrow bleaching was distributed randomly to female patients attending the outpatient clinics at a university hospital between June and August 2008. RESULTS: The response rate was 87.2%; with 567 of the 650 distributed questionnaires returned. The mean age was 32.01+/-10.17 years. 48.4% (253/522) of the participants reported having bleached their eyebrows. Of these individuals, 55.8% (101/181) experienced side effects related to eyebrow bleaching. These side effects included increased or decreased density of the eyebrow hair, and redness, itching, and scaling of the eyebrow skin. The motives behind eyebrow bleaching varied widely, but were primarily esthetic in nature. Younger women, students, and participants with higher monthly incomes reported bleaching their eyebrows a greater number of times than others (P<0.001, 0.04 and 0.003, respectively). CONCLUSION: In this sample of female patients, eyebrow bleaching was reported to be a common practice. Bleaching was associated with local side effects in over 50% of those who use the technique. Thus, there is a need to educate the public about these side effects. PMID- 21649815 TI - Analytic assessment under ultraviolet light of actinic lentigines under bleaching treatment. AB - BACKGROUND: Actinic (solar) lentigines are melanotic tumors frequently developed during photoaging on the dorsum of the hands. Bleaching (whitening) agents are commonly offered to fade their darker aspect. In general, regular colorimetric methods show poor sensitivity to disclose any bleaching effect. METHOD: The present randomized controlled study on 24 women was designed to objectively assess the clinical efficacy of a combination of bleaching agents on actinic lentigines. In the endeavor of improving sensitivity, the ultraviolet light enhanced visualization (ULEV) method was used to derive analytical measurements of lentigo areas and darkness. The test product was a commercially available formulation associating glycolic acid, kojic acid, lipohydroxyacid, and a Vitreoscilla extract. The Analysis(r) Olympus and Adobe Photoshop(r) quantitative methods were applied to the ULEV pictures. RESULTS: Data indicated a rapid bleaching effect arising as early as after 1 month of daily applications. The effect progressively increased over 3 months of therapy. CONCLUSION: The presently described analytical method appears to be sensitive to document some bleaching effects on actinic lentigines. PMID- 21649816 TI - Retinaldehyde/hyaluronic acid fragments: a synergistic association for the management of skin aging. AB - BACKGROUND: Retinaldehyde (RAL) was proven effective in treating photodamaged skin. Topical treatments with specific intermediate-size hyaluronate fragments (HAFi, 50-400 kDa) have been shown to stimulate keratinocytes proliferation and epidermal hyperplasia. The aim of this open, multicentric, international study was to assess the efficacy of the combination RAL-HAFi in the correction of skin photoaging. PATIENTS/METHODS: Either RAL 0.05%-HAFi 0.5% (Eluage(r) cream; group 1) or RAL 0.05%-HAFi 1% (Eluage(r) antiwrinkle concentrate; group 2) or both products (group 3) were applied daily to the 1462 subjects during 90 days. Overall photoaging severity was evaluated in the three groups by the dermatologists at D0, D30, and D90 based on the Larnier's scale. Wrinkles and/or furrows and clinical signs of aging were evaluated using a 4-point scale. The skin microrelief of the crow's feet, evaluated by optical profilometry, was performed in subjects from group 3. RESULTS: The 3-month application significantly improved overall photoaging through decrease of the Larnier's score in the three groups (P<0.001). At D90, significant improvement of wrinkles was shown in groups 2 and 3 [forehead wrinkles (-19% and -10%, respectively, P<0.001), nasolabial folds (-20% and -16%, P<0.001), crow's feet (-27% in the two groups, P<0.001), and perioral wrinkles (-34% and -23%, P<0.001)]. Clinical signs of photoaging on the entire face improved significantly in groups 1 and 3 [elasticity (-32% and -33%, respectively, P<0.001), hyperpigmentation (-34% and 31%, P<0.001), and ptosis (-18% and -22%; P<0.001)]. Results were confirmed using an optical profilometry technique. Products were very well tolerated. CONCLUSION: This clinical study showed the efficacy and value of the RAL-HAFi combination in the management of aging skin in a large cohort of patients. PMID- 21649817 TI - Comparative study of a new dermal filler Uma Jeunesse(r) and Juvederm(r). AB - INTRODUCTION: Innovation in technology has resulted in the emergence of better, longer-lasting hyaluronic acid implants with fewer side effects. The new dermal implant Uma Jeunesse(r) was compared to Juvederm(r) in this split-face study. METHODS: Uma Jeunesse(r) is crosslinked with butanediol diglycidyl ether (BDDE) using a new crosslinking technology. Uma Jeunesse(r) and Juvederm(r) Ultra 3 were injected in a split-face study on 17 healthy volunteers, whose ages ranged from 33-58 years. There were 14 women and three men with medium to deep nasolabial folds. All subjects randomly received either Uma Jeunesse(r) or Juvederm(r)) Ultra 3 on one half of their face. Patients were followed up for 9 months. RESULTS: Juvederm(r) was easier to inject with lesser injection pain because of lidocaine, but late postinjection pain was much less with Uma Jeunesse(r) as compared to Juvederm(r). Overall rate of early and late complications as well as adverse events was lower with Uma Jeunesse(r) than Juvederm((r)) . After 9 months of follow-up, Uma Jeunesse(r) lasted in tissues for longer as compared to Juvederm((r)) even in patients injected for the first time (P<0.0001). Patient acceptability rate of Uma Jeunesse(r) was also much higher. Perception of pain during injection was lesser with Juvederm(r) probably because of the presence of lidocaine. CONCLUSION: The new dermal implant Uma Jeunesse(r) is a safe and patient-friendly product which resides in the tissues for longer with maintenance of aesthetic effect over and beyond 6 months, reaching 9 months in over 80% of patients, and Juvederm(r) injection is less painful. PMID- 21649818 TI - Effecting skin renewal: a multifaceted approach. AB - The skin undergoes intrinsic aging as a normal course, but exposure to ultraviolet (UV) light results in major cumulative damage that manifests as the typical aged photodamaged skin. UV irradiation produces a sequence of changes within the skin layers starting with signaling processes following DNA damage and culminating in nonabsorbed fragmentation of collagen and other proteins within the extracellular matrix. These fragments promote the synthesis of matrix metalloproteinases (MMPs) that further aggravate the damage to the ground substance and add to fragment accumulation. This study describes a unique sequential approach to controlling this photodamage - inhibition of signaling, inhibition of MMPs, proteasome stimulation and mopping up of fragments, stimulation of procollagen and collagen production, and uniform packaging of new collagen fibers. Thus, a multifaceted approach is introduced with presentation of a unique product formulation based on these research principles. PMID- 21649820 TI - Minimally invasive esthetic procedures of the male breast. AB - In contrast to the female breast the male breast has gained much less attention by aesthetic surgery and cosmetic dermatology. In this review a focus on minimally invasive procedures to correct aesthetic problems of male breast are discussed. The major indications are gynecomastia, breast asymmetry, and body sculpturing. Minor surgery, laser lipolysis, dermal filler and cell-assisted lipotransfer are among the most promising techniques available. PMID- 21649821 TI - Treatment of lymphangioma circumscriptum with sclerotherapy: an ignored effective remedy. AB - Lymphangioma circumscriptum is a rare lymphatic malformation that involves the skin and may extend to subcutaneous tissue and muscle. It usually presents as grouped micro- to macroscopic vesicles filled with lymph. Surgical excision has been the standard treatment, but it is associated with scarring, infection, injury to the surrounding structures, and a high recurrence rate. Herein, we report a 24-year-old male patient with a lymphangioma circumscriptum on the nape of the neck that was treated with two sessions of an intralesional injection of 1% sodium tetradecyl sulfate sclerotherapy with a very good result. After this treatment, there was no more discharge and a reduction in the lesion's size by 70%. Sclerotherapy using sodium tetradecyl sulfate can be considered a successful minimally invasive treatment option for lymphangioma circumscriptum. PMID- 21649819 TI - Lower-face and neck antiaging treatment and prevention using onabotulinumtoxin A: the 2010 multidisciplinary French consensus--part 2. AB - BACKGROUND: Onabotulinumtoxin A has been used for many years in the aging face treatment. A survey was organized to identify current practices in France. OBJECTIVE: To develop consensual recommendations for treating aging lower face and neck with onabotulinumtoxin A. METHODS AND MATERIALS: Fifty-seven participants to six regional surveys reviewed practices and techniques for each individual treatment indication. From conference summaries and data from a questionnaire, consensual recommendations were developed. RESULTS: General considerations, key treatment rules, injection specifics (dose, site, and techniques), associated procedures/treatments, and procedure follow-up were defined by indication, i.e., nasolabial angle, nasal tip repositioning, dilated nostrils, lips and perioral area, Marionette lines and depressor anguli oris, gingival smile, risorius and zygomatic perioral muscles, masseters, chin, and platysma. For the consensus participants, current onabotulinumtoxin A use is a global preventive and corrective treatment. Overall, judicious treatment of multiple sites and adjunctive modalities, such as fillers, peels, and laser, leads to satisfactory results with a youthful, harmonious, animated, and natural looking face. CONCLUSION: Years of experience using onabotulinumtoxin A result in sophisticated treatment approaches, more specific targeted injections, and better understanding of lower facial and neck aging, leading to satisfying therapeutic results for patients and clinicians. PMID- 21649822 TI - Phosphatidylcholine/deoxycholate lipolysis and hyaluronic acid augmentation to enhance nonsurgical lower facial contouring using botulinum toxin type A. AB - Botulinum toxin type A can produce dramatic improvements in patients with benign masseteric hypertrophy but this method alone is not as effective for patients with a rounded lower face. The paper describes the effective use of selective lower jowl phosphatidylcholine/deoxycholate lipolysis and chin, cheek, and nose augmentation with hyaluronic acid to refine cosmetic lower facial contouring using botulinum toxin type A in a young Asian woman. A series of treatments was administered over 26 months. The patient's lower cheeks were slimmed and jowl definition was improved producing the patient's desired sculptured, heart-shaped face. The injection-based procedures provided much preferable alternative to surgery from the perspective of both the patient and her family. The authors believe that this is the first case report in the published literature reporting these three methods used in conjunction. PMID- 21649823 TI - Mechanobiology and cell tensegrity: the root of ethnic hair curling? AB - BACKGROUND: The hair shape, either straight, crimp, or curly, is basically under genetic influence. It is possibly altered by some drugs such as cytostatic agents. In addition, specific innate molecular characteristics are modulated by some cosmetic procedures to reshape the hair shafts. AIM: To revisit the possible implication of mechanobiology and cell tensegrity in shaping ethnic hair. MATERIALS AND METHODS: Optical and scanning electron microscopy of hairs. RESULTS: It is generally held that the cross-section shape of hair is related to differences in the global aspect of the hair shaft. A possible biologic link between these features may rely on shaping cell tensegrity at any portion of the hair shaft. Cell tensegrity encompasses all intrinsic and extrinsic forces responsible for the three-dimensional arrangement of intracellular macromolecules. CONCLUSION: We offer as a hypothesis that the hair shape in part depends on the organization of the cell proliferation in the hair matrix. This review gathers observations supporting the involvement of cell tensegrity in shaping the hair shaft. PMID- 21649824 TI - Tincture of time: a vital ingredient for dental success. PMID- 21649825 TI - Temporary restoration of maxillary lateral incisor implant sites. PMID- 21649826 TI - An esthetic solution to the screw-retained implant restoration: introduction to the implant crown adhesive plug: clinical report. AB - Screw-retained implant crowns may be clinically demanding, especially managing the esthetic and occlusal challenges of screw access channel closure. Many clinicians have moved away from using screw retention as a means of fixing a crown to an implant in favor of cementation to an underlying abutment. A link has been established between peri-implant disease and excess cement extrusion in cement-retained implant restorations. This article describes a novel technique of bonding a pressed porcelain plug into the screw access channel of an implant restoration that allows for control of occlusion, matches the esthetics of a cement-retained crown, and eliminates the issues of excess cement. CLINICAL SIGNIFICANCE: Overcoming the restorative challenges (esthetic, occlusal) of the screw access channel in a screw-retained implant restoration is difficult. By fabricating a pressed ceramic over metal crown and esthetic plug these challenges can be dealt with in a predictable manner. PMID- 21649827 TI - Commentary. An esthetic solution to the screw-retained implant restoration: introduction to the implant crown adhesive plug: clinical report. PMID- 21649828 TI - Current status and perspectives of mucogingival soft tissue measurement methods. AB - The morphologic and metric assessment of mucogingival soft tissue dimensions is of great multidisciplinary clinical and academic interest, in order to quantify and monitor gingival changes while in treatment, e.g., during periodontal, restorative, prosthetic, orthodontic, or implant therapy. Pink esthetics play an increasingly important role in the overall treatment success, and therefore have to be monitored throughout therapy. The purpose of this article was to identify and summarize methods, which aim at quantifying gingival dimensions in terms of morphology, thickness, and volume, with respect to their accuracy and practicability. The introduced measurement methods should further facilitate personalized treatment planning and monitoring. CLINICAL SIGNIFICANCE: Mucogingival esthetics play an increasingly important role whenever treatment results are evaluated. Several qualitative and (semi)quantitative methods for measuring soft tissue dimensions are available. New methods like CAD/CAM (computer-aided design and computer-aided manufacturing) technologies are emerging and allow practitioners to reliably monitor their patient's soft tissues throughout therapy. Future improvements may help to develop better treatment strategies in terms of optimized preservation and creation of gingival morphology, especially in the esthetic zone. PMID- 21649829 TI - Commentary. Current status and perspectives of mucogingival soft tissue measurement methods. PMID- 21649830 TI - Effect of home-use and in-office bleaching agents containing hydrogen peroxide associated with amorphous calcium phosphate on enamel microhardness and surface roughness. AB - STATEMENT OF THE PROBLEM: The effects of amorphous calcium phosphate (ACP) containing bleaching agents on enamel surface have not been clarified yet. PURPOSE: The study aims to evaluate the effects of different bleaching agents, either associated with ACP, or not, on enamel Knoop microhardness (KHN) and surface roughness (SR). MATERIALS AND METHODS: The home-use hydrogen peroxide (HP) bleaching agents PolaDay 7.5% (HP7.5; SDI Limited, Bayswater, Victoria, Australia), PolaDay 9.5% (HP9.5; SDI Limited); DayWhite ACP-7.5% (ACP7.5; Discus Dental, Culver City, CA, USA) and DayWhite ACP 9.5% (ACP9.5; Discus Dental), and the in-office agents PolaOffice 35% (HP35; SDI Limited) and Opalescence XtraBoost 38% (HP38; Ultradent Products, South Jordan, UT, USA) were applied to polished enamel slabs (N = 10) for 30 minutes/day for 21 consecutive days (home-use) or in one session a week, for 3 weeks (in-office). KHN and SR were tested before (baseline), during (7, 14, 21 days), and after (7 and 14 days in artificial saliva) the bleaching treatment. RESULTS: KHN evaluation revealed no significant difference among bleaching agents (p > 0.05); however, there was a significant decrease during bleaching treatment (p < 0.0001). KHN values attained in the post-treatment phase were statistically similar to baseline values (p > 0.05). SR was not altered during and after treatment, with the exception of PH38, which showed an increase in SR during bleaching treatment and a recovery after treatment. The ACP7.5 showed a trend to decreasing SR values during the bleaching treatment, but this decrease was only significant when associated with 14 days of immersion in artificial saliva, when the enamel was less rough than at baseline. CONCLUSIONS: Bleaching agents caused a decrease in enamel KHN, but values were recovered after treatment, showing the importance of saliva in recovering mineral content. SR was altered during or after treatment, depending on HP concentration/association with ACP. The beneficial effects of adding ACP to bleaching formulas on SR may be restricted to lower HP concentrations in association with the remineralizing effect of saliva. CLINICAL SIGNIFICANCE: No beneficial effects of adding ACP to bleaching formulas on enamel microhardness were observed, but these observations may be attributable to the lower hydrogen peroxide concentrations in association with the remineralizing effect of saliva, when considering the enamel roughness. PMID- 21649831 TI - Commentary. Effect of home-use and in-office bleaching agents containing hydrogen peroxide associated with amorphous calcium phosphate on enamel microhardness and surface roughness. PMID- 21649832 TI - Flow profile of regular and fast-setting elastomeric impression materials using a shark fin testing device. AB - STATEMENT OF THE PROBLEM: Light-bodied impression materials with high flow over time are needed to capture preparation margins, particularly with impressions of multiple preparations. PURPOSE: The flow of five different impression materials (three vinyl polysiloxane, one polyether, and one hybrid) of two setting times (fast and regular) was compared over 30-second intervals. MATERIALS AND METHODS: Flow was measured using a shark fin testing apparatus (3M ESPE, Seefeld, Germany). A weighted metal caste was suspended above a cup of impression material. The caste was dropped into the impression material, which displaced the material and caused it to flow into a triangular notch within the caste, creating a "shark fin." The test was repeated for each specimen at 30-second increments. These shark fin molds were kept in an incubator to allow setting of the impression materials. After complete setting, the height of the "shark fin" was measured. The data were analyzed using separate two-way analysis of variance and Tukey's HSD post hoc analyses to determine significant intergroup differences (p = 0.05). RESULTS: Shark fin values differed significantly among materials and at each time interval (p = 0.05). Polyether impression materials produced the greatest flow when compared with the vinyl polysiloxane and hybrid materials. CONCLUSION: Based on the limitations of this study and the materials used, polyether impression material had a better flow profile compared with the vinyl polysiloxane and hybrid materials. CLINICAL SIGNIFICANCE: An impression material must be selected based on the consistency and flow properties of the material, its setting time, anatomic aspects of the preparation, and speed of the operator. Impressions with deep subgingival margins and/or multiple preparations may be better captured with a polyether impression material. PMID- 21649833 TI - Commentary. Flow profile of regular and fast-setting elastomeric impression materials using a shark fin testing device. PMID- 21649834 TI - Color changes of dental resin composites before and after polymerization and storage in water. AB - The aims of this study were to: (1) evaluate the A2 shades of various types and brands of resin composites to determine if any color differences occurred before and after polymerization and after 1 month of storage in water and (2) examine the correlation among the color changes and changes in Commission internationale de l'eclairage L*, a*, and b* values after polymerization and after 1 month of storage in water. One submicron-hybrid (Spectrum TPH3, DENTSPLY DeTrey, Milford, DE, USA), one nano-filled (Filtek Supreme XT, 3 M ESPE, St. Paul, MN, USA), three micro-hybrid (Filtek Z250, 3 M ESPE; Esthet X, DENTSPLY DeTrey; and Gradia Direct, GC, Tokyo, Japan), and five nano-hybrid (Ceram X, DENTSPLY DeTrey; Clearfil Majesty Esthetics, Kuraray, Osaka, Japan; Premise, Kerr Corporation, Orange, CA, USA; Tetric Evo Ceram, Ivoclar Vivadent, Schaan, Liechtenstein and Tetric N Ceram, Ivoclar Vivadent) light-curing resin composites were tested. The specimens (N = 10 for each composite) were prepared as discs, 12 mm in diameter and 2 mm in thickness, using round molds. The measurements were performed "before polymerization,""after polymerization," and "after 1 month of storage in water" using a contact type dental spectrophotometer (Vita Easyshade, Vident, Brea, CA, USA). The range of DeltaE* values after polymerization (DeltaE*1) and storage in water (DeltaE*2) were 4.59 to 14.13 and 1.26 to 6.29, respectively. Nested analysis of variance and post hoc tests revealed that the type of resin composites significantly affected Deltaa*1, Deltaa*2, Deltab*1, Deltab*2, DeltaE*2-values, whereas the brand of resin composites affected the changes in all color parameters (p < 0.05). In spite of many improvements in chemical compositions and fillers of the contemporary composites, color changes after polymerization were perceptible in all resin composites. However, color changes after storage in water were in the acceptable ranges for all resin composites except Clearfil Majesty Esthetic and Gradia Direct. CLINICAL SIGNIFICANCE: In spite of many improvements in chemical compositions and fillers of the contemporary resin composites, the color changes after polymerization were still perceptible in all the resin composites tested in this study, regardless of their types and brands. Such changes may cause esthetic problems clinically, thus should be taken into account when the shade selections are performed. Alternatively, a piece of unpolymerized resin material can be placed on, or adjacent to the tooth to be restored and polymerized to confirm the selected shade of the esthetic material. PMID- 21649835 TI - Commentary. Color changes of dental resin composites before and after polymerization and storage in water. PMID- 21649837 TI - It is all about flow or, why there will never be one optimal blood pressure goal for every patient with hypertension. PMID- 21649838 TI - High blood pressure and obesity increase the risk of abnormal glucose tolerance in young adult african americans. AB - Higher prevalence of both hypertension and obesity in African Americans is associated with a disproportionately greater burden of cardiovascular diseases in this ethnic group. The purpose of this study was to examine whether there is an interaction between hypertension and obesity that significantly increases the expression of metabolic risk factors for cardiovascular disease. Four groups of young adult African Americans were recruited based on their weight and blood pressure (BP). The effects of weight and BP on metabolic risk factors were analyzed based on data obtained from 484 patients. Results demonstrated that high BP and obesity were independently associated with increased odds of abnormal glucose tolerance, 1.8- and 2.2-fold, respectively. The coexistence of both high BP and obesity further increased the odds of abnormal glucose tolerance 4-fold. In addition, the geometric mean of homeostasis model assessment, an estimate of insulin resistance, increased by 18% with high BP, 60% with obesity, and 90% with the presence of both high BP and obesity. Although no statistically significant interaction between high BP and obesity was detected, the relationships of both high BP and obesity with metabolic risk factors were clearly additive. PMID- 21649839 TI - A titrate-to-goal study of switching patients uncontrolled on antihypertensive monotherapy to fixed-dose combinations of amlodipine and olmesartan medoxomil +/- hydrochlorothiazide. AB - In the prospective, open-label, titrate-to-goal Blood Pressure Control in All Subgroups With Hypertension (BP-CRUSH) study, 999 patients with hypertension uncontrolled on monotherapy (mean age, 55.6 +/- 11.4 years; baseline blood pressure [BP], 153.7 +/- 9.2/91.9 +/- 8.6 mm Hg) were switched to fixed-dose amlodipine/olmesartan medoxomil (AML/OM) 5/20 mg. Patients were uptitrated every 4 weeks to AML/OM 5/40 mg and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM+hydrochlorothiazide (HCTZ) 10/40+12.5 mg and 10/40+25 mg to achieve BP <125/75 mm Hg. The primary end point, the cumulative percentage of patients achieving seated systolic BP < 140 mm Hg (< 130 mm Hg for patients with diabetes) by week 12, was 75.8%. The mean (+/- standard error) BP changes from baseline during the titration periods ranged from -14.2+/-0.4 mm Hg/-7.7 +/- 0.3 mm Hg for AML/OM 5/20 mg to -25.1 +/- 0.7 mm Hg/ 13.7 +/- 0.4 mm Hg for AML/OM+HCTZ 10/40+25 mg. By week 20, the cumulative BP threshold of <140/90 mm Hg was achieved by 90.3% of patients. An ambulatory BP monitoring substudy (n=243) showed that 24-hour efficacy was maintained. Treatment-emergent adverse events (TEAEs), mostly mild to moderate in severity, occurred in 529 patients (53.0%). Drug-related TEAEs occurred in 255 patients (25.5%). This well-tolerated, treat-to-goal algorithm enabled a large proportion of patients with uncontrolled hypertension on monotherapy to safely achieve BP control on single-pill AML/OM combination therapy or triple therapy with the addition of HCTZ. . PMID- 21649840 TI - Diagnosis, treatment, and referral of hypertension or prehypertension in an emergency department after an educational program: preliminary results. AB - The authors prospectively audited 602 randomly selected charts of patients seen in an academic emergency department (ED) for prevalence of hypertension and its management after an educational program (EP) because of results found in auditing 500 charts before the EP. Blood pressure was not measured in 11 of 500 patients (2.2%) before the EP and in 1 of 602 patients (0.2%) after the EP (P < .005). Hypertension was treated in the ED in 14 of 187 patients (8%) before the EP and in 29 of 282 patients (10%) after the EP (P = not significant). Of 187 patients with hypertension before the EP, 99 (53%) were referred to a physician or clinic for follow-up of hypertension, and 281 of 282 patients (99.6%) with hypertension were referred to a physician or clinic for follow-up of hypertension after the EP (P < .001). These data show that an EP administered to the staff of an academic ED significantly increased measurement of blood pressure in the ED, significantly increased obtaining a history of hypertension and of its treatment in ED patients, and significantly increased referral of patients with hypertension to a physician or clinic for follow-up of hypertension. PMID- 21649842 TI - Efficacy of amlodipine and olmesartan medoxomil in hypertensive patients with diabetes and obesity. AB - A subgroup analysis of a prospective, open-label, single-arm titration study in patients with hypertension and type 2 diabetes or obesity is reported. The primary end point was the change from baseline in mean 24-hour ambulatory systolic blood pressure (BP) after 12 weeks. Patients received amlodipine 5 mg/d and were uptitrated (if seated [Se] BP was >= 120/80 mm Hg) at 3-week intervals to amlodipine/olmesartan medoxomil 5/20 mg/d, 5/40 mg/d, and 10/40 mg/d. In patients with diabetes and obesity, baseline 24-hour ambulatory BP (+/- standard deviation) was 145.6 +/- 10.4/83.1 +/- 9.0 mm Hg and 143.7 +/- 9.8/84.9 +/- 8.2 mm Hg, respectively, and baseline SeBP was 159.1 +/- 11.3/90.3 +/- 9.2 mm Hg and 158.2 +/- 12.5/94.2 +/- 8.5mm Hg, respectively. Changes from baseline in mean 24 hour ambulatory BP (+/- standard error of the mean) were -21.5 +/- 1.8/-12.6 +/- 1.1 mm Hg and 21.6 +/- 1.1/13.4 +/- 0.8 mm Hg in patients with diabetes and obesity, respectively. Prespecified 24-hour ambulatory BP targets of < 130/80 mm Hg, < 125/75 mm Hg, and < 120/80 mm Hg were achieved by 79.1%, 53.5%, and 39.5% of patients with diabetes and 75.3%, 58.4%, and 43.8% of obese patients, respectively. The SeBP goal of < 130/80 mm Hg was achieved by 26.1% of patients with diabetes and <140/90 mm Hg was achieved by 78.1% of obese patients. PMID- 21649841 TI - Effects of daily adherence to antihypertensive medication on blood pressure control. AB - Clinicians are often uncertain about how to manage elevated blood pressure (BP) when a patient reports that he/she has recently missed several doses of antihypertensive medications. While we know that better adherence can improve BP during several months, the magnitude of this relationship in the short term is poorly understood. The authors examined this issue using a group of patients who monitored adherence using a Medication Events Monitoring System (MEMS) cap and had BP measurements in the course of routine clinical practice. BP readings were compared following 7 days of excellent adherence (100%) or poor adherence (< 60%), omitting BP values following intermediate adherence. Using several different methods, BP following 7 days of excellent adherence was between 12/7 mm Hg and 15/8 mm Hg lower than after 7 days of poor adherence. Clinicians can use this effect size to calibrate their impressions of what the BP might have been with improved adherence. PMID- 21649843 TI - Sustained blood pressure control following discontinuation of a pharmacist intervention. AB - Team-based care can improve hypertension control. The purpose of the present study was to evaluate blood pressure (BP) control 18 months following the discontinuation of a physician-pharmacist collaborative intervention. This was a retrospective analysis of patients who had previously participated in a prospective, cluster randomized, controlled clinical trial. Six community-based family medicine offices were randomized to control or intervention groups. Research nurses measured BPs using an automated device during the prospective trial. The research nurses then abstracted data from medical records, including BPs, medications, changes in therapy, and laboratory values for 18 months following the discontinuation of the 6-month prospective trial. The study included 228 patients in the control (n = 146) or intervention (n = 82) groups. The control group contained more patients with diabetes or chronic kidney disease (P < .013), were older (P = .047), and had more coexisting conditions (P < .001) than the intervention group. Systolic BP 9 months following discontinuation of the physician-pharmacist intervention was 137.2 +/- 18.2 mm Hg and 129.8 +/- 13.3 mm Hg in the control and intervention groups, respectively (P = .0015). BP control was maintained in 61 (41.8%) control patients and 55 (67.1%) intervention patients (P = .0003). At 18 months post-intervention, systolic BP was 138.1 +/- 20.4 mm Hg and 130.0 +/- 16.0 mm Hg in the control and intervention groups, respectively (P = .023). BP control was maintained in 53 (36.3%) control patients and 55 (67.1%) intervention patients at 18 months post-intervention (P < .0001). A sensitivity analysis was conducted to address the uneven distribution of patients with diabetes or chronic kidney disease, and the differences between groups were still significant. BP control rates remained significantly higher following a physician-pharmacist intervention compared with usual care for 18 months after discontinuation of the intervention. This model has the potential value as a useful long-term strategy to benefit patients with hypertension. PMID- 21649844 TI - Identification and management of albuminuria in the primary care setting. AB - Albuminuria is an important risk marker for adverse cardiovascular (CV) and renal outcomes and mortality. The relationship between albuminuria and risk is continuous and linear, like that of blood pressure and cardiovascular risk. Evidence now supports increased risk even at levels traditionally considered within normal limits. In high-risk patients, routine annual screening can detect changes in urine albumin excretion and improve the timely identification of albuminuria, and therefore should be considered in patients with diabetes, hypertension, and chronic kidney disease. Preferred simple screening methods appropriate for use in the primary care setting include microalbumin-specific dipsticks and urinary albumin:creatinine ratio determination (from a spot urine sample). Cornerstones of albuminuria treatment include risk factor management, ongoing monitoring, and, in patients with hypertension, chronic kidney disease, or diabetes, the use of renin-angiotensin-aldosterone system (RAAS)-blocking agents. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have demonstrated utility in this regard; data from studies of direct renin inhibition are promising. The combined use of an ACE inhibitor and ARB was once considered a viable option for the treatment of albuminuria; however, results of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) raised important questions regarding the benefits and limitations of dual RAAS blockade. Ongoing studies should provide important insight into the effects of this approach on renal outcomes. PMID- 21649845 TI - Managing erectile dysfunction in hypertensive patients. PMID- 21649846 TI - Catheter-based renal sympathetic nerve ablation controls blood pressure in more difficult-to-control patients taking multi-agent pharmacologic therapy. PMID- 21649849 TI - Low platelet reactivity is recovered by transfusion of stored platelets: a healthy volunteer in vivo study. PMID- 21649848 TI - Tilt balance towards regulation: evolving new strategy for treatment of hemophilia inhibitors. PMID- 21649850 TI - PKC inhibition markedly enhances Ca2+ signaling and phosphatidylserine exposure downstream of protease-activated receptor-1 but not protease-activated receptor-4 in human platelets. AB - BACKGROUND: Cytosolic calcium concentration is a critical regulator of platelet activation, and so platelet Ca(2+) signaling must be tightly controlled. Thrombin induced Ca(2+) signaling is enhanced by inhibitors of protein kinase C (PKC), suggesting that PKC negatively regulates the Ca(2+) signal, although the mechanisms by which this occurs and its physiological relevance are still unclear. OBJECTIVES: To investigate the mechanisms by which PKC inhibitors enhance thrombin-induced Ca(2+) signaling, and to determine the importance of this pathway in platelet activation. METHODS: Cytosolic Ca(2+) signaling was monitored in fura-2-loaded human platelets. Phosphatidylserine (PS) exposure, a marker of platelet procoagulant activity, was measured by annexin V binding and flow cytometry. RESULTS: PKC inhibition by bisindolylmaleimide-I (BIM-I) enhanced alpha-thrombin-induced Ca(2+) signaling in a concentration-dependent manner. PAR1 signaling, activated by SFLLRN, was enhanced much more strongly than PAR4, activated by AYPGKF or gamma-thrombin, which is a potent PAR4 agonist but a poor activator of PAR1. BIM-I had little effect on alpha-thrombin-induced signaling following treatment with the PAR1 antagonist, SCH-79797. BIM-I enhanced Ca(2+) release from intracellular stores and Ca(2+) entry, as assessed by Mn(2+) quench. However, the plasma membrane Ca(2+) ATPase inhibitor, 5(6)-carboxyeosin, did not prevent the effect of BIM-I. PKC inhibition strongly enhanced alpha-thrombin induced PS exposure, which was reversed by blockade of PAR1. CONCLUSIONS: Together, these data show that when PAR1 is stimulated, PKC negatively regulates Ca(2+) release and Ca(2+) entry, which leads to reduced platelet PS exposure. PMID- 21649851 TI - Hyperthermia inhibits platelet hemostatic functions and selectively regulates the release of alpha-granule proteins. AB - BACKGROUND: Hyperthermia is one of the main disturbances of homeostasis occurring during sepsis or hypermetabolic states such as cancer. Platelets are important mediators of the inflammation that accompanies these processes, but very little is known about the changes in platelet function that occur at different temperatures. OBJECTIVES: To explore the effect of higher temperatures on platelet physiology. METHODS: Platelet responses including adhesion, spreading (fluorescence microscopy), alpha(IIb)beta(3) activation (flow cytometry), aggregation (turbidimetry), ATP release (luminescence), thromboxane A(2) generation, alpha-granule protein secretion (ELISA) and protein phosphorylation from different signaling pathways (immunoblotting) were studied. RESULTS: Preincubation of platelets at temperatures higher than 37 degrees C (38.5-42 degrees C) inhibited thrombin-induced hemostasis, including platelet adhesion, aggregation, ATP release and thromboxane A(2) generation. The expression of P selectin and CD63, as well as vascular endothelial growth factor (VEGF) release, was completely inhibited by hyperthermia, whereas von Willebrand factor (VWF) and endostatin levels remained substantially increased at high temperatures. This suggested that release of proteins from platelet granules is modulated not only by classical platelet agonists but also by microenvironmental factors. The observed gradation of response involved not only antiangiogenesis regulators, but also other cargo proteins. Some signaling pathways were more stable than others. While ERK1/2 and AKT phosphorylation were resistant to changes in temperature, Src, Syk, p38 phosphorylation and IkappaB degradation were decreased in a temperature-dependent fashion. CONCLUSIONS: Higher temperatures, such as those observed with fever or tissue invasion, inhibit the hemostatic functions of platelets and selectively regulate the release of alpha-granule proteins. PMID- 21649852 TI - A mixed-methods evaluation of the effectiveness of tailored smoking cessation training for healthcare practitioners who work with older people. AB - BACKGROUND: Older people who smoke derive significant health benefits from stopping smoking in later life. Healthcare practitioners have an important role to play in raising the issue of smoking cessation with this client group; however, they often fail to do so. AIM: To assess the effectiveness of smoking cessation training for healthcare practitioners who have regular contact with older adults. METHODS: Mixed-methods were used to explore satisfaction with the training, the participants' learning and any resultant changes in behaviour. The effectiveness of the training was assessed using a two-group parallel design randomised controlled trial, followed by semistructured qualitative interviews. Participants (n = 57) were recruited from a cohort of community nurses and allied health professionals (e.g., occupational therapists) working in Scotland. The intervention was 1-day brief intervention smoking cessation training. Validated measures of knowledge, attitudes and practice, were used to assess learning and behaviour at baseline, 1 week and 3 months post training. Data were analysed using two-factor repeated measure analysis of variance, where the factors were "group" and "time." Qualitative data were gathered from members of the intervention group during semistructured interviews (n = 8) and were analysed thematically. RESULTS/FINDINGS: Levels of satisfaction with the training were high. There was a statistically significant improvement in the knowledge and attitudes of the intervention group following the training, with a noticeable, but nonsignificant, improvement in practice. The qualitative findings demonstrate how the training impacted positively on practice. CONCLUSIONS: Smoking cessation interventions in later life are important, as older smokers generally have long term conditions caused or complicated by smoking. The delivery of brief smoking cessation interventions is known to be highly cost-effective; however, research demonstrates that practitioners often fail to raise the issue of smoking cessation with older adults. This study has demonstrated the effectiveness of a 1 day training course for practitioners. Further research is recommended. PMID- 21649853 TI - A systematic review of methods of eye irrigation for adults and children with ocular chemical burns. AB - AIM: To present the best available research evidence on eye irrigation methods for ocular chemical burns to facilitate better-informed clinical decisions. METHODS: Randomized, quasi-randomized controlled trials and observational studies comparing the effectiveness of eye irrigation methods among adults or children as an active form of emergency treatment for ocular chemical burns were reviewed. Electronic databases in English and Chinese were searched from inception to June 2010. Two reviewers made independent decisions on whether to include each publication in the review and critically appraised the study quality independently. Given the clinical and methodological diversity among the studies, the review findings are presented in a narrative form. RESULTS AND DISCUSSION: Four studies involving 302 adults and children were identified. The results of this review indicate that patients who underwent irrigation with tap water immediately following alkali burns at the scene of injury had significantly better clinical and ocular outcomes. The evidence also suggests that in hospital settings, more patients preferred balanced saline solution (BSS) plus than other irrigation fluids. Irrigation with diphoterine was found in one study that resulted in better ocular outcomes following grade 1 and 2 ocular burns. With regard to duration of eye irrigation, patients with ocular chemical burns treated with prolonged irrigation reported shorter duration of treatment at hospital and absence from work. The results should be treated with caution, as there were significant differences between the comparison groups in some studies. IMPLICATIONS AND CONCLUSIONS: As prompt eye irrigation with tap water immediately after alkali burns had better outcomes, it would be important to commence eye irrigation immediately after burns are sustained. In this review, irrigating fluids including normal saline, lactated Ringer's, normal saline with sodium bicarbonate added, BSS Plus, and diphoterine solutions all yielded positive ocular outcomes suggesting for its use in hospital settings. PMID- 21649854 TI - Preferred information sources for clinical decision making: critical care nurses' perceptions of information accessibility and usefulness. AB - BACKGROUND: Variability in clinical practice may result from the use of diverse information sources to guide clinical decisions. In routine clinical practice, nurses privilege information from colleagues over more formal information sources. It is not clear whether similar information-seeking behaviour is exhibited when critical care nurses make decisions about a specific clinical practice, where extensive practice variability exists alongside a developing research base. PURPOSE: This study explored the preferred sources of information intensive care nurses used and their perceptions of the accessibility and usefulness of this information for making decisions in clinically uncertain situations specific to enteral feeding practice. METHODS: An instrumental case study design, incorporating concurrent verbal protocols, Q methodology and focus groups, was used to determine intensive care nurses' perspectives of information use in the resolution of clinical uncertainty. FINDINGS: A preference for information from colleagues to support clinical decisions was observed. People as information sources were considered most useful and most accessible in the clinical setting. Text and electronic information sources were seen as less accessible, mainly because of the time required to access the information within the documents. DISCUSSION: When faced with clinical uncertainty, obtaining information from colleagues allows information to be quickly accessed and applied within the context of a specific clinical presentation. Seeking information from others also provides opportunities for shared decision-making and potential validation of clinical judgment, although differing views may exacerbate clinical uncertainty. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The social exchange of clinical information may meet the needs of nurses working in a complex, time pressured environment but the extent of the evidence base for information passed through verbal communication is unclear. The perceived usefulness and accessibility of information is premised on the ease of use and access and thus the variability in information may be contributing to clinical uncertainty. PMID- 21649855 TI - Collaboration between researchers and health care providers in bridging the gap between research and practice: some observations from a natural experiment. PMID- 21649856 TI - Teaching and learning about the impact of evidence-based practice implementation. PMID- 21649857 TI - Serotonin receptor 2A gene moderates the effect of childhood maternal nurturance on adulthood social attachment. AB - The ability to form and maintain attachment relations with other people is crucial for mental health and well-being. The origins of attachment behaviors are often assumed to be in early experiences with other people, especially with primary caregivers. Preliminary evidence suggests that serotonergic system may be involved in attachment behaviors. We examined whether the T102C variant of the serotonin receptor 2A gene moderates the effect of childhood maternal nurturance on social attachment in adulthood. The participants were 1070 women and men from the Young Finns Study with 27-year follow-up and two measurement times for the outcomes (n = 1836 person observations). Mothers reported their relationship quality with their children (participants) in childhood or adolescence. Social attachment was assessed by participant's self-reports on two measures (reward dependence scale of the Temperament and Character Inventory and the Relationship Questionnaire). High childhood maternal nurturance predicted high reward dependence and low avoidant attachment in carriers of the T/T genotype but not in the T/C or C/C genotype groups, while low maternal nurturance was associated with low reward dependence and high avoidant attachment in T/T genotype carriers but not in C allele carriers. Our result suggests that T/T genotype carriers were more influenced by their childhood nurturing environment, than their C allele carrying counterparts, thus providing evidence for differential susceptibility to childhood nurturing environment associated with the HTR2A gene. PMID- 21649858 TI - Comparative immunogenetics of autism and schizophrenia. AB - Autism and schizophrenia are highly heritable neurodevelopmental disorders, each mediated by a diverse suite of genetic and environmental risk factors. Comorbidity and familial aggregation of such neurodevelopmental disorders with other disease-related conditions can provide important insights into their etiology. Epidemiological studies have documented reduced rates of rheumatoid arthritis, a systemic autoimmune condition, in schizophrenia, and recent work has shown increased rates of rheumatoid arthritis in first-degree relatives of autistic individuals, especially mothers. Advances in understanding the genetic basis of rheumatoid arthritis have shown that much of the genetic liability to this condition is due to risk and protective alleles at the HLA DRB1 locus. These data allow robust testing of the hypotheses that allelic variation at DRB1 pleiotropically modulates risk of rheumatoid arthritis, autism and schizophrenia. Systematic review of the literature indicates that reported associations of DRB1 variants with these three conditions are congruent with a pleiotropic model: DRB1*04 alleles have been associated with increased risk of rheumatoid arthritis and autism but decreased risk of schizophrenia, and DRB1*13 alleles have been associated with protection from rheumatoid arthritis and autism but higher risk of schizophrenia. These convergent findings from genetics and epidemiology imply that a subset of autism and schizophrenia cases may be underlain by genetically based neuroimmune alterations, and that analyses of the causes of risk and protective effects from DRB1 variants may provide new approaches to therapy. PMID- 21649859 TI - Do complement factor H 402Y and C7 M allotypes predispose to (typical) haemolytic uraemic syndrome? AB - Typical haemolytic uraemic syndrome (HUS) is mainly caused by infections with enterohaemorrhagic Escherichia coli, whereas in atypical, nonbacteria-associated HUS, complement plays a dominant role. Recently, complement has also been shown to be involved in typical HUS. In this study, mostly weakly significant associations with homozygosities of complement allotype C7 M and inversely with factor H 402H were found, suggesting that 402Y and C7 M allotypes predispose to (typical) haemolytic uraemic syndrome. PMID- 21649860 TI - cDNA cloning, genomic structure and mRNA expression pattern of porcine type I interferons receptor 2 gene. AB - Type I interferons (IFN) are important mediators of the host defence against viruses through binding to the cell surface receptors, among which the binding to type I IFN receptor 2 (IFNAR2) is the very first step initiating a complex signal transduction cascade. By using RT-PCR and 5' RACE approaches, we obtained porcine IFNAR2 cDNA, the nucleotide identity of its coding region is 57.53%, 67.45%, 74.07% and 74.63% to those of mouse, human, sheep and cattle, respectively; and the deduced protein of which shares 38.18%, 55.29%, 62.01% and 63.39% identity to those of mouse, human, sheep and cattle, respectively. The genomic structure of porcine IFNAR2 gene consists of nine exons and eight introns. Porcine IFNAR2 mRNA expression was detected in all tissues examined, being strong in the spleen, small intestine, cerebrum and uterus tissues and relatively weak in the stomach tissues. As compared with piglets, the expression of IFNAR2 mRNA was significantly higher in both liver and spleen of Laiwu adult pigs (P < 0.01); in Duroc pigs, however, significantly higher IFNAR2 mRNA expression was only found in adult liver (P < 0.05). In Duroc * Landrace * Yorkshire commercial pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV), the expression of IFNAR2 mRNA in lung tissue was significantly down-regulated as compared to uninfected ones (P < 0.05). PMID- 21649861 TI - Anti-stroke profile of thiazolidin-4-one derivatives in focal cerebral ischemia model in rat. AB - Recently, some PPARgamma agonists like pioglitazone, rosiglitazone, and other newer thiazolidine-2, 4-dione (TZD) derivatives have been shown to be neuroprotective in experimental model of cerebral ischemia/reperfusion (I/R) injury. Replacement of active pharmacophore viz: thiazolidine-2,4-dione of these PPARgamma agonists with biologically privileged scaffold thiazolidin-4-one derivatives have been synthesized and bioevaluated in focal cerebral ischemia model in rats with an aim to ameliorate cerebral ischemic damage. Of 20 synthesized molecules, three of the substituted compounds (2, 6 and 18) have shown significant (p < 0.001) neuroprotection even much better than rosiglitazone at same dose, when administered 1 h prior to 2/24hrI/R cerebral injury in rats, whereas compounds 10, 15, and 17 also showed significant but moderate effect on most of the parameters used in the study. Moreover, compound 2 and 6 also showed curative potential after 6 h post I/R treatment. The compound 2 has also shown significant effect on glutamate uptake by perhaps enhancing the GLT-1 activity. Thus, the present study indicates that some of the synthesized thiazolidin-4-one substituted PPARgamma agonists exhibit better neuroprotection and have potential to ameliorate the ischemic damage. Therefore, this novel class of compounds could be further suitably modified to obtain potent anti-ischemic agents, warranting clinical exploitation. PMID- 21649863 TI - Role of L-arginine uptake mechanisms in renal blood flow responses to angiotensin II in rats. AB - AIM: To examine whether reduced renal arginine transport increases the responsiveness of the renal circulation to angiotensin II in salt sensitivity, renal perfusion responses to angiotensin II were examined in the presence of L arginine transport inhibitor, L-lysine and subsequent L-arginine in Sprague Dawley (SD) and Dahl salt-sensitive (Dahl S) rats. METHODS: Laser Doppler probes and a transonic flow probe were used to measure regional renal perfusion and total renal perfusion respectively. Renal perfusion responses to intravenous (i.v.) angiotensin II were sequentially examined under control conditions and during i.v. infusion of L-lysine, L-arginine or nitric oxide synthase inhibitor, N(G)-nitro-L-arginine. RESULTS: Angiotensin II (10 and 100 ng kg(-1) min(-1) , i.v.) reduced total renal (-10 +/- 3 and -36 +/- 5%) and cortical (-10 +/- 2 and 28 +/- 4%) but not medullary perfusion in SD rats. In these rats L-lysine enhanced the renal perfusion response (P = 0.003), whereas subsequent L-arginine reversed this effect (P = 0.04). Angiotensin II reduced total renal, cortical and medullary perfusion in Dahl S rats. In Dahl S rats fed high salt, L-lysine did not affect renal perfusion responses to angiotensin II, but subsequent L-arginine blunted the renal blood flow response (P = 0.01) and increased the medullary perfusion during angiotensin II infusion (P = 0.006). CONCLUSION: Intact renal L arginine transport attenuates the vasoconstrictor effects of circulating angiotensin II in the renal cortex in SD rats. L-arginine also plays an important role in protecting the renal medullary circulation from the ischemic effects of angiotensin II in Dahl S rats. PMID- 21649862 TI - Effects on blood pressure and autonomic nervous system function of a 12-week exercise or exercise plus DASH-diet intervention in individuals with elevated blood pressure. AB - AIM: Hypertension is related to abnormalities in autonomic nervous system (ANS) function, with increased sympathetic output and decreased parasympathetic tone. Lifestyle interventions are the first line of treatment in hypertension, and decreased blood pressure (BP) effects may be related to changes in ANS function. Using heart rate recovery (HRR) from exercise as an index of parasympathetic tone and plasma noradrenaline as an index of sympathetic tone, we investigated the effects of lifestyle interventions on ANS function in patients with elevated BP. METHODS: Sedentary participants with elevated BP were randomly assigned to either an exercise only (N = 25), exercise plus dietary approaches to stop hypertension (DASH) diet (N = 12), or waitlist control (N = 15) 12-week intervention. Plasma noradrenaline was measured at rest and participants performed a peak exercise test before and after the intervention. HRR was calculated as peak heart rate (HR) minus HR at 1 min post-exercise. RESULTS: Heart rate recovery showed a significant group by time interaction; both intervention groups showed increases in HRR from pre- to post-intervention, while waitlist showed no change. Similarly, both exercise plus diet and exercise groups, but not waitlist, showed significant reductions in BP from pre- to post-intervention. Linear regression revealed that BP post-intervention was significantly predicted by change in HRR when controlling for pre-BP, age, gender and BMI. CONCLUSIONS: Lifestyle interventions induced training-reduced BP and altered autonomic tone, indexed by HRR. This study indicates the importance of behavioural modification in hypertension and that increased parasympathetic function is associated with success in reduction of BP. PMID- 21649864 TI - The G-protein on cholesterol-rich membrane microdomains mediates mucosal sensing of short- chain fatty acid and secretory response in rat colon. AB - AIM: Short-chain fatty acids (SCFA) stimulate colonic contraction and secretion, which are mediated by an enteric reflex via a mucosal sensing and cholinergic mechanisms. The involvement of G-protein signal transduction was examined in the secretory response to luminal propionate sensing in rat distal colon. METHODS: Mucosa-submucosa and mucosa preparations were used to measure short-circuit current (I(sc)) and acetylcholine (ACh) release respectively. Cholesterol-rich membrane microdomains, lipid rafts/caveolae, were fractionated using a sucrose gradient ultra-centrifugation after detergent-free extraction of the isolated colonic crypt. RESULTS: Luminal addition of methyl-beta-cyclodextrin (10 mm) and mastoparan (30 MUm), lipid rafts/caveolae disruptors, significantly inhibited luminal propionate-induced (0.5 mm) increases in I(sc) , but did not affect increases in I(sc) induced by serosal ACh (0.05 mm) or electrical field stimulation (EFS). Luminal addition of YM-254890 (10 MUm), a Galpha(q/11) selective inhibitor, markedly inhibited propionate-induced increase in I(sc) , but did not affect I(sc) responses to ACh and EFS. Both methyl-beta-cyclodextrin and YM-254890 significantly inhibited luminal propionate-induced non-neuronal release of ACh from colonocytes. Real-time PCR demonstrated that in mRNA expression of SCFA receptors, GPR 43 was far higher than that of GPR41 in the colon. Western blotting analysis revealed that the cholesterol-rich membrane microdomains that fractionated from colonic crypt cells were associated with caveolin-1, flotillin-1 and Galpha(q/11) , but not GPR43. Uncoupling of Galpha(q/11) from flotillin-1 in lipid rafts occurred under desensitization of the I(sc) response to propionate. CONCLUSIONS: These data demonstrate that the secretory response to luminal propionate in rat colon is mediated by G-protein on cholesterol-rich membrane microdomains, provably via Galpha(q/11) . PMID- 21649865 TI - Nutrition transition in India: secular trends in dietary intake and their relationship to diet-related non-communicable diseases. AB - India is facing an "epidemic" of diet-related non-communicable diseases (DR NCDs), along with widely prevalent undernutrition resulting in substantial socioeconomic burden. The aim of this paper is to review secular trends in food groups and nutrient intake, and implications for DR-NCDs in India so as to understand optimal choices for healthy diets for the prevention of DR-NCDs. The literature search was carried out in PubMed (National Library of Medicine, Bethesda, MD, USA) and Google Scholar search engines up to April 2011. A manual search for all other references, national and medical databases was also carried out. Nutrition transition over the past 30 years (1973-2004), has resulted in a 7% decrease in energy derived from carbohydrates and a 6% increase in energy derived from fats. A decreasing intake of coarse cereals, pulses, fruits and vegetables, an increasing intake of meat products and salt, coupled with declining levels of physical activity due to rapid urbanization have resulted in escalating levels of obesity, atherogenic dyslipidemia, subclinical inflammation, metabolic syndrome, type 2 diabetes mellitus, and coronary heart disease in Indians. Studies also suggest that adverse perinatal events due to maternal nutritional deprivation may cause low-birth weight infants, which, coupled with early childhood "catch-up growth", leads to obesity in early childhood, thus predisposing to NCDs later in life. In view of rapidly increasingly imbalanced diets, a multisectoral preventive approach is needed to provide balanced diets to pregnant women, children and adults, and to maintain a normal body weight from childhood onwards, to prevent the escalation of DR-NCDs in India. PMID- 21649866 TI - Retinal nerve fibre layer defects associated with cotton-wool spots in patients with interferon retinopathy. PMID- 21649868 TI - Intravitreal bevacizumab (avastin) combined with vitrectomy for recurrences of proliferative vitreoretinopathy in Von Hippel-Lindau disease. PMID- 21649869 TI - Beta blocker use and age-related macular degeneration. PMID- 21649870 TI - Scleral buckling in rhegmatogenous retinal detachment with concomitant full thickness macular hole. PMID- 21649871 TI - Fatal Pneumocystis jirovecii pneumonia following immunosuppressive therapy with rituximab and prednisolone for posterior scleritis. PMID- 21649872 TI - Risk factors for intraoperative floppy iris syndrome: a retrospective study. PMID- 21649873 TI - Dacryoliths in the lacrimal gland ductule. PMID- 21649874 TI - Age-dependent ocular phenotype in hereditary hyperferritinaemia cataract syndrome (HHCS). PMID- 21649875 TI - Benefits, limitations and outcomes of vitreoretinal surgery, Nairobi, Kenya: 8 year experience. PMID- 21649876 TI - Awareness of diabetic retinopathy among diabetic patients in Nepal. PMID- 21649877 TI - A possible strategy for implanting blue-blocking intraocular lenses. PMID- 21649878 TI - Liquid gonioscopy--a new technique. PMID- 21649879 TI - Outbreak of swine erysipelas in a semi-intensive wild boar farm in Spain. AB - Swine erysipelas (SE) is a disease caused by the bacterium Erysipelothrix rhusiopathiae and is one of the best-known and most serious diseases affecting domestic pigs. However, few studies exist concerning the susceptibility of wild boars to this disease and the role of this species as a reservoir. This study investigates and describes an outbreak of SE that occurred on a semi-intensive wild boar breeding farm housing 40 boars in Extremadura (SW Spain) on 11-18 February 2010. Seven animals died, of which four were examined post-mortem. Of these, three (two females and one male) were approximately 3 months old, and one was 1 year old (male). Lesions were consistent with acute septicaemia, consisting of cutaneous erythema/cyanosis and petechial haemorrhages in kidneys, urinary bladder, lungs and meninges. The 1-year-old male also had proliferative polyarthritis. Histopathology confirmed the presence of disseminated intravascular coagulation and vasculitis. Additionally, a bilateral acute panuveitis with concurrent necrotizing vasculitis and diffuse corneal oedema, neither of which have been described before in this disease, were found in the 3 month-old male boar. E. rhusiopathiae was isolated from all four animals in pure cultures from several tissues. Of these four animals, antibodies against E. rhusiopathiae, using an indirect ELISA test, were only detected in the 1-year-old male boar with polyarthritis. Posteriorly, of nine live adults tested for antibodies, four (including an adult male with polyarthritis) were positive. PMID- 21649880 TI - Computational classifiers for predicting the short-term course of Multiple sclerosis. AB - BACKGROUND: The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS). METHODS: We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center. RESULTS: We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later. CONCLUSIONS: The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability. PMID- 21649881 TI - T lymphocytes derived from human cord blood provide effective antitumor immunotherapy against a human tumor. AB - BACKGROUND: Although the graft-versus-tumor (GVT) effect of donor-derived T cells after allogeneic hematopoietic stem cell transplantation has been used as an effective adoptive immunotherapy, the antitumor effects of cord blood (CB) transplantation have not been well studied. METHODS: We established the animal model by transplantation of CB mononuclear cells and/or tumor cells into NOD/SCID mice. The presence of CB derived T cells in NOD/SCID mice or tumor tissues were determined by flow cytometric and immunohistochemical analysis. The anti-tumor effects of CB derived T cells against tumor was determined by tumor size and weight, and by the cytotoxicity assay and ELISPOT assay of T cells. RESULTS: We found dramatic tumor remission following transfer of CB mononuclear cells into NOD/SCID mice with human cervical tumors with a high infiltration of CD3+ T cells in tumors. NOD/SCID mice that receive neonatal CB transplants have reconstituted T cells with significant antitumor effects against human cervical and lung tumors, with a high infiltration of CD3+ T cells showing dramatic induction of apoptotic cell death. We also confirmed that T cells showed tumor specific antigen cytotoxicity in vitro. In adoptive transfer of CD3+ T cells into mice with pre-established tumors, we observed much higher antitumor effects of HPV specific T cells by ELISPOT assays. CONCLUSIONS: Our results show that CB derived T lymphocytes will be useful for novel immunotherapeutic candidate cells for therapy of several tumors in clinic. PMID- 21649882 TI - Recommended beta-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. AB - INTRODUCTION: Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT. METHODS: This open, prospective study enrolled consecutive patients treated with CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Serum concentrations of these antibiotics were determined by high-performance liquid chromatography from samples taken before (t = 0) and 1, 2, 5, and 6 or 12 hours (depending on the beta-lactam regimen) after the administration of each antibiotic. Series of measurements were separated into those taken during the early phase (< 48 hours from the first dose) of therapy and those taken later (> 48 hours). RESULTS: A total of 69 series of serum samples were obtained in 53 patients (MEM, n = 17; TZP, n = 16; FEP, n = 8; CAZ, n = 12). Serum concentrations remained above four times the minimal inhibitory concentration for Pseudomonas spp. for the recommended time in 81% of patients treated with MEM, in 71% with TZP, in 53% with CAZ and in 0% with FEP. Accumulation after 48 hours of treatment was significant only for MEM. CONCLUSIONS: In septic patients receiving CRRT, recommended doses of beta-lactams for Pseudomonas aeruginosa are adequate for MEM but not for TZP, FEP and CAZ; for these latter drugs, higher doses and/or extended infusions should be used to optimise serum concentrations. PMID- 21649883 TI - A comprehensive gene expression atlas of sex- and tissue-specificity in the malaria vector, Anopheles gambiae. AB - BACKGROUND: The mosquito, Anopheles gambiae, is the primary vector of human malaria, a disease responsible for millions of deaths each year. To improve strategies for controlling transmission of the causative parasite, Plasmodium falciparum, we require a thorough understanding of the developmental mechanisms, physiological processes and evolutionary pressures affecting life-history traits in the mosquito. Identifying genes expressed in particular tissues or involved in specific biological processes is an essential part of this process. RESULTS: In this study, we present transcription profiles for ~82% of annotated Anopheles genes in dissected adult male and female tissues. The sensitivity afforded by examining dissected tissues found gene activity in an additional 20% of the genome that is undetected when using whole-animal samples. The somatic and reproductive tissues we examined each displayed patterns of sexually dimorphic and tissue-specific expression. By comparing expression profiles with Drosophila melanogaster we also assessed which genes are well conserved within the Diptera versus those that are more recently evolved. CONCLUSIONS: Our expression atlas and associated publicly available database, the MozAtlas (http://www.tissue atlas.org), provides information on the relative strength and specificity of gene expression in several somatic and reproductive tissues, isolated from a single strain grown under uniform conditions. The data will serve as a reference for other mosquito researchers by providing a simple method for identifying where genes are expressed in the adult, however, in addition our resource will also provide insights into the evolutionary diversity associated with gene expression levels among species. PMID- 21649884 TI - Dissecting gene expression in mosquito. AB - Gene expression is known to vary extensively among tissues and between sexes. However, detailed descriptions of tissue- and sex-specific gene expression are available for only a few model organisms. A new study published in BMC Genomics presents such a data set for the mosquito, Anopheles gambiae, which is the vector of human malaria. In addition to providing a valuable resource for the community of mosquito researchers, the study allows comparative transcriptomic studies of dipteran insects to be extended over 250 million years of evolution, since the divergence of A. gambiae and Drosophila melanogaster. PMID- 21649885 TI - A 5'-uridine amplifies miRNA/miRNA* asymmetry in Drosophila by promoting RNA induced silencing complex formation. AB - BACKGROUND: MicroRNA (miRNA) are diverse in sequence and have a single known sequence bias: they tend to start with uridine (U). RESULTS: Our analyses of fly, worm and mouse miRNA sequence data reveal that the 5'-U is recognized after miRNA production. Only one of the two strands can be assembled into Argonaute protein from a single miRNA/miRNA* molecule: in fly embryo lysate, a 5'-U promotes miRNA loading while decreasing the loading of the miRNA*. CONCLUSION: We suggest that recognition of the 5'-U enhances Argonaute loading by a mechanism distinct from its contribution to weakening base pairing at the 5'-end of the prospective miRNA and, as recently proposed in Arabidopsis and in humans, that it improves miRNA precision by excluding incorrectly processed molecules bearing other 5'-nt. PMID- 21649886 TI - A confirmatory study of the Combined Index of Severity of Fibromyalgia (ICAF*): factorial structure, reliability and sensitivity to change. AB - BACKGROUND: Fibromyalgia (FM) is a complex syndrome that affects many aspects of the patient's life and it is very difficult to evaluate in clinical practice. A recent study has developed the Combined Index of Severity of Fibromyalgia (ICAF), an instrument that evaluates diverse aspects of FM and offers five indices: emotional, physical, active coping, passive coping and total. The objective of this study is to confirm the structure of the ICAF, check its test-retest reliability, assess its sensitivity to change, and compare the results obtained in a sample of patients with fibromyalgia with another sample of healthy controls. METHODS: A total of 232 patients took part in the study, 228 women and 4 men, with a mean age of 47.73 years of age (SD = 8.61) and a time of disease evolution since diagnosis of 4.28 years (SD = 4.03). The patients from the FM group completed the ICAF. Between one and two weeks later, they again attended the clinic and complete the 59 items on the ICAF (retest) and immediately afterwards they began treatment (according to daily clinical practice criteria). A sample of healthy subjects was also studied as a control group: 110 people were included (106 women and 4 men) with a mean age of 46.01 years of age (SD = 9.35). The study was conducted in Spain. RESULTS: The results obtained suggest that the four-factor model obtained in the previous study adequately fits the data obtained in this study. The test-retest reliability and internal consistency were all significant and show a high degree of correlation for all the factors as well as in overall score. With the exception of the passive coping factor, all the other scores, including the overall score, were sensitive to change after the therapeutic intervention. The ICAF scores of the patients with fibromyalgia compared with those of the control group were markedly different. CONCLUSIONS: The findings suggest that the ICAF is a valid, reliable, sensitive to change instrument with the added advantage that it offers some additional domains (factors) that provide very valuable information regarding the most delicate aspects of the patient, which must be addressed at the time of treatment in daily clinical practice. PMID- 21649887 TI - Neutrophilic airways inflammation in lung cancer: the role of exhaled LTB-4 and IL-8. AB - BACKGROUND: Recent advances in lung cancer biology presuppose its inflammatory origin. In this regard, LTB-4 and IL-8 are recognized to play a crucial role in neutrophil recruitment into airways during lung cancer.Notwithstanding the intriguing hypothesis, the exact role of neutrophilic inflammation in tumour biology remains complex and not completely known.The aim of this study was to give our contribution in this field by investigating LTB-4 and IL-8 in the breath condensate of NSCLC patients and verifying their role in cancer development and progression. METHOD: We enrolled 50 NSCLC patients and 35 controls. LTB-4 and IL 8 concentrations were measured in the breath condensate and the blood of all the subjects under study using EIA kits. Thirty NSCLC patients and ten controls underwent induced sputum collection and analysis. RESULTS: LTB-4 and IL-8 resulted higher in breath condensate and the blood of NSCLC patients compared to controls. Significantly higher concentrations were found as the cancer stages progressed. A positive correlation was observed between exhaled IL-8 and LTB-4 and the percentage of neutrophils in the induced sputum. CONCLUSION: The high concentrations of exhaled LTB-4 and IL-8 showed the presence of a neutrophilic inflammation in the airways of NSCLC patients and gave a further support to the inflammatory signalling in lung cancer. These exhaled proteins could represent a suitable non-invasive marker in the diagnosis and monitoring of lung cancer. PMID- 21649888 TI - Prevalence of hepatitis B virus genotypes in HBsAg positive individuals of Afghanistan. AB - BACKGROUND: The structural and functional differences between hepatitis B virus (HBV) genotypes are the mainstay to severity, complications, treatment and possibly vaccination against the virus. This study was conducted to determine the HBV genotypes in HBsAg positive patients of Afghanistan as no such large scale data available previously. METHODS: Two hundred and fourteen HBsAg-positive patients were included in this study. All patients were anti-HCV and anti-HIV negative. All the samples were confirmed for HBV DNA with nested PCR while HBV DNA positive samples were subjected to type specific PCR for HBV genotyping (A F). RESULTS: Of the total samples, 168 (78.5%) were males and 46 (21.49%) females, aged ranged between 18 to 71 years. This study demonstrated that genotype D (35.67%) is the predominant genotype circulating in Afghani's population. Genotype C was observed in 32.16% followed by genotype A (19.30%), and genotype B (7.02%) while 6.07% of the individuals were not typed. CONCLUSION: This study has shown a heterogeneous distribution of HBV genotypes. Further more, extensive studies are required to investigate genetic and geographical divergence and characteristics of the virus in the country, as no such large sample sized study has been carried out so far in this country. PMID- 21649889 TI - A prospective cohort study of dietary patterns of non-western migrants in the Netherlands in relation to risk factors for cardiovascular diseases: HELIUS Dietary Patterns. AB - BACKGROUND: In Western countries the prevalence of cardiovascular disease (CVD) is often higher in non-Western migrants as compared to the host population. Diet is an important modifiable determinant of CVD. Increasingly, dietary patterns rather than single nutrients are the focus of research in an attempt to account for the complexity of nutrient interactions in foods. Research on dietary patterns in non-Western migrants is limited and may be hampered by a lack of validated instruments that can be used to assess the habitual diet of non-western migrants in large scale epidemiological studies. The ultimate aims of this study are to (1) understand whether differences in dietary patterns explain differences in CVD risk between ethnic groups, by developing and validating ethnic-specific Food Frequency Questionnaires (FFQs), and (2) to investigate the determinants of these dietary patterns. This paper outlines the design and methods used in the HELIUS-Dietary Patterns study and describes a systematic approach to overcome difficulties in the assessment and analysis of dietary intake data in ethnically diverse populations. METHODS/DESIGN: The HELIUS-Dietary Patterns study is embedded in the HELIUS study, a Dutch multi-ethnic cohort study. After developing ethnic-specific FFQs, we will gather data on the habitual intake of 5000 participants (18-70 years old) of ethnic Dutch, Surinamese of African and of South Asian origin, Turkish or Moroccan origin. Dietary patterns will be derived using factor analysis, but we will also evaluate diet quality using hypothesis driven approaches. The relation between dietary patterns and CVD risk factors will be analysed using multiple linear regression analysis. Potential underlying determinants of dietary patterns like migration history, acculturation, socio economic factors and lifestyle, will be considered. DISCUSSION: This study will allow us to investigate the contribution of the dietary patterns on CVD risk factors in a multi-ethnic population. Inclusion of five ethnic groups residing in one setting makes this study highly innovative as confounding by local environment characteristics is limited. Heterogeneity in the study population will provide variance in dietary patterns which is a great advantage when studying the link between diet and disease. PMID- 21649890 TI - A novel method to prepare L-arabinose from xylose mother liquor by yeast-mediated biopurification. AB - BACKGROUND: L-arabinose is an important intermediate for anti-virus drug synthesis and has also been used in food additives for diets-controlling in recent years. Commercial production of L-arabinose is a complex progress consisting of acid hydrolysis of gum arabic, followed by multiple procedures of purification, thus making high production cost. Therefore, there is a biotechnological and commercial interest in the development of new cost-effective and high-performance methods for obtaining high purity grade L-arabinose. RESULTS: An alternative, economical method for purifying L-arabinose from xylose mother liquor was developed in this study. After screening 306 yeast strains, a strain of Pichia anomala Y161 was selected as it could effectively metabolize other sugars but not L-arabinose. Fermentation in a medium containing xylose mother liquor permitted enrichment of L-arabinose by a significant depletion of other sugars. Biochemical analysis of this yeast strain confirmed that its poor capacity for utilizing L-arabinose was due to low activities of the enzymes required for the metabolism of this sugar. Response surface methodology was employed for optimization the fermentation conditions in shake flask cultures. The optimum conditions were: 75 h fermentation time, at 32.5 degrees C, in a medium containing 21% (v/v) xylose mother liquor. Under these conditions, the highest purity of L-arabinose reached was 86.1% of total sugar, facilitating recovery of white crystalline L-arabinose from the fermentation medium by simple methods. CONCLUSION: Yeast-mediated biopurification provides a dynamic method to prepare high purity of L-arabinose from the feedstock solution xylose mother liquor, with cost-effective and high-performance properties. PMID- 21649891 TI - The metabolic advantage of tumor cells. AB - 1- Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases. 2- Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas. Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases. 3- Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect) and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis. 4- The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase). 5- IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability. 6- An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them... PMID- 21649892 TI - Socio-demographic and lifestyle factors associated with overweight in a representative sample of 11-15 year olds in France: results from the WHO Collaborative Health Behaviour in School-aged Children (HBSC) cross-sectional study. AB - BACKGROUND: The prevalence of overweight in children and adolescents is high and overweight is associated with poor health outcomes over short- and long-term. Lifestyle factors can interact to influence overweight. Comprehensive studies linking overweight concomitantly with several demographic and potentially modifiable lifestyle factors and health-risk behaviours are limited in adolescents--an age-group characterized by changes in lifestyle behaviours and high prevalence of overweight. Thus, the objective of the current study was to examine the association of overweight with several socio-demographic and lifestyle variables simultaneously in a representative sample of adolescents. METHODS: A nationally representative sample of 11-15 year-olds (n = 7154) in France participated as part of the WHO-Collaborative Health Behaviour in School aged Children (HBSC) study. Students reported data on their age, height, weight, socio-demographic variables, lifestyle factors including nutrition practices, physical activity at two levels of intensity (moderate and vigorous), sedentary behaviours, as well as smoking and alcohol consumption patterns using standardized HBSC protocols. Overweight (including obesity) was defined using the IOTF reference. The multivariate association of overweight with several socio demographic and lifestyle factors was examined with logistic regression models. RESULTS: The adjusted odds ratios for the association with overweight were: 1.80 (95% CI: 1.37-2.36) for low family affluence; 0.73 (0.60-0.88) for eating breakfast daily; 0.69 (0.56-0.84) for moderate to vigorous physical activity (MVPA); and 0.71 (0.59-0.86) for vigorous physical activity (VPA). Significant interactions between age and gender as well as television (TV) viewing and gender were noted: for boys, overweight was not associated with age or TV viewing; in contrast, for girls overweight correlated negatively with age and positively with TV viewing. Fruit and vegetable intake, computer and video-games use, smoking and alcohol consumption were not associated with overweight. CONCLUSIONS: In multivariate model, family affluence, breakfast consumption and moderate to vigorous as well as vigorous physical activity were negatively associated with overweight. These findings extend previous research to a setting where multiple risk and protective factors were simultaneously examined and highlight the importance of multi-faceted approaches promoting physical activity and healthy food choices such as breakfast consumption for overweight prevention in adolescents. PMID- 21649893 TI - Growth and differentiation of primary and passaged equine bronchial epithelial cells under conventional and air-liquid-interface culture conditions. AB - BACKGROUND: Horses develop recurrent airway obstruction (RAO) that resembles human bronchial asthma. Differentiated primary equine bronchial epithelial cells (EBEC) in culture that closely mimic the airway cells in vivo would be useful to investigate the contribution of bronchial epithelium in inflammation of airway diseases. However, because isolation and characterization of EBEC cultures has been limited, we modified and optimized techniques of generating and culturing EBECs from healthy horses to mimic in vivo conditions. RESULTS: Large numbers of EBEC were obtained by trypsin digestion and successfully grown for up to 2 passages with or without serum. However, serum or ultroser G proved to be essential for EBEC differentiation on membrane inserts at ALI. A pseudo stratified muco-ciliary epithelium with basal cells was observed at differentiation. Further, transepithelial resistance (TEER) was more consistent and higher in P1 cultures compared to P0 cultures while ciliation was delayed in P1 cultures. CONCLUSIONS: This study provides an efficient method for obtaining a high-yield of EBECs and for generating highly differentiated cultures. These EBEC cultures can be used to study the formation of tight junction or to identify epithelial-derived inflammatory factors that contribute to lung diseases such as asthma. PMID- 21649894 TI - Pleiotrophin over-expression provides trophic support to dopaminergic neurons in parkinsonian rats. AB - BACKGROUND: Pleiotrophin is known to promote the survival and differentiation of dopaminergic neurons in vitro and is up-regulated in the substantia nigra of Parkinson's disease patients. To establish whether pleiotrophin has a trophic effect on nigrostriatal dopaminergic neurons in vivo, we injected a recombinant adenovirus expressing pleiotrophin in the substantia nigra of 6-hydroxydopamine lesioned rats. RESULTS: The viral vector induced pleiotrophin over-expression by astrocytes in the substantia nigra pars compacta, without modifying endogenous neuronal expression. The percentage of tyrosine hydroxylase-immunoreactive cells as well as the area of their projections in the lesioned striatum was higher in pleiotrophin-treated animals than in controls. CONCLUSIONS: These results indicate that pleiotrophin over-expression partially rescues tyrosine hydroxylase immunoreactive cell bodies and terminals of dopaminergic neurons undergoing 6 hydroxydopamine-induced degeneration. PMID- 21649896 TI - Pitfalls in the diagnosis of a tumefactive demyelinating lesion: A case report. AB - INTRODUCTION: In rare instances, demyelinating disorders manifest as tumefactive lesions that simulate brain tumors. We report a patient with a space-occupying lesion in the parietal lobe, which presented a serious diagnostic dilemma, between a rare tumefactive demyelinating disease, such as Balo concentric sclerosis and a glioma. This case report highlights important diagnostic clues in the differential diagnosis of Balo concentric sclerosis. CASE PRESENTATION: A 20 year-old Caucasian woman with acute onset of left-sided weakness and numbness was admitted to hospital with neurologic signs of left-sided hemiparesis and hypoesthesia. Brain magnetic resonance imaging showed a mass lesion of abnormal signal intensity with concentric enhancing rings in the right parietal lobe, without perifocal edema. The characteristic concentric pattern detected on the magnetic resonance images was highly suggestive of Balo disease, and corticosteroids were administered. Evoked potentials, cerebrospinal fluid analysis, and magnetic spectroscopy findings were not specific, and glioma was also included in the differential diagnosis. A stereotactic biopsy was not diagnostic.After one month the patient showed moderate clinical improvement, and during 12 months follow-up, no further relapses occurred. In the follow-up magnetic resonance imaging, the concentric pattern had completely disappeared, and only a low-signal, gliotic lesion remained. CONCLUSION: We hope this case presentation will advance our understanding of clinical and radiologic appearance of Balo concentric sclerosis, which is a rare demyelinating disease. Although this is a specific entity, it has a broader clinical impact across medicine, because it must be differentiated from other space-occupying lesions in the central nervous system. PMID- 21649895 TI - The institutional review board is an impediment to human research: the result is more animal-based research. AB - Biomedical research today can be generally classified as human-based or nonhuman animal-based, each with separate and distinct review boards that must approve research protocols. Researchers wishing to work with humans or human tissues have become frustrated by the required burdensome approval panel, the Institutional Review Board. However, scientists have found it is much easier to work with the animal-based research review board, the Institutional Animal Care and Use Committee. Consequently, animals are used for investigations even when scientists believe these studies should be performed with humans or human tissue. This situation deserves attention from society and more specifically the animal protection and patient advocate communities, as neither patients nor animals are well served by the present situation. PMID- 21649897 TI - Parents' perception of self-advocacy of children with myositis: an anonymous online survey. AB - BACKGROUND: Children with complex medical issues experience barriers to the transition of care from pediatric to adult providers. We sought to identify these barriers by elucidating the experiences of patients with idiopathic inflammatory muscle disorders. METHODS: We collected anonymous survey data using an online website. Patients and their families were solicited from the US and Canada through established clinics for children with idiopathic inflammatory muscle diseases as well as with the aid of a nonprofit organization for the benefit of such individuals. The parents of 45 older children/young adults suffering from idiopathic inflammatory muscle diseases were surveyed. As a basis of comparison, we similarly collected data from the parents of 207 younger children with inflammatory muscle diseases. The survey assessed transition of care issues confronting families of children and young adults with chronic juvenile myositis. RESULTS: Regardless of age of the patient, respondents were unlikely to have a designated health care provider assigned to aid in transition of care and were unlikely to be aware of a posted policy concerning transition of care at their pediatrician's office. Additionally, regardless of age, patients and their families were unlikely to have a written plan for moving to adult care. CONCLUSIONS: We identified deficiencies in the health care experiences of families as pertain to knowledge, self-advocacy, policy, and vocational readiness. Moreover, as children with complex medical issues grow up, parents attribute less self-advocacy to their children's level of independence. PMID- 21649898 TI - Systemic Epstein-Barr-virus-positive T cell lymphoproliferative childhood disease in a 22-year-old Caucasian man: A case report and review of the literature. AB - INTRODUCTION: Systemic Epstein-Barr-virus-positive T cell lymphoproliferative disease of childhood is an extremely rare disorder, characterized by clonal proliferation of Epstein-Barr-virus-infected T cells with an activated cytotoxic phenotype. The disease is more frequent in Asia and South America, with only few cases reported in Western countries. A prompt diagnosis, though often difficult, is a necessity due to the very aggressive clinical course of the disease. CASE PRESENTATION: We report the clinicopathological features of fulminant T cell lymphoproliferative disease that arose in the setting of acute primary Epstein Barr virus infection. Our patient, a 23-year-old man, presented to our facility with persisting fever, hepatosplenomegaly and severe pancytopenia. On bone marrow biopsy, an abundant lymphoid infiltrate was observed. Immunophenotypic and molecular studies revealed that the atypical lymphoid cells displayed a CD8+, Epstein-Barr-encoded-RNA-positive T cell phenotype with clonal rearrangement of the T cell receptor genes, the final diagnosis being systemic Epstein-Barr-virus positive T cell lymphoproliferative disease. On reviewing the literature we found only 14 similar cases, all presenting with very aggressive clinical courses and requiring extensive phenotyping and molecular techniques for final diagnosis. CONCLUSION: Though extremely rare, this disease can occur in Europe, and a comprehensive diagnostic approach is thus recommended in all case of Epstein-Barr virus-positive lymphoproliferative disorders. Unfortunately, at present no specific treatment is available; however, prompt administration of anti- Epstein Barr virus treatment and rapid attempts to control the hemophagocytic syndrome are indicated. PMID- 21649899 TI - Molecular identification of Clonorchis sinensis and discrimination with other opisthorchid liver fluke species using multiple Ligation-depended Probe Amplification (MLPA). AB - BACKGROUND: Infections with the opisthorchid liver flukes Clonorchis sinensis, Opisthorchis viverrini, and O. felineus cause severe health problems globally, particularly in Southeast Asia. Early identification of the infection is essential to provide timely and appropriate chemotherapy to patients. RESULTS: In this study we evaluate a PCR-based molecular identification method, Multiplex Ligation-dependent Probe Amplification (MLPA), which allows rapid and specific detection of single nucleotide acid differences between Clonorchis sinensis, Opisthorchis viverrini and O. felineus. Three probe pairs were derived from the Internally Transcribed Spacer 1 (ITS1) of three opisthorchid liver flukes using a systematic phylogenetic analysis. Specific loci were detected in all three species, yielding three amplicons with 198,172 and 152 bp, respectively, while no cross reactions were observed. A panel of 66 C. sinensis isolates was screened using MLPA. All species were positively identified, and no inhibition was observed. The detection limit was 10(3) copies of the ITS gene for the three liver flukes, or about 60 pg genomic DNA for Clonorchis sinensis. Amplification products can be detected by electrophoresis on agarose gel or in a capillary sequencer. In addition, genomic DNA of Clonorchis sinensis in fecal samples of infected rats was positively amplified by MLPA. CONCLUSION: The flexibility and specificity make MLPA a potential tool for specific identification of infections by opisthorchid liver flukes in endemic areas. PMID- 21649902 TI - De novo sequence assembly and characterization of the floral transcriptome in cross- and self-fertilizing plants. AB - BACKGROUND: The shift from cross-fertilization to predominant self-fertilization is among the most common evolutionary transitions in the reproductive biology of flowering plants. Increased inbreeding has important consequences for floral morphology, population genetic structure and genome evolution. The transition to selfing is usually characterized by a marked reduction in flower size and the loss of traits involved in pollinator attraction and the avoidance of self fertilization. Here, we use short-read sequencing to assemble, de novo, the floral transcriptomes of three genotypes of Eichhornia paniculata, including an outcrosser and two genotypes from independently derived selfers, and a single genotype of the sister species E. paradoxa. By sequencing mRNA from tissues sampled at various stages of flower development, our goal was to sequence and assemble the floral transcriptome and identify differential patterns of gene expression. RESULTS: Our 24 Mbp assembly resulted in ~27,000 contigs that averaged ~900 bp in length. All four genotypes had highly correlated gene expression, but the three E. paniculata genotypes were more correlated with one another than each was to E. paradoxa. Our analysis identified 269 genes associated with floral development, 22 of which were differentially expressed in selfing lineages relative to the outcrosser. Many of the differentially expressed genes affect floral traits commonly altered in selfing plants and these represent a set of potential candidate genes for investigating the evolution of the selfing syndrome. CONCLUSIONS: Our study is among the first to demonstrate the use of Illumina short read sequencing for de novo transcriptome assembly in non-model species, and the first to implement this technology for comparing floral transcriptomes in outcrossing and selfing plants. PMID- 21649900 TI - Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival. AB - BACKGROUND: Glioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival. METHODS: A novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers. RESULTS: A total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. Pik3r1, E2f3, Akr1c3, Csf1, Jag2, Plcg1, Rpl37a, Sod2, Topors, Hras, Mdm2, Camk2g, Fstl1, Il13ra1, Mtap and Tp53 were associated with multiple survival events.Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for Syne1, Pdcd4, Ighg1, Tgfa, Pla2g7, and Paics. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. C2, Egfr, Prkcb, Igf2bp3, and Gdf10 had gender-dependent associations; Sox10, Rps20, Rab31, and Vav3 had race-dependent associations; Chi3l1, Prkcb, Polr2d, and Apool had therapy dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death. CONCLUSIONS: Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme. PMID- 21649903 TI - Menstrual bleeding patterns: A community-based cross-sectional study among women aged 18-45 years in Southern Brazil. AB - BACKGROUND: Population variation in the duration and amount of menstrual bleeding has received little attention in the literature. This study describes these characteristics and investigates the distribution of self-perceived amount of menstrual bleeding according to socio-demographic, behavioral, and reproductive characteristics. METHODS: A community-based cross-sectional study was conducted among 18-45 years old women users of the 31 primary health care (PHC) facilities in Pelotas city (Brazil). Interviews with structured questionnaire were carried out in the waiting rooms during two work shifts. Heaviness of menstrual bleeding was determined through the answer to the question: "Usually how much blood do you lose in every period?" Crude and adjusted analyses through Poisson regression took into account the aggregation per PHC facility. RESULTS: A total of 865 women were enrolled. Prevalence of heavy menstrual flow was 35.3% (95% CI 32.1-38.6%). In adjusted analyses, heavy menstrual bleeding was higher among the older, less educated and obese women, with higher number of pregnancies and who reported longer menstrual periods, extra-menstrual bleeding and clots in the flow. Use of hormonal contraceptive methods was protective against heavy menses. CONCLUSION: Heavy menstrual bleeding is highly prevalent at the community level, and is associated with socio-demographic and anthropometric women's characteristics, as well as with duration of menstruation, extra-bleeding and presence of clots. PMID- 21649904 TI - Exogenous nitric oxide decreases brain vascular inflammation, leakage and venular resistance during Plasmodium berghei ANKA infection in mice. AB - BACKGROUND: Cerebral malaria (CM) is a lethal complication of Plasmodium falciparum infections. In the Plasmodium berghei ANKA (PbA) murine model, CM is associated with marked brain inflammation, increased expression of endothelial cell adhesion molecules and leukocyte and platelet accumulation in brain vessels, causing vascular occlusion and decreased blood flow, damaging the endothelium and leading to blood-brain barrier breakdown, leakage and hemorrhages. Exogenous nitric oxide (NO) administration largely prevents the syndrome. Here we evaluated whether the mechanism of action of NO in preventing murine CM is related to its anti-inflammatory properties and to protection of the endothelium. METHODS: C57Bl/6 mice infected with PbA were treated twice a day with saline or dipropylenetriamineNONOate (DPTA-NO). Endothelial cell adhesion molecule (ICAM-1, VCAM, E- and P-selectin) expression in brain tissue on day 6 of infection was assessed in both groups by western blot. For intravital microscopy studies, DPTA NO-treated and saline-treated mice with a previously implanted closed cranial window were injected with albumin-FITC, anti-CD45-TxR and anti-CD41-FITC antibodies on day 6 of infection for quantification of albumin leakage, leukocyte and platelet adherence in pial vessels. RESULTS: PbA-infected mice treated with the NO-donor DPTA-NO showed decreased expression of ICAM-1 and P-selectin, but not VCAM-1, in the brain, compared to saline-treated mice. DPTA-NO treatment also decreased the number of adherent leukocytes and platelets in pial vessels, particularly in venules 30-50 MUm in diameter, decreased inflammatory vascular resistance and prevented the occurrence of arteriolar and venular albumin leakage observed in saline-treated PbA-infected mice, as assessed by intravital microscopy. CONCLUSIONS: These results indicate that the protective effect of exogenous NO on murine CM is associated with decreased brain vascular expression of inflammatory markers resulting in attenuated endothelial junction damage and facilitating blood flow. PMID- 21649905 TI - Viral-bacterial co-infection in Australian Indigenous children with acute otitis media. AB - BACKGROUND: Acute otitis media with perforation (AOMwiP) affects 40% of remote Indigenous children during the first 18 months of life. Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis are the primary bacterial pathogens of otitis media and their loads predict clinical ear state. Our hypothesis is that antecedent respiratory viral infection increases bacterial density and progression to perforation. METHODS: A total of 366 nasopharyngeal swabs from 114 Indigenous children were retrospectively examined. A panel of 17 respiratory viruses was screened by PCR, and densities of S. pneumoniae, H. influenzae and M. catarrhalis were estimated by quantitative real time PCR. Data are reported by clinical ear state. RESULTS: M. catarrhalis (96%), H. influenzae (91%), S. pneumoniae (89%) and respiratory viruses (59%) were common; including rhinovirus (HRV) (38%), polyomavirus (HPyV) (14%), adenovirus (HAdV) (13%), bocavirus (HBoV) (8%) and coronavirus (HCoV) (4%). Geometric mean bacterial loads were significantly higher in children with acute otitis media (AOM) compared to children without evidence of otitis media. Children infected with HAdV were 3 times more likely (p < 0.001) to have AOM with or without perforation. CONCLUSION: This study confirms a positive association between nasopharyngeal bacterial load and clinical ear state, exacerbated by respiratory viruses, in Indigenous children. HAdV was independently associated with acute ear states. PMID- 21649906 TI - Effect of household and village characteristics on financial catastrophe and impoverishment due to health care spending in Western and Central Rural China: A multilevel analysis. PMID- 21649907 TI - Happiness and health behaviours in Chilean college students: a cross-sectional survey. AB - BACKGROUND: Happiness has been associated with a range of favourable health outcomes through two pathways: its relationship with favourable biological responses to stress and with healthy lifestyles and prudent health behaviours. There are a substantial number of cross-cultural studies about happiness, but none of them has studied the association of happiness with perceived stress and health behaviours in Latin American samples. Therefore, the aim of this study was to examine the association between general happiness and these variables in a Latin American sample. METHODS: We conducted a survey to examine the status of 3461 students aged between 17 and 24 years old (mean age = 19.89; SD = 1.73) who attended University of Santiago de Chile during 2009. The healthy behaviours indexes assessed were the frequency of daily physical exercise, fruits/vegetables intake, breakfast and lunch intake, smoking, alcohol and other drugs consumption. We also included the assessment of perceived stress and Body Mass Index. All of them were evaluated using a self-report questionnaire. RESULTS: The univariate and multivariate binary logistic regression analyses showed that being female and younger was related to a higher happiness, as well as that people self-reporting daily physical activity, having lunch and fruits and vegetables each day had a higher likelihood (OR between 1.33 and 1.40) of being classified as "very happy". Those who informed felt stressed in normal circumstances and during tests situations showed a lower likelihood (0.73 and 0.82, respectively) of being considered "very happy". Regarding drug consumption, taking tranquilizers under prescription was negative related to "subjective happiness" (OR = 0.62), whereas smoking was positive associated (OR = 1.20). CONCLUSIONS: The findings of this study mainly support the relationship between happiness and health outcomes through the two pathways previously mentioned. They also underscore the importance of that some healthy behaviours and person's cognitive appraisal of stress are integrated into their lifestyle for college students. Additionally, highlight the importance of taking into account these variables in the design of strategies to promote health education in university setting. PMID- 21649908 TI - In vitro anti-angiogenic properties of LGD1069, a selective retinoid X-receptor agonist through down-regulating Runx2 expression on Human endothelial cells. AB - BACKGROUND: LGD1069 (Targretin(r)) is a selective retinoid X receptor (RXR) ligand, which is used in patients for cutaneous T-cell lymphoma. Our published study reported that LGD1069 inhibited tumor-induced angiogenesis in non-small cell lung cancer. In present study, we found that LGD1069 suppressed the proliferation, adhesion, invasion and migration of endothelial cells directly, and affected the expression of vegf and some matrix genes. METHODS: Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. MTT assay and Sulforhodamine B assay were used for cell viability assay; the tube formation assay was used to investigate the effect of LGD1069 on angiogenesis in vitro. In vitro adhesion, migration and invasion of HUVEC cells were analyzed by Matrigel adhesion, migration and invasion assay. Gene expressions were measured by RT-PCR and Western blot analysis. RESULTS: Our data showed here that LGD1069 inhibited the activation of TGF-beta/Smad pathway significantly. Furthermore, it was demonstrated that expression of Runx2 was suppressed pronouncedly during incubation with LGD1069. Runx2 is a DNA-binding transcription factor which plays a master role in tumor-induced angiogenesis and cancer cells metastasis by interaction with the TGF-beta/Smad pathway of transcriptional modulators. CONCLUSIONS: Our results suggested that LGD1069 may impair angiogenic and metastatic potential induced by tumor cells through suppressing expression of Runx2 directly on human endothelial cells, which may point out new pathway through which LGD1069 display anti-angiogenic properties, and provide new molecular evidence to support LGD1069 as a potent anti-metastatic agent in cancer therapy. PMID- 21649909 TI - Experiences of violence before and during pregnancy and adverse pregnancy outcomes: an analysis of the Canadian Maternity Experiences Survey. AB - BACKGROUND: Abuse and violence against women constitute a global public health problem and are particularly important among women of reproductive age. The literature is not conclusive regarding the impact of violence against pregnant women on adverse pregnancy outcomes, such as preterm birth, small for gestational age and postpartum depression. Most studies have been conducted on relatively small samples of high-risk women. Our objective was to investigate what dimensions of violence against pregnant women were associated with preterm birth, small for gestational age and postpartum depression in a nationally representative sample of Canadian women. METHODS: We analysed data of the Maternity Experiences Survey, a nationally representative survey of Canadian women giving birth in 2006. The comprehensive questionnaire included a 19-item section to collect information on different dimensions of abuse and violence, such as type, frequency, timing and perpetrator of violence. The survey design is a stratified simple random sample from the 2006 Canadian Census sampling frame. Participants were 6,421 biological mothers (78% response rate) 15 years and older who gave birth to a singleton live birth and lived with their infant at the time of the survey. Logistic regression was used to compute Odds Ratios. Survey weights were used to obtain point estimates and 95% confidence intervals were obtained with the jacknife method of variance estimation. Covariate control was informed by use of directed acyclic graphs. RESULTS: No statistically significant associations were found for preterm birth or small for gestational age, after adjustment. Most dimensions of violence were associated with postpartum depression, particularly the combination of threats and physical violence starting before and continuing during pregnancy (Adjusted Odds Ratio = 4.1, 95% confidence interval: 1.9, 8.9) and perpetrated by the partner (4.3: 2.1, 8.7). CONCLUSIONS: Our findings provide weak evidence of an association between experiences of abuse before and during pregnancy and preterm birth and small for gestational age but they indicate that several dimensions of abuse and violence are consistently associated with postpartum depression. PMID- 21649910 TI - Cognitive performance in relapsing remitting multiple sclerosis: a longitudinal study in daily practice using a brief computerized cognitive battery. AB - BACKGROUND: There is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS. METHODS: Forty-three mildly disabled, clinically active RRMS patients were repeatedly assessed with the Digit Symbol Substitution Test (DSST), Paced Auditory Serial Addition Test (PASAT) and five composite scores derived from the CDR computerized cognitive test system (CDR System): Power of Attention, Continuity of Attention, Quality of Working Memory, Quality of Episodic Memory and Speed of Memory. The Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) measured disability. RESULTS: The composite scores from the CDR battery generally showed excellent test-retest reliability over the repeated assessments, though was low on occasions for the Quality of Working Memory and Quality of Episodic Memory measures. The CDR measures tended to be highly correlated with other measures of cognition (DSST and PASAT) and were also strongly related to disability (EDSS and MSFC). Baseline scores indicated large impairments to visual information processing speed and attention (DSST, Cohen's d 1.1; Power of Attention d 1.4 [reaction time on tasks of focussed and sustained attention]), and a moderate impairment both to sustained attention (Continuity of Attention d 0.6) and complex information processing speed (Speed of memory d 0.7 [reaction time on tasks of working and episodic Memory]), when compared to normative data derived from healthy volunteers enrolled in a series of separate, prior clinical trials. Working memory (Quality of Working Memory) and episodic memory (Quality of Episodic Memory) were unimpaired. CONCLUSIONS: Preliminary validation of the CDR System indicated that for most, but not all measures psychometric properties were adequate and the measures were related to disability (EDSS and MSFC) and other measures of cognition. PMID- 21649911 TI - Antiretroviral medications disrupt microglial phagocytosis of beta-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders. AB - Up to 50% of long-term HIV infected patients, including those with systemically well-controlled infection, commonly experience memory problems and slowness, difficulties in concentration, planning, and multitasking. Deposition of Abeta plaques is also a common pathological feature of HIV infection. However, it is not clear whether this accumulation is due to AD-like processes, HIV-associated immunosuppression, Tat protein-induced Abeta elevations, and/or the effects of single highly active antiretroviral therapy (ART). Here we evaluated the effects of several ART medications (Zidovudine, Lamivudine, Indinavir, and Abacavir) alone and in combination on: 1) Abeta1-40, 42 generation in murine N2a cells transfected with the human "Swedish" mutant form of APP; 2) microglial phagocytosis of FITC-Abeta1-42 peptides in cultured murine N9 microglia. We report for the first time that these antiretroviral compounds (10 MUM) generally increase Abeta generation (~50-200%) in SweAPP N2a cells and markedly inhibit microglial phagocytosis of FITC-Abeta1-42 peptides in murine microglia. The most significant amyloidogenic effects were observed with combined ART (p < 0.05); suggesting certain ART medications may have additive amyloidogenic effects when combined. As these antiretroviral compounds are capable of penetrating the blood brain barrier and reaching the concentrations employed in the in vitro studies, these findings raise the possibility that ART may play a casual role in the elevated Abeta found in the brains of those infected with HIV. Therefore these compounds may consequently contribute to cognitive decline observed in HIV associated neurocognitive disorders (HAND). PMID- 21649912 TI - Proportion statistics to detect differentially expressed genes: a comparison with log-ratio statistics. AB - BACKGROUND: In genetic transcription research, gene expression is typically reported in a test sample relative to a reference sample. Laboratory assays that measure gene expression levels, from Q-RT-PCR to microarrays to RNA-Seq experiments, will compare two samples to the same genetic sequence of interest. Standard practice is to use the log(2)-ratio as the measure of relative expression. There are drawbacks to using this measurement, including unstable ratios when the denominator is small. This paper suggests an alternative estimate based on a proportion that is just as simple to calculate, just as intuitive, with the added benefit of greater numerical stability. RESULTS: Analysis of two groups of mice measured with 16 cDNA microarrays found similar results between the previously used methods and our proposed methods. In a study of liver and kidney samples measured with RNA-Seq, we found that proportion statistics could detect additional differentially expressed genes usually classified as missing by ratio statistics. Additionally, simulations demonstrated that one of our proposed proportion-based test statistics was robust to deviations from distributional assumptions where all other methods examined were not. CONCLUSIONS: To measure relative expression between two samples, the proportion estimates that we propose yield equivalent results to the log(2)-ratio under most circumstances and better results than the log(2)-ratio when expression values are close to zero. PMID- 21649913 TI - Rapid label-free identification of mixed bacterial infections by surface plasmon resonance. AB - BACKGROUND: Early detection of mixed aerobic-anaerobic infection has been a challenge in clinical practice due to the phenotypic changes in complex environments. Surface plasmon resonance (SPR) biosensor is widely used to detect DNA-DNA interaction and offers a sensitive and label-free approach in DNA research. METHODS: In this study, we developed a single-stranded DNA (ssDNA) amplification technique and modified the traditional SPR detection system for rapid and simultaneous detection of mixed infections of four pathogenic microorganisms (Pseudomonas aeruginosa, Staphylococcus aureus, Clostridium tetani and Clostridium perfringens). RESULTS: We constructed the circulation detection well to increase the sensitivity and the tandem probe arrays to reduce the non specific hybridization. The use of 16S rDNA universal primers ensured the amplification of four target nucleic acid sequences simultaneously, and further electrophoresis and sequencing confirmed the high efficiency of this amplification method. No significant signals were detected during the single-base mismatch or non-specific probe hybridization (P < 0.05). The calibration curves of amplification products of four bacteria had good linearity from 0.1 nM to 100 nM, with all R(2) values of >0.99. The lowest detection limits were 0.03 nM for P. aeruginosa, 0.02 nM for S. aureus, 0.01 nM for C. tetani and 0.02 nM for C. perfringens. The SPR biosensor had the same detection rate as the traditional culture method (P < 0.05). In addition, the quantification of PCR products can be completed within 15 min, and excellent regeneration greatly reduces the cost for detection. CONCLUSIONS: Our method can rapidly and accurately identify the mixed aerobic-anaerobic infection, providing a reliable alternative to bacterial culture for rapid bacteria detection. PMID- 21649914 TI - Association between IL-32 genotypes and outcome in infection-associated acute lung injury. AB - INTRODUCTION: Our purpose was to investigate variation within the IL-32 promoter and gene, and susceptibility to and outcomes from infection associated acute lung injury (ALI). METHODS: Retrospective case-control study involving healthy individuals (controls) and patients (cases) with infection-associated ALI. Two hundred fifty-eight healthy normal controls and 251 patients with infection associated ALI were used for comparison. The IL-32 promoter/gene was sequenced in 52 healthy Caucasian individuals to identify single nucleotide polymorphisms (SNPs). Allelic discrimination was performed on 11 SNPs to determine differences between cases and controls and outcomes in patients with infection associated ALI. RESULTS: Logistic and normal regression models were used to evaluate the associations with SNPs in cases and controls, and outcomes in patients with infection associated ALI. rs12934561, an intronic SNP, was found to be associated with risk for ALI in the case-control study and with more severe clinical course, as shown by increased time on the ventilator and the presence of fluid unresponsive hypotension. Further, it was found that rs12934561 has gender specific effects and strongly interacts with other SNPs. CONCLUSIONS: A common IL 32 genotype, rs12934561, is associated with the risk of ALI as well as the need for prolonged mechanical ventilatory support. This finding suggests that IL-32 is not only involved in the initiating inflammatory and cellular events that result in ALI, but also participates in determining the severity of pulmonary dysfunction associated with ALI. PMID- 21649915 TI - Lung cancer stage at diagnosis: Individual associations in the prospective VITamins and lifestyle (VITAL) cohort. AB - BACKGROUND: Lung cancer is the leading cause of cancer death in the United States. Identifying factors associated with stage of diagnosis can improve our understanding of biologic and behavioral pathways of lung cancer development and detection. We used data from a prospective cohort study to evaluate associations of demographic, health history, and health behaviors with early versus late stage at diagnosis of non-small cell lung cancer (NSCLC). METHODS: We calculated odds ratios (ORs) for the association of patient-level characteristics with advanced stage of diagnosis for NSCLC. The OR's were then adjusted for age, gender, race/ethnicity, smoking status, income, education, chronic obstructive pulmonary disease, and a comorbidity index. RESULTS: We identified 612 cases of NSCLC among 77,719 adults, aged 50 to 76 years from Washington State recruited in 2000-2002, with followup through December 2007. In univariate analyses, subjects who quit smoking <10 years (OR 2.56, 95% CI 1.17 - 5.60) and were college graduates (OR 1.67, 95% CI, 1.00 - 2.76) had increased risks of being diagnosed with advanced stage NSCLC, compared to never smokers and non-college graduates, respectively. Receipt of sigmoidoscopy/colonoscopy, compared to no receipt, was associated with a decreased risk of advanced stage (OR 0.65, 95% CI, 0.43 - 0.99). The adjusted OR for receipt of sigmoidoscopy/colonoscopy was 0.55 (95% CI, 0.36 - 0.86). There was evidence that increasing the number of screening activities was associated with a decreased risk of advanced stage NSCLC (P for trend = 0.049). CONCLUSIONS: Smoking status, education, and a screening activity were associated with stage at diagnosis of NSCLC. These results may guide future studies of the underlying mechanisms that influence how NSCLC is detected and diagnosed. PMID- 21649917 TI - Proximal femoral fracture in a man resulting from modern clipless pedals: a case report. AB - INTRODUCTION: The use of clipless pedals amongst recreational cyclists has become increasingly popular in recent years. We describe a hip fracture, that was sustained due to inadequate set up of such pedals. To the best of our knowledge, this has only been described once before, and this was in the non-English language medical literature. CASE REPORT: A 38-year-old Caucasian man who was a club cyclist sustained a displaced intracapsular fracture of the hip whilst cycling. As a direct result of the incorrect set-up of his clipless pedals he was unable to release his feet whilst slowing to a halt. This resulted in a loss of balance and subsequent fall with a direct impact onto his left hip. The resulting fracture was managed successfully with early closed reduction and fixation. At six month review he was walking unaided without pain but, as yet, has been unable to return to cycling. CONCLUSION: This case highlights the dangers of clipless pedals even in experienced cyclists, and underlines the importance of proper information for their correct setup to minimise the risk of potentially serious injuries, especially in the region of the hip. PMID- 21649916 TI - The role of dietary fatty acids in predicting myocardial structure in fat-fed rats. AB - BACKGROUND: Obesity increases the risk for development of cardiomyopathy in the absence of hypertension, diabetes or myocardial ischemia. Not all obese individuals, however, progress to heart failure. Indeed, obesity may provide protection from cardiovascular mortality in some populations. The fatty acid milieu, modulated by diet, may modify obesity-induced myocardial structure and function, lending partial explanation for the array of cardiomyopathic phenotype in obese individuals. METHODS: Adult male Sprague-Dawley rats were fed 1 of the following 4 diets for 32 weeks: control (CON); 50% saturated fat (SAT); 40% saturated fat + 10% linoleic acid (SAT+LA); 40% saturated fat + 10% alpha linolenic acid (SAT+ALA). Serum leptin, insulin, glucose, free fatty acids and triglycerides were quantitated. In vivo cardiovascular outcomes included blood pressure, heart rate and echocardiographic measurements of structure and function. The rats were sacrificed and myocardium was processed for fatty acid analysis (TLC-GC), and evaluation of potential modifiers of myocardial structure including collagen (Masson's trichrome, hydroxyproline quantitation), lipid (Oil Red O, triglyceride quantitation) and myocyte cross sectional area. RESULTS: Rats fed SAT+LA and SAT+ALA diets had greater cranial LV wall thickness compared to rats fed CON and SAT diets, in the absence of hypertension or apparent insulin resistance. Treatment was not associated with changes in myocardial function. Myocardial collagen and triglycerides were similar among treatment groups; however, rats fed the high-fat diets, regardless of composition, demonstrated increased myocyte cross sectional area. CONCLUSIONS: Under conditions of high-fat feeding, replacement of 10% saturated fat with either LA or ALA is associated with thickening of the cranial LV wall, but without concomitant functional changes. Increased myocyte size appears to be a more likely contributor to early LV thickening in response to high-fat feeding. These findings suggest that myocyte hypertrophy may be an early change leading to gross LV hypertrophy in the hearts of "healthy" obese rats, in the absence of hypertension, diabetes and myocardial ischemia. PMID- 21649918 TI - Mutator dynamics in sexual and asexual experimental populations of yeast. AB - BACKGROUND: In asexual populations, mutators may be expected to hitchhike with associated beneficial mutations. In sexual populations, recombination is predicted to erode such associations, inhibiting mutator hitchhiking. To investigate the effect of recombination on mutators experimentally, we compared the frequency dynamics of a mutator allele (msh2Delta) in sexual and asexual populations of Saccharomyces cerevisiae. RESULTS: Mutator strains increased in frequency at the expense of wild-type strains in all asexual diploid populations, with some approaching fixation in 150 generations of propagation. Over the same period of time, mutators declined toward loss in all corresponding sexual diploid populations as well as in haploid populations propagated asexually. CONCLUSIONS: We report the first experimental investigation of mutator dynamics in sexual populations. We show that a strong mutator quickly declines in sexual populations while hitchhiking to high frequency in asexual diploid populations, as predicted by theory. We also show that the msh2Delta mutator has a high and immediate realized cost that is alone sufficient to explain its decline in sexual populations. We postulate that this cost is indirect; namely, that it is due to a very high rate of recessive lethal or strongly deleterious mutation. However, we cannot rule out the possibility that msh2Delta also has unknown directly deleterious effects on fitness, and that these effects may differ between haploid asexual and sexual populations. Despite these reservations, our results prompt us to speculate that the short-term cost of highly deleterious recessive mutations can be as important as recombination in preventing mutator hitchhiking in sexual populations. PMID- 21649919 TI - Snowbirds and infection--new phenomena in pneumonia and influenza hospitalizations from winter migration of older adults: a spatiotemporal analysis. AB - BACKGROUND: Despite advances in surveillance and prevention, pneumonia and influenza (P&I) remain among the leading causes of mortality in the United States. Elderly adults experience the most severe morbidity from influenza associated diseases, and have the highest rates of seasonal migration within the U.S. compared to other subpopulations. The objective of this study is to assess spatiotemporal patterns in influenza-associated hospitalizations in the elderly, by time, geography, and intensity of P&I. Given the high seasonal migration of individuals to Florida, this state was examined more closely using harmonic regression to assess spatial and temporal patterns of P&I hospitalizations by state of residence. METHODS: Data containing all Medicare-eligible hospitalizations in the United States for 1991-2006 with P&I (ICD-9-CM codes 480 487) were abstracted for the 65+ population. Hospitalizations were classified by state of residence, provider state, and date of admissions, specifically comparing those admitted between October and March to those admitted between April and September. We then compared the hospitalization profile data of Florida residents with that of out-of-state residents by state of primary residence and time of year (in-season or out-of-season). RESULTS: We observed distinct seasonal patterns of nonresident P&I hospitalizations, especially comparing typical winter destination states, such as California, Arizona, Texas, and Florida, to other states. Although most other states generally experienced a higher proportion of non-resident P&I during the summer months (April-September), these states had higher nonresident P&I during the traditional peak influenza season (October March). CONCLUSIONS: This study is among the first to quantify spatiotemporal P&I hospitalization patterns in the elderly, focusing on the change of patterns that are possibly due to seasonal population migration. Understanding migration and influenza-associated disease patterns in this vulnerable population is critical to prepare for and potentially prevent influenza outbreaks in this vulnerable population. PMID- 21649920 TI - Biological in-vivo measurement of dose distribution in patients' lymphocytes by gamma-H2AX immunofluorescence staining: 3D conformal- vs. step-and-shoot IMRT of the prostate gland. AB - BACKGROUND: Different radiation-techniques in treating local staged prostate cancer differ in their dose- distribution. Physical phantom measurements indicate that for 3D, less healthy tissue is exposed to a relatively higher dose compared to SSIMRT. The purpose is to substantiate a dose distribution in lymphocytes in vivo and to discuss the possibility of comparing it to the physical model of total body dose distribution. METHODS: For each technique (3D and SSIMRT), blood was taken from 20 patients before and 10 min after their first fraction of radiotherapy. The isolated leukocytes were fixed 2 hours after radiation. DNA double-strand breaks (DSB) in lymphocytes' nuclei were stained immunocytochemically using the gamma-H2AX protein. Gamma-H2AX foci inside each nucleus were counted in 300 irradiated as well as 50 non-irradiated lymphocytes per patient. In addition, lymphocytes of 5 volunteer subjects were irradiated externally at different doses and processed under same conditions as the patients' lymphocytes in order to generate a calibration-line. This calibration line assigns dose-value to mean number of gamma-H2AX foci/ nucleus. So the dose distributions in patients' lymphocytes were determined regarding to the gamma H2AX foci distribution. With this information a cumulative dose-lymphocyte histogram (DLH) was generated. Visualized distribution of gamma-H2AX foci, correspondingly dose per nucleus, was compared to the technical dose-volume histogram (DVH), related to the whole body-volume. RESULTS: Measured in-vivo (DLH) and according to the physical treatment-planning (DVH), more lymphocytes resulted with low-dose exposure (< 20% of the applied dose) and significantly fewer lymphocytes with middle-dose exposure (30%-60%) during Step-and-Shoot-IMRT, compared to conventional 3D conformal radiotherapy. The high-dose exposure (> 80%) was equal in both radiation techniques. The mean number of gamma-H2AX foci per lymphocyte was 0.49 (3D) and 0.47 (SSIMRT) without significant difference. CONCLUSIONS: In-vivo measurement of the dose distribution within patients' lymphocytes can be performed by detecting gamma-H2AX foci. In case of 3D and SSIMRT, the results of this method correlate with the physical calculated total body dose-distribution, but cannot be interpreted unrestrictedly due to the blood circulation. One possible application of the present method could be in radiation protection for in-vivo dose estimation after accidental exposure to radiation. PMID- 21649921 TI - Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats. AB - BACKGROUND: Hemorrhagic shock followed by resuscitation is conceived as an insult frequently induces a systemic inflammatory response syndrome and oxidative stress that results in multiple-organ dysfunction syndrome including acute lung injury. MK-886 is a leukotriene biosynthesis inhibitor exerts an anti inflammatory and antioxidant activity. OBJECTIVES: The objective of present study was to assess the possible protective effect of MK-886 against hemorrhagic shock-induced acute lung injury via interfering with inflammatory and oxidative pathways. MATERIALS AND METHODS: Eighteen adult Albino rats were assigned to three groups each containing six rats: group I, sham group, rats underwent all surgical instrumentation but neither hemorrhagic shock nor resuscitation was done; group II, Rats underwent hemorrhagic shock (HS) for 1 hr then resuscitated with Ringer's lactate (1 hr) (induced untreated group, HS); group III, HS + MK-886 (0.6 mg/kg i.p. injection 30 min before the induction of HS, and the same dose was repeated just before reperfusion period). At the end of experiment (2 hr after completion of resuscitation), blood samples were collected for measurement of serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). The trachea was then isolated and bronchoalveolar lavage fluid (BALF) was carried out for measurement of leukotriene B4 (LTB4), leukotriene C4 (LTC4) and total protein. The lungs were harvested, excised and the left lung was homogenized for measurement of malondialdehyde (MDA) and reduced glutathione (GSH) and the right lung was fixed in 10% formalin for histological examination. RESULTS: MK-886 treatment significantly reduced the total lung injury score compared with the HS group (P < 0.05). MK-886 also significantly decreased serum TNF-alpha & IL-6; lung MDA; BALF LTB4, LTC4 & total protein compared with the HS group (P < 0.05). MK-886 treatment significantly prevented the decrease in the lung GSH levels compared with the HS group (P < 0.05). CONCLUSIONS: The results of the present study reveal that MK-886 may ameliorate lung injury in shocked rats via interfering with inflammatory and oxidative pathways implicating the role of leukotrienes in the pathogenesis of hemorrhagic shock-induced lung inflammation. PMID- 21649923 TI - Malaria prevalence pattern observed in the highland fringe of Butajira, Southern Ethiopia: a longitudinal study from parasitological and entomological survey. AB - BACKGROUND: In Ethiopia, information regarding highland malaria transmission is scarce, and no report has been presented from Butajira highland so far whether the appearance of malaria in the area was due to endemicity or due to highland malaria transmission. Thus this study aimed to determine the presence and magnitude of malaria transmission in Butajira. METHODS: For parasitological survey, longitudinal study was conducted from October to December 2006. The entomological surveys were done from October to December 2006 and continued from April to May 2007. Both parasitological and entomological surveys were done using standard procedures. RESULTS: The parasitological result in all the survey months (October-December) showed an overall detection rate of 4.4% (48/1082) (CI 95%; 3.2-5.7%) malaria parasite. Among infected individuals, 32 (3.0%) of the infection was due to Plasmodium vivax and the rest 16 (1.5%) were due to Plasmodium falciparum. The highest prevalence 39(3.6%) of the parasite was observed in age groups of above 15 years old. Among the total tested, 25(2.3%) of males and 23(2.1%) of females had malaria infection. Among tested individuals, 38(5.3%) and 10 (2.7%) of infection was occurred in Misrak-Meskan (2100 m a.s.l) and Mirab-Meskan (2280 m a.s.l), respectively which was statistically significant (X2=3.72, P<0.05). Although the prevalence pattern of Plasmodium species declined from October to December, the trend was non-significant (X2 for trend=0.49, P>0.05). The entomological survey showed a collection of 602 larvae and 80 adult Anopheles. Anopheles christyi was the dominant species both in the first (45.3%) and in the second (35.4%) surveys; where as, Anopheles gambiae sensu lato comprised 4.7% and 14.6%, in the first and second surveys, respectively. Anopheles gambiae s.l comprises 55% of the adult collection, and both species were collected more from outdoors (57.5%). The number of An. christyi was higher in Mirab-Meskan (58. 3%) than Misrak-Meskan (41.7%) (P<0.05). CONCLUSION: Malaria parasite and its vectors were found to be common during transmission periods in the highland fringes of Butajira. Thus, health education about the risk of malaria and its control programme in the area must be given adequate attention to minimize potential epidemics. In addition, the current study should be complemented from sero-epidemiological, prospective longitudinal and retrospective studies along with metrological and ecological factors, and socio demographic data before concluding in favour of highland malaria transmission in the area. In light of its abundance, which coincided with the malaria transmission seasons, the possible role of An. christyi as a secondary vector in the highlands must be further investigated by including blood meal sources detection. PMID- 21649922 TI - ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF kappaB-dependent manner. AB - BACKGROUND: Tumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-kappaB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production. METHODS: We interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-kappaB dependence by using pharmacological inhibitors of these signaling pathways. RESULTS: Induction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-kappaB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation. CONCLUSIONS: We conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-kappaB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression. PMID- 21649924 TI - A feasibility study for the provision of electronic healthcare tools and services in areas of Greece, Cyprus and Italy. AB - BACKGROUND: Through this paper, we present the initial steps for the creation of an integrated platform for the provision of a series of eHealth tools and services to both citizens and travelers in isolated areas of the southeast Mediterranean, and on board ships travelling across it. The platform was created through an INTERREG IIIB ARCHIMED project called INTERMED. METHODS: The support of primary healthcare, home care and the continuous education of physicians are the three major issues that the proposed platform is trying to facilitate. The proposed system is based on state-of-the-art telemedicine systems and is able to provide the following healthcare services: i) Telecollaboration and teleconsultation services between remotely located healthcare providers, ii) telemedicine services in emergencies, iii) home telecare services for "at risk" citizens such as the elderly and patients with chronic diseases, and iv) eLearning services for the continuous training through seminars of both healthcare personnel (physicians, nurses etc) and persons supporting "at risk" citizens.These systems support data transmission over simple phone lines, internet connections, integrated services digital network/digital subscriber lines, satellite links, mobile networks (GPRS/3G), and wireless local area networks. The data corresponds, among others, to voice, vital biosignals, still medical images, video, and data used by eLearning applications. The proposed platform comprises several systems, each supporting different services. These were integrated using a common data storage and exchange scheme in order to achieve system interoperability in terms of software, language and national characteristics. RESULTS: The platform has been installed and evaluated in different rural and urban sites in Greece, Cyprus and Italy. The evaluation was mainly related to technical issues and user satisfaction. The selected sites are, among others, rural health centers, ambulances, homes of "at-risk" citizens, and a ferry. CONCLUSIONS: The results proved the functionality and utilization of the platform in various rural places in Greece, Cyprus and Italy. However, further actions are needed to enable the local healthcare systems and the different population groups to be familiarized with, and use in their everyday lives, mature technological solutions for the provision of healthcare services. PMID- 21649925 TI - Joining the dots: conditional pass and programmatic assessment enhances recognition of problems with professionalism and factors hampering student progress. AB - BACKGROUND: Programmatic assessment that looks across a whole year may contribute to better decisions compared with those made from isolated assessments alone. The aim of this study is to describe and evaluate a programmatic system to handle student assessment results that is aligned not only with learning and remediation, but also with defensibility. The key components are standards based assessments, use of "Conditional Pass", and regular progress meetings. METHODS: The new assessment system is described. The evaluation is based on years 4-6 of a 6-year medical course. The types of concerns staff had about students were clustered into themes alongside any interventions and outcomes for the students concerned. The likelihoods of passing the year according to type of problem were compared before and after phasing in of the new assessment system. RESULTS: The new system was phased in over four years. In the fourth year of implementation 701 students had 3539 assessment results, of which 4.1% were Conditional Pass. More in-depth analysis for 1516 results available from 447 students revealed the odds ratio (95% confidence intervals) for failure was highest for students with problems identified in more than one part of the course (18.8 (7.7-46.2) p < 0.0001) or with problems with professionalism (17.2 (9.1-33.3) p < 0.0001). The odds ratio for failure was lowest for problems with assignments (0.7 (0.1-5.2) NS). Compared with the previous system, more students failed the year under the new system on the basis of performance during the year (20 or 4.5% compared with four or 1.1% under the previous system (p < 0.01)). CONCLUSIONS: The new system detects more students in difficulty and has resulted in less "failure to fail". The requirement to state conditions required to pass has contributed to a paper trail that should improve defensibility. Most importantly it has helped detect and act on some of the more difficult areas to assess such as professionalism. PMID- 21649927 TI - Variations in branching of the posterior cord of brachial plexus in a Kenyan population. AB - BACKGROUND: Variations in the branching of posterior cord are important during surgical approaches to the axilla and upper arm, administration of anesthetic blocks, interpreting effects of nervous compressions and in repair of plexus injuries. The patterns of branching show population differences. Data from the African population is scarce. OBJECTIVE: To describe the branching pattern of the posterior cord in a Kenyan population. MATERIALS AND METHODS: Seventy-five brachial plexuses from 68 formalin fixed cadavers were explored by gross dissection. Origin and order of branching of the posterior cord was recorded. Representative photographs were then taken using a digital camera (Sony Cybershot R, W200, 7.2 Megapixels). RESULTS: Only 8 out of 75 (10.7%) posterior cords showed the classical branching pattern. Forty three (57.3%) lower subscapular, 8(10.3%) thoracodorsal and 8(10.3%) upper subscapular nerves came from the axillary nerve instead of directly from posterior cord. A new finding was that in 4(5.3%) and in 3(4%) the medial cutaneous nerves of the arm and forearm respectively originated from the posterior cord in contrast to their usual origin from the medial cord. CONCLUSIONS: Majority of posterior cords in studied population display a wide range of variations. Anesthesiologists administering local anesthetic blocks, clinicians interpreting effects of nerve injuries of the upper limb and surgeons operating in the axilla should be aware of these patterns to avoid inadvertent injury. A wider study of the branching pattern of infraclavicular brachial plexus is recommended. PMID- 21649926 TI - Genome-wide gene expression analysis supports a developmental model of low temperature tolerance gene regulation in wheat (Triticum aestivum L.). AB - BACKGROUND: To identify the genes involved in the development of low temperature (LT) tolerance in hexaploid wheat, we examined the global changes in expression in response to cold of the 55,052 potentially unique genes represented in the Affymetrix Wheat Genome microarray. We compared the expression of genes in winter habit (winter Norstar and winter Manitou) and spring-habit (spring Manitou and spring Norstar)) cultivars, wherein the locus for the vernalization gene Vrn-A1 was swapped between the parental winter Norstar and spring Manitou in the derived near-isogenic lines winter Manitou and spring Norstar. Global expression of genes in the crowns of 3-leaf stage plants cold-acclimated at 6 degrees C for 0, 2, 14, 21, 38, 42, 56 and 70 days was examined. RESULTS: Analysis of variance of gene expression separated the samples by genetic background and by the developmental stage before or after vernalization saturation was reached. Using gene-specific ANOVA we identified 12,901 genes (at p < 0.001) that change in expression with respect to both genotype and the duration of cold-treatment. We examined in more detail a subset of these genes (2,771) where expression was highly influenced by the interaction between these two main factors. Functional assignments using GO annotations showed that genes involved in transport, oxidation-reduction, and stress response were highly represented. Clustering based on the pattern of transcript accumulation identified genes that were up or down-regulated by cold treatment. Our data indicate that the cold-sensitive lines can up-regulate known cold-responsive genes comparable to that of cold-hardy lines. The levels of expression of these genes were highly influenced by the initial rate and the duration of the gene's response to cold. We show that the Vrn-A1 locus controls the duration of gene expression but not its initial rate of response to cold treatment. Furthermore, we provide evidence that Ta.Vrn-A1 and Ta.Vrt1 originally hypothesized to encode for the same gene showed different patterns of expression and therefore are distinct. CONCLUSION: This study provides novel insight into the underlying mechanisms that regulate the expression of cold-responsive genes in wheat. The results support the developmental model of LT tolerance gene regulation and demonstrate the complex genotype by environment interactions that determine LT adaptation in winter annual cereals. PMID- 21649928 TI - Performance and cross-cultural comparison of the short-form version of the CPQ11 14 in New Zealand, Brunei and Brazil. AB - BACKGROUND: The Child Perception Questionnaire (CPQ11-14) is a self-report instrument developed to measure oral-health-related quality of life (OHRQoL) in 11-14-year-olds. Earlier reports confirm that the 16-item short-form version performs adequately, but there is a need to determine the measure's validity and properties in larger and more diverse samples and settings. AIM: The objective of this study was to examine the performance of the 16-item short-form impact version of the CPQ11-14 in different communities and cultures with diverse caries experience. METHOD: Cross-sectional epidemiological surveys of child oral health were conducted in two regions of New Zealand, one region in Brunei, and one in Brazil. Children were examined for dental caries (following WHO guidelines), and OHRQoL was measured using the 16-item short-form item-impact version of the CPQ11 14, along with two global questions on OHRQoL. Children in the 20% with the greatest caries experience (DMF score) were categorised as the highest caries quintile. Construct validity was evaluated by comparing the mean scale scores across the categories of caries experience; correlational construct validity was assessed by comparing mean scores and children's global ratings of oral health and well-being. RESULTS: There were substantial variations in caries experience among the different communities (from 1.8 in Otago to 4.9 in Northland) and in mean CPQ11-14 scores (from 11.5 in Northland to 16.8 in Brunei). In all samples, those in the most severe caries experience quintile had higher mean CPQ11-14 scores than those who were caries-free (P < 0.05). There were also greater CPQ scores in those with worse self-rated oral health, with the Otago sample presenting the most marked gradient across the response categories for self-rated oral health, from 'Excellent' to 'Fair/Poor' (9.6 to 19.7 respectively). CONCLUSION: The findings suggest that the 16-item short-form item impact version of the CPQ11-14 performs well across diverse cultures and levels of caries experience. Reasons for the differences in mean CPQ scores among the communities are unclear and may reflect subtle socio-cultural differences in subjective oral health among these populations, but elucidating these requires further exploration of the face and content validity of the measure in different populations. PMID- 21649929 TI - Liao ning virus in China. AB - BACKGROUND: Liao ning virus is in the genus Seadornavirus within the family Reoviridae and has a genome composed of 12 segments of double-stranded RNA (dsRNA). It is transmitted by mosquitoes and only isolated in China to date and it is the only species within the genus Seadornavirus which was reported to have been propagated in mammalian cell lines. In the study, we report 41 new isolates from northern and southern Xinjiang Uygur autonomous region in China and describe the phylogenetic relationships among all 46 Chinese LNV isolates. FINDINGS: The phylogenetic analysis indicated that all the isolates evaluated in this study can be divided into 3 different groups that appear to be related to geographic origin based on partial nucleotide sequence of the 10th segment which is predicted to encode outer coat proteins of LNV. Bayesian coalescent analysis estimated the date of the most recent common ancestor for the current Chinese LNV isolates to be 318 (with a 95% confidence interval of 30-719) and the estimated evolutionary rates is 1.993 * 10-3 substitutions per site per year. CONCLUSIONS: The results indicated that LNV may be an emerging virus at a stage that evaluated rapidly and has been widely distributed in the north part of China. PMID- 21649930 TI - Ear diseases among secondary school students in Xi'an, China: the role of portable audio device use, insomnia and academic stress. AB - BACKGROUND: Hearing impairment negatively impacts students' development of academic, language and social skills. Even minimal unilateral hearing loss can hinder educational performance. We investigated the prevalence of ear diseases among secondary school students in the city of Xi'an, China in order to provide a foundation for evidence-based hearing healthcare. METHODS: A stratified random sampling survey was conducted in 29 secondary schools. Demographics and medical histories were collected, and otologic examinations were performed. Questionnaires were administered to assess insomnia, academic stress and use of portable audio devices. Logistic regression analysis was used to identify factors associated with hearing impairment, and the association of sensorineural hearing loss with insomnia, academic stress and the use of portable audio devices was analyzed with the chi-square test. RESULTS: The percentage of students with some form of ear disease was 3.32%. External ear disease, middle ear disease and sensorineural hearing loss occurred in 1.21%, 0.64% and 1.47% of the students, respectively. Boys had a relatively higher prevalence of ear disease than girls. According to our survey, the prevalence of sensorineural hearing loss increased significantly among the students with insomnia and extended use of portable audio devices, but not among those with elevated levels of academic stress. Hearing aids and surgical treatment were needed in 1.47% and 0.89% of the students, respectively. CONCLUSIONS: There is a high prevalence of ear disease among secondary school students, and this should be given more attention. Insomnia and the excessive use of portable audio devices may be related to adolescent sensorineural hearing loss. It is important to establish and comply with an evidence-based preventive strategy. PMID- 21649931 TI - Identification of maturation and protein synthesis related proteins from porcine oocytes during in vitro maturation. AB - BACKGROUND: In vitro maturation (IVM) of mammalian oocytes is divided into the GV (germinal vesicle stage), MI (metaphase I stage) and MII (metaphase II stage) stages, and only fully mature oocytes have acquired the ability to be fertilized and initiate zygotic development. These observations have been mostly based on morphological evaluations, but the molecular events governing these processes are not fully understood.The aim of the present study was to better understand the processes involved in the molecular regulation of IVM using 2-DE analysis followed by mass spectrometry to identify proteins that are differentially expressed during oocyte IVM. RESULT: A total of 16 up-regulated and 12 down regulated proteins were identified. To investigate the IVM process, we specifically focused on the proteins that were up-regulated during the MII stage when compared with the GV stage, which included PRDX 2, GST, SPSY, myomegalin, PED4D, PRKAB 1, and DTNA. These up-regulated proteins were functionally involved in redox regulation and the cAMP-dependent pathway, which are essential for the intracellular signaling involved in oocyte maturation. Interestingly, the PDE4D and its partner, myomegalin, during the MII stage was consistently confirmed up regulation by western blot analyses. CONCLUSION: These results could be used to better understand some aspects of the molecular mechanisms underlying porcine oocyte maturation. This study identified some regulatory proteins that may have important roles in the molecular events involved in porcine oocyte maturation, particularly with respect to the regulation of oocyte meiotic resumption, MII arrest and oocyte activation. In addition, this study may have beneficial applications not only to basic science with respect to the improvement of oocyte culture conditions but also to mammalian reproductive biotechnology with potential implications. PMID- 21649932 TI - Evolutionarily conserved bias of amino-acid usage refines the definition of PDZ binding motif. AB - BACKGROUND: The interactions between PDZ (PSD-95, Dlg, ZO-1) domains and PDZ binding motifs play central roles in signal transductions within cells. Proteins with PDZ domains bind to PDZ-binding motifs almost exclusively when the motifs are located at the carboxyl (C-) terminal ends of their binding partners. However, it remains little explored whether PDZ-binding motifs show any preferential location at the C-terminal ends of proteins, at genome-level. RESULTS: Here, we examined the distribution of the type-I (x-x-S/T-x-I/L/V) or type-II (x-x-V-x-I/V) PDZ-binding motifs in proteins encoded in the genomes of five different species (human, mouse, zebrafish, fruit fly and nematode). We first established that these PDZ-binding motifs are indeed preferentially present at their C-terminal ends. Moreover, we found specific amino acid (AA) bias for the 'x' positions in the motifs at the C-terminal ends. In general, hydrophilic AAs were favored. Our genomics-based findings confirm and largely extend the results of previous interaction-based studies, allowing us to propose refined consensus sequences for all of the examined PDZ-binding motifs. An ontological analysis revealed that the refined motifs are functionally relevant since a large fraction of the proteins bearing the motif appear to be involved in signal transduction. Furthermore, co-precipitation experiments confirmed two new protein interactions predicted by our genomics-based approach. Finally, we show that influenza virus pathogenicity can be correlated with PDZ-binding motif, with high virulence viral proteins bearing a refined PDZ-binding motif. CONCLUSIONS: Our refined definition of PDZ-binding motifs should provide important clues for identifying functional PDZ-binding motifs and proteins involved in signal transduction. PMID- 21649934 TI - Facile, high efficiency immobilization of lipase enzyme on magnetic iron oxide nanoparticles via a biomimetic coating. AB - BACKGROUND: Immobilization of lipase on appropriate solid supports is one way to improve their stability and activity, and can be reused for large scale applications. A sample, cost- effective and high loading capacity method is still challenging. RESULTS: A facile method of lipase immobilization was developed in this study, by the use of polydopamine coated magnetic nanoparticles (PD-MNPs). Under optimal conditions, 73.9% of the available lipase was immobilized on PD MNPs, yielding a lipase loading capacity as high as 429 mg/g. Enzyme assays revealed that lipase immobilized on PD-MNPs displayed enhanced pH and thermal stability compared to free lipase. Furthermore, lipase immobilized on PD-MNPs was easily isolated from the reaction medium by magnetic separation and retained more than 70% of initial activity after 21 repeated cycles of enzyme reaction followed by magnetic separation. CONCLUSIONS: Immobilization of enzyme onto magnetic iron oxide nanoparticles via poly-dopamine film is economical, facile and efficient. PMID- 21649933 TI - A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode. AB - BACKGROUND: Interleukin-8 (IL-8) is a potent chemo-attractant cytokine responsible for neutrophil infiltration in lungs with idiopathic pulmonary fibrosis (IPF). The IL-8 protein and mRNA expression are increased in the lung with IPF. We evaluated the effect of single nucleotide polymorphisms (SNPs) of the IL-8 gene on the risk of IPF. METHODS: One promoter (rs4073T>A) and two intronic SNPs (rs2227307T>G and rs2227306C>T) of the IL-8 genes were genotyped in 237 subjects with IPF and 456 normal controls. Logistic regression analysis was applied to evaluate the association of these SNPs with IPF. IL-8 in BAL fluids was measured using a quantitative sandwich enzyme immunoassay, and promoter activity was assessed using the luciferase reporter assay. RESULTS: The minor allele frequencies of rs4073T>A and rs2227307T>G were significantly lower in the 162 subjects with surgical biopsy-proven IPF and 75 subjects with clinical IPF compared with normal controls in the recessive model (OR = 0.46 and 0.48, p = 0.006 and 0.007, respectively). The IL-8 protein concentration in BAL fluids significantly increased in 24 subjects with IPF compared with 14 controls (p = 0.009). Nine IPF subjects homozygous for the rs4073 T>A common allele exhibited higher levels of the IL-8 protein compared with six subjects homozygous for the minor allele (p = 0.024). The luciferase activity of the rs4073T>A common allele was significantly higher than that of the rs4073T>A minor allele (p = 0.002). CONCLUSION: The common allele of a promoter SNP, rs4073T>A, may increase susceptibility to the development of IPF via up-regulation of IL-8. PMID- 21649935 TI - ParaMED Home: a protocol for a randomised controlled trial of paramedic assessment and referral to access medical care at home. AB - BACKGROUND: In Australia approximately 25% of Emergency Department (ED) attendances are via ambulance. ED overcrowding in Australia, as in many countries, is common. Measures to reduce overcrowding include the provision of enhanced timely primary care in the community for appropriate low risk injury and illness. Therefore paramedic assessment and referral to a community home hospital service, in preference to transfer to ED, may confer clinical and cost benefit. METHODS/DESIGN: A randomised controlled trial. Consenting adult patients that call an ambulance and are assessed by paramedics as having an eligible low risk problem will be randomised to referral to ED via ambulance transfer or referral to a rapid response service that will assess and treat the patient in their own residence. The primary outcome measure is requirement for unplanned medical attention (in or out of hospital) in the first 48 hours. Secondary outcomes will include a number of other clinical endpoints. A cost effectiveness analysis will be conducted. DISCUSSION: If this trial demonstrates clinical non-inferiority and cost savings associated with the primary assessment service, it will provide one means to safely address ED overcrowding. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number 12610001064099. PMID- 21649936 TI - Etiology and antimicrobial susceptibility of udder pathogens from cases of subclinical mastitis in dairy cows in Sweden. AB - BACKGROUND: A nationwide survey on the microbial etiology of cases of subclinical mastitis in dairy cows was carried out on dairy farms in Sweden. The aim was to investigate the microbial panorama and the occurrence of antimicrobial resistance. Moreover, differences between newly infected cows and chronically infected cows were investigated. METHODS: In total, 583 quarter milk samples were collected from 583 dairy cows at 226 dairy farms from February 2008 to February 2009. The quarter milk samples were bacteriological investigated and scored using the California Mastitis Test. Staphylococci were tested for betalactamase production and presence of resistance was evaluated in all specific udder pathogens. Differences between newly infected cows and chronically infected cows were statistically investigated using logistic regression analysis. RESULTS: The most common isolates of 590 bacteriological diagnoses were Staphylococcus (S) aureus (19%) and coagulase-negative staphylococci (CNS; 16%) followed by Streptococcus (Str) dysgalactiae (9%), Str. uberis (8%), Escherichia (E.) coli (2.9%), and Streptococcus spp. (1.9%). Samples with no growth or contamination constituted 22% and 18% of the diagnoses, respectively. The distribution of the most commonly isolated bacteria considering only bacteriological positive samples were: S. aureus--31%, CNS--27%, Str. dysgalactiae--15%, Str. uberis--14%, E. coli -4.8%, and Streptococcus spp.--3.1%. There was an increased risk of finding S. aureus, Str. uberis or Str. dysgalactiae in milk samples from chronically infected cows compared to findings in milk samples from newly infected cows. Four percent of the S. aureus isolates and 35% of the CNS isolates were resistant to penicillin G. Overall, resistance to other antimicrobials than penicillin G was uncommon. CONCLUSIONS: Staphylococcus aureus and CNS were the most frequently isolated pathogens and resistance to antimicrobials was rare. PMID- 21649937 TI - Socio-demographic and behavioural characteristics of illegal motorcycle street racers in Malaysia. AB - BACKGROUND: This study sought to understand the factors associated with street racing among the illegal motorcycle racers in Malaysia or known as the "Mat Rempit". METHODS: Street outreach interviewer-administered surveys were conducted from June 2008 to January 2009 in this multi-state study. RESULTS: A total of 2022 participants were surveyed, the mean +/- SD age of the participants was 20.5 +/- 3.4 years (age range: 12 to 35 years). Mean duration of street racing was 2.65(SD +/- 1.77) years (range: 2 months to 12 years), with 50.1% and 35.8% reporting stunt riding and alcohol drinking while racing, respectively. With regard to risk behaviours, cigarette smoking was highly prevalent among the study participants (78.3%), followed by alcohol drinking (27.8%) and recreational drug use (18.8%). Participants scored high on the masculinity scale (15.7 +/- 4.0 out of 21.0). The results of the logistic regression analysis showed that socio demographic variables, risk behaviour and masculinity scores were associated with racing frequency. CONCLUSION: Given these associations, tailoring family-centered interventions to the needs of the lower socio-economic groups and interventions recognizing the negative consequences of health risk behaviours related to street racing as an expression of traditional masculinity should be emphasized. PMID- 21649938 TI - Levels of soluble fms-like tyrosine kinase one in first trimester and outcomes of pregnancy: a systematic review. AB - Angiogenic factors are involved in formation of new blood vessels required for placental development and function; and critical for fetal growth and development. Soluble fms-like tyrosine kinase 1(sFlt-1) is an anti-angiogenic protein that inhibits formation of new blood vessels resulting in potential pregnancy complications. The objective of this study was to undertake a systematic review to assess levels of sFlt-1 in early pregnancy and association with adverse pregnancy outcomes. PubMed and Medline databases and reference lists were searched up to July 2010. Inclusion criteria were pregnant women, blood sample taken during first trimester and assessment/reporting of sFlt-1 concentrations and subsequent pregnancy complications. Twelve relevant studies were identified of 71 to 668 women. No pooling of results was undertaken due to variation in sFlt-1 concentrations (range, 166-6,349 pg/ml amongst controls), samples used (serum, plasma), different summary statistics (mean, median, odds ratio) and outcome definitions applied. Levels of sFlt-1 were generally higher among women who developed preeclampsia (11 studies) or gestational hypertension (two studies), but not significantly different to normotensive women in most studies. There was no consistent pattern in association between sFlt-1 concentrations and fetal growth restriction (4 studies); and levels were non significantly higher for women with postpartum bleeding (1 study) and significantly lower for stillbirths (1 study).This review found no clear evidence of an association between sFlt-1 levels in first trimester and adverse pregnancy outcomes. However, findings were affected by methodological, biological and testing variations between studies; highlighting the need for consistent testing of new biomarkers and reporting of outcome measures. PMID- 21649939 TI - Respiratory difficulty caused by an ectopic brain tissue mass in the neck of a two-month-old baby: a case report. AB - INTRODUCTION: Neuroglial heterotopia, heterotopic brain tissue, or differentiated neural tissue outside the cranial vault is uncommon, and these anomalies most commonly occur in the nasal cavity. CASE PRESENTATION: We report a case of rare pure cystic heterotopic brain tissue in a two-month-old Caucasian baby girl that presented as a large cystic neck mass and was confused with a cystic hygroma. Her mother reported a progressive increase in the size of this swelling and mild respiratory difficulty when the girl was sleeping. A computed tomography scan of the brain and neck showed a large heterogeneous mass extending from the base of the skull to the left submandibular region; a cystic component was also noted. Our patient under went total excision of the cystic mass and prevention of airway obstruction by a left submandibular approach. The final gross pathology diagnosis was heterotopic brain tissue. CONCLUSIONS: Pure cystic neck heterotopic brain tissue lesions are very uncommon, and a preoperative diagnosis of this lesion is difficult. Brain heterotopia is a rare, benign condition that should be considered in the differential diagnosis of the neonatal head and neck mass. PMID- 21649940 TI - Stem cell biology and drug discovery. AB - There are many reasons to be interested in stem cells, one of the most prominent being their potential use in finding better drugs to treat human disease. This article focuses on how this may be implemented. Recent advances in the production of reprogrammed adult cells and their regulated differentiation to disease relevant cells are presented, and diseases that have been modeled using these methods are discussed. Remaining difficulties are highlighted, as are new therapeutic insights that have emerged. PMID- 21649941 TI - The individuality of stem cells. PMID- 21649943 TI - [A woman with acute loss of vision and a mass in her neck]. AB - A 64-year-old woman had acute central vision loss of her left eye. She also had a pulsating mass in the left side of her neck. It appeared the vision loss was caused by a thromboembolism that originated from an aneurysm of the left carotid artery. PMID- 21649942 TI - Stochastic dynamics and the evolution of mutations in stem cells. AB - Stem cells are the target of mutations that can lead to life threatening diseases. However, stem cell populations tend to be small and therefore clonal expansion of mutant cells is highly sensitive to stochastic fluctuations. The evolutionary dynamics of mutations in these cells is discussed, taking into consideration the impact of such mutations on the reproductive fitness of cells. We show how stochastic effects can explain clinical observations, including extinction of acquired clonal stem cell disorders. PMID- 21649944 TI - [Interdisciplinary cooperation in occupational health: ethical friction]. AB - OBJECTIVE: To investigate which ethical considerations play a role in the assessment of absenteeism due to sickness and of disability, and how these are dealt with. DESIGN: Qualitative, exploratory study. METHOD: We conducted interviews with 32 individual professional practitioners: 8 occupational health physicians, 8 insurance company physicians, 8 general practitioners, and 8 psychologists, with the aid of a semi-structured questionnaire. During the interview we differentiated between 4 clusters of questions referring to the ethical, legal, interdisciplinary, and professional context, respectively. The study revealed only the spectrum of ethical considerations that played a role, and not the representativeness. For this reason the results did not allow for quantitative conclusions. RESULTS: Differences in the manner of thinking and behaving between health-care providers stem from differences in ethical considerations and in background beliefs. These differences hinder effective cooperation within the occupational health sector. CONCLUSION: To improve professional performance and to achieve more responsible decision-making those involved need to be aware of their ethical considerations and background beliefs and to make them explicit, possibly with the aid of a checklist. PMID- 21649945 TI - [Ultrasound-guided anterior approach to sciatic nerve block]. AB - Ultrasound guidance has made it possible to carry out an anterior approach to sciatic nerve block. This technique can be performed as fast and as successfully as the posterior or subgluteal approach. A major advantage of this technique is that the patient can remain comfortable in a neutral supine position. PMID- 21649946 TI - [Pompe and his disease]. AB - Johannes Cassianus Pompe (1901-1945) studied medicine in Utrecht and trained in Amsterdam as a pathologist. In 1932 he reported on his findings in a girl of 7 months, who had succumbed to extreme hypertrophy of the heart. Microscopical analysis showed accumulation of glycogen not only in the heart, but also in the liver, kidneys and skeletal muscles. Pompe's life was cut short near the end of World War II, when he was arrested and eventually executed by the occupying forces. Currently Pompe's disease has been classified as glycogen storage disease type II, caused by deficiency of the lysosomal enzyme alpha-glucosidase. If the deficiency is partial, the disease manifests later in life, as muscle weakness. Enzyme replacement therapy is now feasible. PMID- 21649947 TI - [Treatment of non-alcoholic fatty liver disease]. AB - Non-alcoholic fatty liver disease (NAFLD) comprises benign steatosis and steatohepatitis (NASH) and may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Its prevalence is estimated to be 20% in the general population and 50-100% in patients with overweight and obesity. In about 15-30% of patients steatosis evolves to NASH which can only be diagnosed by means of a liver biopsy. NAFLD may be described as the hepatic component of the metabolic syndrome and is a consequence of the Western lifestyle. The pathogenesis is multifactorial; oxidative stress plays a crucial role in maintaining inflammation and progressive fibrosis. Lifestyle modification with weight loss and increased physical activity is the cornerstone of the treatment, which should take place in a multidisciplinary setting. To date, no specific registered drug for NAFLD treatment is available. Supportive drug therapy is mainly focused on aspects of the metabolic syndrome and chronic inflammation. PMID- 21649948 TI - [Couching then and now]. AB - Cataracts are the most important cause of acquired blindness worldwide. The oldest known surgical treatment for cataracts dates back to around 1,000 years before Christ. The Indian surgeon Sushruta described the technique of 'couching', in which the opaque lens is pushed from the line of vision using a needle. At the time of Alexander the Great this technique spread across Europe and then to the rest of the world. Couching was the only available treatment for cataracts for a long time, until the discovery of lens extraction by Jacques Daviel in 1748. Since then lens extraction has replaced couching in the western world, because of poor results and high complication rates. This procedure is, however, still practiced in areas of Africa and Asia. PMID- 21649949 TI - [Hypertension in Dutch and English ethnic minorities. Blood pressure better controlled in English groups than in Dutch groups]. AB - OBJECTIVE: To compare blood pressure and the prevalence of hypertension in white Dutch and Dutch of Suriname-hindustani and Suriname-creole ethnic derivation with corresponding ethnic minority groups in England and to assess the quality of hypertension treatment in these groups. DESIGN: Retrospective; comparison of cross-sectional studies. METHOD: Secondary analyses were performed on data from 3 population-based studies with 13,999 participants in total of European, African of South-Asian origin from England and the Netherlands. RESULTS: English South Asian men and women had lower blood pressure and lower prevalence of hypertension than people of South-Asian origin in the Netherlands (Suriname-hindustani), except for systolic blood pressure in men of Indian extraction in England. There was no difference in systolic blood pressure between groups of African origin in the Netherlands and England. Diastolic blood pressure levels, however, were lower in English men and women of African origin than in people of African origin in the Netherlands (Suriname-creole). White Dutch had higher systolic blood pressure levels, but lower diastolic blood pressure levels than white English men and women. There was no difference in the prevalence of hypertension between the white groups. In persons being treated for hypertension, a substantially lower percentage of the Suriname-hindustani and Suriname-creole persons in the Netherlands had well controlled blood pressure (lower than 140/90 mmHg) than their English equivalents, with the exception of English of Indian extraction. CONCLUSION: There were marked differences in blood pressure and prevalence of hypertension between comparable ethnic groups in England and the Netherlands. The relatively poor blood pressure control in Dutch ethnic minority groups partly explained the relatively high blood pressure levels in these groups. PMID- 21649950 TI - FDA notifications. Ongoing safety review of abacavir, possible MI risk. PMID- 21649951 TI - [What colleagues think of guidelines. Bureaucracy monster with unwanted side effects]. PMID- 21649952 TI - [Salary increase for medical assistants. Your "pearl" is now more costly for you ]. PMID- 21649953 TI - [Proctologic know-how for the family physician: from stool consultation to hemorrhoid treatment]. PMID- 21649954 TI - ["Fashionable" therapy in atrial fibrillation: who is really a candidate for ablation?]. PMID- 21649955 TI - Proceedings of the 3rd International Symposium on Cancer Metastasis and the Lymphovascular System: Basis for Rational Therapy. May 6-9, 2009, San Francisco. PMID- 21649956 TI - Hormones, Endocrine Disorders, and Hemostasis. Special issue dedicated to the memory of Gianni Franchini. PMID- 21649958 TI - Proceedings of the Human Tissues Conference, 20 October 2009, House of Lords, England. PMID- 21649957 TI - Proceedings of the 21st International Conference on Genome Informatics, December 16-18, 2010, Hangzhou, China. PMID- 21649959 TI - Proceedings of a Workshop on Molecular Diagnostics for Respiratory Tract Infections, November 12-13, 2009. PMID- 21649960 TI - Unexpected generation of diastereomers by double diboration of a dialkyne. PMID- 21649961 TI - Role of the endocytic pathway in carcinogenesis. AB - This commentary was prompted by many reports that carcinogenesis involving various carcinogens and various types of systems is blocked by inhibitors of endolysosomal proteases (i.e. leupeptin, antipain). These findings have been largely ignored by cancer investigators so far. In this commentary based on these reports a carcinogenesis model is suggested that does not involve direct attack by the carcinogen onto target cell DNA. This model proposes the following steps in the initial phase of carcinogenesis: interaction of a carcinogen with an appropriate cell surface receptor (i.e. possibly the receptor for the epidermal growth factor). This carcinogen-receptor complex is endocytosed and fragmented by various cathepsins to form small peptides (i.e. di-and tripeptides) some of which enter the nucleus and interact very specifically with the protein repressors that normally (during G0 phase) inhibit expression of oncogenes critical to the transformation process. This interaction causes removal of the repressors from these oncogenes. The oncogenes, freed from their repressors are then expressed, culminating in carcinogenesis. This then defines the G0/G1 transition comprising the initial phases of carcinogenesis. Note is taken of reports that the only cells transformed in a heterogeneous collection of cells comprising target organs are in the G0 stem cell subpopulation. The need for such an alternative mechanism is outlined in terms of reports that major kinases (i.e. MAPK and PI3K) operate only after entry into cell cycle (during G1). Thus an answer is provided as to what events occur before entry into cell cycle, the events that define the transition from G0 to G1. In addition, note it taken of the recent reports that suggest that epigenetic mechanisms operate in the carcinogenic process and an attempt is made to harmonize the model presented in this commentary with epigenetic mechanisms as proposed in recent years. PMID- 21649962 TI - In memoriam. JoGayle Howard, D.V.M., Ph.D. 1951-2011. PMID- 21649963 TI - Rivastigmine patches: fatal overdoses. PMID- 21649964 TI - Terpene derivatives: still on the market for use in children. PMID- 21649965 TI - INN commons stems: -retin. PMID- 21649966 TI - Medically assisted reproduction. PMID- 21649967 TI - Colchicine: caution! PMID- 21649968 TI - Shocking news. overdoing ICDs. They can shock a heart back into rhythm and save a life. But are too many of these heart devices being implanted? PMID- 21649969 TI - Talking of walking in three easy pieces. Gait speed, hiking poles, and footwear. PMID- 21649970 TI - The shingles vaccine. Question: if you've had shingles, should you get the vaccine to protect yourself from getting it again? PMID- 21649971 TI - A wash worth its while? Freshens breath! Gives your mouth a tingling sensation! But what do mouthwashes really accomplish? PMID- 21649972 TI - Ask the doctor. Some doctors strongly advise against the use of generic drugs with the argument that manufacturing processes are better controlled in branded medicines. What is your view? PMID- 21649973 TI - Beyond the coronary arteries: possible benefits of statin drugs. Part II: specific syndromes. PMID- 21649974 TI - Acupuncture for ED? PMID- 21649975 TI - Money talks: financial incentives for health. PMID- 21649976 TI - On call. My husband was just released from the hospital after a mild heart attack. He's never been much of a drinker, but now he wants to have wine with dinner every night. We've both heard that wine is good for the heart, but I'm worried that it may not be safe so soon after a heart attack. I hope you can either reassure me or restrain my husband. PMID- 21649977 TI - Gloomy forecast on heart disease. Stepping up prevention efforts could brighten up predictions. PMID- 21649978 TI - Let's put the "public" in public defibrillation. Many people say they would shy away from using a defibrillator. PMID- 21649979 TI - Two-way street between erection problems and heart disease. Paying attention to heart health can be good for a man's sex life. PMID- 21649980 TI - Hysterectomy linked to increase in heart disease. A sudden and dramatic reduction in female hormones after the procedure may explain why. PMID- 21649981 TI - Pre-sports check-up can prevent sudden death among athletes. Whether the check-up should include an electrocardiogram is an unanswered question. PMID- 21649982 TI - HDL function, not just amount, could affect artery health. PMID- 21649984 TI - Health tips. Grilling food safety. PMID- 21649983 TI - Ask the doctor. The "Heart Letter" has said that alcohol can cause heart rhythm problems. I have an implanted defibrillator. Is it okay or me to drink alcohol? PMID- 21649985 TI - Mediterranean diet delivers a punch to LDL cholesterol. PMID- 21649986 TI - Social anxiety. Learning to enjoy others. PMID- 21649987 TI - Chocolate wonders. Healthy perks in small amounts. PMID- 21649988 TI - Is it better to use a hard- or a soft-bristled toothbrush. PMID- 21649989 TI - [Decreased fertility and today's possibility of examination in reproductive immunology]. AB - The aim of reproductive immunology is to look for a futher cause of decreased fertility, immunological reason, which depends on neuro-endocrine relationships. The article explains today's possibility of examination of cell and humoral immunity with regard to human fertility. SETTING: Department of Gynecology & Obsterics Charels University and Faculty Hospital, Pilsen. PMID- 21649990 TI - [Oncofertility--a new trend in reproductive medicine]. AB - Effective treatment of cancer often causes patients irreversible damage of reproductive abilities. New trend in reproductive medicine commonly described as oncofertility offers cancer patients not only infertility treatment, but also potent prevention of irreversible damage of reproductive organs and functions. Efficacious methods of women reproductive function damage prevention has been developed at Brno University Hospital Department of Obstetrics and Gynecology since year 2004. The paper describes current oncofertility techniques implemented to clinical practice--embryo and oocyte banking, ovarian tissue cryopreservation including further possibility of its orthotopic autotransplantation and administration of gonadoliberin analogues for ovarian protection. During past 6 years expert consultation before start of gonadotoxic treatment has been provided to 195 young women with newly diagnosed cancer or autoimmune disease. Attention is applied to pro and contras of previously described methods of ovarian protection in the discussion. Limitations regarding implementation of oncofertility techniques in practice are mentioned. Furthermore short recommendations regarding pre-treatment oncofertility consultation with patients are given. PMID- 21649991 TI - [Preimplantation genetic diagnosis (PGD) in carriers of chromosomal translocations: possibilities and results]. AB - AIM OF THE STUDY: To assess the PGD results in couples with robertsonian and reciprocal translocations. DESIGN: Retrospective study. SETTING: Sanatorium Pronatal, Prague, accredited IVF unit. METHODS: 94 infertile couples with translocation (44 couples with robertsonian and 50 couples with reciprocal translocations) were included in the study. The mean woman's age was not different: 33 +/- 4,4 in robertsonian vers. 33 +/- 3.9 in reciprocal translocations. The performance of FISH probes in specific cases was tested on patient's lymfocytes before the treatment was started. After ovarian stimulation (recombinant FSH or hMG + GnRH agonist, "long" protocol) and transvaginal oocyte pick-up, embryo biopsy of a single cell was performed 72 hours after fertilization. After blastomere fixation, translocated chromosomes + chromosomes 13, 18, 21, X and Y were tested using FISH. The maximum of two embryos euploid for detected chromosomes were transferred, supernumerary euploid embryos were frozen. RESULTS: From the total number of 629 embryos, 126 embryos (21.9%) were detected as normal or with balanced translocation--25.2% (68/270) in couples with robertsonian and 16.4% (59/359) with reciprocal translocation. Embryotransfer was performed in 30 cycles (68.2%) in robertsonian and 27 (54%) in reciprocal translocations. 24 pregnancies were achieved--15 (39% per cycle and 50% per ET) for robertsonian and 9 (19% per cycle and 33% per ET) for reciprocal translocation--this difference was statistically significant (p = 0.033). Only one pregnancy in each group ended as abortion. SUMMARY: IVF is a valuable option for couples with infertility problems and translocation. This technique allows in short-term a conception and delivery of a healthy baby with general better prognosis for couples with robertsonian translocation. PMID- 21649992 TI - [Luteal support in the IVF/ET programme]. AB - OBJECTIVE: The objective of this article is to review the recent information about luteal support in the IVF/ET programme. DESIGN: Review article. CONCLUSIONS: The luteal phase support is a necessary part of treatment in stimulated cycles for IVF/ET. PMID- 21649993 TI - [Clinical effects of recombinant versus urinary gonadotropins in ovulation induction]. AB - OBJECTIVE: To present an overview of trials and discussion focused on the clinical characteristics of recombinant gonadotropins compared with urinary ones in ovulation induction. SUBJECT: Review article. SETTING: Sanatorium Pronatal, Prague. SUBJECT AND METHOD: The subject of the study is to compare the clinical characteristics of recombinant gonadotropins versus urinary ones focused on the daily dose of FSH achieving FSH threshold and the risk of multifollicular development in ovulation induction before intrauterine insemination, number of follicles and oocytes, the risk of ovarian hyperstimulation syndrome (OHSS), total consumption of FSH, cost effectiveness and expected pregnancy rate during in vitro fertilization technique. The method is a MEDLINE research of articles from 1994 to 2010. CONCLUSIONS: Data demonstrates that recombinant FSH (rFSH) offers higher ovarian response, less consumption of gonadotropins, lower risk of complications (multiple pregnancy and OHSS) compared with urinary FSH (uFSH). Expected pregnancy rate is probably comparable. PMID- 21649994 TI - [Comparison of human chorionic gonadotropin (Pregnyl 10 000 IU i.m.) versus GnRH agonist (triptorelin 0,2 mg s.c.) for final oocytes maturation in the same egg donors--clinical and embryological characteristics]. AB - OBJECTIVE: To compare clinical and embryological characteristics in donor cycles triggered for final oocytes maturation with Pregnyl 10 000 IU i.m. versus triptorelin 0.2 mg s.c. in the same patients in two sequential stimulation cycles. The aim of the study is to decrease the risk of the development of ovarian hyperstimulation syndrome (OHSS) at high response donors by the replacement of Pregnyl 10 000 IU i.m. vs. triptorelin 0.2 mg s.c. The administration of a single dose of gonadotropin-releasing hormone agonist (triptorelin 0.2 mg s.c.) induces release of LH from the pituitary gland similarly to a spontaneous LH surge. SUBJECT: Prospective cross-over trial. SETTING: Sanatorium Pronatal, Praha. SUBJECT AND METHOD: From August 2009 to July 2010 we analysed 24 stimulation cycles in 12 egg donors treated with GnRH antagonist protocol with recombinant FSH (follitropin beta). We identified patients with more than 15 follicles during examination by transvaginal ultrasound. When at least 3 leading follicles reached 17 mm in diameter we administrated Pregnyl 10 000 IU i.m. for final oocytes maturation and triptorelin 0.2 mg s.c in the subsequent treatment cycle. RESULTS: The primary outcome measure was number of oocytes, proportion mature oocytes and fertilized oocytes. The secondary outcome were duration of FSH stimulation, total dose of gonadotropins and mean daily dose of gonadotropins. Data was analysed by paired t test. We retrieved 17.2 +/- 8.6 vs. 15.8 +/- 5.3 (ns) oocytes, 12.6 +/- 7.3 vs. 13.0 +/- 5.4 (ns) metaphase II oocytes, proportion of metaphase II oocytes (%) was 73 vs. 83 (ns), number of fertilized oocytes 11.5 +/- 6.7 vs. 11.7 +/- 4.5 (ns), fertilization rate (%) 91 vs. 90 (ns) in Pregnyl's vs. triptorelin's group, resp. Duration of FSH stimulation (days) 12.2 +/- 0.8 vs. 12.4 +/- 0.7 (ns), total dose of gonadotropins (IU) 1744 +/- 277 vs. 1740 +/- 276 (ns), mean daily dose of gonadotropins (IU) 238 +/- 43 vs. 221 +/- 36 (ns), were not statistically different in both groups. CONCLUSIONS: Number of mature oocytes and subsequent embryonic cleavage is comparable to standard hCG treatment. There are no differences in clinical and embryological characteristics in both groups. Only one patient with administration of Pregnyl 10 000 IU i.m. was treated for OHSS grade II by vaginal paracentesis. Administration of triptorelin 0.2 mg s.c. is a safe and effective approach to achieve mature oocytes in egg donation programme, where we do not take care of implantation, which has got some limitations based on several studies. PMID- 21649995 TI - [Extended embryo culture in IVF does not improve pregnancy rate]. AB - OBJECTIVE: Compare the effectiveness of the IVF extended embryo culture day 4 versus day 2. DESIGN: Retrospective analysis. SETTING: Assisted Reproduction centre Apolinar, Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General Faculty Hospital in Prague. METHODS: We compared pregnancy rate (PR) and implantation rate (IR) of all IVF and IVF/ICSI embryo transfers (ET) performed between August 2004 and July 2008, in which 2 embryos were transfered. All transfers were done by the same physician. Maternal age was < or = 35 years (from 22 to 35 years, mean 30.4 years, median 31.1 years). The group of embryos evaluated and transfered on the day 2 was compared with the embryos evaluated and transfered on the day 4. Based on the evaluation, each embryo was assigned to one of the following categories: Grade A (top quality embryo) or grade B (medium quality embryo). RESULTS: On the day 2, ET of A+A embryos led to PR 69.0%; A+B 53.3% and B+B 36.4% (IR 50.0%, 40.0% and 22.7%), where number of transfers was 42, 30 and 11 in every group. On the day 4, ET of A+A embryos led to PR 54.3%, A+B 48.7%, B+B 26.6% (IR 45.6%, 34.6%, 13.3%), where number of transfers was 46.39 and 15 in every group. CONCLUSION: In our group, we found no statistical significant difference (p < 0.05) in PR between day 2 and day 4 embryotransfers. Results of the day 2 transfers have a trend to be better than results of day 4 transfers. Regardless of the transfer day, the prognosis of grade A embryos was significantly better (p < 0.05) than for grade B embryos. PMID- 21649996 TI - [A relation between the polycystic ovary syndrome and the status of ovarian hyperstimulation syndrome in IVF patients after controlled hyperstimulation]. AB - OBJECTIVE: Ovarian Hyperstimulation Syndrome (OHSS) is a severe health complication observed in some patients undergoing hormonal stimulation during IVF. Some authors present that OHSS is associated with Polycystic Ovary (PCO) and with a high count of growing follicles (more than 18) responding to FSH hyperstimulation, although none of them is sufficient to predict the onset of OHSS. The aim of this study is to analyze the association between PCOS and OHSS the Inhibin B-based TFF/SBM index. DESIGN: Retrospective analysis. SETTING: Assisted Reproduction Center, Department of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University and General Faculty Hospital in Prague, Sigma-Aldrich, Prague, Immunotech, a.s., Prague. METHODS: Serum and follicular fluid of 36 women (high responders with more than 18 growing follicles) in IVF program were collected at the day of oocyte pick up and used for analysis of Inhibin B. Age: mean 30.2 years (24-35 years, median 31.0 years), BMI: mean 22.34 (18.3-29.7, median 21.6). For every patient, the TFF/SBM index was calculated as follows: [concentration in FF] x [growing follicle count]/ [concentration in serum] x [body mass]. A distribution of the following parameters were compared: OHSS status, TFF/SBM index based on Inhibin B, growing follicle count and the incidence of PCOS. RESULTS: Values of the TFF/SBM index showed an association with the severe form of OHSS but not with the incidence of PCOS. CONCLUSION: These observations suggested that the incidence of PCOS is not associated with the development of severe form of OHSS, but may be still associated with a high count of growing follicles. PMID- 21649997 TI - [The role of three-dimensional ultrasonography in assisted reproduction]. AB - OBJECTIVE: Clarifying the role of three-dimensional transvaginal sonography in diagnosis sterility and assisted reproduction treatment. DESIGN: Review. SETTING: Institute for the Care of Mother and Child, Department of IVF, Charles University, Prague. METHODS: Study of current literature. SUMMARY: With arrised frequency of ovarian, uterus and another pelvic patologies remains the three dimensional transvaginal sonography in diagnosis of sterility women very actual in the fields of reproductive medicine. Actually the assessment of ovarian reserve belong to the essentials investigations in the diagnosis of primary and secondary sterility at this time. The advance in the three-dimensional transvaginal sonography allows to assess the endometrial volume, echogenity, endometrial vascularity and endometrial receptivity. There is a significant importance of 3D power Doppler angiography by measurement of folicular and ovarian vascularity with three indices (VI, FI, VFI) and provides the calculation of ovarian vascularity from the volume. New Sono-Automatic Volume Calculation (Sono-AVC) software that identifies and quantifies hypoechoic regions within a three-dimensional dataset and provides automatic estimation of their absolute dimensions, mean diameter and volume. An unlimited number of volumes can theoretically be quantified, which makes it an ideal tool for assessment of the ovarian volume and the antral follicle count (AFC) in women undergoing controlled ovarian stimulation. PMID- 21649998 TI - [Selected markers in early prediction of preeclampsia]. AB - OBJECTIVE: Review of actual trends in early prediction of preeclampsia. SUBJECT: Literature review. SETTING: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University, Martin, Slovak Republic. SUBJECT AND METHOD: Literature review of markers used in early prediction of preeclampsia. Review of their reliability and possible advantage of combination. CONCLUSION: Preeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. Onset of clinic symptomes of preeclampsia can appear after 20 weeks of gestation. To find a single marker, or their combination, in early prediction of preeclampsia is one of the goals of modern perinatology. We look at some of the potential markers, which can fulfil these criteria. PMID- 21649999 TI - [Importance of the consultation for combined hormonal contraception's choice- results of CHOICE project in Czech and Slovak Republic]. AB - OBJECTIVE: The aim of this project was to evaluate influence of standardised information on patient's choice of combined hormonal contraception application way. DESIGN: Non-interventional, multicentric, prospecive study. SETTING: Dept. of Obstetrics and Gynecology, 1st Faculty of Medicine, Charles University Prague. METHODS: The choice of application form of combined hormone contraception was evaluate in group of 1944 women in 183 centers of Czech and Slovak republic before and after doctor's consultation. RESULTS: The 1911 women have given replay for all questions. Percentage of women preferring combined oral contraception (46.6%, CI 95% 44%-50%, 906 women) and transdermal patch (4.5%, CI 95% 3%-6%, 87 women) were unchanged. Choice of vaginal ring grew up from 6.2% to 42.6% (CI 95% 40%-46%, 837 women). It means significant elevation by 36.4% (CI 97.5% 33.9% - 38.9%, p < 0.0001). Vaginal ring was choosen by 54.2% of women without any intention and 39.1% from women with preference of nonhormonal contraception. CONCLUSION: Project show to increase the preference of vaginal ring by information about all application forms of combined hormonal contraception. PMID- 21650000 TI - [Prevalence of women with overactive bladders in the Czech Republic]. AB - INTRODUCTION: The term OAB (overactive bladder) was introduced in praxis in the year 2002 by Abrams. This term includes symptoms of urgency, with or without urgent incontinence, and it is generally accompanied by urinary frequency and nocturia. OAB is widespread among our female population. Approximately 20% of women suffer from this problem, but the frequency of the syndrome has not been assessed more precisely by means of questionnaires. The aim of our study was to assess the prevalence of OAB among patients who visited gynecologists in the first line and completed the Bladder Control Self Assessment Questionnaire (BCSAQ). MATERIAL AND METHODS: Five gynecologists in the first line questioned 492 consecutive patients as to whether they suffered from urgency, frequency, nocturia and urgent incontinence, and their answers were later evaluated. The BCSA questionnaires completed by the patients in the waiting room before seeing the doctor were subsequently also evaluated. RESULTS: Due to inquiries made by the gynecologist, 320 patients took the BCSA questionnaires in the waiting room before seeing the doctor, and 314 completed them; 14 patients completed the questionnaires after seeing the doctor who questioned them about problems with urgency. The patients then handed the completed questionnaires to the nurse, i.e. the total of 328 questionnaires were assessed. 159 patients suffered from urgency, and 35% of these patients had problems with leakage of urine. In reply to the question: Is it difficult to hold urine when you have the urge to go? 22% of patients from the whole group of patients (n = 492) answered yes. 24% of patients had problems with frequency, 32% with nocturia and 14% with urgent incontinence. CONCLUSION: OAB syndrome is widespread in our population; it constitutes a major problem which must be treated. Awareness of this problem has now improved; patients feel less embarrassed to discuss about problem, and increasingly they seek treatment, while at the same time gynecologists have improved their knowledge about the diagnosis and treatment of OAB. This means that the quality of life for these patients can be improved. PMID- 21650001 TI - [Uterine fibroids and their treatment]. AB - Uterine fibroids are the most common benign disease of women. They occur in women under 30 years of 20-30% for women over 30 years in 50%. The most frequent indication for hysterectomy, uterine fibroids are just. Symptoms of uterine fibroids are various forms of pelvic pain and trouble from the oppression of the surrounding organs, irregular uterine bleeding and fertility disorders resulting from the inability to conceive or recurrent pregnancy loss. Problems of surgical treatment of fibroids applies not only to symptomatic patients who wish to preserve the uterus, but also women who have uterine fibroids negatively affect their reproduction. Treatment of uterine fibroids include monitoring, administration of medications and surgical techniques that preserve either the uterus or not. In recent years the conservatives have extended performance of minimally invasive surgery, which is a common feature of the endoscopic approach, or uterine fibroid devascularization. Gynecologist surgeon must be familiar with the history of the patient and based on history and examination to consider which procedure is best for the patient. PMID- 21650002 TI - [Colorectal screening program--participation of general gynecologists]. AB - AIM: Colorectal screening program in the Czech republic in 2011 offers faecal occult blood test (FOBT) yearly in the age of 50-54. Patient over 55 years of age chooses either a FOBT once in 2 years or primary screening colonoscopy once in 10 years without using FOBT. There are different types of FOBT in our screening program: quaiac tests, immunochemical tests unquantitative and quantitative tests. The role of general practitioners was enhanced by participation of the gynecologists in the colorectal cancer screening program due to low compliance of population. Alternative ways of distribution of FOBT to the patients are being considered as well. CONCLUSION: Participation of general gynecologists in the Czech colorectal cancer screening program is connected with a great expectation. We would like to achieve such compliance in colorectal cancer screening as there is in the screening of gynecological tumors. Using a right method of screening could play an important role in this process. PMID- 21650003 TI - [Spontaneous rupture of uterine vessels during pregnancy in a patient with previous endometriosis]. AB - Spontaneous rupture of the utero-ovarian vessels during pregnancy is a rare condition that can be life-threatening. Endometriosis is one of the factors associated with this complication of the pregnancy. Location of the pain as well as the course of this complication can simulate various diseases that must be dealt with. We describe the case associated with haemoperitoneum and hemorrhagic shock. PMID- 21650006 TI - [Pelletization of melts and liquids]. AB - During the second half of the last century, pelletization methods based on wetting were developed, e.g. agglomeration in coating pans, pelletization plates or fluid-bed equipment, layering of the drug in solution or suspension on inactive spherical cores, extrusion/spheronization and later on also rotoagglomeration in rotogranulators or rotoprocessors. These technologies have become a requisite part of industrial production of solid dosage forms. At present, numerous experimental papers deal with pellet preparation from melts and liquids. These new pelletization methods are the topic of the present article. Pellet preparation from melts is represented by three methods, i.e. fluid hot melt agglomeration, hot melt extrusion, and freeze pelletization. Jet cutting and cryopelletization are the techniques dealing with pellet preparation from liquids. PMID- 21650005 TI - [Myasthenia gravis--current treatment standards and emerging drugs]. AB - Myasthenia gravis is very rare autoimmune disease of neuromuscular junction, which presents as a weakness and increased fatiquability of striated muscles. Formerly, myasthenia was largely constraining disease and often ended by death. Recently, advanced diagnostic methods and variety of therapeutic options allow the full compensation of the disease and the quality of patient life is restored. In this review, the methods used during the myasthenia treatment along with the description of the disease itself were detailed. PMID- 21650007 TI - [Dyer's Greenweed (Genista tinctoria L.): constituents and biological activity]. AB - The paper aims to specify all important active principles in the herb Genista tinctoria which exert different biological activities. It also mentions the methods of chemical evaluation of these substances. PMID- 21650008 TI - [Bacteriocins produced by lactic acid bacteria]. AB - Lactic acid bacteria comprise several genera of gram-positive bacteria that are known for the production of structurally different antimicrobial substances. Among them, bacteriocins are nowadays in the centre of scientific interest. Bacteriocins, proteinaceous antimicrobial substances, are produced ribosomally and have usually a narrow spectrum of bacterial growth inhibition. According to their structure and the target of their activity, they are divided into four classes, although there are some suggestions for a renewed classification. The most interesting and usable class are lantibiotics. They comprise the most widely commercially used and well examined bacteriocin, nisin. The non-pathogenic character of lactic acid bacteria is advantageous for using their bacteriocins in food preservation as well as in feed supplements or in veterinary medicine. PMID- 21650009 TI - [Generic substitution, replacement and substitution of drugs: contemporary extent]. AB - When dispensing the medication, the dispensing chemist should inform the patient about the possible alternatives to the medicament dispensed and, with his consent, he can replace it with another preparation of identical properties (a generic drug, a bioequivalent preparation) in case it is not forbidden by the physician. A replacement of the prescribed drug is performed in the case that the required preparation is not in stock and its immediate dispensation is necessary. The present paper compares the prices of generics and original preparations and the extent of replacements and substitutions. The method employed was an analysis of data about dispensation in pharmacies. Of 61 generics under study, 10 preparations had a higher price than the original ones. Replacements and substitutions were monitored for a period of 1 year in preparations containing 14 selected active ingredients. Instead of the prescribed preparations containing omeprazole and ranitidine (26 HVLP), generics were dispensed in 31.0%, i.e. 157 cases (13 of it were substitutions). In the groups of drugs used for high blood pressure therapy (9 active ingredients, 63 kinds of mass-produced preparations), generics were dispensed in 14.5%, i.e. 120 cases (112 cases of it were substitutions). Instead of the prescribed preparations containing simvastatin, atorvastatin and fenofibrate (42 mass-produced preparations), generics were dispensed in 17.5%, i.e. 82 cases (67 cases of it were substitutions). The found percentage of realized generic substitutions is low (6.2%-28.0% according to the type of the active ingredient) when calculated to the total amount of the performed replacements and substitutions. PMID- 21650010 TI - [Study of local anaesthetics--Part 194. Evaluation of carbopol hydrogels with lidocaine]. AB - The objective of this article is to describe the formulation and evaluation of dermal semisolid drugs--carbopol hydrogels containing the solution of Bukofit, zinc chloride and the local anaesthetic lidocaine. The hydrogels were evaluated after 2, 7, 14 and 28 days after their preparation and stored at the temperature of 5 degrees C +/- 0.2 degrees C. All prepared hydrogels were found to be stable with respect to pH values and rheological parameters. It follows from the found rheological parameters and flow curves that all evaluated hydrogels belong to non Newtonian thixotropic systems. The extensometric analyses revealed increased deformation values, indicating that the gels can be easily spread out over the mucous membrane which results in the increased ability of the drug to diffuse into it. Based on the results obtained, it can be concluded that the prepared hydrogels have appropriate technological parameters and therefore in the future they may become potential drugs for the treatment of various inflammations in the oral cavity. PMID- 21650011 TI - [Analytical evaluation of mono[{3-[4-(2-etoxyetoxy)-benzoyloxy]-2-hydroxypropyl} isopropylammonium]fumarate]. AB - The present paper deals with a complex spectral and physicochemical evaluation of mono[{3-[4-(2-etoxyetoxy)-benzoyloxy]-2-hydroxypropyl} isopropylammonium]fumarate, a potential ultrashort acting beta1-blocker. The identity of the substance under study (labelled as UPB-1) was confirmed by 1H- and 13C-NMR spectra as well as IR spectrometry. The determined fundamental physicochemical characteristics included the determination of the melting point, solubility in a spectrum of solvents, verification of purity (adsorption thin layer chromatography), determination of surface activity (Traube's stalagmometric method), acidobasic characteristics (pK(a) value by means of alkalimetric titration), determination of log epsilon values using spectrophotometry in UV/VIS region, as well as the evaluation of the effect of acid and basic media on the stability of the substance under the study. Other experimentally determined parameters were lipohydrophilic characteristics essayed by means of RP-HPLC (log k'), and the shake-flask method was employed to determine the values of the partition coefficients P(exp) (resp. log P(exp)) in different lipohydrophilic media. On the basis of log P(exp-) data, the ability of the substance to penetrate the hematoencephalic barrier was predicted. To determine the UPB-1 content, RP-HPLC (reversed-phase HPLC) method of the internal standard and UV/VIS spectrophotometry at the wavelength of 260 nm (aqueous medium) and 258 nm (methanol medium) were used. PMID- 21650012 TI - [60 years of the journal Czech and Slovak Pharmacy]. PMID- 21650013 TI - [On teaching the chemistry of pharmaceutical auxiliary substances within the framework of pharmaceutical education in the Czech and Slovak Republics]. AB - The paper emphasizes the need of the introduction of the subject Chemistry of Pharmaceutical Auxiliaries into the Pharmacy study programme at more colleges in the Czech and Slovak Republics. It also introduces and discusses some topics for possible extension of the content of the courses of the subject (the presented examples are taken form the field of analytical chemistry of pharmaceutical auxiliaries). PMID- 21650014 TI - [Determination of nabumetone and 6-methoxy-2-naphthylacetic acid in plasma using HPLC with UV and MS detection]. AB - The study aimed to establish and validate an analytical method for the determination of nabumetone and 6-methoxy-2-naphthylacetic acid (6-MNA) in human plasma after a single therapeutic dose of the drug. Two methods based on HPLC with UV and MS detection were compared. Optimal results in sample preparation were achieved using solid phase extraction. The recovery reached approximately 84% and 86-90% for nabumetone and 6-MNA, respectively. A reverse C18 column was used for HPLC separation of the analytes. The limit of UV detection was 50 nM and 0.1 microM for 6-MNA and nabumetone, respectively. The limit of MS detection was 1 microM and 0.5 microM for 6-MNA and nabumetone, respectively. Precision ranged between 4.2-14.4% and 4.6-8.5% using UV and MS detection for nabumetone, respectively. The respective values for 6-MNA were 2.4-12.5% and 2.1-9.4%. Accuracy ranged between 93.4-109.6% in UV detection and 86.2-107.9% using UV and MS detection for nabumetone, respectively. The respective values for 6-MNA were 87.8-107.4% and 86.3-106.4%. The method was subsequently applied to determine the pharmacokinetic parameters of nabumetone and 6-MNA in a group of 24 healthy volunteers. PMID- 21650015 TI - [Determination of airborne and surface contamination with cyclophosphamide at the Masaryk Memorial Cancer Institute, Brno, Czech Republic]. AB - Manipulation with cytotoxic drugs (CDs) during the preparation and administration of chemotherapy to cancer patients can potentially lead to contamination of working areas and consequently to occupational exposure of hospital staff. This study aimed to assess the potential of inhalation and dermal contact with CDs. For this purpose, distribution of the marker drug (cyclophosphamide, CP) in the working environment of the Masaryk Memorial Cancer Institute (Czech Republic) was studied. The study determined airborne and surface contamination of the hospital pharmacy and the outpatient clinic. Determination of airborne contamination was based on active stationary sampling of air using a PTFE filter, an impinger filled with distilled water and two solid sorbent tubes (Anasorb 708 and Strata X) as sampling devices. Surface contamination was determined by the wipe sampling method. The airborne contamination was rare and the concentrations were many times lower than the maximal value calculated from the vapour pressure (0.36 mg/m3 at 20 degrees C). Detectable airborne CP was found in Strata-X samples collected at the outpatient clinic (n = 5, all samples positive at concentrations from 0.3 to 4.3 ng/m3). Surface contamination was determined at 75% of wipe samples (n = 65) with a median concentration of 750 ng/m2. In conclusion, inhalation of CDs seems to be of low importance at our hospital, which is up to the standard specified by current legislation (drug preparation performed in a clean room equipped with negative pressure isolators). The main proportion of contamination was present on the surfaces at all workplaces studied. Consequently, attention should be given to the elimination of the sources of surface contamination and to the prevention of dermal contact with contaminated material. PMID- 21650016 TI - [Basic rules for decision making at the bedside. Model for diagnostic reasoning based on Bayesian theory]. PMID- 21650017 TI - [Preface for special issue on bioenergy]. AB - More and more attentions have been being paid to seeking alternatives for fossil fuels. Bioenergy, as a renewable energy, is one of the best solutions. Bioenergy has been developed rapidly in China, which became the third largest producer and consumer of fuel ethanol. In order to promote the research of bioenergy technology in China, this special issue includes latest reports and articles on the fields of bioethanol, biodiesel, microbial lipid and biofuel system analysis. PMID- 21650018 TI - [Fractionating pretreatment of sugarcane bagasse for increasing the enzymatic digestibility of cellulose]. AB - During the bioconversion of lignocellulose to ethanol, the biomass always undergoes pretreatment in order to increase the enzymatic digestibility of cellulose. In present work, we conducted the pretreatment of sugarcane bagasse with aqueous acetic acid for delignification and alkali for deacetylation respectively (Acetoline process) to increase cellulose accessibility for enzymatic hydrolysis. The effects of several factors on the pretreatment effectiveness were investigated. The enzymatic digestibility of pretreated bagasse was further studied. The enzymatic glycan conversion of pretreated solid reached about 80% when it was digested under 7.5% solid consistency with cellulase of 15 FPU/g solid and beta-glucosidase of 10 CBU/g solid for 48 h. Compared with dilute acid pretreatment, Acetoline pretreatment could obtain higher enzymatic glycan conversion. The experimental results indicate that Acetoline is an effective pretreatment method to increase the enzymatic digestibility of sugarcane bagasse. PMID- 21650019 TI - [Optimization of corn stover hydrolysis by fed-batch process]. AB - High-concentration sugars production from stover is an important perspective technology for the cellulosic ethanol industrialization. Fed-batch process is an effective way to achieve this goal in the fermentation industry. In this study, based on fed-batch process, high-concentration sugars were produced from pretreated corn stover by enzymatic hydrolysis. After being pretreated by the dilute sulphuric acid, the impacts of the ratio of solid raw material to liquid culture, the content of supplementary materials and the refilling time on the saccharification rate were investigated. Results showed that the initial ratio of solid raw material to liquid culture was 20% (W/V) and the initial concentrations of enzymes for xylanase, cellulose and pectinase were 220 U, 6 FPU, and 50 U per gram of substrates, respectively. After 24 hours and 48 hours, 8% pretreated corn stovers were added respectively together with the additions of xylanase (20 U) and cellulose (2 FPU) per gram of substrates. After 72 hours, the final concentration of reducing sugar was increased to 138.5 g/L from 48.5 g/L of the non fed-batch process. The rate of enzyme hydrolysis of the raw material was 62.5% of the thoretical value in the fed-batch process. This study demonstrated that the fed-batch process could significantly improve the concentration of reducing sugar. PMID- 21650020 TI - [Influence of ZSM-5(38)/Al-MCM-41 composite molecular sieve catalysts on pyrolysis of cellulose]. AB - Pyrolysis of cellulose with different catalysts has been conducted in a fixed-bed reactor. Micro-mesoporous composite molecular sieves of ZSM-5(38)/A1-MCM-41 with different Si/A1 ratios were prepared under hydrothermal conditions. With powder X ray diffraction (XRD), the catalyst samples were characterized. GC-MS was used to analyze the bio-oil composition. The effects of catalysts on the pyrolysis product yields were investigated and the results were compared with the results of experiments performed without catalyst under the same pyrolitic conditions. The presence of the catalysts decreased the liquid yield, while increased the moisture content. The major improvement in the quality of bio-oil with the use of catalysts was the increase of DL-2,3-Butanediol. ZSM-5(38)/A1-MCM-41(20) favored the formation of phenol and 2-methoxy-phenol. In addition, these catalysts were all benefit for the generation of small molecular compounds. Also, it was found that ZSM-5(38) was better for the production of C4-C5 compounds. And micro mesoporous composite molecular sieves mainly promoted the production of C6-C8 compounds. PMID- 21650021 TI - [Optimization of xylose fermentation for ethanol production by Candida shehatae HDYXHT-01]. AB - Plackett-Burman (PB) design and central composite design (CCD) were applied to optimize of xylose fermentation for ethanol production by Candida shehatae HDYXHT 01. The PB results showed that (NH4)2SO4, KH2PO4, yeast extract and inoculum volume were the main affecting factors. With ethanol productivity as the target response, the optimal fermentation was determined by CCD and response surface analysis (RSM). The optimal fermentation conditions were (NH4)2SO4 1.73 g/L, KH2PO4 3.56 g/L, yeast extract 2.62 g/L and inoculum volume 5.66%. Other fermentation conditions were xylose 80 g/L, MgSO47H20 0.1 g/L, pH 5.0 and 250 mL flask containing 100 mL medium and cultivated at 30 degrees C for 48 h and the agitation speed was 140 r/min. Under this fermentation conditions, ethanol productivity was 26.18 g/L, which was 1.15 times of the initial. PMID- 21650022 TI - [Optimization of ethylene production from ethanol dehydration using Zn-Mn-Co/HZSM 5 by response surface methodology]. AB - The effects of reaction temperature, ethanol concentration and weight hourly space velocity (WHSV) on the ethylene production from ethanol dehydration using zinc, manganese and cobalt modified HZSM-5 catalyst were investigated by response surface methodology (RSM). The results showed that the most significant effect among factors was reaction temperature and the factors had interaction. The optimum conditions were found as 34.4% ethanol concentration, 261.3 0 degrees C of reaction temperature and 1.18 h(-1) of WHSV, under these conditions the yield of ethylene achieved 98.69%. PMID- 21650023 TI - [Fermentation optimization by response surface methodology for enhanced production of beta-glucosidase of Aspergillus niger HDF05]. AB - In order to obtain high beta-glucosidase productivity, we optimized the fermentation parameters for beta-glucosidase production by Aspergillus niger HDF05. First, we screened the important parameters by Plackeet-Burman design. Second, we used the path of steepest ascent to approach to the biggest response region of parameters affecting beta-glucosidase production. Then, we obtained the optimal parameters by central composite design and response surface analysis. We developed a quadratic polynomial equation for predicting beta-glucosidase production level. The results showed that the important parameters were temperature, packing volume, concentrations of wheat bran and (NH4)2SO4. The optimal fermentation parameters were as follows: temperature 28 degrees C, packing volume 71.4 mL/250 mL, wheat bran 36 g/L and (NH4)2SO4 5.5 g/L. Under the optimal conditions, we obtained the maximum enzyme activity of 60.06 U/mL, with an increase of 23.9% compared to the original fermentation parameters. During enzymatic hydrolysis of acid-pretreated corncob, addition of beta-glucosidase from Aspergillus niger HDF05 greatly reduced the inhibition caused by cellobiose, and the hydrolysis yield was improved from 66.7% to 80.4%. PMID- 21650024 TI - [Progress in bioenergy-oriented microbial lipid technology]. AB - Microbial lipid is a potential raw material for biofuel industry. In this review, we summarized recent progress in microbial lipid production by oleaginous fungi in terms of identifying cheap feedstock, developing robust lipid producer, establishing novel strategies and better culture modes for cellular lipid accumulation, as well as revealing the molecular mechanism of oleaginity. We discussed issues, solutions and directions for further development of microbial lipid technology. PMID- 21650025 TI - [Effect of inorganic carbon source on lipid production with autotrophic Chlorella vulgaris]. AB - We studied the effects of three inorganic carbon sources, Na2CO3, NaHCO3 and CO2, and their initial concentrations on lipid production of Chlorella vulgaris. Chlorella vulgaris could utilize Na2CO3, NaHCO3 and CO2 to produce lipids. After 10-day cultivation with each of the three inorganic carbon sources, lipid yield of Chlorella vulgaris reached its peak with the concentration increase of the inorganic carbon source, but dropped again by further increase of the concentration. The pH value of the culture medium for Chlorella vulgaris increased after the cultivation on inorganic carbon source. The optimal concentration of both Na2CO3 and NaHCO3 was 40 mmol/L, and their corresponding biomass dry weight was 0.52 g/L and 0.67 g/L with their corresponding lipid yield 0.19 g/L and 0.22 g/L. When the concentration of CO2 was 6%, Chlorella vulgaris grew the fastest and its biomass dry weight was 2.42 g/L with the highest lipid yield of 0.72 g/L. When the concentration of CO2 was too low, the supply of inorganic carbon was insufficient and lipid yield was low. A too high concentration of CO2 caused a low pH and lipid accumulation was inhibited. Na2CO3 and NaHCO3 were more favorable for Chlorella vulgaris to accumulate unsaturated fatty acids than that of CO2. PMID- 21650026 TI - [Cultivating an oleaginous microalgae with municipal wastewater]. AB - Municipal wastewater is usually problematic for the environment. The process of oleaginous microalgal culture requires large amounts of nutrients and water. Therefore, we studied the feasibility of oleaginous microalgal culture of Scenedesmus dimorphus in bubbled column photobioreactor with municipal wastewater added with different nutrients. S. dimorphus could adapt municipal nutrient-rich wastewater by adding some nutrients as nitrogen, phosphorus, ferric ammonium citrate and trace elements, and the amounts of such nutrients have significant effects on cell growth, biomass yield and lipid accumulation. At optimum compositions of wastewater medium, the algal cell concentration could reach 8.0 g/L, higher than that of 5.0 g/L in standard BG11. Furthermore, S. dimorphus had strong capacity to absorb inorganic nitrogen and phosphorus from its culture water. There was almost no total nitrogen and phosphorus residues in culture medium after three or four days culturing when the adding mounts of nitrate and phosphate in wastewater medium were no more than 185.2 mg/L and 16.1 mg/L respectively under the experimental conditions. As a conclusion, it was feasible to cultivate oleaginous microalgae with municipal nutrient-rich wastewater, not only producing feedstock for algal biodiesel, but also removing inorganic nitrogen and phosphorus from wastewater. PMID- 21650027 TI - [Microbial oil production by Trichosporon cutaneum B3 using cassava starch]. AB - Microbial oil, as raw material for biodiesel, can be produced by Trichosporon cutaneum B3 using cassava starch hydrolysate. Batch cultures demonstrated that there was little inhibitory effect with the concentration of cassava starch hydrolysate up to 90 g/L. The favorable initial pH, C/N molar ratio, nitrogen source and its concentration were 6.0, 116, yeast extract and 3.0 g/L, respectively. Under the optimized conditions, dry biomass reached 15.2 g/L and lipid content reached 40.9% after culture for 144 h in flask. Batch cultures in a 2 L stirred-tank fermenter were run for 44 h and resulted in dry biomass, lipid content and lipid yield of 28.7 g/L, 42.8% and 12.27 g/L, respectively. The chemical compositions of biodiesel prepared from lipids of T cutaneum B3 mainly included palmitic acid methyl ester, stearic acid methyl ester, oleic acid methyl ester and linoleic acid methyl ester etc., and its main physicochemical properties were in compliance with relevant national diesel standards. Therefore, the biodiesel prepared from lipids of T cutaneum B3 can serve as a potential fossil fuel alternatives. PMID- 21650028 TI - [Operating conditions for the rapid mutation of the oleaginous yeast by atmospheric and room temperature plasmas and the characteristics of the mutants]. AB - To obtain oleaginous yeast mutants with improved lipid production and growth rates, an atmospheric and room temperature plasma (ARTP) jet was used with a 96 well plate for high throughput screening. Mutants with changes in growth rates and lipid contents were obtained. At a lethality rate of 99%, the positive mutation rate of the yeast cells was 27.2% evaluated by the growth rates of the mutants and the comparison with the wild strain. The fermentation in a medium composed of yeast extract (10 g/L), peptone (10 g/L) and D-glucose (20 g/L) resulted in the lipid yield of the mutant (C4) with 4.07% (W/W) compared with that of the wild strain (1.87%). PMID- 21650029 TI - [Screening of high lipid production Trichosporon fermentans mutants by transposon tagging mTn-lacZ/leu2 insertion]. AB - To improve microbial lipid production, we inserted mTn-lacZ/leu2 into Trichosporon fermentans 2.1368-Leu(-) to obtain high lipid production mutants. By observing the LacZ chromogenic change, the positive reaction between Cerulenin (inhibitor of fatty acid synthase) and phosphate vanillin, a higher lipid producing mutant 2.1368-Leu(-)-7 grown on corn-stalk hydrolysate was obtained. The lipid content of this mutant reached 38.30% (8.97% higher than that of the control) and the lipid production rate was 8.35% (20.63% higher than that of the control). The rate of sugar utilization was 77%, meaning that 100 g corn-stalk could be converted to 8.32 g lipid. The study provided an effective method for microbial lipid production by using cheap raw materials for biodiesel. PMID- 21650030 TI - [Bio-oil production from biomass pyrolysis in molten salt]. AB - In order to investigate the effects of pyrolysis conditions on bio-oil production from biomass in molten salt, experiments of biomass pyrolysis were carried out in a self-designed reactor in which the molten salt ZnCl2-KCl (with mole ratio 7/6) was selected as heat carrier, catalyst and dispersion agent. The effects of metal salt added into ZnCl2-KCl and biomass material on biomass pyrolysis were discussed, and the main compositions of bio-oil were determined by GC-MS. Metal salt added into molten salt could affect pyrolysis production yields remarkably. Lanthanon salt could enhance bio-oil yield and decrease water content in bio-oil, when mole fraction of 5.0% LaCl3 was added, bio-oil yield could reach up to 32.0%, and water content of bio-oil could reduce to 61.5%. The bio-oil and char yields were higher when rice straw was pyrolysed, while gas yield was higher when rice husk was used. Metal salts showed great selectivity on compositions of bio oil. LiCl and FeCl2 promoted biomass to pyrolyse into smaller molecular weight compounds. CrCl3, CaCl2 and LaCl3 could restrain second pyrolysis of bio-oil. The research provided a scientific reference for production of bio-oil from biomass pyrolysis in molten salt. PMID- 21650031 TI - [Heat-alkaline treatment of excess sludge and the potential use of hydrolysate as nitrogen source for microbial lipid production]. AB - To recover and use protein resources in excess sludge and decrease the cost of microbial lipid production, heat-alkaline was used to treat the sludge, and the hydrolysate was preliminarily used as nitrogen source to cultivate Rhodosporidium toruloides AS 2.1389 for lipid accumulation. Firstly, we treated the excess sludge under different alkaline conditions (pH 10, pH 12, pH 13) within the reaction time of 5-10 h to investigate the effect of nitrogen source release. Secondly, we used the sludge hydolysate to culture R. toruloides AS, and test the effect on cell growth. Results showed that treatment of excess sludge at pH 13 for 5 h was the most effective for nitrogen release. However, the hydrolysate obtained at pH 10 (5 h) was the most suitable for culturing R. toruloides AS, and under this condition, the inner-cellular lipid content could reach 35% of the total biomass weight. PMID- 21650032 TI - [Comparison of 2,3-butanediol production by several strains and optimization of the fermentation medium]. AB - Five Klebsiella pneumonia strains (including two strains whose genes for lactic acid were knocked out) were used to produce 2,3-butanediol, in which K. pneumonia HR521 LDH (gene for lactic acid was knocked out) was the best for the production, and then the fermentation medium was optimized by orthogonal design. The optimum compositions were as follows: glucose 90 g/L, (NH4)2HPO4 3 g/L, CLSP 6 g/L, sodium acetate 5 g/L, KCl 0.4 g/L, MgSO4 0.1 g/L, FeSO4 x 7H2O 0.02 g/L, MnSO4 0.01 g/L. Under the above conditions, final concentration of acetone and 2,3 butanediol could reach 37.46 g/L, 10 g/L higher than that under the initial conditions, the yield was 90.53% of the theory, and the productivity was 1.5 g/(L h), and no lactic acid was detected, which could be benefit for the downstream processing and industrial application. PMID- 21650033 TI - [Progress in down-stream processing of biologically produced 1,3-propanediol]. AB - 1,3-propanediol is an important raw material in chemical industry. Microbial conversion of glycerol or glucose into 1,3-propanediol has been given much attention due to its renewable resource, mild reaction conditions, and other advantages. It is a challenge to efficiently separate 1,3-propanediol from a mixture of multiple components, such as 1,3-propanediol, 2,3-butanediol, water, residual glycerol, ethanol, macromolecules and salts, for the reason that 1,3 propanediol, glycerol and 2,3-butanediol are all very hydrophilic and have intense polarity. The conventional evaporation and distillation techniques used in the purification of 1,3-propanediol suffer from the problem of high energy consumption and low recovery. It makes the recovery of 1,3-propanediol from a fermentation broth become a bottleneck in industrial production. The down-stream processing of biologically produced 1,3-propanediol mainly includes the removal of protein, salts, water and other impurities. This paper analyze the research progress of these separation technologies and point out the developing direction worth further investigation. PMID- 21650034 TI - [Model-based biofuels system analysis: a review]. AB - Model-based system analysis is an important tool for evaluating the potential and impacts of biofuels, and for drafting biofuels technology roadmaps and targets. The broad reach of the biofuels supply chain requires that biofuels system analyses span a range of disciplines, including agriculture/forestry, energy, economics, and the environment. Here we reviewed various models developed for or applied to modeling biofuels, and presented a critical analysis of Agriculture/Forestry System Models, Energy System Models, Integrated Assessment Models, Micro-level Cost, Energy and Emission Calculation Models, and Specific Macro-level Biofuel Models. We focused on the models' strengths, weaknesses, and applicability, facilitating the selection of a suitable type of model for specific issues. Such an analysis was a prerequisite for future biofuels system modeling, and represented a valuable resource for researchers and policy makers. PMID- 21650035 TI - [The water content reference material of water saturated octanol]. AB - The national standards of biofuels specify the technique specification and analytical methods. A water content certified reference material based on the water saturated octanol was developed in order to satisfy the needs of the instrument calibration and the methods validation, assure the accuracy and consistency of results in water content measurements of biofuels. Three analytical methods based on different theories were employed to certify the water content of the reference material, including Karl Fischer coulometric titration, Karl Fischer volumetric titration and quantitative nuclear magnetic resonance. The consistency of coulometric and volumetric titration was achieved through the improvement of methods. The accuracy of the certified result was improved by the introduction of the new method of quantitative nuclear magnetic resonance. Finally, the certified value of reference material is 4.76% with an expanded uncertainty of 0.09%. PMID- 21650036 TI - [Life cycle assessment of energy consumption and greenhouse gas emissions of cellulosic ethanol from corn stover]. AB - Life Cycle Assessment (LCA) is the only standardized tool currently used to assess environmental loads of products and processes. The life cycle analysis, as a part of LCA, is a useful and powerful methodology for studying life cycle energy efficiency and life cycle GHG emission. To quantitatively explain the potential of energy saving and greenhouse gas (GHG) emissions reduction of corn stover-based ethanol, we analyzed life cycle energy consumption and GHG emissions of corn stover-based ethanol by the method of life cycle analysis. The processes are dilute acid prehydrolysis and enzymatic hydrolysis. The functional unit was defined as 1 km distance driven by the vehicle. Results indicated: compared with gasoline, the corn stover-based E100 (100% ethanol) and E10 (a blend of 10% ethanol and 90% gasoline by volume) could reduce life cycle fossil energy consumption by 79.63% and 6.25% respectively, as well as GHG emissions by 53.98% and 6.69%; the fossil energy consumed by biomass stage was 68.3% of total fossil energy input, N-fertilizer and diesel were the main factors which contributed 45.78% and 33.26% to biomass stage; electricity production process contributed 42.06% to the net GHG emissions, the improvement of technology might reduce emissions markedly. PMID- 21650038 TI - [Metabolic pathway of polyamines in plants: a review]. AB - Polyamine is an important physiological regulation substance functioning in a wide variety of biological processes, such as plant growth, development, senescence and adversity stress tolerance, which widely exist in all living organisms. Their biosynthetic pathways have already been revealed, and their physiological roles are being elucidated gradually. Previous work on polyamines biosynthetic deficiency mutants and various transgenic plants facilitates improved understanding of the important roles of polyamines and biosynthetic enzymes in plant growth and development. This paper summarizes researches in the biosynthetic pathways of polyamines in plants, focusing on research advances on functions of genes involved in polyamine metabolism. In addition, the potential research directions, especially the application of the genes in the genetic engineering of plant stress tolerance were also discussed. PMID- 21650037 TI - [Kunjin virus replicon--a novel viral vector]. AB - Viral replicon is a kind of self-replicating viral RNA sourced from viral genome, which contains viral non-structural genes that are critical for viral genome replication with structural proteins deleted or replaced by foreign genes. Kunjin virus is a member of the Flavivirida family, Flavivirus genus, and Kunjin virus replicon is the first and the clearly defined flavivirus replicon. Kunjun virus replicon has been regarded as an excellent viral vector on account of its high expression, lower cytotoxicity and genetic stability. These unique characteristics of kunjin virus replicons make them suitable for the study of viral genome replication, recombinant proteins production, vaccine development and gene therapy. In this article, recent progress in the development, properties and applications of kunjin virus replicon system was briefly reviewed. PMID- 21650039 TI - [Structure, catalytic mechanism and applications of laccases: a review]. AB - Laccases (benzenediol: oxygen oxidoreductases; EC 1.10.3.2) are copper-containing polyphenol oxidases that can oxidize a wide range of aromatic compounds, concomitantly with the transfer of four electrons and the reduction of molecular oxygen to water. The progress on the research of laccases structure and function is reviewed. Their three-dimensional structures and catalytic mechanism, as well as their applications in different fields are emphasized. PMID- 21650040 TI - [Progress in biofixation of CO2 from combustion flue gas by microalgae]. AB - Global warming caused by the increasing CO2 concentration in atmosphere is a serious problem in the international political, economic, scientific and environmental fields in recent years. Intensive carbon dioxide capture and storage (CCS) technologies have been developed for a feasible system to remove CO2 from industrial exhaust gases especially for combustion flue gas. In these technologies, the biofixation of CO2 by microalgae has the potential to diminish CO2 and produce the biomass. In this review, the current status focusing on biofixation of CO2 from combustion flue gases by microalgae including the selection of microalgal species and effect of flue gas conditions, the development of high efficient photobioreactor and the application of microalgae and its biomass product were reviewed and summarized. Finally, the perspectives of the technology were also discussed. PMID- 21650041 TI - [Application of human mucosal explants culture in the HIV-1 sexual transmission]. AB - Sexual transmission has become the major route of acquiring human immunodeficiency virus type 1 (HIV-1) globally. Understanding the mechanism of HIV-1 mucosal infection will be helpful for development of new effective strategies to block HIV-1 mucosal transmission. Currently, study of the mechanism of Hiv-1 mucosal infection majorly depends on in vitro cell culture systems and non-human primate animal models. Recently, a novel tissue explant model (including human vaginal-genital and colorectal tissue) was established, which could elucidate the biological process of HIV-1 mucosal infection from crossing over the membrane to reaching the basal. Therefore, the model can be applied to the study of mechanism, as well as the safety and efficacy evaluation in pre clinical study of biomedical prevention strategies. In this review, we summarized the recent progress about human mucosal explants model including the sources of tissues, technical characteristics and their application to study the mechanism of HIV-1 sexual transmission and evaluation of prevention strategies. Based on our recent study results, we also provided our opinions about development of novel explant models and their application. PMID- 21650042 TI - [Enhanced storage stability of recombinant enzyme preparation of alpha-CGTase from Paenibacillus macerans by chemical additives]. AB - To enhance the thermostability and storage stability of alpha-cyclodextrin glycosyltransferase (a-CGTase), we added specific chemical additives into the preparation of alpha-CGTase, and studied the effect of additives on the storage stability of alpha-CGTase at different temperatures. Then we measured the protein structure of CGTase in the far UV (200-250 nm) and near UV (250-320 nm) ranges respectively by Circular dichroism (CD) spectra under high temperature and analyzed the relationship between thermostability and protein structure. The results indicated that the addition of selected additives (gelatin, glycerin, CaCl2 and PEG400) enhanced the thermostability of alpha-CGTase dramatically. After 45 days, the preparation of alpha-CGTase still had 100% of the enzyme activity with different additives superimposed at the optimum concentration at 40 degrees C. The CD spectra of alpha-CGTase showed that glycerin could protect the secondary and the tertiary structure of the CGTase under high temperature and therefore the enzyme maintained its high activity. Chemical additives can improve the stability of alpha-CGTase significantly and they preserve the enzyme activity by protecting its secondary structure. PMID- 21650043 TI - [Synergistic effect of amorpha-4,11-diene synthase gene in engineered Saccharomyces cerevisiae]. AB - To construct an engineered Saccharomyces cerevisiae producing high titres of amorpha-4,11-diene, we investigated the possible synergistic effect of different vectors containing amorpha-4,11-diene synthase(ADS) gene within one yeast cell. We constructed the ADS recombinant plasmid pGADADS. This plasmid and another ADS recombinant plasmid pYeDP60/G/ADS were alone, or co-transformed into yeast Saccharomyces cerevisiae W303-1B and WK1, respectively, resulting in the following engineered yeasts, W303B[pGADADS], W303B[pYGADS], W303B[pYGADS+pGADADS], WK1[pGADADS], WK1[pYGADS] and WK1[pYGADS+pGADADS]. All of the six strains were cultured for GC-MS analysis of amorpha-4,11-diene. The results showed that all of the engineered yeasts could produce amorpha-4,11 diene. The yield of the product was improved with increasing ADS gene copies while no deleterious effect on the strain growth was found. Moreover, the product yield of the engineered yeast co-transformed with multiple plasmids was much higher than the total yield of the different engineered yeasts with only one plasmid, respectively. In conclusion, there was a distinct synergistic effect between different recombinant ADS plasmids within one cell. Our results facilitate the construction of the engineered yeast with high yield of amorpha 4,11-diene, the precursor of artemisinin. PMID- 21650044 TI - [Medium optimization for antagonistic Streptomyces S24 and its inhibition on Aspergillus flavus]. AB - Streptomyces S24 has broad spectrum against Aspergillus spp. in food and feed, such as Aspergillus flavus, Aspergillus niger and Asperegillus alutacells. The objective of this study was to improve the production of antifungal substances produced by S24 and to test their inhibitory effects on Aspergillus flavus. By using one-factor-at-a-time experiment and orthogonal design method, we optimized the fermentation medium. The composition of an optimized medium for the production of antifungal substances contained (g/L): starch soluble, 10; Glucose, 40; yeast extract, 8; soybean powder, 24; KH2PO4 4; and CaCO3 0.8. As a result, the productivity of antifungal substances could reach to 10 235.45 microg/mL, and this value was 2.81 times higher than that of initial medium before optimization. Additionally, inhibitory effects of the products on Aspergillus flavus were analyzed. Antagonistic tests indicated that the antifungal substances greatly inhibited mycelium growth and spores germination of Aspergillus flavus. We observed through microscope that the mycelia grew abnormally, such as contorting, bulging, vacuole increasing and the cytoplasmic contents inside effusing and the spores appeared unusual, such as gathering, deforming, cytoplasmic contents inside effusing and fracturing. PMID- 21650045 TI - [Implication of post-translational modifications in suppressor activity and stability of the Cucumber mosaic virus 2b protein]. AB - To gain insights into the function of potential post-translational modifications on the activity of the Cucumber mosaic virus (CMV)-encoded silencing suppressor protein 2b, one predicted phosphorylation site (S40) and two predicted ubiquitination/sumoylation sites (K22 and K39) in CMV-Q2b protein were individually or simultaneously mutated by site-directed mutagenesis methods. These Q2b mutants were inserted into plant expression vectors, expressed in plant leaves, and then analyzed for their silencing suppressor activities. The results showed that S40A mutation greatly impaired both the local and systemic silencing suppressor activity, and the K22R mutation has no significant effect on the suppressor activity, while the K22R/K39R double mutation reduced the systemic silencing suppressor activity. To test if the decrease of suppressor activity were due to protein accumulation changes, western blot were performed to monitor the protein level of Q2b mutants. The results indicated that mutations of both K22 and K39 to R or S40 to A all significantly reduced the accumulation of the Q2b protein in plants, while the single mutation of K22 to R did not alter the accumulation of Q2b protein, suggesting that two potential post-translational modification sites, K39 and S40, contribute to the suppressor activity and stability of 2b protein in plant cells. PMID- 21650046 TI - [Expression of anti-avian influenza virus H5N1 secretory IgA in Chinese hamster ovary cells]. AB - Secretory IgA (SIgA) antibodies in external secretions play an important role in mucosal immune response. Polymeric SIgA was advantageous over monomeric IgA (mIgA) and IgG in several aspects. To express secretory IgA antibody against H5N1 virus, we constructed the secretory component and immunoglobulin J expressing plasmids and co-transfected the plasmids into the Chinese hamster ovary cells (CHO) stably expressing immunoglobulin A. Then we used Zeocin to select the positive clone cells, monoclonal cells stably secreting SIgA was screened through fold dilution method at last. The SIgA antibody secreted from the CHO cells was confirmed by Western blotting, which demonstrated that we had got the complete SIgA molecular. The successful expression of this polymeric anti-H5N1 SIgA in CHO cells will contribute to the production of recombinant SIgA as a preventive agent for infectious disease control. PMID- 21650047 TI - [Production and immunogenicity analysis of conformation-stable fragment-C mutant of tetanus toxin]. AB - Tetanus is caused by tetanus toxin synthesized by Clostridium tetani. Fragment C (Hc), the 50 kDa carboxy-terminal portion of tetanus toxin, is nontoxic but has receptor protein binding activities, which has been evaluated as a potential new recombinant subunit vaccine to replace the traditional formaldehyde inactivated toxoid vaccine. It is easy for wild Hc (HcW) to form inter- and intra-molecular disulfide bonds and the different conformations changes unstably, which brings difficulties for vaccine production technology. In our study, the Cys 869 of HcW was mutated to A1a and the conformation-stable fragment-C mutant of tetanus toxin (HcM) was constructed. The HcM was expressed, fermented and purified and its stability, receptor binding and immunogenicity were evaluated. The result showed that the HcM got high-level expression and was purified to > 95% of purity. The purified HcM was conformation-stable at different temperature for different time and kept the binding activities with one of its receptor GT1b. Mice given three vaccinations by HcM developed a protective immune response and were 100% protected against an intraperitoneal administration of 1 x 10(3) 50% lethal doses (LD50s) of tetanus neurotoxin. All the results showed that the conformation stable HcM had potent immunogenicity as a recombinant tetanus vaccine candidate with simple production process and similar immunogenicity with HcW. Whether for routine tetanus therapy or for countries to respond to unexpected events (war, earthquake or other disaster), it is of great significance. PMID- 21650048 TI - [Inhibitory effect of bone sialoprotein silencing on the adhesion ability of breast cancer cells to bone matrix]. AB - We performed this research mainly to explore the effect of bone sialoprotein (BSP) silence by siRNA on the adhesion ability to bone matrix of bone-seeking breast cancer cells (MDA-MB-231BO). Also we aimed to provide experimental data for prevention and treatment of breast cancer bone metastasis by targeting BSP. We explored the effects of BSP gene silence on characteristics of bone-seeking breast cancer cells: proliferation by MTS[3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay, bone adhesion ability by a mouse bone adhesion model in vitro, morphology of the cells by SEM, and secretion of transforming growth factor-beta1 (TGF-beta1) and receptor activator of nuclear factor-kappa B ligand (RANKL) by ELISA kits. We performed intra-cardiac injection in nude mice to explore bone metastatic ability of different cell lines. The results showed that knockdown of BSP significantly inhibited the proliferation of MDA-MB-231BO cells and their adhesion to bone matrix. We also observed bone destruction caused by bone resorption around some adhering cells. The appearances of the cells changed in BSP gene silenced group, and the secretion of TGF-beta1 and RANKL decreased. The results showed BSP gene silence can partial inhibition bone metastasis of breast cancer cells in nude mice by X-ray assay and hematoxylin-eosin staining. Based on our research, siRNA mediated BSP silencing can inhibit proliferation and adhesion to bone matrix of bone-seeking breast cancer cells and change their surface structure, thus inhibits their bone metastatic ability. PMID- 21650049 TI - [Evaluation of the critical process parameters for the cultivation of recombinant Chinese hamster ovary cells in serum-free fed-batch mode]. AB - Taking a suspension adapted recombinant CHO cell line, 11G-S expressing human Pro urokinase (Pro-UK) as the object of study, the impacts of different feeding nutrients, the start time of feeding and cell inoculation density on the growth and Pro-UK production of 11G-S cells in serum-free fed-batch culture were evaluated in 100 mL shacking flasks. The results indicated that amino acids, serum-free supplements and inorganic salts played important role in cell growth, cell viability and protein expression. And the effects of cells fed-batch culture was much better with the initial cell inoculation density at 3 x 10(5)-4 x 10(5) cells/mL and the start time of feeding set at 72 h, a maximum viable cells density of 7.8 x 10(6) cells/mL with a peak Pro-UK activity at 8570 IU/mL was achieved during 12 d fed-batch culture. Further, the mu of the 11G-S cells at the middle phase of the fed-batch culture, and both the q(glu) and q(gln) of the 11G S cells at the middle and later phases of the fed-batch culture was higher than that of the 11G-S cells at the same phase of the batch culture, respectively. PMID- 21650050 TI - [Pilot-scale production of recombinant plasmid pUDK-HGF]. AB - pUDK-HGF, the recombinant plasmid DNA encoding human hepatocyte growth factor (HGF), can treat ischaemic disease. A great quantity of pharmaceutical pUDK-HGF is needed. A pilot-scale production process of pUDK-HGF was established based on a new chromatographic media (plasmidselect), including fermentation, cell harvesting, alkaline lysis, ultrafiltration, RNA removing and buffer exchanging on Sephacryl S-1000, capturing supercoiled plasmid DNA with plasmidselect, and removing the salt with Sepharose 6BFF. The process does not use RNase enzyme and toxic solvents. PMID- 21650051 TI - [Construction and identification of mammary expressional vector for cDNA of human lactoferrin]. AB - The aim of this study was to construct a mammary gland-specific expressional vector pBC1-hLF-Neo for Human Lactoferrin (hLF) gene and then investigate its expression in the mammary gland epithelium cells. The constructed vector contained the 6.2 kb long 5' flank regulation region including promoter, other elements and the 7.1 kb long 3' flank regulation region including transcriptional ending signal of a goat's beta-casein gene. A cassette of Neo gene was also inserted into the vector which gave a total length of 26.736 kb identified by restriction fragment analysis and partial DNA sequencing. The results revealed that the structure of the final constructed vector accords with the designed plasmid map. In order to analyze the bioactivity of the vector, we transfected the lined vector DNA into the dairy goat's mammary gland epithelium cells and C127 cells of a mouse's mammary epithelium by Lipofectamine. After selection with G418 for 8-10 days, G418-risistant clones were obtained. PCR analysis demonstrated that hLF gene cassette had been integrated into the genomic DNA of G418-risistant clones. After proliferation culture, the two kinds of transgenic cells were cultured in serum-free DMEM-F12 medium with prolactin, insulin and hydrocortisone- a medium capable of inducing recombinant hLF expression. RT-PCR, Western blotting and anti-bacteria bioactivity experiments demonstrated that the constructed mammary gland specific vector pBC1-hLF-Neo possessed the desirable bioactivity to efficiently express and could secrete hLF in both mammary gland cells and have the effect of E. coli proliferation inhibition. Paramount to everything, this study laid a firm foundation for preparing the hLF gene transgenic goat fetal-derived fibroblast cells. PMID- 21650052 TI - [Expression and characterization of Huwentoxin-XI (HWTX-XI) and its mutants]. AB - Huwentoxin-XI (HWTX-XI) is a protein isolated from the crude venom of spider Ornithoctonus huwena. It has 55 amino acid residues containing 6 cysteine residues forming 3 disulfide bonds. It shows potent inhibitory effect on trypsin and voltage-gated potassium channels in rat dorsal root ganglion cells. According to the structure-function relationship of HWTX-XI, we designed two mutants through mutation of potassium channel inhibition related amino acid residues (R5I, R10T,R25A and R5I,R25A) and then expressed them with high purity by using the vector pVT102U on Saccharamyces cerevisiae strain S78; The two mutants had the same trypsin inhibition activity as HWTX-XI, whereas their potassium channel inhibition activity and animal toxicity were much lower than those of HWTX-XI. This study is helpful for designing drugs of trypsin related diseases based on HWTX-XI. PMID- 21650053 TI - [Expression and antiviral assay of bovine interferon-gamma]. AB - Bovine interferon-gamma (BoIFN-gamma) gene was amplified by reverse transcription polymerase chain reaction (RT-PCR) from total RNA of bovine spleen lymphocytes stimulated with ConA. The products of RT-PCR were cloned into pVAX1 vector, positive recombinant clone was identified by restriction enzyme digestion and sequencing. The recombinant plasmid pVAX1-BolFN-gamma was transfected into COS-7 cells mediated by lipofectine, indirect immunofluorescent assay analysis confirmed that rBoIFN-gamma was expressed in COS-7 cells. BoIFN-gamma gene (without signal peptide) was cloned into pET-30a(+) and pGEX-6p-1 vector, and transformed into the Escherichia coli cells. After optimizing the induction condition, SDS-PAGE analysis showed that the expression products were all found in soluble form and had a molecular weight of 23 kDa and 43 kDa respectively. BoLFN-gamma precursor gene (with signal peptide) was cloned into transfer vector pFastBac 1, and transformated into DH10Bac E. coli cells. By site-specific transposition, BoIFN-gamma gene was integrated into shuttle vector Bacmid, and transfected into the Sf9 insect cells mediated by lipofectine to produce recombinant baculovirus. Indirect immunofluorescent assay analysis confirmed that rBac-BoLFN-gamma was expressed successfully in Baculovirus vector system. The antiviral activities of rHis-BoIFN-gamma, rGST-BoIFN-gamma and rBac-BoIFN-gamma were up to 8.389 x10(7) U/mg, 6.554 x10(5) U/mg and 4.096 x 10(4) U/mL respectively, which were analyzed in MDBK/VSV system. A sandwich ELISA was established using monoclonal antibodies 3E6 and 5G4, which can detect BoIFN-gamma in quantity and provide a useful method for the clinical practice and research of BolFN-gamma. PMID- 21650054 TI - [Comparison of methods in determining the obstructive sites of obstructive sleep apnea-hypopnea syndrome: flexible pharyngoscopy vs upper airway pressure measurements]. AB - OBJECTIVE: To compare the two methods, flexible pharyngoscopy with Muller's maneuver (FPMM) and continuous upper airway pressure measurements (UAPM), in determining the sites of obstruction in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). METHOD: Thirty-six patients with OSAHS underwent both FPMM and continuous upper airway pressure measurement to determine the sites of obstruction. Different criteria were adopted for retropalatal obstruction and retroglossal obstruction determined by FPMM. RESULT: When reduction of cross section area > or = 75% was considered as obstruction by FPMM, the identical results obtained by both methods were in 27 of 36 (75%) patients and kappa value was 0.138 in retropalatal region, the identical results were in 19 of 36 patients (53%) patients and kappa value was 0.121 in retroglossal region. When reduction of cross section area > or = 90% were considered as retropalatal obstruction, the identical results were in 30 of 36 (83%) and kappa value was 0.526. When reduction of cross section area > or = 50% were considered as retroglossal obstruction, the identical results were in 25 of 36 (69%) patients and kappa value was 0.389. CONCLUSION: Coincidence of FPMM and UAPM in determination of obstructive site was higher in retropalatal region than in retroglossal region. More stringent criterion for retropalatal obstruction and looser criterion for retroglossal obstruction by FPMM may help to increase the coincidence of the two methods in both regions. PMID- 21650055 TI - [A study of modified lateral pharyngoplasty for the treatment of obstructive sleep apnea hypopnea syndrome: primary outcomes analysis]. AB - OBJECTIVE: To describe a modified lateral pharyngoplasty with partial transsection of levator veli palatine muscle in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and report the primary outcomes. METHOD: Retrospective review was performed in sixty patients with OSAHS. All the patients underwent modified surgical procedures, including partial transsection of levator veli palatine muscle and high soft palatoplasty. RESULT: The patients with a reduction of the AHI at least 50% were 6 (6/60, 10%). The patients with a reduction of the AHI at least 50% and a postoperative AHI < 20 were 44 (44/60, 73.3%). The patients with a postoperative AHI < 5 were 10 (10/60, 16.7%). Postoperative complications were postoperative bleeding in two cases (3.3%) and short-term velopharyngeal insufficiency in 10 cases (16.7%). CONCLUSION: Lateral pharyngoplasty with partial transsection of levator veli palatine muscle provides a safe and effective procedure for selected OSAHS patients with oropharyngeal collapse as the main site. PMID- 21650056 TI - [The hypoxia tolerance of children with recurrent respiratory papillomatosis in surgical procedures]. AB - OBJECTIVE: To investigate hypoxia tolerance of children with recurrent respiratory papillomatosis with the spread of trachea in surgical procedures without ventilation via endotracheal tube intermittently under general anesthesia. METHOD: Forty children with recurrent respiratory papillomatosis were enrolled in the observation. The duration of SpO2 from 100% to the points of 99%, 95%, 90%, 85%, the heart rate in each time point above. PaO2, PaCO2, pH valve when SpO2 was 85%, the duration of SpO2 back to 100% were recorded respectively. RESULT: Duration of SpO2 from 100% down to 99%, 95%, 90%, 85% was (168.4 +/- 58.3)s, (204.6 +/- 56.4)s, (224.8 +/- 58.9)s, (239.9 +/- 60.6)s, respectively. Heart rate was (121.6 +/- 14. 6)bpm, (123.3 +/- 15.1) bpm, (124.1 +/- 14.8)bpm, (125.0 +/- 15.1)bpm, respectively. When SpO2 was 85%, pH value was 7.22 +/- 0.05, PCO2 was (69 +/- 8.7)mmHg, PO2 was (52 +/- 7.9)mmHg. Duration of SpO2 up to 100% was (28.6 +/- 2.5)s; When SpO2 back to 100%, pH value was 7.40 +/- 0.02, PCO2 was (40.5 +/- 2.0)mmHg, PO2 was (358 +/- 104.3)mmHg. CONCLUSION: Intermittent apnea during the surgical procedures in RRP children with distal spread of papillomas was safe, hypercapnia and hypoxia caused by the apnea can be corrected soon after the re-ventilation. Duration of apnea should be controlled within 3--5 minutes in each apnea-reoxygenation cycle. PMID- 21650057 TI - [Free perforator flap transfer to reconstruct the defect resulted from resection of head and neck tumor]. AB - OBJECTIVE: To explore the method of free perforator flap reconstructing the defect resulted from head and neck tumor resection. METHOD: Twelve cases treated in our department because of head and neck tumor were reviewed, among which 3 cases employed rectus abdominis flap, 5 cases anterolateral thigh flap, 2 cases latissimus dorsi flap, 2 cases pectoris major flap. RESULT: One case failure with the transfer of latissimus dorsi flap, one case of partial necrosis of anterolateral thigh flap resulting in pharyngeal fistula, one case of artery thrombosis and one case of venous thrombosis occurred and the flap revived after emergent exploration and re-anastomosis. The total survival rate of the transferred flap is 91.6%. CONCLUSION: Free perforator flap is able to be a good choice to reconstruct big defect resulted from head and neck tumor resection because of its simple preparation, big size of donor site. PMID- 21650058 TI - [The clinical research of primary bilateral neck dissection in the head and neck tumors]. AB - OBJECTIVE: To explore the head and neck tumors underwent primary tumor resection and bilateral neck dissection in the same period in the safety, indications, and surgical difficulty. METHOD: Retrospective analysis of 134 cases received primary tumor resection and bilateral neck dissection for head and neck cancer, the way of bilateral neck dissection were: one side was radical neck dissection and another was functional neck dissection (29 cases), one side was radical neck dissection and another was lateral neck dissection (34 cases), bilateral functional neck dissection (14 cases), one side was functional neck dissection and another was lateral neck dissection (48 cases), bilateral sides of lateral neck dissection (6 cases). RESULT: There was no operative death in 134 cases, complications for the wound bleeding in 3 cases, chylous leakage in 4 cases, pharyngeal fistula and infection in 1 case, stress ulcer in 5 cases, 1 case died, cerebral infarction in 1 case. CONCLUSION: The head and neck tumors underwent simultaneous bilateral neck dissection is safe. Appropriate cleaning method selection to reduce cervical lymph node metastasis could reduce the suffering of patients. PMID- 21650059 TI - [Comparison of H-uvulopalatopharyngoplasty and plasma-assisted H uvulopalatopharyngoplasty in the treatment of obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To compare the clinic effectiveness on OSAHS operated respectively by H-UPPP and plasma-assisted H-UPPP procedures,and to explore a utility operation procedure. METHOD: Thirty-five cases operated by H-UPPP and 29 cases by plasma assisted H-UPPP, 6-36 months followed-up, the effectiveness analyzed and compared. RESULT: The difference of polysomnogram results between preoperative and postoperative in the two operation procedures were significantly(P < 0.05). But the total effectiveness of H-UPPP and plasma-assisted H-UPPP procedures were found to be similar (P > 0.05), nevertheless plasma-assisted H-UPPP procedure has a higher curing and excellence rate (P < 0.05). CONCLUSION: The two operation procedures were in effect, the plasma-assisted H-UPPP procedure was more ascendant in extending the left and right diameter on pharyngeal cavity, increasing tension on soft palate. PMID- 21650060 TI - [Clinical application of uvulopalatopharyngoplasty with resection of the musculus uvulae and preservation of uvulae mucosa]. AB - OBJECTIVE: To explore the effect of modified uvulopalatopharyngoplasty with partial resection of the musculus uvulae and preservation of the mucosa of uvulae for obstructive sleep apnea hypopnea syndrome (OSAHS). METHOD: Thirty-six patients with OSAHS were enrolled and determined by physical examination, Muller's Test, and cephalometry whose obstructive plane were in oropharynx. One group (n = 18) only received uvulopalatopharyngoplasty with uvulae preservation, while the other group (n = 18) received uvulopalatopharyngoplasty with partial resection of the musculus uvulae and preservation of the mucosa of uvulae. Polysomnography (PSG), Epworth Sleepiness Scale (ESS) and Level of Snore were measured one day before operation and seix months after operation. RESULT: The apnea hypopnea index (AHI), lowest SaO2 (LSaO2), ESS and Level of Snore have changed in both groups (P < 0.01) after surgery in both groups. There were no statistically significance (t= --0.301, P > 0.05) in validity ratio between two groups. Postoperative Level of Snore were significantly different between two groups while AHI, LSaO2, ESS were not significantly different between two groups. CONCLUSION: Uvulopalatopharyngoplasty with partial resection of the musculus uvulae and preservation of uvulae mucosa is an effective surgical method for patients with OSAHS which obstructive plane is in oropharynx. It can decrease not only the level of snore but also the limited ratio of shrink in uvulae after routine surgery. PMID- 21650061 TI - [The expression and correlation of HMGB1 and VEGF protein in laryngeal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression and biological significance of HMGB1 and VEGF protein in tissue specimens of laryngeal squamous cell carcinoma (LSCC), and further study the correlation between HMGB1 and VEGF protein. METHOD: The expression of HMGB1 and VEGF protein was evaluated by immunohistochemical staining in 69 cases of LSCC specimens and 15 cases of adjacent epithelial tissue samples, and futher correlated with clinicopathologic parameters. RESULT: The positive rates of HMGB1 and VEGF in LSCC tissues were significantly higher than those in adjacent non-cancerous mucosa (P < 0.01), and the expression of these two marks was closely correlated with clinical stage (P < 0.05) and metastasis (P < 0.05) in LSCC. While the expression of HMGB1 and VEGF had no significant correlations with age, sex, histological differentiation and tumor site (P > 0. 05). There was a positive correlation between the expression of HMGB1 and VEGF (P < 0.05). The Kaplan-Meier survival analysis showed that patients with strong expression of HMGB1 or VEGF had poorer overall survival compared with that in patients with relative low HMGB1 or VEGF expression (P < 0.05). Multivariate COX regression analysis revealed that both lymph node metastasis and HMGB1 expression were independent prognostic factors for patients with LSCC. CONCLUSION: This study demonstrated that HMGB1 and VEGF protein overexpression were closely associated with clinical stage, metastasis and poorer prognosis in patients with LSCC. Increased expression of these two proteins in LSCC suggested that HMGB1 and VEGF might play a critical role in the initiation and progression of LSCC. PMID- 21650062 TI - [Latent membrane protein-1 of EB virus and the phenotype of epithelial mesenchymal transition and cervical lymph node metastasis in nasopharyngeal carcinoma]. AB - OBJECTIVE: To evaluate the relation of EB virus latent membrane protein-1 (LMP-1) and the phenotype of epithelial-mesenchymal transition (EMT) and cervical lymph node metastasis in nasopharyngeal carcinoma. METHOD: Based on histopathology and MRI imaging, nasopharyngeal biopsy tissues from 88 patients with nasopharyngeal carcinoma were divided into 3 groups: pathologic metastasis (18), MRI metastasis(40) and without metastasis (30). The expressions of LMP-1, STAT3, Twist, E-Cadherin and Vimentin were examined immunohistochemically in biopsy tissues. RESULT: LMP-1 expression was found in 35 of 88 biopsy tissues with a positive rate of 38.7%. The positive rates of LMP-1 in groups of pathologic metastasis, MRI metastasis and without metastasis were 38.9% (7/18), 47.5% (19/40) and 30.0% (9/30), respectively, and significant difference were not found among three groups. The expression of LMP-1 was positively correlated to both expressions of Twist and Vimentin (r = 0.276 and 0.282, are P < 0.01), but not to both expressions of STAT3 and E-Cadherin. The positive expressions or abnormal expression of STAT3, Twist, Vimentin and E-Cadherin were found in 57 of 88 (64.8%), 48 of 88 (54.5%), 22 of 88 (20.0%)and 53 of 88 (60.2%), respectively. Significant differences in the expression of STAT3, Twist, Vimentin and E Cadherin were all found among groups of pathologic metastasis, MRI metastasis and without metastasis, respectively (are P < 0.05). The expression of STAT3 was positively correlated to both expressions of Twist and Vimentin (r = 0.712 and 0.316, P < 0.01). CONCLUSION: EMT plays important role in cervical lymph node metastasis in nasopharyngeal carcinoma. LMP-1 may be only as one of upstream factors associated with the EMT, but not the decisive factor for cervical lymph node metastasis. PMID- 21650063 TI - [Early NPC detection through serologic risk stratification and clinical follow-up of high risk subjects]. AB - OBJECTIVE: Nasopharyngeal Carcinoma (NPC) can be successfully treated by radiotherapy, if the tumor is confined to nasopharynx, but clinical onset is usually delayed to more advanced stages, when prognosis is poor. The objective is to determine efficacy of a new program for early NPC detection, which entails stratification of the NPC risk of target population according to serum levels of 3 Epstein Barr Virus (EBV) antibodies. METHOD: The sera of 1373 healthy adult residents from Zhongshan were collected and analyzed in this study from Mar 16, 2007 to Dec 31, 2007. The levels of EBNA1/IgA, zta/IgG and EBNA1/IgG were tested by ELISA. To stratify the subjects of 1373 adults into high, moderate and normal NPC risk groups by regression analysis of the levels of the EBV antibody. The high-risk groups of nasopharyngeal carcinoma risk could be followed-up every 3-6 month. RESULT: NPC risk of 1379 adults was stratified according to serum levels of the 3 EBV antibodies. Eleven (0.8%) were identified to be of high risk for NPC, having high levels of all three antibodies and/or IgA EBNA level > 3 rod. Clinical examination of high risk subjects detected 5 NPC cases, 3 cases detected in the first instance and 2 in follow-up examination 3 to 6 months hence. Three cases were diagnosed with UICC Stage I tumor (60%), one in the first instance and 2 in follow-up, and the 5 cases account for all NPC cases detected from the entire cohort over 28 months(100%). CONCLUSION: The new program affords an efficient and efficacious means for early NPC detection. PMID- 21650064 TI - On telephone-based disease management: wrong diagnosis, right prescription. PMID- 21650065 TI - Maggot therapy in wound management in modern era and a review of published literature. AB - Maggot therapy is an old remedy, which is being looked into with renewed interest. The use of medicinal maggots was approved by Food and Drug Administration (FDA) as a medical device in 2004. Maggot therapy appears to be efficacious, well tolerated, and cost-effective. Because American Medical Association (AMA) and Centers for Medicare and Medicaid (CMS) released reimbursement coding guidelines with regards to maggot therapy, there is a potential for a wider use of maggot therapy in United States in the near future. Several mechanisms of action suggested for maggots in debriding wounds are discussed. While maggot therapy demonstrated effectiveness in necrotic wounds, not all wound types respond well to maggot therapy. Future large, randomized, well-designed studies would help better delineate the place of maggot therapy among other options for wound care, and determine whether maggot therapy should be initiated earlier in the course of treatment, or continued to be used as a last resort. PMID- 21650066 TI - Polycystic ovary syndrome: an overview. AB - Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. It affects 6% to 7% of the population and is characterized by hyperandrogenism and ovarian dysfunction. Women with the disorder often present with insulin resistance and obesity, making it importance for health care providers to monitor closely for signs and symptoms of metabolic syndrome and type 2 diabetes. Treatments are targeted toward improving insulin tolerance, reducing signs and symptoms of hyperandrogenism (hirsutism, anovulation, etc), restoring normal menstrual cycle function, and restoring fertility. Major treatment should include weight management through diet and exercise, regardless of body mass index and might include concurrent drug therapy. It is important that pharmacists understand the underlying pathophysiology of the disease and the available treatments, in addition to the importance of reducing risk of metabolic syndrome/type 2 diabetes, and cardiovascular disease in these patients. PMID- 21650067 TI - Case studies: Emollin in practice. PMID- 21650068 TI - Hereditary gingival enlargement. PMID- 21650069 TI - Acute coronary syndromes amongst type 2 diabetics with ischaemic electrocardiograms presenting to accident and emergency department of a Kenyan tertiary institution. AB - OBJECTIVE: To determine the prevalence of acute coronary syndromes among type 2 diabetic patients presenting to Accident and Emergency department. DESIGN: Prospective cross-sectional study. SETTING: Kenyatta National Hospital, a tertiary teaching and referral hospital. SUBJECTS: Type 2 diabetic patients with ischaemic electrocardiograms (ECG). MAIN OUTCOME MEASURES: Demographics, clinical symptoms, cardiovascular status and risk factors--central obesity, hypertension, dyslipidaemia, smoking. RESULTS: From 12,307 accident and emergency attendees, 400 (33%) diabetics aged > OR =30 years were screened with a resting ECG and 95 (24%) with ischaemic ECG were recruited; age range 41-87 years, 60% were male; diabetes duration ranged 0-30 years with 8.4% being newly diagnosed. The commonest enrolling ECG feature was nonspecific ST-T changes. The commonest presenting complaint were fatigue and dyspnoea. Majority had three coronary artery disease (CAD) risk factors: obesity 86%, elevated LDL 73% and hypertension 60%. Therapy in use was OHA 43%, insulin 42%, insulin and OHA 1%; prophylactic aspirin 14.7% and statins 8.4%. Thirty four (35.8%) were classified as acute coronary syndrome (ACS); 29 (30.5%) acute myocardial infarction (ACS-AMI) and five (5.2%) unstable angina (ACS-UA). Majority (79.4%) of the ACS presented more than six hours after symptom onset and majority had features of acute left ventricular failure. CONCLUSIONS: Acute coronary syndrome accounted for 35% of the morbidity in type 2 diabetics with ischaemic ECG's presenting to KNH accident and emergency department; patients presented late and 80% were not on CAD prophylactic therapy. PMID- 21650070 TI - Treatment outcome of TB/HIV positive and negative smear positive pulmonary tuberculosis patients treated using daily self-administered therapy in a Cameroonian district hospital. AB - BACKGROUND: In our previous study we found that half of the patients treated at the Nylon District Hospital tuberculosis (TB) treatment centre were seropositive. HIV does not only fuel the number of tuberculosis (TB) cases worldwide but it is also at least in part, responsible for the non-achievement of the 85% cure rate target. OBJECTIVE: To compare the TB treatment outcome of smear positive pulmonary tuberculosis (SPPT) patients who did an HIV test and those who refused the test as well as compare the treatment outcomes between the HIV positive and HIV negative SPPT patients from 2003 to 2005, all of whom were treated as outpatients under routine programme conditions. DESIGN: A retrospective study. SUBJECTS: Four hundred and twenty patients were registered from 2003 to 2005 as having SPPT. SETTING: The Nylon District Hospital, Cameroon. RESULTS: Thirty five point two per cent of the 386 SPPT patients also had HIV. The overall cure rate, default rate and death rate were 69%, 23.6% and 3.3% respectively. SPPT/HIV co infected patients were significantly more likely to default from treatment (28.7% versus 16.8%, OR 1.943, 95% CI 1.150-3.285) to die in the course of treatment (7.4% versus 0.4%, OR 23.714, 95% CI 2.894-194.330) or not to be cured (58.8% versus 78.8%, OR 0.404, 95% CI 0.250-0.652) compared to SPPT/HIV negative patients. Likewise SPPT patients not tested for HIV were significantly less cured (38.2% versus 71.8%, OR 0.21, 95% CI 0.099-0.445) and defaulted most (52.9% versus 21%, OR 4.773 95% CI 2.281-9.991) compared to SPPT patients tested for HIV. CONCLUSION: SPPT patients infected with HIV or not tested for HIV in the course of TB treatment are likely to suffer from unfavorable treatment outcomes. Thus health personnel prescribing anti- TB drugs should be provided with the necessary expertise to diagnose and manage HIV so that TB/HIV co-infected patients benefit from an integrated package of care in and out of the hospital. PMID- 21650071 TI - Comparison of bedside inoculation of culture media with conventional cerebrospinal fluid culture method in patients with bacterial meningitis. AB - BACKGROUND: The yield of bacterial cultures from cerebrospinal fluid (CSF) at Kenyatta National Hospital (KNH) is very low. Bedside inoculation of culture media with CSF may improve yields. OBJECTIVE: To compare the culture yield of CSF inoculated onto culture medium at the bedside to that of CSF inoculated onto culture medium in the microbiology laboratory. DESIGN: Cross-sectional comparative study. SETTING: Accident and Emergency Department and medical wards at Kenyatta National Hospital. SUBJECTS: Cerebrospinal fluid from patients at KNH with a clinical diagnosis of acute meningitis. RESULTS: Two hundred and twenty CSF specimens were obtained during a four month period. S. pneumaniae was isolated from 24 CSF samples and H. influenzae from one. Bacterial cultures were positive in 25 (11.4%, 95% CI 7.0-15.6%) samples inoculated at the bedside and 23 (10.5%, 95% CI 6.5-14.5%) samples inoculated at the laboratory. Bacteria were isolated 5 hours earlier in samples inoculated at the bedside (95% CI 4.34-6.86 hrs, p < 0.05). Four per cent of S. pneumaniae isolates were resistant to crystalline penicillin. CONCLUSION: There was no significant difference in culture yield after bedside inoculation of culture media with CSF compared to traditional CSF culture method. Bedside inoculation of culture media with CSF resulted in faster time to positive culture. PMID- 21650072 TI - Pregnancy outcomes in mothers with advanced human immunodeficiency virus disease. AB - OBJECTIVE: To determine the impact of HIV disease on immediate maternal and foetal outcomes at the Kenyatta National Hospital, Nairobi, Kenya. DESIGN: Prospective cohort study. SETTING: Kenyatta National Hospital, Nairobi, Kenya, between September 2004 and April 2005. SUBJECTS: Sixty eight mothers with advanced HIV disease (WHO clinical stage 3 and 4) and 68 HIV negative pregnant mothers. RESULTS: Mothers with advanced HIV disease were more likely to be anaemic (55% vs. 16% p < 0.001), to have sexually transmitted diseases (56% vs. 15%, p = 0.004), to have chorioamnionitis (14.8% vs. 2%, p = 0.004), to develop preterm premature rupture of membranes (31% vs. 9%, p < 0.001), to have puerperal pyrexia (16% vs. 2%, p = 0.032) an to die (5% vs. 0.5%, p = 0.028) compared to HIV negative mothers. The mean gestational age at deliver was lower in mothers with advanced HIV disease compared to the seronegative counterparts (73% vs. 32%, delivery <37 weeks, p < 0.001). Infants of mothers with advanced HIV disease compared to infants of seronegative mothers were more likely to be low birth weight infants (58% vs. 21%, p < 0.001), stillborn (4% vs. 2%, p = 0.308) and to have low Apgar scores (28% vs. 12%, Apgar score < 4 at 5 minutes p = 0.02). Perinatal sepsis and perinatal deaths were more common in infants born to mothers with advanced HIV disease compared to infants born to HIV negative mothers (8 vs. 3, p = 0.003 and 14 vs. 5, p = 0.025 respectively). External congenital anomalies were similar in the two groups (5.9% vs. 5.9%). CONCLUSION: Pregnancies complicated by advanced HIV disease are more likely to have adverse outcomes, both maternal and foetal. Advanced HIV disease is associated with increased risk of both maternal and fetal mortality. HIV infected mothers should be counselled on the increased pregnancy risks associated with advanced disease. PMID- 21650073 TI - Morphological and functional traits of malocclusion in 3-5 year-olds in Moshi, Tanzania. AB - OBJECTIVE: To assess the morphological and functional traits of malocclusion. DESIGN: Cross-sectional study. SETTING: Moshi Municipality, Kilimanjaro region, Tanzania. SUBJECTS: Examination for occlusal traits was done on 372 randomly selected 3-5-year olds (157 males and 215 females). RESULTS: The overall prevalence of malocclusion was 26.9%. Females had significantly more occlusal anomalies than males. The flush terminal plane (93.8%) was the commonest anteroposterior relation. Excessive maxillary overjet and deep-bite occurred in 5.1% and 21.5% of the children respectively. Reverse overbite (1.9%), frontal open-bite (1.6%), lateral open-bite (0.8%) and posterior cross-bite (0.3%) were relatively rare. Harmful oral habits were uncommon in this population. The sample mean for inter canine width in the maxilla was 31.1 mm (SD +/- 2.72) and for the mandible 25.3 mm (SD +/- 2.46). Lack of natural spacing in the anterior segment of the maxilla occurred in 34.4% of the children and 33.6% in the mandible. CONCLUSION: Generally, females had significantly more occlusal anomalies than males. The flush terminal plane was the commonest anteroposterior finding. Lack of natural spacing in the anterior segments and deep bite were common. PMID- 21650074 TI - Hereditary gingival fibromatosis: report of family case series. AB - Hereditary gingival hyperplasia (HGF) is a rare condition characterised by hyperplastic, dense fibrous connective tissue with acanthotic gingival epithelium. A family presented at the School of Dental Sciences, University of Nairobi with a complaint that some of the children developed swollen gums very early in life and that this got worse with eruption of the permanent teeth. The first born, a 23-year-old male, had had the swellings for over ten years. Other siblings aged 5, 9 and 12 years were also affected. The swellings had affected the appearance, speech and the psychosocial wellbeing of the children. The parents were unaffected with apparently negative family histories. Following oral examination and appropriate investigations, conventional gingivectomy was performed of the maxillary and the mandibular gingivae for the siblings: the 23- 12- and the nine-year olds. The fourth affected child, a five-year-old, was still in primary dentition and had just started showing mild signs of gingival hyperplasia. The histopathological examination of the specimens from the present cases confirmed features consistent with those of HGF. This article highlights a familial presentation of HGF. PMID- 21650075 TI - Presentation and management of cervicofacial necrotising fasciitis: report of nine cases. AB - Cervicofacial necrotising fasciitis (CNF) is an acute soft tissue infection that primarily involves the subcutaneous, adipose and fascial planes of the head and neck region. Secondary ischaemia of the skin results in widespread ulceration and suppuration. It is imperative that early diagnosis is made and judicious medical and surgical intervention instituted. We present a case series of patients with CNF diagnosed and managed at the division of oral and maxillofacial surgery of the Kenyatta National Hospital in Kenya. PMID- 21650076 TI - Mortality related to caesarean section in rural Matebeleland North Province, Zimbabwe. AB - OBJECTIVES: To describe mortality related to Caesarean sections as well as factors associated with these deaths. DESIGN: Retrospective cross-sectional. SETTING: Seven district hospitals in Matebeleland North. MAIN OUTCOME MEASURES: Proportion of Caesarean sections that resulted in maternal deaths, and the causes thereof. RESULTS: 1093 Caesarean sections were carried out over a 3 year period; 18 women (1.6%) died within 42 days of the operation, 15 of them within 24 hours. Haemorrhage was the major cause of death. A major association with adverse outcome was delayed intervention. CONCLUSION: The decision to perform a CS should take into account local circumstances. Symphysiotomy remains an alternative under the prevailing socio-economic climate. Tubal ligation at the time of a CS must be made available to women who have completed their family to prevent complications in successive pregnancies. PMID- 21650077 TI - A historical perspective of registered cases of malignant ocular tumors in Zimbabwe (1990 to 1999). Is HIV infection a factor? AB - INTRODUCTION: Anecdotal and published reports suggest that ocular tumours are on the increase in Zimbabwe. OBJECTIVES: To determine the trends in incidence rates of common malignant ocular tumours registered with the Zimbabwe Cancer Registry during the last decade (1990 to 1999). DESIGN: Retrospective study. SETTING: Data were collected from the Zimbabwe National Cancer Registry, the Zimbabwe National Census 1992 and 2002 Reports, and patient records from hospitals. SUBJECTS: All cases of malignant ocular tumours registered with the Zimbabwe National Cancer Registry between 1 January 1990 and 31 December 1999. MAIN OUTCOME MEASURES: Age standardized annual incidence rates for registered cases of common ocular tumours. RESULTS: The age-adjusted annual incidence rates of squamous cell carcinoma of the conjunctiva had a more than 10-fold increase from 0.17 to 1.8 per 100,000 people during periods 1990 and 1999 respectively. Retinoblastoma dropped by more than half from 0.8 to 0.34 per 100,000 during the same period. The annual age standardised incidence rates for all ocular tumours showed a significant upward linear trend (chi2: 362.78, df=9 and p < 0.001). There was no significant gender difference in the distribution of these tumours amongst the study population. CONCLUSION: The increasing trend in the age-adjusted annual incidence rates of ocular surface squamous neoplasms could be attributed to the worsening HIV and AIDS pandemic in Zimbabwe or improved access/utilization of health services by the public. PMID- 21650078 TI - Early deaths and other challenges to childhood cancer survival in Ibadan, Nigeria. AB - OBJECTIVES: To determine the frequency of early deaths and the associated risk factors in children suffering from cancer at the University College Hospital, Ibadan. DESIGN: A retrospective study involving review of case notes of children suffering from cancer. SETTING: Department of Paediatrics, University College Hospital, Ibadan, Nigeria. SUBJECTS: All cases of childhood cancer managed in the Department between January 1998 and December 2004. Inclusion criteria were histological or cytological confirmation of diagnosis, suggestive clinical features and availability of details about the course of the illness. MAIN OUTCOME MEASURES: Interval between diagnosis and death, rate of early death (death within 30 days of diagnosis) and risk factors for early death. RESULTS: Eighty eight cases of childhood cancer were seen out of whom 52 died during the period. Four cases with incomplete data were excluded from subsequent statistical analysis. There were 29 (34.5%) early deaths defined as death within 30 days of diagnosis. The odds of early death were increased in the presence of bilateral kidney involvement, masses in the liver, splenic masses, pulmonary metastasis and stage D of Burkitt lymphoma. Logistic regression analysis revealed that pulmonary metastasis was a significant independent predictor ofearly death. CONCLUSIONS: Early childhood cancer mortality rate is high. Early diagnosis and referral for appropriate care may reduce childhood cancer mortality in Nigeria. PMID- 21650079 TI - Critical considerations into the new EMA guideline on bioequivalence. AB - The market of generic drugs has been greatly developing during the last 15 years in various European Union (EU) member states, mainly in the Mediterranean area, including non-EU countries, i.e., in the Middle East. This has required a more detailed support from EMA (European Medicines Agency) as guidelines are concerned. Previous EU guidelines on bioavailability and bioequivalence neglected some relevant issues often met in bioequivalence trials, defined in the literature as "open questions on bioequivalence". In the absence of EU specific directives these problems were managed by EU investigators in compliance with U.S. FDA (Food and Drug Administration) guidelines that had already considered some of these "open problems". The latest EMA guideline operating from August 1, 2010 focuses on various relevant issues, including directions on orodispersible tablets, how to operate in the case of high variability, or how to manage the carryover effect of plasma concentrations, but, e.g., it is still neglecting the issue of the multiple-peak phenomenon. In addition, comprehensive directions are still needed on how to manage clinical studies in which endogenous substances are involved. The present review focuses on situations now appropriately discussed in the latest EU guideline, as well as other situations that still need to be defined and need further attention by the regulatory agency in order to give additional adequate directions to the investigators. PMID- 21650080 TI - Treatment of arterial hypertension in the very elderly: a meta-analysis of clinical trials. AB - The benefits of lowering blood pressure are obvious for the population up to the age of 65 years, but whether and, if so, which treatment is beneficial in the very elderly population remains still a matter of debate. We conducted a meta analysis of randomised controlled clinical trials with duration of at least 12 months and the analysis of cardio- and cerebrovascular endpoints in participants aged 75 years and over. MEDLINE, CENTRAL (Cochrane Central Register of Controlled Trials) and the WHO-ISH Collaboration register were searched until October 20, 2009. Further, references from reviews, trials and previously published meta analyses were analysed. A total of 10 studies were included providing morbidity and mortality data with a total of 8667 participants in the meta-analysis, with separate analyses for studies on isolated systolic hypertension. There were 148 non-fatal strokes and 287 cardiovascular morbidity and mortality events among treated patients, compared with 176 non-fatal strokes (p = 0.02) and 366 cardiovascular morbidity and mortality events (p = 0.0001) among control patients. Rates of heart failure were significantly reduced (64 vs. 121 events; p = 0.00001), total mortality remained unchanged (odds ratio 0.97). Further, 9 studies with 6933 participants were included in the systematic review of blood pressure reduction trials. The average blood pressure achieved at the end of the studies was 164/83 mmHg in the placebo group and 150/83 mmHg in the treatment group. At the beginning of the study blood pressure was 170.6/ 88.6 mmHg in the placebo group and 175.4/94.6 mmHg in the treatment group. Changes were only significant for systolic blood pressure in the treatment group (p = 0.0008). Treating healthy subjects aged 75 years and older with moderate to severe hypertension reduces non-fatal strokes, cardiovascular morbidity and mortality and the incidence of heart failure but does not change total mortality. PMID- 21650081 TI - Effects of agmatine on the survival rate in rats bled to hemorrhage. AB - Agmatine (CAS 2482-00-0), an amine formed by decarboxylation of L-arginine, interacts with several targets like alpha2-adrenergic, imidazoline and N-methyl-D aspartic acid (NMDA) receptors and besides it is involved in the nitric oxide mediated effects. It has also been proposed that it possesses vasodilator effects and increases glomerular filtration rate in rats. The aim of this study was to supply evidence for the effects of agmatine in a rat model of hemorrhagic shock and explain the possible mechanisms of action. The iliac arteries and veins of Sprague-Dawley rats were catheterized under urethane anesthesia and around 2 ml/100 g blood was withdrawn within 20 min until the mean arterial blood pressure was stabilized around 25 mmHg. The rats were either pretreated with physiological saline, yohimbine (an alpha2-adrenergic receptor antagonist) or L-arginine (a nitric oxide donor) intravenously before administration of agmatine (300 microg/kg). Agmatine restored blood pressure in rats pretreated with physiological saline where all rats survived. Pretreatment with L-arginine abolished the increase in blood pressure produced by agmatine and the 1 h survival rate decreased to 67% (p < 0.01). Yohimbine pretreatment also suppressed agmatine induced restoration of blood pressure; however, the survival rate was found to be 17% for 3 min. No statistically significant effect was observed in the heart rate responses. These results may suggest that agmatine may increase survival through alpha2-adrenergic receptors and restores blood pressure through nitric oxide and adrenergic mechanisms in rats bled to hemorrhage. PMID- 21650082 TI - Bioequivalence study of two perindopril erbumine tablet formulations in healthy volunteers. AB - The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16 0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39 121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption. PMID- 21650083 TI - Ameliorative effect of astaxanthin on endothelial dysfunction in streptozotocin induced diabetes in male rats. AB - The present study was designed to examine whether astaxanthin (ASX, 3,3 dihydroxybeta, beta-carotene-4,4-dione, CAS 472-61-7), a dietary antioxidant carotenoid that is naturally present in algae, crustaceans, and fish, has a protective effect on endothelial dysfunction of aortas in diabetic rats and the possible molecular mechanism involved. Male Wistar rats were randomly divided into four groups: control rats, diabetic rats, diabetic rats treated with ASX (10 mg/kg/d), and control rats treated with ASX. Type 1 diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/ kg). STZ-induced diabetes in rats was complicated with excessive oxidative stress and endothelial dysfunction, increased serum oxidized low-density lipoprotein (ox-LDL) and aortic malondialdehyde (MDA) levels, inhibited endothelium-dependent vasorelaxation to acetylcholine (ACh) and unaffected endothelium-dependent vasorelaxation to sodium nitroprusside (SNP). Simultaneously, lectin-like oxLDL receptor-i (LOX-1) expression was enhanced and endothelial nitric oxide (NO) synthase (eNOS) expression was reduced in the aortas of diabetic rats. ASX treatment could significantly decrease serum oxLDL and aortic MDA levels, attenuate blunted endothelium-dependent vasodilator responses to ACh, upregulate eNOS expression, and decrease LOX-1 expression. These results indicated that ASX could ameliorate diabetic endothelial dysfunction by inhibiting the ox-LDLLOX-1-eNOS pathway. Treatment with ASX might be clinically useful for diabetic complications associated with endothelial dysfunction. PMID- 21650084 TI - Relative bioavailability of prasugrel free base in comparison to prasugrel hydrochloride in the presence and in the absence of a proton pump inhibitor. AB - Prasugrel (CAS 150322-43-3), an inhibitor of platelet activation and aggregation, is indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome. If a proton pump inhibitor is co-administered with prasugrel, a pH dependent salt-to-base conversion rate of prasugrel could become clinically meaningful. In an open-label, randomized, four-period, 2 x two-way crossover study, the relative bioavailability of tablets containing prasugrel free base compared to prasugrel hydrochloride (originator product) both in the presence and in the absence of the proton pump inhibitor lansoprazole (CAS 103577 45-3) was investigated. In the absence of lansoprazole, the extent of absorption (AUC) of prasugrel free base was about 8-9% lower, while the rate of absorption (Cmax) after administration of prasugrel free base was 20% lower when compared to prasugrel hydrochloride. When lansoprazole was used to raise the pH level in the upper gastro-intestinal tract, AUC was decreased by 25% after administration of prasugrel hydrochloride and by 41% after prasugrel free base. In addition, the peak plasma levels were decreased by 52% and 72%, respectively (geometric means). The relative bioavailability of the prasugrel free base compared to prasugrel hydrochloride, both in the presence and in the absence of the proton pump inhibitor lansoprazole, differs so much that most probably a generic formulation containing prasugrel free base will not be equivalent in all aspects to the originator product. PMID- 21650085 TI - In vitro and in vivo chemosensitizing activity of LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase and polo-like kinases, against human leukemic B-cell precursors. AB - The present study documents the chemosensitizing anti-leukemic activity of the leflunomide metabolite (LFM) analog, LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase (BTK) and Polo-like kinases (PLK), against human leukemic B-cell precursors. The results in 135 xenografted NOD/SCID mice regarding the anti-leukemic activity of GMP-grade LFM-A13, obtained with only 4 days of LFM-A13 therapy at nontoxic dose levels corresponding to 1-20% of its NOAEL (no observable advserse effect level), alone or in combination with the standard chemotherapy drug vincristine, demonstrate the potential of LFM-A13 as a new anti-leukemic drug candidate. All 82 LFM-A13-treated mice, including those receiving a combination of vincristine + LFM-A13 at the highest dose level of LFM A13, tolerated their treatments well without weight loss, diarrhea, lethargy/ paralysis, other signs of morbidity, or mortality. The present study provides preclinical proof-of-principle for the development of LFM-A13 as a new chemosensitizing and apoptosis-promoting anti-leukemic agent and lends support to the hypothesis that the chemoresistance of relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be overcome by using LFM-A13 in combination with chemotherapy. Also presented are the results of a comprehensive meta analysis of the overexpression of genes for LFM-A13 targeted kinases and their downstream effector molecules in B-lineage lymphoid malignancies utilizing the Oncomine database. PMID- 21650087 TI - Visual perception in the far east: Wolfgang Metzger and Richard Gregory revisited. PMID- 21650086 TI - Efficacy of vitamin C vaginal tablets in the treatment of bacterial vaginosis: a randomised, double blind, placebo controlled clinical trial. AB - A randomised, double blind, parallel groups, placebo controlled clinical trial was conducted to assess the efficacy and safety profile of 250 mg ascorbic acid (Vit. C, Vagi C) in women with bacterial vaginosis (BV). Overall, 277 out patients with at least three of the following signs (white discharge that smoothly coats the vaginal walls, pH of vaginal fluid > 4.5, a fishy odour of vaginal discharge before or after addition of 10% KOH and presence of clue cells on microscopic examination) were randomised to apply a tablet deeply into the vagina once daily for 6 days. The primary efficacy endpoint was the cure rate, defined as the recovery of all inclusion criteria. In the intent-to-treat (ITT) population, cure was achieved by 55.3% of patients with Vit. C (n=141) and by 25.7% of patients with placebo (n=136). The between-group difference was 29.6% (p < 0.001). In the per-protocol (PP) population, cure rate was 66.4% with Vit. C (n=116) and 27.1% with placebo (n = 118), respectively. Between-group difference was 39.3% (p < 0.001). In a subset of patients with centralised evaluation of the vaginal swab, cure in ITT was achieved by 86.3% of patients with Vit. C (n=51) and by 7.6% of patients with placebo (n=53), the between-group difference was 78.7% (p < 0.0001). Cure rate in PP was 86.0% with Vit. C (n=50) and 6.1% with placebo (n=49), between-group difference was 79.9% (p < 0.0001). Both Vit. C and placebo were well tolerated and no differences in safety profile were evident between groups. The results support an effective and safe use of silicon-coated Vit. C vaginal tablets in the management of BV. PMID- 21650088 TI - Perceived motion is influenced by random dynamic information. AB - Distortions of the local spatial-frequency power spectrum caused by motion blur may be used by the visual system to improve motion analysis (e.g., Barlow and Olshausen, 2004 Journal of Vision 4415-426). We tested this hypothesis by measuring the error of perceived motion direction of moving patterns in the presence of random noncoherent motion manipulated to create different spatial power spectra. The results showed that error increased when the background power spectrum was similar to the motion power spectrum; however, when the background power spectrum had an anisotropy consistent with motion blur, the error was reduced. Shifting the power spectrum away from the motion power spectrum reduced the error. PMID- 21650089 TI - The importance of a visual horizon for distance judgments under severely degraded vision. AB - In two experiments we examined the role of visual horizon information on absolute egocentric distance judgments to on-ground targets. Sedgwick [1983, in Human and Machine Vision (New York: Academic Press) pp 425-458] suggested that the visual system may utilize the angle of declination from a horizontal line of sight to the target location (horizon distance relation) to determine absolute distances on infinite ground surfaces. While studies have supported this hypothesis, less is known about the specific cues (vestibular, visual) used to determine horizontal line of sight. We investigated this question by requiring observers to judge distances under degraded vision given an unaltered or raised visual horizon. The results suggest that visual horizon information does influence perception of absolute distances as evident through two different action-based measures: walking or throwing without vision to previously viewed targets. Distances were judged as shorter in the presence of a raised visual horizon. The results are discussed with respect to how the visual system accurately determines absolute distance to objects on a finite ground plane and for their implications for understanding space perception in low-vision individuals. PMID- 21650090 TI - Vection in depth during consistent and inconsistent multisensory stimulation. AB - We examined vection induced during physical or simulated head oscillation along either the horizontal or depth axis. In the first two experiments, during active conditions, subjects viewed radial-flow displays which simulated viewpoint oscillation that was either in-phase or out-of-phase with their own tracked head movements. In passive conditions, stationary subjects viewed playbacks of displays generated in earlier active conditions. A third control, experiment was also conducted where physical and simulated fore-aft oscillation was added to a lamellar flow display. Consistent with ecology, when active in-phase horizontal oscillation was added to a radial-flow display it modestly improved vection compared to active out-of-phase and passive conditions. However, when active fore aft head movements were added to either a radial-flow or a lamellar-flow display, both in-phase and out-of-phase conditions produced very similar vection. Our research shows that consistent multisensory input can enhance the visual perception of self-motion in some situations. However, it is clear that multisensory stimulation does not have to be consistent (i.e., ecological) to generate compelling vection in depth. PMID- 21650091 TI - Footprints sticking out of the sand. Part 2: children's Bayesian priors for shape and lighting direction. AB - The shading information in images that depict surfaces of 3-D objects cannot be perceived correctly unless the direction of the illuminating light source is known and, in the absence of this knowledge, perception in adults is consistent with a light-from-above Bayesian prior assumption. In order to investigate if children make use of a similar assumption, 171 children between the ages of 4.6 and 10.8 years were tested with 20 images containing shading information, where the shape depicted in each image could be perceived as either convex or concave. Each child's Bayesian prior probability that light comes from above was estimated, and (assuming that decision-noise is approximately the same in all children) regression analyses revealed a significant increase in this prior probability of 0.034-0.035 per year, and predict a neutral prior (0.5) at 1.6 years for naturalistic picture stimuli and 3.6 years for abstract symbol stimuli. Additionally, each child's prior probability for perceiving shapes as being convex/concave was estimated, and was found to be close to a neutral value of 0.5 for all ages. Together, these results indicate that children have a neutral prior for shape convexity, and that their prior probability for lighting direction gradually shifts towards an adult-like prior value as they grow older. Finally, the status of these one-dimensional priors is discussed in relation to marginal distributions of high-dimensional priors implicit in the statistical structure of the physical word. PMID- 21650092 TI - I know you are beautiful even without looking at you: discrimination of facial beauty in peripheral vision. AB - Earlier research suggests that facial attractiveness may capture attention at parafovea. However, little is known about how well facial beauty can be detected at parafoveal and peripheral vision. Participants in this study judged relative attractiveness of a face pair presented simultaneously at several eccentricities from the central fixation. The results show that beauty is not only detectable at parafovea but also at periphery. The discrimination performance at parafovea was indistinguishable from the performance around the fovea. Moreover, performance was well above chance even at the periphery. The results show that the visual system is able to use the low-spatial-frequency information to appraise attractiveness. These findings not only provide an explanation why a beautiful face could capture attention when central vision is already engaged elsewhere, but also reveal the potential means by which a crowd of faces is quickly scanned for attractiveness. PMID- 21650093 TI - Superior encoding enhances recall in color-graphemic synesthesia. AB - Synesthesia is a phenomenon in which particular stimuli, such as letters or sound, generate a secondary sensory experience in particular individuals. Reports of enhanced memory in synesthetes raise the question of its cognitive and neurological substrates. Enhanced memory in synesthetes could arise from the explicit or implicit use of a synesthetic cue to aid memory, from changes unique to the synesthete brain, or from both, depending on the task. To assess this question, we tested nine color-graphemic synesthetes using standardized neuropsychological measures that should not trigger color-graphemic synesthesia (visuo-spatial tests) and measures that should trigger color-graphemic synesthesia (verbal tasks). We found a synesthetic advantage on both types of tests, primarily in the initial encoding of information. The pattern of results adds to existing evidence of advantages in synesthetic memory, as well as provides novel evidence that synesthetes may have enhanced encoding rather than superior recall. Synesthetes learn more initially, rather than forgetting less over time. PMID- 21650094 TI - The taste of music. AB - Zarlino, one of the most important music theorists of the XVI century, described the minor consonances as 'sweet' (dolci) and 'soft' (soavi) (Zarlino 1558/1983, in On the Modes New Haven, CT: Yale University Press, 1983). Hector Berlioz, in his Treatise on Modern Instrumentation and Orchestration (London: Novello, 1855), speaks about the 'small acid-sweet voice' of the oboe. In line with this tradition of describing musical concepts in terms of taste words, recent empirical studies have found reliable associations between taste perception and low-level sound and musical parameters, like pitch and phonetic features. Here we investigated whether taste words elicited consistent musical representations by asking trained musicians to improvise on the basis of the four canonical taste words: sweet, sour, bitter, and salty. Our results showed that, even in free improvisation, taste words elicited very reliable and consistent musical patterns:'bitter' improvisations are low-pitched and legato (without interruption between notes), 'salty' improvisations are staccato (notes sharply detached from each other), 'sour' improvisations are high-pitched and dissonant, and 'sweet' improvisations are consonant, slow, and soft. Interestingly, projections of the improvisations of taste words to musical space (a vector space defined by relevant musical parameters) revealed that, in musical space, improvisations based on different taste words were nearly orthogonal or opposite. Decoding methods could classify binary choices of improvisations (i.e., identify the improvisation word from the melody) at performance of around 80%--well above chance. In a second experiment we investigated the mapping from perception of music to taste words. Fifty-seven non-musical experts listened to a fraction of the improvisations. We found that listeners classified with high performance the taste word which had elicited the improvisation. Our results, furthermore, show that associations of taste and music go beyond basic sensory attributes into the domain of semantics, and open a new venue of investigation to understand the origins of these consistent taste-musical patterns. PMID- 21650095 TI - Effects of sound-marker durations on rhythm perception. AB - Our aim in this study was to examine the influence of sound-marker durations on the perception of simple rhythm patterns. These comprised three successive sounds marking two neighbouring time intervals, T1 and T2, with their onsets. We varied the durations of each of the three sound markers to make them either 20 or 60 ms. Durations of T1 and T2 were also varied, but the total duration of T1 and T2 was fixed at either 240 or 480 ms. In experiment 1, participants compared the durations of T1 and T2. In experiment 2, the subjective duration of each interval was measured separately. We found that lengthening the duration of the sound marker which terminated an interval increased the subjective duration of that interval: lengthening the duration of the second marker increased the subjective duration of T1, and lengthening the duration of the third marker increased the subjective duration of T2. Lengthening the duration of the first marker increased the subjective duration of T1 when T1 + T2 = 240 ms, especially when T1 > T2. This effect of first-marker duration, which could not be observed with single intervals used in the control conditions, seemed to enhance the contrast between T1 and T2. The effects of marker durations are associated with previous time perception studies, in which single time intervals were used. They are discussed in the context of rhythm-perception studies, in which more complex sound patterns have been used. PMID- 21650096 TI - On representation of solids: a note. AB - Current theories of representation of 3-D objects assume that they are geometrical facsimiles of represented objects and, therefore, imply that various aspects of the representations are as concordant as are those of the objects themselves. Empirical data presented here question this as they show that subjects' choices of distinct views of objects are not mutually concordant. This being so, it seems unlikely that a facsimile representation of a solid yields a full description of the process of representation. PMID- 21650097 TI - Behavioral responses to light by headless anesthetized Drosophila melanogaster. AB - The bodies of decapitated fruit flies are known to retain a variety of functional sensory inputs, processing, and behavioral responses. Here I report a previously undescribed phenomenon: headless bodies can respond to a light presentation with movement, walking, and flight. Headless anesthetized flies also respond to a light presentation with behavior, albeit to a lesser degree. The mechanism underlying the behavioral response of headless flies to light might include extracephalic photoreceptors or thermoreceptors. PMID- 21650098 TI - Reply to critical review by professor John Smythies. PMID- 21650099 TI - The impact of the 2007-2009 recession on workers' health coverage. AB - IMPACT OF THE RECESSION: The 2007-2009 recession has taken its toll on the percentage of the population with employment-based health coverage. While, since 2000, there has been a slow erosion in the percentage of individuals under age 65 with employment-based health coverage, 2009 was the first year in which the percentage fell below 60 percent, and marked the largest one-year decline in coverage. FEWER WORKERS WITH COVERAGE: The percentage of workers with coverage through their own job fell from 53.2 percent in 2008 to 52 percent in 2009, a 2.4 percent decline in the likelihood that a worker has coverage through his or her own job. The percentage of workers with coverage as a dependent fell from 17 percent in 2008 to 16.3 percent in 2009, a 4.5 percent drop in the likelihood that a worker has coverage as a dependent. These declines occurred as the unemployment rate increased from an average of 5.8 percent in 2008 to 9.3 percent in 2009 (and reached a high of 10.1 percent during 2009). FIRM SIZE/INDUSTRY: The decline in the percentage of workers with coverage from their own job affected workers in private-sector firms of all sizes. Among public-sector workers, the decline from 73.4 percent to 73 percent was not statistically significant. Workers in all private-sector industries experienced a statistically significant decline in coverage between 2008 and 2009. HOURS WORKED: Full-time workers experienced a decline in coverage that was statistically significant while part time workers did not. Among full-time workers, those employed full year experienced a statistically significant decline in coverage from their own job. Those employed full time but for only part of the year did not experience a statistically significant change in coverage. Among part-time workers, those employed full year experienced a statistically significant increase in the likelihood of having coverage in their own name, as did part-time workers employed for only part of the year. ANNUAL EARNINGS: The decline in the percentage of workers with coverage through their own job was limited to workers with lower annual earnings. Statistically significant declines were not found among any group of workers with annual earnings of at least $40,000. DEMOGRAPHICS: Workers with a high school education or less experienced a statistically significant decline in the likelihood of having coverage. Neither workers with a college degree nor those with a graduate degree experienced a statistically significant decline in coverage through their own job. Workers of all races experienced statistically significant declines in coverage between 2008 and 2009. Both men and women experienced a statistically significant decline in the percentage with health coverage through their own job. IMPACT OF STRUCTURAL CHANGES TO THE WORK FORCE: The movement of workers from the manufacturing industry to the service sector continued between 2008 and 2009. The percentage of workers employed on a full-time basis decreased while the percentage working part time increased. While there was an overall decline in the percentage of full-time workers, that decline was limited to workers employed full year. The percentage of workers employed on a full-time, part-year basis increased between 2008 and 2009. The distribution of workers by annual earnings shifted from middle-income workers to lower-income workers between 2008 and 2009. PMID- 21650100 TI - Death wish. Is your conversation someone's last chance? PMID- 21650101 TI - Valuable vitals. Make the most of them. PMID- 21650102 TI - After the storm. When a tornado tears through, just getting to its victims can be difficult. PMID- 21650103 TI - Assessing the eyes. In emergency medicine, much can be learned from a routine eye exam. PMID- 21650104 TI - What's a leader to do? When it comes to good leadership, actions speak louder than words. PMID- 21650105 TI - Behind the scenes. Q&A with Paul Pepe from the Gathering of Eagles. Interview by Marie Nordberg. PMID- 21650106 TI - Behind the scenes. Q&A with Kevin Mackey from the NAEMSP Annual Conference. Interview by John Erich. PMID- 21650107 TI - Hold the coroner. Could double sequential defib stop refractory v-fib? PMID- 21650108 TI - The day the D50 dried up. What one agency did when faced with a drug supply issue could be applied as a best practice nationwide. PMID- 21650109 TI - Different destinations. London's Clinical Assessment Units help steer patients right. PMID- 21650110 TI - A stepping stone to standardization. What does medical subspecialty status mean for EMS? PMID- 21650111 TI - Cardiac arrest management. Adapting AHA Guidelines 2010 to your EMS protocols. PMID- 21650112 TI - Facing the future of EMS. In a time of change, we can't afford to be left behind. PMID- 21650113 TI - Intranasal drug administration: an innovative approach to traditional care. AB - Intranasal drug administration is safe and effective and has many applications to prehospital providers of all levels. Administered drugs do take longer to take effect than drugs administered intravenously; however, the time saved by not needing to establish an i.v. offsets this difference. When evaluating your system's protocols, consider adding IN drug administration, and particularly consider its benefit in patients who may be seizing, hypoglycemic, experiencing a narcotic overdose or in pain. PMID- 21650114 TI - Smoke inhalation. Part 1: Assessing the scene and your patient. PMID- 21650115 TI - When a broken heart fails. What EMS providers need to know about stress cardiomyopathy, which is most common among post-menopausal women. PMID- 21650116 TI - Electrolyte imbalances. Part 4: Calcium balance disorders. PMID- 21650117 TI - Real medics. They're more about competence than cool. PMID- 21650118 TI - Dentistry's green future. PMID- 21650119 TI - A unique opportunity: new role for hygienists in modern practices. PMID- 21650120 TI - Congenitally missing maxillary lateral incisors: treatment. AB - The 2 major treatment approaches for congenitally missing maxillary lateral incisors are space closure via orthodontic therapy, or space opening to allow prosthodontic replacements either with a fixed prosthesis or single-tooth implant. Both of these treatment approaches can potentially compromise aesthetics, periodontal health, and function. It is essential for an interdisciplinary dental specialty team to establish realistic treatment objectives, communicate the sequence of treatment, interact during treatment, evaluate dental and gingival aesthetics, and position teeth to permit proper prosthetic treatment. If this interdisciplinary approach is used, the aesthetics and long-term dental health of the patient following treatment will be greatly enhanced. PMID- 21650121 TI - Protocol for implementing aesthetic implant restorations. PMID- 21650122 TI - Revolutionary advances in endodontics, Part I: CBCT. PMID- 21650123 TI - Fiber post techniques for anatomical root variations. AB - In contemporary dental practice, there is no remaining reason to use metallic posts, custom or prefabricated. Many cases that several years ago would have required a retentive post will not require that post today, because of the many improvements in bonding agents and composite resin restoratives. However, in cases where less than 50% of coronal tooth structure remains--or in other cases wherein the judgment of the clinician a post is indicated--there are now aesthetic, non-corrosive, fracture resistant and radiopaque alternatives for all varieties that save time and money without compromise. Their most compelling advantage, regardless of the geometry or amount of residual tooth structure, is the protection from root fracture that a low modulus restoration provides. In selecting the materials (posts, resins) for these techniques, the dentist is advised not to cut corners, and to seek the strongest and most radiopaque products available. PMID- 21650124 TI - The metrics of anterior diastema closure. PMID- 21650125 TI - Evolutions in CAD/CAM hardware, software, and materials. PMID- 21650126 TI - Multidisciplinary rehabilitation within the general practice. PMID- 21650127 TI - Treating the gummy smile. PMID- 21650128 TI - Digital photography update: 2011. PMID- 21650129 TI - Move to improve your health: the research behind static postures. PMID- 21650130 TI - Revolutionizing the coding and billing cycle with intelligent mobile technology. PMID- 21650131 TI - How do we get to meaningful use? PMID- 21650132 TI - Streamlining scheduling. Ohio Regional Healthcare Enterprise uses web-based workforce-management system to increase efficiency. PMID- 21650133 TI - Creating home medical devices. When it comes to designing products for home healthcare, challenges are universal. PMID- 21650134 TI - Improving medical device connectivity. Both bar coding and RFID technologies can be applied to improve workflow. PMID- 21650135 TI - Spotlight on HIEs and EHRs. How outsourcing fits in. PMID- 21650136 TI - Forecasting risk. Risk management will become increasingly critical in accountable care models. PMID- 21650137 TI - Real-time analytics increase early discharges. Dashboard lowers cost per case, improves patient satisfaction and minimizes staff frustration. PMID- 21650138 TI - Optimizing patent strategies. Maintain a competitive edge by creating a strategic patent portfolio. PMID- 21650139 TI - Outsourcing with control. The benefits of collaboration when reaching out to customers. PMID- 21650140 TI - The end of the record as we know it. PMID- 21650141 TI - DIY ROI. Putting release of information in the hands of patients. PMID- 21650142 TI - Everyday ethics. AHIMA code of ethics guides daily work, complex situations. PMID- 21650143 TI - Rules of spring. PMID- 21650144 TI - Cloud computing 101. PMID- 21650145 TI - Advancing secondary data uses through data standards. PMID- 21650146 TI - A guide to US quality measurement organizations. PMID- 21650147 TI - Data mapping best practices. PMID- 21650148 TI - CY 2011 changes to the hospital OPPS. PMID- 21650149 TI - Developing an ICD-10-CM/PCS coder training strategy. PMID- 21650150 TI - Intermetallic magnetic nanoparticle precipitation by femtosecond laser fragmentation in liquid. AB - Intermetallic Nd(2)Fe(14)B nanoparticles with an average diameter of 30 nm, which are smaller than a theoretical single magnetic domain size of 220 nm, were successfully prepared by the femtosecond laser fragmentation in liquid. The self passivating amorphous carbon layer resulting from the decomposition of the surrounding solvent prevents the Nd(2)Fe(14)B nanoparticle from aggregation and oxidation. The coercivity of Nd(2)Fe(14)B nanoparticle increases with increase of the laser irradiation time, despite the reduction of crystallinity. PMID- 21650151 TI - Effect of organic matters on CO2 hydrate formation in Ulleung Basin sediment suspensions. AB - Marine sediment core samples collected from a gas hydrate deposit site (Ulleung Basin (UB), East Sea, Korea) were explored to identify the role of sediment organic matters (SOMs) on the formation of CO(2) hydrate. Two distinct CO(2) hydrate formation regimes (favorable (<=40 min) and unfavorable (>250 min)) were observed from the hydrate formation tests. CO(2) hydrate induction time in UB sediment suspensions was approximately seven times faster than that in UB sediment suspensions without SOMs (baked UB), showing a direct influence of SOMs. Spectrometric and spectroscopic analyses confirmed the existence of different types of SOMs including nonhumic and humic substances in UB sediment samples. We found SOMs with aromatic ring structures in all sediment extracts and SOMs with amine and amide groups and lignin in alkaline extracts. SOMs were extracted from UB sediment core samples (1 g each). Measured CO(2) hydrate induction times were different in baked UB sediment suspensions with different extracts of UB sediments. The experimental results demonstrated that SOMs can play a significant role to accelerate the formation of CO(2) hydrate in UB sediment suspensions, suggesting that the gas hydrate deposit site at UB may be a proper place for CO(2) sequestration as a form of CO(2) hydrate. PMID- 21650153 TI - Biosynthetic origin of the 3-amino-2,5,7,8-tetrahydroxy-10-methylundecanoic acid moiety and absolute configuration of pahayokolides A and B. AB - Pahayokolides A and B are cyclic undecapeptides that were isolated from the cyanobacterium Lyngbya sp. They contain the unusual alpha-hydroxy-beta-amino acid 3-amino-2,5,7,8-tetrahydroxy-10-methylundecanoic acid (Athmu). The absolute configurations of the amino acids of the pahayokolides, except for the four oxygen-bearing stereocenters of Athmu, have been determined by Marphy's method. Incorporation of labeled leucine and acetate precursors into the pahayokolides has established that Athmu is derived from a leucine or alpha-keto isocaproic acid starter unit, which is further extended with three acetate units. PMID- 21650152 TI - The relevance of higher plants in lead compound discovery programs. AB - Along with compounds from terrestrial microorganisms, the constituents of higher plants have provided a substantial number of the natural product-derived drugs used currently in Western medicine. Interest in the elucidation of new structures of the secondary metabolite constituents of plants has remained high among the natural products community over the first decade of the 21st century, particularly of species that are used in systems of traditional medicine or are utilized as botanical dietary supplements. In this review, progress made in the senior author's laboratory in research work on naturally occurring sweeteners and other taste-modifying substances and on potential anticancer agents from tropical plants will be described. PMID- 21650154 TI - Thermodynamics of boroxine formation from the aliphatic boronic acid monomers R B(OH)2 (R = H, H3C, H2N, HO, and F): a computational investigation. AB - Boroxines are the six-membered cyclotrimeric dehydration products of organoboronic acids, 3R-B(OH)2 -> R3B3O3 + 3H2O, and in recent years have emerged as a useful class of organoboron molecules with applications in organic synthesis both as reagents and catalysts, as structural components in boronic-acid-derived pharmaceutical agents, and as anion acceptors and electrolyte additives for battery materials [Korich, A. L.; Iovine, P. M. Dalton Trans. 2010, 39, 1423 1431]. Second-order Moller-Plesset perturbation theory, in conjunction with the Dunning-Woon correlation-consistent cc-pVDZ, aug-cc-pVDZ, cc-pVTZ, and aug-cc pVTZ basis sets, was used to investigate the structures and relative energies of the endo-exo, anti, and syn conformers of the aliphatic boronic acids R-B(OH)2 (R = H, H3C, H2N, HO, and F), as well as the thermodynamics of their boroxine formation; single-point calculations at the MP2/aug-cc-pVQZ, MP2/aug-cc-pV5Z, and CCSD(T)/aug-cc-pVTZ levels using the MP2/aug-cc-pVTZ optimized geometries were also performed in selected cases. The endo-exo conformer was generally lowest in energy in vacuo, as well as in PCM and CPCM models of aqueous and carbon tetrachloride media. The values of DeltaH(298)(0) for boroxine formation via dehydration from the endo-exo conformers of these aliphatic boronic acids ranged from -2.9 for (H2N)3B3O3 to +12.2 kcal/mol for H3B3O3 at the MP2/aug-cc-pVTZ level in vacuo; for H3B3O3, the corresponding values in PCM/UFF implicit carbon tetrachloride and aqueous media were +11.2 and +9.8 kcal/mol, respectively. On the basis of our calculations, we recommend that DeltaHf(298K) for boroxine listed in the JANAF compilation needs to be revised from -290.0 to approximately 277.0 kcal/mol. PMID- 21650155 TI - New ru(II) complexes containing oxazoline ligands as epoxidation catalysts. Influence of the substituents on the catalytic performance. AB - The synthesis of a family of new Ru complexes containing the facial tridentate ligand with general formula [Ru(II)(T)(D)(X)](n+) (T = trispyrazolylmethane (tpm); D = ((4S,4'S)-(-)-4,4',5,5'-tetrahydro-4,4'-bis(1-methylethyl)-2,2' bioxazole) (iPr-box-C) or N-(1-hydroxy-3-methylbutan-(2S)-(-)-2-yl)-(4S)-(-)-4 isopropyl-4,5-dihydrooxazole-2-carbimidate (iPr-box-O); X = Cl, H(2)O) has been described. All complexes have been spectroscopically characterized in solution through (1)H NMR and UV-vis techniques, and the redox properties of complexes have also been studied by means of cyclic voltammetry (CV). Furthermore, the chloro complexes presented here have been characterized in the solid state through monocrystal X-ray diffraction analysis. The oxazolinic iPr-box-C ligand undergoes a Ru-assisted hydrolysis reaction generating the corresponding amidate anionic ligand iPr-box-O, that keeps coordinated to the Ru metal center and that produces a strong sigma-donation effect over it. The reactivity of the Ru-OH(2) complexes described in this paper together with other similar ones, previously synthesized by us, has been tested with regard to the epoxidation of different olefins. Complexes [Ru(II)(R-box-C)(tpm)OH(2)](BF(4))(2), R = Bz, 3'c/iPr, 3c, show high stereoselectivity in the epoxidation of cis-beta-methylstyrene, with the exclusive formation of the cis-epoxide. However, there is a significant difference in regioselectivity between the two catalysts in the epoxidation of 4 vinylcyclohexene; complex 3'c leads to the regioselective oxidation at the ring alkene position, whereas complex 3c leads to the oxidation at the terminal position. Computational calculations indicate only small energy differences between the two possible products of 4-vinylcyclohexene epoxidation, but the energy barriers for the interaction of the catalytic systems with the alkene groups of 4-vinylcyclohexene agree with the reactivity differences found for the two catalysts having isopropyl or benzyl as substituent of the oxazole ligand. Computed local Fukui functions help to explain the observed reactivity trends. PMID- 21650156 TI - Long-distance indirect excitation of nanoplasmonic resonances. AB - In nanoscopic systems, size, geometry, and arrangement are the crucial determinants of the light-matter interaction and resulting nanoparticles excitation. At optical frequencies, one of the most prominent examples is the excitation of localized surface plasmon polaritons, where the electromagnetic radiation is coupled to the confined charge density oscillations. Here, we show that beyond direct near- and far-field excitation, a long-range, indirect mode of particle excitation is available in nanoplasmonic systems. In particular, in amorphous arrays of plasmonic nanodiscs we find strong collective and coherent influence on each particle from its entire active neighborhood. This dependency of the local field response on excitation conditions at distant areas brings exciting possibilities to engineer enhanced electromagnetic fields through controlled, spatially configured illumination. PMID- 21650157 TI - Phenolic compounds from the roots of Jordanian viper's grass, Scorzonera judaica. AB - Nine new phenolic compounds, 3S-hydrangenol 40-O-R-L-rhamnopyranoysl-(1-->3)-beta D-glucopyranoside (1), thunberginol F 7-O-beta-D-glucopyranoside (2), 2-hydroxy-6 [2-(4-hydroxyphenyl)-2-oxo-ethyl]benzoic acid (3), 2-hydroxy-6-[2-(3,4 dihydroxyphenyl)-2-oxo-ethyl]benzoic acid (4), 2-hydroxy-6-[2-(3,4 dihydroxyphenyl-5-methoxy)-2-oxoethyl]benzoic acid (5), hydrangeic acid 40-O-beta D-glucopyranoside (6), E-3-(3,4-dihydroxybenzylidene)-5-(3,4 dihydroxyphenyl)dihydrofuran-2-one (7), Z-3-(3,4-dihydroxybenzylidene)-5-(3,4 dihydroxyphenyl)-2(3H)-furanone (8), and 4-[beta-D-glucopyranosyl)hydroxy] pinoresinol (9), and nine known compounds were isolated from the roots of Scorzonera judaica. Structures of 1-9 were elucidated by mass spectrometry, extensive 1D and 2D NMR spectroscopy, and CD spectroscopy.All compounds were evaluated for cytotoxic activity. PMID- 21650159 TI - Probing the allosteric mechanism in pyrrolysyl-tRNA synthetase using energy weighted network formalism. AB - Pyrrolysyl-tRNA synthetase (PylRS) is an atypical enzyme responsible for charging tRNA(Pyl) with pyrrolysine, despite lacking precise tRNA anticodon recognition. This dimeric protein exhibits allosteric regulation of function, like any other tRNA synthetases. In this study we examine the paths of allosteric communication at the atomic level, through energy-weighted networks of Desulfitobacterium hafniense PylRS (DhPylRS) and its complexes with tRNA(Pyl) and activated pyrrolysine. We performed molecular dynamics simulations of the structures of these complexes to obtain an ensemble conformation-population perspective. Weighted graph parameters relevant to identifying key players and ties in the context of social networks such as edge/node betweenness, closeness index, and the concept of funneling are explored in identifying key residues and interactions leading to shortest paths of communication in the structure networks of DhPylRS. Further, the changes in the status of important residues and connections and the costs of communication due to ligand induced perturbations are evaluated. The optimal, suboptimal, and preexisting paths are also investigated. Many of these parameters have exhibited an enhanced asymmetry between the two subunits of the dimeric protein, especially in the pretransfer complex, leading us to conclude that encoding of function goes beyond the sequence/structure of proteins. The local and global perturbations mediated by appropriate ligands and their influence on the equilibrium ensemble of conformations also have a significant role to play in the functioning of proteins. Taking a comprehensive view of these observations, we propose that the origin of many functional aspects (allostery and half-sites reactivity in the case of DhPylRS) lies in subtle rearrangements of interactions and dynamics at a global level. PMID- 21650158 TI - PMF analysis of wide-range particle size spectra collected on a major highway. AB - Particle number concentration data have been collected on a very busy road in central London (Marylebone Road). Continuous size distributions from 15 nm to 10 MUm diameter, collected over 21 days, were analyzed using positive matrix factorization which identified 10 factors, five of which were observed to make major contributions (greater than 8%) to either the total number or volume of particulate matter. The sources associated with each factor were identified from the size distribution, directional association, diurnal variation and their relationship to meteorological pollution and traffic volume variables. The factors related to the emissions on Marylebone Road accounted for 40.5% of particle volume and 71.9% of particle number. These comprised nucleation mode exhaust particles (3.6% of total volume and 27.4% of total number), solid mode exhaust particles (18.8% of total volume and 38.0% of total number), brake dust (13.7% of total volume and 1.7% of total number and resuspension (4.4% of total volume and 4.8% of total number). Another six factors were associated with the urban background accounting for 59.5% of total volume and 28.2% of total particle number count. The method is extremely successful at separating the components of on-road emissions including brake wear and resuspension. PMID- 21650160 TI - Use of structure-based design to discover a potent, selective, in vivo active phosphodiesterase 10A inhibitor lead series for the treatment of schizophrenia. AB - Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability. PMID- 21650161 TI - Systematic enumeration of heteroaromatic ring systems as reagents for use in medicinal chemistry. AB - The availability of suitable chemical building blocks, or reagents, is a key factor that determines the degree of effort required to make a target molecule. If a reagent is not available and requires synthesizing, this increases the total number of synthetic steps in the route and may result in a less attractive synthetic target. This can impact most in compound collection enhancement activities or early lead identification (LI) where typically not enough information or data are available to commit to such long multistep syntheses. In lead optimization (LO) projects, having access to commonly used reagents may improve the efficiency of building structure-activity relationships (SARs) and structure-property relationships (SPRs) around a core scaffold. This paper describes the systematic enumeration of key heteroaromatic reagent classes and the subsequent analysis of the availability of these in a number of commonly used databases. PMID- 21650162 TI - Divalent N(I) compounds with two lone pairs on nitrogen. AB - Carbon with the C(0) state has been reported recently, examples of which were known for the past decades. Silicon in the Si(0) state and phosphorus in the P(I) state are also known experimentally. This prompted us to search for divalent N(I) compounds, which resulted in the identification of ::N(<-L)(2)(?) systems with bicoordinated nitrogen in the N(I) formal oxidation state. It was found that several biguanide derivatives (especially in their protonated state) belong to this class. Quantum chemical analysis provided the structural details, molecular orbitals, charge localization (vs delocalization) trends, etc. This class of compounds has been found to be characterized by two lone pairs on the central nitrogen, very similar to the central carbon in divalent C(0) compounds (::C(< L)(2)). The new bonding environment for nitrogen reported in this article, divalent nitrogen N(I), is clearly different from the nitrenium ions NR(2)(?). The electronic structure and reactivity of representative examples of this novel class of divalent nitrogen N(I) systems (::N(<-L)(2)(?)) have been analyzed in detail, in terms of molecular orbitals, atomic charges, protonation energies, complexation energies with Lewis acids like BH(3), AlCl(3), and AuCl and compared with those of divalent C(0) systems. PMID- 21650163 TI - On the oxidation of EuFe4Sb12 and EuRu4Sb12. AB - Rare-earth-filled transition-metal pnictides having the skutterudite-type structure have been proposed for use as high-temperature thermoelectric materials to recover waste heat from vehicle exhaust, among other applications. A previous investigation by this research group of one of the most studied skutterudites, CeFe(4)Sb(12), found that, when exposed to air, this material oxidized at temperatures that are considerably below the proposed maximum operating temperature. Here, by the combined use of TGA, powder XRD, and XANES, it has been found that the substitution of Ce(3+) and Fe(2+) for larger rare-earth and transition-metal elements (Eu(2+) and Ru(2+)) results in a significantly higher oxidation temperature compared to that of CeFe(4)Sb(12). This increase can be related to the increased orbital overlap provided by these larger atoms (Eu(2+) and Ru(2+) vs Ce(3+) and Fe(2+)), enabling the development of stronger bonds. These results show how selective substitution of the constituent elements can significantly improve the thermal stability of materials. PMID- 21650164 TI - Synthesis of spiro-fused pyrazolidoylisoxazolines. AB - Routes to structurally unique spiro-fused pyrazolidoylisoxazolines are reported. These methods start with monosubstituted hydrazines or hydrazides and utilize the nitrile oxide 1,3-dipolar cycloaddition reaction to generate the targeted spiro fused bis-heterocycles. Molecular shape space diversity analyses were performed on these pyrazolidoylisoxazolines showing that manipulation of the appended R groups significantly changes the molecular shape. PMID- 21650165 TI - Giant two-photon absorption in bilayer graphene. AB - We present a quantum perturbation theory on two-photon absorption (2PA) in monolayer and bilayer graphene which is Bernal-stacked. The theory shows that 2PA is significantly greater in bilayer graphene than monolayer graphene in the visible and infrared spectrum (up to 3 MUm) with a resonant 2PA coefficient of up to ~0.2 cm/W located at half of the bandgap energy, gamma(1) = 0.4 eV. In the visible and terahertz region, 2PA exhibits a light frequency dependence of omega( 3) in bilayer graphene, while it is proportional to omega(-4) for monolayer graphene at all photon energies. Within the same order of magnitude, the 2PA theory is in agreement with our Z-scan measurements on high-quality epitaxial bilayer graphene deposited on SiC substrate at light wavelength of 780 and 1100 nm. PMID- 21650166 TI - Investigation of confined ionic liquid in nanostructured materials by a combination of SANS, contrast-matching SANS, and nitrogen adsorption. AB - Small-angle neutron scattering (SANS), contrast-matching SANS, and nitrogen adsorption have been utilized to investigate the confined ionic liquid (IL) [bmim][PF(6)] phase in ordered mesoporous silica MCM-41 and SBA-15. The results suggest that the pores of SBA-15 are completely filled with IL whereas a small fraction of the pore volume, the pore "core", of MCM-41 is empty. The contrast matching SANS measurements confirm the enhanced solubility of water in IL. In addition, they provide strong evidence that water does not enter the empty pore core of MCM-41, possibly because of the preferred orientation of the IL molecules in the adsorbed layer. PMID- 21650167 TI - Ultrafine cellulose fibers produced by Asaia bogorensis, an acetic acid bacterium. AB - The ability to synthesize cellulose by Asaia bogorensis, a member of the acetic acid bacteria, was studied in two substrains, AJ and JCM. Although both strains have identical 16S rDNA sequence, only the AJ strain formed a solid pellicle at the air-liquid interface in static culture medium, and we analyzed this pellicle using a variety of techniques. In the presence of cellulase, glucose and cellobiose were released from the pellicle suggesting that it is made of cellulose. Field emission electron microscopy allowed the visualization of a 3D knitted structure with ultrafine microfibrils (approximately 5-20 nm in width) in cellulose from A. bogorensis compared with the 40-100 nm wide microfibrils observed in cellulose isolated from Gluconacetobacter xylinus, suggesting differences in the mechanism of cellulose biosynthesis or organization of cellulose synthesizing sites in these two related bacterial species. Identifying these differences will lead to a better understanding of cellulose biosynthesis in bacteria. PMID- 21650168 TI - Nature of the binding of a c(2*2)-CO overlayer on Ag(001) and surface mediated intermolecular coupling. AB - We present a first-principles study of the nature of the binding of a c(2*2)-CO overlayer on Ag(001) and of the origin of CO-CO interactions upon adsorption. Electronic structural changes induced by molecular adsorption provide an interpretation for earlier X-ray photoemission valence band spectra of CO/Ag(001). Our results establish that CO chemisorbs on clean Ag(001) and follows the Blyholder model of donation and back-donation between CO and metal orbitals. We analyze the origin of the dispersion of the C-O stretch mode and attest that it is caused by the metal-CO coupling. Specifically, the coupling of CO to Ag, although the weakest of those between it and transition and other noble metals, greatly enhances the intermolecular force constants. We also find that the response of the charge density around CO is much stronger and of longer range when the molecule stretches than when it rigidly vibrates against the surface. This difference explains why the C-O stretch mode disperses while the Ag-CO stretch mode does not. PMID- 21650169 TI - Concise total synthesis of (+/-)-cephalotaxine via a transannulation strategy: development of a facile reductive oxy-Nazarov cyclization. AB - A concise total synthesis of (+/-)-cephalotaxine (1) has been achieved from dioxolanone derivative 15 via a transannulation strategy. The key transformation is a facile reductive oxy-Nazarov cyclization as illustrated above, involving presumably a tethered 1,2-oxidopentadienyl cation species 7a or 7b, which represents a new variant of the oxy-Nazarov cyclization and constitutes an effective, regio- and stereospecific 5-hydroxy cyclopentenone annulation protocol under mild hydride reduction conditions. PMID- 21650170 TI - Light- and heavy-atom tunneling in rearrangement reactions of cyclopropylcarbenes. AB - We investigated both light- and heavy-atom tunneling in the rearrangements of a series of cyclopropylcarbenes using canonical variational transition state theory with multidimensional tunneling corrections (CVT/MT) and the Wentzel-Kramers Brillouin (WKB) formalism. Halogeno- and hydroxy-substituted cyclopropylcarbenes were found not to undergo carbon tunneling owing to wide reaction barriers. However, while carbon tunneling plays a major role in the ring expansion of parent cyclopropylcarbene yielding cyclobutene, cyclopropylmethylcarbene is prone to undergo hydrogen tunneling to give cyclopropylmethylene. PMID- 21650171 TI - Pulling nanotubes from supported bilayers. AB - The force required to form a nanoscale tube from a supported lipid bilayer (SLB) by pulling was measured using an atomic force microscope (AFM). The equilibrium membrane shape during an AFM pulling experiment was calculated and used to derive a general force-distance relationship for pulling a tube from an SLB. We compare these theoretical results with our experimental data and determine the tube radius, the force required to elongate the tube, and, consequently, the surface tension. For a dioleoylphosphatidylcholine (DOPC) SLB, the tension was found to be close to membrane rupture during the pulling experiment. PMID- 21650172 TI - Ion diffusion coefficients through polyelectrolyte multilayers: temperature and charge dependence. AB - The diffusion coefficient is a fundamental parameter for devices exploiting the ion transport properties of polyelectrolyte multilayers (PEMUs) and complexes. Here, the transport of ferricyanide through a multilayer made from poly(diallyldimethylammonium chloride) (PDADMA) and polystyrene sulfonate (PSS) was studied as a function of temperature or salt concentration. Accurate and precise measurements of ion diffusion coefficients were obtained using steady state electrochemistry to determine the flux and Fourier transform infrared (FTIR) spectroscopy to measure the PEMU concentration. It was found that the concentration of ferricyanide inside the film decreased with temperature. Membrane transport is strongly thermally activated with activation energy 98 kJ mol(-1). A potential shift with decreasing salt concentration in cyclic voltammograms was translated into a differential flux caused by significantly higher diffusion coefficients for ferricyanide as compared to ferrocyanide. PMID- 21650173 TI - Effects of substrate constraint on crack pattern formation in thin films of colloidal polystyrene particles. AB - Crack formation and the evolution of stress in drying films of colloidal particles were studied using optical microscopy and a modified cantilever deflection technique, respectively. Drying experiments were performed using polystyrene particles with diameters of 47 +/- 10 nm, 100 +/- 16 nm, and 274 +/- 44 nm that were suspended in water. As the films dried, cracks with a well defined spacing were observed to form. The crack spacing was found to be independent of the particle size used, but to increase with the film thickness. The characteristic crack spacing was found to vary between 20 and 300 MUm for films with thickness values in the range 3-70 MUm. Cantilever deflection measurements revealed that the stresses that develop in the film increase with decreasing film thickness (increasing surface-to-volume ratio). The latter observation was interpreted in terms of the effects of a substrate constraint which causes the build up of stresses in the films. This interpretation was confirmed by crack formation experiments that were performed on liquid mercury surfaces in which removal of the substrate constraint prevented crack formation. Experiments were also performed on compliant elastomer surfaces in which the level of constraint was varied by changing the substrate modulus. The cracking length scale was found to increase with decreasing substrate modulus. A simple theory was also developed to describe the substrate modulus dependence of the cracking length scale. These combined experiments and theory provide convincing evidence that substrate constraints are an important factor in driving crack formation in thin colloidal films. PMID- 21650174 TI - H-bond network around retinal regulates the evolution of ultraviolet and violet vision. AB - Ancestors of vertebrates used ultraviolet vision. Some descendants preserved ultraviolet vision, whereas some others replaced it with violet vision, and then, some of avian lineages reinvented ultraviolet vision. Ultraviolet (absorption at ~360 nm) and violet (410-440 nm) sensitivities of visual pigments are known to be affected by around 20 amino acid substitutions. The present quantum mechanical/molecular mechanical calculations show that these substitutions modify a H-bond network formed by two waters and sites 86, 90, 113, 114, 118, and 295, which determines the protonation state of Schiff base linked 11-cis-retinal. A pigment is ultraviolet-sensitive when it is more stable with an unprotonated retinal (SBR) form than with its protonated analogue (PSBR) and is violet sensitive when the PSBR form is more stable. These results establish for the first time the chemical basis of ultraviolet and violet vision in vertebrates. PMID- 21650175 TI - Relationship between the metabolite profile and technological properties of bovine milk from two dairy breeds elucidated by NMR-based metabolomics. AB - The aim of the present study was to investigate the relationship between the metabolite profile of milk and important technological properties by using nuclear magnetic resonance (NMR)-based metabolomics. The metabolomics approach was introduced for the metabolic profiling of a set of milk samples from two dairy breeds representing a wide span in coagulation properties. The milk metabolite profiles obtained by proton and carbon NMR spectroscopy could be correlated to breed and, more interestingly, also with the coagulation profile, as established by traditional methods by using principal component analysis (PCA). The metabolites responsible for the separation into breed could mainly be ascribed to carnitine and lactose, whereas the metabolites varying in the samples with respect to coagulation properties included citrate, choline, carnitine, and lactose. The results found in the present study demonstrated a promising potential of NMR-based metabolomics for a rapid analysis and classification of milk samples, both of which are useful for the dairy industry. PMID- 21650176 TI - The influence of solutes on the enthalpy/entropy change of the actinomycin D binding to DNA: hydration, energy compensation and long-range deformation on DNA. AB - The effects of the changes in the temperature and in the water chemical potential on the energetic of the actinomycin D (ACTD) interaction with natural DNA are studied. At reduced water chemical potential, induced by the addition of neutral solute (sucrose), the ACTD-to-DNA binding isotherms show that the drug accesses two types of binding sites: strong and weak. The binding constants to the stronger sites are sensitive to changes in the temperature and in the water chemical potential, while the weak sites are practically insensitive to these changes. The van't Hoff analyses of the binding in different water chemical potential shows that the binding process to the more specific sites is endothermic in phosphate buffer (DeltaH(vH) ~ 1 kcal/mol) and becomes exothermic when the water chemical potential decreases (DeltaH(vH) = -11 kcal/mol in sucrose 30%). The number of water molecules released on the binding to the stronger sites, obtained from the slopes of linkage plots in different temperatures, increases with the decrease in the temperature. Ring closure reactions in the presence of neutral solutes have shown that the reduction in the water activity induces DNA unwinding. It was observed that both reduced water chemical potential and small ratios of daunomycin bound per base pairs have the same effects on the ACTD binding isotherms and consequently on the binding thermodynamic parameters. The results presented indicate that the ACTD binding to the recognition site is enthalpycally unfavorable, which should be compensated by the deformation in the DNA. This compensation would probably be the origin of the synergism observed for these two drugs. PMID- 21650177 TI - Dihydrogen activation with (t)Bu3P/B(C6F5)3: a chemically competent indirect mechanism via in situ-generated p-(t)Bu2P-C6F4-B(C6F5)2. AB - A chemically competent indirect pathway for the activation of dihydrogen by the nonmetal Lewis acid/Lewis base pair (t)Bu(3)P/B(C(6)F(5))(3) is described. The reaction between (t)Bu(3)P and B(C(6)F(5))(3) produces [(t)Bu(3)PH](+)[FB(C(6)F(5))(3)](-) and the known phosphinoborane p-(t)Bu(2)P C(6)F(4)-B(C(6)F(5))(2) (1-(t)Bu) with elimination of isobutylene. At 1:1 stoichiometry, 1-(t)Bu is produced rapidly in detectable quantities and can act as a catalyst for the formation of [(t)Bu(3)PH](+)[HB(C(6)F(5))(3)](-) from (t)Bu(3)P and B(C(6)F(5))(3) in the presence of H(2). The extent to which this indirect path competes with the direct path is explored. PMID- 21650178 TI - Bacterial translational motion on the electrode surface under anodic electric field. AB - Application of an electric field (alternating or cathodic polarization) has been suggested as a possible mean of controlling biofilm development. Bacteria on an anodically polarized surface were shown to be active and highly motile when compared with a nonpolarized condition, but no quantitative information on bacterial motion has been reported. This study investigated the effects of environmental conditions (current density and ionic strength) on the translational motion of P. aeruginosa PAO1 cells under an anodic electric field using a quantitative tracking method. Bacterial displacement for 10 s was found to be approximately 1.2 MUm, irrespective of wide-ranging current densities (7.5 30 MUA/cm(2)). However, the local dynamics of bacterial communities differed under varied current densities. The distribution of bacterial displacement appeared to exhibit a more oscillating (subdiffusive) at high current density. At the same time, the number of bacteria with a circular trajectory (superdiffusive) decreased. Bacterial movement decreased with increased ionic strength of the media, because of strong electrostatic interactions. The motion of bacterial communities on an anodically polarized surface under various conditions is discussed, along with possible mechanisms. In addition, the control of biofilm growth was partly demonstrated by changing the motility of bacterial cells under anodic polarization. PMID- 21650179 TI - Autocatalyses. AB - Autocatalysis is a fundamental concept, used in a wide range of domains. From the most general definition of autocatalysis, that is, a process in which a chemical compound is able to catalyze its own formation, several different systems can be described. We detail the different categories of autocatalyses and compare them on the basis of their mechanistic, kinetic, and dynamic properties. It is shown how autocatalytic patterns can be generated by different systems of chemical reactions. With the notion of autocatalysis covering a large variety of mechanistic realizations with very similar behaviors, it is proposed that the key signature of autocatalysis is its kinetic pattern expressed in a mathematical form. PMID- 21650181 TI - Correlating physical changes and enhanced enzymatic saccharification of pine flour pretreated by N-methylmorpholine-N-oxide. AB - Pretreatment of lignocellulosic biomass by N-methylmorpholine-N-oxide (NMMO), a solvent used in the textile industry to dissolve cellulose for production of regenerated cellulose fibers, was observed to enhance significantly enzymatic saccharification and fermentation. The enhancement was speculated to have been caused by reduced cellulose crystallinity after dissolution and precipitation processes. This work focused on assessing several physical changes and their correlations to enzymatic saccharification of pine flour after NMMO pretreatment. Results from microstructure, surface chemical composition, and cellulose accessibility complementarily illustrated the enrichment of cellulose on pine flour surface after NMMO pretreatment. Cellulose accessibility was highly correlated to the overall glucan conversion rate. Changes in crystallinity were correlated to the initial hydrolysis rate but not overall glucan conversion rate. Findings from this work may contribute to lignocellulosic bioenergy from development of novel pretreatment technologies utilizing NMMO. PMID- 21650180 TI - On the low surface tension of lung surfactant. AB - Natural lung surfactant contains less than 40% disaturated phospholipids, mainly dipalmitoylphosphatidylcholine (DPPC). The mechanism by which lung surfactant achieves very low near-zero surface tensions, well below its equilibrium value, is not fully understood. To date, the low surface tension of lung surfactant is usually explained by a squeeze-out model which predicts that upon film compression non-DPPC components are gradually excluded from the air-water interface into a surface-associated surfactant reservoir. However, detailed experimental evidence of the squeeze-out within the physiologically relevant high surface pressure range is still lacking. In the present work, we studied four animal-derived clinical surfactant preparations, including Survanta, Curosurf, Infasurf, and BLES. By comparing compression isotherms and lateral structures of these surfactant films obtained by atomic force microscopy within the physiologically relevant high surface pressure range, we have derived an updated squeeze-out model. Our model suggests that the squeeze-out originates from fluid phases of a phase-separated monolayer. The squeeze-out process follows a nucleation-growth model and only occurs within a narrow surface pressure range around the equilibrium spreading pressure of lung surfactant. After the squeeze out, three-dimensional nuclei stop growing, thereby resulting in a DPPC-enriched interfacial monolayer to reduce the air-water surface tension to very low values. PMID- 21650182 TI - Microstructured cystine dendrites-based impedimetric sensor for nucleic acid detection. AB - We report results of the studies relating to the fabrication and characterization of novel biosensing electrode by covalent immobilization of DNA onto microstructural cystine (Cys) prepared by acoustic cavitation method. The TEM investigations of these structures reveal transformation of microstructured Cys from nanorods to dendritic structure under optimum conditions. The Cys dendrites (denCys) have been investigated by XRD, FT-IR, and SEM studies. These biosensing electrodes have been fabricated by immobilization of Escherichia coli (E. coli) specific DNA probe onto the dendritic cystine. The results of the electrochemical impedance spectroscopy studies reveal that this nucleic acid sensor exhibits linear response to cDNA in the concentration range of 10(-6) to 10(-14) M with response time of 30 min. The biosensing characteristics show that the fabricated E. coli sensor can be reused about 4 times and is stable for ~4 weeks. The studies on cross-reactivity of the sensor for other water-borne pathogens like Salmonella typhimurium, Neisseria meningitides, and Klebsiella pneumonia reveal specificity of the bioelectrode for E. coli detection. PMID- 21650183 TI - Protein structure along the order-disorder continuum. AB - Thermal fluctuations cause proteins to adopt an ensemble of conformations wherein the relative stability of the different ensemble members is determined by the topography of the underlying energy landscape. "Folded" proteins have relatively homogeneous ensembles, while "unfolded" proteins have heterogeneous ensembles. Hence, the labels "folded" and "unfolded" represent attempts to provide a qualitative characterization of the extent of structural heterogeneity within the underlying ensemble. In this work, we introduce an information-theoretic order parameter to quantify this conformational heterogeneity. We demonstrate that this order parameter can be estimated in a straightforward manner from an ensemble and is applicable to both unfolded and folded proteins. In addition, a simple formula for approximating the order parameter directly from crystallographic B factors is presented. By applying these metrics to a large sample of proteins, we show that proteins span the full range of the order-disorder axis. PMID- 21650184 TI - One-step Ge/Si epitaxial growth. AB - Fabricating a low-cost virtual germanium (Ge) template by epitaxial growth of Ge films on silicon wafer with a Ge(x)Si(1-x) (0 < x < 1) graded buffer layer was demonstrated through a facile chemical vapor deposition method in one step by decomposing a hazardousless GeO(2) powder under hydrogen atmosphere without ultra high vacuum condition and then depositing in a low-temperature region. X-ray diffraction analysis shows that the Ge film with an epitaxial relationship is along the in-plane direction of Si. The successful growth of epitaxial Ge films on Si substrate demonstrates the feasibility of integrating various functional devices on the Ge/Si substrates. PMID- 21650185 TI - Surface dilatational moduli of poly(vinyl acetate) (PVAc) and PVAc-poly(n-hexyl isocyanate) (PHIC) blend films at the air-water interface. AB - Surface dilatational moduli of poly(vinyl acetate) (PVAc) film and blend films of PVAc and poly(n-hexyl isocyanate) (PHIC) were measured at the air-water interface. PVAc formed a film that was looser and also more stable against strain than the PHIC film. The apparent surface dilatational modulus and surface pressure of the blend films were superimposed on the lower concentration of PVAc, irrespective of the composition of PVAc. However, the additivity rule was not applicable to the apparent surface dilatational modulus and surface pressure. The scaling exponents of the apparent surface dilatational modulus against the added surface concentration decreased with an increase in the proportion of PVAc, suggesting that blend films gradually change from glass material to expanded films. PMID- 21650187 TI - How thermal curing of an organic paper coating changes topography, chemistry, and wettability. AB - Celluloses are preferred renewable substrates, but hydrophilicity and porosity disfavor their water resistance. We present here an ecofriendly application of imidized nanoparticles and a method to flexibly tune the surface wettability of papers. The soft nanostructured coating is sensitive to thermal curing, which affects both the surface chemistry and morphology. The thermal stability of the coating is first investigated with conventional and modulated differential scanning calorimetry, revealing influences of the imide content and an endotherm reaction below the glass transition temperature at 120-150 degrees C. The latter is studied in detail for an appropriate selection of the copolymer precursors. According to diffuse reflection infrared spectroscopy, Raman spectroscopy, and UV/vis spectroscopy, the endotherm corresponds to an imidization reaction. The morphology of the coatings is followed at various scale levels by contactless roughness measurements and atomic force microscopy. Finally, the experimental values are fitted to the parameters of the Wenzel wetting model, and so-called calibration curves for the relation between contact angles, surface roughness, and surface chemistry are presented. They allow the prediction of the water contact angle of coated papers from the hydrophilic to the hydrophobic range, with a maximum in hydrophobicity after increasing the imide content at 120-150 degrees C curing. PMID- 21650186 TI - Geometry and adhesion of extracellular domains of DC-SIGNR neck length variants analyzed by force-distance measurements. AB - Force-distance measurements have been used to examine differences in the interaction of the dendritic cell glycan-binding receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR (L-SIGN) with membranes bearing glycan ligands. The results demonstrate that upon binding to membrane-anchored ligand, DC-SIGNR undergoes a conformational change similar to that previously observed for DC-SIGN. The results also validate a model for the extracellular domain of DC SIGNR derived from crystallographic studies. Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck. The findings are consistent with an elongated, relatively rigid structure of the neck repeat observed in crystals. In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC SIGNR result from variations in the sequences of the necks. PMID- 21650188 TI - Mild nonepimerizing N-alkylation of amines by alcohols without transition metals. AB - A one-pot two-step sequence involving an oxidation/imine-iminium formation/reduction allowed the N-alkylation of amines by alcohols without any epimerization when optically active alcohols and amines are involved in the process. PMID- 21650190 TI - Highly regio- and diastereoselective construction of spirocyclopenteneoxindoles through phosphine-catalyzed [3 + 2] annulation of Morita-Baylis-Hillman carbonates with isatylidene malononitriles. AB - Phosphine-catalyzed highly regio- and diastereoselective [3 + 2] annulation of Morita-Baylis-Hillman (MBH) carbonates with isatylidene malononitriles has been disclosed to give the corresponding spirocyclopenteneoxindoles in excellent yields under mild conditions. A plausible reaction mechanism has also been proposed on the basis of previous literature. PMID- 21650191 TI - Deuterium magic angle spinning NMR used to study the dynamics of peptides adsorbed onto polystyrene and functionalized polystyrene surfaces. AB - LKalpha14 is a 14 amino acid peptide with a periodic sequence of leucine and lysine residues consistent with an amphipathic alpha-helix. This "hydrophobic periodicity" has been found to result in an alpha-helical secondary structure at air-water interfaces and on both polar and nonpolar solid polymer surfaces. In this paper, the dynamics of LKalpha14 peptides, selectively deuterated at a single leucine and adsorbed onto polystyrene and carboxylated polystyrene beads, are studied using (2)H magic angle spinning (MAS) solid state NMR over a 100 degrees C temperature range. We first demonstrate the sensitivity enhancement possible with (2)H MAS techniques, which in turn enables us to obtain high quality (2)H NMR spectra for selectively deuterated peptides adsorbed onto solid polymer surfaces. The extensive literature shows that the dynamics of leucine side chains are sensitive to the local structural environment of the protein. Therefore, the degree to which the dynamics of leucine side chains and the backbone of the peptide LKalpha14 are influenced by surface proximity and surface chemistry is studied as a function of temperature with (2)H MAS NMR. It is found that the dynamics of the leucine side chains in LKalpha14 depend strongly upon the orientation of the polymer on the surface, which in turn depends on whether the LKalpha14 peptide adsorbs onto a polar or nonpolar surface. (2)H MAS line shapes therefore permit probes of surface orientation over a wide temperature range. PMID- 21650192 TI - Assembly of homolinear alpha(1->2)-linked nonamannoside on ionic liquid support. AB - An improved method for the synthesis of large and complex oligosaccharides on ionic liquid (IL) support was developed. A strategy to attach the acceptor on IL using a more stable ether linker was used to prevent undesirable decomposition and side products. A "dissolution-evaporation-precipitation" purification procedure was also developed by combining the advantages of precipitation and solid-liquid extraction to reduce mechanical loss and purification time. This approach was successfully used for the rapid assembly of ionic liquid supported homolinear alpha(1->2)-linked nonamannoside in 25.2% overall yield within 28.5 h. PMID- 21650193 TI - Gold-nanoparticle-functionalized In2O3 nanowires as CO gas sensors with a significant enhancement in response. AB - We present the room-temperature sensing of gold nanoparticle (AuNP) functionalized In(2)O(3) nanowire field-effect transistor (NW-FET) for low concentration CO gas. AuNPs were functionalized onto In(2)O(3) nanowires via a self-assembled monolayer of p-aminophenyltrimethoxysilane (APhS-SAM). The nanowires were mounted onto the Au electrodes with both ends in Schottky contacts. High sensor response toward low concentration of CO gas (200 ppb-5 ppm) at room temperature is achieved. The presence of AuNPs on the surface of In(2)O(3) nanowire serves to enhance the CO oxidation due to a higher oxygen ion chemisorption on the conductive AuNP surfaces. Detailed studies showed that the sensing capabilities were greatly enhanced in comparison to those of bare nanowires or low coverage of Au NP-decorated nanowires. When the sensor is exposed to CO, the CO molecules interact with the preadsorbed oxygen ions on the AuNP surface. The CO oxidation on the AuNPs leads to the transfer of electrons into the semiconducting In(2)O(3) nanowires and this is reflected as the change in conductance of the NW-FET sensor. This work provides a promising approach for fabricating nanowire devices with excellent sensing capabilities at room temperature. PMID- 21650194 TI - Synthesis of substituted 1,4,5,6-tetrahydrocyclopenta[b]pyrroles by platinum catalyzed cascade cyclization/ring expansion of 2-alkynyl-1-azaspiro[2.3]hexanes. AB - The reaction of 2-alkynyl-1-azaspiro[2.3]hexanes with a platinum catalyst is described. 1,4,5,6-Tetrahydrocyclopenta[b]pyrroles having a variety of substituents were conveniently synthesized via a cascade cyclization/ring expansion process. PMID- 21650195 TI - Preparation and surface properties of novel low surface free energy fluorinated silane-functional polybenzoxazine films. AB - A novel fluorinated silane-functional benzoxazine monomer is synthesized, and the structure is characterized by FTIR and (1)H NMR. Chemical bonds Si-O-Si linkage between the benzoxazine monomer and the substrate are identified through the variation of water contact angles. The low surface free energy calculation and mechanism of the benzoxazine polymer films are proved through contact angle measurement and FTIR. The film formation property and thermal stability of the polybenzoxazine are also investigated. These results clearly show that this novel polybenzoxazine can not only bond to the substrate but also possess even lower surface free energy which is 15.5 mJ/m(2). The polymer also possesses well thermal stability with a glass transition temperature of 188 degrees C and the 5% weight loss temperatures of 276 degrees C. PMID- 21650196 TI - Recognition ability of DNA for carbon nanotubes correlates with their binding affinity. AB - The ability to sort mixtures of carbon nanotubes (CNTs) based on chirality has recently been demonstrated using special short DNA sequences that recognize certain matching CNTs of specific chirality. In this work, we report on a study of the relationship between recognition sequences and the strength of their binding to the recognized CNT. We have chosen the (6,5) CNT and its corresponding DNA recognition sequences for investigation in this study. Binding strength is quantified by studying the kinetics of DNA replacement by a surfactant, which is monitored by following shifts in the absorption spectrum. We find that recognition ability correlates strongly with binding strength thus measured; addition or subtraction of just one base from the recognition sequence can enhance the kinetics of DNA displacement some 20-fold. The surfactant displaces DNA in two steps: a rapid first stage lasting less than a few seconds, followed by progressive removal lasting tens of minutes. The kinetics of the second stage is analyzed to extract activation energies. Fluorescence studies support the finding that the DNA sequence that recognizes the (6,5)-CNT forms a more stable hybrid than its close relatives. PMID- 21650197 TI - Polarizable water networks in ligand-metalloprotein recognition. Impact on the relative complexation energies of Zn-dependent phosphomannose isomerase with D mannose 6-phosphate surrogates. AB - Using polarizable molecular mechanics, a recent study [de Courcy et al. J. Am. Chem. Soc., 2010, 132, 3312] has compared the relative energy balances of five competing inhibitors of the FAK kinase. It showed that the inclusion of structural water molecules was indispensable for an ordering consistent with the experimental one. This approach is now extended to compare the binding affinities of four active site ligands to the Type I Zn-metalloenzyme phosphomannose isomerase (PMI) from Candida albicans. The first three ones are the PMI substrate beta-D-mannopyranose 6-phosphate (beta-M6P) and two isomers, alpha-D mannopyranose 6-phosphate (alpha-M6P) and beta-D-glucopyranose 6-phosphate (beta G6P). They have a dianionic 6-phosphate substituent and differ by the relative configuration of the two carbon atoms C1 and C2 of the pyranose ring. The fourth ligand, namely 6-deoxy-6-dicarboxymethyl-beta-D-mannopyranose (beta-6DCM), is a substrate analogue that has the beta-M6P phosphate replaced by the nonhydrolyzable phosphate surrogate malonate. In the energy-minimized structures of all four complexes, one of the ligand hydroxyl groups binds Zn(II) through a water molecule, and the dianionic moiety binds simultaneously to Arg304 and Lys310 at the entrance of the cavity. Comparative energy-balances were performed in which solvation of the complexes and desolvation of PMI and of the ligands are computed using the Langlet-Claverie continuum reaction field procedure. They resulted into a more favorable balance in favor of beta-M6P than alpha-M6P and beta-G6P, consistent with the experimental results that show beta-M6P to act as a PMI substrate, while alpha-M6P and beta-G6P are inactive or at best weak inhibitors. However, these energy balances indicated the malonate ligand beta 6DCM to have a much lesser favorable relative complexation energy than the substrate beta-M6P, while it has an experimental 10-fold higher affinity than it on Type I PMI from Saccharomyces cerevisiae. The energy calculations were validated by comparison with parallel ab initio quantum chemistry on model binding sites extracted from the energy-minimized PMI-inhibitor complexes. We sought to improve the models upon including explicit water molecules solvating the dianionic moieties in their ionic bonds with the Arg304 and Lys310 side chains. Energy-minimization resulted in the formation of three networks of structured waters. The first water of each network binds to one of the three accessible anionic oxygens. The networks extend to PMI residues (Asp17, Glu48, Asp300) remote from the ligand binding site. The final comparative energy balances also took into account ligand desolvation in a box of 64 waters. They now resulted into a large preference in favor of beta-6DCM over beta-M6P. The means to further augment the present model upon including entropy effects and sampling were discussed. Nevertheless a clear-cut conclusion emerging from this as well as our previous study on FAK kinase is that both polarization and charge transfer contributions are critical elements of the energy balances. PMID- 21650198 TI - Photoreduction kinetics of sodium tetrachloroaurate under synchrotron soft X-ray exposure. AB - We report on the time evolution of the sodium tetrachloroaurate (NaAuCl(4)) chemical properties as a function of soft X-ray exposure in a dried sample on a silicon surface using X-ray photoelectron spectroscopy (XPS). Our investigations provide mechanistic insight into the photoreduction kinetics from Au(III) to Au(I) and then Au(I) to Au(0). We unambiguously show that XPS photoreduction occurs in stepwise fashion via the Au(I) state. Both photoreduction steps undergo first-order kinetics. PMID- 21650199 TI - Electrostatic potential of specific mineral faces. AB - Reaction rates of environmental processes occurring at hydrated mineral surfaces are in part controlled by the electrostatic potential that develops at the interface. This potential depends on the structure of exposed crystal faces as well as the pH and the type of ions and their interactions with these faces. Despite its importance, experimental methods for determining fundamental electrostatic properties of specific crystal faces such as the point of zero charge are few. Here we show that this information may be obtained from simple, cyclic potentiometric titration using a well-characterized single-crystal electrode exposing the face of interest. The method exploits the presence of a hysteresis loop in the titration measurements that allows the extraction of key electrostatic descriptors using the Maxwell construction. The approach is demonstrated for hematite (alpha-Fe(2)O(3)) (001), and thermodynamic proof is provided for the resulting estimate of its point of zero charge. Insight gained from this method will aid in predicting the fate of migrating contaminants, mineral growth/dissolution processes, and mineral-microbiological interactions and in testing surface complexation theories. PMID- 21650200 TI - Ab initio studies of aromatic excimers using multiconfiguration quasi-degenerate perturbation theory. AB - The aromatic excimers of benzene, naphthalene, anthracene, pyrene, and perylene are systematically investigated using the multiconfiguration quasi-degenerate perturbation theory (MCQDPT) method, which is one of high-level ab initio quantum chemical methods. The reference configuration space for MCQDPT is carefully designed for an appropriate description of the target electronic state with a tractable computational cost. The dimers with eclipsed parallel arrangement are investigated. The basis set dependence of the selected spectroscopic parameters is examined for the benzene and naphthalene dimers, and that of the excimer binding energy is found to be significant. In contrast, the equilibrium intermolecular distance and excimer fluorescence energy are less sensitive to the size of the basis sets used, and they agree with the corresponding experimental values, even with a nonextensive basis set size. The calculated spectroscopic parameters for anthracene, pyrene, and perylene dimers are also in good agreement with the experimental results. The electronic properties of the excimers are discussed in relation to those of the corresponding monomers. The wave functions of the excimers are analyzed in detail to clarify the origin of the attractive nature between the two monomers. PMID- 21650201 TI - Colloidal stability of magnetic iron oxide nanoparticles: influence of natural organic matter and synthetic polyelectrolytes. AB - The colloidal behavior of natural organic matter (NOM) and synthetic poly(acrylic acid) (PAA)-coated ferrimagnetic (gammaFe(2)O(3)) nanoparticles (NPs) was investigated. Humic acid (HA), an important component of NOM, was extracted from a peat soil. Two different molecular weight PAAs were also used for coating. The colloidal stability of the coated magnetic NPs was evaluated as a resultant of the attractive magnetic dipolar and van der Waals forces and the repulsive electrostatic and steric-electrosteric interactions. The conformational alterations of the polyelectrolytes adsorbed on magnetic gammaFe(2)O(3) NPs and their role in colloidal stability were determined. Pure gammaFe(2)O(3) NPs were extremely unstable because of aggregation in aqueous solution, but a significant stability enhancement was observed after coating with polyelectrolytes. The steric stabilization factor induced by the polyelectrolyte coating strongly dictated the colloidal stability. The pH-induced conformational change of the adsorbed, weakly charged polyelectrolytes had a significant effect on the colloidal stability. Atomic force microscopy (AFM) revealed the stretched conformation of the HA molecular chains adsorbed on the gammaFe(2)O(3) NP surface at pH 9, which enhanced the colloidal stability through long-range electrosteric stabilization. The depletion of the polyelectrolyte during the dilution of the NP suspension decreased the colloidal stability under acidic solution conditions. The conformation of the polyelectrolytes adsorbed on the NP surface was altered as a function of the substrate surface charge as viewed from AFM imaging. The polyelectrolyte coating also led to a reduction in magnetic moments and decreased the coercivity of the coated gammaFe(2)O(3) NPs. Thus, the enhanced stabilization of the coated maghematite NPs may facilitate their delivery in the groundwater for the effective removal of contaminants. PMID- 21650202 TI - Metastability of native proteins and the phenomenon of amyloid formation. AB - An experimental determination of the thermodynamic stabilities of a series of amyloid fibrils reveals that this structural form is likely to be the most stable one that protein molecules can adopt even under physiological conditions. This result challenges the conventional assumption that functional forms of proteins correspond to the global minima in their free energy surfaces and suggests that living systems are conformationally as well as chemically metastable. PMID- 21650203 TI - Photoinduced intramolecular tryptophan oxidation and excited-state behavior of [Re(L-AA)(CO)3(alpha-diimine)](+) (L = pyridine or imidazole, AA = tryptophan, tyrosine, phenylalanine). AB - Re(I) carbonyl-diimine complexes [Re(L-AA)(CO)(3)(N,N)](+) (N,N = bpy, phen) containing an aromatic amino acid (AA), phenylalanine (Phe), tyrosine (Tyr), or tryptophan (Trp), linked to Re by a pyridine-amido or imidazole-amido ligand L have been synthesized and their excited-state properties investigated by nanosecond time-resolved IR (TRIR) and emission spectroscopy. Near-UV optical excitation populates a Re(I)(CO)(3)->N,N (3)MLCT excited state *[Re(II)(L AA)(CO)(3)(N,N(*-))](+). Decay to the ground state (50-300 ns lifetime) is the only excited-state deactivation process observed in the case of Phe and Tyr complexes, whereas the Trp-containing species undergo a Trp(indole)->*Re(II) electron transfer (ET) producing a charge-separated (CS) state, [Re(I)(L Trp(*+))(CO)(3)(N,N(*-))](+). The ET occurs with a 8-40 ns lifetime depending on L, N,N, and the solvent. The CS state is characterized by nu(CO) IR bands shifted to lower wavenumbers from their respective ground-state positions and two bands at 1278 and 1497 cm(-1) tentatively attributed to Trp(*+). The amido bridge is affected by both the MLCT excitation and the subsequent ET, manifested by the shifts and intensity changes of the amide-I IR band at about 1680 cm(-1). The CS state decays to the ground state by a N,N(*-)->Trp(*+) back-ET the rates of which are comparable to those of the forward ET, 30-60 ns. This study independently demonstrates that Trp can act as an electron-hopping intermediate in photodriven ET systems based on Re-labeled proteins and supramolecules. Photoinduced ET in Trp-containing Re complexes also can be used to generate Trp(*+) and investigate its spectral properties and reactivity. PMID- 21650204 TI - Photoinduced carrier generation and decay dynamics in intercalated and non intercalated polymer:fullerene bulk heterojunctions. AB - The dependence of photoinduced carrier generation and decay on donor-acceptor nanomorphology is reported as a function of composition for blends of the polymer poly(2,5-bis(3-tetradecylthiophen-2-yl)thieno[3,2-b]thiophene) (pBTTT-C(14)) with two electron-accepting fullerenes: phenyl-C(71)-butyric acid methyl ester (PC(71)BM) or the bisadduct of phenyl-C(61)-butyric acid methyl ester (bis PC(61)BM). The formation of partially or fully intercalated bimolecular crystals at weight ratios up to 1:1 for pBTTT-C(14):PC(71)BM blends leads to efficient exciton quenching due to a combination of static and dynamic mechanisms. At higher fullerene loadings, pure PC(71)BM domains are formed that result in an enhanced free carrier lifetime, as a consequence of spatial separation of the electron and hole into different phases, and the dominant contribution to the photoconductance comes from the high-frequency electron mobility in the fullerene clusters. In the pBTTT-C(14):bis-PC(61)BM system, phase separation results in a non-intercalated structure, independent of composition, which is characterized by exciton quenching that is dominated by a dynamic process, an enhanced carrier lifetime and a hole-dominated photoconductance signal. The results indicate that intercalation of fullerene into crystalline polymer domains is not detrimental to the density of long-lived carriers, suggesting that efficient organic photovoltaic devices could be fabricated that incorporate intercalated structures, provided that an additional pure fullerene phase is present for charge extraction. PMID- 21650205 TI - Coadsorption of n monomer species on terraces and nanotubes. AB - The knowledge of the partition function, Z, of a system of particles adsorbed on a surface is all that is required to determine the occupational characteristics of the adsorbates and the thermodynamic properties of the system. The surface considered is a terrace or a nanotube of arbitrary periodic lattice geometry, L atomic sites in length, and M' sites in the width of the terrace or in the normal cross section of the nanotube. The matrix method introduced in 2007 to obtain Z for the adsorption study of one species of monomers is now generalized to the study of the coadsorption of any number, n, of monomer species. We provide proof that Z can be related to the eigenvalues of a real and non-negative matrix (T matrix) of rank (n + 1)(M), where M is an integer multiple of M'. In the infinite L limit, we also prove that Z is the largest eigenvalue of the T matrix, raised to the power of (1)/(M). Because the rank of this matrix increases exponentially with M, we develop a technique for its recursive construction applicable to any lattice geometry, which is easily programmed and efficiently adaptable for supercomputing and multiparallel processing. As examples, we consider the coadsorption on square, equilateral triangular, and honeycomb surfaces. This general formulation can now be applied to model a whole new set of experiments involving the coadsorption of two or more monomer species, on terrace or nanotube surfaces with various periodic lattice structures. PMID- 21650206 TI - Defect-free single-crystal SiGe: a new material from nanomembrane strain engineering. AB - Many important materials cannot be grown as single crystals in bulk form because strain destroys long-range crystallinity. Among them, alloys of group IV semiconductors, specifically SiGe alloys, have significant technological value. Using nanomembrane strain engineering methods, we demonstrate the fabrication of fully elastically relaxed Si(1-x)Ge(x) nanomembranes (NMs) for use as growth substrates for new materials. To do so, we grow defect-free, uniformly and elastically strained SiGe layers on Si substrates and release the SiGe layers to allow them to relax this strain completely as free-standing NMs. These SiGe NMs are transferred to new hosts and bonded there. We confirm the high structural quality of these new materials and demonstrate their use as substrates for technologically relevant epitaxial films by growing strained-Si layers and thick, lattice-matched SiGe alloy layers on them. PMID- 21650207 TI - Assessing the microbiological performance and potential cost of boiling drinking water in urban Zambia. AB - Boiling is the most common method of disinfecting water in the home and the benchmark against which other point-of-use water treatment is measured. In a six week study in peri-urban Zambia, we assessed the microbiological effectiveness and potential cost of boiling among 49 households without a water connection who reported "always" or "almost always" boiling their water before drinking it. Source and household drinking water samples were compared weekly for thermotolerant coliforms (TTC), an indicator of fecal contamination. Demographics, costs, and other information were collected through surveys and structured observations. Drinking water samples taken at the household (geometric mean 7.2 TTC/100 mL, 95% CI, 5.4-9.7) were actually worse in microbiological quality than source water (geometric mean 4.0 TTC/100 mL, 95% CI, 3.1-5.1) (p < 0.001), although both are relatively low levels of contamination. Only 60% of drinking water samples were reported to have actually been boiled at the time of collection from the home, suggesting over-reporting and inconsistent compliance. However, these samples were of no higher microbiological quality. Evidence suggests that water quality deteriorated after boiling due to lack of residual protection and unsafe storage and handling. The potential cost of fuel or electricity for boiling was estimated at 5% and 7% of income, respectively. In this setting where microbiological water quality was relatively good at the source, safe-storage practices that minimize recontamination may be more effective in managing the risk of disease from drinking water at a fraction of the cost of boiling. PMID- 21650208 TI - Application of CSIA to distinguish between vapor intrusion and indoor sources of VOCs. AB - At buildings with potential for vapor intrusion of volatile organic chemicals (VOCs) from the subsurface, the ability to accurately distinguish between vapor intrusion and indoor sources of VOCs is needed to support accurate and efficient vapor intrusion investigations. We have developed a method for application of compound-specific stable isotope analysis (CSIA) for this purpose that uses an adsorbent sampler to obtain sufficient sample mass from the air for analysis. Application of this method to five residences near Hill Air Force Base in Utah indicates that subsurface and indoor sources of tricholorethene and tetrachloroethene often exhibit distinct carbon and chlorine isotope ratios. The differences in isotope ratios between indoor and subsurface sources can be used to identify the source of these chemicals when they are present in indoor air. PMID- 21650209 TI - Thermoelectrics from abundant chemical elements: high-performance nanostructured PbSe-PbS. AB - We report promising thermoelectric properties of the rock salt PbSe-PbS system which consists of chemical elements with high natural abundance. Doping with PbCl(2), excess Pb, and Bi gives n-type behavior without significantly perturbing the cation sublattice. Thus, despite the great extent of dissolution of PbS in PbSe, the transport properties in this system, such as carrier mobilities and power factors, are remarkably similar to those of pristine n-type PbSe in fractions as high as 16%. The unexpected finding is the presence of precipitates ~2-5 nm in size, revealed by transmission electron microscopy, that increase in density with increasing PbS concentration, in contrast to previous reports of the occurrence of a complete solid solution in this system. We report a marked impact of the observed nanostructuring on the lattice thermal conductivity, as highlighted by contrasting the experimental values (~1.3 W/mK) to those predicted by Klemens-Drabble theory at room temperature (~1.6 W/mK). Our thermal conductivity results show that, unlike in PbTe, optical phonon excitations in PbSe-PbS systems contribute to heat transport at all temperatures. We show that figures of merit reaching as high as ~1.2-1.3 at 900 K can be obtained, suggesting that large-scale applications with good conversion efficiencies are possible from systems based on abundant, inexpensive chemical elements. PMID- 21650210 TI - Trypanosomal dihydrofolate reductase reveals natural antifolate resistance. AB - Dihydrofolate reductase (DHFR) is a potential drug target for Trypanosoma brucei, a human parasite, which is the causative agent for African sleeping sickness. No drug is available against this target, since none of the classical antifolates such as pyrimethamine (PYR), cycloguanil, or trimethoprim are effective as selective inhibitors of T. brucei DHFR (TbDHFR). In order to design effective drugs that target TbDHFR, co-crystal structures with bound antifolates were studied. On comparison with malarial Plasmodium falciparum DHFR (PfDHFR), the co crystal structures of wild-type TbDHFR reveal greater structural similarities to a mutant PfDHFR causing antifolate resistance than the wild-type enzyme. TbDHFR imposes steric hindrance for rigid inhibitors like PYR around Thr86, which is equivalent to Ser108Asn of the malarial enzymes. In addition, a missing residue on TbDHFR active-site loop together with the presence of Ile51 widens its active site even further than the structural effect of Asn51Ile, which is observed in PfDHFR structures. The structural similarities are paralleled by the similarly poor affinities of the trypanosomal enzyme for rigid inhibitors. Mutations of TbDHFR at Thr86 resulted in 10-fold enhancement or 7-fold reduction in the rigid inhibitors affinities for Thr86Ser or Thr86Asn, respectively. The co-crystal structure of TbDHFR with a flexible antifolate WR99210 suggests that its greater affinity result from its ability to avoid such Thr86 clash and occupy the widened binding space similarly to what is observed in the PfDHFR structures. Natural resistance to antifolates of TbDHFR can therefore be explained, and potential antifolate chemotherapy of trypanosomiasis should be possible taking this into account. PMID- 21650211 TI - PVK/MWNT electrodeposited conjugated polymer network nanocomposite films. AB - The facile preparation of poly (N-vinyl carbazole) (PVK) and multiwalled carbon nanotubes (MWNTs) solution and conjugated polymer network (CPN) nanocomposite film is described. The stable solutions of PVK/MWNT were prepared in mixed solvents by simple sonication method, which enabled successful deaggregation of the MWNTs with the polymer matrix. MWNT was most effectively dissolved in N cyclohexyl-2-pyrrolidone (CHP) compared to other solvents like N-methyl pyrrolidone (NMP), dimethyl formamide, and dimethyl sulfoxide (DMSO). The composite solution was relatively stable for months with no observable precipitation of the MWNTs. Thermogravimmetric analysis (TGA) revealed the thermal stability of the nanocomposite while the differential scanning calorimetry (DSC) showed an increasing melting (T(m)) and glass transition (T(g)) temperatures as the fraction of the MWNTs in the nanocomposite was increased. Cyclic voltammetry (CV) allowed the electrodeposition of the nanocomposite film on indium tin oxide (ITO) substrates and subsequent cross-linking of the carbazole pendant group of the PVK to form CPN films. Ultraviolet-visible (UV vis), fluorescence, and Fourier transform infrared (FTIR) confirmed film composition while atomic force microscopy (AFM) revealed its surface morphology. Four-point probe measurements revealed an increase in the electrical conductivity of the CPN nanocomposite film as the composition of the MWNTs was increased: 5.53 * 10(-4) (3% MWNTs), 0.53 (5%), and 1.79 S cm(-1) (7%). Finally, the interfacial charge transfer resistance and ion transport on the CPN nanocomposite film was analyzed by electrochemical impedance spectroscopy (EIS) with a measured real impedance value of ~48.10 Omega for the 97% PVK and 3% MWNT ratio of the CPN nanocomposite film. PMID- 21650212 TI - A nonpeptidic reverse-turn scaffold stabilized by urea-based dual intramolecular hydrogen bonding. AB - A novel nonpeptidic reverse-turn scaffold containing urea fragments that are connected by a conformationally constrained D-prolyl-cis-1,2-diaminocyclohexane (D-Pro-DACH) linker is reported. The scaffold adopts a well-defined reverse-turn conformation that is stabilized by dual intramolecular hydrogen bonding in both solution and solid states. PMID- 21650213 TI - Conjugated polymers with pyrrole as the conjugated bridge: synthesis, characterization, and two-photon absorption properties. AB - The synthesis, one- and two-photon absorption (2PA) and emission properties of two novel pyrrole-based conjugated polymers (P1 and P2) are reported. They emitted strong yellow-green and orange fluorescence with fluorescent quantum yields (Phi) of 46 and 33%, respectively. Their maximal 2PA cross sections (delta) measured by the two-photon-induced fluorescence method using femtosecond laser pulses in THF were 2392 and 1938 GM per repeating unit, respectively, indicating that the 2PA chromophores consisting of the triphenylamine with nonplanar structure as the donor and electron-rich pyrrole as the conjugated bridge could be the effective repeating units to enhance the delta values. PMID- 21650214 TI - Magnetic-field-assisted assembly of layered double hydroxide/metal porphyrin ultrathin films and their application for glucose sensors. AB - The ordered ultrathin films (UTFs) based on CoFe-LDH (layered double hydroxide) nanoplatelets and manganese porphyrin (Mn-TPPS) have been fabricated on ITO substrates via a magnetic-field-assisted (MFA) layer-by-layer (LBL) method and were demonstrated as an electrochemical sensor for glucose. The XRD pattern for the film indicates a long-range stacking order in the normal direction of the substrate. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) images of the MFA LDH/Mn-TPPS UTFs reveal a continuous and uniform surface morphology. Cyclic voltammetry, impedance spectroscopy, and chronoamperometry were used to evaluate the electrochemical performance of the film, and the results show that the MFA-0.5 (0.5 T magnetic field) CoFe-LDH/Mn-TPPS-modified electrode displays the strongest redox current peaks and fastest electron transfer process compared with those of MFA-0 (without magnetic-field) and MFA 0.15 (0.15 T magnetic field). Furthermore, the MFA-0.5 CoFe-LDH/Mn-TPPS exhibits remarkable electrocatalytic activity toward the oxidation of glucose with a linear response range (0.1-15 mM; R(2) = 0.999), low detection limit (0.79 MUM) and high sensitivity (66.3 MUA mM(-1) cm(-2)). In addition, the glucose sensor prepared by the MFA LBL method also shows good selectivity and reproducibility as well as resistance to poisoning in a chloride ion solution. Therefore, the novel strategy in this work creates new opportunities for the fabrication of nonenzyme sensors with prospective applications in practical detection. PMID- 21650215 TI - Catalytic steam gasification of biomass: catalysts, thermodynamics and kinetics. PMID- 21650216 TI - The electronically excited states of LH2 complexes from Rhodopseudomonas acidophila strain 10050 studied by time-resolved spectroscopy and dynamic Monte Carlo simulations. II. Homo-arrays of LH2 complexes reconstituted into phospholipid model membranes. AB - We performed time-resolved spectroscopy on homoarrays of LH2 complexes from the photosynthetic purple bacterium Rhodopseudomonas acidophila. Variations of the fluorescence transients were monitored as a function of the excitation fluence and the repetition rate of the excitation. These parameters are directly related to the excitation density within the array and to the number of LH2 complexes that still carry a triplet state prior to the next excitation. Comparison of the experimental observations with results from dynamic Monte Carlo simulations for a model cluster of LH2 complexes yields qualitative agreement without the need for any free parameter and reveals the mutual relationship between energy transfer and annihilation processes. PMID- 21650217 TI - Solution-engineered palladium nanoparticles: model for health effect studies of automotive particulate pollution. AB - Palladium (Pd) nanoparticles are recognized as components of airborne automotive pollution produced by abrasion of catalyst materials in the car exhaust system. Here we produced dispersions of hydrophilic spherical Pd nanoparticles (Pd-NP) of uniform shape and size (10.4 +/- 2.7 nm) in one step by Bradley's reaction (solvothermal decomposition in an alcohol or ketone solvent) as a model particle for experimental studies of the Pd particles in air pollution. The same approach provided mixtures of Pd-NP and nanoparticles of non-redox-active metal oxides, such as Al(2)O(3). Particle aggregation in applied media was studied by DLS and nanoparticle tracking analysis. The putative health effects of the produced Pd nanoparticles and nanocomposite mixtures were evaluated in vitro, using human primary bronchial epithelial cells (PBEC) and a human alveolar carcinoma cell line (A549). Viability of these cells was tracked by vital dye exclusion, and apoptosis was also assessed. In addition, we monitored the release of IL-8 and PGE(2) in response to noncytotoxic doses of the nanoparticles. Our studies demonstrate cellular uptake of Pd nanoparticles only in PBEC, as determined by TEM, with pronounced and dose-dependent effects on cellular secretion of soluble biomarkers in both cell types and a decreased responsiveness of human epithelial cells to the pro-inflammatory cytokine TNF-alpha. When cells were incubated with higher doses of the Pd nanoparticles, apoptosis induction and caspase activation were apparent in PBEC but not in A549 cells. These studies demonstrate the feasibility of using engineered Pd nanoparticles to assess the health effects of airborne automotive pollution. PMID- 21650218 TI - Cytotoxicity of graphene oxide and graphene in human erythrocytes and skin fibroblasts. AB - Two-dimensional carbon-based nanomaterials, including graphene oxide and graphene, are potential candidates for biomedical applications such as sensors, cell labeling, bacterial inhibition, and drug delivery. Herein, we explore the biocompatibility of graphene-related materials with controlled physical and chemical properties. The size and extent of exfoliation of graphene oxide sheets was varied by sonication intensity and time. Graphene sheets were obtained from graphene oxide by a simple (hydrazine-free) hydrothermal route. The particle size, morphology, exfoliation extent, oxygen content, and surface charge of graphene oxide and graphene were characterized by wide-angle powder X-ray diffraction, atomic force microscopy, X-ray photoelectron spectroscopy, dynamic light scattering, and zeta-potential. One method of toxicity assessment was based on measurement of the efflux of hemoglobin from suspended red blood cells. At the smallest size, graphene oxide showed the greatest hemolytic activity, whereas aggregated graphene sheets exhibited the lowest hemolytic activity. Coating graphene oxide with chitosan nearly eliminated hemolytic activity. Together, these results demonstrate that particle size, particulate state, and oxygen content/surface charge of graphene have a strong impact on biological/toxicological responses to red blood cells. In addition, the cytotoxicity of graphene oxide and graphene sheets was investigated by measuring mitochondrial activity in adherent human skin fibroblasts using two assays. The methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, a typical nanotoxicity assay, fails to predict the toxicity of graphene oxide and graphene toxicity because of the spontaneous reduction of MTT by graphene and graphene oxide, resulting in a false positive signal. However, appropriate alternate assessments, using the water-soluble tetrazolium salt (WST-8), trypan blue exclusion, and reactive oxygen species assay reveal that the compacted graphene sheets are more damaging to mammalian fibroblasts than the less densely packed graphene oxide. Clearly, the toxicity of graphene and graphene oxide depends on the exposure environment (i.e., whether or not aggregation occurs) and mode of interaction with cells (i.e., suspension versus adherent cell types). PMID- 21650219 TI - Molecular layer-by-layer self-assembly and mercury sensing characteristics of novel brush polymers bearing thymine moieties. AB - Two new brush polyoxyethylenes bearing thymine moieties at the bristle ends have been synthesized as model polymers in which the chemical loading of the thymine functional group into the polymer is maximized: poly(oxy(11 thyminoacetyloxyundecylthiomethyl)ethylene) (PECH(S)-T) and poly(oxy(11 thyminoacetyloxyundecylsulfonylmethyl)ethylene) (PECH(SO(2))-T). These brush polymers are thermally stable up to around 225 degrees C, and their glass transitions occur in the range 23-27 degrees C, but they have significantly different properties despite the similarity of their chemical structures. In particular, PECH(SO(2))-T films exhibit better performance in sensing mercury ions than PECH(S)-T films. These differences were found to originate in the differences between their morphological structures. The PECH(SO(2))-T film has a multi-bilayer structure without interdigitation, in which the layers stack along the out-of-plane of the film and provide a thymine-rich surface. In contrast, the PECH(S)-T film is amorphous with a relatively low population of thymine moieties at the surface. This study demonstrated that a thymine-rich surface is required for recyclable thymine-based polymers to provide highly improved sensitivity and selectivity as well as full reversibility in the sensing of mercury ions. A thymine-rich surface can be achieved with a brush polymer bearing thymine moieties that can self-assemble into a multi-bilayer structure. Because of the thymine-rich surface, the PECH(SO(2))-T thin films even in only 6 nm thickness demonstrate the detection of mercury ions in aqueous solutions with a detection limit of 10(-6) M. PMID- 21650220 TI - Selective deposition of CdSe nanoparticles on reduced graphene oxide to understand photoinduced charge transfer in hybrid nanostructures. AB - A linker-free reduced graphene oxide (R-GO)-CdSe nanoparticle (CdSe NP) hybrid nanostructure was synthesized using a chemical vapor deposition method. CdSe NPs were selectively deposited on the surface of R-GO with controlled NP size and coverage. The distribution and morphology of CdSe NPs on R-GO were characterized by scanning electron microscopy, transmission electron microscopy, and atomic force microscopy. The resulting hybrid nanostructure exhibited photoresponse to both laser and simulated sunlight AM 1.5G excitation. The hybrid structure with low CdSe NP coverage showed distinct photoresponse times in air, N(2), NH(3), and NO(2), while high CdSe NP coverage led to nearly constant but three orders of magnitude smaller response time in all gases. Such a difference in photoresponse as a function of NP coverage is attributed to the energy band bending at the interface between the R-GO and the CdSe NP. The selective deposition of CdSe NPs on R-GO and the understanding of the subsequent photoinduced charge transfer can potentially lead to high-performance optoelectronic devices. PMID- 21650222 TI - Effects of carbon atom parity and alkyl side chain length on the crystallization and morphology of biscarbamates, a set of model compounds for polyurethanes. AB - Solid state morphology and crystallization behavior of a homologous series of biscarbamate molecules having varying alkyl side chain lengths with different carbon atom parity were investigated. These are model compounds for polyurethanes. We synthesized a set of biscarbamates with double hydrogen bonding motifs separated by a (CH(2))(6) spacer and with alkyl side chains of various lengths ranging from C(3) to C(18) at the ends. Thermal analysis showed an odd even alternation in their melting temperatures and heats of fusion, with the odd number of carbon atoms in the side chain having higher melting temperatures and heats of fusion than the even numbered ones, in contrast to the case of n alkanes. The effect of carbon atom parity in the alkyl side chains on the spherulite size, spherulite growth rate, and isothermal crystallization kinetics was studied. Although the spherulite size increases with the alkyl side chain length, the maximum is seen at an intermediate length and not with a short or long alkyl chain for both the odd and even series. Along this series of molecules, a maximum in spherulite size, spherulite growth rate, and rate of crystallization is seen for C(7)C(6) (odd series) and C(8)C(6) (even series) biscarbamates. There is a significant difference in spherulite size with respect to carbon atom parity in the alkyl side chains as well as sample preparation protocol. Hence the length of the alkyl side chain, carbon atom parity in the alkyl side chains, and the sample preparation protocol (i.e., quenching versus slow cooling) play an important role in the morphology of these molecules. We rationalize this behavior with the relative contributions of hydrogen bonding and van der Waals forces as discerned from IR spectroscopy. While the van der Waals interaction increases with the alkyl side chain length in this series, the hydrogen bond contribution remains invariant. The rate of crystallization follows the trend seen with the spherulitic growth. The Avrami exponent is significantly smaller than 3, varying from 1.6 to 2.5 depending on the side chain length, which indicates that the crystallization is not truly three-dimensional. This study on the influence of alkyl side chains shows that while hydrogen bonding enables self assembly the van der Waals interactions play a significant role in the crystallization and morphology of such self-assembled structures. PMID- 21650221 TI - Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors. AB - Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels. PMID- 21650223 TI - Protein interactions among Fe65, the low-density lipoprotein receptor-related protein, and the amyloid precursor protein. AB - The adapter protein Fe65 has been proposed to be the link between the intracellular domains of the amyloid precursor protein, APP (AICD), and the low density lipoprotein receptor-related protein (LRP-CT). Functional linkage between these two proteins has been established, and mutations within LRP-CT affect the amount of Abeta produced from APP. Previous work showed that AICD binds to protein interaction domain 2 (PID2) of Fe65. Although the structure of PID1 was determined recently, all attempts to demonstrate LRP-CT binding to this domain failed. We used biophysical experiments and binding studies to investigate the binding among these three proteins. Full-length Fe65 bound more weakly to AICD than did N-terminally truncated forms; however, the intramolecular domain-domain interactions that had been proposed to inhibit binding could not be observed using amide H-D exchange. Surprisingly, when LRP-CT is phosphorylated at Tyr4507, it bound to Fe65 PID1 despite the fact that this domain belongs to the Dab-like subclass of PIDs that are not supposed to be phosphorylation-dependent. Mutation of a critical arginine abolished binding, providing further proof of the phosphorylation dependence. Fe65 PID1 thus provides a link between the Dab-like class and the IRS-like class of PIDs and is the first Dab-like family member to show phosphorylation-dependent binding. PMID- 21650224 TI - Lindenane disesquiterpenoids with anti-HIV-1 activity from Chloranthus japonicus. AB - Five new lindenane disesquiterpenoids, chlorajaponilides A-E (1-5), together with 11 known analogues were isolated from whole plants of Chloranthus japonicus. The structure and absolute configuration of 1 was confirmed by X-ray crystallography. Compounds 1 and 2 represent the first examples of lindenane disesquiterpenoids with a C-5 hydroxy group and a C-4-C-15 double bond. Compounds 8, 9, 11, and 12 showed anti-HIV-1 replication activities in both wild-type HIV-1 and two NNRTIs resistant strains. Shizukaol B (8) exhibited the best activity against HIV(wt), HIV(RT-K103N), and HIV(RT-K103N) with EC50 values of 0.22, 0.47, and 0.50 MUM, respectively. Compounds 8, 9, 11, and 12 had significant cytotoxicities against C8166 cells with CC50 values of 0.020, 0.089, 0.047, and 0.022, respectively, and exhibited inhibitory activities against HIV-1 with EC50 values of 0.0014, 0.016, 0.0043, and 0.0033 MUM, respectively. PMID- 21650225 TI - Stimuli-responsive azulene-based conjugated oligomers with polyaniline-like properties. AB - Novel azulene building blocks, prepared via the cycloaddition of thiophene-S,S dioxides and fulvenes, allow for incorporation of the seven-membered ring of the azulene nucleus directly into the backbone of conjugated materials. This unique mode of incorporation gives remarkably stable, stimuli-responsive materials upon exposure to acid. This simple doping/dedoping strategy provides for effective optical band gap control and on/off fluorescence switching, reminiscent of polyaniline. PMID- 21650226 TI - Synthesis and biological evaluation of novel thiazolidinedione analogues as 15 hydroxyprostaglandin dehydrogenase inhibitors. AB - Novel thiazolidinedione analogues as 15-hydroxyprostaglandin dehydrogenase (15 PGDH) inhibitors were synthesized. Compounds 2, 3, and 4 exhibited IC(50) of 25, 8, and 19 nM, respectively. They also significantly increased levels of PGE(2) in A549 cells. To assess the influence of 15-PGDH inhibitor on cochlear blood flow (CBF), 2 was applied intravenously to guinea pigs. It increased their CBFs. Scratch wounds were also analyzed in confluent monolayers of HaCaT cells. Cells exposed to 4 showed significantly improved wound healing with respect to a control. PMID- 21650228 TI - Other/miscellaneous. PMID- 21650230 TI - Other/miscellaneous. PMID- 21650253 TI - Technology Update: Phytic acid immobilizes radionuclides. PMID- 21650231 TI - Prepublishing research on the Web. PMID- 21650254 TI - Technology Update: Microprobe remotely monitors marine waters. PMID- 21650256 TI - EPA Watch: Agency drafts performance measures. PMID- 21650255 TI - EPA Watch: ORD chief Huggett leaves EPA for academia. PMID- 21650257 TI - EPA Watch: Food quality implementation plan released. PMID- 21650258 TI - EPA Watch: New proposal slated for hazardous waste rule. PMID- 21650259 TI - EPA Watch: Rural wastewater treatment grant available. PMID- 21650260 TI - EPA Watch: Superfund incinerator safety faulted by GAO. PMID- 21650261 TI - "Streamlined" water-testing plan frees lab to fine-tune methods. PMID- 21650262 TI - Toxics Release Inventory expanded to cover seven new industries. PMID- 21650264 TI - Federal agencies battle over risks from low-level radiation exposure. PMID- 21650265 TI - Does MTBE biodegrade? PMID- 21650266 TI - California struggles with presence of MTBE in public drinking water wells. PMID- 21650269 TI - EPA toxics office to create "safe haven" for science policy, risk work. PMID- 21650267 TI - New research reveals how contaminants can be "locked" into soil. PMID- 21650271 TI - News briefs: news briefs. PMID- 21650273 TI - Peer Reviewed: China's Air Pollution Risks. AB - Although China is struggling with major urban air quality problems, its most serious health problem is indoors. PMID- 21650274 TI - Peer Reviewed: Science, Uncertainty, and EPA's New Ozone Standards. AB - There are still gray areas in the science about how ozone harms human health and vegetation. PMID- 21650275 TI - Buyer's Guide: Buyer's Guide. PMID- 21650276 TI - Online/In print: online/in print. PMID- 21650280 TI - Other/miscellaneous. PMID- 21650281 TI - Other/miscellaneous. PMID- 21650283 TI - Breadth and depth of knowledge. PMID- 21650284 TI - Letters: Job prospects for engineering undergrads. PMID- 21650306 TI - Technology Update: New chemical reactor design cuts waste. PMID- 21650285 TI - Letters: Job prospects for engineering undergrads. PMID- 21650307 TI - Technology Update: Ryegrass used in soil remediation test. PMID- 21650309 TI - EPA Watch: Indoor air risks evaluated by new panel. PMID- 21650310 TI - EPA Watch: Citing explosions, EPA delays ethylene oxide controls. PMID- 21650311 TI - EPA Watch: Fish consumption advisories are up 26%. PMID- 21650312 TI - EPA Watch: Dust up over proposed rule for cement kiln emissions. PMID- 21650313 TI - EPA Watch: Timetable set for reassessment of pesticide tolerances. PMID- 21650314 TI - EPA Watch: Addressing Superfund lead cleanup inconsistencies. PMID- 21650316 TI - "Dead zone" in Gulf of Mexico draws federal-state attention. PMID- 21650318 TI - EPA plans to publish toxic value of TRI data. PMID- 21650317 TI - Environmental justice assessments get boost under EPA draft guidance. PMID- 21650319 TI - Pennsylvania coal mine reclamation plan to use contaminated harbor sediments. PMID- 21650321 TI - European news. PMID- 21650320 TI - U.S. nuclear waste disposal programs progressing, but slowly. PMID- 21650322 TI - Lab accreditation procedures approved. PMID- 21650323 TI - U.S., Canada planning to study dioxin emissions from iron and steel plants. PMID- 21650325 TI - News briefs: news briefs. PMID- 21650326 TI - Electric power deregulation: will it mean dirtier air? AB - When U.S. utility restructuring arrives, it may bring more polluting power production, critics say. PMID- 21650330 TI - Online/In print: online/in print. PMID- 21650327 TI - Rethinking water quality standards for metals toxicity. AB - A better understanding of the how natural waters inhibit metal uptake may change current regulatory limits. PMID- 21650331 TI - Buyer's Guide: Buyer's Guide. PMID- 21650336 TI - Other/miscellaneous. PMID- 21650339 TI - Growth of environmental biology. PMID- 21650337 TI - Other/miscellaneous. PMID- 21650340 TI - Letters: Authors' response. PMID- 21650341 TI - Letters: Incinerator or recycler? PMID- 21650342 TI - Letters: Less chlorine-free paper. PMID- 21650366 TI - Technology Update: Laser measures metals in off-gas emissions. PMID- 21650367 TI - Technology Update: Wastewater ion exchange with recycled farm products. PMID- 21650369 TI - EPA Watch: States facing new controls for nonpoint sources. PMID- 21650368 TI - Technology Update: Heavy-metal sensors provide fast detection. PMID- 21650370 TI - EPA Watch: Confidential data controls may be tightened. PMID- 21650371 TI - EPA Watch: Court supports PCB import ban despite EPA plea. PMID- 21650372 TI - EPA Watch: Radon offers chance to assess risks across media. PMID- 21650373 TI - EPA Watch: "Onerous" drinking water rules to be revised. PMID- 21650374 TI - EPA Watch: IG calls for more oversight of hard rock mining. PMID- 21650375 TI - EPA Watch: EPA cracks down on underground tasks. PMID- 21650377 TI - Next step for EPA's new air quality regs: Monitoring. PMID- 21650378 TI - As expected, EPA toughens air quality standards. PMID- 21650380 TI - Are regulators relying on inaccurate industrial air emission inventories? PMID- 21650379 TI - States fail to set Great Lakes water quality implementation plans. PMID- 21650381 TI - USDA food survey finds many pesticides, few violations. PMID- 21650382 TI - European news. PMID- 21650383 TI - Scientists link coal fly ash disposal to amphibian abnormalities. PMID- 21650384 TI - Research on synergistic effect of weakly estrogenic chemicals withdrawn by authors. PMID- 21650385 TI - Endocrine disrupter screening strategy to involve two-tiered testing. PMID- 21650386 TI - Panel recommends shifts in EPA research priorities, resources. PMID- 21650388 TI - News briefs: news briefs. PMID- 21650389 TI - Peer reviewed: East central europe: an environment in transition. AB - Major changes in the governments and economies of this highly polluted region are improving air and water quality. PMID- 21650391 TI - Peer reviewed: when pollution prevention meets the bottom line. AB - Cost savings are not always enough to convince industry to adopt prevention actions. PMID- 21650394 TI - Online/In print: online/in print. PMID- 21650400 TI - Other/miscellaneous. PMID- 21650398 TI - Other/miscellaneous. PMID- 21650401 TI - To the green chemistry heroes. PMID- 21650402 TI - Letters: Certification program overlooked. PMID- 21650403 TI - Letters: corrections. AB - MTBE water concentrations raise health concerns, research questions. PMID- 21650404 TI - Letters: PCBs from old paint? PMID- 21650427 TI - EPA Watch: Proposed exemption for engineered pesticides. PMID- 21650428 TI - EPA Watch: States, EPA agree to measure progress. PMID- 21650430 TI - EPA Watch: Effluent trading limited in energy sector. PMID- 21650429 TI - EPA Watch: Agreement targets Cryptosporidium in drinking water. PMID- 21650432 TI - EPA Watch: Closure of N.Y.-N.J. dump provides only partial solution. PMID- 21650431 TI - EPA Watch: Hazardous waste facilities should avoid sensitive areas. PMID- 21650433 TI - OTAG recommends ozone controls tailored to pollution transport. PMID- 21650435 TI - "Accelerated" Department of Energy cleanup plan draws criticism. PMID- 21650436 TI - States pushing for greater regulatory flexibility from EPA. PMID- 21650437 TI - National Research Council recommends sweeping changes to promote technologies. PMID- 21650440 TI - EPA pilot program would allow states to use confidential data in risk assessments. PMID- 21650438 TI - California considers tougher diesel exhaust rule. PMID- 21650441 TI - News briefs: news briefs. PMID- 21650442 TI - Peer reviewed: environmental models undergo international test. AB - The science and art of exposure assessment modeling were tested using real-world data from the Chernobyl accident. PMID- 21650443 TI - Value of ISO 14000 Management Systems Put to the Test. AB - Ten states begin a coordinated research project to evaluate environmental benefits of the new international standard. PMID- 21650445 TI - California's Prop 65: A Better Way to Regulate? AB - The 1986 "right-to-know" statute is receiving renewed attention as a way to regulate toxic chemicals. PMID- 21650447 TI - Online/In print: online/in print. PMID- 21650449 TI - Buyer's Guide: Buyer's Guide. PMID- 21650453 TI - Efficacy of a mycotoxin binder against dietary fumonisin, deoxynivalenol, and zearalenone in rats. AB - It was hypothesized that a mycotoxin binder, Grainsure E, would inhibit adverse effects of a mixture of fumonisin B1, deoxynivalenol, and zearalenone in rats. For 14 and 28 days, 8-10 Sprague-Dawley rats were fed control diet, Grainsure E (0.5%), toxins (7 MUg fumonisin B1/g, 8 MUg of deoxynivalenol/g and 0.2 MUg of zearalenone/g), toxins (12 MUg of fumonisin B1/g, 9 MUg of deoxynivalenol/g, and 0.2 MUg of zearalenone/g + Grainsure E), or pair-fed to control for food intake of toxin-fed rats. After 28 days, decreased body weight gain was prevented by Grainsure E in toxin-fed female rats, indicating partial protection against deoxynivalenol and fumonisin B1. Two effects of fumonisin B1 were partly prevented by Grainsure E in toxin-fed rats, increased plasma alanine transaminase (ALT) and urinary sphinganine/sphingosine, but sphinganine/sphingosine increase was not prevented in females at the latter time point. Grainsure E prevented some effects of fumonisin B1 and deoxynivalenol in rats. PMID- 21650454 TI - Re-evaluation of rhodopsin's relaxation kinetics determined from femtosecond stimulated Raman lineshapes. AB - This work presents a theoretical treatment of the vibrational line shape generated in a femtosecond stimulated Raman spectroscopy (FSRS) experiment under conditions in which the probed vibration undergoes a significant frequency shift during its free induction decay. This theory is applied to simulate the FSRS lineshapes previously observed in rhodopsin (Kukura et al. Science 2005, 310, 1006). The previously determined relaxation times for formation of the trans photoproduct of rhodopsin were calculated using an incorrect equation for the time dependence of the observed frequency shifts. Here the data are reanalyzed by calculation of the corrected frequency sweep occurring during the vibrational free induction decay. It is shown that the calculated frequency shifts and general conclusions of the original work are sound but that the coherent vibrational frequency shifts of the C(10), C(11), and C(12) hydrogen-out-of-plane vibrations occur with a 140 fs time constant rather than the previously reported 325 fs time constant. This time constant provides an important constraint for models of the dynamics of the cis to trans isomerization process. PMID- 21650455 TI - Consecutive enzymatic modification of ornithine generates the hydroxamate moieties of the siderophore erythrochelin. AB - Biosynthesis of the hydroxamate-type siderophore erythrochelin requires the generation of delta-N-acetyl-delta-N-hydroxy-L-ornithine (L-haOrn), which is incorporated into the tetrapeptide at positions 1 and 4. Bioinformatic analysis revealed the FAD-dependent monooxygenase EtcB and the bifunctional malonyl-CoA decarboxylase/acetyltransferase Mcd to be putatively involved in the generation of L-haOrn. To investigate if EtcB and Mcd constitute a two-enzyme pathway for the biosynthesis of L-haOrn, they were produced in a recombinant manner and subjected to biochemical studies in vitro. Hydroxylation assays employing recombinant EtcB gave rise to delta-N-hydroxy-L-ornithine (L-hOrn) and confirmed the enzyme to be involved in building block assembly. Acetylation assays were carried out by incubating L-hOrn with recombinant Mcd and malonyl-CoA as the acetyl group donor. Substrate turnover was increased by substituting malonyl-CoA with acetyl-CoA, bypassing the decarboxylation reaction which represents the rate limiting step. Consecutive enzymatic synthesis of L-haOrn was accomplished in coupled assays employing both the L-ornithine hydroxylase and Mcd. In summary, a biosynthetic route for the generation of delta-N-acetyl-delta-N-hydroxy-L ornithine starting from L-ornithine has been established in vitro by tandem action of the FAD-dependent monooxygenase EtcB and the bifunctional malonyl-CoA decarboxylase/acetyltransferase Mcd. PMID- 21650456 TI - Thermodynamics of molecular recognition of mRNA 5' cap by yeast eukaryotic initiation factor 4E. AB - Molecular mechanisms underlying the recognition of the mRNA 5' terminal structure called "cap" by the eukaryotic initiation factor 4E (eIF4E) are crucial for cap dependent translation. To gain a deeper insight into how the yeast eIF4E interacts with the cap structure, isothermal titration calorimetry and the van't Hoff analysis based on intrinsic protein fluorescence quenching upon titration with a series of chemical cap analogs were performed, providing a consistent thermodynamic description of the binding process in solution. Equilibrium association constants together with thermodynamic parameters revealed similarities and differences between yeast and mammalian eIF4Es. The yeast eIF4E complex formation was enthalpy-driven and entropy-opposed for each cap analog at 293 K. A nontrivial isothermal enthalpy-entropy compensation was found, described by a compensation temperature, T(c) = 411 +/- 18 K. For a low affinity analog, 7 methylguanosine monophosphate, a heat capacity change was detected, DeltaC(p) degrees = +5.2 +/- 1.3 kJ.mol(-1).K(-1). The charge-related interactions involving the 5'-5' triphosphate bridge of the cap and basic amino acid side chains at the yeast eIF4E cap-binding site were significantly weaker (by DeltaDeltaH degrees (vH) of about +10 kJ.mol(-1)) than those for the mammalian homologues, suggesting their optimization during the evolution. PMID- 21650457 TI - Backbone cyclic peptide inhibitors of protein kinase B (PKB/Akt). AB - Elevated levels of activated protein kinase B (PKB/Akt) have been detected in many types of cancer. Substrate-based peptide inhibitors have the advantage of selectivity due to their extensive interactions with the kinase-specific substrate binding site but often lack necessary pharmacological properties. Chemical modifications of potent peptide inhibitors, such as cyclization, may overcome these drawbacks while maintaining potency. We present an extensive structure-activity relationship (SAR) study of a potent peptide-based PKB/Akt inhibitor. Two backbone cyclic (BC) peptide libraries with varying modes of cyclization, bridge chemistry, and ring size were synthesized and evaluated for in vitro PKB/Akt inhibition. Backbone-to-backbone urea BC peptides were more potent than N-terminus-to-backbone amide BC peptides. Several analogues were up to 10-fold more active than the parent linear peptide. Some activity trends could be rationalized using computational surface mapping of the PKB/Akt kinase catalytic domain. The novel molecules have enhanced pharmacological properties which make them promising lead candidates. PMID- 21650458 TI - Pore spanning lipid bilayers on mesoporous silica having varying pore size. AB - Synthetic lipid bilayers have similar properties as cell membranes and have been shown to be of great use in the development of novel biomimicry devices. In this study, lipid bilayer formation on mesoporous silica of varying pore size, 2, 4, and 6 nm, has been investigated using quartz crystal microbalance with dissipation monitoring (QCM-D), fluorescent recovery after photo bleaching (FRAP), and atomic force microscopy (AFM). The results show that pore-spanning lipid bilayers were successfully formed regardless of pore size. However, the mechanism of the bilayer formation was dependent on the pore size, and lower surface coverages of adsorbed lipid vesicles were required on the surface having the smallest pores. A similar trend was observed for the lateral diffusion coefficient (D) of fluorescently labeled lipid molecules in the membrane, which was lowest on the surface having the smallest pores and increased with the pore size. All of the pore size dependent observations are suggested to be due to the hydrophilicity of the surface, which decreases with increased pore size. PMID- 21650459 TI - Investigation of the metabolism of ergot alkaloids in cell culture by fourier transformation mass spectrometry. AB - Ergot alkaloids are known toxic secondary metabolites of the fungus Claviceps purpurea occurring in various grains, especially rye products. The liver is responsible for converting the ergot alkaloids into metabolites; however, the toxic impact of these end products of metabolism is still unknown. The aim of this study was to analyze the metabolism of ergot alkaloids in colon and liver cell lines (HT-29, HepG2), as well as in human primary renal cells (RPTEC). It was shown that cells in vitro are able to metabolize ergot alkaloids, forming a variety of metabolic compounds. Significant differences between the used cell types could be identified, and a suitable model system was established using HT 29 cells, performing an intensive metabolism to hydroxylated metabolites. The formed substances were analyzed by coupling of high-performance liquid chromatography with fluorescence detection and Fourier transformation mass spectrometry (HPLC-FLD-FTMS) as a powerful tool to identify known and unknown metabolites. PMID- 21650460 TI - Bioinspired aquatic microrobot capable of walking on water surface like a water strider. AB - Walking on the water surface is a dream of humans, but it is exactly the way of life for some aquatic insects. In this study, a bionic aquatic microrobot capable of walking on the water surface like a water strider was reported. The novel water strider-like robot consisted of ten superhydrophobic supporting legs, two miniature dc motors, and two actuating legs. The microrobot could not only stand effortlessly but also walk and turn freely on the water surface, exhibiting an interesting motion characteristic. A numerical model describing the interface between the partially submerged leg and the air-water surface was established to fully understand the mechanism for the large supporting force of the leg. It was revealed that the radius and water contact angle of the legs significantly affect the supporting force. Because of its high speed, agility, low cost, and easy fabrication, this microrobot might have a potential application in water quality surveillance, water pollution monitoring, and so on. PMID- 21650461 TI - Controllable synthesis and photoluminescence of single-crystalline BaHfO3 hollow micro- and nanospheres. AB - This paper presents a facile hydrothermal route to synthesize monodispersive and single-crystalline BaHfO(3) hollow micro- and nanospheres in a concentrated basic environment. The hollow spheres were size tunable from submicrometer to nanoscale by simply adjusting the base concentration at a suitable temperature. The base concentration played the key role on forming BaHfO(3) hollow spheres. Detailed investigations on base concentration, reaction temperature, and duration indicated that the formation of BaHfO(3) hollow spheres was driven by Ostwald ripening process. Because of the abundance of defects, the as-prepared BaHfO(3) hollow nanospheres exhibited a blue light emission under UV-light excitation at room temperature. Calcination led to the photoluminescence declination due to the decrease of defects. PMID- 21650462 TI - Pseudosaccharide functionalized dendrimers as potent inhibitors of DC-SIGN dependent Ebola pseudotyped viral infection. AB - The development of compounds with strong affinity for the receptor DC-SIGN is a topic of remarkable interest due to the role that this lectin plays in several pathogen infection processes and in the modulation of the immune response. DC SIGN recognizes mannosylated and fucosylated oligosaccharides in a multivalent manner. Therefore, multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. We have previously demonstrated that linear pseudodi- and pseudotrisaccharides are adequate ligands for DC-SIGN. In this work, we show that multivalent presentations of these glycomimetics based on polyester dendrons and dendrimers lead to very potent inhibitors (in the nanomolar range) of cell infection by Ebola pseudotyped viral particles by blocking DC-SIGN receptor. Furthermore, SPR model experiments confirm that the described multivalent glycomimetic compounds compete in a very efficient manner with polymannosylated ligands for binding to DC-SIGN. PMID- 21650463 TI - Self-assembly of polyion-surfactant ion complex salts in mixtures with water and n-alcohols. AB - Phase behavior and structural features were investigated for "complex salts", consisting of the cationic hexadecyltrimethylammonium (CTA) surfactant with polyacrylate (PA(n), n = 30 or 6000) counterions, mixed with water and different n-alcohols (ethanol, butanol, hexanol, octanol, and decanol). The liquid crystalline structures formed were identified by small-angle X-ray scattering measurements, which provided information about the changes in the geometry of the aggregates as functions of the concentration and chain length of the added n alcohol. The obtained results were compared with a previous work on similar ternary mixtures of the same cationic surfactant but with the monomeric bromide counterion, CTABr (Fontell, K.; Khan, A.; Lindstrom, B.; Maciejewska, D.; Puang Ngern, S. Colloid Polym. Sci., 1991, 269, 727). In general, the same phases were detected in systems with the complex salts CTAPA(n) as in systems with CTABr, but the swelling of the various liquid crystalline phases by water was much more limited in the complex salt systems. An isotropic alcoholic phase was observed with all alcohols and the size of this region of the phase diagram increased for the shorter alcohols, except for ethanol. For mixtures with octanol and ethanol, in particular, the extensions of the disordered isotropic phases were larger for the complex salt with the shorter polyacrylate ions. PMID- 21650464 TI - Luminscent graphene quantum dots for organic photovoltaic devices. AB - Recent research in organic photovoltaic (OPV) is largely focused on developing low cost OPV materials such as graphene. However, graphene sheets (GSs) blended conjugated polymers are known to show inferior OPV characteristics as compared to fullerene adduct blended with conjugated polymer. Here, we demonstrate that graphene quantum dots blended with regioregular poly(3-hexylthiophene-2,5-diyl) or poly(2-methoxy-5-(2-ethylhexyloxy)-1,4phenylenevinylene) polymer results in a significant improvement in the OPV characteristics as compared to GSs blended conjugated polymers. This work has implications for inexpensive and efficient solar cells as well as organic light emitting diodes. PMID- 21650465 TI - Construction and structural analysis of tethered lipid bilayer containing photosynthetic antenna proteins for functional analysis. AB - The construction and structural analysis of a tethered planar lipid bilayer containing bacterial photosynthetic membrane proteins, light-harvesting complex 2 (LH2), and light-harvesting core complex (LH1-RC) is described and establishes this system as an experimental platform for their functional analysis. The planar lipid bilayer containing LH2 and/or LH1-RC complexes was successfully formed on an avidin-immobilized coverglass via an avidin-biotin linkage. Atomic force microscopy (AFM) showed that a smooth continuous membrane was formed there. Lateral diffusion of these membrane proteins, observed by a fluorescence recovery after photobleaching (FRAP), is discussed in terms of the membrane architecture. Energy transfer from LH2 to LH1-RC within the tethered membrane was observed by steady-state fluorescence spectroscopy, indicating that the tethered membrane can mimic the natural situation. PMID- 21650466 TI - Effect of water and temperature on absorption of CO2 by amine-functionalized anion-tethered ionic liquids. AB - Amine-functionalized anion-tethered ionic liquids (ILs) trihexyl(tetradecyl)phosphonium asparaginate [P(66614)][Asn], glutaminate [P(66614)][Gln], lysinate [P(66614)][Lys], methioninate [P(66614)][Met], prolinate [P(66614)][Pro], taurinate [P(66614)][Tau], and threoninate [P(66614)][Thr] were synthesized and investigated as potential absorbents for CO(2) capture from postcombustion flue gas. Their physical properties, including density, viscosity, glass transition temperature, and thermal decomposition temperature were determined. Furthermore, the CO(2) absorption isotherms of [P(66614)][Lys], [P(66614)][Tau], [P(66614)][Pro], and [P(66614)][Met] were measured using a volumetric method, and the results were modeled with two different Langmuir-type absorption models. The most important result of this study is that the viscosity of [P(66614)][Pro] only increased by a factor of 2 when fully complexed with 1 bar of CO(2) at room temperature. This is in stark contrast to the other chemically reacted ILs investigated here and all other amino acid-based ILs reported in the literature, which dramatically increase in viscosity, typically by 2 orders of magnitude, when complexed with CO(2). The unique behavior of [P(66614)][Pro] is likely due to its ring structure, which limits the number and availability of hydrogen atoms that can participate in a hydrogen bonding network. We found that water can be used to further reduce the viscosity of the CO(2)-complexed IL, while only slightly decreasing the CO(2) capacity. Finally, from temperature-dependent isotherms, we estimate a heat of absorption of -63 kJ/mol of CO(2) for the 1:1 reaction of CO(2) with [P(66614)][Pro], when we use the two-reaction model. PMID- 21650467 TI - Importance of electrostatic interactions in the mobility of cations in Nafion. AB - A molecular level understanding of the mobility of cations in the Nafion membrane has been attempted, using the excited state proton transfer (ESPT) process in the fluorescent probe Coumarin 102. ESPT is hindered significantly upon decreasing the water content. Using TRANES (time-resolved area normalized emission spectroscopy), the evolution of the ESPT state is clearly observed over hundreds of picoseconds in lower water content, implying that ESPT is hindered even in the nanovolume probed by the dye. Most remarkably, in the partially dried membrane, the predominant fluorescent species is the zwitterionic form, generated by excited state deprotonation of the cationic form. This implies that the molecule loses a proton from its nitrogen center in the excited state, as usual, but cannot recapture it readily at the oxygen center, at low water contents. This phenomenon is rationalized in light of an increased electrostatic attraction that is experienced by cations upon drying. PMID- 21650468 TI - AGE-induced interference of glucose uptake and transport as a possible cause of insulin resistance in adipocytes. AB - The purpose of this study was to investigate the distinct roles of advanced glycation end products (AGEs) on insulin-mediated glucose disposal in 3T3-L1 adipocytes and C2C12 skeletal muscle cells. AGE-modified proteins, namely, GO AGEs, were prepared by incubating bovine serum albumin (BSA) with glyoxal (GO) for 7 days. Glucose utilization rates and the expression of insulin signaling associated proteins, including Akt, insulin receptor substrate-1, and glucose transporter 4, were determined. GO-AGEs caused insulin resistance (IR) by suppressing insulin-stimulated glucose uptake both in 3T3-L1 adipocytes and C2C12 muscle cells. Interestingly, an unexpected finding was that insulin-stimulated glucose transport in adipocytes was affected by GO-AGEs in a biphasic manner, with an initial steep increase (168%) during the first 8 h of incubation followed by a significantly impaired uptake after extended culture times (24-48 h, p < 0.05). Treatment with GO-AGEs for 24 h markedly accelerated lipid droplet formation compared to the BSA control; however, it was blocked by incubation with an anti-RAGE antibody. Our study suggests that GO-AGEs induce an early dramatic elevation of glucose transport in adipocytes that may be related to the activation of insulin signaling; however, subsequent IR may result from increased oxidative stress and proinflammatory TNF-alpha production. PMID- 21650471 TI - Other/miscellaneous. PMID- 21650469 TI - Factors affecting the bioaccessibility of methylmercury in several marine fish species. AB - Bioaccessibility refers to the maximum bioavailability of pollutant ingested with food, and its measurements can lead to a more accurate risk assessment as compared to the measurements of total concentrations of pollutant in food. This study examined the factors affecting the bioaccessibility of methylmercury (MeHg) in nine species of marine fish with an aim to identify ways of reducing MeHg bioaccessibility. MeHg bioaccessibility without any treatment in the nine species of marine fish ranged from 16.0 to 67.7%. Steaming, grilling, and frying reduced MeHg bioaccessibility by 29.4-77.4% for rabbitfish and 74.6-95.8% for grouper. Co consumption of phytochemical-rich foods such as green tea decreased the bioaccessibility of MeHg by 72.2% for rabbitfish and 74.0% for grouper, whereas meso-2,3-dimercaptosuccinic acid increased it by 39.2-108% for rabbitfish and 45.3-75.7% for grouper. The bioaccessibilities of both MeHg and inorganic mercury were independent of the total Hg concentration and the exposure route (dietary vs dissolved). In eight of the nine species studied, bioaccessibility was negatively correlated with the extent to which MeHg was partitioned into the metal-rich granule fraction and the trophically available fraction. It was positively correlated with partitioning into the cellular debris fraction. This study demonstrated the important control of subcellular distribution in MeHg bioaccessibility. PMID- 21650473 TI - Other/miscellaneous. PMID- 21650474 TI - Homespun wisdom. PMID- 21650475 TI - Panel urges quick validation of endocrine disrupter tests. PMID- 21650476 TI - Results of low-dose exposure research may challenge the theoretical basis of toxicology. PMID- 21650477 TI - DNA fingerprinting holds promise for identifying nonpoint sources of pollution. PMID- 21650478 TI - Worldwide effort underway to reduce SF6 greenhouse gas emissions. PMID- 21650479 TI - Models gauge pollution in environmental justice disputes. PMID- 21650480 TI - International treaty aims to stem flow of toxics. PMID- 21650481 TI - Cost-effective testing effort demonstrates new cleanup technologies. PMID- 21650483 TI - EPA Watch: Industrial water permit backlog rising. PMID- 21650482 TI - News briefs: news briefs. PMID- 21650484 TI - Technology Update: Novel barrier remediates chlorinated solvents. PMID- 21650485 TI - Reclaimed wastewater continues flow toward tap. AB - Potable reuse of water is growing, despite remaining scientific uncertainties and public resistance. PMID- 21650486 TI - A renaissance for genotoxicity testing? AB - Test results are driving a rebirth of interest in the use of the technique to evaluate pollution. PMID- 21650487 TI - Peer reviewed: finding solutions for tough environmental problems. AB - At the frontiers of research, environmental engineers are using novel tools to obtain knowledge about complex environmental systems. PMID- 21650488 TI - Peer reviewed: low-level chemical exposures: a challenge for science and policy. PMID- 21650511 TI - Research Watch: Pollutants in aquatic systems. PMID- 21650498 TI - Research Watch: Dissolution of cinnabar by DOM. PMID- 21650516 TI - Online/In print: online/in print. PMID- 21650520 TI - Other/miscellaneous. PMID- 21650522 TI - Other/miscellaneous. PMID- 21650524 TI - Rethinking a national institute. PMID- 21650550 TI - Technology Update: Electrochemical oxidation on organic wastes. PMID- 21650551 TI - Technology Update: TPH soil cleanup aided by ground cover. PMID- 21650552 TI - Technology Update: Lasers could eliminate precision cleaning solvents. PMID- 21650553 TI - EPA Watch: Methyl parathion cleanup strains Superfund. PMID- 21650554 TI - EPA Watch: Labeling report recommends simpler language. PMID- 21650555 TI - EPA Watch: Agency considers options to HWIR proposal. PMID- 21650556 TI - EPA Watch: Credible evidence rule draws industry suit. PMID- 21650557 TI - EPA Watch: New radionuclide drinking water tests approved. PMID- 21650558 TI - EPA Watch: Wetlands plan due out this summer. PMID- 21650559 TI - Controversial EPA mercury study endorsed by science panel. PMID- 21650560 TI - Contaminated sediment management needs better assessment tools, NRC says. PMID- 21650561 TI - International body says dioxin is a human carcinogen. PMID- 21650563 TI - Chemical industry groups pledge $8 million for endocrine research. PMID- 21650562 TI - Endocrine disrupter research reviewed by EPA. PMID- 21650564 TI - "Common Sense" reform initiatives falters. PMID- 21650566 TI - Genetically engineered microbes notification required. PMID- 21650565 TI - Unified European water quality regulatory system proposed. PMID- 21650567 TI - News briefs: news briefs. PMID- 21650571 TI - A new environment for undergraduate engineers. AB - The growth of environmental engineering programs raises questions about curriculum and careers. PMID- 21650569 TI - Resurrecting brownfields. AB - Regulatory changes open the door to remediation, but so far the action is more stage-setting than cleanup. PMID- 21650572 TI - Grads also engineering pollution prevention. PMID- 21650579 TI - Other/miscellaneous. PMID- 21650575 TI - Online/In print: online/in print. PMID- 21650580 TI - Other/miscellaneous. PMID- 21650582 TI - Letters: Priorities: Social science. PMID- 21650583 TI - Letters: "Good turmoil" at EPA labs. PMID- 21650597 TI - Technology Update: New testing methods detect gaseous mercury species. PMID- 21650584 TI - Letters: priorities: education. PMID- 21650598 TI - Technology Update: DNAPL cleanup strategy achieves 99% removal. PMID- 21650599 TI - Technology Update: Field test compares NAPL cleanup methods. PMID- 21650600 TI - EPA Watch: Master testing list doubles in size. PMID- 21650601 TI - EPA Watch: Cost of drinking water system upgrades assessed. PMID- 21650602 TI - EPA Watch: Interim policy will drive pesticide approval process. PMID- 21650603 TI - EPA Watch: Locomotive air emission limits proposed. PMID- 21650604 TI - EPA Watch: New manual standardizes radiation cleanup testing. PMID- 21650605 TI - EPA Watch: Report sees ecosystem protection trend. PMID- 21650606 TI - EPA Watch: Superfund administrative reforms working, says report. PMID- 21650607 TI - Children's health to be new focus for EPA, research, says Browner. PMID- 21650609 TI - Pediatrician named EPA children's environmental health adviser. PMID- 21650608 TI - Clinton proposes 12% increase for EPA. PMID- 21650610 TI - Particulates, ozone standards due July 19. PMID- 21650612 TI - EPA issues new guidance to improve states' water quality reports. PMID- 21650613 TI - Courts push states, EPA to create TMDL water programs. PMID- 21650611 TI - MTBE water contamination raises health concerns, research questions. PMID- 21650614 TI - Smaller SITE program changes direction. PMID- 21650615 TI - White House studies U.S. environmental technology industry, R&D. PMID- 21650616 TI - News briefs: news briefs. PMID- 21650620 TI - On the trail of bioremediating microbes. AB - By tracking bacteria as they "swim" toward contaminants, researchers are improving models for bioremediation. PMID- 21650618 TI - Phytoremediation on the brink of commericialization. AB - Plants ranging from pennycress to poplar trees are proving their worth as cleanup tools. PMID- 21650621 TI - Fingering carcinogens with genetic evidence. AB - Predictable mutation patterns in DNA give researchers another tool to identify potential environmental carcinogens. PMID- 21650622 TI - Online/In print: online/in print. PMID- 21650623 TI - Buyer's Guide: Buyer's Guide. PMID- 21650629 TI - Other/miscellaneous. PMID- 21650627 TI - Other/miscellaneous. PMID- 21650630 TI - Revisiting our editorial policy. PMID- 21650632 TI - Letters: Eye of the beholder. PMID- 21650631 TI - Letters: Complexity of remediation. PMID- 21650633 TI - Letters: Dioxin effects challenged. PMID- 21650635 TI - Congress fits controversial riders into budget. PMID- 21650634 TI - Growing acceptance of soil contaminant bioavailability kicks off national meeting. PMID- 21650636 TI - National Science Foundation funds catalyze collaborations. PMID- 21650638 TI - EU pushes congeneration to reduce greenhouse gas emissions. PMID- 21650637 TI - Executive order targets invasive species blamed for altering ecosystems. PMID- 21650639 TI - NRC finds science, cooperation needed to support watershed management policy. PMID- 21650641 TI - News Briefs: Poor organization, weak leadership, and an unclear mission. PMID- 21650640 TI - Corps proposes $7.8 billion plan to restore Everglades' natural hydrology. PMID- 21650642 TI - News Briefs: Trading of nitrogen oxide (NOX) emissions will reduce airborne nitrate loadings. PMID- 21650643 TI - News Briefs: The earth lost nearly one-third of its biological wealth over the last 25 years. PMID- 21650644 TI - News Briefs: Stakeholder involvement in environmental decision making will continue to expand. PMID- 21650646 TI - News Briefs: Hurricanes should be considered a major secondary feedback mechanism in the global carbon cycle. PMID- 21650645 TI - News Briefs: Children are more likely to be affected by airborne fine particulates that adults or adolescents. PMID- 21650647 TI - News Briefs: The general belief that persistent organic pollutants accumulate in northern regions. PMID- 21650649 TI - EPA WATCH: Ecosystem research strategy takes proactive approach. PMID- 21650648 TI - EPA Watch: Control strategy proposed for animal feeding lots. PMID- 21650650 TI - EPA WATCH: NAS finds low cancer risk from random in water. PMID- 21650651 TI - EPA WATCH: PCB-laden sediment cleanup plans set for Mass. sites. PMID- 21650652 TI - EPA WATCH: Congress approves four new policy directors. PMID- 21650654 TI - Technology Update: High-flying instrument helps scientists evaluate aircraft impacts. PMID- 21650653 TI - EPA WATCH: GAO promotes release of new chemical data. PMID- 21650655 TI - Taking stock of green tax reform initiatives. AB - The call for carbon and energy taxes to control CO2 emissions has sparked national and international debate. PMID- 21650660 TI - Departments: PCDD. PMID- 21650657 TI - Growing concern about disinfection byproducts. AB - EPA is under increasing public pressure to assess potential short-term health risks of chlorinated drinking water. PMID- 21650668 TI - Research Watch: MTBE in lakes. PMID- 21650676 TI - Research Watch: Leachate test failure. PMID- 21650684 TI - Online/In print: online/in print. PMID- 21650687 TI - A-page index: 1998 a-page index. PMID- 21650685 TI - Buyer's Guide: Buyer's Guide. PMID- 21650691 TI - Other/miscellaneous. PMID- 21650693 TI - Other/miscellaneous. PMID- 21650720 TI - Technology Update: Native aquatic plants remove explosives. PMID- 21650722 TI - Technology Update: Toluene boosts bioremediation of TCE. PMID- 21650721 TI - Technology Update: Lysimeters promoted for pesticide research. PMID- 21650723 TI - EPA Watch: EPA prepares for state nonpoint source controls. PMID- 21650725 TI - EPA Watch: First U.S. contaminated sediments report released. PMID- 21650724 TI - EPA Watch: Groundwater cleanup test sites listed. PMID- 21650726 TI - EPA Watch: Draft guidance will require drinking water assessments. PMID- 21650727 TI - EPA Watch: RCRA proposal tightens mining industry exclusion. PMID- 21650729 TI - EPA Watch: CAM rule would cost $80 million annually. PMID- 21650728 TI - EPA Watch: Voluntary TSCA data collection recommended. PMID- 21650730 TI - EPA Watch: Water agencies sue EPA over health research funding. PMID- 21650733 TI - EPA proposes a national low-emission vehicle program. PMID- 21650734 TI - U.S. toxic wastes increase, prompting push for chemical use reporting. PMID- 21650735 TI - National fish survey links pesticides with sex hormone imbalance. PMID- 21650739 TI - Supercritical CO2-based cleaning system among Green Chemistry award winners. PMID- 21650737 TI - G7 nations to focus on children's health. PMID- 21650740 TI - News briefs: news briefs. PMID- 21650741 TI - European bans on surfactant trigger transatlantic debate. AB - U.S. and European regulators and researchers disagree over risks of a common class of surfactants. PMID- 21650742 TI - Data slim on APE role in endocrine disruption. PMID- 21650744 TI - Watershed management approach gains with States. AB - Nearly half of U.S. states have adopted watershed approaches to tackle recalcitrant water quality problems. PMID- 21650745 TI - Amphibian deformities continue to puzzle researchers. AB - Studies are under way to discover the cause of widespread malformations in wild amphibians. PMID- 21650746 TI - Online/In print: online/in print. PMID- 21650747 TI - Buyer's Guide: Buyer's Guide. PMID- 21650751 TI - Other/miscellaneous. PMID- 21650753 TI - Protecting children's health. PMID- 21650754 TI - Letters: ORD mired in bureaucracy. PMID- 21650755 TI - Letters: Changing statues. PMID- 21650756 TI - Letters: Great Lakes dispute. PMID- 21650757 TI - Letters: Great Lakes dispute. PMID- 21650758 TI - Letters: Author's Response. PMID- 21650787 TI - EPA Watch: OSHA, EPA jointly fight accidental chemical spills. PMID- 21650788 TI - EPA Watch: New manufacturing plants are targets of toxics rule. PMID- 21650789 TI - EPA Watch: Public interest groups target Project XL permit. PMID- 21650790 TI - EPA Watch: Agency begins drafting drinking water rules. PMID- 21650791 TI - EPA Watch: Pollution prevention option offered pesticide formulators. PMID- 21650792 TI - EPA Watch: New financial assurance test for local landfill owners. PMID- 21650795 TI - Sound science, regulatory review, top list as new Congress convenes. PMID- 21650796 TI - Army Corps closes regulatory loopholes for small wetlands fills. PMID- 21650797 TI - Hazardous waste incinerator rule delayed by EPA for more than a year. PMID- 21650798 TI - Continuous emissions monitors for toxics need more work. PMID- 21650799 TI - Proposed sediment contamination guidelines to look at chemical mixtures. PMID- 21650800 TI - N.Y. state begins 5-year Love Canal health study that includes noncancer effects. PMID- 21650801 TI - News briefs: news briefs. PMID- 21650803 TI - Environmental taxes gaining ground in europe. AB - National "green taxes" are environmentally effective and catching on, says the European Environment Agency. PMID- 21650805 TI - "Green" manufacturing one part at a time. AB - New process analysis tools bring "design for the environment" to the plant floor. PMID- 21650808 TI - Online/In print: online/in print. PMID- 21650809 TI - Buyer's Guide: Buyer's Guide. PMID- 21650813 TI - Other/miscellaneous. PMID- 21650815 TI - Other/miscellaneous. PMID- 21650816 TI - More about data. PMID- 21650818 TI - Letters: Pollution plume photo misleads readers. PMID- 21650819 TI - Letters: Environmental industry hit by prevention. PMID- 21650820 TI - International POPs treaty faces implementation hurdles. PMID- 21650821 TI - British study finds endocrine disruption widespread in native fish. PMID- 21650822 TI - New wetlands permits draw criticism. PMID- 21650823 TI - Strong winds push back "dead zone" in Gulf. PMID- 21650825 TI - EU proposes tighter rules on ozone depleters. PMID- 21650824 TI - Urban heat island models may help states meet NOX air standards. PMID- 21650826 TI - EU position on HCFC phaseout seen as "hypocritical". PMID- 21650827 TI - News Briefs: Total volatile organic compound (VOC) emissions during vehicle refueling may be significantly higher. PMID- 21650828 TI - News Briefs: Older, grandfathered power plants emit 4 to 10 times more pollution than modern plants. PMID- 21650829 TI - News Briefs: All production and use of DDT should be banned worldwide by 2007. PMID- 21650830 TI - News Briefs: Sustainable development could benefit their business. PMID- 21650831 TI - News Briefs: Canal estates and marinas should be designed to maximize wetland flushing. PMID- 21650832 TI - News Briefs: 200 million metric tons of carbon dioxide and 1.3 million metric tons of methane emissions could be eliminated. PMID- 21650833 TI - News Briefs: People in the news. PMID- 21650834 TI - News Briefs: By 2005, the phytoremediation market will swell to between $214 and $370 million. PMID- 21650836 TI - EPA Watch: Are states sidestepping the TMDL program? PMID- 21650838 TI - Technology Update: Field trial for MTBE bioremediation method. PMID- 21650839 TI - Peer reviewed: fires in indonesia: crisis and reaction. AB - Alarmed by fire and smoke pollution impacts, area nations are organizing to avoid another catastrophe. PMID- 21650840 TI - Peer reviewed: toward a nonpolluting energy system. AB - The goal seems more realistic as a result of advances in fuel cell and photovoltaic technology. PMID- 21650842 TI - A new "green" building on campus. AB - Montana State University's planned $40 million science building will be a test bed for emerging clean technologies. PMID- 21650846 TI - Research Watch: Photolysis of humic acid. PMID- 21650869 TI - Research Watch: Humic acid desorption. PMID- 21650870 TI - Online/in Print: Online/in Print. PMID- 21650876 TI - Other/miscellaneous. PMID- 21650871 TI - Buyer's Guide: Buyer's Guide. PMID- 21650878 TI - Other/miscellaneous. PMID- 21650879 TI - Goodbye and thanks. PMID- 21650880 TI - EPA decision to revise selenium standard stirs debate. PMID- 21650882 TI - Green chemistry award competition heats up. PMID- 21650881 TI - Kyoto Treaty: Slow progress on CO2 emissions trading plans. PMID- 21650883 TI - Auto industry calls for low-sulfur fuel. PMID- 21650884 TI - No simple answer to recent amphibian declines. PMID- 21650885 TI - Census Bureau conducts first environmental survey. PMID- 21650886 TI - Adapting to climate change. PMID- 21650888 TI - News Briefs: The environmental laws in their contries "don't go far enough,". PMID- 21650887 TI - Endocrine Disrupters: Consumer Safety Commission assessing PVC toy risk. PMID- 21650889 TI - News Briefs: The United States exported at least 21 million pounds of pesticides prohibited for domestic use. PMID- 21650890 TI - News Briefs: Sixteen percent of U.S. counties produce more manure than can be used by crops. PMID- 21650891 TI - News Briefs: People in the news. PMID- 21650893 TI - News Briefs: Cutting sulfur concentrations in gasoline would reduce the number of air pollution-related deaths. PMID- 21650892 TI - News Briefs: Hazards will remain at two-thirds of contaminated sites from the nuclear weapons complex. PMID- 21650894 TI - News Briefs: Transportation and agriculture are the causes of many of Europe's environmental problems. PMID- 21650895 TI - News Briefs: A more complete method for accounting for the world's carbon sources and sinks needs to be developed. PMID- 21650896 TI - EPA Watch: EPA softens rules for small drinking water systems. PMID- 21650898 TI - Technology Update: Technology combination cuts DNAPL cleanup time at Superfund site. PMID- 21650899 TI - "Natural" Remediation of DDT, PCBs Debated. AB - The dispute over chlorinated contaminant cleanups is heating up amid claims about benefits of natural processes. PMID- 21650900 TI - The challenge of watershed cleanup. AB - States are finding innovative ways to implements the Clean Water Act's TMDL program. PMID- 21650901 TI - Peer reviewed: toward a zero-emissions economy. PMID- 21650902 TI - Peer reviewed: are toxics release inventory reductions real? PMID- 21650908 TI - Research Watch: Pollutant uptake in soils. PMID- 21650916 TI - Research Watch: Reductive dechlorination. PMID- 21650926 TI - Online/In print: online/in print. PMID- 21650931 TI - Other/miscellaneous. PMID- 21650927 TI - Buyer's Guide: Buyer's Guide. PMID- 21650932 TI - Other/miscellaneous. PMID- 21650935 TI - Budget: "Clean Water Plan" calls for national wetlands gains. PMID- 21650936 TI - Budget: Energy efficiency research gains in Department of Energy's 1999 budget request. PMID- 21650937 TI - Draft report urges inclusion of mixtures in endocrine disrupter testing program. PMID- 21650938 TI - Miscarriages associated with drinking water disinfection byproducts, study says. PMID- 21650939 TI - Toxic Substances: International heavy metals, POPs protocols finalized. PMID- 21650940 TI - Budget: EPA's 1999 budget request highlights climate change, water quality programs. PMID- 21650941 TI - Waste Management: EU Parliament strengthens draft landfill law. PMID- 21650942 TI - News Briefs: The U.S. chemical industry's Responsible Care program "has not encouraged pollution prevention or greater public access to information about toxic threats,". PMID- 21650944 TI - News Briefs: The American Water Works Association Research Foundation is funding 35 research projects. PMID- 21650943 TI - News Briefs: A database of soil cleanup technologies and soil remediation companies in North America and Europe. PMID- 21650945 TI - News Briefs: As many as 24,000 people die prematurely in the United Kingdom each year following short-term air pollution episodes. PMID- 21650947 TI - News Briefs: Asthma, endocrine disruption, childhood cancers, and nervous system and developmental effects are priority research areas for children's health. PMID- 21650946 TI - News Briefs: U.S. air quality was the "best on record" in 1996. PMID- 21650948 TI - News Briefs: Decreases in nutrient loading of watersheds will lower the risk of toxic outbreaks of Pfiesteriai-like dinoflagellates. PMID- 21650949 TI - News Briefs: States took the leads in 1997 in reclaiming blighted industrial areas. PMID- 21650950 TI - News Briefs: A new private, nonprofit "National Spatial Data Council" is needed to guide the development and maintenance of geographic information. PMID- 21650951 TI - EPA Watch: New focus on urban environmental problems. PMID- 21650953 TI - Technology Update: Trench captures highway runoff metals. PMID- 21650954 TI - Where is mercury deposition coming from? AB - Uncertainties about the roles of different natural and synthetic sources are fueling the debate on how to regulate emissions. PMID- 21650955 TI - Intrinsic remediation under the microscope. AB - Concerns about the use of "natural attenuation" have led to a major review of the method's effectiveness. PMID- 21650959 TI - Research Watch: Pollutant sequestration in soils. PMID- 21650968 TI - Research Watch: A novel water treatment process. PMID- 21650972 TI - Buyer's Guide: Buyer's Guide. PMID- 21650971 TI - Online/In print: online/in print. PMID- 21650978 TI - Other/miscellaneous. PMID- 21650976 TI - Other/miscellaneous. PMID- 21650980 TI - Letters: Linking monitoring to modeling. PMID- 21650982 TI - Letters: Setting health risk benchmarks. PMID- 21650981 TI - Letters: response. PMID- 21650983 TI - Letters: Cleanup boom or bust? PMID- 21650984 TI - Letters: response. PMID- 21650985 TI - Long-running dioxin reassessment nears SAB review. PMID- 21650986 TI - Credibility of ISO 14000 questioned. PMID- 21650987 TI - UN commission calls for review of voluntary environmental initiatives. PMID- 21650988 TI - Drinking Water: California proposes tighter MTBE standard. PMID- 21650989 TI - New health research on particulates sheds light on possible mechanism. PMID- 21650990 TI - Hormone effects in men and fish subject of new UK study. PMID- 21650991 TI - Several states pass laws to regulate animal waste. PMID- 21650992 TI - The contaminated sediment management strategy. PMID- 21650993 TI - EPA softens stand on controversial contaminated sediment standards. PMID- 21650994 TI - News Briefs: Environmental professionals are needed to review environmental impact assessments in developing countries. PMID- 21650995 TI - News Briefs: The fastest mass extinction of plants and animals in Earth's history is underway. PMID- 21650996 TI - News Briefs: Industry pollution prevention efforts are more likely to flourish. PMID- 21650997 TI - News Briefs: Agricultural pollution is the most common threat to U.S. rivers. PMID- 21650999 TI - News Briefs: The world is economically richer and environmentally poorer than ever before. PMID- 21650998 TI - News Briefs: Worldwide energy consumption is expected to grow 75% between 1995 and 2020. PMID- 21651000 TI - News Briefs: Particulates emissions from 1991-model diesel engines is 15 to 35 times greater than that of 1998 diesel engines. PMID- 21651001 TI - News Briefs: People in the news. PMID- 21651002 TI - News Briefs: Eleven million childhood deaths occur each year primarily because of preventable, environmentally related diseases. PMID- 21651003 TI - EPA Watch: Pilot projects unite air and water regulations. PMID- 21651005 TI - Technology Update: DOE lab predicts future envirotech breakthroughs. PMID- 21651006 TI - Unraveling cancer risk with cellular and molecular tools. AB - Innovative techniques and mechanistic insights are reducing uncertainties in risk assessments. PMID- 21651008 TI - Preventing pollution by design. AB - New manufacturing software could give product designers instant information on how to avoid pollution. PMID- 21651013 TI - Research Watch: Leaching of phosphorus from soils. PMID- 21651033 TI - Research Watch: Toxicity of aerosol-bound PAHs. PMID- 21651037 TI - Online/In print: online/in print. PMID- 21651038 TI - Buyer's Guide: Buyer's Guide. PMID- 21651041 TI - Benefits and limitations of porous substrates as biosensors for protein adsorption. AB - Porous substrates have gained widespread interest for biosensor applications based on molecular recognition. Thus, there is a great demand to systematically investigate the parameters that limit the transport of molecules toward and within the porous matrix as a function of pore geometry. Finite element simulations (FES) and time-resolved optical waveguide spectroscopy (OWS) experiments were used to systematically study the transport of molecules and their binding on the inner surface of a porous material. OWS allowed us to measure the kinetics of protein adsorption within porous anodic aluminum oxide membranes composed of parallel-aligned, cylindrical pores with pore radii of 10 40 nm and pore depths of 0.8-9.6 MUm. FES showed that protein adsorption on the inner surface of a porous matrix is almost exclusively governed by the flux into the pores. The pore-interior surface nearly acts as a perfect sink for the macromolecules. Neither diffusion within the pores nor adsorption on the surface are rate limiting steps, except for very low rate constants of adsorption. While adsorption on the pore walls is mainly governed by the stationary flux into the pores, desorption from the inner pore walls involves the rate constants of desorption and adsorption, essentially representing the protein-surface interaction potential. FES captured the essential features of the OWS experiments such as the initial linear slopes of the adsorption kinetics, which are inversely proportional to the pore depth and linearly proportional to protein concentration. We show that protein adsorption kinetics allows for an accurate determination of protein concentration, while desorption kinetics could be used to capture the interaction potential of the macromolecules with the pore walls. PMID- 21651042 TI - Comment on "Electrochemical detection of peroxynitrite using a biosensor based on a conducting polymer-manganese ion complex". PMID- 21651043 TI - Measuring photochemical kinetics in submonolayer films by transient ATR spectroscopy on a multimode planar waveguide. AB - Understanding the kinetics of reactions in molecular thin films can aid in the molecular engineering of organic photovoltaics and biosensors. We have coupled two analytical methods, transient absorbance spectroscopy (TAS) and attenuated total reflectance (ATR), in a relatively simple arrangement when compared with previous TAS/ATR instruments to interrogate molecular structure and photochemistry at interfaces. The multimode planar waveguide geometry provides a significant path length enhancement relative to a conventional transmission geometry, making it feasible to perform measurements on low-surface-coverage films. The performance of the instrument was assessed using a thin film composed of purple membrane (PM) fragments containing bacteriorhodopsin deposited onto PDAC, a positively charged polymer. The surface coverage of retinal chromophore in this film is ~0.1 monolayer and its orientation distribution is anisotropic, with a mean tilt angle of 68 degrees from surface normal. After photoinduced formation of the transient M state, the chromophore decays to the ground state in 4.4 +/- 0.6 ms, equivalent to the decay of suspended PM fragments, which shows that deposition on PDAC does not alter M-state photokinetics. The surface coverage of the M state is calculated to be 2 pmol/cm(2), which is ~1% of a close packed monolayer. This work demonstrates that TAS/ATR can be used to probe structure and photochemical kinetics in molecular films at extremely low surface coverages. PMID- 21651045 TI - Other/miscellaneous. PMID- 21651046 TI - Other/miscellaneous. PMID- 21651047 TI - Federal research publishing houses? PMID- 21651049 TI - Letter to the Editor: Methyl mercury revisited. PMID- 21651051 TI - In AC Research: In AC Research. PMID- 21651052 TI - Analytical Currents: Microfabrication in the FLO. PMID- 21651053 TI - Analytical Currents: Miniaturized mixer. PMID- 21651054 TI - Analytical Currents: A hydrogel never forgets. PMID- 21651055 TI - Analytical Currents: To catch a plasmid. PMID- 21651056 TI - Analytical Currents: Surface secrets revealed. PMID- 21651057 TI - Analytical Currents: Electrospray of large DNA. PMID- 21651058 TI - Analytical Currents: K+ chemosensor. PMID- 21651059 TI - Analytical Currents: VCD of oligosaccharides. PMID- 21651060 TI - Analytical Currents: New metalloprotein tool. PMID- 21651061 TI - Analytical Currents: Filtered probes improve tissue Raman spectra. PMID- 21651062 TI - Science: Tailing of peaks. PMID- 21651063 TI - Science: Microchip gets a tip. PMID- 21651064 TI - Science: QCMs in multiples. PMID- 21651065 TI - Science: Getting the measure of polymers. PMID- 21651067 TI - News from BioMEMS: CDs that use the force. PMID- 21651066 TI - News from BioMEMS: Living chips. PMID- 21651068 TI - News from the Australian International Symposium on Analytical Science: Chromatography with tunable selectivity for inorganic anions. PMID- 21651069 TI - News from BioMEMS: Biochemical IC chips. PMID- 21651070 TI - Business: Agilent unveiled. PMID- 21651071 TI - Government and Society: NELAP begins. PMID- 21651072 TI - Business: Changes in store for Perkin-Elmer. PMID- 21651073 TI - People: Graduate fellowship awards. PMID- 21651074 TI - People: Nucleic acid review. PMID- 21651075 TI - People: DAC fellowship nominations. PMID- 21651076 TI - People: Crystallography scholarship awards. PMID- 21651077 TI - People: Benedetti-Pichler award. PMID- 21651080 TI - Peer reviewed: x-ray photoelectron spectroscopy and archaeology. AB - XPS offers unique advantages for analyzing a wide range of artifacts. PMID- 21651081 TI - Focus: Tearing down the tower of Babel. AB - First steps toward a common language for analytical data. PMID- 21651084 TI - A: E-commerce: Il buono, il brutto, il cattivo. PMID- 21651083 TI - Product Review: Near-IR gets the job done. AB - Infrared brings to mind spectra with narrow, well-separated peaks; anybody expecting something similar from near-IR needs to think again. PMID- 21651085 TI - Books and Software: Getting down to the basics of sensors. AB - A review of Principles of Chemical and Biological Sensors. PMID- 21651087 TI - Meetings: 99 FACSS. PMID- 21651086 TI - Books and Software: A fitting tribute to Cal Giddings. PMID- 21651088 TI - Meetings: conferences. PMID- 21651089 TI - New products: new products. PMID- 21651090 TI - Other/miscellaneous. PMID- 21651093 TI - Other/miscellaneous. PMID- 21651091 TI - Information express: information express. PMID- 21651094 TI - Other/miscellaneous. PMID- 21651095 TI - Radiochemical analysis. PMID- 21651099 TI - In AC Research: In AC Research. PMID- 21651101 TI - Analytical Currents: Tilting at rough surfaces. PMID- 21651102 TI - Analytical Currents: Fast LC/MS. PMID- 21651104 TI - Analytical Currents: Chemical limit on miniaturization. PMID- 21651103 TI - Analytical Currents: CID MS/MS competes with NMR. PMID- 21651105 TI - Analytical Currents: Dynamic CE. PMID- 21651106 TI - Analytical Currents: Conformation by electrochemistry. PMID- 21651107 TI - Analytical Currents: A dissection of cross section. PMID- 21651108 TI - Analytical Currents: Better beads. PMID- 21651109 TI - Science: Shorter sample cleanup times. PMID- 21651110 TI - Science: The dope on dopamine. PMID- 21651112 TI - News from Pittcon: Teaching DNA to do chemistry. PMID- 21651111 TI - Science: MCE stacks up. PMID- 21651113 TI - News from Pittcon: Instrument manufacturers restructure. AB - The staff of Analytical Chemistry reports from Orlando, FL. PMID- 21651114 TI - Government and Society: CRMMA resurfaces. PMID- 21651115 TI - Government and Society: Unified protection. PMID- 21651116 TI - Government and Society: NACLA still seeks members. PMID- 21651118 TI - Peer reviewed: fluorescent molecular sensor for drug discovery. AB - The tyranny of large numbers of drug compounds to screen is the raison d'etre for a fluorescent assay system. PMID- 21651117 TI - Peer Reviewed: On-Line Coupling of Capillary Separation Techniques with 1H NMR. AB - Improved sensitivity, deuterated solvents, and less sample make this approach feasible for many applications. PMID- 21651119 TI - Focus: Uncertainty in NELAC's financial future. PMID- 21651121 TI - Product Review: Chromatography data systems. PMID- 21651122 TI - Meetings: ASMS in Dallas. PMID- 21651123 TI - Meetings: Jekyll Island Symposium: ISEAC '99. PMID- 21651125 TI - Meetings: Short courses. PMID- 21651124 TI - Meetings: conferences. PMID- 21651126 TI - A: Unweaving the rainbow: Zero administration. AB - There was an awful rainbow once in heaven: We know her woof, her texture; ... Unweave a rainbow, as it erewhile made The tender-person'd [user] melt into a shade. (John Keats, from Part II of "Lamia", 1820). PMID- 21651129 TI - New products: new products. PMID- 21651128 TI - Books and Software: The essential guide for biosensors. AB - A review of Affinity Biosensors, Techniques, and Protocols. PMID- 21651131 TI - Other/miscellaneous. PMID- 21651132 TI - Information express: information express. PMID- 21651134 TI - Other/miscellaneous. PMID- 21651136 TI - Molecular recognition. PMID- 21651135 TI - Other/miscellaneous. PMID- 21651140 TI - In AC Research: In AC Research. PMID- 21651143 TI - Analytical Currents: Backscatter detection for CE. PMID- 21651144 TI - Analytical Currents: Matching spectra. PMID- 21651145 TI - Analytical Currents: Molecular beacons put down roots. PMID- 21651146 TI - Analytical Currents: Beaming through water droplets. PMID- 21651148 TI - Analytical Currents: New stationary phase. PMID- 21651147 TI - Analytical Currents: More than low flow. PMID- 21651149 TI - Analytical Currents: Electronic dot blot for SNPs. PMID- 21651150 TI - Analytical Currents: MIP for estrogenic compounds. PMID- 21651151 TI - Science: Just say NO. PMID- 21651152 TI - Analytical Currents: Lions, tigers, and bears. PMID- 21651153 TI - Analytical Currents: Understanding chemisorbed CO. PMID- 21651154 TI - Science: Shaping up. PMID- 21651156 TI - Science: Rapid MIPs screening. PMID- 21651155 TI - News from ABRF '99: New biological standards considered. PMID- 21651157 TI - News from the ACS National Meeting: Putting ion traps to the test. PMID- 21651159 TI - News from the ACS National Meeting: Keep away from the surface. PMID- 21651158 TI - News from ABRF '99: Virtual electrophoresis. PMID- 21651161 TI - People: Simon scholarships. PMID- 21651160 TI - Business: Net effect of bidding. PMID- 21651162 TI - People: 1999 EAS award winners. PMID- 21651167 TI - Meetings:International Symposium on Chiral Discrimination. PMID- 21651165 TI - Product Review: GC/MS: Not the same old combination. AB - GC/MS systems are on the bench but still in the game. PMID- 21651168 TI - Meetings: gordon research conference on analytical chemistry. PMID- 21651169 TI - Meetings:Waste Testing and quality assurance. PMID- 21651170 TI - Meetings: conferences. PMID- 21651171 TI - Meetings: Short courses. PMID- 21651172 TI - Books and Software: Indepth scintillation analysis. PMID- 21651173 TI - Books and Software: SFC for all stages. AB - A review of Supercritical Fluid Chromatography with Packed Columns-Techniques and Applications. PMID- 21651175 TI - New products: new products. PMID- 21651174 TI - Books and Software: GC/MS guide. PMID- 21651177 TI - Other/miscellaneous. PMID- 21651176 TI - Other/miscellaneous. PMID- 21651178 TI - Information express: information express. PMID- 21651180 TI - Other/miscellaneous. PMID- 21651181 TI - Other/miscellaneous. PMID- 21651184 TI - Letter to the Editor: Artifact formation of methylmercury in sediments. PMID- 21651182 TI - The scientific method. PMID- 21651187 TI - In AC Research: In AC Research. PMID- 21651191 TI - Analytical Currents: Go for the gold. PMID- 21651190 TI - Analytical Currents: Studying protein ionization with charge ladders. PMID- 21651193 TI - Analytical Currents: Controlling fluid motion and position. PMID- 21651192 TI - Analytical Currents: Subattomole detection of catecholamines. PMID- 21651195 TI - Analytical Currents: Cancer cell profiles with MALDI-TOFMS. PMID- 21651194 TI - Analytical Currents: New spray chamber for USN. PMID- 21651196 TI - Analytical Currents: MALDI spectra reflect solution phase. PMID- 21651197 TI - Analytical Currents: Redox switching. PMID- 21651198 TI - Analytical Currents: Simplified ESI spectra. PMID- 21651199 TI - Analytical Currents: The origin of limestone fluorescence. PMID- 21651200 TI - Science: Sorting cells. PMID- 21651201 TI - Science: Living sensors for saccharides. PMID- 21651202 TI - Business: Perkin-Elmer to sell Analytical Instruments Division. PMID- 21651203 TI - Government and Society: NELAC prepares for implementation. PMID- 21651204 TI - Science: Probing the plume. PMID- 21651205 TI - Government and Society: Comparability protocols ease changes. PMID- 21651206 TI - People: Keene P. Dimick nominations. PMID- 21651207 TI - People: Beckman receives NAS honor. PMID- 21651208 TI - People: SACP starter grant award. PMID- 21651209 TI - Peer reviewed: Raman chemical imaging spectroscopy. PMID- 21651211 TI - Peer Reviewed: Membrane Preconcentration CE. AB - A new approach to preconcentrating samples before separation. PMID- 21651215 TI - Product Review: Electrospray in flight. AB - Orthogonal acceleration brings the advantages of time of flight to electrospray. PMID- 21651213 TI - Focus: Pinning down PCR. AB - Widespread interest in gene quantitation and high-throughput assays are putting quantitative PCR back in the spotlight. PMID- 21651216 TI - Meetings: ACS in Anaheim. PMID- 21651218 TI - Meetings: Short course. PMID- 21651217 TI - Meetings: ABRF '99. PMID- 21651219 TI - Meetings: conferences. PMID- 21651221 TI - A: A course of one's own: Distance learning. PMID- 21651222 TI - Books and Software: Worldwide textbook? PMID- 21651223 TI - Books and Software: Welcome to biosensors. AB - A review of Introduction to Bioanalytical Sensors. PMID- 21651224 TI - Books and Software: GC practical advice. PMID- 21651227 TI - New products: new products. PMID- 21651229 TI - Other/miscellaneous. PMID- 21651230 TI - Information express: information express. PMID- 21651231 TI - High-throughput small molecule identification using MALDI-TOF and a nanolayered substrate. AB - Encoderless combinatorial chemistry requires high-throughput product identification without the use of chemical or other tags. We developed a novel nanolayered substrate plate and combined it with a microarraying robot, matrix assisted laser desorption/ionization (MALDI) mass spectrometry, and custom software to produce a high-throughput small molecule identification system. To optimize system performance, we spotted 5 different chemical entities, spanning a m/z range of 195 to 1338, in 20,304 spots for a total of 101,520 molecules. The initial spot identification rate was 99.85% (20,273 spots), and after a proofreading algorithm was added, 100% of 20,304 spots and 101,520 molecules were identified. An internal recalibration algorithm also significantly improved mass accuracy to as low as 45 ppm. Using this optimized system, 47 different chemical entities, spanning a m/z range of 138 to 1,592, were spotted over 5,076 spots and could be identified with 100% accuracy. Our study lays the foundation for improved encoderless combinatorial chemistry. PMID- 21651232 TI - Three different approaches for the clarification of the interactions between lipoproteins and chondroitin-6-sulfate. AB - Two different experimental approaches were used for obtaining a comprehensive view and understanding of the interactions between apolipoprotein B-100 (ApoB 100) of low-density lipoprotein and apolipoprotein E (ApoE) of high-density lipoprotein and chondroitin-6-sulfate (C6S) of arterial proteoglycan. The techniques employed were partial filling affinity capillary electrophoresis (PF ACE) and continuous flow quartz crystal microbalance (QCM). In addition, molecular dynamic (MD) simulations were used to provide a supportive visual insight into the interaction mechanism. A new tool for analysis of QCM-data was utilized, i.e., adsorption energy distribution calculations, which allowed a deeper understanding of the interactions, especially at different temperatures. The PF-ACE technique probed mainly the strong adsorption interactions whereas in the MD calculations short- and long-range interactions could be distinguished. Although there are differences in the techniques, a pretty good agreement was achieved between the three approaches for the interaction of 19 amino acid peptide of ApoB with C6S giving log affinity constants of 4.66 by QCM, 5.02 by PF ACE, and 7.39 by MD, and for 15 amino acid peptide of ApoE with C6S 5.34 by QCM, 5.28 by PT-ACE, and 4.60 by MD at physiological temperature 37.0 degrees C. PMID- 21651233 TI - Analysis of counterfeit pharmaceutical tablet cores utilizing macroscopic infrared spectroscopy and infrared spectroscopic imaging. AB - Advantages and limitations of analyzing authentic and counterfeit pharmaceutical tablets with both macro (nonimaging) attenuated total internal reflection Fourier transform infrared (ATR-FT-IR) spectroscopy and micro ATR-FT-IR spectroscopic imaging have been evaluated. The results of this study demonstrated that micro ATR imaging was more effective for extracting formulation information (sourcing), whereas a macro ATR approach was better suited for counterfeit detection (screening). More importantly, this study demonstrated that a thorough analysis of the counterfeit core can be achieved by combining the results of both techniques. PMID- 21651234 TI - Remotely detected NMR for the characterization of flow and fast chromatographic separations using organic polymer monoliths. AB - An application of remotely detected magnetic resonance imaging is demonstrated for the characterization of flow and the detection of fast, small molecule separations within hypercrosslinked polymer monoliths. The hyper-cross-linked monoliths exhibited excellent ruggedness, with a transit time relative standard deviation of less than 2.1%, even after more than 300 column volumes were pumped through at high pressure and flow. Magnetic resonance imaging enabled high resolution intensity and velocity-encoded images of mobile phase flow through the monolith. The images confirm that the presence of a polymer monolith within the capillary disrupts the parabolic laminar flow profile that is characteristic of mobile phase flow within an open tube. As a result, the mobile phase and analytes are equally distributed in the radial direction throughout the monolith. Also, in line monitoring of chromatographic separations of small molecules at high flow rates is shown. The coupling of monolithic chromatography columns and NMR provides both real-time peak detection and chemical shift information for small aromatic molecules. These experiments demonstrate the unique power of magnetic resonance, both direct and remote, in studying chromatographic processes. PMID- 21651235 TI - Effect of uncontrolled factors in a validated liquid chromatography-tandem mass spectrometry method question its use as a reference method for marine toxins: major causes for concern. AB - Chromatographic techniques coupled to mass spectrometry is the method of choice to replace the mouse bioassay (MBA) to detect marine toxins. This paper evaluates the influence of different parameters such as toxin solvents, mass spectrometric detection method, mobile-phase-solvent brands and equipment on okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) quantification. In addition, the study compares the results obtained when a toxin is quantified against its own calibration curve and with the calibration curve of the other analogues. The experiments were performed by liquid chromatography (LC) and ultraperformance liquid chromatography (UPLC) with tandem mass spectrometry detection (MS/MS). Three acetonitrile brands and two toxin solvents were employed, and three mass spectrometry detection methods were checked. One method that contains the transitions for azaspiracid-1 (AZA-1), azaspiracid-2 (AZA-2), azaspiracid-3(AZA-3), gimnodimine (GYM), 13-desmethyl spirolide C (SPX-1), pectenotoxin-2 (PTX-2), OA, DTX-1, DTX-2, yessotoxin (YTX), homoYTX, and 45-OH YTX was compared in both instruments. This method operated in simultaneous positive and negative ionization mode. The other two mass methods operated only in negative ionization mode, one contains transitions to detect DTX-1, OA DTX-2, YTX, homoYTX, and 45-OH-YTX and the other only the transitions for the toxins under study OA, DTX-1, and DTX-2. With dependence on the equipment and mobile phase used, the amount of toxin quantified can be overestimated or underestimated, up to 44% for OA, 46% for DTX-1, and 48% for DTX-2. In addition, when a toxin was quantified using the calibration curve of the other analogues, the toxin amount obtained is different. The maximum variability was obtained when DTX-2 was quantified using either OA or a DTX-1 calibration curve. In this case, the overestimation was up to 88% using the OA calibration curve and up to 204% using the DTX-1 calibration curve. In summary, the correct quantification of DSP toxins by MS detection depends on multiple factors. Since these factors are not taken into account in a validated protocol, these results question the convenience of having MS/MS as a reference method for protecting consumers of marine toxins, moreover if toxicity of each group is considered independently and total toxicity is not summed anymore as it is in the MBA. PMID- 21651236 TI - MS analysis of nucleic acids in the post-genomic era. AB - Alternative approaches complementing the existing technologies for analysis of nucleic acids and their assemblies are necessary to take on the new challenges posed by the postgenomic era. The versatility of MS in biopolymer analysis and its ability to reach beyond sequence information are the basis of ever expanding applications aimed at the elucidation of nucleic acid structure-function relationships. This Feature summarizes the current state of MS-based approaches devised to overcome the limitations of traditional techniques and to advance different facets of nucleic acids research. PMID- 21651237 TI - Wavelet- and Fourier-transform-based spectrum similarity approaches to compound identification in gas chromatography/mass spectrometry. AB - The high-throughput gas chromatography/mass spectrometry (GC/MS) technology offers a powerful means of analyzing a large number of chemical and biological samples. One of the important analyses of GC/MS data is compound identification. In this work, novel spectral similarity measures based on the discrete wavelet and Fourier transforms were proposed. The proposed methods are composite similarities that are composed of weighted intensities and wavelet/Fourier coefficients using cosine correlation. The performance of the proposed approaches along with the existing similarity measures was evaluated using the NIST Chemistry WebBook mass database maintained by the National Institute of Standards and Technology (NIST) as a library of reference spectra and repetitive mass spectral data as query spectra. The analysis results showed that the identification accuracies of the wavelet- and Fourier-transform-based methods were improved by 2.02% and 1.95%, respectively, compared to that of the weighted dot product (cosine correlation) and by 3.01% and 3.08%, respectively, compared to that of the composite similarity measure. The improved identification accuracy demonstrates that the proposed approaches outperformed the existing similarity measures in the literature. PMID- 21651238 TI - Optically Gated Capillary Electrophoresis of o-Phthalaldehyde/beta Mercaptoethanol Derivatives of Amino Acids for Chemical Monitoring. AB - Optically gated capillary electrophoresis (CE) of amino acids derivatized with o phthalaldehyde/beta-mercaptoethanol (OPA/beta-ME) was explored as a means to monitor amino acids with high temporal resolution. In agreement with a theoretical model described herein, 98% of a given concentration of OPA/beta-ME derivatives can be photobleached by a few milliwatts of the 350-nm line of an argon ion laser with just 0.7-ms exposure times in 5-MUm-i.d. capillaries. The low background from such high photobleaching efficiency allows detection limits in the low-nanomolar range for all amino acids tested. The short injection times possible with optical gating allow separation efficiencies of nearly 200 000 plates to be achieved in less than 1 s under ideal conditions. Under mock in vivo conditions, separations were slower and had lower efficiency due to reduced electroosmotic flow associated with the high salt content. To demonstrate chemical monitoring, the optically gated CE system was interfaced to two different sampling probes with on-line derivatization with OPA/beta-ME. With microdialysis sampling, the optically gated CE system could assay the sample stream every 2 s but actual temporal resolution for monitoring was limited by band broadening in the dialysis probe to ~12 s. Optically gated CE was also interfaced to a 10-MUm-i.d. sampling capillary that continuously pulled samples into the separation capillary at 6.5 nL/min. This direct sampling probe allowed monitoring of multiple amino acids with 10-s temporal resolution with several advantages compared to microdialysis including improved detection limits and spatial resolution. PMID- 21651239 TI - Surface-confined living radical polymerization for coatings in capillary electrophoresis. AB - Surface-confined living radical polymerization is shown to be a controlled means of covalently bonding both linear and cross-linked polymer films on silica. CuCl/bipyridine initiates radical formation through atom transfer with a self assembled monolayer of benzyl chloride, onto which polymer then grows. The polymerization is intrinsically confined to the surface, avoiding problems associated with polymer formed in the solution. The surface-confined polymerization scheme is generally applicable to radical polymerization of vinyl monomers and was studied here for the case of acrylamide. Infrared spectroscopy shows that the film growth is controllable, and atomic force microscopy reveals that smooth films are prepared. The surface-confinement polymerization scheme was tested for both linear and cross-linked polyacrylamide. Capillary electrophoresis of strongly basic proteins confirms that the coated capillaries provide the high efficiency expected for polyacrylamide. The cross-linked coating exhibits higher reproducibility with respect to migration time than does the linear coating. Surface-confined living radical polymerization prepares linear and cross-linked polymer films without danger of clogging narrow capillaries and will ultimately facilitate cross-laboratory comparisons by enabling control of film thickness. PMID- 21651240 TI - Capillary electrophoresis with electrochemical detection for chiral separation of optical isomers. AB - The enantiomers of two amine derivatives were directly separated by capillary electrophoresis (CE), employing beta-cyclodxtrin (beta-CD) as a chiral additive in strongly alkaline solutions. The analytes were detected by electrochemistry, using a copper disk electrode at +675 mV vs Ag/AgCl reference electrode. Both the free enantiomers and the enantiomer-cyclodxtrin inclusion complexes could be detected using this approach, although the complexed forms gave lower oxidation currents than the free forms. Factors affecting the chiral CE separation of the analytes, such as working potential, concentration of running buffer and beta-CD, and applied voltage, were extensively investigated. Under the optimum conditions, baseline separation of the enantiomers could be accomplished in less than 18 min. In addition, a successful application of the method to the enantiomeric purity determination confirmed its validity and practicability. PMID- 21651241 TI - Systematic Approach to Links between Separations in MEKC and Reversed-Phase HPLC. AB - Retention factors and partition coefficients in micellar electrokinetic chromatography (MEKC) and reversed-phase high-performance liquid chromatography (RP-HPLC) are compared for a series of alkylbenzenes and substituted phenols. In both techniques, separations are based on partitioning between an aqueous phase and an alkyl phase. In MEKC, this was an SDS (C12) micellar pseudostationary phase, and in RP-HPLC an ODS 2 (C18) stationary phase. A nonporous silica (Micra 1.5-MUm NPS), which has a low carbon loading, was used rather than a standard porous silica to avoid excessive retention in HPLC and to allow identical mobile phase conditions to be used in both separation modes. The average ratio of analyte retention factors, k(MEKC):k(HPLC), was found to be equal to the ratio beta(MEKC):beta(HPLC), where beta is the phase ratio. This implies that partition coefficients, P, are similar in both MEKC and HPLC, since P = k/beta, and that the dominant contribution to stability within each alkyl phase arises from hydrophobic interactions which are common to both separation media. Since partition coefficients are similar in MEKC and HPLC under aqueous buffer conditions, information on retention in one technique may be transferred to the other, provided that the phase ratios are known. In MEKC and HPLC, linear correlations of log octanol-water partition coefficients, K(ow), vs log k for the test compounds were transformed, knowing the phase ratio, to give log P values as a function of log K(ow). This allows quantitative links between MEKC and HPLC to be extended to include octanol-water partitioning. The addition of acetonitrile as an organic modifier over the concentration range 0-20% (v/v) was found to have a greater effect on k in HPLC than in MEKC. This could be a result of a decrease in the MEKC phase ratio due to an increase in the critical micelle concentration. PMID- 21651242 TI - Chromatographic selectivity of rare Earth elements on iminodiacetate-type chelating resins having spacer arms of different lengths: importance of steric flexibility of functional group in a polymer chelating resin. AB - Three types of chelating resins containing iminodiacetic acid homologues (IDA resins) with spacer arms of different lengths were prepared and examined as the column stationary phase for ion chromatography. The chromatographic retention behavior of rare earth elements (REEs) on the IDA resins was evaluated with respect to a capacity factor (k') to elucidate the selectivity profile of the resins. The k' values for a series of REEs on the IDA resins were compared with the chelate formation constants (K(ML)) of the corresponding free ligands of analogous structure. Selectivity of the chelating resins having longer spacer arms between the ligand group and the polymer matrix showed a better correlation with the corresponding monomeric ligands in solution. This trend has been attributed to the increase in steric flexibility of the ligand group by the presence of the spacer arm. PMID- 21651243 TI - Extraction and analysis of trifluoroacetic Acid in environmental waters. AB - Trifluoroacetic acid (TFA), a mildly phytotoxic compound, is a stable atmospheric breakdown product of HFC-134a, HCFC-123, and HCFC-124. An extraction and analytical method has been developed for the routine analysis of low ppt levels of TFA in aqueous samples. TFA can be quantitatively recovered from most environmental waters by an extraction procedure using a commercial anion-exchange disk. In saline samples (conductivity >620 MUS), where the presence of competing anions interfered with recovery, a liquid-liquid extraction cleanup was necessary. After extraction of TFA from water, the dried disk was placed in a headspace vial containing 10% sulfuric acid in methanol and the vial sealed and then vortexed for 30 s. The sulfuric acid-methanol solution extracts trifluoroacetate anion (TFA) from the anion-exchange matrix and, when heated, quantitatively converts it to the methyl ester, which is then analyzed by automated headspace gas chromatography using electron capture or mass spectrometry detection. Several environmental samples in addition to laboratory spike solutions were successfully extracted and analyzed with this technique. Recoveries averaged 108.2% for reagent water spiked at levels from 53 to 2110 ng/L with relative standard deviations ranging from 0.3 to 8.4%. The instrument's limit of detection for TFA standard was 3.3 ng. The limit of quantitation for the extraction and analytical technique was 36 ng/L. Three water samples can be prepared for automated analysis in 20 min using this technique. PMID- 21651244 TI - Photooxidation of 3-substituted pyrroles: a postcolumn reaction detection system for singlet molecular oxygen in HPLC. AB - A postcolumn photochemical reaction detection scheme, based on the reaction of 3 substituted pyrroles with singlet molecular oxygen ((1)O(2)), has been developed. The method is selective and sensitive for the determination of a class of organic compounds called (1)O(2)-sensitizers and is readily coupled to HPLC. Following separation by HPLC, analytes ((1)O(2)-sensitizers) are excited by a Hg pen-ray lamp. Analytes that are efficient (1)O(2)-sensitizers promote ground-state O(2) ((3)Sigma(g)(-)) to an excited state ((1)Sigma(g)(+) or (1)Delta(g)), which reacts rapidly with tert-butyl-3,4,5-trimethylpyrrolecarboxylate (BTMPC) or N benzyl-3-methoxypyrrole-2-tert-carboxylate (BMPC), which is added to the mobile phase. Detection is based on the loss of pyrrole (BTMPC or BMPC). The reaction is catalytic in nature since one analyte molecule may absorb light many times, producing large amounts of (1)O(2). Detection limits for several (1)O(2) sensitizers were improved by 1-2 orders of magnitude over optimized UV-absorbance detection. This paper discusses the optimization of the reaction conditions for this photochemical reaction detection scheme and its application to the detection of PCBs, nitrogen heterocycles, nitro and chloro aromatics, and other substituted aromatic compounds. PMID- 21651245 TI - Effects of Mobile-Phase Composition and Temperature on the Selectivity of Poly(N isopropylacrylamide)-Bonded Silica Gel in Reversed-Phase Liquid Chromatography. AB - We developed a simple preparation method for poly(N-isopropylacrylamide) (poly(NIPAM))-bonded silica using a water-organic two-phase system to directly copolymerize N-isopropylacrylamide with 3-(methacryloxy)propyl moieties on the silica surfaces. The stationary phase showed a phase transition with the change in temperature or in methanol content, resulting in notable changes in selectivity which cannot be expected with alkyl-type stationary phases. The packing material showed an increase in retention and column efficiency with the increase in temperature between 30 and 40 degrees C or in methanol content between 10 and 20%. The temperature-responsive properties were reduced with the increase in methanol content of the mobile phase and lost at 40% or higher. Significant changes in retention selectivity by the addition of methanol were observed for benzene derivatives below the transition temperature of poly(NIPAM). The preferential retention of hydrogen bond acceptors was observed at low temperatures in the mobile phase of low methanol content, while dominant contribution of the hydrophobic interaction to the retention of solutes was observed at the higher temperature in aqueous mobile phase or at the higher methanol concentration. The temperature increase brought about similar changes in retention behavior of the poly(NIPAM)-bonded silica packing materials to the addition of methanol to the mobile phase. PMID- 21651246 TI - All-hydrocarbon liquid crystalline polysiloxane polymer as stationary phase in gas chromatography capillary column for separation of isomeric compounds of polynuclear aromatic hydrocarbons. AB - Two new and high-purity all-hydrocarbon side-chain liquid crystalline polysiloxane polymers were synthesized by grafting all-hydrocarbon liquid crystal monomers onto a polymethylhydrosiloxane backbone. The two polysiloxane polymers show both smectic B and E mesophases which were characterized by (differential scanning calorimetry and X-ray analysis. As stationary phases, these liquid crystalline polysiloxane polymers were coated on the inner surface of a capillary column (i.d. = 0.32 mm, film thickness d(f) ~ 0.25 MUm) using the static coating method. The capillary column was installed on a GC/MS instrument. We used a standard commercial mixture of 21 species of polynuclear aromatic hydrocarbons (purchased from Supelco Co. and Merck Co.) to test the chromatographic behavior of the coated stationary phase. Test results of the isomeric pair compounds show a better separation resolution than identical tests using the commercial HP-5 capillary column, which is a standard and state-of-the-art analytical tool for the chromatographic resolution of PAHs. PMID- 21651247 TI - Low blank isotope ratio measurements of rhenium, osmium, and platinum using tantalum filaments with negative thermal ionization mass spectrometry. AB - Platinum is most commonly used as a filament for Re and Os isotopic measurements, but it contains impurities of Re and Os. Tantalum is low in platinum group elements (PGE) and in Re, but it is not used for negative thermal ionization mass spectrometry because of high electron emission and high reactivity with O(2). High thermal electron emission from Ta distorts the preoptimized ion source optics. In addition, Ta consumes O(2), leaving little for samples, but O(2) is essential for isotopic ratio measurements of PGE and Re as they are measured as negatively charged oxides, such as OsO(3)(-) and PtO(2)(-). These problems are solved by prebaking a filament to remove tantalum oxides before sample loading, keeping relatively high filament temperatures and high O(2) pressures (P(O)((2))) during the sample run, and lowering the potential difference between the filament and the draw-out plate. At P(O)((2)) of ~1 * 10(-)(5) Torr in the source, strong (>10 V) stable (>6 h) peaks of ReO(4)(-), OsO(3)(-), and PtO(2)(-) are obtained at 750 degrees C for Re, 850 degrees C for Pt, and over 900 degrees C for Os. Accurate isotopic ratio measurements of Re, Os, and Pt at picogram levels are possible using Ta filaments. PMID- 21651248 TI - Application of Continuous-Flow HPLC-Proton-Nuclear Magnetic Resonance Spectroscopy and HPLC-Thermospray-Mass Spectroscopy for the Structural Elucidation of Phototransformation Products of 2,4,6-Trinitrotoluene. AB - An aqueous solution of 2,4,6-trinitrotoluene (TNT) was irradiated by natural sunlight for a period of 1 month to generate phototransformation products of this compound. After solid-phase extraction on a poly(styrene-divinylbenzene) copolymer at pH 1, the structures of several acidic nitroaromatic compounds were identified by means of continuous-flow HPLC/(1)H NMR and HPLC/TSP-MS measurements of this extract. By interpretation of both NMR and MS spectra, it was even possible to characterize noncommercially available phototransformation products of TNT. The results obtained by continuous-flow HPLC/(1)H NMR were compared with those obtained by the investigation of a groundwater sample of a former ammunition site near Elsnig, Germany. The results show that several identified phototransformation products of TNT are also present in this groundwater sample. PMID- 21651249 TI - Variable selection in discriminant partial least-squares analysis. AB - Variable selection enhances the understanding and interpretability of multivariate classification models. A new chemometric method based on the selection of the most important variables in discriminant partial least-squares (VS-DPLS) analysis is described. The suggested method is a simple extension of DPLS where a small number of elements in the weight vector w is retained for each factor. The optimal number of DPLS factors is determined by cross-validation. The new algorithm is applied to four different high-dimensional spectral data sets with excellent results. Spectral profiles from Fourier transform infrared spectroscopy and pyrolysis mass spectrometry are used. To investigate the uniqueness of the selected variables an iterative VS-DPLS procedure is performed. At each iteration, the previously found selected variables are removed to see if a new VS-DPLS classification model can be constructed using a different set of variables. In this manner, it is possible to determine regions rather than individual variables that are important for a successful classification. PMID- 21651250 TI - Optimization and characterization of a flow injection electrochemical system for pentachlorophenol assay. AB - A flow injection (FI) electrochemical detection system has been developed and optimized for the determination of pentachlorophenol (PCP) in contaminated soil. PCP was oxidized to tetrachloro-1,4-benzoquinone (1,4-TCBQ) with a high yield using bis(trifluoroacetoxy)iodobenzene in 0.1 M tartaric acid, pH 2.0, at ambient temperature. Upon rapid reaction with immobilized glucose oxidase, the detection and amplification scheme was completed as the reduced form of 1,4-TCBQ or tetrachloro-1,4-hydroquinone was reoxidized to 1,4-TCBQ at the surface of the glassy carbon electrode (+ 0.40 V vs Ag/AgCl). Rapid electron exchange between the enzyme and its glucose substrate provided a non-rate-limiting current toward the electrode. The FI electrochemical system was linear up to 1 MUM oxidized PCP with a detection limit of 10 nM and exhibited a reproducibility of +/-0.6% over 165 repeated analyses during 14 h of continuous operation. When applied to PCP contaminated soil samples, the results obtained from the FI electrochemical system compared well with those of the HPLC standard method. PMID- 21651251 TI - Electrochemistry of tert-Butylcalix[8]arene-C(60) Films Using a Scanning Electrochemical Microscope-Quartz Crystal Microbalance. AB - The electrochemical reduction of tert-butylcalix[8]arene-C(60) particle films was studied using the scanning electrochemical microscope combined with a quartz crystal microbalance (QCM) for several electrolytes in MeCN. Complexation of the fullerene within the film results in a negative shift of the peak potential of the first cathodic wave by about 400 mV compared to the reduction of a pure C(60) film. The QCM indicates a mass loss during reduction of the film. Even in electrolytes where C(60) anions normally remain in the surface film, a loss of fullerene electrochemical activity occurs. The complex breaks apart upon reduction of the fullerene center, with the fullerene escaping from the calixarene basket into the MeCN solution, leaving the calixarene as an insoluble film on the electrode surface. These results show that the pi electron sharing of the complex is decreased by the additional electron density added to the fullerene by reduction to C(60)(-). PMID- 21651252 TI - Voltage-Controlled Fluorometry of the Transfer of Nonfluorescent Ions across the 1,2-Dichloroethane/Water Interface Using Fluorescent Ionophores. AB - The voltage-driven transfer of alkali and alkaline-earth metal ions across the polarized 1,2-dichloroethane (DCE)/water interface has been measured fluorometrically by using two fluorescent ionophores, coumarin 153-linked monoaza 15-crown-5 (C153-crown(O(4))) and two-coumarin 153-linked diaza-18-crown-6 ((C153)(2)-K(22)). The 1:1 complex formation prevails for both monovalent and divalent ion transfer, when the concentration of C153-crown(O(4)) in DCE is at the micromolar level. In the Mg(2+) ion transfer, the formation of the 1:2 (metal ligand) complex becomes significant at the millimolar level of C153-crown(O(4)). C153-crown(O(4)) seems to adsorb at the interface. The complexation of Ba(2+) with (C153)(2)-K(22) is significantly slower than the complexation with C153 crown(O(4)). PMID- 21651253 TI - Electrochemiluminescence of Tris(2,2'-bipyridine)ruthenium in Water at Carbon Microelectrodes. AB - Electrochemiluminescence (ECL) of Ru(bpy)(3)(2+) in water only, without any added electrolyte or reducing agents, has been obtained at carbon interdigitated microelectrode arrays (C-IDAs) of 2 MUm width and spacing. In a generation/collection biasing mode, ECL can be clearly seen with the naked eye in normal room lighting at concentrations greater than 1 mM. Using a conventional photomultiplier tube (PMT), a detection limit of 10(-)(7) M Ru(bpy)(3)(2+) has been achieved for an electrode area of 0.25 mm(2). In comparison, the ECL intensity produced at Pt-IDA of the same geometry, under identical experimental conditions, was more than 300 times less. The ECL obtained at C-IDAs is attributed to the annihilation reaction of the reduced and oxidized forms of the Ru(bpy)(3)(2+) made possible due to the small electrode spacing. PMID- 21651254 TI - Modulation of firefly luciferase bioluminescence at bioelectrochemical interfaces. AB - This paper describes a method by which the activity of an immobilized enzyme can be modulated electrochemically at an electrode. The particular example studied, involving the enzyme firefly luciferase being immobilized in a gelatin film of thickness <1 MUm, provides a useful model system since changes in the catalytic activity can be measured instantaneously through the natural bioluminescent emission. Using this biointerfacial arrangement, we have been able to demonstrate the reversible switching off and on of the enzyme's activity. Through a series of mechanistic studies, we have been able to determine that the bioluminescence response is modulated (on long time scales) as a consequence of the electrochemical depletion of protons at the electrode interface resulting in a local increase in pH. PMID- 21651255 TI - Quantitative study of the resolving power of arrays of carbon black-polymer composites in various vapor-sensing tasks. AB - A statistical metric, based on the magnitude and standard deviations along linear projections of clustered array response data, was utilized to facilitate an evaluation of the performance of detector arrays in various vapor classification tasks. This approach allowed quantification of the ability of a 14-element array of carbon black-insulating polymer composite chemiresistors to distinguish between members of a set of 19 solvent vapors, some of which vary widely in chemical properties (e.g., methanol and benzene) and others of which are very similar (e.g., n-pentane and n-heptane). The data also facilitated evaluation of questions such as the optimal number of detectors required for a specific task, whether improved performance is obtained by increasing the number of detectors in a detector array, and how to assess statistically the diversity of a collection of detectors in order to understand more fully which properties are underrepresented in a particular set of array elements. In addition, the resolving power of arrays of carbon black-polymer composites was compared to the resolving power of specific collections of bulk conducting organic polymer or tin oxide detector arrays in a common set of vapor classification tasks. PMID- 21651256 TI - Sample storage artifacts affecting the measurement of dissolved copper in sulfidic waters. AB - Sample preservation and storage procedures (acidification with HNO(3) and storage in plastic bottles) normally employed prior to the determination of dissolved Cu in sulfidic waters were compared with sample preservation involving the initial oxidation of sulfide with H(2)O(2) or S(2)O(5)(2-) followed by acidification. Acidification alone was demonstrated to be inadequate and resulted in a significant underestimation of dissolved Cu (losses ranging from 50% to >90%). Similar losses were observed in both polyethylene and Teflon storage bottles. Experiments suggest that losses of copper occur following sample acidification owing to the formation of stable copper sulfide phases which adsorb onto container surfaces. It is therefore recommended that an oxidative pretreatment step is carried out prior to the acidification of porewaters collected for metal analysis. The results of this study suggest that much of the previous data reporting dissolved Cu concentrations in sulfidic waters and porewaters may be in error. PMID- 21651257 TI - Optimization in locally weighted regression. AB - The application of locally weighted regression (LWR) to nonlinear calibration problems and strongly clustered calibration data often yields more reliable predictions than global linear calibration models. This study compares the performance of LWR that uses PCR and PLS regression, the Euclidean and Mahalanobis distance as a distance measure, and the uniform and cubic weighting of calibration objects in local models. Recommendations are given on how to apply LWR to near-infrared data sets without spending too much time in the optimization phase. PMID- 21651258 TI - Analysis of the solvatochromic behavior of the disubstituted triphenylmethane dye brilliant green. AB - The coincident spectral components of the main visible absorption band of the triphenylmethane dye Brilliant Green can be resolved using a nonlinear least squares fitting routine. This analysis reveals two Gaussian components, with centers near 600 and 630 nm, that possess additional spectral characteristics with a pronounced sensitivity to the dye's microenvironment. In particular, both the ratio of the heights of these Gaussian peaks and the ratio of their areas exhibit an inverted dependence on solvent dielectric constant, i.e., a reversal of solvatochromic behavior in media of low polarity. Such an absorption spectrum analysis facilitates the use of triphenylmethane dyes that lack symmetric trisubstitution of the phenyl rings as environment-sensitive spectroscopic probes. We demonstrate further the utility of this approach through the spectrophotometric determination of the critical micelle concentration of the anionic surfactant sodium dodecyl sulfate using Brilliant Green as an optical probe. PMID- 21651259 TI - Removal of Carbonaceous Contamination from SERS-Active Silver by Self-Assembly of Decanethiol. AB - The presence of carbonaceous contamination on common surface-enhanced Raman scattering (SERS) surfaces has been a primary limitation to the analytical utility of SERS; background contamination significantly affects reproducibility and often determines the limit of detection. Due to the strong interaction between thiols and Ag or Au, self-assembly of alkanethiols onto these metals results in the displacement of "adventitious material" from the metal. The cleaning procedure presented here utilized self-assembly of decanethiol on an electrochemically roughened Ag foil for removal of surface contamination. The self-assembled layer was subsequently removed by rapid oxidation with ozone, followed by rinsing in methanol. The clean Ag surface exhibited a tremendously improved background and a 3-fold increase in the enhancement factor for a probe molecule. PMID- 21651260 TI - Time-condensed analyses by mass spectrometry. AB - Research has focused on the development of a new set of mathematical algorithms, encoded in C(++), when combined with a thermal desorption sample introduction system provides quantitative analysis of a wide mixture of organic compounds in under 10 min by gas chromatography/mass spectrometry. The overall goal is to condense the time of analysis, including both the times required for sample preparation and for chromatographic separation. In this paper, results are presented where compound identification has been made for polychlorinated biphenyls, chlorinated pesticides, and polycyclic aromatic hydrocarbons present in the same solution and where gas chromatography separation times have been reduced from 40 to 5 min. For the latter, all compounds elute within 3.5 min, with structural isomers identified as the same compound. The 5-min analysis provides the foundation for rapid screening and on-line chemical measurements of multicomponent mixtures. Results are also presented where these same compounds are quantitatively analyzed in 10 min, with structural isomers identified individually, in the presence of a (25% v/v) weathered gasoline/engine oil mixture. Time-condensed complex mixture detection is now feasible making possible quantitative, high-throughput sample analyses. PMID- 21651261 TI - Atomic absorption by free atoms in solution following chemical reduction from the ionic state. AB - The initial stages of chemical reduction of metallic ions in solution must proceed through the formation of single atoms, followed by the rapid formation of clusters with other atoms until continued coalescence produces observable precipitates or evidence of stable sol formation. Dilute solutions of sodium borohydride (0.0025%) merged with microgram per milliliter concentration solutions of Ag, Pd, and Cu in a custom spectrophotometric flow cell produce transient background-corrected atomic absorption signals during the initial few seconds of the reaction. High-resolution atomic absorption with both a hollow cathode line source and a continuum source reveals that the absorption line profile of the absorbing species is extremely narrow (11 pm for Ag) and not influenced by the aqueous environment. Such selective absorption of radiation suggests that free atoms are being observed in aqueous solution. PMID- 21651262 TI - Influence of lipophilic inert electrolytes on the selectivity of polymer membrane electrodes. AB - Lipophilic inert electrolytes, i.e., salts without ion-exchange properties, may influence the selectivity of ionophore-based liquid membrane electrodes by affecting the activity coefficients in the organic phase. It is expected by a theoretical model that the addition of a lipophilic salt renders the ion selective electrode more selective for divalent over monovalent ions. These predictions are confirmed with Ca(2+)-responsive membranes containing the ionophores ETH 2120, ETH 1001, and ETH 129. The effect is especially pronounced with nonpolar membrane phases containing a low concentration of charged species, where up to 2 orders of magnitude selectivity improvement is observed. PMID- 21651263 TI - Interpretation of ion-exchange chromatographic retention based on an electrical double-layer model. AB - An ion-exchange chromatographic model based on the Stern-Gouy-Chapman electrical double-layer theory is presented. We assume several equilibria occurring at the surface of an ion-exchange resin, such as the ion-pair formation of counterions with an ion-exchange site, the adsorption of ions, and the ion-pair formation of an adsorbed ions with their counterions. These equilibria are affected by the potential at the planes (the surface and the Stern layer potential) where the reactions occur. In addition, the nonselective accumulation of ions in the diffuse layer is also taken into account. Based on the developed model and derived equations, the nature of log k'-log X (X is the concentration of an eluent ion) plots is investigated for various sets of parameters and is compared with that of possible experimental results. Three extreme cases can be distinguished: (1) ion-pair-controlled, (2) adsorption-controlled, and (3) accumulation in the diffuse layer-controlled retention. Though log k'-log X plots, when they are studied over wide eluent concentration ranges (more than 2 orders), do not necessarily show precise linearity especially in the presence of eluent adsorption and extremely high eluent ion-pair formation, the linear regression analyses give negative unit slopes (within 10% deviations) for monovalent solute-eluent combinations. Since the deviation from linearity relation is mostly found in very low k' ranges (e.g., k' < 1), it is possible only in very limited cases to confirm nonlinearity experimentally. This may have mistakenly led to the idea that selectivity coefficients can be regarded as constants and thus the log k'-log X plots should be linear with the slope equal to (charge ratios) * (-1) in ion-exchange chromatographic experiments. The efficiency of the developed model is verified by its ability to predict experimental results, e.g., nonlinear log k'-log X plots, changes in separation factors with varying ion-exchange affinity of an eluent ion, adsorption isotherms at different salt concentration, etc. PMID- 21651264 TI - Channel microband electrode arrays for mechanistic electrochemistry. Two dimensional voltammetry: transport-limited currents. AB - A channel electrode array, with electrodes ranging in size from the millimeter to the submicrometer scale, is used for the amperometric interrogation of mechanistically complex electrode processes. In this way, the transport-limited current, measured as a function of both electrode size and electrolyte flow rate (convection), is shown to provide a highly sensitive probe of mechanism and kinetics. The application of "two-dimensional voltammetry" to diverse electrode processes, including E, ECE, ECEE, EC', and DISP2 reactions, is reported. PMID- 21651265 TI - Thionine covalently tethered to multilayer horseradish peroxidase in a self assembled monolayer as an electron-transfer mediator. AB - A new approach to construct a reagentless enzyme biosensor is described. Based on multilayer horseradish peroxidase in a self-assembled monolayer configuration, the biosensor was constructed using multilayer thionine covalently tethered to the enzyme as an electron-transfer mediator. The multilayer enzyme and the multilayer mediator were stepwisely synthesized onto an l-cysteine-assembled gold electrode using glutaraldehyde as a bifunctional reagent. The multilayer mediator tethered to the multilayer enzyme could effectively and stably shuttle electrons between the electrode and the multilayer enzyme linked onto the monolayer. The sensitivity of the resulting enzyme biosensor with eight layers of enzyme and three layers of mediator was more than 250 MUA cm(-)(2) for 1.0 * 10(-)(4) mol/L hydrogen peroxide under optimal conditions, whereas such a modified electrode with one layer of enzyme and one layer of mediator did not yield a detectable response to 1.0 * 10(-)(4) mol/L hydrogen peroxide. PMID- 21651266 TI - Evaluation techniques for two-way data from in situ fourier transform mid infrared reaction monitoring in aqueous solution. AB - A model chemical reaction was monitored with in situ Fourier transform mid infrared spectroscopy using an attenuated total reflectance probe. The evaluation of the IR spectra is complicated by the fact that the reaction runs in nonisothermal aqueous solution with large variations in pH. Despite this, it was possible to extract large amounts of useful information on the reaction after suitable pretreatment of the spectra. Alternating least-squares (ALS) multivariate curve resolution is shown to be a useful technique for obtaining pure component spectra and concentrations if suitable spectral regions are analyzed. Rank mapping methods are used as the basis for this sectioning into smaller regions. Techniques for finding and analyzing selective spectral regions are also shown to be applicable to this type of data. Partial least-squares (PLS) regression models based on spectral data were used to verify the results where possible. The correlation between the concentrations predicted from PLS and ALS is excellent. PMID- 21651267 TI - Dimethyl sulfide measurement by fluorine-induced chemiluminescence. AB - We have developed a high-speed sensor for dimethyl sulfide (DMS) based on its fast chemiluminescent reaction with molecular fluorine. Emission in the wavelength range 450-650 nm is monitored via photon counting. The instrument can continuously measure DMS with a response time of 0.1 s and is highly linear and sensitive. Limits of detection (S/N = 1) are 39, 12, and 4 pptv DMS for 0.1-, 1-, and 10-s integration times, respectively. Sensitivity and response time allow the direct measurement of DMS fluxes in the marine atmospheric boundary layer by the eddy correlation technique. Selectivity has previously been measured and is sufficient for monitoring DMS in the marine boundary layer without significant interferences. PMID- 21651268 TI - A dual-beam optical microscope for observation and cleavage of single DNA molecules. AB - An integrated epifocal and evanescent-wave optical microscope has been developed for real-time observation and bond cleavage studies of single DNA molecules. Large genomic DNA is stretched in a laminar flow stream and is immobilized on a polylysine-coated glass surface by strong electrostatic interactions. Unlike previous single-molecule dynamics and single-enzyme studies, this work takes advantage of the elastic nature of double-stranded DNA and measures DNA relaxation events that are triggered by two phosphodiester (P-O) bond breaks. The ability to follow chemical reactions on individual DNA molecules opens new possibilities for DNA mapping and for studying DNA-protein interactions. PMID- 21651269 TI - Expanded dynamic range of free zinc ion determination by fluorescence anisotropy. AB - We demonstrate that by use of a biosensor approach employing wild type human apocarbonic anhydrase II and a newly synthesized fluorescent ligand, ABD-M, free Zn(II) may be determined in solution at concentrations in the picomolar range with good accuracy by fluorescence anisotropy. Fluorescence anisotropy enjoys the same freedom from artifact as wavelength ratiometric approaches widely used for determining metal ions in solution such as Ca(II). In addition, we demonstrate that anisotropy-based determinations exhibit an important advantage, a broad dynamic range, which has not been demonstrated for wavelength ratiometric approaches. In particular, by judicious choice of excitation and emission wavelengths, the concentration range over which Zn(II) may be determined accurately can be increased by approximately 2 orders of magnitude. As ABD-M also exhibits significant changes in excitation and emission spectra as well as lifetime upon binding to the active-site Zn(II) in holocarbonic anhydrase, it should also be useful for wavelength ratiometric and lifetime-based determinations. PMID- 21651270 TI - Bacterial endospore detection using terbium dipicolinate photoluminescence in the presence of chemical and biological materials. AB - A determination of the viability of an endospore detection technique using terbium dipicolinate photoluminescence in the presence of other chemical and biological materials was performed. The compounds and organisms examined, possible environmental constituents, covered three broad categories: organic compounds, inorganic compounds, and biological materials. Each substance was tested for a false positive, which occurs if the intrinsic terbium photoluminescence is enhanced in the absence of a bacterial endospore. The detection technique was also investigated for false negatives, which occur if a known positive endospore signal is inhibited significantly. Although several materials may give rise to false negative signals, none caused a false positive signal to be observed. PMID- 21651271 TI - Influence of temperature on vibrational spectra and consequences for the predictive ability of multivariate models. AB - Temperature, pressure, viscosity, and other process variables fluctuate during an industrial process. When vibrational spectra are measured on- or in-line for process analytical and control purposes, the fluctuations influence the shape of the spectra in a nonlinear manner. The influence of these temperature-induced spectral variations on the predictive ability of multivariate calibration model is assessed. Short-wave NIR spectra of ethanol/water/2-propanol mixtures are taken at different temperatures, and different local and global partial least squares calibration strategies are applied. The resulting prediction errors and sensitivity vectors of a test set are compared. For data with no temperature variation, the local models perform best with high sensitivity but the knowledge of the temperature for prediction measurements cannot aid in the improvement of local model predictions when temperature variation is introduced. The prediction errors of global models are considerably lower when temperature variation is present in the data set but at the expense of sensitivity. To be able to build temperature-stable calibration models with high sensitivity, a way of explicitly modeling the temperature should be found. PMID- 21651272 TI - Phase and Curing Behavior of Polybutadiene/Diallyl Phthalate Blends Monitored by FT-IR Imaging Using Focal-Plane Array Detection. AB - The phase morphology and interfacial regions of cured and uncured polybutadiene/diallyl phthalate (PBD/DAP) blends that exhibit upper critical solution temperature (UCST) behavior have been characterized using an FT-IR microscopic imaging technique with focal-plane array detection. The observations of domain size and structure were based on monitoring characteristic infrared C H, C [Formula: see text] O, and C-O modes of the blend components. The basic phase morphology of the uncured blend was monitored immediately after sample preparation and after 24 h. The average domain sizes of the uncured blend increased with aging by coalescence of smaller particles. The chemical compositions of the separated domains were determined by measuring ratios of integrated intensities and analyzed using a calibration curve. Finally, the blends were cured above the UCST and an apparently homogeneous network was obtained. PMID- 21651273 TI - Differentiation of algae clones on the basis of resonance Raman spectra excited by visible light. AB - Fourteen algae clones belonging to four different classes, including clones of Pseudo-nitzschia (Bacillariophyceae), some of which are capable of producing the toxin domoic acid, have been studied by means of resonance Raman spectra excited at 457.9 and 488 nm. Spectra taken at both excitation wavelengths are of high quality and are sufficiently distinct to differentiate clones at the algal class level. All spectra contain major features near 1000, 1153, and 1523 cm(-)(1), which are strongly resonance enhanced due to carotenoid pigments. Weaker features between 920-980 and 1170-1230 cm(-)(1), also due to carotenoid pigments, are more characteristic of the algae clones and more directly reflect different carotenoid composition. Similarities and differences among spectra have been analyzed by the method of principal component analysis (PCA). A distinct clustering of spectral data according to algal class has been shown by PCA score plots. All Pseudo nitzschia clones can be separated from other classes of algae on the basis of spectra, but it is not possible to distinguish toxic Pseudo-nitzschia from nontoxic clones on the basis of these spectra, which reflect only differences in carotenoid composition. PMID- 21651274 TI - Use of a clustering reaction to detect low levels of moisture in bulk oxygen using an atmospheric pressure ionization mass spectrometer. AB - Atmospheric pressure ionization mass spectrometry (APIMS) is being routinely used to quantify trace impurities in bulk gases used in the manufacture of semiconductor devices. APIMS has been successfully applied for the quantification of ppt levels of O(2), H(2)O, CO(2), and CH(4) in Ar, N(2), and He. However, it has not been successfully used to quantify trace impurities in bulk O(2) due to the low ionization potential of O(2). APIMS relies on charge-transfer reaction between the ions of the bulk gas molecules and impurity molecules. Since all the relevant impurity molecules have ionization potentials higher than that of O(2), APIMS has not been used to analyze for impurities in O(2). We report here the detection of sub-ppb levels of H(2)O in O(2) by making use of the clustering reaction between O(2)(+) and H(2)O. The declustering region in an APIMS, which is normally used to break apart unwanted and interfering clusters, has to be carefully adjusted to keep intact the weakly bound cluster O(2)(+).H(2)O. Our results indicate a statistical detection limit of less than 300 ppt for the detection of H(2)O in O(2). PMID- 21651275 TI - Probing the effects of cone potential in the electrospray ion source: consequences for the determination of molecular weight distributions of synthetic polymers. AB - Shifts in the relative intensities of oligomer ions are found to accompany changes in the cone potential in the electrospray ion source, which introduce uncertainties into average molecular weight determinations for polymer distributions. Similar shifts with changes in cone potential have long been recognized in the multiple-charge distributions of proteins and other biomolecules. In the case of multiple-charge distributions of a single, or small number of, species there are no major consequences for calculation of molecular weight; however, mass distributions and the averages thereof, are of major concern with synthetic polymers and understanding the shifts in relative intensities becomes critically important. We report here an evaluation of the effects of cone potentials on the molecular weight distributions of synthetic polymers, which we compare with the effects on charge-state distributions of peptides. The effects of cone potential have been modeled mathematically, from which we conclude that cone potentials exert a focusing effect dependent on the mass-to-charge ratios of ions. It is largely this focusing effect that determines the dependence of oligomer ion intensities upon cone potential in the ESI mass spectra of polymers. The influence of cone potential on molecular weight determinations of polymers of varying polydispersities (P(o)) is compared and discussed. For polymers with low polydispersities (e.g., narrow molecular weight poly(ethyleneglycol) standards with P(o) < 1.5), the variation in molecular weight determinations tends to be small (typically <5%), whereas with synthetic polymers with polydispersities greater than 2, variations in cone potential can influence molecular weight determinations significantly (by 100% or even more). PMID- 21651276 TI - Identification of an original non-terpenoid varnish from the early 20th century oil painting "the white horse" (1929), by h. Menzel. AB - Different mass spectrometric approaches were used to identify an original non terpenoid varnish. Direct temperature-resolved MS and pyrolysis-GC/MS mainly showed the phenolic components, whereas thermally assisted (trans)methylation with tetramethylammonium hydroxide (TMAH) strongly enhanced the evidence for tung oil as part of the varnish. Transethylation studies of the fatty acids confirmed the TMAH data. The degree of hydrolysis of the oil network was found to be low. No evidence was found for a direct link between the drying oil and phenolic resin. On the basis of the MS information, the aged varnish is identified as an open-structure tert-butylphenol-formaldehyde resin which entangles the tung oil polymer. PMID- 21651277 TI - Separation of Neutral Compounds and Basic Drugs by Capillary Electrophoresis in Acidic Solution Using Laurylpoly(oxyethylene) Sulfate as an Additive. AB - Working at pH 2.4 with uncoated silica capillaries has the advantage that electroosmotic flow is virtually eliminated. Excellent separations of protonated organic bases were obtained when ethanesulfonic acid was added to the running electrolyte to coat the capillary surface by a dynamic equilibrium. The effect of adding a new surfactant, sulfonated Brij-30, to the acidic electrolyte was also investigated. Use of this surfactant in acidic organic-aqueous solutions changes the elution order of many organic cations and also permits the separation of neutral organic compounds. Excellent resolution of a mixture of 19 PAHs and similar compounds was obtained in 40% organic solvent in only 20 min. The largest organic compounds form the most stable association complexes with the sulfonated Brij-30 and, thus, have the shortest migration times. It is shown that the type and concentration of surfactant, as well as the composition of the aqueous organic solution, are conditions that can be varied over a broad range to obtain superior separations of both neutral and cationic organic compounds. The type of organic solvent is yet another condition that can be manipulated advantageously. For example, the use of equal volumes of acetonitrile and 2-propanol in water organic solutions can give better resolution of neutral organic analytes than either solvent used alone. PMID- 21651278 TI - Adsorption versus Absorption of Polychlorinated Biphenyls onto Solid-Phase Microextraction Coatings. AB - Absorption-based polymeric solid-phase microextraction (SPME) fibers with poly(dimethylsiloxane) (PDMS) coatings were used to determine the partitioning coefficients of polychlorinated biphenyls (PCBs) between the sorptive fiber coatings and water. Previous models showing very good correlations between octanol-water partitioning coefficients (K(ow)) and absorption-based fiber-water partitioning coefficients (K(dv)) for low-molecular-weight analytes failed to predict K(dv) values for PCBs. In fact, K(dv) values for PCBs were 1-7 orders of magnitude lower than those predicted by K(ow) and actually showed a strong negative correlation between K(ow) and K(dv) for higher molecular weight analytes (MW >~200). K(dv) values obtained using PDMS fibers with 7- and 100-MUm coatings also disagree, demonstrating that K(dv) cannot be used to describe the partitioning behavior of PCBs between PDMS and water. However, when PCB partitioning coefficients were calculated on the basis of surface area (K(ds)), the K(ds) values obtained using 7- and 100-MUm PDMS fibers agreed reasonably well, demonstrating that surface adsorption is the primary mechanism controlling PCB (and likely other higher molecular weight solutes) partitioning from water to SPME sorbents. PMID- 21651279 TI - Numerical simulation of electroosmotic flow. AB - We have developed a numerical scheme to simulate electroosmotic flows in complicated geometries. We studied the electroosmotic injection characteristics of a cross-channel device for capillary electrophoresis. We found that the desired rectangular shape of the sample plug at the intersection of the cross channel can be obtained when the injection is carried out at high electric field intensities. The shape of the sample plug can also be controlled by applying an electric potential or a pressure at the side reservoirs. Flow induced from the side channels into the injection channel squeezes the streamlines at the intersection, thus giving a less distorted sample plug. Results of our simulations agree qualitatively with experimental observations. PMID- 21651280 TI - A sonic spray interface for the mass analysis of highly charged ions from protein solutions at high flow rates. AB - We have improved the sonic spray interface to enable the analysis of multiply charged ions of protein from a solution at a flow rate of 1 mL/min using a conventional liquid chromatograph/mass spectrometer. In this interface, we added a multihole plate in front of the sampling orifice of a mass spectrometer. This plate does not have a hole coaxial to the sampling orifice but has small holes around the central region of the plate. The plate reduces the density of the solvent molecules in the sprayed gas introduced into the vacuum region through the sampling orifice from the atmosphere and prevents the ions from being solvated and becoming charged droplets due to the cooling that follows adiabatic expansion of the sprayed gas. With this improvement, multiply charged ions whose charge distribution ranged from 11+ to 16+ were analyzed from a 1 MUM cytochrome c solution at a high flow rate of 1 mL/min without using a splitter. PMID- 21651281 TI - Separation of nonionic surfactants by capillary electrophoresis and high performance liquid chromatography. AB - Fatty alcohol ethoxylates (FAEs) are applied in commercial formulations (laundry detergents) as complex mixtures of alkyl and ethoxylate homologues. Therefore, efficient analytical methods are required for product control. Capillary electrophoresis, a modern analytical separation technique, was used to separate FAEs in technical products and household formulations after derivatization with phthalic anhydride. The well-established high-performance liquid chromatography was used as reference and supplementary method. UV detection after derivatization with phenyl isocyanate or light scattering detection has been carried out. Sample components have been identified by standard addition or by comparison to known products. The peak pattern can be considered as a "fingerprint" of the product and is characteristic for a defined composition. PMID- 21651282 TI - On-line concentration of neutral analytes for micellar electrokinetic chromatography. 5. Field-enhanced sample injection with reverse migrating micelles. AB - Elementary conditions for the on-line concentration of neutral analytes by field enhanced sample injection with reverse migrating micelles for micellar electrokinetic chromatography is presented. Acidic phosphate buffers containing micelles of sodium dodecyl sulfate are utilized as both sample solvent and separation solution. After the capillary is conditioned with a separation solution, a water plug is hydrodynamically injected to achieve field enhancement at the injection end of the capillary during injection by application of voltage. A model is provided to give insight into the stacking scheme. Significant detector response improvements are confirmed experimentally. Moreover, utility of the technique for the analysis of a real sample is tested using urine spiked with testosterone and progesterone. PMID- 21651283 TI - Characterization of reaction dynamics in a trypsin-modified capillary microreactor. AB - Application of mild vibration to an immobilized trypsin capillary microreactor can enhance digestion rates for many globular and glycosylated proteins (12-70 kDa range) without additional sample handling. A sinusoid wave form generator and a simple piezoelectric transducer were used to apply vibration in a wide frequency range to the 50-MUm-i.d. enzyme microreactor over its entire length. The mass transport properties of the microreactor were quantitatively examined for protein digestions through the use of an artificial globular protein. This was synthesized by covering the surface of 35-nm-diameter latex beads with a peptide (Leu-Arg-Leu). Capillary electrophoresis analysis of the microreactor products showed there were no mass transport-related effects for vibration of the capillary. Digestions of a range of globular protein structures were performed and the products analyzed by capillary electrophoresis. The rate enhancements were found to be related to the stability of the protein tertiary and secondary structure. Cytochrome c showed a dramatic acceleration in rate of digestion as the vibration frequency increased over a range of 200 Hz to 7.1 kHz. The ability to enhance reaction rates for very stable proteins can be gained by additional means of destabilizing the protein, as shown by removal of calcium from alpha lactalbumin. Vibration of the enzyme capillary will have the greatest utility for extremely limited protein samples since chemical modification to completely denature proteins usually requires considerable sample handling. PMID- 21651284 TI - An Application of X-ray Fluorescence Spectrometry to the Study of Thin-Layer Chromatography. AB - The combination of thin-layer chromatography (TLC) with X-ray fluorescence spectrometry (XRF) has been accomplished without any interfaces. It enables the direct, nondestructive visualization of elements developed on a TLC plate. In addition to inorganic compounds, organic compounds including electronegative elements can be detected simultaneously that cannot always be measured satisfactorily by competitive techniques; e.g., phenolic compounds containing chlorine, bromine, or iodine were distinctly detected by individual elemental imaging. The background of commercially available TLC plates with various thicknesses of the stationary phase and an outline of element detection limits were also investigated. TLC/XRF was found suitable for in situ TLC imaging of elements. PMID- 21651285 TI - HPLC separation of oligonucleotides in isocratic and temperature-programming mode. AB - In HPLC, temperature programming and isocratic separation were investigated for resolving a mixture of nucleotide polymers. A mixture of short oligonucleotides pd(A)(12)(-)(18) was resolved in less than 4 min by utilizing isocratic separation. The method is sensitive to organic modifier concentration; a 0.5% change of organic modifier in the mobile phase leads to more than doubling of the total analysis time. Temperature programming was used to optimize the separation of larger oligonucleotides pd(A)(25)(-)(30) and pd(A)(40)(-)(60). When the column temperature was changed by programming during the separation, the analysis time was 75% less than for an isocratic/isothermal run. The low amounts of ion-pairing agent in the mobile phase (between 5 and 10 mM) make these methods suitable for electrospray ionization mass spectrometry. PMID- 21651286 TI - Factors affecting high-pressure solvent extraction (accelerated solvent extraction) of additives from polymers. AB - Irganox 1010 (pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)] propionate) is successfully extracted from polypropylene using solvents at high temperatures and pressures in a homemade accelerated solvent extraction system. For example, using freeze-ground polymer, 90% extraction is possible within 5 min with 2-propanol at 150 degrees C. Extraction curves for 2-propanol and acetone fit well to the "hot ball" model, previously developed for supercritical fluid extraction. Diffusion coefficients are determined for extractions with 2 propanol, acetone, and cyclohexane over a range of temperatures, and the activation energies for the diffusion are 134, 107, and 61 kJ mol(-)(1), respectively. The lower figure for acetone and cyclohexane indicates that these solvents swell the polymer more than does 2-propanol. The polymer dissolves in the solvent at too high a temperature, which causes blockage of the transfer lines. For maximum extraction rates, the highest temperature for each solvent that avoids dissolution of the polymer should be used. The use of mixed solvents is investigated and shows advantages in some cases, with the aim of producing a solvent that will swell the polymer but not dissolve it. PMID- 21651287 TI - Three-way multivariate calibration procedures applied to high-performance liquid chromatography coupled with fast-scanning fluorescence spectrometry detection. Determination of polycyclic aromatic hydrocarbons in water samples. AB - Three-way partial least-squares and n factor parallel factor analysis have been compared for the analysis of polycyclic aromatic hydrocarbons in water samples. Data were obtained with a chromatographic system set to record short-time chromatograms containing several unresolved peaks. The detection system consisted of a fast-scanning fluorescence spectra detector, which allows one to obtain three-dimensional data, where retention time, emission wavelengths, and fluorescence intensity are represented. The combined use of a multivariate calibration method and the three-dimensional data obtained from the HPLC-FSFS system allows resolution of closely eluting compounds, thus making a complete separation unnecessary. The procedure has been applied to tap water samples (spiked at 0.10 and 0.20 MUg L(-)(1) levels) with good results, similar to those obtained with a HPLC system with a conventional fluorescence detector. PMID- 21651288 TI - Coupling Supercritical CO(2) and Subcritical (Hot) Water for the Determination of Dacthal and Its Acid Metabolites in Soil. AB - Dacthal and its mono- and diacid metabolites were sequentially extracted from soils by first performing a supercritical carbon dioxide extraction to recover Dacthal, followed by a subcritical (hot) water extraction step to recover metabolites. Dacthal was recovered from soil in 15 min by supercritical carbon dioxide at 150 degrees C and 400 bar. The mono- and diacid metabolites were extracted from soil in 10 min under the subcritical water conditions of 50 degrees C and 200 bar. The metabolites were trapped in situ on a strong anion exchange disk placed over the exit frit of the extraction cell. Metabolites are combined with Dacthal by placing the disk into the GC autosampler vial containing the SFE extract. The metabolites then are simultaneously eluted from the disk and derivatized to their ethyl esters by adding 100 MUL of ethyl iodide and heating the vial at 100 degrees C for 1 h. Using this approach, only a single sample is analyzed, and because the disk-catalyzed alkylation reaction does not transesterify Dacthal, the speciation of Dacthal is maintained. In addition, no sample cleanup steps are required, the use of diazomethane for derivatization is avoided, and the method consumes a total of 5 mL of nonchlorinated organic solvent. PMID- 21651289 TI - Structure Elucidation of 2,4-Dinitrophenylhydrazone Derivatives of Carbonyl Compounds in Ambient Air by HPLC/MS and Multiple MS/MS Using Atmospheric Chemical Ionization in the Negative Ion Mode. AB - Ion trap multiple fragmentation mass spectrometry (MS(n)()) combined with high performance liquid chromatography (HPLC) has been used for the structure elucidation and identification of 2,4-dinitrophenylhydrazone derivatives of carbonyl compounds in ambient air samples. Atmospheric pressure chemical ionization in the negative ion mode was the most suitable detection method. Different measures are described to decrease the MS background originating from the HPLC system. Low-picogram quantities were detectable in extracted mass chromatograms generated from full-scan records. Fragment ions produced by MS/MS allowed identification of substructures of the carbonyls. Detailed fragmentation paths were studied by MS(3) to MS(4) using reference compounds. A fragmentation scheme was established which enabled a structure confirmation and identification with 1-10 ng by HPLC/MS/MS. The identification of a compound coeluting with n pentanal-DNPH and of a dimerization byproduct are given as examples. PMID- 21651290 TI - Scanning electrochemical microscopy. 36. A combined scanning electrochemical microscope-quartz crystal microbalance instrument for studying thin films. AB - The design of a combined scanning electrochemical microscope-quartz crystal microbalance (SECM-QCM) with separate potential control of the tip and substrate is described. Both lateral and vertical tip movements near the substrate affect the QCM resonant frequency because of perturbations of the longitudinal and shear waves of the quartz crystal (QC) acoustic wave sensor. The SECM-QCM was used to study etching of a thin Ag layer deposited on the QC contact by generating an etchant, iron(III) tris(bipyridine), at the tip near the surface. The SECM-QCM was also used to monitor film mass and surrounding electrolyte composition during potential cycling of a film of C(60) on an electrode. PMID- 21651291 TI - Detection and correction of biased results of individual analytes in multicomponent spectroscopic analysis. AB - Simultaneous spectroscopic multicomponent analysis based on Beer's law requires the test sample to follow the hard model, independently of whether this model is built with the full spectrum or only with a few sensors selected according to an optimality criterion. We have developed a graphical method based on the net analytical signal concept to detect bias in the predicted results of individual analytes in test samples. When an interference, or other causes which produce bias, are detected, a moving window approach is used to select the subset of sensors that minimize the bias of the predicted results. The method has been validated with UV-vis spectra of binary clorophenol mixtures and of mixtures of four pesticides in water analyzed with a FIA system with diode array detection. PMID- 21651292 TI - Detection and separation of gas-phase carbon-centered radicals from cigarette smoke and diesel exhaust. AB - Carbon-centered radicals were trapped from gas-phase cigarette smoke and diesel engine exhaust by reaction with a nitroxide, 3-amino-2,2,5,5-tetramethyl-1 pyrrolidinyloxy (3AP). The resulting mixture of stable, diamagnetic adducts was derivatized with naphthalenedicarboxaldehyde (NDA) to produce highly fluorescent products. Derivatives were separated by high-performance liquid chromatography (HPLC), which revealed distinctly different suites of radicals present in the two systems. Integration of HPLC peaks gave approximately 22 +/- 7 nmol of radicals per cigarette and 3 +/- 1 nmol of radicals per liter of diesel engine exhaust. An estimated 8-10 different carbon-centered radical species are present in each system. PMID- 21651293 TI - Solution NMR of polypeptides hyperpolarized by dynamic nuclear polarization. AB - Hyperpolarization of nuclear spins through techniques such as dynamic nuclear polarization (DNP) can greatly increase the signal-to-noise ratio in NMR measurements, thus eliminating the need for signal averaging. This enables the study of many dynamic processes which would otherwise not be amenable to study by NMR spectroscopy. A report of solid- to liquid-state DNP of a short peptide, bacitracin A, as well as of a full-length protein, L23, is presented here. The polypeptides are hyperpolarized at low temperature and dissolved for NMR signal acquisition in the liquid state in mixtures of organic solvent and water. Signal enhancements of 300-2000 are obtained in partially deuterated polypeptide when hyperpolarized on (13)C and of 30-180 when hyperpolarized on (1)H. A simulated spectrum is used to identify different resonances in the hyperpolarized (13)C spectra, and the relation between observed signal enhancement for various groups in the protein and relaxation parameters measured from the hyperpolarized samples is discussed. Thus far, solid- to liquid-state DNP has been used in conjunction with small molecules. The results presented here, however, demonstrate the feasibility of hyperpolarizing larger proteins, with potential applications toward the study of protein folding or macromolecular interactions. PMID- 21651294 TI - Spontaneous self-organization enables dielectrophoresis of small nanoparticles and formation of photoconductive microbridges. AB - Detailed understanding of the mechanism of dielectrophoresis (DEP) and the drastic improvement of its efficiency for small size-quantized nanoparticles (NPs) open the door for the convergence of microscale and nanoscale technologies. It is hindered, however, by the severe reduction of DEP force in particles with volumes below a few hundred cubic nanometers. We report here DEP assembly of size quantized CdTe nanoparticles (NPs) with a diameter of 4.2 nm under AC voltage of 4-10 V. Calculations of the nominal DEP force for these NPs indicate that it is several orders of magnitude smaller than the force of the Brownian motion destroying the assemblies even for the maximum applied AC voltage. Despite this, very efficient formation of NP bridges between electrodes separated by a gap of 2 MUm was observed even for AC voltages of 6 V and highly diluted NP dispersions. The resolution of this conundrum was found in the intrinsic ability of CdTe NPs to self-assemble. The species being assembled by DEP are substantially bigger than the individual NPs. DEP assembly should be treated as a process taking place for NP chains with a length of ~140 nm. The self-assembled chains increase the nominal volume where the polarization of the particles takes place, while retaining the size-quantized nature of the material. The produced NP bridges were found to be photoactive, producing photocurrent upon illumination. DEP bridges of quantum confined NPs can be used in fast parallel manufacturing of novel MEMS components, sensors, and optical and optoelectronic devices. Purposeful engineering of self-assembling properties of NPs makes possible further facilitation of the DEP and increase of complexity of the produced nano- and microscale structures. PMID- 21651295 TI - Influence of Bifidobacterium longum CECT 7347 and gliadin peptides on intestinal epithelial cell proteome. AB - Celiac disease is an enteropathy caused by an abnormal immune response to cereal gluten proteins (gliadin). To unravel the possible role of the interactions between gliadin peptides and specific intestinal bacteria, the response of intestinal epithelial (Caco-2) cells to gliadin subjected to gastrointestinal digestion in the presence or absence of Bifidobacterium longum CECT 7347 has been studied. Changes in the proteome of Caco-2 cells were determined by 2DE and MALDI TOF. Gliadins digested without B. longum altered the expression of a higher number of proteins than in the presence of the bacterium (21 versus 9), and these proteins were involved in disorganization of cell cytoskeleton, inflammation, and apoptosis. Gliadins digested in the presence of the bacterium influenced the production of proteins involved in calcium homeostasis and cell survival and function. Therefore, B. longum CECT 7347 might ameliorate gliadin toxicity and modify the responses of intestinal epithelial cells to the gliadin challenge. PMID- 21651296 TI - Synthesis of hollow silica spheres with hierarchical shell structure by the dual action of liquid indium microbeads in vapor-liquid-solid growth. AB - Geometry-based adhesion arising from hierarchical surface structure enables microspheres to adhere to cells strongly, which is essential for inorganic microcapsules that function as drug delivery or diagnostic imaging agents. However, constructing a hierarchical structure on the outer shell of the products via the current microcapsule synthesis method is difficult. This work presents a novel approach to fabricating hollow microspheres with a hierarchical shell structure through the vapor-liquid-solid (VLS) process in which liquid indium droplets act as both templates for the formation of silica capsules and catalysts for the growth of hierarchical shell structure. This hierarchical shell structure offers the hollow microsphere an enhanced geometry-based adhesion. The results provide a facile method for fabricating hollow spheres and enriching their function through tailoring the geometry of their outer shells. PMID- 21651297 TI - Control of effect on the nucleation rate for hen egg white lysozyme crystals under application of an external ac electric field. AB - The effect of an external ac electric field on the nucleation rate of hen egg white lysozyme crystals increased with an increase in the concentration of the precipitant used, which enabled the design of an electric double layer (EDL) formed at the inner surface of the drop in the oil. This is attributed to the thickness of the EDL controlled by the ionic strength of the precipitant used. Control of the EDL formed at the interface between the two phases is important to establishing this novel technique for the crystallization of proteins under the application of an external ac electric field. PMID- 21651298 TI - Light-driven directed motion of azobenzene-coated polymer nanoparticles in an aqueous medium. AB - Azobenzene-coated polymer nanoparticles in the 16-nm-diameter range act as phototriggered nanomotors combining photo to kinetic energy conversion with optical control through light intensity gradients. The grafted dyes act as molecular propellers: their photoisomerization supplies sufficient mechanical work to propel the particles in an aqueous medium toward the intensity minima with velocities of up to 15 MUm/s. It is shown that nanoparticles can be driven over tens of micrometers by translating the intensity gradients in the plane. The analysis of the particles motion demonstrates the decisive role of photoisomerization in the transport with a measured driving force that is 3 to 4 orders of magnitude higher than optical forces. PMID- 21651299 TI - A new angle on pluronic additives: advancing droplets and understanding in digital microfluidics. AB - Biofouling in microfluidic devices limits the type of samples which can be handled and the duration for which samples can be manipulated. Despite the cost of disposing fouled devices, relatively few strategies have been developed to tackle this problem. Here, we have analyzed a series of eight amphiphilic droplet additives, Pluronic coblock polymers of poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO), as a solution to biofouling in digital microfluidics using serum-containing cell culture media as a model fluid. Our analysis shows that species with longer PPO chains are superior for enabling droplet motion and reducing biofouling. Two of the tested species, L92 and P105, were found to lengthen device lifetimes by 2-3 times relative to additives used previously when used at optimal concentrations. Pluronics with low PEO content such as L92 were found to be cytotoxic to an immortalized mammalian cell line, and therefore we recommend that Pluronic additives with greater or equal to 50% PEO composition, such as P105, be used for digital microfluidic applications involving cells. Finally, contact angle measurements were used to probe the interaction between Pluronic-containing droplets and device surfaces. Strong correlations were found between various types of contact angle measurements and the capacity of additives to reduce biofouling, which suggests that contact angle measurements may be useful as a tool for rapidly screening new candidates for the potential to reduce biofouling. We propose that this study will be useful for scientists and engineers who are developing digital microfluidic platforms for a wide range of applications involving protein-containing solutions, and in particular, for applications involving cells. PMID- 21651300 TI - Spontaneous buckling of lipid bilayer and vesicle budding induced by antimicrobial peptide magainin 2: a coarse-grained simulation study. AB - Molecular mechanisms of the action of antimicrobial peptides on bacterial membranes were studied by large scale coarse-grained simulations of magainin 2 dipalmitoylphosphatidylcholine/palmitoyloleoylphosphatidylglycerol (DPPC/POPG) mixed bilayer systems with spatial extents up to 0.1 MUm containing up to 1600 peptides. Equilibrium simulations exhibit disordered toroidal pores stabilized by peptides. However, when a layer of peptides is placed near the lipid head groups on one side of the bilayer only, their incorporation leads to a spontaneous buckling of the bilayer. This buckling is followed by the formation of a quasi spherical vesicular bud connected to the bilayer by a narrow neck. The mean curvature of the budding region is consistent with what is expected based on the dependence of the area per lipid on the peptide-to-lipid ratio in equilibrium simulations. Our simulations suggest that the incorporation of antimicrobial peptides on the exterior surface of a vesicle or a bacterial cell leads to buckling and vesicle budding, presumably accompanied by nucleations of giant transient pores of sizes that are much larger than indicated by equilibrium measurements and simulations. PMID- 21651301 TI - Optical behavior of conjugated Pt-containing polymetallaynes exposed to gamma-ray radiation doses. AB - The effect of (60)Co gamma irradiation on the absorption and emission spectra of the organometallic polymer [-Pt(PBu(3))(2)-C=C-C(6)H(4)-C(6)H(4)-C=C-](n) (Pt DEBP) in chloroform and toluene solutions for dosimetry applications has been studied. The system Pt-DEBP/chloroform can be used for dosimetric applications in two different ways: (i) monitoring of absorption spectra changes for higher doses (higher than 1 Gy), and (ii) monitoring of emission spectra changes for low doses (below 1 Gy). The response of the polymer solution to gamma ray doses has been interpreted with the aid of theoretical studies based on time dependent density functional theory (TD-DFT) calculations on the absorption bands of a model complex and of the possible fragments coming from the degradation of the polymer backbone. It has been proposed that the observed changes are promoted by the attack of radicals, from the radiolysis of the solvent, on the polymer triple bonds. PMID- 21651302 TI - The effect of mutations on the alloreactive T cell receptor/peptide-MHC interface structure: a molecular dynamics study. AB - T cells orchestrate adaptive, pathogen-specific immune responses. T cells have a surface receptor (called TCR) whose ligands are complexes (pMHCs) of peptides (derived from pathogens or host proteins) and major histocompatibility complex proteins (MHCs). MHC proteins vary between hosts. During organ transplants, host TCRs interact with peptides present in complex with genetically different MHCs. This usually causes a vigorous immune response: alloreactivity. Studies of alloreactive protein interactions have yielded results that present a puzzle. Some crystallographic studies concluded that the alloreactive TCR/MHC interface is essentially unaffected by changing the TCR peptide-binding region, suggesting that the peptide does not influence the interface. Another biochemical study concluded from mutation data that different peptides can alter the binding interface with the same TCR. To explore the origin of this puzzle, we used molecular dynamics simulations to study the dependence of the TCR/pMHC interface on changes in both the peptide and the TCR. Our simulations show that the footprint of the TCR on the pMHC is insensitive to mutations of the TCR peptide binding loops, but peptide mutations can make multiple local changes to TCR/pMHC contacts. Therefore, our results demonstrate that the structural and mutation data do not conflict and reveal how subtle, but important, characteristics of the alloreactive TCR/pMHC interface are influenced by the TCR and the peptide. PMID- 21651303 TI - Molecular dynamics study of Acid-catalyzed hydrolysis of dimethyl ether in aqueous solution. AB - The acid-catalyzed hydrolysis of dimethyl ether (DME) to methanol was examined using ab initio density functional metadynamics simulations. Diffusion of the acid proton from the aqueous medium, leading to the formation of a protonated DME, is 12.3 kcal mol(-1) activated and 9.3 kcal mol(-1) endothermic, indicating a greater affinity of the acid proton to water than to the ether group. Subsequent scission of the protonated ether bond is found to be 30.7 kcal mol(-1) activated, leading to the formation of a solvated methyl-carbocation, which is thermodynamically unstable. The methyl-carbocation reacts readily to form methanol and regenerate the acid proton. PMID- 21651305 TI - Formation of hydrophilic nanochannels in the membrane of living cells by the ringlike stable protein-SP1. AB - The assembly of functional junction between nerve cells and electronic sensing pads is a critical problem in the construction of effective neuroelectronic hybrid systems. Here, we demonstrate for the first time that the ringlike Stable Protein 1 (Sp1) and its derivatives can be used to generate hydrophilic nanochannels in the plasma membrane of living cells. Since SP1-derivatives can be linked to both the plasma membrane, gold or silicon surfaces, they may serve to ohmically link between cells interior and electronic sensing devices. PMID- 21651304 TI - Mutants of the base excision repair glycosylase, endonuclease III: DNA charge transport as a first step in lesion detection. AB - Endonuclease III (EndoIII) is a base excision repair glycosylase that targets damaged pyrimidines and contains a [4Fe-4S] cluster. We have proposed a model where BER proteins that contain redox-active [4Fe-4S] clusters utilize DNA charge transport (CT) as a first step in the detection of DNA lesions. Here, several mutants of EndoIII were prepared to probe their efficiency of DNA/protein charge transport. Cyclic voltammetry experiments on DNA-modified electrodes show that aromatic residues F30, Y55, Y75, and Y82 help mediate charge transport between DNA and the [4Fe-4S] cluster. On the basis of circular dichroism studies to measure protein stability, mutations at residues W178 and Y185 are found to destabilize the protein; these residues may function to protect the [4Fe-4S] cluster. Atomic force microscopy studies furthermore reveal a correlation in the ability of mutants to carry out protein/DNA CT and their ability to relocalize onto DNA strands containing a single base mismatch; EndoIII mutants that are defective in carrying out DNA/protein CT do not redistribute onto mismatch containing strands, consistent with our model. These results demonstrate a link between the ability of the repair protein to carry out DNA CT and its ability to relocalize near lesions, thus pointing to DNA CT as a key first step in the detection of base damage in the genome. PMID- 21651306 TI - Are nanoporous materials radiation resistant? AB - The key to perfect radiation endurance is perfect recovery. Since surfaces are perfect sinks for defects, a porous material with a high surface to volume ratio has the potential to be extremely radiation tolerant, provided it is morphologically stable in a radiation environment. Experiments and computer simulations on nanoscale gold foams reported here show the existence of a window in the parameter space where foams are radiation tolerant. We analyze these results in terms of a model for the irradiation response that quantitatively locates such window that appears to be the consequence of the combined effect of two length scales dependent on the irradiation conditions: (i) foams with ligament diameters below a minimum value display ligament melting and breaking, together with compaction increasing with dose (this value is typically ~5 nm for primary knock on atoms (PKA) of ~15 keV in Au), while (ii) foams with ligament diameters above a maximum value show bulk behavior, that is, damage accumulation (few hundred nanometers for the PKA's energy and dose rate used in this study). In between these dimensions, (i.e., ~100 nm in Au), defect migration to the ligament surface happens faster than the time between cascades, ensuring radiation resistance for a given dose-rate. We conclude that foams can be tailored to become radiation tolerant. PMID- 21651307 TI - Trifluoromethanesulfonic acid catalyzed isomerization of kinetic enol derivatives to the thermodynamically favored isomers. AB - Trifluoromethanesulfonic acid catalyzed isomerization of kinetic enol derivatives to the thermodynamically favored isomers was developed. Under the present conditions, kinetic enol phosphates, enol acetates and benzoates, and enol sulfonates were smoothly isomerized to produce the corresponding thermodynamically favored isomers in good to excellent yields. PMID- 21651308 TI - Environment- and sequence-dependence of helical type in membrane-spanning peptides composed of beta3-amino acids. AB - Transmembrane (TM) beta-peptides comprised of acyclic beta(3)-amino acids demonstrate equilibrium between 12- and 14-helical structures in an environment- and sequence-dependent manner. Circular dichroism (CD) spectra of TM beta(3) peptides may be described as linear combinations of the 12- and 14-helical CD spectra. The apparent malleability of beta(3)-substituted acyclic beta-peptides has practical implications for foldamer design, as it suggests that both the 14 helix and 12-helix might be reasonable platforms for molecular recognition. PMID- 21651309 TI - Stereoselective synthesis of core structure of cortistatin A. AB - A stereoselective synthesis of the core structure of cortistatin A (1), a novel antiangiogenic steroidal alkaloid from Indonesian marine sponge, is described. An 8-oxabicyclo[3.2.1]octene system, a characteristic B-ring structure of 1, was elaborated by a 7-endo selective intramolecular Heck cyclization and a subsequent acid-mediated oxy-Michael reaction. PMID- 21651310 TI - Influence of ethylenediaminetetraacetic acid (EDTA) on the structural stability of endoglucanase from Aspergillus aculeatus. AB - The effect of the chelating agent ethylenediaminetetraacetic acid (EDTA) on the structure and function of endoglucanase is studied. In the presence of 2 mM EDTA, endoglucanase showed an enhanced enzymatic activity of 1.5-fold compared to control. No further change in activity was observed with increase in the concentration of EDTA to 5 mM. The K(m) values for control and in the presence of EDTA are 0.060 and 0.044%, respectively, and K(cat) was 1.9 min(-1) in the presence of EDTA. The kinetic parameters indicated a decrease in the K(m) with an increase in the K(cat). Far-ultraviolet circular dichroism (far-UV-CD) results showed a 20% decrease in ellipticity values at 217 nm in the presence of EDTA compared to native enzyme. The apparent T(m) shifted from a control value of 57 +/- 1 to 76 +/- 1 degrees C in the presence of EDTA (5 mM). The above results suggested that the enhanced activity in the presence of EDTA is due to an increase in the K(cat) and flexible conformation of the enzyme. The stability of endoglucanase increased in the presence of EDTA. PMID- 21651311 TI - Does olanzapine warrant clinical pharmacokinetic monitoring in schizophrenia? AB - Olanzapine, a second-generation antipsychotic, is a first-line agent in the treatment of schizophrenia. The objective of this review was to determine whether olanzapine warrants clinical pharmacokinetic monitoring in patients with schizophrenia, using a previously published decision-making algorithm. Although olanzapine is an appropriate therapy for patients with schizophrenia and is readily measurable in biological fluids, significant interindividual variation exists in its pharmacokinetics. While the duration of therapy is expected to be long term, the correlation of olanzapine concentrations with efficacy and toxicity has not been well defined in the literature. There are multiple tools readily available for the assessment of efficacy in schizophrenia, and clinical signs and symptoms can be used to monitor both for efficacy and for adverse effects. Therefore, routine monitoring of olanzapine concentrations does not appear warranted in the general schizophrenic population. However, patients in whom a change in olanzapine pharmacokinetics is expected--such as during addition or removal of an enzyme-inducing or -inhibiting drug, or during initiation or cessation of smoking--may benefit from clinical pharmacokinetic monitoring, as would patients in whom non-compliance is suspected. Patients who fail to respond to maximum recommended doses and those who experience adverse effects from therapeutic doses may also benefit from therapeutic drug monitoring, as they may have inherent variations in hepatic enzyme activity. However, in the population at large who suffer from schizophrenia, monitoring of olanzapine concentrations is not expected to offer additional benefit beyond appropriate clinical monitoring alone. PMID- 21651313 TI - Lidocaine (lignocaine) dosing regimen based upon a population pharmacokinetic model for preterm and term neonates with seizures. AB - BACKGROUND AND OBJECTIVE: The application of lidocaine (lignocaine) as an anticonvulsant in neonates originated more than 40 years ago in Scandinavia. Lidocaine has been shown to be an effective anticonvulsant for the treatment of neonatal seizures that persist in spite of first-line anticonvulsant therapy. However, lidocaine toxicity, mainly in the form of cardiac arrhythmias, can be life threatening. Therapeutic drug monitoring can be useful to prevent toxicity. In a previous study, a dosing regimen was developed for term neonates, but it was not evaluated for preterm neonates. Extrapolation of the previously developed dosing regimen to premature neonates without accounting for differences in pharmacokinetics because of immaturity of phase I metabolism and body fat/water ratio may result in serious toxicity or therapy failure. The objective of this study was to develop an optimized dosing regimen for lidocaine in preterm as well as term neonates, using population pharmacokinetic modelling and simulation. METHODS: The requirements for this dosing regimen were simplicity of implementation, equal initial doses for all weight categories and avoidance of plasma concentrations >9 mg/L. After lidocaine administration, blood samples were collected from an arterial line from a total of 46 preterm and term neonates with convulsion, within 10 days after birth. Lidocaine concentrations were measured in plasma using a fluorescence polarization immunoassay. Population pharmacokinetic modelling started with assessment of two important aspects of paediatric pharmacokinetics: relation to body size and the effects of maturation. RESULTS: In the studied neonatal population (term and preterm neonates with gestational ages up to 10 days), gestational age and bodyweight were closely related. Therefore, the effects of allometry and maturation on lidocaine pharmacokinetics could not be described independently and were described by a combined power estimate of bodyweight on clearance and volume of distribution. Based on this pharmacokinetic model, a dosing strategy for lidocaine for neonatal seizure control was developed, which allows rapid and safe administration of lidocaine in this population. When prospective validation confirms our model, routinely performed therapeutic drug monitoring should no longer be necessary and would only be advised in cases of (suspected) clinical symptoms of over- or underdosing. CONCLUSION: A lidocaine dosing regimen for seizure control in preterm and term neonates has been developed using population pharmacokinetic modelling and simulation. Allometry and maturation exponents were combined into one exponent for each pharmacokinetic parameter and could not be described independently. Based on this model, this regimen allows rapid and safe administration of lidocaine in this population. PMID- 21651312 TI - Structural models describing placebo treatment effects in schizophrenia and other neuropsychiatric disorders. AB - Large variation in placebo response within and among clinical trials can substantially affect conclusions about the efficacy of new medications in psychiatry. Developing a robust placebo model to describe the placebo response is important to facilitate quantification of drug effects, and eventually to guide the design of clinical trials for psychiatric treatment via a model-based simulation approach. In addition, high dropout rates are very common in the placebo arm of psychiatric clinical trials. While developing models to evaluate the effect of placebo response, the data from patients who drop out of the trial should be considered for accurate interpretation of the results. The objective of this paper is to review the various empirical and semi-mechanistic models that have been used to quantify the placebo response in schizophrenia trials. Pros and cons of each placebo model are discussed. Additionally, placebo models used in other neuropsychiatric disorders like depression, Alzheimer's disease and Parkinson's disease are also reviewed with the objective of finding those placebo models that could be useful for clinical studies of both acute and chronic schizophrenic disease conditions. Better understanding of the patterns of dropout and the factors leading to dropouts are crucial in identifying the true placebo response. We therefore also review dropout models that are used in the development of models for treatment effects and in the optimization of clinical trials by simulation approaches. The use of an appropriate modelling strategy that is capable of identifying the potential sources of variable placebo responses and dropout rates is recommended for improving the sensitivity in discriminating between the effects of active treatment and placebo. PMID- 21651314 TI - Asenapine pharmacokinetics in hepatic and renal impairment. AB - BACKGROUND AND OBJECTIVE: The effects of hepatic or renal impairment on the pharmacokinetics of atypical antipsychotics are not well understood. Drug exposure may increase in patients with hepatic disease, owing to a reduction of certain metabolic enzymes. The objective of the present study was to study the effects of hepatic or renal impairment on the pharmacokinetics of asenapine and its N-desmethyl and N+-glucuronide metabolites. METHODS: Two clinical studies were performed to assess exposure to asenapine, desmethylasenapine and asenapine N+-glucuronide in subjects with hepatic or renal impairment. Pharmacokinetic parameters were determined from plasma concentration-time data, using standard noncompartmental methods. The pharmacokinetic variables that were studied included the maximum plasma concentration (C(max)) and the time to reach the maximum plasma concentration (t(max)). Eligible subjects, from inpatient and outpatient clinics, were aged >=18 years with a body mass index of >=18 kg/m2 and <=32 kg/m2. Sublingual asenapine (Saphris(r)) was administered as a single 5 mg dose. RESULTS: Thirty subjects participated in the hepatic impairment study (normal hepatic function, n = 8; mild hepatic impairment [Child-Pugh class A], n = 8; moderate hepatic impairment [Child-Pugh class B], n = 8; severe hepatic impairment [Child-Pugh class C], n = 6). Thirty-three subjects were enrolled in the renal impairment study (normal renal function, n = 9; mild renal impairment, n = 8; moderate renal impairment, n = 8; severe renal impairment, n = 8). Asenapine and N-desmethylasenapine exposures were unaltered in subjects with mild or moderate hepatic impairment, compared with healthy controls. Severe hepatic impairment was associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) values for total asenapine, N desmethylasenapine and asenapine N+-glucuronide (5-, 3-, and 2-fold, respectively), with slight increases in the C(max) of asenapine but 3- and 2-fold decreases in the C(max) values for N-desmethylasenapine and asenapine N+ glucuronide, respectively, compared with healthy controls. The mean AUC(infinity) of unbound asenapine was more than 7-fold higher in subjects with severe hepatic impairment than in healthy controls. Mild renal impairment was associated with slight elevations in the AUC(infinity) of asenapine compared with healthy controls; alterations observed with moderate and severe renal impairment were marginal. N-desmethylasenapine exposure was only slightly altered by renal impairment. No correlations were observed between exposure and creatinine clearance. CONCLUSION: Severe hepatic impairment (Child-Pugh class C) was associated with pronounced increases in asenapine exposure, but significant increases were not seen with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, or with any degree of renal impairment. Asenapine is not recommended in patients with severe hepatic impairment; no dose adjustment is needed in patients with mild or moderate hepatic impairment, or in patients with renal impairment. PMID- 21651315 TI - The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample. AB - Traumatic brain injury (TBI) can result in significant disability, but outcome is variable. The impact of known predictors accounts for a limited proportion of the variance in outcomes. Apolipoprotein E (ApoE) genotype has been investigated as an additional source of variability in injury severity and outcome, with mixed findings reflecting variable methodology and generally limited sample sizes. This study aimed to examine whether possession of the ApoE E4 allele was associated with greater acute injury severity and poorer long-term outcome in patients referred for rehabilitation following TBI. ApoE genotype was determined for 648 patients with TBI, who were prospectively followed up a mean of 1.9 years post injury. Hypotheses that E4 carriers would have lower Glasgow Coma Scale (GCS) scores and longer post-traumatic amnesia (PTA) duration were not supported. Prediction of worse Glasgow Outcome Scale-Extended (GOSE) scores for E4 carriers was supported with greater susceptibility seen in females. These results indicate the ApoE E4 allele may be associated with poorer long-term outcome, but not acute injury severity. Possible mechanisms include differential effects of the E4 allele on inflammatory and cellular repair processes, and/or amyloid deposition. PMID- 21651316 TI - Consecutive daily low-dose S-1 adjuvant chemotherapy after radical treatment for squamous cell carcinoma in head and neck cancer. AB - CONCLUSION: Consecutive daily low-dose S-1 therapy was less toxic and its efficacy was not inferior to the conventional administration schedule. Consecutive daily low-dose S-1 chemotherapy appears to be a treatment option for patients in whom it is difficult to continue the conventional administration schedule of S-1 due to adverse events. OBJECTIVE: To evaluate the safety and efficacy of consecutive daily low-dose S-1 therapy in an adjuvant setting. METHODS: This study investigated 52 patients with absence of local residual tumor, lymph node metastasis or distant metastasis after radical treatment for advanced head and neck squamous cell carcinoma. After receiving informed consent from patients, half of the usual dose of S-1 was administered daily for 2 years. The safety, feasibility, and efficacy of this approach were evaluated. RESULTS: Hematologic toxicity was seen in 51 of 52 patients (98.1%), but grade 3 hematologic toxicity was found in only 2 patients (3.8%). Nonhematologic toxicity was observed in 15 patients (28.8%) and all were grade 1. Forty-three patients (82.7%) were able to complete the chemotherapy for 2 years without dose reduction. The 3-year disease-free survival rate and 3-year survival rate were 82.6% and 94.0%, respectively. PMID- 21651317 TI - CD34-positive primitive vessels and other structures in human fetuses: an immunohistochemical study. AB - CONCLUSION: CD34-positive mesenchymal tissues are likely to play a critical role in the pattern formation of laryngeal and pharyngeal walls. In the ear, nose, and throat regions, a future clinical relevance may be found in their use for muscle repair and regeneration. OBJECTIVES: CD34 is a well-known marker of progenitor cells of blood vessels and stromal tissues. Thus, CD34-positive cells have recently been used clinically in the field of vascular and orthopedic biotechnology because of their capacity to assist regeneration of injured tissues. However, to our knowledge, the in situ distribution of CD34-positive cells has not yet been described in the human fetus, with the exception of a few organs. The purpose of this study was to describe the location of CD34-positive cells in the head and neck regions. METHODS: Immunohistochemistry for CD34 was carried out using seven human fetuses (12 and 15 weeks of gestation). RESULTS: CD34-positive structures showed a vessel-like appearance and were regularly arrayed along the nasal, oral, pharyngeal, and laryngeal mucosal epithelia, whereas in the laryngeal and pharyngeal striated muscles they were distributed diffusely as fibrous tissues such as the fascia and perimysium. PMID- 21651318 TI - Gene localization in a Chinese family with autosomal dominant non-syndromic deafness. AB - CONCLUSIONS: There could be another candidate gene in DFNA2, which could be responsible for the hearing loss phenotype. OBJECTIVE: We collected a four generation family from the southern part of China with autosomal dominant sensorineural hearing impairment. In order to identify the responsible pathogenic mutations in this family, we set out to identify the locus and to sequentially analyze the candidate genes in the identified region. METHODS: After family ascertainment and clinical analysis, exclusive analysis was performed. Then a genome-wide scan was performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Fine-mapping markers were genotyped to identify the locus. Finally, we performed haplotype analyses and candidate gene DNA sequencing for the family. RESULTS: The known genetic loci and genes were not associated with our family. The genome-wide scan and haplotype analyses traced the disease to chromosome 1p34.2-p34.3 with maximum multi-point LOD score of 3.2, which overlaps with DFNA2. We failed to identify any of the known or novel variants within KCNQ4, a voltage-gated potassium channel gene, and GJB3, a gene that encodes the gap junction protein connexin 31, which were the cloned deafness genes in DFNA2. PMID- 21651319 TI - Pharmacogenetics of coumarin dosing: prevalence of CYP2C9 and VKORC1 polymorphisms in the Lebanese population. AB - BACKGROUND: Polymorphisms in the genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and the vitamin K epoxide reductase (VKORC1) are known to contribute to variability in sensitivity to coumarins. Patients with certain common genetic variants of CYP2C9 (*2 & *3) or a VKORC1 polymorphism (-1639A Allele) require a lower dose of coumarin and are also at higher risk for over-anticoagulation and serious bleeding. In August 2007, the FDA label for warfarin was updated to highlight the benefit of genetic testing to predict warfarin response. AIM: Since the prevalence of these variants in the Lebanese population has not yet been reported, our aim was to determine the genotypes of CYP2C9 and VKORC1 in our population and to compare allele frequencies with previous findings from other ethnic groups. MATERIALS AND METHODS: CYP2C9 (*1/*2/*3) and VKORC1 (*A/*G) allelic variants were assessed by polymerase chain reaction-restriction fragment length polymorphism assays in a diversified sample of 161 unrelated healthy Lebanese volunteers. RESULTS: The allele frequencies of CYP2C9 *2 and *3 were 0.112 and 0.096 respectively, whereas VKORC1-1639A was 0.528. Carriers of the CYP2C9 *2 or *3 represented 34.2% of the subjects, whereas those of the VKORC1 1639A represented 73.9%. CONCLUSION: Our data show no significant difference in the frequency of CYP2C9 allelic variants when compared to the Caucasian population, whereas the allelic frequency of VKORC1-1639A was very high. Over 50% of the Lebanese population seem to be carrying more than two independent risk alleles, and is therefore potentially at high risk of over-anticoagulation. PMID- 21651320 TI - Apparent neotelomere in a 46,X,del(X)(qter->p11.2:)/46,X,rea(X)(qter >p11.2::q21.2->qter) novel mosaicism: review of 34 females with a recombinant like dup(Xq) chromosome. AB - A 26-year-old woman with secondary amenorrhea and turneroid stigmata was found to have a 46,X,rea(X)(qter->p11.2::q21.2->qter)/46,X,del(X)(qter->p11.2:) mosaicism in 101 G-banded metaphases (71 and 30, respectively). The mother's karyotype was normal (the father was already deceased). A fully skewed inactivation of both abnormal X-chromosomes was documented in RBG-banded metaphases and by means of the HUMARA assay. In addition, the latter revealed that the involved X-chromosome was the paternal one. The patient's secondary amenorrhea and turneroid stigmata can reliably be ascribed to her nearly complete Xp deletion present in all cells. Thus, this observation is consistent with the well-known gradation of ovarian function depending on the Xp deletion size. We assume that the first event was an intrachromosome recombination during paternal meiosis between paralogous sequences at Xp11.2 and Xq21.2, which resulted in a fertilizing rea(X) spermatozoid. Early in embryogenesis, the rea(X) dissociated at the Xp11.2 junction point to originate the del(X), which in turn was healed by the de novo addition of telomeric repeats (the acentric Xq21.2->qter segment was lost in the process). The reverse sequence appears unlikely because it implies that the del(X) chromosome was healed only after it undergone a postzygotic interchromatid recombination and apposite segregation required to obtain the rea(X) clone. The present observation further expands the cytogenetic heterogeneity in Turner syndrome and may represent another instance of a terminal deletion healed by the de novo addition of telomeric repeats. PMID- 21651321 TI - Haptoglobin genotypes in sickle-cell disease. AB - We compared the frequencies of the haptoglobin (Hp) genotypes of 775 Brazilian patients with sickle-cell disease divided into the following age groups: 3 months 5 years, 6-10 years, 11-15 years, 16-20 years, and over 20 years. The last group (>20 years) was also compared with a healthy control group and was further divided into subgroups including only subjects aged 21-30 years (V.a and Control.a) and over 30 years (V.b and Control.b). There was no significant difference in the frequencies of the Hp genotypes between the different patient groups or between the patients and controls. However, the Hp2-2 genotype was always less frequent than the Hp1-1 genotype in the patient groups, whereas the opposite was observed in healthy controls. The frequency of Hp2-2 was 25.0% in patients in the 21-30 years age group and fell to 19.5% in those over 30 years. In the controls, the corresponding frequency was around 28%. Although our results do not allow us to conclude that Hp genotypes on their own confer greater or lesser selective advantage on sickle-cell disease patients in the population studied, this polymorphism may, when combined with other genetic and environmental factors, contribute to the clinical diversity observed in this disease. PMID- 21651322 TI - Premature mortality in epilepsy: is it preventable? PMID- 21651323 TI - New drug delivery options for migraine. PMID- 21651324 TI - Glioblastoma multiforme: can neural stem cells deliver the therapeutic payload and fulfill the clinical promise? PMID- 21651326 TI - The promise of anti-inflammatory therapies for CNS injuries and diseases. AB - It remains controversial as to whether the inflammatory response plays a beneficial or detrimental role for cerebral tissue. There is substantial evidence that molecules of the innate immune reaction can be harmful to neurons and oligodendrocytes, whereas other observations indicate that inflammation is actually beneficial to recovery after injuries. One of the beneficial consequences of the immune reaction by microglia is the release of neurotrophic factors that have essential roles in brain homeostasis, neuroprotection and repair in cases of injury. Another important action of microglia is the clearance of cell debris and toxic proteins in order to prevent their accumulation in the extracellular space. Such beneficial effects of subsets of innate immune cells have to be taken into serious consideration in the planning of clinical trials using anti-inflammatory drugs for CNS diseases, which have failed so far. This very important subject has been discussed at the 13th Annual Meeting of the American Society for Experimental Neurotherapeutics in Bethesda, MD, USA. PMID- 21651327 TI - Use of diagnostic tests and procedures for disease-modifying therapy users and non-disease-modifying therapy users with multiple sclerosis. AB - We examined the use of 23 diagnostic procedures and monitoring tests for users of disease-modifying therapy (DMT) and non-DMT users with multiple sclerosis (MS). The Medstat MarketScan((r)) Commercial Claims and Encounters database (2003 2007), which is composed of medical and pharmacy claims for approximately 8 million beneficiaries from 45 US commercial health plans, was used to identify DMT users with an index claim for an MS drug and a 6-month baseline period without MS drugs. Patients were followed for 12 months. Logistic regression models were used to estimate differences in rates and proportion of patients receiving procedures and tests between cohorts. Baseline rates for DMT users (n = 12,455) included MRIs (76.8%), spinal taps (15.7%), neuropsychological testing (4.7%), chemistry panels (61.4%), complete blood cell counts (76.7%) and liver function tests (60.5%). Relative to non-DMT users (n = 25,534), DMT users were more likely to receive an MRI, neuropsychological testing, chemistry panels, complete blood cell counts and liver function tests. PMID- 21651328 TI - Wallis interspinous implantation to treat degenerative spinal disease: description of the method and case series. AB - The Wallis interspinous implant is most commonly used in the treatment of intervertebral disc herniation and for tears in the outer layer of the disc. The dynamic vertebral fixation concept was first initiated in 1984 with the goal of imitating the physiologic spinal kinetic. A total of 15 years later, a second generation of implant has been developed, termed the 'Wallis interspinous Implant', which aims to preserve the mobility of the operated spinal segment. To underline our own experience, a retrospective review of 15 patients that were treated with 'Wallis implantation' at our institution between January 2006 and March 2008. Our main inclusion criterion for Wallis implantation was low back pain because of degenerative lumbar spinal stenosis associated with segmental instability along with Modic changes 0-1 and with UCLA arthritic grade II in the adjacent two segments cephalad to implantation. The outcome was analyzed according to clinical and radiological parameters. One (n = 9), two (n = 4) and three levels (n = 2) were operated on using Wallis implantation, ranging from L2-L3 to L5-S1. We used implants of 8-14 mm in size. There was a reduction in low back pain (73 vs 43%) and gait disturbances (73 vs 14%) at the 3-month follow-up compared with preoperative values. In line with these results, the modified Japan Orthopedic Association Score (mJAOS) was increased from 12 preoperatively to 18 at 3 months and 20 at 12 months postoperatively. A reduction in low back pain could only be demonstrated for implants that were 10 mm in size or greater at 3 months and 12-15 months postoperatively. An improvement was seen in Modic grades after the operations as compared with those observed at preoperative MRI. The outcome in our patients was rated as good or excellent according to Odom's criteria in all cases, independent of the levels that were used. Wallis implantation is therefore a safe procedure with a good to excellent outcome in the short- and mid-term follow-up and can lead to disc rehydration, as confirmed by postoperative MRI. Principal postoperative (clinical) success is based on the correct implant size. PMID- 21651329 TI - Pathological gambling in Parkinson's disease: disease related or drug related? AB - Pathological gambling and other impulse-control disorders occur in susceptible Parkinson's disease patients during dopaminergic therapy, particularly in association with dopamine agonists. Additional factors such as age at onset play an important role, and predisposing personality traits have been identified both in treated patients, as well as in patients even before therapy is initiated. The contributions of specific allelic polymorphisms of the dopamine receptor and transporter genes were also tested as predictors of adverse effects of dopaminergic therapy but results are not conclusive. Recent imaging studies have shed light on the mechanism underlying pathological gambling. Resting-state brain perfusion of Parkinson's disease gamblers showed higher activity in 'limbic' areas associated with addictive processes. More importantly, severity of this behavior is associated with the impaired functioning of brain regions that are involved in 'top-down' cognitive monitoring and inhibition of inappropriate behaviors. This evidence is consistent with a significant contribution of disease related factors. PMID- 21651330 TI - Intensive voice treatment in Parkinson's disease: Lee Silverman Voice Treatment. AB - Advances in neuroscience have led to an expanded and improved understanding of neurobiological changes associated with rehabilitation and exercise in Parkinson's disease (PD). This knowledge has led to a direct clinical impact of increased referral for early and continuous exercise programs for individuals with PD (physical, occupational, speech therapy and general exercise programs) and an increased research focus on the impact of such approaches in humans with PD. The purpose of this article is to examine the role of speech therapy in the landscape of exercise-based interventions for individuals with PD. We will specifically focus on the intensive voice treatment protocol, Lee Silverman Voice Treatment, as an example therapy. This article will briefly review the literature on the characteristics and features of speech and voice disorders in individuals with PD, and will discuss the impact of pharmacological and surgical treatment techniques on these disorders. This will be followed by a focus on behavioral speech treatment, specifically Lee Silverman Voice Treatment, including development of the treatment approach, documenting efficacy, discovery of unexpected outcomes and insights into the mechanism of speech disorders in PD gained from treatment-related changes. This research will be placed in the context of other previous and current speech treatment approaches in development for individuals with PD, and will highlight future directions for research. PMID- 21651331 TI - Cell-based therapies for Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, classically characterized by a triad of motor features: bradykinesia, rigidity and resting tremor. Neurodegeneration in PD critically involves the dopaminergic neurons of the substantia nigra pars compacta, which results in a severe reduction in dopamine levels in the dorsal striatum. However, the disease also exhibits extensive non-nigral pathology and as many non-motor as motor features. Nevertheless, owing to the relatively circumscribed nature of the nigrostriatal lesion in PD, dopaminergic cell transplantation has emerged as a potentially reparative therapy for the disease. Sources for such cells are varied and include the developing ventral mesencephalon, several autologous somatic cell types, embryonic stem cells and induced pluripotent stem cells. In this article, we review the origins of dopaminergic transplantation for PD and the emergent hunt for a suitable long-term source of transplantable dopaminergic neurons. PMID- 21651332 TI - Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-beta carboline: a new anti-Parkinson drug? AB - beta-carbolines are potential endogenous and exogenous neurotoxins that may contribute to the pathogenesis of Parkinson's disease (PD). 9-methyl-beta carboline exhibits multimodal effects that could be beneficial in the treatment of PD. It shows stimulatory effects to dopaminergic neurons by increasing the expression of tyrosine hydroxylase and its transcription factors in pre-existing dopa decarboxylase immunoreactive neurons. Furthermore, 9-methyl-beta-carboline has emerged as a substance with the rare property of a protective and regenerative/restorative potential for dopaminergic neurons by inducing gene expression of several neurotrophic factors and decreasing apoptotic cell signals. It reduces protein levels of alpha-synuclein and inhibits monoamine oxidase A and B. Finally, 9-methyl-beta-carboline acts on multiple targets in the inflammatory cascade by inhibiting the proliferation of microglia, by decreasing chemotactic cytokines and by creating an anti-inflammatory environment in the CNS. This article summarizes our current knowledge of 9-methyl-carboline and discusses its potential role as a new drug for the treatment of PD. PMID- 21651333 TI - Etiologies of epilepsy: a comprehensive review. AB - Epilepsy is a heterogeneous disorder, the symptoms of which are preventable and controllable to some extent. Significant inter- and intra-country differences in incidence and prevalence exist because multiple etiologic factors are implicated. Many past reviews have addressed sole etiologies. We considered a comprehensive view of all etiologies (genetic/structural/metabolic) to be significant for both the developing and the developed world as well as routine clinical/epidemiology practice. We therefore carried out a comprehensive search for peer-reviewed articles (irrespective of year, region and language; chosen based on novelty and importance) for each etiology. This article was felt to be essential since newer etiologic knowledge has emerged in recent years. Many new genetic links for rarer epilepsy forms have emerged. Epilepsy risk in limbic encephalitis, mechanisms of Alzheimer's-related epilepsy and the genetic basis of cortical malformations have been detailed. An etiological approach to epilepsy in combination with the conventional classification of epilepsy syndromes is required to gain knowledge. PMID- 21651334 TI - Predicting antiepileptic drug response in children with epilepsy. AB - In clinical practice, after diagnosis and when treatment has begun, it is important to predict as soon as possible which children will become seizure-free and which are likely to develop medically intractable seizures. This article summarizes factors predicting seizure remission in childhood-onset epilepsy treated with antiepileptic drugs (AEDs). Sustained seizure remission can be expected in over 90% of idiopathic epilepsies of childhood and in neurologically normal children with epilepsy having infrequent seizures showing early remission after starting treatment with AEDs. Even in the presence of symptomatic etiology of epilepsy--focal seizures and syndromes; high seizure frequency prior to or during treatment; seizure clustering; and poor or delayed response to first adequate drug therapy--up to 60% of children with treated epilepsy are able to enter long-term remission. However, remission can be expected in only 30% or less of those with catastrophic epilepsies of childhood. PMID- 21651335 TI - Sexual and reproductive dysfunction associated with antiepileptic drug use in men with epilepsy. AB - The association between epilepsy and sexual disorders has long been known. However, the etiology remains uncertain, although it is likely to be multifactorial in origin involving neurological, endocrine, iatrogenic, psychiatric and psychosocial factors. Sexual disorders associated with epilepsy can be directly related to seizures (ictal), or unrelated in time to seizure occurrence (interictal). The most common sexual dysfunction is hyposexuality, even if hypersexuality and different paraphilias have been reported in males with epilepsy. Epilepsy and antiepileptic drugs can also alter sex hormone levels to promote the development of reproductive endocrine disorders. This article aims to explore the prevalence and etiology of sexual and reproductive dysfunctions in men with epilepsy, highlighting the pivotal role of antiepileptic drugs in their pathogenesis. PMID- 21651338 TI - Aerosolized scopolamine protects against microinstillation inhalation toxicity to sarin in guinea pigs. AB - Sarin is a volatile nerve agent that has been used in the Tokyo subway attack. Inhalation is predicted to be the major route of exposure if sarin is used in war or terrorism. Currently available treatments are limited for effective postexposure protection against sarin under mass casualty scenario. Nasal drug delivery is a potential treatment option for mass casualty under field conditions. We evaluated the efficacy of endotracheal administration of muscarinic antagonist scopolamine, a secretion blocker which effectively crosses the blood-brain barrier for protection against sarin inhalation toxicity. Age and weight matched male Hartley guinea pigs were exposed to 677.4 mg/m3 or 846.5 mg/ m3 (1.2 * LCt50) sarin by microinstillation inhalation exposure for 4 min. One minute later, the animals exposed to 846.5 mg/ m3 sarin were treated with endotracheally aerosolized scopolamine (0.25 mg/kg) and allowed to recover for 24 h for efficacy evaluation. The results showed that treatment with scopolamine increased the survival rate from 20% to 100% observed in untreated sarin-exposed animals. Behavioral symptoms of nerve agent toxicity including, convulsions and muscular tremors were reduced in sarin-exposed animals treated with scopolamine. Sarin-induced body weight loss, decreased blood O2 saturation and pulse rate were returned to basal levels in scopolamine-treated animals. Increased bronchoalveolar lavage (BAL) cell death due to sarin exposure was returned to normal levels after treatment with scopolamine. Taken together, these data indicate that postexposure treatment with aerosolized scopolamine prevents respiratory toxicity and protects against lethal inhalation exposure to sarin in guinea pigs. PMID- 21651339 TI - Orange peel products can reduce Salmonella populations in ruminants. AB - Salmonella can live undetected in the gut of food animals and be transmitted to humans. Animal diets can impact intestinal populations of foodborne pathogens, including Salmonella spp. Orange juice production results in a waste product, orange peel and orange pulp, which has a high nutritive value and is often included in cattle diets as a least-cost ration ingredient. Here we show that the inclusion of orange peel products reduced Salmonella Typhimurium populations in the gut of experimentally inoculated sheep. Sheep (n=24) were fed a cracked corn grain-based high grain diet that was supplemented with a 50%/50% (dry matter [DM], w/w) mixture of dried orange pellet and fresh orange peel to achieve a final concentration (DM, basis) of 0%, 10%, or 20% orange product (OP) for 10 days before inoculation with Salmonella Typhimurium. Sheep were experimentally inoculated with 10(10) colony forming units Salmonella Typhimurium, and fecal samples were collected every 24 h after inoculation. Sheep were humanely euthanized at 96 h after oral Salmonella inoculation. Populations of inoculated Salmonella Typhimurium were numerically reduced by OP treatment throughout the gastrointestinal tract, and this reduction only reached significant levels in the cecum (p<0.05) of sheep fed 10% OP diets. Apparent palatability issues decreased the consumption of OP in sheep fed 20% OP to intake levels below that of 10% OP (approximately 7% dry matter intake [DMI]/d feed refusal), thereby reducing the potential effects of OP feeding at this higher level. Our results demonstrate that orange peel and pellets are environmentally friendly and low-cost products that can be used as a pre-harvest intervention as part of an integrated pathogen reduction scheme. PMID- 21651340 TI - Sensory analysis and consumer surveys of fat- and salt-reduced meat products and their use in an energy-reduced diet in overweight individuals. AB - Meat and meat products are of high nutritional value; however, they frequently provide salt and fat in high amounts, which can have negative health effects when consumed in excess. We investigated salt- and fat-reduced meat products, i.e. sensory evaluation and consumer surveys were carried out as well as a dietary intervention study was carried out in overweight individuals who used salt- and fat-reduced products as a part of an energy-restricted diet. Although differences were detected in the sensory evaluation between reduced and regular meat products, the participants in the consumer surveys and in the dietary intervention study gave good ratings for the fat and fat-reduced meat products. The intervention study led to weight loss and improved cardiovascular risk, but did not reveal side effects associated with the consumption of these products. Our study indicates that such products are well accepted by potential consumers and can be included successfully in a weight loss programme. PMID- 21651336 TI - Brain functional domains inform therapeutic interventions in attention deficit/hyperactivity disorder and pediatric bipolar disorder. AB - A deeper understanding of how the relationships between impulsivity, reward systems and executive function deficits may be similar or different in attention deficit/hyperactivity disorder (ADHD) and pediatric bipolar disorder (PBD) is fundamental for better defining phenotypy in these two developmental illnesses, and moving towards improved treatment and intervention. We focus our article on recent neurocognitive and neuroimaging data examining the behavioral and neural aspects of poor behavior regulation, response inhibition and reward systems in ADHD and PBD. In light of recent research evidence, we propose that the common behavioral manifestations of impulsivity in ADHD and PBD may indeed originate from different neural mechanisms mediated by altered reward systems. In order to define and differentiate these mechanisms, unlike previous approaches, our theoretical model examines the interface of the dorsal frontostriatal circuit, involved in behavior regulation, and the ventral frontostriatal circuit, which is involved in reward-related and affect processes. Preliminary evidence suggests that the neural systems involved in impulsivity, reward systems and executive function engage differently in the two illnesses. In PBD, 'emotional impulsivity' is predominantly 'bottom-up' and emotionally/motivationally driven, and stems from ventral frontostriatal circuitry dysfunction. By contrast, in ADHD 'cognitive impulsivity' is predominantly 'top-down' and more 'cognitively driven', and stems from dorsal frontostriatal dysfunction. We discuss this evidence in view of clinically relevant questions and implications for illness based intervention. We conclude that the reward-related mechanisms underlying the interactions between executive function, behavior regulation and impulsivity in PBD and ADHD may be differentially compromised, and in accordance differently shape the clinical symptoms of impulsivity and goal-directed behavior. PMID- 21651341 TI - Disinfection of radish and alfalfa seeds inoculated with Escherichia coli O157:H7 and Salmonella by a gaseous acetic acid treatment. AB - Abstract The majority of seed sprout-related outbreaks have been associated with Escherichia coli O157:H7 and Salmonella. Therefore, we aimed to find an effective method to inactivate these organisms on seeds before sprouting. Treatment with 8.7% (v/v) acetic acid at 55 degrees C for 2-3 h reduced the population of E. coli O157:H7 and Salmonella inoculated on alfalfa (Medicago sativa L.) and radish seeds (Raphanus sativus L.) by more than 5.0 log CFU/g, and a longer treatment time completely eliminated the E. coli O157:H7 population. The E. coli O157:H7 populations were reduced to an undetectable level with a gaseous acetic acid treatment for 48 h. After enrichment, no E. coli O157:H7 were found in the alfalfa and radish seeds (25 g). However, these treatments were unable to eliminate Salmonella in both seed types. No significant difference between the germination rates of treated alfalfa seeds and control seeds was found, and germination rates greater than 95% were obtained for the radish seeds. Although chlorine washing is commonly used for seed decontamination, chlorine washing at 200 and 20,000 ppm resulted in a reduction of pathogens by less than or equal to 3 log CFU/g. Therefore, these results suggested that gaseous acetic acid is more effective than chlorine washing in controlling pathogenic bacteria on sprout seeds. PMID- 21651342 TI - Work-life balancing: challenges and strategies. AB - BACKGROUND: Balancing the personal and the professional is an ongoing struggle for most professionals, and palliative care clinicians are no exception. A sustained lack of balance can lead to feelings of frustration, inadequacy, and guilt. Palliative care physicians may find this balance particularly difficult due to the nature of their work: caring for patients and families who are often suffering and in crisis. DISCUSSION: In this article, we describe challenges to work-life balancing and strategies that may promote balance, including "timeshifting," goal setting, cognitive reframing, and self-care. We argue that the search for balance is a lifelong endeavor that entails self-reflection and continuing examination of one's values and goals. PMID- 21651343 TI - Classification of cell signalling in tissue development. AB - The traditional classification of signalling in biological systems is insufficient and outdated and novel efforts must take into account advances in systems theory, information theory and linguistics. We present some of the classification systems currently used both within and outside of the biological field and discuss some specific aspects of the nature of signalling in tissue development. The analytical methods used in understanding non-biological networks provide a valuable vocabulary, which requires integration and a system of classification to further facilitate development. PMID- 21651344 TI - Endothelin-1 attenuates the hemodynamic response to exogenous epinephrine in a porcine ischemic ventricular fibrillation cardiac arrest model. AB - Endothelin-1 (ET-1) increases in the ischemically induced ventricular fibrillation (VF) swine model of cardiac arrest and affects outcome by potentially attenuating the hemodynamic response to epinephrine. Fifty-one swine underwent percutaneous left anterior descending occlusion. Seven minutes postonset of ischemic VF, cardiopulmonary resuscitation (CPR) was initiated. If VF persisted after 3 shocks, 1 mg of epinephrine was given. ET-1 (collected at baseline and every 5 min until VF onset) was assayed with ELISA. Bayesian multivariate logistic regression analysis compared peak ET-1 levels with the binary outcome of a positive coronary perfusion pressure response of >20 mmHg following epinephrine. Sixteen animals (31%) failed to achieve a positive response. Restoration of spontaneous circulation (ROSC) was observed in 1/16 (6.3%) of epinephrine nonresponders and 20/35 (57.1%) of epinephrine responders (P = 0.0006). The median peak ET-1 level was 2.71 pg/mL [interquartile range (IQR) 1.06-4.40] in nonresponders and 1.69 pg/mL (IQR 0.99-2.35) in responders. ET-1 levels were inversely associated with epinephrine response with a median posterior odds ratio (OR) of a coronary perfusion pressure response of 0.72 (95% confidence interval [CI] 0.48-1.06) for each one-unit increase in ET-1 and a probability that the associated OR is <1 of 0.95. Peak ET-1 levels predict a lack of a hemodynamic response to epinephrine during treatment of cardiac arrest during ischemic VF. PMID- 21651345 TI - End points in irritable bowel syndrome. PMID- 21651347 TI - Linaclotide, a synthetic guanylate cyclase C agonist, for the treatment of functional gastrointestinal disorders associated with constipation. AB - Chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C) are two functional gastrointestinal disorders that are associated with constipation. CC and IBS-C affect approximately 20% of the general population including the elderly, impairing quality of life. Patients not responding to over the-counter treatments require effective and safe long-term therapies. Some treatments introduced in the last decade have been associated with side effects that led to withdrawal from the US market (e.g., tegaserod) or intolerance to treatment (e.g., nausea in patients treated with lubiprostone). Linaclotide is a novel drug, with a unique mechanism of action, low bioavailability and local action in the intestinal epithelial cells. It is currently being developed for patients with CC and IBS-C. From animal studies to human pharmacodynamic Phase Ib trials, and a comprehensive program of Phase IIb and III trials in health and disease, linaclotide demonstrates long-term efficacy and safety in CC and IBS-C. PMID- 21651348 TI - Update on Crohn's disease and ulcerative colitis. AB - The 6th European Crohn's and Colitis Organisation Congress took place in Dublin, Ireland, on the occasion of the 10th European Crohn's and Colitis Organisation anniversary. This key annual event attracted a record number of participants and presented updated information in the field of inflammatory bowel disease in children and adults. The extensive program combined the original basic scientific program that dealt with pathogenesis and new therapeutic targets, while the clinical program focused on the possibility of optimizing current therapies, the importance of mucosal healing and features of inflammatory bowel disease-related cancer. PMID- 21651349 TI - IL-15 modulates the effect of retinoic acid, promoting inflammation rather than oral tolerance to dietary antigens. AB - The physiological immune response in the intestine against dietary proteins and commensal flora is characterized by regulatory mechanisms (tolerance) that prevent harmful consequences. Intestinal dendritic cells (DCs) have a central role in the development of immunosuppressive regulatory T cells owing to their ability to produce TGF-beta and retinoic acid (RA). However, the article under evaluation shows an unexpected effect of RA - that of promoting a proinflammatory phenotype in intestinal DCs involved in the generation of inflammatory immune responses to dietary antigens. By using a double transgenic murine model that resembles human celiac disease, it was demonstrated that RA synergizes with IL-15 in promoting the breakdown of gluten tolerance and the development of enteropathy. The tissue microenvironment modulates DC function, and immune therapies that are based on RA aiming to restore oral tolerance should be used with caution because the presence of IL-15 (and/or other proinflammatory cytokines) may have undesirable effects. PMID- 21651350 TI - Probiotic-mediated modulation of host inflammation. AB - Although much has become known about the pathogenesis of inflammatory bowel disease (IBD), our understanding remains incomplete. As a consequence, IBD conditions are chronic debilitating states without cure. A recent study elegantly describes a mechanism by which host inflammatory responses can be modulated and modified. A series of in vitro and in vivo studies, employing complementary animal models of gut inflammation, illustrates how modification of cell surface molecules on a probiotic bacterium can influence host innate immune responses and, as a result, alter inflammatory events. The article under evaluation provides important new information on the mechanisms by which specific probiotic organisms may be able to be attenuate gut inflammation in individuals with IBD. PMID- 21651351 TI - Treatment of special populations with chronic hepatitis B infection. AB - All therapeutic agents that are currently in use for the treatment of chronic hepatitis B have been administered to a large number of patients in clinical trials in order to be approved as efficacious and safe. Nevertheless, in these trials, many patients have been excluded either because they have decompensated cirrhosis, or they belong to groups with comorbidities that can seriously affect the underlying liver disease, or where the treatment for chronic hepatitis B virus infection can be contraindicated. Such groups of patients are those with hepatitis D virus, hepatitis C virus and HIV coinfections, patients who have undergone transplantation or are immunosuppressed due to chemotherapy or other treatment, patients with end-stage renal disease under dialysis, acute and fulminant hepatitis B and also, children and pregnant women. In this article, all of the aspects of treatment of these special categories are discussed, since for many of these patients, treatment is of a greater importance compared with the standard patient with chronic hepatitis B, and in real life they represent a great percentage of chronic hepatitis B virus infection patients. PMID- 21651352 TI - Animal models in the study of hepatitis C virus-associated liver pathologies. AB - It is estimated that more than 170 million individuals worldwide are chronically infected with hepatitis C virus (HCV), with approximately 20% of the cases developing cirrhosis. Each year, between 1 and 4% of patients exhibiting cirrhosis develop hepatocellular carcinoma. Chronic HCV infection is also linked with the development of several metabolic disorders, including hepatic steatosis and insulin resistance. Research into HCV-related pathologies is hampered by a relative paucity of small animal models. As a result, little is known about the molecular mechanisms involved, and much of our current knowledge is drawn by inference from in vitro studies using overexpressed proteins. In this article, we will review the currently available animal models for the study of HCV pathogenesis, with an emphasis on murine models. Then, we will provide an overview of how these models have contributed to the deciphering of the molecular mechanisms underlying dysregulated lipid metabolism and hepatocellular carcinoma during HCV infection. PMID- 21651353 TI - The role of hepatocyte-specific staining in liver pathology. AB - The advantages of MRI in the investigation of liver disease are well documented. Recent developments, including fast scanning technique and new MRI contrast agents, enable improved detection and characterization of focal liver lesions. Therefore, a definitive diagnosis can be made avoiding invasive procedures, such as liver biopsy. In this article, a special emphasis is placed on the clinical use of combined perfusional and hepatocyte-selective MRI contrast agents, which allow us to obtain morphologic and vascular information, owing to the dynamic study, as well as functional information, owing to the hepatocyte-selective phase of enhancement. Different clinical scenarios are considered in order to highlight the proper use of the hepatocyte phase to noninvasively characterize and detect different focal liver lesions. PMID- 21651354 TI - Rising incidence and demographics of hepatocellular carcinoma in the USA: what does it mean? AB - The incidence of hepatocellular carcinoma (HCC) is increasing in the USA. Traditional factors, such as hepatitis C and hepatitis B, along with new emerging trends suggest that the incidence is not only increasing, but is also likely to be under-represented in the current literature. Emerging knowledge of its incidence and epidemiology reflects an increased incidence in younger patients and certain ethnic groups. Without a clear treatment algorithm for this complex cancer, therapy and its utilization remain unclear. PMID- 21651355 TI - Risk of lymph node metastasis in submucosal esophageal cancer: a review of surgically resected patients. AB - OBJECTIVES: Endoscopic local procedures are increasingly applied in patients with superficial esophageal cancer as an alternative to radical oncologic resection. The objective of this article is to determine the risk of nodal metastases in submucosal (sm) esophageal cancer, comparing the two predominating histologic tumor types, squamous cell cancer (SCC) and adenocarcinoma (ADC). METHODS: A query of PubMed, MEDLINE, Embase and Cochrane Library (1980-2009) using predetermined search terms revealed 675 abstracts, of which 485 full-text articles were reviewed. A total of 105 articles met the selection criteria. A review of article references and consultation with experts revealed additional articles for inclusion. Studies that enrolled patients with submucosal esophageal cancer and provided adequate extractable data were included. RESULTS: The pooled outcomes of 7645 patients with esophageal cancer involving the sm level of infiltration were included in the analysis. Overall, the percentage of lymph node metastasis in submucosal cancer was 37%. Lymph node (N), lymphatic (L) and vascular (V) invasion in sm1 esophageal cancers was 27, 46 and 22%, respectively. Within sm2 lesions, N, L and V invasion were involved in 38, 63 and 38% of patients, respectively. Finally, N, L and V involvement in patients with sm3 lesions was 54, 69 and 47%, respectively. The rates of lymph node metastasis for sm1 and sm2 were higher in SCC compared with ADC, whereas the lymph node metastasis for sm3 was comparable, with >50% involvement in both histologic subtypes. SCC revealed an overall more aggressive behavior compared with ADC (N+: 45 vs 26%; L+: 57 vs 37%; V+: 40 vs 18%). DISCUSSION: While endoscopic therapy may be adequate in selected patients with 'low-risk' sm1 ADC, submucosal SCC necessitates esophageal resection and systematic lymphadenectomy because of its aggressive nature and tendency for early metastasis. PMID- 21651356 TI - Microsatellite instability in the management of colorectal cancer. AB - Microsatellite instability (MSI) is a form of genetic instability caused by alterations in the DNA mismatch repair system. Approximately 15% of colorectal cancers display MSI due to a germline mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) or to epigenetic silencing of MLH1. Colorectal cancers with MSI have distinctive features, including a tendency to arise in the proximal colon, poor differentiation, lymphocytic infiltration and mucinous or signet-ring histology. Patients with MSI tumors appear to have a better prognosis than those with microsatellite stable tumors, but curiously the responses to 5 fluorouracil-based chemotherapy regimens are poorer with MSI tumors. Preliminary data suggest possible advantages of irinotecan-based regimens, but these findings need validation in well-designed clinical trials. PMID- 21651357 TI - Inflammatory bowel disease: beyond the boundaries of the bowel. AB - Dysregulated inflammation in the gut, designated clinically as inflammatory bowel disease (IBD), is manifested by the prototypic phenotypes of an Arthus-like reaction restricted to the mucosa of the colon, as in ulcerative colitis, or a transmural granulomatous reaction, as in Crohn's disease, or an indeterminate form of the two polar types. That the inflammation of IBD can trespass the boundaries of the bowel has long been known, with articular, ophthalmologic, cutaneous, hepatobiliary or other complications/associations - some autoimmune and others not - affecting significant numbers of patients with IBD. Also notable is the frequency of diagnosis of IBD-type diseases on a background of systemic, (mostly myelo-hematological) disorders, associated with alterations of either (or both) innate or adaptive arms of the immune response. Finally, cases of IBD are reported to occur as an adverse effect of TNF inhibitors. Bone marrow transplant has been proven to be the only curative measure for some of the above cases. Thus, in effect, the IBDs should now be regarded as a systemic, rather than bowel localized, disease. Genome-wide association studies have been informative in consolidating the view of three phenotypes of IBD (ulcerative colitis, Crohn's disease and mixed) and, notably, are revealing that the onset of IBD can be linked to polymorphisms in regulatory miRNAs, or to nucleotide sequences coding for regulatory lymphokines and/or their receptors. At the effector level, we emphasize the major role of the Th17/IL-23 axis in dictating the perpetuation of intestinal inflammation, augmented by a failure of physiological control by regulatory T-cells. In conclusion, there is a central genesis of the defects underlying IBD, which therefore, in our opinion, is best accommodated by the concept of IBD as more of a syndrome than an autonomous disease. This altered mindset should upgrade our knowledge of IBD, influence its medical care and provide a platform for further advances. PMID- 21651358 TI - Existing dietary guidelines for Crohn's disease and ulcerative colitis. AB - Patients with inflammatory bowel disease (IBD) often question their doctors about diet. The objectives of this article are to provide clinicians with existing dietary advice by presenting the dietary information proposed by medical societies in the form of clinical practice guidelines as it relates to IBD; listing dietary guidelines from patient-centered IBD-related organizations; and creating a new 'global practice guideline' that attempts to consolidate the existing information regarding diet and IBD. The dietary suggestions derived from sources found in this article include nutritional deficiency screening, avoiding foods that worsen symptoms, eating smaller meals at more frequent intervals, drinking adequate fluids, avoiding caffeine and alcohol, taking vitamin/mineral supplementation, eliminating dairy if lactose intolerant, limiting excess fat, reducing carbohydrates and reducing high-fiber foods during flares. Mixed advice exists regarding probiotics. Enteral nutrition is recommended for Crohn's disease patients in Japan, which differs from practices in the USA. PMID- 21651361 TI - Only one thing you can do when they're "all dead". PMID- 21651362 TI - Medication errors in a specialist palliative care unit. PMID- 21651363 TI - He is very old and he will die anyway .... PMID- 21651364 TI - Post herpetic neuralgia. AB - BACKGROUND: During the past decade, important advances have been made in understanding the epidemiology, pathogenesis, prevention and treatment of post herpetic neuralgia pain as well as treatment of other neuropathic pain conditions. PHN is accepted as a model for management and clinical trials of neuropathic pain of less clear etiologies. In palliative medicine, where the etiology of pain may be nociceptive, neuropathic, or mixed, it is frequently to the research on PHN that we turn in order to extrapolate the data to the patients at hand. OBJECTIVE: To review and summarize what is known about epidemiology, pathogenesis, clinical features and prevention strategies for post herpetic neuralgia. Discuss the available including the most recent therapeutic options as regards to their mechanism of action, efficacy, safety and tolerability in an attempt to explain the rationale for their use. CONCLUSION: A multidisciplinary and integrative approach has the best chance of success in the management of patients with PHN pain, a problem that can be often frustrating to the patient and challenging to the clinician. Prevention strategies for PHN include administration of zoster vaccine, treatment with antiviral therapy within 72 hours of rash onset and aggressive pain control. First and second line pharmacotherapy include anticonvulsants, antidepressants, topical lidocaine, high dose capsaicin, and opioids either used individually or in combination. Interventional techniques play a limited role in the management of PHN although some data indicate that Intrathecal methylprednisolone and spinal cord stimulation may be effective. PMID- 21651365 TI - Teaching communication skills: remembering what it is like to be a novice. PMID- 21651366 TI - Teaching communication skills using role-play: an experience-based guide for educators. AB - Teaching advanced communication skills requires educators who are not only excellent communicators themselves but have the ability to deconstruct the components of the interaction and develop a cognitive approach that can be used across a variety of learners, diverse content, and under different time constraints while helping the learner develop the skill of self-reflection in a 'safe' and effective learning environment. The use of role-play in small groups is an important method to help learners cultivate the skills required to engage in nuanced, often difficult conversations with seriously ill patients. To be effective, educators utilizing role-play must help learners set realistic goals and know when and how to provide feedback to the learners in a way that allows a deepening of skills and a promotion of self-awareness. The challenge is to do this in a manner that does not cause too much anxiety for the learner. In this article we outline an approach to teaching communication skills to advanced learners through the use of different types of role-play, feedback, and debriefing. PMID- 21651367 TI - Screening for intensive care unit delirium #160. PMID- 21651368 TI - Prognostication in severe traumatic brain injury in adults #239. PMID- 21651369 TI - The intern experience: facing death. PMID- 21651370 TI - What to hope for? PMID- 21651371 TI - Do not disturb. PMID- 21651372 TI - The anatomy of a decision. PMID- 21651376 TI - Adrenoleukodystrophy patient perspective: turning despair into a gene therapy breakthrough. PMID- 21651377 TI - Safety of bovine sera for production of mesenchymal stem cells for therapeutic use. PMID- 21651380 TI - Splenectomy influences homing of transplanted stem cells in bone marrow-ablated mice. AB - Cell mobilization, a process that influences circulation, margination, and finally, homing play key roles in the regeneration processes mediated by stem cells. Recent studies as well as prior studies from our group indicate an important role of the spleen in hematopoietic reconstitution, but to date the role of the spleen in hematopoietic reconstitution has been unclear and it has not been precisely documented in ablated animals. Therefore, we undertook the present study to define more closely the role of the spleen in hematopoietic reconstitution in lethally irradiated mice. After transplantation of irradiated mice with lacZ+ -marked lin- / CD117+ bone marrow cells, we compared splenectomized mice (T(S), splenectomy performed prior to irradiation) to nonsplenectomized, irradiated mice (T(N)) as well as to normal (unirradiated) mice. Impaired hematopoietic reconstitution was observed in T(S) mice. Splenectomy markedly altered the distribution of hematopoietic stem cells, as demonstrated by fluorescence-activated cell sorting analysis of endogenous CD117+ cells in the thymus and bone marrow of recipients. Cell engraftment was demonstrated by histochemical and polymerase chain reaction analyses of recipient tissues. These experiments demonstrated that in T(S) animals, transplanted hematopoietic stem cells mobilized to extravascular tissues, particularly the gastrointestinal tract. The number of donor cells in recipient tissues continued to increase for 30 days after transplantation with the highest numbers observed in the T(S) group. DNA marking analysis led to the conclusion that engrafted cells were not only integrated into recipient tissues but were also capable of performing complex cellular processes, including proliferation and repair. Our results are consistent with the novel possibility that cellular repair markedly affects stem cell regenerative functions and that repair is markedly influenced by the integrity and presence of organs not directly involved in specific tissue regeneration processes, particularly the spleen. PMID- 21651381 TI - The power and the promise of liver cancer stem cell markers. AB - Recently, there has been growing support for the cancer stem cell (CSC) hypothesis, which states that primary tumors are initiated and maintained by a small subpopulation of cancer cells that possess "stem-like" characteristics. CSCs have been identified in many tumor types, including hepatocellular carcinoma (HCC). The dye, Hoechst 33342, has been used to enrich CSCs into a side population. Alternatively, liver CSCs (LCSCs) can be identified by several cell surface antigens, including CD133, CD90, CD44, EpCAM, and CD13. In this review, we summarized the recent evidence regarding LCSC markers and discussed the origin and function of these markers. LCSC markers are essential to identify and isolate these cells, to develop future therapies targeting CSCs, and to predict prognosis and efficacy of these therapies. However, definite LCSC markers are still controversial, because none of these markers is exclusively expressed by LCSCs in HCC. By combining several positive or negative markers, it may be possible to isolate and identify CSC fractions beyond the ability of each individual assay. By grouping LCSC markers according to their cellular origin, the properties of LCSC markers may be better studied and new markers may be found. Lastly, markers could be used to estimate the number of LCSCs and therefore predict outcomes. From our point of view, selecting HCC tissue samples from patients with different prognoses and detecting expression patterns of marker combinations may be a new method to identify new and unique markers. PMID- 21651382 TI - A series of systematic reviews on the treatment of acute spinal cord injury: a foundation for best medical practice. AB - The treatment of acute spinal cord injury (SCI) is a multidisciplinary effort that spans from the time of injury through to an acute care center, and in some cases the remainder of the individual's life. Recovery from SCI depends on the care received at each point along this spectrum in time. In order to facilitate the practice of evidence-based medicine and best clinical practices, a multidisciplinary team of clinicians and researchers systematically reviewed the literature on SCI and set out to answer pertinent clinical questions and establish evidence-based recommendations. This article introduces the series of systematic reviews, summarizes the most notable findings, and gives an overview of the questions asked in each review and the evidence-based recommendations for care. Some of the most important recommendations are as follows: (1) Patients should be immobilized before transport to a hospital using a cervical collar, head immobilization, and a spinal board; (2) MRI is strongly recommended for the prognostication of acute SCI; (3) early surgical intervention (from 8-24 h) should be considered following acute traumatic SCI; (4) SCI patients are at significant risk of cardiovascular and respiratory problems and management should proactively anticipate these potential complications; and (5) outcomes can be improved by management in specialized centers with access to intensive care. PMID- 21651383 TI - Likelihood of tetraplegia after CT clearance of the cervical spine in obtunded blunt trauma patients. PMID- 21651385 TI - Photodynamic therapy reduces bone resorption and decreases inflammatory response in an experimental rat periodontal disease model. AB - OBJECTIVE: The purpose of the present study was to analyze inflammatory conditions after application of photodynamic therapy (PDT) in the gingival tissues of Wistar rats with ligature-induced periodontal disease. BACKGROUND DATA: The work investigated the effectiveness of PDT in decreasing the inflammatory response, in order to avoid bone loss. METHODS: Ligatures were positioned at the mandibular first molar of rats (n=6). After 7 days the ligatures were removed and the animals were divided into two groups, one of which received eosin, with both groups subsequently being treated by light-emitting diode irradiation. The animals were killed 7 days after the treatments, and the mandibles were histologically processed (hematoxylin and eosin stain) to assess bone loss, while gingival tissues were removed for quantification of neutrophil infiltration (using the myeloperoxidase assay) and tumor necrosis factor (TNF)-? expression (by ELISA). RESULTS: Histomorphological analysis of periodontal tissues demonstrated that PDT-treated animals presented decreased bone resorption, as well as reduced neutrophil migration and lower TNF-? expression, compared to ligatured animals treated with eosin alone. CONCLUSIONS: Within the limitations of this study, it can be concluded that PDT may be useful in the treatment of periodontal disease, because of immunomodulatory effects that decrease the inflammatory response and consequently the bone resorption. PMID- 21651384 TI - Amphetamine-enhanced motor training after cervical contusion injury. AB - Individually, motor training, pharmacological interventions, and housing animals in an enriched environment (EE) following spinal cord injury (SCI) result in limited functional improvement but, when combined, may enhance motor function. Here, we tested amphetamine (AMPH)-enhanced skilled motor training following a unilateral C3-C4 contusion injury on the qualitative components of reaching and on skilled forelimb function, as assessed using single-pellet and staircase reaching tasks. Kinematic analysis evaluated the quality of the reach, and unskilled locomotor function was also tested. Animals receiving AMPH and skilled forelimb training performed better than operated control animals on qualitative reaching, but not on skilled reaching. Those that received the combination treatment and were housed in EE cages showed significantly less improvement in qualitative reaching and grasping. Kinematic analysis revealed a decrease in digit abduction during skilled reaching among all groups, with no differences among groups. Kinematics provided no evidence that improved function was related to improved quality of reach. There was no evidence of neuroprotection in the cervical spinal cord. The absence of evidence for kinematic improvement or neuroprotection suggested that AMPH-enhanced motor training is due primarily to supraspinal effects, an enhancement of attention during skilled motor training, or plasticity in supraspinal circuitry involved with motor control. PMID- 21651386 TI - Prevalence of sinus augmentation associated with maxillary posterior implants. AB - Pneumatization of the maxillary sinus limits the quantity of alveolar bone available for implant placement and may result in a lack of primary stability and difficulty in achieving osseointegration. The purpose of this study was to retrospectively analyze a group of patients who had implants placed in the posterior maxilla, calculate the prevalence of sinus augmentation, and identify factors related to sinus augmentation. With institutional review board approval, dental records from a population of patients who had implants placed in the maxillary posterior region between January 2000 and December 2004 were used to create a database. Independent variables were classified as continuous (age of the patient at stage 1 implant surgery [S1], time between extraction and S1, time between extraction and sinus augmentation, and time between sinus augmentation and S1) and categorical (gender, implant failure, American Society of Anesthesiologists system classification, smoking, osteoporosis, residual crestal bone height, implant position, implant proximity, prostheses type, and implant diameter and length). The dependent variable was the incidence of a sinus augmentation procedure. Simple logistic regression was used to assess the influence of each factor on the presence of sinus augmentation (P < .05). The final database included 502 maxillary posterior implants with an overall survival rate of 93.2% over a mean follow-up period of 35.7 months. Of 502 implants, 272 (54.2%) were associated with a sinus augmentation procedure. Among variables, residual crestal bone height (P < .001), implant position (P < .001), implant proximity (P < .001), prosthesis type (P < .001), implant failure (P < .01), and implant diameter (P < .01), were statistically associated with sinus augmentation. Within the limitations of this retrospective study, the results suggest that more than half (54.2%) of the maxillary posterior implants were involved with a sinus augmentation procedure. The prevalence of sinus augmentation increased with decreased residual crestal bone height, more posterior implant locations, and complete or partial edentulism. Sinus augmentation was significantly associated with implant failure and wide implants. PMID- 21651387 TI - Medicaid and access to health care--a proposal for continued inaction? PMID- 21651388 TI - New FDA regulation to improve safety reporting in clinical trials. PMID- 21651389 TI - Images in clinical medicine. Pseudoverrucous papules. PMID- 21651390 TI - Going horizontal--shifts in funding of global health interventions. PMID- 21651391 TI - Survivors--dialysis, immigration, and U.S. law. PMID- 21651392 TI - Immediate versus delayed IUD insertion after uterine aspiration. AB - BACKGROUND: Intrauterine devices (IUDs) provide highly effective, reversible, long-term contraception that is appropriate for many women after first-trimester uterine aspiration. However, the effects of immediate versus delayed IUD insertion after uterine aspiration on rates of complications and IUD use are uncertain. METHODS: We performed a randomized noninferiority trial involving women undergoing uterine aspiration for induced or spontaneous abortion at 5 to 12 weeks of gestation who desired an IUD. Subjects were randomly assigned (in a 5:6 ratio) to IUD insertion immediately after the procedure or 2 to 6 weeks afterward (delayed insertion). The primary outcome was the rate of IUD expulsion 6 months after IUD insertion; an expulsion rate 8 percentage points higher in the immediate-insertion group was defined as inferior. RESULTS: Among 575 women who underwent randomization, an IUD was inserted in 100% (258 of 258) of the women in the immediate-insertion group and in 71.3% (226 of 317) of those in the delayed insertion group (difference, 28.7 percentage points; 95% confidence interval [CI], 23.7 to 33.7). The 6-month expulsion risk was 5.0% (13 of 258 women) after immediate insertion and 2.7% (6 of 226) after delayed insertion (difference, 2.3 percentage points; 95% CI, -1.0 to 5.8), which was consistent with the predefined criterion for noninferiority. Six-month rates of IUD use were higher in the immediate-insertion group (92.3%, vs. 76.6% after delayed insertion; P<0.001). Adverse events were rare and did not differ significantly between groups. No pregnancies occurred in the immediate-insertion group; five occurred in the delayed-insertion group (P=0.07), all in women who never received an IUD. CONCLUSIONS: The 6-month rate of expulsion of an IUD after immediate insertion was higher than but not inferior to that after delayed insertion. Immediate insertion resulted in higher rates of IUD use at 6 months, without an increased risk of complications. (Funded by the Susan Thompson Buffett Foundation; ClinicalTrials.gov number, NCT00562276.). PMID- 21651393 TI - Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. AB - The skeletal dysplasia characteristic of acrodysostosis resembles the Albright's hereditary osteodystrophy seen in patients with pseudohypoparathyroidism type 1a, but defects in the alpha-stimulatory subunit of the G-protein (GNAS), the cause of pseudohypoparathyroidism type 1a, are not present in patients with acrodysostosis. We report a germ-line mutation in the gene encoding PRKAR1A, the cyclic AMP (cAMP)-dependent regulatory subunit of protein kinase A, in three unrelated patients with acrodysostosis and resistance to multiple hormones. The mutated subunit impairs the protein kinase A response to stimulation by cAMP; this explains our patients' hormone resistance and the similarities of their skeletal abnormalities with those observed in patients with pseudohypoparathyroidism type 1a. PMID- 21651394 TI - Clinical practice. Mild cognitive impairment. PMID- 21651395 TI - Franklin H. Epstein Lecture: Sirtuins, aging, and medicine. PMID- 21651396 TI - Images in clinical medicine. Calcinosis cutis in systemic sclerosis. PMID- 21651397 TI - Case records of the Massachusetts General Hospital. Case 17-2011. A 49-year-old woman with a mass in the breast and overlying skin changes. PMID- 21651398 TI - Olmesartan, microalbuminuria, and type 2 diabetes. PMID- 21651399 TI - Olmesartan, microalbuminuria, and type 2 diabetes. PMID- 21651400 TI - Olmesartan, microalbuminuria, and type 2 diabetes. PMID- 21651401 TI - Olmesartan, microalbuminuria, and type 2 diabetes. PMID- 21651403 TI - Intensive glucose lowering and cardiovascular outcomes. PMID- 21651404 TI - Intensive glucose lowering and cardiovascular outcomes. PMID- 21651406 TI - Long-acting risperidone and oral antipsychotics in schizophrenia. PMID- 21651407 TI - Long-acting risperidone and oral antipsychotics in schizophrenia. PMID- 21651410 TI - Combating environmental causes of cancer. PMID- 21651409 TI - Combating environmental causes of cancer. PMID- 21651412 TI - Drugs and pheochromocytoma--don't be fooled by every elevated metanephrine. PMID- 21651414 TI - Genotoxicity of endosseous implants using two cellular lineages in vitro. AB - The genotoxic potential of corrosion eluates obtained from a single dental implant using murine fibroblasts or osteoblasts cells in vitro by the single-cell gel (comet) assay was examined. A single commercially available dental implant (Biotechnology) was eluted in a solution consisting of equal amounts of acetic acid and sodium chloride (0.1 M) for 1, 3, 7, 14, and 21 days. Murine fibroblast or osteoblast cultures were then exposed to all corrosion eluates obtained from endosseous dental implants for 30 minutes at 37 degrees C. The results suggest that none of the eluates produced genotoxic changes in murine fibroblasts regardless of the length of exposure to the eluate. Similarly, no genotoxicity was found in osteoblasts. The results suggest that the dental implant eluates tested in this study did not induce genetic damage as depicted by the single-cell gel (comet) assay. Because DNA damage is an important event during oncogenesis, this study represents a relevant contribution to estimate the real risks to the cellular system induced by the corrosion products of a dental implant. PMID- 21651415 TI - A pig model for the histomorphometric evaluation of hard tissue around dental implants. AB - This study aimed to evaluate the frontal bone of Swiss Domestic pigs as an animal model for the histologic-histomorphometric examination of bony tissue around dental implants. We inserted SLA surface implants 4.1 mm in diameter and 10 mm in length into the frontal bones of 9 Swiss-Domestic pigs. Histologic and histomorphometric studies were conducted on the undecalcified sections. Histologic examinations showed that the specimens contain a sufficient amount of bone to provide homogenous bone coverage for standard diameter dental implant placement. The mean bone to implant contact was 61.9% +/- 8.7%. Other histomorphometric parameters revealed the regular trabecular architecture at this site. Pigs' frontal bone appears to be a suitable animal model in short-term dental implant studies because it provides a sufficient amount of bone and favorable bone microarchitecture. PMID- 21651416 TI - A functional open-tray impression technique for implant-retained overdenture prostheses. AB - Several implant impression techniques with different materials have been described in the literature. Generally, border molding, functional, and final impressions have been made with 3 different materials, which makes the procedure technique-sensitive and time-consuming. A combination of open-tray and functional impression techniques is described in this technical report. Border molding and functional impression procedures are made at the same time using a vinyl polysiloxane impression material, which makes this technique a simple and time efficient alternative for clinicians. PMID- 21651417 TI - Gratifications, collective self-esteem, online emotional openness, and traitlike communication apprehension as predictors of Facebook uses. AB - This study explores whether and how gratifications and psychological traits impact people's Facebook use. First, a factor analysis of an online survey (N= 437) outlined a unique set of gratifications obtained from the use of Facebook. Six aspects of gratifications (i.e., social surveillance, entertainment, recognition, emotional support, network extension, and maintenance) were identified. Results from regression analyses showed that psychological traits (i.e., collective self-esteem, online emotional openness, and traitlike communication apprehension) were strong predictors of most Facebook gratifications. Additionally, gratifications and, to a lesser extent, psychological traits significantly predicted Facebook usage, both in perceived importance and different indicators in the level of Facebook use. PMID- 21651418 TI - Prevalence and psychosocial risk factors associated with internet addiction in a nationally representative sample of college students in Taiwan. AB - The aim of this study was to examine the prevalence of Internet addiction in a nationally representative sample of college students and to identify any associated psychosocial risk factors. The present study was constructed using a cross-sectional design with 3,616 participants. Participants were surveyed during the middle of the spring and fall semesters and recruited from colleges around Taiwan using stratified and cluster random sampling methods. Associations between Internet addiction and psychosocial risk factors were examined using stepwise logistic regression analysis. The prevalence of Internet addiction was found to be 15.3 percent (95 percent confidence interval, 14.1 percent to 16.5 percent). More depressive symptoms, higher positive outcome expectancy of Internet use, higher Internet usage time, lower refusal self-efficacy of Internet use, higher impulsivity, lower satisfaction with academic performance, being male, and insecure attachment style were positively correlated with Internet addiction. The prevalence of Internet addiction among college students in Taiwan was high, and the variables mentioned were independently predictive in the logistic regression analysis. This study can be used as a reference for policy making regarding the design of Internet addiction prevention programs and can also aid in the development of strategies designed to help Internet-addicted college students. PMID- 21651419 TI - A controlled trial of an internet-based intervention program for cannabis users. AB - In the last decade, several programs for the treatment of cannabis-related disorders were developed. Until now, no information is available on the efficacy of Internet-based counseling approaches for this target group. This article describes the evaluation of "quit the shit," a web-based intervention developed to help young people to quit or reduce their cannabis use significantly. Cannabis users seeking web-based treatment were included in a two-arm controlled trial conducted on a website for drug-related information and prevention. After the baseline assessment, members of the treatment condition were randomized to a 50 day intervention program. Other trial participants were put on a waiting list. A post-test was conducted 3 months after randomization. Of all 1,292 subjects included in the trial, a total of 206 participants took part at the post-test. Per-protocol- and intention-to-treat analyses were conducted. Members of the treatment condition showed a significantly stronger reduction in cannabis use (primary outcome) than the control group. In the per-protocol analyses, moderate to-strong effects were found for the reduction of the frequency and the reduction of the quantity of consumed cannabis. Small-to-moderate effects were observed on the secondary outcomes (use-related self-efficacy, anxiety, depression, and life satisfaction). Despite limitations concerning the interpretation of the results, the intervention seems to offer an effective treatment option for persons with cannabis-related problems. PMID- 21651420 TI - Isolation and biological characteristics of chicken adipose-derived progenitor cells. AB - Adipose-derived stem cells/adipose-derived progenitor cells (ADPCs) are multipotent stem cells that can differentiate in vitro into many cell types. However, the vast majority of experimental materials were obtained from human, mouse, rabbit, and other mammals but rarely from poultry. In this study, ADPCs were isolated from 1-day-old chicks. Primary ADPCs were subcultured to passage 15. The surface markers of ADPCs, CD29, CD44, CD71, and CD73, were detected by immunofluorescence and RT-polymerase chain reaction assays. The growth curves of different passages were all typically sigmoidal. In addition, ADPCs of different passages were successfully induced to differentiate into osteoblasts, adipocytes, and myocardial cells. The results suggest that the ADPCs isolated from chicken possess similar biological characteristics with those derived from other species, and their multilineage differentiation provides many potential applications. PMID- 21651421 TI - For whom and under what circumstances do school-based energy balance behavior interventions work? Systematic review on moderators. AB - The aim of this review was to systematically review the results and quality of studies investigating the moderators of school-based interventions aimed at energy balance-related behaviors. We systematically searched the electronic databases of Pubmed, EMBASE, Cochrane, PsycInfo, ERIC and Sportdiscus. In total 61 articles were included. Gender, ethnicity, age, baseline values of outcomes, initial weight status and socioeconomic status were the most frequently studied potential moderators. The moderator with the most convincing evidence was gender. School-based interventions appear to work better for girls than for boys. Due to the inconsistent results, many studies reporting non-significant moderating effects, and the moderate methodological quality of most studies, no further consistent results were found. Consequently, there is lack of insight into what interventions work for whom. Future studies should apply stronger methodology to test moderating effects of important potential target group segmentations. PMID- 21651422 TI - Medial midfoot fat pad thickness and plantar pressures: are these related in children? AB - OBJECTIVE: Previous research has shown that obese children have thicker plantar fat pads compared to non-obese children. As it is uncertain how this thickness influences dynamic foot function, this study aimed to investigate the relationship between dynamic plantar pressures generated beneath the feet of school-aged children and their medial midfoot fat pad thickness measures. METHODS AND PROCEDURES: Height and weight were measured, and BMI calculated, for 252 children aged 6.0-9.9 y (mean ? SD 8.1 ? 1.0 y, 112 boys). Medial midfoot plantar fat pad thickness was quantified using ultrasonography and dynamic plantar pressure distributions were measured using a pressure platform. Data were correlated to establish the strength of the relationships among BMI, plantar fat pad thickness and medial midfoot plantar pressures. RESULTS: Both medial midfoot plantar fat pad thickness and medial midfoot plantar pressure were significantly correlated with BMI (r = 0.401, P < 0.001 and r = 0.465, P < 0.001, respectively). Although medial midfoot plantar pressure significantly correlated with midfoot plantar fat pad thickness during non-weight bearing (r = 0.294, P < 0.001) and weight bearing (r = 0.289, P < 0.001), the strength of the relationships was low. CONCLUSION: Additional medial midfoot fat padding in obese school-aged children appears to reflect their excess body mass rather than an adaptation to cushion pressures associated with this increased body mass. Further investigation is required to identify probable short- and long-term functional limitations resulting from increased pressures generated beneath the feet of obese children when walking. PMID- 21651423 TI - Nocturnal blood pressure in untreated essential hypertensives. AB - AIM. Prevalence, correlates and reproducibility of nocturnal hypertension (NH) as defined by fixed cut-off limits in uncomplicated essential hypertension are poorly defined. Therefore, we assessed such issue in a cohort of 658 untreated hypertensives. METHODS. All subjects underwent procedures including cardiac and carotid ultrasonography, 24-h urine collection for microalbuminuria, ambulatory blood pressure monitoring (ABPM), over two 24-h periods within 4 weeks. NH was defined according to current guidelines (i.e. night-time blood pressure, BP ? 120/70 mmHg) and non-dipping status as a reduction in average systolic (SBP) and diastolic BP (DBP) at night lower than 10% compared with daytime values. RESULTS. A total of 477 subjects showed NH during the first and second ABPM period; 62 subjects had normal nocturnal BP (NN) in both ABPM sessions. Finally, 119 subjects changed their pattern from one ABPM session to the other. Overall, 72.5% of subjects had reproducible NH, 18% variable pattern (VP) and 9.5% reproducible NN. In the same group, figures of reproducible non-dipping, variable dipping and reproducible dipping pattern were 24%, 24% and 52%, respectively. Among NH patients, 56% of whom were dippers, subclinical cardiac organ damage was more pronounced than in their NN counterparts. CONCLUSIONS. In uncomplicated essential hypertensives, NH is a more frequent pattern than non-dipping; NH is associated with organ damage, independently of dipping/non-dipping status. This suggests that options aimed at restoring a blunted nocturnal BP fall may be insufficient to prevent cardiovascular complications unless night-time BP values are fully normalized. PMID- 21651424 TI - Nitric oxide and adverse events of vascular endothelial growth factor inhibitors. AB - BACKGROUND: Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways have demonstrated therapeutic efficacy in a wide variety of malignancies. With their increased use, adverse events, some common and certain rare but characteristic complications, are being recognized. The exact mechanisms for the development of at least some of these side effects are not entirely clear. SCOPE: Review of the current literature with respect to mechanisms for the development of side effects to VEGF blocking agents was reviewed. FINDINGS: Nitric oxide is a key molecule in the downstream signalling pathway for VEGF. Blockade of nitric oxide by the VEGF antagonists results in several class-specific adverse events. CONCLUSION: Nitric oxide can be considered as an important factor in the development of most of the common and rare adverse events related to VEGF antagonists. PMID- 21651425 TI - The intraocular pressure reducing effect of brinzolamide as adjunctive therapy to latanoprost. AB - AIM: To determine the intraocular pressure (IOP) lowering effect of brinzolamide when added to latanoprost. MATERIALS AND METHODS: Patients who were simultaneously on brinzolamide and latanoprost were identified from the large prospective database of patients diagnosed with primary open angle glaucoma, normal tension glaucoma or ocular hypertension maintained in our glaucoma clinic. Only patients who had been on latanoprost for at least six weeks before introduction of brinzolamide were included. Their case notes were reviewed to determine the intraocular pressure at baseline, after addition of brinzolamide and prior to subsequent treatment change if any. RESULTS: Ninety-three patients were identified. Data for seventy-two patients were analysed. Average age was 70 with a male to female ratio of 4:5. The mean baseline IOP was 20.8 +/- 4.6 mmHg with 47 diagnosed with primary open angle glaucoma, 16 with normal tension glaucoma and 9 with ocular hypertension. The reduction in IOP was 4.1 +/- 0.9 mmHg (95% confidence limits, p < 0.001) at 4.0 months median follow up. This corresponds to 19.8% reduction of IOP from baseline. A 12.5% proportion of patients did not have a reduction in IOP, 3.2% and 2.1% reported ocular irritation and blurring of vision respectively. At last mean follow up of 45 months, 51% of patients remained on this treatment. CONCLUSIONS: In the majority of patients, brinzolamide reduced IOP by a further 19.8% in patients already on latanoprost monotherapy. This effect was maintained in 51% of patients after 42 months. PMID- 21651426 TI - Cost effectiveness of duloxetine in the treatment of fibromyalgia in the United States. AB - OBJECTIVE: To evaluate the cost effectiveness of duloxetine when considered as an alternative treatment for patients in the United States (US) being treated for fibromyalgia pain. RESEARCH DESIGN AND METHODS: A Markov model was used to evaluate the economic and clinical advantages of duloxetine in controlling fibromyalgia pain symptoms over a 2-year time horizon. A base-case treatment sequence was adopted from clinical guidelines, based on tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, anticonvulsants, and opioids. Treatment response was modeled using changes from baseline in pain severity, and response thresholds: full response (at least a 50% change), response (30-49% change), and no response (less than a 30% change). Clinical efficacy and discontinuation data were taken from placebo- and active-controlled trials identified in a systematic literature review and mixed-treatment comparison. Utility data were based on EQ-5D data. MAIN OUTCOME MEASURES: Additional symptom-control months (SCMs), defined as the amount of time at a response level of 30% or less, and quality-adjusted life-years (QALYs) over a 2 year time horizon. RESULTS: For every 1000 patients, first-line duloxetine resulted in an additional 665 SCMs and 12.3 QALYs, at a cost of $582,911 (equivalent to incremental cost-effectiveness ratios [ICERs] of $877 per SCM and $47,560 per QALY). Second-line duloxetine resulted in an additional 460 SCMs and 8.7 QALYs, at a cost of $143,752 (equivalent to ICERs of $312 per SMC and $16,565 per QALY). LIMITATIONS: Response data for TCAs are limited to 30% improvement levels, reported trials are small, and have low placebo response rates. The model necessarily assumes that response rates are independent of placement in the treatment sequence. CONCLUSIONS: The results suggest that the introduction of duloxetine into the standard treatment sequence for fibromyalgia not only provides additional patient benefits, reflected by time spent in pain control, but also is cost effective when compared with commonly adopted thresholds. PMID- 21651427 TI - Economic impact of using inhaled corticosteroids without prior exacerbation among elderly patients with chronic obstructive pulmonary disorder. AB - OBJECTIVE: To assess the economic impact of initiating inhaled corticosteroids (ICS) without evidence of prior exacerbation among elderly patients with chronic obstructive pulmonary disease (COPD) in the US. METHODS: This retrospective study used administrative claims to identify newly diagnosed COPD patients between 1/1/2005 and 6/30/2006 who were dispensed ICS. The dispense date of the first ICS was set as the index date. Patients with prior diagnoses for asthma, cystic fibrosis, or lung cancer were excluded. Cohorts were constructed based on whether ICS therapy was concordant with recommended guidelines of having prior COPD exacerbation. Each COPD patient with prior exacerbation was matched to four patients without exacerbation based on age, gender, Charlson Comorbidity Index, and whether COPD diagnosis code was not elsewhere specified (i.e., 496). Multivariate regressions were estimated to assess the association between use of ICS therapy without prior exacerbation and total healthcare costs, controlling for demographics and clinical characteristics. RESULTS: The study included 3650 patients: 730 with prior exacerbation and 2920 without prior exacerbation. Patients were 76 years of age and 54% were male. Those with prior exacerbation were more likely to have inpatient stays both prior to (74.4 vs. 44.1%, p<0.05) and following (37.0 vs. 33.1%, p<0.05) the index date. Controlling for patient characteristics, patients who were dispensed ICS without prior exacerbation had $1859 higher in total costs (p<0.05) compared to patients with prior exacerbation during the 12 months following ICS initiation. LIMITATIONS: The retrospective design of this study limits the interpretation of findings as association and not causality. This study is subject to selection bias due to unobservable confounders. CONCLUSIONS: Among COPD patients, initiation of ICS without prior exacerbation appears to be associated with increased healthcare costs. These findings suggest that ICS initiation without evidence of exacerbation as consistent with guidelines is associated with adverse economic consequences. PMID- 21651428 TI - A review of biopsychosocial strategies to prevent and overcome early-recognized poor adherence in growth hormone therapy of children. AB - BACKGROUND: Adherence to growth hormone (GH) therapy among children is variable and remains a problem, possibly affecting growth outcomes and future health, and having economic consequences. OBJECTIVE: To provide a review of the issues related to poor adherence to GH therapy in children and describe integrative strategies that may improve adherence. RESULTS: Poor adherence may be caused by various factors, affecting both the children and their families. The key reasons for adherence difficulties are psychological/emotional problems, social/everyday problems and technical handling issues of the drug delivery device. Correspondingly a broad range of strategies to address adherence to GH therapy often revolve around counseling and education, not just for the patient but also for the family giving care. LIMITATIONS: This review is intended as a general survey of strategies which could help, in clinical practice, to overcome poor adherence to growth hormone therapy in children; it summarizes the representative literature but it does not aim to be a rigorous database literature search in every aspect. CONCLUSIONS: If poor adherence is recognized early on during treatment, appropriate steps may be taken to identify barriers that are amenable to change for encouraging the child to adhere to the treatment regimen. A preventative approach may also be considered; for example, doctors could address adherence issues early and train families of children treated with GH to recognize the resources as well as the barriers to adherence. The broad range of different causes for poor adherence demands a great variety of interventions, making it important to individualize optimal treatment behavior. Additionally, economic studies are required to quantify the cost of poor adherence to GH therapy and to show the financial benefits of good adherence. PMID- 21651429 TI - A comprehensive evaluation of the toxicology of cigarette ingredients: essential oils and resins. AB - CONTEXT: A total of 32 essential oils and resins were added individually to experimental cigarettes. OBJECTIVE: A battery of tests was used to compare the toxicity of mainstream smoke from these experimental cigarettes. The lowest target inclusion level was 100 ppm and the highest was 100,000 ppm. MATERIALS AND METHODS: Smoke from each of the experimental cigarette was evaluated using analytical chemistry and in vitro bacterial (Salmonella, five strains) mutagenicity and cytotoxicity (neutral red uptake) assays. For seven of the ingredients (carob bean, carob bean extract, carrageenan, chamomile flower Hungarian oil, guar gum, peppermint oil, and spearmint oil), 90-day smoke inhalation studies with rats were also performed. RESULTS: In general, inclusion levels resulted in minimal changes in smoke chemistry; the exceptions were PO and SO, where reductions to 40-60% of control values were noted, possibly indicating a tobacco displacement effect. Cytotoxicity and mutagenicity were unaffected by any of the test ingredients, except for a dose-related reduction in cytotoxicity for SO. There were very few statistically significant differences within any of the seven inhalation studies; when present, the differences were sporadic and inconsistent between sexes. The addition of SO appeared to depress body weight gain and increase the atrophy of olfactory epithelia, but only in males. CONCLUSION: The essential oils and resins tested here as ingredients in experimental cigarettes show minimal toxicological sequelae, even at high inclusion levels. The highest inclusion level for SO showed some equivocal responses. PMID- 21651430 TI - A comprehensive evaluation of the toxicology of cigarette ingredients: cocoa derived ingredients. AB - CONTEXT: Cocoa-derived ingredients are used in cigarette tobacco. OBJECTIVE: A battery of tests was used to compare toxicity of mainstream smoke from experimental cigarettes containing different added levels of cocoa-derived ingredients. MATERIALS AND METHODS: Five cocoa-derived ingredients chocolate (CH), cocoa (COC), cocoa-grand prix black (CGPB), cocoa nibs tincture (CNT) and cocoa shells extract (CSE) were added individually to experimental cigarettes at three different levels. Smoke from each of the experimental cigarette types was evaluated using analytical chemistry; in vitro cytotoxicity and mutagenicity testing were performed for four of the five compounds. For CH, COC and CNT, 90 day smoke inhalation studies were performed with 6-week recovery periods. RESULTS: No consistent changes were found in the analytical chemistry results. Results of the cytotoxicity and mutagenicity were unaffected by any of the ingredients. Two of the three inhalation studies showed very few differences between the groups. The inhalation study with COC showed several increases in mean histopathology severity scores in groups exposed to different levels of COC, compared with the controls. These apparent effects of COC on histopathology lesion severity scores were only present in a single sex and none were dose related, which is not consistent with a true increase in biological activity. Also there were effectively no differences in the patterns of recovery for any of the compounds. CONCLUSIONS: Even at high inclusion levels there was a lack of toxicological response in these COC derived ingredients. PMID- 21651431 TI - A comprehensive evaluation of the toxicology of cigarette ingredients: aliphatic carbonyl compounds. AB - CONTEXT: Aliphatic carbonyl compounds are used as ingredients in cigarette tobacco or cigarette filters. OBJECTIVE: A battery of tests was used to compare toxicity of mainstream smoke from experimental cigarettes containing 15 aliphatic carbonyl compounds that were added individually to experimental cigarettes at three different levels. MATERIALS AND METHODS: Smoke from experimental and control cigarettes were evaluated using analytical chemistry, in vitro cytotoxicity (neutral red uptake), and mutagenicity (five bacterial strains) studies. For one compound, glycerol triacetate (GTA), two 90-day inhalation studies were also performed, using different inclusion levels into either tobacco or cigarette filter. RESULTS: Several smoke constituent concentrations were reduced with the highest inclusion level of GTA in tobacco; incorporation of GTA into the filter, and the other compounds into tobacco, produced effectively no changes. Cytotoxicity was reduced by the highest inclusion of GTA into tobacco for both gas-vapor and particulate phases of smoke; incorporation of GTA into the filter, and the other compounds into tobacco, showed no changes. Mutagenicity was reduced by the middle and high inclusion levels of GTA into tobacco (TA1537 strain with S9); incorporation of GTA into the filter, and the other compounds into tobacco, showed no changes. CONCLUSION: Inclusion of GTA in tobacco at 100,000 ppm reduced the biological effects of the smoke in the various test systems reported in this study, although inclusion into the filter did not appear to have any major effect on the endpoints studied. The other 14 aliphatic carbonyl compounds that were tested lacked a toxicological response. PMID- 21651432 TI - A comprehensive evaluation of the toxicology of cigarette ingredients: aliphatic and aromatic carboxylic acids. AB - CONTEXT: Aromatic and aliphatic carboxylic acids are present in tobacco and tobacco smoke. OBJECTIVE: A battery of tests was used to compare the toxicity of mainstream smoke from experimental cigarettes containing eight aromatic and aliphatic carboxylic acids and the salt of one acid that were added individually at three different levels (lowest and highest target inclusions were 100 and 90,000 ppm, respectively). MATERIALS AND METHODS: Mainstream smoke from cigarettes containing each of the test ingredients was evaluated using analytical chemistry and assays to measure in vitro cytotoxicity (neutral red uptake) and Salmonella (five strains) mutagenicity. For four of the compounds (citric, lactic, benzoic acids, and sodium benzoate), 90-day rodent inhalation studies were also performed. RESULTS: Although sporadic statistically significant differences in some experimental cigarette smoke constituents occurred, none resulted in significant changes in mutagenicity or cytotoxicity responses, nor in responses measured in the inhalation studies, except for lactic acid (LA). Inclusion of LA resulted in dose-dependent increase in water and caused a dose dependent decrease in cytotoxicity. Incorporation of LA into cigarettes resulted in several dose-related reductions in histopathology, which were largely restricted to the nasal passages. Incorporation of LA also ameliorated some of the typical decrease in body weight gain seen in cigarette smoke-exposed rats. CONCLUSIONS: Inclusion of these ingredients at exaggerated use levels resulted in sporadic dose-related and treatment effects for some smoke constituents, but no toxicological response was noted in the in vitro and in vivo tests performed. PMID- 21651433 TI - A comprehensive evaluation of the toxicology of cigarette ingredients: aromatic and aliphatic alcohol compounds. AB - CONTEXT: Various aromatic and aliphatic alcohol compounds are found in tobacco and tobacco smoke. OBJECTIVE: A battery of tests was used to compare the toxicity of mainstream smoke from experimental cigarettes containing eight aromatic and aliphatic alcohol compounds that were added individually to experimental cigarettes at three different levels. The lowest target inclusion level was 100 ppm and the highest level was 24,400 ppm. MATERIALS AND METHODS: Mainstream smoke from each of the cigarette types was evaluated using analytical chemistry and assays to measure in vitro cytotoxicity (neutral red uptake) and Salmonella (five strains) mutagenicity. For three of the compounds (benzyl alcohol, propyl paraben, and rum flavor), 90-day smoke inhalation studies with 6-week recovery periods were also performed using rats. RESULTS: Inclusion of eugenol produced several dose-related reductions in concentrations of selected smoke constituents. Cytotoxicity and mutagenicity were unaffected by any of the test ingredients, except for dose-related reductions in cytotoxicity of the gas vapor phase produced by the inclusion of eugenol. The three smoke inhalation studies showed a few sporadic differences between the groups and there were no differences in the patterns of recovery for any of the ingredients. CONCLUSIONS: Despite using exaggerated inclusion levels of the eight aliphatic and aromatic alcohol compounds in experimental cigarettes, there was minimal toxicological response, which is consistent with published reports of studies using mixtures of compounds added to tobacco. PMID- 21651434 TI - Retrospective analysis of risk factors for development of liver dysfunction in transient leukemia of Down syndrome. AB - About 20% of patients with transient leukemia (TL), which is a disease noted in Down syndrome, are reported to develop hepatic fibrosis, which has a poor prognosis. The clinical factors related to the poor prognosis of TL were retrospectively analyzed in 25 patients, and criteria for starting chemotherapy were established. The initiation of chemotherapy was recommended when two or more of the following categories were fulfilled in the process of the disease: (1) a reduced hepatic functional reserve estimated by direct bilirubin, prothrombin time, and the presence of ascites, (2) an elevated level of hyaluronic acid (>500 U/mL), (3) respiratory failure or poor sucking associated with hepatosplenomegaly, and (4) demonstration of fibrosis by liver biopsy. When these criteria were applied to our cases, all patients who received chemotherapy remained alive. Our criteria are useful for selecting patients with TL at high risk of developing hepatic fibrosis and for starting chemotherapy. PMID- 21651435 TI - Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma. AB - Several pre-clinical studies report that statins interfere with the surface binding of rituximab to CD20. This study investigated the effects of statins in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-based chemoimmunotherapy, and the impact of commonly used drugs, metformin and aspirin, on the clinical outcomes of patients receiving chemoimmunotherapy. We included 213 patients with DLBCL who received rituximab-based chemoimmunotherapy. Details of statin, metformin, and aspirin use and initiation of chemoimmunotherapy were abstracted from medical records. All patients received rituximab, and 47 (22.1%) were taking statins. The median age of patients receiving statins was significantly higher compared to those who did not (p <0.001). Response rates between patients receiving and not receiving statins were not significantly different (85.1% vs. 87.3%; p = 0.688). Event-free survival (EFS) was not significantly different (p = 0.352). Overall survival was lower in patients receiving statins compared to those who did not (p = 0.036). However, it was no longer significant after adjustment for age (p = 0.140). Metformin had no impact on the response rate (p = 0.268), EFS (p = 0.574), and overall survival (p = 0.141). Aspirin had no impact on the response rate (p = 0.784), EFS (p = 0.836), and overall survival (p = 0.779). Statins do not interfere with rituximab, and need not be withheld during rituximab administration. Larger studies are needed to confirm the impact of metformin and aspirin on patients with DLBCL receiving chemoimmunotherapy. PMID- 21651436 TI - The virology and developments toward control of human enterovirus 71. AB - Enterovirus 71 (EV71), a member of the Enterovirus genus in the Picornaviridae family, was first recognized as a dermotrophic virus that usually cause mild, self-limiting hand-foot-and-mouth disease (HFMD). However, EV71 infection can sometimes induce a variety of severe neurological complications and even death. Current large outbreaks of EV71 make this virus being a major public health issue. Intense effort has been made to address its underlying pathogenesis and to develop effective means for combating EV71 infections. Here, we aimed to provide an overview of cellular mechanisms underlying EV71 infection and to assess potential agents for prevention and treatment of EV71 infections. PMID- 21651437 TI - Recent status and prospects of the fungal immunomodulatory protein family. AB - With the exception of polysaccharides and triterpenes/triterpenoids compounds, fungal immunomodulatory protein (FIP), a small molecule protein, is also an important bioactive component with immune regulating activity. It plays a significant role in immunomodulating. The objective of this paper was to review the latest advances in various aspects of research on FIPs, including their basic components and structural character, characters of diversity, gene cloning and expression, and their biological function, etc. In addition, prospects of utilization value and the exploitation foreground of FIPs were also discussed. The review will provide a useful reference for further research, development, and utilizations of FIPs. PMID- 21651439 TI - The generic amyloid formation inhibition effect of a designed small aromatic beta breaking peptide. AB - The development of generic inhibitors in order to control the formation of amyloid fibrils and early oligomers is still an unmet medical need. As it is hypothesized that amyloid assemblies represent a generic protein supramolecular structure of low free energy, targeting the key molecular recognition and self assembly events may provide the route for the development of such potential therapeutic agents. We have previously demonstrated the ability of hybrid molecules composed of an aromatic moiety and the alpha-aminoisobutyric acid beta sheet breaker elements to act as excellent inhibitors of amyloid fibril formation. Specifically, the D-Trp-Aib was shown to be a superb inhibitor of the formation of Alzheimer's disease beta-amyloid fibrils and oligomers both in vitro and in vivo. Here, we demonstrate that the rationally designed molecule has the generic ability to inhibit amyloid fibril formation by calcitonin, alpha synuclein, and the islet amyloid polypeptide. Moreover, we demonstrate the inability of two modified peptides, D-Ala-Aib and D-Trp-Ala, to inhibit and disassemble amyloid fibril formation, a fact that provides an additional evidence for the suggested structural basis of the inhibitor activity. Taken together, we believe that the use of beta-breaker elements combined with aromatic moiety may present a promising approach for the development of fibrillization inhibition drug candidate. PMID- 21651440 TI - Prophylactic cancer vaccination by targeting functional non-self. AB - Despite the monumental success of childhood prophylactic vaccination, there is no similar program designed to provide protection as we age against adult onset diseases like breast cancer. Instead, the predominant focus of current cancer vaccine strategy is to vaccinate after the tumors become established. This strategy has at best provided incremental improvement in overall survival. We propose the development of an adult vaccination program modeled on the childhood program that provides protection against diseases we confront as we enter our middle age. Since most cases of adult cancers are not associated with definitive etiopathogenic viruses, we propose extending our selection of vaccine targets to tissue-specific self proteins that are over-expressed in developing tumors but are no longer expressed in normal tissues ('retired or former self'), are expressed in normal tissues under readily avoidable conditions ('conditional self'), or are incapable of targeting any clinically significant autoimmune complications ('irrelevant self'). By extending prophylactic vaccination to such "functional non-self" targets, prophylactic vaccination against adult onset diseases like breast cancer may occur safely in the absence of any autoimmune inflammatory complications and may potentially reduce disease incidence in a manner that mimics the impact of childhood vaccination on diseases like measles and polio. PMID- 21651441 TI - Caveolae, caveolin, and cavins: potential targets for the treatment of cardiac disease. AB - Caveolae are omega-shaped membrane invaginations present in essentially all cell types of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes, and fibroblasts. Numerous functions have been ascribed to this omega-shaped structure. Caveolae are enriched with different signaling molecules and ion channel regulatory proteins and function both in protein trafficking and signal transduction in these cell types. Caveolins are the structural proteins that are necessary for the formation of caveola membrane domains. Mechanistically, caveolins interact with a variety of downstream signaling molecules, as, for example, Src-family tyrosine kinase, p42/44 mitogen-activated protein (MAP) kinase, and endothelial nitric oxide synthase (eNOS) and hold the signal transducers in the inactive condition until activated with proper stimulus. Caveolae are gradually acquiring increasing attention as cellular organelles contributing to the pathogenesis of several structural and functional processes including cardiac hypertrophy, atherosclerosis, and heart failure. At present, very little is known about the role of caveolae in cardiac function and dysfunction, although recent studies with caveolin knock-out mouse have shown that caveolae and caveolins play a pivotal role in various human pathobiological conditions. This review will discuss the possible role and mechanism of action of caveolae and caveolins in different cardiac diseases. PMID- 21651442 TI - Size dependency of PLGA-nanoparticle uptake and antifungal activity against Aspergillus flavus. AB - AIMS: Itraconazole and coumarin-6 loaded polylactic-co-glycolic acid nanoparticles (PLGA-ITZ- and PLGA-C6-NPs) were synthesized and tested for fungal cell uptake and antifungal ability based on particle size. MATERIALS & METHODS: PLGA-ITZ- and PLGA-C6-NPs were synthesized using an oil-in-water emulsion evaporation method. Fungal cell uptake and antifungal activity of the polymeric NPs was tested on Aspergillus flavus. RESULTS: PLGA-C6-NPs of 203 nm associated with fungal cell surfaces and internalized efficiently, while 1206 nm NPs associated with cell surfaces were internalized less efficiently. Antifungal studies of PLGA-ITZ-NPs of 232, 630 and 1060 nm showed differences in inhibitory activity with 232 nm NPs showing superior activity at the lowest ITZ concentration of 0.003 mg/ml, followed by 630 and 1060 nm NPs. No differences in antifungal activity were observed at higher ITZ concentrations. CONCLUSION: The PLGA-ITZ-NP system can increase bioavailability of ITZ by improving its aqueous dispersibility and efficiently delivering ITZ to fungal cells via endocytosis. PMID- 21651443 TI - Multifunctional Fe3O4/alumina core/shell MNPs as photothermal agents for targeted hyperthermia of nosocomial and antibiotic-resistant bacteria. AB - AIMS: The appearance of antibiotic-resistant bacterial strains is a serious problem in medical treatment. Thus, it is imperative to explore new therapeutic approaches and antibiotics with which to treat patients suffering from bacterial infections. MATERIALS & METHODS: In this work, we propose a targeted hyperthermia therapeutic approach using alumina-coated iron oxide magnetic nanoparticles (Fe(3)O(4)/alumina core/shell MNPs) as photothermal agents to selectively kill bacteria. RESULTS: Fe(3)O(4) MNPs possess photothermal capabilities under near infrared (NIR) light illumination. The temperature of the MNP suspension (1.33 ug/ul, 60 ul) under illumination with NIR light increased 20 degrees C over 5 min. Functionalization of the surface of the MNPs with an alumina coating allows them to have targeting capability toward bacteria. The prepared Fe(3)O(4)/alumina core/shell MNPs possess several desirable features, including magnetic properties, absorption capability in the NIR region and the ability to target bacteria. The magnetic properties of the Fe(3)O(4)/alumina MNPs allow conjugated target species to aggregate at a specific location under a magnetic field. A NIR laser can then be used to specifically irradiate the aggregated spot to photokill target bacteria. The cell growth of nosocomial bacteria, including Gram-positive, Gram-negative and antibiotic-resistant bacterial strains, can be effectively inhibited by over 95% within 10 min of light irradiation when targeted by Fe(3)O(4)/alumina MNPs. CONCLUSION: This approach provides a potential therapeutic approach for treating patients suffering from nosocomial and antibiotic-resistant bacterial infections. PMID- 21651444 TI - Nanoparticulate architecture of protein-based artificial viruses is supported by protein-DNA interactions. AB - AIM & METHODS: We have produced two chimerical peptides of 10.2 kDa, each contain four biologically active domains, which act as building blocks of protein-based nonviral vehicles for gene therapy. In solution, these peptides tend to aggregate as amorphous clusters of more than 1000 nm, while the presence of DNA promotes their architectonic reorganization as mechanically stable nanometric spherical entities of approximately 80 nm that penetrate mammalian cells through arginine glycine-aspartic acid cell-binding domains and promote significant transgene expression levels. RESULTS & CONCLUSION: The structural analysis of the protein in these hybrid nanoparticles indicates a molecular conformation with predominance of alpha-helix and the absence of cross-molecular, beta-sheet supported protein interactions. The nanoscale organizing forces generated by DNA protein interactions can then be observed as a potentially tunable, critical factor in the design of protein-only based artificial viruses for gene therapy. PMID- 21651445 TI - Management of myelofibrosis--where next? PMID- 21651446 TI - Pioglitazone: a valuable component of combination therapy for type 2 diabetes mellitus. AB - Several classes of drugs have been developed to treat type 2 diabetes mellitus (T2DM). Pioglitazone is now the only thiazolidinedione approved for the treatment of T2DM and can be administered in combination with metformin, sulfonylureas, exenatide, dipeptidyl peptidase 4 (DPP-4) inhibitors or insulin. It improves glycemic control with an extremely low incidence of hypoglycemia. In addition to reducing insulin resistance, it may also improve pancreatic beta-cell secretory function. Moreover, it exhibits a variety of favorable pleiotropic effects. The latter include anti-inflammatory, antioxidant, vasoprotective, antihypertensive and hypolipidemic actions. Finally, this agent has been shown to improve experimental diabetic neuropathy and alleviate neuropathic pain, as well as decreasing urinary albumin excretion in patients with diabetes. Thus, pioglitazone emerges as a valuable hypoglycemic agent for combination therapy in T2DM. Importantly, however, patients should be appropriately selected, especially to avoid those with heart failure, in order to minimize adverse events attributable to water retention. PMID- 21651447 TI - The effect of pitavastatin calcium on endothelial dysfunction induced by hypercholesterolemia. AB - OBJECTIVE: To investigate whether endothelial function can be improved by the treatment of pitavastatin calcium via its antioxidant properties in hypercholesteremia patients. METHODS: Forty patients with hypercholesteremia were randomized to receive pitavastatin calcium 1 or 2 mg/day for 8 weeks. Among them, four people were lost in the follow-up period. Before and after treatment, clinical and biochemical characteristics, markers of oxidative stress (plasma 8 iso-prostaglandin F(2alpha) and serum gp91phox) were determined and concomitantly endothelium-dependent brachial artery flow-mediated dilation (FMD) was measured by ultrasound examination. Thirty healthy subjects were chosen as controls. RESULTS: For individuals with hypercholesteremia, total cholesterol, low-density lipoprotein cholesterol (LDL-C) and serum gp91phox were significantly increased (p<0.001 for all) and plasma 8-iso-prostaglandinF2alpha (8-iso-PGF2alpha) was significantly higher (p<0.05), while FMD was obviously impaired (p<0.001). Total cholesterol, LDL-C and serum gp91phox were significantly reduced (p<0.001 for all), plasma 8-iso-PGF2alpha was lower and FMD was significantly improved after pitavastatin calcium treatment compared with those before treatment in any group (p<0.05 for both). However, there was no significant difference between the 1-mg and 2-mg pitavastatin calcium groups post-therapy. CONCLUSIONS: Endothelial dysfunction induced by hypercholesteremia can be ameliorated by pitavastatin calcium treatment, which occurs in part through its antioxidative properties. PMID- 21651448 TI - Attainment of optional low-density lipoprotein cholesterol goal of less than 70 mg/dl and impact on prognosis of very high risk stable coronary patients: a 3 year follow-up. AB - OBJECTIVES: We aimed to investigate the proportion of very high-risk patients with coronary heart disease (CHD) who achieve the optional low-density lipoprotein cholesterol (LDL-C) target of <70 mg/dl (1.8 mmol/liter), the factors that influence the success rate and the impact on their prognosis. RESEARCH DESIGN AND METHODS: We enrolled 1337 consecutive patients with stable CHD. Fasting lipids were determined and all cardiovascular events were recorded during a median follow-up of 33 months. RESULTS: The majority (86.5%) of patients were taking lipid-lowering medication (95.5% statins), but only 50.6% had LDL-C levels of <100 mg/dl (2.6 mmol/liter). In total, 941 (70.4%) patients were considered very high risk and only 15.1% of them had LDL-C levels of <70 mg/dl. Tauhe use of intensive lipid-lowering medication was associated with 12-fold (95% CI 6.98 20.76; p<0.001) higher possibility in achieving LDL-C levels of < 70 mg/dl. Attainment of LDL-C levels of < 70 mg/dl by patients at very high risk were independent predictors of all cardiovascular events (HR=0.34, 95% CI 0.17-0.70; p=0.003). CONCLUSIONS: The vast majority of very high-risk patients do not achieve the optional LDL-C goal; this is mainly due to the suboptimal uptitration of statin dose and is translated into loss of clinical benefits. PMID- 21651449 TI - Sitagliptin: a review. AB - INTRODUCTION: The ever-increasing burden of type 2 diabetes mellitus (T2DM) and inadequate control in the majority of patients has led to a quest for newer therapeutic options. There have been recent exciting advances in the treatment of T2DM, targeting the enteroinsular axis with incretin-based therapies that include the dipeptidyl peptidase IV (DPP-IV) inhibitors. AREAS COVERED: The background, pharmacodynamic and pharmacokinetic profile of sitagliptin and important clinical trials with this drug are discussed in this paper. This review is intended to provide a comprehensive overview of the DPP-IV inhibitor sitagliptin, its clinical use and an expert opinion about its place in the treatment algorithm of diabetes management. EXPERT OPINION: Sitagliptin is a well-tolerated, moderately efficacious, weight-neutral oral antidiabetic agent, with a low incidence of hypoglycemia. It may have a particular role in the management of diabetic patients with kidney or liver dysfunction. Animal studies indicate a protective effect on the pancreatic beta cell, thus limiting the progression of the disease, but this remains to be proven in humans. PMID- 21651451 TI - Vitamin K3 suppressed inflammatory and immune responses in a redox-dependent manner. AB - Recent investigations suggest that cellular redox status may play a key role in the regulation of several immune functions. Treatment of lymphocytes with vitamin K3 (menadione) resulted in a significant decrease in cellular GSH/GSSG ratio and concomitant increase in the ROS levels. It also suppressed Concanavalin A (Con A) induced proliferation and cytokine production in lymphocytes and CD4 + T cells in vitro. Immunosuppressive effects of menadione were abrogated only by thiol containing antioxidants. Mass spectrometric analysis showed that menadione directly interacted with thiol antioxidant GSH. Menadione completely suppressed Con A-induced activation of ERK, JNK and NF-kappaB in lymphocytes. It also significantly decreased the homeostasis driven proliferation of syngeneic CD4 + T cells. Further, menadione significantly delayed graft-vs-host disease morbidity and mortality in mice. Menadione suppressed phytohemagglutinin-induced cytokine production in human peripheral blood mononuclear cells. These results reveal that cellular redox perturbation by menadione is responsible for significant suppression of lymphocyte responses. PMID- 21651452 TI - Involvement of NADPH oxidase in up-regulation of plasminogen activator inhibitor 1 and heat shock factor-1 in mouse embryo fibroblasts induced by oxidized LDL and in apolipoprotein E-deficient mice. AB - The present study demonstrated that oxidized LDL (oLDL) increased the generation of superoxide and hydrogen peroxide (H(2)O(2)), the abundances of NADPH oxidase (NOX)4, NOX2, p22-phox and lectin-like oLDL receptor-1 (LOX-1) in wild-type or heat shock factor-1 (HSF1)-deficient mouse embryo fibroblasts (MEF). LOX-1 antibody inhibited LDL or oLDL-induced expression of NOX components in MEF. Abundance of HSF1 or plasminogen activator inhibitor-1 (PAI-1) was increased by oLDL in wild-type, but not in HSF1-deficient MEF. Diphenyleneiodonium or siRNA for NOX or p22-phox inhibited oLDL-induced increases of HSF1, PAI-1 and H(2)O(2) in MEF. Increased NOX4, NOX2, LOX1, HSF1 and PAI-1 were detected in aortae and hearts of apolipoprotein E-knockout (apoE-KO) mice compared to controls, which were associated with increased serum cholesterol or plasma PAI-1. The results suggest that NOX is required for oLDL-induced HSF1 or PAI-1 expression in MEF, which was supported by the up-regulation of NOX, LOX-1, HSF1 and PAI-1 in apoE-KO mice. PMID- 21651453 TI - Photochemical stability of lipoic acid and its impact on skin ageing. AB - It is well known that alpha-lipoic acid (LA) functions as an essential co-factor of the mitochondrial multi-enzyme complex and thus plays an important role in energy metabolism. Currently, it is attracting attention as a nutritional supplement because of its unique antioxidant properties and broad spectra of cellular functions. Skin protection from photodamage and ageing is one of the functional applications of LA. Medical and cosmetic application has been widely realized in the world. However, LA has a unique structure bearing a distorted five membered 1, 2-dithiolane ring, making it quite vulnerable to UV radiation. The present article briefly reviews skin ageing from the viewpoint of oxidative stress and sun exposure and analyses the photochemical properties of LA. It also discusses the effect of LA to cellular signalling and its adequate applications to treat skin ageing caused by oxidation. Data presented in this review suggest that LA is a powerful anti-ageing agent under the appropriate usage. PMID- 21651454 TI - Correlation of urinary inflammatory and oxidative stress markers in very low birth weight infants with subsequent development of bronchopulmonary dysplasia. AB - Currently, bronchopulmonary dysplasia (BPD) occurs almost exclusively in pre-term infants. In addition to prematurity, other factors like oxygen toxicity and inflammation can contribute to the pathogenesis. This study aimed to compare urinary inflammatory and oxidative stress markers between the no/mild BPD group and moderate/severe BPD group and between BPD cases with significant early lung disease like respiratory distress syndrome (RDS) ('classic' BPD) and with minimal early lung disease ('atypical' BPD). A total of 60 patients who were a gestational age < 30 weeks or a birth weight < 1250 g were included. Urine samples were obtained on the 1(st), 3(rd) and 7(th) day of life and measured the levels of leukotriene E(4) (LTE(4)) and 8-hydroxydeoxyguanosine (8-OHdG). The 8 OHdG values on the 3(rd) day showed significant correlation to duration of mechanical ventilation. The 8-OHdG levels on the 7(th) day were the independent risk factor for developing moderate/severe BPD. In 'classic' BPD, the 8-OHdG values on the 3(rd) day were higher than those of 'atypical' BPD. In 'atypical' BPD, the LTE(4) values on the 7(th) day were higher than the values in 'classic' BPD. These results suggest that oxidative DNA damage could be the crucial mechanism in the pathogenesis of current BPD and the ongoing inflammatory process could be an important mechanism in 'atypical' BPD. PMID- 21651455 TI - Enoyl acyl carrier protein reductase inhibitors: a patent review (2006 - 2010). AB - INTRODUCTION: Bacterial enoyl acyl carrier protein reductase (ENR) specificity reduces the double bond in enoyl thioester substrates in the final enzymatic step of the elongation cycle of the fatty acid synthase-II pathway. Its function is essential for bacterial organism survival, making it an attractive target for the development of novel antibiotics. The structural features and therapeutic potential of this enzyme have stimulated the rational design of ENR inhibitors, and important progress has been achieved to date. AREAS COVERED: This review describes recent advances made in the search for ENR inhibitors, as reflected by patent applications filed from 2006 to 2010, together with an overview of the relevant literature. The first section of this paper provides a background of the biology of ENR, followed by a description of its structure and function. The main section describes the substrate specificities for ENR, and the structure-based rational design of patent inhibitors originating from different companies and academic groups. EXPERT OPINION: The increase in the number of ENR inhibitors bodes well for the development of new therapeutics against multidrug-resistant bacteria. The challenge is now to improve the pharmacokinetic parameters of these inhibitors and translate them into clinical studies. PMID- 21651450 TI - Cancer and diet: How are they related? AB - Extensive research in the past decade has revealed cancer to be a multigenic disease caused by perturbation of multiple cell signalling pathways and dysregulation of numerous gene products, all of which have been linked to inflammation. It is also becoming evident that various lifestyle factors, such as tobacco and alcohol use, diet, environmental pollution, radiation and infections, can cause chronic inflammation and lead to tumourigenesis. Chronic diseases caused by ongoing inflammation therefore require chronic, not acute, treatment. Nutraceuticals, compounds derived from fruits, vegetables, spices and cereals, can be used chronically. This study discusses the molecular targets of some nutraceuticals that happen to be markers of chronic inflammation and how they can prevent or treat cancer. These naturally-occurring agents in the diet have great potential as anti-cancer drugs, thus proving Hippocrates, who proclaimed 25 centuries ago, 'Let food be thy medicine and medicine be thy food'. PMID- 21651456 TI - Combination perindopril/indapamide for the treatment of hypertension: a review. AB - INTRODUCTION: Hypertension is an important risk factor for cardiovascular complications and the need to treat this condition has been well established. Despite the availability of many antihypertensive drugs, it is often necessary to combine several of these drugs. The compound perindopril/indapamide offers the opportunity to start with a fixed combination of two effective agents as first line treatment. Large outcome trials so far show that the perindopril/indapamide compound has favourable prognostic effects in elderly hypertensives as well as in patients with high cardiovascular risks, regardless of their level of blood pressure. AREAS COVERED: This review examines the prevalence of hypertension, the major risk factors, its pharmacodynamics, pharmacokinetics and clinical efficacy, and also looks at the results of large outcome trials. This review will allow the reader to put the role of the perindopril/indapamide combination in perspective, at least from a clinical point of view. EXPERT OPINION: Despite the positive trial results, there are still issues that deserve attention, for example safety with respect to drug levels in special patient groups. Also, in the large outcome trials placebo treatment (whether or not in addition to other medication) was taken as the comparator, and it is uncertain whether the combination of perindopril and indapamide performs better than established modes of treatment. More studies are needed to establish whether the combination drug has similar positive effects in the long run in 'ordinary' patients and those with comorbid conditions or those who are treated with other drugs as well. Nevertheless, it is fair to state that the low-dose perindopril/indapamide combination adds to our pharmaceutical arsenal and can be applied as first-line treatment by physicians who care for patients with elevated blood pressure or, more broadly, those with cardiovascular disease. PMID- 21651457 TI - Candesartan cilexetil: an update. AB - INTRODUCTION: Candesartan cilexetil is one of the most often-used first-line drugs regarding the management of arterial hypertension. Moreover, this drug has proven its effectiveness in chronic heart failure and exerts beneficial effects in diabetes, stroke, dementia and atrial fibrillation. AREAS COVERED: This review focuses on the use of candesartan cilexetil in Phase II and Phase III trials and their implications for clinical usage in the treatment of arterial hypertension and heart failure. The usage of candesartan cilexetil in patients with stroke, migraine or atrial fibrillation, hypertrophy obstructive or nonobstructive cardiomyopathy and diabetic or non diabetic renal diseases will be discussed. Relevant publications were identified by an extensive Medline search. EXPERT OPINION: Candesartan cilexetil is a highly effective ARB for the treatment of arterial hypertension and heart failure. Also, recent trials have suggested beneficial effects in diabetic patients, patients with nondiabetic renal diseases, stroke, migraine and atrial fibrillation. PMID- 21651458 TI - Tumor necrosis factor biologics beyond psoriasis in dermatology. AB - INTRODUCTION: TNF-alpha is a cytokine essential for immune response and its receptors has been shown to be dysregulated in a variety of diseases including psoriasis vulgaris. There are a number of TNF-alpha inhibitors approved for psoriasis, however there is a growing body of literature supporting their use in a wide variety of dermatological conditions. AREAS COVERED: The use of biologic TNF-alpha antagonists in conditions for which they have not yet been approved by the FDA ('off-label' uses) and the literature that supports the most appropriate agents and conditions for use. A PubMed/MEDLINE search was performed with the keywords 'TNFalpha antagonist', 'biologic therapy', 'off-label' and 'unapproved'. The list of references and citing articles of the articles retrieved were also used as sources. This complete list was evaluated for inclusion, based on relevance to the proposed goal of this review. EXPERT OPINION: There are a large number of conditions for which biologic antagonists of TNFalpha are effective, beyond those already approved by the FDA. The various agents vary in their efficacy in treatment, with infliximab consistently the most effective, particularly in granulomatous diseases. Although effectiveness varies among these conditions, biologic antagonists of TNF-alpha are promising for the treatment of these diseases. PMID- 21651459 TI - Opioid modulators for alcohol dependence. AB - INTRODUCTION: Studies have shown that opioid antagonists like naltrexone are efficient in reducing heavy drinking. The neurobiological mechanism by which opioid modulators affect drinking behavior is based on the strong connection between the endogenous opioid system, the dopamine system and the influence of the CNS stress response. AREAS COVERED: This review provides an overview of the pathophysiological role of the opioid system in alcohol dependence and the neurobiological mechanisms of possible pharmacological interventions. An extensive Medline and Internet research was performed to retrieve information on existing and currently investigated opioid modulators. The findings were assessed critically and interpreted with regard to an individualized therapy for alcohol dependence. EXPERT OPINION: The opioid system is of crucial importance in the genesis and maintenance of alcohol dependence. Naltrexone- and to a lesser extent nalmefene- is an agent that modulates opioidergic transmission in the CNS and it shows a limited but well-studied efficacy in treating alcohol dependence. Several agents (LY2196044, ALKS-29, ALKS-33) that are currently undergoing Phase II and Phase III studies are of interest but first their efficacy must be proved in clinical practice. PMID- 21651460 TI - The dynamics of urinary N-acetyl-beta-D-glucosaminidase (NAG), a marker of renal tubular dysfunction, in patients with lupus nephritis undergoing oral prednisone therapy. AB - INTRODUCTION AND AIMS: N-Acetyl-beta-D-glucosaminidase (NAG), a marker of renal tubular dysfunction, is increased in patients with lupus nephritis. In addition to the toxic effects of proteinuria, patients with lupus nephritis may exhibit other factors that contribute to tubular dysfunction, such as pathogenic antitubular basement membrane antibodies. The aim of our study was to assess urinary NAG, proteinuria, and glomerular filtration rate (GFR) before treatment and after 7 and 30 days of oral prednisone therapy in patients with lupus nephritis. METHODS: Ten patients with lupus nephritis, all females, mean age: 29.4 +/- 10.17 years, were enrolled into the study. All the patients received oral prednisone 1 mg/kg. Twenty healthy subjects served as controls. We measured urinary NAG before treatment and after 7 and 30 days of oral prednisone therapy. Proteinuria, GFR, blood pressure, and side effects of therapy were also followed up. Urinary NAG was measured using the colorimetrical method and expressed as units per gram of creatinine (U/gCr). Statistical analysis (Wilcoxon signed ranks test and Wilcoxon rank sum test) was performed using SPSS 17. RESULTS: In the 10 patients with lupus nephritis, urinary NAG before treatment was 16.9 +/- 13.39 U/gCr (P = 0.005 compared with controls). NAG in controls was 1.73 +/- 0.51 U/gCr. Proteinuria before treatment was 3.84 +/- 1.93 g/24 h. The GFR before treatment was 50.48 +/- 11.98 mL/min/1.73 m2. After 7 days of prednisone, urinary NAG was 23.55 +/- 25.25 U/gCr (P = 0.878 compared with baseline, and P = 0.02 compared with controls). Proteinuria was 2.94 +/- 1.3 g/24 h (P = 0.005 compared with baseline), and the GFR was 58.11 +/- 13.64 mL/min/1.73 m2 (P = 0.005 compared with baseline). After 30 days of prednisone, urinary NAG was 11.77 +/- 12.18 U/gCr (P = 0.203 compared with baseline, P = 0.022 compared with the value after 7 days of prednisone, and P = 0.01 compared with controls). Proteinuria was 1.73 +/- 0.68 g/24 h (P = 0.005 compared with baseline, and P = 0.005 compared with the value after 7 days of prednisone), and the GFR was 67.49 +/- 16.42 mL/min/1.73 m2 (P = 0.005 compared with baseline and P = 0.009 compared with the value after 7 days of prednisone). Blood pressure measurements did not show any significant changes. No major side effects of steroid therapy were noticed. CONCLUSIONS: Urinary NAG showed a significant reduction between 7 and 30 days of therapy. The reduction in urinary NAG set in later than the decline in proteinuria and the improvement in GFR. Further studies incorporating a longer follow-up are needed to observe whether the reduction in NAG persists upon continuation of prednisone therapy. PMID- 21651462 TI - Esophagogastric cancer: integration of targeted therapies into systemic chemotherapy. AB - Although combination chemotherapy has been shown to be more effective than single agents in advanced esophagogastric cancer, the better response rates have not fulfilled their promise as overall survival times from best combination still range between 8 to 11 months. So far, the development of targeted therapies stays somewhat behind their integration into treatment concepts compared to other gastrointestinal diseases. Thus, the review summarizes the recent advances in the development of targeted therapies in advanced esophagogastric cancer. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors EGFR1 and HER2. For trastuzumab and bevacizumab, phase III trial results have been presented recently. While addition of trastuzumab to cisplatin/5-fluoropyrimidine-based chemotherapy results in a clinically relevant and statistically significant survival benefit in HER 2+ patients, the benefit of the addition of bevacizumab to chemotherapy was not significant. Thus, all patients with metastatic disease should be tested for HER 2 status in the tumor. Trastuzumab in combination with cisplatin/5 fluoropyrimidine-based chemotherapy is the new standard of care for patients with HER2-positive advanced gastric cancer. PMID- 21651461 TI - Anti-cancer activity of nitrones and observations on mechanism of action. AB - The nitrone compound PBN, alpha-phenyl-tert-butylnitrone, and closely related nitrones have anti-cancer activity in several experimental cancer models. The three experimental models most extensively studied include A) the rat choline deficiency liver cancer model, B) the rat C6 glioma model and C) the mouse APC(Min/+) colon cancer model. The two PBN-nitrones mostly studied are PBN and a PBN derivative 2,4-disulfophenyl-tert-butylnitrone, referred as OKN-007. OKN-007 is a proprietary compound that has had extensive commercial development (designated as NXY-059) for another indication, acute ischemic stroke, and after extensive clinical studies was shown to lack efficacy for this indication but was shown to be very safe for human use. This compound administered orally in the rat glioma model has potent activity in treating fully formed gliomas. In this report observations made on the PBN-nitrones in experimental cancer models will be summarized. In addition the experimental results will be discussed in the general framework of the properties of the compounds with a view to try to understand the mechanistic basis of how the PBN-nitrones act as anti-cancer agents. Possible mechanisms related to the suppression of NO production, S-nitrosylation of critical proteins and inhibition of NF-kappaB activation are discussed. PMID- 21651463 TI - Structural diversity of neuritogenic substances and their application perspective. AB - Small molecular weight substances are functional, as neurotrophic factors can be developed as therapeutic drugs to treat neurodegenerative disorder. Recently, a large number of natural and synthetic neuritogenic compounds have been discovered. These compounds have various structural features, including terpenoids, lipids, alkaloids, steroid glycosides, small molecular peptides, and so on. Some of them possess not only neurotrophic properties but also neuroprotective activities. The structure-activity relationships (SARs) and mechanism of action of some important compounds have been studied intensively. Increasing experimental evidence suggests that several of these compounds can be promising candidates for drug development. PMID- 21651464 TI - Synthesis and biological activity of chiral dihydropyrazole: potential lead for drug design. AB - Dihydropyrazole, a small bioactive molecule, is a prominent structural motif found in numerous pharmaceutically active compounds. The chiral dihydropyrazole structure has been demonstrated to bear important biological activities such as anticancer, antimicrobial, antimalarial, antinociceptive, antiviral, antitubercular, antiinflammatory, anticonvulsant and steroidal, and can also act as MAO inhibitors, CB1 receptor antagonists and nitric oxide synthase inhibitors. The review describes the latest advances in the synthesis of dihydropyrazole derivatives incorporating physiologically active substances. It is the first attempt at a general and systematic account of the extensive literature data on this subject. PMID- 21651465 TI - Inhibition of the interaction between HIV-1 integrase and its cofactor LEDGF/p75: a promising approach in anti-retroviral therapy. AB - Although 25 compounds are currently licensed as anti-HIV drugs, the development of multidrug-resistant viruses, as well as their severe side effects, compromise their efficacy and limit treatment options. The search for new targets in order to cure AIDS has revealed that the inhibition of some protein-protein interactions in the HIV life cycle may provide an important new approach to fight this disease. The interaction between HIV-1 integrase (IN) and Lens Epithelium Derived Growth Factor (LEDGF/p75) has increasingly gained attention as a valuable target for a novel anti-retroviral strategy. This article reviews the discovery and development of molecules capable of interrupting the LEDGF/p75-IN interaction reported to date. PMID- 21651467 TI - Epipolythiodioxopiperazines from fungi: chemistry and bioactivities. AB - Epipolythiodioxopiperazines (ETPs), characterized by a unique bridged disulfide or polysulfide dioxopiperazine six-membered ring, occur in many fungi. Due to its broad spectra of bioactivities, ETPs have drawn wide attention in recent years. This review covers diverse natural sources that produce ETPs, the synthetic chemistry of ETPs and an overview of promising bioactivities exhibited by some well studied ETPs. The plausible biosynthetic hypotheses of ETPs and some new results on antitumor activity of ETPs are also reviewed. PMID- 21651466 TI - Synthesis and biological properties of dihydro-oxadiazine-based heterocyclic derivatives. AB - Dihydro-oxadiazine and its derivatives have been demonstrated to be important heterocyclic scaffold platform with bioactive diversity, which present wide activities such as cardiovascular, antitumor, antibacterial, antimicrobial, acricidal, insecticidal, plant-growth regulating, chitin biosynthesis inhibitors and monoamine oxidase inhibition. Versatile features of dihydro-oxadiazine heterocycles have emerged, so the aim of the present paper was to review the recent advances of dihydro-oxadiazine-based heterocyclic derivatives mainly including synthesis and biological activities. PMID- 21651475 TI - Targets for research in the metabolic syndrome. PMID- 21651476 TI - ATP-competitive inhibitors of mTOR: an update. AB - mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives. mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signaling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents. This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD-8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data. PMID- 21651477 TI - The potential role of glycogen synthase kinase 3 inhibitors as amyotrophic lateral sclerosis pharmacological therapy. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Lately, this disease has often been related to the protein kinase called glycogen synthase kinase 3 (GSK-3), through the experimental evidence of alterations of this enzyme on ALS patients. Therefore, there have been several experimental studies using GSK-3 inhibitors, in cellular and animal models and also in clinical studies that showed the potential of the therapeutic role of these molecules. GSK-3 inhibitors might play a pivotal role in the pharmacology of ALS disease with no curative treatment nowadays. In this review we give an overview of the current research in the area, showing all the evidences of the implication of dysfunctional GSK-3 in this disease on one hand, and on the other presenting the potential role of the GSK-3 inhibitors as a future pharmacological ALS therapy. PMID- 21651478 TI - Targeting the human DEAD-box polypeptide 3 (DDX3) RNA helicase as a novel strategy to inhibit viral replication. AB - Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high intrinsic mutation and replication rates of HIV 1 often lead to the emergence of drug resistant strains and consequent therapeutic failure. On this basis, cellular cofactors represent attractive new targets for HIV-1 chemotherapy, since targeting a cellular factor that is required for viral replication should help to overcome the problem of viral resistance. We and others have recently reported the identification of compounds suppressing HIV-1 replication by targeting the cellular DEAD-box helicase DDX3. These results provide a proof-of-principle for the feasibility of blocking HIV-1 infection by rendering the host cell environment less favorable for the virus. The rationale for such an approach and its implications in potentially overcoming the problem of drug resistance related to drugs targeting viral proteins will be discussed in the context of the known cellular functions of the DEAD-box helicase DDX3. PMID- 21651479 TI - Irreversible protein kinase inhibitors. AB - Targeting cancer with small molecule irreversible inhibitors of kinases represents an emerging challenge in drug discovery. Irreversible inhibitors bind to kinase active site in a covalent and irreversible form, most frequently by reacting with a nucleophilic cysteine residue, located near the ATP binding pocket. The most common mechanism is the Michael reaction, that refers to the addition of a nucleophile, such as cysteine, to an alpha,beta unsaturated carbonyl. The nucleophile reacts at the electrophilic beta-position to form an adduct; as a result the inhibitor irreversibly blocks binding of ATP to the kinase, rendering the kinase inactive. Different cysteine-reactive groups have been evaluated, an acrylamide or a substituted acrylamide moiety are the Michael acceptors of choice. There are some advantages for the irreversible kinase inhibition. These compounds are highly selective because they target a specific cysteine and only a limited number of kinases has a cysteine at the corresponding position. Another advantage is that covalent bond formation can overcome competition with the high endogenous concentration of ATP. A further motivation for designing irreversible inhibitors is their longer duration of action respect to conventional inhibitors. In fact, once bound to enzyme, these compounds do not readily dissociate and the inhibition continues even after the inhibitor leaves the circulation. Moreover, these inhibitors have the potential to overcome and prevent the emergence of acquired resistance conferred by mutations. In this review examples of irreversible inhibitors are reported, focusing on chemical structures, SAR and biological activities. The great potential of these compounds could open new and promising perspectives for a broader application of this approach. PMID- 21651480 TI - Managing the liabilities arising from structural alerts: a safe philosophy for medicinal chemists. AB - Bioactivation of xenobiotics can, in certain circumstances, result in the formation of reactive electrophilic species. These reactive metabolites may covalently modify proteins and macromolecules and it has been suggested that protein modification is a key initial step in provoking idiosyncratic adverse drug reactions. Understanding these bioactivation pathways is critical in order to rationally design drug candidates with a lower propensity to form reactive intermediates. Herein, we provide an overview of the importance of Structural Alerts and bioactivation pathways and describe the creation of an in-house database as a tool aimed at informing medicinal chemists about these potential liabilities. PMID- 21651481 TI - Biological potential and structure-activity relationships of most recently developed vascular disrupting agents: an overview of new derivatives of natural combretastatin a-4. AB - Tumor blood vessels are an important emerging target for anti-cancer therapy. The antimitotic agent combretastatin A-4 (CA-4), a cis-stilbene natural product isolated from the South African tree Combretum caffrum Kuntze, is the lead compound of a new class of anti-cancer drugs that target tumor vasculature. CA-4 inhibits tubulin polymerization by interacting at the colchicine binding site on tubulin. This alters the morphology of endothelial cells and causes vascular shutdown and regression of tumor vasculature. Some tubulin-binding vascular disrupting agents (VDAs) are currently in clinical trials for cancer therapy. As a consequence of the potential favorable applications of these compounds, several analogs projected to induce rapid and selective vascular shutdown in tumors have been synthesized during the last few years. Many of these molecules have already been tested for their effects on tubulin polymerization as well as for their antiproliferative activity and other biological properties, and possible mechanisms of action have been investigated. The aim of the present review is to offer an overview of most recently developed combretastatin derivatives, focusing on biological effects exerted by these compounds. The published data about new analogs are presented and compared, and a detailed investigation of structure activity relationships is described. PMID- 21651482 TI - Current progress in antifibrotics. AB - After years of viewing cirrhosis as the irreversible end-stage of liver fibrosis, it has been shown recently that the possibility of its reversal is no longer a dream. Several studies on experimental animal models showed possible spontaneous resolution of fibrosis after the removal of fibrogenic stimulus. Similar results were also observed in human patients with liver fibrosis due to autoimmune hepatitis and biliary etiology. However, the need for other means of treatment is urgent, especially when the removal of the causative factor is unlikely. Recent antifibrotic strategies were designed to target one or more of the three stages involved in the process of fibrosis. These are the triggering stage, fibrogenesis, and extracellular matrix accumulation. In this review, the classification of the current drugs or agents that showed inhibition of one or more of fibrosis stages with their chemical synthesis are presented. PMID- 21651483 TI - Bone metastatic disease: taking aim at new therapeutic targets. AB - Conventional treatment for metastatic bone pain requires a multidisciplinary approach (medical therapy, surgery, and radiation), but is primarily palliative. Biphosphonates introduced the concept of disease-modifying therapy, by effectively reducing bone pain and skeletal related events in patients suffering from bone metastatic cancer. In the past decade, the growing knowledge of bone biology and our understanding of the molecular mechanisms at the basis of the interaction between cancer cells and bone matrix led to the identification of new therapeutic targets for innovative "smart drugs". The most investigated is the RANK/RANKL/OPG pathway, and denosumab, among novel targeted therapies, is the molecule that is in the most advanced development phase. Additional targets have been identified and potential novel therapeutic interventions, classified as inhibitors of bone resorption or stimulators of bone formation, are under preclinical and clinical evaluation. These promising targets include cathepsin K, the Src tyrosine kinases, integrins, chloride channels, the parathyroid hormone related peptide, endotelin-1, sclerostin, and TGF-beta. Other pathways or molecules expressed by bone cells and cancer cells, such as CXCR4, GPNMB, EGF family ligands, Wnt/DKK1, and MIP-1 alpha have recently emerged as potential targets. The aim of this review is to discuss the molecular mechanisms behind these emerging therapeutic targets in bone metastases and to give an overview of results from those in advanced clinical phases. PMID- 21651484 TI - An original deal for new molecule: reversal of efflux pump activity, a rational strategy to combat gram-negative resistant bacteria. AB - The worldwide dissemination of "multi-drug resistant" (MDR) pathogens has severely reduced the efficacy of our antibiotic arsenal and increased the frequency of therapeutic failure. MDR bacteria over-express efflux pumps and this active mechanism can extrude all classes of antibiotics from the cell. It is necessary to clearly decipher the genetic, structural and functional aspects of this transport system in order to combat this polyselective mechanism. By understanding how efflux pumps work we may be able to develop a new group of antibacterial agents, collectively termed efflux reversals, including membrane permeabilisers, efflux pump inhibitors and flux-competitive agents, specific blockers, energy poisons, etc. Several chemical families of efflux pump inhibitors have been described and characterized. Among them several inhibitor compounds demonstrate efficient blocking of the efflux pump activity involved in the MDR phenotype as observed in many Gram-negative clinical isolates. This new family of molecules represents the first antibacterial class of compound specifically targeting active transport in the bacterial cell. PMID- 21651485 TI - Targeting mTOR signaling pathway in ovarian cancer. AB - The mammalian target of rapamycin (mTOR) is frequently activated in epithelial ovarian cancer, and is regarded as an attractive therapeutic target for therapy. Preclinical investigations using rapamycin and its analogs have demonstrated significant growthinhibitory effects on the growth of ovarian cancer both in the setting of monotherapy and in combination with cytotoxic agents. Based on promising preclinical data, mTOR inhibitors are currently being evaluated in several phase I/II trials in patients with ovarian cancer. In an effort to overcome resistance to rapamycin and its analogs, the novel ATP-competitive mTOR inhibitors have recently been developed. In this report, we review the scientific rationale and evidence for the potential clinical benefits provided by mTOR inhibitor therapy for patients with epithelial ovarian cancer. PMID- 21651486 TI - BCR-ABL inhibitors in chronic myeloid leukemia: process chemistry and biochemical profile. AB - Chronic myeloid leukemia (CML) is a myeloproliferative disease originating from a constitutively active tyrosine kinase, called BCR-ABL, expressed by an oncogene resulting from a reciprocal translocation between chromosome 9 and chromosome 22, coded as (t[9,22][q34;q11]). Inhibition of BCR-ABL with tyrosine kinase inhibitors (TKI) proved to be an efficient targeted therapy of Philadelphia positive (Ph+) CML in the chronic phase. This review mainly addresses the synthetic pathways and process chemistry leading to the large scale preparation for pre-clinical demands and clinical supply of the three TKIs approved for Ph+ CML, i.e., imatinib, dasatinib and nilotinib and three more investigational drugs, i.e., bosutinib, ponatinib and bafetinib. Recent progress on the biochemical profiling of the six examined TKIs has been also reported. PMID- 21651487 TI - Fyn kinase in brain diseases and cancer: the search for inhibitors. AB - Fyn is a non-receptor tyrosine kinase belonging to the Src family kinases. It has been shown to play important roles in neuronal functions, including myelination and oligodendrocytes formation, and in inflammatory processes. It has also demonstrated its involvement in signaling pathways that lead to severe brain pathologies, such as Alzheimer's and Parkinson's diseases. Moreover, Fyn is upregulated in some malignancies. Experimental studies demonstrated that Fyn inhibition could be useful in the disruption of metabolic processes involved in cancer neurodegenerative diseases. Unfortunately, no specific Fyn inhibitor has been discovered till today, active compounds on other members of Src family or on different tyrosine kinases have also been reported. However, multitargeted inhibitors might be endowed with therapeutic potential. Indeed, as increasingly reported, also a not completely selective inhibitor of a specific protein could be therapeutically useful, affecting a number of cell pathways involved especially in cancer development. In this review, we report some examples of small molecule tyrosine kinase inhibitors for which data on Fyn inhibition, both in enzymatic and in cell assays, have been reported, with the aim of giving information as starting point for the researchers working in this field. PMID- 21651488 TI - Role of the non-receptor tyrosine kinase fes in cancer. AB - Non receptor protein tyrosine kinases are targets in the treatment of a number of diseases. This review focuses on the role of Fes tyrosine kinase and on the design of inhibitors of this protein. Fes and its homologously related protein Fer are the only two members of a distinct class of non receptor tyrosine kinases and they seem to play a role in cytoskeletal rearrangements and inside-out signaling associated with receptor-ligand, cell-matrix and cell-cell interactions. The knowledge of the three dimensional structure of this protein, in fact, has informed drug design, while at the same time it has helped to shed some light on the molecular mechanism at the basis of kinase activation and functions. PMID- 21651489 TI - Role of phosphorylation in the nuclear biology of HIV-1. AB - The central events of HIV-1 life cycle occur at the nuclear level where the viral genome is integrated into the host cellular DNA in order to be expressed and replicated. The viral pre-integration complexes (PICs) are actively transported in the nuclear compartment where integration occurs in specific regions of the cellular chromatin. Similar to all viruses, HIV-1 encodes for a limited number of proteins that are insufficient to produce new viral progenies. Several cellular pathways are thus hijacked by HIV-1 to efficiently complete the replication cycle. The majority of viral proteins are substrates for cellular kinases indicating a pivotal role of these cellular enzymes at multiple steps of the HIV 1 life cycle. The nuclear biology of the cell is highly controlled by kinases (nuclear transport, DNA replication, repair and transcription) and many of these kinases also sustain the viral nuclear events. This review summarizes our current knowledge on kinases that are involved in HIV-1 replication cycle at the nuclear level, both directly through their catalytic activity on viral proteins and indirectly being activated by the virus. Among viral proteins directly modified by kinases is integrase (IN) the factor that catalyzes the integration of HIV-1 in the cellular genome. Notably, this recent discovery may shed light onto mechanisms underlying the different susceptibility of the main cell types targeted by HIV-1 (CD-4+ T-cell) depending on their activation status. Alternatively, kinases may act indirectly such as in the case of DNA repair factors activated following HIV-1 infection and demonstrated to regulate the viral life cycle. Finally, inhibition of cellular kinases interacting with HIV-1 at the nuclear level has been shown to severely affect the viral replication cycle, thus suggesting potential new therapeutic approaches. PMID- 21651490 TI - Receptor tyrosine kinase kit and gastrointestinal stromal tumours: an overview. AB - Kit is a growth factor receptor of the type III tyrosine kinase family, whose gain-of-function mutations have been identified as driving causes of different kinds of tumours. It thus represents a viable drug target, and the development of Kit inhibitors has been shown to be a promising therapeutic concept. This review will focus on structural and signalling properties of both wild-type and mutant Kit, as well as its role in the development of human cancers. Special attention will be dedicated to gastrointestinal stromal tumours, GISTs. Progress in research on the aetiopathogenesis of GISTs and their therapeutic approaches will be fully discussed, focusing on the latest tendencies for the treatment of these kinds of tumours. PMID- 21651491 TI - Role of the hypoxic microenvironment in the antitumor activity of tyrosine kinase inhibitors. AB - The tumor microenvironment is characterized, not only by marked gradients in drug concentration, but also by gradients in the rate of cell proliferation and by regions of hypoxia and acidity, all of which can influence tumor cell sensitivity to drug treatment. Hypoxia is also an important environmental factor in chronic myeloid leukemia (CML), because bone marrow is intrinsically hypoxic in nature. Systems-wide analyses of tumors have recently identified receptor tyrosine kinase coactivation as an important mechanism by which cancer cells achieve chemoresistance. Recent work suggests that Src activation might play a prominent role in the response to hypoxia to promote cell survival, progression, and metastasis of a variety of human cancer. Other studies also established a functional link between Bcr-Abl and the Src family tyrosine kinases. It is well known that mutations can also cause some tyrosine kinases to become constitutively active, a nonstop functional state that may contribute to initiation or progression of cancer as in CML. Leukemic cells carrying chromosomal alteration, are sensitive to imatinib that induces complete remission in most patients. This inhibitor is a highly selective Bcr-Abl tyrosine kinase inhibitor (TKI). There is a considerable interest in understanding how activated signaling pathways enhance tumor cell survival under hypoxia, because this might lead to the introduction of more effective treatments to target these resistant subpopulations. For all these reasons it is important to identify new TKIs which are also active in hypoxia, the real tumor microenvironment, as possible alternative therapy. PMID- 21651492 TI - The dark side of protein kinase CK2 inhibition. AB - Casein kinase 2 (CK2) is a ubiquitous, highly pleiotropic and essential protein kinase whose abnormally high constitutive activity has been implicated in several human diseases. In the last decade, several ATP competitive inhibitors of CK2, characterized by an in vitro activity that ranges from micromolar to nanomolar, have been discovered. However, until now only one drug candidate has been entered in Phase I clinical trial as a potential anticancer drug. Why this constitutively active kinase is so undruggable? Can ATP competitive inhibitors be considered the most promising drug candidates for the near future? In this review, we would like to underline how targeting binding sites outside the conventional ATP-binding could represent a new promising strategy to inhibit CK2 activity and, consequently, bear a great potentiality in discovering new drug candidates. PMID- 21651493 TI - Peptides or small molecules? Different approaches to develop more effective CDK inhibitors. AB - Cell cycle regulation involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control cell cycle are ordered and directional. Cyclins and cyclin-dependent kinases (CDKs), determine cell progression through the cycle ensuring the orderly coordination of cellular events. Alterations of cell cycle controllers are among the main causes of cancer onset. In the past decades many efforts have been made to develop kinase inhibitors that are able to modulate cyclin and CDK complexes, either by mimicking the function of natural CDK inhibitors, such as p21, p16 and p27, or by modulating the cyclin-CDK complexes or their targets directly. The great debate is whether to use peptides or small molecules. Peptides are more selective being derived by the linear protein sequences, indeed they should mimic the catalytic or the regulatory subunits of the cell cycle controller complexes, but on the other side they usually present poorer pharmacokinetic characteristics. In contrast, small molecules have better pharmacokinetic features but lower specificity because many protein kinases show high sequence similarity within the active site. The purpose of this review article is to provide an overview of the main classes of CDK inhibitors focusing on structure-activity relationship (SAR) studies and discussing the pharmacological and therapeutic implications. PMID- 21651494 TI - Protein kinase homology models: recent developments and results. AB - Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families, and knowledge of their three dimensional structure could be of great help in the rational design of specific ligands. However, only about one quarter of human protein kinase structures has been experimentally defined; thus, kinase homology modeling techniques have been widely diffused. In this review, the most recent kinase homology models are reported, together with the most recent approaches and the main validation methods. PMID- 21651495 TI - Overcoming the drug resistance problem with second-generation tyrosine kinase inhibitors: from enzymology to structural models. AB - Protein phosphorylation is one of the major pathways used by eukaryotic cells to propagate signals to the final effectors, regulating multiple aspects of the living cell, such as metabolism, growth, differentiation, adhesion, motility, genome stability and death. In this context, tyrosine kinases (TKs) play a central role in signal transduction and their overexpression or disregulated activity has been implicated in tumor onset and malignancy progression. To date, eight TKs inhibitors have been approved by FDA for the treatment of specific tumors. In spite of their efficacy, insurgence of resistance is a common feature after prolonged administration. The selective pressure by these drugs, in fact, induces clonal expansion of subsets of cancer cells harboring TKs mutations, leading to decreased inhibition potency. Alternatively, resistance to TK inhibitors can be acquired through the activation of others, often unrelated, TKs. For this reason, while stringent target selectivity of TKs inhibitors has been always considered a desirable feature in order to limit toxicity, molecules targeting different TKs have been recently shown to be promising anti-cancer agents as well. Understanding the molecular mechanisms that confer resistance to TK inhibitors, through a combination of enzymatic, structural and cellular studies, is essential in the development of second generation inhibitors active also towards drug resistant tumors. PMID- 21651496 TI - Cancer multitarget pharmacology in prostate tumors: tyrosine kinase inhibitors and beyond. AB - Tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs, essentially because many kinases and regulators are molecules related to frequently mutated oncogenes and tumor suppressors. Many experiments and clinical data in different tumors show that better cancer therapy can be obtained by blocking several tumor cell biochemical pathways at once, accurately selecting critical targets and adjusting drug dosages for the best results. Through our direct experience in experimental models of prostate cancer (PCa), we discuss in this review the issues of tyrosine kinase inhibition in neoplastic cells and illustrate the opportunities to extend cancer proliferation control to other key biological targets of clinical interest, aiming at the realization of better polypharmacology applications in cancer chemotherapy. Briefly, in this review the main experimental evidences on the efficacy of tyrosine kinase inhibitors (TKIs) on PCa are described, together with a reasoned analysis of biological data which may be useful for a general extension to other clinical areas of cancer multitargeted and possibly individualized polychemotherapy. PMID- 21651498 TI - Immunological basis of reversible and fixed airways disease. AB - Asthma is characterized by airflow obstruction that is usually completely reversible either spontaneously or in response to treatment. However, a small subset of patients with asthma display FAO (fixed airflow obstruction) despite optimal treatment, a feature more commonly associated with smoking-induced COPD (chronic obstructive pulmonary disease). Why some asthma patients develop FAO is not understood, and it is not clear whether (i) they represent a subset of patients with more severe disease, (ii) they share some characteristics of patients who develop COPD, or (iii) they represent a different disease entity altogether. The present review compares the pulmonary inflammatory profile of asthma patients with FAO with those without FAO, as well as COPD sufferers. The inflammation in asthma patients with FAO can vary from neutrophilic with CD8 T cell involvement, similar to that of COPD, to eosinophilic with CD4 Th2 cell involvement, akin to that of asthma patients without FAO. Although studies of FAO in asthma sufferers would benefit hugely from consistent inclusion criteria, further research work is also required to shed more light on the immunological processes involved. PMID- 21651497 TI - Protein kinases in cancer: recent findings. PMID- 21651499 TI - Molecular diversity of the Trypanosoma cruzi TcSMUG family of mucin genes and proteins. AB - The surface of the protozoan Trypanosoma cruzi is covered by a dense coat of mucin-type glycoconjugates, which make a pivotal contribution to parasite protection and host immune evasion. Their importance is further underscored by the presence of >1000 mucin-like genes in the parasite genome. In the present study we demonstrate that one such group of genes, termed TcSMUG L, codes for previously unrecognized mucin-type glycoconjugates anchored to and secreted from the surface of insect-dwelling epimastigotes. These features are supported by the in vivo tracing and characterization of endogenous TcSMUG L products and recombinant tagged molecules expressed by transfected parasites. Besides displaying substantial homology to TcSMUG S products, which provide the scaffold for the major Gp35/50 mucins also present in insect-dwelling stages of the T. cruzi lifecycle, TcSMUG L products display unique structural and functional features, including being completely refractory to sialylation by parasite trans sialidases. Although quantitative real time-PCR and gene sequencing analyses indicate a high degree of genomic conservation across the T. cruzi species, TcSMUG L product expression and processing is quite variable among different parasite isolates. PMID- 21651500 TI - Catalytic properties of the Gas family beta-(1,3)-glucanosyltransferases active in fungal cell-wall biogenesis as determined by a novel fluorescent assay. AB - BGTs [beta-(1,3)-glucanosyltransglycosylases; EC 2.4.1.-] of the GH72 (family 72 of glycosylhydrolases) are GPI (glycosylphosphatidylinositol)-anchored proteins that play an important role in the biogenesis of fungal cell walls. They randomly cleave glycosidic linkages in beta-(1,3)-glucan chains and ligate the polysaccharide portions containing newly formed reducing ends to C(3)(OH) at non reducing ends of other beta-(1,3)-glucan molecules. We have developed a sensitive fluorescence-based method for the assay of transglycosylating activity of GH72 enzymes. In the new assay, laminarin [beta-(1,3)-glucan] is used as the glucanosyl donor and LamOS (laminarioligosaccharides) fluorescently labelled with SR (sulforhodamine) serve as the acceptors. The new fluorescent assay was employed for partial biochemical characterization of the heterologously expressed Gas family proteins from the yeast Saccharomyces cerevisiae. All the Gas enzymes specifically used laminarin as the glucanosyl donor and a SR-LamOS of DP (degree of polymerization) >=5 as the acceptors. Gas proteins expressed in distinct stages of the yeast life cycle showed differences in their pH optima. Gas1p and Gas5p, which are expressed during vegetative growth, had the highest activity at pH 4.5 and 3.5 respectively, whereas the sporulation-specific Gas2p and Gas4p were most active between pH 5 and 6. The novel fluorescent assay provides a suitable tool for the screening of potential glucanosyltransferases or their inhibitors. PMID- 21651501 TI - The consequences of uniparental disomy and copy number neutral loss-of heterozygosity during human development and cancer. AB - UPD (uniparental disomy) describes the inheritance of a pair of chromosomes from only one parent. Mechanisms that lead to UPD include trisomy rescue, gamete complementation, monosomy rescue and somatic recombination. Most of these mechanisms can involve aberrant chromosomes, particularly isochromosomes and Robertsonian translocations. In the last decade, the number of UPD cases reported in the literature has increased exponentially. This is partly due to the advances in genomic technologies that have allowed for high-resolution SNP (single nucleotide polymorphism) studies, which have complemented traditional methods relying on polymorphic microsatellite markers. In this review, we discuss aberrant cellular mechanisms leading to UPD and their impact on gene expression. Special emphasis is placed on the unmasking of mutant recessive alleles and the disruption of imprinted gene dosage, which give rise to specific and recurrent imprinting phenotypes. Finally, we discuss how copy number maps determined from SNP array datasets have helped identify not only deletions and duplications but also recurrent copy number neutral regions of loss-of-heterozygosity, which have been reported in many cancer types and that may constitute an important driving force in cancer. These tiny regions of UPD also alter imprinted gene dosage, which may have cumulative tumourgenic effects in addition to that of unmasking homozygous cancer-associated mutations. PMID- 21651502 TI - Alterations of T cell subsets in ALS: a systemic immune activation? AB - INTRODUCTION: There is evidence that immunological factors may involved in pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Few studies to date have explored the status of the systemic immune response in patients with ALS. PATIENTS AND METHODS: In order to examine whether systemic immune activation is observed in patients with ALS, we measured the number of T cell subsets by flow cytometry in 36 patients with ALS and 35 normal controls. RESULTS: CD8 cytotoxic T cells and natural killer (NK) T cells were significantly increased in our patients with ALS compared with the control group (P = 0.02 and P = 0.04, respectively). Treg cells were significantly reduced compared with normal controls (P = 0.01). Treg cells were also negatively correlated with progression of the disease (P = 0.017). CONCLUSIONS: Our results suggest a systemic immune activation in patients with ALS. The high production of CD8(+) T and NKT cells may suggest an immunological reaction to some unknown or undetected endogenous proteins or viruses. A probably dual (neurodestructive or neuroprotective) inflammatory function of Treg cells cannot be excluded. PMID- 21651503 TI - Primary Sjogren's syndrome: cognitive symptoms, mood, and cognitive performance. AB - OBJECTIVE: To investigate the relationships between self-reported cognitive abilities, psychological symptoms and neuropsychological outcomes in PSS. METHODS: Patients with Primary Sjogren's syndrome (PSS) and healthy controls completed a comprehensive neuropsychometric battery and questionnaires: the Centers for Epidemiological Scale-Depression, the Profile of Fatigue-mental domain (Prof-M) for cognitive symptoms, Fatigue Severity Scale, and the Short Form McGill Pain Questionnaire. RESULTS: Female patients with PSS (N = 39) were similar to controls (N = 17) in estimated premorbid intellectual function, age and education. Depression (P = 0.002), cognitive symptoms (P = 0.001), fatigue (P = 0.000003), and pain (P = 0.024) scores were greater in the patient group. Patients with PSS demonstrated inferior performance relative to controls in psychomotor processing (P = 0.027) and verbal reasoning (P = 0.007). Patients with PSS with and without depression had similar performance on multiple tests, but depressed patients had significantly lower scores for executive function (P = 0.041). Cognitive symptoms correlated with verbal memory (P = 0.048), whereas pain correlated with executive function measures (Stroop, P = 0.017) and working memory (Trails B, P = 0.036). In the regression model, depression and verbal memory were independent predictors that accounted for 61% of the variance in cognitive symptoms. CONCLUSION: The Prof-M is a simple self-report measure which could be useful in screening PSS subjects who may benefit from detailed psychometric evaluation. Our results are consistent with the hypothesis that depression and verbal memory impairment are overlapping but independent aspects of neural involvement in PSS. While pain and depression are significant confounders of cognitive function in PSS, this study suggests that impaired verbal reasoning ability in PSS is not attributable to pain or depression. PMID- 21651504 TI - Implementation of a new CSF dynamic device: a multicenter feasibility study in 562 patients. AB - OBJECTIVES: The cerebrospinal fluid (CSF) infusion test is frequently used when selecting hydrocephalus patients for shunt surgery. Very little has been reported regarding adverse events. We present a prospective feasibility study. METHODS: Standardized devices for measuring CSF dynamics were built and 562 patients investigated: Needles were placed by lumbar puncture (LP). An automatic CSF infusion protocol was performed. Course of events during the investigation as well as adverse events were registered. RESULTS: Preoperative evaluation of normal-pressure hydrocephalus was the most common indication (63%), followed by evaluation of shunt function (23%) and intracranial pressure recordings (14%). The LP was successfully performed in all but nine cases with 24 patients (4.3%) reporting major discomfort. Ringer infusion was performed in 474 investigations, and a valid measurement of the outflow resistance was received in 439 (93%). During the infusion phase, 17 (4%) patients reported severe headache. Infusion volume was significantly higher in patients having subjective symptoms during the infusion phase compared with those without adverse events. During 269 preoperative CSF tap tests, six (2%) patients had severe headache. Post investigational headache was reported by 83 (15%) patients at the 24-h follow-up. No serious adverse events were observed. CONCLUSION: Infusion testing was safe and without serious adverse events with a high rate of successful procedures. The investigation was associated with expected mild to moderate discomfort. PMID- 21651505 TI - Phenytoin-induced gingival overgrowth. AB - Gingival overgrowth is a common adverse effect of therapy with Phenytoin, having important medical and cosmetic implications. Poor periodontal hygiene is an important risk factor for severity of Phenytoin-induced gingival overgrowth (PIGO), which is a time-dependent process. There is complex interplay of altered fibroblast biology, connective tissue turnover, inflammatory processes, and growth factors on a background of genetic susceptibility to produce increase in various components of interstitial matrix in PIGO tissue. Treatment options have included change of PHT to another anti-seizure drug, measures to improve periodontal hygiene and gingivectomy. There is conclusive evidence that folic acid supplementation significantly decreases the incidence of PIGO. PMID- 21651506 TI - Pregnancy worries: a longitudinal study of Spanish women. AB - OBJECTIVE: To identify pregnancy worries in women by assessing the intensity of these worries and how they change over the course of pregnancy, as well as their relations with sociodemographic and clinical variables. DESIGN: Longitudinal study using a postal questionnaire. SETTING: University hospital in Madrid. POPULATION: 285 pregnant women. METHOD: Women were asked about their pregnancy specific worries in their first trimester (mean gestational age 14.4 weeks) and third trimester (mean gestational age 34.3 weeks). MAIN OUTCOME MEASURES: The women completed a questionnaire that included sociodemographic information and the Cambridge Worry Scale. RESULTS: Pregnancy worries were significantly reduced during the third trimester. The main concern throughout gestation was worry about fetal health. Multiparity and pregnancy planning protected women from pregnancy worries, whereas having had a miscarriage had a negative effect. A younger age and being employed contributed to greater socioeconomic worries. CONCLUSIONS: Worries related to the health of the fetus are universal across different nationalities. A first pregnancy, unplanned pregnancy, and previous miscarriage are risk factors that influence the intensity of a woman's worries. To improve the health and quality of life of pregnant women, a holistic approach to their care should include evaluation of their worries and appropriate intervention in particular groups considered at risk. PMID- 21651507 TI - Anti-haemolytic effect of senicapoc and decrease in NT-proBNP in adults with sickle cell anaemia. PMID- 21651508 TI - Latent class models for testing monotonicity and invariant item ordering for polytomous items. AB - Two assumptions that are relevant to many applications using item response theory are the assumptions of monotonicity (M) and invariant item ordering (IIO). A latent class model is proposed for ordinal items with inequality constraints on the class-specific item means. This model is used as a tool for testing for violations of M and IIO. A Gibbs sampling scheme is used for estimating the model parameters. It is shown that the deviance information criterion can be used as an overall test of M and IIO, while posterior predictive checks can be used to test these assumptions at the item level. A real data application illustrates a model fitting strategy for detecting items that violate M and IIO. PMID- 21651509 TI - Data interpretation: using probability. PMID- 21651510 TI - Exome sequencing in Parkinson's disease. AB - Exome sequencing is rapidly becoming a fundamental tool for genetics and functional genomics laboratories. This methodology has enabled the discovery of novel pathogenic mutations causing mendelian diseases that had, until now, remained elusive. In this review, we discuss not only how we envisage exome sequencing being applied to a complex disease, such as Parkinson's disease, but also what are the known caveats of this approach. PMID- 21651513 TI - Is PATCHED an important candidate gene for neural tube defects? Cranial and thoracic neural tube defects in a family with Gorlin syndrome: a case report. AB - . The relationship of mutations in the patched gene PTCH and nevoid basal cell carcinoma (NBCC) or Gorlin syndrome is well established. Animal studies have implicated the hedgehog-patched signalling pathway in neurulation and neural tube defects (NTDs). Spina bifida occulta and bifid vertebrae are well recognized in NBCCS, but there appears to be only one report of open spina bifida. We report a father and two sons with a truncating PTCH mutation and the major features of NBCCS. One son had open thoracic spina bifida and the other had an occipital meningocoele. We believe this to be the first report of cranial NTD in NBCCS and suggest that consideration be given to including PTCH analysis in genetic association studies in NTDs as the hedgehog pathway is integral to normal human neurulation. PMID- 21651514 TI - Clinical heterogeneity in Italian patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disorder. The majority of cases are sporadic ALS (SALS), with 5-10% being familial ALS (FALS), and are inherited mostly as autosomal dominant. Mutations in Cu/Zn superoxide dismutase (SOD1) and the TAR DNA-binding protein (TARDBP) gene are the most commonly known cause of ALS. We analyzed these genes in 61 Italian ALS patients using high-resolution melting analysis to confirm the role of SOD1 and TARDBP in the physiopathology of ALS. The screenings showed a single mutation in SOD1 (Asp109Tyr) and three in TARBDP (Ala382Thr, Gly295Ser, Gly294Val) in five unrelated ALS patients. This report enlarges the spectrum of clinical phenotypes associated with genetic mutations in SOD1 and TARDBP genes confirming the variability of phenotypes associated with the same mutation and emphasizes the importance of genetic analysis. The different genotype-phenotype correlations suggest the implication of other factors possibly influencing clinical manifestation of the disease, such as an epigenetic or epistatic effect with other genes not yet identified. PMID- 21651511 TI - CGG repeat in the FMR1 gene: size matters. AB - The FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs (full mutation: FM) generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The absence of FMR1 protein, FMRP, seen in FM is the cause of the mental retardation in patients with FXS. The premutation (PM) is defined as 55-200 CGGs. Female PM carriers are at risk of developing primary ovarian insufficiency. Elderly PM carriers might develop a progressive neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome (FXTAS). Although arising from the mutations in the same gene, distinct mechanisms lead to FXS (absence of FMRP), FXTAS (toxic RNA gain-of-function) and FXPOI. The pathogenic mechanisms thought to underlie these disorders are discussed. This review gives insight on the implications of all possible repeat length categories seen in fragile X families. PMID- 21651512 TI - Rab GTPases as regulators of endocytosis, targets of disease and therapeutic opportunities. AB - Rab GTPases are well-recognized targets in human disease, although are underexplored therapeutically. Elucidation of how mutant or dysregulated Rab GTPases and accessory proteins contribute to organ specific and systemic disease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab GTPases or associated regulatory proteins causes numerous human genetic diseases. Cancer, neurodegeneration and diabetes represent examples of acquired human diseases resulting from the up- or downregulation or aberrant function of Rab GTPases. The broad range of physiologic processes and organ systems affected by altered Rab GTPase activity is based on pivotal roles in responding to cell signaling and metabolic demand through the coordinated regulation of membrane trafficking. The Rab-regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate fusion with the target membranes control cell metabolism, viability, growth and differentiation. In this review, we focus on Rab GTPase roles in endocytosis to illustrate normal function and the consequences of dysregulation resulting in human disease. Selected examples are designed to illustrate how defects in Rab GTPase cascades alter endocytic trafficking that underlie neurologic, lipid storage, and metabolic bone disorders as well as cancer. Perspectives on potential therapeutic modulation of GTPase activity through small molecule interventions are provided. PMID- 21651515 TI - ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. AB - Germline mutations in genes encoding members of the transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II-like kinase-1 (ACVRL1) gene mutations are usually identified. We report a remarkable ACVRL1 germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non-mutant ACVRL1 allele in a woman diagnosed with PAH at the age 40. She also met the Curacao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of ACVRL1 identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation-associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele-specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non-mutant ACVRL1 allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure-mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability. PMID- 21651516 TI - 5-Oxoprolinase deficiency: report of the first human OPLAH mutation. AB - Gamma-glutamyl cycle is a six-enzyme cycle that represents the primary pathway for glutathione synthesis and degradation. 5-Oxoprolinase deficiency is an extremely rare disorder of the gamma-glutamyl cycle with only eight patients reported to date. Debate continues as to whether this is a benign biochemical defect because of the heterogeneity of the clinical presentation which ranges from normal to significant neurological involvement. Here, we report the first molecularly characterized patients with 5-oxoprolinase deficiency due to a mutation in OPLAH (which encodes 5-oxoprolinase). The largely benign clinical course of the patients described herein despite persistent 5-oxoprolinuria highlights the importance of establishing a molecular diagnosis in the few cases with abnormal neurological outcome to exclude potentially overlapping biochemical defects and to explore potential genotype/phenotype correlation. PMID- 21651517 TI - Trefoil factor family peptides in the human foetus and at birth. AB - BACKGROUND: Trefoil factors (TFF1-3) are cysteine-rich peptides secreted by mucosal surfaces. Changing levels of expression are reflected in serum concentrations. Serum levels of TFF2 and TFF3 are highly elevated during pregnancy. Here, we explore a possible foetal origin of these increased levels. MATERIALS AND METHODS: We examined the expression of trefoil peptides in foetal tissues, placentas and foetal membranes from midterm abortions by immunohistochemistry. Employing in-house ELISAs, serum concentrations of TFF1-3 were measured in 92 paired samples of cord and maternal blood prior to delivery. Size exclusion chromatography was used to investigate the molecular forms of TFF1 3. RESULTS: Immunohistochemistry showed all trefoil peptides to be present during foetal life, but compared to adults with a more widespread expression of TFF2 and TFF3 in the stomach and Brunner's glands. No trefoil peptides were seen in placentas or foetal membranes. Median serum concentrations of TFF1 in cord blood were comparable to those observed in the (mother) [0.42 (0.37) nM, P = 0.25], whereas TFF2 and TFF3 showed lower values than in the mother [0.11 (0.69), and 1.2 (6.7) nM, respectively, P < 0.0001 for both peptides]. Size exclusion chromatography showed comparable patterns in mothers and newborns. CONCLUSIONS: All three trefoil peptides are expressed in foetal tissues but not in placenta or foetal membranes. Cord blood contains high levels of all three peptides, although for TFF2 and TFF3 at considerably lower levels than observed in the mother. Thus, the elevated serum levels of TFF2 and TFF3 in the pregnant women were most likely not of foetal origin. PMID- 21651518 TI - The biology of Syngnathidae: pipefishes, seadragons and seahorses. PMID- 21651519 TI - The evolutionary origins of Syngnathidae: pipefishes and seahorses. AB - Despite their importance as evolutionary and ecological model systems, the phylogenetic relationships among gasterosteiforms remain poorly understood, complicating efforts to understand the evolutionary origins of the exceptional morphological and behavioural diversity of this group. The present review summarizes current knowledge on the origin and evolution of syngnathids, a gasterosteiform family with a highly developed form of male parental care, combining inferences based on morphological and molecular data with paleontological evidence documenting the evolutionary history of the group. Molecular methods have provided new tools for the study of syngnathid relationships and have played an important role in recent conservation efforts. Despite recent insights into syngnathid evolution, however, a survey of the literature reveals a strong taxonomic bias towards studies on the species-rich genera Hippocampus and Syngnathus, with a lack of data for many morphologically unique members of the family. The study of the evolutionary pressures responsible for generating the high diversity of syngnathids would benefit from a wider perspective, providing a comparative framework in which to investigate the evolution of the genetic, morphological and behavioural traits of the group as a whole. PMID- 21651520 TI - The genetics and genomics of Syngnathidae: pipefishes, seahorses and seadragons. AB - The goal of this review was to provide a historical overview of how molecular techniques have increased the understanding of the ecology and evolution of the family Syngnathidae (pipefishes, seahorses and seadragons). Molecular studies based primarily on mitochondrial DNA markers have proved their worth by elucidating complex phylogenetic relationships within the family. Phylogeographic studies, which have revealed how life-history traits and past climatic events shape geographic distributions and patterns of genetic variation within syngnathid species, also provide interesting case studies for the conservation and management of threatened species. The application of microsatellite DNA markers has opened a floodgate of studies concerned with the breeding biology of these fishes, which are interesting due to their unique reproductive mode of male pregnancy. Research in this area has contributed significantly to the understanding of mating patterns and sexual selection. Molecular markers may also be employed in studies of demography, migration and local breeding population sizes. Genomic studies have identified genes that are probably involved in male pregnancy and promise additional insights into various aspects of syngnathid biology at the level of the gene. Despite these advances, much more remains to be explored. Goals for future research should include: (1) a more inclusive phylogeny to resolve outstanding issues concerning the relationships within the family and higher order taxa, (2) a broader use of molecular studies to aid management and conservation efforts, (3) the inclusion of more genera in comparative behavioural studies and (4) the continued development of genomic resources for syngnathids to facilitate comparative genomic work. PMID- 21651521 TI - Sexual signals and mating patterns in Syngnathidae. AB - Male pregnancy in the family Syngnathidae (pipefishes, seahorses and seadragons) predisposes males to limit female reproductive success; sexual selection may then operate more strongly on females and female sexual signals may evolve (sex-role reversal). A bewildering array of female signals has evolved in Syngnathids, e.g. skin folds, large body size, colouration, markings on the body and elaborate courtship. These female sexual signals do not seem quantitatively or qualitatively different from those that evolve in males in species with conventional sex roles where males provide females or offspring with direct benefits. In several syngnathid species, males also evolve ornaments, females are choosy in addition to being competitive and males compete as well as choosing partners. Thus, sex roles form a continuum, spanning from conventional to reversed within this group of fishes. Cases are presented here suggesting that stronger sexual selection on females may be most extreme in species showing classical polyandry (one male mates with several females, such as many species where males brood their eggs on the trunk), intermediate in polygynandrous species (males and females both mate with more than one partner, as in many species where males brood their eggs on the tail) and least extreme, even exhibiting conventional sex roles, in monogamous species (one male mates solely with one female, as in many seahorses and tropical pipefishes). At the same time caution is needed before unanimously establishing this pattern: first, the connection between mating patterns, strength of sexual selection, sex roles and ornament expression is far from simple and straightforward, and second, knowledge of the actual morphology, ecology and behaviour of most syngnathid species is scanty. Basically only a few Nerophis, Syngnathus and Hippocampus species have been studied in any detail. It is known, however, that this group of fishes exhibits a remarkable variation in sex roles and ornamentation, making them an ideal group for the study of mating patterns, sexual selection and sexually selected signals. PMID- 21651522 TI - Reproductive endocrinology of Syngnathidae. AB - Few studies have examined the underlying hormonal mechanisms that mediate reproductive cyclicity, male pregnancy and reproductive behaviour in syngnathids. Progress in these areas has been hampered by the small size of most species in the family and a lack of validated techniques for assessing endocrine function. Research on a relatively small number of species has suggested that androgens are likely regulators of spermatogenesis and the development of the male brood pouch prior to pregnancy whereas prolactin and corticosteroids synergistically promote brood pouch function during pregnancy. No evidence supports a reversal of reproductive steroid hormone function in sex-role reversed behaviour, but neuropeptides such as arginine vasotocin or isotocin should be examined for their role in regulating parturition and mating behaviour. The diversity of reproductive patterns exhibited by syngnathids suggests that they will provide a unique opportunity to assess how hormonal regulation of integumentary function, gametogenesis and reproductive behaviour have evolved within a teleost lineage. Additionally, their coastal distribution and embryo retention make them potentially important subjects for studies on the effect of endocrine disruption on fitness. PMID- 21651523 TI - Conservation and management of seahorses and other Syngnathidae. AB - This article analyses the pressures on seahorses and explores conservation responses. It focuses on seahorses (Hippocampus spp.) but also considers pipefishes and seadragons, especially where they can fill gaps in seahorse knowledge. The charisma of many syngnathids can make them good flagship species for threats and solutions in marine conservation. The article combines a synthesis of published literature with new data on the trade in seahorses for traditional medicine, aquarium display and curiosities. Most traded seahorses come from trawl by-catch, although seahorses are also targeted. The total extraction is large, tens of millions of animals annually, and unsustainable. A first review of the effect of habitat change on syngnathids raises many questions, while suggesting that some species may cope better than others. The combination of pressures means that many species of syngnathid are now included in the IUCN Red List of Threatened Species or national equivalents. In addition, seahorse exports from 175 countries are limited to sustainable levels under the Convention on International Trade in Endangered Species (CITES) of Wild Fauna and Flora. Possible conservation measures include marine protected areas, fisheries management, select aquaculture ventures, trade regulation, improved governance (particularly) and consumer engagement. PMID- 21651524 TI - Evidence of paternal nutrient provisioning to embryos in broad-nosed pipefish Syngnathus typhle. AB - In two experiments, radioactively labelled nutrients (either (3)H-labelled amino acid mixture or (14)C-labelled glucose) were tube-fed to brooding male Syngnathus typhle. Both nutrients were taken up by the males and radioactivity generally increased in the brood pouch tissue with time. Furthermore, a low but significant increase of (3)H-labelled amino acids in embryos was found over the experimental interval (48 h), whereas in the (14)C-glucose experiment the radioactivity was taken up by the embryos but did not increase over the experimental time (320 min). Uptake of radioisotopes per embryo did not differ with embryo size. A higher uptake mg(-1) tissue of both (3)H-labelled amino acids and (14)C-labelled glucose was found in smaller embryos, possibly due to a higher relative metabolic rate or to a higher surface-area-to-volume ratio compared to larger embryos. Uptake in embryos was not influenced by male size, embryonic developmental advancement or position in the brood pouch. It is concluded that brooding males provide amino acids, and probably also glucose, to the developing embryos in the brood pouch. PMID- 21651525 TI - Historical and contemporary population genetic connectivity of the European short snouted seahorse Hippocampus hippocampus and implications for management. AB - This first genetic study of Hippocampus hippocampus covers the species' entire geographic range and employs two mtDNA markers (control region and cytochrome b) to establish patterns of population structuring. A total of 255 specimens from 21 locations were used to obtain 89 concatenated haplotypes. The common haplotype was present in all but one population, however, most haplotypes were unique. The haplotype network had a star-like construction, suggesting expansion from a bottleneck event. F(ST) and AMOVA revealed population subdivision into three geographic regions (English Channel + Bay of Biscay, Mediterranean Sea + Atlantic Ocean Iberian coast + Macaronesian Islands, and West Africa) with barriers to gene flow indentified at Cape Finisterre and the Cape Verde frontal zone. Neutrality tests and nested clade analysis suggest a complex demographic history, with both historic events and contemporary processes shaping patterns of genetic differentiation. The genetic population subdivision detected in this study indicates that H. hippocampus should be managed as three separate units. This is especially pertinent as H. hippocampus populations within the West African region are the only ones known to be specifically targeted for exploitation. PMID- 21651526 TI - Photo-identification of individual weedy seadragons Phyllopteryx taeniolatus and its application in estimating population dynamics. AB - Forty-three individual adult weedy seadragons Phyllopteryx taeniolatus were identified from underwater images using patterns of spots and blotches on the lateral surface of the abdomen. These patterns were unique and did not change over the 18 month course of the study and could therefore be used to identify individuals when estimating population variables using non-invasive capture-mark recapture and accumulation curve methods. Two similar neighbouring sites in southern Tasmania showed considerable differences in their estimated populations of P. taeniolatus. Estimated annual survival was >80% at one site suggesting that P. taeniolatus may be considerably longer lived than other syngnathids with a maximum life span in excess of 10 years. Males incubating embryos were observed from October to March and at least two clutches could be borne during this period. This technique of photo-identification could provide a cheap and effective way to monitor populations of this iconic species across its range, particularly in conjunction with optimized pattern-recognition software. PMID- 21651527 TI - Advances in tagging syngnathids, with the effects of dummy tags on behaviour of Hippocampus guttulatus. AB - Artificial marking and tagging techniques have been used to study movement, population dynamics, behaviour, ecology, survival and growth of at least 25 syngnathid species. External necklace-style tags and injection of visible implant elastomer have been the most used techniques, uniquely identifying hundreds of individual syngnathids to study population dynamics, mortality, behaviour, ecology and growth in at least 13 and 12 species, respectively. Only two studies, both on larger syngnathid species, have tested the use of internal or electronic tags. This new case study reveals that dummy tags, weighing up to 6% of individual body mass, have minimal effect on normal ex situ behaviour of the long snouted seahorse Hippocampus guttulatus, a smaller syngnathid. In paired aquarium trials, tags did not affect movement, holdfast use or general behavioural state, and only had a short-term effect (1 day) on vertical orientation. Tagged H. guttulatus gained more mass during the 5 day trials, a result which warrants further exploration but indicates that tags did not reduce feeding. This study shows promise for using electronic tagging to study H. guttulatus and similarly sized syngnathids in the wild. PMID- 21651528 TI - Why the long face? A comparative study of feeding kinematics of two pipefishes with different snout lengths. AB - This study showed that the mouth of Doryrhamphus dactyliophorus, a species with a relatively long snout, travels a greater distance compared with Doryrhamphus melanopleura, a species with a considerably shorter snout, allowing it to strike at prey that are farther away from the mouth. The long-snouted species also tended to reach significantly higher linear velocities of the mouth approaching the prey. On the other hand, D. melanopleura needed less time to capture its prey. A striking difference in prey-capture success was observed between species: D. melanopleura and D. dactyliophorus had a prey-capture success of 91 and 31%, respectively. The small prey size and the relatively large distance between eyes and prey are potential reasons why directing the mouth accurately to the prey is difficult in D. dactyliophorus, hence possibly explaining the lower prey-capture success in this long-snouted species. PMID- 21651529 TI - Musculoskeletal structure of the feeding system and implications of snout elongation in Hippocampus reidi and Dunckerocampus dactyliophorus. AB - A thorough morphological description of the feeding apparatus in Hippocampus reidi, a long-snouted seahorse, and Dunckerocampus dactyliophorus, an extremely long-snouted pipefish, revealed specialized features that might be associated with the fast and powerful suction feeding, like the two ligamentous connections between the lower jaw and the hyoid, the saddle joint of the latter with the suspensorium and the vertebro-pectoral fusion that articulates on three points with the cranium. Despite the conserved morphology of the feeding apparatus, it was found that in H. reidi the orientation of the occipital joint is ventrocaudal, the sternohyoideus and epaxial muscles are more bulky and both have a short tendon. In D. dactyliophorus, on the other hand, the protractor hyoidei muscle is enclosed by the mandibulo-hyoid ligament, the sternohyoideus and epaxial tendons are long and a sesamoid bone is present in the latter. These features were compared to other syngnathid species with different snout lengths to evaluate the implications of snout elongation on the musculoskeletal structure of the cranium. The arched path of the adductor mandibulae and the greater rigidity of the lower jaw might be related to elongation of the snout, as it yields an increased mechanical advantage of the lower jaw system and a reduced torque between the elements of the lower jaw during protractor hyoidei muscle contraction, respectively. Nevertheless, most observed features did not seem to be related to snout length, but might be associated with different force generating strategies. PMID- 21651530 TI - Fine-scale spatial and temporal variations in diets of the pipefish Stigmatopora nigra within seagrass patches. AB - Diets of the pipefish Stigmatopora nigra were analysed to determine if food availability was causing S. nigra to distribute according to habitat edge effects. Gut analysis found little difference in the diets of S. nigra at the edge and interior of seagrass patches, regardless of time of day or season. Fish diets did, however, vary with seagrass density: S. nigra in denser seagrass consumed more harpacticoid copepods and fewer planktonic copepods. The lack of difference in prey eaten by S. nigra at the edge and interior of patches suggests either that food was not determining S. nigra distribution patterns within patches or that differences in fish densities across patches meant that relative fish-prey densities were similar at edge and interior positions. Alternatively, any edge effects in diet might be masked by gradients in seagrass structure. PMID- 21651531 TI - The ovarian structure and mode of egg production in two polygamous pipefishes: a link to mating pattern. AB - In this study, the ovarian structure and mode of egg production were examined in two pipefishes, the broad-nosed pipefish Syngnathus typhle and the straight-nosed pipefish Nerophis ophidion, which show different types of polygamous mating patterns. Syngnathus typhle showed an ovary with one germinal ridge and asynchronous egg production, corresponding to previous findings in other polygamous Syngnathus pipefishes. In contrast, the ovary of N. ophidion had two germinal ridges and eggs were produced synchronously in groups, similar to what has been observed in monogamous syngnathids. The egg production of N. ophidion, however, is clearly distinguished from that of monogamous syngnathids by the additional egg production after an ovulation. It is suggested that the differences in female mating strategies result from the difference in egg production process and that this is related to the difference in mating pattern between these two polygamous species. PMID- 21651532 TI - The relationship between female body size and egg size in pipefishes. AB - Comparing five species of pipefish, egg size was significantly larger in species with brood pouches (Syngnathus typhle, Syngnathus acus and Syngnathus rostellatus) than in species without brood pouches (Entelurus aequoreus and Nerophis ophidion). Egg size correlated positively with female body size in species with brood pouches, but was similar across female sizes in the species lacking pouches. These results may reflect differences in offspring competition as a consequence of variable offspring relatedness within a brood, due to the mating systems adopted by the different species and the presence or absence of a brood pouch. PMID- 21651533 TI - Straight-nosed pipefish Nerophis ophidion and broad-nosed pipefish Syngnathus typhle avoid eelgrass overgrown with filamentous algae. AB - In a habitat choice experiment straight-nosed pipefish Nerophis ophidion and broad-nosed pipefish Syngnathus typhle avoided eelgrass Zostera marina covered with filamentous algae. Both juveniles as well as brooding adult males of the two species clearly preferred to position themselves in Z. marina without growth of filamentous algae. PMID- 21651534 TI - Male broad-nosed pipefish Syngnathus typhle do not locate females by smell. AB - Broad-nosed pipefish Syngnathus typhle were used to investigate whether males used scent in their search for mates. When the males in an experiment had access to olfactory cues only, they did not locate females better than they located males. Thus, S. typhle, was less successful in mate search when visual cues were absent. PMID- 21651537 TI - Timothy Bracegirdle Bagenal 1925-2011 (fish ecologist). PMID- 21651538 TI - Implications of a warming North Sea for the growth of haddock Melanogrammus aeglefinus. AB - The present study aimed firstly, to test for a temperature effect on North Sea haddock Melanogrammus aeglefinus growth and secondly, to develop a model that could be used to assess total length (L(T)) and mass (M)-at-age response to different temperature scenarios. The von Bertalanffy growth model was fitted on a cohort-by-cohort basis from 1970 to 2006. The asymptotic L(T) (L(infinity)) was negatively correlated with temperature while the rate at which L(infinity) is reached (K) was positively correlated with temperature. K was negatively correlated with density, whereas no effect on L(infinity) was observed. These effects were incorporated into a von Bertalanffy model which was extended to include temperature and density as explanatory variables. Only the temperature variable was significant. Fitting the extended von Bertalanffy model revealed that L(infinity) decreased while K increased with increasing temperature, resulting in up to a 40% loss of individual yield at older ages. The dramatic decline observed in the mean age at which 50% of the population becomes mature suggests that higher temperatures resulted in larger young M. aeglefinus that matured earlier and therefore reached a smaller maximum size. In a global warming context, the loss of individual yield observed at old ages is likely to reduce the fisheries yield for M. aeglefinus in the North Sea. PMID- 21651539 TI - Proposed standard mass equations for European chub Leuciscus cephalus in Italy. AB - Total length (L(T)) and mass measurements of 28,596 specimens of European chub Leuciscus cephalus, collected from a variety of waterways across Italy, were used to compute standard mass (W(s)) equations by both empirical percentile (EmP) and regression line percentile (RLP) methods. The use of the EmP W(s) equation [log(10) W(s) = -4.79 + 2.68log(10) L(T) + 0.10(log(10) L(T))(2)] to compute relative mass (W(r)) of L. cephalus in Italy is suggested, as it was not influenced by length-related bias (L(T) range of application = 70-470 mm). PMID- 21651540 TI - Gonadal development of triploid Atlantic Cod Gadus morhua. AB - During their third and fourth years of life, triploid Atlantic cod Gadus morhua females exhibited diminished ovarian development at both macroscopic and microscopic levels, with significantly lower gonado-somatic indices (I(G)) and higher carcass yields (Y(C)) than diploid females during spawning periods. In contrast, diploid and triploid testes were indistinguishable through macroscopic and histological assessment. No significant differences were found in male I(G) or Y(C) in relation to ploidy, with the exception of a higher Y(C) for triploids during the first of the two monitored spawning seasons. As a result of suppressed oogenesis, triploid female G. morhua, but not triploid males, can be used to eliminate sexual maturation in this species and advance the development of the G. morhua aquaculture industry. PMID- 21651541 TI - To what extent are the dietary compositions of three abundant, co-occurring labrid species different and related to latitude, habitat, body size and season? AB - This study demonstrated that the dietary composition of each of three abundant reef-associated labrid species in temperate Western Australia differed significantly with latitude and changed with increasing body size and almost invariably differed among those species when they co-occurred. These results were derived from comparisons and multivariate analyses of volumetric dietary data, obtained from the foregut contents of Coris auricularis, Notolabrus parilus and Ophthalmolepis lineolatus from the Jurien Bay Marine Park (JBMP) and waters off Perth, 250 km to the south. Latitudinal differences in the dietary compositions of each species in exposed reefs typically reflected greater contributions by large crustaceans, bivalve molluscs, echinoids and annelids to the diets in the waters off Perth than in the JBMP, whereas the reverse was true for gastropods and small crustaceans. The diet of each species exhibited similar, but not identical, quantitative changes with increasing body size, with the contributions of small crustaceans declining and those of large crustaceans and echinoids increasing, while that of gastropods underwent little change. Within the JBMP, the dietary compositions of both C. auricularis and N. parilus were similar in exposed and sheltered reefs and the same was true for N. parilus in the sheltered reefs and interspersed areas of seagrass. The latter similarity demonstrated that, in both of those divergent habitat types, N. parilus feeds on prey associated with either the sand or the macrophytes that cover and lie between the reefs. Although the main dietary components of each species were the same, i.e. gastropods, small crustaceans (mainly amphipods and isopods), large crustaceans (particularly penaeids and brachyuran crabs) and echinoids, their contributions varied among those species, which accounts for the significant interspecific differences in diet. Coris auricularis had the most distinct diet, due mainly to an ingestion of greater volumes of small crustaceans, e.g. amphipods and isopods, and lesser volumes of large crustaceans, e.g. brachyuran crabs, which was associated with a relatively narrower mouth and smaller teeth and the absence of prominent canines at the rear of the jaw. The above intra and interspecific differences in dietary composition would reduce, on the south-west coast of Australia, the potential for competition for food among and within these three abundant labrids, each of which belongs to different genera within the Julidine clade. PMID- 21651542 TI - Round goby Neogobius melanostomus attraction to conspecific and heterospecific egg odours. AB - In this study, cannibalistic and predatory responses of juvenile Neogobius melanostomus (either fed or deprived of food and caught during the reproductive summer or non-reproductive winter season) to water washings of fertilized eggs from conspecifics (N. melanostomus), heterospecifics (rainbow trout Oncorhynchus mykiss) and control lake water were tested. Fed juveniles (summer season) spent significantly more time on the side of the flume containing stimuli from conspecific eggs over control water, while significantly preferring control water to heterospecific stimuli. In addition, fish showed a significant preference towards stimuli from conspecific eggs over heterospecific stimuli by associating near conspecific egg odours 1.5 times longer [Correction added after online publication 28 April 2011, text changed]. Fish that were deprived of food, regardless of whether caught during the summer or winter season, did not show any preference towards either conspecific or heterospecific stimuli. These findings show that conspecific egg odours attract fed juveniles and that there is a potential to lure fish to odour traps as a means of control. PMID- 21651543 TI - Interplay of individual interactions and turbidity affects the functional response of three-spined sticklebacks Gasterosteus aculeatus. AB - The effects of turbidity, size and the presence of conspecifics on the functional response, feeding latency and activity in the three-spined stickleback Gasterosteus aculeatus were examined. A significant interaction between standard length and presence of conspecifics demonstrated an increase in attack rates of larger individuals in the presence of conspecifics. Attack rate was also higher in turbid water. Feeding latency decreased with prey concentration and presence of conspecifics, but was not affected by turbidity. Activity level did not change with prey levels, but increased with turbidity. These results can help to better understand how individual flexibility in the functional response can affect prey mortality according to environmental perturbation and social interaction at the level of the predator. PMID- 21651544 TI - Experimental quantification of the swimming performance and behaviour of spawning run river lamprey Lampetra fluviatilis and European eel Anguilla anguilla. AB - Using a large-scale open-channel flume, the swimming ability and behaviour of individual adult European eel Anguilla anguilla and river lamprey Lampetra fluviatilis, species that exhibit anguilliform locomotion, were quantified under complex hydraulic conditions created by a 0.2-0.3 m high under- or overshot weir during four discharge regimes. Fishes were allowed to approach the weirs from both up- and downstream. All fishes passed the undershot weir, independent of discharge and direction of movement, and under high flow (mean +/-S.E. 194.63 +/- 6.48 l s(-1)) moved upstream against velocities that ranged between 1.75 and 2.12 m s(-1), suggesting greater maximum swimming capability than previously reported. In comparison, passage efficiency during upstream movement was lower for the overshot weir for both L. fluviatilis and A. anguilla. Downstream moving A. anguilla took longer to pass the over- than undershot weir. This study describes a methodology to attain realistic measures of swimming ability and behavioural performance required to develop multispecies fish passage criteria. PMID- 21651545 TI - Residency time, migration route and survival of Atlantic salmon Salmo salar smolts in a Canadian fjord. AB - Atlantic salmon Salmo salar smolts (n = 181) from two rivers were surgically implanted with acoustic transmitters and released to determine migration route, residency time and survival in a 50 km long estuarine fjord located on the south coast of Newfoundland, Canada. Data obtained from automated receivers placed throughout the Bay d'Espoir fjord indicated that migrating smolts used different routes to reach the outer areas of the fjord. The duration of time that smolts spent in the immediate estuary zone also differed between the two localities (7 and 17 days) although the total time smolts were resident in the fjord was similar and extensive (40 days). Many smolts were resident for periods of 4-8 weeks moving back and forth in the outer part of the fjord where maximum water depths range from 300 to 700 m. Survival in the estuary zone was greater for smolts with prolonged residency in estuarine habitat. Overall smolt survival to the fjord exit was moderately high (54-85%), indicating that the initial phase of migration did not coincide with a period of unusually high mortality. PMID- 21651546 TI - Age and growth of the round goby Neogobius melanostomus in the Gulf of Gdansk several years after invasion. Is the Baltic Sea a new Promised Land? AB - The ages of 8 to 23.5 cm total length (L(T)) round goby Neogobius melanostomus collected monthly during 2006 and 2007 in the Gulf of Gdansk (Baltic Sea) ranged from 2 to 6 years, with age class 4+ years dominant. Males were larger at age than females. The fastest growth occurred in the first 2 years of life in both sexes. Females were heavier at a given L(T) than males, but only for fish > c. 15 cm. A strong relationship between N. melanostomus otolith size and fish size was found, with no difference between males and females, and a significant relationship between fish growth rate and otolith growth rate, which enabled backcalculation of growth rates. Marginal increment width analysis confirmed the periodicity of annual ring formation in otoliths and showed that the most intense opaque zone formation occurs in July to August, while hyaline zone formation starts as early as September to October. It was concluded that the N. melanostomus that have colonized the southern Baltic Sea exhibit the largest size and longest life span ever recorded for this species. PMID- 21651547 TI - Migration ecology of juvenile temperate seabass Lateolabrax japonicus: a carbon stable-isotope approach. AB - The migration pattern of juvenile temperate seabass Lateolabrax japonicus in the stratified estuary of the Yura River was examined using carbon stable-isotope ratios (delta(13)C). delta(13)C values of mysids, which are the most important prey items for this species, were consistently enriched in the lower estuary and surf zone (LES), while depleted in the freshwater zone (FW). delta(13)C values of juveniles in LES were enriched, while those in FW were depleted, consistent with the delta(13)C difference in prey items. The results of delta(13)C showed that many juveniles migrated upstream from April to June and most of them stayed in FW until at least July. Juveniles that stayed in FW and LES for a relatively longer period (> c. 20 days) showed higher condition factors than those that stayed in FW for a short period (several days). This indicates that residence in FW enabled juveniles to achieve as good a body condition as residence in LES. PMID- 21651548 TI - The life histories of endangered hammerhead sharks (Carcharhiniformes, Sphyrnidae) from the east coast of Australia. AB - The life histories of two globally endangered hammerhead sharks, Sphyrna lewini and Sphyrna mokarran, were examined using samples collected from a range of commercial fisheries operating along the east coast of Australia. The catch of S. lewini was heavily biased towards males, and there were significant differences in von Bertalanffy growth parameters (L(infinity) and k) and maturity [stretched total length (L(ST)) and age (A) at which 50% are mature, L(ST50) and A(50)] between those caught in the tropics (L(infinity) = 2119 mm, k = 0.163, L(ST50) = 1471 mm, A(50) = 5.7 years) and those caught in temperate waters (L(infinity) = 3199 mm, k = 0.093, L(ST50) = 2043 mm, A(50) = 8.9 years). The best-fit estimates for a three-parameter von Bertalanffy growth curve fit to both sexes were L(infinity) = 3312 mm, L(0) = 584 mm and k = 0.076. Males attained a maximum age of 21 years and grew to at least 2898 mm L(ST). The longevity, maximum length and maturity of females could not be estimated as mature animals could not be sourced from any fishery. Length at birth inferred from neonates with open umbilical scars was 465-563 mm L(ST). There was no significant difference in length and age at maturity of male and female S. mokarran, which reached 50% maturity at 2279 mm L(ST) and 8.3 years. Sphyrna mokarran grew at a similar rate to S. lewini and the best-fit estimates for a two-parameter von Bertalanffy equation fit to length-at age data for sexes combined with an assumed mean length-at-birth of 700 mm were L(infinity) = 4027 mm and k = 0.079. Females attained a maximum age of 39.1 years and grew to at least 4391 mm L(ST). The oldest male S. mokarran was 31.7 years old and 3691 mm L(ST). Validation of annual growth-band deposition in S. mokarran was achieved through a mark, tag and recapture study. PMID- 21651549 TI - Diet and food selection by Ramnogaster arcuata (Osteichthyes, Clupeidae). AB - The goals of this study were to describe the diet and estimate the trophic level and food selection of Jenyns's sprat Ramnogaster arcuata, one of the common fishes in the Bahia Blanca estuary in Argentina. The copepods Acartia tonsa [53.7% index of relative importance (I(RI))] and Eurytemora americana (13.4% I(RI)), the mysid Arthromysis magellanica (13.9%I(RI)) and the small shrimp Peisos petrunkevitchi (8.2% I(RI)) were the most important food items for this species, and its diet exhibited monthly variability with respect to the principal prey categories. The zooplankton species in the study area consisted of 32 taxa. Acartia tonsa was the most abundant species [54% individuals (N) m(-3)], followed by Balanus glandula (13.8% N m(-3)) and E. americana (10.1% N m(-3)). The rest of the zooplankton groups represented <3% N m(-3). The most preferred items throughout the year were A. magellanica and Idotea sp. The trophic level value estimated was 3.1. PMID- 21651550 TI - Reproductive cycles of Mugil cephalus, Liza ramada and Liza aurata (Teleostei: Mugilidae). AB - The reproductive cycles of three mullet species from the Eastern Adriatic coast were described using several biological parameters (gonado-somatic index, oocyte diameter and sex ratio) to improve knowledge about their reproduction. PMID- 21651551 TI - Successful extraction of DNA from archived alcohol-fixed white-eye fish specimens using an ancient DNA protocol. AB - A protocol used routinely for rapid ancient DNA extraction was applied to fish tissue archived over 80 years ago. The method proved successful, whereas other extraction protocols failed. Researchers working on DNA from older archived fish samples are encouraged to continue to concentrate their efforts on 'white-eye' specimens, which indicate an alcohol-based fixative and are thus likely to yield viable DNA. PMID- 21651552 TI - Discriminating two races of Liobagrus marginatoides by cytogenetic analysis. AB - Although two kinds of Liobagrus marginatoides should belong to the same species according to the taxonomy of fish morphology, the results of cytogenetic analysis showed they are two different races. PMID- 21651553 TI - Hypoxia and male behaviour in an African cichlid Pseudocrenilabrus multicolor victoriae. AB - This study tested the prediction that hypoxia may reduce the frequency of energetically expensive behaviours by quantifying male mating and aggressive displays in the cichlid Pseudocrenilabrus multicolor victoriae after long-term acclimation (5 months) to either high dissolved oxygen (DO) or low DO. Regardless of DO treatment, males engaged in more aggressive displays than mating displays; however, males acclimated to low DO reduced their total number of displays compared to high DO-acclimated males. PMID- 21651558 TI - Influence of signalment on developing cranial cruciate rupture in dogs in the UK. AB - OBJECTIVES: To investigate risk factors associated with cranial cruciate ligament rupture in dogs. METHODS: Retrospective case-control study: medical records of a first-opinion veterinary practice were searched for dogs diagnosed with cranial cruciate ligament rupture (1995 to 2007). For each case, six unaffected dogs were randomly selected from all dogs presenting that day for comparison. Multi variable binary logistic regression was performed to assess the association of variables on likelihood of cruciate rupture. RESULTS: Frequency of cranial cruciate ligament rupture was 1.19% [95% confidence interval (CI) 1.02 to 1.36%]. West Highland white terriers (n=17), Yorkshire terriers (n=14) and Rottweilers (n=11) were at significantly increased risk of cranial cruciate ligament rupture (P<=0.002). Rottweilers were at five times greater risk compared with other pure breeds (OR 5.12, 95% CI 2.281 to 11.494, P<0.001), obesity quadrupled the risk of cranial cruciate ligament rupture (OR 3.756, 95% CI 1.659 to 8.502, P=0.001) and females were twice as likely to suffer cranial cruciate ligament failure compared to males (OR 2.054, 95% CI 1.467 to 2.877, P<0.001). Dogs less than two years old were statistically less likely to sustain cranial cruciate ligament rupture than dogs older than eight years (OR 0.246, 95% CI 0.127 to 0.477, P<0.001). There was no significant difference in median weights (in kilograms) of neutered dogs, compared to their entire counterparts in either the case group (P=0.994) or in the control group (P=0.630). There was also no significant difference in body condition (-underweight/normal weight/overweight/obese) of neutered versus entire dogs among the cases (P=0.243), or the controls (P=0.211). CLINICAL SIGNIFICANCE: Cranial cruciate ligament rupture is more likely in Rottweilers and in female dogs, older dogs and obese dogs. Following multi-variable analysis, it was established that neutering was not associated with increased risk of cranial cruciate ligament rupture. PMID- 21651557 TI - Cytochrome P450 mediates dopamine formation in the brain in vivo. AB - The cytochrome P450-mediated synthesis of dopamine from tyramine has been shown in vitro. The aim of the present study was to demonstrate the ability of rat cytochrome P450 (CYP) 2D to synthesize dopamine from tyramine in the brain in vivo. We employed two experimental models using reserpinized rats with a blockade of the classical pathway of dopamine synthesis from tyrosine. Model A estimated dopamine production from endogenous tyramine in brain structures in vivo (ex vivo measurement of a tissue dopamine level), while Model B measured extracellular dopamine produced from exogenous tyramine (an in vivo microdialysis). In Model A, quinine (a CYP2D inhibitor) given intraperitoneally caused a significant decrease in dopamine level in the striatum and nucleus accumbens and tended to fall in the substantia nigra and frontal cortex. In Model B, an increase in extracellular dopamine level was observed after tyramine given intrastructurally (the striatum). After joint administration of tyramine and quinine, the amount of the dopamine formed was significantly lower compared to the group receiving tyramine only. The results of the two complementary experimental models indicate that the hydroxylation of tyramine to dopamine may take place in rat brain in vivo, and that CYP2D catalyzes this reaction. PMID- 21651559 TI - A eukaryotic-like sulfiredoxin involved in oxidative stress responses and in the reduction of the sulfinic form of 2-Cys peroxiredoxin in the cyanobacterium Anabaena PCC 7120. AB - The overoxidation of 2-Cys peroxiredoxins (Prxs) into a sulfinic form was thought to be an irreversible protein inactivation process until sulfiredoxins (Srxs) were discovered. These are enzymes occurring among eukaryotes, which are able to reduce sulfinylated Prxs. Although Prxs are present in the three domains of life, their reduction by Srxs has been described only in eukaryotes so far. Here it was established that the cyanobacterium Anabaena PCC 7120 has a Srx homologue (SrxA), which is able to specifically reduce the sulfinic form of the 2-Cys Prx (PrxA) both in vivo and in vitro. A mutant lacking the srxA gene was found to be more sensitive than the wild type to oxidative stress. Sulfiredoxin homologues are restricted to the cyanobacterial and eukaryotic genomes sequenced so far. The present phylogenetic analysis of Srx and 2-Cys Prx sequences showed a pattern of coevolution of the enzyme and its substrate that must have involved an ancient gene transfer between ancestors of Cyanobacteria and Eukaryotes, followed by a more recent transfer from Cyanobacteria to Plantae through the chloroplastic endosymbiosis. This is the first functional characterization of a Srx enzyme in a prokaryotic organism. PMID- 21651560 TI - Seven years of carbon dioxide enrichment, nitrogen fertilization and plant diversity influence arbuscular mycorrhizal fungi in a grassland ecosystem. AB - * We tested the prediction that the abundance and diversity of arbuscular mycorrhizal (AM) fungi are influenced by resource availability and plant community composition by examining the joint effects of carbon dioxide (CO(2) ) enrichment, nitrogen (N) fertilization and plant diversity on AM fungi. * We quantified AM fungal spores and extramatrical hyphae in 176 plots after 7 yr of treatment with all combinations of ambient or elevated CO(2) (368 or 560 ppm), with or without N fertilization (0 or 4 g Nm(-2) ), and one (monoculture) or 16 host plant species (polyculture) in the BioCON field experiment at Cedar Creek Ecosystem Science Reserve, Minnesota, USA. * Extramatrical hyphal lengths were increased by CO(2) enrichment, whereas AM spore abundance decreased with N fertilization. Spore abundance, morphotype richness and extramatrical hyphal lengths were all greater in monoculture plots. A structural equation model showed AM fungal biovolume was most influenced by CO(2) enrichment, plant community composition and plant richness, whereas spore richness was most influenced by fungal biovolume, plant community composition and plant richness. * Arbuscular mycorrhizal fungi responded to differences in host community and resource availability, suggesting that mycorrhizal functions, such as carbon sequestration and soil stability, will be affected by global change. PMID- 21651561 TI - Selective seed abortion induced by nectar robbing in the selfing plant Comastoma pulmonarium. AB - * Self-pollination often provides plants with the benefit of reproductive assurance; thus, it is generally assumed that species' interactions that alter floral attractiveness or rewards, such as nectar robbing, will have little effect on the seed production of selfing species. We challenge this view with experimental data from Comastoma pulmonarium, a selfing annual experiencing a high ratio of nectar robbing in the Qinghai-Tibet Plateau. * We manipulated robbing (robbed or netted) and pollination mode (hand-selfed or hand-outcrossed) in a factorial design and measured the number of developing ovules and mature seeds, together with seed weight and seed germination, in each treatment. * Robbing decreased the number of mature seeds, but not the number of developing ovules, suggesting a negative influence of robbers through indirect effects via selective seed abortion. We found no evidence for early-acting inbreeding depression, but found later-acting inbreeding depression. Our data also suggested that later-acting inbreeding depression of progeny from robbed flowers could be reduced in comparison with that from unrobbed flowers. * We suggest that nectar robbing can have both negative and positive effects on the quantity and quality, respectively, of progeny produced in selfing plants, and challenge the view that robbing has no effect on selfing species. PMID- 21651562 TI - Phenotypic consequences of polyploidy and genome size at the microevolutionary scale: a multivariate morphological approach. AB - * Chromosomal duplications and increases in DNA amount have the potential to alter quantitative plant traits like flower number, plant stature or stomata size. This has been documented often across species, but information on whether such effects also occur within species (i.e. at the microevolutionary or population scale) is scarce. * We studied trait covariation associated with polyploidy and genome size (both monoploid and total) in 22 populations of Dianthus broteri s.l., a perennial herb with several cytotypes (2x, 4x, 6x and 12x) that do not coexist spatially. Principal component scores of organ size/number variations were assessed as correlates of polyploidy, and phylogenetic relatedness among populations was controlled using phylogenetic generalized least squares. * Polyploidy covaried with organ dimensions, causing multivariate characters to increase, remain unchanged, or decrease with DNA amount. Variations in monoploid DNA amount had detectable consequences on some phenotypic traits. According to the analyses, some traits would experience phenotypic selection, while others would not. * We show that polyploidy contributes to decouple variation among traits in D. broteri, and hypothesize that polyploids may experience an evolutionary advantage in this plant lineage, for example, if it helps to overcome the constraints imposed by trait integration. PMID- 21651563 TI - Type-2 histone deacetylases as new regulators of elicitor-induced cell death in plants. AB - * Plant resistance to pathogen attack is often associated with a localized programmed cell death called hypersensitive response (HR). How this cell death is controlled remains largely unknown. * Upon treatment with cryptogein, an elicitor of tobacco defence and cell death, we identified NtHD2a and NtHD2b, two redundant isoforms of type-2 nuclear histone deacetylases (HDACs). These HDACs are phosphorylated after a few minutes' treatment, and their rate of mRNAs are rapidly and strongly reduced, leading to a 40-fold decrease after 10 h of treatment. * By using HDAC inhibitors, RNAi- and overexpression-based approaches, we showed that HDACs, and especially NtHD2a/b, act as inhibitors of cryptogein induced cell death. Moreover, in NtHD2a/b-silenced plants, infiltration with cryptogein led to HR-like symptoms in distal leaves. * Taken together, these results show for the first time that type-2 HDACs, which are specific to plants, act as negative regulators of elicitor-induced cell death in tobacco (Nicotiana tabacum), suggesting that the HR is controlled by post-translational modifications including (de)acetylation of nuclear proteins. PMID- 21651564 TI - The neuroevolution of empathy. AB - There is strong evidence that empathy has deep evolutionary, biochemical, and neurological underpinnings. Even the most advanced forms of empathy in humans are built on more basic forms and remain connected to core mechanisms associated with affective communication, social attachment, and parental care. Social neuroscience has begun to examine the neurobiological mechanisms that instantiate empathy, especially in response to signals of distress and pain, and how certain dispositional and contextual moderators modulate its experience. Functional neuroimaging studies document a circuit that responds to the perception of others' distress. Activation of this circuit reflects an aversive response in the observer, and this information may act as a trigger to inhibit aggression or prompt motivation to help. Moreover, empathy in humans is assisted by other domain-general high-level cognitive abilities, such as executive functions, mentalizing, and language, which expand the range of behaviors that can be driven by empathy. PMID- 21651565 TI - Social isolation. AB - Social species, by definition, form organizations that extend beyond the individual. These structures evolved hand in hand with behavioral, neural, hormonal, cellular, and genetic mechanisms to support them because the consequent social behaviors helped these organisms survive, reproduce, and care for offspring sufficiently long that they too reproduced. Social isolation represents a lens through which to investigate these behavioral, neural, hormonal, cellular, and genetic mechanisms. Evidence from human and nonhuman animal studies indicates that isolation heightens sensitivity to social threats (predator evasion) and motivates the renewal of social connections. The effects of perceived isolation in humans share much in common with the effects of experimental manipulations of isolation in nonhuman social species: increased tonic sympathetic tonus and HPA activation; and decreased inflammatory control, immunity, sleep salubrity, and expression of genes regulating glucocorticoid responses. Together, these effects contribute to higher rates of morbidity and mortality in older adults. PMID- 21651566 TI - Lifestyle factors and sensitization in children - the ALADDIN birth cohort. AB - BACKGROUND: Several cross-sectional studies indicate that an anthroposophic lifestyle reduces the risk of allergy in children. We initiated the Assessment of Lifestyle and Allergic Disease During Infancy (ALADDIN) birth cohort to elucidate the role of specific factors supposed to mediate this effect. The aims of this study are to describe the ALADDIN cohort and to report patterns of exposure and allergic sensitization during the first years of life. METHODS: The ALADDIN study is a prospective birth cohort study of 330 children from families with an anthroposophic, partly anthroposophic, or nonanthroposophic lifestyle. The children and their parents were following an extensive data collection scheme, including repeated questionnaires and biological samples. Blood samples were collected from the parents and from the child at birth as well as at 6, 12, and 24 months of age. RESULTS: Several lifestyle factors differed between the groups, such as diet, medication, and place of delivery. Children of families with an anthroposophic lifestyle had a markedly decreased risk of sensitization during the first 2 years of life compared with children of nonanthroposophic families with adjusted OR 0.25 (95% CI 0.10-0.64) and P-value 0.004. A similar situation held true for children from families with a partly anthroposophic lifestyle, adjusted OR 0.31 (95% CI 0.15-0.54), and P-value 0.002. CONCLUSIONS: The anthroposophic lifestyle comprises several factors of interest for allergy development and is here shown to be associated with reduced risk of IgE sensitization already in infancy. Identifying the factors responsible for this association would be of significant clinical importance. PMID- 21651567 TI - Tropomyosin IgE-positive results are a good predictor of shrimp allergy. AB - BACKGROUND: Shrimp is a common cause of food allergy. Our aims were to determine the value of IgE antibodies in the diagnosis of shrimp allergy and to study red shrimp (Solenocera melantho) tropomyosin both as a new allergen and as a cross reactive IgE-binding protein. METHODS: We have studied 45 subjects. Skin prick test (SPT) was carried out in all subjects, and specific IgE (sIgE) to shrimp, recombinant and natural shrimp tropomyosins rPen a 1 and nPen m 1, recombinant Der p 10, and Dermatophagoides pteronyssinus was assessed by fluoroimmunoassay and/or immunoblotting. Double-blind, placebo-controlled food challenges were carried out to confirm diagnosis of shrimp allergy. Also, in vitro inhibition tests were performed to evaluate cross-reactivity. RESULTS: Shrimp allergy was confirmed in 18 shrimp-allergic patients. Skin prick test and IgE antibodies to shrimp were positive in all shrimp-allergic patients; sIgE to rPen a 1 was detected in 98% of these patients. Of the 18 shrimp-tolerant patients, 61% had positive SPT to shrimp, 55% were IgE-positive to shrimp, and 33% showed IgE antibodies to rPen a 1. Determination of IgE to rPen a 1 yielded a positive predictive value of 0.72 and a negative predictive value of 0.91. CONCLUSION: IgE levels to rPen a 1 provided additional value to the diagnosis of shrimp allergy. Some allergens in mite extract are recognized by patients who are allergic to shrimp, though their clinical relevance remains unknown. PMID- 21651568 TI - Hormonal male contraception in men with normal and subnormal semen parameters. AB - Hormonal male contraception based on testosterone alone or on a combination of testosterone with a gestagen has been shown to suppress spermatogenesis effectively and to be fully reversible. However, clinical studies to date have only included volunteers with so-called 'normal' semen values by WHO standards. As a male contraceptive should be available to all interested men regardless of their semen parameters, we investigated how volunteers with subnormal semen parameters would respond to hormonal male contraception. During a 34-week treatment phase, the volunteers received injections of 1000 mg testosterone undecanoate in weeks 0, 6, 14 and 24. This was followed by a 24-week recovery and follow-up period. As it was not known whether men with subnormal semen parameters would recover to starting levels, cryopreservation of semen was offered to all subnormal volunteers. Twenty-three men with normal semen parameters and 18 with sperm counts below 20 million completed the trial. The normal volunteers showed the expected response with 17 suppressing sperm counts below 1 million/ejaculate (13 showing azoospermia) and six not-suppressing below 1 million sperm/ejaculate. By the end of the recovery period, all sperm counts had returned to the range of starting values. The subnormal group showed a similar pattern with 13 of 18 (= 72%) men suppressing below 1 million/ejaculate (8/18 = 44% showing azoospermia) and the remaining 5 of 18 (= 28%) not-suppressing sperm counts below 1 million/ejaculate. All sperm counts returned to the starting range. The study shows that in Caucasian men with normal sperm counts as well as in men with subnormal sperm counts, testosterone alone can produce azoospermia in about half and suppression below one million in about two-thirds of the volunteers. The same proportion of men in both groups appears to require an additional gestagen for full contraceptive protection. Most importantly, regarding suppressibility and reversibility, volunteers with normal and subnormal sperm counts display the same pattern. PMID- 21651569 TI - Clinical management of male infertility in assisted reproduction: ICSI and beyond. AB - The advent of in vitro fertilization and its augmentation with intracytoplasmic sperm injection (ICSI) has allowed a large number of couples suffering from moderate to severe male infertility, and also presenting with female pathologies, to achieve their reproductive dreams. Notwithstanding the existence of fundamental questions about the pathophysiological mechanisms leading to sperm dysfunction, and still unanswered concerns about health risks following ICSI, it appears that overall ICSI is safe and here to stay. Although on one hand ICSI possibly hampered advances of the knowledge in some areas of gamete biology and interaction, on the other it definitely gave impulse to studies designed to unveil the sperm contributions during and beyond fertilization, including the normalcy of the DNA/chromatin as well as molecular mechanisms of genetic/epigenetic control and nuclear organization status. In all, almost entering the fourth decade of assisted reproductive technologies, we should continue monitoring the safety of the technique and long-term development of offspring, whereas at the same time prioritizing areas of research addressing these fundamental questions. PMID- 21651570 TI - Androgen receptor signalling in peritubular myoid cells is essential for normal differentiation and function of adult Leydig cells. AB - Testosterone synthesis depends on normal Leydig cell (LC) development, but the mechanisms controlling this development remain unclear. We recently demonstrated that androgen receptor (AR) ablation from a proportion of testicular peritubular myoid cells (PTM-ARKO) did not affect LC number, but resulted in compensated LC failure. The current study extends these investigations, demonstrating that PTM AR signalling is important for normal development, ultrastructure and function of adult LCs. Notably, mRNAs for LC markers [e.g. steroidogenic factor 1 (Nr5a1), insulin-like growth factor (Igf-1) and insulin-like factor 3 (Insl3)] were significantly reduced in adult PTM-ARKOs, but not all LCs were similarly affected. Two LC sub-populations were identified, one apparently 'normal' sub population that expressed adult LC markers and steroidogenic enzymes as in controls, and another 'abnormal' sub-population that had arrested development and only weakly expressed INSL3, luteinizing hormone receptor, and several steroidogenic enzymes. Furthermore, unlike 'normal' LCs in PTM-ARKOs, the 'abnormal' LCs did not involute as expected in response to exogenous testosterone. Differential function of these LC sub-populations is likely to mean that the 'normal' LCs work harder to compensate for the 'abnormal' LCs to maintain normal serum testosterone. These findings reveal new paracrine mechanisms underlying adult LC development, which can be further investigated using PTM-ARKOs. PMID- 21651571 TI - Acquired undescended testis: putting the pieces together. AB - Acquired undescended testis is now a well-recognized disorder. It is seen in 1.5% of pre-pubertal boys and accounts for the 1-2% orchidopexy rate in older boys. Its pathogenesis remains largely unclear, but it may be caused by a fibrous remnant of the processus vaginalis. There is much controversy over its management, and the proper management awaits a randomized-controlled trial. Until now, follow-up data are available only for cases of spontaneous descent or pubertal orchidopexy. It is speculated that acquired undescended testis is in fact congenital and because of a short funiculus at birth, allowing a low-scrotal position early in life. However, as the boy grows, the testis might evolve into an undescended state. When testosterone surges at puberty, spontaneous descent occurs in three of every four cases. PMID- 21651573 TI - The testicular germ cell tumour transcriptome. AB - Testicular germ cell tumours (TGCTs) are characterized by young age of onset and a complex pattern of histological subtypes. Transcriptomic studies have tried to uncover the gene expression patterns underlying this. Here, we present a systematic review of transcriptome studies of TGCTs of adolescents and young adults and identify genes common across the various studies, both for TGCTs in general as well as the histological subtypes, hence elucidating both transcriptional changes associated with malignant transformation and differentiation patterns. A meta-analysis of this type adds power and significance to the genes thus found, where most studies have included only a limited number of samples. Both known (KRAS, MYCN and TPD52) and novel (CCT6A, IGFBP3 and SALL2) cancer genes are implicated in TGC tumorigenesis. Gene expression patterns characteristic to embryonic stem cells are also found deregulated in TGC tumorigenesis. This is reflected in how pluripotent embryonal carcinoma cells commonly differentiate into a variety of embryonic and extra embryonic histological types, each with unique transcriptomes. The embryonal carcinomas in particular are found to overexpress pluripotency genes, while gene signatures for seminomas, teratomas and yolk sac tumours were also identified. This underlines the distinctive transcriptomic programme across histological subtypes, especially striking given that the TGCT genome is largely similar across the same subtypes. PMID- 21651572 TI - Spontaneous metastasis in mouse models of testicular germ-cell tumours. AB - Testicular germ-cell tumours (TGCTs) are the most common cancer in young men; the incidence is increasing worldwide and they have an unusually high rate of metastasis. Despite significant work on TGCTs and their metastases in humans, absence of a mouse model of spontaneous metastasis has greatly limited our understanding of the mechanisms by which metastatic potential is acquired and on their modes of dissemination. We report a new model of spontaneous TGCT metastasis in the 129 family of mice and provide evidence that these are true metastases derived directly from primary testicular cancers rather than independently from ectopic stem cells. These putative metastases (pMETs) occur at similar frequencies among TGCT-affected males in six genetically distinct TGCT susceptible strains and were largely found in anatomical sites that are consistent with patterns of TGCT metastasis in humans. Various lines of evidence support their pluripotency and germ-cell origin, including presence of multiple endodermal, mesodermal and ectodermal derivatives as well as cells showing OCT4 and SSEA-1 pluripotency markers. In addition, pMETs were never found in males that did not have a TGCT, suggesting that metastases are derived from primary tumours. Finally, pMETS and primary TGCTs shared several DNA copy number variants suggesting a common cellular and developmental origin. Together, these results provide the first evidence for spontaneous TGCT metastasis in mice and show that these metastases originate from primary TGCTs rather than independently from ectopic stem cells. PMID- 21651574 TI - Characterization of the kisspeptin system in human spermatozoa. AB - Kisspeptin, the product of the KISS1 gene, plays an essential role in the regulation of spermatogenesis acting primarily at the hypothalamic level of the gonadotropic axis. However, the presence of kisspeptin and its canonical receptor, KISS1R, in spermatozoa has not been explored nor the direct effects of kisspeptin on sperm function have been studied so far. In the present study, we analysed the expression of kisspeptin and its receptor in sperm cells by western blot and immunocytochemistry assays and evaluated the effects of exposure to kisspeptin on sperm intracellular Ca(2+) concentration, [Ca(2+)]i, sperm motility, sperm hyperactivation and the acrosome reaction. Changes in [Ca(2+)]i were monitored using Fura-2, sperm kinematic parameters were measured using computer-assisted sperm analysis (CASA), and the acrosome reaction was measured using fluorescein isothiocyanate-coupled Pisum sativum agglutinin lectin (FITC PSA method). We found that kisspeptin and its receptor are present in sperm cells, where both are mainly localized in the sperm head, around the neck and in the flagellum midpiece. Exposure to kisspeptin caused a slow, progressive increase in [Ca(2+)]i, which reached a plateau about 3-6 min after kisspeptin exposure. In addition, kisspeptin modulated sperm progressive motility causing a biphasic (stimulatory and inhibitory) response and also induced transient sperm hyperactivation. The effects of kisspeptin on sperm motility and hyperactivation were inhibited by the antagonist of KISS1R, peptide 234. Kisspeptin did not induce the acrosome reaction in human spermatozoa. These data show for the first time that kisspeptin and its receptor are present in human spermatozoa and modulate key parameters of sperm function. This may represent an additional mechanism for their crucial function in the control of male fertility. PMID- 21651575 TI - Treatment options for carcinoma in situ testis. AB - Carcinoma in situ testis (CIS) is known as the precursor of germ cell cancer of the testis. International guidelines on diagnosis and treatment are inconsistent. Some countries offer routine biopsies of the contralateral testicle in relation to orchidectomy for testicular cancer, whereas other countries only offer this to high-risk patients. The treatment options range from orchidectomy and chemotherapy to radiotherapy and in rare cases surveillance. Results of the different treatment strategies are presented in this review. The optimal radiation dose is still not clarified. Most patients have been treated in the dose range of 16-20 Gy. Higher doses involve a higher risk of androgen insufficiency. Radiotherapy is recommended in patients with contralateral CIS. Orchidectomy should be offered in extragonadal germ cell cancer and CIS in one testicle, whereas patients with bilateral CIS should be offered radiation therapy. Patients who have undergone chemotherapy for testicular cancer are still at risk of developing CIS and we also recommend radiotherapy to the affected testicle in these patients. Cryopreservation should be offered before treatment is initiated and all patients should have their androgen status measured on a regular basis to find those cases where hormone substitution is needed. PMID- 21651576 TI - Immature rhesus monkey (Macaca mulatta) testis xenografts show increased growth, but not enhanced seminiferous differentiation, under human chorionic gonadotropin treatment of nude mouse recipients. AB - Prepubertal male cancer patients facing gonadotoxic therapy cannot be offered a procedure to create a fertility reserve, in contrast to the options available for men. Sperm production by testis xenografting has been proposed for boys, but as the efficacy of sperm production in animal trials is low, hormonal stimulation of recipients carrying xenografts has been proposed to enhance graft development. We confirm that spermatogonia are the only germ cells present in immature rhesus testis. We xenografted immature tissues into nude mice and treated them with human chorionic gonadotropin (hCG) at a low (1IU) and high (10IU) dose twice weekly for 3months. We observe significantly larger grafts in treated recipients, and significantly larger recipient body weight and seminal vesicle weight in the high dose group. However, histological analysis demonstrates that no significant increase in seminiferous maturation is induced by hCG treatment. Moreover, grafts in control recipients develop spermatozoa within 5months. Thus, although hCG treatment of hosts enhances the growth of xenografted prepubertal primate testis tissue and stimulates androgen production in the grafts, the treatment does not enhance the differentiation of the seminiferous epithelium. PMID- 21651577 TI - Premature ejaculation in patients with ankylosing spondylitis. AB - We aimed to evaluate the premature ejaculation (PE) among ankylosing spondylitis (AS) patients. Fifty male patients with AS who were diagnosed according to the modified New York criteria and fifty normal healthy controls (NHC) were included in this study. The details of patient age, disease duration, morning stiffness, laboratory activity, disease severity and medication use were obtained by reviewing the medical record. The Bath AS Functional Index (BASFI) was used to measure the functional status of the patients with AS. By taking a careful medical and sexual history, patients were classified as lifelong, natural variable, acquired PE or premature ejaculatory dysfunction. In addition to medical and sexual history, self-estimated intravaginal ejaculatory latency times (IELT) of patients were used in the classification of patients. To our knowledge, this is the first study of frequency of PE in men with AS. The prevalence rates of PE in patient and healthy controls were 32 and 30%, respectively (p = 0.331). The prevalence of PE was not significantly different between AS patients and NHC groups as regards the four PE syndromes. Average estimated IELT was 10,009 +/- 51.9 sec in the PE group and 145.26 +/- 43.01 sec in the non-PE group (p = 0.000). Patients with lifelong PE had a significantly lower mean estimated IELT than the other group (p = 0.000). Patients with premature-like ejaculatory dysfunction had the highest estimated IELT (p = 0.000). There was a significant association between self-estimated IELT and distribution of the patients according to the four PE syndromes (p = 0.01). Both AS patients and NHC groups have the same results. The present study demonstrates that PE in men with AS is as prevalent as it is in the general population. Although this study is restricted in terms of the number of patients, it is the first study ever conducted. For more meaningful results, multi centred studies with more patients are required. PMID- 21651578 TI - Mapping the stem cell state: eight novel human embryonic stem and embryonal carcinoma cell antibodies. AB - The antigenic profile of human embryonic stem (ES) and embryonal carcinoma (EC) cells has served as a key element of their characterization, with a common panel of surface and intracellular markers now widely used. Such markers have been used to identify cells within the 'undifferentiated state', yet it appears that this categorization may be an oversimplification, because a number of sub-states appear to exist within this state. To increase the resolution of the undifferentiated state, we have generated eight novel monoclonal antibodies, all capable of recognizing undifferentiated human ES and EC cells, and herein describe their characterization. The reactivity of these antibodies against a range of cell lines is reported, as well as their developmental regulation, basic biochemistry and reactivity in immunohistochemistry of testicular germ cell tumours. Our data reveal a range of reactivity for all antibodies against both ES and EC cells, suggesting that these markers will afford recognition of unique sub states within the undifferentiated stem cell compartment. PMID- 21651579 TI - Effects of polydeoxyribonucleotide on the histological damage and the altered spermatogenesis induced by testicular ischaemia and reperfusion in rats. AB - The effects of polydeoxyribonucleotide (PDRN), an agonist of the A2A adenosine receptors which when activated positively influences sperm activity, were tested in an experimental testicular ischaemia/reperfusion injury model. Anaesthetized male Sprague-Dawley rats were subjected to testicular torsion-induced ischaemia, followed by reperfusion (TI/R). Immediately after detorsion, randomized animals, including SHAM, received intraperitoneal injections of: (i) vehicle (1 mL/kg 0.9% NaCl solution); (ii) PDRN (8 mg/kg); (iii) DMPX (3,7-dimethyl-1 propargilxanthine, 0.1 mg/kg); or (iv) PDRN (8 mg/kg) + DMPX (0.1 mg/kg). Animals were euthanized at 1, 7 and 30 days following reperfusion. Vascular endothelial growth factor (VEGF) expression is normally associated with adenosine A2A receptor stimulation. After treatment, VEGF mRNA/protein expression quantified by qPCR and Western blot, vascular endothelial growth factor receptor-1 (VEGFR1) and endothelial nitric oxide synthase (eNOS) mRNA measured by qPCR, VEGF and VEGFR1 assessed using immunohistochemical methods, histological staining and spermatogenic activity were all analysed. Testis ischaemia-reperfusion (TI/R) injury caused increases in VEGF mRNA and protein, VEGFR1 and eNOS mRNA, histological damage and reduced spermatogenic activity. Immunostaining showed a lower expression of VEGF in germinal epithelial cells and a strong expression of VEGFR1 in Leydig cells after TI/R. PDRN administration increased significantly VEGF message/protein, VEGFR1 and eNOS message, decreased histological damage and ameliorated spermatogenic activity. PDRN might be useful in the management of testicular torsion. PMID- 21651580 TI - Up-regulation of microRNAs in brain of human alcoholics. AB - BACKGROUND: MicroRNAs (miRNAs) are small, noncoding oligonucleotides with an important role in posttranscriptional regulation of gene expression at the level of translation and mRNA degradation. Recent studies have revealed that miRNAs play important roles in a variety of biological processes, such as cell proliferation, neuronal differentiation, developmental timing, synapse function, and neurogenesis. A single miRNA can target hundreds of mRNA transcripts for either translation repression or degradation, but the function of many human miRNAs is not known. METHODS: miRNA array analysis was performed on the prefrontal cortex of 27 individual human cases (14 alcoholics and 13 matched controls). Target genes for differentially expressed miRNAs were predicted using multiple target prediction algorithms and a consensus approach, and predicted targets were matched against differentially expressed mRNAs from the same samples. Over- and under-representation analysis was performed using hypergeometric probability and z-score tests. RESULTS: Approximately 35 miRNAs were significantly up-regulated in the alcoholic group compared with controls. Target prediction showed a large degree of overlap with our published cDNA microarray data. Functional classification of the predicted target genes of the regulated miRNAs includes apoptosis, cell cycle, cell adhesion, nervous system development, and cell-cell signaling. CONCLUSIONS: These data suggest that the reduced expression of genes in human alcoholic cases may be because of the up regulated miRNAs. Cellular processes fundamental to neuronal plasticity appear to represent major targets of the suggested miRNA regulation. PMID- 21651581 TI - The effects of gonadectomy on age- and sex-typical patterns of ethanol consumption in Sprague-Dawley rats. AB - BACKGROUND: Ethanol intake levels characteristic of adult males and females emerge postpubertally. The present set of experiments examined the consequences of prepubertal and adult gonadectomies to explore whether the presence of gonadal hormones at puberty exerts organizational influences and/or plays an activational role in age- and sex-typical patterns of ethanol consumption. METHODS: Male and female Sprague-Dawley rats were gonadectomized (GX), received sham gonadectomy (SH), or were left nonmanipulated (NM) at 1 of 2 ages, either prepubertally on postnatal day (P) 23 (early) or postpubertally in adulthood on P70 (late). Early surgery animals were tested for ethanol consumption either during adolescence (P28 to 39) or in adulthood at the same age that late surgery animals were tested (P75 to 86). Voluntary ethanol consumption was indexed using a 2-hour limited access paradigm, with access to 2 bottles: one containing water and the other a sweetened ethanol solution. RESULTS: Age of GX did not impact patterns of ethanol consumption. Removal of testicular hormones in males, regardless of age of removal, elevated consumption levels in adulthood to female-typical levels. Ovariectomy did not have notable effects on ethanol drinking in females. Ethanol intake and preference of early SH males were significantly greater than those of both late SH and NM males. Removal of the gonads prior to puberty did not influence ethanol drinking or preference during adolescence in either males or females. CONCLUSIONS: These results suggest that testicular hormones play an activational role in lowering ethanol intake and preference of adult male rats. Pubertal hormones, in contrast, were found to exert little influence on ethanol drinking or preference during adolescence, although the effect of surgical manipulation itself during development was found to exert a long-lasting facilitatory effect on ethanol consumption in adulthood. PMID- 21651583 TI - Comment on the paper by Quinn and Fromme entitled subjective response to alcohol challenge: a quantitative review. AB - BACKGROUND: This commentary discusses the recent paper by Quinn and Fromme (2011), placing their results into perspective. RESULTS: Quinn and Fromme's meta analysis is an important and useful synthesis of a complex literature. It is clear, well written, and well reasoned, with conclusions that are relevant to both the Low Level of Response Model and the Differentiator Model. CONCLUSIONS: Drs. Quinn and Fromme use a thorough and thoughtful approach, and I encourage researchers to address the important questions raised by their meta-analysis. PMID- 21651582 TI - Effects of early postnatal exposure to ethanol on retinal ganglion cell morphology and numbers of neurons in the dorsolateral geniculate in mice. AB - BACKGROUND: The adverse effects of fetal and early postnatal ethanol intoxication on peripheral organs and the central nervous system are well documented. Ocular defects have also been reported in about 90% of children with fetal alcohol syndrome, including microphthalmia, loss of neurons in the retinal ganglion cell (RGC) layer, optic nerve hypoplasia, and dysmyelination. However, little is known about perinatal ethanol effects on retinal cell morphology. Examination of the potential toxic effects of alcohol on the neuron architecture is important because the changes in dendritic geometry and synapse distribution directly affect the organization and functions of neural circuits. Thus, in the present study, estimations of the numbers of neurons in the ganglion cell layer and dorsolateral geniculate nucleus (dLGN), and a detailed analysis of RGC morphology were carried out in transgenic mice exposed to ethanol during the early postnatal period. METHODS: The study was carried out in male and female transgenic mice expressing yellow fluorescent protein (YFP) controlled by a Thy-1 (thymus cell antigen 1) regulator on a C57 background. Ethanol (3 g/kg/d) was administered to mouse pups by intragastric intubation throughout postnatal days (PDs) 3 to 20. Intubation control (IC) and untreated control (C) groups were included. Blood alcohol concentration was measured in separate groups of pups on PDs 3, 10, and 20 at 4 different time points, 1, 1.5, 2, and 3 hours after the second intubation. Numbers of neurons in the ganglion cell layer and in the dLGN were quantified on PD20 using unbiased stereological procedures. RGC morphology was imaged by confocal microscopy and analyzed using Neurolucida software. RESULTS: Binge-like ethanol exposure in mice during the early postnatal period from PDs 3 to 20 altered RGC morphology and resulted in a significant decrease in the numbers of neurons in the ganglion cell layer and in the dLGN. In the alcohol exposure group, out of 13 morphological parameters examined in RGCs, soma area was significantly reduced and dendritic tortuosity significantly increased. After neonatal exposure to ethanol, a decrease in total dendritic field area and an increase in the mean branch angle were also observed. Interestingly, RGC dendrite elongation and a decrease in the spine density were observed in the IC group, as compared to both ethanol-exposed and pure control subjects. There were no significant effects of alcohol exposure on total retinal area. CONCLUSIONS: Early postnatal ethanol exposure affects development of the visual system, reducing the numbers of neurons in the ganglion cell layer and in the dLGN, and altering RGCs' morphology. PMID- 21651584 TI - The value of unusual animal models for alcohol research: a commentary on: Anacker, Loftis, and Ryabinin, "alcohol intake in prairie voles is influenced by the drinking level of a peer". AB - The recent study by Anacker, Loftis, and Ryabinin used a novel animal model, the prairie vole, to investigate social effects on drinking. Their finding that same sex peers modulate their drinking to match each other has intriguing implications for the fields of alcohol research as well as research on social relationships. PMID- 21651586 TI - Alcohol and the heart. AB - Alcohol consumption and disease or mortality display a J-shaped curve, with moderate amounts of alcohol being more protective than abstention, binge drinking, or heavy drinking. Red wine appears to be particularly protective for cardiovascular disease and associated conditions such as type 2 diabetes. There are, however, controversies concerning the effect of red wine on hypertension, in which there may be significant gender and ethnic differences. Overall, it seems that both ethanol and the polyphenols in red wine may contribute to the protective effect. PMID- 21651587 TI - Imaginary link between alcoholism and energy drinks. PMID- 21651588 TI - A case of focal fibrosis near the fascicle as a possible cause of incessant ventricular tachycardia. AB - A 22-year-old woman presented with ventricular tachycardia and heart failure of acute onset, and rapid hemodynamic deterioration despite medical treatment. The heart failure required extracorporeal membrane oxygenation followed by cardiac transplantation. The histopathological mapping of the ventricular conduction system of the explanted heart revealed focal fibrosis of the myocardium in close proximity to the left posterior fascicle. There was no other evidence of myocardial infarction or myocarditis. Immunohistochemical staining did not demonstrate any cause of this lesion; however, atrophy of cardiac muscle fibers around the lesion was noted. The focal fibrosis was presumed to be the cause of the ventricular tachycardia. PMID- 21651589 TI - Tachycardia triggering frequent ICD therapy in a patient with dilated cardiomyopathy-what is the mechanism? PMID- 21651590 TI - Epicardial scar in a patient with no apparent heart disease. AB - A 35-year-old man, who had an episode of aborted sudden cardiac death due to ventricular fibrillation, suffered from multiple storms of ventricular tachycardia (VT). Conventional cardiac examinations did not reveal any structural heart diseases, and he had been treated by an implantable cardioverter defibrillator since 2007. At the latest admission, epicardial but not endocardial voltage mapping revealed a small area of low voltage at the left ventricular (LV) postero-lateral wall where a delayed potential was recorded during sinus rhythm. Excellent pacemapping with a prolonged stimulus to QRS interval was obtained from the area, and a mid-diastolic potential was recorded during the VT. Radiofrequency application terminated the VT and any VT became noninducible after the ablation. In some patients diagnosed as LV-VT with no apparent heart disease, arrhythmogenic substrate may exist on the epicardial surface of the ventricle. PMID- 21651591 TI - Complete epicardial resynchronization device implantation in a patient who underwent a replacement of mitral and tricuspid valve. AB - A 71-year-old woman with severe nonischemic dilated cardiomyopathy and low ejection fraction with severe mitral regurgitation and tricuspid regurgitation and pulmonary hypertension underwent multiple valve repairs and cardiac resynchronization therapy implantation with epicardial shock leads. PMID- 21651592 TI - Management of phrenic stimulation in CRT patients over the long term: still an unmet need ? AB - BACKGROUND: Phrenic stimulation (PS) may cause intolerable symptoms and prevent CRT delivery in 2-5% of patients. We sought to ensure effective cardiac resynchronization therapy (CRT) delivery by management of PS at the left ventricular (LV) target site. METHODS AND RESULTS: Two hundred and eleven consecutive patients received a CRT device despite PS occurrence at the LV target site at implantation, when a PS-LV difference >2V was achieved by LV stimulation programming (cathode, pacing vector). PS management strategy both at implantation and at follow-up (FU) aimed to keep the target LV implantation site. LV reverse remodeling was assessed by echocardiography before implantation and at follow-up. LV lead placement was lateral/posterolateral in all the 211 patients; 51 of 211 had detectable PS at FU, 26 of 211 (12.3%) were symptomatic. Symptoms occurred more frequently when PS-LV difference was <3V (16/16 vs 10/35, P < 0.001). Cathode and pacing vector reprogramming improved the PS-LV difference and symptoms in 14 of 23 patients. LV output as threshold +0.5V was helpful to manage PS symptoms in patients with a PS-LV <=2V at FU. Median FU was 34.9 (16-50) months: 12 patients had tolerable PS symptoms, 76% (39/51) were objective responders at echocardiography compared to 74% (119/160) in patients without PS (P = NS). CONCLUSIONS: CRT delivery at long term is feasible despite PS at the target LV site. PS management is mandatory in about 12.3% of patients at FU, with 6.6% remaining symptomatic. Symptoms improve at FU when a PS-LV >3V is achieved. Further improvement in lead manufacturing and pacing electronics are awaited to meet this clinical need. PMID- 21651593 TI - Correlation between AF substrate ablation difficulty and left atrial fibrosis quantified by delayed-enhancement cardiac magnetic resonance. AB - BACKGROUND: Studies have shown that the presence of left atrial (LA) fibrosis can be assessed by LA delayed-enhancement cardiac magnetic resonance (LA DE-CMR) and may be predictive of outcome after ablation for atrial fibrillation (AF). We sought to test the hypothesis that the amount of LA fibrosis evaluated by DE-CMR correlates with the difficulty of complex fractionated atrial electrograms (CFAE) ablation. METHODS: Twenty-two consecutive patients (86.4% nonparoxysmal AF) underwent substrate CFAE radiofrequency (RF) ablation (+/-Pulmonary veins isolation) with AF termination as the endpoint. LA DE-CMR was performed prior to ablation. A global index of DE was defined by an average of six LA segmental scores based on a four-grade scale (no enhancement to maximum enhancement). Time between first RF application and AF termination, and RF duration until AF termination, was recorded. CFAE area/total LA surface was also measured on CARTO maps (Biosense Webster, Diamond Bar, CA, USA). These measures served to evaluate ablation difficulty, and were correlated with CMR images by double-blinded analysis. RESULTS: Ablation restored sinus rhythm in 20 of 22 patients (91%), with a time to terminate AF of 140 +/- 91 minutes. There was a significant correlation between the global averaged DE-CMR fibrosis grade and the electrophysiological substrate indexes such as "time to terminate AF" (Rho = 0.70, P = 0.0003), "RF duration until AF termination" (Rho = 0.65, P = 0.001), and a trend toward correlation with "CFAE area/LA surface" (Rho = 0.47, P = 0.03). CONCLUSIONS: LA DE-CMR can predict increased difficulty of CFAE ablation in AF. This tool may be beneficial in both selection of patients and ablation strategy. PMID- 21651594 TI - High resolution manometry to detect transient lower oesophageal sphincter relaxations: diagnostic accuracy compared with perfused-sleeve manometry, and the definition of new detection criteria. AB - BACKGROUND: Inhibition of transient lower oesophageal sphincter relaxations (tLESRs) has become one of the most relevant therapeutic objectives in patients with reflux symptoms resistant to proton pump inhibitors. tLESRs are currently detected by oesophageal perfused-sleeve manometry (PSM), but oesophageal high resolution manometry (HRM), which combines closely spaced pressure sensors and oesophageal pressure topography plots, may prove to be a better tool. AIM: To evaluate the efficacy, reproducibility and interobserver agreement of HRM for the detection of tLESRs, in comparison with PSM. METHODS: Twenty-four healthy volunteers underwent HRM alone and on a separate occasion with PSM simultaneously. LES pressure was monitored for 1 h during fasting and 2 h postprandial. Criteria for tLESRs were defined by characterising spontaneous LES relaxation associated with common cavity and then applied to all spontaneous LES relaxations. Interobserver agreement and the rates of tLESRs detected by HRM and PSM were compared. RESULTS: New HRM criteria for the detection of tLESRs have been established. A similar number of tLESRs were identified during the two HRM recordings (median per subject 15 and 13 (P = 0.07) and less with PSM (median per subject 11, P < 0.01). The overall concordance rate between the two procedures was substantial (kappa = 0.61). The interobserver agreement was almost perfect (kappa = 0.83) with HRM and only fair (kappa = 0.38) with PSM. CONCLUSIONS: High resolution manometry is reproducible and more sensitive than PSM to detect tLESRs. HRM provides a better interobserver agreement. These results confirm that HRM is the gold standard for detecting tLESRs (NTC00931593). PMID- 21651595 TI - Association of participation in a mindfulness programme with bowel symptoms, gastrointestinal symptom-specific anxiety and quality of life. AB - BACKGROUND: Stress perception and GI-specific anxiety play key roles in irritable bowel syndrome (IBS). Mindfulness-based stress reduction (MBSR) is a widely available stress reduction course, which has not been evaluated for IBS. AIM: To determine whether participation in MBSR is associated with improvement in bowel symptoms, GI-specific anxiety, and IBS-Quality of Life. METHODS: This is a prospective study of 93 participants in MBSR. We applied measures of Rome III IBS status, bowel symptoms (IBS-Severity Scoring System, IBS-SSS), IBS-Quality of Life (IBS-QOL), GI-specific anxiety (Visceral Sensitivity Index, VSI), mindfulness (Five Facet Mindfulness Questionnaire-FFMQ), and functional status (SF-8) at baseline and 2 and 6 months after enrolment. RESULTS: At 2 months, participation in MBSR was associated with small nonsignificant changes in IBS SSS, IBS-QOL and VSI: d = -0.25, d = 0.08, d = -0.16, respectively. At 6 months, there was no significant change in IBS-SSS (d = -0.36); whereas for IBS-QOL and VSI there were significant improvements (IBS-QOL: d = 0.33, P = 0.044; VSI: d = 0.40, P = 0.014). For patients meeting Rome III IBS criteria (n = 43), changes in IBS-SSS, IBS-QOL and VSI were not statistically significant, but there was a significant correlation between the change in VSI and the change in FFMQ across the three time periods (r = 0.33). CONCLUSIONS: Participation in MBSR is associated with improvement IBS-related quality of life and GI-specific anxiety. Randomised controlled trials are warranted to further assess the role of MBSR for IBS symptomatology. PMID- 21651596 TI - The crucial role of nomothetic and idiographic conceptions of time: interdisciplinary collaboration in nuclear waste management. AB - The disposal of nuclear waste involves extensive time scales. Technical experts consider up to 1 million years for the disposal of spent fuel and high-level waste in their safety assessment. Yet nuclear waste is not only a technical but also a so-called sociotechnical problem and, therefore, requires interdisciplinary collaboration between technical, natural, social sciences, and the humanities in its management. Given that these disciplines differ in their language, epistemics, and interests, such collaboration might be problematic. Based on evidence from cognitive psychology, we suggest that, in particular, a concept like time is presumably critical and can be understood differently. This study explores how different scientific disciplines understand extensive time scales in general and then focuses on nuclear waste. Eighteen qualitative exploratory interviews were conducted with experts for time-related phenomena of different disciplines, among them experts working in nuclear waste management. Analyses revealed two distinct conceptions of time corresponding to idiographic and nomothetic research approaches: scientists from the humanities and social sciences tend to have a more open, undetermined conception of time, whereas natural scientists tend to focus on a more determined conception that includes some undetermined aspects. Our analyses lead to reflections on potential difficulties for interdisciplinary teams in nuclear waste management. We focus on the understanding of the safety assessment, on potential implications for communication between experts from different disciplines (e.g., between experts from the humanities and engineering for risk assessment and risk communication), and we reflect on the roles of different disciplines in nuclear waste management. PMID- 21651597 TI - Validation of a novel air toxic risk model with air monitoring. AB - Three modeling systems were used to estimate human health risks from air pollution: two versions of MNRiskS (for Minnesota Risk Screening), and the USEPA National Air Toxics Assessment (NATA). MNRiskS is a unique cumulative risk modeling system used to assess risks from multiple air toxics, sources, and pathways on a local to a state-wide scale. In addition, ambient outdoor air monitoring data were available for estimation of risks and comparison with the modeled estimates of air concentrations. Highest air concentrations and estimated risks were generally found in the Minneapolis-St. Paul metropolitan area and lowest risks in undeveloped rural areas. Emissions from mobile and area (nonpoint) sources created greater estimated risks than emissions from point sources. Highest cancer risks were via ingestion pathway exposures to dioxins and related compounds. Diesel particles, acrolein, and formaldehyde created the highest estimated inhalation health impacts. Model-estimated air concentrations were generally highest for NATA and lowest for the AERMOD version of MNRiskS. This validation study showed reasonable agreement between available measurements and model predictions, although results varied among pollutants, and predictions were often lower than measurements. The results increased confidence in identifying pollutants, pathways, geographic areas, sources, and receptors of potential concern, and thus provide a basis for informing pollution reduction strategies and focusing efforts on specific pollutants (diesel particles, acrolein, and formaldehyde), geographic areas (urban centers), and source categories (nonpoint sources). The results heighten concerns about risks from food chain exposures to dioxins and PAHs. Risk estimates were sensitive to variations in methodologies for treating emissions, dispersion, deposition, exposure, and toxicity. PMID- 21651598 TI - Accommodation steps, target spatial frequency and refractive error. AB - PURPOSE: Errors in the accommodation response of myopes have been reported in many studies although questions remain about the exact differences in accommodation steps when compared with emmetropic individuals. METHODS: The characteristics of the accommodation step response to large (4/1D) and small (3/2D) steps in targets with low (0.5 cpd), mid (4 cpd) and high (16 cpd) spatial frequency (SF) information was measured in myopes (MYOs) and emmetropes (EMMs). RESULTS: In terms of step size, the larger steps showed a greater response in the 4 cpd condition than the 0.5 and 16 cpd conditions and an improved percentage correct response in the 4 cpd compared to the 16 cpd steps. In small step conditions target SF had less effect upon the magnitude of the response. In terms of refractive group differences, MYOs had a lower proportion of correct accommodation responses compared to EMMs during the small steps only, however, when correct steps were performed there were no differences in the characteristics of both large and small step responses between MYOs and EMMs. CONCLUSIONS: These findings suggest that MYOs have some difficulty interpreting small changes in defocus to initiate or possibly fine tune a small accommodation response, however, when a correct accommodation step response is made, the MYOs accommodation plant responds in a similar manner to EMMs. PMID- 21651599 TI - Ejaculate fractions of asthenozoospermic and teratozoospermic patients have differences in the sperm DNA integrity. AB - The initial fraction of the human ejaculate mainly contains prostatic secretions and the subsequent fraction holds majority of the spermatozoa suspended in the secretions from the seminal vesicle. Apart from large series of proteins, human ejaculate also contains antioxidants and reactive oxygen species that are specific to certain accessory sexual glands; however, the influence of these components on the sperm DNA integrity has not been elucidated till date. The present investigation was conducted using split (first and second) ejaculate fractions of forty-one subjects having various semen abnormalities. Sperm DNA integrity was assessed in the individual fractions by comet assay and quantified. The amount of sperm DNA damage between the split fractions is not significantly different in normozoospermic semen samples. In contrast, split fraction-2 had significantly elevated level of DNA-damaged spermatozoa in asthenozoospermic (P < 0.01) and teratozoospermic groups (P < 0.001) when compared to whole ejaculate. The split fraction analysis using various types of ejaculates demonstrated the difference in sperm DNA integrity, which has not been reported till date. Hence, in a clinical point of view, the use of initial ejaculate fraction may be considered superior to whole ejaculate in assisted conception if the DNA integrity is a concern especially in asthenozoospermic and teratozoospermic samples. PMID- 21651600 TI - Seminal plasma reactive oxygen species-antioxidants relationship with varicocele grade. AB - This work aimed to assess seminal plasma reactive oxygen species (ROS) antioxidants relationship with varicocele grade in infertile men with oligoasthenoteratozoospermia (OAT). The study included 89 infertile OAT men with varicocele divided into grade I (n = 22) and grade II (n = 43), grade III (n = 24) and compared with 20 healthy fertile controls. In their seminal plasma, two ROS parameters (malondialdehyde [MDA], hydrogen peroxide [H(2) O(2) ]) and four antioxidants (superoxide dismutase [SOD], catalase [Cat], glutathione peroxidase [GPx], vit.C) were estimated. There was significant increase in seminal MDA, H(2) O(2) and significant decrease in seminal SOD, Cat, GPx, vit.C in varicocele associated OAT cases when compared with the controls. Compared with grade I cases, varicocele cases with grades II, III demonstrated significant increase in estimated seminal MDA, H(2) O(2) and significant decrease in seminal SOD, Cat, GPx, vit.C. It is concluded that seminal oxidative stress (OS) is related to increased varicocele grade in infertile OAT men associated with varicocele. PMID- 21651601 TI - Ganoderma lucidum is an inhibitor of testosterone-induced prostatic hyperplasia in rats. AB - The aim of the present study was to find out whether Ganoderma lucidum (GL) can be used as a clinically effective medicine for the management of prostatic hyperplasia. In vitro studies were conducted to assess the 5alpha-reductase inhibitory potential of GL. A biochemical marker viz. beta-sitosterol was identified and characterised in the extracts utilising high-performance thin layer chromatography. Testosterone (3 mg kg(-1) s.c.) was administered to the rats along with the test extracts (10, 20 and 50 mg kg(-1) p.o.) and beta sitosterol (10 and 20 mg kg(-1) p.o.) for a period of 28 days. Finasteride was used as a positive control (1 mg kg(-1) p.o.). GL extracts attenuated the increase in the prostate/body weight ratio induced by testosterone. Petroleum ether extract exhibiting the best activity. Ethanolic extract also exhibited significant activity. The urine output also improved significantly, which emphasise the clinical implications of the study. Testosterone levels measured weekly and prostate-specific antigen (PSA) levels measured at the end of the study also support our claims. The PSA levels decreased in the extract-treated groups, indicating their usefulness in the treatment of benign prostatic hyperplasia. Histological studies have shown a considerable improvement in the prostatic histoarchitecture in the extract-treated groups when compared to the testosterone-treated group. PMID- 21651602 TI - Beneficial effect of tamoxifen on sperm recovery in infertile men with nonobstructive azoospermia. AB - About 10% of infertile men have azoospermia. After the introduction of microinjection [intracytoplasmic sperm injection (ICSI)], many of these men obtain the chance to be a father. But still in many cases of nonobstructive azoospermia, we are not able to find spermatozoa for ICSI. Medications may be able to increase the chance of finding spermatozoa in testis samples. So in this study, we evaluated the effect of tamoxifen citrate on the results of sperm recovery from testis tissue in infertile men with nonobstructive azoospermia. Thirty-two azoospermic infertile men with proved nonobstructive azoospermia were selected. Tamoxifen was administered for 3 months. Semen samples and in the cases of azoospermia second testis biopsy were taken, and the results were compared with the first samples. According to first testis samples, 13 patients had hypospermatogenesis, 9 had maturation arrest and 10 patients sertoli cell syndrome. After tamoxifen treatment, six patients showed spermatozoa in their ejaculates. From other patients all in hypospermatogenesis group, 75% in maturation arrest group and 20% in sertoli cell group showed spermatozoa in their second testis samples. Our study showed that treatment of patients with nonobstructive azoospermia with anti-oestrogenic drugs like tamoxifen can improve the results of sperm recovery in testis samples and also increase the chance of pregnancy by microinjection. PMID- 21651603 TI - Evaluation of different doses of mashua (Tropaeolum tuberosum) on the reduction of sperm production, motility and morphology in adult male rats. AB - Mashua is an edible-tuber crop that grows in the Andean region. Folk medicine describes the use of mashua to reduce reproductive function in men. The present study aimed: (i) to determine whether different doses of mashua (0.01, 0.1, 1 and 2 g kg(-1)) produced a dose-response reduction on sperm production and quality; and, (ii) to determine whether these anti-reproductive effects of mashua can be reversible after cessation of treatment (12 and 24 days of recovery time). Mashua treated rats showed lower values of daily sperm production, epididymal and vas deferens sperm count and sperm motility; meanwhile, mashua increased the percentage of abnormal sperm morphology and epididymal sperm transit rate. The following variables follow a dose-response effect: sperm number in vas deferens, sperm motility and sperm transit rate. In addition, it was demonstrated that the reduction in reproduction function in male rats treated with mashua was reversible after 24 days of recovery time. Finally, lower doses mashua reduces sperm number and quality (motility and morphology), and these adverse effects on male reproductive system may be reversible after 24 days after cessation of the treatment. PMID- 21651604 TI - Evaluation of the effect of cooling and of the addition of collagenase on llama sperm DNA using toluidine blue. AB - The effect cryopreservation has on sperm chromatin condensation has been studied in many species but not in South American camelids. The objectives of this study were to evaluate with toluidine blue (TB) the effects of cooling and of adding collagenase on llama sperm DNA condensation. The optimum incubation time (30 s, 1.5 and 3 min) with a reducing agent (dithiothreitol) was also determined. When comparing cooled samples with the raw ejaculate, a significant increase in sperm showing a high degree of decondensation (TB positive) was observed (P = 0.005). A positive correlation was observed, both in raw and cooled semen, between sperm head morphological abnormalities observed in TB-stained cells and TB-positive sperm (highly decondensed DNA), but not with TB-intermediate spermatozoa (moderately decondensed DNA). No significant differences (P > 0.05) were observed in samples incubated with or without 0.1% collagenase. In cooled semen, but not in raw, a significant increase (P = 0.000) in reacted sperm (TB positive) was observed using 3-min incubation with 1% dithiothreitol (DTT). To conclude, cooling would seem to produce an increase in llama sperm chromatin decondensation. Also, 0.1% collagenase in H-TALP-BSA could be added to raw semen to aid its manipulation as it would not seem to increase DNA decondensation. PMID- 21651605 TI - A comparison of doctors', parents' and children's reports of health states and health-related quality of life in children with chronic conditions. AB - BACKGROUND: Health-related quality of life is an important outcome. Self-report is the gold standard, but in the paediatric setting we often rely on proxy reporting. Our understanding of the differences between self- and proxy reports and the factors that influence them is limited. These differences can impact on treatment choices and the patient-doctor relationship. OBJECTIVE: To evaluate differences between children's, parents' and doctors' perceptions of health states and health-related quality of life in children with chronic illness and explore factors which explain these differences. METHODS: Consecutive families attending eligible clinics at a tertiary paediatric centre were invited to complete the Health Utilities Index (HUI) 23 questionnaire. Percentage agreement and kappas were calculated as a measure of the agreement between pairs. Chi squared tests or Fisher's exact test, if appropriate, were performed to determine if there was an association between level of agreement and participant variables. RESULTS: Data were collected for 130 parent-doctor pairs, 59 child-parent pairs and 59 child-doctor pairs. Overall health-related quality of life scores did not differ between responders, but there was poorer agreement for subjective domains. Doctor-child agreement was lower than parent-child agreement. Children with a diagnosis of cerebral palsy or chronic neurological condition were more likely to have lower inter-rater agreement for both subjective and objective domains. On the HUI2, agreement was lower for parent-child pairs when the father was the respondent. For child-doctor pairs, an increased frequency of patient-doctor visits and doctors' seniority were predictors of poorer agreement on the HUI3 and HUI2 respectively. CONCLUSIONS: We identified factors associated with level of agreement for self- and proxy reporting on the HUI23. Parent-child agreement was higher than doctor-child agreement. Patients with significant pain or emotional distress and patients with a diagnosis of severe cerebral palsy or chronic neurological conditions were more susceptible to under-reporting of subjective aspects of well-being by doctors and parents and may benefit from formal assessment of health-related quality of life in the clinical setting. PMID- 21651606 TI - The impact of maternal post-partum depression on the language development of children at 12 months. AB - BACKGROUND: Language is one of the most important acquisitions made during childhood. Before verbal language, a child develops a range of skills and behaviours that allow the child to acquire all communication skills. Factors such as environmental factors, socio-economic status and interaction with parents can affect the acquisition of vocabulary in children. Post-partum depression can negatively affect the first interactions with the child and, consequently, the emotional, social and cognitive development of the child. OBJECTIVE: To analyse the effect of the duration of the mother's depression on the language development of children at 12 months old. METHODS: This was a longitudinal study. The participants of this study were mothers who had received prenatal care from the Brazilian National System of Public Health in Pelotas city, State of Rio Grande do Sul, Brazil. The mothers were interviewed at two different time points: from 30 to 90 days after delivery and at 12 months after delivery; the children were also evaluated at this later time point. To diagnose maternal depression, we used the Mini International Neuropsychiatric Interview, and to assess child development, we used the language scale of the Bayley Scales of Infant Development III. RESULTS: We followed 296 dyads. Maternal depression at both time points (post partum and at 12 months) was significantly associated with the language development of infants at 12 months of age. This impact was accentuated when related to the duration of the disorder. Older women and women with more than two children were more likely to have children with poorer language development, while women who were the primary caregiver had children with higher scores on the language test. CONCLUSION: The findings indicate that maternal age, parity, primary caregiver status and duration of post-partum depression are associated with the language development of the child. PMID- 21651607 TI - A community-based study of sleep and behaviour problems in 12- to 36-month-old children. AB - BACKGROUND: While evidence suggests sleep problems are common in young children and linked to behavioural problems, studies of toddlers are rare. This community based cross-sectional study examined associations between sleep problems and daytime behaviour among 58 children aged 1 to 3 years who attended daycare centres. METHODS: Mothers and daycare providers completed four and three questionnaires, respectively, about children's sleep patterns and behaviour. Two hypotheses were tested: (1) children with higher sleep problem scores would have more behavioural problems by parental and daycare provider report; (2) problematic napping behaviours would be associated with night sleep problems. RESULTS: Mothers' reports of sleep problems were positively associated with children's behavioural problems at home and daycare providers' reports of nap problems were positively correlated with children's behavioural problems at daycare. Daycare providers' reports of children's behavioural problems at daycare were associated with maternal reports of behavioural problems. Older children in the sleep problem group had maternal reports of more behavioural problems. Daycare providers reported that children with sleep problems were less happy at daycare. Children who were happier following naps had less reported night settling difficulties. Children with difficulty settling for naps at daycare had maternal reports of more behavioural problems. CONCLUSIONS: Napping in daycare settings is an important component of toddlers' sleep. Crossover effects between children's sleep and behaviour at daycare and home indicate similarities in mothers' and daycare providers' perceptions. Findings suggest parent and daycare provider interactions include discussions about sleep problems and settling at home and in daycares. Parents and daycare providers would benefit from education about relationships between sleep and behavioural problems. PMID- 21651608 TI - Maternal depression and perceived social support as predictors of cognitive function trajectories during the first 3 years of life for preterm infants in Wisconsin. AB - BACKGROUND: Among families of infants born preterm, the association between post natal depression and children's cognitive function is not well understood, but thought to be compromised. The purpose of this study is to investigate maternal depressive symptoms and perceived social support as predictors of children's cognitive function trajectories. METHODS: This is a longitudinal study of a sample of infants born preterm (less than 37 weeks) in Wisconsin. This study includes 130 infants who were hospitalized in one of three Wisconsin neonatal intensive care units in 2002-2005 and followed until 36 months of age. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Social support was measured using the Maternal Support Scale. Children's cognitive function was measured using the Bayley Scales of Infant Development, 2nd Edition, and the Stanford-Binet Intelligence Scale, 5th Edition. RESULTS: Children's cognitive function trajectories declined initially and then increased. Being female (coefficient = 5.14, SE = 1.89) and non-poor (coefficient = 11.26, SE = 5.78), and having a mother who has a graduate degree (coefficient = 7.67, SE = 3.37) was associated with higher levels of cognition initially. Being white was associated with a more optimal cognitive trajectory. Although depression did not predict children's cognitive trajectories, the presence of clinically elevated depressive symptoms at 9 months post term was associated with lower cognitive functioning at 16 months when mothers reported low social support. CONCLUSION: Post-natal depressive symptoms appear to have a meaningful, dynamic influence on the cognitive outcomes of children born preterm, above and beyond family socio-demographic risk when the presence and timing of perceived social support are considered. Interventions to ameliorate developmental risk associated with preterm birth should include repeated assessments of maternal social support and post-natal depression and be targeted towards socially disadvantaged families. PMID- 21651609 TI - Health-related quality of life and children's happiness with their childcare. AB - BACKGROUND: Almost without exception, research into the range and quality of childcare provision, and its correlates with children's development, comes from the perspective of adults. Parents, childcare workers, teachers and the general public have all been asked for their views on childcare. In contrast, there is a dearth of information on attitudes to childcare provision and its correlates from the perspective of the children themselves. METHODS: A total of 3657 Primary 7 children, who are 10 or 11 years of age, completed the KIDSCREEN-27 health related quality of life (HRQoL) measure along with questions on their childcare provision as part of an online survey carried out in schools. RESULTS: Most children receiving childcare from people other than their parents were completely happy with their care. Childcare was related to poorer HRQoL for girls on four of the five KIDSCREEN domains, although the effect sizes were small. For both boys and girls, there were statistically significant, although modest, correlations between happiness with childcare and scores on all five domains of the KIDSCREEN 27. CONCLUSIONS: Overall, the findings suggest that most children are happy with their care and that any differences between the HRQoL of those who are cared for by their parents and those who are not are small to moderate. PMID- 21651610 TI - The ability to mentally represent action is associated with low motor ability in children: a preliminary investigation. AB - BACKGROUND: Theory and anatomical research suggest that the ability to mentally represent intended actions affect level of execution. This study presents preliminary data examining the association between children's ability to mentally represent action and general motor ability. METHODS: Children aged 7- to 10 years were assessed for motor imagery ability using a simulation of reach task and motor ability via the Movement ABC-2. Motor ability values, based on percentile rank, ranged from 2 to 91, with a mean of 36. RESULTS: The overall correlation between mental representation and motor ability yielded a moderately positive relationship (r = .39). Interestingly, when looking at motor ability subcategories, only Balance was significant in the model, explaining 20% of the variance. CONCLUSIONS: These results provide preliminary evidence that children's motor ability and the ability to mentally represent action are associated in a positive direction. Furthermore, given the results for Balance, we speculate that there are clinical implications regarding work with potentially at-risk children. PMID- 21651611 TI - School-based physical activity interventions: challenges and pitfalls. PMID- 21651612 TI - Clinical accuracy of a non-contact infrared skin thermometer in paediatric practice. AB - BACKGROUND: Rectal thermometry is considered the most reliable method for measuring the temperature in the paediatric population. Recently, a new non contact skin infrared thermometer for children was introduced in the market with excellent acceptance by parents. METHODS: A prospective, analytical, cross sectional study was designed in order to assess the effectiveness of the infrared non-contact thermometer (Thermofocus) in comparison with two other known methods used to measure body temperature. Children aged 1 to 48 months were included from the emergency room and inpatient unit. All patients selected were assessed with three different thermometers: (1) non-contact infrared thermometer (Thermofocus); (2) temporal artery thermometer (Exergen); and (3) rectal glass mercury thermometer. RESULTS: Four hundred and thirty-four patients were eligible to complete the study. One hundred and sixty-seven were identified with fever. The mean age of the patients studied was 14.6 +/- 10.7 months. Both devices were strongly correlated with the rectal temperature: r = 0.950 for Exergen and r = 0.952 for Thermofocus. The mean difference in temperature between the rectal temperature and the non-contact thermometer was 0.029 +/- 0.01 degrees C (P < 0.001), while the mean difference between the temporal artery thermometer and the rectal temperature was -0.20 +/- 0.27 degrees C (P < 0.001). The sensitivity and specificity for the non-contact thermometer is 97%. The negative predictive value is 99%, which is especially important to rule out fever and avoid unnecessary laboratory work-up. CONCLUSIONS: The non-contact infrared thermometer is a reliable, comfortable and accurate option for measurement of temperature and is very useful for the screening of fever in the paediatric population. More studies are recommended to support the evidence found in this study and compare its accuracy with more complex devices. PMID- 21651613 TI - The experiences of Latino siblings of children with developmental disabilities. AB - OBJECTIVE: This qualitative study explored the experiences of Latino siblings of children with developmental disabilities. METHODS: Parents and typically developing siblings from 15 Latino families with a child with a developmental disability participated in separate interviews. RESULTS: Using consensual qualitative research methodology, domains reflecting siblings' relationships, emotional experiences and communication about the disability were identified. The child's need for caregiving was a prominent topic in the sibling and parent narratives. Parents reported concerns about siblings' experience of differential treatment, whereas siblings reported concerns about restricted social activities because of their brother/sister. CONCLUSIONS: Including multiple informants revealed commonalities and differences in parents' and siblings' perspectives on the impact of a child's disability. The importance of considering sibling adaptation in sociocultural context is discussed. PMID- 21651614 TI - Vanishing clinical psychopharmacology. PMID- 21651615 TI - Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects. AB - AIM: To investigate the effect of co-administration of rifampicin, a potent inducer of cytochrome P450 (CYP) 3A4 enzymes, on the pharmacokinetics (PK) and pharmacodynamics (PD) of saxagliptin and 5-hydroxy saxagliptin in healthy subjects. Saxagliptin is metabolized by CYP3A4/3A5 to 5-hydroxy saxagliptin, its major pharmacologically active metabolite. METHODS: In a non-randomized, open label, single sequence design, 14 healthy subjects received single oral doses of saxagliptin 5 mg with and without steady-state rifampicin (600 mg once daily for 6 days). PK (saxagliptin and 5-hydroxy saxagliptin) and PD (plasma DPP-4 activity) were measured for up to 24 h on days 1 and 7. RESULTS: Concomitant administration with rifampicin resulted in 53% (point estimate 0.47, 90% CI 0.38, 0.57) and 76% (point estimate 0.24, 90% CI 0.21, 0.27) decreases in the geometric mean C(max) and AUC values of saxagliptin, respectively, with a 39% (point estimate 1.39, 90% CI 1.23, 1.56) increase in the geometric mean C(max) and no change (point estimate 1.03, 90% CI 0.97, 1.09) in the AUC of 5-hydroxy saxagliptin. Similar maximum % inhibition and area under the % inhibition-time effect curve over 24 h for DPP-4 activity were observed when saxagliptin was administered alone or with rifampicin. The saxagliptin total active moieties exposure (AUC) decreased by 27% (point estimate 0.73, 90% CI 0.66, 0.81). Saxagliptin with or without rifampicin in this study was generally well tolerated. CONCLUSIONS: Lack of change of PD effect of saxagliptin is consistent with the observed 27% reduction in systemic exposure to the total active moieties, which is not considered clinically meaningful. Based on these findings, it is not necessary to adjust the saxagliptin dose when co-administered with rifampicin. PMID- 21651616 TI - Possible drug-drug interaction between quetiapine and lamotrigine--evidence from a Swedish TDM database. AB - AIM: The aim of the present study was to investigate a previously proposed interaction between quetiapine and lamotrigine resulting in reduced serum quetiapine concentrations. METHODS: Data on 402 patients subjected to analysis of quetiapine concentration in serum were extracted from a routine therapeutic drug monitoring database. Among these patients, those concomitantly treated with lamotrigine (n= 22) were identified and matched with 22 controls receiving quetiapine while unexposed to lamotrigine. The dose-corrected quetiapine concentrations (C : D ratios) in the two groups were compared in both paired and unpaired analyses. RESULTS: Patients co-treated with lamotrigine had a lower mean C : D ratio (0.71, 95% CI 0.46, 0.97) compared with controls (1.64, 95% CI 1.00, 2.28). Dose-corrected quetiapine concentrations were 58% lower in patients co medicated with lamotrigine. CONCLUSIONS: This study indicates that lamotrigine exposure is associated with substantially reduced serum concentrations of quetiapine, possibly due to induced glucuronidation. These findings need to be confirmed in experimental studies. PMID- 21651618 TI - Venous outflow obstruction after orthotopic liver transplantation: use of a breast implant to maintain graft position. AB - Hepatic venous outflow obstruction (HVOO) is a rare complication after orthotopic liver transplantation (OLT) usually related to technical issues or to malposition or kinking of the hepatic graft. When HVOO is diagnosed during the early post transplant period, surgical options are technically very demanding and outcomes discouraging. Therefore, angioplasty and stent placement have been indicated to avoid a chronic lesion of the graft. Three cases of HVOO after OLT are reported. HVOO was diagnosed during the early post-transplant period and was due to graft malposition in two patients and kinking of the vena cava anastomosis in one. All patients were successfully treated with a 300-cc gel-filled breast implant surgically placed in the right hepatic fossa with the liver graft resting on it. Massive ascites in all three patients disappeared and renal impairment resolved within two wk post-implant placement. No prosthesis-related complications have been observed after a follow-up ranging from 30 to 58 months. We describe a simple and effective method of maintaining the liver graft in an adequate position to achieve prolonged relief of the outflow obstruction for the whole graft and discuss the advantages of a breast implant over stent placement or the use of different balloon catheters. PMID- 21651619 TI - Pre-transplant course and risk of kidney transplant failure in IgA nephropathy patients. AB - BACKGROUND: There is lack of knowledge to what degree clinical/morphological presentation and course of IgA nephropathy (IgAN) prior to end-stage renal disease are risk factors for graft loss after kidney transplantation. MATERIAL AND METHODS: Patients with IgAN between 1988 and 2006 (registered in the Norwegian Kidney Biopsy Registry) who later received a kidney transplant (registered in the Norwegian Renal Registry) were included. The cohort was followed up regarding death-censored graft loss throughout 2008. Graft survival with a rapid progressive (RP) vs. a slow progressive (SP) course of pre-Tx IgAN (annual GFR > or <30 mL/min/1.73 m(2) ) was studied. RESULTS: Among 106 included patients, there were 14 graft losses giving a graft loss rate of 1.9/100 patient years. Follow-up until the first kidney transplant was 6.9 +/- 4.4 (range 0.1-19) yr. Patients with pre-Tx RP had a higher graft loss rate compared with SP patients (6.3 vs.1.3/100 patient years, p < 0.001). Graft loss rate with living related donor (LRD) was similar to unrelated donor (UD) grafts. Most RP patients had received LRD grafts, and in SP patients, graft survival with LRD grafts was better than UD grafts (0.3 vs.2.1/100 patient years, p = 0.055). CONCLUSIONS: A rapid pre-transplant course is a strong risk factor for transplant failure in patients with IgAN. PMID- 21651620 TI - Treatment of keloids and hypertrophic scars using topical and intralesional mitomycin C. AB - BACKGROUND: Keloids develop due to the overgrowth of fibrous tissue. Currently, there is no gold standard treatment for keloids and hypertrophic scars (HTS). Their propensity for local invasion and recurrence has prompted many investigations on antineoplastic agents. OBJECTIVES: To investigate the efficacy of topical and intralesional mitomycin C for the treatment of keloids and HTS. METHODS: Nine patients with clinically diagnosed keloids and HTS were treated using topical mitomycin C (1 mg/mL) for 3 min after shaving excision. The Vancouver Scars Scale, patient satisfaction, and adverse effects were checked after 6 months. The keloids and HTS were photographed at each monthly visit. Intralesional mitomycin C (1 mg/mL) was administered to study the effect on the regression of keloids in 2 patients. RESULTS: Application of mitomycin C to the base of shave-removed keloids and HTS showed good results. Six out of 9 patients were very satisfied with the outcome of treatment; none were disappointed. The results of intralesional mitomycin C treatment were disappointing. Both cases worsened, with increased ulceration after treatment. CONCLUSIONS: Topical application of mitomycin C following shaving excision was safe and effective for the treatment of keloids and HTS. However, intralesional mitomycin C therapy aggravated both lesions. PMID- 21651621 TI - Expression of CD163 in granulomatous dermatitis is not the tool that makes the difference. PMID- 21651622 TI - Production performance, stress tolerance and intestinal integrity of sunshine bass fed increasing levels of soybean meal. AB - Soybean meal (SBM) is perhaps the most common fish meal (FM) alternative used in aquafeeds; however, SBM cannot fully replace FM in sunshine bass Morone chrysops * M. saxatilis feeds without impacting growth. Reduced production performance may be the result of subtle changes in morphology and/or physiological status. Accordingly, our objective was to assess growth, gastrointestinal integrity and stress tolerance of sunshine bass fed increasing amounts of SBM. Fish (approximately 14.5 g) were fed diets (14% lipid and 40% protein) containing increasing amounts of SBM at the expense of FM (30% FM, 20% FM, 15% FM, 10% FM, 5% FM and 0% FM) for 8 weeks. As expected, complete replacement of FM reduced growth. Although some signs of enteritis were noted, no significant differences in gut integrity were observed. Following 15-min low-water stress challenge, plasma glucose levels were elevated, particularly among fish fed increasing amounts of SBM. Cortisol response was similar, but statistical differences were not resolved for this parameter. Completely replacing FM in feeds for sunshine bass elicits overt reductions in growth. More subtle physiological changes may also result from FM replacement, including alterations in stress tolerance, and these may be important to consider in terms of the suitability of aquafeed formulations and optimal nutrition of sunshine bass. PMID- 21651623 TI - Effect of a rumen-protected conjugated linoleic acid mixture on hepatic lipid metabolism in heifers. AB - This study was performed to assess the effects of rumen-protected conjugated linoleic acid (CLA) on hepatic lipid metabolism in heifers. In particular, it was of interest whether feeding CLA causes development of fatty liver as observed recently in mice. Thirty-six growing heifers with an initial body weight of 185 kg were allotted to three treatment groups and fed daily 250 g of different rumen protected fats for 16 weeks: The control group received 250 g of a CLA-free control fat, the CLA100 group received 100 g of a CLA fat containing 2.4% of cis 9, trans-11 CLA and 2.1% of trans-10, cis-12 CLA and 150 g control fat and the CLA250 group received 250 g of the CLA fat. CLA supplementation had no effect on animal performance parameters, liver weight and hepatic triglyceride concentration. Moreover, mRNA expression of hepatic genes involved in lipogenesis, beta-oxidation and fatty acid transport was not influenced by dietary CLA. The fatty acid composition of hepatic total lipids, with particular consideration of ratios of fatty acids indicative of Delta9-, Delta6- and Delta5 desaturation, was also less influenced by dietary CLA. In conclusion, the study shows that dietary rumen-protected CLA has less effect on hepatic lipid metabolism in young heifers and does not induce the development of a fatty liver such as in mice. PMID- 21651624 TI - Close encounters: contact-dependent interactions in bacteria. AB - Bacterial cells interact extensively within and between species. These interactions can be divided into those that rely on diffusible factors and those that depend on direct cell-to-cell contacts. An example of a contact-dependent interaction is the transfer of lipoproteins between Myxococcus xanthus cells that leads to transient stimulation of motility in certain motility mutants. In this issue of Molecular Microbiology, Wei et al. (2011) provide mechanistic insights into this contact-dependent transfer of lipoproteins. Briefly, a heterologous protein fused to a type II (lipoprotein) signal sequence that targets the protein to the outer membrane is required and sufficient for transfer. Moreover, evidence is provided that transfer may depend on specific contacts between donor and recipient cells. The data demonstrate that lipoprotein transfer in M. xanthus is not restricted to a few odd motility proteins but could be a wide-spread phenomenon in M. xanthus and possibly other bacteria. Recent years have been fruitful in identifying contact-dependent interactions between bacterial cells. These interactions can be grouped into those that involve delivery of cargo to a recipient and those that seem to be involved in cell-to-cell signalling. Several contact-dependent interactions involve widely conserved proteins, suggesting that cell contact-dependent processes may be widespread among bacteria. PMID- 21651626 TI - SMC is recruited to oriC by ParB and promotes chromosome segregation in Streptococcus pneumoniae. AB - Segregation of replicated chromosomes is an essential process in all organisms. How bacteria, such as the oval-shaped human pathogen Streptococcus pneumoniae, efficiently segregate their chromosomes is poorly understood. Here we show that the pneumococcal homologue of the DNA-binding protein ParB recruits S. pneumoniae condensin (SMC) to centromere-like DNA sequences (parS) that are located near the origin of replication, in a similar fashion as was shown for the rod-shaped model bacterium Bacillus subtilis. In contrast to B. subtilis, smc is not essential in S. pneumoniae, and Deltasmc cells do not show an increased sensitivity to gyrase inhibitors or high temperatures. However, deletion of smc and/or parB results in a mild chromosome segregation defect. Our results show that S. pneumoniae contains a functional chromosome segregation machine that promotes efficient chromosome segregation by recruitment of SMC via ParB. Intriguingly, the data indicate that other, as of yet unknown mechanisms, are at play to ensure proper chromosome segregation in this organism. PMID- 21651625 TI - Staphylococcus aureus regulates the expression and production of the staphylococcal superantigen-like secreted proteins in a Rot-dependent manner. AB - Staphylococcus aureus overproduces a subset of immunomodulatory proteins known as the staphylococcal superantigen-like proteins (Ssls) under conditions of pore mediated membrane stress. In this study we demonstrate that overproduction of Ssls during membrane stress is due to the impaired activation of the two component module of the quorum-sensing accessory gene regulator (Agr) system. Agr dependent repression of ssl expression is indirect and mediated by the transcription factor repressor of toxins (Rot). Surprisingly, we observed that Rot directly interacts with and activates the ssl promoters. The role of Agr and Rot as regulators of ssl expression was observed across several clinically relevant strains, suggesting that overproduction of immunomodulatory proteins benefits agr-defective strains. In support of this notion, we demonstrate that Ssls contribute to the residual virulence of S. aureus lacking agr in a murine model of systemic infection. Altogether, these results suggest that S. aureus compensates for the inactivation of Agr by producing immunomodulatory exoproteins that could protect the bacterium from host-mediated clearance. PMID- 21651627 TI - Biogenic ammonia modifies antibiotic resistance at a distance in physically separated bacteria. AB - Bacteria release low-molecular-weight by-products called secondary metabolites, which contribute to bacterial ecology and biology. Whereas volatile compounds constitute a large class of potential infochemicals, their role in bacteria bacteria interactions remains vastly unexplored. Here we report that exposure to gaseous ammonia released from stationary-phase bacterial cultures modifies the antibiotic resistance spectrum of all tested Gram-negative and Gram-positive bacteria. Using Escherichia coli K12 as a model organism, and increased resistance to tetracycline as the phenotypic read-out, we demonstrate that exposure to ammonia generated by the catabolism of l-aspartate increases the level of intracellular polyamines, in turn leading to modifications in membrane permeability to different antibiotics as well as increased resistance to oxidative stress. We show that the inability to import ammonia via the Amt gas channel or to synthesize polyamines prevent modification in the resistance profile of aerially exposed bacteria. We therefore provide here the first detailed molecular characterization of widespread, long-range chemical interference between physically separated bacteria. PMID- 21651629 TI - A substrate translocation trajectory in a cytoplasm-facing topological model of the monocarboxylate/H+ symporter Jen1p. AB - Previous mutational analysis of Jen1p, a Saccharomyces cerevisiae monocarboxylate/H+ symporter of the Major Facilitator Superfamily, has suggested that the consensus sequence 379NXX[S/T]HX[S/T]QD387 in transmembrane segment VII (TMS-VII) is part of the substrate translocation pathway. Here, we rationally design, analyse and show that several novel mutations in TMS-V and TMS-XI directly modify Jen1p function. Among the residues studied, F270 (TMS-V) and Q498 (TMS-XI) are critical specificity determinants for the distinction of mono- from dicarboxylates, and N501 (TMS-XI) is a critical residue for function. Using a model created on the basis of Jen1p similarity with the GlpT permease, we show that all polar residues critical for function within TMS-VII and TMS-XI (N379, H383, D387, Q498, N501) are perfectly aligned in an imaginary axis that lies parallel to the protein pore. This model and subsequent mutational analysis further reveal that an additional polar residue facing the pore, R188 (TMS-II), is irreplaceable for function. Our model also justifies the role of F270 and Q498 in substrate specificity. Finally, docking calculations reveal a 'trajectory like' substrate displacement within the Jen1p pore, where R188 plays a major dynamic role mediating the orderly relocation of the substrate by subsequent H bond interactions involving itself and residues H383, N501 and Q498. PMID- 21651630 TI - Aural carcinoma with chondroid metaplasia at metastatic sites in a dog. AB - A case of aural carcinoma with chondroid metaplasia at metastatic foci in an 8 year-old male pug is described. Multiple metastases in both lungs and the right submandibular, parotid, retropharyngeal, cervical and prescapular lymph nodes were detected. Histologically, the skin of the right ear canal appeared to be diffusely infiltrated by cords and nests of neoplastic epithelial cells, showing multifocal contiguity with the overlying hyperplastic squamous epithelium. Most of the carcinomatous cells were arranged in a glandular-like pattern, with formation of lumens containing epithelial cells attached to the peripheral cell layer by elongated intercellular bridges. Scattered foci of keratinization with central accumulations of compact, laminated keratin were also observed, and histochemical stains failed to detect mucinous secretory material. Even though histological and histochemical findings were compatible with a diagnosis of acantholytic squamous cell carcinoma, CAM5.2 immunostaining was detectable in the majority, although not all, neoplastic cells, confirming a diagnosis of poorly differentiated ceruminous gland carcinoma. Pulmonary metastatic nodules revealed multifocal areas of cartilaginous metaplasia with apparent transition of carcinomatous cells to chondroid cells, showing nuclear atypia and focal cytokeratin immunostaining. Carcinomatous cells surrounding chondroid areas also revealed focal vimentin and S100 immunoreactivity. Histological evidence of transition between the two components, as well as the presence of intermediate cells displaying both epithelial and mesenchymal immunohistochemical features, strongly indicated a final diagnosis of carcinosarcoma, in which chondrosarcomatous elements were derived from carcinoma cells. PMID- 21651628 TI - The N-terminal amphipathic region of the Escherichia coli type III secretion system protein EspD is required for membrane insertion and function. AB - Enterohemorrhagic Escherichia coli is a causative agent of gastrointestinal and diarrheal diseases. These pathogenic E. coli express a syringe-like protein machine, known as the type III secretion system (T3SS), used for the injection of virulence factors into the cytosol of the host epithelial cell. Breaching the epithelial plasma membrane requires formation of a translocation pore that contains the secreted protein EspD. Here we demonstrate that the N-terminal segment of EspD, encompassing residues 1-171, contains two amphipathic domains spanning residues 24-41 and 66-83, with the latter of these helices being critical for EspD function. Fluorescence and circular dichroism analysis revealed that, in solution, His6-EspD1-171 adopts a native disordered structure; however, on binding anionic small unilamellar vesicles composed of phosphatidylserine, His6-EspD1-171 undergoes a pH depended conformational change that increases the alpha-helix content of this protein approximately sevenfold. This change coincides with insertion of the region circumscribing Trp47 into the hydrophobic core of the lipid bilayer. On the HeLa cell plasma membrane, His6-EspD1-171 forms a homodimer that is postulated to promote EspD-EspD oligomerization and pore formation. Complementation of DeltaespD null mutant bacteria with an espDDelta66 83 gene showed that this protein was secreted but non-functional. PMID- 21651631 TI - Detection of feline herpes virus 1 via polymerase chain reaction and immunohistochemistry in cats with ulcerative facial dermatitis, eosinophilic granuloma complex reaction patterns and mosquito bite hypersensitivity. AB - Ulcerative dermatitis caused by feline herpes virus 1 (FHV-1) is an uncommon disease characterized by cutaneous ulcers secondary to epidermal, adnexal and dermal necrosis. Differential diagnoses for FHV-1 lesions include, but are not limited to, mosquito bite hypersensitivity and eosinophilic granuloma complex. Histopathological diagnosis of FHV-1 dermatitis is based on the detection of the intranuclear inclusion bodies. In cases where intranuclear inclusions are missing but clinical and histological findings are compatible with FHV-1 dermatitis, immunohistochemistry (IHC) and PCRs have been used. In this retrospective study, we evaluated the presence of FHV-1 by IHC and PCR in skin biopsies and compared the results of the two tests. Sixty-four skin biopsy specimens from cats with compatible lesions were reviewed and tested via PCR and IHC for evidence of FHV 1. Polymerase chain reaction was positive in 12 of 64 biopsies; PCR and IHC were positive only in two of 64 biopsies, and these cases were considered true positive cases. The higher number of PCR-positive cases was possibly attributed to amplification of viral DNA from a live attenuated vaccination, but a previous FHV-1 infection with subsequent amplification of latently inserted FHV-1 could not be excluded. If clinical signs and histopathology suggest FHV-1 infection in the absence of typical inclusion bodies, IHC is the preferred diagnostic test; PCR may be useful for initial screening, but due to false positives is not sufficient for a definitive diagnosis. PMID- 21651632 TI - Psychometric properties of the Chinese version of State Self-Esteem Scale: an analysis of data from a cross-sectional survey of patients in the first four months after stroke. AB - AIM: To establish the psychometric properties of the Chinese version of the State Self-Esteem Scale in stroke patients. BACKGROUND: Self-esteem is seen to enhance peoples' ability to cope with disease: low self-esteem may inhibit participation in rehabilitation and thus result in poor health and social outcomes. Although the Chinese version of the State Self-Esteem Scale has been used as an outcome measure for stroke rehabilitation, no study has examined its factor structure in this patient group. DESIGN: A cross-sectional design. METHODS: A convenience sample of 265 Chinese stroke patients (mean age 71.4, SD 10.3 years), with a minimum score of 18 out of a possible 30 for the Mini Mental State Exam recruited from two regional rehabilitation hospitals in Hong Kong. An exploratory factor analysis and an internal consistency analysis of the State Self-Esteem Scale were conducted. Pearson's correlation coefficients were calculated between the State Self-Esteem Scale and the Geriatric Depression Scale to determine convergent validity. RESULTS: The final factor solution comprised a three-factor model with correlated constructs and accounted for 49.5% of the total variance. Significant negative correlations were found between the Geriatric Depression Scale and the State Self-Esteem Scale subscale scores (r-0.31 to -0.55, p < 0.01), indicating that the State Self-Esteem Scale had acceptable convergent validity. The new three-factor structure had higher Cronbach's alphas when compared with the original three-factor structure. RELEVANCE TO CLINICAL PRACTICE: The State Self Esteem Scale appears to be a useful measure for assessing state self-esteem in stroke patients. To establish the concurrent, discriminative and construct validities, the factor structure of the SSES could be further developed and tested. PMID- 21651633 TI - The effectiveness of therapeutic play, using virtual reality computer games, in promoting the psychological well-being of children hospitalised with cancer. AB - AIMS: To examine the effectiveness of therapeutic play, using virtual reality computer games, in minimising anxiety and reducing depressive symptoms in Hong Kong Chinese children hospitalised with cancer. BACKGROUND: There has been an increase in the use of therapeutic play intervention to help children cope with the stress of hospitalisation. However, it is not clear whether therapeutic play is an appropriate psychological intervention for Chinese children hospitalised with cancer. DESIGN: A non-equivalent control group pretest-post-test, between subject design was employed. METHOD: Hong Kong Chinese Children (8-16 years of age), admitted to a paediatric oncology ward for the treatment of cancer during a 14-month period, were invited to participate in the study. Of the 122 children, 70 formed the control group receiving routine nursing care and 52 in the experimental group receiving therapeutic play interventions. RESULTS: The results showed that children in the experimental group reported statistically significant fewer depressive symptoms than children in the control group on day 7. The results, however, find no differences in children's anxiety scores between the two groups on day 7. CONCLUSION: The study provides empirical evidence to support the effectiveness of therapeutic play, using virtual reality computer games, in the psychological preparation of children hospitalised with cancer, thus charting a path towards promoting holistic and quality care. RELEVANCE TO CLINICAL PRACTICE: The findings heighten the awareness in healthcare professionals that play is a very important part of children's life and that they need play even when they are ill. PMID- 21651634 TI - Genome-wide association mapping identifies the genetic basis of discrete and quantitative variation in sexual weaponry in a wild sheep population. AB - Understanding the genetic architecture of phenotypic variation in natural populations is a fundamental goal of evolutionary genetics. Wild Soay sheep (Ovis aries) have an inherited polymorphism for horn morphology in both sexes, controlled by a single autosomal locus, Horns. The majority of males have large normal horns, but a small number have vestigial, deformed horns, known as scurs; females have either normal horns, scurs or no horns (polled). Given that scurred males and polled females have reduced fitness within each sex, it is counterintuitive that the polymorphism persists within the population. Therefore, identifying the genetic basis of horn type will provide a vital foundation for understanding why the different morphs are maintained in the face of natural selection. We conducted a genome-wide association study using ~36000 single nucleotide polymorphisms (SNPs) and determined the main candidate for Horns as RXFP2, an autosomal gene with a known involvement in determining primary sex characters in humans and mice. Evidence from additional SNPs in and around RXFP2 supports a new model of horn-type inheritance in Soay sheep, and for the first time, sheep with the same horn phenotype but different underlying genotypes can be identified. In addition, RXFP2 was shown to be an additive quantitative trait locus (QTL) for horn size in normal-horned males, accounting for up to 76% of additive genetic variation in this trait. This finding contrasts markedly from genome-wide association studies of quantitative traits in humans and some model species, where it is often observed that mapped loci only explain a modest proportion of the overall genetic variation. PMID- 21651635 TI - Stored sperm differs from ejaculated sperm by proteome alterations associated with energy metabolism in the honeybee Apis mellifera. AB - Sperm are exposed to substantially different environments during their life history, such as seminal fluid or the female sexual tract, but remarkably little information is currently available about whether and how much sperm composition and function alters in these different environments. Here, we used the honeybee Apis mellifera and quantified differences in the abundance and activity of sperm proteins sampled either from ejaculates or from the female's sperm storage organ. We find that stored and ejaculated sperm contain the same set of proteins but that the abundance of specific proteins differed substantially between ejaculated and stored sperm. Most proteins with a significant change in abundance are related to sperm energy metabolism. Enzymatic assays performed for a subset of these proteins indicate that specific protein activities differ between stored and ejaculated sperm and are typically higher in ejaculated compared to stored sperm. We provide evidence that the cellular machinery of sperm is plastic and differs between sperm within the ejaculate and within the female's storage organ. Future work will be required to test whether these changes are a consequence of active adaptation or sperm senescence and whether they alter sperm performance indifferent chemical environments or impact on the cost of sperm storage by the female.However, these changes can be expected to influence sperm performance and therefore determine sperm viability or sperm competitiveness for storage or egg fertilization. PMID- 21651637 TI - Family members' experiences of personal assistance given to a relative with disabilities. AB - Personal assistance is a type of home care common to many countries even though entitlement and legislative framework may vary from country to country. At present, there exists no knowledge about the family members' experiences of such assistance; therefore, the aim of this study was to investigate family members' experiences of personal assistance given to a relative of working age with a functional disability. Twenty-five family members who had a relative with a severe neurological disease in Sweden were interviewed about the significance of personal assistance, and the qualitative interviews were subjected to qualitative latent content analysis. The overall findings verify the close connection between the family members' experiences and their perception of the quality of the caring relationship between the personal assistant and the person with disability. The main finding was an appreciation of the personal assistance on the part of the family members. However, in situations where the encounter between the assistant and the relative with disability was perceived negatively, the family members experienced great anxiety. The shortcomings were the inability to maintain a private life with assistance and the limitation of choice because of the shortage of personal assistants. Beyond these general findings, this study found that personal assistance was experienced by the family members in terms of dignity and empowering care. This theme was generated from seven subthemes: Insight into private life, Security through the close relation, Social life through freedom of movement, Influence over the organisation of assistance, Self-determination and understanding, Friendship and mutual respect and Adaption to the dependency on assistance. The findings indicate that responsible officials, work leaders and assistants need constantly to improve the implementation of the law. In such efforts, the experiences of family members described in this study are a source of knowledge. PMID- 21651638 TI - A qualitative study about self-medication in the community among market vendors in Fuzhou, China. AB - Despite government efforts to increase healthcare insurance and access in China, many individuals, regardless of insurance status, continue to engage in high levels of self-medication. To understand the factors influencing common self medication behaviour in a community of food market vendors in Fuzhou China, a total of 30 market vendors were randomly recruited from six food markets in 2007. In-depth interviews were conducted with each participant at their market stalls by trained interviewers using a semi-structured open-ended interview protocol. Participants were asked broad questions about their health-seeking behaviours as well as their past experiences with self-medication and hospital care. ATLAS. ti was used to manage and analyse the interview data. The results showed that hospital-based healthcare services were perceived as better quality. However, self-medication was viewed as more affordable in terms of money and time. Other factors prompting self-medication, included confidence in understanding the health problem, the easy accessibility of local pharmacies and the influences of friends/peers and advertising. Three broad domains, attitude, cost and effectiveness, were all seen to determine past decisions and experiences with self-medication. Interestingly, the effective management of self-medication via pharmacy resources raised particular concern because of perceived variation in quality. In conclusion, self-medication was found to be an important and common health-seeking behaviour driven by multiple factors. A sound and comprehensive public health system should systematically attend to these behaviours and the pharmacies, where much of the behaviour occurs. PMID- 21651639 TI - Organisation and delivery of home care re-ablement: what makes a difference? AB - Home-care re-ablement or 'restorative' services are a cornerstone of preventive service initiatives in many countries. Many English local authorities are transforming their former in-house home-care services to provide intensive, short term re-ablement instead. The focus of this paper is on the organisation and content of re-ablement services and the features of their organisation and delivery that have the potential to enhance or detract from their effectiveness. Qualitative data were collected from five sites with well-established re-ablement services. Data included semi-structured interviews with senior service managers in each site; observation of 26 re-ablement visits to service users across the five sites (four to six in each site) and a focus group discussion with front line staff in each site (in total involving 37 front-line staff). The data generated from all three sources were analysed using the framework approach. All five services had developed from selective pilot projects to inclusive 'intake' service, accepting almost all referrals for home-care services. A number of features were identified as contributing to the effectiveness of re-ablement services. These included: service user characteristics and expectations; staff commitment, attitudes and skills; flexibility and prompt intervention; thorough and consistent recording systems; and rapid access to equipment and specialist skills in the team. Factors external to the re-ablement services themselves also had implications for their effectiveness; these included: a clear, widely understood vision of the service; access to a wide range of specialist skills; and capacity within long-term home-care services. The paper argues that re ablement can be empowering for all service users in terms of raising their confidence. However, the move to a more inclusive 'intake' service suggests that outcomes are likely to be considerably lower for service users who have more limited potential to be independent. The paper discusses the implications for practice. PMID- 21651640 TI - Prosthetic rehabilitation of a maxillectomy with a two-piece hollow bulb obturator. A clinical report. AB - Extensive bilateral midfacial defects involving the upper jaw, palate, and sinus present a formidable reconstructive challenge. A combination of total and subtotal maxillectomy is, in general, a rare surgical procedure that affects the cosmetic, functional, and psychological aspects of a patient's life. Prosthetic restoration has become the preferred method for the rehabilitation of such conditions. The use of magnets is an efficient means of providing combined prostheses with retention, quality, and stability. This clinical report describes the rehabilitation of a total and subtotal maxillectomy patient with a two-piece hollow bulb obturator retained with the help of magnets and a retention clasp. PMID- 21651641 TI - Intracystic papillary carcinoma of breast harbors significant genomic alteration compared with intracystic papilloma: genome-wide copy number and LOH analysis using high-density single-nucleotide polymorphism microarrays. PMID- 21651642 TI - The efficacy of chest radiographs in detecting parapneumonic effusions. AB - BACKGROUND AND OBJECTIVE: Current guidelines recommend parapneumonic effusions (PPEs) with a thickness of >= 10 mm be sampled via thoracentesis. We hypothesized that anteroposterior (AP) CXRs are not as sensitive as posteroanterior (PA) and lateral radiographs in identifying PPEs and should not be routinely used in patients with suspected pneumonia. METHODS: Sixty-one hospitalized patients with pneumonia and PPE were retrospectively studied, all of whom had a CXR and CT scan within 24 h of each other. The CXRs of these patients were independently read by three pulmonologists for an effusion in each hemithorax, which was correlated with measured pleural fluid thickness on chest CT. RESULTS: Lateral, PA and AP radiographs were equivalent in identifying the presence of PPEs. All three views missed more than 10% of PPEs. The sensitivities of lateral, PA and AP CXRs were 85.7%, 82.1% and 78.4%, respectively (P = 0.749); the specificity was 87.5%, 81.3% and 76.4%, respectively (P = 0.198). The majority of effusions missed in each view were on films with lower lobe consolidation. CONCLUSIONS: All three CXR views missed effusions of a size significant enough to warrant thoracentesis. Consideration should be given to obtaining additional imaging at the time patients present with pneumonia, particularly in those with lower lobe consolidation. PMID- 21651643 TI - Effect of repeated administration of low-dose silver nitrate for pleurodesis in a rabbit model. AB - BACKGROUND AND OBJECTIVE: Both the efficacy and toxicity of sclerosing agents are likely to be dose-dependent. Clinical pleurodesis strategies typically involve single bolus dose administration of drugs. This study was designed to test whether repeated administration of low doses of silver nitrate (SN) could lead to effective pleurodesis. METHODS: Intrapleural administration, to rabbits, of decreasing doses of SN or normal saline was undertaken daily over 1, 5 or 14days. Assessment of the degree of pleurodesis was by visual inspection (score 1-8) and histological examination and scoring of inflammation and fibrosis (score 0-4). The untreated contralateral side was used as a control. A visual pleurodesis score of >=5 was considered to be positive. RESULTS: The lowest concentrations of SN leading to a visual pleurodesis score >=5 were 0.425%, 0.085% and 0.05% for 1, 5 and 14day administration protocols respectively (P<0.05 vs control side). Visual pleurodesis scores decreased as the dose of SN decreased within each administration regimen groups (P<0.05 for single and 14day groups, P=0.058 in 5day group). A significant correlation was noted between visual pleurodesis scores and histology fibrosis scores. CONCLUSIONS: Effective pleurodesis can be achieved in an animal model with repeated daily administration of SN at doses significantly lower than the lowest effective single day dose. This finding could lead to better tolerated pleurodesis regimens. PMID- 21651644 TI - Expression and clinical significance of lung-specific X protein mRNA in bronchial brushing specimens from patients with or without lung cancer. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the diagnostic utility of lung-specific X protein (LUNX) mRNA expression in bronchial brushing specimens from patients with lung cancer. METHODS: LUNX mRNA levels were assessed by performing RT-PCR on liquid-based cytology bronchial brushing specimens from patients with lung cancer (n=104) or benign lung disease (n=91). RESULTS: LUNX mRNA expression was significantly more frequent in patients with all carcinomas, squamous cell carcinomas, adenocarcinomas, as well as patients with central, peripheral and diffuse carcinomas (P<0.01), and non-small cell lung carcinomas (P<0.05) compared with patients with benign disease. The diagnostic performance of RT-PCR analysis of LUNX mRNA was significantly better than that of cytology in terms of sensitivity (93.3+/-4.8% vs 64.4+/-9.2%), negative predictive value (91.6+/-6.0% vs 71.1+/-7.9%) and accuracy (88.7+/-4.4% vs 81.0+/-5.5%), whereas specificity (83.5+/-7.6%) and positive predictive value (86.6+/-6.3%) were lower than those of cytology (100%). CONCLUSIONS: Liquid-based cytology and RT-PCR can be performed to detect LUNX mRNA expression in bronchial brushing specimens, and this technique may be a useful adjunct to cytological diagnosis of lung cancer. The sensitivity of the technique was greater than that of cytology but its lower specificity should be taken into account. PMID- 21651645 TI - KL-6 and CEA levels in epithelial lining fluid microsamples predict response to gefitinib in patients with advanced non-small cell lung cancer. AB - BACKGROUND AND OBJECTIVE: Both Krebs von den Lungen-6 (KL-6) and carcinoembryonic antigen (CEA) are known to be tumour markers in non-small cell lung cancer (NSCLC). The aim of the present study was to assess whether or not intrabronchial epithelial lining fluid (ELF) levels of these markers predicted tumour response better than serum levels in patients with advanced NSCLC treated with gefitinib. METHODS: ELF samples were obtained both from near the tumour and from the contralateral lung using a bronchoscopic microsampling technique, before and 2 weeks after the start of gefitinib treatment. Serum samples were taken concurrently. Among the 22 patients enrolled in the study, 14 (64%) showed partial responses or stabilization of disease with gefitinib treatment (treatment responders), while 8 (36%) showed progression of disease (treatment non responders), 4 weeks after the start of treatment. RESULTS: ELF KL-6 levels near the tumour decreased significantly after 2 weeks in the treatment responders group (P = 0.011), whereas there was a marginal increase in the treatment non responders group (P = 0.049). ELF CEA levels near the tumour decreased significantly after 2 weeks in the treatment responders group (P = 0.004), whereas there was no significant change in the treatment non-responders group. For both markers, neither the serum levels nor the levels in contralateral ELF showed any significant changes in either group of patients. CONCLUSIONS: Both KL 6 and CEA levels in ELF near the tumour predicted tumour response in NSCLC patients treated with gefitinib, whereas serum levels did not. PMID- 21651646 TI - Gastro-oesophageal reflux, eosinophilic airway inflammation and chronic cough. AB - BACKGROUND AND OBJECTIVE: Patients with eosinophilic airway inflammation (EAI) often show a therapeutic response to corticosteroids. Non-invasive methods of diagnosing EAI are potentially useful in guiding therapy, particularly in conditions such as chronic cough, for which corticosteroids may not be the first line treatment. METHODS: The value of exhaled nitric oxide (ENO) in the diagnosis of EAI was prospectively investigated in a cohort of 116 patients with chronic cough of varying aetiology. An optimum cut-off value was derived for differentiating between EAI and non-EAI causes of chronic cough. As the diagnosis was gastro-oesophageal reflux in 70 patients (60.3% of the total), the possible relationship between ENO and EAI in the presence or absence of reflux was subsequently investigated. RESULTS: The optimum value of ENO for differentiating EAI (32% of patients) from non-EAI causes of cough was 33 parts per billion (sensitivity 60.5%, specificity 84.6%). In the subgroup of patients with reflux, ENO was highly specific for the diagnosis of EAI (sensitivity 66%, specificity 100%). Conversely, in the patients without reflux, ENO did not discriminate between cough due to EAI or other causes (sensitivity 100%, specificity 28.9%). CONCLUSIONS: These results suggest that the presence or absence of reflux should be taken into consideration when interpreting ENO measurements in the diagnosis of chronic cough associated with EAI. PMID- 21651647 TI - Impact of maternal age on the incidence of obstetrical complications in Japan. AB - AIM: To clarify the effect of maternal age on obstetrical complications through a cohort and case-cohort study. METHODS: We studied 242 715 births at 125 centers of a perinatal network in Japan from 2001 through 2005 as a base cohort. Women with single pregnancies who delivered after 22 weeks of gestation were included in the study. Six classes of maternal age were selected: <20; 20-24; 25-29; 30 34; 35-39; and >=40 years. The cohort study was used to investigate whether age is related to obstetrical complications. By random selection 3749 births were determined as a subcohort. Risk ratio (RR) was determined using multivariate analysis in the case-cohort study. RESULTS: The incidence proportion (per 100 births) of pregnancy-induced hypertension, cervical insufficiency, placenta previa, and placental abruption increased with age, whereas the incidence proportion of preterm labor and chorioamnionitis were higher at younger maternal age. The RR of women in the age groups 35-39 years and >=40 years (with the reference of 1.0 for women in the age group of 20-34 years) were determined: pregnancy-induced hypertension, 1.66, 2.55; placenta previa, 1.76, 2.19; and placental abruption, 1.18, 1.5. The RR of preterm labor for women in the age group of <20 years was 1.78. CONCLUSION: The effect of maternal age differs for each obstetrical complication, and thus, it is important to understand these differences for management of individual pregnant patients. PMID- 21651648 TI - Soft tissue metastasis of an immature teratoma of the ovary. AB - In patients with immature teratoma of the ovary, blood-borne metastasis to organ parenchyma, such as the lungs, liver, or brain, are uncommon. Moreover, soft tissue metastasis is extremely rare. We describe a 31-year-old woman with an immature teratoma of the left ovary, which metastasized to soft tissue of the right thigh after surgery. Because of the rarity of this condition, we report the results of treatment and review the literature. PMID- 21651649 TI - Primary adenoid cystic carcinoma of sweat glands in vulva: report of an unusual case and review of the literature. AB - Adenoid cystic carcinoma arising from the vulvar sweat glands is a rare malignancy of the female genital tract. We report a case of adenoid cystic carcinoma of sweat glands occurring in the left labia majora of a 52-year-old female patient. The patient underwent radical hemivulvectomy and left inguinal lymph node dissection with negative surgical margins and negative inguinal lymph node metastasis. Then, four episodes of combined chemotherapy without further radiotherapy were given. However, the tumor recurred after 3 months. Currently, the patient has been followed up for 2 years with no distant metastasis. According to our experience, although the tumor has a high tendency of local recurrence after resection, an acceptable survival time of the patient can be achieved with primary surgery. PMID- 21651650 TI - Velamentous cord insertion caused by oblique implantation after in vitro fertilization and embryo transfer. AB - We present a case of a 36-year-old pregnant female after intracytoplasmic sperm injection. Ultrasonographic examination at 8 weeks' gestation revealed umbilical cord insertion with a viable fetus located on the septum membrane of dichorionic twin pregnancy near the anterior wall, while the other fetus was observed to have vanished. Next, this umbilical cord was seen to connect to the anterior wall and the placenta developed on the posterior wall later in the pregnancy. As a result, velamentous cord insertion with long membranous umbilical vessels developed at the time of delivery. The present case indicates that the assessment of the cord insertion site during the early gestation period is very important to predict any abnormality of the cord insertion site at the time of delivery. Furthermore, this case is valuable to understand the pathophysiological development of the placenta and velamentous cord insertion. PMID- 21651651 TI - Borderline papillary serous tumor of the fimbriated end of the fallopian tube with peritoneal implants. AB - Diagnosis of Borderline papillary serous tumor of the fallopian tube was comprehensively established by Zheng in 1996 supported mostly by a histological similarity to its ovarian counterpart. It is a very rare entity with eight cases published so far and the ninth case described here as a 41-year-old woman presented with non-specific lower abdominal pain, dyspareunia and dysuria. Left adnexal mass was identified and she was operated on. It turned out the tumor was attached exclusively to the left tube, with no connection to any of the surrounding structures and with histology of borderline serous tumor with non invasive implants in the left and right ovary and visceral peritoneum. Reviewing available data on genetics of these tumors there was diploid status in one examined tumor, and in our case no mutations of KRAS, BRAF and p53 genes were found. Histomorphology remains the mainstay of diagnosis and staging operation is the mainstay of patient management. Prognosis is uncertain with a 6-year survival documented in one case. PMID- 21651653 TI - What's in this issue? PMID- 21651652 TI - The effect of vitamin D receptor BsmI genotype on the response to osteoporosis treatment in postmenopausal women: a pilot study. AB - AIM: The purpose of our study was to investigate the possible effect of BsmI vitamin D receptor (VDR's) polymorphism on changes in bone mineral density (BMD) and bone turnover markers in postmenopausal women receiving different treatments. MATERIAL AND METHODS: This pilot study included 42 postmenopausal women with elevated fracture risk, randomized into 1-year treatment with weekly oral alendronate or daily subcutaneous teriparatide. Both groups received daily supplements of 1000 mg calcium and 800 IU vitamin D. Blood samples were obtained for biochemical evaluation and genotyping. BMD at the lumbar spine and femoral neck were assessed with dual energy X-ray absorptiometry. Baseline, follow-up BMD and markers of bone turnover were assessed according to the BsmI genotype. RESULTS: BMD at the lumbar spine increased in patients carrying at least one b allele, while it decreased in patients with the BB genotype (P = 0.041). Whereas no gene-treatment interaction was observed in teriparatide-receiving patients, women with the BB genotype receiving alendronate resulted in negative BMD (-0.056 +/- 0.032 g/m(2) ) and T-score (-0.295 +/- 0.190) gradient, compared to carriers of the b allele (BMD: +0.020 +/- 0.017 g/m(2) , P = 0.054; T-score: +0.217 +/- 0.100, P = 0.030). No effect of genotype was apparent with respect to gradients of biochemical bone markers. CONCLUSIONS: These preliminary results indicate that alendronate has a differential effect on BMD, depending on the VDR genotype. Carriers of the b allele may be more responsive to treatment compared to patients with the BB genotype. The interaction of VDR's BsmI polymorphism with the efficacy of the anti-osteoporotic treatment needs further investigation by larger prospective studies. PMID- 21651654 TI - The art of nursing: crossing the quality chasm and promoting patient safety in critical care. PMID- 21651655 TI - Remembering the art of nursing in a technological age. PMID- 21651656 TI - Nursing documentation prior to emergency admissions to the intensive care unit. AB - BACKGROUND: Early identification of prodromal signs of acute deterioration of patients is essential in high quality care. Rigorous monitoring of patients is facilitated by risk assessment tools, e.g. the Modified Early Warning Score (MEWS). AIMS AND OBJECTIVES: The purpose of the study was to estimate the accuracy of nursing documentation according to parameters that comprise MEWS in patients prior to emergency admission to the intensive care unit (ICU). METHODS: The research design was retrospective and descriptive. Data was collected from medical records of in-patients who presented as emergency admission to two ICUs at a university hospital between 1 October and 31 December 2006. RESULTS: Data was collected from 65 patients' records over the 3-month period. Most admissions occurred between the hours of 8 a.m. and 4 p.m. Respiratory failure was the primary reason for admission, followed by septic shock. Respiratory rate was documented for 14% of patients (n = 9) prior to ICU admission, which was the least documented observation. Urine output and fluid balance were documented for 40% of the patients, level of consciousness in 48% of patients (n = 31), temperature for 69% (n = 45) and oxygen saturation for 80% of the patients (n = 53). DISCUSSION: Respiratory failure was the primary cause of emergency admission of in-patients to the ICUs with respiratory rate the least documented vital sign. Nursing documentation according to the MEWS was insufficient. CONCLUSIONS/RELEVANCE TO CLINICAL PRACTICE: Nurses need to be alerted to the necessity of documenting early signs of deterioration of patients, particularly the respiratory rate. With better monitoring and documentation of physiological parameters, emergency admission to the ICU might be avoided. PMID- 21651657 TI - Neurovascular assessment in the critically ill patient. AB - AIM: To outline the pathophysiological processes involved in neurovascular impairment and compartment syndrome and examine common contributory factors within the development and clinical presentation of neurovascular impairment in critical care patients with musculoskeletal trauma. BACKGROUND: Thorough and systematic assessment of neurovascular status in critically ill patients with musculoskeletal trauma is crucial to detect secondary ischaemic injury and implement appropriate and timely treatment of any neurovascular deficits. METHOD: Current literature relating to neurovascular assessment and associated patient care was reviewed and utilised to outline distinct assessment components, indicators of neurovascular impairment and highlight the important issues for critical care nursing practice. RESULTS: Diminished limb perfusion secondary to vascular impairment and compartment syndrome are well documented. Complications associated with musculoskeletal trauma and surgical intervention can have wide ranging effects on the patient's functional ability and overall outcome. It is crucial that appropriate neurovascular assessment is undertaken for patients admitted to the critical care unit following musculoskeletal trauma, crush injury, orthopaedic surgery (involving internal or external fixation of fractures) and those who may have experienced prolonged external pressure from casts or tight-fitting bandages. Several elements of neurovascular assessment are, however, more complex to undertake in the context of the unconscious or sedated critically ill patient. CONCLUSIONS: Effective practice requires that the critical care nurse has a comprehensive understanding of the aetiology, pathophysiology, physiological responses and clinical presentation associated with neurovascular impairment, secondary ischaemia and compartment syndrome. RELEVANCE TO CLINICAL PRACTICE: Undertaking an effective neurovascular assessment for patients at risk of neurovascular impairment or acute compartment syndrome (ACS) in the critical care setting can be problematic when patients are unable to communicate with the nurse. The risk of long-term functional impairment or limb loss can be significant in this group of patients, particularly following musculoskeletal trauma. This article reviews the aetiology and pathophysiology of neurovascular impairment in the critical care context and provides guidance for nurses undertaking this important element of nursing assessment with non-verbal, critically unwell patients. Informed practice in neurovascular assessment has the potential to enable early detection and timely management for these patients, which is crucial to optimise patient outcomes. PMID- 21651658 TI - Pain assessment in turning procedures for patients with invasive mechanical ventilation. AB - BACKGROUND: The assessment of pain is particularly difficult in critical patients unable to self-report or with cognitive impairment. In such cases, the use of scales which evaluate pain through patient behaviour is important. AIMS: To compare the behavioural responses to pain, measured on the Critical-Care Pain Observation Tool (CPOT) scale, and the physiological responses prior to, during and after the positioning procedure in patients with invasive mechanical ventilation. We also sought to analyse whether there are differences in the CPOT scores between medical and surgical patients, and between conscious and unconscious patients. METHOD: Pain scores were evaluated in 96 patients. The data gathering was carried out 1 min before, during and 10 min after the turning by means of the CPOT scale which includes four behavioural indicators, each indicator scored from 0 to 2. Likewise, mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR) and arterial oxygen saturation (SpO(2)) were recorded. RESULTS: The total mean score on the CPOT scale prior to the positioning procedure was 0.27; during turning it was 1.93 and 0.10 after the procedure (p < 0.05). Facial expression was the indicator that increased most with reference to the baseline situation, followed by body movements; compliance with the ventilator, and finally, muscle tension. There were also slight variations in these physiological variables during the turning procedure (p < 0.05). The total mean score on the CPOT scale during the turning of surgical patients was 2.02 and 1.80 for medical patients (p = 0.162). CONCLUSIONS: The observation of the patient's behaviour during the turning and the physiological changes produced allow professionals to objectify pain in critical patients with verbal communication difficulties. Moreover, our results also highlight the need to administer of additional analgesia before a painful procedure, particularly in post-surgical patients. RELEVANCE TO CLINICAL PRACTICE: The good measurement qualities of the CPOT scale obtained during a painful procedure recommend its use in intensive care units (ICUs) for adult patients with artificial ventilation. PMID- 21651659 TI - Delirium incidents in three Danish intensive care units. AB - BACKGROUND: Delirium as a result of hospitalization in an intensive care unit (ICU) is defined by a mental state different from the patients' normal state and an acute fluctuating course. Both morbidity and mortality are increased in relation to delirium. The incidence of delirium has been reported from 16% to 87% in international studies primarily in elderly patients. AIMS: The purpose of this study was to evaluate the incidence of delirium in adult intensive care patients in Denmark and to identify correlations between delirium, sedatives, opioid analgesics and age. METHODS: In a prospective follow-up study, 139 adult patients were screened for delirium using the confusion assessment method for the ICU (CAM ICU) from 48 h after admission to ICU, twice a day until discharged. RESULTS: A total of 41 patients had at least one positive score for delirium, 61 had only negative scores and 37 were too heavily sedated to be scored during the study period. Thus, the incidence of delirium was 40% among patients who were able to be CAM-ICU scored. Patients who were lightly sedated had a 10-fold increased risk of delirium. There was no difference in incidence by age. Patients who received Fentanyl were more at risk of developing delirium compared with patients who received other or no analgesics. Sedative drugs did not influence the incidence. CONCLUSION: In this study delirium occurred in 40% of adult ICU patients of all ages. PMID- 21651661 TI - Nurses new to intensive care: perceptions of their clinical learning environment. AB - BACKGROUND: All nurses entering intensive care unit (ICU) for the first time are required to master many critical nursing skills. Providing a clinical learning environment that is, conducive to mastering these essential skills is a key component of ensuring clinical competence. Yet there are few publications worldwide that focus on clinical learning for qualified nurses entering ICU for the first time. Factors that affect clinical learning in ward environments have been clearly identified. It remains unclear if these factors are applicable to the ICU environment. AIMS AND OBJECTIVES: (1) To describe how registered nurses new to ICU environment perceive their clinical learning environment; (2) to identify the factors that influence these perceptions. DESIGN: Descriptive quantitative survey design. METHOD: Sixty-four nurses were recruited from five Irish teaching hospitals. The participants completed a modified version of Dunn and Burnett's clinical learning environment scale, with five subscales, that measures perceived factors that influence clinical learning. RESULTS AND CONCLUSIONS: Nurses new to ICU perceived the environment as conducive to clinical learning. Factors positively affecting clinical learning include: educational staff and clinical nurse managers' commitment to supporting learning and good interpersonal relationships. Non-European qualified nurses who did not do an induction course and those with longest experience on the unit were more satisfied with ICU as a clinical learning. RELEVANCE TO CLINICAL PRACTICE: These findings will provide nurse educationalists with some further insight as to the factors that promote optimal learning in ICU. PMID- 21651660 TI - Acute cardiogenic pulmonary oedema: reflecting on the management of an intensive care unit patient. AB - AIM: The aim of this paper is to reflect upon the management interventions of non invasive ventilation (NIV) and diuretic therapy that were implemented for a patient admitted to an intensive care unit (ICU) with acute cardiogenic pulmonary oedema. BACKGROUND: Acute pulmonary oedema is a serious and life-threatening complication of acute heart failure, particularly if this results from an ischaemic event. Statistics highlight that of those patients treated for acute cardiogenic pulmonary oedema, approximately only one third were alive after 1 year. Many of these patients will require intensive care management in order to restore homeostasis. It is therefore imperative that nurses understand the condition and the relevant management of it in order to maximize the already poor prognosis. RESULTS: Using Driscoll's (2000) reflective model to guide critical thinking, this paper reflects on the management of one patient who was admitted to ICU with acute cardiogenic pulmonary oedema as a result of heart failure. Although there are many aspects of patient management that can be explored, specific care interventions that this patient received in relation to NIV and diuretic therapy will be considered. The evidence base for their use, together with the relevant nursing management issues, and patient implications will be critically analysed and outlined. CONCLUSIONS: This paper identifies that standard therapy for acute cardiogenic pulmonary oedema is largely supportive and aimed at promoting gaseous exchange. It also highlights that nurses have a key role in ensuring that these essential treatments are as efficacious as possible. RELEVANCE TO CLINICAL PRACTICE: By using a reflective analysis approach, this paper highlights how reflecting on practice improves knowledge and understanding of the use of NIV and diuretic therapy interventions and should facilitate nurses working in ICU to become more competent in ensuring that the treatment provided for acute cardiogenic pulmonary oedema is as successful as possible. PMID- 21651668 TI - Prospective comparison of biopsy results from curettage and hysteroscopy in postmenopausal uterine bleeding. AB - AIM: To evaluate the diagnostic accuracy of biopsy by dilatation and curettage in postmenopausal women with abnormal uterine bleeding. MATERIAL AND METHODS: A prospective observational study conducted with 112 consecutive postmenopausal women. Biopsy by dilatation and curettage was immediately followed by hysteroscopic biopsy and the histologic results were compared. RESULTS: By curettage, although performed under anesthesia, 3/3 (100%) cases of endometrial hyperplasia were reported as normal proliferative endometrium. There were two endometrial cancers (1.8%) and one case was missed as normal endometrium by curettage. Among endometrial polyps, only 3/39 (7.7%) cases were diagnosed by curettage. CONCLUSIONS: In postmenopausal women with abnormal uterine bleeding, biopsy by curettage may be not reliable for evaluation of endometrial pathology. PMID- 21651669 TI - Primary extraskeletal myxoid chondrosarcoma of the vulva. AB - Primary extraskeletal myxoid chondrosarcoma (EMC) of the vulva is extremely rare. There is little available information about the biological behavior and treatment strategy for primary EMC of the vulva. We report a rare case of primary EMC of the vulva treated surgically. A 24-year-old Japanese woman had demonstrated a small and elastic mass of the vulva and underwent enucleation of the mass at a previous hospital, but a definitive histopathological diagnosis was not obtained. Therefore, the patient was referred to our hospital for further evaluation and treatment. We histopathologically diagnosed the tumor as primary EMC of the vulva and performed vulvectomy with vulvoperineal reconstruction. Microscopic examination of the resected specimens demonstrated residual tumor nodules of EMC. However, there were no viable tumor cells at the surgical margin. Approximately two years after wide local excision was performed, the patient is doing well and there is no apparent recurrence of EMC. PMID- 21651670 TI - Jaundice as the first manifestation of primary biliary cirrhosis during pregnancy: measurement of portal vein blood flow. PMID- 21651671 TI - Retained products of conception with marked vascularity: pseudoaneurysm hidden behind it. PMID- 21651672 TI - Valproic acid alleviates generalized hyperalgesia in mice with induced adenomyosis. AB - Emerging evidence suggests that adenomyosis, like endometriosis, may also be an epigenetic disease. In this study, we evaluated the effect of valproic acid (VPA) in ICR mice with adenomyosis, induced by neonatal dosing with tamoxifen. For all mice, we evaluated the bodyweight and the response to thermal stimuli by hotplate and tail-flick tests 4, 8, and 12 weeks after dosing, respectively, and then treated mice with low- and high-dose of VPA, progesterone (P4), P4 + VPA, or vehicle only. Three weeks after treatment, both bodyweight and thermal response tests were evaluated again before sacrifice, and the depth of myometrial infiltration was evaluated. We found that: (i) the induction of adenomyosis resulted in progressive generalized hyperalgesia as measured by hotplate and tail flick tests, along with decreased bodyweight; (ii) treatment with VPA, P4, or a combination was efficacious in improving generalized hyperalgesia; and (iii) drug treatment appeared to reduce the myometrial infiltration, but the difference did not reach statistical significance. Thus, VPA seems to be a promising therapeutics for treating adenomyosis, as reported recently in some case series in humans. PMID- 21651673 TI - Aberrant DNA methylation status of endometriosis: epigenetics as the pathogenesis, biomarker and therapeutic target. AB - Endometriosis, a common, benign, estrogen-dependent disease affecting 3-10% of women of reproductive age, is characterized by the ectopic growth of endometrial tissue that is found primarily in the peritoneum, ovaries and rectovaginal septum. Recently, endometriosis has been alternatively described as an immune disease, a genetic disease and a disease caused by exposure to environmental factors, in addition to its usual description as a hormonal disease. In addition, accumulating evidence suggests that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis. Epigenetic alterations reported to date in endometriosis include the genomic DNA methylation of progesterone receptor-B, E-cadherin, homeobox A10, estrogen receptor-beta, steroidogenic factor-1 and aromatase. Aberrant expression of DNA methyltransferases, which attach a methyl group to the 5-carbon position of cytosine bases in the CpG island of the promoter region and silence the corresponding gene expression, has also been demonstrated in endometriosis. This review summarizes the recent studies on the aberrant DNA methylation status and aberrant expression of DNA methyltransferases, which regulate DNA methylation, in endometriosis. We also discuss the recent information on the diagnostic and therapeutic implications of epigenetic alterations occurring in endometriosis. PMID- 21651675 TI - Web-enabled registry of inherited bleeding disorders in Portugal: conditions and perception of the patients. AB - Local and national haemophilia registries are powerful instruments to support the healthcare and researchers and improve the communication between Comprehensive Haemophilia Diagnostic and Treatment Centres (HTCs) and patients. Hemo@care is an example of a Local Haemophilia Registry Systems (LHR_Sys) based on the Web, developed in collaboration with a HTC located in Portugal, to support the haemophilia treatments registry, collect and manage the clinical information and provide mechanisms to control the clotting factor concentrates (CFC) stock. To extend this solution (the hemo@care) to other Portuguese HTCs and consequently to meet the preconditions to create a National Haemophilia Registry Systems (NHR_Sys), a study based on a questionnaire was carried out at nationwide. This study aims to assess the conditions and motivations of people with haemophilia (PWH) geographically scattered throughout the country, to use a potential Web enabled registry with the purpose of replacing the traditional paper-diaries, to understand their judgment about a potential NHR_Sys currently non-existent in Portugal, and at the same time, to characterize demographically and pathologically those people at the nationwide. The results based on the analysis of 168 responses (response rate of 31%) confirmed the high prevalence of the disease in haemophilia A (75%) compared with haemophilia B (11.3%) and a large incidence in the severe levels, or the existence of people with mild severity without diagnosis and treatment. Furthermore, the results also revealed the need, conditions and motivation for using a registry system by PWH; thus it is deemed to justify the extension of the hemo@care to other HTCs in Portugal and consequently to create the NHR_Sys. PMID- 21651676 TI - HCV-related liver cancer in people with haemophilia. AB - The topic of this monograph is liver cancer associated with chronic HCV infection. We start with some background information on chronic HCV infection and its long-term sequelae, one of which is liver cancer. The rest of the article is concerned with liver cancer or hepatocellular carcinoma (HCC). Epidemiology, risk factors, treatment and outcomes are discussed. We focus on those aspects that are of specific interest in people with haemophilia: studies performed in haemophilia populations, the use of invasive diagnostic and therapeutic tools and the outcome of liver transplantation. Throughout the paper, recommendations are given on surveillance for and diagnosis of HCC and on the practical aspects of invasive procedures. These recommendations are based on professional guidelines, other published evidence and the authors' experience. In general, diagnostic and therapeutic options are the same in persons with and without haemophilia. PMID- 21651677 TI - Attitudes of haemophilic patients towards their health and socio-economic problems in Iran. AB - Although new technologies and treatments have improved the quality of life of people with haemophilia, they still face many health and socio-economic problems. We designed this study to identify some of these problems according to patients' attitudes towards efforts to solve them. This cross-sectional study was conducted in Shiraz, southern Iran, during January and May 2010. The participants were 100 patients with haemophilia who were referred to Shiraz Hemophilia Center, a major referral centre in southern Iran. A questionnaire was used to obtain data on the attitudes of haemophilic patients about some of their health and socio-economic problems. Mean age of the patients was 28.2 +/- 9.0 (range of 16-67 years). In univariate analysis, disease severity, joint involvement, HCV status, income level and educational level of the patients were found to have possible effect on patients' attitude towards their health and socio-economic problems. However, in multivariate model we found that only income level, educational level and HCV status as independent factors influencing the patients' attitude towards childbearing, employment problems, occupational problems, social and friend relationship and continuing education. Haemophilic patients had many social and health problems, which could be alleviated with interdisciplinary interventions to improve their quality of life. Financial support of these patients should be taken into account to reduce their economic problems. Also, encouraging them and providing facilities to achieve a higher educational level could help them to have a better attitude towards their health and overcome the disease-related problems. PMID- 21651678 TI - Evaluation of bone mineral density in Turkish children with severe haemophilia A: Ankara hospital experience. AB - This study was conducted to understand the pathogenetic mechanisms that are involved in the development of bone loss in children with severe haemophilia A (HA). Fourty-four children with severe HA and 40 age- and gender-matched healthy control subjects were enrolled in this study. Markers of bone remodelling and osteoclast regulation including serum bone specific alkaline phosphatase, parathormone, 25-hydroxy-vitamin D(3) (25HOvitD(3)), osteocalcin and calcitonin levels were studied. Bone mineral density (BMD) was also studied in all children. The measurement of markers of bone remodelling and osteoclast regulation suggested increased osteoclast-mediated resorption activity in children with severe HA. Although serum parathormone levels were significantly increased, serum 25HOvitD(3) and osteocalcin levels were significantly reduced. BMD was significantly reduced in severe haemophilics compared with healthy controls. There was also significant inverse correlation between BMD z-score and total joint scores, and insignificant inverse correlation between BMD z-score and single joint scores. There were also significant inverse correlation between 25HOvitD(3) and osteocalcin levels and total joint scores. Children with severe HA could have significantly reduced BMD, compared with gender- and age-matched healthy control subjects. Our results of the markers of bone remodelling and osteoclast regulation suggested that increased osteoclast-mediated resorption and decreased osteoblastic activity in children with severe HA. All children with severe HA should be routinely screened in terms of BMD. PMID- 21651679 TI - The identification of risk factors for critically ill patients with acute fever and formulation of activation criteria to alert outpatient clinic doctors. AB - RATIONALE, AIMS AND OBJECTIVES: Acute fever is the most common early clinical symptom of many critical illnesses with a high mortality rate. It is necessary to identify patients with severe acute fever early and accurately. The aim of this study is to identify risk factors for critically ill outpatients with acute fever and formulate activation criteria of adult fever state score (AFSS) to alert outpatient clinic doctors. METHODS: Retrospectively, 357 adult patients with acute fever were divided into two groups: 180 patients with a severe state and 177 patients with a mild state. Logistic regression was used to determine risk factors for the severe state. Risk factors were weighted and an AFSS was formulated. A receiver operating characteristic (ROC) analysis of weighted cumulative scores was performed to evaluate the diagnostic accuracy of AFSS, and the kappa test was used to confirm diagnostic reliability. A chi(2) -test for trend was applied to determine the relevance between AFSS and admission rate and in-hospital mortality. A Kruskal-Wallis test was used to examine the relationship between AFSS and length of stay. RESULTS: Risk factors for state included: old age, long fever course, past medical history, abnormal temperature, abnormal respiratory rate, abnormal heart rate, abnormal mean arterial pressure and abnormal peripheral white blood cell count. The area under the ROC curve of AFSS was 0.964 and >=8 points predicted severe state; the Kappa value was 0.801. With an increase in score, there was an increase in admission rate, mortality rate and length of stay. The forecast performance of AFSS was superior to the modified early warning score. CONCLUSIONS: The AFSS has high diagnostic accuracy and reliability for the early identification of patients with severe acute fever. PMID- 21651680 TI - Effects of sodium bisulfate on the bacterial population structure of dairy cow waste. AB - AIMS: To determine the effects of sodium bisulfate (SBS) on the bacterial populations in cattle waste. METHODS AND RESULTS: We applied SBS at 0, 60, 70 or 100 kg week(-1) to cattle waste as it accumulated on the floors of four cattle pens, housing eight cattle each. We observed significant pH decreases in all of the treated wastes on day one; however, the 60 kg week(-1) treatment returned to control levels by day four, while the others remained significantly lower. Heterotrophic plate counts of the waste revealed that all treatments reduced the bacterial populations in the wastes on day one; however, all returned to control levels by day four. The 16S rRNA gene libraries derived from the wastes revealed significant reductions in sequences associated with the phyla Bacteroidetes and Firmicutes and increases in the Proteobacteria, Actinobacteria and Spirochaetes on day one, but resembled the control by day seven. Sequences associated with Escherichia coli increased significantly after SBS application, but became undetectable by day seven. CONCLUSIONS: SBS application significantly alters the bacterial population structure of waste during the first few days of application, but the populations return to almost normal after 7 days. SIGNIFICANCE AND IMPACT OF THE STUDY: Application of SBS to animal waste can reduce emissions; however, biosecurity precautions must be rigorously maintained during the initial application to ensure that pathogenic E. coli is not released into the environment. PMID- 21651681 TI - Survival of Mycobacterium tuberculosis during experimental aerosolization and implications for aerosol challenge models. AB - AIMS: We undertook a series of experiments to investigate factors that contribute to variation in Mycobacterium tuberculosis viability and infectivity, during experimental aerosolization, with an aim to optimize a strategy to enable a more reproducible delivered dose within animal models of tuberculosis. METHODS AND RESULTS: The viability and infectivity of the challenge suspension was determined in relation to aerosolization time, concentration, method of preparation and M. tuberculosis strain. Challenge stocks generated from frozen aliquots of M. tuberculosis were shown to undergo a 1 log(10) CFU ml(-1) decrease in viability during the first 10 min of aerosolization. This correlated with a decrease in surface lung lesions developing in guinea pigs challenged during this time. The phenomenon of decreased viability in vitro was not observed when using freshly grown, nonfrozen cells of M. tuberculosis. The viability of aerosolized bacilli at the point of inhalation relative to the point of aerosolization always remained constant. CONCLUSION: Based on these findings, we have developed an improved strategy by which to reproducibly deliver aerosol infection doses to individually challenged animals and separately challenged groups of animals. SIGNIFICANCE AND IMPACT OF THE STUDY: Study of the aerobiological characteristics of micro-organisms is a critical step in the validation of methodology for aerosol infection animal models, particularly where large numbers of animals and nonhuman primates are used. PMID- 21651682 TI - Vertebrate predators have minimal cascading effects on plant production or seed predation in an intact grassland ecosystem. AB - The strength of trophic cascades in terrestrial habitats has been the subject of considerable interest and debate. We conducted an 8-year experiment to determine how exclusion of vertebrate predators, ungulates alone (to control for ungulate exclusion from predator exclusion plots) or none of these animals influenced how strongly a three-species assemblage of rodent consumers affected plant productivity. We also examined whether predator exclusion influenced the magnitude of post-dispersal seed predation by mice. Both ungulates and rodents had strong direct effects on graminoid biomass. However, rodent impacts on plant biomass did not differ across plots with or without predators and/or ungulates. Deer mice removed more seeds from seed depots on predator exclusion plots, suggesting trait-mediated indirect effects of predators, but this short-term behavioural response did not translate into longer-term impacts on seed survival. These results suggest that vertebrate predators do not fundamentally influence primary production or seed survival in our system. PMID- 21651683 TI - Vacuolated Beggiatoa-like filaments from different hypersaline environments form a novel genus. AB - In this study, members of a specific group of thin (6-14 um filament diameter), vacuolated Beggiatoa-like filaments from six different hypersaline microbial mats were morphologically and phylogenetically characterized. Therefore, enrichment cultures were established, filaments were stained with fluorochromes to show intracellular structures and 16S rRNA genes were sequenced. Morphological characteristics of Beggiatoa-like filaments, in particular the presence of intracellular vacuoles, and the distribution of nucleic acids were visualized. In the intracellular vacuole nitrate reached concentrations of up to 650 mM. Fifteen of the retrieved 16S rRNA gene sequences formed a monophyletic cluster and were phylogenetically closely related (>= 94.4% sequence identity). Sequences of known filamentous sulfide-oxidizing genera Beggiatoa and Thioploca that comprise non vacuolated and vacuolated filaments from diverse habitats clearly delineated from this cluster. The novel monophyletic cluster was furthermore divided into two sub clusters: one contained sequences originating from Guerrero Negro (Mexico) microbial mats and the other comprised sequences from five distinct Spanish hypersaline microbial mats from Ibiza, Formentera and Lake Chiprana. Our data suggest that Beggiatoa-like filaments from hypersaline environments displaying a thin filament diameter contain nitrate-storing vacuoles and are phylogenetically separate from known Beggiatoa. Therefore, we propose a novel genus for these organisms, which we suggest to name 'Candidatus Allobeggiatoa'. PMID- 21651685 TI - Genetic structure of marine Borrelia garinii and population admixture with the terrestrial cycle of Lyme borreliosis. AB - Despite the importance of population structure for the epidemiology of pathogenic bacteria, the spatial and ecological heterogeneity of these populations is often poorly characterized. Here, we investigated the genetic diversity and population structure of the Lyme borreliosis (LB) spirochaete Borrelia garinii in its marine cycle involving colonial seabirds and different host races of the seabird tick Ixodes uriae. Multilocus sequence analyses (MLSA) on eight chromosomal and two plasmid loci (ospA and ospC) indicate that B. garinii circulating in the marine system is highly diverse. Microevolution in marine B. garinii seems to be mainly clonal, but recombination and selection do occur. Sequence types were not evenly distributed among geographic regions, with substantial population subdivision between Atlantic and Pacific Ocean basins. However, no geographic structuring was evident within regions. Results of selection analyses and phylogenetic discordance between chromosomal and plasmid loci indicate adaptive evolution is likely occurring in this system, but no pattern of host or vector-associated divergence was found. Recombination analyses showed evidence for population admixture between terrestrial and marine strains, suggesting that LB spirochaetes are exchanged between these enzootic cycles. Importantly, our results highlight the need to explicitly consider the marine system for a complete understanding of the evolutionary ecology and global epidemiology of Lyme borreliosis. PMID- 21651686 TI - The genome sequence of Desulfatibacillum alkenivorans AK-01: a blueprint for anaerobic alkane oxidation. AB - Desulfatibacillum alkenivorans AK-01 serves as a model organism for anaerobic alkane biodegradation because of its distinctive biochemistry and metabolic versatility. The D. alkenivorans genome provides a blueprint for understanding the genetic systems involved in alkane metabolism including substrate activation, CoA ligation, carbon-skeleton rearrangement and decarboxylation. Genomic analysis suggested a route to regenerate the fumarate needed for alkane activation via methylmalonyl-CoA and predicted the capability for syntrophic alkane metabolism, which was experimentally verified. Pathways involved in the oxidation of alkanes, alcohols, organic acids and n-saturated fatty acids coupled to sulfate reduction and the ability to grow chemolithoautotrophically were predicted. A complement of genes for motility and oxygen detoxification suggests that D. alkenivorans may be physiologically adapted to a wide range of environmental conditions. The D. alkenivorans genome serves as a platform for further study of anaerobic, hydrocarbon-oxidizing microorganisms and their roles in bioremediation, energy recovery and global carbon cycling. PMID- 21651687 TI - A distinct freshwater-adapted subgroup of ANME-1 dominates active archaeal communities in terrestrial subsurfaces in Japan. AB - Anaerobic methane-oxidizing archaea (ANME) are known to play an important role in methane flux, especially in marine sediments. The 16S rRNA genes of ANME have been detected in terrestrial freshwater subsurfaces. However, it is unclear whether ANME are actively involved in methane oxidation in these environments. To address this issue, Holocene sediments in the subsurface of the Kanto Plain in Japan were collected for biogeochemical and molecular analysis. The potential activity of the anaerobic oxidation of methane (AOM) (0.38-3.54 nmol cm-3 day-1) was detected in sediment slurry incubation experiments with a (13) CH(4) tracer. Higher AOM activity was observed in low-salinity treatment compared with high salinity condition (200/00), which supports the adaptation of ANME in freshwater habitats. The 16S rRNA sequence analysis clearly revealed the presence of a distinct subgroup of ANME-1, designated ANME-1a-FW. Phylogenetic analysis of the mcrA genes also implied the presence of the distinct subgroup in ANME-1. ANME-1a FW was found to be the most dominant active group in the archaeal communities on the basis of 16S rRNA analysis (75.0-93.8% of total archaeal 16S rRNA clones). Sulfate-reducing bacteria previously known as the syntrophic bacterial partners of ANME-1 was not detected. Our results showed that ANME-1a-FW is adapted to freshwater habitats and is responsible for AOM in terrestrial freshwater subsurface environments. PMID- 21651688 TI - Omics for understanding microbial functional dynamics. PMID- 21651689 TI - Characterization of the cryptic Escherichia lineages: rapid identification and prevalence. AB - Strains phenotypically indistinguishable from Escherichia coli and belonging to at least five distinct cryptic lineages, named Escherichia clades I to V, that are genetically divergent from E. coli yet members of the genus have been recently found using multi-locus sequence typing (MLST). Very few epidemiological data are available on these strains as their detection by MLST is not suitable for large-scale studies. In this work, we developed a rapid PCR method based on aes and chuA allele-specific amplifications that assigns a strain a cryptic lineage membership. By screening more than 3500 strains with this approach, we show that the cryptic lineages of Escherichia are unlikely to be detected in human faecal samples (2-3% frequency) and even less likely to be isolated from extra-intestinal body sites (< 1% frequency). They are more abundant in animal faeces ranging from 3-8% in non-human mammals to 8-28% in birds. Overall, the strains from the clade V are the most abundant and from the clade II very rare. These results suggest that members of the cryptic clades are unlikely to be of significance to human and health but may influence the use of 'E. coli' as an indicator of water quality. PMID- 21651690 TI - Glucagon-like peptide-1 receptor agonists versus insulin in inadequately controlled patients with type 2 diabetes mellitus: a meta-analysis of clinical trials. AB - To compare the effect and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RA) with insulin therapy on type 2 diabetes mellitus (T2DM) patients inadequately controlled with metformin and/or sulfonylurea. A systematic literature search on MEDLINE, Embase and Cochrane for randomized controlled trials (RCTs) was conducted using specific search terms 'GLP-1 insulin type 2 diabetes clinical trials' and eight eligible studies were retrieved. Data on mean change in haemoglobin A1c (HbA1C), weight loss, fasting plasma glucose (FPG), incidence of hypoglycaemia and gastrointestinal adverse events were extracted from each study and pooled in meta-analysis. Data on postprandial plasma glucose (PPG) and adverse events were also described or tabulated. Data from eight RCTs enrolling 2782 patients were pooled using a random-effects model. The mean net change [95% confidence interval (CIs)] for HbA1c, weight loss and FPG for patients treated with GLP-1 RA as compared with insulin was -0.14% (-2 mmol/mol) [95% CI; (-0.27, -0.02)%; p = 0.03]; -4.40 kg [95% CI; (-5.23, -3.56) kg; p < 0.01] and 1.18 mmol/l [95% CI; (0.43, 1.93) mmol/l; p < 0.01], respectively, with negative values favouring GLP-1 and positive values favouring insulin. The GLP-1 group was associated with a greater reduction in PPG than the insulin group. Overall, hypoglycaemia was reported less in the GLP-1 group [Mantel-Haenszel odds ratio (M-H OR) 0.45 (0.27, 0.76); p < 0.01], while there was no significant difference in occurrence of severe hypoglycaemia [M-H OR 0.65 (0.29,1.45); p = 0.29]. A significantly higher number of gastrointestinal adverse events were reported with GLP-1 group [M-H OR 15.00 (5.44,41.35) p < 0.01]. GLP-1 RA are promising new agents compared with insulin. Further prospective clinical trials are expected to fully evaluate the long-term effectiveness and safety of these therapies within the T2DM treatment paradigm. PMID- 21651691 TI - Collagen levels are normalized after decompression of experimentally obstructed colon. AB - AIM: Our aim was to define the dynamics in collagen concentrations in the large bowel wall following decompression of experimental obstruction. METHOD: Colonic obstruction was created in 28 male rats by the placement of a silicone ring around the distal colon. The ring was removed after 4 days to mimic endoscopical decompression by stent deployment. Colon circumference and collagen concentration were measured proximal to the obstructed segment immediately and at 3 and 10 days after decompression. The corresponding colonic sites of 23 sham-operated and eight nonoperated control animals were subjected to identical analyses. RESULTS: Four days of obstruction resulted in a more than twofold increase in colonic circumference (20 vs 8 mm), with a concomitant 43% reduction (P = 0.001) in collagen concentration in the bowel wall proximal to the obstruction compared with sham animals. Three days after decompression, collagen concentrations remained reduced (P < 0.05), while there was no significant difference after 10 days with either sham-operated or nonoperated controls. Colonic circumference of the obstructed colon remained slightly distended (11 mm) on day 10 and tended to correlate (r(S) = 0.51, P = 0.053) with total matrix metalloproteinase activity. CONCLUSION: The marked reduction in collagen concentration in an experimentally obstructed colon is normalized 10 days after decompression. These findings may have clinical implications for the timing of surgical resection. PMID- 21651692 TI - Quality of life measures in Islamic rectal carcinoma patients receiving counselling. AB - AIM: This prospective study was conducted to compare changes in the health related quality of life (HRQoL) and religious practices of patients who underwent surgery for rectal cancer. METHOD: We prospectively followed 93 Muslim patients after surgery for colorectal carcinoma: abdominoperineal excision (APE, n = 50), sphincter-saving resection (LAR, n = 22) or anterior resection including sigmoid colectomy (AR, n = 1). The HRQoL was measured pre- and postoperatively at 15-18 months with the Medical Outcomes Study Short Form 36 Health Survey (SF-36) and a modified version of the American Society of Colorectal Surgeons (ASCRS) Fecal Incontinence questionnaire. Life standards, including religious practice, were measured using the Ankara University Life Standard Questionnaire. RESULTS: No difference was detected in any SF-36 Health Survey HRQoL domain among the groups, although there were differences within groups before and after surgery. The ASCRS Fecal Incontinence questionnaire scales of lifestyle, coping/behaviour and depression/self-perception were similar in the APE and AR groups and were significantly worse than in the AR group (P <= 0.004). The embarrassment scale was worse in the APE than in the LAR and AR groups (P < 0.001). Religious worship (praying alone, praying in mosques, fasting during Ramadan and purifying alms) was not significantly different among the groups. CONCLUSION: HRQoL measured by the SF-36 questionnaire and religious practices were not significantly different after APE compared with AR. Ostomy support and pre- and postoperative health related and religious counselling may have had beneficial effects. PMID- 21651684 TI - Multi-locus sequence analysis, taxonomic resolution and biogeography of marine Synechococcus. AB - Conserved markers such as the 16S rRNA gene do not provide sufficient molecular resolution to identify spatially structured populations of marine Synechococcus, or 'ecotypes' adapted to distinct ecological niches. Multi-locus sequence analysis targeting seven 'core' genes was employed to taxonomically resolve Synechococcus isolates and correlate previous phylogenetic analyses encompassing a range of markers. Despite the recognized importance of lateral gene transfer in shaping the genomes of marine cyanobacteria, multi-locus sequence analysis of more than 120 isolates reflects a clonal population structure of major lineages and subgroups. A single core genome locus, petB, encoding the cytochrome b(6) subunit of the cytochrome b(6) f complex, was selected to expand our understanding of the diversity and ecology of marine Synechococcus populations. Environmental petB sequences cloned from contrasting sites highlight numerous genetically and ecologically distinct clusters, some of which represent novel, environmentally abundant clades without cultured representatives. With a view to scaling ecological analyses, the short sequence, taxonomic resolution and accurate automated alignment of petB is ideally suited to high-throughput and high-resolution sequencing projects to explore links between the ecology, evolution and biology of marine Synechococcus. PMID- 21651693 TI - Familial spontaneous sigmoid perforation. Aetiology and management. PMID- 21651694 TI - Abdominoperineal excision rate: a marker of quality in rectal cancer surgery. PMID- 21651695 TI - Commentary on Nielsen et al. PMID- 21651696 TI - Consensus conference on laparoscopic appendectomy: development of guidelines. AB - AIM: Laparoscopic appendectomy (LA) is not yet unanimously considered the gold standard treatment for appendicitis, despite the increasing use of advanced laparoscopic operations and the high incidence of the disease. METHOD: Due to the results of an audit which classified LA as widespread in Italy, a Consensus Conference was organized, in order to give evidence-based answers to the most debated problems regarding the operation. After researching the literature, a panel of 20 experts were selected and interviewed on hot topics; a subsequent discussion using the Delphi methodology was utilized in the course of the consensus conference and submitted to the evaluation of an audience of surgeons. RESULTS: Checkpoint statements were formulated whenever an agreement was reached. A level of evidence was then assigned to single statements and the process revised by two external reviewers. CONCLUSION: Consensus development guidelines are herein reported and regard diagnostic pathway, diagnostic laparoscopy, indications, behaviour in case of innocent appendix, technical aspects, learning curve; however, some questions remain unsolved due to the lack of evidence. PMID- 21651699 TI - The global health burden of hepatitis C virus infection. PMID- 21651700 TI - Applying a system approach to forecast the total hepatitis C virus-infected population size: model validation using US data. AB - BACKGROUND: Hepatitis C virus (HCV) infection is associated with chronic progressive liver disease. Its global epidemiology is still not well ascertained and its impact will be confronted with a higher burden in the next decade. AIM: The goal of this study was to develop a tool that can be used to predict the future prevalence of the disease in different countries and, more importantly, to understand the cause and effect relationship between the key assumptions and future trends. METHODS: A system approach was used to build a simulation model where each population was modeled with the appropriate inflows and outflows. Sensitivity analysis was used to identify the key drivers of future prevalence. RESULTS: The total HCV-infected population in the US was estimated to decline 24% from 3.15 million in 2005 to 2.47 million in 2021, while disease burden will increase as the remaining infected population ages. During the same period, the mortality rate was forecasted to increase from 2.1 to 3.1%. The diagnosed population was 50% of the total infections, while less than 2% of the total infections were treated. CONCLUSION: We have created a framework to evaluate the HCV-infected populations in countries around the world. This model may help assess the impact of policies to meet the challenges predicted by the evolution of HCV infection and disease. This prediction tool may help to target new public health strategies. PMID- 21651701 TI - Trends and projections of hepatitis C virus epidemiology in Latin America. AB - BACKGROUND AND AIM: The purpose of the present investigation is to provide an analysis of previous works on the epidemiology of the hepatitis C virus (HCV) infection from six countries throughout Latin America, to forecast the future HCV prevalence trends in Argentina, Brazil, Mexico and Puerto Rico, and to outline deficiencies in available data, highlighting the need for further research. METHODS: Data references were identified through indexed journals and non-indexed sources. Overall, 1080 articles were reviewed and 150 were selected based on their relevance to this work. When multiple data sources were available for a key assumption, a systematic process using multi-objective decision analysis (MODA) was used to select the most appropriate sources. When data were missing, analogues were used. Data from other countries with similar risk factors and/or population compositions were used as a proxy to help predict the future trends in prevalence. RESULTS: The review indicates that the dominant genotype is type 1. HCV prevalence in the analysed countries ranges from 1 to 2.3%. The Latin American countries have been very proactive in screening their blood supplies, thus minimizing the risk of transmission through transfusion. This suggests that other risk factors are set to play a major role in continued new infections. The number of diagnosed and treated patients is low, thereby increasing the burden of complications such as liver cirrhosis or hepatocellular carcinoma. The HCV prevalence, according to our modelling is steady or increasing and the number of infected individuals will increase. CONCLUSIONS: The results herein reported should provide a foundation for informed planning efforts to tackle hepatitis. PMID- 21651702 TI - A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel. AB - BACKGROUND AND AIM: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel. METHODOLOGY: Data references were identified through indexed journals and non-indexed sources. In this work, 13,000 articles were reviewed and 860 were selected based on their relevance. RESULTS: Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (<= 0.5%) estimates were from northern European countries and the highest (>= 3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel. CONCLUSION: Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region. PMID- 21651706 TI - Unintended pregnancy rates at the state level. AB - CONTEXT: Unintended pregnancy is a key reproductive health indicator, but rates have never been calculated for all 50 states. METHODS: State-level estimates of unintended pregnancy rates in 2006 were calculated using data from several sources. The proportion of births resulting from unintended pregnancies was obtained from the Pregnancy Risk Assessment Monitoring System and similar state surveys, and the intention status of pregnancies ending in abortion from a national survey of abortion patients. These proportions were applied to birth and abortion counts for each state, and fetal losses were estimated. Rates of unintended pregnancy were obtained by dividing relevant figures by the number of women aged 15-44 in each state. Six states and the District of Columbia had no appropriate survey data; their rates were predicted using multivariate linear regression. RESULTS: In 2006, the median state unintended pregnancy rate was 51 per 1,000 women aged 15-44. Most rates fell within a range of 40-65 unintended pregnancies per 1,000 women. The highest rate was in Mississippi (69); the lowest rate was in New Hampshire (36). Rates were generally highest in the South and Southwest, and in states with large urban populations. In 29 states and the District of Columbia, more than half of pregnancies were unintended; in nine, a consistent upward trend in unintended pregnancy rates between 2002 and 2006 was apparent; no state had a consistent decline. CONCLUSIONS: These rates provide benchmarks for measuring the impact on unintended pregnancy of state policies and practices, such as those governing sex education and the funding of contraceptive services. PMID- 21651703 TI - A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. AB - BACKGROUND: The hepatitis C pandemic has been systematically studied and characterized in North America and Europe, but this important public health problem has not received equivalent attention in other regions. AIM: The objective of this systematic review was to characterize hepatitis C virus (HCV) epidemiology in selected countries of Asia, Australia and Egypt, i.e. in a geographical area inhabited by over 40% of the global population. METHODOLOGY: Data references were identified through indexed journals and non-indexed sources. In this work, 7770 articles were reviewed and 690 were selected based on their relevance. RESULTS: We estimated that 49.3-64.0 million adults in Asia, Australia and Egypt are anti-HCV positive. China alone has more HCV infections than all of Europe or the Americas. While most countries had prevalence rates from 1 to 2% we documented several with relatively high prevalence rates, including Egypt (15%), Pakistan (4.7%) and Taiwan (4.4%). Nosocomial infection, blood transfusion (before screening) and injection drug use were identified as common risk factors in the region. Genotype 1 was common in Australia, China, Taiwan and other countries in North Asia, while genotype 6 was found in Vietnam and other Southeast Asian countries. In India and Pakistan genotype 3 was predominant, while genotype 4 was found in Middle Eastern countries such as Egypt, Saudi Arabia and Syria. CONCLUSION: We recommend implementation of surveillance systems to guide effective public health policy that may lead to the eventual curtailment of the spread of this pandemic infection. PMID- 21651707 TI - Unintended pregnancy and taxpayer spending. AB - CONTEXT: Nearly half of all pregnancies in the United States are unintended. These pregnancies likely represent a substantial cost to taxpayers, but national level estimates of these public costs have been lacking. METHODS: Taxpayer spending on unintended pregnancy is measured by multiplying estimates of the 2001 incidence of publicly financed unintended pregnancy outcomes (abortions, fetal losses, births and need for infant medical care) by average per-incident costs. Public savings that would result from preventing unintended pregnancies are estimated by assuming that the prevention of an unwanted pregnancy would save the full cost of financing the pregnancy, while the prevention of a mistimed pregnancy would save the cost of financing the pregnancy today minus the present value of the cost of financing the pregnancy when it eventually occurs. RESULTS: Lower-bound, mean and upper-bound estimates of the annual cost of unintended pregnancy are, respectively, $9.6 billion, $11.3 billion and $12.6 billion. Corresponding estimates of the savings that would accrue to taxpayers by preventing unintended pregnancies are $4.7 billion, $5.6 billion and $6.2 billion. The mean estimate of the taxpayer cost per publicly subsidized unintended pregnancy is $9,000; the prevention of such a pregnancy would save taxpayers about half that amount. CONCLUSIONS: The prevention of unintended pregnancy represents an important opportunity for the public to reap substantial savings, especially given the current fiscal climate. The enactment or expansion of cost-effective policies to prevent unintended pregnancies is therefore a timely and sensible strategy. PMID- 21651708 TI - The public costs of births resulting from unintended pregnancies: national and state-level estimates. AB - CONTEXT: Births resulting from unintended pregnancies are associated with substantial maternity and infant care costs to the federal and state governments; these costs have never been estimated at the national and state levels. METHODS: The proportions of births paid for by public insurance programs in 2006 were estimated, by pregnancy intention status, using data from the Pregnancy Risk Assessment Monitoring System and similar state surveys, or were predicted by multivariate linear regression. Public costs were calculated using state-level estimates of the number of births, by intention status, and of the cost of a publicly funded birth. RESULTS: In 2006, 64% of births resulting from unintended pregnancies were publicly funded, compared with 48% of all births and 35% of births resulting from intended pregnancies. The proportion of births resulting from unintended pregnancies that were publicly funded varied by state, from 42% to 81%. Of the 2.0 million publicly funded births, 51% resulted from unintended pregnancies, accounting for $11.1 billion in costs-half of the total public expenditures on births. In seven states, the costs for births from unintended pregnancies exceeded a half billion dollars. CONCLUSIONS: Public insurance programs are central in assisting American families in affording pregnancy and childbirth; however, they pay for a disproportionately high number of births resulting from unintended pregnancy. The resulting budgetary impact warrants increased public efforts to reduce unintended pregnancy. PMID- 21651709 TI - Social sources of women's emotional difficulty after abortion: lessons from women's abortion narratives. AB - CONTEXT: The experiences of women who have negative emotional outcomes, including regret, following an abortion have received little research attention. Qualitative research can elucidate these women's experiences and ways their needs can be met and emotional distress reduced. METHODS: Twenty-one women who had emotional difficulties related to an abortion participated in semi-structured, in depth telephone interviews in 2009. Of these, 14 women were recruited from abortion support talklines; seven were recruited from a separate research project on women's experience of abortion. Transcripts were analyzed using the principles of grounded theory to identify key themes. RESULTS: Two social aspects of the abortion experience produced, exacerbated or mitigated respondents' negative emotional experience. Negative outcomes were experienced when the woman did not feel that the abortion was primarily her decision (e.g., because her partner abdicated responsibility for the pregnancy, leaving her feeling as though she had no other choice) or did not feel that she had clear emotional support after the abortion. Evidence also points to a division of labor between women and men regarding pregnancy prevention, abortion and childrearing; as a result, the majority of abortion-related emotional burdens fall on women. Experiencing decisional autonomy or social support reduced respondents' emotional distress. CONCLUSIONS: Supporting a woman's abortion decision-making process, addressing the division of labor between women and men regarding pregnancy prevention, abortion and childrearing, and offering nonjudgmental support may guide interventions designed to reduce emotional distress after abortion. PMID- 21651710 TI - Risky adolescent sexual behaviors and reproductive health in young adulthood. AB - CONTEXT: Little research links adolescent risk behaviors to reproductive health outcomes beyond adolescence, although young adults--men and women in their early 20s--bear a disproportionate burden of STDs and unintended childbearing. METHODS: To assess whether individuals who engaged in risk behaviors during adolescence had increased risk of negative reproductive health outcomes in young adulthood, data from Waves 1-4 of the National Longitudinal Study of Adolescent Health on 5,798 sexually active respondents were analyzed. Logistic and multinomial logistic regressions examined associations between risk behaviors (cumulatively and individually) and each of three outcomes. RESULTS: Four in 10 youth reported at least three risk factors during adolescence. Women who were exposed to an increasing number of risks had an elevated likelihood of having had multiple sex partners in the last year, rather than none (relative risk ratio, 1.3); having had an STD (odds ratio, 1.1); and having had an intended or unintended birth, as opposed to no birth (relative risk ratio, 1.1 for each). Inconsistent contraceptive use and having had multiple partners, a non-monogamous partner or a non-romantic partner were associated with reporting multiple partners in the last year; inconsistent use, sexual debut after age 16 and not discussing contraception with a partner were associated with having any birth. CONCLUSIONS: Teenagers' sexual behaviors have both short-term and long-term consequences, and interventions that focus on multiple domains of risk may be the most effective in helping to promote broad reproductive health among young adults. PMID- 21651711 TI - Relationship characteristics and contraceptive use among young adults. AB - CONTEXT: Young adults have high rates of unintended childbearing and STDs, yet little research has examined the role of relationship characteristics in their contraceptive use. METHODS: Data collected from the 2002-2005 rounds of the National Longitudinal Survey of Youth yielded a sample of 4,014 dating relationships among sexually active 18-26-year-olds. Bivariate analysis and multivariate logistic and multinomial logistic regressions assessed associations between relationship characteristics and contraceptive use at last sex. RESULTS: In three-quarters of the relationships, respondents had used some method at last intercourse; respondents in 26% of the relationships had used a condom only, in 26% a hormonal method only and in 23% dual methods. Compared with respondents in relationships in which first sex occurred within two months of starting to date, those who first had sex before dating were more likely to have used any method at last sex (odds ratio, 1.4), particularly condoms or dual methods (relative risk ratio, 1.5 for each). The relative risk of using a hormonal method only, rather than no method or condoms only, increased with relationship duration (1.01) and level of intimacy (1.1-1.2). Discussing marriage or cohabitation was associated with reduced odds of having used any method (0.7) and a reduced relative risk of having used condoms alone or dual methods (0.6 for each). Increasing levels of partner conflict and asymmetry were also linked to reduced odds of any method use (0.97 and 0.90, respectively). CONCLUSIONS: Prevention programs should address relationship context in contraceptive decision making, perhaps by combining relationship and sex education curricula to foster communication and negotiation skills. PMID- 21651719 TI - Autoantibody signatures: progress and perspectives for early cancer detection. AB - Becoming invasive is a crucial step in cancer development, and the early spread of tumour cells is usually undetected by current imaging technologies. In patients with cancer and no signs of overt metastases, sensitive methods have been developed to identify circulating autoantibodies and their antigen counterparts in several cancers. These technologies are often based on proteomic approaches, and recent advances in protein and antibody microarrays have greatly facilitated the discovery of new antibody biomarkers in sera from cancer patients. Interestingly, in a clinical application setting, combinations of multiple autoantibody reactivities into panel assays have recently been proposed as relevant screening tests and validated in several independent trials. In addition, autoantibody signatures seem to be particularly relevant for early detection of cancer in high-risk cancer patients. In this review, we highlight the concept that immunogenic epitopes associated with the humoural response and key pathogenic pathways elicit serum autoantibodies that can be considered as relevant cancer biomarkers. We outline the proteomic strategies employed to identify and validate their use in clinical practice for cancer screening and diagnosis. We particularly emphasize the clinical utility of autoantibody signatures in several cancers. Finally, we discuss the challenges remaining for clinical validation. PMID- 21651721 TI - Histopathological diagnostics of malignant melanoma in accordance with the recent AJCC classification 2009: Review of the literature and recommendations for general practice. AB - BACKGROUND: TNM classifications are the basis for diagnostic and therapeutic procedures in oncology. Histopathological reports have to enable a proper indexing of tumor specific findings into recent classifications. METHODS: A systematic review of the literature was performed to identify reports dealing with the assessment of mitotic rate and the processing and evaluation of sentinel node biopsies in malignant melanoma. On the basis of this review an expert panel of dermatopathologists and general pathologists discussed and agreed recommendations for general practice. RESULTS: Following recommendations were agreed with a broad consensus (93-100 % agreement): The determination of the mitotic rate in primary melanoma is performed on HE slides. The evaluation of an area of 1 mm(2) is sufficient. Only dermal mitoses are considered. The counted number of mitoses is provided as an integer value. The mitotic rate shall be determined in primary melanomas of <=1.00 mm vertical tumor thickness according to the hot-spot method and provided as an integer value in relation to an area of 1 mm(2) . The determination of the mitotic rate in the case of thicker primary melanomas is desirable. In general, for the evaluation of each sentinel lymph node, 4 slides should be prepared. For diagnostic purposes, immunohistochemistry (preferably with antibodies against S100beta, Melan A and HMB-45) should be performed in addition to HE staining. The pathology report should provide information about micro-metastases and their longest extension (one-tenth of a millimeter). CONCLUSIONS: These recommendations are suitable for standardizing the histopathological diagnosis of malignant melanoma and for providing a common basis for clinical decisions and scientific research. PMID- 21651720 TI - Brain-derived neurotrophic factor induces proliferation of human airway smooth muscle cells. AB - Airway diseases such as asthma involve increased airway smooth muscle (ASM) contractility and remodelling via enhanced proliferation. Neurotrophins (NTs) such as brain-derived neurotrophic factor (BDNF), well-known in the nervous system, can regulate Ca(2+) signalling, and interact with cytokines in contributing to airway hyperreactivity. In this study, we determined whether and how BDNF regulates human ASM cell proliferation in the presence of inflammation, thus testing its potential role in airway remodelling. Cells were treated with 10 nM BDNF, 25 ng/ml tumour necrosis factor (TNF-alpha) or interleukin-13 (IL-13), or 10 ng/ml platelet-derived growth factor (PDGF). Proliferation was measured using CyQuant dye, with immunoblotting of cell cycle proteins predicted to change with proliferation. Forty-eight hours of BDNF enhanced ASM proliferation to ~ 50% of that by PDGF or cytokines. Transfection with small interfering RNAs (siRNAs) targeting high-affinity tropomyosin-related kinase B receptor abolished BDNF effects on proliferation, whereas low-affinity 75 kD neurotrophin receptor (p75NTR) siRNA had no effect. Systematic pharmacologic inhibition of different components of ERK1/2 and PI3K/Akt1 pathways blunted BDNF or TNF-alpha-induced proliferation. BDNF also induced IkappaB phosphorylation and nuclear translocation of p50 and p65 NF-kappaB subunits, with electron mobility shift assay confirmation of NF-kappaB binding to consensus DNA sequence. These results demonstrate that NTs such as BDNF can enhance human ASM cell proliferation by activating proliferation-specific signalling pathways and a versatile transcription factor such as NF-kappaB, which are common to cytokines and growth factors involved in asthma. PMID- 21651722 TI - Diseases of the male nipple and areola. AB - The male nipple-areola-complex (NAC) is a residual organ without physiologic functions in the male. It possesses similar hormone sensitivity and sexual sensitivity as the female organ. The location of the NAC on the chest wall with respect to other surface features is relevant for the male appearance. All known disseminated skin diseases may involve the nipple and areola. A number of specific localized diseases have been described in the literature, such as mammillary eczema, demodicidosis, lymphadenosis cutis benigna, nevoid hyperkeratosis, and thelalgia. Special attention is required if nipple discharge is observed. Areolar sebaceous hyperplasia and nearly all kinds of benign cutaneous tumors occur on the nipple and areola. Malignant tumors such as basal cell carcinoma, melanoma, Paget disease and other forms of breast cancer may also be found. In addition, aberrant mammary tissue may occur with a broad clinical spectrum, while absence of the nipple is an unusual observation and occurs in rare syndromes. The association of aberrant mammary tissue with urinary tract malformations has not been confirmed. PMID- 21651723 TI - Perianal ulcer - amebiasis cutis. PMID- 21651724 TI - The development and standardization of testing methods for genetically modified organisms and their derived products. AB - As the worldwide commercialization of genetically modified organisms (GMOs) increases and consumers concern the safety of GMOs, many countries and regions are issuing labeling regulations on GMOs and their products. Analytical methods and their standardization for GM ingredients in foods and feed are essential for the implementation of labeling regulations. To date, the GMO testing methods are mainly based on the inserted DNA sequences and newly produced proteins in GMOs. This paper presents an overview of GMO testing methods as well as their standardization. PMID- 21651725 TI - The carbohydrate recognition domain of collectins. AB - Collectins are effector molecules of the innate immune system that play an important role in the first line of defence against bacteria, viruses and fungi. Most of their interactions with microorganisms are mediated through their carbohydrate recognition domain (CRD), which binds in a Ca(2+)-dependent manner to glycoconjugates. This domain is a well-known structure that is present in a larger group of proteins comprising the C-type lectin domain family. Collectins form a subgroup within this family based on the presence of a collagen domain and the trimerization of CRDs, which are essential for the ligand-binding properties of these proteins. The ligand specificity among the nine collectin members is significantly different as a result of both the structural organization of the trimers and specific sequence changes in the binding pocket of the CRD. In addition, some collectin members have additional features, such as N-linked glycosylation of CRD residues and additional loop structures within the CRD that have a large impact on their interaction with the glycoconjugates present on microorganisms or host cells. The availability of crystal structures of three members of the collectin family (surfactant proteins A and D and mannan-binding protein) provides an important tool for addressing the impact of these CRD differences on ligand binding. In this review, the structural differences and similarities between the CRDs of collectins are summarized and their relationship with their ligand-binding characteristics is discussed. PMID- 21651726 TI - The association of heavy and light chain variable domains in antibodies: implications for antigen specificity. AB - The antigen-binding site of immunoglobulins is formed by six regions, three from the light and three from the heavy chain variable domains, which, on association of the two chains, form the conventional antigen-binding site of the antibody. The mode of interaction between the heavy and light chain variable domains affects the relative position of the antigen-binding loops and therefore has an effect on the overall conformation of the binding site. In this article, we analyze the structure of the interface between the heavy and light chain variable domains and show that there are essentially two different modes for their interaction that can be identified by the presence of key amino acids in specific positions of the antibody sequences. We also show that the different packing modes are related to the type of recognized antigen. PMID- 21651727 TI - Selection of a CXCR4 antagonist from a human heavy chain CDR3-derived phage library. AB - Phage display technology is a powerful selection approach to identify strong and specific binders to a large variety of targets. In this study, we compared the efficacy of a phage library displaying human heavy chain complementarity determining region 3 (HCDR3) repertoires with a set of conventional random peptide libraries for the identification of CXCR4 antagonists using a peptide corresponding to the second extracellular loop of the receptor CXCR4 as target. A total of 11 selection campaigns on this target did not result in any specific ligand from the random peptide libraries. In contrast, a single selection campaign with an HCDR3 library derived from the IgM repertoire of a nonimmunized donor resulted in nine specific peptides with lengths ranging from 10 to 19 residues. Four of these HCDR3 sequences interacted with native receptor and the most frequently isolated peptide displayed an affinity of 5.6 MUm and acted as a CXCR4 antagonist (IC(50) = 23 MUm). To comprehend the basis of the highly efficient HCDR3 library selection, its biochemical properties were investigated. The HCDR3 length varied from 3 to 21 residues and displayed a biased amino acid content with a predominant proportion of Tyr, Gly, Ser and Asp. Repetitive and conserved motifs were observed in the majority of the HCDR3 sequences. The strength and efficacy of the HCDR3 libraries reside in the combination of multiple size peptides and a naturally biased sequence variation. Therefore, HCDR3 libraries represent a powerful and versatile alternative to fully randomized peptide libraries, in particular for difficult targets. PMID- 21651728 TI - Metabolism of P450 probe substrates by cynomolgus monkey CYP2C76. PMID- 21651729 TI - Cost-effectiveness of a topically applied pre-operative tissue expansion device for radial forearm free flaps: a cohort study. AB - OBJECTIVES: The objective of this study is to test the hypothesis that using a non-invasive and inexpensive pre-operative tissue expansion device (DynaClose) for radial forearm free-flap donor sites will result in a significant reduction in the cost of both in-hospital and out-of-hospital wound care compared with that of unexpanded radial forearm free-flap donor sites. DESIGN: A cohort study consisting of patients previously randomised in a randomised controlled trial. An intention to treat design was utilised. SETTING: A large tertiary care centre in eastern Ontario, Canada. PATIENTS: Thirty-four patients presenting to Otolaryngology Head and Neck clinic were enroled. Of these patients, 29 were previously enroled in a randomised controlled trial, while an additional five patients were enroled and randomised for the purpose of this study. INTERVENTIONS: Patients were randomised to either the treatment (pre-operative tissue expansion, DynaClose Expansion System) or control group. MAIN OUTCOME MEASURES: Wound care costs (in US dollars) were calculated for all patients for both in-hospital care and for patients requiring home care. Non-parametric data analysis was utilised for statistical assessment. RESULTS: There was a 93% reduction in the use of split-thickness skin grafts in the treatment group. There was a significant reduction in total wound care cost for patients in the treatment group versus the control group (P < 0.0001). Patients in the treatment group required a mean (SD) total of $36.00 (23.50) per patient, while the control group required $277.00 (325.00) of wound care. After excluding the cost of home care, the treatment group continued to have a significant reduction in total and in-hospital wound care costs compared with the control group (P < 0.001). CONCLUSIONS: Using a simple, inexpensive and non-invasive method of pre-operative tissue expansion results in a significant reduction in the costs of wound care for both in-hospital and out-of-hospital treatment. The DynaClose dynamic skin expansion system results in a cost-effective method to reduce the need of a split thickness skin graft for coverage of a radial forearm free-flap donor site. PMID- 21651730 TI - Human bocavirus is not detectable in bone marrow from patients with myelodysplastic syndromes. PMID- 21651731 TI - Rash, an uncommon but existing feature of H1N1 influenza among children. PMID- 21651732 TI - Isolation of Aspergillus in three 2009 H1N1 influenza patients. AB - OBJECTIVES: To describe the association of Aspergillus with influenza. DESIGN/SETTING/SAMPLE: Three case reports of ICU patients with influenza complicated by the isolation of Aspergillus species are described and a review of the literature on the topic was performed. CONCLUSIONS: Severe influenza cases can be complicated by Aspergillus infection. PMID- 21651733 TI - Clinical features, complications and mortality in critically ill patients with 2009 influenza A(H1N1) in Sfax,Tunisia. AB - PURPOSE: Africa, as the rest of the world, was touched by the 2009 pandemic influenza A(H1N1). In the literature, a few publications covering this subject emerged from this continent. We prospectively describe baseline characteristics, treatment and outcomes of consecutive critically ill patients with confirmed 2009 influenza A(H1N1) in the intensive care unit (ICU) of Sfax hospital. METHODS: From 29 November 2009 through 21 January 2010, 32 patients with confirmed 2009 influenza A(H1N1) were admitted to our ICU. We prospectively analysed data and outcomes of these patients and compared survivors and dead patients to identify any predictors of death. RESULTS: Patients were young (mean, 36.1 [SD], 20.7 years) and 21 (65.6%) of whom had co-morbidities. During ICU care, 29 (90.6%) patients had respiratory failure; among these, 15 (46.9%) patients required invasive ventilation with a median duration of 9 (IQR 3-12) days. In our experience, respiratory dysfunction can remain isolated but may also be associated with other dysfunctions or complications, such as, septic shock, seizures, myasthenia gravis exacerbation, Guillan-Barre syndrome, acute renal failure, nosocomial infections and biological disturbances. The nine patients (28.1%) who died had greater initial severity of illness (SAPS II and sequential organ failure assessment (SOFA) scores) but also a higher SOFA score and increasing severity of organ dysfunction during their ICU evolution. CONCLUSION: Critical illness from the 2009 influenza A(H1N1) in Sfax occurred in young individuals and was associated with severe acute respiratory and additional organ system failure. SAPS II and SOFA scores at ICU admission, and also during evolution, constitute a good predictor of death. PMID- 21651734 TI - Clinical epidemiology comparison of H1N1 RT-PCR-positive and RT-PCR-negative pneumonia during the 2009-2010 pandemic in Mansoura University hospitals, Egypt. AB - BACKGROUND: Worldwide, the infectivity and disease burden of the H1N1 pandemic were overestimated because of limited clinical experience concerning patient presentation and outcome of those infected with the novel H1N1 virus. OBJECTIVE: This study aimed to compare the epidemiologic clinical data among H1N1 RT-PCR positive and RT-PCR-negative pneumonic patients during the 2009-2010 pandemic in Mansoura University Hospitals, Egypt. METHODS: A record-based, case-control study was conducted for 43 adult patients admitted to the chest department isolation unit with community-acquired pneumonia during the 2009-2010 H1N1 pandemic after reviewing of 198 suspected and confirmed H1N1 hospitalized cases. Of these patients, 20 cases were confirmed to be H1N1-positive using an RT-PCR detection technique. The remaining 23 patients were RT-PCR-negative. Demographic, clinical, laboratory and radiological data were collected and analyzed using spss version 11. RESULTS: A review of 198 hospital case records for revealed one main peak of H1N1 influenza during the last week of December 2009. Pneumonic patients who were H1N1-positive were more likely to present with sore throat (P = 0.005), dyspnea (P = 0.002), and gastrointestinal (GIT) complaints (vomiting and diarrhea P = 0.02) when compared to the H1N1-negative group. Also, complications were significantly more frequent (P = 0.01) in the H1N1-confirmed group than in the non-confirmed group. However, no significant differences were found between the groups regarding length of hospital stay, intensive care unit (ICU), and admission or mortality. CONCLUSION: Sore throat, dyspnea, and presence of GIT complaints increase the suspicion of H1N1 positivity in pneumonia acquired during an H1N1 pandemic. However, H1N1 did not worsen the disease burden of pneumonia. PMID- 21651735 TI - Risk factors for hospitalization and severe outcomes of 2009 pandemic H1N1 influenza in Quebec, Canada. AB - BACKGROUND/OBJECTIVE: This case-control study was carried out to estimate risk factors associated with hospitalizations and severe outcomes [intensive care unit (ICU) admission or death] among patients with illness because of laboratory confirmed 2009 pandemic A/H1N1 virus (pH1N1) during the first wave of pH1N1 activity in the province of Quebec, Canada. PATIENTS/METHODS: We collected epidemiologic information by phone using a standardized questionnaire from patients with laboratory-confirmed pH1N1 illness during the first spring/summer pandemic wave in Quebec, Canada. Risk factors associated with hospitalization were assessed by comparing hospitalized to community cases and for ICU admission or death through comparison with hospitalized cases. RESULTS: Cases (321 hospitalized patients including 47 ICU admissions and 15 deaths) were compared to controls (395 non-hospitalized patients) by using multivariable logistic regression adjusted for gender, age, education, being a health care worker, smoking, seasonal influenza vaccination, delay to consultation, antiviral use before admission, pregnancy, underlying medical conditions, and obesity. Age <5 years, underlying medical conditions (neuromuscular, cardiac, pulmonary, and renal conditions, diabetes, asthma, and other), and delayed consultation were associated with hospitalization. The strongest association with hospitalization was observed for neuromuscular disorders. Antiviral medication before hospital admission protected against severe disease. Association of obesity with hospitalization was not significant after adjustment in multivariable analysis. Among hospitalized patients, age >=60 years and immune suppression were associated with death. CONCLUSIONS: Previously identified risk factors for seasonal influenza were also associated with increased risk of severe pH1N1 outcomes. The independent role of obesity needs to be further defined. PMID- 21651736 TI - Findings from a household randomized controlled trial of hand washing and face masks to reduce influenza transmission in Bangkok, Thailand. AB - BACKGROUND: Evidence is needed on the effectiveness of non-pharmaceutical interventions (NPIs) to reduce influenza transmission. METHODOLOGY: We studied NPIs in households with a febrile, influenza-positive child. Households were randomized to control, hand washing (HW), or hand washing plus paper surgical face masks (HW + FM) arms. Study nurses conducted home visits within 24 hours of enrollment and on days 3, 7, and 21. Respiratory swabs and serum were collected from all household members and tested for influenza by RT-PCR or serology. PRINCIPAL FINDINGS: Between April 2008 and August 2009, 991 (16.5%) of 5995 pediatric influenza-like illness patients tested influenza positive. Four hundred and forty-two index children with 1147 household members were enrolled, and 221 (50.0%) were aged <6 years. Three hundred and ninety-seven (89.8%) households reported that the index patient slept in the parents' bedroom. The secondary attack rate was 21.5%, and 56/345 (16.3%; 95% CI 12.4-20.2%) secondary cases were asymptomatic. Hand-washing subjects reported 4.7 washing episodes/day, compared to 4.9 times/day in the HW + FM arm and 3.9 times/day in controls (P = 0.001). The odds ratios (ORs) for secondary influenza infection were not significantly different in the HW arm (OR = 1.20; 95% CI 0.76-1.88; P-0.442), or the HW + FM arm (OR = 1.16; 95% CI .0.74-1.82; P = 0.525). CONCLUSIONS: Influenza transmission was not reduced by interventions to promote hand washing and face mask use. This may be attributable to transmission that occurred before the intervention, poor facemask compliance, little difference in hand-washing frequency between study groups, and shared sleeping arrangements. A prospective study design and a careful analysis of sociocultural factors could improve future NPI studies. PMID- 21651737 TI - Detection of influenza viral gene in European starlings and experimental infection. AB - BACKGROUND: European starlings (Sturnus vulgaris) are common, widely distributed birds in North America that frequently come into contact with agricultural operations. However, starlings have been one of the neglected land-based wild bird species for influenza surveillance. OBJECTIVES: To study the potential role of starlings in the ecology and epidemiology of influenza virus. METHODS: We collected 328 digestive and 156 tracheal samples from starlings in Ohio in years 2007 (July) to 2008 (August) and screened for the presence of influenza virus by real-time RT-PCR, standard RT-PCR and virus isolation using embryonated chicken eggs. In addition, we conducted an experimental infection study to evaluate the replication and induction of antibody response by two low pathogenic avian influenza (AI) viruses in starlings. RESULTS: Although virus isolation was negative, we confirmed 21 influenza positive digestive and tracheal samples by real-time and standard RT-PCR tests. Phylogenetic analysis revealed that five NS genes recovered from Starlings belonged to NS subtype A and were most similar to the NS genes from a wild aquatic bird origin isolate from Ohio. Experimental infection studies using two low pathogenic AI strains showed that starlings could be infected, shed virus, and seroconvert. CONCLUSIONS: This study shows that starlings can carry influenza virus that is genetically similar to wild aquatic bird origin strains and may serve as a carrier of influenza virus to domestic animals. PMID- 21651738 TI - Analysis of influenza A viruses of subtype H1 from wild birds, turkeys and pigs in Germany reveals interspecies transmission events. AB - BACKGROUND: Despite considerable host species barriers, interspecies transmissions of influenza A viruses between wild birds, poultry and pigs have been demonstrated repeatedly. In particular, viruses of the subtypes H1 and H3 were transmitted between pigs and poultry, predominantly turkeys, in regions with a high population density of both species. The recovery of a swine influenza H1N1 virus from a turkey flock in Germany in 2009 prompted us to investigate molecularly the subtype H1 viruses recently detected in wild birds, pigs and poultry. OBJECTIVES: The goal of this study was to investigate the relationship between H1N1 viruses originating from wild and domestic animals of Germany and to identify potential trans-species transmission or reassortment events. METHODS: Hemagglutinin and neuraminidase gene or full-length genome sequences were generated from selected, current H1N1 viruses from wild birds, pigs and turkeys. Phylogenetic analyses were combined with genotyping and analyses of the deduced amino acid sequences with respect to biologically active sites. Antigenic relationships were assessed by hemagglutination inhibition reactions. RESULTS: Phylogenetic analysis of the hemagglutinin sequences showed that viruses from distinct H1 subgroups co-circulate among domestic animals and wild birds. In addition, these viruses comprised different genotypes and were distinguishable antigenically. An H1N1 virus isolated from a turkey farm in northern Germany in 2009 showed the highest similarity with the avian-like porcine H1N1 influenza viruses circulating in Europe since the late 1970s. CONCLUSIONS: The data demonstrate the genetic and antigenic heterogeneity of H1 viruses currently circulating in domestic and wild animals in Germany and points to turkeys as a possible bridge between avian and mammalian hosts. PMID- 21651739 TI - Sole infection by human metapneumovirus among children with radiographically diagnosed community-acquired pneumonia in a tropical region. AB - BACKGROUND: Limited information is available on the role of human metapneumovirus (HMPV) as the unique pathogen among children hospitalized for community-acquired pneumonia (CAP) in a tropical region. OBJECTIVE: We aimed to describe HMPV infection among children with CAP investigating bacterial and viral co infections. PATIENTS AND METHODS: A prospective study was carried out in Salvador, North-East Brazil. Overall, 268 children aged <5 years hospitalized for CAP were enrolled. Human metapneumovirus RNA was detected in nasopharyngeal aspirates (NPA) by reverse transcription polymerase chain reaction. Sixteen other bacterial and viral pathogens were investigated by an expanded panel of laboratory methods. Chest X-ray taken on admission was read by an independent paediatric radiologist unaware of clinical information or the established aetiology. RESULTS: Human metapneumovirus RNA was detected in NPAs of 11 (4.1%) children, of which 4 (36%) had sole HMPV infection. The disease was significantly shorter among patients with sole HMPV infection in comparison with patients with mixed infection (4 +/- 1 versus 7 +/- 2 days, P = 0.03). Three of those four patients had alveolar infiltrates. CONCLUSION: Sole HMPV infection was detected in children with CAP in Salvador, North-East Brazil. HMPV may play a role in the childhood CAP burden. PMID- 21651740 TI - Immune correlates of protection against influenza: challenges for licensure of seasonal and pandemic influenza vaccines, Miami, FL, USA, March 1-3, 2010. AB - The emergence of a novel swine-origin pandemic influenza virus in 2009, together with the continuing circulation of highly pathogenic avian H5N1 viruses and the urgent global need to produce effective vaccines against such public health threats, has prompted a renewed interest in improving our understanding of the immune correlates of protection against influenza. As new influenza vaccine technologies, including non-HA based approaches and novel production platforms are developed and undergo clinical evaluation, it has become clear that existing immune correlates such as serum hemagglutination-inhibition antibodies may be unsuitable to estimate vaccine immunogenicity and protective efficacy of such vaccines. This International Society for Influenza and other Respiratory Virus Diseases (ISIRV) sponsored international meeting held in Miami, Florida USA on March 1-3, 2010, brought together scientists from industry, academia, and government agencies that develop and evaluate seasonal and pandemic influenza vaccines and scientists from regulatory authorities that approve them, to identify approaches to develop expanded immune correlates of protection to aid in vaccine licensure. PMID- 21651741 TI - Serum LDH in chronic cough: a potential marker of airway inflammation. AB - INTRODUCTION AND OBJECTIVES: Lactate dehydrogenase (LDH) is found in almost all tissues of the body and five different isoenzymes are known (LDH-1 to LDH-5). LDH can be elevated in many pathological conditions. We have observed serum LDH to be increased in patients with chronic cough. We wanted to confirm this finding, study the reproducibility and determine the origin of the LDH. METHODS: Patients prospectively seen at the Hull Cough Clinic had total and specific LDH isoenzyme levels in serum determined. A subgroup of patients also had a serum creatine phosphokinase (CK) measured. Patients completed cough symptom scores and the Hull Airway Reflux Questionnaire (HARQ). Spirometry was performed. RESULTS: Eighty three patients were included. Forty-two percent had LDH values above the reference range and 78% had LDH values in the fourth quartile of the reference range or above. This increase in LDH was predominantly because of a rise in isoenzymes 4 and 5. The increase in LDH was found to be reproducible at 8 weeks. Ten percent had CK values above the normal range. There was no correlation observed between LDH values and the cough scores, HARQ scores or lung function. CONCLUSION: Serum LDH levels are elevated in a substantial proportion of patients with chronic cough. This rise is likely to be due to airway inflammation known to be associated with chronic cough. PMID- 21651742 TI - Diagnostic yield and efficacy of endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal lymphadenopathy. AB - INTRODUCTION: Endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA) is an emerging minimally invasive option for pathologic examination of intrathoracic lymphadenopathy as well as for staging lung cancer. OBJECTIVES: To evaluate the diagnostic yield and possible learning curve effects on diagnostic performance using EBUS-TBNA in mediastinal lymphadenopathy. METHODS: A retrospective analysis was performed on 243 consecutive patients who underwent EBUS-TBNA over a 4-year period. Demographic and clinical data and pathology results were analysed for different time frames in order to evaluate potential learning curve effects. The procedures were performed by two experienced bronchoscopists at a single university medical centre. RESULTS: Samples were representative in 83% (200/243) of the patients. The overall diagnostic yield was 66% (n = 161/243). The diagnostic accuracy of EBUS-TBNA for detecting malignancy was 98.0% and for lung cancer 98.5%. The sensitivity, specificity, positive and negative predictive values for lung cancer stage >=N1 and malignant disease were 100% for the first three studied periods and slightly less favourable in the most recent study period. Representative samples were obtained more frequently in the latter study periods (P < 0.001). CONCLUSION: EBUS-TBNA is a safe method with a learning curve that is easily overcome, although previous experience with ultrasound may be necessary. The diagnostic yield of EBUS-TBNA is in accordance with previously reported yield of standard cervical mediastinoscopy. At present, however, the relationship between EBUS-TBNA and mediastinoscopy appears to be complementary rather than substitutive. PMID- 21651743 TI - Pemetrexed in malignant pleural mesothelioma and the clinical outcome. AB - INTRODUCTION: Pemetrexed has emerged as standard chemotherapy for malignant pleural mesothelioma (MPM). OBJECTIVES: MPMs at two Finnish University Hospitals during 7 years (2000-2006) were reviewed in order to evaluate the treatments, survival and prognostic factors. The results in two periods (before pemetrexed use in 2000-2002 and with pemetrexed in 2003-2006) were compared. METHODS: Data were collected from the individual patient records retrospectively, and analysed. RESULTS: Altogether 197 patients were diagnosed with following histologies: 136 (69%) epithelioid, 19 (10%) sarcomatoid, 17 (9%) mixed, 25 (13%) not specified; 141 (72%) patients received treatment (five extrapleural pneumonectomy, 36 pleurectomy/decortication, 126 chemotherapy). Median survival was 12.9 months and the 1-, 2- and 3-year survivals were 51.8%, 21.8% and 12.1%, respectively. Univariate analysis showed no significant difference in survival between the patients diagnosed before or during the pemetrexed era (P = 0.124). The patients receiving pemetrexed or other chemotherapy had median survivals of 16.7 and 15.3 months, respectively. The independent prognostic factors for survival were histology and asbestos exposure. Non-epithelioid histology yielded 17 times higher risk of dying than epithelioid. Asbestos exposure doubled the risk of dying, but only in patients diagnosed in 2003-2006. CONCLUSIONS: Pemetrexed is beneficial for selected patients, but it has not changed the outcome of the whole MPM population as much as perhaps anticipated. Patient groups with various treatments or symptomatic care only reached survival results comparable to those reported in chemotherapy trials, thus emphasising the need for better subtyping of mesothelioma and individualising the treatment. PMID- 21651744 TI - Prognostic significance of PaO2/PaCO2 ratio in normotensive patients with pulmonary embolism. AB - INTRODUCTION: Risk stratification remains controversial in patients with normotensive pulmonary embolism (PE). The debate has recently focused right ventricular dysfunction detected by echocardiography or spiral computed tomography (CT) and cardiac biomarkers. OBJECTIVES: The utility of the PaO(2)/PaCO(2) ratio to predict the short-term prognosis of PE is not currently known and that is the aim of the present study. MATERIALS AND METHODS: This study retrospectively enrolled 99 (34 males, 65 females, 67 +/- 15 years) consecutive patients with acute PE, diagnosed by spiral chest tomography pulmonary angiography (CTPA). On admission, cardiac troponin T (cTn-T) was measured and on CTPA both right ventricle diameter and left ventricle diameter was calculated (RV/LV ratio). During the first 24 h after admission, all the patients had initial arterial blood gas collected under room air. Receiver-operating characteristic (ROC) analysis was performed to determine the optimal PaO(2)/PaCO(2), RV/LV ratio and cTn-T cutoff level with regard to prognosis. RESULTS: In-hospital mortality was 12.1% and all-cause 90-day mortality was 15.2%. Ten of 15 patients who died had a PaO(2)/PaCO(2) <= 1.8 based on ROC analysis (P < 0.014).The cutoff level of PaO(2)/PaCO(2) <= 1.8 had a high negative predictive value of 93% for mortality. Multivariable analysis revealed that PaO(2)/PaCO(2) <= 1.8 Hazard Ratio (HR): 16.8 [95% CI: 2.6-108, P < 0.003] was the most significant independent predictor, whereas cTn-T, pO(2) < 60 mmHg and cardiac failure were nonsignificant factors. In addition, PaO(2)/PaCO(2) <= 1.8 showed significant survival differences for overall mortality rates in Kaplan Meier analysis (P < 0.012). CONCLUSION: The PaO(2)/PaCO(2) measurement is a highly useful and practical measurement to predict prognosis in patients with acute PE. Moreover, it appears to be a more accurate predictor than RV/LV ratio and cTn-T levels in patients with normotensive PE. PMID- 21651745 TI - Outcomes and complications following medical thoracoscopy. AB - INTRODUCTION: Thoracoscopy is an invasive procedure that may be performed by physicians for the investigation of exudative pleural effusion using local anaesthesia, conscious sedation and a rigid thoracoscope. OBJECTIVES: We sought to evaluate the safety and outcome of thoracoscopy in Portsmouth Hospitals, UK, a dockyard city with high previous asbestos usage. METHODS: Retrospective casenote, radiology and laboratory result analysis of patients undergoing thoracoscopy in our institution over a 12-month period. RESULTS: Fifty-seven of 58 casenotes were available for analysis. Median (interquartile range) age was 73.0 (66.5-79.0) years and 44 (77.2%) were male. Median time with chest drain post-procedure was 3.0 (2.0-5.0) days, and length of stay (LOS) was 4.0 (2.0-8.0) days. Malignant histology was reported in 40 (70.2%), with 25 (62.5%) cases of mesothelioma. There were no deaths related to the procedure. Hospital-acquired infection (HAI) occurred in six (10.5%: pneumonia four, empyema two), all had malignancy. The presence of HAI significantly prolonged the LOS 9.0 (7.5-23.5) vs no HAI 4.0 (2.0 7.0) days; P = 0.006). Four patients died within 1 month of the procedure, three had a malignant diagnosis, all had suffered HAI. Trapped lung (persistent hydropneumothorax 5 days post-procedure) occurred in 11 (19.2%), six of whom had benign histology. Performance status (European Cooperative Oncology Group) prior did not differ with reported histological type: benign 2.0 (2.0-2.0), malignant 2.0 (2.0-3.0), P = 0.170. CONCLUSIONS: Serious complications following thoracoscopy are rare. HAI is associated with malignancy and prolonged hospital stay. Benign histology may still confer significant morbidity. PMID- 21651746 TI - Genetic variations in detoxification enzymes and HIF-1alpha in Japanese patients with COPD. AB - INTRODUCTION: Genetic factors contribute as major determinants in the pathophysiological mechanisms of chronic obstructive pulmonary disease (COPD). Therefore, identification of candidate genes and various gene polymorphisms have improved our understanding of COPD. OBJECTIVES: Clarify the genes, including HIF1A, that contribute to the development of COPD. METHODS: We compared the genotype frequencies of 12 polymorphisms in seven detoxification-related genes (GSTM1, GSTT1, GSTP1 exon 5, CYP1A1 exon 7, CYP1A1 3'-flanking, CYP2E1 intron 6, CYP2E1 5'-flanking, EPHX1 exon 3, EPHX1 exon 4 and HMOX1 promoter) and the hypoxia-related HIF1A (C1772T and G1790A) genes between 48 Japanese patients with work-related COPD who had a working history in a poison gas factory during World War II and two control groups (n=172 and 110 subjects, respectively). RESULTS: As expected, wild homozygotes for GSTP1 Ile105Val and EPHX1 slow/very slow phenotypes were associated with susceptibility (P=0.031) and severity (P=0.036) of COPD, respectively. Moreover, compound heterozygosity of transcription activating HIF1A polymorphisms was observed in two patients with COPD, but not in control individuals (P=0.091). CONCLUSION: This is the first report that examined HIF1A polymorphisms in COPD and demonstrated a possible role of HIF-1alpha in COPD, as well as GSTP1 and EPHX1. PMID- 21651747 TI - A randomised study of the effects of supplemental exercise sessions after a 7 week chronic obstructive pulmonary disease rehabilitation program. AB - BACKGROUND: Several studies have suggested that the effects of chronic obstructive pulmonary disease (COPD) rehabilitation programs tend to attenuate with time. We aimed to investigate the effects of supplemental exercise sessions following an initial 7-week COPD rehabilitation program with regard to exercise capacity and disease-specific quality of life (QoL). METHODS: We performed a 7 week COPD rehabilitation program in 140 COPD patients. Patients (n = 118) who completed the initial program were randomised for additional six supervised supplemental exercise sessions or three follow-up examinations without exercise. Both groups were followed for 12 months. Primary end-points were QoL as measured by the St. George's Respiratory Questionnaire total score and exercise capacity as measured by the endurance shuttle walking time (ESWT). RESULTS: A marked increase in ESWT (from 193 to 921 s) and a moderate decrease in total SGRQ score (2.5 points) was obtained during the initial 7 weeks rehabilitation program. The ESWT declined moderately and was 645 s at week 52 in both the intervention and control group. Unexpectedly, QoL increased slightly in the control group, while it decreased slightly in the intervention group. However, there were no statistically significant differences between the groups in the observed changes in QoL or ESWT at any time point. CONCLUSIONS: In conclusion, a program of six supplemental exercise sessions following the initial 7-week COPD rehabilitation program did not have any effect on ESWT or QoL during a 1-year follow-up. PMID- 21651748 TI - The prevalence of chronic obstructive pulmonary disease in Uppsala, Sweden--the Burden of Obstructive Lung Disease (BOLD) study: cross-sectional population-based study. AB - OBJECTIVES: To estimate chronic obstructive pulmonary disease (COPD) prevalence in Uppsala and the impact of risk factors on disease prevalence using the standardised methods of the Burden of Obstructive Lung Disease (BOLD) study initiative. METHODS: Randomly selected participants, aged 40 years or more (n = 548) responded to a questionnaire regarding smoking habits, respiratory symptoms, medical history, and exposure to airway irritants. Spirometry, with a post bronchodilator test, was performed and COPD defined as post-bronchodilatory forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) < 0.70 or FEV(1)/FVC < lower limit of normality (LLN). Circulatory inflammatory markers were measured. RESULTS: COPD prevalence was 16.2%, which was the fourth lowest prevalence of COPD, compared with 12 other BOLD centres. Main risk factors for COPD were increasing age [odds ratio (OR) = 2.08 per 10 years] and smoking (OR = 1.33 per 10 pack years). Higher education was protective (OR = 0.70 per 5 years). Previous tuberculosis was an almost significant risk factor for COPD (P = 0.08). Subjects with COPD reported more respiratory symptoms but only 29% had previous doctor diagnosed COPD, asthma, chronic bronchitis or emphysema. Participants with COPD had higher levels of C-reactive protein (P = 0.01), but no difference was observed in interleukin 6 (IL-6) levels. Using LLN instead of the fixed FEV(1) /FVC ratio reduced the prevalence of COPD to 10%. CONCLUSION: COPD prevalence in Uppsala was similar to other BOLD centres in high-income countries. Apart from known COPD risk factors (age, smoking, lower educational level), a history of tuberculosis may be associated with COPD even in high-income countries. COPD remains under-diagnosed, as only 29% of subjects with COPD had a previously diagnosed lung disorder. PMID- 21651749 TI - The relationship of glutathione-S-transferases copy number variation and indoor air pollution to symptoms and markers of respiratory disease. AB - INTRODUCTION: Exposure to particulate matter (PM) may induce inflammation and oxidative stress in the airways. Carriers of null polymorphisms of glutathione S transferases (GSTs), which detoxify reactive oxygen species, may be particularly susceptible to the effects of PM. OBJECTIVES: To investigate whether deletions of GSTM1 and GSTT1 modify the potential effects of exposure to indoor sources of PM on symptoms and objective markers of respiratory disease. METHODS: We conducted a population-based, cross-sectional study of 3471 persons aged 18-69 years. Information about exposure to indoor sources of PM and respiratory symptoms was obtained by a self-administered questionnaire. In addition, measurements of lung function (spirometry) and fractional exhaled nitric oxide were performed. Copy number variation of GSTM1 and GSTT1 was determined by polymerase chain reaction based assays. RESULTS: We found that none of the symptoms and objective markers of respiratory disease were significantly associated with the GST null polymorphisms. An increasing number of positive alleles of the GSTM1 polymorphism tended to be associated lower prevalence of wheeze, cough, and high forced expiratory volume in 1 s (FEV(1) ), but these trends were not statistically significant. Furthermore, we did not observe any statistically significant interactions between GST copy number variation and exposure to indoor sources of PM in relation to respiratory symptoms and markers. CONCLUSIONS: In this adult population, GST copy number variations were not significantly associated with respiratory outcomes and did not modify the effects of self-reported exposure to indoor sources of PM on respiratory outcomes. PMID- 21651750 TI - Association between self-rated health and asthma: a population-based study. AB - INTRODUCTION: Self-rated health (SRH) is a relevant measure of health as it can predict morbidity, mortality and health-care use. Studies have shown an association between poor SRH and elevated levels of circulating inflammatory cytokines. It is therefore interesting to learn more about the association between asthma, a chronic inflammatory disease with a recognised systemic component and SRH. OBJECTIVES: To compare SRH ratings in respondents with and without current asthma. A second aim was to compare SRH with quality-of-life ratings in the same groups. METHODS: In 1995, we randomly selected 8200 persons >= 18 years from the population of Stockholm County, Sweden and mailed them a questionnaire. A total of 5355 persons (67.5%) responded. Respondents were divided in two groups, those with and those without current asthma. The groups were further divided by sex and age (18-44 and >= 45 years). SRH was measured with the question 'How do you rate your general health status?' and quality of life with the Gothenburg Quality of Life Instrument and the Ladder of Life. RESULTS: Respondents with asthma rated their health significantly worse than did those without asthma, except women aged 18-44 years. SRH was associated at least as strong as quality of life to asthma with the advantage of being easier to apply (only one item). CONCLUSION: Information on SRH is easy to obtain and represents an important dimension of health status that potentially can be used as a complement to identify patients who need extra attention to manage their asthma and its consequences. PMID- 21651751 TI - Determinants of health-related quality of life in patients with asthma. PMID- 21651752 TI - Dermolipoma surgery with rotational conjunctival flaps. AB - PURPOSE: To describe a useful technique of surgical resection of dermolipomas. METHODS: This is a retrospective, noncomparative and interventional case series. Sixteen eyes of 16 patients with dermolipomas and large areas of conjunctiva strongly adherent to the masses underwent surgical removal of the dermolipomas. The anterior portion of the mass, including closely adherent conjunctiva and pilosebaceous areas, was excised, and the conjunctival defects were covered with rotational conjunctival flaps from the superior or inferior bulbar conjunctiva. RESULTS: The mean follow-up time was 12.5 months (range, 6-47 months). The cosmetic outcome was satisfactory in all 16 patients. There were no cases of reappearance of the mass, symblepharon or significant scar formation during follow-up. One patient developed blepharoptosis and another showed limitation of medial gaze postoperatively. Both were resolved spontaneously within 3 months. There were no other significant complications. CONCLUSION: Rotational conjunctival flap is a useful technique of conjunctival reconstruction following removal of large dermolipomas and the overlying epithelium. PMID- 21651753 TI - A comparative study of trabeculectomy and the new clear-cornea filtering procedure, intrastromal diathermal keratostomy (IDK). AB - PURPOSE: For the first time to compare the 1-year success rates of trabeculectomy and the new clear-cornea filtering procedure, intrastromal diathermal keratostomy (IDK). METHODS: Prospective clinical observational study including 99 consecutively operated eyes (69 patients) with well-established primary open angle glaucoma referred for filtering operation. We compared the change in intraocular pressure (IOP), number of anti-glaucomatous medication, complications and reoperations after 1 year. Seventy-four eyes were operated with trabeculectomy, and 25 with IDK. Complete success was defined as IOP <= 18 mmHg, IOP lowered >= 30%, no medication and no reoperation. Qualified success was defined as IOP <= 18 mmHg, and IOP lowered >= 30% with or without medication or reoperation. RESULTS: Intraocular pressure pre- and postoperatively in the trabeculectomy group was 25.3 and 14.1 mmHg versus 23.8 and 15.8 mmHg in the IDK group. The number of medications pre- and postoperatively in the trabeculectomy group was 3.1 and 0.5 versus 3.2 and 1.3 in the IDK group. Forty-four (59%) of the eyes in the trabeculectomy group met the complete success criteria compared with 5 (20%) in the IDK group (p < 0.01). Sixty-eight (92%) in the trabeculectomy group and 16 (64%) in the IDK fulfilled the qualified success criteria (p < 0.01). CONCLUSION: Both the complete and qualified 1-year success rates of IDK are significantly lower compared with the success rates of trabeculectomy. The IDK does not reduce the IOP as much as the procedure of trabeculectomy, and it carries a higher frequency of reoperations and more medication postoperatively. Thus, our prospective data do not support the procedure of IDK as 'the gold standard' for filtering surgery in patients with open-angle glaucoma. PMID- 21651754 TI - Diet and serum lipids: changes over socio-economic transition period in Lithuanian rural population. AB - BACKGROUND: Since regaining of independence in 1990, Lithuania has been undergoing substantial political, economic, and social changes that affected the nutrition habits of population. Dietary changes might have impact on the trends of dietary related risk factors of chronic diseases. The aim of the study was to compare trends in diet and lipid profile of Lithuanian rural population aged 25 64 during two decades of transition period (1987-2007). METHODS: Four cross sectional surveys were conducted within the framework of the Countrywide Integrated Noncommunicable Diseases Intervention Programme in five regions of Lithuania in 1987, 1993, 1999, and 2007. For each survey, a stratified independent random sample was drawn from the lists of the inhabitants aged 25-64 years registered at the primary health care centres. Altogether 3127 men and 3857 women participated in the surveys. 24-hour recall was used for evaluation of dietary habits. Serum lipids were determined using enzymatic methods. Predicted changes of serum cholesterol were calculated by Keys equation. RESULTS: The percentage of energy from saturated fatty acids has decreased from 18.0 to 15.1 among men and from 17.6 to 14.8 among women over the period of 20 years. The average share of polyunsaturated fatty acids in total energy intake increased from 5.3% to 7.1% among men and from 4.9% to 7.3% among women. The mean intake of cholesterol declined among women. Favourable trends in fatty acids composition were caused by increased use of vegetable oil for cooking and replacement of butter spread with margarine. Since 1987, the mean value of total cholesterol has decreased by 0.6 mmol/l. Total dietary effect accounts for a 0.26 mmol/l (43.3%) decline in serum cholesterol among men and 0.31 mmol/l (50.8%) decline among women. CONCLUSIONS: Improvement in the quality of fat intake was observed in Lithuanian rural population over two decades of transition period. Positive changes in diet, mainly reduction in saturated fatty acids intake, contributed to decline in serum cholesterol level. Strengthening of favourable trends in nutrition habits in Lithuanian population should be one of the most important strategies of cardiovascular diseases prevention. PMID- 21651755 TI - Evaluation of formalin-fixed paraffin-embedded tissues in the proteomic analysis of parathyroid glands. AB - BACKGROUND: Proteomic research in the field of parathyroid tissues is limited by the very small dimension of the glands and by the low incidence of cancer lesions (1%). Formalin-fixed paraffin-embedded (FFPE) tissue specimens are a potentially valuable resource for discovering protein cancer biomarkers. In this study we have verified the applicability of a heat induced protein extraction from FFPE parathyroid adenoma tissues followed by a gel-based or gel-free proteomic approach in order to achieve protein separation and identification. RESULTS: The best results for high quality MS spectra and parameters, were obtained by using a gel-free approach, and up to 163 unique proteins were identified. Similar results were obtained by applying both SDS-out and SDS-out + TCA/Acetone techniques during the gel-free method. Western blot analysis carried out with specific antibodies suggested that the antigenicity was not always preserved, while specific immunoreactions were detected for calmodulin, B box and SPRY domain containing protein (BSPRY), peroxiredoxin 6 (PRDX 6) and parvalbumin. CONCLUSIONS: In spite of some limitations mainly due to the extensive formalin induced covalent cross-linking, our results essentially suggest the applicability of a proteomic approach to FFPE parathyroid specimens. From our point of view, FFPE extracts might be an alternative source, especially in the validation phase of protein biomarkers when a large cohort of samples is required and the low availability of frozen tissues might be constraining. PMID- 21651757 TI - Survey of domestic cattle for anti-Leishmania antibodies and Leishmania DNA in a visceral leishmaniasis endemic area of Bangladesh. AB - BACKGROUND: Visceral leishmaniasis (VL), caused by an intracellular parasite Leishmania donovani in the Indian subcontinent, is considered to be anthroponotic. The role of domestic animals in its transmission is still unclear. Although cattle are the preferred blood host for Phlebotomus argentipes, the sandfly vector of VL in the Indian subcontinent, very little information is available for their role in the disease transmission. In this study, we examined domestic cattle for serological and molecular evidence of Leishmania infection in a VL-endemic area in Bangladesh. Blood samples from 138 domestic cattle were collected from houses with active or recently-treated VL and post-kala-azar dermal leishmaniasis patients. The presence of anti-leishmanial antibodies in serum was investigated using enzyme-linked immunosorbent assay (ELISA) and then with direct agglutination tests (DAT). Nested PCR (Ln PCR) was performed to amplify the ssu-rRNA gene using the DNA extracted from Buffy coat. Recently developed molecular assay loop-mediated isothermal amplification (LAMP) was also performed for further sensitive detection of parasite DNA. RESULTS: In this study, 9.4% (n=13) of the cattle were found to be positive by ELISA. Of the 13 ELISA-positive cattle, only four (30.8%) were positive in DAT. Parasite DNA was not detected in either of the molecular assays (Ln PCR and LAMP). CONCLUSIONS: The study confirmed the presence of antibodies against Leishmania parasite in cattle. However, the absence of Leishmania DNA in the cattle indicates clearly that the cattle do not play a role as reservoir host. Similar study needs to be undertaken in the Indian subcontinent to determine the role of other domestic animals on which sandflies feed. PMID- 21651756 TI - FTO gene polymorphisms and obesity risk: a meta-analysis. AB - BACKGROUND: The pathogenesis of obesity is reportedly related to variations in the fat mass and an obesity-associated gene (FTO); however, as the number of reports increases, particularly with respect to varying ethnicities, there is a need to determine more precisely the effect sizes in each ethnic group. In addition, some reports have claimed ethnic-specific associations with alternative SNPs, and to that end there has been a degree of confusion. METHODS: We searched PubMed, MEDLINE, Web of Science, EMBASE, and BIOSIS Preview to identify studies investigating the associations between the five polymorphisms and obesity risk. Individual study odds ratios (OR) and their 95% confidence intervals (CI) were estimated using per-allele comparison. Summary ORs were estimated using a random effects model. RESULTS: We identified 59 eligible case-control studies in 27 articles, investigating 41,734 obesity cases and 69,837 healthy controls. Significant associations were detected between obesity risk and the five polymorphisms: rs9939609 (OR: 1.31, 95% CI: 1.26 to 1.36), rs1421085 (OR: 1.43, 95% CI: 1.33 to 1.53), rs8050136 (OR: 1.25, 95% CI: 1.13 to 1.38), rs17817449 (OR: 1.54, 95% CI: 1.41 to 1.68), and rs1121980 (OR: 1.34, 95% CI: 1.10 to 1.62). Begg's and Egger's tests provided no evidence of publication bias for the polymorphisms except rs1121980. There is evidence of higher heterogeneity, with I2 test values ranging from 38.1% to 84.5%. CONCLUSIONS: This meta-analysis suggests that FTO may represent a low-penetrance susceptible gene for obesity risk. Individual studies with large sample size are needed to further evaluate the associations between the polymorphisms and obesity risk in various ethnic populations. PMID- 21651758 TI - Comprehensive genetic dissection of wood properties in a widely-grown tropical tree: Eucalyptus. AB - BACKGROUND: Eucalyptus is an important genus in industrial plantations throughout the world and is grown for use as timber, pulp, paper and charcoal. Several breeding programmes have been launched worldwide to concomitantly improve growth performance and wood properties (WPs). In this study, an interspecific cross between Eucalyptus urophylla and E. grandis was used to identify major genomic regions (Quantitative Trait Loci, QTL) controlling the variability of WPs. RESULTS: Linkage maps were generated for both parent species. A total of 117 QTLs were detected for a series of wood and end-use related traits, including chemical, technological, physical, mechanical and anatomical properties. The QTLs were mainly clustered into five linkage groups. In terms of distribution of QTL effects, our result agrees with the typical L-shape reported in most QTL studies, i.e. most WP QTLs had limited effects and only a few (13) had major effects (phenotypic variance explained > 15%). The co-locations of QTLs for different WPs as well as QTLs and candidate genes are discussed in terms of phenotypic correlations between traits, and of the function of the candidate genes. The major wood property QTL harbours a gene encoding a Cinnamoyl CoA reductase (CCR), a structural enzyme of the monolignol-specific biosynthesis pathway. CONCLUSIONS: Given the number of traits analysed, this study provides a comprehensive understanding of the genetic architecture of wood properties in this Eucalyptus full-sib pedigree. At the dawn of Eucalyptus genome sequence, it will provide a framework to identify the nature of genes underlying these important quantitative traits. PMID- 21651759 TI - The relationship between social support and self-reported health status in immigrants: an adjusted analysis in the Madrid Cross Sectional Study. AB - BACKGROUND: Social support is an important factor in the adaptation process of immigrants, helping for their integration in a new environment. The lack of social support may influence on well-being and health status. The aim of this study is to describe the social support of immigrant and native population and study the possible association between immigration and lack social support after adjusting for sociodemographic factors, income, stress and self-reported health status. METHODS: Cross-sectional population based study of immigrants and national patients without mental disorders of 15 urban primary health centers in the north-eastern area of Madrid. Participants provided information on social support, stress level, perceived health status and socio-economic characteristics. Descriptive and multiple logistic regression were conducted. RESULTS: The proportion of the global perception of social support among immigrants and natives was 79.2% and 94.2%, respectively. The lack of global social support adjusted prevalence ratio (PR) of immigrant was 2.72 (95% Confidence Interval=1.81-4.09), showing a significant association with being male (PR=2.26), having monthly income below 500 euros (PR=3.81) and suffering stress (PR=1.94). For the dimensions of lack of social support the higher association was being an immigrant and suffering stress. CONCLUSIONS: We conclude that with regardless of the level of monthly income, stress level, self-reported health status, and gender, immigrant status is directly associated with lack social support. The variable most strongly associated with lack social support has been monthly income below 500 euros. PMID- 21651760 TI - Transfer of manualized Short Term Psychodynamic Psychotherapy (STPP) for social phobia into clinical practice: study protocol for a cluster-randomised controlled trial. AB - BACKGROUND: Psychodynamic psychotherapy is frequently applied in the treatment of social phobia. Nevertheless, there has been a lack of studies on the transfer of manualized treatments to routine psychodynamic practice. Our study is the first one to examine the effects of additional training in a manualized Short Term Psychodynamic Psychotherapy (STPP) procedure on outcome in routine psychotherapy for social phobia. This study is an extension to a large multi-site RCT (N = 512) comparing the efficacy of STPP to Cognitive-Behavioral Therapy (CBT) of Social Phobia. METHODS/DESIGN: The manualized treatment is designed for a time limited approach with 25 individual sessions of STPP over 6 months. Private practitioners will be randomized to training in manualized STPP vs. treatment as usual without a specific training (control condition). We plan to enrol a total of 105 patients (84 completers). Assessments will be conducted before treatment starts, after 8 and 15 weeks, after 25 treatment sessions, at the end of treatment, 6 months and 12 months after termination of treatment. The primary outcome measure is the Liebowitz Social Anxiety Scale. Remission from social phobia is defined scoring with 30 or less points on this scale. DISCUSSION: We will investigate how the treatment can be transferred from a controlled trial into the less structured setting of routine clinical care. This question represents Phase IV of psychotherapy research. It combines the benefits of randomized controlled and naturalistic research. The study is genuinely designed to promote faster and more widespread dissemination of effective interventions. It will answer the questions whether manualized STPP can be implemented into routine outpatient care, whether the new methods improve treatment courses and outcomes and whether treatment effects reached in routine psychotherapeutic treatments are comparable to those of the controlled, strictly manualized treatment of the main study. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00000570. PMID- 21651761 TI - Anopheles gambiae distribution and insecticide resistance in the cities of Douala and Yaounde (Cameroon): influence of urban agriculture and pollution. AB - BACKGROUND: Urban malaria is becoming a major health priority across Africa. A study was undertaken to assess the importance of urban pollution and agriculture practice on the distribution and susceptibility to insecticide of malaria vectors in the two main cities in Cameroon. METHODS: Anopheline larval breeding sites were surveyed and water samples analysed monthly from October 2009 to December 2010. Parameters analysed included turbidity, pH, temperature, conductivity, sulfates, phosphates, nitrates, nitrites, ammonia, aluminium, alkalinity, iron, potassium, manganese, magnesium, magnesium hardness and total hardness. Characteristics of water bodies in urban areas were compared to rural areas and between urban sites. The level of susceptibility of Anopheles gambiae to 4% DDT, 0.75% permethrin, 0.05% deltamethrin, 0.1% bendiocarb and 5% malathion were compared between mosquitoes collected from polluted, non polluted and cultivated areas. RESULTS: A total of 1,546 breeding sites, 690 in Yaounde and 856 in Douala, were sampled in the course of the study. Almost all measured parameters had a concentration of 2- to 100-fold higher in urban compare to rural breeding sites. No resistance to malathion was detected, but bendiocarb resistance was present in Yaounde. Very low mortality rates were observed following DDT or permethrin exposure, associated with high kdr frequencies. Mosquitoes collected in cultivated areas, exhibited the highest resistant levels. There was little difference in insecticide resistance or kdr allele frequency in mosquitoes collected from polluted versus non-polluted sites. CONCLUSION: The data confirm high selection pressure on mosquitoes originating from urban areas and suggest urban agriculture rather than pollution as the major factor driving resistance to insecticide. PMID- 21651762 TI - Healthcare workers' participation in a healthy-lifestyle-promotion project in western Sweden. AB - BACKGROUND: Healthcare professionals play a central role in health promotion and lifestyle information towards patients as well as towards the general population, and it has been shown that own lifestyle habits can influence attitudes and counselling practice towards patients. The purpose of this study was to explore the participation of healthcare workers (HCWs) in a worksite health promotion (WHP) programme. We also aimed to find out whether HCWs with poorer lifestyle related health engage in health-promotion activities to a larger extent than employees reporting healthier lifestyles. METHOD: A biennial questionnaire survey was used in this study, and it was originally posted to employees in the public healthcare sector in western Sweden, one year before the onset of the WHP programme. The response rate was 61% (n = 3207). In the four-year follow-up, a question regarding participation in a three-year-long WHP programme was included, and those responding to this question were included in the final analysis (n = 1859). The WHP programme used a broad all-inclusive approach, relying on the individual's decision to participate in activities related to four different themes: physical activity, nutrition, sleep, and happiness/enjoyment. RESULTS: The participation rate was around 21%, the most popular theme being physical activity. Indicators of lifestyle-related health/behaviour for each theme were used, and regression analysis showed that individuals who were sedentary prior to the programme were less likely to participate in the programme's physical activities than the more active individuals. Participation in the other three themes was not significantly predicted by the indicators of the lifestyle-related health, (body mass index, sleep disturbances, or depressive mood). CONCLUSION: Our results indicate that HCWs are not more prone to participate in WHP programmes compared to what has been reported for other working populations, and despite a supposedly good knowledge of health-related issues, HCWs reporting relatively unfavourable lifestyles are not more motivated to participate. As HCWs are key actors in promoting healthy lifestyles to other groups (such as patients), it is of utmost importance to find strategies to engage this professional group in activities that promote their own health. PMID- 21651763 TI - Feeding behaviour of potential vectors of West Nile virus in Senegal. AB - BACKGROUND: West Nile virus (WNV) is a widespread pathogen maintained in an enzootic cycle between mosquitoes and birds with occasional spill-over into dead end hosts such as horses and humans. Migratory birds are believed to play an important role in its dissemination from and to the Palaearctic area, as well as its local dispersion between wintering sites. The Djoudj Park, located in Senegal, is a major wintering site for birds migrating from Europe during the study period (Sept. 2008- Jan. 2009). In this work, we studied the seasonal feeding behaviour dynamics of the potential WNV mosquito vectors at the border of the Djoudj Park, using a reference trapping method (CDC light CO2-baited traps) and two host-specific methods (horse- and pigeon-baited traps). Blood meals of engorged females were analysed to determine their origin. RESULTS: Results indicated that Culex tritaeniorhynchus and Cx. neavei may play a key role in the WNV transmission dynamics, the latter being the best candidate bridging-vector species between mammals and birds. Moreover, the attractiveness of pigeon- and horse-baited traps for Cx. neavei and Cx. tritaeniorhynchus varied with time. Finally, Cx. tritaeniorhynchus was only active when the night temperature was above 20 degrees C, whereas Cx. neavei was active throughout the observation period. CONCLUSIONS: Cx. neavei and Cx. tritaeniorhynchus are the main candidate vectors for the transmission of WNV in the area. The changes in host attractiveness might be related to variable densities of the migratory birds during the trapping period. We discuss the importance of these results on the risk of WNV transmission in horses and humans. PMID- 21651764 TI - Human teneurin-1 is a direct target of the homeobox transcription factor EMX2 at a novel alternate promoter. AB - BACKGROUND: Teneurin-1 is a member of a family of type II transmembrane proteins conserved from C.elegans to vertebrates. Teneurin expression in vertebrates is best studied in mouse and chicken, where the four members teneurin-1 to -4 are predominantly expressed in the developing nervous system in area specific patterns. Based on their distinct, complementary expression a possible function in the establishment of proper connectivity in the brain was postulated. However, the transcription factors contributing to these distinctive expression patterns are largely unknown. Emx2 is a homeobox transcription factor, known to be important for area specification in the developing cortex. A study of Emx2 knock out mice suggested a role of Emx2 in regulating patterned teneurin expression. RESULTS: 5'RACE of human teneurin-1 revealed new alternative untranslated exons that are conserved in mouse and chicken. Closer analysis of the conserved region around the newly identified transcription start revealed promoter activity that was induced by EMX2. Mutation of a predicted homeobox binding site decreased the promoter activity in different reporter assays in vitro and in vivo in electroporated chick embryos. We show direct in vivo binding of EMX2 to the newly identified promoter element and finally confirm that the endogenous alternate transcript is specifically upregulated by EMX2. CONCLUSIONS: We found that human teneurin-1 is directly regulated by EMX2 at a newly identified and conserved promoter region upstream of the published transcription start site, establishing teneurin-1 as the first human EMX2 target gene. We identify and characterize the EMX2 dependent promoter element of human teneurin-1. PMID- 21651765 TI - Examination of viability and quality of ovarian tissue after cryopreservation using simple laboratory methods in ewe. AB - BACKGROUND: The objective of the present study is to assess viability tests and to evaluate follicle ovarian tissue quality after freezing-thawing procedures. METHODS: Ewe's ovaries were harvested at the slaughterhouse, after dissection each ovarian specimen was divided into two groups: fresh tissue (control group) and frozen tissue.In the first part of the study, the follicles viability was assessed by trypan blue staining, calcein AM/ethidium homodimer-1 staining (LIVE/DEAD viability/cytotoxicity kit, Molecular Probes) and morphology in the two groups. In the second part of the study the quality of the whole ovarian tissue was evaluated by the quantification of the release of lactate dehydrogenase measurement (Cytotoxicity Detection kit ROCHE), DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) in primordial and primary follicles (ApopDETEK Kit system Enzo) and morphology in the two groups. 100 Follicles (primordial and primary) were counted on both fresh and frozen hemiovary to assess this various tests. RESULTS: Ovarian follicle viability assessment was similar using trypan blue or calcein/ethidium staining. Follicles showed a decreased viability after freezing-thawing.After cryopreservation, a significant correlation between the percentage of normal follicles and viability rate was found using trypan blue (r=0.82, p<0.05) or calcein AM/ethidium homodimer-1 staining (r=0.76, p<0.05). Increased cytotoxicity showed by enhancement of LDH release was found after cryopreservation (21.60+/ 1.1% vs 52.2+/-7.7%). A significant negative correlation between the percentage of morphologically normal follicles and cytotoxicity was observed. No significant difference in DNA fragmentation rate between frozen and control groups was found (26+/-8.2% vs 38+/-4.5%). CONCLUSION: We suggest the use of trypan blue staining for the histological assessment of viability, the use of LDH assay for the cytotoxicity assessement and finally the use of DNA fragmentation assessment to valid different freezing-thawing protocols. PMID- 21651766 TI - Intracisternal administration of NR2 subunit antagonists attenuates the nociceptive behavior and p-p38 MAPK expression produced by compression of the trigeminal nerve root. AB - BACKGROUND: We investigated the role of the central NMDA receptor NR2 subunits in the modulation of nociceptive behavior and p-p38 MAPK expression in a rat model with compression of the trigeminal nerve root. To address this possibility, changes in air-puff thresholds and pin-prick scores were determined following an intracisternal administration of NR2 subunit antagonists. We also examined effects of NR2 subunit antagonists on the p-p38 MAPK expression. RESULTS: Experiments were carried out using male Sprague-Dawley rats weighing (200-230 g). Compression of the trigeminal nerve root was performed under pentobarbital sodium (40 mg/kg) anesthesia. Compression of the trigeminal nerve root produced distinct nociceptive behavior such as mechanical allodynia and hyperalgesia. Intracisternal administration of 10 or 20 MUg of D-AP5 significantly increased the air-puff threshold and decreased the pin-prick scores in a dose-dependent manner. The intracisternal administration of PPPA (1, 10 MUg), or PPDA (5, 10 MUg) increased the air-puff threshold and decreased the pin-prick scores ipsilateral as well as contralateral to the compression of the trigeminal root. Compression of the trigeminal nerve root upregulated the expression of p-p38 MAPK in the ipsilateral medullary dorsal horn which was diminished by D-AP5, PPPA, PPDA, but not Ro25-6981. CONCLUSIONS: Our findings suggest that central NMDA receptor NR2 subunits play an important role in the central processing of trigeminal neuralgia-like nociception in rats with compression of the trigeminal nerve root. Our data further indicate that the targeted blockade of NR2 subunits is a potentially important new treatments strategy for trigeminal neuralgia-like nociception. PMID- 21651767 TI - Overwhelming postsplenectomy infection due to Mycoplasma pneumoniae in an asplenic cirrhotic patient: case report. AB - BACKGROUND: Mycoplasma pneumoniae infection is usually self-limited, but some fulminant cases are fatal, even when occurring in previously healthy individuals. It can also be the cause of overwhelming postsplenectomy infection (OPSI). CASE PRESENTATION: We report a case of OPSI in a 41-year-old woman with hypersplenism associated with hepatitis B cirrhosis. We detected a significant Mycoplasma pneumoniae agglutination titer, but no evidence of infection with Chlamydia pneumoniae, Legionnella spp., or any other bacterial or fungal pathogens. She eventually died despite aggressive therapy. CONCLUSIONS: M. pneumoniae could be an underestimated cause of OPSI, and should be suspected in fulminant infectious cases in asplenic patients. PMID- 21651768 TI - Associations between quality indicators of internal medicine residency training programs. AB - BACKGROUND: Several residency program characteristics have been suggested as measures of program quality, but associations between these measures are unknown. We set out to determine associations between these potential measures of program quality. METHODS: Survey of internal medicine residency programs that shared an online ambulatory curriculum on hospital type, faculty size, number of trainees, proportion of international medical graduate (IMG) trainees, Internal Medicine In Training Examination (IM-ITE) scores, three-year American Board of Internal Medicine Certifying Examination (ABIM-CE) first-try pass rates, Residency Review Committee-Internal Medicine (RRC-IM) certification length, program director clinical duties, and use of pharmaceutical funding to support education. Associations assessed using Chi-square, Spearman rank correlation, univariate and multivariable linear regression. RESULTS: Fifty one of 67 programs responded (response rate 76.1%), including 29 (56.9%) community teaching and 17 (33.3%) university hospitals, with a mean of 68 trainees and 101 faculty. Forty four percent of trainees were IMGs. The average post-graduate year (PGY)-2 IM-ITE raw score was 63.1, which was 66.8 for PGY3s. Average 3-year ABIM-CE pass rate was 95.8%; average RRC-IM certification was 4.3 years. ABIM-CE results, IM-ITE results, and length of RRC-IM certification were strongly associated with each other (p<0.05). PGY3 IM-ITE scores were higher in programs with more IMGs and in programs that accepted pharmaceutical support (p<0.05). RRC-IM certification was shorter in programs with higher numbers of IMGs. In multivariable analysis, a higher proportion of IMGs was associated with 1.17 years shorter RRC accreditation. CONCLUSIONS: Associations between quality indicators are complex, but suggest that the presence of IMGs is associated with better performance on standardized tests but decreased duration of RRC-IM certification. PMID- 21651769 TI - Pontine Tegmental Cap Dysplasia: developmental and cognitive outcome in three adolescent patients. AB - Pontine Tegmental Cap Dysplasia (PTCD) is a recently described, rare disorder characterized by a peculiar cerebellar and brainstem malformation. Nineteen patients have been reported to date, of which only one in the adolescent age, and data on the clinical, cognitive and behavioural outcome of this syndrome are scarce. Here we describe three adolescent patients with PTCD. All presented bilateral deafness and multiple cranial neuropathies, variably associated with skeletal, cardiac and gastro-intestinal malformations. Feeding and swallowing difficulties, that are often causative of recurrent aspiration pneumonias and death in the first years of life, completely resolved with age in all three patients. Neuropsychological assessment showed borderline to moderate cognitive impairment, with delay in adaptive functioning, visual-spatial and language deficits. Two of three patients also showed mild behavioural problems, although their overall socialization abilities were well preserved. Cochlear implantation in two patients significantly improved their relational and learning abilities. Fibre tractography confirmed the abnormal bundle of transversely oriented fibres forming the typical pontine "tegmental cap" and absence of decussation of the superior cerebellar peduncles, supporting the hypothesis that PTCD results from abnormal axonal guidance and/or migration.These data indicate that PTCD may have a favourable long-term outcome, with borderline cognitive deficit or even normal cognition and partially preserved speech. PMID- 21651770 TI - Schizophrenia in Malaysian families: A study on factors associated with quality of life of primary family caregivers. AB - BACKGROUND: Schizophrenia is a chronic illness which brings detrimental effects in the caregivers' health. This study was aimed at highlighting the socio demographic, clinical and psychosocial factors associated with the subjective Quality of Life (QOL) of Malaysian of primary family caregivers of subjects with schizophrenia attending an urban tertiary care outpatient clinic in Malaysia. METHODS: A cross-sectional study was performed to study patient, caregiver and illness factors associated with the QOL among 117 individuals involved with caregiving for schizophrenia patients. The study used WHOQOL-BREF to assess caregivers' QOL and Brief Psychiatric Rating Scale (BPRS) to assess the severity of patients' symptoms. Social Readjustment Rating Scale (SRRS) assessed the stress level due to life events. RESULTS: The mean scores of WHOQOL-BREF in physical, psychological, social and environmental domains were 66.62 (14.36), 61.32 (15.52), 62.77 (17.33), 64.02 (14.86) consecutively. From multiple regression analysis, factors found to be significantly associated with higher QOL were higher educational level among caregivers in social and environmental domains; caregivers not having medical problem/s in physical and psychological domains; later onset and longer illness duration of illness in social domains; patients not attending day care program in environmental domain; lower BPRS score in physical and environmental domains. SRRS score of caregivers was also found to have a significant negative correlation with QOL in environmental and psychological domains. Other factors were not significantly associated with QOL. CONCLUSION: Caregivers with more social advantages such as higher educational level and physically healthier and dealing with less severe illness had significantly higher QOL in various aspects. Supporting the caregivers in some of these modifiable factors in clinical practice is important to achieve their higher level QOL. PMID- 21651771 TI - Fatty acids intake in the Mexican population. Results of the National Nutrition Survey 2006. AB - BACKGROUND: There is growing evidence that quality, rather that quantity of fat is the determinant of cardiovascular risk. The objective of the study is to describe quantitatively the intake and adequacy of fatty acid classes among the Mexican population aged 5-90 years from a probabilistic survey. METHODS: Dietary intake of individual and classes of fatty acids was computed from the dataset of the 2006 Mexican National Health and Nutrition Survey (ENSANUT2006), collected by a food frequency questionnaire. Adequacy was calculated in reference to authoritative recommendations. RESULTS: The mean intake of total fatty acids (TFA ~ 25%E) fell within WHO recommendations; the intakes of saturated fatty acids (SFA) among all age-groups (45-60%) and of trans fatty acids (TrFA) in 30% of school-age children and adolescents and 20% of adults exceeded international recommendations. The mean intake of polyunsaturated fatty acids (PUFA) and particularly of n6 and n3 PUFAS, was inadequately insufficient in 50% of the sample. CONCLUSIONS: The main public health concerns are the high intake of SFA and the suboptimal intake of PUFA in Mexican population. The TrFA intake represents a low public health risk. PMID- 21651772 TI - Expansion of CD4+CD25+ helper T cells without regulatory function in smoking and COPD. AB - BACKGROUND: Regulatory T cells have been implicated in the pathogenesis of COPD by the increased expression of CD25 on helper T cells along with enhanced intracellular expression of FoxP3 and low/absent CD127 expression on the cell surface. METHOD: Regulatory T cells were investigated in BALF from nine COPD subjects and compared to fourteen smokers with normal lung function and nine never-smokers. RESULTS: In smokers with normal lung function, the expression of CD25+CD4+ was increased, whereas the proportions of FoxP3+ and CD127+ were unchanged compared to never-smokers. Among CD4+ cells expressing high levels of CD25, the proportion of FoxP3+ cells was decreased and the percentage of CD127+ was increased in smokers with normal lung function. CD4+CD25+ cells with low/absent CD127 expression were increased in smokers with normal lung function, but not in COPD, when compared to never smokers. CONCLUSION: The reduction of FoxP3 expression in BALF from smokers with normal lung function indicates that the increase in CD25 expression is not associated with the expansion of regulatory T cells. Instead, the high CD127 and low FoxP3 expressions implicate a predominantly non-regulatory CD25+ helper T-cell population in smokers and stable COPD. Therefore, we suggest a smoking-induced expansion of predominantly activated airway helper T cells that seem to persist after COPD development. PMID- 21651773 TI - Five-years surveillance of invasive aspergillosis in a university hospital. AB - BACKGROUND: As the most common invasive fungal infection, invasive aspergillosis (IA) remains a serious complication in immunocompromised patients, leading to increased mortality. Antifungal therapy is expensive and may result in severe adverse effects.The aim of this study was to determine the incidence of invasive aspergillosis (IA) cases in a tertiary care university hospital using a standardized surveillance method. METHODS: All inpatients at our facility were screened for presence of the following parameters: positive microbiological culture, pathologist's diagnosis and antifungal treatment as reported by the hospital pharmacy. Patients fulfilling one or more of these indicators were further reviewed and, if appropriate, classified according to international consensus criteria (EORTC). RESULTS: 704 patients were positive for at least one of the indicators mentioned above. Applying the EORTC criteria, 214 IA cases were detected, of which 56 were proven, 25 probable and 133 possible. 44 of the 81 (54%) proven and probable cases were considered health-care associated. 37 of the proven/probable IA cases had received solid organ transplantation, an additional 8 had undergone stem cell transplantation, and 10 patients were suffering from some type of malignancy. All the other patients in this group were also suffering from severe organic diseases, required long treatment and experienced several clinical complications. 7 of the 56 proven cases would have been missed without autopsy. After the antimycotic prophylaxis regimen was altered, we noticed a significant decrease (p = 0.0004) of IA during the investigation period (2003 2007). CONCLUSION: Solid organ and stem cell transplantation remain important risk factors for IA, but several other types of immunosuppression should also be kept in mind. Clinical diagnosis of IA may be difficult (in this study 13% of all proven cases were diagnosed by autopsy only). Thus, we confirm the importance of IA surveillance in all high-risk patients. PMID- 21651774 TI - Troponin utilization in patients presenting with atrial fibrillation/flutter to the emergency department: retrospective chart review. AB - BACKGROUND: There are few recommendations about the use of cardiac markers in the investigation and management of atrial fibrillation/flutter. Currently, it is unknown how many patients with atrial fibrillation/flutter undergo troponin testing, and how positive troponin results are managed in the emergency department. We sought to look at the emergency department troponin utilization patterns. METHODS: We performed a retrospective chart review of patients with atrial fibrillation/flutter presenting to the emergency department at three centers. Outcome measures included the rates of troponins ordered by emergency doctors, number of positive troponins, and those with positive troponins treated as acute coronary syndrome (ACS) by consulting services. RESULTS: Four hundred fifty-one charts were reviewed. A total of 388 (86%) of the patients had troponins ordered, 13.7% had positive results, and 4.9% were treated for ACS. CONCLUSIONS: Troponin tests are ordered in a high percentage of patients with atrial fibrillation/flutter presenting to emergency departments. Five percent of our total patient cohort was diagnosed as having acute coronary syndrome by consulting services. PMID- 21651775 TI - Intensity modulated radiation therapy (IMRT): differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma. AB - BACKGROUND: A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT), to reduce dose to adjacent organs at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT) in standard, preoperative treatment for rectal cancer. METHODS: Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1) or node-positive (N = 9), and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. RESULTS: IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2 Gy 3DCRT; p = 0.005), bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005), pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005), and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005), with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005). We found that the IMRT treatment volumes were typically larger than that covered by classic bony landmark-derived fields, without incurring penalty with respect to adjacent organs-at-risk. CONCLUSIONS: For rectal carcinoma, IMRT, compared to 3DCRT, yielded plans superior with respect to target coverage, homogeneity, and conformality, while lowering dose to adjacent organs-at-risk. This is achieved despite treating larger volumes, raising the possibility of a clinically-relevant improvement in the therapeutic ratio through the use of IMRT with a belly-board apparatus. PMID- 21651776 TI - In a free healthcare system, why do men not consult for lower urinary tract symptoms (LUTS)? AB - BACKGROUND: The prevalence of lower urinary tract symptoms (LUTS) varies among different populations but the rate of seeking medical advice is consistently low. Little is known about the reasons for this low rate. In the city of Macau, China, primary healthcare is free and easily accessible to all citizens. We aim to study the patients' rate of consulting for LUTS and their reasons for not consulting under a free healthcare system. METHOD: A convenience sample of 549 male patients aged 40-85 years in a government health centre filled in the International Prostate Symptoms Scale (IPSS) questionnaire. They were also asked if they had consulted doctors for LUTS, and if not, why not. RESULT: Of the whole sample, 64 men (11.7%) had ever consulted doctors for LUTS. Of 145 with moderate to severe LUTS, 35 (24.1%) consulted. Of 73 who were dissatisfied with their quality of life, 22 (30.1%) consulted. Regarding the symptoms as normal or not problematic was the main reason for not consulting. Advancing age and duration of symptoms were the significant factors for consulting. CONCLUSION: Primary care doctors could help many of LUTS patients by sensitively initiating the discussion when these patients consult for other problems. PMID- 21651777 TI - Body fluid derived exosomes as a novel template for clinical diagnostics. AB - BACKGROUND: Exosomes are small membrane vesicles with a size of 40-100 nm that are released by different cell types from a late endosomal cellular compartment. They can be found in various body fluids including plasma, malignant ascites, urine, amniotic fluid and saliva. Exosomes contain proteins, miRNAs and mRNAs (exosome shuttle RNA, esRNA) that could serve as novel platform for diagnosis. METHOD: We isolated exosomes from amniotic fluid, saliva and urine by differential centrifugation on sucrose gradients. Marker proteins were identified by Western blot and FACS analysis after adsorption of exosomes to latex beads. We extracted esRNA from exosomes, carried out RT-PCR, and analyzed amplified products by restriction length polymorphism. RESULTS: Exosomes were positive for the marker proteins CD24, CD9, Annexin-1 and Hsp70 and displayed the correct buoyant density and orientation of antigens. In sucrose gradients the exosomal fractions contained esRNA that could be isolated with sufficient quantity for further analysis. EsRNAs were protected in exosomes from enzymatic degradation. Amniotic fluid esRNA served as template for the typing of the CD24 single nucleotide polymorphism (rs52812045). It also allowed sex determination of the fetus based on the detection of the male specific ZFY gene product. CONCLUSIONS: Our data demonstrate that exosomes from body fluids carry esRNAs which can be analyzed and offers access to the transcriptome of the host organism. The exosomal lipid bilayer protects the genetic information from degradation. As the isolation of exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostics. PMID- 21651778 TI - Anti-hLAMP2-antibodies and dual positivity for anti-GBM and MPO-ANCA in a patient with relapsing pulmonary-renal syndrome. AB - BACKGROUND: Pulmonary-renal syndrome associated with anti-glomerular basement membrane (GBM) antibodies, also known as Goodpasture's syndrome, is a rare but acute and life-threatening condition. One third of patients presenting as anti GBM antibody positive pulmonary-renal syndrome or rapidly progressive glomerulonephritis are also tested positive for anti-neutrophil cytoplasmic antibodies (ANCA). Whilst anti-GBM disease is considered a non-relapsing condition, the long-term course of double-positive patients is less predictable. CASE PRESENTATION: We report a patient with such dual positivity, who presented with pulmonary hemorrhage, crescentic glomerulonephritis and membranous nephropathy. Plasmapheresis in combination with immunosuppressive therapy led to a rapid remission but the disease relapsed after two years. The serum of the patient was tested positive for antibodies to human lysosomal membrane protein 2 (hLAMP2), a novel autoantigen in patients with active small-vessel vasculitis (SVV). The anti-hLAMP2 antibody levels correlated positively with clinical disease activity in this patient. CONCLUSION: We hypothesize that this antibody may indicate a clinical course similar to ANCA-associated vasculitis in double positive patients. However, this needs to be confirmed on comprehensive patient cohorts. PMID- 21651779 TI - The influence of geographic and climate factors on the timing of dengue epidemics in Peru, 1994-2008. AB - BACKGROUND: Dengue fever is a mosquito-borne disease that affects between 50 and 100 million people each year. Increasing our understanding of the heterogeneous transmission patterns of dengue at different spatial scales could have considerable public health value by guiding intervention strategies. METHODS: Based on the weekly number of dengue cases in Peru by province, we investigated the association between dengue incidence during the period 1994-2008 and demographic and climate factors across geographic regions of the country. RESULTS: Our findings support the presence of significant differences in the timing of dengue epidemics between jungle and coastal regions, with differences significantly associated with the timing of the seasonal cycle of mean temperature. CONCLUSIONS: Dengue is highly persistent in jungle areas of Peru where epidemics peak most frequently around March when rainfall is abundant. Differences in the timing of dengue epidemics in jungle and coastal regions are significantly associated with the seasonal temperature cycle. Our results suggest that dengue is frequently imported into coastal regions through infective sparks from endemic jungle areas and/or cities of other neighboring endemic countries, where propitious environmental conditions promote year-round mosquito breeding sites. If jungle endemic areas are responsible for multiple dengue introductions into coastal areas, our findings suggest that curtailing the transmission of dengue in these most persistent areas could lead to significant reductions in dengue incidence in coastal areas where dengue incidence typically reaches low levels during the dry season. PMID- 21651780 TI - Comparison of RBE values of high-LET alpha-particles for the induction of DNA DSBs, chromosome aberrations and cell reproductive death. AB - BACKGROUND: Various types of radiation effects in mammalian cells have been studied with the aim to predict the radiosensitivity of tumours and normal tissues, e.g. DNA double strand breaks (DSB), chromosome aberrations and cell reproductive inactivation. However, variation in correlations with clinical results has reduced general application. An additional type of information is required for the increasing application of high-LET radiation in cancer therapy: the Relative Biological Effectiveness (RBE) for effects in tumours and normal tissues. Relevant information on RBE values might be derived from studies on cells in culture. METHODS: To evaluate relationships between DNA-DSB, chromosome aberrations and the clinically most relevant effect of cell reproductive death, for ionizing radiations of different LET, dose-effect relationships were determined for the induction of these effects in cultured SW-1573 cells irradiated with gamma-rays from a Cs-137 source or with alpha-particles from an Am-241 source. RBE values were derived for these effects. Ionizing radiation induced foci (IRIF) of DNA repair related proteins, indicative of DSB, were assessed by counting gamma-H2AX foci. Chromosome aberration frequencies were determined by scoring fragments and translocations using premature chromosome condensation. Cell survival was measured by colony formation assay. Analysis of dose-effect relations was based on the linear-quadratic model. RESULTS: Our results show that, although both investigated radiation types induce similar numbers of IRIF per absorbed dose, only a small fraction of the DSB induced by the low-LET gamma-rays result in chromosome rearrangements and cell reproductive death, while this fraction is considerably enhanced for the high-LET alpha radiation. Calculated RBE values derived for the linear components of dose-effect relations for gamma-H2AX foci, cell reproductive death, chromosome fragments and colour junctions are 1.0 +/- 0.3, 14.7 +/- 5.1, 15.3 +/- 5.9 and 13.3 +/- 6.0 respectively. CONCLUSIONS: These results indicate that RBE values for IRIF (DNA DSB) induction provide little valid information on other biologically-relevant end points in cells exposed to high-LET radiations. Furthermore, the RBE values for the induction of the two types of chromosome aberrations are similar to those established for cell reproductive death. This suggests that assays of these aberrations might yield relevant information on the biological effectiveness in high-LET radiotherapy. PMID- 21651781 TI - Codon usage in vertebrates is associated with a low risk of acquiring nonsense mutations. AB - BACKGROUND: Codon usage in genomes is biased towards specific subsets of codons. Codon usage bias affects translational speed and accuracy, and it is associated with the tRNA levels and the GC content of the genome. Spontaneous mutations drive genomes to a low GC content. Active cellular processes are needed to maintain a high GC content, which influences the codon usage of a species. Loss of-function mutations, such as nonsense mutations, are the molecular basis of many recessive alleles, which can greatly affect the genome of an organism and are the cause of many genetic diseases in humans. METHODS: We developed an event based model to calculate the risk of acquiring nonsense mutations in coding sequences. Complete coding sequences and genomes of 40 eukaryotes were analyzed for GC and CpG content, codon usage, and the associated risk of acquiring nonsense mutations. We included one species per genus for all eukaryotes with available reference sequence. RESULTS: We discovered that the codon usage bias detected in genomes of high GC content decreases the risk of acquiring nonsense mutations (Pearson's r = -0.95; P < 0.0001). In the genomes of all examined vertebrates, including humans, this risk was lower than expected (0.93 +/- 0.02; mean +/- SD) and lower than the risk in genomes of non-vertebrates (1.02 +/- 0.13; P = 0.019). CONCLUSIONS: While the maintenance of a high GC content is energetically costly, it is associated with a codon usage bias harboring a low risk of acquiring nonsense mutations. The reduced exposure to this risk may contribute to the fitness of vertebrates. PMID- 21651782 TI - Early prediction of response to radiotherapy and androgen-deprivation therapy in prostate cancer by repeated functional MRI: a preclinical study. AB - BACKGROUND: In modern cancer medicine, morphological magnetic resonance imaging (MRI) is routinely used in diagnostics, treatment planning and assessment of therapeutic efficacy. During the past decade, functional imaging techniques like diffusion-weighted (DW) MRI and dynamic contrast-enhanced (DCE) MRI have increasingly been included into imaging protocols, allowing extraction of intratumoral information of underlying vascular, molecular and physiological mechanisms, not available in morphological images. Separately, pre-treatment and early changes in functional parameters obtained from DWMRI and DCEMRI have shown potential in predicting therapy response. We hypothesized that the combination of several functional parameters increased the predictive power. METHODS: We challenged this hypothesis by using an artificial neural network (ANN) approach, exploiting nonlinear relationships between individual variables, which is particularly suitable in treatment response prediction involving complex cancer data. A clinical scenario was elicited by using 32 mice with human prostate carcinoma xenografts receiving combinations of androgen-deprivation therapy and/or radiotherapy. Pre-radiation and on days 1 and 9 following radiation three repeated DWMRI and DCEMRI acquisitions enabled derivation of the apparent diffusion coefficient (ADC) and the vascular biomarker Ktrans, which together with tumor volumes and the established biomarker prostate-specific antigen (PSA), were used as inputs to a back propagation neural network, independently and combined, in order to explore their feasibility of predicting individual treatment response measured as 30 days post-RT tumor volumes. RESULTS: ADC, volumes and PSA as inputs to the model revealed a correlation coefficient of 0.54 (p < 0.001) between predicted and measured treatment response, while Ktrans, volumes and PSA gave a correlation coefficient of 0.66 (p < 0.001). The combination of all parameters (ADC, Ktrans, volumes, PSA) successfully predicted treatment response with a correlation coefficient of 0.85 (p < 0.001). CONCLUSIONS: We have in a preclinical investigation showed that the combination of early changes in several functional MRI parameters provides additional information about therapy response. If such an approach could be clinically validated, it may become a tool to help identifying non-responding patients early in treatment, allowing these patients to be considered for alternative treatment strategies, and, thus, providing a contribution to the development of individualized cancer therapy. PMID- 21651783 TI - Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. AB - BACKGROUND: The relationship between relative metabolic disturbances and developmental disorders is an emerging research focus. This study compares the nutritional and metabolic status of children with autism with that of neurotypical children and investigates the possible association of autism severity with biomarkers. METHOD: Participants were children ages 5-16 years in Arizona with Autistic Spectrum Disorder (n = 55) compared with non-sibling, neurotypical controls (n = 44) of similar age, gender and geographical distribution. Neither group had taken any vitamin/mineral supplements in the two months prior to sample collection. Autism severity was assessed using the Pervasive Development Disorder Behavior Inventory (PDD-BI), Autism Treatment Evaluation Checklist (ATEC), and Severity of Autism Scale (SAS). Study measurements included: vitamins, biomarkers of vitamin status, minerals, plasma amino acids, plasma glutathione, and biomarkers of oxidative stress, methylation, sulfation and energy production. RESULTS: Biomarkers of children with autism compared to those of controls using a t-test or Wilcoxon test found the following statistically significant differences (p < 0.001): Low levels of biotin, plasma glutathione, RBC SAM, plasma uridine, plasma ATP, RBC NADH, RBC NADPH, plasma sulfate (free and total), and plasma tryptophan; also high levels of oxidative stress markers and plasma glutamate. Levels of biomarkers for the neurotypical controls were in good agreement with accessed published reference ranges. In the Autism group, mean levels of vitamins, minerals, and most amino acids commonly measured in clinical care were within published reference ranges.A stepwise, multiple linear regression analysis demonstrated significant associations between several groups of biomarkers with all three autism severity scales, including vitamins (adjusted R2 of 0.25-0.57), minerals (adj. R2 of 0.22-0.38), and plasma amino acids (adj. R2 of 0.22-0.39). CONCLUSION: The autism group had many statistically significant differences in their nutritional and metabolic status, including biomarkers indicative of vitamin insufficiency, increased oxidative stress, reduced capacity for energy transport, sulfation and detoxification. Several of the biomarker groups were significantly associated with variations in the severity of autism. These nutritional and metabolic differences are generally in agreement with other published results and are likely amenable to nutritional supplementation. Research investigating treatment and its relationship to the co morbidities and etiology of autism is warranted. PMID- 21651784 TI - Evidence that polymorphonuclear neutrophils infiltrate into the developing corpus luteum and promote angiogenesis with interleukin-8 in the cow. AB - BACKGROUND: After ovulation in the cow, the corpus luteum (CL) rapidly develops within a few days with angiogenesis and progesterone production. CL formation resembles an inflammatory response due to the influx of immune cells. Neutrophils play a role in host defense and inflammation, and secrete chemoattractants to stimulate angiogenesis. We therefore hypothesized that neutrophils infiltrate in the developing CL from just after ovulation and may play a role in angiogenesis of the CL. METHODS AND RESULTS: Polymorphonuclear neutrophils (PMN) were detected in CL tissue by Pas-staining, and interleukin-8 (IL-8, a neutrophil-specific chemoattractant) was measured in supernatant of the CL tissue culture: considerable amounts of PMNs and the high level of IL-8 were observed during the early luteal phase (days 1-4 of the estrous cycle). PMNs and IL-8 were low levels in the mid and late luteal phases, but IL-8 was increased during luteal regression. The PMN migration in vitro was stimulated by the supernatant from the early CL but not from the mid CL, and this activity was inhibited by neutralizing with an anti-IL-8 antibody, indicating the major role of IL-8 in inducing active PMN migration in the early CL. Moreover, IL-8 stimulated proliferation of CL derived endothelial cells (LECs), and both the supernatant of activated PMNs and IL-8 stimulated formation of capillary-like structures of LECs. CONCLUSION: PMNs migrate into the early CL partially due to its major chemoattractant IL-8 produced at high levels in the CL, and PMNs is a potential regulator of angiogenesis together with IL-8 in developing CL in the cow. PMID- 21651785 TI - The timing of elective caesarean delivery between 2000 and 2009 in England. AB - BACKGROUND: In 2004, the National Institute for Clinical Excellence (NICE) recommended that an elective caesarean section for an uncomplicated pregnancy should not be carried out before 39 completed weeks due to increased risk of respiratory morbidity in newborns. We describe the trends and variation across 63 English NHS trusts in the timing of elective caesarean section (CS) for low-risk singleton deliveries. METHODS: We identified elective CS deliveries between 1st April 2000 and 28th February 2009 in English NHS trusts using the Hospital Episode Statistics. We selected women with uncomplicated pregnancies who had an elective CS delivery after 34 completed weeks of gestation, and analysed the trends and the trust-level variation in the timing of elective CS. The impact of the NICE guidance on the monthly rate of elective CS deliveries performed after 39 weeks was estimated using an interrupted time-series design with autoregressive integrated moving average (ARIMA). RESULTS: There were 118,456 elective CS deliveries at the 63 NHS trusts. The overall proportion of elective CS deliveries done after 39 completed weeks steadily increased from 39% in 2000/01 to 63% in 2008/09. The proportions rose from 43% to 67% for women with breech presentation and from 35% to 62% for women with a previous CS. There was significant variation across NHS trusts in each year; in 2008/09, with the proportions of elective CS done after 39 weeks ranging from 28% to 89% (Inter quartile range limits: 54% to 72%). We found a small but statistically significant increase in the proportion immediately after the publication of the NICE guidance, but its rate of growth rate declined slightly thereafter. CONCLUSIONS: NHS trusts in our study have responded to the new evidence on the benefits of delaying elective CS to after 39 weeks gestation. However, substantial differences between NHS trusts remain, which indicates there is room for further improvement. We suggest that maternity services and commissioners adopt the "timing of elective caesarean" as a quality indicator to support clinical practice. PMID- 21651786 TI - Molecular interplay between leptin, insulin-like growth factor-1, and beta amyloid in organotypic slices from rabbit hippocampus. AB - BACKGROUND: Evidence shows that the insulin-like growth factor-1 (IGF-1) and leptin reduce beta-amyloid (Abeta) production and tau phosphorylation, two major hallmarks of Alzheimer's disease (AD). IGF-1 expression involves the JAK/STAT pathway and the expression of leptin is regulated by the mammalian target of rapamycin complex 1 (mTORC1). We have previously shown that Abeta reduces leptin by inhibiting the mTORC1 pathway and Abeta was also suggested to inhibit the JAK/STAT pathway, potentially attenuating IGF-1 expression. As IGF-1 can activate mTORC1 and leptin can modulate JAK/STAT pathway, we determined the extent to which IGF-1 and leptin can upregulate the expression of one another and protect against Abeta-induced downregulation. RESULTS: We demonstrate that incubation of organotypic slices from adult rabbit hippocampus with Abeta42 downregulates IGF-1 expression by inhibiting JAK2/STAT5 pathway. Leptin treatment reverses these Abeta42 effects on IGF-1 and treatment with the STAT5 inhibitor completely abrogated the leptin-induced increase in IGF-1. Furthermore, EMSA and ChIP analyses revealed that leptin increases the STAT5 binding to the IGF-1 promoter. We also show that IGF-1 increases the expression of leptin and reverses the Abeta42-induced attenuation in leptin expression via the activation of mTORC1 signaling as the mTORC1 inhibitor rapamycin completely precluded the IGF-1 induced increase in leptin expression. CONCLUSION: Our results demonstrate for the first time that Abeta42 downregulates IGF-1 expression and that leptin and IGF-1 rescue one another from downregulation by Abeta42. Our study provides a valuable insight into the leptin/IGF-1/Abeta interplay that may be relevant to the pathophysiology of AD. PMID- 21651787 TI - Treatment of uncomplicated malaria at public health facilities and medicine retailers in south-eastern Nigeria. AB - BACKGROUND: At primary care facilities in Nigeria, national treatment guidelines state that malaria should be symptomatically diagnosed and treated with artemisinin-based combination therapy (ACT). Evidence from households and health care providers indicates that many patients do not receive the recommended treatment. This study sought to determine the extent of the problem by collecting data as patients and caregivers leave health facilities, and determine what influences the treatment received. METHODS: A cross-sectional cluster survey of 2,039 respondents exiting public health centres, pharmacies and patent medicine dealers was undertaken in urban and rural settings in Enugu State, south-eastern Nigeria. RESULTS: Although 79% of febrile patients received an anti-malarial, only 23% received an ACT. Many patients (38%) received sulphadoxine-pyrimethamine (SP). A further 13% of patients received an artemisinin-derivative as a monotherapy. An estimated 66% of ACT dispensed was in the correct dose. The odds of a patient receiving an ACT was highly associated with consumer demand (OR: 55.5, p < 0.001). CONCLUSION: Few febrile patients attending public health facilities, pharmacies and patent medicine dealers received an ACT, and the use of artemisinin-monotherapy and less effective anti-malarials is concerning. The results emphasize the importance of addressing both demand and supply-side influences on malaria treatment and the need for interventions that target consumer preferences as well as seek to improve health service provision. PMID- 21651788 TI - Ionizing radiation and inhibition of angiogenesis in a spontaneous mammary carcinoma and in a syngenic heterotopic allograft tumor model: a comparative study. AB - BACKGROUND: The combined treatment modality of ionizing radiation (IR) with inhibitors of angiogenesis (IoA) is a promising treatment modality based on preclinical in vivo studies using heterotopic xeno- and allograft tumor models. Nevertheless reservations still exist to translate this combined treatment modality into clinical trials, and more advanced, spontaneous orthotopic tumor models are required for validation to study the efficacy and safety of this treatment modality. FINDINGS: We therefore investigated the combined treatment modality of IR in combination with the clinically relevant VEGF receptor (VEGFR) tyrosine kinase inhibitor PTK787 in the MMTV/c-neu induced mammary carcinoma model and a syngenic allograft tumor model using athymic nude mice. Mice were treated with fractionated IR, the VEGFR-inhibitor PTK787/ZK222584 (PTK787), or in combination, and efficacy and mechanistic-related endpoints were probed in both tumor models. Overall the treatment response to the IoA was comparable in both tumor models, demonstrating minimal tumor growth delay in response to PTK787 and PTK787-induced tumor hypoxia. Interestingly spontaneously growing tumors were more radiosensitive than the allograft tumors. More important combined treatment of irradiation with PTK787 resulted in a supraadditive tumor response in both tumor models with a comparable enhancement factor, namely 1.5 and 1.4 in the allograft and in the spontaneous tumor model, respectively. CONCLUSIONS: These results demonstrate that IR in combination with VEGF-receptor tyrosine kinase inhibitors is a valid, promising treatment modality, and that the treatment responses in spontaneous mammary carcinomas and syngenic allografts tumor models are comparable. PMID- 21651789 TI - Impacts of traditional food consumption advisories: compliance, changes in diet and loss of confidence in traditional foods. AB - BACKGROUND: Food consumption advisories are often posted when industrial activities are expected to affect the quality and availability of traditional foods used by First Nations. We were recently involved in a project and asked to summarize details regarding the impacts of traditional food consumption advisories with respect to compliance, broader changes in diet and loss of confidence in traditional foods by people. METHODS: Our review was not conducted as a formal systematic comprehensive review; rather, we focused on primary and grey literature presenting academic, health practitioner and First Nations viewpoints on the topic available from literature databases (i.e., PubMed, Web of Knowledge (SM)) as well as the internet search engine Google. Some information came from personal communications. RESULTS: Our overview suggests that when communicated effectively and clearly, and when community members are involved in the process, consumption advisories can result in a decrease in contaminant load in people. On the other hand, consumption advisories can lead to cultural loss and have been linked to a certain amount of social, psychological, nutritional, economic and lifestyle disruption. In some cases, communities have decided to ignore consumption advisories opting to continue with traditional lifestyles believing that the benefits of doing so outweigh the risk of following advisories. CONCLUSIONS: We identified that there are both positive and negative aspects to the issuance of traditional food consumption advisories. A number of variables need to be recognized during the development and implementation of advisories in order to ensure a balance between human health, maintenance of cultures and industrial activity. PMID- 21651790 TI - Alternative splicing of the Anopheles gambiae Dscam gene in diverse Plasmodium falciparum infections. AB - BACKGROUND: In insects, including Anopheles mosquitoes, Dscam (Down syndrome cell adhesion molecule) appears to be involved in phagocytosis of pathogens, and shows pathogen-specific splice-form expression between divergent pathogen (or parasite) types (e.g. between bacteria and Plasmodium or between Plasmodium berghei and Plasmodium falciparum). Here, data are presented from the first study of Dscam expression in response to genetic diversity within a parasite species. METHODS: In independent field and laboratory studies, a measure of Dscam splice-form diversity was compared between mosquitoes fed on blood that was free of P. falciparum to mosquitoes exposed to either single or mixed genotype infections of P. falciparum. RESULTS: Significant increases in Anopheles gambiae Dscam (AgDscam) receptor diversity were observed in parasite-exposed mosquitoes, but only weak evidence that AgDscam diversity rises further upon exposure to mixed genotype parasite infections was found. Finally, a cluster of AgDscam exon 4 variants that become especially common during Plasmodium invasion was identified. CONCLUSIONS: While the data clearly indicate that AgDscam diversity increases with P. falciparum exposure, they do not suggest that AgDscam diversity rises further in response to increased parasite diversity. PMID- 21651792 TI - Towards an Age-Phenome Knowledge-base. AB - BACKGROUND: Currently, data about age-phenotype associations are not systematically organized and cannot be studied methodically. Searching for scientific articles describing phenotypic changes reported as occurring at a given age is not possible for most ages. RESULTS: Here we present the Age-Phenome Knowledge-base (APK), in which knowledge about age-related phenotypic patterns and events can be modeled and stored for retrieval. The APK contains evidence connecting specific ages or age groups with phenotypes, such as disease and clinical traits. Using a simple text mining tool developed for this purpose, we extracted instances of age-phenotype associations from journal abstracts related to non-insulin-dependent Diabetes Mellitus. In addition, links between age and phenotype were extracted from clinical data obtained from the NHANES III survey. The knowledge stored in the APK is made available for the relevant research community in the form of 'Age-Cards', each card holds the collection of all the information stored in the APK about a particular age. These Age-Cards are presented in a wiki, allowing community review, amendment and contribution of additional information. In addition to the wiki interaction, complex searches can also be conducted which require the user to have some knowledge of database query construction. CONCLUSIONS: The combination of a knowledge model based repository with community participation in the evolution and refinement of the knowledge base makes the APK a useful and valuable environment for collecting and curating existing knowledge of the connections between age and phenotypes. PMID- 21651791 TI - Antagonistic Gcn5-Hda1 interactions revealed by mutations to the Anaphase Promoting Complex in yeast. AB - BACKGROUND: Histone post-translational modifications are critical for gene expression and cell viability. A broad spectrum of histone lysine residues have been identified in yeast that are targeted by a variety of modifying enzymes. However, the regulation and interaction of these enzymes remains relatively uncharacterized. Previously we demonstrated that deletion of either the histone acetyltransferase (HAT) GCN5 or the histone deacetylase (HDAC) HDA1 exacerbated the temperature sensitive (ts) mutant phenotype of the Anaphase Promoting Complex (APC) apc5CA allele. Here, the apc5CA mutant background is used to study a previously uncharacterized functional antagonistic genetic interaction between Gcn5 and Hda1 that is not detected in APC5 cells. RESULTS: Using Northerns, Westerns, reverse transcriptase PCR (rtPCR), chromatin immunoprecipitation (ChIP), and mutant phenotype suppression analysis, we observed that Hda1 and Gcn5 appear to compete for recruitment to promoters. We observed that the presence of Hda1 can partially occlude the binding of Gcn5 to the same promoter. Occlusion of Gcn5 recruitment to these promoters involved Hda1 and Tup1. Using sequential ChIP we show that Hda1 and Tup1 likely form complexes at these promoters, and that complex formation can be increased by deleting GCN5. CONCLUSIONS: Our data suggests large Gcn5 and Hda1 containing complexes may compete for space on promoters that utilize the Ssn6/Tup1 repressor complex. We predict that in apc5CA cells the accumulation of an APC target may compensate for the loss of both GCN5 and HDA1. PMID- 21651793 TI - Do existing research summaries on health systems match immunisation managers' needs in middle- and low-income countries? Analysis of GAVI health systems strengthening support. AB - BACKGROUND: The GAVI Alliance was created in 2000 to increase access to vaccines. More recently, GAVI has supported evidence-based health systems strengthening to overcome barriers to vaccination. Our objectives were: to explore countries' priorities for health systems strengthening; to describe published research summaries for each priority area in relation to their number, quality and relevance; and to describe the use of national data from surveys in identifying barriers to immunisation. METHODS: From 44 health systems strengthening proposals submitted to GAVI in 2007 and 2008, we analysed the topics identified, the coverage of these topics by existing systematic reviews and the use of nation wide surveys with vaccination data to justify the needs identified in the proposals. RESULTS: Thirty topics were identified and grouped into three thematic areas: health workforce (10 topics); organisation and management (14); and supply, distribution and maintenance (6). We found 51 potentially relevant systematic reviews, although for the topic that appeared most frequently in the proposals ('Health information systems') no review was identified. Thematic and geographic relevance were generally categorised as "high" in 33 (65%) and 25 (49%) reviews, respectively, but few reviews were categorised as "highly relevant for policy" (7 reviews, 14%). With regard to methodological quality, 14 reviews (27%) were categorised as "high".The number of topics that were addressed by at least one high quality systematic review was: seven of the 10 topics in the 'health workforce' thematic area; six of the 14 topics in the area of 'organisation and management'; and none of the topics in the thematic area of 'supply, distribution and maintenance'. Only twelve of the 39 countries with available national surveys referred to them in their proposals. CONCLUSION: Relevant, high quality research summaries were found for few of the topics identified by managers. Few proposals used national surveys evidence to identify barriers to vaccination. Researchers generating or adapting evidence about health systems need to be more responsive to managers' needs. Use of available evidence from local or national surveys should be strongly encouraged. PMID- 21651794 TI - Reliability and validity of the Safe Routes to school parent and student surveys. AB - BACKGROUND: The purpose of this study is to assess the reliability and validity of the U.S. National Center for Safe Routes to School's in-class student travel tallies and written parent surveys. Over 65,000 tallies and 374,000 parent surveys have been completed, but no published studies have examined their measurement properties. METHODS: Students and parents from two Charlotte, NC (USA) elementary schools participated. Tallies were conducted on two consecutive days using a hand-raising protocol; on day two students were also asked to recall the previous days' travel. The recall from day two was compared with day one to assess 24-hour test-retest reliability. Convergent validity was assessed by comparing parent-reports of students' travel mode with student-reports of travel mode. Two-week test-retest reliability of the parent survey was assessed by comparing within-parent responses. Reliability and validity were assessed using kappa statistics. RESULTS: A total of 542 students participated in the in-class student travel tally reliability assessment and 262 parent-student dyads participated in the validity assessment. Reliability was high for travel to and from school (kappa > 0.8); convergent validity was lower but still high (kappa > 0.75). There were no differences by student grade level. Two-week test-retest reliability of the parent survey (n=112) ranged from moderate to very high for objective questions on travel mode and travel times (kappa range: 0.62-0.97) but was substantially lower for subjective assessments of barriers to walking to school (kappa range: 0.31-0.76). CONCLUSIONS: The student in-class student travel tally exhibited high reliability and validity at all elementary grades. The parent survey had high reliability on questions related to student travel mode, but lower reliability for attitudinal questions identifying barriers to walking to school. Parent survey design should be improved so that responses clearly indicate issues that influence parental decision making in regards to their children's mode of travel to school. PMID- 21651795 TI - Cigarette smoke induces beta2-integrin-dependent neutrophil migration across human endothelium. AB - BACKGROUND: Cigarette smoking induces peripheral inflammatory responses in all smokers and is the major risk factor for neutrophilic lung disease such as chronic obstructive pulmonary disease. The aim of this study was to investigate the effect of cigarette smoke on neutrophil migration and on beta2-integrin activation and function in neutrophilic transmigration through endothelium. METHODS AND RESULTS: Utilizing freshly isolated human PMNs, the effect of cigarette smoke on migration and beta2-integrin activation and function in neutrophilic transmigration was studied. In this report, we demonstrated that cigarette smoke extract (CSE) dose dependently induced migration of neutrophils in vitro. Moreover, CSE promoted neutrophil adherence to fibrinogen. Using functional blocking antibodies against CD11b and CD18, it was demonstrated that Mac-1 (CD11b/CD18) is responsible for the cigarette smoke-induced firm adhesion of neutrophils to fibrinogen. Furthermore, neutrophils transmigrated through endothelium by cigarette smoke due to the activation of beta2-integrins, since pre-incubation of neutrophils with functional blocking antibodies against CD11b and CD18 attenuated this transmigration. CONCLUSION: This is the first study to describe that cigarette smoke extract induces a direct migratory effect on neutrophils and that CSE is an activator of beta2-integrins on the cell surface. Blocking this activation of beta2-integrins might be an important target in cigarette smoke induced neutrophilic diseases. PMID- 21651796 TI - Genetic drift evolution under vaccination pressure among H5N1 Egyptian isolates. AB - BACKGROUND: The highly pathogenic H5N1 is a major avian pathogen that intensively affects the poultry industry in Egypt even in spite of the adoption of vaccination strategy. Antigenic drift is among the strategies the influenza virus uses to escape the immune system that might develop due to the pressure of extensive vaccination. H5N1 mutates in an intensified manner and is considered a potential candidate for the possible next pandemic with all the catastrophic consequences such an eventuality will entail. METHODS: H5N1 was isolated from the pooled organ samples of four different affected flocks in specific pathogen free embryonated chicken eggs (SPF-ECE). A reverse transcriptase polymerase chain reaction (RT-PCR) was performed to the haemagglutingin and neuraminidase. Sequencing of the full length haemagglutingin was performed. Sequence analyses of the isolated strains were performed and compared to all available H5N1 from Egyptian human and avian strains in the flu database. Changes in the different amino acid that may be related to virus virulence, receptor affinity and epitope configuration were assigned and matched with all available Egyptian strains in the flu database. RESULTS: One out of the four strains was found to be related to the B2 Egyptian lineage, 2 were related to A1 lineage and the 4th was related to A2 lineage. Comparing data obtained from the current study by other available Egyptian H5N1 sequences remarkably demonstrates that amino acid changes in the immune escape variants are remarkably restricted to a limited number of locations on the HA molecule during antigenic drift. Molecular diversity in the HA gene, in relevance to different epitopes, were not found to follow a regular trend, suggesting abrupt cumulative sequence mutations. However a number of amino acids were found to be subjected to high mutation pressure. CONCLUSION: The current data provides a comprehensive view of HA gene evolution among H5N1 subtype viruses in Egypt. Egyptian H5N1-AIVs are constantly undergoing genetic changes and reveal a complex pattern of drifts. These findings raise the concerns about the value of using influenza vaccines in correlation with the development of antigenic drift in influenza epidemics. PMID- 21651797 TI - Effectiveness of compounded bioidentical hormone replacement therapy: an observational cohort study. AB - BACKGROUND: Bioidentical Hormone Replacement Therapy (BHRT) is believed it to be a safer and equally effective alternative to Conventional Hormone Therapy for the relief of menopausal symptoms; however, data are needed to support these claims. The objective of this study is to evaluate the effectiveness of compounded BHRT provided in six community pharmacies. METHODS: This was an observational cohort study of women between the ages of 18-89 who received a compounded BHRT product from January 1, 2003 to April 30, 2010 in six community pharmacies. Data included patient demographics, comorbidities, therapeutic outcomes, and hormone therapies. Women self-rated menopausal symptoms as absent, mild, moderate, or severe. Descriptive statistics were used to characterize the patient population, BHRT use, and adverse events. Patient symptom severity was compared at baseline and 3 to 6 months follow-up using the Wilcoxon signed-rank test. RESULTS: Women (n = 296) receiving BHRT at Oakdell Pharmacy had a mean (standard deviation) age of 52 (9) years. The most common BHRT dosage forms utilized were topical (71%) and oral (43%). Compounded BHRT regimens were generally initiated at low doses regardless of route. Women experienced a 25% decrease in emotional lability (p < 0.01), a 25% decrease in irritability (p < 0.01), and a 22% reduction in anxiety (p = 0.01) within 3 to 6 months. These women also experienced a 14% reduction in night sweats (p = 0.09) and a 6% reduction in hot flashes (p = 0.50). CONCLUSIONS: This study demonstrates that compounded BHRT improves mood symptoms. Larger studies are needed to examine the impact on vasomotor symptoms, myocardial infarction and breast cancer. PMID- 21651798 TI - Occupational segregation, gender essentialism and male primacy as major barriers to equity in HIV/AIDS caregiving: Findings from Lesotho. AB - BACKGROUND: Gender segregation of occupations, which typically assigns caring/nurturing jobs to women and technical/managerial jobs to men, has been recognized as a major source of inequality worldwide with implications for the development of robust health workforces. In sub-Saharan Africa, gender inequalities are particularly acute in HIV/AIDS caregiving (90% of which is provided in the home), where women and girls make up the informal (and mostly unpaid) workforce. Men's and boy's entry into HIV/AIDS caregiving in greater numbers would both increase the equity and sustainability of national and community-level HIV/AIDS caregiving and mitigate health workforce shortages, but notions of gender essentialism and male primacy make this far from inevitable.In 2008 the Capacity Project partnered with the Lesotho Ministry of Health and Social Welfare in a study of the gender dynamics of HIV/AIDS caregiving in three districts of Lesotho to account for men's absence in HIV/AIDS caregiving and investigate ways in which they might be recruited into the community and home based care (CHBC) workforce. METHODS: The study used qualitative methods, including 25 key informant interviews with village chiefs, nurse clinicians, and hospital administrators and 31 focus group discussions with community health workers, community members, ex-miners, and HIV-positive men and women. RESULTS: Study participants uniformly perceived a need to increase the number of CHBC providers to deal with the heavy workload from increasing numbers of patients and insufficient new entries. HIV/AIDS caregiving is a gender-segregated job, at the core of which lie stereotypes and beliefs about the appropriate work of men and women. This results in an inequitable, unsustainable burden on women and girls. Strategies are analyzed for their potential effectiveness in increasing equity in caregiving. CONCLUSIONS: HIV/AIDS and human resources stakeholders must address occupational segregation and the underlying gender essentialism and male primacy if there is to be more equitable sharing of the HIV/AIDS caregiving burden and any long-term solution to health worker shortages. Policymakers, activists and programmers must redress the persistent disadvantages faced by the mostly female caregiving workforce and the gendered economic, psychological, and social impacts entailed in HIV/AIDS caregiving. Research on gender desegregation of HIV/AIDS caregiving is needed. PMID- 21651799 TI - Dose-response relationship for breast cancer induction at radiotherapy dose. AB - PURPOSE: Cancer induction after radiation therapy is known as a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the patient to be treated including breast cancer. MATERIALS AND METHODS: In this work a dose-response relationship for breast cancer is derived based on(i) the analysis of breast cancer induction after Hodgkin's disease,(ii) a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and(iii) the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy,(iv) the breast cancer induction of the A-bomb survivor data. RESULTS: The fitted model parameters for an alpha/beta = 3 Gy were alpha = 0.067Gy-1 and R = 0.62. The risk for breast cancer is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 20 Gy and drops off only slightly at larger doses. The predicted EAR for breast cancer after radiotherapy of Hodgkin's disease is 11.7/10000PY which can be compared to the findings of several epidemiological studies where EAR for breast cancer varies between 10.5 and 29.4/10000PY. The model was used to predict the impact of the reduction of radiation volume on breast cancer risk. It was estimated that mantle field irradiation is associated with a 3.2-fold increased risk compared with mediastinal irradiation alone, which is in agreement with a published value of 2.7. It was also shown that the modelled age dependency of breast cancer risk is in satisfying agreement with published data. CONCLUSIONS: The dose-response relationship obtained in this report can be used for the prediction of radiation induced secondary breast cancer of radiotherapy patients. PMID- 21651800 TI - Cognitive and cognitive-motor interventions affecting physical functioning: a systematic review. AB - BACKGROUND: Several types of cognitive or combined cognitive-motor intervention types that might influence physical functions have been proposed in the past: training of dual-tasking abilities, and improving cognitive function through behavioral interventions or the use of computer games. The objective of this systematic review was to examine the literature regarding the use of cognitive and cognitive-motor interventions to improve physical functioning in older adults or people with neurological impairments that are similar to cognitive impairments seen in aging. The aim was to identify potentially promising methods that might be used in future intervention type studies for older adults. METHODS: A systematic search was conducted for the Medline/Premedline, PsycINFO, CINAHL and EMBASE databases. The search was focused on older adults over the age of 65. To increase the number of articles for review, we also included those discussing adult patients with neurological impairments due to trauma, as these cognitive impairments are similar to those seen in the aging population. The search was restricted to English, German and French language literature without any limitation of publication date or restriction by study design. Cognitive or cognitive-motor interventions were defined as dual-tasking, virtual reality exercise, cognitive exercise, or a combination of these. RESULTS: 28 articles met our inclusion criteria. Three articles used an isolated cognitive rehabilitation intervention, seven articles used a dual-task intervention and 19 applied a computerized intervention. There is evidence to suggest that cognitive or motor cognitive methods positively affects physical functioning, such as postural control, walking abilities and general functions of the upper and lower extremities, respectively. The majority of the included studies resulted in improvements of the assessed functional outcome measures. CONCLUSIONS: The current evidence on the effectiveness of cognitive or motor-cognitive interventions to improve physical functioning in older adults or people with neurological impairments is limited. The heterogeneity of the studies published so far does not allow defining the training methodology with the greatest effectiveness. This review nevertheless provides important foundational information in order to encourage further development of novel cognitive or cognitive-motor interventions, preferably with a randomized control design. Future research that aims to examine the relation between improvements in cognitive skills and the translation to better performance on selected physical tasks should explicitly take the relation between the cognitive and physical skills into account. PMID- 21651801 TI - An XMRV derived retroviral vector as a tool for gene transfer. AB - BACKGROUND: Retroviral vectors are widely used tools for gene delivery and gene therapy. They are useful for gene expression studies and genetic manipulation in vitro and in vivo. Many retroviral vectors are derived from the mouse gammaretrovirus, murine leukemia virus (MLV). These vectors have been widely used in gene therapy clinical trials. XMRV, initially found in prostate cancer tissue, was the first human gammaretrovirus described. FINDINGS: We developed a new retroviral vector based on XMRV called pXC. It was developed for gene transfer to human cells and is produced by transient cotransfection of LNCaP cells with pXC and XMRV-packaging plasmids. CONCLUSIONS: We demonstrated that pXC mediates expression of inserted transgenes in cell lines. This new vector will be a useful tool for gene transfer in human and non-human cell lines, including gene therapy studies. PMID- 21651802 TI - Cellular transcriptional profiling in human lung epithelial cells infected by different subtypes of influenza A viruses reveals an overall down-regulation of the host p53 pathway. AB - BACKGROUND: Influenza viruses can modulate and hijack several cellular signalling pathways to efficiently support their replication. We recently investigated and compared the cellular gene expression profiles of human lung A549 cells infected by five different subtypes of human and avian influenza viruses (Josset et al. Plos One 2010). Using these transcriptomic data, we have focused our analysis on the modulation of the p53 pathway in response to influenza infection. RESULTS: Our results were supported by both RT-qPCR and western blot analyses and reveal multiple alterations of the p53 pathway during infection. A down-regulation of mRNA expression was observed for the main regulators of p53 protein stability during infection by the complete set of viruses tested, and a significant decrease in p53 mRNA expression was also observed in H5N1 infected cells. In addition, several p53 target genes were also down-regulated by these influenza viruses and the expression of their product reduced. CONCLUSIONS: Our data reveal that influenza viruses cause an overall down-regulation of the host p53 pathway and highlight this pathway and p53 protein itself as important viral targets in the altering of apoptotic processes and in cell-cycle regulation. PMID- 21651803 TI - Validation of a new hand-held electronic data capture method for continuous monitoring of subjective appetite sensations. AB - BACKGROUND: When large scale trials are investigating the effects of interventions on appetite, it is paramount to efficiently monitor large amounts of human data. The original hand-held Electronic Appetite Ratings System (EARS) was designed to facilitate the administering and data management of visual analogue scales (VAS) of subjective appetite sensations. The purpose of this study was to validate a novel hand-held method (EARS II (HP(r) iPAQ)) against the standard Pen and Paper (P&P) method and the previously validated EARS. METHODS: Twelve participants (5 male, 7 female, aged 18-40) were involved in a fully repeated measures design. Participants were randomly assigned in a crossover design, to either high fat (>48% fat) or low fat (<28% fat) meal days, one week apart and completed ratings using the three data capture methods ordered according to Latin Square. The first set of appetite sensations was completed in a fasted state, immediately before a fixed breakfast. Thereafter, appetite sensations were completed every thirty minutes for 4h. An ad libitum lunch was provided immediately before completing a final set of appetite sensations. RESULTS: Repeated measures ANOVAs were conducted for ratings of hunger, fullness and desire to eat. There were no significant differences between P&P compared with either EARS or EARS II (p > 0.05). Correlation coefficients between P&P and EARS II, controlling for age and gender, were performed on Area Under the Curve ratings. R2 for Hunger (0.89), Fullness (0.96) and Desire to Eat (0.95) were statistically significant (p < 0.05). CONCLUSIONS: EARS II was sensitive to the impact of a meal and recovery of appetite during the postprandial period and is therefore an effective device for monitoring appetite sensations. This study provides evidence and support for further validation of the novel EARS II method for monitoring appetite sensations during large scale studies. The added versatility means that future uses of the system provides the potential to monitor a range of other behavioural and physiological measures often important in clinical and free living trials. PMID- 21651804 TI - A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. AB - INTRODUCTION: Increasingly, derived estimates of glomerular filtration, such as the modification of diet in renal disease (MDRD) equation and Cockcroft-Gault (CG) formula are being employed in the intensive care unit (ICU). To date, these estimates have not been rigorously validated in those with augmented clearances, resulting in potentially inaccurate drug prescription. METHODS: Post-hoc analysis of prospectively collected data in two tertiary level ICU's in Australia and Portugal. Patients with normal serum creatinine concentrations manifesting augmented renal clearance (ARC) (measured creatinine clearance (CLCR) > 130 ml/min/1.73 m2) were identified by chart review. Comparison between measured values and MDRD and CG estimates were then undertaken. Spearman correlation coefficients (rs) were calculated to determine goodness of fit, and precision and bias were assessed using Bland-Altman plots. RESULTS: Eighty-six patients were included in analysis. The median [IQR] measured CLCR was 162 [145-190] ml/min/1.73 m2, as compared to 135 [116-171], 93 [83-110], 124[102-154], and 108 [87-135] ml/min/1.73 m2 estimated by CG, modified CG, 4-variable MDRD and 6 variable MDRD formulae. All of the equations significantly under-estimated the measured value, with CG displaying the smallest bias (39 ml/min/1.73 m2). Although a moderate correlation was noted between CLCR and CG (rs = 0.26, P = 0.017) and 4-variable MDRD (rs = 0.22, P = 0.047), neither had acceptable precision for clinical application in this setting. CG estimates had the highest sensitivity for correctly identifying patients with ARC (62%). CONCLUSIONS: Derived estimates of GFR are inaccurate in the setting of ARC, and should be interpreted with caution by the physician. A measured CLCR should be performed to accurately guide drug dosing. PMID- 21651805 TI - The Home-Based Older People's Exercise (HOPE) trial: study protocol for a randomised controlled trial. AB - BACKGROUND: Frailty is common in older age, and is associated with important adverse health outcomes including increased risk of disability and admission to hospital or long-term care. Exercise interventions for frail older people have the potential to reduce the risk of these adverse outcomes by increasing muscle strength and improving mobility. METHODS/DESIGN: The Home-Based Older People's Exercise (HOPE) trial is a two arm, assessor blind pilot randomised controlled trial (RCT) to assess the effectiveness of a 12 week exercise intervention (the HOPE programme) designed to improve the mobility and functional abilities of frail older people living at home, compared with usual care. The primary outcome is the timed-up-and-go test (TUGT), measured at baseline and 14 weeks post randomisation. Secondary outcomes include the Barthel Index of activities of daily living (ADL), EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life measure and the geriatric depression scale (GDS), measured at baseline and 14 weeks post-randomisation. We will record baseline frailty using the Edmonton Frail Scale (EFS), record falls and document muscle/joint pain. We will test the feasibility of collection of data to identify therapy resources required for delivery of the intervention. DISCUSSION: The HOPE trial will explore and evaluate a home-based exercise intervention for frail older people. Although previous RCTs have used operationalised, non-validated methods of measuring frailty, the HOPE trial is, to our knowledge, the first RCT of an exercise intervention for frail older people that includes a validated method of frailty assessment at baseline. TRIAL REGISTRATION: ISRCTN: ISRCTN57066881. PMID- 21651806 TI - Levosimendan and mortality after coronary revascularisation: a meta-analysis of randomised controlled trials. AB - INTRODUCTION: Patients undergoing coronary revascularization often require inotropic support that has been associated with an increased risk for death and morbidity. The purpose of this study was to evaluate the effect of levosimendan versus control on survival after coronary revascularization. METHODS: A systemic review and meta-analysis of the literature was carried out on published randomized controlled clinical trials that investigated the efficacy of levosimendan compared to other therapy in patients having coronary revascularisaion. The databases searched were Pubmed, EMBASE, the Cochrane Registry of Clinical Trials and the metaRegister of Controlled Trials. Studies that compared levosimendan to any other therapy for coronary revascularisation in adult humans and reported at least one outcome of interest were considered for inclusion. Both percutaneous coronary intervention and cardiac surgery were included. Data extraction was performed independently by two reviewers using predefined criteria. Relevant outcomes included mortality, cardiac index, cardiac enzymes, length of stay and post-procedural atrial fibrillation. RESULTS: The meta-analysis included 729 patients from 17 studies. Levosimendan was associated with a mortality reduction after coronary revascularization, (19/386 in the levosimendan group vs 39/343 in the control arm) odds ratio (OR) 0.40 (95% confidence interval (CI) 0.21 to 0.76, P for overall effect 0.005, P for heterogeneity = 0.33, I2 = 12% with a total of 729 patients. Levosimendan also had a favourable effect on cardiac index (standardised mean difference 1.63, 95% CI 1.43 to 1.83, P for overall effect < 0.00001), length of intensive care stay (random effects model, mean difference - 26.18 hours 95% CI 46.20 to 6.16, P for heterogeneity < 0.00001, I2 = 95%, P for overall effect P = 0.01), reductions in the rate of atrial fibrillation (OR 0.54, 95% CI 0.36 to 0.82, P for effect = 0.004, P for heterogeneity 0.84, I2 = 0% for 465 patients) and troponin I levels group (mean difference -1.59, 95% CI 1.78 to 1.40, P for overall effect < 0.00001, P for heterogeneity < 0.00001, I2 = 95%). Limitations of this analysis are discussed. CONCLUSIONS: Levosimendan is associated with a significant improvement in mortality after coronary revascularization. There are also improvements in several secondary endpoints. A suitably powered randomised controlled trial is required to confirm these findings and to address the unresolved questions about the timing and dosing of levosimendan. PMID- 21651807 TI - Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: a longitudinal observational study. AB - INTRODUCTION: Disease remission has become a feasible goal for most rheumatoid arthritis (RA) patients; however, patient-reported symptoms, such as pain, may persist despite remission. We assessed the prevalence of pain in RA patients in remission according to the Disease Activity Score (DAS28-CRP4) and the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria. METHODS: Data were analyzed from RA patients in the Brigham Rheumatoid Arthritis Sequential Study with data at baseline and 1 year. DAS28 remission was defined as DAS28-CRP4 <2.6. The ACR/EULAR remission criteria included (a) one or more swollen joints, (b) one or more tender joints, (c) C-reactive protein <=1 mg/dl, and (d) patient global assessment score <=1. Pain severity was measured by using the pain score from the Multi-Dimensional Health Assessment Questionnaire (MDHAQ). The associations between baseline clinical predictors and MDHAQ pain at baseline and 1 year were assessed by using multivariable linear regression. RESULTS: Among the 865 patients with data at baseline and 1 year, 157 (18.2%) met DAS28-CRP4 remission criteria at both time points. Thirty-seven (4.3%) met the ACR/EULAR remission criteria at baseline and 1 year. The prevalence of clinically significant pain (MDHAQ pain >=4) at baseline ranged from 11.9% among patients meeting DAS28-CRP4 remission criteria to none among patients meeting ACR/EULAR remission criteria. Patient global assessment, MDHAQ function, MDHAQ fatigue, MDHAQ sleep, and arthritis self-efficacy were significantly associated with MDHAQ pain in cross-sectional (P <= 0.0005) and longitudinal analyses (P <= 0.03). Low swollen-joint counts were associated with high MDHAQ pain in longitudinal analyses (P = 0.02) but not cross-sectional analyses. Other measures of inflammatory disease activity and joint damage were not significantly associated with MDHAQ pain at baseline or at 1 year. CONCLUSIONS: Clinically significant pain continues among a substantial proportion of patients in DAS28 remission but not among those in ACR/EULAR remission. Among patients in DAS28 remission, patient global assessment, disability, fatigue, sleep problems, and self-efficacy are strongly associated with pain severity at baseline and 1 year, whereas inflammatory disease activity and joint damage are not significantly associated with elevated pain severity at either baseline or 1 year. PMID- 21651808 TI - Endotoxemia in pediatric critical illness--a pilot study. AB - INTRODUCTION: The aim was to investigate the prevalence of endotoxemia in children admitted to pediatric intensive care unit (PICU), and its association with disease severity and outcome. METHODS: We conducted a prospective, observational cohort study of children admitted to PICU at St. Mary's Hospital, London over a 6-month period. One hundred consecutive patients were recruited. Demographic and clinical data were collected. Severity of illness was assessed by the pediatric index of mortality 2 (PIM2) score. The pediatric logistic organ dysfunction (PELOD) score was performed daily for the first 4 days. Patients were categorized according to primary reason for PICU admission. Blood samples were taken within 24 hours of admission and endotoxemia was measured using the endotoxin activity assay (EAA). Patients were stratified according to EAA level (high, EAA > 0.4, low, EAA < 0.4) and categorized as septic, post-surgical, respiratory or other. Data were analyzed using appropriate non-parametric tests. RESULTS: EAA level was significantly lower in PICU controls versus other PICU admissions (P = 0.01). Fifty-five children had endotoxemia on admission. Forty one (75%) of these were eventually diagnosed with an infectious cause of admission. Nine children without infection had elevated EAA on admission. An infectious cause of admission was significantly associated with endotoxemia (P < 0.005). Of 15 children with gram-negative infection, only 9 (60%) had endotoxemia on admission. Endotoxemia on admission was not associated with shock or death. However, there was a tendency for increased PELOD score and length of stay in endotoxemic children. CONCLUSIONS: Endotoxemia is common in children admitted to intensive care. Understanding the implications of endotoxemia and potential anti endotoxin strategies may have the potential to reduce severity of illness and length of PICU stay in critically ill children. PMID- 21651809 TI - Prevalence of severe mental distress and its correlates in a population-based study in rural south-west Uganda. AB - BACKGROUND: The problem of severe mental distress (SMD) in sub-Saharan Africa is difficult to investigate given that a substantial proportion of patients with SMD never access formal health care.This study set out to investigate SMD and it's associated factors in a rural population-based cohort in south-west Uganda. METHODS: 6,663 respondents aged 13 years and above in a general population cohort in southwestern Uganda were screened for probable SMD and possible associated factors. RESULTS: 0.9% screened positive for probable SMD. The factors significantly associated with SMD included older age, male sex, low socio economic status, being a current smoker, having multiple or no sexual partners in the past year, reported epilepsy and consulting a traditional healer. CONCLUSION: SMD in this study was associated with both socio-demographic and behavioural factors. The association between SMD and high risk sexual behaviour calls for the integration of HIV prevention in mental health care programmes in high HIV prevalence settings. PMID- 21651810 TI - NeurphologyJ: an automatic neuronal morphology quantification method and its application in pharmacological discovery. AB - BACKGROUND: Automatic quantification of neuronal morphology from images of fluorescence microscopy plays an increasingly important role in high-content screenings. However, there exist very few freeware tools and methods which provide automatic neuronal morphology quantification for pharmacological discovery. RESULTS: This study proposes an effective quantification method, called NeurphologyJ, capable of automatically quantifying neuronal morphologies such as soma number and size, neurite length, and neurite branching complexity (which is highly related to the numbers of attachment points and ending points). NeurphologyJ is implemented as a plugin to ImageJ, an open-source Java-based image processing and analysis platform. The high performance of NeurphologyJ arises mainly from an elegant image enhancement method. Consequently, some morphology operations of image processing can be efficiently applied. We evaluated NeurphologyJ by comparing it with both the computer-aided manual tracing method NeuronJ and an existing ImageJ-based plugin method NeuriteTracer. Our results reveal that NeurphologyJ is comparable to NeuronJ, that the coefficient correlation between the estimated neurite lengths is as high as 0.992. NeurphologyJ can accurately measure neurite length, soma number, neurite attachment points, and neurite ending points from a single image. Furthermore, the quantification result of nocodazole perturbation is consistent with its known inhibitory effect on neurite outgrowth. We were also able to calculate the IC50 of nocodazole using NeurphologyJ. This reveals that NeurphologyJ is effective enough to be utilized in applications of pharmacological discoveries. CONCLUSIONS: This study proposes an automatic and fast neuronal quantification method NeurphologyJ. The ImageJ plugin with supports of batch processing is easily customized for dealing with high-content screening applications. The source codes of NeurphologyJ (interactive and high-throughput versions) and the images used for testing are freely available (see Availability). PMID- 21651811 TI - Protein expression based multimarker analysis of breast cancer samples. AB - BACKGROUND: Tissue microarray (TMA) data are commonly used to validate the prognostic accuracy of tumor markers. For example, breast cancer TMA data have led to the identification of several promising prognostic markers of survival time. Several studies have shown that TMA data can also be used to cluster patients into clinically distinct groups. Here we use breast cancer TMA data to cluster patients into distinct prognostic groups. METHODS: We apply weighted correlation network analysis (WGCNA) to TMA data consisting of 26 putative tumor biomarkers measured on 82 breast cancer patients. Based on this analysis we identify three groups of patients with low (5.4%), moderate (22%) and high (50%) mortality rates, respectively. We then develop a simple threshold rule using a subset of three markers (p53, Na-KATPase-beta1, and TGF beta receptor II) that can approximately define these mortality groups. We compare the results of this correlation network analysis with results from a standard Cox regression analysis. RESULTS: We find that the rule-based grouping variable (referred to as WGCNA*) is an independent predictor of survival time. While WGCNA* is based on protein measurements (TMA data), it validated in two independent Affymetrix microarray gene expression data (which measure mRNA abundance). We find that the WGCNA patient groups differed by 35% from mortality groups defined by a more conventional stepwise Cox regression analysis approach. CONCLUSIONS: We show that correlation network methods, which are primarily used to analyze the relationships between gene products, are also useful for analyzing the relationships between patients and for defining distinct patient groups based on TMA data. We identify a rule based on three tumor markers for predicting breast cancer survival outcomes. PMID- 21651812 TI - Decreased therapeutic effects of noscapine combined with imatinib mesylate on human glioblastoma in vitro and the effect of midkine. AB - BACKGROUND: Glioblastoma (GBM) develops resistance to the advances in chemotherapy leading to poor prognosis and life quality. Consequently, new treatment modalities are needed. Our aims were to investigate the effects of combined noscapine (NOS) and imatinib mesylate (IM) on human GBM in vitro and the role of midkine (MK) in this new combination treatment. METHODS: Monolayer and spheroid cultures of T98G human GBM cell line were used to evaluate the effects of IM (10 MUM), Nos (10 MUM) and their combination on cell proliferation and apoptotic indexes, cell cycle, the levels of antiapoptotic MK, MRP-1, p170, PFGFR alpha, EGFR, bcl-2 proteins, apoptotic caspase-3 levels, morphology (SEM) and ultrastructure (TEM) for 72 hrs. Results were statistically analyzed using the Student's t-test. RESULTS: The combination group induced highest decrease in cell proliferation and apoptotic indexes, caspase-3 levels, MRP-1 and PDGFR-alpha levels. The decrease in p170 levels were lower than IM but higher that NOS. The highest increases were in EGFR, MK, bcl-2 and cAMP levels in the combination group. The G0+G1 cell cycle arrest at the end of 72nd hr was the lowest in the combination group. Apoptotic appearence was observed rarely both in the morphologic and ultrastructural evaluation of the combination group. In addition, autophagic vacuoles which were frequently observed in the IM group were observed rarely. CONCLUSIONS: The combination of Nos with IM showed antagonist effect in T98G human GBM cells in vitro. This antagonist effect was correlated highly with MK levels. The effects of NOS on MRP-1, MK and receptor tyrosine kinase levels were firstly demonstrated in our report. In addition, we proposed that MK is one of the modulator in the switch of autophagy to cell death or survival/resistance. PMID- 21651813 TI - Comparative study on the in vitro and in vivo properties of two bovine herpesvirus-5 reference strains. AB - BACKGROUND: Bovine herpesvirus 5 (BoHV-5) is an alphaherpesvirus responsible for meningoencephalitis in young cattle and it is antigenically and genetically related to bovine herpesvirus 1. BoHV-5 outbreaks are sporadic and restricted in their geographical distribution, being mostly detected in the Southern hemisphere. The N569 and A663 strains are prototypes of the "a" and "b" subtypes of BoHV-5, however, scarce information about their in vitro and in vivo properties is currently available. METHODS: For the in vitro comparison between BoHV-5 A663 and N569 strains, viral growth kinetics, lysis and infection plaque size assays were performed. Additionally, an experimental infection of cattle with BoHV-5 A663 and N569 strains was carried out. Viral excretion, development of neurological signs, presence of specific antibodies in serum and nasal swabs and presence of latent BoHV-5 DNA in trigeminal ganglion, were analyzed. Histopathological examination of samples belonging to inoculated animals was also performed. RESULTS: The lytic capacity and the cell-to-cell spread was lower for the A663 strain compared to the N569 strain, however, the production of total infectious viral particles was similar between both strains. Concerning the in vivo properties, the A663 and N569 strains are able to induce similar degrees of pathogenicity in cattle. CONCLUSIONS: Our results show that the A663 strain used in this study is less adapted to in vitro replication in MDBK cells than the N569 strain and, although slight differences were observed, both strains are able to induce a similar degree of virulence in the natural host. PMID- 21651814 TI - Workers dominate male production in the neotropical bumblebee Bombus wilmattae (Hymenoptera: Apidae). AB - BACKGROUND: Cooperation and conflict in social insects are closely linked to the genetic structure of the colony. Kin selection theory predicts conflict over the production of males between the workers and the queen and between the workers themselves, depending on intra-colonial relatedness but also on other factors like colony efficiency, sex ratios, cost of worker reproduction and worker dominance behaviour. In most bumblebee (Bombus) species the queen wins this conflict and often dominates male production. However, most studies in bumblebees have been conducted with only a few selected, mostly single mated species from temperate climate regions. Here we study the genetic colony composition of the facultative polyandrous neotropical bumblebee Bombus wilmattae, to assess the outcome of the queen-worker conflict over male production and to detect potential worker policing. RESULTS: A total of 120 males from five colonies were genotyped with up to nine microsatellite markers to infer their parentage. Four of the five colonies were queen right at point of time of male sampling, while one had an uncertain queen status. The workers clearly dominated production of males with an average of 84.9% +/- 14.3% of males being worker sons. In the two doubly mated colonies 62.5% and 96.7% of the male offspring originated from workers and both patrilines participated in male production. Inferring the mother genotypes from the male offspring, between four to eight workers participated in the production of males. CONCLUSIONS: In this study we show that the workers clearly win the queen-worker conflict over male production in B. wilmattae, which sets them apart from the temperate bumblebee species studied so far. Workers clearly dominated male production in the singly as well the doubly mated colonies, with up to eight workers producing male offspring in a single colony. Moreover no monopolization of reproduction by single workers occurred. PMID- 21651815 TI - Best practices for an insecticide-treated bed net distribution programme in sub Saharan eastern Africa. AB - Insecticide-treated bed nets are the preeminent malaria control means; though there is no consensus as to a best practice for large-scale insecticide-treated bed net distribution. In order to determine the paramount distribution method, this review assessed literature on recent insecticide treated bed net distribution programmes throughout sub-Saharan Eastern Africa. Inclusion criteria were that the study had taken place in sub-Saharan Eastern Africa, targeted malaria prevention and control, and occurred between 1996 and 2007. Forty-two studies were identified and reviewed. The results indicate that distribution frameworks varied greatly; and consequently so did outcomes of insecticide treated bed net use. Studies revealed consistent inequities between urban and rural populations; which were most effectively alleviated through a free insecticide-treated bed net delivery and distribution framework. However, cost sharing through subsidies was shown to increase programme sustainability, which may lead to more long-term coverage. Thus, distribution should employ a catch up/keep up programme strategy. The catch-up programme rapidly scales up coverage, while the keep-up programme maintains coverage levels. Future directions for malaria should include progress toward distribution of long-lasting insecticide treated nets. PMID- 21651816 TI - Headache and musculoskeletal complaints among subjects with self reported whiplash injury: the HUNT-2 study. AB - BACKGROUND: To evaluate the life-time prevalence of self reported whiplash injury and the relationship to chronic musculoskeletal complaints (MSCs) and headache in a large unselected adult population. METHODS: Between 1995 and 1997, all inhabitants 20 years and older in Nord-Trondelag county in Norway were invited to a comprehensive health survey. Out of 92,936 eligible for participation, a total of 59,104 individuals (63.6%) answered the question about whiplash injury (whiplash). Among these, 46,895 (79.3%) responded to the questions of musculoskeletal complaints and headache. RESULTS: The total life-time prevalence of self reported whiplash injury was 2.9%, for women 2.7% and for men 3.0%. There was a significant association between self reported whiplash injury and headache (OR = 2.1; 95% CI 1.8-2.4), and chronic MSCs (OR = 3.3; 95% CI 2.8-3.8), evident for all ten anatomical sites investigated. The association was most pronounced for those with a combination of headache and chronic MSC for both men (OR = 4.8; 95% CI 3.6-6.2) and women (OR = 5.2; 95% CI 3.7-7.1). CONCLUSIONS: Subjects with self reported whiplash injury had significantly more headache and musculoskeletal complaints than those without, and may in part be due to selective reporting. The causal mechanism remains unclear and cannot be addressed in the present study design. PMID- 21651817 TI - Devolution and human resources in primary healthcare in rural Mali. AB - Devolution, as other types of decentralization (e.g. deconcentration, delegation, privatization), profoundly changes governance relations in the health system. Devolution is meant to affect performance of the health system by transferring responsibilities and authority to locally elected governments. The key question of this article is: what does devolution mean for human resources for health in Mali?This article assesses the key advantages and dilemmas associated with devolution such as responsiveness to local needs, downward accountability and health worker retention. Challenges of politics and capacities are also addressed in relation to human resources for health at the local level. Examples are derived from experiences in Mali with a capacity development programme and from case studies of other countries. It is not research findings that are presented, but highlights of key issues at stake aimed at inspiring the debate in Mali and elsewhere.A first lesson from the discussion suggests that in the context of human resources for health, decentralization of authority and resources is not the main issue. The challenge is to develop or strengthen accountability of those who decide and act, whether they are local politicians, bureaucrats or community representatives. If decentralization policies do not address public accountability, they will not fundamentally change human resource management, quality and equity of staffing. A second lesson is that successful devolution requires innovations in capacity development of all actors involved and in designing effective incentive measures. A final key conclusion is that the topic of devolution policy and its effects on human resources for health, and vice versa, merit more attention. A better understanding may lead to more appropriate policy designs and better preparation for the actors involved in countries that are embarking on decentralization, as is the case in Mali. PMID- 21651818 TI - A spectroscopy approach to the study of virus infection in the endophytic fungus Epichloe festucae. AB - BACKGROUND: In this work we propose a rapid method based on visible and near infrared (Vis-NIR) spectroscopy to determine the occurrence of double-stranded RNA (dsRNA) viruses in Epichloe festucae strains isolated from Festuca rubra plants. In addition, we examined the incidence of infections by E. festucae in populations of F. rubra collected in natural grasslands of Western Spain. METHODS: Vis-NIR spectra (400-2498 nm) from 124 virus-infected and virus-free E. festucae isolates were recorded directly from ground and freeze-dried mycelium. To estimate how well the spectra for uninfected and infected fungal samples could be differentiated, we used partial least-squares discriminant analysis (PLS1-DA) and several data pre-treatments to develop calibration models. RESULTS: Applying the best regression model, obtained with two sampling years and using standard normal variate (SNV) combined with first derivative transformation to a new validating data set (42 samples), we obtained a correct classification for 75% of the uninfected isolates and up to 86% of the infected isolates. CONCLUSIONS: The results obtained suggest that Vis-NIR spectroscopy is a promising technology for detection of viral infections in fungal samples when an alternative faster approach is desirable. It provides a tool adequately exact and more time- and cost-saving than the conventional reference analysis. PMID- 21651819 TI - Post-discharge management following hip fracture--get you back to B4: a parallel group, randomized controlled trial study protocol. AB - BACKGROUND: Fall-related hip fractures result in significant personal and societal consequences; importantly, up to half of older adults with hip fracture never regain their previous level of mobility. Strategies of follow-up care for older adults after fracture have improved investigation for osteoporosis; but managing bone health alone is not enough. Prevention of fractures requires management of both bone health and falls risk factors (including the contributing role of cognition, balance and continence) to improve outcomes. METHODS/DESIGN: This is a parallel group, pragmatic randomized controlled trial to test the effectiveness of a post-fracture clinic compared with usual care on mobility for older adults following their hospitalization for hip fracture. Participants randomized to the intervention will attend a fracture follow-up clinic where a geriatrician and physiotherapist will assess and manage their mobility and other health issues. Depending on needs identified at the clinical assessment, participants may receive individualized and group-based outpatient physiotherapy, and a home exercise program. Our primary objective is to assess the effectiveness of a novel post-discharge fracture management strategy on the mobility of older adults after hip fracture. We will enrol 130 older adults (65 years+) who have sustained a hip fracture in the previous three months, and were admitted to hospital from home and are expected to be discharged home. We will exclude older adults who prior to the fracture were: unable to walk 10 meters; diagnosed with dementia and/or significant comorbidities that would preclude their participation in the clinical service. Eligible participants will be randomly assigned to the Intervention or Usual Care groups by remote allocation. Treatment allocation will be concealed; investigators, measurement team and primary data analysts will be blinded to group allocation. Our primary outcome is mobility, operationalized as the Short Physical Performance Battery at 12 months. Secondary outcomes include frailty, rehospitalizations, falls risk factors, quality of life, as well as physical activity and sedentary behaviour. We will conduct an economic evaluation to determine health related costs in the first year, and a process evaluation to ascertain the acceptance of the program by older adults, as well as clinicians and staff within the clinic. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01254942. PMID- 21651820 TI - Peginterferon alpha-based therapy for chronic hepatitis B focusing on HBsAg clearance or seroconversion: a meta-analysis of controlled clinical trials. AB - BACKGROUND: Interferon alpha (IFNalpha) therapy has been widely used in the treatment of chronic hepatitis B (CHB) for decades. Nucleos(t)ide analogues are also increasingly used to treat CHB recently. More and more studies are being carried out concerning the clearance or seroconversion of HBsAg, which is recognized as an ideal goal of CHB therapy. This study conducted a meta-analysis to estimate the effect of pegylated interferon alpha (peginterferon alpha, PEG IFNalpha)-based therapy on HBsAg clearance or seroconversion in CHB. METHODS: All available controlled clinical trials, published from 2004 to 2010, with the following antiviral therapies for CHB patients: PEG-IFNalpha combined with lamivudine (LAM), PEG-IFNalpha only, conventional IFNalpha and LAM, with a course >=24 weeks, were meta-analysed for HBsAg clearance and seroconversion. RESULTS: Fourteen trials (involving a total of 2,682 patients) were identified, including seven high-quality and seven low-quality studies. The analysis results of the different antiviral therapies on HBsAg clearance or seroconversion were as follows: 1. No significant difference in HBsAg clearance or seroconversion was observed between the combination therapy group and PEG-IFNalpha monotherapy group [odds ratio (OR) = 1.16, 95% confidence intervals (CI) (0.73-1.85), P = 0.54 and OR = 1.07, 95% CI (0.58-1.97), P = 0.82, respectively]; 2. HBsAg clearance and seroconversion rates in patients with combination therapy were markedly higher than in those with LAM monotherapy [OR = 9.41, 95% CI (1.18-74.94), P = 0.03, and OR = 12.37, 95% CI (1.60-95.44), P = 0.02, respectively]; 3. There was significant difference in HBsAg clearance between the PEG-IFNalpha group and IFNalpha monotherapy group [OR = 4.95, 95% CI (1.23-20.00), P = 0.02], but not in seroconversion [OR = 2.44, 95% CI (0.35-17.08), P = 0.37]; 4. PEG-IFNalpha was superior to LAM in HBsAg seroconversion [OR = 14.59, 95% CI (1.91-111.49), P = 0.01]. CONCLUSIONS: PEG-IFNalpha facilitated HBsAg clearance or seroconversion in CHB patients. PEG-IFNalpha-based therapy was more effective than LAM monotherapy in achieving HBsAg clearance or seroconversion for both HBeAg-positive and HBeAg negative CHB patients. There was no significant difference in HBsAg clearance or seroconversion between PEG-IFNalpha/LAM combination therapy and PEG-IFNalpha monotherapy. PEG-IFNalpha was obviously superior to conventional IFNalpha in HBsAg clearance, but not in HBsAg seroconversion. Although PEG-IFNalpha produced significantly higher rates of HBsAg clearance and seroconversion, the absolute change in the proportion of HBsAg clearance and seroconversion was low (about 3 6%). Therefore, additional interventions are needed to improve the rate of positive outcomes. PMID- 21651821 TI - Insulin-Like Growth Factor-1 (IGF-1) Reduces ischemic changes and increases circulating angiogenic factors in experimentally - induced myocardial infarction in rats. AB - BACKGROUND: Coronary artery disease is a global health concern in the present day with limited therapies. Extensive efforts have been devoted to find molecular therapies to enhance perfusion and function of the ischemic myocardium. Aim of the present study was to look into the effects of insulin like growth factor -1 (IGF-1) on circulating angiogenic factors after myocardial ischemia in rats. METHODS: Adult male Sprague-Dawley rats were randomly divided into 10-days control, myocardial infarction, IGF-1 alone (2 MUg/rat/day) and ISO+IGF-1 groups. Isoproterenol (ISO), a synthetic catecholamine was used to induce myocardial infarction. Serum transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) levels were checked after 10-days of IGF-1 administration. RESULTS: There was a significant increase in heart weight after IGF-1 treatment. A significant increase in cardiac enzyme level (CK-MB and LDH) was seen in isoproterenol treated rats when compared to control group. IGF 1treatment induced a significant increase in serum angiogenic factors, IGF-1, VEGF and TGF beta levels. IGF-1 also reduced the ischemic changes in the myocardium when compared to the isoproterenol alone treated group. CONCLUSIONS: In conclusion, treatment with insulin-like growth factor-1 (IGF-1) in myocardial infarction significantly increased circulating angiogenic growth factors like IGF 1, VEGF and TGF beta thus, protecting against myocardial ischemia. PMID- 21651823 TI - The impact of endometrioma and laparoscopic cystectomy on serum anti-Mullerian hormone levels. AB - BACKGROUND: Serum anti-Mullerian hormone (AMH) had been proposed as a marker of ovarian reserve. The aim of this study was to evaluate the impact of endometrioma and laparoscopic cystectomy on ovarian reserve as measured by serum AMH levels. METHODS: A total of 1,642 patients were recruited in this retrospective analysis. Control group (group 1) included 1,323 infertility patients without endometrioma. Endometrioma group (group 2) included 141 patients with ovarian endometrioma. Previous cystectomy group (group 3) included 147 patients who underwent unilateral or bilateral laparoscopic cystectomy due to ovarian endometrioma more than 6 months before enrollment. Current cystectomy group (group 4) included 31 patients who underwent cystectomy during study period. Serum anti-mullerian hormone (AMH) levels were measured upon enrollment with all patients. For patients in group 4, AMH levels were measured before and 3 months after cystectomy. RESULTS: Mean AMH level of patients in control group was significantly higher than that of endometrioma group or previous cystectomy group in each age subgroup, while the mean serum AMH level of the endometrioma group was also significantly higher than that of the previous cystectomy group in each age subgroup. The mean AMH level was significantly lower in patients with previous bilateral cystectomy compared to that of patients with unilateral cystectomy. The mean serum AMH level was also significantly lower in patients with bilateral endometrioma compared to that of patients with unilateral endometrioma. In group 4, mean AMH level significantly decreased from 3.95 +/- 0.42 preoperation to 2.01 +/- 0.21 ng/ml at 3-month postoperation. CONCLUSIONS: Both ovarian endometrioma and cystectomy are associated with a significant reduction on ovarian reserve. Bilateral endometrioma exerts a more profound negative impact on ovarian reserve than unilateral endometrioma, regardless of either conservative or surgical intervention. PMID- 21651824 TI - No relationship between the distribution of mast cells and the survival of stage IIIB colon cancer patients. AB - BACKGROUND: Mast cells promote the progression of experimental tumors and might be a valuable therapeutic target. However, the relevant clinical evidence is still controversial. This study analyzed the relationship between the distribution of mast cells and the survival of patients with colon cancer to study whether mast cells contribute to tumor progression. MATERIALS AND METHODS: Ninety-three cases of pathologically confirmed primary cancer tissues matched with adjacent normal mucosa, metastases of regional-draining lymph nodes and regional-draining lymph nodes without metastases were collected from stage IIIB colon carcinoma patients between January 1997 and July 2004 at the Cancer Center of Sun Yat-Sen University. Tryptase-positive mast cells were counted. The relationships of the distribution of mast cells with clinicopathologic parameters and 5-year survival were analyzed. RESULTS: Although the mast cell count in the mucosa adjacent to the primary colon cancer was significantly higher than that in the stroma of the primary colon cancer, no difference in mast cell counts was observed between the stroma in lymph node metastasis and the lymph tissue adjacent to the metastasis. Additionally, the mast cell count in the regional draining lymph node without the invasion of cancer cells was significantly higher than that in the stroma of lymph node metastasis and adjacent lymph tissue. However, none of those mast cell counts was related to 5-year survival. CONCLUSION: Although mast cell count varied with location, none of the mast cell counts was related to 5-year survival, suggesting that mast cells do not contribute to the progression of stage IIIB colon cancer. PMID- 21651826 TI - Firm insoles effectively reduce hemolysis in runners during long distance running - a comparative study. AB - BACKGROUND: Shock absorbing insoles are effective in reducing the magnitude and rate of loading of peak impact forces generated at foot strike during running, whereas the foot impact force during running has been considered to be an important cause of intravascular hemolysis in long distance runners. Objective of this study was to evaluate the intravascular hemolysis during running and compare the effect of two different types of insoles (Soft and Firm) on hemolysis. METHODS: Twenty male long and middle distance runners volunteered to participate in this study. We selected two insoles (Soft and Firm) according to their hardness level (SHORE 'A' scale). Participants were randomly assigned to the soft insole (group 1) and firm insole (group 2) group with ten athletes in each group. Each athlete completed one hour of running at the calculated target heart rate (60-70%). Venous blood samples were collected before and immediately after running. We measured unconjucated bilirubin (mg/dl), lactate dehydrogenase (MU/ml), hemoglobin (g/l) and serum ferritin (ng/ml) as indicators of hemolysis. RESULTS: Our study revealed a significant increase in the mean values of unconjucated bilirubin (P < 0.05) while running with soft insoles indicating the occurrence of hemolysis in this group of athletes. Graphical analysis revealed an inverse relationship between hardness of insoles and hemolysis for the observed values. CONCLUSION: Our results indicate that intravascular hemolysis occurs in athletes during long distance running and we conclude that addition of firm insoles effectively reduces the amount of hemolysis in runners compared to soft insoles. PMID- 21651825 TI - Use of Chinese medicine by cancer patients: a review of surveys. AB - Chinese medicine has been used to treat a variety of cancer-related conditions. This study aims to examine the prevalence and patterns of Chinese medicine usage by cancer patients. We reviewed articles written in English and found only the Chinese medicine usage from the studies on complementary and alternative medicine (CAM). Seventy four (74) out of 81 articles reported rates of CAM usage ranging from 2.6 to 100%. Acupuncture was reported in 71 out of 81 studies. Other less commonly reported modalities included Qigong (n = 17), Chinese herbal medicine (n = 11), Taichi (n = 10), acupressure (n = 6), moxibustion (n = 2), Chinese dietary therapy (n = 1), Chinese massage (n = 1), cupping (n = 1) and other Chinese medicine modalities (n = 19). This review also found important limitations of the English language articles on CAM usage in cancer patients. Our results show that Chinese medicine, in particular Chinese herbal medicine, is commonly used by cancer patients. Further research is warranted to include studies not written in English. PMID- 21651822 TI - Analysis of a viral metagenomic library from 200 m depth in Monterey Bay, California constructed by direct shotgun cloning. AB - BACKGROUND: Viruses have a profound influence on both the ecology and evolution of marine plankton, but the genetic diversity of viral assemblages, particularly those in deeper ocean waters, remains poorly described. Here we report on the construction and analysis of a viral metagenome prepared from below the euphotic zone in a temperate, eutrophic bay of coastal California. METHODS: We purified viruses from approximately one cubic meter of seawater collected from 200 m depth in Monterey Bay, CA. DNA was extracted from the virus fraction, sheared, and cloned with no prior amplification into a plasmid vector and propagated in E. coli to produce the MBv200m library. Random clones were sequenced by the Sanger method. Sequences were assembled then compared to sequences in GenBank and to other viral metagenomic libraries using BLAST analyses. RESULTS: Only 26% of the 881 sequences remaining after assembly had significant (E<=0.001) BLAST hits to sequences in the GenBank nr database, with most being matches to bacteria (15%) and viruses (8%). When BLAST analysis included environmental sequences, 74% of sequences in the MBv200m library had a significant match. Most of these hits (70%) were to microbial metagenome sequences and only 0.7% were to sequences from viral metagenomes. Of the 121 sequences with a significant hit to a known virus, 94% matched bacteriophages (Families Podo-, Sipho-, and Myoviridae) and 6% matched viruses of eukaryotes in the Family Phycodnaviridae (5 sequences) or the Mimivirus (2 sequences). The largest percentages of hits to viral genes of known function were to those involved in DNA modification (25%) or structural genes (17%). Based on reciprocal BLAST analyses, the MBv200m library appeared to be most similar to viral metagenomes from two other bays and least similar to a viral metagenome from the Arctic Ocean. CONCLUSIONS: Direct cloning of DNA from diverse marine viruses was feasible and resulted in a distribution of virus types and functional genes at depth that differed in detail, but were broadly similar to those found in surface marine waters. Targeted viral analyses are useful for identifying those components of the greater marine metagenome that circulate in the subcellular size fraction. PMID- 21651827 TI - Community case management of malaria using ACT and RDT in two districts in Zambia: achieving high adherence to test results using community health workers. AB - BACKGROUND: Access to prompt and effective treatment is a cornerstone of the current malaria control strategy. Delays in starting appropriate treatment is a major contributor to malaria mortality. WHO recommends home management of malaria using artemisininbased combination therapy (ACT) and Rapid Diagnostic tests (RDTs) as one of the strategies for improving access to prompt and efective malaria case management. METHODS: A prospective evaluation of the effectiveness of using community health workers (CHWs) as delivery points for ACT and RDTs in the home management of malaria in two districts in Zambia. RESULTS: CHWs were able to manage malaria fevers by correctly interpreting RDT results and appropriately prescribing antimalarials. All severe malaria cases and febrile non malaria fevers were referred to a health facility for further management. There were variations in malaria prevalence between the two districts and among the villages in each district. 100% and 99.4% of the patients with a negative RDT result were not prescribed an antimalarial in the two districts respectively. No cases progressed to severe malaria and no deaths were recorded during the study period. Community perceptions were positive. CONCLUSION: CHWs are effective delivery points for prompt and effective malaria case management at community level. Adherence to test results is the best ever reported in Zambia. Further areas of implementation research are discussed. PMID- 21651828 TI - Relative costs and effectiveness of treating uncomplicated malaria in two rural districts in Zambia: implications for nationwide scale-up of home-based management. AB - BACKGROUND: Malaria case management is one of the key strategies to control malaria. Various studies have demonstrated the feasibility of home management of malaria (HMM). However, data on the costs and effectiveness of artemisinin-based combination therapy (ACT) and rapid diagnostic tests via HMM is limited. METHOD: Cost-effectiveness of home management versus health facility-based management of uncomplicated malaria in two rural districts in Zambia was analysed from a providers' perspective. The sample included 16 community health workers (CHWs) and 15 health facilities. The outcome measure was the cost per case appropriately diagnosed and treated. Costs of scaling-up HMM nationwide were estimated based on the CHW utilisation rates observed in the study. RESULTS: HMM was more cost effective than facility-based management of uncomplicated malaria. The cost per case correctly diagnosed and treated was USD 4.22 for HMM and USD 6.12 for facility level. Utilization and adherence to diagnostic and treatment guidelines was higher in HMM than at a health facility. CONCLUSION: HMM using ACT and RDTs was more efficient at appropriately diagnosing and treating malaria than the health facility level. Scaling up this intervention requires significant investments. PMID- 21651829 TI - Dose distribution in the thyroid gland following radiation therapy of breast cancer--a retrospective study. AB - PURPOSE: To relate the development of post-treatment hypothyroidism with the dose distribution within the thyroid gland in breast cancer (BC) patients treated with loco-regional radiotherapy (RT). METHODS AND MATERIALS: In two groups of BC patients postoperatively irradiated by computer tomography (CT)-based RT, the individual dose distributions in the thyroid gland were compared with each other; Cases developed post-treatment hypothyroidism after multimodal treatment including 4-field RT technique. Matched patients in Controls remained free for hypothyroidism. Based on each patient's dose volume histogram (DVH) the volume percentages of the thyroid absorbing respectively 20, 30, 40 and 50 Gy were then estimated (V20, V30, V40 and V50) together with the individual mean thyroid dose over the whole gland (MeanTotGy). The mean and median thyroid dose for the included patients was about 30 Gy, subsequently the total volume of the thyroid gland (VolTotGy) and the absolute volumes (cm3) receiving respectively <30 Gy and >=30 Gy were calculated (Vol<30 and Vol>=30) and analyzed. RESULTS: No statistically significant inter-group differences were found between V20, V30, V40 and V50Gy or the median of MeanTotGy. The median VolTotGy in Controls was 2.3 times above VolTotGy in Cases (rho=0.003), with large inter-individual variations in both groups. The volume of the thyroid gland receiving<30 Gy in Controls was almost 2.5 times greater than the comparable figure in Cases. CONCLUSIONS: We concluded that in patients with small thyroid glands after loco-radiotherapy of BC, the risk of post-treatment hypothyroidism depends on the volume of the thyroid gland. PMID- 21651830 TI - Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder. AB - BACKGROUND: Previous studies have suggested that there may be a parent-of-origin effect for attention-deficit/hyperactivity disorder(ADHD) candidate genes. The objective of the present study was to investigate parent-of-origin effects using a genome-wide association analysis of the International Multicentre ADHD Genetics (IMAGE) study sample. METHODS: Family-based association analysis for ADHD using 846 ADHD probands and their parents was performed using the PLINK program, and parent-of-origin effects were studied using a Z score for the difference in paternal versus maternal odds ratios. RESULTS: We identified 44 single nucleotide polymorphisms (SNPs) showing parent-of-origin effects at a significance level of p < 0.001. The most significant SNP, rs7614907, is at position 3q13.33 in the CDGAP gene (p = 0.000064 for parent-of-origin effect). Furthermore, 2 genes (FAS and PDLIM1) showed moderate parent-of-origin effects (p = 0.00086 for rs9658691 and p = 0.00077 for rs11188249) and strong maternal transmission (p = 0.000059 for rs9658691 and p = 0.0000068 for rs11188249). In addition, ZNF775 showed a moderate parent-of-origin effect (p = 0.00036 for rs7790549) and strong paternal transmission (p = 0.000041 for rs7790549). LIMITATIONS: We only had 1 sample available for analysis. CONCLUSION: These results suggest several genes or regions with moderate parent-of-origin effects, and these findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in ADHD. PMID- 21651831 TI - Surgical management of ulcerative colitis: a comparison of Canadian and American colorectal surgeons. AB - BACKGROUND: Ileal pouch anal anastomosis (IPAA) to surgically manage ulcerative colitis may involve multiple separate surgical procedures, impacting treatment costs, length of stay in hospital, complication rates and patient outcomes, and there is currently no accepted standard of care regarding the number of stages that should be performed. The purpose of this study was to compare the practice patterns of Canadian and American colorectal surgeons regarding the surgical management of ulcerative colitis. METHODS: A questionnaire was mailed to all practisng fellows of the American Society of Colon and Rectal Surgeons (ASCRS) in Canada and the United States. Surgeons were asked to describe their typical practices for 3 clinical scenarios. RESULTS: Questionnaires were mailed to 40 Canadian and 873 American ASCRS fellows with response rates of 86% and 62%, respectively. In the case of a patient who has had a prior colectomy, who is not taking steroids and in whom a tension-free IPAA is possible, 44% of Canadian surgeons would perform IPAA alone and 56% would perform IPAA with a loop ileostomy. In contrast, only 26% of American surgeons would perform IPAA alone and 74% would perform IPAA with a loop ileostomy (p = 0.002). In the case of a patient who has not had previous surgery, who is taking 10 mg/day of prednisone and in whom a tension-free IPAA is possible, the majority of both Canadian and American surgeons would perform an IPAA with a loop ileostomy (93% and 89%, respectively, p = 0.06). In the case of a patient who has not had previous surgery, who is taking 40 mg/day of prednisone and in whom a tension-free IPAA is possible, 45% of Canadian surgeons would perform a subtotal colectomy with an end ileostomy compared with 14% of American surgeons (p < 0.001). CONCLUSION: There are significant differences in the surgical management of ulcerative colitis between Canadian and American colorectal surgeons. PMID- 21651832 TI - Assessing the impact of a 2-day laparoscopic intestinal workshop. AB - BACKGROUND: Surgical educators have responded to the demand for increased skills in minimally invasive surgery by offering short technique-focused workshops at academic centres. The purpose of this study was to determine the impact of a comprehensive laparoscopic intestinal workshop for the adoption of laparoscopic colonic surgery. METHODS: A 2-day comprehensive laparoscopic intestinal surgery workshop included didactic teaching and supervised hands-on practice of numerous laparoscopic colon resections on a cadaveric model. Participants completed pre-, post- and 6-month postcourse questionnaires. RESULTS: The participants (n = 39) had been in practice for a mean of 10 (interquartile range 3-18) years. Fifty-one percent (n = 20) were already performing laparoscopic colectomies as part of their practices prior to the course. Regardless of whether they were performing laparoscopic colectomies prior to the course or not, attending the 2-day workshop improved their self-assessed preparedness to perform laparoscopic colectomies. Six months after the intestinal workshop, 10 of 16 respondents who were not performing laparoscopic colectomies prior to the course had performed at least 1 since the course. Seven of these individuals had a preceptor for their first case. Reasons cited for not performing a laparoscopic colectomy since the workshop included perceived inadequate surgical skill set, a lack of preceptor and the lack of an appropriate patient. CONCLUSION: A comprehensive laparoscopic intestinal workshop contributed to the perceived acquisition of advanced laparoscopic surgical skills. Local laparoscopic preceptorship was an important adjunct to the workshop for the incorporation of laparoscopic colorectal surgery into practice. PMID- 21651833 TI - Information on the internet for asplenic patients: a systematic review. AB - BACKGROUND: Asplenic patients in general have poor knowledge about their condition. Patients are increasingly turning to the Internet for their health care information, therefore this is a resource that many asplenic patients will use. The aim of our study was to determine the quality of information on the Internet for asplenic patients. METHODS: We identified websites by entering "splenectomy OR spleen removal" into 3 Internet search engines on July 28, 2008. The top 50 English-language websites from each search engine were included in our analysis. We evaluated the websites with our own 21-point content scale as well as 4 commonly used quality-assessment tools. All websites were analyzed independently by 2 reviewers. Correlations were made between the quality assessment instruments, content, readability and target audience. RESULTS: We included 89 websites in the study. The mean content score percentage for all websites was 49% (95% confidence interval 44%-54%). The long-term risk of infection was mentioned in 84% of websites, and the need for vaccination was mentioned in 79%. The mean quality assessment tool score was 61%, and the mean reading grade level was 11. CONCLUSION: Whereas websites on average did not cover most of the information that asplenic patients should receive, the long-term risk of serious infection and the need for vaccination was consistently mentioned. Websites were inconsistent with respect to adhering to standards advocated by the quality assessment instruments we used, and the mean reading grade level was far above what is recommended for patient literature. PMID- 21651834 TI - Meta-analysis of sentinel lymph node biopsy at the time of prophylactic mastectomy of the breast. AB - BACKGROUND: Prophylactic mastectomy is performed to decrease the risk of breast cancer in women at high risk for the disease. The benefit of sentinel lymph node biopsy (SLNB) at the time of prophylactic mastectomy is controversial, and we performed a meta-analysis of the reported data to assess that benefit. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library databases from January 1993 to December 2009 for studies on patients who underwent SLNB at the time of prophylactic mastectomy. Two reviewers independently evaluated all the identified papers, and only retrospective studies were included. We used a mixed-effect model to combine data. RESULTS: We included 6 studies in this review, comprising a total study population of 1251 patients who underwent 1343 prophylactic mastectomies. Of these 1343 pooled prophylactic mastectomies, the rate of occult invasive cancer (21 cases) was 1.7% (95% confidence interval [CI] 1.1%-2.5%), and the rate of positive SLNs (23 cases) was 1.9% (95% CI 1.2%-2.6%). In all, 36 cases (2.8%, 95% CI 2.0%-3.8%) led to a significant change in surgical management as a result of SLNB at the time of prophylactic mastectomy. In 17 cases, patients with negative SLNs were found to have invasive cancer at the time of prophylactic mastectomy and avoided axillary lymph node dissection (ALND). In 19 cases, patients with positive SLNBs were found not to have invasive cancer at the time of prophylactic mastectomy and needed a subsequent ALND. Of the 23 cases with positive SLNs, about half the patients had locally advanced disease in the contralateral breast. CONCLUSION: Sentinel lymph node biopsy is not suitable for all patients undergoing prophylactic mastectomy, but it may be suitable for patients with contralateral, locally advanced breast cancer. PMID- 21651835 TI - Antibiotics versus appendectomy in the management of acute appendicitis: a review of the current evidence. AB - BACKGROUND: Acute appendicitis remains the most common cause of the acute abdomen in young adults, and the mainstay of treatment in most centres is an appendectomy. However, treatment for other intra-abdominal inflammatory processes, such as diverticulitis, consists initially of conservative management with antibiotics. The aim of this study was to determine the role of antibiotics in the management of acute appendicitis and to assess if appendectomy remains the gold standard of care. METHODS: A literature search using MEDLINE and the Cochrane Library identified studies published between 1999 and 2009, and we reviewed all relevant articles. The articles were critiqued using the Public Health Resource Unit (2006) appraisal tools. RESULTS: Our search yielded 41 papers, and we identified a total of 13 papers within the criteria specified. All of these papers, while posing pertinent questions and demonstrating the role of antibiotics as a bridge to surgery, failed to adequately justify their findings that antibiotics could be used as a definitive treatment of acute appendicitis. CONCLUSION: Appendectomy remains the gold standard of treatment for acute appendicitis based on the current evidence. PMID- 21651837 TI - Can preoperative computed tomography of the chest predict completeness of the major pulmonary fissure at surgery? AB - BACKGROUND: An incomplete major pulmonary fissure can make anatomic lung resection technically more difficult and may increase the risk of complications, such as prolonged postoperative air leak. The objective of this study was to determine if preoperative computed tomography (CT) of the chest could accurately predict the completeness of the major pulmonary fissure observed at the time of surgery. METHODS: From October 2008 to June 2009, patients at a single university institution were enrolled if they underwent surgery for a pulmonary nodule, mass or known cancer. At the time of surgery, completeness of the major pulmonary fissure was graded 1 if pulmonary lobes were entirely separate, 2 if the visceral cleft was complete with an exposed pulmonary artery at the base with some parenchyma fusion, 3 if the visceral cleft was only evident for part of the fissure without a visible pulmonary artery and 4 if the fissure was absent. The preoperative CT scan of each patient was graded by a single, blinded chest radiologist using the same scale. We used the Pearson chi2 test with 2-tailed significance to test the independence of the operative and radiologic grading. RESULTS: In 48% (29 of 61) of patients, the radiologic and operative grading were the same. Of those graded differently, 94% (30 of 32) were within 1 grade. Despite this agreement, we observed no statistically significant correlation between the operative and radiologic grading (p = 0.24). CONCLUSION: The major fissure can often be well-visualized on a preoperative CT scan, but preoperative CT cannot accurately predict the completeness of the major pulmonary fissure discovered at surgery. PMID- 21651836 TI - Factors that determine whether a patient receives completion axillary lymph node dissection after a positive sentinel lymph node biopsy for breast cancer in British Columbia. AB - BACKGROUND: Completion axillary lymph node dissection (CALND) is recommended in the setting of positive sentinel lymph node biopsy (SLNB) but is associated with a higher rate of postoperative complications. In this study, the characteristics and outcomes of patients who did and did not have CALND are compared. METHODS: We identified all patients with breast cancer with positive sentinel lymph nodes (SLNs) who did not have concurrent CALND from 2003 to 2006 using a prospectively collected database (British Columbia Cancer Breast Outcomes database) and retrospective chart review. Patient and tumour characteristics were compared between those who received CALND and those who did not. RESULTS: Among 185 patients with positive SLNs identified by SLNB, 90 had a CALND and 95 had no further surgical therapy. Patients who did not receive CALND had more sentinel nodes removed (p < 0.001), a lower percentage of positive SLNs (p < 0.001) and lower pathologic N stage (p = 0.044) than those who did receive CALND. The size of the breast lesion, size of the largest SLN deposit, estrogen receptor status, grade, lymphovascular invasion, histology and multifocality were not significantly different between groups. Sixty-two percent of women who did not have CALND received radiation to the axilla. Postoperative complication rates (including lymphedema) were higher in the CALND group (21%) compared with the SLNB group (7%). The rates of locoregional recurrence (1% in both groups) and systemic metastases (6% in the CALND group v. 8% in the SLNB group) were similar at 36 months' follow-up. CONCLUSION: Compared with women who had CALND, women who did not receive CALND had on average a lower N stage with 3 or more SLNs removed and less than 50% node positivity. Most of these women received radiation therapy to the axilla and had comparable recurrence rates to those who had CALND. PMID- 21651838 TI - Delay in operative stabilization of spine fractures in multitrauma patients without neurologic injuries: effects on outcomes. AB - BACKGROUND: Optimal timing for surgical stabilization of the fractured spine is controversial. Early stabilization facilitates mobilization and theoretically reduces associated complications. METHODS: We identified consecutive patients without neurologic injury requiring stabilization surgery for a spinal fracture at an academic tertiary-care hospital over a 12-year period. Incidences of postoperative complications were prospectively evaluated. We analyzed results based on the time elapsed before the final surgical stabilization procedure. Multivariate analyses were performed to explore the effects of potential confounders. RESULTS: A total of 83 patients (60 men, 23 women; mean age 39.4 yr) met the eligibility criteria and were enrolled. The mean Injury Severity Score (ISS) was 27.1 (range 12.0-57.0); 35% of patients had a cervical fracture and 65% had a thoraco-lumbar fracture. No statistically significant associations were uncovered between time to surgical stabilization and age, ISS or comorbidities. Comparing patients stabilized after 24 hours with those stabilized within 24 hours, there was an almost 8-fold greater risk of a complication related to prolonged recumbency (p = 0.007). We observed similar effects for other types of complications. Delays of more than 72 hours had a negative effect on complication rates; these effects remained significant after multivariate adjustments for age, comorbidity and ISS. CONCLUSION: This study demonstrates a strong relation between timing of surgical stabilization of spinal fractures in multitrauma patients without neurologic injuries and complications. Further studies with larger samples may allow for better adjustment of potentially confounding factors and identify subgroups in which this effect is most pronounced. PMID- 21651840 TI - [The potential role of regulatory T cells in postburn sepsis]. AB - It has been demonstrated that severe burn per se may contribute to activation and proliferation of regulatory T cells (Treg). This characteristic phenomenon might allow Treg to function for a prolonged period of time to regulate immune response, and to induce suppression of T lymphocyte immune function. Different degrees of elevated levels of cytokines produced by Treg and activation markers on Treg surface could also be involved in the development of sepsis and fatal outcome in patients with severe burn. Thus, the regulation of Treg as a cellular therapeutic strategy might be important to the Th1/Th2 cytokine balance in burn patients complicated with sepsis. PMID- 21651841 TI - [Drug-resistance Acinetobacter baumannii infection in burn patients: current situation and countermeasure]. AB - Infections caused by Acinetobacter baumannii (AB) have emerged as a knotty clinical problem in the burn wards due to its omni-resistance to antibiotics and high prevalence. Although our knowledge in regard to the pathogenesis and the resistance mechanisms of AB is increasing, the available treatment remains much limited. Measures to effectively control nosocomial infection are warranted. Meanwhile, development of novel therapeutic agents or combination of antibiotics should be considered. PMID- 21651839 TI - Resolution of diabetes mellitus by ileal transposition compared with biliopancreatic diversion in a nonobese animal model of type 2 diabetes. AB - BACKGROUND: It has been demonstrated that biliopancreatic diversion (BPD) and ileal transposition (IT) effectively induce weight loss and long-term control of type 2 diabetes in morbidly obese individuals. It is unknown whether the control of diabetes is better after IT or after BPD. The objective of this study was to investigate the effects of IT and BPD on the control of diabetes in an animal model. METHODS: We performed IT and BPD on 10- to 12-week-old Goto-Kakizaki rats with a spontaneous nonobese model of type 2 diabetes, and we performed a series of detection. The rats were observed for 24 weeks after surgery. RESULTS: Animals who underwent IT and BPD demonstrated improved glucose tolerance, insulin sensitivity and the secretion of glucagon-like peptide-1 compared with the sham operated animals. Furthermore, IT resulted in a shorter duration of surgery and better postoperative recovery than BPD. CONCLUSION: This study provides strong evidence for the crucial role of the hindgut in the resolution of diabetes after duodenum-jejunum bypass or IT. We confirmed that IT was associated with better postoperative recovery than BPD and had a similar control of diabetes as BPD in nonobese animals with type 2 diabetes. PMID- 21651842 TI - [Role of angiotensin II-angiotensin II type 1 receptor pathway in the production of proinflammatory cytokines in macrophage]. AB - OBJECTIVE: To investigate the role of angiotensin II (AngII)-angiotensin II type 1 receptor (AT1R) pathway in the production of proinflammatory cytokines in macrophage, and to analyze its mechanisms. METHODS: RAW264.7 macrophages were cultured in vitro in DMEM nutrient medium containing 10% FBS, and then they were divided into control group (ordinary culture for 6 hours without any stimulation), ZD7155 group (pretreated with 38 umol/L AT1R-specific inhibitor ZD7155 for 1 hour, then cultured with fresh nutrient solution for 6 hours), AngII group (cultured with 0.01 umol/L AngII for 6 hours), and ZD7155 + AngII group (pretreated with 38 umol/L AT1R-specific inhibitor ZD7155 for 1 hour, then cultured with 0.01 umol/L AngII for 6 hours) according to the random number table. Contents of TNF-alpha and IL-1beta in the supernatant were measured by ELISA. Expressions of TNF-alpha mRNA and IL-1beta mRNA were determined by RT-PCR. Activity of NF-kappaB and AP-1 were examined by electrophoretic mobility shift assay. Data were processed with one-way analysis of variance. RESULTS: Compared with those in AngII group [(119 +/- 14), (105 +/- 17) pg/mL, respectively], the levels of TNF-alpha and IL-1beta in the supernatant in control group [(24 +/- 11), (24 +/- 6) pg/mL, with F value respectively 1.62, 8.03, P values all below 0.01], ZD7155 group [(22 +/- 11), (25 +/- 8) pg/mL, with F value respectively 1.62, 4.52, P values all below 0.01], and ZD7155 + AngII group [(45 +/- 13), (62 +/- 11) pg/mL, with F value respectively 1.16, 2.29, P < 0.05 or P < 0.01] were all obviously decreased. The expressions of TNF-alpha mRNA and IL-1beta mRNA, and activity of NF-kappaB and AP-1 showed the similar changes as above: (1) The levels of TNF-alpha mRNA and IL-1beta mRNA in AngII group were all higher than those in control group (with F value respectively 7.59, 3.38, P < 0.05 or P < 0.01), ZD7155 group (with F value respectively 10.66, 2.24, P values all below 0.05), and ZD7155 + AngII group (with F value respectively 5.10, 5.09, P values all below 0.01). (2) Activity of NF-kappaB and AP-1 was respectively 69 027 +/- 2502, 36 752 +/- 2055 in AngII group, all higher than those in control group (45 709 +/- 1203, 20 325 +/- 2695, with F value respectively 4.32, 1.72, P values all below 0.01), ZD7155 group (46 303 +/- 1897, 21 951 +/- 2517, with F value respectively 1.74, 1.50, P values all below 0.01), and ZD7155 + AngII group (38 271 +/- 690, 22 365 +/- 3797, with F value respectively 13.13, 3.41, P values all below 0.01). CONCLUSIONS: AngII can mediate activation of transcription factor NF kappaB and AP-1 via combination of AT1R, thereby contributing to the production and release of proinflammatory cytokines TNF-alpha and IL-1beta in macrophage. PMID- 21651843 TI - [Drug-resistance of Acinetobacter baumannii isolated from burn wards and analysis of homogeneity]. AB - OBJECTIVE: To monitor genotypes and drug-resistance trend of Acinetobacter baumannii (AB) isolated from burn wards. METHODS: Twenty-six strains of AB isolated from wound secretion, venous catheter, and blood were collected from burn patients hospitalized in our burn wards from November 2008 to February 2009, and June to September 2010. Homogeneous genotype analysis was performed with repetitive extragenic palindromic PCR, and drug-resistance rate to 13 antibiotics including amikacin, gentamicin, etc., which were commonly used in clinic, was tested by K-B paper disk diffusion. The data of drug-resistance rate were processed with chi-square test. RESULTS: (1) Sixteen AB strains were multi-drug resistant (MDR), 9 AB strains were pan-drug resistant (PDR). Among all strains, the resistance rate to gentamicin, piperacillin, piperacillin/tazobactam, cefuroxime, cefotaxime, ceftazidime, cefepime, ciprofloxacin, imipenem, and meropenem was respectively higher than 90.00%; the resistance rate against cefoperazone/sulbactam was the lowest (11/26, 42.31%). There were obvious difference among the drug-resistance rates of AB strains to 13 antibiotics (with rates from 42.31% to 100.00%, chi(2) = 97.371, P < 0.05). (2) There were 7 genotypes among 26 AB strains, respectively type A (17), type B (3), type C (2), type D (1), type E (1), type F (1), and type G (1). Out of the 17 AB strains in A genotype, 1 strain was from 2008, 1 strain was from 2009, 15 strains were from 2010, and among them 11 strains were collected from wound secretion and 6 strains were obtained from blood and venous catheter. CONCLUSIONS: AB strains in A genotype are dominant in our burn wards in recent years, which are MDR or PDR to commonly used antibiotics. Cefoperazone/sulbactam is the drug of choice for burn patients with AB infection. PMID- 21651844 TI - [The regulatory effect and mechanism of Astragalus polysaccharides on CD11c(high)CD45RB(low) dendritic cell]. AB - OBJECTIVE: To investigate immunomodulatory effect of Astragalus polysaccharides (APS) on IL-12-secreting dendritic cell (DC) subset CD11c(high)CD45RB(low) DC. METHODS: Spleen CD11c(high)CD45RB(low) DC and CD4(+)T lymphocytes in BALB/c mice were purified by magnetic beads sorting, and were treated with 0 (as control), 50, 100, 200 ug/mL APS. Immunofluorescence staining and flow cytometry were used to determine expressions of CD11c(high)CD45RB(low) DC surface molecules, including CD40, CD80, CD86, I-A/E, and Toll-like receptor (TLR) 4. IL-12 level in CD11c(high)CD45RB(low) DC culture supernatant was determined by ELISA. The CD4(+) T lymphocytes were divided into: normal control group, non-stimulation group (CD4(+)T lymphocytes cocultured with APS-unstimulated CD11c(high)CD45RB(low) DC), high-dose APS stimulation group (CD4(+)T lymphocytes cocultured with 200 ug/mL APS-stimulated CD11c(high)CD45RB(low) DC), high-dose APS stimulation+antibody 1 group (CD4(+)T lymphocytes cocultured with 200 ug/mL APS-stimulated CD11c(high)CD45RB(low) DC and IL-12 antibody), high-dose APS stimulation+ antibody 2 group (CD4(+)T lymphocytes cocultured with 200 ug/mL APS-stimulated CD11c(high)CD45RB(low) DC and IL-12 antibody isotype). Proliferation ability of CD4(+) T lymphocytes was determined with MTT method. IL-4 level as well as IFN gamma level in CD4(+)T lymphocyte culture supernatant was determined by flow cytometry. Data were processed with one-way analysis of variance. RESULTS: Compared with those in control, the expressions of CD11c(high)CD45RB(low) DC surface molecules (except for CD86) on CD11c(high)CD45RB(low) DC surface, as well as IL-12-secreting level with dose-dependence were increased in cells stimulated with 50, 100, 200 ug/mL APS. Proliferation ability of CD4(+)T lymphocytes in high dose APS stimulation group was higher as compared with that in non-stimulation group (F = 13.438, P < 0.05). IFN-gamma level in high-dose APS stimulation group ?[(2784 +/- 137) pg/mL?] was higher than that in non-stimulation group ?[(1952 +/ 101) pg/mL, F = 12.177, P < 0.05?]. IL-4 level in high-dose APS stimulation group was (172 +/- 20) pg/mL, which was lower than that in non-stimulation group ?[(193 +/- 19) pg/mL, F = 11.963, P < 0.05?]. Proliferation ability of CD4(+) T lymphocytes, IFN-gamma level, and IL-4 level in high-dose APS stimulation + antibody 1 group were all ameliorated when compared with those in non-stimulation group; while levels of the 3 indexes in high-dose APS stimulation + antibody 2 group were similar to those in high-dose APS stimulation group. CONCLUSIONS: APS can activate IL-12-producing CD11c(high)CD45RB(low) DC, and further induce the activation of immune function of T lymphocyte with shifting of Th2 to Th1 in vitro. APS can enhance the immune response via promoting the phenotypic and functional maturation of CD11c(high)CD45RB(low) DC. PMID- 21651845 TI - [Expressions of pgaABC gene clusters and changes in biofilm phenotype of Acinetobacter baumannii in burn patients]. AB - OBJECTIVE: To observe expressions of pgaABC gene clusters and changes in biofilm (BF) phenotype in Acinetobacter baumannii (AB) isolated from burn patients. METHODS: From January 2009 to October 2010, 24 strains of AB isolated from burn patients hospitalized in our burn wards were collected for the study, while the standard strain ATCC 19606 was used as control. Expressions of pgaABC gene clusters were detected by real time fluorescence quantitative RT-PCR. All strains were cultured for 16 hours in vitro, BF with semi-quantitative detection was respectively evaluated by modified microtiter-plate test under stable condition and tube test under shaking condition for expression of absorbance value. All strains were cultured for 48 hours in vitro, then stained with fluorescent agent and collected for measurement of BF thickness with confocal laser scanning microscopy (CLSM). Data were processed with t test. RESULTS: (1) The expression of pgaB gene (27.91 +/- 7.93) in clinical AB strains was much higher than that of standard strain ATCC 19606 (1.00, t = 5.77, P < 0.05). There was no statistical difference in expression of pgaA and pagC genes between standard strain ATCC 19606 (1.00) and clinical AB strains (1.01 +/- 0.28, 1.15 +/- 0.38, with t value respectively 0.04, 0.64, P values all above 0.05). (2) After being cultured for 16 hours, BF of clinical AB strains cultured under shaking condition formed distinct "purple circle", and its absorbance value (1.25 +/- 0.31) was higher than that in standard strain ATCC 19606 (0.76 +/- 0.03, t = 2.67, P < 0.05). There was no obvious difference in absorbance value between clinical AB strains and standard strain ATCC19606 cultured under stable condition. (3) After being culture for 48 hours, green fluorescence intensity and distribution in extracellular matrix of clinical AB strains were stronger as compared with those of standard strain ATCC 19606, and BF thickness in clinical AB strains [(27.3 +/- 9.4)um] was thicker than that in standard strain ATCC 19606 [(15.6 +/- 1.7) um, t = 2.09, P < 0.05]. CONCLUSIONS: The high expression of pgaB gene in AB strains isolated from burn patients can induce production of extracellular matrix, which may be related to increase in the ability and thickness of BF formation. PMID- 21651846 TI - [Reproduction of a rat model of burn with infection]. AB - OBJECTIVE: To reproduce a reliable rat model of burn with infection for the study of prevention and treatment of infected wound. METHODS: (1) Electrical burn producing apparatus equipped with constant temperature (80 degrees C) and pressure (0.5 kg) was used to reproduce burn injury (with area of 4.5 cm(2)) on both sides of the back in 50 SD rats for different duration (4, 6, 8, 10, 12 s), with 10 rats for each burn duration. On post burn day (PBD) 1, gross condition of wounds was observed with naked eyes. Wounds on the left side were used to observe healing time. The wounds on the right side were used for histological observation to determine the depth of injury, and they were classified into superficial and deep partial-thickness injury. (2) Another 36 SD rats were divided into A (inflicted with superficial partial-thickness burn, n = 18) and B (inflicted with deep partial-thickness burn, n = 18) groups according to the random number table. Rats in both groups were treated in accordance with method of preliminary experiment. Immediately after burn, 0.1 mL of liquid containing 1 * 10(9), 1 * 10(7), 1 * 10(5) CFU Pseudomonas aeruginosa (PA) ATCC 27853 was respectively inoculated to the wounds on one side (with 6 rats for each amount), while the wounds on the other side were treated with the same volume of normal saline as control. Inflammatory reaction of wounds was examined with HE staining on post inoculation day (PID) 1. On PID 1, 2, 3, 5, 7, and 14, the number of subeschar bacteria was respectively counted and the bacteria were identified with Gram stain and biochemical reaction. Wound healing time was recorded. Data were processed with t test. RESULTS: (1) Burn for 6, 8 s was respectively identified as injury time resulting in superficial or deep partial-thickness injury according to histological observation and wound healing time. (2) Obvious inflammatory cell infiltration was observed in the wounds in B group which were inoculated with 1 * 10(7), 1 * 10(9) CFU PA, and the infiltration was less marked in A group with inoculation of 1 * 10(9) CFU PA. (3) The bacteria isolated from wounds of A and B groups was identified as PA. The subeschar bacteria count within PID 14 in A group, in which different amount of PA was inoculated, was mostly less than 1 * 10(5) CFU/g of tissue, while that in B group in which 1 * 10(9) CFU PA was inoculated was more than 1 * 10(5) CFU/g of tissue. (4) There was no obvious difference in wound healing time between wounds inoculated with different amount of PA and wounds treated with normal saline in A group (with t value respectively 1.26, 0.29, 1.07, P values all above 0.05). Wound healing time of wounds in B group, in which 1 * 10(9) CFU PA was inoculated, was longer as compared with that treated with normal saline [(22.5 +/- 1.0) d vs. (19.4 +/- 1.6) d, t = 2.73, P < 0.05]. CONCLUSIONS: In rat, deep partial-thickness burn wound inoculated with 1 * 10(9) CFU PA ATCC 27853 is a reliable model with high reproducibility for the study of infection of burn wound. PMID- 21651847 TI - [Analysis of the drug-resistance of Pseudomonas aeruginosa and the use of antibiotics in burn wards]. AB - OBJECTIVE: To study changes in the drug-resistance of Pseudomonas aeruginosa (PA) and the use of antibiotics in burn wards so as to optimize the use of antibiotic in the future. METHODS: Bacteria were isolated from specimens of blood, venous catheter, stool, sputum, urine, wound tissue from 5717 patients hospitalized in our burn wards within the duration of January 2005 to December 2009. The number of specimens examined and positive rates of bacteria were calculated. Changes in constituent ratio of cocci and bacilli, spectrum of bacteria, the drug-resistance rate of PA, and the usage of antibiotics were analyzed. The number of specimens examined, constituent ratio of cocci and bacilli, drug-resistance rate were processed with chi-square test. Bivariate correlation analysis was performed between the usage of antibiotics and the drug-resistance rate. RESULTS: (1) The number of specimens examined showed no statistical difference during the five years (with rates from 73.2% to 76.1%, chi(2) = 5.583, P > 0.05), while constituent ratio of cocci and bacilli showed statistical difference (with ratios from 105:134 to 169:126, chi(2) = 14.806, P < 0.01). The positive rates of bacteria were increasing in the five years. (2) One thousand six hundred and seventy-five strains were identified during the five years from different kinds of specimens, with 29 from blood, 39 from venous catheter, 3 from stool, 157 from sputum, 13 from urine, and 1434 from wound tissue. Among them, Staphylococcus aureus accounted for 28% to 42%, PA accounted for 10% to 25%, Acinetobacter baumannii accounted for 10% to 19%, and they were the predominant strains. (3) The difference among drug-resistance rates of PA to each kind of 12 antibiotics during the five years were statistically significant (with chi(2) values from 47.911 to 308.095, P values all below 0.01). The drug-resistance rates of PA to some antibiotics showed downward trend in the former four years, including amikacin, ceftazidime, and imipenem/cilastatin, but it rebounded in the fifth year. (4) There was descending trend in usage of cefoperazone/sulbactam and levofloxacin, but vancomycin was always used widely. (5) Drug-resistance rates of PA to 7 antibiotics, including amikacin, imipenem/cilastatin, and ciprofloxacin, etc., were positively correlated with usage of various antibiotics (with r values from 0.879 to 0.978, P < 0.05 or P < 0.01). CONCLUSIONS: In our burn wards, drug resistant PA was prevalent. Disinfection and isolation measures, appropriate use of antibiotics, etc. can reduce PA infection. PMID- 21651848 TI - [Analysis of extubation time and late complications after early tracheotomy in patients with inhalation injury]. AB - OBJECTIVE: To investigate the appropriate extubation time and treatment of late complications after early tracheotomy in patients with moderate or severe inhalation injury. METHODS: One hundred and fifty patients (105 males and 45 females) with inhalation injury were admitted to our hospital from January 2000 to January 2009. Among them, 109 out of 129 cases with moderate inhalation injury received early tracheotomy, and all 21 cases with severe inhalation injury received early tracheotomy. Data were collected for analysis as follows: (1) incidence of re-intubation due to suffocation and pneumonia incidence after extubation within 2 weeks or after 2 weeks post inhalation injury (PII), and mortality rate within the first week after injury were recorded. (2) Conservative treatments including expectorant, oral antibiotics, and absolute bedrest were recommended for patients who had severe cough, hoarseness or poor pulmonary function after late extubation and closure of tracheostomy wound. Fiberoptic bronchoscopy findings (tracheostenosis degree, granuloma formation rate, vocal cord paralysis rate) and pulmonary function index (FEV(1)) data were collected and analyzed in 30 cases with moderate inhalation injury and 10 cases with severe inhalation injury within 3 months after injury for follow-up. Data were processed with t test or chi-square test. RESULTS: There was no obvious difference in the rate of re-intubation after extubation in patients with moderate inhalation injury between those done within 2 weeks PII (15/70, 21.4%) and those done after 2 weeks PII (2/25, 8.0%) (chi(2) = 1.52, P > 0.05). Pneumonia incidence in patients of moderate inhalation injury with extubation within 2 weeks PII (21/70, 30.0%) was lower than those with extubation after 2 weeks PII (15/25, 60.0%) (chi(2) = 7.04, P < 0.05). Levels of above-mentioned indexes in patients with severe inhalation injury extubated in different stages were similar to those of patients with moderate inhalation injury. Within the first week after injury, mortality rate of patients with severe inhalation injury was higher than that of patients with moderate inhalation injury (chi(2) = 11.90, P < 0.05). During follow-up, tracheostenosis rate in patients with moderate or severe inhalation injury was 100.0%; granuloma formation rate and vocal cord paralysis rate in patients with severe inhalation injury were higher than those of patients with moderate inhalation injury (with chi(2) value respectively 4.59, 13.47, P values all below 0.05). The FEV(1) value of patients with moderate inhalation injury in the 1st, 2nd, 3rd month after injury was respectively higher than that of patients with severe inhalation injury (with t value respectively 5.48, 12.10, 6.25, P values all below 0.05). The values recovered to normal level in the 3rd month after injury. CONCLUSIONS: Extubation time of tracheotomy for patients with moderate or severe inhalation injury within 2 weeks or after 2 weeks PII has its own advantage and disadvantage, and it should be performed according to specific conditions of each patient. Conservative treatment is optional for late complications of respiratory system. PMID- 21651849 TI - [Retrospective investigation of inpatients with chronic wounds]. AB - OBJECTIVE: To investigate cause of chronic wounds and related status of patients so as to provide strategy for study and treatment of chronic wounds and establishment of health policy. METHODS: A total of twelve thousand one hundred and sixty-one cases hospitalized in our hospital in 2008 were enrolled in the study. A chronic wound was defined as skin tissue defect which could not heal after one month of treatment. Medical records were thus screened. Then a retrospective study was performed on patients with chronic wounds with analysis of age, gender, injury cause, therapy, and average length of hospital stay. Data were processed with chi-square test and one-way analysis of variance. RESULTS: Investigation showed: 397 out of 12 161 cases (accounting for 3.3%) were recognized as having chronic wounds. (1) The main causes for chronic wound were burn, diabetes, and pressure ulcer, accounting for 59.9% (238/397), 15.6% (62/397), 10.8% (43/397), respectively. The other causes were operative injury, infection, varicosity, etc. There was statistical difference among the numbers of patients with chronic wounds with regard to various causes of injury (chi(2) = 136.21, P = 0.001). (2) Among patients with chronic wound, the ratio of male and female was 2.0:1.0 with mean age of (44 +/- 23) years, and the highest ratio occurred in patients older than 70 years. There was significant difference in the numbers of patients with chronic wound among different age groups (chi(2) = 24.12, P = 0.025). There was statistical difference among the numbers of patients with chronic wound in different age groups with each cause of injury (with chi(2) values from 7.86 to 28.31, P values all below 0.05). (3) All patients with chronic wounds received traditional dressing. In 60.5% (240/397) and 86.4% (343/397) of patients, operative treatment or antibiotics were given. (4) The average length of hospital stay in patients with chronic wound [(38 +/- 27) d] was longer as compared with that of all the inpatients in the same period [(15 +/ 7) d, F = 22.82, P = 0.012]. There was obvious difference in the average length of hospital stay among patients with chronic wound caused by different reasons (F = 24.06, P = 0.036), in which burn injury resulted in the longest length of hospital stay [(47 +/- 27) d]. CONCLUSIONS: Chronic wounds are mainly caused by diabetes and burn, and characterized by old age and longer length of hospital stay. It is necessary to strengthen translational research and related policy making, so that more rational treatment can be applied for patients with chronic wounds. PMID- 21651850 TI - [Relationship between cutaneous glycometabolic disorders and cutaneous neuropathy in diabetic rats]. AB - OBJECTIVE: To analyze the relationship between cutaneous glycometabolic disorders and cutaneous neuropathy in diabetic rats, and to look for the mechanism of neuropathy and impaired wound healing. METHODS: Eighty male SD rats were randomly divided into the normal control group (NC, n = 20), diabetic group (D, n = 20), aminoguanidine-interfered group (AI, n = 20), and insulin-interfered group (II, n = 20) by drawing lots. Diabetes was reproduced in rats of D, AI, and II groups with intraperitoneal injection of streptozotocin (STZ). Then, rats in AI group were fed with 100 mg*kg(-1)*d(-1) aminoguanidine, while rats in II group were subcutaneously injected with insulin for satisfactory control of blood glucose. Changes in mechanical and heat pain thresholds of pad of hind limb were measured at post injection week (PIW) 2, 4, 8. Skin specimens were collected during PIW 2 8 from pads for determination of contents of glucose, advanced glycation end product (AGE), substance P (SP), calcitonin gene-related peptide (CGRP), and observation of distribution and ultrastructure of skin nerve fibers. Data were processed with t test. RESULTS: The mechanical and heat pain thresholds in D group at PIW 2 [(6.3 +/- 1.5) g, (6.0 +/- 0.9) s, respectively ] were obviously lower than those in NC group [(13.0 +/- 3.2) g, (10.3 +/- 1.2) s, with t value respectively 2.71, 3.42, P values all below 0.05]. Contents of glucose and AGE in skin tissue in D group were significantly increased when compared with those in NC group, especially at PIW 8 [(2.85 +/- 0.33) mg/g, (31.7 +/- 3.2) U/mg of hydroxyproline vs. (0.82 +/- 0.22) mg/g, (22.2 +/- 1.9) U/mg of hydroxyproline, with t value respectively 1.65, 6.47, P values all below 0.01]. The myelinated nerve fibers were edematous and degenerated, with axons compressed, while the unmyelinated nerve fibers were vacuolated, with microfilament and microtubule disorderly arranged. Content of SP in skin tissue in D group was lower as compared with that in NC group, especially at PIW 2 [(16.8 +/- 3.4) pg/g vs. (28.5 +/- 5.0) pg/g, t = 2.42, P < 0.01]. There was no obvious difference in content of CGRP between NC and D groups, and also in content of glucose in skin between D and AI groups. Compared with those in D group, content of AGE in AI group at PIW 8 was decreased markedly [(27.2 +/- 1.4) U/mg of hydroxyproline, t = 3.38, P < 0.05]; contents of glucose and AGE in II group at PIW 8 were significantly decreased [(1.42 +/- 0.38) mg/g, (23.6 +/- 1.3) U/mg of hydroxyproline, with t value respectively 1.74, 8.17, P < 0.05 or P < 0.01]. Compared with that in D group, contents of SP in AI and II groups were increased, with a delay in time of trough value. Content of CGRP showed no obvious difference among D, AI, and II groups. CONCLUSIONS: High glucose and accumulation of AGE are key mediators of cutaneous neuropathy and impaired wound healing in diabetes mellitus, which confirms that diabetic wound takes an atypical footing during wound repairing. Aminoguanidine and insulin can reduce contents of glucose and AGE in diabetic skin tissue, and ameliorate diabetic cutaneous neuropathy. PMID- 21651851 TI - [An experimental study on intestinal epithelial barrier dysfunction induced by interferon-gamma and tumor necrosis factor-alpha]. AB - OBJECTIVE: To investigate the effect of combination of interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF-alpha) on intestinal epithelial barrier function. METHODS: The Caco-2 monolayers were cultured in DMEM nutrient solution, and then they were inoculated in 24-well or 6-well plate with Transwell inserts.They were divided into control group (ordinary treatment), IFN-gamma group (with addition of 10 ng/mL IFN-gamma), TNF-alpha group (with addition of 10 ng/mL TNF-alpha), and IFN-gamma plus TNF-alpha group (with addition of 10 ng/mL TNF-alpha and 10 ng/mL IFN-gamma). Monolayers inoculated in 24-well plate were collected for determination of transepithelial electrical resistance (TER) with an ohmmeter at post treatment hour (PTH) 0, 6, 12, 24, 36, and 48, the permeability of monolayers with fluorescein isothiocyanate-labeled dextran (FITC dextran) tracer method at PTH 48, the distribution and morphological change of tight junction occludin with immunofluorescence assay at PTH 48. Monolayers inoculated in 6-well plate were collected for determination of protein expression of occludin, myosin light chain kinase (MLCK), and phosphorylated MLC (pMLC) with Western blot at PTH 24. Data were processed with one-way analysis of variance and t test. RESULTS: (1) There was no obvious difference in TER in control group at each time point (F = 0.86, P > 0.05). TER in IFN-gamma group and TNF-alpha group were gradually decreased during PTH 6-48, but showed no statistical difference as compared with that at PTH 0 (with F value respectively 1.69, 2.47, P values all above 0.05). TER in IFN-gamma plus TNF-alpha group was significantly decreased from PTH 24 as compared with that at PTH 0 (t = 4.97, P < 0.05) and that in each of the other three groups (F = 11.54, P < 0.05). (2) The permeability of monolayers in IFN-gamma plus TNF-alpha group [(1197 +/- 215)pmol] was significantly higher than that in control group, IFN-gamma group, and TNF-alpha group [(303 +/- 93), (328 +/- 76), (797 +/- 177) pmol, with t value respectively 4.8, 5.0, 6.9, P values all below 0.01]. (3) There was no statistical difference in occludin expression at PTH 24 among four groups (F = 0.26, P > 0.05). The occludin in control group at PTH 48 was regular in arrangement, while that in IFN gamma and TNF-alpha groups was irregular in arrangement. The arrangement of occludin in IFN-gamma plus TNF-alpha group at PTH 48 was interrupted, with obvious redistribution in cytoplasm. (4) The protein expression of pMLC in IFN gamma plus TNF-alpha group (0.95 +/- 0.05) was significantly higher than that in control group, IFN-gamma group, or TNF-alpha group (0.57 +/- 0.12, 0.56 +/- 0.07, 0.59 +/- 0.10, respectively, F = 17.97, P < 0.01). The protein expression of MLCK in IFN-gamma plus TNF-alpha group (1.57 +/- 0.36) was also significantly higher than that in control, IFN-gamma, TNF-alpha groups (0.85 +/- 0.18, 1.04 +/- 0.23, 1.00 +/- 0.07, respectively, F = 9.05, P < 0.05). CONCLUSIONS: Combination of IFN gamma and TNF-alpha can induce intestinal epithelial barrier dysfunction by up regulating MLCK protein expression and promoting MLC phosphorylation. PMID- 21651852 TI - [Observation on marrow-derived mesenchymal stem cells differentiating into functional cells in rabbit with smoke inhalation injury]. AB - OBJECTIVE: To observe the homing and differentiation of marrow-derived mesenchymal stem cells (MSC) transplanted intravenously in smoke inhalation injured rabbits. METHODS: Thirty-two New Zealand big ear rabbits were divided into normal control group (NC), inhalation injury group (II), normal control + MSC treatment group (NM), and MSC treatment group (MT) according to the random number table, with 8 rabbits in each group. Rabbits in NC group were injected with 10 mL phosphate buffered saline (PBS) via ear marginal vein. Rabbits in NM group were injected with 10 mL PBS containing the third generation MSC labeled by BrdU (1 * 10(7) per 10 mL PBS) via ear marginal vein. Severe smoke inhalation injury model was reproduced in the other two groups, among them rabbits in II group were treated as rabbits in NC group, rabbits in MT group treated as rabbits in NM group. On the 7th and 28th day post treatment (PTD), lung tissue and trachea tissue were harvested from four groups for observation on injury with HE staining. Homing of MSC in injured tissue was observed with immunohistochemistry staining. The differentiation of MSC into functional cells was observed with immunohistochemical double staining of combining nuclear marker BrdU with lung (trachea) membrane-specific marker aquaporin-5 (AQP-5), alkaline phosphatase (AKP), CD34, and cytokeratin respectively. RESULTS: (1) MSC homing in lung and trachea tissue was observed in MT group on PTD 7, which was not observed in NM group. (2) AQP-5, AKP, and CD34 positive MSC were observed in lung tissue in MT group on PTD 28, while cytokeratin positive MSC was not observed in trachea tissue. No positively marked MSC was observed in NM group. (3) Injury in lung and trachea was less severe in MT group than in II group; and the proliferation of fibroblasts was less in MT group. CONCLUSIONS: Intravenous injection of MSC to rabbits with smoke inhalation injury can migrate to lung and trachea tissue at obviously inflammatory site, and differentiate into alveolar epithelial cells typeI and II, and pulmonary vascular endothelial cells, which may participate in the process of tissue repair in smoke inhalation injury. PMID- 21651853 TI - [Regulation of proliferation and apoptosis of human vascular endothelial cell by Acheron]. AB - OBJECTIVE: To investigate regulatory effect of Acheron (Achn) on proliferation and apoptosis of human vascular endothelial cell. METHODS: (1) Eahy926 cells were cultured in serum-free DMEM medium (96-well plates) and were divided into Achn inhibition group (transfected with plasmid psi-Achn), psi4.1 group (transfected with psi4.1 empty vector), Achn induction group (transfected with pcDNA-Achn), pcDNA3.1 group (transfected with pcDNA3.1 empty vector), cotransfection group [cotransfected with pcDNA-Achn + psi-calcium/calmodulin-dependent serine protein kinase (CASK)], blank control group (treated with PBS) according to the random number table (the same method below). The cell proliferation was determined by MTT assay at post transfection hour (PTH) 1, 24, 48, 72, with expression of absorbance value. (2) Total protein of Eahy926 cells were extracted and quantitated by BCA assay, and then they were divided into Achn antibody precipitation group (100 ug protein), CASK antibody precipitation group (100 ug protein), IgG antibody group (100 ug protein), Western blot group (20 ug protein). Achn and CASK protein levels were determined by immunoprecipitation and Western blot. (3) Synchronously cultured Eahy926 cells were divided into LPS induction group (treated with 5 mol/L LPS), Achn transfection group (transfected with pcDNA-Achn), cotransfection group (cotransfected with psi-CASK and pcDNA Achn), KCl group (treated with 5 mol/L KCl), and blank control group (treated with 5 mol/L PBS). Cells in transfection groups were stimulated by LPS for 12 hours after PTH 24. Caspase-3 protein level was detected by immunohistochemistry. (4) Synchronously cultured Eahy926 cells were divided into Achn inhibition group (transfected with psi-Achn vector), Achn induction group (transfected with pcDNA Achn vector), and blank control group (treated with PBS). Apoptosis rate was determined by FITC/PI with flow cytometry. Data were processed with one-way analysis of variance and t test. RESULTS: (1) The cell proliferation in Achn inhibition group was lower than that in psi4.1 group from PTH 24, and the differences were statistically significant at PTH 48, 72 (with t value respectively 10.777, 6.112, P values all below 0.05). The cell proliferation in Achn induction group during PTH 24-72 were higher that in pcDNA3.1 group (with t value respectively 5.367, 6.053, 9.831, P values all below 0.05). The cell proliferation in cotransfection group at PTH 48, 72 were significantly lower than that in Achn induction group (with t value respectively 5.481, 9.517, P values all below 0.05). (2) Achn protein was detected in CASK antibody precipitation group while CASK protein was also detected in Achn antibody precipitation group. (3) Caspase-3 level in Achn transfection group was lower [(15.6 +/- 0.5)%] as compared with that in LPS induction group [(32.8 +/- 2.6)%, t = 10.083, P < 0.05], and that in cotransfection group showed further inhibition [(7.0 +/- 2.0)%, t = 9.827, P < 0.01]. (4) Apoptosis rate in Achn inhibition group [(45.6 +/- 10.9)%] was higher than that in blank control group [(13.2 +/- 4.3) %, t = 7.043, P < 0.05]; while that in Achn induction group [(5.3 +/- 2.9)%] was lower than that in blank control group (t = 6.499, P < 0.05). CONCLUSIONS: Achn can promote human vascular endothelial cell proliferation, and inhibit its apoptosis induced by LPS or burn serum, and the effect is related to CASK. PMID- 21651854 TI - [The viral acceptor antagonist to entrapment ligand H9 in vitro activeness and the function to human acceptor CX3-CR1]. AB - AIM: To clarify the activeness of H9 in vitro and internalization and modulation of the surface chemokine receptor CX3CR1 induced by H9, To discuss the influence of H9 on the chemokine receptor CX3CR1. METHODS: Inhibition by chemotactic peptide on the physiological detection of chemokine induced cell migration activity. Flowcytometry examined the effection of H9 on intracellular calcium. Laser scanning confocal microscopy and flow cytometry were used to determine the quality and quantity of CX3CR1 internalization. RESULTS: H9 was able to block the migration induced by chemokine receptor. In the chemoattraction test, H9 was unable to induce the chemotactic movement, and it does not affect the signal transduction and activeness of cells. It was found that H9 could induce internalization with a maximal rate of 70%, at the concentration of 200 ng/mL. The internalized CX3CR1 molecules could recycled to the cell surface. CONCLUSION: H9 makes human CX3CR1 internalize. After internalizing, the CX3CR1 receptor recirculates the cell surface. It does not affect CX3CR1 physiology function. H9 could be used as a specificity anti-virus peptide. PMID- 21651855 TI - [Role of glucocorticoid-induced tumor necrosis factor-related protein ligand (GITRL) on lipopolysaccharide indu-ced Kupffer cells apoptosis]. AB - AIM: To study the role of glucocorticoid-induced tumor necrosis factor-related protein ligand (GITRL) on apoptosis of mouse Kupffer cells (KCs) induced by lipopolysaccharide (LPS). METHODS: The KCs were isolated from BALB/c mice and transfected with Control siRNA or GITRL siRNA for 24 h. The KCs were randomly divided into four groups including control group: cultured in media alone, dexamethasone (Dex) group: media with Dex 10 MUmol/L, LPS group: media with LPS 1 mg/L, and LPS+Dex group: media with LPS 1 mg/L and Dex 10 MUmol/L. At 24 h after treatment, the expression of GITRL was detected by immunocytochemistry. The apoptosis of KCs was measured by Annexin V-FITC/PI double staining and FCM. RESULTS: The GITRL expression of KCs was increased by LPS challenge (P < 0.05), whereas Dex treatment attenuated the increase. LPS challenge induced KCs apoptosis, but the LPS induced apoptosis was inhibited by GITRL siRNA transfection or Dex treatment (P < 0.05, respectively). CONCLUSION: LPS could induce mouse KCs apoptosis, which may be depend on GITRL signal transduction. PMID- 21651856 TI - [Neuropeptide Y promotes the proliferation and differentiation of 3T3-L1 preadipocytes]. AB - AIM: To observe the effect of neuropeptide Y on the proliferation and differentiation of 3T3L1 preadipocytes and detect the mechanics. METHODS: 3T3-L1 preadipocytes were induced to differentiation by the cocktail medium containing 3 isobutyl-1-methylxanthine (IBMX), dexamethasone and insulin. After 2 days, the cells were divided into 3 groups: the control group(without inducer), the routine group(insulin used as inducer) and the experiment group(10(-8), 10(-9), 10(-10) mol/L NPY used as inducer). At day 7 and 12, cell differentiation was observed by phase contrast microscope. At day 12, Oil red O staining was performed. Proliferation capacities of 3T3L1 cells were assessed by MTT. Western blot was used to know the protein level of peroxisome proliferator-activated receptor gamma (PPAR-gamma) and The CCAAT/enhancer-binding protein-alpha(C/EBP-alpha). RESULTS: NPY 10(-8) mol/L promotes the differentiation of 3T3L1 preadipocytes, 10(-9) mol/L, 10(-8) mol/L NPY increased 3T3-L1 cells proliferation. The protein levels of PPAR-gamma and C/EBP-alpha were up regulated by 10(-8) mol/L NPY. CONCLUSION: Neuropeptide Y promotes the differentiation and Proliferation of 3T3 L1 cells, this effect may be related to up-regulation of PPAR-gamma and C/EBP alpha. PMID- 21651857 TI - [Expression and distribution of Nrf2 in several hepatocellular carcinoma cell lines]. AB - AIM: The aim of this study was to investigate the expression and the distribution of Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) in several human hepatocellular cancer cell lines (HepG2, Hep3B, SMMC-7721). METHODS: Flow cytometry was used to figure out the percentages of Nrf2-positive cells in these three cell lines. The localization of Nrf2 was estimated by the laser confocal microsopy and the expression levels of Nrf2 in hepatocellular cancer cell lines were detected by Western blot analysis. RESULTS: The percentages of Nrf2 positive cells in HepG2, Hep3B, and SMMC-7721 were 99.39%, 99.94%, and 99.98% through the flow cytometry. The laser confocal microsopy showed that Nrf2 mainly localized in the cytoplasm of HepG2 cells, distributed evenly in the cytoplasm and nucleus of Hep3B cells, and mainly localized in the nucleus of SMMC-7721 cells. Western blot analysis confirmed the result by the laser confocal microsopy. CONCLUSION: The data on the expression and localization of Nrf2 will be helpful for the following research on the role of Nrf2 in the drug resistance of hepatocellular carcinoma to chemotherapy. PMID- 21651858 TI - [The different structure forms of HBx protein influence their intracellular distribution in hepatocellular carcinoma HepG2 cells]. AB - AIM: Different eukaryotic expression vectors were selected in this research, and then we respectively cloned and constructed recombinant plasmids contained HBX gene or its different fusion forms with GFP. We are aimed to explore the influence of the HBX protein with different structure on its intracellular localization. METHODS: Flag-HBX gene was amplified from pcDNA3.0-HBX plasmid in our laboratory, cloned into pMD-18T vectors, sequenced.and then subcloned into different vectors. After right sequenced, respective recombinant plasmids of pFlag- HBX-IRES2-EGFP, pEGFP-C3-Flag-HBX and pFlag-HBX-EGFP-N3 were transiently transfected into hepatoma HepG-2 cells. The intra-cellular localizations and distributions of HBX protein were examined by indirect immunofluorescence. RESULTS: Three different Flag-HBX eukaryotic expression vectors were successfully constructed. After transfection of them into HepG2 cells respectively, indirect immunofluorescence demonstrated that HBX protein fused with GFP in different forms show distint intra-cellular distribution characteristics. CONCLUSION: We have provided significant experimental evidences for research of the role of HBX protein in the development of hepatocellular carcinoma, and especially the references for explanation of the outcomes in vitro transfection experiments. PMID- 21651859 TI - [The inhibitory effect of RNA interference on STAT3 expression in liver cancer cell line SMMC7721]. AB - AIM: To investigate the chemosensitivity small interfering RNA (siRNA) on liver cancer cell line SMMC7721. METHODS: The siRNA sequences design based on signal transducers and activators of transcription 3 (STAT3) gene, siRNA were transfected into SMMC7721 cells through liposome lipofectamine(TM); 2000. The expression inhibition of STAT3 gene in SMMC7721 cells was measured by real-time relative quantitative PCR. The cells growth inhibition rate were measured by MTT colorimetry after 10 MUmol/L 5-fluorouracil (5-Fu) action. RESULTS: The siRNA expression vector to aim directly at STAT3 gene was constructed successfully. The result of real-time PCR revealed that specificity siRNA were transfected into SMMC7721 cells could inhibit the expression of STAT3 gene. STAT3 gene in SMMC7721 cells were specialty and effectually inhibit the expression by RNA interference (RNAi). MTT colorimetry detection result revealed that SMMC7721 cells inhibition rate significantly increasing after siRNA action. CONCLUSION: The siRNA expression vector can active inhibit expression of STAT3 gene in SMMC7721 cells, enhance its sensitivity to chemotherapeutics 5-Fu, to provide experiment based on for the biological therapy of tumor. PMID- 21651860 TI - [Effects of oral type II collagen on serum antibody and the cytokine cxpression in Peyer's patches]. AB - AIM: To explore the effects of oral type II collagen (CII) on the morphology, cytokine expressions of Peyer's patches(PP)and the levels of serum specific IgG, IgA, IgM. METHODS: CII was orally administrated to Kunming mice in continuous 10 days at different dosage. The CII or adjuvant immunization was given at 11 d and 21 d. The blood and Peyer's patches were collected at 11 d, 21 d and 31 d. The PP hyperplasy was observed by light microscope after HE staining. The fluorescent real time RT-PCR was used to detect the mRNA expressions of IL-17, TNF-alpha, IFN gamma and TGF-beta1 in PP lymph node. The serum specific IgG, IgA, IgM contents were detected by ELISA. RESULTS: After oral administration of CII for 10 d, the PP lymph node hyperplasia was active and the cap-shape structure could be seen clearly in high dose group, the serum IgA could be detected, the gene expressions of IL-17, TNF-alpha and IFN-gamma were inhibited. After the CII initial immunity, the IgA, IgM, IL-17 levels were descended and TGF-beta1 level was increased in the experiment groups as compared with control group(P < 0.05 or P < 0.01). After the CII booster, IgA was notably increased in high dose group(P < 0.05), in experiment groups IgM was still suppressed (P < 0.05 or P < 0.01) and TGF-beta1 levels were higher than control group(P < 0.05). In adjuvant immunization groups the cytokine expressions were similar to CII immunization groups, the differences of serum specific IgG, IgA, IgM could not be observed as compared with control group. CONCLUSION: The oral administration of CII can increase the serum specific IgA and suppress the gene expressions of IL-17, TNF-alpha, IFN-gamma in the Peyer's patches. It can still have inhibitory action on the serum specific IgA, IgM and IL-17 gene expressions after CII immunization. The results indicate that the changes of the serum specific antibodies and cytokine gene expressions play an important role on treating rheumatoid arthritis by oral CII to induce immune tolerance. PMID- 21651861 TI - [CTLs induced by hTERT-related multiepitope peptide-sensitived mDCs specifically kill HLA-A24+ tumor cells]. AB - AIM: To study the antigen specific anti-tumor effect of cytotoxic T lymphocytes(CTLs), which was induced by human telomerase reverse transcriptase (hTERT)-related multiple epitope peptides impulsed myeloid dendritic cells(mDCs), against human leukocyte antigen (HLA)-A24(+) tumor cells. METHODS: Four branches of multiple antigen peptides (MAPs) of hTERT epitopes and three separate peptides were solid-phase artificially synthesized, phlebotomize peripheral blood from HLA A24(+) healthy volunteers, sorted the blood through MACS MicroBeads and cultured mDCs, Nylon fiber column purified T lymphocytes, mDCs impulsed with each type of peptides were co-cultured with T lymphocytes to induce CTLs specifically killing effect, and the resultant CTLs were used as effector cells, SMMC-7721 with hTERT and HLA-A24 positive and SKOV3 which are hTERT-positive but HLA-A24-negative tumor cells were used as target cells. The level of human IL-12, TNF-alpha in the culture supernatant was determined by ELISA. Flow cytometry assay was used to assess the killing ability of CTLs against tumor cells. RESULTS: MAPs of hTERT epitopes including I540 (ILAKFLHWL), V461 (VYGFVRACL), L766 (LTDLQPYMRQFVAHL) and three separate peptides could impulse mDCs and then induce CTLs to specifically kill SMMC-7721, CTLs induced by MAPs had stronger cytotoxic effect compared with three separate peptides mixed(P < 0.05). CONCLUSION: mDCs-impulsed with hTERT associated MAPs can induce production and proliferation of allogenic CTLs, which show antigen specific anti-tumor effect against HLA-A24(+) tumor cells. This result has significantly meaning in tumor immunotherapy. PMID- 21651862 TI - [Cloning and expression of human sPD-1-Fc in Cos-7 cells]. AB - AIM: To investigate human soluble PD-1 (sPD-1) biological activity sPD-1 gene be cloned and expressed in eucaryote cells. METHODS: sPD-1 gene was amplified from human PBMC mRNA by RT-PCR and cloned into eucaryotic expression vector pSG5-Fc. And the positive recombinant plasmid pSG5-Fc -sPD-1 was screened by enzyme digestion and sequencing.The correct sequencing of the recombinant plasmid pSG5 Fc-sPD-1 was transfected into COS-7 cells. The expressed recombinant protein in the supernatant was concentrated with protein A-agarose and analyzed by Western blot. The binding activity to PD-L1 which was expressed with prokaryotic cells was detected with Co-IP. RESULTS: The human sPD-1 fragment was obtained through RT-PCR. The plasmid pSG5-Fc-sPD-1 was constructed by double enzyme digestion and ligation of vector pSG5-Fc and fragment sPD-1. Sequenced sPD-1 gene was coincident with the theoretical sequence. sPD-1-Fc fusion protein in the supernatant was expressed in COS-7 cells and identified by Western blot. The activity of recombinant fusion protein sPD-1-Fc bound to PD-L1 had been detected with Co-IP. CONCLUSION: The human sPD-1 has been cloned and expressed in eucaryote cells successfully. The sPD-1-Fc fusion protein can be effective in binding to PD-L1, which can be used for further research in the function and clinical application of sPD-1. PMID- 21651863 TI - [Effect of UBE2C overexpression on the proliferation of 293T cell line]. AB - AIM: To establish a 293T cell line with stable expression of UBE2C and to investigate the effect of UBE2C overexpression on the proliferation of 293T cells. METHODS: Recombinant plasmid pcDNA3.1(-)/UBE2C successfully constructed in previous time was transfected into 293T cells by lipofectamine 2000. After screened with G418 for 4 weeks, Western blot was used to detect the protein level of UBE2C and MTT assay to detect the proliferation of 293T cells. RESULTS: Compared with pcDNA3.1(-) transfected group, Western blot analysis demonstrated that the level of UBE2C was significantly increased in pcDNA3.1(-)/UBE2C transfected group (P < 0.05). MTT assay showed that 293T cells overexpressing UBE2C proliferated faster than control 293T cells. CONCLUSION: A 293T cell line with UBE2C stable expression is successfully established and UBE2C promoted the proliferation of 293T cells. PMID- 21651864 TI - [Cloning, prokaryotic expression of novel swine gene P58IPK and its polyclonal antibody preparation]. AB - AIM: To clone a novel swine gene P58(IPK)[58-kDa(inhibitor of protein kinase) protein] and prepare its polyclonal antibody for further research of influenza and host interaction. METHODS: The swine P58(IPK); gene was first identified in silico through homology searching in the swine EST database. Then this gene was amplified by reverse transcription polymerase chain reaction (RT-PCR). The cDNA of the gene contained the complete open reading frame(ORF) of 1 518 bp, and encoded 505 amino acid residues (Accession No.HQ287801). The gene was first analyzed using bioinformatics methods. Then P58(IPK) was cloned into a prokaryotic expression vector pET-32a to construct a recombinant plasmid named as pET-P58(IPK). The fusion protein his-P58(IPK) was expressed in E.coli BL21 and purified using a his-tag protein purification column. Subsequently rabbits were immunized with the purified protein. RESULTS: Specific polyclonal antibody against the fusion protein his-P58(IPK) was obtained. The activity of the antibody was determined through double-immunodiffusion test. The titer of the antibody was 1:20 000 as shown by ELISA. specifically recognized the protein P58(IPK) by Western blot and immunofluorescence assay. CONCLUSION: The novel swine gene P58(IPK) has been successfully cloned and its polyclonal antibody has been prepared. PMID- 21651865 TI - [Preparation of rabbit anti-recombinant human calreticulin antibody and its characterization]. AB - AIM: To prepare the rabbit anti-recombinant human calreticulin (hCRT) antibody and its characterization. METHODS: The gene coding for hCRT was amplified by PCR and cloned into prokaryotic expression vector pET32a. Then the recombinant plasmid pET32a/hCRT was transformed into E.coli BL21 (DE3) and expressed under IPTG induction. The recombinant hCRT was purified through Ni(2+) -NT agarose gel column and the purified hCRT used as immunogen to immunize the rabbit.The titer and specificity of the rabbit anti-hCRT antibody were analyzed by ELISA, Western blot and immunohistochemical staining, respectively. RESULTS: The recombinant hCRT was successfully expressed and purified, and the polyclonal anit-hCRT antibody was successfully prepared. The titer of the antiserum was 1:51 200 by ELISA. Western blot analysis showed that the antibody reacted specifically to hCRT. Immunohistochemical staining detection manifested the antibody could recognize the native hCRT. CONCLUSION: The rabbit anti-hCRT antibody with high titer and specificity has been successfully prepared, which lays the foundation for further research on detection of hCRT and its clinical application. PMID- 21651866 TI - [Prokaryotic expression, purification of human papillomavirus type 16 E1 protein and preparation of it's antiserum]. AB - AIM: To express and purify the human papillomavirus type 16 E1 protein in E.coli and prepare the antibody against HPV-16 E1. METHODS: HPV-16 E1 gene was amplified by PCR and cloned into prokaryotic expression vector pMAL-p2x, and the recombinant plasmid was transformed into E.coil BL-21. We optimize the soluble expression condition of fusion protein by induction with different IPTG concentration and different temperature. The expressed fusion protein was purified by mahose affinity column Chromatography. To prepare the anti-serum, New Zealand white rabbits were immunized with purified HPV-16 E1 protein via hypodermic and volar. Western blot and ELISA analyzed the serum's specificity against HPV-16 E1 and serum titers. RESULTS: Restriction endonuclease analysis and DNA sequencing showed HPV-16 E1 was cloned into the plasmid pMAL-p2x. Based on the optimization experiments, it concluded that the best soluble expression conditions for the HPV-16 E1 fusion protein involved addition of IPTG to a final concentration of 0.5 mmol/L and then further incubation at 28 degrees C. The purity of the HPV-16 E1 fusion protein was over 95.7% after purification. ELISA and Western blotting showed the titers of the anti-serum were above 1:640 000, and the anti-serum can specifically bind with HPV-16 E1 protein. CONCLUSION: We have ingathered the HPV-16 E1 fusion protein by expressing in E.coli and purifying, and the antibody against HPV-16 E1 was prepared with the fusion protein immunizing New Zealand white rabbits. This work will provide an antigen and detection antibody for further study on the HPV-16 E1 function. PMID- 21651867 TI - [Development, identification and function assay of monoclonal antibody against platelet membrane glycoprotein Ib]. AB - AIM: To prepare and identify a monoclonal antibody (mAb) against human platelet glycoprotein Ib and make its application. METHODS: BALB/c mice were immunized with human platelets washed, and the spleen cells of them were fused with myloma cells. A hybridoma cell was screened by indirect ELISA and cloned, and the mAb were purified from the ascites of mice. Ig subclass was analysed by double immunodiffusion. The antigen recognized by monoclonal antibody was identified by flow cytometry and radioimmunoassy, respectively. The inhibition of mAb on plasma von Willebrand factor ristocetin cofactor activity (vWF:Rcof) was investigated by enzyme linked immunosorbent assay (ELISA). RESULTS: A murine mAb against human platelet membrane glycoprotein (GP) Ib was developed and denominated as SZ-151. SZ-151 belonged to IgG1 subclass and its titer in ascites was 1:20 000. Flow cytometry and radioimmunoassy showed that the antigen recognized by monoclonal antibody SZ-151 was platelet membrane GPIb. ELISA showed that SZ-151 did not inhibit plasma von Willebrand factor ristocetin cofactor activity. CONCLUSION: A mAb, SZ-151 against platelet glycoprotein Ib was developed, which could be useful in assays of plasma von Willebrand factor ristocetin cofactor activity(vWF:Rcof) and can be used for diagnose patients with vWD. PMID- 21651868 TI - [Prokaryotic expression of recombinant bovine IL-4 and development of monoclonal antibodies against bovine IL-4]. AB - AIM: To express recombinant bovine IL-4 (rBoIL-4) in Escherichia coli and prepare monoclonal antibody (mAb) against rBoIL-4. METHODS: The IL-4 gene without coding signal peptides was amplified from pSP73-BoIL-4 by PCR, then inserted into prokaryotic expression vector pGEX-6p-1 and pET-30a(+). The recombinant plasmids pGEX-6p-1-BoIL-4 and pET-BoIL-4 were transformed into DH5alpha for sequencing. After sequencing confirmation, the two recombinant plasmids were transformed into expression bacteria BL21 and BL21(DE3) respectively. BALB/c mice were immunized with the purified protein rHis-BoIL-4. With the purified rGST-BoIL-4 as detecting antigen, mAb-produced hybridoma cells against BoIL-4 were screened by indirect ELISA. The specificity of the mAbs was characterized by indirect ELlSA, Dot-ELlSA and Western blot. RESULTS: The recombinant bacteria BL21(pGEX-6p-1-BoIL-4) and BL21(DE3)(pET-BoIL-4) were developed. After induced by IPTG, SDS-PAGE analysis showed that the expression products of rGST-BoIL-4 and rHis-BoIL-4 had a molecular weight of 39 kD and 19 kD respectively, and expressed in inclusion body form. Seven hybridoma cell lines secreting mAbs against BoIL-4, named 2B8, 4A10, 5D6, 5D8, 7G10, 8B7 and 10F8 were obtained. The immunoglobulin subclasses were IgG1. The ascitic titers of these mAbs were 5 000, 16 0000, 10 000, 640 000, 5 000, 40 000 and 40 000, respectively. In Dot-ELISA, all mAbs could only react to the immunogen and the detecting antigen. Western-blot analysis confirmed that mAbs could only react to the corresponding recombinant proteins. The mAbs also reacted to the standard recombinant boIL-4 with biological activity. CONCLUSION: Seven mAbs specific to rBoIL-4 protein are obtained, which may have important application value in further study on diagnosis and pathogenesis of cattle diseases. PMID- 21651869 TI - [The effect of sevoflurane inhalation anesthesia only and propofol total intravenous anesthesia on perioperative cytokine balance in lung cancer patients]. AB - AIM: To investigate the effects of sevoflurane inhalation anesthesia only and propofol total intravenous anesthesia on perioperative cytokine balance in lung cancer patients. METHODS: ASA I or II patients undergoing lobectomy for lung cancer were randomly divided into two groups with 45 cases each. In group A, patients received g sevoflurane inhalation anesthesia only and patients in group B received propofol total intravenous anesthesia. The cervical venous blood samples were obtained at the following time points: before induetion of anesthesia(T0), before the start of one-lung ventilation(T1), before the end of one-lung ventilation(T2), after closed chest surgery(T3), after 24 h (T4) . The serum concentrations of IL-6, IL-8 and IL-10 were measured by ELISA. RESULTS: (1) In both groups the concentration of IL-6 increased at T1 and kept raising to a high level at T4 which showed significant differences with that of pre operation(P < 0.05).Compared between the groups, the concentration of IL-6 at T1 and T2 in group B was lower than that of group A(P < 0.05). (2) In both groups the concentration of IL-8 kept at T1 and T3 which were significant with that of pre-operation(P < 0.01). The concentration of IL-8 decreased apparantly at T4 in both groups, it was significant with that of pre-operation though(P < 0.01).Compared between the groups, the concentration of IL-8 at T1, T2 and T3 in group B were all lower than that of group A (P < 0.05). (3) In both groups the concentration of IL-10 increased at T1 which was significant with that of pre operation(P < 0.05)and kept at T2 and T3. It dropped somehow at T4 but still maintained at a high level.Compared between the groups, the concentration of IL 10 in group B at T1, T2, T3 and T4 was singicantly higher than that of group A(P < 0.05). CONCLUSION: Propofol causes less inflammatory mediator release and can also modulate the balance of cytokines. It is a better anesthetic for lung cancer than sevoflurane. PMID- 21651870 TI - [Change and significance of Th17 cells and its secretive IL-17 in patients with autoimmune hemolytic anemia]. AB - AIM: To observe the percentage of Th17 cells in the peripheral blood and levels of plasma IL-17 of patients with autoimmune hemolytic anemia (AIHA)before treatment and after glucocorticoid treatment and to explore their clinical significance. METHODS: Flow cytometric assay were used to detect the rate of Th17 cells in AIHA patients. The level of plasma IL-17 in AIHA patients were measured by ELISA. RESULTS: The rate of Th17 cells and the level of plasma IL-17 were significantly increased before treatment as compared with that in normal controls [(2.78 +/- 0.59)%, (126.4 +/- 11.6)ng/L vs (0.59 +/- 0.15)%, (52.3 +/- 4.8) ng/L](P < 0.01). After treatment, The percentage of Th17 cells (1.05+/-0.28)% was significantly decreased (P < 0.01). The same tendency was also found in the levels of plasma IL-17(78.5 +/- 6.4) ng/L(P < 0.01). CONCLUSION: The rate of Th17 cells and the lever of plasma IL-17 significantly elevate in AIHA patients. Glucocorticoid might play a role in AIHA treatment by down-regulating Th17 cells number and concentrations of IL-17. PMID- 21651871 TI - [In vitro cytotox icity effects of cocultured DC-C IK cells combined with sorafenib against hepa to cellular carcinoma]. AB - AIM: To investigate the in vitro inhibitory effects of DC(dendritic cell)-CIK (cytokine-induced killer cell) cocultured cells combined with sorafenib against hepatocellular carcinoma cell line BEL27402. METHODS: DC and CIK cells were generated in vitro by stimulating human peripheral blood mononuclear cells with different cytokines, and then they were cocultured. The cytotoxicity of DC-CIK cocultured cells (DC-CIK) combined with sorafenib against BEL-7402 cells was determined by CCK8 kit. The apoptosis of BEL27402 cells was measured by Annexin V FITC Kit. RESULTS: The cytotoxicity rate of BEL27402 cells in DC-CIK +sorafenib group was significantly higher than those in the other there groups, with cytotoxicity rate in DC-CIK + sorafenib group being (72.24 +/- 2.42)% , which was 1.8 times that in DC-CIK group, 2.1 times that in sorafenib group , and 1.6 times that in CIK group(P < 0.01). The apoptosis rate of BEL-7402 cells in DC-CIK + sorafenib group was significantly higher than those in the sorafenib and DC-CIK groups, with the apop tosis rate in DC-CIK + sorafenib group being (77.36 +/- 1.92)% (P < 0.05). CONCLUSION: DC-CIK cocultured cells combined with sorafenib can inhibit the growth of hepatocellular carcinoma cell line BEL-7402 in vitro. Molecular targeting therapy combined with immunotherapy may be a new way for the comprehensive treatment of hepatocellular carcinoma. PMID- 21651872 TI - [Increase in peripheral and liver infiltrating regulatory T cells favors development of primary hepatocellular carcinoma]. AB - AIM: This study attempted to investigate the features of Treg cells in peripheral blood and liver of patients with primary hepatocellular carcinoma (HCC). METHODS: Peripheral blood samples were obtained from 30 HCC patients and 30 healthy control subjects, then were quantitatively analyzed for Treg cells by using flow cytometry. Liver infiltrating lymphocytes (LIL) isolated from resected tumor samples of 7 HCC patients were simultaneously analyzed. RESULTS: There was a significant increase in the frequency of peripheral Treg cells in HCC patients compared with healthy controls (P < 0.01). Furthermore, we also found that there was a higher frequency of infiltrated Treg within tumor samples than the counterpart in non-tumor region (P < 0.05). In addition, CD4(+) CD25(low) and CD4(+) CD25(-) T cells isolated from resected tumor samples were found to express higher level of FOXP3 molecules. CONCLUSION: Our findings showed that a dramatic increasing increase of Treg in peripheral blood and liver tissue of HCC patients may be associated with the significant increased development of Treg, which favors the disease progression through the suppressive effect of Treg on host immune response in these patients. PMID- 21651873 TI - Nurse-administered early warning score system can be used for emergency department triage. AB - INTRODUCTION: Studies have shown that early warning score systems can identify in patients at high risk of catastrophic deterioration and this may possibly be used for an emergency department (ED) triage. Bispebjerg Hospital has introduced a multidisciplinary team (MT) in the ED activated by the Bispebjerg Early Warning Score (BEWS). The BEWS is calculated on the basis of respiratory frequency, pulse, systolic blood pressure, temperature and level of consciousness. The aim of this study is to evaluate the ability of the BEWS to identify critically ill patients in the ED and to examine the feasibility of using the BEWS to activate an MT response. MATERIAL AND METHODS: This study is based on an evaluation of retrospective data from a random sample of 300 emergency patients. On the basis of documented vital signs, a BEWS was calculated retrospectively. The primary end points were admission to an intensive care unit (ICU) and death within 48 hours of arrival at the ED. This study was registered at clinicaltrials.gov (NCT01243021). RESULTS: A BEWS >= 5 is associated with a significantly increased risk of ICU admission within 48 hours of arrival (relative risk (RR) 4.1; 95% confidence interval (CI) 1.5-10.9) and death within 48 hours of arrival (RR 20.3; 95% CI 6.9-60.1). The sensitivity of the BEWS in identifying patients who were admitted to the ICU or who died within 48 hours of arrival was 63%. The positive predictive value of the BEWS was 16% and the negative predictive value 98% for identification of patients who were admitted to the ICU or who died within 48 hours of arrival. CONCLUSION: The BEWS is a simple scoring system based on readily available vital signs. It is a sensitive tool for detecting critically ill patients and may be used for ED triage and activation of an MT response. PMID- 21651874 TI - Quality of care using a multidisciplinary team in the emergency room. AB - INTRODUCTION: Bispebjerg Hospital has implemented a multidisciplinary team reception of critically ill and severely injured patients at the Emergency Department (ED), termed emergency call (EC) and trauma call (TC). The aim of this study was to describe the course, medical treatment and outcome for patients received by this multidisciplinary team and to evaluate the quality of acute medical treatment of these patients. MATERIAL AND METHODS: A retrospective evaluation was made of all ECs and TCs registered during a six-month period. Information on sex, age, interventions at the ED, time spent at the ED and outcome measures (admission, Intensive Care Unit (ICU) admission and death) were obtained. The quality of the acute medical treatment during the ED stay and the first 48 hours of admission were evaluated by senior consultants from the departments receiving the patients. RESULTS: A total of 150 ECs and 47 TCs were included. The median time spent at the ED was 65 minutes for ECs and 95 minutes for TCs. In EC patients a median of eight interventions were performed at the ED, while a median of five interventions were performed in TC patients. A total of 137 EC patients were admitted to hospital including 32 patients admitted to the ICU. In all, 49 EC patients died during admission. Forty percent of TC patients were discharged to their homes. Only one trauma patient died and none were admitted to the ICU. The acute medical treatment was found to be satisfactory in 87% of EC patients and 96% of TC patients. CONCLUSION: A multidisciplinary team reception ensures early initiation of diagnostic procedures and treatment, short ED stays and admission to relevant departments in critically ill and severely injured patients. PMID- 21651875 TI - Becoming a client of the Danish social service system increases stress in parents of disabled infants. AB - INTRODUCTION: Parents of a young child with severe disabilities are facing a large range of new challenges; furthermore, most of these families have extended social needs regarding information, financial support, day care facilities, disability aids, etc. Many parents with disabled children have been found to be dissatisfied with social services. This study explores parents' experiences with Danish social services during their transition to a new daily life after the birth of a severely disabled child. MATERIAL AND METHODS: Repeated qualitative interviews were performed individually with 16 parents of a severely disabled young child during the first two years after the diagnosis of the child's disabilities. Data were analysed using grounded theory. RESULTS: We found that the encounter with the social services increased stress in the families. Parental expectations were not met, especially regarding information; parents felt clientized, and obtaining social support was very resource consuming. Parents' needs regarding practical support and empathic case-working were not met and they spent much time and effort due to lacking continuity between sectors. CONCLUSION: Parents have specific needs when becoming clients in the social service system whose organisation of social services needs improvement. Health care professionals are advised to identify problems and support cooperation between the parents and the social service system, as well as to report the health related consequences of prolonged and inefficient case-working for the child and its parents. FUNDING: was received from Socialministeriet, Landsforeningen LEV, Ronald McDonalds Bornefond, Susie og Peter Robinsohns fond, Rosalie Petersens fond, PLU-fonden, Ville Heises fond, Sygesikringens forskningsfond, Helsefonden, Elsass fonden. TRIAL REGISTRATION: not relevant. PMID- 21651876 TI - Acceptable results of early closure of loop ileostomy to protect low rectal anastomosis. AB - INTRODUCTION: This was a pilot project performed prior to full implementation of early loop ileostomy closure (within two weeks) following low anterior resection of the rectum in a group of patients selected according to previously recommended criteria for safe, early ileostomy closure. MATERIAL AND METHODS: Retrospective review of medical records. Patients undergoing loop ileostomy closure between December 2009 and October 2010 were analyzed. Data were collected on demographics, tumour characteristics, information about the perioperative period, operative details, postoperative complications, closure operation, the postoperative closure period and follow-up. RESULTS: Eleven patients were included (men, n = 4) with a median age of 58 years (range 47-79 years). Ileostomy closure was performed at a median of ten days (range 8-13 days) following rectum resection. The median hospital stay was 16 days (range 14-24 days). No re-laparotomies were performed. One patient developed a pelvic pus collection ten days post closure and was treated conservatively. One patient died 32 days after closure for reasons not related to surgery. CONCLUSION: The results of this small retrospective study show morbidity rates associated with early loop ileostomy closure that are probably acceptable. Safety, feasibility, timing and selection criteria should be clarified in large randomized studies. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 21651877 TI - Referral of paediatric patients follows geographic borders of administrative units. AB - INTRODUCTION: This observational study examines changes in paediatric hospital seeking behaviour at Kolding Hospital in The Region of Southern Denmark (RSD) following a major change in administrative units in Denmark on 1 January 2007. MATERIAL AND METHODS: Data on the paediatric admissions from 2004 to 2009 reported by department of paediatrics and municipalities were drawn from the Danish National Hospital Registration. Patient hospital-seeking behaviour was related to changes in the political/administrative units. Changes in number of admissions were compared with distances to the corresponding departments. RESULTS: From 2006 to 2009, the number of acute and planned admissions at the Department of Paediatrics in Kolding for children living in the RSD increased by 46.1% and 65.0%, respectively. The corresponding changes for children living in the neighboring region, the Central Denmark Region (CDR), were -69.9% and -78.6%. CONCLUSION: The geographical location of the department under study and the changes in administrative units created a "natural experiment" that showed major changes in paediatric hospital-seeking behaviour. Within the RSD, the free choice of hospitals seemed to work, whereas the new boundary between the CDR and the RSD meant that paediatric patients were admitted at hospitals situated in the CDR even though the distances to these hospitals were considerably longer than those to other hospitals. One could question whether patients really have a free choice across administrative borders as political and economic concerns seemed to outweigh free patient choice. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 21651878 TI - Developmental problems in very prematurely born children. AB - INTRODUCTION: The aim of the present study was to describe the developmental outcome of routine follow-up assessments at the age of five years in a regional cohort of children born at a gestational age < 32 weeks and to investigate neonatal risk factors associated with developmental problems. MATERIAL AND METHODS: The cohort consisted of 237 infants with a gestational age >= 24 and < 32 weeks born in the 1996-2000 period. The children were assessed using the Movement Assessment Battery for Children and Miller Assessment for Preschoolers. The presenting clinical and demographic features were investigated for their association with developmental problems at five years of age by determining odds ratios in univariate analysis. The results are given with 95% confidence intervals. RESULTS: 14% died. 86% of the surviving children were routinely assessed at five years of age. 40% of the children had a normal developmental outcome, 41% were to be observed for developmental deficiencies and 19% had developmental deficiencies. Male gender, low social group, a gestational age < 28 weeks, sepsis, persistent ductus arteriosus, bronchopulmonary dysplasia and abnormal cerebral ultrasound were significantly associated with an unfavourable developmental outcome. CONCLUSION: More than half of the assessed very prematurely born children had developmental problems at five years of age. Children who were to be observed for developmental deficiencies outnumbered children with deficiencies at a two to one ratio. Follow-up assessments of very prematurely born children are still needed to evaluate changes in neonatal practise and developmental outcome in the future. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 21651879 TI - Danish version of Visual Function Questionnaire-25 and its use in age-related macular degeneration. AB - INTRODUCTION: Assessment of visual function can be a complex task and objective means of measurement of visual function do not always correlate with patients' self-perceived visual abilities. The purpose of this study was to translate the visual function questionnaire (VFQ)-25 into Danish with particular focus on its use in patients with late age-related macular degeneration (AMD). MATERIAL AND METHODS: The translation was done in accordance with standard internationally adopted methods. This includes forward translation, back translation, examination of translation quality, and adjudication by bilingual speakers. We presented the questionnaire to 120 consecutive patients with exudative AMD referred to our department and to 25 healthy individuals. We tested the reliability of the Danish version by measuring test-retest reliability, estimated the internal consistency of the questionnaire (Cronbach's alpha-value) and analysed the discriminatory power (validity) of the questionnaire by comparing scores of patients with scores from control individuals without known eye disease. RESULTS: The translated questionnaire produced high test-retest correlations (range 0.8-0.9), had a relatively high-level of internal consistency (range 0.4-0.9) and a high discriminatory power. CONCLUSION: The Danish version of VFQ-25 produces acceptable values of validity and reliability in patients with AMD. PMID- 21651880 TI - Low compliance with a validated system for emergency department triage. AB - INTRODUCTION: Bispebjerg Hospital has introduced a triage system at the Emergency Department (ED) based on "primary criteria" and a physiological scoring system named the Bispebjerg Early Warning Score (BEWS). A BEWS is calculated on the basis of five vital signs which are accessible bedside. Patients who have a "primary criterion" or a BEWS >= 5 are presumed to be critically ill or severely injured and should be received by a multidisciplinary team, termed the Emergency Call (EC) and Trauma Call (TC), respectively. The aim of this study was to examine compliance with this triage system at Bispebjerg Hospital. MATERIAL AND METHODS: Retrospective evaluation of the triage of a random sample of 300 ED patients. ED medical charts were searched for "primary criteria", documentation of vital signs and a BEWS score. If a BEWS score had not been calculated, this was done retrospectively by the author. An evaluation was made to determine whether ECs or TCs had been correctly activated. RESULTS: In 47 patients, all five vital signs for calculation of a BEWS had been documented. A BEWS had been calculated in 22 patients. Nine patients had a TC activation criterion, and in all these cases a TC was activated. A total of 48 patients had an EC activation criterion, but an EC had only been activated in 24 patients. Among the 24 patients for whom an EC had not been activated, eight had a "primary criterion" and 16 patients had a retrospective BEWS >= 5. CONCLUSION: The triage system is not being used systematically and documentation of vital signs is insufficient at Bispebjerg Hospital. As a consequence, many patients who are presumed to be critically ill are not allocated to an EC. Initiatives have been taken to raise compliance with the system. PMID- 21651881 TI - Mammography screening in Denmark. AB - Mammography screening is offered healthy women, and a high standard on professional and organizational level is mandatory not only in the screening programme but even in the diagnostic work-up and treatment. The main goal is to achieve a substantial reduction in disease specific mortality, but it is not possible to evaluate the effect on mortality until several years later, and continuously monitoring of the quality of all aspects of a screening programme is necessary. Based on other European guidelines, 11 quality indicators have been defined, and guidelines concerning organizational requirements for a Danish screening programme as well as recommendations for the radiographic and radiological work have been drawn up. PMID- 21651884 TI - Serological evidence of Histoplasma capsulatum infection among dogs with leishmaniasis in Brazil. AB - Histoplasmosis is a systemic infection caused by the fungus Histoplasma capsulatum. Environmental sources of infection for humans and animals in certain regions and the prevalence of infection in animals are frequently unknown. Because of the clinical and epidemiological similarities between histoplasmosis and leishmaniasis in northeastern Brazil, we decided to investigate the serologic evidence of H. capsulatum in dogs, considering that these animals can act as sentinels for histoplasmosis. A total of 224 serum samples from dogs were tested for antibodies against H. capsulatum through immunodiffusion. A total of 128 (57.14%) samples were positive for leishmaniasis by indirect immunofluorescence assay and four (1.78%) samples were positive for antibodies against H. capsulatum. Immunological evidence of the co-existence of histoplasmosis and leishmaniasis in dogs living in urban areas was observed. Diagnosis and clinical management of these diseases in endemic areas should be improved by veterinarians. PMID- 21651885 TI - Exploring alternative hapten tethering sites for high-affinity anti-picoxystrobin antibody generation. AB - The relevance of the linker tethering site in haptens was investigated for antibody generation and immunoassay development. Three derivatives of the strobilurin fungicide picoxystrobin were synthesized with the same functionalized spacer arm located at three different positions. Protein conjugates of those haptens were employed as immunogens, and novel polyclonal antibodies were produced and characterized. All haptens afforded highly specific antibodies, but different affinities to the free analyte were observed among the obtained antisera. Next, competitive enzyme-linked immunosorbent assays were studied in several formats, and site heterology was confirmed as an effective strategy for detectability improvement. An indirect heterologous immunoassay was eventually selected and optimized, showing a limit of detection for picoxystrobin of 0.02 MUg/L and a working range between 0.03 and 1.30 MUg/L. Finally, the developed extraction and analytical procedures revealed a practical limit of quantification of 5 MUg/kg for this fungicide in soybean sprouts, well below the maximum residue limits in the European Union. PMID- 21651886 TI - Quantification of l-alanyl-l-glutamine in mammalian cell culture broth: Evaluation of different detectors. AB - l-Alanyl-l-glutamine (also known as Ala-Gln or GlutaMAX) is widely used as a stable l-glutamine source in cell culture for the production of biopharmaceuticals. System approaches for the optimization of production processes require the analysis of all major substrates and products. We have compared four alternative detection systems for l-alanyl-l-glutamine in culture broth. Matrix effects prevented the use of ultraviolet or evaporative light scattering detection. Fluorescence detection used in routine amino acid protocols is compatible with culture broth and has a broad linear dynamic range. Mass spectrometry has superior sensitivity and can be integrated into quantitative metabolomic workflows. PMID- 21651887 TI - Amplification and sequencing of mature microRNAs in uncharacterized animal models using stem-loop reverse transcription-polymerase chain reaction. AB - Expression of mature microRNA (miRNA) transcripts can be easily measured in many established animal model systems but is difficult to evaluate using conventional methods in new and uncharacterized animal models. In this study, we were able to expand an existing protocol to evaluate miRNA expression in both vertebrate and invertebrate animals for which mature miRNAs remain unsequenced. This method allows the researcher to sequence reverse transcription-polymerase chain reaction products, validating miRNA-specific amplification and providing the opportunity to add to the current body of knowledge of miRNA annotation. PMID- 21651888 TI - Carotenoids are essential for normal levels of dimerisation of the RC-LH1-PufX core complex of Rhodobacter sphaeroides: characterisation of R-26 as a crtB (phytoene synthase) mutant. AB - Carotenoids play important roles in photosynthesis where they are involved in light-harvesting, in photo-protection and in the assembly and structural stability of light-harvesting and reaction centre complexes. In order to examine the effects of carotenoids on the oligomeric state of the reaction centre-light harvesting 1 -PufX (RC-LH1-PufX) core complex of Rhodobacter sphaeroides two carotenoid-less mutants, TC70 and R-26, were studied. Detergent fractionation showed that in the absence of carotenoids LH2 complexes do not assemble, as expected, but also that core complexes are predominantly found as monomers, although levels of the PufX polypeptide appeared to be unaffected. Analysis of R 26 membranes by electron microscopy and atomic force microscopy reveals arrays of hexagonally packed monomeric RC-LH1-PufX complexes. Transfer of the crtB gene encoding phytoene synthase to TC70 and R-26 restores the normal synthesis of carotenoids demonstrating that the R-26 mutant of Rba. sphaeroides harbours a mutation in crtB, among its other defects. The transconjugant TC70 and R-26 strains containing crtB had regained their ability to assemble wild-type levels of dimeric RC-LH1-PufX core complexes and normal energy transfer pathways were restored, demonstrating that carotenoids are essential for the normal assembly and function of both the LH2 and RC-LH1-PufX complexes in this bacterial photosystem. PMID- 21651889 TI - Influence of detergents on the activity of the ABC transporter LmrA. AB - The ABC transporter LmrA from Lactococcus lactis has been intensively studied and a role in multidrug resistance was proposed. Here, we performed a comprehensive detergent screen to analyze the impact of detergents for a successful solubilization, purification and retention of functional properties of this ABC transporter. Our screen revealed the preference of LmrA for zwitterionic detergents. In detergent solution, LmrA purified with FC-16 was highly active with respect to ATPase activity, which could be stimulated by a substrate (rhodamine 123) of LmrA. Both, high ATPase activity and substrate stimulation were not detected for LmrA solubilized in DDM. Interestingly, reconstituted LmrA showed an opposite behavior, with a high basal ATPase activity and stimulation by rhodamine 123 for a DDM-reconstituted, but only low ATPase activity and no substrate stimulation for a FC-16 reconstituted sample. PMID- 21651890 TI - Perfluorooctane sulfonate triggers tight junction "opening" in brain endothelial cells via phosphatidylinositol 3-kinase. AB - Perfluorooctane sulfonate (PFOS), an environmental pollutant, is widely distributed in humans and wildlife. Accumulation of PFOS in the brain and its neurotoxicity has been reported. Whether PFOS has any effect on the blood-brain barrier (BBB) remains unknown. In this study, human brain microvascular endothelial cells (HBMEC), which are the major components of BBB, were treated with PFOS and indicators of endothelial permeability were measured. Disassembly of endothelial tight junction (TJ) and increase of permeability were observed in response to PFOS. The PFOS-induced TJ disassembly in HBMEC was attenuated by pretreatment with PI3K inhibitors, whereas Rho kinase inhibitor had no such effect. Further results demonstrated that PFOS promoted the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in HBMEC. We found that overexpression of PI3K dominant-negative mutant in HBMEC abolished the PFOS induced TJ disassembly. These data demonstrated that PFOS can trigger the "opening" of tight junction in brain endothelial cells through PI3K signaling pathway. PMID- 21651891 TI - Identification of tripartite motif-containing 22 (TRIM22) as a novel NF-kappaB activator. AB - Increasing evidence suggests that TRIM family proteins may play important roles in the regulation of innate immune signaling pathways. Here we report TRIM22 is involved in the activation of NF-kappaB. It was found that overexpression of TRIM22 could dose-dependently activate NF-kappaB as demonstrated by reporter gene assay and electrophoretic mobility shift assay, but had no effect on the activity of other transcription factors, including NF-AT, AP-1, C/EBP and IRFs. Further study showed that both the N-terminal RING domain and C-terminal SPRY domain were crucial for TRIM22-mediated NF-kappaB activation. Moreover, our results revealed that TRIM22 overexpression could significantly induce the secretion of pro inflammatory cytokines by human macrophage cell line U937 in an NF-kappaB dependent manner. These data suggested that TRIM22 was a positive regulator of NF kappaB-mediated transcription. PMID- 21651892 TI - Selective cell-surface labeling of the molecular motor protein prestin. AB - Prestin, a multipass transmembrane protein whose N- and C-termini are localized to the cytoplasm, must be trafficked to the plasma membrane to fulfill its cellular function as a molecular motor. One challenge in studying prestin sequence-function relationships within living cells is separating the effects of amino acid substitutions on prestin trafficking, plasma membrane localization and function. To develop an approach for directly assessing prestin levels at the plasma membrane, we have investigated whether fusion of prestin to a single pass transmembrane protein results in a functional fusion protein with a surface exposed N-terminal tag that can be detected in living cells. We find that fusion of the biotin-acceptor peptide (BAP) and transmembrane domain of the platelet derived growth factor receptor (PDGFR) to the N-terminus of prestin-GFP yields a membrane protein that can be metabolically-labeled with biotin, trafficked to the plasma membrane, and selectively detected at the plasma membrane using fluorescently-tagged streptavidin. Furthermore, we show that the addition of a surface detectable tag and a single-pass transmembrane domain to prestin does not disrupt its voltage-sensitive activity. PMID- 21651893 TI - Attenuation of neurodegenerative phenotypes in Alzheimer-like presenilin 1/presenilin 2 conditional double knockout mice by EUK1001, a promising derivative of xanomeline. AB - The M1/M4-preferring muscarinic agonist xanomeline was found to have some benefit in the treatment of the memory impairment of Alzheimer's disease (AD), but side effects precluded further development. EUK1001, a fluorinated derivative of xanomeline, because of greater affinity for M1 muscarinic receptors, is likely to have a significantly better side effect profile than xanomeline. We have now studied the effects of 3-month chronic administration of EUK1001 and xanomeline (0.5mg/kg/day) in AD-like presenilin 1/presenilin 2 conditional double knockout (PS cDKO) mice. Only EUK1001 was found to significantly ameliorate the deficit in recognition memory. Histological analysis demonstrated partial attenuation of the brain atrophy in EUK1001-treated PS cDKO mice and minimal effect in the xanomeline-treated mice. Both compounds effectively suppressed the elevation of brain tau phosphorylation in the PS cDKO mice, but neither inhibited the increased inflammatory responses. These results indicate that EUK1001 showed superiority to xanomeline with regard to attenuation of several AD-like neurodegenerative phenotypes in PS cDKO mice. These results suggest further investigation of the development of EUK1001 for the treatment of AD is indicated. PMID- 21651894 TI - Catalytic and glycan-binding abilities of ppGalNAc-T2 are regulated by acetylation. AB - Post-translational acetylation is an important molecular regulatory mechanism affecting the biological activity of proteins. Polypeptide GalNAc transferases (ppGalNAc-Ts) are a family of enzymes that catalyze initiation of mucin-type O glycosylation. All ppGalNAc-Ts in mammals are type II transmembrane proteins having a Golgi lumenal region that contains a catalytic domain with glycosyltransferase activity, and a C-terminal R-type ("ricin-like") lectin domain. We investigated the effect of acetylation on catalytic activity of glycosyltransferase, and on fine carbohydrate-binding specificity of the R-type lectin domain of ppGalNAc-T2. Acetylation effect on ppGalNAc-T2 biological activity in vitro was studied using a purified human recombinant ppGalNAc-T2. Mass spectrometric analysis of acetylated ppGalNAc-T2 revealed seven acetylated amino acids (K103, S109, K111, K363, S373, K521, and S529); the first five are located in the catalytic domain. Specific glycosyltransferase activity of ppGalNAc-T2 was reduced 95% by acetylation. The last two amino acids, K521 and S529, are located in the lectin domain, and their acetylation results in alteration of the carbohydrate-binding ability of ppGalNAc-T2. Direct binding assays showed that acetylation of ppGalNAc-T2 enhances the recognition to alphaGalNAc residue of MUC1alphaGalNAc, while competitive assays showed that acetylation modifies the fine GalNAc-binding form of the lectin domain. Taken together, these findings clearly indicate that biological activity (catalytic capacity and glycan-binding ability) of ppGalNAc-T2 is regulated by acetylation. PMID- 21651895 TI - Topoisomerase I inactivation by a novel thiol reactive naphthoquinone. AB - The naphthoquinone adduct 12,13-dihydro-N-methyl-6,11,13-trioxo-5H benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) contains structural features of both the anthracycline and isoquinone chemotherapeutics. An initial characterization showed TU100 is cytotoxic to mammalian cells and can inhibit topoisomerase I and II. Analysis using topoisomerase I now reveals TU100 is a slow acting inhibitor targeting the enzyme in the absence of DNA. Diluting pre-incubated TU100 and topoisomerase I failed to alleviate inhibition, suggesting the enzyme is being covalently modified. Critical cysteine thiols were identified as the possible target based on the ability of reducing agents to reverse TU100 inhibition. Consistent with this idea, TU100 protected topoisomerase I from inactivation by the sulfhydryl modifying agent N-ethylmaleimide (NEM). Unlike agents nonspecifically reacting with thiols, however, TU100 is specific for topoisomerase because it failed to inhibit a cysteine dependent protease. These results indicate TU100 is a novel naphthoquinone that inactivates free topoisomerase I via alkylation of cysteine residues. PMID- 21651896 TI - Induced pluripotent stem cells' self-renewal and pluripotency is maintained by a bovine granulosa cell line-conditioned medium. AB - Induced pluripotent stem cells (iPSCs) are a promising type of stem cells, comparable to embryonic stem cells (ESCs) in terms of self-renew and pluripotency, generated by reprogramming somatic cells. These cells are an attractive approach to supply patient-specific pluripotent cells, for producing in vitro models of disease, drug discovery, toxicology and potentially treating degenerative disease circumventing immune rejection. In spite of the great advance since iPSCs' establishment, their obtention and propagation is an increasing area of great interest. In a recent work, we have shown that the conditioned medium from a bovine granulosa cell line (BGC-CM) is able to preserve the basic properties of mESCs. Therefore, based on our previous results and the reported resemblance between iPSCs and ESCs, we hypothesized that BGC-CM could provide a favorable context to culturing iPSCs. In this work, we have reprogrammed mouse embryonic fibroblasts obtaining iPSC lines, and showed that they can be propagated in BGC-CM while maintaining self-renewal and pluripotency, evidenced by expression of specific gene markers and capability of in vitro and in vivo differentiation to cell types from the three germ layers. We believe that these findings may provide a novel context to propagate iPSCs to study the molecular mechanisms involved in self-renewal and pluripotency. PMID- 21651897 TI - Role of JAK/STAT signaling in neuroepithelial stem cell maintenance and proliferation in the Drosophila optic lobe. AB - During Drosophila optic lobe development, proliferation and differentiation must be tightly modulated to reach its normal size for proper functioning. The JAK/STAT pathway plays pleiotropic roles in Drosophila development and in the larval brain, has been shown to inhibit medulla neuroblast formation. In this study, we find that JAK/STAT activity is required for the maintenance and proliferation of the neuroepithelial stem cells in the optic lobe. In loss-of function JAK/STAT mutant brains, the neuroepithelial cells lose epithelial cell characters and differentiate prematurely while ectopic activation of this pathway is sufficient to induce neuroepithelial overgrowth in the optic lobe. We further show that Notch signaling acts downstream of JAK/STAT to control the maintenance and growth of the optic lobe neuroepithelium. Thus, in addition to its role in suppression of neuroblast formation, the JAK/STAT pathway is necessary and sufficient for optic lobe neuroepithelial growth. PMID- 21651898 TI - Zinc pyrithione salvages reperfusion injury by inhibiting NADPH oxidase activation in cardiomyocytes. AB - Zinc pyrithione (ZPT), has a strong anti-apoptotic effect when administered just before reperfusion. Because oxidative stress has been proposed to contribute to myocardial reperfusion injury, we tested whether ZPT can reduce the production of reactive oxygen species during reoxygenation in cultured neonatal rat cardiac myocytes and evaluated the role of NADPH oxidase in hypoxia/reoxygenation (H/R) injury. The cells were subjected to 8h of simulated ischemia, followed by either 30 min or 16 h of reoxygenation. ZPT when started just before reoxygenation significantly reduced superoxide generation, LDH release and improved cell survival compared to H/R. Attenuation of the ROS production by ZPT paralleled its capacity to prevent pyknotic nuclei formation. In addition, ZPT reversed the H/R induced expression of NOX2 and p47(phox) phosphorylation indicating that ZPT directly protects cardiomyocytes from reperfusion injury by a mechanism that attenuates NADPH oxidase mediated intracellular oxidative stress. PMID- 21651899 TI - REM sleep deprivation of rats induces acute phase response in liver. AB - REM sleep is essential for maintenance of body physiology and its deprivation is fatal. We observed that the levels of ALT and AST enzymes and pro-inflammatory cytokines like IL-1 beta, IL-6 and IL-12 circulating in the blood of REM sleep deprived rats increased in proportion to the extent of sleep loss. But in contrast the levels of IFN-gamma and a ~200 kDa protein, identified by N-terminal sequencing to be alpha-1-inhibitor-3(A1I3), decreased significantly. Quantitative PCR analysis confirmed that REM sleep deprivation down regulates AII3 gene and up regulates IL1 beta, IL6 and their respective receptors gene expression in the liver initiating its inflammation. PMID- 21651900 TI - The role of the Suppressor of Hairy-wing insulator protein in Drosophila oogenesis. AB - The Drosophila Suppressor of Hairy wing [Su(Hw)] insulator protein has an essential role in the development of the female germline. Here we investigate the function of Su(Hw) in the ovary. We show that Su(Hw) is universally expressed in somatic cells, while germ cell expression is dynamic. Robust levels accumulate in post-mitotic germ cells, where Su(Hw) localization is limited to chromosomes within nurse cells, the specialized cells that support oocyte growth. Although loss of Su(Hw) causes global defects in nurse cell chromosome structure, we demonstrate that these architectural changes are not responsible for the block in oogenesis. Connections between the fertility and insulator functions of Su(Hw) were investigated through studies of the two gypsy insulator proteins, Modifier of (mdg4)67.2 (Mod67.2) and Centrosomal Protein of 190kDa (CP190). Accumulation of these proteins is distinct from Su(Hw), with Mod67.2 and CP190 showing uniform expression in all cells during early stages of oogenesis that diminishes in later stages. Although Mod67.2 and CP190 extensively co-localize with Su(Hw) on nurse cell chromosomes, neither protein is required for nurse cell chromosome development or oocyte production. These data indicate that while the gypsy insulator function requires both Mod67.2 and CP190, these proteins are not essential for oogenesis. These studies represent the first molecular investigations of Su(Hw) function in the germline, which uncover distinct requirements for Su(Hw) insulator and ovary functions. PMID- 21651901 TI - Neuroprotective effect of Cu,Zn-superoxide dismutase fused to a TCTP-derived protein transduction domain. AB - Previously, we have reported that a 10-amino acid peptide (MIIYRDLISH) derived from the NH(2)-terminus of the human translationally controlled tumor protein (TCTP) functions as a protein transduction domain (PTD). In this study, we evaluated the transduction ability of SOD fused to TCTP-PTD (TCTP-SOD) into various cell lines. We also evaluated its ability to protect cells against paraquat-induced cell damage, in vitro and its neuroprotective effect in vivo against kainic acid-induced neuronal damage in an animal model. TCTP-SOD was transduced into various cell lines in a dose- and time-dependent manner without cytotoxic effect. Furthermore, TCTP-SOD showed cytoprotective activity in SH-SY5Y cells, and intraperitoneally, injected TCTP-SOD was delivered into the mouse brain and protected the cells in the hippocampal region against the damage induced by kainic acid. We propose TCTP-SOD as a potential candidate drug for treatment of brain diseases. PMID- 21651902 TI - NOS-1-derived NO is an essential triggering signal for the development of systemic inflammatory responses. AB - Nitric oxide (NO) produced by the NO synthase type 2 (NOS-2) is known to have a prominent role in the course of the inflammatory response but less is known concerning the role of NO derived from the constitutive NOS isoforms. We have examined the role of NO derived from NOS-1 in the initiation of the systemic inflammatory response using sepsis models. Injection of LPS in rats induced an early hypotension, NOS-2 expression, increased lung myeloperoxidase activity and increased NO metabolite (NOx) levels in the skeletal muscle. Pre-treatment with 7 nitroindazol (7-NI) prevented all these changes, but its administration after LPS injection was ineffective. Septic (cecal ligation and puncture method, CLP) rats exhibited signs of organ failure, hyporesponsiveness to vasoconstrictors and 75% mortality over 3 days after surgery. Pre-treatment with 7-NI prevented or significantly reduced these alterations. Injection of 7-NI after sepsis onset was without effect. Wild type mice injected with LPS exhibited increased plasma NOx, NOS-2 and COX-2 expression and 80% mortality. NOS-1(-/-) mice injected with LPS exhibited smaller increase in plasma NOx, no NOS-2 and COX-2 expression and reduced mortality. Injection of an NO donor in CLP rats pre-treated with 7-NI or in NOS-1(-/-) mice returned the mortality rate to those of CLP in rats and LPS in mice. Our results demonstrate that NOS-1-derived NO acts as a signaling element and it is essential for the initiation of systemic inflammation as demonstrated by the reduction of the inflammatory response and mortality by both pharmacological inhibition and genetic deletion of NOS-1. PMID- 21651903 TI - Pregabalin is a potent and selective ligand for alpha(2)delta-1 and alpha(2)delta 2 calcium channel subunits. AB - Pregabalin, a synthetic branched chain gamma-amino acid with anticonvulsant, anxiolytic, and analgesic activities, has been shown to bind with high affinity to the voltage-gated calcium channel alpha(2)delta subunit. Given the broad therapeutic utility of pregabalin, a series of experiments was undertaken to determine the potency, selectivity, and specificity of pregabalin's receptor binding profile at alpha(2)delta-1 and alpha(2)delta-2 subunits of voltage-gated calcium channels along with 38 widely studied receptors and channels. Receptor autoradiography was used to assess regional-binding density of pregabalin throughout the rat spinal cord and brain. In addition, a series of studies using in vivo electrophysiological recordings of gamma-aminobutyric acid (GABA)(A)- and GABA(B)-evoked currents was undertaken to determine the interaction of pregabalin with GABAergic receptor subtypes. Together, the results of these studies demonstrate potent and selective binding of pregabalin to alpha(2)delta-1 and alpha(2)delta-2 subunits in native and recombinant human and porcine systems. Pregabalin did not interact with any of the 38 receptors and ion channels evaluated, and a variety of central nervous system (CNS)-targeted therapeutic drugs did not show activity at the alpha(2)delta subunits of voltage-gated calcium channels. Receptor autoradiography demonstrated extensive [(3)H] pregabalin binding throughout the CNS, with high-level binding in the cortex, hippocampus, cerebellum, dorsal horn of the spinal cord, and amygdala. Finally, receptor-binding and electrophysiological techniques failed to show evidence of an interaction between pregabalin and GABA(A) or GABA(B) receptors. These studies suggest that the clinical effects of pregabalin are likely due to direct and selective interactions with alpha(2)delta-1 and alpha(2)delta-2 subunits of voltage-gated calcium channels. PMID- 21651904 TI - Additive anticonvulsant effects of agmatine and lithium chloride on pentylenetetrazole-induced clonic seizure in mice: involvement of alpha2 adrenoceptor. AB - After 60 years, lithium is still the mainstay in the treatment of mood disorders and widely used in clinic. In addition to its mood stabilizer effects, lithium also shows some anticonvulsant properties. Similar to lithium, agmatine also plays a protective role in the CNS against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on alpha(2)-adrenoceptors. So, we designed this study: 1) to investigate whether agmatine and lithium show an additive effect against clonic seizures induced by pentylenetetrazole; 2) to assess whether this additive effect is mediated through the alpha(2)-adrenoceptor or not. In our study, acute administration of a single effective dose of lithium chloride (30 mg/kg, i.p.) increased the seizure threshold. Pre-treatment with low and, per se, non-effective doses of agmatine (1 and 3mg/kg) potentiated a sub-effective dose of lithium (10mg/kg). Interestingly, the anticonvulsant effects of these effective combinations of lithium and agmatine were prevented by pre-treatment with low and non-effective doses of yohimbine [alpha(2)-adrenoceptor antagonist] (0.1 and 0.5mg/kg). On the other hand, clonidine [alpha(2)-adrenoceptor agonist] augmented the anticonvulsant effect of a sub-effective combination of lithium (5mg/kg i.p.) and agmatine (1mg/kg) at relatively low doses (0.1 and 0.25mg/kg). In summary, our findings demonstrate that agmatine and lithium chloride exhibit additive anticonvulsant properties which seem to be mediated through alpha(2) adrenoceptor. PMID- 21651905 TI - Endothelial angiotensin-converting enzyme and neutral endopeptidase in isolated human umbilical vein: an effective bradykinin inactivation pathway. AB - Kinins are metabolized by metallopeptidases present in different tissues. The aim of this study was to evaluate, employing functional studies in isolated human umbilical vein, the possible participation of angiotensin-converting enzyme, neutral endopeptidase and aminopeptidase P as an inactivation pathway of bradykinin, as well as assess if the endothelial layer is involved in this process. Concentration-response curves to bradykinin were constructed after 120 min incubation period on human umbilical vein rings with and without endothelium and enzymatic inhibitors were applied 30 min before construction of concentration response curves. The presence of endothelium was confirmed by histological studies. Bradykinin-induced contractile responses were potentiated in human umbilical vein without endothelium when compared to intact tissues. Application of captopril 1 MUM (angiotensin-converting enzyme inhibitor) or phosphoramidon 10 MUM (neutral endopeptidase inhibitor) induced a leftward shift of bradykinin elicited responses in human umbilical vein with endothelium while no effect was observed in tissues denuded of endothelium under the same treatment. Exposure to apstatin 10 MUM (aminopeptidase P inhibitor) did not potentiate bradykinin induced effects in intact human umbilical vein. When angiotensin-converting enzyme and neutral endopeptidase were concomitantly inhibited, there was a higher potentiation of bradykinin-elicited responses compared to the effects observed under individual inhibition of either enzyme. Moreover, concentration-response curves to FR190997, a non-peptidic bradykinin B(2) receptor agonist, were not modified under dual enzymatic inhibition. In conclusion, our results demonstrate for the first time the functional relevance of angiotensin-converting enzyme and neutral endopeptidase, localized on the endothelial layer, acting concurrently as a bradykinin inactivating pathway in isolated human umbilical vein. PMID- 21651906 TI - Acotiamide hydrochloride (Z-338) enhances gastric motility and emptying by inhibiting acetylcholinesterase activity in rats. AB - In clinical trials, acotiamide hydrochloride (acotiamide: Z-338) has been reported to be useful in the treatment of functional dyspepsia. Here, we investigated the effects of acotiamide on gastric contraction and emptying activities in rats in comparison with itopride hydrochloride (itopride) and mosapride citrate (mosapride). We also examined in vitro the compound's inhibitory effect on acetylcholinesterase (AChE) activity derived from rat stomach. In in vivo studies, acotiamide (30 and 100mg/kg s.c.) and itopride (100mg/kg s.c.) markedly enhanced normal gastric antral motility in rats. In gastric motility dysfunction models, acotiamide (100mg/kg s.c.) and itopride (100mg/kg s.c.) improved both gastric antral hypomotility and the delayed gastric emptying induced by clonidine, an alpha(2)-adrenoceptor agonist. In contrast, mosapride (10mg/kg s.c.) had no effect on these models. Like the AChE inhibitors itopride (30 mg/kg s.c.) and neostigmine (10 MUg/kg s.c.), acotiamide (10mg/kg s.c.) also clearly enhanced gastric body contractions induced by electrical stimulation of the vagus, which were abolished by atropine and hexamethonium, whereas mosapride (3 and 10mg/kg s.c.) did not. In in vitro studies, acotiamide concentration-dependently inhibited rat stomach-derived AChE activity (IC(50)=2.3 MUmol/l). In addition, stomach tissue concentrations of acotiamide after administration at 10mg/kg s.c. were sufficient to produce inhibition of AChE activity in rat stomach. These results suggest that acotiamide stimulates gastric motility and improves gastric motility dysfunction in rats by inhibiting AChE activity, and may suggest a role for acotiamide in improving gastric motility dysfunction in patients with functional dyspepsia. PMID- 21651907 TI - Anti-oxidative and TNF-alpha suppressive activities of puerarin derivative (4AC) in RAW264.7 cells and collagen-induced arthritic rats. AB - Puerarin is a major active ingredient extracted from the root of P. lobata, a traditional Chinese herb, and possesses anti-oxidative and anti-inflammatory activities. However, the low oral bioavailability of puerarin limits its further application. Therefore, we synthesized tetraacetyl puerarin (4AC) through acetylation to improve its liposolubility and bioavailability. In the present investigations, we tested the anti-oxidative and TNF-alpha suppressive activity of 4AC in lipopolysaccharide (LPS)-induced RAW264.7 macrophages and bovine type II collagen-induced arthritic (CIA) rats. The results showed that 4AC retained the bioactivity of puerarin. And 4AC significantly increased the activity of SOD and reduced the level of MDA both in vitro and in vivo. It also improved the level of GSH-PX and the total antioxidant capacity in vivo. Furthermore, it dramatically decreased TNF-alpha level in the cultured supernatant of RAW264.7 cells treated with LPS and in the serum of CIA rats. These initial results indicated that 4AC had a potential therapeutic effect on CIA rats through an anti oxidative and TNF-alpha suppressive activity. In addition, the molecular mechanism of anti-oxidation of 4AC was explored by testing the MAPKs/NF-kappaB signaling pathway. The results showed that 4AC significantly inhibited NF-kappaB expression and down-regulated the levels of p-ERK and p-JNK in LPS-activated RAW264.7 cells. These results indicated that 4AC had bioactive anti-oxidative effects and suggest the potential value of 4AC for the treatment of rheumatoid arthritis. PMID- 21651908 TI - Effect of sildenafil citrate on intraocular pressure and blood pressure in human volunteers. AB - Anecdotal reports have suggested that the vasodilator, sildenafil citrate, which evokes its effect via a select inhibition of PDE5, has the potential to increase intraocular pressure (IOP) in some individuals. An ocular hypertensive effect by sildenafil was also recently described in a sheep animal model. In contrast, clinical studies have not found a direct association between sildenafil ingestion (commonly consumed as Viagra) and changes in IOP. However, some such studies also reported no effects of sildenafil on systemic blood pressure (BP) at the time of the IOP determination. Given this surprising result, our purpose was to repeat a study in human volunteers in the city of Corrientes, Argentina to corroborate the effects of sildenafil on human IOP and systemic BP. For the present study, 9 healthy volunteers (male and female, 18-74 years old) were selected as subjects after ophthalmic and cardiovascular evaluation indicated that they exhibited normal parameters for their age. In a masked, placebo-controlled study, the subjects ingested 100 mg sildenafil citrate (provided as Vorst from Laboratorios Bernabo, Argentina) in one session, and a placebo on a second separate occasion. IOP was measured with a Goldman applanation tonometer by an ophthalmologist, and BP by a second physician, neither of whom witnessed the tablet ingestion by the volunteers, nor provided with information on the nature of the test compounds. A third individual administered the tablets. The average baseline IOP of this group of 9 was 13.1 +/- 0.6 mm Hg. Subsequent to sildenafil ingestion, IOP increased by 26% to 16.5 +/- 0.8 mm Hg 60 min later (P < 0.005, as paired data), and returned to control values within 2 h. Both systolic and diastolic BP were significantly reduced by sildenafil ingestion. At the point of maximal systemic hypotension (90 min), the systolic and diastolic pressures declined by 15% and 13%, respectively. No significant changes in IOP or BP were recorded after ingestion of the placebo. Our results suggest that sildenafil can elicit a transient IOP increase that may be of importance to patients chronically treated with PDE5 inhibitors for various vascular diseases (e.g., pulmonary hypertension). We discuss possible mechanisms by which PDE5 inhibition might lead to a rise in IOP. PMID- 21651909 TI - Genetic and transcriptional analysis of phosphoinositide-specific phospholipase C in Plasmodium. AB - Phosphoinositide-specific phospholipase C (PI-PLC) is a major regulator of calcium-dependent signal transduction, which has been shown to be important in various processes of the malaria parasite Plasmodium. PI-PLC is generally implicated in calcium liberation from intracellular stores through the action of its product, inositol-(1,4,5)-trisphosphate, and is itself dependent on calcium for its activation. Here we describe the plc genes from Plasmodium species. The encoded proteins contain all domains typically found in PI-PLCs of the delta class but are almost twice as long as their orthologues in mammals. Transcriptional analysis by qRT-PCR of plc during the erythrocytic cycle of P. falciparum revealed steady expression levels that increased at the late schizont stages. Genetic analysis in the P. berghei model revealed that the plc locus was targetable but that plc gene knock-outs could not be obtained, thereby strongly indicating that the gene is essential during blood stage development. Alternatively, we attempted to modify plc expression through a promoter exchange approach but found the gene to be refractory to over-expression indicating that plc expression levels might additionally be tightly controlled. PMID- 21651911 TI - EPR characterization of the new Qrc complex from sulfate reducing bacteria and its ability to form a supercomplex with hydrogenase and TpIc3. AB - The Quinone-reductase complex (Qrc) is a respiratory complex with Type I cytochrome c(3):menaquinone reductase activity, recently described in sulfate reducing bacteria. Qrc is related to the complex iron-sulfur molybdoenzyme family and to the alternative complex III. In this work we report a detailed characterization of the redox properties of the metal cofactors of Qrc using EPR spectroscopy, which allowed the determination of the reduction potentials of five out of six hemes c, one [3Fe-4S](1+/0) center and the three [4Fe-4S](2+/1+) centers. In addition, we show that Qrc forms a supercomplex with [NiFe] hydrogenase and TpIc(3), its physiological electron donors. PMID- 21651910 TI - Opposite effects of P2X7 and P2Y2 nucleotide receptors on alpha-secretase dependent APP processing in Neuro-2a cells. AB - The amyloid precursor protein (APP) is proteolytically processed by beta- and gamma-secretases to release amyloid-beta peptide (Abeta), the main component found in senile plaques of Alzheimer's disease (AD) patient brains. Alternatively, APP can be cleaved within the Abeta sequence by alpha-secretase, thus precluding the generation of Abeta. We have demonstrated that activation of the P2X7 receptor leads to a reduction of alpha-secretase activity in Neuro-2a cells. Moreover, the P2X7 ligand 2'(3')-O-(4-benzoylbenzoyl) ATP (BzATP) can also activate a different P2 receptor in these cells. This receptor, whose pharmacology resembles that of the P2Y(2) receptor, has an opposite effect, leading to increases in alpha-secretase activity. Our study suggests that P2X7R and P2Y(2)R could be novel therapeutic targets in AD. PMID- 21651912 TI - Higher thyroid hormone receptor expression correlates with short larval periods in spadefoot toads and increases metamorphic rate. AB - Spadefoot toad species display extreme variation in larval period duration, due in part to evolution of thyroid hormone (TH) physiology. Specifically, desert species with short larval periods have higher tail tissue content of TH and exhibit increased responsiveness to TH. To address the molecular basis of larval period differences, we examined TH receptor (TR) expression across species. Based on the dual function model for the role of TR in development, we hypothesized that desert spadefoot species with short larval periods would have (1) late onset of TR expression prior to the production of endogenous TH and (2) higher TR levels when endogenous TH becomes available. To test these hypotheses, we cloned fragments of TRalpha and TRbeta genes from the desert spadefoot toads Scaphiopus couchii and Spea multiplicata and their non-desert relative Pelobates cultripes and measured their mRNA levels in tails using quantitative PCR in the absence (premetamorphosis) or presence (natural metamorphosis) of TH. All species express TRalpha and TRbeta from the earliest stages measured (from just after hatching), but S. couchii, which has the shortest larval period, had more TRalpha throughout development compared to P. cultripes, which has the longest larval period. TRbeta mRNA levels were similar across species. Exogenous T3 treatment induced faster TH response gene expression kinetics in S. couchii compared to the other species, consistent with its higher TRalpha mRNA expression and indicative of a functional consequence of more TRalpha activity at the molecular level. To directly test whether higher TRalpha expression may contribute to shorter larval periods, we overexpressed TRalpha via plasmid injection into tail muscle cells of the model frog Xenopus laevis and found an increased rate of muscle cell death in response to TH. These results suggest that increased TRalpha expression evolved in S. couchii and contribute to its higher metamorphic rates. PMID- 21651913 TI - Activated human platelet products induce proarrhythmic effects in ventricular myocytes. AB - Sudden cardiac death remains one of the most prevalent modes of death and is mainly caused by ventricular fibrillation (VF) in the setting of acute ischemia resulting from coronary thrombi. Animal experiments have shown that platelet activation may increase susceptibility of ischemic myocardium to VF, but the mechanism is unknown. In the present study, we evaluated the effects of activated blood platelet products (ABPPs) on electrophysiological properties and intracellular Ca(2+) (Ca(2+)(i)) homeostasis. Platelets were collected from healthy volunteers. After activation, their secreted ABPPs were added to superfusion solutions. Rabbit ventricular myocytes were freshly isolated, and membrane potentials and Ca(2+)(i) were recorded using patch-clamp methodology and indo-1 fluorescence measurements, respectively. ABPPs prolonged action potential duration and induced early and delayed afterdepolarizations. ABPPs increased L type Ca(2+) current (I(Ca,L)) density, but left densities of sodium current, inward rectifier K(+) current, transient outward K(+) current, and rapid component of the delayed rectifier K(+) current unchanged. ABPPs did not affect kinetics or (in)activation properties of membrane currents. ABPPs increased systolic Ca(2+)(i), Ca(2+)(i) transient amplitude, and sarcoplasmic reticulum Ca(2+) content. ABPPs did not affect the Na(+)-Ca(2+) exchange current (I(NCX)) in Ca(2+)-buffered conditions. Products secreted from activated human platelets induce changes in I(Ca,L) and Ca(2+)(i), which result in action potential prolongation and the occurrence of early and delayed afterdepolarizations in rabbit myocytes. These changes may trigger and support reentrant arrhythmias in ischemia models of coronary thrombosis. PMID- 21651914 TI - Eicosapentaenoic acid reduces ischemic ventricular fibrillation via altering monophasic action potential in pigs. AB - Although high intake of n-3 fatty acids is associated with reduced mortality of patients with ischemic heart disease, especially reduction in sudden cardiac death (SCD), the detailed mechanisms remain to be elucidated. Thus, the present study was designed to examine whether long-term treatment with eicosapentaenoic acid (EPA), a major component of n-3 fatty acids, reduces ischemia-induced ventricular fibrillation (VF) in pigs in vivo, and if so, what molecular mechanisms are involved. Male pigs were treated with either a control chow (control group) or a control chow plus EPA (600 mg/kg/day, PO, EPA group) for 3 weeks and were subjected to myocardial ischemia for 90 min (n=8 each) with measurement of the monophasic action potential (MAP), as a marker of ventricular electrophysiological activities. The EPA treatment significantly attenuated the occurrence of VF (control 5.1+/-1.7 vs. EPA 1.5+/-0.8 times/animal, P<0.05) and markedly reduced the mortality (control 50% vs. EPA 0%, P<0.05), with the attenuation of MAP duration shortening during ischemia (control -28.1+/-3.0% vs. EPA -18.2+/-1.4%, P<0.05). These beneficial effects of EPA were abolished by pre treatment with cromakalim, a K(ATP) channel opener (0.3 MUg/kg/min, IC). Furthermore, EPA significantly inhibited the mRNA and protein expression of Kir6.2, a major component of sarcolemmal K(ATP) channels, in both the ischemic region and non-ischemic regions. These results indicate that long-term treatment with EPA reduces ischemia-induced VF and SCD in pigs in vivo, for which attenuation of MAP duration shortening may be involved. PMID- 21651915 TI - Arms race between weevil rostrum length and camellia pericarp thickness: Geographical cline and theory. AB - The geographical cline of the coevolving traits of weevil rostrum (mouthpart) length and camellia pericarp (fruit coat) thickness provides an opportunity to test the arms race theory of defense (pericarp thickness) and countermeasure (rostrum length) between antagonistically interacting species. By extending the previous model for the coevolution of quantitative traits to introduce nonlinear costs for exaggerated traits, the generation overlap, and density-dependent regulation in the host, we studied the evolutionarily stable (ES) pericarp thickness in the Japanese camellia (Camellia japonica) and the ES rostrum length in the camellia-weevil (Curculio camelliae). The joint monomorphic ES system has a robust outcome with nonlinear costs, and we analyzed how the traits of both species at evolutionary equilibrium depend on demographic parameters. If camellia demographic parameters vary latitudinally, data collected over the geographical scale of rostrum length and pericarp thickness should lie on an approximately linear curve with the slope less than that of the equiprobability line A/B of boring success, where A and B are coefficients for the logistic regression of boring success to pericarp thickness and rostrum length, respectively. This is a robust prediction as long as the cost of rostrum length is nonlinear (accelerating). As a result, boring success should be lower in populations with longer rostrum length, as reported in the weevil-camellia system (Toju, H., and Sota, T., 2006a. Imbalance of predator and prey armament: Geographic clines in phenotypic interface and natural selection. American Naturalist 167, 105-117). The nonlinearity (exponent) for the cost of rostrum length estimated from the geographical cline data for the weevil-camellia system was 2.2, suggesting nonlinearity between quadratic and cubic forms. PMID- 21651916 TI - Allometry in the distribution of material properties and geometry of the felid skull: why larger species may need to change and how they may achieve it. AB - Extant members of the cat family (Felidae) have been considered behaviourally and morphologically conservative, i.e., despite great differences in size, there is relatively little variation in either the shape of the felid skull and dentition across species, or in the way in which these structures are used to kill and dismember prey. Consequently felids have been considered an appropriate focus for a number of investigations into the influence of allometry on craniomandibular mechanics and morphology. However, although previous treatments have considered the role of shape, they have not investigated the influence of differences in the distribution of relatively stiff cortical and more compliant cancellous bone on performance. Here, using models that incorporate material properties for both cortical and cancellous bone, we apply three-dimensional (3D) finite element analysis (FEA) to models representing the skulls of seven extant felid species. Our objectives being to determine allometric trends regarding both overall geometry and the relative distributions of cortical and cancellous bone tissue. We also more comprehensively assess variation in the efficiency with which muscular force is converted to bite force and the capacity to resist associated stresses. Our results show that the cheetah (Acinonyx jubatus) may be exceptional regarding both the efficiency with which muscular force is converted to bite force and the distribution of stress. We found a negative allometric trend between cortical bone volume and total skull bone volume, and positive allometry between the total skull bone volume and skull surface area. Results gained from mathematical modelling of beam analogies suggest that these trends reflect a need for larger species to respond to physical challenges associated with increased size, and, that changes in skull shape, bone composition, or a combination of both may be required to accommodate these challenges. With geometrical scaling stress increases by the same factor, and displacement by the same factor squared, but the ultimate failure stress of the material is invariant. We find that as species become larger, overall skull bone volume relative to surface area increases by adding a higher proportion of less dense and more compliant cancellous bone. This results in an increased cross-sectional area and second moment of inertia, which acts to reduce the overall stresses. An overall saving in mass is a likely additional consequence. Although we do find evidence that skull stiffness does diminish with size, we also argue that this is at least in part mitigated through the influence of these allometric trends. We further suggest that these trends and the explanations for them may be universal for vertebrates. PMID- 21651917 TI - Irradiation induced foci (IRIF) as a biomarker for radiosensitivity. AB - It has long been known that the level of radiosensitivity between individuals covers a considerable range. This range is reflected in analysis of patient cell lines with some cell lines showing significantly reduced sensitivity to in vitro radiation exposure. Our increased exposure to radiation from diagnostic medical procedures and other life style changes has raised concerns that there may be individuals who are at an elevated risk from the harmful impact of acute or chronic low dose radiation exposure. Additionally, a subset of patients show an enhanced normal tissue response following radiotherapy, which can cause significant discomfort and, at the extreme, be life threatening. It has long been realised that the ability to identify sensitive individuals and to understand the mechanistic basis underlying the range of sensitivity within the population is important. A reduced ability to efficiently repair DNA double strand breaks (DSB) and/or activate the DSB damage response underlies some, although not necessarily all, of this sensitivity. In this article, we consider the utility of the recently developed gammaH2AX foci analysis to provide insight into radiation sensitivity within the population. We consider the nature of sensitivity including the impact of radiation on cell survival, tissue responses and carcinogenesis and the range of responses within the population. We overview the current utility of the gammaH2AX assay for assessing the efficacy of the DNA damage response to low and high dose radiation and its potential future exploitation. PMID- 21651918 TI - SNPs in DNA repair genes associated to meningitis and host immune response. AB - In vitro and in animal models, APE1, OGG1, and PARP-1 have been proposed as being involved with inflammatory response. In this work, we have investigated if the SNPs APE1 Asn148Glu, OGG1 Ser326Cys, and PARP-1 Val762Ala are associated to meningitis. The patient genotypes were investigated by PIRA-PCR or PCR-RFLP. DNA damages were detected in genomic DNA by Fpg treatment. IgG and IgA were measured from plasma and the cytokines and chemokines were measured from cerebrospinal fluid samples using Bio-Plex assays. A higher frequency (P<0.05) of APE1 Glu allele in bacterial meningitis (BM) and aseptic meningitis (AM) patients was observed. The genotypes Asn/Asn in control group and Asn/Glu in BM group was also higher. For the SNP OGG1 Ser326Cys, the genotype Cys/Cys was more frequent (P<0.05) in BM group. The frequency of PARP-1 Val/Val genotype was higher in control group (P<0.05). The occurrence of combined SNPs is significantly higher in BM patients, indicating that these SNPs may be associated to the disease. Increasing in sensitive sites to Fpg was observed in carriers of APE1 Glu allele or OGG1 Cys allele, suggesting that SNPs affect DNA repair activity. Alterations in IgG production were observed in the presence of SNPs APE1 Asn148Glu, OGG1 Ser326Cys or PARP-1 Val762Ala. Moreover, reduction in the levels of IL-6, IL-1Ra, MCP-1/CCL2 and IL-8/CXCL8 was observed in the presence of APE1 Glu allele in BM patients. In conclusion, we obtained indications of an effect of SNPs in DNA repair genes on the regulation of immune response in meningitis. PMID- 21651919 TI - The use-dependent, nicotinic antagonist BTMPS reduces the adverse consequences of morphine self-administration in rats in an abstinence model of drug seeking. AB - In this study, the use-dependent, nicotinic receptor antagonist bis (2,2,6,6 tetramethyl-4-piperidinyl) sebacate (BTMPS) was evaluated for its ability to attenuate the adverse consequences associated with morphine in rats in all three phases of an abstinence model of drug seeking: self-administration, acute withdrawal, and delayed test of drug seeking. Rats were allowed to self administer morphine (FR1 schedule) with an active response lever, on a 24 h basis inside operant chambers, for 14 days. Each rat was subsequently evaluated for stereotypical behaviors associated with spontaneous morphine withdrawal. Rats were then placed in standard housing cages for a six week period of protracted abstinence from morphine. After this period, each rat was placed back into its respective operant chamber for a 14 day assessment of unrewarded drug seeking responses. BTMPS was administered to the animals in all three clinically relevant phases in three separate sets of experiments. BTMPS treatment during the self administration phase resulted in up to a 34% reduction of lever responses to morphine when compared to vehicle treated control animals, as well as a 32% reduction in the dose of morphine self-administered. When given during self administration and acute withdrawal, BTMPS treatment decreased acute withdrawal symptoms (up to 64%) of morphine use and reduced (up to 45%) drug seeking responses after six weeks of protracted withdrawal compared to control animals. BTMPS treatment after six weeks of abstinence from morphine had no effect. These results offer insight into the role of central cholinergic receptors in the onset and maintenance of drug addiction. PMID- 21651921 TI - The neural substrates of script knowledge deficits as revealed by a PET study in Huntington's disease. AB - INTRODUCTION: Previous neuropsychological investigations have suggested that both the prefrontal cortex and the basal ganglia are involved in the management of script event knowledge required in planning behavior. METHODS: This study was designated to map, the correlations between resting-state brain glucose utilization as measured by FDG-PET (positron emission tomography) and scores obtained by means of a series of script generation and script sorting tasks in 8 patients with early Huntington's disease. RESULTS: These patients exhibited a selectively greater impairment for the organizational aspects of scripts compared to the semantic aspects of scripts. We showed significant negative correlations between the number of sequencing, boundary, perseverative and intrusion errors and the metabolism of several cortical regions, not only including frontal, but also posterior regions. CONCLUSION: Our findings suggest that, within the fronto striatal system, the cortical frontal regions are more crucial in script retrieval and script sequencing than the basal ganglia. PMID- 21651920 TI - Regional differences in the effects of isoflurane on neurotransmitter release. AB - Stimulus evoked neurotransmitter release requires that Na(+) channel-dependent nerve terminal depolarization be transduced into synaptic vesicle exocytosis. Inhaled anesthetics block presynaptic Na(+) channels and selectively inhibit glutamate over GABA release from isolated nerve terminals, indicating mechanistic differences between excitatory and inhibitory transmitter release. We compared the effects of isoflurane on depolarization-evoked [(3)H]glutamate and [(14)C]GABA release from isolated nerve terminals prepared from four regions of rat CNS evoked by 4-aminopyridine (4AP), veratridine (VTD), or elevated K(+). These mechanistically distinct secretegogues distinguished between Na(+) channel- and/or Ca(2+) channel-mediated presynaptic effects. Isoflurane completely inhibited total 4AP-evoked glutamate release (IC(50) = 0.42 +/- 0.03 mM) more potently than GABA release (IC(50) = 0.56 +/- 0.02 mM) from cerebral cortex (1.3 fold greater potency), hippocampus and striatum, but inhibited glutamate and GABA release from spinal cord terminals equipotently. Na(+) channel-specific VTD evoked glutamate release from cortex was also significantly more sensitive to inhibition by isoflurane than was GABA release. Na(+) channel-independent K(+) evoked release was insensitive to isoflurane at clinical concentrations in all four regions, consistent with a target upstream of Ca(2+) entry. Isoflurane inhibited Na(+) channel-mediated (tetrodotoxin-sensitive) 4AP-evoked glutamate release (IC(50) = 0.30 +/- 0.03 mM) more potently than GABA release (IC(50) = 0.67 +/- 0.04 mM) from cortex (2.2-fold greater potency). The magnitude of inhibition of Na(+) channel-mediated 4AP-evoked release by a single clinical concentration of isoflurane (0.35 mM) varied by region and transmitter: Inhibition of glutamate release from spinal cord was greater than from the three brain regions and greater than GABA release for each CNS region. These findings indicate that isoflurane selectively inhibits glutamate release compared to GABA release via Na(+) channel-mediated transduction in the four CNS regions tested, and that differences in presynaptic Na(+) channel involvement determine differences in anesthetic pharmacology. PMID- 21651922 TI - Very preterm adolescents show gender-dependent alteration of the structural brain correlates of spelling abilities. AB - Individuals born very preterm (VPT) are at risk of neurodevelopmental damage and of adverse educational outcomes in childhood and adolescence. The present study used voxel-based morphometry to investigate the association between grey matter and white matter volume and measures of language and executive functioning in VPT born adolescents and term-born controls by gender. VPT individuals (N=218) and controls (N=127) underwent neuropsychological assessment and MRI at age 14-15 as part of a longitudinal study. Differential associations were found between spelling scores and frontal regional grey matter volume when group (VPT and control) and gender (males and females) were investigated. A main effect of group demonstrated a weaker association in VPT adolescents relative to controls between grey matter volume in the left medial and right superior frontal gyri and spelling scores. A main effect of gender revealed spelling scores to be correlated with grey matter volume in the right superior frontal gyrus in females to a greater extent than in males. Furthermore, a significant interaction between group and gender was detected in two regions. Spelling scores showed a stronger association with grey matter volume in a cluster with local maxima in the left medial frontal cortex extending to the caudate nucleus in VPT females than in control females and a weaker association in VPT males compared to control males. In addition, spelling scores showed a stronger association with grey matter volume in left middle frontal gyrus in VPT males compared to control males and a weaker association in VPT females than in control females. When group and gender were investigated, there were no statistically different correlations between structural brain volumes and performance on reading and executive function tests. These data demonstrate that the typical structure-function relationship in respect to spelling abilities appears to be altered in individuals born preterm and the processes underpinning this divergence may be subject to gender-specific influences. PMID- 21651923 TI - Effects of corticotropin releasing factor (CRF) on sleep and body temperature following controllable footshock stress in mice. AB - Rapid eye movement sleep (REM) is increased after controllable stress (modeled by escapable footshock, ES) and decreased after uncontrollable stress (modeled by inescapable footshock, IS). Decreases in REM after IS are exacerbated by corticotropin releasing factor (CRF) and attenuated by a CRF antagonist. In this study, we trained mice with ES following injections of CRF, astressin (AST), or saline (SAL) to determine whether CRF would alter REM after ES. Male BALB/cJ mice (n=7) were implanted for recording sleep, activity and body temperature via telemetry and with a guide cannula aimed into a lateral ventricle. After recovery from surgery, sleep following exposure to a novel chamber was recorded as a handling control (HC). The mice received one day of training with ES without injection followed by weekly training sessions in which they received counterbalanced intracerebroventricular (ICV) microinjections of either SAL or CRF (days 7 & 14) or SAL or AST (days 21 & 28) prior to ES. On each experimental day, sleep was recorded for 20 h. Compared to HC, the mice showed significantly increased REM when receiving either SAL or AST prior to ES whereas CRF prior to ES significantly reduced REM. Stress-induced hyperthermia had longer duration after ES compared to HC, and was not significantly altered by CRF or AST compared to SAL. The current results demonstrate that activity in the central CRF system is an important regulator of stress-induced alterations in REM. PMID- 21651924 TI - Simvastatin induces apoptosis by a Rho-dependent mechanism in cultured cardiac fibroblasts and myofibroblasts. AB - Several clinical trials have shown the beneficial effects of statins in the prevention of coronary heart disease. Additionally, statins promote apoptosis in vascular smooth muscle cells, in renal tubular epithelial cells and also in a variety of cell lines; yet, the effects of statins on cardiac fibroblast and myofibroblast, primarily responsible for cardiac tissue healing are almost unknown. Here, we investigated the effects of simvastatin on cardiac fibroblast and myofibroblast viability and studied the molecular cell death mechanism triggered by simvastatin in both cell types. METHODS: Rat neonatal cardiac fibroblasts and myofibroblasts were treated with simvastatin (0.1-10MUM) up to 72h. Cell viability and apoptosis were evaluated by trypan blue exclusion method and by flow cytometry, respectively. Caspase-3 activation and Rho protein levels and activity were also determined by Western blot and pull-down assay, respectively. RESULTS: Simvastatin induces caspase-dependent apoptosis of cardiac fibroblasts and myofibroblasts in a concentration- and time-dependent manner, with greater effects on fibroblasts than myofibroblasts. These effects were prevented by mevalonate, farnesylpyrophosphate and geranylgeranylpyrophosphate, but not squalene. These last results suggest that apoptosis was dependent on small GTPases of the Rho family rather than Ras. CONCLUSION: Simvastatin triggered apoptosis of cardiac fibroblasts and myofibroblasts by a mechanism independent of cholesterol synthesis, but dependent of isoprenilation of Rho protein. Additionally, cardiac fibroblasts were more susceptible to simvastatin induced apoptosis than cardiac myofibroblasts. Thus simvastatin could avoid adverse cardiac remodeling leading to a less fibrotic repair of the damaged tissues. PMID- 21651925 TI - Participation of covalent modification of Keap1 in the activation of Nrf2 by tert butylbenzoquinone, an electrophilic metabolite of butylated hydroxyanisole. AB - Butylated hydroxyanisole (BHA) is an antioxidant and class-2B carcinogen. It is biotransformed to tert-butylhydroquinone (TBHQ), which readily auto-oxidizes to the electrophilic metabolite tert-butylbenzoquinone (TBQ). BHA and TBHQ activate Nrf2, a transcription factor that is negatively regulated by Keap1 and plays a role in the initial response to chemicals causing oxidative or electrophilic stress, although, the exact mechanism of Nrf2 activation remains unclear. Here, we examined the role of TBQ in Nrf2 activation. Exposure of RAW264.7 cells to TBQ activated Nrf2 and up-regulated its downstream proteins; under these conditions, TBQ produced cellular reactive oxygen species (ROS). However, while pretreatment with catalase conjugated with polyethylene glycol (PEG-CAT) did not affect the TBQ-induced activation of Nrf2, the ROS generation caused by TBQ was entirely abolished by PEG-CAT, suggesting that ROS is not the dominant factor for TBQ dependent Nrf2 activation. A click chemistry technique indicated that TBQ chemically modifies Keap1. Furthermore, ultrahigh performance liquid chromatography-tandem mass spectrometry analysis with purified Keap1 revealed that TBQ covalently binds to Keap1 through Cys23, Cys151, Cys226, and Cys368. These results suggest that TBQ derived from BHA activates Nrf2 through electrophilic modification of Keap1 rather than ROS formation. PMID- 21651926 TI - Disparity biasing in depth from monocular occlusions. AB - Monocular occlusions have been shown to play an important role in stereopsis. Among other contributions to binocular depth perception, monocular occlusions can create percepts of illusory occluding surfaces. It has been argued that the precise location in depth of these illusory occluders is based on the constraints imposed by occlusion geometry. Tsirlin et al. (2010) proposed that when these constraints are weak, the depth of the illusory occluder can be biased by a neighboring disparity-defined feature. In the present work we test this hypothesis using a variety of stimuli. We show that when monocular occlusions provide only partial constraints on the magnitude of depth of the illusory occluders, the perceived depth of the occluders can be biased by disparity defined features in the direction unrestricted by the occlusion geometry. Using this disparity bias phenomenon we also show that in illusory occluder stimuli where disparity information is present, but weak, most observers rely on disparity while some use occlusion information instead to specify the depth of the illusory occluder. Taken together our experiments demonstrate that in binocular depth perception disparity and monocular occlusion cues interact in complex ways to resolve perceptual ambiguity. PMID- 21651927 TI - The 'correlates' in neural correlates of consciousness. AB - In the search for neural correlates of consciousness (NCC), the concept of 'consciousness' remains problematic. We suggest that not only the 'consciousness' in neural correlates of consciousness is a confused term, but 'correlates' is as well. When brain events are found to covary with conscious experience, these brain events can be the neural substrates of the experience, as is often (implicitly) suggested, but they can also be neural prerequisites or neural consequences of the experience. We here disentangle these different sorts of brain processes conceptually. But we also propose a concrete multi-pronged research program that may, in near-future consciousness research, distinguish these brain processes empirically. PMID- 21651928 TI - Vegetables by stealth. An exploratory study investigating the introduction of vegetables in the weaning period. AB - Few studies have examined in detail weaning practices and how mothers introduce vegetables into the diets of their infants. The current exploratory study set out to use both qualitative and quantitative methods to investigate approaches to nutrition in the weaning period and in early infancy with a particular focus on vegetables. 75 mothers of infants aged 24-72 weeks filled out a postal questionnaire regarding infant feeding during the weaning period. Mothers completed the infant feeding questionnaire (IFQ) and a food frequency questionnaire (FFQ) to measure familial fruit and vegetable intake. Mothers introduced solid food to their infants at around 20 weeks of age and those who breast-fed their infants tended to introduce solid foods later compared to formula feeding mothers (21 wks versus 17.8 wks, p<0.05). Infants were offered around 3 different types of vegetable during the first 4 weeks of weaning. 13 mothers then took part in a follow-up in-depth interview. Mothers reported that they relied upon advice from family and friends and their interpretation of cues from their infants indicating the readiness for food, rather than relying on official guidelines. Mothers demonstrated high concern about the nutrient quality of their child's diet and perceived vegetables to be an integral part of the diet. A number of strategies for promoting vegetable intake were identified by mothers, offering vegetables by stealth was one of the most commonly identified strategies. PMID- 21651929 TI - Development of healthy eating habits early in life. Review of recent evidence and selected guidelines. AB - Encouraging healthy eating habit development early in life is a way to prevent the onset of diet-related diseases. This review focuses on the period ranging from the beginning of complementary feeding until the age of 3 years. Its first objective was to review relevant themes in the most recent literature on the development of healthy eating habits in this period. Its second objective was to evaluate to what extent international and national feeding guidelines cover these themes. Analysed guidelines included WHO, European Network for Public Health Nutrition, US and two European national guidelines (UK and France). They were evaluated using a 4-pt scale and compared. Well-covered themes in current literature include the influence of exposure on later acceptance, the role of variety and parental styles. Themes that occur more rarely include the role of texture, the development of autonomy, the optimization of variety, acceptable consumption levels of sweet and salty foods, and the way to cope with food refusal. Guidelines in general cover most of the themes, but some of the national guidelines are incomplete. Finally, guidelines should give more practical tips to parents, especially to help them establish a responsive feeding behaviour. PMID- 21651930 TI - The impact of flavour exposure in utero and during milk feeding on food acceptance at weaning and beyond. AB - An individual's experience of flavours contributes to their unique pattern of food preferences. Exposure to a specific flavour can increase familiarity and result in greater acceptance of this flavour over time. This paper describes the earliest occurrences of flavour exposure; first in utero, via amniotic fluid, and later through breast or formula milk. Evidence suggests these early experiences impact on later food preferences, but the extent to which specific flavour compounds from the mother's diet are transmitted during these pre- and early post natal periods may vary within and between individuals. In contrast with findings with toddlers and older children, infants accept new flavours rapidly, with relatively few exposures required. Early exposure to flavour variety may improve long term dietary outcomes, highlighting the need to promote a varied diet during pregnancy and lactation. PMID- 21651931 TI - Evaluation of dietary habits and assessment of cardiovascular disease risk factors among Greek university students. AB - The aim of this study was the evaluation of dietary habits in regard to cardiovascular risk status in university students in Northern Greece. 215 students (101 males) (age 21.5+/-2.3 years) participated in the study. Dietary intake was determined by using 3-day food record (1 weekend day). Recorded energy and nutrient intakes were compared to RDA and recommendations given by the American Heart Association (AHA). Students' smoking status and familial chronic diseases were recorded. A percentage of 55.8% (males) and 45.7% (females) were physically moderately active. When compared to AHA guidelines, the students had averagely significantly higher intake of total fat, saturated fat, sodium and dietary cholesterol and lower intake of polyunsaturated fat, monounsaturated fat, folate, vitamin E and fiber. 95% of them failed to meet all AHA dietary recommendations, with polyunsaturated to saturated fat ratio and the percentage of total fat being the top two failed parameters and sodium (10.2%) being the one less problematic. Dietary habits of Greek university students differ from what is considered as health promoting and, in the case that it they are not altered, may have an adverse effect on their CV health, despite the fact that their mean body weight is only moderately high. PMID- 21651932 TI - Relationships between parenting style, feeding style and feeding practices and fruit and vegetable consumption in early childhood. AB - Despite substantial evidence suggesting that a diet high in fruit and vegetables (FV) is associated with reduced risk of cancer, only 21% of children in the UK consume the recommended 5 portions of fruit or vegetables a day. This review examines the role of parenting style, feeding style and feeding practices in FV consumption in early childhood. Whilst inconsistencies in concepts and terminology cloud this literature, overall the evidence suggests that the context of an authoritative parenting and feeding style is associated with better FV consumption in the childhood years. This context is typified by emotional warmth but high expectations for children's dietary adequacy and behaviour, accompanied by specific feeding practices such as modeling consumption of FV, making FV available within the home, covertly restricting unhealthy alternative snack foods, and encouraging children to try FV. Further longitudinal and intervention studies are required to determine the efficacy of modification of parenting style and feeding practice on children's FV intake. PMID- 21651933 TI - Children's acceptance of new foods at weaning. Role of practices of weaning and of food sensory properties. AB - Weaning (i.e. introduction of complementary foods) is a transitional process between the consumption of a unique food, milk, and family foods. This review of existing literature regarding factors favouring the development of food acceptance at the beginning of weaning underlines in particular the roles of repeated exposure, of introduction of a variety of foods, of timing of introduction of weaning foods, and of food sensory properties (texture, taste and flavours). All factors appear to play a role in the acceptance of weaning foods. The efficiency, most favourable windows and long-term impact of each of these factors is not known accurately. PMID- 21651934 TI - Inactivated polio vaccine development for technology transfer using attenuated Sabin poliovirus strains to shift from Salk-IPV to Sabin-IPV. AB - Industrial-scale inactivated polio vaccine (IPV) production dates back to the 1960s when at the Rijks Instituut voor de Volksgezondheid (RIV) in Bilthoven a process was developed based on micro-carrier technology and primary monkey kidney cells. This technology was freely shared with several pharmaceutical companies and institutes worldwide. In this contribution, the history of one of the first cell-culture based large-scale biological production processes is summarized. Also, recent developments and the anticipated upcoming shift from regular IPV to Sabin-IPV are presented. Responding to a call by the World Health Organization (WHO) for new polio vaccines, the development of Sabin-IPV was continued, after demonstrating proof of principle in the 1990s, at the Netherlands Vaccine Institute (NVI). Development of Sabin-IPV plays an important role in the WHO polio eradication strategy as biocontainment will be critical in the post-OPV cessation period. The use of attenuated Sabin strains instead of wild-type Salk polio strains will provide additional safety during vaccine production. Initially, the Sabin-IPV production process will be based on the scale-down model of the current, and well-established, Salk-IPV process. In parallel to clinical trial material production, process development, optimization and formulation research is being carried out to further optimize the process and reduce cost per dose. Also, results will be shown from large-scale (to prepare for future technology transfer) generation of Master- and Working virus seedlots, and clinical trial material (for phase I studies) production. Finally, the planned technology transfer to vaccine manufacturers in low and middle-income countries is discussed. PMID- 21651935 TI - Ensuring the safety of vaccine cell substrates by massively parallel sequencing of the transcriptome. AB - Massively parallel, deep, sequencing of the transcriptome coupled with algorithmic analysis to identify adventitious agents (MP-SeqTM) is an important adjunct in ensuring the safety of cells used in vaccine production. Such cells may harbour novel viruses whose sequences are unknown or latent viruses that are only expressed following stress to the cells. MP-Seq is an unbiased and comprehensive method to identify such viruses and other adventitious agents without prior knowledge of the nature of those agents. Here we demonstrate its utility as part of an integrated approach to identify and characterise potential contaminants within commonly used virus and vaccine production cell lines. Through this analysis, in combination with more traditional approaches, we have excluded the presence of porcine circoviruses in the ATCC Vero cell bank (CCL 81), however, we found that a full length betaretrovirus related to SRV can be expressed in these cells, a factor that may be of importance in the production of certain vaccines. Similarly, insect cells are proving to be valuable for the production of virus like particles and sub-unit vaccines, but they can harbour a range of latent viruses. We show that following MP-Seq of the Trichoplusia ni (High Five cell line) transcriptome we were able to detect a contaminating, latent nodavirus and identify an expressed errantivirus genome. Collectively, these studies have reinforced the role of MP-Seq as an integral tool for the identification of contaminating agents in vaccine cell substrates. PMID- 21651936 TI - A microbial platform for rapid and low-cost virus-like particle and capsomere vaccines. AB - Studies on a platform technology able to deliver low-cost viral capsomeres and virus-like particles are described. The technology involves expression of the VP1 structural protein from murine polyomavirus (MuPyV) in Escherichia coli, followed by purification using scaleable units and optional cell-free VLP assembly. Two insertion sites on the surface of MuPyV VP1 are exploited for the presentation of the M2e antigen from influenza and the J8 peptide from Group A Streptococcus (GAS). Results from testing on mice following subcutaneous administration demonstrate that VLPs are self adjuvating, that adding adjuvant to VLPs provides no significant benefit in terms of antibody titre, and that adjuvanted capsomeres induce an antibody titre comparable to VLPs but superior to unadjuvanted capsomere formulations. Antibodies raised against GAS J8 peptide following immunization with chimeric J8-VP1 VLPs are bactericidal against a GAS reference strain. E. coli is easily and widely cultivated, and well understood, and delivers unparalleled volumetric productivity in industrial bioreactors. Indeed, recent results demonstrate that MuPyV VP1 can be produced in bioreactors at multi gram-per-litre levels. The platform technology described here therefore has the potential to deliver safe and efficacious vaccine, quickly and cost effectively, at distributed manufacturing sites including those in less developed countries. Additionally, the unique advantages of VLPs including their stability on freeze drying, and the potential for intradermal and intranasal administration, suggest this technology may be suited to numerous diseases where adequate response requires large-scale and low-cost vaccine manufacture, in a way that is rapidly adaptable to temporal or geographical variation in pathogen molecular composition. PMID- 21651937 TI - Cloning and expression of protease ClpP from Streptococcus pneumoniae in Escherichia coli: study of the influence of kanamycin and IPTG concentration on cell growth, recombinant protein production and plasmid stability. AB - Infections caused by Streptococcus pneumoniae are one of the main causes of death around the world. In order to address this problem, investigations are being made into the development of a protein-based vaccine. The aims of this study were to clone and express ClpP, a protein from S. pneumoniae serotype 14 in Escherichia coli, to optimize protein expression by using experimental design and to study plasmid segregation in the system. ClpP was cloned into the pET28b vector and expressed in E. coli BL21 Star (DE3). Protein expression was optimized by using central composite design, varying the inducer (IPTG) and kanamycin concentration, with a subsequent analysis being made of the concentration of heterologous protein, cell growth and the fraction of plasmid-bearing cells. In all the experiments, approximately the same concentration of ClpP was expressed in its soluble form, with a mean of 240.4mg/L at the center point. Neither the IPTG concentration nor the kanamycin concentration was found to have any statistically significant influence on protein expression. Also, higher IPTG concentrations were found to have a negative effect on cell growth and plasmid stability. Plasmid segregation was identified in the system under all the concentrations studied. Using statistical analysis, it was possible to ascertain that the procedures for determining plasmid stability (serial dilution and colony counting) were reproducible. It was concluded that the inducer concentration could be reduced tenfold and the antibiotic eliminated from the system without significantly affecting expression levels and with the positive effect of reducing costs. PMID- 21651939 TI - Foot and mouth disease (FMD) virus: quantification of whole virus particles during the vaccine manufacturing process by size exclusion chromatography. AB - Foot and mouth disease (FMD) is a highly infectious viral disease that affects cattle, sheep, goats and swine causing severe economic losses worldwide. The efficacy of inactivated vaccines is critically dependent on the integrity of foot and mouth disease virus (FMDV) particles. The recommended method to quantify the active ingredient of vaccines is the 140S quantitative sucrose density gradient analysis. This method has been an immensely valuable tool over the past three decades but it is highly operator dependent and difficult to automate. We developed a method to quantify FMDV particles during the vaccine manufacturing process that is based on separation of components by size-exclusion chromatography and measurement of virus by absorption at 254nm. The method is linear in the 5-70MUg/mL range, it is applicable to different FMDV strains, and has a good correlation with the 140S test. The proposed method uses standard chromatographic media and it is amenable to automation. The method has potential as a process analytical technology and for control of final product by manufacturers, international vaccine banks and regulatory agencies. PMID- 21651938 TI - Different patterns of expansion, contraction and memory differentiation of HIV-1 Gag-specific CD8 T cells elicited by adenovirus type 5 and modified vaccinia Ankara vaccines. AB - The magnitude and functional quality of antiviral CD8 T cell responses are critical for the efficacy of T cell based vaccines. Here, we investigate the influence of two popular viral vectors, adenovirus type 5 (Ad5) and modified vaccinia Ankara (MVA), on expansion, contraction and memory differentiation of HIV-1 Gag insert-specific CD8 T cell responses following immunization and show different patterns for the two recombinant viral vectors. The Ad5 vector primed 6 fold higher levels of insert-specific CD8 effector T cells than the MVA vector. The Ad5-primed effector cells also underwent less contraction (<2-fold) than the MVA-primed cells (>5-fold). The Ad5-primed memory cells were predominantly CD62L negative (effector memory) whereas the MVA-primed memory cells were predominantly CD62L positive (central memory). Consistent with their memory phenotype, MVA primed CD8 T cells underwent higher fold expansion than Ad5-primed CD8 T cells following a homologous or heterologous boost. Impressively, the Ad5 boost changed the quality of MVA-primed memory response such that they undergo less contraction with effector memory phenotype. However, the MVA boost did not influence the contraction and memory phenotype of Ad5-primed response. In conclusion, our results demonstrate that vaccine vector strongly influences the expansion, contraction and the functional quality of insert-specific CD8 T cell responses and have implications for vaccine development against infectious diseases. PMID- 21651940 TI - Efficient influenza B virus propagation due to deficient interferon-induced antiviral activity in MDCK cells. AB - Influenza B virus infections are mainly restricted to humans, which is partially caused by the inability of influenza B virus NS1 protein to counteract the innate immune response of other species. However, for cell culture-based influenza vaccine production non-human cells, such as Madin-Darby canine kidney (MDCK) cells, are commonly used. Therefore, the impact of cellular pathogen defence mechanisms on influenza B virus propagation in MDCK cells was analysed in this study. Activation of the cellular antiviral defence by interferon stimulation slowed down influenza B virus replication at early time points but after 48h the same virus titres were reached in stimulated and control cells. Furthermore, suppression of the antiviral host defence by transient expression of a viral antagonist, the rabies virus phosphoprotein, could not increase influenza B virus replication. Finally, canine Myxovirus resistance (Mx) proteins showed no antiviral activity in an influenza B virus-specific minireplicon assay in contrast to the murine Mx1 protein. Taken together, these results indicate that an insufficient antiviral defence in MDCK cells promotes efficient influenza B virus replication favouring the use of MDCK cells in influenza vaccine production. PMID- 21651941 TI - Vaccine stabilization: research, commercialization, and potential impact. AB - All vaccines are susceptible to damage by elevated temperatures and many are also damaged by freezing. The distribution, storage, and use of vaccines therefore present challenges that could be reduced by enhanced thermostability, with resulting improvements in vaccine effectiveness. Formulation and processing technologies exist that can improve the stability of vaccines at temperature extremes, however, customization is required for individual vaccines and results are variable. Considerations affecting decisions about stabilization approaches include development cost, manufacturing cost, and the ease of use of the final product. Public sector agencies can incentivize vaccine developers to prioritize stabilization efforts through advocacy and by implementing policies that increase demand for thermostable vaccines. PMID- 21651942 TI - Preservative of choice for Prev(e)nar 13TM in a multi-dose formulation. AB - Development of a Prev(e)nar 13TM multi-dose vaccine, in support of vaccinating populations against pneumococcal disease, required the addition of a preservative to the vaccine formulation that met antimicrobial effectiveness tests based on the European Pharmacopoeia (EP) requirements, including deliberate multiple challenge studies and recommendation by the WHO Open Vial Policy. In this study, the antimicrobial effectiveness of several preservatives in Prev(e)nar 13TM formulations was evaluated. A Prev(e)nar 13TM formulation containing 2 Phenoxyethanol (2-PE) at a concentration of 5.0mg/dose was stable and met EP recommended criteria for antimicrobial effectiveness tests when the formulation was kept over a 30 month period. In contrast, a recommended dose of Thimerosal, as a comparator, or other preservatives did not meet EP antimicrobial effectiveness acceptance criteria. The rate of growth inhibition of Thimerosal compared to 2-PE on Staphylococcus aureus, a resilient organism in these tests, was significantly slower in single and multi-challenge studies. These results indicate that 2-PE provides a superior antimicrobial effectiveness over Thimerosal for this vaccine formulation. PMID- 21651943 TI - The epidemiology of community acquired bacteremic pneumonia, due to Streptococcus pneumoniae, in the Top End of the Northern Territory, Australia--over 22 years. AB - BACKGROUND: Diseases caused by Streptococcus pneumoniae continue to cause substantial morbidity and mortality throughout the world. Furthermore, detrimental outcomes are more pronounced in some populations--such as those living in third world poverty, and Indigenous people who live in developed nations. METHODS: This study describes the epidemiology of blood culture positive S. pneumoniae community-acquired pneumonia (CAP) in the Top End of the Northern Territory of Australia. Demographics, indigenous status, medical risk factors, serotype and outcomes were collected from adults presenting to hospital with blood culture positive S. pneumoniae CAP, from 1987 to 2008. RESULTS: We report 205 cases, with a median age of 40 years. The average overall incidence rate ratio was 10.3 for indigenous adults compared with non-indigenous adults. There was no statistical difference between incidence rates pre and post-23-valent pneumococcal polysaccharide vaccine (23vPPV) introduction. Serotypes in presenting cases were predominantly (84.7%) 23vPPV types. The whole-population logistic regression model identified significant adjusted relative risks: 95% CI, for age 45 and older 1.6: 1.1, 2.2, indigenous 5.9: 3.7, 9.5, diabetes 2.3: 1.6, 3.3, excess alcohol 4.8: 2.8, 8.3, smoking 2.7: 1.9, 3.7 with indigenous+excess alcohol 18.5: 17.3, 19.7 as predictive for bacteremic S. pneumoniae CAP presentation. CONCLUSIONS: Our results suggest that, the national 23vPPV program appears to be under-utilized. An integrated Public Health approach vigorously targeting indigenous adolescents, before substances such as alcohol and smoking are habitual, together with increased vaccine coverage, will reduce the burden of pneumococcal disease in this population. PMID- 21651944 TI - Enhancing the role of veterinary vaccines reducing zoonotic diseases of humans: linking systems biology with vaccine development. AB - The aim of research on infectious diseases is their prevention, and brucellosis and salmonellosis as such are classic examples of worldwide zoonoses for application of a systems biology approach for enhanced rational vaccine development. When used optimally, vaccines prevent disease manifestations, reduce transmission of disease, decrease the need for pharmaceutical intervention, and improve the health and welfare of animals, as well as indirectly protecting against zoonotic diseases of people. Advances in the last decade or so using comprehensive systems biology approaches linking genomics, proteomics, bioinformatics, and biotechnology with immunology, pathogenesis and vaccine formulation and delivery are expected to enable enhanced approaches to vaccine development. The goal of this paper is to evaluate the role of computational systems biology analysis of host:pathogen interactions (the interactome) as a tool for enhanced rational design of vaccines. Systems biology is bringing a new, more robust approach to veterinary vaccine design based upon a deeper understanding of the host-pathogen interactions and its impact on the host's molecular network of the immune system. A computational systems biology method was utilized to create interactome models of the host responses to Brucella melitensis (BMEL), Mycobacterium avium paratuberculosis (MAP), Salmonella enterica Typhimurium (STM), and a Salmonella mutant (isogenic DeltasipA, sopABDE2) and linked to the basis for rational development of vaccines for brucellosis and salmonellosis as reviewed by Adams et al. and Ficht et al. [1,2]. A bovine ligated ileal loop biological model was established to capture the host gene expression response at multiple time points post infection. New methods based on Dynamic Bayesian Network (DBN) machine learning were employed to conduct a comparative pathogenicity analysis of 219 signaling and metabolic pathways and 1620 gene ontology (GO) categories that defined the host's biosignatures to each infectious condition. Through this DBN computational approach, the method identified significantly perturbed pathways and GO category groups of genes that define the pathogenicity signatures of the infectious agent. Our preliminary results provide deeper understanding of the overall complexity of host innate immune response as well as the identification of host gene perturbations that defines a unique host temporal biosignature response to each pathogen. The application of advanced computational methods for developing interactome models based on DBNs has proven to be instrumental in elucidating novel host responses and improved functional biological insight into the host defensive mechanisms. Evaluating the unique differences in pathway and GO perturbations across pathogen conditions allowed the identification of plausible host-pathogen interaction mechanisms. Accordingly, a systems biology approach to study molecular pathway gene expression profiles of host cellular responses to microbial pathogens holds great promise as a methodology to identify, model and predict the overall dynamics of the host-pathogen interactome. Thus, we propose that such an approach has immediate application to the rational design of brucellosis and salmonellosis vaccines. PMID- 21651945 TI - Poly(methyl vinyl ether-co-maleic anhydride) nanoparticles as innate immune system activators. AB - Adjuvant research is being oriented to TLR-agonists, but complement activation has been relatively unexplored. In previous studies it was demonstrated that poly(methyl vinyl ether-co-maleic anhydride) nanoparticles (PVMA NPs) used as adjuvant differentially activate dendritic cells through toll like receptors (TLR) stimulation, however, a high dose of these NPs was used. Now, we demonstrated a dose-response effect, with a concentration as low as 20MUg/mL able to stimulate TLR2 and TLR4 transfected dendritic cells. In addition, we investigated whether PVMA NPs are able to exploit also the immunomodulatory benefits of complement activation. Results indicated that the hydroxylated surface of these NPs highly activated the complement cascade, as measured by adsorption studies and a complement fixation bioassay. Stable binding of C3b to NPs was confirmed as indicated by lability to SDS treatment after washing resistance. Complement consumption was confirmed as the lytic capacity of complement exposed to NPs was abolished against antibody-sensitized sheep erythrocytes, with a minimal inhibitory concentration of 50MUg NPs, equivalent to a surface of 1cm(2). On the contrary, nanoparticles prepared with poly(lactic-co glycolic acid) (PLGA), used as a reference, did not consume complement at a concentration >=3mg NPs (>=40cm(2)). Complement consumption was inhibited when PVMA NPs were cross-linked with diamino groups (1,3-diaminopropane), indicating the role of hydroxyl groups as responsible of the phenomenon. These results favour a model whereby PVMA NPs adjuvant activate complement on site to attract immature antigen presenting cells that are activated through TLR2 and TLR4. PMID- 21651946 TI - Fabrication of influenza virus-like particles using M2 fusion proteins for imaging single viruses and designing vaccines. AB - Influenza virus-like particles (VLPs) are noninfectious and the assembly of influenza VLPs depends on the interactions of M1 proteins and/or other viral surface proteins, such as HA, NA, and M2, with the cellular lipid membranes. In this study we propose that M2 protein can be used as a molecular fabricator without disrupting the assembly of VLPs and while retaining the native structures of HA and NA envelope protein oligomers on the particle surfaces. First, we demonstrated that influenza VLPs can be fabricated by the M2 fusion of enhanced green fluorescent protein for imaging single virus entering A549 cells. Second, we engineered two molecular adjuvants (flagellin and profilin) fused to M2 protein to generate molecular adjuvanted VLPs. Theses molecular adjuvanted VLPs had stimulatory functions, including increasing TNF-alpha production and promoting the maturation of dendritic cells. Immunization of mice with molecular adjuvanted VLPs also enhanced the response of the neutralizing antibodies against homologous and heterologous H5N1 viruses. The results can provide useful information for imaging single viruses and designing novel vaccines against influenza virus infection. PMID- 21651947 TI - A comparative study to evaluate the safety and immunogenicity of two lots of Haemophilus influenzae type-B conjugate vaccine manufactured at different scales. AB - OBJECTIVE: To compare the immunogenicity and safety of two different lots of SII Haemophilus influenzae type-B-tetanus toxoid conjugate (SII HibP(RO)) vaccine manufactured at different scales when given in 3-dose schedule. DESIGN: Phase IV, open label, comparative, randomized parallel group study. SETTING: Shirdi Sai Baba Hospital, Vadu Budruk, Pune and Pediatrics Department of King Edward Memorial Hospital Research Centre, Pune. SUBJECTS: 204 normal healthy infants of age 6-8 weeks at the time of first vaccination. METHODS: The eligible subjects received 3 doses of 0.5 ml of SII HibP(RO) vaccine of either lot depending upon randomization number, intramuscularly in right thigh in the EPI schedule of 6, 10 and 14 weeks. They also received concomitantly DTP-HB vaccine intramuscularly on left thigh and Oral Polio vaccine (OPV). Solicited reactions were captured for 7 days following each vaccination; the events beyond 7 days till day 28 were captured as unsolicited adverse events. Serious Adverse Events (SAEs) were looked for throughout the subject participation. Blood samples were collected at baseline (before the first dose) and one month after the third dose for anti-PRP (polyribosylribitol phosphate) antibodies. RESULTS: In both groups, more than 98% subjects achieved short-term seroprotection (anti-PRP >= 0.15 MUg/ml) after 3 doses. The long-term seroprotection (anti-PRP >= 1 MUg/ml) was 87% and 80% in infants receiving lot manufactured at industrial scale and small scale respectively. Short and long term seroprotection and GMTs increased significantly as compared to baseline in both the groups. Overall local pain (52% and 58%), redness (30% and 41%), swelling (34% and 44%), fever (6% and 6%) and irritability (52% and 50%) were reported in infants receiving lot manufactured at industrial scale and small scale respectively. Majority of the reactions were mild and resolved without any sequelae. Four SAEs, none of them causally related to the study vaccine, occurred during study. CONCLUSION: SII HibP(RO) vaccines manufactured in small and industrial scale are equally immunogenic, safe and confer adequate seroprotection to infants of 6-14 weeks of age. Scaling up production process has not affected the safety and immune response in the target population. PMID- 21651949 TI - Asphalt fume dermal carcinogenicity potential: II. Initiation-promotion assay of Type III built-up roofing asphalt. AB - Clark et al. (accepted for publication) reported that a sample of field-matched fume condensate from a Type III built-up roofing asphalt (BURA) resulted in a carcinogenic response in a mouse skin bioassay, with relatively few tumor-bearing animals, long tumor latency and chronic skin irritation. This mouse skin initiation/promotion study was conducted to assess possible mechanisms, i.e., genotoxic initiation vs. tumor promotion subsequent to repeated skin injury and repair. The same Type III BURA fume condensate sample was evaluated in groups of 30 male Crl:CD1(r) mice by skin application twice per week (total dose of 50 mg/week) for 2 weeks during the initiation phase and for 26 weeks during the promotion phase. Positive control substances were 7,12-dimethylbenz(a)anthracene (DMBA, 50 MUg applied once) as an initiator and 12-O-tetradecanoyl-13-acetate (TPA, 5 MUg, applied twice weekly) during the promotion phase. During the 6 months of study with the asphalt fume condensate, eight skin masses were observed when tested for initiation, five of which were confirmed microscopically to be benign squamous cell papillomas. Only two papillomas were observed when tested for promotion. There was no apparent relationship between skin irritation and tumor development in this study. These results are more indicative of genotoxicity rather than a non-genotoxic mode of action. PMID- 21651948 TI - Immunogenicity of a novel engineered HIV-1 clade C synthetic consensus-based envelope DNA vaccine. AB - DNA vaccines require significant engineering in order to generate strong CTL responses in both non-human primates and humans. In this study, we designed a clade C env gene (EY3E1-C) to decrease the genetic distances of virus isolates within clade C and focus the induced T cell responses to conserved clade C epitopes. After generating a consensus sequence by analyzing full-length clade C env early transmitter sequences, several modifications were performed to increase the expression of the EY3E1-C, including codon/RNA optimization, addition of Kozak sequence and addition of an IgE leader sequence. We also shortened the V1 and V2 loops to approximate early transmitter isolate sequences and the cytoplasmic tail was truncated to prevent envelope recycling. When studied as a DNA vaccine in Balb/c mice, compared to a primary codon-optimized clade C envelope DNA vaccine (p96ZM651gp140-CD5), this novel construct is up to three times more potent in driving CTL responses. Importantly this construct not only induces stronger cross-reactive cellular responses within clade C, it also induces stronger immune responses against clade B and group M envelope peptide pools than p96ZM651gp140-CD5. Epitope mapping demonstrated that EY3E1-C was able to induce clade C envelope-specific immune responses against 15 peptide pools, clade B envelope-specific immune responses against 19 peptide pools and group M envelope-specific immune responses against 16 peptide pools out of 29, respectively, indicating that a significant increase in the breadth of induced immune responses. The analysis of antibody responses suggested that vaccination of pEY3E1-C could induce a clade C envelope-specific antibody response. The cellular immune responses of pEY3E1-C could be further enhanced when the DNA was delivered by using electroporation (EP). Thus, the synthetic engineered consensus EY3E1-C gene is capable of eliciting stronger and broader CTL responses than primary clade C envelopes. This finding suggests that such synthetic immunogens could be important for examination of their potential as part of an efficient HIV DNA vaccine. PMID- 21651950 TI - Application of a source-to-outcome model for the assessment of health impacts from dietary exposures to insecticide residues. AB - The paper presents a case study of the application of a "source-to-outcome" model for the evaluation of the health outcomes from dietary exposures to an insecticide, chlorpyrifos, in populations of adults (age 30) and children (age 3). The model is based on publically-available software programs that characterize the longitudinal dietary exposure and anthropometry of exposed individuals. These predictions are applied to a validated PBPK/PD model to estimate interindividual and longitudinal variation in brain and RBC AChE inhibition (key events) and chlorpyrifos concentrations in blood and TCPy in urine (biomarkers of exposure). The predicted levels of chlorpyrifos and TCPy are compared to published measurements of the biomarkers. Predictions of RBC AChE are compared to levels of inhibition associated with reported exposure-related effects in humans to determine the potential for the occurrence of adverse cholinergic effects. The predicted distributions of chlorpyrifos in blood and TCPy in urine were found to be reasonably consistent with published values, supporting the predictive value of the exposure and PBPK portions of the source to-outcome model. Key sources of uncertainty in predictions of dietary exposures were investigated and found to have a modest impact on the model predictions. Future versions of this source-to-outcome model can be developed that consider advances in our understanding of metabolism, to extend the approach to other age groups (infants), and address intakes from other routes of exposure. PMID- 21651951 TI - Hippocampus and amygdalar volumes in patients with somatization disorder. AB - In regard to somatization disorder which covers an important section of our patient population, there is no systematic structural magnetic resonance imaging (MRI) study in the literature. Therefore, we aimed to use structural MRI to evaluate the hippocampus amygdalar complex which is associated with both stress and regulation of emotion that are main basis clinical presentation of somatization disorder in the patients with somatization disorder. Totally 40 subjects (20 patients with somatization disorder and 20 healthy controls) were enrolled. Intracranial volume (ICV), whole brain volume, gray and white matter volumes, and hippocampus and amygdalar volumes of the subjects were measured. In regard to unadjusted mean volumes of measured structures, the patients had significantly smaller mean volumes of the left and right amygdala. However, two groups did not differ significantly in terms of whole brain, total gray and white matter or hippocampus volumes. The repeated measures ANCOVA predicting left and right amygdala volumes demonstrated a significant main effect of diagnostic group. In conclusion, the findings of the present study revealed that the patients with somatization disorder had significantly smaller mean volumes of the left and right amygdala without any differences in regard to whole brain, total gray and white matter or hippocampus volumes. On the basis of the current findings, it seems reasonable to evaluate that abnormalities in connectivity and/or metabolism dimensions and to examine the effects of drugs or psychotherapeutic approaches could be especially informative. PMID- 21651952 TI - First rank symptoms & facial emotion recognition deficits in antipsychotic naive schizophrenia: Implications for social threat perception model. AB - Facial emotion recognition deficits (FERD) have been consistently demonstrated in schizophrenia. However the relation between psychopathology and FERD remains inconclusive. This could possibly be due to the wide heterogeneity in the psychopathology of schizophrenia. First Rank Symptoms (FRS) of schizophrenia is associated with heightened sense of paranoia and rapid processing of threatful emotional stimuli. We studied differences in patterns of FERD between homogenous sub-groups of antipsychotic naive schizophrenia patients (n=63); namely those experiencing FRS (FRS+ group n=26) and those who did not (FRS- group n=37), in comparison to age-, sex-, education matched healthy controls (n=45). FERD was assessed using TRENDS - (Tool for Recognition of Emotions in Neuropsychiatric DisorderS), a culturally sensitive and ecologically valid (consisting of both static and dynamic emotional stimuli) tool. The total number of images of non threatful emotions (sad, happy, neutral) which were identified as any of the threatful emotions (fear, anger, disgust) and vice versa were calculated and termed TRENDS Over-identification and Under-identification score respectively. The patient group made significantly greater errors in emotion recognition as compared to healthy controls. On post hoc analysis (Tukey HSD) the patients in FRS+ group made significantly greater errors in Over-identification as compared to the FRS- group. This study supports that FERD is one of the important deficits in schizophrenia. There is a differential pattern of impairment in FERD, which supports the role of heightened threat perception in the evolution of psychopathology in schizophrenia patients. PMID- 21651953 TI - Autonomic modulation in healthy first-degree relatives of patients with major depressive disorder. AB - BACKGROUND: Cardiac mortality is known to be increased in patients with major depression. Several studies have reported an imbalance within the autonomic nervous system (ANS) of patients with major depressive disorder (MDD) as one putative cause. Since a heritability of autonomic modulation was demonstrated in healthy subjects, we aimed to investigate autonomic modulation in first-degree relatives of patients with MDD to find potential autonomic imbalances. METHODS: We included 30 patients with MDD, 30 of their first-degree relatives (siblings or offspring) and 30 matched healthy controls in our study. We obtained a high resolution electrocardiogram and beat to beat blood pressure measurements for 30 min at rest. Linear and nonlinear parameters of heart rate variability (HRV) and baroreflex sensitivity (BRS) were calculated. RESULTS: Parameters of HRV and BRS did not differ significantly between relatives and controls. We found significant differences between patients and controls for some HRV and BRS parameters confirming results of previous studies. DISCUSSION: Findings of our study suggest that an imbalance of autonomic function is related to patients with depression and not to first-degree relatives. Thus, a genetic background for autonomic dysfunction is rather unlikely. PMID- 21651954 TI - Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice. AB - Androstenedione was marketed as a dietary supplement to increase muscle mass during training. Due to concern over long-term use, the NTP evaluated the subchronic and chronic toxicity and carcinogenicity of androstenedione in male and female F344/N rats and B6C3F1 mice. In subchronic studies, dose limiting effects were not observed. A chronic (2-year) exposure by gavage at 10, 20, or 50 mg/kg in rats and male mice, and 2, 10, or 50 mg/kg in female mice (50 mg/kg, maximum feasible dose) was conducted. Increased incidences of lung alveolar/bronchiolar adenoma and carcinoma occurred in the 20 mg/kg male rats and increases in mononuclear cell leukemia occurred in the 20 and 50 mg/kg female rats, which may have been related to androstenedione administration. In male and female mice, androstenedione was carcinogenic based upon a significant increase in hepatocellular tumors. A marginal increase in pancreatic islet cell adenomas in male (50 mg/kg) and female (2, 10, 50 mg/kg) mice was considered to be related to androstenedione administration. Interestingly, incidences of male rat Leydig cell adenomas and female rat mammary gland fibroadenomas decreased. In conclusion, androstenedione was determined to be carcinogenic in male and female mice, and may have been carcinogenic in rats. PMID- 21651955 TI - Titanium dioxide nanoparticles addition to a conventional glass-ionomer restorative: influence on physical and antibacterial properties. AB - OBJECTIVES: The aim of this study was to evaluate the addition of titanium dioxide (TiO(2)) nanoparticles to a conventional glass-ionomer (GI) on physical and antibacterial properties. METHODS: TiO(2) nanoparticles were incorporated into the powder component of Kavitan((r)) Plus (SpofaDental, Czech Republic) at 3%, 5% and 7% (w/w). Unblended powder was used as control. Fracture toughness, compressive strength, flexural strength and microtensile bond strength were evaluated using a universal testing machine. Surface microhardness was measured using Vickers microhardness tester. Setting time was determined as specified in the ISO standard. The antibacterial activity was evaluated using direct contact test against Streptococcus mutans. Fluoride release and SEM analysis were carried out. Data were analysed using ANOVA and Tukey's test. RESULTS: GI-containing 3% and 5% (w/w) TiO(2) nanoparticles improved the fracture toughness, flexural strength and compressive strength compared to the unmodified GI. However, a decrease in the mechanical properties was found for GI-containing 7% (w/w) TiO(2) nanoparticles. GI-containing 5% and 7% (w/w) TiO(2) nanoparticles compromised the surface microhardness. Setting time of GI-containing TiO(2) nanoparticles decreased but the values remained within ISO limits. The addition of TiO(2) nanoparticles to the conventional GI did not compromise its bond strength with dentine or fluoride release of the GI. GI-containing TiO(2) nanoparticles possessed a potent antibacterial effect. CONCLUSIONS: GI-containing 3% (w/w) TiO(2) nanoparticles is a promising restorative material with improved mechanical and antibacterial properties. This novel experimental GI may be potentially used for higher stress-bearing site restorations such as Class I and II. PMID- 21651956 TI - Swept-source optical coherence tomography as a new tool to evaluate defects of resin-based composite restorations. AB - OBJECTIVES: Current diagnostic imaging modalities for resin-based composites (RBC) do not possess sufficient resolution and cross-sectional tomographic imaging to detect defects of RBC restorations in real-time. The purpose of this in vivo study was to investigate swept-source optical coherence tomography (SS OCT) as a new tool to evaluate defects of RBC restorations. METHODS: We evaluated for the failure of RBC restorations in 52 patients (11 male, 41 female) at the Division of Oral and Dental Surgery, National Centre for Geriatrics and Gerontology, Japan. SS-OCT images of the 132 RBC restorations were obtained in order to investigate their marginal adaptation, porosity and internal integrity. RESULTS: Rates of defective restorations in terms of marginal adaptation, large porosity and gap formation were 65.2 percent, 27.3 percent, and 15.2 percent, respectively. Only 18.9 percent of the RBC restorations had no defects. CONCLUSIONS: SS-OCT has the potential to provide higher-resolution information related to the structure of RBC restorations currently unavailable with any diagnostic or imaging method. PMID- 21651957 TI - Neuroprotective effect of cyanidin-3-O-glucoside anthocyanin in mice with focal cerebral ischemia. AB - The present study sought to determine the neuroprotective effect of anthocyanin cyanidin-3-O-glucoside (CG), isolated and purified from tart cherries, against permanent middle cerebral artery occlusion (pMCAO) in mice and its potential mechanisms of neuroprotection. C57BL/6 mice subjected to pMCAO were treated with CG orally. Twenty-four hours after pMCAO, neurological scoring was used to evaluate functional outcome. The brains were then excised for measuring infarct volume and brain superoxide levels were determined. In a separate set of experiments, the influence of CG on cytochrome c (cyt c) and apoptosis-inducing factor (AIF) release from mitochondria under oxidative stress were assessed in isolated cortical neurons from adult mouse brains. Infarction volume was attenuated by 27% in mice pre-treated with 2mg/kg of CG compared to vehicle treated mice. Delayed treatment with 2mg/kg of CG also showed 25% reduction in infarct size. Neurological functional outcome was significantly improved in mice pre- or post-treated with CG. Compared to vehicle treated mice CG treated mice had lower levels of brain superoxide. CG also blocked the release of AIF from mitochondria under oxidative stress, but did not inhibit the release of cyt c. Our data show that CG is neuroprotective against pMCAO in mice, and this beneficial effect may be mediated by attenuation of brain superoxide levels after ischemia. CG may also exert its neuroprotective effect by blocking AIF release in mitochondria. PMID- 21651958 TI - Immunolocalization of G protein alpha subunits in the olfactory system of Polypterus senegalus (Cladistia, Actinopterygii). AB - In vertebrates, the receptor neurons of the olfactory/vomeronasal systems express different receptor gene families and related G-protein types (in particular the G protein alpha subunit). There are no data in the literature about the molecular features of the olfactory/vomeronasal systems of Cladistia thus, in this work, the presence and distribution of different types of G protein alpha subunits were investigated in the olfactory organs of the bichir Polypterus senegalus, using immunohistochemistry. Galphao-like immunoreactivity was detected in the microvillous receptor neurons, with the cell body in the basal zone of the sensory epithelium, and in the crypt neurons. Galphao-like ir glomeruli were mainly localized in the anterior part of the olfactory bulb. Galphaolf-like immunoreactivity in the sensory epithelium was detected in the ciliated receptor neurons, while the immunoreactive glomeruli in the olfactory bulb were mainly localized in the ventral-posterior part. No Galphaq nor Galphai3 immunoreactivity was detected. These data are partially in agreement with studies that show the distribution of G protein alpha subunits in teleosts, allowing to hypothesize a common organization of the olfactory/vomeronasal systems in the group of Actinopterigians. PMID- 21651959 TI - Repair of facial nerve defects with decellularized artery allografts containing autologous adipose-derived stem cells in a rat model. AB - The purpose of this study was to investigate the effects of a decellularized artery allograft containing autologous adipose-derived stem cells (ADSCs) on an 8 mm facial nerve branch lesion in a rat model. At 8 weeks postoperatively, functional evaluation of unilateral vibrissae movements, morphological analysis of regenerated nerve segments and retrograde labeling of facial motoneurons were all analyzed. Better regenerative outcomes associated with functional improvement, great axonal growth, and improved target reinnervation were achieved in the artery-ADSCs group (2), whereas the cut nerves sutured with artery conduits alone (group 1) achieved inferior restoration. Furthermore, transected nerves repaired with nerve autografts (group 3) resulted in significant recovery of whisking, maturation of myelinated fibers and increased number of labeled facial neurons, and the latter two parameters were significantly different from those of group 2. Collectively, though our combined use of a decellularized artery allograft with autologous ADSCs achieved regenerative outcomes inferior to a nerve autograft, it certainly showed a beneficial effect on promoting nerve regeneration and thus represents an alternative approach for the reconstruction of peripheral facial nerve defects. PMID- 21651960 TI - Xenon fails to inhibit capsaicin-evoked CGRP release by nociceptors in culture. AB - To investigate whether the xenon-induced inhibition of the transient receptor potential vanilloid type 1 (TRPV1) ion channel in rat dorsal root ganglion (DRG) neurons reduces nociceptive processing, we examined the effect of xenon in reducing the release of calcitonin gene-related peptide (CGRP) from those neurons. We found that exposure to xenon failed to effect a reduction of capsaicin-evoked CGRP release from cultured primary sensory neurons when stimulated by capsaicin. This finding suggests that xenon acts on several molecular targets on nociceptive primary sensory neurons, and that xenon's action on one, or more, of those targets serves to offset the inhibitory, pro-analgesic, effect of xenon on TRPV1. It is concluded that xenon may not produce any analgesic effect through peripheral nociceptors. PMID- 21651961 TI - Apolipoprotein E isoform-specific effects on cytokine and nitric oxide production from mouse Schwann cells after inflammatory stimulation. AB - Previously, we reported that apolipoprotein E (apoE) deficiency increased the susceptibility to experimental autoimmune neuritis (EAN), an inflammatory autoimmune disorder of the peripheral nervous system (PNS) and an animal model for human Guillain-Barre syndrome (GBS) by affecting the antigen-presenting function of Schwann cells (SCs) via influence upon IL-6 production. To further elucidate the role of apoE in inflammation of the PNS, here we studied the effect of different isoforms of apoE on SCs in response to inflammatory stimulation. SCs from apoE2, E3 and E4 transgenic (Tg) and wild type (WT) mice were cultured, and their responses to stimulation by lipopolysaccharide (LPS) plus interferon (IFN) gamma were compared. Upon stimulation, the morphology of cultured SCs changed. Pronounced production of interleukin (IL)-6 and IL-10 within SCs, and of IL-6 and nitric oxide (NO) in the supernatants were found in an isoform-dependent manner (apoE3>apoE2~apoE4). Further results indicated that both nuclear factor (NF) kappaB and Akt signaling pathways were involved in the process by the same isoform-dependent pattern. However, the expression of co-stimulatory molecules as showing the antigen-presenting capacity of SCs was not significantly different among these groups. In conclusion, SCs respond to inflammatory insults accompanied by increased productions of IL-6, IL-10 and NO in an apoE-isoform dependent manner. SCs from apoE2 and apoE4 Tg mice seem to bear some dysfunction in producing cytokines (IL-6 and IL-10) and NO as compared with their apoE3 counterparts, probably resulting from their insufficiency to suppress the activation of NFkappaB and Akt pathways. Our findings may help to understand the role of different isoforms of apoE in inflammatory disorders of the PNS. PMID- 21651962 TI - Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity. AB - Glutamate, an excitatory neurotransmitter in the central nervous system, plays an important role in neurological disorders. Previous studies have shown that excess glutamate can cause oxidative stress in a hippocampal HT-22 cell line. 7,8 Dihydroxyflavone (7,8-DHF), a member of the flavonoid family, is a selective tyrosine kinase receptor B (TrkB) agonist that has neurotrophic effects in various neurological diseases such as stroke and Parkinson's disease. In this study, we found that there is no TrkB receptor in HT-22 cells. Despite this, our data demonstrate that 7,8-DHF still protects against glutamate-induced toxicity in HT-22 cells in a concentration-dependent manner, indicating that 7,8-DHF prevents cell death through other mechanisms rather than TrkB receptors in this cell model. We further show that 7,8-DHF increases cellular glutathione levels and reduces reactive oxygen species (ROS) production caused by glutamate in HT-22 cells. Finally, our data demonstrate that 7,8-DHF protects against hydrogen peroxide and menadione-induced cell death, suggesting that 7,8-DHF has an antioxidant effect. In summary, although 7,8-DHF is considered as a selective TrkB agonist, our results demonstrate that 7,8-DHF can still confer neuroprotection against glutamate-induced toxicity in HT-22 cells via its antioxidant activity. PMID- 21651963 TI - Strategies and tools to explore protein S-nitrosylation. AB - BACKGROUND: A biochemical pathway by which nitric oxide accomplishes functional diversity is the specific modification of protein cysteine residues to form S nitrosocysteine. This post-translational modification, S-nitrosylation, impacts protein function, interactions and location. However, comprehensive studies exploring protein signaling pathways or interrelated protein clusters that are regulated by S-nitrosylation have not been performed on a global scale. SCOPE OF REVIEW: To provide insights to these important biological questions, sensitive, validated and quantitative proteomic approaches are required. This review summarizes current approaches for the global identification of S-nitrosylated proteins. MAJOR CONCLUSIONS: The application of novel methods for identifying S nitrosylated proteins, especially when combined with mass-spectrometry based proteomics to provide site-specific identification of the modified cysteine residues, promises to deliver critical clues for the regulatory role of this dynamic posttranslational modification in cellular processes. GENERAL SIGNIFICANCE: Though several studies have established S-nitrosylation as a regulator of protein function in individual proteins, the biological chemistry and the structural elements that govern the specificity of this modification in vivo are vastly unknown. Additionally, a gap in knowledge exists concerning the potential global regulatory role(s) this modification may play in cellular physiology. By further studying S-nitrosylation at a global scale, a greater appreciation of nitric oxide and protein S-nitrosylation in cellular function can be achieved. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation. PMID- 21651964 TI - Human hypothalamus shows differential responses to basic motivational stimuli--an invasive electrophysiology study. AB - The hypothalamus supports basic motivational behaviours such as mating and feeding. Recording directly from the posterior inferior hypothalamus in a male patient receiving a deep brain stimulation (DBS) electrode for the alleviation of cluster headache, we tested the hypothalamic response to different classes of motivational stimuli (sexually relevant: pictures of dressed and undressed women; pictures of food) and pictures of common objects as control. Averaged local field potentials (LFP) to sexually relevant stimuli were characterized by a biphasic significantly enhanced response (relative to objects; bootstrapping statistics) with a first phase starting at around 200 ms and a second phase peaking at around 600 ms. Sexually relevant stimuli also showed a greatly enhanced positivity relative to other stimulus classes in surface event-related potentials in a group of 11 male control participants. It is suggested that the hypothalamus is involved in the recruitment of attentional resources by sexually relevant stimuli reflected in this surface positivity. In a second session, the response to food stimuli relative to objects was tested in two states: after fasting for 14 h, LFPs to food and object stimuli showed significant differences in between 300 and 850 ms, which disappeared after a full high-calorie meal, thus replicating classic studies in monkeys [Rolls et al., Brain Res (1976) 111:53-66]. The current data are the first to demonstrate hypothalamic responses to the sight of motivational stimuli in man and thus shows that recording from DBS electrodes might provide important information about the cognitive functions of subcortical structures. PMID- 21651965 TI - Cellular distribution of metastasis suppressor 1 and the shape of cell bodies are temporarily altered in Engrailed-2 overexpressing cerebellar Purkinje cells. AB - Metastasis suppressor 1 (MTSS1, BEG4, MIM) is well described for its function as a metastasis suppressor gene and is expressed in a variety of tissues. However, only little is known about its expression in the central nervous system (CNS), and functions within the CNS have not been addressed so far. Here, we show that MTSS1 was expressed in postmitotic neurons of the cerebellar cortex. Within Purkinje cells, higher amounts of MTSS1 were temporarily localized in the axonal somatic compartment than in the dendritic compartment. In L7En-2 transgenic mice, in which the segment-polarity gene and regulator of neuronal maturation Engrailed 2 is overexpressed specifically in cerebellar Purkinje cells, MTSS1 was homogenously distributed within Purkinje cell somata throughout development. In parallel to the altered distribution of MTSS1 in L7En-2 Purkinje cells, L7En-2 Purkinje cell somata were distorted and in some cells invaginations of the plasma membrane were observed. These invaginations were only found in L7En-2 neurons, and displayed multiple synapses which could not be seen at the smooth surface of wildtype Purkinje cell somata. Current knowledge about MTSS1 function in vitro and the correlation between MTSS1 localization and the occurrence of membrane alterations in L7En-2 Purkinje cells described here suggest that MTSS1 might be involved in shaping neuronal membranes in vivo. PMID- 21651966 TI - Brain delivery and cellular internalization mechanisms for transferrin conjugated biodegradable polymersomes. AB - Transferrin conjugated biodegradable polymersomes (Tf-PO) were exploited for efficient brain drug delivery, and its cellular internalization mechanisms were investigated. Tf-PO was prepared by a nanoprecipitation method with an average diameter of approximately 100 nm and a surface Tf molecule number per polymersome of approximately 35. It was demonstrated that the uptake of Tf-PO by bEnd.3 was mainly through a clathrin mediated energy-dependent endocytosis. Both the Golgi apparatus and lysosomes are involved in intracellular transport of Tf-PO. Thirty minutes after a 50mg/kg dose of Tf-PO or PO was injected into rats via the tail vein, fluorescent microscopy of brain coronal sections showed a higher accumulation of Tf-PO than PO in the cerebral cortex, the periventricular region of the lateral ventricle and the third ventricle. The brain delivery results proved that the blood-brain barrier (BBB) permeability surface area product (PS) and the percentage of injected dose per gram of brain (%ID/g brain) for Tf-PO were increased to 2.8-fold and 2.3-fold, respectively, as compared with those for PO. These results indicate that Tf-PO is a promising brain delivery carrier. PMID- 21651967 TI - Lactoferrin conjugated PEG-PLGA nanoparticles for brain delivery: preparation, characterization and efficacy in Parkinson's disease. AB - A novel biodegradable brain drug delivery system, the lactoferrin (Lf) conjugated polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticle (Lf-NP) was constructed in this paper with its in vitro and in vivo delivery properties evaluated by a fluorescent probe coumarin-6. Lf was thiolated and conjugated to the distal maleimide function surrounding on the pegylated nanoparticle to form Lf-NP. TEM observation and ELISA analysis confirmed the existence of active Lf on the surface of Lf-NP. The results of qualitative and quantitative uptake studies of coumarin-6 incorporated Lf-NP showed a more pronounced accumulation of Lf-NP in bEnd.3 cells than that of unconjugated nanoparticle (NP). Further uptake inhibition study indicated that the increased uptake of Lf-NP was via an additional clathrin mediated endocytosis processes. Following intravenous administration, a near 3 fold of coumarin-6 was found in the mice brain carried by Lf-NP compared to that carried by NP. Intravenous injection of urocortin loaded Lf-NP effectively attenuated the striatum lesion caused by 6 hydroxydopamine in rats as indicated by the behavioral test, the immunohistochemistry test and striatal transmitter content detection results. The cell viability test and CD68 immunohistochemistry demonstrated the acceptable toxicity of the system. All these results demonstrated that Lf-NP was a promising brain drug delivery system with reasonable toxicity. PMID- 21651968 TI - Neurotrophic activity of DA-9801, a mixture extract of Dioscorea japonica Thunb. and Dioscorea nipponica Makino, in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea japonica Thunb. has been traditionally used to treat polyuria and diabetes in Korea. AIM OF THE STUDY: We previously report the effects of Dioscorea japonica Thunb. extract on glucose control, NGF induction, and neuroprotection in a rodent diabetic model. Since the most potent fraction, DA-9801, was identified from a mixture of Dioscorea japonica Thunb. (DJ) and Dioscorea nipponica Makino (DN) following bioactivity-guided fractionation, here, we investigated the potential mechanism of the extract activity against diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: A 1:3 mixture of DJ and DN was extracted with ethanol (DA-9801) and further fractionated into an ethylacetate-soluble fraction (DA-9801E). Effects of these extracts on neurite outgrowth were measured in PC-12 cells and DRG neurons. Effects on cell viability and TrkA phosphorylation were evaluated in PC-12 cells. NGF induction effect was determined in primary Schwann cells as well as IMS32 cells (immortalized Schwann cells). RESULTS: No cytotoxicity was observed in PC 12 cells at the concentration below 500 MUg/ml of either DA-9801 or DA-9801E. DA 9801 and DA-9801E at 100 MUg/ml and 10 MUg/ml, respectively, showed a significant effect on neurite outgrowth in PC-12 cells and DRG neurons in the presence of or absence a low concentration of NGF (2 ng/ml). The Trk-A phosphorylation effect of DA9801 was confirmed in PC-12 cells. An NGF induction effect of these extracts was not detected in either IMS-32 cells, or primary Schwann cells. CONCLUSIONS: The NGF agonistic activity of DA-9801 and DA-9801E was demonstrated, which may contribute to their neuroprotective effect against DPN. Studies of the detailed mechanism of these extracts as well as identification of the active components are warranted for the development of an anti-DPN drug from DJ and DN. PMID- 21651969 TI - Anti-allergic activity of German chamomile (Matricaria recutita L.) in mast cell mediated allergy model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chamomile is most popular used medicinal plant and extensively consumed as a tea or tisanes. Traditionally this plant was used for treatment of many ailments such as allergy disorders and inflammatory mediated diseases. AIM OF THE STUDY: We investigated the effects of anti-allergic activity of Matricaria recutita L. on mast cell mediated allergic models. MATERIALS AND METHODS: The protective effect of methanol extract of Matricaria recutita against compound 48/80 induced anaphylaxis and pruritis models for acute phase of hypersensitivity reactions were carried out. The late phase hypersensitivity reactions by compound 48/80 induced mast cell degranulation and histamine release from blood along with serum nitric oxide (NO), rat peritoneal fluid nitric oxide (NO) and bronchoalveolar fluid nitric oxide (NO) levels were measured. RESULTS: The methanol extract of Matricaria recutita L. showed inhibitory effects on anaphylaxis induced by compound 48/80 and significant dose dependent anti-pruritis property was observed by inhibiting the mast cell degranulation. Mast cell membrane stabilization activity was also observed in compound 48/80 induced mast cell activation. Dose dependent reduction in the histamine release, along with decreased release of serum, rat peritoneal and BAL fluid nitric oxide (NO) levels were observed. CONCLUSION: These results suggest that the methanol extract of Matricaria recutita showed potent anti-allergic activity by inhibition of histamine release from mast cells. PMID- 21651970 TI - Potential of medicinal plants from the Brazilian semi-arid region (Caatinga) against Staphylococcus epidermidis planktonic and biofilm lifestyles. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants from the Caatinga, a Brazilian xeric shrubland, are used in folk medicine to treat infections. These ethnopharmacological data can contribute to obtaining new antimicrobial/antibiofilm extracts and natural product prototypes for the development of new drugs. The aim of this study was to investigate the antibiofilm and antibacterial activities of 45 aqueous extracts from 24 Caatinga plant species. MATERIALS AND METHODS: The effect of aqueous extracts on planktonic cells and on biofilm formation by Staphylococcus epidermidis was studied by the OD(600) absorbance and by the crystal violet assay, respectively. Scanning electron microscopy (SEM) was used to generate comparative images of extract-treated and untreated biofilms. Chromatographic analyses were performed to characterize the active extracts. RESULTS: The in vitro screening, at 0.4 mg/mL and 4.0mg/mL, showed 20 plants effective in preventing biofilm formation and 13 plants able to inhibit planktonic bacterial growth. SEM images demonstrated distinct profiles of bacterial adhesion, matrix production and cell morphology according to different treatments and surfaces. The phytochemical analysis of the selected active extracts indicates the polyphenols, coumarins, steroids and terpenes as possible active compounds. CONCLUSION: This study describes the first antibiofilm and antibacterial screening of Caatinga plants against S. epidermidis. The evaluation presented in this study confirms several ethnopharmacological reports and can be utilized to identify new antibiofilm and antibacterial products against S. epidermidis from traditional Brazilian medicine. PMID- 21651971 TI - Increased lifespan in hyposulfatemic NaS1 null mice. AB - Sulfate (SO(4)(2-)) plays an important role in mammalian growth and development. In this study, hyposulfatemic NaS1 null (Nas1-/-) mice were used to investigate the consequences of perturbed SO(4)(2-) homeostasis on longevity. Median life spans were increased (by ~25%) in male and female Nas1-/- mice when compared with Nas1+/+ mice. At 1 yr of age, serum SO(4)(2-) levels remained low in Nas1-/- mice (~0.16 mM) when compared to Nas1+/+ mice (~0.96 mM). RT-PCR revealed increased hepatic mRNA levels of Sirt1 (by ~60%), Cat (by ~48%), Hdac3 (by ~22%), Trp53 and Cd55 (by ~36%) in Nas1-/- mice, genes linked to ageing. Histological analyses of livers from 2 yr old mice revealed neoplasms in >50% of Nas1+/+ mice but not in Nas1-/- mice. This is the first study to report increased lifespan, decreased hepatic tumours and increased hepatic expression of genes linked to ageing in hyposulfatemic Nas1-/- mice, implicating a potential role of SO(4)(2-) in mammalian longevity and cancer. PMID- 21651972 TI - Islet-1 expression in thoracic spinal motor neurons in prenatal mouse. AB - The LIM homeodomain protein Islet-1, an embryonic marker for motoneurons in the spinal cord, has been reported to be heterogeneously expressed among motoneuron groups in mouse. In the present study, we examined Islet-1 expression in the thoracic and rostral lumbar spinal cord in prenatal mice. In the thoracic spinal cord at embryonic day 12.5 (E12.5) and E13.5, strong Islet-1 immunoreactivity was observed in the lateral group of the ventral horn, whereas weaker immunoreactivity was observed in the ventral group. Strong Islet-1 immunoreactivity was also observed in the intermediolateral area and more medial part of the intermediate zone. In the rostral lumbar spinal cord at E12.5 and E13.5, strong Islet-1 immunoreactivity was observed in the lateral group of the ventral horn, and in the intermediolateral nucleus, whereas weaker immunoreactivity was observed in the ventral, and dorsolateral groups. At E14.5, the number of Islet-1 immunoreactive neurons was reduced in the spinal cord, but the distribution pattern was similar to that at E12.5 and E13.5. At E15.5, Islet 1 immunoreactivity was almost completely confined to the intermediolateral area. Some weakly immunoreactive neurons were observed in the ventral horn. The findings of the present study indicated that Islet-1 expression at embryonic stages differs among the motoneuron groups in the thoracic and rostral lumbar spinal cord. PMID- 21651973 TI - Premorbid child and family functioning as predictors of post-concussive symptoms in children with mild traumatic brain injuries. AB - STUDY AIM: This study sought to determine whether premorbid child and family functioning accounts for or moderates group differences in post-concussive symptoms following mild traumatic brain injury (TBI) in childhood. METHODS: This prospective, longitudinal cohort study recruited 8- to 15-year-old children, 186 with mild TBI and 99 with orthopedic injuries (OI), from consecutive emergency department admissions. Parents and children rated post-concussive symptoms within 3 weeks of injury and at 1, 3, and 12 months post injury. Parents also provided retrospective ratings of pre-injury symptoms, as well as of premorbid child behavioral adjustment, overall family functioning, and other stressors and resources in the family environment. RESULTS: Children with mild TBI reported more post-concussive symptoms than those with OI, as did their parents, although premorbid child behavioral adjustment and symptoms also were significant predictors of post-concussive symptoms. Group differences in somatic symptoms as reported by parents were more pronounced among children from families that were higher functioning and had more environmental resources. DISCUSSION: Mild TBI during childhood results in more post-concussive symptoms than OI, even after children's premorbid adjustment is taken into account. Counter to expectations, post-concussive symptoms following mild TBI may actually be more apparent among children from higher-functioning families with greater resources. PMID- 21651974 TI - Influence of carboxylic acid functionalization on the cytotoxic effects induced by single wall carbon nanotubes on human endothelial cells (HUVEC). AB - A vast variety of nanomaterials have been developed in the recent years, being carbon nanotubes (CNTs) the ones that have attracted more attention, due to its unique properties which make them suitable for numerous applications. Consequently, it is predicted that tons of CNTs will be produced worldwide every year, being its exposure of toxicological concern. Nanomaterials, once into the body, can translocate from the uptake sites to the blood circulation or the lymphatic system, resulting in distribution throughout the body. Thus, the vascular endothelium can be in contact with them and can suffer from their toxic effects. In this regard, the aim of this work was to investigate the cytotoxicity of single-walled carbon nanotubes (SWCNTs) on human endothelial cells evaluating the influence of acid carboxylic functionalization and also the exposure time (24 and 48 h). Biomarkers assessed were neutral red uptake, protein content, a tetrazolium salt metabolization and cell viability by means of the Trypan blue exclusion test. Cells were exposed to concentrations between 0 and 800 MUg/mL SWCNTs for 24 and 48 h. Results have shown that both SWCNTs and carboxylic acid functionalized single-walled carbon nanotubes (COOH-SWCNTs) induce toxic effects in HUVEC cells in a concentration- and time-dependent way. Moreover, the carboxylic acid functionalization results in a higher toxicity compared to the SWCNTs. PMID- 21651975 TI - High content screening analysis of phospholipidosis: validation of a 96-well assay with CHO-K1 and HepG2 cells for the prediction of in vivo based phospholipidosis. AB - Drug-induced phospholipidosis is marked by an excessive accumulation of phospholipids in lysosomes which can occur after exposure to cationic amphiphilic drugs. Phospholipidosis is considered as an adverse side effect and may delay or negatively affect registration of drug candidates. Currently, the gold standard method of phospholipidosis detection is electron microscopy on tissue samples. This technique is time consuming and only performed relatively late in drug development. Therefore, in vitro screening methods for phospholipidosis are essential in early drug development. In this study, an in vitro phospholipidosis detection assay is developed with CHO-K1 and HepG2 cells by using the fluorescent marker NBD-PE and high content screening analysis. Lysosomal localization of NBD PE was demonstrated by colocalization with Lysotracker and lamellar body formation by electron microscopy. Upon drug exposure, lysosomal NBD-PE accumulation can be visualized and quantified. Validation with 56 reference compounds, divided in 25 phospholipidosis inducers and 31 negative compounds, showed that this new in vitro assay has a high sensitivity (CHO-K1=92.0% and HepG2=88.0%) and specificity (CHO-K1=87.1% and HepG2=80.6%) for predicting phospholipidosis in vivo. Thus a selective screening tool has been developed for early selection of drug candidates with low probability for phospholipidosis. PMID- 21651976 TI - Btrim: a fast, lightweight adapter and quality trimming program for next generation sequencing technologies. AB - Btrim is a fast and lightweight software to trim adapters and low quality regions in reads from ultra high-throughput next-generation sequencing machines. It also can reliably identify barcodes and assign the reads to the original samples. Based on a modified Myers's bit-vector dynamic programming algorithm, Btrim can handle indels in adapters and barcodes. It removes low quality regions and trims off adapters at both or either end of the reads. A typical trimming of 30M reads with two sets of adapter pairs can be done in about a minute with a small memory footprint. Btrim is a versatile stand-alone tool that can be used as the first step in virtually all next-generation sequence analysis pipelines. The program is available at http://graphics.med.yale.edu/trim/. PMID- 21651977 TI - DNA amplification approaches for the diagnosis of key parasitic helminth infections of humans. AB - Parasitic helminths of humans are a major public health threat, particularly in developing countries. The rapid and reliable diagnosis of helminth infections is central to their control as well as for environmental monitoring and disease surveillance. Effective diagnosis is dependent on the sensitivity, specificity and reliability of the tests employed. The most commonly used diagnosis of helminth infections has been the microscopic detection of eggs in faecal samples. However, the eggs of related helminths are often very similar in morphology and morphometry, making diagnosis inaccurate. DNA amplification tests can provide alternative approaches for diagnosis and can be sensitive and specific, provided reliable molecular genetic markers are employed in the tests. Such advanced tools can be used for the quantification of egg numbers, in order to assess infection intensities in infected hosts, and can provide multiplexing capability which can be required for the identification of multiple different helminth species in individual samples. These approaches provide powerful diagnostic techniques that can be used in clinical settings and as laboratory tools for surveillance and for environmental monitoring to support helminth control programs. PMID- 21651978 TI - PGD2 and PGE2 regulate gene expression of Prx 6 in primary macrophages via Nrf2. AB - Peroxiredoxin 6 (Prx 6) is a bifunctional enzyme with both glutathione peroxidase and acidic Ca(2+)-independent phospholipase A(2) activities. We have recently shown that exposure of murine bone marrow-derived macrophages to LPS and IFN gamma leads to induction of COX-2 expression and secretion of PGE(2), up regulating Prx 6 mRNA levels. This study was designed to investigate various prostaglandins (PGs) for their ability to induce gene expression of Prxs, in particular Prx 6, and to determine the underlying regulatory mechanisms. We provide evidence that both conventional and cyclopentenone PGs enhance Prx 6 mRNA expression. Treatment with either activators or inhibitors of adenylate cyclase as well as cAMP analogs indicated that Prx 6 gene expression is regulated by adenylate cyclase in response to PGD(2) or PGE(2). Furthermore, our study revealed that JAK2, PI3K, PKC, and p38 MAPK contribute to the PGD(2)- or PGE(2) dependent Prx 6 induction. Using stimulated macrophages from Nrf2-deficient mice or activators of Nrf2 and PPARgamma, we found that Nrf2, but not PPARgamma, is involved in the PG-dependent increase in Prx 6 mRNA expression. In summary, our data suggest multiple signaling pathways of Prx 6 regulation by PGs and identified Nrf2 as a critical player mediating transcriptional induction. PMID- 21651979 TI - The dysfunction of hepatic transcriptional factors in mice with Huntington's Disease. AB - Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The resultant mutant Htt protein (mHtt) forms aggregates in the brain and several peripheral tissues (e.g., the liver), and causes devastating widespread pathology. Since aggregates of mHtt have been found in the liver, defects in liver function might contribute to peripheral abnormalities in HD mice. We previously reported that two crucial transcription factors PPARgamma (peroxisome proliferator-activated receptor-gamma) and C/EBPalpha (CCAAT/enhancer-binding protein alpha) are potential therapeutic targets of HD. We herein demonstrate that the transcript level of PPARgamma was markedly downregulated in the livers of a transgenic mouse model of HD (R6/2). Treatment of R6/2 mice with an agonist of PPARgamma (thiazolidinedione, TZD) normalized the reduced PPARgamma transcript. By reducing Htt aggregates and thereby ameliorating the recruitment of PPARgamma into Htt aggregates, TZD treatment also elevated the availability of the PPARgamma level and subsequently normalized the expression of its downstream genes [including PGC-1alpha (PPAR coactivator-1alpha) and several mitochondrial genes] and C/EBPalpha in the liver. The aforementioned protective effects appeared to be exerted by a direct activation of the PPARgamma agonist (rosiglitazone) because rosiglitazone reduced mHtt aggregates and rescued energy deficiency in a hepatoma cell line (HepG2). These findings show that the impairment of PPARgamma contributes to the liver dysfunction observed in HD. Treatment with PPARgamma agents (TZD and rosiglitazone) enhanced the function of PPARgamma, and might lead to therapeutic benefits. PMID- 21651981 TI - Terminal fatty-acyl-CoA desaturase involved in sex pheromone biosynthesis in the winter moth (Operophtera brumata). AB - The winter moth (Operophtera brumata L., Lepidoptera: Geometridae) utilizes a single hydrocarbon, 1,Z3,Z6,Z9-nonadecatetraene, as its sex pheromone. We tested the hypothesis that a fatty acid precursor, Z11,Z14,Z17,19-nonadecanoic acid, is biosynthesized from alpha-linolenic acid, through chain elongation by one 2 carbon unit, and subsequent methyl-terminus desaturation. Our results show that labeled alpha-linolenic acid is indeed incorporated into the pheromone component in vivo. A fatty-acyl-CoA desaturase gene that we found to be expressed in the abdominal epidermal tissue, the presumed site of biosynthesis for type II pheromones, was characterized and expressed heterologously in a yeast system. The transgenic yeast expressing this insect derived gene could convert Z11,Z14,Z17 eicosatrienoic acid into Z11,Z14,Z17,19-eicosatetraenoic acid. These results provide evidence that a terminal desaturation step is involved in the winter moth pheromone biosynthesis, prior to the decarboxylation. PMID- 21651982 TI - Chemically modified tetracycline-3 (CMT-3): a novel inhibitor of the serine proteinase, elastase. AB - Two classes of enzymes play an important role in connective tissue breakdown during various inflammatory diseases: serine proteinases and matrix metalloproteinases (MMPs). Tetracyclines (TCs) exhibit important anti inflammatory and MMP-inhibitory properties that are unrelated to their antibacterial activities. Of the various TCs and their chemically modified NON antibiotic analogs (CMTs) tested in vitro and in vivo, CMT-3 (6-demethyl-6-deoxy 4 de-dimethylamino tetracycline) has repeatedly been shown to be the most potent inhibitor of MMP activity and cytokine production. In addition to its anti-MMP function, we have shown that among all CMTs, CMT-3 is the only CMT that can also directly inhibit both the amidolytic activity of human leukocyte elastase (HLE, a serine proteinase) and the extracellular matrix degradation mediated by HLE. In addition, CMT-3 has been found to reduce leukocyte elastase activity in vivo in gingival extracts of rats with experimental periodontal disease. Thus, CMT-3 can inhibit pathologic connective tissue breakdown by (at least) two mechanisms: direct inhibition of neutral proteinases (elastase and MMPs); and protecting their endogenous inhibitors, alpha(1)-PI and TIMPs, from being digested and inactivated by MMPs and HLE, respectively. The pleiotropic properties of CMT-3 including (but not limited to) inhibition of serine proteinases, MMPs, and cytokines provide impressive therapeutic potential to reduce excessive connective tissue breakdown during various pathologic processes including inflammatory diseases, cancer metastasis and metabolic bone diseases. PMID- 21651980 TI - Atorvastatin exerts its anti-atherosclerotic effects by targeting the receptor for advanced glycation end products. AB - Recent studies demonstrated the beneficial role of atorvastatin in reducing the risk of cardiovascular morbidity and mortality in patients with diabetes mellitus and/or metabolic syndrome. To investigate the mechanisms underlying the anti atheroscleroic action of atorvastatin, we examined the expression of the receptor for advanced glycation end products (RAGE) and its downstream target gene, monocyte chemoattractant protein-1 (MCP-1) using real-time PCR. In in vitro studies, exposure to high glucose or AGE induced oxidative stress and activation of the AGE/RAGE system in human umbilical vein endothelial cells. Treatment of the cells with atorvastatin significantly released the oxidative stress by restoring the levels of glutathione and inhibited the RAGE upregulation. In diabetic Goto Kakisaki (GK) rats fed with a high-fat diet for 12weeks, RAGE and MCP-1 were upregulated in the aortas, and there was a significant correlation between RAGE and MCP-1 mRNA abundance (r=0.482, P=0.031). Treatment with atorvastatin (20mg/kg qd) significantly downregulated the expression of RAGE and MCP-1. These data thus demonstrate a novel "pleiotropic" activity of atorvastatin in reducing the risk of cardiovascular diseases by targeting RAGE expression. PMID- 21651983 TI - Research on tea and health. PMID- 21651984 TI - Ferritin M of Cynoglossus semilaevis: an iron-binding protein and a broad spectrum antimicrobial that depends on the integrity of the ferroxidase center and nucleation center for biological activity. AB - Ferritin is a major intracellular iron storage protein in higher vertebrates and plays an important role in iron metabolism. In this study, we identified and analyzed the biological activity of a ferritin M subunit (CsFerM) from half smooth tongue sole (Cynoglossus semilaevis). The open reading frame (ORF) of CsFerM is 534 bp and encodes a protein that shares 79.7-86.4% overall sequence identities with the ferritin M subunits of a number of teleosts. In silico analysis identified in CsFerM a eukaryotic ferritin domain with conserved ferroxidase diiron center and ferrihydrite nucleation center. Quantitative real time RT-PCR analysis showed that under normal physiological conditions, expression of CsFerM was highest in liver, moderate in gill, spleen, and muscle, and low in gut, heart, and brain. Following experimental challenge with bacterial pathogens, CsFerM expression was significantly upregulated in kidney, spleen, and liver in time-dependent manners. Biological activity analysis showed that recombinant CsFerM purified from Escherichia coli exhibited apparent iron-binding activity and, when present in the culture medium of six different species of fish bacterial pathogens, completely inhibited bacterial growth. In contrast, a mutant CsFerM that bears alanine substitution at two conserved residues of the ferroxidase diiron center and ferrihydrite nucleation center was abolished in both iron-binding and antimicrobial capacity. These results demonstrate that CsFerM is a biologically active iron chelator with broad-spectrum antibacterial activity, which suggests a role for CsFerM in not only iron storage but also innate immunity. These results also indicate the importance of the conserved iron uptake and mineralization sites to the function of CsFerM. PMID- 21651986 TI - Individual differences in cognitive style and strategy predict similarities in the patterns of brain activity between individuals. AB - Neuroimaging is being used increasingly to make inferences about an individual. Yet, those inferences are often confounded by the fact that topographical patterns of task-related brain activity can vary greatly from person to person. This study examined two factors that may contribute to the variability across individuals in a memory retrieval task: individual differences in cognitive style and individual differences in encoding strategy. Cognitive style was probed using a battery of assessments focused on the individual's tendency to visualize or verbalize written material. Encoding strategy was probed using a series of questions designed to assess typical strategies that an individual might utilize when trying to remember a list of words. Similarity in brain activity was assessed by cross-correlating individual t-statistic maps contrasting the BOLD response during retrieval to the BOLD response during fixation. Individual differences in cognitive style and encoding strategy accounted for a significant portion of the variance in similarity. This was true above and beyond individual differences in anatomy and memory performance. These results demonstrate the need for a multidimensional approach in the use of fMRI to make inferences about an individual. PMID- 21651985 TI - Decoding intention: a neuroergonomic perspective. AB - Decoding the intentions of other people based on non-linguistic cues such as their body movement is a major requirement of many jobs. Whether it is maintaining security at an airport or negotiating with locals in a foreign country, there is a need to maximize the effectiveness of training or real-time performance in this decoding process. This review considers the potential utility of neuroergonomic solutions, and in particular, of electroencephalographic (EEG) methods for augmenting action understanding. Focus is given to body movements and hand-object interactions, where there is a rapid growth in relevant science. The interpretation of EEG-based signals is reinforced by a consideration of functional magnetic resonance imaging experiments demonstrating underlying brain mechanisms that support goal oriented action. While no EEG method is currently implemented as a practical application for enhancing the understanding of unspoken intentions, there are a number of promising approaches that merit further development. PMID- 21651987 TI - Roles of osmolality, calcium - Potassium antagonist and calcium in activation and flagellar beating pattern of sturgeon sperm. AB - The present study shows the roles of osmolality, calcium (Ca(2+))-potassium (K(+)) antagonist and Ca(2+) in sperm activation and flagellar beating of a sturgeon species, sterlet (Acipenser ruthenus). Sperm motility was activated at hypoosmolality relative to seminal plasma and suppressed at 175 mOsmol kg(-1). Sperm activation was totally suppressed by 0.35mM K(+), but Ca(2+) could fully reverse K(+) inhibitory effect at Ca(2+): K(+) ratio of 0.25. Neither EGTA (a chelator of Ca(2+) ions) nor nifedipine (a Ca(2+) channel blocker) prevented sperm activation. But, sperm motility and velocity were significantly decreased by EGTA, nifedipine and an inhibitor for Ca(2+)/calmodulin activated phosphodiesterase (w-7) that suggest role of Ca(2+) signaling after triggering sperm activation through hypoosmolality. Symmetric flagellar beating was also turned to asymmetric after activation in w-7, which is an evidence for modulation of Ca(2+)-binding proteins activity. Sturgeon sperm, similar to salmonids, is immotile in seminal plasma due to high K(+) concentrations, but the mechanism of sperm activation seems to be closer to other fish species where osmolality prohibits sperm activation in seminal plasma. In these species, hypoosmolality is the primary signal for sperm Ca(2+)-dependent signaling of axonemal beating. PMID- 21651988 TI - Aerosol exposure to Zaire ebolavirus in three nonhuman primate species: differences in disease course and clinical pathology. AB - There is little known concerning the disease caused by Zaire ebolavirus (ZEBOV) when inhaled, the likely route of exposure in a biological attack. Cynomolgus macaques, rhesus macaques, and African green monkeys were exposed to aerosolized ZEBOV to determine which species might be the most relevant model of the human disease. A petechial rash was noted on cynomolgus and rhesus macaques after fever onset but not on African green monkeys. Fever duration was shortest in rhesus macaques (62.7 +/- 16.3 h) and longest in cynomolgus macaques (82.7 +/- 22.3h) and African green monkeys (88.4 +/- 16.7h). Virus was first detectable in the blood 3 days after challenge; the level of viremia was comparable among all three species. Hematological changes were noted in all three species, including decreases in lymphocyte and platelet counts. Increased blood coagulation times were most pronounced in African green monkeys. Clinical signs and time to death in all three species were comparable to what has been reported previously for each species after parenteral inoculation with ZEBOV. These data will be useful in selection of an animal model for efficacy studies. PMID- 21651989 TI - Liver conversion of docosahexaenoic and arachidonic acids from their 18-carbon precursors in rats on a DHA-free but alpha-LNA-containing n-3 PUFA adequate diet. AB - The long-chain polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n 6), are critical for health. These PUFAs can be synthesized in liver from their plant-derived precursors, alpha-linolenic acid (alpha-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6). Vegetarians and vegans may have suboptimal long-chain n-3 PUFA status, and the extent of the conversion of alpha-LNA to EPA and DHA by the liver is debatable. We quantified liver conversion of DHA and other n-3 PUFAs from alpha-LNA in rats fed a DHA-free but alpha-LNA (n-3 PUFA) adequate diet, and compared results to conversion of LA to AA. [U-(13)C]LA or [U-(13)C]alpha-LNA was infused intravenously for 2h at a constant rate into unanesthetized rats fed a DHA-free alpha-LNA adequate diet, and published equations were used to calculate kinetic parameters. The conversion coefficient k(*) of DHA from alpha-LNA was much higher than for AA from LA (97.2*10(-3) vs. 10.6*10(-3)min(-1)), suggesting that liver elongation-desaturation is more selective for n-3 PUFA biosynthesis on a per molecule basis. The net daily secretion rate of DHA, 20.3MUmol/day, exceeded the reported brain DHA consumption rate by 50-fold, suggesting that the liver can maintain brain DHA metabolism with an adequate dietary supply solely of alpha-LNA. This infusion method could be used in vegetarians or vegans to determine minimal daily requirements of EPA and DHA in humans. PMID- 21651990 TI - Effects of short read quality and quantity on a de novo vertebrate transcriptome assembly. AB - For many researchers, next generation sequencing data holds the key to answering a category of questions previously unassailable. One of the important and challenging steps in achieving these goals is accurately assembling the massive quantity of short sequencing reads into full nucleic acid sequences. For research groups working with non-model or wild systems, short read assembly can pose a significant challenge due to the lack of pre-existing EST or genome reference libraries. While many publications describe the overall process of sequencing and assembly, few address the topic of how many and what types of reads are best for assembly. The goal of this project was use real world data to explore the effects of read quantity and short read quality scores on the resulting de novo assemblies. Using several samples of short reads of various sizes and qualities we produced many assemblies in an automated manner. We observe how the properties of read length, read quality, and read quantity affect the resulting assemblies and provide some general recommendations based on our real-world data set. PMID- 21651991 TI - No costs on freeze tolerance in genetically copper adapted earthworm populations (Dendrobaena octaedra). AB - For nearly three centuries the area around Gusum, in south-east Sweden, has been highly polluted with copper. An earlier study in this area showed that populations of the freeze-tolerant earthworm Dendrobaena octaedra were genetically adapted to copper. Apparently, no life-history costs to reproduction or growth were imposed by this adaptation. In the present paper we therefore investigated how laboratory raised F1-generations of these populations coped when exposed to increased copper concentrations in the soil and to sub-zero temperatures. We found that D. octaedra from polluted sites accumulated the same amount of copper as reference worms. Furthermore, earthworms from polluted sites survived equally to reference worms when exposed to freezing temperatures (-8 or 12 degrees C). However, when simultaneously exposed to the lowest temperature and copper, the worms from polluted sites survived significantly better than reference worms. The overall conclusion of this study is that worms from polluted sites seem to be better at handling copper and accrue no costs in terms of reduced cold tolerance in connection to genetic adaptation in these populations. PMID- 21651992 TI - A partnership approach for Electronic Data Capture in small-scale clinical trials. AB - Amid researchers' growing need for study data management, the CTSA-funded Institute for Translational Health Sciences developed an approach to combine technical and scientific resources with small-scale clinical trials researchers in order to make Electronic Data Capture more efficient. In a 2-year qualitative evaluation we found that the importance of ease of use and training materials outweighed number of features and functionality. EDC systems we evaluated were Catalyst Web Tools, OpenClinica and REDCap. We also found that two other systems, Caisis and LabKey, did not meet the specific user needs of the study group. PMID- 21651993 TI - Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 4: One method. AB - Standard methods for testing safety data are needed to ensure the safe conduct of clinical trials. In particular, objective rules for reliably identifying unsafe treatments need to be put into place to help protect patients from unnecessary harm. DMCs are uniquely qualified to evaluate accumulating unblinded data and make recommendations about the continuing safe conduct of a trial. However, it is the trial leadership who must make the tough ethical decision about stopping a trial, and they could benefit from objective statistical rules that help them judge the strength of evidence contained in the blinded data. We design objective early stopping rules for harm that act as continuous safety screens for randomized controlled clinical trials using the accumulating data with blinded treatment information, which could be used by anyone, including trial investigators and trial leadership. A Bayesian framework, with emphasis on the likelihood function, is used to allow for continuous monitoring without adjusting for multiple comparisons. Close collaboration between the statistician and the clinical investigators will be needed in order to design safety screens with good operating characteristics. Though the math underlying this procedure may be computationally intensive, implementation of the statistical rules will be easy and the continuous screening provided will give suitabley early warning when real problems were to emerge. Trial investigators and trial leadership need these safety screens to help them to effectively monitor the ongoing safe conduct of clinical trials with blinded data. PMID- 21651994 TI - Physiological variables and mitochondrial-related genotypes of an athlete who excels in both short and long-distance running. AB - We report the athletic, physiological and mitochondrial-related genomic data of an Israeli endurance runner. He is holding the Israeli record in 10,000, 5000, 1500 and 800 m run, along with being one of the best Israeli 400 m runners. We tested the ACTN3 R577X, and six polymorphisms in the PPARGC1A-NRF-TFAM pathway genes. The case athlete was heterozygous for the ACTN3 R577X variation and had five out of six 'endurance-oriented' genotypes, scoring significantly high in endurance 'optimal' genotype profile. In conclusion, we suggest that the case athlete is favoured by polygenic profile that is more suitable for mitochondrial biogenesis, regardless of his good phenotypic accomplishments in short-term running events. PMID- 21651995 TI - Energy metabolism and ageing regulation: metabolically driven deamidation of triosephosphate isomerase may contribute to proteostatic dysfunction. AB - Research carried out up to 3 decades ago by Gracy and co-workers revealed that the activity of the glycolytic enzyme triosephosphate isomerase (TPI), which converts dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P), gradually declines whilst carrying out its catalytic function, primarily due to deamidation of certain asparagine residues. It is suggested here that excessive or continuous glycolysis increases TPI deamidation and thereby lowers TPI activity and causes accumulation of its substrate, DHAP, which in turn decomposes into methylglyoxal (MG), a well-recognised reactive bicarbonyl whose actions in cells and tissues, as well as at the whole organism level, mimic much age-relate dysfunction. The proposal helps to explain why suppression of glycolysis by caloric restriction, fasting and increased aerobic activity also suppresses generation of altered proteins which characterise the aged phenotype. It is proposed that these effects on TPI activity, though seemingly neglected in biogerontological contexts, reveal a mechanistic link between energy metabolism and age-related proteostatic dysfunction. PMID- 21651996 TI - Nanofibrillated cellulose composite hydrogel for the replacement of the nucleus pulposus. AB - The swelling and compressive mechanical behavior as well as the morphology and biocompatibility of composite hydrogels based on Tween(r) 20 trimethacrylate (T3), N-vinyl-2-pyrrolidone (NVP) and nanofibrillated cellulose (NFC) were assessed in the present study. The chemical structure of T3 was verified by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance, and the degree of substitution was found to be around 3. Swelling ratios of neat hydrogels composed of different concentrations of T3 and NVP were found to range from 1.5 to 5.7 with decreasing concentration of T3. Various concentrations of cellulose nanofibrils (0.2-1.6wt.%) were then used to produce composite hydrogels that showed lower swelling ratios than neat ones for a given T3 concentration. Neat and composite hydrogels exhibited a typical nonlinear response under compression. All composite hydrogels showed an increase in elastic modulus compared to neat hydrogel of about 3- to 8-fold, reaching 18kPa at 0% strain and 62kPa at 20% strain for the hydrogel with the highest NFC content. All hydrogels presented a porous and homogeneous structure, with interconnected pore cells of around 100nm in diameter. The hydrogels are biocompatible. The results of this study demonstrate that composite hydrogels reinforced with NFC may be viable as nucleus pulposus implants due to their adequate swelling ratio, which may restore the annulus fibrosus loading, and their increased mechanical properties, which could possibly restore the height of the intervertebral discs. PMID- 21651997 TI - Biomaterials and implants for orbital floor repair. AB - Treatment of orbital floor fractures and defects is often a complex issue. Repair of these injuries essentially aims to restore the continuity of the orbital floor and to provide an adequate support to the orbital content. Several materials and implants have been proposed over the years for orbital floor reconstruction, in the hope of achieving the best clinical outcome for the patient. Autografts have been traditionally considered as the "gold standard" choice due to the absence of an adverse immunological response, but they are available in limited amounts and carry the need for extra surgery. In order to overcome the drawbacks related to autografts, researchers' and surgeons' attention has been progressively attracted by alloplastic materials, which can be commercially produced and easily tailored to fit a wide range of specific clinical needs. In this review the advantages and limitations of the various biomaterials proposed and tested for orbital floor repair are critically examined and discussed. Criteria and guidelines for optimal material/implant choice, as well as future research directions, are also presented, in an attempt to understand whether an ideal biomaterial already exists or a truly functional implant will eventually materialise in the next few years. PMID- 21651998 TI - Surface mineralization of Ti6Al4V substrates with calcium apatites for the retention and local delivery of recombinant human bone morphogenetic protein-2. AB - Titanium alloys are prevalently used as orthopedic prosthetics. Inadequate bone implant interactions can lead to premature prosthetic loosening and implant failure. Local delivery of osteogenic therapeutics promoting osteointegration of the implant is an attractive strategy to address this clinical challenge. Given the affinity of calcium apatites for bone matrix proteins we hypothesize that titanium alloys surface mineralized with calcium apatites should be explored for the retention and local delivery of osteogenic recombinant human bone morphogenetic protein-2 (rhBMP-2). Using a heterogeneous surface nucleation and growth process driven by the gradual pH elevation of an acidic solution of hydroxyapatite via thermal decomposition of urea, Ti6Al4V substrates were surface mineralized with calcium apatite domains exhibiting good affinity for the substrate. The microstructures, size and surface coverage of the mineral domains as a function of the in vitro mineralization conditions were examined by light and scanning electron microscopy and the surface calcium ion content quantified. An optimal mineralization condition was identified to rapidly (<10h) achieve surface mineral coverage far superior to those accomplished by week long incubation in simulated body fluids. In vitro retention-release profiles of rhBMP 2 from the mineralized and unmineralized Ti6Al4V, determined by an enzyme-linked immunosorbent assay, supported a higher degree of retention of rhBMP-2 on the mineralized substrate. The rhBMP-2 retained on the mineralized substrate after 24h incubation in phosphate-buffered saline remained bioactive, as indicated by its ability to induce osteogenic transdifferentiation of C2C12 myoblasts attached to the substrate. This mineralization technique could also be applied to the surface mineralization of calcium apatites on dense tantalum and titanium and porous titanium substrates. PMID- 21651999 TI - Cell type-specific responses of peripheral blood mononuclear cells to silver nanoparticles. AB - Silver nanoparticles (Ag-NP) are increasingly used in biomedical applications because of their remarkable antimicrobial activity. In biomedicine, Ag-NP are coated onto or embedded in wound dressings, surgical instruments and bone substitute biomaterials, such as silver-containing calcium phosphate cements. Free Ag-NP and silver ions are released from these coatings or after the degradation of a biomaterial, and may come into close contact with blood cells. Despite the widespread use of Ag-NP as an antimicrobial agent, there is a serious lack of information on the biological effects of Ag-NP on human blood cells. In this study, the uptake of Ag-NP by peripheral monocytes and lymphocytes (T-cells) was analyzed, and the influence of nanosilver on cell biological functions (proliferation, the expression of adhesion molecules, cytokine release and the generation of reactive oxygen species) was studied. After cell culture in the presence of monodispersed Ag-NP (5-30MUgml(-1) silver concentration), agglomerates of nanoparticles were detected within monocytes (CD14+) but not in T cells (CD3+) by light microscopy, flow cytometry and combined focused ion beam/scanning electron microscopy. The uptake rate of nanoparticles was concentration dependent, and the silver agglomerates were typically found in the cytoplasm. Furthermore, a concentration-dependent activation (e.g. an increased expression of adhesion molecule CD54) of monocytes at Ag-NP concentrations of 10 15MUgml(-1) was observed, and cytotoxicity of Ag-NP-treated monocytes was observed at Ag-NP levels of 25MUgml(-1) and higher. However, no modulation of T cell proliferation was observed in the presence of Ag-NP. Taken together, our results provide the first evidence for a cell-type-specific uptake of Ag-NP by peripheral blood mononuclear cells (PBMC) and the resultant cellular responses after exposure. PMID- 21652000 TI - Antiviral strategies in plants based on RNA silencing. AB - One of the challenges being faced in the twenty-first century is the biological control of plant viral infections. Among the different strategies to combat virus infections, those based on pathogen-derived resistance (PDR) are probably the most powerful approaches to confer virus resistance in plants. The application of the PDR concept not only revealed the existence of a previously unknown sequence specific RNA-degradation mechanism in plants, but has also helped to design antiviral strategies to engineer viral resistant plants in the last 25 years. In this article, we review the different platforms related to RNA silencing that have been developed during this time to obtain plants resistant to viruses and illustrate examples of current applications of RNA silencing to protect crop plants against viral diseases of agronomic relevance. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. PMID- 21652001 TI - Vertebral fracture status and the World Health Organization risk factors for predicting osteoporotic fracture risk in Japan. AB - INTRODUCTION: Vertebral fractures are the most common osteoporotic fracture and the prevalence of vertebral fracture is commonly assessed in clinical practice in Japan. The objective of this study was to evaluate potential risk factors for osteoporotic fractures, including morphometric spine fracture status and the WHO risk factors for predicting 4-year fracture risk. METHODS: A population-based community cohort, the Adult Health Study, consisting of 2613 men and women with mean age of 65 enrolled in Hiroshima was followed prospectively for 4 years. The prevalence and incidence of spine fractures were identified from lateral and posterior-anterior spine radiographs using a semiquantitative method. Information on incident nonvertebral fragility fractures (hip, proximal humeral, and forearm) was collected at interviews by trained nurses and physicians during biennial health examinations. RESULTS: A model, including spine fracture status in addition to the WHO risk factors, appeared to provide greater prognostic information regarding future fracture risk (gradient of risk/standard deviation: GR/SD=2.73) than a model with the WHO risk factors alone (GR/SD=2.54). In univariate analyses, age, bone mineral density (BMD), prior clinical fracture, and spine fracture status had the highest gradient of risk. The presence of multiple prevalent spine or non-spine fractures significantly increased fracture risk, but, their contributions to the gradient of risk were similar to those when fracture status was categorized as a binary variable. A model considering those four risk factors yielded GR/SD=2.67, indicating that it could capture most of the predictive information provided by the model with spine fracture status plus the WHO risk factors. CONCLUSION: The use of age, BMD, prior clinical fracture and spine fracture predicted future fracture risk with greater simplicity and higher prognostic accuracy than consideration of the risk factors included in the WHO tool. PMID- 21652002 TI - Risk factors for adverse outcome after superior cavopulmonary anastomosis for hypoplastic left heart syndrome. AB - OBJECTIVE: Outcome of staged palliation for hypoplastic left heart syndrome (HLHS) has improved over the past decades. We sought to evaluate the outcome of the second palliative procedure, the superior cavopulmonary anastomosis (SCPA), in a single-centre cohort and to identify risk factors for adverse outcome. METHODS: Full data on all 119 HLHS patients who underwent SCPA in our centre between January 1996 and December 2007 were analysed. RESULTS: Early adverse outcome (death or cardiac transplant within 30 days after surgery or before hospital discharge) was 3.4%. Late adverse outcome (death or transplant after hospital discharge but before the next operative procedure) was 8.7%. Postoperative complications occurred in 30% of patients (n = 36), with transient arrhythmia (n = 11; 9%) and pulmonary artery stenosis or thrombosis (n = 10; 8%) being the most common. The presence of more than moderate tricuspid valve regurgitation after surgery proved to be a strong predictor of late adverse outcome (odds ratio (OR) 16.5 (4.4-62.6), P < 0.001). SCPA at less than 4 months of age did not increase the risk for adverse outcome (OR 1.2 (0.4-3.6), P = 0.78) but increased the risk for postoperative complications (OR 6.3 (2.3-14.9), P < 0.001). CONCLUSIONS: SCPA can nowadays be performed in HLHS patients with low mortality. However, more than moderate tricuspid valve regurgitation should be targeted at surgery as it is a risk factor for adverse outcome such as death or need for cardiac transplant. SCPA should ideally be performed in children older than 4 months to minimise the risk of postoperative complications. PMID- 21652003 TI - Introduction to the special issue of Neurobiology of Learning and Memory on epigenetics and memory. PMID- 21652004 TI - Universal precautions: it's not about the molecule! PMID- 21652006 TI - When dissolved is not truly dissolved--the importance of colloids in studies of metal sorption on organic matter. AB - In controlled metal sorption experiments, the equilibrium distribution coefficient is a key variable quantifying sorbate partitioning across the solid solution interface. Separation of metals into 'dissolved' and 'particulate' fractions is commonly achieved with syringe filtration, where the boundary is somewhat arbitrarily dictated by the limited selection of available pore sizes. Investigations involving natural organic matter, such as bacterial cells or plant tissues, are especially prone to experimental artifacts if the substrate releases abundant colloidal compounds that contribute to sorption by binding free metal cations in a pH-dependent fashion yet pass through conventional filters, causing the truly dissolved fraction to be grossly overestimated. We observed this phenomenon during a study of lanthanide sorption on a marine macroalga, Ulva lactuca, as a function of pH. At low ionic strength, distribution coefficients calculated for a 0.22-MUm size cutoff falsely imply that metal sorption reverses to gradual release above pH 4.6, instead of continuing to increase. Centrifuging the filtrates in Amicon(r) Ultra units (30 and 3 kDa molecular weight cutoff) revealed a mounting proportion of colloid-bound metal, constituting up to 95% of the 'dissolved' (<0.22 MUm) fraction near pH 8. Measurements of DOC concentrations suggest this being due to pH-dependent binding of free metal cations to a fixed pool of organic colloids. The process is well described with a simple 2-site Langmuir isotherm in 0.05, 0.5, and 5.0M NaCl. Using this model to correct the original distribution coefficients not only removed the spurious reversal at low ionic strength, but also uncovered a prominent suppressive effect on the intermediate and high ionic strength data that had initially gone undetected. Ultra-filtration may thus be an essential analytical tool for proper characterization and interpretation of metal sorption on organic matter over a wide range of experimental conditions. Some implications are discussed for the use of biosorbents in the remediation of metal-contaminated waste waters. PMID- 21652007 TI - Mortality in Friedreich ataxia. AB - BACKGROUND: Although cardiac dysfunction is widely accepted as the most common cause of mortality in Friedreich ataxia (FRDA), no studies have evaluated this since the advent of specific clinical and genetic diagnostic criteria. METHODS: We performed a retrospective study of FRDA patients to determine cause of death followed by a case-control analysis comparing characteristics of deceased patients with living, age- and sex-matched FRDA controls. RESULTS: Causes of death were cardiac dysfunction (59%), probable cardiac dysfunction (3.3%), non cardiac (27.9%) or unknown (9.8%). Compared to non-cardiac deaths, cardiac deaths occurred earlier in the disease course (median 29 vs. 17years respectively). Congestive heart failure and arrhythmia were common causes of cardiac-related death. Compared to living, matched FRDA controls, deceased patients had longer triplet repeat lengths and higher rates of arrhythmia and dilated cardiomyopathy. The presence of hypertrophic cardiomyopathy did not differ between deceased and living patients. CONCLUSION: Cardiac dysfunction was the most frequent cause of death (59%), most commonly from congestive heart failure or arrhythmia. Arrhythmia and dilated cardiomyopathy were significantly more common in deceased patients compared to matched FRDA controls, while in contrast, the presence of cardiac hypertrophy did not differ. More research is needed to establish the clinical significance of hypertrophy in FRDA. PMID- 21652008 TI - Interaction between density and Cu toxicity for Enchytraeus crypticus and Eisenia fetida reflecting field scenarios. AB - Effect assessment is usually based on responses obtained from standard tests, in which organisms are well fed and in an optimal population density. For a more thorough assessment of ecotoxicological risk, information is needed for chemical effects in systems that closer reflect the potential exposure in the field systems. Responses measured in standard density experiments do not fully reflect the field scenario, where populations' size fluctuate with environmental conditions, leading to very low organism number in certain season/conditions and high number in others. In the present study, the possible interaction between density and Cu-pollution was investigated in regard to population growth, using Enchytraeus crypticus, and for individual juvenile growth, using Eisenia fetida. The standardized ISO and OECD guidelines for enchytraeids and earthworms were adapted to test four densities and four Cu concentrations. The final population number was used to assess the effects and possible interaction between densities and Cu toxicity for population responses and the increase in individual organism wet weight was used as growth response. The study showed that although initial density itself had tremendous impact on population and individual growth, organisms under different densities had the same sensitivity to Cu. PMID- 21652009 TI - Early diagnosis model for meningitis supports public health decision making. AB - OBJECTIVE: To develop a predictive model for rapid differential diagnosis of meningitis and meningococcal septicaemia to support public health decisions on chemoprophylaxis for contacts. METHODS: Prospective study of suspected cases of acute meningitis and meningococcal septicaemia admitted to hospitals in the South West, West Midlands and London Regions of England from July 2008 to June 2009. Epidemiological, clinical and laboratory variables on admission were recorded. Logistic regression was used to derive a predictive model. RESULTS: Of the 719 suspect cases reported, 385 confirmed cases were included in analysis. Peripheral blood polymorphonuclear count of >16 * 10(9)/l, serum C-reactive protein of >100 mg/l and haemorrhagic rash were strongly and independently associated with diagnosis of bacterial meningitis and meningococcal septicaemia. Using a simple scoring system, the presence of any one of these factors gave a probability of >95% in predicting the final diagnosis. CONCLUSION: We have developed a model using laboratory and clinical factors, but not dependent on availability of CSF, for differentiating acute bacterial from viral meningitis within a few hours of admission to hospital. This scoring system is recommended in public health management of suspected cases of meningitis and meningococcal septicaemia to inform decisions on chemoprophylaxis. PMID- 21652010 TI - Increase of Ki-67+ natural killer cells in multiple sclerosis patients treated with interferon-beta and interferon-beta combined with low-dose oral steroids. AB - Interferon-beta (IFN-beta) is known to expand regulatory CD56(bright) natural killer (NK) cells in multiple sclerosis (MS). In this cross-sectional study we show that MS patients treated with IFN-beta alone or in combination with low-dose prednisolone displayed increased proportion of all NK cell subsets in the active phase of the cell cycle (Ki-67+). There was no difference in NK cell apoptosis markers. In vitro experiments showed that both IFN-beta and IFN-beta in combination with corticosteroids increased the proportion of Ki-67(+) NK cells. This study, although limited, shows that treatment with IFN-beta affects NK cell cycle without altering NK cell apoptosis in MS patients. PMID- 21652011 TI - Notch-ing from T-cell to B-cell lymphoid malignancies. AB - Notch receptors are transmembrane proteins critically determining cell fate and maintenance of progenitor cells in many developmental systems. Notch signaling is involved in stem cell self-renewal and regulates the main functions of cell life at different levels of development: cell proliferation, differentiation and apoptosis. By virtue of its involvement in the regulation of cell physiology, it is not surprising that a deregulation of the Notch pathway leads to the development of different tumors. In this review, we critically discuss the latest findings concerning Notch roles in hematologic oncology, with a special focus on T-cell acute lymphoblastic leukemia and B-cell malignancies. We also describe the molecular mediators of Notch-driven oncogenic effects and the current pharmacological approaches targeting Notch signaling. PMID- 21652012 TI - Antiepileptic drugs in pregnancy: refinement of risk estimates. PMID- 21652013 TI - Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. AB - BACKGROUND: Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses. METHODS: The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes. FINDINGS: After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4.4, 95% CI 2.06 9.23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2.0% [17 events], 95% CI 1.19-3.24) and less than 400 mg per day carbamazepine (3.4% [5 events], 95% CI 1.11-7.71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day. INTERPRETATION: The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential. FUNDING: Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF. PMID- 21652014 TI - Regulatory T cells as modulators of B cell antibody production. PMID- 21652016 TI - In vivo and in vitro exposures for the evaluation of the genotoxic effects of lead on the Neotropical freshwater fish Prochilodus lineatus. AB - In the present study, in vivo and in vitro exposures were used to assess the genotoxicity of lead (Pb) to the freshwater fish Prochilodus lineatus. The comet assay using blood, liver and gill cells, and the occurrence of micronuclei (MN) and other erythrocytic nuclear abnormalities (ENA) were used to assess the genotoxic potential of lead in vivo. Metallothionein content (MT) was measured in fish liver in order to evaluate the protection of fish against Pb toxicity. Fish erythrocytes were exposed to Pb in vitro (1, 3 and 6 h) and the number of viable cells, DNA integrity, using the comet assay, and lysosomal membrane stability, measured by the neutral red retention assay (NRRA) were analyzed. The results of the comet assay after in vivo toxicity tests (6, 24 and 96 h) showed that Pb was genotoxic for all the three tissues analyzed after 96 h exposure. A significant increase in liver MT content was observed after 6 and 24 h of Pb exposure. MN frequency did not increase after Pb exposures, but the frequency of the other ENA, such as kidney-shaped nuclei, segmented nuclei and lobed nuclei, showed a significant increase after 24 and 96 h, indicating that ENA is a better biomarker for Pb exposure than MN alone after short-term exposures. The results of the comet assay performed with erythrocytes in vitro exposed to lead confirmed its genotoxic effect and showed that DNA damage increased with increasing exposure time. Moreover, the NRRA clearly indicated that Pb induces a destabilization of the lysosomal membrane. These results demonstrate the potential genotoxicity and cytotoxicity of lead after acute exposures. PMID- 21652015 TI - Is comprehension necessary for error detection? A conflict-based account of monitoring in speech production. AB - Despite the existence of speech errors, verbal communication is successful because speakers can detect (and correct) their errors. The standard theory of speech-error detection, the perceptual-loop account, posits that the comprehension system monitors production output for errors. Such a comprehension based monitor, however, cannot explain the double dissociation between comprehension and error-detection ability observed in the aphasic patients. We propose a new theory of speech-error detection which is instead based on the production process itself. The theory borrows from studies of forced-choice response tasks the notion that error detection is accomplished by monitoring response conflict via a frontal brain structure, such as the anterior cingulate cortex. We adapt this idea to the two-step model of word production, and test the model-derived predictions on a sample of aphasic patients. Our results show a strong correlation between patients' error-detection ability and the model's characterization of their production skills, and no significant correlation between error detection and comprehension measures, thus supporting a production based monitor, generally, and the implemented conflict-based monitor in particular. The successful application of the conflict-based theory to error detection in linguistic, as well as non-linguistic domains points to a domain general monitoring system. PMID- 21652017 TI - Down-regulation of V1a vasopressin receptors in the cerebellum after myocardial infarction. AB - Vasopressin V1a receptors (V1aR) were found in the cerebellum but their functional role has not been determined. As V1aR are engaged in the central regulation of the cardiovascular system and anxiogenic behavior and their role increases in the heart failure and stress, we decided to find out whether expression of V1aR is altered after myocardial infarction and chronic stressing. RT-PCR and Western blot analysis were performed to determine V1aR mRNA and protein expression in the cerebellum of four groups of rats (control sham operated, infarcted, chronically stressed and infarcted chronically stressed). The myocardial infarct was produced by left coronary artery ligation, and chronic stressing by exposing the rat for four weeks to different types of mild stressors. The rats were sacrificed four weeks after the myocardial surgery or sham operation. Expressions of V1aR mRNA and protein were significantly lower in the infarcted and infarcted chronically stressed rats than in the sham-operated controls and chronically stressed not infarcted rats. No significant differences were found between the sham-operated controls and chronically stressed rats and between the infarcted rats and infarcted rats exposed to chronic stressing. It is concluded that V1aR mRNA and protein expressions are significantly down-regulated in the rats with the post-infarct heart failure but they are not affected by mild chronic stressing. PMID- 21652018 TI - Yeast-based protein delivery to mammalian phagocytic cells is increased by coexpression of bacterial listeriolysin. AB - Yeast-mediated protein delivery to mammalian antigen-presenting cells is a powerful approach for inducing cell-mediated immune responses. We show that coexpression of the pore-forming protein listeriolysin O from Listeria monocytogenes leads to improved translocation of a proteinaceous antigen and subsequent activation of specific T lymphocytes. As the resulting yeast carrier is self-attenuated and killed after antigen delivery without exhibiting any toxic effect on antigen-presenting cells, this novel carrier system suggests itself as promising approach for the development of yeast-based live vaccines. PMID- 21652019 TI - [Papules and nodules in an infant]. PMID- 21652020 TI - Surfactant influence on rivulet droplet flow in minitubes and capillaries and its downstream evolution. AB - During our investigations of two-phase flow in long hydrophobic minitubes and capillaries, we have observed transformation of the main rivulet into different new hydrodynamic modes with the use of different kinds of surfactants. The destabilization of rivulet flow at air velocities <80 m/s occurs primarily due to the strong branching off of sub-rivulets from the main rivulet during the downstream flow in the tube. The addition of some surfactants of not-so-high surface activity was found to increase the frequency of sub-rivulet formation and to suppress the Rayleigh and sinuous instabilities of the formed sub-rivulets. Such instabilities result in subsequent fragmentation of the sub-rivulets and in the formation of linear or sinuous arrays of sub-rivulet fragments (SRFs), which later transform into random arrays of SRFs. In the downstream flow, SRFs further transform into large sliding cornered droplets and linear droplet arrays (LDAs), a phenomenon which agrees with recent theories. At higher surface activity, suppression of the Rayleigh instability of sub-rivulets with surfactants becomes significant, which prevents sub-rivulet fragmentation, and only the rivulet and sub-rivulets can be visualized in the tube. At the highest surface activity, the bottom rivulet transforms rapidly into an annular liquid film. The surfactant influence on the behavior of the rivulets in minitubes is incomparably stronger than the classic example of the known surfactant stabilizing influence on a free jet. The evolution of a rivulet in the downstream flow inside a long minitube includes the following sequence of hydrodynamic modes/patterns: i) single rivulet; ii) rivulet and sub-rivulets; and iii) rivulet, sub-rivulets, sub rivulet fragments, cornered droplets, linear droplet arrays, linear arrays of sub rivulet fragments and annular film. The formation of these many different hydrodynamic patterns downstream is in drastic contrast with the known characteristics of two-phase flow, which demonstrates one mode for the entire tube length. Recent achievements in fluid mechanics regarding the stability of sliding thin films and in wetting dynamics have allowed us to interpret many of our findings. However, the most important phenomenon of the surfactant influence on sub-rivulet formation remains poorly understood. To achieve further progress in this new area, an interdisciplinary approach based on the use of methods of two-phase flow, wetting dynamics and interfacial rheology will be necessary. PMID- 21652021 TI - Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study. AB - PURPOSE: To determine the antibacterial susceptibility profile of bacterial pathogens from ocular infections against relevant aminoglycoside, beta-lactam, cephalosporin, chloramphenicol, fluoroquinolone, glycopeptide, lincosamide, and macrolide antibacterial agents. DESIGN: Laboratory investigation. METHODS: Isolates from patients with bacterial eye infections were collected prospectively by 34 institutions across the United States and were submitted to a central laboratory for inclusion in the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) study. Minimum inhibitory concentrations were determined by microbroth dilution for 200 Staphylococcus aureus (S. aureus), 144 coagulase negative staphylococci, 75 Streptococcus pneumoniae (S. pneumoniae), 73 Haemophilus influenzae (H. influenzae), and 100 Pseudomonas aeruginosa (P. aeruginosa) isolates. RESULTS: A large proportion of S. aureus and coagulase negative staphylococci isolates were resistant to oxacillin/methicillin, azithromycin, or fluoroquinolones; 46.5% of S. aureus, 58.3% of coagulase negative staphylococci, 9.0% of P. aeruginosa, and 9.3% of pneumococcal isolates were nonsusceptible to 2 or more antibacterial drug classes. Only 2.7% of H. influenzae isolates were nonsusceptible to 1 of the agents tested. Methicillin resistant staphylococci were statistically more likely (all P < .0038) also to be resistant to fluoroquinolones, aminoglycosides, and macrolides. CONCLUSIONS: Resistance to 1 or more antibiotics is prevalent among ocular bacterial pathogens. Current resistance trends should be considered before initiating empiric treatment of common eye infections. PMID- 21652022 TI - QuantiFERON-TB gold cut-off value: implications for the management of tuberculosis-related ocular inflammation. AB - PURPOSE: To evaluate the accuracy of QuantiFERON-TB Gold testing in patients with presumptive tuberculosis-ocular inflammation. DESIGN: Prospective nonrandomized case series and clinical laboratory investigation. METHODS: Ninety-six consecutive patients presenting with ocular inflammation between January and October 2007 were tested using QuantiFERON-TB Gold. Positive patients received a 6-month anti-tuberculosis treatment. Patient follow-up ranged from 12 months to 24 months. Treatment was considered effective at the end of follow-up, in cases of no or a 2-point decrease of ocular inflammation (SUN criteria) and systemic corticosteroids stopped or tapered to 10 mg/day. RESULTS: Mean age was 51 +/- 17 years. Types of ocular inflammation included scleritis (n = 7), panuveitis (n = 34), and posterior (n = 15), intermediate (n = 14), and anterior uveitis (n = 15). QuantiFERON-TB Gold was positive in 42 cases (44%), negative in 51 cases (53%), and undetermined in 3 cases (3%). Among positive QuantiFERON-TB Gold patients, 25 received a full anti-tuberculosis treatment, which was effective in 15 cases (60%). Associated systemic steroids were given to 6 patients and tapered to 10 mg/day or less in all cases. Median QuantiFERON-TB Gold value was significantly higher in the group with a successful therapeutic response (7.67 IU/mL [0.46 to 33.37]) compared to the group with treatment failure (1.22 IU/mL [0.61 to 4.4]), P = .026. CONCLUSION: Results of anti-tuberculosis treatment were encouraging in QuantiFERON-TB Gold-positive ocular inflammation, especially with values over 2 IU/mL in our study, suggesting that a higher cut-off value than that given by the manufacturer should be considered to better identify ocular inflammation that can benefit from full anti-tuberculosis treatment. PMID- 21652023 TI - Periocular triamcinolone acetonide injections for cystoid macular edema complicating noninfectious uveitis. AB - PURPOSE: To describe the effectiveness of periocular corticosteroid injections in the treatment of cystoid macular edema (CME) complicating noninfectious uveitis. DESIGN: Retrospective cohort study. METHODS: A total of 126 patients (156 eyes) were evaluated for presence of CME, visual acuity, intraocular pressure, degree of intraocular inflammation, and the presence of ocular complications. Main outcome measures included resolution of CME and visual acuity at the 1- and 3 month visits, failure of periocular injection therapy, and side effects. RESULTS: Twenty-eight percent of the 156 eyes had anterior uveitis, 22% intermediate uveitis, and 31% panuveitis. Of these eyes, 53% demonstrated clinical resolution of CME at 1 month and 57% at 3 months after a single periocular corticosteroid injection. Forty eyes were treated with >1 periocular injection because the CME persisted 1 month after the first injection (1 additional injection in 21 eyes; 2 additional injections in 14 eyes; >2 additional injections in 5 eyes). For the 21 eyes treated with a second periocular corticosteroid injection, 81% had no CME 1 month after the second injection and 48% had no CME 3 months after the second injection. Twenty-three eyes (15%) failed periocular corticosteroid therapy. Of eyes initially responding to periocular injection, CME recurred in 53% (median time to recurrence = 20.2 weeks). A halving of the visual angle was observed in 52% and 57% at the 1- and 3-month visits after injection, respectively. CONCLUSIONS: Fifty-three percent of eyes treated with a single periocular corticosteroid injection had clinical resolution of CME 1 month after the injection. PMID- 21652024 TI - Use of infliximab in the treatment of peripheral ulcerative keratitis in Crohn disease. AB - PURPOSE: To report the effectiveness of infliximab in the treatment of peripheral ulcerative keratitis (PUK) associated with Crohn disease. DESIGN: Retrospective, interventional case series. METHODS: SETTING: Institutional, academic referral setting. patient or study population: Six eyes of 3 patients with PUK associated with Crohn disease that failed or were intolerant to traditional immunosuppression such as oral prednisone and cyclophosphamide. INTERVENTION OR OBSERVATION PROCEDURE(S): Infliximab intravenous infusion 5 mg/kg every 2 to 8 weeks. MAIN OUTCOME MEASURE(S): Subjective outcome such as pain improvement and objective outcomes such as visual acuity, signs of inflammation, and progression of corneal thinning. RESULTS: Symptom of pain improved in all patients. Visual acuity remained stable in 4 of 6 eyes, improved in 1 of 6 eyes, and worsened in 1 of 6 eyes (secondary to stromal scar). Rapid resolution of inflammation and arrest of further thinning were observed in all 6 eyes. Similar effects were observed on recurrence treated with repeat dosing of infliximab in 5 of 6 eyes. CONCLUSIONS: Infliximab produced a rapid, dramatic, repeatable suppression of corneal inflammation, pain, and keratolysis in PUK associated with Crohn disease. Although the effect of long-term therapy with these agents is unknown, infliximab should be considered in patients with Crohn-associated PUK not amenable to traditional therapy. Larger prospective studies are needed to determine the efficacy of infliximab in this aggressive disease entity. PMID- 21652025 TI - Ocular surface reconstruction using the combination of autologous cultivated oral mucosal epithelial transplantation and eyelid surgery for severe ocular surface disease. AB - PURPOSE: To assess the surgical combination of autologous cultivated oral mucosal epithelial transplantation and eyelid surgery used to treat patients with severe ocular surface disease and entropion. DESIGN: Observational case series. METHODS: Three patients with severe thermal and chemical injury were treated by the surgical combination of autologous cultivated oral mucosal epithelial transplantation and everting sutures to correct entropion. Their clinical outcomes and the efficacy of this surgical procedure were assessed. RESULTS: The ocular surfaces were successfully reconstructed with autologous cultivated oral mucosal epithelial sheets and everting sutures without any complications during the operations. In the course of a mean follow-up period of 30 months their clinical outcomes were assessed. Postoperative follow-up showed that the simultaneous everting sutures caused no problems with the cultivated oral mucosal epithelial sheet, and there were no severe complications such as infection or inflammation. During the follow-up period, in 2 of the 3 eyes the ocular surface and eyelid remained stable with no recurrence of entropion. CONCLUSION: This case series presents a surgical approach to treat severely scarred ocular surfaces using the combination of autologous cultivated oral mucosal epithelial transplantation and everting sutures. Clinical outcomes suggest that this combined surgical procedure is a safe and useful method for the treatment of patients with severe ocular surface disease and entropion. PMID- 21652026 TI - Validation of a photographic vitreous haze grading technique for clinical trials in uveitis. AB - PURPOSE: To validate a photographic vitreous haze grading technique using a 9 step logarithmic scale in patients enrolled in a randomized, controlled clinical trial in uveitis. DESIGN: Retrospective study of clinical trials methodology. METHODS: SETTING: University-based department of ophthalmology. STUDY POPULATION: Baseline fundus photographs of patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. OBSERVATIONAL PROCEDURE: Grading of vitreous haze using a previously described photographic scale. Regrading of a subset of photographs to assess intraobserver agreement. MAIN OUTCOME MEASURES: Interobserver and intraobserver intraclass correlation for photographic haze grading, and correlation between photographic and clinical vitreous haze scores, assessment of the clinical findings that significantly affect the photographic haze score. RESULTS: Vitreous haze was graded in 271 eyes (142 patients) by 3 postgraduate ophthalmologists. The interobserver and intraobserver intraclass correlations were excellent, with correlation coefficients between 0.84 and 0.93. There was moderately strong correlation between the photographic and clinical vitreous haze scores (r=0.51; P<.001), with significant differences among the mean and median photographic haze scores for the 3 lowest clinical grades of haze, 0, 1+, and 2+. Other parameters that correlated with photographic vitreous haze score included visual acuity of 20/50 or worse (P=.003), degrees of posterior synechiae (P<.001), lens abnormality (P=.023) or posterior capsule obscuration (P=.001), and amount of anterior vitreous cell (P=.002). CONCLUSIONS: Photographic grading of vitreous haze with a 9-step logarithmic scale is a highly reproducible methodology that may be adaptable to use in future clinical trials. PMID- 21652027 TI - Dermis-fat graft for treatment of exposed porous polyethylene implants in pediatric postenucleation retinoblastoma patients. AB - PURPOSE: To demonstrate the use of the autogenous dermis-fat graft for the treatment of porous polyethylene implant exposure and volume augmentation in postenucleation retinoblastoma children. DESIGN: Retrospective, interventional case series. METHODS: Ten children who received a dermis-fat graft at Seoul National University Hospital between July 1, 2005 and January 31, 2010 were included in this study. The patients had undergone unilateral enucleation for retinoblastoma, and received a subconjunctival dermis-fat graft to repair implant exposure and simultaneously correct enophthalmos. The clinical characteristics of the patients, rate of graft survival, and complications were analyzed. The cosmetic outcome was assessed using a grading system. RESULTS: All patients had enucleation using porous polyethylene implant as a primary orbital implant. The average time to exposure was 89.1 +/- 22.4 months and the median size of defect was 2 * 3 mm. With a mean follow-up of 28 months, 9 of 10 patients showed well survived graft without re-exposure. One patient who experienced a graft failure managed with implant rotation and a scleral graft. Seven patients showed significant improvement of enophthalmos. CONCLUSIONS: Implantation of an autogenous dermis-fat graft is a procedure that can be effectively used to treat porous polyethylene implant exposure and simultaneously correct enophthalmos. Use of this procedure can be particularly advantageous for pediatric postenucleation patients. PMID- 21652028 TI - HLA-DRB1/DQB1 susceptibility for autoimmune polyglandular syndrome type II and III in south of Tunisia. AB - OBJECTIVES: The aim of our study was to investigate the association of HLA-DRB1 and HLA-DQB1 alleles with autoimmune polyglandular syndromes (APS) type II and III in a southern Tunisian population. PATIENTS AND METHODS: Sixty-two unrelated patients with APSII (n=20) and APSIII (n=42) and 146 healthy controls were genotyped for HLA class II alleles (DRB1*, DQB1*) by PCR-SSP technique. RESULTS: An increased frequencies of HLA-DQB1*03:02 (P=0,02; OR=2.98) in APSII patients, HLA-DRB1*03 (P=310(-6); OR=4.28) and HLA-DQB1*02:01 (P=0.04; OR=1.95) in APSIII patients were found compared to healthy controls. Study of the HLA-DRB1*;DQB1* haplotype frequencies showed a higher occurrence of DRB1*04;DQB1*03:02 and DRB1*03;DQB1*02:01 in APSII patients (P=410(-3); OR=3.31 and P=0.03; OR=2.74 respectively) whereas APSIII was only associated with DRB1*03;DQB1*02:01 (P=7.210(-8), OR=4.71). CONCLUSION: Our data suggest that the variation in class II HLA alleles and haplotypes could be a genetic factor involved in the susceptibility of APS syndrome. PMID- 21652029 TI - Exenatide improves weight loss insulin sensitivity and beta-cell function following administration to a type 2 diabetic HIV patient on antiretroviral therapy. AB - The use of retroviral drugs in the treatment of infection by human immunodeficiency virus (HIV) is associated, especially for first generations, with side effects such as lipodystrophy, fatty liver and insulin resistance, which may trigger secondary diabetes or worsen existing diabetes. The use of Glucagon-Like Peptide-1 in obese patients with type 2 diabetes on HIV retroviral as an alternative to insulin therapy is not documented; we report the case of a 47-year-old treated with exenatide when insulin was discontinued. During the first year of treatment, exenatide, in combination with metformin and repaglinide, led to a weight loss of 14 kg and fat mass and waist circumference were respectively reduced from 31 to 25.5% and from 114 to 103 cm. Homeostatic model assessment (HOMA) was used to calculate beta-cell secretion which increased from 50 to 78% and insulin sensitivity which increased from 28 to 51%, reflecting a decrease in HbA(1c) by 1.9%. Exenatide may be a new therapeutic option for HIV infected type 2 diabetes patients undergoing retroviral therapy. PMID- 21652030 TI - Threat-related automatic associations in socially anxious adolescents. AB - Threat-related automatic associations are assumed to play an important role in the development and maintenance of social anxiety. We tested whether threat related automatic associations are already evident in high socially anxious adolescents, by comparing a group of adolescents (age 12-15) with subclinical levels of social anxiety (n=170) to a group of low socially anxious adolescents (n=193). We used a single-target implicit association test to measure threat related automatic associations to social cues. Results showed that indeed in high socially anxious adolescents social cues automatically elicited relatively strong threat-related associations. Supporting the relevance of differentiating between automatic and more explicit measures, both automatic and explicit associations were independently associated with adolescents' level of self-reported social anxiety. The present pattern of findings is not only consistent with the view that automatic and more deliberate threat-related associations are both involved in the etiology of social-anxiety symptoms, but also suggest that both types of associations are proper targets for early intervention programs. PMID- 21652031 TI - Prenatal tactile stimulation attenuates drug-induced behavioral sensitization, modifies behavior, and alters brain architecture. AB - Based on the findings of postnatal tactile stimulation (TS), a favorable experience in rats, the present study examined the influence of prenatal TS on juvenile behavior, adult amphetamine (AMPH) sensitization, and structural alteration in the prefrontal cortex (PFC) and the striatum. Female rats received TS through a baby hair brush throughout pregnancy, and the pups born were tested for open field locomotion, elevated plus maze (EPM), novel object recognition (NOR), and play fighting behaviors. Development and persistence of drug-induced behavioral sensitization in adults were tested by repeated AMPH administration and a challenge, respectively. Structural plasticity in the brain was assessed from the prefrontal cortical thickness and striatum size from serial coronal sections. The results indicate that TS females showed enhanced exploration in the open field. TS decreased the frequency of playful attacks whereas the response to face or evade an attack was not affected. Anxiety-like behavior and cognitive performance were not influenced by TS. AMPH administration resulted in gradual increase in locomotor activity (i.e., behavioral sensitization) that persisted at least for 2 weeks. However, both male and female TS rats exhibited attenuated AMPH sensitization compared to sex-matched controls. Furthermore, the drug associated alteration in the prefrontal cortical thickness and striatum size observed in controls were prevented by TS experience. In summary, TS during prenatal development modified juvenile behavior, attenuated drug-induced behavioral sensitization in adulthood, and reorganized brain regions implicated in drug addiction. PMID- 21652032 TI - Are objects the same as groups? ERP correlates of spatial attentional guidance by irrelevant feature similarity. AB - It has been proposed that the most fundamental units of attentional selection are "objects" that are grouped according to Gestalt factors such as similarity or connectedness. Previous studies using event-related potentials (ERPs) have shown that object-based attention is associated with modulations of the visual-evoked N1 component, which reflects an early cortical mechanism that is shared with spatial attention. However, these studies only examined the case of perceptually continuous objects. The present study examined the case of separate objects that are grouped according to feature similarity (color, shape) by indexing lateralized potentials at posterior sites in a sustained-attention task that involved bilateral stimulus arrays. A behavioral object effect was found only for task-relevant shape similarity. Electrophysiological results indicated that attention was guided to the task-irrelevant side of the visual field due to achromatic-color similarity in N1 (155-205 ms post-stimulus) and early N2 (210 260 ms) and due to shape similarity in early N2 and late N2 (280-400 ms) latency ranges. These results are discussed in terms of selection mechanisms and object/group representations. PMID- 21652033 TI - Central infusion of ketone bodies modulates body weight and hepatic insulin sensitivity by modifying hypothalamic leptin and insulin signaling pathways in type 2 diabetic rats. AB - Although the effects of ketogenic diets on energy and glucose homeostasis have been controversial, elevation of serum ketone levels by subcutaneous injection of beta-hydroxybutyrate (BHB) can improve glucose homeostasis. Ketones may work through the brain; therefore, we evaluated whether the intracerebroventricular (ICV) infusion of beta-hydroxybutyrates would also modulate peripheral energy and glucose homeostasis, and through what mechanisms, in diabetic rats fed a high fat diet in short- and long-term studies. Short-term (3h) central injection of BHB (50 MUg/h) improved serum glucose levels and peripheral insulin sensitivity compared to the artificial cerebrospinal fluid (CSF) group among 90% pancreatectomized (Px) diabetic rats, but not in non-diabetic Sham rats. In addition to short-term infusion, long-term (28 days) central infusion of BHB (12 MUg/h) elevated serum BHB levels. Long-term infusion of BHB potentiated leptin and insulin signaling in the hypothalamus to slightly decrease body weight in Px rats. Central BHB infusion had a greater effect on peripheral glucose metabolism than overall energy metabolism. Hepatic insulin signaling (tyrosine phosphorylation of IRS2->serine phosphorylation of Akt->reduced expression of PEPCK) was potentiated and hepatic glucose production in the hyperinsulinemic state was suppressed in the diabetic rats. In addition, glucose tolerance was improved by central BHB infusion through enhanced whole body glucose disposal rates, but insulin secretion was not affected in the diabetic rats. In conclusion, mild ketosis by central infusion of ketones improves energy and glucose metabolism through the potentiation of leptin and insulin signaling in the hypothalamus of diabetic rats. PMID- 21652035 TI - An upper extremity inverse dynamics model for pediatric Lofstrand crutch-assisted gait. AB - The objective of this study was to develop an instrumented Lofstrand crutch system, which quantifies three-dimensional (3-D) upper extremity (UE) kinematics and kinetics using an inverse dynamics model. The model describes the dynamics of the shoulders, elbows, wrists, and crutches and is compliant with the International Society of Biomechanics (ISB) recommended standards. A custom designed Lofstrand crutch system with four, six-degree-of-freedom force transducers was implemented with the inverse dynamics model to obtain triaxial UE joint reaction forces and moments. The crutch system was validated statically and dynamically for accuracy of computing joint reaction forces and moments during gait. The root mean square (RMS) error of the system ranged from 0.84 to 5.20%. The system was demonstrated in children with diplegic cerebral palsy (CP), incomplete spinal cord injury (SCI), and type I osteogenesis imperfecta (OI). The greatest joint reaction forces were observed in the posterior direction of the wrist, while shoulder flexion moments were the greatest joint reaction moments. The subject with CP showed the highest forces and the subject with SCI demonstrated the highest moments. Dynamic quantification may help to elucidate UE joint demands in regard to pain and pathology in long-term assistive device users. PMID- 21652034 TI - Role of neurokinin-1 and dopamine receptors on the striatal methamphetamine induced proliferation of new cells in mice. AB - A neurotoxic dose of methamphetamine (METH) induces the loss of some striatal neurons. Interestingly, the METH-induced apoptosis in the striatum is immediately followed by the generation of new cells (cytogenesis). In the present study, we investigated the role of the neurokinin-1, dopamine D1 and D2 receptors on the METH-induced cytogenesis. To that end, male mice were given a single injection (30 mg/kg, ip) or a binge of METH (10mg/kg, 4* at two-hour intervals, ip). BrdU (100mg/kg, ip) was given 36 h after the last injection of METH. Newly generated cells were detected by immunohistochemistry and cell counts were performed using unbiased computerized stereology. Either single or binge exposure to METH resulted in the generation of new cells. The single optimized dose was used for subsequent mechanistic studies. Pretreatment with the dopamine D1 receptor antagonist SCH23390 (0.1mg/kg, ip) 30 min prior to METH abrogated the METH induced striatal cytogenesis. Pretreatment with the dopamine D2 receptor antagonist raclopride (1mg/kg, ip) failed to affect this phenomenon. Finally, pretreatment with the neurokinin-1 receptor antagonist WIN 51,708 (5mg/kg, ip) 30 min prior to METH abrogated the METH-induced cytogenesis. In conclusion, neurokinin-1 and dopamine D1 receptors are required for the METH-induced striatal cytogenesis while the D2 receptor is without effect. PMID- 21652036 TI - Use of isopycnic plots in designing operations of supercritical fluid chromatography: I. The critical role of density in determining the characteristics of the mobile phase in supercritical fluid chromatography. AB - In Supercritical Fluid Chromatography (SFC), the key chromatographic parameters of any compound, its retention and efficiency, are known to strongly depend on the density of the mobile phase. This indicates that iso-density, also called isopycnic, plots drawn on the pressure-temperature plane can provide an effective tool to analyze how SFC systems may operate under different combinations of inlet and outlet pressures and column temperature. To effectively use these isopycnic plots in designing the operations of SFC systems, however, a deeper understanding of the factors behind the dependence of the performance of these systems on the mobile phase density is required. The nature of this density dependence is explored with reference to the key physical properties of the mobile phase, its viscosity, diffusivity and solubility. This study is focused on the use of pure carbon dioxide as the mobile phase, but this method of investigation is applicable for other mobile phase combinations as well. PMID- 21652037 TI - Preparative separation of lithospermic acid B from Salvia miltiorrhiza by polyamide resin and preparative high-performance liquid chromatography. AB - Adsorption on polyamide resin was investigated as a means of separating lithospermic acid B (LAB) from a crude extract of the roots of the traditional Chinese medicine Salvia miltiorrhiza Bunge ("Danshen"). Variables affecting adsorption capacity (solution pH, contact time on resin, initial LAB concentration) were studied. Adsorption was strongly dependent upon the initial concentration of LAB and pH. In all conditions, the polyamide resin gave optimal adsorption of LAB at an initial concentration of 2.66 mg/mL and pH <3.0. The adsorption isotherm correlated well with the Langmuir-type adsorption isotherm. Maximal adsorption capacity was calculated to be 380 mg/g at pH 2.0 and 25 degrees C. LAB purity of 85.30% could be obtained by polyamide resin adsorption followed by elution with 70% ethanol solution, and the recovery was 87.1%. After preparative HPLC, the maximum HPLC purity obtained was 99.28% with a recovery of 75.2%. This method provides an efficient and low-cost method for LAB purification for industrial applications. PMID- 21652038 TI - Development and validation of a pre-column reversed phase liquid chromatographic method with fluorescence detection for the determination of primary phenethylamines in dietary supplements and phytoextracts. AB - A sensitive and selective reversed-phase liquid chromatographic (RP-LC) method was developed and validated to determine octopamine, tyramine and Tyrosine (Tyr) in complex matrices as formulations and phytoextracts (Citrus aurantium), after pre-column derivatization with o-phthaldialdehyde (OPA) reagent. The chromatographic separations were performed at room temperature on a Phenomenex Luna C18 column using methanol and sodium acetate buffer (pH 5.5) by varying composition gradient elution as mobile phase and detected flurometrically at lambda(em)=455 nm with lambda(ex)=340 nm. The results obtained by the proposed method were compared with those achieved by a validated direct RP-LC method with fluorescence detection at lambda(em)=310 nm with lambda(ex)=275 nm, as reference method, using a Phenomenex Gemini C18 column under isocratic elution conditions with acetonitrile and sodium 1-heptanesulphonate (pH 3), as mobile phase. The higher sensitivity of the derivatization method (detection limit about 0.06 pmol) allowed the sure determination of octopamine present in traces in the examined samples. The repeatability of method (RSD) was <=1.90% and there was no significant difference between repeatability and intermediate precision data. Recovery studies showed good results 99.5-101.3% with RSD ranging from 0.8 to 1.2%. All analyses were performed by mild conditions in absence of preliminary difficult extraction methodologies or laborious step of sample pre-treatment. PMID- 21652039 TI - Quantitative analysis by liquid chromatography-tandem mass spectrometry of glycidamide using the cob(I)alamin trapping method: validation and application to in vitro metabolism of acrylamide. AB - Glycidamide (GA) is the epoxy metabolite of acrylamide (AA). A sensitive analytical method for quantitative measurement of GA from in vitro metabolism studies is useful in several contexts, e.g. in studies of enzyme kinetics in different species and factors influencing the metabolism of AA to GA. It is however difficult to analyse compounds like GA, mainly due to their inherent reactivity. In the present study cob(I)alamin {Cbl(I)}, a reduced form of vitamin B(12), was used for trapping of GA. Cbl(I) can react with electrophilic species, such as an epoxide, 10(5) times faster than standard nucleophiles. The trapping of GA by Cbl(I) results in the formation of an alkylcobalamin (GA-Cbl) that was used for quantitative analysis of the epoxide. The alkylcobalamin was analysed by LC-MS/MS using an electrospray ionization source in the positive ion mode. The Cbl(I) method was validated for measurement of GA in liver S9 fractions from human and rat. GA levels down to 0.01 MUM were measured in the S9 fractions, providing a sensitivity that was ca. 100 times higher than that earlier estimated by the Cbl(I) method for measurement of other (e.g. butadiene) epoxides. Compared to current analytical methods for measurement of GA, the Cbl(I) method was 10-100 times more sensitive. The method was applied to quantify GA formed from the metabolism of AA in liver S9 from human and rat. PMID- 21652040 TI - Monolithic capillary columns synthesized from a single phosphate-containing dimethacrylate monomer for cation-exchange chromatography of peptides and proteins. AB - Monoliths containing phosphoric acid functional groups were synthesized from only one monomer, bis[2-(methacryloyloxy)ethyl] phosphate (BMEP), in 75-MUm i.d. UV transparent fused-silica capillaries by photo-initiated polymerization for cation exchange chromatography of peptides and proteins. Various synthetic conditions, including porogen solvents, monomer concentration, and polymerization time, were studied. The hydrophobicities of the resulting monoliths were evaluated using propyl paraben under reversed-phase conditions and synthetic peptides under ion exchange conditions. These monoliths exhibited low hydrophobicities and relatively low porosities due to their highly cross-linked structures. A dynamic binding capacity (lysozyme) of 73 mg/mL of column volume was measured using the best performing monolith. Synthetic peptides were eluted in approximately 30 min without addition of acetonitrile to the mobile phase, yielding a peak capacity of 28. Efficiencies of 52,900 plates/m for peptides and 71,000 plates/m for proteins were obtained under isocratic conditions. The effects of separation conditions, i.e., mobile phase pH and salt gradient rate, were studied. Good run-to-run reproducibility was achieved with a relative standard deviation (RSD) less than 1.5% for retention times of proteins. The column-to-column retention time reproducibility for peptides was less than 3.5% RSD. A monolithic column was used to follow the deamidation of ribonuclease A. The kinetics of deamidation were founded to be first order with a half life of 195 h. A cytochrome C digest was also separated using a linear gradient of sodium chloride. PMID- 21652041 TI - Ultra resolution chemical fingerprinting of dense non-aqueous phase liquids from manufactured gas plants by reversed phase comprehensive two-dimensional gas chromatography. AB - Ultra resolution chemical fingerprinting of dense non-aqueous phase liquids (DNAPLs) from former manufactured gas plants (FMGPs) was investigated using comprehensive two-dimensional gas chromatography coupled with time of flight mass spectrometry (GC*GC TOFMS). Reversed phase GC*GC (i.e. a polar primary column coupled to a non-polar secondary column) was found to significantly improve the separation of polycyclic aromatic hydrocarbons (PAHs) and their alkylated homologues. Sample extraction and cleanup was performed simultaneously using accelerated solvent extraction (ASE), with recovery rates between 76% and 97%, allowing fast, efficient extraction with minimal solvent consumption. Principal component analysis (PCA) of the GC*GC data was performed in an attempt to differentiate between twelve DNAPLs based on their chemical composition. Correlations were discovered between DNAPL composition and historic manufacturing processes used at different FMGP sites. Traditional chemical fingerprinting methods generally follow a tiered approach with sample analysis on several different instruments. We propose ultra resolution chemical fingerprinting as a fast, accurate and precise method of obtaining more chemical information than traditional tiered approaches while using only a single analytical technique. PMID- 21652042 TI - Comprehensive two-dimensional gas chromatography for the analysis of synthetic and crude-derived jet fuels. AB - Fully synthetic jet fuel (FSJF) produced via Fischer-Tropsch (FT) technology was recently approved by the international aviation fuel authorities. To receive approval, comparison of FSJF and crude-derived fuel and blends on their qualitative and quantitative hydrocarbon composition was of utmost importance. This was performed by comprehensive two-dimensional gas chromatography (GC*GC) in the reversed phase mode. The hydrocarbon composition of synthetic and crude derived jet fuels is very similar and all compounds detected in the synthetic product are also present in crude-derived fuels. Quantitatively, the synthetic fuel consists of a higher degree of aliphatic branching with less than half the aromatic content of the crude-derived fuel. GC*GC analyses also indicated the presence of trace levels of hetero-atomic impurities in the crude-derived product that were absent in the synthetic product. While clay-treatment removed some of the impurities and improved the fuel stability, the crude-derived product still contained traces of cyclic and aromatic S-containing compounds afterwards. Lower level of aromatics and the absence of sulphur are some of the factors that contribute to the better fuel stability and environmental properties of the synthetic fuel. GC*GC was further applied for the analysis of products during Jet Fuel Thermal Oxidation Testing (JFTOT), which measures deposit formation of a fuel under simulated engine conditions. JFTOT showed the synthetic fuel to be much more stable than the crude-derived fuel. PMID- 21652043 TI - The use of silica nanoparticles for gas chromatographic separation. AB - A new IL-dispersed silica nanoparticles (IL-SNs) capillary column, combining properties of silica nanoparticles and ionic liquid (IL), was used for gas chromatographic separation. By dispersing silica nanoparticles in a conventional IL of 1-butyl-3-methylimidazolium hexafluorophosphate ([BuMIm][BF6]), a layer of homogeneous interconnected particulate silica networks (thickness: 0.4-0.6 MUm) was formed on the inner surface of a capillary column. This coating integrates advantages of silica nanoparticles (high surface area, high dispersed behaviour) and IL (extended liquid-state temperature range, chemical stability), hence increasing interactions between stationary phase and analytes. It was demonstrated that mixtures of a wide range of organic compounds including alcohols, esters, alkanes, aromatic compounds, as well as isomers and non-polar compounds can be well separated using an IL-SNs capillary column. Comparing to traditional support coated open tubular columns, the IL-SNs capillary column displays retention behaviors of separating both polar and non-polar compounds. The much thinner coating film of IL-SNs capillary column, compared to the coating film of SNs capillary column, decreases the resistance to mass transfer, resulting a good column efficiency of 3030 theoretical plates per meter for n butanol (which is about 5 times higher than for the SNs capillary column). Furthermore, the IL-SNs capillary column decreases the IL retention selectivity dominated by IL structures, and has a higher coating value than neat IL stationary phase. Moreover, the preparation is simple as no modification of ILs or adoption of additional reagents is needed in pretreatments. This manuscript is the first report on the use of silica nanoparticles for gas chromatography, which would expand the applicability of silica nanoparticles in analytical chemistry. PMID- 21652044 TI - Ultrasonic nebulization extraction-heating gas flow transfer-headspace single drop microextraction of essential oil from pericarp of Zanthoxylum bungeanum Maxim. AB - The ultrasonic nebulization extraction-heating gas flow transfer coupled with headspace single drop microextraction (UNE-HGFT-HS-SDME) was developed for the extraction of essential oil from Zanthoxylum bungeanum Maxim. The gas chromatography-mass spectrometry was applied to the determination of the constituents in the essential oil. The contents of the constituents from essential oil obtained by the proposed method were found to be more similar to those obtained by hydro-distillation (HD) than those obtained by ultrasonic nebulization extraction coupled with headspace single drop microextraction (UNE HS-SDME). The heating gas flow was firstly used in the analysis of the essential oil to transfer the analytes from the headspace to the solvent microdrop. The relative standard deviations for determining the five major constituents were in the range from 1.5 to 6.7%. The proposed method is a fast, sensitive, low cost and small sample consumption method for the determination of the volatile and semivolatile constituents in the plant materials. PMID- 21652045 TI - Tunable disintegration of layer-by-layer assembly multilayer films based on hydrolytical-polybetaine at wide-range time. AB - A cationic hydrolytical-polycarboxybetaine (HPCB), poly(N-ethyl acetate-4 vinylpyridinium bromide) was synthesized by incorporating ester group into the side chain of polycarboxybetaine (PCB). The hydrolytic behaviors of HPCB samples in pH 7.4 phosphate buffer saline (PBS) were investigated by FT-IR and (1)H NMR. The layer-by-layer (LbL) assembly of HPCB/poly (sodium 4-styrenesulfonate) PSS and the disintegration of HPCB/PSS multilayer films were monitored by UV-vis absorption spectroscopy, quartz crystal microbalance (QCM) and atomic force microscopy (AFM). The disintegrated behavior of multilayer films was studied in detail by changing the cationic degree of HPCB and the pH of the immersion solution (PBS) in the disintegration process. The disintegration time of HPCB/PSS multilayer films could be controlled widely from 2 min to 30 days in PBS. PMID- 21652046 TI - Phenol adsorption on closed carbon nanotubes. AB - We present the results of systematic studies of phenol adsorption on closed commercially available, unmodified carbon nanotubes. Phenol adsorption is determined by the value of tube-specific surface area, the presence of small amount of surface groups influence adsorption only in very small amount. Phenol can be applied as a probe molecule for comparative analysis of tube surface areas. Tube curvature influences adsorption from solution, i.e., we observe increasing adsorption energy (and slower desorption process) with the decrease in tube curvature. This is in full accordance with molecular simulation results. PMID- 21652047 TI - Amyloid-mediated synthesis of giant, fluorescent, gold single crystals and their hybrid sandwiched composites driven by liquid crystalline interactions. AB - We report for the first time on the templating effect of beta-lactoglobulin amyloid-like fibrils to synthesize gold single crystals of several decades of MUm in dimensions. The gold single crystals were produced by reducing an aqueous solution of chloroauric acid by beta-lactoglobulin amyloid protein fibrils. Atomic force microscopy, conventional and scanning transmission electron microscopy, electron diffraction and optical microscopy techniques were combined to characterize the structure of the gold crystals. The single-crystalline features of these macroscopic gold crystals are witnessed by their distinctive hexagonal and triangular shape and are confirmed by selected area electron diffraction (SAED). UV-vis absorption spectrum, recorded after a reaction time of 6h at the heating temperature of 55 degrees C showed a surface plasmon resonance peak at 540 nm. With the increase of reaction time to 24h, the absorption spectrum peaks shift to a very broad and higher wavelength region extending up to near infrared region. Remarkably, these single crystalline gold crystals show auto fluorescence when illuminated to UV lamp. Further increase in beta lactoglobulin amyloid fibrils concentration above the isotropic-nematic transition, drives the formation of gold single crystals microplates stacking together and self-assembling into new hierarchical, layered protein-gold hybrid composites. PMID- 21652048 TI - Head group effects on molecular packing in lamellar liquid crystals. AB - In this study, molecular packing in lamellar liquid crystals in poly(oxyethylene) dodecyl ether(C(12)EO(n)) pure systems and the two surfactant mixtures of C(12)EO(8)/1-dodecanol(C(12)EO(0)), C(12)EO(8)/lipophilic sucrose laurate (L 595), hydrophilic sucrose laurate (L-1695)/C(12)EO(2) is investigated in terms of mean molecular area and partial molecular area (PMA). Lamellar liquid crystals formed in the C(12)EO(8)/C(12)EO(0) mixed system show higher melting temperatures than those in the C(12)EO(n) pure systems, even though the average number of EO units in the mixed surfactant system is the same as in the pure system. We compared the mean molecular area at the interface between hydrophilic and lipophilic moieties in the lamellar liquid crystals in each system. In the mixed system, the molecules are packed more tightly than in the pure system. Among the C(12)EO(n) and sucrose laurate mixtures, the L-1695/C(12)EO(2) mixed system showed a smaller mean molecular area per lipophilic chain than the C(12)EO(8)/L 595 mixed system. We investigated the effect of mixing two surfactants with different head group geometry on molecular packing by comparing the PMA of each surfactant. PMID- 21652050 TI - Effects of the pharmaceuticals gemfibrozil and diclofenac on the marine mussel (Mytilus spp.) and their comparison with standardized toxicity tests. AB - Human pharmaceuticals, like the lipid lowering agent gemfibrozil and the non steroidal anti-inflammatory drug diclofenac are causing environmental concern. In this study, the marine mussel (Mytilus spp.) was exposed by injection to environmentally relevant and elevated (1 MUg/L and 1000 MUg/L) concentrations of both compounds and biomarker expression was observed. Gemfibrozil exposure induced biomarkers of stress (glutathione S-transferase and metallothionein) at both concentrations 24h and 96 h after exposure, respectively. Biomarkers of damage (lipid peroxidation (LPO) and DNA damage) were significantly affected, as well as the biomarker for reproduction, alkali-labile phosphate assay, indicating the potential oxidative stress and endocrine disrupting effect of gemfibrozil. Diclofenac significantly induced LPO after 96 h indicating tissue damage. Additionally standard toxicity tests using the marine species Vibrio fischeri, Skeletonema costatum and Tisbe battagliai showed differences in sensitivity to both drugs in the mg/L range. Results indicate a suite of tests should be used to give accurate information for regulation. PMID- 21652049 TI - Training needs and evaluation of a neuro-HIV training module for non-physician healthcare workers in western Kenya. AB - BACKGROUND: Recent efforts to improve neurological care in resource-limited settings have focused on providing training to non-physician healthcare workers. METHODS: A one-day neuro-HIV training module emphasizing HIV-associated dementia (HAD) and peripheral neuropathy was provided to 71 health care workers in western Kenya. Pre- and post-tests were administered to 55 participants. RESULTS: Mean age of participants was 29 years, 53% were clinical officers and 40% were nurses. Self-reported comfort was significantly higher for treating medical versus neurologic conditions (p<0.001). After training, participants identified more neuropathy etiologies (pre=5.6/9 possible correct etiologies; post=8.0/9; p<0.001). Only 4% of participants at baseline and 6% (p=0.31) post-training could correctly identify HAD diagnostic criteria, though there were fewer mis identified criteria such as abnormal level of consciousness (pre=82%; post=43%; p<0.001) and hallucinations (pre=57%; post=15%; p<0.001). CONCLUSIONS: Healthcare workers were more comfortable treating medical than neurological conditions. This training significantly improved knowledge about etiologies of neuropathy and decreased some misconceptions about HAD. PMID- 21652051 TI - Effect of a single intrauterine administration of recombinant bovine interferon tau on day 7 of the estrous cycle on the luteal phase length and blood profile in dairy cows. AB - This study tested the effect of recombinant bovine interferon-tau (rboIFN-tau) on the length of estrous cycle, luteal lifespan and side effects of rboIFN-tau in the cow. A normal estrous cycle in six non-lactating cycling Holstein cows was observed (non-treated cycle), and either 2.0 mg of liposomalized rboIFN-tau (treated cycle) or bovine serum albumin (BSA; placebo cycle) was infused in the uterus on day 7 of the estrous cycle (day 0=day of ovulation). Rectal temperature, heart rate and respiratory rate were recorded and blood samples were collected before and after the treatments. The length of the estrous cycle and corpus luteum lifespan in rboIFN-tau treated cycles were not significantly different from those of the non-treated and placebo cycles. In contrast, the rboIFN-tau treatment caused a transient increase in rectal temperature and a decrease in the number of peripheral lymphocytes and neutrophils after the treatment. PMID- 21652052 TI - Factors enhancing the control of Buruli ulcer in the Bomfa communities, Ghana. AB - This study examines factors that may enhance the control and holistic treatment of Buruli ulcer in an endemic area of the Ashanti Region in Ghana. A total of 189 Buruli ulcer patients from the Bomfa sub-district were treated at the Global Evangelical Mission Hospital, Apromase-Ashanti, Ghana, from January to December 2005. Diagnosis was based on clinical findings and confirmed by any two positives of Ziehl-Neelson test for acid fast bacilli, polymerase chain reaction and histopathology. Children up to age 14 made up 43.4% of the cases; male: female ratio was 3:2. The mean duration of hospitalization was 77 days and hospital stay was significantly correlated with the time spent at home with the disease prior to admission; also, 76.7% of the cases were late ulcers. Of the 189 patients, 145 (i.e. 76.7%) were treated with antibiotics and surgery which involved excision, skin grafting with or without contracture release. A follow-up survey after the introduction of the psychosocial approach recorded fewer (85) new Buruli ulcer (BU) cases of which, the majority (78.8%, 67) were nodules and only 21.2% (18) were ulcers. Health education plays a major role in the holistic treatment of BU. This paper proposes a further study in other endemic areas on the treatment of BU with emphasis on psychosocial approach for holistic treatment. PMID- 21652053 TI - Elastic surface waves in crystals--part 2: cross-check of two full-wave numerical modeling methods. AB - We obtain the full-wave solution for the wave propagation at the surface of anisotropic media using two spectral numerical modeling algorithms. The simulations focus on media of cubic and hexagonal symmetries, for which the physics has been reviewed and clarified in a companion paper. Even in the case of homogeneous media, the solution requires the use of numerical methods because the analytical Green's function cannot be obtained in the whole space. The algorithms proposed here allow for a general material variability and the description of arbitrary crystal symmetry at each grid point of the numerical mesh. They are based on high-order spectral approximations of the wave field for computing the spatial derivatives. We test the algorithms by comparison to the analytical solution and obtain the wave field at different faces (stress-free surfaces) of apatite, zinc and copper. Finally, we perform simulations in heterogeneous media, where no analytical solution exists in general, showing that the modeling algorithms can handle large impedance variations at the interface. PMID- 21652054 TI - Replication of Varroa destructor virus 1 (VDV-1) and a Varroa destructor virus 1 deformed wing virus recombinant (VDV-1-DWV) in the head of the honey bee. AB - A country-wide screen for viral pathogens in Israeli apiaries revealed significant incidence of deformed wing virus (DWV) and Varroa destructor-1 virus (VDV-1). To understand these viruses' possible involvement in deformed wing syndrome of honey bees, we studied their replication in symptomatically and asymptomatically infected bees qualitatively and quantitatively, using RT-PCR, quantitative real-time RT-PCR, and immunodetection of the major viral capsid protein VP1. We found, for the first time, replication of VDV-1 and/or a VDV-1 DWV recombinant virus in the heads of recently emerged symptomatic bees. These viruses replicated to high copy numbers, yielding the major viral capsid VP1 processed for subsequent assembly of viral particles. Our results clearly distinguished between symptomatic and asymptomatic bees infected with VDV-1 and VDV-1-DWV and suggest the hypothesis that VDV-1, in addition to DWV, may be involved in inducing the deformed wing pathology. Thus VDV-1-DWV recombination may yield virulent strains able to cause overt infections in Varroa-infested bee colonies. PMID- 21652055 TI - Removal and formation of chlorinated triclosan derivatives in wastewater treatment plants using chlorine and UV disinfection. AB - Triclosan, a common antimicrobial agent, may react during the disinfection of wastewater with free chlorine to form three chlorinated triclosan derivatives (CTDs). This is of concern because the CTDs may be photochemically transformed to tri- and tetra-chlorinated dibenzo-p-dioxins when discharged into natural waters. In this study, wastewater influent, secondary (pre-disinfection) effluent, and final (post-disinfection) effluent samples were collected on two occasions each from two activated sludge wastewater treatment plants, one using chlorine disinfection and one using UV disinfection. Concentrations of triclosan and three CTDs were determined using ultra performance liquid chromatography-triple quadrupole mass spectrometry with isotope dilution methodology. Triclosan and the CTDs were detected in every influent sample at levels ranging from 453 to 4530 and 2 to 98 ng L(-1), respectively, though both were efficiently removed from the liquid phase during activated sludge treatment. Triclosan concentrations in the pre-disinfection effluent ranged from 36 to 212 ng L(-1), while CTD concentrations were below the limit of quantification (1 ng L(-1)) for most samples. In the treatment plant that used chlorine disinfection, triclosan concentrations decreased while CTDs were formed during chlorination, as evidenced by CTD levels as high as 22 ng L(-1) in the final effluent. No CTDs were detected in the final effluent of the treatment plant that used UV disinfection. The total CTD concentration in the final effluent of the chlorinating treatment plant reached nearly one third of the triclosan concentration, demonstrating that the chlorine disinfection step played a substantial role in the fate of triclosan in this system. PMID- 21652056 TI - Renal small cell oncocytoma with pseudorosettes A histomorphologic, immunohistochemical, and molecular genetic study of 10 cases. AB - A cohort of a heretofore not described rare subtype of renal oncocytoma, small cell oncocytoma with pseudorosettes is presented. Patients were 6 women and 4 men with ages ranging from 51 to 76 years. The tumors displayed areas composed of small cells ("oncoblasts") featuring scant cytoplasm and small, round monomorphic nuclei. The small cell areas constituted 15% to 60% of the total tumor volume (mean, 28.5%; median, 22.5%). No necrosis or mitotic activity was discerned. All tumors also contained areas composed of characteristic oncocytes comprising 40% to 85% of the total tumor volume. In all cases, a varying number of pseudorosettes were identified. The pseudorosettes were composed of small globules of (periodic acid-Schiff-positive) hyaline basal membrane-like material surrounded by small "oncoblastic" cells. The immunohistochemical profile was variable, including at least focal positivity for AE1-3 (10/10), cytokeratin 7 (7/10), epithelial membrane antigen (10/10), c-kit (6/10), antimitochondrial antigen (MIA;10/10), PAX-2 (9/10), AMACR (racemase;6/10), CD10 (5/10), parvalbumin (8/10), vimentin (6/10), claudin 7 (10/10), and claudin 8 (3/10). No immunoreactivity for carbonic anhydrase 9, HMB-45, S-100A1, and TFE3 was documented. We found no differences in the immunophenotype in the small cell oncocytes/oncoblasts that formed pseudorosettes and those that did not. However, there were differences in the immunohistochemical profile of classic oncocytes and small cell oncocytes/oncoblasts. Using array comparative genomic hybridization, no chromosomal changes were identified in any of the cases examined (n = 3). No numerical changes of chromosomes 7 and 17 were revealed on fluorescence in situ hybridization analysis (n = 3). In conclusion, we herein present the first study on small cell renal oncocytomas with formation of pseudorosettes. This is a rare subtype of oncocytoma, which may, especially on a core biopsy, present differential diagnostic difficulties. The immunohistochemical profile of these tumors is variable and differs in significant respects from that of conventional renal oncocytoma. Awareness of this entity and its immunohistochemical variability should help in distinguishing this rare tumor from malignant tumors with similar (small cell) histomorphologic features. All tumors behaved in a benign fashion during follow-up (mean, 3.1 years; median, 1 year). PMID- 21652057 TI - alpha(1,6)Fucosyltransferase expression is an independent prognostic factor for disease-free survival in colorectal carcinoma. AB - We previously reported that alpha(1,6)fucosyltransferase (Enzyme class 2.4.1.68) activity and expression are increased in colorectal cancer, suggesting a role for this enzyme in tumor development and progression. However, the possible impact of alpha(1,6)fucosyltransferase activity or expression on clinical outcomes in colorectal cancer patients has never been studied. Thus, the present study was conducted to determine the value of alpha(1,6)fucosyltransferase as a prognostic factor for colorectal cancer. alpha(1,6)Fucosyltransferase expression was analyzed using immunohistochemistry in 141 colorectal tumors, and alpha(1,6)fucosyltransferase activity was determined in 39 tumors. A complete standardized follow-up of patients was documented until the end of the observation period of 5 years or patient death. Univariate analysis demonstrated the absence of a correlation between enzyme activity and disease evolution. However, in patients with moderate or strong alpha(1,6)fucosyltransferase expression, a significant decrease in the overall (P = .04) and disease-free (P = .03) survival rates was observed. In addition, when local and distant disease recurrence were considered separately, enzyme expression was found to correlate with local tumor recurrences (P = .01). Furthermore, multivariate analysis showed that alpha(1,6)fucosyltransferase expression has independent value for predicting tumor recurrences and, specifically, local recurrences. These findings suggest that alpha(1,6)fucosyltransferase expression may be a good indicator of poor prognosis in colorectal cancer and, therefore, a helpful tool to choose the most effective treatment. PMID- 21652058 TI - Does human papillomavirus infection imply a different prognosis in vulvar squamous cell carcinoma? AB - BACKGROUND: Two independent pathways in the development of vulvar squamous cell carcinoma (VSCC) have been described, one related to and the other independent of high-risk human papillomavirus (HR-HPV). The aim of our study was to evaluate whether the HPV status has a prognostic significance or can predict response to radiotherapy. METHODS: All VSCC diagnosed from 1995 to 2009 were retrospectively evaluated (n=98). HPV infection was detected by amplification of HPV DNA by PCR using SPF-10 primers and typed by the INNO-LIPA HPV research assay. p16(INK4a) expression was determined by immunohistochemistry. Disease-free and overall survival (DFS and OS) were estimated by Kaplan-Meier analysis with the log-rank test and a multivariate Cox proportional hazard's model. RESULTS: HR-HPV DNA was detected in 19.4% of patients. HPV16 was the most prevalent genotype (73.7% of cases). p16(INK4a) stained 100% HPV-positive and 1.3% HPV-negative tumors (p<.001). No differences were found between HPV-positive and -negative tumors in terms of either DFS (39.8% vs. 49.8% at 5 years; p=.831), or OS (67.2% vs. 71.4% at 5 years; p=.791). No differences in survival were observed between HPV positive and -negative patients requiring radiotherapy (hazard ratio [HR] 1.04, 95% confidence interval [CI] .45 to 2.41). FIGO stages III-IV (p=.002), lymph node metastasis (p=.030), size >= 20 mm (p=.023), invasion depth (p=.020) and ulceration (p=.032) were associated with increased mortality but in multivariated only lymph node metastasis retained the association (HR 13.28, 95% CI 1.19 to 148.61). CONCLUSIONS: HPV-positive and -negative VSCCs have a similar prognosis. Radiotherapy does not increase survival in HPV-positive women. PMID- 21652059 TI - Novel mechanism of reduced proliferation in ovarian clear cell carcinoma cells: cytoplasmic sequestration of CDK2 by p27. AB - OBJECTIVE: Ovarian clear cell carcinoma (CCC) carries a poor prognosis because of its insensitivity to chemotherapy. We previously found an association between reduced proliferation of CCC and chemoresistance; here we investigated the mechanism of the reduced proliferation. METHODS: We assessed cell cycle function by measuring the activity of cyclin-dependent kinases (CDKs) and the protein expression of cyclins, the CDK inhibitors, and p53 in 22 ovarian cancer cell lines and 60 human ovarian cancer specimens. We examined the cellular location of p27, p27 phosphorylated at threonine 157 (p27(Thr157)), and CDK2 protein by confocal microscopy and western blotting. We tested the effect of the inhibitor of phosphatidylinositol-3-kinase (PI3K) and small interfering RNA against p27 (si p27) in two CCC cell lines (RMG-I, SMOV-2). RESULTS: CCC cells had lower CDK2 activity and higher p27 expression than serous adenocarcinoma (SA) cells. Low CDK2 activity correlated with high p27 protein expression. p27(Thr157) sequestered CDK2 in the cytoplasm, but PI3K inhibitor or si-p27 maintained CDK2 in the nucleus and restored its activity. In human specimens, CDK2 was mostly in the cytoplasm and was spatially associated with p27; CDK2 activity was lower in the CCC than in the SA specimens. si-p27 enhanced the cytotoxic effect of cisplatin, doxorubicin, and gemcitabine in both RMG-I cells and SMOV-2 cells. CONCLUSIONS: Reduced CDK2 activity via the cytoplasmic sequestration of CDK2 by p27(Thr157) may contribute to suppression of CCC proliferation. A prospective study is needed to determine whether the cytoplasmic sequestration of CDK2 results in the chemoresistance of CCC. PMID- 21652060 TI - Characterization and short-term storage of Tasmanian devil sperm collected post mortem. AB - The Tasmanian devil is suffering from a severe population decline due to the fatal Devil Facial Tumour Disease (DFTD). The development of assisted reproductive technologies such as AI and long-term sperm storage could facilitate genetic management of captive insurance populations. The aim of this study was to characterise semen samples collected post-mortem, and to develop a suitable diluent for short-term preservation of devil sperm. Low numbers of sperm (1.33 +/ 0.85 * 10(6) sperm per male) were extracted from the epididymides of 17 males. Devil sperm sample characteristics such as concentration and morphology were similar to other dasyurids. The most commonly observed morphological abnormalities were midpiece separation, tail curling, and tail twisting (on the axial plane). Changes in motility occurred throughout the regions of the epididymis with (mean +/- SD) 29.4 +/- 16.8, 46.8 +/- 13.6 and 29.4 +/- 18.1% of sperm exhibiting motility, and 88.9 +/- 11.4, 32.0 +/- 24.3 and 0.1 +/- 0.2% of motile sperm exhibiting forward progressive motility in the cauda, corpus and caput, respectively. Sperm from the cauda and corpus epididymis maintained 31.7 +/- 26.6 and 80.6 +/- 85.9%, respectively, of initial motility after 12 h at 15 degrees C in a TEST yolk buffer diluent. These findings provided new information regarding devil sperm biology and short-term sperm storage; such information is necessary for future development of long-term sperm preservation methods in the Tasmanian devil. PMID- 21652061 TI - Gene expression of WNTs, beta-catenin and E-cadherin during the periimplantation period of pregnancy in pigs--involvement of steroid hormones. AB - WNTs (wingless-type MMTV integration site family, member) are morphogenes considered as important factors taking part in uterus developmental processes and implantation. beta-catenin is a downstream effector of WNTs action within the cell as well as, through E-cadherin, affecting epithelial organization and function. This study was conducted to investigate WNT4, WNT5A, WNT7A, beta catenin (CTNNB1) and E-cadherin (CDH1) gene expression and protein localization in the endometrium during the periimplantation period. Furthermore, the effect of 17beta-estradiol (E(2)) and progesterone (P(4)) on WNTs, CTNNB1 and CDH1 gene expression in the porcine endometrium in vitro was examined. WNT4 protein was localized in the luminal and glandular epithelium as well as in the basal lamina of the uterine mucosa. WNT5A protein was detected only in the luminal epithelium. WNT7A, beta-catenin and E-cadherin protein were identified both in the luminal and glandular epithelial cells, however, WNT7A protein immunoreactivity varied during respective days of estrous cycle and/or pregnancy. Despite unchanged expression of WNT4 mRNA in the endometrium of cyclic and early pregnant pigs, the negative influence of E(2) on WNT4 gene during in vitro experiment was observed. WNT4 and CDH1 gene expression was negatively correlated with blood plasma E(2) and P(4) level in uterine luminal flushings (ULFs) on Day 12 of pregnancy. Expression of WNT5A gene was up-regulated in the endometrium on Day 9 of pregnancy when compared to the respective day of the estrous cycle. A significant decrease of WNT7A gene expression and increase of CDH1 mRNA amount was detected on Day 12 of pregnancy. Overall, the results show the spatial localization of WNT4, WNT5A, WNT7A, beta-catenin and E-cadherin proteins in porcine endometrium during periimplantation period of pregnancy and indicate significant changes of WNT5A, WNT7A and CDH1 gene expression before implantation in the pig. PMID- 21652062 TI - A simple method for producing tetraploid porcine parthenogenetic embryos. AB - The objective was to produce porcine tetraploid parthenogenetic embryos using cytochalasin B, which inhibits polar body extrusion. Porcine cumulus-enclosed oocytes aspirated from antral follicles were cultured for 51 h, and treated with cytochalasin B from 35 h to 42 h after the start of culture. After maturation culture, 74.7% (2074/2775) of oocytes treated with cytochalasin B did not extrude a polar body (0PB oocytes). In contrast, 80.4% (1931/2403) of control oocytes extruded a polar body (1PB oocytes). The 0PB oocytes were electrically stimulated, treated with cytochalasin B again for 3 h, and then cultured without cytochalasin B. Six days after electrical stimulation, 49.8% (321/644) reached the blastocyst stage. The number of cells in these blastocysts derived from 0PB oocytes was significantly lower than that from 1PB oocytes (0PB: 24.9 +/- 10.6; 1PB: 43.0 +/- 17.1; mean +/- SD). A porcine chromosome 1-specific sequence was detected in parthenogenetic 0PB embryos by fluorescence in situ hybridization (FISH) analysis. Typical pronucleus-stage samples derived from 0PB embryos had two pronuclei, each with two signals. In two-cell and blastocyst-stage embryos, four signals were detected in each nucleus derived from 0PB embryos. We inferred that 0PB oocytes, which had a tetraploid number of chromosomes, started to develop as tetraploid parthenotes after electrical stimulation, and that tetraploid status was stably maintained during early embryonic development, at least until the blastocyst stage. PMID- 21652063 TI - Global burden of disease in young people aged 10-24 years: a systematic analysis. AB - BACKGROUND: Young people aged 10-24 years represent 27% of the world's population. Although important health problems and risk factors for disease in later life emerge in these years, the contribution to the global burden of disease is unknown. We describe the global burden of disease arising in young people and the contribution of risk factors to that burden. METHODS: We used data from WHO's 2004 Global Burden of Disease study. Cause-specific disability adjusted life-years (DALYs) for young people aged 10-24 years were estimated by WHO region on the basis of available data for incidence, prevalence, severity, and mortality. WHO member states were classified into low-income, middle-income, and high-income countries, and into WHO regions. We estimated DALYs attributable to specific global health risk factors using the comparative risk assessment method. DALYs were divided into years of life lost because of premature mortality (YLLs) and years lost because of disability (YLDs), and are presented for regions by sex and by 5-year age groups. FINDINGS: The total number of incident DALYs in those aged 10-24 years was about 236 million, representing 15.5% of total DALYs for all age groups. Africa had the highest rate of DALYs for this age group, which was 2.5 times greater than in high-income countries (208 vs 82 DALYs per 1000 population). Across regions, DALY rates were 12% higher in girls than in boys between 15 and 19 years (137 vs 153). Worldwide, the three main causes of YLDs for 10-24-year-olds were neuropsychiatric disorders (45%), unintentional injuries (12%), and infectious and parasitic diseases (10%). The main risk factors for incident DALYs in 10-24-year-olds were alcohol (7% of DALYs), unsafe sex (4%), iron deficiency (3%), lack of contraception (2%), and illicit drug use (2%). INTERPRETATION: The health of young people has been largely neglected in global public health because this age group is perceived as healthy. However, opportunities for prevention of disease and injury in this age group are not fully exploited. The findings from this study suggest that adolescent health would benefit from increased public health attention. FUNDING: None. PMID- 21652064 TI - The global burden of disease in 10-24-year-olds. PMID- 21652065 TI - Targeted delivery of antibiotics to intracellular chlamydial infections using PLGA nanoparticles. AB - Chlamydia trachomatis and Chlamydia pneumoniae are intracellular bacterial pathogens that have been shown to cause, or are strongly associated with, diverse chronic diseases. Persistent infections by both organisms are refractory to antibiotic therapy. The lack of therapeutic efficacy results from the attenuated metabolic rate of persistently infecting chlamydiae in combination with the modest intracellular drug concentrations achievable by normal delivery of antibiotics to the inclusions within which chlamydiae reside in the host cell cytoplasm. In this research, we evaluated whether nanoparticles formulated using the biodegradable poly(d-L-lactide-co-glycolide) (PLGA) polymer can enhance the delivery of antibiotics to the chlamydial inclusion complexes. We initially studied the trafficking of PLGA nanoparticles in Chlamydia-infected cells. We then evaluated nanoparticles for the delivery of antibiotics to the inclusions. Intracellular trafficking studies show that PLGA nanoparticles efficiently concentrate in inclusions in both acutely and persistently infected cells. Further, encapsulation of rifampin and azithromycin antibiotics in PLGA nanoparticles enhanced the effectiveness of the antibiotics in reducing microbial burden. Combination of rifampin and azithromycin was more effective than the individual drugs. Overall, our studies show that PLGA nanoparticles can be effective carriers for targeted delivery of antibiotics to intracellular chlamydial infections. PMID- 21652066 TI - A biofunctionalization scheme for neural interfaces using polydopamine polymer. AB - Chemical surface modification of neuron-surface interfaces is essential for the development of biologically active and functional neural interfaces. Different types of surface modification schemes are required to derivatize either electrode or insulator surfaces, which limits the surface chemistry based neural interface design. Herein, we report a novel and powerful approach for modifying neuron surface interfaces using mussel-inspired polymer ('polydopamine film(polyDA)') for generating effective chemical platforms on both electrode and insulator surfaces simultaneously. We applied polyDAs to common neural interface surfaces (gold, glass, platinum, indium tin oxide, liquid crystal polymer) and subsequently functionalized them by covalently linking biomolecules. The surfaces coated with polyDAs exhibited uniform and reproducible surface properties and they all became neuron-adhesive after linking with poly-D-lysine. In addition, polydopamine-coated microelectrode arrays were readily functional such that spontaneous and evoked neural activities could be recorded from cultured neuronal networks. We have successfully showed that a novel polyDA can be effectively used for the neural interface design. PMID- 21652067 TI - Enhanced MSC chondrogenesis following delivery of TGF-beta3 from alginate microspheres within hyaluronic acid hydrogels in vitro and in vivo. AB - Mesenchymal stem cells (MSCs) are being recognized as a viable cell source for cartilage repair and members of the transforming growth factor-beta (TGF-beta) superfamily are a key mediator of MSC chondrogenesis. While TGF-beta mediated MSC chondrogenesis is well established in in vitro pellet or hydrogel cultures, clinical translation will require effective delivery of TGF-betas in vivo. Here, we investigated the co-encapsulation of TGF-beta3 containing alginate microspheres with human MSCs in hyaluronic acid (HA) hydrogels towards the development of implantable constructs for cartilage repair. TGF-beta3 encapsulated in alginate microspheres with nanofilm coatings showed significantly reduced initial burst release compared to uncoated microspheres, with release times extending up to 6 days. HA hydrogel constructs seeded with MSCs and TGF beta3 containing microspheres developed comparable mechanical properties and cartilage matrix content compared to constructs supplemented with TGF-beta3 continuously in culture media, whereas constructs with TGF-beta3 directly encapsulated in the gels without microspheres had inferior properties. When implanted subcutaneously in nude mice, constructs containing TGF-beta3 microspheres resulted in superior cartilage matrix formation when compared to groups without TGF-beta3 or with TGF-beta3 added directly to the gel. However, calcification was observed in implanted constructs after 8 weeks of subcutaneous implantation. To prevent this, the co-delivery of parathyroid hormone-related protein (PTHrP) with TGF-beta3 in alginate microspheres was pursued, resulting in partially reduced calcification. This study demonstrates that the controlled local delivery of TGF-beta3 is essential to neocartilage formation by MSCs and that further optimization is needed to avert the differentiation of chondrogenically induced MSCs towards a hypertrophic phenotype. PMID- 21652068 TI - First-trimester placental protein 13, PAPP-A, uterine artery Doppler and maternal characteristics in the prediction of pre-eclampsia. AB - OBJECTIVE: To test the hypothesis that a combination of PP13, PAPP-A and first trimester uterine artery Doppler would improve the prediction of pre-eclampsia. METHODS: This is a prospective cohort study of pregnant women followed from the first-trimester to delivery. PP13 and PAPP-A were determined by immunoassay of maternal serum at 11-14 weeks', when uterine artery Doppler measurements were assessed. Cases identified with any form of pre-eclampsia were compared with a control group without pre-eclampsia. The sensitivity of each marker or their combinations in predicting pre-eclampsia for different fixed false positive rates was calculated from the ROC curves. RESULTS: Forty two women were diagnosed with pre-eclampsia and 410 women with pregnancies not complicated by pre-eclampsia were used as controls. For a fixed false positive rate (FPR) of 20%, PP13, PAPP-A and mean uterine artery pulsatility index identified 49%, 58% and 62% respectively, of women who developed any form of pre-eclampsia. PP13 was best in predicting early onset pre-eclampsia with a sensitivity of 79% at a 20% FPR. Combinations of the three first-trimester assessments did not improve the prediction of pre-eclampsia in later pregnancy. CONCLUSION: First-trimester PP13, PAPP-A and uterine artery PI are reasonable, individual predictors of women at risk to develop pre-eclampsia. Combinations of these assessments do not further improve the prediction of pre-eclampsia. PMID- 21652069 TI - Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? AB - The immune system can be harnessed to fight cancer by active (stimulating the patient's intrinsic immune response to cancer) and by passive (transfer of active humoral or cellular immunity) immunotherapy. While for each strategy proof-of principle was provided, clinical benefit was limited likely due to malfunction of lymphocytes. Increasing knowledge of both the mechanism of vaccination through dendritic cells (DCs) and the potency of a subset of natural killer T lymphocytes termed cytokine-induced killer (CIK) cells led to new strategies through combining adoptive and passive immunotherapy. This review summarizes most recent clinical trials indicating that CIK cells can substantially enhance the effect of tumor vaccines and discusses the potential therapeutic benefit in the long-term control of tumor progression. PMID- 21652070 TI - Psychometric properties of a youth self-report measure of neglectful behavior by parents. AB - OBJECTIVE: This study aimed to empirically assess psychometric properties of a multi-dimensional youth self-report measure of neglectful behavior by parents. METHOD: Data were gathered from 593 12-year-old youth participating in the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN) consortium; 272 also had data at age 14. Youth responded to a 25-item measure of their experiences of neglect. Expert raters classified items into 4 factors, followed by confirmatory factor analyses. We evaluated cross group measurement equivalence by gender and longitudinal measurement equivalence from age 12 to age 14. Validity was assessed by the relationships between factor scores and (1) neglect reports to child protective services (CPS), (2) quality of parent-child interactions, and (3) parental monitoring. RESULTS: A 3-factor model (Physical Needs, Emotional Support, and Parental Monitoring) of neglect was obtained, with equivalence across gender and longitudinally (age 12-14). The pattern of correlations between the factor scores, CPS reports, and measures of the parent-child relationship offered modest to moderate support for convergent validity. CONCLUSIONS: The findings suggest a promising and relatively brief youth self-report measure of neglect to help advance research in this area. PMID- 21652071 TI - Caregiver perceptions of sexual abuse and its effect on management after a disclosure. AB - OBJECTIVE: The aim of the study was to examine caregiver management strategies for child sexual abuse (CSA) when presented with hypothetical scenarios that vary in physical invasiveness. METHODS: One hundred fifty three caregivers were given 3 scenarios of CSA with 7 management strategies presented in the 21-item Taking Action Strategies (TAS) scale. Caregivers were asked to rate strategies according to their willingness to carry out each action with rating of 5=greater likelihood of carrying out the action specified while a rating of 1=a lower likelihood of carrying out that action. CSA scenarios included exposure to pornography/masturbation, fondling, and penetration while management strategies including fighting the accused, blaming the child, and outreaching to the authorities. Repeated measures ANOVA was used to compare mean TAS scores for the management strategies across CSA scenarios. RESULTS: The difference between TAS scores across the abuse scenarios was statistically significant (p<.001). Mean TAS scores reflected greater preference for taking action if the abusive act was perceived as more physically intrusive (exposure to pornography/masturbation-TAS 3.5, fondling-TAS 3.7, penetration-TAS 3.8). Caregivers reported being less willing to handle a disclosure of CSA without outreach (TAS 2.5 and 2.0 for fighting and blaming the child, respectively) and more willing to manage a disclosure with outreach to authorities (TAS 3.8, 4.5, and 4.7 for outreaching to Child Protective Services [CPS], to the child's healthcare provider and police, respectively). A predictor of caregiver outreach to authorities identified was the caregiver having past interactions with CPS. CONCLUSION: Perception of the physical invasiveness of CSA and demographic factors can impact caregiver management strategies after a disclosure. PRACTICE IMPLICATIONS: Results suggest that several factors influence caregiver management of sexual abuse. These factors warrant further study, as they are potential contributors to declining trends in CSA cases observed. Other implications include the need for educational efforts targeting caregivers. These interventions should focus on dispelling myths about the perceived physical invasiveness of CSA. These perceptions should not mitigate a caregiver's decision to involve the authorities in their management after a disclosure. Lastly, despite criticisms of the child protective systems, caregivers with past encounters with CPS view these related agencies as valuable resources. PMID- 21652072 TI - Impact of a universal school-based violence prevention program on violent delinquency: distinctive benefits for youth with maltreatment histories. AB - OBJECTIVE: Child maltreatment constitutes a strong risk factor for violent delinquency in adolescence, with cumulative experiences of maltreatment creating increasingly greater risk. Our previous work demonstrated that a universal school based violence prevention program could provide a protective impact for youth at risk for violent delinquency due to child maltreatment history. In this study we conducted a follow-up to determine if participation in a school-based violence prevention program in grade 9 continued to provide a buffering effect on engaging in acts of violent delinquency for maltreated youth, 2 years post-intervention. METHODS: Secondary analyses were conducted using data from a cluster randomized controlled trial of a comprehensive school-based violence prevention program. Students (N=1,722; 52.8% female) from 20 schools participated in 21 75-min lessons in grade 9 health classes. Individual data (i.e., gender, child maltreatment experiences, and violent delinquency in grade 9) and school-level data (i.e., student perception of safety averaged across students in each school) were entered in a multilevel model to predict violent delinquency at the end of grade 11. RESULTS: Individual- and school-level factors predicting violent delinquency in grade 11 replicated previous findings from grade 9: being male, experiencing child maltreatment, being violent in grade 9, and attending a school with a lower perceived sense of safety among the entire student body increased violent delinquency. The cross-level interaction of individual maltreatment history and school-level intervention was also replicated: in non-intervention schools, youth with more maltreatment in their background were increasingly likely to engage in violent delinquency. The strength of this relationship was significantly attenuated in intervention schools. CONCLUSIONS: Follow-up findings are consistent with the buffering effect of the prevention program previously found post-intervention for the subsample of youth with maltreatment histories. PRACTICE IMPLICATIONS: A relative inexpensive school-based violence prevention program that has been shown to reduce dating violence among the whole student body also creates a protective effect for maltreated youth with respect to lowering their likelihood of engaging in violent delinquency. PMID- 21652073 TI - The impact of adverse childhood experiences on an urban pediatric population. AB - OBJECTIVE: The goal of this study was to investigate the adverse childhood experiences (ACEs) in youth in a low-income, urban community. STUDY DESIGN: Data from a retrospective chart review of 701 subjects from the Bayview Child Health Center in San Francisco are presented. Medical chart documentation of ACEs as defined in previous studies were coded and each ACE criterion endorsed by a traumatic event received a score of 1 (range=0-9). This study reports on the prevalence of various ACE categories in this population, as well as the association between ACE score and two pediatric problems: learning/behavior problems and body mass index (BMI)>=85% (i.e., overweight or obese). RESULTS: The majority of subjects (67.2%, N=471) had experienced 1 or more categories of adverse childhood experiences (ACE>=1) and 12.0% (N=84) had experienced 4 or more ACEs (ACE>=4). Increased ACE scores correlated with increased risk of learning/behavior problems and obesity. CONCLUSIONS: There was a significant prevalence of endorsed ACE categories in this urban population. Exposure to 4 or greater ACE categories was associated with increased risk for learning/behavior problems, as well as obesity. PRACTICE IMPLICATIONS: Results from this study demonstrate the need both for screening of ACEs among youth in urban areas and for developing effective primary prevention and intervention models. PMID- 21652074 TI - Screening homeless youth for histories of abuse: prevalence, enduring effects, and interest in treatment. AB - OBJECTIVES: To identify the incidence of self-reported physical and sexual child abuse among homeless youth, the self-perceived effects of past abuse, and current interest in treatment for past abuse among homeless youth with histories of abuse. METHODS: Homeless and street-involved persons aged 18-23 filled out a questionnaire and participated in a structured assessment of histories of abuse, tobacco use and substance abuse. RESULTS: Sixty-four homeless youth in Salt Lake City, Utah completed the study, 43 males and 21 females. Eighty-four percent screened positive for childhood physical and/or sexual abuse occurring before the age of 18; 42% screened positive for both physical and sexual abuse; 72% reported still being affected by their abuse. Among all abuse victims, 44% were interested in treatment for their abuse history and 62% of homeless youth who reported still being affected by their abuse were interested in treatment. Individuals were more likely to be interested in treatment if they were female, had not completed high school or had been previously asked about family dysfunction. Many victims who declined treatment offered spontaneous insight into their decision. Interest in treatment was similar to interest in treatment for other behaviors such as smoking and substance abuse. CONCLUSIONS: Histories of abuse are common among homeless youth. A majority of those reporting a history of abuse are still affected by their abuse. Interest in treatment for a history of abuse was comparable to interest in treatment for other morbidities in the homeless youth population such as tobacco use and substance abuse. Our finding that homeless youth continue to be impacted by their abuse and are interested in treatment should prompt more screening for histories of abuse. PMID- 21652075 TI - PAH concentrations in the moss species Hylocomium splendens (Hedw.) B.S.G. and Pleurozium schreberi (Brid.) Mitt. from the Kielce area (south-central Poland). AB - Forty eight samples of mosses Hylocomium splendens and Pleurozium schreberi from the Kielce area (south-central Poland) were analyzed for seventeen polycyclic aromatic hydrocarbons. The PAH concentrations varied from 558.00 MUg/kg (ppb) to 4457.00 MUg/kg in H. splendens and from 643.00 to 3086.00 MUg/kg in P. schreberi. In both moss species phenanthrene (75.00-732.00 MUg/kg), fluoranthene (101.00 577.00 MUg/kg) and pyrene (68.00-568.00 MUg/kg) predominated, but H. splendens accumulated more PAHs than P. schreberi at eighteen different sites. The highest PAH concentrations were noted at sites located close to the housing estates (sites 1-10) and potential emission sources (e.g. heat and power generating plant "Kielce S.A.") (sites 19-21). The moss samples displayed the diverse ring sequence, but the most prevalent was four>five>three>six. The diagnostic ratios (three+four ring/total PAHs, Flu/Py, Phen/Ant, Phen/Phen+Ant, Flu/Flu+Py, IndPy/IndPy+BghiPe and BaA/BaA+Chr) indicated that coal and petroleum combustion was a principal PAH source in the study area. PMID- 21652076 TI - Tophaceous gout of the spine: case report and review of the literature. AB - Tophaceous gout of the spine is rare. We report here the case of a 68-year-old man with long-standing peripheral gouty arthritis who developed a progressive and painful weakness of the lower extremities. Radiological and histopathological findings confirmed the presence of tophaceous gout of the spine. Also presented is the case history, including the radiological and histopathological findings, and a discussion of the literature. PMID- 21652077 TI - Endothelial keratoplasty: the relationship between donor tissue size and donor endothelial survival. AB - PURPOSE: To determine if donor graft diameter has a relationship with postoperative central endothelial cell density (ECD) and survival in Descemet's stripping automated endothelial keratoplasty (DSAEK). DESIGN: Retrospective, comparative analysis of an interventional case series. PARTICIPANTS: Three hundred thirty-one eyes of 243 patients undergoing DSAEK surgery for Fuchs' endothelial dystrophy without a history of rejection or graft dislocation. METHODS: Descemet's stripping automated endothelial keratoplasty was performed in 331 eyes with Fuchs' dystrophy. After exclusion of confounding variables, postoperative ECD and percentage cell loss was compared for 8.0-mm grafts (n = 154) versus 8.5-mm grafts (n = 165) over a 2-year postoperative period. MAIN OUTCOME MEASURES: Total central ECD and percentage of donor endothelial cell loss as measured by specular microscopy of central ECD. RESULTS: Mean preoperative ECD was 2635 cells/mm(2) for 8.0-mm grafts and 2732 cells/mm(2) for 8.5-mm grafts (P = 0.003). Mean ECD (and percent cell loss from before surgery) was 2011 cells/mm(2) (22.9%) for 8.0-mm grafts and 2078 cells/mm(2) (23.5%) for 8.5-mm grafts at 6 months, 2009 cells/mm(2) (23.3%) and 2113 cells/mm(2) (23.1%) at 1 year, and 2060 cells/mm(2) (23.4%) and 2111 cells/mm(2) (24.3%) at 2 years (P>0.72 for percentage cell loss at all time points). CONCLUSIONS: Descemet's stripping automated endothelial keratoplasty grafts with a diameter of 8.5 mm do not offer a clinical advantage over smaller 8.0-mm grafts for postoperative endothelial cell counts in the first 2 years after surgery. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21652078 TI - Outcomes in 15 patients with conjunctival melanoma treated with adjuvant topical mitomycin C: complications and recurrences. AB - PURPOSE: To report the long-term complications and rate of local recurrence in a cohort of patients with histopathologically confirmed conjunctival melanoma (CM) treated with adjuvant topical mitomycin C (MMC). DESIGN: Retrospective, nonrandomized interventional study. PARTICIPANTS: Fifteen patients with histopathologically confirmed diagnosis of CM treated with topical MMC. METHODS: We identified all patients with histopathologically confirmed diagnosis of CM treated with topical MMC between January 1999 and March 2010. Data extracted from the patients' medical records included demographic, clinical, and histopathologic findings; treatments; long-term complications (>6 months) of MMC therapy; recurrent and metastatic disease; and mortality. MAIN OUTCOME MEASURES: Prevalence of long-term complications of MMC and development of recurrent disease were assessed. RESULTS: Fifteen patients (12 female) received topical MMC a median of 2.8 months (0.37-110.9 months) after the diagnosis of CM. Median age at diagnosis was 62 years (29-82 years), and median length of follow-up was 23.8 months (2.2-130.8 months). Most common complications included injection (n=13), tearing (n=10), irritation (n=9), pain (n=9), and limbal stem cell deficiency with keratopathy (n=4). Twelve patients (80%) experienced at least 1 long-term complication, with failure of resolution of symptoms in 7 of these patients. Local recurrence was associated with longer delay to MMC initiation (2 +/-8.0 vs. 30.8 +/-11 months, P=0.06). Three patients developed metastases. Recurrence was associated with metastatic disease (P=0.001). Exenteration was required in 2 patients, 1 of whom developed metastatic disease and died. CONCLUSIONS: Careful consideration should be given to the use of adjuvant MMC for the treatment of residual intraepithelial disease after the diagnosis of CM given the risk of potential long-term ocular surface toxicities. PMID- 21652079 TI - Intraocular pressure outcome of patients with fluocinolone acetonide intravitreal implant for noninfectious uveitis. AB - PURPOSE: To evaluate the intraocular pressure (IOP) outcomes of patients with noninfectious posterior uveitis treated with a fluocinolone acetonide (FA) intravitreal implant over an 8-year period. DESIGN: Retrospective clinical case series. PARTICIPANTS: Forty-seven eyes of 35 patients. METHODS: Retrospective review of medical records of all patients receiving FA implants between June 2001 and March 2009 was performed. Data were pooled to record visual acuity (VA) and to characterize the incidence and outcome of glaucoma surgical intervention. MAIN OUTCOME MEASURES: Incidence of glaucoma surgery and IOP before and after glaucoma surgical intervention. Visual acuity before and after FA implant placement. RESULTS: Nineteen of 42 eyes (45%) receiving FA implants over the course of the study period required glaucoma surgical intervention. Success of IOP-lowering surgery was achieved in 94%, 94%, and 92% of eyes at 6, 12, and 24 months postoperatively. No patient lost more than 1 line of VA. There was an average 2 line gain of acuity at 3 years after FA implant placement for those patients who underwent IOP-lowering surgery. CONCLUSIONS: Patients receiving FA implants have a significant risk of increased IOP that frequently necessitates glaucoma surgery. Glaucoma surgery, when necessary, offers an effective method to decrease IOP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21652080 TI - Suicide in the United States Air Force: Risk factors communicated before and at death. AB - BACKGROUND: Over the last decade, suicide rates in the U.S. military have steadily increased, resulting in a call for suicide-related research with military populations. The present project aimed to describe and evaluate the communications (i.e., verbally and in suicide notes) of 13 suicide risk factors in the suicide death investigation files of 98 active duty U.S. Air Force (USAF) members. METHODS: Two-hundred thirty-seven suicide death investigation files were coded. Ninety-eight decedents left suicide notes and were included in the current analyses. Descriptive statistics were computed to evaluate the types of risk factors most commonly communicated prior to and at the time of death as well as the medium for their communication. Specifically, verbal and note communications were compared to evaluate which medium decedents most often used to communicate risk factors. Also, the frequency that interpersonal compared to intrapsychic risk factors were communicated was evaluated. RESULTS: Hopelessness (35.7% of cases) and perceived burdensomeness (31.6% of cases) were the risk factors most often communicated in suicide notes but not verbally. Thwarted belongingness (29.6% of cases) was the risk factor most often communicated verbally and in the suicide note. Further, evaluated risk factors were more frequently communicated in suicide notes than verbally. Finally, interpersonal risk factors were more often communicated than intrapsychic risk factors. LIMITATIONS: The validity of the data relies on interviews of decedents' acquaintances and various medical/military records. CONCLUSIONS: Our findings support emphasizing certain risk factors over others in USAF suicide prevention efforts. Further, interpersonal risk factors appeared to be more salient than intrapsychic risk factors in the minds of decedents. PMID- 21652081 TI - Inappropriate prescriptions of antidepressant drugs in patients with subthreshold to mild depression: time for the evidence to become practice. AB - Recent studies indicate that antidepressant drugs are largely ineffective in patients with subthreshold to mild depression when compared to placebo. In spite of this evidence, researchers continue to judge the prescription of antidepressant drugs to patients with subthreshold to mild depression as an adequate treatment, which in turn serves to further reinforce the undifferentiated treatment strategy adopted by clinicians. The present narrative review critically reflects on current research practice and highlights the need for a more differentiated, evidence-based clinical and research practice. PMID- 21652082 TI - The most cited works in major depression: the 'Citation classics'. AB - BACKGROUND: The biomedical literature is growing exponentially, with thousands of articles published each day. While the majority of published papers are of incremental value, every field also has a select, relatively small number of works that have presented important conceptual advances and have had a profound influence. We were interested in identifying such papers in the field of Major Depression. OBJECTIVE: To determine which and what type of articles in the field of Major Depression are citation classics, defined as having received equal to or exceeding 400 citations in the biomedical literature, as a surrogate marker for their impact in the field. METHODS: An online database of research publications was searched using a free, publicly accessible, and downloadable software. The terms "Depression" or "Depressive" were queried in the title of publications with no date restrictions. Out of scope publications not dealing with Major Depression or mood disorders were not considered. RESULTS: 243 citation classics representing the top cited manuscripts (approximately 0.1% of 240,000) in the field of Major Depression were identified. These highly cited works fell into six categories: scales/measures, medical psychiatry, clinical trials/management, mechanisms/translational studies, imaging investigations and epidemiological/population health studies. The journals in which citation classics are published are diverse, but typically are general psychiatric or medical publications. CONCLUSIONS: Despite the size of the field, there is a relatively parsimonious collection of citation classics in the field of Major Depression. These deal primarily with the mechanisms and epidemiology of the disease, with papers dealing with depression management accounting for the fastest growing group of citation classics. PMID- 21652083 TI - Sleep America: managing the crisis of adult chronic insomnia and associated conditions. AB - INTRODUCTION: Chronic insomnia, a public health crisis affecting 10-15% of the U.S. population and costing billions of dollars annually, typically presents with one or more comorbid psychiatric or organic conditions. Historical classification of chronic insomnia as "secondary" to a presenting comorbid condition has resulted in under-recognition and under-treatment of both the insomnia and comorbid condition(s). Though critical in any model of comorbid disease management, chronic insomnia receives little, if any, public policy attention. METHOD: We conducted a systematic review of recent empirical studies, review papers, books, government documents, press releases, advertisements, and articles pertaining to the classification, epidemiology, treatment, and physiology of sleep, insomnia, and comorbid conditions. Data were located primarily through MEDLINE, PsycINFO, SCOPUS, and PUBMED databases. OBJECTIVE AND RESULTS: Our goal was to provide an overview of the systems for classifying insomnia and available epidemiological data, and to review theoretical models regarding the etiology and maintaining factors of chronic insomnia along with research on the complex, bidirectional associations between chronic insomnia and various affective (and other) conditions. CONCLUSIONS: After thorough review of the literature, we propose several public policy measures as an initial step in managing chronic insomnia in the United States. These include introducing a nation-wide multi modal educational and awareness campaign titled "Sleep America;" increasing the availability and demand for behavioral sleep medicine - the initially preferred treatment approach; and increasing the use of monitoring and enforcement activities by regulatory authorities to curtail false and misleading claims by sponsors of supplements or treatments for insomnia. Through the adoption of such measures, we hope to galvanize a national interest in healthy sleep and the evidence-based treatment of chronic insomnia. PMID- 21652084 TI - Comorbidity of delusional disorder with bipolar disorder: report of four cases. AB - BACKGROUND: Although it is accepted that patients with delusional disorder can show co-existing depression, comorbidity with bipolar disorder is not a recognised feature. METHOD: Case report of patients who showed both delusional disorder and mania or hypomania. The patients were examined using lifetime structured psychiatric interview where possible. RESULTS: Four patients are described who met criteria for delusional disorder, with durations ranging from 2 to 15 years, and also experienced one or more episodes of mania or hypomania. LIMITATIONS: Case reports cannot quantify a clinical association. CONCLUSIONS: These cases suggest that there is an association between delusional disorder and affective disorder which goes beyond the occurrence of depressive symptoms in the disorder. PMID- 21652085 TI - Disability weights for suicidal thoughts and non-fatal suicide attempts. AB - BACKGROUND: Although there are disability weights available for a wide range of health states, these do not include suicidality. This makes it difficult to evaluate the severity of suicidality in comparison with other health states. The aim of this study therefore is to estimate disability weights for suicidal thoughts and for mental distress involved in non-fatal suicide attempts. METHODS: A Dutch expert panel of sixteen medical practitioners who were knowledgeable about suicidality estimated disability weights (DWs) for twelve health states by interpolating them on a calibrated Visual Analogue Scale. The DWs for ten of these health states had been estimated in previous studies and were used to determine the external consistency of the panel. The other two concerned health states for suicidal thoughts and non-fatal suicide attempts. The resulting DWs could vary between 0 (best imaginable health state) and 1 (worst imaginable health state). RESULTS: Both internal (Cronbach's alpha = 0.98) and external consistency of the panel were satisfactory. The DWs for suicidal thoughts and non fatal suicide attempts were estimated to be 0.36 and 0.46 respectively. LIMITATIONS: The panel was relatively small, which resulted in broad confidence intervals. CONCLUSIONS: Suicidal thoughts are considered to be as disabling as alcohol dependence and severe asthma. The mental distress involved in non-fatal suicide attempts is thought to be comparable in disability to heroin dependence and initial stage Parkinson's. These results demonstrate the severity of suicidality. PMID- 21652086 TI - GAD is good? Generalized anxiety disorder predicts a superior five-year outcome following an acute coronary syndrome. AB - While differing anxiety disorders have been reported to have quite variable impact on outcome following an acute coronary syndrome (ACS), a recent study quantified generalized anxiety disorder (GAD) as having a distinctly negative impact. We examined anxiety disorder status at baseline for any differential five year impact on cardiac outcome following initial hospitalization for an ACS in 489 subjects. Of those initially assessed, 89% were examined at a five-year review. There were non-significant trends for all non-GAD anxiety disorders to be associated with a worse cardiac outcome. Meeting GAD criteria (both at baseline assessment and over the subjects' lifetime) was associated with a superior five year cardiac outcome, particularly in the sub-set of those experiencing GAD as their only anxiety disorder, and after controlling for depression and medical comorbidities. As our results are at distinct variance with two previous studies specifically examining the impact of GAD on outcome in cardiac patients, we consider methodological and other explanations. We conclude that, if our findings are valid, then they may more reflect GAD patients having a 'constructive worrying' capacity and therefore being more likely to seek help in response to less severe somatic symptoms and to also be more adherent with cardiac rehabilitation programs. PMID- 21652088 TI - More than a surgical mission--pediatric Otolaryngology in Ethiopia. AB - OBJECTIVES: Improving the quality of pediatric healthcare in the developing world poses some formidable challenges. Surgical missions aim to improve the lot of individual children, but do little to alter the wellness of the majority. METHODS: Members of the American Society of Pediatric Otolaryngology (ASPO) are working in coordination with existing programs--universities, mission hospitals and non-governmental organizations--with a focus on public health and education of local physicians. RESULTS: We have completed our first four visits to Ethiopia, teaching, performing surgery and building relationships. CONCLUSIONS: We hope that by moving from the traditional surgical mission format to a long term, integrated educational effort we can enhance otolaryngic care for children in Sub-Saharan Africa. PMID- 21652087 TI - Egg yolk IgY: protection against rotavirus induced diarrhea and modulatory effect on the systemic and mucosal antibody responses in newborn calves. AB - Bovine rotavirus (BRV) is an important cause of diarrhea in newborn calves. Local passive immunity is the most efficient protective strategy to control the disease. IgY technology (the use of chicken egg yolk immunoglobulins) is an economic and practical alternative to prevent BRV diarrhea in dairy calves. The aim of this study was to evaluate the protection and immunomodulation induced by the oral administration of egg yolk enriched in BRV specific IgY to experimentally BRV infected calves. All calves in groups Gp 1, 2 and 3 received control colostrum (CC; BRV virus neutralization Ab titer - VN=65,536; ELISA BRV IgG(1)=16,384) prior to gut closure. After gut closure, calves received milk supplemented with 6% BRV-immune egg yolk [(Gp 1) VN=2048; ELISA IgY Ab titer=4096] or non-immune control egg yolk [(Gp 2) VN<4; ELISA IgY Ab titer<4] twice a day, for 14 days. Calves receiving CC only or colostrum deprived calves (CD) fed antibody (Ab) free milk served as controls (Gp 3 and 4, respectively). Calves were inoculated with 10(5.85)focus forming units (FFU) of virulent BRV IND at 2 days of age. Control calves (Gp 3 and 4) and calves fed control IgY (Gp 2) were infected and developed severe diarrhea. Around 80% calves in Gp 1 (IgY 4096) were infected, but they showed 80% (4/5) protection against BRV diarrhea. Bovine RV-specific IgY Ab were detected in the feces of calves in Gp 1, indicating that avian antibodies (Abs) remained intact after passage through the gastrointestinal tract. At post infection day 21, the duodenum was the major site of BRV specific antibody secreting cells (ASC) in all experimental groups. Mucosal ASC responses of all isotypes were significantly higher in the IgY treated groups, independently of the specificity of the treatment, indicating that egg yolk components modulated the immune response against BRV infection at the mucosal level. These results indicate that supplementing newborn calves' diets for the first 14 days of life with egg yolk enriched in BRV-specific IgY represents a promising strategy to prevent BRV diarrhea. Moreover a strong active ASC immune response is induced in the intestinal mucosa following BRV infection after the administration of egg yolk, regardless the specificity of the treatment. PMID- 21652089 TI - Correlation of cardiovascular risk scores with myocardial high-energy phosphate metabolism. PMID- 21652090 TI - Weight loss in diabetic obese women in comparison to non-diabetic women. PMID- 21652091 TI - Continuous renal replacement therapy: should the cardiologist be able to manage it out of intensive care units? PMID- 21652092 TI - Heart rate variability in the frequency domain in chronic Chagas disease: correlation of autonomic dysfunction with variables of daily clinical practice. PMID- 21652093 TI - Self-rated health predicts adverse events during beta-blocker treatment: the CIBIS-ELD randomised trial analysis. AB - BACKGROUND: Self-rated health (SRH) predicts outcome in patients with heart failure. Beta-blockers are known to improve health-related quality of life and reduce mortality in such patients. We aimed to evaluate the relation between SRH and adverse events during titration of beta-blockers in elderly patients with heart failure. METHODS: The cardiac insufficiency bisoprolol study in the elderly (CIBIS-ELD) is a multicentre, double-blind trial, in which 883 patients aged >= 65 years with chronic heart failure (73 +/- 6 years, 38% women, left ventricular ejection fraction [LVEF] 42% +/- 14%) were randomised to bisoprolol or carvedilol. SRH was assessed at baseline and after 12 weeks, using a 5-grade descriptive scale: excellent, very good, good, fair, and poor. RESULTS: Median SRH at baseline and follow-up was good, but more patients reported fair/poor SRH at baseline (36% vs. 30%, p = 0.012). Women, beta-blocker-naive patients, patients in NYHA class III/IV and those with PHQ-9 score >= 12 were more likely to report fair/poor baseline SRH (p < 0.001 for all). During follow-up, SRH improved in 34% of patients and worsened in 8% (p < 0.001). Adverse events were experienced by 64% patients and 38% experienced > 1 adverse event or serious adverse event, with higher prevalence in lower SRH categories. In a multivariate logistic regression model, SRH, age, distance achieved on the 6-min walk test and LVEF >45% predicted adverse events (p < 0.05 for all). CONCLUSIONS: SRH is an independent predictor of adverse events during titration of beta-blockers and correlates with the proportion and number of adverse events per patient. PMID- 21652094 TI - Subclinical atherosclerosis in a community-based elderly cohort: the Korean Longitudinal Study on Health and Aging. AB - BACKGROUND: Early detection of atherosclerosis in elderly people is important because of high cardiovascular mortality. However, only few studies have evaluated the prevalence of subclinical atherosclerosis in Asian elderly people. We evaluated subclinical atherosclerosis using various methods in a population based cohort study, the Korean Longitudinal Study on Health and Aging (KLoSHA). METHODS: Subjects aged over 65 years without symptomatic chest pain were recruited for the KLoSHA in 2006 by random stratified sampling (439 men and 561 women). Anthropometrics, biochemical parameters, body composition, and abdominal fat by computed tomography (CT) were measured. Multidetector-row cardiac CT for coronary artery calcium score (CACS) and severity of stenosis, and carotid sonography for intima-media thickness (IMT) were used to detect subclinical atherosclerosis. Pulse wave velocity (PWV) and ankle-brachial index (ABI) were also measured. RESULTS: The prevalence of subclinical atherosclerosis defined by coronary stenosis >50%, CACS >100, PWV >9m/s, carotid-IMT >0.8mm, or ABI <0.9 was 17.6%, 28.1%, 37.9%, 39.2%, and 29.6%, respectively. There were significant, but modest correlations among parameters. Although male sex, diabetes mellitus, hypertension, abnormal BMI, and higher insulin resistance were associated with subclinical atherosclerosis, older age was found to be the most robust predictor after controlling for multiple factors. CONCLUSION: Our results suggest that proactive screening with multiple measurements in elderly subjects, particularly in men and those with diabetes mellitus or hypertension, may help to identify asymptomatic patient with atherosclerosis. Further studies exploring the predictive value of diagnostic tools can determine the most appropriate measurement for predicting future cardiovascular events. PMID- 21652095 TI - Long-term retention of aerobic fitness improvements following participation in cardiac rehabilitation. PMID- 21652096 TI - Evidence for a role of advanced glycation end products in atrial fibrillation. AB - BACKGROUND: Recent studies suggested that advanced glycation end-products (AGEs) and their receptor (RAGE) interaction may be promoted by inflammation and oxidative stress. These processes could also contribute to the pathogenesis of atrial fibrillation (AF), but their roles remain poorly defined. We studied the association of AGE-RAGE axis with AF in diabetic and non-diabetic patients, since the axis appears to play a key role in the process. METHODS: Ninety-seven consecutive outpatients were included in this transversal study. Fifty-nine patients were in sinus rhythm (SR) and 38 in permanent AF. Plasma fluorescent AGEs and soluble RAGE (sRAGE) were measured and comparisons between patients with and without AF were performed. A multivariate logistic regression analysis was made to define the independent factors associated with AF. RESULTS: Fluorescent AGEs and sRAGE were higher in AF group (74.9 +/- 25.6 vs. 61.8 +/- 20.1a.u. for fluorescent AGEs, p=0.006; 1714.2 +/- 1105.5 vs. 996.1 +/- 820.7 pg/mL for sRAGE, p=0.001). These differences were specially marked in non-diabetic patients. Both AGEs and sRAGE directly correlated with left atrial dimensions (r=0.496; r=0.536 for atrial area and r=0.491; r=0.511 for atrial volume, for fluorescent AGEs and sRAGE, respectively, p<0.001). In a multivariate analysis, fluorescent AGEs and sRAGE resulted as markers of AF independent of left atrial distension, diabetes and other confounding variables. CONCLUSIONS: AGEs and sRAGE plasma levels were higher in patients with AF, independently of diabetes mellitus, and they positively correlated with atrial dimensions, indicating a role for the AGE-RAGE axis in the arrhythmogenic structural atrial remodelling. PMID- 21652097 TI - Anti-platelet treatments in acute coronary syndrome: simplified network meta analysis. PMID- 21652098 TI - Implantable loop-recorders in myopathic and non-myopathic patients with left ventricular hypertrabeculation/noncompaction. AB - BACKGROUND: Left ventricular noncompaction is associated with arrhythmias. The indication for implantation of devices for primary prophylaxis of sudden cardiac death in noncompaction is controversial, especially for patients without severe systolic dysfunction. The use of implantable loop-recorders to detect arrhythmias has not been reported so far. METHODS: A retrospective analysis of indications and results of implantation of loop-recorders in patients with left ventricular noncompaction. RESULTS: Loop-recorders were implanted in 3 patients with noncompaction and moderately or preserved left ventricular systolic function. The recorders revealed pauses N3 s, leading to pacemaker implantation in one patient, and tachycardia leading to radiofrequency ablation in another patient. In the third patient, no arrhythmias have so far been detected. CONCLUSION: From our limited experience we consider monitoring by a loop-recorder as a useful tool to detect arrhythmias in noncompaction-patients. PMID- 21652100 TI - Toward the nature of ventricular fibrillation from electrophysiological point of view. PMID- 21652099 TI - Ethnic differences in ankle brachial index are present in middle-aged individuals without peripheral arterial disease. AB - INTRODUCTION: To better understand the basis for previously reported ethnic differences in ankle brachial index (ABI), we investigated whether these differences were present in individuals without known peripheral arterial disease (PAD). METHODS: We used data from National Health and Nutrition Examination surveys (NHANES 1999-2004) to determine whether ethnic differences were present in respondents without PAD (1 <= ABI <= 1.3). We assessed whether ethnicity was an independent predictor of ABI and ankle systolic blood pressure (SBP) in linear regression models that adjusted for conventional and novel cardiovascular risk factors. To minimize effects of atherosclerosis on ABI, we studied adults aged <= 60 years, and also repeated our analyses in a subset aged <= 50 years that did not have risk factors for PAD. RESULTS: 3348 participants aged <= 60 years were included in the study. Mean ABI was 1.11 in non-Hispanic Blacks (NHB) and 1.13 in non-Hispanic Whites (NHW) (P < 0.0001). In multivariable linear regression analysis that adjusted for age, gender, ethnicity, smoking, height, diabetes, brachial SBP, dyslipidemia, diabetes, renal function, concurrent cardiovascular disease, and plasma levels of homocysteine, fibrinogen and C-reactive protein, NHB had lower ABI than NHW (beta = -0.03 +/- 0.004, P < 0.00001). Although, NHBs had higher ankle SBP than NHWs (by 5.4 mm Hg), NHBs had a lower mean ankle SBP (beta = -3.663 mm Hg +/- 0.500, P < 0.0001) after adjusting for clinical covariates, including brachial SBP, in multivariable analysis. CONCLUSION: Ethnic differences in ABI are present in middle-aged adults at low risk for peripheral atherosclerosis. PMID- 21652101 TI - Optimal public provision of nursing homes and the role of information. AB - Increasing demand for long-term care poses at least five challenges to the policy maker: (i) How should care be supplied, within a nursing home or within the family? (ii) What level of care should be provided in the different arrangements? (iii) How do the answers relate to the severity of dependence? (iv) How can financial strain be mitigated for families with severely dependent members? (v) What is the role of information constraints for the nature and scope of optimal long-term care policy? We consider a theoretical model of long-term care provision under adverse selection to address these challenges. Our main - and remarkably robust - result is that nursing home care facilitates self selection and mitigates and possibly eliminates distortions in caring levels and transfers. Informational asymmetries may thus lead to care being provided too often within institutions rather than within a family context. PMID- 21652103 TI - Prevalence of staphylococcal enterotoxins, toxin genes and genetic-relatedness of foodborne Staphylococcus aureus strains isolated in the Marmara Region of Turkey. AB - Staphylococcus aureus is a major foodborne pathogen and it has the ability to produce a number of extracellular toxins. We analyzed 1070 food samples obtained from retail markets and dairy farms in the Marmara Region of Turkey for the presence of S. aureus. Out of 147 isolates, 92 (62.6%) were enterotoxigenic. PCR was used to investigate the presence of staphylococcal enterotoxin genes (sea, seb, sec, sed, see, seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq and seu), exfoliative toxin genes (eta and etb) and the toxic-shock syndrome toxin gene (tst). The PCR results showed that 53.3% of the isolates contained staphylococcal enterotoxin-like (SEl) toxin genes (seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq and seu) which were more frequent than classical enterotoxin genes (sea to see). Furthermore, seo, sei, sem, seg, seu and sec were found in 37.0, 32.7, 30.4, 29.3, 29.3 and 27.2% of the isolates, respectively. The tst gene was detected and confirmed by DNA sequencing in 9 isolates. The presence of eta and etb were not found in the isolates. Enterotoxigenic capabilities of isolates with SEA-SEE were investigated by ELISA. Enterotoxigenic S. aureus isolates produced one to three enterotoxins, with the most frequently produced types being enterotoxin A and C. There was a correlation of 72.1% between production of a specific toxin and the presence of the respective genes. PFGE analysis was used to identify genetic-relatedness of enterotoxigenic S. aureus isolates and the results revealed that 13 groups of isolates from different or the same origin that contained the same genes showed 100% homology with indistinguishable band patterns. The other enterotoxigenic isolates showed related band patterns with 72-86% homology in sea-, 61-90% homology in sec-, 80 96% homology in seh-, and 69-96% homology in sep-positive isolates. To our knowledge, this is the first study to examine enterotoxins and related gene contents of S. aureus food isolates in the Marmara Region of Turkey. PMID- 21652102 TI - Development of multiplex loop-mediated isothermal amplification-RFLP (mLAMP-RFLP) to detect Salmonella spp. and Shigella spp. in milk. AB - A multiplex loop-mediated isothermal amplification-RFLP (mLAMP-RFLP) was developed and validated for simultaneous detection of Salmonella strains and Shigella strains in milk. In this system, two sets of LAMP primers were designed to specifically target invA of Salmonella spp. and ipaH of Shigella spp. Under isothermal conditions at 63 degrees C, ladder pattern of DNA bands could be amplified within 60 min in the presence of genomic DNAs of Salmonella strains and Shigella strains, which could be distinguished between Salmonella spp. and Shigella spp. simultaneously based on the different ladder pattern of DNA bands and subsequent restriction enzyme analysis. The overall analysis time was approximately 20 h including the enrichment of the bacterial cells, which greatly saved detection time. The sensitivity of mLAMP was found to be 100 fg DNA/tube with genomic DNAs of Salmonella strains and Shigella strains, comparatively, multiplex PCR was 1 pg DNA/tube. The mLAMP allowed the detection of milk sample artificially contaminated by Salmonella strains and Shigella strains at initial inoculation levels of approximate 5CFU/10 mL. In conclusion, the mLAMP described here can potentially facilitate simultaneous monitoring of Salmonella and Shigella in a large number of food samples, which could be used as a primary screening method and as a supplement to classical detection method. PMID- 21652104 TI - Evaluation of probiotic characteristics of newly isolated Lactobacillus spp.: immune modulation and longevity. AB - In the current study, the probiotic potential of approximately 350 strains of lactic acid bacteria isolated from Korean infant feces and Kimchi was investigated. Common probiotic properties of the bacterial strains, such as acid tolerance, bile tolerance and adhesion to human intestinal epithelial cells (HT 29 cells), were examined. Some strains were found to have immune modulatory and antimicrobial properties. Antagonistic activity against a panel of pathogenic bacteria was found to be strain dependent. To evaluate the immune modulatory activity of the strains, lymphocyte interferon (IFN)-gamma secretion was determined in conjunction with cell proliferation. Some strains of Lactobacillus gasseri, L. fermentum and L. plantarum exhibited increased IFN-gamma levels and lymphocyte proliferation. To evaluate the effects of these immune modulating lactobacilli on host life span, Caenorhabditis elegans was used as an in vivo model. Nematodes that were supplied heat-killed lactobacilli as a food source exhibited obvious differences in life span compared with those fed Escherichia coli OP50. The mean life span (determined as mean percent survival) of worms fed L. plantarum CJLP133 and L. fermentum LA12 was 13.89% and 13.69% greater, respectively, than that of control nematodes after 21 days (P=0.036 and 0.043, respectively). In addition, some of safety profiles, including hemolytic type, gelatin hydration and degradation of urea, were found to be positive. These newly identified lactobacilli hold promise for use as probiotic agents, feed additives and/or in food applications. PMID- 21652105 TI - Oxygenated gasoline release in the unsaturated zone, Part 2: Downgradient transport of ethanol and hydrocarbons. AB - In the event of a gasoline spill containing oxygenated compounds such as ethanol and MTBE, it is important to consider the impacts these compounds might have on subsurface contamination. One of the main concerns commonly associated with ethanol is that it might decrease the biodegradation of aromatic hydrocarbon compounds, leading to an increase in the hydrocarbon dissolved plume lengths. The first part of this study (Part 1) showed that when gasoline containing ethanol infiltrates the unsaturated zone, ethanol is likely to partition to and be retained in the unsaturated zone pore water. In this study (Part 2), a controlled field test is combined with a two-dimensional laboratory test and three dimensional numerical modelling to investigate how ethanol retention in the unsaturated zone affects the downgradient behaviour of ethanol and aromatic hydrocarbon compounds. Ethanol transport downgradient was extremely limited. The appearance of ethanol in downgradient wells was delayed and the concentrations were lower than would be expected based on equilibrium dissolution. Oscillations in the water table resulted in minor flushing of ethanol, but its effect could still be perceived as an increase in the groundwater concentrations downgradient from the source zone. Ethanol partitioning to the unsaturated zone pore water reduced its mass fraction within the NAPL thus reducing its anticipated impact on the fate of the hydrocarbon compounds. A conceptual numerical simulation indicated that the potential ethanol-induced increase in benzene plume length after 20 years could decrease from 136% to 40% when ethanol retention in the unsaturated zone is considered. PMID- 21652106 TI - Microbial physiology-based model of ethanol metabolism in subsurface sediments. AB - A biogeochemical reaction model was developed based on microbial physiology to simulate ethanol metabolism and its influence on the chemistry of anoxic subsurface environments. The model accounts for potential microbial metabolisms that degrade ethanol, including those that oxidize ethanol directly or syntrophically by reducing different electron acceptors. Out of the potential metabolisms, those that are active in the environment can be inferred by fitting the model to experimental observations. This approach was applied to a batch sediment slurry experiment that examined ethanol metabolism in uranium contaminated aquifer sediments from Area 2 at the U.S. Department of Energy Field Research Center in Oak Ridge, TN. According to the simulation results, complete ethanol oxidation by denitrification, incomplete ethanol oxidation by ferric iron reduction, ethanol fermentation to acetate and H(2), hydrogenotrophic sulfate reduction, and acetoclastic methanogenesis: all contributed significantly to the degradation of ethanol in the aquifer sediments. The assemblage of the active metabolisms provides a frame work to explore how ethanol amendment impacts the chemistry of the environment, including the occurrence and levels of uranium. The results can also be applied to explore how diverse microbial metabolisms impact the progress and efficacy of bioremediation strategies. PMID- 21652107 TI - Attenuated phagocytic activity of monocytes in type 2 diabetic Goto-Kakizaki rats. AB - The aim of this study was to determine whether phagocytic activity of leukocytes is altered in type 2 diabetes. Goto-Kakizaki (G-K) rats, a genetic model for type 2 diabetes, and Wistar rats (control) were used to analyze the immunological status of phagocytes. Direct analysis of phagocytes was performed using peripheral whole blood. Phagocytic activity of monocytes induced by Escherichia coli BioParticles was significantly lower in G-K rats than in the control rats, whereas no significant differences in phagocytic activity of granulocytes and lymphocytes were found between G-K and control rats. Monocytes of G-K rats showed significantly lower CD11b/c expression compared with that in monocytes of control rats. However, lipopolysaccharide-stimulated activation of extracellular signal regulated kinase and nuclear factor-kappaB in monocytes was not significantly different between G-K and control rats. Restriction of diet in G-K rats greatly improved their hyperglycemic status, but did not restore the levels of phagocytic activity and CD11b/c expression in monocytes of G-K rats to the levels observed in control rats. The results suggest that the phagocytic activity of monocytes is attenuated in G-K rats and that this attenuation is independent of blood glucose levels and is partly explained by a decrease in CD11b/c expression in G-K rats. PMID- 21652108 TI - [Efficacy of early injection of intravitreal triamcinolone acetonide (IVTA) versus delayed injection for macular edema resulting from retinal vein occlusion]. AB - PURPOSE: To assess the efficacy of early injection of intravitreal triamcinolone acetonide (IVTA) versus delayed injection for macular edema from retinal vein occlusion. METHODS: This was a retrospective monocentric study. Forty-four patients received an IVTA (4 mg) for macular edema resulting from central retinal vein or branch retinal vein occlusion. The patients were assigned to two groups: group 1 consisted of patients who received an IVTA less than 6 weeks after the diagnosis of macular edema, while group 2 consisted of patients who received the injection more than 6 weeks after. All patients underwent a comprehensive ophthalmological examination before the injection and 1, 3, and 6 months after. Each visit included best-corrected visual acuity measurement (BCVA), slit lamp examination, intraocular pressure measurement, fundus examination and central macular thickness (CMT) measurement by OCT. RESULTS: The two groups were comparable in terms of age, sex-ratio, and the percentage of branch retinal vein occlusion (54 and 61% in groups 1 and 2, respectively). In group 1, the BCVA (logMAR) was 0.87 before the IVTA and significantly improved at 1 and 3 months (0.46 and 0.48, respectively; P<0.05) before worsening at the 6-month visit (0.62; P>0.05). The mean CMT was also significantly improved (from 567 MUm before the injection to 276, 307, and 386 MUm at the 1-, 3-, and 6-month visits, respectively) (P<0.05 at 1 and 3 months). In group 2, there were no significant differences in visual acuity at any time point (0.86 before the IVTA, 0.76, 0.76, and 0.78 at the 1-, 3-, and 6-month visits; P>0.05). The CMT was reduced after the injection from 552 MUm to 294, 446, and 456 MUm at the 1-, 3-, and 6-month visits, respectively (P<0.05 at 1 month). CONCLUSION: Patients with macular edema due to retinal vein occlusions, who received a single intravitreal injection of triamcinolone acetate less than 6 months after the diagnosis, displayed both anatomical and functional improvement, whereas patients injected more than 6 weeks after the diagnosis of macular edema showed a CMT reduction but with less improvement in visual acuity. The difference observed at 1 month disappeared after 6 months. PMID- 21652109 TI - [Antibioprophylaxis in ocular surgery: AFSSAPS recommendations]. AB - According to the literature and to the advice of experts, the French Agency for the Safety of Health Products (AFSSAPS) edited recommendations about the antibioprophylaxis in ocular surgery. One goal was to avoid the extensive use of oral and topical fluoroquinolones in antibioprophylaxis, in order to preserve their antibacterial activity for curative treatments of severe eye infections. The medical team decides for the indication and the type of antibioprophylaxis for each patient. A topical antibiotic is recommended for any eye surgery until the etancheity of incisions. Due to the risk of selection of bacterial resistance topical fluoroquinolones are not recommended in this indication. In open eye surgery, an additional antibioprophylaxis is recommended: in cataract surgery, injection in the anterior chamber at the end of the procedure of 1mg of cefuroxime; in other open eye surgeries, only in case of risk factors for endophthalmitis, administration of 500 mg oral levofloxacin tablet 12 hours and two hours before surgery. For ocular punctures and intravitreal injections, only a topical postoperative antibiotic is recommended until healing. PMID- 21652110 TI - [Improve adherence in glaucoma patients: a doctor's duty]. AB - Adherence to treatment through observance and persistence is mandatory to treat any glaucoma patient. Identifying the factors related to nonadherence is therefore crucial. Factors responsible for poor adherence could be related to the patients (doubt, forgetfulness, denial), environmental factors (cost, competing activities, travel, etc.), the treatment regimen (refill, side effects, complexity), and finally the relation with the physician. Physicians should presume that patients have low adherence to their treatment and give clear and precise information about the expected benefits of the treatment, the disease, and its risks of progression. Combined fixed treatments and preservative-free topical treatments should improve adherence and quality of life by simplifying instillation and tolerance of eye drops. PMID- 21652111 TI - [Long-term results of the treatment of optic disc pit associated with serous macular detachment: a review of 20 cases]. AB - INTRODUCTION: The pathogenesis of the macular serous retinal detachment (SRD) associated with congenital optic disc pit remains controversial. The treatment is also discussed. Through this study, which includes the majority of the techniques available, we report our experiment in the treatment of this pathology. PATIENTS AND METHODS: This was a retrospective single-centre study of 20 patients who presented with macular SRD associated with optic disc pit between 1983 and 2009. Various treatments were provided. At the beginning of the study, patients were treated only by juxtapapillary laser photocoagulation. After laser failure then as first-line treatment, laser photocoagulation was associated with intravitreal gas (C3F8) injection with postoperative facedown positioning for 2 weeks. During the past few years, all patients have been systematically treated with vitrectomy with or without internal limiting membrane (ILM) peeling, laser, and gas (C2F6) tamponade. RESULTS: This series consisted of 20 patients: nine men and 11 women. The patients' mean age at presentation was 29 years (range, 9-60 years). The mean time between the onset of the decrease in visual acuity (VA) and treatment was 6.1 months. None of these patients had a posterior vitreous detachment at the time of diagnosis. Six patients were treated by laser photocoagulation alone, which was successful only in two cases. Eleven patients (with laser treatment failure in three) were treated by laser and intravitreal gas injection, with a 72% success rate. We performed vitrectomy with posterior hyaloid dissection, laser, and gas tamponade in eight cases (with laser-gas treatment failure in two) with 87% success rate and no recurrence. Five of these patients had ILM peeling during the vitrectomy. The mean follow-up period was 60 months (range, 2 months to 17 years). CONCLUSION: This study shows that early treatment of macular SRD associated with optic disc pit by vitrectomy, ILM peeling, juxtapapillary photocoagulation, and gas tamponade is followed by good anatomical and functional results. This treatment is superior to the other less invasive procedures. Optical coherence tomography is an important exam for diagnosis and postoperative follow-up of patients. PMID- 21652112 TI - Prevalence of healthcare device-associated infection using point prevalence surveys of antimicrobial prescribing and existing electronic data. AB - This study extended a previously described method for the prevalence of healthcare-associated infection, based on point prevalence surveys of antimicrobial prescribing and electronic data, to estimate the prevalence of device-associated infections. In June 2009, the six-month point prevalence survey of antimicrobial prescribing was carried out in accordance with the European Surveillance of Antimicrobial Consumption Protocol. For patients receiving antimicrobials the presence of devices was recorded. A census on device use was carried out concurrently in the relevant hospitals. We selected patients receiving antimicrobials, started >48h after admission and who had a device, or who were without a device but were receiving antimicrobials for the treatment of bloodstream infection, urinary tract infection, or pneumonia. From existing positive microbiological and radiology reports, these patients were assessed for the presence of device-associated infection according to specified definitions. Of 1354 patients surveyed, 253 (19%) were receiving antimicrobial for treatment; of these, 189 also had devices and 172 (only 13% of all patients surveyed) needed individual assessment for the presence of device-associated infection. It took about 5min per patient to check electronic microbiology and/or radiology reports. Twenty-three patients met the criteria for device-associated infection. The prevalence of catheter-associated urinary tract infection, central-line associated bloodstream infection, local vascular access infection, and ventilator associated pneumonia was 3.9%, 3.1%, 3.8% and 11.6%, respectively. This is a simple method, which can be adopted in other hospitals, to estimate the prevalence of device-associated infection using pre-existing data. PMID- 21652113 TI - Association between risk of bloodstream infection and duration of use of totally implantable access ports and central lines: a 24-month study. AB - BACKGROUND: Prolonged use of totally implantable access ports (APs) and central lines (CLs) has been known to carry a risk of bloodstream infection (BSI), but the safe cutoff day for discontinuing use remains unknown. We performed a receiver operating characteristic (ROC) curve analysis to determine this cutoff. METHODS: A retrospective 24-month study covered a total of 22,481 days of device use. For each day of use, the following findings were recorded: patient age and sex; presence or absence of diabetes mellitus, preexisting sepsis, and renal disease; and occurrence of device-associated BSI. BSI was defined in accordance with the Centers for Disease Control and Prevention's definition of catheter related infection. RESULTS: BSIs occurred in 81 patients with an AP, for a BSI rate of 2.81 cases per 1,000 days of use. Among the 896 patients with a CL, the BSI rate was 5.60 cases per 1,000 days of use. The ROC analysis found a cutoff time of 33 days for APs (median days of use, 48) and 10 days for CLs (median days of use, 20.5). For the total 22,481 days of use, the odds ratio between APs and CLs with respect to BSI was 0.556 (95% confidence interval [CI], 0.256-1.208; P = .138). Days of use beyond the cutoff had an odds ratio of 2.867 (95% CI, 1.823 4.507; P < .001). Among the risk factors, preexisting sepsis had an odds ratio of 7.843 (95% CI, 4.666-13.184; P < .001). CONCLUSION: Use of an AP for more than 33 days and a CL for more than 10 days may carry an increased risk of device associated BSI. These cutoff periods are longer than those expected at the time of device placement and indicate the importance of postplacement care. PMID- 21652114 TI - [Endoscopic and echoendoscopic findings in secondary linitis plastica of the rectum]. AB - Linitis plastica of the rectum consists of intraparietal, subepithelial and circumferential tumoral infiltration of the wall of the rectum leading to a constricted rectum with mural thickening. There is often a delay between symptom onset and diagnosis because this entity mimics a large number of diseases and the findings of endoscopy and conventional biopsies are non-conclusive since the surface mucosa is not usually affected. We present the endoscopic and echoendoscopic findings of two patients with secondary linitis plastica of the rectum. PMID- 21652115 TI - [Severe acute liver failure in a user of drugs of abuse]. PMID- 21652116 TI - [Treatment of refractory hepatic encephalopathy associated with insertion of a transjugular intrahepatic portosystemic shunt through new endovascular techniques: a case report]. AB - Insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is an increasingly used treatment in the management of the complications of portal hypertension. However, one of the complications of this technique is refractory or recurrent hepatic encephalopathy, which poses a difficult clinical problem. We report the case of a patient who underwent TIPS insertion to control bleeding due to esophageal varices. The patient subsequently developed refractory hepatic encephalopathy, requiring reduction of the caliber of the shunt. PMID- 21652117 TI - [Genetic profiles of longevity and healthy cognitive aging in nonagenarians from the Basque Country]. AB - INTRODUCTION: Currently there are notable differences in the aging of individuals in modern populations. While some of them enjoy a long healthy aging, others develop neurodegenerative diseases, such as Alzheimer's disease (AD). Environmental factors are critical, but genetics could explain the differences observed. It has recently been postulated that longevity genes might also be neuroprotective. OBJECTIVES: To assess whether certain genetic variants associated with longevity might have a neuroprotective effect. METHODS: The subjects of this study are people older than 90 years. We will collect sociodemographic and clinical data and multiple assessments, cognitive, functional, anthropometric, nutritional, sensory and physical each participant. In addition, 64 SNPs loci distributed in 13 candidate genes FOXO3, SIRT1, TOMM40, APOE, PICALM, COMT, CETP, CLU, CR1, IL-6, PCK-1, ZNF224 and ACE will be analysed by Taqman array. RESULTS: It is hoped to gain more knowledge about under/over represented alleles in nonagenarians. Furthermore, comparison of the genetic characteristics of nonagenarians with AD with those free of disease will enable links to be seen between certain alleles with protection or the risk of AD. Associated information on the participants will create subgroups showing the interactions between environment and genetic variation in relation to healthy aging and AD. CONCLUSION: The study of the genetic variability of nonagenarians can give us information on the alleles associated with longevity and neuroprotection. PMID- 21652118 TI - [Recurrent acute rhombencephalomyelitis in an adult or neuromyelitis optica? Presentation of a case]. AB - INTRODUCTION: The lack of accepted homogeneous criteria for the definition of some demyelinating diseases makes diagnostic characterization difficult and limits data interpretation and therapeutic recommendations. Recurrent encephalomyelitis (ADE-R) along with borderline cases of neuromyelitis optica (NMO) are especially controversial. OBJECTIVE: To describe the clinical and radiological evolution of an adult-onset ADE-R versus NMO case throughout 9 years of follow-up. PATIENT AND METHODS: Our patient presented with severe symptoms of rhombencephalomyelitis and the cranial and spinal magnetic resonance imaging (MRI) showed large lesions, with gadolinium enhancement in brainstem and spinal cord, correlating with the clinical picture. Infectious aetiology was excluded, IgG index was normal and NMO antibodies were negative. After treatment with intravenous corticosteroids and plasmapheresis, there was excellent recovery in the acute phase. During follow-up, seven relapses have occurred, mainly in the spinal cord, with good recovery and the same symptomatology, albeit with different severity. Immunosuppressive treatment was introduced since the beginning. CONCLUSIONS: Our case shares common features of both ADE-R and NMO, illustrating that diagnostic characterization is not easy in spite of current criteria. PMID- 21652119 TI - [Problematic aspects of the genetic analysis of the specific disorders of the language: FOXP2 as paradigm]. AB - INTRODUCTION: Genetic analysis of specific language disorders is of major interest for both clinical research and linguistic theory. However, the results of this analysis almost always do not show any univocal and compulsory relationships between particular gene mutations and particular disorders or a casual link between the genotype and the phenotype. OBJECTIVES: This paper will review this type of evidence (referring to the "language gene"FOXP2 as a leading example, where possible), try to suggest plausible reasons for such a perplexing output, and ultimately discuss if such reasons really explain the genuine aetiology of these conditions. RESULTS: The key to disentangle and understand the puzzling scenario emerging from the genetic analysis of specific language disorders is to pay attention to the actual role played by genes during ontogeny and, in particular, to the way in which developmental processes are actually regulated: genes are not direct causal agents regarding the emergence of impaired or wild phenotypes, but just one among the diverse types of regulatory factors involved. CONCLUSIONS: When such a complex role as well as development models less focused on the genes are considered, the way in which genetic mutations really contribute to the emergence of these cognitive disorders is quite satisfactorily explained. PMID- 21652120 TI - [Factors associated with dementia caregivers' preference for institutional care]. AB - INTRODUCTION: The prevalence of dementia is growing in Spain, and so is the number of caregivers who are considering the institutionalization of their relatives. The purpose of this study is to identify which variables are associated with caregivers' desire for institutionalization their dementia relatives. PATIENTS AND METHODS: Informal caregivers of 243 individuals suffering from dementia were interviewed. Predisposing variables (sociodemographic and contextual variables), stressors (dementia-related and caregiving-related aspects), appraisals (of circumstances and caregivers' role), resources (personal and community-based resources) and the desire to institutionalize were evaluated. RESULTS: Over half of the caregivers (52.6%) indicated that they had some desire to institutionalize their relatives with dementia. Stepwise regression analysis revealed that caregivers' consideration to institutionalize was associated with being a male caregiver, not being the spouse of the dementia patient, and with a higher consideration and higher use of community-based formal resources (short term nursing home use, adult day care centres and psycho-stimulation). CONCLUSIONS: Assessing and using formal resources outside their homes help caregivers overcome barriers that keep them from considering the institutionalization of their relatives. The difficulty in considering institutionalizing their relatives is more evident among spouses, who have stronger attachments with the dementia patients, especially among females, who probably feel obliged to continue developing caregiver roles because of their gender. PMID- 21652121 TI - [Psychopathological disorders and quality of life in patients with brain infarction]. AB - OBJECTIVES: To study the influence of various factors on the health related quality of life (HRQOL) of patients who have suffered a brain infarction (BI), with special attention to psychopathological disorders (PD). PATIENTS AND METHODS: Prospective observational study on 45 patients admitted due to a BI, evaluated at 4, 12 and 26 weeks of the acute event. Social and demographic data, and medical history were collected; the SF-36 scale was used for the assessment of HRQOL, and the Neuropsychiatric Inventory (NPI), MMSE, Canadian Neurological Scale, Modified Rankin Scale and other instruments for assessing psychopathological, cognitive, neurological and functional status. A linear regression analysis was performed to identify potential predictors of the SF-36 scores at 26 weeks, introducing, as independent variables, medical and psychiatric history, demographic characteristics and the functional, neuropsychological and psychopathological assessments at 4 weeks. RESULTS: Valid predictive models for all the SF-36 domains were obtained, in which a history of pre-morbid depression, higher scores in the NPI and Rankin Scale, and lowest in the Canadian Neurological Scale were the main predictors of a worse HRQOL in the long term. Psychopathology related caregiver's distress (assessed with the NPI) was associated with a lower score in the social function index. CONCLUSIONS: PDs and functional status were the main determinants of HRQOL in patients with BI. PMID- 21652122 TI - Antimicrobial activity of pyrimidinophanes with thiocytosine and uracil moieties. AB - Reactions of pyrimidinophanes with two 6-methylthiocytosine and one 5(6) alkyluracil moieties bridged with each other by polymethylene spacers with methyl or nonyl p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonate and trifluorosulfonate afforded amphiphilic macrocyclic bis-p-toluene-, methane- and trifluorosulfonates. Despite the presence of several reaction centers in the initial pyrimidinophane molecules, protonation and methylation occurred only at the N(1) atom (with quaternization) of the 6-methylthiocytosine moieties. The bacteriostatic and fungistatic activity of the products was estimated. Macrocyclic tosylates exhibit a remarkable selectivity towards Staphylococcus aureus, with MIC values comparable with a reference drug. Bacteriostatic activity of the amphiphilic pyrimidinophanes depends on the size of the macrocycles, and the highest activity corresponds to definite lengths of polymethylene bridges. Besides, the antimicrobial activity of the screened pyrimidine derivatives depends on their topology. While macrocyclic tosylates are more active against bacteria than against fungi, acyclic tosylate with the same structural fragments shows a dramatical decrease of MIC towards mold and yeast with respect to the corresponding macrocycle. It is found that macrocyclic and acyclic tosylates in high dilutions decrease the extracellular lipase activity. PMID- 21652124 TI - Swedish nursing students' experience of aspects important for their learning process and their ability to handle the complexity of the nursing degree program. AB - The aim of the study was to explore nursing students' experiences of aspects important for their learning process and their ability to handle the complexity of the nursing degree program. The study was longitudinal and qualitative based on interviews with nursing students, six women and two men aged 20-36, during their three years of education. In all, seven patterns were found embracing aspects of importance for the students' learning: Having a clear goal, being able to re-evaluate one's ideas, being acknowledged, when the abstract becomes tangible, using one's own experiences as a tool for learning, hovering between closeness and distance regarding one's future profession and handling theory and practice in relation to one another. The results show the importance of providing clinical courses, strongly connected to the theoretical parts of the program and to use reflection and experience-based learning in the nursing program. PMID- 21652123 TI - Conformational study on cyclic melanocortin ligands and new insight into their binding mode at the MC4 receptor. AB - The melanocortin receptors are involved in many physiological functions, including pigmentation, sexual function, feeding behavior, and energy homeostasis, making them potential targets to treat obesity, sexual dysfunction, etc. Understanding the basis of the ligand-receptor interactions is crucial for the design of potent and selective ligands for these receptors. The conformational preferences of the cyclic melanocortin ligands MTII (Ac-Nle(4) c[Asp(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)) and SHU9119 (Ac-Nle(4) c[Asp(5)-His(6)-DNal(2')(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)), which show agonist and antagonist activity at the h-MC4R, respectively, were comprehensively investigated by solution NMR spectroscopy in different environments. In particular, water and water/DMSO (8:2) solutions were used as isotropic solutions and an aqueous solution of DPC (dodecylphosphocholine) micelles was used as a membrane mimetic environment. NMR-derived conformations of these two ligands were docked within h-MC4R models. NMR and docking studies revealed intriguing differences which can help explain the different activities of these two ligands. PMID- 21652125 TI - Nurse students' medication competence--an integrative review of the associated factors. AB - AIM: The aim of this review was to identify factors associated with nurse students' medication competence. BACKGROUND: Registered nurses play an important role in safe and effective medication management. Previous nursing literature has highlighted deficiencies in nurse students' medication competence, yet little is known about specific factors which are associated with their medication competence. METHOD: Integrative literature review. RESULTS: Nineteen articles met the selection criteria for this review. The main competence area the reviewed articles focused on was medication calculation skills of nurse students. However, a total of twelve factors were identified to be associated with nurse students' medication competence. They constitute three main categories: factors associated with individual nurse students' particular circumstances, the clinical learning environment, and the educational institution. Individual factors such as students' attitudes towards mathematics and their self-confidence seem to be associated most strongly with medication competence. CONCLUSION: First, based on this review, the focus in medication competence research has been strongly on nurse students' medication calculation skills. Therefore, in future research and practice, attention needs to be paid to other competency areas as well, such as medication administration and patient medication education skills. Second, overall, only a limited amount of research exists that explores what factors are associated with medication competence. PMID- 21652126 TI - Tongue tremor: a rare initial presentation of essential tremor. AB - Tongue tremor is commonly associated with essential tremor, but rarely presents as an initial finding. Essential tremor is the most common movement disorder and is characterised by 4-12 Hz postural and kinetic tremor, but there is no universally accepted diagnostic criterion. It commonly affects the arms, and to a lesser extent, other regions of the body, and signs and symptoms tend to worsen during emotional or physiological stress. We describe a rare isolated presentation of tongue tremor as a part of essential tremor, its management, and the diagnostic dilemma. To our knowledge isolated tongue tremor as a presentation of essential tremor has not previously been described in maxillofacial publications. PMID- 21652127 TI - Effects of surgical joint destabilization on load sharing between ligamentous structures in the thoracic spine: a finite element investigation. AB - BACKGROUND: In vitro investigations have demonstrated the importance of the ribcage in stabilizing the thoracic spine. Surgical alterations of the ribcage may change load-sharing patterns in the thoracic spine. Computer models are used in this study to explore the effect of surgical disruption of the rib-vertebrae connections on ligament load-sharing in the thoracic spine. METHODS: A finite element model of a T7-8 motion segment, including the T8 rib, was developed using CT-derived spinal anatomy for the Visible Woman. Both the intact motion segment and the motion segment with four successive stages of destabilization (discectomy and removal of right costovertebral joint, right costotransverse joint and left costovertebral joint) were analyzed for a 2000 Nmm moment in flexion/extension, lateral bending and axial rotation. Joint rotational moments were compared with existing in vitro data and a detailed investigation of the load sharing between the posterior ligaments carried out. FINDINGS: The simulated motion segment demonstrated acceptable agreement with in vitro data at all stages of destabilization. Under lateral bending and axial rotation, the costovertebral joints were of critical importance in resisting applied moments. In comparison to the intact joint, anterior destabilization increases the total moment contributed by the posterior ligaments. INTERPRETATION: Surgical removal of the costovertebral joints may lead to excessive rotational motion in a spinal joint, increasing the risk of overload and damage to the remaining ligaments. The findings of this study are particularly relevant for surgical procedures involving rib head resection, such as some techniques for scoliosis deformity correction. PMID- 21652129 TI - Fibrinogen and cardiovascular disease: genetics and biomarkers. AB - Several prospective epidemiological studies and clinical observations provided evidence regarding fibrinogen and coronary artery disease (CAD). Many of these studies firmly correlate fibrinogen with CAD. However, it is uncertain whether this relation is causal or reflects genetic variability and residual confounding by other risk factors. Several polymorphisms on fibrinogen chain genes affect its levels, however only few of the genetic variants are associated with increased cardiovascular risk. As regards the role of fibrinogen in myocardial infarction (MI) studies indicate that genetic variations have at best a modest impact on the process resulting in MI. Therefore, the screening of fibrinogen genes might not be useful for the assessment of the risk of MI. However, the findings that specific genotypes lead to specific differences in fibrinogen levels, but may not be linked to cardiovascular risk, complicates the hypothesis of causality of fibrinogen in the pathogenesis of cardiovascular disease. PMID- 21652128 TI - Kinematic evaluation of the step-up exercise in anterior cruciate ligament deficiency. AB - BACKGROUND: Step-up exercise is one of the most commonly utilized exercises during rehabilitation of patients after both anterior cruciate ligament (ACL) injury and reconstruction. Currently, insurance providers increasingly required a trial of intensified rehabilitation before surgical reconstruction is attempted. The purpose of this study was to investigate whether this "safe" rehabilitation exercise in the setting of ACL deficiency can cause altered knee kinematics. METHODS: Thirty patients with unilateral ACL rupture were recruited for this study. The mean time from injury was 3.3 months. Tibiofemoral kinematics were determined during a step-up exercise using a combination of magnetic resonance imaging (MRI), dual fluoroscopy and advanced computer modeling. FINDINGS: The ACL injured knee displayed an average 5 degrees greater external tibial rotation than the uninjured knee (P<0.05), during the last 30% of step-up. The ACL-injured knee also demonstrated on average 2.5 mm greater anterior tibial shift during the last 40% of stance phase (P<0.01). In addition, during the last 30% of stance the tibia of the ACL-deficient knee tended to shift more medially (~1 mm) as the knee approached full extension (P<0.01). INTERPRETATION: The data confirmed the initial hypothesis as it was found that ACL deficient knees demonstrated significantly increased anterior tibial translation, medial tibial translation and external tibial rotation toward the end of the step-up as the knee approached full extension. Intensive rehabilitation utilizing the step-up exercise in the setting of ACL deficiency can potentially introduce repetitive microtrauma by way of altered kinematics. PMID- 21652130 TI - Leriche's syndrome and thoracic aortic mural thrombus. PMID- 21652131 TI - Failed percutaneous closure of a mitral prosthesis paravalvular leak. PMID- 21652132 TI - [Cardiac malformations in patients with pentalogy of Cantrell and ectopia cordis]. AB - We studied 21 patients who presented with a diagnosis of pentalogy of Cantrell. Their mean age was 40 days. All patients presented with congenital heart disease. Six presented with ectopia cordis. Every patient was subjected to echocardiography. Double outlet right ventricle, an atrial septal defect and dextrocardia were seen in 5 patients (24%). Four patients survived. Seventeen died, 12 from sepsis or septic shock. Autopsies were performed on 10 patients. All of the ectopia cordis patients died. Pentalogy of Cantrell is uncommon, and its association with ectopia cordis indicates poor prognosis. Full English text available from: www.revespcardiol.org. PMID- 21652133 TI - Impact of new criteria for anticoagulant treatment in atrial fibrillation. AB - INTRODUCTION AND OBJECTIVES: The guidelines for the management of atrial fibrillation (AF) incorporate new risk factors for thromboembolism, trying to de emphasize the use of the 'low', 'moderate', and 'high' risk categories. The objective of this study was to determine the impact of the new scheme CHA2DS2 VASc and of the new recommendations for oral anticoagulation (OAC) in a contemporary sample of patients with AF seen by primary physicians and cardiologists. METHODS: Multicenter, observational, cross-sectional study on the epidemiology of hypertension and its control, designed by the arterial hypertension department. Each researcher enrolled the first 6 consenting patients who came for examination during a 5-day period. RESULTS: Of 25 137 individuals recruited, 1544 were diagnosed with AF. The vast majority of the sample had a CHADS2 score >=2 (77.3%). Individuals with a risk score lower than 2 were categorized according to the CHA2DS2-VASc score: 14.4% were aged 75 years or older (CHA2DS2-VASc=2). Of those younger than 75, 42.3% had a CHA2DS2-VASc=2; 23.7% CHA2DS2-VASc=3, and 1.1% CHA2DS2-VASc=4. This means that the 85.1% of the patients with a CHADS2 score <2 and no contraindications are indicated for OAC. CONCLUSIONS: The new recommendations will result in a significant increase in patients with indications for OAC, at the expense of those previously characterized as low-to-moderate risk. Therefore, patients at risk of thromboembolic events must be identified, although an evaluation of bleeding risk should be part of the patient assessment before starting anticoagulation. PMID- 21652134 TI - Comparative study of ambient air particles in patients hospitalized for heart failure and acute coronary syndrome. AB - INTRODUCTION AND OBJECTIVES: Currently air pollution is considered as an emerging risk factor for cardiovascular disease. Our objective was to study the concentrations of particulate matter in ambient air and analyze their relationship with cardiovascular risk factors in patients admitted to a cardiology department of a tertiary hospital with the diagnosis of heart failure or acute coronary syndrome (ACS). METHODS: We analyzed 3950 consecutive patients admitted with the diagnosis of heart failure or ACS. We determined the average concentrations of different sizes of particulate matter (<10, <2.5, and <1 MUm and ultrafine particles) from 1 day or up to 7 days prior to admission (1 to 7 days lag time). RESULTS: There were no statistically significant differences in mean concentrations of particulate matter <10, <2.5 and <1 MUm in size in both populations. When comparing the concentrations of ultrafine particles of patients admitted due to heart failure and acute coronary syndrome, it was observed that the former had a tendency to have higher values (19 845.35 +/- 8 806.49 vs 16 854.97 +/- 8005.54 cm-3, P <.001). The multivariate analysis showed that ultrafine particles are a risk factor for admission for heart failure, after controlling for other cardiovascular risk factors (odds ratio=1.4; confidence interval 95%, from 1.15 to 1.66 P=.02). CONCLUSIONS: In our study population, compared with patients with ACS, exposure to ultrafine particles is a precipitating factor for admission for heart failure. PMID- 21652135 TI - [Impact of malnutrition on long-term mortality in hospitalized patients with heart failure]. AB - INTRODUCTION AND OBJECTIVES: The prevalence of malnutrition among patients with heart failure and the role it might play in prognosis is not currently known. The aim of this study was to analyse the prevalence and risk of malnutrition as well as its possible influence on long-term mortality in patients with heart failure. METHODS: A prospective analysis was conducted on 208 patients discharged consecutively from our centre between January 2007 and March 2008 after being hospitalised with heart failure. Before discharge, a complete nutritional assessment was performed and diagnosis of malnutrition and risk of malnutrition was done with the Mini Nutritional Assessment. Its possible independent association with mortality was assessed by a Cox multivariate analysis. RESULTS: The mean age of the patients was 73 +/- 10 years, with 46% women; the most common aetiology of heart failure was ischaemia (41%). In addition, 13% were classified as malnourished, 59.5% at risk of malnutrition and 27.5% were well-nourished. At a median follow-up of 25 months, mortality in the three groups was 76%, 35.9% and 18.9%, respectively (log-rank, P<.001). In the Cox multivariate analysis, the malnutrition state was an independent predictor of mortality (hazard ratio 3.75, 95% confidence interval, 1.75-8.02, P=.001). CONCLUSIONS: Malnutrition and the risk of malnutrition are highly prevalent in patients hospitalised for heart failure. Furthermore, we found that the state of malnutrition as defined by the Mini Nutritional Assessment survey is an independent predictor of mortality in these patients. PMID- 21652136 TI - Early cardiopulmonary resuscitation and use of Automated External Defibrillators by laypersons in out-of-hospital cardiac arrest using an SMS alert service. AB - AIM: To evaluate an SMS service (SMS=short message service=text message) with which laypersons are alerted to go to patients with suspected out-of-hospital cardiac arrest and perform early cardiopulmonary resuscitation (CPR) and use an Automated External Defibrillator (AED). This study is the first to report on a program in which an emergency medical service (EMS) is able to alert citizens by sending them SMS messages on their mobile phone. METHODS: Web-based questionnaires were completed by laypersons who were sent an alert by the AED Alert system between February 1, 2010 and April 30, 2010. Questions concerned the process of training, receiving alerts, actions taken and follow-up care. RESULTS: AED-Alert was activated for 52 patients suspected of cardiac arrest, sending 3227 alerts to 2287 laypersons. Out of 2168 eligible laypersons 1679 (77%) completed 2098 questionnaires, one for each alert. Action was taken in only 579 alerts. Laypersons were not in the patient's vicinity (41%), noticed alerts too late (35%), or other reasons (24%). In 298 alerts laypersons faced problems with retrieving AEDs (51%), finding addresses (29%), traffic (5%), or other (15%). Aid was provided in 75 alerts, involving 47 patients. Laypersons started early CPR and defibrillation (49%), assisted EMS personnel (52%), or took care of family (39%). Laypersons arrived before EMS personnel in 21 patients, started CPR and defibrillation in 18, and assisted EMS personnel in 9 patients. CONCLUSION: Improvements of the SMS alert service by laypersons, the EMS, and through technical adjustments, could increase the number of laypersons who provide early aid. PMID- 21652137 TI - Macrolide allergy: which tests are really useful? PMID- 21652138 TI - T-cell proliferation by surface molecules expression on polymorphonuclear neutrophils stimulated with IL-4 in superantigen presence. AB - BACKGROUND: Polymorphonuclear neutrophils (PMNs) were originally described as short lived and terminally differentiated phagocytes that contribute only to the innate immune response. Some studies of PMNs cytokine production and expression of numerous cell surface proteins has suggested that PMNs are likely to influence adaptive responses and may satisfy the criteria of antigen presenting cells. AIM OF THE STUDY: This work aimed to study the effect of IL-4 in the function of PMNs as antigen presenting cells. METHODS: Flow cytometry was used in the present study for the detection of cell surface human leukocyte antigen (HLA) class II, CD80 and CD86 required for antigen presentation and subsequent T-cell activation in the presence of Staphylococcus aureus enterotoxin (A). Human peripheral blood neutrophils were used for this purpose. RESULTS: This study has shown that IL-4 stimulated PMNs for 24h expressed HLA class II, CD80 and CD86 that involved in antigen presentation. It also indicated that co-cultivation of IL-4 stimulated PMNs with autologous T-cells and in the presence of S. aureus enterotoxin (A) induced T-cell proliferation. CONCLUSIONS: In vitro stimulation of PMNs with IL-4 showed expression of surface molecules involved in antigen presentation. In addition, the co-culture of T-Cells and stimulated PMNs showed high T-Cells proliferation in the presence of superantigens. PMID- 21652139 TI - Computational strategy for tuning spectral properties of red fluorescent proteins. AB - Computational methods of quantum chemistry are used to characterize structures and vertical excitation energies of the S(0)-S(1) optical transitions in the chromophore binding pockets of the red fluorescent proteins DsRed and of its artificial mutant mCherry. As previously shown, optimizing the equilibrium geometry configurations with B3LYP density functional theory, followed by ZINDO calculations of the electronic excitations, yields positions of the optical bands in good agreement with experimental data. These large scale quantum calculations elucidate the role of the hydrogen bonded network as well as point mutations in the absorption spectra of the DsRed and mCherry proteins. The effect of an external electric field applied to the fluorescent protein chromophores is examined and shows that such fields may result in large shifts in spectral bands. These strategies can be applied for rational design of the fluorescent proteins by site-directed mutagenesis. PMID- 21652140 TI - Resolution of localized small molecule-Abeta interactions by deep-ultraviolet resonance Raman spectroscopy. AB - The mechanism by which flavonoids prevent formation of amyloid-beta (Abeta) fibrils, as well as how they associate with non-fibrillar Abeta is still unclear. Fresh, un-oxidized myricetin exhibited excitation and emission fluorescence maxima at 481 and 531 nm, respectively. Introduction of either Abeta(1-42) or Abeta(25-40) resulted in a fluorescence decrease, when measured at 481 nm, suggesting formation of a myricetin-Abeta complex. Circular dichroism (CD) and ultraviolet resonance Raman (UVRR) studies indicate that the association of myricetin with the Abeta peptide or its hydrophobic fragment, Abeta(25-40), leads to subtle changes in each peptide's conformation. Abeta(25-40) formed amyloid fibrils at a similar rate, when compared to the full-length peptide, Abeta(1-42), using thioflavin T (ThT) fluorescence. Studies also indicated that myricetin was equally effective at preventing the formation of both Abeta(1-42) and Abeta(25 40) fibrils. Although ThT assays indicated that Abeta(1-16) did not form amyloid fibrils, CD studies of the hydrophilic fragment, Abeta(1-16), suggest possible interactions between myricetin and aromatic side chains. UVRR studies of the full length peptide and Abeta(1-16) showed increases in the intensity of the aromatic modes upon introduction of myricetin. Our findings suggest that myricetin interacts with soluble Abeta via two mechanisms, association with the hydrophobic C-terminal region and interactions with the aromatic side chains. PMID- 21652141 TI - Occurrence of high-tonnage anionic surfactants in Spanish sewage sludge. AB - Agricultural application has become the most widespread method of sewage sludge disposal, being the most economical outlet for sludge and also recycling beneficial plant nutrients and organic matter to soil for crop production. As a matter of fact, the European Sewage Sludge Directive 86/278/EEC seeks to encourage the disposal of sewage sludge in agriculture applications and regulate its use to prevent harmful effects on the soil environment. At the present time, the sewage sludge Directive is under revision and a possible cut-off limit for some organic chemicals may be implemented. Linear alkylbenzene sulphonate (LAS), the main synthetic anionic surfactant, has been included in the draft list of chemicals to be limited. The present research work deals with the monitoring of LAS and soap in Spanish sewage sludge. The average concentration of LAS found in anaerobic sewage sludge samples was 8.06 g/kg, higher than the average values for European sludge. Besides, it has been also found that more than 55% of Spanish anaerobic sludge would not fulfil the limit proposed by the 3rd European Working paper on sludge. As a consequence, the implementation of the limit for LAS would make the disposal of most Spanish biosolids for agricultural applications almost impossible. Regarding the mechanisms why anionic surfactants are found in sludge, two surfactants are compared: LAS and soap, both readily biodegraded in aerobic conditions. Irrespective of the anaerobic biodegradability of soap, its concentration found in sludge is higher than LAS (only anaerobically biodegradable under particular conditions). The relevance of anaerobic biodegradation to assure environmental protection is discussed for this case. PMID- 21652142 TI - Water quality requirements for sustaining aquifer storage and recovery operations in a low permeability fractured rock aquifer. AB - A changing climate and increasing urbanisation has driven interest in the use of aquifer storage and recovery (ASR) schemes as an environmental management tool to supplement conventional water resources. This study focuses on ASR with stormwater in a low permeability fractured rock aquifer and the selection of water treatment methods to prevent well clogging. In this study two different injection and recovery phases were trialed. In the first phase ~1380 m(3) of potable water was injected and recovered over four cycles. In the second phase ~3300 m(3) of treated stormwater was injected and ~2410 m(3) were subsequently recovered over three cycles. Due to the success of the potable water injection cycles, its water quality was used to set pre-treatment targets for harvested urban stormwater of <= 0.6 NTU turbidity, <= 1.7 mg/L dissolved organic carbon and <= 0.2 mg/L biodegradable dissolved organic carbon. A range of potential ASR pre-treatment options were subsequently evaluated resulting in the adoption of an ultrafiltration/granular activated carbon system to remove suspended solids and nutrients which cause physical and biological clogging. ASR cycle testing with potable water and treated stormwater demonstrated that urban stormwater containing variable turbidity (mean 5.5 NTU) and organic carbon (mean 8.3 mg/L) concentrations before treatment could be injected into a low transmissivity fractured rock aquifer and recovered for irrigation supplies. A small decline in permeability of the formation in the vicinity of the injection well was apparent even with high quality water that met turbidity and DOC but could not consistently achieve the BDOC criteria. PMID- 21652143 TI - Quantification of uncertainty of experimental measurement in leaching test on cement-based materials. AB - When mineral wastes are reused in construction materials, a current practice is to evaluate their environmental impact using standard leaching test. However, due to the uncertainty of the measurement, it is usually quite difficult to estimate the pollutant potential compared to other materials or threshold limits. The aim of this paper is to give a quantitative evaluation of the uncertainty of leachate concentrations of cement-based materials, as a function of the number of test performed. The relative standard deviations and relative confidence intervals are determined using experimental data in order to give a global evaluation of the uncertainty of leachate concentrations (determination of total relative standard deviation). Various combinations were realized in order to point out the origin of large dispersion of the results (determination of relative standard deviation linked to analytical measured and to leaching procedure), generalisation was suggested and the results were compared to literature. An actual example was given about the introduction of residue (meat and bone meal bottom ash--MBM-BA) in mortar, leaching tests were carried out on various samples with and without residue MBM-BA. In conclusion large dispersion were observed and mainly due to heterogeneity of materials. So heightened attention needed to analyse leaching result on cement-based materials and further more other tests (e.g. ecotoxicology) should be performed to evaluate the environmental effect of these materials. PMID- 21652144 TI - Bowel function remains subjectively unchanged after ileal resection for construction of continent ileal reservoirs. AB - BACKGROUND: Construction of a continent catheterizable urinary reservoir or an orthotopic bladder substitute requires substantial bowel resection, which can cause changes in bowel transit time. The reported incidence of chronic diarrhea after ileocecal resection is about 20%. Studies assessing bowel function after resection of 55-60 cm of ileum without compromising the ileocecal valve are scarce, and long-term results have not been reported. OBJECTIVE: Prospective assessment of possible changes in bowel function (eg, stool frequency, diarrhea) and the potential impact on quality of life in patients with resection of small bowel for urinary diversion. DESIGN, SETTING, AND PARTICIPANTS: A total of 82 patients who underwent radical cystectomy, extended lymph node dissection, orthotopic ileal bladder substitution, or heterotopic continent cutaneous urinary diversion with a follow-up >1 yr after surgery were prospectively evaluated. Patients who had a neurogenic bladder disorder, had undergone previous radiotherapy, or had not completed the questionnaire were excluded from the study. The validated Gastrointestinal Quality of Life Index was completed by the patients preoperatively and at 3, 12, and 24 mo postoperatively. Five points concerning bowel function (frequent bowel movement, urgent bowel movement, diarrhea, constipation, or uncontrolled stool loss) were assessed, and the median scores were compared pre- and postoperatively. RESULTS AND LIMITATIONS: Most patients (>= 80%) were rarely or never troubled by frequent or urgent bowel movements, diarrhea, constipation, or uncontrolled stool loss preoperatively. In the case of stool frequency, a remarkable shift from rarely to never was observed postoperatively at 3, 12, and 24 mo. Scores for constipation and uncontrolled stool loss remained unchanged throughout the whole time period. For urgent bowel movements the median preoperative score of 4 decreased to 3 at 3 mo and 12 mo and returned to 4 at 24 mo. For diarrhea the preoperative score of 4 decreased to 3 at 3 mo and 24 mo and remained at 4 after 12 mo. CONCLUSIONS: No relevant changes in bowel movements were found after resection of 55-60 cm of ileum if the terminal ileum and the ileocecal valve were left intact. PMID- 21652145 TI - Three-year postoperative ultrasensitive prostate-specific antigen following open radical retropubic prostatectomy is a predictor for delayed biochemical recurrence. AB - BACKGROUND: Prostate-specific antigen (PSA) is the only independent predictor of biochemical recurrence (BCR) following radical prostatectomy (RP) subject to change over time. OBJECTIVE: To determine whether an ultrasensitive PSA measured at 3 yr following RP is a predictor of subsequent BCR. DESIGN, SETTING, AND PARTICIPANTS: There were 1197 consecutive men with clinically localized prostate cancer who underwent an open radical retropubic prostatectomy (ORRP) at a tertiary referral academic medical center. Exclusions included 107 men (8.9%) who developed a PSA level >= 0.2 ng/ml or underwent hormone therapy or radiation therapy (RT) within the first 3 r after surgery, 191 men (16%) who did not undergo a 3-yr ultrasensitive PSA assay, and 98 men (8.2%) who had PSA levels >= 0.1 and <0.2 at 3 yr. The remaining 801 men were stratified into two groups based on their ultrasensitive PSA level at 3 yr postoperatively: group 1, which consisted of patients whose PSA was <= 0.04 (n = 765), and group 2, which consisted of patients whose PSA was >0.04 and <0.10 (n = 36). MEASUREMENTS: Delayed BCR was the primary end point and represented those men in this cohort who developed a PSA level >= 0.2 or underwent salvage RT for a persistently rising PSA level after 3 yr of follow-up. RESULTS AND LIMITATIONS: The 7-yr cumulative BCR-free survival rate for groups 1 and 2 was 0.957 (95% confidence interval [CI], 0.920-0.978) and 0.654 (95% CI, 0.318-0.855), respectively. In multivariable Cox proportional hazards models, ultrasensitive PSA level at 3 yr remained the only significant predictor of delayed BCR (likelihood ratio chi(2) for full model: 27.03; df = 1; p < 0.001). A limitation of the study is that no uniform PSA assay was obtained. CONCLUSIONS: Our findings provide compelling evidence that an ultrasensitive PSA at 3 yr following RP provides useful insights into delayed BCR and is a source of reassurance for the overwhelming majority of men being followed for delayed recurrences. PMID- 21652146 TI - Loss of 10q26.1-q26.3 in association with 7q34-q36.3 gain or 17q24.3-q25.3 gain predict poor outcome in pediatric medulloblastoma. AB - Medulloblastoma (MB) is the most common malignant brain tumor of childhood. We have investigated for novel chromosomal imbalances and prognostic markers of pediatric MB. Forty MBs out of 64, were analyzed using high resolution prometaphase comparative genomic hybridization. Chromosome 10q26.1-q26.3 loss combined with 17q24.3-q25.3 gain and/or 7q34-q36.3 gain in tumors predicted poor patient's survival. A minimal deleted region of 14.12cM at 10q26.1-q26.3 was refined by LOH analysis. We propose a new prognostic marker for pediatric MB patient risk stratification based on the presence of 10q26.1-q26.3 loss plus 17q24.3-q25.3 gain and/or 7q34-q36.3 gain associations. PMID- 21652147 TI - Dual inhibition of 5-LOX and COX-2 suppresses esophageal squamous cell carcinoma. AB - COX-2 and 5-LOX are up-regulated in ESCC. This study aims to determine the efficacy of COX-2 inhibitor, 5-LOX inhibitor and their combination on ESCC. Nimesulide can suppress cell growth and promote apoptosis, accompanied with a decrease of PGE(2) production. AA861 has the similar effect with a down regulation of LTB(4). In animal experiment, the tumor volumes in drug-treated groups were significantly smaller with the lowest rates of Ki-67 positive cells. In conclusion, either COX-2 inhibitor or 5-LOX inhibitor can suppress ESCC. Dual inhibition of COX-2 and 5-LOX pathway may present a superior anticancer efficacy to either inhibition of COX-2 or 5-LOX alone. PMID- 21652148 TI - Is adjuvant radiotherapy needed after curative resection of extrahepatic biliary tract cancers? A systematic review with a meta-analysis of observational studies. AB - BACKGROUND: The role for adjuvant radiotherapy (ART) after curative resection in extrahepatic cholangiocarcinoma remains unclear. Due to the lack of randomized trials, available data comes from single center experiences or data-based population studies with inconclusive results. OBJECTIVE: To assess the impact of radiotherapy (with or without concurrent chemotherapy) on toxicity and survival of radically resected patients with extrahepatic bile duct cancer (extrahepatic cholangiocarcinoma, gallbladder cancer and pure ampullary cancer). DATA SOURCES AND STUDY SELECTION: Eligible studies with data on survival, recurrence and toxicity were retrieved from the MEDLINE, ISI web of science, EMBASE and Cochrane databases from January 1995 to December 2008, to ensure that all ART treatments were performed with conventional 3D techniques. In the absence of randomized controlled-studies, all observational cohort studies (longitudinal and historical) were initially considered. Ten retrospective cohort studies (where the use of concurrent CT was reported only in 2), met all inclusion criteria and were enrolled for final meta-analysis. Hazard ratio (HR) had to be extracted from survival curves using the Tierney et al. methods. MIX 1.7 statistical software was used for meta-analysis. RESULTS: All studies on ART used conventional 3D techniques. Patients in the ART cohorts were more likely to have involved surgical margins and positive lymph nodes. For extrahepatic cholangiocarcinoma location, ART significantly improved overall survival (HR 0.62; 95% CI 0.48 to 0.78, p<0.001). Meta-analysis was not feasible for gallbladder cancer and ampullary cancer locations. Late radiation-induced toxicity was low (2-9% late obstruction or GI bleeding). CONCLUSION: In the absence of randomized controlled studies, we found in the present systematic review and meta-analysis of observational studies that, patients with extrahepatic cholangiocarcinoma treated with adjuvant RT have a significant lower risk of dying compared to patients treated with surgery alone. PMID- 21652149 TI - Critical comments for roles of biomarkers in the diagnosis and treatment of cancer. AB - A biomarker is defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic/pharmacodynamic responses to a therapeutic intervention". Various assays, including immunohistochemistry, gene constitution such as amplification, mutation, and rearrangement, gene and protein expression analysis such as single gene or protein expression, exhaustive analysis and gene or protein signature and single nucleotide polymorphism have been used to identify biomarkers in recent years. No therapeutic effects have yet been predicted based on the results of such exhaustive gene analysis because of low reproducibility although some correlate with the prognosis of patients. Biomarkers such as HER2 for breast cancer or EGFR mutation for lung cancer and KRAS mutation in colon cancer have contributed to identify a patient population that might show a good and bad treatment response, respectively. On the other hand, other biomarkers such as bcr abl, c-kit gene mutation and CD20 expression, which are positive for CML, GIST and B cell lymphoma, respectively, have crucial biological significance but have not necessarily been used for practical clinical screening since pathological diagnosis coincide with finding of biomarkers. Hence, much work remains to be done in many areas of biomarker research. PMID- 21652150 TI - Oxytocin as a moderator of hypnotizability. AB - Since hypnosis was popularly recognized in the nineteenth century, the phenomenon of hypnotizability has remained poorly understood. The capacity to increase hypnotizability has important implications because it may increase the number of people who can benefit from hypnotic interventions for psychological and medical conditions. Current theories emphasize that rapport between hypnotist and subject is pivotal to motivate the respondent to engage in strategies that allows them to suspend reality and respond to suggestions. The neuropeptide oxytocin is implicated in social bonding, and enhances a range of social behaviors in animals and humans. This study tested the proposal that oxytocin administration, which enhances social bonding in humans, may enhance hypnotic responding by administering intranasal spray of oxytocin or placebo prior to hypnosis in 40 low hypnotizable male subjects. When low hypnotizable individuals were administered oxytocin via nasal spray, their level of hypnotic responding increased significantly compared to hypnotic responding levels prior to oxytocin administration. This is the first demonstration of a neurochemical basis for hypnotic responding, and points to a potential neural mechanism to explain hypnotizability. PMID- 21652151 TI - Biodiversity and leptospirosis risk: a case of pathogen regulation? AB - Well balanced ecosystems have an essential role in disease regulation, and consequently their correct functioning is increasingly recognised as imperative for maintaining human health. Disruptions to ecosystems have been found to increase the risk of several diseases, including Hantavirus, Lyme disease, Ross River virus, malaria and Ciguatera fish poisoning. Leptospirosis is a globally important emerging zoonosis, caused by spirochaete bacteria, borne by many mammalian hosts, and also transmitted environmentally. We propose that leptospirosis incidence in humans is also linked to ecosystem disruption, and that reduced biodiversity (the diversity of species within an ecological community) may be associated with increased leptospirosis incidence. To investigate this hypothesis, the relationship between biodiversity levels of island nations and their annual leptospirosis incidence rates (adjusted for GDP per capita) was examined by linear correlation and regression. Supportive, statistically significant negative associations were obtained between leptospirosis incidence and (a) total number of species (r2=0.69, p<0.001) and (b) number of mammal species (r2=0.80, p<0.001) in univariate analysis. In multivariable analysis only the number of mammal species remained significantly associated (r2=0.81, p=0.007). An association between biodiversity and reduced leptospirosis risk, if supported by further research, would emphasise the importance of managing the emergence of leptospirosis (and other infectious diseases) at a broader, ecosystem level. PMID- 21652152 TI - Does sleep deprivation and morphine influence wound healing? AB - The contrast between present-day sleep habits and those of the pre-industrial era are quite evident. One study recent has shown that the amount of sleep has decreased 2 h per night over the past 50 years. Such sleep curtailment, ubiquitous in the modern lifestyle, inflicts adverse repercussions upon health and well being. Investigations examining the relationship between stress and the skin have shown that different types of stress affect the healing process. Morphine is an immunosuppressive drug, and when it is used chronically, it can lead to an increased incidence of infections and a delay in the healing process. Therefore, our hypothesis is that the lack of sleep associated with chronic treatment with morphine is detrimental to the healing of the skin in the animal model we have adopted. Thus, it is important that future studies consider the paradigm of sleep curtailment when investigating the mechanisms involved in the process of skin healing in individuals who are dependent on morphine. PMID- 21652153 TI - The association between acyl-CoA synthetase (ACSL4) polymorphism and intramuscular fat content in (Landrace * Yorkshire) * Duroc pigs. AB - The aim of the study was to check whether different genotypes at acyl-CoA synthetase (ACSL4 locus, SNP G2645A) are associated with pork quality. 132 (Landrace * Yorkshire) * Duroc fatteners were genotyped by originally developed PCR-RFLP method. Upon the slaughter, the samples of longissimus lumborum muscle were taken from each carcass to determine the following parameters: content of water, protein and fat, pH (45 min, 24, 48, 96, and 144 h post mortem), electrical conductivity, drip loss, meat lightness, glycolytic potential, glycogen and lactate contents in meat. Among several associations observed, the highly significant (p<0.01) was found for intramuscular fat (IMF) content. Pigs with genotype GG revealed the highest content of IMF - 2.47%. PMID- 21652154 TI - Race/ethnicity and sex differences in progression from drinking initiation to the development of alcohol dependence. AB - BACKGROUND: Prior studies on the course of alcohol use disorders have reported a "telescoping" effect with women progressing from drinking initiation to alcohol dependence faster than men. However, there is a paucity of population-based analyses that have examined progression to alcohol dependence comparing race/ethnicity subgroups, and little is known about whether the telescoping effect for women varies by race/ethnicity. We examined whether a telescoping effect is present in the general population comparing race/ethnicity subgroups and comparing men and women stratified by race. METHODS: This study uses data from Wave I of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to compare a nationally representative sample of White, Black and Hispanic adults 18-44 years of age (n=21,106). Time to event analyses compare the risk of alcohol initiation, onset of alcohol dependence, and the transition from initial use to onset of alcohol dependence in the three race/ethnicity groups and for males and females in each race/ethnicity group. RESULTS: Whites were younger than Blacks and Hispanics of the same sex at drinking onset and progressed to alcohol dependence at a faster rate than both Blacks and Hispanics. In addition, we found no evidence of a telescoping effect in women for any race/ethnicity group. CONCLUSIONS: The present study illustrates differences in the course of transition from alcohol initiation to the development of dependence by race/ethnicity but not sex. Our findings highlight the need for additional study of factors resulting in race/ethnicity differences in order to inform culturally relevant prevention and intervention initiatives. PMID- 21652155 TI - Using NicAlert strips to verify smoking status among pregnant cigarette smokers. AB - BACKGROUND: Decreasing smoking during pregnancy is an important public health priority. An important step towards decreasing smoking during pregnancy is wider dissemination of evidence-based smoking cessation interventions. One such intervention is contingency management wherein mothers earn vouchers exchangeable for retail items contingent on biochemically verified smoking abstinence. Wider dissemination may be possible by using smoking verification methods that require minimal training and equipment. One possibility is to use a cotinine-sensitive dipstick (NicAlert) rather than a bench-top cotinine analyzer, which is expensive and requires relatively extensive technician expertise, or breath carbon monoxide analysis, which is relatively nonspecific. The present study was conducted to begin examining the utility of cotinine-sensitive dipsticks for this purpose. METHODS: Fifty urine samples from pregnant women enrolled in a smoking cessation program were analyzed to compare three different methods for verifying smoking status: NicAlert strips, a bench-top enzyme multiplied immunoassay technique (EMIT) analyzer, and gas chromatography (GC), the current gold standard for determining cotinine levels in urine. RESULTS: Agreement between GC and NicAlert results were high (96%) and comparable to agreement between GC and EMIT results (94%). Semi-quantitative measurements using NicAlert were low with only 30% of samples in agreement between GC and specific ranges given on the strips. CONCLUSIONS: NicAlert strips appear to be a valid measure of determining smoking status among pregnant smokers although not of absolute cotinine concentration. With minimal training and equipment required, NicAlert strips provide a potentially practical method for using urine cotinine to verify smoking status in community treatment settings. PMID- 21652156 TI - Determinants of vaccination coverage for children and teenagers. AB - The official vaccinal program is updated every year. Nevertheless, the observed vaccination coverage does not correspond to the recommended program. OBJECTIVE: Our objective was to identify factors influencing vaccinal practice, especially for hepatitis B. METHOD: We sent a questionnaire to two medical populations of the French Loire subdivision: 100 randomly chosen general practitioners, and 53 pediatricians and physicians working for public office for mother and childcare. RESULTS: The updated official recommendations were considered as the reference document for both populations. The study did not reveal any hesitation or lack of information, which could explain the low hepatitis B vaccinal coverage. Eighty five percent of questioned physicians claimed having changed their practice, thanks to the easy use of Infanrix Hexa(r), probably explaining the current improvement of hepatitis B vaccinal coverage rate. PMID- 21652157 TI - Measurement of tumor size in adult glioblastoma: classical cross-sectional criteria on 2D MRI or volumetric criteria on high resolution 3D MRI? AB - OBJECTIVE: To investigate the added value of volume on post-contrast three dimensional (3D) T1-weighted image (T1WI) over classical cross-sectional area on two dimensional (2D) T1WI in evaluating tumor response in glioblastoma multiforme (GBM). METHODS: Tumor cross-sectional area and volume measurements were performed on 104 MRI studies from 42 adult patients with GBM on post-contrast 5 mm 2D T1WI and isotropic high resolution 3D T1WI, respectively. 52 pairs of MRI scans were analyzed for relative change. Radiographic responses were determined based on change in either area or volume. RESULTS: A high correlation was revealed between tumor size measured by area on thick 2D and volume on high resolution 3D MRI in 104 scans (r=0.82, p<0.001). When four tumor response criteria were used according to the percentage changes (complete response/partial response/stable disease/progression), the kappa coefficient between the area on 2D and volume on 3D was 0.68 (p<0.05) with an overall agreement of 81%. CONCLUSIONS: Tumor cross sectional area on post-contrast 2D T1WI appears comparable to volume on 3D T1WI and should still be a practical alternate of volume on 3D for evaluating tumor response. PMID- 21652158 TI - WITHDRAWN: Inter-observer variability in Breast Imaging Reporting and Data System (BI-RADS) ultrasound final assessments. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21652159 TI - Analysis of co-spray-dried meloxicam-mannitol systems containing crystalline microcomposites. AB - The crystal size, form, wettability and rate of dissolution of a drug are factors limiting its nasal or pulmonary administration. The aim of this work was to achieve an ideal crystal habit, good wettability and the rapid release of meloxicam (MEL), a poorly water-soluble non-steroidal anti-inflammatory drug. The structures of MEL and the carrier-based systems were analysed by differential scanning calorimetry, X-ray diffractometry and Fourier transform infrared spectroscopy. The particle size and morphology were investigated by laser diffraction and SEM analyses. The novelty of this work was the use of a co-spray drying technique, which resulted in mannitol-based crystalline microcomposites (1 6 MUm) containing MEL microcrystals (1-5 MUm). The particle size and form of the MEL microcrystals were adjusted by a top-down method. The presence of mannitol (with a MEL:mannitol mass ratio of 1:1) with additives ensured the homogeneous distribution of MEL in the microcomposites with good wettability and rapid release (100% MEL within 5 min). PMID- 21652160 TI - Biorelevant pK(a) (37 degrees C) predicted from the 2D structure of the molecule and its pK(a) at 25 degrees C. AB - Values of the ionization constants at 37 degrees C, which are scarcely reported, are more meaningful for interpreting mechanisms of cellular transport by ionizable molecules and in mechanistic dissolution studies, which are often performed at the biorelevant temperature. An equation was developed where the pK(a) values of drug-like molecules determined at 25 degrees C can be simply converted to values at 37 degrees C, without additional measurement. The differences between the values, DeltapK(a)=pK(a)37-pK(a)25, were linearly fitted to a function of pK(a)25 and the standard entropy of ionization, DeltaS degrees , where the latter term was approximated by the five Abraham linear free energy solvation descriptors using multiple linear regression. The Abraham descriptors (H-bond donor and acceptor strengths, dipolar solute-solvent interactions potential, the pi- and n-electrons dispersion force, and molar volume) were determined from the 2-dimensional structure of the molecules. A total of 143 mostly drug-like molecules (207 pK(a) values at 25 degrees C and at 37 degrees C) were chosen for the study. The pK(a) values of many were determined here for the first time. Included were 34 weak acids, 85 weak bases, and 24 amphoteric compounds (6 ordinary ampholytes, 18 zwitterions). PMID- 21652161 TI - ACCF/AHA 2011 key data elements and definitions of a base cardiovascular vocabulary for electronic health records: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards. PMID- 21652162 TI - How information about other people's personal experiences can help with healthcare decision-making: a qualitative study. AB - OBJECTIVE: To investigate people's views of using 'general facts' and information about other people's 'personal experiences' for health-related decision-making. METHODS: Sixty-two people, who between them had experience of five different focal health issues, participated in 12 focus groups and 9 interviews. Exploration of uses of the two types of information was supported by discussion of illustrative excerpts. RESULTS: There was less discussion of 'general facts'; participants thought it obvious that good decisions required these. Participants reported having used 'personal experiences' information to: recognise decisions that needed consideration; identify options; appraise options and make selections (including by developing and reflecting on their reasoning about possible choices); and support coping strategies. Their inclination to use 'personal experiences' information was apparently moderated by assessments of personal relevance, the motives of information providers and the 'balance' of experiences presented. CONCLUSION: People can use 'personal experiences' information in various ways to support their decision-making, and exercise some discrimination as they do. PRACTICE IMPLICATIONS: 'Personal experiences' information may help people in a number of ways in relation to decision-making. However, 'personal experiences' information does not replace the need for 'general facts' and care should be taken when it is used in resources for patients. PMID- 21652163 TI - Emotional cues and concerns in hospital encounters with non-Western immigrants as compared with Norwegians: an exploratory study. AB - OBJECTIVE: To identify potential barriers in communication with non-Western immigrant patients by comparing the frequency and nature of emotional cues and concerns, as well as physician responses during consultations, between ethnically Norwegian patients and immigrant patients in a general hospital setting. METHODS: Consultations with 56 patients (30 non-Western immigrants and 26 ethnic Norwegians) were coded using the Verona Coding Definitions of Emotional Sequences (VR-CoDES) and the Verona Codes for Provider Responses (Verona Codes-P). RESULTS: There were no significant differences in frequencies of cues and concerns between immigrant and Norwegian patients. However, the immigrant patients with high language proficiency expressed more concerns compared to immigrant patients with language problems and Norwegian patients. Moreover, more concerns were expressed during consultations with female physicians than with male physicians. CONCLUSION: Expression of cues and concerns in immigrant patients is dependent on the patient's language proficiency and the physician's gender. PRACTICE IMPLICATIONS: Providers should recognize that immigrant patients may have many emotional cues and concerns, but that language problems may represent a barrier for the expression of these concerns. PMID- 21652164 TI - Thoracic sympathectomy for digital ischemia: a summary of evidence. AB - BACKGROUND: Thoracic sympathectomy is used in the management of a variety of upper limb disorders. We have analyzed the evidence for thoracic sympathectomy in the management of digital ischemia. METHODS: We reviewed the English literature between 1980 and 2010. Our analysis included reports with the clinical end points of relief, recurrence of symptoms or healing of ulcers, or both. Primary Raynaud disease (PRD) and secondary Raynaud phenomenon (SRP) were analyzed separately. RESULTS: An initial postoperative positive effect was reported in 92% of PRD patients and in 89% of SRP patients. Long-term beneficial effect was 58% for PRD and 89% for SRP. Ulcer healing or improvement was achieved in 95%. CONCLUSIONS: The available evidence suggests that thoracic sympathectomy has a role in the treatment of severe PRD and SRP, albeit with better results in SRP patients than in PRD patients. In case of digital ulceration, thoracic sympathectomy may maximize tissue preservation or prevent amputation. PMID- 21652165 TI - A novel mutation in the RYR2 gene leading to catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation: dose-dependent arrhythmia-event suppression by beta-blocker therapy. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic condition that presents with exercise-induced polymorphic arrhythmias. We describe a case report of a 25-year-old woman who had a cardiac arrest due to ventricular fibrillation. Genetic analysis revealed a novel missense mutation in exon 90 of the ryanodine receptor (RyR2) gene resulting in substitution of arginine for serine at residue 4153 (S4153R). The patient received an implantable cardioverter-defibrillator and low-dose beta-blocker therapy. She had recurrent polymorphic ventricular arrhythmias treated with appropriate cardioverter defibrillator shocks and paroxysmal atrial fibrillation. Titration of beta blocker to a much higher dose suppressed further episodes of ventricular arrhythmia and paroxysmal atrial fibrillation, resulting in reduction in device therapies. PMID- 21652166 TI - Plasma cyclic 3',5'-adenosine monophosphate in patients with elevated pulmonary pressure due to left-to-right shunt. AB - BACKGROUND: Increased pulmonary blood flow in patients with left-to-right shunt has been shown to be associated with alterations in prostacyclin-synthesis. There are limited data with respect to the plasma cAMP in patients with elevated pulmonary artery pressure due to left-to-right shunt. We hypothesized that plasma cAMP might be influenced by pulmonary blood flow or pressure in patients with left-to-right shunt. METHODS: Plasma cAMP from venous blood was measured in 122 healthy controls aged 8.3 (0.2 - 14.9) years (median [range]) and in 130 patients with left-to-right shunt aged 1.4 (0.1 - 19.1) years by radioimmunoassay. RESULTS: Plasma cAMP in controls and in patients was similar and decreased with age. Healthy infants (n = 42) showed higher plasma cAMP (46 [27-112] nmol/l) than children > 6 years of age (n = 40, 39 [19-73] nmol/l; P < 0.001). CONCLUSIONS: These values should be taken into consideration when reporting plasma values for cAMP in patients with congenital heart disease. The values for healthy children obtained in this study should allow a better interpretation of plasma cAMP levels in various disease conditions such as chronic renal failure, liver chirrhosis, hyperthyreosis, or children with intellectual disability. PMID- 21652167 TI - Unnecessary controversy regarding dietary sodium: a lot about a little. PMID- 21652168 TI - Influenza myocarditis and myositis: case presentation and review of the literature. AB - Myocarditis, a general inflammatory condition of the heart muscle, can result from a variety of etiologies, the most common being viral. Despite common pathogens, concomitant myocarditis and myositis remains a rare event. Although a common cause of respiratory illness, extrapulmonary infections with influenza are infrequent. We describe the case of a patient who presented to our centre with concomitant "seasonal" H1N1 influenza A myocarditis further complicated by pan myositis. The patient's condition rapidly declined, eventually requiring biventricular mechanical support, in addition to multilimb fasciotomies. The cardiac support required was progressive, from a percutaneous left ventricular assist device, to extracorporeal membrane oxygenation, to eventual biventricular assist device support for bridge-to-transplantation. This case motivated a detailed review of the literature (a total of 29 cases were identified), in which we found that patients with influenza myocarditis/myositis were predominantly female (63%) and young (mean age 33.2 years) and continue to have a high incidence of morbidity and mortality (27%). As a result of its atypical pattern, the 2009 H1N1 pandemic strain has gained attention. From our review, we found 7 patients with of 2009 H1N1 pandemic influenza myocarditis. Serial serum cytokine analysis did not demonstrate a "cytokine storm," which has been associated with other virulent influenza strains. The PB1-F2 marker in particular has been associated with a vigorous cytokine response. The 2009 H1N1 and "seasonal" influenza strains lack this marker. In those patients with community-acquired influenza, interleukin-6 has been shown to correlate with symptoms. For patients with myocarditis resulting in shock, mechanical circulatory support has gained acceptance as a means to recovery or transplantation. PMID- 21652169 TI - Percutaneous closure of postinfarction ventricular septal defect: cardiac magnetic resonance-guided case selection and postprocedure evaluation. AB - Despite modern surgical techniques, complications and early mortality remain high following postinfarction ventricular septal defect (VSD) repair. It is now possible to close these acquired defects percutaneously using, for example, the Amplatzer postinfarct muscular VSD device. Cardiovascular magnetic resonance is an important tool in determining appropriate case selection and device sizing as it can provide a multicomponent assessment of the VSD anatomy, ventricular volumes and function, infarct extent, and left-to-right shunt calculations. PMID- 21652170 TI - Real-world estimated effective radiation doses from commonly used cardiac testing and procedural modalities. AB - BACKGROUND: The volume of cardiac diagnostic tests that are performed has increased significantly in recent years. The benefits of these tests should be weighed against the risks, including exposure to ionizing radiation. We sought to determine the effective radiation doses associated with common cardiac imaging studies performed at a provincial referral heart centre in Vancouver, Canada, between January 1, 2009 and December 31, 2009. METHODS: Effective radiation dose was calculated for all patients who underwent clinically indicated cardiac computed tomography angiography (CCTA), myocardial perfusion imaging (MPI), and diagnostic catheter coronary angiography (CCA) in 2009. The dose from CCTA and CCA studies was estimated from dose-length product and dose area product values, respectively. A conversion factor of 0.014 mSv/(mGy * cm) was used for CCTA and MPI CT attenuation correction. The conversion factor for CCA was 0.22 mSv/(Gy * cm(2)). The effective radiation dose for MPI was calculated using: E = (E/A) * A(o) where E = effective dose, E/A is an effective dose coefficient, and A(o) is the radiotracer activity. RESULTS: There were 673 CCTA studies and 2306 MPI studies performed with average effective doses of 3.7 mSv and 16.8 mSv, respectively. There were 2628 diagnostic CCA studies performed with an average effective dose of 11.4 mSv. CONCLUSIONS: There was a wide range of effective radiation doses between imaging modalities. These tests provide different clinical information and the appropriate test must be chosen with radiation dose in mind. The implementation of dose reduction strategies has the potential to significantly reduce these doses. PMID- 21652171 TI - Clinical implications of direct-to-consumer genetic testing for cardiovascular disease risk. AB - Direct-to-consumer (DTC) genetic testing for cardiovascular disease (CVD) is becoming increasingly accessible due to technological advances, falling prices, and assertive marketing. However, information to guide physicians and patients on how to interpret or react clinically to DTC genetic test results is scarce. We report the case of a 52-year-old man with a family history of CVD who had DTC genetic testing performed. We discuss selected results and interpretation of this testing and the outcome of subsequent lifestyle interventions. Despite the information this new technology seemed to provide, traditional advice on lifestyle modification was central to his management. PMID- 21652172 TI - [Azithromycin as an adjuvant therapy in cryptogenic organizing pneumonia]. AB - There are literature data about the immunomodulatory properties of some macrolides in cryptogenic organizing pneumonia (COP) as an alternative to corticosteroids in mild disease or as adjuvant to standard therapy. A sixty-year old female, with a controlled intrinsic asthma, presented with COP and recurrent respiratory exacerbations despite corticosteroid and immunossupressant therapy. Azithromycin (500mg, on alternate days) as an adjuvant to steroids was then started, with clinical and functional improvement and regression of lung infiltrates. Withdrawal of steroids was possible in one year, without evidence of relapse in the next six months. Azithromycin was maintained (three times per week) with no documentation of adverse side effects. This clinical case reinforces the potential role of macrolides anti-inflammatory properties in COP as corticosteroids adjuvant therapy. PMID- 21652173 TI - Static versus dynamic splinting for proximal interphalangeal joint pyrocarbon implant arthroplasty: a comparison of current and historical cohorts. AB - STUDY DESIGN: Nonrandomized mixed current and historical cohort follow-up study. The purpose of the study was to test the effectiveness of static splinting after arthroplasty in patients with osteoarthritis. Dynamic splinting is recommended after proximal interphalangeal joint pyrocarbon implant arthroplasty; however, static splinting may be more feasible to deliver. Nine consecutive patients received static splinting in this study. These patients were compared with those of a historical control group (n = 10) who received dynamic splinting. Function and performance variables were measured preoperatively and 3 months after surgery. All patients underwent surgery by the same hand surgeon, and most of the patients were treated by the same certified hand therapist. Both static and dynamic groups showed improvement on several function and performance measures. Compared with the dynamic group, the static group showed greater improvements in the Michigan. Hand Outcomes Questionnaire subset of work performance (21.00 +/- 14.75 vs 3.13 +/- 14.13, p < 0.05) and Jebsen-Taylor Test (-11.58 +/- 5.44 vs 2.81 +/- 3.23, p < 0.03). Patients who received static splinting had similar outcomes to those who received the dynamic splinting. Static splinting requires less therapist training and offers greater patient convenience and is a promising protocol that should be evaluated in a larger study. PMID- 21652174 TI - Central aortic stiffness and its association with ascending aorta dilation in subjects with a bicuspid aortic valve. AB - BACKGROUND: Reduced elasticity and dilatation of the proximal aorta are highly prevalent in patients with bicuspid aortic valves (BAVs), even in the absence of valvular dysfunction. The aim of this study was to examine central aortic stiffness and its association with ascending aortic dilation in subjects with BAVs compared with controls. METHODS: Fifty subjects with BAVs (39 men; mean age, 52 +/- 14 years) without significant valve dysfunction and 50 age-matched and gender-matched controls with normal trileaflet aortic valves were studied. Aortic diameter was measured using two-dimensional echocardiography, and central hemodynamics were assessed simultaneously using radial artery tonometry. Subjects with BAVs were divided into two groups on the basis of the median value of the aortic diameter. RESULTS: Subjects with BAVs had larger ascending aortic diameters (20.6 +/- 4.0 vs 17.9 +/- 2.4 mm/m(2), P < .001), higher augmentation indexes normalized for a heart rate of 75 beats/min (25.3 +/- 9.7% vs 16.7 +/- 8.6%, P < .001), higher pulse-wave velocities (7.8 +/- 1.5 vs 7.2 +/- 1.0 m/sec, P = .013), and lower pulse pressure amplification (1.24 +/- 0.27 vs 1.35 +/- 0.18, P = .022) than control subjects. The higher augmentation indexes were significant even in subjects with BAVs with relatively normal sized aortas. The diameter of the ascending aorta was correlated with augmentation index (r = 0.48, P < .001), pulse-wave velocity (r = 0.27, P = .063), and pulse pressure amplification (r = -0.46, P = .001) in subjects with BAVs. CONCLUSION: Subjects with BAVs had stiffer central hemodynamics than controls with tricuspid aortic valves, even in the absence of significant aortic dilation. Central aortic stiffness was positively correlated with the degree of aortic dilation in subjects with BAV. Thus, the evaluation of central aortic stiffness could be useful for the early detection and risk stratification of aortopathy in subjects with BAVs. PMID- 21652175 TI - Utility of time-dependent inverse-probability-of-treatment weights to analyze observational cohorts in the intensive care unit. AB - OBJECTIVE: When analyzing observational databases, marginal structural models (MSMs) may offer an appealing approach to estimate causal effects. We aimed at evaluating MSMs, in accounting for confounding when assessing the benefit of intensive care unit (ICU) admission and on its interaction with patient age, as compared with propensity score (PS) matching. STUDY DESIGN AND SETTING: PS and inverse-probability-of-treatment weights for MSMs were derived from an observational study designed to evaluate the benefit of ICU admission on in hospital mortality. Only first ICU triages (time-fixed weights) or whole triage history (time-dependent weights) were considered. Weights were stabilized by either the prevalence of the actual treatment or the probability of the actual treatment given baseline covariates. Risk difference (RD) was the main outcome measure. RESULTS: MSMs with time-dependent weights offered the best reduction in the baseline imbalances as compared with PS matching. No effect of ICU admission on in-hospital mortality was found (RD=0.010; 95% confidence interval=-0.038, 0.052) with no interaction between age and treatment. CONCLUSION: MSMs appear interesting to handle selection bias in observational studies. When confounding evolves over time, the use of time-dependent weights should be stressed out. PMID- 21652176 TI - Increasing specimen coverage using digital whole-mount breast pathology: implementation, clinical feasibility and application in research. AB - Conventional histopathological evaluation is performed on breast specimens using a highly limited sampling of tissues visualized in a two-dimensional (2D) manner although important tumor measurements are three-dimensional. Here we describe a '3D' technique for whole-mount, whole-specimen processing which reduces conformational change and dramatically increases specimen coverage, based on digitizing whole-specimen, whole-mount (up to 12.7cm*17.8cm) serial sections. We describe hardware and software tools for acquiring, viewing and processing the large image datasets (up to 400GB), validation studies investigating the clinical significance of the additional information gleaned from the 3D approach, and application to radiologic-pathologic correlation and biomarker visualization. PMID- 21652177 TI - Management of serious isolated gingival synechia in a newborn: case report and review of the literature. AB - Congenital synechia of the gums is a rare malformation. The fusion may be partial or complete and may be associated with other facial dysmorphologic malformations. The synechia can be fibrous or bony and may develop between the upper and lower alveolar ridges. The authors report a newborn with partial, but broad and continuous, synechia of the gums and discuss its management during the first days of life. PMID- 21652178 TI - Brief cognitive assessment instruments in schizophrenia and bipolar patients, and healthy control subjects: a comparison study between the Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) and the Screen for Cognitive Impairment in Psychiatry (SCIP). AB - Cognitive impairment in schizophrenia and psychosis is ubiquitous and acknowledged as a core feature of clinical expression, pathophysiology, and prediction of functioning. However, assessment of cognitive functioning is excessively time-consuming in routine practice, and brief cognitive instruments specific to psychosis would be of value. Two screening tools have recently been created to address this issue, i.e., the Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) and the Screen for Cognitive Impairment in Psychiatry (SCIP). The aim of this research was to examine the comparative validity of these two brief instruments in relation to a global cognitive score. 161 patients with psychosis (96 patients diagnosed with schizophrenia and 65 patients diagnosed with bipolar disorder) and 76 healthy control subjects were tested with both instruments to examine their concurrent validity relative to a more comprehensive neuropsychological assessment battery. Scores from the B-CATS and the SCIP were highly correlated in the three diagnostic groups, and both scales showed good to excellent concurrent validity relative to a Global Cognitive Composite Score (GCCS) derived from the more comprehensive examination. The SCIP-S showed better predictive value of global cognitive impairment than the B-CATS. Partial and semi partial correlations showed slightly higher percentages of both shared and unique variance between the SCIP-S and the GCCS than between the B-CATS and the GCCS. Brief instruments for assessing cognition in schizophrenia and bipolar disorders, such as the SCIP-S and B-CATS, seem to be reliable and promising tools for use in routine clinical practice. PMID- 21652179 TI - Influence of natural organic matter on the deposition kinetics of extracellular polymeric substances (EPS) on silica. AB - The influence of humic acid and alginate, two major components of natural organic matter (NOM), on deposition kinetics of extracellular polymeric substances (EPS) on silica was examined in both NaCl and CaCl(2) solutions over a wide range of environmentally relevant ionic strengths utilizing a quartz crystal microbalance with dissipation. Deposition kinetics of both soluble EPS and bound EPS extracted from four bacterial strains with different characteristics was investigated. EPS deposition on humic acid-coated silica surfaces was found to be much lower than that on bare silica surfaces under all examined conditions. In contrast, pre coating the silica surfaces with alginate enhanced EPS deposition in both NaCl and CaCl(2) solutions. More repulsive electrostatic interaction between EPS and surface contributed to the reduced EPS deposition on humic acid-coated silica surface. The trapping effect induced by the rough alginate layer resulted in the greater EPS deposition on alginate-coated surfaces in NaCl solutions, whereas surface heterogeneities on alginate layer facilitated favorable interactions with EPS in CaCl(2) solutions. The presence of dissolved background humic acid and alginate in solutions both significantly retarded EPS deposition on silica surfaces due to the greater steric and electrostatics repulsion. PMID- 21652180 TI - Enhanced removal of bilirubin on molecularly imprinted titania film. AB - Titania film imprinted by bilirubin molecule at the surface of quartz crystal was prepared using molecular imprinting and surface sol-gel process. The molecularly imprinted titania film was characterized by FTIR spectra, and the interaction between bilirubin and imprinted film was investigated using quartz crystal microbalance (QCM) technique. Compared with pure titania film, the molecularly imprinted titania film exhibits a much higher adsorption capacity for the target molecule, and the adsorption kinetic parameter estimated from the in situ frequency measurement is about 1.6*10(8) M(-1), which is ten times higher than that obtained on pure titania film. The photocatalytic measurements indicate that the bilirubin adsorbed on molecularly imprinted titania film can be completely removed under UV illumination. Moreover, our study indicates that the molecularly imprinted titania film possesses a better stability and reusability. PMID- 21652181 TI - In situ formation of chitosan-cyclodextrin nanospheres for drug delivery. AB - Chitosan-cyclodextrin nanospheres were prepared by in situ formation through Michael addition between N-maleated chitosan (NMC) and per-6-thio-beta cyclodextrin sodium salt in an aqueous medium. This facile preparation method did not involve any organic solvent and surfactant. Through adjusting the preparation conditions, the nanospheres with a relatively narrow size distribution could be obtained. The obtained nanospheres were characterized by TEM and particle size analyzer. Doxorubicin hydrochloride (DOX.HCl), a water soluble anticancer drug, was loaded in the nanospheres with a high encapsulation efficiency. The in vitro drug release showed that the release of DOX.HCl from the nanospheres could be effectively sustained. The cytotoxicity evaluation showed the drug loaded nanospheres exhibited efficient inhibition on HeLa cells. PMID- 21652182 TI - Dithiocarbamated chitosan as a potent biopolymer for toxic cation remediation. AB - The biopolymer chitosan was chemically modified with dithiocarbamate, characterized by elemental analysis, IR, (13)C NMR and TG, and applied for lead, copper and cadmium removal. Based on sulfur elemental analysis an amount of 2.66 mmol g(-1) of pendant chain was incorporated in the original biopolymer, as also demonstrated through the appearance of a signal at 201 ppm in the (13)C NMR in the solid state. The TG curve demonstrated that the final product is more stable than the precursor chitosan. The sorption capacity of modified biopolymer was determined through a batchwise methodology, with maximum capacities of 2.24; 1.14 and 0.84 mmol g(-1) for divalent lead, copper and cadmium from aqueous solution, respectively. The highest sorption capacity for lead reflects the soft cation/sulfur interaction. The experimental data were adjusted to the Langmuir, the Freundlich and the Temkin sorption isotherm models using both linear and nonlinear regression analysis. PMID- 21652183 TI - An improved method for the preparations of nanostructured lipid carriers containing heat-sensitive bioactives. AB - Heat-sensitive bioactive compounds such as beta-carotene and tocols, are widely used in the pharmaceutical and cosmetic fields. Their chemical stability in delivery systems is one of the major concerns in the production of nanostructured lipid carriers (NLCs). A previously established high-temperature high-pressure homogenisation technique involved in the preparation of NLCs can cause degradation of heat-sensitive compounds. Therefore, a novel preparation process needs to be developed to minimise the degradation of heat-sensitive active compounds during the preparation of NLCs. In this work, modified methods A and B were designed to minimise the degradation of beta-carotene and tocols during the production of NLCs. These methods improved the chemical stability of heat sensitive bioactive compounds (beta-carotene and tocols) significantly compared to the previously established method. The physical stability of the formulation was maintained throughout study duration. PMID- 21652184 TI - [Identifying addictive behaviors among adolescents: a school-based survey]. AB - French epidemiological data show that adolescents today experiment with tobacco at an earlier age than in the 1990s. Half of them combine tobacco consumption with other psychoactive products such as alcohol or cannabis. Tobacco consumption usually begins in adolescence and early smoking initiation is related to stronger nicotine dependence and problems quitting in adulthood. Occasional tobacco consumption rapidly leads to nicotine dependence. The national smoking cessation questionnaire is a tool to assess addictive behaviors among adolescents. It includes validated scales such as the loss of autonomy over tobacco and psychological evaluation. The aim of this school-based study was to assess addictive behaviors among adolescents (specifically loss of autonomy over tobacco) and psychological profile. Data were collected from a cross-sectional study conducted in a high school in the Paris metropolitan area (Nogent-sur Marne) in 2007 by the smoking cessation team of the Albert-Chenevier Hospital. Three hundred adolescents filled in a questionnaire concerning tobacco, alcohol, and cannabis consumption as well as their psychological profile. Loss of autonomy over tobacco use was evaluated with the Hooked on Nicotine Checklist (HONC). Anxiety and depressive disorders were identified using the Hospital Anxiety and Depression scale (HAD). Self-administered questionnaires were anonymously completed in the classroom by 151 girls and 149 boys aged 15-16 years (mean, 15.4 years): 34% of the adolescents smoked and most of them smoked at least one cigarette a day; 38% had used cannabis at least once in their life and one-third of them smoked more than 10 cannabis joints per month. Adolescents who frequently smoked cannabis had started smoking tobacco earlier than the other smokers (mean, 11.7 years versus 13.2 years). Adolescents often used different tobacco products. Manufactured cigarettes were the most frequently used, followed by shisha (waterpipe) and hand-rolled cigarettes. Among those who only smoked shisha, 76% had declared being non-smokers. Alcohol was the first psychoactive drug experimented by these adolescents; 73% had used alcohol at least once in their life and 10% used alcohol several times a week. According to the HONC, 94% of the smokers had lost control of their tobacco consumption. Concerning anxiety and depressive disorders, anxiety and depression scores were higher among smokers than non-smokers. Less than 6% of never-smokers had a depression score greater than 8 compared to 26% of adolescents smoking cannabis more than 10 times a month. The rapidity of the loss of autonomy among young smokers emphasizes the need for early interventions for tobacco prevention and cessation among adolescents. Tobacco use was often associated with anxiety and depressive symptoms, suggesting a need for professional support. The national smoking cessation questionnaire may be helpful in pediatric wards and consultations. PMID- 21652185 TI - [Street children: a universal phenomenon]. PMID- 21652186 TI - [Suicide attempts by children and teenagers in Brazzaville]. PMID- 21652187 TI - [Apparent life-threatening event in infants: think about star anise intoxication!]. AB - In previous years, several publications have reported cases of infants presenting neurological and gastrointestinal symptoms after ingestion of star anise tea. Such teas are sometimes given in various cultures for the treatment of infant colic pains. In most cases, the cause of intoxication was contamination of Chinese star anise (Illicium verum) by Japanese star anise (Illicium anisatum). Indeed, the toxicity of Illicium anisatum, also known as Shikimi, is caused by its content in potent neurotoxins (anisatin, neoanisatin, and pseudoanisatin), due to their activity as non-competitive antagonists of GABA receptors. The main reasons explaining the frequent contaminations are the strong macroscopic resemblance of the 2 substances, as well as the fact that the fruits are often sold partially broken or in ground form. Therefore, in most cases, chemical analysis is required to determine the possible adulterations. CASE REPORT: A 2 month-old infant, in good general health, was brought to the emergency unit after 3 consecutive episodes of central cyanosis and tetany of the limbs with spontaneous recovery the same afternoon. The child was also very irritable, regurgitated a lot, and positioned himself in opisthotonos. Between these episodes, the neurological exam showed some perturbations (horizontal nystagmus and Bell's phenomenon, hypertony of the extensor muscles, and mild hypotony of the axial flexor muscles) with slow improvement over the following hours. The remaining clinical exam, the laboratory work (complete blood count, renal, hepatic, and muscular tests, capillary blood gas, plasmatic amino acids, and urinary organic acids), and the electroencephalogram findings were all normal. In the course of a detailed interview, the parents reported having given 3 bottles to their child, each one containing 200 mL of an infusion with 4 to 5 fruits of star anise, in the hours preceding the symptoms to relieve colic pains. The last seizure-like event took place approximately 8h after the last ingestion. We could prove the ingestion of anisatin, the toxic substance found in Japanese star anise, and the contamination of Chinese star anise by the Japanese species. Indeed, the anisatin analysis by liquid chromatography and mass spectroscopy (LC MS) in a urine sample taken 22 h after the last infusion ingestion showed trace amounts of the substance. In another urine sample taken 33 h after ingestion, no anisatin could be detected. Furthermore, the analysis of the fruit sample gave an anisatin concentration of 7800 MUg/kg while the maximum tolerance value in Switzerland is 1000 MUg/kg. CONCLUSION: The evaluation of ALTE in infants should always include the possibility of intoxication. Star anise is generally considered a harmless medicine. Nevertheless, it can sometimes cause a severe intoxication resulting in various neurological and gastrointestinal symptoms. To prevent such events, not only the parents, but also the care personnel and pharmacists must be informed about the possible adverse effects caused either by the overdose of Chinese star anise or by the eventual contamination of herbal teas with Japanese star anise. A better control of the substances by the health authorities is also necessary. PMID- 21652188 TI - [The sexuality of HIV-infected-adolescents: literature review and thinking on the unthinkables of sexuality]. AB - The objective of this review was to analyze the scientific literature on the sexuality of HIV-positive adolescents. The first point was to identify how sexuality is addressed and secondly the impact of HIV infection on HIV-positive adolescents. Fifty-four articles were selected for this review. The review demonstrates that sexuality is mainly considered under the angle of sexual and reproductive behavior and preventive practices (condom use and contraception), based on questionnaire studies. Some studies investigated the physiological impact of HIV and its treatment, especially in relation to puberty. On the other hand, the subjective experience of an HIV-positive status among adolescents was rarely studied. Overall, HIV has a negative impact on the sexual life of HIV positive adolescents. The vast majority of them practice sexual abstinence, notably adolescents infected through mother-to-child contamination, for whom the access to sexuality seems to be delayed. Among those who are sexually active, nearly one-half continue having unprotected sex. The problems related to living with HIV induce a climate of anxiety and dissatisfaction that affects behaviors and sexual practices, and disrupts the quality of sexual life. Some results suggest that the type and mode of contamination has an effect on the general sexual experience of being an HIV-positive adolescent. More research should be developed to study the subjective experience of HIV-positive adolescent sexuality and its impact on sexual experience according to the type of contamination in this population. PMID- 21652189 TI - [Attention deficit hyperactivity disorder outcome in adults]. AB - Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood. Although some symptoms of ADHD may diminish this does not mean that functioning is unimpaired in adults. Follow-up studies of children with ADHD show that it persists into adulthood in the majority of cases. Due to genetic factors high rates of ADHD exist among the parents of children with ADHD. More females are identified and become diagnosed in adulthood. There is a greater persistence of inattentive than of hyperactive/impulsive childhood symptoms of ADHD in adulthood. Some experts conceptualise ADHD as primarily a deficit of executive functions impairing planification, time perception and emotional regulation. ADHD often presents as a lifelong condition in adults associated with a range of clinical and psychosocial impairments. Young adults with comorbid antisocial or substance use disorder in adolescence are at significantly increased risk for criminal behaviors. Some predictors of the outcome have been identified such as childhood symptom profile and severity, comorbidity and childhood family adversities. PMID- 21652190 TI - Terminological resources for text mining over biomedical scientific literature. AB - OBJECTIVE: We present a combined terminological resource for text mining over biomedical literature. The purpose of the resource is to allow the detection of mentions of specific biological entities in scientific publications, and their grounding to widely accepted identifiers. This is an essential process, useful in itself, and necessary as an intermediate step for almost every type of complex text mining application. METHODS: We discuss some of the properties of the terminology for this domain, in particular the degree of ambiguity, which constitutes a peculiar problem for text mining applications. Without a correct recognition and disambiguation of the domain entities no reliable results can be produced. RESULTS: We also discuss an application that makes use of the resulting terminological knowledge base. We annotate an existing corpus of sentences about protein interactions. The annotation consists of a normalization step that matches the terms in our resource with their actual representation in the corpus, and a disambiguation step that resolves the ambiguity of matched terms. CONCLUSION: In this paper we present a large terminological resource, compiled through the aggregation of a number of different manually curated sources. We discuss the lexical properties of such resources, specifically the degree of ambiguity of the terms, and we inspect the causes of such ambiguity, in particular for protein names. This information is of vital importance for the implementation of an efficient term normalization and grounding algorithm. PMID- 21652191 TI - Frequency of reporting and predictive factors for anxiety and depression in patients with advanced cancer. AB - AIMS: The prevalence of anxiety and depression in patients with advanced cancer has been reported to be on average 25% and to significantly affect patients' quality of life. Despite high prevalence rates, these disorders remain underdiagnosed and undertreated. The purpose of our study was to examine the self report rates of anxiety and depression with the Edmonton Symptom Assessment System (ESAS) and to assess the predictive factors for these reports in cancer patients with metastatic disease. MATERIALS AND METHODS: Consecutive patients who attended the Rapid Response Radiotherapy Program (RRRP) completed the ESAS as well as baseline demographic information. Ordinal logistic regression analysis was used to determine factors that significantly predicted anxiety and/or depression. Pearson chi(2) was used to test goodness-of-fit for categorical variables and established whether or not an observed frequency distribution differed from a predicted frequency distribution. A univariate analysis was conducted first and those variables with a P value<0.100 were included in a multivariate analysis. A score test was used to test the proportional odds assumption. RESULTS: In total, 1439 patients seen in the RRRP between January 1999 and October 2009 completed ESAS questionnaires. Fifty-five per cent of patients reported at least mild symptoms of depression and 65% reported at least mild anxiety. In the univariate analysis, patients who were female, who had a lower performance status score, or primary lung cancer were more likely to report depressed and anxious feelings. Primary prostate cancer patients were significantly less likely to report depression and anxiety. Patients referred for spinal cord compression were significantly less depressed. The multivariate models showed that younger patients were significantly more anxious than older patients and females reported more anxiety than males. Patients who reported higher feelings of nausea, tiredness, drowsiness, dyspnoea, and worse appetite and overall well-being on the ESAS tool were more likely to report feelings of depression. Patients who reported higher nausea, drowsiness, dyspnoea and worse overall well-being more often reported higher feelings of anxiety. CONCLUSION: The self-report rates of anxiety and depression were consistent with published prevalence rates. However, the explained variance based on factors included in the model remains low. Additional predictive factors should be examined in future studies in this population. The ESAS tool seems to be an efficient screening tool for anxiety and depression; however, future studies should examine its correlative properties with other known screening tools in the advanced cancer population. A prospective study should be conducted to assess the severity cut off point in which the ESAS scores most frequently lead to a further diagnosis of an anxiety or depressive disorder in the advance cancer population. PMID- 21652192 TI - Anti-genotoxic effect of the Sargassum dentifolium extracts: prevention of chromosomal aberrations, micronuclei, and DNA fragmentation. AB - The alga Sargassum dentifolium (Turner) C. Agardh, belongs to Sargassaceae, is a brown seaweed in red sea shores in Egypt. This work aimed to extract different water-soluble polysaccharide extracts (E1, E2, and E3) from S. dentifolium and to investigate their protective effect against cyclophosphamide (CP)-induced genotoxicity. Mice bone marrow cells (BMCs) were collected and analyzed for the chromosomal aberration, micronucleated BMCs (MN-BMCs), the mitotic index, DNA fragmentation by comet assay, and histone deacetylases (HDACs), and radical scavenging capacity of extracts was evaluated by the oxygen radical absorbance capacity assay. The results indicated that E2 and E3 significantly inhibited CP induced multiple chromosomal aberrations, where E1 and E3 significantly suppressed the number of CP-induced formation of tetraploidy. The extracts prohibited the cytotoxic effect of CP and recovered the mitotic activity, whereas E1 possessed the highest recovery and mitosis. In absence of MN, CP induced formation of bi- and poly-nucleated BMCs. E1 prohibited CP-induced formation of bi-nucleated BMCs, while E2 and E3 prohibited CP-induced formation of poly nucleated BMCs. CP-induced MN-BMCs were accompanied with mono-, bi- and poly nucleated cells. E1 and E3 remarkably suppressed mono-nucleated MN-BMCs, while E2 inhibited bi-nucleated MN-BMCs. All the extracts significantly inhibited the CP induced formation of poly-nucleated MN-BMCs. CP-induced DNA fragmentation was inhibited by all extracts, where E1 was the strongest inhibitor as concluded from the comet tail moment. All the extracts were strong OH scavengers, while only E3 was ROO scavenger. The results revealed a drastic decline in HDACs activity by E1 and E3. In conclusion, S. dentifolium polysaccharide extracts E1 and E3 possessed a potential anti-genotoxic and a promising anti-mutagenic activity. PMID- 21652193 TI - Ancient DNA from marine mammals: studying long-lived species over ecological and evolutionary timescales. AB - Marine mammals have long generation times and broad, difficult to sample distributions, which makes inferring evolutionary and demographic changes using field studies of extant populations challenging. However, molecular analyses from sub-fossil or historical materials of marine mammals such as bone, tooth, baleen, skin, fur, whiskers and scrimshaw using ancient DNA (aDNA) approaches provide an opportunity for investigating such changes over evolutionary and ecological timescales. Here, we review the application of aDNA techniques to the study of marine mammals. Most of the studies have focused on detecting changes in genetic diversity following periods of exploitation and environmental change. To date, these studies have shown that even small sample sizes can provide useful information on historical genetic diversity. Ancient DNA has also been used in investigations of changes in distribution and range of marine mammal species; we review these studies and discuss the limitations of such 'presence only' studies. Combining aDNA data with stable isotopes can provide further insights into changes in ecology and we review past studies and suggest future potential applications. We also discuss studies reconstructing inter- and intra-specific phylogenies from aDNA sequences and discuss how aDNA sequences could be used to estimate mutation rates. Finally, we highlight some of the problems of aDNA studies on marine mammals, such as obtaining sufficient sample sizes and calibrating for the marine reservoir effect when radiocarbon-dating such wide ranging species. PMID- 21652195 TI - Questioning the method and utility of ranking drug harms in drug policy. AB - In a 2010 Lancet paper Nutt et al. propose a model for evaluating and ranking drug harms, building on earlier work by incorporating multi criteria decision analysis. It is argued that problems arise in modelling drug harms using rankable single figure indices when determinants of harm reflect pharmacology translated through a complex prism of social and behavioural variables, in turn influenced by a range of policy environments. The delphic methodolgy used is highly vulnerable to subjective judgements and even the more robust measures, such as drug related death and dependence, can be understood as socially constructed. The failure of the model to dissaggregate drug use harms from those related to the policy environment is also highlighted. Beyond these methodological challenges the utility of single figure index harm rankings is questioned, specifically their role in increasingly redundant legal frameworks utilising a harm-based hierarchy of punitive sanctions. If analysis is to include the capacity to capture the complexity relating to drug using behaviours and environments; specific personal and social risks for particular using populations; and the broader socio-cultural context to contemporary intoxication, there will need to be acceptance that analysis of the various harm vectors must remain separate - the complexity of such analysis is not something that can or should be over generalised to suit political discourse or outdated legal frameworks. PMID- 21652194 TI - The narrowing of the CD8 T cell repertoire in old age. AB - Immune function declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. A diverse repertoire of T cells is essential for a vigorous immune response, and an important manifestation of immune aging is the progressive loss of repertoire diversity, predominantly among CD8 T cells in both mice and humans. Importantly, perturbations in the peripheral T cell repertoire, including reduction of the CD4:CD8 ratio and cytomegalovirus-driven T cell clonal expansions, make a major contribution to the 'immune risk phenotype' defined for humans, which predicts two-year mortality in very old individuals. PMID- 21652196 TI - Material and energy recovery in integrated waste management systems: project overview and main results. AB - This paper describes the context, the basic assumptions and the main findings of a joint research project aimed at identifying the optimal breakdown between material recovery and energy recovery from municipal solid waste (MSW) in the framework of integrated waste management systems (IWMS). The project was carried out from 2007 to 2009 by five research groups at Politecnico di Milano, the Universities of Bologna and Trento, and the Bocconi University (Milan), with funding from the Italian Ministry of Education, University and Research (MIUR). Since the optimization of IWMSs by analytical methods is practically impossible, the search for the most attractive strategy was carried out by comparing a number of relevant recovery paths from the point of view of mass and energy flows, technological features, environmental impact and economics. The main focus has been on mature processes applicable to MSW in Italy and Europe. Results show that, contrary to a rather widespread opinion, increasing the source separation level (SSL) has a very marginal effects on energy efficiency. What does generate very significant variations in energy efficiency is scale, i.e. the size of the waste-to-energy (WTE) plant. The mere value of SSL is inadequate to qualify the recovery system. The energy and environmental outcome of recovery depends not only on "how much" source separation is carried out, but rather on "how" a given SSL is reached. PMID- 21652197 TI - Functionalized SnO2 nanobelt field-effect transistor sensors for label-free detection of cardiac troponin. AB - Real-time label-free electrical detection of proteins, including cardiac troponin (cTn), is demonstrated using functionalized SnO2 nanobelt field-effect transistors (FETs) with integrated microfluidics. Selective biomolecular functionalization of the active SnO2 nanobelt channel and effective passivation of the substrate surface were realized and verified through fluorescence microscopy. The validation/verification of the sensing scheme was initially demonstrated via detection of biotin-streptavidin binding: devices with single biotinylated SnO2 nanobelts showed pronounced conductance changes in response to streptavidin binding. Importantly, the pH-dependence of the conductance changes was fully consistent with the charged states of streptavidin at different pH. Moreover, the specificity of the sensors' electrical responses was confirmed by co-labeling with quantum dots. Finally, the sensing platform was successfully applied for detection of the cardiac troponin I (cTnI) subunit within cTn, a clinically important protein marker for myocardial infarction. PMID- 21652198 TI - A method for high throughput bioelectrochemical research based on small scale microbial electrolysis cells. AB - There is great interest in studying exoelectrogenic microorganisms, but existing methods can require expensive electrochemical equipment and specialized reactors. We developed a simple system for conducting high throughput bioelectrochemical research using multiple inexpensive microbial electrolysis cells (MECs) built with commercially available materials and operated using a single power source. MECs were small crimp top serum bottles (5 mL) with a graphite plate anode (92 m2/m(3)) and a cathode of stainless steel (SS) mesh (86 m2/m3), graphite plate, SS wire, or platinum wire. The highest volumetric current density (240 A/m3, applied potential of 0.7 V) was obtained using a SS mesh cathode and a wastewater inoculum (acetate electron donor). Parallel operated MECs (single power source) did not lead to differences in performance compared to non-parallel operated MECs, which can allow for high throughput reactor operation (>1000 reactors) using a single power supply. The utility of this method for cultivating exoelectrogenic microorganisms was demonstrated through comparison of buffer effects on pure (Geobacter sulfurreducens and Geobacter metallireducens) and mixed cultures. Mixed cultures produced current densities equal to or higher than pure cultures in the different media, and current densities for all cultures were higher using a 50 mM phosphate buffer than a 30 mM bicarbonate buffer. Only the mixed culture was capable of sustained current generation with a 200 mM phosphate buffer. These results demonstrate the usefulness of this inexpensive method for conducting in-depth examinations of pure and mixed exoelectrogenic cultures. PMID- 21652199 TI - Self-assembled graphene platelet-glucose oxidase nanostructures for glucose biosensing. AB - Graphene platelet-glucose oxidase (GP-GOD) nanostructures have been prepared through self-assembly of GOD and chitosan (CS) functionalized GPs by electrostatic attraction in aqueous solution. The stable aqueous dispersion of GPs was prepared by chemical reduction of graphene oxide with the use of CS as a reducing and stabilizing agent. UV-vis spectroscopy, X-ray diffraction, transmission electron microscopy, scanning electron microscopy and X-ray photoelectron spectroscopy were used to characterize the resulting GPs and GP-GOD nanostructures. Furthermore, a glucose biosensor was constructed by deposition of the resultant GP-GOD on the surface of glassy carbon electrode. It was found that the resulting biosensor exhibits good response to glucose. The linear detection range is estimated to be from 2 to 22 mM (r=0.9987), and the detection limit is estimated to be 20 MUM at a signal-to-noise ratio of 3. PMID- 21652201 TI - Highly sensitive dopamine biosensors based on organic electrochemical transistors. AB - Organic electrochemical transistors (OECTs) based on poly(3,4 ethylenedioxythiophene):poly(styrene sulfonic acid) (PEDOT:PSS) with different gate electrodes, including graphite, Au and Pt electrode, etc., have been used as dopamine sensor for the first time. The sensitivity of the OECT to dopamine depends on its gate electrode and operation voltage. We find that the device with a Pt gate electrode characterized at the gate voltage of 0.6 V shows the highest sensitivity. The detection limit of the device to dopamine is lower than 5 nM, which is one order of magnitude better than a conventional electrochemical measurement with the same Pt electrode. It is expected that OECT is a good candidate for low cost and highly sensitive biosensor for the detection of dopamine. PMID- 21652200 TI - Amplified electrochemiluminescence of quantum dots by electrochemically reduced graphene oxide for nanobiosensing of acetylcholine. AB - A signal amplification system for electrochemiluminescence (ECL) of quantum dots (QDs) was developed by using electrochemically reduced graphene oxide (ERGO) to construct a nanobiosensing platform. Due to the structural defects of GO, the ECL emission of QDs coated on GO modified electrode was significantly quenched. After the electrochemical reduction of GO, the restoration of structural conjugation was observed with spectroscopic, morphologic and impedance techniques. Thus in the presence of dissolved O2 as coreactant, the QDs/ERGO modified electrode showed ECL intensity increase by 4.2 and 178.9 times as compared with intrinsic QDs and QDs/GO modified electrodes due to the adsorption of dissolved O2 on ERGO and the facilitated electron transfer. After choline oxidase (ChO) or ChO acetylcholinesterase was further covalently cross-linked on the QDs/ERGO modified electrode, two ECL biosensors for choline and acetylcholine were fabricated, which showed the linear response ranges and detection limits of 10-210 MUM and 8.8 MUM for choline, and 10-250 MUM and 4.7 MUM for acetylcholine, respectively. This green and facile approach to prepare graphene-QDs system could be of potential applications in electronic device and bioanalysis. PMID- 21652202 TI - Synthetic, biofunctional nucleic acid-based molecular devices. AB - Structural DNA nanotechnology seeks to create architectures of highly precise dimensions using the physical property that short lengths of DNA behave as rigid rods and the chemical property of Watson-Crick base-pairing that acts as a specific molecular glue with which such rigid rods may be joined. Thus DNA has been used as a molecular scale construction material to make molecular devices that can be broadly classified under two categories (i) rigid scaffolds and (ii) switchable architectures. This review details the growing impact of such synthetic nucleic acid based molecular devices in biology and biotechnology. Notably, a significant trend is emerging that integrates morphology-rich nucleic acid motifs and alternative molecular glues into DNA and RNA architectures to achieve biological functionality. PMID- 21652203 TI - Sensitivity to previous irinotecan treatment does not predict the efficacy of combination chemotherapy with cetuximab plus irinotecan for wild-type KRAS metastatic colorectal cancer. AB - The aim of this study was to evaluate the association of sensitivity to previous irinotecan-based chemotherapy with efficacy of cetuximab plus irinotecan therapy in metastatic colorectal cancer (MCRC) patients with wild-type KRAS. We analysed a pooled data set consisting of data from 87 MCRC patients from two previous phase II studies (n=60) and a group given off-protocol treatment (n=27) following irinotecan-, oxaliplatin-, and fluoropyrimidine-based chemotherapy. Overall objective response rate to cetuximab plus irinotecan was 28.7%, median progression-free survival (PFS) was 5.3 months, and median overall survival was 12.2 months. Objective response rate did not significantly differ between patients with a favourable response to previous irinotecan (n=23), stable disease (n=38), or progressive disease (n=26), with observed rates of 29.2%, 31.6%, and 23.1%, respectively. Additionally, the non-parametric Spearman rank correlation coefficients (rho) between the PFS of previous irinotecan-based chemotherapy and that of cetuximab plus irinotecan were quite low (rho=0.067 and 0.057 in patients with previous irinotecan as first- and second-line therapies, respectively). Although exploratory nature and small sample size may be limitations of this study, these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan. PMID- 21652204 TI - Effectiveness and cost-effectiveness of peri-operative versus post-operative chemotherapy for resectable colorectal liver metastases. AB - BACKGROUND: The role of neo-adjuvant chemotherapy prior to hepatectomy in patients with resectable colorectal liver metastases is currently a matter of debate. The aim of the present study was to analyse life-expectancy, quality adjusted life-expectancy and cost-effectiveness of the two chemotherapeutic strategies. METHODS: A Markov decision model was developed, on the basis of parameters derived from an extensive literature search of the last ten years, to compare outcomes of peri-operative versus post-operative chemotherapy. RESULTS: Life-expectancy observed for peri-operative chemotherapy was 54.56months and 52.62months with post-operative chemotherapy only; the quality-adjusted life expectancy with peri-operative chemotherapy was 39.33 quality-adjusted life months (QALMs) and 37.84 QALMs with post-operative chemotherapy. Peri-operative chemotherapy results in an increase in total costs of 1180? over ten years and in an incremental cost-effectiveness ratio (ICER) of 791.9?/QALM. The model was more sensitive to the expected 3-year recurrence-free survival (RFS) and cost of hepatic resection: with respect to an expected 3-year RFS?25% the peri-operative approach was more cost-effective than post-operative strategy but differences in average cost-effectiveness were small. The relationship between ICER and cost of hepatic resection was inverse because the higher the cost of hepatic resection, the higher the cost saving due to patients becoming unresectable during neo adjuvant therapy. CONCLUSIONS: In the treatment of resectable colorectal liver metastases, the addition of neo-adjuvant chemotherapy could be cost-effective because it makes it possible to avoid hepatic resection in patients who do not respond to the neo-adjuvant approach; however, the life-expectancy of the two strategies is very similar. PMID- 21652205 TI - Fungal solid state fermentation on agro-industrial wastes for acid wastewater decolorization in a continuous flow packed-bed bioreactor. AB - This study was aimed at developing a process of solid state fermentation (SSF) with the fungi Pleurotus ostreatus and Trametes versicolor on apple processing residues for wastewater decolorization. Both fungi were able to colonize apple residues without any addition of nutrients, material support or water. P. ostreatus produced the highest levels of laccases (up to 9U g(-1) of dry matter) and xylanases (up to 80U g(-1) of dry matter). A repeated batch decolorization experiment was set up with apple residues colonized by P. ostreatus, achieving 50% decolorization and 100% detoxification after 24h, and, adding fresh wastewater every 24h, a constant decolorization of 50% was measured for at least 1 month. A continuous decolorization experiment was set up by a packed-bed reactor based on colonized apple residues achieving a performance of 100mg dye L( 1)day(-1) at a retention time of 50h. PMID- 21652206 TI - Active heterotrophic biomass and sludge retention time (SRT) as determining factors for biodegradation kinetics of pharmaceuticals in activated sludge. AB - The present study investigates the biodegradation of pharmaceutically active compounds (PhACs) by active biomass in activated sludge. Active heterotrophs (X(bh)) which are known to govern COD removal are suggested as a determining factor for biological PhAC removal as well. Biodegradation kinetics of five polar PhACs were determined in activated sludge of two wastewater treatment plants which differed in size, layout and sludge retention time (SRT). Results showed that active fractions of the total suspended solids (TSS) differed significantly between the two sludges, indicating that TSS does not reveal information about heterotrophic activity. Furthermore, PhAC removal was significantly faster in the presence of high numbers of heterotrophs and a low SRT. Pseudo first-order kinetics were modified to include X(bh) and used to describe decreasing PhAC elimination with increasing SRT. PMID- 21652207 TI - Design driven HtL: The discovery and synthesis of new high efficacy beta2 agonists. AB - The design and synthesis of a new series of high efficacy beta(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious beta(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of beta(2)-adrenoceptor crystal structure, other biophysical data and modeling studies. PMID- 21652208 TI - Rhamnetin production based on the rational design of the poplar O methyltransferase enzyme and its biological activities. AB - To produce rhamnetin using enzymatic engineering, poplar O-methyltransferase-7 and its mutants were prepared based on the rational enzyme design, and the production of rhamnetin was compared with the results obtained using the wild type enzyme. In addition, the potential of using rhamnetin as a cancer chemopreventive agent was compared with that of quercetin in MDA-MB-231 human breast cancer cells, and their bioavailabilities were tested in Dulbecco's modified Eagle's medium. PMID- 21652209 TI - Synthesis and in vitro evaluation of ambrisentan analogues as potential endothelin receptor antagonists. AB - A series of novel 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3,3-diphenyl butyric acid derivatives were synthesized and evaluated for their antagonistic activity for endothelin-1-induced contraction in rabbit aorta. Within this series of compounds, 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-cyano-3,3-diphenylpropionic acid (4) displays comparable potency with ambrisentan (1), and warrants further investigation. PMID- 21652210 TI - A concise synthesis and antimicrobial activities of 3-polyamino-23,24 bisnorcholanes as steroid-polyamine conjugates. AB - A series of steroid-polyamine conjugates were synthesized and evaluated for their antimicrobial activity. This study was focused on the effect of stereochemistry at the C-3 and C-5 of steroids and types of polyamine at C-3 on activity against various human pathogens. All the conjugates exhibited strong antimicrobial activities against Gram-positive strains. Compound 18 was found to be the most potent in these series with a MIC value as low as 1 MUg/mL against the bacterium Staphylococcus aureus ATCC6538P. PMID- 21652211 TI - Breast cancer after hormone replacement therapy--does prognosis differ in perimenopausal and postmenopausal women? AB - Hormone replacement therapy (HRT) has been associated with higher incidence of breast cancer in postmenopausal women, but it is unclear if breast cancers developing after HRT use have different prognosis. 1053 women with hormone receptor positive non-metastasized breast cancer were analyzed in a retrospective trial, stratifying by HRT use before diagnosis. Postmenopausal HRT users had significantly more early tumor stages (p<0.001). HRT in postmenopausal patients was associated with longer time to progression (TTP) (HR 0.81, 95%CI 0.55-1.19, p=0.28) and overall survival (OS) (HR 0.68, 95%CI 0.45-1.02, p=0.059). Perimenopausal HRT users showed shorter TTP and OS (HR 1.99, 95%CI 0.57-6.91, p=0.28 and HR 4.59, 95%CI 0.91-23.25, p=0.06 respectively). Higher BMI was significantly associated with poorer prognosis in perimenopausal women only (TTP: HR=1.16; OS: HR=1.31). In this retrospective analysis postmenopausal HRT users seemed to have a better breast cancer prognosis. For perimenopausal HRT users however, a trend towards worse prognosis was found. PMID- 21652212 TI - Asymptomatic aneurysm of the cavernous and supraclinoid internal carotid artery in a patient with Balamuthia mandrillaris encephalitis. AB - This is the first report to our knowledge of the successful treatment of an asymptomatic mycotic aneurysm associated with Balamuthia mandrillaris encephalitis. A 27-year-old male with end-stage renal disease presented with generalized seizures following renal transplantation. MRI demonstrated multiple brain masses and an aneurysm of the cavernous and supraclinoid carotid artery. Autopsy of the donor's brain revealed Balamuthia encephalitis. The patient was placed on an anti-amebic regimen, his condition improved, and 126 days after the kidney transplant, MRI brain showed resolution of the aneurysm and improvement of the enhancing lesions. Balamuthia mandrillaris has been shown to cause a granulomatous encephalitis, with prominent vasculitis. This is the first report to demonstrate the risk of aneurysm formation associated with this infection. Prolonged anti-amebic treatment resulted in resolution of the aneurysm without clinical evidence of subarachnoid hemorrhage. PMID- 21652213 TI - An intraneural ganglion cyst causing unilateral hypoglossal nerve palsy. AB - Intracranial ganglion cysts are rare. We report a patient with a rare unilateral hypoglossal nerve palsy caused by an intraneural ganglion cyst. To our knowledge, there are only four reports of ganglion/synovial cysts causing unilateral hypoglossal nerve palsy. Our aim is to present the fifth report, and to compare our findings with the others. PMID- 21652214 TI - Neuroprotective effects of linarin through activation of the PI3K/Akt pathway in amyloid-beta-induced neuronal cell death. AB - Linarin, a natural occurring flavanol glycoside derived from Mentha arvensis and Buddleja davidii is known to have anti-acetylcholinesterase effects. The present study intended to explore the neuroprotective effects of linarin against Abeta(25 35)-induced neurotoxicity with cultured rat pheochromocytoma cells (PC12 cells) and the possible mechanisms involved. For this purpose, PC12 cells were cultured and exposed to 30 MUM Abeta(25-35) in the absence or presence of linarin (0.1, 1.0 and 10 MUM). In addition, the potential contribution of the PI3K/Akt neuroprotective pathway in linarin-mediated protection against Abeta(25-35) induced neurotoxicity was also investigated. The results showed that linarin dose dependently increased cell viability and reduced the number of apoptotic cells as measured by MTT assay, Annexin-V/PI staining, JC-1 staining and caspase-3 activity assay. Linarin could also inhibit acetylcholinesterase activity induced by Abeta(25-35) in PC12 cells. Further study revealed that linarin induced the phosphorylation of Akt dose-dependently. Treatment of PC12 cells with the PI3K inhibitor LY294002 attenuated the protective effects of linarin. Furthermore, linarin also stimulated phosphorylation of glycogen synthase kinase-3beta (GSK 3beta), a downstream target of PI3K/Akt. Moreover, the expression of the anti apoptotic protein Bcl-2 was also increased by linarin treatment. These results suggest that linarin prevents Abeta(25-35)-induced neurotoxicity through the activation of PI3K/Akt, which subsequently inhibits GSK-3beta and up-regulates Bcl-2. These findings raise the possibility that linarin may be a potent therapeutic compound against Alzheimer's disease acting through both acetylcholinesterase inhibition and neuroprotection. PMID- 21652216 TI - Fast determination of impurities in metallurgical grade silicon for photovoltaics by instrumental neutron activation analysis. AB - Standard wafer solar cells are made of near-semiconductor quality silicon. This high quality material makes up a significant part of the total costs of a solar module. Therefore, new concepts with less expensive so called solar grade silicon directly based on physiochemically upgraded metallurgical grade silicon are investigated. Metallurgical grade silicon contains large amounts of impurities, mainly transition metals like Fe, Cr, Mn, and Co, which degrade the minority carrier lifetime and thus the solar cell efficiency. A major reduction of the transition metal content occurs during the unidirectional crystallization due to the low segregation coefficient between the solid and liquid phase. A further reduction of the impurity level has to be done by gettering procedures applied to the silicon wafers. The efficiency of such cleaning procedures of metallurgical grade silicon is studied by instrumental neutron activation analysis (INAA). Small sized silicon wafers of approximately 200mg with and without gettering step were analyzed. To accelerate the detection of transition metals in a crystallized silicon ingot, experiments of scanning whole vertical silicon columns with a diameter of approximately 1cm by gamma spectroscopy were carried out. It was demonstrated that impurity profiles can be obtained in a comparably short time. Relatively constant transition metal ratios were found throughout an entire silicon ingot. This led to the conclusion that the determination of several metal profiles might be possible by the detection of only one "leading element". As the determination of Mn in silicon can be done quite fast compared to elements like Fe, Cr, and Co, it could be used as a rough marker for the overall metal concentration level. Thus, a fast way to determine impurities in photovoltaic silicon material is demonstrated. PMID- 21652215 TI - Vasorelaxant effects of macrocyclic bis(bibenzyls) from liverworts. AB - Vasorelaxant effects of a series of bis(bibenzyls) from liverworts such as Marchantia polymorpha and Marchantia paleacea on rat aorta demonstrated that they relaxed phenylephrine (PE)-induced contractions, which may be mediated through the increased release of NO from endothelial cells as well as opening of K(+) channels, and inhibition of Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCs) and/or receptor-operated Ca(2+) channels (ROCs). Structure activity relationship based on their structures was discussed. The presence of two aromatic rings which can be connected through two atoms bridge spacer may play an important role for vasorelaxant effect. PMID- 21652217 TI - Correction factors for determination of annual average radon concentration in dwellings of Poland resulting from seasonal variability of indoor radon. AB - The method for the calculation of correction factors is presented, which can be used for the assessment of the mean annual radon concentration on the basis of 1 month or 3-month indoor measurements. Annual radon concentration is an essential value for the determination of the annual dose due to radon inhalation. The measurements have been carried out in 132 houses in Poland over a period of one year. The passive method of track detectors with CR-39 foil was applied. Four thermal-precipitation regions in Poland were established and correction factors were calculated for each region, separately for houses with and without basements. PMID- 21652218 TI - Comparison of the cytokine and chemokine dynamics of the early inflammatory response in models of burn injury and infection. AB - The inflammatory response, and its subsequent resolution, are the result of a very complex cascade of events originating at the site of injury or infection. When the response is severe and persistent, Systemic Inflammatory Response Syndrome can set in, which is associated with a severely debilitating systemic hypercatabolic state. This complex behavior, mediated by cytokines and chemokines, needs to be further explored to better understand its systems properties and potentially identify multiple targets that could be addressed simultaneously. In this context, short term responses of serum cytokines and chemokines were analyzed in two types of insults: rats receiving a "sterile" cutaneous dorsal burn on 20% of the total body surface area (TBSA); rats receiving a cecum ligation and puncture treatment (CLP) to induce infection. Considering the temporal variability observed in the baseline corresponding to the control group, the concept of area under the curve (AUC) was explored to assess the dynamic responses of cytokines and chemokines. MCP-1, GROK/KC, IL-12, IL-18 and IL-10 were observed in both burn and CLP groups. While IL-10 concentration was only increased in the burn group, Eotaxin was only elevated in CLP group. It was also observed that Leptin and IP-1 concentrations were decreased in both CLP and sham-CLP groups. The link between the circulating protein mediators and putative transcription factors regulating the cytokine/chemokine gene expression was explored by searching the promoter regions of cytokine/chemokine genes in order to characterize and differentiate the inflammatory responses based on the dynamic data. Integrating multiple sources together with the bioinformatics tools identified mediators sensitive to type and extent of injury, and provided putative regulatory mechanisms. This is essential to gain a better understanding for the important regulatory points that can be used to modulate the inflammatory state at molecular level. PMID- 21652219 TI - Risk factors for hypovitaminosis D in nondialyzed chronic kidney disease patients. AB - BACKGROUND: Hypovitaminosis D is highly prevalent among patients with chronic kidney disease and has been associated with worse outcome even in the earlier stages of the disease. OBJECTIVE: This study aimed to investigate the risk factors for hypovitaminosis D in nondialyzed patients with chronic kidney disease. DESIGN: This cross-sectional study included 120 patients with chronic kidney disease at stages 2 to 5 (62% male, age: 55.4 +/- 11.3 year, estimated glomerular filtration rate: 35.1 +/- 15 mL/minute, body mass index [BMI]: 27.1 +/ 5.2 kg/m(2), 31% diabetics). Serum 25-hydroxivitamin D [25(OH)D] was measured by chemiluminescence. Subjective global assessment, total body fat (dual-energy X ray absorptiometry), visceral and subcutaneous abdominal fat (computed tomography), and several laboratory parameters were assessed. RESULTS: Insufficiency of 25(OH)D (15 to 30 ng/mL) was observed in 55% and deficiency (<15 ng/mL) in 20% of the patients. Patients with diabetes, BMI >=30 kg/m(2), and who had the blood collection during the winter or spring had lower levels of 25(OH)D. Serum 25(OH)D correlated inversely with parathyroid hormone, proteinuria, insulin resistance, leptin, and subcutaneous abdominal fat. The risk factors for hypovitaminosis D were diabetes (odds ratio: 3.8; 95% CI: 1.2 to 11.7; P = .022) and BMI >=30 kg/m(2) (odds ratio: 4.3; 95% CI: 1.2 to 15.3; P = .018). In the logistic regression analysis adjusting for gender, skin color, and season of the year, diabetes and BMI >=30 kg/m(2) were independently associated with hypovitaminosis D. CONCLUSIONS: Diabetes and obesity were the risk factors for hypovitaminosis D in nondialyzed patients with chronic kidney disease. Effective interventional protocols of vitamin D supplementation taking into account these risk factors are warranted for this population. PMID- 21652220 TI - Converting to doxercalciferol capsules from intravenous paricalcitol or doxercalciferol. AB - OBJECTIVE: The purpose of the 2 studies presented in this article was to determine the clinically appropriate dose of doxercalciferol capsules that is required to maintain similar intact parathyroid hormone control when converting from intravenous (IV) paricalcitol or doxercalciferol. DESIGN: Both studies were multicenter, open-label, randomized designs comprising the following 3 periods: a screening period, a 5-week run-in period, and a 5-week treatment period. SETTING: Dialysis centers in the United States. PATIENTS: Patients with stage 5 chronic kidney disease receiving dialysis 3 times weekly for a minimum of 6 months and with recent intact parathyroid hormone measurements between 15.9 and 63.7 pmol/L (150 to 600 pg/mL) were included. INTERVENTION: After a 5-week fixed-dose IV paricalcitol or doxercalciferol run-in period, subjects were randomized to doxercalciferol capsules for the 5-week treatment period. Conversion factors for the paricalcitol study were 0.5, 1.0, and 1.5 times the current paricalcitol dose. Conversion factors for the doxercalciferol study were 1.0, 1.5, and 2.0 times the current doxercalciferol injection dose. RESULTS: The predicted conversion factor for paricalcitol injection to doxercalciferol capsules was 0.92, whereas the factor for doxercalciferol injection to doxercalciferol capsules was 1.49. No statistically significant changes in serum calcium and phosphorus levels were found in either study. The nature of adverse events was consistent with the administration of an active vitamin D therapy to patients with chronic kidney disease receiving dialysis. CONCLUSION: The studies demonstrate patients on dialysis can be safely and effectively converted from IV paricalcitol or doxercalciferol to oral doxercalciferol. PMID- 21652221 TI - The role of fibrinolytic genes and proteins in the development of allograft vascular disease. AB - BACKGROUND: We have previously shown that lack of plasminogen activator inhibitor 1 (PAI-1) expression in donor tissue greatly increases intimal proliferation (IP) after allogeneic transplantation. We sought to determine the relative role of PAI 1 and other fibrinolytic proteins in the development of IP. METHODS: We used an abdominal aortic transplant model in mice to investigate IP in 3 groups of 6 recipients. In the isograft group, CBA/J strain mice were donors and recipients, donors for allograft group were C57BL/6J mice, and for the allograft/knockout group, C57BL/6J PAI-1 knockout mice. All groups received weekly injections of anti-CD8/CD4 monoclonal antibodies. IP was calculated at 50 days, and sections were analyzed for fibrinolytic proteins, messenger RNA (mRNA) and PAI-1 activity using immunohistochemistry (IHC), in situ hybridization (ISH), reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analysis. RESULTS: Significantly more IP developed in the allograft/knockout group vs the isograft (p < 0.001) and the allograft groups (p = 0.003). There was marked intimal expression of tissue plasminogen activator (tPA), urokinase PA (uPA), and uPA receptor (uPAR) proteins and mRNA in the allograft and allograft/knockout groups vs the isograft group. Allografts also showed significant intimal staining for PAI-1 protein and mRNA. RT-PCR demonstrated a stepwise increase in profibrinolytic protein mRNA from isograft to allograft to allograft/knockout groups, particularly uPA (p = 0.02) and uPAR (p = 0.016). Western blot data showed complementary findings. PAI-1 activity was persistently present in isograft and allograft animals, only. Intimas in allograft and allograft/knockout groups were primarily smooth muscle cells. CONCLUSIONS: PAI-1 reduces IP by limiting smooth muscle cell activity, with little change in matrix composition likely by modulating profibrinolytic protein expression. PMID- 21652222 TI - Olfactory illusions: where are they? AB - It has been suggested that there maybe no olfactory illusions. This manuscript examines this claim and argues that it arises because olfactory illusions are not typically accompanied by an awareness of their illusory nature. To demonstrate that olfactory illusions do occur, the relevant empirical literature is reviewed, by examining instances of where the same stimulus results in different percepts, and of where different stimuli result in the same percept. The final part of the manuscript evaluates the evidence favoring the existence of olfactory illusions, and then examines why they may not typically be accompanied by awareness. Three contributory mechanisms are discussed, relating to difficulty of verification and paucity of olfactory knowledge, the role of change blindness, and restricted access consciousness in this sense. PMID- 21652224 TI - Myocardial infarction quantification with late gadolinium-enhanced magnetic resonance imaging in rats using a 7-T scanner. AB - AIMS: The objective of this study was to noninvasively measure the volume of myocardial infarction in rats, using delayed enhancement magnetic resonance imaging (MRI) in a coronary occlusion/reperfusion model on a 7-T scanner. METHODS: At 24 h after cardiac ischemia, contrast-enhanced MRI was performed. Two distinct experimental groups were compared: one was subjected to permanent ischemia (PL) and the other was subjected to 30 min of ischemia followed by 24 h of reperfusion (IR). The sizes of enhanced regions were compared to triphenyltetrazolium chloride (TTC)-stained sections of the excised rat heart. Cardiomyocyte apoptosis was analyzed by TUNEL methods, and neutrophils and macrophages were quantitated after histology and immunohistochemical staining. RESULTS: Twenty-four hours after ischemia, delayed hyperenhancement imaging was clearly visualized in the anterior left ventricular walls corresponding to the infarcted myocardium. In the PL group, infarct size was 37.2+/-9.8% (LV %) as measured by MRI and 38.8+/-9% (LV %) by TTC (P=NS). In the IR group, infarct size was 23.2+/-8.8% (LV %) as measured by MRI and 24.4+/-9.2% (LV %) by TTC (P=NS). Infarction volume measured with MRI was strongly correlated to TTC staining (R=0.82 for PL, R=0.973 for IR). Increased inflammatory cell infiltration was detected in the infarct area of the heart after reperfusion compared to permanent ligation (P<.01). The ratio of TUNEL-positive cardiomyocytes to total number of cardiomyocytes in the IR group was significantly reduced as compared to the PL group (P<.01). CONCLUSIONS: MRI can accurately assess infarct size in intact rats early after MI. After transient arterial occlusion, the size of the myocardial infarct was found to be significantly smaller as compared to permanent occlusion. PMID- 21652225 TI - Metallosis after hemiarthroplasty as a result of glenoid erosion causing contact with retained metallic suture anchors: a case series. PMID- 21652226 TI - Influence of prosthetic design on radiocapitellar concavity-compression stability. AB - BACKGROUND: Radial head prostheses are available with multiple geometric properties. The effect of design features on radiocapitellar stability has not been investigated. HYPOTHESIS: The shape (depth and radius of curvature) of the articulating dish of a radial head prosthesis affects radiocapitellar stability. MATERIALS AND METHODS: Radiocapitellar stability due to concavity-compression was evaluated in 8 fresh frozen elbows before and after radial head replacement with 2 different designs of radial head implants (RH 1 and RH 2). Both functioned as monopolar implants. Peak forces resisting subluxation and force-displacement characteristics were compared between the 2 and to the native radial head. RESULTS: Radial head design significantly affected radiocapitellar stability. RH 1, which had a deeper dish than RH 2, required significantly higher peak forces to subluxate the radiocapitellar joint. The peak subluxation forces and the slopes of the force-displacement curves were not significantly different from the native radial head for RH 1, but they were for RH 2. CONCLUSION: The shape of the articular dish (depth, radius of curvature) of a monopolar radial head implant affects its contribution to radiocapitellar stability. An implant that mimics normal anatomy is more effective than a shallow radial head implant with a radius of curvature that is longer than normal. PMID- 21652227 TI - Pathologic fracture of a calcaneal aneurysmal bone cyst. AB - A 21-year-old man presented with a pathologic fracture through the posterior aspect of the calcaneus into an aneurysmal bone cyst. The patient was treated using curettage, phenol, alcohol, and burr with open reduction and internal fixation. This is the first reported case of a pathologic fracture of an aneurysmal bone cyst of the calcaneus, highlighting the fracture potential of these lesions and the need for early management. PMID- 21652228 TI - Quantification and perception of on-call podiatric surgical resident workload. AB - The general assumption inherent to the design of podiatric surgical residency programs is that all residents will have comparable experiences in terms of patient care interactions and workload throughout their training. Despite this, there is usually the perception that certain residents consistently have greater or smaller workloads when on-call and are considered "black clouds" or "white clouds," respectively. During a prospective investigational period of 1 year, on call podiatric residents at a level 1 trauma center recorded their workload on a nightly basis in terms of three variables: pages/telephone calls, consultations, and hospital admissions. The results of these data suggest that all residents shared a similar workload during the study period without a clinically significant "black cloud" or "white cloud." However, a difference was found in the perception of which resident was a "black cloud" or "white cloud." PMID- 21652229 TI - A guide to stereoscopic 3D displays in medicine. AB - Stereoscopic displays can potentially improve many aspects of medicine. However, weighing the advantages and disadvantages of such displays remains difficult, and more insight is needed to evaluate whether stereoscopic displays are worth adopting. In this article, we begin with a review of monocular and binocular depth cues. We then apply this knowledge to examine how stereoscopic displays can potentially benefit diagnostic imaging, medical training, and surgery. It is apparent that the binocular depth information afforded by stereo displays 1) aid the detection of diagnostically relevant shapes, orientations, and positions of anatomical features, especially when monocular cues are absent or unreliable; 2) help novice surgeons orient themselves in the surgical landscape and perform complicated tasks; and 3) improve the three-dimensional anatomical understanding of students with low visual-spatial skills. The drawbacks of stereo displays are also discussed, including extra eyewear, potential three-dimensional misperceptions, and the hurdle of overcoming familiarity with existing techniques. Finally, we list suggested guidelines for the optimal use of stereo displays. We provide a concise guide for medical practitioners who want to assess the potential benefits of stereo displays before adopting them. PMID- 21652230 TI - A pulmonary nodule view system for the Lung Image Database Consortium (LIDC). AB - RATIONALE AND OBJECTIVES: The aim of this study was to develop a pulmonary nodule viewing system to visualize and retrieve data from the Lung Image Database Consortium. MATERIALS AND METHODS: The pulmonary nodule viewing system, developed using Microsoft C++ and the .NET 2.0 Framework, is composed of a clinical information integrator, a nodule viewer, a search engine, and a data model. RESULTS: A pulmonary nodule viewing system using Lung Image Database Consortium data for computer-aided diagnosis research and training purpose was developed. CONCLUSIONS: The pulmonary nodule viewing system can be used to build a pulmonary nodule database for computer-aided diagnosis research and medical education. It can also be used to view and retrieve large data sets efficiently. PMID- 21652231 TI - Image quality in reduced-dose coronary CT angiography. AB - RATIONALE AND OBJECTIVES: Concerns for patient's risk of radiation-induced cancer have increased demand for reduced-dose coronary computed tomography angiography (CCTA). Previous comparisons of full and reduced-dose CCTA were not conclusive, because results were compared in different groups of patients. Presented here are results in patients examined by a widely used full dose CCTA protocol and a new low-dose alternative. MATERIALS AND METHODS: Standard full-dose and low-dose CCTA with tube voltages of 120/100 kV were applied on 70 patients with intermediate probability of coronary artery disease (CAD). Both protocols used prospective electrocardiogram-gated acquisition on a 320-detector row CT scanner, whereas at low-dose CCTA the phase window was increased from 10% to 75% of R-R interval. RESULTS: Despite a mean dose reduction of 80%, from 4.9 +/- 0.98 to 0.98 +/- 0.24 mSv, visual image quality was not significantly affected at the low-dose protocol. Contrast level, image noise, and CNR for both protocols were similar in the majority of coronary segments. CNR for standard and low-dose protocol were 23.7 +/- 17.1 and 23.2 +/- 26.8, P = NS. Correlation between visual image quality and heart rate variability was strong at low dose: r = -0.58, P = .01, and absent at full dose: r = -0.07, P = .77. CONCLUSION: Image quality of blood vasculature is generally not affected by 80% CCTA dose reduction applied to standard prospective electrocardiogram-gated acquisition. The performance at the low-dose protocol owes to the increased phase window, enhancing image quality at the cost of sensitivity to heart rate variability as compared with standard CCTA. PMID- 21652232 TI - Comparison of CT perfusion and digital subtraction angiography in the evaluation of delayed cerebral ischemia. AB - RATIONALE AND OBJECTIVES: Delayed cerebral ischemia (DCI) is a devastating condition that occurs secondary to aneurysmal subarachnoid hemorrhage (A-SAH). The purpose is to compare computed tomography perfusion (CTP) and digital subtraction angiography (DSA) for determining DCI in A-SAH. MATERIALS AND METHODS: A retrospective study of A-SAH patients admitted at our institution between December 2004 and December 2008 was performed. CTP and DSA were obtained at days 6-8 after aneurysm rupture. Both qualitative and quantitative analyses of CT perfusion deficits were performed. DSA was categorized as presence or absence of vasospasm. The reference standard for determining DCI was based on clinical deterioration or infarction on CT or MRI. The test characteristics of CTP and DSA were calculated and their graphs of conditional probabilities were constructed using Bayesian analysis. RESULTS: Fifty-seven patients were included; 79% (45/57) had DCI. Seventy percent (40/57) had CTP perfusion deficits; 80% (36/45) of the DCI and 33% (4/12) of no DCI patients. Sixty-three percent (36/57) had DSA demonstrating vasospasm; 73% (33/45) of the DCI and 25% (3/12) of no DCI patients. Quantitative analysis of the CTP data revealed a significant difference in cerebral blood flow values for the DCI (29.4 mL/100 g/minute) and no DCI groups (40.5 mL/100 g/minute, P = .0213). The sensitivity, specificity, and positive and negative predictive values for CTP were 0.80 (95% CI 0.68-0.92), 0.67 (95% CI 0.40-0.93), 0.90 (95% CI 0.82-0.96), 0.47 (95% CI 0.27-0.62), and for DSA were 0.73 (95% CI 0.60-0.86), 0.75 (95% CI 0.50-0.99), 0.92 (95% CI 0.82 0.98), and 0.43 (95% CI 0.26-0.53), respectively. CONCLUSION: CTP and DSA have similar test characteristics and Bayesian analysis for determining DCI in A-SAH patients. PMID- 21652233 TI - Triple-negative breast cancer: are the imaging findings different between responders and nonresponders to neoadjuvant chemotherapy? AB - RATIONALE AND OBJECTIVES: The purpose of the present study was to evaluate the imaging findings of triple-negative breast cancer patients receiving neoadjuvant chemotherapy (NAC) and to investigate whether the findings are different between responders and nonresponders, enabling us to predict the final patient response. MATERIALS AND METHODS: The subjects included 22 women ages 35-73 years (mean, 50.4 years) with 23 triple-negative breast cancers who underwent NAC. In all cases, a mammography, ultrasound, and magnetic resonance imaging (MRI) were performed a total of three times: before NAC, after the first half of NAC, and after NAC. The mass shape, mass margin, presence of clear intratumoral necrosis, and presence of intratumoral calcification were analyzed. The presence of clear intratumoral necrosis was evaluated on the MRI. If there was a very high signal intensity (similar to that of water) in the tumor on the fat-suppressed T2 weighted MRI scans, we judged it to be clear intratumoral necrosis. RESULTS: An irregularly shaped mass (P = .018) and the presence of clear intratumoral necrosis (P = .044) were significantly associated with NAC nonresponse in triple negative breast cancer patients. The mass margin and the presence of intratumoral calcification were not related to the effects after NAC. CONCLUSIONS: In cases of triple-negative breast cancer involving clear intratumoral necrosis with an irregular mass shape, it is predicted that the effects of neoadjuvant chemotherapy will likely be poor, and therefore, the presence of such image findings may be useful for determining the optimal application of neoadjuvant chemotherapy. PMID- 21652234 TI - Improved curvature estimation for computer-aided detection of colonic polyps in CT colonography. AB - RATIONALE AND OBJECTIVES: Current schemes for computer-aided detection (CAD) of colon polyps usually use kernel methods to perform curvature-based shape analysis. However, kernel methods may deliver spurious curvature estimations if the kernel contains two surfaces, because of the vanished gradient magnitudes. The aim of this study was to use the Knutsson mapping method to deal with the difficulty of providing better curvature estimations and to assess the impact of improved curvature estimation on the performance of CAD schemes. MATERIALS AND METHODS: The new method was compared to two widely used kernel methods in terms of the performance of two stages of CAD: initial detection and true-positive and false-positive classification. The evaluation was conducted on a database of 130 computed tomographic scans from 67 patients. In these patient scans, there were 104 clinically significant polyps and masses >5 mm. RESULTS: In the initial detection stage, the detection sensitivity of the three methods was comparable. In the classification stage, at a 90% sensitivity level on the basis of the input of this step, the new technique yielded 3.15 false-positive results per scan, demonstrating reductions in false-positive findings of 30.2% (P < .01) and 27.9% (P < .01) compared to the two kernel methods. CONCLUSIONS: The new method can benefit CAD schemes with reduced false-positive rates, without sacrificing detection sensitivity. PMID- 21652235 TI - Quantification of epicardial adipose tissue: correlation of surface area and volume measurements. AB - OBJECTIVES: Epicardial adipose tissue (EAT) is an important structure both as an active secretor of hormones and cytokines that play a role in the development of atherosclerosis, as well as its potential as a cardiac risk marker. The purpose of this article was to determine an easy but accurate quantification of EAT for routine clinical use. METHODS AND RESULTS: We randomly selected coronary computed tomography angiographies of 60 patients (20 lean, 20 overweight, and 20 obese) derived from a larger study. Systolic and diastolic surface areas (SAs) were measured at two axial levels: a) fat pocket (FP) between right atrium and right ventricular outflow tract at origin of right coronary artery (RCA-FP) and b) FP anterior to right ventricular free wall (RVFW-FP) at coronary sinus ostium level. Maximum RVFW-FP thickness and total diastolic EAT volume were measured. EAT SA and thickness measurements were correlated to EAT volume and compared. Both interobserver and intraobserver reliability were assessed for SA and thickness with the intraclass correlation coefficient (ICC) as well as mean relative difference +/- standard deviation (SD). Differences between systolic and diastolic SA measurements were also evaluated. Diastolic RCA-FP showed the highest SA correlation with volume (rho = 0.92) and compared to the correlation of EAT thickness with volume (rho=0.59) demonstrated the largest difference in correlation (+ 0.33, P < .0001). Systolic RCA-FP, systolic RVFW-FP, and diastolic RVFW-FP correlations to volume were less than diastolic RCA-FP (rho = 0.84, rho = 0.82, rho = 0.86 respectively), but all correlations were statistically significantly higher than EAT thickness with volume. Values of systolic SA were mildly higher than diastolic SA for the RCA-FP (relative difference +/- SD = 1.8 +/- 21%, P = .8), but significantly higher for the RVFW-FP (relative difference +/- SD = 17 +/- 35%, P < .0001). Both systolic and diastolic SA measurements showed excellent reproducibility (ICC >0.95). However, for EAT thickness, the inter-observer reliability was comparatively low (ICC = 0.66). CONCLUSION: Diastolic RCA-FP SA is a quick, reproducible estimate of total EAT and compared to EAT thickness demonstrates a significantly better correlation with EAT volume. PMID- 21652237 TI - Comparison of 51chromium-labeled ethylenediamine tetra-acetic acid and iohexol as blood markers for intestinal permeability testing in Beagle dogs. AB - (51)Chromium-labeled ethylenediamine tetra-acetic acid ((51)Cr-EDTA) is the gold standard probe for assessing intestinal permeability (IP) in dogs, but exposure to radioactivity is a disadvantage. Iohexol is a safe contrast medium commonly used for medical imaging purposes and has been successfully applied more recently for the assessment of IP in animal models and humans. This study aimed at comparing (51)Cr-EDTA and iohexol as IP blood markers in dogs. A test solution containing (51)Cr-EDTA and iohexol was administered intragastrically to seven healthy laboratory Beagle dogs, and percentage recoveries in serum were calculated. The strong linear association (correlation, r=0.76 and linear regression, y=0.03+5.04x) between (51)Cr-EDTA and iohexol supports the potential usefulness of iohexol as an IP blood marker in dogs. PMID- 21652236 TI - A systematic review of CPAP adherence across age groups: clinical and empiric insights for developing CPAP adherence interventions. AB - Continuous positive airway pressure (CPAP) is a highly efficacious treatment for obstructive sleep apnea (OSA) but adherence to the treatment limits its overall effectiveness across all age groups of patients. Factors that influence adherence to CPAP include disease and patient characteristics, treatment titration procedures, technological device factors and side effects, and psychological and social factors. These influential factors have guided the development of interventions to promote CPAP adherence. Various intervention strategies have been described and include educational, technological, psychosocial, pharmacological, and multi-dimensional approaches. Though evidence to date has led to innovative strategies that address adherence in CPAP-treated children, adults, and older adults, significant opportunities exist to develop and test interventions that are clinically applicable, specific to sub-groups of patients likely to demonstrate poor adherence, and address the multi-factorial nature of CPAP adherence. The translation of CPAP adherence promotion interventions to clinical practice is imperative to improve health and functional outcomes in all persons with CPAP-treated OSA. PMID- 21652238 TI - Application of trigeminal-evoked responses to headshaking in horses. PMID- 21652239 TI - Partial characterization of cobalamin deficiency in Chinese Shar Peis. AB - A total of 22,462 serum sample results from dogs being evaluated for gastrointestinal disease at the Gastrointestinal Laboratory, College of Veterinary Medicine, Texas A&M University were evaluated retrospectively. The proportion of dogs with serum cobalamin concentrations below the reference interval and median serum concentrations were compared between Shar Peis and other dog breeds. Serum samples were also obtained prospectively from 22 healthy and 32 Shar Peis with chronic gastrointestinal disease and 59 healthy dogs of other breeds, and serum concentrations of cobalamin, folate, and methylmalonic acid were determined and compared. Overall, 64.0% (89/139) of serum samples from Shar Peis showed serum cobalamin concentrations below the limit of the reference interval and 38.1% (53/139) of these were below the detectable limit for the assay. The median serum cobalamin concentration in Shar Peis was significantly lower than in other breeds. Shar Peis with gastrointestinal disease had significantly lower serum cobalamin and higher serum methylmalonic acid concentrations compared to healthy Shar Peis. Healthy Shar Peis had significantly increased serum methylmalonic acid concentrations compared to healthy dogs of other breeds. There were no meaningful differences in folate concentrations between groups. In conclusion, Shar Peis have a high prevalence of cobalamin deficiency compared to other breeds and healthy Shar Peis may have subclinical cobalamin deficiency. PMID- 21652240 TI - Pharmacokinetics of mirtazapine and its main metabolites in Beagle dogs: a pilot study. AB - Mirtazapine (MRT) is a human antidepressant drug mainly metabolised by the cytochrome P450 enzyme system to 8-OH mirtazapine (8-OH) and dimetilmirtazapine (DMR). The drug is usually administered to dogs with anorexia according to doses extrapolated from humans, although it could also have applications as an antidepressant and analgesic in this species. The aim of this study was to assess the pharmacokinetics of MRT and its metabolites, DMT and 8-OH. Six healthy male Beagle dogs were administered MRT orally (20 mg/dog) and plasma MRT and metabolite concentrations were evaluated by high performance liquid chromatography with fluorescence detection. The pharmacokinetic profiles of MRT and DMR were similar (detected from 0.25 up to 10 h), while 8-OH (detected from 0.50 up to 10 h) attained the highest concentrations. The mean half-life of MRT was 6.17 h with a clearance of 1193 mL/h/kg. The study showed that MRT has a different pharmacokinetic profile in the dog compared to other species. PMID- 21652241 TI - Expression of secreted and membrane-bound mucins in the airways of piglets experimentally infected with Mycoplasma hyopneumoniae. AB - Immunohistochemistry was used to demonstrate secreted mucins MUC2, MUC5AC and MUC5B and membrane-bound mucin MUC4 in the pulmonary bronchioles of piglets experimentally infected with Mycoplasma hyopneumoniae. Conventional status, Landrace-Duroc cross-bred piglets, 13 days of age, were randomised to two groups. One group (n=20) was infected by the intra-tracheal route with the SNU98703 strain of M. hyopneumoniae, and a group of 12 animals acted as uninfected controls. Five infected and three uninfected piglets were euthanased on the day of infection and at 7, 21, and 35 days post-inoculation (PI). Membrane-bound MUC4 and secreted MUC5AC were the predominant mucins produced in the bronchioles of the piglets in response to M. hyopneumoniae infection, but by day 35 PI, all labelled mucins had returned to pre-infection levels, contemporaneous with reduced pulmonary lesion scores. The increased mucin production may result from direct stimulation of the epithelium by mycoplasmal infection, or may arise indirectly following M. hyopneumoniae-induced ciliostasis. PMID- 21652242 TI - A comparison of the clinical features of fibromyalgia syndrome in different settings. AB - BACKGROUND: The "funnel hypothesis" of fibromyalgia syndrome (FMS) assumes that the high levels of somatic and psychological symptoms reported by FMS-patients are due to a selection bias of patients seeking for medical specialist care. We tested the hypothesis by comparing FMS-patients from a general population sample and different clinical settings. METHODS: From a cross-sectional survey of a representative sample of the German general population, persons meeting FMS criteria were selected. Consecutive in- and outpatients from German rheumatology, pain medicine, psychosomatic medicine and integrative medicine settings with established or initial diagnosis of FMS were recruited. FMS was diagnosed in all samples by the survey criteria of the regional pain scale. Somatic symptom intensity was measured by 13 items of the Patient Health Questionnaire PHQ 15, depressed mood by the 9-items PHQ 9. RESULTS: 96 persons of the general population, 86 of the rheumatology, 80 of the pain medicine, 69 of the psychosomatic medicine and 58 of the integrative medicine setting were included into the comparison. Patients of the clinical settings reported more pain sites and more somatic and depressive symptoms than FMS-persons of the general population. Patients of the different clinical settings did not differ in the number of pain sites and the intensity of depressive and somatic symptoms. CONCLUSIONS: We found a "funnel" between FMS-persons of the general population and FMS-patients of clinical settings, but not between patients of different levels of care. Patients contacting the health care system did not differ in clinical features. PMID- 21652243 TI - Removal of sidebands in double-rotation NMR in real time. AB - Double-rotation (DOR) is the only technique generally capable of yielding high resolution NMR spectra of half-integer quadrupolar nuclei in one dimension for solids without the need for sophisticated coherence pathway selection. Unfortunately, due to the low outer rotor spinning frequencies currently available, the spectra often contain a large number of spinning sidebands which may overlap with the resonances of interest. We implement a simple, robust, and easy to use family of pulse sequences, which in practice are fully analogous to the 'total suppression of sidebands' (TOSS) sequences, to suppress all sidebands arising from the spinning of the outer rotor in DOR experiments. By removing the rotor phase dependence of the evolution of the sidebands, the sidebands destructively interfere with one another during the course of signal averaging to yield 'solution-like' spectra of half-integer quadrupolar nuclei in solids. Advantages and shortcomings of the method compared to other DOR sideband suppression methods are explored with the aid of simulations. PMID- 21652245 TI - Large lipoleiomyoma of the uterine body. AB - Large or giant lipoleiomyoma of the uterine corpus is a rare condition. A 70-year old Japanese woman consulted our hospital because of a pelvic mass and abnormal uterine bleeding. Physical examination showed a mass in the pelvis. Blood laboratory test showed anemia and leukocytosis. Cholesterol, triglyceride, glucose, and hemoglobin A1c were normal. Tumor markers (CEA, CA19-9, CA125, SCC, and CA72-4) were normal. Imaging modalities including ultrasound and computed tomography revealed a characteristic large (8 * 8 * 9 cm) tumor in the posterior aspect of the uterine body. The tumor was characteristic, and the opacity was heterogenous. Radiologists' diagnosis was angiomyolipoma. Simple hysterectomy and bilateral salpingo-oophorectomy were performed. During the operation, it was found that the mass originated from the posterior aspect of the uterine body. Grossly, the resected mass was heterogenous and whitish yellow. It measured 10 * 9 * 9 cm. The tumor originated from the myometrium and assumed features of subserosal leiomyoma. Histologically, the tumor was composed of adipose tissue and smooth muscle cells. The adipose tissue was mature, and there were no atypical cells or lipoblasts. The smooth muscle areas were composed of red spindle smooth muscle cells. No atypia was seen in the smooth muscles. Mitotic figures were not recognized. Vascular proliferation was not seen. The adipose tissue element accounted for 20% in area; and the smooth muscle element, 80%. Immunohistochemically, the adipose tissue element was positive for vimentin and S100 protein, and negative for pancytokeratins (AE1/3, CAM5.2), alpha-smooth muscle actin, desmin, CD34, HMB45, p53, MDM2, CDK4, and KIT. The smooth muscle element was positive for vimentin, desmin, and alpha-smooth muscle actin, but negative for pancytokeratins (AE1/3, CAM5.2), S100 protein, CD34, HMB45, p53, MDM2, CDK4, and KIT. The Ki-67 labeling was approximately 0.3% in the smooth muscle element and approximately 0.2% in the adipose tissue element. The pathological diagnosis was large lipoleiomyoma of the uterine body. The patient is now free of the tumor 2 years after the operation. PMID- 21652244 TI - Medical and surgical outcomes in childhood glaucoma: a population-based study. AB - INTRODUCTION: To describe the clinical and surgical outcomes among patients younger than 20 years of age diagnosed with glaucoma in a defined population during a 40-year period. METHODS: The medical records of all patients (<20 years) diagnosed with glaucoma in Olmsted County, Minnesota, from January 1, 1965, through December 31, 2004, were retrospectively reviewed. RESULTS: Thirty children (45 eyes) were diagnosed with various forms of glaucoma during the 40 year study period. During a mean follow-up of 12.5 years (range, 7 days to 32 years), 18 (60%) of the 30 children underwent a mean of 2.7 surgeries (range, 1 to 10), including 6 (20%) patients whose sole surgery consisted of enucleation or evisceration for a blind, painful eye. Twenty-eight (93%) of the 30 children required medical management during the follow-up period, including 14 (47%) treated before their first surgery. At the final follow-up examination, 11 (37%) had a visual acuity of 20/200 or worse. The 10-year Kaplan-Meier risk of vision decreasing less than 20/200 in all glaucoma patients was 22.7% (95% CI, 0-40.9), and patients requiring any glaucoma surgery was 68.3% (95% CI, 42.4-82.6). CONCLUSIONS: In this population-based study of children diagnosed with glaucoma during a 40-year period, most patients required surgery, with few being successfully controlled by medications alone. A poor visual outcome or the loss of an eye was relatively common. PMID- 21652246 TI - Endometrial stromal sarcoma: clinicopathological and immunophenotype study of 18 cases. AB - Malignant tumors of the uterine corpus are uncommon. They originate from the endometrial stroma, smooth muscle, blood vessels, or from a mixture of them. The objective of this article was to know the frequency and the clinical, morphologic, and immunophenotype characteristics of the endometrial stromal sarcoma (ESS). We reviewed the cases of ESS observed from 2002 to 2008 at the Pathology Unit of the General Hospital of Mexico. The following data were analyzed: age, clinical stage, degree of differentiation, and immunophenotype. We found 18 cases, and the average age of patients was 48.6 years; 66% were in clinical stages 1 and 2. Fifteen cases (83.3%) were classified as low-grade sarcomas and 3 (16.6%) as high-grade or undifferentiated sarcomas. We determined immunohistochemical markers in 17 cases; receptors to estrogens were positive in 5 (29.4%) and to progesterone in 9 (52.9%). CD10 was expressed in 10 (58.8%) and p53 in 11 cases (64.7%). Two cases were associated to primary tumors of the ovary (papillary cystadenocarcinoma). In conclusion, ESS was present at 0.6% in our institution; and most were low grade. Expression of markers, such as p53, CD10, and hormonal receptors, was positive. PMID- 21652247 TI - Primary CD5-positive mucosa-associated lymphoid tissue lymphoma of the urinary bladder. PMID- 21652248 TI - Thymomas diagnosed during pregnancy: two cases in young women without paraneoplastic or autoimmune disease. AB - We report 2 cases of thymomas diagnosed during pregnancy. Neither of these 2 patients had paraneoplastic autoimmune conditions or previous neoplasia. The first patient had a 7.3-cm lymphocyte-predominant thymoma with capsular invasion. The second patient was diagnosed through fine needle aspiration biopsy after computed tomography showed multiple mediastinal masses. Although cases of thymoma during pregnancy have been reported, the exact cause has yet to be elucidated. We review the clinical, radiologic, pathologic, and immunohistochemical findings including those of podoplanin, estrogen receptor, and progesterone receptor-of 2 previously unreported cases, as well as discuss the relationship of malignancy and pregnancy and review the available literature regarding pregnancy and thymoma. PMID- 21652250 TI - A long femur scan field does not alter proximal femur bone mineral density measurements by dual-energy X-ray absorptiometry. AB - A longer dual-energy X-ray absorptiometry (DXA) femur scan field might be useful for the detection of atypical, subtrochanteric femur fractures (ASFF). Thirty adult subjects underwent triplicate measures of femoral neck (FN) and total hip (TH) bone mineral density (BMD) by DXA using a conventional (i.e., short) and a longer femur scan field. Differences in measured BMD between the 2 scan field lengths were small and less than the precision error inherent in DXA testing. A longer proximal femur scan field does not substantially alter BMD measurements made at the FN and TH and may be useful for the detection of ASFF in clinical practice. PMID- 21652251 TI - Osteoporotic fractures in the Brazilian community-dwelling elderly: prevalence and risk factors. AB - The risk of osteoporotic fractures is known to vary among populations. There are no studies analyzing concomitantly clinical, densitometric, and lab risk factors in miscigenated community-dwelling population of Brazil. A total of 1007 elderly subjects (600 women and 407 men) from Sao Paulo, were evaluated using a questionnaire that included risk factors for osteoporotic fractures. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at the hip and lumbar spine. Laboratory blood tests were also obtained. The prevalence of osteoporotic fractures was 13.2% (133 subjects), and the main fracture sites were distal forearm (6.0%), humerus (2.3%), femur (1.3%), and ribs (1.1%). Women had a higher prevalence (17.5%; 95% confidence interval [CI]: 14.6-20.6) than men (6.9%; 95% CI: 4.4-9.3) (p<0.001). After adjusting for significant variables, logistic regression revealed that female gender (odds ratio [OR]=2.7; 95% CI; 1.6 4.5; p<0.001), current smoking (OR=1.9; 95% CI: 1.2-3.3; p=0.013), and the femoral neck T-score (OR=0.7; 95% CI: 0.5-0.9; p=0.001) remain significant risk factors for osteoporotic fractures in the community-dwelling elderly. Our findings identified that female gender, current smoking, and low hip BMD are independent risk factors for osteoporotic fractures. PMID- 21652249 TI - Lean mass predicts hip geometry in men and women with non-insulin-requiring type 2 diabetes mellitus. AB - Persons with type 2 diabetes mellitus (T2DM) are at increased risk for hip fracture despite normal bone mineral density (BMD). The contribution of body composition to hip geometry, a measure of hip strength, has not been studied in T2DM. We hypothesized that lean mass would predict hip geometry. Subjects (n=134) for this cross-sectional analysis were men and women aged 56 +/- 6yr with non insulin-requiring T2DM. Fat and lean mass were measured with dual-energy X-ray absorptiometry (DXA). Abdominal fat was measured with magnetic resonance imaging. Hip geometry parameters including section modulus, cross-sectional area, and buckling ratio were estimated from DXA using validated formulae. Subjects had normal BMD, elevated body mass indices (29-41 kg/m(2)), and controlled T2DM (hemoglobin A1c: 5.1-8.3%). In bivariate analysis, lean mass was positively associated with section modulus and cross-sectional area in both sexes (r=0.36 0.55, p<0.05). In multivariate analyses, lean mass remained a significant predictor of all hip strength estimates in both sexes. In women alone, fat mass predicted parameters of hip strength. These data demonstrate that lean mass is significantly associated with hip strength in subjects with non-insulin-requiring T2DM. Resistance exercises that build lean mass may be an intervention for hip fracture prevention in T2DM, although additional research is needed. PMID- 21652253 TI - Blurred vision as primary presentation of tuberculosis. PMID- 21652254 TI - [Intensity modulated radiation therapy: analysis of patient specific quality control results, experience of Rene-Gauducheau Centre]. AB - PURPOSE: Systematic verifications of patient's specific intensity-modulated radiation treatments are usually performed with absolute and relative measurements. The results constitute a database which allows the identification of potential systematic errors. MATERIAL AND METHODS: We analyzed 1270 beams distributed in 232 treatment plans. Step-and-shoot intensity-modulated radiation treatments were performed with a Clinac (6 and 23 MV) and sliding window intensity-modulated radiation treatments with a Novalis (6 MV). RESULTS: The distributions obtained do not show systematic error and all the control meet specified tolerances. CONCLUSION: These results allow us to reduce controls specific patients for treatments performed under identical conditions (location, optimization and segmentation parameters of treatment planning system, etc.). PMID- 21652255 TI - Ultrasound assisted one pot synthesis of imidazole derivatives using diethyl bromophosphate as an oxidant. AB - A one pot, three-component condensation of benzoin/benzyl, an aldehyde, and ammonium acetate using diethyl bromophosphate as a mild oxidant is achieved to form trisubstituted imidazole compounds. Under ultrasound irradiation, a smooth condensation occurs to get the 2, 4, 5-triaryl-1H-imidazole compounds in good to excellent yields. The study explores the scope and limitation of diethyl bromophosphate as an oxidant and suggests advantages, viz., simplicity of operation, reduction in time, and an increase in product yields. PMID- 21652256 TI - Sonocatalytic degradation of Rhodamine B in the presence of C60 and CdS coupled TiO2 particles. AB - CdS-TiO2 and CdS-C60/TiO2 were prepared using C60, cadmium acetate dehydrate [(CH3COO)2Cd.2H2O], sodium sulfide (Na2S.5H2O) and titanium (IV) n-butoxide by a sol-gel method. The prepared sonocatalysts were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and transmission electron microscopy (TEM). A rhodamine B (RhB) solution under ultrasonic irradiation was used to determine the catalytic activity. Excellent catalytic degradation of an RhB solution was observed using the CdS C60/TiO2 composites under ultrasonic irradiation. C60 coupled CdS-TiO2 can enhance the Brunauer-Emmett-Teller (BET) surface area and increase the decolorization rate for rhodamine B solution. The results also shows that increase the content of CdS can enhance the catalytic activity. PMID- 21652257 TI - Investigation of sleep disturbance in chronic low back pain: an age- and gender matched case-control study over a 7-night period. AB - Sleep disturbance is frequently reported by people with chronic low back pain (>12 weeks; CLBP), but few studies have comprehensively investigated sleep in this population. This study investigated differences in subjectively and objectively measured sleep patterns of people with CLBP, and compared this to age and gender matched controls. Thirty-two consenting participants (n = 16 with CLBP, n = 16 matched controls), aged 24-65 years (43.8% male) underwent an interview regarding sleep influencing variables, completed the Pittsburgh Sleep Quality Index, Insomnia Severity Index, Pittsburgh Sleep Diary, SF36-v2, Hospital Anxiety and Depression Scale, Oswestry Disability Index, Numerical Pain Rating Scales, and underwent seven consecutive nights of actigraphic measurement in the home environment. Compared to controls, people with CLBP had, on self-report measures, significantly poorer sleep quality [Pittsburgh Sleep Quality Index (range 0-21) mean (SD) 10.9 (4.2)], clinical insomnia [Insomnia Severity Index mean (range 0-28) 13.7 (7.6)], lower sleep efficiency, longer sleep onset latency, more time awake after sleep onset, and more awakenings during sleep (p < 0.05). However, no significant differences between groups were found on objective actigraphy (p > 0.05). The findings provide some evidence to support self reported sleep assessment as an outcome measure in CLBP research, while further research is needed to determine the validity of objective sleep measurement in this population. PMID- 21652258 TI - Overexpression of thioredoxin system proteins predicts poor prognosis in patients with squamous cell carcinoma of the tongue. AB - The human thioredoxin (Trx) system plays a critical role in the regulation of cellular reduction-oxidation (redox) homeostasis, which has been widely investigated in several types of cancer because of its association with cell growth and anti-apoptosis progress. This study aimed to evaluate the expression of Trx and Trx reductase-1 (TrxR-1) and explore the potential role of these proteins in tongue squamous cell carcinoma (TSCC). Immunohistochemistry was employed to analyze the protein expression levels of Trx and TrxR-1 in 65 TSCC tissue samples and 10 normal oral mucosa samples. The results were then evaluated semiquantitatively and compared to other clinicopathological variables. Both Trx and TrxR-1 expression levels were significantly higher in TSCC tissues as compared with the 10 normal oral mucous samples (P<0.01). A highly significant association between Trx and TrxR-1 expression in TSCCs was revealed (P=0.001), and the expression of Trx was correlated with tumour cell differentiation (P=0.001). Moreover, Kaplan-Meier analysis revealed that Trx expression and TNM stage were significantly related with 5-year survival rate (P=0.033, 0.000), while TrxR-1 expression was not associated with survival (P=0.092). The results indicated that high expression of Trx and TrxR-1 was associated with tumourigenesis in TSCC, and overexpression of Trx might predict poor prognosis. PMID- 21652259 TI - Mixed alkali effect and optical properties of Ni2+ doped 20ZnO+xLi2O+(30 x)Na2O+50B2O3 glasses. AB - Optical and physical properties of Ni2+ doped 20ZnO+xLi2O+(30-x)Na2O+50B2O3 (5<=x<=25) glasses are carried out at room temperature. Powder XRD pattern of all the glass samples confirms the amorphous nature. Several physical parameters are evaluated for all the glasses with respect to the composition. The optical absorption spectra confirm the site symmetry of the Ni2+ doped glasses are near octahedral. Crystal field and inter-electronic repulsion parameters are also evaluated. It is interesting to observe that the optical band gap and Urbach energies exhibit the mixed alkali effect. The FT-IR spectral investigations of Ni2+ doped glasses exhibit characteristic vibrations of BO3 and BO4 units. PMID- 21652260 TI - Synthesis of positively charged CdTe quantum dots and detection for uric acid. AB - The CdTe dots (QDs) coated with 2-Mercaptoethylamine was prepared in aqueous solution and characterized with fluorescence spectroscopy, UV-Vis absorption spectra, high-resolution transmission electron microscopy and infrared spectroscopy. When the lambdaex=350 nm, the fluorescence peak of positively charged CdTe quantum dots is at 592 nm. The uric acid is able to quench their fluorescence. Under optimum conditions, the change of fluorescence intensity is linearly proportional to the concentration of uric acid in the range 0.4000-3.600 MUmol L(-1), and the limit of detection calculated according to IUPAC definitions is 0.1030 MUmol L(-1). Compared with routine method, the present method determines uric acid in human serum with satisfactory results. The mechanism of this strategy is due to the interaction of the tautomeric keto/hydroxyl group of uric acid and the amino group coated at the CdTe QDs. PMID- 21652262 TI - Effect of amino group density for prevention of mammary gland tissue detachment from coated glass surface. AB - Tissue detachment from histological glass slides coated with different amino group densities was investigated during heat treatment for immunohistochemical staining. In both sow and piglet mammary gland tissues, the results clearly showed strong adhesion and high retention on self-assembled monolayers with high amino group density. PMID- 21652261 TI - Electrophysiological traces of visuomotor learning and their renormalization after sleep. AB - OBJECTIVE: Adapting movements to a visual rotation involves the activation of right posterior parietal areas. Further performance improvement requires an increase of slow wave activity in subsequent sleep in the same areas. Here we ascertained whether a post-learning trace is present in wake EEG and whether such a trace is influenced by sleep slow waves. METHODS: In two separate sessions, we recorded high-density EEG in 17 healthy subjects before and after a visuomotor rotation task, which was performed both before and after sleep. High-density EEG was recorded also during sleep. One session aimed to suppress sleep slow waves, while the other session served as a control. RESULTS: After learning, we found a trace in the eyes-open wake EEG as a local, parietal decrease in alpha power. After the control night, this trace returned to baseline levels, but it failed to do so after slow wave deprivation. The overnight change of the trace correlated with the dissipation of low frequency (<8 Hz) NREM sleep activity only in the control session. CONCLUSIONS: Visuomotor learning leaves a trace in the wake EEG alpha power that appears to be renormalized by sleep slow waves. SIGNIFICANCE: These findings link visuomotor learning to regional changes in wake EEG and sleep homeostasis. PMID- 21652263 TI - Quality by design in lead optimization: a new strategy to address productivity in drug discovery. AB - The constant decline in drug discovery productivity despite the continuous growth in R&D investments has been on the table for many years and is driving changes in the current business model. We have focused our attention on what appears to be by far the major cause of attrition, the intrinsic quality of drug candidates; with the assumption that candidate quality can be designed and assessed at a rather early stage in drug discovery we have developed tools such as CNS chemical space mapping through PLS analysis, Drug Efficiency (DRUG(eff)) and the mechanistic PK/PD hypothesis. We also introduced best practices that were found extremely valuable which will be discussed in this article. PMID- 21652264 TI - MicroRNA pharmacogenomics: post-transcriptional regulation of drug response. AB - The field of pharmacogenomics aims to predict which drugs will be most effective and safe for a particular individual based on their genome sequence or expression profile, thereby allowing personalized treatment. The bulk of pharmacogenomic research has focused on the role of single nucleotide polymorphisms, copy number variations or differences in gene expression levels of drug metabolizing or transporting genes and drug targets. In this review paper, we focus instead on microRNAs (miRNAs): small noncoding RNAs, prevalent in metazoans, that negatively regulate gene expression in many cellular processes. We discuss how miRNAs, by regulating the expression of pharmacogenomic-related genes, can play a pivotal role in drug efficacy and toxicity and have potential clinical implications for personalized medicine. PMID- 21652265 TI - Exposing the tensions of implementing supervision in pre-registration nurse education. AB - This discussion will examine the complexities of implementing group clinical supervision in pre-registration nurse education. Exploration is based upon the authors' experiences of facilitating clinical supervision with mental health branch students on the Diploma/BSc program at one higher education institution in the UK. It will provide the history and context of clinical supervision in nursing and apply this to the educational setting. This discussion aims to move beyond the rhetoric surrounding clinical supervision to expose the underlying tensions which we propose influence the clinical supervision process in pre registration nurse education. These include the potential confusion of role for the supervisor, conflict of responsibilities and the potentially vulnerable position they may adopt. However, despite these tensions it is proposed that clinical supervision has a key role within graduate pre-registration nursing education. PMID- 21652266 TI - Management of congenital uterine abnormalities. AB - Congenital uterine abnormalities are a heterogeneous group of uterine configurations that may adversely affect reproductive potential. Although subtle variations can occur, the more common abnormalities fall into two broad categories of unilateral development or failure of midline fusion. These abnormalities have been well described for over a century although the mechanisms of their unfavourable impact on fertility and clinical management have not been systematically studied until recently. The quality of the literature on this topic has traditionally fallen below the level on which solid evidence-based decisions can be made. Nonetheless, considerable progress has been made in recent times. The understanding of the aetiology of these abnormalities and how they impact reproduction has matured and evolved and this evolution and the growing body of recent studies better define clinical scenarios in which intervention will clearly and positively impact outcome. This article will review four common congenital abnormalities, their impact on reproduction, options for management and the role of assisted reproduction treatment in maximizing reproductive potential. Recommendations are made with consideration of the quality of the literature in an outcome-driven environment. PMID- 21652267 TI - Which food patterns are predictors of obesity in Tehranian adults? AB - OBJECTIVES: To determine whether changes in food patterns over a period of 6 years were related to obesity in Tehranian adults. DESIGN: Data on dietary intake, using the food frequency questionnaire, and anthropometry were obtained in 2 periods of the survey (1999-2001 and 2005-2007). SETTING: Participants of the Tehran Lipid and Glucose Study. PARTICIPANTS: Two hundred six adults. MAIN OUTCOME MEASURES: Waist circumference, body mass index, and waist-to-hip ratio. ANALYSIS: Food patterns were derived using factor analysis. RESULTS: Three dietary patterns, the healthful (HDP), the western (WDP), and the mix, were identified. Increased WDP score was directly related to change in body mass index (beta = .41, R(2) = 0.22, P < .001) among overweight/obese individuals. Alterations in waist circumference was better predicted by increased WDP score (beta = .49, R(2) = 0.21, P < .01) than by increased HDP score (beta = -.20, R(2) = 0.11, P < .05). Subjects in the higher quartile of increased HDP score had lesser change in waist-to-hip ratio (beta = -.77, R(2) = 0.43, P < .01). CONCLUSIONS AND IMPLICATIONS: Results of this study indicate that increased adherence to the WDP and decreased adherence to the HDP could contribute to obesity. PMID- 21652268 TI - Relationship among food-safety knowledge, beliefs, and risk-reduction behavior in university students in Japan. AB - OBJECTIVE: To identify whether university students who have both food-safety knowledge and beliefs perform risk-reduction behaviors. DESIGN: Cross-sectional research using a questionnaire that included food-safety knowledge, perceptions, risk-reduction behavior, stages for the selection of safer food based on the Transtheoretical Model, and demographic characteristics. SETTING: Four universities in eastern Japan and 2 universities in western Japan. PARTICIPANTS: University students (n = 799). MAIN OUTCOME MEASURES: Food-safety knowledge, beliefs, and risk-reduction behaviors. ANALYSIS: Answers on measures assessing risk perception and food-safety knowledge were combined to form 4 groups of participants. Relationships among demographic characteristics, the 4 groups, risk reduction behaviors, stage of change, and severity and susceptibility were assessed. RESULTS: The proportion of students who had more knowledge of food safety and a belief that "there are no 100% safe food items" was high in the group that frequently performed risk-reduction behaviors, as it was in the group who had taken a basic class about food or health care and who had, or were working toward, a food or nutrition qualification. CONCLUSIONS AND IMPLICATIONS: University students who thought that there were no 100% safe food items and who had more knowledge about food safety were more likely to confirm food-safety information when selecting food. PMID- 21652269 TI - Elevated plasma IL-22 levels correlated with Th1 and Th22 cells in patients with immune thrombocytopenia. PMID- 21652270 TI - Female gender and the risk for death after cardiac surgery in septuagenarians and octogenarians: a retrospective observational study. AB - BACKGROUND: In elderly patients, the impact of gender on outcome after cardiac surgery is a debated topic of ongoing relevance. OBJECTIVE: This study assessed the hypothesis that, among septuagenarians and octogenarians, women have poorer outcomes compared with men after cardiac surgery. METHODS: For this retrospective observational study, the electronic medical records of patients who underwent cardiac surgery between January 2006 and August 2009 at Department of Cardiothoracic Surgery, University Medical Center, Regensburg, Germany, were reviewed. The primary end points were the proportions of women and men with in hospital and 30-day mortality, and postoperative morbidity was considered a secondary end point. RESULTS: The records of 598 patients were reviewed (274 female [137 septuagenarians, 162 octogenarians; mean (SD)] age, 77.8 [4.8] years]; 324 male [137 septuagenarians, 162 octogenarians; mean age, 78.3 [4.8] years]; all, P = NS). At baseline, the gender groups differed significantly with respect to mean logistic European System for Cardiac Operative Risk Evaluation score (EuroSCORE) (used for calculating expected mortality) (11.9% in women, 9.9% in men; P = 0.007), rate of diabetes mellitus did not reach statistical significance ([statistical significance was considered at P < 0.05] 12.4% vs 7.4%; P = 0.052), rate of renal dysfunction (51.5% vs 28.6%; P < 0.001), proportion undergoing isolated valve surgery (43.1% vs 24.7%, respectively; P < 0.0001), and perfusion technique (conventional [83.2% vs 69.4%] vs minimized [16.8% vs 30.6%] extracorporeal circulation) (P < 0.0001). In-hospital mortality (7.3% vs 5.6%; P = 0.404) and 30-day mortality (8.0% vs 5.9%; P = 0.332) were not significantly different between genders. There were no significant differences in mortality with respect to age group. On multivariate analysis, age and female gender were not found to be independent risk factors for early mortality. The between-gender differences in postoperative morbidity, including central neurologic event (P = 0.412), need for dialysis (P = 0.491), and respiratory insufficiency (P = 1.00), were nonsignificant, as were median durations of intensive care unit stay (P = 0.68) and hospital stay (P = 0.52) stay. CONCLUSION: In septuagenarians and octogenarians, female gender was not associated with increased risks for morbidity and mortality after cardiac surgery. PMID- 21652273 TI - Genome-wide expression analysis of roxarsone-stimulated growth of broiler chickens (Gallus gallus). AB - Roxarsone is a commonly used additive in chicken (Gallus gallus) industry. However, little is known on the intrinsic molecular mechanism via which the growth performance of birds improves. This study was therefore performed to investigate the expression profiles of genes induced by roxarsone. Fifty-six broiler chickens were divided into two groups, namely treated and untreated with roxarsone. The treated group was provided a diet of 45.4mg/kg roxarsone medication and the other group acted as control. Data analysis showed that roxarsone consistently and significantly (P<0.05) increased chicken growth performance. In addition to this a significant (P<0.05) increase of arsenic residue in liver has been seen. Microarray expression analysis of 8935 genes in liver showed that 22 genes (10 up- and 12 down-regulated) had altered expression throughout the experimental periods. Two novel genes (GenBank accession no. GU724343 and GU724344) were cloned through rapid amplification of cDNA ends (RACE). Gene GU724343 was predicted to encode an unidentified protein and the second gene GU724344 was presumed to encode a new member of immunoglobulin-like receptor (CHIR) family. Our results suggested for the first time that the role of roxarsone could be mainly to modify the expression levels of cell growth, immunity/defense and energy metabolism associated genes, as a result promoting animal growth. Further research on these genes should help to increase the knowledge of improving animal productivity safely and effectively. PMID- 21652274 TI - Mitochondrial DNA mutations and depletion in pediatric medicine. AB - Mitochondrial disorders are a group of diseases traditionally ascribed to defects of the respiratory chain, which is the only metabolic pathway in the cell that is under the control of the two separate genetic systems, the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). Therefore the genetic classification of the primary mitochondrial diseases distinguishes disorders due to mutations in mtDNA, which are sporadic or maternal inherited, from disorders due to mutations in nDNA, which are governed by the stricter rules of mendelian genetics. Pathological alterations of mtDNA fall into two main categories: primary mutations of mitochondrial DNA (point mutations and rearrangements) and mtDNA perturbation, due to mutations in nuclear genes whose products are involved in mtDNA maintenance or replication. This article will focus on the primary mitochondrial DNA mutations and mtDNA depletion syndromes related to neonatal infant human pathology. PMID- 21652275 TI - Distally extended tensor fascia lata flap including the wide iliotibial tract for reconstruction of trochanteric pressure sores. AB - The distally extended tensor fascia lata flap is a good choice to provide sufficient tissue bulk for a deep trochanteric sore defect. However, this flap can result in necrosis of the distal skin due to inadequate blood supply, failure of primary closure at the donor site or suture separation at the proximal donor site. The viability of the distal flap depends on the longitudinal subcutaneous plexi of the perforators anastomosing through multiple small-calibre vessels. If the subcutaneous and fasciocutaneous plexi are maximally preserved, the distal flap may be viable. It may also allow the flap to be narrower at the proximal portion, allowing the donor site to be primarily closed without tension. We performed a V-shaped, distally de-epithelialised, extended tensor fascia lata flap with a wide base of the iliotibial tract. The de-epithelialised distal flap was double-folded to fill the dead space of the defect. A key surgical tip to improve blood supply to the distal flap was to preserve the iliotibial tract 1.5 cm beyond both borders of the V-shaped skin incision. A total of 14 trochanteric wounds were successfully covered in 11 patients without complication. This flap had the advantages of having soft-tissue bulk, a reliable blood supply and primary donor-site closure. This flap may provide a good option for the reconstruction of deep trochanteric pressure sores. PMID- 21652276 TI - The Tape Locking Screw technique (TLS): A new ACL reconstruction method using a short hamstring graft. AB - The Tape Locking Screw (TLS((r))) system, developed in 2003, is a new anterior cruciate ligament (ACL) reconstruction method that is based on three principles: one hamstring tendon is harvested, prepared into a short (50 to 60mm), four to five strand closed loop, with a diameter of 8 to 10mm and a 500N pre-load; the tunnels are shorter than usual (10 or 15mm) and created in a retrograde manner to match the diameter of each end of the graft. Maximum press-fit into the bone recesses is obtained by a specific graft introduction method; femoral and tibial fixation is provided by polyethylene terephthalate tape strips, or TLS((r)) strips, that pass through each end of the closed tendon loop and attach to bone with a dedicated interference screw, the TLS((r)) screw. Our preliminary clinical evaluation consisted of a follow-up of 134 patients. PMID- 21652277 TI - Dietary fiber in the diets of urban Tunisian women: association of fiber intake with BMI, waist circumference and blood chemistry: preliminary study. AB - BACKGROUND: The change of the way of life and the food practices in Tunisia due inter alia to the improvement of the socioeconomic conditions induced low fuel consumption of food with significant nutritional interest such as those rich in food fibres which have positive effects on the reduction and the prevention of some complications of the metabolic diseases such as the obesity whose prevalence among Tunisian women is increasingly high. OBJECTIVE: We assessed the association between the mean daily fiber intake and anthropometric parameters, the serum lipid profile and the serum glucose concentration among urban Tunisian women. METHODS: We conducted a 7-day food weighing method among 260 women of which 60 are obese (BMI > 30 kg/m(2)). The weighing method was done by trained and experienced workers in the National Institute of Nutrition of Tunisia. All the results were treated with the (Bilnut) software (1991 version) to which a list of 235 special Tunisian foods was added. We calculated their mean daily fiber intake and we prospectively evaluated the correlations between it and the BMI, the waist circumference, total plasma cholesterol, HDL-cholesterol, triglyceridemia and glycaemia. RESULTS: Obese women are found to consume less fiber than non-obese women (21.73 +/- 3.25 g/day vs 26.25 +/- 2.7 g/day; P<0.0001). Very high and significant correlations were observed between dietary fiber intake and the parameters investigated: BMI (r=-0.709, P<0.0001), waist circumference (r=-0.790; P<0.0001), total plasma cholesterol (r=-0.488; P<0.0001), triglyceridemia (r= 0.741; P<0.0001) and glycaemia (r=-0.557, P<0.0001). However, we find a positive but a non significant correlation with the HDL-cholesterol and the mean daily fiber intake (r=0.309; P=0.02). CONCLUSIONS: This study provides additional support to the inverse association between fiber consumption and weight gain, the serum lipid profiles, the glycaemia and the waist circumference. Our findings emphasizes the relevance of increased the intakes of fiber from varied sources that may help avoid weight gain among obese adults. PMID- 21652278 TI - Raf: a key regulatory kinase for transduction of mitogenic and metabolic signals of the probiotic Saccharomyces boulardii. PMID- 21652279 TI - The integrated virtual environment rehabilitation treadmill system. AB - Slow gait speed and interlimb asymmetry are prevalent in a variety of disorders. Current approaches to locomotor retraining emphasize the need for appropriate feedback during intensive, task-specific practice. This paper describes the design and feasibility testing of the integrated virtual environment rehabilitation treadmill (IVERT) system intended to provide real-time, intuitive feedback regarding gait speed and asymmetry during training. The IVERT system integrates an instrumented, split-belt treadmill with a front-projection, immersive virtual environment. The novel adaptive control system uses only ground reaction force data from the treadmill to continuously update the speeds of the two treadmill belts independently, as well as to control the speed and heading in the virtual environment in real time. Feedback regarding gait asymmetry is presented 1) visually as walking a curved trajectory through the virtual environment and 2) proprioceptively in the form of different belt speeds on the split-belt treadmill. A feasibility study involving five individuals with asymmetric gait found that these individuals could effectively control the speed of locomotion and perceive gait asymmetry during the training session. Although minimal changes in overground gait symmetry were observed immediately following a single training session, further studies should be done to determine the IVERT's potential as a tool for rehabilitation of asymmetric gait by providing patients with congruent visual and proprioceptive feedback. PMID- 21652280 TI - Force field adaptation can be learned using vision in the absence of proprioceptive error. AB - It has been shown that people can learn to perform a variety of motor tasks in novel dynamic environments without visual feedback, highlighting the importance of proprioceptive feedback in motor learning. However, our results show that it is possible to learn a viscous curl force field without proprioceptive error to drive adaptation, by providing visual information about the position error. Subjects performed reaching movements in a constraining channel created by a robotic interface. The force that subjects applied against the haptic channel was used to predict the unconstrained hand trajectory under a viscous curl force field. This trajectory was provided as visual feedback to the subjects during movement (virtual dynamics). Subjects were able to use this visual information (discrepant with proprioception) and gradually learned to compensate for the virtual dynamics. Unconstrained catch trials, performed without the haptic channel after learning the virtual dynamics, exhibited similar trajectories to those of subjects who learned to move in the force field in the unconstrained environment. Our results demonstrate that the internal model of the external dynamics that was formed through learning without proprioceptive error was accurate enough to allow compensation for the force field in the unconstrained environment. They suggest a method to overcome limitations in learning resulting from mechanical constraints of robotic trainers by providing suitable visual feedback, potentially enabling efficient physical training and rehabilitation using simple robotic devices with few degrees-of-freedom. PMID- 21652281 TI - A computational multiresolution BOLD fMRI model. AB - Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a widely used method for brain mapping. BOLD fMRI signal detection is based on an intravoxel dephasing mechanism. This model involves bulk nuclear spin precession in a BOLD-induced inhomogeneous magnetic field within a millimeter resolution voxel, that is, BOLD signal formation spans a huge spatial scale range from Angstrom to millimeter. In this letter, we present a computational model for multiresolution BOLD fMRI simulation, which consists of partitioning the nuclear spin pool into spin packets at a mesoscopic scale (~10(-6) m), and calculating multiresolution voxel signals by grouping spin packets at a macroscopic scale range (10(-5) to 10(-3) m). Under a small-angle approximation, we find that the BOLD signal intensity is related to its phase counterpart (or BOLD fieldmap) across two spatial resolution levels. PMID- 21652282 TI - In vivo electrochemical characterization of tissue-electrode interface during metamorphic growth. AB - The domestication of insect locomotion has been recently investigated through microelectrode based systems implanted in the insect to tap into its neuromuscular system. Benefiting from developmental changes, the idea of performing such surgical implantation during metamorphic development enabled the fusion of engineered constructs to these living biological organisms. This study uses electrochemical analysis to provide a preliminary quantitative comparison of tissue-electrode coupling over the course of metamorphic development and after eclosion, where PEDOT:PSS coated gold electrodes are implanted in the insect during the early pupal stages and right after emergence. An average 1 kHz impedance of 8.9 k was obtained with pupal stage inserted electrodes, with a stored charge of 52 mC/cm2 at the interface as characterized by cyclic voltammetry 10 days after emergence. 5.1 mC/cm2 of this charge was successfully injected into the tissue through charge balanced biphasic pulses. In comparison, implanted electrodes in the adult state caused a 1 kHz impedance of 12.1 k, where the stored charge was 38 mC/cm2 with an injectable charge amount of 3.5 mC/cm2. Finally, to shed light on possible reasons for improvement in the bioelectrical coupling, equivalent circuit models were formed and the extracted parameters were correlated with metamorphic development of pupal tissue. PMID- 21652283 TI - Scalp EEG acquisition in a low-noise environment: a quantitative assessment. AB - This pilot study investigates effects of an ultra shielded capsule at the low noise underground laboratory (LSBB), Rustrel, France, when used to acquire scalp electroencephalogram (EEG). Analysis of EEG recordings from three volunteers confirms that clean EEG signals can be acquired in the LSBB capsule without the need for notch filtering. In addition, using different setups for acquiring EEG in the capsule, statistical analysis of power spectral densities based on a geodesic distance measure reveals that the laptop computer and patient module do not introduce any noise on recorded signals. Moreover, the current study shows that the backward counting task as a mental activity can be better detected using the EEG acquired in the capsule due to the higher level of a-band activities. The counting-relaxed a-band energy ratio is calculated using the S transform and compared between the hospital and capsule, revealing significantly higher values in the capsule (p < 0.05). Exploring the relative a-band energy (ratio of a-band energy to that of 0-12 Hz in counting state) reveals that the average of this measure is higher in the capsule for all subjects. Those results demonstrate the potential of the LSBB capsule for novel EEG studies, including establishing novel low-noise EEG benchmarks. PMID- 21652284 TI - Motion-induced phase error estimation and correction in 3D diffusion tensor imaging. AB - A multishot data acquisition strategy is one way to mitigate B0 distortion and T2* blurring for high-resolution diffusion-weighted magnetic resonance imaging experiments. However, different object motions that take place during different shots cause phase inconsistencies in the data, leading to significant image artifacts. This work proposes a maximum likelihood estimation and k-space correction of motion-induced phase errors in 3D multishot diffusion tensor imaging. The proposed error estimation is robust, unbiased, and approaches the Cramer-Rao lower bound. For rigid body motion, the proposed correction effectively removes motion-induced phase errors regardless of the k-space trajectory used and gives comparable performance to the more computationally expensive 3D iterative nonlinear phase error correction method. The method has been extended to handle multichannel data collected using phased-array coils. Simulation and in vivo data are shown to demonstrate the performance of the method. PMID- 21652285 TI - Sparse neural networks with large learning diversity. AB - Coded recurrent neural networks with three levels of sparsity are introduced. The first level is related to the size of messages that are much smaller than the number of available neurons. The second one is provided by a particular coding rule, acting as a local constraint in the neural activity. The third one is a characteristic of the low final connection density of the network after the learning phase. Though the proposed network is very simple since it is based on binary neurons and binary connections, it is able to learn a large number of messages and recall them, even in presence of strong erasures. The performance of the network is assessed as a classifier and as an associative memory. PMID- 21652286 TI - Phase synchronization motion and neural coding in dynamic transmission of neural information. AB - In order to explore the dynamic characteristics of neural coding in the transmission of neural information in the brain, a model of neural network consisting of three neuronal populations is proposed in this paper using the theory of stochastic phase dynamics. Based on the model established, the neural phase synchronization motion and neural coding under spontaneous activity and stimulation are examined, for the case of varying network structure. Our analysis shows that, under the condition of spontaneous activity, the characteristics of phase neural coding are unrelated to the number of neurons participated in neural firing within the neuronal populations. The result of numerical simulation supports the existence of sparse coding within the brain, and verifies the crucial importance of the magnitudes of the coupling coefficients in neural information processing as well as the completely different information processing capability of neural information transmission in both serial and parallel couplings. The result also testifies that under external stimulation, the bigger the number of neurons in a neuronal population, the more the stimulation influences the phase synchronization motion and neural coding evolution in other neuronal populations. We verify numerically the experimental result in neurobiology that the reduction of the coupling coefficient between neuronal populations implies the enhancement of lateral inhibition function in neural networks, with the enhancement equivalent to depressing neuronal excitability threshold. Thus, the neuronal populations tend to have a stronger reaction under the same stimulation, and more neurons get excited, leading to more neurons participating in neural coding and phase synchronization motion. PMID- 21652287 TI - An algorithm for power line detection and warning based on a millimeter-wave radar video. AB - Power-line-strike accident is a major safety threat for low-flying aircrafts such as helicopters, thus an automatic warning system to power lines is highly desirable. In this paper we propose an algorithm for detecting power lines from radar videos from an active millimeter-wave sensor. Hough Transform is employed to detect candidate lines. The major challenge is that the radar videos are very noisy due to ground return. The noise points could fall on the same line which results in signal peaks after Hough Transform similar to the actual cable lines. To differentiate the cable lines from the noise lines, we train a Support Vector Machine to perform the classification. We exploit the Bragg pattern, which is due to the diffraction of electromagnetic wave on the periodic surface of power lines. We propose a set of features to represent the Bragg pattern for the classifier. We also propose a slice-processing algorithm which supports parallel processing, and improves the detection of cables in a cluttered background. Lastly, an adaptive algorithm is proposed to integrate the detection results from individual frames into a reliable video detection decision, in which temporal correlation of the cable pattern across frames is used to make the detection more robust. Extensive experiments with real-world data validated the effectiveness of our cable detection algorithm. PMID- 21652288 TI - Quantitative and comparative assessment of learning in a tongue-operated computer input device. AB - Tongue drive system (TDS) is a wireless, wearable assistive technology that enables individuals with severe motor impairments to access computers, drive wheelchairs, and control their environments using tongue motion. In this paper, we have evaluated the TDS performance as a computer input device in four tasks, commonly known as horizontal, vertical, center-out, and multidirectional rapid tapping, based on Fitts' law and ISO9241-9 Standard. Nine able-bodied subjects, who already had tongue piercing, participated in this trial over five sessions during 5 weeks, allowing us to study the TDS learning process and its current limiting factors. Subjects wore tongue rings made of titanium in the form of a barbell with a small rare-earth magnetic tracer hermetically sealed inside the upper ball. Participants performed the same tasks with a mouse (only in the first session) as a reference as well as a standard keypad for benchmarking. Six performance measures were considered, including throughput, error rate, and reaction time, all of these improved significantly from the first to the last session, and some of these plateaued over the course of the experiment. The comparison between tongue-TDS versus index-finger-keypad provides valuable insights into tongue human factors, which can lead the way in improving the usability of the TDS and similar tongue-operated assistive technologies. PMID- 21652289 TI - Smoking, COPD, and 3-nitrotyrosine levels of plasma proteins. AB - BACKGROUND: Nitric oxide is a physiological regulator of endothelial function and hemodynamics. Oxidized products of nitric oxide can form nitrotyrosine, which is a marker of nitrative stress. Cigarette smoking decreases exhaled nitric oxide, and the underlying mechanism may be important in the cardiovascular toxicity of smoking. Even so, it is unclear if this effect results from decreased nitric oxide production or increased oxidative degradation of nitric oxide to reactive nitrating species. These two processes would be expected to have opposite effects on nitrotyrosine levels, a marker of nitrative stress. OBJECTIVE: In this study, we evaluated associations of cigarette smoking and chronic obstructive pulmonary disease (COPD) with nitrotyrosine modifications of specific plasma proteins to gain insight into the processes regulating nitrotyrosine formation. METHODS: A custom antibody microarray platform was developed to analyze the levels of 3 nitrotyrosine modifications on 24 proteins in plasma. In a cross-sectional study, plasma samples from 458 individuals were analyzed. RESULTS: Average nitrotyrosine levels in plasma proteins were consistently lower in smokers and former smokers than in never smokers but increased in smokers with COPD compared with smokers who had normal lung-function tests. CONCLUSIONS: Smoking is associated with a broad decrease in 3-nitrotyrosine levels of plasma proteins, consistent with an inhibitory effect of cigarette smoke on endothelial nitric oxide production. In contrast, we observed higher nitrotyrosine levels in smokers with COPD than in smokers without COPD. This finding is consistent with increased nitration associated with inflammatory processes. This study provides insight into a mechanism through which smoking could induce endothelial dysfunction and increase the risk of cardiovascular disease. PMID- 21652290 TI - Impact of reduced maternal exposures to wood smoke from an introduced chimney stove on newborn birth weight in rural Guatemala. AB - BACKGROUND: A growing body of evidence indicates a relationship between household indoor air pollution from cooking fires and adverse neonatal outcomes, such as low birth weight (LBW), in resource-poor countries. OBJECTIVE: We examined the effect of reduced wood smoke exposure in pregnancy on LBW of Guatemalan infants in RESPIRE (Randomized Exposure Study of Pollution Indoors and Respiratory Effects). METHODS: Pregnant women (n = 266) either received a chimney stove (intervention) or continued to cook over an open fire (control). Between October 2002 and December 2004 we weighed 174 eligible infants (69 to mothers who used a chimney stove and 105 to mothers who used an open fire during pregnancy) within 48 hr of birth. Multivariate linear regression and adjusted odds ratios (ORs) were used to estimate differences in birth weight and LBW (< 2,500 g) associated with chimney-stove versus open-fire use during pregnancy. RESULTS: Pregnant women using chimney stoves had a 39% reduction in mean exposure to carbon monoxide compared with those using open fires. LBW prevalence was high at 22.4%. On average, infants born to mothers who used a stove weighed 89 g more [95% confidence interval (CI), -27 to 204 g] than infants whose mothers used open fires after adjusting for maternal height, diastolic blood pressure, gravidity, and season of birth. The adjusted OR for LBW was 0.74 (95% CI, 0.33-1.66) among infants of stove users compared with open-fire users. Average birth weight was 296 g higher (95% CI, 109-482 g) in infants born during the cold season (after harvest) than in other infants; this unanticipated finding may reflect the role of maternal nutrition on birth weight in an impoverished region. CONCLUSIONS: A chimney stove reduced wood smoke exposures and was associated with reduced LBW occurrence. Although not statistically significant, the estimated effect was consistent with previous studies. PMID- 21652292 TI - Serum creatinine is independently associated with angiographic extent of coronary artery disease in patients with stable angina pectoris. AB - OBJECTIVE: Renal dysfunction has been shown to be linked to high risk for cardiovascular events. Even milder forms of creatinine elevation are associated with poor cardiovascular outcomes. We designed a retrospective study and searched the association of angiographic extent of coronary artery disease and creatinine levels in patients without overt renal dysfunction. METHODS: We retrospectively reviewed 892 consecutive patients with typical stable angina pectoris (311 female with mean age of 62 +/- 10 years, 581 male with mean age of 56 +/- 11 years) at Turkiye Yuksek Ihtisas Hospital and creatinine level <= 3 mg/dl without history of hemodialysis. Patients without overt renal disease were divided into 3 groups according to level of creatinine (Group A: Cr level <1.2 mg/dl, Group B: Cr level >= 1.2 and <1.5 mg/dl and Group C: Cr level >= 1.5 -<= 3 mg/dl). Additionally after evaluation of coronary angiograms, patients were also classified according to those with high stenosis (stenosis score >= 16) and high extension scores (extension score >50%) versus low stenosis and low extension scores. Logistic regression analysis was performed to establish the clinical predictors of high total stenosis and high extension scores. RESULTS: Each group of patients according to level of creatinine showed marked difference in terms of angiographic extent of coronary artery disease (p<0.001). Those in the highest creatinine group (>= 1.5 mg/dl, but not above 3 mg/dl) had the highest total stenosis (17 +/- 6, p<0.001) and extension (78 +/- 25, p<0.001) scores irrespective of age and gender. Creatinine was shown to be significantly correlated with both stenosis and extension scores. Age (OR:1.035, 95% CI:1.016 1.054, p<0.0001), being male (OR:1.746, 95% CI: 1.135-2.685, p=0.011), presence of hypertension (OR:1.507, 95%CI: 1.005-2.25 p=0.047), presence of diabetes mellitus (OR: 1.865, 95%: 1.250-2.783, p=0.002), previous history of myocardial infarction (OR: 1.624, 95%CI: 1.094-2.413, p=0.016), wall motion score index (OR:1.203, 95%CI: 1.108-1.305, p<0.0001) and creatinine (OR:4.037, 95%CI: 2.530 6.443, p<0.0001) level were found to be independent predictors of high total stenosis score. Furthermore, age (OR:1.042, 95%CI: 1.026-1.059, p<0.0001), being male (OR:2.587, 95%CI: 1.794-3.731, p<0.0001), presence of hypertension (OR:1.536, 95% CI:1.100-2.147, p=0.012), previous myocardial infarction (OR:6.183, 95%CI: 4.340-8.807, p<0.0001), total cholesterol/HDL ratio (OR:1.215, 95%CI: 1.114-1.327, p<0.0001) and creatinine (OR:3.814, 95%CI: 2.149-6.768, p<0.0001) were found to be independent predictors of high extension score. CONCLUSION: Serum creatinine seems to denote severity of angiographic extent of coronary artery disease in patients with typical chest pain. PMID- 21652293 TI - Evaluation of association between obstructive sleep apnea and coronary risk scores predicted by tomographic coronary calcium scoring in asymptomatic patients. AB - OBJECTIVE: This cross-sectional observational study is designed to evaluate direct effects of obstructive sleep apnea syndrome (OSA) on presence and extent of coronary atherosclerosis by using tomographic coronary calcification scoring on a population asymptomatic for coronary artery disease. METHODS: Ninety-seven consecutive patients (49.17 +/- 0.86 years) who were evaluated with sleep study for the suspicion of obstructive sleep apnea syndrome underwent tomographic coronary calcium scoring test. Cardiovascular risk factors, current medications and sleep study recordings of all patients were recorded. Patients were classified into 4 groups according to the apnea-hypopnea index (AHI). Linear and logistic regression analyses were used for assessment of association between variables. RESULTS: Coronary risk scores of patients, assessed by tomographic coronary calcium scoring, were observed to increase linearly from simple snoring group to severe OSA groups (p=0.046). When patients were classified according to their gender, AHI and parameters reflecting severity of OSA-related hypoxia were found to correlate significantly with coronary risk scores of women but not with scores of men. Linear regression analysis revealed age as the only independent associated variable with cardiovascular risk scores assessed by tomographic coronary calcification scoring (Beta coefficient: 0.27, 95% CI 0.007-0.087, p=0.018). Binary logistic regression analysis also revealed age as the only variable which independently predicted the presence of coronary calcification (OR:1.11, 95% CI 1.039-1.188, p=0.002). CONCLUSION: These results suggest that presence of OSA may contribute to coronary artery disease risk of patients in association with its severity; however, association between OSA and subclinical atherosclerosis seems to be primarily dependent on age. PMID- 21652291 TI - Creatinine, diet, micronutrients, and arsenic methylation in West Bengal, India. AB - BACKGROUND: Ingested inorganic arsenic (InAs) is methylated to monomethylated (MMA) and dimethylated metabolites (DMA). Methylation may have an important role in arsenic toxicity, because the monomethylated trivalent metabolite [MMA(III)] is highly toxic. OBJECTIVES: We assessed the relationship of creatinine and nutrition--using dietary intake and blood concentrations of micronutrients--with arsenic metabolism, as reflected in the proportions of InAS, MMA, and DMA in urine, in the first study that incorporated both dietary and micronutrient data. METHODS: We studied methylation patterns and nutritional factors in 405 persons who were selected from a cross-sectional survey of 7,638 people in an arsenic exposed population in West Bengal, India. We assessed associations of urine creatinine and nutritional factors (19 dietary intake variables and 16 blood micronutrients) with arsenic metabolites in urine. RESULTS: Urinary creatinine had the strongest relationship with overall arsenic methylation to DMA. Those with the highest urinary creatinine concentrations had 7.2% more arsenic as DMA compared with those with low creatinine (p < 0.001). Animal fat intake had the strongest relationship with MMA% (highest tertile animal fat intake had 2.3% more arsenic as MMA, p < 0.001). Low serum selenium and low folate were also associated with increased MMA%. CONCLUSIONS: Urine creatinine concentration was the strongest biological marker of arsenic methylation efficiency, and therefore should not be used to adjust for urine concentration in arsenic studies. The new finding that animal fat intake has a positive relationship with MMA% warrants further assessment in other studies. Increased MMA% was also associated, to a lesser extent, with low serum selenium and folate. PMID- 21652294 TI - [The psychometric properties of the Turkish version of Myocardial Infarction Dimensional Assessment Scale (MIDAS)]. AB - OBJECTIVE: The purpose of this study was to describe the psychometric properties of the Myocardial Infarction Dimensional Assessment Scale (MIDAS). METHODS: This is a methodological cultural adaptation study. The MIDAS consists of 35-items covering seven domains: physical activity, insecurity, emotional reaction, dependency, diet, concerns over medication, and side effects which are rated on a five-point Likert scale from 1: never to 5:always. The highest score of MIDAS is 100.Quality of life (QOL) decreases as the score of scale increases. Overall 185 myocardial infarction (MI) patients were enrolled in this study. Cronbach alpha was used for the reliability analysis. The criterion validity, structural validity, and sensitivity analysis approach was used for validity analysis. New York Heart Association (NYHA) and the Canadian Cardiovascular Society Functional Classifications (CCSFC) for testing the criterion validity; SF-36 for construct validity testing of the Turkish version of the MIDAS were used. RESULTS: The range of Cronbach alpha values is 0.79-0.90 for seven domains of the scale. No problematic items were observed for the entire scale. Medication related domains of the MIDAS showed considerable floor effects (35.7%-22.7%). Confirmatory Factor analysis indicators [Comparative Fit Index (CFI) =0.95 and Root Mean Square Error of Approximation (RMSEA) =0.075] supported the construct validity of MIDAS. Convergent validity of the MIDAS was confirmed with correlation of SF-36 scale where appropriate. Criterion validity results was also satisfactory by comparing different stages of the NYHA and the CCSFC (p<0.05). CONCLUSION: Overall results revealed that Turkish version of the MIDAS is a reliable and valid instrument. PMID- 21652295 TI - The effects of acute and intermittent hypoxia on the expressions of HIF-1alpha and VEGF in the left and right ventricles of the rabbit heart. AB - OBJECTIVE: Hypoxia-inducible factor-1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) are involved in signaling mechanisms of cellular responses to hypoxia. These factors have been investigated in tissue samples by simulating different altitudes by changing the percentage of oxygen. We aimed first to evaluate the effect of normobaric, systemic hypoxia (11% O2) on HIF-1alpha and VEGF mRNA levels in the heart muscle; secondly, to compare the levels of HIF 1alpha and VEGF mRNA in the left and right ventricle muscles. METHODS: In this experimental study, 33 New Zealand male rabbits were assigned to control, acute hypoxia (4 hours) and intermittent hypoxia (4 hours/day for 14 days) groups (n=11/group). Total RNA was isolated from right and left ventricles of the heart. The expressions of HIF-1alpha and VEGF mRNAs were investigated by using Reverse Transcription Polymerase Chain Reaction (RT-PCR) method. The obtained data were compared by using ANOVA and paired t-test. RESULTS: The results indicated that left ventricle VEGF mRNA expressions in both acute and intermittent hypoxia groups (1.08 +/- 0.15 and 1.03 +/- 0.19, respectively) were higher than that in the control group (0.88 +/- 0.15) (p=0.03). Hypoxia treatments did not significantly alter HIF-1alpha mRNA in both ventricles (p=0.60 and p=0.51 for left and right ventricles, respectively). CONCLUSION: Since systemic hypoxia results in induction of VEGF mRNA up-regulation only in left ventricle, it could be related to its higher metabolic activity and oxygen utilization. Hypoxia induced changes in the expression of HIF-1alpha mRNA may not be the only determining factor for HIF-1/VEGF pathway induction or the observed VEGF induction could be through other hypoxia sensitive pathways. PMID- 21652296 TI - [Physiology and clinical role of natriuretic peptides]. AB - In the last three decades many members of the natriuretic peptide family was isolated. The function and physiological role of these peptides are pleiotropic. All natriuretic peptides are synthesized from polypeptide precursors. Together with the sympathetic nervous system and other hormones they play key roles, like an endogenous system in the regulation of the body fluid homeostasis and blood pressure. Changes in this balance lead to dysfunction in the endothel and left ventricle, which can cause severe complications. In many cardiovascular diseases natriuretic peptides serve not only as marker for diagnosis and prognosis but they have therapeutic importance. In the last years the potential use of the elevated BNP levels for diagnosis of pre-eclampsia was examined. In our review we discuss the current understanding of molecular biology, biochemistry and clinical relevance of natriuretic peptides. PMID- 21652297 TI - [Experimental food-induced fatty liver and its adjuvant therapy with natural bioactive substances]. AB - Changes of redox-homeostasis generate cytokines, and free radicals influence many intracellular signaling pathways in different liver diseases. Liophylised table beet and carrot powder (GPS Powder Kft. 1361/004/2003BFAEEA) containing bioactive components such as betaine, betanins, betaxanthins, flavonoids, polyphenols, glutamine, beta carotene, vitamins and folic acid may induce changes in various cellular pathways. AIM: The aim of this study was to determine the protecting effects of bioactive agents of the liophylised table beet and carrot powder on fatty liver in a "short term" experiment. METHOD: Male Wistar rats were fed with chow with or without high fat (2% cholesterol, 0.5% cholic acid, 20% sunflower oil) and treated with 0.1 or 1 g/bwkg/day natural product for ten days parallel with the feedings. Cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-alpha mRNA levels were determined using molecular biologic methods. Free radicals, H-donating activity, reducing power and free SH-group concentrations were determined by luminometry and spectrophotometry. Mobilized methyl groups were assayed by high pressure liquid chromatography method in liver homogenates. RESULTS: It was found that the higher dose of the natural product better decreased the induced free radical reactions, cyclooxygenase-2, inducible nitric oxide synthase and tumor necrosis factor-alpha mRNA-levels both in normal and fatty liver tissues. Although treatments failed to exert significant changes in all global antioxidant parameters, mobilized methyl group concentrations were higher after treatments in fatty liver. Favorable tendencies were also noted in the redox-homeostasis of the fatty liver after treatment. CONCLUSIONS: As expected, lyophylised table beet and carrot proved to be a "functional food" in rats with alimentary fat induced fatty liver. It cannot be ruled out that this beneficial effect may have clinical relevance. PMID- 21652298 TI - [Safety of gastrointestinal endoscopy during pregnancy]. AB - There are only few data of gastrointestinal endoscopy in pregnant patients. Only 0.4% of all procedures are carried out during pregnancy. Case reports and some small retrospective studies are available. Because of physiological changes in pregnancy there might be special risks of endoscopy. There might be complaints which can be physiologic during pregnancy, but can be signs of gastrointestinal disorders, too. Therefore, indications for endoscopy are not always clear and easy. Safety of the procedures is also not well studied. Besides the risks of endoscopy, medication given to the mother, electrocoagulation and radiation exposure from fluoroscopy during endoscopic retrograde cholangiopancreatography might be harmful to the fetus. Endoscopy should only be done when indication is unquestionable and strong. Only FDA "A" and "B" category medication is allowed. Gastroscopy is necessary for bleeding and for patients with pyrosis going together with alarm signs. Nausea, vomiting, abdominal pain and fecal occult blood test positivity are not indications for endoscopy, only for gastroenterogical consultation. Sigmoidoscopy is recommended for indication of lower gastrointestinal bleeding and sigmoid or rectal mass. Only therapeutic endoscopic retrograde cholangiopancreatography should be performed. Obstructive jaundice and biliary pancreatitis need immediate endoscopic intervention. The fetus must be shielded from radiation exposure. PMID- 21652299 TI - [Physicians flying in the air in 1811 -- flight of the doctors Menner and Kraskovics in Pest and Pressburg]. PMID- 21652300 TI - [Conviction of surgery professor, Tivadar Huttl by a certification committee in 1946]. PMID- 21652302 TI - The plant tree of life: an overview and some points of view. AB - We provide a brief overview of this special issue on the plant tree of life, describing its history and the general nature of its articles. We then present our estimate for the overall topology and, for land plants, divergence times of the plant tree of life. We discuss several major controversies and unsolved problems in resolving portions of this tree. We conclude with a few thoughts about the prospects for obtaining a comprehensive, robustly resolved, and accurately dated plant tree of life and the importance of such a grand endeavor. PMID- 21652303 TI - Assembling the fungal tree of life: progress, classification, and evolution of subcellular traits. AB - Based on an overview of progress in molecular systematics of the true fungi (Fungi/Eumycota) since 1990, little overlap was found among single-locus data matrices, which explains why no large-scale multilocus phylogenetic analysis had been undertaken to reveal deep relationships among fungi. As part of the project "Assembling the Fungal Tree of Life" (AFTOL), results of four Bayesian analyses are reported with complementary bootstrap assessment of phylogenetic confidence based on (1) a combined two-locus data set (nucSSU and nucLSU rDNA) with 558 species representing all traditionally recognized fungal phyla (Ascomycota, Basidiomycota, Chytridiomycota, Zygomycota) and the Glomeromycota, (2) a combined three-locus data set (nucSSU, nucLSU, and mitSSU rDNA) with 236 species, (3) a combined three-locus data set (nucSSU, nucLSU rDNA, and RPB2) with 157 species, and (4) a combined four-locus data set (nucSSU, nucLSU, mitSSU rDNA, and RPB2) with 103 species. Because of the lack of complementarity among single-locus data sets, the last three analyses included only members of the Ascomycota and Basidiomycota. The four-locus analysis resolved multiple deep relationships within the Ascomycota and Basidiomycota that were not revealed previously or that received only weak support in previous studies. The impact of this newly discovered phylogenetic structure on supraordinal classifications is discussed. Based on these results and reanalysis of subcellular data, current knowledge of the evolution of septal features of fungal hyphae is synthesized, and a preliminary reassessment of ascomal evolution is presented. Based on previously unpublished data and sequences from GenBank, this study provides a phylogenetic synthesis for the Fungi and a framework for future phylogenetic studies on fungi. PMID- 21652304 TI - Diversity and evolutionary history of plastids and their hosts. AB - By synthesizing data from individual gene phylogenies, large concatenated gene trees, and other kinds of molecular, morphological, and biochemical markers, we begin to see the broad outlines of a global phylogenetic tree of eukaryotes. This tree is apparently composed of five large assemblages, or "supergroups." Plants and algae, or more generally eukaryotes with plastids (the photosynthetic organelle of plants and algae and their nonphotosynthetic derivatives) are scattered among four of the five supergroups. This is because plastids have had a complex evolutionary history involving several endosymbiotic events that have led to their transmission from one group to another. Here, the history of the plastid and of its various hosts is reviewed with particular attention to the number and nature of the endosymbiotic events that led to the current distribution of plastids. There is accumulating evidence to support a single primary origin of plastids from a cyanobacterium (with one intriguing possible exception in the little-studied amoeba Paulinella), followed by the diversification of glaucophytes, red and green algae, with plants evolving from green algae. Following this, some of these algae were themselves involved in secondary endosymbiotic events. The best current evidence indicates that two independent secondary endosymbioses involving green algae gave rise to euglenids and chlorarachniophytes, whereas a single endosymbiosis with a red algae gave rise to the chromalveolates, a diverse group including cryptomonads, haptophytes, heterokonts, and alveolates. Dinoflagellates (alveolates) have since taken up other algae in serial secondary and tertiary endosymbioses, raising a number of controversies over the origin of their plastids, and by extension, the recently discovered cryptic plastid of the closely related apicomplexan parasites. PMID- 21652305 TI - Assessing red algal supraordinal diversity and taxonomy in the context of contemporary systematic data. AB - The wondrously diverse eukaryotes that constitute the red algae have been the focus of numerous recent molecular surveys and remain a rich source of undescribed and little known species for the traditional taxonomist. Molecular studies place the red algae in the kingdom Plantae; however, supraordinal classification has been largely confined to debate on subclass vs. class level status for the two recognized subgroups, one of which is widely acknowledged as paraphyletic. This narrow focus has generally masked the extent to which red algal classification needs modification. We provide a comprehensive review of the literature pertaining to the antiquity, diversity, and systematics of the red algae and propose a contemporary classification based on recent and traditional evidence. PMID- 21652306 TI - Biology and systematics of heterokont and haptophyte algae. AB - In this paper, I review what is currently known of phylogenetic relationships of heterokont and haptophyte algae. Heterokont algae are a monophyletic group that is classified into 17 classes and represents a diverse group of marine, freshwater, and terrestrial algae. Classes are distinguished by morphology, chloroplast pigments, ultrastructural features, and gene sequence data. Electron microscopy and molecular biology have contributed significantly to our understanding of their evolutionary relationships, but even today class relationships are poorly understood. Haptophyte algae are a second monophyletic group that consists of two classes of predominately marine phytoplankton. The closest relatives of the haptophytes are currently unknown, but recent evidence indicates they may be part of a large assemblage (chromalveolates) that includes heterokont algae and other stramenopiles, alveolates, and cryptophytes. Heterokont and haptophyte algae are important primary producers in aquatic habitats, and they are probably the primary carbon source for petroleum products (crude oil, natural gas). PMID- 21652307 TI - Dinoflagellates: a remarkable evolutionary experiment. AB - In this paper, we focus on dinoflagellate ecology, toxin production, fossil record, and a molecular phylogenetic analysis of hosts and plastids. Of ecological interest are the swimming and feeding behavior, bioluminescence, and symbioses of dinoflagellates with corals. The many varieties of dinoflagellate toxins, their biological effects, and current knowledge of their origin are discussed. Knowledge of dinoflagellate evolution is aided by a rich fossil record that can be used to document their emergence and diversification. However, recent biogeochemical studies indicate that dinoflagellates may be much older than previously believed. A remarkable feature of dinoflagellates is their unique genome structure and gene regulation. The nuclear genomes of these algae are of enormous size, lack nucleosomes, and have permanently condensed chromosomes. This chapter reviews the current knowledge of gene regulation and transcription in dinoflagellates with regard to the unique aspects of the nuclear genome. Previous work shows the plastid genome of typical dinoflagellates to have been reduced to single-gene minicircles that encode only a small number of proteins. Recent studies have demonstrated that the majority of the plastid genome has been transferred to the nucleus, which makes the dinoflagellates the only eukaryotes to encode the majority of typical plastid genes in the nucleus. The evolution of the dinoflagellate plastid and the implications of these results for understanding organellar genome evolution are discussed. PMID- 21652308 TI - Green algae and the origin of land plants. AB - Over the past two decades, molecular phylogenetic data have allowed evaluations of hypotheses on the evolution of green algae based on vegetative morphological and ultrastructural characters. Higher taxa are now generally recognized on the basis of ultrastructural characters. Molecular analyses have mostly employed primarily nuclear small subunit rDNA (18S) and plastid rbcL data, as well as data on intron gain, complete genome sequencing, and mitochondrial sequences. Molecular-based revisions of classification at nearly all levels have occurred, from dismemberment of long-established genera and families into multiple classes, to the circumscription of two major lineages within the green algae. One lineage, the chlorophyte algae or Chlorophyta sensu stricto, comprises most of what are commonly called green algae and includes most members of the grade of putatively ancestral scaly flagellates in Prasinophyceae plus members of Ulvophyceae, Trebouxiophyceae, and Chlorophyceae. The other lineage (charophyte algae and embryophyte land plants), comprises at least five monophyletic groups of green algae, plus embryophytes. A recent multigene analysis corroborates a close relationship between Mesostigma (formerly in the Prasinophyceae) and the charophyte algae, although sequence data of the Mesostigma mitochondrial genome analysis places the genus as sister to charophyte and chlorophyte algae. These studies also support Charales as sister to land plants. The reorganization of taxa stimulated by molecular analyses is expected to continue as more data accumulate and new taxa and habitats are sampled. PMID- 21652309 TI - Phylogeny and diversification of bryophytes. AB - The bryophytes comprise three phyla of embryophytes that are well established to occupy the first nodes among extant lineages in the land-plant tree of life. The three bryophyte groups (hornworts, liverworts, mosses) may not form a monophyletic clade, but they share life history features including dominant free living gametophytes and matrotrophic monosporangiate sporophytes. Because of their unique vegetative and reproductive innovations and their critical position in embryophyte phylogeny, studies of bryophytes are crucial to understanding the evolution of land plant morphology and genomes. This review focuses on phylogenetic relationships within each of the three divisions of bryophytes and relates morphological diversity to new insights about those relationships. Most previous work has been on the mosses, but progress on understanding the phylogeny of hornworts and liverworts is advancing at a rapid pace. Multilocus multigenome studies have been successful at resolving deep relationships within the mosses and liverworts, whereas single-gene analyses have advanced understanding of hornwort evolution. PMID- 21652310 TI - Phylogeny and evolution of ferns (monilophytes) with a focus on the early leptosporangiate divergences. AB - The phylogenetic structure of ferns (= monilophytes) is explored here, with a special focus on the early divergences among leptosporangiate lineages. Despite considerable progress in our understanding of fern relationships, a rigorous and comprehensive analysis of the early leptosporangiate divergences was lacking. Therefore, a data set was designed here to include critical taxa that were not included in earlier studies. More than 5000 bp from the plastid (rbcL, atpB, rps4) and the nuclear (18S rDNA) genomes were sequenced for 62 taxa. Phylogenetic analyses of these data (1) confirm that Osmundaceae are sister to the rest of the leptosporangiates, (2) resolve a diverse set of ferns formerly thought to be a subsequent grade as possibly monophyletic (((Dipteridaceae, Matoniaceae), Gleicheniaceae), Hymenophyllaceae), and (3) place schizaeoid ferns as sister to a large clade of "core leptosporangiates" that includes heterosporous ferns, tree ferns, and polypods. Divergence time estimates for ferns are reported from penalized likelihood analyses of our molecular data, with constraints from a reassessment of the fossil record. PMID- 21652311 TI - Phylogenetic signal in nucleotide data from seed plants: implications for resolving the seed plant tree of life. AB - Effects of taxonomic sampling and conflicting signal on the inference of seed plant trees supported in previous molecular analyses were explored using 13 single-locus data sets. Changing the number of taxa in single-locus analyses had limited effects on log likelihood differences between the gnepine (Gnetales plus Pinaceae) and gnetifer (Gnetales plus conifers) trees. Distinguishing among these trees also was little affected by the use of different substitution parameters. The 13-locus combined data set was partitioned into nine classes based on substitution rates. Sites evolving at intermediate rates had the best likelihood and parsimony scores on gnepine trees, and those evolving at the fastest rates had the best parsimony scores on Gnetales-sister trees (Gnetales plus other seed plants). When the fastest evolving sites were excluded from parsimony analyses, well-supported gnepine trees were inferred from the combined data and from each genomic partition. When all sites were included, Gnetales-sister trees were inferred from the combined data, whereas a different tree was inferred from each genomic partition. Maximum likelihood trees from the combined data and from each genomic partition were well-supported gnepine trees. A preliminary stratigraphic test highlights the poor fit of Gnetales-sister trees to the fossil data. PMID- 21652312 TI - The origin and diversification of angiosperms. AB - The angiosperms, one of five groups of extant seed plants, are the largest group of land plants. Despite their relatively recent origin, this clade is extremely diverse morphologically and ecologically. However, angiosperms are clearly united by several synapomorphies. During the past 10 years, higher-level relationships of the angiosperms have been resolved. For example, most analyses are consistent in identifying Amborella, Nymphaeaceae, and Austrobaileyales as the basalmost branches of the angiosperm tree. Other basal lineages include Chloranthaceae, magnoliids, and monocots. Approximately three quarters of all angiosperm species belong to the eudicot clade, which is strongly supported by molecular data but united morphologically by a single synapomorphy-triaperturate pollen. Major clades of eudicots include Ranunculales, which are sister to all other eudicots, and a clade of core eudicots, the largest members of which are Saxifragales, Caryophyllales, rosids, and asterids. Despite rapid progress in resolving angiosperm relationships, several significant problems remain: (1) relationships among the monocots, Chloranthaceae, magnoliids, and eudicots, (2) branching order among basal eudicots, (3) relationships among the major clades of core eudicots, (4) relationships within rosids, (5) relationships of the many lineages of parasitic plants, and (6) integration of fossils with extant taxa into a comprehensive tree of angiosperm phylogeny. PMID- 21652313 TI - A survey of tricolpate (eudicot) phylogenetic relationships. AB - The phylogenetic structure of the tricolpate clade (or eudicots) is presented through a survey of their major subclades, each of which is briefly characterized. The tricolpate clade was first recognized in 1989 and has received extensive phylogenetic study. Its major subclades, recognized at ordinal and familial ranks, are now apparent. Ordinal and many other suprafamilial clades are briefly diagnosed, i.e., the putative phenotypic synapomorphies for each major clade of tricolpates are listed, and the support for the monophyly of each clade is assessed, mainly through citation of the pertinent molecular phylogenetic literature. The classification of the Angiosperm Phylogeny Group (APG II) expresses the current state of our knowledge of phylogenetic relationships among tricolpates, and many of the major tricolpate clades can be diagnosed morphologically. PMID- 21652314 TI - Monocot relationships: an overview. AB - In 10 years, the monocots have gone from being one of the least studied and most phylogenetically misunderstood groups of the angiosperms to one of the best characterized. Based on analyses of seven genes representing all three genomes, the following clades have high bootstrap support: Acorales (with the single genus Acorus) is sister to the rest of the monocots, followed successively by Alismatales (including Araceae and Tofieldiaceae), Petrosaviales, Dioscoreales/Pandanales, Liliales, Asparagales, and finally a polytomy of Arecales, Commelinales/Zingiberales, Dasypogonaceae, and Poales. Many of these results also have support from at least some morphological data, but some are unique to the trees created from DNA sequence data. Monocots have been shown in molecular clock studies to be at least 140 million years old, and all major clades and most families date to well before the end of the Cretaceous. More data are required to clarify the positions of the remaining unclearly placed orders, Asparagles, Liliales, and Arecales, as well as Dasypogonaceae. More sequences from the nuclear and mitochondrial genomes are also needed to complement those from the plastid genome, which is the most sampled and thus far most pattern rich. PMID- 21652315 TI - Molecular evidence on plant divergence times. AB - Estimation of divergence times from sequence data has become increasingly feasible in recent years. Conflicts between fossil evidence and molecular dates have sparked the development of new methods for inferring divergence times, further encouraging these efforts. In this paper, available methods for estimating divergence times are reviewed, especially those geared toward handling the widespread variation in rates of molecular evolution observed among lineages. The assumptions, strengths, and weaknesses of local clock, Bayesian, and rate smoothing methods are described. The rapidly growing literature applying these methods to key divergence times in plant evolutionary history is also reviewed. These include the crown group ages of green plants, land plants, seed plants, angiosperms, and major subclades of angiosperms. Finally, attempts to infer divergence times are described in the context of two very different temporal settings: recent adaptive radiations and much more ancient biogeographic patterns. PMID- 21652316 TI - Fossil evidence and phylogeny: the age of major angiosperm clades based on mesofossil and macrofossil evidence from Cretaceous deposits. AB - The fossil record has played an important role in the history of evolutionary thought, has aided the determination of key relationships through mosaics, and has allowed an assessment of a number of ecological hypotheses. Nonetheless, expectations that it might accurately and precisely mirror the progression of taxa through time seem optimistic in light of the many factors potentially interfering with uniform preservation. In view of these limitations, attempts to use the fossil record to corroborate phylogenetic hypotheses based on extensive comparisons among extant taxa may be misplaced. Instead we suggest a method minimum age node mapping-for combining reliable fossil evidence with hypotheses of phylogeny. We use this methodology in conjunction with a phylogeny for angiosperms to assess timing in the history of major angiosperm clades. This method places many clades both with and without fossil records in temporal perspective, reveals discrepancies among clades in propensities for preservation, and raises some interesting questions about angiosperm evolution. By providing a context for understanding the gaps in the angiosperm fossil record this technique lends credibility and support to the remainder of the angiosperm record and to its applications in understanding a variety of aspects of angiosperm history. In effect, this methodology empowers the fossil record. PMID- 21652317 TI - Fossils and plant phylogeny. AB - Developing a detailed estimate of plant phylogeny is the key first step toward a more sophisticated and particularized understanding of plant evolution. At many levels in the hierarchy of plant life, it will be impossible to develop an adequate understanding of plant phylogeny without taking into account the additional diversity provided by fossil plants. This is especially the case for relatively deep divergences among extant lineages that have a long evolutionary history and in which much of the relevant diversity has been lost by extinction. In such circumstances, attempts to integrate data and interpretations from extant and fossil plants stand the best chance of success. For this to be possible, what will be required is meticulous and thorough descriptions of fossil material, thoughtful and rigorous analysis of characters, and careful comparison of extant and fossil taxa, as a basis for determining their systematic relationships. PMID- 21652318 TI - Reconstructing patterns of reticulate evolution in plants. AB - Until recently, rigorously reconstructing the many hybrid speciation events in plants has not been practical because of the limited number of molecular markers available for plant phylogenetic reconstruction and the lack of good, biologically based methods for inferring reticulation (network) events. This situation should change rapidly with the development of multiple nuclear markers for phylogenetic reconstruction and new methods for reconstructing reticulate evolution. These developments will necessitate a much greater incorporation of population genetics into phylogenetic reconstruction than has been common. Population genetic events such as gene duplication coupled with lineage sorting and meiotic and sexual recombination have always had the potential to affect phylogenetic inference. For tree reconstruction, these problems are usually minimized by using uniparental markers and nuclear markers that undergo rapid concerted evolution. Because reconstruction of reticulate speciation events will require nuclear markers that lack these characteristics, effects of population genetics on phylogenetic inference will need to be addressed directly. Current models and methods that allow hybrid speciation to be detected and reconstructed are discussed, with a focus on how lineage sorting and meiotic and sexual recombination affect network reconstruction. Approaches that would allow inference of phylogenetic networks in their presence are suggested. PMID- 21652319 TI - The evolution of nuclear genome structure in seed plants. AB - Plant nuclear genomes exhibit extensive structural variation in size, chromosome number, number and arrangement of genes, and number of genome copies per nucleus. This variation is the outcome of a set of highly active processes, including gene duplication and deletion, chromosomal duplication followed by gene loss, amplification of retrotransposons separating genes, and genome rearrangement, the latter often following hybridization and/or polyploidy. While these changes occur continuously, it is not surprising that some of them should be fixed evolutionarily and come to mark major clades. Large-scale duplications pre-date the radiation of Brassicaceae and Poaceae and correlate with the origin of many smaller clades as well. Nuclear genomes are largely colinear among closely related species, but more rearrangements are observed with increasing phylogenetic distance; however, the correlation between amount of rearrangement and time since divergence is not perfect. By changing patterns of gene expression and triggering genome rearrangements, novel combinations of genomes (hybrids) may be a driving force in evolution. PMID- 21652320 TI - The evolution of plant development. AB - The last decade has witnessed a resurgence in the study of the evolution of plant development, combining investigations in systematics, developmental morphology, molecular developmental genetics, and molecular evolution. The integration of phylogenetic studies, structural analyses of fossil and extant taxa, and molecular developmental genetic information allows the formulation of explicit and testable hypotheses for the evolution of morphological characters. These comprehensive approaches provide opportunities to dissect the evolution of major developmental transitions among land plants, including those associated with apical meristems, the origins of the root/shoot dichotomy, diversification of leaves, and origin and subsequent modification of flower structure. The evolution of these major developmental innovations is discussed within both phylogenetic and molecular genetic contexts. We conclude that it is the combination of these approaches that will lead to the greatest understanding of the evolution of plant development. PMID- 21652321 TI - Role of 2,4-dichlorophenoxyacetic acid (2,4-D) in somatic embryogenesis on cultured zygotic embryos of Arabidopsis: cell expansion, cell cycling, and morphogenesis during continuous exposure of embryos to 2,4-D. AB - The relationship between cell expansion and cell cycling during somatic embryogenesis was studied in cultured bent-cotyledon-stage zygotic embryos of a transgenic stock of Arabidopsis thaliana harboring a cyclin 1 At:beta glucuronidase (GUS) reporter gene construct. In embryos cultured in a medium containing 2,4-dichlorophenoxyacetic acid (2,4-D), following a brief period of growth by cell expansion, divisions were initiated in the procambial cells facing the adaxial side at the base of the cotyledons. Cell division activity later spread to almost the entire length of the cotyledons to form a callus on which globular and heart-shaped embryos appeared in about 10 d after culture. Anatomical and morphogenetic changes observed in cultured embryos were correlated with patterns of cell cycling by histochemical detection of GUS-expressing cells. Although early-stage somatic embryos did not develop further during their continued growth in the auxin-containing medium, maturation of embryos ensued upon their transfer to an auxin-free medium. In a small number of cultured zygotic embryos the shoot apical meristem was found to differentiate a leaf, a green tubular structure, or a somatic embryo. Contrary to the results from previous investigations, which have assigned a major role for the shoot apical meristem and cells in the axils of cotyledons in the development of somatic embryos on cultured zygotic embryos of A. thaliana, the present work shows that somatic embryos originate almost exclusively on the callus formed on the cotyledons. Other observations such as the induction of somatic embryos on cultured cotyledons and the inability of the embryo axis (consisting of the root, hypocotyl, and shoot apical meristem without the cotyledons) to form somatic embryos, reaffirm the important role of the cotyledons in somatic embryogenesis in this plant. PMID- 21652322 TI - Genetics and morphology in a Borrichia frutescens and B. arborescens (Asteraceae) hybrid zone. AB - Interspecific plant hybridization is a common and evolutionarily important phenomenon. Here, the results of a study of hybridization in the Florida Keys between two species of sea oxeye daisy, Borrichia frutescens and B. arborescens, are reported. Nuclear and chloroplast genetic loci, log-likelihood assignment tests, and maximum likelihood estimates of genealogical class frequencies were used to identify hybrid and parent genotypes, to investigate the utility of leaf and flower morphology for hybrid identification, and to study symmetry and degree of introgression between the species. Genetic analyses confirmed the identity of the hybrid and parent plants that were used for the morphological studies. Together, leaf and flower morphology can be used to identify hybrid and parental types with moderate accuracy (4% error rate). Population genetic analyses indicate that, in spite of a significant level of hybridization, pure B. frutescens and B. arborescens are persisting in the hybrid zone. Of the nonparentals, about 18% appear to be F(1) hybrids, over 50% F(2) hybrids, and the remainder backcrossed individuals but only with the B. frutescens parent. It is postulated that the hybrid zone in the Florida Keys is being maintained by a combination of positive assortative mating and clonal reproduction. PMID- 21652323 TI - Miocene winged fruits of Loxopterygium (Anacardiaceae) from the Ecuadorian Andes. AB - A new species of asymmetrically winged fruit is described from Miocene sediments of Andean Ecuador. The new fruit is readily placed in the genus Loxopterygium of the Anacardiaceae based on the size, position of the stigma, wing venation, and serration of the wing tip. The new fossil species is very similar to extant species of Loxopterygium now distributed in dry habitats of coastal Ecuador and Peru, as well as dry interior forests of Bolivia and northern Argentina. We use the fossil to calibrate a molecular-based phylogeny of some members of the Anacardiaceae, showing that dry forest habitats may have been present in South America for more than 10 million years. PMID- 21652324 TI - Effects of pollen quantity and quality on reproduction and offspring vigor in the rare plant Scorzonera humilis (Asteraceae). AB - We studied the effects of pollinator exclusion, interparental distance, and supplementary hand pollination on reproduction and progeny vigor in Scorzonera humilis (Asteraceae), a rare plant of fragmented, nutrient-poor grasslands. Caged flowers produced no seeds and selfed flowers only very rarely, indicating that S. humilis is mainly self-incompatible. Seed production, seed mass, and seed germination following between-population crosses were consistently, but not significantly, higher than after within-population crosses. Seed set increased with local density of conspecifics, indicating that the reduced plant density in fragmented populations may reduce plant reproductive success. Seed set was pollen limited in all four populations studied. Supplementary hand-pollination strongly increased the survival of offspring, indicating that either pollinators transferred pollen from related individuals resulting in inbreeding depression in spite of the incompatibility system or that higher pollen loads increased pollen competition and the selectivity among gametes. In one of the populations, adding pollen from a different population strongly increased progeny fitness compared with both natural pollination and pollen supplementation from the same population. The results indicate that S. humilis is sensitive to inbreeding and that pollen limitation can reduce both the number and quality of offspring. PMID- 21652325 TI - Cytotype segregation on regional and microgeographic scales in snow buttercups (Ranunculus adoneus: Ranunculaceae). AB - Polyploid speciation is an important source of angiosperm diversity. Insights into the origin and establishment of new polyploid species may be gained by studying the distributions of ancestral and derivative cytotypes at multiple spatial scales. Diploid (2n = 16) and tetraploid (2n = 32) snow buttercups (Ranunculus adoneus: Ranunculaceae) occur in the alpine of the central and southern Rocky Mountains. Root-tip squashes and flow cytometry were used to determine the ploidy of 1618 individuals from 35 populations. Samples from 31 of the 35 sites were entirely of one cytotype, either diploid or tetraploid. Diploid and tetraploid snow buttercups have nonoverlapping regional distributions. Where both cytotypes occur on the same site, the two are spatially segregated despite no apparent change in habitat. Triploid snow buttercups were only found at a diploid/tetraploid contact zone, while two hexaploid plants were found in tetraploid populations. Tetraploid establishment once or twice in the history of the species complex could account for the regional distribution of the two cytotypes. Habitat differentiation between cytotypes or reproductive exclusion of minority cytotypes may explain the observed segregation at both microgeographic and regional scales. PMID- 21652326 TI - Population structure in Pseudoroegneria spicata (Poaceae: Triticeae) modeled by Bayesian clustering of AFLP genotypes. AB - Pseudoroegneria spicata (Poaceae: Triticeae) is an abundant, allogamous species widely adapted to the temperate, semiarid steppe and open woodland regions of western North America. Amplified fragment length polymorphism (AFLP), model-based Bayesian clustering, and other methods of hypothesis testing were used to investigate genetic diversity and population structure among 565 P. spicata plants from 82 localities representing much of the species distribution. Comparisons with four Asiatic Pseudoroegneria species and two North American Elymus wawawaiensis accessions demonstrate cohesiveness in P. spicata. However, P. spicata genotypes group by locality and geographic region based on genetic distance analysis. Average DNA polymorphism among P. spicata localities was significantly correlated (r = 0.58) with geographical distance. The optimum Bayesian cluster model included 21 P. spicata groups, indicating that dispersal among sampling locations was not sufficient to group genotypes into one unstructured population. Approximately 18.3% of the DNA polymorphism was partitioned among the 21 regional groups, 14.9% among localities within groups, and 66.8% within accessions. Average DNA polymorphism among Bayesian groups was correlated (r = 0.53) with the average geographic distance among Bayesian groups, which partly reflects isolation by distance. However, conspicuous regional boundaries were discernable among several divergent genetic groups. PMID- 21652327 TI - Maternal and paternal contributions to the fitness of hybrids between red and white mulberry (Morus, Moraceae). AB - The fitness of hybrids depends on the genetic disparity between parental taxa and the magnitude of their nuclear and non-nuclear contributions. To estimate the role of non-nuclear effects, we crossed red (R), white (W) and hybrid (H) mulberry in all combinations and compared the magnitude of maternal and paternal effects on offspring fitness (seed set, germination, survival and aboveground biomass) in a greenhouse environment. Variation in offspring fitness was determined largely by the identity of the maternal parent; specifically, progeny with white mothers had the highest cumulative fitness. As fathers, red, white, and hybrid mulberry had no effect on fitness, and maternal * paternal interactions were significant only for survival. Individual cross-types differed significantly for all fitness components except seed set. Offspring from hybrid crosses (W * R, H * R, H * W) often differed from at least one of the within parent crosses (W * W, R * R) as well as from other hybrid crosses, although their fitness values never exceeded the most fit parent. Reciprocal crosses differed in only two of 15 possible parental combinations: W * H (cumulative fitness) and W * R (aboveground biomass). Overall, the strong asymmetry in magnitude of maternal and paternal effects suggests that fitness of hybrid mulberry is governed largely by non-nuclear, parental effects. PMID- 21652328 TI - Breeding system of Macromeria viridiflora (Boraginaceae) and geographic variation in pollinator assemblages. AB - This study explores the association between variation in pollinator type and flower size in Macromeria viridiflora (Boraginaceae) by studying the breeding system of the plant and the pollinator effectiveness of floral visitors. Studies were conducted at two sites where plants differ in flower size and floral visitors. Breeding system studies showed that while plants are self-compatible and occasionally produce seed autogamously, pollinators are important for reproductive success in the plants. However, plants are not pollinator-limited at these sites. Combining visitation rate and pollen deposition as measures of pollinator effectiveness, I found hummingbirds to be the most effective pollinators at both sites. Although hawkmoths also pollinate the flowers, they visit the flowers less frequently and, at one of the two sites, deposit less pollen. These results are consistent with the hypothesis that geographic variation in corolla size is the result of selection by different hummingbird species. PMID- 21652329 TI - Plant-pollinator interactions in New Caledonia influenced by introduced honey bees. AB - The flora of New Caledonia is characterized by remarkably high species diversity, high endemicity, and an unusual abundance of archaic plant taxa. To investigate community-level pollination mutualism in this endemic ecosystem, we observed flower visitors on 99 plant species in 42 families of various types of vegetation. Among the 95 native plant species, the most dominant pollination system was melittophily (bee-pollinated, 46.3%), followed by phalaenophily (moth pollinated, 20.0%), ornithophily (bird-pollinated, 11.6%), cantharophily (beetle pollinated, 8.4%), myophily (fly-pollinated, 3.2%), chiropterophily (bat pollinated, 3.2%), and anemophily (wind-pollinated, 3.2%). The prevalence of ornithophily by honeyeaters shows an ecological link to pollination mutualism in Australia. The relative dominance of phalaenophily is unique to New Caledonia, and is proposed to be related to the low diversity of the original bee fauna and the absence of long-tongued bees. Although some archaic plants maintain archaic plant-pollinator interactions, e.g., Zygogynum pollinated by micropterigid moths, or Hedycarya pollinated by thrips and staphylinid beetles, the most dominant organism observed on flowers was the introduced honey bee, Apis mellifera. The plant species now visited by honey bees are thought to have originally been pollinated by native solitary short-tongued bees. Our data suggest that the unique systems of pollination mutualism in New Caledonia are now endangered by the establishment of highly invasive honey bees. PMID- 21652330 TI - Clonal variation in floral stage timing in the common dandelion Taraxacum officinale (Asteraceae). AB - We investigated the hypothesis that dandelion clones (Taraxacum officinale Weber, sensu lato; Asteraceae) differ in their floral stage timing characteristics under a constant set of environmental conditions. To test this hypothesis, plants representing nine different dandelion clones (identified by DNA fingerprinting) were grown in groups of five (N = 45) in a growth chamber for a period of 8 mo, with chamber settings similar to environmental conditions at peak dandelion flowering time for their population sites. Five flowering phenology parameters were monitored daily for a total of 301 buds developing during this time: (1) time to bud; (2) time to full opening and inflorescence maturation (i.e., first anthesis); (3) time to re-closure of an inflorescence; (4) time to fruit (full re opening of the inflorescence); and (5) total flowering time. Scape length at the appearance of a fully expanded infructescence was also measured for each individual. Significant differences in mean time to inflorescence, mean time to re-closure, mean time to fruit, and mean total flowering time were revealed among some dandelion clones (Kruskal-Wallis, P <= 0.0005). No differences in mean number of inflorescence buds per plant (P = 0.2217), mean time to bud (P = 0.2396), or mean scape length (P = 0.3688) were detected among the nine clones. These results suggest that differences in floral stage timing may in part involve varying genotypic environmental response characteristics and that these differences may have potential fitness effects. Further research is needed to determine if such clonal differences are observed under a broader range of uniform environmental conditions. PMID- 21652331 TI - Phylogenetic relationships of Betula species (Betulaceae) based on nuclear ADH and chloroplast matK sequences. AB - The phylogenetic relationships within the genus Betula (Betulaceae) were investigated using a part of the nuclear ADH gene and DNA sequences of the chloroplast matK gene with parts of its flanking regions. Two well-supported phylogenetic groups could be identified in the chloroplast DNA sequence: one containing the three American species B. lenta, B. alleghaniensis, and B. papyrifera and the other including all the other species studied. The ADH gene displayed more variation, and three main groups could be identified. In disagreement with the classical division of the genus Betula, B. schmidtii and B. nana grouped with the species in subgenus Betula, and B. ermanii grouped with species in subgenus Chamaebetula, including B. humilis and B. fruticosa. The ADH phylogeny suggests that several independent polyploidizations within the genus Betula could have taken place. The ADH and chloroplast phylogenies were in part incongruent due to the placement of B. papyrifera. The most likely reason for this seems to be cytoplasmic introgression. PMID- 21652332 TI - A phylogeny of legumes (Leguminosae) based on analysis of the plastid matK gene resolves many well-supported subclades within the family. AB - Phylogenetic analysis of 330 plastid matK gene sequences, representing 235 genera from 37 of 39 tribes, and four outgroup taxa from eurosids I supports many well resolved subclades within the Leguminosae. These results are generally consistent with those derived from other plastid sequence data (rbcL and trnL), but show greater resolution and clade support overall. In particular, the monophyly of subfamily Papilionoideae and at least seven major subclades are well-supported by bootstrap and Bayesian credibility values. These subclades are informally recognized as the Cladrastis clade, genistoid sensu lato, dalbergioid sensu lato, mirbelioid, millettioid, and robinioid clades, and the inverted-repeat-lacking clade (IRLC). The genistoid clade is expanded to include genera such as Poecilanthe, Cyclolobium, Bowdichia, and Diplotropis and thus contains the vast majority of papilionoids known to produce quinolizidine alkaloids. The dalbergioid clade is expanded to include the tribe Amorpheae. The mirbelioids include the tribes Bossiaeeae and Mirbelieae, with Hypocalypteae as its sister group. The millettioids comprise two major subclades that roughly correspond to the tribes Millettieae and Phaseoleae and represent the only major papilionoid clade marked by a macromorphological apomorphy, pseudoracemose inflorescences. The robinioids are expanded to include Sesbania and members of the tribe Loteae. The IRLC, the most species-rich subclade, is sister to the robinioids. Analysis of the matK data consistently resolves but modestly supports a clade comprising papilionoid taxa that accumulate canavanine in the seeds. This suggests a single origin for the biosynthesis of this most commonly produced of the nonprotein amino acids in legumes. PMID- 21652333 TI - Phylogenetic relationships of Malvatheca (Bombacoideae and Malvoideae; Malvaceae sensu lato) as inferred from plastid DNA sequences. AB - Previous molecular phylogenetic analyses have revealed that elements of the former families Malvaceae sensu stricto and Bombacaceae together form a well supported clade that has been named Malvatheca. Within Malvatheca, two major lineages have been observed; one, Bombacoideae, corresponds approximately to the palmate-leaved Bombacaceae, and the other, Malvoideae, includes the traditional Malvaceae (the mallows or Eumalvoideae). However, the composition of these two groups and their relationships to other elements of Malvatheca remain a source of uncertainty. Sequence data from two plastid regions, ndhF and trnK/matK, from 34 exemplars of Malvatheca and six outgroups were analyzed. Parsimony, likelihood, and Bayesian analyses of the sequence data provided a well-resolved phylogeny except that relationships among five lineages at the base of Malvatheca are poorly resolved. Nonetheless, a 6-bp insertion in matK suggests that Fremontodendreae is sister to the remainder of Malvatheca. Our results suggest that the Malvoideae originated in the Neotropics and that a mangrove taxon dispersed across the Pacific from South America to Australasia and later radiated out of Australasia to give rise to the ca. 1700 living species of Eumalvoideae. Local clock analyses imply that the plastid genome underwent accelerated molecular evolution coincident with the dispersal out of the Americas and again with the radiation into the three major clades of Eumalvoideae. PMID- 21652334 TI - The circumscription and phylogenetic relationships of Callitropsis and the newly described genus Xanthocyparis (Cupressaceae). AB - A new species of conifer was recently discovered in northern Vietnam. In a preliminary phylogenetic analysis of morphological data a possible sister species, Chamaecyparis nootkatensis (D. Don) Spach, was identified; however, because of the presumed phylogenetic remoteness of these two species to the remainder of the Cupressaceae, a new genus-Xanthocyparis-was described to accommodate both species. Here an analysis of ITS (nrDNA), matK, and rbcL sequence data in combination with 58 informative morphological characters was aimed at testing the monophyly of the remainder of Chamaecyparis and evaluating the placement and monophyly of Xanthocyparis. Chamaecyparis, minus C. nootkatensis, was resolved as a monophyletic group, remote from Cupressus and Xanthocyparis. Cupressus, Juniperus, and Xanthocyparis formed a very highly supported monophyletic group. However, Cupressus was not monophyletic. Instead the Old World species sampled were resolved sister to a clade containing a monophyletic Juniperus, a monophyletic Xanthocyparis, and a clade of New World Cupressus species. If both species of Xanthocyparis are to be treated as members of the same genus, then due to the principal of priority they will have to be recognized in the genus Callitropsis. Research is continuing to resolve the status of New World and Old World Cupressus. PMID- 21652335 TI - Molecular phylogenetic analysis of Phyllanthaceae (Phyllanthoideae pro parte, Euphorbiaceae sensu lato) using plastid RBCL DNA sequences. AB - Analysis of plastid rbcL DNA sequence data of the pantropical family Phyllanthaceae (Malpighiales) and related biovulate lineages of Euphorbiaceae sensu lato is presented. Sampling for this study includes representatives of all 10 tribes and 51 of the 60 genera attributed to Euphorbiaceae-Phyllanthoideae. Centroplacus and Putranjivaceae (Phyllanthoideae-Drypeteae) containing a paraphyletic Drypetes are excluded from Phyllanthaceae. Croizatia, previously thought to be a "basal" member of Euphorbiaceae-Oldfieldioideae (Picrodendraceae), falls within Phyllanthaceae. Phyllanthaceae with the mentioned adjustments form a monophyletic group consisting of two sister clades that mostly correspond to the distribution of tanniniferous leaf epidermal cells and inflorescence structure. With the exception of bigeneric Hymenocardieae and monotypic Bischofieae, none of the current Phyllanthoideae (Phyllanthaceae) tribal circumscriptions are supported by rbcL. Antidesma, Bischofia, Hymenocardia, Martretia, and Uapaca, all of which have previously been placed in monogeneric families, are confirmed as members of Phyllanthaceae. Savia is polyphyletic, and Cleistanthus appears paraphyletic. Paraphyly of Phyllanthus is also indicated, but this pattern lacks bootstrap support. Morphological characters are discussed and mapped for inflorescence structure, tanniniferous epidermal cells, breeding system, and fruit and embryo type. A table summarizes the main characters of six euphorbiaceous lineages. PMID- 21652336 TI - Phylogeny and infrageneric classification of Symplocos (Symplocaceae) inferred from DNA sequence data. AB - Symplocos comprises ~300 species of woody flowering plants with a disjunct distribution between the warm-temperate to tropical regions of eastern Asia and the Americas. Phylogenetic analyses of 111 species of Symplocos based on the nuclear ribosomal internal transcribed spacer (ITS) region and the chloroplast genes rpl16, matK, and trnL-trnF yielded topologies in which only one of the four traditionally recognized subgenera (Epigenia; Neotropics) is monophyletic. Section Cordyloblaste (subgenus Symplocos; eastern Asia) is monophyletic and sister to a group comprising all other samples of Symplocos. Section Palura (subgenus Hopea; eastern Asia) is sister to a group comprising all other samples of Symplocos except those of section Cordyloblaste. Symplocos wikstroemiifolia (eastern Asia) and S. tinctoria (southeastern United States), both of subgenus Hopea, form a clade that groups with S. longipes (tropical North America) and the species of subgenus Epigenia. The remaining samples of subgenus Hopea (eastern Asia) form a clade. Section Neosymplocos (subgenus Microsymplocos; Neotropics) is well nested within a clade otherwise comprising the samples of section Symplocastrum (subgenus Symplocos; Neotropics). Section Urbaniocharis (subgenus Microsymplocos; Antilles) groups as sister to the clade comprising Symplocastrum and Neosymplocos. The data support the independent evolution of deciduousness among section Palura and S. tinctoria. The early initial divergence of sections Cordyloblaste and Palura from the main group warrants their recognition at taxonomic levels higher than those at which they are currently placed. An inferred eastern Asian origin for Symplocos with subsequent dispersal to the Americas is consistent with patterns from other phylogenetic studies of eastern Asian-American disjunct plant groups but contrary to a North American origin inferred from the earliest fossil occurrences of the genus. PMID- 21652337 TI - The origins of an important cactus crop, Opuntia ficus-indica (Cactaceae): new molecular evidence. AB - Opuntia ficus-indica is a long-domesticated cactus crop that is important in agricultural economies throughout arid and semiarid parts of the world. The biogeographic and evolutionary origins of this species have been obscured through ancient and widespread cultivation and naturalization. The origin of O. ficus indica is investigated through the use of Bayesian phylogenetic analyses of nrITS DNA sequences. These analyses support the following hypotheses: that O. ficus indica is a close relative of a group of arborescent, fleshy-fruited prickly pears from central and southern Mexico; that the center of domestication for this species is in central Mexico; and that the taxonomic concept of O. ficus-indica may include clones derived from multiple lineages and therefore be polyphyletic. PMID- 21652338 TI - Sequence variation at cpDNA regions of watermelon and related wild species: implications for the evolution of Citrullus haplotypes. AB - Sequencing analysis of one coding and four noncoding cpDNA regions was conducted to infer biogeographic and evolutionary relationships in the genus Citrullus. Eighteen taxa from diverse geographical areas were included. A low number of parsimony informative characters (1.1%) was observed at the ~4 kb section of cpDNA. Variability within Citrullus was detected primarily at noncoding regions of high A + T content. Substitution rates varied from 0-0.48% for ndhF with A + T content of 68.4% to 0.39- 1.69% for the intergenic region of atpA with A + T content of 82.8%, mainly resulting in indels and transversions. Indels at several regions acted as valuable parsimony informative markers. Citrullus lanatus var. lanatus, the cultivated watermelon, and C. ecirrhosus and C. rehmii from Namibia, lacked molecular variability. The genus Citrullus is supported monophyletically and shows two main clades, one of which contains C. colocynthis. In the other clade, C. rehmii is sister to a clade containing C. ecirrhosus and C. lanatus. Two clades were recovered within C. lanatus, consisting of domesticated watermelon and wild citron, var. citroides. Five haplotypes within C. colocynthis were used to deduce colonization routes of the species. Biogeographic patterns point to separate colonization events into Africa and the Far East. PMID- 21652339 TI - Morphological variation in Sarracenia purpurea (Sarraceniaceae): geographic, environmental, and taxonomic correlates. AB - Geographic variation in morphology reflects phenotypic responses to environmental gradients and evolutionary history of populations and species and may indicate local or regional changes in environmental conditions. The pitcher plant (Sarracenia purpurea) illustrates these principles. At local scales, its morphology reflects nutrient availability. At points along its broad geographic range (from Florida to northern Canada) morphology has been used to distinguish subspecies and varieties, but there has been no detailed study of the continuum of morphological variation across this entire range. Patterns of morphological variation in S. purpurea were characterized as a function of climatic and environmental conditions at 39 sites spanning its range. Differences in pitcher size and shape were strongly correlated with temperature, annual precipitation, and availability of ammonium and calcium in peat pore water. Pitcher shape (lip width, mouth diameter, and pitcher width) in Florida panhandle populations differed significantly from pitcher shape of all other populations, even after accounting for environmental correlations. In contrast, the northern and southern subspecies of S. purpurea (the latter exclusive of the Florida panhandle populations) cannot be distinguished based on these morphological measurements alone. These results support a recent proposal that identifies the Florida populations as a distinct species, Sarracenia rosea. PMID- 21652340 TI - The mechanical role of the endodermis in Equisetum plant stems. AB - The endodermis of different species of the genus Equisetum has different configurations, two or one continuous layers or a sheath only around the vascular bundles. The question whether the endodermis contributes to the mechanical stability of the aerial shoots is investigated in two ways: In a direct approach, the endodermis of segments of E. hyemale was dissected longitudinally and the mechanical stability against ovalization measured as a function of the orientation of the cuts with respect to the forces applied. A comparative approach tested the mechanical stability of eight different species of Equisetum against ovalization of the cross-section for samples, which were either fully turgescent or had reduced turgor pressure. The double-layer endodermis substantially contributed to the mechanical stability of E. affinis and E. hyemale. Equisetum arvense, E. pratense, E. sylvaticum, and E. telmateja are mechanically stabilized by their single layer of endodermis at least under conditions of low turgor pressure. PMID- 21652341 TI - Does pollen competition reduce the cost of inbreeding? AB - We hypothesize that floral features promoting pollen competition in angiosperms may have evolved, in some cases, in response to selection generated by the negative effects of inbreeding, at least in plants with mixed-mating systems. Screening of haploid genotypes through pollen competition may purge recessive (or additive) deleterious alleles that are expressed in haploid pollen and hence may reduce the fitness cost of self-pollination, geitonogamy, or biparental inbreeding. We tested one prediction of this hypothesis, that offspring produced by more intense competition among self-pollen have higher fitness than offspring produced by less intense competition. Dalechampia scandens (Euphorbiaceae) flowers were pollinated with pollen from other flowers on the same plant (geitonogamous self-fertilization). Those flowers experiencing more intense pollen competition as a result of low pollen dispersion (positional variance) on the stigma produced heavier seeds and seedlings with faster-growing radicles than flowers experiencing less intense pollen competition (high pollen dispersion), as predicted by our hypothesis. PMID- 21652342 TI - American Journal of Botany at 90: a librarian perspective. AB - The American Journal of Botany (AJB) is available on the shelves of most college and university libraries in the U.S., as well as in many faculty offices, and in research libraries affiliated with botanical gardens. This article presents information on how librarians view AJB, the role that scientific associations play in the perceived quality of the journals they publish, the unique nature of botany literature (compared to other sciences), AJB as a core journal, and a general discussion of the factors that influence librarians decisions when deciding to cancel a subscription or keep a journal in their collection. PMID- 21652343 TI - The criteria for biomass partitioning of the current shoot: water transport versus mechanical support. AB - In this study, we determine the theoretical criteria for biomass partitioning into the leaf and stem of the current shoot, using two quantitative models. The water transport model, based on the biochemical model of CO(2) assimilation, predicts the relationship between the water transport capacity per biomass investment in the stem (stem mass specific conductivity) and the partitioning of biomass that maximizes shoot productivity. The mechanical support model, based on Euler's buckling formula, predicts the relationship between the mechanical strength per biomass investment in the stem (the inverse relationship of stem mass density) and the partitioning of biomass to avoid mechanical failures such as lodging. These models predict the stem properties of mass specific conductivity and stem mass density that result in optimum partitioning just sufficient to provide adequate water transport and static mechanical support. In reality, the stem properties of plants differ from those predicted for optimum partitioning: the partitioning of biomass in the current shoot of both angiosperms and gymnosperms is mainly governed by the mechanical support criterion, although gymnosperms are probably more affected by the water transport criterion. This tendency is supported by actual measurements of biomass partitioning in plants. PMID- 21652344 TI - Recovery from drought stress in Lolium perenne (Poaceae): are fungal endophytes detrimental? AB - Perennial ryegrass (Lolium perenne) is a cool-season, perennial species widely used for forage and turf. It is often infected by a clandestine, endophytic fungus (Neotyphodium lolii) that has the potential to affect host growth responses to abiotically stressful conditions. In some species, the grass endophyte symbiosis is mutualistic, but the relationship is reported to be contingent on environmental conditions and host genotype in L. perenne. The objective of this research was to determine the potential effects of endophyte infection on recovery from severe drought stress in variable genotypes of a perennial ryegrass cultivar. Sixteen infected (+E) and 16 uninfected (-E) ramets were planted in the greenhouse for each of 10 ryegrass genotypes. Eight +E and eight -E plants per genotype were exposed to three sequential droughts where water was withheld for 11-14 d, resulting in <5% soil moisture; the others (control) were watered as needed. Response variables were tiller numbers 1 wk and 4 wk after drought, and leaf area and dry mass of shoots and roots 7 wk after drought. In both control and drought, -E plants had more tillers, and greater leaf area and total mass, than +E plants, suggesting a detrimental effect of endophytic fungi. Fungal hyphae survived the drought and were abundant in post drought, +E plants. The effects of endophytes were specific for particular host genotypes, as exemplified by significant genotype * endophyte interactions. Root : shoot ratio and percent of mass allocated to tiller bases (a rough measure of resource storage) showed genotype * endophyte * drought interactions. There was plasticity for root : shoot ratio and genetic variation in the ability to restore root growth during recovery from drought. For 7 of 10 genotypes, -E plants showed an equal or greater allocation to tiller bases than +E plants following drought recovery, illustrating a cost to endophyte infection for some genotypes. The symbiotic relationship between L. perenne and its endophyte primarily benefits the fungus, not the host, under many environmental conditions. PMID- 21652345 TI - Chemical composition of anther volatiles in Ranunculaceae: genera-specific profiles in Anemone, Aquilegia, Caltha, Pulsatilla, Ranunculus, and Trollius species. AB - Anther volatiles of 12 Ranunculaceae species distributed in six genera (Anemone, Aquilegia, Caltha, Pulsatilla, Ranunculus, and Trollius) were investigated by thermal desorption of anthers in quartz microvials inserted into a modified injector. Chemical analysis (GC-MS) yielded a total of 116 compounds from which 103 compounds could be identified. A great diversity of compounds was observed, including aliphatic compounds, aromatics, mono- and sesquiterpenoids, and nitrogen-bearing compounds. Intraspecific variation in the chemical profiles was significantly lower than interspecific variation. Eight compounds explained 96.1% of the observed total variation between the taxa: protoanemonin, octanal, (E,E) alpha-farnesene, 2-phenyl ethanol, pentadecane, alpha-muurolene, phenyl acetaldehyde, and linalool oxide (pyranoid) were either present only in specific taxa or varied greatly in their relative amount between the taxa. An analysis of the scent data using the chord-normalized expected species shared (CNESS) distances of chemical profiles of the species, followed by visualization of the data with nonmetric multidimensional scaling (NMDS) showed that most species belonging to the same genus have similar chemical compositions. The differences in the chemical composition of anther volatiles are discussed with respect to the taxonomy and pollination biology of the species. PMID- 21652346 TI - Changes in crown development patterns and current-year shoot structure with light environment and tree height in Fagus crenata (Fagaceae). AB - The relative effects of light and tree height on the architecture of leader crowns (i.e., the leading section of the main trunk, 100 cm in length) and current-year shoots for a canopy species, Fagus crenata, occupying both the ridge top and the valley bottom in a cool-temperate forest in Japan were investigated. For leader crowns, the number of current-year shoots and leaves increased with increasing tree height, whereas the mean length of current-year shoots increased with increasing relative photon flux density (PFD). The leader crown area decreased, and the depth and leaf area index of leader crowns increased, with increasing relative PFD. The mass of current-year shoots increased with relative PFD. However, this total mass was allocated differently between stems and leaves depending on tree height, such that the relative allocation to stems increased with increasing tree height. Furthermore, stem structures within current-year shoots also changed with height, such that taller trees produced thicker and shorter stems of the same volume. In contrast, leaf structure and leaf biomass allocations changed with relative PFD. Specific leaf area decreased with increasing relative PFD. In addition, leaf number increased more rapidly with increasing individual leaf mass for trees exposed to greater relative PFD. Consequently, the total leaf area supported by a stem of a given diameter decreased with increasing tree height and relative PFD. Thus, the architecture of leader crowns and current-year shoots were related differently to light and tree height, which are considered important for efficient light capture and the growth of small and tall trees in different environments. PMID- 21652347 TI - Polymorphic buttonwood: effects of disturbance on resistance to herbivores in green and silver morphs of a Bahamian shrub. AB - We studied consequences of storm damage on buttonwood (Conocarpus erectus) shrubs and their herbivores in the Bahamian islands. Buttonwood is polymorphic, with green shrubs producing few leaf trichomes and silver shrubs covered in dense trichomes. We first characterize traits of green vs. silver shrubs relevant for herbivores, and then assay damage by two prominent insects. Next, on replicated islands, we experimentally address how different types of storm damage (simulated hurricane surge damage vs. simulated intense wind) affected phenotypic traits of both buttonwood morphs and subsequent herbivory over a one-year sampling period. Our results show that although leaves produced by green shrubs are 21% tougher than leaves produced by silver shrubs, green leaves have 16% higher nitrogen concentrations and greater levels of herbivory. Consistent with previous observational studies of a natural hurricane at our study site, we found stronger effects of simulated surge damage than simulated wind damage. Experimental pruning of shrubs resulted in reduced toughness, higher nitrogen concentration, fewer trichomes, and greater herbivory compared to controls and compared to shrubs with their leaves stripped. The results were stronger for the silver compared to the green morph. Morph differences in buttonwood have strong consequences for herbivores, and these effects are modified by disturbance. PMID- 21652348 TI - Heterogeneous reflected light influences asymmetry in leaf anatomy and gas exchange. AB - Soil and vegetative groundcovers reflect light heterogeneously in habitats lacking a continuous overhead canopy, however the effects of reflected light on vegetation in these habitats has received little attention. We test the hypothesis that reflected light flux affects leaf optical properties, anatomy, and photosynthesis of Ipomoea pes-caprae (Convolvulacae), a common sand dune vine with functionally symmetric leaves, by comparing leaves growing over patches of high and low reflected light flux. Patches of high reflected light were found directly over sand and reflected 26.0 +/- 0.9% (mean +/- 1 SE) of incident photosynthetically active radiation (PAR) while patches of low reflected light were found over vegetation and reflected 6.1 +/- 0.7% of incident PAR. Using a novel in situ method to simultaneously illuminate and measure gas exchange of one leaf surface at a time, we show that abaxial surface photosynthetic maxima and palisade parenchyma in sand patches were, respectively, 2.6 times greater and 20% thicker than those found over vegetation patches. Our results suggest that reflected light strongly influences leaf anatomy and gas exchange of I. pes caprae, demonstrating that reflected light can be an important component of the light environment for vegetation of habitats characterized by high-albedo substrates. PMID- 21652349 TI - Genetic diversity of the narrow endemic Astragalus oniciformis (Fabaceae). AB - Astragalus oniciformis Barneby is a narrow endemic xerophyte of the upper Snake River Plain of central Idaho, USA, where it inhabits stabilized, aeolian sand deposits and previously burned, sandy sites over Quaternary basalt flows. The objective of this study was to determine the levels and distribution of genetic differentiation within and among populations of A. oniciformis. Fifteen individuals from each of eight populations, chosen from throughout the range of the species, were selected based on accessibility, density of individuals, and large population size. Inter-simple sequence repeats were chosen as the marker to assess genetic differentiation. The two primers selected yielded 40 polymorphic loci in A. oniciformis. In an analysis of molecular variance, 88.69% of the variation was significantly attributed to variation within populations. High gene flow (N(m) = 3.91-3.93; SD = 0.01) and a low percentage deviation from Hardy Weinberg equilibrium due to population subdivision (G(ST) = 0.113-0.1134; SD = 0.0002) were found among sampled populations. These results suggest that current threats to this species, including changing fire patterns and habitat loss from grazing disturbance, have not yet affected the genetic diversity of this species. Preservation of large populations and smaller, intervening, dispersed patches will help preserve the genetic integrity and the genetic diversity found in A. oniciformis. PMID- 21652350 TI - Population genetic diversity of the clonal plant Geum reptans (Rosaceae) in the Swiss Alps. AB - In the alpine landscape most plant populations are spatially isolated due to extreme patchiness and strong natural fragmentation. We used RAPD-PCR (randomly amplified polymorphic DNA polymerase chain reaction) for a study of the genetic diversity within and among 20 populations of Geum reptans, an outcrossing clonal plant species in the Swiss Alps. Populations were sampled at different altitudes, in early-, medium- and late-successional habitats (population origin) using a spatially hierarchical design, with distances among populations ranging from 0.2 to 208 km. Seed and pollen dispersibility was estimated by direct measurements. Seed dispersibility by wind was low with only 0.015% of the seeds flying over 100 m. Observed pollen flow was even more restricted. Molecular diversity within populations was irrespective of population origin (H(e) = 0.22 +/- 0.004) and similar to the average of other RAPD studies. Contrary to our expectation, populations were only moderately differentiated (G(st) = 0.14). However, there was a clear spatial genetic structure and a positive relationship between pairwise genetic and geographic distances. Our results indicate considerable gene flow among populations within the same regional area, and we found no indication for genetic depletion during succession or in peripheral habitats. We conclude that, despite the high natural fragmentation and the importance of vegetative reproduction in this alpine plant, gene flow and repeated seedling recruitment during succession might be more frequent than commonly suggested. PMID- 21652351 TI - Cryptic species in an endangered pondweed community (Potamogeton, Potamogetonaceae) revealed by AFLP markers. AB - Cryptic species are morphologically indistinguishable, yet reproductively isolated. Morphological boundaries between species can also be obscured by hybridization and clonality. Determining the roles of reproductive isolation, hybridization, and clonality in morphologically indistinguishable taxa is essential to determining appropriate species-level taxonomic rankings for conservation purposes. The taxonomic status of the endangered Little Aguja pondweed of west Texas, Potamogeton clystocarpus, is uncertain due to a lack of fixed morphological differences between it and two sympatric congeners. Morphology, amplified fragment length polymorphisms (AFLPs), and sequences of the internal transcribed spacer (ITS) region and trnL-F intron and spacer were used to determine the degree of genetic distinctiveness, hybridization and clonality for this rare species. AFLPs indicate that P. clystocarpus is a genetically distinct lineage compared to P. pusillus and P. foliosus. No hybrids involving P. clystocarpus were detected, but two putative hybrids involving P. pusillus and P. foliosus were identified. Clonal growth was only detected in P. pusillus. A combination of morphological and molecular markers was successful in determining the genetic distinctiveness of an endangered cryptic species, Potamogeton clystocarpus. Further sampling in this and adjacent drainages is necessary to assess the degree of endemism of P. clystocarpus and confidently rule out hybridization and clonality in this taxon. PMID- 21652352 TI - Architectural effects mimic floral sexual dimorphism in Solanum (Solanaceae). AB - Factors underlying apparent floral sexual dimorphism were examined in six species of andromonoecious Solanum section Lasiocarpa (Solanaceae). Both multivariate and univariate analyses show that hermaphroditic flowers are significantly larger than staminate flowers for all features measured. Thus, flowers could be characterized as sexually size dimorphic. However, when size variation due to flower position (architecture) is controlled experimentally, differences between the floral genders for the nongynoecial characters disappear; there is no difference in corolla or androecium size. Staminate flowers appear to be generally smaller than hermaphroditic flowers, not because of any difference related to primary sexual function, but because they tend to occur in the distal regions of each inflorescence. In contrast, significant differences between hermaphroditic and staminate flowers for primary female traits (ovary, style, and stigma) remain after controlling for position: the two floral types are truly dimorphic for these characters. We show that consideration of architectural effects can direct and refine hypotheses concerning the evolution of andromonoecy. More generally, if architectural effects on flower size are common among taxa with unisexual flowers, then these effects may contribute to the common perception of size dimorphism in taxa with unisexual flowers. PMID- 21652353 TI - Life history, floral development, and mating system in Clarkia xantiana (Onagraceae): do floral and whole-plant rates of development evolve independently? AB - Autogamously self-fertilizing taxa have evolved from outcrossing progenitors at least 12 times in the annual wildflower genus, Clarkia (Onagraceae). In C. xantiana, individuals of the selfing subspecies (ssp. parviflora) flower at an earlier age, produce successive flowers more rapidly, and produce flowers that complete their development more rapidly than their outcrossing counterparts (ssp. xantiana). Two hypotheses have been proposed to explain the joint evolution of these whole-plant and individual floral traits. The accelerated life cycle hypothesis proposes that selection favoring a short life cycle in environments with short growing seasons (such as those typically occupied by parviflora) has independently favored genotypes with early reproduction, synchronous flower production, and rapidly developing, self-fertilizing flowers. The correlated response to selection hypothesis similarly proposes that selection in environments with short growing seasons favors early reproduction, but that rapid floral development and increased selfing evolve as correlated responses to selection due to genetic linkage (or pleiotropy) affecting both whole-plant and floral development. We conducted a greenhouse experiment using maternal families from two field populations of each subspecies to examine covariation between floral and whole-plant traits within and among populations to seek support for either of these hypotheses. Our results are consistent with the accelerated life cycle hypothesis but not with the correlated response to selection hypothesis. PMID- 21652354 TI - Temporal changes in calyx tube length of Clematis stans (Ranunculaceae): a strategy for pollination by two bumble bee species with different proboscis lengths. AB - We examined the adaptive significance of a temporal decrease in the calyx tube length of Clematis stans, a dioecious species pollinated by Bombus diversus (long proboscis) and B. honshuensis (short proboscis). We compared visitation frequency, pollen removal, pollen deposition, and fruit set after a single visit among three flower stages, differentiated by calyx tube length. Bombus diversus frequently visited and removed significantly more pollen from long flowers. Bombus honshuensis visited and tended to remove more pollen from short flowers. Both pollinators deposited more pollen in short flowers, resulting in higher fruit set. These results indicate that size correspondence between the proboscis and the calyx tube enhances visitation frequency and pollen removal, but not pollen deposition. Because a single visit does not fertilize all ovules of a flower, multiple visits by two bumble bee species may increase seed production and genetic diversity of offspring. By temporally changing calyx tube length, C. stans can use two bumble bee pollinators and maintain specialized relationships with each. This strategy may be adaptive when the pollinator fauna fluctuates, and is economical because it eliminates costs required to produce different types of flowers. This constitutes a novel pattern of temporal specialization in flower pollinator relationships. PMID- 21652355 TI - Pollination and seed production in Xerophyllum tenax (Melanthiaceae) in the Cascade Range of central Oregon. AB - Xerophyllum tenax is a mass-flowering, nectarless herb in which self-pollination is unavoidable as anthers shed pollen onto the three, receptive stigmatic ridges attached to each pistil within a few hours after expansion of the perianth. We compared the pollination system with reproductive success in this species through controlled, hand-pollination experiments. Ovaries of flowers sampled from unbagged inflorescences were visited by pollen-eating flies (primarily members of the family Syrphidae), beetles (primarily Cosmosalia and Epicauta spp.), and small bees, and produced normal-sized capsules and mature seeds. Ovaries of flowers from inflorescences bagged to prevent insect pollination produced small capsules containing undeveloped or no seeds. Epifluorescence analyses suggest that 0.95 of the uncovered flowers are cross-pollinated by insects with pollen tubes penetrating style and ovary tissue. Flowers show a "leaky" but early-acting self-incompatibility system. While hundreds of pollen tubes germinate on each stigmatic surface following self-pollination, few pollen tubes penetrate the stigmatic surface and none penetrate the ovary. In contrast, when stigmas are cross-pollinated by hand with pollen from a second inflorescence pollen tubes were seen penetrating style and ovary. Self-incompatibility in X. tenax parallels that of some species of Trillium, a sister genus within the Melanthiaceae. PMID- 21652356 TI - Phylogenetic relationships within the New World endemic Zeltnera (Gentianaceae Chironiinae) inferred from molecular and karyological data. AB - The New World endemic genus Zeltnera consists of 25 species mainly distributed in the western part of the United States and Mexico. Chromosome counts performed on 113 populations (24 species) reveal extensive congruence between chromosomal groups and the assemblages obtained from analyses of nuclear ribosomal DNA (ITS) and chloroplast DNA (trnL intron and trnL-F intergenic spacer) sequences. Karyological and molecular data sets support three main biogeographic groups for Zeltnera. A first and mainly unresolved cluster (n = 17 and n = 20) occurs in California, whereas two other clades are centered in the Texas region (n = 20 and n = 21) and in Mexico (n = 21 and n = 22). Under the assumption of a molecular clock, and using both dispersal and vicariance explanations for the current distribution of the respective species, the genus is thought to have a North American origin with considerable diversification in the early Pliocene (ca. 5 million years ago). Geological events, such as desert formation and mountain orogenies, have created insuperable barriers that today separate the three major and likely vicariant groups. PMID- 21652357 TI - Intraspecific diversification in North American Boechera stricta (= Arabis drummondii), Boechera xdivaricarpa, and Boechera holboellii (Brassicaceae) inferred from nuclear and chloroplast molecular markers--an integrative approach. AB - We performed a combined evolutionary analysis of North American Boechera stricta, Boechera holboellii, and their hybrid Boechera *divaricarpa using information on ploidy level estimators, allelic microsatellite variation, noncoding regions of the plastidic genome (cpDNA), and sequences of the internal transcribed spacers 1 and 2 of the nuclear ribosomal DNA (ITS). Somatic ploidy levels of herbarium specimens were estimated based on comparison of pollen size and the number of alleles per locus at seven microsatellites. Results indicate that B. stricta and B. holboellii are genetically distinct from each other, although we also find evidence for occasional introgression between both parental species. Microsatellite patterns for B. stricta from northeastern North America are genetically distinct from western populations, suggesting isolation in glacial refugia along the southeastern margin of the continuous ice shield. Microsatellites supported recent origin of B. *divaricarpa. Correspondence of nrDNA with cpDNA genetic variation for the majority of diploid B. holboellii accessions suggests a basal, sexual evolutionary unit within a polymorphic B. holboellii group. Hybridization of genetically distinct lineage(s) evidently played an important role in the establishment of polyploid B. holboellii. Frequency of polyploid B. holboellii is substantially higher in the southern United States. This trend corresponds to a southerly distribution of derived chloroplast haplotypes, suggesting an evolutionary advantage of polyploidy and associated apomixis in the colonization of the Sierra Nevada and the Southern Rocky Mountains. PMID- 21652358 TI - Phylogeny and diversification of B-function MADS-box genes in angiosperms: evolutionary and functional implications of a 260-million-year-old duplication. AB - B-function MADS-box genes play crucial roles in floral development in model angiosperms. We reconstructed the structural and functional implications of B function gene phylogeny in the earliest extant flowering plants based on analyses that include 25 new AP3 and PI sequences representing critical lineages of the basalmost angiosperms: Amborella, Nuphar (Nymphaeaceae), and Illicium (Austrobaileyales). The ancestral size of exon 5 in PI-homologues is 42 bp, typical of exon 5 in other plant MADS-box genes. This 42-bp length is found in PI homologues from Amborella and Nymphaeaceae, successive sisters to all other angiosperms. Following these basalmost branches, a deletion occurred in exon 5, yielding a length of 30 bp, a condition that unites all other angiosperms. Several shared amino acid strings, including a prominent "DEAER" motif, are present in the AP3- and PI-homologues of Amborella. These may be ancestral motifs that were present before the duplication that yielded the AP3 and PI lineages and subsequently were modified after the divergence of Amborella. Other structural features were identified, including a motif that unites the previously described TM6 clade and a deletion in AP3-homologues that unites all Magnoliales. Phylogenetic analyses of AP3- and PI-homologues yielded gene trees that generally track organismal phylogeny as inferred by multigene data sets. With both AP3 and PI amino acid sequences, Amborella and Nymphaeaceae are sister to all other angiosperms. Using nonparametric rate smoothing (NPRS), we estimated that the duplication that produced the AP3 and PI lineages occurred approximately 260 mya (231-290). This places the duplication after the split between extant gymnosperms and angiosperms, but well before the oldest angiosperm fossils. A striking similarity in the multimer-signalling C domains of the Amborella proteins suggests the potential for the formation of unique transcription-factor complexes. The earliest angiosperms may have been biochemically flexible in their B function and "tinkered" with floral organ identity. PMID- 21652359 TI - Gene flow between Impatiens radicans and I. javensis (Balsaminaceae) in Gunung Pangrango, central Java, Indonesia. AB - This study reports the natural hybridization of two species of Impatiens in the mountain forests of Gunung Gede-Pangrango, in central Java, Indonesia. Impatiens radicans, which inhabits the highest altitude zone in the mountains of this park, and I. javensis, which inhabits a zone of lower altitude, can be easily distinguished by their morphological features. However, some populations that inhabit regions between the two zones have characteristics that appear to be combinations of traits of I. radicans and I. javensis. Sequence analysis of the 800-bp nuclear ITS region and 449-bp plastid trnL-F locus demonstrated that hybridization between the two species has occurred, and suggests gene flow between the species. PMID- 21652360 TI - Structural integration at the shoot apical meristem: models, measurements, and experiments. AB - The shoot apical meristem (SAM) produces stem and initiates leaves. Its structure is maintained despite a continuous flow of cells basipetally from the distal portion of the meristem. The apoplasm and symplasm are the obvious means of cell integration, and their role in chemical cell-to-cell signaling is known. However, the cell wall apoplasm is most likely also involved in a mechanical integration mode, in which mechanical stress and strains (elastic and plastic strain, i.e., growth) are putative signaling factors. Shoot apex cells grow symplastically and their growth is in general anisotropic. Therefore tensor of growth rates that depends on the displacements caused by growth is the most suitable physical entity to describe growth. The tensor approach introduces the concept of principal directions of growth, i.e., the directions in which growth rates attain extremal values. Because of the symplastic mode of growth, the cell wall pattern within the shoot apical meristem informs us about the sequence and planes of cell divisions and about the deformation of existing walls. In consequence, within the meristem, periclines and anticlines can be recognized, both representing the principal directions of growth. PMID- 21652361 TI - Physical mapping of the 5S and 18S-25S rRNA genes by FISH as evidence that Arachis duranensis and A. ipaensis are the wild diploid progenitors of A. hypogaea (Leguminosae). AB - The 5S and the 18S-25S rRNA genes were physically mapped by fluorescent in situ hybridization (FISH) in all botanical varieties of cultivated peanut Arachis hypogaea (2n = 4x = 40), in the wild tetraploid A. monticola, and in seven wild diploid species considered as putative ancestors of the tetraploids. A detailed karyotype analysis including the FISH signals and the heterochromatic bands was carried out. Molecular cytogenetic landmarks are provided for the construction of a FISH-based karyotype in Arachis species. The size, number, and chromosome position of FISH signals and heterochromatic bands are similar in all A. hypogaea varieties and A. monticola, but vary among the diploid species. Genome constitution of the species is discussed and several chromosome homeologies are established. The bulk of the chromosome markers mapped, together with data on geographical distribution of the taxa, suggest that peanut originated upon domestication of A. monticola and evidence that the diploids A. duranensis and A. ipaensis are the most probable ancestors of both tetraploid species. Allopolyploidy could have arisen by a single event or, if by multiple events, always from the same diploid species. PMID- 21652362 TI - Inhibition of peptide deformylase in Nicotiana tabacum leads to decreased D1 protein accumulation, ultimately resulting in a reduction of photosystem II complexes. AB - Eukaryotic homologs of bacterial peptide deformylases were recently found in several vascular plants and may be essential in chloroplast protein processing. Treating tobacco seedlings with the peptide deformylase inhibitor actinonin resulted in leaf chlorosis and reduced growth and development, indicative of a systemic movement of the inhibitor. Photosystem II (PSII) activity was reduced, manifested as a significant decrease in the maximum quantum efficiency of photosystem II. Accumulation and assembly of nascent D1 protein into PSII monomers was also reduced, eventually leading to PSII disassembly and leaf necrosis. Processing and assembly of D1 protein in tobacco was a major and potentially critical target of peptide deformylase inhibition. These results confirm that N-terminal deformylation is an essential step in the accumulation and assembly of PSII subunit polypeptides in the chloroplasts of vascular plants. PMID- 21652363 TI - Chloroplast small heat-shock proteins protect photosynthesis during heavy metal stress. AB - Plants can accumulate heavy metals when exposed to them at high levels. These metals can interfere with photosynthesis. Limited evidence suggests that increased synthesis of some heat-shock proteins (Hsps) may be a general plant response to metal stress, but the specific functions or structures protected by Hsps remain unidentified. Chloroplast small Hsps (smHsps) protect photosynthetic electron transport (Ph(et)) during heat, oxidative, and photoinhibitory stress, but it is not known if chloroplast smHsps are synthesized during metal stress and protect photosynthesis. Zea mays (corn) plants were exposed to varying soil concentrations of Cu, Ni, Pb, and Zn to determine if chloroplast smHsps are induced by heavy metals, if smHsps protect Ph(et), and any effects on chloroplast smHsp and photosynthesis. Net photosynthesis (Ph(n)) decreased with all metals more so at higher levels and with longer exposures. Decreases in Ph(n) resulted from damage to photosynthetic metabolism, including Ph(et). All metals increased chloroplast smHsp content, which increased with time of exposure. In vitro, Ph(et) was protected from Pb (but not Ni) by purified chloroplast smHsp added to thylakoids. In vivo, Ph(n) was protected from Ni and Pb by increases in smHsp in a heat-tolerant Agrostis stolonifera selection genotype expressing additional chloroplast smHsps compared to a near-isogenic heat-sensitive genotype. These results are evidence that Hsps protect photosynthesis from heavy metals and are among the first to demonstrate specific functions protected by Hsps during metal stress. PMID- 21652364 TI - Obligate pollination mutualism in Breynia (Phyllanthaceae): further documentation of pollination mutualism involving Epicephala moths (Gracillariidae). AB - This paper reports obligate seed-parasitic pollination mutualisms in Breynia vitis-idea and B. fruticosa (Phyllanthaceae). The genus Breynia is closely related to Glochidion and Gomphidium (a subgenus of Phyllanthus), in which pollination by species-specific, seed-parasitic Epicephala moths (Gracillariidae) have been previously reported. At night, female Epicephala moths carrying numerous pollen grains on their proboscises visited female flowers of B. vitis idea, actively pollinated flowers, and each subsequently laid an egg. Examination of field-collected flowers indicated that pollinated flowers of B. vitis-idea and B. fruticosa almost invariably had Epicephala eggs, suggesting that these moths are the primary pollinators of the two species. Single Epicephala larvae consumed a fraction of seeds within developing fruit in B. vitis-idea and all seeds in B. fruticosa. However, some of the fruits were left untouched, and many of these had indication of moth oviposition, suggesting that egg/larval mortality of Epicephala moths is an important factor assuring seed set in these plants. The overall similarity of the specialized floral structure among Breynia species may indicate that this pollination system is fairly widespread within the genus. PMID- 21652365 TI - The consequences of clone size for paternal and maternal success in domestic apple (Malus x domestica). AB - Clonal growth in plants can increase pollen and ovule production per genet. However, paternal and maternal reproductive success may not increase because within-clone pollination (geitonogamy) can reduce pollen export to adjacent clones (pollen discounting) and pollen import to the central ramets (pollen limitation). The relationship between clone size and mating success was investigated using clones of Malus * domestica at four orchards (blocks of 1-5 rows of trees). For each block, maternal function was measured as fruit and seed set in all rows and paternal function as siring rate estimated from isozyme profiles in the first row of the adjacent block. Expected relations between reproductive success and clone size were generated from simulations and data on pollen dispersal in this species. Siring rate per clone averaged 70% and did not increase significantly with block size, consistent with simulations of pollen dispersal under pollen discounting. Simulations also indicated that the ratio of compatible to incompatible pollen received by a tree should decline with increased block size and from the periphery to the center of blocks. However, female function was not significantly reduced among block sizes or within blocks. The results suggest that paternal function may be more sensitive to the effects of clonality than female function. PMID- 21652366 TI - Hybridization and gene flow between a day- and night-flowering species of Zaluzianskya (Scrophulariaceae s.s., tribe Manuleeae). AB - Despite apparent ethological isolation based on specialized pollination systems, hybridization between day-flowering Zaluzianskya microsiphon and night-flowering Z. natalensis has been proposed due to intermediate individuals found in sympatric populations of these species. The extent of this putative hybridization was investigated using inter-simple sequence repeat (ISSR) markers and principal components analysis (PCA) of morphological traits. The species are genetically similar, but show some intra- and interspecific variation in band frequencies. Neighbor-joining analyses of the ISSR data demonstrated that although the species largely formed distinct groups, several individuals from the sympatric populations of each species and the "hybrids" clustered together rather than with members of their own species. These results are consistent with hybridization, although they could also indicate historical similarity. Nine loci were present only in individuals of Z. microsiphon, the "hybrids," and sometimes the sympatric individuals of Z. natalensis. In contrast, only one locus showed the reverse pattern. This suggests unidirectional gene flow from Z. microsiphon to Z. natalensis, which is also supported by population-level examinations of four loci. Ordination revealed separate phenotype clusters for each species, with hybrid individuals located in between but often closer to the Z. natalensis cluster. One hypothesis is that hybrids are backcrossing with Z. natalensis, leading to introgression of Z. microsiphon genetic material. PMID- 21652367 TI - Multi-scale genetic analysis of Uniola paniculata (Poaceae): a coastal species with a linear, fragmented distribution. AB - Geographic and fine-scale population genetic structures of Uniola paniculata, the dominant coastal dune grass in the southeastern USA, were examined. The linear, naturally fragmented distribution of this native perennial was hypothesized to lead to high genetic structure and lower genetic diversity at the margin of the species range. The extensive ramet production and low seed germination of this species were also expected to cause populations to be dominated by a few large clones. At 20 sites throughout the range of the species, leaf tissue was collected from 48 individuals. Clonal structure was examined using leaf tissue collected from an additional 60 individuals, each in four patches at two sites. Starch gel electrophoresis was used to resolve 27 allozyme loci. The results indicated that Uniola had greater genetic structure (G(ST) = 0.304) than most other outcrossing species, indicating moderate barriers to gene flow. There was a weak but significant positive relationship between genetic distance and geographic distance, supporting an isolation-by-distance model of gene flow. There were no obvious disjunctions between regions. Genetic diversity (H(e)) was relatively uniform throughout most of the range of the species but was lower in all western Gulf of Mexico populations. Clonal diversity varied both within and among sites, but clones were often small, suggesting that sexual reproduction and recruitment from seeds are important factors maintaining genetic diversity. PMID- 21652368 TI - Natural hybridization and hybrid zones between Quercus crassifolia and Quercus crassipes (Fagaceae) in Mexico: morphological and molecular evidence. AB - Hybrid zones provide interesting systems to study genetic and ecological interaction between different species. The correct identification of hybrids is necessary to understand the evolutionary process involved in hybridization. An oak species complex occurring in Mexico formed by two parental species, Quercus crassifolia H. & B. and Q. crassipes H. & B., and their putative hybrid species, Q. dysophylla, was analyzed with molecular markers (random amplified polymorphic DNA [RAPDs]) and morphological tools in seven hybrid zones (10 trees per taxa in each hybrid zone) and two pure sites for each parental species (20 trees per site). We tested whether geographic proximity of hybrid plants to the allopatric site of a parental species increases its morphological and genetic similarity with its parent. Seventeen morphological traits were measured in 8700 leaves from 290 trees. Total DNA of 250 individuals was analyzed with six diagnostic RAPD primers. Quercus crassifolia differed significantly from Q. crassipes in all the examined characters. Molecular markers and morphological characters were highly coincident and support the hypothesis of hybridization in this complex, although both species remain distinct in mixed stands. Clusters and a hybrid index (for molecular and morphological data) showed that individuals from the same parental species were more similar among themselves than to putative hybrids, indicating occasional hybridization with segregation in hybrid types or backcrossing to parents. Evidence does not indicate a unidirectional pattern of gene flow. PMID- 21652369 TI - Testing the adaptive nature of radiation: growth form and life history divergence in the African grass genus Ehrharta (Poaceae: Ehrhartoideae). AB - In most documented examples of adaptive radiation, the processes underlying divergence in form and function are poorly explored and remain speculative. Here, data from a comparative seedling growth experiment are used to explore growth form divergence in Ehrharta, a group of grasses that radiated in seasonally arid environments of the Cape region of South Africa. Seedlings of eight Ehrharta species of variable growth form were grown in liquid culture under conditions of high resource availabilty for 56 d, during which time changes in dry mass, allocation, and leaf parameters were measured. The results of this experiment reveal the existence of distinct seedling growth patterns that are associated with differences in adult plant form and seasonal drought survival strategy. Specifically, species that utilize a reseeding strategy have higher seedling growth rates and flower earlier than species that persist by vegetative means. A correlation between species' growth rates and their native substrates suggests that edaphic heterogeneity has been central in directing the evolution of alternative persistence strategies and growth forms. Parsimony reconstruction identifies slow growth and an association with nutrient-deficient sandstone derived soils as ancestral in Ehrharta, with fast growth evolving after a transition to richer shale- and granite-derived soils. The emergence of annual species in two fast-growth lineages suggests that the latter is a key step in the evolution of an ephemeral strategy. An association between plant function and habitat identifies the radiation of Ehrharta as adaptive. PMID- 21652370 TI - Leaf longevity of Oxalis acetosella (Oxalidaceae) in the Catskill Mountains, New York, USA. AB - Leaf habit correlates with multiple physiological traits. Understanding ecophysiology is therefore dependent on knowledge of leaf habit. A variety of leaf habits exists within forest understory plant communities. Oxalis acetosella is one such understory plant and has long been considered a wintergreen, meaning that it keeps a set of leaves for one full year, replacing them with a new set during spring. To assess the leaf habit of O. acetosella and place it into a classification scheme of leaf habits, leaves of four populations of O. acetosella were repeatedly censused for two years in a northern hardwood forest of the Catskill Mountains, New York, USA. New leaves developed and old leaves senesced throughout the year, yielding a continual replacement of leaves and a summer peak in leaf number. Leaves that developed in the fall and winter had longer maximum life spans than leaves that developed during the summer. The name "seasonalgreen" is suggested to describe the continual development, senescence, and presence of leaves and annual peak in leaf number within O. acetosella. The functional significance of this leaf habit in this species and the possibility of its presence in other species deserve further study. PMID- 21652371 TI - Long-term trends in annual reproductive output of the scrub hickory: factors influencing variation in size of nut crop. AB - Reproductive output by the Florida-endemic scrub hickory (Carya floridana Sargent) was studied over a 28-yr period in three south-central Florida vegetation associations: southern ridge sandhill, sand pine scrub, and scrubby flatwoods. The objectives were to describe multi-annual patterns of variation in nut production, identify factors involved in this variation, and investigate differences in patterns among associations. Peaks (higher values bracketed by lower values) in nut production occurred in 7 yr in sandhill and scrub and 8 yr in scrubby flatwoods during the 22-yr period for which we had continuous data. Of the total of 22 peaks in the three associations combined, 17 occurred at intervals of 2 or 3 yr, and peaks occurred in the same years in 18 of the 22 cases. Periodicities of nut production generated by spectral analyses (Fourier transforms) generally agreed with the observed peaks. Numbers of nuts per bearing ramet, proportion of ramets bearing nuts, ramet height, and light availability were positively correlated with nut production. Weather variables, specifically winter rainfall and minimum spring temperatures, accounted for a total of about one-quarter to one-half of the variance in nut production depending on the vegetation association. Following a prescribed fire in a sandhill plot, scrub hickory quickly regained fruit production, but over a 5-yr period following the fire nut production by ramets in the largest size class was reduced compared with the unburned control plot. PMID- 21652372 TI - Radiation of the Australian Salicornioideae (Chenopodiaceae)--based on evidence from nuclear and chloroplast DNA sequences. AB - In phylogenetic analyses of nuclear ITS and chloroplast trnL DNA sequences, the mostly endemic Australian genera; Halosarcia, Pachycornia, Sclerostegia, Tecticornia, and Tegicornia of the subfamily Salicornioideae (Chenopodiaceae) together form a monophyletic group, congruent with the hypothesis that they evolved from a common ancestor. However, limited genetic differentiation evident in both nrDNA and cpDNA sequences among these taxa suggests a possible rapid radiation. Based on fossil pollen records and climatic models of other authors, it is hypothesized that the expansion of the Australian endemic Salicornioideae most likely occurred during the Late Miocene to Pliocene, when increasing aridity caused the formation of extensive salt lakes along endorheic paleodrainage channels. Moreover, Australian Sarcocornia representatives were supported as monophyletic, nested within a paraphyletic Sarcocornia clade that also comprised European Salicornia in the ITS analysis. This suggests that Sarcocornia arrived in Australia subsequent to the ancestor of the Australian endemic genera most likely via long-distance dispersal. PMID- 21652373 TI - Phylogeny of Populus (Salicaceae) based on nucleotide sequences of chloroplast TRNT-TRNF region and nuclear rDNA. AB - The species of the genus Populus, collectively known as poplars, are widely distributed over the northern hemisphere and well known for their ecological, economical, and evolutionary importance. The extensive interspecific hybridization and high morphological diversity in this group pose difficulties in identifying taxonomic units for comparative evolutionary studies and systematics. To understand the evolutionary relationships among poplars and to provide a framework for biosystematic classification, we reconstructed a phylogeny of the genus Populus based on nucleotide sequences of three noncoding regions of the chloroplast DNA (intron of trnL and intergenic regions of trnT-trnL and trnL trnF) and ITS1 and ITS2 of the nuclear rDNA. The resulting phylogenetic trees showed polyphyletic relationships among species in the sections Tacamahaca and Aigeiros. Based on chloroplast DNA sequence data, P. nigra had a close affinity to species of section Populus, whereas nuclear DNA sequence data suggested a close relationship between P. nigra and species of the section Aigeiros, suggesting a possible hybrid origin for P. nigra. Similarly, the chloroplast DNA sequences of P. tristis and P. szechuanica were similar to that of the species of section Aigeiros, while the nuclear sequences revealed a close affinity to species of the section Tacamahaca, suggesting a hybrid origin for these two Asiatic balsam poplars. The incongruence between phylogenetic trees based on nuclear- and chloroplast-DNA sequence data suggests a reticulate evolution in the genus Populus. PMID- 21652374 TI - Tribal and intergeneric relationships of Mesechiteae (Apocynoideae, Apocynaceae): evidence from three noncoding plastid DNA regions and morphology. AB - The Neotropical tribe Mesechiteae (Apocynaceae) is currently considered to include nine genera: Allomarkgrafia, Galactophora, Macrosiphonia, Mandevilla, Mesechites, Quiotania, Secondatia, Telosiphonia, and Tintinnabularia. Tribal and intergeneric relationships, however, are in dispute. To test the monophyly of the tribe and evaluate intratribal relationships, a maximum parsimony analysis was conducted based on DNA sequences from the plastid rpl16 intron, rps16 intron, and trnS-G intergenic spacer region as well as morphological data for 23 taxa of Mesechiteae and 11 taxa from other tribes of Apocynoideae. Mesechiteae, as currently circumscribed, was found to be polyphyletic. Only removal of Secondatia and Galactophora and inclusion of Forsteronia rendered the tribe monophyletic. Thus defined, Mesechiteae forms a strongly supported clade including seven genera in three subclades: the Mesechites subclade (comprising Tintinnabularia, Allomarkgrafia, and Mesechites), the Forsteronia subclade (containing only Forsteronia) and the Mandevilla subclade (comprising Macrosiphonia, Mandevilla, and Telosiphonia). Allomarkgrafia is nested in Mesechites. Macrosiphonia and Telosiphonia form two distinct monophyletic clades. Both, however, are nested in Mandevilla. Results suggest upholding the following genera in Mesechiteae: Allomarkgrafia, Forsteronia, Mandevilla, Mesechites, and Tintinnabularia. The status of Quiotania could not be evaluated. PMID- 21652375 TI - Dactylorhiza (Orchidaceae) in European Russia: combined molecular and morphological analysis. AB - Four plastid and two nuclear (internal transcribed spacer [ITS] ribosomal DNA) markers were used in this study of the Dactylorhiza maculata and D. incarnata complexes (Orchidaceae: Orchidinae) to determine diversity and taxonomic distribution of haplotypes, hybridization frequencies, and maternal parentage of hybrids in 125 samples from 78 populations from European Russia and the Caucasus. A morphometric study of all populations revealed significant correspondence between morphological and plastid DNA data. Most D. maculata sensu stricto (s.s.) specimens from Russia have D. fuchsii haplotypes; this could be evidence for introgression or widespread hybridization between these species in northern Russia. Heterogeneity within populations is much higher for ITS data and is strongly correlated with latitude. Both plastid and nuclear data are significantly correlated with distribution along a south-north axis. Several haplotypes and ITS alleles uncommon in western Europe are more widely distributed in Russia, whereas some frequent haplotypes from western Europe are absent. PMID- 21652376 TI - Bayesian analysis of combined chloroplast loci, using multiple calibrations, supports the recent arrival of Melastomataceae in Africa and Madagascar. AB - A new biogeographic scenario for Melastomataceae (Morley and Dick, American Journal of Botany 90(11) pp. 1638-1645, 2003) accepts an ndhF-based phylogeny for the family by Renner et al. (American Journal of Botany 88(7): 1290-1300, 2001), but rejects those authors' divergence time estimates. Morley and Dick concluded that Gondwanan vicariance, rather than the more recent long dispersal proposed by Renner et al. explains the presence of the family in Africa and Madagascar. To assess the strength of this conclusion, a Bayesian analysis was conducted on three times the amount of sequence data used before (ndhF, rbcL, rpl16; 3100 base pairs [bp], excluding all gaps). The Bayesian approach to divergence time estimation does not rely on a strict molecular clock and employs multiple simultaneous minimal or maximal bounds on node ages. Reliance on northern mid latitude fossils of Melastomataceae for calibrations was avoided or reduced by using alternative fossil and tectonic calibrations, including all those suggested by Morley and Dick. Results reaffirm the relatively recent spread of melastome lineages among the southern continents and refute the breakup of Gondwana as a plausible explanation for the presence of Dissochaeteae/Sonerileae in Madagascar and Africa and the presence of Melastomeae in Africa and Southeast Asia. Melastomeae appear to have reached Africa around 17-15 million years (my) ago, while Dissochaeteae and Sonerileae apparently reached Madagascar at 17-15 and 20 18 my ago. I also explored the effects of constraining Melastomeae to minimally 76 my old (to have reached Africa by island hopping as postulated by Morley and Dick). This resulted in an estimate for their arrival in Africa of 35 my ago and for Dissochaeteae and Sonerileae in Madagascar of 28 and 33 my ago, still implying long-distance dispersal. The Bayesian 95% credibility ranges around these dates, however, are large. Regardless of the increasing sophistication of molecular estimates of divergence time, Gondwanan scenarios will remain untestable as long as biases in the fossil record can justifiably be invoked to explain away the absence of fossils. PMID- 21652377 TI - American journal of botany--past, present and future. PMID- 21652378 TI - Volatile composition, emission pattern, and localization of floral scent emission in Mirabilis jalapa (Nyctaginaceae). AB - We elucidated scent components, daily emission patterns, and the localization of floral scent release of Mirabilis jalapa. Volatiles emitted by the whole plant as well as by detached flowers were investigated using dynamic headspace analysis and gas chromatography/ mass spectrometry. Among several constituents including (Z)-3-hexenyl acetate, beta-myrcene, (Z)-ocimene, and benzyl benzoate, the monoterpene (E)-beta-ocimene was the major fragrance component. Fragrance release occurred in a time-dependent manner. The emission of volatiles, including (E) beta-ocimene, showed an evening-specific maximum (1700-2000 pm). The emission of (Z)-3-hexenyl acetate reached its maximum 3 h later. Histological (neutral red staining) and morphological studies (electron and light microscopy) of the flower surface and tissues of M. jalapa revealed differences in surface structures and tissue characteristics. The flower could be divided into four main sections, including the tube, the transition zone between tube and limb, a star-shaped center of the limb, and petaloid lobes of the limb. These petaloid lobes are the site of (E)-beta-ocimene release. Stomata and trichomes found on the abaxial flower surface were not directly involved in fragrance release. Clear indications of osmophores involved in scent release could not be found. Thus, the results indicate that floral volatiles probably are released by diffuse emission in M. jalapa. PMID- 21652379 TI - Plant generalization on pollinators: species property or local phenomenon? AB - Despite recent increased interest in the frequency and evolutionary consequences of generalization in plant-pollinator systems, little is known on whether plant generalization on pollinators actually is a species-level trait. This paper addresses the following questions for the insect-pollinated shrub Lavandula latifolia: (1) Are different populations of this pollinator-generalist plant similarly generalized? (2) Within a highly generalized population, are all plants similarly pollinator-generalists? Comparable values for richness in pollinator species were obtained from individual- or population-specific rarefaction curves as the projected number of distinct pollinator species implicated in 100 flower visits (S(RAR100)). Simple counts of pollinator species recorded per individual or population (S(OBS)) were weakly or nonsignificantly correlated with corresponding S(RAR100) figures and closely correlated with flower visitation frequency. The pollination system of L. latifolia was highly generalized at the regional level, but populations differed greatly in pollinator species richness (S(RAR100)). Within the population intensively studied, individual plants had quite variable degrees of generalization, comparable in magnitude to variation among populations. It is concluded that generalization was not an invariant, species-level property in L. latifolia. Furthermore, pollinator diversity estimates based on S(OBS) data may be heavily contingent on aspects related to both research design (sampling effort) and biological phenomena (variation in pollinator abundance or visitation rates), which may either mask or distort underlying ecological patterns of interest. PMID- 21652380 TI - Phenotypic plasticity to light competition and herbivory in Chenopodium album (Chenopodiaceae). AB - Competition and herbivory are ubiquitous environmental challenges that affect most plants. We examined the influence of phenotypic responses to either competition or herbivory on the subsequent response of the plants to the other factor. The stem-elongation response of Chenopodium album to light competition attenuated its resistance to caterpillar herbivory in terms of herbivore mortality, but not in terms of growth of the survivors. Plant responses to herbivory did not affect subsequent responses to light competition. Thus, plants were largely able to express phenotypic plasticity (a proportional increase in the phenotype) following previous exposure to a different environmental factor. Although plants were able to express sequential plasticity, the final phenotype expressed was limited by exposure to previous environmental factors: induced resistance reduced plant height and stem elongation made plants more palatable to herbivores. Phenotypic plasticity in response to competition and herbivory may thus limit the subsequent expression of adaptive phenotypes. PMID- 21652381 TI - Colonization of volcanic deserts from productive patches. AB - Dense vegetation can augment landscape biodiversity, promote recovery of surrounding ecosystems, and facilitate colonization. However, dispersal limits affect vegetation structure early in succession to a degree that is not widely appreciated. We studied two contrasting densely vegetated habitats located on Mount St. Helens to explore their effects on surrounding vegetation. We sampled refugia and adjacent barrens and compared them to a study conducted 5 yr earlier. We sampled isolated wetlands and their surroundings. Species richness, total cover, cover of most dispersal types, the information statistic (H'), and the complement of Simpson's Index (D) were negatively correlated with distance from the refugia up to 32 m. Compared to 1997, the 2002 transects had higher cover, and adjacent samples were more similar to one another. Dominance had shifted from wind-dispersed species to more persistent species with less effective dispersal mechanisms. The pattern of these results demonstrated that refugia were a major, but indirect source of recruitment for many species. The influence of wetlands on surrounding vegetation recovery was even more spatially localized. This study demonstrates that dispersal from surviving and rapidly recovered vegetation has been overemphasized as a mechanism for vegetation recovery. The effects of dense vegetation did not extend beyond 32 m in our studies, and local effects appear to diminish over time. PMID- 21652382 TI - Mechanisms of selection for drought stress tolerance and avoidance in Impatiens capensis (Balsaminaceae). AB - For longer lived annual plants, high water-use efficiency (WUE) and low stomatal conductance are hypothesized to confer a fitness advantage under drought stress. To directly test the adaptive significance of WUE and stomatal conductance under drought stress, inbred lines of Impatiens capensis were grown in two field environments (watered and not-watered), in a year of unusual early-season drought. In contrast to the results from a previous study of late-season drought in the same system, selection was detected for lower WUE, increased stomatal conductance, and early flowering time. These findings suggest that early-season drought conditions may select for drought avoidance traits such as low WUE and early reproduction, whereas later drought selects for tolerance traits such as high WUE. PMID- 21652383 TI - Differences in growth trajectory and strategy of two sympatric congeneric species in an Indonesian floodplain forest. AB - Whole-plant development trajectories and sapling leaf displays were compared for two sympatric congeneric species, Pterospermum diversifolium and P. javanicum, in a tropical floodplain forest in East Kalimantan, Indonesia. We assessed their growth strategies and developed hypotheses for their coexistence within the community. Pterospermum diversifolium retains a monoaxial growth habit that promotes quick stem elongation; thus, it is taller when branches are initiated than is P. javanicum. The species differed significantly in height growth and total crown expansion per unit increment of biomass: monoaxial P. diversifolium saplings devote more effort to stem elongation, whereas branched P. javanicum saplings devote more effort to branch expansion. Monoaxial P. diversifolium sustained more severe self-shading than P. javanicum. The sapling growth strategy of P. diversifolium appears to be dynamic, emphasizing the opportunistic use of light following a disturbance, whereas that of P. javanicum appears to be static, optimizing leaf display for current light conditions. The advantages of these strategies depend on context, and the two species may coexist within a community by adopting different regeneration niches based on differing understory light conditions: P. diversifolium is favored over P. javanicum at high light levels, but the opposite is true at low light levels. PMID- 21652384 TI - Evaluation of new Lesquerella and Physaria (Brassicaceae) oilseed germplasm. AB - The seed oil of Lesquerella and the closely related genus Physaria (Brassicaceae) is rich in hydroxy fatty acids (HFAs). HFAs and their derivatives are used to produce a variety of industrial products including lubricants, nylon-11, plastics, drying agents, protective coatings, surfactants, cosmetics, and pharmaceuticals. Lesquerella fendleri is being developed as a new crop for arid regions of the southwestern United States as an alternative source of HFAs. Between 1995 and 2001, 66 accessions from 28 species of Lesquerella were collected in the United States, 33 accessions from four species were collected in Mexico, and 41 accessions from 15 species of Physaria were collected from the southwestern United States. Mean seed mass ranged from 0.54 to 2.30 mg for Lesquerella compared to 1.70 to 5.80 mg for Physaria. Seed oil content ranged from a high of 32.2% in Lesquerella to a high of 35.4% in Physaria. The fatty acid profile of all species of Physaria and most of the lesquerolic-acid-rich species of Lesquerella contained from 30 to 55% lesquerolic acid, although several species contained >60%. These collections of wild germplasm provide a diverse gene pool that should enhance our breeding program in developing a domestic source of HFAs. PMID- 21652385 TI - Trans-species shared polymorphisms at orthologous nuclear gene loci among distant species in the conifer Picea (Pinaceae): implications for the long-term maintenance of genetic diversity in trees. AB - For each of three nuclear gene loci, intraspecific- as well as trans-specific shared polymorphisms were detected in DNA among three distantly related species in the genus Picea. Few fixed interspecific polymorphisms were observed. Allele genealogies did not match species phylogenies, and species lineages were not reciprocally monophyletic. Based on molecular clocks and morphological evidence from the fossil record, the divergence time between species was estimated at 13 20 million years (my), and a mutation rate of 2.23 * 10(-10) to 3.42 * 10(-10) per site per year was estimated. Large historical population sizes in excess of 100 000 were inferred, which would have delayed the fixation of polymorphisms. These numbers translated into allele coalescence times in the order of 10 to 18 my, which implies the sharing of polymorphisms since common ancestry. These results suggest that trans-species shared polymorphisms might be frequent at plant nuclear gene loci, leading to high allelic diversity. Such a trend is more likely in trees and plants characterized by ecological and life-history determinants favoring large population sizes such as an outcrossing mating system, wind pollination, and a dominant position in ecosystem. These polymorphisms also call for caution in estimating congeneric species phylogenies from nuclear gene sequences in such plant groups. PMID- 21652386 TI - The Crepidotaceae (Basidiomycota, Agaricales): phylogeny and taxonomy of the genera and revision of the family based on molecular evidence. AB - Advances in phylogenetic systematics have clarified the position of most major homobasidiomycete lineages. In contrast, the status of the Crepidotaceae, a historically controversial family of dark-spored agarics, remains unaddressed. In this paper, current morphology-based classifications of the agaric genera of the Crepidotaceae were evaluated by parsimony and constraint analyses of sequence data from the nuclear large subunit rDNA. Taxa analyzed included the type species for each agaric genus allied in the family by Singer: Crepidotus, Simocybe, Pleurotellus, Tubaria, and Melanomphalia. Contrary to traditional classifications, results suggest that the crepidotoid fungi have three separate origins within the euagarics. The Crepidotaceae sensu stricto (s.s.) includes Crepidotus and Simocybe and represents a separate lineage of dark-spored euagarics. Pleurotellus is congeneric with Crepidotus. Results indicate the exclusion of both Tubaria and Melanomphalia from the Crepidotaceae s.s. Tubaria is allied with the strophariaceous taxa Phaeomarasmius and Flammulaster, while Melanomphalia has arisen from within a lineage of light-spored omphalinoid euagarics representing an independent acquisition of basidiospore pigmentation. Other pleisiomorphic and newly uncovered synapomorphic characters are discussed in detail along with the taxonomic status of each genus, and a revised family description is provided. PMID- 21652387 TI - New perspective on the architecture of the Late Devonian arborescent lycopsid Leptophloeum rhombicum (Leptophloeaceae). AB - A reinvestigation of the previously described Leptophloeum rhombicum trunk from the Late Devonian (Frasnian) Huangchiateng Formation of Hubei, China provides a new perspective on the architecture of this arborescent lycopsid. It is preserved as a flattened, silicified petrification with an unevenly permineralized primary vasculature and spirally arranged rhombic leaf cushions, which agree with the diagnosis of L. rhombicum Dawson distributed worldwide in the Late Devonian. Taxonomically, this plant should be assigned to its own family and within the order Isoetales sensu lato. The anatomy, from different levels of the trunk, demonstrates that the ontogeny of the plant may conform to a determinate growth pattern. Combining previous data with current architectural analysis, it suggested that the L. rhombicum tree had a pseudomonopodial branching pattern rather than an iso-dichotomous branching crown as previously proposed. New reconstruction of the general habit for this tree is given and consists of three major architectural units: a stigmarian rhizomorph, a main trunk, and lateral branches. When these results are considered with recent cladistic work, L. rhombicum may have developed similar growth architecture to some Famennian and Carboniferous arborescent lycopsids. This growth represents one of the archetypal architectures found in the Isoetales s.l. extending from the early Late Devonian. PMID- 21652388 TI - Geographic pattern of genetic diversity in Pinus resinosa: contact zone between descendants of glacial refugia. AB - Although red pine (Pinus resinosa) generally has low or completely lacks variation for molecular markers, some variation is observed for chloroplast microsatellites (cpSSRs). We sampled and examined 10 cpSSRs for 19 populations. Analysis of these populations plus 10 previously studied populations shows that the geographic distribution of genetic diversity over the range of P. resinosa is markedly nonuniform. Although the pattern exhibits little isolation by distance, there is a region centered in northeastern New England where populations contain much greater chloroplast haplotype diversity than elsewhere. This area is band shaped, with the longer axis nearly parallel with latitude, and very sharply delineated. The area of high diversity was buried by the Laurentide ice sheet. The geographic pattern indicates that P. resinosa is not at equilibrium, and the species has had a more complex postglacial history than typically purported for forest trees in eastern North America. The results suggest that the area of high diversity is a stable transition zone between descendants of two distinct refugia, one in the southern Appalachians and another near the North Atlantic coastline of the Wisconsinian glacial period. Plausible explanations are given that selection between two lineages, along latitudinal zones, may have maintained the transition zone. PMID- 21652389 TI - Coarse- versus fine-grained water stress in Arabidopsis thaliana (Brassicaceae). AB - The effects of coarse vs. fine-grained variation in water regime on 13 accessions of Arabidopsis thaliana were compared and it was found that the scale of environmental variation can lead to differences in which traits are affected and in the magnitude and direction of effect. Coarse-grained (between individual) variation was studied by comparing plants that received high or low amounts of water on a daily basis. Fine-grained (within individual) variation was distributed across the coarse-grained treatments; plants in the fine-grained treatment received the same amount of water per week as the corresponding high and low coarse-grained treatments; however, in the fine-grained treatments, plants received their entire weekly water allotment over 2 days. The number of leaves produced, days to bolting, length of bolt, number of basal and lateral branches, and survival to 30 days after bolting were measured and analyzed by ANOVA. Plants grown in high water generally produced more leaves, taller main axes, more branches and had increased survival, relative to those in low water. Bolting date showed a significant genotype specific effect of water level. Plants grown under fine-grained variation in watering had taller main axes relative to constant water. There were significant interactions between both types of variation for bolting date, main axis height, and survival. Principal components for all traits were loaded such that the components themselves were also independently affected by genotype, water level, variability of water level (grain), and level-by-grain interactions in ways that were largely predicted by their component traits. Overall, the effects of fine-grained variation were subtler than those of coarse-grained variation: fewer traits responded, and the magnitude of the responses was smaller. Nevertheless, the responses to fine grained variation are distinct from those of coarse-gained variation, differing with respect to which traits respond and in the direction of response, and must therefore be treated as independent sources of environmental variation. PMID- 21652390 TI - A comparison of male and female responses to inbreeding in Cucurbita pepo subsp. texana (Cucurbitaceae). AB - Accurate estimates of inbreeding depression are necessary in order to predict the evolutionary dynamics of a population, but many studies estimate inbreeding depression based solely on components of female function such as fruit set, seed set, and seed quality. Because total fitness is achieved through both male and female functions in hermaphroditic plants, estimates of both male and female fitness are needed to estimate accurately the magnitude of inbreeding depression. Seedlings of a wild gourd, Cucurbita pepo subsp. texana, with coefficients of inbreeding of 0 and 0.75 were planted in an experimental garden, and several components of male and female fitness were measured over the course of the growing season. Fitness in inbred plants was confounded by both maternal and genetic inbreeding effects. Inbred individuals produced significantly fewer fruits than outcrossed individuals, and percentage germination of seeds from inbred individuals was significantly lower than seeds from outcrossed individuals. Inbred plants also produced significantly fewer staminate flowers and marginally fewer and smaller pollen grains per flower. Pollen from inbred plants also grew significantly more slowly in vitro than pollen from outcrossed plants. Multiplicative estimates of inbreeding depression revealed inbreeding depression for both male and female functions in wild gourd, but inbreeding depression through female function was stronger than inbreeding depression through male function. PMID- 21652391 TI - Environmentally induced variation in fecundity compensation in the morph-biased male-sterile distylous shrub Erythroxylum havanense (Erythroxylaceae). AB - The evolution of male-sterile individuals in hermaphroditic species represents the first step in the evolution of sex specialization. For male-sterile individuals to persist they must have some fitness advantage that compensates for their loss of the male function. Female fecundity also depends on environmental factors as those determining the likelihood of pollination and fertilization. Here we assessed the effects of both male sterility and reproductive synchrony (an environmentally affected trait) on the magnitude of female compensation of Erythroxylum havanense, a distylous shrub with morph-biased male sterility. In vitro measurements of pollen germination showed that thrums were more male sterile than pins. The compensatory advantage of thrums changed by a factor of five depending on flowering synchrony. Flowering in synchrony with the population increased fruit production in both morphs. However, because pins that flowered out of synchrony produced almost no fruits, the reproductive compensation of thrums was higher in these circumstances. Because the magnitude of compensation is frequently considered as a key factor in the evolution of sex specialization, the environmentally induced variation in the magnitude of the reproductive compensation of thrum plants may have profound effects on the evolutionary dynamics of the reproductive system of E. havanense. PMID- 21652392 TI - Do gymnosperm needles pull water through the xylem produced in the same year as the needle? AB - This research investigated the longevity of functional connections between leaf traces and stem xylem in 16 species of conifers to better understand the spatial use of sapwood for water transport. The first question was which ring(s) stained when a vacuum was applied to the distal end of the cut surface of a needle attached to a short stem segment. The vacuum was applied to either 1- or 2-yr-old foliage taken from 4-6-yr-old saplings. The 16 species were then categorized based on the growth ring that most consistently stained when the vacuum was applied to the 2-yr-old needles. There were three distinct stain patterns for the evergreen conifers and one pattern for the deciduous conifers. Three evergreen species could not be categorized. The second question used needle fall data to ask whether the leaf trace appeared to break because of age or stem diameter in 5 yr-old Pseudotsuga menziesii saplings. An apparent threshold stem diameter at which needles tended to be shed was more related to diameter than age. These xylem connection patterns could affect leaf cohort physiology and the spatial pattern of water flux in sapwood. PMID- 21652393 TI - Molecular phylogenetics of Phyllanthaceae: evidence from plastid MATK and nuclear PHYC sequences. AB - Plastid matK and a fragment of the low-copy nuclear gene PHYC were sequenced for 30 genera of Phyllanthaceae to evaluate tribal and generic delimitation. Resolution and bootstrap percentages obtained with matK are higher than that of PHYC, but both regions show nearly identical phylogenetic patterns. Phylogenetic relationships inferred from the independent and combined data are congruent and differ from previous, morphology-based classifications but are highly concordant with those of the plastid gene rbcL previously published. Phyllanthaceae is monophyletic and gives rise to two well-resolved clades (T and F) that could be recognized as subfamilies. DNA sequence data for Keayodendron and Zimmermanniopsis are presented for the first time. Keayodendron is misplaced in tribe Phyllantheae and belongs to the Bridelia alliance. Zimmermanniopsis is sister to Zimmermannia. Phyllanthus and Cleistanthus are paraphyletic. Savia and Phyllanthus subgenus Kirganelia are not monophyletic. PMID- 21652394 TI - The tortoise and the hare II: relative utility of 21 noncoding chloroplast DNA sequences for phylogenetic analysis. AB - Chloroplast DNA sequences are a primary source of data for plant molecular systematic studies. A few key papers have provided the molecular systematics community with universal primer pairs for noncoding regions that have dominated the field, namely trnL-trnF and trnK/matK. These two regions have provided adequate information to resolve species relationships in some taxa, but often provide little resolution at low taxonomic levels. To obtain better phylogenetic resolution, sequence data from these regions are often coupled with other sequence data. Choosing an appropriate cpDNA region for phylogenetic investigation is difficult because of the scarcity of information about the tempo of evolutionary rates among different noncoding cpDNA regions. The focus of this investigation was to determine whether there is any predictable rate heterogeneity among 21 noncoding cpDNA regions identified as phylogenetically useful at low levels. To test for rate heterogeneity among the different cpDNA regions, we used three species from each of 10 groups representing eight major phylogenetic lineages of phanerogams. The results of this study clearly show that a survey using as few as three representative taxa can be predictive of the amount of phylogenetic information offered by a cpDNA region and that rate heterogeneity exists among noncoding cpDNA regions. PMID- 21652395 TI - The molecular phylogeny of Alpinia (Zingiberaceae): a complex and polyphyletic genus of gingers. AB - Alpinia is the largest, most widespread, and most taxonomically complex genus in the Zingiberaceae with 230 species occurring throughout tropical and subtropical Asia. Species of Alpinia often predominate in the understory of forests, while others are important ornamentals and medicinals. Investigations of the evolutionary relationships of a subset of species of Alpinia using DNA sequence based methods specifically test the monophyly of the genus and the validity of the previous classifications. Seventy-two species of Alpinia, 27 non-Alpinia species in the subfamily Alpinioideae, eight species in the subfamily Zingiberoideae, one species in the subfamily Tamijioideae, and three species in the outgroup genus Siphonochilus (Siphonochiloideae) were sequenced for the plastid matK region and the nuclear internal transcribed spacer (ITS) loci. Parsimony analyses of both individual and combined data sets identified six polyphyletic clades containing species of Alpinia distributed across the tribe Alpinieae. These results were supported by a Bayesian analysis of the combined data set. Except in a few specific cases, these monophyletic groupings of species do not correspond with either Schumann's (1904) or Smith's (1990) classification of the genus. Here we build on previous molecular analyses of the Alpinioideae and propose the next steps necessary to recognize new generic boundaries in the Alpinieae. PMID- 21652396 TI - Molecular phylogenetic systematics and biogeography of tribe Neillieae (Rosaceae) using DNA sequences of cpDNA, rDNA, and LEAFY. AB - A phylogeny of the tribe Neillieae (Rosaceae), which comprises Neillia, Stephanandra, and Physocarpus, was reconstructed based on nucleotide sequences of several regions of cpDNA, the ITS and ETS regions of rDNA, and the second intron of LEAFY, to elucidate relationships among genera and species in Neillieae and to assess the historical biogeography of the tribe. Phylogenetic analyses indicated that Physocarpus and Neillia-Stephanandra were strongly supported as monophyletic and suggested that Stephanandra may have originated by hybridization between two lineages of Neillia. Dispersal-vicariance analyses suggested that the most recent common ancestor of Neillieae may have occupied eastern Asia and western North America and that Physocarpus and Neillia-Stephanandra may have been split by an intercontinental vicariance event in the early Miocene. The biogeographic analyses also suggested that species of Neillia and Stephanandra diversified in eastern Asia, whereas in Physocarpus one dispersal event from western North America to eastern Asia occurred. Two divergent types of LEAFY sequences were found in the eastern North American species, P. opulifolius, but only one type was present in each plant. The two types of sequences may represent homeologous genes that originated by hybridization between P. capitatus and P. monogynus, both western North American species. PMID- 21652397 TI - Sources and consequences of seed size variation in Lupinus perennis (Fabaceae): adaptive and non-adaptive hypotheses. AB - Seed size variation within species and individuals is common. This variation may be adaptive in heterogeneous landscapes if the fitness consequences of seed size differ among environments or through time. Variation may also arise from constraints that limit control of seed size. I manipulated resource availability in both maternal and offspring environments to test conditions underlying these explanations for seed size variation in the herbaceous perennial Lupinus perennis. A fivefold variation in seed size arose primarily from differences among individuals and within-plant variability rather than from environmental conditions manipulated in the experiment. Environmental conditions had little effect on mean seed size; in contrast, within-plant variation in seed size increased with reduced resources. Fitness benefits from large seed size were similar across offspring environments, suggesting that environmental heterogeneity alone may not maintain seed size variation in this species. Surprisingly, seed size affected long-term fitness measures, including a plant's size and probability of flowering through its second year. These results are consistent with non-adaptive but not adaptive explanations for seed size variation. They also suggest that offspring size variation per se may contribute to variation in maternal fitness. PMID- 21652398 TI - Leaf optical responses to light and soil nutrient availability in temperate deciduous trees. AB - Leaf optical parameters influence light availability at the cellular, leaf, and canopy scale of integration. While recent studies have focused on leaf optical responses to acute plant stress, the effects of changes in plant resources on leaf optics remain poorly characterized. We examined leaf optical and anatomical responses of five temperate deciduous tree species to moderate changes in nutrient and light availability. Spectral reflectance in the visible waveband generally increased at high light, but decreased with increased nutrient availability. Patterns of both spectral reflectance and absorptance were primarily determined by chlorophyll concentration although carotenoid concentration was also influential. While most anatomical features did not explain residual variation in reflectance, cuticle thickness was significantly related to reflectance at complementary angles compared to the angle of incidence. Absorptance did not change with light environment; however, absorption efficiency per unit biomass increased by approximately 40% under low light, due to reduced leaf mass per area. We conclude that changes in resource availability differentially influence leaf optical properties and that such changes are driven primarily by changes in pigment concentrations. The magnitude of leaf optical responses to moderate changes in resource availability was comparable to those of acute stress responses and varied among species. PMID- 21652399 TI - Comparison of ectomycorrhizas of Quercus garryana (Fagaceae) on serpentine and non-serpentine soils in southwestern Oregon. AB - The diversity of ectomycorrhizal communities associated with Quercus garryana on and off serpentine soils was compared and related to landscape-level diversity. Serpentine soils are high in magnesium, iron, and heavy metals and low in fertility. In plant communities on serpentine soils, a high proportion of flowering plant species are endemic. At three sites with paired serpentine and nonserpentine soils in southwestern Oregon, we sampled Q. garryana roots and categorized ectomycorrhizas by morphotyping and by restriction fragment length patterns. Ectomycorrhizas were abundant at all sites; no single fungal species dominated in the ectomycorrhizas. Of 74 fungal species characterized by morphotype and pattern of restriction fragment length polymorphisms, 46 occurred on serpentine soils, and 32 were unique to serpentine soil. These species are potentially endemic to serpentine soil. Similarities in species composition between paired serpentine and nonserpentine soils were not significantly lower than among three serpentine sites or among three nonserpentine sites. We conclude that mycorrhizal communities associated with oaks on serpentine soil do not differ in species richness or species evenness from those on neighboring nonserpentine soil. PMID- 21652400 TI - Morphology and affinities of an Early Cretaceous Ephedra (Ephedraceae) from China. AB - Detailed investigations on Lower Cretaceous Ephedra L. fossils (Gnetopsida) reveal morphological characters similar to those of extant Ephedra rhytidosperma Pachomova, including articulate branches with many fine longitudinal striations, a dichasial branching pattern, uni- or bi-ovulate cones with paired bracts, cones terminal on branchlets, and seeds with a short, straight micropylar tubes, covered by numerous regular and prominent transverse laminar protuberances. Fossils are similar to extant E. rhytidosperma reproductive organs but differ in some vegetative structures and are described and discussed here as Ephedra archaeorhytidosperma Y. Yang et al. Because E. rhytidosperma is currently considered one of the most specialized members in Ephedra L. section Pseudobaccatae Stapf, the occurrence of E. archaeorhytidosperma in the Yixian Formation suggests that Ephedra L. was perhaps a more diverse genus in the Lower Cretaceous. Perhaps the evolution and diversity of Ephedra L. was already in place by the Lower Cretaceous and certainly before the end of the Mesozoic. PMID- 21652401 TI - Shirleya grahamae gen. et sp. nov. (Lythraceae), Lagerstroemia-like fruits from the middle Miocene Yakima Canyon flora, central Washington State, USA. AB - Shirleya grahamae Pigg & DeVore gen. et sp. nov. (Lythraceae) is established for silicified fruits from the middle Miocene Yakima Canyon of central Washington State, USA. The capsules are 10 mm long * 11.5-12.5 mm wide, enclosed in a persistent floral tube and contain 5-7 locules. They are loculicidally dehiscent, fracturing into fragments and leaving the central axis free. Placentation is axile. Five to seven mature seeds are tightly packed per locule, often with several smaller seeds. Seeds are winged, anatropous, and narrowly attached subapically to the central axis, curving basally and radially within the fruit. They are up to ~4.6 mm long * 1.9 mm wide, with a small, triangular embryo cavity and a prominent distal wing. The inflated wing is filled with a bilobed parenchymatous pad of tissue with a central cavity. Shirleya grahamae is assigned to the Lythraceae, and is most similar to Lagerstroemia, based on the synapomorphies of distally winged seeds and revolute cotyledons. Shirleya differs from Lagerstroemia in seed arrangement, and pericarp and wing anatomy. This study provides the first anatomical information about a Miocene Lagerstroemia-like fruit and documents further diversity of the Lythraceae in the Neogene of northwestern North America. PMID- 21652402 TI - Gene flow and fine-scale genetic structure in a wind-pollinated tree species, Quercus lobata (Fagaceaee). AB - California Valley oak (Quercus lobata), one of the state's most distinctive oak species, has experienced serious demographic attrition since the 19th century, due to human activities. Recent estimates of pollen dispersal suggest a small reproductive neighborhood. Whether small neighborhood size is a recent phenomenon, a consequence of reduced gene flow caused by demographic changes, or whether it has been historically restricted, remains unclear. To examine this question, we have characterized the spatial genetic structure of N = 191 Q. lobata individuals, spread over an area of 230 ha, using eight microsatellite loci. The observed autocorrelogram suggests an historical standard deviation of gene flow distance of about 350 m per generation, higher than contemporary pollen dispersal estimates. To determine whether our estimates were affected by strong prevailing winds from the west-northwest, we developed and utilized a novel anisotropic autocorrelation analysis. We detected no more than a hint of anisotropy, and we concluded that adult spatial structure is indicative of strong historical signature of "isolation by distance." This historical estimate provides a useful reference value against which to gauge the future gene flow consequences of ongoing anthropogenic disturbance. PMID- 21652403 TI - A two-generation analysis of pollen pool genetic structure in flowering dogwood, Cornus florida (Cornaceae), in the Missouri Ozarks. AB - Anthropogenic landscape change can disrupt gene flow. As part of the Missouri Ozark Forest Ecosystem Project, this study examined whether silvicultural practices influence pollen-mediated gene movement in the insect-pollinated species, Cornus florida L., by comparing pollen pool structure (Phi(st)) among clear-cutting, selective cutting, and uncut regimes with the expectation that pollen movement should be least in the uncut regime. Using a sample of 1500 seedlings-10 each from 150 seed parents (43 in clear-cut, 74 in selective, and 33 in control sites) from six sites (each ranging from 266 to 527 ha), eight allozyme loci were analyzed with a pollen pool structure approach known as TwoGener (Smouse et al., 2001; Evolution 55: 260-271). This analysis revealed that pollen pool structure was less in clear-cut (Phi(C) = 0.090, P < 0.001) than in uncut areas (Phi(U) = 0.174, P < 0.001), with selective-cut intermediate (Phi(S) = 0.125, P < 0.001). These estimates translate into more effective pollen donors (N(ep)) in clear-cut (N(ep) = 5.56) and selective-cut (N(ep) = 4.00) areas than in uncut areas (N(ep) = 2.87). We demonstrate that Phi(C) <= Phi(S) <= Phi(U), with Phi(C) significantly smaller than Phi(U) (P < 0.034). The findings imply that, as long as a sufficiently large number of seed parents remain to provide adequate reproduction and to avoid a genetic bottleneck in the effective number of mothers, silvicultural management may not negatively affect the effective number of pollen parents, and hence subsequent genetic diversity in Cornus florida. PMID- 21652404 TI - Clonal diversity and distribution in Stenocereus eruca (Cactaceae), a narrow endemic cactus of the Sonoran Desert. AB - Stenocereus eruca (Cactaceae), a prostrate cactus endemic to the Sonoran Desert, is thought to be highly clonal. We examined its clonal diversity and distribution: (1) at the population level, in four distinct populations along its distribution range; and (2) at a micro scale level, within a single population. Our objective was to evaluate the importance of sexual versus clonal recruitment through the use of RAPD markers. Contrary to previous field observations, clonal diversity was relatively high across the distribution range. This finding suggests that sexual recruitment is an important regeneration mechanism. The proportions of distinguishable genotypes (G/N = 0.83) and genotypic diversity (D = 0.987) were greater than in other clonal cacti, suggesting that clonal propagation is not the major regeneration mechanism. Autocorrelation analyses revealed a spatial genetic structure that may be the result of restricted gene flow (via pollen or seeds) and clonal propagation. A molecular variance analysis (AMOVA) indicated that most of the variation (66.3%) was found within and not across populations. Future studies on pollen and seed dispersal are needed to understand the role of the clonal habit in the mating system of S. eruca. PMID- 21652405 TI - Floral costs in Nigella sativa (Ranunculaceae): compensatory responses to perianth removal. AB - Because internal resources are finite, it has been assumed that attractive, floral organs represent a significant drain on the energy and nutrient budget of a plant. Despite the broad significance of such trade-offs, in relatively few studies have investigators manipulated floral investments, then evaluated allocation to subsequently produced flowers, fruits, and seeds. In the present study of Nigella sativa, the cost of maturing and/or maintaining perianths was documented after all sepals and nectaries were removed at the bud stage and a significant increase in mean seed mass, the total amount of biomass allocated to seed production, and mean germination rate of the maternal seed crop were measured. The increased biomass, carbon, and nitrogen allocated to seeds were similar in magnitude to the reduction in biomass, carbon, and nitrogen invested in sepals and nectaries after perianth removal. Perianth removal did not significantly affect flower production, maternal fecundity, or progeny seed number. Taken together, these observations indicate the potential for selection mediated through resource trade-offs with seed mass and time to germination-to cause, or at least facilitate, evolutionary reductions in flower size. PMID- 21652406 TI - Dating the Dipsacales: comparing models, genes, and evolutionary implications. AB - Dipsacales is an asterid angiosperm clade of ca. 1100 species, with most of its lineages occupying temperate regions of the Northern Hemisphere. A recent phylogenetic analysis based on 7593 nucleotides of chloroplast DNA recovered a well-resolved and strongly supported phylogenetic hypothesis, which we use here to estimate divergence times within the group. A molecular clock is strongly rejected, regardless of data partition. We used recently proposed methods that relax the assumption of rate constancy among lineages (local clocks, nonparametric rate smoothing, penalized likelihood, and Bayesian relaxed clock) to estimate the ages of major lineages. Age estimates for Dipsacales varied widely among markers and codon positions, and depended on the fossils used for calibration and method of analysis. Some methods yielded dates for the Dipsacales diversification that appear to be too old (prior to the presumed 125 my [million years] age of eudicots), and others suggested ages that are too young based on well-documented Dipsacales fossils. Concordant penalized likelihood and Bayesian studies imply that Dipsacales originated in the Cretaceous, as did its two major lineages, Adoxaceae and Caprifoliaceae. However, diversification of crown Adoxaceae and Caprifoliaceae mainly occurred in the Tertiary, with the origin of major lineages within these clades mainly occurring during the Eocene. Another round of diversification appears to have occurred in the Miocene. Several radiations, such as Valerianaceae in South America and Dipsacaceae around the Mediterranean, are even more recent. This study demonstrates the wide range of divergence times that can be obtained using different methods and data sets, and cautions against reliance on age estimates based on only a single gene or methodology. Despite this variance, significant conclusions can be made about the timing of Dipsacales evolution. PMID- 21652407 TI - Piecing together the "new" Plantaginaceae. AB - Scrophulariaceae is one of the families that has been divided extensively due to the results of DNA sequence studies. One of its segregates is a vastly enlarged Plantaginaceae. In a phylogenetic study of 47 members of Plantaginaceae and seven outgroups based on 3561 aligned characters from four DNA regions (the nuclear ribosomal ITS region and the plastid trnL-F, rps16 intron, and matK-trnK intron regions), the relationships within this clade were analyzed. The results from parsimony and Bayesian analyses support the removal of the Lindernieae from Gratioleae to a position outside Plantaginaceae. A group of mainly New World genera is paraphyletic with respect to a clade of Old World genera. Among the New World taxa, those offering oil as a pollinator reward cluster together. Ourisia is sister to this clade. Gratioleae consist of Gratiola, Otacanthus, Bacopa, Stemodia, Scoparia, and Mecardonia. Cheloneae plus Russelia and Tetranema together constitute the sister group to a clade predominantly composed of Old World taxa. Among the Old World clade, Ellisiophyllum and Lafuentea have been analyzed for the first time in a molecular phylogenetic analysis. The former genus is sister to Sibthorpia and the latter is surprisingly the sister to Antirrhineae. PMID- 21652408 TI - Molecular systematics of the Catesbaeeae-Chiococceae complex (Rubiaceae): flower and fruit evolution and biogeographic implications. AB - The classification of the Catesbaeeae and Chiococceae tribes, along with that of the entire Rubiaceae, has long been debated. The Catesbaeeae-Chiococceae complex (CCC) includes approximately 28 genera and 190 species primarily concentrated in the Greater Antilles (nearly 70% of the species), Central and South America, and in the western Pacific (three genera). Previous molecular studies, with broad sampling of the Rubiaceae, have shown the CCC to be a monophyletic group. The present study is a more detailed examination of the generic relationships within the CCC using two data sets, the nuclear ribosomal ITS regions and the trnL-F chloroplast intron and spacer. Maximum parsimony analyses lend further support to the previous hypotheses that the CCC is monophyletic and sister to Strumpfia maritima. However, within the complex several genera do not form monophyletic groups. Previous studies of the Rubiaceae suggest that the ancestral fruit type in the CCC is a multiseeded capsule. Indehiscent, fleshy fruits appear to have evolved three to four times within this lineage. Changes in floral morphologies within the complex tend to correspond to cladogenesis among and within genera. Finally, molecular analyses suggest one or possibly two long-distance dispersals from the Americas to the western Pacific. PMID- 21652409 TI - Phylogeny of Eastern North American Coreopsis (Asteraceae-Coreopsideae): insights from nuclear and plastid sequences, and comments on character evolution. AB - A molecular phylogenetic study of eastern North American Coreopsis and representatives of other genera of tribe Coreopsideae was conducted using combined sequences from nuclear ITS and two plastid regions (matK, rpl16). A total of 25-30 species has been recognized in five sections of Coreopsis in eastern North America. Based on morphological characters, these taxa have generally been considered a monophyletic group. Our well-resolved phylogeny supports the monophyly of sections that have been recognized in Coreopsis, but the sections collectively do not comprise a monophyletic group because species of north temperate Bidens occur within one of the two major Coreopsis clades. The most notable departure of present results from prior views of relationships among sections is the lack of a sister group relationship between sections Calliopsis and Eublepharis; the shared presence of four-lobed disk floret corollas had been used to support a close relationship between these two sections. Relationships within sections show both similarities and differences with the results of previous studies based primarily on morphological characters. Mapping of morphological characters used taxonomically in Coreopsis and related genera onto the phylogeny indicates that the evolution of these characters has been complex, and this compromises their value for defining monophyletic groups. Examples include the annual habit, alternate leaves, winged fruits, red or brown basal spots on the yellow ligules, and four-lobed disk floret corollas. PMID- 21652410 TI - Phylogenetic relationships in subfamily Tillandsioideae (Bromeliaceae) based on DNA sequence data from seven plastid regions. AB - Molecular phylogenetic studies of seven plastid DNA regions were used to resolve circumscriptions at generic and infrageneric levels in subfamily Tillandsioideae of Bromeliaceae. One hundred and ten tillandsioid samples were analyzed, encompassing 10 genera, 104 species, and two cultivars. Two species of Bromelioideae, eight species of the polymorphic Pitcairnioideae, and two species of Rapateaceae were selected as outgroups. Parsimony analysis was based on sequence variation of five noncoding (partial 5' and 3' trnK intron, rps16 intron, trnL intron, trnL-trnF intergenic spacer, atpB-rbcL intergenic spacer) and two coding plastid regions (rbcL and matK). Phylogenetic analyses of individual regions produced congruent, but mostly weakly supported or unresolved clades. Results of the combined data set, however, clearly show that subfamily Tillandsioideae is monophyletic. The earliest divergence separates a lineage comprised of Glomeropitcairnia and Catopsis from the "core" tillandsioids. In their present circumscriptions, genera Vriesea and Tillandsia, and their subgenera or sections, as well as Guzmania and Mezobromelia, are poly- and/or paraphyletic. Genera Alcantarea, Werauhia, Racinaea, and Viridantha appear monophyletic, but separation of these from Vriesea and Tillandsia makes the remainder paraphyletic. Nevertheless, Tillandsioideae separates into four main clades, which are proposed as tribes, viz., Catopsideae, Glomeropitcairnieae, Vrieseeae, and Tillandsieae. PMID- 21652411 TI - Molecular analyses of the genus Ilex (Aquifoliaceae) in southern South America, evidence from AFLP and ITS sequence data. AB - In order to clarify the relationships among southern South American (sSA) representatives of the genus Ilex, an amplified fragment length polymorphism (AFLP) analysis was accomplished. In addition, the phylogenetic relationships of the species were studied using ribosomal internal transcribed spacer (ITS) sequence data alone and in combination with AFLP data, taking into account the possible existence of paralogous sequences and the influence of alignment parameters. To explore stability of phylogenetic hypotheses, a sensitivity analysis was performed using 15 indel-substitution models. Within each species assayed, the AFLPs allowed the recognition of several diagnostic bands. Furthermore, the AFLP analysis revealed that individuals belonging to the same morpho-species formed coherent clades. In addition, some cases of geographical association were noted. Studies on ITS sequences revealed divergence between data obtained herein and sequence data downloaded from GenBank. The sensitivity analyses yielded different interspecific hypotheses of relationships. Notwithstanding, analyses of the ITS data alone and in combination with AFLPs, rendered clades stable to variation in the analytical parameters. Topologies obtained for the AFLPs, the ITS data alone and the combined analyses, demonstrated the existence of a group formed by I. argentina, I. brasiliensis, I. brevicuspis, I. integerrima, and I. theezans, and that I. dumosa and I. paraguariensis were distantly related to the former. Incongruence with traditional taxonomical treatments was found. PMID- 21652412 TI - Effects of pollination by bats on the mating system of Ceiba pentandra (Bombacaceae) populations in two tropical life zones in Costa Rica. AB - The identity and behavior of pollinators are among the main factors that determine the reproductive success and mating system of plants; however, few studies have directly evaluated the relationship between pollinators and the breeding system of the plants they pollinate. It is important to document this relationship because the global decline in pollinators may significantly affect the breeding systems of many animal-pollinated plants, particularly specialized systems. Ceiba pentandra is a tropical tree that has chiropterophilic flowers and a variable breeding system throughout its distribution, ranging from fully self incompatible, to a mixed system with different degrees of selfing. To determine if regional differences in pollinators may result in regional differences in the outcrossing rate of this species, we used systematic observations of pollinator behavior in two tropical life zones and high-resolution genetic analysis of the breeding system of populations from these two regions using microsatellites. We found a predominantly self-incompatible system in regions with high pollinator visitation, while in environments with low pollinator visitation rates, C. pentandra changed to a mixed mating system with high levels of self-pollination. PMID- 21652413 TI - Seedling expression of cross-generational plasticity depends on reproductive architecture. AB - Through adaptive cross-generational plasticity, stressed plants can alter their offspring in specific ways that promote seedling success. As yet, very little is known about the expression of such plasticity, and whether it varies within a plant due to offspring position. The effects of parental light deprivation on distinct reproductive structures were tested in the annual Polygonum hydropiper, which produces both long terminal racemes and inconspicuous axial inflorescences. Inbred replicate parents from four genetic lines were grown in full greenhouse sunlight and simulated shade, and the initial mass, germination rate, and seedling growth traits of their terminal and axial offspring measured under uniform growth chamber conditions. Although parent light environment did not significantly influence seedlings from axial achenes, growth traits of those from terminal achenes were significantly enhanced as a result of parental light deprivation. In shaded conditions where resources are limiting, P. hydropiper plants appear to prioritize terminal achenes through increased provisioning as well as specific growth changes. These results show that the expression of cross generational plasticity may vary depending on architectural position of offspring on the maternal plant. PMID- 21652414 TI - Development of nonlignified fibers in leaves of Gnetum gnemon (Gnetales). AB - Leaves of Gnetum gnemon have an extensive anastomosing network of thick-walled cellulosic fibers that permeate mesophyll tissues. Brochidodromus venation is precise with major veins originating by uniseriate plate meristems. In mesophyll differentiation, laticifers appear before fibers and more or less parallel to major veins. Fiber initials appear later, mostly within the subhypodermal mesophyll cell layers, but otherwise adjacent to the leaf margin or the major veins. Fibers are early binucleate and sometimes become four-nucleate. Fiber initials extend by symplastic but mainly intrusive apical growth, become irregular, little branched and interpenetrate other mesophyll layers. They make frequent contact with other fibers forming the anatomosing system, but remain thin-walled until leaf expansion is complete. Sclereids are little developed, thus fibers become the main mechanical system of the mature leaf. Once expansion is complete, maturation of fibers involves rapid formation of a cellulosic but unlignified secondary wall that is non-lamellate and almost occludes the cell lumen. These fibers are contrasted with the gelatinous (tension) fibers developed eccentrically in stems of Gnetum. Apart from their mechanical function, fibers may also have a hydraulic function in maintaining a highly hydrated internal leaf atmosphere. PMID- 21652415 TI - Structural and mechanical peculiarities of the petioles of giant leaves of Amorphophallus (Araceae). AB - Petioles (up to 4 m tall) of huge solitary leaves of mature plants of Amorphophallus titanum and A. gigas resemble tree trunks supporting an umbrella like crown. In a mechanical sense, the petiole is a shell, composed of compact parenchyma with embedded collenchyma strands. The core of the shell is filled with aerenchyma. Mechanical stability of the petiole strongly depends upon the turgor pressure in the parenchyma of the shell and the core. The petiole collapses upon senescence when the turgor pressure decreases as a result of increasing osmolality of the solution permeating cell walls. The present study supports the postulate that aerenchyma serves a mechanical function. The petiole can be easily broken by animals during a collision. This risk is proposed to be lowered by the mimicry of the color pattern of the petiole's surface, which resembles a stiff tree trunk covered with lichen thalli (in both species) and with bark in the case of A. gigas. The cellular basis of these color patterns is described. PMID- 21652416 TI - Is there a cost to resprouting? Seedling growth rate and drought tolerance in sprouting and nonsprouting Ceanothus (Rhamnaceae). AB - Many woody plant species that depend upon fire-cued seed germination lack the ability to resprout. As the ability to resprout is widely assumed to be the ancestral condition in most plant groups, the failure to sprout is an evolutionary derived trait. Models for the evolutionary loss of sprouting assume a trade-off between seedling success and vegetative resprouting ability of adults. Such models require higher seedling success rates in nonsprouters than in sprouters. On the other hand, there seem to be few a priori reasons why a strong sprouter might not also have highly competitive post-fire seedlings. To test the hypothesis that nonsprouting plants have higher growth rates and/or drought survival, we grew seedlings of Ceanothus tomentosus from sprouting and nonsprouting populations in a common garden experiment. Each of these C. tomentosus populations was paired with a sympatric Ceanothus species that differed in resprouting ability. Sprouters exhibited greater allocation to root carbohydrate storage than did nonsprouters, but overall relative growth rates did not differ. Nonsprouters had earlier onset of flowering. These results provide mixed support for models of a sprouting/nonsprouting allocation trade-off. PMID- 21652417 TI - Microhabitat distribution of two Florida scrub endemic plants in comparison to their habitat-generalist congeners. AB - Habitat-specialist species may be restricted to a narrower range of microhabitats than habitat-generalist species. We addressed this hypothesis by comparing microhabitats of two pairs of congeners that differ in habitat specificity and co occur in one distinct habitat type, Florida rosemary scrub. We characterized microhabitats of rosemary scrub specialists, Polygonella basiramia and Lechea cernua, their habitat-generalist congeners, Polygonella robusta and Lechea deckertii, and random points in the rosemary scrub habitat. Plants of both habitat specialists occurred in microhabitats with significantly more bare sand than plants of habitat-generalist species and random points. Plants of all four species occurred in microhabitats that were farther from dominant shrubs, Ceratiola and Quercus spp., than random points. Seedlings of both habitat specialists grew larger in bare sand microhabitats, whereas ground lichens and litter did not affect seedling growth of the habitat generalists. As the time since fire increases, bare sand cover decreases, Ceratiola density increases, Quercus density remains constant, and shrubs become taller. Physical characteristics, such as soil temperature, soil carbon, and soil moisture, differ slightly with respect to microhabitat. Our results suggest that P. basiramia and L. cernua are specialized on bare sand microhabitats that characterize their preferred habitat, rosemary scrub. Microhabitat specialization may limit the distribution of these rare species. PMID- 21652418 TI - Onset of flowering and climate variability in an alpine landscape: a 10-year study from Swedish Lapland. AB - Long-term studies on phenology are rarely reported from arctic and alpine areas, but are essential for understanding biotic and abiotic controls on flowering. We monitored first flowering day (FFD) for 144 species in a subarctic-alpine area in Swedish Lapland over a period of 10 yr (1992-2001). Temperature and global radiation were monitored continuously, and snowcover duration was observed. Thawing degree-days and snowcover duration (exposure) were the dominant environmental controls on phenology. We introduce a lability index (LI) to describe the interannual variability in FFD among species. The temporal sequence of species is very constant among years, although a few species are more labile. The species were also classified into the catagories "Functional type," "Raunkiaer's life form," and "Sorensen's wintering floral type." The last two reflected the environmental data best, and together with "Exposure" they were combined into a phenology index (PI). The index was subsequently used in a triangular ordination together with FFD. The ordination illustrates whether species flower earlier or later than expected from their preconditions. We hypothesize that species having a delayed flowering respond more readily to global warming than species having an already optimized flowering. PMID- 21652419 TI - Only seed size matters for germination in different populations of the dimorphic Tragopogon pratensis subsp. pratensis (Asteraceae). AB - Many studies have focused on the ecology of seed dimorphism, the production of two seed types by a single plant. Morphology and seed size are usually correlated, but how morphology affects germination percentage and seedling growth is poorly understood. Here we explicitly separate these effects for nine populations of the dimorphic species Tragopogon pratensis subsp. pratensis. Larger seeds yielded higher germination percentages, yet seed morphology had no additional direct effect on germination. Neither seed size nor seed morphology affected seedling growth. Neither germination nor seedling growth varied among populations, but seed head varied significantly. Results show that germination is mainly controlled by seed size rather than by seed morphology. This study is one of the few to distinguish explicitly between seed size and seed morphology effects on ecological characteristics and suggests that seed dimorphism may exert its ecological effects predominantly through its correlated size. PMID- 21652420 TI - Fruit maturation, not deteriorating light conditions, is the primary cue of senescence in a spring ephemeral annual plant--Floerkea proserpinacoides (Limnanthaceae). AB - In monocarpic plants, reproduction is closely associated with senescence, which is itself often correlated to specific environmental signals. Floerkea proserpinacoides (Limnanthaceae) is a spring ephemeral annual of the deciduous forests of eastern North America. The phenology of its growth and reproduction is considered to be a specific adaptation to the short period during which there is a high availability of resources (mostly light). Indeed, flowering starts 2-3 wk following seedling emergence soon after snowmelt and continues until tree canopy closure. However, fruit maturation is postponed for several weeks and is followed by the plant's death. The objective of this study is to determine if senescence in F. proserpinacoides is primarily cued by fruit maturation or deteriorating light conditions associated with tree canopy closure. Plants for which reproductive investment was manipulated by removing their carpels were grown either in full light or in the shade. Carpel-removal plants reached a higher biomass than control plants (46.0- 57.5% higher), especially in full light. However, longevity was greater in carpel-removal plants, particularly in the shade (25.3-37.8% greater). These results thus suggest that fruit maturation, not deteriorating light conditions associated with canopy closure, is the primary cue of plant senescence in F. proserpinacoides. PMID- 21652421 TI - Rainfall exclusion in an eastern Amazonian forest alters soil water movement and depth of water uptake. AB - Deuterium-labeled water was used to study the effect of the Tapajos Throughfall Exclusion Experiment (TTEE) on soil moisture movement and on depth of water uptake by trees of Coussarea racemosa, Sclerolobium chrysophyllum, and Eschweilera pedicellata. The TTEE simulates an extended dry season in an eastern Amazonian rainforest, a plausible scenario if the El Nino phenomenon changes with climate change. The TTEE excludes 60% of the wet season throughfall from a 1-ha plot (treatment), while the control 1-ha plot receives precipitation year-round. Mean percolation rate of the label peak in the control plot was greater than in the treatment plot during the wet season (0.75 vs. 0.07 m/mo). The rate was similar for both plots during the dry season (ca. 0.15 m/mo), indicative that both plots have similar topsoil structure. Interestingly, the label peak in the control plot during the dry season migrated upward an average distance of 64 cm. We show that water probably moved upward through soil pores-i.e., it did not involve roots (hydraulic lift)-most likely because of a favorable gradient of total (matric + gravitational) potential coupled with sufficient unsaturated hydraulic conductivity. Water probably also moved upward in the treatment plot, but was not detectable; the label in this plot did not percolate below 1 m or beyond the depth of plant water uptake. During the dry season, trees in the rainfall exclusion plot, regardless of species, consistently absorbed water significantly deeper, but never below 1.5-2 m, than trees in the control plot, and therefore may represent expected root function of this understory/subcanopy tree community during extended dry periods. PMID- 21652422 TI - Correlation but no causation between leaf nitrogen and maximum assimilation: the role of drought and reproduction in gas exchange in an understory tropical plant Miconia ciliata (Melastomataceae). AB - Alternative hypotheses were tested to explain a previously reported anomaly in the response of leaf photosynthetic capacity at light saturation (A(max)) in Miconia ciliata to dry-season irrigation. The anomaly is characterized by an abrupt increase in leaf A(max) for nonirrigated plants at the onset of the rainy season to values that significantly exceeded corresponding measurements for plants that were irrigated during the previous dry season. Hypothesis 1 posits that a pulse in leaf nitrogen increases CO(2) assimilation in nonirrigated plants at the onset of the wet season and is dampened for irrigated plants; this hypothesis was rejected because, although a wet-season nitrogen pulse did occur, it was identical for both irrigated and nonirrigated plants and was preceded by the increase in assimilation by nonirrigated plants. Hypothesis 2 posits that a reproduction-related, compensatory photosynthetic response occurs in nonirrigated plants following the onset of the wet season and is dampened in irrigated plants; consistent with hypothesis 2, high maximum assimilation rates for control plants in the wet season were significantly correlated with fruiting and flowering, whereas irrigation caused flowering and fruiting in the dry season, spreading M. ciliata reproductive activity in irrigated plants across the entire year. PMID- 21652423 TI - Relative humidity and temperature modify the mechanical properties of isolated tomato fruit cuticles. AB - The mechanical properties of enzymatically isolated cuticular membrane (CM) from ripe tomato fruits were investigated at 10 to 45 degrees C and relative humidity (RH) of 40 to wet. CM samples were stressed by uniaxial tension loads to determine their tensile modulus, E, breaking stress (strength), sigma(max), and maximum elongation, epsilon(max). The CM stress-strain curves revealed a biphasic behavior when tested at RH values below wet conditions. In the first phase, CM responded to the loads by instantaneous extension with no further extension recorded until a further load was added: defined as pure elastic strain (E(e)). In the second phase, CM responded by instantaneous extension and by some additional time-dependent extension, defined as viscoelastic strain (E(v)). When CMs were submerged in aqueous solution (wet), the stress-strain curves were monophasic, with both elastic and viscoelastic strain. E(e) depended on RH and was higher than E(v), which was independent of RH. Temperature decreased E(e) and sigma(max) of tomato fruit CM. Temperature response was not linear but consisted of two temperature-independent phases separated by a transition temperature. This transition zone has been related previously to the presence of a secondary phase transition in the cutin matrix of the tomato fruit CM. PMID- 21652424 TI - Hybrid origins and F1 dominance in the free-floating, sterile bladderwort, Utricularia australis f. australis (Lentibulariaceae). AB - Abandonment of sexual reproduction is a well-known characteristic in aquatic plants, while the causes, levels, and consequences of sterility are often unknown. Utricularia australis f. australis (Lentibulariaceae) is a free floating, sterile bladderwort distributed widely in temperate and tropical regions. Experimental crosses in cultivated conditions, AFLP analysis, and cpDNA haplotypes of natural populations clearly demonstrated that U. australis f. australis originates from the asymmetric hybridization between two parental taxa: U. australis f. tenuicaulis (mostly as female) and U. macrorhiza (mostly as male). No post-F(1) hybrids were detected using the additive patterns of AFLP bands combined with the observation of extensive sterility in U. australis f. australis. Recurrent hybridizations and subsequent perpetuation by asexual reproduction were demonstrated by the unique, but monomorphic, AFLP genotypes observed in each U. australis f. australis population. Hybrids and parental species did not coexist, implying the superiority of the hybrid U. australis f. australis in certain environmental conditions. It remains unclear whether populations of U. australis f. australis are maintained by colonizing propagules or as relicts of past hybridization events. PMID- 21652425 TI - Marked genetic divergence among sky island populations of Sedum lanceolatum (Crassulaceae) in the Rocky Mountains. AB - Climate change during the Quaternary played an important role in the differentiation and evolution of plants. A prevailing hypothesis is that alpine and arctic species survived glacial periods in refugia at the periphery of glaciers. Though the Rocky Mountains, south of the southernmost extent of continental ice, served as an important glacial refuge, little is known about how climate cycles influenced populations within this region. We inferred the phylogeography of Sedum lanceolatum (Crassulaceae) within the Rocky Mountain refugium to assess how this high-elevation plant responded to glacial cycles. We sequenced 884 base pairs (bp) of cpDNA intergenic spacers (tRNA-L to tRNA-F and tRNA-S to tRNA-G) for 333 individuals from 18 alpine populations. Our highly variable markers allowed us to infer that populations persisted across the latitudinal range throughout the climate cycles, exhibited significant genetic structure, and experienced cycles of range expansion and fragmentation. Genetic differentiation in S. lanceolatum was most likely a product of short-distance elevational migration in response to climate change, low seed dispersal, and vegetative reproduction. To the extent that Sedum is a good model system, paleoclimatic cycles were probably a major factor preserving genetic variation and promoting divergence in high-elevation flora of the Rocky Mountains. PMID- 21652426 TI - Pollen and resource limitation in a gynodioecious species. AB - Differences between plant sex morphs in pollen or resource availability may affect their relative fitness and thereby the sex ratio of dimorphic species. In gynodioecious species, in which hermaphroditic and female plants coexist, a variety of factors (e.g., hermaphrodite self-fertility or rarity or pollinator discrimination against females) might be expected to lead to stronger pollen limitation in females than in hermaphrodites. On the other hand, females have been found to be superior compared to hermaphrodites in low-nutrient conditions. The effects of supplemental hand-pollination and resource addition on the reproductive output of the self-fertile gynodioecious perennial Geranium sylvaticum (Geraniaceae) were tested for several populations that differ in their female frequency (4.4-23.0%). Both pollen and resource availability limited fruit set and the number of seeds produced per plant; however, seed set (i.e., the number of seeds produced per fruit) was limited only by resources. Because pollen limitation in females did not correlate with female frequency, our results suggest that pollen limitation in females does not depend on the frequency of the pollen-producing hermaphrodites. Furthermore, because pollen and resource availability limited reproductive output of both sex morphs, these factors may not contribute significantly to maintenance and evolution of gynodioecy in G. sylvaticum. PMID- 21652427 TI - Evolutionary increase in sexual and clonal reproductive capacity during biological invasion in an aquatic plant Butomus umbellatus (Butomaceae). AB - To test the hypothesis that increased allocation to reproduction is selected during biological invasion, we compared germination, survival, growth, and reproduction of native vs. introduced populations of the invasive aquatic plant Butomus umbellatus in a common greenhouse environment. Although seedling emergence and establishment did not differ consistently, survival thereafter was twice as high for eight introduced North American than eight native European populations. As predicted, introduced plants were more likely to produce sexual inflorescences and clonal asexual vegetative bulbils, and they invested much more biomass in both reproductive modes. Higher reproductive investment was due to higher proportional allocation of biomass rather than larger plant size. These results are consistent with selection for increased reproduction during range expansion. However, population genetic surveys indicate that recruitment from seed rarely occurs in introduced populations. Hence increased sexual allocation is not an adaptive response to invasion. Although increased clonal reproduction may be advantageous in expanding populations, genetic evidence from introduced populations of B. umbellatus suggests that increased clonal allocation may have arisen via stochastic processes during long-distance transport or a selective filter right at introduction, rather than incremental natural selection during range expansion. PMID- 21652428 TI - Pollination ecology of Stenocereus queretaroensis (Cactaceae), a chiropterophilous columnar cactus, in a tropical dry forest of Mexico. AB - Flowers of columnar cacti are animal-pollinated, often displaying a chiropterophylic syndrome. This study examined if the columnar cactus Stenocereus queretaroensis, a tropical species endemic to western Mexico, is bat-pollinated, by studying its pollination biology and the foraging behavior of potential pollinators. Flowers were produced in winter through spring, peaking in April. Anthesis was nocturnal, and stigma and anther turgidity began around 2200 hours. Production of nectar secretion and highest sugar concentration and energy supply were nocturnal, peaking between 2200 and 2400 hours. Manual auto-pollination and exclusion experiments showed that self-pollination yielded no fruits, while nocturnal pollinators resulted in high fruit set and seed set compared to diurnal pollination treatments. The nectar-feeding bat Leptonycteris curasoae (Phyllostomidae) was the main nocturnal pollinator with the highest effective pollination. Peak bat visitation coincided with peaks in nectar production. The high abundance of L. curasoae throughout the 4-yr study, suggests that it is a seasonally reliable pollinator for this columnar cactus. While pollination syndromes have been increasingly called into question in recent years, this study suggests that at least for this system, there is a fairly close fit between pollinator and pollination syndrome. PMID- 21652429 TI - Explosive seed dispersal in two perennial Mediterranean Euphorbia species (Euphorbiaceae). AB - The distance of explosive dispersal, its pattern in time, and the relative importance of autochory have been studied in two diplochorous species: Euphorbia boetica and E. nicaeensis. The seeds of E. boetica released by explosive dispersal reached a median distance of 156 cm and a maximum of almost 8 m, while the distances reached by the seeds of E. nicaeensis were lower: a median of 132 cm and a maximum of 5 m. The differences in explosive dispersal distance between species seem to depend on both seed mass and caruncle retention. The seeds of both species present a caruncle, but in E. boetica this is tiny, and in most cases is shed during the explosion of the capsules. The distances reached by the seeds of these species, dispersed just by capsule explosion, were similar to or greater than the distances to which ants disperse seeds in the Mediterranean sclerophyllous vegetation. Diplochorous plants may maximize either the distance of primary dispersal or that of secondary dispersal. Given that the seeds of E. boetica, that lose their caruncles, are not gathered by myrmecochorous ants, the results suggest that E. boetica maximizes its primary dispersal distance, whereas E. nicaeensis favors its secondary dispersal. PMID- 21652430 TI - Predicting mating patterns from pollination syndromes: the case of "sapromyiophily" in Tacca chantrieri (Taccaceae). AB - Tacca, a genus of tropical herbs, possesses near black flowers, conspicuous involucral bracts and whisker-like filiform bracteoles. These features have been assumed to function as a "deceit syndrome" in which reproductive structures resemble decaying organic material attracting flies that facilitate cross pollination (sapromyiophily). We investigated pollination and mating in Tacca chantrieri populations from SW China to evaluate this assumption. Contrary to this expectation, populations were highly selfing. Pollinator visitation was infrequent and bagged flowers set abundant seed. Pollen loads on stigmas indicated autonomous self-pollination, some of which occurred prior to flower opening. The seed set of inflorescences with bracts and bracteoles removed was not significantly different from unmanipulated inflorescences, suggesting that these structures play a limited role in pollinator attraction, at least at our study sites. Pollen : ovule ratios averaged 49, a value expected in a highly selfing species. Selfing rates estimated in four populations using allozyme markers averaged 0.86 (range 0.76-0.94), thus corroborating this inference. Our results indicate that despite considerable investment in extravagant display, populations of T. chantrieri are highly selfing. We propose several hypotheses to resolve this paradox and argue that future studies of pollination syndromes would benefit by investigation of both pollination and mating biology. PMID- 21652431 TI - Hybrid origin of "Bauhinia blakeana" (Leguminosae: Caesalpinioideae), inferred using morphological, reproductive, and molecular data. AB - Bauhinia blakeana (Leguminosae subfam. Caesalpinioideae tribe Cercideae), or the Hong Kong Orchid Tree, is of great horticultural value. It is completely sterile and is shown here to be the result of hybridization between the largely sympatric species, B. purpurea and B. variegata. Although the analysis of patterns of morphological variation revealed only a few examples of phenotypic intermediacy, study of intersimple sequence repeat (ISSR) markers enabled unequivocal identification of the parental species due to the presence of additive inheritance of alleles and the absence of any bands that are unique to B. blakeana. Investigation of aspects of the reproductive biology of the taxa furthermore revealed that the parental species are largely xenogamous, have flowering periods that overlap seasonally and temporally, and share common pollinators. Evidence is provided to show that B. blakeana is not naturally stabilized and is only maintained horticulturally by artificial propagation. It is therefore recommended that the hybrid be regarded as a horticultural cultivar rather than a naturally occurring species; a new cultivar name, Bauhinia 'Blakeana', is accordingly validated. PMID- 21652432 TI - Aglaia (Meliaceae): an evaluation of taxonomic concepts based on DNA data and secondary metabolites. AB - We performed maximum parsimony and Bayesian analyses (nuclear ITS rDNA, plastid rps16 intron) to estimate phylogenetic relationships within Aglaia (over 100 species in Southeast Asia, the Pacific, and Australia) and its relations among Aglaieae (Meliaceae). Based on 67 accessions of Aglaieae, three taxa of Guareae, and two taxa of Melieae (outgroup), this study provides the first assessment of the current circumscription of Aglaieae, Aglaia, and its sections and to a more limited extent of species concepts in Aglaia. DNA data are compared to recently collected data on chemical profiles. Our analyses indicate (1) the monophyly of Aglaieae; (2) the polyphyly of Aphanamixis; (3) the paraphyly of Aglaia; (4) the existence of at least three entities with respect to Aglaia: (a) the core group of Aglaia section Amoora (dehiscent fruits) with close relationships to Lansium and Reinwardtiodendron, (b) a group comprising morphological intermediates between the two sections, and (c) the core group of Aglaia section Aglaia (indehiscent fruits). Macro- and micromolecular data indicate that complex species are more heterogeneous, i.e., probably containing more than one taxon each, than taxonomically isolated species. A third section in Aglaia is recognized to accommodate A. lawii, A. teysmanniana, and A. beccarii. PMID- 21652433 TI - Polyphyly of Mussaenda inferred from ITS and trnT-F data and its implication for generic limits in Mussaendeae (Rubiaceae). AB - Although recognition of Mussaenda as a separate genus has been widely accepted, its generic circumscriptions have always been controversial. In this first molecular phylogenetic study focused specifically on Mussaenda sensu lato (s.l.) and its allied genera, parsimony analyses were based on both ITS and trnT-F sequence data to (1) test the monophyly of Mussaenda s.l. as presently circumscribed, (2) assess the phylogenetic relationships within the tribe Mussaendeae as currently delimited, (3) evaluate the phylogenetic value of the morphological characters traditionally and/or currently used to circumscribe Mussaendeae, (4) and make inferences on the biogeographical origin of Mussaenda. Of the 63 trnT-F and 38 ITS sequences included in our studies, 52 and 36 sequences, respectively, are newly published here. Our results highly support the polyphyly of Mussaenda s.l. as currently delimited but further support the monophyly of Mussaendeae sensu Bremer and Thulin. The Malagasy Mussaenda are more closely related to Landiopsis than they are to the African and Asian Mussaenda. Pseudomussaenda and the Afro-Asian Mussaenda clade are resolved as sister groups. Aphaenandra is nested within the Afro-Asian Mussaenda clade. As a result, we merge Aphaenandra in Mussaenda, which is now restricted to include only the African and Asian Mussaenda representatives. We describe a new genus Bremeria to accommodate all Indian Ocean (Madagascar and the Mascarenes) Mussaenda species and make 19 new combinations. The newly delimited Mussaenda is diagnosed by reduplicate-valvate aestivation and glabrous styles, whereas Bremeria can be distinguished from the remaining Mussaendeae genera by having both reduplicate- and induplicate-valvate aestivation and densely pubescent styles. Our studies strongly suggest an African origin of the newly delimited Mussaenda. Finally, descriptions of the newly circumscribed Mussaenda and Bremeria are provided. PMID- 21652434 TI - Nectar spur evolution in the Mexican lobelias (Campanulaceae: Lobelioideae). AB - Phylogenetic studies are often hampered by the independent evolution of characters that may potentially obscure relationships. The adaptive significance of the nectar spur and its evolution within the Mexican lobeliads (Campanulaceae) is considered here. The taxonomic delimitations of Heterotoma from the Mexican species within the genera Lobelia and Calcaratolobelia were tested. Independent molecular data were gathered to determine whether the Mexican spurred lobeliads should be treated as distinct genera. The internal transcribed spacer (ITS) region from 18-26S nuclear rDNA and chloroplast DNA from the 3' trnK intron were sequenced from 14 representative species. Our data suggest that Heterotoma, as originally conceived, is a good evolutionary unit within Lobelia and that the presence of a nectar spur is an important morphological character that can be used in defining phylogenetic position. This study also suggests that morphological changes associated with hummingbird pollination have evolved more than once in the Mexican lobeliads, from small blue-flowered, insect-pollinated relatives. PMID- 21652435 TI - Inflorescence, spikelet, and floral development in Panicum maximum and Urochloa plantaginea (Poaceae). AB - Inflorescence development in Panicum maximum and Urochloa plantaginea was comparatively studied with scanning electron and light microscopy to test the transfer of P. maximum to Urochloa and to look for developmental features applicable to future cladistic studies of the phosphoenol pyruvate carboxykinase (PCK) subtype of C(4) photosynthesis clade (P. maximum and some species of Brachiaria, Chaetium, Eriochloa, Melinis, and Urochloa). Eleven developmental features not discernable in the mature inflorescence were found: direction of branch differentiation; origins of primary branches; apical vs. intercalary development of the main axis; direction of spikelet differentiation; direction of glume, lemma and palea differentiation; position of the lower glume (in some cases); size of the floret meristem; pattern of distal floret development; pattern of gynoecium abortion; differential pollen development between proximal and distal floret; and glume elongation. Inflorescence homologies between P. maximum and U. plantaginea are also clarified. Panicum maximum and U. plantaginea differ not only in their mature inflorescence structure but also in eight fundamental developmental features that exclude P. maximum from Urochloa. The following developmental events are related to sex expression: size of floret meristem, gynoecium abortion, pollen development delay in the proximal floret, glume elongation and basipetal floret maturation at anthesis. PMID- 21652436 TI - Post-meiotic cytokinesis and pollen aperture pattern ontogeny: comparison of development in four species differing in aperture pattern. AB - Pollen aperture patterns vary widely in angiosperms. An increasing number of studies indicate that aperture pattern ontogeny is correlated with the way in which cytokinesis that follows male meiosis is completed. The formation of the intersporal callose walls that isolate the microspores after meiosis was studied in four species with different aperture patterns (two monocots, Phormium tenax and Asphodelus albus, and two eudicots, Helleborus foetidus and Protea lepidocarpodendron). The way in which post-meiotic cytokinesis is performed differs between all four species, and variation in callose deposition appears to be linked to aperture pattern definition. PMID- 21652437 TI - Phylogenetic relationships within the tribe Malveae (Malvaceae, subfamily Malvoideae) as inferred from ITS sequence data. AB - Phylogenetic relationships among genera of tribe Malveae (Malvaceae, subfamily Malvoideae) were reconstructed using sequences of the internal transcribed spacer (ITS) region of the 18S-26S nuclear ribosomal repeat. Newly generated sequences were combined with those available from previous generic level studies to assess the current circumscription of the tribe, monophyly of some of the larger genera, and character evolution within the tribe. The ITS data do not support monophyly of most generic alliances as presently defined, nor do the data support monophyly of several Malveae genera. Two main well-supported clades were recovered, which correspond primarily to taxa that either possess or lack involucral bracts, respectively. Chromosomal evolution has been dynamic in the tribe with haploid numbers varying from n = 5 to 36. Aneuploid reduction, hybridization, and/or polyploidization have been important evolutionary processes in this group. PMID- 21652438 TI - A four-gene study of evolutionary relationships in Solanum section Acanthophora. AB - The "spiny solanums," Solanum subgenus Leptostemonum (Solanaceae), comprise a large lineage with over 350 species and include the cultivated eggplant, Solanum melongena. Despite the importance of this subgenus, phylogenetic relationships among these taxa are currently unclear. The present research contributes to this understanding while focusing on Solanum section Acanthophora, a group of ca. 19 species defined by the presence of simple hairs, rather than the stellate hairs common across the rest of subgenus Leptostemonum. In this study we inferred phylogenetic relationships among 29 Solanum taxa, including 14 species of section Acanthophora, using DNA sequence data from two nuclear regions (ITS and the granule-bound starch synthase gene [GBSSI or waxy]) and two chloroplast regions (trnT-trnF and trnS-trnG). This combination of gene regions resulted in a well resolved phylogenetic hypothesis, with results strongly suggesting that Solanum sect. Acanthophora is not monophyletic, although the majority of taxa comprise a monophyletic lineage that is sister to Solanum section Lasiocarpa. Of the four gene regions, waxy was especially useful for phylogenetic inference, with both a high percentage of parsimony-informative sites as well as a low level of homoplasy. Further studies in progress will help elucidate relationships of sect. Acanthophora with respect to other members of subgenus Leptostemonum. PMID- 21652439 TI - An overview of the phylogenetic relationships within Epidendroideae inferred from multiple DNA regions and recircumscription of Epidendreae and Arethuseae (Orchidaceae). AB - Phylogenetic relationships within the epidendroid orchids with emphasis on tribes Epidendreae and Arethuseae were assessed with parsimony and model-based analyses of individual and combined DNA sequence data from ITS nuclear ribosomal DNA and plastid trnL intron, the trnL-F spacer, matK (gene and spacers), and rbcL regions. Despite the absence of boostrap support for some of the relationships, a well-resolved and supported consensus was found, for which most clades were present in more than one individual analysis. Most clades of this consensus attained high posterior probabilities with a Bayesian approach. Circumscription of Arethuseae and Epidendreae are different from most orchid systems based on morphology, but they correspond to a combination of patterns from several less comprehensive orchid phylogenetic analyses previously published. A new circumscription of Epidendreae includes only Neotropical subtribes (Bletiinae, Chysiinae, Laeliinae, Ponerinae, and Pleurothallidinae), whereas Arethuseae include Coelogyninae (all Old World) and Arethusinae (pantropical). Many previously included genera will need to be moved to other tribes. Taxa previously assigned to be Old World Epidendreae are related to different groups of Old World orchids, and this study can serve as a guide for sampling strategies in future studies to resolve troublesome epidendroid orchid clades. PMID- 21652440 TI - Molecular phylogeny of Incarvillea (Bignoniaceae) based on ITS and trnL-F sequences. AB - Incarvillea is a herbaceous and temperate member of Bignoniaceae, previously divided into four subgenera, Niedzwedzkia, Amphicome, Incarvillea, and Pteroscleris. Niedzwedzkia and Amphicome have in the past been treated as independent genera. Different relationships have been proposed for the four subgenera. Here, maximum parsimony analysis using ITS and trnL-F sequences resulted in similar trees and showed that the genus is monophyletic. Analysis of the combined data resulted in a single tree with five major clades highly supported and well resolved. The relationships of the five major clades are (subgenus Niedzwedzkia (Incarvillea olgae (subgenus Amphicome (subgenus Incarvillea, subgenus Pteroscleris)))). All four subgenera are well supported for monophyly, with the exception of subgenus Incarvillea, represented here by I. sinensis and I. olgae. Incarvillea olgae is not closely related to I. sinensis, a conclusion supported by morphology. The two basal monotypic subgenera are found in Central Asia. The most species-rich subgenus, Pteroscleris, has 10 species in the Himalaya-Hengduan Mountains and may have dispersed early from central Asia to eastern Asia. Short branch lengths on the molecular trees within Pteroscleris suggest a recent and rapid radiation of this rosette-forming subgenus, perhaps connected with the uplift of the Himalaya-Hengduan massif. PMID- 21652441 TI - Extinction threat in the Pedilanthus clade (Euphorbia, Euphorbiaceae), with special reference to the recently rediscovered E. conzattii (P. pulchellus). AB - The type locality of the slipper spurge Euphorbia conzattii has been in doubt because the 1917 type is a mixed collection with vague label data. In recent field work, the species was found on Cerro Espino, Pochutla District, Oaxaca, Mexico. We used the Method for Evaluation of Risk of Extinction for Mexican Wild Species (MER), required to protect a species under Mexican law, to assess the conservation status of E. conzattii and found it to be endangered. We discuss the mixture in the type of this species with E. calcarata and present an updated description and an illustration of E. conzattii. Preliminary MER assessments of the other Mexican Pedilanthus clade species show two species to be extinct (E. cyri, E. dressleri) and four threatened (including E. colligata, E. finkii, E. tehuacana). The remaining eight have more favorable outlooks. We comment on MER robustness and aspects vulnerable to confusion and offer clarifications. Extinction risk is not distributed evenly throughout the clade, with a subclade of leafy treelets from a variety of habitats having the greatest number of endangered species. Extinction risk is distributed across all Pedilanthus-clade habitats; the strongest association noted is that both species from moist highlands are endangered. PMID- 21652442 TI - Monophyly of Kelloggia Torrey ex Benth. (Rubiaceae) and evolution of its intercontinental disjunction between western North America and eastern Asia. AB - Kelloggia Torrey ex Bentham (Rubiaceae) consists of two species disjunctly distributed in western North America (K. galioides Torrey) and the western part of eastern Asia (K. chinensis Franch.). The two species exhibit a high level of morphological divergence. To test its monophyly and to infer its biogeographic history, we estimated the phylogeny of Kelloggia and its relatives from sequences of three chloroplast DNA regions (rbcL gene, atpB-rbcL spacer, and rps16 intron). The monophyly of Kelloggia was strongly supported, and it forms a sister relationship with the tribe Rubieae. The divergence time between the two disjunct species of Kelloggia was estimated to be 5.42 +/- 2.32 million years ago (mya) using the penalized likelihood method based on rbcL sequence data with fossil calibration. Our result does not support the Madrean-Tethyan hypothesis, which assumes an earlier divergence time of 20-25 mya. Ancestral area analysis, as well as dispersal-vicariance (DIVA) analysis, suggests the Asian origin of Kelloggia and the importance of Eurasia in the diversification of its close relatives in the Rubieae-Theligoneae-Paederieae group. The intercontinental disjunction in Kelloggia is suggested to have evolved via long-distance dispersal from Asia into western North America. PMID- 21652443 TI - Viburnum phylogeny based on combined molecular data: implications for taxonomy and biogeography. AB - We investigated Viburnum phylogeny using separate and combined analyses of DNA sequence data from two chloroplast and three nuclear loci. Separate analyses of nuclear and chloroplast data sets resulted in gene trees that were generally congruent with one another and with trees from two previous analyses. Our gene trees do differ in the position of section Pseudotinus, as well as in species relationships within sections Pseudotinus and Lentago. However, tests for incongruence indicate that differences between the nuclear and chloroplast data are not significant. Furthermore, gene trees from combined analyses were highly similar to those found in separate analyses, suggesting that these localized differences do not affect other parts of the tree. Our analyses provide convincing support for numerous relationships, although there is still uncertainty at the base of the tree. To facilitate future study, we propose informal names for 12 well-supported species groups, as well as for several higher-level clades. We also discuss the biogeographic implications of our phylogeny, focusing on repeated, although apparently temporally incongruent, patterns of disjunction between the Old and New Worlds. PMID- 21652444 TI - Phylogenetic relationships among New Caledonian Sapotaceae (Ericales): molecular evidence for generic polyphyly and repeated dispersal. AB - The phylogeny of a representative group of genera and species from the Sapotaceae tribe Chrysophylleae, mainly from Australia and New Caledonia, was studied by jackknife analyses of sequences of nuclear ribosomal DNA. The phylogeny conflicts with current opinions on generic delimitation in Sapotaceae. Pouteria and Niemeyera, as presently circumscribed, are both shown to be nonmonophyletic. In contrast, all species currently assigned to these and other segregate genera confined to Australia, New Caledonia, or neighboring islands, form a supported clade. Earlier classifications in which more genera are recognized may better reflect relationships among New Caledonian taxa. Hence, there is need for a revision of generic boundaries in Chrysophylleae, and particularly within the Pouteria complex, including Leptostylis, Niemeyera, Pichonia, Pouteria pro parte (the main part of section Oligotheca), and Pycnandra. Section Oligotheca have been recognized as the separate genus Planchonella, a monophyletic group that needs to be resurrected. Three clades with strong support in our jackknife analysis have one Australian species that is sister to a relatively large group of New Caledonian endemics, suggesting multiple dispersal events between this small and isolated tropical island and Australia. The phylogeny also suggests an interesting case of a relatively recent and rapid radiation of several lineages of Sapotaceae within New Caledonia. PMID- 21652445 TI - Ramet demography of a nurse bromeliad in Brazilian restingas. AB - Restingas are sandy coastal plains that stand between the sea and the Brazilian Atlantic forest mountains. The predominant restinga vegetation type in northern Rio de Janeiro, Brazil, is characterized by the formation of islands that begins with colonization by some pioneer herbs and/or woody plants. Pioneer plants are stress-resistant and nurse many other less-resistant plant species. Determining the spatiotemporal variation in the dynamics of nurse plants is essential to understand the ecological functioning of restingas as a whole. The goal of this study was to analyze the spatiotemporal variation in population dynamics of the nurse bromeliad Aechmea nudicaulis. We monitored A. nudicaulis ramets in different habitats, microhabitats, and years. We analyzed the spatiotemporal variation in demographic traits and in population growth rate. Results showed young ramet traits were more variable at the microhabitat level, and when variable, vegetative ramet traits varied at all spatiotemporal scales. Overall, lambda values indicated that A. nudicaulis basically remained spatiotemporally stable as most of the lambda values did not significantly differ from unity. Hence, the stability of A. nudicaulis in different microhabitats and habitats in the restinga may create several settlement opportunities for many other less resistant species. PMID- 21652446 TI - Growth and photosynthetic responses of the federally endangered shrub, Lindera melissifolia (Lauraceae), to varied light environments. AB - Photosynthetic, morphological, and growth responses to light environment can be useful measurements to determine favorable habitat conditions for the conservation of endangered species. For Lindera melissifolia (Walt.) Blume, we compared morphological and photosynthetic responses under natural and controlled light regimes, and growth under three light treatments: 100%, 42%, and 19% full sunlight. Typical sun-shade morphological responses to decreasing light levels included decreased stomatal density, increased specific leaf area, and increased leaf area ratio. Photosynthetic capacity (3-6 MUmol CO(2) . m(-2) . s(-1)) was consistent with other shade-tolerant species. Light-saturated rates of photosynthesis of experimental plants increased with increasing light up to 42% sunlight, but declined at 100% sunlight. The 100% light treatment also resulted in lower plant biomass, primarily from a reduction in root biomass. Results indicate that canopy conditions at levels below 40% sunlight are optimal for plant growth and should be considered in management and reintroduction efforts for this species. PMID- 21652447 TI - Stomatal frequency responses in hardwood-swamp vegetation from Florida during a 60-year continuous CO2 increase. AB - In a stomatal frequency analysis of leaf remains of Quercus nigra, Acer rubrum, Myrica cerifera, Ilex cassine, and Osmunda regalis that were preserved in precisely dated peat deposits of north-central Florida, the stomatal index decreased as a response to an atmospheric CO(2) increase from 310 ppmv to 370 ppmv over the past 60 years. The observations indicate that CO(2) responsiveness may occur in different canopy levels of hardwood-swamp vegetation. Apart from common woody plants, long-lived ferns of the undergrowth appear to be affected by CO(2) changes. Response rates are most pronounced in M. cerifera, I. cassine, and O. regalis. The potential of these species for quantifying past atmospheric CO(2) levels is assessed by a combined analysis of the well-dated buried leaf record and herbarium material collected during the past century. Leaf remains of the widely occurring species M. cerifera and I. cassine are concluded to be highly suitable for CO(2) reconstructions, by which the application range of the stomatal frequency proxy is extended into the warm-temperate to subtropical realm of North America. PMID- 21652448 TI - Endozoochorous dispersal of aquatic plants: does seed gut passage affect plant performance? AB - The ingestion of seeds by vertebrates can affect the germinability and/or germination rate of seeds. It is, however, unclear if an earlier germination as a result of ingestion affects later plant performance. For sago pondweed, Potamogeton pectinatus, the effects of seed ingestion by ducks on both germinability and germination rate have been previously reported from laboratory experiments. We performed an experiment to determine the effects of seed ingestion by ducks on germination, seedling survival, plant growth and asexual multiplication. Both at the start and end of the winter, seeds were fed to three captive shovelers (Anas clypeata) and planted outdoors in water-filled containers. Plant biomass and its allocation to vegetative parts (shoot and roots), tubers, and seeds were determined in autumn. More duck-ingested seeds than control (uningested) seeds germinated in early winter, but this difference disappeared for seeds planted in late winter, when the treatments were first stratified for 3 mo. None of the variables for measuring seedling survival and plant performance varied between treatments. Under our experimental conditions (no herbivory or competition), ingestion by ducks in early winter resulted in increased performance for seeds surviving gut passage due to enhanced seed germinability, without other costs or benefits for the seedlings. PMID- 21652449 TI - Does cladode inclination restrict microhabitat distribution for Opuntia puberula (Cactaceae)? AB - In contrast with other Opuntia species, most of the cladodes of Opuntia puberula have a horizontal position. This study explores whether the horizontal cladodes are an adaptive trait to increase light interception in the understory or are a neutral trait, and if this characteristic may prevent its distribution in full sun habitats. Cladode inclination angle and its effect on light interception, cladode temperature, and carbon gain are characterized, and anatomical and physiological traits of upper and lower cladode surfaces are described. Inclination angle was under 50 degrees for 95% of the cladodes, and the frequency of low inclination angles increases as light availability decreases. Nocturnal acid accumulation increased with total daily PPFD intercepted, but no significant differences were detected between typical horizontal cladodes and the few vertical cladodes. Chlorophyll content differed in the upper and lower surfaces of horizontal cladodes; however, chlorenchyma thickness, stomatal conductance, and nocturnal acid accumulation were similar between surfaces. The horizontal position of O. puberula cladodes, which is anatomically determined, restricts it to shaded habitats, where the plants do not overheat, but seems to have no effect on carbon gain. PMID- 21652450 TI - Cuticular anatomy of Sphenobaiera huangii (Ginkgoales) from the Lower Jurassic of Hubei, China. AB - Sphenobaiera huangii (Sze) Hsu is typical Early Mesozoic fossil foliage of Ginkgoales in China. It has been recorded from the Upper Triassic to the Lower Jurassic. The cuticular anatomy is investigated based on material from the type locality, Lower Jurassic Hsiangchi Formation, Zigui County, Hubei Province. The specimens are similar to S. huangii, but contain new information about leaf morphology and cuticular anatomy. Lower and upper cuticle is investigated using light and electron microscopy (LM, SEM, and TEM). Many features are described for the first time, including general structures of lower and upper cuticle, stomata, papillae, and cuticular ultrastructure. At the ultrastructural level, two layers have been distinguished in both lower and upper cuticle, including a homogeneous outer layer with granules and a heterogeneous inner layer with fibrils. Based on a literature comparison between S. huangii and other relevant species of Sphenobaiera, S. huangii may represent the best-known taxon in the genus Sphenobaiera in both leaf morphology and cuticular structures. This study provides the first detailed ultrastructural data on the leaf cuticle of Sphenobaiera, one of the oldest foliage taxa of Ginkgoales, and offers further evidence for potential discussion on the taxonomic relationships of S. huangii with other ginkgoalean taxa. PMID- 21652451 TI - Genetic diversity in Chihuahuan Desert populations of creosotebush (Zygophyllaceae: Larrea tridentata). AB - We examined isozyme variation in the dominant Chihuahuan Desert shrub, Larrea tridentata (creosotebush), to determine the genetic variation within and among populations, the biogeographic relationships of populations, and the potential inbreeding in the species. We surveyed 17 populations consisting of 20 to 50 individuals per population along a 1600-km north-south transect across the Chihuahuan Desert. The southernmost population was near Villa Hidalgo, Mexico, and the northernmost near Isleta Pueblo, New Mexico. All 12 isozyme loci examined were polymorphic (H(t) = 0.416), with up to nine alleles per locus. Despite high levels of variation, we detected moderate inbreeding in L. tridentata populations. Most variation was found within rather than among populations (G(ST) = 0.118). Furthermore, recently established populations in the northern limits of the Chihuahuan Desert did not show decreased levels of genetic variation (H(o) = 0.336). A significant correlation was found between pairwise genetic and geographic distances (r = 0.305). Larrea tridentata showed and continues to show a massive range expansion into the arid and semi-arid regions of the American Southwest, but as shown by the high genetic variation, this expansion took place as a wave, rather than a series of founder events. PMID- 21652452 TI - Pollen competition among two species of Senecio (Asteraceae) that form a hybrid zone on Mt. Etna, Sicily. AB - Hybridization between interfertile, sympatric or parapatric, plant species can be reduced significantly by conspecific pollen advantage (CPA), whereby conspecific pollen has an advantage over heterospecific pollen in terms of ovule fertilization. We examined CPA in two interfertile species of Senecio, S. aethnensis, and S. chrysanthemifolius (Asteraceae), which form a hybrid zone on Mt. Etna, Sicily. Individuals of both species were pollinated with pollen mixtures containing 0, 25, 50, 75, or 100% heterospecific pollen, and offspring were genotyped to determine if they were products of conspecific or heterospecific pollen fertilizing the ovules. The mean proportion of hybrid offspring produced on S. aethnensis plants was not significantly different to that expected based on the proportion of heterospecific pollen applied to the flower head. However, S. chrysanthemifolius mother plants showed moderate CPA, with the proportion of hybrid offspring significantly less than expected. Seed set or seed germination was not reduced, hence the CPA found for S. chrysanthemifolius acts before ovule fertilization. The consequences of asymmetry in CPA on the reproductive isolation of S. aethnensis are briefly discussed, along with other mechanisms that may play a role in the maintenance of the hybrid zone on Mt. Etna. PMID- 21652453 TI - Floral phenology and compatibility of sawgrass, Cladium jamaicense (Cyperaceae). AB - Sawgrass, Cladium jamaicense, is the dominant macrophyte in the Florida Everglades. We examined sawgrass flowering phenology and compatibility reactions in ex situ and in situ populations over 2 yr. Sawgrass flowers in May in southern Florida. Flower maturation was relatively synchronous within an inflorescence. Along the entire inflorescence, functionally male flowers emerged initially, followed by stigmas, then anthers of hermaphroditic flowers. Flowers of each sex expanded over 2 d with less than 1 d in between, totaling 6- 7 d for an inflorescence to complete flowering. Hand pollinations showed that sawgrass was self-compatible and not pollen-limited, because open pollinations produced fruit set similar to self- and cross-pollinations. Fruit set was low in autogamy and manipulation treatments. Manipulation treatments were used to study the effect of exposure to airborne pollen during hand pollinations. This treatment thus provides a useful technique for studies on the in situ compatibility of wind pollinated graminoids. Sawgrass was able to self-fertilize, but the timing of flower maturation on an inflorescence promoted outcrossing. Actual outcrossing rates in sawgrass thus depend on clonal architecture and the timing of floral maturation on other inflorescences within a clone rather than on inflorescences of other genets in a population. PMID- 21652454 TI - Evolution of self-fertilization at geographical range margins? A comparison of demographic, floral, and mating system variables in central vs. peripheral populations of Aquilegia canadensis (Ranunculaceae). AB - Biogeographic models predict that geographically peripheral populations should be smaller, more sparsely distributed, and have a lower per-capita reproductive rate than populations near the center of a species' range. Plants in peripheral populations may, therefore, receive less pollinator visitation and outcross pollination, which may select for self-fertilization to provide reproductive assurance. We tested these predictions by comparing population size, plant density, seed production, floral traits, and mating system parameters between 10 populations of Aquilegia canadensis near the northern margin of the range with 10 near the range center. Contrary to predictions, peripheral populations were not smaller, less dense, nor less productive than central populations. Nevertheless, we detected substantial regional differences in key floral traits. Plants in central populations produced larger flowers with 68% greater herkogamy and had 30% more flowers open simultaneously than plants in northern populations. However, there was no regional difference in the mating system. In northern populations, 73% (range = 60-88%) of seeds were self-fertilized compared to 76% (51-100%) in central populations. In both regions, adult inbreeding coefficients were near zero, indicating very strong inbreeding depression despite high selfing. Marked geographic variation in key floral traits does not reflect evolutionary differentiation in the mating system. PMID- 21652455 TI - Floral developmental evidence for the systematic position of Batis (Bataceae). AB - Molecular phylogenies have associated Bataceae with Salvadoraceae and Koeberliniaceae in an expanded Brassicales. Despite a long taxonomic history, the knowledge of the flower of Batis is still fragmentary. The floral development of pistillate and staminate inflorescences of Batis maritima was investigated to understand homologies of floral structures and to discuss the phylogenetic position of Bataceae within the Brassicales. There has been considerable controversy in the past about the male flower, especially on the nature of the petals and the tubular structure enclosing the flower. Developmental evidence confirms that the male flower is built on a basic tetramerous bauplan and that the tubular structure is derived from four congenitally fused sepal lobes with the three anterior lobes highly reduced. The development of petals and stamens is unidirectional, and the androecium initiates the median stamens before the lateral stamens, suggesting the existence of two whorls. The pistillate flowers are reduced to the bare minimum with two transversal carpels enclosed by a bract. Partial inflorescences function as a swollen dispersal unit. The vestigial stipules probably represent colleters and are not homologous with true stipules. Several characters of Batis are reminiscent of the Brassicaceae, although a link with Salvadoraceae and Koeberliniaceae cannot be excluded. PMID- 21652456 TI - Genome evolution among cruciferous plants: a lecture from the comparison of the genetic maps of three diploid species--Capsella rubella, Arabidopsis lyrata subsp. petraea, and A. thaliana. AB - Comparative mapping in cruciferous plants is ongoing, and recently two additional genetic maps of diploid Capsella and Arabidopsis lyrata subsp. petraea have been presented. We compared both maps with each other using the sequence map and genomic data resources from Arabidopsis thaliana as a reference. The ancestors of the species pair Capsella-Arabidopsis diverged from one another approximately 10 14 million years ago (mya), whereas Arabidopsis thaliana and Arabidopsis lyrata have been separated since roughly 5-6 mya. Our analysis indicated that among diploid Capsella and Arabidopsis lyrata all eight genetic linkage groups are totally colinear to each other, with only two inversions significantly differentiating these two species.By minimizing the number of chromosomal rearrangements during genome evolution, we presented a model of chromosome evolution involving all three species. From this scenario, it is obvious that Arabidopsis thaliana underwent a dramatic genome reconstruction, with a base chromosome number reduction from five to eight and with approximately 1.3 chromosomal rearrangements per million years. In contrast, the terminal lineage leading to Capsella has only undergone less than 0.09 rearrangements per million years. This is the same rate as calculated for Arabidopsis lyrata since its separation from the Capsella lineage 10-14 mya. These results are in strong contrast to all overestimated rates calculated from comparisons of the systems Arabidopsis thaliana and Brassica, and our data demonstrate the problematic nature of both model systems. PMID- 21652457 TI - Phylogeny of PgiC gene in Shorea and its closely related genera (Dipterocarpaceae), the dominant trees in Southeast Asian tropical rain forests. AB - Dipterocarpaceae, trees that dominate tropical rain forests in Southeast Asia consist of many economically and ecologically important species. We determined partial sequences of the PgiC gene from species of Shorea, Hopea, Neobalanocarpus, and Parashorea to elucidate phylogenetic relationships among the species of these genera, which have been regarded as interrelated. The sequences generated a gene tree with better resolution than previous cpDNA trees. The PgiC tree is essentially consistent with cpDNA trees, except for the placement of Neobalanocarpus. The PgiC tree shows that Neobalanocarpus is nested within White Meranti of Shorea, whereas this genus forms a clade with Hopea in cpDNA trees. This conflict suggests that Neobalanocarpus is derived via hybridization between White Meranti of Shorea and Hopea. Species belonging to each of three timber groups (Yellow Meranti, Balau, and Red Meranti) within Shorea are monophyletic. Together they form a monophyletic clade distinct from White Meranti. Botanical sections within Red Meranti appear not to be monophyletic. An extensive number of shared polymorphisms among species and consequential lack of monophyly of intraspecific haplotypes are found in Red Meranti. Potential causes of this phenomenon, including persistence of ancestral polymorphisms and gene flow via interspecific hybridization, are discussed. PMID- 21652458 TI - Solar radiation as a factor in the evolution of scleromorphic leaf anatomy in Proteaceae. AB - Species of the major Southern Hemisphere family, Proteaceae, have many scleromorphic anatomical structures in their leaves. Many of these structures (very thick cuticles and five anatomically distinct structures beneath the epidermis) are associated with the leaf surface exposed to direct light. These structures increase the path through which solar radiation must pass before reaching the mesophyll. In this study, such structures are proposed to protect the mesophyll from excess solar radiation, including photosynthetically active, ultraviolet, and possibly infrared radiation. Scleromorphic structures of the upper leaf surface and nonscleromorphic photoprotective structures (dense trichomes and papillae of the upper surface) occur almost exclusively in open vegetation. Open vegetation species of Proteaceae occur in oligotrophic and/or cold and/or dry places, where protection from light in excess of photosynthetic capacity and damage from ultraviolet light should be most important. Data from 123 species and a supertree constructed from available molecular phylogenies are used to show that the proposed photoprotective structures evolved many times within Proteaceae. In tests of correlated evolution, the proposed photoprotective structures are significantly associated with open vegetation, but not with dry habitats. PMID- 21652459 TI - Floral venation patterns in Siphocampylus (Campanulaceae). AB - Siphocampylus is a neotropical genus that comprises 221 species distributed from Costa Rica to Argentina and in the Greater Antilles. Twenty-eight species have been reported from Brazil, mainly occupying mountainous terrain. The floral venation patterns and the origin of the hypanthium in eight Brazilian species, including three varieties, are described. Eleven ovarian vascular bundles depart from the siphonostele or receptacular stele: five of these bundles result from sepalar and staminal adnation and are alternate to five petalar bundles; the remaining bundle is central carpellary. The staminal bundles diverge from the sepalar bundles at the sinus, while the carpellary bundles form a cross, resulting in four ventral bundles; two of these feed the ovules; the other two feed the style. Apparently, the dorsal carpellary bundles diverge at the same site and then ramify profusely. The venation pattern observed is unprecedented in Siphocampylus and is quite different from other reports on genera of Campanulaceae. Further, these findings suggest that the origin of the hypanthium is appendicular, increasing knowledge of venation in this group, thus providing data for phylogenetic considerations. PMID- 21652460 TI - On the occurrence of adventitious branch roots on root axes of trees. AB - Based on positive results for 11 of 17 species included in an anatomical survey of tree roots, we concluded that the origin of adventitious branch roots (ABR) on established, undisturbed woody parental root axes is a widespread occurrence. ABR were morphologically indistinguishable from branch roots formed in primary tissues of a parental axis, and they occurred without increase in branch root density. We concluded that ABR are an unrecognized component of undamaged root systems. Using continuous serial sectioning to perform a census of branch roots within parental root axes, we obtained definitive evidence that ABR participate in root turnover. Comparisons of older and younger axes, and the chronology of root formation in older axes fulfilled the expectation that with greater age of parental axis, ABR become increasingly predominant among intact branch roots. We confirmed this trend for one of the species scoring negative in the survey, which means that our survey results were probably influenced by age variation. Thus, any of the six negative results obtained in the survey may have been dependent on the young age and slenderness of the axes that were available for examination in those six species. PMID- 21652461 TI - Morphological responses to simulated wind in the genus Brassica (Brassicaceae): allopolyploids and their parental species. AB - Thigmomorphogenesis refers to the widespread ability of sessile organisms to modify their morphology in response to a variety of mechanical stimulations, from direct contact with the stem by insects or other plants to flexure caused by wind, water, or snow. In this paper we investigated the differences in the reaction norms to wind exposure of seven species of the Brassicaceae that constitute a well-studied complex of known phylogenetic relationships. The goals included the characterization of differences between allopolyploids and their parental species and the comparison of wild and fast-cycling accessions within each species. We found statistically significant variation for plasticity among species or accessions for several characters, but the majority of the phenotypic variance was accounted for by overall (across-environment) differences among species and accessions and not by variation in plasticity. Allopolyploids displayed an array of behaviors when compared to their parents, from co-dominance to complete dominance to exceeding both parental means. Furthermore, fast-cycling plants showed distinct features from their wild relatives, suggesting that wild populations should be included with artificially selected lines in ecological studies. We proposed further steps to gain a more comprehensive understanding of thigmomorphogenetic responses, by integrating current research on the molecular bases of thigmomorphogenesis with insights into the ecology and evolution of plants exposed to wind. PMID- 21652462 TI - Phenotypic plasticity in vegetative and reproductive traits in an invasive weed, Lythrum salicaria (Lythraceae), in response to soil moisture. AB - In colonizing species, high phenotypic plasticity can contribute to survival and propagation in heterogenous adventive environments, and it has been suggested as a predictor of invasiveness. Observation of natural populations of an invasive species, Lythrum salicaria salicaria, indicated extensive variation in its growth and reproductive traits. Phenotypic plasticity of different life history traits of L. salicaria was investigated using vegetative clones of each of 12 genotypes from one population in Ontario, Canada. We chose soil moisture as the treatment factor because of its importance in wetland species and raised all 12 genotypes in each of four soil moisture treatments. We examined an array of vegetative and reproductive traits, including root and shoot mass, shoot and inflorescence length, total seed set, floral mass, and morphometric variables. All observed vegetative as well as reproductive traits demonstrated significant phenotypic plasticity in response to soil moisture treatment. Even the stigma-anther separation involved significant genotype by environment interactions, suggesting that soil moisture may modify the relative positions of anthers and stigma. Compared to vegetative traits, most reproductive traits demonstrated crossing reaction norms, implying that the average differences in those traits among genotypes vary with the environment maintaining the genetic variation in a population. PMID- 21652463 TI - Reproduction and progeny of Silene latifolia (Caryophyllaceae) as affected by atmospheric CO2 concentration. AB - Sexual dimorphism in plants has been known for over two millennia. However, little is known about how male and female reproduction of dioecious species will respond to anthropogenic environmental perturbations. Using growth chambers, the effects of CO(2) enrichment on male and female reproduction in Silene latifolia were examined and whether parental CO(2) environment affected progeny germination and sex ratio. Reproduction of male and female S. latifolia was enhanced by a similar magnitude at elevated CO(2). Over the growing season, males produced 16 times as many flowers as females did fruits per plant, but no difference in reproductive biomass between genders was observed at ambient or elevated CO(2). Germination of seeds produced by plants grown at different CO(2) concentrations was significantly different. Female seeds from higher CO(2)-grown plants tended to emerge earlier than those from ambient-CO(2)-grown plants, but emergence of male seeds was little affected. Overall, seeds from elevated-CO(2)-grown plants had 20% higher germination and were more female-biased than those from ambient CO(2)-grown plants. Because of the enhanced reproduction and more female-biased progeny under elevated CO(2), the population structure of this cosmopolitan weedy species will likely be altered in a future environment. PMID- 21652464 TI - Microsatellite analysis reveals genetically distinct populations of red pine (Pinus resinosa, Pinaceae). AB - Red pine (Pinus resinosa Ait.) is an ecologically and economically important forest tree species of northeastern North America and is considered one of the most genetically depauperate conifer species in the region. We have isolated and characterized 13 nuclear microsatellite loci by screening a partial genomic library with di-, tri-, and tetranucleotide repeat oligonucleotide probes. In an analysis of over 500 individuals representing 17 red pine populations from Manitoba through Newfoundland, five polymorphic microsatellite loci with an average of nine alleles per locus were identified. The mean expected and observed heterozygosity values were 0.508 and 0.185, respectively. Significant departures from Hardy-Weinberg equilibrium with excess homozygosity indicating high levels of inbreeding were evident in all populations studied. The population differentiation was high with 28-35% of genetic variation partitioned among populations. The genetic distance analysis showed that three northeastern (two Newfoundland and one New Brunswick) populations are genetically distinct from the remaining populations. The coalescence-based analysis suggests that "northeastern" and "main" populations likely became isolated during the most recent Pleistocene glacial period, and severe population bottlenecks may have led to the evolution of a highly selfing mating system in red pine. PMID- 21652465 TI - Effects of crossing distance on offspring fitness and developmental stability in Dalechampia scandens (Euphorbiaceae). AB - Crosses between genetically close and distant populations of Dalechampia scandens (Euphorbiaceae) were made to test whether the responses of various fitness components and measurements of developmental stability were affected by the outcrossing distance (level of outbreeding). Two fecundity traits, seed set and seed mass, decreased consistently with increasing level of outbreeding, and hybrids between the most divergent populations were sterile. Effects of the genetic distance between parental populations on viability traits, survival and vigor at 1 month of age, were highly idiosyncratic. Hybrids of one long-distance combination had no reduction in survival and vigor, while both traits were greatly reduced in the other long-distance combination. The expression of outbreeding depression on fecundity traits differed between reciprocal crosses in some hybrids but not others; thus, hybrid breakdown may have been due to cytoplasmic-by-nuclear gene interactions, reduced endosperm formation, or an interaction between progeny and maternal genotype. None of the measures of developmental stability had a consistent relationship with either genetic distance between parental populations or seedling vigor. These results suggest that fecundity and viability traits may be differentially affected by hybridization, probably due to differences in genetic architecture among populations. This study also confirms that developmental stability, as measured by the level of fluctuating asymmetry, is not a reliable index of genetic stress. PMID- 21652466 TI - The response of plasma membrane lipid composition in callus of the halophyte Spartina patens (Poaceae) to salinity stress. AB - Callus cultures of the salt marsh grass Spartina patens were examined to determine changes and consistencies in membrane lipid composition in response to salt. Major membrane lipid classes remained stable at all salinity levels (0, 170, 340 mmol/L). However, the membrane protein to lipid ratio decreased significantly in response to elevated NaCl. Callus plasma membrane (PM) consisted predominantly of sterols, about 60% (mol%) of the total lipids. Glycolipid was the second largest lipid class, making up about 20% (mol%) of the total. With increasing salinity, the relative percentage of sitosterol decreased, while that of campesterol increased. The phospholipid species detected were phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidylinositol (PI). When callus was grown at 340 mmol/L NaCl, PC increased significantly. PI and PS were also significantly elevated in salinity treatments. Only 24-32% of the PM fatty acids were common plant membrane fatty acids, C16, C18, C20, and C22, while over 60% were the less common fatty acids, C11 and C14. Membrane fluidity remained stable in response to growth medium salinity. The findings on membrane responses to salinity will facilitate a better understanding of this halophyte's tactics for salt tolerance. PMID- 21652467 TI - Linking frugivores to the dynamics of a fruit color polymorphism. AB - Although fruit color polymorphisms are a widespread phenomenon, the role of frugivores in their maintenance is unknown. Selection would require that frugivores interact differentially with fruit color morphs to alter their relative fitnesses, but such a pattern has yet to be demonstrated. In a 3-yr field study, the interactions of ants and birds with Acacia ligulata, an Australian shrub with a red/yellow/ orange aril color polymorphism, were examined. Bird species fell into three feeding guilds: seed dispersers, seed predators, and aril thieves; ant species acted either as seed dispersers or aril thieves. While there was no evidence of morph bias in ants, in some years birds fed more frequently on the yellow and orange morphs. Based on patterns of seedling survival and juvenile recruitment in seed deposition sites, bird seed dispersers increased the fitness of yellow and orange morphs (relative to red) in some populations, but decreased their relative fitness in others. Bird seed predators uniformly reduced relative fitness of yellow and orange morphs, while bird aril thieves had unknown effects. Altogether, consumer biases produced spatiotemporal variability in the relative fitness of A. ligulata color morphs, a pattern qualitatively consistent with maintenance of the polymorphism. PMID- 21652468 TI - Physiological mechanism of population differentiation in shade-avoidance responses between woodland and clearing genotypes of Impatiens capensis. AB - Forest understory plants often respond less intensely to reduced ratios of red to far red (R : FR) light, an important signal of foliage shade, than conspecific or congeneric plants from open-canopy sites. Reduced responsiveness to low R : FR in plants from closed-canopy sites could be caused by two physiological mechanisms. First, closed-canopy plants could have less sensitive shade-avoidance responses to low R : FR. Second, the high irradiance response to FR (FR-HIR), which allows seedling de-etiolation under low R : FR, might be stronger or persist longer after de-etiolation in closed-canopy plants, thus counteracting shade-avoidance responses to low R : FR. These hypotheses were tested using diodes that emit red and far-red light to distinguish the responses to altered R : FR of genotypes of Impatiens capensis collected from a pair of open- and closed-canopy populations that have previously been shown to differ in sensitivity to R : FR. Genotypes from the open-canopy environment exhibited typical shade-avoidance responses, elongating in response to supplemental FR. However, genotypes from the closed canopy environment responded to supplemental FR by elongating less than under ambient control conditions, indicating a persistent FR-HIR. Thus, the observed population differentiation in response to low R : FR may be linked to population differences in FR-HIR. PMID- 21652469 TI - Genetic diversity and structure of natural and managed populations of Cedrus atlantica (Pinaceae) assessed using random amplified polymorphic DNA. AB - Cedrus atlantica (Pinaceae) is a large and exceptionally long-lived conifer native to the Rif and Atlas Mountains of North Africa. To assess levels and patterns of genetic diversity of this species, samples were obtained throughout the natural range in Morocco and from a forest plantation in Arbucies, Girona (Spain) and analyzed using RAPD markers. Within-population genetic diversity was high and comparable to that revealed by isozymes. Managed populations harbored levels of genetic variation similar to those found in their natural counterparts. Genotypic analyses of molecular variance (AMOVA) found that most variation was within populations, but significant differentiation was also found between populations, particularly in Morocco. Bayesian estimates of F(ST) corroborated the AMOVA partitioning and provided evidence for population differentiation in C. atlantica. Both distance- and Bayesian-based clustering methods revealed that Moroccan populations comprise two genetically distinct groups. Within each group, estimates of population differentiation were close to those previously reported in other gymnosperms. These results are interpreted in the context of the postglacial history of the species and human impact. The high degree of among group differentiation recorded here highlights the need for additional conservation measures for some Moroccan populations of C. atlantica. PMID- 21652470 TI - Patterns of multiple paternity in fruits of Mimulus ringens (Phrymaceae). AB - Multiply sired fruits provide unambiguous evidence that pollen from two or more donors was deposited on a stigma and successfully fertilized ovules. Such multiple paternity within fruits can have important consequences for both parental and offspring fitness, but little is known about the frequency of multiple paternity or the mechanisms causing it. In this study we quantify the extent of multiple paternity in replicate experimental arrays of Mimulus ringens (square-stem monkeyflower) and use observations of pollinator behavior to infer mechanisms generating multiply sired fruits. In each array, floral displays were trimmed to two, four, eight, or 16 flowers per plant to span the range of display sizes observed in nature. In our sample of 204 fruits, more than 95% had two or more outcross pollen donors. The number of sires per fruit averaged 4.63 +/- 0.10 (mean +/- 1 SE), including selfs, and did not vary significantly with floral display treatment. Patterns of bumble bee foraging, combined with limited pollen carryover, suggest that observed levels of multiple paternity cannot be fully explained by single probes that deposited mixed pollen loads. Multiple probes to flowers, each delivering pollen from 1-3 different sires, are more likely to have caused the observed patterns. These sequential visits may reduce the potential for pollen competition and female choice based on pollen tube growth rate. PMID- 21652471 TI - Are flower-visiting ants mutualists or antagonists? A study in a gynodioecious wild strawberry. AB - Ants are common flower visitors, but their effects on plant reproductive fitness have not often been assessed. Flower-visiting ants were studied to determine whether they are antagonists or mutualists and whether they could influence floral or breeding system evolution in gynodioecious wild strawberry (Fragaria virginiana). Ant and flying pollinator (bees/flies) access to plants was manipulated, and visitation, fruit, and seed set were assessed. Ants visited flowers of hermaphrodites more often than those of females when bees and flies were excluded, but visited the sex morphs equally when they were present. Insect class did not influence fruit or seed set of hermaphrodites. In contrast, ants had both positive and negative effects on seed set in females. Females visited only by ants had 90% of the seed set of those visited only by bees/flies, and their seed set increased with ant visitation. The spatial pattern of seed set, however, suggests that ants may also damage pistils. Lastly, in contrast to bees and flies, ants failed to increase visitation with floral display size, suggesting that ant presence at flowers could reduce selection on this attractive trait. Findings suggest that when in high abundance, flower-visiting ants could affect breeding system and floral evolution in this gynodioecious plant. PMID- 21652472 TI - Sex-specific effect of Microbotryum violaceum (Uredinales) spores on healthy plants of the gynodioecious Gypsophila repens (Caryophyllaceae). AB - Females of gynodioecious species need to have reproductive advantages to compensate for their lack of male function and assure their maintenance in natural populations. Females may be more fecund than hermaphrodites because they reallocate resources from male to female function, avoid selfing and inbreeding depression, or produce higher quality offspring by screening arriving pollen better. A novel type of female advantage is proposed that may be important for several species of gynodioecious Caryophyllaceae. The anther smut fungus Microbotryum violaceum generally sterilizes its infected hosts but even without infection, spore deposition can negatively affect the reproduction of healthy individuals. In Gypsophila repens, flowers of hermaphrodite plants experimentally pollinated with both fungal spores and pollen produced significantly fewer fruits and seeds than those that received pollen alone, whereas female reproduction was unaffected by spore deposition. This unexplored reproductive advantage of females is probably due to the larger stigmatic surface in pistillate flowers, that allows pollen germination despite the presence of spores. Because longer stigmas may also lead to increased spore deposition, these results raise questions regarding the infection probability for each sex, possible sex-specific defense mechanisms, and the general role of pathogens in the maintenance of females in natural gynodioecious populations. PMID- 21652473 TI - Evidence of polar auxin flow in 375 million-year-old fossil wood. AB - In living woody seed plants (conifers and dicotyledons), when various obstacles such as buds and branches disrupt the axial polar auxin flow, auxin whirlpools are formed that induce the differentiation of circular tracheary elements in the secondary xylem. Identical circular patterns also occur at the same positions in the wood of the 375 million-year-old Upper Devonian fossil progymnosperm Archaeopteris. We propose that this is the earliest clear fossil evidence of polar auxin flow. Such spiral patterns do not occur in the primary xylem of the ca. 390-385 million-year-old Lower Devonian fossil land plants, fossil progymnosperms, Psilotum nudum, living ferns, and current seed plants that we examined. This discovery reveals an exciting potential for plant fossils to provide structural evidence of evolutionarily diagnostic physiological and developmental mechanisms and for the use of a combination of fossil evidence and developmental biology to characterize evolutionary patterns in terms of genetic changes in growth regulation. PMID- 21652474 TI - A comparison of the sexual systems in the trees from the Australian tropics with other tropical biomes--more monoecy but why? AB - Rainforests in tropical Australia occupy a very small, discontinuous area (<1% of the continent), yet they are floristically diverse (c. 2800 vascular species) with high endemicity. There is a distinctive Gondwanan and autochthonous element, and some of the world's ancestral links to the basal angiosperms are uniquely found here. The rainforests can be evergreen or deciduous, but there is a distinct dry season with intermittent drought years. With these characters, the evolutionary pressures on species may be very different to that experienced elsewhere. Sexual systems of 1113 tree species (83 families) from northern Australia were compared with published accounts from the paleo- and neotropics. Hermaphroditic systems dominated all tree floras, and within all floras but Australia dioecy was the most common unisexual system. In tropical Australia, however, significantly more monoecy than dioecy occurred at landscape and community levels. Incorporating phylogeny revealed that sex and fruit types are significantly clustered. The Euphorbiaceae and Sapindaceae contributed c. 50% of the monoecious taxa. Inefficient pollinators (e.g., beetles) may have favored the maintenance of monoecy at the expense of dioecy in the Australian tropics although <1% of the flora has been studied for pollinators and none of the monoecious tree species. PMID- 21652475 TI - Phenotypic plasticity, parental effects, and parental care in plants? I. An examination of spike reflectance in Plantago lanceolata (Plantaginaceae). AB - We explore the relationships among phenotypic plasticity, parental effects, and parental care in plants by presenting data from four experiments examining reflectance/color patterns in Plantago lanceolata. In three experiments, we measured spike (inflorescence) reflectance between 362 and 850 nm using a spectrophotometer with an integrating sphere. Experiments show that (1) spike reflectance changes seasonally within and outside the visible portion of the spectrum of radiant energy, (2) increasing ambient temperature causes an individual plant to produce flowering and fruiting spikes that reflect more/lighten in color (the greatest changes occur in the regions around 550 nm and between 750 and 850 nm, the visible and near-infrared regions, respectively), (3) responses are reversible, (4) genotypes within populations and populations from different latitudes differ in mean reflectance and degree of phenotypic plasticity. In a fourth experiment, we measured internal spike temperature. Darker spikes, those produced at lower temperature, got hotter than did lighter spikes in full sun. Thus, plants can partially thermoregulate reproduction and the embryonic development of their offspring. In light of a previous experiment, data suggest that thermoregulation produces adaptive parental effects and is a mechanism by which P. lanceolata provides parental care. PMID- 21652476 TI - Pollination of Australian Macrozamia cycads (Zamiaceae): effectiveness and behavior of specialist vectors in a dependent mutualism. AB - Complementary field and laboratory tests confirmed and quantified the pollination abilities of Tranes sp. weevils and Cycadothrips chadwicki thrips, specialist insects of their respective cycad hosts, Macrozamia machinii and M. lucida. No agamospermous seeds were produced when both wind and insects were excluded from female cones; and the exclusion of wind-vectored pollen alone did not eliminate seed set, because insects were able to reach the cone. Based on enclosure pollination tests, each weevil pollinates an average 26.2 ovules per cone and each thrips 2.4 ovules per cone. These pollinators visited similar numbers of ovules per cone in fluorescent dye tests that traced insect movement through cones. Fluorescent dye granules deposited by Cycadothrips were concentrated around the micropyle of each visited ovule, the site of pollen droplet release, where pollen must be deposited to achieve pollination. In contrast, Tranes weevils left dye scattered on different areas of each visited ovule, indicating that chance plays a greater role in this system. Each weevil and 25 thrips delivered 6.2 and 5.2 pollen grains, respectively, on average, to each visited ovule per cone, based on examination of dissected pollen canals. In sum, the pollination potential of 25 Cycadothrips approximates that of one Tranes weevil. PMID- 21652477 TI - Relationships within balsaminoid Ericales: a wood anatomical approach. AB - Wood samples of 49 specimens representing 31 species and 11 genera of woody balsaminoids, i.e., Balsaminaceae, Marcgraviaceae, Pellicieraceae, and Tetrameristaceae, were investigated using light microscopy and scanning electron microscopy. The wood structure of Marcgraviaceae, Pellicieraceae, and Tetrameristaceae is characterized by radial vessel multiples with simple perforation plates, alternate vessel pitting, apotracheal and paratracheal parenchyma, septate libriform fibers, and the presence of raphides in ray cells. Tetrameristaceae and Pellicieraceae are found to be closely related based on the occurrence of unilaterally compound vessel-ray pitting and multiseriate rays with long uniseriate ends. The narrow rays in Pelliciera are characteristic of this genus, but a broader concept of Tetrameristaceae including Pelliciera is favored. Within Marcgraviaceae, wide rays (more than five-seriate) are typical of the genus Marcgravia. Furthermore, there is evidence that the impact of altitude and habit plays an important role in the wood structure of this family. The wood structure of Balsaminaceae cannot be compared systematically with other balsaminoids because of their secondary woodiness. Balsaminaceae wood strongly differs due to the presence of exclusively upright ray cells in Impatiens niamniamensis, the absence of rays in Impatiens arguta, and the occurrence of several additional paedomorphic features in both species. PMID- 21652478 TI - Branching responses in Silphium integrifolium (Asteraceae) following mechanical or gall damage to apical meristems and neighbor removal. AB - Branching in plants increases plant access to light and provides pathways for regrowth following damage or loss of the apical meristem. We conducted two experiments in an eastern Kansas tallgrass prairie to determine how apical meristem loss (by clipping), apical meristem damage (by insect galling), and increased light availability affected growth, reproduction, and branching in Silphium integrifolium (Asteraceae). The first experiment compared clipping with galling. Clipping increased axillary shoot numbers, while galling increased axillary shoot lengths, reflecting different allocation responses among damage types and inhibition of branching by galls. However, total capitulum production was less in all gall/clip treatments than in intact shoots. The second experiment compared clipping with mowing the surrounding vegetation to increase light availability. Mowing increased total leaf, total capitulum, and axillary shoot length and axillary capitulum production in clipped and unclipped plants and in large vs. small shoots. The presence of the neighboring canopy, not of an intact apical meristem, was therefore the stronger limitation on leaf and capitulum production. These experiments suggest that damage and light competition affected both branching frequency and the partitioning of resources among shoots, branches, and leaves. Because Silphium's growth form is widespread, similar responses may occur in other grassland forbs. PMID- 21652479 TI - Density-dependent processes influencing the evolutionary dynamics of dispersal: a functional analysis of seed dispersal in Arabidopsis thaliana (Brassicaceae). AB - We conducted a functional analysis of seed dispersal and its plasticity in response to density in Arabidopsis thaliana by growing morphologically diverse ecotypes under high and low density and measuring seed dispersion patterns under controlled conditions. Maternal plant architectural traits such as height and branching, and fruit traits such as dehiscence and silique length influenced various measures of seed dispersion patterns, including the average dispersal distance, kurtosis of the seed dispersion pattern, and post-dispersal seed density. The density at which plants grew determined which traits influenced dispersal. A change in density would therefore change which maternal characters would be subjected to natural selection through selection on dispersal. Density mediated maternal effects on dispersal contributed to a negative correlation between parents and offspring for sibling density after dispersal, which could impede the response to selection on post-dispersal sibling density. Plant traits that influenced dispersal also influenced maternal fitness- sometimes opposing selection on dispersal and sometimes augmenting it-and the direction of the relationship sometimes depended on density. These density-dependent relationships between plant traits, dispersal, and maternal fitness can increase or reduce evolutionary constraints on dispersal, depending on the trait and depending on post-dispersal density itself. PMID- 21652480 TI - Evolutionary and ecological correlates of early seedling morphology in East African trees and shrubs. AB - Seed size and cotyledon morphology are two key juvenile traits that have evolved in response to changes in plant species life-history strategies and habitat associations. Correlations of these traits with each other and with other juvenile traits were examined for 70 species of trees and shrubs in Kibale National Park, Uganda. Although species with photosynthetic cotyledons were more abundant than in other tropical floras, both univariate and multivariate analyses supported trait associations expected from the literature. Trait values varied continuously across species, yet mean trait values differed significantly among habitat association types. Species with large seeds, large seedlings, thick storage cotyledons, slow germination, large-stature adults, and dispersal by large animals were common in forest and gap habitats. An opposite suite of traits was common in open habitats (grassland and edge). Analyses incorporating phylogeny (independent contrasts and omnibus tests) confirmed that these suites of traits showed correlated evolution. Cotyledon functional morphology yielded a strong phylogenetic signal, while seed mass was labile. Nevertheless, contingent change tests found that evolutionary change from photosynthetic to reserve cotyledons was more likely when disperser and perhaps seed size of ancestral species were already large, suggesting a strong interdependency among these traits. PMID- 21652481 TI - Theory for why dioecious plants have equal length sex chromosomes. AB - Dioecy and sex chromosomes almost certainly evolved from ancestral hermaphrodites that only possessed autosomes. There is a growing body of evidence that genes for female or male function were then epigenetically suppressed in some of these hermaphrodites, creating the first males or females and nascent sex chromosomes. The incipient sex-determining epigenetic signals, such as cytosine methylation, then drove Muller's ratchet in many animals, resulting in shorter Y chromosomes. Based on this theory of sex chromosome evolution and limited data on gametophyte gene expression, I argue that plants should be largely immune from Muller's ratchet and therefore retain their ancestral state of equal length sex chromosomes, unless they incur chromosomal rearrangements or large-scale insertions of duplicated genomes. Usually heteromorphic sex chromosomes canalize dioecy, but extensive polyploidy or polysomy can provide an escape from this canalized dioecy. This theory implies that dioecy due to heteromorphic sex chromosomes should be evolutionarily ephemeral in bryophytes and homosporous pteridophytes because of their extraordinarily high incidences of polyploidy. And, if anything, these very high incidences of polyploidy are responsible for translocation or gradual addition of beneficial genes, rather than gradual reduction in the length of a sex chromosome. PMID- 21652482 TI - The evaluation of Murray's law in Psilotum nudum (Psilotaceae), an analogue of ancestral vascular plants. AB - Previous work has shown that the xylem of seed plants follows Murray's law when conduits do not provide structural support to the plant. Here, compliance with Murray's law was tested in the stem photosynthesizer Psilotum nudum, a seedless vascular plant. Psilotum nudum was chosen because the central stele does not provide structural support, which means that Murray's law is applicable, and because its simple shoot structure resembles the earliest vascular plants. Murray's law predicts that the sum of the conduit radii cubed (Sigmar(3)) should decrease in direct proportion with the volume flow rate (Q) to maximize the hydraulic conductance per unit vascular investment. Agreement with Murray's law was assessed by estimating the transpiration rate distal to a cross-section, which should determine Q under steady state conditions, and comparing that with the Sigmar(3) of that cross-section. As predicted, regressions between the Sigmar(3) of the cross-section and Q resulted in a linear relationship with a y intercept that was not different from zero. Two more rigorous statistical tests were also unable to reject Murray's law. Psilotum nudum plants also increased their conductance per investment by having more conduits distally than proximally, which is more efficient hydraulically than equal or declining conduit numbers distally. PMID- 21652483 TI - Genetic variability is correlated with population size and reproduction in American wild-rice (Zizania palustris var. palustris, Poaceae) populations. AB - American wild-rice (Zizania palustris var. palustris) has served as a staple for indigenous North Americans for thousands of years, but has had significant habitat losses in recent centuries. We investigated genetic variability among 17 wild-rice populations in northern Wisconsin using 13 isozyme markers. We then compared these genetic patterns to differences in habitat and population characteristics and phenotypic variation in plant growth and reproduction across sites. Wild-rice's mean genetic diversity (0.15) is moderate compared to wind pollinated outcrossers but lower than the mean (0.20) reported for the Poaceae. Estimated inbreeding coefficients within populations (f) average 0.12 but vary greatly among the populations (from -0.44-0.52), suggesting heterogeneous population histories. Larger populations in larger lakes express higher levels of genetic variability and smaller inbreeding coefficients than smaller or more isolated populations. The number of panicles per plant is also higher in populations with greater genetic variability. Estimated genetic differentiation among the 17 populations (F(ST)) was high (0.30), suggesting limited gene flow among drainages. Wild-rice population size and degree of isolation have opposing effects on its genetic variability, and plant performance is positively associated with genetic variability. PMID- 21652484 TI - Seed size, dispersal, and aerodynamic constraints within the Bombacaceae. AB - The aerodynamic constraints operating on the wind-dispersed, drag-producing diaspores of several species of the tropical family Bombacaceae were examined. Kapok (the drag-promoting appendage) was best characterized as a moderately flattened hemisphere impervious to air movement. The kapok shape was not isometric: kapok planform area was proportional to the kapok mass raised to the power 0.52 rather than to the 0.67 expected from isometry. Thus, necessarily, terminal velocity rises with seed mass much faster in this group than among taxa with winged seeds. Further, we derived the optimality argument to show that the kapok mass ought to be about 50% of the total diaspore mass (seed plus kapok). While seven of eight species had a lower kapok investment than this, and none were especially close to the theoretically optimal value, nonetheless the kapok investment values were hardly draws from a random distribution. Finally, the kapok fibers of these Bombacaceae species begin to bend at a drag of about 0.005 N, and this sets an upper limit on the efficient diaspore size of about 250 mg for the seed mass. This latter value is similar to the mass of the largest seed we know of in this family. PMID- 21652485 TI - Patterns of molecular and morphological differentiation in Fagus (Fagaceae): phylogenetic implications. AB - To study phylogenetic relationships among species of Fagus, the internal transcribed spacer regions ITS1 and ITS2 of the nuclear ribosomal DNA and morphological data were analyzed. Both molecular and morphologically based phylogenies suggest that Eurasian species of Fagus subgenus Fagus are basal to the North American Fagus grandifolia. The subgenus Fagus is a paraphyletic group basal to three East Asian species forming the subgenus Engleriana. Due to a considerably large amount of DNA polymorphism, relationships among basal species of Fagus could not be entirely resolved when analyzing ITS sequences with standard methods. Morphological trees helped to resolve more clearly relationships within the subgenus Fagus. The East Asian F. hayatae is suggested to be basal to the rest of the genus. This hypothesis is further supported by distinctive patterns of nucleotide variability found for ITS regions, allowing for basic and derived types to be distinguished. The high degree of ITS polymorphism within Fagus can be explained by (1) the complex evolutionary behavior of this marker, (2) the stenoecious ecological characteristic of Fagus with respect to its continuous geographic range throughout much of the Cenozoic, and (3) the absence of major radiations into further habitats as occurred in other Fagaceae. PMID- 21652486 TI - Evolution of Cyrtandra (Gesneriaceae) in the Pacific Ocean: the origin of a supertramp clade. AB - Cyrtandra comprises at least 600 species distributed throughout Malesia, where it is known for many local endemics and in Polynesia and Micronesia, where it is present on most island groups, and is among the most successfully dispersing genera of the Pacific. To ascertain the origin of the oceanic Pacific island species of Cyrtandra, we sequenced the internal transcribed spacers of nuclear ribosomal DNA of samples from throughout its geographical range. Because all oceanic Pacific island species form a well-supported clade, these species apparently result from a single initial colonization into the Pacific, possibly by a species from the eastern rim of SE Asia via a NW-to-SE stepping stone migration. Hawaiian species form a monophyletic group, probably as a result of a single colonization. The Pacific island clade of Cyrtandra dispersed across huge distances, in contrast to the apparent localization of the SE Asian clades. Although highly vagile, the Pacific clade is restricted to oceanic islands. Individual species are often endemic to a single island, characteristic of the "supertramp" life form sensu Diamond (1974, Science 184: 803-806). The evolution of fleshy fruit within Cyrtandra provided an adaptation for colonization throughout the oceanic Pacific via bird dispersal from a single common ancestor. PMID- 21652487 TI - Leave it to the leaves: a molecular phylogenetic study of Malaxideae (Epidendroideae, Orchidaceae). AB - Nuclear ITS and plastid matK sequences were collected for 71 taxa of Malaxideae (Orchidaceae). Resulting cladograms are highly resolved and well supported by jackknife analyses. These indicate that the traditional classification system of the tribe using characters primarily related to floral morphology does not reflect the evolutionary history of these taxa. Rather, the tribe is split into two major clades: one of terrestrial species and another of epiphytes. Within the epiphytic clade, taxa with laterally compressed leaves (Oberonia) are monophyletic, whereas the remaining taxa (Liparis pro parte) have elongate conduplicate leaves and form a paraphyletic grade of at least two additional monophyletic lineages. Within the terrestrial clade, taxa with plicate leaves (Liparis p.p. and Malaxis p.p.) clearly separate from taxa with conduplicate leaves (Liparis p.p. and Malaxis p.p.). Although further taxon sampling should take place before nomenclature is changed, it seems evident that Malaxideae will need to be divided into at least seven genera. Furthermore, the transition from epiphytic to terrestrial habit is documented to have occurred only once in Malaxideae, and the value of vegetative over reproductive features in classifying some groups of orchids is again demonstrated. PMID- 21652488 TI - Species relationships in the genus Vasconcellea (Caricaceae) based on molecular and morphological evidence. AB - Validity of the taxa currently recognized in the genus Vasconcellea was analyzed by investigating morphological and molecular data from 105 specimens of this genus and six specimens of the related genus Carica. Taxon identification of these specimens was compared with clustering in two phenetic dendrograms generated with 36 morphological characters and 254 amplified fragment length polymorphic (AFLP) markers. Moreover, cytoplasmic haplotypes were assessed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) of one mitochondrial and two chloroplast DNA regions. Results show that the morphological data set, containing mainly vegetative characteristics, merely reveals external resemblance between specimens, which is not directly associated with genetic relationships and taxon validity. Phenotypic plasticity and intercompatibility between several species are likely to confuse morphological delimitation of the taxa. Based on the results of our study, several specimens that could not be identified with the currently used identification key (1) could be attributed to a known taxon, which should be extended to include a higher range of morphological variability or (2) could be hypothesized to be of hybrid origin. Because of the high intraspecific variation within V. microcarpa and V. * heilbornii, revision of these taxa is recommended. PMID- 21652489 TI - The {beta}-amylase genes of grasses and a phylogenetic analysis of the Triticeae (Poaceae). AB - There are two forms of beta-amylase in the Triticeae crop plants wheat, barley, and rye: an endosperm-specific form encoded by two or three closely linked genes, and a tissue-ubiquitous form encoded by a single gene. Both rice and corn have one ubiquitously expressed form encoded by a single gene. This study focuses on two phylogenetic analyses of beta-amylase gene sequences. First, a phylogenetic analysis of coding sequences from wheat, barley, rye, rice, and corn was expected to clarify the relationship between the endosperm-specific and tissue-ubiquitous forms of the protein. Instead, it illustrates possible effects of distant outgroups, based on conflicting patterns of character state variation consistent with different root positions. Next, a broad sample of the monogenomic Triticeae was included in a phylogenetic analysis based on sequences from a portion of the tissue-ubiquitous beta-amylase gene. The results were compared to existing Triticeae gene trees, among which extensive conflict had been noted in the past. One additional gene tree has not completely clarified the complexity of the group, but has shed additional light on reticulate phylogenetic patterns within the tribe, including relationships involving Eremopyrum, Thinopyrum, and the Triticum/Aegilops group. PMID- 21652490 TI - The Physiology undergraduate major in the University of Arizona College of Medicine: past, present, and future. AB - The American Physiological Society (APS) and APS Council encourage the teaching of physiology at the undergraduate, graduate, and medical school levels to support the continued prominence of this area of science. One area identified by the APS Council that is of particular importance for the development of future physiologists (the "physiology pipeline") is the teaching of physiology and physiology-related topics at the undergraduate level. In this article, we describe the historical development and implementation of an undergraduate program offered through the Department of Physiology, a basic science department in the College of Medicine at the University of Arizona, culminating in a Bachelor of Science in Health Sciences degree with a major in Physiology. Moreover, we discuss the current Physiology curriculum offered at our institution and explain how this program prepares our students for successful entry into a variety of postbaccalaureate professional programs, including medical school and numerous other programs in health professions, and in graduate study in the Masters and Doctoral programs in biomedical sciences. Finally, we cover the considerable challenges that we have faced, and continue to face, in developing and sustaining a successful physiology undergraduate major in a college of medicine. We hope that the information provided on the Physiology major offered by the Department of Physiology in the College of Medicine at the University of Arizona will be helpful for individuals at other institutions who may be contemplating the development and implementation of an undergraduate program in Physiology. PMID- 21652491 TI - The work by Giulio Ceradini in explaining the mechanism of semilunar cardiac valve function. AB - Using an excised pig heart preparation with tubes, a manometer, and a visualizing apparatus, Giulio Ceradini, an Italian physiologist working in the years of 1871 1872 in Carl Ludwig's famous laboratory in Leipzig, Germany, illustrated the mechanism of closure of the semilunar valves. He was the first to conceive that the closure of the heart valves depends not on a static back pressure nor upon eddies but is primarily the consequence of the decelerated systolic efflux. This pioneer research of Ceradini was first published in German in 1872 (4). The purpose of the present report is to revisit Ceradini's pioneering experiments and his interpretation of heart valve closure, which remains as true as it was in 1872. PMID- 21652492 TI - Teaching the renal tubular reabsorption of glucose using two classic papers by Shannon et al. AB - Most of the transport along the nephron uses membrane proteins and exhibits the three characteristics of mediated transport: saturation, specificity, and competition. Glucose reabsorption in the nephron is an excellent example of the consequences of saturation. Two classic papers by James A. Shannon and colleagues clearly show the ability of the kidney in transporting glucose and its saturation process, providing students with examples of the handling of glucose by the kidney. In addition, these articles demonstrate how stable and reproducible is the transport maximum of glucose in the proximal tubule under different experimental conditions. One key figure from each classic paper can be used to give students insight into how glucose transport becomes saturated, resulting in the excretion of glucose in urine, and will also give students a clear example of how careful experimentation and a clear interest in renal physiology led Shannon and colleagues to advance the field. PMID- 21652493 TI - Is virtual reality a useful tool in the teaching of physiology? AB - This opinion statement points out some of the considerations and pitfalls in using virtual reality computer programs in the teaching of life sciences. Emphasis is placed on the possibility of such programs leading to reductionist thinking including how reductionist thinking could foster the formation of misconceptions. Negative feedback is used as the classic example of reductionist thinking in physiological regulation, including how classic negative feedback is inconsistent with evidence of complexity in living systems. This statement concludes that virtual reality can be a useful tool in the teaching of physiology so long as the complexity of living systems is taken into account. PMID- 21652494 TI - Academic genealogy and direct calorimetry: a personal account. AB - Each of us as a scientist has an academic legacy that consists of our mentors and their mentors continuing back for many generations. Here, I describe two genealogies of my own: one through my PhD advisor, H. T. (Ted) Hammel, and the other through my postdoctoral mentor, Knut Schmidt-Nielsen. Each of these pathways includes distingished scientists who were all major figures in their day. The striking aspect, however, is that of the 14 individuals discussed, including myself, 10 individuals used the technique of direct calorimetry to study metabolic heat production in humans or other animals. Indeed, the patriarchs of my PhD genealogy, Antoine Lavoisier and Pierre Simon Laplace, were the inventors of this technique and the first to use it in animal studies. Brief summaries of the major accomplishments of each my scientific ancestors are given followed by a discussion of the variety of calorimeters and the scientific studies in which they were used. Finally, readers are encouraged to explore their own academic legacies as a way of honoring those who prepared the way for us. PMID- 21652495 TI - Statistics: all together now, one step at a time. PMID- 21652496 TI - Show the data, don't conceal them. AB - Current standards of data presentation and analysis in biological journals often fall short of ideal. This is the first of a planned series of short articles, to be published in a number of journals, aiming to highlight the principles of clear data presentation and appropriate statistical analysis. This article considers the methods used to show data, in particular the value of the dot plot, and methods to summarise the distribution of values. The uses of measures such as standard deviation, standard error of the mean, and confidence intervals are contrasted. PMID- 21652497 TI - Data interpretation: using probability. PMID- 21652498 TI - Resources and practices to help graduate students and postdoctoral fellows write statements of teaching philosophy. AB - Graduate students and postdoctoral fellows currently encounter requests for a statement of teaching philosophy in at least half of academic job announcements in the United States. A systematic process for the development of a teaching statement is required that integrates multiple sources of support, informs writers of the document's purpose and audience, helps writers produce thoughtful statements, and encourages meaningful reflection on teaching and learning. This article for faculty mentors and instructional consultants synthesizes practices for mentoring graduate students, postdoctoral fellows, and junior faculty members as they prepare statements of teaching philosophy. We review background information on purposes and audiences, provide writing resources, and synthesize empirical research on the use of teaching statements in academic job searches. In addition, we integrate these resources into mentoring processes that have helped graduate students in a Health Sciences Pedagogy course to collaboratively and critically examine and write about their teaching. This summary is intended for faculty mentors and instructional consultants who want to refine current resources or establish new mentoring programs. This guide also may be useful to graduate students, postdoctoral fellows, and junior faculty members, especially those who lack mentoring or who seek additional resources, as they consider the many facets of effective teaching. PMID- 21652499 TI - Medical students' evaluation of physiology learning environments in two Nigerian medical schools. AB - The expansion of biomedical knowledge and the pursuit of more meaningful learning have led to world-wide evidence-based innovative changes in medical education and curricula. The recent emphasis on problem-based learning (PBL) and student centred learning environments are, however, not being implemented in Nigerian medical schools. Traditional didactic lectures thus predominate, and learning is further constrained by funding gaps, poor infrastructure, and increasing class sizes. We reviewed medical students' perceptions of their exposed learning environment to determine preferences, shortcomings, and prescriptions for improvements. The results confirm declining interest in didactic lectures and practical sessions with preferences for peer-tutored discussion classes, which were considered more interactive and interesting. This study recommends more emphasis on student-centered learning with alternatives to passive lecture formats and repetitive cookbook practical sessions. The institutionalization of student feedback processes in Nigerian medical schools is also highly recommended. PMID- 21652500 TI - Teaching cardiovascular physiology with equivalent electronic circuits in a practically oriented teaching module. AB - Here, we report on a new tool for teaching cardiovascular physiology and pathophysiology that promotes qualitative as well as quantitative thinking about time-dependent physiological phenomena. Quantification of steady and presteady state (transient) cardiovascular phenomena is traditionally done by differential equations, but this is time consuming and unsuitable for most undergraduate medical students. As a result, quantitative thinking about time-dependent physiological phenomena is often not extensively dealt with in an undergraduate physiological course. However, basic concepts of steady and presteady state can be explained with relative simplicity, without the introduction of differential equation, with equivalent electronic circuits (EECs). We introduced undergraduate medical students to the concept of simulating cardiovascular phenomena with EECs. EEC simulations facilitate the understanding of simple or complex time-dependent cardiovascular physiological phenomena by stressing the analogies between EECs and physiological processes. Student perceptions on using EEC to simulate, study, and understand cardiovascular phenomena were documented over a 9-yr period, and the impact of the course on the students' knowledge of selected basic facts and concepts in cardiovascular physiology was evaluated over a 3-yr period. We conclude that EECs are a valuable tool for teaching cardiovascular physiology concepts and that EECs promote active learning. PMID- 21652501 TI - Student-centered physiology in high schools. AB - Student test score percentages in the Physiology and Disease (PAD) course at the Illinois Mathematics and Science Academy, a high school for students of the state of Illinois gifted in math and science, were studied over a period of 5 yr. Inquiry-based laboratory experiences in the course were slowly converted during this time from partly student centered and mostly teacher led to completely student centered beginning in fall 2008. Quarterly analysis of the effect of increased inquiry upon average weekly report submissions of 400 students over 4 yr showed a significant improvement in submission (P < 0.0002) between quarters 1 and 2 and also improvement from year to year between the academic years of 2006/2007 and 2009/2010 (P < 0.0001). A comparison of student test score percentages from 346 students in 4 major tests showed a significant increase (P = 0.0125) beginning in the academic year of 2008/2009, when the conversion of all laboratories in the course from partly student centered to completely student centered was concluded compared with scores over the 2 yr from 2006/2007 up to this point. There was also a significant difference (P < 00001) in test score percentages between the individual tests themselves over the 4 yr studied. Taking the study a step further, the 35 students registered in the two PAD classes offered in the fall 2010 semester were divided in each of their classes into student-centered and teacher-centered groups, with the former designing all their experiments and the latter following instructions from the teacher. Student score percentages on specific test questions from the four major tests that focused on transfer of student understanding were compared between these two groups. There was a significant improvement (P = 0.012) when students designed their own laboratories (student-centered group) compared with doing what the teacher asked (teacher-centered group). There was also a significant difference between these student score percentages among the individual tests (P < 0.0001). These data suggest that an increase in student-centered experiments may lead to a corresponding increase in test performance on questions involving student transfer. PMID- 21652502 TI - Monitoring physiology trainee needs to focus professional society responses: the APS Trainee Needs Surveys. AB - In 2004 and 2007, the American Physiological Society (APS) Trainee Advisory Committee (TAC) conducted surveys of graduate students, postdoctoral fellows, and new investigators in physiology to identify topics and issues important to those trainees. Two major trends emerged from the data. First, trainees in 2007 expressed somewhat greater interest in professional development information than did those in 2004. Second, needs expressed by trainees in both years were closely related to their specific career development stage. Survey findings guided the TAC and other APS committees and groups to focus their efforts toward the issues that were of the greatest interest to trainees. It also led to improved communication with trainees and increased involvement of trainees in APS governance. PMID- 21652503 TI - Peer assessment in large undergraduate classes: an evaluation of a procedure for marking laboratory reports and a review of related practices. AB - This study provides evidence that peer marking can be a reliable tool for assessing laboratory reports in large cohorts. It was conducted over a 4-yr period with first-year undergraduates (~180 students/cohort) taking a mammalian physiology course, but the procedure adopted would be applicable to any other laboratory-based discipline. The process was found to be efficient in staff time, enabling a summative practical report to be marked in <1 h (<5% of the time that had previously been required for staff marking), facilitating rapid feedback to students on their performance. When samples of the peer-assessed reports were marked by a single member of staff, there was excellent correlation between peer and staff marks (r = 0.96-0.98), although peer-awarded marks exceeded staff marks by an average of 2.5-3.0%. The validity of peer marking was independent of both the sex of the marker and the staff score awarded to the marker for the same piece of work. Feedback from students was largely positive; they reported that the procedure adopted was effective in increasing their understanding of the underlying physiology and contributed to their understanding of best practice in presenting a laboratory report. Seventy percent of students agreed that it was acceptable for peer assessment to contribute a small (up to 5%) component of the overall mark for the course. The results are discussed in relation to other reports of peer marking, particularly when used to assess an academic product or process in a scientific discipline. PMID- 21652504 TI - The zebrafish brain in research and teaching: a simple in vivo and in vitro model for the study of spontaneous neural activity. AB - Recently, the zebrafish (Danio rerio) has been established as a key animal model in neuroscience. Behavioral, genetic, and immunohistochemical techniques have been used to describe the connectivity of diverse neural circuits. However, few studies have used zebrafish to understand the function of cerebral structures or to study neural circuits. Information about the techniques used to obtain a workable preparation is not readily available. Here, we describe a complete protocol for obtaining in vitro and in vivo zebrafish brain preparations. In addition, we performed extracellular recordings in the whole brain, brain slices, and immobilized nonanesthetized larval zebrafish to evaluate the viability of the tissue. Each type of preparation can be used to detect spontaneous activity, to determine patterns of activity in specific brain areas with unknown functions, or to assess the functional roles of different neuronal groups during brain development in zebrafish. The technique described offers a guide that will provide innovative and broad opportunities to beginner students and researchers who are interested in the functional analysis of neuronal activity, plasticity, and neural development in the zebrafish brain. PMID- 21652505 TI - Undergraduate student attitudes and perceptions toward low- and high-level inquiry exercise physiology teaching laboratory experiences. AB - The purpose of this investigation was to compare student attitudes toward two different science laboratory learning experiences, specifically, traditional, cookbook-style, low-inquiry level (LL) activities and a high-inquiry level (HL) investigative project. In addition, we sought to measure and compare students' science-related attitudes and attitudes toward science. Students participated in 5 wk of LL activities followed by a 5-wk HL project. An open-ended survey administered at the end of the semester and analyzed by a chi(2)-test revealed that 1) students enjoyed the HL project more than the LL activities, 2) high level inquiry did not have a negative effect on student motivation in the laboratory, and 3) students perceived that they learned more about physiology principles with the LL activities. Most students liked the HL project, particularly the independence, responsibility, freedom, and personal relevance. Of the students who did not like the HL project, many reported being uncomfortable with the lack of structure and guidance. Many students gained a more positive and realistic view about scientific research, often reporting an increased respect for science. Likert scale surveys administered before and after each 5-wk period showed no significant changes in student attitudes to scientific inquiry, adoption of scientific attitudes, enjoyment of science lessons, or motivation toward science when the three time points were compared. The findings in this study have helped to provide suggestions for better implementation of HL projects in the future. PMID- 21652506 TI - Cross-disciplinary thermoregulation and sweat analysis laboratory experiences for undergraduate Chemistry and Exercise Science students. AB - Cross-disciplinary (CD) learning experiences benefit student understanding of concepts and curriculum by offering opportunities to explore topics from the perspectives of alternate fields of study. This report involves a qualitative evaluation of CD health sciences undergraduate laboratory experiences in which concepts and students from two distinct disciplines [chemistry (CHEM) and exercise physiology (EPHE)] combined to study exercise thermoregulation and sweat analysis. Twenty-eight senior BSc Kinesiology (EPHE) students and 42 senior BSc CHEM students participated as part of their mutually exclusive, respective courses. The effectiveness of this laboratory environment was evaluated qualitatively using written comments collected from all students as well as from formal focus groups conducted after the CD laboratory with a representative cohort from each class (n = 16 CHEM students and 9 EPHE students). An open coding strategy was used to analyze the data from written feedback and focus group transcripts. Coding topics were generated and used to develop five themes found to be consistent for both groups of students. These themes reflected the common student perceptions that the CD experience was valuable and that students enjoyed being able to apply academic concepts to practical situations as well as the opportunity to interact with students from another discipline of study. However, students also reported some challenges throughout this experience that stemmed from the combination of laboratory groups from different disciplines with limited modification to the design of the original, pre-CD, learning environments. The results indicate that this laboratory created an effective learning opportunity that fostered student interest and enthusiasm for learning. The findings also provide information that could inform subsequent design and implementation of similar CD experiences to enhance engagement of all students and improve instructor efficacy. PMID- 21652507 TI - Molecular motors: how to make models that can be used to convey the concept of molecular ratchets and thermal capture. AB - A wide variety of cellular processes use molecular motors, including processive motors that move along some form of track (e.g., myosin with actin, kinesin or dynein with tubulin) and polymerases that move along a template (e.g., DNA and RNA polymerases, ribosomes). In trying to understand how these molecular motors actually move, many apply their understanding of how man-made motors work: the latter use some form of energy to exert a force or torque on its load. However, quite a different mechanism has been proposed to possibly account for the movement of molecular motors. Rather than hydrolyzing ATP to push or pull their load, they might use their own thermal vibrational energy as well as that of their load and their environment to move the load, capturing those movements that occur along a desired vector or axis and resisting others; ATP hydrolysis is required to make backward movements impossible. This intriguing thermal capture or Brownian ratchet model is relatively more difficult to convey to students. In this report, we describe several teaching aids that are very easily constructed using widely available household materials to convey the concept of a molecular ratchet. PMID- 21652508 TI - The case of thyroid hormones: how to learn physiology by solving a detective case. AB - Thyroid diseases are prevalent among endocrine disorders, and careful evaluation of patients' symptoms is a very important part in their diagnosis. Developing new pedagogical strategies, such as problem-based learning (PBL), is extremely important to stimulate and encourage medical and biomedical students to learn thyroid physiology and identify the signs and symptoms of thyroid dysfunction. The present study aimed to create a new pedagogical approach to build deep knowledge about hypo-/hyperthyroidism by proposing a hands-on activity based on a detective case, using alternative materials in place of laboratory animals. After receiving a description of a criminal story involving changes in thyroid hormone economy, students collected data from clues, such as body weight, mesenteric vascularization, visceral fat, heart and thyroid size, heart rate, and thyroid stimulating hormone serum concentration to solve the case. Nevertheless, there was one missing clue for each panel of data. Four different materials were proposed to perform the same practical lesson. Animals, pictures, small stuffed toy rats, and illustrations were all effective to promote learning, and the detective case context was considered by students as inviting and stimulating. The activity can be easily performed independently of the institution's purchasing power. The practical lesson stimulated the scientific method of data collection and organization, discussion, and review of thyroid hormone actions to solve the case. Hence, this activity provides a new strategy and alternative materials to teach without animal euthanization. PMID- 21652509 TI - Human clay models versus cat dissection: how the similarity between the classroom and the exam affects student performance. AB - This study examined the effect of different anatomic representations on student learning in a human anatomy class studying the muscular system. Specifically, we examined the efficacy of using dissected cats (with and without handouts) compared with clay sculpting of human structures. Ten undergraduate laboratory sections were assigned to three treatment groups: cat dissection only, cat dissection with handouts, and human clay sculpting with handouts. Exams included higher-order questions that presented novel anatomic images and scenarios that the students did not practice in class. The higher-order anatomy exam questions varied the degree to which students in the different treatments had to transform the anatomic representation studied during laboratory activities to match the representation used in the exam questions. In this respect, exam questions manipulated the similarity between the surface features of the anatomic representations used in the classroom versus the exam. When identifying anatomic structures presented in a photograph or diagram, student performance improved significantly when transformation demands decreased, i.e., students in the human clay sculpting treatment group performed best on human anatomy questions and students in the cat dissection treatment group performed better on cat anatomy questions (independent of the use of handouts). There were similar, but nonsignificant, trends when students were asked functional anatomy questions presented in human and cat contexts. On survey questions designed to measure student attitudes about dissection versus nonanimal alternatives, students typically preferred the method used in their treatment group, suggesting that student preference is too fluid to factor into curricular decisions. When designing curricula, instructors must choose anatomic representations that support their course goals. Human representations are most effective when teaching the human muscular system. PMID- 21652510 TI - Trial of integrated laboratory practice. AB - In most laboratory practices for students in medical schools, a laboratory guidebook is given to the students, in which the procedures are precisely described. The students merely follow the guidebook without thinking deeply, which spoils the students and does not entice them to think creatively. Problem based learning (PBL) could be one means for the students themselves to actively learn, find problems, and resolve them. Such a learning attitude nurtures medical students with lifelong learning as healthcare professionals. We merged PBL and laboratory practices to promote deep thinking habits and developed an integrated laboratory practice. We gave a case sheet to groups of students from several schools. The students raised hypotheses after vivid discussion, designed experimental protocols, and performed the experiments. If the results did not support or disproved the hypothesis, the students set up another hypothesis followed by experiments, lasting for 4 or 5 consecutive days. These procedures are quite similar to those of professional researchers. The main impact achieved was the fact that the students developed the experimental design by themselves, for the first time in their college lives. All students enjoyed the laboratory practice, which they had never experienced before. This is an antidote to the guidebook-navigated traditional laboratory practice, which disappoints many students. As educators in basic medical sciences stand on the edge in terms of educating the next generation, there is a need to provide a strong foundation for medical students to design and perform scientific experiments. The integrated laboratory practice may provide the solution. PMID- 21652511 TI - Active learning by play dough modeling in the medical profession. PMID- 21652512 TI - "Pioneers in physiology": a project by first-year medical graduates. PMID- 21652513 TI - From dyad to dialogue: language and the early relationship in American psychoanalytic theory. AB - The centrality of language for a Freudian theory of mind and treatment has not been retained by most post-Freudian theorists. American writers have turned to academic developmental research on mother-child interactions to depict the preoedipal period as preverbal, presymbolic, nonconscious. This view presents the early relationship as developing in linear stages in which visual observational data (e.g., contingent behavior action patterns between two persons) are privileged over aural-oral data of communicational exchanges. An alternative view is presented that redefines the earliest relationship in terms of communicational exchanges, mediation, and dialogue. The claim is that understanding the nature of mediated communication keeps language central to psychoanalysis and reestablishes an intrapsychic dimension in the concept of relationship that is lost when relationship is reduced to behavioral patterns. PMID- 21652514 TI - A trio of microRNAs that control Toll-like receptor signalling. AB - Toll-like receptors (TLRs) in the host recognize conserved microbial products and defend against pathogenic attack by initiating an immune response via signalling pathways that lead to an increase in immune and inflammatory gene expression. TLR signalling must be stringently regulated in order to ensure sufficient clearance of pathogens and a timely return to homeostasis after infection. MicroRNAs (miRNAs) are a newly discovered class of gene regulators which bind to the 3' untranslated region of target mRNA and direct their post-transcriptional repression. They are global regulators potentially controlling up to 30% of the human genome. Several miRNAs have been shown to be up-regulated in response to TLR ligands, and many directly target components of the TLR signalling system, revealing a whole extra level of control of TLR signalling which is being extensively researched. The dysregulation of miRNAs may be involved in many inflammatory diseases and cancers and thus merits further investigation. In this review, we focus in on a trio of miRNA which have proven to be key in many immune and inflammatory pathways; miR-155, miR-21 and miR-146. PMID- 21652515 TI - CD4+CD25+FoxP3+ regulatory T cells enhance the allogeneic activity of endothelial specific CD8+/CD28-CTL. AB - Numerous data indicate that CD4+CD25+FoxP3+ regulatory T cells (Treg cells) can attenuate alloresponses of conventional T lymphocytes against professional antigen-presenting cells and thus qualify for clinical use in various transplant settings. However, it is unknown whether Treg cells also influence T cell endothelial cell interactions. CD8+ PBMC (CD8+ PBMC, CTL) from healthy human donors were stimulated for 7 days with an allogeneic microvascular endothelial cell line (CDC/EU. HMEC-1, an immortalized human microvascular endothelial cell line, further referred to as HMEC) and additional endothelial cell types and analysed for their lytic activity against these target cells in the presence or absence of Treg cells. Addition of Treg cells (1:1:1) to the CTL/HMEC co-cultures in the efferent immune phase (day -1 prior to the assay) led to an increased cytotoxicity against HMEC. In contrast, Treg cells alone did not lyse HMEC. Treg cell-mediated enhancement of CTL activity was endothelial cell specific since lysis of HLA-matched Epstein-Barr virus-transformed B lymphoblastoid cells (B LCL) was not influenced by the addition of Treg cells. Further analysis of CD28 positive and CD28-negative CTL sub-populations revealed that only the CD28 negative CTL showed an increased activity against HMEC after Treg cell co culture. Although there is no doubt about the potential therapeutic efficacy of Treg cells to ameliorate outcome of allogeneic transplants, the endothelium might require additional protective interventions to prevent endothelial cell type specific alloreactivity. PMID- 21652517 TI - The effect of daily weather conditions on myocardial infarction incidence in a subarctic population: the Tromso Study 1974-2004. AB - BACKGROUND: Meteorological factors like cold temperatures and heavy snowfalls have been reported to increase myocardial infarction (MI) incidence, but there are inconsistencies in results as well as in methodology in previous studies. The objective of this study was to examine the impact of meteorological factors on incidence of MI in a population-based study in Tromso, Norway (69 degrees 39'N). METHODS: A total of 32110 participants from the Tromso Study enrolled between 1974 and 2001 were followed throughout 2004. Each incident case of MI was validated by the review of medical records and death certificates. Meteorological data from the Tromso Weather Station were collected from the Norwegian Meteorological Institute database. Poisson regression models were applied to analyse the impact of meteorological factors on MI incidence. All analyses were stratified by sex and age. RESULTS: A total of 1882 first-ever MIs were registered. The main finding was an increase in MI incidence among persons older than 65 years with decreasing temperatures (p=0.016) and increasing snowfall (p=0.030). When comparing the lower and upper limits of the temperature distribution (-10 degrees C with 20 degrees C), the MI risk increased by 47% (RR=1.47, 95% CI 1.09 to 2.13). Comparing limits of the snowfall distribution (10 with 0 mm), the MI risk increased by 44% (RR=1.44, 95% CI 1.07 to 1.94). CONCLUSIONS: In this subarctic population, MI incidence was little affected by the weather, probably due to behavioural protection. However, cold weather and heavy snowfall may be associated with increased risk of MI among older people. PMID- 21652516 TI - Coupling presentation of MHC class I peptides to constitutive activation of antigen-presenting cells through the product of a single gene. AB - Priming of naive CD8 T cells by dendritic cells (DCs) entails both effective antigen presentation on MHC class I products and co-stimulatory signaling. Their optimal coupling is a major goal in the development of CTL-inducing vaccines. We recently reported that a membranal derivative of the invariant MHC-I light chain, beta(2)-microglobulin (beta(2)m), markedly stabilizes MHC-I molecules and can serve as a universal platform for exceptional presentation of genetically linked peptides. To test whether it is possible to equip the resulting MHC-I complexes with an inherent ability to activate antigen-presenting cells, we engrafted the intracellular Toll/IL-1 receptor domain of mouse Toll-like receptor (TLR) 4 or TLR2 onto the peptide-beta(2)m scaffold. We evaluated the level of peptide presentation and status of cell activation conferred by such constructs in stably transfected mouse RAW264.7 macrophages and mRNA-transfected mouse DC2.4 DCs. We show that the encoded peptide-beta(2)m-TLR polypeptides are expressed at the cell surface, pair with endogenous heavy chains, stabilize MHC-I products, prompt efficient peptide-specific T-cell recognition and confer a constitutively activated phenotype on the transfected cells, as judged by the up-regulation of pro-inflammatory genes and surface co-stimulatory molecules. Our results provide evidence that the product of a single recombinant gene can couple MHC peptide presentation to TLR-mediated signaling and offer a safe, economical and highly versatile modality for a novel category of genetic CTL-inducing vaccines. PMID- 21652518 TI - Damned if you do, damned if you don't: subgroup analysis and equity. AB - The final report from the WHO Commission on the social determinants of health recently noted: 'For policy, however important an ethical imperative, values alone are insufficient. There needs to be evidence on what can be done and what is likely to work in practice to improve health and reduce health inequities.' This is challenging, because understanding how to reduce health inequities between the poorest and better-off members of society may require a greater use of subgroup analysis to explore the differential effects of public health interventions. However, while this may produce evidence that is more policy relevant, the requisite subgroup analyses are often seen as tantamount to statistical malpractice. This paper considers some of the methodological problems with subgroup analysis, and its applicability to considerations of equity, using both clinical and public health examples. Finally, it suggests how policy needs for information on subgroups can be met while maintaining rigour. PMID- 21652519 TI - Does living in a food insecure household impact on the diets and body composition of young children? Findings from the Southampton Women's Survey. AB - BACKGROUND: Little is known about food insecurity in the UK. The aims of this study were to assess the prevalence and factors associated with food insecurity in a UK cohort and to examine whether the diets, reported health and anthropometry of young food insecure children differed from those of other children. METHODS: The Southampton Women's Survey is a prospective cohort study in which detailed information about the diets, lifestyle and body composition of 3000 women was collected before and during pregnancy. Between 2002 and 2006, 1618 families were followed up when the child was 3 years old. Food insecurity was determined using the Household Food Security Scale. The child's height and weight were measured; diet was assessed by food frequency questionnaire. RESULTS: 4.6% of the households were food insecure. Food insecurity was more common in families where the mothers were younger, smokers, of lower social class, in receipt of financial benefits and who had a higher deprivation score (all p<0.05). In comparison with other 3-year-old children, those living in food insecure households were likely to have worse parent-reported health and to have a diet of poorer quality, characterised by greater consumption of white bread, processed meat and chips, and by a lower consumption of vegetables (all p<0.05). They did not differ in height or body mass index. CONCLUSIONS: Our data suggest that there are significant numbers of food insecure families in the UK. The poorer reported health and diets of young food insecure children have important implications for their development and lifelong health. PMID- 21652520 TI - Socioeconomic inequalities in circulatory and all-cause mortality after retirement: the impact of mid-life income and old-age pension. Evidence from the Uppsala Birth Cohort Study. AB - BACKGROUND: The aim of this study was to explore the impact of mid-life income and old-age pensions on the risk of mortality in later life. Furthermore, the study explored whether income inequalities in old-age mortality can be explained by differences in early childhood development, social class during childhood, education or marital status. METHODS: The study sample comprises all individuals born at Uppsala Academic Hospital during the period 1915-1924 who had retired but not died or emigrated by 1991 (n=4156). Information on social and biological conditions was retrieved from national registries. RESULTS: The results show that income during mid-life and income during retirement were associated with old-age mortality. However, mutually adjusted models showed that income in mid-life was more important for women's late-life mortality and that income during retirement was more important for men's late-life mortality. Furthermore, differences in education and marital status seemed to explain a substantial part of income inequalities in late-life mortality. CONCLUSIONS: It is unlikely that egalitarian social policies aimed at older populations can eradicate health inequalities accumulated over the life course. However, retirement income appears to have an effect on late-life mortality that is independent of the effect of income in mid life, suggesting that egalitarian pension schemes could affect health inequalities in later life or, at the very least, slow down further accumulation of inequalities. PMID- 21652521 TI - To RCT or not to RCT: deciding when 'more evidence is needed' for public health policy and practice. AB - BACKGROUND: Amid the calls for 'more public health evidence', we also need simple understandable methods of determining when more research really is needed. This paper describes a simple decision aid to help policymakers, researchers and other decision makers assess the potential 'information value' of a new public health randomised controlled trial. METHODS: The authors developed a flow chart to help make explicit (1) the user's information needs, (2) the intended use of the new information that the study will produce, (3) the added value of the evidence to be derived from the new study and (4) the levels of precision, bias and generalisability required by the user. RESULTS: The flow chart is briefly illustrated, first in generic form and then in a worked example, showing how it may be used in deciding whether a new study should be commissioned to evaluate the health impact of allowing motorcycles to use bus lanes in London. CONCLUSIONS: In this paper, the authors have presented a flow chart for enacting an informal 'Value-of-Information'-like approach to deciding when a new public health evaluation is needed. The authors do not suggest that the flow chart approach is technically the equivalent of Value-of-Information methods. Nonetheless, it represents a valuable perspective and process to adopt, and this structured approach will be more revealing than an unstructured thought experiment as the basis for decisions about a new study. To aid in its development as an effective tool, we invite users from a variety of perspectives and contexts to review it, to use it in practice and to send us their comments. PMID- 21652522 TI - Outcome reporting bias in evaluations of public health interventions: evidence of impact and the potential role of a study register. AB - BACKGROUND: Systematic reviews of the effectiveness of interventions are increasingly used to inform recommendations for public health policy and practice, but outcome reporting bias is rarely assessed. METHODS: Studies excluded at full-text stage screening for a systematic review of a public health intervention were assessed for evidence of study exclusion resulting from non reporting of relevant outcomes. Studies included in the review were assessed for evidence of outcome reporting bias and the impact that this had on the evidence synthesised using a formal tool (Outcome Reporting Bias in Trials (ORBIT)). RESULTS: None of the reports excluded at full-text stage were excluded because of non-reporting of relevant outcomes. Of the 26 included papers, six were identified as having evidence of missing or incompletely reported outcomes, with 64% of unreported or incompletely reported outcomes identified as to leading to a high risk of bias according to the ORBIT tool. Where there was evidence of the effectiveness of interventions before an assessment of outcome reporting bias was undertaken, identifying possible instances of outcome reporting bias generally led to a reduction in the strength of evidence for the effectiveness of the interventions. CONCLUSION: The findings from this single evaluation provide empirical data to support the call for a prospective public health interventions study registry to aid the identification of unreported or incompletely reported outcomes. Critical appraisal tools can also be used to identify incompletely reported outcomes, but a tool such as ORBIT requires development to be suitable for public health intervention evaluations. PMID- 21652523 TI - The balance between mutators and nonmutators in asexual populations. AB - Mutator alleles, which elevate an individual's mutation rate from 10 to 10,000 fold, have been found at high frequencies in many natural and experimental populations. Mutators are continually produced from nonmutators, often due to mutations in mismatch-repair genes. These mutators gradually accumulate deleterious mutations, limiting their spread. However, they can occasionally hitchhike to high frequencies with beneficial mutations. We study the interplay between these effects. We first analyze the dynamics of the balance between the production of mutator alleles and their elimination due to deleterious mutations. We find that when deleterious mutation rates are high in mutators, there will often be many "young," recently produced mutators in the population, and the fact that deleterious mutations only gradually eliminate individuals from a population is important. We then consider how this mutator-nonmutator balance can be disrupted by beneficial mutations and analyze the circumstances in which fixation of mutator alleles is likely. We find that dynamics is crucial: even in situations where selection on average acts against mutators, so they cannot stably invade, the mutators can still occasionally generate beneficial mutations and hence be important to the evolution of the population. PMID- 21652524 TI - On the fixation process of a beneficial mutation in a variable environment. AB - A population that adapts to gradual environmental change will typically experience temporal variation in its population size and the selection pressure. On the basis of the mathematical theory of inhomogeneous branching processes, we present a framework to describe the fixation process of a single beneficial allele under these conditions. The approach allows for arbitrary time-dependence of the selection coefficient s(t) and the population size N(t), as may result from an underlying ecological model. We derive compact analytical approximations for the fixation probability and the distribution of passage times for the beneficial allele to reach a given intermediate frequency. We apply the formalism to several biologically relevant scenarios, such as linear or cyclic changes in the selection coefficient, and logistic population growth. Comparison with computer simulations shows that the analytical results are accurate for a large parameter range, as long as selection is not very weak. PMID- 21652525 TI - Successive and targeted DNA integrations in the Drosophila genome by Bxb1 and phiC31 integrases. AB - At present phiC31 is the only phage integrase system available for directionally regulated site-specific DNA integration in the Drosophila genome. Here we report that mycobacteriophage Bxb1 integrase also mediates targeted DNA integration in Drosophila with high specificity and efficiency. By alternately using Bxb1 and phiC31, we were able to carry out multiple rounds of successive and targeted DNA integrations in our genomic engineering founder lines for the purpose of generating complex knock-in alleles. PMID- 21652526 TI - A role for histone H4K16 hypoacetylation in Saccharomyces cerevisiae kinetochore function. AB - Hypoacetylated H4 is present at regional centromeres; however, its role in kinetochore function is poorly understood. We characterized H4 acetylation at point centromeres in Saccharomyces cerevisiae and determined the consequences of altered H4 acetylation on chromosome segregation. We observed low levels of tetra acetylated and K16 acetylated histone H4 (H4K16Ac) at centromeres. Low levels of H4K16Ac were also observed at noncentromeric regions associated with Cse4p. Inhibition of histone deacetylases (HDAC) using nicotinamide (NAM) caused lethality in cse4 and hhf1-20 kinetochore mutants and increased centromeric H4K16Ac. Overexpression of Sas2-mediated H4K16 acetylation activity in wild-type cells led to increased rates of chromosome loss and synthetic dosage lethality in kinetochore mutants. Consistent with increased H4K16 acetylation as a cause of the phenotypes, deletion of the H4K16 deacetylase SIR2 or a sir2-H364Y catalytic mutant resulted in higher rates of chromosome loss compared to wild-type cells. Moreover, H4K16Q acetylmimic mutants displayed increased rates of chromosome loss compared to H4K16R nonacetylatable mutants and wild-type cells. Our work shows that hypoacetylated centromeric H4 is conserved across eukaryotic centromeres and hypoacetylation of H4K16 at centromeres plays an important role in accurate chromosome segregation. PMID- 21652529 TI - The interdrought conference in perspective. PMID- 21652527 TI - Novel genetic selection system for quantitative trait loci of quality protein maize. AB - Quality protein maize combines a high-lysine trait with kernel hardness, for which a new, simpler genetic selection was designed. PMID- 21652530 TI - Role of HSP101 in the stimulation of nodal root development from the coleoptilar node by light and temperature in maize (Zea mays L.) seedlings. AB - Nodal roots (NRs) constitute the prevalent root system of adult maize plants. NRs emerge from stem nodes located below or above ground, and little is known about their inducing factors. Here, it is shown that precocious development of NRs at the coleoptilar node (NRCNs) occurred in maize seedlings when: (i) dark grown and stimulated by the concurrent action of a single light shock of low intensity white light (2 MUmol m(-2) s(-1)) and a single heat shock; (ii) grown under a photoperiod of low intensity light (0.1 MUmol m(-2) s(-1)); or (iii) grown in the dark under a thermoperiod (28 degrees C/34 degrees C). The light shock effects were synergistic with heat shock and with the photoperiod, whereas the thermoperiodical and photoperiodical effects were additive. Dissection of the primary root or the root cap, to mimic the fatal consequences of severe heat shock, caused negligible effects on NRCN formation, indicating that the shoot is directly involved in perception of the heat shock-inducible signal that triggered NRCN formation. A comparison between hsp101-m5::Mu1/hsp101-m5::Mu1 and Hsp101/Hsp101 seedlings indicated that the heat shock protein 101 (HSP101) chaperone inhibited NRCN formation in the light and in the dark. Stimulation of precocious NRCN formation by light and heat shocks was affected by genetic background and by the stage of seedling development. HSP101 protein levels increased in the coleoptilar node of induced wild-type plants, particularly in the procambial region, where NRCN formation originated. The adaptive relevance of development of NRCNs in response to these environmental cues and hypothetical mechanisms of regulation by HSP101 are discussed. PMID- 21652531 TI - Functional characterization of BjCET3 and BjCET4, two new cation-efflux transporters from Brassica juncea L. AB - Brassica juncea is promising for metal phytoremediation, but little is known about the functional role of most metal transporters in this plant. The functional characterization of two B. juncea cation-efflux family proteins BjCET3 and BjCET4 is reported here. The two proteins are closely related to each other in amino acid sequence, and are members of Group III of the cation-efflux transporters. Heterologous expression of BjCET3 and BjCET4 in yeast confirmed their functions in exporting Zn, and possibly Cd, Co, and Ni. Yeast transformed with BjCET4 showed higher metal resistance than did BjCET3 transformed. The two BjCET-GFP fusion proteins were localized to the plasma membrane in the roots when expressed in tobacco, and significantly enhanced the plants' Cd tolerance ability. Under Cd stress, tobacco plants transformed with BjCET3 accumulated significant amounts of Cd in shoots, while maintaining similar shoot biomass production with vector-control subjects. Transformed BjCET4 tobacco plants showed significantly enhanced shoot biomass production with markedly decreased shoot Cd content. The two transporter genes have a lower basal transcript expression in B. juncea seedling tissues when grown in normal conditions than under metal-stress, however, their transcripts levels could be substantially increased by Zn, Cd, NaCl or PEG, suggesting that BjCET3 and BjCET4 may play roles in several stress conditions, roles which appear to be different from those of previous characterized cation-efflux transporters, for example, AtMTP1, BjCET2, and BjMTP1. PMID- 21652532 TI - A mobile signal transported over a long distance induces systemic transcriptional gene silencing in a grafted partner. AB - Transcriptional gene silencing (TGS) can be induced by promoter-targeted small interfering RNA (siRNA). Long-distance transmission of TGS by viral infection in plants has been reported. However, systemic TGS has not been observed in the case of using an inverted repeat transgene as the silencing trigger. Here it is reported that a mobile signal, presumably the siRNA, produced from a hairpin structure transgene controlled by a companion cell-specific promoter can also induce transmissible TGS in both a modified agroinfiltration and a grafting system. Although the transmissible TGS occurred only in cells located in the vicinity of a leaf vein in the scion, very strong silencing was observed in the root system, especially the lateral roots, including the root apical meristem. The transmissible TGS was maintained through tissue culture and subsequently inherited by the progeny. The results suggest the potential application of mobile promoter-targeting siRNA in horticulture for improvement of plant cultivars by grafting. PMID- 21652535 TI - Of models and methods. PMID- 21652533 TI - Exploiting the engine of C(4) photosynthesis. AB - Ever since the discovery of C(4) photosynthesis in the mid-1960s, plant biologists have envisaged the introduction of the C(4) photosynthetic pathway into C(3) crops such as rice and soybeans. Recent advances in genomics capabilities, and new evolutionary and developmental studies indicate that C(4) engineering will be feasible in the next few decades. Furthermore, better understanding of the function of C(4) photosynthesis provides new ways to improve existing C(4) crops and bioenergy species, for example by creating varieties with ultra-high water and nitrogen use efficiencies. In the case of C(4) engineering, the main enzymes of the C(4) metabolic cycle have already been engineered into various C(3) plants. In contrast, knowledge of the genes controlling Kranz anatomy lags far behind. Combining traditional genetics, high-throughput sequencing technologies, systems biology, bioinformatics, and the use of the new C(4) model species Setaria viridis, the discovery of the key genes controlling the expression of C(4) photosynthesis can be dramatically accelerated. Sustained investment in the research areas directly related to C(4) engineering has the potential for substantial return in the decades to come, primarily by increasing crop production at a time when global food supplies are predicted to fall below world demand. PMID- 21652536 TI - Testicular choriocarcinoma: an unusual case of paraneoplastic thyrotoxicosis. PMID- 21652537 TI - Estimating glomerular filtration rate: comparison of the CKD-EPI and MDRD equations in a large UK cohort with particular emphasis on the effect of age. AB - BACKGROUND: The chronic kidney disease (CKD)-Epidemiology Collaboration (CKD-EPI) equation was developed to address the underestimation of measured glomerular filtration rate (GFR) by the Modification of Diet in Renal Disease (MDRD) equation at levels >60 mL/min/1.73 m(2). AIM: To assess the impact of the CKD-EPI equation on the estimation of GFR in a large adult UK population (n = 561,400), particularly looking at the effect of age. DESIGN: Serum creatinine results (ID MS-aligned enzymatic assay) were extracted from the pathology database during 1 year on adult (>= 18 years) patients from primary care. METHODS: The first available creatinine result from 174,448 people was used to estimate GFR using both equations and agreement assessed. RESULTS: Median CKD-EPI GFR was significantly higher than median MDRD GFR (82 vs. 76 mL/min/1.73 m(2), P < 0.0001). Overall mean bias between CKD-EPI and MDRD GFR was 5.0%, ranging from 13.0% in the 18-29 years age group down to -7.5% in those aged >= 90 years. Although statistically significant at all age groups the difference diminished with age and the agreement in GFR category assignment increased. Age-adjusted population prevalence of CKD Stages 3-5 was lower by CKD-EPI than by MDRD (4.4% vs. 4.9%). CONCLUSION: CKD-EPI produces higher GFR and lower CKD estimates, particularly among 18-59 year age groups with MDRD estimated GFRs of 45-59 mL/min/1.73 m(2) (Stage 3A). However, at ages >70 years there is very little difference between the equations, and among the very elderly CKD-EPI may actually increase CKD prevalence estimates. PMID- 21652538 TI - Influence of surface conditioning on ceramic microstructure and bracket adhesion. AB - The objective of this study was to investigate the influence of different conditioning procedures on various ceramic microstructures and bracket adhesion. Ceramic specimens (feldspathic, leucite, leucite-free, and fluorapatite) were mechanically conditioned (n = 20 per ceramic type) with conventional hydrofluoric acid (5 per cent HF; 60/30 seconds), buffered hydrofluoric acid (9.6 per cent BHF; 60/30 seconds), or sandblasting (Al(2)O(3)/SiO(2) particles). Silane coupling agents were added for chemical conditioning before bracket bonding. Bracket adhesion was calculated with a shear test in a universal testing machine. The bracket-composite-ceramic interface was further evaluated using the adhesive remnant index (ARI). One specimen of each ceramic/conditioning combination was subjected to qualitative electron microscopy investigation. One-way analysis of variance followed by Tukey's honestly significant difference test were applied for inferential statistics. Conditioning with conventional 5 per cent HF or sandblasting resulted in significantly (P < 0.001) higher bond strengths (mean values: 34.11 and 32.86 MPa, respectively) than with 9.6 per cent BHF (mean value: 12.49 MPa). Etching time or sandblasting particles had no statistical (P > 0.001) influence on bond strength. Higher ARI scores were found in the conventional 5 per cent HF and sandblasted groups, when compared with the 9.6 per cent BHF group. Microscopic examination of the conditioned ceramic surfaces showed that leucite and leucite-free ceramics differed most with respect to their surface roughness, though without an influence on shear bond strength (SBS; P < 0.001). Bracket adhesion was mostly influenced by the conditioning procedure itself. Sandblasted ceramic surfaces showed sufficient conditioning and bracket adhesion; however, the increased bracket adhesion was associated with a risk of ceramic surface damage. PMID- 21652539 TI - Rebond strength of bonded lingual wire retainers. AB - There is no consensus in the literature concerning the rebonding procedure for orthodontic retainers. The aim of this in vitro study was to evaluate the bond and rebond strength of retainers bonded to enamel surfaces with and without composite remnants. The retainers were bonded with Excite and Tetric Flow on three different surfaces: clean enamel, enamel where the composite had been removed by a tungsten carbide bur, and with cured composite remnants roughened by a tungsten carbide bur. The bond strength was determined by means of a cantilever tensile bond strength test using a repeated crossover design. Each tooth was rebonded twice and tested three times (N = 114). The surface was examined by scanning electron microscopy (SEM), electron backscatter diffraction and micro X ray fluorescence (EDAX), and scored using the adhesive remnant index (ARI). Two way analysis of variance of the mean bond strengths did not show significant differences between the three different enamel surface treatments. However, the specimens with cured composite remnants showed a higher standard deviation. This was confirmed by Weibull analyses. The ARI score showed that 96.5 per cent of bond fractures occurred at the retainer-resin interface. In contrast to the ARI score obtained in this study, the clinical ARI scores also showed failures at the resin-enamel interface. Based on these results, it is recommended that for rebonding the bond site is controlled, and the enamel surfaces are free of old composites remnants. PMID- 21652540 TI - ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients. AB - Identification and reversal of treatment resistance mechanisms of clinically refractory tumor cells is critical for successful cancer therapy. Here we show that ATP-binding cassette member B5 (ABCB5) identifies therapy-refractory tumor cells in colorectal cancer patients following fluorouracil (5-FU)-based chemoradiation therapy and provide evidence for a functional role of ABCB5 in colorectal cancer 5-FU resistance. Examination of human colon and colorectal cancer specimens revealed ABCB5 to be expressed only on rare cells within healthy intestinal tissue, whereas clinical colorectal cancers exhibited substantially increased levels of ABCB5 expression. Analysis of successive, patient-matched biopsy specimens obtained prior to and following neoadjuvant 5-FU-based chemoradiation therapy in a series of colorectal cancer patients revealed markedly enhanced abundance of ABCB5-positive tumor cells when residual disease was detected. Consistent with this finding, the ABCB5-expressing tumor cell population was also treatment refractory and exhibited resistance to 5-FU-induced apoptosis in a colorectal cancer xenograft model of 5-FU monotherapy. Mechanistically, short hairpin RNA-mediated ABCB5 knockdown significantly inhibited tumorigenic xenograft growth and sensitized colorectal cancer cells to 5-FU-induced cell killing. Our results identify ABCB5 as a novel molecular marker of therapy-refractory tumor cells in colorectal cancer patients and point to a need for consistent eradication of ABCB5-positive resistant tumor cell populations for more effective colorectal cancer therapy. PMID- 21652541 TI - Vorinostat-induced apoptosis in mantle cell lymphoma is mediated by acetylation of proapoptotic BH3-only gene promoters. AB - PURPOSE: Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm with generally poor prognosis, for which current therapies have shown limited efficacy. Vorinostat is a histone deacetylase inhibitor (HDACi) that has been approved for the treatment of cutaneous T-cell lymphoma. Our purpose was to describe the molecular mechanism whereby vorinostat induces apoptosis in MCL with particular emphasis on the role of proapoptotic BH3-only proteins. EXPERIMENTAL DESIGN: The sensitivity to vorinostat was analyzed in eight MCL cell lines and primary cells from 10 MCL patients. Determination of vorinostat mechanism of action was done by flow cytometry, immunoblotting, HDAC activity assay kit, quantitative reverse transcription PCR, chromatin immunoprecipitation, and siRNA mediated transfection. RESULTS: Vorinostat inhibited total histone deacetylase activity leading to selective toxicity toward tumor cells. Vorinostat-mediated cell death implied the activation of mitochondrial apoptosis, as attested by BAX and BAK conformational changes, mitochondrial depolarization, reactive oxygen species generation, and subsequent caspase-dependent cell death. This phenomenon was linked to H4 hyperacetylation on promoter regions and consequent transcriptional activation of the proapoptotic BH3-only genes BIM, BMF, and NOXA. Selective knockdown of the three corresponding proteins rescued cells from vorinostat-induced apoptosis. Moreover, vorinostat enhanced the activity of the BH3-mimetic ABT-263 in MCL cells, leading to synergistic apoptosis induction. CONCLUSION: These results indicated that transcriptional upregulation of BH3-only proteins plays an important role in the antitumoral activity of vorinostat in MCL, and that HDACi alone or in combination with BH3-mimetizing agents may represent a promising therapeutic approach for MCL patients. PMID- 21652543 TI - Expression and functional analysis of a CLV3-like gene in the model legume Lotus japonicus. AB - Plant aerial parts are differentiated from stem cells that are located in the shoot apical meristem (SAM). CLAVATA3 (CLV3)-CLV1 is a well-known ligand-receptor pair, which functions in SAM maintenance. In Lotus japonicus, HYPERNODULATION ABERRANT ROOT FORMATION1 (HAR1) shows the highest similarity with CLV1 of all Arabidopsis receptor-like kinases (RLKs). However, HAR1 functions in the systemic regulation of root nodule development, but does not appear to function in SAM maintenance. Therefore, the gene that is responsible for SAM maintenance in L. japonicus is largely unknown. Here, we identified the L. japonicus CLV3-like (LjCLV3) gene as a counterpart of AtCLV3 and performed expression and functional analysis. LjCLV3 transcripts were detected in the central region of the shoot meristems. However, unlike AtCLV3, LjCLV3 expression was not detected in the epidermal layer, but in the inner layers of the shoot meristems. RNA interference (RNAi) of LjCLV3 caused enlargement of not only the SAM, but also the primary and secondary inflorescence meristems (IMs). Furthermore, LjCLV3-silenced plants exhibited fasciated stems and an increased number of flowers per peduncle. These results reveal that LjCLV3 is responsible for the maintenance of the SAM as well as the primary and secondary IMs. PMID- 21652542 TI - MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma. AB - INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Diagnosis and management of PDAC are hampered by the absence of sensitive and specific disease biomarkers. MicroRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC. EXPERIMENTAL DESIGN: miRNA expression was characterized by fluorescence-based in situ hybridization using locked nucleic acid-modified DNA probes against miR-10b, miR 21, miR-155, miR-196a, and miR-210, followed by codetection of proteins by immunohistochemistry on the same tissue sections. miRNA expression in surgically resected PDAC tissues and in endoscopic ultrasonography (EUS)-guided fine-needle aspirate (EUS-FNA) samples was analyzed in cytokeratin 19 (CK19)-positive epithelial cells using optical intensity analysis. RESULTS: In 10 resected PDAC samples, miR-10b was the most frequently and consistently overexpressed miRNA among characterized miRNAs, exhibiting a four-fold increase in the cancer cells (P = 0.012). Given this preferential overexpression of miR-10b, we sought to determine whether miR-10b expression was clinically relevant. Accordingly, miR 10b expression was examined in 106 EUS-FNA samples obtained from pancreatic lesions. miR-10b expression was increased in cancer cells compared with CK19 positive epithelial cells in benign lesions (P = 0.0001). In patients with PDACs, lower levels of miR-10b were associated with improved response to multimodality neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival. CONCLUSION: miR-10b is a novel diagnostic biomarker for PDACs when assessing pancreatic lesions. Expression of miR-10b is predictive of response to neoadjuvant therapy and outcome in this disease. PMID- 21652544 TI - Effect of donor/recipient body weight ratio, donor weight, recipient weight and donor age on kidney graft function in children. AB - BACKGROUND: We hypothesized that supplementing a higher mass of renal parenchyma from adult donors, and their younger age, would improve graft function in paediatric recipients. METHODS: We calculated estimated glomerular filtration rate (eGFR; Schwartz formula) and absolute glomerular filtration rate (absGFR) in 57 renal-grafted children (1995-2007) aged 3.1-17.9 years, weighing 12.9-85.0 kg, on discharge from the hospital after transplantation (TPL), 1 year after TPL and at the last follow-up (1.5-11.7 years after TPL). We correlated their eGFR with the individual ratio between the donor and the recipient body weight at the time of TPL (donor/recipient body weight ratio; D/R BWR), and we evaluated the effect of the donor and the actual recipient body weight on the eGFR and absGFR. RESULTS: The D/R BWR varied from 0.65 to 5.23. We found a significant positive correlation between D/R BWR and eGFR at discharge from the hospital (P < 0.001), 1-year post-TPL (P < 0.001) and at the last follow-up (P < 0.05). Using multiple linear regression analyses, we found that both eGFR and absGFR values were much more determined by the actual recipient weight than by the donor weight (27/6% and 43/4% at discharge, by 24/4% and 57/0% 1 year after TPL, and 0/0% and 20/0% at the end of the follow-up). A tendency for lower eGFR with increasing age of donors was apparent at discharge and 1 year after TPL, but it reached statistical significance only at the last follow-up (r = 0.4254, P < 0.01). CONCLUSION: In paediatric renal transplants, the value of D/R BWR directly correlated with eGFR in the early and late posttransplant periods. However, this correlation was mainly influenced by the recipient weight, while the donor weight played only a minor or negligible role. PMID- 21652545 TI - Obstructive sleep apnoea: a stand-alone risk factor for chronic kidney disease. PMID- 21652546 TI - The melatonin receptor 1A (MTNR1A) gene is associated with recurrent and idiopathic calcium nephrolithiasis. AB - BACKGROUND: Experimental evidence indicate that melatonin regulates some renal tubular functions via specific melatonin receptors (MTNRs) located in the kidney of several avian and mammalian species, including humans. We hypothesized that single nucleotide polymorphisms (SNPs) in the melatonin receptor 1A gene (MTNR1A) might influence the risk of calcium nephrolithiasis. METHODS: We performed a systematic analysis of the MTNR1A gene in 246 recurrent calcium stone formers (136 men, 110 women; mean age 40.2 +/- 12.0 years; body mass index 25.8 +/- 4.5 kg/m2) and 269 healthy controls comparable for age and gender without a history of nephrolithiasis. RESULTS: Two SNPs in Intron 1 of MTNR1A were significantly associated with calcium nephrolithiasis: rs13140012 (P = 0.0004) and rs6553010 (P = 0.009). The haplotypes resulting from the two SNPs were also differently distributed between stone formers and controls, the haplotype A-T being more represented among stone formers (P = 0.00001) and the haplotype T-C being more common in healthy controls (P = 0.00001). Preliminary functional studies showed that the SNP rs13140012 could modify the binding sites for transcription factors. CONCLUSION: The results of this case-control study indicate a strong association between allelic variants of MTNR1A and recurrent calcium nephrolithiasis. PMID- 21652547 TI - Apoptosis occurs differentially according to glomerular size in diabetic kidney disease. AB - BACKGROUND: Apoptosis, which is involved in the process of mesangial cell and podocyte loss in diabetic nephropathy, is known to be regulated by protein kinase B/Akt (Akt). A number of studies have therefore investigated the activity of Akt under diabetic conditions, but the results have not been consistent. In this study, we hypothesized that apoptosis may occur differentially and that Akt may be differentially activated according to glomerular size in diabetic kidney disease. METHODS: Fifty male Sprague-Dawley rats were injected intraperitoneally with diluent (C, n = 25) or streptozotocin (DM, n = 25). After 3 months, glomeruli were isolated using sieves with pore sizes of 250, 150, 125 and 75 MUm and then classified into large glomeruli (on the 125-MUm sieve, LG) and small glomeruli (on the 75-MUm sieve, SG) groups. Western blot analyses for phospho Akt, apoptosis-related molecules (Bax, Bcl-2, active fragments of Caspase-3 and phospho-p53) and cyclin-dependent kinase inhibitors were performed. CONCLUSIONS: The numbers of total cells and podocytes in isolated glomeruli were determined using transmission electron microscopy. Akt phosphorylation was significantly decreased in DM-LG, while it was significantly increased in DM-SG (P < 0.05). The ratio of Bax/Bcl-2 protein expression and active fragments of Caspase-3 and phospho-p53 protein expression were significantly increased in DM-LG compared to DM-SG and C-SG (P < 0.001 and P < 0.01, respectively). In contrast, the expression of p27(Kip1) and p21(Cip1) was significantly increased in DM-SG compared to DM-LG and C-SG (P < 0.05). The numbers of total glomerular cells and podocytes were significantly decreased in DM-LG (P < 0.05). In conclusion, these data show differential expression of Akt activity and apoptosis-related molecules according to glomerular size in diabetic nephropathy, suggesting that apoptosis may be more operative in more hypertrophic glomeruli, resulting in fewer glomerular cells and podocytes in diabetic nephropathy. PMID- 21652548 TI - Acute kidney injury in patients admitted to a liver intensive therapy unit with paracetamol-induced hepatotoxicity. AB - BACKGROUND: Paracetamol overdose can cause acute kidney injury (AKI) independent of its hepatotoxic effects. We aimed to determine the prevalence of AKI (AKI Network definition) in those with paracetamol-induced hepatotoxicity, identify factors associated with development, assess impact on the outcomes of patient survival and length of stay and determine the proportion of patients recovering renal function (estimated glomerular filtration rate > 60 mL/min) by the time of hospital discharge or transfer out. METHODS: Between 2000 and 2007, patients admitted to a tertiary referral liver intensive therapy unit (LITU) with paracetamol-induced hepatotoxicity were identified from a prospectively maintained database and evaluated. RESULTS: Those receiving a liver transplant were excluded (n = 54), leaving 302 patients. Renal function remained normal in 21%, the remainder developing AKI (Stages 1-8%, 2-6% and 3-65%). Vasopressor requirement, mechanical ventilation, higher admission phosphate and lower sodium levels along with a higher Day 3 lactate and lower haematocrit were associated with AKI. In survivors with AKI, 51% had recovery of renal function, while 7% remained dialysis dependant although none required it chronically. Overall, there was 25% mortality, all having Stage 3 AKI but AKI was only a univariate not multivariate predictor of reduced patient survival. AKI independently predicted longer length of stay. CONCLUSIONS: AKI is very common in critically ill patients with paracetamol-induced hepatotoxicity requiring LITU admission. Although outcomes are poorer with AKI than with normal renal function, they are better than those found in other intensive therapy unit populations. Gradual recovery of renal function is seen in all patients. PMID- 21652549 TI - Incidence, complications and risk factors for severe falls in patients on maintenance haemodialysis. AB - BACKGROUND: Falls have been insufficiently studied in patients on maintenance haemodialysis (MHD). This study assessed the incidence and complications of severe falls and the ability of risk factors, including the Performance-Oriented Mobility Assessment (POMA) test, to predict them in this population. METHODS: All patients on MHD from our centre were asked to participate in this survey. POMA test and a record of risk factors for falls were obtained at baseline. Severe falls, as defined by an admission in an emergency ward, were documented prospectively. RESULTS: Eighty-four patients (median age 69.5 years, minimum 26 years, maximum 85 years) were enrolled. Predialytic POMA scores were low (median 20, minimum 5, maximum 26). After a mean follow-up of 20.6 months (142.2 patient years), 31 severe falls were recorded in 24 patients (28.6%; incidence 0.22 per patient-year) and complicated by fractures in 54.8% of severe falls. In univariate analysis, age, a past history of falls, malnutrition, depression, but not POMA score, were associated with severe falls. A POMA score of >21 had a negative predictive value of 82%. CONCLUSIONS: Severe falls were common in MHD patients in this study and resulted in fractures in >50% of the cases. They were associated with ageing, a past history of falls, malnutrition and depression. Although there was a trend towards a lower POMA score in fallers as compared to non-fallers, the POMA score was not an independent predictor of severe falls in this study. These data may help to stratify the patient's risk of falling in order to target programmes to prevent falls in this population. PMID- 21652550 TI - Diagnostic usefulness of bone mineral density and biochemical markers of bone turnover in predicting fracture in CKD stage 5D patients--a single-center cohort study. AB - BACKGROUND: In chronic kidney disease stage 5D, diagnostic usefulness of bone mineral density (BMD) in predicting fracture has not been established because of variable results in previous studies. The reason for this may be the heterogeneity of underlying pathogenesis of the fracture. METHODS: BMD was measured annually and serum biochemistry monthly for 485 hemodialyzed patients from April 2003 to March 2008, and all fractures were recorded. RESULTS: Forty six new episodes of any type of fracture and 29 cases of prevalent spine fracture were recorded. Serum bone-specific alkaline phosphatase (b-AP) was a very useful surrogate marker for any type of incident fracture risk [area under curve (AUC) = 0.766, P < 0.0001]. A significantly greater risk of any type of incident fracture was associated with parathyroid hormone (PTH) levels either <150 pg/mL [hazard ratio (HR) = 3.47, P < 0.01] or >300 pg/mL (HR = 5.88, P < 0.0001) compared with 150-300 pg/mL. Receiver-operating characteristic analysis demonstrated a significant predictive power for incident of any type of fracture by BMD at the total hip (AUC = 0.760, P < 0.0001) and other hip regions in females in the lower PTH group (PTH < 204 pg/mL). BMDs at every site but whole body or lumbar spine had significant power to discriminate prevalent spine fracture regardless of gender or PTH. CONCLUSIONS: Hemodialyzed patients with low or high PTH or increased b-AP had a high fracture risk. BMD by Dual Energy X-ray Absorptiometry (DEXA), especially at the total hip region, was useful to predict any type of incident of fracture for females with low PTH or to discriminate prevalent spine fracture for every patient. PMID- 21652551 TI - Predicting survival in pulmonary arterial hypertension: time to combine markers. PMID- 21652552 TI - Retro is the rage!: Ventilation-perfusion scanning is alive and well in the diagnosis of pulmonary embolism. PMID- 21652553 TI - Achieving adherence to positive airway pressure therapy: modifying pressure and the Holy Grail. PMID- 21652554 TI - Point: Is measuring sputum eosinophils useful in the management of severe asthma? Yes. PMID- 21652555 TI - Counterpoint: Is measuring sputum eosinophils useful in the management of severe asthma? No, not for the vast majority of patients. PMID- 21652556 TI - Translational behavioral research in respiratory medicine. AB - Human behavior can prevent or invite disease and is a major determinant of treatment success. Consequently, many efforts have been directed toward developing interventions to promote behaviors essential to managing or preventing respiratory disease. The process of developing, testing, and disseminating health behavior interventions should closely follow the translational research paradigm. However, most behavioral investigators have failed to adequately apply the translational research paradigm to behavioral research. The final stage of translation, consisting of testing the effectiveness of interventions in broad clinical settings after efficacy has been demonstrated in randomized controlled trials, is too often omitted. Additionally, the important task of understanding why any given health behavior intervention succeeds with some people but fails to change behavior in others is inconsistently pursued and seldom used to develop the robust theories of behavior change needed to improve respiratory health. Bringing health behavior research through the full translational process has the potential to significantly enhance respiratory health with specific behavioral targets, including smoking cessation, obesity prevention, TB control, and adherence to a multitude of respiratory treatments. PMID- 21652557 TI - p38 mitogen-activated protein kinase pathways in asthma and COPD. AB - The mitogen-activated protein kinase (MAPK) family includes the p38 kinases, which consist of highly conserved proline-directed serine-threonine protein kinases that are activated in response to inflammatory signals. Of the four isoforms, p38alpha is the most abundant in inflammatory cells and has been the most studied through mainly the availability of small molecule inhibitors. The p38 substrates include transcription factors; other protein kinases, which in turn phosphorylate transcription factors; cytoskeletal proteins and translational components; and other enzymes. Both asthma and COPD are characterized by chronic airflow obstruction, airway and lung remodeling, and chronic inflammation. p38 is involved in the inflammatory responses induced by cigarette smoke exposure, endotoxin, and oxidative stress through activation and release of proinflammatory cytokines/chemokines, posttranslational regulation of these genes, and activation of inflammatory cell migration. Inhibition of p38 MAPK prevented allergen-induced pulmonary eosinophilia, mucus hypersecretion, and airway hyperresponsiveness, effects that may partly result from p38 activation on eosinophil apoptosis and on airway smooth muscle cell production of cytokines/chemokines. In addition, p38 regulates the augmented contractile response induced by oxidative stress. The activation of p38 observed in epithelial cells and macrophages also may underlie corticosteroid insensitivity of severe asthma and COPD. Therefore, p38 inhibitors present a potential attractive treatment of these conditions. Second-generation p38 inhibitors have been disappointing in the treatment of rheumatoid arthritis. In two 6-week studies in patients with COPD, the results were encouraging. Side effects such as liver toxicity remain a possibility, and whether the beneficial effects of p38 inhibitors are clinically significant and sustained need to be determined. PMID- 21652558 TI - Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment. AB - Recent advances in basic science have greatly expanded our understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the chloride and bicarbonate channel that is encoded by the gene, which is mutated in patients with CF. We review the structure, function, biosynthetic processing, and intracellular trafficking of CFTR and discuss the five classes of mutations and their impact on the CF phenotype. The therapeutic discussion is focused on the significant progress toward CFTR mutation-specific therapies. We review the results of encouraging clinical trials examining orally administered therapeutics, including agents that promote read-through of class I mutations (premature termination codons); correctors, which overcome the CFTR misfolding that characterizes the common class II mutation F508del; and potentiators, which enhance the function of class III or IV mutated CFTR at the plasma membrane. Long term outcomes from successful mutation-specific treatments could finally answer the question that has been lingering since and even before the CFTR gene discovery: Will therapies that specifically restore CFTR-mediated chloride secretion slow or arrest the deleterious cascade of events leading to chronic infection, bronchiectasis, and end-stage lung disease? PMID- 21652559 TI - A brief historical and theoretical perspective on patient autonomy and medical decision making: Part II: The autonomy model. AB - As part of a larger series addressing the intersection of law and medicine, this essay is the second of two introductory pieces. Beginning with the Hippocratic tradition and lasting for the next 2,400 years, the physician-patient relationship remained relatively unchanged under the beneficence model, a paternalistic framework characterized by the authoritative physician being afforded maximum discretion by the trusting, obedient patient. Over the last 100 years or so, in response to certain changes taking place in both research and clinical practice, the bioethics movement ushered in the autonomy model, and with it, a profoundly different way of approaching decision making in medicine. The shift from the beneficence model to the autonomy model is governed legally by the informed consent doctrine, which emphasizes disclosure to patients of information sufficient to permit them to make intelligent choices regarding treatment alternatives. As this legal doctrine became established, philosophers identified an inherent value in respecting patients as autonomous agents, even where patient choice seems to conflict with the physician's duty to act in the patient's best interests. Whereas the beneficence model presumed that the physician knew what was in the patient's best interests, the autonomy model starts from the premise that the patient knows what treatment decision is in line with his or her true sense of well-being, even where that decision is the refusal of treatment and the result is the patient's death. PMID- 21652560 TI - Pulmonary rehabilitation: a classic tune with a new beat, but is anyone listening? AB - Comprehensive pulmonary rehabilitation and respiratory therapy services benefit patients with chronic lung disease and other diseases of the lung by reducing symptoms and restoring independent function. Although the science of these therapies is not new, commercial payers and Medicare have generally been slow to support adequate coverage and reimbursement. These therapies are described as a multidisciplinary approach to individual patient care through a physician supervised program that usually includes physician-prescribed exercise, education and/or training, psychosocial assessment, and an outcomes assessment comprehensively documented using an individualized treatment plan. This article includes a review of the requirements based on the July 2008 Congressional enactment of a new national policy for comprehensive pulmonary rehabilitation program coverage. Passage of Section 144 of the Medicare Improvements for Patients and Providers Act authorizes comprehensive pulmonary rehabilitation programs to be a covered Medicare benefit. Variability of coverage by various payers will be examined. Also discussed are various coding schema for the provision and reporting of comprehensive pulmonary rehabilitation and respiratory therapy services. The variability of requirements to establish medical necessity among several major payers of respiratory therapy services and comprehensive pulmonary rehabilitation programs will be explored. Despite these therapies being recognized universally as the standard of care for certain diseases and a new national mandate establishing coverage regulations, the continuation, expansion, and patient access for such therapies may be limited. Pitfalls and pluses are discussed. PMID- 21652561 TI - Warfarin-induced pulmonary metastatic calcification and calciphylaxis in a patient with end-stage renal disease. AB - Patients with end-stage renal disease (ESRD) receiving hemodialysis (HD) suffer from a number of metabolic derangements. Ectopic deposition of calcium in the skin, soft tissues, blood vessels, and viscera is a potentially devastating consequence of disorders of calcium and phosphorus homeostasis. We report the case of a patient with ESRD and secondary hyperparathyroidism receiving HD who developed metastatic pulmonary calcification and calciphylaxis following initiation of warfarin therapy after mechanical valve replacement. Because not all patients with ESRD receiving HD develop ectopic calcification, there appears to be a complex cascade of metabolic interactions that predispose patients to this process. Warfarin is a vitamin K antagonist with inhibitory effects not only on proteins of the coagulation cascade, but also on other important protein systems. Its role in ectopic calcium deposition has been the subject of theories and has been reported in the literature, but no link with metastatic pulmonary calcification has been made. Patients receiving HD have an increased incidence of conditions that require chronic anticoagulation with warfarin, such as VTE, atrial fibrillation, and valvular heart disease requiring valve replacement surgery. Bioprosthetic valves should be considered in these patients because of the potential risk of metastatic calcification when warfarin is used in the setting of mechanical valve replacement. PMID- 21652562 TI - Endovascular embolization of the complete type of anomalous systemic arterial supply to normal basal lung segments: a report of four cases and literature review. AB - The complete type of anomalous systemic arterial supply to normal basal lung segments is characterized by anomalous systemic artery supply to all or some of the normal basal segments with an absent corresponding pulmonary artery. Surgical intervention generally is required. This study reports on four patients with this anomaly with hemoptysis or a combination of other symptoms who underwent successful transarterial embolization using metallic coils or an Amplatzer vascular plug. To our knowledge, only six such cases treated with transarterial embolization have been reported previously in adult patients. PMID- 21652564 TI - A 70-year-old man with hypoglycemia, clubbing of fingers and toes, and a large mass of the right hemithorax. PMID- 21652563 TI - Wrist actigraphy. AB - To record sleep, actigraph devices are worn on the wrist and record movements that can be used to estimate sleep parameters with specialized algorithms in computer software programs. With the recent establishment of a Current Procedural Terminology code for wrist actigraphy, this technology is being used increasingly in clinical settings as actigraphy has the advantage of providing objective information on sleep habits in the patient's natural sleep environment. Actigraphy has been well validated for the estimation of nighttime sleep parameters across age groups, but the validity of the estimation of sleep-onset latency and daytime sleeping is limited. Clinical guidelines and research suggest that wrist actigraphy is particularly useful in the documentation of sleep patterns prior to a multiple sleep latency test, in the evaluation of circadian rhythm sleep disorders, to evaluate treatment outcomes, and as an adjunct to home monitoring of sleep-disordered breathing. Actigraphy has also been well studied in the evaluation of sleep in the context of depression and dementia. Although actigraphy should not be viewed as a substitute for clinical interviews, sleep diaries, or overnight polysomnography when indicated, it can provide useful information about sleep in the natural sleep environment and/or when extended monitoring is clinically indicated. PMID- 21652565 TI - A 47-year-old woman with progressive dyspnea and hypoxemia after lung transplantation. PMID- 21652566 TI - An 83-year-old man with bilateral spontaneous pneumothoraces and multiple cysts. PMID- 21652567 TI - Revisiting the issue of VTE in the setting of chronic liver disease: an examination of National Surgical Quality Improvement Program data. PMID- 21652568 TI - 2009 influenza A(H1N1) infection and associated myocardial dysfunction. PMID- 21652569 TI - Femoral venous oxygen saturation may still be a valuable tool. PMID- 21652570 TI - Survival in pulmonary hypertension registries: the importance of incident cases. PMID- 21652571 TI - Pulmonary diseases: first cause of mortality in the world. PMID- 21652572 TI - Hearing losses in wholetime firefighters occurring early in their careers. AB - BACKGROUND: Most research on firefighter hearing loss has concentrated on effects over a substantial part of, or entire, firefighting career. AIMS: To examine short-term changes in hearing in a group of local authority firefighters during their early careers METHODS: Results of pure-tone audiometry examinations on enlistment and assessment for initial issue of a large goods vehicle (LGV) driving licence were compared. RESULTS: Altogether, 118 firefighters, all male, were examined for an LGV licence over a 2.5-year period to September 2005. Data were available for 89/99 right/left ears on enlistment and 99/100 for LGV. Mean time between examinations was 4.1 years (range 1.4-12.6 years). By the LGV examination, there was deterioration in 69/99 right and 77/100 left ears, with the hearing loss in 8% of right and 13% of left ears falling into the 'warning' or 'referral' categories (Control of Noise at Work Regulations 2005) compared with 1% at enlistment. These differences reached statistical significance (P < 0.05 and < 0.001, respectively) CONCLUSIONS: Statistically significant hearing losses occur in some firefighters during the early stages of their careers. Further work needs to be done to establish if this continues, and steps taken to reduce the noise hazard at work. PMID- 21652573 TI - Skin disease in sheep farmers. AB - BACKGROUND: An unusual inflammation of the pinna has been reported to occur in some sheep farmers at the time of lambing. AIMS: To explore the prevalence of this disorder and its possible causal associations. METHODS: While on attachment to sheep farms during lambing, veterinary students used a standardized questionnaire to interview a sample of farmers about their work and about symptoms of skin inflammation in their hands, face and ears. RESULTS: Interviews were completed by 76 (67%) of the farmers approached. Among 74 farmers who had carried out lambing, 3 (4%, 95% CI 1-11%) had experienced temporally related ear symptoms, all on multiple occasions. No farmers with ear symptoms had ever been involved in calving or farrowing, and no ear symptoms were reported in relation to shearing or dipping sheep. There was also an excess of hand symptoms related to lambing outdoors (24% of those who had done such work) and indoors (also 24%) compared with other farming activities. CONCLUSIONS: Our findings suggest that temporally related ear inflammation occurs in at least 1% of farmers who carry out lambing but not in association with the other farming activities investigated. Lambing appears to be associated also with hand inflammation, but the pathology may differ from that in the pinna. PMID- 21652574 TI - The burden of sickness absence from musculoskeletal causes in Great Britain. AB - BACKGROUND: National initiatives to prevent and/or manage sickness absence require a database from which trends can be monitored. AIMS: To evaluate the information provided by surveillance schemes and publicly available data sets on sickness absence nationally from musculoskeletal disorders (MSDs). METHODS: A grey literature search was undertaken using the search engine Google, supplemented by leads from consultees from academia, industry, employers, lay interest groups and government. We abstracted data on the outcomes and populations covered and made quantitative estimates of MSD-related sickness absence, overall and, where distinguishable, by subdiagnosis. The coverage and limitations of each source were evaluated. RESULTS: Sources included the Labour Force Survey (LFS) and its Self-reported Work-related Illness survey module, the THOR-GP surveillance scheme, surveys by national and local government, surveys by employers' organizations and a database of benefit statistics. Each highlighted MSDs as a leading cause of sickness absence. Data limitations varied by source, but typically included lack of diagnostic detail and restriction of focus to selected subgroups (e.g. work-ascribed or benefit-awarded cases, specific employment sectors). Additionally, some surveys had very low response rates, were completed only by proxy respondents or ranked only the perceived importance of MSD-related sickness absence, rather than measuring it. CONCLUSIONS: National statistics on MSD-related sickness absence are piecemeal and incomplete. This limits capacity to plan and monitor national policies in an important area of public health. Simple low-cost additions to the LFS would improve the situation. PMID- 21652575 TI - Child healthcare workers in resource-limited areas improve health with innovative low-cost projects. AB - Most child health workers in resource-limited communities are dedicated, imaginative, innovative practitioners with ideas that would improve the care of children and families. However, they often lack experience in seeking funds and implementing their ideas. In 2006, the Section on International Child Health in the American Academy of Pediatrics launched a program, I-CATCH to fill this gap. The program provides mentors to assist in writing a proposal for the community conceived and community-driven idea to improve child health, makes a small amount of funds available to the selected proposals, and offers mentors to help with the project's implementation. To date, 29 projects in 20 different non-industrialized countries have been funded. The impressive results achieved by the four completed and three ongoing projects are presented. PMID- 21652576 TI - Determinants of hanging and use of ITNs in the context of near universal coverage in Zambia. AB - Roll Back Malaria recently recommended a policy of universal coverage with insecticide-treated nets (ITNs) so that all age groups can benefit from protection against malaria. Countries adopting the 'universal access' policy include Zambia. Policy implementation in many settings involves mass distribution of free ITNs to achieve a measure of universal coverage. This study examines ITN deployment and use in the context of mass distribution efforts towards achieving universal coverage in a malaria-endemic district in Zambia. We use multiple logistic regression to identify predictors of ITN deployment and use by anyone in the household and by children under five. Among ITN-owning households with a child under five, 69% used at least one ITN the night before the survey. About half of those children (54%) in ITN-owning households were covered the previous night. A strong and consistent predictor of use is household deployment of at least one ITN. Just over half of all ITNs were observed hanging, and reported use of nets for purposes other than malaria prevention was only 3%. Net characteristics, including shape, colour and whether or not the ITN was purchased, were not associated with net deployment. However, ITNs in poor condition are more likely to be observed hanging than ITNs in new or good condition. In the context of free mass distribution of ITNs, behaviour change communication and activities are necessary to improve use. Results suggest campaigns and messages that persuade recipients to hang up their ITNs would contribute towards closing the gap between ownership and use. PMID- 21652578 TI - Genetic polymorphisms in androgen receptor-binding sites predict survival in prostate cancer patients receiving androgen-deprivation therapy. AB - BACKGROUND: Activated androgen receptor binds to androgen-responsive elements (AREs) in genome to regulate target gene transcription and, consequently, mediates physiological or tumorigenic processes of the prostate. Our aim was to determine whether genetic variants in AREs are associated with clinical outcomes after androgen-deprivation therapy (ADT) in prostate cancer patients. PATIENTS AND METHODS: We systematically investigated 55 common single-nucleotide polymorphisms (SNPs) in the genome-wide insilico-predicted AREs in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed by Kaplan Meier analysis and Cox regression model. RESULTS: In univariate analysis, two, five, and four SNPs were associated with disease progression, PCSM, and ACM, respectively. After adjusting for known prognostic factors, ARRDC3 rs2939244, FLT1 rs9508016, and SKAP1 rs6504145 remained as significant predictors for PCSM and FBXO32 rs7830622 and FLT1 rs9508016 remained as significant predictors for ACM in multivariate analysis. Moreover, strong combined genotype effects on PCSM and ACM were also observed (P(trend) < 0.001). CONCLUSION: Our results suggest that SNPs in AREs influence prostate cancer survival and may further advance our understanding of the disease progression. PMID- 21652577 TI - Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER+) node-negative breast cancer. AB - BACKGROUND: This study examined the impact of the Recurrence Score (RS) in Spanish breast cancer patients and explored the associations between clinicopathological markers and likelihood of change in treatment recommendations. PATIENTS AND METHODS: Enrollment was offered consecutively to eligible women with estrogen receptor-positive; human epidermal growth factor receptor 2-negative, node-negative breast cancer. Oncologists recorded treatment recommendation and confidence in it before and after knowing the patient's RS. RESULTS: Treatment recommendation changed in 32% of 107 patients enrolled: in 21% from chemohormonal (CHT) to hormonal therapy (HT) and in 11% from HT to CHT. RS was associated with the likelihood of change from HT to CHT (P < 0.001) and from CHT to HT (P < 0.001). Confidence of oncologists in treatment recommendations increased for 60% of cases. Higher tumor grade (P = 0.007) and a high proliferative index (Ki-67) (P = 0.023) were significantly associated with a greater chance of changing from HT to CHT, while positive progesterone receptor status (P = 0.002) with a greater probability of changing from CHT to HT. CONCLUSIONS: Results from the first prospective European study are consistent with published experience and use of the RS as proposed in European clinical practice guidelines and provide evidence on how Oncotype DX and clinicopathological factors are complementary and patient selection may be improved. PMID- 21652579 TI - Chemotherapy dose reductions in obese patients with colorectal cancer. AB - BACKGROUND: In cancer patients with a large Body Surface Area, chemotherapy drug doses are often reduced, as studies have suggested that their pharmacokinetics may be altered. However, this strategy may result in underdosing obese patients. PATIENTS AND METHODS: In three Medical Research Council trials of chemotherapy for advanced colorectal cancer, dose reductions were not mandated. This provided the opportunity to compare the toxicity levels in those obese patients fully dosed and to investigate if those under dosed experienced a worse survival. Body Mass Index (BMI) was used to classify patients as normal weight (BMI < 25), overweight (BMI 25-29), or obese (BMI 30+). RESULTS: Of the 4781 patients, 2158 (45%) were classified as normal weight, 1753 (37%) as overweight, and 870 (18%) as obese. There was no evidence that, in those patients fully dosed, obese patients experienced more toxicity or that dose-reducing obese patients resulted in less toxicity. However, there was a suggestion that those obese patients who were given reduced doses had a worse progression-free survival [hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.06-1.39, P = 0.006] and a slightly worse overall survival (HR 1.12, 95% CI 0.96-1.30, P = 0.152). CONCLUSION: These results, although not a randomised comparison, do not support the policy of reducing chemotherapy doses for obese patients with colorectal cancer. PMID- 21652580 TI - The International Scoring System (ISS) for multiple myeloma remains a robust prognostic tool independently of patients' renal function. AB - BACKGROUND: The International Staging System (ISS) is the most widely used staging system for patients with multiple myeloma (MM). However, serum beta2 microglobulin increases in renal impairment (RI) and there have been concerns that ISS-3 stage may include 'up-staged' MM patients in whom elevated beta2 microglobulin reflects the degree of renal dysfunction rather than tumor load. PATIENTS AND METHODS: In order to assess the impact of RI on the prognostic value of ISS, we analyzed 1516 patients with symptomatic MM and the degree of RI was classified according to the Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease (CKD) criteria. RESULTS: Forty-eight percent patients had stages 3 5 CKD while 29% of patients had ISS-1, 38% had ISS-2 and 33% ISS-3. The frequency and severity of RI were more common in ISS-3 patients. RI was associated with inferior survival in univariate but not in multivariate analysis. When analyzed separately, ISS-1 and ISS-2 patients with RI had inferior survival in univariate but not in multivariate analysis. In ISS-3 MM patients, RI had no prognostic impact either in univariate or multivariate analysis. Results were similar, when we analyzed only patients with Bence-Jones >200 mg/day. CONCLUSIONS: ISS remains unaffected by the degree of RI, even in patients with ISS-3, which includes most patients with renal dysfunction. PMID- 21652581 TI - Phase II trial of preoperative chemoradiotherapy with oxaliplatin, cisplatin, and 5-FU in locally advanced esophageal and gastric cancer. AB - BACKGROUND: Based on a phase I study showing the feasibility of combining of oxaliplatin, cisplatin, and 5-fluorouracil (5-FU) (OCF) with radiation therapy (RT) in esophageal cancer, the efficacy of this regimen in esophageal, gastroesophageal (GE), and gastric (G) cancer was assessed in this phase II multicenter study. PATIENTS AND METHODS: Patients with resectable tumors were eligible. Treatment included two cycles of oxaliplatin 85 mg/m(2), cisplatin 55 mg/m(2), and continuously infused 5-FU 3 g/m(2) in 96 h and concurrent RT (45 Gy), followed by surgery after 6-8 weeks. Primary end point was complete pathologic response (pCR). RESULTS: Forty-one patients were enrolled. Tumor location was esophagus 39% (squamous 10/adenocarcinoma 6), GE junction 32%, and stomach 29%. G3-G4 adverse events included asthenia (27%) and neutropenia (14%). One toxic death occurred. Thirty-one patients (75.6%) underwent surgery (R0 in 94%). Pathologic response was achieved in 58% of patients, with pCR in 50% and 16% of esophageal and GE/G cancer, respectively. pCR was achieved in 67% of squamous cell carcinoma. Survival: median follow-up, 50.4 months; median progression-free survival and overall survival were 23.2 and 28.4 months, respectively. CONCLUSION: Preoperative OCF plus RT showed an acceptable toxicity and promising activity especially in squamous cell esophageal cancer. PMID- 21652582 TI - Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients. AB - BACKGROUND: The aim of this study was to evaluate whether cytidine deaminase (CDA) polymorphisms 79A>C and 435C>T and/or CDA enzymatic activity influenced clinical outcome in 126 advanced non-small-cell lung cancer patients treated with gemcitabine-platinum-regimens. PATIENTS AND METHODS: CDA polymorphisms and activity were analysed by PCR and high-performance liquid chromatography, respectively. Univariate and multivariate analyses compared biological/clinical parameters with response, clinical benefit, time to progression (TtP) and overall survival (OS) using Pearson's chi(2) test, log-rank test and Cox proportional hazards model. RESULTS: Patients with CDA A79A/A79C genotypes had significantly longer TtP (6.0 versus 3.0 months; P = 0.001) and OS (11.0 versus 5.0 months; P = 0.001) than patients with C79C genotype. Patients harbouring CDA C435C/C435T genotypes also had a longer OS (P = 0.025), but no correlations were observed with TtP. Conversely, patients with low-CDA activity had a significantly higher response rate (37.7% versus 13.8%; P = 0.006), clinical benefit (91.8% versus 51.7%; P < 0.001), as well as longer TtP (8.0 versus 3.0 months; P < 0.001) and OS (19.0 versus 6.0 months; P < 0.001). Furthermore, enzymatic activity emerged as an independent predictor for death/progression risk at multivariate analysis. CONCLUSIONS: CDA enzymatic activity appears to be the strongest candidate biomarker of activity and efficacy of platinum-gemcitabine-based chemotherapy and should be validated in a prospective study. PMID- 21652583 TI - High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label, randomized controlled trial. AB - BACKGROUND: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients. PATIENTS AND METHODS: Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7. RESULTS: From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity. CONCLUSION: This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC. PMID- 21652584 TI - Evidence for the efficacy of complementary and alternative medicines in the management of rheumatoid arthritis: a systematic review. AB - OBJECTIVE: To critically evaluate the evidence regarding complementary and alternative medicine (CAM) taken orally or applied topically (excluding fish oil) in the treatment of RA. METHODS: Randomized controlled trials (RCTs) of RA using CAMs, in comparison with other treatments or placebo, published in English up to August 2010, were eligible for inclusion. They were identified using systematic searches of bibliographic databases and manual searching of reference lists. Information was extracted on outcomes and statistical significance, in comparison with alternative treatments, and reported side effects. The methodological quality of the primary studies was determined using the Jadad scoring system. RESULTS: Reported RCTs were available for 18 CAMs in the management of RA. There was no consistent evidence available for any of the reviewed substances to suggest that they were efficacious as complementary medicines to standard treatment. Nevertheless, the studies conducted on borage seed oil (n = 2) and thunder god vine (n = 3) have been positive and may warrant further investigation. Not all CAM compounds studied were free of major adverse effects. CONCLUSION: The major limitation in reviewing the evidence for CAMs is the paucity of RCTs in the area. The available evidence does not support their current use in the management of RA. PMID- 21652585 TI - Causes and management of infertility in systemic lupus erythematosus. AB - SLE is a multi-system, autoimmune condition that can influence both male and female fertility. Inability to conceive may be attributed to several factors that may act singly or in combination: (i) older age in patients with SLE compared with healthy controls; (ii) disease-related infertility; and (iii) infertility through gonadotoxic treatments. In addition, psychosocial factors related to the disease may lower fecundity and may be associated with apparent infertility. Many therapeutic avenues are open to counteract reproductive damage in the management of SLE and to assist conception once infertility is diagnosed. These treatments can include the administration of gonadotrophin-receptor hormone analogues while receiving CYC treatment, the use of assisted reproductive technologies, such as in vitro fertilization and psychosocial intervention to promote a healthier relationship with their partner. Knowledge of how these reproductive problems occur and its prevention/treatment in SLE patients should avert irreversible infertility as well as give hope to SLE patients with infertility. PMID- 21652586 TI - Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. AB - OBJECTIVE: To identify the risk factors associated with pregnancy failure in patients with APS treated with conventional therapy. METHODS: A multicentre, case control study was conducted to compare APS patients with successful and unsuccessful pregnancy outcomes. We retrospectively considered 410 pregnancies of women diagnosed with primary APS. The study focused on 57 unsuccessful pregnancies (considered the study population) and 57 successful pregnancies (considered the control population) matched for age and therapy. All the patients had been treated with conventional protocol treatments including low-dose aspirin and/or heparin. The clinical and laboratory features of the two groups of women diagnosed with APS were compared. RESULTS: The independent risk factors for pregnancy failure were: (i) the presence of SLE or other autoimmune diseases [odds ratio (OR) 6.0; 95% CI 1.7, 20.8; P = 0.01]; (ii) history of both thrombosis and pregnancy morbidity (OR 12.1; 95% CI 1.3, 115.3; P = 0.03); and (iii) triple [Immunoglobulin (Ig) G/IgM aCLs plus IgG/IgM anti-beta(2) glycoprotein I antibodies plus LA] aPL positivity (OR 4.1; 95% CI 1.0, 16.7; P = 0.05). APS patients diagnosed on the basis of a single positive test and/or history of pregnancy morbidity alone were generally found to have successful pregnancies. CONCLUSION: It would seem from these findings that the risk of pregnancy failure in APS women planning to conceive can be stratified on the basis of some specific clinical and laboratory features. PMID- 21652587 TI - Real-time fMRI: a tool for local brain regulation. AB - Real-time fMRI permits simultaneous measurement and observation of brain activity during an ongoing task. One of the most challenging applications of real-time fMRI in neuroscientific and clinical research is the possibility of acquiring volitional control of localized brain activity using real-time fMRI-based neurofeedback protocols. Real-time fMRI allows the experimenter to noninvasively manipulate brain activity as an independent variable to observe the effects on behavior. Real-time fMRI neurofeedback studies demonstrated that learned control of the local brain activity leads to specific changes in behavior. Here, the authors describe the implementation and application of real-time fMRI with particular emphasis on the self-regulation of local brain activity and the investigation of brain-function relationships. Real-time fMRI represents a promising new approach to cognitive neuroscience that could complement traditional neuroimaging techniques by providing more causal insights into the functional role of circumscribed brain regions in behavior. PMID- 21652589 TI - Spontaneous resolution of atraumatic intrauterine ping-pong fractures in newborns delivered by cesarean section. AB - Two cases of spontaneous intrauterine ping-pong fractures are reported in newborns delivered by cesarean section. Skull fractures occurred with no evidence of extrinsic trauma or cephalopelvic disproportion. Subsequent clinical follow-up at 6 and 12 months revealed normal skull reshaping and growth, with no associated neurological deficits. Spontaneous intrauterine ping-pong fractures in newborns delivered by cesarean section is a distinctly rare condition. These 2 cases demonstrate that, even without complicated spontaneous vaginal delivery or history of external trauma, congenital ping-pong fracture of the skull can occur. The existence of this clinical condition and its spontaneous resolution is important knowledge that can assist in the prepartum and postpartum management of children with this pathology. PMID- 21652591 TI - Brief electroencephalography rhythmic discharges (BERDs) in the neonate with seizures: their significance and prognostic implications. AB - We aimed to explore the significance and prognostic implications of paroxysmal brief electroencephalography (EEG) rhythmic discharges (BERDs) in neonatal seizures. The 52 neonates in this study were divided into 3 groups: (1) BERDs only: 9 neonates, (2) BERDs + conventional EEG seizures: 11 babies, (3) Conventional EEG seizures only: 32 babies. We analyzed the BERDs and compared outcomes in the 3 groups: there was no significant difference in mortality and neurodevelopmental or background EEG impairment. Similar to conventional EEG seizures, BERDs are also associated with an increased mortality, morbidity, and EEG background abnormalities. Fewer babies with BERDS appear to develop postneonatal seizures suggesting their epileptogenic potential is less. In the appropriate clinical context, BERDs should be considered as miniseizures. PMID- 21652588 TI - Specific sets of intrinsic and extrinsic factors drive excitatory and inhibitory circuit formation. AB - How are excitatory (glutamatergic) and inhibitory (GABAergic) synapses established? Do distinct molecular mechanisms direct differentiation of glutamatergic and GABAergic synapses? In the brain, glutamatergic and GABAergic synaptic connections are formed with specific patterns. To establish such precise synaptic patterns, neurons pass through multiple checkpoints during development, such as cell fate determination, cell migration and localization, axonal guidance and target recognition, and synapse formation. Each stage offers key molecules for neurons/synapses to obtain glutamatergic or GABAergic specificity. Some mechanisms are based on intrinsic systems to induce gene expression, whereas others are based on extrinsic systems mediated by cell-cell or axon-target interactions. Recent studies indicate that specific formation of glutamatergic and GABAergic synapses is controlled by the expression or activation of different sets of molecules during development. In this review, the authors outline stages critical to the determination of glutamatergic or GABAergic specificity and describe molecules that act as determinants of specificities in each stage, with a particular focus on the synapse formation stage. They also discuss possible mechanisms underlying glutamatergic and GABAergic synapse formation via synapse type specific synaptic organizers. PMID- 21652590 TI - A sensitive diffusion tensor imaging quantification method to detect language laterality in children: correlation with the Wada test. AB - Using diffusion tensor imaging tractography and color-coded anisotropy map quantification, we investigated asymmetry of the arcuate fasciculus to determine language laterality in children and compared it with the Wada test. Arcuate fasciculus volume and fractional anisotropy were measured after tractography. We also quantified the fiber orientation distribution in the arcuate fasciculus region, ie, the fraction of arcuate fasciculus fibers oriented in the anteroposterior and mediolateral directions. A Laterality Index was calculated for each of the measured parameters. Volumetric analysis of the arcuate fasciculus showed asymmetry favoring the language dominant hemisphere (P = .02), while fractional anisotropy showed no significant asymmetry (P = .07). The mean anteroposterior and mediolateral components on the language dominant side were significantly higher than on the nondominant side (P = .003 and .002, respectively). The Laterality Index values were concordant with the Wada test results except for 1 case. Fractional anisotropy also falsely lateralized language in 1 case. PMID- 21652592 TI - The use of stem cells to repair the injured lung. AB - INTRODUCTION: The structure of the lung is complex, it contains at least 40 different cell types. The lung interacts with the outside environment and the circulatory system. These features make the lung particularly susceptible to injury and disease. AREAS OF AGREEMENT: Stem cells with reparative properties can be found within the lung. Also, outside sources of stem cells can contribute to the repair of the injured lung. These include multipotent stem cells from the bone marrow and pluripotent stem cells derived from the early embryo or from adult cells, which are made to reverse to a pluripotent state by the addition of viral vectors or non-viral agents. For stem cells of outside sources to have a reparative function, the cells need to reach the injured lung, either by internal mobilization of stem cells from other parts of the body (e.g. bone marrow) or by administration of exogenous cell sources. AREAS OF CONTROVERSY: Much research is currently undertaken to define the mechanisms by which stem cells repair the injured tissue. These include the possibility of engraftment of exogenous cells or the release of growth factors from the cells to aid repair. There is not as yet a clear consensus as to the mechanisms of repair. CURRENT RESEARCH AND TIMELINES: Interest is now focused on developing appropriate animal models to test the safety and efficacy of stem cell therapies and to understand the mechanisms by which stem cells undertake this task. PMID- 21652593 TI - Genetic susceptibility to aseptic loosening following total hip arthroplasty: a systematic review. AB - Introduction Aseptic loosening is the most common cause of total hip arthroplasty (THA) failure and revision surgery. Genetic polymorphisms could be determinant factors for implant loosening. Source of data We performed a comprehensive search of Medline, CINAHL, Googlescholar, Embase and Cochrane databases, using various combinations of the keyword terms 'aseptic loosening', 'gene', 'hip arthoplasty', 'genetics', 'loosening'. Twelve studies detailing the genetic investigation of patients with aseptic loosening of a THA were identified. Areas of agreement SNPs of GNAS1, TNF-238 A allele, TNF-alpha promoter (-308G->A) transition, IL6-174 G allele, interleukin (IL)-6 (-597) and (-572), MMP-1 promoting gene, C/C genotype for the MMP1, MT1-MMP, MMP-2, transforming growth factor-beta1 signal sequence (29T->C) transitions, A/A genotype for the OPG-163, and MBL were overexpressed in patients with aseptic loosening and periprosthetic osteolysis. Areas of controversy Data from single centre studies do not allow one to compare the results of different studies. Conclusion Several gene pathways and genes contribute to the genetic susceptibility to aseptic loosening following THA. Further studies will enhance the understanding of prosthesis failure, and may inform and direct pharmaceutical interventions. Growing points Further multi-centre prospective studies are necessary to confirm the general validity of the findings reported. Single-centre findings should be replicated in other centres and populations to open new avenues for pre-surgical genetic testing and to investigate immune response modulation in THA. Areas timely for developing research Research in this field could lead to better understanding of mechanisms behind aseptic osteolysis, and improve the results of THA. PMID- 21652596 TI - The association of mode of delivery and common childhood illnesses. AB - Participants enrolled in a randomized control trial (RCT) were eligible for this cross-sectional study to determine if children born via cesarean (C)-section had higher rates of common infectious diseases and change in normal daily activities due to illness than children born vaginally. The RCT collected parent-reported health information and mode of delivery was assessed during follow-up calls. Parent-reported rates of infectious sequelae and changes in daily activities were compared between C-section and vaginally delivered children. In total, 72.4% of the 522 children were delivered vaginally. After accounting for age, siblings, breast-feeding as an infant, and clustering within families, C-section delivered children had significantly higher rates of cumulative infectious diseases, lower respiratory tract infections, and cough than vaginally born children. Mode of delivery appears to have some lasting effect on child health 3 to 6 years after birth, specifically respiratory health. Further research is imperative to elucidate the causative effect of mode of delivery on child health. PMID- 21652597 TI - Multilateral analysis of increasing collective dose and new ALARA programme. AB - JAPC (The Japan Atomic Power Company) is the only electric power company that operates different types of nuclear reactors in Japan; it operates two BWRs (boiling water reactors), one pressurised water reactor and one gas cooled reactor. JAPC has been conducting various activities aimed at reducing radiation dose received by workers for over 45 y. Recently, the collective dose resulting from periodic maintenance has increased at each plant because of the replacement of large equipment and the unexpected extension of the outage period. In particular, the collective dose at Tokai-2 is one of the highest among Japanese BWR plants((1)), owing to the replacement and strengthening of equipment to meet earthquake-proof requirements. In this study, the authors performed a multilateral analysis of unacceptably a large collective dose and devised a new ALARA programme that includes a 3D dose prediction map and the development of machines to assist workers. PMID- 21652595 TI - Cardiac cell therapy: where we've been, where we are, and where we should be headed. AB - INTRODUCTION: Stem cell therapy has emerged as a promising strategy for the treatment of ischemic cardiomyopathy. SOURCES OF DATA: Multiple candidate cell types have been used in preclinical animal models and in clinical trials to repair or regenerate the injured heart either directly (through formation of new transplanted tissue) or indirectly (through paracrine effects activating endogenous regeneration). AREAS OF AGREEMENT: (i) Clinical trials examining the safety and efficacy of bone marrow derived cells in patients with heart disease are promising, but results leave much room for improvement. (ii) The safety profile has been quite favorable. (iii) Efficacy has been inconsistent and, overall, modest. (iv) Tissue retention of cells after delivery into the heart is disappointingly low. (v) The beneficial effects of adult stem cell therapy are predominantly mediated by indirect paracrine mechanisms. AREAS OF CONTROVERSY: The cardiogenic potential of bone marrow-derived cells, the mechanism whereby small numbers of poorly-retained cells translate to measurable clinical benefit, and the overall impact on clinical outcomes are hotly debated. GROWING POINTS/AREAS TIMELY FOR DEVELOPING RESEARCH: This overview of the field leaves us with cautious optimism, while motivating a search for more effective delivery methods, better strategies to boost cell engraftment, more apt patient populations, safe and effective 'off the shelf' cell products and more potent cell types. PMID- 21652598 TI - Searching for the ideal inotropic agent to rescue a failing heart. PMID- 21652599 TI - Why do people postpone parenthood? Reasons and social policy incentives. AB - BACKGROUND: Never before have parents in most Western societies had their first children as late as in recent decades. What are the central reasons for postponement? What is known about the link between the delay of childbearing and social policy incentives to counter these trends? This review engages in a systematic analysis of existing evidence to extract the maximum amount of knowledge about the reasons for birth postponement and the effectiveness of social policy incentives. METHODS: The review followed the PRISMA procedure, with literature searches conducted in relevant demographic, social science and medical science databases (SocINDEX, Econlit, PopLine, Medline) and located via other sources. The search focused on subjects related to childbearing behaviour, postponement and family policies. National, international and individual-level data sources were also used to present summary statistics. RESULTS: There is clear empirical evidence of the postponement of the first child. Central reasons are the rise of effective contraception, increases in women's education and labour market participation, value changes, gender equity, partnership changes, housing conditions, economic uncertainty and the absence of supportive family policies. Evidence shows that some social policies can be effective in countering postponement. CONCLUSIONS: The postponement of first births has implications on the ability of women to conceive and parents to produce additional offspring. Massive postponement is attributed to the clash between the optimal biological period for women to have children with obtaining additional education and building a career. A growing body of literature shows that female employment and childrearing can be combined when the reduction in work-family conflict is facilitated by policy intervention. PMID- 21652600 TI - Guillain-Barre syndrome, influenzalike illnesses, and influenza vaccination during seasons with and without circulating A/H1N1 viruses. AB - The role of influenzalike illnesses and influenza vaccination in the development of Guillain-Barre syndrome (GBS), particularly the role of A/H1N1 epidemics and A/H1N1 vaccination, is debated. Data on all incident GBS cases meeting the Brighton Collaboration criteria that were diagnosed at 25 neurology centers in France were prospectively collected between March 2007 and June 2010, covering 3 influenzavirus seasons, including the 2009-2010 A/H1N1 outbreak. A total of 457 general practitioners provided a registry of patients from which 1,080 controls were matched by age, gender, index date (calendar month), and region to 145 cases. Causal relations were assessed by multivariate case-control analysis with adjustment for risk factors (personal and family history of autoimmune disorders, among others), while matching on age, gender, and calendar time. Influenza (seasonal or A/H1N1) or influenzalike symptoms in the 2 months preceding the index date was associated with GBS, with a matched odds ratio of 2.3 (95% confidence interval (CI): 0.7, 8.2). The difference in the rates of GBS occurring between influenza virus circulation periods and noncirculation periods was highly statistically significant (P = 0.004). Adjusted odds ratios for GBS occurrence within 6 weeks after seasonal and A/H1N1 vaccination were 1.3 (95% CI: 0.4, 4.1) and 0.9 (95% CI: 0.1, 7.6), respectively. Study results confirm that influenza virus is a likely risk factor for GBS. Conversely, no new concerns have arisen regarding influenza vaccination. PMID- 21652601 TI - Intra- and interindividual variability in lymphocyte chromosomal aberrations: implications for cancer risk assessment. AB - Chromosomal aberration frequency in peripheral lymphocytes of healthy individuals has been found to be predictive of future cancer risk. The variability of chromosomal aberrations over time, which is largely unknown, should be clarified to interpret the strength of this association and to determine its use in cancer prediction. Intra- and interindividual variability in chromosomal aberration frequency was therefore determined. From a pooled database comprising 11 national cohorts (1965-2002), the authors included 9,433 blood samples from 3,550 subjects with at least one repeated chromosomal aberration measurement. The generalized concordance correlation coefficient of 0.19 was low, indicating high intraindividual variability compared with interindividual variability, resulting in a high likelihood of misclassification. The relation between chromosomal aberration frequency and future cancer risk has probably been underestimated in previous studies. A single chromosomal aberration measurement seems not to be representative of the whole lifespan level of chromosome instability and greatly limits the use of chromosomal aberration frequency-as measured with Giemsa staining-for individual risk assessment. PMID- 21652602 TI - Confounding of indirect effects: a sensitivity analysis exploring the range of bias due to a cause common to both the mediator and the outcome. AB - Several investigators have demonstrated that the assessment of indirect and direct effects is biased in the presence of a cause that is common to both the mediator and the outcome if one has not controlled for this variable in the analysis. However, little work has been done to quantify the bias caused by this type of unmeasured confounding and determine whether this bias will materially affect conclusions regarding mediation. The author developed a sensitivity analysis program to address this crucial issue. Data from 2 well-known studies in the methodological literature on mediation were reanalyzed using this program. The results of mediation analyses were found not to be as vulnerable to the impact of confounding as previously described; however, these findings varied sharply between the 2 studies. Although the indirect effect observed in one study could potentially be due to a cause common to both the mediator and the outcome, such confounding could not feasibly explain the results of the other study. These disparate results demonstrate the utility of the current sensitivity analysis when assessing mediation. PMID- 21652603 TI - Intermittent hypoxia conditioning prevents endothelial dysfunction and improves nitric oxide storage in spontaneously hypertensive rats. AB - Although intermittent hypoxia is often associated with hypertension, experimental and clinical studies have demonstrated definite antihypertensive effects of some intermittent hypoxia conditioning (IHC) regimens. Mechanisms of this antihypertensive response are unknown. Endothelial dysfunction related to disturbed synthesis and/or reduced availability of nitric oxide (NO) has been linked to hypertension. Thus, experiments were conducted to determine if IHC can improve endothelium-dependent relaxation and formation of releasable vascular NO stores of young (4-8-week-old) spontaneously hypertensive rats (SHR). Rats were subjected to either IHC (9.5-10% O(2), 5-10 min, 5-8 times per day, 20 d) or to sham conditioning. Endothelium-dependent relaxation to acetylcholine was measured in norepinephrine-precontracted, isolated aortic rings, and the size of NO stores was evaluated by percent relaxation to N-acetylcysteine (NAC), which releases stored NO. The capacity of aortic rings for NO storage was evaluated by the relaxation to NAC after prior incubation with an NO donor. IHC significantly suppressed the development of hypertension in young SHR. Endothelial function decreased from 54.7 +/- 4.6% to 28.1 +/- 6.4% relaxation to acetylcholine after 20 d of sham IHC, whereas endothelial function was sustained (60.3 +/- 6.0% relaxation) in IHC rats. IHC also induced formation of available NO stores and enhanced the capacity of aortic rings to store NO. Therefore, the antihypertensive effect of IHC in young SHR is associated with prevention of endothelial dysfunction and with increased accumulation of NO stores in vascular walls. PMID- 21652604 TI - Protective effect of dammarane sapogenins against chemotherapy-induced myelosuppression in mice. AB - Chemotherapy is the most common way to treat malignancies, but myelosuppression, one of its common side-effects, is a formidable problem. The present study described the protective role of dammarane sapogenins (DS), an active fraction from oriental ginseng, on myelosuppression induced by cyclophosphamide (CP) in mice. DS was orally administered at different dosages (37.5, 75, and 150 mg/kg) for 10 d after CP administration (200 mg/kg intraperitoneally). The results showed that DS increased the number of white blood cells (WBC) on day 3 and day 7 (P < 0.05), such that WBC levels were increased by 105.7 +/- 29.5% at 75 mg/kg of DS on day 3 (P < 0.05, compared with the CP group). Similar results were observed in red blood cells and platelets in DS-treated groups. The colony-forming assay demonstrated that the depressed numbers of CFU-GM (colony-forming unit granulocyte and macrophage), CFU-E (colony-forming unit-erythroid), BFU-E (burst forming unit-erythroid), CFU-Meg (colony-forming unit-megakaryocyte) and CFU-GEMM (colony-forming unit-granulocyte, -erythrocyte, -monocyte and -megakaryocyte) induced by CP were significantly reversed after DS treatment. Moreover, the ameliorative effect of DS on myelosuppression was also observed in the femur by hematoxylin/eosin staining. In DS-treated groups, ConA-induced splenocyte proliferation was enhanced significantly at all the doses (37.5, 75, 150 mg/kg) on day 3 at the rate of 50.3 +/- 8.0%, 77.6 +/- 8.5% and 44.5 +/- 8.4%, respectively, while lipopolysaccharide-induced proliferation was increased mainly on day 7 (P < 0.01), with an increased rate of 39.8 +/- 5.6%, 34.9 +/- 6.6% and 38.3 +/- 7.3%, respectively. The thymus index was also markedly increased by 70.4% and 36.6% at 75 mg/kg on days 3 and 7, respectively, as compared with the CP group. In summary, DS has a protective function against CP-induced myelosuppression. Its mechanism might be related to stimulating hematopoiesis recovery, as well as enhancing the immunological function. PMID- 21652605 TI - Psychopharmacology of the endocannabinoids: far beyond anandamide. AB - The study of endocannabinoid pharmacology has proceeded from the discovery of Delta9-tetrahydrocannabinol, the main psychoactive compound in Cannabis sativa, to the identification of an endogenous endocannabinoid system that is essential for physiological modulation of neuronal functions. We have not yet achieved a complete understanding of the various roles of the endocannabinoids, but this is one of the fastest-growing fields in psychopharmacology. This review starts with a brief historical description of the discovery of the endocannabinoids and then focuses on recent pharmacological advances and recently discovered endocannabinoid mechanisms of action (e.g. functional selectivity, allosterism, and receptor trafficking). Finally, we will discuss the contention that the existence of evidence-based therapeutic applications for cannabinoids and the wide range of physiological functions affected by endocannabinoids suggests that the careful study of the endocannabinoid system may lead to the development of novel therapeutic drugs with higher societal acceptability and lower side effects profiles. PMID- 21652606 TI - A pharmacogenetic study of risperidone on histamine H3 receptor gene (HRH3) in Chinese Han schizophrenia patients. AB - Evidence suggests that the human histamine H3 receptor (HRH3) may be involved in the pharmacodynamics of risperidone and influence clinical efficacy. More information on the pharmacogenetics of this receptor may therefore be useful in developing individualized therapy. However, to our knowledge, no study has been reported in this area. The aim of this investigation was to clarify whether H3 receptor polymorphism could affect risperidone efficacy. We genotyped tag single nucleotide polymorphisms (SNPs) of the HRH3 gene (rs3787429 and rs3787430) and analyzed their association with the reduction of Brief Psychiatric Rating Scale (BPRS) score in Chinese Han schizophrenia patients (N = 129), following an eight week period of risperidone monotherapy. The confounding effects of non-genetic factors were estimated, and then the significant one was included as the covariate for adjustment in statistical analysis. Baseline symptom score was the only significant confounding effect and thus the covariate. After adjustment, significant association of HRH3 with antipsychotic efficacy was detected (for rs3787429, p = 0.013, 0.087 after 4 weeks and 8 weeks of treatment, respectively; for rs3787430, p = 0.024, 0.010 after 4 weeks and 8 weeks of treatment, respectively) and stood up to conservative Bonferroni correction. Our results demonstrate that polymorphism of the HRH3 gene may be a potential genetic marker for predicting the therapeutic effect of risperidone, and suggest novel pharmacological links between HRH3 and risperidone. Further studies with larger samples and different ethnic populations are warranted to confirm our results. PMID- 21652607 TI - Treatment-induced downregulation of antiphospholipid antibodies: effect of rituximab alone on clinical and laboratory features of antiphospholipid syndrome. PMID- 21652608 TI - The IDDEA project: a strategy for the detection of alpha-1 antitrypsin deficiency in COPD patients in the primary care setting. AB - OBJECTIVE: Primary care provides the main route for access to health care for patients with common chronic illnesses such as chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin (AAT) deficiency is an underdiagnosed pathology associated with COPD risk which has a very low prevalence. The Information and Detection of the Deficiency of AAT (IDDEA) project was developed to identify AAT-deficient patients at primary care centres by providing adequate diagnostic tools to family doctors. METHODS: Patients with COPD were identified and registered on a specially designed website. Dried blood samples were collected on filter papers and sent to the laboratory for AAT levels and AAT deficiency-related genotype determinations. RESULTS: were uploaded to the website and analysed. RESULTS: Between January 2008 and April 2009, 596 patients were identified by 90 participating physicians. The number of patients who did not have AAT deficiency (serum concentrations >=60 mg AAT/dl) was 549 (98.9%). Nineteen patients (3.2%) were carriers of the allelic variant Pi*Z among which two were homozygous PiZZ (one of them was an index case) and one was heterozygous PiSZ. These three newly detected cases were registered in the Spanish Registry of Patients with AAT Deficiency. An estimate of the gene frequency of the S allele was 7.65% and the severe deficiency Z allele was 1.76%. CONCLUSIONS: Results confirm that ATT deficiency is still underdiagnosed. The IDDEA system appears to be a useful tool for the detection of AAT deficiency in the primary care setting. PMID- 21652609 TI - Delayed fingolimod-associated asystole. AB - Oral fingolimod (Gilenya) is a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Fingolimod reduces relapses and delays disability progression in patients with relapsing forms of multiple sclerosis (MS). We report a patient with MS who developed asystole and sustained bradycardia 21 hours after the first dose of fingolimod. PMID- 21652610 TI - Epidemiology of multiple sclerosis in south-western Sardinia. AB - BACKGROUND: Sardinia is a known high-risk area for multiple sclerosis (MS), but no data for south-western Sardinia (SWS) are available. SWS has a genetically homogeneous population, apart from St Peter Island, and represents a peculiar environment related to the industrial, mineralogical and military economy. OBJECTIVE: To estimate prevalence and incidence and to evaluate temporal trends and geographical distribution of MS in SWS. METHODS: MS prevalence was evaluated on 31 December 2007 and crude mean annual incidence rate was defined between 2003 and 2007. Temporal trend in MS incidence was assessed using the Armitage test. To identify MS clusters, Standard Morbidity Ratio (SMR) was calculated for each village and geographical distribution prevalence by means of a Bayesian hierarchical model. RESULTS: Total crude prevalence rate was 210.4 (95% CI 186.3 234.5): 280.3 (95% CI 241.4-319.3) for females, 138 (95% CI 110.1-165.8) for males. The crude mean annual incidence rate was 9.7/100,000 (95% CI 3.4-13.2): 4.7/100,000 (95% CI 2.4-17.0) and 14.6/100,000 (95% CI 11.8-34.8) for males and females respectively. MS incidence has increased over the last 50 years. Cluster analysis showed an SMR of 0.2 (95% CI 0.05-0.68, p = 0.002) on the island of San Pietro, and 2.0 (95% CI 1.35-2.95, p = 0.001) in Domusnovas. Spatial distribution of MS was confirmed by Bayesian geographical analysis. CONCLUSIONS: Our data confirm Sardinia as a high-risk area for MS and support the relevance of genetic factors in MS, as evidenced in St Peter Island. However, we found an unexpectedly high MS prevalence in one village, in particular in males, suggesting an environmental influence on MS occurrence. PMID- 21652611 TI - Fatigue in multiple sclerosis: which patient should be referred to a sleep specialist? PMID- 21652613 TI - Large-scale phylogenomic analyses indicate a deep origin of primary plastids within cyanobacteria. AB - The emergence of photosynthetic eukaryotes has played a crucial role in evolution and has strongly modified earth's ecology. Several phylogenetic analyses have established that primary plastids arose from a cyanobacterium through endosymbiosis. However, the question of which present-day cyanobacterial lineage is most closely related to primary plastids has been unclear. Here, we have performed an extensive phylogenomic investigation on the origin of primary plastids based on the analysis of up to 191 protein markers and over 30,000 aligned amino acid sites from 22 primary photosynthetic eukaryotes and 61 cyanobacteria representing a wide taxonomic sampling of this phylum. By using a number of solutions to circumvent a large range of systematic errors, we have reconstructed a robust global phylogeny of cyanobacteria and studied the placement of primary plastids within it. Our results strongly support an early emergence of primary plastids within cyanobacteria, prior to the diversification of most present-day cyanobacterial lineages for which genomic data are available. PMID- 21652612 TI - Long-term balancing selection at the blood group-related gene B4galnt2 in the genus Mus (Rodentia; Muridae). AB - Recent surveys of the human genome have highlighted the significance of balancing selection in relation to understanding the evolutionary origins of disease associated variation. Cis-regulatory variation at the blood group-related glycosyltransferase B4galnt2 is associated with a phenotype in mice that closely resembles a common human bleeding disorder, von Willebrand disease. In this study, we have performed a survey of the 5' flanking region of the B4galnt2 gene in several Mus musculus subspecies and Mus spretus. Our results reveal a clear pattern of trans-species polymorphism and indicate that allele classes conferring alternative tissue-specific expression patterns have been maintained for >2.8 My in the genus Mus. Furthermore, analysis of B4galnt2 expression patterns revealed the presence of an additional functional class of alleles, supporting a role for gastrointestinal phenotypes in the long-term maintenance of expression variation at this gene. PMID- 21652614 TI - Unhealthy weight control behaviors among adolescents. AB - This article examined moderators of the association between BMI and unhealthy weight control behaviors suggested by the Dual Pathway Model among 4,529 adolescents from the Health Behavior in School-Aged Children survey. An obese classification was associated with unhealthy weight control behaviors for boys and girls. Low life satisfaction, high negative affect, and body size dissatisfaction were associated with unhealthy weight control behaviors among boys as was low life satisfaction for girls. Among girls, healthy weight classification, coupled with low negative affect or body size satisfaction, was protective against unhealthy weight control behaviors. Improved self-care may decrease obesity and unhealthy weight control behaviors. PMID- 21652615 TI - Randomized clinical trial of the i-gelTM and Magill tracheal tube or single-use ILMATM and ILMATM tracheal tube for blind intubation in anaesthetized patients with a predicted difficult airway. AB - BACKGROUND: The single-use supraglottic airway device i-gelTM has been described in several case reports as a conduit for intubation, but no prospective data about success rates of blind intubation are available. Therefore, we performed this prospective randomized controlled trial to compare the success rate of blind tracheal intubation with a Magill PVC tube through the i-gelTM with intubation using an sILMATM PVC tube through the single-use intubating laryngeal mask airway (sILMATM). METHODS: With ethics committee approval and written informed consent, 80 patients with predictors of a difficult airway were computer randomized to either supraglottic airway device (SAD). The corresponding tracheal tube (TT) was introduced through the SAD under fibreoptic visualization but without fibreoptic guidance. Primary outcome was blind intubation success rate. Times, airway leak pressure, fibreoptic view, and adverse events were recorded. To control for the influence of the TT, we compared data from 40 patients described in an accompanying study (sILMATM with Magill TT and i-gelTM with sILMATM TT). RESULTS: Blind intubation success rate through the sILMATM (69%) was higher than with the i-gelTM (15%, P<0.001). Data from the other patient group excluded the TT type as the primary cause for the difference in success rate. Removal of SADs was without problems with no difference between the type of SAD. CONCLUSIONS: Blind tracheal intubation using the sILMATM tube through the sILMATM is much more successful than blind intubation with a Magill PVC tube through the i-gelTM. Because of its low success rate, we would not recommend blind intubation through the i-gelTM. PMID- 21652616 TI - Randomized trial comparing the i-gelTM and Magill tracheal tube with the single use ILMATM and ILMATM tracheal tube for fibreoptic-guided intubation in anaesthetized patients with a predicted difficult airway. AB - BACKGROUND: The i-gelTM is a single-use supraglottic airway device (SAD) that allows fibreoptic-guided tracheal intubation through the device. Until now, no prospective data for this procedure are available. Therefore, in a prospective randomized controlled trial, we evaluated fibreoptic-guided tracheal intubation with a standard RuschTM PVC tracheal tube (TT) through the i-gelTM compared with the single-use ILMATM (sILMATM) TT through the sILMATM in patients with a predicted difficult airway. METHODS: With ethics committee approval and written informed consent, 160 patients were randomly assigned to either SAD. After placement of the SAD, a fibreoptic bronchoscope was introduced into the trachea as a railroad for the TT. Primary outcome variable was the first-attempt fibreoptic-guided intubation success rate. Secondary variables included time for insertion and intubation, airway leak pressures, fibreoptic view, and adverse events. Data are presented as mean (sd) or percentages. A P-value of < 0.05 was considered statistically significant. RESULTS: Fibreoptic-guided intubation was successful at the first attempt in 76 patients (96%) using the i-gelTM and in 71 patients (90%) using the sILMATM (P=0.21). Most of the failed intubations were rescued by conventional laryngoscopy. Airway leak pressure was higher for the sILMATM. There were no problems during removal of either type of SAD. CONCLUSIONS: Fibreopic-guided tracheal intubation through the i-gelTM using a standard RuschTM Magill TT is successful and an alternative to the sILMATM with the sILMATM TT. PMID- 21652617 TI - Open lung approach vs acute respiratory distress syndrome network ventilation in experimental acute lung injury. AB - BACKGROUND: Setting and strategies of mechanical ventilation with positive end expiratory pressure (PEEP) in acute lung injury (ALI) remains controversial. This study compares the effects between lung-protective mechanical ventilation according to the Acute Respiratory Distress Syndrome Network recommendations (ARDSnet) and the open lung approach (OLA) on pulmonary function and inflammatory response. METHODS: Eighteen juvenile pigs were anaesthetized, mechanically ventilated, and instrumented. ALI was induced by surfactant washout. Animals were randomly assigned to mechanical ventilation according to the ARDSnet protocol or the OLA (n=9 per group). Gas exchange, haemodynamics, pulmonary blood flow (PBF) distribution, and respiratory mechanics were measured at intervals and the lungs were removed after 6 h of mechanical ventilation for further analysis. RESULTS: PEEP and mean airway pressure were higher in the OLA than in the ARDSnet group [15 cmH(2)O, range 14-18 cmH(2)O, compared with 12 cmH(2)O; 20.5 (sd 2.3) compared with 18 (1.4) cmH(2)O by the end of the experiment, respectively], and OLA was associated with improved oxygenation compared with the ARDSnet group after 6 h. OLA showed more alveolar overdistension, especially in gravitationally non-dependent regions, while the ARDSnet group was associated with more intra alveolar haemorrhage. Inflammatory mediators and markers of lung parenchymal stress did not differ significantly between groups. The PBF shifted from ventral to dorsal during OLA compared with ARDSnet protocol [-0.02 (-0.09 to -0.01) compared with -0.08 (-0.12 to -0.06), dorsal-ventral gradients after 6 h, respectively]. CONCLUSIONS: According to the OLA, mechanical ventilation improved oxygenation and redistributed pulmonary perfusion when compared with the ARDSnet protocol, without differences in lung inflammatory response. PMID- 21652618 TI - Directly acting antivirals against hepatitis C virus. AB - The approval of directly acting antivirals (DAA) for the treatment of chronic hepatitis C virus (HCV) infection will represent a major breakthrough for the 180 million persons infected worldwide. Paradoxically, hepatitis C is the only human chronic viral disease that can be cured, as all other pathogenic viruses infecting humans either display self-limited courses or establish non-eradicable persistent infections. Until now, treatment of chronic hepatitis C consisted of the combination of peginterferon-alpha plus ribavirin, which provided limited rates of cure and was associated with frequent side effects. Several DAA have been identified that inhibit the NS3 protease, the NS5B polymerase or the NS5A replication complex, and have entered the final steps of clinical development. These molecules, coupled with significant progress made in the recognition of more potent and safe interferon forms (e.g. interferon-lambda) and host protein targets (e.g. alisporivir), are opening a new era in hepatitis C therapeutics. The expectations are so great that, to some extent, it is reminiscent of what happened in 1996 in the HIV field when the introduction of the first protease inhibitors as part of triple combinations revolutionized antiretroviral therapy. To maximize treatment success and reduce the likelihood of drug resistance selection, a proper individualization of hepatitis C therapy will be required, choosing the most convenient drugs and strategies according to distinct viral and host profiles. The complexity of HCV therapeutics has reached a point that presumably will lead to the birth of a new specialist, the HCV doctor. PMID- 21652619 TI - 96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA <50 copies/mL at baseline. AB - BACKGROUND: In virologically suppressed patients, switching to darunavir/ritonavir monotherapy could avoid resistance and adverse events from continuing nucleoside analogues. METHODS: Two hundred and fifty-six patients with HIV RNA <50 copies/mL on current antiretrovirals were switched to darunavir/ritonavir 800/100 mg once daily, either as monotherapy (n = 127) or with two nucleoside analogues (n = 129). Treatment failure was defined as two consecutive HIV RNA levels at least 50 copies/mL by week 96, or discontinuation of study drugs. The trial had 80% power to show non-inferiority (delta = -12%) at week 48. Results Patients were 81% male, 91% Caucasian, and had a median baseline CD4 count of 575 cells/mm(3). There were more patients with hepatitis C co infection at baseline in the monotherapy arm (18%) compared with the triple therapy arm (12%). In the efficacy analysis, HIV RNA <50 copies/mL by week 96 (per protocol, time to loss of virological response, switch equals failure) was 78% versus 82% in the monotherapy and triple therapy arms [difference -4.2%, 95% confidence interval (CI) -14.3% to +5.8%]; in a switch included analysis, HIV RNA <50 copies/mL was 93% versus 92% (difference +1.6%, 95% CI -5.0% to +8.1%). The percentage of patients with HIV RNA <5 copies/mL (optical density from the sample equal to the negative control) remained constant over time in both treatment arms. Conclusions In the week 96 analysis of the MONotherapy in Europe with TMC114 (MONET) trial, switching to darunavir/ritonavir monotherapy showed non inferior efficacy to darunavir/ritonavir plus two nucleoside analogues in the switch included and observed failure analyses, but not in the main switch equals failure analysis. PMID- 21652620 TI - Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukaemia. AB - BACKGROUND: Vincristine is one of the cornerstones of the treatment of children with acute lymphoblastic leukaemia (ALL). Constipation, and peripheral and central neurotoxicities are the most common side effects. A comparative study exploring vincristine toxicity in individual patients receiving vincristine with and without azoles, however, is lacking. METHODS: In total, 20 paediatric patients with de novo ALL were included. In each patient, vincristine toxicity in the period with and without azole co-medication was retrospectively graded according to the US National Cancer Institute toxicity scale. Statistical analysis was performed using the Wilcoxon signed rank test and McNemar's test. RESULTS: Patients receiving vincristine in combination with azole treatment experienced significantly more constipation and peripheral neurotoxicity (P = 0.001 and P < 0.001, respectively). Vincristine-induced CNS toxicity was only seen in patients (30%) receiving vincristine in combination with azole treatment. CONCLUSIONS: Vincristine toxicity is significantly enhanced when combined with azole treatment and can even be life threatening. Therefore, we advise avoidance of the combination of azole and vincristine treatments in patients with ALL. PMID- 21652621 TI - Genetic analysis of new 16S rRNA mutations conferring aminoglycoside resistance in Mycobacterium abscessus. AB - OBJECTIVES: We studied the development and fitness cost of 2-deoxystreptamine aminoglycoside resistance of Mycobacterium abscessus. METHODS: Spontaneous 2 deoxystreptamine aminoglycoside-resistant mutants were selected and the frequency of their appearance was determined. The 3' part of the rrs gene was sequenced to characterize mutations. Additionally, we determined the MICs of aminoglycoside drugs for the different mutants obtained. The dominance/recessivity traits of the different mutations were examined and we explored the potential cost conferred by the mutations selected in vitro on the fitness of these isolates compared with the wild-type strain. RESULTS: The in vitro mutation rate for 2-deoxystreptamine aminoglycoside resistance was ~10(-7) mutations/cell division. In addition to the known rrs A->G substitution at position 1408 (Escherichia coli numbering), which confers kanamycin resistance (Kan(R)), three new substitutions in rrs were identified in M. abscessus Kan(R) mutants, i.e. T->A at 1406, C->T at 1409 and G >T at 1491. Heterodiploids carrying genomic mutations T->A at 1406 and A->G at 1408 with the wild-type rrs gene carried by the pNBV1 vector showed a resistant phenotype. In contrast, heterodiploids carrying genomic mutations C->T at 1409 and G->T at 1491 with the wild-type rrs gene carried by the pNBV1 vector had a susceptible phenotype. No burden on fitness was observed for the different mutations. CONCLUSION: Mutations in the rrs gene that confer high-level 2 deoxystreptamine aminoglycoside resistance on M. abscessus differ in their dominance/recessivity traits and have no biological cost under our experimental conditions. PMID- 21652622 TI - Risk factors for prolonged carriage of vancomycin-resistant Enterococcus faecium among patients in intensive care units: a case-control study. AB - OBJECTIVES: The aim of this study was to identify the risk factors for prolonged carriage of vancomycin-resistant Enterococcus faecium (VREF) in intensive care units (ICUs). METHODS: A retrospective case-control study was performed in the ICUs of a university hospital in Korea from September 2006 to July 2009. VREF carriage was identified through weekly active surveillance rectal cultures. Clinical characteristics and the risk factors for VREF acquisition were compared between cases with prolonged VREF carriage (>= 5 weeks, n = 58) and controls with shorter VREF carriage (<3 weeks, n = 36) in a multivariate logistic regression model. The effect of vancomycin consumption on vancomycin-resistant enterococci (VRE) colonization pressure was investigated using time-series analysis with an autoregressive error model. RESULTS: Out of a total of 6327 rectal swab cultures examined, 1915 (30.3%) specimens from 266 patients were positive for VREF. The weekly VRE colonization pressure ranged from 0.77% to 42.42%. Vancomycin use after VREF acquisition significantly increased VREF carriage (adjusted odds ratio = 4.09; 95% confidence interval = 1.32-12.65). The case group had higher in hospital mortality than the control group [21 (36.2%) versus 4 (11.1%), P = 0.007]. Increment of VRE colonization pressure was significantly associated with vancomycin consumption of 1week before (i.e. time t - 1) (P = 0.0028) and moderately associated with that of the corresponding week (i.e. time t) (P = 0.0595). CONCLUSIONS: Vancomycin use in patients with VREF colonization might prolong the duration of carriage. Restriction of vancomycin use should be strengthened in these patients through infection control measures. PMID- 21652623 TI - Transmission electron microscopy investigation of colloids and particles from landfill leachates. AB - Leachates collected at two (active and closed) municipal solid waste (MSW) landfills were examined for colloids and particles by transmission electron microscopy, energy dispersive spectrometry, selected area electron diffraction and for the chemical compositions of the filtrates after the filtration to 0.1 um and ultrafiltration to 1 kDa (~ 1 nm). Six groups of colloids/particles in the range 5 nm to 5 um were determined (in decreasing order of abundance): carbonates, phyllosilicates (clay minerals and micas), quartz, Fe-oxides, organics and others (salts, phosphates). Inorganic colloids/particles in leachates from the active landfill predominantly consist of calcite (CaCO(3)) and minor clay minerals and quartz (SiO(2)). The colloids/particles in the leachates from the closed landfill consist of all the observed groups with dominant phyllosilicates. Whereas calcite, Fe-oxides and phosphates can precipitate directly from the leachates, phyllosilicates and quartz are more probably either derived from the waste or formed by erosion of the geological environment of the landfill. Low amounts of organic colloids/particles were observed, indicating the predominance of organic molecules in the 'truly dissolved' fraction (fulvic compounds). Especially newly formed calcite colloids forming particles of 500 nm and stacking in larger aggregates can bind trace inorganic contaminants (metals/metalloids) and immobilize them in landfill environments. PMID- 21652624 TI - Application of material flow analysis to estimate the efficiency of e-waste management systems: the case of Lithuania. AB - Electrical and electronic equipment (EEE) has penetrated everyday life. The EEE industry is characterized by a rapid technological change which in turn prompts consumers to replace EEE in order to keep in step with innovations. These factors reduce an EEE life span and determine the exponential growth of the amount of obsolete EEE as well as EEE waste (e-waste). E-waste management systems implemented in countries of the European Union (EU) are not able to cope with the e-waste problem properly, especially in the new EU member countries. The analysis of particular e-waste management systems is essential in evaluation of the complexity of these systems, describing and quantifying the flows of goods throughout the system, and all the actors involved in it. The aim of this paper is to present the research on the regional agent based material flow analysis in e-waste management systems, as a measure to reveal the potential points for improvement. Material flow analysis has been performed as a flow of goods (EEE). The study has shown that agent-based EEE flow analysis incorporating a holistic and life cycle thinking approach in national e-waste management systems gives a broader view to the system than a common administrative one used to cover. It helps to evaluate the real efficiency of e-waste management systems and to identify relevant impact factors determining the current operation of the system. PMID- 21652625 TI - Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function. AB - LIS1, a WD40 repeat scaffold protein, interacts with components of the cytoplasmic dynein motor complex to regulate dynein-dependent cell motility. Here, we reveal that cAMP-specific phosphodiesterases (PDE4s) directly bind PAFAH1B1 (also known as LIS1). Dissociation of LIS1-dynein complexes is coupled with loss of dynein function, as determined in assays of both microtubule transport and directed cell migration in wounded monolayers. Such loss in dynein functioning can be achieved by upregulation of PDE4, which sequesters LIS1 away from dynein, thereby uncovering PDE4 as a regulator of dynein functioning. This process is facilitated by increased intracellular cAMP levels, which selectively augment the interaction of long PDE4 isoforms with LIS1 when they become phosphorylated within their regulatory UCR1 domain by protein kinase A (PKA). We propose that PDE4 and dynein have overlapping interaction sites for LIS1, which allows PDE4 to compete with dynein for LIS1 association in a process enhanced by the PKA phosphorylation of PDE4 long isoforms. This provides a further example to the growing notion that PDE4 itself may provide a signalling role independent of its catalytic activity, exemplified here by its modulation of dynein motor function. PMID- 21652626 TI - Involvement of afadin in barrier function and homeostasis of mouse intestinal epithelia. AB - Afadin interacts with the cytoplasmic region of nectins, which are immunoglobulin like cell adhesion molecules at adherens junctions, and links them to the actin cytoskeleton. Afadin regulates activities of cells in culture such as directional motility, proliferation and survival. We used Cre-loxP technology to generate mice conditionally lacking afadin specifically in the intestinal epithelia after birth. The loss of afadin caused increased paracellular permeability in the intestinal mucosa and enhanced susceptibility to the tissue destruction induced by dextran sulfate sodium. The junctional architecture of the intestinal epithelia appeared to be preserved, whereas the deficiency of afadin caused the mislocalization of nectin-2 and nectin-3 from adherens junctions to basolateral membrane domains but not that of other components of apical junctions. By contrast, such phenotypic changes were undetected in mice lacking nectin-2, nectin-3 or both. These findings suggest that afadin plays crucial roles, independently of the role as the nectin-afadin module, in barrier function and homeostasis of the intestinal epithelia once the epithelial structure has been established. PMID- 21652628 TI - Arabidopsis RHD3 mediates the generation of the tubular ER network and is required for Golgi distribution and motility in plant cells. AB - In plant cells, the endoplasmic reticulum (ER) and Golgi apparatus form a unique system in which single Golgi stacks are motile and in close association with the underlying ER tubules. Arabidopsis has three RHD3 (ROOT HAIR DEFECTIVE 3) isoforms that are analogous to the mammalian atlastin GTPases involved in shaping ER tubules. We used live-cell imaging, genetic complementation, split ubiquitin assays and western blot analyses in Arabidopsis and tobacco to show that RHD3 mediates the generation of the tubular ER network and is required for the distribution and motility of Golgi stacks in root and leaf epidermal cells. We established that RHD3 forms homotypic interactions at ER punctae. In addition, the activity of RHD3 on the tubular ER is specifically correlated with the cellular distribution and motility of Golgi stacks because ER to Golgi as well as Golgi to plasma membrane transport was not affected by RHD3 mutations in the conserved GDP/GTP motifs. We found a possible partial redundancy within the RHD3 isoforms in Arabidopsis. However, yeast Sey1p, a functional atlastin homologue, and RHD3 are not interchangeable in complementing the respective loss-of-function mutants, suggesting that the molecular mechanisms controlling ER tubular morphology might not be entirely conserved among eukaryotic lineages. PMID- 21652627 TI - Identifying an uptake mechanism for the antiepileptic and bipolar disorder treatment valproic acid using the simple biomedical model Dictyostelium. AB - Valproic acid (VPA) is the most highly prescribed epilepsy treatment worldwide and is also used to prevent bipolar disorder and migraine. Surprisingly, very little is known about its mechanisms of cellular uptake. Here, we employ a range of cellular, molecular and genetic approaches to characterize VPA uptake using a simple biomedical model, Dictyostelium discoideum. We show that VPA is taken up against an electrochemical gradient in a dose-dependent manner. Transport is protein-mediated, dependent on pH and the proton gradient and shows strong substrate structure specificity. Using a genetic screen, we identified a protein homologous to a mammalian solute carrier family 4 (SLC4) bicarbonate transporter that we show is involved in VPA uptake. Pharmacological and genetic ablation of this protein reduces the uptake of VPA and partially protects against VPA dependent developmental effects, and extracellular bicarbonate competes for VPA uptake in Dictyostelium. We further show that this uptake mechanism is likely to be conserved in both zebrafish (Danio rerio) and Xenopus laevis model systems. These results implicate, for the first time, an uptake mechanism for VPA through SLC4-catalysed activity. PMID- 21652629 TI - Differential altered stability and transcriptional activity of DeltaNp63 mutants in distinct ectodermal dysplasias. AB - Heterozygous mutations of p63, a key transcription factor in epithelial development, are causative in a variety of human ectodermal dysplasia disorders. Although the mutation spectrum of these disorders displays a striking genotype phenotype association, the molecular basis for this association is only superficially known. Here, we characterize the transcriptional activity and protein stability of DeltaNp63 mutants (that is, mutants of a p63 isoform that lacks the N-terminal transactivation domain) that are found in ectrodactyly ectodermal dysplasia-cleft syndrome (EEC), ankyloblepharon-ectodermal dysplasia clefting syndrome (AEC) and nonsyndromic split-hand/split-foot malformation (SHFM). DNA-binding and sterile alpha motif (SAM) domain mutants accumulate in the skin of EEC and AEC syndrome patients, respectively, and show extended half lives in vitro. By contrast, C-terminal mutations found in SHFM patients have half-lives similar to that of the wild-type protein. The increased half-life of EEC and AEC mutant proteins was reverted by overexpression of wild-type DeltaNp63. Interestingly, the mutant proteins exhibit normal binding to and degradation by the E3 ubiquitin ligase Itch. Finally, EEC and AEC mutant proteins have reduced transcriptional activity on several skin-specific gene promoters, whereas SHFM mutant proteins are transcriptionally active. Our results, therefore, provide evidence for a regulatory feedback mechanism for p63 that links transcriptional activity to regulation of protein homeostasis by an unknown mechanism. Disruption of this regulatory mechanism might contribute to the pathology of p63-related developmental disorders. PMID- 21652630 TI - Characterization of Mug33 reveals complementary roles for actin cable-dependent transport and exocyst regulators in fission yeast exocytosis. AB - Although endocytosis and exocytosis have been extensively studied in budding yeast, there have been relatively few investigations of these complex processes in the fission yeast Schizosaccharomyces pombe. Here we identify and characterize fission yeast Mug33, a novel Tea1-interacting protein, and show that Mug33 is involved in exocytosis. Mug33 is a Sur7/PalI-family transmembrane protein that localizes to the plasma membrane at the cell tips and to cytoplasmic tubulovesicular elements (TVEs). A subset of Mug33 TVEs make long-range movements along actin cables, co-translocating with subunits of the exocyst complex. TVE movement depends on the type V myosin Myo52. Although mug33Delta mutants are viable, with only a mild cell-polarity phenotype, mug33Delta myo52Delta double mutants are synthetically lethal. Combining mug33 Delta with deletion of the formin For3 (for3Delta) leads to synthetic temperature-sensitive growth and strongly reduced levels of exocytosis. Interestingly, mutants in non-essential genes involved in exocyst function behave in a manner similar to mug33Delta when combined with myo52Delta and for3Delta. By contrast, combining mug33Delta with mutants in non-essential exocyst genes has only minor effects on growth. We propose that Mug33 contributes to exocyst function and that actin cable-dependent vesicle transport and exocyst function have complementary roles in promoting efficient exocytosis in fission yeast. PMID- 21652631 TI - Transgenic overexpression of the alpha7 integrin reduces muscle pathology and improves viability in the dy(W) mouse model of merosin-deficient congenital muscular dystrophy type 1A. AB - Merosin-deficient congenital muscular dystrophy 1A (MDC1A) is a devastating neuromuscular disease that results in children being confined to a wheelchair, requiring ventilator assistance to breathe and premature death. MDC1A is caused by mutations in the LAMA2 gene, which results in the partial or complete loss of laminin-211 and laminin-221, the major laminin isoforms found in the basal lamina of skeletal muscle. MDC1A patients exhibit reduced alpha7beta1 integrin; however, it is unclear how the secondary loss of alpha7beta1 integrin contributes to MDC1A disease progression. To investigate whether restoring alpha7 integrin expression can alleviate the myopathic phenotype observed in MDC1A, we produced transgenic mice that overexpressed the alpha7 integrin in the skeletal muscle of the dy(W-/ ) mouse model of MDC1A. Enhanced expression of the alpha7 integrin restored sarcolemmal localization of the alpha7beta1 integrin to laminin-alpha2-deficient myofibers, changed the composition of the muscle extracellular matrix, reduced muscle pathology, maintained muscle strength and function and improved the life expectancy of dy(W-/-) mice. Taken together, these results indicate that enhanced expression of alpha7 integrin prevents muscle disease progression through augmentation and/or stabilization of the existing extracellular matrix in laminin alpha2-deficient mice, and strategies that increase alpha7 integrin in muscle might provide an innovative approach for the treatment of MDC1A. PMID- 21652632 TI - Arginine methylation of G3BP1 in response to Wnt3a regulates beta-catenin mRNA. AB - Wnt/beta-catenin signaling is essential for normal mammalian development. Wnt3a activates the Wnt/beta-catenin pathway through stabilization of beta-catenin; a process in which the phosphoprotein Dishevelled figures prominently. Protein arginine methylation in signaling complexes containing Dishevelled was investigated. Mass spectrometry of a prominent arginine-methylated, Dishevelled associated protein identified the Ras GTPase activating protein-binding protein 1 G3BP1. Stimulation of totipotent mouse embryonic F9 cells with Wnt3a provoked increased methylation of G3BP1. We show that G3BP1 is a novel Ctnnb1 mRNA binding protein. Methylation of G3BP1 constitutes a molecular switch that regulates Ctnnb1 mRNA in response to Wnt3a. Thus, the protein arginine methylation that targets G3BP1 acts as a novel regulator of Ctnnb1 mRNA. PMID- 21652633 TI - Malin and laforin are essential components of a protein complex that protects cells from thermal stress. AB - The heat-shock response is a conserved cellular process characterized by the induction of a unique group of proteins known as heat-shock proteins. One of the primary triggers for this response, at least in mammals, is heat-shock factor 1 (HSF1)--a transcription factor that activates the transcription of heat-shock genes and confers protection against stress-induced cell death. In the present study, we investigated the role of the phosphatase laforin and the ubiquitin ligase malin in the HSF1-mediated heat-shock response. Laforin and malin are defective in Lafora disease (LD), a neurodegenerative disorder associated with epileptic seizures. Using cellular models, we demonstrate that these two proteins, as a functional complex with the co-chaperone CHIP, translocate to the nucleus upon heat shock and that all the three members of this complex are required for full protection against heat-shock-induced cell death. We show further that laforin and malin interact with HSF1 and contribute to its activation during stress by an unknown mechanism. HSF1 is also required for the heat-induced nuclear translocation of laforin and malin. This study demonstrates that laforin and malin are key regulators of HSF1 and that defects in the HSF1 mediated stress response pathway might underlie some of the pathological symptoms in LD. PMID- 21652634 TI - Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3-Galphaq coupling. AB - Recent evidence suggests that inflammation is involved in malignant progression of breast cancer. Sphingosine 1-phosphate (S1P), acting on the G-protein-coupled receptors, is known as a potent inflammatory mediator. In this study, the effect of the inflammatory lipid S1P on the regulation of invasive/migratory phenotypes of MCF10A human breast epithelial cells was investigated to elucidate a causal relationship between inflammation and the control of invasiveness of breast cells. We show that S1P causes induction of matrix metalloproteinase-9 (MMP-9) in vitro and in vivo, and thus enhances invasion and migration. We also show that fos plays a crucial role in the transcriptional activation of MMP-9 by S1P. In addition, activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2), p38 and alpha serine/threonine-protein kinase (Akt) are involved in the process of S1P-mediated induction of MMP-9 expression and invasion. Activation of the S1P receptor S1P3 and G(alphaq) are required for S1P-induced invasive/migratory responses, suggesting that the enhancement of S1P-mediated invasiveness is triggered by the specific coupling of S1P3 to the heterotrimeric G(alphaq) subunit. Activation of phospholipase C-beta4 and intracellular Ca2+ release are required for S1P-induced MMP-9 upregulation. Taken together, this study demonstrated that S1P regulates MMP-9 induction and invasiveness through coupling of S1P3 and G(alphaq) in MCF10A cells, thus providing a molecular basis for the crucial role of S1P in promoting breast cell invasion. PMID- 21652635 TI - Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells. AB - Fbxo7 is an unusual F-box protein because most of its interacting proteins are not substrates for ubiquitin-mediated degradation. Fbxo7 directly binds p27 and Cdk6, enhances the level of cyclin D-Cdk6 complexes, and its overexpression causes Cdk6-dependent transformation of immortalised fibroblasts. Here, we test the ability of Fbxo7 to transform haematopoietic pro-B (Ba/F3) cells which, unexpectedly, it was unable to do despite high levels of Cdk6. Instead, reduction of Fbxo7 expression increased proliferation, decreased cell size and shortened G1 phase. Analysis of cell cycle regulators showed that cells had decreased levels of p27, and increased levels of S phase cyclins and Cdk2 activity. Also, Fbxo7 protein levels correlated inversely with those of CD43, suggesting direct regulation of its expression and, therefore, of B cell maturation. Alterations to Cdk6 protein levels did not affect the cell cycle, indicating that Cdk6 is neither rate-limiting nor essential in Ba/F3 cells; however, decreased expression of Cdk6 also enhanced levels of CD43, indicating that expression of CD43 is independent of cell cycle regulation. The physiological effect of reduced levels of Fbxo7 was assessed by creating a transgenic mouse with a LacZ insertion into the Fbxo7 locus. Homozygous Fbxo7(LacZ) mice showed significantly increased pro-B cell and pro-erythroblast populations, consistent with Fbxo7 having an anti proliferative function and/or a role in promoting maturation of precursor cells. PMID- 21652637 TI - Evidence for the conservation of biological activity of ovulation-inducing factor in seminal plasma. AB - An ovulation-inducing factor (OIF) in the seminal plasma of llamas and alpacas (induced ovulators) and cattle (spontaneous ovulators) suggests that OIF is a conserved constituent of seminal plasma among mammals. In this study, three experiments were designed to determine the biological effects of OIF in different species. In experiment 1, superstimulated prepubertal female CD-1 mice (n=36 per group) were given a single 0.1 ml i.p. dose of 1) phosphate-buffered saline (PBS), 2) 5 MUg gonadotropin-releasing hormone (GNRH), 3) 5 IU hCG, or 4) llama seminal plasma. The proportion of mice that ovulated was similar among groups treated with GNRH, hCG, or seminal plasma, and all were higher than the saline treated group (P<0.001). In experiment 2, female llamas (n=8 or 9 per group) were intramuscularly treated with 1) 2 ml PBS, 2) 1 ml diluted llama seminal plasma, 3) 3 ml equine seminal plasma, or 4) 3 ml porcine seminal plasma. Experiment 3 was the same as experiment 2 except that the dose of equine and porcine seminal plasma was increased to 8 and 10 ml respectively. All llamas that were treated with llama seminal plasma ovulated and none that were treated with saline ovulated (P<0.0001). The proportion of llamas that ovulated in response to equine and porcine seminal plasma was intermediate. We conclude that the mechanism for the biological response to OIF is present in prepubertal CD-1 mice and that OIF is present in equine and porcine seminal plasma. PMID- 21652636 TI - Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function. AB - One of the mechanisms of tumorigenesis is that the failure of cell division results in genetically unstable, multinucleated cells. Here we show that pVHL, a tumor suppressor protein that has been implicated in the pathogenesis of renal cell carcinoma (RCC), plays an important role in regulation of cytokinesis. We found that pVHL-deficient RCC 786-O cells were multinucleated and polyploid. Reintroduction of wild-type pVHL into these cells rescued the diploid cell population, whereas the mutant pVHL-K171G failed to do so. We demonstrate that lysine 171 of pVHL is important for the final step of cytokinesis: the midbody abscission. The pVHL-K171G caused failure to localize the ESCRT-1 interacting protein Alix and the v-SNARE complex component Endobrevin to the midbody in 786-O cells, leading to defective cytokinesis. Moreover, SUMOylation of pVHL at lysine 171 might modulate its function as a cytokinesis regulator. pVHL tumor suppressor function was also disrupted by the K171G mutation, as evidenced by the xenograft tumor formation when 786-O clones expressing pVHL-K171G were injected into mice. Most RCC cell lines show a polyploid chromosome complement and consistent heterogeneity in chromosome number. Thus, this study offers a way to explain the chromosome instability in RCC and reveals a new direction for the tumor suppressor function of pVHL, which is independent of its E3 ubiquitin ligase activity. PMID- 21652638 TI - Chromatoid body and small RNAs in male germ cells. AB - The chromatoid body (CB) is a germ granule in the cytoplasm of postmeiotic haploid round spermatids that is loaded with RNA and RNA-binding proteins. Following the discovery of small non-coding RNA-mediated gene regulation and the identification of PIWI-interacting RNAs (piRNAs) that have crucial roles in germ line development, the function of the CB has slowly begun to be revealed. Male germ cells utilise small RNAs to control the complex and specialised process of sperm production. Several microRNAs have been identified during spermatogenesis. In addition, a high number of piRNAs are present both in embryonic and postnatal male germ cells, with their expression being impressively induced in late meiotic cells and haploid round spermatids. At postmeiotic stage of germ cell differentiation, the CB accumulates piRNAs and proteins of piRNA machinery, as well as several other proteins involved in distinct RNA regulation pathways. All existing evidence suggests a role for the CB in mRNA regulation and small RNA mediated gene control, but the mechanisms remain uncharacterised. In this review, we summarise the current knowledge of the CB and its association with small RNA pathways. PMID- 21652639 TI - ChIP-seq analysis reveals distinct H3K27me3 profiles that correlate with transcriptional activity. AB - Transcriptional control is dependent on a vast network of epigenetic modifications. One epigenetic mark of particular interest is tri-methylation of lysine 27 on histone H3 (H3K27me3), which is catalysed and maintained by Polycomb Repressive Complex 2 (PRC2). Although this histone mark is studied widely, the precise relationship between its local pattern of enrichment and regulation of gene expression is currently unclear. We have used ChIP-seq to generate genome wide maps of H3K27me3 enrichment, and have identified three enrichment profiles with distinct regulatory consequences. First, a broad domain of H3K27me3 enrichment across the body of genes corresponds to the canonical view of H3K27me3 as inhibitory to transcription. Second, a peak of enrichment around the transcription start site (TSS) is commonly associated with 'bivalent' genes, where H3K4me3 also marks the TSS. Finally and most surprisingly, we identified an enrichment profile with a peak in the promoter of genes that is associated with active transcription. Genes with each of these three profiles were found in different proportions in each of the cell types studied. The data analysis techniques developed here will be useful for the identification of common enrichment profiles for other histone modifications that have important consequences for transcriptional regulation. PMID- 21652640 TI - High-level transgene expression by homologous recombination-mediated gene transfer. AB - Gene transfer and expression in eukaryotes is often limited by a number of stably maintained gene copies and by epigenetic silencing effects. Silencing may be limited by the use of epigenetic regulatory sequences such as matrix attachment regions (MAR). Here, we show that successive transfections of MAR-containing vectors allow a synergistic increase of transgene expression. This finding is partly explained by an increased entry into the cell nuclei and genomic integration of the DNA, an effect that requires both the MAR element and iterative transfections. Fluorescence in situ hybridization analysis often showed single integration events, indicating that DNAs introduced in successive transfections could recombine. High expression was also linked to the cell division cycle, so that nuclear transport of the DNA occurs when homologous recombination is most active. Use of cells deficient in either non-homologous end joining or homologous recombination suggested that efficient integration and expression may require homologous recombination-based genomic integration of MAR containing plasmids and the lack of epigenetic silencing events associated with tandem gene copies. We conclude that MAR elements may promote homologous recombination, and that cells and vectors can be engineered to take advantage of this property to mediate highly efficient gene transfer and expression. PMID- 21652641 TI - Structural basis for RNA recognition by NusB and NusE in the initiation of transcription antitermination. AB - Processive transcription antitermination requires the assembly of the complete antitermination complex, which is initiated by the formation of the ternary NusB NusE-BoxA RNA complex. We have elucidated the crystal structure of this complex, demonstrating that the BoxA RNA is composed of 8 nt that are recognized by the NusB-NusE heterodimer. Functional biologic and biophysical data support the structural observations and establish the relative significance of key protein protein and protein-RNA interactions. Further crystallographic investigation of a NusB-NusE-dsRNA complex reveals a heretofore unobserved dsRNA binding site contiguous with the BoxA binding site. We propose that the observed dsRNA represents BoxB RNA, as both single-stranded BoxA and double-stranded BoxB components are present in the classical lambda antitermination site. Combining these data with known interactions amongst antitermination factors suggests a specific model for the assembly of the complete antitermination complex. PMID- 21652642 TI - Computational identification of insertional mutagenesis targets for cancer gene discovery. AB - Insertional mutagenesis is a potent forward genetic screening technique used to identify candidate cancer genes in mouse model systems. An important, yet unresolved issue in the analysis of these screens, is the identification of the genes affected by the insertions. To address this, we developed Kernel Convolved Rule Based Mapping (KC-RBM). KC-RBM exploits distance, orientation and insertion density across tumors to automatically map integration sites to target genes. We perform the first genome-wide evaluation of the association of insertion occurrences with aberrant gene expression of the predicted targets in both retroviral and transposon data sets. We demonstrate the efficiency of KC-RBM by showing its superior performance over existing approaches in recovering true positives from a list of independently, manually curated cancer genes. The results of this work will significantly enhance the accuracy and speed of cancer gene discovery in forward genetic screens. KC-RBM is available as R-package. PMID- 21652643 TI - The structural basis for partitioning of the XRCC1/DNA ligase III-alpha BRCT mediated dimer complexes. AB - The ultimate step common to almost all DNA repair pathways is the ligation of the nicked intermediate to form contiguous double-stranded DNA. In the mammalian nucleotide and base excision repair pathways, the ligation step is carried out by ligase III-alpha. For efficient ligation, ligase III-alpha is constitutively bound to the scaffolding protein XRCC1 through interactions between the C terminal BRCT domains of each protein. Although structural data for the individual domains has been available, no structure of the complex has been determined and several alternative proposals for this interaction have been advanced. Interpretation of the models is complicated by the formation of homodimers that, depending on the model, may either contribute to, or compete with heterodimer formation. We report here the structures of both homodimer complexes as well as the heterodimer complex. Structural characterization of the heterodimer formed from a longer XRCC1 BRCT domain construct, including residues comprising the interdomain linker region, revealed an expanded heterodimer interface with the ligase III-alpha BRCT domain. This enhanced linker-mediated binding interface plays a significant role in the determination of heterodimer/homodimer selectivity. These data provide fundamental insights into the structural basis of BRCT-mediated dimerization, and resolve questions related to the organization of this important repair complex. PMID- 21652645 TI - L'enfant terrible at 30: the maturation of evolutionary developmental biology. AB - The recent Keystone Symposium on Evolutionary Developmental Biology at Tahoe City in February 2011 provided an opportunity to take stock of where the past three decades have brought this interdisciplinary field. It revealed maturation on several fronts, including increased experimental rigor, the softening of dichotomies that were crucial to its founding and growth, and its growing relevance to both basic and biomedical biology. PMID- 21652644 TI - Experimental strategies for microRNA target identification. AB - MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression in most biological processes. They act by guiding the RNAi-induced silencing complex (RISC) to partially complementary sequences in target mRNAs to suppress gene expression by a combination of translation inhibition and mRNA decay. The commonly accepted mechanism of miRNA targeting in animals involves an interaction between the 5'-end of the miRNA called the 'seed region' and the 3' untranslated region (3'-UTR) of the mRNA. Many target prediction algorithms are based around such a model, though increasing evidence demonstrates that targeting can also be mediated through sites other than the 3'-UTR and that seed region base pairing is not always required. The power and validity of such in silico data can be therefore hindered by the simplified rules used to represent targeting interactions. Experimentation is essential to identify genuine miRNA targets, however many experimental modalities exist and their limitations need to be understood. This review summarizes and critiques the existing experimental techniques for miRNA target identification. PMID- 21652646 TI - Evolutionary crossroads in developmental biology: sea urchins. AB - Embryos of the echinoderms, especially those of sea urchins and sea stars, have been studied as model organisms for over 100 years. The simplicity of their early development, and the ease of experimentally perturbing this development, provides an excellent platform for mechanistic studies of cell specification and morphogenesis. As a result, echinoderms have contributed significantly to our understanding of many developmental mechanisms, including those that govern the structure and design of gene regulatory networks, those that direct cell lineage specification, and those that regulate the dynamic morphogenetic events that shape the early embryo. PMID- 21652647 TI - Ectodysplasin and Wnt pathways are required for salivary gland branching morphogenesis. AB - The developing submandibular salivary gland (SMG) is a well-studied model for tissue interactions and branching morphogenesis. Its development shares similar features with other ectodermal appendages such as hair and tooth. The ectodysplasin (Eda) pathway is essential for the formation and function of several ectodermal organs. Mutations in the signaling components of the Eda pathway lead to a human syndrome known as hypohidrotic ectodermal dysplasia (HED), which is characterized by missing and malformed teeth, sparse hair and reduced sweating. Individuals with HED suffer also from dry mouth because of reduced saliva flow. In order to understand the underlying mechanism, we analyzed salivary gland development in mouse models with altered Eda pathway activities. We have found that Eda regulates growth and branching of the SMG via transcription factor NF-kappaB in the epithelium, and that the hedgehog pathway is an important mediator of Eda/NF-kappaB. We also sought to determine whether a similar reciprocal interplay between the Eda and Wnt/beta-catenin pathways, which are known to operate in other skin appendages, functions in developing SMG. Surprisingly and unlike in developing hair follicles and teeth, canonical Wnt signaling activity did not colocalize with Edar/NF-kappaB in salivary gland epithelium. Instead, we observed high mesenchymal Wnt activity and show that ablation of mesenchymal Wnt signaling either in vitro or in vivo compromised branching morphogenesis. We also provide evidence suggesting that the effects of mesenchymal Wnt/beta-catenin signaling are mediated, at least in part, through regulation of Eda expression. PMID- 21652648 TI - The WASp-based actin polymerization machinery is required in somatic support cells for spermatid maturation and release. AB - WASp family proteins serve as conserved regulators of branched microfilament array formation via the Arp2/3 actin polymerization machinery. We have identified a specific role during spermatogenesis for the Drosophila WASp homolog (Wsp) and associated elements. Spermatogenesis within the fly testis is carried out in cysts, where a pair of somatic cyst cells encloses differentiating sperm. The final phase of the process involves the attachment of matured cysts to a specialized epithelium at the base of the testis, followed by release of individual motile spermatids into the adjoining seminal vesicle. Wsp mutant cysts contain fully mature sperm, but spermatid release does not occur, resulting in male sterility. Our data suggest that the Wsp-Arp2/3-based machinery acts in the cyst cells to influence proper microfilament organization and to enable cyst attachment to the base of the testis. Wsp activity in this context is mediated by the small GTPase Cdc42. Involvement of the cell surface protein Sticks and stones and the Wsp adapter protein D-WIP (Vrp1) is also crucial. In parallel, we demonstrate that N-WASp (Wasl), the major mammalian WASp family protein, is required in the somatic Sertoli cells of the mouse testis for sperm maturation. A requirement for WASp-based activity in somatic support cells therefore appears to be a universal feature of spermatogenesis. PMID- 21652649 TI - Direct targets of the D. melanogaster DSXF protein and the evolution of sexual development. AB - Uncovering the direct regulatory targets of doublesex (dsx) and fruitless (fru) is crucial for an understanding of how they regulate sexual development, morphogenesis, differentiation and adult functions (including behavior) in Drosophila melanogaster. Using a modified DamID approach, we identified 650 DSX binding regions in the genome from which we then extracted an optimal palindromic 13 bp DSX-binding sequence. This sequence is functional in vivo, and the base identity at each position is important for DSX binding in vitro. In addition, this sequence is enriched in the genomes of D. melanogaster (58 copies versus approximately the three expected from random) and in the 11 other sequenced Drosophila species, as well as in some other Dipterans. Twenty-three genes are associated with both an in vivo peak in DSX binding and an optimal DSX-binding sequence, and thus are almost certainly direct DSX targets. The association of these 23 genes with optimum DSX binding sites was used to examine the evolutionary changes occurring in DSX and its targets in insects. PMID- 21652650 TI - Polarity mediates asymmetric trafficking of the Gbeta heterotrimeric G-protein subunit GPB-1 in C. elegans embryos. AB - Asymmetric cell division is an evolutionarily conserved process that gives rise to daughter cells with different fates. In one-cell stage C. elegans embryos, this process is accompanied by asymmetric spindle positioning, which is regulated by anterior-posterior (A-P) polarity cues and driven by force generators located at the cell membrane. These force generators comprise two Galpha proteins, the coiled-coil protein LIN-5 and the GoLoco protein GPR-1/2. The distribution of GPR 1/2 at the cell membrane is asymmetric during mitosis, with more protein present on the posterior side, an asymmetry that is thought to be crucial for asymmetric spindle positioning. The mechanisms by which the distribution of components such as GPR-1/2 is regulated in time and space are incompletely understood. Here, we report that the distribution of the Gbeta subunit GPB-1, a negative regulator of force generators, varies across the cell cycle, with levels at the cell membrane being lowest during mitosis. Furthermore, we uncover that GPB-1 trafficks through the endosomal network in a dynamin- and RAB-5-dependent manner, which is most apparent during mitosis. We find that GPB-1 trafficking is more pronounced on the anterior side and that this asymmetry is regulated by A-P polarity cues. In addition, we demonstrate that GPB-1 depletion results in the loss of GPR-1/2 asymmetry during mitosis. Overall, our results lead us to propose that modulation of Gbeta trafficking plays a crucial role during the asymmetric division of one cell stage C. elegans embryos. PMID- 21652651 TI - Evolutionary plasticity of segmentation clock networks. AB - The vertebral column is a conserved anatomical structure that defines the vertebrate phylum. The periodic or segmental pattern of the vertebral column is established early in development when the vertebral precursors, the somites, are rhythmically produced from presomitic mesoderm (PSM). This rhythmic activity is controlled by a segmentation clock that is associated with the periodic transcription of cyclic genes in the PSM. Comparison of the mouse, chicken and zebrafish PSM oscillatory transcriptomes revealed networks of 40 to 100 cyclic genes mostly involved in Notch, Wnt and FGF signaling pathways. However, despite this conserved signaling oscillation, the identity of individual cyclic genes mostly differed between the three species, indicating a surprising evolutionary plasticity of the segmentation networks. PMID- 21652653 TI - Dynamic control of head mesoderm patterning. AB - The embryonic head mesoderm gives rise to cranial muscle and contributes to the skull and heart. Prior to differentiation, the tissue is regionalised by the means of molecular markers. We show that this pattern is established in three discrete phases, all depending on extrinsic cues. Assaying for direct and first wave indirect responses, we found that the process is controlled by dynamic combinatorial as well as antagonistic action of retinoic acid (RA), Bmp and Fgf signalling. In phase 1, the initial anteroposterior (a-p) subdivision of the head mesoderm is laid down in response to falling RA levels and activation of Fgf signalling. In phase 2, Bmp and Fgf signalling reinforce the a-p boundary and refine anterior marker gene expression. In phase 3, spreading Fgf signalling drives the a-p expansion of MyoR and Tbx1 expression along the pharynx, with RA limiting the expansion of MyoR. This establishes the mature head mesoderm pattern with markers distinguishing between the prospective extra-ocular and jaw skeletal muscles, the branchiomeric muscles and the cells for the outflow tract of the heart. PMID- 21652652 TI - A context-dependent combination of Wnt receptors controls axis elongation and leg development in a short germ insect. AB - Short germ embryos elongate their primary body axis by consecutively adding segments from a posteriorly located growth zone. Wnt signalling is required for axis elongation in short germ arthropods, including Tribolium castaneum, but the precise functions of the different Wnt receptors involved in this process are unclear. We analysed the individual and combinatorial functions of the three Wnt receptors, Frizzled-1 (Tc-Fz1), Frizzled-2 (Tc-Fz2) and Frizzled-4 (Tc-Fz4), and their co-receptor Arrow (Tc-Arr) in the beetle Tribolium. Knockdown of gene function and expression analyses revealed that Frizzled-dependent Wnt signalling occurs anteriorly in the growth zone in the presegmental region (PSR). We show that simultaneous functional knockdown of the Wnt receptors Tc-fz1 and Tc-fz2 via RNAi resulted in collapse of the growth zone and impairment of embryonic axis elongation. Although posterior cells of the growth zone were not completely abolished, Wnt signalling within the PSR controls axial elongation at the level of pair-rule patterning, Wnt5 signalling and FGF signalling. These results identify the PSR in Tribolium as an integral tissue required for the axial elongation process, reminiscent of the presomitic mesoderm in vertebrates. Knockdown of Tc-fz1 alone interfered with the formation of the proximo-distal and the dorso-ventral axes during leg development, whereas no effect was observed with single Tc-fz2 or Tc-fz4 RNAi knockdowns. We identify Tc-Arr as an obligatory Wnt co-receptor for axis elongation, leg distalisation and segmentation. We discuss how Wnt signalling is regulated at the receptor and co-receptor levels in a dose-dependent fashion. PMID- 21652656 TI - Fertility and whelping complications in bitches following correction of vaginal abnormalities. AB - The fertility and whelping complications of normal bitches and of bitches that had had surgery to correct a vaginal abnormality of varying severities were compared retrospectively. Reproductive performance and whelping statistics were compared between 37 bitches that had been diagnosed with a vaginal abnormality and 37 age- and breed-matched bitches with no history of vaginal abnormalities. There were no significant differences in reproductive performance between the affected and control bitches. When analysed by the severity of the abnormality, pregnancy rates were significantly lower for the group of bitches with the most severe abnormalities compared with the group of bitches that had mild vaginal abnormalities. Furthermore, the bitches that had severe abnormalities were significantly more likely to require a caesarean section than those with mild abnormalities. PMID- 21652655 TI - The GUDMAP database--an online resource for genitourinary research. AB - The GenitoUrinary Development Molecular Anatomy Project (GUDMAP) is an international consortium working to generate gene expression data and transgenic mice. GUDMAP includes data from large-scale in situ hybridisation screens (wholemount and section) and microarray gene expression data of microdissected, laser-captured and FACS-sorted components of the developing mouse genitourinary (GU) system. These expression data are annotated using a high-resolution anatomy ontology specific to the developing murine GU system. GUDMAP data are freely accessible at www.gudmap.org via easy-to-use interfaces. This curated, high resolution dataset serves as a powerful resource for biologists, clinicians and bioinformaticians interested in the developing urogenital system. This paper gives examples of how the data have been used to address problems in developmental biology and provides a primer for those wishing to use the database in their own research. PMID- 21652654 TI - LMO4 functions as a co-activator of neurogenin 2 in the developing cortex. AB - The proneural protein neurogenin 2 (NGN2) is a key transcription factor in regulating both neurogenesis and neuronal radial migration in the embryonic cerebral cortex. However, the co-factors that support the action of NGN2 in the cortex remain unclear. Here, we show that the LIM-only protein LMO4 functions as a novel co-factor of NGN2 in the developing cortex. LMO4 and its binding partner nuclear LIM interactor (NLI/LDB1/CLIM2) interact with NGN2 simultaneously, forming a multi-protein transcription complex. This complex is recruited to the E box containing enhancers of NGN2-target genes, which regulate various aspects of cortical development, and activates NGN2-mediated transcription. Correspondingly, analysis of Lmo4-null embryos shows that the loss of LMO4 leads to impairments of neuronal differentiation in the cortex. In addition, expression of LMO4 facilitates NGN2-mediated radial migration of cortical neurons in the embryonic cortex. Our results indicate that LMO4 promotes the acquisition of cortical neuronal identities by forming a complex with NGN2 and subsequently activating NGN2-dependent gene expression. PMID- 21652657 TI - Emergence of suspected type D botulism in ruminants in England and Wales (2001 to 2009), associated with exposure to broiler litter. AB - Scanning surveillance by the Veterinary Laboratories Agency revealed the emergence of suspected botulism in ruminants in 2003, presented as flaccid paralysis. From 2003 to 2009, 168 cattle and 19 sheep incidents were recorded, with mortality between 5 and 80 per cent. All sheep incidents and 95 per cent of cattle incidents had proximity to broiler litter. From July 2006, the gut contents collected from 74 affected cattle and 10 affected sheep were tested for Clostridium botulinum toxins using mice bioassays and for organisms by culture. Type D toxin was identified in 32 per cent of cattle and 18 per cent of sheep samples. C botulinum type D organisms were identified in 40 per cent of cattle and 30 per cent of sheep samples, but broth from one sample reacted with C and D antisera. Type C botulism has previously been reported more commonly than type D in the UK and has been associated with the use of poultry litter as fertiliser, bedding or feed. The almost exclusive association with C botulinum type D toxins or organisms in the gut contents in this survey suggests a change in the source or epidemiology of botulism in the UK. The source of C botulinum type D was uncertain. Broilers may carry C botulinum type D in their gut flora subclinically. The emergence of a new type D strain, or changes in broiler husbandry and nutrition, medication and other enteric infections may have affected colonisation with C botulinum. Further investigation of poultry and farm environments for sources of type D awaits the development of tests for C botulinum toxins that do not require the use of mice. PMID- 21652658 TI - Gill disease in marine farmed Atlantic salmon at four farms in Ireland. AB - A study of four marine salmon farms was undertaken in Ireland in 2008, with a focus on gill health and disease. All four farms suffered severe gill disease resulting in mortalities and, in some cases, failure to thrive. The aetiology of the gill pathologies in some cases was associated with small gelatinous zooplankton and bacteria, but also involved epitheliocystis and parasites such as marine costia (Ichthyobodo species) and amoebae (Neoparamoeba species). Treatments with oral broad-spectrum antibiotics and/or freshwater baths had equivocal benefits. There was a strong association of susceptibility to gill disease with one genetic strain of salmon. PMID- 21652659 TI - Lymphoid depletion in two dogs with nodularin intoxication. PMID- 21652660 TI - Induction of fertile oestrus in dioestrous bitches using prostaglandin F2alpha and a GnRH agonist. PMID- 21652661 TI - Effects of soaking on the water-soluble carbohydrate and crude protein content of hay. AB - The aim of this study was to determine the amounts of water-soluble carbohydrate (WSC), WSC constituents and protein leached from a range of U.K. hays soaked according to common practice. Initial hay WSC content ranged from 123 to 230 g/kg dry matter (DM). Soaking the hays for up to 16 hours in water at a mean temperature of 8 degrees C resulted in a mean loss of 27 per cent (range 6 to 54 per cent) of hay WSC. The mean percentage losses of WSC constituents were 24 per cent (range 14 to 31) for fructan, 41 per cent (range 21 to 70) for fructose, 45 per cent (range 28 to 100) for sucrose and 56 per cent (range 29 to 100) for glucose. The mean crude protein content of the initial hays was 58.7 g/kg DM (range 30 to 86 g/kg DM) and this value was not affected significantly by soaking. Despite a mean WSC loss of 27 per cent, the WSC contents of seven of the hays remained above the suggested upper limit for laminitic animals of 100 g/kg DM. PMID- 21652662 TI - Optimal contemporary management of symptomatic and asymptomatic carotid artery stenosis. AB - This commentary addresses the issue of optimal contemporary management of symptomatic and asymptomatic carotid artery stenosis. Based on current data, carotid endarterectomy (CEA) should be performed in the majority of patients with symptomatic carotid artery stenosis. Carotid artery stenting (CAS) should be reserved for a minority of these symptomatic patients, in whom CEA is contraindicated. In asymptomatic patients, all should be placed on best medical treatment (BMT). With the use of one or more of the proposed stroke risk stratification models or some as yet undetermined method, the identification of those asymptomatic individuals may be possible in whom stroke risk is higher than usual with BMT. This asymptomatic subgroup, which may be small and is yet to be determined with certainty, could be offered an invasive carotid procedure (either CAS or CEA). PMID- 21652663 TI - Endoscopic type 2 endoleak repair following endovascular aortic aneurysm repair: acute results and follow-up experience. AB - The purpose of this study was to evaluate immediate and long-term results of endoscopic type 2 endoleak repair (EER) following endovascular abdominal aortic aneurysm repair. The basic methods include a retrospective review of electronic and paper medical records of patients admitted or referred to our institution for EER. Between July 1999 and October 2007, eight consecutive patients underwent EER. Mean operative time was 190 (104-355) min. One patient died preoperatively, due to profuse venous bleeding . One procedure was redone due to a missed pair of lumbar arteries. Mean hospital stay was five days (2-10). During mean follow-up, 50 months (29-91), one patient required additional coil embolization for a persistent type 2 endoleak. Four patients were diagnosed with a type 1 and one with a type 3 endoleak; three of these patients required an additional procedure. In conclusion, in this small series EER proved not to be beneficial. PMID- 21652664 TI - Endovascular infrarenal aneurysm repair in patients with horseshoe kidneys: case series and literature review. AB - Horseshoe kidney may cause technical and access problems during open aortic aneurysm repair. The aim of this study is to report two cases from our institution and to review the world's literature on successful endovascular infrarenal aneurysm repair in patients with horseshoe kidneys. A retrospective review of a prospectively entered departmental computerized database was performed for the two patients from our institution. Articles were searched electronically from PubMed and Medline, using the terms 'horseshoe kidney' and 'aneurysm'. Endovascular cases were reviewed from the world's literature. In addition to the two patients from our institution, there were 19 patients with infrarenal aneurysms and horseshoe kidneys in published literature who underwent successful endovascular aneurysm repair. The occlusion of lower-pole or accessory renal arteries does not seem to cause significant endoleak or renal impairment in the long run. In conclusion, our experience and current literature seem to suggest that endovascular repair of infrarenal aortic aneurysms for patients with horseshoe kidneys is safe. Renal impairment will depend on the area of kidney perfused by the accessory renal arteries. The endovascular treatment option is less invasive than open repair, and circumvents the problem of difficult exposure, especially in those patients with significant co-morbidity. PMID- 21652665 TI - Long-term outcomes of endovascular aneurysm repair for challenging aortic necks using the Talent endograft. AB - The aim of the present paper is to evaluate the long-term outcomes of endovascular aneurysm repair (EVAR) for challenging aortic necks. Subgroup analyses were performed on 156 patients from the prospective multicenter Talent eLPS (enhanced Low Profile Stent Graft System) trial. Patients with high-risk aortic necks (length < 15 mm or diameter >=28 mm) were compared with the remaining patients. Patients with high-risk (n = 86) and low-risk necks (n = 70) had similar age and gender distribution. Despite similar prevalences of co morbidities, the high-risk group had higher Society for Vascular Surgery scores. The high-risk group also had larger maximum aneurysm diameters (56.6 versus 53.0 mm, P < 0.02). There were lower freedoms from major adverse events (MAEs) for the high-risk group at 30 days (84.9 versus 95.7%; P < 0.04) and 365 days (73.4 versus 89.2%; P = 0.02). Effectiveness endpoints at 12 m showed no significant differences. Freedom from all-cause mortality at 30 days (96.5 versus 100%) and aneurysm-related mortality at 365 days (96.0 versus 100%) were similar. At five years, there were no differences in endoleaks or change in aneurysm diameter. All migrations occurred in the high-risk group. The five-year freedom from aneurysm related mortality for the high- and low-risk groups was 93.2 and 100%, respectively. In conclusion, despite a higher rate of MAEs within the first year and higher migration rates at five years, EVAR in aneurysms with challenging aortic necks can be treated with acceptable long-term results. PMID- 21652666 TI - A review on thromboangiitis obliterans pathophysiology: thrombosis and angiitis, which is to blame? AB - A century has passed since thromboangiitis obliterans (TAO), or Buerger's disease, was first described, but the etiology remains unclear. It is still uncertain as to whether thrombosis or vascular inflammation is the first event. TAO is an episodic inflammatory and thrombotic-occlusive vascular disease of unknown origin. The involvement of the distal vessels and nerves within the neuro vascular bundles occurs almost always in legs and occasionally in arms. The cumulative data demonstrate that at the cellular and molecular levels, at least four main components of inflammatory reactions, including endothelial cells, platelets, leukocytes and sensory neurons, might be involved in TAO pathogenesis. The interactions among these cells in an altered microenvironment of small- and medium-sized vessels may also orchestrate the onset of TAO events. In this review, the factors that may promote thrombosis and angiitis are reconsidered at three levels: (1) host characteristics such as male gender and genetic background; (2) probable triggers including cigarette smoking and infectious agents; and (3) environmental factors such as chronic anxiety and mental stress as a consequence of low socioeconomic status. At each level, the interactions among vascular endothelium, platelets, leukocytes and sensory neurons are discussed. PMID- 21652667 TI - Recurrent collapse of a Gore TAG endograft in treating an aortoesophageal fistula. AB - As the utility of the Gore TAG endograft expands in an off-label fashion to include various aortic pathologies like aortoesophageal fistulas (AEFs), more TAG endograft collapses are being described in the literature. We report a case of a recurrent endograft collapse in a patient with a right-sided aortic arch, who was treated for a hemorrhage from an AEF. One month following the initial endograft placement, angiography detected infolding of the endograft, which was then re expanded with another endograft. Four months later, the patient developed an acute biventricular dysfunction with an ejection fraction (EF) less than 20%. Cardiac catheterization revealed that the patient had an 80 mmHg pressure gradient across the endograft suggesting another collapse. A balloon-expandable stent was used to re-expand the endografts and restore the EF. On follow-up, the patient's endograft has remained patent without evidence of further collapse. PMID- 21652668 TI - Abdominal aortic endograft proximal collapse resulting in aortic aneurysm rupture. AB - An 82-year-old man was transferred to our emergency department due to acute abdominal pain. He had undergone an endovascular abdominal aortic aneurysm repair (EVAR) six years ago. An intravenous contrast-enhanced abdominal computed tomography revealed the rupture of the abdominal aortic aneurysm (AAA) with a large retroperitoneal hematoma. A Talent (Medtronic, Santa Rosa, CA, USA) modular bifurcated endoprosthesis had vertically collapsed approximately 7 cm after losing its infrarenal fixation. As a result, it led to the repressurization of the aneurysm sac and rupture. The patient was successfully treated by placing three Talent (Medtronic) aortic cuffs. To our knowledge, this is the first reported case of endograft collapse that has manifested with aortic aneurysm rupture. Although they are gradually declining, considerable rates of complications create the 'Achilles' heel' of endovascular repair of AAAs. A lifelong follow-up strategy for patients treated for AAA with EVAR is essential for the early detection and treatment of complications of the procedure. PMID- 21652669 TI - Cystic adventitial disease of the popliteal artery: is there a consensus in management? AB - Cystic adventitial disease (CAD) is a well described disease entity that commonly affects the popliteal artery, presenting as a rare cause of non-atherosclerotic claudication. The traditional surgical approaches are cyst resection and bypass, or cyst evacuation or aspiration. We report the case of a 58-year-old female with CAD of the popliteal artery treated successfully with cyst resection and bypass using an autologous graft. We reviewed the literature over the last 25 years on management and outcomes of CAD of the popliteal artery. We identified a total of 123 cases; most cases were treated using a traditional repair, while 3 cases used an endovascular approach. The overall success rate using bypass was 93.3%, compared to 85% in the evacuation/aspiration cohort. All cases treated endovascularly resulted in failure. While no consensus exists regarding the preferred modality to treat CAD, we believe that resection of the cyst and bypass affords the best outcomes. PMID- 21652670 TI - A rare complication of radial artery catheterization. AB - An arterial pseudoaneurysm is a cavity which does not consist of three layers of arterial wall and is generally seen at femoral and radial artery sites due to bone fractures, arterial injuries and iatrogenic reasons such as catheterization. The treatment choice may be either surgical or conservative. Patients with pseudoaneurysm should be carefully followed and the treatment choice should be immediately decided to avoid possible complications. We report a case of pseudoaneurysm formation in the radial artery that occurred one week after arterial catheterization for coronary angiography. The treatment choice for this patient was surgical and he was discharged without any complications. PMID- 21652671 TI - Severe diffuse hypoplasia of the aorta associated with multiple vascular abnormalities. AB - Hypoplasia of the thoracic and abdominal aorta is an extremely rare vascular pathology. The most common clinical manifestation is severe uncontrolled hypertension in adolescents and young adults. Medical treatment alone can decrease blood pressure, but often very high doses of antihypertensive drugs are needed. When hypertension is refractory to the antihypertensive medications, surgical revascularization is considered as the treatment of choice. We report the case of a severe and diffuse hypoplasia of the aorta, beginning with the aortic isthmus, to the aortic bifurcation, associated with an aberrant celiac trunk and superior mesenteric artery, and with other multiple vascular abnormalities. Unlikely, the only manifestation of this extensive vascular malformation was medicamentously controllable hypertension. To our knowledge, this severe vascular anomaly, with such a minimal clinical manifestation, has not been previously described in the English literature. PMID- 21652672 TI - Discrimination accuracy between real and sham needles using the Park sham device in the upper and lower limbs. AB - OBJECTIVE: To evaluate the blinding effectiveness of the Park sham acupuncture device using participants' ability to discriminate between the real and sham acupuncture needles in the (1) upper limb (TE points) compared with pure guessing and (2) lower limb (BL points) compared with pure guessing. METHODS: 20 healthy acupuncture-naive university students and staff were recruited through convenience sampling. Participants made Yes-No judgements on whether the real or sham needle was administered to four TE acupoints on the dominant upper limb, and four acupoints along the BL meridian on the dominant lower limb. The proportion of correct judgements, P(C), for each participant was calculated to indicate the discrimination accuracy of participants in distinguishing between the real and sham needles. Separate P(C) were computed for the upper limb acupoints and lower limb acupoints. The data were also pooled to calculate a P(C) for a combination of both body regions. RESULTS: The participants' discrimination accuracy between the real and sham needles was not statistically significant from P(C)=0.5 (chance level) for the lower limb alone and combined body regions' acupoint comparisons (lower limb: t(19)=0.00, unadjusted p=1.00; combined: t(19)=1.75, unadjusted p=0.10). However, the participants' discrimination accuracy was statistically significant from P(C)=0.5 for the upper limb acupoints alone comparison (t(19)=2.36, unadjusted p=0.03). CONCLUSIONS: This study showed that the Park sham device is more likely to blind participants in differentiating between the real and sham needles in the lower limb (BL meridian) acupoints than in the upper limb (TE meridian). However, the participants' ability to differentiate between the needle types for the upper limb acupoints was significantly different from chance levels. PMID- 21652673 TI - CalDAG-GEFI deficiency protects mice in a novel model of Fcgamma RIIA-mediated thrombosis and thrombocytopenia. AB - Platelet activation via Fcgamma receptor IIA (FcgammaRIIA) is a critical event in immune-mediated thrombocytopenia and thrombosis syndromes (ITT). We recently identified signaling by the guanine nucleotide exchange factor CalDAG-GEFI and the adenosine diphosphate receptor P2Y12 as independent pathways leading to Rap1 small GTPase activation and platelet aggregation. Here, we evaluated the contribution of CalDAG-GEFI and P2Y12 signaling to platelet activation in ITT. Mice transgenic for the human FcgammaRIIA (hFcR) and deficient in CalDAG-GEFI(-/ ) (hFcR/CDGI(-/-)) were generated. Compared with controls, aggregation of hFcR/CDGI(-/-) platelets or P2Y12 inhibitor-treated hFcR platelets required more than 5-fold and approximately 2-fold higher concentrations of a FcgammaRIIA stimulating antibody against CD9, respectively. Aggregation and Rap1 activation were abolished in P2Y12 inhibitor-treated hFcR/CDGI(-/-) platelets. For in vivo studies, a novel model for antibody-induced thrombocytopenia and thrombosis was established. FcgammaRIIA-dependent platelet thrombosis was induced by infusion of Alexa750-labeled antibodies to glycoprotein IX (CD42a), and pulmonary thrombi were detected by near-infrared imaging technology. Anti-GPIX antibodies dose dependently caused thrombocytopenia and pulmonary thrombosis in hFcR-transgenic but not wild-type mice. CalDAG-GEFI-deficient but not clopidogrel-treated hFcR transgenic mice were completely protected from ITT. In summary, we established a novel mouse model for ITT, which was used to identify CalDAG-GEFI as a potential new target in the treatment of ITT. PMID- 21652674 TI - Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models. AB - Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R-like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed EMU-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression. PMID- 21652675 TI - FlnA-null megakaryocytes prematurely release large and fragile platelets that circulate poorly. AB - Filamin A (FlnA) is a large cytoplasmic protein that crosslinks actin filaments and anchors membrane receptors and signaling intermediates. FlnA(loxP) PF4-Cre mice that lack FlnA in the megakaryocyte (MK) lineage have a severe macrothrombocytopenia because of accelerated platelet clearance. Macrophage ablation by injection of clodronate-encapsulated liposomes increases blood platelet counts in FlnA(loxP) PF4-Cre mice and reveals the desintegration of FlnA null platelets into microvesicles, a process that occurs spontaneously during storage. FlnA(loxP) PF4-Cre bone marrows and spleens have a 2.5- to 5-fold increase in MK numbers, indicating increased thrombopoiesis in vivo. Analysis of platelet production in vitro reveals that FlnA-null MKs prematurely convert their cytoplasm into large CD61(+) platelet-sized particles, reminiscent of the large platelets observed in vivo. FlnA stabilizes the platelet von Willebrand factor receptor, as surface expression of von Willebrand factor receptor components is normal on FlnA-null MKs but decreased on FlnA-null platelets. Further, FlnA-null platelets contain multiple GPIbalpha degradation products and have increased expression of the ADAM17 and MMP9 metalloproteinases. Together, the findings indicate that FlnA-null MKs prematurely release large and fragile platelets that are removed rapidly from the circulation by macrophages. PMID- 21652677 TI - Blood doping and its detection. AB - Hemoglobin mass is a key factor for maximal exercise capacity. Some athletes apply prohibited techniques and substances with intent to increase hemoglobin mass and physical performance, and this is often difficult to prove directly. Autologous red blood cell transfusion cannot be traced on reinfusion, and also recombinant erythropoietic proteins are detectable only within a certain timeframe. Novel erythropoietic substances, such as mimetics of erythropoietin (Epo) and activators of the Epo gene, may soon enter the sports scene. In addition, Epo gene transfer maneuvers are imaginable. Effective since December 2009, the World Anti-Doping Agency has therefore implemented "Athlete Biologic Passport Operating Guidelines," which are based on the monitoring of several parameters for mature red blood cells and reticulocytes. Blood doping may be assumed, when these parameters change in a nonphysiologic way. Hematologists should be familiar with blood doping practices as they may play an important role in evaluating blood profiles of athletes with respect to manipulations, as contrasted with the established diagnosis of clinical disorders and genetic variations. PMID- 21652676 TI - Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells. AB - The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions. PMID- 21652678 TI - Endothelial cell substrate stiffness influences neutrophil transmigration via myosin light chain kinase-dependent cell contraction. AB - A vast amount of work has been dedicated to the effects of shear flow and cytokines on leukocyte transmigration. However, no studies have explored the effects of substrate stiffness on transmigration. Here, we investigated important aspects of endothelial cell contraction-mediated neutrophil transmigration using an in vitro model of the vascular endothelium. We modeled blood vessels of varying mechanical properties using fibronectin-coated polyacrylamide gels of varying physiologic stiffness, plated with human umbilical vein endothelial cell (HUVEC) monolayers, which were activated with tumor necrosis factor-alpha. Interestingly, neutrophil transmigration increased with increasing substrate stiffness below the endothelium. HUVEC intercellular adhesion molecule-1 expression, stiffness, cytoskeletal arrangement, morphology, and cell-substrate adhesion could not account for the dependence of transmigration on HUVEC substrate stiffness. We also explored the role of cell contraction and observed that large holes formed in endothelium on stiff substrates several minutes after neutrophil transmigration reached a maximum. Further, suppression of contraction through inhibition of myosin light chain kinase normalized the effects of substrate stiffness by reducing transmigration and eliminating hole formation in HUVECs on stiff substrates. These results provide strong evidence that neutrophil transmigration is regulated by myosin light chain kinase-mediated endothelial cell contraction and that this event depends on subendothelial cell matrix stiffness. PMID- 21652680 TI - Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion. AB - Multiple mechanisms operate to ensure T-cell tolerance toward self-antigens. Three main processes have been described: clonal deletion, anergy, and deviation to CD4(+) regulatory T cells (Tregs) that suppress autoreactive T cells that have escaped the first 2 mechanisms. Although it is accepted that dendritic cells (DCs) and B cells contribute in maintaining T-cell tolerance to self-antigens, their relative contribution and the processes involved under physiologic conditions remain only partially characterized. In this study, we used different transgenic mouse models to obtain chimeras where a neo self-antigen is expressed by thymic epithelium and/or by DCs or B cells. We found that expression of cognate ligand in the thymus enhances antigen-specific FoxP3(+) cells independently of whether the self-antigen is expressed on thymic epithelium or only on DCs, but not on B cells. On the contrary, self-antigen expression by B cells was very efficient in inducing FoxP3(+) cells in the periphery, whereas self-antigen expression by DC led mainly to deletion and anergy of antigen specific FoxP3(-) cells. The results presented in this study underline the role of B cells in Treg induction and may have important implications in clinical protocols aimed at the peripheral expansion of Tregs in patients. PMID- 21652679 TI - Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures. AB - During vertebrate angiogenesis, Notch regulates the cell-fate decision between vascular tip cells versus stalk cells. Canonical Notch signaling depends on sequential proteolytic events, whereby interaction of Notch with membrane anchored ligands triggers proteolytic processing, first by Adam10 and then presenilins. This liberates the Notch intracellular domain, allowing it to enter the nucleus and activate Notch-dependent genes. Here we report that conditional inactivation of Adam10 in endothelial cells (A10DeltaEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling. Moreover, A10DeltaEC mice have additional vascular abnormalities, including aberrant subcapsular hepatic veins, enlarged glomeruli, intestinal polyps containing endothelial cell masses, abnormal endochondral ossification, leading to stunted long bone growth and increased pathologic neovascularization following oxygen-induced retinopathy. Our findings support a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions, most likely because of its essential role in canonical Notch signaling. PMID- 21652681 TI - IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors. AB - Deficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D(-) multipotent CLPs, the formation of the lineage restricted LY6D(+) CLP population was dramatically reduced. This was reflected in a low level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D(+) CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D(+) cells develop in Ebf-1-deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D(+) CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors. PMID- 21652682 TI - Decay-accelerating factor regulates T-cell immunity in the context of inflammation by influencing costimulatory molecule expression on antigen presenting cells. AB - Recent studies have indicated a role of complement in regulating T-cell immunity but the mechanism of action of complement in this process remains to be clarified. Here we studied mice deficient in decay-accelerating factor (DAF), a key membrane complement regulator whose deficiency led to increased complement dependent T-cell immune responses in vivo. By crossing OT-II and OT-I T-cell receptor transgenic mice with DAF-knockout mice, we found that lack of DAF on T cells did not affect their responses to antigen stimulation. Similarly, lack of DAF on antigen-presenting cells (APCs) of naive mice did not alter their T-cell stimulating activity. In contrast, APCs from DAF-knockout mice treated with inflammatory stimuli were found to be more potent T-cell stimulators than cells from similarly treated wild-type mice. Acquisition of higher T-cell stimulating activity by APCs in challenged DAF-knockout mice required C3 and C5aR and was correlated with decreased surface PD-L1 and/or increased CD40 expression. These findings implied that DAF suppressed T-cell immunity as a complement regulator in the context of inflammation but did not play an intrinsic role on T cells or APCs. Collectively, our data suggest a systemic and indirect role of complement in T-cell immunity. PMID- 21652683 TI - Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. AB - As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and dexamethasone (CTDa; n = 426) with melphalan and prednisolone (MP; n = 423) in patients with newly diagnosed multiple myeloma ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate, progression-free survival, and overall survival (OS). The overall response rate was significantly higher with CTDa than MP (63.8% vs 32.6%; P < .0001), primarily because of increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses (16.9% vs 1.7%). Progression-free survival and OS were similar between groups. In this population, OS correlated with the depth of response (P < .0001) and favorable interphase fluorescence in situ hybridization profile (P < .001). CTDa was associated with higher rates of thromboembolic events, constipation, infection, and neuropathy than MP. In elderly patients with newly diagnosed multiple myeloma (median age, 73 years), CTDa produced higher response rates than MP but was not associated with improved survival outcomes. We highlight the importance of cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at International Standard Randomized Controlled Trials Number as #68454111. PMID- 21652684 TI - Responsiveness of HIV-specific CD4 T cells to PD-1 blockade. AB - Defining the T helper functions impaired by programmed death-1 (PD-1) is crucial for understanding its role in defective HIV control and determining the therapeutic potential of targeting this inhibitory pathway. We describe here the relationships among disease stage, levels of PD-1 expression, and reversibility of CD4 T-cell impairment. PD-L1 blockade in vitro enhanced HIV-specific production of Th0 (IL-2), Th1 (IFN-gamma), Th2 (IL-13), and TFH (IL-21) cytokines by CD4 T cells. PD-L1 blockade caused an early increase in cytokine transcription and translation that preceded cell proliferation. Although the impact of PD-L1 blockade on cytokine expression and, to a lesser extent, cell proliferation was associated with markers of disease progression, restoration of cytokine secretion was also observed in most subjects with undetectable viremia. PD-L1 blockade restored cytokine secretion in both PD-1intermediate and PD-1high sorted CD4 T cell subsets. Compared with PD-1high HIV-specific CD8 T cells, PD-1high HIV specific CD4 T cells showed lower expression of the inhibitory molecules CD160 and 2B4, demonstrating marked differences in expression of inhibitory receptors between T-cell subsets. These data show that PD-1 impairs HIV-specific T helper responses both by limiting expansion of these cells and by inhibiting effector functions of multiple differentiated CD4 T-cell subsets. PMID- 21652685 TI - Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS). AB - HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N = 145), whereas conventionally treated survivors (N = 7207) and siblings (N = 4020) were drawn from CCSS. Self-reported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported >= 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/life-threatening (relative risk [RR] = 8.1, P < .01) and 2 or more (RR = 5.7, P < .01) conditions, as well as functional impairment (RR = 7.7, P < .01) and activity limitation (RR = 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/life threatening conditions: RR = 3.9, P < .01; multiple conditions: RR = 2.6, P < .01; functional impairment: RR = 3.5, P < .01; activity limitation: RR = 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population. PMID- 21652686 TI - Remnant lipoprotein-cholesterol is a predictive biomarker for large artery atherosclerosis in apparently healthy women: usefulness as a parameter for annual health examinations. AB - BACKGROUND: Recently, remnant lipoprotein is expected to be a new therapeutic target in the age of 'beyond LDL-cholesterol'. The aim of this study was to clarify the clinical significance of remnant lipoprotein cholesterol (RemL-C) determination in annual health examinations with the focus on large artery atherosclerosis. Methods and results Subjects investigated were men (n = 528) and women (n = 318) who underwent annual health examinations at Osaka University. RemL-C was measured with a newly developed homogeneous assay. Carotid and aortic atherosclerosis was estimated by intima-media thickness (IMT) and cardio-ankle vascular index (CAVI), respectively. First, simple regression analysis revealed that the RemL-C levels positively correlated with maximum IMT, mean IMT and CAVI in the whole group (P < 0.05). Next, receiver operating characteristic curve analysis showed that the most effective levels of RemL-C for predicting carotid and aortic atherosclerosis were 0.21 mmol/L (P < 0.05) and 0.22 mmol/L (P < 0.01) or more, respectively. Odds ratios (ORs) of high RemL-C levels (0.21 mmol/L or more) for carotid and aortic atherosclerosis were significantly increased, especially in low-risk, apparently healthy women (OR: 4.20, P < 0.05 and 3.79, P < 0.01, respectively). Five out of 13 female low-risk cases (38%) with carotid atherosclerosis showed high serum RemL-C levels. It should be emphasized that conventional risk factors are still strong predictors for large artery atherosclerosis in the whole group. CONCLUSIONS: Our results indicate that high serum RemL-C level is a predictive hallmark for large artery atherosclerosis in apparently healthy women. Determination of RemL-C should be employed as one of the parameters in annual health examinations. PMID- 21652687 TI - Sweat analysis using indirect ion-selective electrode on the routine chemistry analyser meets UK guidelines. AB - BACKGROUND: According to consensus documents, sweat testing remains the standard for diagnosing cystic fibrosis. We studied a novel method of sweat analysis on two chemistry platforms: Dimension Vista (Siemens Healthcare Diagnostics) and Aeroset (Abbott). METHODS: Sweat collected from healthy individuals and aqueous samples in the critical range for sweat analysis were measured using the Orion 290 plus (Thermo Electron Corporation), Chiron 925 chloride analyser (Sherwood Scientific Ltd), flame photometry, sweat-chek analyser and indirect ion-selective electrodes (ISE) of Vista and Aeroset. For measurement on ISE, an addition protocol was designed. RESULTS: Within-run and between-run variation coefficients of Aeroset and Vista remained <5% as prescribed by UK guidelines. The correlation between the chloride analyser and chloride concentrations analysed on Vista or Aeroset was, respectively, y = 0.96x + 7.61 (r(2) 0.990) and y = 0.97x + 1.10 (r(2) 0.930) and between sweat-chek (conductivity) and sodium concentrations analysed on Vista or Aeroset was, respectively, y = 1.08x - 4.0 (r(2) 0.967) and y = 1.13x - 1.00 (r(2) 0.939). When classified according to medical decision rules (30 mmol/L and 60 mmol/L chloride, combined with sodium concentration), the same classification was found with the ISE-module and conventional methods for all samples. CONCLUSION: We describe a simple procedure for sweat analysis using the ISE-module of two different chemistry platforms. This procedure meets the requirements as described in UK guidelines. PMID- 21652688 TI - A practical assessment of the short-term in vitro stability of troponin I at the 99 th percentile. AB - BACKGROUND: Serial troponin measurement is important for the diagnosis of myocardial infarction. As troponin concentrations approach the cut-off for detectable myocardial necrosis, smaller changes in troponin as a result of decreased in vitro stability may be sufficient to generate changes of apparent clinical significance. This is particularly relevant regarding retrospective 'add on' testing on samples several hours after venepuncture. We investigated the stability of troponin I (cTnI) at values close to the 99th percentile limit. METHODS: Serum samples with baseline cTnI concentrations in the range 0.04-0.15 MUg/L were analysed routinely using the Siemens TnI-Ultra assay. Follow-up analysis was carried out at 6, 9, 12, 24 and 48 h post-venepuncture after storage at room temperature and in the cold room. RESULTS: There was a significant decrease in cTnI concentration after 6 h post-venepuncture compared with baseline levels (P < 0.001). The maximum percentage change was -17.1% observed after 48 h storage at room temperature. Of samples with baseline cTnI concentration 0.040 MUg/L, 80% had a cTnI concentration below 0.040 MUg/L on re-analysis after 6 h. CONCLUSIONS: Requests for retrospective addition of troponin measurement on samples several hours after venepuncture is commonplace in many laboratories. Analysis of samples drawn >6 h previously may produce values below the cut-off for myocardial necrosis (0.040 MUg/L) that would have been detectable if measured earlier as a result of decreased in vitro stability. Significant percentage decreases in cTnI concentration following storage may also have implications in lowering the threshold for an apparently clinically significant change to occur. PMID- 21652689 TI - Dose-finding design for multi-drug combinations. AB - BACKGROUND: Most of the current designs used for Phase I dose finding trials in oncology will either involve only a single cytotoxic agent or will impose some implicit ordering among the doses. The goal of the studies is to estimate the maximum tolerated dose (MTD), the highest dose that can be administered with an acceptable level of toxicity. A key working assumption of these methods is the monotonicity of the dose-toxicity curve. PURPOSE: Here we consider situations in which the monotonicity assumption may fail. These studies are becoming increasingly common in practice, most notably, in phase I trials that involve combinations of agents. Our focus is on studies where there exist pairs of treatment combinations for which the ordering of the probabilities of a dose limiting toxicity cannot be known a priori. METHODS: We describe a new dose finding design which can be used for multiple-drug trials and can be applied to this kind of problem. Our methods proceed by laying out all possible orderings of toxicity probabilities that are consistent with the known orderings among treatment combinations and allowing the continual reassessment method (CRM) to provide efficient estimates of the MTD within these orders. The design can be seen to simplify to the CRM when the full ordering is known. RESULTS: We study the properties of the design via simulations that provide comparisons to the Bayesian approach to partial orders (POCRM) of Wages, Conaway, and O'Quigley. The POCRM was shown to perform well when compared to other suggested methods for partial orders. Therefore, we comapre our approach to it in order to assess the performance of the new design. LIMITATIONS: A limitation concerns the number of possible orders. There are dose-finding studies with combinations of agents that can lead to a large number of possible orders. In this case, it may not be feasible to work with all possible orders. CONCLUSIONS: The proposed design demonstrates the ability to effectively estimate MTD combinations in partially ordered dosefinding studies. Because it relaxes the monotonicity assumption, it can be considered a multivariate generalization of the CRM. Hence, it can serve as a link between single and multiple-agent dosefinding trials. PMID- 21652690 TI - The association between angiotensin-converting enzyme insertion/deletion gene variant and risk of focal segmental glomerulosclerosis: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: The association of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism with the risk of focal segmental glomerulosclerosis (FSGS) is still controversial. A meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and FSGS susceptibility. METHOD: We performed a predefined literature search and selection of eligible relevant studies to collect data from electronic databases. RESULTS: In total, 12 articles were identified for the analysis of the association between ACE I/D gene polymorphism and FSGS risk. One report included an investigation in Arab and Jewish populations separately. Thus, there were seven reports in Asians, two in Caucasians, one in Africans, two in Arabs and one in Jews. In Asians, there was a markedly positive association between the D allele or DD genotype and FSGS susceptibility (p = 0.008; p = 0.002), and the II genotype may play a protective role against FSGS onset (p = 0.002). However, a link between ACE I/D gene polymorphism and FSGS risk was not found in Caucasians, Africans, Arabs or Jews (Caucasians: D: p = 0.11, DD: p = 0.19, II: p = 0.70; Africans: D: p = 0.40, DD: p = 0.49, II: p = 0.61; Arabs: D: p = 0.34, DD: p = 0.10, II: p = 0.42; Jews: D: p = 0.90, DD: p = 0.97, II: p = 0.83). CONCLUSION: The D allele or DD homozygosity may become a significant genetic molecular marker for the onset of FSGS in Asians, but not for Caucasians, Africans, Arabs or Jews. PMID- 21652691 TI - CDC73-related hereditary hyperparathyroidism: five new mutations and the clinical spectrum. AB - OBJECTIVE: Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of benign and malignant parathyroid tumours, ossifying jaw tumours, various cystic and neoplastic renal abnormalities and benign and malignant uterine tumours. Disease-causing mutations have been localised in the tumour suppressor gene CDC73. There is limited information available on the mutations, and resulting phenotypes and long-term follow-up data are especially scarce. DESIGN: We analysed the clinical data from 16 patients (including three families) carrying mutations in the CDC73 gene. We describe five new mutations/gene variants, the corresponding phenotypes of these carriers and the long-term follow-up. METHODS: The 16 patients were evaluated at an endocrine outpatient clinic and at a surgical department. DNA samples were obtained for sequence analysis of the CDC73 gene. RESULTS: Clinical features of HPT-JT syndrome were detected in 13 of the 15 carriers with germline CDC73 mutations. The major features were benign (n=7; 47%) or cancerous (n=3; 20%) HPT-JT was present in eight cases (53%). Most patients had severe hypercalcaemia, and median serum calcium levels were 3.36 mmol/l. A patient with non-secretory parathyroid carcinoma was included. HPT was diagnosed at a median age of 28.5 years. Mutational analysis of the CDC73 gene identified eight sequence changes, three of them have been reported previously, whereas five are novel: c.1346delG, c.88_94delTTCTCCT, the non-coding variants, c.307+5G>T and c.424-5T>C and c.*12C>A of unknown significance. CONCLUSIONS: This study significantly increases the information available on the mutations and phenotypes of HPT-JT syndrome. PMID- 21652692 TI - Neisserial Omp85 protein is selectively recognized and assembled into functional complexes in the outer membrane of human mitochondria. AB - As a consequence of their bacterial origin, mitochondria contain beta-barrel proteins in their outer membrane (OMM). These proteins require the translocase of the outer membrane (TOM) complex and the conserved sorting and assembly machinery (SAM) complex for transport and integration into the OMM. The SAM complex and the beta-barrel assembly machinery (BAM) required for biogenesis of beta-barrel proteins in bacteria are evolutionarily related. Despite this homology, we show that bacterial beta-barrel proteins are not universally recognized and integrated into the OMM of human mitochondria. Selectivity exists both at the level of the TOM and the SAM complex. Of all of the proteins we tested, human mitochondria imported only beta-barrel proteins originating from Neisseria sp., and only Omp85, the central component of the neisserial BAM complex, integrated into the OMM. PorB proteins from different Neisseria, although imported by the TOM, were not recognized by the SAM complex and formed membrane complexes only when functional Omp85 was present at the same time in mitochondria. Omp85 alone was capable of integrating other bacterial beta-barrel proteins in human mitochondria, but could not substitute for the function of its mitochondrial homolog Sam50. Thus, signals and machineries for transport and assembly of beta barrel proteins in bacteria and human mitochondria differ enough to allow only a certain type of beta-barrel proteins to be targeted and integrated in mitochondrial membranes in human cells. PMID- 21652693 TI - A crucial sequence for transglutaminase type 2 extracellular trafficking in renal tubular epithelial cells lies in its N-terminal beta-sandwich domain. AB - Transglutaminase type 2 (TG2) catalyzes the formation of an epsilon-(gamma glutamyl)-lysine isopeptide bond between adjacent peptides or proteins including those of the extracellular matrix (ECM). Elevated extracellular TG2 leads to accelerated ECM deposition and reduced clearance that underlie tissue scarring and fibrosis. The extracellular trafficking of TG2 is crucial to its role in ECM homeostasis; however, the mechanism by which TG2 escapes the cell is unknown as it has no signal leader peptide and therefore cannot be transported classically. Understanding TG2 transport may highlight novel mechanisms to interfere with the extracellular function of TG2 as isoform-specific TG2 inhibitors remain elusive. Mammalian expression vectors were constructed containing domain deletions of TG2. These were transfected into three kidney tubular epithelial cell lines, and TG2 export was assessed to identify critical domains. Point mutation was then used to highlight specific sequences within the domain required for TG2 export. The removal of beta-sandwich domain prevented all TG2 export. Mutations of Asp(94) and Asp(97) within the N-terminal beta-sandwich domain were identified as crucial for TG2 externalization. These form part of a previously identified fibronectin binding domain ((88)WTATVVDQQDCTLSLQLTT(106)). However, siRNA knockdown of fibronectin failed to affect TG2 export. The sequence (88)WTATVVDQQDCTLSLQLTT(106) within the beta-sandwich domain of TG2 is critical to its export in tubular epithelial cell lines. The extracellular trafficking of TG2 is independent of fibronectin. PMID- 21652694 TI - Blockade of human group X secreted phospholipase A2 (GX-sPLA2)-induced airway inflammation and hyperresponsiveness in a mouse asthma model by a selective GX sPLA2 inhibitor. AB - Group X (GX) phospholipase A(2), a member of a large group of secreted phospholipases A(2) (sPLA(2)s), has recently been demonstrated to play an important in vivo role in the release of arachidonic acid and subsequent formation of eicosanoids. In a Th2 cytokine-driven mouse asthma model, deficiency of mouse GX (mGX)-sPLA(2) significantly impairs development of the asthma phenotype. In this study, we generated mGX-sPLA(2)(-/-) mice with knock-in of human GX (hGX)-sPLA(2) (i.e. hGX-sPLA(2)(+/+) knock-in mice) to understand more fully the role of GX-sPLA(2) in these allergic pulmonary responses and to assess the effect of pharmacological blockade of the GX-sPLA(2)-mediated responses. Knock-in of hGX-sPLA(2) in mGX-sPLA(2)(-/-) mice restored the allergen-induced airway infiltration by inflammatory cells, including eosinophils, goblet cell metaplasia, and hyperresponsiveness to methacholine in the mGX-sPLA(2)-deficient mice. This knock-in mouse model enabled the use of a highly potent indole-based inhibitor of hGX-sPLA(2), RO061606 (which is ineffective against mGX-sPLA(2)), to assess the potential utility of GX-sPLA(2) blockade as a therapeutic intervention in asthma. Delivery of RO061606 via mini-osmotic pumps enabled the maintenance in vivo in the mouse asthma model of plasma inhibitor concentrations near 10 MUm, markedly higher than the IC(50) for inhibition of hGX-sPLA(2) in vitro. RO061606 significantly decreased allergen-induced airway inflammation, mucus hypersecretion, and hyperresponsiveness in the hGX-sPLA(2)(+/+) knock-in mouse. Thus, development of specific hGX-sPLA(2) inhibitors may provide a new pharmacological opportunity for the treatment of patients with asthma. PMID- 21652695 TI - Cytokine-like 1 knock-out mice (Cytl1-/-) show normal cartilage and bone development but exhibit augmented osteoarthritic cartilage destruction. AB - We have shown that cytokine-like 1 (Cytl1) is a novel autocrine regulatory factor that regulates chondrogenesis of mouse mesenchymal cells (Kim, J. S., Ryoo, Z. Y., and Chun, J. S. (2007) J. Biol. Chem. 282, 29359-29367). In this previous work, we found that Cytl1 expression was very low in mesenchymal cells, increased dramatically during chondrogenesis, and decreased during hypertrophic maturation, both in vivo and in vitro. Moreover, exogenous addition or ectopic expression of Cytl1 caused chondrogenic differentiation of mouse limb bud mesenchymal cells. In the current study, we generated a Cytl1 knock-out (Cytl1(-/-)) mouse to investigate the in vivo role of Cytl1. Deletion of the Cytl1 gene did not affect chondrogenesis or cartilage development. Cytl1(-/-) mice also showed normal endochondral ossification and long bone development. Additionally, ultrastructural features of articular cartilage, such as matrix organization and chondrocyte morphology, were similar in wild-type and Cytl1(-/-) mice. However, Cytl1(-/-) mice were more sensitive to osteoarthritic (OA) cartilage destruction. Compared with wild-type littermates, Cytl1(-/-) mice showed more severe OA cartilage destruction upon destabilization of the medial meniscus of mouse knee joints. In addition, expression levels of Cytl1 were markedly decreased in OA cartilage of humans and experimental mice. Taken together, our results suggest that, rather than regulating cartilage and bone development, Cytl1 is required for the maintenance of cartilage homeostasis, and loss of Cytl1 function is associated with experimental OA cartilage destruction in mice. PMID- 21652696 TI - Baicalin, a flavone, induces the differentiation of cultured osteoblasts: an action via the Wnt/beta-catenin signaling pathway. AB - Flavonoids, a group of natural compounds found in a variety of vegetables and herbal medicines, have been intensively reported on regarding their estrogen-like activities and particularly their ability to affect bone metabolism. Here, different subclasses of flavonoids were screened for their osteogenic properties by measuring alkaline phosphatase activity in cultured rat osteoblasts. The flavone baicalin derived mainly from the roots of Scutellaria baicalensis showed the strongest induction of alkaline phosphatase activity. In cultured osteoblasts, application of baicalin increased significantly the osteoblastic mineralization and the levels of mRNAs encoding the bone differentiation markers, including osteonectin, osteocalcin, and collagen type 1alpha1. Interestingly, the osteogenic effect of baicalin was not mediated by its estrogenic activity. In contrast, baicalin promoted osteoblastic differentiation via the activation of the Wnt/beta-catenin signaling pathway; the activation resulted in the phosphorylation of glycogen synthase kinase 3beta and, subsequently, induced the nuclear accumulation of the beta-catenin, leading to the transcription activation of Wnt-targeted genes for osteogenesis. The baicalin-induced osteogenic effects were fully abolished by DKK-1, a blocker of Wnt/beta-catenin receptor. Moreover, baicalin also enhanced the mRNA expression of osteoprotegerin, which could regulate indirectly the activation of osteoclasts. Taken together, our results suggested that baicalin could act via Wnt/beta-catenin signaling to promote osteoblastic differentiation. The osteogenic flavonoids could be very useful in finding potential drugs, or food supplements, for treating post-menopausal osteoporosis. PMID- 21652697 TI - The interaction between nesprins and sun proteins at the nuclear envelope is critical for force transmission between the nucleus and cytoskeleton. AB - Maintaining physical connections between the nucleus and the cytoskeleton is important for many cellular processes that require coordinated movement and positioning of the nucleus. Nucleo-cytoskeletal coupling is also necessary to transmit extracellular mechanical stimuli across the cytoskeleton to the nucleus, where they may initiate mechanotransduction events. The LINC (Linker of Nucleoskeleton and Cytoskeleton) complex, formed by the interaction of nesprins and SUN proteins at the nuclear envelope, can bind to nuclear and cytoskeletal elements; however, its functional importance in transmitting intracellular forces has never been directly tested. This question is particularly relevant since recent findings have linked nesprin mutations to muscular dystrophy and dilated cardiomyopathy. Using biophysical assays to assess intracellular force transmission and associated cellular functions, we identified the LINC complex as a critical component for nucleo-cytoskeletal force transmission. Disruption of the LINC complex caused impaired propagation of intracellular forces and disturbed organization of the perinuclear actin and intermediate filament networks. Although mechanically induced activation of mechanosensitive genes was normal (suggesting that nuclear deformation is not required for mechanotransduction signaling) cells exhibited other severe functional defects after LINC complex disruption; nuclear positioning and cell polarization were impaired in migrating cells and in cells plated on micropatterned substrates, and cell migration speed and persistence time were significantly reduced. Taken together, our findings suggest that the LINC complex is critical for nucleo cytoskeletal force transmission and that LINC complex disruption can result in defects in cellular structure and function that may contribute to the development of muscular dystrophies and cardiomyopathies. PMID- 21652698 TI - Studies of the mechanistic details of the pH-dependent association of botulinum neurotoxin with membranes. AB - Botulinum neurotoxin (BoNT) belongs to a large class of toxic proteins that act by enzymatically modifying cytosolic substrates within eukaryotic cells. The process by which a catalytic moiety is transferred across a membrane to enter the cytosol is not understood for any such toxin. BoNT is known to form pH-dependent pores important for the translocation of the catalytic domain into the cytosol. As a first step toward understanding this process, we investigated the mechanism by which the translocation domain of BoNT associates with a model liposome membrane. We report conditions that allow pH-dependent proteoliposome formation and identify a sequence at the translocation domain C terminus that is protected from proteolytic degradation in the context of the proteoliposome. Fluorescence quenching experiments suggest that residues within this sequence move to a hydrophobic environment upon association with liposomes. EPR analyses of spin labeled mutants reveal major conformational changes in a distinct region of the structure upon association and indicate the formation of an oligomeric membrane associated intermediate. Together, these data support a model of how BoNT orients with membranes in response to low pH. PMID- 21652699 TI - Collagen XXIII, novel ligand for integrin alpha2beta1 in the epidermis. AB - Cellular receptors for collagens belong to the family of beta(1) integrins. In the epidermis, integrin alpha(2)beta(1) is the only collagen-binding integrin present. Its expression is restricted to basal keratinocytes with uniform distribution on the cell surface of those cells. Although alpha(2)beta(1) receptors localized at the basal surface interact with basement membrane proteins collagen IV and laminin 111 and 332, no interaction partners have been reported for these integrin molecules at the lateral and apical membranes of basal keratinocytes. Solid phase binding and surface plasmon resonance spectroscopy demonstrate that collagen XXIII, a member of the transmembrane collagens, directly interacts with integrin alpha(2)beta(1) in an ion- and conformation dependent manner. The two proteins co-localize on the surface of basal keratinocytes. Furthermore, collagen XXIII is sufficient to induce adhesion and spreading of keratinocytes, a process that is significantly reduced in the absence of functional integrin alpha(2)beta(1). PMID- 21652700 TI - Transcriptional and post-translational modulation of myo-inositol oxygenase by high glucose and related pathobiological stresses. AB - Renal-specific oxidoreductase/myo-inositol oxygenase (RSOR/MIOX) catabolizes myo inositol and is implicated in the pathogenesis of diabetic nephropathy. How high glucose (HG) ambience up-regulates its expression and enzyme activity was investigated. MIOX up-regulation was associated with an increase in enzyme activity, which was reduced to basal levels with phosphatase treatment. Using phosphothreonine, protein kinase A (PKA), and PKC substrate antibodies, analyses of kidney lysates of diabetic animals and LLC-PK1/HK-2 cells subjected to HG ambience indicated MIOX to be a phosphoprotein. Kinase phosphorylated recombinant RSOR/MIOX proteins had increased activity confined to exons 2-5. Mutants with substituted phosphorylation sites had a minimal increase in activity. Treatment of cells with PKC, PKA, and PDK1 kinase activators increased activity, whereas inhibitors reduced it. Inhibitors also reduced the phosphorylation and activity of MIOX induced by HG. Besides HG, exposure of cells to oxidants H(2)O(2) and methylglyoxal up-regulated MIOX expression and its phosphorylation and activity, whereas antioxidants N-acetylcysteine, beta-naphthoflavone, and tertiary butyl hydroquinone reduced MIOX expression. Treatment with HG or oxidants or overexpression of MIOX induced nuclear translocation of redox-sensitive transcription factor Nrf2, which binds to antioxidant response elements of various promoters. Promoter analyses revealed an increase in luciferase activity with HG and oxidants. Analyses of antioxidant response elements and carbohydrate response elements revealed an accentuation of DNA-protein interactions with oxidants and under HG ambience. ChIP-PCR and immunofluorescence studies revealed nuclear translocation of carbohydrate response element-binding protein. These findings suggest that phosphorylation of RSOR/MIOX enhances its activity, which is augmented by HG via transcriptional/translational events that are also modulated by diabetes-related pathobiological stresses. PMID- 21652701 TI - Probing the folded state of fibronectin type III domains in stretched fibrils by measuring buried cysteine accessibility. AB - Fibronectin (FN) is an extracellular matrix protein that is assembled into fibrils by cells during tissue morphogenesis and wound healing. FN matrix fibrils are highly elastic, but the mechanism of elasticity has been debated: it may be achieved by mechanical unfolding of FN-III domains or by a conformational change of the molecule without domain unfolding. Here, we investigate the folded state of FN-III domains in FN fibrils by measuring the accessibility of buried cysteines. Four of the 15 FN-III domains (III-2, -3, -9, and -11) appear to unfold in both stretched fibrils and in solution, suggesting that these domains spontaneously open and close even in the absence of tension. Two FN-III domains (III-6 and -12) appear to unfold only in fibrils and not in solution. These results suggest that domain unfolding can at best contribute partially to the 4 fold extensibility of fibronectin fibrils. PMID- 21652702 TI - Pancreatic lipase-related protein-2 (PLRP2) can contribute to dietary fat digestion in human newborns. AB - In newborn mice, PLRP2 is essential for fat digestion. In human infants, the role of PLRP2 in fat digestion is unclear, as it has poor activity against long-chain triglycerides in vitro. Also, many infants carry a genetic polymorphism resulting in a truncated protein, PLRP2 W340X, which may impact function significantly. We re-examined the properties of recombinant human PLRP2 and studied the impact of W340X mutation on its function. In the presence of bile salt micelles and colipase, human PLRP2 hydrolyzed long-chain tri-, di-, and monoglycerides. It hydrolyzed triolein at a level much lower than that of pancreatic triglyceride lipase, but close to that of carboxyl ester lipase, after a long lag phase, which could be eliminated by the addition of oleic acids. Human PLRP2 W340X was poorly secreted and largely retained inside the cell. The retention of the mutant protein triggered endoplasmic reticulum stress and unfolded protein responses. Our results show that earlier studies underestimated human PLRP2 activity against triolein by employing suboptimal assay conditions. In vivo, dietary fat emulsions contain fatty acids as a result of the action of gastric lipase. Consequently, PLRP2 can contribute to fat digestion during early infancy. Furthermore, infants with homozygous W340X alleles will not secrete functional PLRP2 and may have inefficient dietary fat digestion, particularly when breastfeeding is unavailable. Additionally, the aberrant folding of W340X mutant may cause chronic cellular stress and increase susceptibility of pancreatic exocrine cells to other metabolic stressors. PMID- 21652703 TI - Pigment epithelium-derived factor (PEDF) shares binding sites in collagen with heparin/heparan sulfate proteoglycans. AB - Pigment epithelium-derived factor (PEDF) is a collagen-binding protein that is abundantly distributed in various tissues, including the eye. It exhibits various biological functions, such as anti-angiogenic, neurotrophic, and neuroprotective activities. PEDF also interacts with extracellular matrix components such as collagen, heparan sulfate proteoglycans (HSPGs), and hyaluronan. The collagen binding property has been elucidated to be important for the anti-angiogenic activity in vivo (Hosomichi, J., Yasui, N., Koide, T., Soma, K., and Morita, I. (2005) Biochem. Biophys. Res. Commun. 335, 756-761). Here, we investigated the collagen recognition mechanism by PEDF. We first narrowed down candidate PEDF binding sequences by taking advantage of previously reported structural requirements in collagen. Subsequent searches for PEDF-binding sequences employing synthetic collagen-like peptides resulted in the identification of one of the critical binding sites for PEDF, human alpha1(I)(929-938) (IKGHRGFSGL). Further analysis revealed that the collagen recognition by PEDF is sequence- and conformation-specific, and the high affinity binding motif is KGXRGFXGL in the triple helix. The PEDF-binding motif significantly overlapped with the heparin/HSPG-binding motif, KGHRG(F/Y). The interaction of PEDF with collagen I was specifically competed with by heparin but not by chondroitin sulfate-C or hyaluronan. The binding sequences for PEDF and heparin/HSPG also overlapped with the covalent cross-linking sites between collagen molecules. These findings imply a functional relationship between PEDF and HSPGs during angiogenesis, and the interaction of these molecules is regulated by collagen modifications. PMID- 21652704 TI - The non-phagocytic route of collagen uptake: a distinct degradation pathway. AB - The degradation of collagens, the most abundant proteins of the extracellular matrix, is involved in numerous physiological and pathological conditions including cancer invasion. An important turnover pathway involves cellular internalization and degradation of large, soluble collagen fragments, generated by initial cleavage of the insoluble collagen fibers. We have previously observed that in primary mouse fibroblasts, this endocytosis of collagen fragments is dependent on the receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180. Others have identified additional mechanisms of collagen uptake, with different associated receptors, in other cell types. These receptors include beta1-integrins, being responsible for collagen phagocytosis, and the mannose receptor. We have now utilized a newly developed monoclonal antibody against uPARAP/Endo180, which down-regulates the receptor protein level on treated cells, to examine the role of uPARAP/Endo180 as a mediator of collagen internalization by a wide range of cultured cell types. With the exception of macrophages, all cells that proved capable of efficient collagen internalization were of mesenchymal origin and all of these utilized uPARAP/Endo180 for their collagen uptake process. Macrophages internalized collagen in a process mediated by the mannose receptor, a protein belonging to the same protein family as uPARAP/Endo180. beta1-Integrins were found not to be involved in the endocytosis of soluble collagen, irrespectively of whether this was mediated by uPARAP/Endo180 or the mannose receptor. This further distinguishes these pathways from the phagocytic uptake of particulate collagen. PMID- 21652705 TI - Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing. AB - beta-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate beta-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating beta-catenin and found an increase in beta catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3beta-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased beta-catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of beta-catenin signaling. Because fibronectin is a transcriptional target of beta-catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair. PMID- 21652706 TI - Myocyte enhancer factor 2c, an osteoblast transcription factor identified by dimethyl sulfoxide (DMSO)-enhanced mineralization. AB - Rapid mineralization of cultured osteoblasts could be a useful characteristic in stem cell-mediated therapies for fracture and other orthopedic problems. Dimethyl sulfoxide (DMSO) is a small amphipathic solvent molecule capable of stimulating cell differentiation. We report that, in primary human osteoblasts, DMSO dose dependently enhanced the expression of osteoblast differentiation markers alkaline phosphatase activity and extracellular matrix mineralization. Furthermore, similar DMSO-mediated mineralization enhancement was observed in primary osteoblast-like cells differentiated from mouse mesenchymal cells derived from fat, a promising source of starter cells for cell-based therapy. Using a convenient mouse pre-osteoblast model cell line MC3T3-E1, we further investigated this phenomenon showing that numerous osteoblast-expressed genes were elevated in response to DMSO treatment and correlated with enhanced mineralization. Myocyte enhancer factor 2c (Mef2c) was identified as the transcription factor most induced by DMSO, among the numerous DMSO-induced genes, suggesting a role for Mef2c in osteoblast gene regulation. Immunohistochemistry confirmed expression of Mef2c in osteoblast-like cells in mouse mandible, cortical, and trabecular bone. shRNAi-mediated Mef2c gene silencing resulted in defective osteoblast differentiation, decreased alkaline phosphatase activity, and matrix mineralization and knockdown of osteoblast specific gene expression, including osteocalcin and bone sialoprotein. A flow on knockdown of bone-specific transcription factors, Runx2 and osterix by shRNAi knockdown of Mef2c, suggests that Mef2c lies upstream of these two important factors in the cascade of gene expression in osteoblasts. PMID- 21652707 TI - Comparative analysis of different peptidyl-prolyl isomerases reveals FK506 binding protein 12 as the most potent enhancer of alpha-synuclein aggregation. AB - FK506-binding proteins (FKBPs) are members of the immunophilins, enzymes that assist protein folding with their peptidyl-prolyl isomerase (PPIase) activity. Some non-immunosuppressive inhibitors of these enzymes have neuroregenerative and neuroprotective properties with an unknown mechanism of action. We have previously shown that FKBPs accelerate the aggregation of alpha-synuclein (alpha SYN) in vitro and in a neuronal cell culture model for synucleinopathy. In this study we investigated whether acceleration of alpha-SYN aggregation is specific for the FKBP or even the PPIase family. Therefore, we studied the effect of several physiologically relevant PPIases, namely FKBP12, FKBP38, FKBP52, FKBP65, Pin1, and cyclophilin A, on alpha-SYN aggregation in vitro and in neuronal cell culture. Among all PPIases tested in vitro, FKBP12 accelerated alpha-SYN aggregation the most. Furthermore, only FKBP12 accelerated alpha-SYN fibril formation at subnanomolar concentrations, pointing toward an enzymatic effect. Although stable overexpression of various FKBPs enhanced the aggregation of alpha SYN and cell death in cell culture, they were less potent than FKBP12. When FKBP38, FKBP52, and FKBP65 were overexpressed in a stable FKBP12 knockdown cell line, they could not fully restore the number of alpha-SYN inclusion-positive cells. Both in vitro and cell culture data provide strong evidence that FKBP12 is the most important PPIase modulating alpha-SYN aggregation and validate the protein as an interesting drug target for Parkinson disease. PMID- 21652708 TI - Characterization of oligomer formation of amyloid-beta peptide using a split luciferase complementation assay. AB - Amyloid-beta peptide (Abeta) is the amyloid component of senile plaques in Alzheimer disease (AD) brains. Recently a soluble oliomeric form of Abeta in Abeta precursor protein transgenic mouse brains and AD brains was identified as a potential causative molecule for memory impairment, suggesting that soluble Abeta oligomers cause neurodegeneration in AD. Further characterization of this species has been hampered, however, because the concentrations are quite small and it is difficult to monitor Abeta oligomers specifically. Here we developed a novel method for monitoring Abeta oligomers using a split-luciferase complementation assay. In this assay, the N- and C-terminal fragments of Gaussia luciferase (Gluc) are fused separately to Abeta. We found that conditioned media from both N and C-terminal fragments of Gluc-tagged Abeta1-42 doubly transfected HEK293 cells showed strong luminescence. We used gel filtration analyses to analyze the size of oligomers formed by the luciferase complementation assay, and found that it matched closely with oligomers formed by endogenous Abeta in Tg2576 neurons. Large oligomers (24-36-mers), 8-mers, trimers, and dimers predominate. In both systems, Abeta formed oligomers intracellularly, which then appear to be secreted as oligomers. We then evaluated several factors that might impact oligomer formation. The level of oligomerization of Abeta1-40 was similar to that of Abeta1-42. Homodimers formed more readily than heterodimers. The level of oligomerization of murine Abeta1-42 was similar to that of human Abeta1-42. As expected, the familial AD-linked Arctic mutation (E22G) significantly enhanced oligomer formation. These data suggest that Gluc-tagged Abeta enables the analysis of Abeta oligomers. PMID- 21652709 TI - Protein kinase C (PKC) delta suppresses keratinocyte proliferation by increasing p21(Cip1) level by a KLF4 transcription factor-dependent mechanism. AB - PKCdelta increases keratinocyte differentiation and suppresses keratinocyte proliferation and survival. However, the mechanism of proliferation suppression is not well understood. The present studies show that PKCdelta overexpression increases p21(Cip1) mRNA and protein level and promoter activity and that treatment with dominant-negative PKCdelta, PKCdelta-siRNA, or rottlerin inhibits promoter activation. Analysis of the p21(Cip1) promoter upstream regulatory region reveals three DNA segments that mediate PKCdelta-dependent promoter activation. The PKCdelta response element most proximal to the transcription start site encodes six GC-rich DNA elements. Mutation of these sites results in a loss of PKCdelta-dependent promoter activation. Gel mobility supershift and chromatin immunoprecipitation reveal that these DNA elements bind the Kruppel like transcription factor KLF4. PKCdelta increases KLF4 mRNA and protein level and KLF4 binding to the GC-rich elements in the p21(Cip1) proximal promoter. In addition, KLF4-siRNA inhibits PKCdelta-dependent p21(Cip1) promoter activity. PKCdelta increases KLF4 expression leading to enhanced KLF4 interaction with the GC-rich elements in the p21(Cip1) promoter to activate transcription. PMID- 21652710 TI - The P2Y(2) nucleotide receptor mediates tissue factor expression in human coronary artery endothelial cells. AB - The discovery of the role of P2Y(12) receptor in platelet aggregation leads to a new anti-thrombotic drug Plavix; however, little is known about non-platelet P2Y receptors in thrombosis. This study tested the hypothesis that endothelial P2Y receptor(s) mediates up-regulation of tissue factor (TF), the initiator of coagulation cascade. Stimulation of human coronary artery endothelial cells (HCAEC) by UTP/ATP increased the mRNA level of TF but not of its counterpart tissue factor pathway inhibitor, which was accompanied by up-regulation of TF protein and cell surface activity. RT-PCR revealed a selective expression of P2Y(2) and P2Y(11) receptors in HCAEC. Consistent with this, TF up-regulation was inhibited by suramin or by siRNA silencing of P2Y(2) receptor, but not by NF-157, a P2Y(11)-selective antagonist, suggesting a role for the P2Y(2) receptor. In addition, P2Y(2) receptor activated ERK1/2, JNK, and p38 MAPK pathways without affecting the positive NF-kappaB and negative AKT regulatory pathways of TF expression. Furthermore, TF up-regulation was abolished or partially suppressed by inhibition of p38 or JNK but not ERK1/2. Interestingly, blockade of the PLC/Ca(2+) pathway did not affect P2Y(2) receptor activation of p38, JNK, and TF induction. However, blockade of Src kinase reduced phosphorylation of p38 but not JNK, eliminating TF induction. In contrast, inhibition of Rho kinase reduced phosphorylation of JNK but not p38, decreasing TF expression. These findings demonstrate that P2Y(2) receptor mediates TF expression in HCAEC through new mechanisms involving Src/p38 and Rho/JNK pathways, possibly contributing to a pro thrombotic status after vascular injury. PMID- 21652711 TI - A kinase anchor protein 150 (AKAP150)-associated protein kinase A limits dendritic spine density. AB - The A kinase anchor protein AKAP150 recruits the cAMP-dependent protein kinase (PKA) to dendritic spines. Here we show that in AKAP150 (AKAP5) knock-out (KO) mice frequency of miniature excitatory post-synaptic currents (mEPSC) and inhibitory post-synaptic currents (mIPSC) are elevated at 2 weeks and, more modestly, 4 weeks of age in the hippocampal CA1 area versus litter mate WT mice. Linear spine density and ratio of AMPAR to NMDAR EPSC amplitudes were also increased. Amplitude and decay time of mEPSCs, decay time of mIPSCs, and spine size were unaltered. Mice in which the PKA anchoring C-terminal 36 residues of AKAP150 are deleted (D36) showed similar changes. Furthermore, whereas acute stimulation of PKA (2-4 h) increases spine density, prolonged PKA stimulation (48 h) reduces spine density in apical dendrites of CA1 pyramidal neurons in organotypic slice cultures. The data from the AKAP150 mutant mice show that AKAP150-anchored PKA chronically limits the number of spines with functional AMPARs at 2-4 weeks of age. However, synaptic transmission and spine density was normal at 8 weeks in KO and D36 mice. Thus AKAP150-independent mechanisms correct the aberrantly high number of active spines in juvenile AKAP150 KO and D36 mice during development. PMID- 21652712 TI - Suppression of the pancreatic duodenal homeodomain transcription factor-1 (Pdx-1) promoter by sterol regulatory element-binding protein-1c (SREBP-1c). AB - Overexpression of sterol regulatory element-binding protein-1c (SREBP-1c) in beta cells causes impaired insulin secretion and beta cell dysfunction associated with diminished pancreatic duodenal homeodomain transcription factor-1 (PDX-1) expression in vitro and in vivo. To identify the molecular mechanism responsible for this effect, the mouse Pdx-1 gene promoter (2.7 kb) was analyzed in beta cell and non-beta cell lines. Despite no apparent sterol regulatory element-binding protein-binding sites, the Pdx-1 promoter was suppressed by SREBP-1c in beta cells in a dose-dependent manner. PDX-1 activated its own promoter. The E-box ( 104/-99 bp) in the proximal region, occupied by ubiquitously expressed upstream stimulatory factors (USFs), was crucial for the PDX-1-positive autoregulatory loop through direct PDX-1.USF binding. This positive feedback activation was a prerequisite for SREBP-1c suppression of the promoter in non-beta cells. SREBP-1c and PDX-1 directly interact through basic helix-loop-helix and homeobox domains, respectively. This robust SREBP-1c.PDX-1 complex interferes with PDX-1.USF formation and inhibits the recruitment of PDX-1 coactivators. SREBP-1c also inhibits PDX-1 binding to the previously described PDX-1-binding site (-2721/ 2646 bp) in the distal enhancer region of the Pdx-1 promoter. Endogenous up regulation of SREBP-1c in INS-1 cells through the activation of liver X receptor and retinoid X receptor by 9-cis-retinoic acid and 22-hydroxycholesterol inhibited PDX-1 mRNA and protein expression. Conversely, SREBP-1c RNAi restored Pdx-1 mRNA and protein levels. Through these multiple mechanisms, SREBP-1c, when induced in a lipotoxic state, repressed PDX-1 expression contributing to the inhibition of insulin expression and beta cell dysfunction. PMID- 21652713 TI - Inositol hexakisphosphate kinases induce cell death in Huntington disease. AB - Inositol pyrophosphate diphosphoinositol pentakisphosphate is ubiquitously present in mammalian cells and contains highly energetic pyrophosphate bonds. We have previously reported that inositol hexakisphosphate kinase type 2 (InsP(6)K2), which converts inositol hexakisphosphate to inositol pyrophosphate diphosphoinositol pentakisphosphate, mediates apoptotic cell death via its translocation from the nucleus to the cytoplasm. Here, we report that InsP(6)K2 is localized mainly in the cytoplasm of lymphoblast cells from patients with Huntington disease (HD), whereas this enzyme is localized in the nucleus in control lymphoblast cells. The large number of autophagosomes detected in HD lymphoblast cells is consistent with the down-regulation of Akt in response to InsP(6)K2 activation. Consistent with these observations, the overexpression of InsP(6)Ks leads to the depletion of Akt phosphorylation and the induction of cell death. These results suggest that InsP(6)K2 activation is associated with the pathogenesis of HD. PMID- 21652714 TI - The role and specificity of the catalytic and regulatory cation-binding sites of the Na+-pumping NADH:quinone oxidoreductase from Vibrio cholerae. AB - The Na(+)-translocating NADH:quinone oxidoreductase is the entry site for electrons into the respiratory chain and the main sodium pump in Vibrio cholerae and many other pathogenic bacteria. In this work, we have employed steady-state and transient kinetics, together with equilibrium binding measurements to define the number of cation-binding sites and characterize their roles in the enzyme. Our results show that sodium and lithium ions stimulate enzyme activity, and that Na(+)-NQR enables pumping of Li(+), as well as Na(+) across the membrane. We also confirm that the enzyme is not able to translocate other monovalent cations, such as potassium or rubidium. Although potassium is not used as a substrate, Na(+) NQR contains a regulatory site for this ion, which acts as a nonessential activator, increasing the activity and affinity for sodium. Rubidium can bind to the same site as potassium, but instead of being activated, enzyme turnover is inhibited. Activity measurements in the presence of both sodium and lithium indicate that the enzyme contains at least two functional sodium-binding sites. We also show that the binding sites are not exclusively responsible for ion selectivity, and other steps downstream in the mechanism also play a role. Finally, equilibrium-binding measurements with (22)Na(+) show that, in both its oxidized and reduced states, Na(+)-NQR binds three sodium ions, and that the affinity for sodium is the same for both of these states. PMID- 21652715 TI - Npr1 Ser/Thr protein kinase links nitrogen source quality and carbon availability with the yeast nitrate transporter (Ynt1) levels. AB - Ynt1, the single high affinity nitrate and nitrite transporter of the yeast Hansenula polymorpha, is regulated by the quality of nitrogen sources. Preferred nitrogen sources cause Ynt1 dephosphorylation, ubiquitinylation, endocytosis, and vacuolar degradation. In contrast, under nitrogen limitation Ynt1 is phosphorylated and sorted to the plasma membrane. We show here the involvement of the Ser/Thr kinase HpNpr1 in Ynt1 phosphorylation and regulation of Ynt1 levels in response to nitrogen source quality and the availability of carbon. In Deltanpr1, Ynt1 phosphorylation does not take place, although Ynt1 ubiquitin conjugates increase. As a result, in this strain Ynt1 is sorted to the vacuole, from both plasma membrane and the later biosynthetic pathway in nitrogen-free conditions and nitrate. In contrast, overexpression of NPR1 blocks down regulation of Ynt1, increasing Ynt1 phosphorylation at Ser-244 and -246 and reducing ubiquitinylation. Furthermore, Npr1 is phosphorylated in response to the preferred nitrogen sources, and indeed it is dephosphorylated in nitrogen-free medium. Under conditions where Npr1 is phosphorylated, Ynt1 is not and vice versa. We show for the first time that carbon starvation leads to Npr1 phosphorylation, whereas Ynt1 is dephosphorylated and degraded in the vacuole. Rapamycin prevents this, indicating a possible role of the target of rapamycin signaling pathway in this process. We concluded that Npr1 plays a key role in adapting Ynt1 levels to the nitrogen quality and availability of a source of carbon. PMID- 21652716 TI - KAP1 protein: an enigmatic master regulator of the genome. AB - In mammalian cells, multiple cellular processes, including gene silencing, cell growth and differentiation, pluripotency, neoplastic transformation, apoptosis, DNA repair, and maintenance of genomic integrity, converge on the evolutionarily conserved protein KAP1, which is thought to regulate the dynamic organization of chromatin structure via its ability to influence epigenetic patterns and chromatin compaction. In this minireview, we discuss how KAP1 might execute such pleiotropic effects, focusing on genomic targeting mechanisms, protein-protein interactions, specific post-translational modifications of both KAP1 and associated histones, and transcriptome analyses of cells deficient in KAP1. PMID- 21652717 TI - Site-1 protease is essential to growth plate maintenance and is a critical regulator of chondrocyte hypertrophic differentiation in postnatal mice. AB - Site-1 protease (S1P) is a proprotein convertase with essential functions in lipid homeostasis and unfolded protein response pathways. We previously studied a mouse model of cartilage-specific knock-out of S1P in chondroprogenitor cells. These mice exhibited a defective cartilage matrix devoid of type II collagen protein (Col II) and displayed chondrodysplasia with no endochondral bone formation even though the molecular program for endochondral bone development appeared intact. To gain insights into S1P function, we generated and studied a mouse model in which S1P is ablated in postnatal chondrocytes. Postnatal ablation of S1P results in chondrodysplasia. However, unlike early embryonic ablations, the growth plates of these mice exhibit a lack of Ihh, PTHrP-R, and Col10 expression indicating a loss of chondrocyte hypertrophic differentiation and thus disruption of the molecular program required for endochondral bone development. S1P ablation results in rapid growth plate disruption due to intracellular Col II entrapment concomitant with loss of chondrocyte hypertrophy suggesting that these two processes are related. Entrapment of Col II in the chondrocytes of the prospective secondary ossification center precludes its development. Trabecular bone formation is dramatically diminished in the primary spongiosa and is eventually lost. The primary growth plate is eradicated by apoptosis but is gradually replaced by a fully functional new growth plate from progenitor stem cells capable of supporting new bone growth. Our study thus demonstrates that S1P has fundamental roles in the preservation of postnatal growth plate through chondrocyte differentiation and Col II deposition and functions to couple growth plate maturation to trabecular bone development in growing mice. PMID- 21652718 TI - Early transcriptional responses of HepG2-A16 liver cells to infection by Plasmodium falciparum sporozoites. AB - Invasion of hepatocytes by Plasmodium sporozoites deposited by Anopheles mosquitoes, and their subsequent transformation into infective merozoites is an obligatory step in the initiation of malaria. Interactions between the sporozoites and hepatocytes lead to a distinct, complex and coordinated cellular and systemic host response. Little is known about host liver cell response to sporozoite invasion, or whether it is primarily adaptive for the parasite, for the host, or for both. Our present study used gene expression profiling of human HepG2-A16 liver cells infected with Plasmodium falciparum sporozoites to understand the host early cellular events and factors influencing parasite infectivity and sporozoite development. Our results show that as early as 30 min following wild-type, non-irradiated sporozoite exposure, the expressions of at least 742 genes was selectively altered. These genes regulate diverse biological functions, such as immune processes, cell adhesion and communications, metabolism pathways, cell cycle regulation, and signal transduction. These functions reflect cellular events consistent with initial host cell defense responses, as well as alterations in host cells to sustain sporozoites growth and survival. Irradiated sporozoites gave very similar gene expression pattern changes, but direct comparative analysis between liver gene expression profiles caused by irradiated and non-irradiated sporozoites identified 29 genes, including glypican-3, that were specifically up-regulated only in irradiated sporozoites. Elucidating the role of this subset of genes may help identify the molecular basis for the irradiated sporozoites inability to develop intrahepatically, and their usefulness as an immunogen for developing protective immunity against pre erythrocytic stage malaria. PMID- 21652719 TI - Deletion of multispecific organic anion transporter Oat1/Slc22a6 protects against mercury-induced kidney injury. AB - The primary site of mercury-induced injury is the kidney due to uptake of the reactive Hg(2+)-conjugated organic anions in the proximal tubule. Here, we investigated the in vivo role of Oat1 (organic anion transporter 1; originally NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478)) in handling of known nephrotoxic doses of HgCl(2). Oat1 (Slc22a6) is a multispecific organic anion drug transporter that is expressed on the basolateral aspects of renal proximal tubule cells and that mediates the initial steps of elimination of a broad range of endogenous metabolites and commonly prescribed pharmaceuticals. Mercury induced nephrotoxicity was observed in a wild-type model. We then used the Oat1 knock-out to determine in vivo whether the renal injury effects of mercury are mediated by Oat1. Most of the renal injury (both histologically and biochemically as measured by blood urea nitrogen and creatinine) was abolished following HgCl(2) treatment of Oat1 knock-outs. Thus, acute kidney injury by HgCl(2) was found to be mediated mainly by Oat1. Our findings raise the possibility that pharmacological modulation of the expression and/or function of Oat1 might be an effective therapeutic strategy for reducing renal injury by mercury. This is one of the most striking phenotypes so far identified in the Oat1 knock-out. (Eraly, S. A., Vallon, V., Vaughn, D. A., Gangoiti, J. A., Richter, K., Nagle, M., Monte, J. C., Rieg, T., Truong, D. M., Long, J. M., Barshop, B. A., Kaler, G., and Nigam, S. K. (2006) J. Biol. Chem. 281, 5072-5083). PMID- 21652720 TI - Domain and functional analysis of a novel breast tumor suppressor protein, SCUBE2. AB - Signal peptide CUB (complement proteins C1r/C1s, Uegf, and Bmp 1)-EGF domain containing protein 2 (SCUBE2) is a secreted, membrane-associated multidomain protein composed of five recognizable motifs: an NH(2)-terminal signal peptide sequence, nine copies of epidermal growth factor (EGF)-like repeats, a spacer region, three cysteine-rich repeats, and one CUB domain at the COOH terminus. Our previous clinical study showed that SCUBE2 may act as a novel breast tumor suppressor gene and serve as a useful prognostic marker. However, the specific domain responsible for its tumor suppressor activity and the precise mechanisms of its anti-tumor effect remain unknown. Using a combination of biochemical, molecular, and cell biology techniques, we further dissected the molecular functions and signal pathways mediated by the NH(2)-terminal EGF-like repeats or COOH-terminal CUB domain of SCUBE2. Independent overexpression of the NH(2) terminal EGF-like repeats or COOH-terminal CUB domain resulted in suppression of MCF-7 breast cancer cell proliferation and reduced MCF-7 xenograft tumor growth in nude mice. Molecular and biochemical analyses revealed that the COOH-terminal CUB domain could directly bind to and antagonize bone morphogenetic protein activity in an autocrine manner, whereas the NH(2)-terminal EGF-like repeats could mediate cell-cell homophilic adhesions in a calcium-dependent fashion, interact with E-cadherin (a master tumor suppressor), and decrease the beta catenin signaling pathway. Together, our data demonstrate that SCUBE2 has growth inhibitory effects through a coordinated regulation of two distinct mechanisms: antagonizing bone morphogenetic protein and suppressing the beta-catenin pathway in breast cancer cells. PMID- 21652721 TI - Perturbation of BRD4 protein function by BRD4-NUT protein abrogates cellular differentiation in NUT midline carcinoma. AB - NUT midline carcinoma (NMC) belongs to a class of highly lethal and poorly differentiated epithelial cancers arising mainly in human midline organs. NMC is caused by the chromosome translocation-mediated fusion of the NUT (nuclear protein in testis) gene on chromosome 15 to a few other genes, most frequently the BRD4 gene on chromosome 19. The mechanism by which the BRD4-NUT fusion product blocks NMC cellular differentiation and contributes to oncogenesis remains elusive. In this study, we show that BRD4-NUT and BRD4 colocalize in discrete nuclear foci that are hyperacetylated but transcriptionally inactive. BRD4-NUT recruits histone acetyltransferases to induce histone hyperacetylation in these chromatin foci, which provide docking sites for accumulation of additional BRD4 and associated P-TEFB (positive transcription elongation factor b) complexes in the transcriptionally inactive BRD4-NUT foci. These molecular events lead to repression of a BRD4.P-TEFB downstream target gene c-fos, a component of activator protein 1 (AP-1), that directly regulates epithelial differentiation. Knockdown of BRD4-NUT in NMC cells disperses the transcriptionally inactive chromatin foci and releases the transcriptional activators to stimulate c-fos expression, leading to restoration of cellular differentiation. Our study provides a novel mechanism by which the BRD4-NUT oncogene perturbs BRD4 functions to block cellular differentiation and to contribute to the oncogenic progression in the highly aggressive NMC. PMID- 21652722 TI - Double mutant cycle analysis identified a critical leucine residue in the IIS4S5 linker for the activation of the Ca(V)2.3 calcium channel. AB - Mutations in distal S6 were shown to significantly alter the stability of the open state of Ca(V)2.3 (Raybaud, A., Baspinar, E. E., Dionne, F., Dodier, Y., Sauve, R., and Parent, L. (2007) J. Biol. Chem. 282, 27944-27952). By analogy with K(V) channels, we tested the hypothesis that channel activation involves electromechanical coupling between S6 and the S4S5 linker in Ca(V)2.3. Among the 11 positions tested in the S4S5 linker of domain II, mutations of the leucine residue at position 596 were found to destabilize significantly the closed state with a -50 mV shift in the activation potential and a -20 mV shift in its charge voltage relationship as compared with Ca(V)2.3 wt. A double mutant cycle analysis was performed by introducing pairs of glycine residues between S4S5 and S6 of Domain II. Strong coupling energies (DeltaDeltaG(interact) > 2 kcal mol(-1)) were measured for the activation gating of 12 of 39 pairs of mutants. Leu-596 (IIS4S5) was strongly coupled with distal residues in IIS6 from Leu-699 to Asp-704. In particular, the double mutant L596G/I701G showed strong cooperativity with a DeltaDeltaG(interact) ~6 kcal mol(-1) suggesting that both positions contribute to the activation gating of the channel. Altogether, our results highlight the role of a leucine residue in S4S5 and provide the first series of evidence that the IIS4S5 and IIS6 regions are energetically coupled during the activation of a voltage-gated Ca(V) channel. PMID- 21652724 TI - A nonselenoprotein from amphioxus deiodinates triac but not T3: is triac the primordial bioactive thyroid hormone? AB - Thyroid hormone (TH) is important for metamorphosis in many species, including the cephalochordate Branchiostoma floridae, a marine invertebrate (amphioxus) living in warmer coastal areas. Branchiostoma expresses a TH receptor, which is activated by 3,3',5-triiodothyroacetic acid (TA(3)) but not by T(3). The Branchiostoma genome also contains multiple genes coding for proteins homologous to iodothyronine deiodinases in vertebrates, selenoproteins catalyzing the activation or inactivation of TH. Three Branchiostoma deiodinases have been cloned: two have a catalytic Sec, and one, bfDy, has a Cys residue. We have studied the catalytic properties of bfDy in transfected COS1 cells by HPLC analysis of reactions with (125)I-labeled substrates and dithiothreitol as cofactor. We could not detect deiodination of T(4), T(3), or rT(3) by bfDy but observed rapid and selective inner ring deiodination (inactivation) of TA(3) and 3,3',5,5'-tetraiodothyroacetic acid (TA(4)). Deiodination of TA(3) by bfDy was optimal at 25 C and 10 mm dithiothreitol. bfDy was extremely labile at 37 C, showing a half-life of less than 2 min, in contrast with a half-life of more than 60 min at 25 C. Deiodination of labeled TA(3) was inhibited dose dependently by unlabeled TA(3)~TA(4)>T(4)~T(3). Michaelis-Menten analysis yielded Michaelis Menten constant values of 6.8 and 68 nm and maximum velocity values of 1.4 and 5.4 pmol/min.mg protein for TA(3) and TA(4), respectively. bfDy was not inhibited by propylthiouracil and iodoacetate and only weakly by goldthioglucose and iopanoic acid. In conclusion, we demonstrate rapid inactivation of TA(3) and TA(4) but not of T(3) and T(4) by the first reported natural nonselenodeiodinase. Our findings support the hypothesis that TA(3) is a primordial bioactive TH. PMID- 21652723 TI - Structural and functional relationships between the lectin and arm domains of calreticulin. AB - Calreticulin and calnexin are key components in maintaining the quality control of glycoprotein folding within the endoplasmic reticulum. Although their lectin function of binding monoglucosylated sugar moieties of glycoproteins is well documented, their chaperone activity in suppressing protein aggregation is less well understood. Here, we use a series of deletion mutants of calreticulin to demonstrate that its aggregation suppression function resides primarily within its lectin domain. Using hydrophobic peptides as substrate mimetics, we show that aggregation suppression is mediated through a single polypeptide binding site that exhibits a K(d) for peptides of 0.5-1 MUM. This site is distinct from the oligosaccharide binding site and differs from previously identified sites of binding to thrombospondin and GABARAP (4-aminobutyrate type A receptor-associated protein). Although the arm domain of calreticulin was incapable of suppressing aggregation or binding hydrophobic peptides on its own, it did contribute to aggregation suppression in the context of the whole molecule. The high resolution x-ray crystal structure of calreticulin with a partially truncated arm domain reveals a marked difference in the relative orientations of the arm and lectin domains when compared with calnexin. Furthermore, a hydrophobic patch was detected on the arm domain that mediates crystal packing and may contribute to calreticulin chaperone function. PMID- 21652725 TI - Acquisition of sexual receptivity: roles of chromatin acetylation, estrogen receptor-alpha, and ovarian hormones. AB - Sexually naive, hormone-primed, C57BL/6J female mice are not receptive to mating attempts by conspecific males. Repeated experience with sexually active males and concurrent treatment with estradiol and progesterone gradually increases female receptivity over the course of five trials to maximal levels. Ovarian hormones activate their cognate nuclear steroid receptors estrogen receptor-alpha and progesterone receptor to induce female sexual receptivity. Nuclear receptors recruit coactivators of transcription that include histone acetyltransferases to hormone responsive genes. In this set of studies, we found that the histone deacetylase inhibitor sodium butyrate enhances the experiential acquisition of receptivity. Evidence is provided that the actions of sodium butyrate on receptivity require activated estrogen receptor-alpha and progesterone. PMID- 21652726 TI - Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. AB - PTH is a potent calcium-regulating factor that has skeletal anabolic effects when administered intermittently or catabolic effects when maintained at consistently high levels. Bone cells express PTH receptors, but the cellular responses to PTH in bone are incompletely understood. Wnt signaling has recently been implicated in the osteo-anabolic response to the hormone. Specifically, the Sost gene, a major antagonist of Wnt signaling, is down-regulated by PTH exposure. We investigated this mechanism by treating Sost-deficient mice and their wild-type littermates with anabolic and catabolic regimens of PTH and measuring the skeletal responses. Male Sost(+/+) and Sost(-/-) mice were injected daily with human PTH 1-34 (0, 30, or 90 MUg/kg) for 6 wk. Female Sost(+/+) and Sost(-/-) mice were continuously infused with vehicle or high-dose PTH (40 MUg/kg . d) for 3 wk. Dual energy x-ray absorptiometry-derived measures of intermittent PTH (iPTH)-induced bone gain were impaired in Sost(-/-) mice. Further probing revealed normal or enhanced iPTH-induced cortical bone formation rates but concomitant increases in cortical porosity among Sost(-/-) mice. Distal femur trabecular bone was highly responsive to iPTH in Sost(-/-) mice. Continuous PTH (cPTH) infusion resulted in equal bone loss in Sost(+/+) and Sost(-/-) mice as measured by dual energy x-ray absorptiometry. However, distal femur trabecular bone, but not lumbar spine trabecular bone, was spared the bone-wasting effects of cPTH in Sost(-/-) mice. These results suggest that changes in Sost expression are not required for iPTH-induced anabolism. iPTH-induced resorption of cortical bone might be overstimulated in Sost-deficient environments. Furthermore, Sost deletion protects some trabecular compartments, but not cortical compartments, from bone loss induced by high-dose PTH infusion. PMID- 21652728 TI - Fetal hypothalamic neuroprogenitor cell culture: preferential differentiation paths induced by leptin and insulin. AB - In response to temporally orchestrated growth factor stimulation, developing neural stem/progenitor cells undergo extensive self-renewal and then generate neurons and astrocytes. Fetal neonatal leptin and insulin deficiency results in reduced hypothalamic axonal pathways regulating appetite, which may predispose to offspring hyperphagia and obesity. Neural development of the arcuate nucleus, a key target of adiposity signals, leptin and insulin, is immature at birth. Hence, to explore proximate effects of leptin/insulin on hypothalamic development, we determined trophic and differentiation effects on neural stem/progenitor cells using a model of fetal hypothalamic neurospheres (NS). NS cultures were produced from embryonic d 20 fetal rats and passage 1 and passage 2 cells examined for proliferation and differentiation into neurons (neuronal nuclei, class IIIbeta tubulin, and doublecortin) and astrocytes (glial fibrillary acidic protein). Leptin-induced NS proliferation was significantly greater than that induced by insulin, although both effects were blocked by Notch, extracellular signal regulated kinase, or signal transducer and activator of transcription 3 inhibition. Leptin preferentially induced neuronal, whereas insulin promoted astrocyte differentiation. Extracellular signal-regulated kinase inhibition suppressed both leptin and insulin-mediated differentiation, whereas signal transducer and activator of transcription inhibition only affected leptin mediated responses. These findings demonstrate preferential and disparate differentiation paths induced by leptin and insulin. Altered fetal exposure to leptin or insulin, resulting from fetal growth restriction, macrosomia, or maternal diabetes, may potentially have marked effects on fetal brain development. PMID- 21652727 TI - Type-2 iodothyronine 5'deiodinase (D2) in skeletal muscle of C57Bl/6 mice. II. Evidence for a role of D2 in the hypermetabolism of thyroid hormone receptor alpha-deficient mice. AB - Mice with ablation of the Thra gene have cold intolerance due to an as yet undefined defect in the activation of brown adipose tissue (BAT) uncoupling protein (UCP). They develop an alternate form of facultative thermogenesis, activated at temperatures below thermoneutrality and associated with hypermetabolism and reduced sensitivity to diet-induced obesity. A consistent finding in Thra-0/0 mice is increased type-2 iodothyronine deiodinase (D2) mRNA in skeletal muscle and other tissues. With an improved assay to measure D2 activity, we show here that this enzyme activity is increased in proportion to the mRNA and as a function of the ambient cold. The activation is mediated by the sympathetic nervous system in Thra-0/0, as it is in wild-type genotype mice, but the sympathetic nervous system effect is greater in Thra-0/0 mice. Using D2 ablated mice (Dio2-/-), we reported elsewhere and show here that, in spite of sharing a severe deficiency in BAT thermogenesis with Thra-0/0 and UCP1-knockout mice, they do not have an increase in oxygen consumption, and they gain more weight than wild-type controls when fed a high-fat diet. UCP3 mRNA is highly responsive to thyroid hormone, and it is increased in Thra-0/0 mice, particularly when fed high-fat diets. We show here that muscle UCP3 mRNA in hypothyroid Thra 0/0 mice is responsive to small dose-short regimens of T(4), indicating a role for locally, D2-generated T(3). Lastly, we show that bile acids stimulate not only BAT but also muscle D2 activity, and this is associated with stimulation of muscle UCP3 mRNA expression provided T(4) is present. These observations strongly support the concept that enhanced D2 activity in Thra-0/0 plays a critical role in their alternate form of facultative thermogenesis, stimulating increased fat oxidation by increasing local T(3) generation in skeletal muscle. PMID- 21652730 TI - Insulin-like growth factor-binding protein-3 mediates high glucose-induced apoptosis by increasing oxidative stress in proximal tubular epithelial cells. AB - IGF-binding protein-3 (IGFBP-3) is the major circulating carrier protein for IGF, and also acts as a potent antiproliferative agent in various cell types. Recently, IGFBP-3 was reported to mediate high glucose-induced apoptosis in mesangial cells and podocytes. In this study, we investigated the role of IGFBP-3 in high glucose-induced apoptosis in proximal tubular epithelial cells (PTEC). Expression of IGFBP-3 protein and mRNA in a porcine PTEC line (LLC-PK1 cells) was measured after exposure to either standard (5.5 mM) or high-glucose (30 mM) medium. We quantified apoptosis after treatment with small interfering RNA against IGFBP-3 (siRNA:IGFBP-3) in high-glucose medium or in cells that overexpressed IGFBP-3. Oxidative stress was measured in high-glucose medium, in the presence of siRNA:IGFBP-3, or in IGFBP-3-overexpressing cells. IGFBP-3 protein and mRNA expression in LLC-PK1 cells was higher in high-glucose medium than in standard-glucose medium. Exposure to high-glucose medium increased apoptosis, and high-glucose-induced apoptosis was abolished by siRNA:IGFBP-3. IGFBP-3 overexpression induced apoptosis in LLC-PK1 cells. Both high-glucose medium and IGFBP-3 overexpression increased reactive oxygen species, and siRNA:IGFBP-3 reduced this increase. Antioxidant treatment decreased IGFBP-3 expression and apoptosis, whereas oxidative stress from hydrogen peroxide increased IGFBP-3 expression, suggesting that oxidative stress increases IGFBP-3 expression. Our results suggest that increased IGFBP-3 expression by high glucose mediates high-glucose-induced apoptosis in PTEC. Increased oxidative stress from high glucose enhances IGFBP-3 expression, inducing apoptosis. Increased expression of IGFBP-3 by high glucose induces additional oxidative stress, which may result in amplification of hyperglycemic damage. PMID- 21652729 TI - Gastrin-deficient mice have disturbed hematopoiesis in response to iron deficiency. AB - Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. Here we report the effect of long-term dietary iron modification on gastrin-deficient (Gas(-/-)) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r(-/-)) mice, both of which have reduced basal gastric acid secretion. Iron homeostasis in both strains appeared normal unless the animals were challenged by iron deficiency. When fed an iron-deficient diet, Gas(-/-) mice, but not Cck2r(-/-) mice, developed severe anemia. In iron-deficient Gas(-/-) mice, massive splenomegaly was also apparent with an increased number of splenic megakaryocytes accompanied by thrombocytosis. The expression of the mRNA encoding the iron regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r(-/-) and Gas( /-) mice on a low-iron diet, but, interestingly, the reduction was greater in Cck2r(-/-) mice and smaller in Gas(-/-) mice than in the corresponding wild-type strains. These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in hematopoiesis under conditions of iron deficiency. PMID- 21652732 TI - Still another activity by the highly promiscuous enzyme CYP3A4: 25-hydroxylation of cholesterol. PMID- 21652731 TI - Caveolins/caveolae protect adipocytes from fatty acid-mediated lipotoxicity. AB - Mice and humans lacking functional caveolae are dyslipidemic and have reduced fat stores and smaller fat cells. To test the role of caveolins/caveolae in maintaining lipid stores and adipocyte integrity, we compared lipolysis in caveolin-1 (Cav1)-null fat cells to that in cells reconstituted for caveolae by caveolin-1 re-expression. We find that the Cav1-null cells have a modestly enhanced rate of lipolysis and reduced cellular integrity compared with reconstituted cells as determined by the release of lipid metabolites and lactic dehydrogenase, respectively, into the media. There are no apparent differences in the levels of lipolytic enzymes or hormonally stimulated phosphorylation events in the two cell lines. In addition, acute fasting, which dramatically raises circulating fatty acid levels in vivo, causes a significant upregulation of caveolar protein constituents. These results are consistent with the hypothesis that caveolae protect fat cells from the lipotoxic effects of elevated levels fatty acids, which are weak detergents at physiological pH, by virtue of the property of caveolae to form detergent-resistant membrane domains. PMID- 21652733 TI - A sensitized RNA interference screen identifies a novel role for the PI3K p110gamma isoform in medulloblastoma cell proliferation and chemoresistance. AB - Medulloblastoma is the most common malignant brain tumor in children and is associated with a poor outcome. We were interested in gaining further insight into the potential of targeting the human kinome as a novel approach to sensitize medulloblastoma to chemotherapeutic agents. A library of small interfering RNA (siRNA) was used to downregulate the known human protein and lipid kinases in medulloblastoma cell lines. The analysis of cell proliferation, in the presence or absence of a low dose of cisplatin after siRNA transfection, identified new protein and lipid kinases involved in medulloblastoma chemoresistance. PLK1 (polo like kinase 1) was identified as a kinase involved in proliferation in medulloblastoma cell lines. Moreover, a set of 6 genes comprising ATR, LYK5, MPP2, PIK3CG, PIK4CA, and WNK4 were identified as contributing to both cell proliferation and resistance to cisplatin treatment in medulloblastoma cells. An analysis of the expression of the 6 target genes in primary medulloblastoma tumor samples and cell lines revealed overexpression of LYK5 and PIK3CG. The results of the siRNA screen were validated by target inhibition with specific pharmacological inhibitors. A pharmacological inhibitor of p110gamma (encoded by PIK3CG) impaired cell proliferation in medulloblastoma cell lines and sensitized the cells to cisplatin treatment. Together, our data show that the p110gamma phosphoinositide 3-kinase isoform is a novel target for combinatorial therapies in medulloblastoma. PMID- 21652734 TI - Divergence by ADHD subtype in smoking cessation response to OROS-methylphenidate. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition subclassified in DSM-IV according to its core symptoms domains as (a) predominantly inattentive (ADHD-IN), (b) predominantly hyperactive/impulsive (ADHD-H), and (c) combined inattentive and hyperactive/impulsive (ADHD-C). Whether these subtypes represent distinct clinical entities or points on a severity continuum is controversial. Divergence in treatment response is a potential indicator of qualitative heterogeneity. This study examined smoking cessation response by ADHD subtype to osmotic-release oral system methylphenidate (OROS-MPH). METHODS: Male and female adult smokers (ADHD-C = 167 and ADHD-IN = 87) were randomized to receive OROS-MPH or placebo as augmentation treatment to nicotine patch and counseling. Logistic regression was conducted to test the effect of OROS-MPH versus placebo on prolonged smoking abstinence by ADHD subtype. RESULTS: The subtypes were similar in baseline demographic, smoking, and psychiatric history but differed in smoking cessation response to OROS-MPH or placebo as a function of nicotine dependence level. The 3 way interaction was significant; chi(2)(1) = 8.22, p < .01. Among highly dependent smokers, the prolonged abstinence rates were greater with OROS-MPH than with placebo in the ADHD-C group (60% vs. 31.3%, respectively, p < .05) but higher with placebo than with OROS-MPH in the ADHD-IN group (60% vs. 11.8%, respectively, p < .01). Abstinence rates did not differ by subtype or treatment among smokers who were less nicotine dependent. CONCLUSION: Contrasting treatment response and divergence in the impact of nicotine dependence level support the hypothesis of ADHD subtypes as distinct clinical entities and may indicate the need and directions for personalized targeted treatments of smokers with ADHD. PMID- 21652735 TI - Efficacy of varenicline to prompt quit attempts in smokers not currently trying to quit: a randomized placebo-controlled trial. AB - INTRODUCTION: Nicotine replacement therapy to aid smoking reduction increases the probability of a future quit attempt among smokers not currently planning to quit smoking. We tested whether varenicline, a partial nicotine agonist, would also increase future quit attempts. METHODS: This randomized, placebo-controlled trial recruited 218 smokers who were interested in quitting but had no plans to quit in the next month. Participants used varenicline (2 mg/day) or placebo for 2-8 weeks plus received brief counseling on methods to reduce cigarettes/day. The primary measure was the incidence of a quit attempt within 6 months of study entry. Secondary measures were point prevalence abstinence, motivation to stop smoking, and reduction in cigarettes/day. RESULTS: Varenicline increased the incidence of a quit attempt more than placebo at the Nebraska site (73% vs. 41%; p < .001) but not at the Vermont site (45% vs. 51%; p = .45). Varenicline increased most other measures of quit attempts, motivation and abstinence, independent of site. The beneficial effects of varenicline in quit attempts appeared to be mediated by greater reductions in cigarettes/day, dependence, craving, and cigarette satisfaction. Varenicline had a greater effect on quit attempts in less-dependent smokers, in minority smokers, and in those who had less prior cessation or reduction activity. Adverse events were minimal. CONCLUSIONS: Varenicline increased quit attempts in smokers who are not currently trying to quit at one of the two study sites and improved most all secondary outcomes independent of site. This appeared to be due to decreasing cigarettes/day and level of dependence. PMID- 21652736 TI - The effect of menthol vapor on nasal sensitivity to chemical irritation. AB - INTRODUCTION: Among other effects, menthol added to cigarettes may modulate sensory response to cigarette smoke either by masking "harshness" or contributing to a desirable "impact." However, harshness and impact have been imprecisely defined and assessed using subjective measures. Thus, the current experiments used an objective measure of sensitivity to chemical irritation in the nose to test the hypothesis that menthol vapor modulates sensitivity to chemical irritation in the airways. METHODS: Nasal irritation thresholds were measured for 2 model compounds (acetic acid and allyl isothiocyanate) using nasal lateralization. In this technique, participants simultaneously sniff clean air in one nostril and chemical vapor in the other and attempt to identify the stimulated nostril. People cannot lateralize based on smell alone but can do so when chemicals are strong enough to feel. In one condition, participants were pretreated by sniffing menthol vapor. In a control condition, participants were pretreated by sniffing an odorless blank (within-subjects design). RESULTS: Pretreatment with menthol vapor decreased sensitivity to nasal irritation from acetic acid (participants required higher concentrations to lateralize) but increased sensitivity to allyl isothiocyanate (lower concentrations were required). CONCLUSIONS: The current experiments provide objective evidence that menthol vapor can modulate sensitivity to chemical irritation in the upper airways in humans. Cigarette smoke is a complex mixture of chemicals and particulates, and further work will be needed to determine exactly how menthol modulates smoking sensation. A better understanding could lead to treatments tailored to help menthol smokers quit by replacing the sensation of mentholated cigarettes. PMID- 21652737 TI - Physicochemical characterization and in vitro hemolysis evaluation of silver nanoparticles. AB - Silver nanomaterials are increasingly being used as antimicrobial agents in medical devices. This study assessed the in vitro hemolytic potential of unbound silver particles in human blood to determine which physical and chemical particle properties contribute to mechanisms of red blood cell (RBC) damage. Four silver particle powders (two nano-sized and two micron-sized) were dispersed in water and characterized using transmission electron microscopy, dynamic light scattering, surface-enhanced Raman spectroscopy, and zeta potential measurement. Particle size and agglomeration were dependent on the suspension media. Under similar conditions to the hemolysis assay, with the particles added to phosphate buffered saline (PBS) and plasma, the size of the nanoparticles increased compared with particles suspended in water alone due to interaction with chloride ions and plasma proteins. To determine hemolysis response, aqueous particle suspensions were mixed with heparinized human blood diluted in PBS for 3.5 h at 37 degrees C. Both nanoparticle preparations were significantly more hemolytic than micron-sized particles at equivalent mass concentrations > 220 MUg/ml and at estimated surface area concentrations > 10 cm(2)/ml. The presence or absence of surface citrate on nanoparticles showed no significant difference in hemolysis. However, the aqueous nanoparticle preparations released significantly more silver ions than micron-sized particles, which correlated with increased hemolysis. Although significant size changes occurred to the silver particles due to interaction with media components, the higher level of in vitro hemolysis observed with nanoparticles compared with micron-sized particles may be related to their greater surface area, increased silver ion release, and direct interaction with RBCs. PMID- 21652738 TI - Nodulation of Thermopsis lupinoides by a Mesorhizobium huakuii strain with a unique nodA gene in Kamtchatka, Russia. AB - Very little is known about rhizobia that form nodules on Thermopsis spp. We report the isolation of a Mesorhizobium huakuii strain with a unique nodA gene that form nodules on Thermopsis lupinoides in Kamtchatka, Russia. The isolate did not form nodules on Thermopsis chinensis or Thermopsis caroliniana, which suggests it may be host specific. PMID- 21652739 TI - Identification and characterization of UndAHRCR-6, an outer membrane endecaheme c type cytochrome of Shewanella sp. strain HRCR-6. AB - UndA(HRCR-6) was identified from the metal-reducing bacterium Shewanella sp. strain HRCR-6. Both in vivo and in vitro characterization results indicate that UndA(HRCR-6) is an outer membrane endecaheme c-type cytochrome and probably has a key functional role in the extracellular reduction of iron [Fe(III)] oxides and uranium [U(VI)] by Shewanella sp. HRCR-6. PMID- 21652740 TI - Detection of murine norovirus-1 by using TAT peptide-delivered molecular beacons. AB - A TAT peptide-delivered molecular beacon was developed and utilized to enumerate murine norovirus 1, a human norovirus (NoV) surrogate, in RAW 264.7 cells. This allowed the detection of a single infective virus within 6 h, a 12-fold improvement in time required for viral detection and quantification compared to that required by the conventional plaque assay. PMID- 21652741 TI - Microbial community profile of a lead service line removed from a drinking water distribution system. AB - A corroded lead service line was removed from a drinking water distribution system, and the microbial community was profiled using 16S rRNA gene techniques. This is the first report of the characterization of a biofilm on the surface of a corroded lead drinking water service line. The majority of phylotypes have been linked to heavy-metal-contaminated environments. PMID- 21652742 TI - Production in Escherichia coli of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with differing monomer compositions from unrelated carbon sources. AB - The industrial production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) has been hindered by high cost and a complex control strategy caused by the addition of propionate. In this study, based on analysis of the PHBV biosynthesis process, we developed a PHBV biosynthetic pathway from a single unrelated carbon source via threonine biosynthesis in Escherichia coli. To accomplish this, we (i) overexpressed threonine deaminase, which is the key factor for providing propionyl-coenzyme A (propionyl-CoA), from different host bacteria, (ii) removed the feedback inhibition of threonine by mutating and overexpressing the thrABC operon in E. coli, and (iii) knocked out the competitive pathways of catalytic conversion of propionyl-CoA to 3-hydroxyvaleryl-CoA. Finally, we constructed a series of strains and mutants which were able to produce the PHBV copolymer with differing monomer compositions in a modified M9 medium supplemented with 20 g/liter xylose. The largest 3-hydroxyvalerate fraction obtained in the copolymer was 17.5 mol%. PMID- 21652743 TI - Submerged conidiation and product formation by Aspergillus niger at low specific growth rates are affected in aerial developmental mutants. AB - Exposure to an aerial environment or severe nutrient limitation induces asexual differentiation in filamentous fungi. Submerged cultivation of Aspergillus niger in carbon- and energy-limited retentostat cultures both induces and fuels conidiation. Physiological and transcriptomic analyses have revealed that this differentiation strongly affects product formation. Since conidiation is inherent in the aerial environment, we hypothesized that product formation near zero growth can be influenced by affecting differentiation or development of aerial hyphae in general. To investigate this idea, three developmental mutants (DeltafwnA, scl-1, and scl-2 mutants) that have no apparent vegetative growth defects were cultured in maltose-limited retentostat cultures. The secondary metabolite profile of the wild-type strain defined flavasperone, aurasperone B, tensidol B, and two so far uncharacterized compounds as associated with conidium formation, while fumonisins B(2), B(4), and B(6) were characteristic of early response to nutrient limitation by the vegetative mycelium. The developmental mutants responded differently to the severe substrate limitation, which resulted in distinct profiles of growth and product formation. fwnA encodes the polyketide synthase responsible for melanin biosynthesis during aerial differentiation, and we show that conidial melanin synthesis in submerged retentostat cultures and aurasperone B production are fwnA dependent. The scl-1 and scl-2 strains are two UV mutants generated in the DeltafwnA background that displayed reduced asexual conidiation and formed sclerotium-like structures on agar plates. The reduced conidiation phenotypes of the scl-1 and scl-2 strains are reflected in the retentostat cultivation and are accompanied by elimination or severely reduced accumulation of secondary metabolites and distinctly enhanced accumulation of extracellular protein. This investigation shows that submerged conidiation and product formation of a mitosporic fungus cultured at low specific growth rates can be fundamentally affected by interfering with the genetic program for differentiation of aerial hyphae, opening new perspectives for tailoring industrial performance. PMID- 21652745 TI - The international alliance of patients' organisations. PMID- 21652744 TI - Comparison of innovative molecular approaches and standard spore assays for assessment of surface cleanliness. AB - A bacterial spore assay and a molecular DNA microarray method were compared for their ability to assess relative cleanliness in the context of bacterial abundance and diversity on spacecraft surfaces. Colony counts derived from the NASA standard spore assay were extremely low for spacecraft surfaces. However, the PhyloChip generation 3 (G3) DNA microarray resolved the genetic signatures of a highly diverse suite of microorganisms in the very same sample set. Samples completely devoid of cultivable spores were shown to harbor the DNA of more than 100 distinct microbial phylotypes. Furthermore, samples with higher numbers of cultivable spores did not necessarily give rise to a greater microbial diversity upon analysis with the DNA microarray. The findings of this study clearly demonstrated that there is not a statistically significant correlation between the cultivable spore counts obtained from a sample and the degree of bacterial diversity present. Based on these results, it can be stated that validated state of-the-art molecular techniques, such as DNA microarrays, can be utilized in parallel with classical culture-based methods to further describe the cleanliness of spacecraft surfaces. PMID- 21652746 TI - AIDS at 30: a chance to treat is now a chance to prevent. PMID- 21652747 TI - European E coli outbreak claims further victims. PMID- 21652748 TI - Chronic chilblains. PMID- 21652749 TI - Treatments for common and plantar warts. PMID- 21652750 TI - Cryotherapy versus salicylic acid for the treatment of plantar warts (verrucae): a randomised controlled trial. AB - OBJECTIVE: To compare the clinical effectiveness of cryotherapy versus salicylic acid for the treatment of plantar warts. DESIGN: A multicentre, open, two arm randomised controlled trial. SETTING: University podiatry school clinics, NHS podiatry clinics, and primary care in England, Scotland, and Ireland. PARTICIPANTS: 240 patients aged 12 years and over, with a plantar wart that in the opinion of the healthcare professional was suitable for treatment with both cryotherapy and salicylic acid. INTERVENTIONS: Cryotherapy with liquid nitrogen delivered by a healthcare professional, up to four treatments two to three weeks apart. Patient self treatment with 50% salicylic acid (Verrugon) daily up to a maximum of eight weeks. MAIN OUTCOME MEASURES: Complete clearance of all plantar warts at 12 weeks. Secondary outcomes were (a) complete clearance of all plantar warts at 12 weeks controlling for age, whether the wart had been treated previously, and type of wart, (b) patient self reported clearance of plantar warts at six months, (c) time to clearance of plantar wart, (d) number of plantar warts at 12 weeks, and (e) patient satisfaction with the treatment. RESULTS: There was no evidence of a difference between the salicylic acid and cryotherapy groups in the proportions of participants with complete clearance of all plantar warts at 12 weeks (17/119 (14%) v 15/110 (14%), difference 0.65% (95% CI -8.33 to 9.63), P=0.89). The results did not change when the analysis was repeated but with adjustment for age, whether the wart had been treated previously, and type of plantar wart or for patients' preferences at baseline. There was no evidence of a difference between the salicylic acid and cryotherapy groups in self reported clearance of plantar warts at six months (29/95 (31%) v 33/98 (34%), difference -3.15% (-16.31 to 10.02), P=0.64) or in time to clearance (hazard ratio 0.80 (95% CI 0.51 to 1.25), P=0.33). There was also no evidence of a difference in the number of plantar warts at 12 weeks (incident rate ratio 1.08 (0.81 to 1.43), P=0.62). CONCLUSIONS: Salicylic acid and the cryotherapy were equally effective for clearance of plantar warts. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18994246, National Research Register N0484189151. PMID- 21652751 TI - Causes rather than effects. PMID- 21652752 TI - Bowel cancer screening. Beware next wave of propaganda. PMID- 21652753 TI - NICE's reply. PMID- 21652754 TI - Authors' response to editorial. PMID- 21652755 TI - Refer scalp lumps requiring excisional biopsy to a surgeon. PMID- 21652757 TI - Cost of single use instruments. PMID- 21652756 TI - Analysis of absolute incidence tells different story. PMID- 21652758 TI - Triad in neuropathy from metal on metal hips. PMID- 21652759 TI - A reanalysis too far? PMID- 21652760 TI - Wanted: an appropriate evaluation template. PMID- 21652761 TI - Evidence of harm is unconvincing. PMID- 21652763 TI - Acute neurology services must be provided by neurologists, report says. PMID- 21652762 TI - Claims do not hold water. PMID- 21652764 TI - Quality and antioxidant properties of fresh-cut apple wedges from 10 cultivars during modified atmosphere packaging storage. AB - Antioxidant activity and quality parameters of skin-on apple wedges from 10 cultivars were examined during chill storage and over two growing seasons. Storage of fresh-cut apple wedges had a significant impact on quality parameter indices such as browning index (p < 0.001) and texture firmness (p < 0.001). Headspace gas analysis indicated that the degree of browning negatively correlated to oxygen (-0.69) and positively (0.70) correlated to carbon dioxide levels. Antioxidant capacity as assessed by three in vitro methods (DPPH, FRAP and ORAC) decreased significantly for 9 of the 10 cultivars after 5 days of storage at 3 +/- 1 degrees C (p < 0.001). These indices increased in case of Shampion apples over the same storage period for all three assays. With regard to antioxidant capacity and quality parameters, the cultivars Gloster, Alwa, Idared and Jonica were the best performing overall and could therefore be recommended as a core ingredient in fresh-cut fruit products. PMID- 21652765 TI - Quality evaluation of functional chicken nuggets incorporated with ground carrot and mashed sweet potato. AB - This study was envisaged to evaluate the effect of ground raw carrot (0%, 5%, 10% and 15%) and mashed sweet potato (0%, 5%, 10% and 15%) as functional ingredients on the quality of chicken meat nuggets. The products were evaluated for physicochemical quality, proximate composition, nutritive value, sensory quality as well as color and texture profile analyses. Additions of either raw carrot or mashed sweet potato represent an improvement in the nutritional value and have some beneficial effects due to the presence of dietary fibers and beta-carotene. They were also found to be effective in sustaining the desired cooking yield and emulsion stability. Treated samples showed lower (p > 0.05) protein, fat and ash contents but higher (p < 0.05) moisture content than control. There were differences among the nugget samples with respect to sensory qualities, and control samples as well as samples with 10% added carrot/sweet potato had higher overall acceptability scores. Hunter color values (L*, a* and b* values) were higher (p < 0.05) for both the formulated products, while their textural parameters were nearly unchanged. In conclusion, carrot and sweet potato at 10% added level have greater potential as good source of dietary fibers and beta carotene and may find their way in meat industry. PMID- 21652766 TI - Bioactive compounds and prebiotic activity in Thailand-grown red and white guava fruit (Psidium guajava L.). AB - This research involves the comparison of bioactive compounds, volatile compounds and prebiotic activity of white guava (Psidium guajava L.) cv. Pansithong and red guava cv. Samsi. The antioxidant activity values determined by 2-diphenyl-1 picryhydrazyl (DPPH) free radical scavenging and ferric reducing antioxidant power (FRAP) assays were 10.28 ug fresh weight (fw)/ug DPPH and 78.56 ug Trolox equivalent (TE)/g fw for white guava and 7.82 ug/ug DPPH, fw and 111.06 uM TE/g fw for red guava. Ascorbic acid contents were 130 and 112mg/100g fw total phenolics contents 145.52 and 163.36 mg gallic acid equivalents (GAE)/100 g fw and total flavonoids contents 19.06 and 35.85 mg catechin equivalents (CE)/100 g fw, in white and red guava, respectively. Volatile compounds in guava were analyzed by the solid-phase microextraction (SPME)/gas chromatography (GC)/mass spectrometry (MS) method. The major constituents identified in white and red guavas were cinnamyl alcohol, ethyl benzoate, beta-caryophyllene, (E)-3-hexenyl acetate and alpha-bisabolene. Prebiotic activity scores for Lactobacillus acidophilus LA-5 and Bifidobacterium lactis BB-12 were 0.12 and 0.28 in white guava, respectively, and 0.13 and 0.29 in red guava, respectively. PMID- 21652767 TI - Antioxidant activity, color, carotenoids composition, minerals, vitamin C and sensory quality of organic and conventional mandarin juice, cv. Orogrande. AB - The effects of organic farming on antioxidant activity, CIE L*a*b* color, carotenoids composition, minerals contents, vitamin C and sensory quality of Orogrande mandarin juices were studied. Independent of the farming type, mandarin juices can be considered as good source of some important nutrients, such as potassium and antioxidant chemicals, for example, beta-cryptoxanthin. Organic farming of mandarin resulted in juices with higher antioxidant activity, total carotenoids concentrations, minerals (Ca, K and Fe) contents, vitamin C content, more appealing and intense orange color and better sensory quality. For instance, organic Orogrande juice contained significantly (p < 0.001) higher total carotenoids content (22.7 +/- 0.3 mg/L) than conventional juice (15.7 +/- 0.4 mg/L); a similar pattern was observed for the antioxidant activity, with values being 0.076+/-0.004 and 0.053 +/- 0.003 mM Trolox m/L in organic and conventional juices, respectively. A trained panel stated that organic Orogrande juices had higher intensities of orange color, fresh mandarin and floral aromas than conventional juices. PMID- 21652768 TI - Chromosome-substituted rat strains provide insights into the genetics of placentation. AB - The rat possesses a hemochorial form of placentation. Pronounced intrauterine trophoblast cell invasion and vascular remodeling characterize this type of placentation. Strain-specific patterns of placentation are evident in the rat. Some rat strains exhibit deep intrauterine trophoblast invasion and an expanded junctional zone [Holtzman Sprague-Dawley (HSD), Dahl salt sensitive (DSS)], whereas placentation sites of other rat strains are characterized by shallow invasion and a restricted junctional zone [Brown Norway (BN)]. In this report, we identified a quantitative trait that was used to distinguish strain-specific features of rat placentation. Junctional zone prolactin family 5, subfamily a, member 1 (Prl5a1) transcript levels were significantly greater in BN rats than in HSD or DSS rats. Prl5a1 transcript levels were used as a quantitative trait to screen placentation sites from chromosome-substituted rat strains (BN chromosomes introgressed into the DSS inbred strain; DSS-BN panel). Litter size, placental weights, and fetal weights were not significantly different among the chromosome substituted strains. Regulation of the junctional zone Prl5a1 transcript-level quantitative trait was multifactoral. Chromosome-substituted strains possessing BN chromosomes 14 or 17 introgressed into the DSS inbred rat strain displayed Prl5a1 transcript levels that were significantly different from the DSS pattern and more closely resembled the BN pattern. The in situ placental distribution of Prl5a1 mRNA and the structure of the junctional zone of DSS-BN17 rats mimicked that observed for the BN rat. Prl5a1 gene expression was also assessed in BN vs. HSD trophoblast stem cells and following reciprocal BN and HSD embryo transfer. Strain differences intrinsic to trophoblast and maternal environment were identified. In summary, we have identified chromosomes 14 and 17 as possessing regulatory information controlling a quantitative trait associated with rat placentation. PMID- 21652769 TI - Comparative gene responses to collected ambient particles in vitro: endothelial responses. AB - Epidemiologic studies associate exposure to ambient particulate matter (APM) with increased cardiovascular mortality. Since both pulmonary inflammation and systemic circulation of ultrafine particles are hypothesized as initiating cardiovascular effects, we examined responses of potential target cells in vitro. Human aortic endothelial cells (HAEC) were exposed to 10 MUg/ml fine and ultrafine APM collected in an urban setting in summer 2006 or winter 2007 in the San Joaquin Valley, California. RNA isolated after 3 h was analyzed with high density oligonucleotide arrays. Summer APM treatment affected genes involved in xenobiotic and oxidoreductase activity, transcription factors, and inflammatory responses in HAEC, while winter APM had a robust xenobiotic but lesser inflammatory response. Real-time polymerase chain reaction analysis confirmed that particulate matter (PM)-treated HAEC increased mRNA levels of xenobiotic response enzymes CYP1A1, ALDH1A3, and TIPARP and cellular stress response transcription factor ATF3. Inflammatory response genes included E-selectin, PTGS2, CXCL-2 (MIP-2alpha), and CCL-2 (MCP-1). Multiplex protein assays showed secretion of IL-6 and MCP-1 by HAEC. Since induction of CYP1A1 is mediated through the ligand-activated aryl hydrocarbon receptor (AhR), we demonstrated APM induced AhR nuclear translocation by immunofluorescence and Western blotting and activation of the AhR response element using a luciferase reporter construct. Inhibitor studies suggest differential influences of polycyclic aromatic hydrocarbon signaling, ROS-mediated responses and endotoxin alter stress and proinflammatory endothelial cell responses. Our findings demonstrate gene responses correlated with current concepts that systemic inflammation drives cardiovascular effects of particulate air pollution. We also demonstrate a unique pattern of gene responses related to xenobiotic metabolism in PM-exposed HAEC. PMID- 21652770 TI - Y-box binding protein-1 promotes castration-resistant prostate cancer growth via androgen receptor expression. AB - The androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer (PCa). In several studies, AR was overexpressed in castration-resistant PCa (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. Y-box binding protein-1 (YB-1) is a pleiotropic transcription factor that is upregulated in CPRC. We aimed to elucidate the role of YB-1 in castration resistance of PCa and identify therapeutic potential of targeting YB-1. Using immunohistochemistry, we found that nuclear YB-1 expression significantly correlated with the Gleason score and AR expression in PCa tissues. In PCa cells, YB-1 regulated AR expression at the transcriptional level. Furthermore, YB-1 expression and nuclear localization were upregulated in CRPC cells. Overexpression of AR, as well as YB-1, conferred castration-resistant growth in LNCaP and 22Rv1 cells. Conversely, knocking down YB-1 resulted in suppressed cell growth and induced apoptosis, which was more efficient than knocking down AR in LNCaP cells. In other types of PCa cells, such as CRPC cells, knocking down YB-1 resulted in a significant reduction of cell growth. In conclusion, these findings suggested that YB-1 induces castration resistance in androgen-dependent PCa cells via AR expression. Thus, YB-1 may be a promising therapeutic target for PCa, as well as CRPC. PMID- 21652771 TI - Cue relevance effects in conjunctive visual search: cueing for location, color, and orientation. AB - Performance in visual search tasks where the target differs from distractors by a conjunction of features can improve when a precue signals observers to limit their search by attending to a subset of elements. The current experiments were designed to study the temporal characteristics of precueing the location or feature (color or orientation) of targets in color-orientation conjunctive searches. Color (sensory or symbolic), location, or orientation precues preceded the search stimulus with cue-to-stimulus onset asynchrony (SOA) in the range of 50-750 ms. The stimuli consisted of elements formed by combining horizontal/vertical and red/green features. Observers responded to the presence/absence of an odd element in an "odd-man-out" paradigm. Reaction time and accuracy were used as measures of performance. Color and location precues improved search performance. The magnitude of improvement did not vary as the SOA changed. The color and location cues exhibited their effects in guiding visual search even at 50 ms after cue onset. However, orientation precue did not facilitate nor inhibit the search processing. These results indicate that in conjunctive search it takes at most 50 ms after cue onset for the visual system to exert the guidance effects using color and location precueing. We speculate that color may be a stronger feature than orientation for segmenting the search elements, thus facilitating visual search. PMID- 21652772 TI - Spatiotemporal averaging of perceived brightness along an apparent motion trajectory. AB - Objects are critical functional units for many aspects of visual perception and recognition. Many psychophysical experiments support the concept of an "object file" consisting of characteristics attributed to a single object on the basis of successive views of it, but there has been little evidence that object identity influences apparent brightness and color. In this study, we investigated whether the perceptual identification of successive flashed stimuli as views of a single moving object could affect brightness perception. Our target stimulus was composed of eight wedge-shaped sectors. The sectors were presented successively at different inter-flash intervals along an annular trajectory. At inter-flash intervals of around 100 ms, the impression was of a single moving object undergoing long-range apparent motion. By modulating the luminance between successive views, we measured the perception of luminance modulation along the trajectory of this long-range apparent motion. At the inter-flash intervals where the motion perception was strongest, the luminance difference was perceptually underestimated, and forced-choice luminance discrimination thresholds were elevated. Moreover, under such conditions, it became difficult for the observer to correctly associate or "bind" spatial positions and wedge luminances. These results indicate that the different luminances of wedges that were perceived as a single object were averaged along its apparent motion trajectory. The large spatial step size of our stimulus makes it unlikely that the results could be explained by averaging in a low-level mechanism that has a compact spatiotemporal receptive field (such as V1 and V2 neurons); higher level global motion or object mechanisms must be invoked to account for the averaging effect. The luminance averaging and the ambiguity of position-luminance "binding" suggest that the visual system may evade some of the costs of rapidly computing apparent brightness by adopting the assumption that the characteristics of an object are invariant over successive views. PMID- 21652773 TI - Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer. AB - Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotype, establishing that diet and genetic factors impact risk by distinct combinatorial mechanisms. In a mouse model of dietary-induced sporadic small and large intestinal cancer in WT mice in which tumor etiology, lag, incidence, and frequency reflect >90% of intestinal cancer in Western societies, dietary-induced risk altered gene expression profiles predominantly in villus cells of the histologically normal mucosa, in contrast to targeting of crypt cells by inheritance of an Apc(1638N) allele or homozygous inactivation of p21(Waf1/cip1), and profiles induced by each risk factor were distinct at the gene or functional group level. The dietary-induced changes in villus cells encompassed ectopic expression of Paneth cell markers (a lineage normally confined to the bottom of small intestinal crypts), elevated expression of the Wnt receptor Fzd5 and of EphB2 (genes necessary for Paneth cell differentiation and localization to the crypt bottom), and increased Wnt signaling in villus cells. Ectopic elevation of these markers was also present in the colon crypts, which are also sites of sporadic tumors in the nutritional model. Elevating dietary vitamin D(3) and calcium, which prevents tumor development, abrogated these changes in the villus and colon cells. Thus, common intestinal cancer driven by diet involves mechanisms of tumor development distinct from those mechanisms that cause tumors induced by the rare inheritance of a mutant adenomatous polyposis coli (Apc) allele. This is fundamental for understanding how common sporadic tumors arise and in evaluating relative risk in the population. PMID- 21652774 TI - Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. AB - Spinal muscular atrophy (SMA), caused by the deletion of the SMN1 gene, is the leading genetic cause of infant mortality. SMN protein is present at high levels in both axons and growth cones, and loss of its function disrupts axonal extension and pathfinding. SMN is known to associate with the RNA-binding protein hnRNP-R, and together they are responsible for the transport and/or local translation of beta-actin mRNA in the growth cones of motor neurons. However, the full complement of SMN-interacting proteins in neurons remains unknown. Here we used mass spectrometry to identify HuD as a novel neuronal SMN-interacting partner. HuD is a neuron-specific RNA-binding protein that interacts with mRNAs, including candidate plasticity-related gene 15 (cpg15). We show that SMN and HuD form a complex in spinal motor axons, and that both interact with cpg15 mRNA in neurons. CPG15 is highly expressed in the developing ventral spinal cord and can promote motor axon branching and neuromuscular synapse formation, suggesting a crucial role in the development of motor axons and neuromuscular junctions. Cpg15 mRNA previously has been shown to localize into axonal processes. Here we show that SMN deficiency reduces cpg15 mRNA levels in neurons, and, more importantly, cpg15 overexpression partially rescues the SMN-deficiency phenotype in zebrafish. Our results provide insight into the function of SMN protein in axons and also identify potential targets for the study of mechanisms that lead to the SMA pathology and related neuromuscular diseases. PMID- 21652775 TI - MU-Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve. AB - Voltage-gated sodium channels (VGSCs) are important for action potentials. There are seven major isoforms of the pore-forming and gate-bearing alpha-subunit (Na(V)1) of VGSCs in mammalian neurons, and a given neuron can express more than one isoform. Five of the neuronal isoforms, Na(V)1.1, 1.2, 1.3, 1.6, and 1.7, are exquisitely sensitive to tetrodotoxin (TTX), and a functional differentiation of these presents a serious challenge. Here, we examined a panel of 11 MU conopeptides for their ability to block rodent Na(V)1.1 through 1.8 expressed in Xenopus oocytes. Although none blocked Na(V)1.8, a TTX-resistant isoform, the resulting "activity matrix" revealed that the panel could readily discriminate between the members of all pair-wise combinations of the tested isoforms. To examine the identities of endogenous VGSCs, a subset of the panel was tested on A and C-compound action potentials recorded from isolated preparations of rat sciatic nerve. The results show that the major subtypes in the corresponding A- and C-fibers were Na(V)1.6 and 1.7, respectively. Ruled out as major players in both fiber types were Na(V)1.1, 1.2, and 1.3. These results are consistent with immunohistochemical findings of others. To our awareness this is the first report describing a qualitative pharmacological survey of TTX-sensitive Na(V)1 isoforms responsible for propagating action potentials in peripheral nerve. The panel of MU-conopeptides should be useful in identifying the functional contributions of Na(V)1 isoforms in other preparations. PMID- 21652777 TI - Self-regulation of priming effects on behavior. AB - In three experiments, we tested whether people can protect their ongoing goal pursuits from antagonistic priming effects by using if-then plans (i.e., implementation intentions). In Experiment 1, concept priming did not influence lexical decision time for a critical stimulus when participants had formed if then plans to make fast responses to that stimulus. In Experiment 2, participants who were primed with a prosocial goal allowed a confederate who asked for help to interrupt their work on a focal task for a longer time if they had merely formed goal intentions to perform well than if they had also formed implementation intentions for concentrating on the task. In Experiment 3, priming the goal of being fast increased driving speed and errors for participants who had formed mere goal intentions to drive only as fast as safety allowed or who had formed no goal intentions, whereas the driving of participants who had formed such goal intentions as well as implementation intentions showed no such priming effects. Our findings indicate that implementation intentions are an effective self regulatory tool for shielding actions from disruptive concept- or goal-priming effects. PMID- 21652776 TI - Primary care colorectal cancer screening recommendation patterns: associated factors and screening outcomes. AB - BACKGROUND: The relationship of a primary care provider's (PCP's) colorectal cancer (CRC) screening strategies to completion of screening is poorly understood. OBJECTIVE: To describe PCP test recommendation patterns and associated factors and their relationship to patient test completion. DESIGN: This cross-sectional study used a PCP survey, in-depth PCP interviews, and electronic medical records. SETTING: Kaiser Permanente Northwest health maintenance organization. PARTICIPANTS: Participants included 132 PCPs and 49,259 eligible patients aged 51 to 75. MEASUREMENTS: The authors grouped PCPs by patterns of CRC screening recommendations based on reported frequency of recommending fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), and colonoscopy. They then compared PCP demographics, reported CRC screening test influences, concerns, decision-making and counseling processes, and actual rates of patient CRC screening completion by PCP group. RESULTS: The authors identified 4 CRC screening recommendation groups: a "balanced" group (n = 54; 40.9%) that recommended the tests nearly equally, an FOBT group (n = 31; 23.5%) that largely recommended FOBT, an FOBT + FS group (n = 25; 18.9%), and a colonoscopy + FOBT group (n = 22; 16.7%) that recommended these tests nearly equally. Internal medicine (v. family medicine) PCPs were more common in groups more frequently recommending endoscopy. The FOBT and FOBT + FS groups were most influenced by clinical guidelines. Groups recommending more endoscopy were most concerned that FOBT generates a relatively high number of false positives and FOBT can miss cancers. The FOBT and FOBT + FS groups were more likely to recommend a specific screening strategy compared to the colonoscopy + FOBT and balanced groups, which were more likely to let the patient decide. CRC screening rates were 63.9% balanced, 62.9% FOBT, 61.7% FOBT + FS, and 62.2% colonoscopy + FOBT; rates did not differ significantly by group. LIMITATIONS: Small numbers within PCP groups. CONCLUSIONS: Specialty, the influence of guidelines, test concerns, and the "jointness" of the test selection decision distinguished CRC screening recommendation patterns. All patterns were associated with similar overall screening rates. PMID- 21652778 TI - Cryptococcus neoformans requires a functional glycolytic pathway for disease but not persistence in the host. AB - Cryptococcus neoformans is an important fungal pathogen of immunocompromised individuals, with a close relative, Cryptococcus gattii, emerging as a serious threat for the immunocompetent. During initial infection, C. neoformans colonizes the airspaces of the lungs, resulting in pneumonia, and subsequently migrates to the central nervous system (CNS). We sought to understand fungal carbon utilization during colonization of these fundamentally different niches within the host, in particular the roles of gluconeogenesis and glycolysis. We created mutants at key points in the gluconeogenesis/glycolysis metabolic pathways that are restricted for growth on lactate and glucose, respectively. A phosphoenolpyruvate carboxykinase mutant (the pck1Delta mutant), blocked for entry of 2- and 3-carbon substrates into gluconeogenesis and attenuated for virulence in a murine inhalation model, showed wild-type (WT) persistence in a rabbit cerebrospinal fluid (CSF) model of cryptococcosis. Conversely, both the pyruvate kinase (pyk1Delta) and the hexose kinase I and II (hxk1Delta/hxk2Delta) mutants, which show impaired glucose utilization, exhibited severely attenuated virulence in the murine inhalation model of cryptococcosis and decreased persistence in the CNS in both the rabbit CSF and the murine inhalation models while displaying adequate persistence in the lungs of mice. These data suggest that glucose utilization is critical for virulence of C. neoformans and persistence of the yeast in the CNS. PMID- 21652779 TI - Chromosomal rearrangements in Salmonella enterica serovar Typhi strains isolated from asymptomatic human carriers. AB - Host-specific serovars of Salmonella enterica often have large-scale chromosomal rearrangements that occur by recombination between rrn operons. Two hypotheses have been proposed to explain these rearrangements: (i) replichore imbalance from horizontal gene transfer drives the rearrangements to restore balance, or (ii) the rearrangements are a consequence of the host-specific lifestyle. Although recent evidence has refuted the replichore balance hypothesis, there has been no direct evidence for the lifestyle hypothesis. To test this hypothesis, we determined the rrn arrangement type for 20 Salmonella enterica serovar Typhi strains obtained from human carriers at periodic intervals over multiple years. These strains were also phage typed and analyzed for rearrangements that occurred over long-term storage versus routine culturing. Strains isolated from the same carrier at different time points often exhibited different arrangement types. Furthermore, colonies isolated directly from the Dorset egg slants used to store the strains also had different arrangement types. In contrast, colonies that were repeatedly cultured always had the same arrangement type. Estimated replichore balance of isolated strains did not improve over time, and some of the rearrangements resulted in decreased replicore balance. Our results support the hypothesis that the restricted lifestyle of host-specific Salmonella is responsible for the frequent chromosomal rearrangements in these serovars. PMID- 21652780 TI - The "10 keys" to healthy aging: 24-month follow-up results from an innovative community-based prevention program. AB - The purpose of this report was to evaluate a prevention program to reduce risk factors for common diseases among older individuals in a lower income community. This randomized community-based study enrolled older adults into a Brief Education and Counseling Intervention or a Brief Education and Counseling Intervention plus a physical activity and (for those with hypertension) a dietary sodium intervention. Outcomes were collected on 389 adults with a mean age of 73.9 years over 24 months. Adherence to the "10 Keys" improved significantly in the proportion meeting goals for low-density lipoprotein cholesterol (+14%), bone mineral density testing (+11%), pneumonia vaccination (+11%), colonoscopy (+14%), and adherence to antihypertensive medication (+9%). This program resulted in significant reductions in key risk factors, increases in immunizations, and adherence to established prevention guidelines over 2 years. Further research is needed to refine the use of community health counselors for translating prevention knowledge into community settings. A major limitation of these studies is the low participation percentage. PMID- 21652781 TI - 2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone inhibits skin cancer M21 cell proliferation through aberrant expression of microtubules and the cell cycle. AB - Microtubules are a proven target for anticancer drug development because they are critical for mitotic spindle formation and the separation of chromosomes at mitosis. 2-(Naphthalene-1-yl)-6-pyrrolidinyl-4-quinazolinone (HL66) induced cell death with the large cells and multiple micronuclei in M21 skin cancer cells. We demonstrated that HL66-induced cell death is caspase-independent and accompanied by the failure of cell cycle progression. Therefore, HL66-induced cell death may be a mitotic catastrophe. HL66 inhibits the dephosphorylation on Thr14 or Tyr15 of cyclin-dependent kinase (Cdk) 1 and the formation of Cdk1/cyclin B1 complex, which might be associated with cell cycle arrest at the S and G(2)/M phases. HL66 is an antimicrotubule agent by molecular modeling on the basis of ligand binding to tubulin molecule. Furthermore, we also demonstrated that HL66, like vinblastine, is a tubulin-destabilizing agent via microtubule disruption in M21 cells. These results describe a novel pharmacological property of HL66 as a microtubule inhibitor, which may make it an attractive new agent for the treatment of skin cancer. PMID- 21652782 TI - Neuroprotective efficacy from a lipophilic redox-modulating Mn(III) N Hexylpyridylporphyrin, MnTnHex-2-PyP: rodent models of ischemic stroke and subarachnoid hemorrhage. AB - Intracerebroventricular treatment with redox-regulating Mn(III) N hexylpyridylporphyrin (MnPorphyrin) is remarkably efficacious in experimental central nervous system (CNS) injury. Clinical development has been arrested because of poor blood-brain barrier penetration. Mn(III) meso-tetrakis (N hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP) was synthesized to include four six-carbon (hexyl) side chains on the core MnPorphyrin structure. This has been shown to increase in vitro lipophilicity 13,500-fold relative to the hydrophilic ethyl analog Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). In normal mice, we found brain MnTnHex-2-PyP accumulation to be ~9-fold greater than MnTE-2-PyP 24 h after a single intraperitoneal dose. We then evaluated MnTnHex-2-PyP efficacy in outcome-oriented models of focal cerebral ischemia and subarachnoid hemorrhage. For focal ischemia, rats underwent 90-min middle cerebral artery occlusion. Parenteral MnTnHex-2-PyP treatment began 5 min or 6 h after reperfusion onset and continued for 7 days. Neurologic function was improved with both early (P = 0.002) and delayed (P = 0.002) treatment onset. Total infarct size was decreased with both early (P = 0.03) and delayed (P = 0.01) treatment. MnTnHex-2-PyP attenuated nuclear factor kappaB nuclear DNA binding activity and suppressed tumor necrosis factor-alpha and interleukin-6 expression. For subarachnoid hemorrhage, mice underwent perforation of the anterior cerebral artery and were treated with intraperitoneal MnTnHex-2-PyP or vehicle for 3 days. Neurologic function was improved (P = 0.02), and vasoconstriction of the anterior cerebral (P = 0.0005), middle cerebral (P = 0.003), and internal carotid (P = 0.015) arteries was decreased by MnTnHex-2-PyP. Side-chain elongation preserved MnPorphyrin redox activity, but improved CNS bioavailability sufficient to cause improved outcome from acute CNS injury, despite delay in parenteral treatment onset of up to 6 h. This advance now allows consideration of MnPorphyrins for treatment of cerebrovascular disease. PMID- 21652783 TI - Resveratrol ameliorates muscular pathology in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy. AB - Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. We previously showed that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and activator of the NAD(+) dependent protein deacetylase SIRT1, delays the progression of heart failure and prolongs the lifespan of delta-sarcoglycan-deficient hamsters. Because a defect of dystroglycan complex causes muscular dystrophies, and delta-sarcoglycan is a component of this complex, we hypothesized that resveratrol might be a new therapeutic tool for muscular dystrophies. Here, we examined resveratrol's effect in mdx mice, an animal model of Duchenne muscular dystrophy. mdx mice that received resveratrol in the diet for 32 weeks (4 g/kg diet) showed significantly less muscle mass loss and nonmuscle interstitial tissue in the biceps femoris compared with mdx mice fed a control diet. In the muscles of these mice, resveratrol significantly decreased oxidative damage shown by the immunostaining of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine and suppressed the up-regulation of NADPH oxidase subunits Nox4, Duox1, and p47(phox). Resveratrol also reduced the number of alpha-smooth muscle actin (alpha-SMA)(+) myofibroblast cells and endomysial fibrosis in the biceps femoris, although the infiltration of CD45(+) inflammatory cells and increase in transforming growth factor-beta1 (TGF-beta1) were still observed. In C2C12 myoblast cells, resveratrol pretreatment suppressed the TGF-beta1-induced increase in reactive oxygen species, fibronectin production, and expression of alpha-SMA, and SIRT1 knockdown blocked these inhibitory effects. SIRT1 small interfering RNA also increased the expression of Nox4, p47(phox), and alpha-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies. PMID- 21652784 TI - Akathisia induced by gabapentin withdrawal. AB - OBJECTIVE: To report a case of akathisia in a patient with type 2 diabetes after abrupt discontinuation of gabapentin. CASE SUMMARY: A 76-year-old female with type 2 diabetes was admitted for change in mental status, agitation, and restless limb movements. She had been taking gabapentin 3600 mg daily for approximately 1 month for diabetic neuropathy. Her other home medications were glyburide 10 mg twice daily, oxycodone/acetaminophen 5 mg/325 mg every 6 hours as needed for leg pain, and zolpidem 5 mg at bedtime. She had taken none of these drugs for 4 days prior to admission because she was unable to have the prescriptions refilled. Subsequently, the patient exhibited repeated arm and leg motions in response to an inner restlessness. Upon admission to the emergency department, she was agitated and restless; all vital signs and results of laboratory studies were within normal limits. Gabapentin was restarted at the original dosage and the symptoms resolved within 8 hours. Because the patient developed lethargy, the gabapentin dosage was reduced and titrated to the original level over 2 days. After 3 days, the patient was well oriented and experienced no further symptoms. She was discharged on the original dosage of gabapentin. DISCUSSION: To our knowledge, this is the first reported cases of akathisia induced by gabapentin withdrawal. Available case reports suggest that gabapentin withdrawal can occur at doses ranging from 400-8000 mg/day. Patients experienced symptoms similar to those that develop with benzodiazepine withdrawal and were taking gabapentin for as little as 3 weeks to as long as 5 years. This is the first case report to describe akathisia induced by gabapentin withdrawal. The Naranjo probability scale revealed a probable relationship between akathisia and gabapentin withdrawal. CONCLUSIONS: If gabapentin discontinuation is desired, it is prudent to gradually taper the dose to avoid withdrawal symptoms, which may occur after as little as 1 month of treatment. Should the patient experience withdrawal symptoms, the optimal treatment is to restart gabapentin. PMID- 21652785 TI - Nebulized antibiotics for the treatment of refractory bacterial chronic rhinosinusitis. AB - OBJECTIVE: To review the safety and efficacy of nebulized antibiotics for refractory bacterial chronic rhinosinusitis (CRS) in adults. DATA SOURCES: PubMed (up to February 2011) and The Cochrane Library (up to February 2011) were searched using the terms nebulizer, nebulized, antibiotics, and chronic sinusitis. STUDY SELECTION AND DATA EXTRACTION: All English-language articles reporting clinical trials in adults were evaluated; 4 relevant studies were identified. DATA SYNTHESIS: Conventional therapy for CRS, including pharmacologic treatments (eg, oral antibiotics, corticosteroids, antihistamines) and surgery, are not effective for all patients, which has led to experimentation with nebulized antibiotics. The 4 trials analyzing the effectiveness of nebulized antibiotics for refractory CRS in adults identified in our literature search were diverse in their methods, and different antibiotics were used in each trial. Furthermore, all of the trials had small sample sizes, with the largest comprising 42 patients. Two of the studies compared nebulized antibiotics to nebulized saline, and even though rhinosinusitis symptoms improved, nebulized antibiotics were found to offer no additional benefit over saline. The 2 other trials had no control groups and found that nebulized antibiotics led to an improvement in symptoms. In 1 trial, antibiotics were selected based on the results of sinus cultures, which led to infection resolution in 38 of 50 (76%) treatment courses. Nebulized antibiotics were well tolerated, with only minor adverse effects noted. CONCLUSIONS: Based on current studies, use of nebulized antibiotics for refractory CRS cannot be recommended at this time. Although supportive evidence is limited, nebulized antibiotics appear to improve rhinosinusitis symptoms in some patients with minimal adverse effects. With further studies, culture-directed nebulized antibiotic therapy may be a treatment option in patients with CRS refractory to conventional treatments. PMID- 21652786 TI - Vancomycin dosing: assessment of time to therapeutic concentration and predictive accuracy of pharmacokinetic modeling software. AB - BACKGROUND: Therapeutic drug monitoring is usually required for safe and effective administration of vancomycin. However, dosing recommendations from published guidelines are not suitable in achieving therapeutic vancomycin concentrations in a timely manner in patients with normal renal function. OBJECTIVE: To audit vancomycin dosing and concentrations at our institution and evaluate the predictive accuracy of a pharmacokinetic simulation program, with a view to implementing a pharmacy-based pharmacokinetic service for vancomycin monitoring. METHODS: Patients receiving vancomycin were identified prospectively through the therapeutic drug monitoring archives. Patient information was obtained from medication charts and medical records that were located on wards. Data were entered into the MM-USC*Pack program (Jelliffe R, University of Southern California, 2008, version 12.10). This software was used to predict initial and subsequent concentrations of vancomycin based on patient parameters. The predictive accuracy of this software was evaluated by comparing the predicted concentrations to the observed concentrations. RESULTS: During a 6-week period, 204 concentrations were measured in 77 patients. The most common dosing regimen was 1 g every 12 hours. Overall, initial trough concentrations were subtherapeutic (<10 mg/L) in 58% of patients and trough concentrations did not become therapeutic at any stage throughout therapy in 25% of patients. The pharmacokinetic modeling software demonstrated little systematic bias (-3.1%), but the precision (median prediction error) was 23% (interquartile range, 11 45%). Predictions were poorer in obese patients (body mass index >35 kg/m(2)) and in patients with unstable renal function. CONCLUSIONS: A delay in attaining target trough concentrations was observed in a significant proportion of patients. Pharmacokinetic modeling software is a potential tool to improve the timeliness of achieving adequate dosing by allowing concentrations to be determined prior to steady-state. The program was able to predict vancomycin concentrations across a heterogeneous patient population with little systematic bias, but only moderate precision. PMID- 21652787 TI - Persistent hiccups associated with epidural ropivacaine in a newborn. AB - OBJECTIVE: To report a case of persistent hiccups associated with epidural ropivacaine in a newborn infant. CASE SUMMARY: A term female infant (3.05 kg) received epidural ropivacaine for pain control during and after an operative procedure to correct a tracheoesophageal fistula. Three intermittent doses of ropivacaine were administered during the operative period (total dose 2.29 mg/kg) followed by a continuous epidural (caudal) infusion (0.1% ropivacaine; initial dose 0.23 mg/kg/h plus fentanyl 0.46 MUg/kg/h). The infant was extubated in the recovery area and transferred to the intensive care unit. Within hours of transfer, she developed persistent hiccups. The epidural infusion was titrated for pain control, up to 0.32 mg/kg/h (ropivacaine). The hiccup frequency increased to every 10-30 seconds, with the patient appearing hypotonic with lip trembling and intermittent tongue fasciculation. An electroencephalogram did not show any epileptiform activity or focal features consistent with seizure activity. The epidural infusion was reduced to 0.26 mg/kg/h (ropivacaine), with dramatic improvement in hiccups and tone. The infusion was discontinued and complete resolution of hiccups was observed. DISCUSSION: Ropivacaine is commonly used for infiltration anesthesia and peripheral and epidural block anesthesia. Use of the Naranjo probability scale determined that our patient's hiccups were probably caused by ropivacaine. To our knowledge, this is the first report of persistent hiccups associated with epidural ropivacaine. CONCLUSIONS: Clinicians should consider the potential of neurotoxicity, manifested as persistent hiccups, when epidural ropivacaine is administered to young infants. PMID- 21652788 TI - Colchicine for the primary prevention of the postpericardiotomy syndrome. AB - OBJECTIVE: To review literature regarding the safety and efficacy of colchicine for the primary prevention of the postpericardiotomy syndrome (PPS). DATA SOURCES: Searches of MEDLINE (1966-April 2011) and Cochrane Database (1993-April 2011) were conducted. Key search terms included postpericardiotomy syndrome, postcardiac injury syndrome, and colchicine. Limits were set for articles written in English with human subjects. Additional data were identified through bibliographic reviews. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. All primary data were eligible for inclusion if they evaluated the safety and/or efficacy of colchicine for the primary prevention of PPS. Two prospective trials were identified and included for review. DATA SYNTHESIS: PPS occurs in 10-40% of patients who undergo cardiac surgery and is associated with significant morbidity. Effective medications used for the treatment of PPS include nonsteroidal antiinflammatory drugs or corticosteroids. Unfortunately, effective drug therapy for the primary prevention of PPS does not exist. Colchicine, an antiinflammatory agent with possible immunopathic antifibroblast properties, has shown benefit in the treatment and secondary prevention of pericarditis; thus, its use for primary prevention of PPS has been investigated. Limited data evaluating colchicine for the primary prevention of PPS have been published. However, results of the largest, well-designed trial showed positive efficacy outcomes for colchicine reducing the incidence of PPS with minimal adverse effects. CONCLUSIONS: At this time, there are not sufficient data to recommend colchicine as routine therapy for the primary prevention of PPS in patients undergoing cardiac surgery. Large clinical trials need to be conducted. PMID- 21652789 TI - Effects of carbamazepine/oxycodone coadministration in the treatment of trigeminal neuralgia. AB - OBJECTIVE: To report on a patient with trigeminal neuralgia who responded positively to combined carbamazepine/oxycodone treatment. CASE SUMMARY: A 48-year old woman with a 4-month history of left facial pain consisting of episodes lasting less than 5 minutes was brought to our institution for clinical evaluation. Clinical, laboratory, and neuroradiologic findings led to a diagnosis of idiopathic trigeminal neuralgia. Carbamazepine treatment was started at 200 mg every 12 hours and increased at discharge to 300 mg every 8 hours. Two weeks later the patient was readmitted with trigeminal neuralgia symptoms that had persisted since the previous admission, although they had decreased in intensity. Carbamazepine was reduced to 200 mg every 8 hours and oxycodone 5 mg every 12 hours was added to the treatment regimen, with a complete resolution of pain within 7 days. DISCUSSION: Pathophysiological mechanisms involved in both the genesis and the maintenance of trigeminal neuralgia have not yet been defined. Several hypotheses could explain this disorder, ranging from peripheral neural ectopic pacemaker to central disinhibition. Both the interruption of the sodium channel and the modulation of both kappa- and MU-opioid receptors contributed to antinociceptive effects in trigeminal neuralgia. CONCLUSIONS: Treatment with a combination of carbamazepine, a sodium channel blocker, and oxycodone, a mixed kappa- and MU-opioid receptor agonist, may be useful in alleviating symptoms of trigeminal neuralgia. PMID- 21652790 TI - Pregabalin-induced hepatotoxicity. AB - OBJECTIVE: To report a case of acute elevation of hepatic enzyme levels as a probable adverse reaction associated with pregabalin. CASE SUMMARY: A 59-year-old man with a history of mantle cell lymphoma developed neuropathic pain and was treated with pregabalin 25 mg daily. Fourteen days after beginning pregabalin therapy, he developed left ankle edema and elevation of liver enzyme levels. Peak values were aspartate transaminase 907 U/L, alanine transaminase 1582 U/L, and gamma-glutamyltransferase 510 U/L. Pregabalin was discontinued and hepatic enzyme levels returned gradually (over 4 months) to baseline levels. DISCUSSION: Many medications are commonly associated with liver injury; few cases of pregabalin associated hepatotoxicity have been documented. A MEDLINE search (1966-November 2010) revealed 2 reports of acute liver injury with the initiation of pregabalin. In our patient, with hemosiderosis after hematopoietic cell transplantation, pregabalin worsened the underlying liver injury. The low pregabalin dosage and the short time to elevation of liver enzyme levels suggest an idiosyncratic reaction. According to the Naranjo probability scale and the Council for International Organizations of Medical Sciences probability scale, this reaction was probably due to pregabalin. CONCLUSIONS: Prescribers should be alert to the possibility of idiosyncratic hepatotoxicity associated with pregabalin use. PMID- 21653190 TI - WEREWOLF, a regulator of root hair pattern formation, controls flowering time through the regulation of FT mRNA stability. AB - A key floral activator, FT, integrates stimuli from long-day, vernalization, and autonomous pathways and triggers flowering by directly regulating floral meristem identity genes in Arabidopsis (Arabidopsis thaliana). Since a small amount of FT transcript is sufficient for flowering, the FT level is strictly regulated by diverse genes. In this study, we show that WEREWOLF (WER), a MYB transcription factor regulating root hair pattern, is another regulator of FT. The mutant wer flowers late in long days but normal in short days and shows a weak sensitivity to vernalization, which indicates that WER controls flowering time through the photoperiod pathway. The expression and double mutant analyses showed that WER modulates FT transcript level independent of CONSTANS and FLOWERING LOCUS C. The histological analysis of WER shows that it is expressed in the epidermis of leaves, where FT is not expressed. Consistently, WER regulates not the transcription but the stability of FT mRNA. Our results reveal a novel regulatory mechanism of FT that is non cell autonomous. PMID- 21653191 TI - Rapid, organ-specific transcriptional responses to light regulate photomorphogenic development in dicot seedlings. AB - The dicotyledon seedling undergoes organ-specific photomorphogenic development when exposed to light. The cotyledons open and expand, the apical hook opens, and the hypocotyl ceases to elongate. Using the large and easily dissected seedlings of soybean (Glycine max 'Williams 82'), we show that genes involved in photosynthesis and its regulation dominate transcripts specific to the cotyledon, even in etiolated seedlings. Genes for cell wall biosynthesis and metabolism are expressed at higher levels in the hypocotyl, while examination of genes expressed at higher levels in the hook region (including the shoot apical meristem) reveals genes involved in cell division and protein turnover. The early transcriptional events in these three organs in response to a 1-h treatment of far-red light are highly distinctive. Not only are different regulatory genes rapidly regulated by light in each organ, but the early-responsive genes in each organ contain a distinctive subset of known light-responsive cis-regulatory elements. We detected specific light-induced gene expression for the root phototropism gene RPT2 in the apical hook and also phenotypes in Arabidopsis (Arabidopsis thaliana) rpt2 mutants demonstrating that the gene is necessary for normal photomorphogenesis in the seedling apex. Significantly, expression of the RPT2 promoter fused to a beta glucuronidase reporter gene shows differential expression across the hook region. We conclude that organ-specific, light-responsive transcriptional networks are active early in photomorphogenesis in the aerial parts of dicotyledon seedlings. PMID- 21653192 TI - Mimicking the inflammatory cell adhesion cascade by nucleic acid aptamer programmed cell-cell interactions. AB - Nature has evolved effective cell adhesion mechanisms to deliver inflammatory cells to inflamed tissue; however, many culture-expanded therapeutic cells are incapable of targeting diseased tissues following systemic infusion, which represents a great challenge in cell therapy. Our aim was to develop simple approaches to program cell-cell interactions that would otherwise not exist toward cell targeting and understanding the complex biology of cell-cell interactions. We employed a chemistry approach to engineer P- or L-selectin binding nucleic acid aptamers onto mesenchymal stem cells (MSCs) to enable them to engage inflamed endothelial cells and leukocytes, respectively. We show for the first time that engineered cells with a single artificial adhesion ligand can recapitulate 3 critical cell interactions in the inflammatory cell adhesion cascade under dynamic flow conditions. Aptamer-engineered MSCs adhered on respective selectin surfaces under static conditions >10 times more efficiently than controls including scrambled-DNA modified MSCs. Significantly, engineered MSCs can be directly captured from the flow stream by selectin surfaces or selectin-expressing cells under flow conditions (<=2dyn/cm2). The simple chemistry approach and the versatility of aptamers permit the concept of engineered cell-cell interactions to be generically applicable for targeting cells to diseased tissues and elucidating the biology of cell-cell interactions. PMID- 21653193 TI - ROP GTPases act with the receptor-like protein PAN1 to polarize asymmetric cell division in maize. AB - Plant Rho family GTPases (ROPs) have been investigated primarily for their functions in polarized cell growth. We previously showed that the maize (Zea mays) Leu-rich repeat receptor-like protein PANGLOSS1 (PAN1) promotes the polarization of asymmetric subsidiary mother cell (SMC) divisions during stomatal development. Here, we show that maize Type I ROPs 2 and 9 function together with PAN1 in this process. Partial loss of ROP2/9 function causes a weak SMC division polarity phenotype and strongly enhances this phenotype in pan1 mutants. Like PAN1, ROPs accumulate in an asymmetric manner in SMCs. Overexpression of yellow fluorescent protein-ROP2 is associated with its delocalization in SMCs and with aberrantly oriented SMC divisions. Polarized localization of ROPs depends on PAN1, but PAN1 localization is insensitive to depletion and depolarization of ROP. Membrane-associated Type I ROPs display increased nonionic detergent solubility in pan1 mutants, suggesting a role for PAN1 in membrane partitioning of ROPs. Finally, endogenous PAN1 and ROP proteins are physically associated with each other in maize tissue extracts, as demonstrated by reciprocal coimmunoprecipitation experiments. This study demonstrates that ROPs play a key role in polarization of plant cell division and cell growth and reveals a role for a receptor-like protein in spatial localization of ROPs. PMID- 21653194 TI - A new role for ROP GTPases in the polarization of cell division. PMID- 21653195 TI - Transcriptional programming and functional interactions within the Phytophthora sojae RXLR effector repertoire. AB - The genome of the soybean pathogen Phytophthora sojae contains nearly 400 genes encoding candidate effector proteins carrying the host cell entry motif RXLR dEER. Here, we report a broad survey of the transcription, variation, and functions of a large sample of the P. sojae candidate effectors. Forty-five (12%) effector genes showed high levels of polymorphism among P. sojae isolates and significant evidence for positive selection. Of 169 effectors tested, most could suppress programmed cell death triggered by BAX, effectors, and/or the PAMP INF1, while several triggered cell death themselves. Among the most strongly expressed effectors, one immediate-early class was highly expressed even prior to infection and was further induced 2- to 10-fold following infection. A second early class, including several that triggered cell death, was weakly expressed prior to infection but induced 20- to 120-fold during the first 12 h of infection. The most strongly expressed immediate-early effectors could suppress the cell death triggered by several early effectors, and most early effectors could suppress INF1-triggered cell death, suggesting the two classes of effectors may target different functional branches of the defense response. In support of this hypothesis, misexpression of key immediate-early and early effectors severely reduced the virulence of P. sojae transformants. PMID- 21653197 TI - XX males SRY negative: a confirmed cause of infertility. AB - BACKGROUND: SOX9 is a widely expressed transcription factor playing several relevant functions during development and essential for testes differentiation. It is considered to be the direct target gene of the protein encoded by SRY and its overexpression in an XX murine gonad can lead to male development in the absence of Sry. Recently, a family was reported with a 178 kb duplication in the gene desert region ending about 500 kb upstream of SOX9 in which 46,XY duplicated persons were completely normal and fertile whereas the 46,XX ones were males who came to clinical attention because of infertility. METHODS AND RESULTS: We report a family with two azoospermic brothers, both 46,XX, SRY negative, having a 96 kb triplication 500 kb upstream of SOX9. Both subjects have been analyzed trough oligonucleotide array-CGH and the triplication was confirmed and characterised through qPCR, defining the minimal region of amplification upstream of SOX9 associated with 46,XX infertile males, SRY negative. CONCLUSIONS: Our results confirm that even in absence of SRY, complete male differentiation may occur, possibly driven by overexpression of SOX9 in the gonadal ridge, as a consequence of the amplification of a gene desert region. We hypothesize that this region contains gonadal specific long-range regulation elements whose alteration may impair the normal sex development. Our data show that normal XX males, with alteration in copy number or, possibly, in the critical sequence upstream to SOX9 are a new category of infertility inherited in a dominant way with expression limited to the XX background. PMID- 21653198 TI - Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer. PMID- 21653196 TI - Parameters affecting telomere-mediated chromosomal truncation in Arabidopsis. AB - Conversion of a double-strand break into a telomere is a dangerous, potentially lethal event. However, little is known about the mechanism and control of de novo telomere formation (DNTF). DNTF can be instigated by the insertion of a telomere repeat array (TRA) into the host genome, which seeds the formation of a new telomere, resulting in chromosome truncation. Such events are rare and concentrated at chromosome ends. Here, we introduce tetraploid Arabidopsis thaliana as a robust genetic model for DNTF. Transformation of a 2.6-kb TRA into tetraploid plants resulted in a DNTF efficiency of 56%, fivefold higher than in diploid plants and 50-fold higher than in human cells. DNTF events were recovered across the entire genome, indicating that genetic redundancy facilitates recovery of DNTF events. Although TRAs as short as 100 bp seeded new telomeres, these tracts were unstable unless they were extended above a 1-kb size threshold. Unexpectedly, DNTF efficiency increased in plants lacking telomerase, and DNTF rates were lower in plants null for Ku70 or Lig4, components of the nonhomologous end-joining repair pathway. We conclude that multiple competing pathways modulate DNTF, and that tetraploid Arabidopsis will be a powerful model for elucidating the molecular details of these processes. PMID- 21653199 TI - Detection of APC germ line mosaicism in patients with de novo familial adenomatous polyposis: a plea for the protein truncation test. AB - BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited colorectal cancer predisposition caused by germ line mutations in the APC (adenomatous polyposis coli) gene. Current recommendations for APC mutation analysis advise full gene sequencing to identify point mutations and small insertions/deletions as well as the multiplex ligation dependent probe amplification (MLPA) technique to detect gene dosage alterations. Use of the protein truncation test (PTT) as a pre-screening tool has thus been largely replaced with direct end-to-end sequencing, mainly because of its limited sensitivity and failure to identify APC missense alterations. METHODS AND RESULTS: This report describes two unrelated patients with classical polyposis coli and unremarkable family history in whom neither full sequencing nor MLPA on leucocyte derived DNA could identify a pathogenic APC mutation. Applying the PTT, however, provided evidence of aberrant bands in both patients. Subsequent targeted mutation analysis of their tumour derived DNA allowed the identification of two novel, pathogenic APC alterations present in a mosaic state, at blood levels (1-15%) below the detection limits of conventional Sanger sequencing. CONCLUSION: The findings demonstrate the value of the PTT in identifying mosaic mutations in apparently APC mutation negative FAP patients with de novo classical polyposis and the need to keep the PTT within the diagnostic repertoire for APC mutation analysis. PMID- 21653201 TI - Unique configuration of the four-lumen oesophagogastric tamponade tube (Minnesota tube) for the control of massive upper GI bleeding. PMID- 21653202 TI - Crush syndrome in the rural setting. PMID- 21653203 TI - Emergency department crowding: towards an agenda for evidence-based intervention. AB - OBJECTIVE: To determine the causes of emergency department (ED) crowding and to identify evidence-based solutions. DESIGN: The review used a 'conceptual synthesis' approach to identify knowledge and opinion around the issue of ED crowding, not just effective interventions. Recommendations from the literature were classified according the quality of evidence and the extent to which they were under ED control. DATA SOURCES: SCOPUS and ISI were searched for studies of 'ED' AND 'crowding OR overcrowding' and backward citation retrieval was undertaken. To help identify systematic review evidence of effective interventions, the Cochrane Database, the National Institute of Health and Clinical Excellence (NICE) and NHS Evidence were searched. A Google search was included to identify relevant grey literature. ELIGIBILITY CRITERIA: Papers were included if they added to substantive knowledge of ED crowding. Empirical studies, studies from the UK and studies of physical space were privileged in the review. RESULTS: There is an established international literature on ED crowding. It suggests consistently that crowding has significant negative consequences. However, the literature offers limited practical help to practitioners for a number of reasons, such as a lack of shared definition and measurement of crowding and lack of evaluation of interventions. Many studies are single case studies from the USA. CONCLUSIONS: While current evidence is poor, this does not justify maintaining current practice which risks lives. Building up an evidence base is critical, but requires agreed definitions, measures and methods, which can be applied to systematic evaluation of plausible solutions. PMID- 21653204 TI - Epizootic myocarditis associated with encephalomyocarditis virus in a group of rhesus macaques (Macaca mulatta). AB - Six cases of fatal myocarditis associated with encephalomyocarditis virus occurred over a 14-month period in a group of outdoor-housed juvenile rhesus macaques. All animals were younger than 3 years of age and died or were euthanized following acute onset of dyspnea or pulmonary effusion (3 of 6) or were found dead without premonitory signs (3 of 6). Gross findings included pulmonary congestion (6 of 6), variable degrees of pleural effusion (4 of 6), multifocal pale tan foci throughout the myocardium (3 of 6), hepatomegaly and hepatic congestion (3 of 6), and pericardial effusion (1 of 6). Histologically, affected myocardium was infiltrated multifocally by lymphoplasmacytic and histiocytic inflammation admixed with necrotic and degenerate myofibers and infrequent mineralization (6 of 6). Pulmonary edema was present in all animals. Encephalomyocarditis virus was confirmed in 6 of 6 hearts by immunohistochemistry, and virus was isolated from one case by polymerase chain reaction. Sequencing of virus isolated from 1 affected animal indicated infection with a novel encephalomyocarditis virus. Encephalomyocarditis virus should be considered as a differential etiology in outbreaks of myocarditis and pulmonary edema in juvenile primates. PMID- 21653205 TI - Muscle ischaemia in patients with orthostatic hypotension assessed by velocity recovery cycles. AB - OBJECTIVE: Patients with orthostatic hypotension may experience neck pain radiating to the occipital region of the skull and the shoulders while standing (so-called coat-hanger ache). This study assessed muscle membrane potential in the trapezius muscle of patients with orthostatic hypotension and healthy subjects during head-up tilt (HUT), by measuring velocity recovery cycles (VRCs) of muscle action potentials as an indicator of muscle membrane potential. METHODS: Eight patients with multiple system atrophy (MSA), orthostatic hypotension and a positive history for coat-hanger pain and eight normal controls (NCs) were included in this study. Repeated VRCs were recorded from the trapezius muscle by direct muscle stimulation in the supine position and during HUT for 10 min. RESULTS: Muscle VRC recordings did not differ between MSA patients and NCs in the supine position. During HUT, early supernormality decreased progressively and relative refractory period increased in MSA patients whereas VRC measures remained unchanged in NCs. Ten minutes after the start of HUT, early supernormality was reduced by 44% and relative refractory period was increased by 17%. CONCLUSIONS: Muscle membranes in patients with orthostatic hypotension become progressively depolarised during standing. Membrane depolarisation is most likely the result of muscle ischaemia, related to the drop in perfusion pressure caused by orthostatic hypotension. Coat-hanger ache is most likely a consequence of this muscle ischaemia. PMID- 21653206 TI - Pachymeningeal involvement in POEMS syndrome: MRI and histopathological study. AB - Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes (POEMS) syndrome is a rare plasma cell disease. Vascular endothelial growth factor (VEGF) seems to play a pathogenic role. Peripheral neuropathy is the main neurological feature. Cranial pachymeningitis has occasionally been reported, but no histopathological studies have been performed. The authors extensively evaluated the central nervous system MRI in 11 patients (seven men, four women; mean age at diagnosis 54.45 years) with POEMS syndrome. In two patients, meningeal histopathology with staining for VEGF and VEGF receptor was performed, and pachymeningeal involvement characterised at histopathological, immunohistochemical and confocal microscopy levels. Nine patients presented with cranial pachymeningitis. One patient suffered from migraine, and none complained of cranial nerve palsies or visual loss. None showed any MRI signs of spinal pachymeningitis. No correlation was found with disease duration and VEGF serum level. Histopathology showed hyperplasia of meningothelial cells, neovascularisation and obstructive vessel remodelling, without inflammation. VEGF and VEGF receptor were strongly coexpressed on endothelium, smooth-muscle cells of arterioles and meningothelial cells. In conclusion, POEMS patients present a high prevalence of meningeal involvement. The histological changes, different from those present in chronic pachymeningitis of other aetiology, suggest a possible VEGF role in the pathogenesis of the meningeal remodelling. PMID- 21653207 TI - Hippocampal resection length and memory outcome in selective epilepsy surgery. AB - OBJECTIVE: In temporal lobe epilepsy surgery, there is a trend towards becoming more selective in order to achieve seizure control with an optimal neuropsychological outcome. The present study evaluated whether mesial resection length matters for memory outcome after selective amygdalo-hippocampectomy (SAH). Therefore, a sub-analysis of the larger SFB/TR3/A1 multicentre randomised trial on seizure outcome and mesial resection length in temporal lobe surgery was performed. METHODS: A homogeneous group of 67 selectively operated patients with hippocampal sclerosis as the sole pathology were allocated to a short (2.5 cm, n=34) or a long (3.5 cm, n=33) mesial resection. Repeated memory assessment and three-dimensional MRI data sets served as dependent within group variables, and intraoperatively determined resection lengths (short/long), resected hippocampal volumes (small/large) and side of surgery were independent between group variables. RESULTS: Resection length did not have a significant effect on seizure or on memory outcome. The resected hippocampal volume also did not affect seizure outcome but it did make a difference with regard to memory outcome. Outcome in verbal learning and memory was poorer after resection of larger left hippocampal volumes. Figural memory outcome was poorer with larger resected volumes on either side. INTERPRETATION: The data indicate that in SAH, mesial resection length and resected volumes have no differential effect on seizure outcome. The findings on memory outcome are best explained by suggesting that hippocampal volumes take the degree of preoperative pathology into account whereas resection length does not. This suggests resection of non-pathological functional tissues as the basis for memory outcome after SAH. PMID- 21653208 TI - Pre-existing blindness in a cohort of patients with bacterial keratitis. PMID- 21653209 TI - A novel procedure for treating canalicular obstruction by re-canaliculisation and bicanalicular intubation. AB - AIM: The aim of this study was to evaluate a new procedure for treating canalicular obstruction by re-canaliculisation and bicanalicular intubation (RC BCI). METHODS: Thirty adult patients (32 eyes) with canalicular obstruction were treated with RC-BCI from September 2005 to December 2007 at Zhongshan Ophthalmic Centre (Guangzhou, China). Silicone tubes were left in place for 2-3 months and were removed when patients had relief by tearing. Patients were evaluated postoperatively by symptoms, lacrimal irrigation and satisfaction rate. RESULTS: Mean follow-up time after tube removal was 21.5 (range 6-26) months. Twenty-six eyes (81.25%) had complete epiphora relief, two eyes (6.25%) had partial relief and four eyes (12.5%) had no improvement after the removal of the tubes. One eye (3.13%) had lower punctum splitting 2 months after the surgery. The overall satisfaction rate was 93.3% in 30 patients. No other complications occurred. CONCLUSION: Our findings demonstrated that the RC-BCI was an effective procedure for treating canalicular obstruction with few complications. PMID- 21653211 TI - Detection of mild papilloedema using spectral domain optical coherence tomography. AB - OBJECTIVE: To propose a method of diagnosis of mild papilloedema (PO) using peripapillary total retinal (PTR) thickness measurement by spectral domain optical coherence tomography (OCT). METHODS: 24 eyes in 24 patients with PO caused by increased intracranial pressure and 22 eyes in 22 normal subjects were studied. OCT high-quality fundus images were analysed and graded by three masked observers using the Modified Frisen Scale. Eyes with PO were divided into two subgroups: those with mild PO (n=18) and those with moderate-severe PO (n=6). Two methods of measurements were evaluated and compared: retinal nerve fibre layer (RNFL) thickness measurements using standard optic disc cube 200 * 200 acquisition protocol and PTR thickness measurements using the 'macular' cube 512 * 128 acquisition protocol centred on the optic disc. Thickness values were calculated globally and for each quadrant (temporal, superior, nasal, inferior) and compared among the three groups (control, mild PO, moderate-severe PO). The main outcome measures were RNFL and PTR thickness. RESULTS: Average RNFL and PTR thickness in the moderate-severe PO, mild PO and control groups were 299.3 +/- 10.9, 112.4 +/- 6.3, 96 +/- 5.7 and 804.5 +/- 17, 463.1 +/- 9.8 and 332.4 +/- 8.9 MUm, respectively. Moderate-severe PO differed from mild PO and control groups using both RNLF thicknesses and PTR thicknesses measurements. Mild PO did not differ from controls using RNLF thickness measurement (p=0.17), but was statistically different using PTR thickness measurement (p<0.001). CONCLUSION: PTR thickness measurement increases the sensitivity of detection of mild PO compared with conventional RNFL measurement. This new way of using OCT may be useful for clinicians to detect mild PO. PMID- 21653210 TI - Incidence and patterns of detection and management of childhood-onset hereditary retinal disorders in the UK. AB - BACKGROUND: A prospective, national population-based cross-sectional study to enable understanding of the burden and management in the UK of hereditary retinal disorders presenting in childhood. METHODS: Children aged <16 years with a new diagnosis of an inherited retinal disorder made between September 2006 and February 2008 in the UK were identified through two national active surveillance schemes. Clinical and socio-demographic information was collected on each child at diagnosis and 9 months later using standardised questionnaires. RESULTS: 241 patients were reported with 24 distinct diagnoses. 14% had additional systemic disorders and 13% had dual sensory impairment. Annual incidence was 1.4/100,000 children (aged 0-15 years) and the cumulative incidence by age 16 years was 22.3/100,000 children. The most common mode of inheritance was autosomal recessive. A significantly higher rate was seen in males than females (relative rate (RR) 1.53), in children of Asian compared with White ethnicity (RR 7.12) and in those in the worst quintile of socio-economic deprivation compared with those in the best (RR 1.43). Parents most commonly detected a problem with their child's vision. Up to seven different health professionals were involved in a child's early management, and variations were noted in the proportion of eligible children having assessments for low vision aids, statement of educational needs and certification as sight-impaired. CONCLUSIONS: These findings illustrate the highly heterogeneous nature of childhood retinal dystrophies and provide previously unavailable data on disease incidence, distributions and management, which are important for service provision and for planning future treatment programmes, particularly as novel therapies become available. PMID- 21653212 TI - The effect of perioperative allergic conjunctivitis on corneal lymphangiogenesis after corneal transplantation. AB - INTRODUCTION: Perioperative allergic conjunctivitis accelerates the speed of corneal allograft rejection. This study examines the effect of allergic conjunctivitis, with and without dexamethasone treatment, on the early inflammatory response and lymphangiogenesis in the host cornea following corneal transplantation. METHODS: Allogeneic fully MHC-mismatched C57Bl/6 strain donor corneas were transplanted into naive A/J mice and into A/J mice with active allergic conjunctivitis. Further groups of allograft recipients with allergic conjunctivitis were treated post-operatively with twice daily topical dexamethasone 0.1% or phosphate-buffered saline. Mice were killed on days 2 and 6 and corneas were examined by (i) fluorescent immunohistochemistry of frozen sections using anti-CD11b, anti-F4/80 and anti-Gr-1 antibodies, or (ii) whole mount staining with anti-LYVE-1 antibody. Lymphatic ingrowth and numbers of cells infiltrating the host cornea were compared between groups. RESULTS: There were significantly higher numbers of CD11b(+) cells and LYVE-1(+) vessels in the host cornea at day 2 in allergic compared with naive recipients, but no differences between naive and allergic recipients at day 6. In allergic eyes, dexamethasone treatment significantly inhibited LYVE-1 expression at days 2 and 6, and significantly improved allograft survival in recipients with allergic conjunctivitis if maintained for a week. CONCLUSIONS: The innate immune response to allogeneic corneal tissue is more vigorous in the presence of allergic conjunctivitis than in naive eyes and is associated with accelerated lymphatic ingrowth to host cornea. Topical dexamethasone inhibits lymphatic ingrowth and this may be one mechanism by which topical steroid enhances graft survival. PMID- 21653213 TI - A novel technique of tangential, circumferential, scleral tunnel in 20-gauge transconjunctival sutureless vitrectomy: optical coherence tomography-aided analysis of wound integrity and clinical outcome. AB - AIM: To describe a novel technique of sclerotomy construction to facilitate 20 gauge transconjunctical sutureless vitrectomy (TSV) along with the evaluation of the wound integrity. METHODS: The surgical technique is described. One hundred consecutive patients who underwent TSV were evaluated for wound leaks, postoperative hypotony, endophthalmitis and any other complication related to surgery. The sclerotomies of eight patients (24 ports) were analysed by imaging with anterior segment optical coherence tomography immediately after surgery, and on the first postoperative day and after the first postoperative month. RESULTS: 104 eyes of 100 patients were evaluated with a mean follow-up of 9.6 months. All cases underwent surgery with standard 20-gauge instrumentation and vitrectomy techniques. Five sclerotomies were found to leak at the end of surgery, requiring a suture. Anterior segment optical coherence tomography images were obtained from eight eyes with good apposition of the tunnel noted in all the cases. Mean intraocular pressure was 18.7 mm Hg on the first postoperative day. One patient had hypotony without leak and this patient had pre-existing hypotony due to chronic panuveitis. There was no instance of postoperative endophthalmitis. CONCLUSIONS: This technique of 20-gauge TSV achieves good wound apposition with a low incidence of complications while using standard 20-gauge instrumentation and vitrectomy techniques. PMID- 21653214 TI - Retinopathy of prematurity as a major cause of severe visual impairment and blindness in children in schools for the blind in Guadalajara city, Mexico. AB - AIM: To determine the causes of blindness in students attending schools for the blind in Guadalajara city, Mexico and to assess the availability of screening for retinopathy of prematurity (ROP) in local neonatal intensive care units. METHODS: Information on causes of blindness was obtained by interview with parents and teachers, review of records and examination. Causes of visual loss in children with a distance visual acuity of <6/60 (ie, severely visually impaired or blind) were determined and classified according to the WHO's classification system for children. RESULTS: Of 153 children in the two participating schools, 144 were severely visual impaired or blind. Their ages ranged from 4 months to 15 years and 58% were female. ROP was the most common cause of visual loss (34.7%), followed by optic nerve lesions (17.4%) and glaucoma (14.6%). 25/59 (42.3%) children aged 0-4 years were blind from ROP compared with 6/32 (18.8%) children aged 10-15 years. 78% of children blind from ROP had psychomotor delay and less than half (46%) had not received treatment for ROP. All five privately funded neonatal intensive care units in the city regularly screen for ROP compared with only four of the 12 units in the public sector. CONCLUSIONS: ROP is the leading cause of blindness in children in Mexico despite national guidelines being in place. Health policies promoting primary prevention through improved neonatal care need to be implemented. Advocacy is required so that the time ophthalmologists spend screening and treating ROP is included in their job description and hence salaried. PMID- 21653215 TI - Bevacizumab for Coats' disease with exudative retinal detachment and risk of vitreoretinal traction. AB - AIM: To evaluate the effect of supplemental intravitreal bevacizumab for management of Coats' disease. METHODS: Retrospective analysis of eight patients with Coats' disease manifesting total or partial exudative retinal detachment where the retinal telangiectasia was treated with standard laser photocoagulation and/or cryotherapy plus additional intravitreal bevacizumab (1.25 mg/0.05 ml). RESULTS: The mean patient age was 88 (range 7-240) months and 63% were male. Coats' disease was classified as stage 2 (n=1, 12%), 3a (n=3, 38%) and 3b (n=4, 50%). Features included retinal detachment (n=8, 100% with mean detachment extent involving 8 clock hours), telangiectasia (n=8, 100% with mean extent of 8 clock hours), peripheral retinal ischaemia on fluorescein angiography (n=7, 88%) and no evidence of neovascularisation. Treatment consisted of cryotherapy (n=8, 100%), laser photocoagulation (n=4, 50%) and bevacizumab intravitreal injection (n=8) with median number of one injection per eye (mean 1.75, and range 1-4 injections). After a mean follow-up of 8.5 months, resolution of retinopathy (n=8, 100%), Coats'-related subretinal fluid (n=8, 100%) and retinal exudation (n=6, 75%) was noted. However, vitreous fibrosis developed (n=4, 50%) at a mean of 5 months following a mean of 1.75 bevacizumab injections with three (38%) evolving into traction retinal detachment. CONCLUSION: Coats' disease treated with intravitreal bevacizumab in addition to standard therapy can develop to vitreoretinal fibrosis and potentially traction retinal detachment. These tractional features are not often found in Coats' disease treated with standard measures without bevacizumab. Caution is advised in the use of bevacizumab for patients with Coats' disease. PMID- 21653216 TI - Combination of carotid intima-media thickness and plaque for better predicting risk of ischaemic cardiovascular events. AB - BACKGROUND: Several indices of carotid atherosclerosis have been studied to investigate their associations with the risk of cardiovascular disease. However, the best index of carotid atherosclerosis that predicts the risk of cardiovascular disease remains unclear. OBJECTIVE: To investigate the index that best reflects the relationship between carotid atherosclerosis and subsequent ischaemic cardiovascular disease (ICVD) events. DESIGN: An observational longitudinal study with a 5-year follow-up. PARTICIPANTS: 1734 Chinese subjects (623 men, 1111 women) aged 43-79 years at baseline. MAIN OUTCOME MEASURES: ICVD events, including coronary heart disease and ischaemic stroke. RESULTS: Carotid intima-media thickness (IMT) at baseline was significantly associated with the risk of ICVD among participants without carotid plaque (multivariable adjusted HR=1.59, 95% CI 1.04 to 2.45) but not among those with plaque (HR=1.04, 95% CI 0.78 to 1.39). However, the total area of plaques (HR=1.29, 95% CI 1.08 to 1.55), the number of plaques (HR=1.14, 95% CI 1.02 to 1.27) and the number of segments with plaque (HR=1.45, 95% CI 1.09 to 1.93) were all significantly associated with ICVD in participants with plaque. Thus, carotid IMT and the number of segments with plaque were combined to establish a summary index-the total burden score (TBS) of carotid atherosclerosis-which was shown to improve the prediction of the 5-year risk of ICVD significantly compared with IMT or the number of segments with plaque alone. The c-statistics and net reclassification index showed that TBS improved the risk prediction by increases of 6.0% and 17.1%, respectively, compared with the conventional risk score. CONCLUSION: The TBS could significantly improve the prediction of ICVD risk and should be used in clinical practice and future studies. PMID- 21653217 TI - Gender differences in the utilisation of surgery for congenital heart disease in India. AB - BACKGROUND: Corrective surgery for congenital heart disease may be life-saving, but its utilisation depends upon several social and economic factors. Girls with cardiac defects may not receive equitable care in India, but this has not been systematically studied. METHODS: In this prospective study, parents or guardians of 405 consecutive children aged up to 12 years (mean +/- SD age 3.43 +/- 3.44 years; 271 boys) who had been advised to undergo elective paediatric cardiac surgery were interviewed using a validated questionnaire. The status of the patients was reviewed after a year and the factors associated with non-compliance with treatment were analysed. In a qualitative sub-study the parents of 20 children who had not undergone surgery were interviewed. Qualitative data were analysed using an inductive analytical approach. RESULTS: Of the 405 patients studied, 44% (59/134) of girls had undergone surgery at 1 year compared with 70% (189/271) of boys (chi2=24.97; p<0.001). Independent predictors for non compliance with surgery included female gender (OR 3.46, 95% CI -2.06 to 5.80; p<0.0001), lower socioeconomic classes (lower-middle: OR 18.62, 95% CI -2.14 to 161.8, p=0.008; upper-lower: OR 34.27, 95% CI -3.72 to 316.0, p=0.002) and higher cost of surgery (OR 1.92, 95% CI -1.06 to 3.47, p=0.03). In the in-depth interviews, apprehensions about future matrimonial prospects of girls and lack of social support emerged as the major factors responsible for delays in undergoing surgery. CONCLUSIONS: Female gender is an important determinant of non-compliance with paediatric cardiac surgery. Deep-seated social factors underlie this gender bias. PMID- 21653218 TI - Clinical outcomes of exercise-induced pulmonary hypertension in subjects with preserved left ventricular ejection fraction: implication of an increase in left ventricular filling pressure during exercise. AB - OBJECTIVE: To investigate clinical outcomes of exercise-induced pulmonary hypertension (PH) and implications of an increase in left ventricular (LV) filling pressure during exercise in subjects with preserved LV ejection fraction. DESIGN: Longitudinal follow-up study. SETTING: Subjects who were referred for diastolic stress echocardiography. PATIENTS AND METHODS: The ratio of transmitral and annular velocities (E/Ea) and pulmonary artery systolic pressure (PASP) at rest and during exercise were measured in 498 subjects (57+/-11 years; 201 male). Exercise-induced PH was defined as present if PASP >=50 mm Hg at 50 W of exercise, and an increase in LV filling pressure during exercise was present if E/Ea >=15 at 50 W. MAIN OUTCOME MEASURES: A combination of major cardiovascular events and any cause of death. RESULTS: During a median follow-up of 41 months, there were 14 hospitalisations and four deaths. Subjects with exercise-induced PH had significantly worse clinical outcomes than those without (p=0.014). Subjects with exercise-induced PH associated with an increase in E/Ea during exercise had significantly worse outcomes than other groups (p<0.001). However, prognosis was similar between subjects with exercise-induced PH without an increase in E/Ea and those without exercise-induced PH. In subjects with exercise-induced PH, E/Ea at 50 W was an independent predictor of adverse outcomes (HR 1.37; 95% CI 1.02 to 1.83; p=0.036). CONCLUSIONS: Exercise-induced PH provides prognostic information in subjects with preserved LV ejection fraction. The excess risk of exercise induced PH is restricted to subjects with an increase in estimated LV filling pressure during exercise. PMID- 21653219 TI - Impact of left ventricular longitudinal diastolic functional reserve on clinical outcome in patients with type 2 diabetes mellitus. AB - BACKGROUND: Left ventricular longitudinal diastolic functional reserve (DFR), as assessed by the change in early diastolic mitral annular velocity (E') during exercise, is abnormal in patients with type 2 diabetes mellitus (DM). However, the impact of left ventricular longitudinal DFR on clinical outcome has not been explored. This study evaluated the incremental prognostic value of left ventricular DFR in patients with type 2 DM without overt heart disease. METHODS: Of 1485 patients who were referred for exercise stress echocardiography, 197 consecutive patients (mean age, 58 years; 84 men) with type 2 DM without overt heart disease were identified. Left ventricular longitudinal DFR was defined as the change in E' from resting to exercise (DeltaE'). The endpoint was a composite of death and hospitalisation for heart failure (HF). RESULTS: During a median follow-up of 57 months (range 6-90), 18 of 197 patients (9.1%) had adverse events (12 deaths, six hospitalisations for HF). Independent predictors of adverse events in a Cox regression analysis were estimated glomerular filtration rate (HR 0.97; 95% CI 0.95 to 0.98; p<0.001), DM duration (HR 1.07; 95% CI 1.01 to 1.14; p=0.018) and DeltaE' (HR 0.58; 95% CI 0.40 to 0.85; p=0.005). In an incremental model, the addition of stress echo data significantly increased the chi2 of the clinical and resting left ventricular function model, from 40.5 to 46.6 (p=0.005). CONCLUSION: Assessment of left ventricular longitudinal DFR during exercise provided incremental prognostic information in patients with type 2 DM without overt heart disease. PMID- 21653220 TI - Detection of disrupted plaques by coronary CT: comparison with angioscopy. AB - BACKGROUND: Disrupted plaques are the major cause of acute coronary syndrome (ACS). Although the detection of vulnerable plaques by coronary CT (CCT) has been examined and reported, there has been no report on the detection of disrupted plaques by CCT. OBJECTIVES: To test the ability of CCT to detect disrupted coronary plaques. METHODS: 32 consecutive patients with suspected ischaemic heart disease who underwent successful coronary angioscopic examination and CCT were analysed. Yellow plaques of colour grade 1-3 and disrupted yellow plaques were examined by angioscopy. CCT findings (low attenuation, positive remodelling and ring-like enhancement) were examined for each site of yellow plaques. RESULTS: In the 32 patients, 65 yellow plaques were detected. Higher-colour-grade yellow plaques and disrupted yellow plaques had a significantly higher incidence of CCT findings: low attenuation (grade 1 vs grade 2 vs grade 3, 18% vs 59% vs 69%; non disrupted vs disrupted, 36% vs 66%), positive remodelling (24% vs 59% vs 75%; 33% vs 75%), and ring-like enhancement (0% vs 19% vs 25%; 6% vs 44%). Positive and negative predictive values for ring-like enhancement to detect disrupted plaque were 88% and 63%, respectively; those for the combined CCT findings (low attenuation, positive remodelling and ring-like enhancement) to detect disrupted plaque were 90% and 58%, respectively. CONCLUSION: CCT findings were associated with disrupted plaques confirmed by angioscopy. Ring-like enhancement had a high positive predictive value for detecting disrupted plaque. PMID- 21653221 TI - Leucine-rich amelogenin peptides regulate mineralization in vitro. AB - Amelogenin's capacity to regulate enamel formation is related to its conserved N- and C-terminal domains, its ability to self-assemble, and its ability to stabilize amorphous calcium phosphate (ACP) - a capacity enhanced by amelogenin phosphorylation. This in vitro study provides further insight into amelogenin function, using variations of the Leucine-Rich Amelogenin Peptide (LRAP), an alternative splice product comprised solely of amelogenin's N- and C-terminal domains. Peptide self-assembly was studied by dynamic light-scattering and transmission electron microscopy (TEM). TEM, selected area electron diffraction, and Fourier transform-infrared spectroscopy were also used to determine the effect of phosphorylated and non-phosphorylated LRAP on calcium phosphate formation. Results show that phosphorylated and non-phosphorylated LRAP can self assemble into chain-like structures in a fashion dependent on the C-terminal domain. Notably, this capacity was enhanced by added calcium and to a much greater degree for phosphorylated LRAP. Furthermore, phosphorylated LRAP was found to stabilize ACP and prevent its transformation to hydroxyapatite (HA), while aligned HA crystals formed in the presence of non-phosphorylated LRAP. The N- and C-terminal amelogenin domains in non-phosphorylated LRAP are, therefore, sufficient to guide ACP transformation into ordered bundles of apatite crystals, making LRAP an excellent candidate for biomimetic approaches for enamel regeneration. PMID- 21653222 TI - Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. AB - Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25-30%. During exercise, humoral factors are released from the working muscles for endocrinal signaling to other organs. We hypothesized that these myokines mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase in caspase activity was found after incubation of MCF-7 cells with conditioned media from electrically stimulated myotubes. PCR array analysis (CAPM-0838E; SABiosciences) revealed that seven genes were upregulated in the muscles after exercise, and of these oncostatin M (OSM) proved to inhibit MCF-7 proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis, gastronemius, and soleus, after an exercise bout. In contrast, OSM expression remained unchanged in subcutaneous and visceral adipose tissue, liver, and spleen (mononuclear cells). We conclude that postexercise serum inhibits mammary cancer cell proliferation and induces apoptosis of these cells. We suggest that one or more myokines secreted from working muscles may be mediating this effect and that OSM is a possible candidate. These findings emphasize that role of physical activity in cancer treatment, showing a direct link between exercise-induced humoral factors and decreased tumor cell growth. PMID- 21653223 TI - A homozygous missense mutation in SCNN1A is responsible for a transient neonatal form of pseudohypoaldosteronism type 1. AB - Pseudohypoaldosteronism type 1 (PHA1) is a monogenic disorder of mineralocorticoid resistance characterized by salt wasting, hyperkalemia, high aldosterone levels, and failure to thrive. An autosomal recessive form (AR-PHA1) is caused by mutations in the epithelial sodium channel ENaC with usually severe and persisting multiorgan symptoms. The autosomal dominant form of PHA1 (AD-PHA1) is due to mutations in the mineralocorticoid receptor causing milder and transient symptoms restricted to the kidney. We identified a homozygous missense mutation in the SCNN1A gene (c.727T>C/p.Ser(243)Pro), encoding alpha-subunit of ENaC (alpha-ENaC) in a prematurely born boy with a severe salt-losing syndrome. The patient improved rapidly under treatment, and dietary salt supplementation could be stopped after 6 mo. Interestingly, the patient's sibling born at term and harboring the same homozygous Ser(243)Pro mutation showed no symptom of salt losing nephropathy. In vitro expression of the alphaSer(243)Pro ENaC mutant revealed a slight but significant decrease in ENaC activity that is exacerbated in the presence of high Na(+) load. Our study provides the first evidence that ENaC activity is critical for the maintenance of salt balance in the immature kidney of preterm babies. Together with previous studies, it shows that, when the kidney is fully mature, the severity of the symptoms of AR-PHA1 is related to the degree of the ENaC loss of function. Finally, this study identifies a novel functional domain in the extracellular loop of ENaC. PMID- 21653224 TI - Effect of exercise and training on phospholemman phosphorylation in human skeletal muscle. AB - Phospholemman (PLM, FXYD1) is a partner protein and regulator of the Na(+)-K(+) ATPase (Na(+)-K(+) pump). We explored the impact of acute and short-term training exercise on PLM physiology in human skeletal muscle. A group of moderately trained males (n = 8) performed a 1-h acute bout of exercise by utilizing a one legged cycling protocol. Muscle biopsies were taken from vastus lateralis at 0 and 63 min (non-exercised leg) and 30 and 60 min (exercised leg). In a group of sedentary males (n = 9), we determined the effect of a 10-day intense aerobic cycle training on Na(+)-K(+)-ATPase subunit expression, PLM phosphorylation, and total PLM expression as well as PLM phosphorylation in response to acute exercise (1 h at ~72% Vo(2peak)). Biopsies were taken at rest, immediately following, and 3 h after an acute exercise bout before and at the conclusion of the 10-day training study. PLM phosphorylation was increased both at Ser(63) and Ser(68) immediately after acute exercise (75%, P < 0.05, and 30%, P < 0.05, respectively). Short-term training had no adaptive effect on PLM phosphorylation at Ser(63) and Ser(68), nor was the total amount of PLM altered posttraining. The protein expressions of alpha(1)-, alpha(2)-,and beta(1)-subunits of Na(+)-K(+) ATPase were increased after training (113%, P < 0.05, 49%, P < 0.05, and 27%, P < 0.05, respectively). Whereas an acute bout of exercise increased the phosphorylation of PKCalpha/betaII on Thr(638/641) pre- and posttraining, phosphorylation of PKCzeta/lambda on Thr(403/410) was increased in response to acute exercise only after the 10-day training. In conclusion, we show that only acute exercise, and not short-term training, increases phosphorylation of PLM on Ser(63) and Ser(68), and data from one-legged cycling indicate that this effect of exercise on PLM phosphorylation is not due to systemic factors. Our results provide evidence that phosphorylation of PLM may play a role in the acute regulation of the Na(+)-K(+)-ATPase response to exercise. PMID- 21653225 TI - cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle. AB - There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulin-mediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic clamps (3 mU.min(-1).kg(-1)) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity. PMID- 21653226 TI - Beyond the balance of activator and repressor. AB - Cell differentiation during development is controlled by extracellular morphogens, which induce responding cells to differentiate into distinct cell fates based on the dose of morphogen they receive. Genes that specify the distinct cell fates are differentially responsive to morphogens, and the extracellular morphogen gradient is converted in responding cells to graded activity of transcription factors. In the case of Hedgehog, the gradient is converted to opposing gradients of transcriptional activator and repressor forms of the transcription factor Cubitus interruptus (Ci). It has been generally assumed that the balance between activator and repressor determines target gene responses within this gradient. However, new evidence shows that enhancers can respond selectively to the activator and repressor forms of Ci, and that this selectivity is determined by the affinity of Ci sites within the enhancers. PMID- 21653227 TI - TWIK-1 two-pore domain potassium channels change ion selectivity and conduct inward leak sodium currents in hypokalemia. AB - Background potassium (K+) channels, which are normally selectively permeable to K+, maintain the cardiac resting membrane potential at around -80 mV. In subphysiological extracellular K+ concentrations ([K+]o), which occur in pathological hypokalemia, the resting membrane potential of human cardiomyocytes can depolarize to around -50 mV, whereas rat and mouse cardiomyocytes become hyperpolarized, consistent with the Nernst equation for K+. This paradoxical depolarization of cardiomyocytes in subphysiological [K+]o, which may contribute to cardiac arrhythmias, is thought to involve an inward leak sodium (Na+) current. Here, we show that human cardiac TWIK-1 (also known as K2P1) two-pore domain K+ channels change ion selectivity, becoming permeable to external Na+, and conduct inward leak Na+ currents in subphysiological [K+]o. A specific threonine residue (Thr118) within the pore selectivity sequence TxGYG was required for this altered ion selectivity. Mouse cardiomyocyte-derived HL-1 cells exhibited paradoxical depolarization with ectopic expression of TWIK-1 channels, whereas TWIK-1 knockdown in human spherical primary cardiac myocytes eliminated paradoxical depolarization. These findings indicate that ion selectivity of TWIK 1 K+ channels changes during pathological hypokalemia, elucidate a molecular basis for inward leak Na+ currents that could trigger or contribute to cardiac paradoxical depolarization in lowered [K+]o, and identify a mechanism for regulating cardiac excitability. PMID- 21653228 TI - The cis-regulatory logic of Hedgehog gradient responses: key roles for gli binding affinity, competition, and cooperativity. AB - Gradients of diffusible signaling proteins control precise spatial patterns of gene expression in the developing embryo. Here, we use quantitative expression measurements and thermodynamic modeling to uncover the cis-regulatory logic underlying spatially restricted gene expression in a Hedgehog (Hh) gradient in Drosophila. When Hh signaling is low, the Hh effector Gli, known as Cubitus interruptus (Ci) in Drosophila, acts as a transcriptional repressor; when Hh signaling is high, Gli acts as a transcriptional activator. Counterintuitively and in contrast to previous models of Gli-regulated gene expression, we found that low-affinity binding sites for Ci were required for proper spatial expression of the Hh target gene decapentaplegic (dpp) in regions of low Hh signal. Three low-affinity Ci sites enabled expression of dpp in response to low signal; increasing the affinity of these sites restricted dpp expression to regions of maximal signaling. A model incorporating cooperative repression by Ci correctly predicted the in vivo expression of a reporter gene controlled by a single Ci site. Our work clarifies how transcriptional activators and repressors, competing for common binding sites, can transmit positional information to the genome. It also provides an explanation for the widespread presence of conserved, nonconsensus Gli binding sites in Hh target genes. PMID- 21653229 TI - Antigen potency and maximal efficacy reveal a mechanism of efficient T cell activation. AB - T cell activation, a critical event in adaptive immune responses, depends on productive interactions between T cell receptors (TCRs) and antigens presented as peptide-bound major histocompatibility complexes (pMHCs). Activated T cells lyse infected cells, secrete cytokines, and perform other effector functions with various efficiencies, which depend on the binding parameters of the TCR-pMHC complex. The mechanism through which binding parameters are translated to the efficiency of T cell activation, however, remains controversial. The "affinity model" suggests that the dissociation constant (KD) of the TCR-pMHC complex determines the response, whereas the "productive hit rate model" suggests that the off-rate (koff) is critical. Here, we used mathematical modeling to show that antigen potency, as determined by the EC50 (half-maximal effective concentration), which is used to support KD-based models, could not discriminate between the affinity and the productive hit rate models. Both models predicted a correlation between EC50 and KD, but only the productive hit rate model predicted a correlation between maximal efficacy (Emax), the maximal T cell response induced by pMHC, and koff. We confirmed the predictions made by the productive hit rate model in experiments with cytotoxic T cell clones and a panel of pMHC variants. Thus, we propose that the activity of an antigen is determined by both its potency (EC50) and maximal efficacy (Emax). PMID- 21653230 TI - Global rinderpest eradication: lessons learned and why humans should celebrate too. PMID- 21653231 TI - Systemic mast cell degranulation increases mortality during polymicrobial septic peritonitis in mice. AB - MCs are required for an effective host response during septic peritonitis. Local MC degranulation facilitates neutrophil recruitment, activation, and bacterial killing. However, the role of MCs located distant from the site of infection is unknown. We studied the temporal and spacial degranulation of MCs following CLP induced septic peritonitis. The functional importance of systemic MC degranulation during infection was evaluated by compartment-specific MC reconstitution. Serum histamine, reflecting MC degranulation, was elevated 4 h after onset of septic peritonitis. Histologic examination revealed progressive MC degranulation in select tissues during the first 24 h of infection. MC-deficient Wsh mice, reconstituted only in the peritoneal compartment, had improved survival after CLP compared with controls. However, reconstitution in peritoneal plus systemic compartments worsened survival after CLP. IL-6 contributed to the detrimental effects of systemic MCs on survival, as mice systemically reconstituted with IL-6(-/-) MCs were more likely to survive than control mice. These results indicate that in contrast to the benefits of local MC activation during infection, systemic MC activation worsens survival during CLP-induced sepsis. PMID- 21653232 TI - Glia maturation factor-gamma mediates neutrophil chemotaxis. AB - Chemotaxis is fundamental to the directional migration of neutrophils toward endogenous and exogenous chemoattractants. Recent studies have demonstrated that ADF/cofilin superfamily members play important roles in reorganizing the actin cytoskeleton by disassembling actin filaments. GMFG, a novel ADF/cofilin superfamily protein that is expressed in inflammatory cells, has been implicated in regulating actin reorganization in microendothelial cells, but its function in neutrophils remains unclear. Here, we show that GMFG is an important regulator for cell migration and polarity in neutrophils. Knockdown of endogenous GMFG impaired fMLF- and IL-8 (CXCL8)-induced chemotaxis in dHL-60 cells. GMFG knockdown attenuated the formation of lamellipodia at the leading edge of cells exposed to fMLF or CXCL8, as well as the phosphorylation of p38 and PAK1/2 in response to fMLF or CXCL8. Live cell imaging revealed that GMFG was recruited to the leading edge of cells in response to fMLF, as well as CXCL8. Overexpression of GMFG enhanced phosphorylation of p38 but not of PAK1/2 in dHL-60 cells. In addition, we found that GMFG is associated with WAVE2. Taken together, our findings suggest that GMFG is a novel factor in regulating neutrophil chemotaxis by modulating actin cytoskeleton reorganization. PMID- 21653233 TI - Protein kinase Cdelta is a critical component of Dectin-1 signaling in primary human monocytes. AB - Zymosan, a mimic of fungal pathogens, and its opsonized form (ZOP) are potent stimulators of monocyte NADPH oxidase, resulting in the production of O(2)(.-), which is critical for host defense against fungal and bacterial pathogens and efficient immune responses; however, uncontrolled O(2)(.-) production may contribute to chronic inflammation and tissue injury. Our laboratory has focused on characterizing the signal transduction pathways that regulate NADPH oxidase activity in primary human monocytes. In this study, we examined the involvement of various pattern recognition receptors and found that Dectin-1 is the primary receptor for zymosan stimulation of O(2)(.-) via NADPH oxidase in human monocytes, whereas Dectin-1 and CR3 mediate the activation by ZOP. Further studies identified Syk and Src as important signaling components downstream of Dectin-1 and additionally identified PKCdelta as a novel downstream signaling component for zymosan-induced O(2)(.-) as well as phagocytosis. Our results show that Syk and Src association with Dectin-1 is dependent on PKCdelta activity and expression and demonstrate direct binding between Dectin-1 and PKCdelta. Finally, our data show that PKCdelta and Syk but not Src are required for Dectin-1 mediated phagocytosis. Taken together, our data identify Dectin-1 as the major PRR for zymosan in primary human monocytes and identify PKCdelta as a novel downstream signaling kinase for Dectin-1-mediated regulation of monocyte NADPH oxidase and zymosan phagocytosis. PMID- 21653235 TI - Modulation of regulatory T cell-Th17 balance by plasmacytoid dendritic cells. AB - Tregs represent an interesting therapeutic tool to modulate immune responses that could be deleterious in autoimmune diseases and in transplantation. However, phenotype and functions of Tregs do not seem to be stable, and recent data suggest that FoxP3-expressing Tregs can be driven to produce IL-17. In this study, we have analyzed the role of pDCs versus cDCs on Treg responses and underlined that pDCs have an intrinsic, unique capacity to induce IL-17 secretion from T cells. We showed in rats that FoxP3(+) Tregs were able to secrete IL-17 only when stimulated by allogeneic, mature pDCs but not cDCs. In addition, in rats and mice, mature pDCs but not cDCs inhibited in vitro Treg-suppressive functions and in the presence of Tregs, supported Th17 differentiation from naive T cells through secretion of high amounts of IL-6. These data suggest an important role for pDCs in modulating or switching Treg function and allowing Th17 differentiation. PMID- 21653234 TI - 17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of primary human macrophages to purified LPS and live E. coli. AB - Detection and clearance of bacterial infection require balanced effector and resolution signals to avoid chronic inflammation. Detection of GNB LPS by TLR4 on m induces inflammatory responses, contributing to chronic inflammation and tissue injury. LXs and Rvs are endogenous lipid mediators that enhance resolution of inflammation, and their actions on primary human m responses toward GNB are largely uncharacterized. Here, we report that LXA(4), LXB(4), and RvD1, tested at 0.1-1 MUM, inhibited LPS-induced TNF production from primary human m, with ATL and 17(R)-RvD1, demonstrating potent inhibition at 0.1 MUM. In addition, 17(R) RvD1 inhibited LPS-induced primary human m production of IL-7, IL-12p70, GM-CSF, IL-8, CCL2, and MIP-1alpha without reducing that of IL-6 or IL-10. Remarkably, when stimulated with live Escherichia coli, m treated with 17(R)-RvD1 demonstrated increased TNF production and enhanced internalization and killing of the bacteria. 17(R)-RvD1-enhanced TNF, internalization, and killing were not evident for an lpxM mutant of E. coli expressing hypoacylated LPS with reduced inflammatory activity. Furthermore, 17(R)-RvD1-enhanced, E. coli-induced TNF production was evident in WT but not TLR4-deficient murine m. Thus, Rvs differentially modulate primary human m responses to E. coli in an LPS- and TLR4 dependent manner, such that this Rv could promote resolution of GNB/LPS-driven inflammation by reducing m proinflammatory responses to isolated LPS and increasing m responses important for clearance of infection. PMID- 21653236 TI - Specificity of eicosanoid production depends on the TLR-4-stimulated macrophage phenotype. AB - Eicosanoid metabolism differs in profile and quantity between macrophages of different tissue origin and method of elicitation, as well as between primary and immortalized macrophages after activation with inflammatory stimuli. Using a lipidomic approach, we comprehensively analyzed the eicosanoids made by murine RPMs, TGEMs, BMDM, and the macrophage-like cell line RAW after stimulation with the TLR-4-specific agonist KLA. Direct correlation among total COX metabolites, COX side-products (11-HETE, 15-HETE), COX-2 mRNA, and protein at 8 h was found when comparing each cell type. Comprehensive qPCR analysis was used to compare relative transcript levels between the terminal prostanoid synthases themselves as well as between each cell type. Levels of PGE(2), PGD(2), and TxB(2) generally correlated with enzyme transcript expression of PGES, PGDS, and TBXS, providing evidence of comparable enzyme activities. PGIS transcript was expressed only in RPM and TGEM macrophages and at an exceptionally low level, despite high metabolite production compared with other synthases. Presence of PGIS in RPM and TGEM also lowered the production of PGE(2) versus PGD(2) by approximately tenfold relative to BMDM and RAW cells, which lacked this enzyme. Our results demonstrate that delayed PG production depends on the maximal level of COX-2 expression in different macrophages after TLR-4 stimulation. Also, the same enzymes in each cell largely dictate the profile of eicosanoids produced depending on the ratios of expression between them, with the exception of PGIS, which appears to have much greater synthetic capacity and competes selectively with mPGES-1. PMID- 21653237 TI - Technical advance: immunophenotypical characterization of human neutrophil differentiation. AB - The current study reports a flow cytometry-based protocol for the prospective purification of human BM populations representing six successive stages of terminal neutrophil differentiation, including early promyelocytes and late promyelocytes, myelocytes, metamyelocytes, band cells, and PMN neutrophilic granulocytes. Validation experiments revealed a high purity of each bone marrow population and biological meaningful expression profiles for marker genes of neutrophil differentiation at a hitherto unprecedented resolution. Hence, the present protocol should be useful for studying neutrophil differentiation in vivo in the human setting and constitutes an important alternative to models that are based on in vitro differentiation of myeloid cell lines and HPCs. PMID- 21653239 TI - Nod-like receptors in intestinal homeostasis, inflammation, and cancer. AB - NLRs have been shown in a number of models to protect against microbial infection through their ability to participate in "pattern recognition" and their triggering of inflammatory pathways to control infection. Over the past few years, however, the role of NLRs, especially Nod1, Nod2, and NLRP3, in intestinal homeostasis has been highlighted. Indeed, these specific NLRs have been implicated in IBD, in particular, the association of Nod2 with CD, yet a clear understanding of how dysfunctional NLR activation leads to aberrant inflammation is still the focus of much investigation. In this review, we will examine how NLRs participate in the maintenance of gut homeostasis and how upset of this regulation can tip the balance toward chronic inflammation and intestinal cancer. PMID- 21653238 TI - Technical advance: soluble OX40 molecule mimics regulatory T cell modulatory activity on FcepsilonRI-dependent mast cell degranulation. AB - Tregs play a central role in modulating FcepsilonRI-dependent MC effector functions in the course of the allergic response. Cellular interaction depends on the constitutive expression of OX40 on Tregs and the OX40L counterpart on MCs. Study of OX40L signaling on MCs is hampered by the need of a highly purified molecule, which triggers OX40L specifically. We now report that sOX40 mimics the physiological activity of Treg interaction by binding to activated MCs. When treated with sOX40, activated MCs showed decreased degranulation and Ca(++) influx, whereas PLC-gamma2 phosphorylation remained unaffected. Once injected into experimental animals, sOX40 not only located within the endothelium but also in parenchyma, where it could be found in close proximity and apparently bound to MCs. This soluble molecule triggers MC-OX40L without the requirement of Tregs, thus allowing study of OX40L signaling pathways in MCs and in other OX40L expressing cell populations. Importantly, as sOX40 inhibits MC degranulation, it may provide an in vivo therapeutic tool in allergic disease. PMID- 21653240 TI - Frequencies of FoxP3+ naive T cells are related to both viral load and naive T cell proliferation responses in HIV disease. AB - HIV infection results in depletion and dysfunction of naive CD4(+) T cells. The mechanisms underlying these deficiencies are not understood. We investigated the frequencies of CD4(+) naive subsets in HIV disease as defined by expression of CD25 and/or FoxP3 and the relationship of these frequencies to naive T cell proliferation function. We observed increased proportions of CD25(+)FoxP3(+) and CD25(+)FoxP3(-) cells and decreased proportions of CD25(-)FoxP3(-) cells within the naive CD4(+) cell compartment from HIV-infected persons compared with findings in healthy donors. These perturbations were related to higher plasma HIV RNA levels but not with higher immune activation, as measured by the proportions of CD38(+) memory CD4(+) T cells. Naive T cell proliferation responses to mitogen stimulation were inversely related to the frequencies and absolute numbers of FoxP3(+) naive T cells. MDA, a marker of oxidative stress, and sCD14, a marker of monocyte activation and a surrogate for microbial translocation, were increased in serum samples from HIV(+) donors; however, neither marker was related to naive T cell function in HIV(+) donors. These observations suggest that alterations in naive T cell subset frequencies could contribute to naive T cell dysfunction in HIV disease, but these alterations are not necessarily the result of chronic immune activation. PMID- 21653241 TI - Effects of mother's dietary exposure to acesulfame-K in Pregnancy or lactation on the adult offspring's sweet preference. AB - This study investigates whether mother's exposure to the artificial sweetener acesulfame-K (AK) during pregnancy or lactation affected her adult offspring's sweet preference. It was found that mother's dietary exposure to AK in pregnancy or lactation decreased the preference thresholds for AK and sucrose solutions in the adult offspring, whereas the preference pattern and the most preferred concentration for AK or sucrose solution were unchanged. Furthermore, the preference scores in the exposure groups were increased significantly when compared with the control group at a range of concentrations for AK or sucrose solution. The existence of AK and its dynamic changes within 24 h in amniotic fluid during pregnancy or in mother's milk during lactation after a single oral infusion of AK solution were revealed by the methods of reversed-phase high performance liquid chromatography and mass spectrometry. Our data suggest that AK can be ingested by the prenatal or postnatal mice through their mother's amniotic fluid or breast milk, producing a long-dated function on the adult's sweet preference. PMID- 21653242 TI - Appetitive and aversive learning in Spodoptera littoralis larvae. AB - Adult Lepidoptera are capable of associative learning. This helps them to forage flowers or to find suitable oviposition sites. Larval learning has never been seriously considered because they have limited foraging capabilities and usually depend on adults as concerns their food choices. We tested if Spodoptera littoralis larvae can learn to associate an odor with a tastant using a new classical conditioning paradigm. Groups of larvae were exposed to an unconditioned stimulus (US: fructose or quinine mixed with agar) paired with a conditioned stimulus (CS: hexanol, geraniol or pentyl acetate) in a petri dish. Their reaction to CS was subsequently tested in a petri dish at different time intervals after conditioning. Trained larvae showed a significant preference or avoidance to CS when paired with US depending on the reinforcer used. The training was more efficient when larvae were given a choice between an area where CS-US was paired and an area with no CS (or another odor). In these conditions, the memory formed could be recalled at least 24 h after pairing with an aversive stimulus and only 5 min after pairing with an appetitive stimulus. This learning was specific to CS because trained larvae were able to discriminate CS from another odor that was present during the training but unrewarded. These results suggest that Lepidoptera larvae exhibit more behavioral plasticity than previously appreciated. PMID- 21653243 TI - A social public health. PMID- 21653244 TI - The effect of HIV field-based testing on the proportion of notified partners who test for HIV in New York City. AB - HIV partner services can effectively reach populations with high HIV prevalence. However, located and notified sex and needle-sharing partners of persons infected with HIV often fail to test. Field testing may increase the proportion of notified partners who test for HIV. In 2008, New York City's health department incorporated field testing into partner services. After the introduction of field testing, the proportion of notified partners who tested for HIV rose from 52% to 76% (P<.001). HIV prevalence fell slightly among notified partners who accepted testing (12% to 9%, P=.82), but we identified more than double the number of new positives (11 vs 25). All positive and 97% of negative results were received by the person tested. PMID- 21653245 TI - Tuberculosis in racial types with special reference to Mexicans. 1929. PMID- 21653246 TI - Changing the patterns in international health: motivation and relationships. 1979. PMID- 21653247 TI - Carl E. Taylor, (1916-2010): a beloved pioneer in international health. PMID- 21653248 TI - Pregnant women's and community health workers' perceptions of root causes of malnutrition among infants and young children in the slums of Dhaka, Bangladesh. AB - Research in Bangladesh shows that malnutrition among infants and young children is most severe in urban slums. We examined the root causes of malnutrition as perceived by pregnant women and community health workers. We conducted 10 focus group discussions in the slums of Dhaka in 2008 and 2009. Participants accurately perceived inappropriate care, inappropriate environment, inappropriate food, and flooding to be major causes. Recurrent flooding has not traditionally been identified by experts as a cause of malnutrition. We recommend further research to address the nutritional risks flooding creates for vulnerable slum populations. PMID- 21653249 TI - Screening for tuberculosis at an adult education center: results of a community based participatory process. AB - OBJECTIVES: We used a community-based participatory research (CBPR) approach to plan and implement free TB skin testing at an adult education center to determine the efficacy of CBPR with voluntary tuberculosis (TB) screening and the prevalence of TB infection among immigrant and refugee populations. METHODS: We formed a CBPR partnership to address TB screening at an adult education center that serves a large immigrant and refugee population in Rochester, Minnesota. We conducted focus groups involving educators, health providers, and students of the education center, and used this input to implement TB education and TB skin testing among the center's students. RESULTS: A total of 259 adult learners volunteered to be skin-tested in April 2009; 48 (18.5%) had positive TB skin tests. CONCLUSIONS: Our results imply that TB skin testing at adult education centers that serve large foreign-born populations may be effective. Our findings also show that a participatory process may enhance the willingness of foreign born persons to participate in TB skin-testing efforts. PMID- 21653250 TI - Staphylococcus aureus colonization and infection among drug users: identification of hidden networks. AB - OBJECTIVES: We combined social-network analysis and molecular epidemiology to investigate Staphylococcus aureus among drug users. METHODS: From 2003 through 2005, we recruited adult drug users in Brooklyn, New York. Of 501 individuals recruited, 485 participated. Participants were screened for HIV infection and S. aureus carriage, and they answered a questionnaire assessing risk factors for S. aureus. Participants were asked to nominate up to 10 members of their social networks, and they were invited to recruit nominees to participate. RESULTS: We identified 89 sociocentric risk networks, 1 of which contained 327 (67%) members. One third of participants were either colonized (20%) or infected (19%) with S. aureus. Overall strain similarity was unusually high, suggesting spread within and across networks. In multivariate analysis, 7 health-related and drug-use variables remained independently associated with infection. Moreover, 27% of nominees were not drug users. CONCLUSIONS: We found a large, linked, hidden network among participants, with no discernible clustering of closely related strains. Our results suggest that once a pathogen is introduced into a sociocentric network of active drug users, an identifiable community S. aureus reservoir is likely created, with significant linkages to the general population. PMID- 21653251 TI - What's in a name: integrative medicine or simply good medical practice? AB - OBJECTIVE: Integrative medicine, a popular movement in the USA and Europe, is taught in many US medical schools. This study describes how Australian doctors define integrative medicine, what motivates them to work in integrative medicine and the incorporation of complementary and alternative medicines (CAM) into their practice. METHODS: Semi-structured interviews were conducted between May and December 2009 with 23 doctors in two Australian states working in integrative medicine. A thematic analysis of interview transcripts was undertaken. RESULTS: Doctors' interpretations of the term 'integrative medicine' varied considerably. All maintained a strong belief in the usefulness of conventional medicine, while a holistic and patient-centred approach, promoting well-being, was central to their practice. Doctors' motivations for choosing an integrative approach to their practice of medicine also varied, but personal and professional experiences of alternative approaches to illness were influential in this decision. The nature of their clinical practice was also diverse; few doctors in this sample practice or professionally use CAM; a small number were happy to advise patients on the use of different modalities while even less referred to complementary practitioners. CONCLUSIONS: The concept and practice of integrative medicine among the doctors interviewed were diverse. This has implications for the Royal Australian College of General Practitioners inclusion criteria for the membership of their integrative medicine chapter. More broadly, the findings have implications for all medical practice and the education of medical students, as much of what integrative medicine doctors do may be considered simply as 'good medical practice'. PMID- 21653252 TI - De novo discovery of mutated driver pathways in cancer. AB - Next-generation DNA sequencing technologies are enabling genome-wide measurements of somatic mutations in large numbers of cancer patients. A major challenge in the interpretation of these data is to distinguish functional "driver mutations" important for cancer development from random "passenger mutations." A common approach for identifying driver mutations is to find genes that are mutated at significant frequency in a large cohort of cancer genomes. This approach is confounded by the observation that driver mutations target multiple cellular signaling and regulatory pathways. Thus, each cancer patient may exhibit a different combination of mutations that are sufficient to perturb these pathways. This mutational heterogeneity presents a problem for predicting driver mutations solely from their frequency of occurrence. We introduce two combinatorial properties, coverage and exclusivity, that distinguish driver pathways, or groups of genes containing driver mutations, from groups of genes with passenger mutations. We derive two algorithms, called Dendrix, to find driver pathways de novo from somatic mutation data. We apply Dendrix to analyze somatic mutation data from 623 genes in 188 lung adenocarcinoma patients, 601 genes in 84 glioblastoma patients, and 238 known mutations in 1000 patients with various cancers. In all data sets, we find groups of genes that are mutated in large subsets of patients and whose mutations are approximately exclusive. Our Dendrix algorithms scale to whole-genome analysis of thousands of patients and thus will prove useful for larger data sets to come from The Cancer Genome Atlas (TCGA) and other large-scale cancer genome sequencing projects. PMID- 21653253 TI - A novel late embryogenesis abundant like protein associated with chilling stress in Nicotiana tabacum cv. bright yellow-2 cell suspension culture. AB - Low temperature is one of the major abiotic stresses limiting the productivity and geographical distribution of many important crops. To identify proteins associated with chilling stress in Nicotiana tabacum cv. bright yellow-2 (BY-2) cell suspension culture, we utilized a proteomic approach with two-dimensional electrophoresis to compare proteins from samples of treated with or without chilling treatment at 4 degrees C. One protein specifically more abundant in chilling treated sample was identified and designated as NtLEA7-3. Rapid amplification of cDNA ends gave rise to a full-length NtLEA7-3 cDNA with a complete open reading frame of 1267 bp, encoding a 322 amino acid polypeptide. Homology search and sequence multi-alignment demonstrated that the deduced NtLEA7 3 protein sequence shared a high identity with LEA-like proteins from other plants. Subcellular localization analysis indicated that the NtLEA7-3 was localized exclusively in the nucleus. When the gene was overexpressed in bright yellow-2 cells, the transgenic bright yellow-2 cells show more resistant to chilling stress than the wild-type cells. In addition, transgenic Arabidopsis plants overexpressing the NtLEA7-3 are much more resistant to cold, drought, and salt stresses. Interestingly, the expression of NtLEA7-3 in tobacco was not tissue-specific and induced by chilling, drought and salt stresses. All of these, taken together, suggest that NtLEA7-3 is worthwhile to elucidate the contribution of the proteins to the tolerance mechanism to chilling stress, and can be considered as a potential target for crop genetic improvement in the future. PMID- 21653255 TI - Mental health rehabilitation of detained juveniles: using time wisely. PMID- 21653256 TI - Sexual boundary violations committed by female forensic workers. AB - A vast literature has focused on sexual boundary violations in professional practice. Much of this analysis has focused on the intersection between gender and professional authority in cases of misconduct committed by male professionals against female clients and patients. Although certainly of importance, such power based gender analysis may overlook instances of misconduct in which a female professional engages in a sexual encounter with a male client. This article provides a review and analysis of the literature regarding sexual misconduct committed by female forensic workers. Aspects considered include the characteristics of the male forensic patient or prisoner, the characteristics of the female forensic worker, the organizational milieu, and the consequences of the misconduct. Recommendations for practice are offered. PMID- 21653254 TI - Integrated proteomic profiling of cell line conditioned media and pancreatic juice for the identification of pancreatic cancer biomarkers. AB - Pancreatic cancer is one of the leading causes of cancer-related deaths, for which serological biomarkers are urgently needed. Most discovery-phase studies focus on the use of one biological source for analysis. The present study details the combined mining of pancreatic cancer-related cell line conditioned media and pancreatic juice for identification of putative diagnostic leads. Using strong cation exchange chromatography, followed by LC-MS/MS on an LTQ-Orbitrap mass spectrometer, we extensively characterized the proteomes of conditioned media from six pancreatic cancer cell lines (BxPc3, MIA-PaCa2, PANC1, CAPAN1, CFPAC1, and SU.86.86), the normal human pancreatic ductal epithelial cell line HPDE, and two pools of six pancreatic juice samples from ductal adenocarcinoma patients. All samples were analyzed in triplicate. Between 1261 and 2171 proteins were identified with two or more peptides in each of the cell lines, and an average of 521 proteins were identified in the pancreatic juice pools. In total, 3479 nonredundant proteins were identified with high confidence, of which ~ 40% were extracellular or cell membrane-bound based on Genome Ontology classifications. Three strategies were employed for identification of candidate biomarkers: (1) examination of differential protein expression between the cancer and normal cell lines using label-free protein quantification, (2) integrative analysis, focusing on the overlap of proteins among the multiple biological fluids, and (3) tissue specificity analysis through mining of publically available databases. Preliminary verification of anterior gradient homolog 2, syncollin, olfactomedin 4, polymeric immunoglobulin receptor, and collagen alpha-1(VI) chain in plasma samples from pancreatic cancer patients and healthy controls using ELISA, showed a significant increase (p < 0.01) of these proteins in plasma from pancreatic cancer patients. The combination of these five proteins showed an improved area under the receiver operating characteristic curve to CA19.9 alone. Further validation of these proteins is warranted, as is the investigation of the remaining group of candidates. PMID- 21653257 TI - Commentary: Boundary violations in the correctional versus therapeutic setting- are the standards the same? AB - Education and training provide psychotherapists with tools for self-awareness which help to prevent boundary violations. Corrections officers are not similarly equipped and therefore should not be held to the same standard, particularly when they are being subjected to abuse and intimidation. While it is important to understand gender-specific patterns which lead to boundary violations in correctional and forensic settings, the differences in occupational roles should be considered when examining ethics-based responsibilities. PMID- 21653258 TI - Commentary: Female forensic worker sexual misconduct--who is the captive? AB - The risk of sexual misconduct by forensic professionals appears at first glance to be far less than the risk of sexual misconduct by other clinical professionals. Yet, Faulkner and Regehr's article draws our attention to the unique and intriguing situation of females working in forensic settings and the very real risk of their engaging in sexual misconduct with male prisoners. The female workers described are professionals: nurses, prison staff, and security officers. Analogies are made between Gabbard's proposed categories of professionals who commit sexual boundary violations and groups of female forensic workers' sexual misconduct with male prisoners. Faulkner and Regehr detail the characteristics of prisoners and the prison setting and how they relate to detrimental interpersonal behavior by female forensic workers. The role of security officers is discussed along with the need for policy-makers to minimize the risks inherent in working with incarcerated populations. The potential for gender-biased explanations of misconduct among female forensic workers is also considered. PMID- 21653259 TI - Brief Rating of Aggression by Children and Adolescents (BRACHA): development of a tool for assessing risk of inpatients' aggressive behavior. AB - This study evaluated the Brief Rating of Aggression by Children and Adolescents Preliminary Version (BRACHA 0.8), an actuarial method of assessing the risk of aggressive behavior by hospitalized children and adolescents. Licensed psychiatric social workers used a 16-item questionnaire to assess all patients seen in the emergency department (ED) of a major urban children's hospital. Over a six-month period, 418 patients (age range, 3.5-19.0 years) underwent psychiatric hospitalization after ED evaluation. The hospital nursing staff recorded the inpatients' behavior, with the Overt Aggression Scale (OAS). Inpatients were deemed aggressive if, during the first six days of their hospital stay, they scored one or higher on any OAS subscale. We evaluated questionnaire properties, items, and demographic covariates (e.g., age, sex, and living situation) by using factor analyses, logistic regression models, and receiver operating characteristic (ROC) methods. A total of 292 aggressive acts were committed by 120 (29% of 418) patients. Fourteen of the 16 items predicted (p < .007) inpatient aggression and showed good internal consistency (Cronbach's alpha = 0.837). Age was inversely related to probability of aggression and was incorporated into the final assessment instrument. Predictive power was comparable with other published risk assessment instruments (ROC areas of .75 for any aggression and .82 for aggression toward others). BRACHA 0.8 shows promise in rapidly assessing risk of inpatient aggression, but further studies are needed to establish the reliability and validity of the instrument. PMID- 21653260 TI - Commentary: Predicting aggression in youth. AB - Aggression in youth is common and encompasses a wide range of behaviors that vary along such dimensions as direction (toward self or others), degree of action (ideation, verbal threats, or actual assaults), degree of planning (reactive or impulsive, planned or predatory), system level (biological, psychological, or social), and seriousness of intent. Risk factors vary, depending on the range of behavior being predicted and the developmental level of the youth being assessed. The Brief Rating of Aggression by Children and Adolescents (BRACHA) shows promise for assessing the general risk of aggressiveness in a developmentally diverse child and adolescent inpatient population. Further research may show whether patterns of risk factors also have treatment and prognostic implications that will aid in working with this population. PMID- 21653261 TI - Evaluating psychiatric disability: differences by forensic expertise. AB - The task of evaluating psychiatric disability poses several ethics-related and practical challenges for psychiatrists, especially when they are responding to a request from a third party for a disability evaluation on their own patient. This study sought to evaluate the differences in how forensic and nonforensic psychiatrists approach and view evaluations for Social Security disability benefits. Thirty-two forensic and 75 nonforensic psychiatrists were surveyed on their practice patterns and perceptions of role, objectivity, and dual agency in the disability evaluation process. Significant differences were found between forensic and nonforensic psychiatrists' perceptions of the dual-agency conflict, beliefs about who should perform evaluations, and beliefs about the weight given to different opinions when decisions of whether to award disability benefits are made. A minority of respondents in both groups reported having identified a patient as disabled, despite believing otherwise. The implications of these findings are discussed. PMID- 21653262 TI - Commentary: Challenges in providing psychiatric disability evaluations. AB - Christopher et al., in their study of differences between general psychiatrists and forensic psychiatrists in the evaluation of psychiatric disability relative to Social Security Disability Insurance claims, have provided useful information regarding statistically significant differences in practice and beliefs. Despite the relatively small number of participants in this unique survey study, the authors have identified important sources of potential bias among both general and forensic psychiatrists. The study also highlights the profound disconnect between the historically prevalent medical model of disability, in which treating clinicians are considered experts in assessing disability, and the actuality that most general and forensic psychiatrists lack training in disability evaluations. This misperception creates additional practical and ethics-related problems for clinicians when their patients file disability claims. PMID- 21653263 TI - Commentary: Disability evaluations--are the evaluators able? AB - Disability assessments of patients are among the most common nontherapeutic evaluations requested of treating psychiatrists. Yet, there has been relatively little empirical analysis of how psychiatrists approach these evaluations in real clinical practice. Treating psychiatrists, those both with and without forensic expertise, struggle with the challenge of dual agency and overlapping therapeutic and forensic roles. Making the different roles clear to the patient can allow for more therapeutic exploration and alliance around further treatment goals, expectations, and interventions. Given the high prevalence of psychiatric disability and requested evaluations, psychiatric trainees would benefit from formal teaching, and it should be considered an important area for psychiatric continuing education. PMID- 21653264 TI - Male victims of sexual assault: phenomenology, psychology, physiology. AB - Myths, stereotypes, and unfounded beliefs about male sexuality, in particular male homosexuality, are widespread in legal and medical communities, as well as among agencies providing services to sexual assault victims. These include perceptions that men in noninstitutionalized settings are rarely sexually assaulted, that male victims are responsible for their assaults, that male sexual assault victims are less traumatized by the experience than their female counterparts, and that ejaculation is an indicator of a positive erotic experience. As a result of the prevalence of such beliefs, there is an underreporting of sexual assaults by male victims; a lack of appropriate services for male victims; and, effectively, no legal redress for male sexual assault victims. By comparison, male sexual assault victims have fewer resources and greater stigma than do female sexual assault victims. Many male victims, either because of physiological effects of anal rape or direct stimulation by their assailants, have an erection, ejaculate, or both during the assault. This is incorrectly understood by assailant, victim, the justice system, and the medical community as signifying consent by the victim. Studies of male sexual physiology suggest that involuntary erections or ejaculations can occur in the context of nonconsensual, receptive anal sex. Erections and ejaculations are only partially under voluntary control and are known to occur during times of extreme duress in the absence of sexual pleasure. Particularly within the criminal justice system, this misconception, in addition to other unfounded beliefs, has made the courts unwilling to provide legal remedy to male victims of sexual assault, especially when the victim experienced an erection or an ejaculation during the assault. Attorneys and forensic psychiatrists must be better informed about the physiology of these phenomena to formulate evidence-based opinions. PMID- 21653265 TI - Commentary: Causes and consequences of male adult sexual assault. AB - Bullock and Beckson add to a growing body of literature on the negative consequences of adult sexual assault on male victims. There are similarities as well as important differences between male sexual assault victims and their female counterparts. Their analyses of societal contributions and myths about adult male sexual assault and of the difficulties that male victims experience in accessing and interacting with the medical and legal systems improve professional understanding of this complex subject. PMID- 21653266 TI - The probate judge and involuntary civil commitment in South Carolina. AB - Previous studies have scrutinized the decision-making process of physicians involved in the civil commitment of mentally ill persons, but few have examined the process used by probate judges when deciding to issue orders of detention and when conducting commitment hearings. This study consisted of a written survey sent to all probate court judges (n = 68) in South Carolina. Factors examined in the survey included the education and experience of the judges, their approach to the decision-making process, their view of lay and expert testimony at commitment hearings, and their knowledge about four items: two common psychiatric terms (delusion and psychosis), the leading suicide risk factor (previous attempt), and the standard of proof required for civil commitment (clear and convincing evidence). We attempt to analyze existing training standards for South Carolina probate judges and to explore possible areas for improvement so that proper dispositions of emergency psychiatric detainees are made and overcrowded emergency centers are less burdened. PMID- 21653267 TI - Managing negative reactions in forensic trainees. AB - The treatment of adolescent offenders often provokes strong feelings in providers on the treatment team. These feelings, or countertransference reactions, can hinder effective patient care. However, with supervision and acknowledgment, these reactions can also be used effectively in becoming aware of the patient's internal state. In this article, a resident and her supervisor discuss reactions to a particular patient on a subacute unit for adolescent offenders. We also discuss methods of teaching trainees to recognize these countertransference reactions and to work through them to provide more effective patient care. PMID- 21653268 TI - Throwing the baby out with the bath water: is it time for clinical judgment to supplement actuarial risk assessment? AB - The assessment of the potential for sexual violence is one of three prongs that must be met to satisfy the requirements for civil confinement of dangerous sex offenders in the 21 U.S. jurisdictions that have these laws. In a recent issue of The Journal, Sreenivasan et al. argued that, because of a host of methodological problems, actuarial risk assessment methods in general and the Static-99 and its progeny in particular are insufficient for accurate assessment of risk for dangerous sex offenders. They propose using a combination of clinical judgment with actuarial science as a solution. This analysis and review of Sreenivasan et al. reveals and corrects flaws in the arguments they employed to support their position and shows how the combination of actuarial science with clinical judgment is more error prone than the actuarial approach only, and cannot be forensically defended in court. Recommendations on reporting Static-99R data in expert testimony are provided, taking into account the limitations of the instrument. PMID- 21653269 TI - Autonomy, criminal responsibility, and competence. AB - Recently, Juth and Lorentzon proposed to replace the concept of free will, as considered relevant in criminal responsibility, with the concept of autonomy. In addition, they conceived of the assessment of criminal responsibility in terms of a decision-making process. In this article, I suggest that, based on these characterizations, there is an essential similarity between assessments of criminal responsibility and assessments of competent decision-making within the context of informed consent. In both assessments, autonomy and decision-making would be central factors. If one accepts this basic similarity, I argue, interesting opportunities are opened up in the sense that research on criminal responsibility could be directly informed by research on competent decision making. PMID- 21653270 TI - Critical appraisals of the proposed DSM-5 paraphilia diagnoses. PMID- 21653271 TI - Forensic and diagnostic concerns arising from the proposed DSM-5 criteria for sexual paraphilic disorder. AB - This article reviews proposed revisions to the DSM-5 diagnostic criteria for the paraphilic disorders. It is argued that the proposed revisions will decrease the diagnostic accuracy of the diagnoses. A more effective diagnostic scheme is suggested. PMID- 21653272 TI - Commentary on pedophilia diagnostic criteria in DSM-5. AB - Human beings differ in sexual makeup. Most adults are not sexually attracted to prepubescent children, but some are. Societal values can be of relevance in determining whether such a difference is considered to be a psychiatric condition. Were a society to believe that adult-child sexual interactions should not be prohibited, such a difference might not be viewed as a disorder. According to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), a difference in sexual makeup can be considered a disorder when it causes interpersonal difficulty or marked distress. In contemporary society, pedophilia can do both. According to DSM-IV-TR, for a diagnosis of pedophilia, there must be both a qualitative difference in sexual makeup (i.e., sexualized urges directed toward children) and a quantitative difference (i.e., the sexualized urges must be intense). However, just as a heterosexual man with low (i.e., nonintense) sexual urges is still heterosexual, DSM-5 should similarly allow that individuals with low sexual urges in response to children qualify for a diagnosis of pedophilia. PMID- 21653273 TI - Sexual disorders: new and expanded proposals for the DSM-5--do we need them? AB - The sexual disorders in the current and proposed DSM contain a potpourri of categories that increasingly intersect with the criminal justice system. Caveats saying the DSM is designed for clinical and not legal purposes notwithstanding, our classification system has difficulty distinguishing what we consider criminal behavior from culturally unacceptable behavior and mental disorder. Several current proposals continue this trend and seem more responsive to criminal justice concerns than mental illness considerations. They also lack sufficient specificity to warrant being called a disorder. PMID- 21653274 TI - The inclusion of child pornography in the DSM-5 diagnostic criteria for pedophilia: conceptual and practical problems. AB - The proposal to add use of child pornography to Criterion B of pedophilia is in direct conflict with the newly proposed distinction between paraphilia and paraphilic disorder, muddying rather than clarifying the diagnostic definition of pedophilia. The proposal to distinguish paraphilic disorder from paraphilia derives from the fact that the diagnostic criteria for the paraphilias have two components: Criterion A, defining the presence of a paraphilic erotic interest, and Criterion B, requiring clinically significant distress, impairment, or acting out the paraphilia with a nonconsenting person. Meeting Criteria A and B is necessary for a diagnosis of paraphilic disorder; meeting only Criterion A indicates a paraphilia. Use of pornography is better placed within Criterion A, perhaps as an example of a behavioral manifestation of pedophilia. If the Sexual and Gender Identity Disorders Work Group's true intent was to add a third prong to Criterion B, then the criterion must be modified to restrict it to the use of illegal forms of pornography (i.e., visual depictions of real children), excluding written or aural forms or virtual images. PMID- 21653275 TI - Classically insane. PMID- 21653276 TI - Stigma and violence: isn't it time to connect the dots? AB - Stigma against mentally ill persons is a major problem and has increased in incidence. Multiple studies have suggested that the perception of violent behavior by seriously mentally ill individuals is an important cause of stigma. It is also known that treating seriously mentally ill people decreases violent behavior. Therefore, the most effective way to decrease stigma is to make sure that patients receive adequate treatment. PMID- 21653277 TI - A genome-wide quantitative linkage scan of niacin skin flush response in families with schizophrenia. AB - Schizophrenia patients frequently display reduced niacin flush responses, and similar characteristics are also observed in their nonpsychotic relatives. This study aimed to identify loci influencing flush response to niacin in schizophrenia using genome-wide quantitative linkage scan. In a nationwide sample of families with at least 2 siblings affected with schizophrenia in each family, 115 families that had at least 2 affected siblings with information on the niacin skin test were subjected to quantitative trait loci linkage analysis, either involving affected individuals only or the whole family. Nonparametric linkage z (NPL-Z) scores were calculated for each of 386 microsatellite markers spaced at an average of 9-cM intervals. Niacin patches of 3 concentrations (0.001 M, 0.01, and 0.1 M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Determination of genome wide empirical significance was implemented using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified at chromosomal region 14q32.12 for 0.01 M concentration at 5 minutes (NPL-Z scores = 3.39, genome-wide empirical P = .03) in affected individuals, and the corresponding linkage signal remained strong (NPL-Z scores = 2.87) for the analyses of the whole family. This locus is distinct from the chromosomal region identified in the previous genome-wide scan for the diagnosis of schizophrenia, and the signal was higher than the peak linkage signal in that study. These findings indicate that there might be modifier or susceptibility-modifier genes at 14q32.12 for schizophrenia-related attenuation of flush response to niacin. PMID- 21653278 TI - High vs low frequency neural oscillations in schizophrenia. AB - There is growing recognition that neural oscillations are important in a wide range of perceptual and cognitive functions. One of the key issues in electrophysiological studies of schizophrenia is whether high or low frequency oscillations, or both, are related to schizophrenia because many brain functions are modulated with frequency specificities. Many recent electrophysiological studies of schizophrenia have focused on high frequency oscillations at gamma band and in general support gamma band dysfunction in schizophrenia. We discuss the concept that gamma oscillation abnormalities in schizophrenia often occur in the background of oscillation abnormalities of lower frequencies. The review discusses the basic neurobiology for the emergence of oscillations of all frequency bands in association with networks of inhibitory interneurons and the convergence and divergence of such mechanisms in generating high vs low frequency oscillations. We then review the literature of oscillatory frequency abnormalities identified in each frequency band in schizophrenia. By describing some of the key functional roles exerted by gamma, low frequencies, and their cross-frequency coupling, we conceptualize that even isolated alterations in gamma or low frequency oscillations may impact the interactions of high and low frequency bands that are involved in key cognitive functions. The review concludes that studying the full spectrum and the interaction of gamma and low frequency oscillations may be critical for deciphering the complex electrophysiological abnormalities observed in schizophrenia patients. PMID- 21653279 TI - Interleukin 1 beta (IL1B) promoter polymorphism and cancer risk: evidence from 47 published studies. AB - Interleukin 1beta (IL-1B) is a pro-inflammatory cytokine against infection, playing an important role in the pathogenesis of cancers. The -31T/C polymorphism of the interleukin 1beta gene (IL1B) has been implicated in cancer risk through its influence on the IL1B transcription. However, results from studies are conflicting. To clarify the association, a meta-analysis was performed for 11 125 cases and 14 415 controls from 47 published case-control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. No significant associations were observed for total cancer from all the comparisons. Through the stratified analyses, there was a statistically significant decreased risk of hepatocellular cancer in carriers of the C allele than non-carriers (CC versus TT: OR = 0.87, 95% CI: 0.77-0.98, P(heterogeneity) = 0.103; TC versus TT: OR = 0.77, 95% CI: 0.62-0.95, P(heterogeneity) = 0.734; TC + CC versus TT: OR = 0.74, 95% CI: 0.61-0.91, P(heterogeneity) = 0.472). Similarly, decreased risk was observed for gastric cancer of the C/C genotype compared with the T/T genotype (OR = 0.87, 95% CI: 0.77-0.98, P(heterogeneity) = 0.103). Using the recessive model, a significantly decreased risk was observed for gastric cancer (OR = 0.88, 95% CI: 0.80-0.97, P(heterogeneity) = 0.158), European population (OR = 0.84, 95% CI: 0.73-0.97, P(heterogeneity) = 0.070) and positive infection-matched studies (OR = 0.75, 95% CI: 0.60-0.94, P(heterogeneity) = 0.220); however, an increased risk was found for breast cancer (OR = 1.34, 95% CI: 1.18-1.61, P(heterogeneity) = 0.116). Although some modest bias could not be eliminated, this meta-analysis suggests that the IL1B -31C allele is a low penetrance protective factor for the development of cancer, in particular for that associated with infection. PMID- 21653280 TI - The Psb32 protein aids in repairing photodamaged photosystem II in the cyanobacterium Synechocystis 6803. AB - Photosystem II (PSII), a membrane protein complex, catalyzes the photochemical oxidation of water to molecular oxygen. This enzyme complex consists of approximately 20 stoichiometric protein components. However, due to the highly energetic reactions it catalyzes as part of its normal activity, PSII is continuously damaged and repaired. With advances in protein detection technologies, an increasing number of sub-stoichiometric PSII proteins have been identified, many of which aid in the biogenesis and assembly of this protein complex. Psb32 (Sll1390) has previously been identified as a protein associated with highly active purified PSII preparations from the cyanobacterium Synechocystis sp. PCC 6803. To investigate its function, the subcellular localization of Psb32 and the impact of deletion of the psb32 gene on PSII were analyzed. Here, we show that Psb32 is an integral membrane protein, primarily located in the thylakoid membranes. Although not required for cell viability, Psb32 protects cells from oxidative stress and additionally confers a selective fitness advantage in mixed culture experiments. Specifically, Psb32 protects PSII from photodamage and accelerates its repair. Thus, the data suggest that Psb32 plays an important role in minimizing the effect of photoinhibition on PSII. PMID- 21653281 TI - Analysis of gene expression patterns during seed coat development in Arabidopsis. AB - The seed coat is important for embryo protection, seed hydration, and dispersal. Seed coat composition is also of interest to the agricultural sector, since it impacts the nutritional value for humans and livestock alike. Although some seed coat genes have been identified, the developmental pathways controlling seed coat development are not completely elucidated, and a global genetic program associated with seed coat development has not been reported. This study uses a combination of genetic and genomic approaches in Arabidopsis thaliana to begin to address these knowledge gaps. Seed coat development is a complex process whereby the integuments of the ovule differentiate into specialized cell types. In Arabidopsis, the outermost layer of cells secretes mucilage into the apoplast and develops a secondary cell wall known as a columella. The layer beneath the epidermis, the palisade, synthesizes a secondary cell wall on its inner tangential side. The innermost layer (the pigmented layer or endothelium) produces proanthocyanidins that condense into tannins and oxidize, giving a brown color to mature seeds. Genetic separation of these cell layers was achieved using the ap2-7 and tt16-1 mutants, where the epidermis/palisade and the endothelium do not develop respectively. This genetic ablation was exploited to examine the developmental programs of these cell types by isolating and collecting seed coats at key transitions during development and performing global gene expression analysis. The data indicate that the developmental programs of the epidermis and the pigmented layer proceed relatively independently. Global expression datasets that can be used for identification of new gene candidates for seed coat development were generated. These dataset provide a comprehensive expression profile for developing seed coats in Arabidopsis, and should provide a useful resource and reference for other seed systems. PMID- 21653283 TI - PDZ domain proteins: 'dark matter' of the plant proteome? AB - PDZ domain proteins in metazoans function in diverse roles, and in conjunction with PDZ domain-binding proteins form macromolecular complexes for signaling at synapses and cell junctions. Bioinformatics approaches using the SMART tool indicate there are only a modest number of Arabidopsis PDZ proteins. However, there are hundreds of proteins predicted to possess PDZ domain-binding motifs, suggesting that there are many PDZ domain proteins not detectable by conventional bioinformatic approaches. Our Scansite analysis of PDZ domain-binding proteins indicates that PDZ domain proteins may play key roles in cytoskeletal organization including actin microfilaments, microtubules, and nuclear cytoskeletal proteins, and in the organization of macromolecular complexes involved in cell-to-cell signaling, transport, and cell wall formation. PMID- 21653282 TI - Regulation of the SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE genes/microRNA156 module by the homeodomain proteins PENNYWISE and POUND-FOOLISH in Arabidopsis. AB - The morphology of inflorescences is regulated in part by the temporal and spatial events that regulate flower specification. In Arabidopsis, an endogenous flowering time pathway mediated by a subset of SQUAMOSA PROMOTER-BINDING PROTEIN LIKE (SPL) transcription factors, including SPL3, SPL4, and SPL5, function to specify flowers by activating floral meristem identity genes. During shoot development, SPL3, SPL4, and SPL5 are post-transcriptionally regulated by microRNA156 (miR156). The photoperiod regulated florigenic signal, FLOWERING LOCUS T (FT), promotes floral induction, in part by activating SPL3, SPL4, and SPL5. In turn, these SPLs function in parallel with FT to specify flower meristems. Two related BELL1-like homeobox genes PENNYWISE (PNY) and POUND FOOLISH (PNF) expressed in the shoot apical meristem are absolutely required for the specification of floral meristems. Genetic studies show that the floral specification function of FT depends upon PNY and PNF; however, the interplay between these homeodomain proteins and SPLs is not known. In this manuscript, we show that the photoperiodic floral induction of SPL3, SPL4, and SPL5 is dependent upon PNY and PNF. Further, PNY and PNF also control SPL3, SPL4, and SPL5 expression by negatively regulating miR156. Lastly, ectopic expression of SPL4 partially rescues the pny pnf non-flower-producing phenotype, while overexpression of SPL3 or SPL5 in pny pnf plants was unable to restore flower specification. These results suggest that: (1) SPL3, SPL4, and SPL5 function is dependent upon PNY and PNF, or (2) expression of multiple SPLs is required for floral specification in pny pnf plants. PMID- 21653284 TI - Spatiotemporal effects of microsaccades on population activity in the visual cortex of monkeys during fixation. AB - During visual fixation, the eyes make fast involuntary miniature movements known as microsaccades (MSs). When MSs are executed they displace the visual image over the retina and can generate neural modulation along the visual pathway. However, the effects of MSs on neural activity have substantial variability and are not fully understood. By utilizing voltage-sensitive dye imaging, we imaged the spatiotemporal patterns induced by MSs in V1 and V2 areas of behaving monkeys while they were fixating and presented with visual stimuli. We then investigated the neuronal modulation dynamics, induced by MSs, under different visual stimulation. MSs induced monophasic or biphasic neural responses depending on stimulus size. These neural responses were accompanied by different spatiotemporal patterns of synchronization. Finally, we show that a local patch of population response evoked by a small stimulus was clearly shifted over the V1 retinotopic map after each MS. Our results demonstrate the lack of visual stability in V1 following MSs and help clarify the substantial variability reported for MSs effects on neuronal responses. The observed neural effects suggest that MSs are associated with a continuum of neuronal responses in V1 area reflecting diverse spatiotemporal dynamics. PMID- 21653285 TI - Typical neural representations of action verbs develop without vision. AB - Many empiricist theories hold that concepts are composed of sensory-motor primitives. For example, the meaning of the word "run" is in part a visual image of running. If action concepts are partly visual, then the concepts of congenitally blind individuals should be altered in that they lack these visual features. We compared semantic judgments and neural activity during action verb comprehension in congenitally blind and sighted individuals. Participants made similarity judgments about pairs of nouns and verbs that varied in the visual motion they conveyed. Blind adults showed the same pattern of similarity judgments as sighted adults. We identified the left middle temporal gyrus (lMTG) brain region that putatively stores visual-motion features relevant to action verbs. The functional profile and location of this region was identical in sighted and congenitally blind individuals. Furthermore, the lMTG was more active for all verbs than nouns, irrespective of visual-motion features. We conclude that the lMTG contains abstract representations of verb meanings rather than visual-motion images. Our data suggest that conceptual brain regions are not altered by the sensory modality of learning. PMID- 21653286 TI - The architecture of cross-hemispheric communication in the aging brain: linking behavior to functional and structural connectivity. AB - Contralateral recruitment remains a controversial phenomenon in both the clinical and normative populations. To investigate the neural correlates of this phenomenon, we explored the tendency for older adults to recruit prefrontal cortex (PFC) regions contralateral to those most active in younger adults. Participants were scanned with diffusion tensor imaging and functional magnetic rresonance imaging during a lateralized word matching task (unilateral vs. bilateral). Cross-hemispheric communication was measured behaviorally as greater accuracy for bilateral than unilateral trials (bilateral processing advantage [BPA]) and at the neural level by functional and structural connectivity between contralateral PFC. Compared with the young, older adults exhibited 1) greater BPAs in the behavioral task, 2) greater compensatory activity in contralateral PFC during the bilateral condition, 3) greater functional connectivity between contralateral PFC during bilateral trials, and 4) a positive correlation between fractional anisotropy in the corpus callosum and both the BPA and the functional connectivity between contralateral PFC, indicating that older adults' ability to distribute processing across hemispheres is constrained by white matter integrity. These results clarify how older adults' ability to recruit extra regions in response to the demands of aging is mediated by existing structural architecture, and how this architecture engenders corresponding functional changes that allow subjects to meet those task demands. PMID- 21653287 TI - Driving strategy alters neuronal responses to self-movement: cortical mechanisms of distracted driving. AB - We presented naturalistic combinations of virtual self-movement stimuli while recording neuronal activity in monkey cerebral cortex. Monkeys used a joystick to drive to a straight ahead heading direction guided by either object motion or optic flow. The selected cue dominates neuronal responses, often mimicking responses evoked when that stimulus is presented alone. In some neurons, driving strategy creates selective response additivities. In others, it creates vulnerabilities to the disruptive effects of independently moving objects. Such cue interactions may be related to the disruptive effects of independently moving objects in Alzheimer's disease patients with navigational deficits. PMID- 21653293 TI - Nontypeable Haemophilus influenzae invasive disease in The Netherlands: a retrospective surveillance study 2001-2008. AB - BACKGROUND: Nontypeable (unencapsulated) strains of Haemophilus influenzae (ntHi) are usually involved in respiratory tract infections and otitis media but may also cause invasive disease. The epidemiology, the course of disease, and the outcome of ntHi invasive disease are not well established. For prevention, risk groups that might benefit from vaccination have to be defined. METHODS: All patients with ntHi invasive disease confirmed by culture of samples collected by the Netherlands Reference Laboratory for Bacterial Meningitis from 41 sentinel hospitals and representative of ~45% of all Dutch hospitalized ntHi case patients over the period from 2001 through 2008 were included in the study. Data on clinical presentation, course of disease, and outcome as well as patient characteristics and comorbidity were retrospectively retrieved from hospital records. RESULTS: Clinical presentations of 396 cases included mainly invasive pneumonia (190 cases [48%]) and bacteremia without a clinical focus (75 cases [19%]). Comorbidities were present in 327 [83%] and immunodeficiency in 173 [44%] of all cases. The overall case fatality rate within the first month after diagnosis was 12% and the lowest (2%) was among patients aged 5-54 years. The highest extrapolated age-specific incidence rates occurred within the first 6 weeks of life (19.0 cases per 100,000 persons), concerning mostly prematurely born infants with bacteremia within 24 h after birth, and in the first year of life (5.6 cases per 100,000 persons). The highest rate in adults was among elderly patients aged >65 years (2.2 cases per 100,000 persons). CONCLUSIONS: This study provides a detailed overview of invasive ntHi disease cases in the Netherlands. Risk groups are prematurely born infants, elderly patients aged >65 years, and immunocompromised patients. PMID- 21653296 TI - Is transesophageal echocardiography dispensable in hospital-acquired Staphylococcus aureus bacteremia? PMID- 21653295 TI - Use of a simple criteria set for guiding echocardiography in nosocomial Staphylococcus aureus bacteremia. AB - BACKGROUND: Infective endocarditis (IE) is a severe complication in patients with nosocomial Staphylococcus aureus bacteremia (SAB). We sought to develop and validate criteria to identify patients at low risk for the development of IE in whom transesophageal echocardiography (TEE) might be dispensable. METHODS: Consecutive patients with nosocomial SAB from independent cohorts in Europe (Invasive S. aureus Infection Cohort [INSTINCT]) and North America (S. aureus Bacteremia Group [SABG]) were evaluated for the presence of clinical criteria predicting an increased risk for the development of IE (ie, prolonged bacteremia of >4 days' duration, presence of a permanent intracardiac device, hemodialysis dependency, spinal infection, and nonvertebral osteomyelitis). Patients were observed closely for clinical signs and symptoms of IE during hospitalization and a 3-month follow-up period. RESULTS: IE was present in 13 (4.3%) of 304 patients in the INSTINCT cohort and in 40 (9.3%) of 432 patients in the SABG cohort. Within 14 days after the first positive blood culture result, echocardiography was performed in 39.8% and 57.4% of patients in the INSTINCT and SABG cohorts, respectively. In patients with IE, the most common clinical prediction criteria present were prolonged bacteremia (69.2% vs 90% for INSTINCT vs SABG, respectively) and presence of a permanent intracardiac device (53.8% vs 32.5%). In total, 13 of 13 patients in the INSTINCT cohort and 39 of 40 patients in the SABG cohort with documented IE fulfilled at least 1 criterion (sensitivity, 100% vs. 97.5%; negative predictive value, 100% vs 99.2%). CONCLUSIONS: A simple criteria set for patients with nosocomial SAB can identify patients at low risk of IE. Patients who meet these criteria may not routinely require TEE. PMID- 21653297 TI - Poliomyelitis-related case-fatality ratio in India, 2002-2006. AB - BACKGROUND: On the basis of studies from developed countries, the case-fatality ratio (CFR) of poliomyelitis generally ranges from 2%-5% among children <5 years of age to 10%-30% among adults. However, little information is available for poliomyelitis-related CFR in developing countries. We conducted a study to determine the CFR in India, 1 of the 4 remaining countries with endemic wild poliovirus (WPV) circulation, during outbreaks of WPV infection during 2002 and 2006 and during the inter-epidemic years of 2003-2005. METHODS: We conducted a descriptive analysis with use of data from the acute flaccid paralysis surveillance system in India. Variables analyzed included age, caregiver-reported vaccination status, date of paralysis onset, laboratory results, final case classification, and survival outcome. Our analysis also accounted for surveillance changes that occurred in 2005, impacting case definitions and final classification. RESULTS: In 2006, 45 deaths occurred among 676 WPV cases in India, yielding a CFR of 6.7%. By comparison, in 2002, there were 66 deaths among 1600 reported WPV cases (CFR, 4.2%) and during 2002-2005, CFR was 1.5%-5.2%. All 45 deaths were among 644 (95%) WPV cases in children aged <5 years (CFR, 7.0%). Among those who died, 33 (73%) were children aged <2 years (CFR, 7.1%). CONCLUSIONS: The CFR among children aged <2 years in India is high compared with previously published CFRs for young children, in part because of improved case finding through enhanced surveillance techniques. Fatal cases emphasize the lethal nature of the disease and the importance of achieving polio eradication in India. PMID- 21653298 TI - The impact of ICD-9-CM code rank order on the estimated prevalence of Clostridium difficile infections. AB - BACKGROUND: US estimates of the Clostridium difficile infection (CDI) burden have utilized International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Whether ICD-9-CM code rank order affects CDI prevalence estimates is important because the National Hospital Discharge Survey (NHDS) and the Nationwide Inpatient Sample (NIS) have varying limits on the number of ICD-9-CM codes collected. METHODS: ICD-9-CM codes for CDI (008.45), C. difficile toxin assay results, and dates of admission and discharge were collected from electronic hospital databases for adult patients admitted to 4 hospitals in the United States from July 2000 through June 2006. CDI prevalence per 1000 discharges was calculated and compared for NHDS and NIS limits and toxin assay results from the same hospitals. CDI prevalence estimates were compared using the chi(2) test, and the test of equality was used to compare slopes. RESULTS: CDI prevalence measured by NIS criteria was significantly higher than that measured using NHDS criteria (10.7 cases per 1000 discharges versus 9.4 cases per 1000 discharges; P<.001) in the 4 hospitals. CDI prevalence measured by toxin assay results was 9.4 cases per 1000 discharges (P=.57 versus NHDS). However, the CDI prevalence increased more rapidly over time when measured according to the NHDS criteria than when measured according to toxin assay results (beta=1.09 versus 0.84; P=.008). CONCLUSIONS: Compared with the NHDS definition, the NIS definition captured 12% more CDI cases and reported significantly higher CDI rates. Rates calculated using toxin assay results were not different from rates calculated using NHDS criteria, but CDI prevalence appeared to increase more rapidly when measured by NHDS criteria than when measured by toxin assay results. PMID- 21653299 TI - Outbreak of campylobacteriosis associated with consumption of raw peas. AB - BACKGROUND: Campylobacter jejuni is a leading cause of acute gastroenteritis worldwide, and most cases are identified as sporadic events rather than as parts of recognized outbreaks. We report findings from a substantial 2008 campylobacteriosis outbreak with general implications for fresh produce safety. METHODS: We conducted a matched case-control study to determine the source of the outbreak and enhanced surveillance to identify additional cases. Clinical and environmental specimens were tested for Campylobacter, and isolates were subtyped by pulsed-field gel electrophoresis (PFGE). RESULTS: By routine surveillance, we identified 63 cases of laboratory-confirmed infection. Only raw peas, consumed by 30 (67%) of 45 case-patients and by 15 (17%) of 90 control participants, were associated with illness (adjusted odds ratio: 8.2; P<.001). An additional 69 patients (26 laboratory-confirmed) who reported eating raw peas within 10 days of illness onset were identified through enhanced surveillance. In all, 5 cases were hospitalized, and Guillain-Barre syndrome developed in 1 case; none died. The implicated pea farm was located near a Sandhill crane (Grus canadensis) stopover and breeding site. Of 36 environmental samples collected, 16 were positive for C. jejuni-14 crane-feces samples and 2 pea samples. We identified 25 unique combined SmaI-KpnI PFGE patterns among clinical isolates; 4 of these combined PFGE patterns identified in 15 of 55 human isolates were indistinguishable from PFGE patterns identified in environmental samples. CONCLUSIONS: This investigation established a rare laboratory-confirmed link between a campylobacterosis outbreak and an environmental source and identified wild birds as an underrecognized source of produce contamination. PMID- 21653300 TI - Reduction in antibiotic use following a cluster randomized controlled multifaceted intervention: the Israeli judicious antibiotic prescription study. AB - BACKGROUND: Antibiotic overuse is of great public health concern. This study assessed whether intervention among physicians and their treated population could achieve a sustained reduction in antibiotic use, specifically in classes known to promote antibiotic resistance among children in a community setting. METHODS: We performed a cluster randomized controlled multifaceted trial among 52 primary care pediatricians and the 88,000 children registered in their practices. The intervention was led by local leaders and engaged the participating physicians. It included physician focus group meetings, workshops, seminars, and practice campaigns. These activities focused on self-developed guidelines, improving parent and physician knowledge, diagnostic skills, and parent-physician communication skills that promoted awareness of antibiotic resistance. The main outcome measure was the change in annual antibiotic prescription rates (APRs) of children treated by the intervention group physicians as compared with rates among those treated by control group physicians. The study comprised a 2-year pre intervention period, a 3-year intervention period, and a 1-year follow-up period. Mixed-effect models were used to assess risk ratios to account for the clustered study design. RESULTS: A decrease in the total APR among children treated by the intervention physicians compared with those treated by the control physicians was observed in the first intervention year (APR decrease among control physicians, 40%; APR decrease among intervention physicians, 22%; relative risk [RR], .76; 95% confidence interval [CI], .75-.78). This reduction crossed over all antibiotic classes but was most prominent for macrolides (macrolide prescription rate among control physicians, 58%; macrolide prescription rate among intervention physicians, 27%; RR, .58; 95% CI, .55-.62). The effect was sustained during the 4 following years. CONCLUSIONS. Multifaceted intervention that engages the physicians in an educational process is effective in reducing APRs and can be sustained. CLINICAL TRIALS REGISTRATION: NCT01187758. PMID- 21653301 TI - Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. AB - BACKGROUND: Clostridium difficile infection (CDI) is a major cause of hospital acquired diarrhea and is most commonly associated with changes in normal intestinal flora caused by administration of antibiotics. Few studies have examined the risk of CDI associated with total dose, duration, or number of antibiotics while taking into account the complex changes in exposures over time. METHODS: A retrospective cohort study conducted from 1 January to 31 December 2005 among hospitalized patients 18 years or older receiving 2 or more days of antibiotics. RESULTS: The study identified 10,154 hospitalizations for 7,792 unique patients and 241 cases of CDI, defined as the detection of C. difficile toxin in a diarrheal stool sample within 60 days of discharge. We observed dose dependent increases in the risk of CDI associated with increasing cumulative dose, number of antibiotics, and days of antibiotic exposure. Compared to patients who received only 1 antibiotic, the adjusted hazard ratios (HRs) for those who received 2, 3 or 4, or 5 or more antibiotics were 2.5 (95% confidence interval [CI] 1.6-4.0), 3.3 (CI 2.2-5.2), and 9.6 (CI 6.1-15.1), respectively. The receipt of fluoroquinolones was associated with an increased risk of CDI, while metronidazole was associated with reduced risk. CONCLUSIONS: Cumulative antibiotic exposures appear to be associated with the risk of CDI. Antimicrobial stewardship programs that focus on the overall reduction of total dose as well as number and days of antibiotic exposure and the substitution of high-risk antibiotic classes for lower-risk alternatives may reduce the incidence of hospital-acquired CDI. PMID- 21653302 TI - Country-to-country transfer of patients and the risk of multi-resistant bacterial infection. AB - Management of patients with a history of healthcare contact in multiple countries is now a reality for many clinicians. Leisure tourism, the burgeoning industry of medical tourism, military conflict, natural disasters, and changing patterns of human migration may all contribute to this emerging epidemiological trend. Such individuals may be both vectors and victims of healthcare-associated infection with multiresistant bacteria. Current literature describes intercountry transfer of multiresistant Acinetobacter spp and Klebsiella pneumoniae (including Klebsiella pneumoniae carbapenemase- and New Delhi metallo-beta-lactamase producing strains), methicillin-resistant Staphylococcus aureus, vancomycin resistant enterococci, and hypervirulent Clostridium difficile. Introduction of such organisms to new locations has led to their dissemination within hospitals. Healthcare institutions should have sound infection prevention strategies to mitigate the risk of dissemination of multiresistant organisms from patients who have been admitted to hospitals in other countries. Clinicians may also need to individualize empiric prescribing patterns to reflect the risk of multiresistant organisms in these patients. PMID- 21653303 TI - Use of a computer alert increases detection of early, asymptomatic syphilis among higher-risk men who have sex with men. AB - Our study assessed the impact of a computer alert that reminded clinicians to test men who were at higher risk for syphilis on the rate of syphilis testing and diagnoses. The percentage of high-risk men who have sex with men who were tested for syphilis increased from 77% to 89% (P>.001), and the percentage of such men with asymptomatic syphilis increased from 16% to 53% (P=.001). PMID- 21653304 TI - Cavitary lung lesions in a renal transplant recipient. PMID- 21653305 TI - Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. AB - Over the past 10 years, dissemination of Klebsiella pneumoniae carbapenemase (KPC) has led to an increase in the prevalence of carbapenem-resistant Enterobacteriaceae (CRE) in the United States. Infections caused by CRE have limited treatment options and have been associated with high mortality rates. In the previous year, other carbapenemase subtypes, including New Delhi metallo-beta lactamase, have been identified among Enterobacteriaceae in the United States. Like KPC, these enzymes are frequently found on mobile genetic elements and have the potential to spread widely. As a result, preventing both CRE transmission and CRE infections have become important public health objectives. This review describes the current epidemiology of CRE in the United States and highlights important prevention strategies. PMID- 21653306 TI - Hepatitis B and the need for a booster dose. AB - After several decades of vaccination against hepatitis B virus in newborns, infants, adolescents, and adults, the question remains whether a booster dose is ever needed. Long-term protection is most commonly measured through 4 methods: the anamnestic response after administration of a booster dose, infection rate in vaccinated populations, in vitro B and T cell activity testing, and seroepidemiological studies. Long-term protection is present despite a decrease in anti-hepatitis B surface antibodies over time. The exact mechanism of long term protection, however, is not yet fully understood. There is no need for boosters in immunologically potent persons as long as a full course was adequately administered that respected the recommended timelines, as evidenced by studies conducted up to 20 years after the original immunization course. However, a booster dose should be planned for immunocompromised patients, based on serological monitoring. PMID- 21653307 TI - A randomized noninferiority trial of standard versus enhanced risk reduction and adherence counseling for individuals receiving post-exposure prophylaxis following sexual exposures to HIV. AB - BACKGROUND: The National HIV/AIDS Strategy proposes to scale-up post-exposure prophylaxis (PEP). Intensive risk reduction and adherence counseling appear to be effective but are resource intensive. Identifying simpler interventions that maximize the HIV prevention potential of PEP is critical. METHODS: A randomized noninferiority study comparing 2 (standard) or 5 (enhanced) risk reduction counseling sessions was performed. Adherence counseling was provided in the enhanced arm. We measured changes in unprotected sexual intercourse acts at 12 months, compared with baseline; HIV acquisition; and PEP adherence. Outcomes were stratified by degree of baseline risk. RESULTS: We enrolled 457 individuals reporting unprotected intercourse within 72 h with an HIV-infected or at-risk partner. Participants were 96% male and 71% white. There were 1.8 and 2.3 fewer unprotected sex acts in the standard and enhanced groups. The maximum potential risk difference, reflected by the upper bound of the 95% confidence interval, was 3.9 acts. The difference in the riskier subset may have been as many as 19.6 acts. The incidence of HIV seroconversion was 2.9% and 2.6% among persons randomized to standard and enhanced counseling, respectively, with a maximum potential difference of 3.4%. The absolute and maximal HIV seroconversion incidence was 9.9% and 20.4% greater in the riskier group randomized to standard, compared with enhanced, counseling. Adherence outcomes were similar, with noninferiority in the lower risk group and concerning differences among the higher-risk group. CONCLUSIONS: Risk assessment is critical at PEP initiation. Standard counseling is only noninferior for individuals with lower baseline risk; thus, enhanced counseling should be targeted to individuals at higher risk. PMID- 21653308 TI - Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. AB - BACKGROUND: Some studies have suggested that exposure to antiretroviral therapy (ART) with abacavir is associated with an increased risk of acute myocardial infarction (AMI). METHODS: Using the Veterans Health Administration's Clinical Case Registry we calculated the risk of AMI and cerebrovascular events (CVA) associated with the cumulative use of abacavir and other nucleoside combinations. We also evaluated the impact of pre-existing chronic kidney disease on the selection of abacavir versus tenofovir in the last recorded ART regimen, and on highly active antiretroviral therapy-associated AMI and CVA risks. RESULTS: A total of 19,424 human immunodeficiency virus-infected patients contributed 76,376 patient-years of follow. After adjusting for age, hypercholesterolemia, hypertension, type 2 diabetes, and smoking, the hazard ratio (HR) for each year of abacavir use was 1.18 (95% confidence interval [CI], .92-1.50; P=.191) for AMI and 1.16 (95% CI, .98-1.37; P=.096) for CVA. Abacavir use was more common among patients with prior chronic kidney disease than was tenofovir use (12.46% versus 7.15%; P=.0001), and chronic kidney disease was associated with a significantly higher risk of AMI (HR, 2.41; 95% CI, 1.73-3.36), and CVA (HR, 1.80; 95% CI, 1.44 2.24). Compared with patients who received neither tenofovir nor abacavir, patients who received tenofovir had lower risk of AMI (HR, 0.16; 95% CI, .08-.33; P=.0001) and CVA (HR, 0.22; 95% CI, .15-.32; P=.001). Use of abacavir was associated with lower risk of CVA (HR, 0.60; 95% CI, .45-.79). CONCLUSIONS: We observed no association between cumulative or current abacavir use and AMI or CVA. Abacavir use was more common than was tenofovir use among patients with prior chronic kidney disease, and chronic kidney disease independently predicted higher rates of AMI and CVA. PMID- 21653309 TI - HIV and Cardiovascular Disease. PMID- 21653312 TI - Pulmonary hypertension in HIV-infected individuals. PMID- 21653313 TI - Methicillin-resistant Staphylococcus aureus guidelines: a myriad of open questions. PMID- 21653314 TI - Rifampin and methicillin-resistant Staphylococcus aureus bone and joint infections. PMID- 21653316 TI - The infection attack rate and severity of 2009 pandemic H1N1 influenza in Hong Kong: accuracy amidst ambiguity. PMID- 21653318 TI - Structural and functional analysis of a new subfamily of glycosyltransferases required for glycosylation of serine-rich streptococcal adhesins. AB - Serine-rich repeat glycoproteins (SRRPs) are a growing family of bacterial adhesins found in many streptococci and staphylococci; they play important roles in bacterial biofilm formation and pathogenesis. Glycosylation of this family of adhesins is essential for their biogenesis. A glucosyltransferase (Gtf3) catalyzes the second step of glycosylation of a SRRP (Fap1) from an oral streptococcus, Streptococcus parasanguinis. Although Gtf3 homologs are highly conserved in SRRP-containing streptococci, they share minimal homology with functionally known glycosyltransferases. We report here the 2.3 A crystal structure of Gtf3. The structural analysis indicates that Gtf3 forms a tetramer and shares significant structural homology with glycosyltransferases from GT4, GT5, and GT20 subfamilies. Combining crystal structural analysis with site directed mutagenesis and in vitro glycosyltransferase assays, we identified residues that are required for UDP- or UDP-glucose binding and for oligomerization of Gtf3 and determined their contribution to the enzymatic activity of Gtf3. Further in vivo studies revealed that the critical amino acid residues identified by the structural analysis are crucial for Fap1 glycosylation in S. parasanguinis in vivo. Moreover, Gtf3 homologs from other streptococci were able to rescue the gtf3 knock-out mutant of S. parasanguinis in vivo and catalyze the sugar transfer to the modified SRRP substrate in vitro, demonstrating the importance and conservation of the Gtf3 homologs in glycosylation of SRRPs. As the Gtf3 homologs only exist in SRRP-containing streptococci, we conclude that the Gtf3 homologs represent a unique subfamily of glycosyltransferases. PMID- 21653319 TI - Targeting RAD51 phosphotyrosine-315 to prevent unfaithful recombination repair in BCR-ABL1 leukemia. AB - Chronic myeloid leukemia chronic phase (CML-CP) CD34(+) cells contain numerous DNA double-strand breaks whose unfaithful repair may contribute to chromosomal instability and disease progression to blast phase (CML-BP). These phenomena are often associated with the appearance of imatinib-resistant BCR-ABL1 kinase mutants (eg, T315I) and overexpression of BCR-ABL1. Here we show that BCR-ABL1 (nonmutated and T315I mutant) promoted RAD51 recombinase-mediated unfaithful homeologous recombination repair (HomeoRR) in a dosage-dependent manner. BCR-ABL1 SH3 domain interacts with RAD51 proline-rich regions, resulting in direct phosphorylation of RAD51 on Y315 (pY315). RAD51(pY315) facilitates dissociation from the complex with BCR-ABL1 kinase, migrates to the nucleus, and enhances formation of the nuclear foci indicative of recombination sites. HomeoRR and RAD51 nuclear foci were strongly reduced by RAD51(Y315F) phosphorylation-less mutant. In addition, peptide aptamer mimicking RAD51(pY315) fragment, but not that with Y315F phosphorylation-less substitution, diminished RAD51 foci formation and inhibited HomeoRR in leukemia cells. In conclusion, we postulate that BCR-ABL1 kinase-mediated RAD51(pY315) promotes unfaithful HomeoRR in leukemia cells, which may contribute to accumulation of secondary chromosomal aberrations responsible for CML relapse and progression. PMID- 21653320 TI - A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. AB - An unmet need in cell engineering is the availability of a single transgene encoded, functionally inert, human polypeptide that can serve multiple purposes, including ex vivo cell selection, in vivo cell tracking, and as a target for in vivo cell ablation. Here we describe a truncated human EGFR polypeptide (huEGFRt) that is devoid of extracellular N-terminal ligand binding domains and intracellular receptor tyrosine kinase activity but retains the native amino acid sequence, type I transmembrane cell surface localization, and a conformationally intact binding epitope for pharmaceutical-grade anti-EGFR monoclonal antibody, cetuximab (Erbitux). After lentiviral transduction of human T cells with vectors that coordinately express tumor-specific chimeric antigen receptors and huEGFRt, we show that huEGFRt serves as a highly efficient selection epitope for chimeric antigen receptor(+) T cells using biotinylated cetuximab in conjunction with current good manufacturing practices (cGMP)-grade anti-biotin immunomagnetic microbeads. Moreover, huEGFRt provides a cell surface marker for in vivo tracking of adoptively transferred T cells using both flow cytometry and immunohistochemistry, and a target for cetuximab-mediated antibody-dependent cellular cytotoxicity and in vivo elimination. The versatility of huEGFRt and the availability of pharmaceutical-grade reagents for its clinical application denote huEGFRt as a significant new tool for cellular engineering. PMID- 21653321 TI - Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML. AB - In a zebrafish mutagenesis screen to identify genes essential for myelopoiesis, we identified an insertional allele hi1727, which disrupts the gene encoding RNA helicase dead-box 18 (Ddx18). Homozygous Ddx18 mutant embryos exhibit a profound loss of myeloid and erythroid cells along with cardiovascular abnormalities and reduced size. These mutants also display prominent apoptosis and a G1 cell-cycle arrest. Loss of p53, but not Bcl-xl overexpression, rescues myeloid cells to normal levels, suggesting that the hematopoietic defect is because of p53 dependent G1 cell-cycle arrest. We then sequenced primary samples from 262 patients with myeloid malignancies because genes essential for myelopoiesis are often mutated in human leukemias. We identified 4 nonsynonymous sequence variants (NSVs) of DDX18 in acute myeloid leukemia (AML) patient samples. RNA encoding wild-type DDX18 and 3 NSVs rescued the hematopoietic defect, indicating normal DDX18 activity. RNA encoding one mutation, DDX18-E76del, was unable to rescue hematopoiesis, and resulted in reduced myeloid cell numbers in ddx18(hi1727/+) embryos, indicating this NSV likely functions as a dominant-negative allele. These studies demonstrate the use of the zebrafish as a robust in vivo system for assessing the function of genes mutated in AML, which will become increasingly important as more sequence variants are identified by next-generation resequencing technologies. PMID- 21653322 TI - Late effects among pediatric patients followed for nearly 4 decades after transplantation for severe aplastic anemia. AB - Aplastic anemia (AA), a potentially fatal disease, may be cured with marrow transplantation. Survival in pediatric patients has been excellent early after transplantation, but only limited data are available regarding late effects. This study evaluates late effects among 152 patients followed 1-38 years (median, 21.8 years). Transplantation-preparative regimes were mostly cyclophosphamide with or without antithymocyte globulin. Survival at 30 years for the acquired AA patients is 82%, and for the Fanconi anemia patients it is 58% (P = .01). Multivariate analysis demonstrated that chronic GVHD (P = .02) and Fanconi anemia (P = .03) negatively impacted survival. Two Fanconi patients and 18 acquired AA patients developed a malignancy that was fatal for 4. There was an increased incidence of thyroid function test abnormalities among those who received total body irradiation. Cyclophosphamide recipients demonstrated normal growth, basically normal development, and pregnancies with mostly normal offspring. Quality-of-life studies in adult survivors of this pediatric transplantation cohort indicated that patients were comparable with control patients except for difficulty with health and life insurance. These data indicate that the majority of long-term survivors after transplantation for AA during childhood can have a normal productive life. PMID- 21653323 TI - ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria. AB - Mutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders. PMID- 21653324 TI - The critical role of agrin in the hematopoietic stem cell niche. AB - Hematopoiesis is the process leading to the sustained production of blood cells by hematopoietic stem cells (HSCs). Growth, survival, and differentiation of HSCs occur in specialized microenvironments called "hematopoietic niches," through molecular cues that are only partially understood. Here we show that agrin, a proteoglycan involved in the neuromuscular junction, is a critical niche-derived signal that controls survival and proliferation of HSCs. Agrin is expressed by multipotent nonhematopoietic mesenchymal stem cells (MSCs) and by differentiated osteoblasts lining the endosteal bone surface, whereas Lin(-)Sca1(+)c-Kit(+) (LSK) cells express the alpha-dystroglycan receptor for agrin. In vitro, agrin deficient MSCs were less efficient in supporting proliferation of mouse Lin(-)c Kit(+) cells, suggesting that agrin plays a role in the hematopoietic cell development. These results were indeed confirmed in vivo through the analysis of agrin knockout mice (Musk-L;Agrn(-/-)). Agrin-deficient mice displayed in vivo apoptosis of CD34(+)CD135(-) LSK cells and impaired hematopoiesis, both of which were reverted by an agrin-sufficient stroma. These data unveil a crucial role of agrin in the hematopoietic niches and in the cross-talk between stromal and hematopoietic stem cells. PMID- 21653325 TI - Redirected tumor-specific allogeneic T cells for universal treatment of cancer. AB - Adoptive cell transfer of allogeneic tumor-specific T cells could potentially be used as a universal treatment for cancer. We present a novel approach for adoptive immunotherapy using fully MHC-mismatched allogeneic T cells redirected with tumor-specific, non-MHC-restricted antibody-based chimeric antigen receptor (T-bodies) in the absence of GVHD. Mice bearing systemic metastatic disease were lymphodepleted by irradiation and treated with Her2/neu re-directed T cells. Lymphodepletion created a 'therapeutic window', which allowed the allo-T-bodies to attack the tumor before their rejection. A single split dose administration of allogeneic T-bodies extended the survival of tumor-bearing mice similarly to syngeneic T-bodies, and to a significantly greater extent than nonspecific allogeneic T cells. Blocking egress of lymphocytes from lymphoid organs using the sphingosine-1-phosphate agonist, FTY720, extended the persistence of allogeneic T cells such that allogeneic T-bodies provided superior therapeutic benefit relative to syngeneic ones, and dramatically extended the median survival time of the treated mice for more than a year. Therefore, we suggest that ex-vivo generated MHC-mismatched T-bodies can be used universally for off-the-shelf cancer immunotherapy and that their graft-versus-host reactivity can be safely harnessed to potentiate adoptive cell therapy. PMID- 21653326 TI - Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. AB - New official nomenclature subdivides human monocytes into 3 subsets: the classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), and nonclassical (CD14(+)CD16(++)) monocytes. This introduces new challenges, as monocyte heterogeneity is mostly understood based on 2 subsets, the CD16(-) and CD16(+) monocytes. Here, we comprehensively defined the 3 circulating human monocyte subsets using microarray, flow cytometry, and cytokine production analysis. We find that intermediate monocytes expressed a large majority (87%) of genes and surface proteins at levels between classical and nonclassical monocytes. This establishes their intermediary nature at the molecular level. We unveil the close relationship between the intermediate and nonclassic monocytes, along with features that separate them. Intermediate monocytes expressed highest levels of major histocompatibility complex class II, GFRalpha2 and CLEC10A, whereas nonclassic monocytes were distinguished by cytoskeleton rearrangement genes, inflammatory cytokine production, and CD294 and Siglec10 surface expression. In addition, we identify new features for classic monocytes, including AP-1 transcription factor genes, CLEC4D and IL-13Ralpha1 surface expression. We also find circumstantial evidence supporting the developmental relationship between the 3 subsets, including gradual changes in maturation genes and surface markers. By comprehensively defining the 3 monocyte subsets during healthy conditions, we facilitate target identification and detailed analyses of aberrations that may occur to monocyte subsets during diseases. PMID- 21653329 TI - Floral development and morphology of Vochysiaceae. I. The structure of the gynoecium. AB - Vochysiaceae are divided into two tribes on the basis of ovary structure (superior trilocular or inferior unilocular). The superior trilocular ovary has been considered basal in the family, and the term "pseudomonomerous" was used to indicate the presumed evolutionary derivation of the unilocular condition from the trilocular. However, recent evidence that Vochysiaceae are Myrtalean suggests that the superior ovary may be secondarily derived. In addition, published figures cast doubt on the interpretation of the putatively unilocular ovaries. To understand these features, floral ontogeny and anatomy were examined using scanning electron microscopy and serial sectioning. In all taxa examined, the ovary develops in an epigynous fashion, on a concave floral apex, supporting the hypothesis that the superior ovary is secondarily derived. Subsequent to initiation of the ovary, differential growth results in ovaries that are superior, inferior, or partly inferior in different genera. Sections of floral buds of the two unilocular genera, Erisma and Erismadelphus, show aborted locules in the latter but not in the former. The application of the term "pseudomonomerous" to both genera obscures this significant difference. The position of the placenta in the truly unilocular genus varies among species, suggesting a character transformation series from multilocular through intermediates to truly unilocular. PMID- 21653328 TI - New mutations and pathogenesis of myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature blood cells. In the majority of classic MPN- polycythemia vera, essential thrombocythemia, and primitive myelofibrosis--driver oncogenic mutations affecting Janus kinase 2 (JAK2) or MPL lead to constitutive activation of cytokine-regulated intracellular signaling pathways. LNK, c-CBL, or SOCSs (all negative regulators of signaling pathways), although infrequently targeted, may either drive the disease or synergize with JAK2 and MPL mutations. IZF1 deletions or TP53 mutations are mainly found at transformation phases and are present at greater frequency than in de novo acute myeloid leukemias. Loss-of function mutations in 3 genes involved in epigenetic regulation, TET2, ASXL1, and EZH2, may be early events preceding JAK2V617F but may also occur late during disease progression. They are more frequently observed in PMF than PV and ET and are also present in other types of malignant myeloid diseases. A likely hypothesis is that they facilitate clonal selection, allowing the dominance of the JAK2V617F subclone during the chronic phase and, together with cooperating mutations, promote blast crisis. Their precise roles in hematopoiesis and in the pathogenesis of MPN, as well as their prognostic impact and potential as a therapeutic target, are currently under investigation. PMID- 21653327 TI - Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification. AB - The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways. PMID- 21653330 TI - Floral development and morphology of Vochysiaceae. II. The position of the single fertile stamen. AB - A conspicuous feature of Vochysiaceae flowers is their single fertile stamen. In some genera, the stamen is in front of a petal, whereas in others it is in front of a sepal. This difference has been attributed to two independent reductions, which implies the stamen is not homologous across the family. The observation that genera with an antesepalous stamen have only one petal, whereas those with an antepetalous stamen have three or five petals, led us to the hypothesis that in all genera the stamen arises in an antepetalous position, but that it is displaced during development in single-petaled taxa. We examined developing buds of five genera using scanning electron microscopy and serial sectioning and conclude that the stamen in all genera is fundamentally antepetalous. The stamen is not displaced. The petal, however, appears to be displaced in some genera. Further, the position of the fertile stamen in Erisma has been misinterpreted. We discuss the evolution of the androecium in this family in a phylogenetic context and consider the significance of symmetry and of loss vs. suppression in the development of Vochysiaceae flowers. PMID- 21653331 TI - Interactions between a blue-green reversible photoreceptor and a separate UV-B receptor in stomatal guard cells. AB - Stomatal opening exhibits two main peaks of activity in the visible range-a red peak, mediated by photosynthesis, and a blue peak, mediated by one or more blue light (BL) photoreceptors. In addition, a pronounced peak in the UV-B region has been characterized, as has a smaller UV-A peak. The BL-induced stomatal opening can be reversed by green light (GL). Here we report that UV-B-induced opening is also antagonized by GL. To determine whether UV-B is being absorbed by the BL photoreceptor or by a separate UV-B receptor, the UV-B responses of two different Arabidopsis mutants, npq1 and phot1/phot2, were tested. Both putative BL photoreceptor mutants exhibited normal stomatal opening in response to UV-B, consistent with the existence of a separate UV-B photoreceptor. Moreover, GL failed to antagonize UV-B-induced stomatal opening in the phot1/phot2 double mutant and only partially antagonized UV-B opening in npq1. Thus, both phot1 and phot 2, as well as zeaxanthin, are required for the normal GL inhibition of UV-B. A model for a photoreceptor network that regulates stomatal opening is presented. Unlike the situation in guard cells, the UV-B bending response of Arabidopsis hypocotyls during phototropism appears to be mediated by phototropins. PMID- 21653332 TI - A comparative flower and fruit anatomical study of Quercus acutissima, a biennial fruiting oak from the Cerris group (Fagaceae). AB - A developmental series of flowers and fruits of Quercus acutissima (subgenus Quercus section Cerris) was collected over a growing season and examined for an intersectional, comparative anatomical study. Pistillate flowers of the current growing season, each consisting of a pistil with three long, slightly recurved styles, six tepals, and an inconspicuous ovary subtended by a few cycles of cupule scales, emerged in early May, were pollinated by mid-May, and then were quiescent for the remainder of the growing season. Flowers from the previous growing season resumed growth in mid-May, each forming three locules delimited by septa in the ovary, with two bitegmic, epitropous ovules developing in each locule. Mature embryo sacs were present by mid-July of the second growing season, although embryos were not observed until early August. Fruit maturation was complete by late September. Features that have not been described previously for the section Cerris include early-lignifying endocarp trichomes, persistent septa, and leaf primordia buttresses on the embryo. A comparison of flower and fruit developmental features with sections Quercus sensu stricto and Lobatae revealed a mosaic of shared features among the three sections. PMID- 21653333 TI - The Enigmatic Paleozoic plants Spermopteris and Phasmatocycas reconsidered. AB - Ovule-bearing leaves from the Paleozoic of North America assigned to Spermopteris and Phasmatocycas have been interpreted as primitive cycad megasporophylls. According to this hypothesis, Cycas megasporophylls were derived from a Spermopteris-like ancestor via Phasmatocycas and various other taeniopterid forms. This putative transformation entailed the phyletic shift of ovule attachment from the abaxial lamina surface of Spermopteris to the leaf midrib in Phasmatocyas. However, reexamination of the original Spermopteris specimens from the Lawrence Shale of Kansas has shown that the ovules are attached to the leaf midrib. Therefore, Spermopteris and Phasmatocyas differ only in a few details of lamina morphology. The apical cleft of the ovules of both forms is interpreted as an original feature rather than a preservational artifact; however, the abaxial flange is probably a result of compression of a terete midrib. Spermopteris is typified by sterile specimens of Taeniopteris coriacea from Europe, which are of uncertain affinity to the fertile leaves. Therefore, we propose that the ovule bearing leaves now known as Spermopteris coriacea be named as a new species of Phasmatocycas (Phasmatocycas bridwellii sp. nov.). The new concept of Phasmatocyas is less cycad-like than previously thought, and the phylogenetic position of the genus is unclear. PMID- 21653334 TI - Evolution of genome size in the angiosperms. AB - Genome size varies extensively across the flowering plants, which has stimulated speculation regarding the ancestral genome size of these plants and trends in genome evolution. We investigated the evolution of C-values across the angiosperms using a molecular phylogenetic framework and C-values not previously available for crucial basal angiosperms, including Amborella, Illiciaceae, and Austrobaileya. Reconstructions of genome size across the angiosperms and extant gymnosperms indicate that the ancestral genome size for angiosperms is very small (1C <= 1.4 pg), in agreement with an earlier analysis of Leitch et al. (1998). Furthermore, a very small genome size (1C <= 1.4 pg) is ancestral not only for the angiosperms in general, but also for most major clades of flowering plants, including the monocots and the eudicots. The ancestral genome of core eudicots may also have been very small given that very low 1C-values appear to be ancestral for major clades of core eudicots, such as Caryophyllales, Saxifragales, and asterids. Very large genomes occur in clades that occupy derived positions within the monocots and Santalales. PMID- 21653335 TI - Under how wide a set of conditions will nonrandom mating occur in Raphanus sativus (Brassicaceae)? AB - Studies of the weedy annual Raphanus sativus have demonstrated that nonrandom mating, a prerequisite for sexual selection, can occur in greenhouse plants. To determine whether this nonrandom mating pattern can occur under a wide range of conditions, including conditions that might occur in the field, we considered variation in both maternal condition and pollen load size. Maternal condition was varied by altering the watering regime. Pollen load size was varied from approximately 26 to 343 pollen grains per stigma. At the smallest pollen load size, patterns of seed paternity were altered in two of the three pollen donor pairs; seed paternity became more equal among donors. For one of three pollen donor pairs, seed paternity was more divergent among donors on stressed maternal plants. Finally, for one pollen donor pair, rank order of pollen donor performance changed from the medium to the small pollen loads on stressed vs. control maternal plants. Thus, some field conditions may alter patterns of nonrandom mating in wild radish. PMID- 21653336 TI - Linking pollinator visitation rate and pollen receipt. AB - The majority of flowering plants require animals for pollination, a critical ecosystem service in natural and agricultural systems. However, quantifying useful estimates of pollinator visitation rates can be nearly impossible when pollinator visitation is infrequent. We examined the utility of an indirect measure of pollinator visitation, namely pollen receipt by flowers, using the hummingbird-pollinated plant, Ipomopsis aggregata (Polemoniaceae). Our a priori hypothesis was that increased pollinator visitation should result in increased pollen receipt by stigmas. However, the relationship between pollinator visitation rate and pollen receipt may be misleading if pollen receipt is a function of both the number of pollinator visits and variation in pollinator efficiency at depositing pollen, especially in the context of variable floral morphology. Therefore, we measured floral and plant characters known to be important to pollinator visitation and/or pollen receipt in I. aggregata (corolla length and width and plant height) and used path analysis to dissect and compare the effect of pollinator visitation rate vs. pollinator efficiency on pollen receipt. Of the characters we measured, pollinator visitation rate (number of times plants were visited multiplied by the mean percentage of flowers probed per visit) had the strongest direct positive effect on pollen receipt, explaining 36% of the variation in pollen receipt. Plant height had a direct positive effect on pollinator visitation rate and an indirect positive effect on pollen receipt. Despite the supposition that floral characters would directly affect pollen receipt as a result of changes in pollinator efficiency, corolla length and width only weakly affected pollen receipt. These results suggest a direct positive link between pollinator visitation rate and pollen receipt across naturally varying floral morphology in I. aggregata. Understanding the relationship between pollinator visitation rate and pollen receipt may be of critical importance in systems where pollinator visitation is difficult to quantify. PMID- 21653337 TI - Integrating gene flow, crop biology, and farm management in on-farm conservation of avocado (Persea americana, Lauraceae). AB - Maintaining crop diversity on farms where cultivars can evolve is a conservation goal, but few tools are available to assess the long-term maintenance of genetic diversity on farms. One important issue for on-farm conservation is gene flow from crops with a narrow genetic base into related populations that are genetically diverse. In a case study of avocado (Persea americana var. americana) in one of its centers of diversity (San Jeronimo, Costa Rica), we used 10 DNA microsatellite markers in a parentage analysis to estimate gene flow from commercialized varieties into a traditional crop population. Five commercialized genotypes comprised nearly 40% of orchard trees, but they contributed only about 14.5% of the gametes to the youngest cohort of trees. Although commercialized varieties and the diverse population were often planted on the same farm, planting patterns appeared to keep the two types of trees separated on small scales, possibly explaining the limited gene flow. In a simulation that combined gene flow estimates, crop biology, and graft tree management, loss of allelic diversity was less than 10% over 150 yr, and selection was effective in retaining desirable alleles in the diverse subpopulation. Simulations also showed that, in addition to gene flow, managing the genetic makeup and life history traits of the invasive commercialized varieties could have a significant impact on genetic diversity in the target population. The results support the feasibility of on farm crop conservation, but simulations also showed that higher levels of gene flow could lead to severe losses of genetic diversity even if farmers continue to plant diverse varieties. PMID- 21653338 TI - Population genetic structure of Venezuelan chiropterophilous columnar cacti (Cactaceae). AB - We conducted allozyme surveys of three Venezuelan self-incompatible chiropterophilous columnar cacti: two diploid species, Stenocereus griseus and Cereus repandus, and one tetraploid, Pilosocereus lanuginosus. The three cacti are pollinated by bats, and both bats and birds disperse seeds. Population sampling comprised two spatial scales: all Venezuelan arid zones (macrogeographic) and two arid regions in northwestern Venezuela (regional). Ten to 15 populations and 17-23 loci were analyzed per species. Estimates of genetic diversity were compared with those of other allozyme surveys in the Cactaceae to examine how bat-mediated gene dispersal affects the population genetic attributes of the three cacti. Genetic diversity was high for both diploid (P(s) = 94.1-100, P(p) = 56.7-72.3, H(s) = 0.182-0.242, H(p) = 0.161-0.205) and tetraploid (P(s) = 93.1, P(p) = 76.1, H(s) = 0.274, H(p) = 0.253) species. Within-population heterozygote deficit was detected in the three cacti at macrogeographic (F(IS) = 0.145-0.182) and regional (F(IS) = 0.057-0.174) levels. Low genetic differentiation was detected at both macrogeographic (G(ST) = 0.043-0.126) and regional (G(ST) = 0.009-0.061) levels for the three species, suggesting substantial gene flow among populations. Gene exchange among populations seems to be regulated by distance among populations. Our results support the hypothesis that bat-mediated gene dispersal confers high levels of genetic exchange among populations of the three columnar cacti, a process that enhances levels of genetic diversity within their populations. PMID- 21653339 TI - Missing fossils, molecular clocks, and the origin of the Melastomataceae. AB - In a recent analysis of the historical biogeography of Melastomataceae, Renner, Clausing, and Meyer (2001; American Journal of Botany 88(7): 1290-1300) rejected the hypothesis of a Gondwana origin. Using a fossil-calibrated chloroplast DNA (ndhF) phylogeny, they placed the early diversification of Melastomataceae in Laurasia at the Paleocene/Eocene boundary (ca. 55 Ma) and suggested that long distance oceanic dispersals in the Oligocene and Miocene (34 to 5 Ma) account for its range expansion into South America, Africa, and Madagascar. Their critical assumption-that oldest northern mid-latitude melastome fossils reflect tribal ages and their geographic origins-may be erroneous, however, because of the sparse fossil record in the tropics. We show that rates of synonymous nucleotide substitutions derived by the Renner et al. (2001) model are up to three times faster than most published rates. Under a Gondwana-origin model advocated here, which includes dispersals from Africa to Southeast Asia via the "Indian ark" and emphasizes filter rather than either sweepstakes dispersal or strict vicariance, rates of nucleotide substitution fall within the range of published rates. We suggest that biogeographic reconstructions need to consider the paucity of Gondwanan fossils and that frequently overlooked interplate dispersal routes provide alternatives to vicariance, boreotropical dispersal, and long-distance oceanic dispersal as explanations for the amphi-oceanic disjunctions of many tropical rain forest plants. PMID- 21653340 TI - Distinct geographic structure as evidenced by chloroplast DNA haplotypes and ploidy level in Japanese Aucuba (Aucubaceae). AB - The geographic distribution of diploid and tetraploid cytotypes and cpDNA haplotypes throughout the entire range of Aucuba japonica was investigated. We measured relative genome size using flow cytometry and sequenced two cpDNA intergenic regions, atpB-rbcL and psbA-trnH (GUG). Two haplotypes include both diploids and tetraploids; four others are all tetraploids. Based on the combination of these haplotypes and cytotypes, eight "haplo-cytotypes" can be defined, which show a distinct geographic structure. Two diploid haplo-cytotypes are distributed in the southwestern part and six tetraploid ones in the northeastern part of the Japanese archipelago. Diploid and tetraploid haplo cytotypes with the same haplotype are, in one case, disjunctively distributed, and in another case, in contact. The phylogenetic relationships of haplo cytotypes indicate that the traditional circumscription of A. japonica is paraphyletic. One lineage consists of four tetraploid haplo-cytotypes and another of diploid and tetraploid haplo-cytotypes plus A. chinensis. Tetraploidization occurred independently at least three times, once at the base of the former lineage and twice in the latter. Taking the geographic, cytological, and phylogenetic evidence into account, the formation of the present geographic differentiation pattern of haplo-cytotypes through postglacial expansion from glacial refugia is discussed. PMID- 21653341 TI - An ITS phylogeny of Balsamorhiza and Wyethia (Asteraceae: Heliantheae). AB - The relationships among the species of Balsamorhiza and Wyethia (Asteraceae: Heliantheae) were examined using data from the internal transcribed spacer (ITS) region of the nuclear ribosomal DNA. The ITS sequences were obtained from nine species of Balsamorhiza and 14 species of Wyethia as well as seven outgroup genera. Five of the outgroup genera were members of the subtribe Engelmanniinae of the tribe Heliantheae, the subtribe that includes Balsamorhiza and Wyethia. The resulting trees show that Balsamorhiza and Wyethia together form a monophyletic group. Balsamorhiza alone is monophyletic, but neither of its two sections is monophyletic. Wyethia is paraphyletic. One group of Wyethia species, including all members of sections Alarconia and Wyethia as well as W. bolanderi from section Agnorhiza, is monophyletic and sister to Balsamorhiza. The other species of Wyethia (all placed in section Agnorhiza) are part of a polytomy along with the clade composed of Balsamorhiza plus the rest of Wyethia. PMID- 21653342 TI - Endophytic Xylaria (Xylariaceae) among liverworts and angiosperms: phylogenetics, distribution, and symbiosis. AB - Nuclear ribosomal 18S and internal transcribed spacer (ITS) sequence data were used to identify endophytic fungi cultured from six species of liverworts collected in Jamaica and North Carolina. Comparisons with other published fungal sequences and phylogenetic analyses yielded the following conclusions: (1) the endophytes belong to the ascomycete families Xylariaceae, Hypocreaceae, and Ophiostomataceae, and (2) liverwort endophytes in the genus Xylaria are closely related to each other and to endophytes isolated from angiosperms in China, Puerto Rico, and Europe. Liverwort endophytes are expected to be foragers or endophytic specialists, although little is known about the role of these fungi in symbioses. Features that may indicate a mutualistic role for these endophytes are discussed. PMID- 21653343 TI - Development of biochemical specialization and organelle partitioning in the single-cell C4 system in leaves of Borszczowia aralocaspica (Chenopodiaceae). AB - The terrestrial plant Borszczowia aralocaspica (Chenopodiaceae) has recently been shown to contain the entire C(4) photosynthesis mechanism within individual, structurally and biochemically polarized chlorenchyma cells rather than in a dual cell system, as has been the paradigm for this type of carbon fixation (Nature 414: 543-546, 2001). Analysis of carbon isotope composition and (14)CO(2) fixation shows that photosynthesis and growth of B. aralocaspica occurs through carbon acquired by C(4) photosynthesis. The development of this unique single cell C(4) system in chlorenchyma cells was studied by analysis of young (0.2-0.3 cm length), intermediate (ca. 0.5-0.6 cm length), and mature leaves (ca. 3 cm length). The length of chlorenchyma cells approximately doubles from young to intermediate and again from intermediate to the mature leaf stage. In young chlorenchyma cells, there is a single type of chloroplast; the chloroplasts are evenly distributed throughout the cytosol, and all contain starch and rubisco. During leaf development, the activities of phosphoenolpyruvate carboxylase (PEPC; which is cytosolic), rubisco, and pyruvate,Pi dikinase (PPDK) increase on a chlorophyll basis. As leaves mature, chloroplasts differentiate into two distinct structural and biochemical types that are spatially separated into the proximal and distal parts of the cell (the proximal end being closest to the center of the leaf). The early stages of this polarization are observed in intermediate leaves, and the polarization is fully developed in mature leaves. The chloroplasts in the distal ends of the cell have reduced grana and little starch, while those at the proximal ends have well-developed grana and abundant starch. In mature leaves, PPDK is expressed in chloroplasts at the distal end of the cells, while rubisco and adenosine diphosphate glucose (ADPG) pyrophosphorylase are selectively expressed in chloroplasts at the proximal end of the cell. Mitochondrial polarization also occurs during development as nicotinamide-adenine dinucleotide phosphate-malic enzyme (NAD-ME) and the photorespiratory enzyme glycine decarboxylase are expressed in mature but not young leaves and are localized in mitochondria at the proximal end of the cells. The data show that single-cell C(4) develops from a single pool of identical organelles that develop differential biochemical functions and spatial partitioning in the cell during maturation. PMID- 21653344 TI - Variation at a chloroplast minisatellite locus reveals the signature of habitat fragmentation and genetic bottlenecks in the rare orchid Anacamptis palustris (Orchidaceae). AB - Geoclimatic changes during the Oligocene and more recent anthropogenic influences have shaped the current distribution and population structure of Mediterranean plant species. Anacamptis palustris (Orchidaceae) is a typical member of coastal wetlands, which have become increasingly fragmented and isolated. As a consequence, this orchid has become rare in the recent past. Length variation at a chloroplast minisatellite locus was used to estimate genetic variation within and between the largest extant populations of A. palustris. Genetic diversity was positively correlated with population size. Estimation of observed and expected gene diversity and analyses of haplotype number and haplotype frequency distributions provided evidence for population bottlenecks in the history of small populations. Comparison with an earlier study suggests that nuclear allozyme diversity was most likely lost during the Oligocene and could not recover subsequently due to low mutation rates, whereas genetic variation was restored at the highly variable chloroplast minisatellite locus. Population bottlenecks indicated by cpDNA variation occurred most likely as a consequence of more recent anthropogenic changes. The comparison of molecular markers with different levels of polymorphism provided valuable insights into the processes shaping genetic diversity and population structure in this rare orchid. PMID- 21653345 TI - Analysis of within-population spatial genetic structure in Antirrhinum microphyllum (Scrophulariaceae). AB - Random amplified polymorphic DNA (RAPD) markers were used to study the spatial genetic structure in two populations (Bolarque and Entrepenas) of endangered cliff specialist Antirrhinum microphyllum Rothm. (Scrophulariaceae). Mantel tests found no significant linear correlations between geographic and genetic data. However, redundancy analysis (RDA) models developed using the spatial data as the constraining matrix were highly significant, and spatial data explained 13.6% and 11.1% of total genetic variation in Bolarque and Entrepenas, respectively. Moran's I correlograms and Mantel correlograms revealed a positive autocorrelation in the first distance class (15 m), which suggests a patchy distribution of genetic diversity. This distribution is consistent with the genetic vicinities that are expected from the territorial behavior of main pollinator Rhodanthidium sticticum (Megachilidae), the predominant short-distance seed dispersal, and the patchy spatial distribution of available safe sites. The gradient pattern obtained in Entrepenas was consistent with standard isolation-by distance models. However, a differential sinusoidal pattern was obtained in Bolarque, which would indicate a more frequent gene flow between patches and might be due to lower plant density there. The spatial genetic structure coexists with a strict self-incompatibility system in the species. Simplified RDA models obtained using a stepwise forward selection comprised the easting component in Entrepenas and the easting and northing components in Bolarque. Similar results were obtained with directional correlograms. These differential patterns can be explained by the distinct spatial arrangement of the populations (linear and bidimensional in Entrepenas and Bolarque, respectively). PMID- 21653346 TI - Meristem fate and bulbil formation in Titanotrichum (Gesneriaceae). AB - Titanotrichum oldhamii (a monotypic genus from Taiwan, Okinawa, and adjacent regions of China) has inflorescences bearing either showy yellow flowers or asexual bulbils. Asexual reproduction by bulbils is important in natural populations, and bulbil production increases in August and September at the end of the flowering season (which runs from June to the end of September). The bulbils are small (~1-2.5 mm long) and numerous. They consist of a small portion of stem (bract-stem) topped by opposite storage bracts that enclose a minute apical meristem. A secondary root develops from the side of the bract-stem. The floral meristem of T. oldhamii has three possible fates: (1) bulbil formation, (2) flower formation, or (3) bracteose proliferation. Bracteose proliferation rarely occurs and appears to be a developmental transition between the bulbiliferous and racemose inflorescence forms. It is strongly reminiscent of the floricaula and squamosa mutants of Antirrhinum. In the bulbiliferous form a single floral primordium, which would normally produce one flower, gives rise to ~50-70 bulbils by repeated subdivision of the meristem. This form of bulbil production appears to be unique to Titanotrichum. Occasionally a floral meristem divides, but the subdivision forms multiflowered units of up to four flowers rather than bulbils, suggesting that meristem fate is reversible up to the first or second meristem subdivision. In Titanotrichum, therefore, primordium fate is apparently not determined at inception but becomes irreversibly determined shortly after the appearance of developmental characteristics of the floral or bulbil pathway. PMID- 21653347 TI - Origin(s) of the diploid hybrid species Helianthus deserticola (Asteraceae). AB - Homoploid hybrid speciation has traditionally been considered a rare event, dependent on the establishment of both a novel, balanced genotype and reproductive isolating barriers between the new species and its progenitors. However, more recent studies have shown that synthetic hybrids converge toward the chromosomal structure of natural hybrids after only a few generations, suggesting that this phenomenon may be more frequent than previously assumed. Here, the possibility that the diploid hybrid species Helianthus deserticola arose from more than one hybrid speciation event was investigated using patterns of variation from cpDNA, 18 nuclear microsatellite loci, and population interfertility. Helianthus deserticola contains cpDNA haplotypes characteristic of both parental species, is polyphyletic with one parental species based on nine microsatellite loci, and has a high degree of interfertility among populations. The data are consistent with either a single origin followed by introgression with the parental species or multiple origins. Analysis of microsatellite variation places the origin of H. deserticola between 170 000 and 63 000 years before present, making it unlikely that anthropogenic disturbances influenced its origin. Finally, the hybrid species generally has lower levels of genetic diversity but higher levels of differentiation among populations than either parental species. PMID- 21653348 TI - Responses of common and successional heathland species to manipulated salt spray and water availability. AB - Coastal sandplain heathlands are a rare plant community in the northeastern United States. Salt spray and water availability are likely important factors determining heathland distribution. Field surveys and manipulative experiments were performed to examine heathland species' responses to salt spray and water availability. We surveyed field distributions of four typical heathland species: Solidago puberula, Solidago rugosa, Gaylussacia baccata, and Myrica pensylvanica. The distributions of two native tree species, Pinus rigida and Quercus ilicifolia, were also surveyed because they succeed into coastal heathlands with low disturbance frequency. We then manipulated salt spray and water in the field and measured species' water status, necrosis, and growth responses to the treatments. Predawn xylem pressure potential and necrosis were strongly affected by high salt spray and low water availability. Shoot elongation was also limited in S. puberula and S. rugosa grown in high salt, low water treatments. Gaylussacia baccata and Q. ilicifolia were particularly sensitive to high salt spray and low water, suggesting that they might excluded be from areas with those conditions. The interaction between salt spray and water availability could affect the landscape scale and should be incorporated into conservation management plans. PMID- 21653349 TI - Local differentiation and plasticity in size and sex expression in jack-in-the pulpit, Arisaema triphyllum (Araceae). AB - The size advantage hypothesis suggests that natural selection will favor size dependent sex expression when one sex gains more than the other by being large. But members of a minority sex will also have a higher reproductive value, on average. Thus, an individual's reproductive success depends on the reproductive decisions made by neighboring individuals. As a result, the optimal relationship between size and sex may differ among populations. In Arisaema triphyllum, the probability for an individual to be female increases with size, regardless of the character measured. A reciprocal transplant experiment showed the relationship between size and sexual expression is environmentally plastic. Plants originating from our two study sites became female at a larger average size when grown at one site than when grown at the other. In addition to environmental influence on sex expression, the experiment demonstrated genetic differences in the relationship between size and sex. Plants collected from one site became female at a larger size than those from the other, regardless of where they were grown. Thus, while the environment in which an individual was grown had a substantial influence on its sex expression, populations only a few kilometers apart have genetically different relationships between size and sex. PMID- 21653350 TI - Effects of inbreeding on male function and self-fertility in the partially self incompatible herb Campanula rapunculoides (Campanulaceae). AB - We examined the effect of inbreeding on fitness (through both male and female functions) and changes in self-fertility in the partially self-incompatible species Campanula rapunculoides. Individuals in natural populations of C. rapunculoides varied extensively in their strength of self-incompatibility (SI). We crossed 11 individuals that differed in their strength of SI to generate families with four levels of inbreeding (f = 0.0, 0.25, 0.5, and 0.75). Progeny were scored for three traits related to male fitness and for outcrossed and selfed seed production. Analyses of variance revealed significant inbreeding depression for the three male traits and seed set. Families with strong or weak SI differed in their response to inbreeding. Families with weak SI had lower levels of inbreeding depression for most traits than families with strong SI, but strong SI families had a greater increase in selfed seed set, but not self fertility, with inbreeding. Finally, we found evidence of a significant linear response to inbreeding for all three male reproductive traits and outcrossed seed, indicating that inbreeding depression was primarily caused by partially or fully recessive deleterious alleles. Variation in genetic load was associated with variation in self-fertility, a finding that suggests an evolutionary role for partial self-fertility in natural populations of C. rapunculoides. PMID- 21653351 TI - Effects of natural rates of geitonogamy on fruit set in Asclepias speciosa (Apocynaceae): evidence favoring the plant's dilemma. AB - The role of geitonogamy in the evolution of inflorescence design is not well understood. The plant's dilemma hypothesis proposes that evolution of larger inflorescences is driven by selection for greater pollinator attraction, but constrained by higher rates of geitonogamy experienced by larger inflorescences. Here we investigate the role of geitonogamy on fruit set in natural populations of Asclepias speciosa. We compared fruit set from three pollination treatments: (1) inflorescences bagged before and after receiving 6 hand outcross pollinia (Bag), (2) inflorescences unbagged and receiving 6 hand outcross pollinia (Open), and (3) naturally pollinated inflorescences (Control). The Bag and Open treatments initiated significantly more fruits than the Control. Bag aborted significantly fewer fruits than Open or Control. Fruit set was significantly higher in Bag than Open, and Open had significantly higher fruit set than Control. From these results, we conclude that (1) high rates of geitonogamy significantly increase fruit abortion and reduce fruit set in natural populations of A. speciosa and (2) natural populations are compatible pollen limited. Both findings are consistent with the plant's dilemma hypothesis. PMID- 21653352 TI - Floral color change in Weigela middendorffiana (Caprifoliaceae): reduction of geitonogamous pollination by bumble bees. AB - We examined the significance of retaining color-changed flowers in pollination success of Weigela middendorffiana through a single visit of bumble bees. Inner parts of flowers changed color with age from yellow to red. In an investigation of the mating system, duration of each color phase, reproductive ability of each of the color-phase flowers, and the effects of color-changed flowers on bumble bee behavior (1) flowers of this species were self-incompatible, (2) color changed flowers provided little reward to pollinators and little residual reproductive ability, (3) the timing of floral color change was delayed with the progress of flowering season within individual plants, while the duration of the red phase shortened with the progress of flowering season, and (4) red-phase flowers did not attract bumble bees at a distance but did contribute to reducing the number of successive flower visits during a single stay within the plants. Red-phase flowers seemed to indicate the low reward level of old flowers and functioned as a cue to discourage pollinators from staying longer on the same plant. Our results predict that the retention of color-changed flowers without sexual function can enhance the pollination success of a whole plant through male function by reducing successive flower visits during a single stay of pollinators, i.e., geitonogamous pollination. PMID- 21653353 TI - Angiosperm phylogeny based on matK sequence information. AB - Plastid matK gene sequences for 374 genera representing all angiosperm orders and 12 genera of gymnosperms were analyzed using parsimony (MP) and Bayesian inference (BI) approaches. Traditionally, slowly evolving genomic regions have been preferred for deep-level phylogenetic inference in angiosperms. The matK gene evolves approximately three times faster than the widely used plastid genes rbcL and atpB. The MP and BI trees are highly congruent. The robustness of the strict consensus tree supercedes all individual gene analyses and is comparable only to multigene-based phylogenies. Of the 385 nodes resolved, 79% are supported by high jackknife values, averaging 88%. Amborella is sister to the remaining angiosperms, followed by a grade of Nymphaeaceae and Austrobaileyales. Bayesian inference resolves Amborella + Nymphaeaceae as sister to the rest, but with weak (0.42) posterior probability. The MP analysis shows a trichotomy sister to the Austrobaileyales representing eumagnoliids, monocots + Chloranthales, and Ceratophyllum + eudicots. The matK gene produces the highest internal support yet for basal eudicots and, within core eudicots, resolves a crown group comprising Berberidopsidaceae/Aextoxicaceae, Santalales, and Caryophyllales + asterids. Moreover, matK sequences provide good resolution within many angiosperm orders. Combined analyses of matK and other rapidly evolving DNA regions with available multigene data sets have strong potential to enhance resolution and internal support in deep level angiosperm phylogenetics and provide additional insights into angiosperm evolution. PMID- 21653354 TI - Polarity of peatmoss (Sphagnum) evolution: who says bryophytes have no roots? AB - The class Sphagnopsida (Bryophyta) includes two genera: Ambuchanania and Sphagnum. Ambuchanania contains just one rare species known from two Tasmanian localities, but Sphagnum comprises a speciose clade of mosses that dominates many wetland ecosystems, especially in the boreal zone of the Northern Hemisphere. Recent phylogenetic analyses have resolved well-supported clades within Sphagnum, but polarizing Sphagnum evolution has been problematic because the genus is so isolated that it is difficult to determine homologies between morphological and/or molecular traits within Sphagnum with those of any potential outgroup. DNA sequences from 16 genomic regions representing the mitochondrial, chloroplast, and nuclear genomes (ca. 16 kilobases) were obtained from 24 species of Sphagnum plus one species each from Takakia and Andreaea in order to resolve a rooted phylogeny. Two tropical species, S. sericeum and S. lapazense, were resolved as sister to the rest of the genus and are extremely divergent from all other sphagna. The main Sphagnum lineage consists of two clades; one includes the sections Sphagnum, Rigida, and Cuspidata, and the other includes Subsecunda, Acutifolia, and Squarrosa. The placement of section Subsecunda is weakly supported, but other nodes are strongly supported by maximum parsimony, maximum likelihood, and Bayesian analyses. In addition to homogeneous Bayesian analyses, heterogeneous models were employed to account for different patterns of nucleotide substitution among genomic regions. PMID- 21653355 TI - Chromosome studies of cheilanthoid ferns (Pteridaceae: Cheilanthoideae) from the western United States and Mexico. AB - Although analyses of chromosome numbers represent a fundamental step in the study of any group of organisms, the xeric-adapted cheilanthoid ferns (Pteridaceae: subfamily Cheilanthoideae) have received little attention from cytogeneticists due to the difficulty in obtaining samples and accurate chromosome counts. In an effort to clarify patterns of chromosomal evolution in this group, we present 131 chromosome counts representing 75 taxa of cheilanthoid ferns from the western United States and Mexico. First reports are provided for 24 taxa, including the first count for the genus Cheiloplecton. Nine other taxa yielded numbers that had not been reported previously. Our data suggest that chromosome base numbers are more stable than previously thought and that much of the reported variation may involve erroneous counts. When coupled with published DNA sequence data, our counts suggest that the plesiomorphic base number of subfamily Cheilanthoideae is x = 30 and that x = 29 has arisen just once or twice among the taxa studied. PMID- 21653356 TI - New evidence from mitochondrial DNA of a progenitor-derivative species relationship between black spruce and red spruce (Pinaceae). AB - Mitochondrial DNA (mtDNA) markers were used to assess the genetic diversity in allopatric populations of black spruce (Picea mariana [Mill.] BSP) and red spruce (P. rubens Sarg.). Patterns of mitochondrial haplotypes (mitotypes) were strikingly different between the two species. All mtDNA markers surveyed were polymorphic in black spruce, revealing four different mitotypes and high levels of mtDNA diversity (P(p) = 100%, A = 2.0, H = 0.496). In contrast, populations of red spruce had only two mitotypes and harbored low levels of ggenetic diversity (P(p) = 13.2%, A = 1.1, H = 0.120). When the southernmost allopatric populations of red spruce were considered, only one mitotype was detected. As previously reported for nuclear gene loci, the diversity observed for mtDNA in red spruce was a subset of that found in black spruce. Comparison of present and previously published data supports the hypothesis of a recent progenitor-derivative relationship between these species, red spruce presumably being derived by allopatric speciation of an isolated population of black spruce during the Pleistocene. PMID- 21653357 TI - Age and sex-specific rates of leaf regeneration in the Mojave Desert moss Syntrichia caninervis. AB - The extremely skewed female-biased sex ratio in the desert moss Syntrichia caninervis was investigated by assessing the regeneration capacity of detached leaves. Juvenile, green, yellow-green, and brown leaves equating to approximately 0, 2, 6, and 12 yr of age, respectively, were detached from individuals of S. caninervis collected from 10 field populations and grown in a growth chamber for 58 d at a light intensity of 33-128 MUmol . m(-2) . s(-1). Younger leaves (0-2 yr old) tended to have a greater viability, regenerate more quickly, extend their protonemal filaments farther, produce shoots (gametophores) more quickly, produce more shoots, and accumulate a greater biomass than older leaves (6 and 12 yr old). Among younger leaf classes, regenerating female leaves were more likely to produce a shoot than male leaves and produced more shoots than male leaves. The sexes did not differ significantly in time until protonemal emergence, linear extension of protonemata, or rate of biomass accumulation. However, protonemata of male leaves tended to emerge more quickly and produce a greater total biomass, ultimately consisting mostly of protonemata, than did female leaves. The more rapid proliferation of shoots by female leaf regenerants may help to explain the rarity of males in this species. PMID- 21653358 TI - Tree fern growth strategy in the Late Devonian cladoxylopsid species Pietzschia levis from the study of its stem and root system. AB - Portions of stems from five new anatomically preserved specimens of Pietzschia levis from a new Late Devonian plant locality of eastern Tafilalt, Anti-Atlas (Morocco), were analyzed to complete the preliminary reconstruction previously done with a single specimen. The basal part of the longest new specimen consists of an obconical portion of stem surrounded by a thick mantle of adventitious roots. Roots are connected to the peripheral strands of primary xylem specific to the stele of Pietzschia stems. Roots grow outwardly; they cross the cortex and the broad central pith at a steep angle and emerge from the stem lower down. The number of roots produced at one level increases conspicuously from the base towards the distal end of the obconical portion of stem. By contrast, cross sectional dimensions of roots at their origin level decrease distally. Individual roots increase in diameter, and their stele gets more lobed as they grow through stem tissues. The large number of roots at the specimen base and their wider dimensions at this level contribute to the conspicuous enlargement of the stem base. Patterns assessed from the reconstruction of the Pietzschia levis root system may be close to those of the older cladoxylopsids Pseudosporochnales comprising an upright trunk. Growth strategies in the small-statured species P. levis and in younger arborescent ferns of the Psaronius type are compared. They differ mainly in the relative lengths of epidogenetic vs. apoxogenetic growth phases of the stem. PMID- 21653359 TI - Sympodial structure of spikelets in the tribe Schoeneae (Cyperaceae). AB - Spikelet morphology of 250 specimens of 47 species of Schoeneae was examined using light microscopy and scanning electron microscopy. We confirmed that spikelet structure in Schoeneae is cymose with a sympodial "rachilla." Monopodial spikelets, as described by most current literature, were not found in Schoeneae. Prophylls are not always present in sympodial spikelets and cannot be used to determine whether a spikelet is sympodial or monopodial. Spikelets of Schoeneae develop acropetally, and the uppermost glume may or may not produce a flower. The last feature may be variable within species and within individual plants, so presence or absence of this flower is not an indication of sympodial or monopodial spikelet structure in Schoeneae. Relative position of flower, glume, and axis is a reliable criterion to judge whether spikelets are sympodial or monopodial. In some species of Schoenus and in Ptilothrix, formation of the arch shaped base of the fertile glume relates to the shape of the inclined nodes on which the glume grows. This study highlights the need to reinvestigate spikelet structure in other tribes of Cyperaceae. PMID- 21653360 TI - Reproductive strategy and population variability in the facultative apomict Hieracium pilosella (Asteraceae). AB - Molecular studies of apomictic plant species often detect more genotypic variation than predicted from their assumed reproductive mode. The two most commonly invoked mechanisms to explain these high levels of variation are recombination, via facultative sexuality, and mutation. The potential for sexual reproduction in the facultative apomict Hieracium pilosella (Asteraceae) was determined at three field sites by artificially pollinating with the closely related, but morphologically distinct, H. aurantiacum. The level of genotypic variation at the three sites was recorded using inter-simple sequence repeats (ISSRs). There was a significant, positive relationship between the measured potential for sexual reproduction and population genotypic variability, indicating that sex has played a role in the structuring of these populations; however, a causal relationship cannot be stated because of the use of regression. We also applied the recently developed method of compatibility analysis. Compatibility analysis can determine, using the occurrence of "character incompatibilities," whether patterns of variation observed in populations are most parsimoniously explained by mutation or recombination. Compatibility analysis also indicated that sexual reproduction had played a role in generating genotypic diversity in these populations. Combining these different types of data may give a greater understanding of the potential for the generation of genotypic diversity in facultative apomictic populations. PMID- 21653361 TI - Testing for sex differences in biparental inbreeding and its consequences in a gynodioecious species. AB - In many gynodioecious species cross-pollinated seeds from females outperform those from hermaphrodites. Using the gynodioecious alpine perennial Silene acaulis, I investigated whether this was the result of greater biparental inbreeding among hermaphrodites leading to greater biparental inbreeding depression. I also determined the influence of relatedness on progeny fitness. Experiments were performed using individuals from a site whose population structure and coefficient of inbreeding was known. In the first experiment, crosses were made on plants in the field to determine the effect of seven different crossing distances, plus selfing, on germination and early seedling survival and growth. Although selfed seeds died more often and grew slower than crossed seeds, the effect of crossing distance was negligible for all measured fitness traits, refuting the biparental inbreeding hypothesis as a mechanism to explain why seeds from hermaphrodites die more often than those from females. Nonetheless, cross-pollinated seeds from hermaphrodites did die more, indicating that another mechanism must be responsible. In the second experiment, the effect of different levels of inbreeding on germination and seedling survival was determined by growing seeds from experimental matings varying in relatedness. Inbreeding depression for a multiplicative fitness estimate was significant for all levels of inbreeding, suggesting that inbred individuals are unlikely to become established in the population and providing insight into the results of the first experiment. Alternative hypotheses are discussed to explain why seeds from hermaphrodites die more often, which together with the results of this study, suggest that the restoration of male function in hermaphrodites comes with a correlated cost to seedling survival. PMID- 21653362 TI - Spatial genetic structure in populations of the terrestrial orchid Cephalanthera longibracteata (Orchidaceae). AB - Orchid seeds are unusual for being the smallest among flowering plants. These dust-like seeds are wind-borne and, thus, would seem to have the potential for long-distance dispersal (a common perception); this perception has led to a prediction of near-random spatial genetic structure within orchid populations. Mathematical models (e.g., simple ballistic model) for wind-dispersed seeds and wind-tunnel experiments, in contrast, indicate that most seeds of orchids should fall close to the maternal plant (<6 m), supporting a prediction of significant fine-scale genetic structure within populations. In reality we do not know much about seed dispersion in orchids. To determine which of these two predictions is more appropriate, Wright's F statistics and spatial autocorrelation analysis were used to examine the genetic structure within two adult populations of the terrestrial orchid Cephalanthera longibracteata (Orchidaceae) in southern Korea. In results comparable to those of other self-compatible, mixed-mating plant species, C. longibracteata populations exhibited low levels of genetic diversity (mean H(e) = 0.036) and a significant excess of homozygosity (mean F(IS) = 0.330), consistent with substantial inbreeding via selfing and/or mating among close relatives in a spatially structured population. Spatial autocorrelation analysis revealed significant positive genetic correlations among plants located <10 m, with relatedness at <3 m comparable to that expected for half sibs and first cousins. This genetic structure supports the prediction that the majority of seed dispersal occurs over distances of less than 10 m and is responsible for generating substantial overlap in seed shadows within C. longibracteata populations. PMID- 21653363 TI - Mating system and population structure of Acacia aroma and A. macracantha (Fabaceae). AB - Acacia aroma and A. macracantha are closely related species that inhabit northern and central Argentina. The reproductive barriers between them seem to be weak. They exhibit low genetic differentiation, high levels of interspecific gene flow, and extensive areas of sympatry. Isoenzymatic approaches were used to evaluate the population structure and mating system parameters in natural Argentine populations of A. aroma and A. macracantha and to provide new tools for the analysis of relationships between these two species. All studied populations had high levels of genetic variability and no significant departures from Hardy Weinberg expectations, but the two species did not differ from each other. Most variability occured within populations. Mating system analysis showed high levels of outcrossing, no biparental inbreeding, and a high probability that individuals within progeny arrays are full rather than half sibs. In all A. aroma and A. macracantha populations, polymorphic loci had the same allelic variants, and no geographic or genetic isolation between species was found. The results favor the hypothesis that these two entities represent a single polymorphic species rather than two distinct species. PMID- 21653364 TI - Genetic structure of hybrid zones between Pinus pumila and P. parviflora var. pentaphylla (Pinaceae) revealed by molecular hybrid index analysis. AB - Pinus species have three differently inherited genomes: paternal chloroplast, maternal mitochondrial, and biparental nuclear. Our previous study on the hybrid zones between alpine Pinus pumila and montane to subalpine P. parviflora var. pentaphylla demonstrated contrasting patterns of introgression of two cytoplasmic genomes, i.e., the paternal cpDNA flowed from P. parviflora var. pentaphylla to P. pumila, and the maternal mtDNA flowed in the reverse direction. In the present study, we developed codominant nuclear DNA markers diagnostic or mostly diagnostic for each parental species by single-strand conformation polymorphism (SSCP) of polymerase chain reaction (PCR) products, using expressed sequence tag (EST) primers of Pinus taeda. To describe the introgressive patterns of the nuclear genes, the molecular hybrid index (MHI) showing the overall proportion of alleles inferred to be derived from P. pumila was determined for each plant collected in hybrid zones on Mt. Asahidake and Mt. Higashiazuma, Japan. At Mt. Asahidake, the MHI values changed clinally according to the altitudes at which the plants were collected. However, at Mt. Higashiazuma, there was a gap in the MHI values between the plants above and below the Abies and Tsuga forest zone (alt. 1800-1900 m). This suggested that the zone plays a role in creating an effective barrier to gene flow in the hybrid zone. PMID- 21653365 TI - Chloroplast DNA diversity of Hieracium Pilosella (Asteraceae) introduced to New Zealand: reticulation, hybridization, and invasion. AB - The European hawkweed Hieracium pilosella is a successful invader and a troublesome weed in New Zealand. The systematics of the genus Hieracium is extremely complex and contentious, probably due to recent speciation, hybridization, polyploidy, and diverse reproductive strategies. In the first chloroplast DNA survey of the group, we sequenced 285 plants (including H. pilosella and 12 other species of subgenus Pilosella) from New Zealand and Europe for 900 bp of trnL-trnF. Eleven haplotypes were identified with much sharing among species. Three haplotypes (A, D, G) were found in seven, three, and four species, respectively, but two species (H. lactucella and H. auricula) had single, private haplotypes. Our cpDNA data for subgenus Pilosella are consistent with the group's having incomplete lineage sorting and/or recent reticulate evolution. Six haplotypes were identified in H. pilosella, four of these unique to this taxon in our sample. In New Zealand, haplotype A was common and occurred in plants of different ploidy (i.e., 4*, 5*, 6*), whereas haplotypes C, B, and M were restricted to 4*, 5*, and 6* plants, respectively. The distribution of haplotype variation suggests that some or all of the H. pilosella seeds accidentally introduced into New Zealand probably came from east Europe rather than the United Kingdom and that a minimum of four lineages were introduced. Within New Zealand, hybridization of H. pilosella with a related taxon (probably H. praealtum) has occurred at least three times, involving both obligate sexual tetraploids and facultative apomictic pentaploids of H. pilosella. PMID- 21653366 TI - Relationships, origin, and diversity of Galapagos tomatoes: implications for the conservation of natural populations. AB - Endemic Galapagos tomatoes (Lycopersicon cheesmanii) are of great value for cultivated tomato (L. esculentum) breeding, and therefore their conservation is of significance. Although within L. cheesmanii there is heterogeneity for many traits and formal infraspecific classification is not justified, here we distinguish three forms, without taxonomic significance, of L. cheesmanii that are of interest to breeders because of their distinctive morphology and habitat preferences: L. cheesmanii 'short' (one- to two-pinnate leaves, short internodes, and coastal habitats), L. cheesmanii 'long' (one- to two-pinnate leaves, long internodes, and inland habitats), and L. cheesmanii forma minor (three- to four pinnate leaves, short internodes, and coastal habitats). In a recent survey of tomato populations in the Galapagos Islands, we found that several populations of L. cheesmanii reported 30-50 years earlier had disappeared, mostly as a consequence of human activity. In addition, a previously unreported invasive wild red-fruited form, which we named L. esculentum 'Gal cer,' was found on the island of Santa Cruz. The total diversity (estimated with amplified fragment length polymorphisms [AFLPs]) within L. cheesmanii (H(T) = 0.051) is almost as high as that for the mainland wild species L. pimpinellifolium (H(T) = 0.072). Lycopersicon esculentum 'Gal cer,' on the other hand, has a much lower diversity (H(T) = 0.014). Comparison of AFLP fragments shared by L. esculentum 'Gal cer' with other species showed that it is closely related to weedy tomato L. esculentum var. cerasiforme and, therefore, likely of recent origin. Genetic differentiation among the three native L. cheesmanii forms is low (G(ST) = 0.235), indicating that they share a common genetic background. Nonetheless, L. cheesmanii 'short' is about twice as diverse as L. cheesmanii 'long' or L. cheesmanii f. minor. UPGMA cluster and principal components analysis distinguish four groups within Eulycopersicon: L. pimpinellifolium, cultivated L. esculentum, L. esculentum var. cerasiforme including L. esculentum 'Gal cer,' and L. cheesmanii. The geographic distance and genetic distance in the wild forms of Galapagos tomatoes were not correlated. Apart from the pressure of humans, some native L. cheesmanii populations, especially L. cheesmanii 'long,' might be displaced by invasive L. esculentum 'Gal cer' because they share a similar habitat. We did not find evidence of intercrossing of L. cheesmanii with introduced L. esculentum, but occasional hybridization that contributes to loss of genetic integrity of L. cheesmanii cannot be ruled out. Establishment of reserves of L. cheesmanii to protect this species from introduced herbivorous animals and from hybridization with L. esculentum 'Gal cer' would help to conserve L. cheesmanii. Furthermore, accessions collected by C. M. Rick and others in the 1950s-1970s and now stored in germplasm banks could be used to reinstate some extinct populations. PMID- 21653367 TI - The phylogeny, evolution, and classification of the genus Globba and tribe Globbeae (Zingiberaceae): appendages do matter. AB - The genus Globba (100 species) is one of the largest genera in the primarily tropical Zingiberaceae. Globba along with the small genera Gagnepainia, Hemiorchis, and Mantisia comprise the Globbeae, one of the two tribes of subfamily Zingiberoideae. Traditional infrageneric classification in Globba has focused on the number of anther appendages: zero, two, or four. Parsimony and Bayesian analyses were conducted on nuclear internal transcribed spacer (ITS) and plastid trnK-matK data from a broad sampling of Globba and related genera. Results show Mantisia to be monophyletic but nested within Globba, while Hemiorchis and Gagnepainia are monophyletic genera that are sister to each other. Anther appendage number and shape, along with inflorescence and fruit morphology, are the most important characters for understanding evolutionary relationships in Globba. A new infrageneric classification system for Globba, recognizing three subgenera and seven sections is presented. The four species of Mantisia are formally transferred into Globba but retained as a distinct section. Within Globba, a notable biogeographic boundary is seen at the Isthmus of Kra in southern Thailand. PMID- 21653368 TI - Comparative biogeography of the cytotypes of annual Microthlaspi perfoliatum (Brassicaceae) in Europe using isozymes and cpDNA data: refugia, diversity centers, and postglacial colonization. AB - In the last few years, the biogeography of many European plant species has been analyzed using molecular markers, and some consistent patterns of Pleistocenic differentiation and range fluctuations have been established. These studies mostly focused on perennial herbs or woody species, rarely considering annual taxa. This study focused on the annual Microthlaspi perfoliatum, which is distributed all over Europe and comprises three cytotypes. Morphologically, these cytotypes are hard to distinguish, although, based on molecular markers, they should be treated as two different species. Diploid and polyploid cytotypes had a different biogeographical history, with distinct glacial refugia. For the polyploids, a well-known distribution pattern of relict areas was confirmed, with Iberia, Italy, and the Balkans serving as primary Pleistocene refugia. Secondary refuge areas have been detected in southeastern France and neighboring Switzerland, with closer affinity to the Iberian refugium than to any other region based on allozyme and cpDNA haplotype data. For the diploids, two refugia have been characterized, one of which is congruent to the secondary refugium of the polyploids in France and Switzerland. The second refuge of diploid populations is located in unglaciated lowland areas of East Austria and Croatia. Isozyme and cpDNA haplotype data favor a postglacial colonization of diploid populations into Germany from Austrian lowland areas along the Danube River as well as from Switzerland. This scenario is also true for polyploids in Germany, Belgium, and Sweden. PMID- 21653369 TI - A phylogeny of all species of Arceuthobium (Viscaceae) using nuclear and chloroplast DNA sequences. AB - The genus Arceuthobium (dwarf mistletoes, Viscaceae) comprises 42 species that parasitize hosts in Pinaceae and Cupressaceae in the Old and New Worlds. Maximum parsimony analyses were conducted on two data partitions (separately and combined): nuclear ribosomal internal transcribed spacer (ITS) sequences for all 42 currently recognized species and chloroplast trnT-L-F sequences for 34 New World species. The Old and New World species were phylogenetically distinct using ITS, thus making subgenus Arceuthobium paraphyletic. Arceuthobium pendens and A. guatemalense comprise the basalmost clade of subgenus Vaginata, characterized by the presence of flabellate secondary branching. The trnT-L-F sequences, which vary widely in length depending upon taxon, contain three times less phylogenetic signal than ITS, although homoplasy for this partition is lower. Several of the clades obtained from analysis of nuclear ITS sequences are also recovered using trnT-L-F sequences such as A. guatemalense and A. pendens, the A. rubrum group, the A. vaginatum group, and the A. campylopodum group. The ITS + trnT-L-F tree is well resolved except for four internal nodes. A revised classification of the genus is discussed that recognizes only monophyletic species that are well differentiated by molecular data. PMID- 21653370 TI - The phylogeny of Gaura (Onagraceae) based on ITS, ETS, and trnL-F sequence data. AB - Gaura (Onagraceae: Onagreae) is a small North American genus of 21 species consisting mostly of night-blooming, moth-pollinated annuals and perennials. The current infrageneric classification based on differences in habit, floral symmetry, and fruit morphology recognizes eight sections within the genus. We examine the phylogenetic relationships of all 21 species of Gaura using DNA sequence data from the internal transcribed spacer region (ITS), the external transcribed spacer region (ETS), and the plastid trnL-F region. Combined analysis of these regions indicate Gaura is monophyletic only if it includes Stenosiphon, a monotypic genus comprised of S. linifolius. Within Gaura, our studies indicate that sections Gauridium, Schizocarya, Campogaura, Stipogaura, Xenogaura, and Gaura are monophyletic, but sections Xerogaura and Pterogaura are not and should be reevaluated. In addition, molecular data provide support for the hypothesis that G. sinuata and G. drummondii arose via interspecific hybridization followed by genome doubling; their influence on phylogenetic reconstruction is discussed. PMID- 21653371 TI - An expanded plastid DNA phylogeny of Orchidaceae and analysis of jackknife branch support strategy. AB - An expanded plastid DNA phylogeny for Orchidaceae was generated from sequences of rbcL and matK for representatives of all five subfamilies. The data were analyzed using equally weighted parsimony, and branch support was assessed with jackknifing. The analysis supports recognition of five subfamilies with the following relationships: (Apostasioideae (Vanilloideae (Cypripedioideae (Orchidoideae (Epidendroideae))))). Support for many tribal-level groups within Epidendroideae is evident, but relationships among these groups remain uncertain, probably due to a rapid radiation in the subfamily that resulted in short branches along the spine of the tree. A series of experiments examined jackknife parameters and strategies to determine a reasonable balance between computational effort and results. We found that support values plateau rapidly with increased search effort. Tree bisection-reconnection swapping in a single search replicate per jackknife replicate and saving only two trees resulted in values that were close to those obtained in the most extensive searches. Although this approach uses considerably more computational effort than less extensive (or no) swapping, the results were also distinctly better. The effect of saving a maximal number of trees in each jackknife replicate can also be pronounced and is important for representing support accurately. PMID- 21653372 TI - Inflorescence development in a new teosinte: Zea nicaraguensis (Poaceae). AB - Inflorescence development in a newly discovered teosinte, Zea nicaraguensis (Poaceae), from Nicaragua has been investigated using scanning electron microscopy (SEM). The SEM examination revealed that the pattern of both male and female inflorescence development was similar to previously described inflorescence in other Zea taxa. Branch primordia were initiated acropetally in a distichous pattern along the rachis of male and female inflorescences. Spikelet pair primordia bifurcated into pedicellate and sessile spikelet primordia. Predictably, pedicellate spikelet development was arrested and aborted in the female teosinte inflorescence. Organogenesis of functional spikelets and florets was similar to that previously described in maize and teosintes. The results were consistent with our hypothesis that both femininity and masculinity share a common mechanism of inflorescence development in Zea and Tripsacum and are in accord with a putative common mechanism of sex determination in the Andropogoneae. Interestingly, this population of teosinte, unique in its ability to grow in water-logged soils, showed a stable pattern of early inflorescence development. Our results also revealed the uncharacteristic presence of inflorescence polystichy in this population of Zea nicaraguensis. We propose this novel phenotypic variation raises the possibility that a domestic evolution of polystichy in maize was enabled by an occasional polystichous phenotypic in teosinte. PMID- 21653373 TI - De novo variation in life-history traits and responses to growth conditions of resynthesized polyploid Brassica napus (Brassicaceae). AB - Variation that arises in generations immediately following polyploidization may be important for the establishment, adaptation, and persistence of new polyploid species. We previously showed divergence for flowering time among lines from a resynthesized Brassica napus allopolyploid lineage derived from a cross of diploid B. rapa and B. oleracea. In this study, we more fully assess phenotypic differentiation of lines from the previously studied lineage and of lines derived from an additional resynthesized B. napus lineage. Nine polyploid lines and their diploid parents were grown under four growth conditions and measured for eight life-history traits. Polyploid lines within a lineage were expected to be genetically identical because they were derived from individual, chromosome doubled amphihaploid plants. However, significant differences were found among lines within lineages for every phenotypic trait measured and in response to different growth conditions (genotype by environment interactions). When phenotypes of each polyploid line for each trait in each environment were compared with their diploid progenitors, approximately 30% were like one or the other parent, 50% were intermediate, and 20% were transgressive. Our results demonstrate extensive de novo variation in new polyploid lineages. Such changes could contribute to the evolutionary potential in naturally occurring polyploids. PMID- 21653374 TI - Identification of a novel gene, HAABRC5, from Helianthus annuus (Asteraceae) that is upregulated in response to drought, salinity, and abscisic acid. AB - Using differential display of mRNA transcripts, we obtained a partial cDNA clone, RSC5-U, that is upregulated by exposure to high salinity. A longer cDNA of 812 nucleotides, designated HaABRC5, was then cloned by rapid amplification of cDNA ends. This full-length cDNA contains an open reading frame of 423 nucleotides encoding 141 amino acids, including a "bipartite nuclear targeting sequence." The deduced amino acid sequence had no similarity to known genes in the database. The expression of HaABRC5 was investigated in more detail using quantitative reverse transcriptase-polymerase chain reaction. HaABRC5 is upregulated by drought, high salinity, and exogenous application of abscisic acid (ABA). The promoter sequence of 229 nucleotides, upstream of HaABRC5, was cloned using rapid amplification of genomic ends. Three ABA-responsive elements were found within the HaABRC5 promoter region. Therefore, HaABRC5 is probably an ABA-responsive nuclear protein playing a role in plant stress response. PMID- 21653375 TI - Seed production from the mixed mating system of Chesapeake Bay (USA) eelgrass (Zostera marina; Zosteraceae). AB - In monoecious plants, gametes can be exchanged in three ways: among unrelated genets (outbreeding), with close relatives (inbreeding), or within individuals (geitonogamous selfing). These different mating systems may have consequences for population demography and fitness. The experiment presented herein used artificial crosses to examine the mating system of Chesapeake Bay, Virginia, USA eelgrass (Zostera marina L; Zosteraceae), a bisexual submerged aquatic plant that can outbreed, inbreed, and self. Genetic data indicate severe heterozygosity deficiencies and patchy genotype distribution in these beds, suggesting that plants therein reproduce primarily by vegetative propagation, autogamy, or geitonogamy. To clarify eelgrass reproductive strategies, flowers from three genetically and geographically distinct beds were hand-pollinated in outbred, inbred, and selfed matings. Fertilization success and seed production, life history stages which contribute greatly to the numeric maintenance of populations, were monitored. We found no evidence that inbreeding had negative consequences for seed production. On the contrary, selfed matings produced seeds significantly more frequently than outcrossed matings and produced significantly larger numbers of seeds than either inbred or outbred matings. These results contrast with patterns for eelgrass in other regions but might be expected for similar populations in which pollen limitation or a short reproductive season renders selfing advantageous. PMID- 21653376 TI - The reproductive biology of Sophora fernandeziana (Leguminosae), a vulnerable endemic species from Isla Robinson Crusoe. AB - Sophora fernandeziana is the only legume endemic to Isla Robinson Crusoe (Archipelago Juan Fernandez, Chile); it is uncommon and becoming rare. Although its preservation status is listed as "vulnerable," as with many species, little is known of its reproductive biology. Flowering phenology, floral morphology, nectar features, breeding system, and visitors were analyzed in two populations. Flowering is from late winter to early spring. Flowers last 6 d and have a number of ornithophilous features. A floral nectary begins to secrete highly concentrated nectar 48 h after flowers open. Nectar secretion increases as the flower ages but culminates in active nectar reabsorption as the flower senesces. Nectar production is negatively affected by nectar removal. Self-pollen germinates and tubes grow down the style. However, pollen tubes were only observed to enter the ovaries in open pollinated styles, suggesting the possibility of an ovarian self-incompatibility mechanism. Both sexes of the two hummingbird species that inhabit the island are regular visitors. Low fruit and seed set, low genetic diversity, and a shrinking number of populations all contribute to increased concern about the future of this species-and perhaps the hummingbirds that depend on it. PMID- 21653377 TI - Breeding system evolution in Tarasa (Malvaceae) and selection for reduced pollen grain size in the polyploid species. AB - Polyploidy, primarily allopolyploidy, has played a major role throughout flowering plant evolution with an estimated 30-80% of all extant angiosperms carrying traces of ancient or recent polyploidy. One immediate and seemingly invariant phenotypic consequence of genome doubling is larger cell size in polyploids relative to their diploid progenitors. In plants, increases in pollen grain and guard cell sizes exemplify this rule and are often used as surrogate evidence for polyploidy. Tarasa (Malvaceae), a genus of 27 species primarily distributed in the high (>3000 m) Andes, has numerous independently generated tetraploid species, most of which have pollen grains smaller than their putative diploid parents. The tetraploids are also unusual because they are annual, rather than perennial, in habit. Data correlate these apparent anomalies to a change in the breeding system within the genus from xenogamy (outcrossing) in the diploid species to autogamy (inbreeding) in the tetraploids, leading to a convergence in reduced floral morphology. The harsh environment of the high-elevation Andean habitats in which all the tetraploid annuals are found is implicated as a critical factor in shaping the evolution of these unusual polyploids. PMID- 21653378 TI - Phosphatized multicellular algae in the Neoproterozoic Doushantuo Formation, China, and the early evolution of florideophyte red algae. AB - Phosphatic sediments of the Late Neoproterozoic (ca. 600 million years old [Myr]) Doushantuo Formation at Weng'an, South China, contain fossils of multicellular algae preserved in anatomical detail. As revealed by light microscopy and scanning electron microscopy, these fossils include both simple pseudoparenchymatous thalli with apical growth but no cortex-medulla differentiation and more complex thalli characterized by cortex-medulla differentiation and structures interpretable as carposporophytes, suggesting a multiphasic life cycle. Simple pseudoparenchymatous thalli, represented by Wengania, Gremiphyca, and Thallophycoides, are interpreted as stem group florideophytes. In contrast, complex pseudoparenchymatous thalli, such as Thallophyca and Paramecia, compare more closely to fossil and living corallinaleans than to other florideophyte orders, although they also differ in some important aspects (e.g., lack of biocalcification). These more complex thalli are interpreted as early stem group corallinaleans that diverged before Paleozoic stem groups such as Arenigiphyllum, Petrophyton, Graticula, and Archaeolithophyllum. This phylogenetic interpretation implies that (1) the phylogenetic divergence between the Florideophyceae and its sister group, the Bangiales, must have taken place before Doushantuo time-an inference supported by the occurrence of bangialean fossils in Mesoproterozoic rocks; (2) the initial diversification of the florideophytes occurred no later than the Doushantuo time; and (3) the corallinalean clade had a "soft" (uncalcified) evolutionary history in the Neoproterozoic before evolving biocalcification in the Paleozoic and undergoing crown group diversification in the Mesozoic. PMID- 21653379 TI - Adaptive radiation of photosynthetic physiology in the Hawaiian lobeliads: light regimes, static light responses, and whole-plant compensation points. AB - Six endemic genera/sections of lobeliads (Campanulaceae) occupy nearly the full range of light regimes on moist sites in the Hawaiian Islands, from open alpine bogs and seacliffs to densely shaded rainforest interiors. To determine whether this clade has undergone a corresponding adaptive radiation in photosynthetic adaptations, we studied the natural light habitats and physiological characteristics of 11 species representing each sublineage. Across species in the field, average photon flux density (PFD) varies from 2.3 to 30.0 mol . m(-2) . d( 1), and maximum assimilation rate (A(max)) ranges from 0.17 to 0.35 MUmol CO(2) . g(-1) . s(-1). Across species, A(max), dark respiration rate (R), Michaelis Menten constant (k), light compensation point, specific leaf area (SLA), maximum carboxylation rate (V(cmax)), maximum rate of electron transport (J(max)), photosynthesis at saturating CO(2) (A(satCO(2))), and carboxylation efficiency (alpha) all increase significantly and in tightly coupled fashion with PFD, in accord with classical economic theory. Area-based rates have a higher degree of physiological integration with each other and tighter coupling to PFD than the corresponding mass-based rates, despite the energetic importance of the latter. Area-based rates frequently show adaptive cross-over: high-light species outperform low-light species at high PFD and vice versa at low PFD. A(max)-mass has little relationship to leaf mass per unit area (LMA), leaf N content, or leaf lifespan individually, but a multiple regression explains 96% of the variance in A(max)-mass across species in terms of SLA, leaf N content, and average PFD. Instantaneous leaf compensation points range from 0.1 to 1.2% full sunlight, far lower than the ecological (whole-plant) compensation points (ECPs) of 1.1 to 29.0% sunlight calculated based on photosynthetic parameters, leaf longevity, and allocation to leaf vs. nonleaf tissue. The ECPs are much closer to the lower limits of PFD actually experienced by lobeliads, suggesting they may play an important role in restricting species distributions. Taken together, these data provide evidence for an adaptive radiation in photosynthetic traits that is strongly correlated with-and indeed may help determine-the light regime that each species inhabits. PMID- 21653380 TI - Phylogeny and biogeography of Caltha (Ranunculaceae) based on chloroplast and nuclear DNA sequences. AB - The genus Caltha (Ranunculaceae) consists of 10 species of low-growing, perennial herbs distributed throughout the moist temperate and cold regions of both the Northern and Southern Hemispheres. Traditionally, the species have been divided into two sections: section Psychrophila in the Southern Hemisphere with diplophyllous leaves and section Caltha in the Northern Hemisphere with leaves lacking inflexed appendages. This study uses chloroplast and nuclear DNA sequences to determine the relationships among the 10 species, test the monophyly of sections Psychrophila and Caltha, trace the evolutionary history of diplophylly, and explore biogeographical hypotheses for the genus. Analysis of these data resulted in a well-resolved and well-supported phylogeny. Section Psychrophila (C. sagittata, C. appendiculata, C. dionaeifolia, C. obtusa, C. introloba, and C. novae-zelandiae) was resolved as monophyletic, indicating a single origin of diplophylly. The species of section Caltha (C. natans, C. scaposa, C. palustris, and C. leptosepala) formed a paraphyletic grade. The resulting phylogeny strongly supports a Northern Hemisphere origin for Caltha, followed by dispersal to the Southern Hemisphere (Gondwanaland). A vicariance model is invoked to explain present-day distributions in South America, Australia, and New Zealand. PMID- 21653381 TI - Molecular evidence for bicontinental hybridogenous genomic constitution in Lepidium sensu stricto (Brassicaceae) species from Australia and New Zealand. AB - Lepidium sensu stricto (s.s.) (Brassicaceae) (ca. 150 species) is distributed worldwide with endemic species on every continent. It is represented in Australia and New Zealand by 19 and seven native species, respectively. In the present study we used a nuclear ribosomal internal transcribed spacer (ITS) phylogeny in comparison with a cpDNA phylogeny to unravel the origin of Australian/New Zealand species. Although phylogenetic relationships within Lepidium s.s. were not fully resolved, the cpDNA data were in agreement with a Californian origin of Lepidium species from Australia/New Zealand. Strongly conflicting signals between the cp- and nuclear DNA phylogenetic analysis clearly indicated hybridogenous genomic constitution of Australian Lepidium s.s. species: All 18 studied Australian/New Zealand Lepidium s.s. species examined shared a Californian cpDNA type. While eleven Australian/New Zealand species appeared to harbor a Californian ITS type, a group of seven species shared a South African ITS type. This pattern is most likely explained by two trans-oceanic dispersals of Lepidium from California and Africa to Australia/New Zealand and subsequent hybridization followed by homogenization of the ribosomal DNA either to the Californian or South African ITS type in the two different lineages. Calibration of our molecular trees indicates a Pliocene/Pleistocene origin of Lepidium in Australia/New Zealand. Low levels of cpDNA and ITS sequence divergence and unresolved topologies within Australian/New Zealand species suggest a rapid and recent radiation of Lepidium after the hybridization event. This coincides with dramatic climatic changes in that geological epoch shaping the composition of the vegetation. PMID- 21653382 TI - Elatinaceae are sister to Malpighiaceae; Peridiscaceae belong to Saxifragales. AB - Phylogenetic data from plastid (ndhF and rbcL) and nuclear (PHYC) genes indicate that, within the order Malpighiales, Elatinaceae are strongly supported as sister to Malpighiaceae. There are several putative morphological synapomorphies for this clade; most notably, they both have a base chromosome number of X = 6 (or some multiple of three or six), opposite or whorled leaves with stipules, unicellular hairs (also uniseriate in some Elatinaceae), multicellular glands on the leaves, and resin (Elatinacae) or latex (Malpighiaceae). Further study is needed to determine if these features are synapomorphic within the order. Malpighiaceae have previously been inferred as sister to Peridiscaceae based on rbcL sequence data, but the rbcL sequence of Whittonia is a chimera of two sequences, neither of which appears to be Whittonia. Our data from plastid (atpB, rbcL) and nuclear (18S rDNA) genes instead place Peridiscaeace as a member of the Saxifragales. PMID- 21653383 TI - Phylogenetics and biogeography of the neotropical fern genera Jamesonia and Eriosorus (Pteridaceae). AB - Jamesonia and Eriosorus are two traditionally recognized fern genera in the Neotropics that together form a monophyletic group. Molecular phylogenetic analyses for this study suggest, however, that neither genus is itself monophyletic and that several independent lineages with the jamesonia morphotype have each undergone a fairly recent radiation in paramo ecosystems. A robust phylogeny was generated based on sequence data of the nuclear external transcribed spacer (ETS) of 18S-26S rDNA, the plastid gene rps4 and the intergenic spacer rps4-trnS. Several conclusions can be made concerning the evolutionary history and biogeographic patterns of the Jamesonia-Eriosorus complex: (1) "jamesonia" is polyphyletic, making "eriosorus" paraphyletic; (2) all analyses recover three major clades in the Andes; (3) two well-supported clades can be recognized, corresponding to the northern vs. central Andes; and (4) the sister taxon of the Andean radiation is the Brazilian taxon Eriosorus myriophyllus. Jamesonia is a potential example of a recent adaptive radiation because the group is characterized as being morphologically and ecologically diverse and its habitat is of recent origin. PMID- 21653384 TI - Allelopathic inhibition of germination by Alliaria petiolata (Brassicaceae). AB - Garlic mustard (Alliaria petiolata, Brassicaceae) is an invasive, nonindigenous species currently invading the understory of North American woodlands where it is a serious threat to the native flora. Part of this success might be due to allelopathic interference by garlic mustard. Two congeneric species, the European Geum urbanum and the North American Geum laciniatum, were tested for allelopathic inhibition of germination by garlic mustard. Seeds were germinated either on substrate contaminated by garlic mustard or on substrate with contamination neutralized by activated carbon. Allelopathic effects of native European and invasive North American garlic mustard populations were also compared. Activated carbon increased germination by 14%, indicating that garlic mustard contaminated the substrate through root exudates. Activated carbon in turn counteracted this effect. The two test species differed in their sensitivity to allelopathic interference. North American G. laciniatum had a much stronger increase in germination when activated carbon was added to the substrate, independent of the origin of garlic mustard. In contrast, the European G. urbanum germinated better in substrate precultivated with North American garlic mustard, whereas activated carbon increased its germination only in substrate precultivated with European garlic mustard. PMID- 21653385 TI - The floral biology of Curcumorpha longiflora (Zingiberaceae): a ginger with two day flowers. AB - Curcumorpha longiflora is a perennial chasmophyte (rock fissure plant) ginger that usually grows in crevices of calcareous rocks and forms patches on the understory of limestone monsoon rainforests. The pollination ecology of C. longiflora was studied by monitoring phenology and flowering behavior, observing pollinator activity (frequency and behavior of visitors), and the quantity and quality of pollination services. We also investigated the germination of pollen grains and growth of pollen tubes after different pollination treatments to detect its breeding system. Based on the results: (1) for the first time in Zingiberaceae a new protandrous mechanism was found with a two-day flowering to avoid autogamy in this species; (2) under field conditions, all individuals of C. longiflora usually produced only one flower every other day to keep geitonogamy to a minimum; (3) germination of pollen grains and growth rates of pollen tubes under different pollination treatments were the same 4 h later after pollination, suggesting that C. longiflora is completely self-compatible; (4) among the limited visitors, Bombus sp. and Apis florae were effective pollinators, but they were active at different times and at different stages of the flower, probably receiving different rewards. PMID- 21653386 TI - Anatomy of the unusual stigma in Orchidantha (Lowiaceae). AB - The stigma of Orchidantha is unlike any other stigma in the Zingiberales. It is zygomorphic and dorsiventral, and its complicated structure has confused botanists resulting in many different descriptions and interpretations. Basally and ventrally on the three-lobed stigma, a specialized "secretion tissue"-here called the viscidium-is found. When a pollinator enters the flower, mucilage from the viscidium becomes smeared over the dorsal side of the body, making it sticky so that pollen may adhere to it. The viscidium probably originates from secretory pollen-receptive epidermal cells, and in O. maxillarioides a gradual change in morphology between these cells and the viscidium is found. However, in O. fimbriata such a transition is lacking. In the "one-way" flower of O. fimbriata, the peripheral parts of the style consist of sclerenchymatous tissue making the style rigid. In O. maxillarioides, however, the pollinator enters and leaves the flower the same way, and to avoid self-pollination, the stigma is pushed upwards when the pollinator enters the flower. In this position, the pollinator cannot touch the receptive parts of the stigma when it leaves the flower. The flexibility of the style that maintains its dislocated position is accomplished by collenchymatous rather than sclerenchymatous tissue in the peripheral parts of the style. PMID- 21653387 TI - Comparative analysis of leaf shape development in Eschscholzia californica and other Papaveraceae-Eschscholzioideae. AB - Dissected leaves in Papaveraceae-Eschscholzioideae have an architecture frequently encountered in the basal eudicot clade Ranunculales that could represent an ancestral condition for eudicots. Developmental morphology of foliage leaves was investigated using scanning electron microscopy and focusing on primordium formation activity (primary morphogenesis) at the leaf margin. Eschscholzia californica, E. lobii, and Hunnemannia fumariaefolia had a polyternate-acropetal mode of leaf dissection. Segment formation continued around the whole leaf blade periphery. Differences in mature leaf architecture was traced to variations in regional blastozone activity and duration. Epidermal cell size measurements in E. californica indicated that the leaf tip tissue starts to differentiate already at the onset of organogenic activity and that tip cells remain larger than epidermal cells at the basal margins during further growth. It is argued that early differentiation of the tip does not set up a general basipetal differentiation gradient, but is a local effect that allows acropetal pinna initiation to occur in subapical blastozones. In Dendromecon, secondarily entire leaves have evolved through the loss of primordium formation activity. Marginal corrugations found in Dendromecon form late in development and are not reminiscent of lateral primordia. PMID- 21653388 TI - Cytokinesis in Coleochaete orbicularis (Charophyceae): an ancestral mechanism inherited by plants. AB - Recently, highly vacuolate cells of Arabidopsis were shown to exhibit "polarized" cytokinesis, in which the phragmoplast and cell plate contact the mother cell wall and then progress from one side of the cell to the other, rather than forming uniformly outward from the cell center (Cutler and Ehrhardt, 2002, Proceedings of the National Academy of Sciences, USA 99: 2812-2817). It was not known if such a mechanism was unique to flowering plants or whether it occurred more broadly in the plant clade. To determine if a polar mechanism of cell division might have been characteristic of the first plants, differential interference contrast optics were used to examine living cells of the charophycean green alga Coleochaete orbicularis, a close relative of plants, with cytokinesis involving a phragmoplast. By recording images in different focal planes over time, such "polarized" cytokinesis was found in cells dividing either parallel or perpendicular to the edge of this radially symmetrical organism. Previously reported differences between these two types of division in Coleochaete were clarified. Polarized cytokinesis appears to be an ancestral mechanism of plant cell division inherited from the highly vacuolate cells of the charophycean algal ancestors of plants. PMID- 21653389 TI - Floral development and molecular phylogeny support the generic status of Tasmannia (Winteraceae). AB - The taxonomic status of and evolutionary relationship between Tasmannia and Drimys (Winteraceae) have been subjects of controversy for many years. In this paper, a molecular phylogenetic analysis of the family with sequences of previously unpublished Tasmannia and Drimys species confirms earlier conclusions that Tasmannia and Drimys do not form a monophyletic group, despite the fact that they appear to share distinctive inflorescence and floral morphological attributes. Examination of alternative hypotheses of relationships with likelihood-ratio tests and parametric bootstrapping supports the separation of Tasmannia and Drimys. A detailed analysis of floral development in Tasmannia lanceolata and T. xerophila indicates that timing and position of sepal initiation differs between them, but that the position of subsequent organ initiation predictably follows from sepal position. This is in contrast to Drimys winteri, where a prolonged delay between sepal and petal initiation leads to the production of many phyllotactic patterns. The prolonged period of calyx tube growth leading to the formation of a calyptra in Tasmannia and Drimys probably evolved in parallel in the two lineages. PMID- 21653390 TI - The four-celled female gametophyte of Illicium (Illiciaceae; Austrobaileyales): implications for understanding the origin and early evolution of monocots, eumagnoliids,and eudicots. AB - The recent consensus that Amborellaceae, Nymphaeales, and Austrobaileyales form the three earliest-diverging lineages of angiosperms has led comparative biologists to reconsider the origin and early developmental evolution of the angiosperm seven-celled/eight-nucleate (Polygonum-type) female gametophyte. Illicium mexicanum (Illiciaceae; Austrobaileyales) develops a four-celled/four nucleate female gametophyte. The ontogenetic sequence of the Illicium female gametophyte is consistent with that of all other Austrobaileyales and also with all Nymphaeales and is likely a plesiomorphy of angiosperms. A character analysis based on more than 250 embryological studies indicates that a transition from an ancestrally four-celled/four-nucleate Illicium-like female gametophyte to a seven celled/eight-nucleate female gametophyte occurred in the common ancestor of the sister group to Austrobaileyales (a clade that includes monocots, eumagnoliids, and eudicots). Comparative analysis of reconstructed ancestral female gametophyte ontogenies identifies specific early stages of ontogeny that were modified during this transition. These modifications generated two important angiosperm novelties a set of three persistent antipodal cells and a binucleate central cell, which upon fertilization yields a triploid endosperm. Early angiosperms are anatomically quite diverse in these two features, although triploid endosperm, composed of one paternal genome and two maternal genomes, is a conserved feature of the overwhelming majority of angiosperms. PMID- 21653391 TI - Biomechanics and anatomy of Lycopersicon esculentum fruit peels and enzyme treated samples. AB - We report the biomechanics and anatomy of fruit wall peels (before and after cellulase/pectinase treatment) from two Lycopersicon esculentum cultivars (i.e., Inbred 10 and Sweet 100 cherry tomatoes). Samples were tested before and after enzyme treatment in uniaxial tension to determine their rate of creep, plastic and instantaneous elastic strains, breaking stress (strength), and work of fracture. The fruit peels of both cultivars exhibited pronounced viscoelastic and strain-hardening behavior, but differed significantly in their rheological behavior and magnitudes of material properties, e.g., Inbred 10 peels crept less rapidly and accumulated more plastic strains (but less rapidly), were stiffer and stronger, and had a larger work of fracture than Sweet 100 peels. The cuticular membrane (CM) also differed; e.g., Sweet 100 CM strain-softened at forces that caused Inbred 10 to strain-harden. The mechanical behavior of peels and their CM correlated with anatomical differences. The Inbred 10 CM develops in subepidermal cell layers, whereas the Sweet 100 CM is poorly developed below the epidermis. Based on these and other observations, we posit that strain-hardening involves the realignment of CM fibrillar elements and that this phenomenon is less pronounced for Sweet 100 because fewer cell walls contribute to its CM compared to Inbred 10. PMID- 21653392 TI - Ontogeny of triovulate cones of Ephedra intermedia and origin of the outer envelope ofovules of Ephedraceae. AB - The origin of the two envelopes of ovules of extant species of Ephedraceae has been discussed previously in different ways based only on investigation of bimerous female cones. To generalize the characteristics of the two envelopes, ontogenetic and metamorphic patterns of the two envelopes of ovules of trimerous female cones of Ephedra intermedia Schrenk et C. A. Meyer were studied using scanning electron microscopy. The outer envelope of the ovules of triovulate female cones of Ephedra intermedia is initiated as two adaxial lateral protuberances. Thus, the outer envelope of extant Ephedraceae may have been derived from three foliar components of the second proximal whorl of the secondary reproductive shoot of the ancestral compound female cone. Two adaxial lateral foliar components likely gave rise to the outer envelope by fusion, while the third abaxial foliar component was reduced. These new findings suggest that the Gnetales derived their female cones from trimerous multiaxial female reproductive organs of their progenitors. Some evolutionary aspects of female cones of Ephedra are also discussed. PMID- 21653393 TI - Analysis of circular bordered pit function I. Angiosperm vessels with homogenous pit membranes. AB - A model predicted pit and vessel conductivity, the air-seed pressure for cavitation, and the implosion pressure causing vessel collapse. Predictions were based on measurements from 27 angiosperm species with circular bordered pits and air-seed pressures of 0.2-11.3 MPa. Vessel implosion pressure exceeded air-seed pressure by a safety factor of 1.8 achieved by the increase in vessel wall thickness per vessel diameter with air-seed pressure. Intervessel pitting reduced the implosion pressure by 20 to 40%. Pit hydraulic conductivity decreased by 30 fold from low (<1 MPa) to high (>10 MPa) air-seed pressure primarily because of decreasing pit membrane conductivity. Vessel conductivity (per length and wall area) increased with vessel length as higher lumen conductivity overcame low pit conductivity. At the "saturating vessel length," vessel conductivity maximized at the Hagen-Poiseuille value for the lumen per wall area. Saturated vessel conductivity declined by sixfold with increasing air-seed pressure because of increased wall thickness associated with increased implosion resistance. The saturated vessel length is likely the optimal length because: (a) shorter vessels have lower conductivities, (b) longer vessels do not increase conductivity when functional yet decrease it more when cavitated, (c) observed pit structure most closely optimized vessel conductivity at the saturated length, and (d) saturated lengths were similar to measured lengths. PMID- 21653394 TI - Analysis of circular bordered pit function II. Gymnosperm tracheids with torus margo pit membranes. AB - A model of xylem conduit function was applied to gymnosperm tracheids with torus margo pit membranes for comparison with angiosperm vessels. Tracheids from 17 gymnosperm tree species with circular bordered pits and air-seed pressures from 0.8 to 11.8 MPa were analyzed. Tracheids were more reinforced against implosion than vessels, consistent with their double function in transport and support. Tracheid pits were 3.3 to 44 times higher in hydraulic conductivity than vessel pits because of greater membrane conductivity of the torus-margo configuration. Tight scaling between torus and pit size maximized pit conductivity. Higher pit conductivity allowed tracheids to be 1.7-3.4 times shorter than vessels and still achieve 95% of their lumen-limited maximum conductivity. Predicted tracheid lengths were consistent with measured lengths. The torus-margo structure is important for maximizing the conductivity of the inherently length-limited tracheid: replacing the torus-margo membrane with a vessel membrane caused stem tracheid conductivity to drop by 41%. Tracheids were no less hydraulically efficient than vessels if they were long enough to reach their lumen-limiting conductivity. However, this may only be possible for lumen diameters below approximately 60-70 MUm. PMID- 21653395 TI - Morphological and RAPD analysis of hybridization between Quercus affinis and Q. laurina (fagaceae), two Mexican red oaks. AB - Quercus affinis and Q. laurina are two closely related Mexican red oaks with partially overlapping distributions. Within the area of overlap, there are localities where morphological intergradation occurs. A previous hypothesis explained this pattern as a result of secondary contact between the two species, followed by hybridization and introgression. This possibility was analyzed here by examining foliar and genetic variation in 16 localities situated along a macrogeographic gradient, which included morphologically representative populations of both species and populations from within the area of overlap. Maximum-likelihood hybrid index scores calculated from nine semi-diagnostic RAPD markers indicated a shift in the genetic composition of populations from one species to the other along the macrogeographic gradient, with genetically intermediate populations situated in the area of overlap. Foliar variation followed a partially congruent pattern, but Q. laurina-like morphology predominated in some of the genetically intermediate populations. There were several instances of correlated frequency changeovers of single RAPD markers and morphological characters along the macrogeographic gradient and a few cases of markedly parallel patterns between markers. The results were interpreted as consistent with a hypothesis of secondary contact between the two oak species that has resulted in some differential introgression among markers. PMID- 21653396 TI - Evolution of obligate pollination mutualism in New Caledonian Phyllanthus (Euphorbiaceae). AB - About half a dozen obligate pollination mutualisms between plants and their seed consuming pollinators are currently recognized, including fig-fig wasp, yucca yucca moth, and the recently discovered Glochidion tree-Epicephala moth mutualisms. A common principle among these interactions is that the pollinators consume only a limited amount of the seed crop within a developing fruit (or fig in the case of fig-fig wasp mutualism), thereby ensuring a net benefit to plant reproduction. A novel obligate, seed-parasitic pollination mutualism between two species of New Caledonian Phyllanthus (Euphorbiaceae), a close relative of Glochidion, and Epicephala moths (Gracillariidae) is an exception to this principle. The highly specialized flowers of Phyllanthus are actively and exclusively pollinated by species-specific Epicephala moths, whose larvae consume all six ovules of the developing fruit. Some flowers pollinated by the moths remain untouched, and thus a fraction of the fruits is left intact. Additional evidence for a similar association of Epicephala moths in other Phyllanthus species suggests that this interaction is a coevolved, species-specific pollination mutualism. Implications for the evolutionary stability of the system, as well as differences in mode of interaction with respect to the Glochidion Epicephala mutualism, are discussed. PMID- 21653397 TI - Belowground bud banks and meristem limitation in tallgrass prairieplant populations. AB - Rhizome meristem populations were sampled in tallgrass prairie to quantify the size, grass : forb composition, and temporal and spatial variability of the soil bud bank and to compare fire effects on bud bank and seed bank composition. Soil cores (10.5 cm diameter, 15 cm deep) were collected from replicate annually and infrequently burned tallgrass prairie sites, and intact rhizomes and rhizome buds were censused. Bud bank densities ranged from approximately 600 to 1800 meristems/m(2) among sites and had high spatial and seasonal variability. In annually burned prairie, the total bud bank density was two-fold greater and the grass : forb meristem ratio was more than 30-fold greater than that of infrequently burned prairie. These patterns are opposite those observed in soil seed banks at this site. The rhizome population in annually burned prairie was 34% larger than the established aboveground tiller population. By contrast, the bud bank density in unburned prairie was significantly lower than aboveground stem densities, indicating possible belowground meristem limitation of stem density and net primary production on infrequently burned prairie. The patterns observed in this study suggest that the densities and dynamics of tallgrass prairie plant populations, as well as their response to disturbance (e.g., fire and grazing) and climatic variability, may be mediated principally through effects on the demography of belowground bud populations. Patterns of seed reproduction and seed bank populations have little influence on short-term aboveground population dynamics of tallgrass prairie perennials. PMID- 21653398 TI - Caribou-induced changes in species dominance of lichen woodlands: an analysis ofplant remains. AB - Plant communities in northern Quebec-Labrador, Canada have been severely grazed and trampled since the early 1980s by the increasingly large George River caribou herd (GRCH). To evaluate changes in species dominance associated with caribou disturbance, we compared past and present ground vegetation from 14 lichen woodlands. Plant remains from superficial organic horizons indicate that ground vegetation was largely dominated by lichens (especially Cladina) before the onset of caribou disturbance. In enlargments of aerial photos taken before 1975 (i.e., prior to maximum size of the GRCH), all sites were free of caribou trails and were dominated by a continuous lichen (Cladina) carpet. Principal components analysis showed that partial or complete destruction of the Cladina-dominated lichen carpet was the most striking change in ground vegetation. Severe trampling degraded superficial organic horizons, subsequently exposing mineral soil in heavily used sites. With reduced caribou activity in the 1990s, exposed ground was colonized by crustose lichens and Cladonia. Sites that faced severe grazing but light trampling were recolonized mainly by small podetia of Cladina stellaris sprouting from the lichen litter. However, patterns of post-caribou disturbance lichen succession differed from those of post-fire succession, because species from different successional stages are present at the same time in a stand and also because caribou can modify the successional trajectory at any time. PMID- 21653399 TI - Allometric gender allocation in Ambrosia Artemisiifolia (Asteraceae) has adaptive plasticity. AB - Evidence is reported for size-dependent (allometric) gender allocation in the monoecious, wind-pollinated annual Ambrosia artemissifolia. Consistent with established theory, the pattern of allometry displayed adaptive plasticity, depending on the environmental cause of variation in plant size. Plant size gradients were generated in both field and greenhouse experiments using separate and combined gradients of shading, soil nutrient levels, and neighbor proximity. When plant size constraints involved light limitation from shading (e.g., because of close neighbor proximity), decreasing plant size was generally associated with decreasing maleness and increasing femaleness (based on relative male and female flower production, respectively). This is consistent with the "pollen-dispersal" hypothesis in which the consequences of relatively small plant size (among larger neighbors) imposes less severe limitation for female reproductive success than for male reproductive success (because success as an outcrossing donor of wind dispersed pollen increases with increasing plant height, especially when neighbors are present). However, when size was constrained by soil nutrient limitation alone (i.e., without shading effects), the results had the converse allometric relationship; i.e., decreasing plant size was generally associated with increasing maleness and decreasing femaleness. This is consistent with the "size-advantage" and "time-limitation" hypotheses in which energetic and time limitations (respectively) associated with relatively small plant size impose a less severe limitation for male reproductive success than for female reproductive success. PMID- 21653400 TI - Chromosome numbers and karyotype evolution in holoparasitic Orobanche (Orobanchaceae) and related genera. AB - Chromosome numbers and karyotypes of species of Orobanche, Cistanche, and Diphelypaea (Orobanchaceae) were investigated, and 108 chromosome counts of 53 taxa, 19 counted for the first time, are presented with a thorough compilation of previously published data. Additionally, karyotypes of representatives of these genera, including Orobanche sects. Orobanche and Trionychon, are reported. Cistanche (x = 20) has large meta- to submetacentric chromosomes, while those of Diphelypaea (x = 19) are medium-sized submeta- to acrocentrics. Within three analyzed sections of Orobanche, sects. Myzorrhiza (x = 24) and Trionychon (x = 12) possess medium-sized submeta- to acrocentrics, while sect. Orobanche (x = 19) has small, mostly meta- to submetacentric, chromosomes. Polyploidy is unevenly distributed in Orobanche and restricted to a few lineages, e.g., O. sect. Myzorrhiza or Orobanche gracilis and its relatives (sect. Orobanche). The distribution of basic chromosome numbers supports the groups found by molecular phylogenetic analyses: Cistanche has x = 20, the Orobanche-group (Orobanche sect. Orobanche, Diphelypaea) has x = 19, and the Phelipanche-group (Orobanche sects. Gymnocaulis, Myzorrhiza, Trionychon) has x = 12, 24. A model of chromosome number evolution in Orobanche and related genera is presented: from two ancestral base numbers, x(h) = 5 and x(h) = 6, independent polyploidizations led to x = 20 (Cistanche) and (after dysploidization) x = 19 (Orobanche-group) and to x = 12 and x = 24 (Phelipanche-group), respectively. PMID- 21653401 TI - Phylogenetic classification of peltigeralean fungi (Peltigerales, Ascomycota) based on ribosomal RNA small and large subunits. AB - To provide a comprehensive molecular phylogeny for peltigeralean fungi and to establish a classification based on monophyly, phylogenetic analyses were carried out on sequences from the nuclear ribosomal large (LSU) and small (SSU) subunits obtained from 113 individuals that represent virtually all main lineages of ascomycetes. Analyses were also conducted on a subset of 77 individuals in which the ingroup consisted of 59 individuals representing six families, 12 genera, and 54 species potentially part of the Peltigerineae/Peltigerales. Our study revealed that all six families together formed a strongly supported monophyletic group within the Lecanoromycetidae. We propose here a new classification for these lichens consisting of the order Peltigerales and two suborders-Collematineae subordo nov. (Collemataceae, Placynthiaceae, and Pannariaceae) and Peltigerineae (Lobariaceae, Nephromataceae, and Peltigeraceae). To accommodate these new monophyletic groups, we redefined the Lecanorineae, Pertusariales, and Lecanorales sensu Eriksson et al. (Outline of Ascomycota-2003, Myconet 9: 1-103, 2003). Our study confirms the monophyly of the Collemataceae, Lobariaceae, Nephromataceae, and Peltigeraceae, and the genera Nephroma, Sticta, and Peltigera. However, Leptogium, Lobaria, Pseudocyphellaria, and Solorina were found to be nonmonophyletic genera. Reconstruction of ancestral symbiotic states within the Peltigerales, using maximum likelihood (ML) and a Bayesian approach to account for phylogenetic uncertainty, revealed an evolutionary scenario in which bimembered associations with cyanobacteria were ancestral, followed by multiple independent acquisitions of green algae to form tripartite symbioses and rare subsequent losses of the cyanobiont to form bimembered symbioses with green algae. PMID- 21653402 TI - Post-glacial history of Trillium grandiflorum (Melanthiaceae) in eastern North America: inferences from phylogeography. AB - Dispersal and migration are important processes affecting the evolutionary history and genetics of species. Here we investigate post-glacial migration and gene flow in Trillium grandiflorum (Melanthiaceae), a wide-ranging, forest herb from eastern North America. Using phylogeographic approaches, we examined cpDNA and allozyme diversity in 35 populations of T. grandiflorum sampled from throughout the geographic range of the species. Nested clade analysis (NCA) of cpDNA haplotypes indicated that T. grandiflorum likely survived in two refugia in the southeastern US during the last glaciation and that long-distance dispersal characterized the post-glacial recolonization of northern areas. There was no evidence for reduced allozyme diversity in populations from glaciated compared to ice-free regions, probably because of the greater abundance and larger effective size of populations in the north. An analysis of isolation-by-distance based on the allozyme data suggested a pattern of population differentiation consistent with restricted gene flow. Notwithstanding the significance of rare seed dispersal events for migration, a comparison of allozyme and cpDNA genetic structure indicates that pollen flow between populations is more likely than seed dispersal. These results for T. grandiflorum represent the first phylogeographic analysis of a temperate woodland herb in eastern North America and support the importance of occasional long-distance dispersal events in the post-glacial migration of plants. PMID- 21653403 TI - Patterns of evolution in western North American Mimulus (Phrymaceae). AB - A well-supported phylogeny is presented from both chloroplast DNA (the trnL/F region) and two regions of nuclear rDNA (ITS [internal transcribed spacer] and ETS [external transcribed spacer]) with nearly complete sampling for Mimulus (Phrymaceae) in western North America. Three separate genera are derived from within the clade that contains all the Mimulus species in western North America. The taxonomic status of the proposed sections of Mimulus and the relationships of many taxonomically difficult species are considered with observations on morphological evolution. Discordance between data sources provides support for the hypothesis that M. evanescens is a hybrid between M. latidens and M. breviflorus. In two major clades (Eunanus and Diplacus), patterns of genetic variation do not match the current taxonomy. The clustering of taxa in Eunanus is strongly associated with geographic distributions. Mimulus aurantiacus sensu Thompson, M. nanus, and M. floribundus are found to be progenitor species to other species that appear to be derived from within them. Polyploidy and aneuploidy events are clustered near the tips of the phylogeny. Thus, these two mechanisms are concluded to have played a relatively small role in the evolution of persistent lineages in Mimulus. The phylogenetic distribution of rare taxa is also examined. PMID- 21653404 TI - Intergeneric and infrafamilial phylogeny of subfamily Monsteroideae (Araceae) revealed by chloroplast trnL-F sequences. AB - The chloroplast trnL-F region was used as an independent data set for phylogenetic analysis of 118 aroid taxa. We investigated the intergeneric relationships of subfamily Monsteroideae (Araceae) and used this as a basis for an interspecific phylogenetic study of Rhaphidophora Hassk., the largest genus of the Monsteroideae. Results of the molecular tree were useful for inferring subfamilial and tribal circumscription and evolution in Araceae. Our results show that family Araceae consists of five clades that correspond to the subfamilies traditionally recognized. Starting from the most basal clade, these correspond to subfamilies Gymnostachydoideae and Orontioideae (proto aroids), with Lemna sp. (Lemnaceae) embedded in the Araceae and sister to the true aroids consisting of Pothoideae sister to Monsteroideae, immediately sister to Lasioideae and Aroideae. There is less agreement with existing tribal classifications. Complex relationships exist between members of the Monsteroideae. Our results show that Rhaphidophora and Epipremnum are paraphyletic with species of Rhaphidophora sampled, forming three informal groups with other genera of the Monstereae. Phylogenetic results may be used to suggest taxonomic changes to the current systematics of the monsteroids. PMID- 21653405 TI - Anatomically preserved Liquidambar (Altingiaceae) from the middle Miocene of Yakima Canyon, Washington state, USA, and its biogeographic implications. AB - Liquidambar changii Pigg, Ickert-Bond & Wen sp. nov. (Altingiaceae) is established for anatomically preserved, middle Miocene infructescences from Yakima Canyon, Washington, USA. Specimens are spherical, ~2.5 cm in diameter, and have ~25-30 tightly packed, bilocular fruits per head. Fruits are 3.4-4.7 mm wide * 2.6-3.5 mm long and wedge shaped, fused at the base, and free distally. Each locule contains 1-2 mature, elongate seeds proximally and 5-9 aborted seeds of more irregular shape distally. Mature seeds are 1.5 mm long * 1.2 mm wide, elongate, and triangular transversely, with a slight flange. Seeds have a seed coat for which three zones can be well defined, a uniseriate outer palisade layer, a middle region of isodiametric cells comprising most of the integument, and a uniseriate inner layer of tangentially elongate cells lining the embryo cavity. Liquidambar changii is most similar to the eastern Asian L. acalycina H. T. Chang on features of infructescence, fruit, and seed morphology and quite unlike the North American L. styraciflua L. and other species. Such a close relationship between these two species supports a Beringian biogeographic track between eastern Asia and western North America during the Miocene. Previous phylogenetic and allozyme analysis of modern Liquidambar demonstrates a close relationship between North American-western Asian taxa and suggests a North Atlantic biogeographic track in the middle Miocene. Together, these biogeographic tracks underscore the complexity of the biogeographic history of the Altingiaceae in the Northern Hemisphere throughout the Neogene. PMID- 21653406 TI - The intertidal marine lichen formed by the pyrenomycete fungus Verrucaria tavaresiae (Ascomycotina) and the brown alga Petroderma maculiforme (Phaeophyceae): thallus organization and symbiont interaction. AB - The thallus formed by the marine pyrenomycete fungus Verrucaria tavaresiae and the phaeophycean alga Petroderma maculiforme was studied to elucidate the organization of the symbionts, determine the type of cellular contacts between them, and evaluate the status of the symbiosis as a lichen. Hand-sectioned and resin-embedded samples were examined with light and transmission electron microscopy. Within the uppermost portion of the cellular fungal tissue, separate algal filaments were arranged anticlinally. Protrusions of the fungal cell wall penetrated into adjacent algal walls but did not enter the cell lumen. A striking feature of these penetrations was the frequent separation of algal cell wall layers and insertion of fungal wall material between them. Algal filaments grew downward intrusively between fungal cells, often penetrating deeply into the fungal cell wall. Despite the exceptional nature of the phycobiont involved, the Verrucaria tavaresiae-Petroderma maculiforme symbiosis unequivocally fits the prevailing concept of a lichen. The distinctive interpenetrations observed between symbionts may be related to the integration of their different growth forms within a coherent tissue regularly subject to mechanical stresses. Periclinal cell divisions within and just below the algal layer may serve to replenish surface tissues lost to abrasion and herbivory. PMID- 21653407 TI - Viability and longevity of pollen from transgenic and nontransgenic tall fescue (Festuca arundinacea) (Poaceae) plants. AB - Pollen is an important vector of gene flow in plants, particularly for outcrossing species like tall fescue. Several aspects of pollination biology were investigated using pollen from transgenic and nontransgenic plants of tall fescue (Festuca arundinacea Schreb.), the most important forage species worldwide of the Festuca genus. To effectively assess in vitro pollen viability in tall fescue, an optimized germination medium (0.8 mol/L sucrose, 1.28 mmol/L boric acid and 1.27 mmol/L calcium nitrate) was developed. Treatment with relatively high temperatures (36 degrees and 40 degrees C) and high doses of UV-B irradiation (900-1500 MUW/cm(2)) reduced pollen viability, while relative humidity did not significantly influence pollen viability. Viability of pollen from transgenic progenies (T1 and T2) was similar to that from seed-derived control plants. Pollen from primary transgenics (T0) and primary regenerants (R0) had various levels of viability. Hand pollination using the primary regenerants and transgenics revealed that no seed set could be obtained when pollen viability was lower than 5%. Pollen from transgenic progenies and nontransgenic control plants could survive up to 22 h under controlled conditions in growth chamber. However, under sunny atmospheric conditions, viability of transgenic and nontransgenic pollen reduced to 5% in 30 min, with a complete loss of viability in 90 min. Under cloudy atmospheric conditions, pollen remained viable up to 240 min, with about 5% viability after 150 min. This report is the first on pollen viability and longevity in transgenic forage grasses and could be useful for risk assessment of transgenic plants. PMID- 21653408 TI - Natural selection favors rapid reproductive phenology in Potentilla pulcherrima (Rosaceae) at opposite ends of a subalpine snowmelt gradient. AB - In high altitude plants, flowering quickly ensures reproductive success within a short snow-free period, but limits maturation time and fecundity. Natural selection on prefloration intervals may therefore vary in contrasting snowmelt environments and could influence the outcome of phenological responses to climatic change. This study investigated adaptive differentiation and plasticity of prefloration intervals in the subalpine perennial Potentilla pulcherrima. Three years of in situ field observations were combined with phenotypic selection analyses and a common garden experiment. Plants from high, intermediate, and low altitudes expressed similar prefloration intervals and plasticity when grown at common altitude, indicating no evidence for adaptive differentiation. Selection on the prefloration interval was negative at both low and high altitudes before and after accounting for strong positive selection on size. Environmental differences between high and low altitudes indicated that long, dry seasons and short, wet seasons both favored rapid reproduction. Therefore, quicker reproduction was adaptive in response to late snowmelt, but slower reproduction in response to earlier snowmelt appeared to be maladaptive. Selection differed marginally between late snowmelt years and dry ones. Plastic responses to future precipitation patterns may therefore have positive or negative effects on fitness within a single species, depending upon altitude and year. PMID- 21653409 TI - Genetic diversity in harvested and protected populations of wild American ginseng, Panax quinquefolius L. (Araliaceae). AB - Genetic diversity was examined at 16 allozyme loci in 21 wild populations of the medicinal plant American ginseng, Panax quinquefolius L. (Araliaceae). This species has been harvested from forests in North America for more than 250 years. Average expected heterozygosity was significantly greater within protected populations (H(e) = 0.076) than within populations in which harvesting was permitted (H(e) = 0.070). More notably, genetic structure was greater among unprotected populations (G(ST) = 0.491) than among protected populations (G(ST) = 0.167). These differences in the level and distribution of genetic diversity in American ginseng populations indicate that harvesting may have significant evolutionary implications for this species. Age class structure also shifted toward smaller, nonreproductive plants in unprotected populations. Juvenile plants had lower genetic diversity (H(e) = 0.067) than reproductive plants (H(e) = 0.076) suggesting that conserving a proportion of the largest (oldest) plants in each population is important to protect reproductive fitness and the evolutionary potential of the species. Due to its high genetic structure, conservation recommendations include protecting populations throughout the range of P. quinquefolius. PMID- 21653410 TI - Microsatellite analysis of spatial structure among seedlings in populations of Pinus strobus (pinaceae). AB - In a detailed analysis of how limited seed dispersal can create spatial structuring of genetic variation, several nuclear microsatellites were assayed in seedlings from two forests of Pinus strobus, one old growth (OG) and the other (second site, SS) logged in ca. 1900. By using loci with a large number of alleles and new statistical methods on averaged spatial correlation coefficients, unusually precise estimates of spatial genetic structure were obtained, even though the structure was expected to be very weak. This high precision allowed the spatial patterns to be contrasted across loci and populations. At the OG site, the average spatial correlation coefficient for short distances (<15 m) exceeded its random expected value by 0.035, providing an indirect estimate of ca. 230 for Wright's neighborhood size. The value is similar to that estimated in a previous study of adult trees at OG and probably represents the natural level of spatial structure. A very similar value, 0.030, was obtained for seedlings at SS, despite the fact that unlike OG, genotypes of adults are randomly distributed, a likely result of logging. The results show that a single cycle of limited seed dispersal recreated the natural level of spatial structuring. In addition, one microsatellite, Rps50, had far greater amounts of allele variation, likely implicating it as having a higher mutation rate. The spatial structure of Rps50 also was significantly reduced, in a way that could be consistent with theoretical effects of high mutation rates (up to MU = 10(-2)). The choice of markers may influence estimates of spatial genetic structure. For example, if Rps50 is omitted the values are nearly doubled to 0.058 and 0.051 for SS and OG, respectively, both indicating a much smaller neighborhood size of ca. 100. PMID- 21653411 TI - Effect of temperature on pollen tube kinetics and dynamics in sweet cherry, Prunus avium (Rosaceae). AB - Prevailing ambient temperature during the reproductive phase is one of several important factors for seed and fruit set in different plant species, and its consequences on reproductive success may increase with global warming. The effect of temperature on pollen performance was evaluated in sweet cherry (Prunus avium L.), comparing as pollen donors two cultivars that differ in their adaptation to temperature. 'Sunburst' is a cultivar that originated in Canada with a pedigree of cultivars from Northern Europe, while 'Cristobalina' is a cultivar native to southeast Spain, adapted to warmer conditions. Temperature effects were tested either in controlled-temperature chambers or in the field in a plastic cage. In both genotypes, an increase in temperature reduced pollen germination, but accelerated pollen tube growth. However, a different genotypic response, which reflected the overall adaptation of the pollen donor, was obtained for pollen tube dynamics, expressed as the census of the microgametophyte population that successfully reached the base of the style. While both cultivars performed similarly at 20 degrees C, the microgametophyte population was reduced at 30 degrees C for Sunburst and at 10 degrees C for Cristobalina. These results indicate a differential genotypic response to temperature during the reproductive phase, which could be important in terms of the time needed for a plant species to adapt to rapid temperature changes. PMID- 21653412 TI - Growth, nitrogen uptake, and metabolism in two semiarid shrubs grown at ambient and elevated atmospheric CO2 concentrations: effects of nitrogen supply and source. AB - The effect of differences in nitrogen (N) availability and source on growth and nitrogen metabolism at different atmospheric CO(2) concentrations in Prosopis glandulosa and Prosopis flexuosa (native to semiarid regions of North and South America, respectively) was examined. Total biomass, allocation, N uptake, and metabolites (e.g., free NO(3)(-), soluble proteins, organic acids) were measured in seedlings grown in controlled environment chambers for 48 d at ambient (350 ppm) and elevated (650 ppm) CO(2) and fertilized with high (8.0 mmol/L) or low (0.8 mmol/L) N (N(level)), supplied at either 1 : 1 or 3 : 1 NO(3)(-) : NH(4)(+) ratios (N(source)). Responses to elevated CO(2) depended on both N(level) and N(source), with the largest effects evident at high N(level). A high NO(3)(-) : NH(4)(+) ratio stimulated growth responses to elevated CO(2) in both species when N was limiting and increased the responses of P. flexuosa at high N(level). Significant differences in N uptake and metabolites were found between species. Seedlings of both species are highly responsive to N availability and will benefit from increases in CO(2), provided that a high proportion of NO(3)- to NH(4)-N is present in the soil solution. This enhancement, in combination with responses that increase N acquisition and increases in water use efficiency typically found at elevated CO(2), may indicate that these semiarid species will be better able to cope with both nutrient and water deficits as CO(2) levels rise. PMID- 21653413 TI - Leaf support biomechanics of neotropical understory herbs. AB - Plants in light-limited tropical rainforest understories face an important carbon allocation trade-off: investment of available carbon into photosynthetic tissue should be advantageous, while risk of damage and mortality from falling debris favors investment into nonphotosynthetic structural tissue. We examined the modulus of rupture (sigma(max)), Young's modulus of elasticity (E), and flexural stiffness (F) of stems and petioles in 14 monocot species from six families. These biomechanical properties were evaluated with respect to habitat, rates of leaf production, clonality, and growth form. Species with higher E and sigma(max), indicating greater resistance per unit area to bending and breaking, respectively, tended to be shade-tolerant, slow growing, and nonclonal. This result is consistent with an increase in carbon allocation to structural tissue in shade-tolerant species at the expense of photosynthetic tissue and growth. Forest- edge species were weaker per unit area (had a lower E), but had higher flexural stiffness due to increases in stem and petiole diameter. While this is inefficient in requiring more carbon per unit of structural support, it may enable forest-edge species to support larger and heavier leaves. Our results emphasize the degree to which biomechanical traits vary with ecological niche and illustrate suites of characteristics associated with different carbon allocation strategies. PMID- 21653414 TI - Developmental and physiological correlates of leaf size in Hyeronima alchorneoides (Euphorbiaceae). AB - The tropical emergent tree Hyeronima alchorneoides has large decreases in leaf size with tree age: 1200 cm(2) at 1 yr, 900 cm(2) at 3 yr, 200 cm(2) at 11 yr, and 80 cm(2) in old (>30 yr) individuals. We tracked leaf growth and physiological attributes on trees of three different ages (1, 3, and 11 yr) to determine the developmental basis and functional consequences of this variation. Leaves on young trees grew faster and sustained maximum rates of leaf expansion longer than leaves on older trees. Leaf mass per area (LMA) did not differ among age classes. Maximum photosynthetic rates reflected differences in leaf nitrogen concentration, in which leaves from the lower crown of younger trees outperformed those at a comparable crown position in older trees. One-year-old trees had the lowest stomatal conductance and the greatest instantaneous water use efficiency. Ontogenetic plasticity in mature leaf size, structure, and physiology may be a balance between the advantages conferred by rapid height growth when trees are young and the benefits derived from producing branches that increase light harvesting ability as trees reach the canopy. PMID- 21653415 TI - Identifying clades in Asian Annonaceae: monophyletic genera in the polyphyletic Miliuseae. AB - The tribe Miliuseae (Annonaceae) comprises six genera distributed in Asia: Alphonsea, Mezzettia, Miliusa, Orophea, Platymitra, and Phoenicanthus. A phylogenetic study to investigate the putative monophyly of the tribe and the intergeneric relationships is presented here. Nucleotide sequences of the plastid gene rbcL, trnL intron, and trnL-trnF intergenic spacer were analyzed from 114 Annonaceae taxa, including 24 Miliuseae species and two outgroups using maximum parsimony and Bayesian inference. The two data sets (rbcL and the trnL-trnF regions) were analyzed separately and in combination. Miliuseae were found to be polyphyletic due to the position of Mezzettia and are part of a large, predominantly Asian and Central-American clade (miliusoid clade). Although intergeneric relationships were poorly resolved, all genera, except Polyalthia, were monophyletic, supporting previous generic delimitation based on morphology. A group of three Polyalthia species seems the most likely sister group of Miliusa. Several infrageneric groups of Miliusa, Orophea, and Polyalthia are supported by both molecular and morphological data. No morphological synapomorphies have yet been found for the miliusoid clade. Molecular clades within the miliusoid clade, however, can be characterized by size and the shape of the outer petals, number of ovules per carpel, and the size of the fruits. PMID- 21653416 TI - Phylogenetic relationships and biogeography of Fuchsia (Onagraceae) based on noncoding nuclear and chloroplast DNA data. AB - To examine relationships and test previous sectional delimitations within Fuchsia, this study used parsimony and maximum likelihood analyses with nuclear ITS and chloroplast trnL-F and rpl16 sequence data for 37 taxa representing all sections of Fuchsia and four outgroup taxa. Results support previous sectional delimitations, except for F. verrucosa, which is related to a Central American clade rather than to section Fuchsia and is described here as a new section Verrucosa. The basal relationships within Fuchsia are poorly resolved, suggesting an initial rapid diversification of the genus. Among the species sampled, there is strong support for a single South Pacific lineage, a southern South American/southern Brazilian lineage, a tropical Andean lineage, and one or two Central American and Mexican lineages. There is no clear support for an austral origin of the genus, as previously proposed, which is more consistent with Fuchsia's sister group relationship with the boreal Circaea. An ultrametric molecular clock analysis (all minimal dates) places the split between Fuchsia and Circaea at 41 million years ago (mya), with the diversification of the modern-day lineages of Fuchsia beginning at 31 mya. The South Pacific Fuchsia lineage branches off around 30 mya, consistent with fossil records from Australia and New Zealand. The large Andean section Fuchsia began to diversify around 22 mya, preceded by the divergence of the Caribbean F. triphylla at 25 mya. The Brazilian members of section Quelusia separated from the southern Andean F. magellanica around 13 mya, and the ancestor of the Tahitian F. cyrtandroides split off from the New Zealand species of section Skinnera approximately 8 mya. PMID- 21653417 TI - DNA sequences from Miocene fossils: an ndhF sequence of Magnolia latahensis (Magnoliaceae) and an rbcL sequence of Persea pseudocarolinensis (Lauraceae). AB - We report a partial ndhF sequence (1528 bp) of Magnolia latahensis and a partial rbcL sequence (699 bp) of Persea pseudocarolinensis from the Clarkia fossil beds of Idaho, USA (Miocene; 17-20 million years [my] BP). The ndhF sequence from M. latahensis was identical to those of extant M. grandiflora, M. schiediana, M. guatemalensis, and M. tamaulipana. Parsimony analysis of the ndhF sequence of M. latahensis and previously reported ndhF sequences for Magnoliaceae placed M. latahensis within Magnolia as a member of the Theorhodon clade. This result is reasonable considering that: (1) the morphology of M. latahensis is very similar to that of extant M. grandiflora, and (2) a recent molecular phylogenetic study of Magnoliaceae showed that the maximum sequence divergence of ndhF among extant species is very low (1.05% in subfamily Magnolioideae) compared with other angiosperm families. We reanalyzed the previously reported rbcL sequence of M. latahensis with sequences for all major lineages of extant Magnoliales and Laurales. This sequence is sister to Liriodendron, rather than grouped with a close relative of M. grandiflora as predicted by morphology and the results of the ndhF analysis, possibly due to a few erroneous base calls in the sequences. The rbcL sequence of P. pseudocarolinensis differed from rbcL of extant Persea species by 3-6 nucleotides and from rbcL of extant Sassafras albidum by two nucleotides. Phylogenetic analyses of rbcL sequences for all major lineages of Magnoliales and Laurales placed the fossil P. pseudocarolinensis within Lauraceae and as sister to S. albidum. These results reinforce the suggestion that Clarkia and other similar sites hold untapped potential for molecular analysis of fossils. PMID- 21653418 TI - A floral ontogenetic study on the sister group relationship between the genus Samolus (Primulaceae) and the Theophrastaceae. AB - The former Primulales used to be subdivided into the woody Theophrastaceae and Myrsinaceae, from the tropics and subtropics, and the herbaceous Primulaceae, which are mainly found in the temperate regions of the northern hemisphere. Recent analyses based on morphological as well as molecular data revealed a close relationship between the genus Samolus L. of Primulaceae and the monophyletic family Theophrastaceae. We studied the floral development of six species from four different genera of Theophrastaceae and compared it to floral ontogenetical data of Samolus valerandi L. to find support for a close relationship. Samolus and the members of Theophrastaceae share the presence of staminodes and a similar development of the placenta and the ovules. Apart from the different habit and distribution, however, we also observed some major differences between both lineages, such as the absence of common primordia in Theophrastaceae, the development of a gynoecial cap in Samolus, and the difference in development, shape, and structure of the staminodes. Therefore, we propose to keep Samolus separated from the genera of the Theophrastaceae, and we suggest that it be raised to family level. PMID- 21653419 TI - The development of the superior ovary in Tetraplasandra (Araliaceae). AB - Tetraplasandra is a small Hawaiian genus of seven species with remarkable diversity in ovary position, ranging from inferior to completely superior. Tetraplasandra gymnocarpa is the only member of the Araliaceae with a fully superior ovary. A comparative study of floral anatomy and development in superior and inferior ovary species of Tetraplasandra revealed that the superior ovary in T. gymnocarpa is unusual in that it develops within an epigynous ground plan. During the course of development, the ovary changes from inferior to secondarily superior primarily by an upward expansion of the ovary from the insertion point of the perianth and androecium to the ovary apex. The superior ovary of T. gymnocarpa, evident in late ontogeny, is a modified inferior ovary; thus it is not structurally homologous to a truly superior ovary. The adaptive significance of the switch from inferior to superior ovary is reexamined. A recent phylogeny of Tetraplasandra and the biogeography of the extant species provide evidence that the change in ovary position may be associated with a shift in pollination strategy that may have occurred as recently as 2.6 million years ago. PMID- 21653420 TI - The potential for genetic assimilation of a native dandelion species, Taraxacum ceratophorum (Asteraceae), by the exotic congener T. officinale. AB - Exotic plant species can threaten closely related native congeners through asymmetric hybridization and subsequent backcrossing, the process known as genetic assimilation. I explore the initial stages of this process in Taraxacum ceratophorum (Asteraceae), the native alpine dandelion, and the invasive apomict T. officinale. In central Colorado, seven T. ceratophorum populations all occur in sympatry with T. officinale. In one large population on Pennsylvania Mountain, surveys further revealed that flowering phenologies and visiting insect taxa overlap almost completely for both Taraxacum species. Together these results indicated that heterospecific pollen transfer is likely. Crossing experiments showed that T. ceratophorum is an obligate outcrosser, and interspecific hand pollinations resulted in 37.3% seed set. However, molecular analysis of the F1 offspring indicated that only 33.2% of germinating seeds were hybrids; the remainder were selfed offspring produced from a breakdown in self-incompatibility (the mentor effect). Although the mentor effect helps reduce the production of hybrids, the asymmetrical direction of hybridization creates the potential for genetic assimilation of T. ceratophorum by T. officinale. PMID- 21653421 TI - Correlation between distyly and ploidy level in Damnacanthus (Rubiaceae). AB - Somatic chromosomes were observed in 661 individuals of 14 taxa, nine species and five varieties, of Damnacanthus (Rubiaceae). Chromosome numbers are reported for the first time for 13 taxa. Diploid (2n = 22) and tetraploid (2n = 44) counts were obtained. Distyly is reported for the first time for four species, D. angustifolius, D. henryi, D. labordei, and D. officinarum. A strong correlation exists between chromosome number and occurrence of distyly. Regardless of taxa in Damnacanthus, distylous populations are diploid, and monomorphic populations are tetraploid. Flowers of the monomorphic populations observed have a long style and short stamens with few exceptions. Polyploidization may have caused the breakdown of distylous to monomorphic flowers. In D. indicus, leaves from the tetraploid populations tend to be larger than those from the diploid populations. Populations of tetraploid D. indicus were distributed in more northern areas than those of the diploid. Three types of sympatric distribution were found for the varieties of D. indicus in Japan: diploid and tetraploid, two diploids, and two tetraploids. Based on the present chromosome number study, the taxonomy of the varieties of D. indicus should be revised. PMID- 21653422 TI - Self-pollination in island and mainland populations of the introduced hummingbird pollinated plant, Nicotiana glauca (Solanaceae). AB - Traits associated with self-pollination are common in island plants. This pattern could simply reflect the vestige of selection during colonization. Alternatively (or in addition), the ability to self-pollinate may provide a reproductive assurance benefit in established island plant populations due to inferior island pollinator service. To test these alternatives I studied an introduced plant (Nicotiana glauca; Solanaceae) on the California mainland and on two Channel Islands colonized at different times (approximately 30 and 100 yr ago). I compared these populations in terms of (1) capacity for self-pollination (self compatibility, autogamy, stigma-anther distance, and incidence of a crumpled floral morph) and (2) current selection for the ability to self-pollinate (pollinator service by hummingbirds and the effect of emasculation on reproductive success). In general, island plants exhibited a higher capacity for self-pollination than mainland plants, especially on the most recently colonized island. However, island plants were not visited less frequently or more variably, nor did I detect current selection for selfing on islands. This supports the hypothesis that selfing traits in island plants are the product of a filter to successful establishment during colonization and not of selection for selfing in established island populations. PMID- 21653423 TI - Analysis of fern spore banks from the soil of three vegetation types in the central region of Mexico. AB - The vertical structure of fern spore banks was studied in a xerophilous shrubland, montane rain forest, and pine-oak forest in Hidalgo, Mexico, using the emergence method. Soil samples were collected in April 1999 at depths of 0-10, 10 20, and 20-30 cm. Viable spores decreased significantly with depth in all vegetation types, and the highest number of prothallia and sporophytes was found in the uppermost layer. The montane rain forest and the xerophilous shrubland had the largest and the richest banks, respectively. Twenty-three fern taxa were registered in the aboveground vegetation, 12 in the soil banks, and 43.5% were in both. Aboveground and in the soil bank, the xerophilous shrubland, the montane rain forest, and the pine-oak forest had, 17 and 7, 1 and 6, and 7 and 3 taxa, respectively. These were distributed differentially in relation to depth. The Sorensen index indicated a similarity of 61.5% between the xerophilous shrubland and the montane rain forest, and the Czeckanovsky index indicated 19.75%. The presence of viable spores in the soil of all vegetation types confirmed the existence of natural spore banks. Long-distance dispersal was an important factor determining the specific composition of the xerophilous shrubland and the pine oak forest. PMID- 21653424 TI - Seedling recruitment and survival of an endangered limestone endemic in its natural habitat and experimental reintroduction sites. AB - The largest and most fecund population of the endangered Purshia subintegra is restricted to limestone mesas in Verde Valley, Arizona, USA, where habitat destruction is imminent. To examine factors limiting its distribution and potential for expansion, we compared recruitment and survival of seedlings growing in soils from occupied and unoccupied habitat in caged field experiments and compared survival of caged and wild seedling cohorts from 1998 to 2003. In field tests, seeds germinated in soils from occupied and unoccupied habitats. Seedling survival, however, was greatest in currently occupied habitat and dropped to zero in some unoccupied habitats with the onset of severe drought. Among 16 factors measured, soil moisture significantly explained between 62% and 71% of the variation in recruitment in both wild and caged plots. Shrubs conferred protection to wild seedlings, but decreased caged seedling survival. For 5 yr following germination, caged seedlings had greater survival than natural seedling cohorts indicating that reintroduction was comparatively more successful than natural recruitment. Expansion of P. subintegra into novel habitats is limited by soil moisture capacity, and this condition varied during the experimental time frame. Reintroductions to limestone mesas are possible and most promising if cages and supplemental watering are used. PMID- 21653425 TI - Drought tolerance associated with vertical stratification of two co-occurring epiphytic bromeliads in a tropical dry forest. AB - Vertical stratification of epiphytes generally has not been reported for dry forests. For two epiphytic Crassulacean acid metabolism bromeliads that segregate vertically, it was hypothesized that different potentials for photoprotection or shade tolerance rather than drought tolerance is responsible for the observed stratification. The light environment, capacity for photoprotection, germination response to light quality, and responses to light and drought were thus examined for Tillandsia brachycaulos and T. elongata. Vertical and light-environment distributions differed for the two species but photoprotection and photodamage did not where they occurred at similar field locations; T. brachycaulos had a higher pigment acclimation to light. Tillandsia brachycaulos had higher acid accumulation under low light as opposed to T. elongata, which responded similarly to all but the highest light treatment. Tillandsia brachycaulos maintained positive total daily net CO(2) uptake through 30 d of drought; T. elongata had a total daily net CO(2) loss after 7 d of drought. The vertical stratification was most likely the result of the sensitivity to drought of T. elongata rather than differences in photoprotection or shade tolerance between the two species. Tillandsia elongata occurs in more exposed locations, which may be advantageous for rainfall interception and dew formation. PMID- 21653426 TI - Molecular and cytological examination of Calopogon (Orchidaceae, Epidendroideae): circumscription, phylogeny, polyploidy, and possible hybrid speciation. AB - The orchid genus Calopogon R.Br. (Orchidaceae), native to eastern North America and the northern Caribbean, currently contains five species and up to three varieties. Using nuclear internal transcribed spacer (ITS) ribosomal DNA sequences, amplified fragment length polymorphisms (AFLPs), chloroplast DNA restriction fragments, and chromosome counts, we present a phylogenetic and taxonomic study of the genus. Calopogon multiflorus and C. pallidus are consistently sister species, but the relationships of C. barbatus, C. oklahomensis, and C. tuberosus are not as clear. In the ITS analysis C. oklahomensis is sister to C. barbatus, whereas it is sister to C. tuberosus in the plastid restriction fragment analysis. Furthermore, all species were found to have chromosome numbers of 2n = 38 and 40, with the exception of the putatively hybrid-derived C. oklahomensis with 2n = 114 and 120. The hexaploidy of the latter, plus the discrepancy in its position between the ITS and plastid restriction fragment trees, could suggest that it is of hybrid origin. However, the presence of unique morphological and molecular characters might indicate that it is either an ancient hybrid or not of hybrid derivation at all. Finally, using these molecular methods all taxa appear to generally be discrete groups, with the exception of C. tuberosus vars. latifolius and tuberosus, the former of which is best combined with the latter. PMID- 21653427 TI - Phylogenetic relationships among Strobilanthes s.l. (Acanthaceae): evidence from ITS nrDNA, trnL-F cpDNA, and morphology. AB - Chloroplast trnL-F sequence data, nuclear ribosomal internal transcribed spacer (ITS) sequence data, and morphology were used to analyze phylogenetic relationships among members of the subtribe Strobilanthinae. Parsimony and maximum likelihood analyses of trnL-F indicate that the Strobilanthinae are a monophyletic group. While parsimony analysis of ITS recovers a nonmonophyletic subtribe, maximum likelihood analysis of ITS corroborates results from trnL-F and suggests that systematic error is impacting on ITS parsimony analysis. A combined ITS and trnL-F analysis strengthens the signal and also recovers a monophyletic subtribe. All analyses indicate that Hemigraphis, Sericocalyx, and Strobilanthes are nonmonophyletic. With one exception, all morphological characters included in a combined ITS and morphological analysis are homoplastic. The prospect for a new informative generic classification of the Strobilanthinae aiming to recognize and diagnose only monophyletic groups is considered. While some groups can be diagnosed, adequate diagnosis of the majority of groups remains problematic. Consequently, a single expanded genus Strobilanthes sensu lato is proposed at the level of the well-supported and monophyletic Strobilanthinae. PMID- 21653428 TI - Reticulate evolution in kiwifruit (Actinidia, Actinidiaceae) identified by comparing their maternal and paternal phylogenies. AB - Evolutionary relationships within Actinidia, a genus known for the contrasting mode of inheritance of its plastids and mitochondria, were studied. The phylogenetic analysis is based on chloroplast (cp) and mitochondrial (mt) restriction site and sequence data (matK, psbC-trnS, rbcL, and trnL-trnF for cpDNA; nad1-2/3 and nad4-1/2 for mtDNA). The analysis of cp sequence data confirms the hypothesis that the four currently recognized sections are not monophyletic. The detection of incongruences among phylogenies (mtDNA vs. cpDNA tree) coupled with the detection of intraspecific polymorphisms confirms some of the reticulations previously emphasized, diagnoses new hybridization/introgression events, and provides evidence for multiple origin of at least two polyploid taxa. A number of hybridization/introgression events at the diploid, tetraploid, and possibly hexaploid levels are documented. The extensive reticulate evolution undergone by Actinidia could account for the lack of clear morphological discontinuities at the species level. PMID- 21653429 TI - Phylogenetic inferences in the dung-moss family Splachnaceae from analyses of cpDNA sequence data and implications for the evolution of entomophily. AB - The moss family Splachnaceae is characterized by half of its members relying on insects for spore dispersal. These species grow on dung or other animal substrates. They produce small and aggregated spores, and their capsule is modified to attract coprophilous insects or carrion flies using olfactory and visual cues. Systematic concepts and implicit evolutionary inferences have relied much on variation in characters associated with the spore dispersal syndrome. Phylogenetic reconstructions based on sequence variation of two chloroplast loci (trnL-trnF region and the rps4 gene) suggest that most supraspecific taxa are poly- or paraphyletic. Transformations in morphological characters associated to the syndrome thus offer little if any phylogenetically informative signal. Brachymitrion is resolved in a nested position within Tayloria. A new combination, Tayloria immersa (Goffinet) Goffinet, Shaw & Cox is proposed for B. immersum. Only one of the five subgenera of Tayloria (subg. Orthodon) is potentially monophyletic. Voitia shares a common ancestor with Tetraplodon and is thus nested within the Splachnoideae. The affinities of Aplodon remain ambiguous. Reconstruction of shifts between wind and insect spore dispersal syndromes suggests that entomophily arose more than once and may have been followed by a reversal to the generalist strategy in two lineages. PMID- 21653430 TI - Complex origins of breadfruit (Artocarpus altilis, Moraceae): implications for human migrations in Oceania. AB - Breadfruit (Artocarpus altilis, Moraceae), a traditional starch crop in Oceania, has enjoyed legendary status ever since its role in the infamous mutiny aboard the H.M.S. Bounty in 1789, yet its origins remain unclear. Breadfruit's closest relatives are A. camansi and A. mariannensis. DNA fingerprinting data (AFLP, amplified fragment length polymorphisms) from over 200 breadfruit cultivars, 30 A. camansi, and 24 A. mariannensis individuals were used to investigate the relationships among these species. Multivariate analyses and the identification of species-specific AFLP markers indicate at least two origins of breadfruit. Most Melanesian and Polynesian cultivars appear to have arisen over generations of vegetative propagation and selection from A. camansi. In contrast, most Micronesian breadfruit cultivars appear to be the result of hybridization between A. camansi-derived breadfruit and A. mariannensis. Because breadfruit depends on humans for dispersal, the data were compared to theories on the human colonization of Oceania. The results agree with the well-supported theory that humans settled Polynesia via Melanesia. Additionally, a long-distance migration from eastern Melanesia into Micronesia is supported. PMID- 21653431 TI - On the origin of the fig: phylogenetic relationships of Moraceae from ndhF sequences. AB - The majority of species in the mulberry family (Moraceae) are figs (Ficus), marked by a specialized inflorescence (syconium) and an obligate mutualism with pollinating fig wasps. Because of the unique morphology of the syconium, it has been difficult to investigate the evolutionary position of the fig. We sequenced the chloroplast gene ndhF to examine relationships in Moraceae and to elucidate shifts in reproductive traits. The reclassification of tribes is warranted, and the limits of Artocarpeae, Moreae, and Castilleae are revised to reflect evolutionary relationships. The results point to ancestral dioecy in Moraceae and multiple origins of monoecy, androdioecy, and gynodioecy. Ancestral wind pollination gave way to insect pollination at least twice. Strong support for the sister-group relationship of a revised Castilleae with Ficus suggests that entomophily and involucral bracts encircling the flowers preceded the evolution of the syconium. Bracts surround flowers in Castilleae only during early development, but in Ficus the involucre and the receptacle enclose the fruit as well. Molecular dating suggests that fig pollination is at least 80-90 million years old. The diversity of Ficus relative to its sister group is a likely consequence of ancient specialization and cospeciation with pollinating fig wasps. PMID- 21653432 TI - Anatomy of the vessel network within and between tree rings of Fraxinus lanuginosa (Oleaceae). AB - The three-dimensional (3-D) arrangement of vessels and the vessel-to-vessel connections in the secondary xylem of the stem of the ring-porous hardwood tree Fraxinus lanuginosa were studied in series of thick transverse sections with epifluorescence microscope and confocal laser scanning microscope. Vessels were traced in sequential sections, and vessel networks were reconstructed in two segments of wood with dimensions of 2 * 1.4 * 21.2 mm(3) and 2 * 1.4 * 5.8 mm(3) (tangential * radial * axial). The arrangement of vessels and intervessel pits were visualized by scanning electron microscopy in low-density polyethylene microcasts and on exposed tangential faces of growth-ring boundaries. The vessels deviated from the stem axis in the tangential direction and, to a lesser extent, in the radial direction. Some neighboring vessels were twisted around each other. Vessels that appeared solitary in single sections were found to be sequentially contiguous with a number of other vessels, forming networks that extended in the tangential direction and across growth-ring boundaries. In the 21.2-mm wood block, all earlywood vessels at the growth-ring boundary made contact with latewood vessels in the previous tree ring. Within a growth ring however, only a single contact was observed between individual earlywood and latewood vessels. Densely arranged intervessel pits were characteristic in the regions where adjacent vessels made contact with each other. Such bordered pits were abundant in the tangential walls of vessel elements adjacent to growth-ring boundaries. Therefore, bordered pits appear to provide the pathway for the radial transport of water via the vessel network across growth-ring borders. Fiber-tracheids, observed as terminal cells in the tree rings, might also contribute to the apoplastic transfer of water across ring borders. PMID- 21653433 TI - Damped oscillations of the giant reed Arundo donax (Poaceae). AB - The slender upright culms of the giant reed (Arundo donax L.) are often exposed to dynamic wind loads causing significant swaying. The giant reed has slightly tapered hollow stems (4-6 m high) with flat leaves and an extensive underground rhizomatous system with solid branches bearing adventitious roots. Quantitative analyses of videorecordings prove that A. donax responds to dynamic deflections of the stem with damped harmonic bending oscillations. The logarithmic decrement can be used to calculate the relative damping, as a measure of the plant's capacity to dissipate vibrational energy. Plants with leaves have a significantly higher damping compared to plants without leaves. A comparison of the relative damping of plants with and without leaves shows that this finding is only partly due to aerodynamic resistance of the leaves. Structural damping also contributes considerably to the overall damping of the foliate A. donax stem. By stepwise removal of the underground plant organs the influence of rhizome, roots, and soil on the vibrational behavior was determined. The data indicate that underground plant organs as well as leaf sheaths covering the nodes have no significant influence on damping. PMID- 21653434 TI - Correlation between molecular markers and adaptively significant genetic variation in Bromus tectorum (Poaceae), an inbreedingannual grass. AB - Single sequence repeat (SSR) and amplified fragment length polymorphic (AFLP) molecular marker genotypes in cheatgrass (Bromus tectorum) were compared to published data on phenotypic variation in seed dormancy, vernalization requirement, and resistance to the pathogen Ustilago bullata. Several features of cheatgrass facilitated this study: it is a recent invader in the western United States, has considerable phenotypic polymorphism, and is an obligate self pollinator. Forty self-pollinating lines from four populations common to the three phenotypic data sets were analyzed for molecular genetic variation using seven SSR loci and 31 AFLP loci. We examined correlations between distance matrices using the Mantel test for each pair of studies. The two molecular data sets were significantly correlated (r = 0.636). The AFLP markers often distinguished among several lines with identical SSR genotypes. The AFLP data were also significantly correlated with the phenotypic data (r values from 0.4640 to 0.5658), but the SSR data were much more highly correlated (r values from 0.677 to 0.844). The difference between molecular marker systems was especially notable when an outlier population from Potosi Pass, Nevada, was excluded from the analysis. These results suggest that SSR markers may be good surrogates for phenotypic traits in population genetic studies of strongly inbreeding species such as cheatgrass. PMID- 21653435 TI - Chromosome numbers, meiotic behavior, and pollen viability of species of Vriesea and Aechmea genera (Bromeliaceae) native to Rio Grande do Sul, Brazil. AB - Chromosome number, meiotic behavior, and pollen viability were analyzed in 15 species of two genera, Vriesea and Aechmea, native to Rio Grande do Sul, Brazil. This study is the first cytogenetic analysis of these taxa. The chromosome numbers are all n = 25, consistent with the proposed base number of x = 25 for Bromeliaceae. All examined taxa displayed regular bivalent pairing and chromosome segregation at meiosis. Observed meiotic abnormalities include univalents in metaphase I; missing or extra chromosomes and precocious division of centromeres in metaphase II; laggards in telophase I and anaphase II/telophase II. The high pollen viability (>88%) reflects a regular meiosis. PMID- 21653436 TI - Mitosis in the yeast phase of the basidiomycetes Bensingtonia yuccicola and Stilbum vulgare and its phylogenetic implications. AB - Phylogenetic studies of yeasts rely on an extensive molecular and biochemical data set, but structural characters are scarce. Details of mitosis in yeasts have been studied with transmission electron microscopy and immunofluorescence. Of these two methods immunofluorescence is faster and easier and yields sufficient detail for cytological comparisons. Only three basidiomycetous yeasts have been studied thus far with immunofluorescence. Mitosis in budding cells of ascomycetous yeasts occurs in the parent, while in basidiomycetous yeasts, except in Agaricostilbum pulcherrimum, it occurs in the bud. Mitosis in additional yeasts in the Agaricostilbomycetidae of the Urediniomycetes was observed using immunofluorescence localization of freeze-substituted material. In Stilbum vulgare, mitosis occurred in the parent, but in Bensingtonia yuccicola it occurred in the bud as in most other basidiomycetous yeasts. Stilbum vulgare also had predominantly binucleate yeast cells. Nuclear small subunit rDNA sequence data showed that A. pulcherrimum and S. vulgare are more closely related to each other than to B. yuccicola within the Agaricostilbomycetidae. Based on the few taxa examined, mitotic and cytoskeletal characters provide phylogenetic information. PMID- 21653437 TI - Cytological and ultrastructural preservation in Eocene Metasequoia leaves from the Canadian High Arctic. AB - The ultrastructural examination by transmission electron microscopy of 45-million year-old mummified leaves of Metasequoia extracted from the Upper Coal member of the Buchanan Lake Formation in Napartulik on Axel Heiberg Island revealed the preservation of intact chloroplasts and chloroplast components. Abundant tanniferous cell inclusions may indicate that the 3-mo period of constant daylight during the Artic summer induced high concentrations of tannins in the leaf tissues, which may have arrested microbial degradation of the litter. Quantified differences in the extent of chloroplast preservation through a vertical section of the lignite suggest that short-term shifts in the depositional environment took place, perhaps influencing the exposure of the leaf tissues to conditions that would either promote or inhibit decomposition. PMID- 21653438 TI - Genetic variation in flowering time induces phenological assortative mating: quantitative genetic methods applied to Brassica rapa. AB - It has been argued from first principles that plants mate assortatively by flowering time. However, there have been very few studies of phenological assortative mating, perhaps because current methods to infer paternal phenotype are difficult to apply to natural populations. Two methods are presented to estimate the phenotypic correlation between mates-the quantitative genetic metric for assortative mating-for phenological traits. The first method uses individual flowering schedules to estimate mating probabilities for every potential pairing in a sample. These probabilities are then incorporated into a weighted phenotypic correlation between all potential mates and thus yield a prospective estimate based on mating opportunities. The correlation between mates can also be estimated retrospectively by comparing the regression of offspring phenotype over one parent, which is inflated by assortative mating, to the regression over mid parent, which is not. In a demonstration experiment with Brassica rapa, the prospective correlation between flowering times (days from germination to anthesis) of pollen recipients and their potential donors was 0.58. The retrospective estimate of this correlation strongly agreed with the prospective estimate. The prospective method is easily employed in field studies that explore the effect of phenological assortative mating on selection response and population differentiation. PMID- 21653439 TI - Life-history variation and adaptation in the historically mobile plant Arabidopsis thaliana (Brassicaceae) in North America. AB - We used field-collected seeds of Arabidopsis thaliana (Brassicaceae) to simulate a colonization event of plants from diverse locations into a common environment to compare regionally "local" and "foreign" populations of this historically mobile species. Life history varied among regional groups, but most variation was found among populations within regions. While we found significant differences among populations and regional groups for important life-history characters, we did not find significant differences in performance of plants from different populations or regional groups. Rather, we found evidence that differences in life history contributed to the ability of plants from foreign regions to perform comparably to local Kentucky plants. Had plants from different regions not differed in the timing and size of reproduction, we would have seen that Kentucky (local) plants had higher total fitness via greater reproductive success of individuals that survived to reproduce and that Michigan plants would have had the lowest fitness. The populations are comparably adapted to the environment in Kentucky but through different combinations of life-history characters. Therefore, the life-history variation in this mobile species appears to contribute not to fitness differences among populations but rather to success in colonizing new locations. PMID- 21653440 TI - Geographic differentiation in the pollination system of the columnar cactus Pachycereus pecten -aboriginum. AB - The pollination biology of the cactus Pachycereus pecten-aboriginum was studied in a tropical location in western Mexico (ca. 18 degrees N latitude) to compare with data from a northern population (ca. 28 degrees N latitude). Throughout this range, the nectar-feeding bat Leptonycteris curasoae is resident within the tropics but migratory in its northern range. The hypothesis was tested that if a predictable bat presence has been an important force in the evolution of pollination systems in columnar cacti, P. pecten-aboriginum will have a specialized pollination system within the tropics and a generalized pollination system in northern populations. In both areas, pollination experiments showed that P. pecten-aboriginum has a self-incompatible, hermaphroditic breeding system. In the tropical area, flowers open at night and close early in the morning. Nectar is secreted only during the night, and flowers are exclusively pollinated by three species of nectar-feeding bats, indicating a specialized pollination system. In contrast, anthesis and nectar secretion in northern populations occur during the night and day, allowing visitation and effective pollination by both nocturnal and diurnal pollinators. This study provides evidence of divergence mediated by pollinator predictability (resident vs. migrant), through shifts from short to long anthesis and nectar production periods from southern to northern populations. PMID- 21653441 TI - Palatability and tolerance to simulated herbivory in native and introduced populations of Alliaria petiolata (Brassicaceae). AB - The European herb garlic mustard (Alliaria petiolata) is a serious invader of North American deciduous forests. One explanation for its success could be that in the absence of specialized herbivores, selection has favored less defended but more vigorous genotypes. This idea was addressed by comparing offspring from several native and introduced Alliaria populations with respect to their palatability to insect herbivores and their tolerance to simulated herbivory. Feeding rates of a specialist weevil from the native range were significantly greater on American plants, suggesting a loss of resistance in the introduced range. In contrast, there was significant population variation but no continent effect in the feeding rates of a generalist caterpillar. After simulated herbivory, A. petiolata showed a substantial regrowth capacity that involved changes in plant growth, architecture, and allocation. Removal of 75% leaf area or of all bolting stems reduced plant fitness to 81% and 58%, respectively, of the fitness of controls. There was no indication of a difference in tolerance between native and introduced Alliaria populations or of a trade-off between tolerance and resistance. PMID- 21653442 TI - Ecological correlates of seed desiccation tolerance in tropical African dryland trees. AB - In the tropics, species with recalcitrant or desiccation-sensitive, Type III seeds are largely restricted to regions with comparatively high rainfall, because desiccation-induced seed death will be minimal in these environments. However, species with recalcitrant seeds do occur in drylands, although little is known about ecological adaptations to minimize seed death in these environments. Here we present data for the seed desiccation tolerance of 10 African dryland species and examine the relationships between seed size, rainfall at the time of seed shed, and desiccation tolerance for these and a further 70 species from the scientific literature. The combined data set encompasses species from 33 families. Three species (Syzygium cumini, Trichilia emetica, and Vitellaria paradoxa) had desiccation-sensitive seeds, and the remaining seven species investigated were desiccation-tolerant. The desiccation-sensitive species had large (>0.5 g) seeds, germinated rapidly, and had comparatively small investments in seed physical defenses. Furthermore, seed was shed in months of high rainfall (>60 mm). In comparison, for species with desiccation-tolerant seeds, seed mass varied across five orders of magnitude, and seed was shed in wet and dry months. Although infrequent in dryland environments (approximately 11% of the species examined here), species with desiccation-sensitive seeds do occur; large size, rapid germination, and the timing of dispersal all reduce the likelihood of seed drying. Furthermore, desiccation-sensitivity may be advantageous for large-seeded species by increasing the efficiency of resource use in seed provisioning. PMID- 21653443 TI - Trade-offs among anti-herbivore resistance traits: insights from Gossypieae (Malvaceae). AB - Plant defense theories commonly predict negative correlations among anti herbivore resistance traits. Although this prediction has been widely accepted, the majority of empirical studies have failed to account for similarities among species due to common ancestry, thus risking pseudoreplication. Wild cotton plants possess traits conferring both direct resistance (toxic leaf glands and trichomes) and indirect resistance (extrafloral nectaries that reward enemies of herbivores). The evidence for negative phenotypic correlations among these resistance traits was examined at two levels: within Gossypium thurberi (wild cotton) and across species in the cotton clade (Gossypieae). A phylogenetic analysis controlled for shared ancestry among species. Across the Gossypieae, a strong negative correlation emerged between the direct resistance traits, leaf gland and trichomes. This correlation may reflect costs of these traits, a negative genetic correlation, or redundancy in their actions against herbivores. In contrast, the direct resistance traits (glands and trichomes) were not correlated with the indirect resistance trait of extrafloral nectar, either within or across species. The robust lack of correlation suggests that these direct and indirect resistance mechanisms evolve independently over evolutionary time scales. This conclusion conflicts with both predictions of plant defense theory and the majority of prior comparisons of direct and indirect resistance traits and may reflect the facultative nature of indirect resistance in Gossypieae. PMID- 21653444 TI - A chloroplast phylogeny of Arisaema (Araceae) illustrates Tertiary floristic links between Asia, North America, and East Africa. AB - The evolution of Arisaema is reconstructed, based on combined sequences (2048 aligned bases) from the chloroplast trnL intron, trnL-trnF spacer, and rpl20 rps12 spacer obtained for species from all 11 sections, including sectional type species and geographically disjunct East African and North American/Mexican species. Analyses were rooted with a representative sample of the closest outgroups, Pinellia and Typhonium, to rigorously test the monophyly of Arisaema. Sections in Arisaema are mostly based on leaf, stem, and inflorescence characters and, with one exception, are not rejected by the molecular data; however, statistical support for sectional relationships in the genus remains poor. Section Tortuosa, which includes eastern North American A. dracontium and Mexican A. macrospathum, is demonstrably polyphyletic. The third New World species, A. triphyllum, also occurs in eastern North America and groups with a different Asian clade than do A. dracontium/A. macrospathum. The genus thus appears to have entered North America twice. Fossil infructescences similar to those of A. triphyllum are known from approximately 18 million-year-old deposits in Washington State and can serve to calibrate a molecular clock. Constraining the age of A. triphyllum to 18 million years (my) and applying either a semiparametric or an ultrametric clock model to the combined data yields an age of approximately 31-49 my for the divergence of A. dracontium/A. macrospathum from their Asian relatives and of 19-32 my for the divergence between African A. schimperianum and a Tibetan/Nepalese relative. The genus thus provides an example of the Oligocene/Miocene floristic links between East Africa, Arabia, the Himalayan region, China, and North America. The phylogeny also suggests secondary loss of the environmental sex determination strategy that characterizes all arisaemas except for two subspecies of A. flavum, which have consistently bisexual spathes. These subspecies are tetraploid and capable of selfing, while a third subspecies of A. flavum is diploid and retains the sex-changing strategy. In the molecular trees, the sex-changing subspecies is sister to the two non-sex changing ones, and the entire species is not basal in the genus. PMID- 21653445 TI - Diploid and polyploid cytotype distribution in Melampodium cinereum and M. leucanthum (Asteraceae, Heliantheae). AB - Previous chromosomal studies within Melampodium (Asteraceae, Heliantheae) of Mexico and Central America have documented chromosome numbers n = 9, 10, 11, 12, 18, 20, 23, 25 +/- 1, 27, 30, and 33. Some species also have been shown to exhibit infra- and interpopulational polyploidy. The presence of cytotype mixtures is especially pronounced in the white-rayed complex, which occurs in the southwestern United States and adjacent Mexico. This group includes M. cinereum (n = 10 and 20), M. leucanthum (n = 10 and 20), and M. argophyllum (n = 30). Cytotype distribution has been newly analyzed in 415 plants from 152 populations and added to existing data from 185 plants from 113 populations, yielding information from a total of 600 individuals from 265 populations. Within M. cinereum and M. leucanthum are parapatric distributions of cytotypes, with tetraploids centered in the eastern and diploids in the western portions of their ranges. Tetraploids are most likely of autopolyploid origin, forming recurrently, with adaptations that allow colonization and establishment in new ecological regions. Contact zones are relatively narrow and only two triploid individuals have been detected. The tetraploid cytotypes probably extended eastward into central and southern Texas to the natural barriers at the edge of the Edward's Plateau in M. leucanthum and the low sandy plains in M. cinereum. The hexaploid M. argophyllum is interpreted as a relict surviving in the low mountains of northern Mexico; it may be an allopolyploid of hybrid origin between ancestors of the evolutionary lines that eventually yielded M. cinereum and M. leucanthum. PMID- 21653446 TI - Revealing unknown or extinct lineages within Isoetes (Isoetaceae) using DNA sequencesfrom hybrids. AB - Isoetes, a heterosporous lycopod with a fossil record dating back to the Paleozoic, has numerous putative allopolyploids (resulting from hybridization events coupled with doubling of chromosome number). By using the highly variable nucleotide sequences from the second intron of a LFY homologue in Isoetes, species could be delimited and hybrid origins determined. The data suggest that reticulate evolution is both common and complex within a more derived species complex of Isoetes. Sequences of identifiable parentage and sequences that are unlike any diploid species known were recovered, leading to the conclusion that one or both of the putative parents have not yet been discovered or are extinct. A range of observations concerning allopolyploid speciation were categorized as follows: (1) verification of previous hypotheses regarding parentage (e.g., I. riparia, I. appalachiana), (2) determination that two morphologically distinct allotetraploid species can share the same parentage (I. azorica and I. acadiensis), (3) recognition of a cryptic allotetraploid species, indicated by the presence of different parental genomes (I. "appalachiana" from Florida), and (4) identification of allotetraploid species with one or two unknown parents (e.g., I. tuckermanii, I. acadiensis, I. azorica, and I. hyemalis). Some sequences from diploid species are remarkably uniform among populations (e.g., I. echinospora from various locations in North America, Iceland, and Wales), while others are variable at the subspecies level (e.g., northern and southern populations within I. engelmannii). PMID- 21653447 TI - Phylogenetic position and biogeography of Hillebrandia sandwicensis (Begoniaceae): a rare Hawaiian relict. AB - The Begoniaceae consist of two genera, Begonia, with approximately 1400 species that are widely distributed in the tropics, and Hillebrandia, with one species that is endemic to the Hawaiian Islands and the only member of the family native to those islands. To help explain the history of Hillebrandia on the Hawaiian Archipelago, phylogenetic relationships of the Begoniaceae and the Cucurbitales were inferred using sequence data from 18S, rbcL, and ITS, and the minimal age of both Begonia and the Begoniaceae were indirectly estimated. The analyses strongly support the placement of Hillebrandia as the sister group to the rest of the Begoniaceae and indicate that the Hillebrandia lineage is at least 51-65 million years old, an age that predates the current Hawaiian Islands by about 20 million years. Evidence that Hillebrandia sandwicensis has survived on the Hawaiian Archipelago by island hopping from older, now denuded islands to younger, more mountainous islands is presented. Various scenarios for the origin of ancestor to Hillebrandia are considered. The geographic origin of source populations unfortunately remains obscure; however, we suggest a boreotropic or a Malesian Pacific origin is most likely. Hillebrandia represents the first example in the well-studied Hawaiian flora of a relict genus. PMID- 21653448 TI - Phylogenetic relationships of North American Antirrhinum (Veronicaceae). AB - Species of the genus Antirrhinum (Veronicaceae) provide excellent opportunities for research on plant evolution given their extensive morphological and ecological diversity. These opportunities are enhanced by genetic and developmental data from the model organism Antirrhinum majus. The genus Antirrhinum includes 15 New World species in section Saerorhinum and 21 Old World species in sections Antirrhinum and Orontium. Phylogenetic analyses of sequences of the internal transcribed spacer region (ITS) of nuclear ribosomal DNA were conducted for 19 Antirrhinum species, including all species from the New World, and 13 related genera in the tribe Antirrhineae. These analyses confirm the monophyly of Antirrhinum given the inclusion of the small genus Mohavea and exclusion of A. cyathiferum. The New World species, all of which are tetraploid, form a clade that is weakly supported as sister to the Old World sect. Orontium. The Old World species in sect. Antirrhinum form a well-supported clade that is sister to the remainder of the genus. In addition, both molecular and morphological data are used in the most comprehensive effort to date focused on recovering the phylogenetic relationships among the extremely diverse species in section Saerorhinum. PMID- 21653449 TI - Buzz-pollinated Dodecatheon originated from within the heterostylous Primula subgenus Auriculastrum (Primulaceae): a seven-region cpDNA phylogeny and its implications for floral evolution. AB - We sequenced seven cpDNA regions from 70 spp. in Dodecatheon, Primula subgenus Auriculastrum, and outgroups, reconstructed their cpDNA phylogeny with maximum parsimony, and determined branch support with bootstrap frequencies and Bayesian posterior probabilities. Strongly supported conclusions include the (1) paraphyly of Primula subgenus Auriculastrum with respect to a monophyletic Dodecatheon, (2) sister relationship between the North American Dodecatheon and the Californian P. suffrutescens, (3) novel basal split in Dodecatheon to produce one clade with rugose and one clade with smooth anther connectives, (4) monophyly of all sections of Primula subgenus Auriculastrum, and (5) exclusion of the enigmatic Primula section Amethystina from the similar Primula subgenus Auriculastrum. These results support the origin of the monomorphic, buzz-pollinated flower of Dodecatheon from the heterostylous flower of Primula. We marshal evidence to support the novel hypothesis that the solanoid flower of Dodecatheon represents the fixation of recessive alleles at the heterostyly linkage group (pin phenotype). Of the remaining traits associated with their solanoid flowers, we recognize at least six likely to have arisen with the origin of Dodecatheon, one that preceded it (flower coloration, a transfer exaptation in Dodecatheon), and one that followed it (rugose anther connectives, an adaptation to buzz pollination). PMID- 21653450 TI - Northern hemisphere biogeography of Cerastium (Caryophyllaceae): insights from phylogenetic analysis of noncoding plastidnucleotide sequences. AB - Phylogenetic relationships and biogeography of the genus Cerastium were studied using sequences of three noncoding plastid DNA regions (trnL intron, trnL-trnF spacer, and psbA-trnH spacer). A total of 57 Cerastium taxa was analyzed using two species of the putative sister genus Stellaria as outgroups. Maximum parsimony analyses identified four clades that largely corresponded to previously recognized infrageneric groups. The results suggest an Old World origin and at least two migration events into North America from the Old World. The first event possibly took place across the Bering land bridge during the Miocene. Subsequent colonization of South America occurred after the North and South American continents joined during the Pliocene. A more recent migration event into North America probably across the northern Atlantic took place during the Quaternary, resulting in the current circumpolar distribution of the Arctic species. Molecular clock dating of major biogeographic events was internally consistent on the phylogenetic trees. The arctic high-polyploid species form a polytomy together with some boreal and temperate species of the C. tomentosum group and the C. arvense group. Lack of genetic variation among the arctic species probably indicates a recent origin. The annual life form is shown to be of polyphyletic origin. PMID- 21653451 TI - A multivariate analysis of Hyospathe (Palmae). AB - Previous systematic treatments of the neotropical palm genus Hyospathe have recognized from two to 18 species. An explicit, quantitative, repeatable sequence of operations for delimiting and testing groups of specimens and applying species concepts is carried out. Multivariate statistical analysis of morphological data is used to delimit and test groups of specimens. Cluster analysis is used to distinguish between characters and traits. Analysis of qualitative and quantitative characters reveals six groups of specimens, and the Phylogenetic Species Concept is applied to these groups. Two species, H. peruviana Henderson and H. frontinensis Henderson, are described as new. One of the specimen groups is large and widespread, and six geographically separate subgroups can be recognized within it. These subgroups can be distinguished by one or more significantly different quantitative characters. A Phylogenetic Subspecies Concept is applied to these subgroups. Three subspecies, H. elegans subsp. costaricensis Henderson, H. elegans subsp. sanblasensis Henderson, and H. elegans subsp. tacarcunensis Henderson are described as new, and two new combinations are made: H. elegans subsp. sodiroi (Dammer ex Burret) Henderson and H. elegans subsp. concinna (H. E. Moore) Henderson. One subspecies occurring in the Amazon region is complex morphologically and is not resolved by the methods used here. PMID- 21653452 TI - A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). AB - Cannabinoids are important chemotaxonomic markers unique to Cannabis. Previous studies show that a plant's dry-weight ratio of Delta(9)-tetrahydrocannabinol (THC) to cannabidiol (CBD) can be assigned to one of three chemotypes and that alleles B(D) and B(T) encode alloenzymes that catalyze the conversion of cannabigerol to CBD and THC, respectively. In the present study, the frequencies of B(D) and B(T) in sample populations of 157 Cannabis accessions were determined from CBD and THC banding patterns, visualized by starch gel electrophoresis. Gas chromatography was used to quantify cannabinoid levels in 96 of the same accessions. The data were interpreted with respect to previous analyses of genetic and morphological variation in the same germplasm collection. Two biotypes (infraspecific taxa of unassigned rank) of C. sativa and four biotypes of C. indica were recognized. Mean THC levels and the frequency of B(T) were significantly higher in C. indica than C. sativa. The proportion of high THC/CBD chemotype plants in most accessions assigned to C. sativa was <25% and in most accessions assigned to C. indica was >25%. Plants with relatively high levels of tetrahydrocannabivarin (THCV) and/or cannabidivarin (CBDV) were common only in C. indica. This study supports a two-species concept of Cannabis. PMID- 21653453 TI - Molecular genetic evidence for interspecific hybridization among endemic Hispaniolan Bursera (Burseraceae). AB - Historically, genetic introgression among species as well as hybrid origins for species of the diploid tree genus Bursera (Burseraceae) have been proposed based on the supposition that individuals morphologically intermediate between sympatric "parent" species must be derived from hybridization. This study reports the first molecular genetic evidence for both unidirectional and reciprocal interspecific hybridization within Bursera. Phylogenies of hybrids and other species in B. subgenus Bursera are reconstructed based on nuclear and chloroplast sequence data. Compelling evidence supports the hybrid origin of three endemic Hispaniolan species: B. brunea (B. nashii * B. simaruba), B. gracilipes (B. spinescens * B. simaruba), and B. ovata (B. simaruba * B. spinescens). Cloning studies of nuclear markers from B. ovata suggests that this species is an introgressed or later backcross generation hybrid and thus reproduces sexually. PMID- 21653454 TI - Addressing the "hardest puzzle in American pomology:" Phylogeny of Prunus sect. Prunocerasus (Rosaceae) based on seven noncoding chloroplast DNA regions. AB - Prunus subg. Prunus sect. Prunocerasus (Rosaceae) is a North American taxon with 17 commonly recognized taxa. To test the hypothesis of monophyly for the section we sequenced the trnG and rpL16 introns and the trnH-psbA and trnS-trnG intergenic spacers for at least two representatives of each of the five subgenera in Prunus. Additionally we sampled heavily among Prunus subg. Prunus sections Prunus and Armeniaca and Prunus subg. Amygdalus because these groups are putatively most closely related to Prunocerasus. Once monophyly of sect. Prunocerasus was shown we added the sequences of trnL and rpS16 introns and the trnL-trnF spacer in an attempt to increase resolution within the section. The species of sect. Prunocerasus showed an initial split with P. subcordata, the only species from western North America, sister to the rest of the group. The remaining species fell into three primary clades. Within each of the three primary clades there was little phylogenetic resolution. Lastly, we present evidence that P. texana, previously classified in subg. Amygdalus, may be a plum or at least contain a Prunocerasus chloroplast. This is the first phylogenetic hypothesis presented for sect. Prunocerasus, and the clades recovered contrast sharply with previously defined groups based on morphological characters. PMID- 21653455 TI - Amborella not a "basal angiosperm"? Not so fast. AB - The sequence of the plastid genome of Amborella trichopoda, the putative sister to all other extant angiosperms, was recently reported (Molecular Biology and Evolution 20: 1499-1505). Goremykin et al. used sequence data for 61 plastid genes from Amborella and 12 other embryophytes in phylogenetic analyses and concluded that Amborella is not the sister to the remaining flowering plants; the monocots instead occupy this position. The authors attributed their results, which differ substantially from all recent phylogenetic analyses of angiosperms, to the increased character sampling (30 017 nucleotides in their aligned matrix) in their analysis relative to published studies that included fewer genes but more taxa. We hypothesized that the difference in topology is not due to limited character sampling in previous studies but to limited taxon sampling in the analysis by Goremykin et al. To test this, we conducted a series of phylogenetic analyses using a three-gene, 12 (or more)-taxon data set to evaluate the topological effects of (i) including three vs. 61 genes for (nearly) the same set of taxa, (ii) analyzing different codon positions, (iii) substituting representatives of other basal lineages for Amborella, (iv) replacing the grasses used to represent the monocots with other monocots, selected either for their phylogenetic position or randomly, and (v) adding other basal taxa-Nymphaea, Austrobaileya, magnoliids, and monocots-to the 12-taxon data set. Our results demonstrate that the "monocots basal" topology obtained by Goremykin et al. is not due to increased character sampling of the plastid genome; their topology was obtained using only two plastid genes or two plastid genes and one nuclear gene. This topology was also retained when either Nymphaea or Austrobaileya was substituted for Amborella, demonstrating that any of the three basal lineages will attach to Calycanthus for lack of any other close branch. Furthermore, the "monocots basal" topology is not robust to changes in sampling of monocots. Simply adding Oncidium, for example, places Amborella sister to the other angiosperms. Thus, limited taxon sampling, focusing on organisms with complete genome sequences, can lead to artifactual results. PMID- 21653456 TI - Suppression of branches in Eucalyptus trees. AB - The effect of neem oil, which acts as a suckericide in tobacco, on branch suppression in Eucalyptus tereticornis was assessed to help maximize stem biomass. Lateral branches of selected trees were pruned, and neem oil solutions at concentrations of either 80%, 40%, 20%, 10%, or 0% (untreated control) were applied to leaf axils of the pruned branches. Regeneration of branches was suppressed, and the magnitude of suppression was proportional to the concentration of neem oil. Compared to the control, the percentage reduction in branching at 80% neem oil was 41.6%. When regenerated branches were repruned and neem oil applied at either 100%, 80%, or 0% (control), the regenerating ability of these branches was severely repressed by 78% at 100% neem oil relative to the control. Apical shoots were also topped and treated at either 100% or 0% (control) neem oil to identify the principal suppressive component in neem oil. The principal component azadirachtin was tested at 375, 750, 1500, 3125, 6250, 12 500, 25 000, 50 000, and 100 000 ppm and 0 ppm as the control. Reduction in the coppicing shoot was as high as 85%. Azadirachtin was responsible for the suppression. By pruning the lateral branches with neem oil, wasteful consumption of photosynthates can be precluded and the stem biomass maximized. PMID- 21653457 TI - Phylogenetic reconstruction of the evolution of stylar polymorphisms in Narcissus (Amaryllidaceae). AB - We investigated the origin of stylar polymorphisms in Narcissus, which possesses a remarkable range of stylar conditions and diverse types of floral morphology and pollination biology. Reconstruction of evolutionary change was complicated by incomplete resolution of trees inferred from two rapidly evolving chloroplast regions, but we bracketed reconstructions expected on the fully resolved plastid based tree by considering all possible resolutions of polytomies on the shortest trees. Stigma-height dimorphism likely arose on several occasions in Narcissus and persisted across multiple speciation events. As proposed in published models, this rare type of stylar polymorphism is ancestral to distyly. While there is no evidence in Narcissus that dimorphism preceded tristyly, a rapid transition between them may explain the lack of a phylogenetic footprint for this evolutionary sequence. The single instances of distyly and tristyly in Narcissus albimarginatus and N. triandrus, respectively, are clearly not homologous, an evolutionary convergence unique to Amaryllidaceae. Floral morphology was likely an important trigger for the evolution of stylar polymorphisms: Concentrated changes tests indicate that a long, narrow floral tube may have been associated with the emergence of stigma-height dimorphism and that this type of tube, in combination with a deep corona, likely promoted, or at least was associated with, the parallel origins of heterostyly. PMID- 21653459 TI - Environmental and genetic effects on flowering differences between northern and southern populations of Arabidopsis lyrata (Brassicaceae). AB - Arabidopsis lyrata (Brassicaceae) is a close outcrossing relative of A. thaliana. We examine flowering time variation of northern and southern A. lyrata populations in controlled environmental conditions, in a common garden experiment with A. thaliana, and in the field. Southern populations of A. lyrata flowered earlier than northern ones in all environmental conditions. Individuals from southern populations were more likely to flower in short days (14 h light) than northern ones, and all populations had a higher probability of flowering and flowered more rapidly in long days (20 h). The interaction of population and day length significantly affected flowering probability, and flowering time in one of two comparisons. The common garden experiment demonstrated differences between populations in the response to seed cold treatment, but growth chamber experiments showed no vernalization effect after 4 wk of rosette cold treatment. In a field population in Norway, a high proportion of the plants flowered in each year of the study. The plants progressed to flowering more rapidly in the field and common garden than in the growth chamber. The genetic basis of these flowering time differences here can be further studied using A. thaliana genetic tools. PMID- 21653458 TI - Molecular cytogenetic analysis of recently evolved Tragopogon (Asteraceae) allopolyploids reveal a karyotype that is additive of the diploid progenitors. AB - Tragopogon mirus and T. miscellus (both 2n = 4x = 24) are recent allotetraploids derived from T. dubius * T. porrifolius and T. dubius * T. pratensis (each 2n = 2x = 12), respectively. The genome sizes of T. mirus are additive of those of its diploid parents, but at least some populations of T. miscellus have undergone genome downsizing. To survey for genomic rearrangements in the allopolyploids, four repetitive sequences were physically mapped. TPRMBO (unit size 160 base pairs [bp]) and TGP7 (532 bp) are tandemly organized satellite sequences isolated from T. pratensis and T. porrifolius, respectively. Fluorescent in situ hybridization to the diploids showed that TPRMBO is a predominantly centromeric repeat on all 12 chromosomes, while TGP7 is a subtelomeric sequence on most chromosome arms. The distribution of tandem repetitive DNA loci (TPRMBO, TGP7, 18S-5.8S-26S rDNA, and 5S rDNA) gave unique molecular karyotypes for the three diploid species, permitting the identification of the parental chromosomes in the polyploids. The location and number of these loci were inherited without apparent changes in the allotetraploids. There was no evidence for major genomic rearrangements in Tragopogon allopolyploids that have arisen multiple times in North America within the last 80 yr. PMID- 21653460 TI - Herbivory alters the expression of a mixed-mating system. AB - The direct and indirect effects of vegetative herbivory on the mating system of Impatiens capensis were analyzed through a survey of herbivory in natural I. capensis populations and manipulation of leaf damage in the field. Across 10 wild populations of I. capensis proportion of cleistogamous flowers had a significant positive exponential relationship with natural levels of herbivory. Similarly, experimental leaf damage increased the proportion of flowers and seeds that were cleistogamous. Leaf damage also reduced the biomass of cleistogamous progeny more severely relative to that of chasmogamous progeny. The cumulative effect of leaf damage was to increase plant reliance on fitness derived from cleistogamous progeny. Leaf damage indirectly affected mating system traits by reducing chasmogamous flower size, leading to a reduction in pollinator visitation. Under these experimental conditions, herbivory did not significantly reduce the number of simultaneously open flowers and potential for geitonogamy, nor did it result in significant changes in the composition of the pollinator fauna. These findings are among the first to demonstrate that herbivory has consequences for mating system and should be considered a factor shaping mating system evolution. PMID- 21653461 TI - Reproductive ecology of distylous Palicourea Padifolia (Rubiaceae) in a tropical montane cloud forest. I. Hummingbirds' effectiveness as pollen vectors. AB - The adaptiveness of distyly has been typically investigated in terms of its female function, specifically pollen receipt. However, pollen loads on stigmas can only provide moderate support for Darwin's hypothesis of the promotion of legitimate crosses. To determine the effectiveness of hummingbirds as pollen vectors between floral morphs and the consequences in terms of male (pollen transfer) and female function (pollen receipt) in Palicourea padifolia (Rubiaceae), floral visitors, their foraging modes, and temporal patterns of floral visitation were observed and documented. Differences in pollen and stigma morphology, pollen flow, rates of pollen deposition, and/or stigmatic pollen loads were then evaluated for their contribution toward differences in reproductive output between floral morphs. A pollination experiment with stuffed hummingbirds that varied in bill size was done to evaluate the contribution of bill variation toward differences between floral morphs in pollen receipt and pollen transfer and female reproductive output. Anthers of long-styled flowers contained significantly more and smaller pollen grains than those of short-styled flowers, independently of corolla and anther lengths. The shape and orientation of the stigma lobes differed between morphs and were significantly longer among short-styled flowers. Hummingbird visitation rates did not differ significantly between floral morphs, and foraging movements from focal plants towards neighboring plants were independent of floral morph. Stigmatic pollen loads under field conditions and those after controlled hummingbird visitation, along with rates of pollen accumulation through the day indicated that stigmas of short styled flowers receive proportionately more legitimate (intermorph) pollen grains than did those of long-styled flowers. However, the species of hummingbird was marginally significant in explaining variation in pollen deposition on stigmas. Lastly, intermorph pollinations of P. padifolia resulted in significant differences in fruit production between floral morphs, independent of pollination treatment and pollinator species; short-styled flowers proportionately developed almost twice the number of fruits developed by long-styled flowers. PMID- 21653462 TI - Reproductive ecology of distylous Palicourea padifolia (Rubiaceae) in a tropical montane cloud forest. II. Attracting and rewarding mutualistic and antagonistic visitors. AB - By definition, the floral morphs of distylous plants differ in floral architecture. Yet, because cross-pollination is necessary for reproductive success in both morphs, they should not differ in attributes that contribute to attracting and rewarding floral visitors. Floral and vegetative attributes that function in distylous polymorphism in hummingbird-pollinated Palicourea padifolia (Rubiaceae) and the responses of pollinators and insect herbivores to the resources offered by both morphs were investigated. The performance of each morph along multiple stages of the reproductive cycle, from inflorescence and nectar production to fruit production, was surveyed, and pollinator behavior and nectar standing crops were then observed. Costs associated with such attractiveness were also evaluated in terms of herbivore attack and of plant reproductive fitness (female function) as a function of leaf herbivory. The number of inflorescences, floral buds, open flowers, and ripe fruits offered by either floral morph were similar, but short-styled plants almost doubled the number of developing fruits of long-styled plants. Long-styled flowers produced higher nectar volumes and accumulated more nectar over time than short-styled flowers. Measures of nectar standing crop and data on pollinator behavior suggest that hummingbirds respond to this morph-specific scheduling of nectar production. Lastly, long-styled plants suffered a higher herbivore attack and lost more leaf area over time than those with short-styled flowers. Herbivory was negatively correlated with fruit number and fruit mass, and long-styled plants set significantly less fruit mass than short-styled plants. The results suggest that pollinators and herbivores may exert selective pressures on floral and vegetative traits that could also influence gender function. PMID- 21653463 TI - Relationships of the Macaronesian and Mediterranean floras: molecular evidence for multiple colonizations into Macaronesia and back-colonization of the continent in Convolvulus (Convolvulaceae). AB - A molecular phylogenetic analysis of the Macaronesian endemic species of Convolvulus was undertaken using data from the nuclear ribosomal internal transcribed spacer (ITS) regions. The results of the analysis support two introductions into Macaronesia from distantly related clades within Convolvulus and a subsequent back-colonization to the continent from within one of the clades. Hypothesized relationships between Macaronesian species and New World taxa and between the Canarian endemic C. caput-medusae and the Moroccan C. trabutianus are refuted. Both Macaronesian clades are shown to have Mediterranean sister groups although one is predominantly western Mediterranean and the other predominantly eastern Mediterranean in distribution. The patterns of colonization into Macaronesia demonstrated by Convolvulus and also by other multiple colonizing genera conform to either a pattern of phylogenetic distinctiveness or a checkerboard distribution of island lineages. Both are consistent with the hypothesis that niche preemption is responsible for the limited number of colonizations into the region. A review of sister group relationships demonstrates that, in common with Convolvulus, most Macaronesian groups have sister groups distributed in the near-continent (i.e., western Mediterranean). Disjunct sister group relationships (including Eastern Mediterranean disjunctions) occur in only 18% of groups. PMID- 21653464 TI - Phylogenetic studies of Mammillaria (Cactaceae)--insights from chloroplast sequence variation and hypothesis testing using the parametric bootstrap. AB - The genus Mammillaria is likely the most species-rich and morphologically variable genus in the Cactaceae. There is doubt as to whether the genus is monophyletic, and past infrageneric treatments differ regarding generic circumscription. Phylogenetic questions about Mammillaria were addressed using chloroplast DNA sequence data from the rpl16 intron and the psbA-trnH intergenic spacer for 125 taxa (113 Mammillaria, 10 Coryphantha, Escobaria, Neolloydia, Pelecyphora, Ortegocactus, and two outgroup taxa from Ferocactus and Stenocactus). Parsimony analyses were conducted using various heuristic search strategies. Bayesian analyses were conducted using the F81 and F81 + I + G models of sequence evolution. Tree topologies from the parsimony and Bayesian analyses were largely congruent. Hypothesis testing was undertaken using the parametric bootstrap to test the monophyly of the genus and the taxonomic status of Mammillaria candida. Phylogenies derived from the parsimony and Bayesian analyses indicate that Mammillaria is not monophyletic and that the genus Mammilloydia (synonym Mammillaria) is embedded within a "core" group of Mammillaria species. Both these results were corroborated by the parametric bootstrap tests. The entire rpl16 intron was deleted from species in the Mammillaria crinita group. PMID- 21653465 TI - A molecular phylogenetic study of Graptopetalum (Crassulaceae) based on ETS, ITS, RPL16, and TRNL-F nucleotide sequences. AB - Nuclear ETS and ITS, as well as plastid rpl16 and trnL-F DNA sequences were used to determine relationships among species of Graptopetalum (Crassulaceae) and closely related genera. Graptopetalum is member of a group of taxa restricted to North America, one of the centers of diversity of Crassulaceae; however, their phylogenetic relationships are not yet understood. Nineteen species of Graptopetalum and 24 species from nine other genera of Crassulaceae were sampled for use in three separate parsimony analyses: ITS alone, ETS alone, and a combined nuclear + plastid DNA analysis using all four gene regions. The ETS data set had the highest number of parsimony-informative sites, about 30% more than in ITS, but the most fully resolved tree resulted when the four DNA regions were combined. Only four subclades of the tree received moderate to strong bootstrap support, one of which includes all species of Graptopetalum having a single whorl of stamens. However, Graptopetalum is not monophyletic. Instead, Tacitus bellus and select species of Cremnophila, Sedum, and Echeveria are interspersed among species of Graptopetalum and show evidence of grouping according to geographical range of distribution more so than habit or floral morphology. PMID- 21653466 TI - Phylogeny and circumscription of the near-endemic Brazilian tribe Microlicieae (Melastomataceae). AB - The members of tribe Microlicieae in the flowering plant family Melastomataceae are nearly all endemic to the cerrado biome of Brazil. Traditional classifications of the Melastomataceae have attributed between 15 and 17 genera to the Microlicieae, but subsequent revisions have circumscribed the tribe more narrowly. The monophyly and intergeneric relationships of the Microlicieae were evaluated through phylogenetic analyses with molecular and morphological data sets. Incorporation of DNA sequences from the intron of the chloroplast gene rpl16 into a previously generated family-wide data set yielded a clade comprising Chaetostoma, Lavoisiera, Microlicia, Rhynchanthera, Stenodon, and Trembleya ("core Microlicieae"), with Rhynchanthera as the first-diverging lineage. The other four genera of Microlicieae sampled are placed in other clades: Eriocnema with Miconieae; Siphanthera with Aciotis, Nepsera, and Acisanthera of Melastomeae; Castratella as sister to Monochaetum of Melastomeae; and Cambessedesia as part of an unresolved polytomy in a large clade that includes most Melastomataceae. Analyses of the chloroplast genes rbcL and ndhF that included three core genera produced similar results, as did the combined analysis of all three data sets. Combined parsimony analyses of DNA sequences from rpl16 and the nuclear ribosomal intercistronic transcribed spacer (ITS) region of 22 species of core Microlicieae yielded generally low internal support values. Lavoisiera, recently redefined on the basis of several morphological characters, was strongly supported as monophyletic. A morphological phylogenetic analysis of the Microlicieae based on 10 parsimony-informative characters recovered a monophyletic core Microlicieae but provided no further resolution among genera. Penalized likelihood analysis with two calibration time windows produced an age estimate of 3.7 million years for the time of initial divergence of strictly Brazilian core Microlicieae. This date is in general agreement with the estimated age of the most active stage of development of cerrado vegetation and implies an adaptive shift from hydric to seasonally dry habitats during the early evolution of this group. PMID- 21653467 TI - Salvia (Lamiaceae) is not monophyletic: implications for the systematics, radiation, and ecological specializations of Salvia and tribe Mentheae. AB - Salvia, with over 900 species from both the Old and New World, is the largest genus in the Lamiaceae. Unlike most members of the subfamily Nepetoideae to which it belongs, only two stamens are expressed in Salvia. Although the structure of these stamens is remarkably variable across the genus, generally each stamen has an elongate connective and divergent anther thecae, which form a lever mechanism important in pollination. In a preliminary investigation of infrageneric relationships within Salvia, the monophyly of the genus and its relationship to other members of the tribe Mentheae were investigated using the chloroplast DNA regions rbcL and trnL-F. Significant conclusions drawn from the data include: Salvia is not monophyletic, Rosmarinus and Perovskia together are sister to an Old World clade of Salvia, the section Audibertia is sister to subgenus Calosphace or the monotypic Asian genus Dorystaechas, and the New World members of section Heterosphace are sister to section Salviastrum. Owing to the non monophyly of Salvia, relationships at the next clearly monophyletic level, tribe Mentheae, were investigated. PMID- 21653468 TI - Duabanga-like leaves from the Middle Eocene Princeton chert and comparative leaf histology of Lythraceae sensu lato. AB - A permineralized lythraceous leaf type found in close association with fruits, stems, and roots of Decodon allenbyensis Cevallos-Ferriz et Stockey in the Middle Eocene Princeton chert of British Columbia, Canada, is described. Midribs have a prominent C-shaped midvein surrounded by sclerenchyma, with an adaxial epidermis of rectangular to rounded cells lacking enlarged mucilage cells. Leaves are dorsiventral, 180-270 MUm thick at the lamina, with a double palisade layer. Abaxial epidermal cells have prominent papillae, and these epidermal cells can be infected by fungi, forming dark sterile stromata. Fossil leaves are similar to those of Myrtales and are compared to those of Lythraceae sensu lato. Although these leaves are thought to belong to the previously described Decodon allenbyensis found in the same chert layer, they lack the diagnostic features of extant Decodon leaves. Instead they share most anatomical similarities with Duabanga grandiflora Roxburgh ex DC Walpers (Lythraceae, subfamily Duabangoideae) including vascular tissues, palisade and spongy mesophyll, bundle fibers, and abaxial epidermal papillae. Duabanga grandiflora differs from the fossil in having mucilaginous cells and a consistently V-shaped abaxial midrib. Although anatomically similar to Duabanga, the fossil leaves are considered those of D. allenbyensis, based on association and the depositional environment prior to preservation. Recent phylogenetic analyses place Duabanga and Decodon in separate clades within Lythraceae, but relationships between these clades are not well supported, indicating that fossil leaves should provide useful anatomical characters for elucidating relationships within Lythraceae. PMID- 21653469 TI - Incidence, size and spatial structure of clones in second-growth stands of coast redwood, Sequoia sempervirens (Cupressaceae). AB - The ecology and evolutionary potential of coast redwood (Sequoia sempervirens) is significantly influenced by the important role clonal spread plays in its reproduction and site persistence. In nine second-growth stands, amplified fragment length polymorphisms (AFLPs) were used to identify redwood clonal architecture. Clones (multistem genets) dominated sites by representing an average of 70% of stems measured, ranging in size from two to 20 stems. As a result, a relatively small number of genets can monopolize a disproportionate amount of site resources, are more likely to persist over time, and have greater on-site genetic representation. Clones were not limited to fairy-ring structures, but consisted of a wide range of shapes including concentric rings, ring chains, disjunct, and linear structures. Between-ramet distances of up to 40 m were measured, indicating that clonal reproduction is not limited to basal stump resprouting. Clonal structure in second-growth stands was similar to earlier reports from old growth, emphasizing the importance of site persistence and long term, gradual site development. Smaller ramet numbers per genet in old growth is probably due to local within-genet self thinning. Management and conservation of redwoods will benefit from a better understanding of the dynamics and structure of clonal spread in these forests. PMID- 21653470 TI - Seedling establishment and life history trade-offs in alpine plants. AB - Seedling establishment is central to population maintenance for nonclonal plant species. Plants with low recruitment rates are expected to have high survival rates, and life history theory indicates there should be a single curve for the trade-off between recruitment and mortality that applies to most or all plant species. Alpine perennials are thought to have extraordinarily low recruitment rates because of the harsh environment, but the importance of recruitment in the life history of these plants is unknown. Two alpine cushion plant species, Minuartia obtusiloba and Paronychia pulvinata, were used to (1) determine the role of recruitment in population maintenance and (2) determine whether the fecundity/mortality trade-off for these alpine plants falls on or off of the curve for other perennial plant species. Using size-based population projection matrices, we determined that the life history of Minuartia and Paronychia emphasizes recruitment less than that of any other nonclonal species in a literature survey. Estimated maximum life spans of these two species are 200 and 324 yr, respectively, and a regression with other perennial species from the literature indicated that the relationship between fecundity and mortality in these alpine species is consistent with the predicted trade-off curve for perennial species from other environments. PMID- 21653471 TI - Genetic variation of introduced Hawaiian and native Costa Rican populations of an invasive tropical shrub, Clidemia hirta (Melastomataceae). AB - Clidemia hirta is one of the most common woody invasive plants in mesic to wet forests in Hawaii, where it was introduced around 1940. The species is relatively uncommon by comparison in its native range of Central and South America and some Caribbean Islands. We examined genetic variation in allozymes of 20 C. hirta populations on four Hawaiian Islands to determine the introduction history. For comparison, we measured genetic variation in 20 native populations across Costa Rica. Mean levels of genetic variation in Hawaiian and Costa Rican populations were low compared to other woody or introduced plants (11.5-12.5% polymorphic loci, 2.05-2.50 alleles per polymorphic locus, and 0.045-0.063 expected heterozygosity). Most genetic diversity was held within rather than among populations in both areas (G(ST) = 0.120 and 0.271 in Hawaii and Costa Rica, respectively). Hawaiian populations had a high degree of genetic similarity, and no genetic differentiation was found among the four Hawaiian Islands sampled. These patterns of genetic variation in Hawaii suggest that no intraspecific hybridization of genotypes from different parts of the native range has occurred and that introductions to the different islands came from the same or similar source populations. The low levels of genetic diversity in parts of both the native and introduced ranges suggest that genetic variation is unrelated to invasiveness in C. hirta. PMID- 21653472 TI - Cushion size, surface roughness, and the control of water balance and carbon flux in the cushion moss Leucobryum glaucum (Leucobryaceae). AB - We explored the size dependence of water balance and carbon flux in the cushion moss Leucobryum glaucum (Leucobryaceae). Conductance to water vapor (g(a)) was modeled empirically using 4-24 cm diameter cushions (N = 14) evaluated across wind speeds from 0.7 to 4.3 m/s in a wind tunnel. Model parameters included wind speed (u), kinematic viscosity (v), cushion diameter (L(d)), and surface roughness (L(r)). The model g(a) = -9.62(u/v)(1.21) . L(d)(-0.35) . L(r-in)( 1.85) (where L(r-in) represents a dimensionless form of L(r); R(2) = 0.88) indicates negative relationships between g(a) and both L(d) and L(r). These predictions were evaluated during a 5-d field experiment where water loss and net carbon exchange (estimated by DeltaF/F(m)') were monitored. In the field (N = 18, 4-34 cm diameter cushions), L(r), but not L(d), controlled rates of evaporation due to additional turbulence that reduced size dependence of cushions along the forest floor. However, the duration of positive net carbon gain varied from 1.4 to 4.4 d and was significantly longer in larger diameter cushions. Thus, under field conditions, size-dependent changes in surface-area-to-volume relationships influence the duration of net carbon gain more than differences in water flux and lead to a strong size dependence of water balance and carbon flux. PMID- 21653473 TI - Bryophyte dispersal inferred from colonization of an introduced substratum on Whiteface Mountain, New York. AB - A long-standing debate in bryophyte biogeography concerns the frequency of long distance spore dispersal. The diversity of bryophytes on mortared rock walls along the Veterans Memorial Highway on Whiteface Mountain, New York, USA, was studied to document the recruitment of species over the 65 years since the highway was constructed. The highway is situated in the Adirondack Mountains, a relatively unpopulated region with a largely acidic flora. The introduction of mortar has increased the bryophyte diversity by 50% above that of native lithic substrata on the mountain. The composition of the native and mortar floras differed greatly, suggesting that the walls were not colonized by locally abundant ruderal species. Many of the species sampled on the walls are typically found only in lower elevation forested sites, distant (~5 km or more) from the highway, and not on anthropogenic calcium carbonate. These results suggest that a bryophyte community consisting of common and uncommon species assembled from distant sites at the rate of at least one species per year in the last 65 years. These data provide the ecological context for experimental and phylogeographic studies and suggest that some bryophytes may be capable of routine dispersal over distances of at least 5 km. PMID- 21653474 TI - Evaluation of the extent of among-family variation in inbreeding depression in the perennial herb Scabiosa columbaria (Dipsacaceae). AB - Significantly different maternal line responses to inbreeding provide a mechanism for the invasion of a selfing variant into a population. The goal of this study was to examine the extent of family-level variation in inbreeding depression in the mixed-mating, perennial herb Scabiosa columbaria. Plants from one population were raised, and hand-pollinated to produce selfed and outcrossed progeny, and the effects of inbreeding depression on life-cycle traits were analyzed. Inbreeding depression significantly affected early life cycle traits. The pollination treatment by family interaction was significant for almost all traits, indicating a high family-level variation in inbreeding depression. The correlations between inbreeding depression values (e.g., percentage germination and flowering date, and flowering date and aboveground biomass) exhibited alternate signs, illustrating the type of association between inbreeding depression loci for different traits across the life cycle. Overall, it is concluded that the extent of among-family variation in inbreeding depression might allow a selfing variant of S. columbaria to invade an outcrossing population, though the pattern of correlations between inbreeding depression values might prevent effective purging of the deleterious genetic load. PMID- 21653476 TI - Erratum. PMID- 21653475 TI - Localization of production and emission of pollinator attractant on whole leaves of Chamaerops humilis (Arecaceae). AB - Volatile compounds, which frequently play important roles in plant-insect interaction, can be produced either by flowers to attract pollinators or by leaves to deter herbivores. The specialized structures associated with odor production differ in these two organs. The European dwarf palm Chamaerops humilis represents a unique intermediate between these two. In previous work, its leaves were shown to produce volatile organic compounds (VOCs) that attract pollinators only during flowering. Because the leaf sinuses look like a gland, the sinus was examined histologically and with environmental scanning electron microscopy (ESEM) for evidence that the sinus emits VOCs. Volatile compounds emitted by the different parts of the leaf were extracted by washes and headspace then analyzed by gas chromatograph-mass spectrometer (GC-MS). The sinus does not have the expected gland-like structure; the VOCs are actually produced by the whole leaf, even if the composition of the VOCs emitted by the sinus slightly differs. Thus, attraction of pollinators does not result from specialized secreting cells in leaves of flowering European dwarf palms. The results are discussed in the context of a convergent evolution of leaves toward petals. PMID- 21653477 TI - Variation in sex allocation and male-female trade-offs in six populations of Collinsia parviflora (Scrophulariaceae s.l.). AB - Assumed trade-offs between male and female functions in hermaphroditic flowers have been difficult to demonstrate. Collinsia parviflora (Scrophulariaceae) is a winter annual that exhibits significant among-population variation in corolla size in British Columbia, Canada. We asked whether reduction in secondary male allocation (i.e., the attractive corolla), a preliminary indicator of mating system, was matched by a reduction in primary male allocation (i.e., pollen production), and whether there were allocation trade-offs between male and female function both within and among six study populations. Larger-flowered populations allocated more to male function (androecium and corolla biomass), and because populations did not vary in female biomass allocation (gynoecium and calyx), population differences were not due to simple allometric scaling. Populations also differed in per-flower gamete production (pollen and ovules). We found male female trade-offs within populations between androecium and gynoecium mass and between corolla and calyx mass. Among populations, there was a marginal trade-off between pollen and ovule production and a significant within-male trade-off between pollen grain size and number. Trade-offs between the sexes were primarily apparent when we controlled for flower size in the analysis. Variation among populations in sex allocation may reflect different optima related to the mating system. PMID- 21653478 TI - Systematics of Ipomoea subgenus Quamoclit (Convolvulaceae) based on ITS sequence data and a Bayesian phylogenetic analysis. AB - A Bayesian phylogenetic analysis of 36 Ipomoea species using sequence data from the internal transcribed spacer region was compared with classification schemes based on traditional methods and a previously published cpDNA restriction fragment length polymorphism (RFLP) study. These molecular studies support a diversity of groups that were circumscribed on the basis of phenetic principles and agree generally with the results from cpDNA RFLP analyses. The congruence between the phylogenetic hypotheses based on new molecular data and the understanding of relationships developed in earlier studies indicate that these classifications may reflect evolutionary history. Two large clades of species, with one including sections Tricolores, Calonyction, and Pharbitis and the other including sections Mina and Leptocallis, were identified. Furthermore, morphologically distinct groups of Ipomoea species received support from the DNA sequence data. Indices of convergence for the Markov chain Monte Carlo (MCMC) in the Bayesian phylogenetic analysis were evaluated. A limited range of posterior probabilities for each node in the trees from a set of five MCMC samples provides a useful index of convergence. Bayesian node support values were generally higher than bootstrap values from a maximum parsimony analysis. This is consistent with the notion that these measures of support estimate different qualities of the data. PMID- 21653479 TI - Phylogeny of amorpheae (fabaceae: papilionoideae). AB - The legume tribe Amorpheae comprises eight genera and 240 species with variable floral form. In this study, we inferred a phylogeny for Amorpheae using DNA sequence data from the plastid trnK intron, including matK, and the nuclear ribosomal ITS1, 5.8S, and ITS2. Our data resulted in a well-resolved phylogeny in which the tribe is divided into the daleoids (Dalea, Marina, and Psorothamnus), characterized by generally papilionaceous corollas, and the amorphoids (Amorpha, Apoplanesia, Errazurizia, Eysenhardtia, and Parryella), characterized by non papilionaceous flowers. We found evidence for the paraphyly of Psorothamnus and for the monophyly of Dalea once D. filiciformis is transferred to monophyletic Marina. Errazurizia rotundata is more closely related to Amorpha than to the other errazurizias, and Eysenhardtia is supported to be monophyletic. The monotypic Parryella and Apoplanesia are placed within the amorphoids. Among Papilionoideae, trnK/matK sequence data provide strong evidence for the monophyly of Amorpheae and place Amorpheae as sister to the recently discovered dalbergioid clade. PMID- 21653480 TI - Origin of the disjunct tetraploid Cardamine amporitana (Brassicaceae) assessed with nuclear and chloroplast DNA sequence data. AB - Seventy-four nucleotide sequences from the ITS regions of nuclear ribosomal DNA and 76 from the trnL-trnF spacer of chloroplast DNA were used to address the origin of tetraploid Cardamine amporitana, the conspecifity of central Italian and northeastern Spanish populations, and the possible cause for such geographic disjunction. Because of the complex lineage relationships in Cardamine, the sampling included 22 taxa. In the results, both data sets are highly congruent in supporting a close relationship of C. amporitana to the widespread Eurasian C. amara. Low genetic variability in northeastern Spanish populations of C. amporitana suggests long-distance dispersal from central Italy. The interior position of the single northeastern Spanish haplotype in a statistical parsimony network of trnL-trnF haplotypes however does not support this scenario and invokes other plausible phylogeographic explanations. The disappearance of geographically intermediate populations and genetic impoverishment by migration and isolation, both probably associated with Quaternary climatic oscillations, appears as an alternative hypothesis to explain the phylogeographic pattern. A recent hybridization event is reported between C. amporitana and a diploid from the C. pratensis group in central Italy on the basis of additive polymorphisms in ITS for all the 22 distinguishing nucleotides. PMID- 21653481 TI - Atmospheric invasion of non-native pollen in the Mediterranean region. AB - Most research on the impacts of plant invasion focuses on native plant performance, community structure, and ecosystem functioning. Some non-native species can also pose a risk to human health. One such risk is the allergenic nature of the pollen of some introduced plants. We examined whether patterns of airborne pollen differed between non-native and native taxa by summarizing data from seven Spanish Mediterranean localities monitored over 13 yr. The pollen spectra contained 27 native pollen taxa and 18 non-native taxa. Even though pollen from native taxa were more diverse and were present longer in the atmosphere than the non-native, in some years neither the prevalence of the two nor their weekly maximum pollen values differed significantly. However, maximum values for non-native taxa were found earlier in the season than for native pollen. A small percentage of non-native pollen includes pollen from introduced taxa that have not invaded natural habitats (e.g., ornamental plants). Non-native pollen has a larger proportion of allergenic pollen than native pollen. Therefore, the results reveal that the presence of non-native airborne pollen from naturalized and non-naturalized plant species increases the total amount of airborne allergenic pollen grains and the period of allergenic susceptibility. PMID- 21653482 TI - Variation in wetland seed banks across a tidal freshwater landscape. AB - Almost nothing is known about landscape-level variation in seed bank composition across complexes of hydrologically connected wetlands. We examined species composition of seed and spore banks in three habitats of tidal freshwater wetlands (marshes, swamp hollows, and swamp hummocks) along 48 km of tributaries throughout the tidal freshwater portions of the Nanticoke River watershed (Maryland and Delaware). Taxa and seedling density decreased with increasing distance upstream in the swamp hollows and hummocks, but increased or remained constant proceeding upstream in the marshes. Species rarefaction curves indicated equal taxa richness (28) between marshes and swamp hummocks at 175 individuals, with lower richness in swamp hollows (19). However, communities in swamp hollows were patchier and had an estimated total taxa richness of 52, similar to the marshes (50) and higher than swamp hummocks (41). Coefficients of variation for seedling emergence densities (136-180%) were greater than those of published seed bank studies conducted at smaller spatial scales in tidal freshwater marshes (36 117%). Our literature searches suggest that ours is the first study to document significant spatial trends in seed bank diversity and density across a wetland landscape. PMID- 21653483 TI - Herbarium specimens demonstrate earlier flowering times in response to warming in Boston. AB - Museum specimens collected in the past may be a valuable source of information on the response of species to climate change. This idea was tested by comparing the flowering times during the year 2003 of 229 living plants growing at the Arnold Arboretum in Boston, Massachusetts, USA, with 372 records of flowering times from 1885 to 2002 using herbarium specimens of the same individual plants. During this period, Boston experienced a 1.5 degrees C increase in mean annual temperature. Flowering times became progressively earlier; plants flowered 8 d earlier from 1980 to 2002 than they did from 1900 to 1920. Most of this shift toward earlier flowering times is explained by the influence of temperature, especially temperatures in the months of February, March, April, and May, on flowering time. Plants with a long flowering duration appear to be as useful for detecting responses to changing temperatures as plants with a short flowering duration. Additional studies using herbarium specimens to detect responses to climate change could examine specimens from specific, intensively collected localities, such as mountain peaks, islands, and unique habitats. PMID- 21653484 TI - Anatomically preserved seeds of Nuphar (Nymphaeaceae) from the Early Eocene of Wutu, Shandong Province, China. AB - Well-preserved seeds from the early Eocene of Wutu, Shandong, China are assigned to the genus Nuphar (Nymphaeaceae) based on morphology and anatomy. The seeds of Nuphar wutuensis sp. nov. are ellipsoidal to ovoid, 4-5 mm long with a clearly visible raphe ridge, and a truncate apex capped by a circular operculum ca. 1 mm in diameter bearing a central micropylar protrusion. These features, along with the testa composed of a uniseriate outer layer of equiaxial pentagonal to hexagonal surface cells and a middle layer 4-6 cells thick composed of thick walled, periclinally elongate sclereids, correspond to the morphology and anatomy of extant Nuphar and distinguish this fossil species from all other extant and extinct genera of Nymphaeales. These seeds provide the oldest record for the genus in Asia and are supplemented by a similar well-preserved specimen from the Paleocene of North Dakota, USA. These data, together with the prior recognition of Brasenia (Cabombaceae) in the middle Eocene, indicate that the families Nymphaeaceae and Cabombaceae had differentiated by the early Tertiary. PMID- 21653485 TI - Molecular evidence for limited dispersal of vegetative propagules in the epiphytic lichen Lobaria pulmonaria. AB - Propagation, whether sexual or asexual, is a fundamental step in the life cycle of every organism. In lichenized fungi, a great variety of vegetative propagules have evolved in order for the symbiotic partners to disperse simultaneously. For lichens with the ability of sexual and asexual reproduction, the relative contribution of vegetative dispersal is unknown but could, nonetheless, be inferred by studying genotype distribution. The genetic structure of three Lobaria pulmonaria (Lobariaceae) populations from Switzerland was investigated based on the observed variation at six microsatellite loci. All three populations had a clustered distribution of identical genotypes at small spatial scales. The maximum distance between identical genotypes was 230 m. At a distance of 350 m from a source tree, seemingly suitable habitat patches were too far apart to be colonized. Some multilocus genotypes were frequent within local populations but no genotypes were shared among populations. The restricted occurrences of common genotypes as well as the clustered distributions are evidence for a limited dispersal of vegetative propagules in L. pulmonaria. Gene flow among isolated populations will ultimately depend on the capacity of long-distance dispersal and thus probably depend on sexual reproduction. PMID- 21653486 TI - Survival strategies of male homeless adolescents. AB - BACKGROUND: A total of 1.7 million youth are homeless in America and nearly half are lesbian, gay, bisexual, or transgender. The purpose of this study is to investigate survival strategies, anxiety, and self-esteem among male homeless adolescents. OBJECTIVES: This study tested two hypotheses: (a) Survival strategies of homeless adolescents differ by sexual orientation/gender identity. (b) There is a relationship between survival strategies and sexual orientation/gender identity, amount of time homeless, self-esteem, and state/trait anxiety. DESIGN: A comparative-descriptive study was conducted in six large cities. Seventy 16- to 20-year-old homeless male adolescents were recruited. RESULTS: Survival strategies did not significantly vary by sexual orientation; however, some differences may be of clinical relevance. CONCLUSIONS: Homeless youth of all sexual orientations/gender identities were using diverse strategies to survive. Psychiatric nurses are in a unique position to assist these youth. PMID- 21653488 TI - Position statement: electroconvulsive therapy. PMID- 21653487 TI - Depression, interferon therapy, hepatitis C, and substance use: potential treatments and areas for research. PMID- 21653489 TI - Our patients' lives are worth fighting for and electroconvulsive therapy (ECT) saves lives: a compendium of the evidence. PMID- 21653490 TI - Electroconvulsive therapy does not damage the brain. PMID- 21653491 TI - Brain stimulation therapies for mood disorders: the continued necessity of electroconvulsive therapy. PMID- 21653492 TI - Electroconvulsive therapy: how effective is it? PMID- 21653493 TI - Informed consent and electroconvulsive therapy. PMID- 21653494 TI - Shocking the shrink. PMID- 21653495 TI - The brief cognitive-behavioral COPE intervention for depressed adolescents: outcomes and feasibility of delivery in 30-minute outpatient visits. AB - BACKGROUND: Despite a U.S. prevalence of 9%, less than 25% of depressed adolescents receive treatment because of time constraints in clinical practice and lack of mental health providers available to deliver it. OBJECTIVE: To assess the feasibility and effects of a brief manualized seven-session cognitive behavioral skills building intervention entitled COPE (Creating Opportunities for Personal Empowerment) delivered to 15 depressed adolescents in routine 30-minute mental health medication management outpatient visits. STUDY DESIGN: A preexperimental one group pre- and posttest design was used. RESULTS: Adolescents reported significant decreases in depression, anxiety, anger, and destructive behavior as well as increases in self-concept and personal beliefs about managing negative emotions. Evaluations indicated that COPE was a positive experience for teens and parents. CONCLUSION: COPE is a promising brief cognitive-behavior therapy-based intervention that can be delivered within 30-minute individual outpatient visits. With this intervention, advanced practice nurses can work with practice time limitations and still provide evidence-based treatment for depressed teens. PMID- 21653496 TI - Major depressive disorder in persons exposed to trauma: relationship between emotional intelligence and social support. AB - BACKGROUND: Traumatic events are often linked to the onset of major depressive disorder (MDD) and for the increase of nonremittance of symptoms; however, psychological factors that contribute to the relationship between trauma and chronic depression are not well defined. OBJECTIVE: The objective of this study is to determine if emotional intelligence (EI) and social support differ in traumatized depressed patients when compared with controls. METHOD: The present study examines two psychosocial factors that may contribute to this link: EI and social support. Participants who experienced a trauma and had current MDD (n=38) were compared with nontraumatized healthy controls ( n=40). RESULTS: Traumatized depressed participants exhibited lower total EI, because of reductions in strategic EI ability, as well as lower levels of social support compared with the control group. CONCLUSIONS: EI and social support were significantly correlated. These findings suggest that EI may be a novel target for intervention to prevent and treat MDD. PMID- 21653497 TI - A clinical translation of the research article titled "major depressive disorder in persons exposed to trauma: relationship between emotional intelligence and social support". PMID- 21653498 TI - Shaping the future of PMH-APRN practice through engagement. PMID- 21653499 TI - Evaluation of simulated learning: looking backward and forward. PMID- 21653500 TI - Identification and cross-species transferability of 112 novel unigene-derived microsatellite markers in tea (Camellia sinensis). AB - PREMISE OF THE STUDY: Tea Unigene-derived MicroSatellite (TUGMS) markers were identified from the publicly available EST data in Camellia sinensis for characterization and future genome mapping studies in tea. METHODS AND RESULTS: One hundred twelve novel TUGMS markers were identified from 4356 unigenes derived by clustering of 12788 random ESTs in C. sinensis. Amplification-based validation of the TUGMS loci proved them to be highly polymorphic [an average (av.) of 5.24 alleles], heterozygous (H(E), av. 0.746; H(o), av. 0.566) and informative (PIC, av. 0.392). TUGMS loci were 100% transferable in cultivated C. assamica and C. assamica subsp. lasiocalyx and highly cross-transferrable to the related species C. japonica, C. rosiflora, and C. sasanqua. CONCLUSIONS: These 112 novel highly polymorphic TUGMS markers with proven cross-species transferability will facilitate the future genetic diversity and genome mapping studies in tea. PMID- 21653501 TI - Development of microsatellites in the Hawaiian endemic palm Pritchardia martii (Arecaceae) and their utility in congeners. AB - PREMISE OF THE STUDY: Pritchardia (loulu palm) is the seventh largest flowering plant genus in the Hawaiian archipelago, and many species are of high conservation concern. The island radiation has produced many cryptic species complexes across fine ecological gradients. Microsatellite primers were optimized to investigate genetic diversity of Pritchardia martii (Gaudich.) H. Wendl. and species boundaries among the Hawaiian Pritchardia. METHODS AND RESULTS: Six new loci and three previously described loci for a closely related genus, Phoenix, were optimized and tested. Five loci were polymorphic, and 72 alleles were detected across loci within P. martii. The five loci were also polymorphic across the other 27 currently recognized Pritchardia species. * CONCLUSIONS: These results indicate the utility of these microsatellite markers for understanding the conservation genetics of P. martii and species delimitation and hybridization across the genus. PMID- 21653502 TI - Isolation and characterization of 20 new microsatellite loci in Coriaria nepalensis (Coriariaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for Coriaria nepalensis, a traditional Chinese medicinal and ornamental plant, to investigate its genetic diversity and population genetic structure as well as its evolutionary history. METHODS AND RESULTS: Twenty-eight dinucleotide microsatellite loci were identified in C. nepalensis, 20 of which showed polymorphism among five populations. The expected heterozygosities were 0-1 (mean 0.469). CONCLUSIONS: These markers may be useful for further investigation of the population genetics, systematics, and phylogeography of Coriaria nepalensis. PMID- 21653503 TI - New microsatellite loci for water yam (Dioscorea alata, Dioscoreaceae) and cross amplification for other Dioscorea species. AB - PREMISE OF THE STUDY: Dioscorea alata L. is one of the most widely distributed species of the genus in the humid and semihumid tropics and is associated with traditional agriculture. Only a few microsatellite markers have been developed so far for this and other Dioscorea species. METHODS AND RESULTS: We isolated 14 codominant polymorphic microsatellite markers using a microsatellite-enriched genomic library technique. Ten microsatellite loci were selected, and 80 D. alata accessions from different regions in Brazil were evaluated with nine polymorphic loci. The polymorphism information content (PIC) varied from 0.39 to 0.78 and the power discrimination (PD) ranged from 0.15 to 0.91. Six of the markers showed transferability for the species D. bulbifera, D. cayenensis-D. rotundata, and D. trifida. CONCLUSIONS: The SSR markers obtained are an important tool for further studies aiming to characterize the genetic diversity in D. alata and other Dioscorea spp. accessions. PMID- 21653504 TI - Isolation and characterization of microsatellite loci in Schoenoplectus juncoides (Cyperaceae)1. AB - PREMISE OF THE STUDY: We developed microsatellite markers for Schoenoplectus juncoides, a weed found in rice paddy fields in eastern Asia. METHODS AND RESULTS: Ten dinucleotide microsatellite loci were isolated, and genetic variability within and among local populations were characterized. The number of alleles per locus ranged from 2 to 6 with a mean of 3.6. Expected heterozygosity per locus ranged from 0.067 to 0.471, whereas observed heterozygosity showed much lower values ranging from 0.000 to 0.083. Most of the loci showed significant deviation from Hardy-Weinberg equilibrium and high inbreeding coefficient values (0.525-1.000). CONCLUSIONS: All the 10 microsatellite loci displayed polymorphism within and among populations. These loci are useful genetic markers for microevolution and ecological studies of S. juncoides populations. PMID- 21653505 TI - Isolation and characterization of microsatellite primers for an invasive weed, Solanum rostratum (Solanaceae). AB - PREMISE OF THE STUDY: We developed microsatellite primers and tested the polymorphism of seven populations of Solanum rostratum distributed throughout their range in China. These will be useful for biologists to study the mating systems and genetic diversity and differentiation of S. rostratum in its native range in Mexico and in its current distribution throughout the world. METHODS AND RESULTS: Five polymorphic microsatellites were identified for Solanum rostratum. The number of alleles per locus ranged from 1 to 8 (average = 4) for 195 individuals examined from seven populations. The observed and expected heterozygosities ranged from 0.000 to 1.000 and 0.000 to 0.778, respectively. CONCLUSIONS: These five markers can be used in studies examining population genetics and the mating system of Solanum rostratum to investigate its invasive mechanisms and to provide information for developing management strategies for this species. PMID- 21653506 TI - Development of ten polymorphic microsatellite loci for Fosbergia shweliensis (Rubiaceae), a potentially crisis endangered tree. AB - PREMISE OF THE STUDY: Fosbergia shweliensis (Anth.) Tirveng. & Sastre (Rubiaceae) is a potentially endangered tree endemic to China. Microsatellite markers were developed to investigate population genetics of this plant. METHODS AND RESULTS: Ten polymorphic microsatellite loci were identified and screened in 32 individuals from four wild populations of F. shweliensis. Alleles numbered 2 to 5, and their levels of observed heterozygosity and expected heterozygosity ranged from 0.0564 to 0.7214 and from 0.2794 to 0.7912, respectively. CONCLUSIONS: These new microsatellite loci will facilitate further studies of the population genetics of F. shweliensis, allowing us to design reasonable conservation and management strategies. PMID- 21653507 TI - Patterns of hybridization between diploid and derived allotetraploid species of Dactylorhiza (Orchidaceae) co-occurring in Belgium. AB - PREMISE OF THE STUDY: Although the potential for gene flow between species with large differences in chromosome numbers has long been recognized, only few studies have thoroughly investigated in situ hybridization across taxa with different ploidy levels. We combined morphological, cytological, and genetic marker data with pollination experiments to investigate the degree, direction, and spatial pattern of hybridization between the diploid Dactylorhiza incarnata and its tetraploid derivative, D. praetermissa. METHODS: To identify hybrids, 169 individuals were genotyped using AFLPs and morphologically characterized. Individuals were clustered on the basis of their AFLP profile using the program Structure. To reduce the dimensionality of the plant-trait matrix, PCA was applied. The origin of suspected hybrid individuals was verified using flow cytometry. An AMOVA and spatial autocorrelation analysis were used to indirectly infer the extent of gene flow. KEY RESULTS: Only five individuals were regarded as putative hybrids on the basis of the AFLP data; all had been assigned to the D. praetermissa morphotype. Only one had deviating DNA content and was presumably a triploid. High Phi(ST) values between different subpopulations and significant spatial genetic structure were observed, suggesting localized gene flow. CONCLUSIONS: Using combined data to study hybridization between D. incarnata and D. praetermissa, very few unequivocal hybrids were observed. We propose several non-mutually exclusive explanations. Localized pollen flow, in combination with different microhabitat preferences, is probably one of the reasons for the low frequency of hybrids. Also, the triploid first-generation hybrids may experience difficulties in successful establishment, as a result of genic incompatibilities. PMID- 21653508 TI - Drivers of morphological diversity and distribution in the Hawaiian fern flora: trait associations with size, growth form, and environment. AB - PREMISE OF THE STUDY: Hawaii is home to 238 native and 35 alien fern and lycophyte taxa distributed across steep gradients in elevation and resource availability. The fern flora spans a wide range of growth forms, with extraordinary diversity in morphology and plant size. Yet the potential factors underlying this diversity have remained enigmatic. METHODS: We used a trait database generated from the most recent and comprehensive survey of Hawaiian ferns and lycophytes to test hypotheses of size-scaling and trait associations with environment and growth form as factors underlying this diversity. We also tested relationships among morphology, taxon abundance and distribution and identified key differences between native and alien taxa. KEY RESULTS: Strong trait-trait relationships included geometric scaling of plant dimensions with a tendency for more divided fronds in larger ferns. Trait-environment relationships independent of size included more divided fronds at higher elevation, longer blades in shaded habitats, and fronds with shorter stipes and fewer pinnae in drier habitats. Growth forms differed in mean size with epiphytic and epipetric taxa smaller than terrestrial ferns. Plant size was independent of taxon abundance and distribution across islands, and native and alien ferns did not differ in mean size. Alien taxa were more abundant, especially at lower elevations, apparently due to human land use. CONCLUSIONS: These relationships point to linkages of fern form and demography with biogeography and highlight potential flora-scale physiological and morphological adaptations in ferns across contrasting environments. PMID- 21653509 TI - Effect of natural root grafting on growth response of jack pine (Pinus banksiana; Pinaceae). AB - PREMISE OF STUDY: Trees are traditionally considered as distinct entities even though they can share a communal root system through root grafts, which are morphological unions between two or more roots. Little is known regarding the ecological significance of natural root grafting, but because grafted trees can share resources and secondary compounds, growth of linked trees can be affected directly by the presence of root grafts. Traditional forest ecology concepts may have to be revised to include direct interactions between connected trees. METHODS: We hydraulically excavated six 30-50-m(2) plots (three natural stands and three plantations). We measured yearly radial growth and determined the influence of root grafting on radial growth of grafted trees. KEY RESULTS: During periods of root graft formation, root grafting tended to reduce radial growth of jack pine trees, after which growth generally increased. The influence of root grafting on growth was more significant in natural stands, where root grafting was more frequent than in plantations. CONCLUSIONS: These results suggest that root grafting initially is an energetically costly process but that it is afterward nonprejudicial and maybe beneficial to tree growth. The use of a communal root system allows for a maximum use of resources by redistributing them among trees, leading to increased tree growth. PMID- 21653510 TI - Selection on seedling emergence timing and size in an annual plant, Helianthus annuus (common sunflower, Asteraceae). AB - PREMISE: Variation in seedling emergence timing is considered adaptive over the long term in wild populations, but early emergence can result in a fitness advantage. To explore the adaptive significance of seedling emergence timing, it should be studied under realistic conditions and in the context of other traits that influence fitness. METHODS: In a common garden, we monitored maternal families from seed to flowering (including over winter) with intra- and interspecific competition. We assessed the effects of emergence timing and plant size on survival to anthesis in different genetic backgrounds and under varying competition. KEY RESULTS: We found genetic variation for emergence (probability and timing), size, and survival to anthesis. We also found negative selection, both phenotypic and genetic, on emergence time, such that early emergers (day 8) had almost twice as great a predicted probability of surviving as later emergers (day 28). Size had strong positive effects on survival and, furthermore, the beneficial effects of early emergence may be mediated through size. Maternal family and competitive environment can also affect selection on emergence timing. CONCLUSIONS: Our results indicate that early emergence is related to greater survival in wild sunflower, although there may be little direct selection on this trait; rather, its importance may be mediated by its effects on highly adaptive traits associated with size. Also, the effects of early emergence may vary across genetic backgrounds and competitive conditions, facilitating the maintenance of variation for this trait across a diverse landscape. PMID- 21653511 TI - Seed germination, seedling traits, and seed bank of the tree Moringa peregrina (Moringaceae) in a hyper-arid environment. AB - PREMISE OF THE STUDY: Water-limited hot environments are good examples of hyper aridity. Trees are scarce in these environments but some manage to survive, such as the tree Moringa peregrina. Understanding how trees maintain viable populations in extremely arid environments may provide insight into the adaptive mechanisms by which trees cope with extremely arid weather conditions. This understanding is relevant to the current increasing aridity in several regions of the world. METHODS: Seed germination experiments were conducted to assess variation in seed mass, seed germination, and seedling traits of Moringa peregrina plants and the correlations among these traits. A seed burial experiment was also designed to study the fate of M. peregrina seeds buried at two depths in the soil for two time periods. KEY RESULTS: On average, seeds germinated in three days and seedling shoots grew 0.7 cm per day over three weeks. Larger seeds decreased germination time and increased seedling growth rates relative to smaller seeds. Seeds remained quiescent in the soil and germination was very high at both depths and burial times. CONCLUSIONS: The after ripening time of Moringa peregrina seeds is short and seeds germinate quickly after imbibition. Plants of M. peregrina may increase in hyper-arid environments from seeds with larger mass, shorter germination times, and faster seedling growth rates. The results also illustrate the adjustment in allocation to seed biomass and correlations among seed and seedling traits that allows M. peregrina to be successful in coping with aridity in its environment. PMID- 21653512 TI - Postglacial north-south expansion of populations of Rhizophora mangle (Rhizophoraceae) along the Brazilian coast revealed by microsatellite analysis. AB - PREMISE OF THE STUDY: Red mangrove (Rhizophora mangle) dominates tropical tidal areas along both sides of the Atlantic, yet little is known about its degree of population differentiation over large geographical scales. Information on the genetic variability of mangrove species along the Brazilian coast is important not only for understanding the recent gene flow dynamic between populations, but also to evaluate models of evolutionary diversification and develop effective strategies for conservation. We investigated the genetic variability of the red mangrove along the Brazilian coast. METHODS: Eight microsatellite loci were used to genotype 145 individuals across 10 populations spanning more than 4500 km of coast line. We estimated the genetic variability and structure of the populations and the historical gene flow between them. KEY RESULTS: The level of genetic variability was low, with only 27 different alleles being detected and allele richness between 1.25 and 2.75. On the other hand, there was substantial population differentiation (R(st) = 0.48; P < 0.001), especially between the northern and southern populations. The populations from Para and Maranhao had significantly greater genetic variability than did the remaining locations. CONCLUSIONS: This difference might reflect the older age of the northern mangroves, which likely remained stable during the Quaternary glaciations. The lowest variability observed in the southern populations of the red mangrove most likely reflects their recent age, associated with allelic reduction, resulting from the consecutive founder events that followed subsequent colonization of estuaries during the gradual warming by the end of the last glacial period. PMID- 21653513 TI - FACIL: Fast and Accurate Genetic Code Inference and Logo. AB - MOTIVATION: The intensification of DNA sequencing will increasingly unveil uncharacterized species with potential alternative genetic codes. A total of 0.65% of the DNA sequences currently in Genbank encode their proteins with a variant genetic code, and these exceptions occur in many unrelated taxa. RESULTS: We introduce FACIL (Fast and Accurate genetic Code Inference and Logo), a fast and reliable tool to evaluate nucleic acid sequences for their genetic code that detects alternative codes even in species distantly related to known organisms. To illustrate this, we apply FACIL to a set of mitochondrial genomic contigs of Globobulimina pseudospinescens. This foraminifer does not have any sequenced close relative in the databases, yet we infer its alternative genetic code with high confidence values. Results are intuitively visualized in a Genetic Code Logo. AVAILABILITY AND IMPLEMENTATION: FACIL is available as a web-based service at http://www.cmbi.ru.nl/FACIL/ and as a stand-alone program. PMID- 21653514 TI - Cdc45: the missing RecJ ortholog in eukaryotes? AB - DNA replication is one of the most ancient of cellular processes and functional similarities among its molecular machinery are apparent across all cellular life. Cdc45 is one of the essential components of the eukaryotic replication fork and is required for the initiation and elongation of DNA replication, but its molecular function is currently unknown. In order to trace its evolutionary history and to identify functional domains, we embarked on a computational sequence analysis of the Cdc45 protein family. Our findings reveal eukaryotic Cdc45 and prokaryotic RecJ to possess a common ancestry and Cdc45 to contain a catalytic site within a predicted exonuclease domain. The likely orthology between Cdc45 and RecJ reveals new lines of enquiry into DNA replication mechanisms in eukaryotes. PMID- 21653515 TI - Prediction of transporter targets using efficient RBF networks with PSSM profiles and biochemical properties. AB - SUMMARY: Transporters are proteins that are involved in the movement of ions or molecules across biological membranes. Currently, our knowledge about the functions of transporters is limited due to the paucity of their 3D structures. Hence, computational techniques are necessary to annotate the functions of transporters. In this work, we focused on an important functional aspect of transporters, namely annotation of targets for transport proteins. We have systematically analyzed four major classes of transporters with different transporter targets: (i) electron, (ii) protein/mRNA, (iii) ion and (iv) others, using amino acid properties. We have developed a radial basis function network based method for predicting transport targets with amino acid properties and position specific scoring matrix profiles. Our method showed a 10-fold cross validation accuracy of 90.1, 80.1, 70.3 and 82.3% for electron transporters, protein/mRNA transporters, ion transporters and others, respectively, in a dataset of 543 transporters. We have also evaluated the performance of the method with an independent dataset of 108 proteins and we obtained similar accuracy. We suggest that our method could be an effective tool for functional annotation of transport proteins. AVAILABILITY: http://rbf.bioinfo.tw/~sachen/ttrbf.html PMID- 21653516 TI - HAPGEN2: simulation of multiple disease SNPs. AB - MOTIVATION: Performing experiments with simulated data is an inexpensive approach to evaluating competing experimental designs and analysis methods in genome-wide association studies. Simulation based on resampling known haplotypes is fast and efficient and can produce samples with patterns of linkage disequilibrium (LD), which mimic those in real data. However, the inability of current methods to simulate multiple nearby disease SNPs on the same chromosome can limit their application. RESULTS: We introduce a new simulation algorithm based on a successful resampling method, HAPGEN, that can simulate multiple nearby disease SNPs on the same chromosome. The new method, HAPGEN2, retains many advantages of resampling methods and expands the range of disease models that current simulators offer. AVAILABILITY: HAPGEN2 is freely available from http://www.stats.ox.ac.uk/~marchini/software/gwas/gwas.html. CONTACT: zhan@well.ox.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21653517 TI - genBlastG: using BLAST searches to build homologous gene models. AB - MOTIVATION: BLAST users frequently expect to obtain homologous genes with certain similarity to their query genes. But what they get from BLAST searches are often collections of local alignments called high-scoring segment pairs (HSPs). On the other hand, most homology-based gene finders have been built using computation intensive algorithms, without taking full advantage of BLAST searches that have been perfected over the last decades. RESULTS: Here we report an efficient algorithm, genBlastG that directly uses the HSPs reported by BLAST to define high quality gene models. AVAILABILITY: http://genome.sfu.ca/genblast/download.html PMID- 21653518 TI - Mathematical modeling of 16S ribosomal DNA amplification reveals optimal conditions for the interrogation of complex microbial communities with phylogenetic microarrays. AB - MOTIVATION: Many current studies of complex microbial communities rely on the isolation of community genomic DNA, amplification of 16S ribosomal RNA genes (rDNA) and subsequent examination of community structure through interrogation of the amplified 16S rDNA pool by high-throughput sequencing, phylogenetic microarrays or quantitative PCR. RESULTS: Here we describe the development of a mathematical model aimed to simulate multitemplate amplification of 16S ribosomal DNA sample and subsequent detection of these amplified 16S rDNA species by phylogenetic microarray. Using parameters estimated from the experimental results obtained in the analysis of intestinal microbial communities with Microbiota Array, we show that both species detection and the accuracy of species abundance estimates depended heavily on the number of PCR cycles used to amplify 16S rDNA. Both parameters initially improved with each additional PCR cycle and reached optimum between 15 and 20 cycles of amplification. The use of more than 20 cycles of PCR amplification and/or more than 50 ng of starting genomic DNA template was, however, detrimental to both the fraction of detected community members and the accuracy of abundance estimates. Overall, the outcomes of the model simulations matched well available experimental data. Our simulations also showed that species detection and the accuracy of abundance measurements correlated positively with the higher sample-wide PCR amplification rate, lower template-to template PCR bias and lower number of species in the interrogated community. The developed model can be easily modified to simulate other multitemplate DNA mixtures as well as other microarray designs and PCR amplification protocols. PMID- 21653519 TI - MixupMapper: correcting sample mix-ups in genome-wide datasets increases power to detect small genetic effects. AB - MOTIVATION: Sample mix-ups can arise during sample collection, handling, genotyping or data management. It is unclear how often sample mix-ups occur in genome-wide studies, as there currently are no post hoc methods that can identify these mix-ups in unrelated samples. We have therefore developed an algorithm (MixupMapper) that can both detect and correct sample mix-ups in genome-wide studies that study gene expression levels. RESULTS: We applied MixupMapper to five publicly available human genetical genomics datasets. On average, 3% of all analyzed samples had been assigned incorrect expression phenotypes: in one of the datasets 23% of the samples had incorrect expression phenotypes. The consequences of sample mix-ups are substantial: when we corrected these sample mix-ups, we identified on average 15% more significant cis-expression quantitative trait loci (cis-eQTLs). In one dataset, we identified three times as many significant cis eQTLs after correction. Furthermore, we show through simulations that sample mix ups can lead to an underestimation of the explained heritability of complex traits in genome-wide association datasets. AVAILABILITY AND IMPLEMENTATION: MixupMapper is freely available at http://www.genenetwork.nl/mixupmapper/ PMID- 21653520 TI - A probabilistic method for the detection and genotyping of small indels from population-scale sequence data. AB - MOTIVATION: High-throughput sequencing technologies have made population-scale studies of human genetic variation possible. Accurate and comprehensive detection of DNA sequence variants is crucial for the success of these studies. Small insertions and deletions represent the second most frequent class of variation in the human genome after single nucleotide polymorphisms (SNPs). Although several alignment tools for the gapped alignment of sequence reads to a reference genome are available, computational methods for discriminating indels from sequencing errors and genotyping indels directly from sequence reads are needed. RESULTS: We describe a probabilistic method for the accurate detection and genotyping of short indels from population-scale sequence data. In this approach, aligned sequence reads from a population of individuals are used to automatically account for context-specific sequencing errors associated with indels. We applied this approach to population sequence datasets from the 1000 Genomes exon pilot project generated using the Roche 454 and Illumina sequencing platforms, and were able to detect a significantly greater number of indels than reported previously. Comparison to indels identified in the 1000 Genomes pilot project demonstrated the sensitivity of our method. The consistency in the number of indels and the fraction of indels whose length is a multiple of three across different human populations and two different sequencing platforms indicated that our method has a low false discovery rate. Finally, the method represents a general approach for the detection and genotyping of small-scale DNA sequence variants for population scale sequencing projects. AVAILABILITY: A program implementing this method is available at http://polymorphism.scripps.edu/~vbansal/software/piCALL/ PMID- 21653521 TI - nucleR: a package for non-parametric nucleosome positioning. AB - SUMMARY: nucleR is an R/Bioconductor package for a flexible and fast recognition of nucleosome positioning from next generation sequencing and tiling arrays experiments. The software is integrated with standard high-throughput genomics R packages and allows for in situ visualization as well as to export results to common genome browser formats. AVAILABILITY: Additional information and methodological details can be found at http://mmb.pcb.ub.es/nucleR PMID- 21653523 TI - The Biological Connection Markup Language: a SBGN-compliant format for visualization, filtering and analysis of biological pathways. AB - MOTIVATION: Many models and analysis of signaling pathways have been proposed. However, neither of them takes into account that a biological pathway is not a fixed system, but instead it depends on the organism, tissue and cell type as well as on physiological, pathological and experimental conditions. RESULTS: The Biological Connection Markup Language (BCML) is a format to describe, annotate and visualize pathways. BCML is able to store multiple information, permitting a selective view of the pathway as it exists and/or behave in specific organisms, tissues and cells. Furthermore, BCML can be automatically converted into data formats suitable for analysis and into a fully SBGN-compliant graphical representation, making it an important tool that can be used by both computational biologists and 'wet lab' scientists. AVAILABILITY AND IMPLEMENTATION: The XML schema and the BCML software suite are freely available under the LGPL for download at http://bcml.dc-atlas.net. They are implemented in Java and supported on MS Windows, Linux and OS X. PMID- 21653524 TI - Increased risk of multiple sclerosis following herpes zoster: a nationwide, population-based study. AB - (See the editorial commentary by Corona and Flores, on pages 177-8.) OBJECTIVE: Varicella zoster virus (VZV) has been proposed to be involved in the pathogenesis of multiple sclerosis (MS). However, the epidemiological data regarding the MS occurrence rate following herpes zoster are still scanty. The goal of this study is to investigate the frequency and risk for MS following occurrence of herpes zoster. METHODS: This study used the Taiwan National Health Insurance Research Database. A total of 315,550 patients with herpes zoster were included as the study group, and the control group consisted of 946,650 randomly selected subjects. The stratified Cox proportional hazard regression was performed to calculate the 1-year MS-free survival rate. RESULTS: Of 1,262,200 sampled patients, 29 from the study group (.009%) and 24 from the control group (.003%) had MS during the 1-year follow-up period. After adjusting for monthly income and geographic region, the hazard of MS was 3.96 times greater (95% CI = 2.22-7.07, p < 0.001) for the study group than controls. CONCLUSIONS: Our findings support the notion that occurrence of MS could be associated with herpes zoster attack. We found a significantly higher risk for MS within 1 year of herpes zoster attack compared with the control population. PMID- 21653525 TI - Herpes zoster and multiple sclerosis. PMID- 21653526 TI - Cell plasticity in lung injury and repair: report from an NHLBI workshop, April 19-20, 2010. AB - In April 2010, a NIH workshop was convened to discuss the current state of understanding of lung cell plasticity, including the responses of epithelial cells to injury, with the objectives of summarizing what is known, what the field needs to know, and how to get there. The proximal stimulus for this workshop is the body of recent evidence suggesting that plasticity is a prominent but incompletely characterized property of lung epithelial cells, and that a focus on understanding this aspect of epithelial cell biology in particular, may be an important window into disease pathobiology and pathogenesis. In addition to their many vital functions in maintaining tissue homeostasis, epithelial cells have emerged as both a central target of disease initiation and an active contributor to disease progression, making a workshop to investigate the role of cell plasticity in lung injury and repair timely. The workshop was organized around four major themes: lung epithelial cell plasticity, signaling control of plasticity, fibroblast plasticity and crosstalk, and translation to human disease. Although this breakdown was recognized to be somewhat artificial, it was felt that this approach would promote cross-fertilization among groups that ordinarily do not communicate and lend itself to the generation of new approaches. The summary reports of individual group discussions below are followed by consensus priorities and recommendations of the workshop participants. PMID- 21653528 TI - HIV-associated lung infections and complications in the era of combination antiretroviral therapy. AB - The spectrum of lung diseases associated with HIV is broad, and many infectious and noninfectious complications of HIV infection have been recognized. The nature and prevalence of lung complications have not been fully characterized since the Pulmonary Complications of HIV Infection Study more than 15 years ago, before antiretroviral therapy (ART) increased life expectancy. Our understanding of the global epidemiology of these diseases in the current ART era is limited, and the mechanisms for the increases in the noninfectious conditions, in particular, are not well understood. The Longitudinal Studies of HIV-Associated Lung Infections and Complications (Lung HIV) Study (ClinicalTrials.gov number NCT00933595) is a collaborative multi-R01 consortium of research projects established by the National Heart, Lung, and Blood Institute to examine a diverse range of infectious and noninfectious pulmonary diseases in HIV-infected persons. This article reviews our current state of knowledge of the impact of HIV on lung health and the development of pulmonary diseases, and highlights ongoing research within the Lung HIV Study. PMID- 21653529 TI - HIV-1 and bacterial pneumonia in the era of antiretroviral therapy. AB - Community-acquired pneumonia affects approximately 4 million people in the United States, with 40,000 deaths per year. The incidence is increased about 35-fold in HIV-infected individuals, and this rate has decreased since the antiretroviral era has begun. Bacterial pneumonia has decreased from 5 to 20 cases per 100 person-years to less than 1 to 5 cases per 100 person-years in the era of antiretroviral therapy. HIV-1 infection impairs the function of neutrophils in the lung and infects CD4+ cells and alveolar macrophages. Opportunistic infections dramatically increase local HIV replication in the lung cells, especially alveolar macrophages and CD4+ cells. This enhanced replication increases viral mutations and provides opportunities for viral escape from latent reservoirs. Mortality is increased with more comorbidities in this highly susceptible population. Immunization with vaccines is recommended, especially pneumococcal vaccines, although the vaccine itself may stimulate viral replication. Recent studies show that the lower respiratory tract is a microbial reservoir in HIV-infected individuals rather than being a sterile environment, as originally thought. This may provide new opportunities for preventing opportunistic infections in HIV-infected subjects. Bacterial pneumonia presents an ongoing challenge in these high-risk individuals, particularly in studying the functions of the innate and acquired immune response. PMID- 21653530 TI - Epidemiology of tuberculosis and HIV: recent advances in understanding and responses. AB - Although tuberculosis (TB) continues to cause enormous suffering and overwhelm health care systems in areas with high HIV prevalence, there have been a number of recent significant advances in knowledge regarding the epidemiology, management, and control of HIV-related TB. TB remains the most common serious opportunistic infection in people with HIV infection and the leading cause of death. However, there is some reason for optimism. First, two trials addressing when to start antiretroviral therapy (ART) in HIV-infected adults with newly diagnosed TB have shown that earlier initiation of ART reduces mortality significantly. Second, there is trial evidence of efficacy in giving long-term isoniazid preventive treatment (IPT) to HIV-infected adults in high HIV prevalence settings where TB reinfection is frequent (much like cotrimoxazole). Third, the search for an inexpensive, rapid, sensitive, and specific TB diagnostic that is able to replace smear and delayed mycobacterial culture has yielded promising results. Responding to massive TB epidemics in high HIV prevalence settings, the World Health Organization has supplemented its directly observed treatment short-course strategy with one called the 3I's to actively screen and diagnose TB cases (intensified case finding), prevent new cases of TB with IPT, and prevent transmission of TB in congregate settings such as hospitals and clinics (infection control). Combating TB in high HIV-prevalence settings requires rapid and massive implementation of the 3I's with initiation of antiretrovirals and more effective efforts to prevent new HIV infections. PMID- 21653531 TI - HIV-associated Pneumocystis pneumonia. AB - During the past 30 years, major advances have been made in our understanding of HIV/AIDS and Pneumocystis pneumonia (PCP), but significant gaps remain. Pneumocystis is classified as a fungus and is host-species specific, but an understanding of its reservoir, mode of transmission, and pathogenesis is incomplete. PCP remains a frequent AIDS-defining diagnosis and is a frequent opportunistic pneumonia in the United States and in Europe, but comparable epidemiologic data from other areas of the world that are burdened with HIV/AIDS are limited. Pneumocystis cannot be cultured, and bronchoscopy with bronchoalveolar lavage is the gold standard procedure to diagnose PCP, but noninvasive diagnostic tests and biomarkers show promise that must be validated. Trimethoprim-sulfamethoxazole is the recommended first-line treatment and prophylaxis regimen, but putative trimethoprim-sulfamethoxazole drug resistance is an emerging concern. The International HIV-associated Opportunistic Pneumonias (IHOP) study was established to address these knowledge gaps. This review describes recent advances in the pathogenesis, epidemiology, diagnosis, and management of HIV-associated PCP and ongoing areas of clinical and translational research that are part of the IHOP study and the Longitudinal Studies of HIV associated Lung Infections and Complications (Lung HIV). PMID- 21653532 TI - Critical illness in HIV-infected patients in the era of combination antiretroviral therapy. AB - As HIV-infected persons on combination antiretroviral therapy (ART) are living longer and rates of opportunistic infections have declined, serious non-AIDS related diseases account for an increasing proportion of deaths. Consistent with these changes, non-AIDS-related illnesses account for the majority of ICU admissions in more recent studies, in contrast to earlier eras of the AIDS epidemic. Although mortality after ICU admission has improved significantly since the earliest HIV era, it remains substantial. In this article, we discuss the current state of knowledge regarding the impact of ART on incidence, etiology, and outcomes of critical illness among HIV-infected patients. In addition, we consider issues related to administration of ART in the ICU and identify important areas of future research. PMID- 21653533 TI - Pathogenesis of HIV-associated pulmonary hypertension: potential role of HIV-1 Nef. AB - Infection with HIV increases the risk for lung diseases, including noninfectious pulmonary hypertension (PH). HIV-associated PH (HIV-PH) is an important lung disease in HIV-infected persons who live longer with antiretrovirals. The early stages of HIV-PH may be overlooked by healthcare providers due to nonspecific symptoms, including progressive dyspnea and nonproductive cough. HIV-PH may be detected via chest radiographs, CT scans, or electrocardiograms, but Doppler echocardiography is the most useful screening test to identify candidates for right heart catheterization. HIV-PH has a poor prognosis with high mortality; improved biomarkers to identify earlier stages of PH would benefit clinical care. The HIV-PH mechanism remains unknown, but HIV proteins such as Tat and Nef may play a role. HIV-1 Nef is a broad-spectrum adaptor protein that may affect HIV infected and uninfected pulmonary vascular cells. Studies in macaques suggest that Nef is important in HIV-PH pathogenesis because monkeys infected with a chimeric simian immunodeficiency virus (SIV) expressing HIV-nef (SHIVnef) alleles, but not monkeys infected with the native SIV, develop pulmonary vascular remodeling. Four consistent amino acid mutations arose spontaneously in Nef passaged in the monkeys. To translate these findings to humans, one research endeavor of the Lung HIV Study focuses on the identification of HIV nef mutations in HIV-infected individuals with PH compared with HIV-infected normotensive patients. We present some of the preliminary evidence. Ongoing longitudinal studies will establish the connection between Nef mutations and the propensity for HIV-PH. PMID- 21653522 TI - The variant call format and VCFtools. AB - SUMMARY: The variant call format (VCF) is a generic format for storing DNA polymorphism data such as SNPs, insertions, deletions and structural variants, together with rich annotations. VCF is usually stored in a compressed manner and can be indexed for fast data retrieval of variants from a range of positions on the reference genome. The format was developed for the 1000 Genomes Project, and has also been adopted by other projects such as UK10K, dbSNP and the NHLBI Exome Project. VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API. AVAILABILITY: http://vcftools.sourceforge.net PMID- 21653534 TI - Cigarette smoking in the HIV-infected population. AB - As mortality due to AIDS-related causes has decreased with the use of antiretroviral therapy, there has been a rise in deaths related to non-AIDS defining illnesses. Given the exceedingly high prevalence of cigarette smoking among individuals living with HIV infection, tobacco has been implicated as a major contributor to this paradigm shift. Evidence suggests that smoking-related illnesses, such as cardiovascular disease, respiratory illnesses, and certain malignancies, contribute substantially to morbidity and mortality among HIV infected persons. In this review, we summarize the adverse health consequences of smoking relevant to HIV-infected individuals and discuss smoking cessation in this unique population, including a discussion of barriers to quitting and a review of studies that have examined smoking cessation interventions. PMID- 21653527 TI - Stem cells and cell therapies in lung biology and lung diseases. AB - The University of Vermont College of Medicine and the Vermont Lung Center, with support of the National Heart, Lung, and Blood Institute (NHLBI), the Alpha-1 Foundation, the American Thoracic Society, the Emory Center for Respiratory Health,the Lymphangioleiomyomatosis (LAM) Treatment Alliance,and the Pulmonary Fibrosis Foundation, convened a workshop,''Stem Cells and Cell Therapies in Lung Biology and Lung Diseases,'' held July 26-29, 2009 at the University of Vermont,to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy approaches for lung diseases. These are rapidly expanding areas of study that provide further insight into and challenge traditional views of the mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. PMID- 21653535 TI - HIV and chronic obstructive pulmonary disease: is it worse and why? AB - Smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are of particular concern in the HIV-infected population. Smoking rates are high in this population, and long-term exposure to cigarette smoke in the setting of HIV infection may increase the number of complications seen. Before the era of combination antiretroviral therapy, HIV-infected persons were noted to have an accelerated form of COPD, with significant emphysematous disease seen in individuals less than 40 years old. Unlike many of the AIDS-defining opportunistic infections, HIV-associated COPD may be more common in the current era of HIV because it is frequently reported in patients without a history of AIDS-related pulmonary complications and because many aging HIV-infected individuals have had a longer exposure to smoking and HIV. In this review, we document the epidemiology of HIV-associated COPD before and after the institution of combination antiretroviral therapy, review data suggesting that COPD is accelerated in those with HIV, and discuss possible mechanisms of HIV-associated COPD, including an increased susceptibility to chronic, latent infections; an aberrant inflammatory response; altered oxidant-antioxidant balance; increased apoptosis associated with HIV; and the effects of antiretroviral therapy. PMID- 21653537 TI - 'Radiologically compatible CLIPPERS' may conceal a number of pathologies. PMID- 21653536 TI - HIV infection in the etiology of lung cancer: confounding, causality, and consequences. AB - Persons infected with HIV have an elevated risk of lung cancer, but whether the increase simply reflects a higher smoking prevalence continues to be debated. This review summarizes existing data on the association of HIV infection and lung cancer, with particular attention to study design and adjustment for cigarette smoking. Potential mechanisms by which HIV infection may lead to lung cancer are discussed. Finally, irrespective of causality and mechanisms, lung cancer represents an important and growing problem confronting HIV-infected patients and their providers. Substantial efforts are needed to promote smoking cessation and to control lung cancer among HIV-infected populations. PMID- 21653538 TI - N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. AB - Mutant ataxin-3 is aberrantly folded and proteolytically cleaved in spinocerebellar ataxia type 3. The C-terminal region of the protein includes a polyglutamine stretch that is expanded in spinocerebellar ataxia type 3. Here, we report on the analysis of an ataxin-3 mutant mouse that has been obtained by gene trap integration. The ataxin-3 fusion protein encompasses 259 N-terminal amino acids including the Josephin domain and an ubiquitin-interacting motif but lacks the C-terminus with the polyglutamine stretch, the valosin-containing protein binding region and part of the ubiquitin-interacting motif 2. Homozygous ataxin-3 mutant mice were viable and showed no apparent anatomical defects at birth. However, at the age of 9 months, homozygous and heterozygous mutant mice revealed significantly altered behaviour and progressing deficits of motor coordination followed by premature death at ~12 months. At this time, prominent extranuclear protein aggregates and neuronal cell death was found in mutant mice. This was associated with disturbances of the endoplasmic reticulum-mediated unfolded protein response, consistent with the normal role of ataxin-3 in endoplasmic reticulum homeostasis. Thus, the ataxin-3 gene trap model provides evidence for a contribution of the non-polyglutamine containing ataxin-3 N-terminus, which mimics a calpain fragment that has been observed in spinocerebellar ataxia type 3. Consistent with the disease in humans, gene trap mice develop cytoplasmic inclusion bodies and implicate impaired unfolded protein response in the pathogenesis of spinocerebellar ataxia type 3. PMID- 21653541 TI - The impact of dementia prevalence on the utility of the AD8. PMID- 21653540 TI - Leucoaraiosis, nigrostriatal denervation and motor symptoms in Parkinson's disease. AB - Leucoaraiosis is associated with motor symptoms in otherwise normal older adults. Comorbid leucoaraiosis is predicted to contribute also to motor features in Parkinson's disease but previous studies of white matter changes in Parkinson's disease show variable results. No prior studies have compared directly the effects of both leucoaraiosis and the degree of nigrostriatal dopaminergic denervation on motor features. We investigated the effect of leucoaraiosis severity on motor impairment independent of the degree of nigrostriatal dopaminergic denervation in Parkinson's disease. Seventy-three subjects with Parkinson's disease (Hoehn and Yahr stages 1-3) underwent brain magnetic resonance and [(11)C]dihydrotetrabenazine vesicular monoamine transporter type 2 positron emission tomography imaging. Automated assessment of supratentorial fluid-attenuated inversion recovery magnetic resonance hyperintense white matter voxels was performed using cerebellar white matter as the intensity reference. White matter signal hyperintensity burden was log-transformed and normalized for brain volume. Unified Parkinson's Disease Rating Scale total and subscore ratings were assessed to determine motor impairment. Subjects receiving dopaminergic medications were examined in the clinically defined 'OFF' state. Multivariate regression analysis with measures of white matter signal hyperintensity burden and nigrostriatal denervation as independent variables demonstrated a significant overall model for total motor Unified Parkinson's Disease Rating Scale scores (F = 11.4, P < 0.0001) with significant regression effects for both white matter signal hyperintensity burden (t = 2.0, beta = 0.22, P = 0.045) and striatal monoaminergic binding (t = -3.5, beta = -0.38, P = 0.0008). Axial motor impairment demonstrated a robust association with white matter signal hyperintensity burden (t = 4.0, beta = 0.43, P =0.0001) compared with striatal monoaminergic binding (t = -2.1, beta = 0.22, P = 0.043). White matter signal hyperintensity burden regression effects for bradykinesia had borderline significance. No significant white matter signal hyperintensity burden effects were found for rigidity or tremor subscores. White matter signal hyperintensity burden was significantly higher in the subgroup with postural instability and gait difficulties compared with the tremor-predominant subgroup despite no significant differences in age or duration of disease. These findings indicate that increased white matter signal hyperintensity burden is associated with worse motor performance independent of the degree of nigrostriatal dopaminergic denervation in Parkinson's disease. Comorbid white matter disease is a greater determinant of axial motor impairment than nigrostriatal dopaminergic denervation. PMID- 21653539 TI - Oxidative damage in multiple sclerosis lesions. AB - Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are currently poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Since mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, we analysed by immunocytochemistry the presence and cellular location of oxidized lipids and oxidized DNA in lesions and in normal-appearing white matter of 30 patients with multiple sclerosis and 24 control patients without neurological disease or brain lesions. As reported before in biochemical studies, oxidized lipids and DNA were highly enriched in active multiple sclerosis plaques, predominantly in areas that are defined as initial or 'prephagocytic' lesions. Oxidized DNA was mainly seen in oligodendrocyte nuclei, which in part showed signs of apoptosis. In addition, a small number of reactive astrocytes revealed nuclear expression of 8-hydroxy-d-guanosine. Similarly, lipid peroxidation-derived structures (malondialdehyde and oxidized phospholipid epitopes) were seen in the cytoplasm of oligodendrocytes and some astrocytes. In addition, oxidized phospholipids were massively accumulated in a fraction of axonal spheroids with disturbed fast axonal transport as well as in neurons within grey matter lesions. Neurons stained for oxidized phospholipids frequently revealed signs of degeneration with fragmentation of their dendritic processes. The extent of lipid and DNA oxidation correlated significantly with inflammation, determined by the number of CD3 positive T cells and human leucocyte antigen-D expressing macrophages and microglia in the lesions. Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis. PMID- 21653543 TI - Identification and evaluation of the Atlantic razor clam (Ensis directus) for biologically inspired subsea burrowing systems. AB - In this article, we identify and analyze a subsea organism to serve as a model for biologically inspired burrowing technology to be used in applications such as anchoring, installation of cables, and recovery of oil. After inspecting myriad forms of life that live on or within ocean substrates, the Atlantic razor clam, Ensis directis, stood out as an attractive basis for new burrowing technology because of its low-energy requirements associated with digging (0.21 J/cm), its speed and depth of burrrowing (~1 cm/s and 70 cm, respectively), and its size and simplicity relative to man-made machines. As anchoring is a prime application for the technology resulting from this work, the performance of an Ensis directus based anchoring system was compared to existing technologies. In anchoring force per embedment energy, the E. directus-based anchor beats existing technology by at least an order of magnitude. In anchoring force per weight of device, the biologically inspired system weighs less than half that of current anchors. The article concludes with a review of E. directus's digging strategy, which involves motions of its valves to locally fluidize the substrate to reduce burrowing drag and energy, and the successful adaptation of E. directus's burrowing mechanisms into an engineering system: the RoboClam burrowing robot, which, like the animal, uses localized fluidization to achieve digging energy that scales linearly with depth, rather than depth squared, for moving through static soil. PMID- 21653542 TI - Ontogenetic changes in Mammalian feeding: insights from electromyographic data. AB - All infant mammals make a transition from suckling milk to eating solid foods. Yet, the neuromuscular implications of the transition from a liquid-only diet to solid foods are unknown even though the transport and swallowing of liquids is different from that of solids. We used legacy electromyography (EMG) data to test hypotheses concerning the changes in motor pattern and neuromuscular control that occur during the transition from an all-liquid diet to consumption of solid food in a porcine model. EMG signals were recorded from five oropharyngeal muscles in pigs at three developmental stages (infants, juveniles, and adults) feeding on milk, on food of an intermediate consistency (porridge), and on dry chow (juveniles and adults only). We measured cycle frequency and its variation in "transport cycles" and "swallow cycles". In the swallow cycles, a measure of variation of the EMG signal was also calculated. Variation in cycle frequency for transport and swallow cycles was lowest in adults, as predicted, suggesting that maturation of feeding mechanisms occurs as animals reach adulthood. Infants had lower variation in transport cycle frequency than did juveniles drinking milk, which may be due to the greater efficiency of the infant's tight oral seal against the teat during suckling, compared to a juvenile drinking from a bowl where a tight seal is not possible. Within juveniles, variation in both transport and swallow cycle frequencies was directly related to food consistency, with the highest variation occurring when drinking milk and the lowest when feeding on solid food. There was no difference in the variation of the EMG activity between intact infants and juveniles swallowing milk, although when the latter swallow porridge the EMG signals were less variable than for milk. These results suggest that consistency of food is a highly significant determinant of the variation in motor pattern, particularly in newly weaned animals. PMID- 21653544 TI - Use of biorobotic models of highly deformable fins for studying the mechanics and control of fin forces in fishes. AB - Bony fish swim with a level of agility that is unmatched in human-developed systems. This is due, in part, to the ability of the fish to carefully control hydrodynamic forces through the active modulation of the fins' kinematics and mechanical properties. To better understand how fish produce and control forces, biorobotic models of the bluegill sunfish's (Lepomis macrochirus) caudal fin and pectoral fins were developed. The designs of these systems were based on detailed analyses of the anatomy, kinematics, and hydrodynamics of the biological fins. The fin models have been used to investigate how fin kinematics and the mechanical properties of the fin-rays influence propulsive forces and to explore kinematic patterns that were inspired by biological motions but that were not explicitly performed by the fish. Results from studies conducted with the fin models indicate that subtle changes to the kinematics and mechanical properties of fin rays can significantly impact the magnitude, direction, and time course of the 3D forces used for propulsion and maneuvers. The magnitude of the force tends to scale with the fin's stiffness, but the direction of the force is not invariant, and this causes disproportional changes in the magnitude of the thrust, lift, and lateral components of force. Results from these studies shed light on the multiple strategies that are available to the fish to modulate fin forces. PMID- 21653545 TI - Strategies for coping with the costs of inpatient care: a mixed methods study of urban and rural poor in Vadodara District, Gujarat, India. AB - BACKGROUND: In India, coping mechanisms for inpatient care costs have been explored in rural areas, but seldom among urbanites. This study aims to explore and compare mechanisms employed by the urban and rural poor for coping with inpatient expenditures, in order to help identify formal mechanisms and policies to provide improved social protection for health care. METHODS: A three-step methodology was used: (1) six focus-group discussions; (2) 800 exit survey interviews with users of public and private facilities in both urban and rural areas; and (3) 18 in-depth interviews with poor (below 30th percentile of socio economic status) hospital users, to explore coping mechanisms in greater depth. RESULTS: Users of public hospitals, in both urban and rural areas, were poor relative to users of private hospitals. Median expenditures per day were much higher at private than at public facilities. Most respondents using public facilities (in both urban and rural areas) were able to pay out of their savings or income; or by borrowing from friends, family or employer. Those using private facilities were more likely to report selling land or other assets as the primary source of coping (particularly in rural areas) and they were more likely to have to borrow money at interest (particularly in urban areas). Poor individuals who used private facilities cited as reasons their closer proximity and higher perceived quality of care. CONCLUSIONS: In India, national and state governments should invest in improving the quality and access of public first-referral hospitals. This should be done selectively-with a focus, for example, on rural areas and urban slum areas-in order to promote a more equitable distribution of resources. Policy makers should continue to explore and support efforts to provide financial protection through insurance mechanisms. Past experience suggests that these efforts must be carefully monitored to ensure that the poorer among the insured are able to access scheme benefits, and the quality and quantity of health care provided must be monitored and regulated. PMID- 21653546 TI - Oseltamivir use in low-birth weight infants during the 2009 nH1N1 influenza a outbreak in the Western Cape, South Africa. AB - Before vaccination against nH1N1 influenza was available in South Africa our hospital experienced an outbreak of nH1N1 infection on the maternal and neonatal platform. Oseltamivir was administered to nine low birth weight infants, five for therapy and four for prophylaxis. The median gestational age was 31 (27-37) weeks and the birth weight was 1660 (720-2360) g. Respiratory function improved in those with confirmed disease and none receiving prophylaxis developed worsening respiratory symptoms. One neonate receiving prophylaxis developed self-limiting conjunctivitis; another succumbed from necrotizing enterocolitis (NEC) three days post completion of oseltamivir treatment. A causal relationship between oseltamivir and NEC, although unlikely, cannot be confirmed or excluded. PMID- 21653547 TI - PILGRM: an interactive data-driven discovery platform for expert biologists. AB - PILGRM (the platform for interactive learning by genomics results mining) puts advanced supervised analysis techniques applied to enormous gene expression compendia into the hands of bench biologists. This flexible system empowers its users to answer diverse biological questions that are often outside of the scope of common databases in a data-driven manner. This capability allows domain experts to quickly and easily generate hypotheses about biological processes, tissues or diseases of interest. Specifically PILGRM helps biologists generate these hypotheses by analyzing the expression levels of known relevant genes in large compendia of microarray data. Because PILGRM is data-driven, it complements a user's knowledge and literature analysis with mining of diverse functional genomic data, thereby generating novel predictions that can drive experimental follow-up. This server is free, does not require registration and is available for use at http://pilgrm.princeton.edu. PMID- 21653548 TI - Concerted action at eight phosphodiester bonds by the BcgI restriction endonuclease. AB - The BcgI endonuclease exemplifies a subset of restriction enzymes, the Type IIB class, which make two double-strand breaks (DSBs) at each copy of their recognition sequence, one either side of the site, to excise the sequence from the remainder of the DNA. In this study, we show that BcgI is essentially inactive when bound to a single site and that to cleave a DNA with one copy of its recognition sequence, it has to act in trans, bridging two separate DNA molecules. We also show that BcgI makes the two DSBs at an individual site in a highly concerted manner. Intermediates cut on one side of the site do not accumulate during the course of the reaction: instead, the DNA is converted straight to the final products cut on both sides. On DNA with two sites, BcgI bridges the sites in cis and then generally proceeds to cut both strands on both sides of both sites without leaving the DNA. The BcgI restriction enzyme can thus excise two DNA segments together, by cleaving eight phosphodiester bonds within a single-DNA binding event. PMID- 21653549 TI - The human DEK oncogene regulates DNA damage response signaling and repair. AB - The human DEK gene is frequently overexpressed and sometimes amplified in human cancer. Consistent with oncogenic functions, Dek knockout mice are partially resistant to chemically induced papilloma formation. Additionally, DEK knockdown in vitro sensitizes cancer cells to DNA damaging agents and induces cell death via p53-dependent and -independent mechanisms. Here we report that DEK is important for DNA double-strand break repair. DEK depletion in human cancer cell lines and xenografts was sufficient to induce a DNA damage response as assessed by detection of gammaH2AX and FANCD2. Phosphorylation of H2AX was accompanied by contrasting activation and suppression, respectively, of the ATM and DNA-PK pathways. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end joining (NHEJ) when compared to their wild-type counterparts. Taken together, the data demonstrate new molecular links between DEK and DNA damage response signaling pathways, and suggest that DEK contributes to DNA repair. PMID- 21653550 TI - A novel occluded RNA recognition motif in Prp24 unwinds the U6 RNA internal stem loop. AB - The essential splicing factor Prp24 contains four RNA Recognition Motif (RRM) domains, and functions to anneal U6 and U4 RNAs during spliceosome assembly. Here, we report the structure and characterization of the C-terminal RRM4. This domain adopts a novel non-canonical RRM fold with two additional flanking alpha helices that occlude its beta-sheet face, forming an occluded RRM (oRRM) domain. The flanking helices form a large electropositive surface. oRRM4 binds to and unwinds the U6 internal stem loop (U6 ISL), a stable helix that must be unwound during U4/U6 assembly. NMR data indicate that the process starts with the terminal base pairs of the helix and proceeds toward the loop. We propose a mechanistic and structural model of Prp24's annealing activity in which oRRM4 functions to destabilize the U6 ISL during U4/U6 assembly. PMID- 21653551 TI - Visualization of single mRNAs reveals temporal association of proteins with microRNA-regulated mRNA. AB - Although many proteins are known to function in microRNA (miRNA)-based translational repression, we lack a comprehensive understanding of temporal relationships between the mRNA, miRNA and their constituent proteins. To understand the dynamics of miRNA and protein interactions, we created a synthetic inducible miRNA system in mammalian cells. By visualizing single mRNAs and observing their co-localization with proteins over time, we produced a temporal association map of miRNA-associated factors. Argonaute2, Dcp1a, hedls and Rck co localize with miRNA-regulated mRNA after 24 h of miRNA induction, and RNAi knockdown of any one of these proteins affected the co-localization of any of the other proteins with miRNA-regulated mRNA, demonstrating that these proteins could interact with each other in a complex. We identified Argonaute2 and hedls as proteins that co-localize and interact with miRNA-regulated mRNA, indicating that processing body components are involved in long-term storage of miRNA-regulated mRNA. PMID- 21653552 TI - Comprehensive insights into Mycobacterium tuberculosis DevR (DosR) regulon activation switch. AB - DevR regulon function is believed to be crucial for the survival of Mycobacterium tuberculosis during dormancy. In this study, we undertook a comprehensive analysis of the DevR regulon. All the regulon promoters were assigned to four classes based on the number of DevR binding sites (Dev boxes). A minimum of two boxes are essential for complete interaction and their tandem arrangement is an architectural hallmark at all promoters. Initial interaction of DevR with the conserved box is essential for its cooperative binding to adjacent sites bearing low to very poor sequence conservation and is the universal mechanism underlying DevR-mediated transcriptional induction. The functional importance of tandem arrangement was established by analyzing promoter variants harboring Dev boxes with altered spacing. Conserved sequence logos were generated from 47 binding sequences which included 24 newly discovered Dev boxes. In each half site of an 18-bp binding motif, G(5) and C(7) are essential for DevR binding. Finally, we show that DevR regulon induction occurs in a temporal manner and genes that are induced early are also usually powerfully induced. The information theory-based approach along with binding and temporal expression studies provide us with comprehensive insights into the complex pattern of DevR regulon activation. PMID- 21653553 TI - Centromere binding specificity in assembly of the F plasmid partition complex. AB - The segregation of plasmid F of Escherichia coli is highly reliable. The Sop partition locus, responsible for this stable maintenance, is composed of two genes, sopA and sopB and a centromere, sopC, consisting of 12 direct repeats of 43 bp. Each repeat carries a 16-bp inverted repeat motif to which SopB binds to form a nucleoprotein assembly called the partition complex. A database search for sequences closely related to sopC revealed unexpected features that appeared highly conserved. We have investigated the requirements for specific SopB-sopC interactions using a surface plasmon resonance imaging technique. We show that (i) only 10 repeats interact specifically with SopB, (ii) no base outside the 16 bp sopC sites is involved in binding specificity, whereas five bases present in each arm are required for interactions, and (iii) the A-C central bases contribute to binding efficiency by conforming to a need for a purine-pyrimidine dinucleotide. We have refined the SopB-sopC binding pattern by electro-mobility shift assay and found that all 16 bp are necessary for optimal SopB binding. These data and the model we propose, define the basis of the high binding specificity of F partition complex assembly, without which, dispersal of SopB over DNA would result in defective segregation. PMID- 21653554 TI - Targeted plasmid integration into the human genome by an engineered zinc-finger recombinase. AB - The development of new methods for gene addition to mammalian genomes is necessary to overcome the limitations of conventional genetic engineering strategies. Although a variety of DNA-modifying enzymes have been used to directly catalyze the integration of plasmid DNA into mammalian genomes, there is still an unmet need for enzymes that target a single specific chromosomal site. We recently engineered zinc-finger recombinase (ZFR) fusion proteins that integrate plasmid DNA into a synthetic target site in the human genome with exceptional specificity. In this study, we present a two-step method for utilizing these enzymes in any cell type at randomly-distributed target site locations. The piggyBac transposase was used to insert recombinase target sites throughout the genomes of human and mouse cell lines. The ZFR efficiently and specifically integrated a transfected plasmid into these genomic target sites and into multiple transposons within a single cell. Plasmid integration was dependent on recombinase activity and the presence of recombinase target sites. This work demonstrates the potential for broad applicability of the ZFR technology in genome engineering, synthetic biology and gene therapy. PMID- 21653555 TI - Roles of Trm9- and ALKBH8-like proteins in the formation of modified wobble uridines in Arabidopsis tRNA. AB - Uridine at the wobble position of tRNA is usually modified, and modification is required for accurate and efficient protein translation. In eukaryotes, wobble uridines are modified into 5-methoxycarbonylmethyluridine (mcm(5)U), 5 carbamoylmethyluridine (ncm(5)U) or derivatives thereof. Here, we demonstrate, both by in vitro and in vivo studies, that the Arabidopsis thaliana methyltransferase AT1G31600, denoted by us AtTRM9, is responsible for the final step in mcm(5)U formation, thus representing a functional homologue of the Saccharomyces cerevisiae Trm9 protein. We also show that the enzymatic activity of AtTRM9 depends on either one of two closely related proteins, AtTRM112a and AtTRM112b. Moreover, we demonstrate that AT1G36310, denoted AtALKBH8, is required for hydroxylation of mcm(5)U to (S)-mchm(5)U in tRNA(Gly)(UCC), and has a function similar to the mammalian dioxygenase ALKBH8. Interestingly, atalkbh8 mutant plants displayed strongly increased levels of mcm(5)U, and also of mcm(5)Um, its 2'-O-ribose methylated derivative. This suggests that accumulated mcm(5)U is prone to further ribose methylation by a non-specialized mechanism, and may challenge the notion that the existence of mcm(5)U- and mcm(5)Um containing forms of the selenocysteine-specific tRNA(Sec) in mammals reflects an important regulatory process. The present study reveals a role in for several hitherto uncharacterized Arabidopsis proteins in the formation of modified wobble uridines. PMID- 21653556 TI - miR-122 activates hepatitis C virus translation by a specialized mechanism requiring particular RNA components. AB - In animals, microRNAs (miRNAs) generally repress gene expression by binding to sites in the 3'-untranslated region (UTR) of target mRNAs. miRNAs have also been reported to repress or activate gene expression by binding to 5'-UTR sites, but the extent of such regulation and the factors that govern these different responses are unknown. Liver-specific miR-122 binds to sites in the 5'-UTR of hepatitis C virus (HCV) RNA and positively regulates the viral life cycle, in part by stimulating HCV translation. Here, we characterize the features that allow miR-122 to activate translation via the HCV 5'-UTR. We find that this regulation is a highly specialized process that requires uncapped RNA, the HCV internal ribosome entry site (IRES) and the 3' region of miR-122. Translation activation does not involve a previously proposed structural transition in the HCV IRES and is mediated by Argonaute proteins. This study provides an important insight into the requirements for the miR-122-HCV interaction, and the broader consequences of miRNAs binding to 5'-UTR sites. PMID- 21653557 TI - Gene amplification system based on double rolling-circle replication as a model for oncogene-type amplification. AB - Gene amplification contributes to a variety of biological phenomena, including malignant progression and drug resistance. However, details of the molecular mechanisms remain to be determined. Here, we have developed a gene amplification system in yeast and mammalian cells that is based on double rolling-circle replication (DRCR). Cre-lox system is used to efficiently induce DRCR utilizing a recombinational process coupled with replication. This system shows distinctive features seen in amplification of oncogenes and drug-resistance genes: (i) intra- and extrachromosomal amplification, (ii) intensive chromosome rearrangement and (iii) scattered-type amplification resembling those seen in cancer cells. This system can serve as a model for amplification of oncogenes and drug-resistance genes, and improve amplification systems used for making pharmaceutical proteins in mammalian cells. PMID- 21653559 TI - Single-molecule force spectroscopy of the add adenine riboswitch relates folding to regulatory mechanism. AB - Riboswitches regulate gene expression via ligand binding to an aptamer domain which induces conformational changes in a regulatory expression platform. By unfolding and refolding single add adenine riboswitch molecules in an optical trap, an integrated picture of the folding was developed and related to the regulatory mechanism. Force-extension curves (FECs) and constant-force folding trajectories measured on the aptamer alone revealed multiple partially-folded states, including several misfolded states not on the native folding pathway. All states were correlated to key structural components and interactions within hierarchical folding pathways. FECs of the full-length riboswitch revealed that the thermodynamically stable conformation switches upon ligand binding from a structure repressing translation to one permitting it. Along with rapid equilibration of the two structures in the absence of adenine, these results support a thermodynamically-controlled regulatory mechanism, in contrast with the kinetic control of the closely-related pbuE adenine riboswitch. Comparison of the folding of these riboswitches revealed many similarities arising from shared structural features but also essential differences related to their different regulatory mechanisms. PMID- 21653560 TI - Increased risk of atrial fibrillation in patients with coeliac disease: a nationwide cohort study. AB - AIMS: Inflammatory markers are established risk factors for atrial fibrillation (AF), but the role of autoimmune diseases is unknown. The aim of the study was to examine the association between coeliac disease (CD) and AF in a large cohort of patients with biopsy-verified CD. METHODS AND RESULTS: We identified 28,637 patients with CD through biopsy reports (defined as Marsh 3: villous atrophy) from all pathology departments (n = 28) in Sweden. Biopsies had been performed between 1969 and 2008. Age- and sex-matched reference individuals (n = 141,731) were identified from the Swedish Total Population Register. Data on AF were obtained from the Swedish Hospital Discharge Register, the Hospital Outpatient Register, and the Cause of Death Register. Hazard ratios (HRs) for AF were estimated using Cox regression. In the CD cohort, 941 individuals developed AF (vs. 2918 reference individuals) during a median follow-up of 9 years. The corresponding adjusted HR for AF was 1.34 (95% CI = 1.24-1.44). The absolute risk of AF in CD was 321 of 100,000 person-years, with an excess risk of 81 of 100,000. A prior AF diagnosis was also associated with an increased risk of subsequent CD (odds ratio = 1.45, 95% CI = 1.31-1.62). CONCLUSIONS: Atrial fibrillation is more common both before and after CD diagnosis in patients with CD though the excess risk is small. Potential explanations for the increased risk of AF in CD include chronic inflammation and shared risk factors, but ascertainment bias may also have contributed. CLINICAL IMPLICATIONS: Coeliac disease affects 1-2% of the Western population. Our results indicate that patients with coeliac disease, verified by intestinal biopsy, are at increased risk of atrial fibrillation. This observation is consistent with previous findings that elevation of inflammatory markers predicts atrial fibrillation. Additional studies are needed to clarify the mechanistic link between atrial fibrillation and autoimmune diseases such as coeliac disease. PMID- 21653558 TI - RNA degradome--its biogenesis and functions. AB - RNA degradation is among the most fundamental processes that occur in living cells. The continuous decay of RNA molecules is associated not only with nucleotide turnover, but also with transcript maturation and quality control. The efficiency of RNA decay is ensured by a broad spectrum of both specific and non specific ribonucleases. Some of these ribonucleases participate mainly in processing primary transcripts and in RNA quality control. Others preferentially digest mature, functional RNAs to yield a variety of molecules that together constitute the RNA degradome. Recently, it has become increasingly clear that the composition of the cellular RNA degradome can be modulated by numerous endogenous and exogenous factors (e.g. by stress). In addition, instead of being hydrolyzed to single nucleotides, some intermediates of RNA degradation can accumulate and function as signalling molecules or participate in mechanisms that control gene expression. Thus, RNA degradation appears to be not only a process that contributes to the maintenance of cellular homeostasis but also an underestimated source of regulatory molecules. PMID- 21653561 TI - Circulating surfactant protein-D and the risk of cardiovascular morbidity and mortality. AB - AIMS: Surfactant protein-D (SP-D) is a lung-specific protein that is detectable in human plasma. We determined the relationship of circulating SP-D to cardiovascular disease (CVD) and total mortality in subjects with and without CVD. METHODS AND RESULTS: Plasma SP-D levels were measured in 806 patients who underwent coronary angiography to assess its predictive value for cardiovascular mortality. Serum SP-D levels were also measured in a replication cohort to assess its relationship with CVD events in 4468 ex- and current smokers without a known history of coronary artery disease (CAD). Patients who died during follow-up had significantly higher plasma SP-D levels than those who survived (median 85.4 vs. 64.8 ng/mL; P < 0.0001). Those in the highest quintile of SP-D had 4.4-fold higher risk of CVD mortality than those in the lowest quintile (P < 0.0001) independent of age, sex, and plasma lipid levels. In a group of current and ex smokers without a known history of CAD, serum SP-D levels were elevated in those who died or were hospitalized for CVD compared with those who did not (median 99.8 vs. 90.6 ng/mL; P = 0.0001). CONCLUSION: Circulating SP-D is a good predictor of cardiovascular morbidity and mortality and adds prognostic information to well-established risk factors such as age, sex, and plasma lipids and is a promising biomarker to link lung inflammation/injury to CVD. PMID- 21653562 TI - Rising adiposity curbing decline in the incidence of myocardial infarction: 20 year follow-up of British men and women in the Whitehall II cohort. AB - Aims To estimate the contribution of risk factor trends to 20-year declines in myocardial infarction (MI) incidence in British men and women. Methods and results From 1985 to 2004, 6379 men and 3074 women in the Whitehall II cohort were followed for incident MI and risk factor trends. Over 20 years, the age-sex adjusted hazard of MI fell by 74% (95% confidence interval 48-87%), corresponding to an average annual decline of 6.5% (3.2-9.7%). Thirty-four per cent (20-76%) of the decline in MI hazard could be statistically explained by declining non-HDL cholesterol levels, followed by increased HDL cholesterol (17%, 10-32%), reduced systolic blood pressure (13%, 7-24%), and reduced cigarette smoking prevalence (6%, 2-14%). Increased fruit and vegetable consumption made a non-significant contribution of 7% (-1-20%). In combination, these five risk factors explained 56% (34-112%). Rising body mass index (BMI) was counterproductive, reducing the scale of the decline by 11% (5-23%) in isolation. The MI decline and the impact of the risk factors appeared similar for men and women. Conclusion In men and women, over half of the decline in MI risk could be accounted for by favourable risk factor time trends. The adverse role of BMI emphasizes the importance of addressing the rising population BMI. PMID- 21653563 TI - Metamorphosing reef fishes avoid predator scent when choosing a home. AB - Most organisms possess anti-predator adaptations to reduce their risk of being consumed, but little is known of the adaptations prey employ during vulnerable life-history transitions when predation pressures can be extreme. We demonstrate the use of a transition-specific anti-predator adaptation by coral reef fishes as they metamorphose from pelagic larvae to benthic juveniles, when over half are consumed within 48 h. Our field experiment shows that naturally settling damselfish use olfactory, and most likely innate, predator recognition to avoid settling to habitat patches manipulated to emit predator odour. Settlement to patches emitting predator odour was on average 24-43% less than to control patches. Evidence strongly suggests that this avoidance of sedentary and patchily distributed predators by nocturnal settlers will gain them a survival advantage, but also lead to non-lethal predator effects: the costs of exhibiting anti predator adaptations. Transition-specific anti-predator adaptations, such as demonstrated here, may be widespread among organisms with complex life cycles and play an important role in prey population dynamics. PMID- 21653564 TI - Remembrance of things past: modelling the relationship between species' abundances in living communities and death assemblages. AB - Accumulations of dead skeletal material are a valuable archive of past ecological conditions. However, such assemblages are not equivalent to living communities because they mix the remains of multiple generations and are altered by post mortem processes. The abundance of a species in a death assemblage can be quantitatively modelled by successively integrating the product of an influx time series and a post-mortem loss function (a decay function with a constant half life). In such a model, temporal mixing increases expected absolute dead abundance relative to average influx as a linear function of half-life and increases variation in absolute dead abundance values as a square-root function of half-life. Because typical abundance distributions of ecological communities are logarithmically distributed, species' differences in preservational half-life would have to be very large to substantially alter species' abundance ranks (i.e. make rare species common or vice-versa). In addition, expected dead abundances increase at a faster rate than their range of variation with increased time averaging, predicting greater consistency in the relative abundance structure of death assemblages than their parent living community. PMID- 21653565 TI - Explaining the heritability of an ecologically significant trait in terms of individual quantitative trait loci. AB - Most natural populations display substantial genetic variation in behaviour, morphology, physiology, life history and the susceptibility to disease. A major challenge is to determine the contributions of individual loci to variation in complex traits. Quantitative trait locus (QTL) mapping has identified genomic regions affecting ecologically significant traits of many species. In nearly all cases, however, the importance of these QTLs to population variation remains unclear. In this paper, we apply a novel experimental method to parse the genetic variance of floral traits of the annual plant Mimulus guttatus into contributions of individual QTLs. We first use QTL-mapping to identify nine loci and then conduct a population-based breeding experiment to estimate V(Q), the genetic variance attributable to each QTL. We find that three QTLs with moderate effects explain up to one-third of the genetic variance in the natural population. Variation at these loci is probably maintained by some form of balancing selection. Notably, the largest effect QTLs were relatively minor in their contribution to heritability. PMID- 21653566 TI - Social environment determines degree of chemical signalling. AB - Few studies have attempted to distinguish between cues and signals in the context of chemical communication. A number of chemical substances have been shown to vary with physiological state, such as stage of oestrus cycle, fertility, dominance status or nutritional condition, but little is known about whether this variation is incidental or adaptive. Here, we provide evidence of a substance whose emission varies with breeding state, but is not merely an incidental by product of physiological state, but rather, an evolved signal. Breeding females of the facultative biparental burying beetle, Nicrophorus vespilloides, release methyl geranate, a substance that helps males to identify breeding status and to distinguish between their female partners and non-breeding intruders. We demonstrate that females respond flexibly to their social environment and emit high amounts of methyl geranate only in the presence of a male partner, i.e. a receiver. In contrast, cuticular hydrocarbons, which also have been shown to change with breeding status, are not modulated and do not differ between single and paired breeding females. Receiver-dependent chemical signalling is expected to evolve when costs are involved in the production or transmission of the signal; such signal modulation might be more common than previously thought. PMID- 21653567 TI - Alzheimer's disease: rapid and slow progression. AB - The variability in the progression of Alzheimer's disease (AD) across patients has made identification of disease-delaying treatments difficult. Quantitative analysis of this variability has important implications in understanding the pathophysiology of AD and identifying disease-delaying treatments. The functional assessment staging (FAST) procedure characterizes seven stages in the course of AD from normal ageing to severe dementia. The present study applied statistical methods to analyse FAST stage durations from a dataset of 648 AD patients. These methods uncovered two distinct types of disease progression, characterized by different mean progression rates. We identified two separate distributions of FAST stage progression times differing by up to 2 years in mean duration within each stage. These results further indicate that if a patient progresses rapidly through a given FAST stage, then their further progression is also likely to be rapid. These findings support the hypothesis that progression of AD can occur via two different pathophysiological mechanisms that lead to distinct average rates of decline. PMID- 21653570 TI - Searching for the most cost-effective strategy for controlling epidemics spreading on regular and small-world networks. AB - We present a combined epidemiological and economic model for control of diseases spreading on local and small-world networks. The disease is characterized by a pre-symptomatic infectious stage that makes detection and control of cases more difficult. The effectiveness of local (ring-vaccination or culling) and global control strategies is analysed by comparing the net present values of the combined cost of preventive treatment and illness. The optimal strategy is then selected by minimizing the total cost of the epidemic. We show that three main strategies emerge, with treating a large number of individuals (global strategy, GS), treating a small number of individuals in a well-defined neighbourhood of a detected case (local strategy) and allowing the disease to spread unchecked (null strategy, NS). The choice of the optimal strategy is governed mainly by a relative cost of palliative and preventive treatments. If the disease spreads within the well-defined neighbourhood, the local strategy is optimal unless the cost of a single vaccine is much higher than the cost associated with hospitalization. In the latter case, it is most cost-effective to refrain from prevention. Destruction of local correlations, either by long-range (small-world) links or by inclusion of many initial foci, expands the range of costs for which the NS is most cost-effective. The GS emerges for the case when the cost of prevention is much lower than the cost of treatment and there is a substantial non-local component in the disease spread. We also show that local treatment is only desirable if the disease spreads on a small-world network with sufficiently few long-range links; otherwise it is optimal to treat globally. In the mean field case, there are only two optimal solutions, to treat all if the cost of the vaccine is low and to treat nobody if it is high. The basic reproduction ratio, R(0), does not depend on the rate of responsive treatment in this case and the disease always invades (but might be stopped afterwards). The details of the local control strategy, and in particular the optimal size of the control neighbourhood, are determined by the epidemiology of the disease. The properties of the pathogen might not be known in advance for emerging diseases, but the broad choice of the strategy can be made based on economic analysis only. PMID- 21653571 TI - Biohydrogenation of linolenic acid to stearic acid by the rumen microbial population yields multiple intermediate conjugated diene isomers. AB - The current literature suggests that linolenic acid biohydrogenation converts to stearic acid without the formation of CLA. However, a multitude of CLA were identified in the rumen that are generally attributed to linoleic acid biohydrogenation. This study used a stable isotope tracer to investigate the biohydrogenation intermediates of (13)C-linolenic acid, including CLA. A continuous culture fermenter was used to maintain a mixed microbial population obtained from the rumen of cattle at pH 6.5 for 6 d. The mixed fermenter contents were then transferred to batch cultures containing either (13)C-labeled or unlabeled linolenic acid, which were run in triplicate for 0, 3, 24, and 48 h. The (13)C enrichment was determined by GC-MS. After 48 h of incubation, 8 CLA isomers were significantly enriched, suggesting that these CLA isomers originated directly from linolenic acid. The cis-10, cis-12 CLA isomer exhibited the highest enrichment (21.7%), followed by cis-9, cis-11 and trans-8, trans-10 CLA. The enrichment of these 2 CLA isomers ranged from 20.1 to 21.1% and the remaining 5 CLA including cis-9, trans-11 CLA were <15.0%. A multitude of nonconjugated and partially conjugated 18:2 and 18:3 isomers was enriched during the 48 h of incubation. The results of this study confirm that mixed ruminal microbes are capable of the formation of several CLA and 18:3 isomers from linolenic acid, indicating that linolenic acid biohydrogenation pathways are more complex than previously reported. PMID- 21653569 TI - Transmission of Chlamydia trachomatis through sexual partnerships: a comparison between three individual-based models and empirical data. AB - Chlamydia trachomatis is the most common bacterial sexually transmitted infection (STI) in many developed countries. The highest prevalence rates are found among young adults who have frequent partner change rates. Three published individual based models have incorporated a detailed description of age-specific sexual behaviour in order to quantify the transmission of C. trachomatis in the population and to assess the impact of screening interventions. Owing to varying assumptions about sexual partnership formation and dissolution and the great uncertainty about critical parameters, such models show conflicting results about the impact of preventive interventions. Here, we perform a detailed evaluation of these models by comparing the partnership formation and dissolution dynamics with data from Natsal 2000, a population-based probability sample survey of sexual attitudes and lifestyles in Britain. The data also allow us to describe the dispersion of C. trachomatis infections as a function of sexual behaviour, using the Gini coefficient. We suggest that the Gini coefficient is a useful measure for calibrating infectious disease models that include risk structure and highlight the need to estimate this measure for other STIs. PMID- 21653568 TI - Non-thermal dielectric barrier discharge plasma induces angiogenesis through reactive oxygen species. AB - Vascularization plays a key role in processes such as wound healing and tissue engineering. Non-thermal plasma, which primarily produces reactive oxygen species (ROS), has recently emerged as an efficient tool in medical applications including blood coagulation, sterilization and malignant cell apoptosis. Liquids and porcine aortic endothelial cells were treated with a non-thermal dielectric barrier discharge plasma in vitro. Plasma treatment of phosphate-buffered saline (PBS) and serum-free medium increased ROS concentration in a dose-dependent manner, with a higher concentration observed in serum-free medium compared with PBS. Species concentration inside cells peaked 1 h after treatment, followed by a decrease 3 h post treatment. Endothelial cells treated with a plasma dose of 4.2 J cm(-2) had 1.7 times more cells than untreated samples 5 days after plasma treatment. The 4.2 J cm(-2) plasma dose increased two-dimensional migration distance by 40 per cent compared with untreated control, while the number of cells that migrated through a three-dimensional collagen gel increased by 15 per cent. Tube formation was also enhanced by plasma treatment, with tube lengths in plasma-treated samples measuring 2.6 times longer than control samples. A fibroblast growth factor-2 (FGF-2) neutralizing antibody and ROS scavengers abrogated these angiogenic effects. These data indicate that plasma enhanced proliferation, migration and tube formation is due to FGF-2 release induced by plasma-produced ROS. Non-thermal plasma may be used as a potential tool for applying ROS in precise doses to enhance vascularization. PMID- 21653572 TI - Lifelong low-phylloquinone intake is associated with cognitive impairments in old rats. AB - In a previous report, we showed vitamin K to preferentially accumulate in brain regions rich in white matter and to positively correlate with certain sphingolipids. In rodents, pharmacological vitamin K deficiency has resulted in behavioral perturbations. To gain insight on the role of vitamin K status on brain function, we investigated learning abilities (Morris water maze), motor activity (open field), and anxiety (elevated plus maze) in distinct groups of 6-, 12-, and 20-mo-old female Sprague-Dawley rats that had been fed diets containing low (L; ~80 MUg/kg diet), adequate (A; ~500 MUg/kg diet), or high (H; ~2000 MUg/kg diet) levels of phylloquinone (MUg/kg diet; n = 9-12/diet) since weaning. In 20-mo-old rats, sphingolipids (cerebroside, sulfatide, sphingomyelin, ceramide, and gangliosides), phylloquinone, and menaquinone-4 were also assessed in cerebellum, midbrain, pons medulla, striatum, and hippocampus. Lifetime consumption of a low-vitamin K diet resulted in cognitive deficits in the 20-mo old rats, with those in the L group having longer latencies than those in the H group (P < 0.05); this was associated with higher concentrations of ceramides in the hippocampus (P < 0.05) and lower gangliosides in the pons medulla and midbrain (P < 0.05). The low-vitamin K diet did not affect cognition at 6 and 12 mo of age, nor did it affect motor activity or anxiety at any age. Although much remains to be elucidated about the mechanism of action of vitamin K in cognition, this report points to vitamin K as an important nutritional factor contributing to cognitive health during aging. PMID- 21653573 TI - Dietary selenomethionine increases exon-specific DNA methylation of the p53 gene in rat liver and colon mucosa. AB - The regulation of site-specific DNA methylation of tumor suppressor genes has been considered as a leading mechanism by which certain nutrients exert their anticancer property. This study was to investigate whether selenium (Se) affects the methylation of globe genomic DNA and the exon-specific p53 gene. Three groups of rats (n = 6-7/group) were fed the AIN-93G basal diet supplemented with 0 [Se deficient (D)], 0.15 [Se adequate (A)], or 4 mg [Se supranutritional (S)] (Se as l-selenomethionine)/kg diet for 104 d, respectively. Rats fed the A or S diet had greater plasma and liver glutathione peroxidase activity, liver thioredoxin reductase activity, and plasma homocysteine concentration than those fed the D diet. However, compared with the A diet, rats fed the S diet did not further increase these Se-dependent enzyme activities or homocysteine concentration. In contrast, Se concentrations in kidney, liver, gastrocnemius muscle, and plasma were increased in a Se-dose-dependent manner. Interestingly, rats fed the S diet had significantly less global liver genomic DNA methylation than those fed the D diet. However, the S diet significantly increased the methylation of the p53 gene (exons 5-8) but not the beta-actin gene (exons 2-3) DNA in liver and colon mucosa compared with those fed the D diet. Taken together, long-term Se consumption not only affects selenoprotein enzyme activities, homocysteine, tissue Se concentrations, and global genomic DNA methylation but also increases exon specific DNA methylation of the p53 gene in a Se-dose-dependent manner in rat liver and colon mucosa. PMID- 21653574 TI - Higher biomarker-calibrated protein intake is not associated with impaired renal function in postmenopausal women. AB - With aging, renal function tends to decline, as evidenced by reduced glomerular filtration rate. High-protein intake may further stress the kidneys by causing sustained hyperfiltration. To investigate whether dietary protein is associated with impaired renal function, we used data from 2 nested case-control studies within the Women's Health Initiative Observational Study (n = 2419). We estimated protein intake using a FFQ and estimated glomerular filtration rate (eGFR) from cystatin C. To account for the original study designs, inverse probability weights were applied. Self-reported energy and protein were calibrated using biomarkers of energy and protein intake. Associations between protein intake and renal function were estimated by weighted linear and logistic regression models. Average calibrated protein intake (mean +/- SD) was 1.1 +/- 0.2 g/(kg body weight.d).Twelve percent (n = 292) of women had impaired renal function. The odds of impaired renal function, defined as eGFR <60 mL/(min.1.73m(2)), was not associated with calibrated protein intake. When eGFR was modeled continuously, there was no association with calibrated protein when protein was expressed in absolute (g/d) or relative to energy (protein % energy/d), but protein relative to body weight [g/(kg body weight.d)] was associated with higher eGFR. There was no evidence for effect modification by age, BMI, or general health status. These data suggest higher protein intake is not associated with impaired renal function among postmenopausal women without a diagnosis of chronic kidney disease. PMID- 21653576 TI - An energy-dense, nutrient-poor dietary pattern is inversely associated with bone health in women. AB - Measures of dietary patterns have been increasingly used to capture the complex nature of dietary intake. Few studies have investigated the impact of specific dietary patterns on bone health. Areal bone mineral density (BMD) at the lumbar spine and total hip and total body bone mineral content (BMC) were measured using DXA in Australian women aged 18-65 y (n = 527). Dietary patterns were assessed using a 4-d food diary and factor analysis. Scores were calculated based on the amount of each food consumed in the pattern and the weightings determined by factor analysis. Analysis was conducted using generalized estimating equation methods. Factor analysis revealed 5 dietary patterns. Pattern 1 (high consumption of refined cereals, soft drinks, fried potatoes, sausages and processed meat, vegetable oils, beer, and takeaway foods and low consumption of other vegetables, vegetable dishes, tea, coffee, fruit, wholegrain breads, and breakfast cereals) were significantly inversely associated with total body BMC (g) [beta = -15.4 (95% CI -27.4, -3.3), adjusted for age, height, physical activity, smoking, education, energy, and calcium intake]. Pattern 4 (high consumption of legumes, seafood, seeds, nuts, wine, rice and rice dishes, other vegetables, and vegetable dishes and low consumption of bacon and ham) were directly associated with BMD at both sites and total body BMC in adjusted models [BMC (g): beta = 15.2 (95% CI 2.84, 27.6), fully adjusted model]. The remaining dietary patterns were not consistently associated with BMD or BMC. This study identified specific dietary patterns associated with BMD and total body BMC among women and provides evidence that will contribute to potential food-based strategies for improving bone health. PMID- 21653575 TI - Decreases in dietary glycemic index are related to weight loss among individuals following therapeutic diets for type 2 diabetes. AB - This study assessed the effect of changes in glycemic index (GI) and load (GL) on weight loss and glycated hemoglobin (HbA1c) among individuals with type 2 diabetes beginning a vegan diet or diet following the 2003 American Diabetes Association (ADA) recommendations. The study was a 22-wk, randomized trial of 99 participants with type 2 diabetes who were counseled to follow 1 of 2 diet treatments. GI and GL changes were assessed based on 3-d dietary records. The relationships between GI/GL and changes in weight and HbA1C were calculated. In an intention-to-treat analysis (n = 99), the vegan group reduced GI to a greater extent than the ADA group (P < 0.05), but GL was reduced further in the ADA than the vegan group (P < 0.001). GI predicted changes in weight (P = 0.001), adjusting for changes in fiber, carbohydrate, fat, alcohol, energy intake, steps per day, group, and demographics, such that for every point decrease in GI, participants lost ~0.2 kg (0.44 lb). GI was not a predictor for changes in HbA1C after controlling for weight loss (P = 0.33). Weight loss was a predictor of changes in HbA1C (P = 0.047). GL was not related to weight loss or changes in HbA1C. A low-GI diet appears to be one of the determinants of success of a vegan or ADA diet in reducing body weight among people with type 2 diabetes. The reduction of body weight, in turn, was predictive of decreasing HbA1C. PMID- 21653577 TI - Dietary micronutrient intakes are associated with markers of inflammation but not with markers of subclinical atherosclerosis. AB - Few studies have examined associations of dietary micronutrients with markers of inflammation and subclinical atherosclerosis. The present study investigated associations of heme iron, nonheme iron, zinc (Zn), magnesium (Mg), beta carotene, vitamin C, and vitamin E with C-reactive protein (CRP), IL-6, total homocysteine (tHcy), fibrinogen, coronary artery calcium, and common and internal carotid artery intima media thickness. Micronutrient intakes and markers of inflammation and subclinical atherosclerosis were studied in 5,181 participants from the Multi-Ethnic Study of Atherosclerosis who were aged 45-84 y and free of diabetes and cardiovascular disease. Models were adjusted for energy intake, demographics, lifestyle characteristics, and BMI. Dietary nonheme iron and Mg intakes were inversely associated with tHcy concentrations (mean tHcy: 9.11, 8.86, 8.74, 8.71, and 8.50 MUmol/L, and 9.20, 9.00, 8.65, 8.76, and 8.33 MUmol/L across increasing quintiles of nonheme iron and Mg, respectively; P-trend < 0.001 for both). However, dietary Zn and heme iron were positively associated with CRP [mean: 1.73, 1.75, 1.78, 1.88, and 1.96 mg/L across increasing quintiles of Zn and 1.72, 1.76, 1.83, 1.86, and 1.94 mg/L across increasing quintiles of heme iron (P-trend = 0.002 and 0.01, respectively). Other tested micronutrient-marker associations were not significant. In conclusion, of the 49 tested associations, only 7 were significant. Although this study does not provide strong support for associations between the micronutrients and markers of inflammation and subclinical atherosclerosis, the results are consistent with dietary guidelines that advocate for a balanced diet that includes a variety of plant foods containing Mg, Zn, and nonheme iron. PMID- 21653578 TI - "Instant success": turning temptations into cues for goal-directed behavior. AB - Contrary to lay intuition, counteractive control theory posits that tempting food cues can help individuals to act in accordance with their long-term dieting goal. However, studies have shown that temptations trigger goal-directed behavior only in successful but not in unsuccessful self-regulators. The aim of the present study was to test whether it is possible to create facilitated temptation-goal associations in unsuccessful dieters using implementation intentions (e.g., "If I see or smell chocolate then I will follow my goal to diet") and whether this indeed stimulates more successful self-regulation. It was found that implementation intentions linking a temptation to a dieting goal lead to self perceived improved resistance to (Study 1) as well as reduced consumption (Study 2) of tempting snacks compared to a control condition. Moreover, Study 2 revealed that the reduced snack consumption was indeed related to facilitated temptation goal associations in participants who had formed implementation intentions. PMID- 21653579 TI - Social class rank, threat vigilance, and hostile reactivity. AB - Lower-class individuals, because of their lower rank in society, are theorized to be more vigilant to social threats relative to their high-ranking upper-class counterparts. This class-related vigilance to threat, the authors predicted, would shape the emotional content of social interactions in systematic ways. In Study 1, participants engaged in a teasing interaction with a close friend. Lower class participants--measured in terms of social class rank in society and within the friendship--more accurately tracked the hostile emotions of their friend. As a result, lower-class individuals experienced more hostile emotion contagion relative to upper-class participants. In Study 2, lower-class participants manipulated to experience lower subjective socioeconomic rank showed more hostile reactivity to ambiguous social scenarios relative to upper-class participants and to lower-class participants experiencing elevated socioeconomic rank. The results suggest that class affects expectations, perception, and experience of hostile emotion, particularly in situations in which lower-class individuals perceive their subordinate rank. PMID- 21653580 TI - Power fosters context-independent, analytic cognition. AB - The present research tested the hypothesis that power, defined as the capacity to influence others, promotes analytic cognitive processing, by examining the use of linguistic categories and the categorization of objects. Supporting the hypothesis, recalling instances of influencing others facilitated the use of adjectives and discouraged the use of verbs to describe others (Study 1). Recalling instances of influencing others also promoted taxonomic, instead of thematic, categorization (Study 2). Furthermore, the authors also examined the effect of power in a real-life context. They examined whether socioeconomic status (SES) differences in cognitive processing can be partly explained by sense of agency, an antecedent of power (Study 3); high SES individuals made more taxonomic categorization than did low SES individuals, and a sense of agency partially mediated the SES differences in categorization. These findings underscore the role of power in shaping cognitive processes. PMID- 21653581 TI - Framing matters: contextual influences on interracial interaction outcomes. AB - Previous studies indicate that interracial interactions frequently have negative outcomes but have typically focused on social contexts. The current studies examined the effect of manipulating interaction context. In Study 1, Black and White participants worked together with instructions that created either a social focus or a task focus. With a task focus, interracial pairs were more consistently synchronized, Black participants showed less executive function depletion, and White participants generally showed reduced implicit bias. Follow up studies suggested that prejudice concerns help explain these findings: White participants reported fewer concerns about appearing prejudiced when they imagined an interracial interaction with a task focus rather than a social focus (Study 2a), and Black participants reported less vigilance against prejudice in an imagined interracial interaction with a task focus rather than a social focus (Study 2b). Taken together, these studies illustrate the importance of interaction context for the experiences of both Blacks and Whites. PMID- 21653582 TI - Neutron spectrometry with Bonner Spheres for area monitoring in particle accelerators. AB - Selecting the instruments to determine the operational quantities in the neutron fields produced by particle accelerators involves a combination of aspects, which is peculiar to these environments: the energy distribution of the neutron field, the continuous or pulsed time structure of the beam, the presence of other radiations to which the neutron instruments could have significant response and the large variability in the dose rate, which can be observed when moving from areas near the beam line to free-access areas. The use of spectrometric techniques in support of traditional instruments is highly recommended to improve the accuracy of dosimetric evaluations. The multi-sphere or Bonner Sphere Spectrometer (BSS) is certainly the most used device, due to characteristics such as the wide energy range, large variety of active and passive detectors suited for different workplaces, good photon discrimination and the simple signal management. Disadvantages are the poor energy resolution, weight and need to sequentially irradiate the spheres, leading to usually long measurement sessions. Moreover, complex unfolding analyses are needed to obtain the neutron spectra. This work is an overview of the BSS for area monitoring in particle accelerators. PMID- 21653583 TI - Trophic network structure emerges through antagonistic coevolution in temporally varying environments. AB - Understanding the mechanisms underlying ecological specialization is central to our understanding of community ecology and evolution. Although theoretical work has investigated how variable environments may affect specialization in single species, little is known about how such variation impacts bipartite network structure in antagonistically coevolving systems. Here, we develop and analyse a general model of victim-enemy coevolution that explicitly includes resource and population dynamics. We investigate how temporal environmental heterogeneity affects the evolution of specialization and associated community structure. Environmental productivity influences victim investment in resistance, which will shape patterns of specialization through its regulating effect on enemy investment in infectivity. We also investigate the epidemiological consequences of environmental variability and show that enemy population density is maximized for intermediate lengths of productive seasons, which corresponds to situations where enemies can evolve higher infectivity than victims can evolve defence. We discuss our results in the light of empirical studies, and further highlight ways in which our model applies to a range of natural systems. PMID- 21653584 TI - Leaf evolution in Southern Hemisphere conifers tracks the angiosperm ecological radiation. AB - The angiosperm radiation has been linked to sharp declines in gymnosperm diversity and the virtual elimination of conifers from the tropics. The conifer family Podocarpaceae stands as an exception with highest species diversity in wet equatorial forests. It has been hypothesized that efficient light harvesting by the highly flattened leaves of several podocarp genera facilitates persistence with canopy-forming angiosperms, and the angiosperm ecological radiation may have preferentially favoured the diversification of these lineages. To test these ideas, we develop a molecular phylogeny for Podocarpaceae using Bayesian-relaxed clock methods incorporating fossil time constraints. We find several independent origins of flattened foliage types, and that these lineages have diversified predominantly through the Cenozoic and therefore among canopy-forming angiosperms. The onset of sustained foliage flattening podocarp diversification is coincident with a declining diversification rate of scale/needle-leaved lineages and also with ecological and climatic transformations linked to angiosperm foliar evolution. We demonstrate that climatic range evolution is contingent on the underlying state for leaf morphology. Taken together, our findings imply that as angiosperms came to dominate most terrestrial ecosystems, competitive interactions at the foliar level have profoundly shaped podocarp geography and as a consequence, rates of lineage diversification. PMID- 21653585 TI - Reconciling the influence of predictiveness and uncertainty on stimulus salience: a model of attention in associative learning. AB - Theories of selective attention in associative learning posit that the salience of a cue will be high if the cue is the best available predictor of reinforcement (high predictiveness). In contrast, a different class of attentional theory stipulates that the salience of a cue will be high if the cue is an inaccurate predictor of reinforcement (high uncertainty). Evidence in support of these seemingly contradictory propositions has led to: (i) the development of hybrid attentional models that assume the coexistence of separate, predictiveness-driven and uncertainty-driven mechanisms of changes in cue salience; and (ii) a surge of interest in identifying the neural circuits underpinning these mechanisms. Here, we put forward a formal attentional model of learning that reconciles the roles of predictiveness and uncertainty in salience modification. The issues discussed are relevant to psychologists, behavioural neuroscientists and neuroeconomists investigating the roles of predictiveness and uncertainty in behaviour. PMID- 21653586 TI - Fixed and dilutable benefits: female choice for good genes or fertility. AB - Benefits accruing to females who exercise mate choice have been defined to be either 'direct' or 'indirect'. We suggest an alternative distinction: benefits can be considered 'fixed', meaning they are on average equal to all females mating with the same male (e.g. good genes' benefits) or 'dilutable', meaning they are shared between females mating with the same male, so that the more mates a male has, the lower the average benefit to each (e.g. fertility benefits or many forms of direct benefit). Using a simple model, we show that this distinction has a major effect on the form of female preference. We predict that mating skew will be far greater in species where the benefits are fixed when compared with those where the benefits are dilutable. PMID- 21653588 TI - Cambrian stalked echinoderms show unexpected plasticity of arm construction. AB - Feeding arms carrying coelomic extensions of the theca are thought to be unique to crinoids among stemmed echinoderms. However, a new two-armed echinoderm from the earliest Middle Cambrian of Spain displays a highly unexpected morphology. X ray microtomographic analysis of its arms shows they are polyplated in their proximal part with a dorsal series of uniserial elements enclosing a large coelomic lumen. Distally, the arm transforms into the more standard biserial structure of a blastozoan brachiole. Phylogenetic analysis demonstrates that this taxon lies basal to rhombiferans as sister-group to pleurocystitid and glyptocystitid blastozoans, drawing those clades deep into the Cambrian. We demonstrate that Cambrian echinoderms show surprising variability in the way their appendages are constructed, and that the appendages of at least some blastozoans arose as direct outgrowths of the body in much the same way as the arms of crinoids. PMID- 21653587 TI - Ontogenetic immune challenges shape adult personality in mallard ducks. AB - Consistent individual differences in behaviour are widespread in animals, but the proximate mechanisms driving these differences remain largely unresolved. Parasitism and immune challenges are hypothesized to shape the expression of animal personality traits, but few studies have examined the influence of neonatal immune status on the development of adult personality. We examined how non-pathogenic immune challenges, administered at different stages of development, affected two common measures of personality, activity and exploratory behaviour, as well as colour-dependent novel object exploration in adult male mallard ducks (Anas platyrhynchos). We found that individuals that were immune-challenged during the middle (immediately following the completion of somatic growth) and late (during the acquisition of nuptial plumage) stages of development were more active in novel environments as adults relative to developmentally unchallenged birds or those challenged at an earlier developmental time point. Additionally, individuals challenged during the middle stage of development preferred orange and avoided red objects more than those that were not immune-challenged during development. Our results demonstrate that, in accordance with our predictions, early-life immune system perturbations alter the expression of personality traits later in life, emphasizing the role that developmental plasticity plays in shaping adult personality, and lending support to recent theoretical models that suggest that parasite pressure may play an important role in animal personality development. PMID- 21653589 TI - Trade-off between warning signal efficacy and mating success in the wood tiger moth. AB - The coloration of species can have multiple functions, such as predator avoidance and sexual signalling, that directly affect fitness. As selection should favour traits that positively affect fitness, the genes underlying the trait should reach fixation, thereby preventing the evolution of polymorphisms. This is particularly true for aposematic species that rely on coloration as a warning signal to advertise their unprofitability to predators. Nonetheless, there are numerous examples of aposematic species showing remarkable colour polymorphisms. We examined whether colour polymorphism in the wood tiger moth is maintained by trade-offs between different functions of coloration. In Finland, males of this species have two distinct colour morphs: white and yellow. The efficacy of the warning signal of these morphs was tested by offering them to blue tits in the laboratory. Birds hesitated significantly longer to attack yellow than white males. In a field experiment, the survival of the yellow males was also higher than white males. However, mating experiments in the laboratory revealed that yellow males had lower mating success than white males. Our results offer an explanation for the maintenance of polymorphism via trade-off between survival selection and mating success. PMID- 21653590 TI - Conflict, sticks and carrots: war increases prosocial punishments and rewards. AB - Unlike most species, humans cooperate extensively with group members who are not closely related to them, a pattern sustained in part by punishing non-cooperators and rewarding cooperators. Because internally cooperative groups prevail over less cooperative rival groups, it is thought that violent intergroup conflict played a key role in the evolution of human cooperation. Consequently, it is plausible that propensities to punish and reward will be elevated during intergroup conflict. Using experiments conducted before, during and after the 2006 Israel-Hezbollah war, we show that, during wartime, people are more willing to pay costs to punish non-cooperative group members and reward cooperative group members. Rather than simply increasing within-group solidarity, violent intergroup conflict thus elicits behaviours that, writ large, enhance cooperation within the group, thereby making victory more likely. PMID- 21653591 TI - Limited potential for adaptation to climate change in a broadly distributed marine crustacean. AB - The extent to which acclimation and genetic adaptation might buffer natural populations against climate change is largely unknown. Most models predicting biological responses to environmental change assume that species' climatic envelopes are homogeneous both in space and time. Although recent discussions have questioned this assumption, few empirical studies have characterized intraspecific patterns of genetic variation in traits directly related to environmental tolerance limits. We test the extent of such variation in the broadly distributed tidepool copepod Tigriopus californicus using laboratory rearing and selection experiments to quantify thermal tolerance and scope for adaptation in eight populations spanning more than 17 degrees of latitude. Tigriopus californicus exhibit striking local adaptation to temperature, with less than 1 per cent of the total quantitative variance for thermal tolerance partitioned within populations. Moreover, heat-tolerant phenotypes observed in low-latitude populations cannot be achieved in high-latitude populations, either through acclimation or 10 generations of strong selection. Finally, in four populations there was no increase in thermal tolerance between generations 5 and 10 of selection, suggesting that standing variation had already been depleted. Thus, plasticity and adaptation appear to have limited capacity to buffer these isolated populations against further increases in temperature. Our results suggest that models assuming a uniform climatic envelope may greatly underestimate extinction risk in species with strong local adaptation. PMID- 21653592 TI - Persistence of high diversity in non-equilibrium ecological communities: implications for modern and fossil ecosystems. AB - Explaining the origin and maintenance of biodiversity is critical for understanding the potential consequences of present-day environmental change on ecological communities, as well as the evolutionary history of ecosystems in the Earth's past. Much effort in theoretical ecology has focused on identifying mechanisms that promote stable coexistence of species at equilibrium. However, in a consumer-resource model of competition along an environmental gradient, high diversity assemblages have the potential to persist in non-equilibrium states for millions of generations with very little species loss. Species' populations in such competitively accommodated communities show slow drift; if disrupted, they rapidly reorganize into alternative persistent states. Fossil examples of prolonged ecological stability lasting 1-5 Myr punctuated by rapid reorganization (e.g. brachiopods from the Permian Reef of west Texas) suggest that some palaeocommunities represent a record of periodically disrupted transient states rather than stable equilibria. The similarity between the theoretical results reported here and palaeontological data suggests that the maintenance of high diversity communities, both in the past and present, may reflect long-duration, non-equilibrium transient dynamics. If so, this has implications for the response of such communities to present-day environmental change, as well as for the evolution of lineages in such systems. PMID- 21653593 TI - Aerobic capacity influences the spatial position of individuals within fish schools. AB - The schooling behaviour of fish is of great biological importance, playing a crucial role in the foraging and predator avoidance of numerous species. The extent to which physiological performance traits affect the spatial positioning of individual fish within schools is completely unknown. Schools of juvenile mullet Liza aurata were filmed at three swim speeds in a swim tunnel, with one focal fish from each school then also measured for standard metabolic rate (SMR), maximal metabolic rate (MMR), aerobic scope (AS) and maximum aerobic swim speed. At faster speeds, fish with lower MMR and AS swam near the rear of schools. These trailing fish required fewer tail beats to swim at the same speed as individuals at the front of schools, indicating that posterior positions provide hydrodynamic benefits that reduce swimming costs. Conversely, fish with high aerobic capacity can withstand increased drag at the leading edge of schools, where they could maximize food intake while possibly retaining sufficient AS for other physiological functions. SMR was never related to position, suggesting that high maintenance costs do not necessarily motivate individuals to occupy frontal positions. In the wild, shifting of individuals to optimal spatial positions during changing conditions could influence structure or movement of entire schools. PMID- 21653594 TI - Proliferative and metabolic markers in incompletely excised pediatric pilocytic astrocytomas--an assessment of 3 new variables in predicting clinical outcome. AB - Although pilocytic astrocytoma (PA) is the most common brain tumor diagnosed in children, few prognostic variables have been delineated that stratify the risk of clinical progression in patients with this tumor. In this study, the MIB-1 labeling index was compared with 2 other immunohistochemical markers of cell proliferation, phospho-histone H3 (PHH3) and mini-chromosomal maintenance protein 2 (MCM2) in 80 incompletely resected PAs to see which was best able to identify patients at risk for tumor progression. 0(6)-Methylguanine-DNA methyltransferase (MGMT) protein expression, which has been predictive of progression-free survival (PFS) in high-grade gliomas in children, was also evaluated in these cases. The mean follow-up period was 7.81 +/- 3.9 years, and 42.8% of tumors have shown progression at the time of censoring. A MIB-1 labeling index >=2.0 was associated with shortened PFS as a grouped variable by log-ranked analysis (P = .03) and by Cox regression analysis as a continuous variable (P = .007). None of the other potential biomarkers was significantly predictive of PFS. Although the amount of MCM2 staining correlated with the MIB-1 labeling index (P < .001), MCM2 reactivity was not independently associated with outcome. We conclude that MIB-1 labeling remains the best predictor of PFS in pediatric PAs. PMID- 21653595 TI - Magnetic resonance spectroscopic detection of lactate is predictive of a poor prognosis in patients with diffuse intrinsic pontine glioma. AB - Diffuse brainstem glioma has a poor prognosis, and there are few long-term survivors. We looked for clinical, conventional magnetic resonance (MR), and MR spectroscopic (MRS) findings predictive of the prognosis of patients with brainstem glioma. Our institutional review board approved this retrospective study of 23 patients with diffuse intrinsic pontine or diffuse medullary brainstem glioma treated during the period 2000-2009. To evaluate prognostic values, we performed a Kaplan-Meier survival analysis (log-rank test) that incorporated the patients' age and sex, symptom duration, the presence or absence of cranial nerve palsy, long tract sign, ataxia, and cysts, the chemotherapeutic regimen, Gd enhancement, longitudinal and cerebellar extension, basilar artery encasement, and MRS parameters. Of the 23 diffuse brainstem gliomas, 19 were located at the pons (ratio of male to female patients, 1.1:1). The mean age of the 23 patients was 15.9 years (range, 4-50 years); 16 were aged <20 years. The duration of overall survival was 19.7 months; in patients with diffuse intrinsic pontine glioma, it was 16.6 months, and in patients aged <20 years, it was 11.8 months. Clinical and conventional MR findings at presentation were not predictive of the prognosis in children with diffuse intrinsic pontine glioma. In addition, a patient age <20 years and the detection of lactate by MRS were poor prognostic factors. The MRS detection of lactate is a prognostic factor in patients with diffuse intrinsic pontine glioma. Additional studies of larger patient populations using other imaging modalities are needed. PMID- 21653596 TI - Establishment and characterization of clinically relevant models of ependymoma: a true challenge for targeted therapy. AB - The development of new therapies for ependymoma is dramatically limited by the absence of optimal in vivo and in vitro models. Successful ependymoma treatment requires a profound understanding of the disease's biological characteristics. This study focuses on the establishment and characterization of in vivo and in vitro models of ependymoma to study the molecular pathways necessary for growth and progression in ependymoma. In addition, this study also emphasizes the use of these models for therapeutic intervention of ependymomas. We established optimal conditions for the long-term growth of 2 tumor xenografts and cultures of 2 human ependymoma cell lines. This study also describes the establishment of in vivo models. Histopathologic features of tumors from both intracranial and subcutaneous sites in mice revealed perivascular pseudorosettes and ependymal rosettes, which are typical morphologic features of ependymoma similar to those observed in human specimens. The in vitro models revealed glial fibrillary acidic protein and vimentin expression, and ultrastructural studies demonstrated numerous microvilli, caveolae, and microfilaments commonly seen in human ependymoma. To study signaling pathway alterations in ependymoma, we profiled established ependymoma models with Western blot analysis that demonstrated aberrant activation mainly of the phosphoinositide 3-kinase and epidermal growth factor receptor signaling pathways. Targeting phosphoinositide 3-kinase and epidermal growth factor receptor signaling pathways with small molecule inhibitors showed growth inhibitory effects. These models can also be used to study the standard therapies used for ependymomas, as shown by some of the drugs used in this study. Therefore, the models developed will assist in the biological studies and preclinical drug screening for ependymomas. PMID- 21653598 TI - Left ventricular systolic performance is improved in elite athletes. AB - AIMS: We sought to investigate the systolic time interval (STI) and efficiency of left ventricular (LV) contraction comparatively in elite athletes and healthy sedentary controls by means of three-dimensional echocardiography (3DE). METHODS AND RESULTS: Four hundred and twenty-nine elite athletes, involved in skill (n = 41), power (n = 63), mixed (n = 167), and endurance (n = 158) disciplines and 98 sedentary controls, matched for age, underwent 3DE. By off-line analysis, we measured the absolute and relative (normalized by the R-R interval) timing of LV systolic emptying (STI and STI%) and the systolic flow velocity (SFV = stroke volume/STI). Both STI and STI% were shorter in athletes, regardless of the sport discipline, compared with controls (respectively, 324 +/- 36 vs. 345 +/- 33 ms, P < 0.001; 30 +/- 4 vs. 40 +/- 4%; P< 0.001). Regression analysis showed that heart rate was the most important determinant of STI (R(2) = 0.38; P < 0.001), while age, body surface area, blood pressure, LV volumes, and mass had no significant association. After removing the effects of heart rate and gender, athletes showed a significant reduction (by 50.4 ms; 95% confidence interval, from 57.7 to 43.1) in STI compared with untrained subjects. Finally, higher SFV were identified in skill (256 +/- 60 mL/s; P < 0.001), strength (297 +/- 78 mL/s; P < 0.001), mixed (308 +/- 67 mL/s; P < 0.001), and endurance (334 +/- 74 mL/s; P < 0.001) athletes compared with controls (204 +/- 50 mL/s). CONCLUSION: Elite athletes show a significant shortening of the systolic time duration in comparison with sedentary controls, in association with a significant increase in LV emptying velocity. This pattern characterizes the physiological LV adaptation of the athletes and may potentially be useful in differential diagnosis of the 'athlete heart'. PMID- 21653597 TI - Inhibition of LSD1 sensitizes glioblastoma cells to histone deacetylase inhibitors. AB - Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM. PMID- 21653599 TI - Long-term carriage of NDM-1-producing Escherichia coli. PMID- 21653600 TI - Successful treatment of methicillin-resistant Staphylococcus aureus mitral valve endocarditis with sequential linezolid and telavancin monotherapy following daptomycin failure. PMID- 21653601 TI - Human immunodeficiency virus infection is associated with accelerated atherosclerosis. AB - OBJECTIVES: Cardiovascular risk is increased in HIV-infected individuals compared with the general population, making HIV disease an ideal model to investigate the pathogenesis and natural history of atherosclerosis. In this pilot study, we compared the progression of coronary artery calcium (CAC) between HIV-infected and uninfected patients. METHODS: Atherosclerosis progression was assessed in 25 HIV-infected men and 13 HIV-negative controls by means of sequential CAC scans using CT. A CAC score progression >= 15%/year was used as a surrogate marker of increased risk of cardiovascular events. RESULTS: During a median follow-up of 11 months, a CAC score increase >= 15%/year was detected in 14 HIV-infected patients (56%) and 4 HIV-negative individuals (31%). HIV infection, age and hypercholesterolaemia were independently associated with a CAC score increase >= 15%/year in an adjusted Cox regression model. CONCLUSIONS: HIV infection, age and hypercholesterolaemia were independently associated with CAC progression. HIV as well as traditional risk factors contribute to accelerate atherosclerosis in HIV infected patients. PMID- 21653602 TI - Acinetobacter baumannii and Acinetobacter genospecies 13TU and 3 bacteraemia: comparison of clinical features, prognostic factors and outcomes. AB - OBJECTIVES: To investigate the clinical impact of different genospecies of the Acinetobacter calcoaceticus-Acinetobacter baumannii complex (ACB complex; A. baumannii, Acinetobacter gen. sp. 13TU and Acinetobacter gen. sp. 3) on the severity of bacteraemia. METHODS: We retrospectively compared the clinical features and outcomes of patients with bacteraemia caused by A. baumannii, Acinetobacter gen. sp. 13TU or Acinetobacter gen. sp. 3. The genospecies were identified using oligonucleotide array sequence analysis (interspacer sequence), and the clonality of Acinetobacter gen. sp. 13TU and 3 isolates was determined by PFGE analysis. RESULTS: A total of 215 patients with bacteraemia due to ACB complex were evaluated. Among them, 117 (54.4%) had A. baumannii bacteraemia, 77 (35.8%) had Acinetobacter gen. sp. 13TU bacteraemia and 21 (9.8%) had Acinetobacter gen. sp. 3 bacteraemia. A. baumannii bacteraemia was associated with a higher 14 day mortality rate (P < 0.001), a higher 30 day mortality rate (P < 0.001) and a higher in-hospital mortality rate than bacteraemia due to Acinetobacter gen. sp. 13TU or Acinetobacter gen. sp. 3. Independent prognostic factors for the 30 day mortality included the Charlson co-morbidity index (P < 0.001) and Pitt bacteraemia score (P < 0.001). Bloodstream infection caused by a multidrug-resistant A. baumannii isolate appeared to be associated with a poor outcome (P = 0.069). There was no clonal spread of Acinetobacter gen. sp. 13TU or Acinetobacter gen. sp. 3 during the study period. CONCLUSIONS: Bacteraemia due to multidrug-resistant strains but not A. baumannii per se appears to be associated with poor outcome. PMID- 21653603 TI - Optimizing ciprofloxacin dosing in intensive care unit patients through the use of population pharmacokinetic-pharmacodynamic analysis and Monte Carlo simulations. AB - OBJECTIVES: To explore different ciprofloxacin dosage regimens for the treatment of intensive care unit (ICU) patients with respect to clinical outcome and the development of bacterial resistance for the major Gram-negative pathogens. METHODS: A population pharmacokinetic model was first developed on ciprofloxacin serum concentrations obtained in 102 ICU patients. Then, based on this model, pharmacokinetic-pharmacodynamic Monte Carlo simulations (MCSs) were carried out to explore the appropriateness of different ciprofloxacin dosage regimens in ICU patients. The defined targets were free AUC(24)/MIC >=90 h (as a predictor of clinical outcome) and T(MSW) <=20% (as a predictor of selecting resistance), where T(MSW) is the time spent within the mutant selection window over 24 h. Two simulation trials were conducted: Trial 1 took into account the whole MIC distribution for each causative pathogen in line with empirical antibiotherapy; Trial 2 used MIC breakpoints given by the Antibiogram Committee of the French Microbiology Society in order to treat the 'worst-case' scenario. RESULTS: Trial 1 showed that for Pseudomonas aeruginosa and Acinetobacter baumannii, the common dosage regimens of 400 mg twice or three times a day did not achieve the desired target attainment rates (TARs) with respect to T(MSW), while suboptimal TARs were found for AUC(24)/MIC. Trial 2 showed that <= 18% of patients reached the target of T(MSW) <= 20% for MIC breakpoints of 0.5 and 1 mg/L, regardless of the administered dose. CONCLUSIONS: Based on the mutant selection window concept, our simulations truly question the use of ciprofloxacin for the treatment of P. aeruginosa and A. baumannii infections in ICU patients due to the potential for developing resistance. PMID- 21653604 TI - Multilocus sequence typing of IncN plasmids. AB - OBJECTIVES: Incompatibility group N (IncN) plasmids have been associated with the dissemination of antimicrobial resistance and are a major vehicle for the spread of bla(VIM-1) in humans and bla(CTX-M-1) in animals. A plasmid multilocus sequence typing (pMLST) scheme was developed for rapid categorization of IncN plasmids. METHODS: Twelve fully sequenced IncN plasmids available at GenBank were analysed in silico for selecting the loci for the IncN-specific pMLST. A total of 58 plasmids originating from different reservoirs (human, pig, poultry, cattle and horses) and geographic regions (Italy, Greece, Denmark, UK and The Netherlands) were classified by DNA sequencing of the amplicons obtained for the repA, traJ and korA loci. RESULTS: Eleven sequence types (STs) were defined on the basis of allele sequences of the three selected loci. Most plasmids carrying bla(CTX-M-1) (24/27) isolated in different countries from both animals and humans belonged to ST1, suggesting dissemination of an epidemic plasmid through the food chain. Fifteen of 17 plasmids carrying bla(VIM-1) from Klebsiella pneumoniae and Escherichia coli, isolated during a 5 year period in Greece were assigned to ST10, suggesting that spread and persistence of this particular IncN-carrying bla(VIM-1) lineage in Greece. CONCLUSIONS: This study proposes the use of pMLST as a suitable and rapid method for identification of IncN epidemic plasmid lineages. The recent spread of bla(CTX-M-1) among humans and animals seems to be associated with the dissemination of an epidemic IncN plasmid lineage. PMID- 21653605 TI - Pseudomonas aeruginosa carbapenem resistance mechanisms in Spain: impact on the activity of imipenem, meropenem and doripenem. AB - OBJECTIVES: To investigate the mechanisms of carbapenem resistance in the 175 Pseudomonas aeruginosa isolates (39%; 175/448) showing non-susceptibility (European Committee on Antimicrobial Susceptibility Testing breakpoints) to imipenem (35%), meropenem (33%) and/or doripenem (33%) recovered in 2008-09 from 16 Spanish hospitals during the Comparative Activity of Carbapenem Testing (COMPACT) surveillance study. METHODS: MICs (Etest), clonal relatedness (PFGE) and metallo-beta-lactamase (MBL) production (Etest-MBL, PCR and sequencing) were determined. Mutation-driven resistance was studied in 60 non-MBL producers according to the doripenem MICs (15 isolates from each of four MIC groups: <= 1, 2-4, 8-16 and >= 32 mg/L). The expression of ampC, mexB, mexY, mexD and mexF was determined by real-time reverse transcription-PCR and the presence of mutations in oprD by PCR and sequencing. Isogenic mutants expressing combinations of mutation-driven carbapenem resistance were constructed. RESULTS: Twelve (6.9%) isolates were MBL (VIM-20, VIM-2 or VIM-13) producers and all showed high-level resistance (MIC 32 mg/L) to all three carbapenems. Regarding mutation-driven resistance, all but 1 of the 60 isolates were non-susceptible (MIC >32 mg/L) to imipenem, linked to oprD inactivation. In addition, 50% of the isolates overexpressed ampC, 33% mexY, 32% mexB and 15% mexF, while none overexpressed mexD. Increasing prevalence of ampC overexpression correlated with increasing doripenem MICs (<= 1, 13%; 2-4, 53%; 8-16, 60%; and >= 32, 73%) while overexpression of efflux pumps correlated only with moderate resistance. Doripenem showed slightly higher activity than meropenem against isolates overexpressing ampC, especially mexB or mexY. The analysis of a collection of isogenic laboratory mutants supported this finding. CONCLUSIONS: Although the prevalence of MBL producers is increasing, mutation-driven resistance is still more frequent in Spain. Imipenem resistance was driven by OprD inactivation, while additional AmpC and particularly efflux pump hyperproduction had a lower impact on the activity of doripenem compared with meropenem. PMID- 21653606 TI - GIsul2, a genomic island carrying the sul2 sulphonamide resistance gene and the small mobile element CR2 found in the Enterobacter cloacae subspecies cloacae type strain ATCC 13047 from 1890, Shigella flexneri ATCC 700930 from 1954 and Acinetobacter baumannii ATCC 17978 from 1951. PMID- 21653607 TI - Interactions between obesity, parental history of hypertension, and age on prevalent hypertension: the People's Republic of China Study. AB - Age, family history, and body mass index (BMI) influence the prevalence of hypertension, but very little is known about the interplay of these factors in Chinese populations. The authors examined this issue in Chinese adults (n = 4104) in the People's Republic of China Study. In young adults (24-39 years), the prevalence of hypertension/1000 persons (95% confidence interval [CI]) at the referent BMI was greater among subjects with a parental history of hypertension (35; 15-54) compared with those without (7; 3-11). Among middle-aged (40-71 years) adults, the prevalence of hypertension was similar regardless of parental history; however, the effect of BMI was modified by parental history status. For example, at BMI = 25 kg/m(2), the prevalence difference/1000 persons was 375 (95% CI = 245-506) and 97 (95% CI = 51-144) among subjects with and without a parental history, respectively. These large differences call for further investigation of the genetic and environmental factors that could be driving this interaction. PMID- 21653608 TI - Fatty liver and metabolic syndrome in nonabdominally obese Taiwanese adults. AB - The aim of this study was to examine the relationship between fatty liver (FL), abdominal obesity, and metabolic syndrome (MetS). A total of 3058 adults who underwent health examinations in 2005 were enrolled. MetS was defined according to the National Cholesterol Educational Program's Adult Treatment Panel III criteria. The relationship between FL, abdominal obesity, and MetS was analyzed using multiple logistic regression. The authors found that participants with FL alone [FL(+)/abdominal obesity(-)] had a significantly higher odds ratio for hyperglycemia (odds ratio [OR] = 2.2; 95% confidence interval [CI] = 1.5-3.3), hypertriglyceridemia (OR = 2.2; 95% CI = 1.6-3.0), low high-density lipoprotein cholesterol (OR = 2.2; 95% CI = 1.6-3.2) and a clustering of MetS components (OR = 2.5; 95% CI = 1.8-3.4) compared with participants with only abdominal obesity [FL(-)/abdominal obesity(+)]. Participants who had FL and abdominal obesity [FL(+)/abdominal obesity(+)] had the highest odds ratio for developing MetS and its components. It is concluded that FL is associated with the components of MetS independent of abdominal obesity. For nonabdominally obese patients, FL provides important information on MetS. PMID- 21653609 TI - Equity of access to primary care among older adults in Incheon, South Korea. AB - The present study examines the extent to which equity in the use of physician services for the elderly has been achieved in Incheon, Korea. It is based on the Aday and Andersen Access Framework. The results indicate that a universal health insurance system has not yielded a fully equitable distribution of services. The limitation of benefit coverage as well as high out-of-pocket payment can be a barrier to health care utilization, which results in inequity and differential medical care utilization between subgroups of older adults. Health policy reforms in South Korea must continue to concentrate on extending insurance coverage to the uninsured and establishing a financially separate insurance system for poor older adults. In addition, further research is needed to identify the nonfinancial barriers that persist for certain demographic subgroups, that is, those 80 years and older, men, those who lack a social network, and those who have no religion. PMID- 21653611 TI - Symmetry breaking in mouse oocytes requires transient F-actin meshwork destabilization. AB - Female meiotic divisions are extremely asymmetric, giving rise to a large oocyte and small degenerating polar bodies, keeping the maternal stores for further embryo development. This asymmetry is achieved via off-center positioning of the division spindle. Mouse oocytes have developed a formin-2-dependent actin-based spindle positioning mechanism that allows the meiotic spindle to migrate towards the closest cortex. Using spinning disk microscopy and FRAP analysis, we studied the changes in the organization of the cytoplasmic F-actin meshwork during the first meiotic division. It is very dense in prophase I, undergoes a significant density drop upon meiosis resumption and reforms progressively later on. This meshwork remodeling correlates with endogenous formin 2 regulation. High formin 2 levels at meiosis I entry induce meshwork maintenance, leading to equal forces being exerted on the chromosomes, preventing spindle migration. Hence, the meshwork density drop at meiosis resumption is germane to the symmetry-breaking event required for successful asymmetric meiotic divisions. PMID- 21653610 TI - tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration. AB - Recent lineage-tracing studies have produced conflicting results about whether the epicardium is a source of cardiac muscle cells during heart development. Here, we examined the developmental potential of epicardial tissue in zebrafish during both embryonic development and injury-induced heart regeneration. We found that upstream sequences of the transcription factor gene tcf21 activated robust, epicardium-specific expression throughout development and regeneration. Cre recombinase-based, genetic fate-mapping of larval or adult tcf21(+) cells revealed contributions to perivascular cells, but not cardiomyocytes, during each form of cardiogenesis. Our findings indicate that natural epicardial fates are limited to non-myocardial cell types in zebrafish. PMID- 21653612 TI - DeltaC and DeltaD interact as Notch ligands in the zebrafish segmentation clock. AB - We describe the production and characterisation of two monoclonal antibodies, zdc2 and zdd2, directed against the zebrafish Notch ligands DeltaC and DeltaD, respectively. We use our antibodies to show that these Delta proteins can bind to one another homo- and heterophilically, and to study the localisation of DeltaC and DeltaD in the zebrafish nervous system and presomitic mesoderm (PSM). Our findings in the nervous system largely confirm expectations from previous studies, but in the PSM we see an unexpected pattern in which the localisation of DeltaD varies according to the level of expression of DeltaC: in the anterior PSM, where DeltaC is plentiful, the two proteins are colocalised in intracellular puncta, but in the posterior PSM, where DeltaC is at a lower level, DeltaD is seen mainly on the cell surface. Forced overexpression of DeltaC reduces the amount of DeltaD on the cell surface in the posterior PSM; conversely, loss-of function mutation of DeltaC increases the amount of DeltaD on the cell surface in the anterior PSM. These findings suggest an explanation for a long-standing puzzle regarding the functions of the two Delta proteins in the somite segmentation clock--an explanation that is based on the proposition that they associate heterophilically to activate Notch. PMID- 21653613 TI - Serial specification of diverse neuroblast identities from a neurogenic placode by Notch and Egfr signaling. AB - We used the brain insulin-producing cell (IPC) lineage and its identified neuroblast (IPC NB) as a model to understand a novel example of serial specification of NB identities in the Drosophila dorsomedial protocerebral neuroectoderm. The IPC NB was specified from a small, molecularly identified group of cells comprising an invaginated epithelial placode. By progressive delamination of cells, the placode generated a series of NB identities, including the single IPC NB, a number of other canonical Type I NBs, and a single Type II NB that generates large lineages by transient amplification of neural progenitor cells. Loss of Notch function caused all cells of the placode to form as supernumerary IPC NBs, indicating that the placode is initially a fate equivalence group for the IPC NB fate. Loss of Egfr function caused all placodal cells to apoptose, except for the IPC NB, indicating a requirement of Egfr signaling for specification of alternative NB identities. Indeed, both derepressed Egfr activity in yan mutants and ectopic EGF activity produced supernumerary Type II NBs from the placode. Loss of both Notch and Egfr function caused all placode cells to become IPC NBs and survive, indicating that commitment to NB fate nullified the requirement of Egfr activity for placode cell survival. We discuss the surprising parallels between the serial specification of neural fates from this neurogenic placode and the fly retina. PMID- 21653614 TI - Neuroblast migration along the anteroposterior axis of C. elegans is controlled by opposing gradients of Wnts and a secreted Frizzled-related protein. AB - The migration of neuroblasts along the anteroposterior body axis of C. elegans is controlled by multiple Wnts that act partially redundantly to guide cells to their precisely defined final destinations. How positional information is specified by this system is, however, still largely unknown. Here, we used a novel fluorescent in situ hybridization methods to generate a quantitative spatiotemporal expression map of the C. elegans Wnt genes. We found that the five Wnt genes are expressed in a series of partially overlapping domains along the anteroposterior axis, with a predominant expression in the posterior half of the body. Furthermore, we show that a secreted Frizzled-related protein is expressed at the anterior end of the body axis, where it inhibits Wnt signaling to control neuroblast migration. Our findings reveal that a system of regionalized Wnt gene expression and anterior Wnt inhibition guides the highly stereotypic migration of neuroblasts in C. elegans. Opposing expression of Wnts and Wnt inhibitors has been observed in basal metazoans and in the vertebrate neurectoderm. Our results in C. elegans support the notion that a system of posterior Wnt signaling and anterior Wnt inhibition is an evolutionarily conserved principle of primary body axis specification. PMID- 21653615 TI - Sector analysis and predictive modelling reveal iterative shoot-like development in fern fronds. AB - Plants colonized the terrestrial environment over 450 million years ago. Since then, shoot architecture has evolved in response to changing environmental conditions. Our current understanding of the innovations that altered shoot morphology is underpinned by developmental studies in a number of plant groups. However, the least is known about mechanisms that operate in ferns--a key group for understanding the evolution of plant development. Using a novel combination of sector analysis, conditional probability modelling methods and histology, we show that shoots, fronds ('leaves') and pinnae ('leaflets') of the fern Nephrolepis exaltata all develop from single apical initial cells. Shoot initials cleave on three faces to produce a pool of cells from which individual frond apical initials are sequentially specified. Frond initials then cleave in two planes to produce a series of lateral merophyte initials that each contributes a unit of three pinnae to half of the mediolateral frond axis. Notably, this iterative pattern in both shoots and fronds is similar to the developmental process that operates in shoots of other plant groups. Pinnae initials first cleave in two planes to generate lateral marginal initials. The apical and marginal initials then divide in three planes to coordinately generate the determinate pinna. These findings impact both on our understanding of fundamental plant developmental processes and on our perspective of how shoot systems evolved. PMID- 21653616 TI - Sclerotome-derived Slit1 drives directional migration and differentiation of Robo2-expressing pioneer myoblasts. AB - Pioneer myoblasts generate the first myotomal fibers and act as a scaffold to pattern further myotome development. From their origin in the medial epithelial somite, they dissociate and migrate towards the rostral edge of each somite, from which differentiation proceeds in both rostral-to-caudal and medial-to-lateral directions. The mechanisms underlying formation of this unique wave of pioneer myofibers remain unknown. We show that rostrocaudal or mediolateral somite inversions in avian embryos do not alter the original directions of pioneer myoblast migration and differentiation into fibers, demonstrating that regulation of pioneer patterning is somite-intrinsic. Furthermore, pioneer myoblasts express Robo2 downstream of MyoD and Myf5, whereas the dermomyotome and caudal sclerotome express Slit1. Loss of Robo2 or of sclerotome-derived Slit1 function perturbed both directional cell migration and fiber formation, and their effects were mediated through RhoA. Although myoblast specification was not affected, expression of the intermediate filament desmin was reduced. Hence, Slit1 and Robo2, via RhoA, act to pattern formation of the pioneer myotome through the regulation of cytoskeletal assembly. PMID- 21653617 TI - WikiProject medicine. PMID- 21653618 TI - Oxfam warns of future global hunger crisis unless rules on food markets are changed. PMID- 21653619 TI - Doctors will be asked to help identify people at risk of becoming terrorists. PMID- 21653620 TI - How useful are laboratory tests in diagnosing serious infections in febrile children? PMID- 21653622 TI - Sing and dance. PMID- 21653621 TI - Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. AB - OBJECTIVE: To collate all available evidence on the diagnostic value of laboratory tests for the diagnosis of serious infections in febrile children in ambulatory settings. DESIGN: Systematic review. DATA SOURCES: Electronic databases, reference tracking, and consultation with experts. STUDY SELECTION: Studies were selected on six criteria: design (studies of diagnostic accuracy or deriving prediction rules), participants (otherwise healthy children and adolescents aged 1 month to 18 years), setting (first contact ambulatory care), outcome (serious infection), features assessed (in first contact care), and data reported (sufficient to construct a 2*2 table). DATA EXTRACTION: Quality assessment was based on the quality assessment tool of diagnostic accuracy studies (QUADAS) criteria. Meta-analyses were done using the bivariate random effects method and hierarchical summary receiver operating characteristic curves for studies with multiple thresholds. DATA SYNTHESIS: None of the 14 studies identified were of high methodological quality and all were carried out in an emergency department or paediatric assessment unit. The prevalence of serious infections ranged from 4.5% to 29.3%. Tests were carried out for C reactive protein (five studies), procalcitonin (three), erythrocyte sedimentation rate (one), interleukins (two), white blood cell count (seven), absolute neutrophil count (two), band count (three), and left shift (one). The tests providing most diagnostic value were C reactive protein and procalcitonin. Bivariate random effects meta-analysis (five studies, 1379 children) for C reactive protein yielded a pooled positive likelihood ratio of 3.15 (95% confidence interval 2.67 to 3.71) and a pooled negative likelihood ratio of 0.33 (0.22 to 0.49). To rule in serious infection, cut-off levels of 2 ng/mL for procalcitonin (two studies, positive likelihood ratio 13.7, 7.4 to 25.3 and 3.6, 1.4 to 8.9) and 80 mg/L for C reactive protein (one study, positive likelihood ratio 8.4, 5.1 to 14.1) are recommended; lower cut-off values of 0.5 ng/mL for procalcitonin or 20 mg/L for C reactive protein are necessary to rule out serious infection. White blood cell indicators are less valuable than inflammatory markers for ruling in serious infection (positive likelihood ratio 0.87-2.43), and have no value for ruling out serious infection (negative likelihood ratio 0.61-1.14). The best performing clinical decision rule (recently validated in an independent dataset) combines testing for C reactive protein, procalcitonin, and urinalysis and has a positive likelihood ratio of 4.92 (3.26 to 7.43) and a negative likelihood ratio of 0.07 (0.02 to 0.27). CONCLUSION: Measuring inflammatory markers in an emergency department setting can be diagnostically useful, but clinicians should apply different cut-off values depending on whether they are trying to rule in or rule out serious infection. Measuring white blood cell count is less useful for ruling in serious infection and not useful for ruling out serious infection. More rigorous studies are needed, including studies in primary care, to assess the value of laboratory tests alongside clinical diagnostic measurements, including vital signs. PMID- 21653623 TI - Shocking treatment. PMID- 21653624 TI - We need cooperation rather than competition. PMID- 21653625 TI - Acute intoxication with the adjuvant itself for Gramoxone INTEON. AB - The adjuvant for Gramoxone INTEON is composed of 20% methanol, 20% sodium lingo sulphonate, 10% alkylaryl polyoxyethylene ether, and 50% water. Although the adjuvant is a potential source of intoxication due to the widespread use of Gramoxone INTEON, there has been no prior report characterizing the acute toxicity of this adjuvant. This study evaluated the acute toxicity of adjuvant ingestion. Seven patients presenting with acute adjuvant intoxication at Chonnam National University Hospital were enrolled in this retrospective study. The patients had intentionally or accidentally ingested 20-150 mL of adjuvant. Gastrointestinal symptoms such as nausea and vomiting were most common, and no ocular symptoms were reported. Cardiovascular symptoms were limited to electrocardiogram changes such as corrected QT interval (QTc) prolongation (71.4%) and sinus tachycardia (28.6%). All patients had an elevated serum osmolar gap and lactate levels. One patient had metabolic acidosis with a high anion gap that required administration of sodium bicarbonate. These clinical symptoms were resolved within 3 days with supportive treatment without any sequelae. There were no life-threatening symptoms and no deaths. However, the physician should keep in mind the possibility of methanol intoxication in patients poisoned with this adjuvant. PMID- 21653626 TI - Anti-diabetic and anti-oxidative effects of 4-hydroxypipecolic acid in C57BL/KsJ db/db mice. AB - Hypoglycemic effect of ethanol extracts of Peganum harmala (commonly known as 'Harmal') seeds has been reported on normal and streptozotocin-induced diabetic rats. In the present study, the authors determine anti-diabetic and anti oxidative properties of 4-hydroxypipecolic acid (4-HPA) isolated from seeds of P. harmala in C57BL/KsJ-db/db mice. Twelve week old male mice were administered 50 mg/kg body weight (4-HPA suspension were made in 1% gum acacia) for the period of 10 days, and a significant reduction in the fasting blood glucose, plasma triglycerides (TG), cholesterol, free fatty acid, low-density lipoprotein cholesterol and a significant increase in high-density lipoprotein-cholesterol level was observed with respect to vehicle-treated db/db mice. The anti-oxidant activity of 4-hydroxypipecolic acid was studied in liver and kidney tissues by assessing malondialdehyde levels for lipid peroxidation and enzyme activity of catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). Treatment of 4-HPA significantly lowered the lipid peroxidation in hepatic and renal tissue and increased the activity of CAT, GSH-Px and SOD in treated mice. PMID- 21653627 TI - A context for normalizing impulsiveness at work for adults with attention deficit/hyperactivity disorder (combined type). AB - Impaired executive function and impulsiveness or intolerance to boredom in adult attention deficit/hyperactivity disorder (ADHD) are thought to compromise performance at work. Several task parameters help people with ADHD to perform better on computerized cognitive tasks, namely reduced response-to-stimulus interval, discriminative feedback, or a format resembling a videogame. However, still very little is known about how these contexts might be helpful in a real work environment. We developed a computerized task resembling a fast-paced videogame with no response-to-stimulus interval and constant and diverse discriminative error feedback. The task included several measurements of high order executive function (planning, working memory, and prospective memory) formatted as a single multitask simulating occupational activities (SOA). We also administered the Continuous Performance Test-II (CPT-II), a very simple vigilance task without discriminative feedback and with long response-to-stimulus intervals. We tested 30 adults answering to DSM-IV criteria of ADHD (combined type) and 30 IQ-matched adults without ADHD. As has been reported many times, the ADHD participants made significantly more errors of commission than the control participants on the CPT-II, whereas the two groups made the same number of errors of commission on the SOA. The ADHD group also sought discriminative feedback significantly more actively on the SOA than the control group and performed at par with the control group in all respects. There was no speed/accuracy trade off, nor was there any evidence of other costs of normalization on the SOA. Impulsiveness in adult ADHD is compensable on a task simulating the work environment. PMID- 21653628 TI - The effectiveness of the JOBS program among the long-term unemployed: a randomized experiment in the Netherlands. AB - Given the adverse effects of long-term unemployment, it is of major concern that evidence-based interventions are available for the long-term unemployed. Therefore, we examined the effectiveness of the JOBS program, a group training for the unemployed [Caplan, R. D., Vinokur, A. D., Price, R. H. and Van Ryn, M. (1989). Journal of Applied Psychology, 74, 759-769], among long-term unemployed individuals. In a randomly controlled trial, JOBS was compared with a control condition and a voucher intervention, in which individuals were given the opportunity to spend a certain budget on services that could help them reintegrate. After 6 months JOBS participants had more often found a job and were more satisfied with the intervention. After 12 months effects were still visible, but less pronounced. PMID- 21653629 TI - Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation. AB - We recently standardized a model (L(Lact)) of severe chronic kidney disease based on impaired nephrogenesis by suppression of angiotensin II activity during lactation (Machado FG, Poppi EP, Fanelli C, Malheiros DM, Zatz R, Fujihara CK. Am J Physiol Renal Physiol 294: F1345-F1353, 2008). In this new study of the L(Lact) model, we sought to gain further insight into renal injury mechanisms associated with this model and to verify whether the renoprotection obtained with the association of the angiotensin II receptor blocker losartan (L) and hydrochlorothiazide (H), which arrested renal injury in the remnant kidney model, would provide similar renoprotection. Twenty Munich-Wistar dams, each nursing six pups, were divided into control, untreated, and L(Lact) groups, given losartan (L; 250 mg.kg(-1).day(-1)) until weaning. The male L(Lact) offspring remained untreated until 7 mo of age, when renal functional and structural parameters were studied in 17 of them, used as pretreatment control (L(Lact)Pre), and followed no further. The remaining rats were then divided among groups L(Lact)+V, untreated; L(Lact)+L, given L (50 mg.kg(-1).day(-1)) now as a therapy; L(Lact)+H, given H (6 mg.kg(-1).day(-1)); and L(Lact)+LH, given L and H. All parameters were reassessed 3 mo later in these groups and in age-matched controls. At this time, L(Lact) rats exhibited hypertension, severe albuminuria, glomerular damage, marked interstitial expansion/inflammation, enhanced cell proliferation, myofibroblast infiltration, and creatinine retention. L monotherapy normalized albuminuria and prevented hypertension and the progression of renal injury, inflammation, and myofibroblast infiltration. In contrast to the remnant model, the LH combination promoted only slight additional renoprotection, perhaps because of a limited tendency to retain sodium in L(Lact) rats. PMID- 21653630 TI - Reversal of anemia with allogenic RBC transfusion prevents post-cardiopulmonary bypass acute kidney injury in swine. AB - Anemia during cardiopulmonary bypass (CPB) is strongly associated with acute kidney injury in clinical studies; however, reversal of anemia with red blood cell (RBC) transfusions is associated with further renal injury. To understand this paradox, we evaluated the effects of reversal of anemia during CPB with allogenic RBC transfusion in a novel large-animal model of post-cardiac surgery acute kidney injury with significant homology to that observed in cardiac surgery patients. Adult pigs undergoing general anesthesia were allocated to a Sham procedure, CPB alone, Sham+RBC transfusion, or CPB+RBC transfusion, with recovery and reassessment at 24 h. CPB was associated with dilutional anemia and caused acute kidney injury in swine characterized by renal endothelial dysfunction, loss of nitric oxide (NO) bioavailability, vasoconstriction, medullary hypoxia, cortical ATP depletion, glomerular sequestration of activated platelets and inflammatory cells, and proximal tubule epithelial cell stress. RBC transfusion in the absence of CPB also resulted in renal injury. This was characterized by endothelial injury, microvascular endothelial dysfunction, platelet activation, and equivalent cortical tubular epithelial phenotypic changes to those observed in CPB pigs, but occurred in the absence of severe intrarenal vasoconstriction, ATP depletion, or reductions in creatinine clearance. In contrast, reversal of anemia during CPB with RBC transfusion prevented the reductions in creatinine clearance, loss of NO bioavailability, platelet activation, inflammation, and epithelial cell injury attributable to CPB although it did not prevent the development of significant intrarenal vasoconstriction and endothelial dysfunction. In conclusion, contrary to the findings of observational studies in cardiac surgery, RBC transfusion during CPB protects pigs against acute kidney injury. Our study underlines the need for translational research into indications for transfusion and prevention strategies for acute kidney injury. PMID- 21653631 TI - Inhibition of estradiol synthesis attenuates renal injury in male streptozotocin induced diabetic rats. AB - We previously showed that the male streptozotocin (STZ)-induced diabetic rat exhibits decreased circulating testosterone and increased estradiol levels. While supplementation with dihydrotestosterone is partially renoprotective, the aim of the present study was to examine whether inhibition of estradiol synthesis, by blocking the aromatization of testosterone to estradiol using an aromatase inhibitor, can also prevent diabetes-associated renal injury. The study was performed on male Sprague-Dawley nondiabetic, STZ-induced diabetic, and STZ induced diabetic rats treated with 0.15 mg/kg of anastrozole, an aromatase inhibitor (Da) for 12 wk. Treatment with anastrozole reduced diabetes-associated increases in plasma estradiol by 39% and increased plasma testosterone levels by 187%. Anastrozole treatment also attenuated urine albumin excretion by 42%, glomerulosclerosis by 30%, tubulointerstitial fibrosis by 32%, along with a decrease in the density of renal cortical CD68-positive cells by 50%, and protein expression of transforming growth factor-beta by 20%, collagen type IV by 29%, tumor necrosis factor-alpha by 28%, and interleukin-6 by 25%. Anastrozole also increased podocin protein expression by 18%. We conclude that blocking estradiol synthesis in male STZ-induced diabetic rats is renoprotective. PMID- 21653632 TI - Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. AB - Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thebault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss. PMID- 21653633 TI - pH-dependent regulation of the alpha-subunit of H+-K+-ATPase (HKalpha2). AB - The H(+)-K(+)-ATPase alpha-subunit (HKalpha(2)) participates importantly in systemic acid-base homeostasis and defends against metabolic acidosis. We have previously shown that HKalpha(2) plasma membrane expression is regulated by PKA (Codina J, Liu J, Bleyer AJ, Penn RB, DuBose TD Jr. J Am Soc Nephrol 17: 1833 1840, 2006) and in a separate study demonstrated that genetic ablation of the proton-sensing G(s)-coupled receptor GPR4 results in spontaneous metabolic acidosis (Sun X, Yang LV, Tiegs BC, Arend LJ, McGraw DW, Penn RB, Petrovic S. J Am Soc Nephrol 21: 1745-1755, 2010). In the present study, we investigated the ability of chronic acidosis and GPR4 to regulate HKalpha(2) expression in HEK-293 cells. Chronic acidosis was modeled in vitro by using multiple methods: reducing media pH by adjusting bicarbonate concentration, adding HCl, or by increasing the ambient concentration of CO(2). PKA activity and HKalpha(2) protein were monitored by immunoblot analysis, and HKalpha(2) mRNA, by real-time PCR. Chronic acidosis did not alter the expression of HKalpha(2) mRNA; however, PKA activity and HKalpha(2) protein abundance increased when media pH decreased from 7.4 to 6.8. Furthermore, this increase was independent of the method used to create chronic acidosis. Heterologous expression of GPR4 was sufficient to increase both basal and acid-stimulated PKA activity and similarly increase basal and acid stimulated HKalpha(2) expression. Collectively, these results suggest that chronic acidosis and GPR4 increase HKalpha(2) protein by increasing PKA activity without altering HKalpha(2) mRNA abundance, implicating a regulatory role of pH activated GPR4 in homeostatic regulation of HKalpha(2) and acid-base balance. PMID- 21653634 TI - Activation of P2Y1 and P2Y2 receptors induces chloride secretion via calcium activated chloride channels in kidney inner medullary collecting duct cells. AB - Dysregulation of urinary sodium chloride (NaCl) excretion can result in extracellular fluid (ECF) volume expansion and hypertension. Recent studies demonstrated that urinary nucleotide excretion increases in mice ingesting a high salt diet and that these increases in extracellular nucleotides can signal through P2Y(2) receptors in the kidney collecting duct to inhibit epithelial Na(+) channels (ENaC). However, under conditions of ECF volume expansion brought about by high-dietary salt intake, ENaC activity should already be suppressed. We hypothesized that alternative pathways exist by which extracellular nucleotides control renal NaCl excretion. We used an inner medullary collecting duct (mIMCD K2) cell line in an Ussing chamber system as a model to study additional ion transport pathways that are regulated by extracellular nucleotides. When ENaC was inhibited, the addition of adenosine triphosphate (ATP) to the basal side of cell sheets activated both P2Y(1) and P2Y(2) receptors, inducing a transient increase in short-circuit current (I(sc)); addition of ATP to the apical side activated only P2Y(2) receptors, inducing first a transient and then a sustained increase in I(sc). The ATP-induced increases in I(sc) were blocked by pretreatment with a phospholipase C (PLC) inhibitor, a calcium (Ca(2+)) chelator, or Ca(2+)-activated Cl(-) channel (CACC) inhibitors, suggesting that ATP signals through both PLC and intracellular Ca(2+) to activate CACC. We propose that P2Y(1) and P2Y(2) receptors operate in tandem in IMCD cells to provide an adaptive mechanism for enhancing urinary NaCl excretion in the setting of high-dietary NaCl intake. PMID- 21653635 TI - Extracellular cAMP-adenosine pathways in the mouse kidney. AB - The renal extracellular 2',3'-cAMP-adenosine and 3',5'-cAMP-adenosine pathways (extracellular cAMPs->AMPs->adenosine) may contribute to renal adenosine production. Because mouse kidneys provide opportunities to investigate renal adenosine production in genetically modified kidneys, it is important to determine whether mouse kidneys express these cAMP-adenosine pathways. We administered (renal artery) 2',3'-cAMP and 3',5'-cAMP to isolated, perfused mouse kidneys and measured renal venous secretion rates of 2',3'-cAMP, 3',5'-cAMP, 2' AMP, 3'-AMP, 5'-AMP, adenosine, and inosine. Arterial infusions of 2',3'-cAMP increased (P < 0.0001) the mean venous secretion of 2'-AMP (390-fold), 3'-AMP (497-fold), adenosine (18-fold), and inosine (adenosine metabolite; 7-fold), but they did not alter 5'-AMP secretion. Infusions of 3',5'-cAMP did not affect venous secretion of 2'-AMP or 3'-AMP, but they increased (P < 0.0001) secretion of 5'-AMP (5-fold), adenosine (17-fold), and inosine (6-fold). Energy depletion (metabolic inhibitors) increased the secretion of 2',3'-cAMP (8-fold, P = 0.0081), 2'-AMP (4-fold, P = 0.0028), 3'-AMP (4-fold, P = 0.0270), 5'-AMP (3 fold, P = 0.0662), adenosine (2-fold, P = 0.0317), and inosine (7-fold, P = 0.0071), but it did not increase 3',5'-cAMP secretion. The 2',3'-cAMP-adenosine pathway was quantitatively similar in CD73 -/- vs. +/+ kidneys. However, 3',5' cAMP induced a 6.7-fold greater increase in 5'-AMP, an attenuated increase (61% reduction) in inosine and a similar increase in adenosine in CD73 -/- vs. CD73 +/+ kidneys. In mouse kidneys, 1) 2',3'-cAMP and 3',5'-cAMP are metabolized to their corresponding AMPs, which are subsequently metabolized to adenosine; 2) energy depletion activates the 2',3'-cAMP-adenosine, but not the 3',5'-cAMP adenosine, pathway; and 3) although CD73 is involved in the 3',5'-AMP-adenosine pathway, alternative pathways of 5'-AMP metabolism and reduced metabolism of adenosine to inosine compensate for life-long deficiency of CD73. PMID- 21653636 TI - Establishment of conditionally immortalized human glomerular mesangial cells in culture, with unique migratory properties. AB - The aim of this study was to establish an immortalized human mesangial cell line similar to mesangial cells in vivo for use as a tool for understanding glomerular cell function. Mesangial cells were isolated from glomerular outgrowths from a normal human kidney, then retrovirally transfected with a temperature-sensitive SV40T antigen+human telomerase (hTERT). Mesangial cells exhibited features of compact cells with small bodies in a confluent monolayer at 33 degrees C, but the cell shape changed to flat and stellate after 5 days in growth-restrictive conditions (37 degrees C). Western blot and immunofluorescence analysis showed that podocyte markers (nephrin, CD2AP, podocin, Wilms' tumor-1) and an endothelial-specific molecule (VE-cadherin) were not detectable in this cell line, whereas markers characteristic of mesangial cells (alpha-SMA, fibronectin, and PDGFbeta-R) were strongly expressed. In migration assays, a significant reduction in wound surface was observed in podocyte and endothelial cells as soon as 12 h (75 and 62%, respectively) and complete wound closure after 24 h. In contrast, no significant change was observed in mesangial cells after 12 h, and even after 48 h the wounds were not completely closed. Until now, conditionally immortalized podocyte and endothelial cell lines derived from mice and humans have been described, and this has greatly boosted research on glomerular physiology and pathology. We have established the first conditionally immortalized human glomerular mesangial cell line, which will be an important adjunct in studies of representative glomerular cells, as well as in coculture studies. Unexpectedly, mesangial cells' ability to migrate seems to be slower than for other glomerular cells, suggesting this line will demonstrate functional properties distinct from previously available mesangial cell cultures. This conditionally immortalized human mesangial cell line represents a new tool for the study of human mesangial cell biology in vitro. PMID- 21653637 TI - Understanding 'what' others do: mirror mechanisms play a crucial role in action perception. AB - Neurophysiological and imaging studies suggest that the inferior frontal cortex (IFC) implements a mechanism that matches perceived actions to one's motor representation of similar actions (mirror mechanism) and recent lesion studies have also established that IFC is critical for action perception. However, to date causative evidence that action perception requires activation within the same populations of IFC neurons involved in action execution is lacking. In this issue, Cattaneo and colleagues provide the first direct evidence that mirror mechanisms in IFC influence action perception. We discuss the implications of these findings for the understanding of the functional role of mirror mechanisms. PMID- 21653638 TI - A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP J/Su(H) in modulating the pathological outcome. AB - Expanded polyglutamine (polyQ) tract in the human TATA-box-binding protein (hTBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). To investigate the pathological effects of polyQ expansion, we established a SCA17 model in Drosophila. Similar to SCA17 patients, transgenic flies expressing a mutant hTBP protein with an expanded polyQ tract (hTBP80Q) exhibit progressive neurodegeneration, late-onset locomotor impairment and shortened lifespan. Microarray analysis reveals that hTBP80Q causes widespread and time-dependent transcriptional dysregulation in Drosophila. In a candidate screen for genetic modifiers, we identified RBP-J/Su(H), a transcription factor that contains Q/N rich domains and participates in Notch signaling. Knockdown of Su(H) by RNAi further enhances hTBP80Q-induced eye defects, whereas overexpression of Su(H) suppresses such defects. While the Su(H) transcript level is not significantly altered in hTBP80Q-expressing flies, genes that contain Su(H)-binding sites are among those that are dysregulated. We further show that hTBP80Q interacts more efficiently with Su(H) than wild-type hTBP, suggesting that a reduction in the fraction of Su(H) available for its normal cellular functions contributes to hTBP80Q-induced phenotypes. While the Notch signaling pathway has been implicated in several neurological disorders, our study suggests a possibility that the activity of its nuclear component RBP-J/Su(H) may modulate the pathological progression in SCA17 patients. PMID- 21653640 TI - Pathway-driven gene stability selection of two rheumatoid arthritis GWAS identifies and validates new susceptibility genes in receptor mediated signalling pathways. AB - Rheumatoid arthritis (RA) is the commonest chronic, systemic, inflammatory disorder affecting ~1% of the world population. It has a strong genetic component and a growing number of associated genes have been discovered in genome-wide association studies (GWAS), which nevertheless only account for 23% of the total genetic risk. We aimed to identify additional susceptibility loci through the analysis of GWAS in the context of biological function. We bridge the gap between pathway and gene-oriented analyses of GWAS, by introducing a pathway-driven gene stability-selection methodology that identifies potential causal genes in the top associated disease pathways that may be driving the pathway association signals. We analysed the WTCCC and the NARAC studies of ~5000 and ~2000 subjects, respectively. We examined 700 pathways comprising ~8000 genes. Ranking pathways by significance revealed that the NARAC top-ranked ~6% laid within the top 10% of WTCCC. Gene selection on those pathways identified 58 genes in WTCCC and 61 in NARAC; 21 of those were common (P(overlap)< 10(-21)), of which 16 were novel discoveries. Among the identified genes, we validated 10 known RA associations in WTCCC and 13 in NARAC, not discovered using single-SNP approaches on the same data. Gene ontology functional enrichment analysis on the identified genes showed significant over-representation of signalling activity (P< 10(-29)) in both studies. Our findings suggest a novel model of RA genetic predisposition, which involves cell-membrane receptors and genes in second messenger signalling systems, in addition to genes that regulate immune responses, which have been the focus of interest previously. PMID- 21653639 TI - A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. AB - The primary cilium is emerging as a crucial regulator of signaling pathways central to vertebrate development and human disease. We identified atrioventricular canal 1 (avc1), a mouse mutation that caused VACTERL association with hydrocephalus, or VACTERL-H. We showed that avc1 is a hypomorphic mutation of intraflagellar transport protein 172 (Ift172), required for ciliogenesis and Hedgehog (Hh) signaling. Phenotypically, avc1 caused VACTERL-H but not abnormalities in left-right (L-R) axis formation. Avc1 resulted in structural cilia defects, including truncated cilia in vivo and in vitro. We observed a dose dependent requirement for Ift172 in ciliogenesis using an allelic series generated with Ift172(avc1) and Ift172(wim), an Ift172 null allele: cilia were present on 42% of avc1 mouse embryonic fibroblast (MEF) and 28% of avc1/wim MEFs, in contrast to >90% of wild-type MEFs. Furthermore, quantitative cilium length analysis identified two specific cilium populations in mutant MEFS: a normal population with normal IFT and a truncated population, 50% of normal length, with disrupted IFT. Cells from wild-type embryos had predominantly full-length cilia, avc1 embryos, with Hh signaling abnormalities but not L-R abnormalities, had cilia equally divided between full-length and truncated, and avc1/wim embryos, with both Hh signaling and L-R abnormalities, were primarily truncated. Truncated Ift172 mutant cilia showed defects of the distal ciliary axoneme, including disrupted IFT88 localization and Hh-dependent Gli2 localization. We propose a model in which mutation of Ift172 results in a specific class of abnormal cilia, causing disrupted Hh signaling while maintaining L-R axis determination, and resulting in the VACTERL-H phenotype. PMID- 21653641 TI - Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. AB - Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease of the central nervous system, and numerous studies have shown that MS has a strong genetic component. Independent studies to identify MS-associated genes have often indicated multiple signals in physically close genomic regions, although by their proximity it is not always clear if these data indicate redundant or truly independent genetic signals. Recently, three MS study samples were genotyped in parallel using an Illumina Custom BeadChip. These revealed multiple significantly associated single-nucleotide polymorphisms within a 600 kb stretch on chromosome 16p13. Here we present a detailed analysis of variants in this region that clarifies the independent nature of these signals. The linkage disequilibrium patterns in the region and logistic regression analysis of the associations suggest that this region likely harbors three independent MS disease loci. Further, we examined cis-expression QTLs, histone modifications and CCCTC-binding factor (CTCF) binding data in the region. We also tested for correlated expression of the genes from the region using whole-genome expression array data from lymphoblastoid cell lines. Three of the genes show expression correlations across loci. Furthermore, in the GM12878 lymphoblastoid cell line, these three genes are in a continuous region devoid of H3K27 methylation, suggesting an open chromatin configuration. This region likely only contributes minimal risk to MS; however, investigation of this region will undoubtedly provide insight into the functional mechanisms of these genes. These data highlight the importance of taking a closer look at the expression and function of chromosome 16p13 in the pathogenesis of MS. PMID- 21653643 TI - Trends in colorectal cancer test use among vulnerable populations in the United States. AB - BACKGROUND: Evaluating trends in colorectal cancer (CRC) screening use is critical for understanding screening implementation, and whether population groups targeted for screening are receiving it, consistent with guidelines. This study examines recent national trends in CRC test use, including among vulnerable populations. METHODS: We used the 2000, 2003, 2005, and 2008 National Health Interview Survey to examine national trends in CRC screening use overall and for fecal occult blood test (FOBT), sigmoidoscopy, and colonoscopy. We also assessed trends by race/ethnicity, educational attainment, income, time in the United States, and access to health care. RESULTS: During 2000 to 2008, significant declines in FOBT and sigmoidoscopy use and significant increases in colonoscopy use and in the percentages of adults up-to-date with CRC screening occurred overall and for most population subgroups. Subgroups with consistently lower rates of colonoscopy use and being up-to-date included Hispanics; people with minimal education, low income, or no health insurance; recent immigrants; and those with no usual source of care or physician visits in the past year. Among up to-date adults, there were few subgroup differences in the type of test by which they were up-to-date (i.e., FOBT, sigmoidoscopy, or colonoscopy). CONCLUSIONS: Although use of CRC screening and colonoscopy increased among U.S. adults, including those from vulnerable populations, 45% of adults aged 50 to 75-or nearly 35 million people-were not up-to-date with screening in 2008. IMPACT: Continued monitoring of CRC screening rates among population subgroups with consistently low utilization is imperative. Improvement in CRC screening rates among all population groups in the United States is still needed. PMID- 21653644 TI - Risk of primary non-breast cancer after female breast cancer by age at diagnosis. AB - BACKGROUND: Women diagnosed with breast cancer at young age have been shown to be at higher risk of developing a new primary cancer than women diagnosed at older ages, but little is known about whether adjustment for calendar year of breast cancer diagnosis, length of follow-up, and/or breast cancer treatment alters the risk pattern by age. METHODS: We identified 304,703 women diagnosed with breast cancer during 1943 to 2006 in the Cancer Registries of Denmark, Norway, and Finland. Relative risks (RR) of subsequent non-breast cancer by age at cancer diagnosis were calculated using Poisson regression models adjusted for country, calendar period, length of follow-up, and treatment. Excess absolute risks (EAR) were also calculated. RESULTS: The RR for all cancer sites except breast cancer decreased with increasing age both with and without adjustments. The RR and the EAR differed for each age at diagnosis category until the women reached their late 70s. Many specific cancer forms contributed to the overall risk pattern by age with endometrial cancer as 1 exception. CONCLUSIONS: The age at breast cancer diagnosis is an essential risk factor for being diagnosed with a new primary non breast cancer and the level of risk for specific ages at diagnosis may hold for many years after the diagnosis. Occurrence of endometrial cancer after breast cancer seems to follow a distinct age pattern different from that seen for most other cancer types. IMPACT: Future studies should aim at exploring the underlying explanations for the age-related findings. PMID- 21653642 TI - EGFR signals downregulate tumor suppressors miR-143 and miR-145 in Western diet promoted murine colon cancer: role of G1 regulators. AB - Epidermal growth factor receptors (EGFR) contribute to colonic tumorigenesis in experimental models of colon cancer. We previously showed that EGFR was also required for colonic tumor promotion by Western diet. The goal of this study was to identify EGFR-regulated microRNAs that contribute to diet-promoted colonic tumorigenesis. Murine colonic tumors from Egfr(wt) and hypomorphic Egfr(wa2) mice were screened using micro RNA (miRNA) arrays and miR-143 and miR-145 changes confirmed by Northern, real-time PCR, and in situ analysis. Rodent and human sporadic and ulcerative colitis (UC)-associated colon cancers were examined for miR-143 and miR-145. Effects of EGFR on miR-143 and miR-145 expression were assessed in murine and human colonic cells and their putative targets examined in vitro and in vivo. miR-143 and miR-145 were readily detected in normal colonocytes and comparable in Egfr(wt) and Egfr(wa2) mice. These miRNAs were downregulated in azoxymethane and inflammation-associated colonic tumors from Egfr(wt) mice but upregulated in Egfr(wa2) tumors. They were also reduced in human sporadic and UC colon cancers. EGFR signals suppressed miR-143 and miR-145 in human and murine colonic cells. Transfected miR-143 and miR-145 inhibited HCT116 cell growth in vitro and in vivo and downregulated G(1) regulators, K-Ras, MYC, CCND2, cdk6, and E2F3, putative or established targets of these miRNAs. miRNA targets Ras and MYC were increased in colonic tumors from Egfr(wt) but not Egfr(wa2) mice fed a Western diet. EGFR suppresses miR-143 and miR-145 in murine models of colon cancer. Furthermore, Western diet unmasks the tumor suppressor roles of these EGFR-regulated miRNAs. PMID- 21653645 TI - Do community health worker interventions improve rates of screening mammography in the United States? A systematic review. AB - BACKGROUND: Community health workers (CHW) are lay individuals who are trained to serve as liaisons between members of their communities and health care providers and services. METHODS: A systematic review was conducted to synthesize evidence from all prospective controlled studies on effectiveness of CHW programs in improving screening mammography rates. Studies reported in English and conducted in the United States were included if they: (i) evaluated a CHW intervention designed to increase screening mammography rates in women 40 years of age or older without a history of breast cancer; (ii) were a randomized controlled trial (RCT), case-controlled study, or quasi-experimental study; and (iii) evaluated a CHW intervention outside of a hospital setting. RESULTS: Participation in a CHW intervention was associated with a statistically significant increase in receipt of screening mammography [risk ratio (RR): 1.06 (favoring intervention); 95% CI: 1.02-1.11, P = 0.003]. The effect remained when pooled data from only RCTs were included in meta-analysis (RR: 1.07; 95% CI: 1.03-1.12, P = 0.0005) but was not present using pooled data from only quasi-experimental studies (RR: 1.03; 95% CI: 0.89-1.18, P = 0.71). In RCTs, participants recruited from medical settings (RR: 1.41; 95% CI: 1.09-1.82, P = 0.008), programs conducted in urban settings (RR: 1.23; 95% CI: 1.09, 1.39, P = 0.001), and programs where CHWs were matched to intervention participants on race or ethnicity (RR: 1.58, 95% CI: 1.29-1.93, P = 0.0001) showed stronger effects on increasing mammography screening rates. CONCLUSIONS: CHW interventions are effective for increasing screening mammography in certain settings and populations. IMPACT: CHW interventions are especially associated with improvements in rate of screening mammography in medical settings, urban settings, and in participants who are racially or ethnically concordant with the CHW. PMID- 21653646 TI - Genetically lowered microsomal epoxide hydrolase activity and tobacco-related cancer in 47,000 individuals. AB - BACKGROUND: Two functional polymorphisms of the microsomal epoxide hydrolase (mEH) gene (EPHX1), Tyr113His (rs1051740) and His139Arg (rs2234922), have variably been found to influence susceptibility to various cancer forms. We tested whether genetically lowered mEH activity affects risk of developing cancer in the general population. METHODS: We genotyped 47,089 individuals from the Danish general population for the Tyr113His and His139Arg polymorphisms in the EPHX1 gene and divided them into groups with predicted fast, intermediate, and slow mEH activity. Using Cox proportional hazards models, we calculated HRs for 26 individual cancer diagnoses and for groups of any cancer, tobacco-related cancers, estrogen-related female cancers, and other cancers. RESULTS: Of the 47,089 individuals, 7,590 experienced a cancer event, and of these, 1,466 were tobacco-related. After multifactorial adjustment, the HRs (95% CI) for tobacco related cancer were 1.1 (0.8-1.5) and 1.5 (1.1-2.0) in individuals with intermediate and slow mEH activity versus individuals with the fast phenotype (P(trend) = 0.003). The corresponding HRs among ever-smokers were 1.1 (0.8-1.5) and 1.5 (1.1-2.0; P(trend) = 0.003), whereas HRs among never-smokers did not differ from 1.0. CONCLUSIONS: Our results indicate that genetically lowered mEH activity is associated with increased risk of developing tobacco-related cancer among smokers in the general population; however, additional studies are needed to confirm our findings. IMPACT: To our knowledge, this is the largest study to investigate the association of mEH phenotype and genotype with tobacco-related cancers combined in the general population. PMID- 21653648 TI - Some Jewish thoughts on genetic enhancement. AB - The issues of the ethics of germ line modification in general and of enhancement by germ line modification in particular have been the subject of hundreds of articles in the bioethical literature. Both because the techniques are far from perfected and because the potential long term side effects are unkown, there is a widespread consensus that germ line modification for enhancement is absolutely unethical and beyond the pale at the present time. The author considers a thought expperiment projecting into the future in which perhaps the safety and reversibility of germ line modification have been clearly demonstrated. Under such circumstances it is contended that the dividing line between treatment and enhancement is difficult and indeed perhaps impossible to maintain. The Jewish tradition is examined and from the various sources cited it would seem that the benefits of certain kinds of genetic enhancements might well outweigh the objections to such manipulations. PMID- 21653647 TI - Profound deficit of IL10 at birth in children who develop childhood acute lymphoblastic leukemia. AB - BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) may originate via abnormal immune responses to infectious agents. It is unknown whether prenatal immune development may differ in children who develop the disease. The current study examines the association between neonatal cytokine profiles, a proxy measure for a child's prenatal immune development, and childhood ALL. METHODS: Neonatal blood spots of 116 childhood ALL cases and 116 controls living in California were ascertained. Eleven cytokines associated with Th1, Th2, and Th17 lymphocytes were measured using a multiplex bead-based assay. Unconditional logistic regression was done to estimate the odds ratio (OR) by measuring the association between neonatal cytokines and ALL adjusted for age, sex, race/ethnicity, and household income. RESULTS: Of the 11 cytokines measured, 5 [interleukin (IL)4, IL6, IL10, IL12, and IL13] were detectable. Except for IL12, the other 4 cytokines were all significantly lower among cases than controls. In a multivariable model including the 5 cytokines, only IL10 remained independently associated with childhood ALL with an OR = 0.04, 95% CI: 0.01 to 0.18, comparing the highest tertile to the lowest tertile. CONCLUSIONS: A child's neonatal level of IL10, a key regulator for modulating the intensity and duration of immune responses, is associated with his/her subsequent risk of developing ALL. IMPACT: The current analysis shows that children with ALL may have a dysregulated immune function present at birth. PMID- 21653649 TI - Are there adverse consequences of quizzing during informed consent for HIV research? AB - INTRODUCTION: While quizzing during informed consent for research to ensure understanding has become commonplace, it is unclear whether the quizzing itself is problematic for potential participants. In this study, we address this issue in a multinational HIV prevention research trial enrolling injection drug users in China and Thailand. METHODS: Enrolment procedures included an informed consent comprehension quiz. An informed consent survey followed. RESULTS: 525 participants completed the informed consent survey (Heng County, China1/4255, Xinjiang, China1/4229, Chiang Mai, Thailand1/441). Mean age was 33 and mean educational level was 8 yrs. While quizzing was felt to be a good way to determine if a person understands the nature of clinical trial participation (97%) and participants did not generally find the quiz to be problematic, minorities of respondents felt pressured (6%); anxious (5%); bored (5%); minded (5%); and did not find the questions easy (13%). In multivariate analysis, lower educational level was associated with not minding the quizzing (6e10 yrs vs 0e5 yrs: OR1/40.27, p1/40.03; more than 11 yrs vs 0e5 yrs: OR1/40.18, p1/40.03). There were also site differences (Heng County vs Xinjiang) in feeling anxious (OR1/40.07; p1/4<0.01), not minding (OR1/40.26; p1/40.03), being bored (OR1/40.25; p1/40.01) and not finding the questions easy (OR1/40.10; p1/4<0.01). CONCLUSIONS: Quizzing during the informed consent process can be problematic for a minority of participants. These problems may be associated with the setting in which research takes place and educational level. Further research is needed to develop, test and implement alternative methods of ensuring comprehension of informed consent. TRIAL REGISTRATION: clinicaltrials.gov number NCT00270257. PMID- 21653650 TI - The 6-PACK programme to decrease fall-related injuries in acute hospitals: protocol for a cluster randomised controlled trial. AB - BACKGROUND AND AIMS: In-hospital fall-related injuries are a source of personal harm, preventable hospitalisation costs, and access block through increased length of stay. Despite increased fall prevention awareness and activity over the last decade, rates of reported fall-related fractures in hospitals appear not to have decreased. This cluster randomised controlled trial (RCT) aims to determine the efficacy of the 6-PACK programme for preventing fall-related injuries, and its generalisability to other acute hospitals. METHODS: 24 acute medical and surgical wards from six to eight hospitals throughout Australia will be recruited for the study. Wards will be matched by type and fall-related injury rates, then randomly allocated to the 6-PACK intervention (12 wards) or usual care control group (12 wards). The 6-PACK programme includes a nine-item fall risk assessment and six nursing interventions: 'falls alert' sign; supervision of patients in the bathroom; ensuring patient's walking aids are within reach; establishment of a toileting regime; use of a low-low bed; and use of bed/chair alarm. Intervention wards will be supported by a structured implementation strategy. The primary outcomes are fall and fall-related injury rates 12 months following 6-PACK implementation. DISCUSSION: This study will involve approximately 16,000 patients, and as such is planned to be the largest hospital fall prevention RCT to be undertaken and the first to be powered for the important outcome of fall related injuries. If effective, there is potential to implement the programme widely as part of daily patient care in acute hospital wards where fall-related injuries are a problem. PMID- 21653651 TI - The Bicyclists' Injuries and the Cycling Environment study: a protocol to tackle methodological issues facing studies of bicycling safety. AB - BACKGROUND AND AIMS: Bicycling may be less appealing in parts of the world where cycling is less safe. Differences between jurisdictions suggest route design is key to improving safety and increasing ridership. Previous studies faced difficulties in effectively assessing denominators for risk calculations and controlling confounding. This paper describes the advantages of the case crossover design of the Bicyclists' Injuries and the Cycling Environment study to address these challenges to observational studies of cycling safety. METHODS: Injured cyclists were recruited from the emergency departments of five hospitals in Vancouver and Toronto, Canada. In 18 months, 690 participants were successfully recruited and interviewed. Each participant was interviewed to map the route of their injury trip, identify the injury site and select two control sites at random from the same route. Infrastructural characteristics at each study site were scored by site observers who were blinded as to whether sites were crash or comparison sites. Analyses will compare infrastructural variables between case and control sites with conditional logistic regression. DISCUSSION: This study presents a novel application of the case-crossover design to the evaluation of relationships between infrastructure and cycling safety while controlling confounders and exposure to risk. It is hoped that the value of this method and the efficiency of the recruitment process will encourage replication in other locations, to expand the range of cycling infrastructure compared and to facilitate evidence-based cycling infrastructure choices that can make cycling safer and more appealing. PMID- 21653652 TI - Statistical modelling of falls count data with excess zeros. AB - OBJECTIVE: To examine the appropriateness of different statistical models in analysing falls count data. METHODS: Six count models (Poisson, negative binomial (NB), zero-inflated Poisson (ZIP), zero-inflated NB (ZINB), hurdle Poisson (HP) and hurdle NB (HNB)) were used to analyse falls count data. Empirical evaluation of the competing models was performed using model selection criteria and goodness of-fit through simulation. Data used were from a prospective cohort study of women aged 40-80 years. RESULTS: Of the 465 women analysed, 330 (71%) did not fall at all. The analyses identified strong evidence of overdispersion in the falls data. The NB-based regression models (HNB, ZINB, NB) were better performed than the Poisson-based regression models (Poisson, ZIP, HP). Vuong tests favoured the HNB model over the NB and ZINB models and the NB model over the ZINB model. Model accuracy measures and Monte Carlo simulation of goodness-of-fit confirmed the lack of fit of the Poisson-based regression models and demonstrated the best fit for the HNB model with comparable good fit for the ZINB and NB models. CONCLUSIONS: Falls count data consisting of a considerable number of zeros can be appropriately modelled by the NB-based regression models, with the HNB model offering the best fit. The evaluation procedure presented in this paper provides a defensible guideline to appropriately model falls or similar count data with excess zeros. PMID- 21653653 TI - Economics of tobacco control in Pakistan: estimating elasticities of cigarette demand. AB - BACKGROUND: Despite ongoing global efforts for tobacco control, low-income countries with struggling economies have challenges to effectively implement tobacco policies and programs. Due to the complexity of the tobacco control issue and lack of comprehensive policies, tobacco use is increasing in Pakistan. OBJECTIVE: The aim of this study was to assess the effect of taxes on tobacco demand in Pakistan. METHODS: Various surveillance indicators of tobacco use were assessed from 2001 to 2009. Price elasticities of cigarette demand in Pakistan were investigated. RESULTS: During 2003-2009, annual per capita cigarette consumption increased by 30%. Analysis of economic data indicated that a 10% increase in cigarette prices would lead to 4.8% decrease in cigarette consumption while controlling for per capita income in the short term. The long-term price elasticities of cigarette demand were estimated at -1.17. The estimations provided support for myopic addiction model for cigarette consumption in Pakistan. CONCLUSIONS: Increasing tobacco taxes would have a significant impact on tobacco consumption in Pakistan. Cigarette consumption could decrease by 11.7% in the long term if there was a 10% increase in its price. The results of this study should benefit policymakers as it provides information on the characteristics of the cigarette consumption and cigarette demand function that may help in planning tobacco control strategies in low-income and middle-income countries. PMID- 21653654 TI - Alpha-internexin expression in gliomas: relationship with histological type and 1p, 19q, 10p and 10q status. AB - BACKGROUND: The alpha-internexin (INA) gene encodes an intermediate filament involved in neurogenesis and maps in 10q24.33. A strong INA protein expression has been reported in oligodendroglial tumours and was associated with 1p19q deletion. To assess the relevance of INA immunohistochemistry in glioma typing, this paper studied the relationship between INA expression, histological type, genomic status and patient outcome. METHODS: The study analysed INA, nestin, Olig2 and p53 expression, loss of heterozygosity of microsatellite markers from telomere to centromere of 10p, 10q, 1p and 19q chromosomes and epidermal growth factor receptor gene (EGFR) amplification in 40 gliomas (five astrocytomas, 12 oligodendrogliomas, 11 oligoastrocytomas, 12 glioblastomas). INA expression was scored as absent, weak (<10% of labelled tumour cells) or strong (>10%). RESULTS: Oligodendrogliomas showed strong INA and Olig2 expression, and 1p19q whole loss of heterozygosity (wLOH). Astrocytomas and glioblastomas were characterised by no or weak INA expression, high p53 and nestin expression, 10p10q wLOH, and epidermal growth factor receptor amplification. Most oligoastrocytomas had characteristics of astrocytic tumours. All tumours with strong INA expression retained the 10q chromosome arm and, except for one, had a 1p19q wLOH status. However, despite a strong link between INA expression, 1p19q wLOH and 10q retention, discrepancies were observed in 10% of cases. The presence of INA expression, whether weak or strong, was related to a better prognosis. CONCLUSION: INA expression study can be helpful for glioma typing and prognosis determination in combination with other markers. Nevertheless, INA immunohistochemistry cannot replace the genomic analysis to determine 1p19q and 10p10q status. PMID- 21653655 TI - Practical considerations in the detection of HER2 status: the pathological perspective. PMID- 21653656 TI - Ezrin expression predicts local recurrence and development of metastases in soft tissue sarcomas. AB - BACKGROUND: Ezrin is a cytoskeletal protein involved in tumour growth and invasion. Ezrin expression has been suggested to play a role in metastasis in paediatric osteosarcoma and rhabdomyosarcoma. AIM: To evaluate the prognostic role of ezrin in a large series of soft tissue sarcoma of the extremities and trunk wall. METHODS: Ezrin expression was evaluated by immunohistochemistry on tissue microarrays from a mixed series of 256 soft tissue sarcomas. The expression patterns were correlated to local recurrence and metastasis as well as to established prognostic factors in soft tissue sarcoma. RESULTS: Increased ezrin expression predicted development of metastasis (HR=1.8, 95% CI 1.1 to 2.8; p=0.007) and local recurrence, also after adjustment for surgical margin (HR=2.4, 95% CI 1.4 to 4.3; p=0.02). Correlations to established prognostic factors showed strong associations between ezrin and necrosis (OR=3.9, p<0.0001) and ezrin and growth pattern (OR=3.1, p=0.03). CONCLUSIONS: Ezrin independently predicts development of local recurrences and metastases in soft tissue sarcomas. The possibility of preoperative evaluation makes ezrin a potential marker for identification of high-risk sarcoma patients who would benefit from neoadjuvant therapy. PMID- 21653657 TI - Sporadic Burkitt lymphoma in southern China: 12 years' experience in a single institution in Guangzhou. AB - AIM: To analyse the clinicopathological features of sporadic Burkitt lymphoma (sBL). METHODS: In a review of 1682 cases of non-Hodgkin lymphoma diagnosed in the First Affiliated Hospital and Zhongshan School of Medicine, from 1998 to 2010, 20 cases (1.2%) of sBL were identified. Histopathological examination, immunohistochemistry and in situ hybridisation were used to analyse the clinicopathological features of these cases. RESULTS: Of the 20 cases of sBL, 18 patients were male and two were female. The mean age was 18 years (range 2-67 years). Extranodal presentation was more common than nodal presentation (55% vs 15%). Histopathologically, 18 cases (90%) showed monotonous medium-sized tumour cells, and two cases showed cells that were slightly pleomorphic in nuclear size and shape. Immunophenotypically, MUM1 was positive in three of 17 cases (17.6%). EBER expression was shown in five of 17 cases (29.4%), and all EBER-positive sBLs were Bcl-6+/MUM1-. CONCLUSION: sBL is rare and mainly affects male children, with predominantly extranodal presentation. MUM1 expression was found in some sBLs. EBER expression was found in 29.4% of sBLs from southern China, an area with a well-known high incidence of nasopharyngeal carcinoma, which is closely associated with Epstein-Barr virus infection. PMID- 21653658 TI - mTOR-RAPTOR and 14-3-3sigma immunohistochemical expression in high grade prostatic intraepithelial neoplasia and prostatic adenocarcinomas: a tissue microarray study. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase which associates with regulatory-associated protein of TOR (RAPTOR), forming the mTORC1 complex, which is necessary for activation of the mTOR pathway. 14-3-3sigma belongs to a family of proteins known to regulate the mTOR-RAPTOR interaction and signalling of this cascade. The mTOR pathway is a key regulator of protein synthesis and growth and is up-regulated in many cancers. The correlation of mTOR, RAPTOR and 14-3-3sigma in high grade prostatic intraepithelial neoplasia (HGPIN) and prostate cancer has not previously been investigated. AIMS: To examine the immunohistochemical expression of phosphorylated mTOR (p-mTOR), RAPTOR and 14-3-3sigma in HGPIN and prostatic adenocarcinoma (PCa) using tissue microarrays. METHODS AND RESULTS: There were contrasting immunohistochemical patterns of expression for mTOR and 14-3-3sigma in HGPIN and PCa. Cochran-Armitage analysis demonstrated decreasing p-mTOR and increasing 14-3-3sigma expression, progressing from PIN through GL6 and GL7 to high grade PCa. In cores with coexistent staining for 14-3-3sigma and p-mTOR, the expression of each marker was restricted to different geographical areas of an individual core. CONCLUSION: The inverse correlation of p-mTOR and 14-3-3sigma expression supports the role of 14-3-3sigma as an inhibitor of p-mTOR activity in the prostate. The extent of 14-3-3sigma and mTOR expression in an individual patient with prostate cancer would determine how effective the use of mTOR inhibitors would be as potential therapeutic agents. PMID- 21653659 TI - Lymphoid aggregates may contribute to the migration and epithelial commitment of bone marrow-derived cells in colonic mucosa. AB - AIMS: Colonic inflammation is followed by regeneration supported by bone marrow derived cells (BMDCs) including multipotent cells. They migrate to the colonic epithelial layer and may transdifferentiate into epithelial-like cells or keep their stem cell characteristics and produce progenies. The aim was to study the role of lymphoid aggregates in the migration and transition of BMDCs in both healthy colons and non-specific colitis (NSC). METHODS: Samples of normal colon (n=5) and NSC (n=5) from female patients who were initially transplanted with male bone marrow were studied. After detecting XY chromosomes using fluorescent in situ hybridisation, tissue sections were digitalised, the coverslips were eliminated and the samples were double stained for CD45 and cytokeratin with immunofluorescence. Then CDX2 expression, as a sign of intestinal epithelial commitment of Musashi-1+ stromal BMDCs, was also tested with both immunoperoxidase and parallel immunofluorescence stainings. The slides were digitalised again and analysed simultaneously. RESULTS: A significant increase in intraepithelial CD45-BMDCs was found in regions adjacent to lymphoid aggregates (median: 1.01) compared with healthy epithelial regions (median: 0.0175) or NSC (median: 0.04) samples. The stromal Musashi-1+ cells were positive for CDX2 as well, as a sign of epithelial differentiation. The CDX2+ cells bearing the Y chromosome proved the epithelial commitment of several stromal BMDCs. CONCLUSION: Elevated number of intraepithelial CD45-BMDCs at lymphoid aggregates suggests that BMDCs play a role in epithelial regeneration and that lymphoid aggregates serve as their migration route. PMID- 21653660 TI - Acupuncture for hot flushes in perimenopausal and postmenopausal women: a randomised, sham-controlled trial. AB - OBJECTIVES: To determine the effect of acupuncture in treating hot flushes in perimenopausal or postmenopausal women. METHODS: The study was a randomised single-blind sham-controlled clinical trial. Perimenopausal or postmenopausal women with moderate or severe hot flushes were randomised to receive real or sham acupuncture. Both groups underwent a 4-week run-in period before the treatment. The real acupuncture group received 11 acupuncture treatments for 7 weeks, and the control group underwent sham acupuncture on non-acupuncture points during the same period. Both groups were followed for 8 weeks after the end of treatment period. Changes from baseline in the hot flush scores at week 7, measured by multiplying the hot flush frequency and severity, were the primary outcome. Hot flush frequency, severity and menopause-related symptoms measured with the Menopause Rating Scale Questionnaire were regarded as secondary outcomes. RESULTS: 54 participants were randomised into the real acupuncture group (n=27) and the sham acupuncture group (n=27). The mean change in hot flush scores was 6.4+/-5.2 in the real acupuncture group and -5.6+/-9.2 in the sham group at week 7 from values at the start of the acupuncture treatment (10.0+/-8.1 vs 11.7+/ 12.6), respectively (p=0.0810). No serious adverse events were observed during the whole study period. CONCLUSIONS: Compared to sham acupuncture, acupuncture failed to show significantly different effects on the hot flush scores but showed partial benefits on the hot flush severity. Further consideration is needed to develop appropriate strategies for distinguishing non-specific effects from observed overall effectiveness of acupuncture for hot flushes. Whether acupuncture has point-specific effects for hot flushes should be also considered in designing future researches. PMID- 21653661 TI - Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry. AB - The analysis of HIV-1 envelope carbohydrates is critical to understanding their roles in HIV-1 transmission as well as in binding of envelope to HIV-1 antibodies. However, direct analysis of protein glycosylation by glycopeptide based mass mapping approaches involves structural simplification of proteins with the use of a protease followed by an isolation and/or enrichment step before mass analysis. The successful completion of glycosylation analysis is still a major analytical challenge due to the complexity of samples, wide dynamic range of glycopeptide concentrations, and glycosylation heterogeneity. Here, we use a novel experimental workflow that includes an up-front complete or partial enzymatic deglycosylation step before trypsin digestion to characterize the glycosylation patterns and maximize the glycosylation coverage of two recombinant HIV-1 transmitted/founder envelope oligomers derived from clade B and C viruses isolated from acute infection and expressed in 293T cells. Our results show that both transmitted/founder Envs had similar degrees of glycosylation site occupancy as well as similar glycan profiles. Compared to 293T-derived recombinant Envs from viruses isolated from chronic HIV-1, transmitted/founder Envs displayed marked differences in their glycosylation site occupancies and in their amounts of complex glycans. Our analysis reveals that the glycosylation patterns of transmitted/founder Envs from two different clades (B and C) are more similar to each other than they are to the glycosylation patterns of chronic HIV-1 Envs derived from their own clades. PMID- 21653662 TI - Infection of primary neurons mediated by nipah virus envelope proteins: role of host target cells in antiviral action. AB - We have previously described heterotypic peptides from parainfluenza virus that potently inhibit Nipah virus in vitro but are not efficacious in vivo. In contrast, our second-generation inhibitors, featuring a cholesterol moiety, are also efficacious in vivo. The difference between in vitro and in vivo results led us to investigate the basis for this discrepancy. Here, we compare the activities of the compounds in standard laboratory cells and in cells relevant to the natural tropism of Nipah virus, i.e., primary neurons, and show that while our first-generation inhibitors are poorly active in primary neurons, the cholesterol conjugated compounds are highly potent. These results highlight the advantage of evaluating antiviral potency in cells relevant to natural host target tissue. PMID- 21653663 TI - Inhibitory effect of a nucleotide analog on infectious salmon anemia virus infection. AB - The infectious salmon anemia virus (ISAV), which belongs to the Orthomyxoviridae family, has been responsible for major losses in the salmon industry, with mortalities close to 100% in areas where Atlantic salmon (Salmo salar) is grown. This work studied the effect of ribavirin (1-beta-d-ribofuranosyl-1,2,3-triazole 3-carbaxaide), a broad-spectrum antiviral compound with proven ability to inhibit the replicative cycle of the DNA and RNA viruses. The results show that ribavirin was able to inhibit the infectivity of ISAV in in vitro assays. In these assays, a significant inhibition of the replicative viral cycle was observed with a 50% inhibitory concentration (IC50) of 0.02 MUg/ml and an IC90 of 0.4 MUg/ml of ribavirin. After ribavirin treatment, viral proteins were not detectable and a reduction of viral mRNA association with ribosomes was observed. Ribavirin does not affect the levels of EF1a, nor its association with polysomes, suggesting that the inhibition of RNA synthesis occurs specifically for the virus mRNAs and not for cellular mRNAs. Moreover, ribavirin caused a significant reduction in genomic and viral RNA messenger levels. The study of the inhibitory mechanism showed that it was not reversed by the addition of guanosine. Furthermore, in vivo assays showed a reduction in the mortality of Salmo salar by more than 90% in fish infected with ISAV and treated with ribavirin without adverse effects. In fact, these results show that ribavirin is an antiviral that could be used to prevent ISAV replication either in vitro or in vivo. PMID- 21653664 TI - Evolution of human immunodeficiency virus type 1 in a patient with cross-reactive neutralizing activity in serum. AB - Analysis of longitudinally obtained HIV-1 env sequences from an individual with reported cross-reactive neutralizing activity revealed that the majority of viral variants obtained from serum between 4 and 7 years after seroconversion were unable to persist in peripheral blood. Here we show that these viral variants were more sensitive to autologous serum neutralization, had shorter envelopes with fewer potential N-linked glycosylation sites, and showed lower replication kinetics than successfully evolving HIV-1 variants. These data reflect the host selection pressures on phenotypic characteristics of HIV-1 and illustrate in detail the dynamic interaction between HIV-1 and its host's humoral immune responses. PMID- 21653665 TI - Crystal structure of Zebrafish interferons I and II reveals conservation of type I interferon structure in vertebrates. AB - Interferons (IFNs) play a major role in orchestrating the innate immune response toward viruses in vertebrates, and their defining characteristic is their ability to induce an antiviral state in responsive cells. Interferons have been reported in a multitude of species, from bony fish to mammals. However, our current knowledge about the molecular function of fish IFNs as well as their evolutionary relationship to tetrapod IFNs is limited. Here we establish the three-dimensional (3D) structure of zebrafish IFNphi1 and IFNphi2 by crystallography. These high resolution structures offer the first structural insight into fish cytokines. Tetrapods possess two types of IFNs that play an immediate antiviral role: type I IFNs (e.g., alpha interferon [IFN-alpha] and beta interferon [IFN-beta]) and type III IFNs (lambda interferon [IFN-lambda]), and each type is characterized by its specific receptor usage. Similarly, two groups of antiviral IFNs with distinct receptors exist in fish, including zebrafish. IFNphi1 and IFNphi2 represent group I and group II IFNs, respectively. Nevertheless, both structures reported here reveal a characteristic type I IFN architecture with a straight F helix, as opposed to the remaining class II cytokines, including IFN-lambda, where helix F contains a characteristic bend. Phylogenetic trees derived from structure-guided multiple alignments confirmed that both groups of fish IFNs are evolutionarily closer to type I than to type III tetrapod IFNs. Thus, these fish IFNs belong to the type I IFN family. Our results also imply that a dual antiviral IFN system has arisen twice during vertebrate evolution. PMID- 21653666 TI - Polymorphism in human APOBEC3H affects a phenotype dominant for subcellular localization and antiviral activity. AB - The APOBEC3 family of cytidine deaminases is part of the innate host defense targeted toward retroviruses and retroelements. APOBEC3H is the most distantly related member of the family and carries functional polymorphisms in current human populations. Haplotype II of APOBEC3H, which is more commonly found in individuals of African descent, encodes a protein with the highest antiviral activity in cells, whereas the other haplotypes encode proteins with weak or no antiviral activity. Here, we show that the different human APOBEC3H haplotypes exhibit differential subcellular localizations, as the haplotype I protein is mostly found in the nucleus and the haplotype II protein is mostly localized to the cytoplasm. The determinant responsible for this phenotype maps to a single amino acid that is also important for APOBEC3H protein stability. Furthermore, we show that the cytoplasmic localization is dominant over nuclear localization, by using fusion proteins of APOBEC3H. Our data support a model in which the APOBEC3H protein encoded by haplotype II is actively retained in the cytoplasm by interacting with specific host factors, whereas the less active protein encoded by haplotype I is allowed to enter the nucleus by a passive mechanism. Together, cytoplasmic localization and its link with protein stability correlate with the ability of APOBEC3H to inhibit HIV replication, providing a mechanistic basis for the differential antiviral activities of different APOBEC3H haplotypes. PMID- 21653667 TI - Nonvirion protein of novirhabdovirus suppresses apoptosis at the early stage of virus infection. AB - Viral hemorrhagic septicemia virus (VHSV) and infectious hematopoietic necrosis virus (IHNV) are members of the genus Novirhabdovirus within the Rhabdoviridae family, which can cause severe hemorrhagic disease in fresh- and saltwater fish worldwide. These viruses carry an additional nonvirion (NV) gene, which codes for the nonstructural NV protein that has been implicated to play a role in viral pathogenesis. To determine the precise biological function of this NV gene and its gene product, we generated NV-deficient and NV knockout recombinant VHSVs, using reverse genetics. Comparisons of the replication kinetics and markers for virus-induced apoptosis indicated that the NV-deficient and NV knockout mutant viruses induce apoptosis earlier in cell culture than the wild-type recombinant VHSV. These results suggest that the NV protein has an antiapoptotic function at the early stage of virus infection. Furthermore, we created a chimeric VHSV, in which the NV gene of VHSV was replaced by the IHNV NV gene, which was capable of suppressing apoptosis in cell culture. These results show that the NV protein of other members of Novirhabdovirus can restore the NV protein function. In this study, we also investigated the kinetics of VHSV replication during a single round of viral replication and examined the mechanism of VHSV-induced apoptosis. Our results show that VHSV infection induced caspases 3, 8 and 9 in cell culture. PMID- 21653668 TI - Active depletion of host cell inhibitor-of-apoptosis proteins triggers apoptosis upon baculovirus DNA replication. AB - Apoptosis is an important antivirus defense by virtue of its impact on virus multiplication and pathogenesis. To define molecular mechanisms by which viruses are detected and the apoptotic response is initiated, we examined the antiviral role of host inhibitor-of-apoptosis (IAP) proteins in insect cells. We report here that the principal IAPs, DIAP1 and SfIAP, of the model insects Drosophila melanogaster and Spodoptera frugiperda, respectively, are rapidly depleted and thereby inactivated upon infection with the apoptosis-inducing baculovirus Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV). Virus-induced loss of these host IAPs triggered caspase activation and apoptotic death. Elevation of IAP levels by ectopic expression repressed caspase activation. Loss of host IAP in both species was triggered by AcMNPV DNA replication. By using selected inhibitors, we found that virus-induced IAP depletion was mediated in part by the proteasome but not by caspase cleavage. Consistent with this conclusion, mutagenic disruption of the SfIAP RING motif, which acts as an E3 ubiquitin ligase, stabilized SfIAP during infection. Importantly, SfIAP was also stabilized upon the removal of its 99-residue N-terminal leader, which serves as a critical determinant of IAP turnover. These data indicated that a host pathway initiated by virus DNA replication and acting through instability motifs embedded within IAP triggers IAP depletion and thereby causes apoptosis. Taken together, the results of our study suggest that host modulation of cellular IAP levels is a conserved mechanism by which insects mount an apoptotic antiviral response. Thus, host IAPs may function as critical sentinels of virus invasion in insects. PMID- 21653669 TI - Herpes simplex virus 1 glycoprotein B and US3 collaborate to inhibit CD1d antigen presentation and NKT cell function. AB - Herpes simplex viruses (HSVs) are prevalent human pathogens that establish latency in human neuronal cells and efficiently evade the immune system. It has been a major medical challenge to eradicate them and, despite intensive efforts, an effective vaccine is not available. We previously showed that upon infection of antigen-presenting cells, HSV type 1 (HSV-1) rapidly and efficiently downregulates the major histocompatibility complex class I-like antigen presenting molecule, CD1d, and potently inhibits its recognition by CD1d restricted natural killer T (NKT) cells. It suppresses CD1d expression primarily by inhibiting its recycling to the cell surface after endocytosis. We identify here the viral glycoprotein B (gB) as the predominant CD1d-interacting protein. gB initiates the interaction with CD1d in the endoplasmic reticulum and stably associates with it throughout CD1d trafficking. However, an additional HSV-1 component, the serine-threonine kinase US3, is required for optimal CD1d downregulation. US3 expression in infected cells leads to gB enrichment in the trans-Golgi network (TGN) and enhances the relocalization of both gB and CD1d to this compartment, suggesting that following internalization CD1d is translocated from the endocytic pathway to the TGN by its association with gB. Importantly, both US3 and gB are required for efficient inhibition of CD1d antigen presentation and NKT cell activation. In summary, our results suggest that HSV-1 uses gB and US3 to rapidly inhibit NKT cell function in the initial antiviral response. PMID- 21653670 TI - Retinoic acid as a vaccine adjuvant enhances CD8+ T cell response and mucosal protection from viral challenge. AB - Vaccine-induced memory T cells localized at mucosal sites can provide rapid protection from viral infection. All-trans-retinoic acid (ATRA) has been shown to act physiologically to induce the expression of gut-homing receptors on lymphocytes. We tested whether the administration of exogenous ATRA during a systemic vaccination of mice could enhance the generation of mucosal CD8(+) T cell immunity, which might represent a strategy for establishing better protection from viral infection via mucosal routes. ATRA induced the expression of CCR9 and alpha4beta7 on both mouse and human CD8(+) T cells activated in vitro. The administration of ATRA to mice during in vivo priming with a replication-defective recombinant adenovirus vector expressing the lymphocytic choriomeningitis virus glycoprotein (LCMVgp) (Ad5gp) increased numbers of both effector and memory T cells in intestinal mucosal tissues and showed higher frequencies of systemic central memory-like T cells that exhibited enhanced proliferation during boosting immunization with recombinant modified vaccinia virus Ankara expressing LCMVgp (MVAgp). Mice that received ATRA during Ad5gp vaccination were more resistant to intravaginal challenge by recombinant vaccinia virus expressing LCMVgp (VVgp), reflecting in part stronger T cell recall responses in situ. Thus, ATRA appears to be useful as an adjuvant during vaccination to increase memory T cell responses and protection from viral infection at mucosal sites and may facilitate the development of more effective vaccines against mucosally transmitted pathogens such as HIV. PMID- 21653671 TI - The HIV-1-specific protein Casp8p41 induces death of infected cells through Bax/Bak. AB - Casp8p41, a novel protein generated when HIV-1 protease cleaves caspase 8, independently causes NF-kappaB activation, proinflammatory cytokine production, and cell death. Here we investigate the mechanism by which Casp8p41 induces cell death. Immunogold staining and electron microscopy demonstrate that Casp8p41 localizes to mitochondria of activated primary CD4 T cells, suggesting mitochondrial involvement. Therefore, we assessed the dependency of Casp8p41 induced death on Bax/Bak and caspase 9. In wild-type (WT) mouse embryonic fibroblast (MEF) cells, Casp8p41 causes rapid mitochondrial depolarization (P < 0.001), yet Casp8p41 expression in Bax/Bak double-knockout (DKO) MEF cells does not. Similarly, caspase 9-deficient T cells (JMR cells), which express Casp8p41, undergo minimal cell death, whereas reconstituting these cells with caspase 9 (F9 cells) restores Casp8p41 cytotoxicity (P < 0.01). The infection of caspase 9 deficient cells with a green fluorescent protein (GFP) HIV-1 reporter virus results in cell death in 32% of infected GFP-positive cells, while the restoration of caspase 9 expression in these cells restores infected-cell killing to 68% (P < 0.05), with similar levels of viral replication between infections. Our data demonstrate that Casp8p41 requires Bax/Bak to induce mitochondrial depolarization, which leads to caspase 9 activation following either Casp8p41 expression or HIV-1 infection. This understanding allows the design of strategies to interrupt this form of death of HIV-1-infected cells. PMID- 21653672 TI - Influenza A virus N5 neuraminidase has an extended 150-cavity. AB - There are 9 serotypes of neuraminidase (NA) from influenza A virus (N1 to N9), which are classified into two groups based on primary sequences (groups 1 and 2). The structural hallmark of the two groups is the presence or absence of an extra 150-cavity (formed by the 150-loop) in the active site. Thus far, structures of NAs from 6 out of the 9 serotypes have been solved. Here, we solved the N5 structure, the last unknown structure group 1 serotype with a unique Asn147 residue in its 150-loop, demonstrating that it has an extended 150-cavity that closes upon inhibitor binding. PMID- 21653674 TI - Intrauterine thrombosis of the ductus venosus leading to neonatal demise. PMID- 21653673 TI - Direct antibody access to the HIV-1 membrane-proximal external region positively correlates with neutralization sensitivity. AB - On the prereceptor-engaged HIV-1 envelope glycoprotein (Env) spike, epitope access by the membrane-proximal external region (MPER)-directed broadly neutralizing antibodies 2F5 and 4E10 remains unresolved. Data on binding to cell surface Env and entry data using primary isolates suggest inaccessibility of the 2F5 and 4E10 epitopes on the viral spike prior to receptor engagement, but trimer gel shift analysis and slow kinetics of shedding induced by 2F5 and 4E10 indicate otherwise. Therefore, it remains unclear if the epitopes themselves are formed in their antibody-bound state (or at least sampled) prior to receptor/coreceptor engagement or if receptor interactions both expose and form the MPER epitopes, presumably in the putative prefusion transitional intermediate. Here, we performed antibody-virus "washout experiments" using both lab-adapted and a panel of clade B primary isolates to analyze MPER accessibility. The neutralization activity of 2F5 and 4E10 against lab-adapted viruses and sensitive and moderately resistant viruses was largely unaffected by relatively rapid antibody-virus washing, suggesting direct interaction with the "static" spike. However, for more neutralization-resistant viruses, the 2F5 and 4E10 antibodies could neutralize only under the "no antibody-virus wash" conditions, implying that the MPER epitopes were not accessible prior to receptor engagement. Accessibility in the washout conditions could be precisely predicted by the relative resistance to neutralization in a standard neutralization format. These data are consistent with a model in which the local MPER antibody epitope conformations may be sampled on the native spike but are occluded to antibody by local steric or distal quaternary constraints adopted by highly resistant HIV-1 isolates. PMID- 21653675 TI - Circulating endothelial progenitor cells in women with gestational alterations of glucose tolerance. AB - Endothelial progenitor cells (EPCs) play a role in angiogenesis during pregnancy. The aim of this study was to evaluate circulating EPCs in pregnant women with gestational alterations of glucose tolerance. Glucose tolerance, insulin sensitivity and beta-cell function were derived from oral glucose tolerance tests in 23 women with normal glucose tolerance (NGT), 18 with gestational impaired glucose tolerance (GIGT) and 24 with gestational diabetes mellitus (GDM). Circulating cells expressing CD34 in combination with CD133, kinase insert domain receptor (KDR) or both were quantified by flow cytometry. Women with GIGT and GDM had lower CD34(+)KDR(+) and CD34(+)CD133( +)KDR(+) cells at 27+/-3.2 weeks' gestation compared with NGT (ANOVA p<0.02 for both). CD34(+)KDR(+) and CD34(+)CD133(+)KDR(+) cells were inversely correlated with the area-under-the glucose-curve (p<0.005, for both) and positively to insulin secretion-sensitivity index (p<0.05, for both). Alterations of glucose tolerance during pregnancy are associated with a decrease in EPCs. Hyperglycaemia might exert a direct effect on depletion of EPCs. PMID- 21653676 TI - Cardiovascular safety of liraglutide assessed in a patient-level pooled analysis of phase 2: 3 liraglutide clinical development studies. AB - We assessed the cardiovascular safety of liraglutide, a glucagon-like peptide-1 receptor agonist, using existing clinical data. Patient-level results from all completed phase 2 and 3 studies from the liraglutide clinical development programme were pooled to determine rates of major adverse cardiovascular events (MACE): cardiovascular death, myocardial infarction, stroke. MACE were identified by querying the study database using Medical Dictionary for Regulatory Activities (MedDRA) terms combined with serious adverse events recorded by study investigators. Broad, narrow, and custom groups of MedDRA queries were used. Candidate events from each query were independently adjudicated post hoc. In 15 studies (6638 patients; 4257 liraglutide treated), there were 114 patients with MACE identified using the broad MedDRA query. Of these, 44 were classified as serious adverse events and 39 were adjudicated as MACE. The incidence ratio for adjudicated broad/serious MACE associated with liraglutide was 0.73 (95% CI 0.38 1.41) versus all comparator drugs (metformin, glimepiride, rosiglitazone, insulin glargine, placebo), within cardiovascular safety limits defined by the United States Food & Drug Administration for diabetes therapies under current investigation. PMID- 21653677 TI - Impaired microvascular properties in uncomplicated type 1 diabetes identified by Doppler ultrasound of the ocular circulation. AB - OBJECTIVE: Quantification of Doppler flow velocity waveforms has been shown to predict adverse cardiovascular outcomes and identify altered downstream haemodynamics and vascular damage in a number of organ beds. We employed novel techniques to quantify Doppler flow velocity waveforms from the retro bulbar circulation. METHODS AND RESULTS: In total, 39 patients with uncomplicated Type 1 diabetes mellitus, and no other significant cardiovascular risk factors were compared with 30 control subjects. Flow velocity waveforms were captured from the ophthalmic artery (OA), central retinal artery (CRA) and the common carotid artery. The flow velocity profiles were analysed in the time domain to calculate the resistive index (RI), and time-frequency domain using novel discrete wavelet transform methods for comparison. Analysis of flow waveforms from the OA and CRA identified specific frequency band differences between groups, occurring independently of potential haemodynamic or metabolic confounding influences. No changes were identified in the calculated RI from any arterial site. CONCLUSION: Novel analysis of the arterial flow velocity waveforms recorded from the retro bulbar circulation identified quantifiable differences in Doppler flow velocity waveform morphology in patients with diabetes prior to the development of overt retinopathy. The technique may be useful as an additional marker of cardiovascular risk. PMID- 21653678 TI - IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. AB - The switch of tumor cells from an epithelial to a mesenchymal-like phenotype [designated as epithelial-to-mesenchymal transition (EMT)] is known to induce tumor cell motility and invasiveness, therefore promoting metastasis of solid carcinomas. Although multiple studies have focused on elucidating the signaling events that initiate this phenotypic switch, there has been so far no characterization of the pattern of soluble mediators released by tumor cells undergoing EMT, and the potential impact that this phenotypic switch could have on the remodeling of the tumor microenvironment. Here we show that induction of EMT in human carcinoma cells via overexpression of the transcription factor Brachyury is associated with enhanced secretion of multiple cytokines, chemokines, and angiogenic factors and, in particular, with the induction of the IL-8/IL-8R axis. Our results also indicate the essential role of interleukin 8 (IL-8) signaling for the acquisition and/or maintenance of the mesenchymal and invasive features of Brachyury-overexpressing tumor cells and show that IL-8 secreted by tumor cells undergoing EMT could potentiate tumor progression by inducing adjacent epithelial tumor cells into EMT. Altogether, our results emphasize the potential role of EMT in the modulation of the tumor microenvironment via secretion of multiple soluble mediators and suggest that IL 8 signaling blockade may provide a means of targeting mesenchymal-like, invasive tumor cells. PMID- 21653679 TI - Interleukin-1alpha mediates the antiproliferative effects of 1,25 dihydroxyvitamin D3 in prostate progenitor/stem cells. AB - Vitamin D(3) is a promising preventative and therapeutic agent for prostate cancer, but its implementation is hampered by a lack of understanding about its mechanism of action. Upon treatment with 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3), vitamin D(3)], the metabolically active form of vitamin D(3), adult prostate progenitor/stem cells (PrP/SC) undergo cell-cycle arrest, senescence, and differentiation to an androgen receptor-positive luminal epithelial cell fate. Microarray analyses of control- and vitamin D(3)-treated PrP/SCs revealed global gene expression signatures consistent with induction of differentiation. Interestingly, one of the most highly upregulated genes by vitamin D(3) was the proinflammatory cytokine interleukin-1alpha (IL-1alpha). Systems biology analyses supported a central role for IL-1alpha in the vitamin D(3) response in PrP/SCs. siRNA-mediated knockdown of IL-1alpha abrogated vitamin D(3)-induced growth suppression, establishing a requirement for IL-1alpha in the antiproliferative effects of vitamin D(3) in PrP/SCs. These studies establish a system to study the molecular profile of PrP/SC differentiation, proliferation, and senescence, and they point to an important new role for IL-1alpha in vitamin D(3) signaling in PrP/SCs. PMID- 21653680 TI - Tumor microenvironment-derived proteins dominate the plasma proteome response during breast cancer induction and progression. AB - Tumor development relies upon essential contributions from the tumor microenvironment and host immune alterations. These contributions may inform the plasma proteome in a manner that could be exploited for cancer diagnosis and prognosis. In this study, we employed a systems biology approach to characterize the plasma proteome response in the inducible HER2/neu mouse model of breast cancer during tumor induction, progression, and regression. Mass spectrometry data derived from approximately 1.6 million spectra identified protein networks involved in wound healing, microenvironment, and metabolism that coordinately changed during tumor development. The observed alterations developed prior to cancer detection, increased progressively with tumor growth and reverted toward baseline with tumor regression. Gene expression and immunohistochemical analyses suggested that the cancer-associated plasma proteome was derived from transcriptional responses in the noncancerous host tissues as well as the developing tumor. The proteomic signature was distinct from a nonspecific response to inflammation. Overall, the developing tumor simultaneously engaged a number of innate physiologic processes, including wound repair, immune response, coagulation and complement cascades, tissue remodeling, and metabolic homeostasis that were all detectable in plasma. Our findings offer an integrated view of tumor development relevant to plasma-based strategies to detect and diagnose cancer. PMID- 21653681 TI - Could thyroid dysfunction influence outcome in sunitinib-treated metastatic renal cell carcinoma? AB - BACKGROUND: Sunitinib is a standard of care for metastatic renal cell carcinoma (mRCC). Hypothyroidism is frequently observed under sunitinib therapy. This study was conducted to prospectively determine the correlation between thyroid function and progression-free survival (PFS) in this population. PATIENTS AND METHODS: One hundred and eleven mRCC patients treated with sunitinib were evaluated for serum thyroid-stimulating hormone (TSH) and T4 levels before treatment and every 6 weeks during treatment. Survival was analysed according to a landmark method with a cut-off of 6 months, excluding early progressive or early-censored patients. RESULTS: Out of the 102 patients with normal baseline thyroid function, 53% developed thyroid dysfunction, including 95% hypothyroidisms out of which 90.9% received L-thyroxine replacement. Median time to TSH alteration was 5.4 months. Median PFS was 11.7 months for the entire population. Median PFS was not different between the groups with abnormal or normal thyroid function after 6 months of treatment (18.9 and 15.9 months, respectively, log-rank P = 0.94, hazard ratio = 1.02, 95% confidence interval = 0.54-1.93). There was no difference even after adjustment for Memorial Sloan-Kettering Cancer Centre classification and therapy line. CONCLUSIONS: Abnormal thyroid function with hormonal substitution did not increase survival in our population, independent of initial prognosis and previous treatments. Larger comparative studies are deserved to validate these conclusions. PMID- 21653682 TI - Dietary patterns and the risk of esophageal cancer. AB - BACKGROUND: The role of dietary habits on esophageal cancer risk has been rarely considered in terms of dietary patterns. PATIENTS AND METHODS: We analyzed data from an Italian case-control study, including 304 cases with squamous cell carcinoma of the esophagus and 743 hospital controls. Dietary habits were evaluated using a food frequency questionnaire. A posteriori dietary patterns were identified through principal component factor analysis performed on 28 selected nutrients. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained from multiple logistic regression models applied on quartiles of factor scores, adjusting for potential confounding variables. RESULTS: We identified five major dietary patterns, named 'animal products and related components', 'vitamins and fiber', 'starch-rich', 'other polyunsaturated fatty acids and vitamin D', and 'other fats'. The 'animal products and related components' pattern was positively related to esophageal cancer (OR = 1.64, 95% CI:1.06-2.55, for the highest versus the lowest quartile of factor scores category). The 'vitamins and fiber' (OR = 0.50, 95% CI: 0.32-0.78) and the 'other polyunsaturated fatty acids and vitamin D' (OR = 0.48, 95% CI: 0.31-0.74) were inversely related to esophageal cancer. No significant association was observed for the other patterns. CONCLUSION: Our findings suggest that a diet rich in foods from animal origin and poor in foods containing vitamins and fiber increase esophageal cancer risk. PMID- 21653683 TI - Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix. AB - BACKGROUND: Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). PATIENTS AND METHODS: A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. RESULTS: One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). CONCLUSIONS: Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology. PMID- 21653684 TI - Peloruside- and laulimalide-resistant human ovarian carcinoma cells have betaI tubulin mutations and altered expression of betaII- and betaIII-tubulin isotypes. AB - Peloruside A and laulimalide are potent microtubule-stabilizing natural products with a mechanism of action similar to that of paclitaxel. However, the binding site of peloruside A and laulimalide on tubulin remains poorly understood. Drug resistance in anticancer treatment is a serious problem. We developed peloruside A- and laulimalide-resistant cell lines by selecting 1A9 human ovarian carcinoma cells that were able to grow in the presence of one of these agents. The 1A9 laulimalide resistant cells (L4) were 39-fold resistant to the selecting agent and 39-fold cross-resistant to peloruside A, whereas the 1A9-peloruside A resistant cells (R1) were 6-fold resistant to the selecting agent while they remained sensitive to laulimalide. Neither cell line showed resistance to paclitaxel or other drugs that bind to the taxoid site on beta-tubulin nor was there resistance to microtubule-destabilizing drugs. The resistant cells exhibited impaired peloruside A/laulimalide-induced tubulin polymerization and impaired mitotic arrest. Tubulin mutations were found in the betaI-tubulin isotype, R306H or R306C for L4 and A296T for R1 cells. This is the first cell based evidence to support a beta-tubulin-binding site for peloruside A and laulimalide. To determine whether the different resistance phenotypes of the cells were attributable to any other tubulin alterations, the beta-tubulin isotype composition of the cells was examined. Increased expression of betaII- and betaIII-tubulin was observed in L4 cells only. These results provide insight into how alterations in tubulin lead to unique resistance profiles for two drugs, peloruside A and laulimalide, that have a similar mode of action. PMID- 21653685 TI - Enhanced antitumor effects by chemical modified IGb3 analogues. AB - Certain glycolipid antigens for natural killer T (NKT) cells can direct the overall cytokine balance of the immune response. However, the molecular mechanism of Th1- or Th2-biased cytokine secretion by NKT cells is still unknown. Previously, we synthesized isoglobotrihexosylceramide (iGb3) analogues by introducing a hydroxyl group at C4 on the ceramide portion of iGb3 to produce 4 HO-iGb3 or to further deoxylation on the terminal galactose to produce 4'''-dh iGb3. Both modified iGb3, especially 4'''-dh-iGb3, stimulated more IFN-gamma production by hepatic NKT cells, and thus elicited preferential Th1 responses. Here, we found that 4'''-dh-iGb3-loaded bone marrow-derived dendritic cells (DC) could significantly inhibit growth of subcutaneous melanoma and suppress lung metastasis in C57BL/6 mice compared with unmodified iGb3-loaded DCs. In investigating the mechanisms of this improved activity, we found that 4'''-dh iGb3 stimulation increased STAT1 signaling by NKT cells, whereas the phosphorylation of Th2 type cytokine-associated transcription factor STAT6 signaling was not affected. Analysis of the structures of iGb3 and 4'''-dh-iGb3 revealed that 4'''-dh-iGb3 provides greater stability and affinity between glycolipid and CD1d or NKT TCR complex than iGb3. Thus, 4'''-dh-iGb3 can improve the antitumor effects of a DC-based vaccine possibly by stabilizing the CD1d/glycolipid/TCR complex and stimulating IFN-gamma signaling of NKT cells. Furthermore, chemical modification of iGb3 can elicit Th1-biased responses by NKT cells, and 4'''-dh-iGb3 combined with a DC vaccine may serve as a potent new NKT based therapy against tumors and infectious diseases. PMID- 21653686 TI - Expression of amphiregulin and EGFRvIII affect outcome of patients with squamous cell carcinoma of the head and neck receiving cetuximab-docetaxel treatment. AB - PURPOSE: Constitutive activation of epidermal growth factor receptor (EGFR) as a result of gene amplification, mutation, or overexpression of its ligands has been associated with response to EGFR targeting strategies. The role of these molecular mechanisms for the responsiveness of squamous cell carcinoma of the head and neck (SCCHN) to cetuximab-containing regimens remains unknown. EXPERIMENTAL DESIGN: Tumor biopsies from 47 patients, enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic SCCHN with cetuximab and docetaxel, were analyzed by immunohistochemistry for expression of EGFR, its deletion variant III (EGFRvIII) and its ligand amphiregulin (AREG). The relation between expression levels and disease control rate (DCR) was evaluated by logistic regression. Association between expression levels, progression-free survival (PFS), and overall survival (OS) was determined by Kaplan-Meier analysis, log-rank test, and uni- and multivariate Cox regression analysis. RESULTS: High expression of EGFR, EGFRvIII, and AREG was detected in 73%, 17%, and 45% of SCCHN cases, respectively. Expression levels of EGFR had no impact on PFS or OS. High expression levels of EGFRvIII were significantly associated with reduced DCR and shortened PFS (HR: 3.3, P = 0.005) but not with OS. Patients with high AREG expression in tumor cells had significantly shortened OS (HR: 2.2, P = 0.002) and PFS (HR 2.2, P = 0.019) compared with patients with low expression score. Multivariate Cox analysis revealed an independent association of AREG and EGFRvIII with PFS but only AREG was an independent prognosticator of OS. CONCLUSIONS: High EGFRvIII and AREG expression levels identify SCCHN patients who are less likely to benefit from combination treatment with cetuximab and docetaxel. PMID- 21653687 TI - Mitoxantrone inhibits HIF-1alpha expression in a topoisomerase II-independent pathway. AB - PURPOSE: Solid tumors encounter a growth-limiting hypoxic microenvironment as they develop. Hypoxia-inducible factors (HIF) play important roles in hypoxia associated tumor development and therapeutic resistance. Targeting the HIF pathway (especially HIF-1alpha) represents a promising cancer treatment strategy. Here, we report a novel class of HIF-1alpha inhibitors and the possible molecular basis of inhibition. EXPERIMENTAL DESIGN: We analyzed the inhibitory effects of clinically used topoisomerase II (TOP2)-targeting drugs on HIF-1alpha expression with a primary focus on mitoxantrone. The potential role of TOP2 in mitoxantrone inhibited HIF-1alpha expression was studied using pharmacologic inhibition, a knockdown approach, and TOP2 mutant cells. Moreover, involvement of mitoxantrone in proteasome-mediated degradation, transcription, and translation of HIF-1alpha was examined. RESULTS: The TOP2-targeting mitoxantrone, but neither doxorubicin nor etoposide (VP-16), strongly inhibited HIF-1alpha expression under hypoxic conditions in a dose- and time-dependent manner. Surprisingly, the mitoxantrone mediated inhibition of HIF-1alpha expression was largely independent of two TOP2 isozymes, proteasomal degradation, and transcription. Furthermore, mitoxantrone inhibited HIF-1alpha expression and function in a similar fashion as cycloheximide, suggesting that mitoxantrone might inhibit HIF-1alpha via a blockage at its translation step. In vitro translation experiments using HIF 1alpha mRNA further confirmed inhibition of HIF-1alpha translation by mitoxantrone. Interestingly, levels of the polysome-bound HIF-1alpha and VEGF-A mRNA were elevated and decreased after mitoxantrone treatment, respectively. CONCLUSIONS: We have identified the TOP2-targeting compound, mitoxantrone, as an HIF-1alpha inhibitor possibly through a translation inhibition mechanism, suggesting the possibility of an additional anticancer activity for mitoxantrone. PMID- 21653689 TI - Population analysis of erlotinib in adults and children reveals pharmacokinetic characteristics as the main factor explaining tolerance particularities in children. AB - PURPOSE: The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients. EXPERIMENTAL DESIGN: Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults. RESULTS: A significant difference in erlotinib clearance (P = 0.0001), when expressed in L.h(-1).kg(-1), was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference = 0.051 L.h(-1).kg(-1), SD = 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK-PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC. CONCLUSIONS: The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m(2)/day) compared with adults (90 mg/m(2)/day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities. PMID- 21653688 TI - Targeting GPCR-mediated p70S6K activity may improve head and neck cancer response to cetuximab. AB - PURPOSE: Epidermal growth factor receptor (EGFR) overexpression is correlated with decreased survival in head and neck cancer (HNC) where the addition of EGFR inhibition to standard chemoradiation approaches has improved treatment responses. However, the basis for the limited efficacy of EGFR inhibitors in HNC is incompletely understood. G-protein-coupled receptors (GPCR) have been shown to be overexpressed in HNC where GPCR activation induces HNC growth via both EGFR dependent and -independent pathways. We hypothesized that targeting GPCR-induced EGFR-independent signaling would improve the efficacy of EGFR inhibition. EXPERIMENTAL DESIGN: Using a high-throughput phosphoproteome array, we identified proteins that were phosphorylated in HNC cells where EGFR expression was downmodulated by RNA interference (RNAi) in the presence or absence of a GPCR ligand. We confirmed the findings from the array by Western blotting followed by in vitro and in vivo phenotypic assays. RESULTS: p70S6K phosphorylation was elevated approximately sixfold in EGFR siRNA-transfected cells treated with a GPCR ligand. In addition to RNAi-mediated EGFR downmodulation, GPCR-mediated phosphorylation of p70S6K was modestly increased by EGFR inhibitor cetuximab approved by the Food and Drug Administration. Biopsies from cetuximab-treated patients also displayed increased phospho-p70S6K staining compared with pretreatment biopsies. HNC cells were growth inhibited by both genetic and pharmacologic p70S6K targeting strategies. Furthermore, p70S6K targeting in combination with cetuximab resulted in enhanced antitumor effects in both in vitro and in vivo HNC models. CONCLUSIONS: These results indicate that increased phosphorylation of p70S6K in cetuximab-treated patients may be due to increased GPCR signaling. Therefore, the addition of p70S6K targeting strategies may improve treatment responses to EGFR inhibition. PMID- 21653690 TI - Comparison of clinical and immunological effects of intravenous and intradermal administration of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells. AB - PURPOSE: Human Valpha24+Vbeta11+ natural killer T-cells (NKT cells) have antitumor activity via direct cytotoxicity and by induction of antitumor actions of T and NK cells. Activation of NKT cells is crucial for their antitumor activity and is induced by alpha-galactosylceramide (alpha-GalCer, KRN7000) presented by CD1d on dendritic cells (DC). We conducted a phase I clinical trial of therapy with alpha-GalCer-pulsed DC to determine safety, tolerability, immune effects and an optimal dose, and administration route. EXPERIMENTAL DESIGN: Twelve subjects (3 cohorts) with metastatic malignancy received 4 treatments of alpha-GalCer-pulsed DC, 2 treatments intravenously (IV), and 2 treatments intradermally (ID). Each successive cohort received a log higher cell dose. Clinical and immunological outcomes were evaluated, including secondary effects on NK and T cells. RESULTS: Substantial effects on peripheral blood NKT cells were observed but were greater following IV treatment. Secondary immune effects including activation of T and NK cells, increases in T- and NK-cell cytoplasmic interferon-gamma, and increases in serum interferon-gamma levels were seen after IV but not after ID treatment. Therapy was well tolerated, but 9 of 12 subjects had tumor flares with clinical findings consistent with transient tumor inflammation. Disease response (minor) or stabilization of disease progressing up to enrollment was observed in 6 of the 12 subjects. Stabilization of previously progressive disease lasted for at least one year in three subjects. CONCLUSION: We conclude that therapy with alpha-GalCer-pulsed DC induced clinically beneficial immune responses that are highly dependent on cell dose and administration route. PMID- 21653691 TI - Circulating cell-free DNA in plasma of never smokers with advanced lung adenocarcinoma receiving gefitinib or standard chemotherapy as first-line therapy. AB - PURPOSE: Circulating cell-free DNA (CFDNA) was investigated as potential screening or prognostic markers in a variety of cancers. This study investigated its clinical significance in a homogeneous group of lung cancer patients. EXPERIMENTAL DESIGN: We analyzed the blood samples of 134 never smokers with advanced lung adenocarcinoma, who were enrolled in a prospective randomized phase III study (First-SIGNAL) comparing gefitinib with gemcitabine plus cisplatin (GP) as first-line therapy. The amount of plasma CFDNA was measured by real-time quantitative PCR targeting the human ACTB genomic sequence. The patients were divided into three groups according to the tertiles of baseline plasma CFDNA. RESULTS: Baseline plasma CFDNA did not correlate with primary tumor size (P = 0.961), whereas the number of metastatic sites correlated significantly with baseline plasma CFDNA (P = 0.015). In the GP arm, the low-CFDNA group showed a lower response rate than the middle- or high-CFDNA group (26.1%, 57.9%, and 60.9%, respectively; P = 0.035). However, in the gefitinib arm, there was no difference in response rate between the three CFDNA groups (57.1%, 47.4%, and 51.9%; respectively; P = 0.825). The high tertile CFDNA group showed a significantly shorter survival than the low tertile CFDNA group (median overall survival, 16.0 vs. 28.6 months, respectively; P = 0.030). The risk of death increased with increased baseline plasma CFDNA (HR = 1.23, 95% CI, 1.01-1.50; P = 0.045). CONCLUSION: High plasma CFDNA is associated with aggressive tumor behavior and poor survival outcomes in these patients. PMID- 21653692 TI - Enhanced metastasis suppression by targeting TRAIL receptor 2 in a murine model of triple-negative breast cancer. AB - PURPOSE: Metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer. EXPERIMENTAL DESIGN: Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo. RESULTS: Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab. CONCLUSION: Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer. PMID- 21653693 TI - Contribution of retinoid X receptor signaling to the specification of skeletal muscle lineage. AB - Pluripotent stem cells possess a tremendous potential for the treatment of many diseases because of their capacity to differentiate into a variety of cell lineages. However, they provide little promise for muscle-related diseases, mainly because of the lack of small molecule inducers to efficiently direct myogenic conversion. Retinoic acid, acting through the retinoic acid receptor (RAR) and retinoid X receptor (RXR), affects stem cell fate determination in a concentration-dependent manner, but it only has a modest efficacy on the commitment of ES cells into skeletal muscle lineage. The RXR is very important for embryonic development but is generally considered to act as a silent partner of RAR in a non-permissive mode. In this study, we have examined whether activation of the RXR by rexinoid or RXR-specific signaling play a role in the specification of stem cells into muscle lineage. Our findings demonstrate that mouse ES cells generate skeletal myocytes effectively upon treatment with rexinoid at the early stage of differentiation and that on a molecular level, rexinoid-enhanced myogenesis simulates the sequential events observed in vivo. Moreover, RXR-mediated myogenic conversion requires the function of beta-catenin but not RAR. Our studies establish the feasibility of applying the RXR agonist in cell-based therapies to treat muscle-related diseases. The aptitude of mouse ES cells to generate skeletal myocytes following rexinoid induction also provides a model system to study the convergence of different signaling pathways in myogenesis. PMID- 21653694 TI - Specific and modular binding code for cytosine recognition in Pumilio/FBF (PUF) RNA-binding domains. AB - Pumilio/fem-3 mRNA-binding factor (PUF) proteins possess a recognition code for bases A, U, and G, allowing designed RNA sequence specificity of their modular Pumilio (PUM) repeats. However, recognition side chains in a PUM repeat for cytosine are unknown. Here we report identification of a cytosine-recognition code by screening random amino acid combinations at conserved RNA recognition positions using a yeast three-hybrid system. This C-recognition code is specific and modular as specificity can be transferred to different positions in the RNA recognition sequence. A crystal structure of a modified PUF domain reveals specific contacts between an arginine side chain and the cytosine base. We applied the C-recognition code to design PUF domains that recognize targets with multiple cytosines and to generate engineered splicing factors that modulate alternative splicing. Finally, we identified a divergent yeast PUF protein, Nop9p, that may recognize natural target RNAs with cytosine. This work deepens our understanding of natural PUF protein target recognition and expands the ability to engineer PUF domains to recognize any RNA sequence. PMID- 21653696 TI - Retuning Rieske-type oxygenases to expand substrate range. AB - Rieske-type oxygenases are promising biocatalysts for the destruction of persistent pollutants or for the synthesis of fine chemicals. In this work, we explored pathways through which Rieske-type oxygenases evolve to expand their substrate range. BphAE(p4), a variant biphenyl dioxygenase generated from Burkholderia xenovorans LB400 BphAE(LB400) by the double substitution T335A/F336M, and BphAE(RR41), obtained by changing Asn(338), Ile(341), and Leu(409) of BphAE(p4) to Gln(338), Val(341), and Phe(409), metabolize dibenzofuran two and three times faster than BphAE(LB400), respectively. Steady state kinetic measurements of single- and multiple-substitution mutants of BphAE(LB400) showed that the single T335A and the double N338Q/L409F substitutions contribute significantly to enhanced catalytic activity toward dibenzofuran. Analysis of crystal structures showed that the T335A substitution relieves constraints on a segment lining the catalytic cavity, allowing a significant displacement in response to dibenzofuran binding. The combined N338Q/L409F substitutions alter substrate-induced conformational changes of protein groups involved in subunit assembly and in the chemical steps of the reaction. This suggests a responsive induced fit mechanism that retunes the alignment of protein atoms involved in the chemical steps of the reaction. These enzymes can thus expand their substrate range through mutations that alter the constraints or plasticity of the catalytic cavity to accommodate new substrates or that alter the induced fit mechanism required to achieve proper alignment of reaction-critical atoms or groups. PMID- 21653695 TI - Alpha-synuclein interacts with Glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. AB - The presynaptic protein alpha-synuclein (alpha-syn), particularly in its amyloid form, is widely recognized for its involvement in Parkinson disease (PD). Recent genetic studies reveal that mutations in the gene GBA are the most widespread genetic risk factor for parkinsonism identified to date. GBA encodes for glucocerebrosidase (GCase), the enzyme deficient in the lysosomal storage disorder, Gaucher disease (GD). In this work, we investigated the possibility of a physical linkage between alpha-syn and GCase, examining both wild type and the GD-related N370S mutant enzyme. Using fluorescence and nuclear magnetic resonance spectroscopy, we determined that alpha-syn and GCase interact selectively under lysosomal solution conditions (pH 5.5) and mapped the interaction site to the alpha-syn C-terminal residues, 118-137. This alpha-syn-GCase complex does not form at pH 7.4 and is stabilized by electrostatics, with dissociation constants ranging from 1.2 to 22 MUm in the presence of 25 to 100 mm NaCl. Intriguingly, the N370S mutant form of GCase has a reduced affinity for alpha-syn, as does the inhibitor conduritol-beta-epoxide-bound enzyme. Immunoprecipitation and immunofluorescence studies verified this interaction in human tissue and neuronal cell culture, respectively. Although our data do not preclude protein-protein interactions in other cellular milieux, we suggest that the alpha-syn-GCase association is favored in the lysosome, and that this noncovalent interaction provides the groundwork to explore molecular mechanisms linking PD with mutant GBA alleles. PMID- 21653697 TI - G Protein binding sites on Calnuc (nucleobindin 1) and NUCB2 (nucleobindin 2) define a new class of G(alpha)i-regulatory motifs. AB - Heterotrimeric G proteins are molecular switches modulated by families of structurally and functionally related regulators. GIV (Galpha-interacting vesicle associated protein) is the first non-receptor guanine nucleotide exchange factor (GEF) that activates Galpha(i) subunits via a defined, evolutionarily conserved motif. Here we found that Calnuc and NUCB2, two highly homologous calcium-binding proteins, share a common motif with GIV for Galpha(i) binding and activation. Bioinformatics searches and structural analysis revealed that Calnuc and NUCB2 possess an evolutionarily conserved motif with sequence and structural similarity to the GEF sequence of GIV. Using in vitro pulldown and competition assays, we demonstrate that this motif binds preferentially to the inactive conformation of Galpha(i1) and Galpha(i3) over other Galpha subunits and, like GIV, docks onto the alpha3/switch II cleft. Calnuc binding was impaired when Lys-248 in the alpha3 helix of Galpha(i3) was replaced with M, the corresponding residue in Galpha(o), which does not bind to Calnuc. Moreover, mutation of hydrophobic residues in the conserved motif predicted to dock on the alpha3/switch II cleft of Galpha(i3) impaired the ability of Calnuc and NUCB2 to bind and activate Galpha(i3) in vitro. We also provide evidence that calcium binding to Calnuc and NUCB2 abolishes their interaction with Galpha(i3) in vitro and in cells, probably by inducing a conformational change that renders the Galpha(i)-binding residues inaccessible. Taken together, our results identify a new type of Galpha(i) regulatory motif named the GBA motif (for Galpha-binding and -activating motif), which is conserved across different proteins throughout evolution. These findings provide the structural basis for the properties of Calnuc and NUCB2 binding to Galpha subunits and its regulation by calcium ions. PMID- 21653698 TI - Endo-beta-1,3-galactanase from winter mushroom Flammulina velutipes. AB - Arabinogalactan proteins are proteoglycans found on the cell surface and in the cell walls of higher plants. The carbohydrate moieties of most arabinogalactan proteins are composed of beta-1,3-galactan main chains and beta-1,6-galactan side chains, to which other auxiliary sugars are attached. For the present study, an endo-beta-1,3-galactanase, designated FvEn3GAL, was first purified and cloned from winter mushroom Flammulina velutipes. The enzyme specifically hydrolyzed beta-1,3-galactan, but did not act on beta-1,3-glucan, beta-1,3:1,4-glucan, xyloglucan, and agarose. It released various beta-1,3-galactooligosaccharides together with Gal from beta-1,3-galactohexaose in the early phase of the reaction, demonstrating that it acts on beta-1,3-galactan in an endo-fashion. Phylogenetic analysis revealed that FvEn3GAL is member of a novel subgroup distinct from known glycoside hydrolases such as endo-beta-1,3-glucanase and endo beta-1,3:1,4-glucanase in glycoside hydrolase family 16. Point mutations replacing the putative catalytic Glu residues conserved for enzymes in this family with Asp abolished activity. These results indicate that FvEn3GAL is a highly specific glycoside hydrolase 16 endo-beta-1,3-galactanase. PMID- 21653699 TI - Cellular inhibitor of apoptosis protein-1 (cIAP1) can regulate E2F1 transcription factor-mediated control of cyclin transcription. AB - The inhibitor of apoptosis protein cIAP1 (cellular inhibitor of apoptosis protein 1) is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. However, in some primary cells and tumor cell lines, cIAP1 is expressed in the nucleus, and its nuclear function remains poorly understood. Here, we show that the N-terminal part of cIAP1 directly interacts with the DNA binding domain of the E2F1 transcription factor. cIAP1 dramatically increases the transcriptional activity of E2F1 on synthetic and CCNE promoters. This function is not conserved for cIAP2 and XIAP, which are cytoplasmic proteins. Chromatin immunoprecipitation experiments demonstrate that cIAP1 is recruited on E2F binding sites of the CCNE and CCNA promoters in a cell cycle- and differentiation-dependent manner. cIAP1 silencing inhibits E2F1 DNA binding and E2F1-mediated transcriptional activation of the CCNE gene. In cells that express a nuclear cIAP1 such as HeLa, THP1 cells and primary human mammary epithelial cells, down-regulation of cIAP1 inhibits cyclin E and A expression and cell proliferation. We conclude that one of the functions of cIAP1 when localized in the nucleus is to regulate E2F1 transcriptional activity. PMID- 21653700 TI - Sulfated glycosaminoglycans are required for specific and sensitive fibroblast growth factor (FGF) 19 signaling via FGF receptor 4 and betaKlotho. AB - Secreted from intestine, human fibroblast growth factor 19 (hFGF19) is an endocrine metabolic regulator that controls bile acid synthesis in the liver. Earlier studies have suggested that hFGF19 at 10-100 nM levels signals through FGF receptor 4 (FGFR4) in the presence of a co-receptor, betaKlotho, but its activity and receptor specificity at physiological concentrations (picomolar levels) remain unclear. Here we report that hFGF19 at picomolar levels require sulfated glycosaminoglycans (sGAGs), such as heparan sulfate, heparin, and chondroitin sulfates, for its signaling via human FGFR4 in the presence of human betaKlotho. Importantly, sGAGs isolated from liver are highly active in enhancing the picomolar hFGF19 signaling. At nanomolar levels, in contrast, hFGF19 activates all types of human FGFRs, i.e. FGFR1c, FGFR2c, FGFR3c, and FGFR4 in the co-presence of betaKlotho and heparin and activates FGFR4 even in the absence of betaKlotho. These results show that sGAGs play crucial roles in specific and sensitive hFGF19 signaling via FGF receptors and suggest that hepatic sGAGs are involved in the highly potent and specific signaling of picomolar hFGF19 through FGFR4 and betaKlotho. The results further suggest that hFGF19 at pathological concentrations may evoke aberrant signaling through various FGF receptors. PMID- 21653701 TI - Sequence-specific long range networks in PSD-95/discs large/ZO-1 (PDZ) domains tune their binding selectivity. AB - Protein-protein interactions mediated by modular protein domains are critical for cell scaffolding, differentiation, signaling, and ultimately, evolution. Given the vast number of ligands competing for binding to a limited number of domain families, it is often puzzling how specificity can be achieved. Selectivity may be modulated by intradomain allostery, whereby a remote residue is energetically connected to the functional binding site via side chain or backbone interactions. Whereas several energetic pathways, which could mediate intradomain allostery, have been predicted in modular protein domains, there is a paucity of experimental data to validate their existence and roles. Here, we have identified such functional energetic networks in one of the most common protein-protein interaction modules, the PDZ domain. We used double mutant cycles involving site directed mutagenesis of both the PDZ domain and the peptide ligand, in conjunction with kinetics to capture the fine energetic details of the networks involved in peptide recognition. We performed the analysis on two homologous PDZ ligand complexes and found that the energetically coupled residues differ for these two complexes. This result demonstrates that amino acid sequence rather than topology dictates the allosteric pathways. Furthermore, our data support a mechanism whereby the whole domain and not only the binding pocket is optimized for a specific ligand. Such cross-talk between binding sites and remote residues may be used to fine tune target selectivity. PMID- 21653702 TI - Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia. AB - Behavioral variant frontotemporal dementia (bvFTD) erodes complex social emotional functions as the anterior cingulate cortex (ACC) and frontoinsula (FI) degenerate, but the early vulnerable neuron within these regions has remained uncertain. Previously, we demonstrated selective loss of ACC von Economo neurons (VENs) in bvFTD. Unlike ACC, FI contains a second conspicuous layer 5 neuronal morphotype, the fork cell, which has not been previously examined. Here, we investigated the selectivity, disease-specificity, laterality, timing, and symptom relevance of frontoinsular VEN and fork cell loss in bvFTD. Blinded, unbiased, systematic sampling was used to quantify bilateral FI VENs, fork cells, and neighboring neurons in 7 neurologically unaffected controls (NC), 5 patients with Alzheimer's disease (AD), and 9 patients with bvFTD, including 3 who died of comorbid motor neuron disease during very mild bvFTD. bvFTD showed selective FI VEN and fork cell loss compared with NC and AD, whereas in AD no significant VEN or fork cell loss was detected. Although VEN and fork cell losses in bvFTD were often asymmetric, no group-level hemispheric laterality effects were identified. Right-sided VEN and fork cell losses, however, correlated with each other and with anatomical, functional, and behavioral severity. This work identifies region specific neuronal targets in early bvFTD. PMID- 21653703 TI - Distinctive neurons of the anterior cingulate and frontoinsular cortex: a historical perspective. AB - Human anterior cingulate and frontoinsular cortices participate in healthy social emotional processing. These regions feature 2 related layer 5 neuronal morphotypes, the von Economo neurons and fork cells. In this paper, we review the historical accounts of these neurons and provide a German-to-English translation of von Economo's seminal paper describing the neurons which have come to bear his name. We close with a brief discussion regarding the functional and clinical relevance of these neurons and their home regions. PMID- 21653704 TI - Repolarization of the mammalian heart action potential is modulated by changes in osmotic strength. PMID- 21653705 TI - The impact of brief exposure to high contrast on the contrast response of neurons in primate lateral geniculate nucleus. AB - Prolonged exposure to an effective stimulus generally reduces the sensitivity of neurons early in the visual pathway. Yet eye and head movements bring about frequent changes in the retinal image, and it is less clear that exposure to brief presentations will produce similar desensitization. To address this, we made extracellular recordings from single neurons in the lateral geniculate nucleus of anesthetized marmosets, a New World primate. We measured the contrast response for drifting gratings before and after 0.5-s exposure to a high-contrast drifting grating, a stationary grating, or a blank screen. Prior exposure to the drifting grating reduced the contrast sensitivity of cells in the magnocellular pathway, on average by 23%; this reduction remained strong when the adapting and test stimuli were separated by 0.4 s. Exposure to a stationary grating of the preferred spatial phase did not change the contrast response; exposure to the opposite spatial phase did. None of the brief adaptors reduced the sensitivity of parvocellular cells. We conclude that brief periods of high contrast, such as those that would be expected to occur during a normal visual fixation, are sufficient to reduce the sensitivity of magnocellular-pathway cells. PMID- 21653706 TI - Facilitation of postural limb reflexes in spinal rabbits by serotonergic agonist administration, epidural electrical stimulation, and postural training. AB - In quadrupeds, spinalization in the thoracic region severely impairs postural control in the hindquarters. The goal of this study was to improve postural functions in chronic spinal rabbits by regular application of different factors: intrathecal injection of the 5-HT(2) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl) 2-aminopropane hydrochloride (DOI), epidural electrical spinal cord stimulation (EES), and specific postural training (SPT). The factors were used either alone (SPT group) or in combination (DOI+SPT, EES+SPT, and DOI+EES+SPT groups) or not used (control group). It was found that in none of these groups did normal postural corrective movements in response to lateral tilts of the supporting platform reappear within the month of treatment. In control group, reduced irregular electromyographic (EMG) responses, either correctly or incorrectly phased in relation to tilts, were observed. By contrast, in DOI+SPT and EES+SPT groups, a gradual threefold increase in the proportion of correctly phased EMG responses (compared with control) was observed. The increase was smaller in DOI+EES+SPT and SPT groups. Dissimilarly to these long-term effects, short-term effects of DOI and EES were weak or absent. In addition, gradual development of oscillatory EMG activity in the responses to tilts, characteristic for the control group, was retarded in DOI+SPT, EES+SPT, DOI+EES+SPT, and SPT groups. Thus regular application of the three tested factors and their combinations caused progressive, long-lasting plastic changes in the isolated spinal networks, resulting in the facilitation of spinal postural reflexes and in the retardation of the development of oscillatory EMG activity. The facilitated reflexes, however, were insufficient for normal postural functions. PMID- 21653707 TI - Somatosensory response properties of excitatory and inhibitory neurons in rat motor cortex. AB - In sensory cortical networks, peripheral inputs differentially activate excitatory and inhibitory neurons. Inhibitory neurons typically have larger responses and broader receptive field tuning compared with excitatory neurons. These differences are thought to underlie the powerful feedforward inhibition that occurs in response to sensory input. In the motor cortex, as in the somatosensory cortex, cutaneous and proprioceptive somatosensory inputs, generated before and during movement, strongly and dynamically modulate the activity of motor neurons involved in a movement and ultimately shape cortical command. Human studies suggest that somatosensory inputs modulate motor cortical activity in a center excitation, surround inhibition manner such that input from the activated muscle excites motor cortical neurons that project to it, whereas somatosensory input from nearby, nonactivated muscles inhibit these neurons. A key prediction of this hypothesis is that inhibitory and excitatory motor cortical neurons respond differently to somatosensory inputs. We tested this prediction with the use of multisite extracellular recordings in anesthetized rats. We found that fast-spiking (presumably inhibitory) neurons respond to tactile and proprioceptive inputs at shorter latencies and larger response magnitudes compared with regular-spiking (presumably excitatory) neurons. In contrast, we found no differences in the receptive field size of these neuronal populations. Strikingly, all fast-spiking neuron pairs analyzed with cross correlation analysis displayed common excitation, which was significantly more prevalent than common excitation for regular-spiking neuron pairs. These findings suggest that somatosensory inputs preferentially evoke feedforward inhibition in the motor cortex. We suggest that this provides a mechanism for dynamic selection of motor cortical modules during voluntary movements. PMID- 21653708 TI - Neuronal activation times to simple, complex, and natural sounds in cat primary and nonprimary auditory cortex. AB - Interactions between living organisms and the environment are commonly regulated by accurate and timely processing of sensory signals. Hence, behavioral response engagement by an organism is typically constrained by the arrival time of sensory information to the brain. While psychophysical response latencies to acoustic information have been investigated, little is known about how variations in neuronal response time relate to sensory signal characteristics. Consequently, the primary objective of the present investigation was to determine the pattern of neuronal activation induced by simple (pure tones), complex (noise bursts and frequency modulated sweeps), and natural (conspecific vocalizations) acoustic signals of different durations in cat auditory cortex. Our analysis revealed three major cortical response characteristics. First, latency measures systematically increase in an antero-dorsal to postero-ventral direction among regions of auditory cortex. Second, complex acoustic stimuli reliably provoke faster neuronal response engagement than simple stimuli. Third, variations in neuronal response time induced by changes in stimulus duration are dependent on acoustic spectral features. Collectively, these results demonstrate that acoustic signals, regardless of complexity, induce a directional pattern of activation in auditory cortex. PMID- 21653709 TI - Modulation of shifting receptive field activity in frontal eye field by visual salience. AB - In the monkey frontal eye field (FEF), the sensitivity of some neurons to visual stimulation changes just before a saccade. Sensitivity shifts from the spatial location of its current receptive field (RF) to the location of that field after the saccade is completed (the future field, FF). These shifting RFs are thought to contribute to the stability of visual perception across saccades, and in this study we investigated whether the salience of the FF stimulus alters the magnitude of FF activity. We reduced the salience of the usually single flashed stimulus by adding other visual stimuli. We isolated 171 neurons in the FEF of 2 monkeys and did experiments on 50 that had FF activity. In 30% of these, that activity was higher before salience was reduced by adding stimuli. The mean magnitude reduction was 16%. We then determined whether the shifting RFs were more frequent in the central visual field, which would be expected if vision across saccades were only stabilized for the visual field near the fovea. We found no evidence of any skewing of the frequency of shifting receptive fields (or the effects of salience) toward the central visual field. We conclude that the salience of the FF stimulus makes a substantial contribution to the magnitude of FF activity in FEF. In so far as FF activity contributes to visual stability, the salience of the stimulus is probably more important than the region of the visual field in which it falls for determining which objects remain perceptually stable across saccades. PMID- 21653711 TI - Differential activity patterns of putaminal neurons with inputs from the primary motor cortex and supplementary motor area in behaving monkeys. AB - Activity patterns of projection neurons in the putamen were investigated in behaving monkeys. Stimulating electrodes were implanted chronically into the proximal (MI(proximal)) and distal (MI(distal)) forelimb regions of the primary motor cortex (MI) and the forelimb region of the supplementary motor area (SMA). Cortical inputs to putaminal neurons were identified by excitatory orthodromic responses to stimulation of these motor cortices. Then, neuronal activity was recorded during the performance of a goal-directed reaching task with delay. Putaminal neurons with inputs from the MI and SMA showed different activity patterns, i.e., movement- and delay-related activity, during task performance. MI recipient neurons increased activity in response to arm-reach movements, whereas SMA-recipient neurons increased activity during delay periods, as well as during movements. The activity pattern of MI + SMA-recipient neurons was of an intermediate type between those of MI- and SMA-recipient neurons. Approximately one-half of MI(proximal)-, SMA-, and MI + SMA-recipient neurons changed activities before the onset of movements, whereas a smaller number of MI(distal)- and MI(proximal + distal)-recipient neurons did. Movement-related activity of MI recipient neurons was modulated by target directions, whereas SMA- and MI + SMA recipient neurons had a lower directional selectivity. MI-recipient neurons were located mainly in the ventrolateral part of the caudal aspect of the putamen, whereas SMA-recipient neurons were located in the dorsomedial part. MI + SMA recipient neurons were found in between. The present results suggest that a subpopulation of putaminal neurons displays specific activity patterns depending on motor cortical inputs. Each subpopulation receives convergent or nonconvergent inputs from the MI and SMA, retains specific motor information, and sends it to the globus pallidus and the substantia nigra through the direct and indirect pathways of the basal ganglia. PMID- 21653710 TI - Nicotine excites hypothalamic arcuate anorexigenic proopiomelanocortin neurons and orexigenic neuropeptide Y neurons: similarities and differences. AB - Two of the biggest health problems facing us today are addiction to nicotine and the increased prevalence of obesity. Interestingly, nicotine attenuates obesity, but the underlying mechanism is not clear. Here we address the hypothesis that if weight-reducing actions of nicotine are mediated by anorexigenic proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus, nicotine should excite these cells. Nicotine at concentrations similar to those found in smokers, 100-1,000 nM, excited POMC cells by mechanisms based on increased spike frequency, depolarization of membrane potential, and opening of ion channels. This was mediated by activation of both alpha7 and alpha4beta2 nicotinic receptors; by itself, this nicotine-mediated excitation could explain weight loss caused by nicotine. However, in control experiments nicotine also excited the orexigenic arcuate nucleus neuropeptide Y (NPY) cells. Nicotine exerted similar actions on POMC and NPY cells, with a slightly greater depolarizing action on POMC cells. Immunocytochemistry revealed cholinergic axons terminating on both cell types. Nicotine actions were direct in both cell types, with nicotine depolarizing the membrane potentials and reducing input resistance. We found no differences in the relative desensitization to nicotine between POMC and NPY neurons. Nicotine inhibited excitatory synaptic activity recorded in NPY, but not POMC, cells. Nicotine also excited hypocretin/orexin neurons that enhance cognitive arousal, but the responses were smaller than in NPY or POMC cells. Together, these results indicate that nicotine has a number of similar actions, but also a few different actions, on POMC and NPY neurons that could contribute to the weight loss associated with smoking. PMID- 21653712 TI - Between-subject variance in the magnitude of corticomuscular coherence during tonic isometric contraction of the tibialis anterior muscle in healthy young adults. AB - Oscillatory activity of the sensorimotor cortex has been reported to show coherence with muscle activity in the 15- to 35-Hz frequency band (beta-band) during weak to moderate intensity of isometric contraction. The present study examined the variance of the magnitude of the corticomuscular coherence across a large number of subjects. We quantified the coherence between EEG over the sensorimotor cortex and rectified electromyogram (EMG) from the tibialis anterior muscle during tonic isometric contraction at 30% of maximal effort in 100 healthy young individuals. We estimated the maximal peak of EEG-EMG coherence (Cohmax) and the ratio of the sum of the autopower spectral density function within the beta-band to that of all frequency ranges for both EEG (EEGbeta-PSD) and EMG (EMGbeta-PSD) signals. The frequency histogram of Cohmax across all subjects showed a broad bell-shaped continuous distribution (range, 0.048-0.816). When the coherence was thresholded at the estimated significance level of P < 0.05 (0.114), 46 out of 100 subjects showed significant EEG-EMG coherence. Cohmax occurred within the beta-band in the majority of subjects who showed significant EEG-EMG coherence (n = 43). Furthermore, Cohmax showed significant positive correlations with both EEGbeta-PSD (r = 0.575, P < 0.001) and EMGbeta-PSD (r = 0.606, P < 0.001). These data suggest that even during simple tonic isometric contraction, the strength of oscillatory coupling between the sensorimotor cortex and spinal motoneurons varies among individuals and is a contributory factor determining muscle activation patterns such as the degree of grouped discharge in muscle activity within the beta-band for each subject. PMID- 21653713 TI - Cross talk in implicit assignment of error information during bimanual visuomotor learning. AB - When a neural movement controller, called an "internal model," is adapted to a novel environment, the movement error needs to be appropriately associated with the controller. However, their association is not necessarily guaranteed for bimanual movements in which two controllers--one for each hand--result in two movement errors. Considering the implicit nature of the adaptation process, the movement error of one hand can be erroneously associated with the controller of the other hand. Here, we investigated this credit-assignment problem in bimanual movement by having participants perform bimanual, symmetric back-and-forth movements while displaying the position of the right hand only with a cursor. In the training session, the cursor position was gradually rotated clockwise, such that the participants were unaware of the rotation. The movement of the right hand gradually rotated counterclockwise as a consequence of adaptation. Although the participants knew that the cursor reflected the movement of the right hand, such gradual adaptation was also observed for the invisible left hand, especially when the cursor was presented on the left side of the display. Thus the movement error of the right hand was implicitly assigned to the left-hand controller. Such cross talk in credit assignment might influence motor adaptation performance, even when two cursors are presented; the adaptation was impaired when the rotations imposed on the cursors were opposite compared with when they were in the same direction. These results indicate the inherent presence of cross talk in the process of associating action with consequence in bimanual movement. PMID- 21653714 TI - A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. AB - Levetiracetam (LEV) is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs. PMID- 21653715 TI - Grasping with the eyes. AB - When observing someone else acting on an object, people implement goal-specific eye movement programs that are driven by their own motor representation of the observed action. Usually, however, we observe people acting in contexts where more objects, different in shape and size, are present. Is our brain able to select the intended target even when there are different objects in the visual scene? And if this is the case, what kind of information does our motor system capitalize on? We recorded eye movements while participants observed an actor reaching for and grasping one of two objects requiring two different kinds of grip to be picked up. In a control condition, the actor merely reached for and touched one of the two objects without preshaping her hand according to the target features. Results showed higher accuracy and earlier saccadic movements when participants observed an actually grasping hand than when they observed a mere reaching hand devoid of any kind of target-related preshaping. This clearly suggests that the hand preshaping provided the observer with enough motor cues to proactively and reliably saccade toward the object to be grasped, thus identifying it even when the action target was not previously known. Our findings strongly corroborate the direct matching hypothesis suggesting that in processing others' actions, we take advantage of the same motor knowledge that enables us to efficiently perform those actions. PMID- 21653716 TI - Modules in the brain stem and spinal cord underlying motor behaviors. AB - Previous studies using intact and spinalized animals have suggested that coordinated movements can be generated by appropriate combinations of muscle synergies controlled by the central nervous system (CNS). However, which CNS regions are responsible for expressing muscle synergies remains an open question. We address whether the brain stem and spinal cord are involved in expressing muscle synergies used for executing a range of natural movements. We analyzed the electromyographic (EMG) data recorded from frog leg muscles before and after transection at different levels of the neuraxis-rostral midbrain (brain stem preparations), rostral medulla (medullary preparations), and the spinal-medullary junction (spinal preparations). Brain stem frogs could jump, swim, kick, and step, while medullary frogs could perform only a partial repertoire of movements. In spinal frogs, cutaneous reflexes could be elicited. Systematic EMG analysis found two different synergy types: 1) synergies shared between pre- and posttransection states and 2) synergies specific to individual states. Almost all synergies found in natural movements persisted after transection at rostral midbrain or medulla but not at the spinal-medullary junction for swim and step. Some pretransection- and posttransection-specific synergies for a certain behavior appeared as shared synergies for other motor behaviors of the same animal. These results suggest that the medulla and spinal cord are sufficient for the expression of most muscle synergies in frog behaviors. Overall, this study provides further evidence supporting the idea that motor behaviors may be constructed by muscle synergies organized within the brain stem and spinal cord and activated by descending commands from supraspinal areas. PMID- 21653717 TI - Sensitivity of human visual cortical area V6 to stereoscopic depth gradients associated with self-motion. AB - The principal visual cue to self-motion (egomotion) is optic flow, which is specified in terms of local 2D velocities in the retinal image without reference to depth cues. However, in general, points near the center of expansion of natural flow fields are distant, whereas those in the periphery are closer, creating gradients of horizontal binocular disparity. To assess whether the brain combines disparity gradients with optic flow when encoding egomotion, stereoscopic gradients were applied to expanding dot patterns presented to observers during functional MRI scanning. The gradients were radially symmetrical, disparity changing as a function of eccentricity. The depth cues were either consistent with egomotion (peripheral dots perceived as near and central dots perceived as far) or inconsistent (the reverse gradient, central dots near, peripheral dots far). The BOLD activity generated by these stimuli was compared in a range of predefined visual regions in 13 participants with good stereoacuity. Visual area V6, in the parieto-occipital sulcus, showed a unique pattern of results, responding well to all optic flow patterns but much more strongly when they were paired with consistent rather than inconsistent or zero disparity gradients. Of the other areas examined, a region of the precuneus and parietoinsular vestibular cortex also differentiate between consistent and inconsistent gradients, but with weak or suppressive responses. V3A, V7, MT, and ventral intraparietal area responded more strongly in the presence of a depth gradient but were indifferent to its depth-flow congruence. The results suggest that depth and flow cues are integrated in V6 to improve estimation of egomotion. PMID- 21653719 TI - Sound frequency representation in primary auditory cortex is level tolerant for moderately loud, complex sounds. AB - The distribution of neuronal characteristic frequencies over the area of primary auditory cortex (AI) roughly reflects the tonotopic organization of the cochlea. However, because the area of AI activated by any given sound frequency increases erratically with sound level, it has generally been proposed that frequency is represented in AI not with a rate-place code but with some more complex, distributed code. Here, on the basis of both spike and local field potential (LFP) recordings in the anesthetized cat, we show that the tonotopic representation in AI is much more level tolerant when mapped with spectrotemporally dense tone pip ensembles rather than with individually presented tone pips. That is, we show that the tuning properties of individual unit and LFP responses are less variable with sound level under dense compared with sparse stimulation, and that the spatial frequency resolution achieved by the AI neural population at moderate stimulus levels (65 dB SPL) is better with densely than with sparsely presented sounds. This implies that nonlinear processing in the central auditory system can compensate (in part) for the level dependent coding of sound frequency in the cochlea, and suggests that there may be a functional role for the cortical tonotopic map in the representation of complex sounds. PMID- 21653718 TI - Evidence for the use of rotational optic flow cues for locomotor steering in healthy older adults. AB - Optic flow is a powerful visual cue for the control of locomotion. Considerable research has focused on how healthy young people use and perceive optic flow. However, little is known on how older adults use this type of visual motion to control walking. The purpose of this study is to investigate the ability of young and older adults to adjust their physical walking trajectory in response to a rotation of the optic flow presented in a virtual environment. Ten healthy young adults (mean age 23.49 +/- 4.72 yr) and 10 healthy older adults (mean age 76.22 +/- 3.11 yr) participated in the study. Subjects were instructed to walk straight in a virtual environment viewed within a head-mounted display unit as they walked overground for 5 m, while the focus of expansion was gradually rotated to the left or the right by 40 degrees . All subjects responded with a similar strategy by rotating their head and body in the direction away from the orientation of the perturbation. The younger subjects achieved almost complete corrections and had very small net heading errors. In contrast, the older adults had delayed and smaller reorientations, particularly in the head, thus showing significantly larger heading errors compared with younger subjects. We conclude that older adults retain the ability to use optic flow to control their walking trajectory, although smaller, delayed head rotations and larger heading errors may indicate an age-dependent effect on sensorimotor coordination. PMID- 21653720 TI - Impact of cortical plasticity on information signaled by populations of neurons in the cerebral cortex. AB - The performance of neural codes to represent attributes of sensory signals has been evaluated in the vertebrate peripheral and central nervous system. Here, we determine how information signaled by populations of neurons is modified by plasticity. Suprathreshold neuronal responses from a large number of neurons were recorded in the juvenile mouse barrel cortex using dithered random-access scanning. Pairing of one input with another resulted in a long-lasting, input specific modification of the cortical responses. Mutual information analysis indicated that cortical plasticity efficiently changed information signaled by populations of neurons. The contribution of neural correlations to the change in mutual information was negative. The largest factor limiting fidelity of mutual information after pairing was a low reliability of the modified cortical responses. PMID- 21653721 TI - Tetrodotoxin-, dihydropyridine-, and riluzole-resistant persistent inward current: novel sodium channels in rodent spinal neurons. AB - Recently, we reported the tetrodotoxin (TTX)- and dihydropyridine (DHP)-resistant (TDR) inward currents in neonatal mouse spinal neurons. In this study, we further characterized these currents in the presence of 1-5 MUM TTX and 20-30 MUM DHP (nifedipine, nimodipine, or isradipine). TDR inward currents were recorded by voltage ramp (persistent inward current, TDR-PIC) and step (TDR-I(p)) protocols. TDR-PIC and TDR-I(p) were found in 80.2% of recorded neurons (101/126) crossing laminae I to X from T12 to L6. TDR-PIC activated at -28.6 +/- 13 mV with an amplitude of 80.6 +/- 75 pA and time constant of 470.6 +/- 240 ms (n = 75). TDR I(p) had an amplitude of 151.2 +/- 151 pA and a voltage threshold of -17.0 +/- 9 mV (n = 54) with a wide range of kinetics parameters. The half-maximal activation was -21.5 +/- 8 mV (-37 to -12 mV, n = 29) with a time constant of 5.2 +/- 2 ms (1.2-11.2 ms, n = 19), whereas the half-maximal inactivation was -26.9 +/- 9 mV ( 39 to -18 mV, n = 14) with a time constant of 1.4 +/- 0.4 s (0.5-2.2 s, n = 19). TDR-PIC and TDR-I(p) could be reduced by 60% in zero calcium and completely removed in zero sodium solutions, suggesting that they were mediated by sodium ions. Furthermore, the reversal potential of TDR-I(p) was estimated as 56.6 +/- 3 mV (n = 10). TDR-PIC and TDR-I(p) persisted in 1-205 MUM TTX, 20-100 MUM DHP, 3 30 MUM riluzole, 50-300 MUM flufenamic acid, and 2-30 mM intracellular BAPTA. They also persisted with T-, N-, P/Q-, and R-type calcium channel blockers. In conclusion, we demonstrated novel TTX-, DHP-, and riluzole-resistant sodium channels in neonatal rodent spinal neurons. The unique pharmacological and electrophysiological properties would allow these channels to play a functional role in spinal motor system. PMID- 21653722 TI - Dopamine triggers skeletal muscle tone by activating D1-like receptors on somatic motoneurons. AB - The dopamine system plays an integral role in motor physiology. Dopamine controls movement by modulation of higher-order motor centers (e.g., basal ganglia) but may also regulate movement by directly controlling motoneuron function. Even though dopamine cells synapse onto motoneurons, which themselves express dopamine receptors, it is unknown whether dopamine modulates skeletal muscle activity. Therefore, we aimed to determine whether changes in dopaminergic neurotransmission at a somatic motor pool affect motor outflow to skeletal muscles. We used microinjection, neuropharmacology, electrophysiology, and histology to determine whether manipulation of D(1)- and D(2)-like receptors on trigeminal motoneurons affects masseter and/or tensor palatini muscle tone in anesthetized rats. We found that apomorphine (a dopamine analog) activated trigeminal motoneurons and triggered a potent increase in both masseter and tensor palatini tone. This excitatory effect is mediated by D(1)-like receptors because specific D(1)-like receptor activation strengthened muscle tone and blockade of these receptors prevented dopamine-driven activation of motoneurons. Blockade of D(1)-like receptors alone had no detectable effect on basal masseter/tensor palatini tone, indicating the absence of a functional dopamine drive onto trigeminal motoneurons, at least during isoflurane anesthesia. Finally, we showed that D(2)-like receptors do not affect either trigeminal motoneuron function or masseter/tensor palatini muscle tone. Our results provide the first demonstration that dopamine can directly control movement by manipulating somatic motoneuron behavior and skeletal muscle tone. PMID- 21653724 TI - Impaired sensory nerve function and axon morphology in mice with diabetic neuropathy. AB - Diabetes is the most prevalent metabolic disorder in the United States, and between 50% and 70% of diabetic patients suffer from diabetes-induced neuropathy. Yet our current knowledge of the functional changes in sensory nerves and their distal terminals caused by diabetes is limited. Here, we set out to investigate the functional and morphological consequences of diabetes on specific subtypes of cutaneous sensory nerves in mice. Diabetes was induced in C57Bl/6 mice by a single intraperitoneal injection of streptozotocin. After 6-8 wk, mice were characterized for behavioral sensitivity to mechanical and heat stimuli followed by analysis of sensory function using teased nerve fiber recordings and histological assessment of nerve fiber morphology. Diabetes produced severe functional impairment of C-fibers and rapidly adapting Abeta-fibers, leading to behavioral hyposensitivity to both mechanical and heat stimuli. Electron microscopy images showed that diabetic nerves have axoplasm with more concentrated organelles and frequent axon-myelin separations compared with control nerves. These changes were restricted to the distal nerve segments nearing their innervation territory. Furthermore, the relative proportion of Abeta-fibers was reduced in diabetic skin-nerve preparations compared with nondiabetic control mice. These data identify significant deficits in sensory nerve terminal function that are associated with distal fiber loss, morphological damage, and behavioral hyposensitivity in diabetic C57Bl/6 mice. These findings suggest that diabetes damages sensory nerves, leading to functional deficits in sensory signaling that underlie the loss of tactile acuity and pain sensation associated with insensate diabetic neuropathy. PMID- 21653723 TI - The organization of the human cerebral cortex estimated by intrinsic functional connectivity. AB - Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition. PMID- 21653725 TI - Common muscle synergies for control of center of mass and force in nonstepping and stepping postural behaviors. AB - We investigated muscle activity, ground reaction forces, and center of mass (CoM) acceleration in two different postural behaviors for standing balance control in humans to determine whether common neural mechanisms are used in different postural tasks. We compared nonstepping responses, where the base of support is stationary and balance is recovered by returning CoM back to its initial position, with stepping responses, where the base of support is enlarged and balance is recovered by pushing the CoM away from the initial position. In response to perturbations of the same direction, these two postural behaviors resulted in different muscle activity and ground reaction forces. We hypothesized that a common pool of muscle synergies producing consistent task-level biomechanical functions is used to generate different postural behaviors. Two sets of support-surface translations in 12 horizontal-plane directions were presented, first to evoke stepping responses and then to evoke nonstepping responses. Electromyographs in 16 lower back and leg muscles of the stance leg were measured. Initially (~100-ms latency), electromyographs, CoM acceleration, and forces were similar in nonstepping and stepping responses, but these diverged in later time periods (~200 ms), when stepping occurred. We identified muscle synergies using non-negative matrix factorization and functional muscle synergies that quantified correlations between muscle synergy recruitment levels and biomechanical outputs. Functional muscle synergies that produce forces to restore CoM position in nonstepping responses were also used to displace the CoM during stepping responses. These results suggest that muscle synergies represent common neural mechanisms for CoM movement control under different dynamic conditions: stepping and nonstepping postural responses. PMID- 21653726 TI - Development of new peptide-based tools for studying synaptic ribbon function. AB - Synaptic ribbons are proteinaceous specialized electron-dense presynaptic structures found in nonspiking sensory cells of the vertebrate nervous system. Understanding the function of these structures is an active area of research (reviewed in Matthews G, Fuchs P. Nat Rev Neurosci 11: 812-822, 2010). Previous work had shown that ribbons could be effectively labeled and visualized using peptides that bind to the synaptic ribbon protein RIBEYE via a PXDLS motif (Zenisek D, Horst NK, Merrifield C, Sterling P, Matthews G. J Neurosci 24: 9752 9759, 2004). Here, we expand on the previous work to develop new tools and strategies for 1) better visualizing synaptic ribbons, and 2) monitoring and manipulating calcium on the synaptic ribbon. Specifically, we developed a new higher-affinity peptide-based label for visualizing ribbons in live cells and two strategies for localizing calcium indicators to the synaptic ribbon. PMID- 21653727 TI - Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons. AB - In the present study, we investigated whether intradermal cheek injection of pruritogens or algogens differentially elicits hindlimb scratches or forelimb wipes in Sprague-Dawley rats, as recently reported in mice. We also investigated responses of primary sensory trigeminal ganglion (TG) and dorsal root ganglion (DRG) cells, as well as second-order neurons in trigeminal subnucleus caudalis (Vc), to pruritic and algesic stimuli. 5-HT was the most effective chemical to elicit dose-dependent bouts of hindlimb scratches directed to the cheek, with significantly less forelimb wiping, consistent with itch. Chloroquine also elicited significant scratching but not wiping. Allyl isothiocyanate (AITC; mustard oil) elicited dose-dependent wiping with no significant scratching. Capsaicin elicited equivalent numbers of scratch bouts and wipes, suggesting a mixed itch and pain sensation. By calcium imaging, ~ 6% of cultured TG and DRG cells responded to 5-HT. The majority of 5-HT-sensitive cells also responded to chloroquine, AITC, and/or capsaicin, and one-third responded to histamine. Using a chemical search strategy, we identified single units in Vc that responded to intradermal cheek injection of 5-HT. Most were wide dynamic range (WDR) or nociceptive specific (NS), and a few were mechanically insensitive. The large majority additionally responded to AITC and/or capsaicin and thus were not pruritogen selective. These results suggest that primary and second-order neurons responsive to pruritogens and algogens may utilize a population coding mechanism to distinguish between itch and pain, sensations that are behaviorally manifested by distinct hindlimb scratching and forelimb wiping responses. PMID- 21653728 TI - Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5-HT1B and 5-HT1F receptors. AB - Sensory afferent transmission and associated spinal reflexes are normally inhibited by serotonin (5-HT) derived from the brain stem. Spinal cord injury (SCI) that eliminates this 5-HT innervation leads to a disinhibition of sensory transmission and a consequent emergence of unusually long polysynaptic excitatory postsynaptic potentials (EPSPs) in motoneurons. These EPSPs play a critical role in triggering long polysynaptic reflexes (LPRs) that initiate muscles spasms. In the present study we examined which 5-HT receptors modulate the EPSPs and whether these receptors adapt to a loss of 5-HT after chronic spinal transection in rats. The EPSPs and associated LPRs recorded in vitro in spinal cords from chronic spinal rats were consistently inhibited by 5-HT(1B) or 5-HT(1F) receptor agonists, including zolmitriptan (5-HT(1B/1D/1F)) and LY344864 (5-HT(1F)), with a sigmoidal dose-response relation, from which we computed the 50% inhibition (EC(50)) and potency (-log EC(50)). The potencies of 5-HT receptor agonists were highly correlated with their binding affinity to 5-HT(1B) and 5-HT(1F) receptors, and not to other 5-HT receptors. Zolmitriptan also inhibited the LPRs and general muscle spasms recorded in vivo in the awake chronic spinal rat. The 5-HT(1B) receptor antagonists SB216641 and GR127935 and the inverse agonist SB224289 reduced the inhibition of LPRs by 5-HT(1B) agonists (zolmitriptan). However, when applied alone, SB224289, SB216641, and GR127935 had no effect on the LPRs, indicating that 5-HT(1B) receptors do not adapt to chronic injury, remaining silent, without constitutive activity. The reduction in EPSPs with zolmitriptan unmasked a large glycine-mediated inhibitory postsynaptic current (IPSC) after SCI. This IPSC and associated chloride current reversed at -73 mV, slightly below the resting membrane potential. Zolmitriptan did not change motoneuron properties. Our results demonstrate that 5-HT(1B/1F) agonists, such as zolmitriptan, can restore inhibition of sensory transmission after SCI without affecting general motoneuron function and thus may serve as a novel class of antispastic drugs. PMID- 21653729 TI - Information conveyed by inferior colliculus neurons about stimuli with aligned and misaligned sound localization cues. AB - Previous studies have demonstrated that single neurons in the central nucleus of the inferior colliculus (ICC) are sensitive to multiple sound localization cues. We investigated the hypothesis that ICC neurons are specialized to encode multiple sound localization cues that are aligned in space (as would naturally occur from a single broadband sound source). Sound localization cues including interaural time differences (ITDs), interaural level differences (ILDs), and spectral shapes (SSs) were measured in a marmoset monkey. Virtual space methods were used to generate stimuli with aligned and misaligned combinations of cues while recording in the ICC of the same monkey. Mutual information (MI) between spike rates and stimuli for aligned versus misaligned cues were compared. Neurons with best frequencies (BFs) less than ~11 kHz mostly encoded information about a single sound localization cue, ITD or ILD depending on frequency, consistent with the dominance of ear acoustics by either ITD or ILD at those frequencies. Most neurons with BFs >11 kHz encoded information about multiple sound localization cues, usually ILD and SS, and were sensitive to their alignment. In some neurons MI between stimuli and spike responses was greater for aligned cues, while in others it was greater for misaligned cues. If SS cues were shifted to lower frequencies in the virtual space stimuli, a similar result was found for neurons with BFs <11 kHz, showing that the cue interaction reflects the spectra of the stimuli and not a specialization for representing SS cues. In general the results show that ICC neurons are sensitive to multiple localization cues if they are simultaneously present in the frequency response area of the neuron. However, the representation is diffuse in that there is not a specialization in the ICC for encoding aligned sound localization cues. PMID- 21653730 TI - Spatial structure of multiwhisker receptive fields in the barrel cortex is stimulus dependent. AB - The tactile sensations mediated by the whisker-trigeminal system allow rodents to efficiently detect and discriminate objects. These capabilities rely strongly on the temporal and spatial structure of whisker deflections. Subthreshold but also spiking receptive fields in the barrel cortex encompass a large number of vibrissae, and it seems likely that the functional properties of these multiwhisker receptive fields reflect the multiple-whisker interactions encountered by the animal during exploration of its environment. The aim of this study was to examine the dependence of the spatial structure of cortical receptive fields on stimulus parameters. Using a newly developed 24-whisker stimulation matrix, we applied a forward correlation analysis of spiking activity to randomized whisker deflections (sparse noise) to characterize the receptive fields that result from caudal and rostral directions of whisker deflection. We observed that the functionally determined principal whisker, the whisker eliciting the strongest response with the shortest latency, differed according to the direction of whisker deflection. Thus, for a given neuron, maximal responses to opposite directions of whisker deflections could be spatially separated. This spatial separation resulted in a displacement of the center of mass between the rostral and caudal subfields and was accompanied by differences between response latencies in rostral and caudal directions of whisker deflection. Such direction dependent receptive field organization was observed in every cortical layer. We conclude that the spatial structure of receptive fields in the barrel cortex is not an intrinsic property of the neuron but depends on the properties of sensory input. PMID- 21653731 TI - Preconception omega-3 fatty acid supplementation of adult male mice with a history of developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure prevents preterm birth in unexposed female partners. AB - We have recently reported that adult male C57BL/6 mice exposed in utero to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) confer an increased risk of preterm birth (PTB) to unexposed females. Risk of PTB was coincident with decreased placental progesterone receptor (Pgr) mRNA expression and increased toll-like receptor 4 (Tlr4) mRNA expression, suggesting that toxicant exposure induced a heightened inflammatory response at the maternal fetal interface. Since omega-3 fatty acids exhibit anti-inflammatory activity, in this study, we provided TCDD-exposed males a fish oil-enriched diet prior to mating. Although PTB was common in control females mated to TCDD-exposed males on the standard diet, fish oil supplementation of TCDD-exposed males eliminated PTB in unexposed partners. We also determined the influence of preconception, paternal fish oil supplementation on the placental inflammatory response in late pregnancy (E18.5) by examining the expression of Pgr and Tlr4 mRNA as well as the expression of 15-hydroxyprostaglandin dehydrogenase (PGDH). PGDH catabolizes the inflammatory PGE2 to an inactive form; thus, reduced expression of this enzyme would promote tissue inflammation. Compared with control pregnancies, examination of E18.5 placentas arising from TCDD-exposed males on the standard diet revealed a significant increase in Tlr4 mRNA expression corresponding to a reduction in Pgr mRNA and PGDH protein expression. In contrast, fish oil supplementation of toxicant-exposed males led to normalization of placental expression of both Pgr and Tlr4 mRNA and a marked increase in PGDH expression. These studies suggest that a paternal preconception diet that includes omega-3 fatty acids prevents the toxicant-associated increase in the placental inflammatory response at late gestation, preventing PTB. PMID- 21653733 TI - eNOS activation and NO function: differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia. AB - Nitric oxide (NO) plays a role in a wide range of physiological processes. Aside from its widely studied function in the regulation of vascular function, NO has been shown to impact steroidogenesis in a number of different tissues. The goal of this review is to explore the effects of NO on steroid production and further, to discern its source(s) and mechanism of action. Attention will be given to the regulation of NO synthases in specific endocrine tissues including ovaries, testes, and adrenal glands. The effects of hypoxia on generation of NO and subsequent effects on steroid biosynthesis will also be examined. Finally, a potential model for the interaction of hypoxia on NO synthesis and steroid production is proposed. PMID- 21653732 TI - Role of ATRX in chromatin structure and function: implications for chromosome instability and human disease. AB - Functional differentiation of chromatin structure is essential for the control of gene expression, nuclear architecture, and chromosome stability. Compelling evidence indicates that alterations in chromatin remodeling proteins play an important role in the pathogenesis of human disease. Among these, alpha thalassemia mental retardation X-linked protein (ATRX) has recently emerged as a critical factor involved in heterochromatin formation at mammalian centromeres and telomeres as well as facultative heterochromatin on the murine inactive X chromosome. Mutations in human ATRX result in an X-linked neurodevelopmental condition with various degrees of gonadal dysgenesis (ATRX syndrome). Patients with ATRX syndrome may exhibit skewed X chromosome inactivation (XCI) patterns, and ATRX-deficient mice exhibit abnormal imprinted XCI in the trophoblast cell line. Non-random or skewed XCI can potentially affect both the onset and severity of X-linked disease. Notably, failure to establish epigenetic modifications associated with the inactive X chromosome (Xi) results in several conditions that exhibit genomic and chromosome instability such as fragile X syndrome as well as cancer development. Insight into the molecular mechanisms of ATRX function and its interacting partners in different tissues will no doubt contribute to our understanding of the pathogenesis of ATRX syndrome as well as the epigenetic origins of aneuploidy. In turn, this knowledge will be essential for the identification of novel drug targets and diagnostic tools for cancer progression as well as the therapeutic management of global epigenetic changes commonly associated with malignant neoplastic transformation. PMID- 21653734 TI - BRAF(V600E) mutation and expression of proangiogenic molecular markers in papillary thyroid carcinomas. AB - OBJECTIVE: Tyrosine kinase inhibitors (TKIs) are evaluated for treatment of radioiodine refractory thyroid cancer. Their effects in this setting are based on blockade of proangiogenic signaling mediated by receptors for vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGF). Most TKIs also block other cancer-relevant kinases, such as B-type Raf kinase (BRAF), which are constitutively activated in approximately half of papillary thyroid carcinomas (PTCs), but the impact of these effects is not clear. DESIGN: The aim of our study was to investigate the impact of BRAF(V600E) on proangiogenic gene expression and microvascular features of PTCs. METHODS: mRNA levels for VEGFA, VEGF receptors, and coreceptors (VEGFRs 1, 2, and 3, neuropilin 1), and PDGF receptor beta (PDGFRbeta or PDGFRB) were measured with real-time PCR in BRAF(V600E) (n=55) and wild-type BRAF (BRAF-wt; n=35) PTCs. VEGF and VEGFR protein expression and microvessel densities (MVD) and lymphatic vessel densities (LVDs) were assessed by immunohistochemistry in 22 of the 90 PTCs (including 11 BRAF(V600E) cases). Angiogenic gene expression was also studied in vitro after induction/silencing of the BRAF(V600E) mutation in thyrocyte lines. RESULTS: Transcript levels of proangiogenic factors were significantly lower in BRAF(V600E) PTCs versus BRAF-wt PTCs (P<0.0001), but MVD and LVDs were not significantly different. VEGFA mRNA levels in thyroid cell lines decreased when BRAF(V600E) mutation was induced (P=0.01) and increased when it was silenced (P=0.01). CONCLUSIONS: Compared with BRAF-wt PTCs, those harboring BRAF(V600E) exhibit downregulated VEGFA, VEGFR, and PDGFRbeta expression, suggesting that the presence of BRAF mutation does not imply a stronger prediction of response to drugs targeting VEGF and PDGFB signaling pathways. PMID- 21653735 TI - Increased serum and bone matrix levels of transforming growth factor {beta}1 in patients with GH deficiency in response to GH treatment. AB - OBJECTIVE: Patients with adult onset GH deficiency (aoGHD) have secondary osteoporosis, which is reversed by long-term GH substitution. Transforming growth factor beta1 (TGFbeta1 or TGFB1) is abundant in bone tissue and could mediate some effects of GH/IGFs on bone. We investigated its regulation by GH/IGF1 in vivo and in vitro. DESIGN AND METHODS: The effects of GH substitution (9-12 months, placebo controlled) on circulating and cortical bone matrix contents of TGFbeta1 were investigated in patients with aoGHD. The effects of GH/IGF1 on TGFbeta1 secretion in osteoblasts (hFOB), adipocytes, and THP-1 macrophages as well as the effects on release from platelets were investigated in vitro. RESULTS: In vivo GH substitution increased TGFbeta1 protein levels in cortical bone and serum. In vitro, GH/IGF1 stimulation induced a significant increase in TGFbeta1 secretion in hFOB. In contrast, no major effect of GH/IGF1 on TGFbeta1 was found in adipocytes and THP-1 macrophages. Finally, a minor modifying effect on SFLLRN-stimulated platelet release of TGFbeta1 was observed in the presence of IGF1. CONCLUSION: GH substitution increases TGFbeta1 in vivo and in vitro, and this effect could contribute to improved bone metabolism during such therapy, potentially reflecting direct effect of GH/IGF1 on bone cells. PMID- 21653736 TI - Review: probiotics prevented necrotising enterocolitis and reduced mortality in preterm neonates. PMID- 21653737 TI - Review: physical interventions may reduce the transmission of respiratory viruses. PMID- 21653739 TI - Multicentric evaluation of new commercial enzyme immunoassays for the detection of immunoglobulin M and total antibodies against hepatitis A virus. AB - A multicentric clinical study was conducted on representative sera from 1,738 European and U.S. subjects for the evaluation of new anti-hepatitis A virus enzyme immunoassays from Bio-Rad Laboratories. Comparison with reference DiaSorin S.p.A. tests confirmed the good performance of Bio-Rad assays (99.85% and 99.47% overall agreement in detecting total antibodies and IgM, respectively). PMID- 21653738 TI - High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. AB - All immunoglobulin G molecules carry N-glycans, which modulate their biological activity. Changes in N-glycosylation of IgG associate with various diseases and affect the activity of therapeutic antibodies and intravenous immunoglobulins. We have developed a novel 96-well protein G monolithic plate and used it to rapidly isolate IgG from plasma of 2298 individuals from three isolated human populations. N-glycans were released by PNGase F, labeled with 2-aminobenzamide and analyzed by hydrophilic interaction chromatography with fluorescence detection. The majority of the structural features of the IgG glycome were consistent with previous studies, but sialylation was somewhat higher than reported previously. Sialylation was particularly prominent in core fucosylated glycans containing two galactose residues and bisecting GlcNAc where median sialylation level was nearly 80%. Very high variability between individuals was observed, approximately three times higher than in the total plasma glycome. For example, neutral IgG glycans without core fucose varied between 1.3 and 19%, a difference that significantly affects the effector functions of natural antibodies, predisposing or protecting individuals from particular diseases. Heritability of IgG glycans was generally between 30 and 50%. The individual's age was associated with a significant decrease in galactose and increase of bisecting GlcNAc, whereas other functional elements of IgG glycosylation did not change much with age. Gender was not an important predictor for any IgG glycan. An important observation is that competition between glycosyltransferases, which occurs in vitro, did not appear to be relevant in vivo, indicating that the final glycan structures are not a simple result of competing enzymatic activities, but a carefully regulated outcome designed to meet the prevailing physiological needs. PMID- 21653740 TI - Identification of antigenic targets for immunodetection of Balamuthia mandrillaris infection. AB - The free-living amoeba Balamuthia mandrillaris causes granulomatous amoebic encephalitis (GAE) in humans. Rapid identification of balamuthiasis is critical for effective therapeutic intervention and case management. In the present study we identified target antigens for the development of a serological assay for B. mandrillaris infection. We demonstrated by silver staining that protein profiles for all eight isolates of B. mandrillaris, independent of human or animal origin or geographic origin, appeared to be similar except for some minor differences, indicating the molecular homogeneity of these strains. The profiles of all isolates, which ranged from 200 to 10 kDa, were similar, with a prominent protein visible around 30 kDa; all appeared considerably different from protein profiles of the control E6 cells and Acanthamoeba castellanii and Naegleria fowleri isolates. Western blot analysis with rabbit hyperimmune serum identified the major immunodominant antigens of 25, 50, 75, and 80 kDa; positive human sera reacted strongly with proteins around 25, 40, 50, and 75 kDa. Proteins around 40 kDa detected by human serum were not recognized by hyperimmune rabbit serum. None of the target proteins were detected by uninfected control sera. Reactivities of five patients' sera with 4 different isolates of B. mandrillaris (2 strains of human and 2 strains of animal origins) revealed that patients' sera reacted slightly differently with different B. mandrillaris isolates, although major proteins of approximately 25, 50, and 75 kDa were present in all extracts. PMID- 21653741 TI - Disturbed homeostasis and multiple signaling defects in the peripheral blood B cell compartment of patients with severe chronic sarcoidosis. AB - The presence of hypergammaglobulinemia, autoantibodies, and circulating immune complexes suggests that humoral immunity may contribute to the pathogenesis of sarcoidosis. However, little is known about the role played by B cells in the development of this disease. Here we investigated the subpopulation distribution, response to stimulation, and levels of the nuclear transcription factor NF kappaB/p65 in peripheral blood B cells from patients with severe chronic sarcoidosis. Patients with severe chronic sarcoidosis had absolute B-cell lymphopenia and exhibited significantly decreased frequencies and total numbers of memory (CD19(+) CD27(+)) B cells. The reduced numbers of memory B cells in these patients reflected a decrease in the total numbers of class-switched (CD19(+) CD27(+) IgD(-)) and unswitched (CD19(+) CD27(+) IgD(+)) memory B cells and coincided with an increased frequency of circulating (CD19(+/-) CD20(-) CD27(++)) plasmablasts. Polyclonal stimulation of sarcoid B cells resulted in reduced expression of activation markers (i.e., CD25, CD69, and CD86), decreased proliferation, and impaired plasma cell differentiation. Baseline expression of p65 in B cells was reduced in 65% of the patients. These results suggest disturbed homeostasis, intrinsic signaling defects, and anergy within the peripheral B-cell compartments of patients with severe chronic sarcoidosis. PMID- 21653742 TI - OdDHL inhibits T cell subset differentiation and delays diabetes onset in NOD mice. AB - Some infectious diseases have been shown to halt the onset of autoimmune disease in animal models and have been suggested to also influence autoimmune pathology in humans. The isolation and study of small molecules and proteins from the infectious agents responsible for the protective effect will enable a mechanistic understanding of how these components may prevent or delay the onset of autoimmunity. In this study we confirm that the quorum-sensing signal molecule OdDHL from Pseudomonas aeruginosa can delay the onset of type 1 diabetes in the NOD mouse model. Furthermore, using an antigen-presenting cell-free system, we find not only that OdDHL inhibits the proliferation of naive T cells but also that it directly inhibits the differentiation of T cell subsets. OdDHL was shown to have no effect on the inhibition of primed and committed differentiated T cell responses, suggesting that that immune mechanism mediated by this molecule may be more restricted to initial stages of infection. PMID- 21653743 TI - Seroprevalence to influenza A(H1N1) 2009 virus--where are we? AB - Age-specific seroprevalences for influenza virus make important contributions to estimating the burden of infection and determining the vulnerable populations. It is especially difficult to know the true clinical attack rates of the 2009 influenza A(H1N1) pandemic; however, we can estimate infection rates through analyses of seroprevalences based on national studies from different continents and countries with different demographics. After the 2009 influenza A(H1N1) pandemic, seroprevalence studies found 5 to 60% of populations across different continents and age groups having antibodies against the A(H1N1) 2009 virus. The seropositivity was highest in children and teenagers (20 to 60%) as well as in the elderly older than 80 years (20 to 40%). Preexisting cross-reactive antibodies against the virus were present mostly in sera of older people (born before 1950) who could have encountered viruses descended from the 1918 pandemic viruses. Experience with the 2009 pandemic indicates how essential early and timely serology data against the emerging virus can be for informing decisions on use of antivirals and vaccination campaigns, especially in regard to risk groups. The objectives of this review were to summarize the current data available on seroprevalence before and after the 2009 influenza A(H1N1) pandemic and the lessons learned for future pandemic preparedness. PMID- 21653744 TI - Streptococcus agalactiae alpha-like protein 1 possesses both cross-reacting and Alp1-specific epitopes. AB - Most isolates of group B streptococci (GBS) express an alpha-like protein (Alp), Calpha (encoded by bca), Alp1 (also called epsilon; alp1), Alp2 (alp2), Alp3 (alp3), Alp4 (alp4), or R4/Rib (rib). These proteins are chimeras with a mosaic structure and with antigenic determinants with variable immunological cross reactivities between the Alps, including Alp1 and Calpha cross-reactivity. This study focused on antigenic domains of Alp1, studied by using rabbit antisera in immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA)-based tests and whole cells of GBS or trypsin-extracted and partially purified antigens from the strains A909 (serotype Ia/Calpha, Cbeta) and 335 (Ia/Alp1). Alp1 and Calpha shared an antigenic determinant, Alp1/Calpha common, not harbored by other Alps, probably located in the Alp1 and Calpha repeat units, as these units are nearly identical in genomic sequence. An antigenic Alp1 determinant was Alp1 specific and was most likely located in the N-terminal unit of Alp1 in which an Alp1-specific primer site for PCR is also located. In addition, Alp1 possessed a domain with low immunogenicity which cross-reacted immunologically with Alp2 and Alp3, with unknown location in Alp1. Alp1 was partially degraded by trypsin during antigen extraction but with the antigenic domains preserved. The results indicate that Calpha and Alp1 are immunologically related in the same manner that R4 (Rib) and Alp3 are related. The domain called Alp1 specific should be important in GBS serotyping as a surface-anchored serosubtype marker. The Alp1/Calpha common determinant may be of prime interest as an immunogenic domain in a GBS vaccine. PMID- 21653745 TI - A live-attenuated chimeric porcine circovirus type 2 (PCV2) vaccine is transmitted to contact pigs but is not upregulated by concurrent infection with porcine parvovirus (PPV) and porcine reproductive and respiratory syndrome virus (PRRSV) and is efficacious in a PCV2b-PRRSV-PPV challenge model. AB - The live chimeric porcine circovirus type 2 (PCV2) vaccine with the capsid gene of the emerging subtype 2b cloned in the genomic backbone of the nonpathogenic PCV1 is attenuated in vivo and induces protective immunity against PCV2. To further determine the safety and efficacy of this experimental vaccine, we tested for evidence of pig-to-pig transmission by commingling nonvaccinated and vaccinated pigs, determined potential upregulation by simultaneous vaccination and infection with porcine parvovirus (PPV) and porcine reproductive and respiratory syndrome virus (PRRSV), and determined vaccine efficacy by challenging pigs 4 weeks after vaccination with PCV2b, PRRSV, and PPV. Forty-six 21-day-old, PCV2-naive pigs were randomly assigned to one of six groups. Twenty nine of 46 pigs were challenged with PCV2b, PRRSV, and PPV at day 28, 8/46 remained nonvaccinated and nonchallenged and served as negative controls, and 9/46 remained nonchallenged and served as vaccination controls. All animals were necropsied at day 49. PCV1-PCV2 viremia was detected in nonvaccinated contact pigs commingled with vaccinated pigs, indicating pig-to-pig transmission; however, PCV1-PCV2 DNA levels remained low in all vaccinated and contact pigs regardless of concurrent infection. Finally, vaccination 28 days before challenge resulted in significantly (P < 0.05) decreased amounts of PCV2 in tissues and sera and significantly (P < 0.05) reduced macroscopic and microscopic lesions. The results of this study indicate that the experimental live-attenuated chimeric PCV2 vaccine, although transmissible to contact pigs, remains attenuated in pigs concurrently infected with PRRSV and PPV and induces protective immunity against PCV2b when it is administered 28 days before PCV2 exposure. PMID- 21653746 TI - Temporal development of the infant gut microbiota in immunoglobulin E-sensitized and nonsensitized children determined by the GA-map infant array. AB - At birth, the human infant gut is sterile, but it becomes fully colonized within a few days. This initial colonization process has a major impact on immune development. Our knowledge about the correlations between aberrant colonization patterns and immunological diseases, however, is limited. The aim of the present work was to develop the GA-map (Genetic Analysis microbiota array platform) infant array and to use this array to compare the temporal development of the gut microbiota in IgE-sensitized and nonsensitized children during the first 2 years of life. The GA-map infant array is composed of highly specific 16S rRNA gene targeted single nucleotide primer extension (SNuPE) probes, which were designed based on extensive infant 16S rRNA gene sequence libraries. For the clinical screening, we analyzed 216 fecal samples collected from a cohort of 47 infants (16 sensitized and 31 nonsensitized) from 1 day to 2 years of age. The results showed that at a high taxonomic level, Actinobacteria was significantly overrepresented at 4 months while Firmicutes was significantly overrepresented at 1 year for the sensitized children. At a lower taxonomic level, for the sensitized group, we found that Bifidobacterium longum was significantly overrepresented at the age of 1 year and Enterococcus at the age of 4 months. For most phyla, however, there were consistent differences in composition between age groups, irrespective of the sensitization state. The main age patterns were a rapid decrease in staphylococci from 10 days to 4 months and a peak of bifidobacteria and bacteroides at 4 months. In conclusion, our analyses showed consistent microbiota colonization and IgE sensitization patterns that can be important for understanding both normal and diseased immunological development in infants. PMID- 21653747 TI - Effects of progesterone and estradiol sex hormones on the release of microparticles by RAW 264.7 macrophages stimulated by Poly(I:C). AB - Microparticles (MPs) are small membrane-bound vesicles that display proinflammatory and prothrombotic properties. These particles can be released by macrophages stimulated by ligands of the Toll-like receptors (TLRs) in a process that depends on nitric oxide (NO) production. Since sex hormones can modulate macrophage responses, we investigated the effects of progesterone and estradiol on macrophage particle release in vitro, comparing the responses with those induced by the glucocorticoid dexamethasone. As a model system for particle release, RAW 264.7 cells were stimulated in vitro with poly(I:C), a ligand of TLR3. Microparticles were measured by flow cytometry, while NO was measured by the Griess reaction. As the results of these studies showed, progesterone but not estradiol can block particle release by RAW264.7 cells treated with poly(I:C); dexamethasone was also active. Furthermore, while progesterone and dexamethasone inhibited NO production under the same culture conditions, neither agent blocked the production of particles stimulated by the NO donors dipropylenetriamine NONOate {(z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino] diazen-1-ium-1,2 diolate} and (z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate. Studies using RU486 to assess the role of hormone receptors indicated that while this agent blocked the inhibition of particle and NO production by dexamethasone, it did not affect the inhibition by progesterone. Together, these results indicate that progesterone but not estradiol can inhibit particle release by stimulated macrophages and suggest a mechanism that may contribute to the immunomodulatory effects of this sex hormone. PMID- 21653749 TI - Publish and be damned? PMID- 21653748 TI - Identification, bioinformatics analyses, and expression of immunoreactive antigens of Mycoplasma haemofelis. AB - Mycoplasma haemofelis infection frequently causes anemia in cats. Despite an intense immune response and/or antibiotic treatment, cats often remain asymptomatic carriers following infection. Our hypothesis is that detection of antibodies to M. haemofelis is a sensitive approach for identifying infected cats, particularly carriers. To date, no immunoassay has been developed. This is due largely to the inability to culture M. haemofelis in vitro; hence, a source of antigen is not readily available. The objective of this study was to identify, express, and purify immunogenic proteins of M. haemofelis. To accomplish this, two whole-genomic expression libraries were created in the Lambda ZapII vector and immunoscreened with preimmune plasma, plasma from specific-pathogen-free cats, and pooled acute- and convalescent-phase plasma from experimentally infected cats. The inserts from 21 immunoreactive clones were sequenced, resulting in the identification of 60 genes coding for putative proteins necessary for diverse cellular functions, along with several novel genes of M. haemofelis. Fragments of selected genes based on bioinformatic analyses were PCR amplified, cloned into a high-level protein expression system, and subsequently expressed in Escherichia coli as a His(6)-fusion protein. The recombinant fusion proteins of M. haemofelis were purified and evaluated as an antigen in a Western blot to verify the findings of previous immunoscreening. Together with bioinformatics analyses of individual genes, this approach provided several putative candidate antigens. Five antigens of M. haemofelis were reactive by Western blotting against the immune plasma and negative against nonimmune plasma; these antigens might be useful serologic or even vaccine targets. PMID- 21653750 TI - Increased detection of cystic-fibrosis-related diabetes in Australia. AB - OBJECTIVES: To estimate the incidence of cystic-fibrosis-related diabetes (CFRD) in youth from New South Wales (NSW) and the Australian Capital Territory (ACT), Australia and to examine demographic/clinical features at diagnosis. METHODS: Incident cases of CFRD in young people aged <= 18 years diagnosed during 2000 to 2008 were identified from four paediatric cystic fibrosis (CF) clinics and the NSW/ACT Australasian Paediatric Endocrine Group Diabetes Register. RESULTS: CFRD was diagnosed in 41 cases (59% girls). The estimated mean annual incidence of CFRD among patients with CF was 9.4 per 1000 person years (95% CI 6.8 to 12.8). Incidence increased from 2.0 per 1000 person years in 2000 to 22.1 per 1000 in 2008 (incidence RR 1.3, 95% CI 1.1 to 1.4). Haemoglobin A1c (HbA1c) was abnormal in the majority at diagnosis: median HbA1c was 6.9% (6.2-8.1%). More cases were diagnosed using an oral glucose tolerance test in 2007-2008 compared with previous years (61% vs 6%, p<0.001). CONCLUSIONS: CFRD is increasingly recognised and now affects approximately one in five young people with CF. The rising incidence is likely to be due to increased detection, resulting from greater awareness and changes in screening practices. Widespread uptake of consensus guidelines for screening will ensure accurate case detection, but will also impact on patient care and resource allocation. PMID- 21653751 TI - Sperm motility: is viscosity fundamental to progress? AB - The success of internal fertilization is reliant upon successful sperm migration through the female tract. Timely location of the oocyte in what is a complex three-dimensional, highly invaginated series of moist opposed surfaces is a challenge at which only tens of sperm ever succeed. In part this could be due to the differences in scale, with a 50 um long cell facing a probable migration of well over 20 cm due to the complex architecture. Many groups have focused upon the role for a chemotactic 'attractive egg' effect in guiding sperm to increase numbers at the fertilization site. What most research has neglected to consider is the role that the viscosity of the mucous layers, which coat the entire tract and through which sperm must swim, plays in both sperm selection and ongoing modulation of their behaviour. From allowing sperm to enter through the cervix during the ovulation phase, to denying them entrance through action of the female contraceptive pill, viscous effects are fundamental in controlling the migrating sperm population throughout the tract. The physiological effects of viscosity are also crucial to consider when designing and extrapolating data from in vitro experiments to the in vivo situation. PMID- 21653752 TI - Cross-protective immunity against influenza pH1N1 2009 viruses induced by seasonal influenza A (H3N2) virus is mediated by virus-specific T-cells. AB - Influenza A (H1N1) viruses of swine origin were introduced into the human population in 2009 and caused a pandemic. The disease burden in the elderly was relatively low, which was attributed to the presence of cross-reacting serum antibodies in this age group, which were raised against seasonal influenza A (H1N1) viruses that circulated before 1957. It has also been described how infection with heterosubtypic influenza viruses can induce some degree of protection against infection by a novel strain of influenza virus. Here, we assess the extent of protective immunity against infection with the 2009 influenza A (H1N1) pandemic influenza virus that is afforded by infection with a seasonal influenza A (H3N2) virus in mice. Mice that experienced a primary A (H3N2) influenza virus infection displayed reduced weight loss after challenge infection and cleared the 2009 influenza A (H1N1) virus infection more rapidly. To elucidate the correlates of protection of this heterosubtypic immunity to pandemic H1N1 virus infection, adoptive transfer experiments were carried out by using selected post-infection lymphocyte populations. Virus-specific CD8(+) T cells in concert with CD4(+) T-cells were responsible for the observed protection. These findings may not only provide an explanation for epidemiological differences in the incidence of severe pandemic H1N1 infections, they also indicate that the induction of cross-reactive virus-specific CD8(+) and CD4(+) T-cell responses may be a suitable approach for the development of universal influenza vaccines. PMID- 21653753 TI - A rep-based hairpin inhibits replication of diverse maize streak virus isolates in a transient assay. AB - Maize streak disease, caused by the A strain of the African endemic geminivirus, maize streak mastrevirus (MSV-A), threatens the food security and livelihoods of subsistence farmers throughout sub-Saharan Africa. Using a well-established transient expression assay, this study investigated the potential of a spliceable intron hairpin RNA (hpRNA) approach to interfere with MSV replication. Two strategies were explored: (i) an inverted repeat of a 662 bp region of the MSV replication-associated protein gene (rep), which is essential for virus replication and is therefore a good target for post-transcriptional gene silencing; and (ii) an inverted repeat of the viral long intergenic region (LIR), considered for its potential to trigger transcriptional silencing of the viral promoter region. After co-bombardment of cultured maize cells with each construct and an infectious partial dimer of the cognate virus genome (MSV-Kom), followed by viral replicative-form-specific PCR, it was clear that, whilst the hairpin rep construct (pHPrepDeltaI(662)) completely inhibited MSV replication, the LIR hairpin construct was ineffective in this regard. In addition, pHPrepDeltaI(662) inhibited or reduced replication of six MSV-A genotypes representing the entire breadth of known MSV-A diversity. Further investigation by real-time PCR revealed that the pHPrepDeltaI(662) inverted repeat was 22-fold more effective at reducing virus replication than a construct containing the sense copy, whilst the antisense copy had no effect on replication when compared with the wild type. This is the first indication that an hpRNA strategy targeting MSV rep has the potential to protect transgenic maize against diverse MSV-A genotypes found throughout sub-Saharan Africa. PMID- 21653754 TI - Deubiquitination activity associated with hepatitis E virus putative papain-like cysteine protease. AB - Hepatitis E virus (HEV) ORF1 protein (pORF1) contains methyltransferase (MetT), papain-like cysteine protease (PCP), RNA helicase (Hel) and RNA-dependent RNA polymerase (RdRp) domains. ORF1 sequence analysis showed two consensus LXGG cleavage sites at 664 and 1205. LXGG sequence is recognized by viral and cellular deubiquitinating enzymes. The protein encompassing the predicted MetT-PCP domains of HEV ORF1 was tested for deubiquitinating activity using fluorogenic substrates - ubiquitin-7-amino-4-methylcoumarin (AMC), IFN-stimulated gene 15 (ISG15)-AMC, Nedd8-AMC and SUMO-AMC. MetT-PCP cleaved all four substrates but processing of ISG15-AMC was more robust. There was no processing of the Hel and RdRp domains having the conserved (1205) LXGG site by the protein. MetT-PCP carried out deISGylation of the ISG15-conjugated cellular proteins, suggesting a possible role in combating cellular antiviral pathways. PMID- 21653755 TI - Hepatitis C virus infection induces the expression of amphiregulin, a factor related to the activation of cellular survival pathways and required for efficient viral assembly. AB - Amphiregulin (AREG) is a ligand of the epidermal growth factor (EGF) receptor and may play a role in the development of cirrhosis and hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). AREG showed an enhanced expression in HCV-infected human hepatoma cells according to gene array analysis. Therefore, we addressed the question about the role of AREG in HCV infection. AREG expression level was elevated in hepatoma cells containing a subgenomic HCV replicon or infected by HCV. Using a reporter assay, AREG promoter activity was found to be upregulated upon HCV infection. The enhanced AREG expression in hepatoma cells was partly caused by dsRNAs, HCV NS3 protein and autocrine stimulation. AREG was able to activate cellular signalling pathways including ERK, Akt and p38, promote cell proliferation, and protect cells from HCV-induced cell death. Further, knockdown of AREG expression increased the efficiency of HCV entry, as proven by HCV pseudoparticles reporter assay. However, the formation and release of infectious HCV particles were reduced by AREG silencing with a concomitant accumulation of intracellular HCV RNA pool, indicating that the assembly and release of HCV progeny may require AREG expression. Blocking the MAPK-ERK pathway by U0126 in Huh7.5.1 cells had a similar effect on HCV replication. In conclusion, HCV infection leads to an increase in AREG expression in hepatocytes. AREG expression is essential for efficient HCV assembly and virion release. Due to the activation of the cellular survival pathways, AREG may counteract HCV-induced apoptosis of infected hepatocytes and facilitate the development of liver cirrhosis and hepatocellular carcinoma. PMID- 21653756 TI - School nurses' role in identifying and referring children at risk of noise induced hearing loss. AB - Young people are likely to experience noise-induced hearing loss (NIHL), as the use of personal listening devices and other damaging factors (e.g., video games) increases. Little research has examined the role of school health personnel in the prevention and early identification of hearing impairment. A 32-item, valid and reliable survey was developed regarding elementary and middle school nurses' practices concerning hearing loss screening and prevention. The survey instrument was based on the Stages of Change theory and the Health Belief Model. A random sample of 800 nurses was obtained from The National Association of School Nurses. A two-wave mailing was used to achieve a 58% response rate. Forty eight percent indicated there were not many educational programs that addressed NIHL in students. Performing hearing screenings routinely can help identify those students at risk. School nurses need to become advocates for policies and programs that mandate hearing screenings and educational programs to help reduce hearing loss. PMID- 21653757 TI - Antifungal susceptibilities of Sporothrix albicans, S. brasiliensis, and S. luriei of the S. schenckii complex identified in Brazil. AB - We studied 40 strains of the species complex formerly classified as the single species Sporothrix schenckii to identify new species within this complex and evaluate their antifungal susceptibility profiles. Based on phenotypic tests (ability to grow at 37 degrees C, colony diameters, and pigmentation of the colonies, as well as assimilation of sucrose and raffinose) and molecular assays (amplification of a fragment of the calmodulin gene), here we report the identification of S. albicans, S. brasiliensis, S. luriei, and S. schenckii; two isolates of these species were detected as itraconazole-resistant strains. PMID- 21653758 TI - Evaluation of high-resolution typing methods for Chlamydia trachomatis in samples from heterosexual couples. AB - We aimed to compare conventional ompA typing of Chlamydia trachomatis with multilocus sequence typing (MLST) and multilocus variable-number tandem-repeat (VNTR) analysis (MLVA). Previously used MLST and MLVA systems were compared to modified versions that used shorter target regions and nested PCR. Heterosexual couples were selected from among persons with urogenital C. trachomatis infections visiting the sexually transmitted infection outpatient clinic in Amsterdam, The Netherlands. We identified 30 couples with a total of 65 C. trachomatis-positive samples on which MLST and MLVA for eight target regions were performed. All regions were successfully sequenced in 52 samples, resulting in a complete profile for 18 couples and 12 individuals. Nine ompA genovars from D to K, with two variants of genovar G, were found. The numbers of sequence type and MLVA type profiles were 20 for MLST and 21 for MLVA, and a combination of MLST and MLVA yielded 28 profiles, with discriminatory indexes (D) ranging from 0.95 to 0.99. Partners in 17 couples shared identical profiles, while partners in 1 couple had completely different profiles. Three persons had infections at multiple anatomical locations, and within each of these three individuals, all profiles were identical. The discriminatory capacity of all MLST and MLVA methods is much higher than that of ompA genotyping (D = 0.78). No genotype variation was found within the samples of the same person or from heterosexual couples with a putative single transmission. This shows that the chlamydial genome in clinical specimens has an appropriate polymorphism to enable epidemiological cluster analysis using MLST and MLVA. PMID- 21653759 TI - New diagnostic microarray (Check-KPC ESBL) for detection and identification of extended-spectrum beta-lactamases in highly resistant Enterobacteriaceae. AB - The performance of a microarray for the detection of extended-spectrum beta lactamases was determined on a collection of 638 highly resistant members of the family Enterobacteriaceae collected from patients in 18 hospitals in The Netherlands. The microarray had a significantly higher specificity than the phenotypic assays. It also detects carbapenemases and characterizes the resistance genes, providing epidemiological insight. PMID- 21653760 TI - Incidence of moxifloxacin resistance in clinical Mycobacterium tuberculosis isolates in Houston, Texas. AB - Comprehensive data on the prevalence of quinolone resistance in Mycobacterium tuberculosis clinical isolates in the United States are scarce. By use of a systematic population-based approach, M. tuberculosis strains from tuberculosis (TB) cases were collected in Harris County, TX, in 2007 to 2008. The susceptibilities of M. tuberculosis isolates to moxifloxacin and ofloxacin were determined by the agar proportion indirect susceptibility method. Spoligotyping and 12-locus mycobacterial interspersed repetitive unit (MIRU12)-based genotyping of M. tuberculosis isolates were performed, and the gyrA, gyrB, Rv2686c, Rv2687c, and Rv2688c genes in quinolone-resistant and year-of-diagnosis-matched M. tuberculosis isolates were sequenced. Susceptibility testing was performed on 557 M. tuberculosis isolates, of which 10 (1.8%) were resistant to moxifloxacin. There was 100% concordance between ofloxacin and moxifloxacin susceptibilities. A quinolone was prescribed to at least 5 (50%) patients in the period preceding TB diagnosis. Multidrug-resistant TB (MDR-TB) was significantly associated with quinolone resistance (P = 0.01). Mutations in the quinolone resistance determining region of gyrA were found for 50% of the resistant isolates. No other presumptive quinolone resistance-associated mutations were identified. We conclude that the incidence of moxifloxacin-resistant TB is low in Harris County and is associated with MDR-TB. Previous exposure to quinolones is common among patients with moxifloxacin resistance and warrants more careful evaluation. PMID- 21653761 TI - Controlled comparison of BacT/Alert MB system, manual Myco/F lytic procedure, and isolator 10 system for diagnosis of Mycobacterium tuberculosis Bacteremia. AB - We compared the performance of the BacT/Alert MB system, that of the manual Bactec Myco/F Lytic procedure, and that of the Isolator 10 lysis-centrifugation system in the detection of Mycobacterium tuberculosis bacteremia. Mean times to detection were 16.4 days for BacT/Alert MB versus 20.0 days for Myco/F Lytic, 16.5 days for BacT/Alert MB versus 23.8 days for Isolator 10, and 21.1 days for Bactec Myco/F Lytic versus 22.7 days for Isolator 10. There were no significant differences in yields. The mean (range) magnitude of mycobacteremia was 30.0 (0.4, 90.0) CFU/ml and was correlated with the time to positivity in the BacT/Alert MB system (r = -0.4920). M. tuberculosis bacteremia was detected more rapidly in a continuously monitored liquid blood culture system, but the mean time to positivity exceeded 3 weeks. PMID- 21653762 TI - Rapid identification of Cryptococcus neoformans and Cryptococcus gattii by matrix assisted laser desorption ionization-time of flight mass spectrometry. AB - Compared to DNA sequence analysis, matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS) correctly identified 100% of Cryptococcus species, distinguishing the notable pathogens Cryptococcus neoformans and C. gattii. Identification was greatly enhanced by supplementing a commercial spectral library with additional entries to account for subspecies variability. PMID- 21653763 TI - Genetic characterization of multidrug-resistant, extended-spectrum- beta lactamase-producing Vibrio cholerae O1 outbreak strains, Mpumalanga, South Africa, 2008. AB - Thirty-one antimicrobial-resistant, extended-spectrum-beta-lactamase-producing strains of Vibrio cholerae O1 serotype Ogawa associated with an outbreak of cholera in South Africa (2008) were investigated. Ten selected cholera strains were PCR positive for the SXT element, harbored mutations in the quinolone resistance-determining regions of GyrA (Ser83-Ile) and ParC (Ser85-Leu), and produced TEM-63 beta-lactamase. PMID- 21653764 TI - Detection of AmpC beta-lactamase in Escherichia coli: comparison of three phenotypic confirmation assays and genetic analysis. AB - Two mechanisms account for AmpC activity in Escherichia coli, namely, mutations in the ampC promoter and attenuator regions resulting in ampC overexpression and acquisition of plasmid-carried ampC genes. In this study, we analyzed 51 clinical E. coli isolates with reduced susceptibility to amoxicillin-clavulanic acid, piperacillin-tazobactam, or extended-spectrum cephalosporins for the presence of AmpC production. Three phenotypic AmpC confirmation assays (cefoxitin-cloxacillin disk diffusion test, cefoxitin-EDTA disk diffusion test, and AmpC Etest) were compared for the detection of AmpC activity. All 51 isolates were characterized genetically by mutational analysis of the chromosomal ampC promoter/attenuator region and by PCR detection of plasmid-carried ampC genes. Altogether, 21/51 (41%) E. coli isolates were considered true AmpC producers. AmpC activity due to chromosomal ampC promoter/attenuator mutations was found in 12/21 strains, and plasmid-carried ampC genes were detected in 8/21 isolates. One strain contained both ampC promoter mutations and a plasmid-carried ampC gene. All three phenotypic tests were able to detect the majority (>90%) of AmpC-positive strains correctly. Cefoxitin resistance was found to be a discriminative parameter, detecting 20/21 AmpC-producing strains. Susceptibility to extended-spectrum cephalosporins, e.g., ceftriaxone, ceftazidime, and cefotaxime, was found in 9 of the 21 AmpC-positive strains. Considering the elevated zone diameter breakpoints of the 2010 CLSI guidelines, 2/21 AmpC-positive strains were categorized as susceptible to extended-spectrum cephalosporins. PMID- 21653765 TI - First report of community-associated methicillin-resistant Staphylococcus aureus (USA300) in Mexico. PMID- 21653767 TI - Development of a highly sensitive genus-specific quantitative reverse transcriptase real-time PCR assay for detection and quantitation of plasmodium by amplifying RNA and DNA of the 18S rRNA genes. AB - A highly sensitive genus-specific quantitative reverse transcriptase real-time PCR (qRT-PCR) assay for detection of Plasmodium has been developed. The assay amplifies total nucleic acids (RNA and DNA) of the 18S rRNA genes with a limit of detection of 0.002 parasite/MUl using cultured synchronized ring stage 3D7 parasites. Parasite densities as low as 0.000362 parasite/MUl were detected when analyzing clinical samples. Analysis of clinical samples showed that detection of 18S rRNA genes from total nucleic acids increased the analytical sensitivity of the assay by more than 1 log unit compared to DNA only. When clinical samples with no parasites present by microscopy were analyzed by qRT-PCR, 90% (117 of 130) were positive for the presence of Plasmodium nucleic acids. Quantification of clinical samples by qRT-PCR using total nucleic acid versus DNA was compared to microscopy. There was a significantly greater correlation of parasite density to microscopy when DNA alone was used than with total nucleic acid. We conclude that analysis of total nucleic acids by qRT-PCR is a suitable assay for detection of low parasite levels in patients with early-stage malaria and/or submicroscopic infections and could greatly benefit malaria diagnosis, intervention trials, and malaria control and elimination efforts. PMID- 21653766 TI - Harnessing the glucosyltransferase activities of Clostridium difficile for functional studies of toxins A and B. AB - The incidence of Clostridium difficile infection (CDI) has been increasing within the last decade. Pathogenic strains of C. difficile produce toxin A and/or toxin B, which are important virulence factors in the pathogenesis of this bacterium. Current methods for diagnosing CDI are mostly qualitative tests that detect either the bacterium or the toxins. We have developed an assay (Cdifftox activity assay) to detect C. difficile toxin A and B activities that is quantitative and cost-efficient and utilizes a substrate that is stereochemically similar to the native substrate of the toxins (UDP-glucose). To characterize toxin activity, toxins A and B were purified from culture supernatants by ammonium sulfate precipitation and chromatography through DEAE-Sepharose and gel filtration columns. The activities of the final fractions were quantitated using the Cdifftox activity assay and compared to the results of a toxin A- and B-specific enzyme-linked immunosorbent assay (ELISA). The affinity for the substrate was >4 fold higher for toxin B than for toxin A. Moreover, the rate of cleavage of the substrate was 4.3-fold higher for toxin B than for toxin A. The optimum temperature for both toxins ranged from 35 to 40 degrees C at pH 8. Culture supernatants from clinical isolates obtained from the stools of patients suspected to be suffering from CDI were tested using the Cdifftox activity assay, and the results were compared to those of ELISA and PCR amplification of the toxin genes. Our results demonstrate that this new assay is comparable to the current commercial ELISA for detecting the toxins in the samples tested and has the added advantage of quantitating toxin activity. PMID- 21653768 TI - Determination of disk diffusion and MIC quality control guidelines for JNJ-Q2, a novel quinolone. AB - JNJ-Q2 is a novel fluorinated 4-quinolone in development for treatment of acute bacterial skin and skin structure infection and community-acquired bacterial pneumonia. This quality control (QC) study was performed to establish ranges for control strains: Staphylococcus aureus ATCC 29213 (0.004 to 0.015 MUg/ml), Enterococcus faecalis ATCC 29212 (0.015 to 0.06 MUg/ml), Pseudomonas aeruginosa ATCC 27853 (0.5 to 2 MUg/ml and 17 to 23 mm), Escherichia coli ATCC 25922 (0.008 to 0.03 MUg/ml and 30 to 36 mm), Haemophilus influenzae ATCC 49247 (0.002 to 0.015 MUg/ml and 31 to 39 mm), Streptococcus pneumoniae ATCC 49619 (0.004 to 0.015 MUg/ml and 28 to 35 mm), and S. aureus ATCC 25923 (32 to 38 mm). These ranges will be crucial in evaluating JNJ-Q2 potency as it progresses through clinical trial development. PMID- 21653769 TI - Diagnostic consequences of cytomegalovirus glycoprotein B polymorphisms. AB - Failure of a cytomegalovirus (CMV) real-time PCR assay targeting glycoprotein B (gB) was investigated. A multiplex assay targeting gB and immediate-early 2 (IE2) genes showed discordant results (gB negative and IE positive or a >10-fold-higher viral load with IE primers) in saliva from 14.6% of CMV-infected newborns. Sequencing revealed 3 patterns of gB variations. PMID- 21653770 TI - Prototheca wickerhamii mimicking yeast: a cautionary tale. AB - Prototheca spp. are environmental algae that may cause serious infection in the immunocompromised patient. Clinical manifestations may mimic other diseases. We present a case of fatal infection in a 78-year-old cardiac transplant recipient and discuss pitfalls in the clinical and laboratory diagnoses. PMID- 21653771 TI - Suitability of Xpert MTB/RIF and genotype MTBDRplus for patient selection for a tuberculosis clinical trial. AB - Participation criteria for clinical trials in pulmonary tuberculosis commonly include confirmation of sputum positive for mycobacteria and an indication of drug susceptibility before treatment is initiated. We investigated the suitability of two novel sputum-based nucleic acid amplification methods for patient selection in a recent early bactericidal activity study. Spontaneously expectorated sputum samples of 140 consecutive pulmonary tuberculosis patients were examined with direct fluorescence microscopy, Genotype MTBDRplus assay (MTBDR), Xpert MTB/RIF assay (Xpert), and liquid mycobacterial culture. The methods detected mycobacteria or mycobacterial DNA in 96.8%, 90.5%, 92.9%, and 92.1% of samples, respectively. MTBDR, Xpert, and liquid culture were 100% concordant for detection of resistance to rifampin. Sensitivity and specificity of MTBDR for detection of isoniazid resistance were 83.3% and 100%, respectively. For quantification of mycobacterial sputum load, we found a correlation between Xpert DNA amplification cycle thresholds, time to positivity, and microscopy smear grade. The best correlation was found between Xpert and time to positivity (r = 0.54), which were both correlated with smear microscopy with r values equal to -0.40 and -0.48, respectively. We conclude that MTBDR and Xpert are suitable screening tools for determining rifampin resistance in sputum microscopy smear positive patients before participation in tuberculosis trials. Xpert should be further explored as a surrogate measurement for sputum mycobacterial load. PMID- 21653772 TI - Colletotrichum truncatum: an unusual pathogen causing mycotic keratitis and endophthalmitis. AB - In recent years, the well-known plant pathogens of the Colletotrichum genus were increasingly reported to cause ophthalmic infections in humans. Among 66 species in the Colletotrichum genus, only a few are known to be pathogenic for humans. We report here five cases of ophthalmic infections due to Colletotrichum truncatum, a species never reported earlier to cause human infection. The isolates were identified by morphological characteristics and the sequencing of internal spacer regions of ribosomal DNA. The progress of lesions in those patients was slow compared to that of lesions caused by Aspergillus or Fusarium infections. The surgical management included total penetrating keratoplasty in patients with keratitis and pars plana vitrectomy in endophthalmitis. Two patients were treated additionally with intravitreal amphotericin B deoxycholate, one patient with oral itraconazole, and another patient with oral and topical fluconazole therapy. The present series therefore highlights the expanding spectrum of agents causing eye infections and the inclusion of C. truncatum as a human pathogen. PMID- 21653773 TI - Identification by 16S rRNA gene sequencing of Negativicoccus succinicivorans recovered from the blood of a patient with hemochromatosis and pancreatitis. AB - We describe a case of Negativicoccus succinicivorans bacteremia in an adult man with hemochromatosis and acute pancreatitis. Conventional phenotypic tests and commercial identification systems failed to definitively identify the tiny anaerobic Gram-negative coccus isolated from two sets of blood cultures. The bacterium was identified by 16S rRNA gene sequencing and analysis using the SmartGene Integrated Database Network System software. This is the first published report of the recovery of this organism from a patient with invasive infection. PMID- 21653774 TI - Comparison of serial Hepatitis C virus detection in samples submitted through serology for reflex confirmation versus samples directly submitted for quantitation. AB - Using real-time technology, we reliably identified chronic hepatitis C virus (HCV) infection and quantified virus from reflex samples originally submitted for serologic testing. There was no need to process specimens obtained directly for quantitation separately. Whether the initial source is a reflex sample or one obtained directly, a repeat HCV RNA test is needed before starting treatment. PMID- 21653776 TI - First human isolate of Mycobacterium poriferae in the sputum of a patient with chronic bronchitis. PMID- 21653775 TI - Comparison of two molecular methods for rapid diagnosis of extrapulmonary tuberculosis. AB - Application of real-time PCR for the detection of Mycobacterium tuberculosis enables results to be obtained in about 2 h. A total of 340 nonrespiratory samples were processed using two real-time PCR assay kits: Xpert MTB/RIF and Cobas TaqMan MTB. The sensitivity and specificity of the Xpert assay were 95% and 100%, respectively, compared to 78% and 98% for the Cobas assay. PMID- 21653777 TI - Frequency of panton-valentine leukocidin-producing methicillin-sensitive Staphylococcus strains in patients with complicated skin and soft tissue infection in bronx, new york. AB - lukF-PV was present in 36% of skin and soft tissue infection (SSTI)-derived methicillin-susceptible Staphylococcus aureus (MSSA) strains and comprised six distinct clones, which contained fewer enterotoxin genes than strains without lukF-PV. Clinical presentations and outcomes of lukF-PV(+) methicillin-resistant S. aureus (MRSA) and MSSA SSTIs were comparable. In multivariable analysis, the presence of lukF-PV remained a significant predictor for incision and drainage among MSSA strains. PMID- 21653778 TI - Precision across the analytical measuring range of a quantitative real-time PCR assay for cytomegalovirus detection among three clinical laboratories. AB - This study measured the precision of a quantitative laboratory-developed real time PCR test for cytomegalovirus performed at three different clinical laboratories that use the same methodology. The overall standard deviation (adjusted for analyte level) was 0.18 log(10) copies/ml, and there was no significant relationship between standard deviation and analytical measuring range. PMID- 21653779 TI - Amyloid histology stain for rapid bacterial endospore imaging. AB - Bacterial endospores are some of the most resilient forms of life known to us, with their persistent survival capability resulting from a complex and effective structural organization. The outer membrane of endospores is surrounded by the densely packed endospore coat and exosporium, containing amyloid or amyloid-like proteins. In fact, it is the impenetrable composition of the endospore coat and the exosporium that makes staining methodologies for endospore detection complex and challenging. Therefore, a plausible strategy for facile and expedient staining would be to target components of the protective surface layers of the endospores. Instead of targeting endogenous markers encapsulated in the spores, here we demonstrated staining of these dormant life entities that targets the amyloid domains, i.e., the very surface components that make the coats of these species impenetrable. Using an amyloid staining dye, thioflavin T (ThT), we examined this strategy. A short incubation of bacillus endospore suspensions with ThT, under ambient conditions, resulted in (i) an enhancement of the fluorescence of ThT and (ii) the accumulation of ThT in the endospores, affording fluorescence images with excellent contrast ratios. Fluorescence images revealed that ThT tends to accumulate in the surface regions of the endospores. The observed fluorescence enhancement and dye accumulation, coupled with the sensitivity of emission techniques, provide an effective and rapid means of staining endospores without the inconvenience of pre- or posttreatment of samples. PMID- 21653780 TI - Molecular detection and identification of mycobacterium tuberculosis complex and four clinically important nontuberculous mycobacterial species in smear-negative clinical samples by the genotype mycobacteria direct test. AB - Although the sensitivity and specificity of nucleic acid amplification assays are high with smear-positive samples, the sensitivity with smear-negative and extrapulmonary samples for the diagnosis of tuberculosis in suspicious tuberculosis cases still remains to be investigated. This study evaluates the performance of the GenoType Mycobacteria Direct (GTMD) test for rapid molecular detection and identification of the Mycobacterium tuberculosis complex and four clinically important nontuberculous mycobacteria (M. avium, M. intracellulare, M. kansasii, and M. malmoense) in smear-negative samples. A total of 1,570 samples (1,103 bronchial aspiration, 127 sputum, and 340 extrapulmonary samples) were analyzed. When we evaluated the performance criteria in combination with a positive culture result and/or the clinical outcome of the patients, the overall sensitivity, specificity, and positive and negative predictive values were found to be 62.4, 99.5, 95.9, and 93.9%, respectively, whereas they were 63.2, 99.4, 95.7, and 92.8%, respectively, for pulmonary samples and 52.9, 100, 100, and 97.6%, respectively, for extrapulmonary samples. Among the culture-positive samples which had Mycobacterium species detectable by the GTMD test, three samples were identified to be M. intracellulare and one sample was identified to be M. avium. However, five M. intracellulare samples and an M. kansasii sample could not be identified by the molecular test and were found to be negative. The GTMD test has been a reliable, practical, and easy tool for rapid diagnosis of smear-negative pulmonary and extrapulmonary tuberculosis so that effective precautions may be taken and appropriate treatment may be initiated. However, the low sensitivity level should be considered in the differentiation of suspected tuberculosis and some other clinical condition until the culture result is found to be negative and a true picture of the clinical outcome is obtained. PMID- 21653781 TI - Early detection of colonization by VIM-1-producing Klebsiella pneumoniae and NDM 1-producing Escherichia coli in two children returning to France. AB - Rapid identification of metallo-beta-lactamase-producing Gram-negative species is crucial for the timely implementation of infection control measures. We describe two pediatric cases in which colonization by VIM-1- and New Delhi metallo-beta lactamase 1-producing Enterobacteriaceae was rapidly detected by phenotypic and genotypic methods. Phenotypic methods can be useful for routine detection of carbapenemase production. PMID- 21653782 TI - Sporisorium reilianum infection changes inflorescence and branching architectures of maize. AB - Sporisorium reilianum is a biotrophic maize (Zea mays) pathogen of increasing economic importance. Symptoms become obvious at flowering time, when the fungus causes spore formation and phyllody in the inflorescences. To understand how S. reilianum changes the inflorescence and floral developmental program of its host plant, we investigated the induced morphological and transcriptional alterations. S. reilianum infection promoted the outgrowth of subapical ears, suggesting that fungal presence suppressed apical dominance. Female inflorescences showed two distinct morphologies, here termed "leafy ear" and "eary ear." In leafy ears, all floral organs were replaced by vegetative organs. In eary ears, modified carpels enclosed a new female inflorescence harboring additional female inflorescences at every spikelet position. Similar changes in meristem fate and organ identity were observed in the tassel of infected plants, which formed male inflorescences at spikelet positions. Thus, S. reilianum triggered a loss of organ and meristem identity and a loss of meristem determinacy in male and female inflorescences and flowers. Microarray analysis showed that these developmental changes were accompanied by transcriptional regulation of genes proposed to regulate floral organ and meristem identity as well as meristem determinacy in maize. S. reilianum colonization also led to a 30% increase in the total auxin content of the inflorescence as well as a dramatic accumulation of reactive oxygen species. We propose a model describing the architectural changes of infected inflorescence as a consequence of transcriptional, hormonal, and redox modulation, which will be the basis for further molecular investigation of the underlying mechanism of S. reilianum-induced alteration of floral development. PMID- 21653784 TI - Gene discovery and tissue-specific transcriptome analysis in chickpea with massively parallel pyrosequencing and web resource development. AB - Chickpea (Cicer arietinum) is an important food legume crop but lags in the availability of genomic resources. In this study, we have generated about 2 million high-quality sequences of average length of 372 bp using pyrosequencing technology. The optimization of de novo assembly clearly indicated that hybrid assembly of long-read and short-read primary assemblies gave better results. The hybrid assembly generated a set of 34,760 transcripts with an average length of 1,020 bp representing about 4.8% (35.5 Mb) of the total chickpea genome. We identified more than 4,000 simple sequence repeats, which can be developed as functional molecular markers in chickpea. Putative function and Gene Ontology terms were assigned to at least 73.2% and 71.0% of chickpea transcripts, respectively. We have also identified several chickpea transcripts that showed tissue-specific expression and validated the results using real-time polymerase chain reaction analysis. Based on sequence comparison with other species within the plant kingdom, we identified two sets of lineage-specific genes, including those conserved in the Fabaceae family (legume specific) and those lacking significant similarity with any non chickpea species (chickpea specific). Finally, we have developed a Web resource, Chickpea Transcriptome Database, which provides public access to the data and results reported in this study. The strategy for optimization of de novo assembly presented here may further facilitate the transcriptome sequencing and characterization in other organisms. Most importantly, the data and results reported in this study will help to accelerate research in various areas of genomics and implementing breeding programs in chickpea. PMID- 21653783 TI - The Arabidopsis mitochondria-localized pentatricopeptide repeat protein PGN functions in defense against necrotrophic fungi and abiotic stress tolerance. AB - Pentatricopeptide repeat (PPR) proteins (PPRPs) are encoded by a large gene family in Arabidopsis (Arabidopsis thaliana), and their functions are largely unknown. The few studied PPRPs are implicated in different developmental processes through their function in RNA metabolism and posttranscriptional regulation in plant organelles. Here, we studied the functions of Arabidopsis PENTATRICOPEPTIDE REPEAT PROTEIN FOR GERMINATION ON NaCl (PGN) in plant defense and abiotic stress responses. Inactivation of PGN results in susceptibility to necrotrophic fungal pathogens as well as hypersensitivity to abscisic acid (ABA), glucose, and salinity. Interestingly, ectopic expression of PGN results in the same phenotypes as the pgn null allele, indicating that a tight regulation of the PGN transcript is required for normal function. Loss of PGN function dramatically enhanced reactive oxygen species accumulation in seedlings in response to salt stress. Inhibition of ABA synthesis and signaling partially alleviates the glucose sensitivity of pgn, suggesting that the mutant accumulates high endogenous ABA. Accordingly, induction of NCED3, encoding the rate-limiting enzyme in stress-induced ABA biosynthesis, is significantly higher in pgn, and the mutant has higher basal ABA levels, which may underlie its phenotypes. The pgn mutant has altered expression of other ABA-related genes as well as mitochondria-associated transcripts, most notably elevated levels of ABI4 and ALTERNATIVE OXIDASE1a, which are known for their roles in retrograde signaling induced by changes in or inhibition of mitochondrial function. These data, coupled with its mitochondrial localization, suggest that PGN functions in regulation of reactive oxygen species homeostasis in mitochondria during abiotic and biotic stress responses, likely through involvement in retrograde signaling. PMID- 21653794 TI - Gender differentials in disability and mortality transitions: the case of older adults in Japan. AB - OBJECTIVE: This study has two aims: (a) to examine gender differentials in disability transitions and active life expectancies among older adults in Japan and (b) to determine whether these gender differentials vary by age, socioeconomic characteristics, and disease profile. METHOD: Active and inactive states are defined as living with and without disabilities using activities of daily living. Expected years of life and active life are examined by constructing multistate life-tables, which employ probabilities of health and mortality transitions derived from hazard models. RESULTS: Results indicate that older women in Japan live longer than older men and spend a proportion of these extra years with and without disability. DISCUSSION: The discussion highlights a projected increase in the number of years that individuals, in particular women, will need long-term care. Policy implications include the need to bolster long term care services in Japan. PMID- 21653785 TI - AUXIN UP-REGULATED F-BOX PROTEIN1 regulates the cross talk between auxin transport and cytokinin signaling during plant root growth. AB - Plant root development is mediated by the concerted action of the auxin and cytokinin phytohormones, with cytokinin serving as an antagonist of auxin transport. Here, we identify the AUXIN UP-REGULATED F-BOX PROTEIN1 (AUF1) and its potential paralog AUF2 as important positive modifiers of root elongation that tether auxin movements to cytokinin signaling in Arabidopsis (Arabidopsis thaliana). The AUF1 mRNA level in roots is strongly up-regulated by auxin but not by other phytohormones. Whereas the auf1 single and auf1 auf2 double mutant roots grow normally without exogenous auxin and respond similarly to the wild type upon auxin application, their growth is hypersensitive to auxin transport inhibitors, with the mutant roots also having reduced basipetal and acropetal auxin transport. The effects of auf1 on auxin movements may be mediated in part by the misexpression of several PIN-FORMED (PIN) auxin efflux proteins, which for PIN2 reduces its abundance on the plasma membrane of root cells. auf1 roots are also hypersensitive to cytokinin and have increased expression of several components of cytokinin signaling. Kinematic analyses of root growth and localization of the cyclin B mitotic marker showed that AUF1 does not affect root cell division but promotes cytokinin-mediated cell expansion in the elongation/differentiation zone. Epistasis analyses implicate the cytokinin regulator ARR1 or its effector(s) as the target of the SKP1-Cullin1-F Box (SCF) ubiquitin ligases assembled with AUF1/2. Given the wide distribution of AUF1/2-type proteins among land plants, we propose that SCF(AUF1/2) provides additional cross talk between auxin and cytokinin, which modifies auxin distribution and ultimately root elongation. PMID- 21653795 TI - Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR). AB - Short-term breastfeeding and early exposure to complex dietary proteins, such as cow milk proteins and cereals, or to fruit, berries, and roots have been implicated as risk factors for beta cell autoimmunity, clinical type 1 diabetes, or both. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) is an international, randomized, double-blind, controlled intervention trial designed to answer the question of whether weaning to an extensively hydrolyzed formula in infancy will decrease the risk of type 1 diabetes later in childhood. In our pilot study, weaning to a highly hydrolyzed formula decreased by ~ 50% the cumulative incidence of one or more diabetes associated autoantibodies by a mean age of 4.7 y. This finding was confirmed in a recent follow-up analysis to 10 y of age. Currently, the full-scale TRIGR takes place in 77 centers in 15 countries. The TRIGR initially recruited 5606 newborn infants with a family member affected by type 1 diabetes and enrolled 2159 eligible subjects who carried a risk-conferring HLA genotype. All recruited mothers were encouraged to breastfeed. The intervention lasted for 6-8 mo with a minimum study formula exposure time of 2 mo, and hydrolyzed casein and standard cow milk-based weaning formulas were compared. Eighty percent of the participants were exposed to the study formula. The overall retention rate over the first 5 y was 87%, and protocol compliance was 94%. The randomization code will be opened when the last recruited child turns 10 y of age (ie, in 2017). PMID- 21653796 TI - Vitamin D intake and risk of cardiovascular disease in US men and women. AB - BACKGROUND: Although studies have linked vitamin D deficiency to an increased risk of cardiovascular disease (CVD), evidence regarding whether vitamin D intake from foods or supplements is prospectively associated with lower CVD risk in healthy humans is limited and inconclusive. OBJECTIVE: The objective was to comprehensively evaluate the associations between both dietary and supplemental vitamin D and CVD risk. DESIGN: In the Nurses' Health Study (1984-2006) and the Health Professionals Follow-Up Study (1986-2006)-consisting of 74,272 women and 44,592 men, respectively, who were free of CVD and cancer at baseline-we prospectively examined the association between vitamin D intake and incident CVD. RESULTS: Over a total of 2,280,324 person-years of follow-up, we identified 9886 incident cases of coronary heart disease and stroke. After multivariate adjustment for age and other CVD risk factors, a higher total vitamin D intake (from foods and supplements) was associated with a decreased risk of CVD in men but not in women; the relative risks (95% CIs) for a comparison of participants who met the Dietary Reference Intake of vitamin D (>=600 IU/d) with participants whose vitamin D intake was <100 IU/d were 0.84 (0.72, 0.97; P for trend = 0.009) for men and 1.02 (0.89, 1.17; P for trend = 0.12) for women. CONCLUSIONS: These observations suggest that a higher intake of vitamin D is associated with a lower risk of CVD in men but not in women. Further research is needed to confirm these findings and to elucidate a biological basis for potential sex differences. PMID- 21653797 TI - New frontiers in science and technology: nuclear techniques in nutrition. AB - The use of nuclear techniques in nutrition adds value by the increased specificity and sensitivity of measures compared with conventional techniques in a wide range of applications. This article provides a brief overview of well established stable-isotope techniques to evaluate micronutrient bioavailability and assess human-milk intake in breastfed infants to monitor the transfer of micronutrients from the mother to the infant. Recent developments are highlighted in the use of nuclear techniques to evaluate biological interactions between food, nutrition, and health to move the agenda forward. PMID- 21653798 TI - Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status? AB - BACKGROUND: In elderly individuals with low serum vitamin B-12, those who have high serum folate have been reported to have greater abnormalities in the following biomarkers for vitamin B-12 deficiency: low hemoglobin and elevated total homocysteine (tHcy) and methylmalonic acid (MMA). This suggests that folate exacerbates vitamin B-12-related metabolic abnormalities. OBJECTIVE: We determined whether high serum folate in individuals with low serum vitamin B-12 increases the deleterious effects of low vitamin B-12 on biomarkers of vitamin B 12 cellular function. DESIGN: In this cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobin, plasma tHcy, and MMA, holotranscobalamin, and ferritin in serum. RESULTS: In subjects with low vitamin B-12 concentrations (<148 pmol/L), those who had high folate concentrations (>30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (<=30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. CONCLUSIONS: In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population. PMID- 21653800 TI - Red meat consumption and risk of stroke in Swedish men. AB - BACKGROUND: Red and processed meat consumption has been implicated in several diseases. However, data on meat consumption in relation to stroke incidence are sparse. OBJECTIVE: Our objective was to examine the associations of red meat and processed meat consumption with stroke incidence in men. DESIGN: We prospectively followed 40,291 men aged 45-79 y who had no history of cardiovascular disease or cancer at baseline. Meat consumption was assessed with a self-administered questionnaire in 1997. RESULTS: During a mean follow-up of 10.1 y, 2409 incident casesof stroke (1849 cerebral infarctions, 350 hemorrhagic strokes, and 210 unspecified strokes) were identified from the Swedish Hospital Discharge Registry. Consumption of processed meat, but not of fresh red meat, was positively associated with risk of stroke. The multivariable relative risks (RRs) of total stroke for the highest compared with the lowest quintiles of consumption were 1.23 (95% CI: 1.07, 1.40; P for trend = 0.004) for processed meat and 1.07 (95% CI: 0.93, 1.24; P for trend = 0.77) for fresh red meat. Processed meat consumption was also positively associated with risk of cerebral infarction in a comparison of the highest with the lowest quintile (RR: 1.18; 95% CI: 1.01, 1.38; P for trend = 0.03). CONCLUSION: The findings from this prospective cohort of men indicate that processed meat consumption is positively associated with risk of stroke. The Cohort of Swedish Men is registered at clinicaltrials.gov as NCT01127711. PMID- 21653799 TI - Fat mass modifies the association of fat-free mass with symptom-limited treadmill duration in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - BACKGROUND: The assessment of fat mass and fat-free mass in relation to the symptom-limited maximal exercise duration (Max(dur)) of a treadmill test allows for insight into the association of body composition with treadmill performance potential. OBJECTIVE: We investigated the complex associations between fat mass and fat-free mass and Max(dur) in a population setting. DESIGN: The Max(dur) of a graded exercise treadmill test and body composition by dual-energy X-ray absorptiometry were estimated in 2413 black and white men and women aged 38-50 y from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. RESULTS: The mean Max(dur) was ~7.5 s shorter per kilogram of fat mass in both men and women and independent of fat-free mass, height, race, television watching, physical activity, systolic blood pressure, lung function, and education. Fat mass modified the association of fat-free mass with the Max(dur) (2-way interaction P < 0.001), and the interaction was stronger in women than in men. In men in the lowest fat-mass quartile, the Max(dur) was 1.3 s longer per kilogram of fat-free mass and was 0.5 s shorter per kilogram of fat-free mass in the highest fat-mass quartile. In contrast, in women with the least fat mass, the Max(dur) was 2.7 s longer per kilogram of fat-free mass and was 2.8 s shorter per kilogram of fat-free mass in the highest fat-mass quartile. CONCLUSIONS: The Max(dur) was negatively related to fat mass. Fat-free mass in obese people contributed little to the treadmill performance potential as assessed by the Max(dur), although the contribution of fat-free mass was positive in thinner people. PMID- 21653801 TI - Differences between liking and wanting signals in the human brain and relations with cognitive dietary restraint and body mass index. AB - BACKGROUND: Eating behavior is determined, to a significant extent, by the rewarding value of food (ie, liking and wanting). OBJECTIVE: We determined brain regions involved in liking and wanting and related brain signaling to body mass index (BMI; in kg/m(2)) and dietary restraint. DESIGN: Fifteen normal-weight female subjects [mean +/- SEM age: 21.5 +/- 0.4 y; BMI: 22.2 +/- 0.2] completed a food-choice paradigm by using visually displayed food items during functional magnetic resonance imaging scans. Two scans were made as follows: one scan was made in a fasted condition, and one scan was made in a satiated condition. The paradigm discriminated between liking and wanting, and subjects were offered items rated highly for wanting immediately after each scan. Imaging contrasts for high and low liking and wanting were made, and data for regions of interest were extracted. Activation related to liking and wanting, respectively, was determined. Outcomes were correlated to cognitive dietary restraint and BMI. RESULTS: Dietary restraint predicted liking task-related signaling (TRS) in the amygdala, striatum, thalamus, and cingulate cortex (r = -0.5 +/- 0.03, P < 0.00001). In the nucleus accumbens, the premeal liking and wanting TRS and premeal to postmeal liking TRS changes correlated positively with dietary restraint [bilateral average r = 0.6 +/- 0.02, P < 0.04 (Bonferroni corrected)]. BMI and hunger predicted wanting TRS in the hypothalamus and striatum (P < 0.05). Postmeal liking TRS in the striatum, anterior insula, and cingulate cortex and wanting TRS in the striatum predicted the energy intake (liking: r = -0.3 +/- 0.05, P < 0.0001; wanting: r = -0.3 +/- 0.03, P < 0.00001). CONCLUSIONS: Successful dietary restraint was supported by liking TRS from premeal to postmeal in the nucleus accumbens. Reward-related signaling was inversely related to BMI and energy intake, indicating reward deficiency. PMID- 21653802 TI - Contribution made by biomarkers of status to an FP6 Network of Excellence, EURopean micronutrient RECommendations Aligned (EURRECA). AB - Dietary reference values for micronutrients vary considerably among countries, and harmonization is needed to facilitate nutrition policy and public health strategies at the European and global levels. The EURopean micronutrient RECommendations Aligned (EURRECA) Network of Excellence is developing generic instruments for systematically deriving and updating micronutrient reference values and dietary recommendations. These include best practice guidelines, interlinked web pages, online databases, and decision trees. Journal supplements have been published on micronutrient intakes and status, and an ongoing activity of EURRECA is the completion of systematic reviews on associations between intakes, status, and various health outcomes for priority micronutrients (ie, iron, zinc, folate, vitamin B-12, and iodine), which were selected by using a triage technique. Future activities include meta-analyses to identify dose response relations and the variability, factorial estimates of requirements, bioavailability from whole diets, effects of genotype, and modeling techniques for addressing dietary recommendations for combinations of nutrients with common health endpoints. PMID- 21653803 TI - Docosahexaenoic acid suppresses apolipoprotein A-I gene expression through hepatocyte nuclear factor-3beta. AB - BACKGROUND: Dietary fish-oil supplementation has been shown in human kinetic studies to lower the production rate of apolipoprotein (apo) A-I, the major protein component of HDL. The underlying mechanism responsible for this effect is not fully understood. OBJECTIVE: We investigated the effect and the mechanism of action of the very-long-chain n-3 (omega-3) polyunsaturated fatty acid docosahexaenoic acid (DHA), relative to the saturated fatty acid palmitic acid (PA), on the hepatic expression of apo A-I in HepG2 cells. DESIGN: HepG2 cells were treated with different doses of DHA and PA (0-200 MUmol/L). mRNA expression levels of apo A-I were assessed by real-time polymerase chain reaction, and apo A I protein concentrations were measured by immunoassay. DHA dose-dependently suppressed apo A-I mRNA levels and also lowered apo A-I protein concentrations in the media, with maximum effects at 200 MUmol/L. This concentration of fatty acids was used in all subsequent experiments. RESULTS: To elucidate the mechanism mediating the reduction in apo A-I expression by DHA, transfection experiments were conducted with plasmid constructs containing serial deletions of the apo A-I promoter. The DHA-responsive region was mapped to the -185 to -148 nucleotide region of the apo A-I promoter, which binds the hepatocyte nuclear factor (HNF) 3beta. Nuclear extracts from cells treated with DHA or PA had a similar nuclear abundance of HNF-3beta. However, electrophoresis mobility shift assays showed less binding of HNF-3beta to the -180 to -140 sequence of the apo A-I promoter than did PA-treated cells. As shown by chromatin immunoprecipitation analysis, less HNF-3beta was recruited to the apo A-I promoter in DHA-treated cells than in PA-treated cells, which supports the concept of an interference of DHA with the binding of HNF-3beta to the apo A-I promoter. CONCLUSION: These findings suggest that, in human hepatoma HepG2 cells, DHA inhibits the binding of HNF-3beta to the apo A-I promoter, resulting in the repression of apo A-I promoter transactivity and thus a reduction in apo A-I expression. PMID- 21653804 TI - Development and validation of a utility weighting function for the patient oriented prostate utility scale (PORPUS). AB - BACKGROUND: Previously, we developed a prostate cancer (PC)-specific health state classification system, the Patient Oriented Prostate Utility Scale (PORPUS). In this study, we developed a scoring system to allow indirect calculation of utilities from the PORPUS. METHODS: We interviewed 234 PC outpatients, including those with newly diagnosed and metastatic disease, to obtain rating scale (RS) values on 4 to 6 levels of each of the 10 attributes of the PORPUS, and on 10 corner states (worst level on 1 attribute, best on 9). Patients also completed standard gamble (SG) and RS tasks on 4 multiattribute states (impotence and pain corner states, mild and severe PC symptoms). We used the RS and SG scores for multiattribute states to determine a risk aversion function for mapping values to utilities. We then tested 15 different strategies to estimate the multiattribute utility function (MAUF), using the single attribute disutilities for each level of the 10 PORPUS attributes, and the disutilities for the corner states. The root mean squared error (RMSE) of prediction of the SG on the 4 multiattribute states was used to identify the optimal strategy and scoring system. RESULTS: The optimal strategy gave an RMSE of 0.06. Comparison of mean MAUF-predicted utilities to directly elicited SG utilities for the 2 multiattribute states from patients in 2 previously published studies (n = 248 and n = 141) supported the validity of the MAUF. CONCLUSIONS: The scoring system together with the PORPUS comprise an indirect utility instrument, the PORPUS-U, which can be used in clinical and research settings. PMID- 21653805 TI - Accounting for methodological, structural, and parameter uncertainty in decision analytic models: a practical guide. AB - Accounting for uncertainty is now a standard part of decision-analytic modeling and is recommended by many health technology agencies and published guidelines. However, the scope of such analyses is often limited, even though techniques have been developed for presenting the effects of methodological, structural, and parameter uncertainty on model results. To help bring these techniques into mainstream use, the authors present a step-by-step guide that offers an integrated approach to account for different kinds of uncertainty in the same model, along with a checklist for assessing the way in which uncertainty has been incorporated. The guide also addresses special situations such as when a source of uncertainty is difficult to parameterize, resources are limited for an ideal exploration of uncertainty, or evidence to inform the model is not available or not reliable. METHODS: for identifying the sources of uncertainty that influence results most are also described. Besides guiding analysts, the guide and checklist may be useful to decision makers who need to assess how well uncertainty has been accounted for in a decision-analytic model before using the results to make a decision. PMID- 21653806 TI - Emergence of complex behavior: an interactive model of cardiac excitation provides a powerful tool for understanding electric propagation. PMID- 21653807 TI - Insulin-like growth factor (IGF) signalling and genome-wide transcriptional regulation in fast muscle of zebrafish following a single-satiating meal. AB - Male zebrafish (Danio rerio) were fasted for 7 days and fed to satiation over 3 h to investigate the transcriptional responses to a single meal. The intestinal content at satiety (6.3% body mass) decreased by 50% at 3 h and 95% at 9 h following food withdrawal. Phosphorylation of the insulin-like growth factor (IGF) signalling protein Akt peaked within 3 h of feeding and was highly correlated with gut fullness. Retained paralogues of IGF hormones genes were regulated with feeding, with igf1a showing a pronounced peak in expression after 3 h and igf2b after 6 h. Igf-I receptor transcripts were markedly elevated with fasting, and decreased to their lowest levels 45 min after feeding. igf1rb transcripts increased more quickly than igf1ra transcripts as the gut emptied. Paralogues of the insulin-like growth factor binding proteins (IGFBPs) were constitutively expressed, except for igfbp1a and igfbp1b transcripts, which were significantly elevated with fasting. Genome-wide transcriptional responses were analysed using the Agilent 44K oligonucleotide microarray and selected genes validated by qPCR. Fasting was associated with the upregulation of genes for the ubiquitin-proteasome degradation pathway, anti-proliferative and pro-apoptotic genes. Protein chaperones (unc45b, hspd1, hspa5, hsp90a.1, hsp90a.2) and chaperone interacting proteins (ahsa1 and stip1) were upregulated 3 h after feeding along with genes for the initiation of protein synthesis and mRNA processing. Transcripts for the enzyme ornithine decarboxylase 1 showed the largest increase with feeding (11.5-fold) and were positively correlated with gut fullness. This study demonstrates the fast nature of the transcriptional responses to a meal and provides evidence for differential regulation of retained paralogues of IGF signalling pathway genes. PMID- 21653808 TI - Renal responses to salinity change in snakes with and without salt glands. AB - To understand renal responses to salinity change in aquatic reptiles, we examined the structure and function of the kidney in three species of snake: a marine species with a salt gland (Laticauda semifasciata), a marine species without a salt gland (Nerodia clarkii clarkii) and a freshwater species without a salt gland (Nerodia fasciata). Both marine species maintained relatively constant plasma ions, even after acclimation to saltwater. By contrast, both plasma Cl(-) and mortality increased with salinity in the freshwater species. To investigate putative renal ion regulatory mechanisms, we examined the distribution and abundance of Na(+)/K(+)-ATPase (NKA) and the Na(+)/K(+)/2Cl(-) cotransporter (NKCC2). In all species, NKA localized to the basolateral membranes of the distal tubule and the connecting segments and collecting ducts only; there was no effect of salinity on the distribution of NKA or on the abundance of NKA mRNA in any species. NKCC2 protein was undetectable in the kidney of any of the species and there was no effect of salinity on NKCC2 mRNA abundance. We also examined the distribution and abundance of aquaporin 3 (AQP3) in the kidney of these species; although putative AQP3 localized to the basolateral membranes of the connecting segments and collecting ducts of all three species, there was no effect of salinity on the localization of the protein or the abundance of the transcript. Interestingly, we found very few differences across species, suggesting that the snake kidney may play a trivial role in limiting habitat use. PMID- 21653809 TI - Decreased hydrophobicity of iridescent feathers: a potential cost of shiny plumage. AB - Honest advertisement models posit that sexually selected traits are costly to produce, maintain or otherwise bear. Brightly coloured feathers are thought to be classic examples of these models, but evidence for a cost in feathers not coloured by carotenoid pigments is scarce. Unlike pigment-based colours, iridescent feather colours are produced by light scattering in modified feather barbules that are characteristically flattened and twisted towards the feather surface. These modifications increase light reflectance, but also expose more surface area for water adhesion, suggesting a potential trade-off between colour and hydrophobicity. Using light microscopy, spectrometry, contact angle goniometry and self-cleaning experiments, we show that iridescent feathers of mallards, Anas platyrhynchos, are less hydrophobic than adjacent non-iridescent feathers, and that this is primarily caused by differences in barbule microstructure. Furthermore, as a result of this decreased hydrophobicity, iridescent feathers are less efficient at self-cleaning than non-iridescent feathers. Together, these results suggest a previously unforeseen cost of iridescent plumage traits that may help to explain the evolution and distribution of iridescence in birds. PMID- 21653811 TI - The diving bell and the spider: the physical gill of Argyroneta aquatica. AB - Argyroneta aquatica is a unique air-breathing spider that lives virtually its entire life under freshwater. It creates a dome-shaped web between aquatic plants and fills the diving bell with air carried from the surface. The bell can take up dissolved O(2) from the water, acting as a 'physical gill'. By measuring bell volume and O(2) partial pressure (P(O(2))) with tiny O(2)-sensitive optodes, this study showed that the spiders produce physical gills capable of satisfying at least their resting requirements for O(2) under the most extreme conditions of warm stagnant water. Larger spiders produced larger bells of higher O(2) conductance (G(O(2))). G(O(2)) depended on surface area only; effective boundary layer thickness was constant. Bells, with and without spiders, were used as respirometers by measuring G(O(2)) and the rate of change in P(O(2)). Metabolic rates were also measured with flow-through respirometry. The water-air P(O(2)) difference was generally less than 10 kPa, and spiders voluntarily tolerated low internal P(O(2)) approximately 1-4 kPa before renewal with air from the surface. The low P(O(2)) in the bell enhanced N(2) loss from the bell, but spiders could remain inside for more than a day without renewal. Spiders appeared to enlarge the bells in response to higher O(2) demands and lower aquatic P(O(2)). PMID- 21653810 TI - Physiological adaptation of an Antarctic Na+/K+-ATPase to the cold. AB - Because enzymatic activity is strongly suppressed by the cold, polar poikilotherms face significant adaptive challenges. For example, at 0 degrees C the catalytic activity of a typical enzyme from a temperate organism is reduced by more than 90%. Enzymes embedded in the plasma membrane, such as the Na(+)/K(+) ATPase, may be even more susceptible to the cold because of thermal effects on the lipid bilayer. Accordingly, adaptive changes in response to the cold may include adjustments to the enzyme or the surrounding lipid environment, or synergistic changes to both. To assess the contribution of the enzyme itself, we cloned orthologous Na(+)/K(+)-ATPase alpha-subunits from an Antarctic (Pareledone sp.; -1.8 degrees C) and a temperate octopus (Octopus bimaculatus; ~18 degrees C), and compared their turnover rates and temperature sensitivities in a heterologous expression system. The primary sequences of the two pumps were found to be highly similar (97% identity), with most differences being conservative changes involving hydrophobic residues. The physiology of the pumps was studied using an electrophysiological approach in intact Xenopus oocytes. The voltage dependence of the pumps was equivalent. However, at room temperature the maximum turnover rate of the Antarctic pump was found to be 25% higher than that of the temperate pump. In addition, the Antarctic pump exhibited a lower temperature sensitivity, leading to significantly higher relative activity at lower temperatures. Orthologous Na(+)/K(+) pumps were then isolated from two tropical and two Arctic octopus. The temperature sensitivities of these pumps closely matched those of the temperate and Antarctic pumps, respectively. Thus, reduced thermal sensitivity appears to be a common mechanism driving cold adaptation in the Na(+)/K(+)-ATPase. PMID- 21653812 TI - No apparent ecological trend to the flight-initiating jump performance of five bat species. AB - The jump performance of five insectivorous bat species (Miniopterus schreibersii, Myotis blythii, Myotis capaccinii, Myotis myotis and Rhinolophus blasii) was filmed using a high-speed camera. All study bats jumped using a similar technique, with the wing musculature providing the force. The bats jumped off the wrist joint of their wings, typically with their feet already off the ground. Contrary to expectations, jump performance did not correlate with ecology and was instead strongly determined by body size. In general, the larger bats produced more jump force, left the ground at higher speeds and jumped higher than the smaller bats. The differences in force production disappeared when the data were corrected for body size, with the exception of Myotis capaccinii, which produced significantly less force. Scaling of jump performance with body size measured here was compared against two existing muscle performance scaling models. The model suggesting that muscle contraction velocity is proportional to muscle length was better supported than that based on muscle cross-sectional area. Both models, however, failed to accurately predict the scaling of jump forces, with the slope of the relationship being significantly steeper than predicted, highlighting the need for further investigations of vertebrate muscle performance scaling. The results of this study indicate that a bat's jumping ability is a secondary locomotor ability that uses the strongly selected-for flight apparatus with no apparent ecological trend present, i.e. flight so dominates bat locomotor morphology that other locomotor abilities tend to be derivative. PMID- 21653813 TI - Perch size and structure have species-dependent effects on the arboreal locomotion of rat snakes and boa constrictors. AB - Arboreal habitats create diverse challenges for animal locomotion, but the numerical and phylogenetic diversity of snakes that climb trees suggest that their overall body plan is well suited for this task. Snakes have considerable diversity of axial anatomy, but the functional consequences of this diversity for arboreal locomotion are poorly understood because of the lack of comparative data. We simulated diverse arboreal surfaces to test whether environmental structure had different effects on the locomotion of snakes belonging to two distantly related species with differences in axial musculature and stoutness. On most cylindrical surfaces lacking pegs, both species used concertina locomotion, which always involved periodic stopping and gripping but was kinematically distinct in the two species. On horizontal cylinders that were a small fraction of body diameter, the boa constrictors used a balancing form of lateral undulation that was not observed for rat snakes. For all snakes the presence of pegs elicited lateral undulation and enhanced speed. For both species maximal speeds decreased with increased incline and were greatest on cylinders with intermediate diameters that approximated the diameter of the snakes. The frictional resistances that we studied had small effects compared with those of cylinder diameter, incline and the presence of pegs. The stouter and more muscular boa constrictors were usually faster than the rat snakes when using the gripping gait, whereas rat snakes were faster when using lateral undulation on the surfaces with pegs. Thus, variation in environmental structure had several highly significant effects on locomotor mode, performance and kinematics that were species dependent. PMID- 21653814 TI - Energetics of burrowing by the cirratulid polychaete Cirriformia moorei. AB - Burrowing through marine sediments has been considered to be much more energetically expensive than other forms of locomotion, but previous studies were based solely on external work calculations and lacked an understanding of the mechanical responses of sediments to forces applied by burrowers. Muddy sediments are elastic solids through which worms extend crack-shaped burrows by fracture. Here we present data on energetics of burrowing by Cirriformia moorei. We calculated the external energy per distance traveled from the sum of the work to extend the burrow by fracture and the elastic work done to displace sediment as a worm moves into the newly formed burrow to be 9.7 J kg(-1) m(-1) in gelatin and 64 J kg(-1) m(-1) in sediment, much higher than for running or walking. However, because burrowing worms travel at slow speeds, the increase in metabolic rate due to burrowing is predicted to be small. We tested this prediction by measuring aerobic metabolism (oxygen consumption rates) and anaerobic metabolism (concentrations of the anaerobic metabolite tauropine and the energy-storage molecule phosphocreatine) of C. moorei. None of these components was significantly different between burrowing and resting worms, and the low increases in oxygen consumption rates or tauropine concentrations predicted from external work calculations were within the variability observed across individuals. This result suggests that the energy to burrow, which could come from aerobic or anaerobic sources, is not a substantial component of the total metabolic energy of a worm. Burrowing incurs a low cost per unit of time. PMID- 21653815 TI - Honeybee flight: a novel 'streamlining' response. AB - Animals that move rapidly through the air can save considerable energy by reducing the drag that they need to overcome during flight. We describe a novel 'streamlining' response in tethered, flying honeybees in which the abdomen is held in a raised position when the visual system is exposed to a pattern of image motion that is characteristic of forward flight. This visually evoked response, which can be elicited without exposing the insect to any airflow, presumably serves to reduce the aerodynamic drag that would otherwise be produced by the abdomen during real flight. The response is critically dependent on the presence of appropriate image motion everywhere within the large field of view of the insect. Thus, our results also underscore the importance of using panoramic stimulation for the study of visually guided flight in insects, and reveal the relative importance of various regions of the visual field in assessing the speed of flight through the environment. PMID- 21653816 TI - Effects of shell morphology on mechanics of zebra and quagga mussel locomotion. AB - Although zebra mussels (Dreissena polymorpha) initially colonized shallow habitats within the North American Great Lakes, quagga mussels (Dreissena bugensis) are becoming dominant in both shallow- and deep-water habitats. Shell morphology differs among zebra, shallow quagga and deep quagga mussels but functional consequences of such differences are unknown. We examined effects of shell morphology on locomotion for the three morphotypes on hard (typical of shallow habitats) and soft (characteristic of deep habitats) sedimentary substrates. We quantified morphology using the polar moment of inertia, a parameter used in calculating kinetic energy that describes shell area distribution and resistance to rotation. We quantified mussel locomotion by determining the ratio of rotational (K(rot)) to translational kinetic energy (K(trans)). On hard substrate, K(rot):K(trans) of deep quagga mussels was fourfold greater than for the other morphotypes, indicating greater energy expenditure in rotation relative to translation. On soft substrate, K(rot):K(trans) of deep quagga mussels was approximately one-third of that on hard substrate, indicating lower energy expenditure in rotation on soft substrate. Overall, our study demonstrates that shell morphology correlates with differences in locomotion (i.e. K(rot):K(trans)) among morphotypes. Although deep quagga mussels were similar to zebra and shallow quagga mussels in terms of energy expenditure on sedimentary substrate, their morphology was energetically maladaptive for linear movement on hard substrate. As quagga mussels can possess two distinct morphotypes (i.e. shallow and deep morphs), they might more effectively utilize a broader range of substrates than zebra mussels, potentially enhancing their ability to colonize a wider range of habitats. PMID- 21653817 TI - Constraints on the adhesion of viscous threads spun by orb-weaving spiders: the tensile strength of glycoprotein glue exceeds its adhesion. AB - In this study we tested the hypothesis that a viscous thread releases its hold on a surface because its glycoprotein glue pulls from the surface and not because its elongating droplets break near their attachment to the surface. We compared the values obtained when three species' viscous threads adhered to four smooth surfaces, which differed in their total surface energy and in the proportions of their dispersion and polar energy components. Although water comprised 43-70% of the volume of these viscous droplets, only the dispersion surface energies of test materials and not their polar surface energies impacted thread adhesion. These results support the droplet pull-off hypothesis and are consistent with a previous finding that capillary force contributes little to thread adhesion. Just as a viscous thread's stickiness is constrained by the tensile strength of its supporting axial fibers, our findings suggest that glycoprotein adhesion is constrained by glycoprotein tensile strength. PMID- 21653818 TI - Hypothalamic neuropeptides, not leptin sensitivity, contributes to the hyperphagia in lactating Brandt's voles, Lasiopodomys brandtii. AB - Both pregnancy and lactation are associated with hyperphagia, and circulating leptin levels are elevated during pregnancy but decreased during lactation in Brandt's voles, Lasiopodomys brandtii. Previous findings suggest that impaired leptin sensitivity contributes to hyperphagia during pregnancy. The present study aimed to examine whether the decreased circulating leptin level and/or hypothalamic leptin sensitivity contributed to the hyperphagia during lactation in Brandt's voles. The serum leptin level and mRNA expression of the long form of the leptin receptor (Ob-Rb), suppressor-of-cytokine-signalling-3 (SOCS-3), neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus were examined on dioestrous, day 5, day 17 of lactation and day 27 (1 week after weaning) in Brandt's voles. Compared with controls, hypothalamic Ob-Rb and SOCS-3 mRNA expression was not significantly changed during lactation. The serum leptin level was significantly lower in lactating females than in the non-reproductive group. Hypothalamic NPY and AgRP mRNA expression significantly increased whereas POMC mRNA expression was significantly decreased during lactation compared with controls. However, there were no significant changes in hypothalamic CART mRNA expression. Food intake was positively correlated with NPY and AgRP mRNA expression but negatively correlated with POMC mRNA expression during lactation. These data suggest that hyperphagia during lactation was associated with low leptin levels, but not impaired leptin sensitivity, and that the hypothalamic neuropeptides NPY, AgRP and POMC are involved in mediating the role of leptin in food intake regulation in lactating Brandt's voles. PMID- 21653819 TI - In ovo thyroxine exposure alters later UVS cone loss in juvenile rainbow trout. AB - Thyroid hormones (THs) play a vital role in vertebrate neural development, and, together with the beta isoform of the thyroid hormone receptor (TRbeta), the development and differentiation of cone photoreceptors in the vertebrate retina. Rainbow trout undergo a natural process of cone cell degeneration during development and this change in photoreceptor distribution is regulated by thyroxine (T4; a thyroid hormone). In an effort to further understand the role of T4 in photoreceptor ontogeny and later developmental changes in photoreceptor subtype distribution, the influence of enhanced in ovo T4 content on the onset of opsin expression and cone development was examined. Juvenile trout reared from the initial in ovo-treated embryos were challenged with exogenous T4 at the parr stage of development to determine if altered embryonic exposure to yolk THs would affect later T4-induced short-wavelength-sensitive (SWS1) opsin transcript downregulation and ultraviolet-sensitive (UVS) cone loss. In ovo TH manipulation led to upregulation of both SWS1 and long-wavelength-sensitive (LWS) opsin transcripts in the pre-hatch rainbow trout retina and to changes in the relative expression of TRbeta. After 7 days of exposure to T4, juveniles that were also treated with T4 in ovo had greatly reduced SWS1 expression levels and premature loss of UVS cones relative to T4-treated juveniles raised from untreated eggs. These results suggest that changes in egg TH levels can have significant consequences much later in development, particularly in the retina. PMID- 21653820 TI - Dive behaviour impacts the ability of heart rate to predict oxygen consumption in Steller sea lions (Eumetopias jubatus) foraging at depth. AB - The predictive relationship between heart rate (f(H)) and oxygen consumption (VO2) has been derived for several species of marine mammals swimming horizontally or diving in tanks to shallow depths. However, it is unclear how dive activity affects the f(H):VO2 relationship and whether the existing equations apply to animals diving to deeper depths. We investigated these questions by simultaneously measuring the f(H) and VO2 of Steller sea lions (Eumetopias jubatus) under different activity states (surface resting or diving), types of dives (single dives or dive bouts), and depths (10 or 40 m). We examined the relationship over dives only and also over dive cycles (dive + surface interval). We found that f(H) could only predict VO2 over a complete single dive cycle or dive bout cycle (i.e. surface intervals had to be included). The predictive equation derived for sea lions resting on the surface did not differ from that for single dive cycles. However, the equation derived over dive bout cycles (multiple dives + surface intervals) differed from those for single dive cycles or surface resting, with similar f(H) for multiple dive bout equations yielding higher predicted VO2 than that for single dive bout cycles (or resting). The f(H):VO2 relationships were not significantly affected by dive duration, dive depth, water temperature or cumulative food consumed under the conditions tested. Ultimately, our results demonstrate that f(H) can be used to predict activity specific metabolic rates of diving Steller sea lions, but only over complete dive cycles that include a post-dive surface recovery period. PMID- 21653821 TI - Optimal walking speed following changes in limb geometry. AB - The principle of dynamic similarity states that the optimal walking speeds of geometrically similar animals are independent of size when speed is normalized to the dimensionless Froude number (Fr). Furthermore, various studies have shown similar dimensionless optimal speed (Fr ~0.25) for animals with quite different limb geometries. Here, we wondered whether the optimal walking speed of humans depends solely on total limb length or whether limb segment proportions play an essential role. If optimal walking speed solely depends on the limb length then, when subjects walk on stilts, they should consume less metabolic energy at a faster optimal speed than when they walk without stilts. To test this prediction, we compared kinematics, electromyographic activity and oxygen consumption in adults walking on a treadmill at different speeds with and without articulated stilts that artificially elongated the shank segment by 40 cm. Walking on stilts involved a non-linear reorganization of kinematic and electromyography patterns. In particular, we found a significant increase in the alternating activity of proximal flexors-extensors during the swing phase, despite significantly shorter normalized stride lengths. The minimal metabolic cost per unit distance walked with stilts occurred at roughly the same absolute speed, corresponding to a lower Fr number (Fr ~0.17) than in normal walking (Fr ~0.25). These findings are consistent with an important role of limb geometry optimization and kinematic coordination strategies in minimizing the energy expenditure of human walking. PMID- 21653822 TI - Characteristics of vortex formation and thrust performance in drag-based paddling propulsion. AB - Several characteristics of drag-based paddling propulsion are studied with a simple mechanical model and a measurement technique for mapping three-dimensional flow fields. In drag-based propulsion, the temporal change of the vortex strength is an important parameter in the relationship between vortex formation and thrust generation. Our results indicate that spanwise flow behind the paddling propulsor significantly affects tip vortex development and thrust generation. The distribution of spanwise flow is dependent on the propulsor shape and the Reynolds number. A delta-shaped propulsor generates strong spanwise flow compared with a rectangular propulsor. For the low Reynolds number case, spanwise flow is not as strong as that for the high Reynolds number case. Without sacrificing total impulse, the flexible propulsor can smooth out thrust peaks during sudden stroke motions, which is favorable for avoiding structural failures and stabilizing body motion. We also explored the role of stopping vortex shedding in efficient thrust generation by determining the relationship between stroke angles and total impulses generated by paddling propulsors. PMID- 21653823 TI - A laminopathic mutation disrupting lamin filament assembly causes disease-like phenotypes in Caenorhabditis elegans. AB - Mutations in the human LMNA gene underlie many laminopathic diseases, including Emery-Dreifuss muscular dystrophy (EDMD); however, a mechanistic link between the effect of mutations on lamin filament assembly and disease phenotypes has not been established. We studied the DeltaK46 Caenorhabditis elegans lamin mutant, corresponding to EDMD-linked DeltaK32 in human lamins A and C. Cryo-electron tomography of lamin DeltaK46 filaments in vitro revealed alterations in the lateral assembly of dimeric head-to-tail polymers, which causes abnormal organization of tetrameric protofilaments. Green fluorescent protein (GFP):DeltaK46 lamin expressed in C. elegans was found in nuclear aggregates in postembryonic stages along with LEM-2. GFP:DeltaK46 also caused mislocalization of emerin away from the nuclear periphery, consistent with a decreased ability of purified emerin to associate with lamin DeltaK46 filaments in vitro. GFP:DeltaK46 animals had motility defects and muscle structure abnormalities. These results show that changes in lamin filament structure can translate into disease-like phenotypes via altering the localization of nuclear lamina proteins, and suggest a model for how the DeltaK32 lamin mutation may cause EDMD in humans. PMID- 21653824 TI - Interaction of the human prostacyclin receptor with the PDZ adapter protein PDZK1: role in endothelial cell migration and angiogenesis. AB - Prostacyclin is increasingly implicated in re-endothelialization and angiogenesis but through largely unknown mechanisms. Herein the high-density lipoprotein (HDL) scavenger receptor class B, type 1 (SR-B1) adapter protein PDZ domain-containing protein 1 (PDZK1) was identified as an interactant of the human prostacyclin receptor (hIP) involving a Class I PDZ ligand at its carboxyl terminus and PDZ domains 1, 3, and 4 of PDZK1. Although the interaction is constitutive, it may be dynamically regulated following cicaprost activation of the hIP through a mechanism involving cAMP-dependent protein kinase (PK)A-phosphorylation of PDZK1 at Ser-505. Although PDZK1 did not increase overall levels of the hIP, it increased its functional expression at the cell surface, enhancing ligand binding and cicaprost-induced cAMP generation. Consistent with its role in re endothelialization and angiogenesis, cicaprost activation of the hIP increased endothelial cell migration and tube formation/in vitro angiogenesis, effects completely abrogated by the specific IP antagonist RO1138452. Furthermore, similar to HDL/SR-B1, small interfering RNA (siRNA)-targeted disruption of PDZK1 abolished cicaprost-mediated endothelial responses but did not affect VEGF responses. Considering the essential role played by prostacyclin throughout the cardiovascular system, identification of PDZK1 as a functional interactant of the hIP sheds significant mechanistic insights into the protective roles of these key players, and potentially HDL/SR-B1, within the vascular endothelium. PMID- 21653825 TI - The yeast kinase Yck2 has a tripartite palmitoylation signal. AB - The yeast kinase Yck2 tethers to the cytoplasmic surface of the plasma membrane through dual palmitoylation of its C-terminal Cys-Cys dipeptide, mediated by the Golgi-localized palmitoyl-transferase Akr1. Here, the Yck2 palmitoylation signal is found to consist of three parts: 1) a 10-residue-long, conserved C-terminal peptide (CCTP) that includes the C-terminal Cys-Cys dipeptide; 2) the kinase catalytic domain (KD); and mapping between these two elements; and 3) a 176 residue-long, poorly conserved, glutamine-rich sequence. The CCTP, which contains the C-terminal cysteines as well as an important Phe-Phe dipeptide, likely serves as an Akr1 recognition element, because CCTP mutations disrupt palmitoylation within a purified in vitro palmitoylation system. The KD contribution appears to be complex with roles for both KD activity (e.g., Yck2-mediated phosphorylation) and structure (e.g., Akr1 recognition elements). KD and CCTP mutations are strongly synergistic, suggesting that, like the CCTP, the KD may also participate at the Yck2-Akr1 recognition step. The long, glutamine-rich domain, which is located between the KD and CCTP, is predicted to be intrinsically disordered and may function as a flexible, interdomain linker, allowing a coupled interaction of the KD and CCTP with Akr1. Multipart palmitoylation signals may prove to be a general feature of this large class of palmitoylation substrates. These soluble proteins have no clear means of accessing membranes and thus may require active capture out of the cytoplasm for palmitoylation by their membrane-localized transferases. PMID- 21653826 TI - VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation. AB - In endothelial cells, neuropilin-1 (NRP1) binds vascular endothelial growth factor (VEGF)-A and is thought to act as a coreceptor for kinase insert domain containing receptor (KDR) by associating with KDR and enhancing VEGF signaling. Here we report mutations in the NRP1 b1 domain (Y297A and D320A), which result in complete loss of VEGF binding. Overexpression of Y297A and D320A NRP1 in human umbilical vein endothelial cells reduced high-affinity VEGF binding and migration toward a VEGF gradient, and markedly inhibited VEGF-induced angiogenesis in a coculture cell model. The Y297A NRP1 mutant also disrupted complexation between NRP1 and KDR and decreased VEGF-dependent phosphorylation of focal adhesion kinase at Tyr407, but had little effect on other signaling pathways. Y297A NRP1, however, heterodimerized with wild-type NRP1 and NRP2 indicating that nonbinding NRP1 mutants can act in a dominant-negative manner through formation of NRP1 dimers with reduced binding affinity for VEGF. These findings indicate that VEGF binding to NRP1 has specific effects on endothelial cell signaling and is important for endothelial cell migration and angiogenesis mediated via complex formation between NRP1 and KDR and increased signaling to focal adhesions. Identification of key residues essential for VEGF binding and biological functions provides the basis for a rational design of antagonists of VEGF binding to NRP1. PMID- 21653827 TI - A phosphodegron controls nutrient-induced proteasomal activation of the signaling protease Ssy5. AB - Regulated proteolysis serves as a mechanism to control cellular processes. The SPS (Ssy1-Ptr3-Ssy5) sensor in yeast responds to extracellular amino acids by endoproteolytically activating transcription factors Stp1 and Stp2 (Stp1/2). The processing endoprotease Ssy5 is regulated via proteasomal degradation of its noncovalently associated N-terminal prodomain. We find that degradation of the prodomain requires a conserved phosphodegron comprising phosphoacceptor sites and ubiquitin-accepting lysine residues. Upon amino acid induction, the phosphodegron is modified in a series of linked events by a set of general regulatory factors involved in diverse signaling pathways. First, an amino acid-induced conformational change triggers phosphodegron phosphorylation by the constitutively active plasma membrane-localized casein kinase I (Yck1/2). Next the prodomain becomes a substrate for polyubiquitylation by the Skp1/Cullin/Grr1 E3 ubiquitin ligase complex (SCF(Grr1)). Finally, the modified prodomain is concomitantly degraded by the 26S proteasome. These integrated events are requisite for unfettering the Ssy5 endoprotease, and thus Stp1/2 processing. The Ssy5 phosphoacceptor motif resembles the Yck1/2- and Grr1-dependent degrons of regulators in the Snf3/Rgt2 glucose-sensing pathway. Our work defines a novel proteolytic activation cascade that regulates an intracellular signaling protease and illustrates how general signaling components are recruited to distinct pathways that achieve conditional and specific signaling outputs. PMID- 21653828 TI - Transplantation tolerance: memories that haunt us. AB - Transplant tolerance, which allows grafts--allogeneic cells, tissues, or organs- to be accepted without host immunosuppression, can be achieved in mice but not in primates. In this issue of Science Translational Medicine, Nadazdin et al. report that a high pretransplant frequency of graft-reactive memory T cells may inhibit the induction of transplant tolerance in nonhuman primates and lead to transplant rejection. Knowing the frequency of allograft-specific memory T cells in potential transplant recipients could aid clinical decision-making by guiding selection of the antigenic profile of the donor organ or by influencing the type of tolerance-induction protocol pursued. PMID- 21653829 TI - Protein interactome reveals converging molecular pathways among autism disorders. AB - To uncover shared pathogenic mechanisms among the highly heterogeneous autism spectrum disorders (ASDs), we developed a protein interaction network that identified hundreds of new interactions among proteins encoded by ASD-associated genes. We discovered unexpectedly high connectivity between SHANK and TSC1, previously implicated in syndromic autism, suggesting that common molecular pathways underlie autistic phenotypes in distinct syndromes. ASD patients were more likely to harbor copy number variations that encompass network genes than were control subjects. We also identified, in patients with idiopathic ASD, three de novo lesions (deletions in 16q23.3 and 15q22 and one duplication in Xq28) that involve three network genes (NECAB2, PKM2, and FLNA). The protein interaction network thus provides a framework for identifying causes of idiopathic autism and for understanding molecular pathways that underpin both syndromic and idiopathic ASDs. PMID- 21653830 TI - Off-target lapatinib activity sensitizes colon cancer cells through TRAIL death receptor up-regulation. AB - Lapatinib, a dual HER2/EGFR (human epidermal growth factor receptor 2/epidermal growth factor receptor) inhibitor, is a recently approved targeted therapy for metastatic breast cancer. Because lapatinib enhances the efficacy of the chemotherapeutic agent capecitabine in breast cancer patients, we tested whether lapatinib also enhances the activity of anticancer agents in colorectal cancer. We found that lapatinib improved the proapoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two TRAIL receptor agonists, the antibodies mapatumumab and lexatumumab. Tumors from mice treated with a combination of lapatinib and TRAIL exhibited more immunostaining for cleaved caspase-8, a marker of the extrinsic cell death pathway, than did tumors from mice treated with lapatinib or TRAIL alone. Furthermore, combination therapy suppressed tumor growth more effectively than either agent alone. Lapatinib up regulated the proapoptotic TRAIL death receptors DR4 and DR5, leading to more efficient induction of apoptosis in the presence of TRAIL receptor agonists. This activity of lapatinib was independent of EGFR and HER2. The off-target induction of DR5 by lapatinib resulted from activation of the c-Jun amino-terminal kinase (JNK)/c-Jun signaling axis. This activity of lapatinib on TRAIL death receptor expression and signaling may confer therapeutic benefit when increased doses of lapatinib are used in combination with TRAIL receptor-activating agents. PMID- 21653831 TI - Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. AB - Transplant tolerance, defined as indefinite allograft survival without immunosuppression, has been regularly achieved in laboratory mice but not in nonhuman primates or humans. In contrast to laboratory mice, primates regularly have high frequencies of alloreactive memory T cells (TMEMs) before transplantation. These TMEMs are poorly sensitive to conventional immunosuppression and costimulation blockade, and the presence of donor-reactive TMEMs in primates may account for their resistance to transplant tolerance protocols that have proven consistently effective in mice. We measured the frequencies of anti-donor TMEMs before and after transplantation in a series of rejecting and tolerant monkeys that underwent nonmyeloablative conditioning, short-term immunosuppression, and combined allogeneic kidney/cell transplantation. Transplants were acutely rejected in all the monkeys with high numbers of donor-specific TMEMs before transplantation. In contrast, long-term survival was observed in the recipients harboring lower frequencies of anti-donor TMEMs before transplantation. Similar amounts of TMEM homeostatic expansion were recorded in all transplanted monkeys upon hematopoietic reconstitution; however, only the tolerant monkeys had no expansion or activation of donor-reactive TMEMs after transplantation. These results indicate that the presence of high frequencies of host donor-reactive TMEMs before transplantation impairs tolerance induction to kidney allografts in this nonhuman primate model. Indeed, recipients harboring a low anamnestic reactivity to their donor before transplantation were successfully rendered tolerant via infusion of donor cells and short-term immunosuppression. This suggests that selection of allogeneic donors with low memory responses in recipients may be essential to successful transplant tolerance induction in patients. PMID- 21653832 TI - Gab2, via PI-3K, regulates ARF1 in FcepsilonRI-mediated granule translocation and mast cell degranulation. AB - Mast cells are major players in allergic responses. IgE-dependent activation through FcepsilonR leads to degranulation and cytokine production, both of which require Gab2. To clarify how the signals diverge at Gab2, we established Gab2 knock-in mice that express Gab2 mutated at either the PI3K or SH2 domain containing protein tyrosine phosphatase-2 (SHP2) binding sites. Examination of these mutants showed that both binding sites were required for the degranulation and anaphylaxis response but not for cytokine production or contact hypersensitivity. Furthermore, the PI3K, but not the SHP2, binding site was important for granule translocation during degranulation. We also identified a small GTPase, ADP-ribosylation factor (ARF)1, as the downstream target of PI3K that regulates granule translocation. FcepsilonRI stimulation induced ARF1 activation, and this response was dependent on Fyn and the PI3K binding site of Gab2. ARF1 activity was required for FcepsilonRI-mediated granule translocation. These data indicated that Fyn/Gab2/PI3K/ARF1-mediated signaling is specifically involved in granule translocation and the anaphylaxis response. PMID- 21653833 TI - Increased frequencies of myelin oligodendrocyte glycoprotein/MHC class II-binding CD4 cells in patients with multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease characterized by infiltration of pathogenic immune cells in the CNS resulting in destruction of the myelin sheath and surrounding axons. We and others have previously measured the frequency of human myelin-reactive T cells in peripheral blood. Using T cell cloning techniques, a modest increase in the frequency of myelin-reactive T cells in patients as compared with control subjects was observed. In this study, we investigated whether myelin oligodendrocyte glycoprotein (MOG)-specific T cells could be detected and their frequency was measured using DRB1*0401/MOG(97 109(107E-S)) tetramers in MS subjects and healthy controls expressing HLA class II DRB1*0401. We defined the optimal culture conditions for expansion of MOG reactive T cells upon MOG peptide stimulation of PMBCs. MOG(97-109)-reactive CD4(+) T cells, isolated with DRB1*0401/MOG(97-109) tetramers, and after a short term culture of PMBCs with MOG(97-109) peptides, were detected more frequently from patients with MS as compared with healthy controls. T cell clones from single cell cloning of DRB1*0401/MOG(97-109(107E-S)) tetramer(+) cells confirmed that these T cell clones were responsive to both the native and the substituted MOG peptide. These data indicate that autoantigen-specific T cells can be detected and enumerated from the blood of subjects using class II tetramers, and the frequency of MOG(97-109)-reactive T cells is greater in patients with MS as compared with healthy controls. PMID- 21653834 TI - Yersinia pestis YopE contains a dominant CD8 T cell epitope that confers protection in a mouse model of pneumonic plague. AB - Septic bacterial pneumonias are a major cause of death worldwide. Several of the highest priority bioterror concerns, including anthrax, tularemia, and plague, are caused by bacteria that acutely infect the lung. Bacterial resistance to multiple antibiotics is increasingly common. Although vaccines may be our best defense against antibiotic-resistant bacteria, there has been little progress in the development of safe and effective vaccines for pulmonary bacterial pathogens. The Gram-negative bacterium Yersinia pestis causes pneumonic plague, an acutely lethal septic pneumonia. Historic pandemics of plague caused millions of deaths, and the plague bacilli's potential for weaponization sustains an ongoing quest for effective countermeasures. Subunit vaccines have failed, to date, to fully protect nonhuman primates. In mice, they induce the production of Abs that act in concert with type 1 cytokines to deliver high-level protection; however, the Y. pestis Ags recognized by cytokine-producing T cells have yet to be defined. In this study, we report that Y. pestis YopE is a dominant Ag recognized by CD8 T cells in C57BL/6 mice. After vaccinating with live attenuated Y. pestis and challenging intranasally with virulent plague, nearly 20% of pulmonary CD8 T cells recognize this single, highly conserved Ag. Moreover, immunizing mice with a single peptide, YopE(69-77), suffices to confer significant protection from lethal pulmonary challenge. These findings suggest YopE could be a valuable addition to subunit plague vaccines and provide a new animal model in which sensitive, pathogen-specific assays can be used to study CD8 T cell-mediated defense against acutely lethal bacterial infections of the lung. PMID- 21653835 TI - Targeting FcalphaRI on polymorphonuclear cells induces tumor cell killing through autophagy. AB - Neutrophils are the most abundant circulating FcR-expressing WBCs with potent cytotoxic ability. Currently, they are recognized as promising effector cells for Ab-mediated immunotherapy of cancer, because their capacity to kill tumor cells is greatly enhanced by tumor Ag-specific mAbs. The FcalphaRI represents the most potent FcR on neutrophils for induction of Ab-mediated tumor cell killing. However, the mechanisms of cell death that are induced are poorly understood. Because these mechanisms can be used for modulation of anticancer treatment, we investigated the tumor cell death induced by neutrophil-mediated Ab-dependent killing via FcalphaRI. Human mammary carcinoma cells were efficiently killed when incubated with human neutrophils and tumor-specific FcalphaRI bispecific or IgA Abs. Interestingly, we observed characteristics of autophagy such as autophagic structures by electron microscopy and LC3B(+) autophagosomes in different human epithelial carcinoma cells, which resulted in tumor cell death. To a lesser extent, necrotic features, such as cellular membrane breakdown and spillage of intracellular content, were found. By contrast, apoptotic features including fragmented nuclei, Annexin V-positivity, and presence of cleaved caspase-3 were not observed. These findings indicate that neutrophils mainly facilitate autophagy to induce tumor cell death rather than the more commonly recognized apoptotic cell death mechanisms induced by NK cells or cytotoxic T cells. This knowledge not only reveals the type of tumor cell death induced in neutrophil mediated, Ab-dependent cellular cytotoxicity, but importantly opens up additional perspectives for modulation of anticancer therapy in, for example, apoptosis resistant tumor cells. PMID- 21653836 TI - Cutting edge: T cells monitor N-myristoylation of the Nef protein in simian immunodeficiency virus-infected monkeys. AB - The use of the host cellular machinery is essential for pathogenic viruses to replicate in host cells. HIV and SIV borrow the host-derived N-myristoyl transferase and its substrate, myristoyl-CoA, for coupling a saturated C(14) fatty acid (myristic acid) to the N-terminal glycine residue of the Nef protein. This biochemical reaction, referred to as N-myristoylation, assists its targeting to the plasma membrane, thereby supporting the immunosuppressive activity proposed for the Nef protein. In this study, we show that the host immunity is equipped with CTLs capable of sensing N-myristoylation of the Nef protein. A rhesus macaque CD8(+) T cell line was established that specifically recognized N myristoylated, but not unmodified, peptides of the Nef protein. Furthermore, the population size of N-myristoylated Nef peptide-specific T cells was found to increase significantly in the circulation of SIV-infected monkeys. Thus, these results identify N-myristoylated viral peptides as a novel class of CTL target Ag. PMID- 21653837 TI - Two modes of GABAB: specific localized inhibition and global network inhibition. PMID- 21653838 TI - Overexpression of the dominant-negative form of interferon regulatory factor 1 in oligodendrocytes protects against experimental autoimmune encephalomyelitis. AB - Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the pathogenesis of the human autoimmune demyelinating disease multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of the present study was to directly examine the role of IRF-1 in oligodendrocyte injury and inflammatory demyelination. For the purpose of this study, we generated a transgenic mouse line (CNP/dnIRF-1) that overexpresses the dominant-negative form of IRF-1 (dnIRF1) specifically in oligodendrocytes. CNP/dnIRF-1 mice exhibited no phenotypic abnormalities but displayed suppressed IRF-1 signaling in oligodendrocytes. The major finding of our study was that the CNP/dnIRF-1 mice, compared with the wild-type mice, were protected against EAE, a phenomenon associated with significant reduction of inflammatory demyelination and with oligodendrocyte and axonal preservation. The observed protection was related to suppressed IRF-1 signaling and impaired expression of immune and proapoptotic genes in oligodendrocytes. No significant differences in the peripheral immune responses between the wild-type and the CNP/dnIRF-1 mice were identified throughout the experiments. This study indicates that IRF-1 plays a critical role in the pathogenesis of EAE by mediating oligodendrocyte response to inflammation and injury. It also suggests that oligodendrocytes are actively involved in the neuroimmune network, and that exploring oligodendrocyte-related pathogenic mechanisms, in addition to the conventional immune-based ones, may have important therapeutic implications in MS. PMID- 21653839 TI - Circadian regulation of ATP release in astrocytes. AB - Circadian clocks sustain daily oscillations in gene expression, physiology, and behavior, relying on transcription-translation feedback loops of clock genes for rhythm generation. Cultured astrocytes display daily oscillations of extracellular ATP, suggesting that ATP release is a circadian output. We hypothesized that the circadian clock modulates ATP release via mechanisms that regulate acute ATP release from glia. To test the molecular basis for circadian ATP release, we developed methods to measure in real-time ATP release and Bmal1::dLuc circadian reporter expression in cortical astrocyte cultures from mice of different genotypes. Daily rhythms of gene expression required functional Clock and Bmal1, both Per1 and Per2, and both Cry1 and Cry2 genes. Similarly, high-level, circadian ATP release also required a functional clock mechanism. Whereas blocking IP(3) signaling significantly disrupted ATP rhythms with no effect on Bmal1::dLuc cycling, blocking vesicular release did not alter circadian ATP release or gene expression. We conclude that astrocytes depend on circadian clock genes and IP(3) signaling to express daily rhythms in ATP release. PMID- 21653840 TI - Notch signaling alters sensory or neuronal cell fate specification of inner ear stem cells. AB - Multipotent progenitor cells in the otic placode give rise to the specialized cell types of the inner ear, including neurons, supporting cells, and hair cells. The mechanisms governing acquisition of specific fates by the cells that form the cochleovestibular organs remain poorly characterized. Here we show that whereas blocking Notch signaling with a gamma-secretase inhibitor increased the conversion of inner ear stem cells to hair cells by a mechanism that involved the upregulation of bHLH transcription factor, Math1 (mouse Atoh1), differentiation to a neuronal lineage was increased by expression of the Notch intracellular domain. The shift to a neuronal lineage could be attributed in part to continued cell proliferation in cells that did not undergo sensory cell differentiation due to the high Notch signaling, but also involved upregulation of Ngn1. The Notch intracellular domain influenced Ngn1 indirectly by upregulation of Sox2, a transcription factor expressed in many neural progenitor cells, and directly by an interaction with an RBP-J binding site in the Ngn1 promoter/enhancer. The induction of Ngn1 was blocked partially by mutation of the RBP-J site and nearly completely when the mutation was combined with inhibition of Sox2 expression. Thus, Notch signaling had a significant role in the fate specification of neurons and hair cells from inner ear stem cells, and decisions about cell fate were mediated in part by a differential effect of combinatorial signaling by Notch and Sox2 on the expression of bHLH transcription factors. PMID- 21653841 TI - Cellular and network contributions to vestibular signal processing: impact of ion conductances, synaptic inhibition, and noise. AB - Head motion-related sensory signals are transformed by second-order vestibular neurons (2 degrees VNs) into appropriate commands for retinal image stabilization during body motion. In frogs, these 2 degrees VNs form two distinct subpopulations that have either tonic or highly phasic intrinsic properties, essentially compatible with low-pass and bandpass filter characteristics, respectively. In the present study, physiological data on cellular properties of 2 degrees VNs of the grass frog (Rana temporaria) have been used to construct conductance-based spiking cellular models that were fine-tuned by fitting to recorded spike-frequency data. The results of this approach suggest that low threshold, voltage-dependent potassium channels in phasic and spike-dependent potassium channels in tonic 2 degrees VNs are important contributors to the differential, yet complementary response characteristics of the two vestibular subtypes. Extension of the cellular model with conductance-based synapses allowed simulation of afferent excitation and evaluation of the emerging properties of local feedforward inhibitory circuits. This approach revealed the relative contributions of intrinsic and synaptic factors on afferent signal processing in phasic 2 degrees VNs. Additional extension of the single-cell model to a population model allowed testing under more natural conditions including asynchronous afferent labyrinthine input and synaptic noise. This latter approach indicated that the feedforward inhibition from the local inhibitory network acts as a high-pass filter, which reinforces the impact of the intrinsic membrane properties of phasic 2 degrees VNs on peak response amplitude and timing. Thus, the combination of cellular and network properties enables phasic 2 degrees VNs to work as a noise-resistant detector, suitable for central processing of short duration vestibular signals. PMID- 21653842 TI - Role of central leptin signaling in the starvation-induced alteration of B-cell development. AB - Nutritional deprivation or malnutrition suppresses immune function in humans and animals, thereby conferring higher susceptibility to infectious diseases. Indeed, nutritional deprivation induces atrophy of lymphoid tissues such as thymus and spleen and decreases the number of circulating lymphocytes. Leptin, a major adipocytokine, is exclusively produced in the adipose tissue in response to the nutritional status and acts on the hypothalamus, thereby regulating energy homeostasis. Although leptin plays a critical role in the starvation-induced T cell-mediated immunosuppression, little is known about its role in B-cell homeostasis under starvation conditions. Here we show the alteration of B-cell development in the bone marrow of fasted mice, characterized by decrease in pro B, pre-B, and immature B cells and increase in mature B cells. Interestingly, intracerebroventricular leptin injection was sufficient to prevent the alteration of B-cell development of fasted mice. The alteration of B lineage cells in the bone marrow of fasted mice was markedly prevented by oral administration of glucocorticoid receptor antagonist RU486 (11beta-[p-(dimethylamino)phenyl]-17beta hydroxy-17-(1-propynyl)estra-4,9-dien-3-one). It was also effectively prevented by intracerebroventricular injection of neuropeptide Y Y(1) receptor antagonist BIBP3226 [(2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(4 hydroxyphenyl)methyl]pentanamide], along with suppression of the otherwise increased serum corticosterone concentrations. This study provides the first in vivo evidence for the role of central leptin signaling in the starvation-induced alteration of B-cell development. The data of this study suggest that the CNS, which is inherent to integrate information from throughout the organism, is able to control immune function. PMID- 21653843 TI - The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry. AB - Netrins are guidance cues involved in neural connectivity. We have shown that the netrin-1 receptor DCC (deleted in colorectal cancer) is involved in the functional organization of the mesocorticolimbic dopamine (DA) system. Adult mice with a heterozygous loss-of-function mutation in dcc exhibit changes in indexes of DA function, including DA-related behaviors. These phenotypes are only observed after puberty, a critical period in the maturation of the mesocortical DA projection. Here, we examined whether dcc heterozygous mice exhibit structural changes in medial prefrontal cortex (mPFC) DA synaptic connectivity, before and after puberty. Stereological counts of tyrosine-hydroxylase (TH)-positive varicosities were increased in the cingulate 1 and prelimbic regions of the pregenual mPFC. dcc heterozygous mice also exhibited alterations in the size, complexity, and dendritic spine density of mPFC layer V pyramidal neuron basilar dendritic arbors. Remarkably, these presynaptic and postsynaptic partner phenotypes were not observed in juvenile mice, suggesting that DCC selectively influences the extensive branching and synaptic differentiation that occurs in the maturing mPFC DA circuit at puberty. Immunolabeling experiments in wild-type mice demonstrated that DCC is segregated to TH-positive fibers innervating the nucleus accumbens, with only scarce DCC labeling in mPFC TH-positive fibers. Netrin had an inverted target expression pattern. Thus, DCC-mediated netrin-1 signaling may influence the formation/maintenance of mesocorticolimbic DA topography. In support of this, we report that dcc heterozygous mice exhibit a twofold increase in the density of mPFC DCC/TH-positive varicosities. Our results implicate DCC-mediated netrin-1 signaling in the establishment of mPFC DA circuitry during puberty. PMID- 21653844 TI - Interplay among cGMP, cAMP, and Ca2+ in living olfactory sensory neurons in vitro and in vivo. AB - The mechanism of cGMP production in olfactory sensory neurons (OSNs) is poorly understood, although this messenger takes part in several key processes such as adaptation, neuronal development, and long-term cellular responses to odorant stimulation. Many aspects of the regulation of cGMP in OSNs are still unknown or highly controversial, such as its subcellular heterogeneity, mechanism of coupling to odorant receptors and downstream targets. Here, we have investigated the dynamics and the intracellular distribution of cGMP in living rat OSNs in culture transfected with a genetically encoded sensor for cGMP. We demonstrate that OSNs treated with pharmacological stimuli able to activate membrane or soluble guanylyl cyclase (sGC) presented an increase in cGMP in the entire neuron, from cilia-dendrite to the axon terminus-growth cone. Upon odorant stimulation, a rise in cGMP was again found in the entire neuron, including the axon terminus, where it is locally synthesized. The odorant-dependent rise in cGMP is due to sGC activation by nitric oxide (NO) and requires an increase of cAMP. The link between cAMP and NO synthase appears to be the rise in cytosolic Ca(2+) concentration elicited by either plasma membrane Ca(2+) channel activation or Ca(2+) mobilization from stores via the guanine nucleotide exchange factor Epac. Finally, we show that a cGMP rise can elicit both in vitro and in vivo the phosphorylation of nuclear CREB, suggesting that this signaling pathway may be relevant for both local events (pathfinding, neurotransmitter release) and more distal processes involving gene expression regulation. PMID- 21653845 TI - Tracking the temporal evolution of a perceptual judgment using a compelled response task. AB - Choice behavior and its neural correlates have been intensely studied with tasks in which a subject makes a perceptual judgment and indicates the result with a motor action. Yet a question crucial for relating behavior to neural activity remains unresolved: what fraction of a subject's reaction time (RT) is devoted to the perceptual evaluation step, as opposed to executing the motor report? Making such timing measurements accurately is complicated because RTs reflect both sensory and motor processing, and because speed and accuracy may be traded. To overcome these problems, we designed the compelled-saccade task, a two alternative forced-choice task in which the instruction to initiate a saccade precedes the appearance of the relevant sensory information. With this paradigm, it is possible to track perceptual performance as a function of the amount of time during which sensory information is available to influence a subject's choice. The result-the tachometric curve-directly reveals a subject's perceptual processing capacity independently of motor demands. Psychophysical data, together with modeling and computer-simulation results, reveal that task performance depends on three separable components: the timing of the motor responses, the speed of the perceptual evaluation, and additional cognitive factors. Each can vary quickly, from one trial to the next, or can show stable, longer-term changes. This novel dissociation between sensory and motor processes yields a precise metric of how perceptual capacity varies under various experimental conditions and serves to interpret choice-related neuronal activity as perceptual, motor, or both. PMID- 21653846 TI - Initiation of locomotion in adult zebrafish. AB - Motor behavior is generated by specific neural circuits. Those producing locomotion are located in the spinal cord, and their activation depends on descending inputs from the brain or on sensory inputs. In this study, we have used an in vitro brainstem-spinal cord preparation from adult zebrafish to localize a region where stimulation of descending inputs can induce sustained locomotor activity. We show that a brief stimulation of descending inputs at the junction between the brainstem and spinal cord induces long-lasting swimming activity. The swimming frequencies induced are remarkably similar to those observed in freely moving adult fish, arguing that the induced locomotor episode is highly physiological. The motor pattern is mediated by activation of ionotropic glutamate and glycine receptors in the spinal cord and is not the result of synaptic interactions between neurons at the site of the stimulation in the brainstem. We also compared the activity of motoneurons during locomotor activity induced by electrical stimulation of descending inputs and by exogenously applied NMDA. Prolonged NMDA application changes the shape of the synaptic drive and action potentials in motoneurons. When escape activity occurs, the swimming activity in the intact zebrafish was interrupted and some of the motoneurons involved became inhibited in vitro. Thus, the descending inputs seem to act as a switch to turn on the activity of the spinal locomotor network in the caudal spinal cord. We propose that recurrent synaptic activity within the spinal locomotor circuits can transform a brief input into a well coordinated and long lasting swimming pattern. PMID- 21653847 TI - Mitochondrial calcium signaling mediates rhythmic extracellular ATP accumulation in suprachiasmatic nucleus astrocytes. AB - The master circadian pacemaker located within the suprachiasmatic nuclei (SCN) controls neural and neuroendocrine rhythms in the mammalian brain. Astrocytes are abundant in the SCN, and this cell type displays circadian rhythms in clock gene expression and extracellular accumulation of ATP. Still, the intracellular signaling pathways that link the SCN clockworks to circadian rhythms in extracellular ATP accumulation remain unclear. Because ATP release from astrocytes is a calcium-dependent process, we investigated the relationship between intracellular Ca(2+) and ATP accumulation and have demonstrated that intracellular Ca(2+) levels fluctuate in an antiphase relationship with rhythmic ATP accumulation in rat SCN2.2 cell cultures. Furthermore, mitochondrial Ca(2+) levels were rhythmic and maximal in precise antiphase with the peak in cytosolic Ca(2+). In contrast, our finding that peak mitochondrial Ca(2+) occurred during maximal extracellular ATP accumulation suggests a link between these cellular rhythms. Inhibition of the mitochondrial Ca(2+) uniporter disrupted the rhythmic production and extracellular accumulation of ATP. ATP, calcium, and the biological clock affect cell division and have been implicated in cell death processes. Nonetheless, rhythmic extracellular ATP accumulation was not disrupted by cell cycle arrest and was not correlated with caspase activity in SCN2.2 cell cultures. Together, these results demonstrate that mitochondrial Ca(2+) mediates SCN2.2 rhythms in extracellular ATP accumulation and suggest a role for circadian gliotransmission in SCN clock function. PMID- 21653848 TI - Transsynaptic EphB/Ephrin-B signaling regulates growth of presynaptic boutons required for classical conditioning. AB - Learning-related presynaptic remodeling has been documented in only a few systems, and its molecular mechanisms are largely unknown. Here we describe a role for the bidirectional EphB/ephrin-B signaling system in structural plasticity of presynaptic nerve terminals using an in vitro model of classical conditioning. Conditioning or BDNF application induced significant growth of auditory nerve presynaptic boutons that convey the conditioned stimulus to abducens motor neurons. Interestingly, bouton enlargement occurred only for those synapses apposed to motor neuron dendrites rather than to somata. Phosphorylation of ephrin-B1, but not EphB2, was induced by both conditioning and BDNF application and was inhibited by postsynaptic injections of ephrin-B antibody. Finally, suppression of postsynaptic ephrin-B function inhibited presynaptic bouton enlargement that was rescued by activation of EphB2 by ephrin-B1-Fc. These data provide evidence for ephrin-B-induced EphB2 forward signaling in presynaptic structural plasticity during classical conditioning. They also reveal a functional interaction between BDNF/TrkB and the Eph/ephrin signaling systems in the coordination of presynaptic and postsynaptic modifications during conditioning. PMID- 21653849 TI - The transcription factor Sp8 is required for the production of parvalbumin expressing interneurons in the olfactory bulb. AB - Interneurons in the olfactory bulb (OB) represent a heterogeneous population, which are first produced at embryonic stages and persisting into adulthood. Using the BrdU birthdating method combined with immunostaining for several different neuronal markers, we provide the integrated temporal patterns of distinct mouse OB interneuron production from embryonic day 14 to postnatal day 365. We show that although the majority of OB interneuron subtypes continue to be generated throughout life, most subtypes show a similar "bell-like" temporal production pattern with a peak around birth. Tyrosine hydroxylase and calretinin-expressing interneurons are produced at a relatively low rate in the adult OB, while parvalbumin-expressing (PV+) interneuron production is confined to later embryonic and early postnatal stages. We also show that Dlx5/6-expressing progenitors contribute to PV+ interneurons in the OB. Interestingly, all PV+ interneurons in the external plexiform layer (EPL) express the transcription factor Sp8. Genetic ablation of Sp8 by cre/loxP-based recombination severely reduces the number of PV+ interneurons in the EPL of the OB. Our results suggest that Sp8 is required for the normal production of PV+ interneurons in the EPL of the OB. These data expand our understanding of the temporal and molecular regulation of OB interneuron neurogenesis. PMID- 21653850 TI - Multiple preconditioning paradigms converge on interferon regulatory factor dependent signaling to promote tolerance to ischemic brain injury. AB - Ischemic tolerance can be induced by numerous preconditioning stimuli, including various Toll-like receptor (TLR) ligands. We have shown previously that systemic administration of the TLR4 ligand LPS or the TLR9 ligand unmethylated CpG oligodeoxynucleotide before transient brain ischemia in mice confers substantial protection against ischemic damage. To elucidate the molecular mechanisms of preconditioning, we compared brain genomic profiles in response to preconditioning with these TLR ligands and with preconditioning via exposure to brief ischemia. We found that exposure to the TLR ligands and brief ischemia induced genomic changes in the brain characteristic of a TLR pathway-mediated response. Interestingly, all three preconditioning stimuli resulted in a reprogrammed response to stroke injury that converged on a shared subset of 13 genes not evident in the genomic profile from brains that were subjected to stroke without prior preconditioning. Analysis of the promoter region of these shared genes showed sequences required for interferon regulatory factor (IRF) mediated transcription. The importance of this IRF gene network was tested using mice deficient in IRF3 or IRF7. Our data show that both transcription factors are required for TLR-mediated preconditioning and neuroprotection. These studies are the first to discover a convergent mechanism of neuroprotection induced by preconditioning--one that potentially results in reprogramming of the TLR mediated response to stroke and requires the presence of IRF3 and IRF7. PMID- 21653851 TI - Cell-type-specific modulation of feedback inhibition by serotonin in the hippocampus. AB - Midbrain raphe nuclei provide strong serotonergic projections to the hippocampus, in which serotonin (5-HT) exerts differential effects mediated by multiple 5-HT receptor subtypes. The functional relevance of this diversity of information processing is poorly understood. Here we show that serotonin via 5-HT(1B) heteroreceptors substantially reduces synaptic excitation of cholecystokinin expressing interneurons in area CA1 of the rat hippocampus, in contrast to parvalbumin-expressing basket cells. The reduction is input specific, affecting only glutamatergic synaptic transmission originating from CA1 pyramidal cells. As a result, serotonin selectively decreases feedback inhibition via 5-HT(1B) receptor activation and subsequently increases the integration time window for spike generation in CA1 pyramidal cells. Our data imply an important role for serotonergic modulation of GABAergic action in subcortical control of hippocampal output. PMID- 21653852 TI - Mesocorticolimbic glutamatergic pathway. AB - The mesocorticolimbic dopamine (DA) system plays important roles in reward, motivation, learning, memory, and movement. This system arises from the A10 region, comprising the ventral tegmental area and three adjacent midline nuclei (caudal linear nucleus, interfascicular nucleus, and rostral linear nucleus of the raphe). DAergic and GABAergic neurons are intermingled in this region with recently discovered glutamatergic neurons expressing the vesicular glutamate transporter 2 (VGluT2). Here, we show by in situ hybridization and immunohistochemistry that there are two subpopulations of neurons expressing VGluT2 mRNA in the A10 region: (1) a major subpopulation that expresses VGluT2 but lacks tyrosine hydroxylase (TH; VGluT2-only neurons), present in each nucleus of the A10 region, and (2) a smaller subpopulation that coexpresses VGluT2 and TH (VGluT2-TH neurons). By quantitative real-time PCR, we determined the mRNA copy numbers encoding VGluT2 or TH in samples of individual microdissected TH immunoreactive (IR) neurons. Data from both in situ hybridization and from mRNA quantification showed that VGluT2 mRNA is not present in every TH-IR neuron, but restricted to a subset of TH-IR neurons located in the medial portion of the A10 region. By integration of tract tracing, in situ hybridization, and immunohistochemistry, we found that VGluT2-only neurons and VGluT2-TH neurons each innervate both the prefrontal cortex and the nucleus accumbens. These findings establish that in addition to the well-recognized mesocorticolimbic DA only and GABA-only pathways, there exist parallel mesocorticolimbic glutamate only and glutamate-DA pathways. PMID- 21653854 TI - Dynamic updating of working memory resources for visual objects. AB - Recent neurophysiological and imaging studies have investigated how neural representations underlying working memory (WM) are dynamically updated for objects presented sequentially. Although such studies implicate information encoded in oscillatory activity across distributed brain networks, interpretation of findings depends crucially on the underlying conceptual model of how memory resources are distributed. Here, we quantify the fidelity of human memory for sequences of colored stimuli of different orientation. The precision with which each orientation was recalled declined with increases in total memory load, but also depended on when in the sequence it appeared. When one item was prioritized, its recall was enhanced, but with corresponding decrements in precision for other objects. Comparison with the same number of items presented simultaneously revealed an additional performance cost for sequential display that could not be explained by temporal decay. Memory precision was lower for sequential compared with simultaneous presentation, even when each item in the sequence was presented at a different location. Importantly, stochastic modeling established this cost for sequential display was due to misbinding object features (color and orientation). These results support the view that WM resources can be dynamically and flexibly updated as new items have to be stored, but redistribution of resources with the addition of new items is associated with misbinding object features, providing important constraints and a framework for interpreting neural data. PMID- 21653853 TI - Specific regulation of NRG1 isoform expression by neuronal activity. AB - Neuregulin 1 (NRG1) is a trophic factor that has been implicated in neural development, neurotransmission, and synaptic plasticity. NRG1 has multiple isoforms that are generated by usage of different promoters and alternative splicing of a single gene. However, little is known about NRG1 isoform composition profile, whether it changes during development, or the underlying mechanisms. We found that each of the six types of NRG1 has a distinct expression pattern in the brain at different ages, resulting in a change in NRG1 isoform composition. In both human and rat, the most dominant are types III and II, followed by either type I or type V, while types IV and VI are the least abundant. The expression of NRG1 isoforms is higher in rat brains at ages of E13 and P5 (in particular type V), suggesting roles in early neural development and in the neonatal critical period. At the cellular level, the majority of NRG1 isoforms (types I, II, and III) are expressed in excitatory neurons, although they are also present in GABAergic neurons and astrocytes. Finally, the expression of each NRG1 isoform is distinctly regulated by neuronal activity, which causes significant increase in type I and IV NRG1 levels. Neuronal activity regulation of type IV expression requires a CRE cis-element in the 5' untranslated region (UTR) that binds to CREB. These results indicate that expression of NRG1 isoforms is regulated by distinct mechanisms, which may contribute to versatile functions of NRG1 and pathologic mechanisms of brain disorders such as schizophrenia. PMID- 21653855 TI - Endophilin drives the fast mode of vesicle retrieval in a ribbon synapse. AB - Compensatory endocytosis of exocytosed membrane and recycling of synaptic vesicle components is essential for sustained synaptic transmission at nerve terminals. At the ribbon-type synapse of retinal bipolar cells, manipulations expected to inhibit the interactions of the clathrin adaptor protein complex (AP2) affect only the slow phase of endocytosis (tau = 10-15 s), leading to the conclusion that fast endocytosis (tau = 1-2 s) occurs by a mechanism that differs from the classical pathway of clathrin-coated vesicle retrieval from the plasma membrane. Here we investigate the role of endophilin in endocytosis at this ribbon synapse. Endophilin A1 is a synaptically enriched N-BAR domain-containing protein, suggested to function in clathrin-mediated endocytosis. Internal dialysis of the synaptic terminal with dominant-negative endophilin A1 lacking its linker and Src homology 3 (SH3) domain inhibited the fast mode of endocytosis, while slow endocytosis continued. Dialysis of a peptide that binds endophilin SH3 domain also decreased fast retrieval. Electron microscopy indicated that fast endocytosis occurred by retrieval of small vesicles in most instances. These results indicate that endophilin is involved in fast retrieval of synaptic vesicles occurring by a mechanism that can be distinguished from the classical pathway involving clathrin-AP2 interactions. PMID- 21653856 TI - A unifying framework underlying mechanotransduction in the somatosensory system. AB - Rodents use their whiskers to sense their surroundings. As most of the information available to the somatosensory system originates in whiskers' primary afferents, it is essential to understand the transformation of whisker motion into neuronal activity. Here, we combined in vivo recordings in anesthetized rats with mathematical modeling to ascertain the mechanical and electrical characteristics of mechanotransduction. We found that only two synergistic processes, which reflect the dynamic interactions between (1) receptor and whisker and (2) receptor and surrounding tissue, are needed to describe mechanotransduction during passive whiskers deflection. Interactions between these processes may account for stimulus-dependent changes in the magnitude and temporal pattern of tactile responses on multiple scales. Thus, we are able to explain complex electromechanical processes underlying sensory transduction using a simple model, which captures the responses of a wide range of mechanoreceptor types to diverse sensory stimuli. This compact and precise model allows for a ubiquitous description of how mechanoreceptors encode tactile stimulus. PMID- 21653857 TI - IQGAP1 regulates NR2A signaling, spine density, and cognitive processes. AB - General or brain-region-specific decreases in spine number or morphology accompany major neuropsychiatric disorders. It is unclear, however, whether changes in spine density are specific for an individual mental process or disorder and, if so, which molecules confer such specificity. Here we identify the scaffolding protein IQGAP1 as a key regulator of dendritic spine number with a specific role in cognitive but not emotional or motivational processes. We show that IQGAP1 is an important component of NMDAR multiprotein complexes and functionally interacts with the NR2A subunits and the extracellular signal regulated kinase 1 (ERK1) and ERK2 signaling pathway. Mice lacking the IQGAP1 gene exhibited significantly lower levels of surface NR2A and impaired ERK activity compared to their wild-type littermates. Accordingly, primary hippocampal cultures of IQGAP1(-/-) neurons exhibited reduced surface expression of NR2A and disrupted ERK signaling in response to NR2A-dependent NMDAR stimulation. These molecular changes were accompanied by region-specific reductions of dendritic spine density in key brain areas involved in cognition, emotion, and motivation. IQGAP1 knock-outs exhibited marked long-term memory deficits accompanied by impaired hippocampal long-term potentiation (LTP) in a weak cellular learning model; in contrast, LTP was unaffected when induced with stronger stimulation paradigms. Anxiety- and depression-like behavior remained intact. On the basis of these findings, we propose that a dysfunctional IQGAP1 gene contributes to the cognitive deficits in brain disorders characterized by fewer dendritic spines. PMID- 21653858 TI - Neuronal responses to texture-defined form in macaque visual area V2. AB - Human and macaque observers can detect and discriminate visual forms defined by differences in texture. The neurophysiological correlates of visual texture perception are not well understood and have not been studied extensively at the single-neuron level in the primate brain. We used a novel family of texture patterns to measure the selectivity of neurons in extrastriate cortical area V2 of the macaque (Macaca nemestrina, Macaca fascicularis) for the orientation of texture-defined form, and to distinguish responses to luminance- and texture defined form. Most V2 cells were selective for the orientation of luminance defined form; they signaled the orientation of the component gratings that made up the texture patterns but not the overall pattern orientation. In some cells, these luminance responses were modulated by the direction or orientation of the texture envelope, suggesting an interaction of luminance and texture signals. We found little evidence for a "cue-invariant" representation in monkey V2. Few cells showed selectivity for the orientation of texture-defined form; they signaled the orientation of the texture patterns and not that of the component gratings. Small datasets recorded in monkey V1 and cat area 18 showed qualitatively similar patterns of results. Consistent with human functional imaging studies, our findings suggest that signals related to texture-defined form in primate cortex are most salient in areas downstream of V2. V2 may still provide the foundation for texture perception, through the interaction of luminance- and texture-based signals. PMID- 21653859 TI - Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. AB - Evaluation of infarct volumes and infiltrating immune cell populations in mice after middle cerebral artery occlusion (MCAO) strongly implicates a mixture of both pathogenic and regulatory immune cell subsets in stroke pathogenesis and recovery. Our goal was to evaluate the contribution of B cells to the development of MCAO by comparing infarct volumes and functional outcomes in wild-type (WT) versus B-cell-deficient MUMT(-/-) mice. The results clearly demonstrate larger infarct volumes, higher mortality, more severe functional deficits, and increased numbers of activated T cells, macrophages, microglial cells, and neutrophils in the affected brain hemisphere of MCAO-treated MUMT(-/-) versus WT mice. These MCAO-induced changes were completely prevented in B-cell-restored MUMT(-/-) mice after transfer of highly purified WT GFP(+) B cells that were detected in the periphery, but not the CNS. In contrast, transfer of B cells from IL-10(-/-) mice had no effect on infarct volume when transferred into MUMT(-/-) mice. These findings strongly support a previously unrecognized activity of IL-10-secreting WT B cells to limit infarct volume, mortality rate, recruitment of inflammatory cells, and functional neurological deficits 48 h after MCAO. Our novel observations are the first to implicate IL-10-secreting B cells as a major regulatory cell type in stroke and suggest that enhancement of regulatory B cells might have application as a novel therapy for this devastating neurologic condition. PMID- 21653861 TI - Synchrony makes neurons fire in sequence, and stimulus properties determine who is ahead. AB - The synchronized activity of cortical neurons often features spike delays of several milliseconds. Usually, these delays are considered too small to play a role in cortical computations. Here, we use simultaneous recordings of spiking activity from up to 12 neurons to show that, in the cat visual cortex, the pairwise delays between neurons form a preferred order of spiking, called firing sequence. This sequence spans up to ~ 15 ms and is referenced not to external events but to the internal cortical activity (e.g., beta/gamma oscillations). Most importantly, the preferred sequence of firing changed consistently as a function of stimulus properties. During beta/gamma oscillations, the reliability of firing sequences increased and approached that of firing rates. This suggests that, in the visual system, short-lived spatiotemporal patterns of spiking defined by consistent delays in synchronized activity occur with sufficient reliability to complement firing rates as a neuronal code. PMID- 21653860 TI - Presynaptic induction and expression of timing-dependent long-term depression demonstrated by compartment-specific photorelease of a use-dependent NMDA receptor antagonist. AB - NMDA receptors are important for synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). To help investigate the precise location of the NMDA receptors that are required for different types of synaptic plasticity, we synthesized a caged form of the use-dependent NMDA receptor antagonist MK801, which we loaded into individual neurons in vitro, followed by compartment-specific uncaging. We used this method to investigate timing-dependent plasticity at layer 4-layer 2/3 synapses of mouse barrel cortex. Somatodendritic photorelease of MK801 in the postsynaptic neuron produced a use dependent block of synaptic NMDA receptor-mediated currents and prevented the induction of LTP. Compartment-specific photorelease of MK801 in the presynaptic neuron showed that axonal, but not somatodendritic, presynaptic NMDA receptors are required for induction of LTD. The rate of use-dependent block of postsynaptic NMDA receptor current was slower following induction of LTD, consistent with a presynaptic locus of expression. Thus, this new caged compound has demonstrated the axonal location of NMDA receptors required for induction and the presynaptic locus of expression of LTD at layer 4-layer 2/3 synapses. PMID- 21653862 TI - Functional dissection of the Oct6 Schwann cell enhancer reveals an essential role for dimeric Sox10 binding. AB - The POU domain transcription factor Pou3f1 (Oct6/Scip/Tst1) initiates the transition from ensheathing, promyelinating Schwann cells to myelinating cells. Axonal and other extracellular signals regulate Oct6 expression through the Oct6 Schwann cell enhancer (SCE), which is both required and sufficient to drive all aspects of Oct6 expression in Schwann cells. Thus, the Oct6 SCE is pivotal in the gene regulatory network that governs the onset of myelin formation in Schwann cells and provides a link between myelin promoting signaling and activation of a myelin-related transcriptional network. In this study, we define the relevant cis acting elements within the SCE and identify the transcription factors that mediate Oct6 regulation. On the basis of phylogenetic comparisons and functional in vivo assays, we identify a number of highly conserved core elements within the mouse SCE. We show that core element 1 is absolutely required for full enhancer function and that it contains closely spaced inverted binding sites for Sox proteins. For the first time in vivo, the dimeric Sox10 binding to this element is shown to be essential for enhancer activity, whereas monomeric Sox10 binding is nonfunctional. As Oct6 and Sox10 synergize to activate the expression of the major myelin-related transcription factor Krox20, we propose that Sox10-dependent activation of Oct6 defines a feedforward regulatory module that serves to time and amplify the onset of myelination in the peripheral nervous system. PMID- 21653863 TI - The projective field of a retinal amacrine cell. AB - In sensory systems, neurons are generally characterized by their receptive field, namely the sensitivity to activity patterns at the input of the circuit. To assess the role of the neuron in the system, one must also know its projective field, namely the spatiotemporal effects the neuron exerts on all of the outputs of the circuit. We studied both the receptive and projective fields of an amacrine interneuron in the salamander retina. This amacrine type has a sustained OFF response with a small receptive field, but its output projects over a much larger region. Unlike other amacrine cells, this type is remarkably promiscuous and affects nearly every ganglion cell within reach of its dendrites. Its activity modulates the sensitivity of visual responses in ganglion cells but leaves their kinetics unchanged. The projective field displays a center-surround structure: depolarizing a single amacrine suppresses the visual sensitivity of ganglion cells nearby and enhances it at greater distances. This change in sign is seen even within the receptive field of one ganglion cell; thus, the modulation occurs presynaptically on bipolar cell terminals, most likely via GABA(B) receptors. Such an antagonistic projective field could contribute to the mechanisms of the retina for predictive coding. PMID- 21653864 TI - Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity. AB - Hippocampal sharp waves (SPWs) and associated fast ("ripple") oscillations (SPW Rs) in the CA1 region are among the most synchronous physiological patterns in the mammalian brain. Using two-dimensional arrays of electrodes for recording local field potentials and unit discharges in freely moving rats, we studied the emergence of ripple oscillations (140-220 Hz) and compared their origin and cellular-synaptic mechanisms with fast gamma oscillations (90-140 Hz). We show that (1) hippocampal SPW-Rs and fast gamma oscillations are quantitatively distinct patterns but involve the same networks and share similar mechanisms; (2) both the frequency and magnitude of fast oscillations are positively correlated with the magnitude of SPWs; (3) during both ripples and fast gamma oscillations the frequency of network oscillation is higher in CA1 than in CA3; and (4) the emergence of CA3 population bursts, a prerequisite for SPW-Rs, is biased by activity patterns in the dentate gyrus and entorhinal cortex, with the highest probability of ripples associated with an "optimum" level of dentate gamma power. We hypothesize that each hippocampal subnetwork possesses distinct resonant properties, tuned by the magnitude of the excitatory drive. PMID- 21653865 TI - Resting-state functional connectivity indexes reading competence in children and adults. AB - Task-based neuroimaging studies face the challenge of developing tasks capable of equivalently probing reading networks across different age groups. Resting-state fMRI, which requires no specific task, circumvents these difficulties. Here, in 25 children (8-14 years) and 25 adults (21-46 years), we examined the extent to which individual differences in reading competence can be related to resting state functional connectivity (RSFC) of regions implicated in reading. In both age groups, reading standard scores correlated positively with RSFC between the left precentral gyrus and other motor regions, and between Broca's and Wernicke's areas. This suggests that, regardless of age group, stronger coupling among motor regions, as well as between language/speech regions, subserves better reading, presumably reflecting automatized articulation. We also observed divergent RSFC behavior relationships in children and adults, particularly those anchored in the left fusiform gyrus (FFG) (the visual word form area). In adults, but not children, better reading performance was associated with stronger positive correlations between FFG and phonology-related regions (Broca's area and the left inferior parietal lobule), and with stronger negative relationships between FFG and regions of the "task-negative" default network. These results suggest that both positive RSFC (functional coupling) between reading regions and negative RSFC (functional segregation) between a reading region and default network regions are important for automatized reading, characteristic of adult readers. Together, our task-independent RSFC findings highlight the importance of appreciating developmental changes in the neural correlates of reading competence, and suggest that RSFC may serve to facilitate the identification of reading disorders in different age groups. PMID- 21653866 TI - Dissociable contributions by prefrontal D1 and D2 receptors to risk-based decision making. AB - Choices between certain and uncertain rewards of different magnitudes have been proposed to be mediated by both the frontal lobes and the mesocorticolimbic dopamine (DA) system. In rats, systemic manipulations of DA activity or inactivation of the medial prefrontal cortex (PFC) disrupt decision making about risks and rewards. However, it is unclear how PFC DA transmission contributes to these processes. We addressed this issue by examining the effects of pharmacological manipulations of D(1) and D(2) receptors in the medial (prelimbic) PFC on choice between small, certain and large, yet probabilistic rewards. Rats were trained on a probabilistic discounting task where one lever delivered one pellet with 100% probability, and the other delivered four pellets, but the probability of receiving reward decreased across blocks of trials (100, 50, 25, 12.5%). D(1) blockade (SCH23390) in the medial PFC decreased preference for the large/risky option. In contrast, D(2) blockade (eticlopride) reduced probabilistic discounting and increased risky choice. The D(1) agonist SKF81297 caused a slight, nonsignificant increase in preference for the large/risky lever. However, D(2) receptor stimulation (quinpirole) induced a true impairment in decision making, flattening the discounting curve and biasing choice away from or toward the risky option when it was more or less advantageous, respectively. These findings suggest that PFC D(1) and D(2) receptors make dissociable, yet complementary, contributions to risk/reward judgments. By striking a fine balance between D(1)/D(2) receptor activity, DA may help refine these judgments, promoting either exploitation of current favorable circumstances or exploration of more profitable ones when conditions change. PMID- 21653868 TI - Subcortical mechanisms of feature-based attention. AB - The degree to which spatial and feature-based attention are governed by similar control mechanisms is not clear. To explore this issue, I measured, during conditions of spatial or feature-based attention, activity in the human subcortical visual nuclei, which have precise retinotopic maps and are known to play important roles in the regulation of spatial attention but have limited selectivity of nonspatial features. Subjects attended to and detected changes in separate fields of moving or colored dots. When the fields were disjoint, spatially attending to one field enhanced hemodynamic responses in the superior colliculus (SC), lateral geniculate nucleus (LGN), and two retinotopic pulvinar nuclei. When the two dot fields were spatially overlapping, feature-based attention to the moving versus colored dots enhanced responses in the pulvinar nuclei and the majority of the LGN, including the magnocellular layers, and suppressed activity in some areas within the parvocellular layers; the SC was inconsistently modulated among subjects. The results demonstrate that feature based attention operates throughout the visual system by prioritizing neurons encoding the attended information, including broadly tuned thalamic neurons. I conclude that spatial and feature-based attention operate via a common principle, but that spatial location is a special feature in that it is widely encoded in the brain, is used for overt orienting, and uses a specialized structure, the SC. PMID- 21653867 TI - Transient receptor potential channel type M5 is essential for fat taste. AB - Until recently, dietary fat was considered to be tasteless, and its primary sensory attribute was believed to be its texture (Rolls et al., 1999; Verhagen et al., 2003). However, a number of studies have demonstrated the ability of components in fats, specifically free fatty acids, to activate taste cells and elicit behavioral responses consistent with there being a taste of fat. Here we show for the first time that long-chain unsaturated free fatty acid, linoleic acid (LA), depolarizes mouse taste cells and elicits a robust intracellular calcium rise via the activation of transient receptor potential channel type M5 (TRPM5). The LA-induced responses depend on G-protein-phospholipase C pathway, indicative of the involvement of G-protein-coupled receptors (GPCRs) in the transduction of fatty acids. Mice lacking TRPM5 channels exhibit no preference for and show reduced sensitivity to LA. Together, these studies show that TRPM5 channels play an essential role in fatty acid transduction in mouse taste cells and suggest that fatty acids are capable of activating taste cells in a manner consistent with other GPCR-mediated tastes. PMID- 21653870 TI - Prefrontal cortex deactivation in macaques alters activity in the superior colliculus and impairs voluntary control of saccades. AB - The cognitive control of action requires both the suppression of automatic responses to sudden stimuli and the generation of behavior specified by abstract instructions. Though patient, functional imaging and neurophysiological studies have implicated the dorsolateral prefrontal cortex (dlPFC) in these abilities, the mechanism by which the dlPFC exerts this control remains unknown. Here we examined the functional interaction of the dlPFC with the saccade circuitry by deactivating area 46 of the dlPFC and measuring its effects on the activity of single superior colliculus neurons in monkeys performing a cognitive saccade task. Deactivation of the dlPFC reduced preparatory activity and increased stimulus-related activity in these neurons. These changes in neural activity were accompanied by marked decreases in task performance as evidenced by longer reaction times and more task errors. The results suggest that the dlPFC participates in the cognitive control of gaze by suppressing stimulus-evoked automatic saccade programs. PMID- 21653869 TI - Darks are processed faster than lights. AB - Recent physiological studies claim that dark stimuli have access to greater neuronal resources than light stimuli in early visual pathway. We used two sets of novel stimuli to examine the functional consequences of this dark dominance in human observers. We show that increment and decrement thresholds are equal when controlled for adaptation and eye movements. However, measurements for salience differences at high contrasts show that darks are detected pronouncedly faster and more accurately than lights when presented against uniform binary noise. In addition, the salience advantage for darks is abolished when the background distribution is adjusted to control for the irradiation illusion. The threshold equality suggests that the highest sensitivities of neurons in the ON and OFF channels are similar, whereas the salience difference is consistent with a population advantage for the OFF system. PMID- 21653871 TI - mGluR control of interneuron output regulates feedforward tonic GABAA inhibition in the visual thalamus. AB - Metabotropic glutamate receptors (mGluRs) play a crucial role in regulation of phasic inhibition within the visual thalamus. Here we demonstrate that mGluR dependent modulation of interneuron GABA release results in dynamic changes in extrasynaptic GABA(A) receptor (eGABA(A)R)-dependent tonic inhibition in thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (dLGN). Application of the group I selective mGluR agonist dihydroxyphenylglycine produces a concentration-dependent enhancement of both IPSC frequency and tonic GABA(A) current (I(GABA)tonic) that is due to activation of both mGluR1a and mGluR5 subtypes. In contrast, group II/III mGluR activation decreases both IPSC frequency and I(GABA)tonic amplitude. Using knock-out mice, we show that the mGluR-dependent modulation of I(GABA)tonic is dependent upon expression of delta subunit containing eGABA(A)Rs. Furthermore, unlike the dLGN, no mGluR-dependent modulation of I(GABA)tonic is present in TC neurons of the somatosensory ventrobasal thalamus, which lacks GABAergic interneurons. In the dLGN, enhancement of IPSC frequency and I(GABA)tonic by group I mGluRs is not action potential dependent, being insensitive to TTX, but is abolished by the L-type Ca(2+) channel blocker nimodipine. These results indicate selective mGluR dependent modulation of dendrodendritic GABA release from F2-type terminals on interneuron dendrites and demonstrate for the first time the presence of eGABA(A)Rs on TC neuron dendritic elements that participate in "triadic" circuitry within the dLGN. These findings present a plausible novel mechanism for visual contrast gain at the thalamic level and shed new light upon the potential role of glial ensheathment of synaptic triads within the dLGN. PMID- 21653872 TI - A-kinase anchoring protein 150 mediates transient receptor potential family V type 1 sensitivity to phosphatidylinositol-4,5-bisphosphate. AB - A-kinase anchoring protein 150 (AKAP150) is a scaffolding protein that controls protein kinase A- and C-mediated phosphorylation of the transient receptor potential family V type 1 (TRPV1), dictating receptor response to nociceptive stimuli. The phospholipid phosphatidylinositol-4,5-bisphosphate (PIP(2)) anchors AKAP150 to the plasma membrane in naive conditions and also affects TRPV1 activity. In the present study, we sought to determine whether the effects of PIP(2) on TRPV1 are mediated through AKAP150. In trigeminal neurons and CHO cells, the manipulation of cellular PIP(2) led to significant changes in the association of AKAP150 and TRPV1. Following PIP(2) degradation, increased TRPV1:AKAP150 coimmunoprecipitation was observed, resulting in increased receptor response to capsaicin treatment. Phospholipase C activation in neurons isolated from AKAP150(-/-) animals indicated that PIP(2)-mediated inhibition of TRPV1 in the whole-cell environment requires expression of the scaffolding protein. Furthermore, the addition of PIP(2) to neurons isolated from AKAP150 wild-type mice reduced PKA sensitization of TRPV1 compared with isolated neurons from AKAP150(-/-) mice. These findings suggest that PIP(2) degradation increases AKAP150 association with TRPV1 in the whole-cell environment, leading to sensitization of the receptor to nociceptive stimuli. PMID- 21653875 TI - Retraction. Glucagon-like peptide 1 stimulates hypothalamic proopiomelanocortin neurons. PMID- 21653874 TI - Retraction. Activated protein C reduces the severity of compression-induced spinal cord injury in rats by inhibiting activation of leukocytes. PMID- 21653873 TI - Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons. AB - ATP-sensitive potassium channels (K(ATP) channels) are important sensors of cellular metabolic state that link metabolism and excitability in neuroendocrine cells, but their role in nonglucosensing central neurons is less well understood. To examine a possible role for K(ATP) channels in modulating excitability in hippocampal circuits, we recorded the activity of single K(ATP) channels in cell attached patches of granule cells in the mouse dentate gyrus during bursts of action potentials generated by antidromic stimulation of the mossy fibers. Ensemble averages of the open probability (p(open)) of single K(ATP) channels over repeated trials of stimulated spike activity showed a transient increase in p(open) in response to action potential firing. Channel currents were identified as K(ATP) channels through blockade with glibenclamide and by comparison with recordings from Kir6.2 knock-out mice. The transient elevation in K(ATP) p(open) may arise from submembrane ATP depletion by the Na(+)-K(+) ATPase, as the pump blocker strophanthidin reduced the magnitude of the elevation. Both the steady state and stimulus-elevated p(open) of the recorded channels were higher in the presence of the ketone body R-beta-hydroxybutyrate, consistent with earlier findings that ketone bodies can affect K(ATP) activity. Using perforated-patch recording, we also found that K(ATP) channels contribute to the slow afterhyperpolarization following an evoked burst of action potentials. We propose that activity-dependent opening of K(ATP) channels may help granule cells act as a seizure gate in the hippocampus and that ketone-body-mediated augmentation of the activity-dependent opening could in part explain the effect of the ketogenic diet in reducing epileptic seizures. PMID- 21653876 TI - Estrogen regulation of the dopamine-activated GIRK channel in pituitary lactotrophs: implications for regulation of prolactin release during the estrous cycle. AB - Prolactin (PRL), synthesized and secreted from lactotrophs of the anterior pituitary gland, is tonically inhibited by hypothalamic dopamine (DA) throughout the female reproductive (estrous) cycle. Our laboratory has shown that DA hyperpolarizes these cells by activating G protein-coupled inwardly rectifying K(+) (GIRK) channels; however, this response is only observed on proestrus. While the cellular mechanisms that allow for functional expression of this unique DA signaling pathway are unclear, we hypothesized that activation of the DA-GIRK effector pathway is due to the rise in circulating estrogen (E2) during the preceding day of diestrus. Thus, we examined the effects of E2 on primary lactotrophs isolated from female rats. Treatment with a physiological concentration of E2 (40-80 pg/ml, in vivo or in vitro) induced a proestrous phenotype in diestrous lactotrophs. These cells exhibited a DA-induced membrane hyperpolarization, as well as a secretory rebound of PRL following DA withdrawal (characteristic of proestrous cells). Internal dialysis of GTPgammaS demonstrated that E2 exposure enabled functional expression of GIRK channels, and this regulation by E2 did not involve the D2R. The effect of E2 was blocked by the receptor antagonist, ICI 182,780, and by the protein synthesis inhibitor, cycloheximide. Single-cell analysis revealed increased mRNA expression of GIRK channel subunits in E2-treated lactotrophs. While E2 is known to have multiple actions on the lactotroph, the present findings illuminate a novel action of E2 in lactotrophs-regulation of the expression of a DA effector, the GIRK channel. PMID- 21653878 TI - Digestive physiology: a view from molecules to ecosystem. AB - Digestive physiology links physiology to applications valued by society, such as understanding ecology and ecological toxicology and managing and conserving species. Here I illustrate this applied and integrative perspective with several avian case studies. The match between digestive features and diet provides evidence of tradeoffs that preclude doing well on all possible substrates with a single digestive design, and this influences ecological niche partitioning. But some birds, such as wild house sparrow (Passer domesticus) nestlings, are digestively very flexible. Their intestinal maltase activity and mRNA for intestinal maltase glucoamylase specifically and reversibly change when they switch among foods with different starch content. Houses sparrows and many other birds absorb hydrolyzed water-soluble monomers, such as glucose, mainly passively via tight junctions between enterocytes (i.e., paracellular absorption). Such species might be good models for studying this process, which is important biomedically for absorption of drugs. High paracellular absorption may enhance absorption of low molecular weight, natural water-soluble toxins. Also, reliance of American robins (Turdus migratorius) on passive absorption makes them less sensitive to types of plant toxins that inhibit mediated glucose absorption, such as phlorizin or the flavanoid isoquercetrin. Determining absorption of environmental contaminants is another important ecological application. Common loon (Gavia immer) chicks absorbed 83% of methyl mercury in fish meals, eliminate the mercury slowly, and consequently are predicted in the wild to bioaccumulate mercury to higher concentrations than in their foods. The quantitative details can be used to set regulatory levels for mercury that will protect wildlife. PMID- 21653877 TI - Neural and hormonal control of food hoarding. AB - Many animals hoard food, including humans, but despite its pervasiveness, little is known about the physiological mechanisms underlying this appetitive behavior. We summarize studies of food hoarding in humans and rodents with an emphasis on mechanistic laboratory studies of species where this behavior importantly impacts their energy balance (hamsters), but include laboratory rat studies although their wild counterparts do not hoard food. The photoperiod and cold can affect food hoarding, but food availability is the most significant environmental factor affecting food hoarding. Food-deprived/restricted hamsters and humans exhibit large increases in food hoarding compared with their fed counterparts, both doing so without overeating. Some of the peripheral and central peptides involved in food intake also affect food hoarding, although many have not been tested. Ad libitum-fed hamsters given systemic injections of ghrelin, the peripheral orexigenic hormone that increases with fasting, mimics food deprivation-induced increases in food hoarding. Neuropeptide Y or agouti-related protein, brain peptides stimulated by ghrelin, given centrally to ad libitum-fed hamsters, duplicates the early and prolonged postfood deprivation increases in food hoarding, whereas central melanocortin receptor agonism tends to inhibit food deprivation and ghrelin stimulation of hoarding. Central or peripheral leptin injection or peripheral cholecystokinin-33, known satiety peptides, inhibit food hoarding. Food hoarding markedly increases with pregnancy and lactation. Because fasted and/or obese humans hoard more food in general, and more high-density/high fat foods specifically, than nonfasted and/or nonobese humans, understanding the mechanisms underlying food hoarding could provide another target for behavioral/pharmacological approaches to curb obesity. PMID- 21653879 TI - Osmoregulatory defect in adult mice associated with deficient prenatal expression of six2. AB - Suboptimal kidney development resulting from a genetic deficit in nephron number can have lifelong consequences that may lead to cardiorenal complications upon exposure to secondary insults in later life. To determine whether the inherited reduced renal reserve compromises the ability to handle osmotic stress in the adult animal, we challenged the heterozygous 3H1 Brachyrrhine (Br/+) mouse, which displays heritable renal hypoplasia associated with reduced embryonic six2 expression, to a solution of 2% NaCl for 5 days or to fluid restriction for 48 h. Blood chemistry, fluid intake, and physiological parameters, including renal measurements, were determined. Systemic hypertonicity by prolonged salt loading led to significant increases in plasma osmolality and plasma Na(+), along with polydipsia and polyuria, with a significant urine-concentrating defect that was resistant to DDAVP treatment in the adult Br/+ mouse compared with wild-type littermates. The Br/+ mouse also developed a significant increase in blood urea nitrogen at baseline that was further elevated when 2% NaCl was given. Fluid restriction for 48 h further enhanced plasma osmolality and plasma Na(+) responses, although the Br/+ mouse was evidently able to produce a small amount of concentrated urine at this time. Hypothalamic c-Fos expression was appropriately activated in the Br/+ mouse in response to both osmotic challenges, indicating an intact central neuroendocrine pathway that was not affected by the lack of congenital six2 expression. Collectively, our results demonstrate impaired osmoregulatory mechanisms consistent with chronic renal failure in the Br/+ mouse and indicate that six2 haploinsufficiency has a direct effect on postnatal fluid and electrolyte handling associated with fluid imbalance. PMID- 21653880 TI - Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction. AB - Developmental programming of postnatal pancreatic beta-cell and peripheral insulin function by maternal nutrient reduction (MNR) has been extensively investigated in rodents and sheep, but no data exist from nonhuman primate offspring of MNR mothers. We hypothesized that moderate levels of MNR would result in developmental programming of postnatal beta-cell function and peripheral insulin sensitivity that lead to emergence of a prediabetic state prior to puberty. Prepregnancy phenotype of 18 nonpregnant baboons was matched. During pregnancy and lactation 12 mothers ate chow ad libitum (controls), while six ate 70% of chow consumed by controls (weight-adjusted MNR). Weaned offspring ate normal chow. At 3.5 +/- 0.18 yr (mean +/- SE) in an intravenous glucose tolerance test, conscious, tethered MNR juvenile offspring (2 females and 4 males) showed increased fasting glucose (P < 0.04), fasting insulin (P < 0.04), and insulin area under the curve (AUC; P < 0.01) compared with controls (8 females and 4 males). Insulin AUC also increased following an arginine challenge (P < 0.02). Baseline homeostatic model assessment insulin beta-cell sensitivity was greater in MNR offspring than controls (P < 0.03). In a hyperinsulinemic, euglycemic clamp, the glucose disposal rate decreased 26% in MNR offspring. Changes observed were not sex dependent. MNR in pregnancy and lactation programs offspring metabolic responses, increasing insulin resistance and beta-cell responsiveness, resulting in emergence of an overall phenotype that would predispose to later life type-2 diabetes, especially, should other dietary challenges such as a Westernized diet be experienced. PMID- 21653881 TI - Regulation of growth factor receptor degradation by ADP-ribosylation factor domain protein (ARD) 1. AB - ADP-ribosylation factor domain protein 1 (ARD1) is a 64-kDa protein containing a functional ADP-ribosylation factor (GTP hydrolase, GTPase), GTPase-activating protein, and E3 ubiquitin ligase domains. ARD1 activation by the guanine nucleotide-exchange factor cytohesin-1 was known. GTPase and E3 ligase activities of ARD1 suggest roles in protein transport and turnover. To explore this hypothesis, we used mouse embryo fibroblasts (MEFs) from ARD1-/- mice stably transfected with plasmids for inducible expression of wild-type ARD1 protein (KO WT), or ARD1 protein with inactivating mutations in E3 ligase domain (KO-E3), or containing persistently active GTP-bound (KO-GTP), or inactive GDP-bound (KO-GDP) GTPase domains. Inhibition of proteasomal proteases in mifepristone-induced KO WT, KO-GDP, or KO-GTP MEFs resulted in accumulation of these ARD1 proteins, whereas KO-E3 accumulated without inhibitors. All data were consistent with the conclusion that ARD1 regulates its own steady-state levels in cells by autoubiquitination. Based on reported growth factor receptor-cytohesin interactions, EGF receptor (EGFR) was investigated in induced MEFs. Amounts of cell-surface and total EGFR were higher in KO-GDP and lower in KO-GTP than in KO WT MEFs, with levels in both mutants greater (p = 0.001) after proteasomal inhibition. Significant differences among MEF lines in content of TGF-beta receptor III were similar to those in EGFR, albeit not as large. Differences in amounts of insulin receptor mirrored those in EGFR, but did not reach statistical significance. Overall, the capacity of ARD1 GTPase to cycle between active and inactive forms and its autoubiquitination both appear to be necessary for the appropriate turnover of EGFR and perhaps additional growth factor receptors. PMID- 21653882 TI - PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes. AB - Cardiac transient receptor potential canonical (TRPC) channels are crucial upstream components of Ca(2+)/calcineurin/nuclear factor of activated T cells (NFAT) signaling, thereby controlling cardiac transcriptional programs. The linkage between TRPC-mediated Ca(2+) signals and NFAT activity is still incompletely understood. TRPC conductances may govern calcineurin activity and NFAT translocation by supplying Ca(2+) either directly through the TRPC pore into a regulatory microdomain or indirectly via promotion of voltage-dependent Ca(2+) entry. Here, we show that a point mutation in the TRPC3 selectivity filter (E630Q), which disrupts Ca(2+) permeability but preserves monovalent permeation, abrogates agonist-induced NFAT signaling in HEK293 cells as well as in murine HL 1 atrial myocytes. The E630Q mutation fully retains the ability to convert phospholipase C-linked stimuli into L-type (Ca(V)1.2) channel-mediated Ca(2+) entry in HL-1 cells, thereby generating a dihydropyridine-sensitive Ca(2+) signal that is isolated from the NFAT pathway. Prevention of PKC-dependent modulation of TRPC3 by either inhibition of cellular kinase activity or mutation of a critical phosphorylation site in TRPC3 (T573A), which disrupts targeting of calcineurin into the channel complex, converts cardiac TRPC3-mediated Ca(2+) signaling into a transcriptionally silent mode. Thus, we demonstrate a dichotomy of TRPC-mediated Ca(2+) signaling in the heart constituting two distinct pathways that are differentially linked to gene transcription. Coupling of TRPC3 activity to NFAT translocation requires microdomain Ca(2+) signaling by PKC-modified TRPC3 complexes. Our results identify TRPC3 as a pivotal signaling gateway in Ca(2+) dependent control of cardiac gene expression. PMID- 21653883 TI - Legume cyclotides shed light on the genetic origin of knotted circular proteins. PMID- 21653884 TI - Atypical protein kinase C (aPKCzeta and aPKClambda) is dispensable for mammalian hematopoietic stem cell activity and blood formation. AB - The stem-cell pool is considered to be maintained by a balance between symmetric and asymmetric division of stem cells. The cell polarity model proposes that the facultative use of symmetric and asymmetric cell division is orchestrated by a polarity complex consisting of partitioning-defective proteins Par3 and Par6, and atypical protein kinase C (aPKCzeta and aPKClambda), which regulates planar symmetry of dividing stem cells with respect to the signaling microenvironment. However, the role of the polarity complex is unexplored in mammalian adult stem cell functions. Here we report that, in contrast to accepted paradigms, polarization and activity of adult hematopoietic stem cell (HSC) do not depend on either aPKCzeta or aPKClambda or both in vivo. Mice, having constitutive and hematopoietic-specific (Vav1-Cre) deletion of aPKCzeta and aPKClambda, respectively, have normal hematopoiesis, including normal HSC self-renewal, engraftment, differentiation, and interaction with the bone marrow microenvironment. Furthermore, inducible complete deletion of aPKClambda (Mx1 Cre) in aPKCzeta(-/-) HSC does not affect HSC polarization, self-renewal, engraftment, or lineage repopulation. In addition, aPKCzeta- and aPKClambda deficient HSCs elicited a normal pattern of hematopoietic recovery secondary to myeloablative stress. Taken together, the expression of aPKCzeta, aPKClambda, or both are dispensable for primitive and adult HSC fate determination in steady state and stress hematopoiesis, contrary to the hypothesis of a unique, evolutionary conserved aPKCzeta/lambda-directed cell polarity signaling mechanism in mammalian HSC fate determination. PMID- 21653885 TI - FLOWERING LOCUS T duplication coordinates reproductive and vegetative growth in perennial poplar. AB - Annual plants grow vegetatively at early developmental stages and then transition to the reproductive stage, followed by senescence in the same year. In contrast, after successive years of vegetative growth at early ages, woody perennial shoot meristems begin repeated transitions between vegetative and reproductive growth at sexual maturity. However, it is unknown how these repeated transitions occur without a developmental conflict between vegetative and reproductive growth. We report that functionally diverged paralogs FLOWERING LOCUS T1 (FT1) and FLOWERING LOCUS T2 (FT2), products of whole-genome duplication and homologs of Arabidopsis thaliana gene FLOWERING LOCUS T (FT), coordinate the repeated cycles of vegetative and reproductive growth in woody perennial poplar (Populus spp.). Our manipulative physiological and genetic experiments coupled with field studies, expression profiling, and network analysis reveal that reproductive onset is determined by FT1 in response to winter temperatures, whereas vegetative growth and inhibition of bud set are promoted by FT2 in response to warm temperatures and long days in the growing season. The basis for functional differentiation between FT1 and FT2 appears to be expression pattern shifts, changes in proteins, and divergence in gene regulatory networks. Thus, temporal separation of reproductive onset and vegetative growth into different seasons via FT1 and FT2 provides seasonality and demonstrates the evolution of a complex perennial adaptive trait after genome duplication. PMID- 21653886 TI - Toward caring for oneself in a life of intense ups and downs: a reflexive collaborative exploration of recovery in bipolar disorder. AB - In this article, we discuss processes of recovery in bipolar disorder. We utilized a hermeneutical-phenomenological approach developed within a reflexive collaborative framework to examine what individuals do to promote improvement and positive change in their own lives. The study was designed and carried out in collaboration with an expert-by-experience group of 12 coresearchers with firsthand experiences of mental distress and recovery. In-depth interviews were conducted with 13 participants who acknowledged having lived and dealt with a bipolar disorder. Four core themes were drawn from our analysis: (a) handling ambivalence about letting go of manic states; (b) finding something to hang on to when the world is spinning around; (c) becoming aware of signals from self and others; and (d) finding ways of caring for oneself. Interrelationships between the four themes, along with limitations, strengths, and implications of the study are discussed. PMID- 21653887 TI - The geography of epilepsy: a fatal disease in resource-poor settings. PMID- 21653888 TI - Causes of death among people with convulsive epilepsy in rural West China: a prospective study. AB - BACKGROUND: Epilepsy is a serious health problem associated with an increased risk of premature mortality. Few studies have investigated risk factors for this. Understanding these risks may enable the implementation of preventative measures to reduce premature mortality. METHODS: A management program for convulsive forms of epilepsy has been in place at the primary health care level in rural West China since May 2005. Demographic data and putative causes of death of attendees of the program since inception to the end of December 2009 have been recorded. Case fatality (CF), the proportional mortality ratios (PMRs) for each cause, and standardized mortality ratios (SMRs) for each age and cause were estimated based on the 2007 Chinese rural population. RESULTS: There were 106 reported deaths (70 male) among 3,568 people. CF was 2.97% during a median of 28 months' follow-up. The highest PMRs were for accidental death (59%) including drowning (45.1%); probable sudden unexpected death in epilepsy (SUDEP) (14.7%); status epilepticus (6.9%), and neoplasm (6.9%). The overall SMR was 4.92 (95% confidence interval 4.0-6.1); the risks were high in young people. The risk of drowning was 82-fold higher in the cohort than the general population. CONCLUSION: In rural West China, the risk of premature death is nearly 5 times higher in people with convulsive epilepsy than in the general Chinese population and especially high among young people. Accidental death, including drowning, and probable SUDEP are the leading putative causes of death in people with convulsive epilepsy in rural West China. PMID- 21653889 TI - Lower prevalence of silent brain infarcts in the physically active: the Northern Manhattan Study. AB - OBJECTIVE: To examine the independent association between physical activity and subclinical cerebrovascular disease as measured by silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV). METHODS: The Northern Manhattan Study (NOMAS) is a population-based prospective cohort examining risk factors for incident vascular disease, and a subsample underwent brain MRI. Our primary outcomes were SBI and WMHV. Baseline measures of leisure-time physical activity were collected in person. Physical activity was categorized by quartiles of the metabolic equivalent (MET) score. We used logistic regression models to examine the associations between physical activity and SBI, and linear regression to examine the association with WMHV. RESULTS: There were 1,238 clinically stroke free participants (mean age 70 +/- 9 years) of whom 60% were women, 65% were Hispanic, and 43% reported no physical activity. A total of 197 (16%) participants had SBI. In fully adjusted models, compared to those who did not engage in physical activity, those in the upper quartile of MET scores were almost half as likely to have SBI (adjusted odds ratio 0.6, 95% confidence interval 0.4-0.9). Physical activity was not associated with WMHV. CONCLUSIONS: Increased levels of physical activity were associated with a lower risk of SBI but not WMHV. Engaging in moderate to heavy physical activities may be an important component of prevention strategies aimed at reducing subclinical brain infarcts. PMID- 21653890 TI - DDX4 (VASA) is conserved in germ cell development in marsupials and monotremes. AB - DDX4 (VASA) is an RNA helicase expressed in the germ cells of all animals. To gain greater insight into the role of this gene in mammalian germ cell development, we characterized DDX4 in both a marsupial (the tammar wallaby) and a monotreme (the platypus). DDX4 is highly conserved between eutherian, marsupial, and monotreme mammals. DDX4 protein is absent from tammar fetal germ cells but is present from Day 1 postpartum in both sexes. The distribution of DDX4 protein during oogenesis and spermatogenesis in the tammar is similar to eutherians. Female tammar germ cells contain DDX4 protein throughout all stages of postnatal oogenesis. In males, DDX4 is in gonocytes, and during spermatogenesis it is present in spermatocytes and round spermatids. A similar distribution of DDX4 occurs in the platypus during spermatogenesis. There are several DDX4 isoforms in the tammar, resulting from both pre- and posttranslational modifications. DDX4 in marsupials and monotremes has multiple splice variants and polyadenylation motifs. Using in silico analyses of genomic databases, we found that these previously unreported splice variants also occur in eutherians. In addition, several elements implicated in the control of Ddx4 expression in the mouse, including RGG (arginine-glycine-glycine) and dimethylation of arginine motifs and CpG islands within the Ddx4 promoter, are also highly conserved. Collectively these data suggest that DDX4 is essential for the regulation of germ cell proliferation and differentiation across all three extant mammalian groups eutherians, marsupials, and monotremes. PMID- 21653892 TI - Deficiency in the omega-3 fatty acid pathway results in failure of acrosome biogenesis in mice. AB - An omega-3 fatty acid, docosahexaenoic acid (DHA), is enriched in testicular membrane phospholipids, but its function is not well understood. The Fads2 gene encodes an enzyme required for the endogenous synthesis of DHA. Using Fads2-null mice (Fads2-/-), we found in our preceding studies that DHA deficiency caused the arrest of spermiogenesis and male infertility, both of which were reversed by dietary DHA. In this study, we investigated a cellular mechanism underlying the DHA essentiality in spermiogenesis. Periodic acid-Schiff staining and acrosin immunohistochemistry revealed the absence of acrosomes in Fads2-/- round spermatids. Acrosin, an acrosomal marker, was scattered throughout the cytoplasm of the Fads2-/- spermatids, and electron microscopy showed that proacrosomal granules were formed on the trans-face of the Golgi. However, excessive endoplasmic reticulum and vesicles were present on the cis-face of the Golgi in Fads2-/- spermatids. The presence of proacrosomal vesicles but lack of a developed acrosome in Fads2-/- spermatids suggested failed vesicle fusion. Syntaxin 2, a protein involved in vesicle fusion, colocalized with acrosin in the acrosome of wild-type mice. In contrast, syntaxin 2 remained scattered in reticular structures and showed no extensive colocalization with acrosin in the Fads2-/- spermatids, suggesting failed fusion with acrosin-containing vesicles or failed transport and release of syntaxin 2 vesicles from Golgi. Dietary supplementation of DHA in Fads2-/- mice restored an intact acrosome. In conclusion, acrosome biogenesis under DHA deficiency is halted after release of proacrosomal granules. Misplaced syntaxin 2 suggests an essential role of DHA in proper delivery of membrane proteins required for proacrosomal vesicle fusion. PMID- 21653891 TI - Estrogen-regulated genes in rat testes and their relationship to recovery of spermatogenesis after irradiation. AB - Despite numerous observations of the effects of estrogens on spermatogenesis, identification of estrogen-regulated genes in the testis is limited. Using rats in which irradiation had completely blocked spermatogonial differentiation, we previously showed that testosterone suppression with gonadotropin-releasing hormone-antagonist acyline and the antiandrogen flutamide stimulated spermatogenic recovery and that addition of estradiol (E2) to this regimen accelerated this recovery. We report here the global changes in testicular cell gene expression induced by the E2 treatment. By minimizing the changes in other hormones and using concurrent data on regulation of the genes by these hormones, we were able to dissect the effects of estrogen on gene expression, independent of gonadotropin or testosterone changes. Expression of 20 genes, largely in somatic cells, was up- or downregulated between 2- and 5-fold by E2. The unexpected and striking enrichment of transcripts not corresponding to known genes among the E2-downregulated probes suggested that these might represent noncoding mRNAs; indeed, we have identified several as miRNAs and their potential target genes in this system. We propose that genes for which expression levels are altered in one direction by irradiation and in the opposite direction by both testosterone suppression and E2 treatment are candidates for controlling the block in differentiation. Several genes, including insulin-like 3 (Insl3), satisfied those criteria. If they are indeed involved in the inhibition of spermatogonial differentiation, they may be candidate targets for treatments to enhance recovery of spermatogenesis following gonadotoxic exposures, such as those resulting from cancer therapy. PMID- 21653893 TI - Preimplantation exposure of mouse embryos to palmitic acid results in fetal growth restriction followed by catch-up growth in the offspring. AB - Free fatty acids (FFAs) are energy substrates for many cell types, but in excess, some FFAs can accumulate in nonadipose cells, inducing apoptosis. Also known as lipotoxicity, this phenomenon may play a role in the development of obesity related disease. Obesity is common among reproductive age women and is associated with adverse pregnancy and fetal outcomes; however, little is known about the effects of excess FFAs on embryos and subsequent fetal development. To address this knowledge gap, murine blastocysts were cultured in excess palmitic acid (PA), the most abundant saturated FFA in human serum, and ovarian follicular fluid. Targets susceptible to aberrations in maternal physiology, including embryonic IGF1 receptor (IGF1R) expression, glutamic pyruvate transaminase (GPT2) activity, and nuclei count, were measured. PA-exposed blastocysts demonstrated altered IGF1R expression, increased GPT2 activity, and decreased nuclei count. Trophoblast stem cells derived from preimplantation embryos were also cultured in PA. Cells exposed to increasing doses of PA demonstrated increased apoptosis and decreased proliferation. To demonstrate long-term effects of brief PA exposure, blastocysts cultured for 30 h in PA were transferred into foster mice, and pregnancies followed through Embryonic Day (ED)14.5 or delivery. Fetuses resulting from PA-exposed blastocysts were smaller than controls at ED14.5. Delivered pups were also smaller but demonstrated catch-up growth and ultimately surpassed control pups in weight. Altogether, our data suggest brief PA exposure results in altered embryonic metabolism and growth, with lasting adverse effects on offspring, providing further insight into the pathophysiology of maternal obesity. PMID- 21653894 TI - Stage-specific changes in GDNF expression by rat Sertoli cells: a possible regulator of the replication and differentiation of stem spermatogonia. AB - In the adult testis, the precise control of the self-renewing replication and differentiation of stem spermatogonia is fundamental to male fertility. Previous studies have shown that the replication of A single (A(s)) spermatogonia, a population that includes the stem cells, is maximal at stage I of the cycle of the rat seminiferous epithelium and minimal at stage VII, while the ratio of A paired spermatogonia to A(s) spermatogonia increases from stages I to VII. It has been hypothesized that these changes in A(s) spermatogonia replication and differentiation result from changes in the expression of glial cell-line derived neurotrophic factor (GDNF) by Sertoli cells. To directly test this hypothesis, we used immunocytochemistry and confocal microscopy to demonstrate that within intact seminiferous tubules, GDNF is detectable only in Sertoli cells and that its amount and its location within these cells changes with progression of the stages of the cycle. The identification of Sertoli cells as the primary source of GDNF was confirmed by RT-PCR analysis of RNA isolated from purified populations of Sertoli cells, pachytene spermatocytes, and round spermatids. Stage-specific changes in GDNF expression were confirmed by quantifying GDNF mRNA in seminiferous tubules at defined stages of the cycle. Expression of this transcript was maximal at stage I, fell 14-fold by stage VIIc,d, and then increased 12-fold by stages XIII-XIV. This pattern of expression was the opposite of the control, cathepsin L mRNA. Taken together, these data support the hypothesis that cyclical changes in GDNF expression by Sertoli cells are responsible for the stage-specific replication and differentiation of stem spermatogonia, the foundational cells of spermatogenesis. PMID- 21653895 TI - Role of luteinizing hormone in changes in concentrations of progesterone and luteal blood flow during the hours of a simulated pulse of 13,14-dihydro-15-keto prostaglandin F(2alpha) (PGFM) in heifers. AB - A bolus treatment (e.g., 25 mg) of prostaglandin F(2alpha) (PGF) in the study of luteolysis in cattle results in dubious interpretations. Therefore, in experiment 1 of the present study, a 13,14-dihydro-15-keto-PGF (PGFM) pulse was simulated by incremental intrauterine (IU) infusion of PGF for 2.7 h on Day 14 postovulation. Concentrations of PGFM during the first hour of infusion and at the maximum were not different between simulated (n = 7) and spontaneous (n = 7) pulses. In experiment 2, four groups (n = 6 per group) were treated at Minute 0 (beginning of infusion) as follows: saline (infused IU), PGF (infused IU), acyline/saline, and acyline/PGF. Two hours before Minute 0, each heifer was given flunixin meglumine to inhibit endogenous PGF secretion, and heifers in the acyline/saline and acyline/PGF groups were given acyline to inhibit luteinizing hormone (LH). Plasma progesterone concentrations were similar among groups during Minutes 0 to 60, with no indication of an initial transient progesterone increase in the two PGF groups. Progesterone began to decrease in the PGF groups at Minute 60 and to rebound at Minute 135 after the PGFM peak at Minute 120. The rebound was complete in association with an increase in LH in the PGF group, but it was not complete when LH was inhibited in the acyline/PGF group. Luteal blood flow increased during PGF infusion in the two PGF groups and remained elevated for approximately 2 h after the PGFM peak in the PGF group but not in the acyline/PGF group. Novel findings were that an initial transient increase in progesterone did not occur with the simulated PGFM pulse and that LH stimulated a progesterone rebound and maintained the elevated luteal blood flow after the PGFM peak. PMID- 21653896 TI - Nongenomic steroid- and ceramide-induced maturation in amphibian oocytes involves functional caveolae-like microdomains associated with a cytoskeletal environment. AB - Stimulation of full-grown amphibian oocytes with progesterone initiates a nontranscriptional signaling pathway that converges in the activation of Cdc2/cyclin B and reentry into meiosis. We observed that cholesterol depletion mediated by methyl-beta-cyclodextrin (MbetaCD) inhibited meiotic maturation, suggesting involvement of membrane rafts. In the present study, we further characterized caveolae-like membranes from Rhinella arenarum oocytes biochemically and functionally. The identification by mass spectrometry of a nonmuscle myosin heavy-chain associated with caveolar membranes showed evidence of direct involvement of the underlying cytoskeletal environment in the structure of oocyte rafts. Biophysical analysis using the fluorescent probe Laurdan revealed that MbetaCD-mediated cholesterol depletion affected membrane lipid order. In line with this finding, cholesterol removal also affected the localization of the raft marker lipid GM1. Results demonstrated that ceramide is an effective inducer of maturation that alters the distribution of the raft markers caveolin-1, SRC, and GM1, while progesterone seems not to affect membrane microdomain integrity. Cholesterol depletion had a greater effect on ceramide induced maturation, thus suggesting that ceramide is an inducer more vulnerable to changes in the plasma membrane. MbetaCD treatment delayed tyrosine phosphorylation and MAPK activation in progesterone-induced maturation. Functional studies regarding tyrosine phosphorylation raise the possibility that the hormone receptor is located in the nonraft membrane in the absence of ligand and that it translocates to the caveola when it binds to progesterone. The presence of raft markers and the finding of signaling molecules from MAPK cascade functionally associated to oocyte light membranes suggest that this caveolae-rich fraction efficiently recreates, in part, maturation signaling. PMID- 21653897 TI - Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. AB - Endothelial migration is a crucial aspect of a variety of physiologic and pathologic conditions including atherosclerosis and vascular repair. Reactive oxygen species (ROS) function as second messengers during endothelial migration. Multiple intracellular sources of ROS are regulated by cellular context, external stimulus, and the microenvironment. However, the predominant source of ROS during endothelial cell (EC) migration and the mechanisms by which ROS regulate cell migration are incompletely understood. In this study, we tested the hypothesis that mitochondria-derived ROS (mtROS) regulate EC migration. In cultured human umbilical vein endothelial cells, VEGF increased mitochondrial metabolism, promoted mtROS production, and induced cell migration. Either the targeted mitochondrial delivery of the antioxidant, vitamin E (Mito-Vit-E), or the depletion of mitochondrial DNA abrogated VEGF-mediated mtROS production. Overexpression of mitochondrial catalase also inhibited VEGF-induced mitochondrial metabolism, Rac activation, and cell migration. Furthermore, these interventions suppressed VEGF-stimulated EC migration and blocked Rac1 activation in endothelial cells. Constitutively active Rac1 reversed Mito-Vit-E-induced inhibition of EC migration. Mito-Vit-E also attenuated carotid artery reendothelialization in vivo. These results provide strong evidence that mtROS regulate EC migration through Rac-1. PMID- 21653899 TI - Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. AB - Recent studies have shown that overexpression of the transmembrane protein Zrt- and Irt-like protein 14 (Zip14) stimulates the cellular uptake of zinc and nontransferrin-bound iron (NTBI). Here, we directly tested the hypothesis that Zip14 transports free zinc, iron, and other metal ions by using the Xenopus laevis oocyte heterologous expression system, and use of this approach also allowed us to characterize the functional properties of Zip14. Expression of mouse Zip14 in RNA-injected oocytes stimulated the uptake of (55)Fe in the presence of l-ascorbate but not nitrilotriacetic acid, indicating that Zip14 is an iron transporter specific for ferrous ion (Fe(2+)) over ferric ion (Fe(3+)). Zip14-mediated (55)Fe(2+) uptake was saturable (K(0.5) ~ 2 MUM), temperature dependent (apparent activation energy, E(a) = 15 kcal/mol), pH-sensitive, Ca(2+) dependent, and inhibited by Co(2+), Mn(2+), and Zn(2+). HCO(3)(-) stimulated (55)Fe(2+) transport. These properties are in close agreement with those of NTBI uptake in the perfused rat liver and in isolated hepatocytes reported in the literature. Zip14 also mediated the uptake of (109)Cd(2+), (54)Mn(2+), and (65)Zn(2+) but not (64)Cu (I or II). (65)Zn(2+) uptake also was saturable (K(0.5) ~ 2 MUM) but, notably, the metal-ion inhibition profile and Ca(2+) dependence of Zn(2+) transport differed from those of Fe(2+) transport, and we propose a model to account for these observations. Our data reveal that Zip14 is a complex, broad scope metal-ion transporter. Whereas zinc appears to be a preferred substrate under normal conditions, we found that Zip14 is capable of mediating cellular uptake of NTBI characteristic of iron-overload conditions. PMID- 21653898 TI - Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception. AB - Transient receptor potential (TRP) ankyrin 1 (TRPA1) is a Ca(2+)-permeant, nonselective cationic channel. It is predominantly expressed in the C afferent sensory nerve fibers of trigeminal and dorsal root ganglion neurons and is highly coexpressed with the nociceptive ion channel transient receptor potential vanilloid 1 (TRPV1). Several physical and chemical stimuli have been shown to activate the channel. In this study, we have used electrophysiological techniques and behavioral models to characterize the properties of TRPA1. Whole cell TRPA1 currents induced by brief application of lower concentrations of N-methyl maleimide (NMM) or allyl isothiocyanate (AITC) can be reversed readily by washout, whereas continuous application of higher concentrations of NMM or AITC completely desensitized the currents. The deactivation and desensitization kinetics differed between NMM and AITC. TRPA1 current amplitude increased with repeated application of lower concentrations of AITC, whereas saturating concentrations of AITC induced tachyphylaxis, which was more pronounced in the presence of extracellular Ca(2+). The outward rectification exhibited by native TRPA1-mediated whole cell and single-channel currents was minimal as compared with other TRP channels. TRPA1 currents were negatively modulated by protons and polyamines, both of which activate the heat-sensitive channel, TRPV1. Interestingly, neither protein kinase C nor protein kinase A activation sensitized AITC-induced currents, but each profoundly sensitized capsaicin induced currents. Current-clamp experiments revealed that AITC produced a slow and sustained depolarization as compared with capsaicin. TRPA1 is also expressed at the central terminals of nociceptors at the caudal spinal trigeminal nucleus. Activation of TRPA1 in this area increases the frequency and amplitude of miniature excitatory or inhibitory postsynaptic currents. In behavioral studies, intraplantar and intrathecal administration of AITC induced more pronounced and prolonged changes in nociceptive behavior than those induced by capsaicin. In conclusion, the characteristics of TRPA1 we have delineated suggest that it might play a unique role in nociception. PMID- 21653900 TI - Real-time observation of flow-induced cytoskeletal stress in living cells. AB - The mechanical stress due to shear flow has profound effects on cell proliferation, transport, gene expression, and apoptosis. The mechanisms for flow sensing and transduction are unclear, but it is postulated that fluid flow pulls upon the apical surface, and the resulting stress is eventually transmitted through the cytoskeleton to adhesion plaques on the basal surface. Here we report a direct observation of this flow-induced stress in the cytoskeleton in living cells using a parallel plate microfluidic chip with a fluorescence resonance energy transfer (FRET)-based mechanical stress sensor in actinin. The sensing cassette was genetically inserted into the cytoskeletal host protein and transfected into Madin-Darby canine kidney cells. A shear stress of 10 dyn/cm(2) resulted in a rapid increase in the FRET ratio indicating a decrease in stress across actinin with flow. The effect was reversible, and cells were able to respond to repeated stimulation and showed adaptive changes in the cytoskeleton. Flow-induced Ca(2+) elevation did not affect the response, suggesting that flow induced changes in actinin stress are insensitive to intracellular Ca(2+) level. The reduction in FRET ratio suggests actin filaments are under normal compression in the presence of flow shear stress due to changes in cell shape, and/or actinin is not in series with actin. Treatment with cytochalasin-D that disrupts F-actin reduced prestress and the response to flow. The FRET/flow method is capable of resolving changes of stress in multiple proteins with optical spatial resolution and time resolution >1 Hz. This promises to provide insight into the force distribution and transduction in all cells. PMID- 21653902 TI - Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1. AB - Activated neutrophils interacting with the vessel wall can alter vascular permeability to macromolecules such as albumin via release of various secretion products that induce changes in the endothelial monolayer. In the current work we used cremaster microvessels of anesthetized mice to show that, in addition to this paracrine mechanism, leukocyte ligation of endothelial ICAM-1 directly activates endothelial cell (EC) signaling, altering EC permeability to albumin [i.e., solute permeability (P(s))]. We show that antibody cross-linking of surface ICAM-1 in intact microvessels is sufficient to increase P(s) even in the absence of interacting leukocytes. Unstimulated arterioles do not support leukocyte-EC interactions, but despite this, antibody ligation of ICAM-1 in these vessels induced a twofold increase in P(s). Similarly, in venules that were depleted of interacting neutrophils, P(s) was decreased to below resting levels and was restored by ligation of ICAM-1. Use of function-blocking antibodies to separately block leukocyte rolling or adhesion under unstimulated or TNF-alpha activated conditions established that both rolling and adhered leukocytes contribute to P(s) regulation in situ. Both rolling and adhesion activated EC dependent signaling mechanisms that increased P(s). ICAM-1 ligation with primary antibody alone or primary followed by secondary antibodies showed that regulation of P(s) is directly dependent on the degree of ICAM-1 clustering. Under physiological versus inflamed conditions, respectively, this ICAM-1 clustering dependent regulation of P(s) switches from PKC dependent and Src independent to Src dependent and PKC independent. This study thus identifies a new mechanism by which antiadhesion treatment may constitute a potential therapy for tissue edema. PMID- 21653901 TI - Contributions of VEGF to age-dependent transmural gradients in contractile protein expression in ovine carotid arteries. AB - The present study explores the hypothesis that arterial smooth muscle cells are organized into layers with similar phenotypic characteristics that vary with the relative position between the lumen and the adventitia due to transmural gradients in vasotrophic factors. A corollary hypothesis is that vascular endothelial growth factor (VEGF) is a factor that helps establish transmural variations in smooth muscle phenotype. Organ culture of endothelium-denuded ovine carotid arteries with 3 ng/ml VEGF-A(165) for 24 h differentially and significantly influenced potassium-induced (55% increase) and stretch-induced (36% decrease) stress-strain relations in adult (n = 18) but not term fetal (n = 21) arteries, suggesting that smooth muscle reactivity to VEGF is acquired during postnatal maturation. Because inclusion of fetal bovine serum significantly inhibited all contractile effects of VEGF (adult: n = 11; fetus: n = 11), it was excluded in all cultures. When assessed in relation to the distance between the lumen and the adventitia in immunohistochemically stained coronal artery sections, expression of smooth muscle alpha-actin (SMalphaA), myosin light chain kinase (MLCK), and 20-kDa regulatory myosin light chain exhibited distinct protein-dependent and age-dependent gradients across the artery wall. VEGF depressed regional SMalphaA abundance up to 15% in adult (n = 6) but not in fetal (n = 6) arteries, increased regional MLCK abundance up to 140% in fetal (n = 8) but not in adult (n = 10) arteries, and increased regional MLC(20) abundance up to 28% in fetal arteries (n = 7) but decreased it by 17% in adult arteries (n = 9). Measurements of mRNA levels verified that VEGF receptor transcripts for both Flt-1 and kinase insert domain receptor (KDR) were expressed in both fetal and adult arteries. Overall, the present data support the unique hypothesis that smooth muscle cells are organized into lamina of similar phenotype with characteristics that depend on the relative position between the lumen and the adventitia and involve the direct effects of growth factors such as VEGF, which acts independently of the vascular endothelium in an age-dependent manner. PMID- 21653903 TI - Hospitalization of the elderly in the United States for nonspecific gastrointestinal diseases: a search for etiological clues. AB - The frequency of hospitalization among the elderly in the United States caused by gastrointestinal diseases between 1991 and 2004 increased dramatically, especially hospitalization of elderly individuals with nonspecific diagnoses. We analyzed 6 640 304 gastrointestinal disease-associated hospitalization records in this 14-year period by comparing the peak times of nonspecific gastrointestinal diseases with those of specific diseases. We found that most nonspecific gastrointestinal diseases peak concurrently with viral enteritis, suggesting a lack of diagnostic testing for viruses, which may adversely affect the efficiency of prevention, surveillance, and treatment efforts. PMID- 21653904 TI - Using extended cognitive behavioral treatment and medication to treat dependent smokers. AB - OBJECTIVES: We evaluated smoking-cessation efficacy of an extended course of sustained-release bupropion (bupropion SR) and cognitive-behavioral treatment (CBT). METHODS: Participants who smoked at least 10 cigarettes per day and who smoked within 30 minutes of arising (n = 406) completed a 12-week smoking cessation treatment including group counseling, nicotine-replacement therapy, and bupropion SR. Participants were then randomly assigned to 1 of 5 conditions: (1) no further treatment, (2) active bupropion SR for 40 weeks, (3) placebo for 40 weeks, (4) active bupropion SR and 11 sessions of CBT for 40 weeks (A-CBT), or (5) placebo and 11 sessions of CBT for 40 weeks. Participants were assessed at baseline and at weeks 12, 24, 52, 64, and 104. RESULTS: A-CBT was not superior to the other 3 extended treatments. From weeks 12 through 104, all extended treatment conditions were superior to standard treatment. At weeks 64 and 104, the 2 CBT conditions produced significantly higher abstinence rates than did the other 3 conditions. CONCLUSIONS: Brief contact with providers can increase abstinence during treatment. CBT may increase long-term abstinence after extended treatment is terminated. PMID- 21653905 TI - Hypersusceptibility to respiratory viruses as a shared mechanism for asthma, chronic obstructive pulmonary disease, and cystic fibrosis. PMID- 21653906 TI - Polarized alloantigen presentation by airway epithelial cells contributes to direct CD8+ T cell activation in the airway. AB - Activated T lymphocytes are abundant in the airway during lung allograft rejection. Based on respiratory viral studies, it is the current paradigm that T cells cannot divide in the airway, and that their accumulation in the lumen of the respiratory tract is the exclusive result of recruitment from other sites, such as mediastinal lymph nodes. Here, we show that CD8(+) T cell activation and proliferation can occur in the airway after orthotopic lung transplantation. We also demonstrate that airway epithelium expresses major histocompatibility class I predominantly on the apical surface, both in vitro and in vivo, and initiates CD8(+) T cell responses in a polarized fashion, favoring luminal activation. Our data identify a unique site for CD8(+) T cell activation after lung transplantation, and suggest that attenuating these responses may provide a clinically relevant target. PMID- 21653908 TI - Social influence modulates the neural computation of value. AB - Social influence--individuals' tendency to conform to the beliefs and attitudes of others--has interested psychologists for decades. However, it has traditionally been difficult to distinguish true modification of attitudes from mere public compliance with social norms; this study addressed this challenge using functional neuroimaging. Participants rated the attractiveness of faces and subsequently learned how their peers ostensibly rated each face. Participants were then scanned using functional MRI while they rated each face a second time. The second ratings were influenced by social norms: Participants changed their ratings to conform to those of their peers. This social influence was accompanied by modulated engagement of two brain regions associated with coding subjective value--the nucleus accumbens and orbitofrontal cortex--a finding suggesting that exposure to social norms affected participants' neural representations of value assigned to stimuli. These findings document the utility of neuroimaging to demonstrate the private acceptance of social norms. PMID- 21653907 TI - Mucin production during prenatal and postnatal murine lung development. AB - Mucus is a protective gel that lines respiratory tract surfaces. To identify potential roles for secreted gel--forming mucins in lung development, we isolated murine lungs on embryonic days (E) 12.5-18.5, and postnatal days (PN) days 5, 14, and 28. We measured the mucin gene expression by quantitative RT-PCR, and localization by histochemical and immunohistochemical labeling. Alcian blue/periodic acid--Schiff--positive cells are present from E15.5 through PN28. Muc5b transcripts were abundant at all time points from E14.5 to PN28. By contrast, transcript levels of Muc5ac and Muc2 were approximately 300 and 85,000 times lower, respectively. These data are supported by immunohistochemical studies demonstrating the production and localization of Muc5ac and Muc5b protein. This study indicates that mucin production is prominent in developing murine lungs and that Muc5b is an early, abundant, and persistent marker of bronchial airway secretory cells, thereby implicating it as an intrinsic component of homeostatic mucosal defense in the lungs. PMID- 21653909 TI - Fitting in but getting fat: identity threat and dietary choices among U.S. immigrant groups. AB - In two experiments, we tested the hypothesis that pressure felt by U.S. immigrant groups to prove they belong in America causes them to consume more prototypically American, and consequently less healthy, foods. Asian Americans were three times more likely to report a prototypically American food as their favorite after being asked whether they spoke English than when they had not been asked; in contrast, questioning the English abilities of White Americans had no effect on their reports (Experiment 1). Also, Asian Americans ordered and ate dishes that were more American and contained an average of 182 additional calories and 12 extra grams of fat when their American identity was directly challenged than when their American identity was not challenged (Experiment 2). Identity-based psychological processes may help explain why the diets of U.S. immigrant groups tend to decline in nutritional value with longer residence in the United States and over generations. PMID- 21653910 TI - A journey within a journey: the lived experience of parents who do not live near their child's tertiary cancer center. AB - Much research has been directed at childhood cancer survivors and their families to learn how to best provide care. However, little is known about parents' experiences of transitioning to a time when their child has completed treatment for cancer when living at a distance to the tertiary cancer center. The purpose of this study was to talk to such parents about their experiences. Five Canadian parents of children who had completed treatment for cancer in the past 3 months to 5 years took part in qualitative opened-ended interviews using a phenomenological hermeneutic approach. Data analysis revealed the essence of the parents' lived experience as a journey within a journey; 4 themes characterized the essence. Parents living a 2.5- to 5-hour drive from the cancer center expressed a willingness to travel wherever necessary in order to receive specialized care for their child. Parents emphasized the importance of having a local health care provider in whom they trusted. Assessing families' needs, support systems, and readiness to return home are important nursing roles throughout the cancer trajectory. PMID- 21653912 TI - Parental experiences of information within pediatric oncology. AB - Parents of children with cancer use information to create knowledge about their child's disease. Information can help parents reduce chaos and create a feeling of control, but there are often obstacles to its acquisition, which has been described as similar to learning a new language. The purpose of this study was to describe parents' experiences of acquiring and using information to create knowledge about their child's cancer during the course of the illness. The authors used qualitative content analysis on data from focus groups and individual interviews with 14 parents of children with cancer. Two themes were constructed: (a) feeling acknowledged as a person of significance included feeling safe and secure in spite of uncertainty, having one's hopes supported, and getting relief from other families' experiences; (b) feeling like an unwelcome guest included feeling abandoned at important milestones, feeling forced to nag for information, and feeling burdened by the obligation to inform others. Parents may need extra attention at important milestones such as treatment cessation, with information meetings grounded in the parents' own needs. PMID- 21653911 TI - A grounded theory of the process of adherence to oral chemotherapy in Hispanic and caucasian children and adolescents with acute lymphoblastic leukemia. AB - Children and adolescents with acute lymphoblastic leukemia (ALL) receive treatment that relies on daily self- or parent/caregiver-administered oral chemotherapy for approximately 2 years. Despite the fact that pediatric ALL is uniformly fatal without adequate treatment, nonadherence to oral chemotherapy has been observed in up to one third of patients. Little is known about the reasons for nonadherence in these patients. This study used Straussian grounded theory methodology to develop and validate a model to explain the process of adherence to oral chemotherapy in children and adolescents with ALL. Thirty-eight semistructured interviews (with 17 patients and 21 parents/caregivers) and 4 focused group discussions were conducted. Three stages were identified in the process of adherence: (a) Recognizing the Threat, (b) Taking Control, and (c) Managing for the Duration. Doing Our Part was identified as the core theme explaining the process of adherence and involves the parent (or patient) taking responsibility for assuring that medications are taken as prescribed. Understanding the association between taking oral chemotherapy and control/cure of leukemia (Making the Connection) appeared to mediate adherence behaviors. PMID- 21653913 TI - Rats display a robust bimodal preference profile for sucralose. AB - Female Sprague-Dawley rats display considerable variability in their preference for the artificial sweetener sucralose over water. While some rats can be classified as sucralose preferrers (SP), as they prefer sucralose across a broad range of concentrations, others can be classified as sucralose avoiders (SA), as they avoid sucralose at concentrations above 0.1 g/L. Here, we expand on a previous report of this phenomenon by demonstrating, in a series of 2-bottle 24-h preference tests involving water and an ascending series of sucralose concentrations, that this variability in sucralose preference is robust across sex, stage of the estrous cycle, and 2 rat strains (Long-Evans and Sprague Dawley). In a second experiment involving a large sample of rats (n = 50), we established that the ratio of SP to SA is approximately 35-65%. This bimodal behavioral response to sucralose appears to be driven by taste because rats display a similar bimodal licking response to a range of sucralose solutions presented during brief-access tests. Finally, we have shown that sucralose avoidance is extremely robust as 23-h water-deprived SA continue to avoid sucralose in 1-h single-bottle intake tests. Based on their reduced licking responses to sucralose during brief-access (taste driven) tests, and the fact that their distaste for sucralose cannot be overcome by the motivation to rehydrate, we conclude that SA detect a negative taste quality of sucralose that SP are relatively insensitive to. PMID- 21653915 TI - Silent cries, dancing tears: the metapsychology of art revisited/revised. AB - Against the backdrop of a broad survey of the literature on applied psychoanalysis, a number of concepts underpinning the metapsychology of art are revisited and revised: sublimation; interrelationships between primary and secondary processes; symbolization; "fantasy"; and "cathexis." Concepts embedded in dichotomous or drive/energic contexts are examined and reformulated in terms of a continuum of semiotic processes. Freudian dream structure is viewed as a biological/natural template for nonrepressive artistic forms of sublimation. The synthesis presented proposes a model of continuous rather than discontinuous processes, in a nonenergic, biosemiotic metatheoretical framework. PMID- 21653914 TI - Investigation of correlation among safety biomarkers in serum, histopathological examination, and toxicogenomics. AB - This article addresses the issue of miscorrelation between hepatic injury biomarkers and histopathological findings in the drug development context. Our studies indicate that the use of toxicogenomics can aid in the drug development decision-making process associated with such miscorrelated data. BLZ945 was developed as a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor. Treatment of BLZ945 in rats and monkeys increased serum alanine aminotransferase (ALT) and aspartate transaminase (AST). However, liver hypertrophy was the only histopathological liver finding in rats, and there was no change in the livers of monkeys. Longer treatment of BLZ945 in rats for 6 weeks caused up to 6-fold elevation of ALT, yet hepatocyte necrosis was not detected microscopically. Toxicogenomic profiling of liver samples demonstrated that the genes associated with early response to liver injury, apoptosis/necrosis, inflammation, oxidative stress, and metabolic enzymes were upregulated. Studies are ongoing to evaluate the mechanisms underlying BL945-induced ALT and AST elevations. PMID- 21653916 TI - The enduring presence of Heinz Kohut: empathy and its vicissitudes. AB - This paper expands upon and further develops the centrality of empathy in psychoanalysis as offered by Heinz Kohut. Using clinical examples, it differentiates sustained empathy as the distinctive component of psychoanalysis, and it demonstrates some of the difficulties in determining the boundaries of empathy in the practice of psychoanalysis. A further distinction is from mind reading, a purely cognitive exercise, as is intuition (Carruthers 2009). To pursue a psychoanalytic perception of empathy one must confront its limitations and go beyond the somewhat simplistic claim of its unquestioned therapeutic effect. Empathy is more than a cognitive act, and as sustained over time it can be difficult to achieve, can be misunderstood, and can at times have no therapeutic effect. PMID- 21653917 TI - From archaic narcissism to empathy for the self: the evolution of new capacities in psychoanalysis. AB - The concept of the selfobject was central to Heinz Kohut's psychology of the self. With an eye to studying the development of narcissism and its implications for the growth of new psychic structure, this concept is reviewed and reassessed. Post-Kohutian complexities regarding its definition and use extend our consideration of the development of narcissism beyond archaic configurations toward further evolution of the self and the nature of mature narcissism. The hypothesis is offered that developing narcissism and the growth of self regulation impact the acquisition of new structure and new capacities through the emergence of newly potentiated aspects of the self. The implications of these emergent qualities of the self are examined in the context of our understanding of self-esteem regulation, the state of the self, and the goals of psychoanalysis. A clinical example illustrates how technique and process in an analysis may be organized around the development of such new capacities. PMID- 21653918 TI - The waiting room as boundary and bridge between self-States and unformulated experience. AB - For both patient and analyst, the waiting room serves containing and expressive functions. The waiting room may serve as both a boundary between the analytic couple and a bridge to engagement. At times it can provide a means of titrating the intensity and duration of the affects activated by immersion in the analytic process: it can also serve to extend the boundaries of the analytic frame by providing a holding environment to facilitate metabolizing the impact of comings and goings. It also may be viewed as a membrane between self-states through which oscillating facets of dissociated or unformulated experience are enacted. Clinical material from the analysis of an adolescent girl illustrates these ideas. PMID- 21653919 TI - The olympian delusion. PMID- 21653921 TI - Dual neofunctionalization of a rapidly evolving aquaporin-1 paralog resulted in constrained and relaxed traits controlling channel function during meiosis resumption in teleosts. AB - The preovulatory hydration of teleost oocytes is a unique process among vertebrates. The hydration mechanism is most pronounced in marine acanthomorph teleosts that spawn pelagic (floating) eggs; however, the molecular pathway for water influx remains poorly understood. Recently, we revealed that whole-genome duplication (WGD) resulted in teleosts harboring the largest repertoire of molecular water channels in the vertebrate lineage and that a duplicated aquaporin-1 paralog is implicated in the oocyte hydration process. However, the origin and function of the aquaporin-1 paralogs remain equivocal. By integrating the molecular phylogeny with synteny and structural analyses, we show here that the teleost aqp1aa and -1ab paralogs (previously annotated as aqp1a and -1b, respectively) arose by tandem duplication rather than WGD and that the Aqp1ab C terminus is the most rapidly evolving subdomain within the vertebrate aquaporin superfamily. The functional role of Aqp1ab was investigated in Atlantic halibut, a marine acanthomorph teleost that spawns one of the largest pelagic eggs known. We demonstrate that Aqp1ab is required for full hydration of oocytes undergoing meiotic maturation. We further show that the rapid structural divergence of the C terminal regulatory domain causes ex vivo loss of function of halibut Aqp1ab when expressed in amphibian oocytes but not in zebrafish or native oocytes. However, by using chimeric constructs of halibut Aqp1aa and -1ab and antisera specifically raised against the C-terminus of Aqp1ab, we found that this cytoplasmic domain regulates in vivo trafficking to the microvillar portion of the oocyte plasma membrane when intraoocytic osmotic pressure is at a maximum. Interestingly, by coinjecting polyA(+) mRNA from postvitellogenic halibut follicles, ex vivo intracellular trafficking of Aqp1ab is rescued in amphibian oocytes. These data reveal that the physiological role of Aqp1ab during meiosis resumption is conserved in teleosts, but the remarkable degeneracy of the cytoplasmic domain has resulted in alternative regulation of the trafficking mechanism. PMID- 21653922 TI - Dealing with dietary measurement error in nutritional cohort studies. AB - Dietary measurement error creates serious challenges to reliably discovering new diet-disease associations in nutritional cohort studies. Such error causes substantial underestimation of relative risks and reduction of statistical power for detecting associations. On the basis of data from the Observing Protein and Energy Nutrition Study, we recommend the following approaches to deal with these problems. Regarding data analysis of cohort studies using food-frequency questionnaires, we recommend 1) using energy adjustment for relative risk estimation; 2) reporting estimates adjusted for measurement error along with the usual relative risk estimates, whenever possible (this requires data from a relevant, preferably internal, validation study in which participants report intakes using both the main instrument and a more detailed reference instrument such as a 24-hour recall or multiple-day food record); 3) performing statistical adjustment of relative risks, based on such validation data, if they exist, using univariate (only for energy-adjusted intakes such as densities or residuals) or multivariate regression calibration. We note that whereas unadjusted relative risk estimates are biased toward the null value, statistical significance tests of unadjusted relative risk estimates are approximately valid. Regarding study design, we recommend increasing the sample size to remedy loss of power; however, it is important to understand that this will often be an incomplete solution because the attenuated signal may be too small to distinguish from unmeasured confounding in the model relating disease to reported intake. Future work should be devoted to alleviating the problem of signal attenuation, possibly through the use of improved self-report instruments or by combining dietary biomarkers with self-report instruments. PMID- 21653924 TI - A multi-country qualitative study of clinicians' and patients' views on point of care tests for lower respiratory tract infection. AB - BACKGROUND: Point of care tests (POCTs) are being promoted to better target antibiotic prescribing with the aim of improving outcomes and containing antibiotic resistance. OBJECTIVE: We aimed to explore clinician and patient views about POCTs to assist with the diagnosis and management of lower respiratory tract infection (LRTI) in primary care. METHODS: Multi-country European qualitative interview study with 80 primary care clinicians and 121 adult patients in nine primary care networks who had recently consulted with symptoms of acute cough/LRTI. Transcripts were subjected to a five-stage analytic framework approach (familiarization, developing a thematic framework from the interview questions and the themes emerging from the data, indexing, charting, and mapping to search for interpretations in the data), with local network facilitators commenting on preliminary reports. RESULTS: Clinicians who did not routinely use POCTs for acute cough/LRTI felt that the tests' advantages included managing patient expectations for antibiotics. Perceived disadvantages included questionable test performance, problems interpreting results, a detraction from clinical reasoning, costs, time and patients not wanting, or demanding, the tests. Clinicians who routinely used POCTs echoed these disadvantages. Almost all patients would be happy to be managed with the addition of a POCT. Patients with experience of POCTs accepted it as part of routine care. CONCLUSIONS: Acceptability of POCTs to clinicians is likely to be improved if tests perform well on accuracy, time to result, simplicity and cost. Including POCTs in the routine management of acute cough/LRTI is likely to be acceptable to most patients. PMID- 21653923 TI - Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening. AB - BACKGROUND: Chromosomal translocations generating oncogenic transcription factors are the hallmark of a variety of tumors, including many sarcomas. Ewing sarcoma family of tumors (ESFTs) are characterized by the t(11;22)(q24;q12) translocation that generates the Ewing sarcoma breakpoint region 1 and Friend leukemia virus integration 1 (EWS-FLI1) fusion transcription factor responsible for the highly malignant phenotype of this tumor. Although continued expression of EWS-FLI1 is believed to be critical for ESFT cell survival, a clinically effective small molecule inhibitor remains elusive likely because EWS-FLI1 is a transcription factor and therefore widely felt to be "undruggable." METHODS: We developed a high-throughput screen to evaluate more than 50 000 compounds for inhibition of EWS-FLI1 activity in TC32 ESFT cells. We used a TC32 cell-based luciferase reporter screen using the EWS-FLI1 downstream target NR0B1 promoter and a gene signature secondary screen to sort and prioritize the compounds. We characterized the lead compound, mithramycin, based on its ability to inhibit EWS-FLI1 activity in vitro using microarray expression profiling, quantitative reverse transcription-polymerase chain reaction, and immunoblot analysis, and in vivo using immunohistochemistry. We studied the impact of this inhibition on cell viability in vitro and on tumor growth in ESFT xenograft models in vivo (n = 15 20 mice per group). All statistical tests were two-sided. RESULTS: Mithramycin inhibited expression of EWS-FLI1 downstream targets at the mRNA and protein levels and decreased the growth of ESFT cells at half maximal inhibitory concentrations between 10 (95% confidence interval [CI] = 8 to 13 nM) and 15 nM (95% CI = 13 to 19 nM). Mithramycin suppressed the growth of two different ESFT xenograft tumors and prolonged the survival of ESFT xenograft-bearing mice by causing a decrease in mean tumor volume. For example, in the TC32 xenograft model, on day 15 of treatment, the mean tumor volume for the mithramycin-treated mice was approximately 3% of the tumor volume observed in the control mice (mithramycin vs control: 69 vs 2388 mm(3), difference = 2319 mm(3), 95% CI = 1766 to 2872 mm(3), P < .001). CONCLUSION: Mithramycin inhibits EWS-FLI1 activity and demonstrates ESFT antitumor activity both in vitro and in vivo. PMID- 21653925 TI - Validation and use of a parametric model for projecting cystic fibrosis survivorship beyond observed data: a birth cohort analysis. AB - BACKGROUND: The current lifetable approach to survival estimation is favoured by CF registries. Recognising the limitation of this approach, we examined the utility of a parametric survival model to project birth cohort survival estimates beyond the follow-up period, where short duration of follow-up meant median survival estimates were indeterminable. METHODS: Parametric models were fitted to observed survivorship data from the US CF Foundation (CFF) Patient Registry 1980 1994 birth cohort. Model-predicted median survival was estimated. The best fitting model was applied to a Cystic Fibrosis Registry of Ireland dataset to allow an evaluation of the model's ability to estimate predicted median survival. This involved a comparison of birth cohort lifetable predicted and observed (Kaplan-Meier) median survival estimates. RESULTS: A Weibull model with main effects of gender and birth cohort was developed using a US CFF dataset (n=13,115) for which median survival was not directly estimable. Birth cohort lifetable predicted median survival for male and female patients born between 1985 and 1994 and surviving their first birthday was 50.9 and 42.4 years respectively. To evaluate the accuracy of a Weibull model in predicting median survival, a model was developed for the 1980-1984 Cystic Fibrosis Registry of Ireland birth cohort (n=243), which had an observed (Kaplan-Meier) median survival of 27.7 years. Model-predicted median survival estimates were calculated using data censored at different follow-up periods. The estimates converged to the true value as length of follow-up increased. CONCLUSIONS: Accurate prognostic information that is clinically critical for care of patients affected by rare, life-limiting disorders can be provided by parametric survival models. Problems associated with short duration of follow-up for recent birth cohorts can be overcome using this approach, providing better opportunities to monitor survival and plan services locally. PMID- 21653926 TI - Elevated high-sensitivity cardiac troponin T is associated with increased mortality after acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Cardiovascular co-morbidities are common in chronic obstructive pulmonary disease (COPD). Retrospective studies on selected patients have indicated that cardiac troponin elevation is frequent during acute exacerbations of COPD (AECOPD), and that this is associated with poor survival. In the present prospective study the prevalence and prognostic value of elevated cardiac troponin T (cTnT) in unselected patients with AECOPD have been investigated, using a novel high-sensitivity assay (hs-cTnT assay). METHODS AND RESULTS: 99 patients hospitalised for AECOPD were included. They were followed until death or study termination. During a median follow-up time of 1.9 years, 57 patients (58%) died. 97 patients (98%) had measurable levels of hs-cTnT and 73 (74%) had hs-cTnT above the normal range (>=14.0 ng/l). The crude mortality rates in patients having hs-cTnT <14.0, 14.0-39.9 and >=40 ng/l were 4.6, 30.2 and 58.3 per 100 patient-years, respectively. Adjusting for relevant covariables using an extended Cox regression analysis, the HRs (95% CI) for death were 4.5 (1.2 to 16) and 8.9 (2.4 to 32) among patients having hs-cTnT 14.0-39.9 and >=40 ng/l, respectively, compared with patients with hs-cTnT <14.0 ng/l. The association between mortality and hs-cTnT was strongly modified by heart rate at admission (p<0.001)-that is, the association between mortality and hs-cTnT was stronger among patients with tachycardia. CONCLUSION: Elevated hs-cTnT during AECOPD is frequent, and it is associated with increased mortality. The effect is stronger among patients having tachycardia than among patients with normal heart rate. PMID- 21653927 TI - Relationship of vitamin D status to adult lung function and COPD. AB - BACKGROUND: There is considerable interest in the possible role of vitamin D in respiratory disease, but only one population-based study has reported associations with lung function. METHODS: The cross-sectional relationships of total dietary vitamin D intake, serum 25 hydroxy vitamin D (25(OH)D) concentrations and three vitamin D receptor (VDR) polymorphisms (Apa1, Fok1 and Cdx2) with lung function and spirometrically-defined chronic obstructive pulmonary disease (COPD) were investigated in men and women aged 59-73 years in the Hertfordshire Cohort Study, UK. RESULTS: After controlling for confounders, total vitamin D intake was positively associated with forced expiratory volume in 1 s (FEV(1); difference in FEV(1) between top and bottom quintiles of intake 0.079 l (95% CI 0.02 to 0.14), p trend=0.007, n=2942), ratio of FEV(1) to forced vital capacity (FEV(1)/FVC; p trend=0.008) and negatively associated with COPD (OR comparing top and bottom quintiles 0.57 (95% CI 0.38 to 0.87), p trend=0.02). In contrast, serum 25(OH)D concentrations were not related to FEV(1) (p trend=0.89, n=1197) but were positively associated with COPD (p trend=0.046). VDR genotypes were unrelated to lung function and did not modify the effects of dietary intake or 25(OH)D concentrations on lung function. CONCLUSIONS: The results of this study did not confirm a positive association between blood 25(OH)D concentrations and adult lung function. The apparent relationships with dietary vitamin D are likely to be explained by other highly correlated nutrients in the diet. PMID- 21653928 TI - Sarcoidosis is a Th1/Th17 multisystem disorder: wider implications. PMID- 21653929 TI - Cardiovascular mechanisms of death in severe COPD exacerbation: time to think and act beyond guidelines. PMID- 21653930 TI - A fluorescent assay to quantitatively measure in vitro acyl CoA:diacylglycerol acyltransferase activity. AB - Triacylglycerols (TG) are the major storage form of energy in eukaryotic organisms and are synthesized primarily by acyl CoA:1,2-diacylglycerol acyltransferase (DGAT) enzymes. In vitro DGAT activity has previously been quantified by measuring the incorporation of either radiolabeled fatty acyl CoA or diacylglycerol (DG) into TG. We developed a modified acyltransferase assay using a fluorescent fatty acyl CoA substrate to accurately quantify in vitro DGAT activity. In the modified assay, radioactive fatty acyl CoA is replaced with fluorescent NBD-palmitoyl CoA, which is used as a substrate by DGAT with DG to produce NBD-TG. After extraction with organic solvents and separation by thin layer chromatography, NBD-TG formation can be detected and accurately quantified using a fluorescent imaging system. We demonstrate that this method can be adapted to detect other acyltransferase activities. Because NBD-palmitoyl CoA is commercially available at a much lower cost compared with radioactive acyl CoA substrates, it is a more economical alternative to radioactive tracers. In addition, the exposure of laboratory personnel to radioactivity is greatly reduced. PMID- 21653931 TI - The glue ear 'epidemic': a historical perspective. AB - This paper explores the historical context of the dramatic rise in surgery for glue ear in the mid-20th century, and questions the published assertion that this represented a manufactured 'epidemic'. In examining historical sources, the reader's theoretical viewpoint greatly influences their conclusions: the sustained rise in treatment for glue ear may be seen as the advance of science in a golden age or the resistance of insular professionals to reason in the light of new scientific study methods. Current views on the practice of medicine, consumerism, science and standardisation, rationing and the nature of 'truth' all affect the way that we see this period. Technological advances clearly allowed better diagnosis and more effective treatment, but these did not appear to drive an 'epidemic', rather they were developed to meet the pre-existing challenges of otological practice. The proposition that an 'epidemic' was created does not appear to have any solid grounding. Society's perception of what constitutes disease and what needs treatment may have evolved, but the prevalence of other important diseases changed dramatically over this time period, and a real change in the epidemiology of glue ear cannot be dismissed. In defining the case for and against surgical treatment, a solely positivist, quantitative worldview cannot give us a complete picture of benefit and risk to individuals, families and society at large. PMID- 21653933 TI - Selection of Mycoplasma genitalium strains harbouring macrolide resistance associated 23S rRNA mutations by treatment with a single 1 g dose of azithromycin. AB - OBJECTIVE: A single 1 g dose regimen of azithromycin has been recommended for the treatment of Mycoplasma genitalium infections. The authors evaluated whether this regimen could select M genitalium strains with macrolide resistance after treatment for M genitalium-positive non-gonococcal urethritis. METHODS: In seven men with non-gonococcal urethritis, who were infected with M genitalium without macrolide resistance-associated mutations but experienced microbiological azithromycin treatment failure, M genitalium DNAs in their post-treatment urine specimens were examined for mutations in the 23S rRNA gene and the ribosomal protein genes of L4 and L22. To assess the relatedness of M genitalium strains before and after treatment, their DNAs in pretreatment and post-treatment urine were genotyped by analysing short tandem repeats of an AGT/AAT unit in the MG309 gene and single nucleotide polymorphisms in the MG191 gene. RESULTS: In four of seven patients, M genitalium in post-treatment urine had an A-to-G transition at nucleotide position 2071 or 2072, corresponding to 2058 or 2059 in the 23S rRNA gene of Escherichia coli. In one of the four strains, Pro81Ser in the ribosomal protein L4 accompanied the mutation in the 23S rRNA gene. The genotyping of M genitalium DNAs suggested that these four post-treatment strains were selected from the respective closely related or identical pretreatment strains without macrolide resistance-associated mutations by the treatment. CONCLUSIONS: The single 1 g dose treatment of azithromycin could select M genitalium strains harbouring macrolide resistance-associated mutations. For M genitalium, this regimen might increase the risk of macrolide resistance selection after treatment. PMID- 21653932 TI - Patterns of herpes simplex virus shedding over 1 month and the impact of acyclovir and HIV in HSV-2-seropositive women in Tanzania. AB - OBJECTIVES: Few studies have examined the frequency and duration of genital herpes simplex virus (HSV) shedding in sub-Saharan Africa. This study describes HSV shedding patterns among a sample of HSV-2-seropositive women enrolled in a placebo-controlled trial of HSV suppressive therapy (acyclovir 400 mg twice a day) in Tanzania. METHODS: Trial participants were invited to participate in a substudy involving 12 clinic visits over 4 weeks. At each visit, cervical, vaginal and external skin swabs were taken and analysed for HSV DNA using inhouse real-time PCR. RESULTS: HSV shedding was mainly subclinical (90%; 57/63 shedding days in the placebo arm). The most frequent shedding site was the external skin, but HSV DNA was detected from all three sites on 42% (27/63) of shedding days. In HIV-negative women, HSV DNA was detected on 3% (9/275) of days in the acyclovir versus 11% (33/309) in the placebo arm, while in HIV-positive women, detection was on 14% (23/160) versus 19% (30/155) of days, respectively. CONCLUSIONS: HSV shedding was common, varying greatly by individual. Shedding rates were similar to studies in African and non-African settings. Among HIV-negative women, shedding rates were lower in the acyclovir arm; however, acyclovir did not substantially impact on HSV shedding in HIV-positive women. PMID- 21653934 TI - Do rates of unprotected anal intercourse among HIV-positive MSM present a risk for hepatitis C transmission? AB - OBJECTIVES: To compare the rates of unprotected anal intercourse (UAI) among men who have sex with men (MSM) in HIV-seropositive sexual relationships with that among men in HIV-seronegative and serodiscordant relationships in the context of an emerging hepatitis C virus (HCV) epidemic among HIV-positive MSM. METHODS: Time-location sampling was used to obtain a cross-sectional sample of MSM who attended public venues in San Francisco between November 2007 and October 2008 (N = 1199). Behavioural measures of sexual risk-taking at the level of the sexual dyad were administered to the sample. RESULTS: Men in HIV-positive/positive sexual relationships are significantly more likely to have UAI and combine sex and drugs than men in negative/negative sexual relationships. CONCLUSIONS: If it is possible to spread HCV infection between HIV-positive men via UAI, very high levels of behavioural risk among positive MSM should exist to facilitate HCV transmission. Identifying the precise behavioural risk factors for HCV among HIV positive MSM has become an important public health priority. PMID- 21653936 TI - The clinical governance development index: results from a New Zealand study. AB - BACKGROUND: Clinical governance is seen as pivotal to improving healthcare quality, yet there are few available tools for tracking progress on its implementation. With this in mind, the authors developed a Clinical Governance Development Index (CGDI) designed to track performances between healthcare organisations and over time. METHODS: A survey on implementation of government policy on clinical governance was sent to 3402 New Zealand public hospital specialists. Responses to seven survey items were weighted and combined to form the CGDI. Final scores for each of New Zealand's 21 District Health Boards were converted to percentages. RESULTS: The mean CGDI score was 47.3%, with significant differences in performances across the 21 District Health Boards (F(20, 1178)=3.233, p=0.0000). Scores were higher in boards where respondents perceived governing boards and management worked to support clinical leadership. CONCLUSION: The CGDI offers a simple method for measuring the extent to which a healthcare organisation is working to develop clinical governance. Its use in New Zealand provides a baseline for tracking clinical governance over time. The CGDI could be easily adapted for use in other healthcare systems. PMID- 21653935 TI - A behavioural intervention to reduce persistence of bacterial vaginosis among women who report sex with women: results of a randomised trial. AB - OBJECTIVES: Bacterial vaginosis (BV) is common in lesbians, and treatment fails in up to 28%. Risks include sexual behaviours that transmit vaginal fluid. The authors measured efficacy of a behavioural intervention to reduce sexual transfer of vaginal fluid between female sex partners in reducing BV persistence. METHODS: Women aged 16-35 years with BV who reported sex with women (prior year) were eligible. Participants were randomised to intervention (motivational interviewing designed to reduce sharing of vaginal fluid on hands or sex toys post-treatment, by provision of condoms, gloves and water-based lubricant) or control (general STI education) arms. All were treated with vaginal metronidazole and underwent computer-assisted self-interview to ascertain sexual behaviours, with test-of cure at 30 days. RESULTS: Of 129 women with BV, 108 (84%) were eligible; 89 (69%) agreed to enrol. 43 were randomised to control and 46 to intervention; 81 (91%) returned for test-of-cure. BV persisted in 12 (27.9%) of 43 women in intervention and 8 (21.1%) of 38 women in control arms (p1/40.6). Digital-vaginal sex was common post-treatment (50% intervention and 68% control); women randomised to the intervention were less likely to report receptive digital-vaginal sex without gloves than control (31% vs 61%; p1/40.01), without reported lower frequency of other sexual practices. Shared vaginal use of sex toys was infrequent. CONCLUSIONS: Although the intervention effected a significant increase in glove use during digital-vaginal sex post-BV treatment, this was not associated with reduction in BV persistence. Shared use of vaginal sex toys was infrequent, suggesting that other mechanisms promote BV in lesbians. PMID- 21653937 TI - Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are associated with recurrent activating mutations of signaling proteins such as Janus kinase 2 (JAK2). However, the actual downstream signaling events and how these alter myeloid homeostasis are poorly understood. We developed an assay to measure basal levels of phosphorylated signaling intermediates by flow cytometry during myeloid differentiation in MPN patients. Our study provides the first systematic demonstration of specific signaling events and their comparison with disease phenotype and JAK2 mutation status. We demonstrate increased basal signaling in MPN patients, which occurs in both early and later stages of myeloid differentiation. In addition, the pattern of signaling is not correlated with JAK2 mutation status and signaling intensity is poorly correlated with mutant JAK2 allele burden. In contrast, signaling differences are detected between different MPN disease phenotypes. Finally, we demonstrate that signaling can be inhibited by a JAK2-selective small molecule, but that this inhibition is not JAK2 V617F specific, because MPN patients with mutant JAK2, wild-type JAK2, and control patients were inhibited to a similar degree. Our data suggest that, in addition to JAK2 mutations, other factors contribute significantly to the MPN phenotype, results that are relevant to both the pathogenesis and therapy of MPN. PMID- 21653938 TI - Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells. AB - Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitors (TKIs) imatinib mesylate and nilotinib represents a successful application of molecularly targeted anticancer therapy. However, the effect of TKIs on leukemic stem cells remains incompletely understood. On the basis of a statistical modeling approach that used the 10-year imatinib mesylate treatment response of patients with CML and a patient cohort receiving first-line nilotinib therapy, we found that successful long-term therapy results in a triphasic exponential decline of BCR-ABL1 transcripts in many patients. Within our framework, the first slope of -0.052 +/- 0.018 (imatinib mesylate) and -0.042 +/- 0.015 (nilotinib) per day represents the turnover rate of leukemic differentiated cells, whereas the second slope of -0.0057 +/- 0.0038 (imatinib mesylate) and -0.0019 +/- 0.0013 (nilotinib) per day represents the turnover rate of leukemic progenitor cells. The third slope allows an inference of the behavior of immature leukemic cells, potentially stem cells. This third slope is negative in most patients, positive in others, and not observable in some patients. This variability in response may be because of insufficient follow-up, missing data, disease heterogeneity, inconsistent compliance to drug, or acquired resistance. Our approach suggests that long-term TKI therapy may reduce the abundance of leukemic stem cells in some patients. PMID- 21653939 TI - Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. AB - The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged >= 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged >= 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL. PMID- 21653940 TI - IL-17-producing invariant NKT cells in lymphoid organs are recent thymic emigrants identified by neuropilin-1 expression. AB - Despite increasing knowledge on the mechanisms of invariant natural killer T (iNKT)-cell development in the thymus, the function of recent thymic emigrant (RTE) iNKT cells remains largely unexplored, principally because of a lack of bona fide markers to distinguish RTE from long-lived iNKT cells. Whether the recently described IL-17-producing iNKT cell subset is part of RTE has notably not been addressed. In the present study, we show that neuropilin-1 (Nrp-1), a transmembrane receptor mainly found on T-regulatory (Treg) cells in the murine immune system, is specifically expressed on RTE iNKT cells in naive mice. We used the Nrp-1 marker to discriminate RTE from mature iNKT cells and compare their functions. We show that RTE iNKT cells proliferate more than mature iNKT cells after in vitro activation; that, unlike mature iNKT cells, most RTE iNKT cells fail to rapidly produce IFN-gamma and IL-4 after in vivo activation; and, most importantly, that IL-17-producing iNKT cells in lymphoid organs of naive mice are contained within the RTE iNKT cell pool. Our results establish an accurate marker of RTE iNKT cells and reveal that continuous thymic output is required for pro inflammatory IL-17 secretion, a key function of adult iNKT cells. PMID- 21653941 TI - Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein. AB - Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially lethal genetic disorder of immune dysregulation that requires prompt and accurate diagnosis to initiate life-saving immunosuppressive therapy and to prepare for hematopoietic stem cell transplantation. In the present study, 85 patients with hemophagocytic lymphohistiocytosis were screened for FHL3 by Western blotting using platelets and by natural killer cell lysosomal exocytosis assay. Six of these patients were diagnosed with FHL3. In the acute disease phase requiring platelet transfusion, it was difficult to diagnose FHL3 by Western blot analysis or by lysosomal exocytosis assay. In contrast, the newly established flow cytometric analysis of intraplatelet Munc13-4 protein expression revealed bimodal populations of normal and Munc13-4-deficient platelets. These findings indicate that flow cytometric detection of intraplatelet Munc13-4 protein is a sensitive and reliable method to rapidly screen for FHL3 with a very small amount of whole blood, even in the acute phase of the disease. PMID- 21653942 TI - Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated vasorelaxation in transgenic cystathionine beta synthase-deficient mice. AB - Hyperhomocysteinemia (HHcy) is associated with endothelial dysfunction (ED), but the mechanism is largely unknown. In this study, we investigated the role and mechanism of HHcy-induced ED in microvasculature in our newly established mouse model of severe HHcy (plasma total homocysteine, 169.5 MUM). We found that severe HHcy impaired nitric oxide (NO)- and endothelium-derived hyperpolarizing factor (EDHF)-mediated, endothelium-dependent relaxations of small mesenteric arteries (SMAs). Endothelium-independent and prostacyclin-mediated endothelium-dependent relaxations were not changed. A nonselective Ca(2+)-activated potassium channel (K(Ca)) inhibitor completely blocked EDHF-mediated relaxation. Selective blockers for small-conductance K(Ca) (SK) or intermediate-conductance K(Ca) (IK) failed to inhibit EDHF-mediated relaxation in HHcy mice. HHcy increased the levels of SK3 and IK1 protein, superoxide (O(2)(-)), and 3-nitrotyrosine in the endothelium of SMAs. Preincubation with antioxidants and peroxynitrite (ONOO(-)) inhibitors improved endothelium-dependent and EDHF-mediated relaxations and decreased O(2)( ) production in SMAs from HHcy mice. Further, EDHF-mediated relaxation was inhibited by ONOO(-) and prevented by catalase in the control mice. Finally, L homocysteine stimulated O(2)(-) production, which was reversed by antioxidants, and increased SK/IK protein levels and tyrosine nitration in cultured human cardiac microvascular endothelial cells. Our results suggest that HHcy impairs EDHF relaxation in SMAs by inhibiting SK/IK activities via oxidation- and tyrosine nitration-related mechanisms. PMID- 21653943 TI - Chromatin boundaries require functional collaboration between the hSET1 and NURF complexes. AB - Chromatin insulators protect erythroid genes from being silenced during erythropoiesis, and the disruption of barrier insulator function in erythroid membrane gene loci results in mild or severe anemia. We showed previously that the USF1/2-bound 5'HS4 insulator mediates chromatin barrier activity in the erythroid-specific chicken beta-globin locus. It is currently not known how insulators establish such a barrier. To understand the function of USF1, we purified USF1-associated protein complexes and found that USF1 forms a multiprotein complex with hSET1 and NURF, thus exhibiting histone H3K4 methyltransferase- and ATP-dependent nucleosome remodeling activities, respectively. Both SET1 and NURF are recruited to the 5'HS4 insulator by USF1 to retain the active chromatin structure in erythrocytes. Knock-down of NURF resulted in a rapid loss of barrier activity accompanied by an alteration of nucleosome positioning, increased occupancy of the nucleosome-free linker region at the insulator site, and increased repressive H3K27me3 levels in the vicinity of the HS4 insulator. Furthermore, suppression of SET1 reduced barrier activity, decreased H3K4me2 and acH3K9/K14, and diminished the recruitment of BPTF at several erythroid-specific barrier insulator sites. Therefore, our data reveal a synergistic role of hSET1 and NURF in regulating the USF-bound barrier insulator to prevent erythroid genes from encroachment of heterochromatin. PMID- 21653944 TI - Nocturnal enuresis in patients taking clozapine, risperidone, olanzapine and quetiapine: comparative cohort study. AB - BACKGROUND: Nocturnal enuresis has been reported in patients taking clozapine, but the incidence has not been accurately established. The incidence of enuresis in patients taking risperidone, olanzapine or quetiapine is unknown. Aims To compare nocturnal enuresis in patients taking clozapine with that in patients taking risperidone, olanzapine or quetiapine. METHOD: Observational cohort study using prescription event monitoring methods. Patients prescribed atypical antipsychotic medicines were followed up by questionnaires that were sent to their medical practitioner. Practitioners were asked to directly ask their patients about bed-wetting. RESULTS: Nocturnal enuresis was reported by 17 of 82 (20.7%) patients taking clozapine, 11 of 115 (9.6%) taking olanzapine, 7 of 105 (6.7%) taking quetiapine and 12 of 195 (6.2%) taking risperidone. Compared with clozapine, the risk of nocturnal enuresis was significantly lower in patients taking olanzapine (odds ratio, OR = 0.43, 95% CI 0.19-0.96), quetiapine (OR = 0.33, 95% CI 0.13-0.59) or risperidone (OR = 0.27, 0.12-0.59), with odds ratios adjusted for age, gender and duration of treatment. CONCLUSIONS: Approximately one in five patients prescribed clozapine experienced bed-wetting. This was significantly higher than the rate of nocturnal enuresis in patients taking olanzapine, quetiapine or risperidone. PMID- 21653945 TI - Creativity and mental disorder: family study of 300,000 people with severe mental disorder. AB - BACKGROUND: There is a long-standing belief that creativity is coupled with psychopathology. AIMS: To test this alleged association and to investigate whether any such association is the result of environmental or genetic factors. METHOD: We performed a nested case-control study based on Swedish registries. The likelihood of holding a creative occupation in individuals who had received in patient treatment for schizophrenia, bipolar disorder or unipolar depression between 1973 and 2003 and their relatives without such a diagnosis was compared with that of controls. RESULTS: Individuals with bipolar disorder and healthy siblings of people with schizophrenia or bipolar disorder were overrepresented in creative professions. People with schizophrenia had no increased rate of overall creative professions compared with controls, but an increased rate in the subgroup of artistic occupations. Neither individuals with unipolar depression nor their siblings differed from controls regarding creative professions. CONCLUSIONS: A familial cosegregation of both schizophrenia and bipolar disorder with creativity is suggested. PMID- 21653946 TI - Prevalence of dementia in African-Caribbean compared with UK-born White older people: two-stage cross-sectional study. AB - BACKGROUND: Preliminary studies in the UK, all using screening instruments of unknown cultural validity, indicate that there may be an increased prevalence of dementia in African-Caribbean people, possibly related to vascular risk factors and potentially amenable to preventative measures. AIMS: To determine the prevalence of dementia in older people of African-Caribbean country of birth compared with their White UK-born counterparts. METHOD: A total of 218 people of African-Caribbean country of birth and 218 White UK-born people aged >=60 years were recruited from five general practices in North London. Those who screened positive for cognitive impairment using a culturally valid instrument were offered a standardised diagnostic interview. Two independent assessors diagnosed dementia according to standard operationalised criteria. RESULTS: African Caribbean participants were 2 years younger, and those with dementia nearly 8 years younger than their White counterparts. The prevalence of dementia was significantly higher in the African-Caribbean (9.6%) than the White group (6.9%) after adjustment for the confounders age and socioeconomic status (odds ratio (OR) = 3.1, 95%CI 1.3-7.3, P = 0.012). CONCLUSIONS: There is an increased prevalence of dementia in older people of African-Caribbean country of birth in the UK and at younger ages than in the indigenous White population. These findings have implications for service provision and preventive interventions. Further research is needed to explore the role of vascular risk factors and social adversity in the excess of dementia in this population. PMID- 21653947 TI - Predictors of screening mammography among a North and South Carolina Medicare population. AB - Despite guidelines recommending that women aged 40 years and older undergo screening mammography at least biennially, reports find that many women do not adhere to these recommendations. The authors' objective was to investigate the factors associated with undergoing a screening mammography. Eligible women were enrolled in Medicare during 2004 and 2005 and resided in North or South Carolina. Information on morbidities, demographics, and physician visits were assessed as predictors for whether a woman underwent a screening mammography. Approximately 50% of the women included in the study had undergone a screening mammography during the study period. An increasing number of physician visits was positively associated with having a screening mammography. Women making at least 1 visit to a gynecologist were more likely to be screened compared with women who saw only a primary care physician and/or a medical specialist. Older age, having certain morbidities, and Medicaid eligibility were inversely related to being screened. PMID- 21653949 TI - Vaccines, children, and fulfilling human potential. PMID- 21653950 TI - Slow going for the global health initiative. AB - The program of US foreign assistance to advance health and health care in developing countries survived the 2011 budget battles, but it continues to face other challenges. PMID- 21653951 TI - During the 'decade of vaccines,' the lives of 6.4 million children valued at $231 billion could be saved. AB - Governments constantly face the challenge of determining how much they should spend to prevent premature deaths and suffering in their populations. In this article we explore the benefits of expanding the delivery of life-saving vaccines in seventy-two low- and middle-income countries, which we estimate would prevent the deaths of 6.4 million children between 2011 and 2020. We present the economic benefits of vaccines by using a "value of statistical life" approach, which is based on individuals' perceptions regarding the trade-off between income and increased risk of mortality. Our analysis shows that the vaccine expansion described above corresponds to $231 billion (uncertainty range: $116-$614 billion) in the value of statistical lives saved. This analysis complements results from analyses based on other techniques and is the first of its kind for immunizations in the world's poorest countries. It highlights the major economic benefits made possible by improving vaccine coverage. PMID- 21653952 TI - Estimated economic benefits during the 'decade of vaccines' include treatment savings, gains in labor productivity. AB - In 2010 the Bill & Melinda Gates Foundation announced a $10 billion commitment over the next ten years to increase access to childhood vaccines in the world's poorest countries. The effort was labeled the "Decade of Vaccines." This study estimates both the short- and long-term economic benefits from the introduction and increased use of six vaccines in seventy-two of the world's poorest countries from 2011 to 2020. Increased rates of vaccination against pneumococcal and Haemophilus influenzae type b pneumonia and meningitis, rotavirus, pertussis, measles, and malaria over the next ten years would save 6.4 million lives and avert 426 million cases of illness, $6.2 billion in treatment costs, and $145 billion in productivity losses. Monetary estimates based on this type of analysis can be used to determine the return on investment in immunization from both the international community and local governments, and they should be considered in policy making. PMID- 21653953 TI - The moral case for the routine vaccination of children in developed and developing countries. AB - In developed countries some parents have decided not to provide routine vaccinations for their children, while in many developing countries there are inadequate rates of vaccination for various reasons. The consequences for children, and members of the community in which they live, can be significant and even tragic. Although some parents may worry that vaccines will harm their child, there is a broader moral case for vaccination that parents and policy makers should consider. This case has four components: benefits and harms, best interests, community benefits, and justice. This moral case should be central to deliberations about vaccination by parents and policy makers. PMID- 21653954 TI - A global road map is needed for vaccine research, development, and deployment. AB - The world is witnessing a tremendous interest in the discovery, development, and use of vaccines as an important contributor to disease prevention and control. However, current global vaccine efforts are not coordinated, and they face many challenges. One is scientific: Most vaccines in use today are based on the scientific knowledge of past centuries. To usher in a new era, there is an urgent need to draw upon new science and scientific disciplines and recruit a new generation of talent trained in the basic and computational sciences of the twenty-first century. In addition, a global road map is urgently needed for making the scientific discoveries necessary to produce new vaccines; developing these into effective vaccines; and drawing up priorities and undertaking the necessary planning for rolling out these vaccines in developing countries. The developing countries themselves must play the lead role in these activities and contribute their own resources as well. This article aims to initiate a wide ranging debate and discussion that will ultimately result in some agreement on the future of vaccine development and deployment. PMID- 21653955 TI - Vaccines as a global imperative--a business perspective. AB - During the past thirty years, vaccines have experienced a renaissance. Advances in science, business, and distribution have transformed the field to the point where vaccines are recognized as a "best buy" in global health, a driver of pharmaceutical industry growth, and a key instrument of international development. With many new vaccines available and others on the horizon, the global community will need to explore new ways of ensuring access to vaccines in developing nations. So-called tiered pricing, which makes vaccines available at different prices for countries at different levels of economic development; innovative financing mechanisms such as advance market commitments or offers of long-term and high-volume contracts to vaccine producers; and technology transfers such as sharing intellectual property and production techniques among companies and countries can all play a part in bringing new life-saving vaccines for pneumonia, rotavirus, malaria, and other diseases to developing countries. PMID- 21653956 TI - Eliminating epidemic Group A meningococcal meningitis in Africa through a new vaccine. AB - A new affordable vaccine against Group A meningococcus, the most common cause of large and often fatal African epidemics of meningitis, was introduced in Burkina Faso, Mali, and Niger in 2010. Widespread use of the vaccine throughout much of Africa may prevent more than a million cases of meningitis over the next decade. The new vaccine is expected to be cost-saving when compared to current expenditures on these epidemics; for example, an analysis shows that introducing it in seven highly endemic countries could save $350 million or more over a decade. International donors have already committed funds to support the new vaccine's introduction in Burkina Faso, Niger, and Mali, but an estimated US$400 million is needed to fund mass immunization campaigns in people ages 1-29 over six years in all twenty-five countries of the African meningitis belt. The vaccine's low cost--less than fifty cents per dose--makes it possible for the affected countries themselves to purchase vaccines for future birth cohorts. PMID- 21653957 TI - Product development partnerships hit their stride: lessons from developing a meningitis vaccine for Africa. AB - The Meningitis Vaccine Project, a so-called product development partnership, developed a new vaccine against bacterial meningitis, an inflammation of brain tissues that causes an estimated 10,000 deaths among African children and young people each year. The vaccine--known as MenAfriVac and specifically targeted for use in low-income countries in Africa--was designed to be made available to governments at a price of fifty cents per dose. The Meningitis Vaccine Project is an example of how product development partnerships have reinvigorated research on vaccines for neglected diseases. These partnerships disperse the multiple tasks of product development across a network of partners that are best suited for each task. The vaccine was rapidly embraced by African health officials, and in its first few weeks on the market, in late 2010, more than nineteen million people in Burkina Faso, Mali, and Niger were vaccinated. PMID- 21653958 TI - Producing a successful malaria vaccine: innovation in the lab and beyond. AB - With approximately 225 million new cases and 800,000 deaths annually, malaria exacts a tremendous toll--mostly on African children under the age of five. Late stage trials of an advanced malaria vaccine candidate--which, if approved, would become the world's first malaria vaccine--are under way, and it may be ready for use by 2015. This article recounts the pivotal roles in that achievement played by collaborations of nonprofit organizations, pharmaceutical companies, private and public donors, and countries whose citizens would benefit most directly from a vaccine. Just as it takes a village to raise a child, it has taken a huge number of stakeholders around the world to reach this point. Developing even more effective vaccines for malaria and other diseases will require continued hard work and creative thinking from scientists, regulators, and policy makers. PMID- 21653959 TI - The challenges of developing new tuberculosis vaccines. AB - The World Health Organization estimates that tuberculosis is causing nearly two million deaths annually, mostly in developing countries. Widespread administration of the current tuberculosis vaccine to newborns is not a reliable route for preventing the disease in adults, the population that drives the epidemic. Several new vaccine candidates are in development, and a few have entered clinical trials. However, the field faces formidable scientific and policy challenges. A collaborative approach to solving scientific, policy, and resource obstacles--as well as new partnerships among emerging economies and vaccine development organizations--will be critical to developing a new tuberculosis vaccine that could achieve its public health potential to save lives and reduce the burden of disease. PMID- 21653960 TI - A handful of 'antipoverty' vaccines exist for neglected diseases, but the world's poorest billion people need more. AB - So-called neglected tropical diseases are the most common infections of the world's poor. Almost all of the "bottom billion"--the 1.4 billion people who live below the poverty level defined by the World Bank--suffer from one or more neglected diseases including hookworm infection, sleeping sickness, or Chagas disease. These diseases are actually a cause of poverty because of their adverse effects on child growth and development and worker productivity. Vaccines to combat such diseases have come to be known as "antipoverty vaccines." Unfortunately, the recent surge in the development and delivery of vaccines to combat the major childhood killers--such as pneumococcal pneumonia and measles- has bypassed neglected diseases. Nevertheless, some vaccines for these neglected diseases are now entering the clinical pipeline. In this article I describe how some antipoverty vaccine development is proceeding and offer recommendations for stimulating further development such as through pooled funding for innovation, developing-country manufacturers, and public-private partnerships for product development. PMID- 21653961 TI - Targeting hookworm, Chagas, and other neglected diseases. PMID- 21653962 TI - Providing vaccines against human papillomavirus to adolescent girls in the Americas: battling cervical cancer, improving overall health. AB - Vaccines against the human papillomavirus (HPV)--the primary cause of cervical cancer--target adolescent girls, many of whom have limited contact with health services. Countries in the Americas are beginning to use HPV vaccines to increase the impact of cervical cancer programs and as an entry point to broader health services for girls. This strategy opens new opportunities to improve lifelong health habits; encourage regular cervical cancer screening and treatment, when necessary; and offer associated services such as reproductive health and nutrition guidance. Some of the early experiences with this strategy illustrate challenges and opportunities that may arise with other new vaccines. PMID- 21653963 TI - India's vaccine deficit: why more than half of Indian children are not fully immunized, and what can--and should--be done. AB - Although India is a leading producer and exporter of vaccines, the country is home to one-third of the world's unimmunized children. Fewer than 44 percent of India's young children receive the full schedule of immunizations. India's vaccine deficit has several causes: little investment by the government; a focus on polio eradication at the expense of other immunizations; and low demand as a consequence of a poorly educated population and the presence of anti-vaccine advocates. In this article we describe India's vaccine deficit and recommend that the government move quickly to increase spending on, and otherwise strengthen, national immunization programs. PMID- 21653964 TI - Challenges to building capacity for evidence-based new vaccine policy in developing countries. AB - There are many challenges to ensuring that people in developing countries have equitable access to new vaccines. Two of the most important are having the capacity to make evidence-based new vaccine policy decisions in developing countries, and then when appropriate actually distributing those new vaccines to those who will most benefit from them. Based on our review of the Pan American Health Organization's ProVac Initiative in the Americas, we found that when national governments in developing countries develop the expertise to make the best technical decisions about immunization programs; take responsibility for helping to pay for and distribute vaccines; and are supported by strong partnerships with international organizations, they succeed in saving more lives more quickly. PMID- 21653965 TI - Vaccine supply chains need to be better funded and strengthened, or lives will be at risk. AB - In the next decade, at least twelve additional vaccines that target such diseases as typhoid, malaria, and dengue will become available to lower- and middle-income countries. These vaccines must travel along what are called supply chains, which include all personnel, systems, equipment, and activities involved in ensuring that vaccines are effectively delivered from the point of production to the people who need them. But for various reasons, supply chains are already strained in many developing countries, and the potential inability to distribute new vaccines will place lives at risk. Among the many steps needed to strengthen the global vaccine supply chain, we suggest that the international community pursue improved coordination between organizations that donate and ship vaccines and the host-country officials who receive and distribute the vaccines, as well as better training for supply-chain managers. PMID- 21653966 TI - An analysis of how the GAVI alliance and low- and middle-income countries can share costs of new vaccines. AB - Immunization is one of the "best buys" in global health. However, for the poorest countries, even modest expenditures may be out of reach. The GAVI Alliance is a public-private partnership created to help the poorest countries introduce new vaccines. Since 2008 GAVI has required that countries cover a share of the cost of vaccines introduced with GAVI support. To determine how much countries can contribute to the cost of vaccines--without displacing spending on other essential programs--we analyzed their fiscal capacity to contribute to the purchase of vaccines over the coming decade. For low-income countries, external financing will be required to purchase vaccines supported by GAVI, so co financing needs to be modest. Relatively better-off "intermediate" countries could support initially modest but gradually increasing co-financing levels. The countries soon to graduate from GAVI can generally afford to follow a rapid path to self-sufficiency. Co-financing for these countries needs to ramp up so that national budgets fully cover the costs of the new generation of vaccines once GAVI support ends. PMID- 21653967 TI - Creating sustainable financing and support for immunization programs in fifteen developing countries. AB - Immunization programs are important tools for reducing child mortality, and they need to be in place for each new generation. However, most national immunization programs in developing countries are financially and organizationally weak, in part because they depend heavily on funding from foreign sources. Through its Sustainable Immunization Financing Program, launched in 2007, the Sabin Vaccine Institute is working with fifteen African and Asian countries to establish stable internal funding for their immunization programs. The Sabin program advocates strengthening immunization programs through budget reforms, decentralization, and legislation. Six of the fifteen countries have increased their national immunization budgets, and nine are preparing legislation to finance immunization sustainably. Lessons from this work with immunization programs may be applicable in other countries as well as to other health programs. PMID- 21653969 TI - Confidence about vaccines in the United States: understanding parents' perceptions. AB - The United States has made tremendous progress in using vaccines to prevent serious, often infectious, diseases. But concerns about such issues as vaccines' safety and the increasing complexity of immunization schedules have fostered doubts about the necessity of vaccinations. We investigated parents' confidence in childhood vaccines by reviewing recent survey data. We found that most parents -even those whose children receive all of the recommended vaccines--have questions, concerns, or misperceptions about them. We suggest ways to give parents the information they need and to keep the US national vaccination program a success. PMID- 21653968 TI - The benefits to all of ensuring equal and timely access to influenza vaccines in poor communities. AB - When influenza vaccines are in short supply, allocating vaccines equitably among different jurisdictions can be challenging. But justice is not the only reason to ensure that poorer counties have the same access to influenza vaccines as do wealthier ones. Using a detailed computer simulation model of the Washington, D.C., metropolitan region, we found that limiting or delaying vaccination of residents of poorer counties could raise the total number of influenza infections and the number of new infections per day at the peak of an epidemic throughout the region-even in the wealthier counties that had received more timely and abundant vaccine access. Among other underlying reasons, poorer counties tend to have high-density populations and more children and other higher-risk people per household, resulting in more interactions and both increased transmission of influenza and greater risk for worse influenza outcomes. Thus, policy makers across the country, in poor and wealthy areas alike, have an incentive to ensure that poorer residents have equal access to vaccines. PMID- 21653970 TI - Fighting child malnutrition in Africa through the use of micronutrient supplements. PMID- 21653971 TI - Analysis raises questions on whether pay-for-performance in Medicaid can efficiently reduce racial and ethnic disparities. AB - In 2006 Massachusetts took the novel approach of using pay-for-performance--a payment mechanism typically used to improve the quality of care--to specifically target racial and ethnic disparities in hospital care for Medicaid patients. We describe the challenges of implementing such an ambitious effort in a short time frame, with limited resources. The early years of the program have yielded little evidence of racial or ethnic disparity in hospital care in Massachusetts, and raise questions about whether pay-for-performance as it is now practiced is a suitable tool for addressing disparities in hospital care. PMID- 21653972 TI - Practicing medicine versus pushing paper. AB - A neurologist reflects on the realities of his workday after a patient asks why doctors complain about payers' bureaucratic oversight. PMID- 21653975 TI - The FDA's humanitarian device exemption program. PMID- 21653977 TI - A humanitarian device exemption for deep brain stimulation. PMID- 21653979 TI - Partnerships in health markets need regulation. PMID- 21653980 TI - A flawed analysis of self-referral. PMID- 21653983 TI - Supervising US medical trainees abroad. PMID- 21653984 TI - Guidelines for global health training. PMID- 21653986 TI - Should postpartum depression screening policies be reevaluated? PMID- 21653987 TI - Increasing the organizational capacity of small practices. PMID- 21653991 TI - Pharmacoepidemiology in the postmarketing assessment of the safety and efficacy of drugs in older adults. AB - Much of the information on safety and efficacy of drugs in older people is obtained after marketing. Pharmacoepidemiologic studies play an increasing role in obtaining this information. Pharmacoepidemiologic studies contribute significantly to knowledge of risks associated with medicines in older people and less so to that of benefits. Recent improvements in methodology in both pharmacoepidemiology and geriatric medicine have improved the validity and reduced the bias of these studies. Pharmacoepidemiologic studies are a critical component of assessing the risks of medicines in older people. Where possible, findings of pharmacoepidemiologic studies should be tested with well-conducted interventional randomized trials in relevant populations of older people. PMID- 21653990 TI - Weight loss and low-intensity exercise for the treatment of metabolic syndrome in obese postmenopausal women. AB - BACKGROUND: The prevalence of the metabolic syndrome (MetSyn) approaches 50% in postmenopausal women. This study examines the efficacy of lifestyle modification for the treatment of MetSyn and its associated risk for cardiovascular disease and diabetes in this population. METHODS: This prospective controlled study examines the effects of a 6-month weight loss and low-intensity exercise program (WL+LEX) on body composition (dual-energy X-ray absorptiometry and abdominal computed tomography scans), fasting glucose and lipid levels, cytokines, and blood pressure in postmenopausal women with and without MetSyn. RESULTS: WL+LEX reduced body weight (MetSyn: -5% vs non-MetSyn: -7%) and fat mass (-11% vs -15%) and increased VO(2max) (+2% vs +3%) in both MetSyn (N = 35) and non-MetSyn (N = 41) groups. Constituents of MetSyn decreased comparably in both groups. Fifteen (45%) MetSyn participants responded (R) by converting to non-MetSyn, 18 remained MetSyn (NR), and 2 had missing data. Reduction in fat mass (-15% vs -8%, p = .02) was greater in R than NR, but there were no between-group differences in changes in VO(2max), cytokines, or other variables. The decrease in the number of MetSyn criteria was greater in R than in NR (-27 vs -13, p < .0001) due to decreases in blood pressure (p < .01), glucose (p = .02), and with a trend for triglyceride (p = .07). Reductions in fat mass best predicted resolution of MetSyn (p = .04). CONCLUSIONS: Women who lose more fat are more likely to lower blood pressure, glucose, and triglyceride levels to resolve MetSyn. Thus, a WL+LEX program effectively treats postmenopausal women with MetSyn. PMID- 21653992 TI - [Delay of reward in borderline personality disorder: systematic literature review]. AB - BACKGROUND AND AIM: Numerous studies report on high impulsivity and preference for "here and now" of patients suffering from Borderline Personality Disorder (BPD). In our paper, we aimed to explore and summarise those studies which explored the connection between BPD and delay discounting using empirical approach. METHOD: In July 2010 five databases (PsycInfo, ScienceDirect, MedLine, Web of Science and PubMed) were searched using the keywords borderline, reward, "delay discount*" and "delay gratification". RESULTS: Out of five we identified as relevant, only two studies found any difference in delaying gratification of BPDpatients compared to controls. CONCLUSION: The analysis of results, sampling (sample size, age, fitted control) and methods (hypothetical questions)used by the studies reveal new hypotheses, and directions in this field of research. PMID- 21653993 TI - [Different effect of sleep on working memory and skill learning: cognitive function in obstructive sleep apnea]. AB - In obstructive sleep apnea syndrome (OSAS) hypoxia and sleep deprivation lead to neuropsychological impairments. Our goal in this study to evaluate working memory and skill learning to get a complex picture about cortical and sub-cortical function in patients with sleep apnea. Twenty-one OSAS patients and 21 healthy controls participated in the study. We analyzed verbal-, vizuo-spatial, complex working memory, general skill learning and sequence specific learning separately. Our data show that complex working memory was impaired in OSAS patients, in contrary OSAS patients represented better achievement in the vizuo-spatial task compared to the control group. We found that OSAS patients showed general skill learning and implicit learning of probabilistic sequences similar to that of controls. Taken together, we found dissociation between working memory and implicit sequence learning in OSAS. These findings suggest that sleep has less influence on the functions related to sub-cortical structures like cortical functions. PMID- 21653994 TI - [Determination of psychological types of completed suicides based on the content analysis of suicide notes]. AB - INTRODUCTION: Coherently classifying the numerous information gathered by suicide research may contribute to defining the major points of this research topic, furthermore the gathered data becomes more easy to handle. Similarly, the suicide classes help a deeper understanding. METHOD: Examinees committed fatal suicide were investigated using content analysis. The obtained emotional and cognitive contents were classified by cluster algorithms. RESULTS: Having analysed suicide notes of patients completed suicide we could distinguish 5 different suicidal motives: dependent; remorse-lead - perfectionist; physically suffering - seeking for greater autonomy; aggressive-narcissistic; masochist- revenge seeking. CONCLUSION: The types reveal which personality traits and motives are the most definitive risk factors of committed suicide. Our results are affirmed by other typologies and research results. PMID- 21653995 TI - [Psychometric properties of the Hungarian version of the Cognitive Emotion Regulation Questionnaire]. AB - OBJECTIVE: The Cognitive Emotion Regulation Questionnaire (CERQ) measures conscious attentional and thinking processes that people often use to regulate their emotions. The English version of the CERQ - consisting of nine subscales: self-blame, rumination, catastrophizing, other blame, acceptance, positive refocusing, planning, positive reappraisal and putting into perspective - showed excellent psychometric properties in previous investigations and is widely used in current research and clinical practice. The present study describes the psychometric properties of the Hungarian version of the CERQ. METHOD: The forward and back-translation method was used for the adaptation. 261 undergraduate and graduate students completed the Hungarian version of the CERQ, the Shortened Beck Depression Inventory (BDI-S), the 5-item version of the WHO Well-being Index (WBS 5) and a short demographical form. RESULTS: CERQ subscales showed acceptable to very good internal consistency (Cronbach's alphas ranging from 0.68 to 0.88) and strong test-retest reliability (Pearson's correlations ranging from 0.58 to 0.85, p<0.001 ). No associations were found between the emotion regulation strategies and gender and socioeconomic status. Confirmatory and exploratory factor analysis supported the theoretical model with nine independent factors. Multiple linear regression analyses revealed significant relationships between BDI-S and self blame, acceptance, planning, positive reappraisal and catastrophizing (F=14,28 p<0,001, adjusted R2=0,320), and WBI-5 and self-blame, rumination, positive refocusing and positive reappraisal (F=5,89 p<0,001; adjusted R2=0,26). CONCLUSION: Results indicate that the Hungarian version of the CERQ is a reliable and useful instrument for assessment of cognitive emotion regulation strategies. PMID- 21653996 TI - [Puer aeternus]. AB - The social changes of the last few decades have resulted in the revaluation of the classic life-stage models. The time of finding active employment and establishing a family have been postponed, thus not supporting self reliance and undertaking adult roles. In our comprehensive study we discuss the social and demographic phenomena that have contributed to the formation of post-adolescence. We analyse the significance of optional life-patterns which appeared instead of the standard life-course, as well as the change in the criteria system of adulthood and the separation dimensions. We review the psychoanalytic and psychosocial theories of adolescence- the theory of the Erikson adolescent crisis and Marcia's psychosocial moratorium theory, together with the cognitive patterns that lie in the background of post-adolescence, and the changes in lifestyle that characterize the social adaptation of youngsters. The differences between the Peter Pan syndrome and prolonged adolescence crisis are examined in the aspect of transaction-analysis. We take account of the psychic disorders, due to which these people seek for psychiatric help. PMID- 21653997 TI - [The mystery of schizophrenia. The role of a preventive approach in the treatment of mental illness]. AB - Despite decades of research, there is still a disquieting amount of unanswered questions concerning the genesis as well as the efficient therapy of schizophrenia. The classic approaches emphasizing genetic and family influences were followed by more comprehensive ones that focus on the interplay between the cognitive and the emotional social symptoms of the illness. The demand-access matching model and, perhaps even more clearly, the cognitive appraisal model seek to integrate biological and early childhood experience factors and show their impact on cognitive as well as emotional functioning. The health-psychosis continuum model, on the other hand, offers a possible answer to the quantity quality dilemma of psychotic symptoms. Following a review of the different approaches as well as recent findings in research, the present study outlines a possible route to the development of mental illness starting from a genetically determined more general vulnerability leading to non-specific cognitive dysfunct on in early childhood on to an impaired synchronicity finally leading to a distancing from external reality in the form of overt psychotic symptoms. The second part of the study focuses on the advantages and difficulties of the different therapeutic approaches to mental illness. Based on these approaches, the study outlines an alternative preventive model that, rather than focusing on the former dichotomies lays the emphasis on the early identification and detection of non-specific childhood cognitive dysfunction and early intervention to correct these. These interventions certainly require the close cooperation between psychologists, psychiatrists and special education experts. PMID- 21653998 TI - [Psychiatric aspects of autocastration]. AB - In 1982, first time in Hungary, the author published the detailed description of a transsexual, schizophrenic patient performing autocastration and reviewed the literature. Later,in 1988, he described 2 more cases of them, this time jointly observed and treated with urologist. As since the early 1980's no publication dealing with autocastration has appeared in Hungary, the author now reviews the current literature as well as the other recent possibilities of therapeutical microreplantation and individual and family therapeutical possibilities. A part of the paper introduces the current international literature of female autocastration. PMID- 21654000 TI - Newborn Hearing Screening Program. PMID- 21653999 TI - p21-activated kinase 1: PAK'ed with potential. AB - The p21-activated kinases (PAKs) are central players in growth factor signaling networks and morphogenetic processes that control proliferation, cell polarity, invasion and actin cytoskeleton organization. This raises the possibility that interfering with PAK activity may produce significant anti-tumor activity. In this perspective, we summarize recent data concerning the contribution of the PAK family member, PAK1, in growth factor signaling and tumorigenesis. We further discuss mechanisms by which inhibition of PAK1 can arrest tumor growth and promote cell apoptosis, and the types of cancers in which PAK1 inhibition may hold promise. PMID- 21654001 TI - Early identification of hearing loss and centralized newborn hearing screening facility-the Cochin experience. AB - Significant hearing loss is one of the most common major abnormalities present at birth. If undetected, it will impede speech, language and cognitive development. Significant bilateral hearing loss is present in 1 to 3 per 1000 new born infants in the well-baby nursery population and in 2 to 4 per 100 infants in the intensive care unit population. It is an established fact that if hearing loss is present it should be detected and remediated before the baby is 6 months old. Neither universal screening nor a high risk screening, exists in majority of the hospitals in our country. In such a situation, a centralized facility catering to all hospitals in the city is a practical option. A two-stage screening protocol is projected, in which infants are screened first with otoacoustic emissions (OAE). Infants who fail the OAE are screened with auditory brainstem response (ABR). This two tier screening program (the second tier being ABR, which is more expensive) is required only for a selected few, making the program more practical and viable. It is the practicability of this program that makes it relevant for replication in other cities of the country, making it a model screening program for any developing country. PMID- 21654002 TI - Deliberate self-harm in children- a growing problem. PMID- 21654003 TI - H1N1 2009 pandemic - lessons learnt. PMID- 21654004 TI - Introduction strategy of a second dose measles containing vaccine in India. PMID- 21654005 TI - Stenotrophomonas maltophilia causing early onset neonatal sepsis. AB - Stenotrophomonas maltophilia, a multi drug resistant non fermenting Gram negative bacillus is an increasingly common nosocomial pathogen, especially in intensive care units. Comparatively few cases of infection have been reported in neonatal population. We present two cases of early onset neonatal sepsis due to S.maltophilia and a brief review of documented isolation in neonates. PMID- 21654006 TI - Partial monosomy 7q. AB - We report a case of partial monosomy 7q and partial trisomy 14q in a 4 year old male with microcephaly, prominent eyes, arched eyebrows, malformed ears and overlapping of toes. The unbalanced rearrangement resulted in monosomy of 7q33- >qter and trisomy of 14q32.2-->qter. The clinical phenotype was similar to the other cases of 7q deletion. PMID- 21654007 TI - Mosaic pentasomy X/tetrasomy X syndrome and premature ovarian failure. AB - A 16 year-old girl with pentasomy X mosaicism (47,XXX(1) 48,XXXX(12)/49,XXXXX) presented with primary amenorrhea. She had epicanthal folds, long philtrum, high arched palate, facial asymmetry, short webbed neck, low posterior hairline, mild scoliosis, cubitus valgus, mental retardation and clinodactily. She was diagnosed with osteoporosis and premature ovarian failure. PMID- 21654008 TI - Pericardial tamponade in a newborn following umbilical catheter insertion. AB - We present a case of cardiac tamponade following umbilical venous catheterization in a neonate, an uncommon, yet potentially fatal complication. Timely diagnosis by echocardiography and urgent pericardiocentesis proved lifesaving. PMID- 21654009 TI - Reversal of severe Wilson arthropathy by liver transplantation. AB - Wilson disease is associated with multisystem involvement. We describe a patient of Wilson disease with severe arthropathy, which completely reversed following liver transplantation. This is the first case report in literature describing the complete reversal of Wilson disease related arthropathy by liver transplantation. PMID- 21654011 TI - Informed consent and withdrawal of life support. PMID- 21654013 TI - Short-course antibiotics for neonatal septicemia. PMID- 21654014 TI - Lesson from fate of rejected paper. PMID- 21654016 TI - Etiology and clinical spectrum of constipation in Indian children. PMID- 21654017 TI - Advertisement of "Complan". PMID- 21654018 TI - Misleading health claims for food products need to be banned. PMID- 21654019 TI - Special section on Breath Gas Analysis. PMID- 21654020 TI - Increased concentrations of breath haloamines are not detectable in airways inflammation using SIFT-MS. AB - The haloamines, including the chloramines (H(2)NCl, HNCl(2)) and bromamine (H(2)NBr), are diffusible gases that are likely to be produced during inflammation and so may be present as markers of lung inflammation on breath. Although haloamines are quite reactive, it is possible to measure these compounds in humid samples using SIFT-MS. Until recently the quantification of haloamines in breath suffered from interference from other common breath compounds. This was overcome by heating the flow tube which removed major water cluster product ions. Despite the improvements to the method, previous attempts to measure the haloamines in breath samples from normal volunteers had found no evidence to support their presence. Since it is proposed that the haloamines may be present in higher concentrations during airways inflammation we have attempted to detect the compounds in the exhaled breath of patients with airways inflammatory conditions. On-line and off-line breath samples were analyzed; however, there was no discernable change to any of product ions when compared to ambient air or normal subjects. This suggests that despite sensitivity in the mid part per trillion range haloamines are not significantly raised in airways inflammation. PMID- 21654021 TI - Inhaled today, not gone tomorrow: pharmacokinetics and environmental exposure of volatiles in exhaled breath. AB - The chemical analysis of exhaled breath gas to assess state of health or identify disease biomarkers has gained growing interest in recent years, with advances in new technologies providing scientists and physicians with a powerful analytical arsenal with which to tackle pertinent issues. The application of these methods for pharmacokinetic studies, however, has received less attention despite its enormous potential in this field. For instance, breath gas analysis may be employed to characterize uptake and distribution within the body of exogenous volatile compounds, either from a pharmaceutical point of view, or in relation to environmental inhalation exposure. Both of these topics can benefit greatly from utilizing breath gas complementarily or as a surrogate to blood as an analytical medium, since breath sampling is non-invasive, inexhaustible, and is achievable with a frequency far exceeding that which is feasible for blood. However, because of the efficiency with which certain exogenous compounds are reflected in breath, this can also often be a significant source of confounding variables that require consideration in routine breath gas analyses. This paper provides an overview of the possibilities of breath gas analysis for pharmacokinetics and environmental exposure investigations and discusses the presence of exogenous compounds in standard breath analyses and their repercussions in terms of erroneous data interpretation. PMID- 21654022 TI - Observing the human exposome as reflected in breath biomarkers: heat map data interpretation for environmental and intelligence research. AB - Over the past decade, the research of human system biology and the interactions with the external environment has permeated all phases of environmental, medical and public health research. Similar to the fields of genomics and proteomics research, the advent of new instrumentation for measuring breath biomarkers and their associated meta-data also provide very useful, albeit complex, data structures. The biomarker research community is beginning to invoke tools from system biology to assess the impact of environmental exposures, as well as from internal health states, on the expression of suites of chemicals in exhaled breath. This new approach introduces the concept of the exposome as a complement to the genome in exploring the environment-gene interaction. In addition to answering questions regarding health status for the medical community, breath biomarker patterns are useful for assessing public health risks from environmental exposures. Furthermore, breath biomarker patterns can inform security risks from suspects via covert interrogation of blood borne chemical levels that reflect previous activities. This paper discusses how different classes of exhaled breath biomarker measurements can be used to rapidly assess patterns in complex data. We present exhaled breath data sets to demonstrate the value of the graphical 'heat map' approach for hypothesis development and subsequent guidance for stochastic and mixed effect data interpretation. We also show how to graphically interpret exhaled breath measurements of exogenous jet fuel components, as well as exhaled breath condensate measurements of endogenous chemicals. PMID- 21654023 TI - Breath ammonia levels in a normal human population study as determined by photoacoustic laser spectroscopy. AB - Photoacoustic laser spectroscopy was used as a technique to measure real-time levels of ammonia in exhaled human breath in a small, locally recruited, normal healthy population (n = 30). This yielded an average level of breath ammonia of 265 ppb, ranging from 29 to 688 ppb. Although average levels were marginally higher in male volunteers, this was not statistically significant. In addition, no correlation could be found between age, body mass index, or breath carbon dioxide levels. Monitoring of the daily routine of two individuals showed a consistent decrease in oral breath ammonia concentrations by the early afternoon (post-prandial), but was followed by a gradual increase towards late afternoon. However, in a comparison of oral and nasal breath in two volunteers, nasal breath ammonia levels were found to be significantly lower than oral levels. In addition, the daily variation was only seen in oral rather than nasal measurements which may indicate that significant background levels are predominantly of oral origin and that nasal sampling is the preferred route to eradicate this background in future studies. These results provide a healthy human breath ammonia baseline upon which other studies may be compared. PMID- 21654024 TI - The role of mathematical modeling in VOC analysis using isoprene as a prototypic example. AB - Isoprene is one of the most abundant endogenous volatile organic compounds (VOCs) contained in human breath and is considered to be a potentially useful biomarker for diagnostic and monitoring purposes. However, neither the exact biochemical origin of isoprene nor its physiological role is understood in sufficient depth, thus hindering the validation of breath isoprene tests in clinical routine. Exhaled isoprene concentrations are reported to change under different clinical and physiological conditions, especially in response to enhanced cardiovascular and respiratory activity. Investigating isoprene exhalation kinetics under dynamical exercise helps to gather the relevant experimental information for understanding the gas exchange phenomena associated with this important VOC. The first model for isoprene in exhaled breath has been developed by our research group. In this paper, we aim at giving a concise overview of this model and describe its role in providing supportive evidence for a peripheral (extrahepatic) source of isoprene. In this sense, the results presented here may enable a new perspective on the biochemical processes governing isoprene formation in the human body. PMID- 21654026 TI - The structure of heart rate asymmetry: deceleration and acceleration runs. AB - A family of new heart rate asymmetry measures is introduced, namely deceleration and acceleration runs, as well as entropic measures summarizing their distribution. We introduce the theoretical run distribution for shuffled data and use it as a reference for interpreting the results. The measures defined in the paper are applied to actual 24 h Holter ECG recordings from 87 healthy people, and it is demonstrated that the patterns of accelerations are different from those of decelerations. Acceleration runs are longer and more numerous: all runs of accelerations, with the exception of lengths 3 and 4, are more numerous than those of decelerations. These findings are reflected in the difference between the entropic measures for acceleration and deceleration runs: for 74 subjects the acceleration-related entropic parameter is greater than that of decelerations (p < 0.001). For shuffled data there is no difference in the above parameters, and there are more short runs and fewer long runs than in physiological data. The influence of the measuring equipment resolution is also discussed. PMID- 21654025 TI - 'Multi-associations': predisposed to misinterpretation of peripheral tissue oxygenation and circulation in neonates. AB - Interpretation of peripheral circulation in ill neonates is crucial but difficult. The aim was to analyse parameters potentially influencing peripheral oxygenation and circulation. In a prospective observational cohort study in 116 cardio-circulatory stable neonates, peripheral muscle near-infrared spectroscopy (NIRS) with venous occlusion was performed. Tissue oxygenation index (TOI), mixed venous oxygenation (SvO(2)), fractional oxygen extraction (FOE), fractional tissue oxygen extraction (FTOE), haemoglobin flow (Hbflow), oxygen delivery (DO(2)), oxygen consumption (VO(2)), and vascular resistance (VR) were assessed. Correlation coefficients between NIRS parameters and demographic parameters (gestational age, birth weight, age, actual weight, diameter of calf, subcutaneous adipose tissue), monitoring parameters (heart rate, arterial oxygen saturation (SaO(2)), mean blood pressure (MAP), core/peripheral temperature, central/peripheral capillary refill time) and laboratory parameters (haemoglobin concentration (Hb-blood), pCO(2)) were calculated. All demographic parameters except for Hbflow and DO(2) correlated with NIRS parameters. Heart rate correlated with TOI, SvO(2), VO(2) and VR. SaO(2) correlated with FOE/FTOE. MAP correlated with Hbflow, DO(2), VO(2) and VR. Core temperature correlated with FTOE. Peripheral temperature correlated with all NIRS parameters except VO(2). Hb blood correlated with FOE and VR. pCO(2) levels correlated with TOI and SvO(2). The presence of multiple interdependent factors associated with peripheral oxygenation and circulation highlights the difficulty in interpreting NIRS data. Nevertheless, these findings have to be taken into account when analysing peripheral oxygenation and circulation data. PMID- 21654028 TI - Facile synthesis and growth mechanism of Ni-catalyzed GaAs nanowires on non crystalline substrates. AB - GaAs nanowires (NWs) have been extensively explored for next generation electronics, photonics and photovoltaics due to their direct bandgap and excellent carrier mobility. Typically, these NWs are grown epitaxially on crystalline substrates, which could limit potential applications requiring high growth yield to be printable or transferable on amorphous and flexible substrates. Here, utilizing Ni as a catalytic seed, we successfully demonstrate the synthesis of highly crystalline, stoichiometric and dense GaAs NWs on amorphous SiO(2) substrates. Notably, the NWs are found to grow via the vapor solid-solid (VSS) mechanism with non-spherical NiGa catalytic tips and low defect densities while exhibiting a narrow distribution of diameter (21.0 +/- 3.9 nm) uniformly along the entire length of the NW (>10 um). The NWs are then configured into field-effect transistors showing impressive electrical characteristics with I(ON)/I(OFF) > 10(3), which further demonstrates the purity and crystal quality of NWs obtained with this simple synthesis technique, compared to the conventional MBE or MOCVD grown GaAs NWs. PMID- 21654027 TI - New indices for quantification of the power spectrum of heart rate variability time series without the need of any frequency band definition. AB - This paper presents a new family of indices for the frequency domain analysis of heart rate variability time series that do not need any frequency band definition. After proper detrending of the time series, a cumulated power spectrum is obtained and frequencies that contain a certain percentage of the power below them are identified, so median frequency, bandwidth and a measure of the power spectrum asymmetry are proposed to complement or improve the classical spectral indices as the ratio of the powers of LF and HF bands (LF/HF). In normal conditions the median frequency provides similar information as the classical indices, while the bandwidth and asymmetry can be complementary measures of the physiological state of the tested subject. The proposed indices seem to be a good choice for tracking changes in the power spectrum in exercise stress, and they can guide in the determination of frequency band limits in other animal species. PMID- 21654029 TI - Tailoring the surface properties and carrier dynamics in SnO2 nanowires. AB - We report a study of the role of mid-gap defect levels due to surface states in SnO(2) nanowires on carrier trapping. Ultrafast pump-probe spectroscopy provides carrier relaxation time constants that reveal the nature and positions of various defect levels due to the surface states which in turn provide details on how the carriers relax after their injection. The effect of oxygen annealing on carrier concentration is also studied through XPS valence band photoemission spectroscopy, a sensitive non-contact surface characterization technique. These measurements show that charge transfer associated with chemisorption of oxygen in different forms produces an upward band bending and leads to an increase in the depletion layer width by approximately 70 nm, thereby decreasing surface conductivity and forming the basis for the molecular sensing capability of the nanowires. PMID- 21654030 TI - Impact of carbondiimide crosslinker used for magnetic carbon nanotube mediated GFP plasmid delivery. AB - 1-Ethyl-3-(3-dimethylaminopropyl) carbondiimide hydrochloride (EDC) is commonly used as a crosslinker to help bind biomolecules, such as DNA plasmids, with nanostructures. However, EDC often remains, after a crosslink reaction, in the micro-aperture of the nanostructure, e.g., carbon nanotube. The remaining EDC shows positive green fluorescent signals and makes a nanostructure with a strong cytotoxicity which induces cell death. The toxicity of EDC was confirmed on a breast cancer cell line (MCF-7) and two leukemic cell lines (THP-1 and KG-1). The MCF-7 cells mainly underwent necrosis after treatment with EDC, which was verified by fluorescein isothiocyanate (FITC) annexin V staining, video microscopy and scanning electronic microscopy (SEM). If the EDC was not removed completely, the nanostructures with remaining EDC produced a green fluorescent background that could interfere with flow cytometry (FACS) measurement and result in false information about GFP plasmid delivery. Effective methods to remove residual EDC on macromolecules were also developed. PMID- 21654031 TI - CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow cytometric detection of acute myeloid leukaemia. AB - Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with ~ 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of ~ 0.8 nm were prepared by bovine serum albumin assisted reduction-cum stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in ~ 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of ~ 12 nm retained bright fluorescence over an extended duration of ~ a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of ~ 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of ~ 8.2% in human peripheral blood cells (PBMCs) which are CD33(low). The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells. PMID- 21654032 TI - Monolithic ZnTe-based pillar microcavities containing CdTe quantum dots. AB - Micropillars of different diameters have been prepared by focused ion beam milling out of a planar ZnTe-based cavity. The monolithic epitaxial structure, deposited on a GaAs substrate, contains CdTe quantum dots embedded in a ZnTe lambda-cavity delimited by two distributed Bragg reflectors (DBRs). The high refractive index material of the DBR structure is ZnTe, while for the low index material a short-period triple MgTe/ZnTe/MgSe superlattice is used. The CdTe quantum dots are formed by a novel Zn-induced formation process and are investigated by scanning transmission electron microscopy. Micro photoluminescence measurements show discrete optical modes for the pillars, in good agreement with calculations based on a vectorial transfer matrix method. The measured quality factor reaches a value of 3100. PMID- 21654033 TI - Facile and green fabrication of organic single-crystal hollow micro/nanostructures. AB - Under high humidity and appropriate temperature, tris (8-hydroxyquinoline) aluminum (Alq3) solid micro/nanostructures may be etched into hollow structures and still retain their crystalline structures and surface morphologies. The shapes and sizes of the hollow structures are easily adjusted by varying the experimental parameters. Throughout the entire process, water is introduced into the system instead of organic or corrosive solvents, making this method convenient and environmentally friendly; it can also be extended to application in other materials such as TCNQ. PMID- 21654034 TI - Template-assisted self-assembly of individual and clusters of magnetic nanoparticles. AB - The deliberate control over the spatial arrangement of nanostructures is the desired goal for many applications such as, for example, in data storage, plasmonics or sensor arrays. Here we present a novel method to assist the self assembly process of magnetic nanoparticles. The method makes use of nanostructured aluminum templates obtained after anodization of aluminum discs and the subsequent growth and removal of the newly formed alumina layer, resulting in a regular honeycomb-type array of hexagonally shaped valleys. The iron oxide nanoparticles, 20 nm in diameter, are spin-coated onto the surface of honeycomb nanostructured Al templates. Depending on the size, each hexagon site can host up to 30 nanoparticles. These nanoparticles form clusters of different arrangements within the valleys, such as collars, chains and hexagonally closed islands. Ultimately, it is possible to isolate individual nanoparticles. The strengths of the magnetic interaction between particles in a cluster are probed using the memory effect known from the coupled state in superspin glass systems. PMID- 21654035 TI - Three-dimensional nano-networked P3MT/PCBM solar cells. AB - The bulk heterojunction has been widely applied for the construction of efficient organic polymer solar cells. Typically, the heterojunction is formed as a result of the phase segregation of the donor and acceptor mixture. Here, we report a study in which, differently than the common annealing approach, efficient bulk heterojunction solar cells were fabricated using electrochemically grown 3 dimension (3D) poly-3-methyl-thiophene (P3MT) nano-networked structures. Porous and interconnected P3MT (donor) nano-structures were first electrochemically grown on a transparent Au electrode; then PCBM (acceptor) was infiltrated into the openings of the 3D P3MT nano-structure structure to form the bulk heterojunction. With this approach, efficient exciton dissociation can be realized, and importantly, excellent continuity of both donor and acceptor phases can be accomplished; and proper connection of each phase to the corresponding electrode is insured, therefore allowing effective collection of the free carriers. A power conversion efficiency (PCE) of 3.0% has been demonstrated. PMID- 21654036 TI - Thio-glucose bound gold nanoparticles enhance radio-cytotoxic targeting of ovarian cancer. AB - The treatment of ovarian cancer has traditionally been intractable, and required novel approaches to improve therapeutic efficiency. This paper reports that thio glucose bound gold nanoparticles (Glu-GNPs) can be used as a sensitizer to enhance ovarian cancer radiotherapy. The human ovarian cancer cells, SK-OV-3, were treated by gold nanoparticles (GNPs) alone, irradiation alone, or GNPs in addition to irradiation. Cell uptake was assayed using inductively coupled plasma atomic emission spectroscopy (ICP-AES), while cytotoxicity induced by radiotherapy was measured using both 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide and clonogenic assays. The presence of reactive oxygen species (ROS) was determined using CM-H2-DCFDA confocal microscopy and cell apoptosis was determined by an Annexin V-FITC/propidium iodide (PI) kit with flow cytometry. The cells treated by Glu-GNPs resulted in an approximate 31% increase in nanoparticle uptake compared to naked GNPs (p < 0.005). Compared to the irradiation alone treatment, the intracellular uptake of Glu-GNPs resulted in increased inhibition of cell proliferation by 30.48% for 90 kVp and 26.88% for 6 MV irradiation. The interaction of x-ray radiation with GNPs induced elevated levels of ROS production, which is one of the mechanisms by which GNPs can enhance radiotherapy on ovarian cancer. PMID- 21654037 TI - In vivo deployment of mechanically adaptive nanocomposites for intracortical microelectrodes. AB - We recently introduced a series of stimuli-responsive, mechanically adaptive polymer nanocomposites. Here, we report the first application of these bio inspired materials as substrates for intracortical microelectrodes. Our hypothesis is that the ideal electrode should be initially stiff to facilitate minimal trauma during insertion into the cortex, yet become mechanically compliant to match the stiffness of the brain tissue and minimize forces exerted on the tissue, attenuating inflammation. Microprobes created from mechanically reinforced nanocomposites demonstrated a significant advantage compared to model microprobes composed of neat polymer only. The nanocomposite microprobes exhibit a higher storage modulus (E' = ~5 GPa) than the neat polymer microprobes (E' = ~2 GPa) and can sustain higher loads (~12 mN), facilitating penetration through the pia mater and insertion into the cerebral cortex of a rat. In contrast, the neat polymer microprobes mechanically failed under lower loads (~7 mN) before they were capable of insertion into cortical tissue. Further, we demonstrated the material's ability to morph while in the rat cortex to more closely match the mechanical properties of the cortical tissue. Nanocomposite microprobes that were implanted into the rat cortex for up to eight weeks demonstrated increased cell density at the microelectrode-tissue interface and a lack of tissue necrosis or excessive gliosis. This body of work introduces our nanocomposite-based microprobes as adaptive substrates for intracortical microelectrodes and potentially for other biomedical applications. PMID- 21654039 TI - The effects of blood vessels on electrocorticography. AB - Electrocorticography, primarily used in a clinical context, is becoming increasingly important for fundamental neuroscientific research, as well as for brain-computer interfaces. Recordings from these implanted electrodes have a number of advantages over non-invasive recordings in terms of band width, spatial resolution, smaller vulnerability to artifacts and overall signal quality. However, an unresolved issue is that signals vary greatly across electrodes. Here, we examine the effect of blood vessels lying between an electrode and the cortex on signals recorded from subdural grid electrodes. Blood vessels of different sizes cover extensive parts of the cortex causing variations in the electrode-cortex connection across grids. The power spectral density of electrodes located on the cortex and electrodes located on blood vessels obtained from eight epilepsy patients is compared. We find that blood vessels affect the power spectral density of the recorded signal in a frequency-band-specific way, in that frequencies between 30 and 70 Hz are attenuated the most. Here, the signal is attenuated on average by 30-40% compared to electrodes directly on the cortex. For lower frequencies this attenuation effect is less pronounced. We conclude that blood vessels influence the signal properties in a non-uniform manner. PMID- 21654040 TI - A new approach to account for the medium-dependent effect in model-based dose calculations for kilovoltage x-rays. AB - This study presents a new approach to accurately account for the medium-dependent effect in model-based dose calculations for kilovoltage (kV) x-rays. This approach is based on the hypothesis that the correction factors needed to convert dose from model-based dose calculations to absorbed dose-to-medium depend on both the attenuation characteristics of the absorbing media and the changes to the energy spectrum of the incident x-rays as they traverse media with an effective atomic number different than that of water. Using Monte Carlo simulation techniques, we obtained empirical medium-dependent correction factors that take both effects into account. We found that the correction factors can be expressed as a function of a single quantity, called the effective bone depth, which is a measure of the amount of bone that an x-ray beam must penetrate to reach a voxel. Since the effective bone depth can be calculated from volumetric patient CT images, the medium-dependent correction factors can be obtained for model-based dose calculations based on patient CT images. We tested the accuracy of this new approach on 14 patients for the case of calculating imaging dose from kilovoltage cone-beam computed tomography used for patient setup in radiotherapy, and compared it with the Monte Carlo method, which is regarded as the 'gold standard'. For all patients studied, the new approach resulted in mean dose errors of less than 3%. This is in contrast to current available inhomogeneity corrected methods, which have been shown to result in mean errors of up to -103% for bone and 8% for soft tissue. Since there is a huge gain in the calculation speed relative to the Monte Carlo method (~two orders of magnitude) with an acceptable loss of accuracy, this approach provides an alternative accurate dose calculation method for kV x-rays. PMID- 21654038 TI - Use of a Bayesian maximum-likelihood classifier to generate training data for brain-machine interfaces. AB - Brain-machine interface decoding algorithms need to be predicated on assumptions that are easily met outside of an experimental setting to enable a practical clinical device. Given present technological limitations, there is a need for decoding algorithms which (a) are not dependent upon a large number of neurons for control, (b) are adaptable to alternative sources of neuronal input such as local field potentials (LFPs), and (c) require only marginal training data for daily calibrations. Moreover, practical algorithms must recognize when the user is not intending to generate a control output and eliminate poor training data. In this paper, we introduce and evaluate a Bayesian maximum-likelihood estimation strategy to address the issues of isolating quality training data and self-paced control. Six animal subjects demonstrate that a multiple state classification task, loosely based on the standard center-out task, can be accomplished with fewer than five engaged neurons while requiring less than ten trials for algorithm training. In addition, untrained animals quickly obtained accurate device control, utilizing LFPs as well as neurons in cingulate cortex, two non traditional neural inputs. PMID- 21654041 TI - The performance of monotonic and new non-monotonic gradient ascent reconstruction algorithms for high-resolution neuroreceptor PET imaging. AB - Iterative expectation maximization (EM) techniques have been extensively used to solve maximum likelihood (ML) problems in positron emission tomography (PET) image reconstruction. Although EM methods offer a robust approach to solving ML problems, they usually suffer from slow convergence rates. The ordered subsets EM (OSEM) algorithm provides significant improvements in the convergence rate, but it can cycle between estimates converging towards the ML solution of each subset. In contrast, gradient-based methods, such as the recently proposed non-monotonic maximum likelihood (NMML) and the more established preconditioned conjugate gradient (PCG), offer a globally convergent, yet equally fast, alternative to OSEM. Reported results showed that NMML provides faster convergence compared to OSEM; however, it has never been compared to other fast gradient-based methods, like PCG. Therefore, in this work we evaluate the performance of two gradient based methods (NMML and PCG) and investigate their potential as an alternative to the fast and widely used OSEM. All algorithms were evaluated using 2D simulations, as well as a single [(11)C]DASB clinical brain dataset. Results on simulated 2D data show that both PCG and NMML achieve orders of magnitude faster convergence to the ML solution compared to MLEM and exhibit comparable performance to OSEM. Equally fast performance is observed between OSEM and PCG for clinical 3D data, but NMML seems to perform poorly. However, with the addition of a preconditioner term to the gradient direction, the convergence behaviour of NMML can be substantially improved. Although PCG is a fast convergent algorithm, the use of a (bent) line search increases the complexity of the implementation, as well as the computational time involved per iteration. Contrary to previous reports, NMML offers no clear advantage over OSEM or PCG, for noisy PET data. Therefore, we conclude that there is little evidence to replace OSEM as the algorithm of choice for many applications, especially given that in practice convergence is often not desired for algorithms seeking ML estimates. PMID- 21654042 TI - TIPS bilateral noise reduction in 4D CT perfusion scans produces high-quality cerebral blood flow maps. AB - Cerebral computed tomography perfusion (CTP) scans are acquired to detect areas of abnormal perfusion in patients with cerebrovascular diseases. These 4D CTP scans consist of multiple sequential 3D CT scans over time. Therefore, to reduce radiation exposure to the patient, the amount of x-ray radiation that can be used per sequential scan is limited, which results in a high level of noise. To detect areas of abnormal perfusion, perfusion parameters are derived from the CTP data, such as the cerebral blood flow (CBF). Algorithms to determine perfusion parameters, especially singular value decomposition, are very sensitive to noise. Therefore, noise reduction is an important preprocessing step for CTP analysis. In this paper, we propose a time-intensity profile similarity (TIPS) bilateral filter to reduce noise in 4D CTP scans, while preserving the time-intensity profiles (fourth dimension) that are essential for determining the perfusion parameters. The proposed TIPS bilateral filter is compared to standard Gaussian filtering, and 4D and 3D (applied separately to each sequential scan) bilateral filtering on both phantom and patient data. Results on the phantom data show that the TIPS bilateral filter is best able to approach the ground truth (noise-free phantom), compared to the other filtering methods (lowest root mean square error). An observer study is performed using CBF maps derived from fifteen CTP scans of acute stroke patients filtered with standard Gaussian, 3D, 4D and TIPS bilateral filtering. These CBF maps were blindly presented to two observers that indicated which map they preferred for (1) gray/white matter differentiation, (2) detectability of infarcted area and (3) overall image quality. Based on these results, the TIPS bilateral filter ranked best and its CBF maps were scored to have the best overall image quality in 100% of the cases by both observers. Furthermore, quantitative CBF and cerebral blood volume values in both the phantom and the patient data showed that the TIPS bilateral filter resulted in realistic mean values with a smaller standard deviation than the other evaluated filters and higher contrast-to-noise ratios. Therefore, applying the proposed TIPS bilateral filtering method to 4D CTP data produces higher quality CBF maps than applying the standard Gaussian, 3D bilateral or 4D bilateral filter. Furthermore, the TIPS bilateral filter is computationally faster than both the 3D and 4D bilateral filters. PMID- 21654043 TI - A methodology for automatic intensity-modulated radiation treatment planning for lung cancer. AB - In intensity-modulated radiotherapy (IMRT), the quality of the treatment plan, which is highly dependent upon the treatment planner's level of experience, greatly affects the potential benefits of the radiotherapy (RT). Furthermore, the planning process is complicated and requires a great deal of iteration, and is often the most time-consuming aspect of the RT process. In this paper, we describe a methodology to automate the IMRT planning process in lung cancer cases, the goal being to improve the quality and consistency of treatment planning. This methodology (1) automatically sets beam angles based on a beam angle automation algorithm, (2) judiciously designs the planning structures, which were shown to be effective for all the lung cancer cases we studied, and (3) automatically adjusts the objectives of the objective function based on a parameter automation algorithm. We compared treatment plans created in this system (mdaccAutoPlan) based on the overall methodology with plans from a clinical trial of IMRT for lung cancer run at our institution. The 'autoplans' were consistently better, or no worse, than the plans produced by experienced medical dosimetrists in terms of tumor coverage and normal tissue sparing. We conclude that the mdaccAutoPlan system can potentially improve the quality and consistency of treatment planning for lung cancer. PMID- 21654044 TI - An octahedral shear strain-based measure of SNR for 3D MR elastography. AB - A signal-to-noise ratio (SNR) measure based on the octahedral shear strain (the maximum shear strain in any plane for a 3D state of strain) is presented for magnetic resonance elastography (MRE), where motion-based SNR measures are commonly used. The shear strain, gamma, is directly related to the shear modulus, MU, through the definition of shear stress, tau = MUgamma. Therefore, noise in the strain is the important factor in determining the quality of motion data, rather than the noise in the motion. Motion and strain SNR measures were found to be correlated for MRE of gelatin phantoms and the human breast. Analysis of the stiffness distributions of phantoms reconstructed from the measured motion data revealed a threshold for both strain and motion SNR where MRE stiffness estimates match independent mechanical testing. MRE of the feline brain showed significantly less correlation between the two SNR measures. The strain SNR measure had a threshold above which the reconstructed stiffness values were consistent between cases, whereas the motion SNR measure did not provide a useful threshold, primarily due to rigid body motion effects. PMID- 21654045 TI - Structure and dynamics determined by neutron and x-ray scattering. PMID- 21654046 TI - Contribution of molecular dynamics simulations and ab initio calculations to the interpretation of Mg K-edge experimental XANES in K(2)O-MgO-3SiO(2) glass. AB - The structural environment of Mg in a K-bearing silicate glass of composition K(2)MgSi(3)O(8) is investigated by x-ray absorption near-edge structure (XANES) spectroscopy at the Mg K-edge. XANES calculations are performed using a plane wave electronic structure code, and a structural model obtained by classical molecular dynamics coupled to ab initio relaxation. Bond valence theory is used to validate plausible environments within the structural models. Comparison between the experimental and calculated spectra enables us to conclude that the Mg atoms are located in distorted tetrahedral sites. Site distortions are found to be correlated to the theoretical shift of the XANES edge position. PMID- 21654048 TI - Morphology of thin nanocomposite films of asymmetric diblock copolymer and magnetite nanoparticles. AB - Thin self-assembled nanocomposite films of an asymmetric diblock copolymer and nanoparticles are fabricated. The morphologies of the films of the diblock copolymer poly(styrene-block-n-butyl methacrylate), P(Sd-b-BMA), with different volume fractions of large magnetite Fe(3)O(4) nanoparticles are studied before and after annealing. Neutron reflectometry reveals remarkable evidence that confining asymmetric copolymer to a limit of two layers forces the film, after the annealing, to form a mixed cylindrical-lamellar two-layer structure. This complex morphology is very stable and is preserved after the incorporation of nanoparticles up to 10% volume fraction. The other striking result is that the monodispersed nanoparticles with affinity to the polystyrene (PS) domain and with a size of 10 nm, which is close to the size of the PS chains, are assembled by the diblock copolymer matrix, so the distribution of the nanoparticles is reduced solely to the PS domain of the film. Our studies demonstrate that for asymmetric block copolymers in thin film geometry the self-assembly is strongly influenced by the interfacial and surface energies of the blocks and substrate. PMID- 21654047 TI - A dipole polarizable potential for reduced and doped CeO(2) obtained from first principles. AB - In this paper we present the parameterization of a new interionic potential for stoichiometric, reduced and doped CeO(2). We use a dipole polarizable potential (DIPPIM: the dipole polarizable ion model) and optimize its parameters by fitting them to a series of density functional theory calculations. The resulting potential was tested by calculating a series of fundamental properties for CeO(2) and by comparing them against experimental values. The values for all the calculated properties (thermal and chemical expansion coefficients, lattice parameters, oxygen migration energies, local crystalline structure and elastic constants) are within 10-15% of the experimental ones, an accuracy comparable to that of ab initio calculations. This result suggests the use of this new potential for reliably predicting atomic scale properties of CeO(2) in problems where ab initio calculations are not feasible due to their size limitations. PMID- 21654049 TI - In situ observation of cluster formation during nanoparticle solution casting on a colloidal film. AB - We present a real-time study of the nanostructuring and cluster formation of gold nanoparticles deposited in aqueous solution on top of a pre-structured polystyrene colloidal thin film. Cluster formation takes place at different length scales, from the agglomerations of the gold nanoparticles to domains of polystyrene colloids. By combining in situ imaging ellipsometry and microbeam grazing incidence small-angle x-ray scattering, we are able to identify different stages of nanocomposite formation, namely diffusion, roughness increase, layer build-up and compaction. The findings can serve as a guideline for nanocomposite tailoring by solution casting. PMID- 21654050 TI - In situ studies of mass transport in liquid alloys by means of neutron radiography. AB - When in situ techniques became available in recent years this led to a breakthrough in accurately determining diffusion coefficients for liquid alloys. Here we discuss how neutron radiography can be used to measure chemical diffusion in a ternary AlCuAg alloy. Neutron radiography hereby gives complementary information to x-ray radiography used for measuring chemical diffusion and to quasielastic neutron scattering used mainly for determining self-diffusion. A novel Al(2)O(3) based furnace that enables one to study diffusion processes by means of neutron radiography is discussed. A chemical diffusion coefficient of Ag against Al around the eutectic composition Al(68.6)Cu(13.8)Ag(17.6) at.% was obtained. It is demonstrated that the in situ technique of neutron radiography is a powerful means to study mass transport properties in situ in binary and ternary alloys that show poor x-ray contrast. PMID- 21654051 TI - Hydrogen release from sodium alanate observed by time-resolved neutron backscattering. AB - Innermolecular motion in Na(3)AlH(6) gives rise to a Lorentzian spectrum with a wavenumber-independent width of about 1 ueV at 180 degrees C, which is probably due to the rotation of AlH(6) tetrahedra. There is no such quasielastic line in NaAlH(4) or NaH. Based on this finding, time-resolved measurements on the neutron backscattering spectrometer SPHERES were used to monitor the decomposition kinetics of sodium alanate, [Formula: see text] NaH. Both reaction steps were found to be accelerated by autocatalysis, most likely at the surfaces of Na(3)AlH(6) and NaH crystallites. PMID- 21654052 TI - Magnetic spin structure of pyroxene-type MnGeO(3). AB - Polycrystalline MnGeO(3) material was synthesized at 1473 K and ambient pressures using ceramic sintering techniques. Under these conditions the pyroxene-type compound crystallizes in the orthorhombic modification with space group Pbca, as determined from the refinement of the neutron diffraction data. The monoclinic modification, space group C 2/c, was also present at a level of 8.8(4) wt% and the magnetic structures for the two polymorphs at low temperatures have been found simultaneously. The monoclinic form orders magnetically below 34 K; the spin structure can be described using k = (0, 0, 0) in the magnetic space group C 2'/c, having an antiferromagnetic spin arrangement within and between the chains of M1 and M2 sites. The orthorhombic phase of MnGeO(3) transforms to a magnetically ordered state with k = (0, 0, 0) and magnetic space group Pb'c'a below 12 K. Spins on M1 sites are aligned along the crystallographic a-axis with a slight non-collinear antiferromagnetic spin arrangement with and between the M1 chains. Spins on M2 sites are also antiferromagnetically coupled; however, one of the three different M1-M2 superexchange pathways within the band of M1 and M2 sites displays a ferromagnetic interaction, while the other two allow antiferromagnetic interaction. PMID- 21654053 TI - High-dose atorvastatin treatment in patients with peripheral arterial disease: effects on platelet aggregation, blood rheology and plasma homocysteine. AB - BACKGROUND: Statins are used for the treatment of hypercholesterolemia. Although they are well known to have pleiotropic effects, their dose-dependent influence on platelet aggregation, hemorheologic properties and the plasma levels of homocysteine in patients with peripheral arterial disease (PAD) has not been thoroughly investigated so far. METHODS AND RESULTS: From a total of 100 patients with PAD 48 patients were randomized to a treatment with atorvastatin 80 mg/d for six months, and 52 patients served as controls who continued their medication including statins in lower doses. At baseline and at six months' follow up we assessed platelet aggregation upon stimulation with ADP, collagen and epinephrine using light transmission aggregometry. Furthermore, we determined major hemorheologic variables as well as the plasma levels of homocysteine, folic acid, and vitamin B6 and B12. No patient had obtained folic acid or B vitamin supplement. Platelet aggregation upon agonist-induced stimulation did not differ between patients under high-dose atorvastatin therapy and controls at baseline and after six months (p > 0.05). All hemorheologic parameters (plasma viscosity, red cell aggregation, whole blood viscosity, hematocrit, platelets, leucocytes) measured at baseline and after six months were not significantly different between both groups, too. After therapy with 80 mg atorvastatin homocysteine levels were significantly elevated as compared with baseline values (p = 0.0007), whereas levels remained unchanged in the control group. Folic acid levels were higher in the patients receiving high-dose atorvastatin as compared with controls both at baseline (p = 0.002) and at six months' follow up (p = 0.034). No significant difference in vitamin B6 and B12 levels both at baseline and after six months could be detected in either group. CONCLUSIONS: Treatment with 80 mg atorvastatin did not affect platelet aggregation and major hemorheologic parameters. The finding of an increase of homocysteine plasma levels in the presence of rather elevated levels of folic acid needs further investigation. PMID- 21654054 TI - Optimal haematocrit in subjects with normal haemoglobin genotype (HbAA), sickle cell trait (HbAS), and homozygous sickle cell disease (HbSS). AB - The determination of an optimal haematocrit (H0) has important clinical implications if such a level can be attained, and more importantly, maintained. This is defined as a haematocrit level, above or below which oxygen delivery is deleteriously affected. This study is designed to determine an optimal haematocrit in normal (AA), sickle cell trait (AS) and sickle cell disease (SS) subjects. Twenty-seven apparently healthy subjects having normal haemoglobin genotype, 24 with sickle cell trait and 42 with homozygous sickle cell disease were recruited into the study. Whole blood viscosity (WBV) was measured by a Wells Brookfield Cone and Plate Viscometer at a shear rate of 230 sec-1. Haematocrit was determined by an AC.Tron Coulter Counter. The optimal haematocrit was calculated as the inverse of a constant, K, which was derived from the haematocrit and viscosity data. Our findings showed that the H0 varied significantly among the 3 haemoglobin genotypes, in the order AA vs SS and AS vs SS. Additionally, the data indicated an increased H0 in subjects with sickle cell trait, suggesting a possible impairment in oxygen delivery in these individuals. PMID- 21654055 TI - Endurance running trial in tropical environment: a blood rheological study. AB - PURPOSE: The aim of this study was to clarify whether exercising in a tropical climate induces blood rheology alterations despite ad libitum hydration. METHODS: Hematological, biochemical and hemorheological changes were investigated in young healthy adults (N = 9 men, 20.7 +/- 0.8 yrs) after a 10-km race in hot and humid conditions. Subjects' maximal aerobic abilities were tested using a maximal ramp exercise. Blood was sampled at rest (TR), at the end of the race (TEx), and after 24 hours of recovery (T24). Ad libitum hydration was allowed during the race. Blood viscosity (etab), red blood cell deformability (EI), aggregation (AI) and disaggregation shear rate (gamma) were measured. RESULTS: Hematocrit, hemoglobin and plasma concentration of chlorine, sodium and potassium did not change in response to exercise. No functional consequence was observed on RBC deformability since EI remained unchanged. Percentages of echinocytes, schizocytes and stomatocytes remained in the subclinical range at all times. AI, gamma and etab did not present change. CONCLUSION: Running exercise in tropical climate with ad libitum hydration does not alter the main rheological properties of blood. PMID- 21654056 TI - Comparison of soluble CD40L concentrations and release capacities in apheresis and prestorage pooled platelet concentrates. AB - INTRODUCTION: Soluble CD40L (sCD40L) is expressed by platelets and is involved in the stabilization of arterial thrombi. Additionally, it was shown that sCD40L accumulation occurred in stored blood products triggering adverse transfusion reactions like TRALI. To study the influence of the preparation technique on sCD40L accumulation and platelet function we examined CD40L concentrations in prestorage pooled platelet concentrates compared to apheresis products. In addition, sCD40L release capacity was determined as a marker for platelet viability. MATERIAL AND METHODS: sCD40L concentrations were determined in prestorage pooled platelet concentrates (n = 8) and in platelet apheresis concentrates (n = 8) before and after platelet stimulation (recalcification and clot formation) at day 1, 3 and 5 under routine storage conditions. sCD40L concentrations were determined by a commercially available ELISA kit. RESULTS: sCD40L concentrations in storage medium increased over time in prestorage pooled platelet concentrates (from 1,185 pg/mL +/- 87 pg/mL at day 1 to 4,464 pg/mL +/- 212 pg/mL at day 5) as well as in apheresis products (from 581 pg/mL +/- 124 pg/mL at day 1 to 2,718 pg/mL +/- 154 pg/mL at day 5) in a hyperbolic manner. Recalcification and clot formation caused an increase in sCD40L concentrations (for example 3,842 pg/mL +/- 769 pg/mL before platelet activation to 31,219 pg/mL +/- 2,063 pg/mL after platelet activation at day 3), and we observed comparable release capacities for both preparation techniques, however, decreasing over storage time up to 50% (day 5) of the respective control value (day 1). CONCLUSIONS: Amounts of sCD40L accumulation and release capacity during storage of platelet concentrates were dependent on storage duration, but showed no relevant differences regarding the preparation technique. After 5 days of storage, CD40L basal levels were increased, in contrast sCD40L release capacity was decreased. By recalcification and clot formation sCD40L release capacity could be easily induced and is assumed to be used as a marker for platelet viability. PMID- 21654057 TI - Erythrocyte aggregation in patients with systemic lupus erythematosus. AB - Systemic Lupus Erythematosus (SLE) is an autoimmune, chronic inflammatory, non organ specific disease. SLE patients present a high prevalence of thrombotic and arteriosclerotic disease. The aim of the present work was to study the erythrocyte aggregation kinetics, and the effect of plasma factors, namely, immunoglobulin and fibrinogen concentration, as well as cell factors such as deformability and erythrocyte membrane lipid fluidity on the erythrocyte aggregation, in SLE patients and healthy controls. The results show that SLE patients red blood cells aggregate at higher rate and the aggregates size are also greater than controls due to an increase of immunoglobulin and plasma fibrinogen. The negative correlation between aggregation parameters and rigidity index could point out that the altered deformability diminishes the erythrocyte aggregation. Correlation between rigidity index and anisotropy suggests that the decrease of membrane lipid fluidity might be a cause of deformability decrease. The erythrocyte aggregation increase in these patients could induce a decreased flow that might contribute to the thromboembolic process present in SLE patients. PMID- 21654058 TI - Hemorheological profile in primary Sjogren's syndrome: a case-control study. AB - Rheological blood behavior in primary Sjogren's syndrome (SS) has been scarcely investigated. We evaluated the rheological profile (blood viscosity, plasma viscosity, erythrocyte deformability, erythrocyte aggregation, erythrocyte aggregation time and erythrocyte disaggregation threshold) along with fibrinogen, high-sensitive C reactive protein, plasma lipids, immunoglobulins, total proteins and erythrocyte sedimentation rate in 22 patients with primary SS (2 males, 20 females, aged 58 +/- 9 years) and in 22 healthy volunteers (3 males, 19 females, aged 57 +/- 5 years). Patients showed statistically higher plasma viscosity, erythrocyte sedimentation rate and G immunoglobulin (IgG) levels and lower total cholesterol than controls (p = 0.006, p = 0.023, p = 0.034, p = 0.036, respectively). Three patients with extraglandular involvement showed the highest plasma viscosity values: 1.98 cP, 1.70 cP and 1.65 cP, respectively. No differences were observed for the other rheological parameters analyzed. In a multivariate regression analysis, only fibrinogen, triglycerides and IgG were independent determinants for plasma viscosity values (beta coefficient: 0.335; p = 0.001; beta coefficient: 0.242; p = 0.019; beta coefficient: 0.660; p < 0.001, respectively). Our results indicate that patients with primary SS show increased plasma viscosity, mostly related with IgG levels without other alterations in the rheological profile. Further research with a larger sample size achieved by multicenter studies would be desirable. PMID- 21654059 TI - Measurement of red blood cell aggregation in disposable capillary tubes. AB - A new method is described in this paper that allows measurement of red blood cell (RBC) aggregation indexes in disposable glass tubes within minutes. Light transmission through the RBC suspension filled into a microhematocrit capillary at stasis is recorded during RBC aggregation; a novel method assures an initial dispersion of aggregates in the capillary. The resulting light transmittance-time data are analyzed to calculate various parameters. Measurement of erythrocyte sedimentation rate (ESR) and RBC aggregation using well established methods and the newly developed capillary tube aggregometer in blood samples with a wide range of RBC aggregation indicated significant correlations between these parameters. Additionally, light transmittance during complete disaggregation allows estimating hematocrit, thereby enabling hematocrit correction of the measured and calculated parameters. The newly developed capillary tube RBC aggregometer is suitable for use as a method to rapidly monitor disease activity and the acute phase response, especially at the point-of-care (e.g., health care facilities, physician's office) and for field studies. PMID- 21654060 TI - Novel anti-inflammatory compound SEN1176 alleviates behavioral deficits induced following bilateral intrahippocampal injection of aggregated amyloid-beta1-42. AB - Behavioral effects of a novel anti-inflammatory SEN1176 were investigated. This pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine suppresses amyloid-beta (Abeta)1 42-induced macrophage production of nitric oxide, TNF-alpha, IL-1beta, and IL-6 in a dose-dependent fashion, an activity profile consistent with SEN1176 being a neuroinflammation inhibitor. Using male Sprague-Dawley rats, SEN1176 was examined relative to detrimental behavioral effects induced following bilateral intrahippocampal (IH) injections of aggregated Abeta1-42. The rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement, enabling measurement of parameters of operant performance that reflect aspects of learning and memory. Under the ALCR schedule, orally administered SEN1176 at 5, 20, or 30 mg/kg was effective in reducing the behavioral deficit caused by bilateral IH aggregated Abeta1-42 injections in a dose-related manner over a 90-day treatment period. SEN1176 at 20 and 30 mg/kg significantly reduced lever switching errors and, at doses of 5, 10, and 30 mg/kg, significantly reduced incorrect lever perseverations, indicating a reduction of the behavioral deficit induced as a result of inflammation following IH Abeta1-42 injections. When treatment with SEN1176 was instigated 30 days after IH Abeta1-42 injections, it resulted in progressive protection, and withdrawal of SEN1176 treatment 60 days after IH Abeta1-42 injections revealed partial retention of the protective effect. SEN1176 also significantly reduced numbers of activated astrocytes adjacent to the aggregated Abeta1-42 injection sites. These results indicate the potential of SEN1176 for alleviating chronic neuroinflammatory processes related to brain Abeta deposition that affect learning and memory in Alzheimer's disease. PMID- 21654061 TI - Swallowing intentional off-state in aging and Alzheimer's disease: preliminary study. AB - Frontal cortical activation is elicited when subjects have been instructed not to initiate a sensorimotor task. The goal of this preliminary fMRI study was to examine BOLD response to a "Do Not Swallow" instruction (an intentional "off state") in the context of other swallowing tasks in 3 groups of participants (healthy young, healthy old, and early Alzheimer's disease (AD)). Overall, the older group had larger, bilaterally active clusters in the cortex, including the dorsomedial prefrontal cortex during the intentional swallowing off-state; this region is commonly active in response inhibition studies. Disease-related differences were evident where the AD group had significantly greater BOLD response in the insula/operculum than the old. These findings have significant clinical implications for control of swallowing across the age span and in neurodegenerative disease. Greater activation in the insula/operculum for the AD group supports previous studies where this region is associated with initiating swallowing. The AD group may have required more effort to "turn off" swallowing centers to reach the intentional swallowing off-state. PMID- 21654062 TI - APOE and AbetaPP gene variation in cortical and cerebrovascular amyloid-beta pathology and Alzheimer's disease: a population-based analysis. AB - Cortical and cerebrovascular amyloid-beta (Abeta) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) epsilon4 is a major genetic modulator of Abeta deposition and AD risk. Variants of the amyloid-beta protein precursor (AbetaPP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and AbetaPP variants in cortical and cerebrovascular Abeta deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged >= 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the epsilon4 allele with cortical (p = 4.91 * 10-17) and cerebrovascular (p = 9.87 * 10-11) Abeta deposition as well as with NIA-RI AD (p = 1.62 * 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the AbetaPP locus. In single SNP or haplotype analyses there were no statistically significant AbetaPP locus associations with cortical or cerebrovascular Abeta deposition or with NIA-RI AD. We sequenced the promoter of the AbetaPP gene in 40 subjects with very high Abeta deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular Abeta depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE epsilon4 variant. Promoter mutations or common allelic variation in the AbetaPP gene do not have a major contribution to cortical or cerebrovascular Abeta deposition, or very late-onset AD in this Finnish population based study. PMID- 21654063 TI - Alveolar bone regeneration in post-extraction socket: a review of materials to postpone dental implant. AB - Tooth extraction usually involves alveolar bone loss and reduction in height and width of the remaining alveolar socket, owing to the physiological bone resorption. This occurrence may perform an inadequate bone profile, that make difficult orthodontic applications, compromising the functional and aesthetic restoration of dental implants. The present review will provide an update on the biological and clinical profile of materials currently in use and those under investigation, in the recovering of bone margins of edentulous sockets. PMID- 21654064 TI - Osteoblast differentiation and disinfection induced by nitrogen plasma-treated surfaces. AB - Plasma technology is widely employed to tailor the surface chemistry of polymeric biomaterials. In this work, nitrogen-containing functional groups were generated on a polymer surface by N2 plasma immersion ion implantation (PIII). We evaluated the abilities of the resulting surface to inhibit bacterial growth and to enhance osteoblast differentiation from the perspective of bone tissue engineering. Our results demonstrate that the N2 PIII-treated polymer surface exhibits antibacterial properties against Escherichia coli. Moreover, the N2 PIII-treated polymer surface has the ability to enhance differentiation of osteoblasts. N2 PIII-treated polymer surface may therefore be useful in bone tissue engineering. PMID- 21654065 TI - Comparison of electrode materials for the use of retinal prosthesis. AB - Retinal implants may provide vision for people suffering from photoreceptor degeneration caused by different eye diseases. Electrode size in retinal implant should be decreased in order to increase the resolution provided by the implant. We defined electric properties of five different electrode materials (Au, Ir-b, Ti, TiN, Pt-b) widely used in retinal prostheses. The comparison of different electrode materials requires that the electrical properties of different materials are defined using exactly the same measurement conditions and devices. Existing studies about electrode material properties are often made using slightly different measurement parameters or electrode processing conditions making the comparison between different materials difficult. Here, the electrochemical characterization included cyclic voltammetry and electrochemical impedance spectroscopy. Ir-b and Pt-b had greater charge injection capacity than other materials. The fabricated material samples showed that in this experiment the electrode diameter larger than 200 MUm should be used to suppress irreversible reaction of stimulus electrodes with the needed stimulus currents. Thus, either we have to find novel electrode materials or surface treatment methods to decrease the electrode area providing increased electrode and pixel number of the prosthesis or we have to show that stimulus currents smaller than 40 MUA are enough to induce phosphenes. PMID- 21654066 TI - Electrospun chitosan-gelatin nanofiberous scaffold: fabrication and in vitro evaluation. AB - In this study, chitosan and gelatin solutions were blended at five different ratios. Samples were fed into electrospinning apparatus to produce non-woven nanofibrous mats. Scanning electron microscopy (SEM) showed that the low viscosity sample with 30% chitosan and 70% gelatin (sample 30/70) formed the least amount of beads and droplets and yielded fibers with the highest morphological uniformity. To examine the effect of processing parameters on fibers morphology and nanofibers diameter, flow rate, voltage and distance between needle to the collector were changed in the sample 30/70. SEM revealed that high voltages (25 kV) and flow rates (1.5 ml.h-1) decrease the uniformity of fibers and lead to bead and droplet formation. It has also shown that the distance between the tip and the collector have no significant effect on fibers' structure. The values of 15 kV (voltage), 0.2 ml.h-1 (flow rate) and the fixed distance of 15 cm were identified as the optimal electrospinning conditions, which produce fibers with a mean diameter of 180+/-20 nm. Fourier transform infrared (FTIR) experiment revealed an increase in N-H bending and decrease in C O stretching vibration in both chitosan and gelatin at 1060 and 1148 cm-1. The in vitro biocompatibility tests performed with human skin fibroblasts showed excellent cell proliferation (MTT assay) and attachment (SEM) on these scaffolds confirming its highly acceptable biological properties. PMID- 21654067 TI - Synergistic responses of superficial chemistry and micro topography of titanium created by wire-type electric discharge machining. AB - Wire-type electric discharge machining has been applied to the manufacture of endosseous titanium implants as this computer associated technique allows extremely accurate complex sample shaping with an optimal micro textured surface during the processing. Since the titanium oxide layer is sensitively altered by each processing, the authors hypothesized that this technique also up-regulates biological responses through the synergistic effects of the superficial chemistry and micro topography. To evaluate the respective in vitro cellular responses on the superficial chemistry and micro topography of titanium surface processed by wire-type electric discharge, we used titanium-coated epoxy resin replica of the surface. An oxide layer on the titanium surface processed by wire-type electric discharge activated the initial responses of osteoblastic cells through an integrin-mediated mechanism. Since the mRNA expression of ALP on those replicas was up-regulated compared to smooth titanium samples, the micro topography of a titanium surface processed by wire-type electric discharge promotes the osteogenic potential of cells. The synergistic response of the superficial chemistry and micro topography of titanium processed by wire-type electric discharge was demonstrated in this study. PMID- 21654068 TI - Influence of water/O2 plasma treatment on cellular responses of PCL and PET surfaces. AB - In this study, low pressure water/O2 plasma treatment was performed in order to obtain COOH functionalities on the surface of poly-epsilon-caprolactone (PCL) membranes as well as non-woven polyester fabric (NWPF) discs. The plasma treatments were performed in a cylindrical, capacitively coupled RF-plasma reactor and then following steps were performed: in situ (oxalyl chloride vapors) gas/solid reaction to convert -OH functionalities into -COCl groups; and hydrolysis under open laboratory conditions using air moisture for final-COOH functionalities. COOH and OH functionalities on modified surfaces were detected quantitatively by using fluorescent labeling technique and an UVX 300G sensor. Electron spectroscopy for chemical analysis (ESCA) was used to evaluate the relative surface atomic compositions and the carbon and oxygen linkages located in non-equivalent atomic positions of untreated and modified surfaces. Atomic force microscope (AFM) analysis showed that nanoscale features of the PCL surfaces are dramatically changed during the surface treatments. Scanning electron microscopy (SEM) results indicated the changes in the relatively smooth appearance of the untreated NWPF discs after the plasma treatment. Periodontal ligament (PDL) fibroblasts were used in cell culture studies. Cell culture results showed that plasma treated PCL membranes and NWPF discs were favorable for the PDL cell spreading, growth and viability due to the presence of functional groups and/or nanotopographies on their surfaces. PMID- 21654069 TI - ABL/BCR gene variant with two-step mechanism: Unusual localization and rare/novel chromosomal rearrangements in CML patients. AB - AIMS: Variant translocations involving 9q, 22q and at least one additional genomic locus occur in 5-10% of the patients with chronic myeloid leukemia (CML). The mechanisms for the formation of these variant translocations are not fully characterized. Here we report CML cases presenting a variant translocation indicating two-step mechanism with rare/novel chromosomal rearrangement. METHODS: Karyotype analysis was performed on metaphases obtained through short-term cultures of bone marrow and blood. Detection of BCR-ABL fusion gene was performed using dual-color dual-fusion (D-FISH) and extra signal (ES) translocation probes. BAC-FISH was also carried out. RESULTS: In Patient 1, the third partner chromosome was der(11)(p15) with a 2F2G1R signal pattern, which is an unusual signal pattern with the two-step mechanism. Patients 2 and 3 showed typical positive (2F1G1R) signal pattern. In Patient 2, both the chromosome 22s were involved in variant formation. The second fusion was observed below the BCR gene of the second homologue. In Patient 3 the third chromosome was der(13)(q14). The fourth patient showed a variant pattern with BCR/ABL-ES probe involving der(X)(q13) region. CONCLUSION: The presence of different rearrangements of both 9q34 and 22q11 regions highlights the genetic heterogeneity of this subgroup of CML. In each case with variants, further studies with FISH, BAC-FISH or more advanced technique such as microarray should be performed. Future studies should be performed to confirm the presence of true breakpoint hot spots and assess their implications in CML with variant Ph. PMID- 21654070 TI - Variations in MALT1 Gene Disruptions Detected by FISH in 109 MALT Lymphomas Occurring in Different Primary Sites. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of B-cell non-Hodgkin lymphoma that can originate in the gastrointestinal (GI) tract, thyroid, breasts, lungs, and skin. The most common genetic abnormality occurring in MALT lymphomas involves t(11;18)(q21;q21) in the gene MALT1. This translocation results in a chimeric fusion product between the genes ATI2 and MALT1, which generates a survival advantage in the lymphoma cells. The MALT1 disruption is more common in some MALT lymphomas, distinguished by site, than others. If identified, this variation in frequency could affect treatment courses and outcomes for each type of MALT lymphoma. The study included 109 MALT lymphoma sample specimens. The sample paraffin-embedded slides were pretreated, hybridized for FISH using a MALT1 break-apart probe, post-washed, and viewed using a fluorescent microscope. On each slide, 100 individual cells were counted by two independent readers, totaling 200 cells per case, and the percentage of cells containing a translocation within each sample was recorded. A conservative threshold of 8% was used to make a positive call. There were a total of 18 positive results in the 109 samples tested. The tissue specimens tested that yielded positive results include the colon (62.5%), lung (57.14%), skin (25%), eyelid/lacrimal gland (16.67%), stomach (6.45%), kidney (50%), and thyroid (100%). The sites that yielded only negative results (0%) include the breast, salivary gland, salivary gland/parotid, soft tissue/skin, conjunctiva/orbital, small intestine, nasal, and epidural mass. As hypothesized, a variation in the MALT1 disruption was found. This is the first study to examine MALT1 disruption in the soft tissue, nasal, and epidural mass. The positive results of this study, specifically the results for the colon and lung, and the negative breast and salivary gland results are consistent with previous studies examining the genetic aberrations in MALT lymphomas. These results indicate that MALT lymphoma at different locations differentially display MALT1 disruption, and these disruptions may be responsible for the variance in patient response to therapy. Surgery, radiation therapy, and/or administration of cladribine (2CdA) result in the best outcomes in treating MALT lymphomas with MALT1 disruption. PMID- 21654071 TI - A model for rewarding professional growth in the diagnostic molecular oncology laboratory. AB - The University of Texas M.D. Anderson Cancer Center (UTMDACC), Department of Pathology and Laboratory Medicine is committed to the endless pursuit of innovative research, education, training and administration for the prevention, diagnosis and clinical management of cancer and associated diseases. The molecular genetic technology professional development model promotes personal development, recognizes increased competencies, and sets high standards for all skills and services provided. There are four competency levels that comprise our Professional Development Model (PDM): Discovery, Application, Maturation, and Expert. The skill, knowledge, education, and certification requirements for each level are defined based on the business needs of each lab. When a genetic technologist successfully completes all skills, knowledge, proficiency, education and certification requirements within the appropriate time frame for a particular competency level, his/her salary would be adjusted to the entry point for the competency level he/she has completed. PMID- 21654072 TI - Brain-muscle interface: the next-generation BMI. PMID- 21654073 TI - Public germplasm collections and revolutions in biotechnology. PMID- 21654074 TI - What history tells us XXIV. The attempt of Nikolai Koltzoff (Koltsov) to link genetics, embryology and physical chemistry. PMID- 21654075 TI - Towards hemerythrin-based blood substitutes: comparative performance to hemoglobin on human leukocytes and umbilical vein endothelial cells. AB - Hemerythrin is a dioxygen-carrying protein whose oxidative/nitrosative stress related reactivity is lower than that of hemoglobin, which may warrant investigation of hemerythrin as raw material for artificial oxygen carriers ('blood substitutes'). We report here the first biological tests for hemerythrin and its chemical derivatives, comparing their performance with that of a representative competitor, glutaraldehyde-polymerized bovine hemoglobin. Hemerythrin (native or derivatized) exhibits a proliferative effect on human umbilical vein endothelial cell (HUVEC) cultures, as opposed to a slight inhibitory effect of hemoglobin. A similar positive effect is displayed on human lymphocytes by glutaraldehyde-polymerized hemerythrin, but not by native or polyethylene glycol-derivatized hemerythrin. PMID- 21654077 TI - Stylish lengths: mate choice in flowers. AB - The styles of flowers may represent an arena for pollen competition in the race to fertilize ovules. Accordingly, selection should favour a longer 'race' to better discriminate among variable pollen by increasing style length. Sampling across a taxonomically diverse range of wild and outcrossed species, we found that the distribution of style lengths within plants were skewed towards longer styles, as predicted. In self-pollinated domesticated species, where discrimination among pollen is less important, we found no such pattern. We conclude that style length is under directional selection towards longer styles as a mechanism for mate choice among pollen of variable quality. PMID- 21654078 TI - Effects of gamma-ray-induced free radicals on the metal content and amino acid composition of human metallothionein-1. AB - Metallothioneins (MTs), a low-mass class of metalloproteins, are characterized by a high thiolate sulphur and metal content. MTs are involved in metal homeostasis and heavy metal detoxification, and are efficient scavengers of free radicals. This article describes zinc release from human MT-1 and modification of its amino acid composition when subjected to free radicals generated during gamma ray radiolysis. The effect of gamma ray radiolysis of untreated and metal-depleted human MT-1 was tested under multiple aerobic and anaerobic conditions at increasing irradiation doses. Under all conditions, a rapid increase of serine in the early stages of irradiation was observed. Irradiation for longer times led to cysteic acid formation, except under argon atmosphere. Several other amino acid concentrations gradually decreased. Formation of limited amounts of hydroxyproline, hydroxylysine and ornithine as well as some less common derivatives such as cystathionine occurred as side-effects. PMID- 21654079 TI - Effect of surgical stress on nuclear and mitochondrial DNA from healthy sections of colon and rectum of patients with colorectal cancer. AB - Surgical resection at any location in the body leads to stress response with cellular and subcellular change, leading to tissue damage. The intestine is extremely sensitive to surgical stress with consequent postoperative complications. It has been suggested that the increase of reactive oxygen species as subcellular changes plays an important role in this process. This article focuses on the effect of surgical stress on nuclear and mitochondrial DNA from healthy sections of colon and rectum of patients with colorectal cancer. Mitochondrial DNA copy number, mitochondrial common deletion and nuclear and mitochondrial 8-oxo-2'-deoxyguanosine content were measured. Both the colon and rectal tissue were significantly damaged either at the nuclear or mitochondrial level. In particular, mitochondrial DNA was more damaged in rectum than in colon. The present investigation found an association between surgical stress and nuclear and mitochondrial DNA damage, suggesting that surgery may generate an increase in free radicals, which trigger a cascade of molecular changes, including alterations in DNA. PMID- 21654080 TI - Water-mediated ionic interactions in protein structures. AB - It is well known that water molecules play an indispensable role in the structure and function of biological macromolecules. The water-mediated ionic interactions between the charged residues provide stability and plasticity and in turn address the function of the protein structures. Thus, this study specifically addresses the number of possible water-mediated ionic interactions, their occurrence, distribution and nature found in 90% non-redundant protein chains. Further, it provides a statistical report of different charged residue pairs that are mediated by surface or buried water molecules to form the interactions. Also, it discusses its contributions in stabilizing various secondary structural elements of the protein. Thus, the present study shows the ubiquitous nature of the interactions that imparts plasticity and flexibility to a protein molecule. PMID- 21654081 TI - Pleiotropic consequences of misexpression of the developmentally active and stress-inducible non-coding hsromega gene in Drosophila. AB - The non-coding hsromega gene of Drosophila melanogaster is expressed in nearly all cell types and developmental stages. However, in the absence of conventional mutant alleles of this gene, its developmental functions remain largely unknown. In the present study, we used a variety of GAL4 drivers to overexpress or ablate this gene's transcripts in specific tissues and examined the developmental consequences thereof. Our results show that a balanced expression of these non coding transcripts is critical for survival and normal development in all the tissue types tested, since any change in cellular levels of these transcripts in a given cell type generally has detrimental effects, with extreme cases resulting in organismal lethality, although in a few cases the misexpression of these transcripts also suppresses the mutant phenotype due to other genetic conditions. Evidence is also presented for existence of a new spliced variant of the hsromega n nuclear transcript. Following the RNAi-mediated down-regulation of hsromega transcripts, the omega speckles disappear so that the nucleoplasmic hnRNPs get diffusely distributed, while upregulation of these transcripts results in greater sequestration of these proteins into omega speckle clusters; either of these conditions would affect activities of the hnRNPs and other hsromega-RNA interacting proteins, which is likely to have cascading consequences. The present findings, together with our earlier observations on effects of altered levels of the hsromega transcripts on induced apoptosis and expanded polyQ-mediated neurodegeneration, further confirm that ncRNA species like the hsromega, far from being evolutionary hangovers, provide critical information for important functions in normal cells. PMID- 21654076 TI - Isolation and expression analysis of LEA genes in peanut (Arachis hypogaea L.). AB - Late embryogenesis abundant (LEA) protein family is a large protein family that includes proteins accumulated at late stages of seed development or in vegetative tissues in response to drought, salinity, cold stress and exogenous application of abscisic acid. In order to isolate peanut genes, an expressed sequence tag (EST) sequencing project was carried out using a peanut seed cDNA library. From 6258 ESTs, 19 LEA-encoding genes were identified and could be classified into eight distinct groups. Expression of these genes in seeds at different developmental stages and in various peanut tissues was analysed by semi quantitative RT-PCR. The results showed that expression levels of LEA genes were generally high in seeds. Some LEA protein genes were expressed at a high level in non-seed tissues such as root, stem, leaf, flower and gynophore. These results provided valuable information for the functional and regulatory studies on peanut LEA genes. PMID- 21654082 TI - Splicing aberrations caused by constitutional RB1 gene mutations in retinoblastoma. AB - Analysis of RB1 mRNA from blood leukocytes of patients with retinoblastoma identified the effects of mutations involving consensus splice site, exonic substitution and whole-exon deletions identified in genomic DNA of these patients. In addition, this study identified mutations in cases in which no mutations were detectable in the genomic DNA. One proband had mutation at the canonical splice site at +5 position of IVS22, and analysis of the transcripts in this family revealed skipping of exon 22 in three members of this family. In one proband, a missense substitution of c.652T greater than G (g.56897T greater than G; Leu218Val) in exon 7 led to splicing aberrations involving deletions of exons 7 and 8, suggesting the formation of a cryptic splice site. In two probands with no detectable changes in the genomic DNA upon screening of RB1 exons and flanking intronic sequences, transcripts were found to have deletions of exon 6 in one, and exons 21 and 22 in another family. In two probands, RNA analysis confirmed genomic deletions involving one or more exons. This study reveals novel effects of RB1 mutations on splicing and suggests the utility of RNA analysis as an adjunct to mutational screening of genomic DNA in retinoblastoma. PMID- 21654083 TI - Genome-wide screening reveals the emergence and divergence of RTK homologues in basal Metazoan Hydra magnipapillata. AB - Receptor tyrosine kinases (RTKs) are key components of cell-cell signalling required for growth and development of multicellular organisms. It is therefore likely that the divergence of RTKs and associated components played a significant role in the evolution of multicellular organisms. We have carried out the present study in hydra, a diploblast, to investigate the divergence of RTKs after parazoa and before emergence of triploblast phyla. The domain-based screening using Hidden Markov Models (HMMs) for RTKs in Genomescan predicted gene models of the Hydra magnipapillata genome resulted in identification of 15 RTKs. These RTKs have been classified into eight families based on domain architecture and homology. Only 5 of these RTKs have been previously reported and a few of these have been partially characterized. A phylogeny-based analysis of these predicted RTKs revealed that seven subtype duplications occurred between 'parazoan eumetazoan split' and 'diploblast-triploblast split' in animal phyla. These results suggest that most of the RTKs evolved before the radiata-bilateria divergence during animal evolution. PMID- 21654084 TI - Growth inhibitory, apoptotic and anti-inflammatory activities displayed by a novel modified triterpenoid, cyano enone of methyl boswellates. AB - Triterpenoids are pentacyclic secondary metabolites present in many terrestrial plants. Natural triterpenoids have been reported to exhibit anti-inflammatory and anti-carcinogenic activities. Here, we show that modifications of ring A of boswellic acid (2 cyano, 3 enone) resulted in a highly active growth inhibitory, anti-inflammatory, prodifferentiative and anti-tumour triterpenoid compound called cyano enone of methyl boswellates (CEMB). This compound showed cytotoxic activity on a number of cancer cell lines with IC50 ranging from 0.2 to 0.6 MUM. CEMB inhibits DNA synthesis and induces apoptosis in A549 cell line at 0.25 MUM and 1 MUM concentrations, respectively. CEMB induces adipogenic differentiation in 3T3-L1 cells at a concentration of 0.1 MUM. Finally, administration of CEMB intra-tumourally significantly inhibited the growth of C6 glioma tumour xenograft in immuno-compromised mice. Collectively, these results suggest that CEMB is a very potent anti-tumour compound. PMID- 21654085 TI - Modulation of synaptic potentials and cell excitability by dendritic KIR and KAs channels in nucleus accumbens medium spiny neurons: a computational study. AB - The nucleus accumbens (NAc), a critical structure of the brain reward circuit, is implicated in normal goal-directed behaviour and learning as well as pathological conditions like schizophrenia and addiction. Its major cellular substrates, the medium spiny (MS) neurons, possess a wide variety of dendritic active conductances that may modulate the excitatory post synaptic potentials (EPSPs) and cell excitability. We examine this issue using a biophysically detailed 189 compartment stylized model of the NAc MS neuron, incorporating all the known active conductances. We find that, of all the active channels, inward rectifying K+ (KIR) channels play the primary role in modulating the resting membrane potential (RMP) and EPSPs in the down-state of the neuron. Reduction in the conductance of KIR channels evokes facilitatory effects on EPSPs accompanied by rises in local input resistance and membrane time constant. At depolarized membrane potentials closer to up-state levels, the slowly inactivating A-type potassium channel (KAs) conductance also plays a strong role in determining synaptic potential parameters and cell excitability. We discuss the implications of our results for the regulation of accumbal MS neuron biophysics and synaptic integration by intrinsic factors and extrinsic agents such as dopamine. PMID- 21654086 TI - Mutagenesis in ORF AV2 affects viral replication in Mungbean yellow mosaic India virus. AB - Mungbean yellow mosaic India virus (MYMIV) is a whitefly-transmitted begomovirus with a bipartite genome. We investigate the functions of the MYMIV-AV2 protein, the open reading frame present upstream of the coat protein gene in DNA A component. The ability of MYMIV-AV2 mutants to replicate, spread and cause symptoms in legume hosts, blackgram, cowpea and French bean was analysed. Plants agroinoculated with mutants K73R, C86S and the double mutant C84S,C86S showed increase in severity of symptoms compared with the wild type. However, mutants W2S and H14Q,G15E caused marked attenuation of symptoms. While the double mutants C84S,C86S caused a 50-fold increase in double-stranded supercoiled and single stranded DNA accumulation, the mutations W2S and H14Q,G15E showed a decrease in double-stranded supercoiled and single-stranded viral DNA accumulation. Because AV2 mutants affect the ratio between open circular and supercoiled DNA forms, we hypothesize that these mutations may modulate the functions of the replication initiation protein. PMID- 21654088 TI - Fibrinogenolytic toxin from Indian monocled cobra (Naja kaouthia) venom. AB - A fibrinogenolytic toxin of molecular weight 6.5 kDa has been purified from the venom of Indian monocled cobra (Naja kaouthia) by repeated cation exchange chromatography on CM-sephadex C-50. The purified toxin did not show any phospholipase activity but was mildly hemolytic on human erythrocytes. This toxin, called Lahirin, cleaved fibrinogen in a dose- and time-dependent manner. The digestion process apparently started with the A alpha chain, and gradually other lower-molecular-weight chains were also cleaved to low-molecular-weight peptides. The fibrinolytic activity was completely lost after treatment with ethylene di-amine tetra acetic acid (EDTA). However, exposure to 100 degree C for 1 min or pre-treatment with phenyl methyl sulfonyl fluoride (PMSF) did not affect the fibrinolytic activity. Cleavage of di-sulphide bonds by beta-mercaptoethanol or unfolding the protein with 4 M urea caused complete loss of activity of pure Lahirin. PMID- 21654087 TI - Inhibitory activity of the peptides derived from buffalo prolactin on angiogenesis. AB - The peptide fragments obtained by cathepsin digestion of purified buffalo prolactin (buPRL) monomer have been characterized using SDS-PAGE and FPLC with regard to size and pI. Their antiangiogenic activity was tested in chick embryo chorioallantoic membrane (CAM) assay and the human endothelial cells wound healing assay. Antiangiogenic activity was observed in cathepsin-cleaved fragments from buPRL. Further, a peptide sequence 45A- 46Q-47G-48K-49G-50F-51I 52T-53M-54A-55L-56N-57S-58C, which matched with human somatostatin (hSST), a known antiangiogenic factor, was located in the second loop between the first and second alpha-helices in the three dimensional structure of buPRL, obtained by homology modelling. The synthetic peptide matching with SST sequence was found to exhibit antiangiogenic activity in both in vitro and ex vivo assays. It was also observed that all the peptides related to buPRL could antagonize the vascular endothelial growth factor (VEGF) and bradykinin (BK)- dependent production of endothelial nitric oxide (NO), which is a pre-requisite for endothelial tube formation. It is concluded therefore that an internal sequence in buPRL and peptide fragments derived from cathepsin-digested buPRL exhibit antiangiogenic activities. PMID- 21654089 TI - Detrimental effect of expression of Bt endotoxin Cry1Ac on in vitro regeneration, in vivo growth and development of tobacco and cotton transgenics. AB - High levels of expression of the cry1Ac gene from Bacillus thuringiensis cannot be routinely achieved in transgenic plants despite modifications made in the gene to improve its expression. This has been attributed to the instability of the transcript in a few reports. In the present study, based on the genetic transformation of cotton and tobacco, we show that the expression of the Cry1Ac endotoxin has detrimental effects on both the in vitro and in vivo growth and development of transgenic plants. A number of experiments on developing transgenics in cotton with different versions of cry1Ac gene showed that the majority of the plants did not express any Cry1Ac protein. Based on Southern blot analysis, it was also observed that a substantial number of lines did not contain the cry1Ac gene cassette although they contained the marker gene nptII. More significantly, all the lines that showed appreciable levels of expression were found to be phenotypically abnormal. Experiments on transformation of tobacco with different constructs expressing the cry1Ac gene showed that in vitro regeneration was inhibited by the encoded protein. Further, out of a total of 145 independent events generated with the different cry1Ac gene constructs in tobacco, only 21 showed expression of the Cry1Ac protein, confirming observations made in cotton that regenerants that express high levels of the Cry1Ac protein are selected against during regeneration of transformed events. This problem was circumvented by targeting the Cry1Ac protein to the chloroplast, which also significantly improved the expression of the protein. PMID- 21654090 TI - Marmorkrebs: natural crayfish clone as emerging model for various biological disciplines. PMID- 21654091 TI - Metabolic and molecular action of Trigonella foenum-graecum (fenugreek) and trace metals in experimental diabetic tissues. AB - Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycaemia resulting in defective insulin secretion, resistance to insulin action or both. The use of biguanides, sulphonylurea and other drugs are valuable in the treatment of diabetes mellitus; their use, however, is restricted by their limited action, pharmacokinetic properties, secondary failure rates and side effects. Trigonella foenum-graecum, commonly known as fenugreek, is a plant that has been extensively used as a source of antidiabetic compounds from its seeds and leaf extracts. Preliminary human trials and animal experiments suggest possible hypoglycaemic and antihyperlipedemic properties of fenugreek seed powder taken orally. Our results show that the action of fenugreek in lowering blood glucose levels is almost comparable to the effect of insulin. Combination with trace metal showed that vanadium had additive effects and manganese had additive effects with insulin on in vitro system in control and diabetic animals of young and old ages using adipose tissue. The Trigonella and vanadium effects were studied in a number of tissues including liver, kidney, brain peripheral nerve, heart, red blood cells and skeletal muscle. Addition of Trigonella to vanadium significantly removed the toxicity of vanadium when used to reduce blood glucose levels. Administration of the various combinations of the antidiabetic compounds to diabetic animals was found to reverse most of the diabetic effects studied at physiological, biochemical, histochemical and molecular levels. Results of the key enzymes of metabolic pathways have been summarized together with glucose transporter, Glut-4 and insulin levels. Our findings illustrate and elucidate the antidiabetic/insulin mimetic effects of Trigonella, manganese and vanadium. PMID- 21654092 TI - Efficacy of trunk balance exercises for individuals with chronic low back pain: a randomized clinical trial. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To determine the efficacy of trunk balance exercises for individuals with chronic low back pain. BACKGROUND: The majority of exercises focusing on restoring lumbopelvic stability propose targeting the feedforward control of the lumbopelvic region. Less attention has been paid to feedback control during balance adjustments. METHODS: Seventy-nine patients were randomly allocated to 2 different groups. The experimental group performed trunk balance exercises in addition to standard trunk flexibility exercises. The control group performed strengthening exercises in addition to the same standard trunk flexibility exercises. The primary outcome measures were pain intensity (visual analogue scale), disability (Roland-Morris Questionnaire), and quality of life (12-Item Short-Form Health Survey). Secondary outcomes were painful positions, use of analgesic drugs, and referred pain. Analysis of variance and relative risk were used to analyze the data for the primary and secondary outcome measures, respectively. The number of participants reaching the minimal clinically important difference in the 2 groups for each outcome measure was compared using relative risk. RESULTS: A significant difference in scores on the Roland-Morris Questionnaire (P = .011) and the physical component of the 12 Item Short-Form Health Survey (P = .048), and in the number of participants reaching the minimal clinically important difference for the Roland-Morris Questionnaire (relative risk, 1.79; 95% confidence interval [CI]: 1.05, 3.04) and the secondary outcome of painful positions (relative risk, 1.37; 95% CI: 1.03, 1.83) were found in favor of the experimental treatment. CONCLUSIONS: Trunk balance exercises combined with flexibility exercises were found to be more effective than a combination of strength and flexibility exercises in reducing disability and improving the physical component of quality of life in patients with chronic low back pain. PMID- 21654093 TI - Hip strengthening prior to functional exercises reduces pain sooner than quadriceps strengthening in females with patellofemoral pain syndrome: a randomized clinical trial. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVES: To determine if females with patellofemoral pain syndrome (PFPS) who perform hip strengthening prior to functional exercises demonstrate greater improvements than females who perform quadriceps strengthening prior to the same functional exercises. BACKGROUND: Although PFPS has previously been attributed to quadriceps dysfunction, more recent research has linked this condition to impairment of the hip musculature. Lower extremity strengthening has been deemed an effective intervention. However, research has often examined weight-bearing exercises, making it unclear if increased strength in the hip, quadriceps, or both is beneficial. METHODS: Thirty three females with PFPS performed either initial hip strengthening (hip group) or initial quadriceps strengthening (quad group) for 4 weeks, prior to 4 weeks of a similar program of functional weight-bearing exercises. Self-reported pain, function, and functional strength were measured. Isometric strength was assessed for hip abductors, external rotators, and knee extensors. A mixed-model analysis of variance was used to determine group differences over time. RESULTS: After 4 weeks, there was less mean +/- SD pain in the hip group (2.4 +/- 2.0) than in the quad group (4.1 +/- 2.5) (P = .035). From baseline to 8 weeks, the hip group demonstrated a 21% increase (P<.001) in hip abductor strength, while that remained unchanged in the quad group. All participants demonstrated improved subjective function (P<.006), objective function (P<.001), and hip external rotator strength (P = .004) from baseline to testing at 8 weeks. CONCLUSION: Both rehabilitation approaches improved function and reduced pain. For patients with PFPS, initial hip strengthening may allow an earlier dissipation of pain than exercises focused on the quadriceps. PMID- 21654094 TI - Physical game demands in elite rugby union: a global positioning system analysis and possible implications for rehabilitation. AB - STUDY DESIGN: Descriptive. OBJECTIVES: To evaluate the physical demands of an international Rugby Union-level game using a global positioning system (GPS). BACKGROUND: Elite Rugby Union teams currently employ the latest technology to monitor and evaluate physical demands of training and games on their players. METHODS: GPS data from 2 players, a back and a forward, were collected during an international Rugby Union game. Locomotion speed, total body load, and body load sustained in tackles and scrums were analyzed. RESULTS: Players completed an average distance of 6715 m and spent the major portion of the game standing or walking, interspersed with medium- and high-intensity running activities. The back performed a higher number of high-intensity sprints and reached a greater maximal speed. Body load data revealed that high levels of gravitational force are sustained in tackling and scrum tasks. CONCLUSION: The current study provides a detailed GPS analysis of the physical demands of international Rugby Union players. These data, when combined with game video footage, may assist sports medicine professionals in understanding the demands of the game and mechanism of injury, as well as improving injury rehabilitation. PMID- 21654095 TI - Magnetic resonance imaging: the underlying principles. AB - The creation of a magnetic resonance image (MRI) and its inherent contrast are controlled by a variety of anatomical structure- and sequence-dependent parameters. While these may seem confusing to the uninitiated, they provide MRI with great flexibility and make it a powerful clinical tool. This article describes the principles of basic physics behind magnetic resonance spectroscopy (MRS) and imaging, including a basic description of the properties of magnetic resonance compatible nuclei, how a radiofrequency (RF) pulse produces a signal, and how this signal can be spatially encoded to produce an image. The relaxation properties of the MRI signal depend on biological tissue type and can provide information on tissue composition, environment, and pathological changes. The contrast properties within an image can be manipulated based on the relaxation properties of the anatomical sample and the nature of the imaging sequence. The benefits of T1- and T2-weighted images in musculoskeletal imaging and the common sequences used (including turbo spin echo [TSE], fat suppression sequences such as STIR, and rapid breath-hold sequences such as HASTE and FISP) are discussed. The principles behind contrast agents and diffusion-weighted imaging and how they can be applied in the body are considered. PMID- 21654096 TI - Factors associated with care seeking from physicians, physical therapists, or chiropractors by persons with spinal pain: a population-based study. AB - STUDY DESIGN: Secondary analysis of longitudinal population-based survey data. OBJECTIVES: To investigate factors associated with care seeking for physician referred physical therapy (MD/PT), as compared to physician-only (MD) or chiropractic-only (DC) care for spinal pain. BACKGROUND: Although a large proportion of ambulatory physical therapy visits are related to spinal pain, physical therapists are not the most commonly seen provider. The majority of visits are to physicians, followed by chiropractors. We attempted to understand more about this disparity by examining social and demographic factors that differentiate between persons who see these providers. METHODS: Episodes of care were constructed from participants in 2 panels from the Medical Expenditure Panel Survey who had spinal pain. The provider of care was identified for each episode, and logistic regression was used to determine factors associated with MD/PT use compared to MD use, and MD/PT use compared to DC use. RESULTS: The majority of patients (61%) received MD care for spinal pain, followed by those who received DC (28%) and MD/PT (11%) care. Female sex, higher levels of education, and higher income were significantly associated with MD/PT care over MD care. Increased age, female sex, lower self-health rating, and presence of at least 1 disability day were all significantly associated with MD/PT care over DC care. CONCLUSION: Sociodemographic and clinical factors are associated with those who get MD/PT care as compared to MD or DC care. We found evidence of an access disparity for physical therapy and identified population characteristics that both increase and reduce the likelihood of physical therapy service use. PMID- 21654097 TI - An exploration of the relationship between back muscle endurance and familial, physical, lifestyle, and psychosocial factors in adolescents and young adults. AB - STUDY DESIGN: Cross-sectional investigation. OBJECTIVE: To explore the relationship between back muscle endurance (BME) and a range of familial, physical, lifestyle, and psychosocial variables in adolescents and young adults. BACKGROUND: There is evidence that low back pain interventions which focus on improved BME are effective. However, the mechanisms associated with BME performance in adolescents and young adults are largely unclear. In particular, the potential familial relationship between parents and their children remains unexplored. METHODS: This study utilized a subset of participants from the Joondalup Spinal Health Study cohort. One hundred nine children (47 boys, 62 girls) and 101 parents (39 fathers, 62 mothers) completed a series of physical, lifestyle, and psychosocial assessments. The univariable relationship between each covariate and BME was explored. Those found to have an association with child BME (P<.2) were included in an initial multivariable model and sequentially removed, until all remaining covariates were statistically significant (P<.05). RESULTS: Mothers' BME performance was related to children's performance, accounting for 14.4% of the variance in the children's BME. Fathers' BME performance had a similar, albeit nonsignificant effect. Children's sitting trunk angle, pain sensitivity, percent trunk fat, waist girth, and body mass index were associated with their BME performance, accounting for between 5.2% and 20.9% of BME. CONCLUSIONS: The final multivariable model, including mother's BME, percent trunk fat, and sitting trunk angle, explained 28% of the variance in BME performance, suggesting that for successful BME intervention a range of multidimensional variables should be considered. PMID- 21654098 TI - Ultrasound imaging and muscle function. AB - There is a growing trend in the physical therapy profession to use conventional grayscale brightness (B-mode) ultrasound imaging (USI) as a tool to assess the morphological (form and structure) and morphometric (measures of form) characteristics of muscle, and to use these findings to draw conclusions regarding muscle function. This trend is reflected in numerous published investigations. As many physical therapists may lack training in the principles and instrumentation underlying USI use, it is critical that therapists gain a clear understanding of the information that USI can, and cannot, provide about muscle function before employing the technique for either research or clinical applications. Failure to do so may result in the propagation of inaccurate terminology and beliefs. This paper aims to clarify the role that USI has in the assessment of muscle function, first, by briefly reviewing how conventional grayscale B-mode ultrasound images and clips are generated, and second, by summarizing the types of information that these images can provide. It also discusses the various factors that need to be considered when interpreting a dynamic USI assessment of muscle specifically as it relates to the assessment of muscle function. PMID- 21654099 TI - Total number and severity of comorbidities do not differ based on anatomical region of musculoskeletal pain. AB - STUDY DESIGN: Secondary analysis, cross-sectional study. OBJECTIVES: To (1) compare differences in individual comorbidity rates among patients with cervical, lumbar, and extremity pain complaints and (2) compare rates based on total number and severity in these same patient groups. BACKGROUND: Comorbidities can impact recovery, prognosis, and potentially hinder participation in rehabilitation. Few studies have compared comorbidity rates among patients with different anatomical region of pain, to determine whether specific screening is warranted in physical therapy settings. METHODS: Included in the analyses were 2375 patients who reported complete demographic, clinical, and comorbidity information using Patient Inquiry software. Comorbidity data were collected from the Functional Comorbidity Index (18 items) and 6 additional comorbidities, to assess the presence of medical disease across multiple body systems. Comorbidities were further classified as "nonsevere" or "severe," based on inclusion in the Charlson Comorbidity Index. Chi-square analyses investigated differences in the rates of total number and severe comorbidities. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated on rates with statistically significant differences (P<.001), using the lumbar spine as the reference group. RESULTS: Of the 24 comorbid conditions included in this analysis, 3 nonsevere medical conditions (degenerative disc disease, obesity, and headache) had different rates among anatomical region. A lower rate for degenerative disc disease was associated with the extremity conditions (chi2 = 66.3; OR = 0.40; 95% CI: 0.32, 0.50). Higher rate of headache (chi2 = 115.3; OR = 3.01; 95% CI: 2.45, 3.70) and lower rate of obesity (chi2 = 16.2; OR = 0.64; 95% CI: 0.51, 0.80) were associated with cervical conditions. There were no differences among the 3 anatomical regions for total number or severe comorbidities. CONCLUSION: Focused screening for degenerative disc disease, obesity, and headache may be warranted. However, the same strategy was not supported for total number or severe comorbidities, at least when considering comparative rates from this cohort. Physical therapists should consider the potential influence of total number and severe comorbidities equally for all anatomical regions of musculoskeletal pain. LEVEL OF EVIDENCE: Differential diagnosis/symptom prevalence, level 3b. PMID- 21654100 TI - Antimicrobial resistance: no action today, no cure tomorrow. PMID- 21654101 TI - Could the products of Indian medicinal plants be the next alternative for the treatment of infections? AB - Indian medicinal plants are now recognized to have great potential for preparing clinically useful drugs that could even be used by allopathic physicians. Traditionally, practitioners of Indian medicine have used plant products in powder, syrup or lotion forms, without identification, quantification and dose regulation, unlike their allopathic counterparts. The present review explores the immense potential of the demonstrated effect of Indian medicinal plants on microbes, viruses and parasites. In the present context, with the available talent in the country like pharmaceutical chemists, microbiologists, biotechnologists and interested allopathic physicians, significant national effort towards identification of an "active principle" of Indian medicinal plants to treat human and animal infections should be a priority. PMID- 21654102 TI - Comparison of a conventional polymerase chain reaction with real-time polymerase chain reaction for the detection of neurotropic viruses in cerebrospinal fluid samples. AB - PURPOSE: To compare a conventional polymerase chain reaction (PCR) and real-time PCR for the detection of neurotropic DNA viruses. MATERIALS AND METHODS: A total of 147 cerebrospinal fluid (CSF) samples was collected from patients attending a tertiary care hospital in South India for a period from 2005 to 2008. All these samples were tested using a conventional multiplex/uniplex PCR and a real-time multiplex/uniplex PCR. This technique was used to detect a large number of herpes viruses responsible for central nervous system infections, including HSV-1, HSV 2, VZV, CMV and EBV and the polyoma virus JCV. RESULTS: Overall, in the entire set of samples, the real-time PCR yielded 88 (59.9%) positives and conventional PCR had six (4.1%) positives. CONCLUSION: Our results suggest that the real-time PCR assay was more sensitive compared with the conventional PCR. The advantage of real-time PCR is that it can be performed much faster than conventional PCR. Real time PCR is less time-consuming, less labour-intensive and also reduces the chance of contamination as there is no post-amplification procedure. In the entire study population, the major viruses detected using real-time PCR were EBV (34%), HSV-2 (10.8%) and VZV (6.8%). PMID- 21654103 TI - Development of a new method for diagnosis of Group B Coxsackie genome by reverse transcription loop-mediated isothermal amplification. AB - BACKGROUND: Coxsackie B viruses (genus, Enterovirus; family, Picornaviridae) can cause aseptic meningitis, encephalitis, pleurodynia, and fatal myocarditis, and are implicated in the pathogenesis of dilated cardiomyopathy. The differentiation of the group B Coxsackieviruses into their subtypes has potential clinical and epidemiological implications. OBJECTIVE: In this study, we developed a one-step, single-tube genogroup-specific reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for the detection of group B Coxsackie genomes targeting 5' UTR region. MATERIALS AND METHODS: The amplification can be obtained in less than 1 hour by incubating all the reagents in a single tube with reverse transcriptase and Bst DNA polymerase at 63 degrees C. Detection of gene amplification could be accomplished by agarose gel electrophoresis and the monitoring of gene amplification can also be visualised with the naked eye by using SYBR green I fluorescent dye. RESULTS: A total of 40 samples comprising 31 positive samples and 9 negative samples were used in this study for comparative evaluation. The results were compared with those from Real-Time Polymerase Chain Reaction (RT-PCR). None of the RT-PCR-positive samples were missed by RT-LAMP, thereby indicating a higher sensitivity of the RT-LAMP assay. CONCLUSION: Thus, due to easy operation without a requirement of sophisticated equipment and skilled personnel, the RT-LAMP assay reported here is extremely rapid, cost effective, highly sensitive, and specific and has potential usefulness for rapid detection of non-polio enterovirus (NPEV) not only by well-equipped laboratories but also by peripheral diagnostic laboratories with limited financial resources in developing countries. PMID- 21654104 TI - High frequency of integrons related to drug-resistance in clinical isolates of Acinetobacter baumannii. AB - PURPOSE: As an opportunistic pathogen, Acinetobacter baumannii causes various nosocomial infections. In recent years, the increasing cumulative infection outbreaks involving A. baumannii have appeared worldwide. In addition, a perplexing trouble for clinical treatment is a severe drug-resistance problem with A. baumannii. In this study, we investigated the drug-resistance rates and integrons' distribution in A. baumannii clinical strains in East China. Furthermore, we explored the relationship between integrons and drug resistance. MATERIALS AND METHODS: Strains were identified using non-fermenting bacteria identification cards by Vitek-32 system. Disk-diffusion method (Kirby-Bauer) was used to judge antimicrobial sensitivity. Integrons and the gene cassettes of integrons were identified by PCR, restriction enzyme digestion and DNA sequencing. RESULTS: Except imipenem and cefoperazone/sulbactam, the drug resistance rates of the A. baumannii clinical isolates to other 15 kinds of antibacterials, all surpassed 30%. Of 96 A. baumannii clinical isolates, 66 strains carried class 1 integrons (no class 2 or 3 integrons were found). Overall, the drug-resistance rates in integrons-positive A. baumannii to 14 kinds of antibacterials were higher than those in integrons-negative A. baumannii. Gene sequencing showed that 9 of 12 integrons contained seven different gene cassettes (aacA4, catB3, dfrA1, blam-1, orfX, aadA1, and sat2). The cassette arrays aacA4 catB3-dfrA1 was found in five detected integrons. CONCLUSIONS: High resistances in A. baumannii clinical strains to most common antimicrobial agents have appeared in East China, which was closely related with high frequencies class 1 integrons. A. baumannii integrons cassettes carried multi-drug-resistant gene codes. We believe that integrons cassettes gene could be taken as a marker of prognosticating A. baumannii antimicrobial resistance, but only reveal partial drug resistance profiles. PMID- 21654105 TI - Evaluation of the therapeutic use of antibiotics in Aegean Region hospitals of Turkey: a multicentric study. AB - PURPOSE: The antibiotic restriction policy has been validated nationwide since February 2003 by the Ministry of Health because the excessive consumption of antimicrobials causes a high cost. The aim of this study was to evaluate the therapeutic use of antibiotics in Aegean Region hospitals and to assess the impact of this nationwide antibiotic restriction policy. This new policy is based on justification that the infectious disease (ID) physicians should be primarily responsible for the prescription of antimicrobials. MATERIALS AND METHODS: Eight university and government hospitals were included in the study. The criteria of the Council for Appropriate and Rational Antibiotic Therapy (CARAT) were considered. Both patient-based and antibiotic-based analyses were performed. For the analysis of inappropriate use, logistic regression was modeled. RESULTS: Therapeutic use was determined in 540 patients by a total of 29 ID physicians.In the study, 30.2% of the patients were given antimicrobials and empirically started antibiotics accounted for 79% cases of therapeutic antibiotic use, and 60% of those were inappropriate (P = 0.001). The appropriate use of ID level antibiotics (P = 0.000) were very compatible with other antimicrobial groups. CONCLUSION: The study shows that the Turkish government's new intervention policy on antimicrobial prescribing has been effective. PMID- 21654106 TI - An outbreak of CTX-M-15-producing Klebsiella pneumoniae isolates in an intensive care unit of a teaching hospital in Kuwait. AB - OBJECTIVE: This study reports an outbreak of Klebsiella pneumoniae infections in 14 patients during a 2-month period (August-September, 2008) in the intensive care unit (ICU) of a teaching hospital in Kuwait. MATERIALS AND METHODS: The clinical sources were blood (9), urine (3) and respiratory secretions (2) identified by the automated VITEK-2 ID System. Susceptibility testing was performed by the E-test method. Extended-spectrum beta-lactamase (ESBL) production was assessed using the ESBL E-test and confirmed by PCR. Carriage of bla genes was determined by PCR and sequence analysis. The transferability of resistance phenotypes was demonstrated by conjugation experiments and clonal relatedness was determined by PFGE. RESULTS: The isolates were susceptible to imipenem, meropenem, and tigecycline and produced ESBL. All isolates yielded an amplicon of 499 bp with universal consensus primers (MA primers). DNA sequence analysis showed that they all harboured bla CTX-M-15 and bla TEM-1 genes. The environmental isolate obtained from a suction machine was also CTX-M-15/TEM-1 producer. The resistance phenotypes were transferrable to the Escherichia coli J53 r strain. PFGE, revealed two clones, A and B, related with a Dice coefficient of >94.1%. A mortality rate of 21.4% was recorded. CONCLUSION: The outbreak was contained by robust and aggressive infection control measures. This study highlights the first outbreak of CTX-M-15-producing K. pneumoniae associated with high mortality in an adult medical ICU in Kuwait. PMID- 21654107 TI - Comparison of enzyme immunoassays detecting Helicobacter pylori specific IgG in serum and saliva with endoscopic and biopsy findings in patients with dyspepsia. AB - PURPOSE: To compare the performance of two indirect enzyme-linked immunosorbent assays (ELISA) detecting Helicobacter pylori (HP)-specific IgG antibodies in serum and saliva with endoscopic observations and histologic findings of biopsies from dyspeptic patients, in an area of high HP prevalence. MATERIALS AND METHODS: Sera, saliva and antral biopsies were obtained from 55 dyspeptic patients. IgG antibodies against HP were assayed in sera and saliva utilizing two indirect ELISAs. Biopsies were processed according to standard procedures in order to detect histological changes and the presence or absence of Helicobacter pylori. Laboratory data thus obtained were compared and statistically analyzed. RESULTS: Forty-two (76.36%) biopsies were positive for HP. The organisms were detected in 4 of 16 (25%) cases with normal endoscopic findings, in all 16 cases of gastritis and in 22 of the 23 (95.6%) cases of duodenal ulcers (DU). Serum and saliva HP specific IgG antibodies were detected in 4 normal cases with positive biopsies, in 12 and 14 cases of gastritis, respectively, and in all 22 (100%) biopsy positive cases of DU. The sensitivities of the serum and saliva tests were 90.5% and 95%, respectively, while the specificities were 84.5% and 70%, respectively. CONCLUSION: Due to their high sensitivity and specificity in diagnosing HP associated DU and gastritis, serum and saliva antibody testing seems to offer a valuable alternative to invasive procedures especially in areas of high HP prevalence such as ours; saliva antibody testing is simple and practical especially in children and in difficult patients who resent venipuncture. PMID- 21654108 TI - Evaluation of small-subunit rRNA touchdown polymerase chain reaction for direct detection of Entamoeba histolytica in human pus samples from patients with amoebic liver abscess. AB - PURPOSE: The aim of the present study was to evaluate the use of touchdown polymerase chain reaction (TD-PCR) for the detection of Entamoeba histolytica in liver pus samples obtained from patients with a clinical diagnosis of amoebic liver abscess (ALA) using small-subunit rRNA (SSU rRNA) as the target gene. MATERIALS AND METHODS: Microscopic examination in vitro culture and serological test for the detection of E. histolytica in 67 pus samples obtained from ALA patients was performed. Molecular studies were carried out by both conventional PCR and TD-PCR targeting the SSU rRNA gene using the same sets of primers and the results were compared. RESULTS: TD-PCR detected the presence of E. histolytica in 86.5% of the liver pus samples within 2.5 h as compared with 82.08% by conventional PCR within 3.5-4 h. CONCLUSION: TD-PCR assay may serve as a relatively better detection method for E. histolytica over conventional PCR with respect to the turnaround time, increased sensitivity, specificity and yield. PMID- 21654109 TI - Risk factors for acquiring Strongyloides stercoralis infection among patients attending a tertiary hospital in south India. AB - PURPOSE: Strongyloides stercoralis causes persistent and fatal disseminated infections in immunocompromised hosts. In this study, we aimed to determine the risk factors for acquiring strongyloidiasis and the associated morbidity in south India. MATERIALS AND METHODS: The study was carried out in two parts. This included a 6-month chart review of cases with strongyloidiasis and randomly selected controls conducted to determine the association with immunocompromised states. Secondly, a cross-sectional study was conducted to investigate hyperinfection in human immunodeficiency virus (HIV)-infected adults where the stool and sputum samples were examined by microscopy for Strongyloides larvae. RESULTS: In the chart review, 118 cases were compared with 240 controls. A higher proportion of patients on corticosteroids [8 (53.3%)] and with HIV infection [3 (60%)] had the risk of acquiring strongyloidiasis than not, although the difference was not statistically significant in this population. In the cross sectional study, 14/239 HIV-positive individuals had Strongyloides larvae in the stool samples but none had Strongyloides detectable in their sputum samples. The CD4 cell counts were significantly lower in cases with Strongyloides compared with HIV-infected individuals with no parasites in their stool samples (P < 0.001). CONCLUSIONS: In this setting, strongyloidiasis was seen more often in patients on corticosteroid therapy and with HIV infection. In HIV, an association with lower CD4 counts indicates the need for inclusion of Strongyloides as an opportunistic parasite. Gram negative sepsis was an important complication of strongyloidiasis hyperinfection in both HIV and steroid therapy. Further prospective studies on the risk of developing complicated Strongyloides infection are required. PMID- 21654110 TI - The presence of dsRNA virus in Trichomonas vaginalis isolates from symptomatic and asymptomatic Indian women and its correlation with in vitro metronidazole sensitivity. AB - PURPOSE: Trichomonas vaginalis, a protozoan parasite, is the causative agent of human trichomoniasis, the most common non-viral sexually transmitted disease. The infection encompasses from a complete asymptomatic presentation to severe sequelae; yet, the virulence markers have been poorly understood. It is suggested that the presence of Trichomonas vaginalis virus (TVV) in T. vaginalis may have an impact on its virulence, and its relatedness to in vitro metronidazole resistance has been reported. The aim of the study was to assess the presence of TVV in fresh and Long -Term Cultivated ( LTC) maintained T. vaginalis isolates from symptomatic (S) and asymptomatic (AS) Indian women and its relatedness, if any, with symptomatology and in vitro drug sensitivity. MATERIALS AND METHODS: One thousand women (537 S and 463 AS) were screened for the presence of T. vaginalis by wet smear and culture examination of vaginal swab and urine sample. Fresh and LTC (6 months-2 years) maintained 15 isolates each from 15 S and 15 AS women were subjected to agarose gel electrophoresis following total cellular RNA extraction to evaluate the presence of double stranded (ds) RNA viral infection. The susceptibility of isolates to metronidazole was determined in vitro. RESULTS: On agarose gel electrophoresis, three bands (5.5, 2.5 and 1.5 kb) were observed in all the 30 fresh isolates from 15 S and 15 AS women and only in 7 LTC isolates from 3 S and 4 AS women. All the fresh isolates harbouring TVV were found to be sensitive to metronidazole in vitro irrespective of the symptomatology of subjects, and out of seven LTC isolates harbouring TVV, six were sensitive to metronidazole and one showed borderline resistance. CONCLUSIONS: The results suggest that the presence of TVV alone may not be a virulence marker and loss of TVV on LTC appears to be related to drug resistance. The T. vaginalis Indian isolates are sensitive to metronidazole. PMID- 21654111 TI - Multi locus sequence type comparison of invasive and commensal Haemophilus influenzae isolates from Delhi. AB - Haemophilus influenzae is a major public health concern in the developing world. The most virulent strain is H. influenzae Type b (Hib). Hib also constitutes a major portion of nasopharyngeal commensal flora in otherwise healthy individuals. Through dendogram based on composite gene sequences of seven multi locus sequence type genes, it was observed that invasive and commensal isolates made two completely separate clusters which are indicative of independent evolution of these two groups of H. influenzae in the Indian subcontinent. PMID- 21654112 TI - Correlation of TEM, SHV and CTX-M extended-spectrum beta lactamases among Enterobacteriaceae with their in vitro antimicrobial susceptibility. AB - PURPOSE: The present study was carried out to characterize the ESBL types and evaluated their in vitro activity against a collection of Gram negative bacteria (GNB) from a multicentric Indian surveillance study. MATERIAL AND METHODS: During January 2005 to June 2006, six tertiary care centres in India forwarded 778 non duplicate GNB to our reference laboratory. Three hundred GNB from this collection were selected based on clinical significance and were used in the present study. Tested isolates included Escherichia coli (167), Klebsiella spp. (122) and Enterobacter spp. (11). ESBL screening and confirmation was performed for all the isolates. Minimum inhibitory concentration of imipenem, meropenem, ertapenem, levofloxacin, amikacin, piperacillin/tazobactam and ceftriaxone was determined by the E-test method. Molecular typing of the ESBLs was performed by polymerase chain reaction among the 121 selected isolates. RESULTS: The study showed excellent susceptibility among the strains to imipenem (100%), meropenem (100%) and ertapenem (98.7%); good susceptibility to amikacin (89.7%) and piperacillin/tazobactam (85.3%) was observed. TEM and CTX-M were predominantly found in E. coli (39.2%) while, among the Klebsiella spp., TEM, SHV and CTX-M occurred together in 42.6% of the isolates. CONCLUSION: More than one ESBL was produced by many strains, and this was correlated with increased resistance levels. Carbapenems continue to show good in vitro activity and ertapenem is a potential alternative to imipenem and meropenem. Continued antimicrobial resistance surveillance is warranted in light of these findings. PMID- 21654113 TI - Biotypes and virulence factors of Gardnerella vaginalis isolated from cases of bacterial vaginosis. AB - The present study was conducted to correlate the biotypes of Gardnerella vaginalis strains isolated from cases of bacterial vaginosis and their virulence factors. Thirty-two strains of G. vaginalis isolated from cases of bacterial vaginosis were biotyped. Adherence to vaginal epithelial cells, biofilm production, surface hydrophobicity, phospholipase C and protease activity were tested on these isolates. Biotype 1 was the most prevalent (8; 25%), followed by biotype 2 (7; 21.9%) and biotypes 5 and 8 (5; 15.6%). We did not find any statistical correlation between G. vaginalis biotypes and its virulence factors. Virulence factors expressed by G. vaginalis were not associated with a single biotype. PMID- 21654114 TI - Central venous catheter-related blood stream infection rate in critical care units in a tertiary care, teaching hospital in Mumbai. AB - Blood stream infections related to central venous catheterization are one of the major device-associated infections reported. Patients admitted in critical care units requiring central venous catheterization and presenting with signs of septicemia during catheterization period were investigated for catheter-related blood stream infections (CRBSI). The CRBSI rate was 9.26 per 1000 catheter days in general with highest rate in neonatal intensive care unit (27.02/1000 days). Site of insertion of catheter and duration of catheterization did not show the influence on the CRBSI rate. Coagulase-negative Staphylococci were the predominant cause. Mortality of 33% was observed in patients with CRBSI. Since central venous catheters are increasingly being used in the critical care, regular surveillance for infection associated them are essential. PMID- 21654115 TI - Yeast identification in routine clinical microbiology laboratory and its clinical relevance. AB - Rapid identification of yeast infections is helpful in prompt appropriate antifungal therapy. In the present study, the usefulness of chromogenic medium, slide culture technique and Vitek2 Compact (V2C) has been analysed. A total of 173 clinical isolates of yeast species were included in the study. An algorithm to identify such isolates in routine clinical microbiology laboratory was prepared and followed. Chromogenic medium was able to identify Candida albicans, C. tropicalis, C. krusei, C. parapsilosis and Trichosporon asahii. Chromogenic medium was also helpful in identifying "multi-species" yeast infections. The medium was unable to provide presumptive identification of C. pelliculosa, C. utilis, C. rugosa, C. glabrata and C. hemulonii. Vitek 2 compact (V2C) differentiated all pseudohypae non-producing yeast species. The algorithm followed was helpful in timely presumptive identification and final diagnosis of yeast infections, including multi-species yeast infections. PMID- 21654116 TI - Fatal rabies despite post-exposure prophylaxis. AB - Only sporadic reports of failure of post-exposure prophylaxis for rabies exist in the published literature. We are reporting such a case in a 3-year-old boy. The child had Category III dog bite on his right thigh. He presented with progressive ascending paralysis, finally developing quadriplegia and respiratory paralysis. Typical hydrophobia and aerophobia were absent. He received four doses of antirabies cell culture vaccine. He did not receive antirabies immunoglobulin. The boy succumbed on the 23 rd day of the dog bite. Diagnosis of rabies was confirmed in the laboratory by demonstration of Negri bodies, direct fluorescent antibody test and reverse transcriptase-polymerase chain reaction either on impression smear of brain or a piece of brain taken during autopsy. PMID- 21654117 TI - A rare case of disseminated cysticercosis: case report and literature review. AB - Cysticercosis is a common tropical disease. One of the uncommon manifestations of cysticercosis and a rare complication is its disseminated form. We report an immunocompetent patient with disseminated cysticercosis who had involvement of the brain, subcutaneous tissues, lungs and skeletal muscles and presented with arthritis. He was otherwise asymptomatic in spite of the extensive involvement of multiple organs. A planned approach to therapy is necessary to prevent complications. PMID- 21654118 TI - Case of sparganosis: a diagnostic dilemma. AB - Sparganosis, also known as larval diphyllobothriasis, is a rare disease of humans as man is not a natural host in the life cycle of Spirometra spp. Diagnosis of the latter is difficult as it mimics other conditions that commonly cause subcutaneous or visceral fluid collection. Clinical diagnosis of this particular case was also erroneously labelled as tuberculosis but later labelled as a case of sparganosis. To the best of our knowledge, this is the first case from India where a sparganum-like parasite was isolated in drain fluid from the perinephric area. PMID- 21654119 TI - Intestinal obstruction due to Basidiobolus ranarum: an unusual case. AB - A case of intestinal obstruction caused by extensive soft tissue fungal infection of the perineum due to Basidiobolus ranarum is presented here. There was excellent response to antifungal treatment. A literature search revealed the case report of intestinal obstruction due to intrinsic mucosal involvement by the fungus, but extensive soft tissue involvement of the perineum resulting in extraneous obstruction to the rectum, has not been reported so far. PMID- 21654121 TI - Hydatid cyst in the spleen: a rare presentation. PMID- 21654120 TI - A rare case of Histoplasma fungemia in an AIDS patient. AB - Disseminated cases of histoplasmosis in acquired immune deficiency syndrome (AIDS) are rarely reported from India. Most of these cases report isolation of this fungus from the bone marrow, lymph node aspirate, spleenic aspirate, and biopsies. We report isolation of Histoplasma capsulatum from the blood of an AIDS patient. A 30-year-old male from Utter Pradesh was admitted with fever, loss of appetite, and nausea since two months. Few intracellular and extracellular budding cells were observed on bone marrow examination on the fifth day of admission. Diagnosis was confirmed by blood cultures taken on the 11th day of admission. Amphotericin B was started, but the patient's condition deteriorated and he died. PMID- 21654122 TI - H1N1: are our critical units prepared? PMID- 21654123 TI - A pilot cross-sectional study to determine the utility of an oral HIV1/2 point of care test on sputum for screening TB/HIV co-infection in Central India. PMID- 21654124 TI - A combined diagnostic approach to rheumatoid arthritis using anti-cyclic citrullinated peptide antibodies and rheumatoid factor. PMID- 21654125 TI - Chryseobacterium indologenes bacteraemia in a preterm baby. PMID- 21654126 TI - VITEK 2 and PHOENIX fail to detect high-level gentamicin-resistant Enterococcus faecium isolates with aac-aph gene. PMID- 21654127 TI - Prevention of pre-eclampsia with low-dose aspirin. PMID- 21654128 TI - A meta-analysis of low-dose aspirin for prevention of preeclampsia. AB - BACKGROUND: Low-dose aspirin (LDA) is widely used for prevention of preeclampsia. However, conflicting results have been obtained from various studies. AIM: The aim of our study was to evaluate the effect of LDA in prevention of preeclampsia in high-risk and low-risk women. MATERIALS AND METHODS: A total of 19 randomized control trials were identified using PUBMED search engine and Cochrane Clinical Trial register. The study population was divided into high-risk and low-risk groups. The effect measured was incidence of preeclampsia in women taking either LDA or placebo where the relative risk (RR) and the 95% confidence interval (CI) were calculated for both groups. RESULTS: A total of 28237 women were studied, out of which 16550 were in the low-risk group while 11687 were in the high-risk group. The overall incidence of preeclampsia was 7.4%. With the aspirin group it was 6.9% while in the placebo group it was 7.8%. In the high-risk group there was 21% reduction in the risk of preeclampsia associated with the use of aspirin (RR 0.79, 95% CI 0.65-0.97). However, LDA is not effective in reducing the risk in low-risk population (RR 0.86, 95% CI 0.64-1.17). CONCLUSION: LDA has a small effect in the prevention of preeclampsia in women considered to be at high risk for the disease. However, it is not effective in reducing the risk in the low risk group. PMID- 21654129 TI - Salutary effect of parathyroidectomy on neuropsychiatric symptoms in patients with primary hyperparathyroidism: evaluation using PAS and SF-36v2 scoring systems. AB - BACKGROUND: Indian patients with primary hyperparathyroidism (pHPT) usually present with a triad of advanced disease of bones, stones, and psychic moans. There are hardly any reports from India on the outcome of successful parathyroidectomy on psychiatric symptoms. AIMS: To evaluate the outcome of parathyroidectomy on psychiatric symptoms in Indian patients with advanced pHPT. SETTINGS AND DESIGN: Prospective study done in a tertiary care super-specialty hospital in northern India. MATERIALS AND METHODS: Health surveys using parathyroid assessment of symptom score (PAS) and SF-36v2 were carried out, to evaluate the outcome of parathyroidectomy on the psychiatric symptoms of patients. The study included 42 patients of pHPT admitted between November 2007 and December 2009 (two years). Scoring was done preoperatively; and one week, three months, six months, and one year postoperatively. STATISTICAL ANALYSIS USED: SPSS 15 software and nonparametric tests (k Independent Sample test, Kruskal-Wallis H). RESULTS: The mean preoperative PAS score was 430.87 +/- 215.61 (range 40 - 880). Statistically significant reduction in scoring was observed postoperatively at one week (293.65 +/- 118.31, P < 0.001), three months (109.44 +/- 85.09, P < 0.015), six months (70.00 +/- 71.65, P 1 < 0.05), and one year (60.10 +/- 104.48, P < 0.02). Although the surgery scores for feeling irritability, forgetfulness, difficulty in getting out of chair, headache, and itchy skin did not reduce appreciably at one week, they later showed significant reduction. All other parameters showed significant reduction. The SF-36v2 TM survey also showed significant improvement on all scores except social functioning, while physical functioning improved only after one week. CONCLUSIONS: Indian patients with advanced pHPT, after a successful parathyroidectomy, showed significant improvement in their quality of life, as evaluated by the PAS and SF-36v2 systems. PMID- 21654131 TI - D-dimer assays--a help or hindrance in suspected pulmonary thromboembolism assessment? AB - BACKGROUND: Suspected pulmonary thromboembolism (PTE) is a common presentation to acute medical units and can cause diagnostic difficulty. National guidelines on PTE management highlight the need for clinical probability assessment and D-dimer assays to ensure appropriate use of diagnostic imaging. D-dimers are used widely in UK hospitals, yet concern exists regarding their misuse. AIMS: In this study we aimed to assess the impact of the introduction of D-dimer assays, combined with clinical probability assessment, for evaluation of suspected PTE in our unit. MATERIALS AND METHODS: This was a prospective audit of all patients presenting with suspected PTE over two 12-week periods, exactly 1 year apart. D dimers were introduced into our unit between these two periods. We recorded the clinical probability score, potential causes of false-positive D-dimer assay, diagnostic imaging result, patient outcome, admission rates, and length of inpatient stay. STATISTICAL ANALYSIS: Categorical variables were compared using a 2 x 2 chi-square test or Fisher's exact test. Groups were compared utilizing the two-sample t-test or Mann-Whitney U test. RESULTS: A total of 190 patients were included in the study; 65% were female. PTE was confirmed in 8.4%. Patients in both audit periods were comparable with regard to suitability for D-dimer measurement. Following D-dimer introduction, 40 out of 110 patients in period 2 could be discharged directly from the emergency department. Of those admitted to hospital, the median length of stay was significantly reduced in period 2 (3 days in period 1 vs 1 day in period 2; P=0.0007). Use of diagnostic imaging was significantly reduced following the introduction of D-dimers (90% in period 1 vs 40% in period 2; P<0.0001). The positive diagnostic yield for PTE on CT pulmonary angiogram (CTPA) increased significantly from 10% in period 1 to 23% in period 2 (P=0.039). CONCLUSION: D-dimers must be used judiciously in the assessment of suspected PTE. Appropriate use of D-dimers can provide many benefits, including reductions in diagnostic imaging (and thus radiation exposure), admission rates, and length of inpatient stay. PMID- 21654130 TI - A clinical trial to assess the immunogenicity and safety of Inactivated Influenza Vaccine (Whole Virion) IP (Pandemic Influenza (H1N1) 2009 Monovalent Vaccine; VaxiFlu-STM) in healthy Indian adult population. AB - BACKGROUND: The pandemic of H1N1 2009 influenza has spread world over and low degree of virus transmission has continued in several regions of India. AIMS: To assess the immunogenicity and safety of Pandemic Influenza (H1N1) 2009 Monovalent Vaccine in healthy adult Indian population. SETTINGS AND DESIGN: Prospective, open label, multicentric, phase 2/3 clinical trial. MATERIALS AND METHODS: Healthy adult Indian subjects belonging to either 18-59 years or >= 60 years age groups were enrolled and administered a single 0.5 ml (>= 15 mcg of hemagglutinin antigen) dose of vaccine in the deltoid muscle. Anti-hemagglutinin antibody titer was assessed at baseline and 21 (+/- 2) days after vaccination by Hemagglutination Inhibition (HI) test. Safety assessments were done for a period of 42 days. STATISTICAL ANALYSIS USED: Percentages of appropriate population with 95% confidence intervals calculated, log transformation of the data to calculate Geometric Mean Titers (GMTs) and chi-square test and student's t-test applied for significance testing. RESULTS: 182/198 and 53/63 volunteers in age groups of 18 59 years and >= 60 years, respectively, achieved an HI titer >= 1 : 40 at Day 21 (91.9% [95% confidence interval: 88.1-95.7%] and 84.1% [75.1-93.2%]; P=0.072). Further, 171/198 and 50/63 volunteers in the respective age groups achieved seroconversion/four-fold increase in titer at Day 21 (86.4% [81.6-91.1%] and 79.4% [69.4-89.4%]; P=0.179). A significant rise of 22.6-fold [18.0-28.4] and 10.5-fold [7.4-15.0] was noted in GMT in the respective age groups (P<0.001 for both groups as compared to baseline). Nine vaccine-related adverse events were reported (3.4% incidence [1.2-5.6%]), which were of low severity only. CONCLUSIONS: Pandemic Influenza (H1N1) 2009 Monovalent Vaccine produces excellent immunogenic response with a good tolerability profile in adult Indian population. PMID- 21654132 TI - Drug-induced Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap: a multicentric retrospective study. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare immune-mediated severe cutaneous adverse reactions with incidence rate of 0.05 to 2 persons per million populations per year. Drugs are the most commonly implicated in 95% of cases. AIMS: To audit the causative drugs, clinical outcome, and cost of management in SJS, TEN, and SJS-TEN overlap. SETTING AND DESIGN: Tertiary care hospitals-based multicentric retrospective study (case series). MATERIALS AND METHODS: Indoor case papers of SJS, TEN, and SJS-TEN overlap admitted between January 2006 and December 2009 in four tertiary care hospitals of Gujarat were scrutinized. Data were collected for demographic information, causative drugs, investigations, treatment given, duration of hospital stay, time interval between onset of symptoms and drug intake, clinical outcome, and complications. Data were analyzed to find out proportion of individual drugs responsible, major complications, and clinical outcome in SJS, TEN, and SJS-TEN overlap. Total cost of management was calculated by using cost of drugs, investigations, and consumables used during entire hospital stay. STATISTICAL ANALYSIS: One-way Analysis of Variance followed by Tukey-Kramer multiple comparison test was used for comparison of incubation period, duration of hospital stay, and cost of management. RESULTS: Antimicrobials (50%), nonsteroidal anti-inflammatory drugs (22.41%), and antiseizure drugs (18.96%) were the most commonly associated groups. Nevirapine (28.12%) was the most common drug. Antiseizure drugs were more often associated with serious form of adverse reaction (TEN: 81.8%) than other drugs. Duration of hospital stay (20.6 vs 9.7 days) and cost of management (7,910/- vs 2,460/-) were significantly higher in TEN than SJS (P=0.020 and P<0.001, respectively). Time duration between drug intake and onset of symptoms (17.7 vs 27.5 days) was nonsignificantly lower in TEN as compared with SJS. Secondary infection (28.12%) was the most common complication noted. Mortality rate was 15.6% among all cases; 9% in SJS and 26.7% in TEN. CONCLUSION: Antimicrobial drugs are the most commonly implicated drugs and cost of managing these adverse drug reactions is higher than other serious ADRs. PMID- 21654133 TI - Surgery in Hashimoto's thyroiditis: indications, complications, and associated cancers. AB - BACKGROUND: Indications for surgery in Hashimoto's thyroiditis (HT) patients are compressive symptoms and suspicion of malignancy. A high incidence of thyroid malignancy has been reported in patients with HT. The effect of surgery on discomfort in swallowing and tightness in the neck has not been properly evaluated. AIMS: The aim of our study is to compare the indications, complications, and associated cancers in patients operated for HT with those surgically treated for other benign goitres. The effect of surgery on minor symptoms like tightness in the neck and discomfort in swallowing is included. SETTING AND DESIGN: This was a retrospective case-control study at a tertiary care centre. PATIENTS AND METHODS: A total of 271 patients who had undergone surgery for benign thyroid diseases were included. Group A consisted of 35 patients who had HT and Group B consisted of patients operated for other benign thyroid diseases (236 patients). STATISTICAL ANALYSIS: Data were analyzed using SPSS 12 software. Independent group's t-test was used to compare the means and Fisher's exact test was used for categorical data. RESULTS: In Group A, the common indications for surgery were discomfort associated with swelling (45.7%), cosmesis (34.3%), and pain with swelling (11.4%) whereas in Group B, the indication was predominantly cosmetic (80%). A total of 22.9% patients of Group A and 6% of Group B were hyperthyroid. The sensitivity of FNAC for diagnosing thyroiditis was 62.8% (n = 22). Postoperative complication rates were similar in both the groups. The mean operating time was higher in Group A even though the gland was smaller. Incidental malignancy was 3.4% in Group B whereas there was none in Group A. Discomfort in swallowing and tightness in the neck were relieved at 3 months after surgery. CONCLUSIONS: Large, euthyroid and apparently asymptomatic HT occasionally need surgical intervention. Discomfort in swallowing and tightness in the neck are relieved after surgery. Thyroidectomy is safe to perform and has a low incidence of permanent complications. There was no associated malignancy in our series of HT. PMID- 21654134 TI - Utility of ventricular access in an acute deterioration after endoscopic third ventriculostomy. AB - Endoscopic third ventriculostomy (ETV) has now been accepted widely as a safe procedure for treatment of non-communicating hydrocephalus. Despite its learning curve, most of the neurosurgeons have understood its technical details, benefits, and risks and have started to practice it to perfection. The benefit of shunt independence with minimal risks offers a remarkable advantage which has made this procedure widely popular. However, late closure of stoma leading to morbidity and even death has been reported off late. We report a case of a 7-year-old girl with hydrocephalus due to tectal glioma who deteriorated after 7 months following a successful procedure. She developed a cardio-respiratory arrest and was resuscitated with aspiration of cerebrospinal fluid from the ommaya reservoir kept during the primary surgery. Keeping all the patients under strict surveillance for stoma patency is mandatory and in addition, ommaya reservoir in certain high-risk patients may be a useful option for achieving quick ventricular access by medical and nonmedical personnel in case of deterioration. This case is the first reported case of acute deterioration after ETV from India. Previously, 14 such cases have been reported worldwide and only 2 of them have survived. PMID- 21654135 TI - Unilateral common peroneal nerve palsy following renal transplantation: a case report of tacrolimus neurotoxicity. AB - Neurologic complications are not uncommon in renal transplant recipients. Acute femoral neuropathy, lumbosacral plexopathy, and sciatic neuropathy have been reported after kidney transplantation probably due to perioperative nerve compression and ischemia. To the best of our knowledge, common peroneal nerve (CPN) palsy has not been described in the early postoperative period following renal transplantation. Also, mononeuropathy due to tacrolimus (TAC) therapy has not been described so far. We report a case of isolated CPN palsy presenting as unilateral foot drop following renal transplantation and that improved only after replacing TAC with cyclosporine. PMID- 21654136 TI - An unusual cause for sicca syndrome. AB - We present a case of a 47-year-old female who presented with sicca symptoms since three months. As per the Revised International Classification Criteria for Sjogren's syndrome, patient was diagnosed as primary Sjogren's syndrome (SS). Patients with SS are known to have circulating monoclonal immunoglobulins. Serum electrophoresis revealed M band with serum gamma globulin concentration of 46 g/L. Bone marrow aspiration revealed 28% plasma cells. In absence of myeloma related organ damage, a diagnosis of smouldering myeloma (MM) was made. Patient was treated with thalidomide and dexamethasone. Sicca symptoms resolved with anti myeloma treatment. Although MM can occur as a complication of SS, MM can also rarely present as SS. In the present case, the short duration of sicca symptoms and response of these symptoms to anti-myeloma treatment support the diagnosis of MM presenting as SS. The present case highlights the importance of serum electrophoresis in patients presenting as SS. PMID- 21654137 TI - Autoimmune lymphoproliferative disorder in an adult patient. AB - A 50-year-old male patient presented with fever, epistaxis and multiple lymphadenopathy since 15 days. In the light of the above presentation a complete workup was initiated to exclude common conditions like tuberculosis, acquired immunodeficiency syndrome, lymphoid malignancy and sarcoidosis. After excluding common conditions a biopsy of cervical lymph node demonstrated reactive lymphadenitis with paracortical hyperplasia. Immunohistochemistry demonstrated double negative lymphocytes (CD4-, CD8-). A diagnosis of autoimmune lymphoproliferative disorder syndrome (ALPS) (probable) was made and patient was started on 1 mg/kg of steroids. Patient showed a dramatic improvement with respect to general wellbeing, fever and regression of lymphadenopathy. This entity of ALPS has been recently identified and classified; most of the reports are from the pediatric population. To the best of our knowledge ours is one of the few cases of this entity being reported in an adult patient from India. PMID- 21654138 TI - Endotipsitis: a diagnostic challenge. PMID- 21654139 TI - Cecal endometriosis as an unusual cause of right iliac fossa pain. PMID- 21654141 TI - Fresh look at the Doppler changes in pregnancies with placental-based complications. AB - Placental-based complications of pregnancy can be classified as acute and chronic. An example of acute placental complication is abruptio placenta. The chronic placental complications include pregnancy induced hypertension (PIH) and idiopathic Intrauterine growth restriction (IUGR). The fetus is at risk for perinatal complications in both acute and chronic conditions. Here we take a look at the natural history of the Doppler parameters in chronic conditions. The techniques used for assessing the fetal well-being include, clinical methods, biophysical tests, conventional ultrasonography, and fetal Doppler studies. Arterial Doppler studies are used to assess the well-being of the fetus and to determine the timing of delivery. However, arterial Dopplers predict only the subset of fetuses at risk of having perinatal complications. Venous Dopplers have been used to improve upon the prognostication. However, by the time the commonly used venous Doppler signs, that is, 'A' wave reversal in ductus venosus (DV) is present, the fetus is likely to be already compromised. The fetus tries to adapt to the environment of deprivation by making a series of changes in the umbilical artery circulation, cerebral circulation, and hepatic circulation. As a result of these adaptations, the fetus overcomes the state of chronic hypoxia. This article takes a look at these changes and also the effect of these adaptations. It is suggested that serial comparisons of the venous flow characteristics of the DV and inferior vena cava (IVC) can provide an early indication of the impending decompensation and can be used to predict the time the delivery. PMID- 21654140 TI - Acute pulmonary thromboembolism in a patient with primary pulmonary hypertension: a diagnostic challenge. PMID- 21654142 TI - EMO syndrome. PMID- 21654143 TI - Unusual clinical presentation of tuberculoma. PMID- 21654144 TI - Adult purpura fulminans associated with non-steroidal anti-inflammatory drug use. AB - Purpura fulminans is an acute illness characterized by rapidly progressive dermal vascular thrombosis, leading to hemorrhagic necrosis of the skin. Here, we describe the case of a healthy woman who developed acute disseminated intravascular coagulation (DIC) with purpura fulminans after intramuscular administration of a single dose of ketorolac. Review of literature showed only one case description of non-steroidal anti-inflammatory drug (diclofenac)-related purpura fulminans with DIC. PMID- 21654145 TI - An unusual recurrence of antitubercular drug induced hepatotoxicity in a child. PMID- 21654146 TI - Drug repositioning: re-investigating existing drugs for new therapeutic indications. AB - Drug discovery and development is an expensive, time-consuming, and risky enterprise. In order to accelerate the drug development process with reduced risk of failure and relatively lower costs, pharmaceutical companies have adopted drug repositioning as an alternative. This strategy involves exploration of drugs that have already been approved for treatment of other diseases and/or whose targets have already been discovered. Various techniques including data mining, bioinformatics, and usage of novel screening platforms have been used for identification and screening of potential repositioning candidates. However, challenges in clinical trials and intellectual property issues may be encountered during the repositioning process. Nevertheless, such initiatives not only add value to the portfolio of pharmaceutical companies but also provide an opportunity for academia and government laboratories to develop new and innovative uses of existing drugs for infectious and neglected diseases, especially in emerging countries like India. PMID- 21654147 TI - Management of nonvariceal upper gastrointestinal bleeding. AB - Nonvariceal upper gastrointestinal bleeding is unique from variceal bleeding in terms of patient characteristics, management, rebleeding rates, and prognosis, and should be managed differently. The majority of nonvariceal upper gastrointestinal bleeds will not rebleed once treated successfully. The incidence is 80 to 90% of all upper gastrointestinal bleeds and the mortality is between 5 to 10%. The causes include nonacid-related ulceration from tumors, infections, inflammatory disease, Mallory-Weiss tears, erosions, esophagitis, dieulafoy lesions, angiodysplasias, gastric antral vascular ectasia, and portal hypertensive gastropathy. Rarer causes include hemobilia, hemosuccus pancreaticus, and aortoenteric fistulas. Hematemesis and melena are the key features of bleeding from the upper gastrointestinal tract, but fresh per rectal bleeding may be present in a rapidly bleeding lesion. Resuscitation and stabilization before endoscopy leads to improved outcomes. Fluid resuscitation is essential to avoid hypotension. Though widely practiced, there is currently insufficient evidence to show that routine red cell transfusion is beneficial. Coagulopathy requires correction, but the optimal international normalized ratio has not been determined yet. Risk stratification scores such as the Rockall and Glasgow-Blatchford scores are useful to predict rebleeding, mortality, and to determine the urgency of endoscopy. Evidence suggests that high-dose proton pump inhibitors (PPI) should be given as an infusion before endoscopy. If patients are intolerant of PPIs, histamine-2 receptor antagonists can be given, although their acid suppression is inferior. Endoscopic therapy includes thermal methods such as coaptive coagulation, argon plasma coagulation, and hemostatic clips. Four quadrant epinephrine injections combined with either thermal therapy or clipping reduces mortality. In hypoxic patients, endoscopy masks allow high-flow oxygen during upper gastrointestinal endoscopy. The risk of rebleeding reduces after 72 hours. In rebleeding, repeat endoscopy is useful and persistent failure of endoscopic therapy mandates either embolization or surgery. In this review, we analyze the management of nonvariceal upper gastrointestinal bleeding with evidence from the currently published clinical trials. PMID- 21654148 TI - Obstructive sleep apnea: not just a sleep disorder. AB - Obstructive sleep apnea (OSA) has long been recognized as a disorder characterized by snoring and frequent cessations of breathing resulting in fragmentation of sleep, which eventually leads to cumulative sleep debt in affected patients. Until two decades ago, snoring and apneas drew attention mainly as a social curiosity and sleep apnea was not thought of as a serious disorder with multisystem involvement. Impairment of quality of work and high incidence of motor vehicle accidents associated with OSA were recognized toward the end of the last century. Since the turn of this millennium physicians have become increasingly aware of the various cardiovascular complications, metabolic disturbances, and neuropsychologic deficits. It has become very clear in the last decade that patients with OSA have a high recurrence of atrial fibrillation after elective cardioversion if their sleep apnea is not treated with continuous positive airway pressure (CPAP). Poor control of diabetes mellitus and resistant hypertension in the setting of OSA has also been recognized and significant progress in our understanding in this area has been accomplished. Unless physicians include sleep in their system review, many cases will go undiagnosed, which will eventually result in cardiovascular complications. Patients are also not readily forthcoming with the symptoms of sleep apnea, as they often assume that symptoms, such as snoring and daytime sleepiness, are not something serious to be discussed with their physician. In this review, the characteristics, the pathophysiology, and epidemiology of OSA are discussed. Furthermore, the mechanisms by which OSA affects the cardiovascular, endocrine, and metabolic functions have been explored. PMID- 21654149 TI - Negative studies published in medical journals of India do not give sufficient information regarding power/sample size calculation and confidence interval. PMID- 21654150 TI - Continuing medical education. PMID- 21654151 TI - Moderate cytopenias in asymptomatic individuals: is screening for autoimmune connective tissue diseases warranted? PMID- 21654152 TI - Diagnostic value of a urine-based tumor marker for screening lower urinary tract in low-risk patients with asymptomatic microscopic hematuria. AB - BACKGROUND: To evaluate the use of NMP22 BladderChek(r) (NMP22BC) as an initial test in comparison to voided urine cytology for screening subjects with asymptomatic microscopic hematuria (AMH); those who are <40 years of age and have a low risk for bladder cancer based on a non-smoking history, and by discussing the guidelines on this subject. METHODS: From October 2005 to September 2007, 164 patients (56 male, 108 female) were evaluated. Patients with risk factors according to AUA Best Practice Policy Recommendations on AMH were strictly excluded from the study. For upper urinary tract imaging, ultrasonography (USG) was performed and prior to the cystoscopic procedure freshly voided urine was sampled for urine cytology and NMP22BC assay in all patients. Biopsy was performed if suspicious lesions were seen or positive cytology was obtained. RESULTS: The mean age was 30.8 years. As some benign urological pathologies were detected in 21 patients by USG, NMP22BC was positive in 26 patients where the cytology was confirmed as atypia in 5. Two TaG1 tumors were detected cystoscopically in a 39-year-old man and a 33-year-old woman where the NMP22BC test was positive and the cytology was negative in both patients. NMP22BC tests sensitivity, PPV and NPV values were detected to be higher compared to cytology and the likelihood ratio was 6.75. CONCLUSION: We recommend in evaluation of low risk patients with AMH that, as an initial test, two non-invasive and cost effective methods be chosen: an upper tract imaging by USG as recommended by guidelines, followed by an NMP22BC test for lower tract investigation instead of urine cytology. PMID- 21654153 TI - Motivations and perceptions of early adopters of personalized genomics: perspectives from research participants. AB - BACKGROUND/AIMS: To predict the potential public health impact of personal genomics, empirical research on public perceptions of these services is needed. In this study, 'early adopters' of personal genomics were surveyed to assess their motivations, perceptions and intentions. METHODS: Participants were recruited from everyone who registered to attend an enrollment event for the Coriell Personalized Medicine Collaborative, a United States-based (Camden, N.J.) research study of the utility of personalized medicine, between March 31, 2009 and April 1, 2010 (n = 369). Participants completed an Internet-based survey about their motivations, awareness of personalized medicine, perceptions of study risks and benefits, and intentions to share results with health care providers. RESULTS: Respondents were motivated to participate for their own curiosity and to find out their disease risk to improve their health. Fewer than 10% expressed deterministic perspectives about genetic risk, but 32% had misperceptions about the research study or personal genomic testing. Most respondents perceived the study to have health-related benefits. Nearly all (92%) intended to share their results with physicians, primarily to request specific medical recommendations. CONCLUSION: Early adopters of personal genomics are prospectively enthusiastic about using genomic profiling information to improve their health, in close consultation with their physicians. This suggests that early users (i.e. through direct-to-consumer companies or research) may follow up with the health care system. Further research should address whether intentions to seek care match actual behaviors. PMID- 21654154 TI - Staphylococcus aureus evades the extracellular antimicrobial activity of mast cells by promoting its own uptake. AB - In this study, we investigated the interactions of Staphylococcus aureus with mast cells, which are multifunctional sentinels lining the surfaces of the body. We found that bone marrow-derived murine mast cells (BMMC) exerted a powerful phagocytosis-independent antimicrobial activity against S. aureus. Both the release of extracellular traps as well as discharge of antimicrobial compounds were the mechanisms used by the BMMC to kill extracellular S. aureus. This was accompanied by the secretion of mediators such as TNF-alpha involved in the recruitment of effector cells. Interestingly, S. aureus subverted the extracellular antimicrobial activity of the BMMC by internalizing within these cells. S. aureus was also capable to internalize within human mast cells (HMC-1) and within murine skin mast cells during in vivo infection. Bacteria internalization was, at least in part, mediated by the alpha5beta1 integrins expressed on the surface of the mast cell. In the intracellular milieu, the bacterium survived and persisted by increasing the cell wall thickness and by gaining access into the mast cell cytosol. The expression of alpha-hemolysin was essential for staphylococci intracellular persistence. By hiding within the long life mast cells, staphylococci not only avoid clearance but also establish an infection reservoir that could contribute to chronic carriage. PMID- 21654155 TI - Effect of progesterone withdrawal on hypothalamic mechanisms related to prolactin release in late pregnant rats. AB - BACKGROUND/AIMS: Progesterone (P(4)) fall provoked by spontaneous or prostaglandin F2alpha (PGF2alpha)-induced luteolysis in late pregnant rats triggers a prolactin (PRL) surge 12-24 h later. METHODS: To investigate the hypothalamic mechanism mediating this response, we determined expression of tyrosine hydroxylase (TH), PRL receptors (long form, PRLR(long)), estrogen-alpha (ERalpha) and ERbeta, P(4) (PR) A and B receptors, and STAT5a, STAT5b, suppressors of cytokine signaling 1 (SOCS1), SOCS3 and CIS at mRNA (by semiquantitative and real-time RT-PCR) and protein (by Western blot only for TH, ERalpha and PRs) levels, and dopamine and DOPAC (by high-performance liquid chromatography) contents in the mediobasal hypothalamus (MBH) 24 h after luteolysis induced by a PGF2alpha analogue (cloprostenol, 25 MUg/rat s.c. at 8 and 12 h on day 19 of pregnancy). RESULTS: PGF2alpha treatment decreased circulating P(4) and estradiol and increased PRL and the estradiol/P(4) ratio. MBH DOPAC and DOPAC/dopamine ratio fell, indicating decreased dopaminergic transmission. PRLR(long), PRB and ERalpha mRNA increased. ERalpha and PR proteins were not modified. However, TH protein and mRNA did not change. PRA, the small PR isoform, was much more abundant than PRB, the isoform considered to mediate P(4) genomic actions. STAT5a, SOCS1 and SOCS3 mRNA were also increased. CONCLUSION: The P(4) fall induced by PGF2alpha treatment induces PRL release through diminution in MBH dopaminergic transmission without change in TH expression. The increased PRLR along with elevated circulating PRL may be responsible for maintaining high TH expression through activation of short-loop feedback mechanisms, counteracting the effect of the fall in circulating P(4). In parallel, SOCS expression contributes to limit PRL signaling. PMID- 21654156 TI - Bcar3 is expressed in sertoli cells and germ cells of the developing testis in mice. AB - We identified Bcar3 in the course of a screen for developmentally regulated genes at early developmental stages in mouse embryos. In this study, we explored the spatio-temporal expression pattern of Bcar3 during the critical time period of sex determination using in situ hybridization, real-time RT-PCR, and immunohistochemistry. We found that Bcar3 is expressed in XY gonads during early stages of gonad development and that BCAR3 localizes to Sertoli cells and germs cells. In addition, we identified a new alternative Bcar3 transcript in which exons 4-7 are deleted. This deletion could result in the generation of a truncated BCAR3 protein lacking functional domains including the SH2 domain. The data presented here suggest that Bcar3 could play a role in gonad development. PMID- 21654157 TI - Partial deletion of the NR5A1 (SF1) gene detected by synthetic probe MLPA in a patient with XY gonadal disorder of sex development. AB - Steroidogenic factor 1 (SF1, officially NR5A1) is a nuclear receptor involved in adrenal and gonadal development. NR5A1 mutations have been identified in patients with various forms of 46,XY disorders of sex development (DSD), including complete gonadal dysgenesis with or without adrenal insufficiency, mild testicular dysgenesis with ambiguous external genitalia or female external genitalia with clitoromegaly, and penoscrotal hypospadias. We developed a synthetic probe set for MLPA analysis of the NR5A1 gene covering its 7 exons and analyzed 20 patients with 46,XY gonadal DSD in whom analyses failed to identify a genetic cause. We identified a partial NR5A1 deletion affecting exons 2 and 3, leading to NR5A1 haploinsufficiency in 1 patient presenting with female external genitalia with clitoromegaly, absence of a uterus, and mildly dysgenetic testes. This is the first partial NR5A1 gene deletion identified by MLPA in a patient with 46,XY gonadal DSD. This finding stresses the importance of investigating copy number changes, even at the exon level, in genes involved in gonadal DSD. As NR5A1 mutations can cause a wide spectrum of DSD with relatively high frequency, the analysis of the NR5A1 gene by MLPA is quite important and should be extended to larger groups of patients. PMID- 21654158 TI - Ontogenesis of Ap-2gamma expression in rat testes. AB - Searching for useful markers of spermatogonial stem cells and their differentiation, we used rat testes from ages representing different stages of testicular maturation to investigate the expression profile of transcription factor activation protein-2gamma (Ap-2gamma). The immunohistochemical and immunocytochemical evaluation using Ap-2gamma and promyelocytic leukemia zinc finger in combination with sorting of CD9 and CD90 positive cells (undifferentiated spermatogonia) by fluorescence-activated cell sorting was performed. Our experiments revealed that Ap-2gamma is detectable in testes of late fetal age and up to 60 days postnatally and is expressed in gonocytes and spermatogonia from late fetal age throughout all maturational stages. Restricted nuclear expression of Ap-2gamma to undifferentiated male germ cells was verified by coexpression of Ap-2gamma with promyelocytic leukemia zinc finger in sections of paraffin-embedded testes as well as in cells sorted positive for CD9 and CD90 expression. Our study demonstrated clearly that nuclear expression of Ap-2gamma is a useful marker for identifying undifferentiated male germ cells, although its functional role is yet to be fully explored. PMID- 21654159 TI - Partial trisomy 3p and partial monosomy 11q associated with atrial septal defect, cleft palate, and developmental delay: a case report. AB - Unbalanced translocation involving both chromosome 3p duplication and 11q deletion in the same patient is extremely rare; only 1 live-born case was reported previously. This karyotype was also detected during prenatal diagnosis of 2 different pregnancies in a Taiwanese family which were both terminated. In all 3 cases, only standard karyotyping was done to detect the abnormal karyotypes. Here, we report a 4-year-old boy with cleft palate, atrial septal defect, and hypotonia with gross and fine motor delay. Oligonucleotide-based array comparative genomic hybridization showed copy number gain from 3pter to 3p24.2 (approximately 24.5 Mb) and copy number loss from 11q25 to 11qter (approximately 5.8 Mb). This de novo unbalanced translocation event involving a terminal 3p duplication and a terminal 11q deletion provides candidate genes for further investigation of dosage effect leading to the patient's multiple phenotypic abnormalities. Genotype-phenotype correlation is difficult to make in this case due to the large number of genes involved. However, the description of such cases together with precise gene-level mapping of chromosomal breakpoints will add to further refinement of candidate genes to be investigated for terminal imbalances in 3p and 11q when more similar cases are reported. PMID- 21654160 TI - Physical mapping of 5S rDNA in two species of Knifefishes: Gymnotus pantanal and Gymnotus paraguensis (Gymnotiformes). AB - Physical mapping of 5S rDNA in 2 species of knifefishes, Gymnotuspantanal and G. paraguensis (Gymnotiformes), was performed using fluorescence in situ hybridization with a 5S rDNA probe. The 5S rDNA PCR product from the genomes of both species was also sequenced and aligned to determine non-transcribed spacer sequences (NTS). Both species under study had different patterns of 5S rDNA gene cluster distribution. While in the karyotype of G. pantanal two 5S rDNA-bearing pairs were observed, the karyotype of G. paraguensis possessed as many as 19 such pairs. Such multiplication of 5S rDNA gene clusters might be caused by the involvement of transposable elements because the NTS of G. paraguensis was 400 bp long with high identity (90%) with a mobile transposable element called Tc1-like transposon, described from the cyprinid fish Labeo rohita. PMID- 21654161 TI - Pure red cell aplasia induced only by intravenous administration of recombinant human erythropoietin. AB - Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare but important side effect in patients with chronic kidney disease who receive recombinant human erythropoietin (rhEPO). Ab-mediated PRCA was first reported in the 1990s, and the incidence subsequently increased and reached a peak in 2001. After improvements in rhEPO products and the administration route, the incidence was reduced by 90%, and now Ab-mediated PRCA only develops in a limited number of patients who receive rhEPO subcutaneously for a long period. We describe here the clinical course of one such rare patient with Ab-mediated PRCA. The patient was a 70-year old man with chronic renal failure secondary to diabetic nephropathy. He had not received rhEPO therapy before the initiation of hemodialysis. He started hemodialysis and began to receive rhEPO therapy intravenously. Three months later, his hemoglobin level started declining and he became transfusion dependent. A diagnosis of Ab-mediated PRCA was made by bone marrow examination and detection of anti-EPO Abs. He was successfully treated with cyclosporine and became independent of blood transfusions. This case is a reminder that vigilance is required regarding the development of Ab-mediated PRCA upon rhEPO therapy, regardless of the administration route. PMID- 21654162 TI - Temporal increases in urinary carboxymethyllysine correlate with albuminuria development in diabetes. AB - BACKGROUND/AIMS: Advanced glycation end products (AGEs) mediate progressive tissue damage in diabetic nephropathy; however, their utility as a noninvasive reliable biomarker of progressive diabetic nephropathy remains to be determined. In this study, we investigated the temporal accumulation of the AGE carboxymethyllysine (CML) at various sites in a model of experimental diabetic nephropathy. METHODS: Diabetic rats were followed for 1, 4, 8, 16 and 32 weeks. Glomerular filtration rate and urinary albumin excretion were measured. CML was determined in the plasma, urine, renal cortical mitochondria and cytosol by an in house ELISA. Gene expression of AGE receptors were quantified by real-time PCR and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined by EIA. RESULTS: Four weeks after diabetes induction, urinary CML excretion was increased, which preceded the excretion of urinary albumin and continued to rise progressively until 32 weeks. Circulating, mitochondrial and cytosolic CML content and urinary excretion of 8-OHdG were increased 4 weeks after diabetes induction, but did not increase further with diabetes duration. Renal gene expression of AGE receptors was transiently upregulated at 1 week of diabetes, but this was not a sustained phenomenon. CONCLUSIONS: The most informative marker of progressive renal damage linked to the AGE pathway in experimental diabetic nephropathy is urinary excretion of CML, which now warrants clinical investigation as a potential noninvasive sensitive marker of progressive diabetic nephropathy. PMID- 21654163 TI - Reproducibility of and correspondence among different hepcidin forms in blood and urine and their relationships to iron status in healthy, male Guatemalan volunteers observed over 9 weeks. AB - BACKGROUND/AIMS: Prohepcidin and the active form hepcidin-25 are two variants of the peptide hormone hepcidin for iron homoeostasis. Their regulatory role and usefulness as biomarkers of the iron status are uncertain. Our aim is to describe the intra-individual variance of serum and urinary hepcidin-25 and prohepcidin concentrations, the mutual associations of the 4 hepcidin formats, and their correspondence with iron status variables in male Guatemalan volunteers. METHODS: Eight healthy adult males provided serial samples of serum and urine without previous iron dosing over 6 intervals during a 9-week protocol period. Prohepcidin was assayed by a commercial enzyme immunoassay, and hepcidin-25 species in serum and urine were analysed by time-of-flight mass spectrometry after prior enrichment procedures. RESULTS: Serum hepcidin-25 levels correlated significantly with urinary hepcidin-25 concentrations, whereas serum and urinary prohepcidin were not associated with one another or with the homologous or converse formats for hepcidin-25. Serum ferritin and transferrin saturation were significantly correlated with serum hepcidin-25 concentrations, but not with urine hepcidin-25 or with either format of prohepcidin. CONCLUSION: Hepcidin-25 shows correspondence across biological fluids, and the background 'status' of hepcidin activation may be related to the host's iron stores, whereas prohepcidin concentrations showed no promise in this regard. PMID- 21654164 TI - Distribution of isoflavones in samples of serum, liver and mammary glands of rats or pigs fed dietary isoflavones. AB - BACKGROUND/AIMS: There has been great interest in the potential beneficial and adverse health effects of dietary isoflavones. Determination of tissue concentrations of isoflavone metabolites provides an insight into the potential bioactivity of dietary isoflavones. However, data on the distribution of isoflavones in animal models fed dietary isoflavones are limited. In this study, additional data on the distribution of isoflavones in serum and/or tissues of rats and pigs fed dietary isoflavones were generated. METHODS: Rats (male and female) were fed a casein control diet (containing no isoflavones) and an isoflavone-supplemented diet (containing an alcohol-washed soy protein isolate plus NOVASOY, providing a total of 1,047 mg/kg of total isoflavones). Female pigs were fed a control diet (without soy) containing 17.5 mg/kg of isoflavones, a soy diet containing 582.8 mg/kg of isoflavones or a soy diet supplemented with a daily dose of 2.3 g (equivalent to 42.0 and 14.5 mg/kg of body weight at the onset and end of treatment, respectively) of crystalline genistein. The concentrations of isoflavones in serum and tissues (liver and mammary gland) and in tissues (liver and mammary gland) of pigs were determined via a sensitive and rapid method using liquid chromatography/mass spectrometry. RESULTS: Rats fed the control diet containing no isoflavones had nondetectable levels of isoflavone metabolites in serum, liver and mammary gland samples. Rats fed the isoflavone supplemented diet had the greatest levels of equol, followed by genistein, daidzein and glycitein, respectively, in their serum, livers and mammary glands. The concentrations of total isoflavones (daidzein, equol and genistein plus glycitein) in serum were significantly (p < 0.05) greater in male rats vs. female rats, but the reverse was true in the case of livers. Concentrations of daidzein, equol, genistein and glycitein were lowest (p < 0.05) in the livers of pigs fed the control diet, and in the mammary glands of female pigs there was only an effect of feeding soy plus genistein on the concentrations of daidzein and equol (p <0.05). CONCLUSIONS: The current data therefore show gender as well as species differences in the tissue distribution of isoflavones. PMID- 21654165 TI - Evaluation of a new polysulfone hemofilter for continuous renal replacement therapy. AB - New strategies using continuous renal replacement therapy as a tool to achieve immunomodulation in septic acute kidney injury have been proposed. The hypothesis is based on the possibility to remove inflammatory mediators and oxidants in a wide spectrum of molecular weights, thanks to new, highly permeable synthetic membranes. A new polysulfone hemofilter with high permeability and a sharp high cut-off membrane (CUREFLOTM; Asahi Kasei Kuraray Medical Co., Ltd., Tokyo, Japan) has been evaluated in this study to assess IL-6 and advanced oxidation protein product removal in critically ill patients undergoing continuous renal replacement therapy. Unit performance, sieving coefficients and clearances were evaluated in fourteen patients undergoing continuous veno-venous hemofiltration and continuous veno-venous hemodialysis. PMID- 21654166 TI - Hemoperfusion treatment in a septic shock patient with autosomal dominant polycystic kidney disease and increased HMGB1 protein levels. AB - This case report describes polymyxin B-immobilized fiber (PMX-F) treatment of septic shock caused by pyelonephritis in a 68-year-old woman with autosomal dominant polycystic kidney disease. She was admitted for severe lower left abdominal pain, high fever (40 degrees C) and gross hematuria. Her endotoxin and high-mobility group box-1 protein (HMGB1) levels were extremely elevated. Her blood pressure was 68/36 mm Hg. Urinalysis revealed innumerable white blood cells (WBCs). Blood and urine cultures were positive for Klebsiella pneumoniae and Pseudomonas aeruginosa. Plain abdominal radiography showed large kidney shadows and calcium deposition. Septic shock with endotoxemia was diagnosed. Her symptoms of septic shock persisted for 3 days with antibiotics, gamma-globulin and dopamine. Direct hemoperfusion was performed twice with a PMX-F column. The patient's body temperature, WBC count and C-reactive protein level decreased. Her blood endotoxin level and blood HMGB1 level also decreased to an almost normal level. She was discharged on day 23 after admission. PMID- 21654167 TI - Water saving in dialysis care through the consequent use of an environmental management system. PMID- 21654168 TI - Optimization of small-cell lung cancer chemotherapy with heparin: a comprehensive retrospective study of 239 patients treated in a single specialized center. AB - PURPOSE: In first-line management for small-cell lung cancer (SCLC), the combination of a platinum salt and etoposide is recommended, with thoracic radiotherapy and prophylactic cranial irradiation in selected patients. Anticoagulants, including heparin, are rarely used. We analyzed the results of these different treatments in a comprehensive population of patients with SCLC. PATIENTS AND METHODS: We retrospectively analyzed clinical and therapeutic characteristics of SCLC patients managed in our center during the period 1990 2002. RESULTS: First-, second- and third-line chemotherapy was received by 98.3, 47.3 and 11.7%, respectively; 55% received curative heparin. The 2-year survival rates were 31 and 7% among patients with localized and metastatic disease, 33 and 15% among patients treated with the PCDE (cisplatin-cyclophosphamide-doxorubicin etoposide) regimen with and without heparin, and 27 and 12% among patients treated with the PE (cisplatin or carboplatin-etoposide) regimen with and without heparin, respectively. The 2-year survival rate among the 27 patients who received an optimal combination of PCDE, heparin, thoracic radiotherapy and prophylactic cranial irradiation was 44.2%. In multivariate analysis, localized disease, younger age, use of heparin and inclusion in a clinical trial were independently associated with a better outcome. CONCLUSION: Despite the bias inherent in a retrospective, single-center study, these results support chemotherapy optimization for SCLC patients and confirm the value of heparin in this setting. PMID- 21654169 TI - Evaluation of elution and mechanical properties of two injectable chemotherapeutic bone cements. AB - Chemotherapeutic bone cements can both stabilize the bone fractures as well as deliver chemotherapy agents directly to the bone metastatic site and adjacent soft tissue tumors. This study evaluated the in vitro elution and flexural properties of VertebroplasticTM and Confidence UltraTM bone cements (Depuy Spine Inc., Raynham, Mass., USA) containing methotrexate. In vitro elution was measured by placing bone cement specimens containing 4 different methotrexate amounts in 20 ml saline, and the methotrexate elution was measured at regular intervals for 672 h. The flexural properties of bone cement containing 2 different initial methotrexate amounts after storage in physiological saline were measured using a 3-point bending test. The drug elution rate depended on the initial methotrexate amount added and the type of bone cement used. The relationship between the initial drug amount added and the drug elution rate was not linear. Methotrexate elution decreased the flexural modulus and strength of specimens; this decrease was not proportional to the initial amount of methotrexate added. The results show that bone cements are well suited for use with chemotherapy agents. However, the elution and mechanical properties of each bone cement-drug amount combination should be thoroughly quantified in vitro before using such a combination in a clinical setting. PMID- 21654170 TI - The effect of sinus rhythm restoration on high-sensitivity C-reactive protein levels and their association with long-term atrial fibrillation recurrence after electrical cardioversion. AB - OBJECTIVE: Recent studies have shown that high-sensitivity C-reactive protein (hs CRP) measured before cardioversion (CV) plays a significant role in predicting atrial fibrillation (AF) relapse. The time course of changes in hs-CRP after successful electrical CV remains controversial. The aim of the present study was to assess the prognostic value of pre- and post-CV hs-CRP levels in predicting the long-term risk of AF. Additionally, we evaluated changes in hs-CRP levels over time following a successful CV. METHODS: This prospective study comprised 216 patients with persistent AF who underwent CV (mean age 51.94 +/- 8.07 years; 55.6% men). hs-CRP levels were examined in all patients, and blood samples were taken prior to and 1, 2, 7 and 30 days after CV. AF relapse was determined by 24 hour ambulatory electrocardiogram (ECG) monitoring and 12-lead standard ECG during 12 months of follow-up. We further divided the study population into two groups according to their rhythm at the end of the follow-up period (group A: patients with AF at the end of follow-up; group B: patients with sinus rhythm at the end of the follow-up period). RESULTS: The AF recurrence rate was 42.2% throughout the 12-month follow-up period. The basal hs-CRP levels were higher in patients with an AF relapse than in those without (1.68 +/- 0.57 vs. 1.12 +/- 0.53 mg/dl; p < 0.01). The hs-CRP levels were significantly decreased at 30 days in group B, whereas there was no significant decrease in group A (from 1.12 +/- 0.53 to 0.69 +/- 0.33 mg/dl, p < 0.01, and from 1.68 +/- 0.57 to 1.69 +/- 0.76 mg/dl, p > 0.05, respectively). By multivariate Cox analysis, the independent predictors of AF relapse time points were the basal and day-2 hs-CRP levels. Receiver operating characteristic curve analysis showed that the cutoff value of hs-CRP on the 2nd day for predicting AF relapse was 1.85 mg/dl, with a sensitivity of 62%, a specificity of 82%, a positive predictive value of 85.7% and a negative predictive value of 81.6%. CONCLUSION: The hs-CRP levels both prior to and after CV predict the long-term risk of AF relapse. In the present study, hs-CRP levels were significantly decreased in patients who remained in sinus rhythm at the end of the study. In contrast, hs-CRP levels remained high throughout the follow-up in patients with an AF relapse. PMID- 21654171 TI - Multifactorial analysis of factors associated with the incidence and progression of erosive tooth wear. AB - To prevent erosive tooth wear, early diagnosis and identification of causative factors are essential. The aim of the present 3-year longitudinal study was to investigate the association between a broad collection of biological and behavioural factors and the incidence and progression of erosive tooth wear among adolescents. The study sample consisted of 656 attendees of a dental clinic with at baseline a mean age of 11.9 years (SD = 0.9). The criteria for the assessment of erosive wear were a modification of the erosion criteria developed by Lussi [Eur J Oral Sci 1996;104:191-198]. Information on biological and behavioural factors was gathered by clinical examinations (at baseline, after 1.5 and 3 years) and by self-reported questionnaires (completed semi-annually). Of the erosion-free children at baseline, 24.2% developed erosive wear. In children with erosion at baseline, 68.3% showed progression. Multivariate analyses showed significant associations between the incidence of erosive tooth wear and alcoholic mixed drinks (odds ratio, OR = 1.82), sour vegetables (OR = 1.16) and tooth grinding (OR = 4.03). The intake of yoghurt products was significantly negatively associated with the incidence of erosive wear (OR = 0.79). The interaction of acidic products and tooth grinding showed a significant extra risk (OR = 1.2). The intake of vitamins was positively associated with progression (OR = 2.03). Erosive wear was less likely to progress in subjects who consumed milk and yoghurt products (OR = 0.89 and 0.76, respectively). The present study showed that the aetiology of erosive tooth wear is complex. Possible aetiological factors include more than acidic drinks, and factors such as tooth grinding play a large role. PMID- 21654172 TI - Laparoscopy-assisted distal gastrectomy compared to open distal gastrectomy in early gastric cancer. AB - BACKGROUND: This study aimed to evaluate the feasibility of laparoscopy-assisted distal gastrectomy (LADG) in early gastric cancer (EGC) with special interest in a learning curve effect. METHODS: The clinical outcomes of EGC patients who underwent LADG (n = 100) and sex-, age- and body mass index- (BMI) matched EGC patients who underwent open distal gastrectomy (ODG; n = 100) were compared retrospectively. In addition, the outcomes between the early (n = 50) and late LADG group (n = 50) were compared. RESULTS: The mean number of retrieved lymph nodes was significantly smaller in the LADG group than in the ODG group (29.3 vs. 36.4, p < 0.001). The operative time of the LADG group was significantly longer than in the ODG group (249.1 vs. 152.9 min, p < 0.001). The complication rates were comparable between both groups (14 vs. 13%, p = 0.84). No cancer-related death was observed in either group. Between early and late LADG groups, the operative time was shorter (p < 0.001) and the number of retrieved lymph nodes was higher (p = 0.016) in the late group. CONCLUSIONS: LADG seems to be a safe and feasible procedure in treating EGC, as it shows comparable outcomes with ODG. The potential disadvantages of LADG, such as longer operation time and smaller number of retrieved lymph nodes, diminished after overcoming the learning curve. PMID- 21654173 TI - Apparent diffusion coefficient values measured by diffusion-weighted imaging predict chemoradiotherapeutic effect for advanced esophageal cancer. AB - BACKGROUND: The purpose of this study was to assess whether apparent diffusion coefficient (ADC) values of esophageal squamous cell carcinoma (ESCC) predict responses to chemoradiotherapy (CRT) and/or patient prognosis. METHODS: Magnetic resonance images were acquired to construct the diffusion-weighted images, and the ADC values were calculated before CRT in 80 patients with ESCC. A high-ADC group responded better to CRT than did a low-ADC group (p < 0.01). We divided the 80 patients into two groups based on the operating characteristic analysis: one group comprised patients with ADC values higher than the average ADC of the esophageal cancer tissue (1.10 * 10(-3) mm2/s), and the other group comprised those whose ADC values were less than the average value. A Kaplan-Meier analysis showed that the survival rate in the high-ADC group was significantly better than that in the low-ADC group (p = 0.04). CONCLUSION: Our results indicate that the ADC value may be a useful marker to predict treatment response as well as survival for patients with ESCC. PMID- 21654174 TI - Angiotensin-converting enzyme gene insertion/deletion polymorphism in patients with chronic pancreatitis and pancreatic cancer. AB - The purpose of this study was to determine the frequency of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and to investigate its role as a potential risk factor in patients with chronic pancreatitis and pancreatic cancer. Deletion polymorphism of the 287-bp fragment of intron 16 of the ACE gene results in higher levels of circulating enzyme and therefore may represent a risk factor for disease development. The study included 55 patients with chronic pancreatitis, 45 patients with pancreatic cancer and 128 healthy subjects. The presence of I and D variants in the ACE gene was analyzed by a polymerase chain reaction (PCR) method. Distribution of ACE ID genotypes was analyzed by means of logistic regression. When chronic pancreatitis and pancreatic cancer groups were compared in the univariate analysis, the following factors were identified as statistically significant predictors of pancreatic disease: age, gender, smoking, fat intake, ACE II genotype and ACE DD genotype. However, in the multivariate analysis, only age, gender and smoking were singled out as predictors for the occurrence of pancreatic disease. Our findings indicate that the ACE I/D polymorphism could play a role in the development of chronic pancreatitis and pancreatic cancer through interaction with other genetic and environmental factors. PMID- 21654175 TI - The Geneva Appetitive Alcohol Pictures (GAAP): development and preliminary validation. AB - This study describes a new database of alcohol-related pictures: The Geneva Appetitive Alcohol Pictures (GAAP). 60 alcohol-related pictures (beverages, drinking-related behaviors, alcohol-related cues) were presented to 101 participants (ranging from social drinkers to problem drinkers), who assessed them according to the classic emotional pictures validation provided by the International Affective Picture System (Center for the Study of Emotion and Attention (CSEA[-]NIMH), 2002). Participants were also screened with the Alcohol Use Disorders Identification Test. Normative ratings for valence, arousal and dominance of the pictures are provided separately for problem/risky users (n = 49) and non-risky drinkers (n = 52). The GAAP is a normative database that provides a large number of stimuli for investigators who conduct research on alcohol. PMID- 21654176 TI - Attention deficit hyperactivity disorder among pathological and at-risk gamblers seeking treatment: a hidden disorder. AB - BACKGROUND: The links between attention deficit hyperactivity disorder (ADHD) and substance use disorders have been the subject of numerous papers. Few studies, however, have focused specifically on the relationship between ADHD and behavioural addictions. The aim of this study was to (i) examine the frequency of pathological and at-risk gamblers having a previous history of ADHD; (ii) give details of the characteristics of this association, and (iii) identify risk factors for a history of ADHD. METHODS: 84 pathological and at-risk gamblers were assessed about socio-demographic, gambling and clinical characteristics. RESULTS: Over 25% of the subjects had a history of ADHD. They were characterized as having more severe gambling problems and a higher level of gambling-related cognitions, a higher frequency of psychiatric comorbidities and an elevated risk of suicide. Finally, they differed in their level and type of impulsivity. Among pathological and at-risk gamblers, a high level of impulsivity, or a history of anxiety disorders, constitute risk factors for a comorbidity with ADHD. CONCLUSION: The association 'ADHD-problem gambling' therefore appears to be not only frequent, but also linked to factors that are known to worsen the prognosis. Researching this relationship is therefore important to adapt strategies for effective future therapy. PMID- 21654177 TI - The vicious circle of perceived stigmatization, depressiveness, anxiety, and low quality of life in substituted heroin addicts. AB - BACKGROUND: Perceived stigmatization of drug addicts may interact with negative mood states and thus may contribute to the maintenance of addictive behavior. METHODS: Opiate maintenance patients (n = 106) and an unselected comparison group (n = 144) rated self-report questionnaires about perceived stigmatization, quality of life (QoL), depressiveness, anxiety, self-esteem, addiction characteristics, and social support. RESULTS: 63% of opiate maintenance patients felt discriminated in contrast to 16% of the comparison group. Perceived stigmatization was rated higher by opiate maintenance patients, and all domains of QoL were rated lower, even when statistically controlling depressiveness, anxiety and social factors. Perceived stigmatization was correlated to depressiveness, anxiety, low self-esteem and low QoL, but not addiction characteristics and social support. Structural equation models revealed anxiety and the pathway depressiveness enhancing feelings of being stigmatized resulting in low self-esteem to explain 74% of variance in mental QoL, whereas anxiety and a pathway stigmatization inducing depressiveness leading to low self-esteem explained 49% of variance in physical QoL. CONCLUSIONS: A vicious circle of stigmatization, negative affective states and low QoL was confirmed. In addition to societal antistigma campaigns, antidepressive and anxiolytic therapy might have the potential to diminish feelings of being stigmatized and to improve QoL. PMID- 21654178 TI - Moderate strontium loading induces rickets in rats with mild chronic renal failure. AB - BACKGROUND/AIMS: Renal osteodystrophy and eventually osteoporosis are serious long-term complications in children with end-stage renal disease before and after renal transplantation. Strontium (Sr) salts are used for treatment of osteoporosis in adults. METHODS: To evaluate the time-dependent effects of Sr on growth plate morphology and their reversibility, chronic renal failure (CRF) rats received either normal or Sr-loaded drinking water (2 g/l; +/-200 mg/kg/day) for periods of 2, 6 and 12 weeks with or without subsequent washout periods of 0, 2, 4 or 8 weeks. RESULTS: While weight gain was not affected by Sr loading, a significant enlargement of the entire growth plate, mainly due to expansion of the hypertrophic zone, was already present after 2 weeks. Sr-loaded animals showed increased osteoid areas and reduced bone formation rates at 2, 6 and 12 weeks compared to controls. This was accompanied by reduced PTH levels and increased serum bone alkaline phosphatase activity. After the washout periods these effects were reversed. In general, the height of the hypertrophic zone was positively correlated with osteoid area and negatively correlated with bone formation rate. CONCLUSION: Moderate Sr loading in CRF rats results in rapid development of rickets, which is reversible after washout. PMID- 21654179 TI - Varicella zoster infection in renal transplant recipients: prevalence, complications and outcome. AB - Varicella zoster virus (VZV) is an important pathogen after renal transplantation. In the present study, we examined the prevalence, clinical presentation and outcome of VZV infections in renal transplant recipients. Charts and medical records of adult renal allotransplant recipients were investigated to find patients with VZV infection. From December 1972 until July 2010, 1,139 patients received kidney allograft at our institution. VZV infection was diagnosed in 40 patients (3.51%). 28 patients (70%) had intensified immunosuppression prior to VZV infection occurrence. Median time of onset was 2.13 years after transplantation (range 9 days to 19.2 years). 35 patients developed VZV during the first post-transplant year (median 0.61 years). Four patients developed VZV infection more than 12 years after transplantation. 33 patients (82.5%) had dermatomal distribution, 5 (12.5%) disseminated herpes zoster (HZ), and 2 patients (5%) who were VZV IgG-negative before transplantation, developed chickenpox. Immunosuppression was reduced and patients received acyclovir. Cutaneous scarring was recorded in 7 cases (17.5%). Two patients developed post-herpetic neuralgia, which was accompanied by scarring and skin depigmentation in 1 of them. Five patients (12.5%) experienced relapse of HZ. Timely initiation of therapy may prevent development of complications and the visceral form of disease. Based on our experience with development of chickenpox, we suggest active immunization for all seronegative patients before organ transplantation. PMID- 21654180 TI - Parallel deterioration of albuminuria, arterial stiffness and left ventricular mass in essential hypertension: integrating target organ damage. AB - BACKGROUND: Albuminuria, arterial stiffening and left ventricular hypertrophy (LVH) constitute target organ damage. We estimated whether increased urinary albumin excretion, assessed by albumin-to-creatine ratio (ACR), and carotid to femoral pulse wave velocity (c-f PWV) were accompanied by augmented left ventricular (LV) mass index (LVMI) in hypertension. METHODS: In 428 non-diabetic untreated hypertensives (257 men, mean age = 52 years, office blood pressure (BP) = 146/93 mm Hg) the distributions of ACR and c-f PWV were split by the median (8 mg/g and 7.8 m/s, respectively). RESULTS: Age, male sex, 24 h systolic BP, ACR and c-f PWV were the independent predictors of LVMI (R(2) = 0.478, p < 0.0001). Among patients with low ACR (n = 198), those with high c-f PWV (n = 84) compared to those with low c-f PWV (n = 114) were characterized by increased LVMI (by 8.9 g/m(2), p = 0.012) and prevalence of LVH (30 vs. 14%, p = 0.015). Similarly among patients with high ACR (n = 230), those with high c-f PWV (n = 123) compared to those with low c-f PWV (n = 107) exhibited heightened LVMI (by 13.6 g/m(2), p = 0.001). CONCLUSIONS: Increased ACR in conjunction with pronounced arterial stiffness is accompanied by augmented LV mass and higher LVH rates. Furthermore, the interrelationships between albuminuria, c-f PWV and LVMI suggest parallel target organ damage progression. PMID- 21654181 TI - Prevalence of chronic kidney disease and associated risk factors, and risk of end stage renal disease: data from the PREVADIAB study. AB - BACKGROUND/AIMS: Chronic kidney disease (CKD) is a growing public health problem. However, data on risk factors and prevalence of CKD exist only in a small number of countries. Portugal has the highest incidence of end-stage renal disease (ESRD) among European countries, but there are huge disparities among countries. Whether these disparities reflect differences in risk factors, prevalence of CKD or other factors is currently unknown. METHODS: We analyzed data from a nationally representative sample of 5,167 subjects, and estimated the prevalence of CKD and associated risk factors, and combined these prevalence estimates with available data on ESRD. RESULTS: The prevalence of risk factors such as diabetes (11.7%), obesity (33.7%), and metabolic syndrome (41.5%) was similar to that in the US, but greater than in most European countries. The prevalence of CKD stages 3-5 was 6.1%, which is similar to that in other Western countries. The risk of ESRD was greater than in other European countries, but lower than in the US. CONCLUSION: The high incidence of ESRD among the Portuguese population is not due to a greater prevalence of CKD. A higher rate of progression associated with the high prevalence of risk factors may account for the high incidence of ESRD. The role of unmeasured factors needs to be evaluated in further studies. PMID- 21654184 TI - Message from the president: the future of IAP. PMID- 21654182 TI - A time to be born and a time to die: ethical challenges in the neonatal intensive care unit. PMID- 21654185 TI - Statistical alchemy for drug treatment of generalized anxiety disorder: a commentary on the meta-analysis by Baldwin et al. [BMJ 2011;342:d1199]. PMID- 21654186 TI - Expression and functional analysis of Dkk1 during early gonadal development. AB - WNT signalling plays a central role in mammalian sex determination by promoting ovarian development and repressing aspects of testis development in the early gonad. Dickkopf homolog 1 (DKK1) is a WNT signalling antagonist that plays critical roles in multiple developmental systems by modulating WNT activity. Here, we examined the role of DKK1 in mouse sex determination and early gonadal development. Dkk1 mRNA was upregulated sex-specifically during testis differentiation, suggesting that DKK1 could repress WNT signalling in the developing testis. However, we observed overtly normal testis development in Dkk1 null XY gonads, and found no significant upregulation of Axin2 or Sp5 that would indicate increased canonical WNT signalling. Nor did we find significant differences in expression of key markers of testis and ovarian development. We propose that DKK1 may play a protective role that is not unmasked by loss-of function in the absence of other stressors. PMID- 21654187 TI - Ischemic postconditioning protects cardiomyocytes against ischemia/reperfusion injury by inducing MIP2. AB - Cardiomyocytes can resist ischemia/reperfusion (I/R) injury through ischemic postconditioning (IPoC) which is repetitive ischemia induced during the onset of reperfusion. Myocardial ischemic preconditioning up-regulated protein 2 (MIP2) is a member of the WD-40 family proteins, we previously showed that MIP2 was up regulated during ischemic preconditioning (IPC). As IPC and IPoC engaged similar molecular mechanisms in cardioprotection, this study aimed to elucidate whether MIP2 was up-regulated during IPoC and contributed to IPoC-mediated protection against I/R injury. The experiment was conducted on two models, an in vivo open chest rat coronary artery occlusion model and an in vitro model with H9c2 myogenic cells. In both models, 3 groups were constituted and randomly designated as the sham, I/R and IPoC/hypoxia postconditioning (HPoC) groups. In the IPoC group, after 45 min of ischemia, hearts were allowed three cycles of reperfusion/ischemia phases (each of 30 s duration) followed by reperfusion. In the HPoC group, after 6 h of hypoxia, H9c2 cells were subjected to three cycles of 10 minute reoxygenation and 10 minute hypoxia followed by reoxygenation. IPoC significantly reduced the infarct size, plasma level of Lactate dehydrogenase and creatine kinase MB in rats. 12 h after the reperfusion, MIP2 mRNA levels in the IPoC group were 10 folds that of the sham group and 1.4 folds that of the I/R group. Increased expression of MIP2 mRNA and attenuation of apoptosis were similarly observed in the HPoC group in the in vitro model. These effects were blunted by transfection with MIP2 siRNA in the H9c2 cells. This study demonstrated that IPoC induced protection was associated with increased expression of MIP2. Both MIP2 overexpression and MIP2 suppression can influence the IPoC induced protection. PMID- 21654188 TI - Roles of gangliosides in mouse embryogenesis and embryonic stem cell differentiation. AB - Gangliosides have been suggested to play important roles in various functions such as adhesion, cell differentiation, growth control, and signaling. Mouse follicular development, ovulation, and luteinization during the estrous cycle are regulated by several hormones and cell-cell interactions. In addition, spermatogenesis in seminiferous tubules of adult testes is also regulated by several hormones, including follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and cell-cell interactions. The regulation of these processes by hormones and cell-cell interactions provides evidence for the importance of surface membrane components, including gangliosides. During preimplantation embryo development, a mammalian embryo undergoes a series of cleavage divisions whereby a zygote is converted into a blastocyst that is sufficiently competent to be implanted in the ma ternal uterus and continue its development. Mouse embryonic stem (mES) cells are pluripotent cells derived from mouse embryo, specifically, from the inner cell mass of blastocysts. Differentiated neuronal cells are derived from mES cells through the formation of embryonic bodies (EBs). EBs recapitulate many aspects of lineage-specific differentiation and temporal and spatial gene expression patterns during early embryogenesis. Previous studies on ganglioside expression during mouse embryonic development (including during in vitro fertilization, ovulation, spermatogenesis, and embryogenesis) reported that gangliosides were expressed in both undifferentiated and differentiated (or differentiating) mES cells. In this review, we summarize some of the advances in our understanding of the functional roles of gangliosides during the stages of mouse embryonic development, including ovulation, spermatogenesis, and embryogenesis, focusing on undifferentiated and differentiated mES cells (neuronal cells). PMID- 21654189 TI - Myeloid differentiation primary response protein 88 blockade upregulates indoleamine 2,3-dioxygenase expression in rheumatoid synovial fibroblasts. AB - Indoleamine 2,3-dioxygenase (IDO) is a key negative regulator of immune responses and has been implicated in tumor tolerance, autoimmune disease and asthma. IDO was detected in the joint synovial tissue in the inflammatory microenvironment of rheumatoid arthritis (RA), but IDO expression in joint synovial tissue is not sufficient to overcome the inflamed synovial environment. This study aimed to unravel the mechanisms involving the failure to activate tolerogenic IDO in the inflamed joint. We demonstrate that both poly (I:C) and lipopolysaccharide (LPS) induce expression of IDO in synovial fibroblasts. However, inflammatory cytokines such as IL-17, TNF-alpha, IL-12, IL-23 and IL-16 did not induce IDO expression. Poly (I:C) appeared to induce higher IDO expression than did LPS. Surprisingly, toll-like receptor (TLR)4-mediated IDO expression was upregulated after depletion of myeloid differentiation primary response protein 88 (MyD88) in synovial fibroblasts using small interfering RNA (siRNA). IDO, TLR3 and TLR4 were highly expressed in synovial tissue of RA patients compared with that of osteoarthritis patients. In addition, RA patients with severe disease activity had higher levels of expression of IDO, TLR3 and TLR4 in the synovium than patients with mild disease activity. These data suggest that upregulation of IDO expression in synovial fibroblasts involves TLR3 and TLR4 activation by microbial constituents. We showed that the mechanisms responsible for IDO regulation primarily involve MyD88 signaling in synovial fibroblasts, as demonstrated by siRNAmediated knockdown of MyD88. PMID- 21654190 TI - Accelerated aging in the tumor microenvironment: connecting aging, inflammation and cancer metabolism with personalized medicine. AB - Cancer is thought to be a disease associated with aging. Interestingly, normal aging is driven by the production of ROS and mitochondrial oxidative stress, resulting in the cumulative accumulation of DNA damage. Here, we discuss how ROS signaling, NFkappaB- and HIF1-activation in the tumor microenvironment induces a form of "accelerated aging," which leads to stromal inflammation and changes in cancer cell metabolism. Thus, we present a unified model where aging (ROS), inflammation (NFkappaB) and cancer metabolism (HIF1), act as co-conspirators to drive autophagy ("self-eating") in the tumor stroma. Then, autophagy in the tumor stroma provides high-energy "fuel" and the necessary chemical building blocks, for accelerated tumor growth and metastasis. Stromal ROS production acts as a "mutagenic motor" and allows cancer cells to buffer-at a distance-exactly how much of a mutagenic stimulus they receive, further driving tumor cell selection and evolution. Surviving cancer cells would be selected for the ability to induce ROS more effectively in stromal fibroblasts, so they could extract more nutrients from the stroma via autophagy. If lethal cancer is a disease of "accelerated host aging" in the tumor stroma, then cancer patients may benefit from therapy with powerful antioxidants. Antioxidant therapy should block the resulting DNA damage, and halt autophagy in the tumor stroma, effectively "cutting off the fuel supply" for cancer cells. These findings have important new implications for personalized cancer medicine, as they link aging, inflammation and cancer metabolism with novel strategies for more effective cancer diagnostics and therapeutics. PMID- 21654191 TI - Bid as a potential target of apoptotic effects exerted by low doses of PPARgamma and RXR ligands in breast cancer cells. AB - The combined treatment with nanomolar doses of the PPARgamma ligand Rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) induces a p53-dependent apoptosis in MCF7, SKBR3 and T47D human breast cancer cells. Since MCF7 cells express a wild-type p53 protein, while SKBR3 and T47D cells harbor endogenous mutant p53, we elucidated the mechanism through which PPARgamma and RXR ligands triggered apoptotic processes independently of p53 transcriptional activity. We showed an upregulation of Bid expression enhancing the association between Bid/p53 in both cytosol and mitochondria after the ligand treatment. Particularly in the mitochondria, the complex involves the truncated Bid that plays a key role in the apoptotic process induced by BRL and 9RA, since the disruption of mitochondrial membrane potential, the induction of PARP cleavage and the percentage of TUNEL-positive cells were reversed after knocking down Bid. Moreover, PPARgamma and RXR ligands were able to reduce mitochondrial GST activity, which was no longer noticeable silencing Bid expression, suggesting the potential of Bid in the regulation of mitochondrial intracellular reactive oxygen species scavenger activity. Our data, providing new insight into the role of p53/Bid complex at the mitochondria in promoting breast cancer cell apoptosis upon low doses of PPARgamma and RXR ligands, address Bid as a potential target in the novel therapeutical strategies for breast cancer. PMID- 21654192 TI - Azacitidine-resistant SKM1 myeloid cells are defective for AZA-induced mitochondrial apoptosis and autophagy. AB - Azacitidine (AZA) is the current treatment for patients with high-risk myelodysplastic syndrome, but resistance is a common feature of AZA-treated patients. To investigate the mechanisms associated with AZA resistance in vitro, we generated AZA-resistant SKM1 myeloid cells, called hereafter AZA-R. AZA-R cells exhibit impaired mitochondrial membrane permeabilization and caspase activation in response to AZA compared to their AZA-sensitive (AZA-S) counterpart. AZA induced LC3-II accumulation and cathepsin B activity in AZA-S cells, two hallmarks of autophagy. AZA-R cells displayed increased basal autophagy but are resistant to AZA-mediated autophagy. Inhibition of autophagy using LC3 siRNA revealed that autophagy is protective in AZA-S cells and AZA-R cells in basal conditions. By contrast, AZA-R cells exhibited impaired autophagy in response to AZA. Collectively, our findings indicate that AZA promotes apoptosis and autophagy in SKM1 cells, and that AZA-R cells are resistant to both apoptosis and autophagy induced by AZA. PMID- 21654193 TI - Hypomethylating agents reactivate FOXO3A in acute myeloid leukemia. AB - The deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agent, notably azacitidine, constitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine, and to a lesser degree azacitidine, induced the activation of checkpoint kinases Chk-1 and Chk-2 and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box O3, best known as FOXO3A, whose phosphorylation has been related to poor prognosis in AML. The dephoasphorylation of FOXO3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FOXO3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML derived, azacitidine-sensitive SKM-1S cells upregulated FOXO3A and the pro apoptotic FOXO3A targets BIM and PUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the reactivation of FOXO3A may contribute to the effects of hypomethylating agents in malignant blasts. PMID- 21654195 TI - Stem cell induced cardiac regeneration: fusion/mitochondrial exchange and/or transdifferentiation? AB - Potentially, adult stem cell-based therapy provides a new therapeutic option for myocardial regeneration. However, to date, with regard to the benefits seen, the mechanisms involved in stem cell-based therapy are not well understood. Suggested pathways proposed so far include fusion of stem cells with cardiomyocytes, transdifferentiation into cardiac and vascular cells and secretion of paracrine factors. In a recent study, our group examined the fate of human adipose tissue derived stem cells (hASCs) fused with rat cardiomyocytes after treatment with fusion-inducing hemagglutinating virus of Japan (HVJ). In this study, we demonstrated that cells of fused hASC cardiomyocytes display a cardiomyocyte phenotype and spontaneous rhythmic contraction and generate an action potential in vitro. As part of the work underlying this paper, we co-cultured rat neonatal cardiomyocytes with hASCs or pig bone marrow-derived mesenchymal stem cells (MSCs), where ASCs or MSCs had previously been transduced with a lentivirus encoding eGFP. Our data evidence early cardiac contractile proteins, such as Titin and MF20, identified in eGFP-positive cells, suggesting a cardiomyogenic phenotype. Recent work by others has shown that the myogenic conversion increased when BMSCs were cultured with apoptotic cells. In this Extra View article, we review the current understanding of stem cell-derived factors, fusion/partial fusion and the manner in which the exchange of cellular contents between stem cells and cardiomyocytes might contribute to the reprogramming of fully differentiated cardiomyocytes based on recently published literature. PMID- 21654196 TI - Ral's engagement with the exocyst: breaking up is hard to do. AB - Small GTPases are key intermediates that operate at the crossroads of signaling and trafficking. During insulin-stimulated glucose transport, activation of the vesicular-localized small GTPase RalA leads to its engagement with the vesicle tethering exocyst complex, mediating the plasma membrane targeting of Glut4 vesicles. Activation of RalA is achieved via inhibition of the Ral GAP Complex (RGC), comprised of the regulatory subunit RGC1 and the catalytic subunit RGC2. RGC1/2 share homology with the Rheb GAP complex TSC1/2 and can also be inactivated by Akt-catalyzed phosphorylation to produce RalA activation and exocyst engagement. Disengagement between the GTPase and the exocyst occurs through phosphorylation of its effector Sec5 in its Ral-binding domain, thus allowing continuation of exocytic program and recycling of the tether. Phosphorylation of Sec5 is catalyzed by protein kinase C (PKC) and can be reversed by an exocyst-associated phosphatase activity. Therefore, integration of the GTPase cycle and the phosphorylation cycle orchestrates the engagement disengagement switch between Ral GTPases and the effector exocyst. PMID- 21654194 TI - From Plk1 to Plk5: functional evolution of polo-like kinases. AB - Mammalian polo-like kinases (Plks) are characterized by the presence of an N terminal protein kinase domain and a C-terminal polo-box domain (PBD) involved in substrate binding and regulation of kinase activity. Plk1-4 have traditionally been linked to cell cycle progression, genotoxic stress and, more recently, neuron biology. Recently, a fifth mammalian Plk family member, Plk5, has been characterized in murine and human cells. Plk5 is expressed mainly in differentiated tissues such as the cerebellum. Despite apparent loss of catalytic activity and a stop codon in the middle of the human gene, Plk5 proteins retain important functions in neuron biology. Notably, its expression is silenced by epigenetic alterations in brain tumors, such as glioblastomas, and its re expression prevents cell proliferation of these tumor cells. In this review, we will focus on the non-cell cycle roles of Plks, the biology of the new member of the family and the possible kinase- and PBD-independent functions of polo-like kinases. PMID- 21654197 TI - Engraftment of cells from porcine islets of Langerhans following transplantation of pig pancreatic primordia in non-immunosuppressed diabetic rhesus macaques. AB - Transplantation therapy for human diabetes is limited by the toxicity of immunosuppressive drugs. If toxicity can be minimized, there will still be a shortage of human donor organs. Xenotransplantation of porcine islets is a strategy to overcome supply problems. Xenotransplantation in mesentery of pig pancreatic primordia obtained very early during organogenesis [embryonic day 28 (E28)] is a way to obviate the need for immunosuppression in rats or rhesus macaques and to enable engraftment of a cell component originating from porcine islets implanted beneath the renal capsule of rats. Here, we show engraftment in the kidney of insulin and porcine proinsulin mRNA-expressing cells following implantation of porcine islets beneath the renal capsule of diabetic rhesus macaques transplanted previously with E28 pig pancreatic primordia in mesentery. Donor cell engraftment is confirmed using fluorescent in situ hybridization (FISH) for the porcine X chromosome and is supported by glucose-stimulated insulin release in vitro. Cells from islets do not engraft in the kidney without prior transplantation of E28 pig pancreatic primordia in mesentery. This is the first report of engraftment following transplantation of porcine islets in non immunosuppressed, immune-competent non-human primates. The data are consistent with tolerance to a cell component of porcine islets induced by previous transplantation of E28 pig pancreatic primordia. PMID- 21654198 TI - The 21(st) Ion Channel Meeting, September 2010, France. AB - On September 12-15, 2010 the French Ion Channels Association organized its annual scientific meeting on the French coast of Mediterranean Sea. This meeting takes place in an attractive location and provides a great opportunity for principal investigators as well as young researchers to present and discuss their recent advances and future challenges in the field of ion channels and transporters. The French Ion Channels Association was created more than 20 years ago and its goal is to organize an annual meeting and more recently to promote interactions (through the website www.canaux-ioniques.fr) between active members of the international scientific community in the field of ion channels. In this report of the 21(st) edition of the meeting, we are summarizing the five main symposia that reflect original works and relevant developments in the domain of ions channels and transporters. PMID- 21654199 TI - The calmodulin antagonist W-7 inhibits the epithelial Na+/H+ exchanger via modulating membrane surface potential. AB - NHE3 is regulated via alterations in membrane surface charge. This is achieved through altered binding of cationic regions in the cytosolic-terminus of the exchanger with the inner leaflet of the plasma membrane. Calmodulin antagonists, including W-7, regulate surface potential and inhibit NHE3 activity. Utilizing fluorescent protein conjugated membrane probes we show that binding of cationic, but not hydrophobic peptides, to the plasma membrane is prevented by W-7. An interaction between cationic regions in the regulatory, cytosolic domain of NHE3 to anionic phospholipids in either reconstituted liposomes or the plasma membrane in cell culture is similarly prevented by W-7, at a concentration that inhibits the exchanger. We propose therefore that W-7 inhibits NHE3 activity, at least in part, by altering the association of cationic segments within the carboxy terminus of the exchanger with anionic phospholipids in the plasma membrane. PMID- 21654200 TI - Nano-environmental changes by KCNE proteins modify KCNQ channel function. AB - The KCNQ1 channel is a voltage-dependent potassium channel, which is widely expressed in various tissues of the human body including heart, inner ear, intestine, kidney and pancreas. The ion channel properties of KCNQ1 change remarkably when auxiliary subunit KCNE proteins co-exist. The mechanisms of KCNQ1 channel regulation by KCNE proteins are of longstanding interest but are still far from being fully understood. The pore region (S5-S6 segments) of KCNQ1 is thought to be the main interaction site for KCNE proteins. However, some recent reports showed that the voltage-sensing domain (S1-S4 segments) is critically involved in the regulation of KCNQ1 by KCNE proteins. In addition, we recently re-examined the stoichiometry of the KCNQ1-KCNE1 complex and found that the stoichiometry is not fixed but rather flexible and the KCNQ1 channel can have up to four associated KCNE1 proteins. We will review these recent findings concerning the mechanisms of KCNQ1 regulation by KCNE proteins. PMID- 21654202 TI - Dissecting TRPV1: lessons to be learned? AB - The transient receptor potential channel TRPV1 is a polymodal nociceptor. It is primarily expressed in dorsal root ganglia and peripheral sensory nerve endings, and to a much lesser extent, in the central nervous system. It has also been implicated in the functional properties of e.g. urinary and bronchial epithelia. TRPV1 has long been under intensive investigation by the pharmaceutical industry as a candidate drug target especially for pain conditions. This review summarizes the current knowledge of the molecular determinants of TRPV1 channel activation by heat, protons and capsaicin. Newly discovered heat and proton activation sites within the pore domain are discussed as well as potential consequences for drug discovery. Polymodal TRPV1 antagonists were found to cause hyperthermia in a species-dependent manner in-vivo, hence the discovery of euthermic compounds with an appropriate modality selectivity profile will be crucial for TRPV1's future as a drug target. PMID- 21654201 TI - Transsynaptic channelosomes: non-conducting roles of ion channels in synapse formation. AB - Recent findings demonstrate that synaptic channels are directly involved in the formation and maintenance of synapses by interacting with synapse organizers. The synaptic channels on the pre- and postsynaptic membranes possess non-conducting roles in addition to their functional roles as ion-conducting channels required for synaptic transmission. For example, presynaptic voltage-dependent calcium channels link the target-derived synapse organizer laminin beta2 to cytomatrix of the active zone and function as scaffolding proteins to organize the presynaptic active zones. Furthermore, postsynaptic delta2-type glutamate receptors organize the synapses by forming transsynaptic protein complexes with presynaptic neurexins through synapse organizer cerebellin 1 precursor proteins. Interestingly, the synaptic clustering of AMPA receptors is regulated by neuronal activity-regulated pentraxins, while postsynaptic differentiation is induced by the interaction of postsynaptic calcium channels and thrombospondins. This review will focus on the non-conducting functions of ion-channels that contribute to the synapse formation in concert with synapse organizers and active-zone-specific proteins. PMID- 21654203 TI - Unaltered prion protein expression in Alzheimer disease patients. AB - The suggested role of cellular prion protein (PrP (C) ) in mediating the toxic effects of oligomeric amyloid beta peptide (Abeta) in Alzheimer disease (AD) is controversial. To address the hypothesis that variable PrP (C) expression is involved in AD pathogenesis, we analyzed PrPC expression in the frontal and temporal cortices and hippocampus of individuals with no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), mild AD (mAD), and AD. We found that PrP (C) expression in all brain regions was not significantly altered among the various patient groups. In addition, PrP (C) levels in all groups did not correlate with expression of methionine (M) or valine (V) at codon 129 of the PrP gene, a polymorphism that has been linked in some studies to increased risk for AD, and which occurs in close proximity to the proposed binding region for the oligomeric Abeta peptide. Our results indicate that, if PrP (C) is involved in mediating the toxic effects of the oligomeric Abeta peptide, these effects occur independently of steady state levels of PrP or the codon 129 polymorphism. PMID- 21654205 TI - Bispecific antibodies and ADCs: Once and future kings? PMID- 21654204 TI - Insights into prion biology: integrating a protein misfolding pathway with its cellular environment. AB - Protein misfolding and assembly into ordered, self-templating aggregates (amyloid) has emerged as a novel mechanism for regulating protein function. For a subclass of amyloidogenic proteins known as prions, this process induces transmissible changes in normal cellular physiology, ranging from neurodegenerative disease in animals and humans to new traits in fungi. The severity and stability of these altered phenotypic states can be attenuated by the conformation or amino-acid sequence of the prion, but in most of these cases, the protein retains the ability to form amyloid in vitro. Thus, our ability to link amyloid formation in vitro with its biological consequences in vivo remains a challenge. In two recent studies, we have begun to address this disconnect by assessing the effects of the cellular environment on traits associated with the misfolding of the yeast prion Sup35. Remarkably, the effects of quality control pathways and of limitations on protein transfer in vivo amplify the effects of even slight differences in the efficiency of Sup35 misfolding, leading to dramatic changes in the associated phenotype. Together, our studies suggest that the interplay between protein misfolding pathways and their cellular context is a crucial contributor to prion biology. PMID- 21654206 TI - Comparability analysis of protein therapeutics by bottom-up LC-MS with stable isotope-tagged reference standards. AB - Comparability studies lie at the heart of assessments that evaluate differences amongst manufacturing processes and stability studies of protein therapeutics. Low resolution chromatographic and electrophoretic methods facilitate quantitation, but do not always yield detailed insight into the effect of the manufacturing change or environmental stress. Conversely, mass spectrometry (MS) can provide high resolution information on the molecule, but conventional methods are not very quantitative. This gap can be reconciled by use of a stable isotope tagged reference standard (SITRS), a version of the analyte protein that is uniformly labeled (13)C6-arginine and (13)C6-lysine. The SITRS serves as an internal control that is trypsin-digested and analyzed by liquid chromatography (LC)-MS with the analyte sample. The ratio of the ion intensities of each unlabeled and labeled peptide pair is then compared to that of other sample(s). A comparison of these ratios provides a readily accessible way to spot even minute differences among samples. In a study of a monoclonal antibody (mAb) spiked with varying amounts of the same antibody bearing point mutations, peptides containing the mutations were readily identified and quantified at concentrations as low as 2% relative to unmodified peptides. The method is robust, reproducible and produced a linear response for every peptide that was monitored. The method was also successfully used to distinguish between two batches of a mAb that were produced in two different cell lines while two batches produced from the same cell line were found to be highly comparable. Finally, the use of the SITRS method in the comparison of two stressed mAb samples enabled the identification of sites susceptible to deamidation and oxidation, as well as their quantitation. The experimental results indicate that use of a SITRS in a peptide mapping experiment with MS detection enables sensitive and quantitative comparability studies of proteins at high resolution. PMID- 21654207 TI - Anti-cetuximab IgE ELISA for identification of patients at a high risk of cetuximab-induced anaphylaxis. AB - Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, has proven effective in the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck. However, a high incidence of immediate hypersensitivity reactions (HSR) to cetuximab after the first infusion has been observed. We have developed a test for identification of patients likely to show treatment-related HSR to cetuximab. An enzyme-linked immunosorbent assay (ELISA) for detecting anti-cetuximab IgEs was developed and tested on serum samples collected from cancer patients before start of cetuximab treatment, and from healthy blood donors. Similar levels of anti-cetuximab IgE were detected in pre-treatment patient sera (24/92, 26.1%) and sera from healthy blood donors (33/117, 28.2%). HSR were observed in 14 out of the 92 patients (15.2%), and 8 of these (57.1%) were grade 3-4. Anti-cetuximab IgEs were detected in 7/8 of the patients (87.5%) with severe HSRs as compared with 14/78 patients (17.9%) with no HSR (p=0.0002). Predictive value of the anti-cetuximab IgE test for HSR events of grades 3-4 was calculated using Receiver Operating Characteristics analysis. With a cut-off value of 29 arbitrary units for the anti cetuximab IgE, the ELISA test showed a sensitivity of 87.5%, specificity of 82.1%, positive predictive value of 33.3% and negative predictive value of 98.5%. Anti-cetuximab IgE ELISA detection could be a valuable tool to help the physician anticipate an anaphylaxis episode following cetuximab infusion and opt for a suitable alternative treatment. PMID- 21654208 TI - Prognostic significance of Beclin 1 in intrahepatic cholangiocellular carcinoma. AB - Autophagy enables cells to recycle long-lived proteins or damaged organelles. Beclin 1 plays important roles in autophagy, differentiation, apoptosis and the development and progression of cancer, but the expression of Beclin 1 and its possible role in primary intrahepatic cholangiocarcinoma (ICC) has not been reported yet. This study aimed to investigate Beclin 1 expression and its prognostic significance in ICC. First, we assessed the expression levels of Becn1 by real-time PCR in 50 ICC samples and found Becn1 mRNA expression was markedly increased in 78% (39 of 50) samples compared with normal bile duct epithelium. Beclin 1 protein expression in 108 tumor specimens from patients diagnosed with ICC was examined by immunohistochemistry and the correlation between Beclin 1 expression and clinicopathological factors were investigated. Immunopositivity for Beclin 1 was found in 72.2% (78 of 108) samples and low Beclin 1 expression was significantly associated with lymph node metastasis. The correlation between Beclin 1 expression and metastasis was validated in 46 ICC samples with lymph node metastasis. In survival analysis, low Beclin 1 expression was associated with worse overall survival (OS; p = 0.025) and disease-free survival (DFS; p = 0.027). In multivariate analysis, Beclin 1 expression, intrahepatic metastasis, lymph node metastasis and tumor size were found to be independent prognostic factors of OS. Thus, our results suggested the expression of Beclin 1 was correlated with progression and metastasis of ICC and it might serve as a novel prognostic marker for patients with ICC. PMID- 21654209 TI - Requirement of evading apoptosis for HIF-1alpha-induced malignant progression in mouse cells. AB - Tumor hypoxia is correlated with genetic alteration and malignant progression. Our previous studies indicated that the hypoxia-inducible transcription factor, HIF-1alpha, is responsible for hypoxic suppression of DNA repair in tumor cells by a non-canonical mode of action that requires the HIF-1alpha PAS-B subdomain. The involvement of HIF-1alpha in genetic alteration has raised an intriguing question as to whether normal cells would respond to hypoxic stress differently to avert genetic alteration. In this study, we chose several mouse cell types ranging from benign to malignant, apoptosis-proficient to apoptosis-deficient, and determined their responses to HIF-1alpha expression. In agreement with our previous findings, transient hypoxia and HIF-1alpha expression inhibited DNA repair and induced DNA damage in all cell types examined; however, cumulative DNA damage only occurred in apoptosis-deficient, malignant cells transduced for sustained expression of HIF-1alpha or HIF-1alpha PAS-B itself. In keeping with the theory of apoptosis as a cancer barrier, only these apoptosis-deficient cells acquired anchorage-independent growth and epithelial-mesenchymal transition. Furthermore, these cells exhibited increased Akt activity and resistance to etoposide by inhibiting autophagy. Altogether, our results define an essential role for apoptosis to prevent HIF-1alpha-induced genetic alteration and thereby malignant progression. PMID- 21654210 TI - Mixer Cell formation during dorsal closure: a new developmental model of JNK dependent natural cell reprogramming in Drosophila. AB - What triggers a differentiated cell to naturally change its cell fate? Cell reprogramming is a rare and intriguing phenomenon, from a developmental point of view. It has been mostly involved in boundary sharpening during development, tissue regeneration and cancer. Developmental models of the understanding of pathology-related cell reprogramming are yet to be established. Here we comment on the recently discovered "Mixer Cells" undergoing highly stereotyped developmental reprogramming during Drosophila epidermal morphogenesis. The JNK signaling pathway, which is involved in regenerative cell reprogramming, is essential to Mixer Cell formation. Thus the Mixer Cell model may provide a link between developmental cell reprogramming and regeneration. PMID- 21654211 TI - Tissue-specific cell sorting from Drosophila embryos: application to gene expression analysis. AB - Comprehensive understanding of tissues and organs development requires a detailed description of tissues specific developmental programs. In particular, Gene Regulatory Networks need to be analyzed at the tissue level, requiring organ specific transcriptional landscapes to be established. Here, we describe an efficient and stringent strategy for cell purification of differentiating cells from Drosophila embryos by flow cytometry. This, combined to mRNA amplification, can be used for transcriptomic analysis of small, tissue-specific cell populations. We present an application to the Drosophila cardiac system, whose cell population represents 0.5 to 1% of total cells within the whole embryo. Based on widely available fluorescent reporter transgenes, this method should be applicable to a number of tissues and organs. PMID- 21654212 TI - Formation and maintenance of morphogen gradients: an essential role for the endomembrane system in Drosophila melanogaster wing development. AB - As early as 1964 it was suggested that simple diffusion of morphogens away from their secretion source did not provide an adequate explanation for the formation and maintenance of morphogen gradients. Involvement of the endosome in morphogen distribution models provides an explanation for the slow, directional movement of morphogens, as well as their ability to form intracellular and extracellular gradients independent of morphogen production rates. Drosophila melanogaster morphogens Wg and Dpp form stable, steep, long-range gradients that specify the polarity of the wing disc. The process of endocytosis is imperative to the two central themes in gradient formation: active transport facilitating long-range signaling and degradation of morphogen to sustain gradient shape. This review investigates the endomembrane-mediated processes of re-secretion, degradation and argosome transport of Wg and Dpp in the hope that a better understanding of the endomembrane system will contribute to a more accurate and comprehensive model for morphogen gradient formation and maintenance. PMID- 21654214 TI - Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway. AB - Insertional mutagenesis and the inherent risk of malignancy compromise the clinical use of DNA-based therapies. Being a transient copy of genetic material, mRNA is a safe alternative, overcoming this limitation. As a prerequisite for the development of efficient mRNA-based therapies, we investigated the cellular uptake and intracellular fate of mRNA for the first time. To this end we determined cell-type, dose and energy dependence of mRNA internalisation. Moreover, we employed markers for uptake pathways and cellular compartments to analyse the route of mRNA internalisation and its intracellular destination. Finally, we addressed the involvement of receptors and their nature using a competitor-based approach. We found that all cell types tested were amenable to uptake and expression of naked mRNA. Internalisation mainly occurred via caveolae/lipid raft-rich membrane domains and involved scavenger-receptor(s). Following endocytosis, mRNA eventually accumulated in lysosomes, while part of it escaped into the cytosol giving rise to protein synthesis. Taken together, our findings provide unprecedented insights into the internalisation and trafficking of exogenous mRNA, greatly facilitating the development of effective mRNA-based therapies in the future. PMID- 21654213 TI - Alternative splicing in spinal muscular atrophy underscores the role of an intron definition model. AB - Humans have two nearly identical copies of the Survival Motor Neuron (SMN) gene: SMN1 and SMN2. The two SMN genes code for identical proteins; however, SMN2 predominantly generates a shorter transcript due to skipping of exon 7, the last coding exon. Skipping of SMN2 exon 7 leads to production of a truncated SMN protein that is highly unstable. The inability of SMN2 to compensate for the loss of SMN1 results in spinal muscular atrophy (SMA), the second most prevalent genetic cause of infant mortality. Since SMN2 is almost universally present in SMA patients, correction of SMN2 exon 7 splicing holds the promise for cure. Consistently, SMN2 exon 7 splicing has emerged as one of the best studied splicing systems in humans. The vast amount of recent literature provides a clue that SMN2 exon 7 splicing is regulated by an intron definition mechanism, which does not require cross-exon communication as prerequisite for exon inclusion. Our conclusion is based on the prominent role of intronic cis-elements, some of them have emerged as the frontrunners among potential therapeutic targets of SMA. Further, the widely expressed T-cell-restricted intracellular antigen-1 (TIA1), a member of the Q-rich domain containing RNA-binding proteins, has recently been found to regulate SMN exon 7 splicing by binding to intron 7 sequences away from the 5' ss. These findings make a strong argument for an "intron definition model", according to which regulatory sequences within a downstream intron are capable of enforcing exon inclusion even in the absence of a defined upstream 3' ss of an alternatively spliced exon. PMID- 21654215 TI - 3'-UTR-mediated post-transcriptional regulation of cancer metastasis: beginning at the end. AB - Epithelial-mesenchymal transition (EMT) and the underlying mechanisms and signaling pathways regulating such transitions have generated a lot of interest among cancer researchers. Much of this can be attributed to the apparent similarities in the molecular processes regulating embryonic EMT that can be recapitulated during tumor progression and metastasis. It appears that both embryonic and oncogenic EMT are regulated by an intricate interplay of transcriptional and post-transcriptional programs, and the recent discovery of a transcript-selective translational regulatory pathway controlling expression of EMT-associated mRNAs demonstrates the high fidelity and tight regulation associated with the process of EMT and metastatic progression. Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) is emerging as a critical and integral modulator of TGFbeta-induced EMT and subsequent tumor metastasis. Through its RNA binding ability, hnRNP E1 binds distinct 3'-UTR structural elements present in mRNA transcripts required for EMT and translationally silences their expression. Translational silencing, mediated by hnRNP E1, occurs specifically at the translation elongation step through effects on the eukaryotic elongation factor-1 A1 (eEF1A1), and is relieved by Akt2-mediated phosphorylation. Interestingly, modulation of either the steady-state expression or the posttranscriptional modification of hnRNP E1 has a temporo-spatial effect on translational repression, tumorigenesis and cancer metastasis. PMID- 21654216 TI - ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP2 sensitivity. AB - ATP-sensitive potassium (K(ATP)) channels are inhibited by ATP and activated by phosphatidylinositol 4,5-bisphosphate (PIP(2)). Both channel subunits Kir6.2 and sulfonylurea receptor 1 (SUR1) contribute to gating: while Kir6.2 interacts with ATP and PIP(2), SUR1 enhances sensitivity to both ligands. Recently, we showed that a mutation, E128K, in the N-terminal transmembrane domain of SUR1 disrupts functional coupling between SUR1 and Kir6.2, leading to reduced ATP and PIP(2) sensitivities resembling channels formed by Kir6.2 alone. We show here that when E128K SUR1 was co-expressed with Kir6.2 mutants known to disrupt PIP(2) gating, the resulting channels were surprisingly stimulated rather than inhibited by ATP. To explain this paradoxical gating behavior, we propose a model in which the open state of doubly mutant channels is highly unstable; ATP binding induces a conformational change in ATP-unbound closed channels that is conducive to brief opening when ATP unbinds, giving rise to the appearance of ATP-induced stimulation. PMID- 21654218 TI - The importance of staff training in the prevention of delirium. PMID- 21654217 TI - 2'-O-methylation of the wobble residue of elongator pre-tRNA(Met) in Haloferax volcanii is guided by a box C/D RNA containing unique features. AB - The wobble residue C34 of Haloferax volcanii elongator tRNA(Met) is 2'-O methylated. Neither a protein enzyme nor a guide RNA for this modification has been described. In this study, we show that this methylation is guided by a box C/D RNA targeting the intron-containing precursor of the tRNA. This guide RNA is starkly different from its homologs. This unique RNA of approximately 75 bases, named sR-tMet, is encoded in the genomes of H. volcanii and several other haloarchaea. A unique feature of sR-tMet is that the mature RNA in H. volcanii is substantially larger than its predicted size, whereas those in other haloarchaea are as predicted. While the 5'-ends of all tested haloarchaeal sR-tMets are equivalent, H. volcanii sR-tMet possesses an additional 51-base extension at its 3' end. This extension is present in the precursor but not in the mature sR-tMet of Halobacterium sp., suggesting differential 3'-end processing of sR-tMet in these two closely related organisms. Archaeal box C/D RNAs mostly contain a K loop at the C'/D' motif. Another unique feature of sR-tMet is that its C'/D' motif lacks either a conventional K-turn or a K-loop. Instead, it contains two tandem, sheared G*A base pairs and a pyrimidine-pyrimidine pair in the non canonical stem; the latter may form an alternative K-turn. Gel shift assays indicate that the L7Ae protein can form a stable complex with this unusual C'/D' motif, suggesting a novel RNA structure for L7Ae interaction. PMID- 21654219 TI - Erdheim-Chester disease: a case study and literature review. AB - Diagnosis and treatment of patients who present with respiratory compromise are challenging. What happens when these patients do not respond to your intervention, and their condition declines rapidly? Having a variety of differential diagnoses is key. An addition to your differential list can include a rare disorder of non-Langerhans cells histiocytosis also known as Erdheim Chester disease. This disease often presents as an interstitial lung disease that fails many different treatment modalities. A full understanding of how this disease process works is still being investigated. Provided are a literature review and case study for better understanding of this disease. PMID- 21654220 TI - Introduction to forensic nursing: a student's work: female genital mutilation. AB - This article was written by a student interested in female genital mutilation as part of a school project. The article reviews exactly what female genital mutilation entails, its history, and the role of the forensic and critical-care nurse. PMID- 21654222 TI - The rights and responsibilities of patients and nurses. AB - This is a brief reminder of the rights and responsibilities of patients and nurses. An overview of these topics is presented. PMID- 21654223 TI - A personal reflection: the slippery slope of hope. AB - Sometimes, families and patients compel intensive care unit clinicians to continue aggressive therapies even when the odds of patient recovery are grim. This experienced critical-care nurse suggests that such scenarios are more likely when clinicians use imprecise or ambiguous language when discussing patient prognoses. PMID- 21654227 TI - Rapid response team effectiveness. AB - The purpose of this integrated review of the literature was to summarize the evidence surrounding the effectiveness of rapid response teams. Studies included in this review were written within the last 10 years, in English, and examined the effectiveness of having a rapid response team. Pediatric studies were excluded from this review. There was a reduction in all cardiac arrests found in 60% of the studies reviewed as well as a reduction in mortality associated with cardiac arrests. PMID- 21654229 TI - A far-view intensive care unit monitoring display enables faster triage. AB - Although nurses perform the majority of the clinical tasks in an intensive care unit, current patient monitors were not designed to support a nurse's workflow. Nurses constantly triage patients, deciding which patient is currently in the most need of care. To make this decision, nurses must observe the patient's vital signs and therapeutic device information from multiple sources. To obtain this information, they often have to enter the patient's room. This study addresses 3 hypotheses. Information provided by far-view monitoring displays (1) reduces the amount of time to determine which patient needs care first, (2) increases the accuracy of assigning priority to the right patient, and (3) reduces nurses mental workload. We developed 2 far-view displays to be read from a distance of 3 to 5 m without entering the patient's room. Both display vital signs, trends, alarms, infusion pump status, and therapy support indicators. To evaluate the displays, nurses were asked to use the displays to decide which of 2 patients required their attention first. They made 60 decisions: 20 with each far-view display and 20 decisions with a standard patient monitor next to an infusion pump. Sixteen nurses (median age of 27.5 years with 2.75 years of experience) participated in the study. Using the 2 far-view displays, nurses more accurately and rapidly identified stable patients and syringe pumps that were nearly empty. Median decision times were 11.3 and 12.4 seconds for the 2 far-view displays and 17.2 seconds for the control display. The 2 far-view displays reduced median decision-making times by 4.8 to 5.9 seconds, increased accuracy in assignment of priority in 2 of 7 patient conditions, and reduced nurses' frustration with the triaging task. In a clinical setting, the proposed far-view display might reduce nurses' mental workload and thereby increase patient safety. PMID- 21654231 TI - Effects of depression on sexual activity and sexual satisfaction in heart failure. AB - Patients with heart failure often suffer from depression. However, little is known about the influence of depression on sexual activity and satisfaction. This secondary analysis of descriptive cross-sectional data study examines the role of depression on sexual activity and sexual satisfaction in heart failure. Results highlight the need for acute care nurses to routinely screen for depression and sexual concerns in HF. PMID- 21654235 TI - Advanced directives. PMID- 21654240 TI - Discharge data--some words of caution. PMID- 21654241 TI - Restorative proctocolectomy and primary sclerosing cholangitis: an acceptable pairing? PMID- 21654242 TI - The magnetic anal sphincter versus the artificial bowel sphincter: a comparison of 2 treatments for fecal incontinence. AB - BACKGROUND: Fecal incontinence is a debilitating ailment, and surgery offers the only recourse for the patients in whom conservative treatment fails. OBJECTIVE: This study aims to report the first matched comparison between patients implanted with the magnetic anal sphincter and the artificial bowel sphincter. PATIENTS AND INTERVENTIONS: From December 2008 to June 2010, 10 female patients, median age 64.5 years (range, 42-76), with severe fecal incontinence for a median of 7.5 years (range, 1-40), were implanted with the magnetic anal sphincter. Ten female patients implanted with the artificial bowel sphincter were identified. Both groups were matched for age, etiology, duration of incontinence, and preoperative functional scores. MAIN OUTCOME MEASURES: Outcomes measures included length of hospitalization, complications, and changes in functional scores (anorectal physiology, incontinence, and quality of life). RESULTS: Patients with the magnetic anal sphincter had a shorter median operative time (62 vs 97.5 min, P = .0273), length of hospitalization(4.5 vs 10 days, P < .001), and follow-up duration (8 vs 22.5 mo, P = .0068), without a statistically significant difference in 30-day complications (4 vs 2, P = .628) and revision/explantation (1 vs 4, P = .830). Both groups achieved significant improvements in preoperative incontinence (P < .0002) and quality-of-life scores (P < .009). In a comparison of baseline resting anal pressures, patients with the artificial bowel sphincter had significantly higher pressures with the cuff inflated (P = .0082), and those with the magnetic anal sphincter had a significant increase as well (P = .0469). At the latest review, both groups had similar quality-of-life scores (P = .374); patients with the artificial bowel sphincter had higher (median) closed-cuff anal pressures compared with the anal resting pressure of those with a magnetic anal sphincter (89 vs 58.5 cmH2O, P = .0147), together with more constipation (4 vs 1, P = .830) and a trend toward better incontinence scores (P = .0625). LIMITATIONS: This was a nonrandomized study with small patient numbers. CONCLUSION: In the short term, the magnetic anal sphincter is as effective as the artificial bowel sphincter in restoring continence and quality of life. PMID- 21654243 TI - Specialized practice reduces inpatient mortality, length of stay, and cost in the care of colorectal patients. AB - OBJECTIVE: This study aimed to determine whether specialized surgeon practice improves clinical outcomes for major inpatient adult colorectal resections. DESIGN: The Nationwide Inpatient Sample was queried for elective colorectal resections performed from 2001 through 2007. Specialization was determined by first identifying surgeons' procedures as either colorectal or noncolorectal. Surgeons were then stratified as either a specialized surgeon, if colorectal cases comprised more than 75% of their caseload, or a nonspecialized surgeon if colorectal cases comprised less than 75%. MAIN OUTCOME MEASURES: The data points collected for these cases were: cost, length of stay, mortality, demographics, comorbidities, acuity of admission, hospital region, hospital location and teaching status, and primary payer information. Cost and length of stay were analyzed using a linear regression model with a log transformation for length of stay. A logistic regression analysis was performed for mortality. These models were adjusted for all other covariates including surgeon volume. RESULTS: A total of 13,925 surgeons performing 115,540 procedures were analyzed. Specialized surgeons comprised 4.6% of surgeons and performed 17.0% of resections. In multivariate analysis, specialized surgeons had a lower risk of mortality (OR 0.72; CI 0.57-0.90, P = .0044), decreased length of stay (absolute difference in days 0.23; CI 0.11-0.49, P = .0022), and similar hospital cost (absolute cost difference $420 less; CI $238 more to $1079 less, P = .211) compared with nonspecialized surgeons. Although cost was not significant at a 75% specialization cutoff, a relationship exists between lower hospitalization cost and increased surgeon specialization even when controlled for surgeon volume. CONCLUSIONS: Surgical specialization leads to reductions in mortality, hospital days, and cost for inpatient colorectal care. PMID- 21654244 TI - Short- and long-term surgical outcomes in patients undergoing proctocolectomy with ileal pouch-anal anastomosis in the setting of primary sclerosing cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis occurs in approximately 10% of patients with ulcerative colitis, but studies involving IPAA in patients with cholangitis have been reported in limited numbers. OBJECTIVE: This study aimed to examine surgical outcomes in patients with ulcerative colitis and sclerosing cholangitis undergoing total proctocolectomy with IPAA and to identify variables associated with surgical complications. DESIGN: This is a retrospective cohort study. SETTINGS: This study was conducted at a single tertiary referral institution. PATIENTS: Included were all patients with cholangitis and ulcerative colitis who underwent proctocolectomy with IPAA from 1994 to 2005. MAIN OUTCOME MEASURES: Perioperative morbidity, long-term pouch function, and pouch survival were the main outcome measures. RESULTS: One hundred patients (62 male) were studied. Forty-three percent were on steroids. There was no perioperative mortality, and 51 30-day complications occurred in 39 patients (39%). Median follow-up time was 5.9 years (range, 0.14-16.2 y). Pouch failure occurred in 3 patients (3%). The single variable that predicted 30-day morbidity was previous abdominal surgery (P = .03). Prednisone use, body mass index, age, ASA score, preoperative Model for End Stage Liver Disease score, and year of surgery were not significantly associated with short-term complications. CONCLUSIONS: IPAA can be performed safely in the setting of sclerosing cholangitis. The preoperative Model for End-stage Liver Disease Score and the use of preoperative immunosuppressive agents are not associated with an increased risk of complications. The likelihood of long-term pouch survival is excellent. PMID- 21654245 TI - Favorable pathologic and long-term outcomes from the conventional approach to abdominoperineal resection. AB - BACKGROUND: Suboptimal oncologic outcomes from abdominoperineal resection have been related to high rates of circumferential margin involvement. The extralevator approach has gained popularity as a means of reducing circumferential margin involvement, but it remains unknown whether comparable outcomes are achievable with a conventional approach to abdominoperineal resection. OBJECTIVE: This study aimed to determine the rate of circumferential margin involvement, to identify factors predictive for a positive circumferential margin, and to relate these findings to long-term outcomes. DESIGN: This is a retrospective analysis of a prospective clinical database. SETTINGS: This study was conducted at a single center, Mount Sinai Hospital, Toronto. PATIENTS: Patients were included who underwent abdominoperineal resection for low rectal adenocarcinoma between 1997 and 2006. MAIN OUTCOME MEASURES: The main outcome measures included the rate of circumferential margin involvement, local recurrence, and disease-free survival. RESULTS: A total of 115 patients underwent abdominoperineal resection for primary adenocarcinoma of the rectum. A positive circumferential margin was demonstrated in 18 patients (15.7%). Intraoperative perforations occurred in 7 patients (6.1%). Tumors located anteriorly had a higher rate of circumferential margin involvement (31.6%) compared with lateral (13%), posterior (10%), and circumferential tumors (0%) (P = .024). This finding was reflected by a reduced median distance to the circumferential margin in anterior tumors. Curative resections (n = 108) were followed up for a median of 55.5 months. The 5-year local recurrence rate was 10.6% and the 5-year disease free survival was 67.4%. Cox regression analysis revealed that circumferential margin involvement was an independent predictor for local recurrence; and T category, N-category, and circumferential margin involvement for disease-free survival. LIMITATIONS: This study was limited by its sample size and the number of outcome events. CONCLUSIONS: The conventional approach to abdominoperineal resection can produce oncologic outcomes comparable to the extralevator approach. However, the rate of circumferential margin involvement is higher than in restorative procedures and may be related to difficulties in obtaining adequate clearance in anterior tumors. PMID- 21654246 TI - Single-port access laparoscopic surgery for rectal cancer: initial experience with 10 cases. AB - BACKGROUND: Single-port access laparoscopic surgery is emerging as a method to improve the morbidity and cosmetic benefits of conventional laparoscopic surgery and minimize the surgical trauma. However, the feasibility of this procedure in rectal surgery has not yet been determined. OBJECTIVE: This study aimed to evaluate our initial experience using single-port access in laparoscopic rectal surgery. DESIGN: This investigation was designed as a prospective clinical study. SETTINGS: The study took place in a university hospital. PATIENTS: Ten patients with nonmetastatic rectal cancer underwent rectal resections. MAIN OUTCOME MEASURES: The main outcome measures are perioperative data including intraoperative and postoperative complications, pathological outcome, length of stay, and short-term follow-up. RESULTS: The median age of the patients was 67 (range, 49-83) and the median body mass index was 23.5 kg/m (range, 20-25 kg/m). Six patients had previously had abdominal surgery. The operations were 6 low anterior resections (4 receiving diverting ileostomy), 2 anterior resections, 1 Hartmann procedure, and 1 abdominoperineal resection. The median operative time was 229 minutes (range, 185-318), and blood loss ranged from 0 to 100 mL. In 2 cases, it was necessary to add an extra 5-mm port to deal with intraoperative complications. The median hospital stay was 7 days (range, 4-14). There were no anastomotic leaks and no mortality. All of the resection margins were clear, and the circumferential resection margin was a median of 11 mm (range, 2.5-25). The median number of lymph nodes examined was 14 (range, 3-20). LIMITATIONS: This study's limitations include the lack of registration of postoperative pain, immunological parameters, and long-term clinical and oncological outcome. The small sample size makes it difficult to ascertain complication and conversion rates. CONCLUSIONS: Single-port access laparoscopic surgery for rectal cancer can be performed safely in slim patients with a small tumor. This technique can be an alternative option for selected patients in the hands of skilled laparoscopic surgeons. Prospective comparative studies are needed to determine the role for this technique approach in the future. PMID- 21654247 TI - Bowel preparation for colectomy and risk of Clostridium difficile infection. AB - BACKGROUND: Mechanical bowel preparation before colectomy is controversial for several reasons, including a theoretically increased risk of Clostridium difficile infection. OBJECTIVE: The primary aim of this study was to compare the incidence of C difficile infection among patients who underwent mechanical bowel preparation and those who did not. A secondary objective was to assess the association between C difficile infection and the use of oral antibiotics. DESIGN: This was an observational cohort study. SETTING: The Michigan Surgical Quality Collaborative Colectomy Project (n = 24 hospitals) participates in the American College of Surgeons-National Surgical Quality Improvement Program with additional targeted data specific to patients undergoing colectomies. PATIENTS: Included were adult patients (21 years and older) admitted to participating hospitals for elective colectomy between August 2007 and June 2009. MAIN OUTCOME MEASURE: The main outcome measure was laboratory detection of a positive C difficile toxin assay or stool culture. RESULTS: Two thousand two hundred sixty three patients underwent colectomy and fulfilled inclusion criteria. Fifty-four patients developed a C difficile infection, for a hospital median rate of 2.8% (range, 0-14.7%). Use of mechanical bowel preparation was not associated with an increased incidence of C difficile infection (P = .95). Among 1685 patients that received mechanical bowel preparation, 684 (41%) received oral antibiotics. The proportion of patients in whom C difficile infection was diagnosed after the use of preoperative oral antibiotics was smaller than the proportion of patients with C difficile infection who did not receive oral antibiotics (1.6% vs 2.9%, P = .09). LIMITATIONS: The potential exists for underestimation of C difficile infection because of the study's strict data collection criteria and risk of undetected infection after postoperative day 30. CONCLUSIONS: In contrast to previous single-center data, this multicenter study showed that the preoperative use of mechanical bowel preparation was not associated with increased risk of C difficile infection after colectomy. Moreover, the addition of oral antibiotics with mechanical bowel preparation did not confer any additional risk of infection. PMID- 21654248 TI - Differing risk factors for incisional and organ/space surgical site infections following abdominal colorectal surgery. AB - OBJECTIVE: Surgical site infections are a major source of morbidity after colorectal surgery. The aim of this study was to explore differences between incisional and organ/space surgical site infection types by evaluating risk factors, National Nosocomial Risk Index Scores, and clinical outcomes. DESIGN: A random sample of adults undergoing abdominal colorectal surgery between June 2001 and July 2008 was extracted from a colorectal surgery practice database. Patient factors, comorbidities, intraoperative factors, postoperative factors, and infection were collected; risk score (from -1 to 3 points) was calculated. Variables associated with surgical site infection by univariate analysis were incorporated in a multivariable model to identify risk factors by infection type. Infection risk by risk score was evaluated by logistic regression. Length of stay, readmission, and mortality were examined by infection type. RESULTS: Six hundred fifty subjects were identified: 312 were male, age was 59.8 (SD 17.8) years. Common preoperative diagnoses included colorectal cancer (36.9%) and inflammatory bowel disease (21.7%). Forty-five cases were emergencies, and 171 included rectal resections. Eighty-two patients developed incisional and 64 developed organ/space surgical site infections. Body mass index was associated with incisional infection (OR 1.05, 95% CI 1.00-1.09), whereas previous radiation (OR 4.49, 95% CI 1.53-13.18), postoperative hyperglycemia (OR 2.99, 95% CI 1.41 6.34), preoperative [albumin] (OR 0.52, 95% CI 0.36-0.76), and case length (OR 1.26, 95% CI 1.08-1.47) were associated with organ/space infection. A risk score of 2 and above, compared with a score of <2, predicted organ/space (OR 5.92, 95% CI 3.16-11.09) but not incisional infection (OR 0.95, 95% CI 0.41-2.16). Organ/space infections were associated with longer length of stay (P = .006) and higher readmission rates (P < .001) than incisional infections. CONCLUSIONS: Risk factors for surgical site infections differ by type of infection. Clinical outcomes and value of the risk index score are different by infection type. It may be prudent to consider incisional and organ/space surgical site infections as different entities for patients undergoing colorectal surgery. PMID- 21654249 TI - Application of an electrolyzed strongly acidic aqueous solution before wound closure in colorectal surgery. AB - BACKGROUND: Electrolyzed strongly acidic aqueous solution which is produced by electrolysis of a sodium chloride solution has been used in Japan for the irrigation of wounds or body cavities even in the absence of particular evidence. OBJECTIVE: The purpose of this study is to investigate the efficacy or harmful effects of the disinfectant when applied before wound closure in colorectal surgery. DESIGN: We performed a prospective, randomized study. SETTING: The study was conducted at Surgical Department of Hyogo College of Medicine PATIENTS: Patients who underwent elective colorectal surgery were randomly assigned to 2 groups. The surgical wound was irrigated with >500 mL of the disinfectant or saline solution after the completion of fascia closure. Patients with dirty/infected wounds were excluded from the study. MAIN OUTCOME MEASURES: The primary end point of this study was comparison of the frequency of incisional surgical site infection. The secondary end point was the occurrence of wound dehiscence or wound hernia. RESULTS: One hundred eighty patients in the disinfectant group and 183 patients in the saline solution group were analyzed. In multivariate analysis, IBD and contaminated wounds were independent risk factors for incisional surgical site infection. Application of the disinfectant tended to lower the risk of the infection (OR 0.457, 95% CI 0.206-1.013). In the analysis of poor wound healing, preoperative hospital stay of >2 weeks, stoma creation, and use of the disinfectant (OR 2.28, 95% CI 1.03-5.04) were independent risk factors. LIMITATION: This study was not a double-blind trial. CONCLUSIONS: Application of electrolyzed strongly acidic aqueous solution to the wound impaired wound healing. Routine use of electrolyzed strongly acidic aqueous solution is not recommended in patients undergoing elective colorectal surgery. As for the contribution of the disinfectant to preventing wound infections, further study is needed to make a definitive conclusion. PMID- 21654250 TI - Enhanced recovery after surgery versus conventional perioperative care in rectal surgery. AB - BACKGROUND: Enhanced recovery after surgery programs have been developed to improve recovery, shorten hospital stays, and reduce morbidity. OBJECTIVE: The aim of the current study was to examine the effects of the enhanced recovery program on the outcome of rectal surgery. DESIGN: A cohort of patients who underwent open rectal surgery after an enhanced recovery program was compared with a historic case-matched control group receiving conventional perioperative care. Patients were matched for type of surgery, disease, comorbidity, and demographic characteristics. Data regarding fast-track targets, length of hospital stay, mortality, complications, relaparotomies, and readmissions were collected. RESULTS: Forty-one patients in the enhanced recovery group were compared with 82 case-matched patients receiving conventional care. The length of hospital stay (median: 8 days vs 12 days, P < .005) was reduced in the enhanced recovery after surgery group. There were no significant differences in epidural use, mortality, morbidity, and readmission rates between groups. LIMITATIONS: This study performed an intention-to-treat analysis for the multimodal enhanced recovery program in rectal surgery. Specific elements of the program were not analyzed separately. The study used nonrandomly assigned historic controls for comparison. CONCLUSION: Enhanced recovery after surgery programs help to reduce the length of hospital stay after rectal surgery. PMID- 21654251 TI - Enhanced recovery after colon surgery in a community hospital system. AB - BACKGROUND: Enhanced recovery after colon surgery has not been widely adopted in the United States and Europe, despite evidence that postoperative complications and hospital length of stay are decreased. OBJECTIVE: We sought to evaluate the introduction of a comprehensive care process for enhanced recovery after colon surgery in 8 community hospitals. DESIGN: A system-wide, surgeon-directed, multidisciplinary committee developed a comprehensive enhanced-care quality improvement program. Surgeons and operations leaders in each hospital developed the internal structure to implement the process. PATIENTS: Surgeons had the option of entering or not entering patients in the enhanced-care pathway. Other than trauma patients, there were no exclusion criteria. MAIN OUTCOME MEASURES: To limit selection bias, the study population included all patients undergoing colon resections (those entered and not entered in the care process). Length of stay, postoperative days, hospital costs, 30-day readmission rate, and return to surgery for the study population were compared with a 2-year historical baseline. RESULTS: Forty-two percent of the study population was entered in the enhanced care process. The average length of stay and the number of postoperative days in the study population decreased by 1.5 (P < .0001) and 1.3 (P < .0001) days. The rate of readmissions and returns to surgery remained stable (P > .05), and the average hospital cost decreased by $1763 (P = .02). Generalized linear regression analysis demonstrated that the enhanced-care process was a more significant variable than was the surgical approach (laparoscopic vs open surgery) in decreasing length of stay. LIMITATIONS: The degree of compliance with care process elements and the relative contribution of each element of the care process are unknown. CONCLUSIONS: A comprehensive enhanced-care colon surgery care process was successfully introduced in a community hospital system, as indicated by the clinical outcome measures. PMID- 21654252 TI - Biofeedback for fecal incontinence: a randomized study comparing exercise regimens. AB - BACKGROUND: Fecal incontinence affects up to 11% of Australian community-dwelling adults and 72% of nursing home residents. Biofeedback is a recommended conservative therapy when medication and pelvic floor exercises have failed to improve patient outcomes. OBJECTIVE: This study aimed to investigate the impact of a new exercise regimen on the severity of fecal incontinence and the quality of life of participants. DESIGN: This was a randomized clinical study. SETTINGS: This study was conducted at the Anorectal Physiology Clinic, Townsville Hospital, Queensland, Australia. PATIENTS: Seventy-two participants (19 male), with a mean age of 62.1 years, attended 5 clinic sessions: 4 weekly sessions followed by 4 weeks of home practice and a follow-up assessment session. A postal survey was conducted 2 years later. INTERVENTION: Thirty-seven patients (12 male) were randomly assigned to the standard clinical protocol (sustained submaximal anal and pelvic floor exercises) and 35 patients (7 male) were randomly assigned to the alternative group (rapid squeeze plus sustained submaximal exercises). MAIN OUTCOME MEASURES: The main outcomes were measured by use of the Cleveland Clinic Florida Fecal Incontinence score and the Fecal Incontinence Quality of Life Scale survey tool. RESULTS: No significant differences were found between the 2 exercise groups at the beginning or at the end of the study or as a result of treatment in objective, quality-of-life, or fecal incontinence severity measures. Sixty-nine participants completed treatment. The severity of fecal incontinence decreased significantly (11.5/20 to 5.0/20, P < .001). Eighty-six percent (59/69) of participants reported improved continence. Quality of life significantly improved for all participants (P < .001). Results were sustained 2 years later. Patients who practiced at least the prescribed number of exercises had better outcomes than those who practiced fewer exercises. LIMITATIONS: This study was limited because it involved a heterogeneous sample, it was based on subjective reporting of exercise performance, and loss to follow-up occurred because of the highly mobile population. CONCLUSIONS: Patients attending this biofeedback program attained significant improvement in the severity of their fecal incontinence and in their quality of life. Although introduction of rapid muscle squeezes had little impact on fecal incontinence severity or patient quality of life, patient exercise compliance at prescribed or greater levels did. PMID- 21654253 TI - Is the outcome of transanal advancement flap repair affected by the complexity of high transsphincteric fistulas? AB - BACKGROUND: Transanal advancement flap repair for the treatment of high transsphincteric fistulas fails in 1 of every 3 patients. Until now no definite risk factors for failure have been identified. The question is whether the more complex fistulas, such as those with horseshoe extensions and associated abscesses, have a less favorable outcome. OBJECTIVE: Aim of the present study was to indentify whether more complex fistulas have a less favorable outcome. DESIGN: This study is a retrospective case series review. PATIENTS: Between 1995 and 2007 a series of 162 patients underwent endoanal MR imaging before transanal advancement flap repair. Two investigators, without prior knowledge of the surgical findings, reviewed all MR images. RESULTS: Lateral fistulas were identified in 5 patients. Because of the small number, these patients were excluded from further analysis. Posterior fistulas were identified in 119 patients (76%). These fistulas had 3 types of extensions: a direct course (36%), a classic horseshoe extension (23%), or an intersphincteric horseshoe extension (41%). The corresponding healing rates were 37%, 81%, and 73%. Anterior fistulas were observed in 23% of the patients. These fistulas had 2 types of extensions: a direct course (61%) or a classic horseshoe extension (39%). The corresponding healing rates were 60% and 52%. The healing rate of fistulas with a direct course was significantly lower than the healing rate of fistulas with a classic or intersphincteric horseshoe extension. Associated abscesses were found in 47% of the posterior fistulas and 5% of the anterior fistulas. Once adequately drained, these abscesses did not affect the outcome of transanal advancement flap repair. CONCLUSION: The complexity of high transsphincteric fistulas does not affect the outcome of transanal advancement flap repair. PMID- 21654254 TI - Self-reported abdominal symptoms in relation to health status in adult patients with familial adenomatous polyposis. AB - BACKGROUND: Patients with familial adenomatous polyposis who undergo surgery to prevent colorectal cancer experience various abdominal symptoms that may affect their physical and mental health. OBJECTIVE: This study was designed to investigate self-reported presence, frequency, and troublesomeness of abdominal symptoms in such patients in relation to gender, type of surgery, and physical and mental health. DESIGN: A cohort study with a descriptive and comparative cross-sectional design. SETTING AND PARTICIPANTS: All adult patients in the Swedish Polyposis Registry (Karolinska University Hospital, Stockholm, Sweden) who were diagnosed with familial adenomatous polyposis, had undergone prophylactic colorectal surgery, and were aged 18 to 75 years were invited to return a mailed questionnaire. MAIN OUTCOME MEASURES: Self-reported presence, frequency, and troublesomeness of 21 abdominal symptoms were assessed with the Abdominal Symptom Questionnaire. Physical health and mental health were evaluated with the Medical Outcomes Study Short Form 36 Health Survey. RESULTS: Of 275 eligible patients, 209 (76%) responded. Of respondents, 190 (91%) reported having had at least 1 symptom during the last 3 months. All 21 symptoms investigated were reported. A higher number of symptoms was reported by women than by men: mean, 7.55 (SD, 4.89) vs 5.14 (4.49); P < .01. No significant difference was found between women and men in overall troublesomeness of symptoms: 3.15 (1.30) vs 3.09 (1.27); P = .763. Self-reported number of symptoms was an independent predictor of physical and mental health, with a high number of symptoms related to poor physical and mental health. LIMITATIONS: The Abdominal Symptom Questionnaire has not been previously used in patients with FAP, and measurement of physical and mental health with the Short Form 36 Health Survey may not capture all aspects of health status in patients with familial adenomatous polyposis. CONCLUSION: Patients with familial adenomatous polyposis suffer from a wide variety of abdominal symptoms after colorectal surgery. Identification of patients with a high number of abdominal symptoms is especially important because the number of abdominal symptoms affects patients' physical and mental health. PMID- 21654255 TI - Patient characteristics and treatment outcome in functional anorectal pain. AB - BACKGROUND: Functional anorectal pain occurs in the absence of any clinical abnormality. It is common and disabling; it has previously been reported in only a few studies involving small patient numbers. OBJECTIVE: This study aimed to report the clinical characteristics and treatment outcomes for patients with functional anorectal pain. SETTINGS AND PATIENTS: Patient demographics, clinical history, and tests results for all referrals for anorectal physiological testing between 1997 and 2009 were prospectively recorded. For patients with functional anorectal pain, further information was gained from clinical notes. MAIN OUTCOME MEASURES: Clinical history, anorectal physiology, and radiological imaging data were recorded for all patients; treatment outcome was noted for patients treated and followed up at the present unit. RESULTS: One hundred seventy patients, 99 female, with a median age of 48 years (range, 18-86), were studied. Patients were classified as having chronic proctalgia (pain duration >=20 min, 158 patients) or proctalgia fugax (pain duration <20 min, 12 patients). The pain was most commonly located in the anal canal (90%) and aggravated by defecation or sitting (66%). A third of patients had a history of psychological disturbance. Internal anal sphincter thickness correlated with resting anal pressures. Patients with proctalgia fugax had a higher internal anal sphincter thickness and resting pressure than patients with chronic proctalgia, whereas patients with a family history of similar symptoms were more likely to have proctalgia fugax and higher resting pressures and internal anal sphincter thickness compared with those without a family history of these symptoms. Patients referred for treatment underwent a range of interventions including biofeedback (29 patients, 17 improved), tricyclic antidepressants (26 patients, 10 improved), Botox injection (9 patients, 5 improved), and sacral nerve stimulation (3 patients, 2 improved). Biofeedback had the greatest treatment effect, especially in patients with defecatory dysfunction. CONCLUSIONS: Biofeedback is beneficial in the subset of patients with functional anorectal pain and difficulty with defecation. Tricyclic antidepressants, Botox, and sacral nerve stimulation may also have a role. PMID- 21654256 TI - Cost-effectiveness of mass screening for colorectal cancer: choice of fecal occult blood test and screening strategy. AB - BACKGROUND: Colorectal cancer is a major cause of mortality. This gives high public health priority to mass screening using a noninvasive, fecal occult blood test of asymptomatic individuals. A positive test selects those who should undergo colonoscopy to ensure early detection of colorectal cancer. Guaiac fecal occult blood test has low sensitivity. Automated immunochemical tests that measure the fecal human hemoglobin concentration are more sensitive and can be simplified as a 1- to 3-sample format with optimum cutoff points. OBJECTIVE: The aim was to improve the sensitivity of the test by choosing an accurate format (1- to 3-sample and optimum hemoglobin concentration) while maintaining acceptable specificity and avoiding alteration of the screening program in terms of quality of life and economic outputs. METHODS: We used a Markov model to estimate the cost-effectiveness of a screening program for a population of 100,000 asymptomatic individuals by use of immunological fecal tests with different cutoffs, leading to different sensitivity/specificity ratios, and to compare its incremental cost-effectiveness ratio compared with the guaiac fecal test program. RESULTS: The results suggest that a 3-sample immunological test with 50 ng/mL as a positive cutoff is cost-effective. It provides more asymptomatic cancer detection without significantly increasing normal colonoscopies. CONCLUSION: This format should be prospectively evaluated in mass screening. PMID- 21654258 TI - Cleft-lift operation for pilonidal sinuses under tumescent local anesthesia: a prospective cohort study of peri- and postoperative pain. AB - BACKGROUND: The use of tumescent local anesthesia in the Bascom cleft-lift procedure has not been described before. OBJECTIVE: This study aimed to find whether moderate to complex pilonidal sinuses could be treated using the cleft lift procedure with local anesthesia, with only minor postoperative pain and brief sick leave. DESIGN: This is a prospective cohort study. SETTING: The study was conducted in a day-surgical department. PATIENTS: Eighty-three consecutive cleft-lift operations for pilonidal sinus were performed with tumescent local anesthesia. INTERVENTIONS: Tumescent local anesthesia with a saline water solution of 0.8 mg/mL mepivacaine and 0.001 mg/mL adrenalin buffered with sodium bicarbonate to pH 7.2 was infused subcutaneously. Seventy-five patients were interviewed daily by phone for 1 week to register their ability to return to work and to score their pain on a Numerical Rating Scale pain score from 0 (no pain) to 10. MAIN OUTCOME MEASURES: Outcome measures were the rate of conversion to general anesthesia, peri- and postoperative pain, and the times to discharge and to return to work. RESULTS: Eighty-two (99%) of the 83 procedures were performed with local anesthesia. In one patient, local was converted to general anesthesia. The mean maximum pain score experienced during the infusion was 3.7 (CI: 3.3 4.1), and during surgery, the score was 1.9 (CI: 1.4-2.3). Sixty-three (76%) of the patients were discharged directly from the operating room and 90% in less than an hour after the last stitch. The maximum pain after 2 days was none or mild (pain score <=3) in 80% of the patients. Work could be resumed the next day by 35%, and after 4 days by 87% of the patients with a mean time of 3.0 (CI: 2.2 3.7) days. LIMITATIONS: This study might be limited by its noncomparative design. CONCLUSION: Most patients with moderate to complex pilonidal sinuses can be treated under local anesthesia without notable pain, and discharged minutes after the operation. The Bascom cleft-lift procedure causes only mild postoperative pain, and patients can resume work a few days later. PMID- 21654257 TI - Inverse relationship between moderate alcohol intake and rectal cancer: analysis of the North Carolina Colon Cancer Study. AB - BACKGROUND: The relationship between alcohol intake and rectal cancer is uncertain. OBJECTIVE: We sought to evaluate whether alcohol consumption is associated with distal colorectal cancer and rectal cancer specifically. DESIGN: Data on alcohol intake were examined from the North Carolina Colon Cancer Study, a population-based case-control study of distal colorectal cancer. SETTING: This study encompassed 33 counties in the central and eastern part of North Carolina. PATIENTS: Cases had adenocarcinoma of the rectum, rectosigmoid, and sigmoid colon. Controls were frequency-matched on age, race, and sex. INTERVENTIONS: Demographic and dietary intake data were collected with use of a validated questionnaire. MAIN OUTCOME MEASURES: Logistic regression was used to estimate odds ratios for the relationship between alcohol consumption and distal colorectal cancer. RESULTS: Included in the study were 1033 cases and 1011 controls. The odds ratio for rectal cancer comparing any vs no alcohol intake was 0.73 (95% CI 0.60, 0.90), adjusted for age, sex, race, smoking status, obesity, education, red meat intake, use of nonsteroidal anti-inflammatory medications, and family history of colorectal cancer. The odds ratio for moderate alcohol (<=14 g/day) was 0.66 (95% CI 0.53, 0.82), whereas the odds ratio for heavy alcohol (>14 g/day) was 0.93 (95% CI 0.70, 1.23). Moderate beer and wine intakes were also inversely associated with distal colorectal cancer: odds ratios 0.76 (95% CI 0.60, 0.96) and 0.69 (95% CI 0.56, 0.86). LIMITATIONS: This was a retrospective, observational study. Residual confounding is possible. CONCLUSIONS: In this study, moderate alcohol intake (especially wine) was inversely associated with distal colorectal cancer. PMID- 21654259 TI - Neoadjuvant therapy in rectal cancer. AB - BACKGROUND: The optimal type of neoadjuvant therapy regimen in rectal cancer is contentious. OBJECTIVE: This study aimed to review the impact of neoadjuvant therapy on oncological outcomes and complications (short and long term) in patients undergoing total mesorectal excision for rectal cancer. DATA SOURCES: An electronic search of MEDLINE, PubMed, EMBASE, and the Cochrane Database of Collected Reviews was performed through March 2010. STUDY SELECTION: Key-word combinations including rectal cancer, total mesorectal excision, radiotherapy, chemotherapy, endorectal ultrasound, and magnetic resonance imaging were used to identify randomized control trials where chemotherapy and/or radiotherapy were deployed before resectional surgery. INTERVENTION(S): Patients underwent total mesorectal excision for rectal cancer who did and did not receive preoperative chemotherapy and/or radiotherapy. MAIN OUTCOME MEASURES: The main outcome measures comprised the impact of the addition of neoadjuvant therapy to total mesorectal excision on the perioperative complication rate, the pathological complete response rate, the rate of local recurrence, and long-term treatment related complications. RESULTS: A total of 12 randomized control trials involving 9410 patients were included. Both short-course radiotherapy and long-course chemoradiation can offer a relative risk reduction of 50% in local recurrence in appropriately selected patients with stage II and III rectal cancer. This oncological benefit comes at the cost of a relative risk increase of 50% in both acute treatment-related toxicity and long-term anorectal dysfunction. LIMITATIONS: Preoperative staging provides only an estimate of the "true" tumor stage that can only be determined by histological assessment of the tumor specimen which renders appropriate patient selection challenging. CONCLUSIONS: The current treatment trade-off of a relative risk reduction of local recurrence of 50% at the cost of a relative increase of 50% in treatment-related complications underpins the need for more accurate patient staging and more precise delivery of neoadjuvant therapy. PMID- 21654261 TI - Endosonographic evaluation of patients with suspected extraluminal compression or subepithelial lesions during upper gastrointestinal endoscopy. AB - BACKGROUND: The aim of this study was to evaluate the endosonographic ultrasound (EUS) findings of patients with suspected extraluminal compression or subepithelial intramural lesions observed during upper gastrointestinal endoscopy. METHODS: EUS findings were grouped as follows; compression by an extramural pathologic lesion, compression by an adjacent vascular structure, compression by adjacent organs, subepithelial intramural lesion, and normal EUS. RESULTS: The data of 211 patients referred to the EUS unit between February 2004 and January 2010 for further evaluation of suspected extraluminal compression or subepithelial intramural lesions after upper gastrointestinal endoscopy were retrospectively analyzed. Mean age of the patients was 51.0+/-15.2 years, 124 (58.9%) of which were female. EUS examination was normal in 48 (22.7%) patients. EUS confirmed the presence of a pathological finding in the esophagus in 38 (92.6%) out of 41 patients when compared with abnormal findings in 122 (73.4%) of 166 patients who were evaluated for suspected lesions of the stomach (P=0.009). Suspected extraluminal compression of the esophagus (n=41) was due to a vascular structure in 17 (41.4% ) patients, an adjacent organ in four (9.7%) patients, an extramural pathological lesion in two (4.9%) patients, and a subepithelial intramural lesions in 15 (36.6%) patients, whereas in three patients (7.4%) EUS findings were normal. Of the 166 patients referred for evaluation of gastric lesions EUS findings were normal in 44 (26.5%) patients, whereas compression due to an adjacent organ was observed in 66 (39.7%) patients followed by compression by an adjacent vascular structure in 34 (20.4%) patients. An extramural pathologic lesion was discovered in 14 (8.6%) patients, whereas suspected compression was due to a subepithelial intramural lesion in eight (4.8%) patients. CONCLUSION: Accurate diagnosis of suspected extraluminal compression or subepithelial intramural lesions, particularly in the stomach, requires meticulous evaluation. EUS provides an invasive but effective option. In one third of cases, suspected extraluminal compression of the esophagus is actually due to a subepithelial intramural lesion. PMID- 21654262 TI - Pregabalin-induced hepatotoxicity. PMID- 21654264 TI - A new standard of care? Studies on febuxostat in the management of hyperuricemia with and without gout. PMID- 21654265 TI - An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. AB - BACKGROUND: Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat is potentially a safe and efficacious alternative. OBJECTIVES: Febuxostat or allopurinol was administered to patients with hyperuricemia including gout for 8 weeks to compare the efficacy and safety of these drugs. METHODS: Doses of febuxostat and allopurinol were 10 and 100 mg/d, respectively, during a 12-day introduction period and were increased to 40 and 200 mg/d for the subsequent treatment period of 44 days. RESULTS: : The percent changes in serum uric acid levels after 8 weeks were -40.75% for the febuxostat group and -34.41% for the allopurinol group (P < 0.001, analysis of variance, closing testing procedure). The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 82.0% for the febuxostat group and 70.0% for the allopurinol group (P = 0.019, logistic regression analysis). Regarding safety, 213 adverse events were observed in the febuxostat group and 220 events in the allopurinol group. For 10 patients (8.2%) in the febuxostat group and 14 patients (11.6%) in the allopurinol group, association with the study drugs could not be ruled out. There were no severe adverse drug reactions in the febuxostat group other than a high frequency of gout attacks induced by the sudden reduction in blood uric acid levels during the early treatment period. CONCLUSIONS: Febuxostat at 40 mg/d demonstrated more potent hypouricemic effects than allopurinol at 200 mg/d, was efficacious regardless of medical history of gout, and is considered safe for treatment of hyperuricemia. PMID- 21654266 TI - Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor Febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. AB - BACKGROUND: : Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. OBJECTIVES: : A multicenter study with randomized, placebo-controlled, double-blind, parallel group comparison was carried out to evaluate the efficacy and safety of febuxostat in 103 patients with hyperuricemia (including patients with gout) in Japan. METHODS: : Subjects were treated with febuxostat (20 or 40 mg/d) or a placebo for 8 weeks. The variables evaluated were the percentage of patients achieving serum uric acid levels 6.0 mg/dL or less and the percent change in serum uric acid levels after 8 weeks. RESULTS: : The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less after 8 weeks was 91.2% in the febuxostat 40-mg/d group, 45.7% in the 20-mg/d group, and 0.0% in the placebo group. The percent changes in serum uric acid levels after 8 weeks were -44.9% in the febuxostat 40-mg/d group, -28.9% in the 20-mg/d group, and -0.6% to -0.5% in the placebo group. No severe or medically significant adverse reaction attributable to febuxostat was noted, and there was no event that could pose a clinical problem. The efficacy did not differ depending on the presence/absence of gout history. CONCLUSIONS: : These results suggest that febuxostat (20 or 40 mg/d) is useful as a new means of treating hyperuricemia and is capable of reducing serum uric acid levels to 6.0 mg/dL or less (goal of treatment) with high safety regardless of the presence/absence of gout history. PMID- 21654267 TI - A repeated oral administration study of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase, in patients with impaired renal function in Japan: pharmacokinetic and pharmacodynamic study. AB - BACKGROUND: Allopurinol has been widely used for treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. OBJECTIVES: A multicenter, open-label, parallel, between-group comparative study was conducted to investigate the effects of renal function on the pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel inhibitor of uric acid synthesis. METHODS: Based on creatinine clearance (Ccr), 29 subjects were assigned to 3 groups: normal renal function (Ccr >= 80 mL/min), mild renal dysfunction (80 mL/min > Ccr >= 50 mL/min), or moderate renal dysfunction (50 mL/min > Ccr >= 30 mL/min). Febuxostat was repeatedly orally administered at a dose of 20 mg/d for 7 days. RESULTS: Impaired renal function caused a slight increase in systemic exposure to unchanged febuxostat and its oxidative metabolites, but the exposure did not increase through repeated administration. Moreover, renal impairment did not markedly reduce the effects of febuxostat on plasma uric acid levels. There were no clinically significant adverse events even in patients with impaired renal function. CONCLUSIONS: Febuxostat is considered an inhibitor of uric acid synthesis that could be used in patients with mild to moderate renal impairment without dose adjustment. PMID- 21654268 TI - Placebo-controlled double-blind dose-response study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. AB - BACKGROUND: Allopurinol has been widely used for the treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. OBJECTIVES: A multicenter study with randomized, placebo-controlled, double-blind, parallel, intergroup comparison was carried out to evaluate the dose-response relationship, efficacy, and safety of febuxostat in 202 patients with hyperuricemia (including patients with gout) in Japan. METHODS: The subjects were treated with febuxostat at fixed maintenance doses (20-80 mg/d) or a placebo for 16 weeks. The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less and the percent change in serum uric acid levels after 16 weeks of treatment were evaluated. RESULTS: The percentage of patients achieving serum uric acid levels 6.0 mg/dL or less at 16 weeks was 87.8% in the 80-mg/d dose group, 83.3% in the 60-mg/d group, 82.9% in the 40-mg/d group, 46.5% in the 20-mg/d group, and 2.6% in the placebo group (P < 0.001, Mantel-Haenszel test). A statistically significant dose response relationship was found. The percent change in serum uric acid levels after 16 weeks of treatment differed significantly between each febuxostat dose group and the placebo group and increased in a dose-dependent manner above 40 mg/d. No deaths, events posing a clinical problem, or serious adverse reactions attributable to febuxostat were noted. Similar results were obtained regardless of gout history. CONCLUSIONS: Febuxostat can safely reduce serum uric acid levels to 6.0 mg/dL or less in 80% or more of patients with hyperuricemia (including gout) at doses of 40 mg/d or higher. PMID- 21654269 TI - An allopurinol-controlled, multicenter, randomized, open-label, parallel between group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study. AB - BACKGROUND: Allopurinol has been widely used for the treatment of hyperuricemia, however, it may be associated with various adverse effects. Febuxostat has been identified as a potentially safe and efficacious alternative. OBJECTIVES: Febuxostat was administered to patients with hyperuricemia including gout in Japan to compare its efficacy and safety with those of allopurinol. METHODS: The starting dose of febuxostat and allopurinol was 10 and 100 mg/d, respectively, and was increased to the fixed maintenance dose of 40 or 60 mg/d for febuxostat and 300 mg/d for allopurinol for 16 weeks. RESULTS: : The percent change in the serum uric acid level at 16 weeks compared with the baseline serum uric acid level was -42.96% +/- 13.33% and -52.47% +/- 9.79% for the febuxostat 40- and 60 mg/d groups, respectively, and -36.55% +/- 18.59% for the allopurinol group, indicating that the hypouricemic effects of febuxostat increased in a dose dependent manner and equaled to or surpassed those of allopurinol (P = 0.0239, 2 sample t test). The percentage of patients with serum uric acid levels of 6.0 mg/dL or less at 16 weeks was 88.9% and 100% for the febuxostat 40- and 60-mg/d groups, respectively, and 68.8% for the allopurinol group, showing higher achievements for the febuxostat groups compared with the allopurinol group. All adverse drug reactions were mild to moderate in severity, and there were no severe symptoms or reactions leading to drug discontinuation. CONCLUSIONS: These results suggest that febuxostat is safe at doses of 40 and 60 mg/d and has equal or greater efficacy than 300 mg/d allopurinol. PMID- 21654270 TI - Multicenter, open-label study of long-term administration of febuxostat (TMX-67) in Japanese patients with hyperuricemia including gout. AB - BACKGROUND: In previous clinical studies of hyperuricemia including gout, although serum uric acid (sUA) levels reduced to 6.0 mg/dL or less in about 80% of patients treated with 40 mg/d febuxostat, a nonpurine selective xanthine oxidase inhibitor, a few patients did not show this result. OBJECTIVE: The objective of the study was to evaluate the efficacy and safety of long-term febuxostat administration at up to 60 mg/d in patients with hyperuricemia and gout. METHODS: In a 52-week, multicenter, open-label trial, febuxostat was initially administered at 10 mg/d; then, the dosage was increased in a stepwise fashion to 40 mg/d. For sUA levels greater than 6.0 mg/dL at week 10, the dosage was increased to 60 mg/d from week 14 onward (60-mg group), but it was maintained at 40 mg/d until the end of the study for patients with sUA levels 6.0 mg/dL or less at week 10 (40-mg group). RESULTS: The sUA levels in both groups decreased dose dependently. At 52 weeks, 84.5% and 85.0% of the 40- and 60-mg groups, respectively, achieved mean sUA levels 6.0 mg/dL or less. There was no marked difference between the 2 dosage groups in terms of the incidence of adverse events. Furthermore, there were no noteworthy adverse events or adverse drug reactions in the patients with renal dysfunction, and no differences in drug efficacy up to 60 mg/d were noted between the patients with moderate or mild renal dysfunction and those with normal renal function. CONCLUSIONS: Febuxostat seems to be a promising therapeutic drug for gout or hyperuricemia, even in patients with renal dysfunction. PMID- 21654271 TI - The growing complexity of the pathology associated with cocaine use. PMID- 21654272 TI - Severe vascular complication after an arm stretch in a child with Ehlers-Danlos syndrome. PMID- 21654273 TI - Bilateral Freiberg disease. PMID- 21654275 TI - Hypothyroidism presenting as puzzling myalgias and cramps in three patients: comment on the article by George. PMID- 21654277 TI - Investigation on Brazilian clinical practices in rheumatoid arthritis: the Brazilian rheumatoid arthritis clinical practices investigation--BRACTICE. AB - Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease causing significant social, medical, and economic impact. Several therapeutic regimens are available within the medical arsenal. The rational and reasoned use of various medications approved for their treatment is imperative. This study aimed to evaluate how Brazilian rheumatologists use the drugs available to combat the disease.For this, 128 Brazilian rheumatologists from public and private health services responded to an 18-item questionnaire, sent over the Internet, about different situations of drug treatment of RA. The answers helped to confirm the trends among Brazilian rheumatologists in the drug treatment of RA.The study results have shown that most Brazilian rheumatologists follow the guidelines and consensus established by the Brazilian Society of Rheumatology for the treatment of RA. A small proportion, however, start the biologic therapy in early stages of the disease, including the very early stage, as the first treatment option. Most experts use corticosteroids in low doses early in the treatment. CONCLUSIONS: This study confirms that the majority but not all Brazilian rheumatologists follow, in their daily practice, established guidelines and consensus for the treatment of RA. However, it also shows that some few rheumatologists start with anti-tumor necrosis factor therapy in very early arthritis independently of disease severity or prognostic factors. PMID- 21654279 TI - Neonatal encephalopathy or hypoxic-ischemic encephalopathy? Appropriate terminology matters. PMID- 21654280 TI - Double-guidewire-assisted cannulation in ERCP: novel applications. AB - Even in experienced hands, a common problem at endoscopic retrograde cholangiopancreatography (ERCP) is difficulty in reaching a selective cannulation of the common bile duct or pancreatic duct. The success rate of biliary cannulation has improved markedly in many centers after the adoption of double guidewire-assisted cannulation technique in cases in which the guidewire repeatedly passes into the pancreatic duct although the common bile duct is intended. Here, we describe 2 novel applications of the double-guidewire technique for difficult cannulation in ERCP. In particular, we emphasize that in addition to difficult biliary cannulation, double-guidewire technique may prove useful in difficult pancreatic cannulation. The double-guidewire technique is feasible also in cases in which the guidewire repeatedly passes into the cystic duct instead of the intended common hepatic duct and intrahepatic radicals. ERCP endoscopists should be aware of all modifications of double-guidewire technique to further increase the success rates of selective cannulations in ERCP. PMID- 21654281 TI - Single-port surgery and NOTES: from transanal endoscopic microsurgery and transvaginal laparoscopic cholecystectomy to transanal rectosigmoid resection. AB - Two different ways have been developed to perform endoscopic surgery. The standard way is multiport laparoscopic surgery. When entering through a natural orifice, we use single-port surgery for transanal work (transanal endoscopic microsurgery). In clinical routine, we moved from intralumenal surgery toward surgery in the perirectal area and finally the free abdomen. In the context of natural orifice translumenal endoscopic surgery, we have modified the length and diameter of optics and tube and developed new mechanisms for steering long curved instruments. This technology is then used for transvaginal cholecystectomy and transanal rectosigmoid resection. Global clinical application of transanal endoscopic microsurgery has proven superiority in preciseness and clinical results for adenomas and early cancer. The initial clinical study for transvaginal cholecystectomy is successfully performed in 6 female patients with an average operation time of 80 minutes and without major complication. Feasibility of transanal rectosigmoid resection is demonstrated in an ex vivo experimental model. PMID- 21654282 TI - In vivo knot scoring model for a multifilament suture. AB - BACKGROUND: A surgical knot is the key feature to assure appropriate wound support while combining tissue edges. Little evidence is available on the in vivo behavior of knots and the evaluation of knots in the living tissue. This study introduces a knot score model, which is defined by microscopic evaluation and the loop-holding capacity. MATERIALS: In a double-blinded and comparative study, 3 surgeons placed 10 intramuscular single-loop sutures in the longissimus muscle group of the dorsolumbar region at each side parallel to the vertrebral column. For accomplishing the study, 72 rabbits and 3 calibers of a test and control suture were used. On the fourth day, the knot safety was assessed by microscopical and mechanical analyses for scoring and classifying the knots of the different suture materials into the defined categories for loop-holding capacity. The statistical evaluation was performed using Hodges-Lehmann rank score. A Wilcoxon test was used to estabilish a significant difference between the suture types. RESULTS: When comparing Novosyn (Aesculap AG) with Vicryl (Johnson & Johnson Medical GmbH) a comparable knot safety was assessed based on a 95% confidence interval. CONCLUSIONS: The new method compares the knot safety between 2 braided multifilament sutures in the living tissue. Results were discussed and examined for statistical significance. PMID- 21654283 TI - Single-port retrieval of peritoneal foreign body using SILS port: report of a case. AB - Foreign body retrieval surgery sometimes does not need excision and reconstruction of the gastrointestinal tract. To avoid unnecessarily large incisions is now feasible for such retrieval surgery. We report herein a case of a patient who underwent retrieval surgery with a single-incision laparoscopic surgery (SILS) to minimize surgical incision. Our case concerns a 72-year-old female with a 3 cm length needle incidentally discovered as a peritoneal foreign body without any apparent symptoms. Retrieval was performed safely with SILS port inserted through a 2.5 cm transverse incision below the umbilicus. Two flexible forceps introduced through the SILS port offer easy operation for retrieving foreign bodies even if dissection or other surgical maneuvers are required. Our technique of abdominal foreign body retrieval with the SILS port is a useful clinical application of minimally invasive surgery for such cases. PMID- 21654284 TI - Bladder migration of Hem-o-Lok clips after laparoscopic radical nephroureterectomy and bladder cuff excision. AB - The Hem-o-Lok clips are widely used in various laparoscopic operations because of its easy application and secure clamping. The Hem-o-Lok clips were adopted to ligate bladder cuff during bladder cuff excision because of its advantages. We report 2 cases of bladder migration of Hem-o-Lok clips after laparoscopic nephroureterectomy and bladder cuff excision. The clips were found during routine follow-up cystoscopy and were removed by cystoscopic procedure. We described the case presentation, treatment, and the alternative method to avoid such shortcomings. PMID- 21654285 TI - Colonic and parastomal ulceration related to nicorandil. AB - Nicorandil is an antianginal medication increasingly used in the treatment of severe ischemic heart disease. It has been implicated in the pathogenesis of perianal and perioral ulceration. We report 2 patients with atypical gastrointestinal ulceration due to nicorandil. PMID- 21654286 TI - Evaluation of commercially available port access devices for single-incision laparoscopy. AB - BACKGROUND: Laparoendoscopic single-site surgery has created a need for new technologies to simplify and expedite these procedures. We evaluated 3 different commercially available single-incision laparoscopic port access devices for their ease of use. METHODS: Four laparoscopic surgeons performed multiple laparoscopic procedures through a single fascial incision in a porcine model. Three different commercially available access devices were used and evaluated for performance on a 5-point Likert scale. RESULTS: All procedures were successfully completed. Tissue dissection and retraction were challenging because of instrument crowding and lack of triangulation. Two of the tested devices included trocars in the design, maximum trocar size of 12 mm versus 15 mm. Quoted cost for the devices varied widely with the sleeve device at the lower end and the disk shaped at the higher end. CONCLUSIONS: All tested devices allowed the performance of the attempted procedures. Challenges continue to exist and continued improvement in design is necessary. PMID- 21654287 TI - Spontaneous fistulization of a pancreatic abscess to colon and duodenum treated with percutaneous drainage. AB - Pancreatic fistulas are rare clinical entities associated with severe pancreatitis. A 39-year-old man who had been diagnosed and treated for severe pancreatitis 2 months ago presented with abdominal pain, fever, and vomiting. The abdominal computed tomography (CT) demonstrated a peripancreatic abscess and a duodenal fistula communicating the first part of duodenum, which was also verified with fluoroscopy. A size 14-French catheter with pig-tail tip was inserted primarily with a Seldinger 2-step technique through percutaneous route under CT-guidance to avoid intervening bowels or solid organs. The patient's clinic improved and treatment was stopped on the 18th day. On the 26th day of the first intervention, the patient had fever and abdominal pain and his clinic was deteriorated. A second fluoroscopic examination revealed that the duodeno pancreatic fistula was closed while a new 1 has developed into the ascending colon. With aggressive nutrition support, antibiotics and repeated drainage of the abscess pouch a dramatic clinical improvement was observed. Control abdominal CT demonstrated the resolution of pancreatic abscess on the 62nd day. PMID- 21654288 TI - Pneumoperitoneum after esophageal cryoablation in a patient with a PEG. AB - There is an increasing use of cryotherapy in the gastrointestinal tract for ablation of a variety of lesions. There is only a single reported case of perforation with spray cryotherapy, which was in a patient with Marfan syndrome. In this report, we describe pneumoperitoneum in a patient with a percutaneous endoscopic gastrostomy tube undergoing cryoablation. It is postulated that barotrauma at the percutaneous endoscopic gastrostomy site led to the pneumoperitoneum, and this can occur even with apparently adequate gas-venting procedures. PMID- 21654289 TI - Right diaphragm injury: an unusual complication in single-port laparoscopic cholecystectomy. AB - Laparoscopic cholecystectomy (LC) is nowadays the standard method for cholecystectomy. Recently, surgeons attempt to introduce even less-invasive surgical procedures, such as single-port LC or LC through natural orifice transluminal endoscopic surgery (NOTES). The number of studies showing the feasibility of these techniques increased during the last years, but specific complications that correlated with these new techniques are still not apparent. Here, we report on a case with an unusual complication, iatrogenic right diaphragm injury in single-port LC. A 72-year-old man underwent single-port LC because of symptomatic cholecystolithiasis. During the operation, the long rigid straight forceps holding the fundus of the gallbladder slipped off toward the right diaphragm and caused a 1-cm full-thickness diaphragmatic tear. Laparoscopic suture repair was performed, and the patient recovered uneventfully. In using long forceps in single-port LC or transvaginal NOTES-LC, reticulating and bent instruments may avoid this unusual but possible complication in these operations. PMID- 21654290 TI - Novel "glove" access port for single port surgery in right hemicolectomy: a pilot study. AB - The trend of single port surgery is increasing recently, and it is technically feasible for right hemicolectomy. However, the operation requires special and expensive access port for the insertion of the instruments. Day et al reported the use of a novel "glove" access port for right hemicolectomy in this pilot study. Four single port right hemicolectomies were performed by using this access port. The access port was found to be user-friendly and durable. No adverse outcome was associated with this access port. This "glove" access port is a suitable device for single port right hemicolectomy. PMID- 21654291 TI - Is a thyroid follicular neoplasm a good indication for endoscopic surgery? AB - Endoscopic thyroidectomy is a safe and feasible alternative as compared with conventional open thyroidectomy in patients with a small thyroid cancer or a benign thyroid tumor. However, despite the many advantages of endoscopic surgery, it can result in unexpected complications. Recently, the authors experienced a case of follicular thyroid cancer recurrence that developed around the operative bed and along the port insertion site after endoscopic thyroidectomy for a large follicular neoplasm. The authors suggest that a smaller follicular neoplasm is a good indication for endoscopic thyroidectomy, but that a large follicular neoplasm should not be viewed as indicators for endoscopic surgery, because of the possibility of malignancy and rupture during manipulation. PMID- 21654292 TI - Laparoscopic management of urachal mucinous borderline tumor associated with pseudomyxoma peritonei. AB - We provide an initial description of laparoscopic diagnosis and management of urachal mucinous borderline tumor associated with pseudomyxoma peritonei. Treatment for pseudomyxoma peritonei remains controversial, with continually evolving surgical procedures; however, we describe our experience and the potential benefits of a laparoscopic approach for pseudomyxoma peritonei. PMID- 21654293 TI - Laparoscopic management of a duplicated gallbladder: a case study and anatomic history. AB - Duplication of the gallbladder is a rare entity. This case highlights a 36-year old woman who presented to Arrowhead Regional Medical Center after referral from an outside institution with gallstone pancreatitis. Ultrasound, computed tomography scan, and magnetic resonance cholangiopancreatography showed evidence of a biliary anomaly preoperatively concerning for a duplicated gallbladder or choledochal cyst. Subsequent laparoscopic cholecystectomy and intraoperative cholangiogram confirmed the presence of a duplicated gallbladder. A second intrahepatic gallbladder with connection to the right hepatic duct was identified and the first gallbladder's connection to the common hepatic duct was noted. Both gallbladders contained hundreds of small stones. The patient did well postoperatively and has had no adverse sequelae. A literature review revealed an incidence of 1 in 4000 autopsies with a duplicated gallbladder. Sixty-seven case reports have been published and only 20 cases were managed laparoscopically. PMID- 21654294 TI - Use of fibrin-based sealants and gelatin-matrix hemostats in laparoscopic liver surgery. AB - BACKGROUND: During surgery, liver tissue is particularly prone to bleeding which can be difficult to control, especially in patients with liver disease-associated coagulopathy. Topical sealants and hemostats can enhance clot formation and wound healing, and can be useful for controlling or preventing troublesome bleeding during surgical interventions where conventional methods of hemostasis are inadequate. METHODS: An extensive customized literature search was conducted using medical reference databases to identify publications related to the use of potential agents in laparoscopic liver surgery. Citations from these articles were also used. Details of the authors' own experience in this area is also included. RESULTS: Routine use of fibrin-based sealants in open liver surgery now seems to be widespread. Data from several large prospective randomized controlled clinical trials have indicated that application of fibrin-based sealants to the cut liver surface during hepatectomy does provide some benefit in terms of a shorter time to hemostasis and a reduction in postoperative drainage fluid, even when compared with argon beam coagulation. Another trial found no additional benefit of fibrin sealants when applied after coagulation of the cut liver surface. A prospective, uncontrolled study found that application of the flowable gelatin matrix-based hemostat Floseal provided rapid effective control of mild-to severe bleeding during surgical removal of primary or metastatic liver tumors, even in those with cirrhosis. Some of these topical hemostatic agents are already being used on a routine basis by many surgeons performing laparoscopic liver surgery. Although there are no randomized clinical trials, there are several anecdotal or case reports of their effective use during laparoscopic liver surgery. CONCLUSIONS: On the basis of current evidence of using hemostats and sealants in open liver surgery, there is potential of developing these strategies in laparoscopic liver surgery. PMID- 21654295 TI - Laparoscopic appendicectomy for complicated appendicitis: is it safe and justified?: A retrospective analysis. AB - BACKGROUND: Although laparoscopic appendectomy has some advantages over open appendectomy, the literature suggests conflicting results regarding postoperative complications for complicated appendicitis. METHODS: A retrospective review of patients with complicated appendicitis managed surgically at Meenakshi Mission Hospital and Research Center, Madurai, Tamilnadu, India was undertaken. A total of 497 patients were admitted with acute appendicitis and operated during the study period of 10 years from January 1999 to July 2009, out of which 119 (24%) patients had complicated appendicitis whereas 378 (76%) had uncomplicated acute appendicitis. The mean age of patients included in the study was 33.42 years (range, 4 to 80 y) with a male: female ratio of 2:1. RESULTS: Ninety-nine patients (83.19%) underwent laparoscopic appendicectomy and 1 patient underwent laparoscopic-assisted right hemicolectomy for suspected mass lesion of the cecum. Eleven patients (9.24%) underwent open appendicectomy because of preoperative clinical features of peritonitis in 10 patients and mass in 1 patient. Seven patients (5.88%) had conversion from laparoscopic to open procedure. The overall mean operating time was 68 minutes (25 to 180 min). For laparoscopic appendicectomy, 66 minutes (25 to 180 min), for open appendicectomy 76 minutes (50 to 110 min), for lap to open conversion 85 minutes (40 to 135 min), and for drainage procedure 67 minutes (60 to 75 min). A total of 28 patients developed complication in the form of wound infection (7), pneumonia (8), intra-abdominal abscess (11), and enterocutaneous fistula (2) after percutaneous drainage of intra-abdominal collection. All were managed conservatively and no mortality occurred. CONCLUSIONS: The morbidity rates, particularly for intra-abdominal abscesses and wound infection were less for laparoscopic appendectomy in complicated appendicitis than those reported in the literature for open appendectomy, whereas operating times and hospital stays were similar. PMID- 21654296 TI - Surgical complications and the risk factors of totally laparoscopic distal gastrectomy. AB - PURPOSE: It has not yet been elucidated whether there are specific complications associated with totally laparoscopic distal gastrectomy (TLDG). We evaluated the complications and the risk factors associated with TLDG. METHODS: A retrospective analysis was performed on 138 consecutive patients who underwent TLDG. The clinical and operative data, which included the body mass index, respiratory function, hematological data, pathological data, and the experience of surgeon, were analyzed. RESULTS: Intraoperative and postoperative complications developed in 10 and 28 patients, respectively. A univariate analysis determined that the patient age, concurrent respiratory disease, and operation time were important risk factors. A multivariate analysis found no significant risk factors in this set, although the operation time was the most promising risk factor. CONCLUSIONS: The present data suggest that TLDG can be performed with acceptable perioperative complication rates, although a longer operation time may cause a higher frequency of postoperative complications. PMID- 21654297 TI - Influence of obesity on early surgical outcomes of laparoscopic-assisted gastrectomy in gastric cancer. AB - BACKGROUND: The aim of this study is to estimate the impact of obesity on surgical outcomes of laparoscopic-assisted gastrectomy for gastric cancer. STUDY DESIGN: Between January 2005 and January 2010, 1100 consecutive patients who underwent laparoscopic-assisted distal gastrectomy for gastric cancer were reviewed to evaluate the impact of obesity. The patients were classified into 3 groups according to the World Health Organization classification, as normal weight [body mass index (BMI) 18.5 to 24.9 kg/m], overweight (BMI 25 to 29.9 kg/m), and obese patients (BMI >=30 kg/m). RESULTS: The postoperative complication rates for normal weight, overweight, and obese patients were 5.7%, 10.0%, 15.4%, respectively. Overweight and obese patients had a significantly prolonged operation time, increased intraoperative blood loss, prolonged first flatus, day of commencement of soft diet, increased number of administration of analgesics, and prolonged hospital stay. CONCLUSIONS: Overweight and obesity were associated with poor early surgical outcomes of laparoscopic-assisted gastrectomy. This study suggested that greater cautions and improved surgical techniques were required to improve early surgical outcomes of laparoscopic assisted gastrectomy for overweight and obese patients. PMID- 21654298 TI - Surgical effects of obesity on laparoscopy-assisted distal gastrectomy. AB - PURPOSE: To compare the effects of obesity on laparoscopy-assisted distal gastrectomy (LADG) and open distal gastrectomy (ODG). METHODS: A retrospective study was conducted on 249 patients, who underwent LADG and 224 patients who underwent ODG. RESULTS: The regression coefficient of the primary regression equation between operative time and body mass index (BMI) for LADG was greater than ODG; and between blood loss and BMI for LADG was almost the same as ODG. In overweight patients (BMI >=25), no significant difference was seen between LADG and ODG regarding postoperative complications, and the benefits of the less invasive nature of LADG were also seen in some parameters. CONCLUSION: Obesity associated difficulties are more while performing LADG than during ODG; however, the influence of obesity on LADG decreases with surgical experience. Moreover, even in overweight patients, the benefits of the less-invasive nature of LADG still remain, but the degree of the benefits is smaller than that in nonobese patients. PMID- 21654299 TI - Initial experience with a gasless unilateral axillo-breast or axillary approach endoscopic thyroidectomy for papillary thyroid microcarcinoma: comparison with conventional open thyroidectomy. AB - The efficacy of various endoscopic thyroidectomy has not been determined for papillary thyroid microcarcinoma (PTMC). We compared 31 consecutive patients with PTMC who underwent endoscopic thyroidectomy by a gasless unilateral axillo-breast or axillary approach, and the 36 PTMC patients who underwent conventional open thyroid lobectomy from August 2005 to December 2008. There were more female patients (P=0.004) in the endoscopic group, and the mean age of endoscopic group was younger than that of the open thyroidectomy group (P=0.006). The entire endoscopic thyroidectomy was successfully completed in all the patients. The operative time was longer for those undergoing endoscopic thyroidectomy (P<0.001). The complication rate did not differ between the 2 groups. The cosmetic satisfaction, as evaluated by questionnaire, was greater in the endoscopic group (P<0.001). Endoscopic thyroidectomy by a gasless unilateral axillo-breast or axillary approach for selected cases of PTMC is a feasible, safe, and cosmetically superior procedure. PMID- 21654300 TI - Iatrogenic colonic perforation: repair using laparoscopic technique. AB - BACKGROUND: Iatrogenic colonic perforation is a rare complication of colonoscopies. Nowadays, there are still no specific guidelines for the optimal management of these complications (open surgery with colonic resection and anastomosis or colonic diversion, primary repair, endoscopic clips, nonoperative management, and laparoscopic approach). METHODS: A retrospective analysis of 9 patients operated on for iatrogenic colonic perforations (February 2002 to August 2009) is reported. These were treated, in 6 cases, with laparoscopic colorrhaphy, in 2 cases with laparoscopic colonic resection and anastomosis (with 1 temporary ileostomy), and the last patient with laparoscopic Hartmann procedure. RESULTS: All patients underwent successful laparoscopic treatment, with no mortality. CONCLUSIONS: Laparoscopic treatment of iatrogenic colonic perforations is a compromise between risks of nonoperative therapy and invasive surgery. According to our early experience, laparoscopic approach could be used as first choice in the management of these complications. Further studies are necessary for full validation of this approach. PMID- 21654301 TI - Outcomes after laparoscopic cholecystectomy in children with biliary dyskinesia. AB - Our objectives were to determine the prevalence of biliary dyskinesia (BD) as an indication for cholecystectomy in children and to identify presenting clinical findings and optimal ejection fraction (EF) associated with the resolution of symptoms after surgery. We conducted a retrospective review of medical records of 212 pediatric patients who underwent cholecystectomy from August, 1998 to November, 2006. Patients who met criteria for BD had their short-term outcomes examined by record review and their long-term postoperative outcomes recorded by questionnaire. To compare EF and clinical presentation to symptom resolution or outcome, chi tests were used. Logistic regression was used to evaluate possible predictors of symptom resolution. BD was the indication for cholecystectomy in 20% of patients (44 of 212). Short-term outcome was not predicted by any of the collected variables. An EF <=11% predicted higher rate of symptom resolution (P=0.02). Although patients with specific right upper quadrant pain had higher rates of long-term improvement than those with nonspecific abdominal pain (57.9% vs. 18.2%), this did not reach significance (P=0.057). The only predictor emerging from the logistic regression was EF cutoff at 11% (odds ratio=17.5; 95% confidence interval, 1.756-174.418). In this series, symptoms of BD were more likely to be resolved by cholecystectomy in children with EF <=11%. PMID- 21654302 TI - Postoperative outcomes and quality of life in patients with cystic fibrosis undergoing laparoscopic cholecystectomy: a retrospective study. AB - BACKGROUND: Approximately 28% of the patients with cystic fibrosis are affected by cholelythiasis. More than 40% of them have a symptomatic disease, which would mandate cholecystectomy. AIM: The aim of this study was to review surgical and respiratory outcomes and quality of life scores of cystic fibrosis patients undergoing laparoscopic cholecystectomy for symptomatic cholelythiasis to verify the hypothesis that cholecystectomy is a low-risk operation by laparoscopy, not affecting unfavorably respiratory function and quality of life. PATIENTS AND METHODS: Study group was consisted of 9 patients with a mean age of 24.8+/-8.1 years (range, 15 to 38 y), 2 male and 7 female patients, with cystic fibrosis and symptomatic cholelithiasis. Three patients also presented common bile duct stones. All the patients underwent perioperative Positive End-Expiratory Pressure mask sessions and aggressive antibiotic regimens. At the middle of the antibiotics regimen period, a standard laparoscopic cholecystectomy was performed. In the 3 cases with common duct lithiasis, the so-called "rendezvous" technique was carried out. Preoperatively, intraoperatively, and postoperatively, respiratory function was strictly monitored by the evaluation of SO2 and of the forced expiratory volume in 1 second (FEV1). Preoperatively and 6 months after laparoscopic cholecystectomy the Gastro Intestinal Quality of Life Index was evaluated on all patients. RESULTS: All the operations were completed laparoscopically. No mortality was observed. The intraoperative mean SO2 was 89.0%+/-5.6% (range, 80% to 95%), versus 82.8%+/-8.5% (range, 66% to 91%) at the extubation (P=0.006). Intraoperative respiratory functions were stable in 6 patients. In 3 patients, a severe bronchospasm occurred determining marked desaturation. Preoperative mean FEV1 was 70.5%+/-7.0% (range, 55% to 75%) versus 61.8%+/-13.2% (range, 39% to 80%) 48 hours after the operation (P=0.132). The 3 patients, who experienced intraoperatively severe bronchospasm, reported a 48 hours postoperative FEV1 under 60%. All the patients showed disappearance of postprandial colicky pain and vomiting. Preoperative mean total Gastro Intestinal Quality of Life Index score was 105.2+/-13.6 versus 117.8+/-10 at 6-month follow up (P=0.015). CONCLUSIONS: On the basis of a proper surgical timing and adequate preoperative physiokinesis therapy, laparoscopic cholecystectomy is a safe and indicated procedure in patients with cystic fibrosis and symptomatic cholelithiasis and it is able to significantly improve the quality of life. Quality of life of these patients it not worsened while symptoms and risks of biliary gallstones are removed. PMID- 21654303 TI - Laparoscopic versus conventional palliative resection for incurable, symptomatic stage IV colorectal cancer: impact on short-term results. AB - BACKGROUND: Issues surroundings the safety and efficacy of palliative laparoscopic resections for patients with stage IV colorectal cancer have not been explicitly examined in the literature. We describe our experience with laparoscopic procedures for patients with stage IV incurable symptomatic colorectal cancer and compare perioperative outcomes with a contemporaneous group of patients who underwent conventional open procedures. METHODS: We retrospectively reviewed data from laparoscopic resections performed in patients for symptomatic stage IV colorectal cancer between 1999 and 2009. Data regarding patient demographics, perioperative morbidity and mortality, intraoperative blood loss, operative time, length of postoperative hospital stay, and time from surgery to chemotherapy were assessed. RESULTS: A total of 29 patients were identified and of these patients, 11 (38%) underwent palliative laparoscopic resections and 18 (62%) underwent conventional open resection for stage IV colorectal cancer. In comparing laparoscopic to conventional procedures, the length of postoperative hospital stay in the laparoscopic resection group was significantly shorter than that in the open resection group (median, 17 vs. 20 d, P<0.05). Significant differences were present between the 2 groups when following features were compared: leukocyte on day 1 (median, 7.87 vs. 8.70 * 10/L) and day 3 (median, 6.40 vs. 7.80 * 10/L), albumin level on day 7 (median, 38.0 vs. 29.8 g/L), and C-reactive protein level on day 7 (median, 0.6 vs. 2.8 mg/dL). There were no significance differences between the 2 groups in intraoperative blood loss (median, 105 vs. 155 mL), operative time (median, 271.5 vs. 187.5 min), time to intake of solid food (median, 4 vs. 4 d), the rate of postoperative complications, perioperative mortality, or a duration from surgery to chemotherapy (median, 22 vs. 28 d). CONCLUSIONS: Palliative laparoscopic resection is a safe and feasible option with acceptable morbidity and mortality in patients with stage IV colorectal cancer. Importantly, in this group of difficult-to-treat patients, our results compare favorably with those from previously published reports on open procedures. PMID- 21654304 TI - Laparoscopic nephropexy using polyprolene mesh. AB - MATERIALS AND METHODS: Laparoscopic nephropexy was performed in 8 consecutive cases with symptomatic nephroptosis through suturing and fixation of a polyprolene mesh between the posterior surface of the kidney and quadratus lumborum muscle. All patients had symptomatic nephroptosis. Preoperatively, intravenous urography and a split renal scan in supine and upright positions were done for all patients. RESULTS: The operation was successfully completed laparoscopically in all cases with a mean operative time of 135 minutes without major perioperative complications. The median blood loss was 60 mL. Hospital stay was 3.2 days (range, 2 to 6 d). Seven cases improved significantly after operation in a mean follow-up of 1.5 years. The success rate of this study is 87.5%. CONCLUSIONS: Laparoscopic nephropexy using polyprolene mesh is a minimally invasive, suitable, and clinically established procedure for the treatment of symptomatic nephroptosis with good results in comparison with open surgery. PMID- 21654305 TI - Yield of diagnostic laparoscopy in abdominal tuberculosis: is it worth attempting? AB - BACKGROUND: Abdominal tuberculosis is extremely common in developing countries such as Pakistan and India. The presentation is varied and nonspecific, making the diagnosis extremely difficult at times. This study was performed to find out the efficacy of diagnostic laparoscopy in establishing the histopathological diagnosis of abdominal tuberculosis. METHODS: An analytical descriptive study of 109 patients with abdominal tuberculosis diagnosed by laparoscopy was conducted over a period of 5 years (between January 2004 and December 2009) in a teaching hospital and in various private hospitals. All patients with vague abdominal symptoms and suspicion of abdominal tuberculosis were admitted and examined thoroughly. Data were collected and statistically analyzed using SPSS version 16. RESULTS: A total of 133 patients with vague abdominal symptoms and an unsettled diagnosis were included in this series, of which 109 (82%) patients were diagnosed with abdominal tuberculosis on laparoscopy. The common symptoms were pain in abdomen, changing bowel habits, loss of weight, and generalized weakness. Clinical examination was not significant, except for anemia in the majority and generalized abdominal tenderness in a few patients. Various tuberculous lesions were detected on laparoscopy. Biopsy of the specimens proved abdominal tuberculosis in 109 patients. Patients were saved from unnecessary laparotomies and were managed on antituberculosis drug therapy. CONCLUSIONS: Diagnostic laparoscopy is an efficient and reliable diagnostic tool for patients suspected with abdominal tuberculosis. PMID- 21654306 TI - Analysis of residual pancreatic bed necrosis using computed tomography following minimally invasive necrosectomy. AB - PURPOSE: In a unit practicing minimally invasive pancreatic necrosectomy (MIPN), our aim was to assess whether tomographic residual necrotic volume was an objective indicator for repeat necrosectomy. METHODS: Prospective study of acute pancreatitis admissions. Patients with infected pancreatic necrosis or deteriorating sepsis had MIPN. Outcome parameters included necrotic volumes, conversion rate, morbidity, and mortality. RESULTS: Thirty patients were admitted with acute pancreatitis of which 15 required organ support. Twenty-nine necrosectomy sessions were performed. Average time from admission to necrosectomy was 39.7 days with an internecrosectomy interval of 6 to 14 days. Mean reduction of necrosis volume was 89.5% and postnecrosectomy volumes were variable. Mean length of hospital and intensive care unit stay was 124.3 and 40.2 days, respectively. Complications included bleeding, pancreatic fistula, and gastric outlet obstruction. No in-hospital deaths or conversions occurred. CONCLUSION: Frequent MIPN achieves substantial pancreatic bed volume reduction with no conversions. Repetitive tomographic scanning is of limited use as an indicator for renecrosectomy. PMID- 21654307 TI - Transumbilical single-port laparoscopic transabdominal preperitoneal repair of inguinal hernia: initial experience of single institute. AB - BACKGROUND: Conventional laparoscopic repair of inguinal hernias is generally performed by using 3 ports. In this study, the authors report their initial experiences of transumbilical single-port transabdominal preperitoneal (TAPP) repair of inguinal hernia using a unique "single port." METHODS: Since November 2008, transumbilical single-port TAPP was performed in 24 patients with an inguinal hernia. A wound retractor and a surgical glove attached with 5 mm trocar and 2 pipes were inserted through a 1.5 cm-sized transumbilical incision. TAPP procedure was performed similarly compared with conventional laparoscopy. RESULTS: Transumbilical single-port TAPP repair of an inguinal hernia was successfully performed in 24 patients (19 male and 5 female; 17 with an indirect hernia and 7 with a recurrent hernia; mean age 54.2 y; mean body mass index 24.2 kg/m). No major or minor intraoperative and postoperative complication was encountered and no conversion to conventional 3-port approach or open surgery was required. Mean operating time was 65.6 minutes and mean hospital stay was 2.1 postoperative days. CONCLUSIONS: Transumbilical single-port TAPP repair of an inguinal hernia is technically feasible, provides nearly scarless surgery and can be performed safely and effectively in selected patients with an inguinal hernia. PMID- 21654308 TI - Transvaginal single port cholecystectomy. AB - BACKGROUND: Transvaginal cholecystectomy encourages researchers to develop new hybrid or pure techniques for natural orifice surgery. We present an approach that combines flexible endoscopes, rigid instruments, and percutaneous needles. METHODS: A 26-year-old female patient with cholelithiasis underwent a single-port culdolaparoscopy cholecystectomy at "Hospital Regional Poza Rica" (Poza Rica, Mexico) on July 2008. The surgery was performed with only 1 transvaginal 16 mm in diameter by 32 cm in length port. The instruments included a gastroscope, laparoscopic 5 mm in diameter by 43 cm in length instruments, percutaneous reins, and hook needle. RESULTS: The patient was discharged 24 hours after surgery, which is customary for the hospital, without pain or visible scars. CONCLUSIONS: Single transvaginal port cholecystectomy using a gastroscope and laparoscopic 5 mm instruments in a parallel path is a feasible procedure in selected patients. This technique requires no abdominal ports assistance. PMID- 21654309 TI - Robotic transaxillary total thyroidectomy using a unilateral approach. AB - There has been a recent interest at performing thyroid procedures robotically through an axillary approach. Although the technique for a unilateral thyroid lobectomy has been well established, there are controversies about whether a unilateral or bilateral axillary approach should be used for total thyroidectomy. Furthermore, there also questions as to whether a robotic total thyroidectomy would be oncologically equivalent to the traditional procedure. We have been performing our robotic total thyroidcetomies through a unilateral axillary approach, using principles learned in traditional surgery for removing substernal goiter. In this report, we describe a technique of robotic unilateral transaxillary total thyroidectomy validated by follow-up radioactive iodine uptake and serum thyroglobulin data. PMID- 21654310 TI - A theory-based primary health care intervention for women who have left abusive partners. AB - Although intimate partner violence is a significant global health problem, few tested interventions have been designed to improve women's health and quality of life, particularly beyond the crisis of leaving. The Intervention for Health Enhancement After Leaving is a comprehensive, trauma informed, primary health care intervention, which builds on the grounded theory Strengthening Capacity to Limit Intrusion and other research findings. Delivered by a nurse and a domestic violence advocate working collaboratively with women through 6 components (safeguarding, managing basics, managing symptoms, cautious connecting, renewing self, and regenerating family), this promising intervention is in the early phases of testing. PMID- 21654311 TI - Chicken skin mucosa surrounding adult colorectal adenomas is a risk factor for carcinogenesis. AB - OBJECTIVES: Transformation of normal mucosa to colorectal adenoma could occur over a span of 5 to 20 years, whereas transformation of colorectal adenoma to colorectal cancer could take an additional 5 to 15 years. This study aims to investigate whether chicken skin mucosa (CSM) surrounding adult colorectal adenomas may be a risk factor for carcinogenesis. METHODS: Patients with colorectal mucosa, colorectal adenomas without CSM, or colorectal adenomas with CSM were enrolled in this study. Immunohistochemistry and enzyme-linked immunosorbent assays were used to determine the expression levels of proliferation markers (ki-67 and COX-2) and apoptosis factors (survivin and caspase-3) in tissues. RESULTS: The expression of ki-67 was significantly higher in colorectal adenomas with CSM compared with colorectal adenoma tissues (P < 0.01). Colorectal adenocarcinoma showed significantly higher levels of COX-2 protein compared with normal colorectal mucosa and colorectal adenoma tissues (P < 0.001). COX-2 expression was significantly higher in adenomas with CSM compared with normal colorectal mucosa (P < 0.001). Adenomas with CSM and adenocarcinomas exhibited significantly higher levels of survivin when compared with colorectal adenoma without CSM and normal tissues (P < 0.001). Although we found no significant difference in caspase-3 levels between adenocarcinomas and adenomas with CSM, caspase-3 expression was significantly lower in these tissues when compared with colorectal adenomas without CSM and normal mucosa (P < 0.001). CONCLUSIONS: The biological characteristics of colorectal adenomas with CSM were different from those of colorectal adenomas without CSM. Colorectal adenomas with CSM exhibited active cell proliferation and inhibition of apoptotic pathways, suggesting an increased risk of carcinogenesis in these adenomas. PMID- 21654313 TI - Prognostic significance of elevated D-dimer for survival in patients with sarcoma. AB - BACKGROUND: Elevated levels of D-dimer, a marker for the systemic activation of the clotting and fibrinolysis, are frequently observed in patients with venous thromboembolism (VTE) and malignancy. We examined the prognostic significance of baseline plasma D-dimer levels for predicting survival in sarcoma. METHODS: The study comprised of 45 patients receiving first-line chemotherapy for inoperable, high-risk for relapse, or metastatic disease. Plasma D-dimer levels was measured before chemotherapy. Univariate and multivariate analysis were performed for association between plasma D-dimer levels and baseline clinical characteristics in predicting survival. RESULTS: D-dimer levels were elevated to >=500 ng/mL in 53% (24 of 45 patients). Six of 45 patients (13%) developed VTE. The Kaplan-Meier analysis showed that the median survival for patients with VTE, metastatic disease, progression on chemotherapy, or D-dimer >=500 ng/mL was shorter (log rank test, P=0.012, 0.001, 0.034, and 0.015, respectively). The mortality rate for patients with D-dimer >=500 ng/mL was higher (P<0.0001) than those with <500 ng/ml for both metastatic (100% vs. 62.5%) and nonmetastatic (58% vs. 31%) groups [median follow-up; 60 mo (range, 9 to 106 mo)]. Using stepwise proportional hazard model, D-dimer levels and metastasis status were independent significant predictors for survival [hazard ratios (95% confidence intervals), 4.24 (1.88 9.60), and 3.28 (1.42-7.58), respectively]. CONCLUSIONS: Elevated D-dimer levels have independent significant prognostic value for survival in sarcoma patients with both metastatic and nonmetastatic disease and may help identify high-risk patients for treatment decisions. PMID- 21654312 TI - The utilization of oncology web-based resources in Spanish-speaking Internet users. AB - OBJECTIVES: There currently are few web-based resources written in Spanish providing oncology-specific information. This study examines utilization of Spanish-language oncology web-based resources and evaluates oncology-related Internet browsing practices of Spanish-speaking patients. METHODS: OncoLink (http://www.oncolink.org) is the oldest and among the largest Internet-based cancer information resources. In September 2005, OncoLink pioneered OncoLink en espanol (OEE) (http://es.oncolink.org), a Spanish translation of OncoLink. Internet utilization data on these sites for 2006 to 2007 were compared. RESULTS: Visits to OncoLink rose from 4,440,843 in 2006 to 5,125,952 in 2007. OEE had 204,578 unique visitors and 240,442 visits in 2006, and 351,228 visitors and 412,153 visits in 2007. Although there was no time predilection for viewing OncoLink, less relative browsing on OEE was conducted during weekends and early morning hours. Although OncoLink readers searched for information on the most common cancers in the United States, OEE readers most often search for gastric, vaginal, osteosarcoma, leukemia, penile, cervical, and testicular malignancies. Average visit duration on OEE was shorter, and fewer readers surveyed OEE more than 15 minutes (4.5% vs. 14.9%, P < 0.001). CONCLUSIONS: Spanish-speaking users of web-based oncology resources are increasingly using the Internet to supplement their cancer knowledge. Limited available resources written in Spanish contribute to disparities in information access and disease outcomes. Spanish-speaking oncology readers differ from English-speaking readers in day and time of Internet browsing, visit duration, Internet search patterns, and types of cancers searched. By acknowledging these differences, content of web-based oncology resources can be developed to best target the needs of Spanish-speaking viewers. PMID- 21654315 TI - Optimizing the surgical effort in patients with advanced neuroendocrine neoplasm hepatic metastases: a critical analysis of 40 patients treated by hepatic resection and cryoablation. AB - BACKGROUND: Surgical extirpation of neuroendocrine neoplasms hepatic metastases (NENHM) provides the best opportunity of long-term survival but is not feasible in the majority of patients given the widespread presentation of liver disease. Combining resection with local ablation can potentially expand the resection criteria and thereby improve survival. The present study critically evaluates the progression-free survival (PFS) and overall survival (OS) of patients with NENHM who underwent concomitant hepatic resection and cryoablation. METHODS: Forty patients with NENHM underwent concomitant hepatic resection and cryoablation between December 1992 and June 2010. PFS and OS were determined; clinicopathologic and treatment-related factors associated with PFS and OS were evaluated through univariate and multivariate analyses. RESULTS: The median follow-up for the patients who were alive was 61 months (range, 1 to 162 mo). The median PFS and OS after hepatic resection were 22 and 95 months, respectively. Five-year and 10-year OS rate was 61% and 40%, respectively. One independent factor was associated with OS: histologic grade (P=0.001). One independent factor was associated with PFS: extrahepatic disease (P=0.003). CONCLUSION: Concomitant hepatic resection and cryoablation to achieve tumor debulking is associated with excellent survival outcomes in selected patients. This approach may increase the number of patients with borderline resectable disease undergoing surgical management of advanced NENHM. PMID- 21654314 TI - Dose escalation and pharmacokinetics study of enzastaurin and sunitinib versus placebo and sunitinib in patients with metastatic renal cell carcinoma. AB - OBJECTIVE: To assess antiangiogenic effects of enzastaurin in combination with sunitinib in patients with renal cell carcinoma (RCC). METHODS: This was a multicenter, phase 2 study of enzastaurin and sunitinib versus placebo and sunitinib for adult patients with metastatic clear cell RCC. Part 1 was a 6-week, open-label, safety lead-in phase with 2 cohorts (sunitinib, both cohorts: 50 mg/d for 4 weeks; enzastaurin, cohort 1: a loading dose of 500 mg, followed by 250 mg daily; cohort 2: a loading dose of 1125 mg, followed by 500 mg daily). Part 2 was to be a randomized, double-blinded phase, with efficacy as the primary objective. Secondary objectives included the assessment of treatment-emergent adverse events (TEAEs) and pharmacokinetics. RESULTS: Seventeen patients received >=1 dose of study medication. Six patients (54.5%) in cohort 1 and 2 patients (33.3%) in cohort 2 received >=6 cycles of treatment. All patients experienced >=1 TEAE possibly related to study drug. Dose reductions were required as follows: cohort 1--enzastaurin, n=4 (36.4%), sunitinib, n=6 (54.5%); cohort 2--enzastaurin, n=3 (50.0%), sunitinib, n=2 (33.3%). CONCLUSIONS: Whereas the hypothesis that combining sunitinib and enzastaurin may result in greater antiangiogenic effects in RCC is based on solid scientific evidence, part 2 of the study was not activated due to the high number of TEAE-related dose reductions at the expected efficacious dose and overall decision by the sponsor not to pursue further development of enzastaurin for solid tumors. PMID- 21654317 TI - PTEN reconstitution alters glioma responses to c-Met pathway inhibition. AB - Mutations/deletions of the tumor-suppressor phosphatase and tensin homolog PTEN result in PI3K/Akt pathway hyperactivation and potentially alter oncogenic responses to targeted receptor tyrosine kinase inhibitors. We previously showed that hepatocyte growth factor (HGF):c-Met pathway inhibition decreases tumor growth and oncogenic signaling responses in PTEN-null/Met+ gliomas. Here, we use two tet-on PTENwt-inducible glioma cell lines and xenograft models to examine the influence of PTEN on oncogenic signaling responses to HGF:c-Met pathway inhibitors. Reconstitution of PTEN inhibited Akt by more than 80% and inhibited cell growth by approximately 70-75% in both cell lines in vitro. C-Met inhibition alone inhibited in-vitro cell growth by approximately 80-85% and the magnitude of growth inhibition was not altered by combining PTEN reconstitution with c-Met inhibition. Combining PTEN reconstitution with Met inhibition arrested a higher percentage of cells in G(1)/G(0) phase of the cell cycle when compared with either PTEN reconstitution or c-Met inhibition alone. Both PTEN reconstitution alone and inhibiting autocrine HGF:c-Met signaling alone, using anti-HGF mAb, robustly inhibited the growth of subcutaneous and intracranial glioma xenografts. Combining anti-HGF therapy with PTEN reconstitution did not significantly alter the magnitude of xenograft growth inhibition. Semiquantitative immunohistopathological analyses revealed that the inhibition of glioma xenograft angiogenesis and cell proliferation by anti-HGF mAb was greatest in conjunction with PTEN reconstitution. In contrast, xenograft cell apoptosis was greatest in response to anti-HGF therapy alone and PTEN reconstitution abrogated the apoptotic response to anti-HGF therapy. These results provide new insights into how PTEN modulates glioma responses to the inhibition of HGF:c-Met signaling and possibly other receptor tyrosine kinase pathways. PMID- 21654318 TI - Accuracy of the HoMedics Walgreens Deluxe Arm Blood Pressure device (WGNBPA-540) compared with auscultation in 85 individuals. AB - PURPOSE: To determine whether the HoMedics Walgreens Deluxe Arm Blood Pressure device (WGNBPA-540) meets the Association for the Advancement of Medical Instrumentation and the Working Group on Blood Pressure Monitoring of the European Society of Hypertension International Protocol accuracy requirements. MATERIALS AND METHODS: Simultaneous auscultatory measurements by two observers were obtained in individuals during measurement with the HoMedics WGNBPA-540. Each individual had three measurements after a minimum of 10 min of rest and 1 min between readings. RESULTS: Two hundred and fifty-five triplicate measurements were made in 85 individuals. The observer minus the WGNBPA-540 mean systolic blood pressure/diastolic blood pressure differences were 0.92/-0.22 mmHg (+/- 0.4.51/4.42 mmHg standard deviation). The observer minus WGNBPA-540 device within 5 mmHg for the systolic blood pressure/diastolic blood pressure was 86.27/92.16%, within 10 mmHg was 99.61/97.65%, and within 15 mmHg was 100/98.82%. CONCLUSION: The HoMedics model, WGNBPA-540, meets the Advancement of Medical Instrumentation (methods 1 and 2) and the International Protocol accuracy standard requirement. PMID- 21654319 TI - European consensus statement for intraoperative fluid therapy in children. AB - The intraoperative infusion of isotonic solutions with 1-2.5% glucose in children is considered well established use in Europe and other countries. Unfortunately, a European marketing authorisation of such a solution is currently missing and as a consequence paediatric anaesthetists tend to use suboptimal intravenous fluid strategies that may lead to serious morbidity and even mortality because of iatrogenic hyponatraemia, hyperglycaemia or medical errors. To address this issue, the German Scientific Working Group for Paediatric Anaesthesia suggests a European consensus statement on the composition of an appropriate intraoperative solution for infusion in children, which was discussed during a working session at the 2nd Congress of the European Society for Paediatric Anaesthesiology in Berlin in September 2010. As a result, it was recommended that an intraoperative fluid should have an osmolarity close to the physiologic range in children in order to avoid hyponatraemia, an addition of 1-2.5% instead of 5% glucose in order to avoid hypoglycaemia, lipolysis or hyperglycaemia and should also include metabolic anions (i.e. acetate, lactate or malate) as bicarbonate precursors to prevent hyperchloraemic acidosis. Thus, the underlying intention of this consensus statement is to facilitate the granting of a European marketing authorisation for such a solution with the ultimate goal of improving the safety and effectiveness of intraoperative fluid therapy in children. PMID- 21654320 TI - Epidemiology of cancer from the oral cavity and oropharynx. AB - The classification of sites in tumors of the oral cavity, oropharynx, pharynx, and hypopharynx varies in the literature. More than 90% of these tumors of the mucosal lining are classified as squamous cell carcinoma developed from premalignant lesions such as leukoplakia and erythroleukoplakia. These carcinomas are associated to environmental and lifestyle risk factors, among which tobacco and alcohol play a major role. In addition to tobacco smoking, tobacco chewing is another risk factor as well as chewing betel quid and areca nut in Asia. Certain strains of virus, such as the sexually transmitted human papilloma virus, also play a carcinogenetic role. The temporal trends in incidence of these tumors relate to environmental factors; there is an increase in tendency in countries without prevention and a decrease in countries having an active policy of prevention of alcohol and tobacco consumption. In contrast, an increased incidence occurs in the world at tumor sites related to human papilloma virus infection in relation to changes in sexual habits. PMID- 21654321 TI - Blunted increase in serum hepcidin as response to oral iron in HFE hemochromatosis. AB - BACKGROUND: HFE hemochromatosis (HFE-H) is the most common and well-defined inherited cause for iron-related morbidity and mortality. Majority of patients with HFE-H are homozygote for C282Y mutation. Recent studies suggest that iron accumulation in most types of hemochromatosis is due to deficiency of hepcidin, a central iron regulator. However, the precise link between hepcidin levels and iron absorption in HFE-H patients has been poorly understood. AIM: To measure hepcidin response to oral iron challenge (200 mg ferrous sulphate), in HFE-H (C282Y/C282Y) patients and compare with healthy controls (HCs). METHODS: Nine patients with C282Y/C282Y HFE-H along with 15 HC were recruited for the study. All HFE-H were iron depleted and studied at a time distant to phlebotomy. Hepcidin was measured using a published immunoassay method after ingestion of 65 mg oral iron challenge. Serum iron, ferritin and transferrin saturation were measured using standard methods. The area under the curve was calculated and compared between the two groups. RESULTS: The basal serum hepcidin levels in patients with HFE-H were significantly low as compared with HC (P=0.0002). Incremental serum hepcidin response seen in HC reached significance at 4 h post iron challenge (P=0.0085) returning to baseline only at 24 h. There was no significant hepcidin response in HFE-H at 4 h (P=0.294). The overall hepcidin response was significantly lower in HFE-H compared with HC (area under the curve: P=0.0127). CONCLUSION: Failure to mount a rapid hepcidin response to an oral iron challenge is the key mechanisms of iron accumulation despite prevailing excess body iron in patients with HFE-H with C282Y/C282Y mutation. PMID- 21654322 TI - Retreatment of patients with chronic hepatitis C relapsers to a previous antiviral treatment. AB - BACKGROUND: The efficacy of retreatment with pegylated interferon (PEG-IFN) plus ribavirin for patients relapsing after a previous treatment remains to be fully elucidated, although extended treatment seems to be the best option in such cases. AIM: To evaluate the efficacy of two extended protocols in patients with genotypes 1 or 4, or those with genotypes 2 or 3. METHODS: A total of 181 patients who had relapsed after a previous antiviral treatment with PEG IFNalpha2a plus weight-based ribavirin were offered retreatment with the same dose of both PEG-IFN plus ribavirin, to be continued for 48 weeks in those with genotypes 2 or 3 (group 1), and for 72 weeks in those with genotypes 1 or 4 (group 2). RESULTS: A total of 59 patients (32.5%) refused the retreatment, while 122 (78 men, 44 women) patients were enrolled in the study: 41 were allocated in group 1 and 81 in group 2. Cirrhosis at baseline (staging 5/6 according to Ishak's score was recorded in 11 patients, six in group 1 and five in group 2). Nine patients (7.3%) in group 2 discontinued the treatment (due to lack of response). The remaining patients completed the treatment and were followed-up for at least 12 months after the treatment. Sustained virological response (SVR) rate was 82.9% in group 1 and 50.6% in group 2. CONCLUSION: Patients with chronic hepatitis C with 'easy genotypes' relapsers to a previous antiviral treatment have more than 80% probability of achieving a SVR with a 48-week retreatment. Patients with 'difficult genotypes' have more than 50% chance of a SVR after a 72 week extended treatment. PMID- 21654323 TI - Unfavourable outcome for women in a study of health-related quality of life, social factors and work disability in Crohn's disease. AB - OBJECTIVE: The aim was to describe health-related quality of life (HRQL) and social factors, sickness and disability variables in a large population-based cohort of patients with Crohn's disease (CD). METHODS: HRQL was measured with Short Form-36 in 497 adult patients with CD at three outpatient clinics. Comparisons were made with age-sex-matched background population and with ulcerative colitis (UC). Social factors, employment, sickness compensation and disability pension for CD were compared with national population registers. RESULTS: CD had a greater negative effect on HRQL than did UC. This difference was more pronounced for women. Compared with background population, patients with CD had lower educational level, and had a two-fold rise in long-term sickness and disability pension rate. Women with CD had higher rates of sickness and disability than men with CD and were more often living single, though procreation was not affected. CONCLUSION: This study characterized the burden of CD in a large population-based cohort. CD had higher impact on HRQL, compared with UC. Women with CD had worse outcome in subjective health status, but not in objective assessment of disease activity. Women also had higher rates of sickness, disability pension and single living. The mechanism underlying the sex-related inequalities in outcome for CD warrants further elucidation. PMID- 21654324 TI - The use of the 6-min walk test as a proxy for the assessment of energy expenditure during gait in individuals with lower-limb amputation. AB - The objective of this study was to determine, and compare, the utility of the 6 min walk test (6 MWT) and self-selected walking speed over 15 m as proxies for the assessment of energy expenditure during gait in individuals with lower-limb amputation. Patients with unilateral, transfemoral amputation (n=6) and patients with unilateral, transtibial amputation (n=10) from community-based support groups participated in this study. Age-matched and body mass index-matched able bodied controls (n=28) from a sample of convenience also participated. The main outcome measures were as follows: (a) distance, heart rate, oxygen consumption and oxygen cost during the 6 MWT and (b) self-selected walking speed over 15 m. Oxygen cost did not correlate significantly with self-selected walking speed over 15 m (rho=-0.329) or average walking speed during the 6 MWT (rho=-0.350). Significant correlations were not present between oxygen cost and the walking speed during the 6 MWT (range, ?rho?: 0.210-0.531), although walking speeds at particular times of the 6 MWT demonstrated stronger correlations than others. Walking speed in the third min of walking during the 6 MWT recorded the strongest correlation with peak oxygen cost (rho=-0.531). The 6 MWT is a submaximal measure in persons with lower-limb amputation. Self-selected walking speed over 15 m was not an appropriate proxy for the assessment of the energy cost of gait. Individuals with a lower-limb amputation require approximately 3 min of continuous walking to re-establish homoeostasis in heart rate, oxygen consumption and oxygen cost. The nonsignificant correlation between walking speeds during the 6 MWT and oxygen cost suggest that the 6 MWT can provide an indication of oxygen cost, but caution should be exercised when using it as a sole proxy for the measurement of oxygen cost in individuals with lower-limb amputation. PMID- 21654325 TI - Effects of glutathione-depleting drug buthionine sulfoximine and aging on activity of endothelium-derived relaxing and contracting factors in carotid artery of Sprague-Dawley rats. AB - The role of the antioxidant glutathione (GSH) in mediating endothelial (dys)function, and how that role may depend on age, is unclear. The main purpose of the current study was to investigate the effect of 10-day treatment with the GSH-depleting drug l-buthionine sulfoximine (BSO) on endothelium-derived relaxing factor and endothelium-derived contracting factor activities in the isolated common carotid artery (CCA) of Adult and Aging animals. CCA blood pressure and flow were unaffected by age or BSO. Endothelium-derived relaxing factor activity, examined in precontracted CCA as relaxation to cumulative acetylcholine (ACh), was largely nitric oxide synthase (NOS) mediated and was not different between Adult and Aging animals at lower ACh; however, at higher ACh, relaxation was blunted in Aging CCA, an effect abolished by cyclooxygenase (COX) inhibition but not by NOS inhibition nor by the reactive oxygen species (ROS) inhibitors 4 hydroxy-TEMPO or Mn(III)tetrakis(1-methyl-4 pyridyl)porphyrin,tetratosylate,hydroxide. Specific examination of endothelium derived contracting factor activity in quiescent NOS-inhibited CCA established that higher ACh elicited a contractile response, ~3.5-fold greater in Aging versus Adult CCA, which was abolished by COX-1-specific inhibition but unaffected by ROS inhibitors. Aging was unrelated to changes in liver or vascular tissue GSH or ROS content. BSO was effective in significantly decreasing GSH and increasing ROS content in both animal cohorts. However, NOS-mediated endothelium-derived relaxing factor activity was well preserved and age-related COX-mediated endothelium-derived contracting factor activity was unaffected in response to these BSO-induced perturbations, as were exogenous H2O2-stimulated NOS/non-NOS mediated relaxation and COX-mediated contractile activities. These data suggest that, regardless of age, chronic partial depletion of GSH in vivo does not necessarily cause endothelium-dependent vasomotor dysfunction. PMID- 21654326 TI - Personalizing medicine for the child with heart disease: a path forward. PMID- 21654328 TI - Reactivation of peroxisome proliferator-activated receptor alpha in spontaneously hypertensive rat: age-associated paradoxical effect on the heart. AB - Prevention of left ventricular hypertrophy remains a challenge in the prevention of hypertension-induced adverse cardiac remodeling. Cardiac hypertrophy is associated with a shift in energy metabolism from predominantly fatty acid to glucose with a corresponding reduction in the expression of fatty acid oxidation enzyme genes. Although initially adaptive, the metabolic switch seems to be detrimental in the long run. This study was taken up with the objective of examining whether the stimulation of fatty acid oxidation by the activation of peroxisome proliferator-activated receptor alpha (PPARalpha), a key regulator of fatty acid metabolism, can prevent cardiac hypertrophy. Fenofibrate was used as the PPARalpha agonist. Spontaneously hypertensive rats (SHRs) in the initial stages of hypertrophy (2 months) and those with established hypertrophy (6 months) were treated with fenofibrate (100 mg.kg.d for 60 days). Cluster of differentiation 36 (CD36)-responsible for myocardial fatty acid uptake, carnitine palmitoyl transferase 1beta-a mitochondrial transporter protein and medium chain acyl-Co-A dehydrogenase-a key enzyme in beta oxidation of fatty acids were selected as indicators of fatty acid metabolism. Hypertrophy was apparent at 2 months and metabolic shift at 4 months of age in SHRs. The treatment prevented cardiac remodeling in young animals but aggravated hypertrophy in older animals. Hypertrophy showed a positive association with malondialdehyde levels and cardiac NF-kappaB gene expression, signifying the role of oxidative stress in the mediation of hypertrophy. Expression of carnitine palmitoyl transferase 1beta and medium chain acyl-Co-A dehydrogenase was upregulated on treatment. However, CD36 showed an age-dependent variation on treatment, with no change in expression in young rats and downregulation in older animals. It is inferred that the stimulation of PPARalpha before the initiation of metabolic remodeling may prevent cardiac hypertrophy, but reactivation after the metabolic adaptation aggravates hypertrophy. Whether the downregulation of CD36 is mediated by decreased substrate availability remains to be explored. Age-dependent paradoxical effect on the heart in response to fenofibrate, used as a lipid lowering drug, can have therapeutic implications. PMID- 21654327 TI - High-fat diet increases and the polyphenol, S17834, decreases acetylation of the sirtuin-1-dependent lysine-382 on p53 and apoptotic signaling in atherosclerotic lesion-prone aortic endothelium of normal mice. AB - Our purpose was to determine if high-fat diet and treatment with a polyphenol regulate the acetylation of lysine-382 of p53, the site regulated by sirtuin-1, and apoptosis in the endothelium of the atherosclerotic lesion-prone mouse aortic arch. In cultured endothelial cells, 2 atherogenic stimuli, hydrogen peroxide and tumor necrosis factor-alpha, increased the acetylation of p53 lysine-382, and caspase-3 cleavage, an indicator of apoptotic signaling. The polyphenol, S17834, significantly prevented these changes. In low-density lipoprotein receptor deficient mice, a high-fat diet increased, and treatment with S17834 attenuated early atherosclerotic lesions on the lesser curvature of the aortic arch. In wild type C57BL6 mice fed the same diet, no atherosclerotic lesions were observed in this lesion-prone area, but p53 acetylation and caspase-3 cleavage increased in the endothelium. In high-fat fed mice, S17834 increased sirtuin-1 protein in the lesion-prone endothelium and prevented both the increase in p53 acetylation and caspase-3 cleavage without affecting blood lipids. These results indicate that high-fat diet increases and S17834 decreases the acetylation of p53 in lesion prone aortic endothelial cells of normal mice independently of blood lipids, suggesting that the polyphenol may regulate endothelial cell p53 acetylation and apoptosis via local actions. PMID- 21654329 TI - Cardiovascular catecholamine receptors in children: their significance in cardiac disease. AB - Adrenoceptors and dopamine receptors are grouped together under the name 'catecholamine receptors.' Catecholamines and catecholaminergic drugs act on catecholamine receptors located on or near the cardiovascular system. The physiological effects of catecholamine receptor stimulation are only partly understood. The catecholaminergic drugs used in critical care medicine today are not selective, or are, at best, in part selective for the various catecholamine receptor subtypes. Many patients, however, depend on them. A variety of animal models has been developed to unravel catecholamine distribution and function. However, the identification of species heterogeneity makes it imperative to determine catecholamine receptor distribution and function in humans. In addition, age-related alterations in catecholamine receptor distribution and function have been identified in human adults. This might have implications for our understanding of the effect of catecholamines in pediatric patients. This article will focus on the pediatric population and will review currently available in vitro data on the distribution and the function of catecholamine receptors in the cardiovascular system of fetuses and children. Also discussed are relevant young animal models and in vivo hemodynamic effects of cardiotonic drugs acting on the catecholamine receptor in children requiring major cardiac surgery. A better understanding of these topics might provide clues for new, receptor subtype-selective, therapeutic approaches in newborns and children with cardiac disease. PMID- 21654330 TI - Pediatric cardiovascular drug development and research: integration of modeling and simulation as one future direction. AB - The integration of the needs of children into the legal drug development process since 1997 in the United States and since 2007 in the European Union has improved health and stimulated innovative approaches in the design of clinical trials and will benefit both current and future populations. According to the US Food and Drug Administration, to date, 394 pediatric labels together with safer medicines and better dosing practices have provided a sound basis for the safer and more effective use of drugs in a pediatric population. This may be measurable with fewer medication errors and perhaps shorter hospital stays in the future. Although relevant data have been generated by clinical trials in pediatric populations, challenges, such as nonefficacy and safety issues, have arisen. Heterogeneity in the physiological maturation and growth processes and differences in the etiology and pathogenesis of disease in patients from birth to 18 years of age may explain these results. The use of cutting-edge technology, such as modeling and simulation of "in silico" pediatric populations, may allow the integration of data from previous trials and experiments into the design of future clinical trials and allow exploration in other areas that have the potential to enhance the outcome of clinical trials in children. PMID- 21654331 TI - Local termination of 3'-5'-cyclic adenosine monophosphate signals: the role of A kinase anchoring protein-tethered phosphodiesterases. AB - A kinase anchoring proteins (AKAPs) belong to a family of functionally related proteins capable of binding protein kinase A (PKA) and tether it to relevant targets. In this way, AKAPs organize macromolecular complexes to segregate PKA activity and retain signal specificity. In the heart, AKAP-PKA interaction is central to the regulation of cardiac contractility. Phosphodiesterases belong to a large superfamily of enzymes that degrade 3'-5'-cyclic adenosine monophosphate (cAMP). They possess diverse catalytic properties and multiple regulatory mechanisms and control the duration and amplitude of the cAMP signal, including its propagation in space. AKAPs, together with PKA, can also assemble phosphodiesterases thereby providing a means to locally control cAMP dynamics at the level of single macromolecular complexes. This allows for the fine tuning of the cAMP response to the specific demands of the cell. PMID- 21654332 TI - In vivo cardioprotection by pitavastatin from ischemic-reperfusion injury through suppression of IKK/NF-kappaB and upregulation of pAkt-e-NOS. AB - Recent studies have uncovered the beneficial effects of statin in cardiovascular diseases; however, the role of pitavastatin in ischemia-reperfusion (IR)-induced apoptosis and myocardial damage is not established. Therefore, in this study, we aim to investigate whether pitavastatin treatment attenuates myocardial IR injury via regulating oxidative stress, inflammation, apoptosis, and phosphorylated protein kinase B (pAkt) endothelial nitric oxide synthase (e-NOS) pathways. After the 14-day treatment with pitavastatin (0.16-0.64 mg.kg.d, po) or saline, rats were subjected to 45 minutes of ischemia by occluding the left anterior descending coronary artery and to 60 minutes of reperfusion to induce myocardial damage. Pitavastatin at a dose of 0.32 and 0.64 mg/kg significantly improved cardiac function as evidenced by the normalization of the mean arterial pressure, heart rate, +/-LVdP/dtmax, and left ventricular end-diastolic pressure as compared with the IR control. Additionally, pitavastatin dose-dependently normalized myocardial antioxidants, lactate dehydrogenase, and thiobarbituric acid reactive substances along with decreased serum tumor necrosis factor-alpha level and creatine kinase isoenzyme-MB activity. Furthermore, pitavastatin enhanced pAkt, (p) e-NOS, Bcl-2, and suppressed IkappaB kinase/nuclear factor kappa B, nitrotyrosine (NO inactivation product), Bax, and capases-3 protein expression in the heart. Morphological assessments of the IR-challenged myocardium showed that 0.32 and 0.64 mg/kg of pitavastatin decrease myocardial necrosis and inflammatory changes. Thus, pitavastatin reduced IR-induced infarction and dysfunction via the augmentation of endogenous antioxidant, suppression of IkappaB kinase/nuclear factor-kappa B, activation of pAkt-e-NOS, and/or decreased NO inactivation and apoptosis. PMID- 21654333 TI - Trauma and hyperactivity: differentiating symptoms and cause. AB - CASE: Quintin is a 7-and-a-half-year-old male who presents to you with his long term foster parents stating that the school "wants to put him in a special behavior class." You have cared for the child since he went into the foster parents/biological aunt and uncle's care at 14 months of age.Quintin has been healthy and is on no medication; he has no chronic diseases or other medical problems. He has never had physical trauma, but when you first met him at 14 months of age, his aunt and uncle could give no history about his infancy. The aunt's sister who is the biological mother is currently incarcerated for drug trafficking, and his biological father is an unknown.His toddler years were fairly uneventful. The aunt and uncle have 2 children of their own who are currently 12 and 15 years of age-at the time Quintin joined the family they were 5 and 8 years of age and so the initial adjustment was stressful for the family. The aunt worked full time throughout Quintin's toddlerhood and often in childcare he would have difficulty with drop-off.When he began at head start, he was often described as "too busy" and "trouble on the playground," but he was highly verbal and intellectually curious, had many friends, and did well. Kindergarten was fairly uneventful in a full-day program, although he began to be more provocative at home, often getting into his cousins video games and once breaking his cousin's smart phone.He did well academically at the beginning of first grade. He was a solid reader by January of the year, but his activity and oppositionality were increasing. He was suspended 4 times between January and March for "unsafe behavior" including bolting from the playground during recess following the dare of an older student. His aunt and uncle present at primary care at their wits end. They state that at home he is increasingly angry. He responds much better to his uncle but can be very provocative with his aunt stating "I don't have to listen to you because you are not my mother." His aunt expressed concern when she was told by his teacher that "Either he starts medication or he needs to go to a special classroom." Where do you go from there? PMID- 21654334 TI - Cerebral palsy grown up. PMID- 21654335 TI - Longitudinal analysis of emotional problems in children with congenital heart defects: a follow-up from age 6 to 36 months. AB - OBJECTIVE: To investigate whether children with varying severity of congenital heart defects (CHDs) have a higher risk of internalizing or externalizing emotional problems at 36 months of age. In addition, to analyze whether a history of emotional problems at 6 or 18 months of age increases the risk of emotional problems at 36 months in children with CHDs. METHODS: Prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health, was linked with a nationwide CHD registry, and 175 children with CHDs were identified in a cohort of 44,104 children aged 36 months. Maternal reports on child characteristics were assessed by questionnaires at child age 6, 18, and 36 months. RESULTS: Children with CHDs did not have elevated scores on internalizing or externalizing problems at 36 months of age compared with controls. Not even the children with CHDs with a history of emotional problems at age 6 or 18 months showed an increased risk. CONCLUSIONS: The absence of risk of emotional problems at 36 months of age in children with CHDs could be a consequence of the completion of the most extensive medical treatment. PMID- 21654336 TI - Use of the Cogan lid twitch to identify myasthenia gravis. AB - BACKGROUND: To evaluate the reliability of the Cogan lid twitch (CLT) test in a neuro-ophthalmology clinic. METHODS: CLT testing was performed on adult patients presenting to the neuro-ophthalmology clinic by the neuro-ophthalmologist. The patients were instructed to look straight ahead, up, down, and straight ahead again. The upper eyelids were carefully evaluated immediately following this movement for the presence of a brief upward twitch of the upper eyelid, which would indicate a positive CLT test. The test was repeated as needed. We evaluated the findings from the ophthalmologic examination along with results of available tests, such as serologic findings, MRIs, and CTs. RESULTS: Of 117 patients evaluated, 24 had myasthenia gravis (MG), and 18 of these patients had a positive lid twitch. Of the 98 patients who did not display a positive Cogan twitch, 6 had MG. We calculated the specificity of the CLT to be 99%, with a sensitivity 75% and false-positive rate 1%. CONCLUSION: The CLT test is a specific and sensitive test to use in a neuro-ophthalmology clinic to evaluate for MG. PMID- 21654337 TI - Trigeminocardiac reflex during temporary clipping in aneurismal surgery: first description. PMID- 21654338 TI - Balloon test occlusion with hypotensive challenge using a novel agent Fenoldopam: a first experience. PMID- 21654339 TI - Digital calcinosis circumscripta: case series and review of the literature. AB - A series of three paediatric cases of digital calcinosis circumscripta is presented. Digital calcinosis circumscripta is an unusual form of calcinosis circumscripta occurring specifically in the digits. The condition is rare among the paediatric population. The cases serve to clarify the clinical and radiographic features of the condition and to discuss suggested treatment options. PMID- 21654340 TI - Radiological criteria for trochlear dysplasia in children and adolescents. AB - Trochlear dysplasia is a well-known cause for recurrent patellar instability. Besides clinical findings, the treatment is based on radiological diagnostic tools. In adults the characteristics of trochlear dysplasia are determined by magnetic resonance imaging (MRI) scans as well as on true lateral radiographs. For children there are no established criteria for the radiological diagnosis of trochlear dysplasia. This study was designed to evaluate if typical radiological findings of trochlear dysplasia on lateral radiographs in adults are also found in children and adolescents with open growth plates. We analyzed true lateral radiographs of children and adolescents with MRI-detected trochlear dysplasia. On lateral radiographs three factors were relevant: crossing sign (deepest part of the trochlea crosses the most anterior point of the lateral condyle), a supratrochlear spur or bump (bulge of the proximal trochlea), and a double contour (due to a hypoplastic medial condyle). In all patients with trochlear dysplasia at least one typical radiological finding usually found in adults could be documented. Only true lateral radiographs allow the diagnosis of trochlear dysplasia in children and adolescents with open physis to be made. MRI scans on a regular basis are, therefore, not mandatory although they are the diagnostic golden standard for the diagnosis of trochlear dysplasia. PMID- 21654341 TI - Kinetic and training comparisons between assisted, resisted, and free countermovement jumps. AB - Elastic band assisted and resisted jump training may be a novel way to develop lower-body power. The purpose of this investigation was to (a) determine the kinetic differences between assisted, free, and resisted countermovement jumps and (b), investigate the effects of contrast training using either assisted, free, or resisted countermovement jump training on vertical jump performance in well-trained athletes. In part 1, 8 recreationally trained men were assessed for force output, relative peak power (PP.kg(-1)) and peak velocity during the 3 types of jump. The highest peak force was achieved in the resisted jump method, while PP.kg(-1) and peak velocity were greatest in the assisted jump. Each type of jump produced a different pattern of maximal values of the variables measured, which may have implications for developing separate components of muscular power. In part 2, 28 professional rugby players were assessed for vertical jump height before and after 4 weeks of either assisted (n = 9), resisted (n = 11), or free (n = 8) countermovement jump training. Relative to changes in the control group (1.3 +/- 9.2%, mean +/- SD), there were clear small improvements in jump height in the assisted (6.7 +/- 9.6%) and the resisted jump training group (4.0 +/- 8.8%). Elastic band assisted and resisted jump training are both effective methods for improving jump height and can be easily implemented into current training programs via contrast training methods or as a part of plyometric training sessions. Assisted and resisted jump training is recommended for athletes in whom explosive lower-body movements such as jumping and sprinting are performed as part of competition. PMID- 21654342 TI - Heart rate and core temperature responses of elite pit crews during automobile races. AB - There is limited information regarding the physiological and psychological demands of the racing environment, and the subsequent effect on the performance of pit crew athletes. The purpose of this study was to evaluate heart rates (HRs) and core body temperatures (CTs) of pit crew athletes in the race environment. The HR and CT of pit crew athletes (n = 7) and control subjects were measured during 6 National Association for Stock Car Automobile Racing Sprint Cup races using ingestible sensors (HQ Inc, Palmetto, FL, USA). The HR and CT were measured before each race, at 15-minute intervals during the race, and upon completion of each pit stop. Compared to the control subject at each race, the pit crew athletes had significantly (p = 0.014) lower core temperatures (CTs). The pit crew athletes displayed higher HRs on the asphalt tracks than on concrete tracks (p = 0.011), and HR responses of the crew members were significantly (p = 0.012) different between pit crew positions, with the tire changers and jackman exhibiting higher HRs than the tire carriers. Unexpectedly, the CTs of the pit crew athletes were not elevated in the race environment, despite high ambient temperatures and the extensive fire-protection equipment (e.g., helmet, suit, gloves) each pit crew athlete wore. The lack of CT change is possibly the result of the increased HR more efficiently shunting blood to the skin and dissipating heat as a consequence of the athletes' extensive training regimen and ensuing heat acclimation. Additionally, it is possible that psychological stress unique to several of the tracks provided an additive effect resulting in increased heart rates. PMID- 21654343 TI - Fosbury flop: predicting performance with a three-variable model. AB - The goal of this study is to (a) find the most predictive anthropometric factors, (b) check the predictability of a new jumping motor test, and (c) predict Fosbury flop (FFP) performance by using a multiregression analysis. The participants of this study were 49 girls (age 13.6 +/- 0.48 years; height = 1.61 +/- 0.07 m) and 68 boys (age 13.6 +/- 0.47 years; height = 1.64 +/- 0.10 m). We measured the height, the sitting height), the highest position touched by the hand in a standing position (HEIGHTARM), the highest position touched by the hand during a running 1-leg vertical jump with a semirestricted curved run-up (HMAX), and the best performance in the FFP. We then calculated the leg length (LEGLENGTH), the skelic index (ratio of legs length to the abdomen length, SKEL), the vertical performance (VP, difference between HMAX and HEIGHTARM). The ability level was deducted from the difference between (LEGLENGTH + VP) and FFP. Pearson correlation coefficients were calculated, and a multiple-regression analysis technique was applied to find the most predictive model (p < 0.05). The FFP was correlated with standing height (HEIGHT; r = 0.398; p < 0.05), HMAX (r = 0.707; p < 0.0005), ABILITY (r = 0.391; p < 0.005) but not with SKEL (r = 0.161; p = 0.01). The best multiple-regression model included HEIGHT, HMAX, and ABILITY with a high level of prediction (r2 = 0.94). In conclusion, the FFP performance can be predicted with equation: FFP = -0.618 HEIGHT + 0.898 HMAX + 0.669 ABILITY - 0.08. This equation is quite similar for both sexes, showing that 13-year-old girls and boys use the same method to jump high, which implies that the way to increase coordination or lower limb strength during training can be the same for junior boys and girls in high jump. PMID- 21654345 TI - ED violence: occupational hazard? PMID- 21654344 TI - Comprehensive analysis of receptor tyrosine kinase activation in human melanomas reveals autocrine signaling through IGF-1R. AB - Melanomas depend on autocrine signals for proliferation and survival; however, no systematic screen of known receptor tyrosine kinases (RTKs) has been performed to identify which autocrine signaling pathways are activated in melanoma. Here, we performed a comprehensive analysis of 42 RTKs in six individual human melanoma tumor specimens as well as 17 melanoma cell lines, some of which were derived from the tumor specimens. We identified five RTKs that were active in almost every one of the melanoma tissue specimens and cell lines, including two previously unreported receptors, insulin-like growth factor receptor 1 (IGF-1R) and macrophage-stimulating protein receptor (MSPR), in addition to three receptors (vascular endothelial growth factor receptor, fibroblast growth factor receptor, and hepatocyte growth factor receptor) known to be autocrine activated in melanoma. We show, by quantitative real time PCR, that all melanoma cell lines expressed genes for the RTK ligands such as HGF, IGF-1, and MSP. Addition of antibodies to either IGF-1 or HGF, but not to MSP, to the culture medium blocked melanoma cell proliferation, and even caused net loss of melanoma cells. Antibody addition deactivated IGF-1R and hepatocyte growth factor receptors, as well as mitogen-activated protein kinase signaling. Thus, IGF-1 is a new growth factor for autocrine driven proliferation of human melanoma in vitro. Our results suggest that IGF-1-IGF-1R autocrine pathway in melanoma is a possible target for therapy in human melanomas. PMID- 21654346 TI - Removal of posteriorly dislocated posterior chamber intraocular lens without removing stable anterior chamber intraocular lens--slide under technique. PMID- 21654347 TI - Intravitreal ranibizumab for polypoidal choroidal vasculopathy with recurrent or residual exudation. AB - PURPOSE: To clarify the efficiency of ranibizumab for polypoidal choroidal vasculopathy in patients with regressed polypoidal lesions after previous photodynamic therapy (PDT) applications but recurrent or residual exudation from branching vascular network vessels. METHODS: We retrospectively reviewed 59 eyes of 59 Japanese patients (47 men and 12 women) with polypoidal choroidal vasculopathy. Treatments were chosen according to the period. Thirty-four patients were treated with PDT (PDT group) and 25 patients were treated with intravitreal injections of ranibizumab (ranibizumab group). RESULTS: In the ranibizumab group, the mean best-corrected visual acuity levels at baseline and 6 months were 0.27 and 0.41, respectively, showing a significant (P < 1* 10) improvement from baseline. In the PDT group, the mean best-corrected visual acuity levels at baseline and 6 months were 0.29 and 0.24, respectively, showing a significant (P < 0.01) decline from baseline. The mean numbers of treatments at 6 months in the ranibizumab and the PDT groups were 3.6 and 1.4, respectively. A subretinal hemorrhage (>1 disk diameter) developed in 5 eyes in the PDT group. CONCLUSION: Intravitreal ranibizumab is an effective treatment for maintaining or improving visual acuity and the anatomical changes in patients with polypoidal choroidal vasculopathy with recurrent or residual exudation from branching vascular network vessels. PMID- 21654348 TI - Performance characteristics of the ARK diagnostics gabapentin immunoassay. AB - BACKGROUND: Gabapentin is an antiepileptic drug used as adjunct therapy in the treatment of seizures. Absorption is saturable, and drug clearance can be reduced if patients have impaired renal function. Therapeutic drug monitoring can be useful for optimizing the dose in patients with impaired renal function, for evaluating individual patient absorption thresholds, and for monitoring compliance. Although chromatographic techniques have historically been used to support gabapentin monitoring, an immunoassay was recently introduced by ARK Diagnostics, for use with open channel chemistry analyzers. Here, we evaluated the immunoassay on a random access instrument. METHODS: The ARK gabapentin assay was validated using a Beckman AU400e automated chemistry analyzer. Imprecision was assessed with 5 replicates of 3 concentrations (2.5, 8.0, and 25.0 mg/L), analyzed for 4 days. The analytical measurement range was evaluated with duplicate measurements of a prepared sample (40.0 mg/L) that was serially diluted. Patients' results were compared with the results generated with a previously validated ultra-high performance liquid chromatography coupled to tandem mass spectrometry method (n = 45, range, 1.5-45.6 mg/L). RESULTS: The within-run and between-run coefficients of variation were <=8.1%. The analytical measurement range was confirmed to be 1.5-40.0 mg/L, as stated by the manufacturer. The Deming regression for the results of 45 patients produced a correlation coefficient of 0.9987, a linear regression slope of 1.01, and an intercept of 0.24 when compared with the ultra-high performance liquid chromatography coupled to tandem mass spectrometry assay. CONCLUSIONS: The ARK immunoassay is suitable for the clinical use of monitoring gabapentin in serum or plasma on the Beckman AU400e. PMID- 21654349 TI - Pharmacokinetic evaluation of voriconazole treatment in critically ill patients undergoing continuous venovenous hemofiltration. AB - INTRODUCTION: Voriconazole represents an essential part of antimicrobial therapy in critically ill patients. The aim of this study was to exclude a significant alteration in voriconazole pharmacokinetics in critically ill patients undergoing continuous venovenous hemofiltration (CVVH). METHODS: Six patients dependent on CVVH with evidence of an invasive mycotic infection treated with intravenous voriconazole at the standard dosing regimen were investigated. The total serum concentration of voriconazole in arterial blood and the concentration in ultrafiltrate were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection. The authors profiled a 5-point pharmacokinetic concentration-time curve during the 12-hour standard maintenance dosing interval and derived the basic pharmacokinetic parameters. RESULTS: The serum voriconazole concentration did not decrease <1.0 mg/L at any time point, and the mean was 4.3 +/- 2.6 mg/L and the median (range) 3.6 (9.0) mg/L. The sieving coefficient of the drug did not exceed 0.30 in any patient (0.22 +/- 0.08). The mean serum AUC0-12, the mean total clearance, and the mean clearance via CVVH were 53.52 +/- 29.97 mg.h/L [the median (range) of 57.74 (62.34) mg.h/L], 0.11 +/- 0.07 L.h-1.kg-1, and 0.007 +/- 0.003 L.h-1.kg-1, respectively. The clearance by the CVVH method ranged from 4% to 20% of the total drug clearance. The disposition of voriconazole was not compromised. The mean elimination half-life was 27.58 +/- 35.82 hours [the median of 13.10 (92.21) hours], and the mean distribution volume value was 3.28 +/- 3.10 L/kg [the median of 2.01 (8.10) L/kg]. Marked variability in serum concentrations, elimination half-life, distribution volume, and total clearance was seen. Half of the patients showed some drug accumulation. CONCLUSIONS: The clearance of voriconazole by CVVH is not clinically significant. In view of this finding, voriconazole dose adjustment in patients undergoing the standard method of CVVH is not required. However, the observed potential for an unpredictable voriconazole accumulation suggests the usefulness for monitoring its levels in critically ill patients. PMID- 21654350 TI - Posaconazole plasma concentrations in critically ill patients. AB - BACKGROUND: Posaconazole is an azole antifungal agent with a broad spectrum of activity and a manageable side-effect profile. Although the pharmacokinetics of posaconazole have been described in healthy volunteers who received the drug by means of a nasogastric tube or with nutritional supplements, the pharmacokinetics of posaconazole have not been reported in critically ill patients. METHODS: Twenty-seven patients in the general intensive care unit managed according to standard protocols were randomly allocated to dose regimens of either 400 mg twice daily or 200 mg 4 times daily. Plasma samples were collected for pharmacokinetic analysis after the first dose and at steady-state. Posaconazole plasma concentrations were compared with suggested effect targets for prophylaxis and treatment. RESULTS: Mean Cmin steady-state plasma concentrations of posaconazole were low for both regimens (306 and 137 ng/mL for 400 mg twice daily and 200 mg 4 times daily regimens, respectively), as was total exposure to posaconazole in each group [area under the concentration-time curve (AUC0-t) for first dose: 761 and 299 MUg.h/L]. Only 17% of patients achieved steady-state Cmin posaconazole plasma concentrations above the suggested target for prophylaxis, and only one patient had a Cmin posaconazole concentration that exceeded the suggested target for treatment effect. Systemic exposure to posaconazole seemed to be subtherapeutic in most patients in this cohort. Poor absorption of posaconazole due to drug interactions may explain the low systemic exposure; however, further investigation is necessary. CONCLUSIONS: These data suggest that there is a need for an intraveneous formulation of the drug if it is to be used effectively in critically ill patients, and therapeutic drug monitoring is an essential tool in this setting to identify patients with low systemic exposure to prevent therapeutic failure. PMID- 21654351 TI - Tacrolimus dosing in mycophenolate-treated patients--can we get away with less? PMID- 21654352 TI - Transesophageal echocardiography-guided technique for extracorporeal membrane oxygenation dual-lumen catheter placement. AB - In acute respiratory distress syndrome (ARDS) with severe hypoxemia or respiratory acidosis, veno-venous extracorporeal membrane oxygenation (VV-ECMO) ensures oxygenation and decarboxylation. Commonly, simultaneous cannulation of jugular and femoral veins is used for VV-ECMO. A recently introduced dual-lumen cannula for VV-ECMO promises single vessel access through the right internal jugular vein and patient ambulation. However, correct direction of the reinfusion jet toward the tricuspid valve during ECMO treatment requires more demanding cannula placement control. We present a new ultrasound-guided technique for the placement of a dual-lumen VV-ECMO cannula in a patient with ARDS and extreme obesity. PMID- 21654353 TI - Impact of histopathology of non-neoplastic thyroid tissue on ablation outcome in patients with papillary thyroid cancer. AB - OBJECTIVE: To assess the impact of histopathology of non-neoplastic thyroid tissue on ablation outcome in patients with papillary thyroid cancer (PTC). METHODS: The study included 124 patients referred for I-131 ablation therapy after total thyroidectomy for unifocal nonmetastatic PTC. All patients received 100 mCi of I-131 ablation dose. Follow-up whole body scan (WBS) and estimation of serum thyroglobulin level were carried out 6-9 months after ablation therapy and results were divided into complete or incomplete ablation. RESULTS: Incomplete ablation was found in 66.6% (12 of 18), 64% (16 of 25), 39.1% (nine of 23), 30% (six of 20), 33% (six of 18), and 20% (four of 20) in patients with PTC in a background of Hashimoto's thyroiditis, lymphocytic thyroiditis, colloid nodular goiter, nodular hyperplasia, multinodular goiter, and normal thyroid tissue, respectively. Patients with Hashimoto's thyroiditis and lymphocytic thyroiditis had statistically significant higher failure rate to achieve complete ablation compared with other groups. This significant difference was lacking between different nonautoimmune histopathologies and normal thyroid tissue. For patients with thyroid disorders of autoimmune origin (Hashimoto's thyroiditis and lymphocytic thyroiditis), incomplete ablation was found in 65.1% (28 of 43) versus 34.4% (21 of 61) for all other nonautoimmune histopathologies collectively; the difference was statistically significant. CONCLUSION: Histopathology of non-neoplastic thyroid tissue has a significant impact on ablation outcome in patients with PTC. Patients with a histopathology of non neoplastic thyroid tissue of autoimmune origin have a significantly lower incidence of successful complete ablation after a single I-131 ablative dose (100 mCi) compared with those with nonautoimmune histopathology or with normal thyroid tissue. PMID- 21654354 TI - A proposal for phosphor imager acceptance testing procedure and routine quality controls in nuclear pharmacy practice. AB - OBJECTIVE: The digital autoradiography system is currently used in nuclear medicine for quantitative imaging of radioactivity distribution (thin layer chromatography samples, tissue sections, and cell cultures). The aim of this study was to define a set of tests for setting up a specific acceptance testing procedure and routine quality controls for this instrument. MATERIALS AND METHODS: Over a 3-month period, we analyzed the active components of the instrument (phosphor screen and photometer) by using suitable self-manufactured equipment (phantoms, lead plate, lead cylinder, and photographic paper) required to realize, in a routine quality program, the following tests: integral uniformity (IU) and differential uniformity (DU) in a useful field of view (UFOV) and a central field of view (CFOV), resolution, geometric linearity, and sensitivity. RESULTS: Screen IU was 19.7 +/- 2.3% (UFOV) and 11.1 +/- 3.7% (CFOV). Screen DU ranged between 1.6 +/- 1.1 and 1.8 +/- 0.9% for UFOV and between 1.2 +/- 0.4 and 1.4 +/- 0.6% for CFOV. Screen resolution measured as full width at half-maximum was 1.94 +/- 0.08 mm. Screen sensitivity was 505.1 +/- 10.4 digital light units and ranged between -3.15 and +3.49% with reference to the mean of measured values. Photometer IU was 17.4 +/- 0.2% (UFOV) and 13.7 +/- 1.1% (CFOV). Photometer DU ranged between 1.9 +/- 0.9 and 2.3 +/- 1.2% for UFOV and between 1.9 +/- 0.8 and 2.1 +/- 1.1% for CFOV. Photometer resolution was good (full-width at half-maximum =0.5 +/- 0.076 mm). CONCLUSION: Our results suggest that the methodology we propose could be an easy, accurate, quick, and low-cost tool to guarantee the correct instrument basic function. PMID- 21654355 TI - 'Reverse discordance' between 68Ga-DOTA-NOC PET/CT and 177Lu-DOTA-TATE posttherapy scan: the plausible explanations and its implications for high-dose therapy with radiolabeled somatostatin receptor analogs. AB - In this technical note, an unusual discordance between diagnostic and posttherapeutic scan resulting from the use of different somatostatin receptor ligands in two settings is described. Such observation, we believe, is multifactorial, but most importantly arises due to different receptor affinity profile of the ligands and different somatostatin receptor subtype expression in different tumors. It is important for the treating physician to be aware of this phenomenon that would aid in improving our understanding of complex ligand receptor interactions in various somatostatin receptor-positive tumors with its possible implications for therapeutic decision making with radiolabeled somatostatin receptor analogues. PMID- 21654356 TI - Cross-talk between innate and adaptive immune responses in infection, transplant and autoimmune models. PMID- 21654357 TI - Modern classification of breast cancer: should we stick with morphology or convert to molecular profile characteristics. AB - Breast cancer represents a heterogeneous group of tumors with varied morphologic and biological features, behavior, and response to therapy. The present routine clinical management of breast cancer relies on the availability of robust prognostic and predictive factors to support decision making. Breast cancer patients are stratified into risk groups based on a combination of classical time dependent prognostic variables (staging) and biological prognostic and predictive variables. Staging variables include tumor size, lymph node stage, and extent of tumor spread. Classical biological variables include morphologic variables such as tumor grade and molecular markers such as hormone receptor and human epidermal growth factor receptor 2 status. Although individual molecular markers were introduced in the field of breast cancer management many years ago, the concept of molecular classification was raised after the introduction of global gene expression profiling and the identification of multigene classifiers. Although there is no doubt that gene expression profiling technology has revolutionized the field of breast cancer research and have been widely expected to improve breast cancer prognostication, the unprecedented speed of progress and publicity associated with the introduction of these commercially-based multigene classifiers should not lead us to expect this technology to replace the classical classification systems. These multigene classifiers have the potential to complement traditional methods through provision of additional biological prognostic and predictive information in presently indeterminate risk groups. Here we present updated information on the present clinical value of classical clinicopathologic factors, molecular taxonomy, and multigene classifiers in routine patients management and provide some critical views and practical expectations. PMID- 21654358 TI - Early gastric neoplasia: diagnosis and implications. AB - Early gastric neoplasia, which includes dysplasia and adenocarcinoma invading no more than the submucosa have been the subject of numerous studies in recent years. For example, different dysplastic phenotypes have been identified, in addition to the traditional adenomatous type, foveolar, pyloric, and tubule-neck dysplasia (associated with diffuse type carcinoma) have been recognized. Each subtype of dysplasia shows a different immunohistochemical profile, and may vary in their risk of progression to adenocarcinoma. With regard to early gastric cancer the emergence of better diagnostic techniques allowed the development of endoscopic techniques such as endoscopic mucosal resection and endoscopic submucosal resection that nowadays allow optimal nonsurgical management. The purpose of this review is to discuss the current concepts in gastric dysplasia and early gastric cancer as they relate to diagnosis and management. PMID- 21654359 TI - Treatment effects in the prostate including those associated with traditional and emerging therapies. AB - Classic treatment options for prostate cancer consist of radical prostatectomy, antiandrogen (or hormonal) therapy, and radiation therapy. Hormonal and radiation therapy, in particular, have well known, often profound effects on the histologic appearance of benign prostate tissue and prostatic carcinoma. The tissue changes induced by these treatments have been comprehensively described in several sources. Novel therapies ranging from focal ablative treatments to highly targeted molecular therapies are beginning to emerge and pathologists will play a central role in documenting the effects of these treatments on normal and malignant prostate tissue. It is therefore important that pathologists have access to basic treatment information and a solid working knowledge of the morphologic changes induced by these therapies. This will ensure accurate interpretation and reporting of posttreatment prostate specimens. This review is based on a presentation given by Dr A. Evans at the International Society of Urological Pathology Companion Society Meeting (Hot Topics in Urological Pathology) at The United States Canadian Academy of Pathology Meeting in Washington DC on March 20, 2010. This review will cover the histopathologic features seen in benign prostate tissue and prostatic carcinoma seen following: hormonal therapy, radiation therapy, ablative therapies such as vascular-targeted photodynamic therapy, interstitial laser thermotherapy, and high-intensity focussed ultrasound. An emphasis is placed on these specific modalities as they are currently in use as primary, salvage, or investigational therapy in the treatment of prostate cancer. PMID- 21654361 TI - International society of urological pathology consensus conference on handling and staging of radical prostatectomy specimens. AB - The 2009 International Society of Urological Pathology consensus conference on handling and staging of radical prostatectomy specimens issued recommendations for standardization of pathology reporting of radical prostatectomy specimens. The conference addressed specimen handling, T2 substaging, prostate cancer volume, extraprostatic extension, lymphovascular invasion, seminal vesicle invasion, lymph node metastases, and surgical margins. This review summarizes the conclusions and recommendations resulting from the consensus process. PMID- 21654360 TI - Update on fatty liver disease and steatohepatitis. AB - Non-alcoholic fatty liver disease (NAFLD) is a broad term that includes liver diseases characterized by abnormal hepatocellular accumulations of lipid that cannot be related to alcohol abuse. It may be found in both adults and children, particularly those who are obese or have insulin resistance. Steatohepatitis is a specific pattern of injury within the spectrum of NAFLD and this pattern is associated with fibrotic progression and cirrhosis. In addition to steatohepatitis, a distinct form of fibrotic fatty liver disease exists in children. There have been a number of recent advances in the characterization of histologic changes in NAFLD. In light of these recent reports, this study will: (1) review the histologic features of steatosis and nonalcoholic steatohepatitis in adults; (2) review the variation of histologic patterns of pediatric fatty liver disease; and (3) discuss the validity and use of the nonalcoholic fatty liver disease Activity Score. PMID- 21654362 TI - Iron in the liver: a review for surgical pathologists. AB - There has been a large increase in data on the genetic causes of iron accumulation. In addition, there is a growing body of literature on the significance of iron in liver biopsy specimens obtained for staging and grading chronic liver disease. In this review, the current literature is discussed with a focus on aspects that are most relevant to the practice of surgical pathology. PMID- 21654363 TI - Primary hepatolithiasis, recurrent pyogenic cholangitis, and oriental cholangiohepatitis: a tale of 3 countries. AB - Primary hepatolithiasis (HL), recurrent pyogenic cholangitis, and oriental cholangiohepatitis are terms commonly used in Japan, Hong Kong, and Korea respectively, and describing the different aspects of the same disease, with "HL" indicating the pathologic changes, "recurrent pyogenic cholangitis" emphasizing the clinical presentation and suppurative inflammation, and "oriental cholangiohepatitis" highlighting its ethnic preference and mysterious nature. HL is predominantly a disease of the far east and shows great regional differences in the incidence and the type of intrahepatic stones. Pathologically, it is characterized by pigmented calcium bilirubinate stones within dilated intrahepatic bile ducts featuring chronic inflammation, mural fibrosis, and proliferation of peribiliary glands, without extrahepatic biliary obstruction. Episodes of suppurative inflammation cumulate in sclerosing cholangitis in peripheral ducts and parenchymal fibrosis from scarring and collapse. Mass forming inflammatory pseudotumor and neoplasms-like intraductal papillary neoplasms and cholangiocarcinoma are increasingly recognized complications. Bacterial infection and dietary factors are believed to be important in the formation of pigment stones within intrahepatic bile ducts, whereas parasitic infestation is likely coincidental. With improvement of environmental conditions and westernization of diet, the incidence of pigment stones has decreased. At the same time, cholesterol stones with milder clinical manifestations and pathologic changes are increasingly recognized, and for which stone dissolution therapy can be considered. Understanding the underlying pathology avoids confusion with other diseases more prevalent in the western world, and allows correct selection of the appropriate treatment. PMID- 21654364 TI - Selected case from the Arkadi M. Rywlin international pathology slide seminar: injection-site high-grade angiosarcoma, subcutis, left buttock region. AB - A high-grade angiosarcoma with epithelioid features located in the buttock of an 87-year-old woman arose in an area of old, palpable fat necrosis at the site of several subcutaneous injections administered 20 years previously. The nature of the injected material is unknown, but is presumed to have been an iron compound. Two weeks before surgery, the buttock lesion started to enlarge and was excised. It consisted of 3 contiguous nodules of old, calcified fat necrosis associated with plentiful hemosiderin. One of the nodules was largely replaced by an angiosarcoma, which was invading the edges of the other 2 nodules. The patient died from wound sepsis 41 days postoperatively, with no clinically apparent metastases. Vaccination injection-site sarcomas are well known to occur in cats, whereas in humans, rare sarcomas associated with prostheses and foreign materials have been reported; however, human injection-site sarcomas are vanishingly rare. The Club members agreed with the diagnosis of angiosarcoma at an injection site, with the majority calling it an epithelioid angiosarcoma. Many accepted that the injected material was probably iron, but one cautioned about regarding the injections as the cause of the angiosarcoma. PMID- 21654365 TI - New revised Clinical and Laboratory Standards Institute Guidelines for Immunohistochemistry and Immunocytochemistry. PMID- 21654366 TI - CLSI releases updated Guideline for the Development of Immunohistochemical Assays. PMID- 21654367 TI - Notes from the board: President's message. PMID- 21654368 TI - Four rights for focusing clinical nurse specialist research: right focus, right projects, right level, and right resources. PMID- 21654369 TI - Electronic portfolios for professional advancement. PMID- 21654370 TI - Can hemoglobin A1c testing in hospital settings help the early identification of diabetes? PMID- 21654371 TI - Reduce disease burden and improve lung function-roflumilast: approved for moderate to severe COPD: update for the clinical nurse specialist. PMID- 21654372 TI - Cognition training interventions for healthy older people and older people with mild cognitive impairment. PMID- 21654373 TI - Improving sepsis outcomes for acutely ill adults using interdisciplinary order sets. AB - PURPOSE/OBJECTIVE: The objective of the study was to measure outcomes following implementation of standardized order sets for managing patients with severe sepsis/septic shock. BACKGROUND/RATIONALE: Sepsis is a severe illness, affecting approximately 750 000 people in the United States, with mortality rates of 28% to 50%, and costing $17 billion each year. PROJECT DESCRIPTION: An interdisciplinary team was created to improve early recognition and process of care in patients with severe sepsis/septic shock. Education was rolled out over 6 months, and sepsis "bundle" order sets were implemented. SETTING AND SAMPLE: Adult patients (N = 674) with a diagnosis of severe sepsis or septic shock who were admitted to an emergency department or critical care unit at a 563-bed tertiary care teaching facility from May 2008 through October 2010 were included in data analysis. METHODS: A plan, do, study, act methodology was used. Outcomes following project implementation were measured prospectively including appropriate recognition of patients with a diagnosis of sepsis, hospital site where the order set was initiated, and attainment of treatment goals within 6 hours of onset of severe sepsis/septic shock. FINDINGS: When order set usage was analyzed, the use of order sets was significantly associated with meeting "6-hour goals" successfully (chi1 [n = 662] = 36.16, P < .001); order set usage explained 24% of the variation in meeting goals, R = 0.24, F1,661 = 38.51, P < .0001. CONCLUSIONS: Order sets improved management of septic patients through effective change in delivery systems to support evidence-based medical care. IMPLICATIONS FOR PRACTICE: Administrative support, team collaboration, and standardized order sets can lead to improved process of care. PMID- 21654374 TI - Complexity of care is associated with distressing environmental factors. AB - PURPOSE: The purpose of this study was to describe work and cognitive complexity patterns and assess predictors of increased complexity of care. DESIGN: Prospective, cross-sectional, correlational design, using a convenience sample and survey method. SETTING: Four nursing units at a large, Midwest tertiary-care medical center. SAMPLE: Participants were 38 nurses. METHODS: A 3-part survey included nurse caregiving complexity, environmental (unit) stress factors, and nurse/work characteristics (including role responsibility level). FINDINGS: Standardized sum score for work complexity was higher than cognitive complexity (P < .001). Nurses with more role responsibilities and environmental stressors had higher work (rho = 0.37, P = .009) and cognitive complexity scores (rho = 0.54, P < .001). After controlling for the number of role responsibilities, environmental stressors, and nurse/work characteristics, work complexity pattern scores were higher for breakdown in communication processes in nurses working off shifts (P = .013) and interruptions in tasks on typical/busy workdays (P < .001). After controlling for nurse/work characteristics, work complexity patterns were not associated with role responsibilities, and cognitive complexity patterns were not associated with role responsibilities or environmental distress. In multivariable analysis, work complexity pattern scores remained associated with environmental distress scores (P = .024) and with 3 work complexity pattern factors: items placed in separate areas (P = .007), waiting for nonavailable systems (P = .010), and difficulty assessing proper resources (P = .015). CONCLUSIONS: After controlling for nurse/work characteristics, role responsibilities, and environmental stressors, work complexity was associated with environmental distress. IMPLICATIONS: Future research may increase understanding of relationships found in this study, and process improvement initiatives may provide targets for decreasing complexity of work patterns. PMID- 21654375 TI - Innovation in engaging hospital staff and university faculty in research. AB - PURPOSE: The purpose of this article was to describe an innovative faculty-staff engagement dinner that was conducted to enhance collaboration between university faculty and hospital staff. Specific steps used to develop the dinner, as well as outcomes gained, are discussed. BACKGROUND/RATIONALE: Collaborative relationships between academic and clinical nurses may promote nursing research and strengthen mutual interest. Unique stressors and demands of clinical and academic nursing often lead to isolated practice roles. Nursing may require new ways of facilitating collaboration between groups. DESCRIPTION OF THE PROJECT: A dinner supported by a health system was planned for nursing staff interested in conducting research. Faculty at 2 local universities interested in collaborating with nursing staff were invited. Forty participants attended, including 8 faculty from 2 universities, 17 staff nurses, and 16 nurse leaders. Seven collaborative research projects were initiated following the dinner meeting. INTERPRETATION/CONCLUSION: Faculty and nursing staff partnerships were established and led to research projects that focused on themes of improving quality. Faculty and nursing staff expressed enthusiasm for the opportunity to connect over shared research ideas. IMPLICATIONS: Mechanisms for enhancing staff nurse and nurse faculty collaborative relationships are needed to promote nursing research that ensures evidence-based bedside practices. A dinner event was an innovative method to partner nurses at the bedside with faculty with expertise in research methods. PMID- 21654376 TI - A journey to patient-centered care in Ontario, Canada: implementation of a best practice guideline. AB - PURPOSE: This article describes the process undertaken to implement the Best Practice Guideline on Client (patient)-centered care. Curriculum development, the application of theoretical frameworks, and the use of a variety of models for care and learning are described. Clinical nurse specialists demonstrated successful curriculum development, facilitation, and research uptake by participants. BACKGROUND: As a Canadian teaching hospital, we are committed to promoting a variety of evidence-based practice guidelines that are systematically developed and framed around a core set of values consistent with our ethical frameworks and based on current research and theories. Many guidelines are prescriptive; however, this particular guideline posed challenges because of its conceptual and philosophical nature. DESCRIPTION: Challenges of curriculum development were resolved using the "know-do-be" framework and "proximity" as the element of the caring component of patient-centered care. Elements of narrative theory and inclusion of nursing and other experiential learning models were utilized. Competing corporate initiatives that linked with client-centered care were included. OUTCOMES: The process resulted in the development of a 12-week course entitled "The Telling Stories of our Practice-Client-Centered Care." Evidence of sustainability and spread of this best-practice guideline to other corporate initiatives through research, patient safety workshops, nursing staff orientation, and other educational activities focusing on professionalism, quality of work life, and falls prevention is described. CONCLUSIONS: Clinical nurses specialists and other advanced practice nurses demonstrated clinical competencies in initiating changes that resulted in increased use of evidence based practice. PMID- 21654377 TI - Profile. PMID- 21654380 TI - Current world literature. PMID- 21654378 TI - Rembrandt's reverence for life. PMID- 21654382 TI - Early and late inflammatory bowel disease: why and how are they different? PMID- 21654383 TI - Inflammatory bowel disease therapy: current state-of-the-art. AB - PURPOSE OF REVIEW: The aim of this article is to review current evidence-based approaches to treatment of ulcerative colitis and Crohn's disease. RECENT FINDINGS: The primary goal of treatment is to induce and to maintain remission in a safe and efficacious fashion. The 5-aminosalicylic acid (5-ASA) agents and oral steroids remain the first-line approach for the treatment of ulcerative colitis and Crohn's disease. The 'step-up' approach includes the use of immunomodulators [azathioprine (AZA), or 6-mercaptopurine (6-MP)] and newer biologic agents (infliximab, adalimumab, and natalizumab). The 'step-down' approach can also be considered individually on the basis of the severity of Crohn's disease. SUMMARY: Current treatment regimens still involve medications with well known efficacy and safety profiles and progress to more potent treatments such as immunomodulators and biologic agents. Adverse events of potent treatment with biologics and immunomodulators have been recognized. In some cases, aggressive approaches with the use of more potent agents as first-line therapy has been proposed, but they are still not considered a routine approach. PMID- 21654384 TI - Current world literature. PMID- 21654387 TI - Bibliography. Hematopoiesis. Current world literature. PMID- 21654386 TI - New therapeutic targets and drugs in non-Hodgkin's lymphoma. AB - PURPOSE OF REVIEW: Although enormous progress has been made in treating non Hodgkin's lymphoma (NHL), and some patients can be cured with combination immunochemotherapy, patients with relapsed and refractory lymphoma often succumb to their disease. Advances in our understanding of lymphoma biology and molecular pathogenesis are yielding new therapeutic targets. RECENT FINDINGS: This article reviews NHL biology and describes how our understanding of molecular pathogenesis is leading to the discovery of many therapeutic targets, including the cell signaling and cell cycle regulatory proteins, pro-apoptotic family members, the B cell antigen receptor (BCR), and histone deacetylase. Recent preclinical and clinical data with inhibitors of phosphatidylinositol 3-kinase, AKT, mammalian target of rapamycin, histone deacetylase, bcl-2, and the Bruton's tyrosine kinase, a pivotal enzyme in the BCR pathway, are discussed. SUMMARY: Understanding these novel targets in the context of NHL biology will bring new therapies and allow us to develop new therapeutic platforms for the treatment of relapsed and refractory NHL, and will hopefully improve the clinical outcome for these patients. PMID- 21654389 TI - The beehive and the merry-go-round in mineral metabolism. PMID- 21654390 TI - Determinants of vitamin D status: focus on genetic variations. AB - PURPOSE OF REVIEW: The role of vitamin D beyond its importance for bone health is under much debate. In this article, we review recent evidence for genetic influences on 25-hydroxyvitamin D [25(OH)D] and discuss the uses of this information and its importance for public health. RECENT FINDINGS: Findings from large-scale genome-wide association meta-analyses on 25(OH)D confirmed the associations for loci nearby genes encoding vitamin D binding protein (GC, group component), 7-dehydrochlesterol reductase (DHCR7), 25-hydroxylase (CYP2R1) and 24 hydroxylase (CYP24A1), all influencing key sites for vitamin D metabolism. Findings from candidate gene studies have been inconsistent, with some implicating an association with 25(OH)D for loci near the gene encoding the hormonal vitamin D activation enzyme (CYP27B1). SUMMARY: The amount of variation in 25(OH)D explained by genetic determinants is small compared with environmental exposures. Information on genetic variants affecting 25(OH)D can be used as tools for Mendelian randomization analyses on vitamin D, and they provide some potential for the use as drug targets. PMID- 21654392 TI - Bibliography. Mineral metabolism. Current world literature. PMID- 21654391 TI - Optimal vitamin D, calcitriol, and vitamin D analog replacement in chronic kidney disease: to D or not to D: that is the question. AB - PURPOSE OF REVIEW: Patients with chronic kidney disease (CKD) are often insufficient in 25(OH) vitamin D and are almost uniformly deficient in 1,25(OH)2 vitamin D, because of decreased renal hydroxylation resulting from hyperphosphatemia and elevated fibroblast growth factor-23 (FGF-23) levels. These same abnormalities lead to secondary hyperparathyroidism for which the administration of calcitriol or vitamin D analogs has been the mainstay of therapy for decades. This review summarizes new trials of vitamin D, calcitriol, and its analogs over the last 2 years. RECENT FINDINGS: In addition to the endocrine effects of the vitamin D axis on bone and mineral metabolism, studies have demonstrated there is also extrarenal conversion of 25(OH) vitamin D to 1,25(OH)2 vitamin D in multiple cells leading to autocrine effects. This advance has led to the speculation that CKD patients may also need to be supplemented with ergocalciferol or cholecalciferol. Unfortunately, to date, the majority of interventional studies have focused on biochemical end points. There are no randomized controlled trials demonstrating that therapy with any formulation of vitamin D results in improved patient level outcomes. SUMMARY: Despite the physiologic importance of vitamin D in health and disease, more research is required to determine which vitamin D derivative is required for optimal health in CKD patients. PMID- 21654394 TI - Bibliography. Supportive care. Current world literature. PMID- 21654397 TI - Bibliography. Refractive surgery. Current world literature. PMID- 21654396 TI - Timing of eyelid surgery in the setting of refractive surgery: preoperative and postoperative considerations. AB - PURPOSE OF REVIEW: With any operation, the surgeon should be aware of predisposing factors that may lead to postoperative complications. Here we review the major factors due for consideration in both eyelid and refractive eye surgery, preoperatively and postoperatively, and consider the importance of timing to lessen the inherent risks of each procedure. RECENT FINDINGS: Refractive surgery can affect corneal sensation by ablating the corneal nerves and can cause serious corneal complications if followed by eyelid surgery. Studies find that patients undergoing eyelid surgery have a change in astigmatic error of as much as 1.0 D during the first 3 postoperative months. The longest reported follow-up period of astigmatic changes in adult patients following eyelid ptosis surgery is 1 year and a considerable number of patients had a change in cylinder of up to 0.3 D postoperatively. Blepharoplastic surgery is also reported to cause astigmatic changes postoperatively, significantly more if entire fat pads are removed. SUMMARY: To prevent corneal exposure, postrefractive eyelid surgery should be performed at least 6 months after lamellar ablative procedures and at least 3 months after surface ablative procedures. Refractive surgery revision may be necessary when astigmatic error occurs and should be carried out no earlier than 6 months postoperatively to allow for stabilization. Cosmetic blepharoplasty with fat pad debulking should be performed at least 6 months prior to refractive surgery to allow for any potential corneal astigmatic change to stabilize, for regained strength in the orbicularis, and for improved tear film distribution. PMID- 21654399 TI - Female urology. PMID- 21654400 TI - Transobturator versus retropubic synthetic slings: comparative efficacy and safety. AB - PURPOSE OF REVIEW: To review the reported effectiveness and safety of transobturator (TransOburator route, TOR) versus retropubic (retropubic tape) synthetic mid-urethral slings discussing the controversy existing on which of these procedures is best. RECENT FINDINGS: From August 2009 to January 2011 three meta-analyses of the pertinent topic were identified. They concluded that TOR was less favourable than the retropubic tape in objective cure rates without any significant difference in subjective cure rates. Moreover TOR showed a shorter operating time and less serious perioperative complications than retropubic tape, also when using a standardized complications grading system. The most recent RCTs confirmed these results. SUMMARY: TOR showed similar short and mid-term subjective cure rates compared to retropubic tape; with a shorter operating time and a lower risk of perioperative complications. Subjective cure rates and patient satisfaction are crucial, thus, patient-report outcomes should be used as the primary outcome measure for all trials of incontinence treatments. The absence of standard methods for assessment of anti-incontinence procedures and the use of different methods to evaluate safety and effectiveness led to reporting of different rates of success and complications for the same procedure, making it difficult to compare data, to draw conclusions or make recommendations. PMID- 21654401 TI - Bibliography. Female urology. Current world literature. PMID- 21654403 TI - The time and practice challenges of developmental-behavioral pediatrics: an Australian national study. AB - OBJECTIVE: : Developmental/behavioral diagnoses are common in pediatric practice but, until the impact on pediatricians of caring for these children is quantified, training and remuneration barriers are unlikely to be addressed. In a prospective audit of Australian office-based pediatricians, developmental behavioral and medical consultations were examined regarding (1) consultation characteristics, (2) child and parent health, and (3) referrals and investigations ordered. METHODS: : In 2008, all 300 eligible members of the nationwide Australian Paediatric Research Network were invited to prospectively record standardized information for every consultation over 2 weeks or 100 consecutive patients, whichever came first. After coding all diagnoses, consultations were classified as developmental/behavioral, medical, or "mixed." These groups were compared using simple 3-group comparisons (Aims 1 and 2) and logistic regression (Aim 3). RESULTS: : One hundred ninety-nine (66%) pediatricians recorded 15,360 diagnoses for 8,335 consultations (34% developmental/behavioral, 48% medical, and 18% mixed). Compared with medical patients, developmental/behavioral patients were older, more likely to be male, and required on average ~9 minutes more time per consultation; self-reported parent health was worse; and referrals were more common (odds ratio 2.2, 95% confidence interval 1.9 to 2.5; p < .0001), but investigations less common (odds ratio 0.4, 95% confidence interval 0.3 to 0.4; p < .0001). Child health was worst in the "mixed" group. CONCLUSION: : Developmental/behavioral consultations are common in pediatric office settings. They are time-consuming, often lead to referrals, and the worse health reported by their parents may pose additional challenges. Pediatric training and funding models must address these barriers if adequate and comprehensive care is to be accorded to these complex patients. PMID- 21654404 TI - Sleep and sensory characteristics in young children with fetal alcohol spectrum disorder. AB - BACKGROUND: : Fetal alcohol spectrum disorder (FASD) is a syndrome that results from prenatal alcohol exposure and is defined by significant neurobehavioral impairments. Sleep disruption has been recognized as a clinically important symptom of FASD that has multiple negative effects on the child's health, ability to function adaptively, as well as on family and caregivers. However, few studies have addressed and characterized the sleep problems in this population. OBJECTIVE: : The objective of this study was to characterize sleep in FASD and describe the impact of sensory processing difficulties on sleep patterns in children with FASD. METHODS: : Children with FASD were compared with age-matched typically developing children between 3 and 6 years of age. Sleep was assessed using actigraphy, a sleep log, and the Children's Sleep Habits Questionnaire. The Sensory ProfileTM, completed by caregivers, was used to evaluate the child's sensory processing abilities. Overall differences in sensory processing were correlated with actigraphic parameters measured in alcohol exposed and control groups. RESULTS: : Data show that children with FASD have significantly more sleep disturbances than typically developing children, including increased bedtime resistance, shortened sleep duration, increased sleep anxiety, and increased night awakenings and parasomnias. Actigraphy reveals a significant difference between groups for sleep onset latency. CONCLUSIONS: : This study demonstrates that sensory processing deficits are widespread in children with FASD and that these deficits are associated with multiple sleep problems. Children with FASD should be screened for sleep-related disorders and would benefit from occupational therapy for sensory-based treatment aimed at sleep regulation and consolidation. PMID- 21654406 TI - Author reply: attention-deficit hyperactivity disorder and high intelligence quotient. PMID- 21654407 TI - Predicting survival in NeuroICU patients. PMID- 21654408 TI - Introduction to the JOEM Supplement nanomaterials and worker health: medical surveillance, exposure registries, and epidemiologic research. PMID- 21654409 TI - Development of a French epidemiological surveillance system of workers producing or handling engineered nanomaterials in the workplace. AB - OBJECTIVE: Concern has been raised about the potential impact of nanomaterials exposure on human health, and France has decided to implement a timely epidemiological surveillance tool of workers likely to be exposed to engineered nanomaterials that could accompany the development of nanotechnologies. METHODS: A comprehensive review of the toxicological and epidemiological literature has been conducted together with an exploratory study among French companies producing or handling nanoobjects. RESULTS: A double surveillance system is proposed consisting of a prospective cohort survey and repeated cross-sectional studies. The aim of the cohort is (1) to monitor long-term health effects and (2) to allow of further research. Setting-up an exposure registry is the first planned step. CONCLUSIONS: The protocol is about to be submitted to the French Government for approval and funding. PMID- 21654410 TI - Engineered nanomaterials: learning from the past, planning for the future. AB - OBJECTIVE: The ongoing explosion in creation and use of engineered nanomaterials leaves stakeholders in government, industry, and labor uncertain of how best to proceed in protecting worker health. METHODS: A synopsis is presented of the conference Nanomaterials and Worker Health, along with considerations of prior, analogous challenges in occupational health. RESULTS: Progress has been made in defining and addressing the occupational threat of engineered nanomaterials, but future success demands coordinated effort. CONCLUSIONS: The conference Nanomaterials and Worker Health laid necessary groundwork for collaboration to proactively and preemptively address the occupational health effects of engineered nanomaterials. PMID- 21654411 TI - Current surveillance plan for persons handling nanomaterials in the National University of Singapore. AB - OBJECTIVE: The number of research projects involving engineered nanomaterials within the National University of Singapore is increasing. We aim to characterize typical exposures in our laboratories and to develop a health surveillance protocol for persons working with nanomaterials in this project that has recently been launched. METHODS: Our surveillance project builds on existing occupational safety and health risk assessment systems in the National University of Singapore. RESULTS: Environmental monitoring will be conducted in all laboratories handling nanomaterials, encompassing airborne nanomaterial concentrations, characterizing chemical and physical properties and assessing dermal exposure potential and significance. Health surveillance will initially follow the occupational health program already in place, to be progressively fine tuned as more nanotoxicity data become available. CONCLUSION: Our vision is to build an adequate base for a cohort study that can provide good data on the health outcomes of nanomaterials-exposed persons. PMID- 21654412 TI - A small business approach to nanomaterial environment, health, and safety. AB - OBJECTIVE: Integral to the commercialization process for nanotechnology enabled products is the methodology for protecting workers potentially exposed to nanomaterials during product development. Occupational health surveillance is a key aspect of protecting employees and involves both hazard identification and surveillance of known medical data. However, when the health effects and exposure pathways of both new and existing "nano-scale" chemical substances are not yet well understood, conservative hazard controls and baseline data collection can facilitate both immediate and long-term worker protection. METHODS: Luna Innovations uses a conservative approach based on risk assessment and the OSHA General Duty Clause. RESULTS: To date, Luna's approach has been effective for our business model. CONCLUSIONS: Understanding and managing potential hazards to our nanotechnology workers is key to the success and acceptance of nanotechnology enabled products. PMID- 21654413 TI - Nanomaterials and worker health: medical surveillance, exposure registries, and epidemiologic research. AB - OBJECTIVE: This article provides an overview of the issues that arise with medical surveillance, exposure registration, and epidemiologic research involving nanomaterial workers. METHODS: An occupational health perspective is applied to detecting risks in nanomaterial workers individually and as a group. RESULTS: General principles for medical surveillance, exposure registration, and epidemiologic research are identified. A model Nanomaterial Worker Health Study is for consideration. CONCLUSIONS: The Nanomaterial Worker Health Study can be developed as a tangible action in assuring the public that steps are being taken to learn of any adverse effects from exposure to nanomaterials. PMID- 21654414 TI - Developing a registry of workers involved in nanotechnology: BASF experiences. AB - OBJECTIVE: To assist BASF in the establishment of a registry of workers involved in nanotechnology. METHODS: The initial step was a complete inventory of nanomaterials and sites of use. Guidance was developed to clarify which particulate nanomaterials were to be included in the survey. Site management was then contacted by the medical department to obtain a list of workers. RESULTS: The time line for collecting data ranged from several months to a year, depending on the information needed, and presented challenges based on the lack of global definition and labeling of nanomaterials. Less than 50 nanomaterials are used as raw materials in less than 10% of the sites globally. In North America, less than 5% of sites and 5% workers use nanomaterials. CONCLUSIONS: Further work is required to integrate the inventory, registry, and exposure assessments. PMID- 21654415 TI - The role of state public health agencies in national efforts to track workplace hazards and the relevance of state experiences to nanomaterial worker surveillance. AB - OBJECTIVE: This essay examines the role state public health agencies could play in the surveillance of emerging workplace hazards including nanotechnology. METHODS: This essay describes existing state occupational health surveillance programs in order to demonstrate their potential applicability, and limitations, in regards to nanomaterial worker surveillance. RESULTS: State public health agencies have access to information and an ability to put surveillance information to use in ways that complement those of industry, academia, regulatory agencies, and federal partners. CONCLUSIONS: Some state public health agencies have significant experience with occupational health surveillance and are therefore valuable partners in the development and implementation of nanotechnology worker surveillance programs. Including states in emerging hazard surveillance enhances surveillance activities and builds state capacity to help workers. PMID- 21654416 TI - Exposure registries: overview and utility for nanomaterial workers. AB - OBJECTIVE: This article provides the background for consideration of exposure registries to address potential disease risks in nanomaterial workers. METHODS: The history of exposure registries is reviewed with a focus on their purpose and criteria for establishment. RESULTS: A rationale is presented for developing registries of nanomaterial workers, and unresolved obstacles and challenges are identified. These include issues on inclusion criteria, funding, potential for legal risks, access to data, confidentiality of business information, privacy, and workers' expectations. CONCLUSION: If society is to gain the benefits from nanotechnology, it must take precautions and demonstrate care for those, such as workers, who may be most at risk of adverse effects. Establishing exposure registries is a part of such a precautionary and caring approach. PMID- 21654417 TI - World Trade Center Health Registry--a model for a nanomaterials exposure registry. AB - OBJECTIVE: To describe the development of and some of the early results from the World Trade Center Health Registry (WTCHR). Is the WTCHR a model for a nanomaterials exposure registry? What lessons may be learned from the WTCHR? METHODS: We describe the steps involved in creation of the WTCHR, from design through implementation. RESULTS: The lessons learned from the WTCHR include thorough documentation of exposure early in the registry, using multimode surveys to maximize response rate, establishing an institutional home with sufficient resources for core as well as in-depth longitudinal and intervention studies, meeting with stakeholders regularly, making data accessible, and timely publication of findings, including wide dissemination of clinical guidelines. CONCLUSIONS: The process of creating and maintaining the WTCHR provides important lessons for the possible creation of a nanomaterials exposure registry. PMID- 21654418 TI - The benefits and challenges of a voluntary occupational exposure database. AB - OBJECTIVE: This article describes the experience of creating and implementing an occupational exposure database for synthetic vitreous fibers (SVFs). The lessons learned and benefits achieved through this experience may be instructive to government and industry when assessing the need, utility, and design of an occupational exposure database for nanomaterials. METHODS: This article consists of an empirical account of the issues faced during the construction and maintenance of an occupational exposure database for SVFs. RESULTS: The occupation exposure database for SVF proved to be beneficial and successful but encountered several challenges relating to data consistency, data quality, and other problems. CONCLUSIONS: The SVF database provides a good case study to illustrate the potential benefits and challenges of creating and administering an occupational exposure database. PMID- 21654419 TI - Epidemiologic challenges for studies of occupational exposure to engineered nanoparticles; a commentary. AB - OBJECTIVE: Identify most likely health effects of occupational exposure to engineered nanoparticles (ENP). Recommend analytic approaches to address epidemiologic challenges. METHODS: Review air pollution and occupational literature on health effects of fine particulate matter (PM). Provide example of mortality study of exposure to PM composed of metalworking fluid. Apply standard Cox models and g-estimation to adjust for potential healthy worker survival effect (HWSE). RESULTS: In contrast with standard methods, g-estimation suggests that exposure to PM may cause chronic heart and lung disease; longer exposure reduces survival. HWSE appears stronger for chronic disease than for cancer. CONCLUSIONS: We recommend hazard surveillance, short-term panel studies of biomarkers, and prospective cohort studies of cardiovascular and respiratory diseases. Building research capacity in g-estimation methods to reduce HWSE is necessary for future studies of chronic disease and ENP. PMID- 21654420 TI - Engineered carbonaceous nanomaterials manufacturers in the United States: workforce size, characteristics, and feasibility of epidemiologic studies. AB - OBJECTIVE: Toxicology studies suggest that carbon nanotube (CNT) exposures may cause adverse pulmonary effects. This study identified all US engineered carbonaceous nanomaterial (ECN) manufacturers, determined workforce size and growth, and characterized the materials produced to determine the feasibility of occupational ECN exposure studies. METHODS: Eligible companies were identified; information was assembled on the companies and nanomaterials they produced; and the workforce size, location, and growth were estimated. RESULTS: Sixty-one companies manufacturing ECN in the United States were identified. These companies employed at least 620 workers; workforce growth was projected at 15% to 17% annually. Most companies produced or used CNT. Half the eligible companies provided information about material dimensions, quantities, synthesis methods, and worker exposure reduction strategies. CONCLUSIONS: Industrywide exposure assessment studies appear feasible; however, cohort studies are likely infeasible because of the small, scattered workforce. PMID- 21654421 TI - Exposure control strategies in the carbonaceous nanomaterial industry. AB - OBJECTIVE: Little is known about exposure control strategies currently being implemented to minimize exposures during the production or use of nanomaterials in the United States. Our goal was to estimate types and quantities of materials used and factors related to workplace exposure reductions among companies manufacturing or using engineered carbonaceous nanomaterials (ECNs). METHODS: Information was collected through phone surveys on work practices and exposure control strategies from 30 participating producers and users of ECN. The participants were classified into three groups for further examination. RESULTS: We report here the use of exposure control strategies. Observed patterns suggest that large-scale manufacturers report greater use of nanospecific exposure control strategies particularly for respiratory protection. CONCLUSION: Workplaces producing or using ECN generally report using engineering and administrative controls as well as personal protective equipment to control workplace employee exposure. PMID- 21654423 TI - Lessons from air pollution epidemiology for studies of engineered nanomaterials. AB - OBJECTIVES: This article discusses evidence from epidemiological studies on air pollution for assessing engineered nano-sized particles in workplace environments. METHODS: Results from epidemiological studies on health effects of fine and ultrafine particles are summarized. These findings are applied to workplaces exposed to engineered nanoparticles. RESULTS: Ultrafine or nano-sized particles smaller than 100 nm represent potential health hazards. Because of their short half-lives in ambient air and their large spatial variability, individual exposures in population-based studies are likely to be misclassified. CONCLUSIONS: Studies of health effects of nanoparticles in occupational settings seem mandated for adequate worker protection but face several challenges, including exposure quantification and adequate confounder characterization. Inclusion of personal measurements of ultrafine particles in future studies will allow exploiting the full scale of temporal-spatial variation of both ambient and engineered nanoparticles. PMID- 21654422 TI - Feasibility of biomarker studies for engineered nanoparticles: what can be learned from air pollution research. AB - OBJECTIVE: Occupational exposure to engineered nanoparticles (NP) may pose health risks to the workers. This article is to discuss the feasibility of identifying biomarkers that are associated with NP exposure. METHODS: Scientific literature on the adverse health effects of ambient ultrafine particles (UFP) and NP was reviewed to discuss the feasibility of conducting biomarker studies to identify NP-induced early biological changes. RESULTS: Various approaches for biomarker studies have been identified, including potential injury pathways that need to be considered and the methodologies that may be used for such studies. CONCLUSIONS: Although NP may have novel mechanisms of injury, much can be learned from our experience in studying UFP. Oxidative stress-related pathways can be an important consideration for identifying NP-associated biomarkers, and one of the most effective approaches for such studies may be proteome profiling. CLINICAL SIGNIFICANCE: Biomarker studies will provide valuable information to identify early biological events associated with the adverse health effects of engineered nanomaterials before the manifestation of clinical outcomes. This is particularly important for the health surveillance of workers who may be at higher risk due to their occupational settings. PMID- 21654424 TI - Identification of systemic markers from a pulmonary carbon nanotube exposure. AB - OBJECTIVE: Interest exists for early monitoring of worker exposure to engineered nanomaterials. Here, we highlight quantitative systemic markers of early effects after carbon nanotube (CNT) exposure. METHODS: Mice were exposed by pharyngeal aspiration to 40-MUg CNT and harvested 24 hours, 7 days, and 28 days postexposure for measurements of whole blood, lung and extrapulmonary tissue gene expression, blood and bronchoalveolar lavage (BAL) differentials, and serum protein profiling. RESULTS: Early effects included increased inflammatory blood gene expression and serum cytokines followed by an acute phase response (eg, CRP, SAA 1, SAP). Beyond 24 hours, there was a consistent increase in blood and BAL eosinophils. At 28 day, serum acute phase proteins with immune function including complement C3, apolipoproteins A-I and A-II, and alpha2-macroglobulin were increased. CONCLUSIONS: Carbon nanotube exposure resulted in measurable systemic markers but lacked specificity to distinguish from other pulmonary exposures. PMID- 21654425 TI - Workshop summary: epidemiologic design strategies for studies of nanomaterial workers. AB - OBJECTIVE: The potential health consequences of exposure to nanomaterials have yet to be elucidated though increasing evidence points to the potential for nanomaterials to cause adverse human health effects. This workshop addressed the feasibility of developing studies to measure health risks among nanomaterial workers. METHODS: Breakout groups discussed different epidemiologic designs and methods to encourage companies to collect and retain exposure and health data. RESULTS: Major challenges include defining and recruitment of appropriate study populations and obtaining adequate exposure data. Both prospective cohort studies and small cross-sectional panel studies utilizing biomarkers of exposure and effect offer approaches to study occupational groups. CONCLUSIONS: Potential exists to assemble cohorts to study the human health effects associated with nanomaterial exposure. Stakeholder partnerships are critical to the success of these studies and international partnerships hold great potential. PMID- 21654426 TI - Carbon nanotube risk assessment: implications for exposure and medical monitoring. AB - OBJECTIVE: Quantitative risk estimates using toxicology data provide information for risk management to protect workers with potential exposure to carbon nanotubes (CNTs). METHODS: Dose-response data from subchronic inhalation studies in rats were used in benchmark dose modeling. Dose was airborne mass concentration of multiwalled CNTs. Responses included pulmonary inflammation, lipoproteinosis, and fibrosis. RESULTS: Estimated human-equivalent concentrations to the rat lowest observed adverse effect levels were similar to some workplace airborne concentrations of CNTs. Working lifetime risk estimates of early-stage adverse lung effects were more than 10% at the limit of quantification (7 MUg/m3) of the National Institute for Occupational Safety and Health analytical method for measuring CNT airborne concentrations. CONCLUSIONS: Exposure monitoring and control are the primary occupational health measures to protect workers from potential exposure to CNT. Medical monitoring for early detection of occupational respiratory diseases may also be warranted. PMID- 21654427 TI - Nanomaterial risk assessment and management experiences related to worker health under the Toxic Substances Control Act. AB - OBJECTIVES: This paper examined the data and experiences gathered through the review of over 100 nanomaterial submissions for industrial nanomaterials, and what these data indicate for worker health at industrial facilities where nanomaterials are synthesized, and/or incorporated into final products for the marketplace. METHODS: The types of nanomaterials, their uses, potential health effects and worker exposures, methods for examining worker and general population exposures, and risk management actions taken under the Toxic Substances Control Act (TSCA) prior to their manufacture are summarized. RESULTS: There is a diversity of nanomaterials are currently entering the marketplace, but there are certain materials reviewed under TSCA such as carbon-based nanomaterials and metal oxides that are more likely to be commercialized than others. There are health and monitoring data that have been received by EPA that are useful in determining potential risks, and risk management approaches such as limiting uses of the nanomaterials and embedding nanomaterials in polymer matrices that reduce concerns for worker exposures. Certain EPA data gathering tools such as those used to collect nanomaterial use and worker exposure information, and screening level approaches for estimating worker exposures are useful and could be enhanced to better estimate worker risks. CONCLUSIONS: The data and experiences with nanomaterials under TSCA should prove useful when considering worker exposure registries, medical surveillance and epidemiological research. PMID- 21654428 TI - Medication adherence, comorbidities, and health risk impacts on workforce absence and job performance. AB - OBJECTIVE: To understand impacts of medication adherence, comorbidities, and health risks on workforce absence and job performance. METHODS: Retrospective observational study using employees' medical/pharmacy claims and self-reported health risk appraisals. RESULTS: Statin medication adherence in individuals with Coronary Artery Disease was significant predictor (P < 0.05) of decreasing absenteeism. Insulin, oral hypoglycemic, or metformin medication adherence in type 2 diabetics was significant (P < 0.05) predictor of decreasing job performance. Number of comorbidities was found as significant (P < 0.5) predictor of absenteeism in five of nine subsamples. Significant links (P < 0.05) between high health risks and lower job performance were found across all nine subsamples. CONCLUSIONS: Results suggest integrated health and productivity management strategies should include an emphasis on primary and secondary prevention to reduce health risks in addition to tertiary prevention efforts of disease management and medication management. PMID- 21654429 TI - The impact of health care reform on employer costs: an analysis of the Massachusetts experience. AB - OBJECTIVE: The objective of this study was to learn if health care reform in Massachusetts lead to significant increases in diagnosis-specific short-term disability (STD) durations associated with specialist physician populations in short supply. METHODS: We examined group STD claim durations for Massachusetts resident claimants, from Liberty Mutual's book of business, whose conditions generally required consultation or treatment by specialist physicians. RESULTS: Two specialties in short supply in Massachusetts, neurology and oncology, showed a significant increase in duration during 2008 and 2009. CONCLUSIONS: Short-term disability durations for certain diagnoses associated with specialists in short supply have increased since the introduction of health care reform in Massachusetts. These increased durations will directly affect employer costs because short-term disability payments are generally borne by employers. PMID- 21654430 TI - Cost-effectiveness and cost-benefit of a lifestyle intervention for workers in the construction industry at risk for cardiovascular disease. AB - OBJECTIVE: To investigate the cost-effectiveness and cost-benefit of a lifestyle intervention for construction workers with an elevated risk of cardiovascular disease. METHODS: In this randomized controlled trial, usual care was compared to a 6-month individual-based lifestyle intervention. At 6 and 12 months, weight, absenteeism, health care use, and lifestyle-related expenses were determined. Missing data were imputed. A cost-effectiveness analysis was performed from a societal perspective. Uncertainty around the incremental cost-effectiveness ratio (ICER) was estimated by bootstrapped cost-effect pairs. A cost-benefit analysis was performed from an employer's perspective, subtracting the incremental costs from the incremental benefits. RESULTS: The ICER was ? 145/kg weight loss. The difference between intervention and control group in net employer costs was ? 254 (95% CI: -1070 to 1536). CONCLUSION: Implementation of this important and effective intervention depends on the societal and employer's willingness to pay. PMID- 21654431 TI - Pulmonary function in a cohort of New York City Police Department emergency responders since the 2001 World Trade Center disaster. AB - OBJECTIVE: Comparing pulmonary function since the 2001 World Trade Center disaster, with preexposure data, in a New York City Police Department Emergency Responder cohort, without history of repetitive respiratory exposures. METHODS: A total of 206 New York City Police Department Emergency Services Unit members reported Arrival Time, Exposure Location, Duration, Smoking History, Respirator Mask Usage, and Respiratory Symptoms, and underwent clinical evaluation and follow-up spirometry, in 2002 and 2007. RESULTS: A mean decline in forced vital capacity of 190 mL (3.7%) was observed 1-year postexposure in 2002, and 330 mL (6.4%) in 2007, compared with baseline data. Forced expiratory volume in the first second was not significantly changed in 2002 but declined 160 mL (3.9%) after 5 further years of follow-up. CONCLUSIONS: Abnormal spirometry was observed in (5.3%) of subjects, particularly individuals experiencing higher Exposure Intensity, Duration, or Respiratory Symptoms. The small number of smokers and subjects failing to wear protective respiratory masks showed greater declines. PMID- 21654432 TI - Occupational factors and sick leave in Australian employees. AB - OBJECTIVES: To investigate occupational factors associated with sick leave over a 4-year period in Australian employees. METHODS: Longitudinal data (self-report) from 2861 Australian full-time employees (69.4% male) were used. Occupational factors and relevant covariates were assessed at baseline with sick leave assessed yearly over a 4-year period. The data were analyzed using multinomial logistic regression models. RESULTS: Job strain and longer commuting time were associated with long sick leave, whereas long work hours were inversely associated with long sick leave. CONCLUSIONS: These results provide further evidence that certain aspects of work are associated with sick leave, whereas other work aspects such as long work hours are inversely associated with sick leave. Organizations need to understand and address these factors to improve the well-being of employees and increase workplace productivity. PMID- 21654433 TI - Employee well-being and sick leave, occupational accident, and disability pension: a cohort study of civil servants. AB - OBJECTIVE: To study the association between employee well-being and sick leave, occupational accident, and disability pension. METHODS: A random population of 967 civil servants participated in a survey on psychosocial factors and health at work in 2000 in Finland. The median follow-up time was 7.3 years. RESULTS: The risks of sick leave and disability pension were decreased by job satisfaction (RR = 0.78, 95% CI = 0.58 to 1.05; RR = 0.47, CI = 0.20 to 1.06; respectively), good work ability (RR = 0.35, CI = 0.22 to 0.56; RR = 0.11, CI = 0.04 to 0.33), good health (RR = 0.42, CI = 0.27 to 0.64; RR = 0.32, CI = 0.11 to 0.98), and strong sense of coherence (RR = 0.53, CI = 0.36 to 0.79; RR = 0.17, CI = 0.07 to 0.37). Employee well-being was also associated with occupational accident but somewhat less consistently. CONCLUSIONS: Employee well-being is associated with sick leave, occupational accident, and disability pension. It is important to find means to support employee well-being both in general and at work. PMID- 21654434 TI - Multiple myeloma and occupational exposures: a population-based case-control study. AB - OBJECTIVE: The present study aims to identify occupational exposures associated with incidence of multiple myeloma (MM). METHODS: A population-based case-control study of MM (ICD-9 203) was conducted among Canadian males, with a total of 342 cases and 1506 controls contributing to the final analyses. Conditional logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI), stratifying by age groups and province of residence. RESULTS: Based on the most parsimonious multivariable model, the following variables were significantly associated with an increased incidence of MM: exposure to coal dust (OR 1.7, 95% CI 1.2-2.4), long-held occupations as a carpenter (OR 3.2, 95% CI 1.4-7.1) or a machinist (OR 2.4, 95% CI 1.0-5.8); and immediate family member having been previously diagnosed with certain cancers (OR 1.4, 95% CI 1.1-1.8). CONCLUSION: In this study of Canadian men, a higher risk of MM may be associated with exposure to coal dust, long-held occupations as a carpenter or machinist, and a positive family history of cancer. PMID- 21654435 TI - A health outcome assessment of the Cardio Metabolic Mission Health Program at Novartis. AB - OBJECTIVE: To assess the impact of the Novartis Cardio Metabolic Program--an education, awareness, and health management initiative--on hypertension, hyperlipidemia, diabetes mellitus, and obesity within the Novartis employee population. METHODS: A prospective, 6-month pre-/post assessment to determine improvement in blood pressure (BP) control and risk factors after implementation of Novartis Cardio Metabolic. RESULTS: A total of 238 subjects with cardiovascular risk factors participated. In the hypertension cohort, overall BP control improved from 38% at baseline to 79% at follow-up (P < 0.0001). In the hyperlipidemia cohort, low-density lipoprotein cholesterol control improved significantly between baseline and study end (22% to 34%, P = 0.0004). In the diabetes mellitus cohort, the rate of glycosylated hemoglobin control increased from 83.7% to 86.2% (P = 0.69). There was a significant decrease in body mass index at follow-up (P < 0.0001). CONCLUSION: Novartis Cardio Metabolic educational and health interventions helped to improve health awareness among Novartis employees. PMID- 21654436 TI - Exposure to nonpermanent employment and health: analysis of the associations with 12 health indicators. AB - OBJECTIVE: To clarify the associations of nonpermanent employment with poor health in longitudinal setting with different health outcomes. METHODS: A population cohort (n = 1071) was surveyed at the age of 30 and then again at the age of 42. They were classified according to exposure to nonpermanent employment. The outcomes included indicators of mental and somatic health and health behavior. RESULTS: When adjusted for baseline level of the outcome under study, the odds ratio of the heavily exposed was 1.90 (1.25 to 2.88) for nervous symptoms, 1.77 (1.03 to 2.05) for psychological distress, and 1.52 (1.03 to 2.25) for suboptimal mood. Among the lightly exposed, the odds ratio for psychological distress was 1.94 (1.10 to 2.10). CONCLUSIONS: Psychological distress is particularly sensitive to exposure to nonpermanent employment. The effects on somatic health or health behavior should be studied only with carefully specified hypotheses. PMID- 21654437 TI - Reduction in personnel and long-term sickness absence for psychiatric disorders among employees in Swedish county councils: an ecological population-based study. AB - OBJECTIVE: The aim was to examine whether staff downsizing was related to long term psychiatric sickness absence. METHODS: We used aggregate data on sickness absence from AFA insurance, as well as information on staff numbers from the Swedish Association of Local Authorities and Regions. Bootstrap regression analyses were used to elucidate whether there was a relationship between reduction in personnel and changes in sickness rates. RESULTS: A staff reduction of 1% increased the sickness rate, on average, by 9%. The associations were similar in men and women as well as in different age groups, although statistical significance was only reached in the groups of women and middle-aged employees. CONCLUSIONS: Our findings suggest that downsizing may be related to subsequent increases in psychiatric sickness absence. The association appeared after a time delay of several years. PMID- 21654438 TI - Restrained eating is related to augmented overweight-associated absenteeism in a prospective study. AB - OBJECTIVE: To replicate in a prospective analysis the earlier cross-sectional moderator effects of physical activity, sports, and dietary restraint on overweight-associated absenteeism. METHODS: Using a web-based life style questionnaire in a large banking corporation responses were obtained from 2298 employees. These data were coupled with the data from the company absenteeism registration in the year preceding (T1) and the year following (T2) the assessment of physical activity, sports, and dietary restraint. In all analyses we controlled for age, sex, level of education, and smoking. In addition, we controlled for possible confounding effects of perceived general health and energy at work and in the analyses with dietary restraint also for emotional and external eating and physical activity and sports. RESULTS: Only restrained eating was found to moderate the relation between overweight and/or obesity on the one hand and absenteeism at T2 on the other hand. The degree of overweight and obesity was more strongly related to augmented absenteeism at T2 in people with higher levels of dietary restraint. CONCLUSION: To reduce absenteeism in overweight and/or obese employees it seems indeed wise to advise them to stop dieting. PMID- 21654439 TI - Examining factors associated with the length of short-term disability-free days among workers with previous short-term disability episodes. AB - OBJECTIVE: The purpose of this study is to examine the timing of short-term disability recurrence among workers who have previously experienced a short-term disability episode. METHODS: The dataset comes from a Canadian resource sector company's 2003 to 2006 short-term disability leave and human resource datasets. The multi-year dataset consists of the records of 3593 employees who experienced at least on short-term disability episode between 2003 and 2006. RESULTS: The overall 1-year disability-free rate was 72.1% +/- 1.6%. About half of workers with previous disability episodes for mental/behavioral disorders were disability free for more than 800 days. In contrast, about 50% of workers with previous disability episodes for physical disorders were disability free for more than 1300 days. CONCLUSIONS: These findings suggest the majority of workers with previous short-term disability episodes for mental/behavioral disorders remain disability free for more than 2 years. However, the duration of disability free days for these workers is half that of other workers with previous episodes. PMID- 21654440 TI - Organizational return to work support and sick leave duration: a cohort of Spanish workers with a long-term non-work-related sick leave episode. AB - OBJECTIVE: To analyze the association between organizational support and time to return to work (RTW) in workers with long-term non-work-related sick leave. METHODS: Cohort participants were 571 workers, with a non-work-related sick leave episode of more than 15 days, recruited during the first visit in a health insurance company (mutua). Workers completed a baseline questionnaire regarding organizational RTW support measures and were followed until the end of the episodes. Return to work and time to RTW were established on the basis of the mutua's register. Multivariate Cox regression models were used. RESULTS: Workers in companies with an overall high organizational RTW support returned to work earlier. This effect was mainly due to workers in companies that provided specific RTW programs. CONCLUSIONS: Our findings suggest that companies play an important role in facilitating RTW for workers with long-term non-work-related sick leave episodes. PMID- 21654441 TI - Effectiveness of phone and e-mail lifestyle counseling for long term weight control among overweight employees. AB - OBJECTIVES: To determine the effectiveness of a weight-management program with personal counseling by phone or e-mail. METHODS: A randomized controlled trial of a 6-month program comparing two modes of intervention delivery (phone, n = 462; Internet, n = 464) with self-directed materials (control, n = 460), among overweight employees. Change in body weight after 2 years was the main outcome. RESULTS: Among complete cases, weight loss in the Internet group was 1.2 kg (95% confidence interval [CI], -1.9 to -0.4) and in the phone group 0.8 kg (95% CI, 1.5 to 0.03), compared with the control group. Multiple imputation of missing body weight resulted in comparative weight losses of -0.9 kg (95% CI, -2.0 to 0.3) and -0.4 kg (95% CI, -1.4 to 0.7). CONCLUSIONS: Among complete cases, the Internet intervention showed modest long-term weight loss, but among all participants neither program version was more effective than self-help. PMID- 21654442 TI - Pandemic influenza guidance for corporations. AB - The purpose of this guidance document is to assist members of the American College of Occupational and Environmental Medicine (ACOEM), and the organizations for which they work, in managing the impact of a pandemic of influenza or other contagious respiratory disease on patients, employees, and business. This guidance document outlines actions to take before and during an influenza pandemic on the basis of two main strategies: (1) reducing the spread of the virus within facilities; and (2) providing medical care and medical surveillance to client/patient populations. Facilities in which ACOEM members serve include government agencies and the military, universities, and corporations, which generally have multiple locations/sites and their own medical staff, with members responsible for medical care and disease control. This guidance is for organizations with outpatient occupational medicine services, to be used as appropriate. Medical centers should also use guidance that addresses additional employee and external patient care needs.1-3 The ACOEM fully supports implementation of occupational influenza programs that conform with guidance from the Centers for Disease Control and Prevention (CDC), with other guidance from the US Department of Health and Human Services (DHHS), and Occupational Safety and Health Administration (OSHA) regulations and guidance. PMID- 21654443 TI - Workplace health protection and promotion: a new pathway for a healthier--and safer--workforce. PMID- 21654446 TI - Comparison of endoscopic surgery and open surgery for gluteal muscle contracture. AB - PURPOSE: To compare the clinical effects of endoscopic surgeries with traditional open surgeries in the treatment of gluteal muscle contracture and discuss their indications and value. METHODS: In this retrospective study, 50 patients received traditional open surgeries and 52 received endoscopic surgeries. The 2 groups were compared in terms of surgery duration, incision lengths, postsurgical pain, complications, off-bed activity times, hospitalization duration, clinical outcome, and 1-year recurrence rates. RESULT: The endoscopic surgery group was significantly superior to the open surgery group in regard to incision length, postsurgical pain, off-bed activity time, hospitalization duration, and patient cosmetic satisfaction. Differences were not statistically significant for the surgery duration, complications, clinical outcome, or the 1-year recurrence rate. All the endoscopic surgery group patients stated that they would choose endoscopic surgery again. CONCLUSIONS: The endoscopic release of gluteal muscle contracture is safe and reliable, with the advantages of less trauma and pain, shorter operative time, earlier rehabilitation, and return of functional activities. Its application, though, should be carefully controlled based on the indications. It is applicable to degree I and II patients, but may be used only very cautiously in degree III patients. LEVEL OF EVIDENCE: Level III. PMID- 21654447 TI - Wilmington robotic exoskeleton: a novel device to maintain arm improvement in muscular disease. AB - BACKGROUND: Upper-extremity movement is limited in individuals with muscular weakness. This paper describes a novel, articulated upper-extremity orthosis, the Wilmington Robotic Exoskeleton (WREX), which helps people overcome this movement deficit. METHODS: This prospective, case-controlled study involved an ambulatory patient with arthrogryposis multiplex congenita and 2 nonambulatory patients with spinal muscular atrophy type II. The WREX uses elastic bands to negate the effects of gravity; it allows a person with neuromuscular weakness to move their arm in 3 dimensions. The WREX can be fixed on a brace for ambulatory patients and on the wheelchair for nonambulatory patients. Assessment was performed through motion analysis (with and without the WREX), clinical examination, and qualitative questionnaire. RESULTS: Motion analysis showed a marked improvement in upper-extremity function with the WREX. The questionnaire illustrated enhanced functionality with the WREX including self-feeding, fine motor control, and use of a television remote control. Enhanced functionality resulted in improved quality of life by increasing participation in school, raising self-esteem, and increasing social interaction. Two unexpected outcomes were increased security with trunk inclination and amelioration of the effects of contractures. CONCLUSIONS: The WREX provided an increase in functionality and improved the quality of life of the patients. The device has become an integral part of the lives of the 3 patients. LEVEL OF EVIDENCE: Level III in Therapeutic Studies Investigating the Results of Treatment. PMID- 21654448 TI - An unusual cause of paralysis of the peroneal nerve: a report of 3 cases. AB - We present 3 cases of a 12-year-old boy, an 8-year-old girl, and a 9-year-old boy with progressive paresis of the peroneal nerve. Peroneal intraneural ganglia are a rare cause of paralysis of the lower limb in children; more often these symptoms occur because of exostosis. Ultrasound imaging in both patients showed a cystic mass near the fibular neck. Magnetic resonance imaging examination revealed that the ganglion is communicating with the proximal tibiofibular joint. Surgical exploration in these patients confirmed a cystic formation involving the common peroneal nerve. The ganglion originates from the articular nerve branch to the proximal tibiofibular joint. Total recovery of nerve function was seen 2 years later for the first patient, whereas the other 2 showed immediate postoperative improvement of peroneal nerve function and complete recovery within 6 to 8 weeks. On the other hand, patients with exostosis showed varying outcomes. In children with symptoms suspicious of nerve compression, fast diagnosis and immediate treatment are necessary to ensure the best possible recovery. PMID- 21654449 TI - Ossifying lipoma of c1-c2 in an adolescent. AB - BACKGROUND: Ossifying lipomas, characterized by their independence of bony connection to the skeleton, are extremely rare benign neoplasms. They have primarily been described in adults older than 50 years of age and occur in the head and neck region. The etiology is unknown. Excision is the preferred treatment. The objective of this study is to report the case of a rare ossifying lipoma immediately anterior to C1 to C2, requiring a transoral approach for excision. METHODS: The case of an adolescent with a retropharyngeal mass is described. RESULTS: A 15-year-old female patient presented with an asymptomatic parapharyngeal mass detected on routine physical examination. Computed tomography and magnetic resonance imaging noted a calcified, left-sided, parapharyngeal mass, approximately 3*2*2 cm, anterior to C1 and C2, most consistent with a benign osseous lesion. A transoral approach was used to excise the mass. Histologic examination demonstrated an ossifying lipoma. Postoperative imaging confirmed complete excision. The postoperative course was unremarkable, and the patient has had no recurrence at 6-month follow-up. CONCLUSIONS: This case demonstrates that a transoral approach to a lesion anterior to C1 to C2 in an adolescent can be safe, complete, and effective. LEVEL OF EVIDENCE: Case Report, level 5. PMID- 21654450 TI - Subscapularis tendon injuries in adolescents: a report of 2 cases. AB - BACKGROUND: Although shoulder injuries in adolescents are relatively common, injuries to the rotator cuff are relatively rare and not well characterized in the literature. We review 2 cases of adolescent subscapularis tendon avulsions treated surgically. METHODS: The 2 patients were high-level athletes, 1 is a baseball pitcher and the other is a boxer. Both were injured during participation in their respective sports. In each case, the diagnosis was made by magnetic resonance imaging. Patients underwent an open repair by a deltopectoral approach, using suture anchors for fixation. RESULTS: After surgery both patients regained full range of motion and returned to their previous levels of activity. Both patients scored 30 and 35 on the American Shoulder and Elbow Surgeons and University of California, Los Angeles shoulder instruments, respectively. CONCLUSIONS: Subscapularis tendon injuries in adolescents are rare. Diagnosis requires careful attention to the physical examination and imaging. A positive lift-off test, belly-press test, or increased passive external rotation should prompt an early magnetic resonance imaging. Good results and return to previous levels of activity can be achieved with open repair. LEVEL OF EVIDENCE: IV. PMID- 21654451 TI - Triplane fracture of the distal femur: a case report. AB - INTRODUCTION: Triplane fractures are well-documented injuries occurring in the distal and proximal tibia, distal humerus, distal radius, and the hand. However, there are no reports in the distal femur. The aim of this study was to document an unusual fracture pattern, and to make recommendations about the evaluation and management of children with such injuries. METHODS: A rare case of distal femoral triplane fracture in a 13-year-old boy is reported. This type of injury consists of a transverse fracture of the physis (Salter-Harris I), and a coronal and sagittal intra-articular fracture of the epiphysis (Salter-Harris III). DISCUSSION: To our knowledge, this pattern was not described before in the English literature. Authors discuss the assessment and management of this unique fracture. A 3-step sequence of reduction is proposed. PMID- 21654452 TI - The role of concurrent fusion to prevent spinal deformity after intramedullary spinal cord tumor excision in children. AB - OBJECTIVES: Spinal deformity is a common development after laminectomy and resection of pediatric intramedullary spinal cord tumors. Our objective is to compare the occurrence of postlaminectomy spinal deformity in children with intramedullary spinal cord tumors that underwent decompression with fusion at the time of surgery to those that did not undergo fusion. METHODS: A retrospective chart review of 255 children with spinal cord tumors treated at 2 tertiary pediatric cancer centers between was performed. Of these, 52 patients with a biopsy-proven intramedullary spinal cord tumor had complete clinical records and radiographic data. Preoperative spinal alignment, surgical treatment, postoperative deformity, and risk factors for deformity were evaluated. All patients had at least 2-year follow-up. RESULTS: There were 18 females and 34 males with an average age of 8.1 +/- 4.1 years. The average time to latest follow up was 7.6 +/- 5.3 years. Moderate or severe postresection spinal deformity (scoliosis > 25 degrees and/or sagittal plane abnormality > 20 degrees requiring bracing or surgery) developed in 57% (21/37) of resections without fusion (laminectomy or laminoplasty alone), and in 27% (4/15) of those with fusion (P = 0.05). Among skeletally mature children, 18 of 28 (64%) developed deformity after laminectomies and laminoplasties, compared with 22% (2/9) of the patients in the fusion group (P = 0.03). Removal of >3 lamina (P = 0.04) was associated with development of postoperative deformity. CONCLUSIONS: In the surgical treatment of patients with intramedullary spinal cord tumors, those that undergo instrumentation or in situ fusion at the time of spinal cord tumor excision are significantly less likely to develop postresection spinal deformity. LEVEL OF EVIDENCE: 3, Retrospective comparative study. PMID- 21654453 TI - Minimum 5-year radiographic results of long scoliosis fusion in juvenile spinal muscular atrophy patients: major curve progression after instrumented fusion. AB - BACKGROUND: Previous studies reported on spinal muscular atrophy (SMA) scoliosis surgery outcomes without focus on major curve progression (MCP). The purpose of this study was to assess minimum 5-year radiographic outcomes, MCP, and factors for MCP after spinal surgery in juvenile SMA patients with open triradiate cartilage at the time of surgery. METHODS: Retrospective review of radiographic and clinical data of 22 SMA patients treated surgically at 3 institutions over 20 years was performed. Major curve Cobb angle, apical vertebral translation, pelvic obliquity, coronal balance, and sagittal Cobb angles (T5-T12 and T12-sacrum) were measured at preoperative, initial, and ultimate follow-up. MCP was defined as an increase in Cobb angle of >= 10 degrees between initial and ultimate follow-up. RESULTS: Overall, SMA patients had significant improvement in radiographic measurements at follow-up. Eight patients (36%) developed MCP and were similar in age (7.8 vs. 8.8 y, P=0.09) to non-MCP patients. Initial major curve Cobb angle correction was greater for MCP patients than for non-MCP patients (19 vs. 36 degrees, P=0.004). MCP patients lost 26 degrees (P=0.001) and non-MCP patients lost 2 degrees of major curve Cobb angle correction during follow-up. Both groups had similar ultimate follow-up radiographic outcomes and remained improved from preoperative deformity. All 14 non-MCP patients had long posterior instrumentation (T4 or higher to sacrum/pelvis), whereas all 4 patients with short posterior instrumentation developed MCP. Six patients underwent anterior posterior spinal fusion (ASF-PSF) and had greater preoperative deformity than PSF only patients, but ultimate major curve Cobb angle (38 vs. 44 degrees, P=0.4) was similar for both the groups. Two ASF-PSF patients developed MCP. CONCLUSIONS: Overall, SMA patients maintained scoliosis correction with nonpedicle screw-based (predominantly Luque-Galveston instrumentation) long spinal instrumentation at minimum 5-year follow-up. MCP >10 degrees developed in 36%, contrary to our expectation of 100% in these young juvenile SMA patients. All non-MCP patients had instrumentation from the upper thoracic spine (T1 to T4) to the sacrum, whereas all 4 patients with short instrumentation developed MCP. MCP and non-MCP patients had similar ultimate correction and remained improved from preoperative deformity. Skeletal immaturity and length of posterior instrumentation may influence MCP in SMA scoliosis surgery and should be considered during preoperative planning. LEVEL OF EVIDENCE: Case Series; Level IV. PMID- 21654454 TI - Intrathecal morphine analgesia in idiopathic scoliosis surgery: does sex or racial group affect optimal dosing? AB - BACKGROUND: We previously determined the intrathecal morphine optimal dose to maximize analgesia in patients undergoing idiopathic scoliosis surgery while minimizing adverse effects. Our purpose was to determine if this protocol was equally effective across sex and racial groups. METHODS: We studied 287 patients given a moderate dose of intrathecal morphine of 9 to 19 MUg/kg (mean 14 MUg/kg): 240 female and 47 male patients and 224 White (W) and 63 African-American (AA) patients. Factors analyzed included postoperative visual analog pain scores (VAS), time to first opioid dose, total morphine over the first 48 hours, and postoperative complications of respiratory depression requiring pediatric intensive care unit (PICU) admission, nausea/vomiting and pruritis. RESULTS: For female and male patients, mean VAS pain scores in postanesthesia care unit (PACU) were 0.48 +/- 1.14 and 0.56 +/- 1.16, mean times to first opioid dose were 16.65 +/- 4.38 and 16.72 +/- 4.97 hours, and total morphine over the first 48 hours were 1.49 +/- 0.53 and 1.49 +/- 0.58 mg/kg, respectively. Respiratory depression and PICU admission occurred in 10 of 240 female (4.1%) and 3 of 47 male (6.4%) patients. Minor complications of nausea/vomiting and pruritis occurred in 78 of 240 female (31.7%) and 12 of 47 male (25.5%) patients. For W and AA patients, mean VAS pain scores in PACU were 0.48 +/- 1.10 and 0.46 +/- 1.13, mean times to first opioid dose were 16.53 +/- 3.77 and 17.12 +/- 6.05 hours, and total morphine over the first 48 hours were 1.54 +/- 0.53 and 1.30 +/- 0.53 mg/kg, respectively. Respiratory depression and PICU admission occurred in 9 of 224 W (4.0%) and 4 of 63 AA (6.3%) patients. Nausea/vomiting and pruritis occurred in 77 of 224 W (34.4%) and 11 of 63 AA (17.5%) patients, respectively. CONCLUSIONS: Intrathecal morphine results in safe and effective for postoperative pain relief in patients undergoing surgery for idiopathic scoliosis irregardless of sex or race. LEVEL OF EVIDENCE: III, retrospective comparative study. PMID- 21654455 TI - Meniscus tears in the young athlete: results of arthroscopic repair. AB - BACKGROUND: The purpose of this study was to evaluate the results of arthroscopic repair of the meniscus in children and young athletes. METHODS: Arthroscopic meniscus repairs performed on 49 knees in 31 male and 14 female patients <18 years old were reviewed. All repairs were done using an inside-out technique, and 31 patients required concomitant anterior cruciate ligament (ACL) reconstruction. Age at time of injury, time to surgery, and the extent, type, and location of meniscus tear were noted. All patients underwent postoperative rehabilitation and clinical evaluation. The level of activity at follow-up and postoperative outcomes scores was determined. Analysis included t tests, Wilcoxon tests, chi tests, and Fisher exact tests, with a level of significance of P >= 0.05. RESULTS: Excellent clinical outcomes were noted in 43 of 45 patients, with mean length of follow-up of 27 months. Between the groups with and without ACL tears, there were no significant differences in mean age at the time of injury or surgery, or in the distribution of open versus closed physes, medial versus lateral repairs, or level-of-activity at follow-up. However, patients with ACL reconstruction had significantly longer return-to-activity times (mean 8.23 mo vs. 5.56 mo) and significantly lower Tegner scores (mean 6.8 vs. 8.0) than patients without simultaneous reconstruction. CONCLUSIONS: The clinical results after arthroscopic meniscus repair in the adolescent were excellent, despite long average time from injury to surgery and a high number of tears in poorly vascularized areas. Meniscal tears in skeletally immature athletes may have greater reparative potential, with and without simultaneous ligament reconstruction. Attempts at repair regardless of time from injury or location of tear should be strongly considered in this age group. LEVEL OF EVIDENCE: Level III retrospective cohort series. PMID- 21654456 TI - Risk factors associated with loss of position after closed reduction of distal radial fractures in children. AB - BACKGROUND: Closed reductions of distal radial fractures are among the most common orthopaedic operations but up to 39% of fractures lose position postoperatively. This study was carried out to determine the most significant risk factors for loss of position so that high-risk patients can be identified early and their management tailored accordingly. METHODS: We retrospectively reviewed 48 consecutive children who had redisplacement of their distal radial fractures after closed reduction and compared them with 48 matched controls. Fourteen risk factors were studied and analyzed with univariate and multivariate logistic regression analysis and receiver operating characteristics analysis. These risk factors included pre-reduction and post-reduction fracture characteristics as well as 4 previously described radiological indices of plaster quality. RESULTS: Significant independent clinical risk factors identified were the initial radial fracture displacement [odds ratio (OR) 1.03, P = 0.001] and obliquity (OR 0.93, P = 0.006), a completely displaced radial fracture (OR 5.21, P =0.003), an ipsilateral ulnar fracture (OR 3.56, P = 0.003), residual radial displacement (OR 1.06, P = 0.009), angulation (OR 1.16, P = 0.011), and failure to achieve anatomical reduction (OR 0.18, P = 0.004). Significant radiological indices included the Padding index (OR >100, P = 0.004), Canterbury index (OR 99, P = 0.014), and 3-point index (OR 19.29, P < 0.001). Nonsignificant risk factors included the angulation of the initial radial fracture, a completely displaced ulnar fracture, plaster changes/splitting and the Cast index. The combined preoperative presence of a completely displaced radial fracture, an ipsilateral ulnar fracture and failure to achieve perfect reduction was found to be the best predictor of redisplacement (receiver operating characteristic area under the curve=0.82). This combination was found to be a better predictor of redisplacement than any of the radiological indices (receiver operating characteristic area under the curve <= 0.74) and it is also a more practical risk factor for the operating surgeon to use. CONCLUSIONS: The combination of a completely displaced distal radial fracture and an ipsilateral ulnar fracture, which then cannot be perfectly reduced, was the best predictor for redisplacement. We recommend that serious consideration be given to primary wire fixation in these patients. LEVEL OF EVIDENCE: III, prognostic. PMID- 21654457 TI - Fixation of displaced midshaft clavicle fractures in skeletally immature patients. AB - BACKGROUND: There is ongoing debate in the adult literature regarding fixation of displaced, closed midshaft clavicle fractures. Functional outcomes of treatment of these fractures in skeletally immature patients have not been previously investigated. METHODS: We retrospectively reviewed 14 skeletally immature patients with closed, displaced, midshaft clavicle fractures treated with open reduction internal fixation. Baseline data acquisition included demographic and radiographic indices. Follow-up data included radiographic and functional outcomes assessment using the Quick Disability of Arm, Shoulder, and Hand Questionnaire (QuickDASH), the simple shoulder test, and additional binary questions. RESULTS: Mean age for operative patients was 12.9 years. There were 12 male and 2 female cases. Twelve patients had injuries to the dominant extremity. Twelve patients had initially been treated nonoperatively, but underwent surgery due to increased displacement at 3 weeks. Minimum follow-up was 24 months. Mean postoperative total QuickDASH score was 7.0. Patients had a mean of 11 questions answered "yes" for the simple shoulder test. Four patients from the operative group underwent a second surgical procedure to remove hardware. Eight (57%) patients complained of numbness at the site of injury/surgery. Preoperative mean fracture shortening and vertical displacement were 14.4 and 19.7 mm, respectively. Follow-up radiographs at mean 3 months demonstrated healed fractures in all cases. Multiple linear regression showed no difference in QuickDASH score after adjusting for age, sex, injury to dominant extremity, shortening, and percent displacement (P = 0.220). CONCLUSIONS: In conclusion, operative treatment of displaced midshaft clavicle fractures in skeletally immature patients resulted in high scores on commonly used instruments of outcomes assessment. Operative patients may require additional surgery to remove prominent or painful hardware and may be prone to numbness at the incision site.Level IV. PMID- 21654458 TI - Incidence and trends in femur shaft fractures in Swedish children between 1987 and 2005. AB - BACKGROUND: The surgical treatment of femur shaft fractures in children is changing, and the time spent in hospital is shorter than before. The purpose of this nationwide epidemiology study is to report incidence of pediatric femur shaft fractures in Sweden during 1987 to 2005 by age, sex, cause of injury, severity of injury, and seasonal variation, and to analyze the change in incidence, treatment modalities, and length of hospital stay over time. METHODS: Children (N = 4984) with a diagnostic code for femur shaft fracture in Sweden 1987 to 2005 were selected from the Swedish National Hospital Discharge Registry. RESULTS: The overall annual incidence per 100,000 children was 22.9 in boys and 9.5 in girls. The incidence declined by 42%, on average 3% per year, from 19.4 to 11.8 between 1987 and 2005 (P < 0.001). The most common cause of injury in children younger than 4 years of age was fall of < 1 m; in children 4 to 12 years of age, sports accidents were the most frequent cause of injury; and in children 13 to 14 years of age, traffic accidents. The month of occurrence for femur shaft fractures had a bimodal seasonal variation with a peak in March and in August. Treatment modalities were changing during the study period from the use of traction to an increased use of external fixation and elastic intramedullary nailing. The length of hospital stay decreased by 81%, from 26 days in 1987 to 5 days in 2005 (P < 0.001), but had no correlation to the introduction of new surgical treatment methods. CONCLUSIONS: The present nationwide study of femur shaft fractures shows a decrease of fracture incidence, a shift in the treatment modalities, and shorter length of hospital stay. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 21654459 TI - Van neck disease: osteochondrosis of the ischiopubic synchondrosis. AB - BACKGROUND: Van Neck disease (VND) is a benign skeletal abnormality of children involving a hyperostosis of the ischiopubic synchondrosis (IPS) seen on radiographs. Patients typically complain of vague groin or buttock pain. Few descriptions of this disorder exist and it easily can be mistaken for other entities, particularly osteomyelitis or tumor. It is often considered a diagnosis of exclusion as laboratory values are usually normal and routine radiographic workup may be nonspecific. We present a series of patients with VND and we compare them with a similar cohort of patients with acute hematogenous ischiopubic osteomyelitis (IPOM). We also draw attention to a new magnetic resonance imaging (MRI) finding that seems to support the theory that VND results from an excessive pull of the hamstring tendon on the ischial tuberosity. METHODS: All patients presenting to our institution for the evaluation of groin or buttock pain during an 8-year period (August 2001 to May 2009) were retrospectively identified. Twenty-five patients demonstrated enhancement of the ischiopubic area on MRI. Five patients were excluded for lack of sufficient laboratory data. Ten patients were diagnosed and treated with culture proven IPOM and 10 patients were diagnosed with VND and treated with observation. History, physical examination, laboratory values, plain films, and MRI were compared to identify the diagnostic differences between these 2 entities. RESULTS: The age range for both groups was between 4 and 12 years old. The mean age was 7 years for the VND group and 7.6 years for the IPOM group. The VND group tended to have more distinct hyperostosis of the IPS on radiographs. The factors that were characteristic of IPOM were: fever, limp, pain with rotation of the hip, elevated erythrocyte sedimentation rate, elevated C-reactive protein (CRP), and positive blood culture. MRI showed obvious myositis, abscess, and free fluid surrounding the IPS in all patients with IPOM, but not in the VND patients. Enhancement was seen in the ischial tuberosity, near the hamstring origin, in nearly all Van Neck patients; this pattern of edema may support stress reaction and callus formation as a mechanism for IPS hypertrophy. CONCLUSIONS: VND is a little-known entity characterized by enlargement of the IPS and should be in the differential of groin or buttock pain in children from the age of 4 to 12 years. IPOM may present similar to VND. Absence of fever, limp, pain with rotation of the hip, elevated C reactive protein/erythrocyte sedimentation rate, and negative blood culture can help to differentiate VND from IPOM. Presence of marrow edema around the IPS and in the ischial tuberosity, along with absence of surrounding myositis, abscess, and free fluid on MRI are reliable findings that can confirm the diagnosis of VND. The absence of these characteristics can eliminate the need for admission, aspiration, or biopsy. The treatment for VND is observation and the symptoms should abate over time with expectant management. LEVEL OF EVIDENCE: Comparative Diagnostic, Level IV. PMID- 21654460 TI - Comparison of hip reduction using magnetic resonance imaging or computed tomography in hip dysplasia. AB - BACKGROUND: The purpose of this paper was to compare the use of computed tomography (CT) versus magnetic resonance imaging (MRI) to evaluate hip reduction in patients with dysplasia of the hip. METHODS: A retrospective review of postoperative pelvic CT and MRI in patients <13 months of age with hip dysplasia was performed. Scanner time, anesthesia requirement, cost, and radiation dosage were recorded. Hips were classified as dislocated, subluxated, or reduced. Sensitivity and specificity of CT and MRI were calculated. The outcomes of the subluxated hips were followed. RESULTS: Thirty-two CT scans and 33 MRI scans in 39 patients were evaluated. CT scanner time was 2.8 minutes, which was significantly less than the 8.9 minutes required for MRI (P=0.0001). Postoperative anesthesia was only required for 1 CT case. Average cost of CT examination was $788 and $1104 for MRI. Average radiation dose with CT examinations was 1 mSv. Of the postoperative nonsubluxated hips (n=30 for CT and n=37 for MRI), CT demonstrated a sensitivity of 100% and a specificity of 96%, whereas MRI exhibited a sensitivity of 100% and a specificity of 100%. Of the postoperative subluxated hips, 66.7% spontaneously reduced, 22.2% remained subluxated, and 11.1% redislocated. CONCLUSIONS: This is the first study to compare these imaging modalities in the evaluation of hip reduction in DDH. This study affirms MRI as an alternative to CT scan. The sensitivity and specificity of both modalities appears excellent. Similar to other studies, a large percentage of subluxated hips in both groups reduce without additional surgical intervention. LEVEL OF EVIDENCE: Diagnostic level II. PMID- 21654461 TI - Acetabular coverage after innominate osteotomy. AB - A criticism of innominate osteotomy is that it may cause relative acetabular retroversion, predisposing to osteoarthritis. This study was designed to address that hypothesis. We had access to standing hip radiographs of 30 patients (36 hips) who had undergone open reduction and innominate osteotomy for late presenting developmental hip dislocation at least 40 years earlier. A single independent investigator used the validated method of Hefti (1995) to measure anterior and posterior acetabular coverage, contact area, and version. Ten operated hips had advanced osteoarthritis obscuring acetabular landmarks. Twenty six operated hips were readable despite some radiographs showing signs of mild-to moderate osteoarthritis. Twenty contralateral hips without developmental hip dysplasia formed a comparison group and 21 age-matched and sex-matched "normal hips" were used as a control. A significant difference between the groups was found for contact area (P < 0.001). There was no significant difference between the other 3 outcomes: anterior coverage (P = 0.509), posterior coverage (P = 0.135), and anteversion (P = 0.845). Anteversion in hips with a good outcome after innominate osteotomy and open reduction was not different to a control group of radiographically normal hips. The early osteoarthritic changes seen in these hips may relate to decreased contact area compared with the normal population. In this series, innominate osteotomy before the age of 5 years did not consistently cause acetabular retroversion that persisted into adulthood. Apparently unaffected hips contralateral to the dislocated side display reduced contact area relative to controls indicating probable occult dysplasia. PMID- 21654462 TI - Evaluation of conventional selection criteria for psoas lengthening for individuals with cerebral palsy: a retrospective, case-controlled study. AB - BACKGROUND: Psoas lengthening surgery has been advocated to improve hip function in patients with spastic cerebral palsy (CP); however, no uniform or standardized selection criteria have been agreed upon. Our study evaluated a proposed algorithm for selecting patients for psoas surgery to be included as part of a single-event multilevel surgery (SEMLS). METHODS: A retrospective, case controlled study was performed on children with CP who underwent a SEMLS and met 2 of 3 of the following proposed selection criteria after gait analysis: (1) maximum hip extension no > 8 degrees of flexion, (2) maximum pelvic tilt > 24 degrees, and (3) pelvic tilt range of motion > 8 degrees. One group had a psoas lengthening surgery as part of their SEMLS (psoas group) and 1 group did not (control group). Among other variables, overall kinematic gait pathology, as measured by the Gait Deviation Index (GDI), Pelvis and Hip kinematic gait pathology, as measured by the Pelvis and Hip Deviation Index (PHiDI), and Gross Motor Function Classification System (GMFCS) levels were compared. RESULTS: Eighty-seven sides met 2 of 3 of the proposed selection criteria; 32 in the psoas group and 55 in the control group. Both groups showed improvement in function after SEMLS. There was a significantly greater improvement in GDI for the psoas group in patients with GMFCS levels 3 and 4 (+12.9 vs. +7.7, P = 0.02). Odds ratio for "poor outcomes" in PHiDI for the control group compared with the psoas group was 5.1 (95% CI, 1.37-18.95), which was significant. CONCLUSIONS: Certain patients that met the proposed selection criteria did functionally better if psoas surgery was included as part of their SEMLS, specifically those that were classified as GMFCS levels 3 and 4. The risk of no improvement in hip function after SEMLS was greater if the parameters were met and psoas lengthening was not performed. The differences between the groups were modest by clinical standards, leaving open the possibility that other selection criteria may better differentiate those that would do well and those that would do poorly after psoas surgery. LEVEL OF EVIDENCE: Retrospective, case-controlled study. Level III. PMID- 21654463 TI - Distal rectus femoris intramuscular lengthening for the correction of stiff-knee gait in children with cerebral palsy. AB - PURPOSE: To evaluate the effects of rectus femoris intramuscular lengthening, a novel procedure to treat stiff-knee gait in ambulatory patients with cerebral palsy, using preoperative and postoperative 3-dimensional gait analysis. METHODS: This study was a retrospective data review of ambulatory patients with a diagnosis of cerebral palsy who had undergone rectus femoris intramuscular lengthening. The indications for rectus femoris intramuscular lengthening were identical to those of rectus femoris transfer. Patients must have had preoperative and postoperative gait analyses at our institution. Three dimensional kinematic and kinetic data was collected using a VICON 512 motion measurement system (VICON Motion Systems, Inc, Lake Forest, CA) after standard techniques. A representative trial was selected for analysis both preoperatively and postoperatively. Preoperative to postoperative differences were measured using a Student t test (P < 0.05). Selected sagittal plane kinematic and kinetic parameters were analyzed. RESULTS: A total of 42 patients (69 sides) treated between 1991 and 2008 with preoperative and postoperative gait analyses after rectus femoris intramuscular lengthening were analyzed. The mean age at surgery was 8.5 years (SD +/- 2.9) and the mean time after surgery at postoperative gait analysis was 17.9 months (range, 7 to 53 mo). There were 26 male and 16 female patients. Compared with preoperative values, postoperative gait analysis revealed patients to have earlier timing of peak knee flexion in swing (82%->80% of gait cycle, P = 0.001), less crouch (average knee flexion in stance 26->20 degrees, P = 0.002), and maintenance (no statistically significant difference) of peak knee flexion. A cohort of patients also showed maintenance of knee function at intermediate-term follow-up (mean 44.6 mo). Patients who underwent soft-tissue surgery only benefited more from the procedure than those who also underwent bony surgery. CONCLUSIONS: Rectus femoris intramuscular lengthening may offer an alternative procedure for the treatment of stiff-knee gait in ambulatory patients with cerebral palsy. When comparing preoperative and postoperative gait analysis data, our cohort showed maintenance of peak knee flexion in swing, earlier timing of peak knee flexion in swing, and less crouch. Patients who underwent soft tissue surgery only showed the most benefit. LEVEL OF EVIDENCE: Level IV. PMID- 21654464 TI - Is radiographic evaluation necessary in children with a clinical diagnosis of calcaneal apophysitis (sever disease)? AB - BACKGROUND: Calcaneal apophysitis (Sever disease) is most often diagnosed clinically, and radiographic evaluation is believed to be unnecessary by many physicians. To evaluate the need for radiographic evaluation in children with a clinical diagnosis of calcaneal apophysitis, we determined the frequency of abnormal radiographic findings in a group of patients with this clinical diagnosis. METHODS: Clinical records and radiographs of all children between the age of 4 and 17 years who presented with a chief complaint of heel pain were retrospectively reviewed. Patients with an insidious onset of heel pain were included; those with acute trauma and a diagnosis of Achilles tendinitis were excluded. Radiographs were reviewed by 3 orthopaedists (blinded to the clinical diagnosis) to determine if any radiographic abnormalities were present. Clinical records were reviewed in an attempt to determine what factors, if any, indicated a diagnosis other than calcaneal apophysitis. RESULTS: Review identified 98 patients (134 feet) with a mean age of 10.8 years who had a clinical diagnosis of calcaneal apophysitis. Positive radiographic findings (all on lateral radiographs) were identified in 5 patients (5 feet): 3 calcaneal unicameral bone cysts, 1 distal tibial nonossifying fibroma, and 2 calcaneal stress fractures (1 patient had both a calcaneal unicameral bone cysts and a stress fracture in the same foot). The rate of abnormal radiographic findings in the 96 patients was 5.1% (3.75% in the 133 feet). CONCLUSIONS: The abnormal radiographic findings seen in 5.1% of children usually led to more aggressive treatment including close radiographic follow-up or immobilization. No common findings in the history or examination indicated patients who were more likely to have positive radiographs. Despite concern about exposure to ionizing radiation and the cost of medical imaging, routine lateral radiographs appear to be justified for screening of pediatric patients with heel pain. If a diagnosis of calcaneal apophysitis is made without obtaining radiographs, a lesion requiring more aggressive treatment could be missed. LEVEL OF EVIDENCE: Level IV, retrospective case study. PMID- 21654465 TI - Navicular excision and cuboid closing wedge for severe cavovarus foot deformities: a salvage procedure. AB - BACKGROUND: The goals of cavus foot correction are to obtain a plantigrade foot with the heel in slight valgus position and to hopefully preserve joint motion in both the tarsal and metatarsal joints. The apex of many cavus deformities is near Chopart joint. We are reporting on a new technique involving navicular excision and cuboid osteotomy to correct severe stiff cavus feet. METHODS: A retrospective review of patients who underwent navicular excision and a cuboid dorsal closing wedge osteotomy to correct a rigid cavus foot deformity was performed. A total of 11 children and 16 feet were treated during the past 8 years at 2 centers. RESULTS: All feet had navicular excision and a cuboid dorsal closing wedge osteotomy to correct a rigid cavus foot deformity. The etiology of the deformity was as follows: multiply operated congenital clubfoot (5 feet), arthrogryposis (6 feet), and neurological deficits (5 feet). At a mean follow-up of 4.9 years, all had a plantigrade foot. CONCLUSIONS: This salvage procedure offers an alternative method to correct a severe stiff cavus deformity. The procedure is performed at the apex of the deformity and thus maximum correction can be obtained by this "wedge resection." The curved articular surfaces of the cuneiforms articulate with the head of the talus post navicular excision if no fusion is desired. Navicular excision has been used to correct children with vertical talus, but not previously reported as a method to handle severe cavus. It is a salvage procedure that should be considered to address severe rigid cavus. LEVEL OF EVIDENCE: Level IV. PMID- 21654466 TI - Talonavicular arthrodesis for the treatment of neurological flat foot deformity in pediatric patients: clinical and radiographic evaluation of 29 feet. AB - BACKGROUND: Patients with cerebral palsy, syndromes, myopathies, and other forms of neurological impairment can develop planovalgus foot deformity of variable degrees of severity. Several techniques have already been described to resolve the deformity with variable results. Talonavicular arthrodesis is a well-known technique in adult patients, but to our knowledge, it has not been described in children with neurological impairment. METHODS: We performed a retrospective chart and radiographic review of 18 neurological patients (10 boys, 8 girls) with a mean age of 11.3 +/- 2.6 years (range, 7 to 19 y) who underwent talonavicular arthrodesis for flat foot deformity between 1998 and 2009, at our center. RESULTS: Of a total of 29 feet, talonavicular arthrodesis was judged satisfactory in 28 feet, whereas 1 had unsatisfactory results according to the Yoo clinical outcome scoring scale. Subjective observations reported that 3 feet from 2 patients were painful preoperatively and none after last follow-up. Functionally, 2 of 13 patients were able to stop using braces after surgery. The significant improvement achieved postoperatively in radiographic measurement angles was maintained at last follow-up without any loss of angle correction. CONCLUSIONS: Talonavicular arthrodesis seems to achieve a reliable hind foot fixation in flat foot in patients with neurological impairment. LEVEL OF EVIDENCE IV: Case series. PMID- 21654467 TI - Congenital vertical talus in multiple pterygium syndrome. AB - BACKGROUND: Congenital vertical talus (CVT) is a rare foot deformity, but it is a commonly associated anomaly in patients with multiple pterygium syndrome (MPS). If left untreated, it can cause pain and morbidity, which will affect the patient's ambulation and quality of life. The aim of this study was to assess the prevalence of CVT among patients with MPS, to characterize the clinical and radiological features and examine the outcome of treatment. METHODS: We reviewed the medical records from 1969 to 2009, and detected 14 patients with a diagnosis of MPS. Data regarding clinical findings, radiographs, associated anomalies, and treatment were collected and analyzed. RESULTS: CVT was seen in 10 of 14 patients (71%). All of them had bilateral involvement. Eight of the 10 (80%) were girls, and 3 of these 10 (30%) were nonambulatory patients. All 7 ambulatory patients had manipulation and casting, followed by a single-stage surgical release. The mean age at surgery was 3.0 +/- 3.7 years (range, 3 mo-9 y 2 mo). At the last follow-up, all of the 7 patients (100%) had painless plantigrade feet and a reduced talonavicular joint, and none had recurrence of the deformity. The overall mean follow-up was 6 years (range, 2-19 y) and the mean age at the last follow-up was 9 years (range, 2-23 y). The commonly associated anomalies were scoliosis (93%), tethered cord (14%), hip dislocation (43%), cardiac (29%), respiratory (43%), and gastrointestinal anomalies (29%). CONCLUSIONS: CVT is common in MPS. The other common anomalies included scoliosis, hip dislocation, and respiratory problems. Treatment with manipulation and casting followed by, a single-stage surgical release resulted in a good outcome. PMID- 21654468 TI - Intercalary segmental reconstruction of long bones after malignant bone tumor resection using primary methyl methacrylate cement spacer interposition and secondary bone grafting: the induced membrane technique. AB - BACKGROUND: Bone reconstruction after surgical resection of malignant bone tumor in children remains a difficult challenge and various techniques exist. Induced membrane reconstruction as described by Masquelet et al has been reported in traumatic large bone defects. We have been using this 2-stage technique after primary malignant bone tumors resection in children since 2000. METHODS: We retrospectively studied 12 cases: 6 Ewing sarcomas and 6 osteosarcomas. Mean age of the patients was 9 years old (range, 3 to 15.5 y). Surgical treatment consisted of wide resection and insertion of a cement spacer then secondary bone grafting. All patients had neoadjuvant and adjuvant chemotherapy and 2 patients had adjuvant radiotherapy. RESULTS: Surgical excision was complete in all cases. There was no local recurrence at 6.2 years (range, 4.6 to 9.1 y) follow-up. Three patients had pulmonary metastasis (of whom 1 deceased) and 1 had a metastasis on the contralateral limb. The 11 patients operated on the lower limb achieved weight bearing 4.1 months (range, 0.2 to 14.2 mo) after the second stage of the procedure. Complications were numerous with 7 nonunions (4 unifocal and 3 bifocal), 5 fractures (in 4 patients), 5 protruding wires (in 4 patients), and 2 femoral varus deformities. There was no infection. CONCLUSIONS: Induced membrane reconstruction seems to be a simple and reliable technique in pediatric bone tumors and these results are promising. Extended use of locking nails could reduce the high rate of nonunion though it is not always possible in skeletally immature patients. LEVEL OF EVIDENCE: IV (case series). PMID- 21654469 TI - Glycobiology and the growth plate: current concepts in multiple hereditary exostoses. AB - BACKGROUND: Multiple hereditary exostoses, also termed as multiple osteochondromas, is a heritable disorder of connective tissue with primarily orthopaedic clinical manifestations. Understanding of its biological underpinnings has been advanced on a variety of fronts in recent years. METHODS: The multifaceted literature regarding osteochondromagenesis and the major clinical challenges in patients with multiple osteochondromas were reviewed. RESULTS: Consideration of recent advances in molecular biology, biochemistry, and animal modeling of osteochondroma pathogenesis yields a unified model. CONCLUSIONS: Mechanistic details and therapeutic targets have yet to be elucidated, but the general biology of osteochondroma formation is increasingly clear, as well as its implications in the orthopaedic clinical setting. PMID- 21654470 TI - Clinical epidemiologic characterization of orthopaedic and neurological manifestations in children with leukodystrophies. AB - BACKGROUND: Leukodystrophies (LKDs) are spectra of clinical conditions characterized primarily by brain white matter abnormalities. Although this condition was previously defined around inherited disorders of the white matter of the brain, current application includes acquired and sporadic conditions and some rare conditions that affect gray matter. Over the past 2 decades, information had become available on the clinical subtypes due to neurodiagnostic imaging and improvement in the genetic studies (cytogenetics and molecular genetics) of LKD. However, the epidemiologic profile of LKD remains largely unknown. We aimed in this study to characterize LKD by demographics, family history, orthopaedic and neurological manifestations, and clinical subtypes. METHODS: Trained medical personnel reviewed medical records of the study population diagnosed with LKD from 1986 to 2008. Using a retrospective review design, we determined the prevalence of the different clinical subtypes of LKD, family history, orthopaedic and neurological manifestations, and the demographics in LKD. The frequency and percentage (proportion, standard error, and 95% confidence interval for proportion) and the chi statistic and Fisher exact test for comparison of clinical subtypes were the statistical techniques used in the data analysis. RESULTS: Forty-four children were diagnosed with LKD between 1986 and 2008, of whom 25.0% had metachromatic LKD and 20.5% had Pelizaeus-Merzbacher LKD, whereas 40.9% were unspecified LKD. LKDs were more common among boys (63.6%), Whites (77.3%), and more likely to be diagnosed at age <3 years. Scoliosis (70.4%), hamstring contractures (81.8%), acquired hip dysplasia (88.6%), and equinus foot deformity (75.0%) were the most common orthopaedic manifestations. Common neurological manifestations were seizures (45.4%) and spasticity (77.3%). There was a statistically significant difference in sex and family history, seizures, hip dislocation, and hip subluxation, with respect to the clinical subtype of LKD, P<0.05. CONCLUSIONS: This epidemiologic characterization of LKD validates basic and clinical data on the familial history of LKD and its higher prevalence among boys. The orthopaedic manifestations common in LKD are scoliosis, hamstring contractures, acquired hip dysplasia, and equinus foot deformity, whereas common neurological manifestations are seizures and spasticity. These data are indicative of the need for orthopaedic surgeons to take into consideration this clinical epidemiologic aspect of LKD in the evaluation, treatment planning, and clinical expectations for these patients. PMID- 21654471 TI - Musculoskeletal manifestations of Sanfilippo Syndrome (mucopolysaccharidosis type III). AB - BACKGROUND: The most pronounced symptom in mucopolysaccharidosis type III (MPS III, Sanfilippo Syndrome) is the severe neurocognitive deterioration of the central nervous system. The effects of MPS III on the musculoskeletal system are less severe than those caused by other forms of MPS, however, it is our experience that many families seek orthopaedic attention for perceived musculoskeletal discomfort, particularly about the hip and spine. The purpose of this study is to report musculoskeletal findings in a case series of patients with MPS III. METHODS: This study represents a retrospective case series of all records available from 2 institutions on patients with MPS III. Chart and radiographic review was performed and outcomes tabulated. Our hypotheses are: (1) Musculoskeletal abnormalities are prevalent in children with MPS III and (2) Musculoskeletal deformities in children with MPS III may require surgical intervention. RESULTS: Eighteen patients were identified (10 female and 8 male) with an average age of 10.3 years. Three had significant scoliosis (21 to 99 degrees) and 2 others had L1 hypoplasia. Four patients had osteonecrosis of the femoral heads. One patient required a carpal tunnel release, and another a trigger thumb release. There were no cases of cervical instability. CONCLUSIONS: In our study with these patients, we have observed several unreported musculoskeletal manifestations of MPS III. Osteonecrosis of the hips can be a source of severe discomfort for these children. Although uncommon, operative intervention for orthopaedic conditions is sometimes warranted. Operative indications in this cohort include progressive scoliosis of large magnitude, carpal tunnel syndrome, and trigger digits. LEVEL OF EVIDENCE: Level IV; case series. PMID- 21654472 TI - Orthopaedic conditions in Ras/MAPK related disorders. AB - BACKGROUND: The RAS/MAPK disorders [Noonan syndrome, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, and Leopard syndrome] are heterogenous conditions with phenotypic overlap. Their orthopaedic manifestations are not well defined, and their phenotypic similarity makes differentiating them difficult. METHODS: We prospectively evaluated 60 individuals: 26 with Noonan syndrome, 32 with CFC syndrome, and 2 with Costello syndrome. Each individual underwent a structured orthopaedic history and physical evaluation by an orthopaedic surgeon, and a syndromic evaluation by a geneticist. RESULTS: All groups had a high prevalence of scoliosis (8/26 Noonan syndrome, 8/32 CFC syndrome, and 1/2 Costello). Those with Noonan syndrome or CFC syndrome had a high instance of serious cervical spine disorders, including cervical stenosis, Arnold-Chiari malformation, and syringomyelia in the Noonan syndrome individuals and hydrocephalus, cervical stenosis, torticollis, and Arnold-Chiari in the CFC syndrome individuals. Noonan syndrome manifestations included chronic pain (n=21), pes planus (n=11), pes cavus (n=5), hip contractures (n=5), hand dysfunction (n=3), and hip dysplasia (n=2). Manifestations of CFC syndrome included pes planovalgus (n=20), knee flexion contractures (n=7), hip dysplasia (n=5), elbow flexion contractures (n=4), pedal calluses (n=4), toe crowding (n=4), and hip contractures (n=4). Individuals with Costello syndrome had shorter stature than the other groups and were prone to have hand contractures. CONCLUSIONS: Orthopaedic manifestations are frequent and diverse in Ras/MAPK disorders and can be used in phenotypic differentiation between these disorders. LEVEL OF EVIDENCE: II. PMID- 21654473 TI - Growing pains: a study of 30 cases and a review of the literature. AB - BACKGROUND: Data from the literature regarding the clinical profile of growing pains are limited. The purpose of this study was to define the clinical features, familial history, laboratory findings, and therapeutic outcome of growing pains in children. METHODS: Thirty children (18 male and 12 female; 3 to 14 y of age) who presented with growing pains between January 2006 and December 2007 were enrolled and prospectively followed up for 1 year. The inclusion criterion was lower extremity pain, which was recurrent and lasted for >3 months. The exclusion criteria were any abnormal systemic or local symptoms and signs, joint involvement, and limp or limitation of activity. Laboratory tests, including complete blood count, erythrocyte sedimentation rate, and serum calcium and phosphorus levels, were performed in all children. RESULTS: The study group had pain during the night and afternoon in 43.3% and 56.7% of cases, respectively. Both lower limbs were involved in 80% of cases, causing awakening and crying episodes in 40% and 37% of cases, respectively. The frequency of pain was as follows: daily, 5%; weekly, 45%; monthly, 35%; and every 3 months, 15%. The pains were relieved by massaging the affected site in 95% of cases and by analgesics in 5% of children. A family history of growing pains was positive in 20% of patients. All patients had laboratory tests within normal values. CONCLUSION: Growing pain is a frequent noninflammatory syndrome consisting of intermittent, often annoying, pains that affect the lower extremities of children. Clinical diagnosis is easy if precise inclusion and exclusion criteria in the history and physical examinations are strictly followed. Patients and family reassurance is mandatory. LEVEL OF EVIDENCE: This is a Level I prospective study. PMID- 21654476 TI - From the editor. Agenda for change. PMID- 21654474 TI - Improving parental satisfaction in pediatric orthopaedics. AB - BACKGROUND: No previous studies have attempted to measure parental satisfaction and service quality with regards to pediatric orthopaedic inpatient care. We performed a prospective observational study to identify areas of inpatient care which might be improved to increase overall parental satisfaction. METHODS: We used the validated Swedish parent satisfaction questionnaire to generate data from 104 pediatric orthopaedic hospital inpatients between August 2009 and May 2010 (49 elective and 55 trauma pediatric orthopaedic admissions; median age range, 2 to 6 y). Questions focused on 8 domains of quality: information on illness, information on routines, accessibility, medical treatment, care processes, staff attitudes, parent participation, and staff work environment. Scores generated a percentage of the maximum achievable for that quality index. Data were analyzed using recognized statistical methods. RESULTS: Overall mean combined scores for the care indices were highest for parents' perception of "medical treatment" (95%) and "staff attitudes" (95%). The medical treatment index includes questions regarding staff member's skill and competence. Lowest scores corresponded to the index "information on routines" (86%). DISCUSSION: Information on routines applies to parental awareness of ward rounds, to whom questions should be directed and which doctors and nursing staff are responsible for their child's care. Lower scores in relation to this index were substantiated by comments from relatives requesting greater information provision. The information parents required was routinely provided suggesting that retention rather than lack of information is the main issue. Provision of information pamphlets tailored to common injuries or elective procedures might prove an effective method for improving parental satisfaction and overall care. Improving information provision and parental retention of this information is the strategy most likely to improve quality of service and parental satisfaction for pediatric orthopaedic inpatient care. LEVEL OF EVIDENCE: Level 2 evidence, prospective comparative study investigating results of treatment. PMID- 21654477 TI - Blueprint for nursing leadership: creating a culture of accountability. AB - Our "Blueprint for Nursing Leadership" emerged from dialogue with our nurse leaders on the daily challenges that managers encounter with competing and compelling priorities in the increasingly complex health care environment. Recognizing this as a transformational opportunity, the reorganized nurse executive council members were invited to a leadership retreat to further explore this topic. From this dialogue, 3 key components, distributed responsibility, nonstop skill development, and accountability became the framework on which the "Blueprint for Nursing Leadership" was created. The blueprint is to empower, engage, and sustain a culture of accountability. PMID- 21654478 TI - A case for measuring governance. AB - Shared governance is promoted as a management innovation designed to improve outcomes of quality patient care, nurse job satisfaction, productivity, and nurse retention. Reported studies have not measured the degree of governance. The Index of Profession Nurse Governance is a valid, reliable tool that can be used to measure the degree of governance, to assess the status and progress of implementation of governance, and in studies relating shared governance to outcomes. An example of the use of the Index of Profession Nurse Governance in one hospital to assess the degree of shared governance over time is described. PMID- 21654480 TI - Shared governance and empowerment in registered nurses working in a hospital setting. AB - Empowerment of registered nurses through professional practice models inclusive of shared governance has been proposed as essential to improve quality patient care, contain costs, and retain nursing staff. The purpose of this study was to determine the relationship between perceptions of governance and empowerment among nurses working in acute care hospital units in which a shared governance model had been in place for 6 to 12 months. The 158 nurses who participated perceived themselves to be moderately empowered and in an early implementation stage of shared governance. There was a statistically significant positive relationship between perceptions of shared governance and empowerment. Recommendations for professional practice and future research are included. PMID- 21654479 TI - Leading an international nursing partnership: the Vietnam Nurse Project. AB - This article describes an international partnership between a US university in San Francisco, California, and a nursing school in Hanoi, Vietnam. The focus of the project is nursing education and practice. All successful partnerships require a great deal of trust, care, nurturing, and determination. However, regardless of the resources available, the first order of business must be to build trust and confidence between the players. PMID- 21654481 TI - On the scene: American University of Beirut Medical Center, Beirut, Lebanon. AB - American University of Beirut Medical Center is the first Magnet hospital in the Middle East. In this article, authors reflect back on the journey to excellence, specifically in establishing shared governance in a challenging cultural and organizational milieu. Perspectives from nurses at different levels are included to highlight their experiences throughout the journey. Evolution of the organization's shared governance model is described and initiatives of the councils are illustrated. PMID- 21654482 TI - Strategic planning--a plan for excellence for South Haven Health System. AB - South Haven Health System has developed an innovative approach to strategic planning. The key to success of this process has been the multidisciplinary involvement of all stakeholders from the first planning session through the final formation of a strategic plan with measurable objectives for each goal. The process utilizes a Conversation Cafe method for identifying opportunities and establishing goals, Strategic Oversight Teams to address each goal and a Champion for implementation of each objective. Progress is measured quarterly by Strategic Oversight Team report cards. Transparency of communication within the organization and the sharing of information move the plan forward. The feedback from participant evaluations has been overwhelmingly positive. They are involved and excited. PMID- 21654483 TI - Slicing and dicing shared governance: in and around the numbers. AB - Hospitals seeking Magnet status must demonstrate empowering structures and processes that involve nurses in governance and decision-making about their practice. Shared governance--an organizational innovation that legitimizes health care professionals' decision-making control over their practice, while extending their influence to administrative areas previously controlled by managers--can achieve this. However, evidence connecting shared governance with clinical, professional, and organizational outcomes has been sparse. Research using the Index of Professional Nursing Governance is changing that. Innovative uses of the Index of Professional Nursing Governance is strengthening new shared governance programs, rejuvenating old ones, and finally connecting innovative models to favorable outcomes. PMID- 21654484 TI - Advancing innovation in health care leadership: a collaborative experience. AB - The changing framework of today's health care system requires leaders to be increasingly innovative in how they approach their daily functions and responsibilities. Sustaining and advancing a level of innovation that already exists can be challenging for health care administrators with the demands of time and resource limitations. Using collaboration to bring new-age teaching and disciplines to front-line leadership, one hospital was able to reinvigorate a culture of innovation through multiple levels and disciplines of the organization. The Innovation Certification Course provided nursing leaders and other managers' an evidence-drive approach, new principles and useful strategies of innovative leadership and graduate program education. PMID- 21654485 TI - Leadership redefined: educating the Doctorate of Nursing Practice nurse leader through innovation. AB - In today's society, health care systems are characterized by change, unpredictability, increasing speed of information and knowledge exchanges, redefined organizational boundaries and hierarchy, emphasis on value, teamwork, interdisciplinary collaboration, diversity, and interconnectedness. This new reality has forced nurse educators to redefine nursing leadership and prepare the Doctorate of Nursing Practice (DNP) leader through innovative courses offering experiential learning based on complex adaptive systems and quantum leadership theory. This article describes the experiential learning approach and integrated learning experience for DNP students. PMID- 21654486 TI - Enhancing shared governance for interdisciplinary practice. AB - Cincinnati Children's Hospital Medical Center has a strong history of embracing staff empowerment and shared decision making. Shared governance for nursing was implemented in 1989; a separate allied health structure was created in 1999. The two operated in parallel with few occasions for interface, and with little collaboration. With the beginning of the medical center's efforts to pursue perfect patient care in 2002, there was a marked increase in the frequency of interprofessional initiatives and collaborations in the organization. By 2005, this increase in collaborative practice precipitated discussions questioning the purpose and efficiency of two separate structures. Over the next two years, planning ensued to merge these structures to better reflect the current interprofessional reality. The enhanced shared governance structure at Cincinnati Children's was launched in 2008. Each discipline now governs its own practice, but as patient care issues overlap, there is a structure in place to resolve patient issues that cross disciplines. The new Patient Care Governance Council includes physician and family representatives. PMID- 21654487 TI - The Department of Veterans Health Administration Office of Nursing Service, "transforming nursing in a national healthcare system: an example of transformation in action". AB - The Department of Veterans Health Administration Office of Nursing Service has embarked on a multiyear transformational process, an example of which is the development of an organization-wide nursing handbook. The development of this handbook offered the opportunity to improve collaboration, redefine expectations and behavior, as well as prepare for the future of Nursing within the Veterans Health Administration. The lessons learned from this process have revolved around the themes of leadership skills for managing high-level change often in a virtual environment; constant collaboration; that the practice of nursing will continue to evolve on the basis of new evidence, technology, customer expectations, and resources; and that the process to accomplish this goal is powerful. PMID- 21654488 TI - The impact of emotional intelligence development on nurse managers. AB - BACKGROUND: The role of nurse managers has a scope and range of accountability that place them at risk for high turnover and role exhaustion. Emotional intelligence (EI) was chosen as a focus for this study because of overwhelming evidence in the literature that relates EI with leadership effectiveness, retention, and both physical and emotional wellness. PURPOSE: This pilot study was undertaken to explore the impact of a peer coaching intervention on EI abilities of nurse managers. DESIGN: An exploratory, quantitative, pre- and posttest design was utilized. SETTING AND POPULATION: The study took place at a private tertiary care medical center in Honolulu, Hawaii. From an initial sample of 31 nurse managers, 48% (15) completed the 6-month intervention and study posttest. METHOD: The intervention consisted of initial training sessions on EI and peer coaching skills, followed by weekly one-to-one peer coaching and monthly check-in group meetings. FINDINGS: All participants who completed the study perceived that the peer coaching intervention improved their EI abilities and general management performance. CONCLUSION: Participants reported peer coaching's positive effect on their EI and performance skills during a period of unusually high organizational stress, providing evidence for the positive effect of the study intervention. PMID- 21654489 TI - Nurse executive practice: creating a new vision for leadership. AB - Creating the future for practice calls for a new view of leadership and the evidence to support it. Gathering practice and research stakeholder to clarify the frame for research and the future of practice is critical to building a preferred future. Focusing on gathering leaders and providing a frame for their dialogue and interaction around executive practice for the future is important to creating the appropriate skills and role characteristics to lead the profession into it. PMID- 21654490 TI - Changes for the valuable clinical nurse specialist: a regulatory conundrum. PMID- 21654492 TI - Pandemic H1N1 influenza infection in adult transplant recipients. PMID- 21654493 TI - From local to global: lipid emulsion (intralipid) makes a move. PMID- 21654494 TI - Numerical and experimental flow analysis of the Wang-Zwische double-lumen cannula. AB - An experimental and numerical analysis was performed for the Wang-Zwische double lumen cannula (DLC) (Avalon Elite). The aim of this work was to provide insight for future improvement by characterizing the fluid dynamic behavior of the novel catheter with metrics often associated with blood trauma. Pressure and flow distributions were measured on a steady-flow rig using a 50% glycerol-water mixture by imposing a 2 L/min flow rate across the drainage and infusion lumens. The fluid was modeled as Newtonian with density of 1050 kg/m3 and dynamic viscosity of 0.0035 kg/m.s. Reynolds numbers typical for transitional flow (Re = 2000-2500) were computed within the lumens because of the changing cross-sections of the cannula geometry. Numerical computations were performed using the steady three-dimensional Reynolds-averaged Navier-Stokes (RANS) equations and the low Reynolds k-omega turbulence model. Discretization of governing equations was based on a cell-centered finite volume method. Numerical results correlated well with global performance of the cannula, allowing evaluation of the geometry toward potential blood trauma. Peak wall shear stress (WSS) in the drainage lumen was higher than that of infusion lumen, mainly due to the presence of side holes. Furthermore, recirculation regions were predicted in transition tubing to connectors of both the drainage and the infusion lumens because of adverse pressure gradients caused by the sudden enlargement of the cannula geometry. In this three-dimensional computational fluid dynamics (CFD) study, we observed higher peak WSS values for the drainage lumen, which may potentially cause blood trauma. Furthermore, recirculation regions were predicted in the proximity of the exit sections of both the infusion and drainage lumens, which may contribute to thrombosis formation. This study provides insight for future DLC modifications in minimizing cannula-induced blood trauma and thrombogenicity in long-term applications. PMID- 21654495 TI - Dynamic contrast-enhanced magnetic resonance imaging predicts immediate therapeutic response of magnetic resonance-guided high-intensity focused ultrasound ablation of symptomatic uterine fibroids. AB - OBJECTIVES: : To evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters in the prediction of the immediate therapeutic response of MR-guided high-intensity focused ultrasound (HIFU) therapy in the treatment of symptomatic uterine fibroids MATERIALS AND METHODS: : Institutional review board approved this study, and informed consent was obtained from all participants. A total of 10 symptomatic uterine fibroids (diameter: mean, 8.9 cm; range, 4.7-12 cm) in 10 female patients (mean age, 42.2 years) were treated with MR-HIFU therapy using the volumetric ablation technique. DCE-MRI and conventional contrast-enhanced MRI were obtained as a baseline and as an immediate follow-up study, respectively. After regions of interest of each treatment cell were properly registered to both MRI studies, DCE-MRI parameters (K, ve, vp) and operator-controllable therapy parameters (power, treatment cell size, sonication depth) were investigated on a cell-by-cell basis to reflect tissue inhomogeneity. Two types of ablation efficacy indices (volume of 240 equivalent minutes at 43 degrees C/treatment-cell volume, nonperfused volume/treatment-cell volume) were then correlated with those parameters using multiple linear regression analysis to determine which factors were significant predictors for ablation efficacy. RESULTS: : We used 293 treatment cells (4 mm, n = 12; 8 mm, n = 115; 12 mm, n = 149; 16 mm, n = 17), and all of them were analyzable. Ablation efficacies were 1.06 +/- 0.58 and 0.67 +/- 0.39. K (B = -12.035, P < 0.001 and B = -11.516, P < 0.001, respectively) among DCE-MRI parameters and acoustic power (B = 0.008, P < 0.001; B = 0.010, P < 0.001, respectively) among therapy parameters were revealed to be independently significant predictors for both types of ablation efficacy. CONCLUSIONS: : A higher K value at baseline DCE-MRI suggested a poor ablation efficacy of MR-HIFU therapy for symptomatic uterine fibroids. PMID- 21654496 TI - Pharmacokinetics of contrast media in humans: model with circulation, distribution, and renal excretion. AB - AIM: : To contribute to the understanding of the pharmacokinetics of intravenously administered, renally excreted contrast media with circulation, distribution, and renal excretion providing access to optimized and patient-based administration protocols. METHOD: : Numerical solutions of the pharmacokinetic equations are presented where the physiological parameters (organ volumes, blood flows) and administration parameters (dose, concentration, and velocity) are fixed and the variable parameters (the exchange rates between plasma and interstitium, the rate for renal excretion) are adjusted to results from clinical studies of healthy individuals. RESULTS: : Recirculation, organ plasma concentrations, and renal excretion are adequately modeled. With the calculated distribution and renal excretion rates, 3 time periods are discriminated: CONCLUSION: : The model describes bolus tracking, recirculation, plasma to interstitium distribution, and renal excretion. For known administration parameters, the relevant pharmacokinetic parameters can be achieved from the results of clinical studies. If the arguments are reversed, the pharmacokinetic parameters obtained allow the calculation of personalized administration protocols for computed tomography and magnetic resonance imaging examinations where the 2 initial time periods are essential. PMID- 21654497 TI - Hypertension and isolated office hypertension in HIV-infected patients determined by ambulatory blood pressure monitoring: prevalence and risk factors. AB - OBJECTIVE: To determine prevalence and risk factors for hypertension and isolated office hypertension diagnosed by ambulatory blood pressure monitoring in HIV infected patients. METHODS: Cross-sectional study of 310 patients. A 24-hour ambulatory blood pressure monitoring procedure was performed on the nondominant arm in those patients showing office systolic blood pressure >=140 mm Hg or diastolic blood pressure >=90 mm Hg. RESULTS: Twenty patients (6.5%) had a prior diagnosis of hypertension. Hypertension was confirmed by ambulatory blood pressure monitoring in 26 patients and isolated office hypertension in 17 patients. Isolated office hypertension and hypertension prevalence were 5.5% (95% confidence interval: 3 to 8) and 14.8% (95% confidence interval; 10.8 to 18.8), respectively. Isolated office hypertension was present in 39% of patients with office hypertension. In the univariate analysis, variables significantly associated with hypertension were age, waist circumference, established cardiovascular disease, family history of hypertension, lipoatrophy, metabolic syndrome, duration of infection, CD4 nadir, HIV RNA <50 copies/mL, and antiretroviral treatment. In the multivariate analysis, family history of hypertension [odds ratio (OR): 2.24; P = 0.027], increasing age (OR: 1.08; P < 0.001), and number of different antiretroviral regimens (OR: 1.2; P = 0.001) were associated with hypertension and female gender (OR: 0.27; P = 0.02) had a protective effect. CONCLUSIONS: The prevalence of hypertension using ambulatory blood pressure monitoring in HIV-infected patients was 15%. Because isolated office hypertension occurs in 39% of HIV-infected patients with office hypertension, ambulatory blood pressure monitoring could be useful to confirm the diagnosis of hypertension. Hypertension is strongly associated with family history of hypertension, male gender, age, and number of antiretroviral regimens. PMID- 21654498 TI - CD4 cell responses to combination antiretroviral therapy in patients starting therapy at high CD4 cell counts. AB - OBJECTIVE: To examine CD4 cell responses to combination antiretroviral therapy (cART) in patients enrolled in the Australian HIV Observational Database who commenced cART at CD4 cell counts >350 cells per microliter. METHODS: CD4 cell counts were modelled using random effects, repeated measurement models in 432 HIV infected adults from Australian HIV Observational Database who commenced their first cART regimen and had a baseline CD4 count >350 cells per microliter. Using published AIDS and/or death incidence rates combined with the data summarized by time and predicted CD4 cell count, we calculated the expected reduction in risk of an event for different starting baseline CD4 strata. RESULTS: Mean CD4 counts increased above 500 cells per microliter in all baseline CD4 strata by 12 months (means of 596, 717, and 881 cells/MUL in baseline CD4 strata 351-500, 501-650, and >650 cells/MUL, respectively) and after 72 months since initiating cART, mean CD4 cell counts (by increasing baseline CD4 strata) were 689, 746, 742 cells per microliter. The expected reduction in risk of mortality for baseline CD4 counts >650 cells per microliter relative to 351-500 cells per microliter was approximately 8%, an absolute risk reduction 0.33 per 1000 treated patient-years. CONCLUSIONS: Patients starting cART at high CD4 cell counts (>650 cells/MUL) tend to maintain this immunological level over 6 years of follow-up. Patients starting from 351 to 500 CD4 cells per microliter achieve levels of >650 cells per microliter after approximately 3 years of cART. Initiating cART with a baseline CD4 count 501-650 or >650 cells per microliter relative to 351-500 cells per microliter indicated a minimal reduction in risk of AIDS incidence and/or death. PMID- 21654499 TI - Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy. AB - BACKGROUND: Tuberculosis-HIV (TB-HIV) coinfection remains an important cause of mortality in antiretroviral therapy (ART) programs. In a cohort of TB-HIV coinfected patients starting ART, we examined the incidence and predictors of early mortality. METHODS: Consecutive TB-HIV-coinfected patients eligible for ART were enrolled in a cohort study at the Mulago National Tuberculosis and Leprosy Program clinic in Kampala, Uganda. Predictors of mortality were assessed using Cox proportional hazards analysis. RESULTS: Three hundred and two patients [median CD4 count 53 cells/MUL (interquartile range, 20-134)] were enrolled. Fifty-three patients died, 36 (68%) of these died within the first 6 months of TB diagnosis. Male sex [hazard (HR): 2.19; 95% confidence interval (CI): 1.19 to 4.03; P = 0.011], anergy to tuberculin skin test [HR: 2.59 (1.10 to 6.12); P = 0.030], a positive serum cryptococcal antigen result at enrollment (HR: 4.27; 95% CI: 1.50 to 12.13; P = 0.006) and no ART use (HR: 4.63; 95% CI: 2. 37 to 9.03; P < 0.001) were independent predictors of mortality by multivariate analysis. Six (10%) patients with TB immune reconstitution inflammatory syndrome died, and in most, an alternative contributing cause of death was identified. CONCLUSIONS: Mortality among these TB-HIV-coinfected patients was high particularly when presenting with advanced HIV disease and not starting ART, reinforcing the need for timely and joint treatment for both infections. Screening for a concomitant cryptococcal infection and antifungal treatment for patients with cryptococcal antigenemia may further improve clinical outcome. PMID- 21654500 TI - Mistaken assumptions and missed opportunities: correlates of undiagnosed HIV infection among black and Latino men who have sex with men. AB - OBJECTIVE: To identify demographic, behavioral, and psychological variables associated with being HIV positive unaware among black and Latino men who have sex with men (MSM). METHODS: Participants recruited in 3 cities completed a computer-assisted interview and were tested for HIV infection (OraSure Technologies, Bethlehem, PA). HIV-positive unaware MSM were compared with MSM who tested HIV negative in bivariate and multivariate analyses. RESULTS: Of 1208 MSM (597 black and 611 Latino), 11% were HIV-positive unaware (18% black; 5% Latino). In multivariate analysis of the Latino MSM, being HIV-positive unaware was associated with nongay identity, high perceived risk of currently being HIV positive, and belief that sex with other Latino men reduces HIV transmission risk. Among black MSM, being HIV-positive unaware was associated with gay identity, moderately higher income, having health insurance, sexuality disclosure to a current health care provider, fewer than 3 lifetime HIV tests, high perceived risk of testing HIV positive, and belief that sex with other black men reduces HIV transmission risk. CONCLUSIONS: HIV prevention efforts should address misperceptions among those black and Latino MSM who believe that assortative (ie, intraracial) sexual mixing reduces risk of HIV infection. Our findings also revealed missed opportunities to diagnose black MSM with HIV infection who were already engaged in care and had disclosed their sexuality to their health care provider. Clinicians should offer HIV testing to all MSM, particularly black MSM, who disclose engaging in recent sex with other men to facilitate earlier diagnosis of HIV infection and reduce transmission risk to sexual partners. PMID- 21654501 TI - Measuring vulnerability among orphans and vulnerable children in rural Malawi: validation study of the Child Status Index tool. AB - OBJECTIVES: To validate the Child Status Index (CSI) as an instrument that can meaningfully measure the vulnerabilities of orphaned and vulnerable children, including those infected and affected by HIV/AIDS. METHODS: Two age-specific instruments, comprised of previously validated tools and indicators commonly considered best practice, were administered to 102 children aged 5-10 years and 100 children aged 11-17 years in Mchinji, Malawi. Respondents were randomly sampled from a roster of children recently scored with the CSI. For each of the CSI's 12 subdomains, we assessed construct validity using Spearman Rank correlation coefficients. We also calculated cross tabulations to explain the resulting correlation coefficients. Analyses were conducted separately for the 2 age groups. RESULTS: No relationships exceeded the standard for high construct validity (>=0.7). Only 2 were moderate (0.3-0.7), both for the younger age group: food security (0.4) and wellness (0.36). All other relationships were weak or negative. In most subcategories, a substantial proportion of surveyed children indicated distress that was not evident from CSI scores. In the abuse and exploitation subdomain, all children were rated as "good" or "fair" by the CSI, but among surveyed children aged 11-17, 20% or more reported being beaten, kicked, locked out of the house, threatened with abandonment, cursed, and made to feel ashamed. CONCLUSIONS: In this rural Malawi population, we were not able to validate the CSI as a tool for assessing the vulnerabilities of orphaned and vulnerable children. We recommend caution in interpreting CSI scores and revisions to the tool before global scale-up in its use. PMID- 21654502 TI - Determinants of differential HIV incidence among women in three southern African locations. AB - INTRODUCTION: We explored factors associated with differential HIV incidence among women participating in a HIV prevention trial in Harare, Durban, and Johannesburg. The trial had shown no effect of the intervention (diaphragm and lubricant gel) on HIV incidence. METHODS: A prospective cohort analysis was conducted of trial participants followed for 12-24 months. Sociodemographic, biological, and behavioral data were collected at baseline and at quarterly visits. Factors associated with HIV incidence were estimated using multivariable Cox regression models, stratified by study location. Attributable risk was calculated from the adjusted hazard ratios (AHR). RESULTS: There were 309 incident HIV infections among the 4948 women in the analysis. HIV incidence was highest in Durban [6.75/100 person-years; 95% confidence interval (CI): 5.74 to 7.93], lower in Johannesburg (3.33/100 person-years; 95% CI: 2.51 to 4.44), and lowest in Harare (2.72/100 person-years; 95% CI: 2.26 to 3.26). Sexually transmitted infections were important risk factors in Harare [prevalent herpes simplex virus type 2 (HSV2) AHR = 2.56, 95% CI: 1.61 to 4.06; incident HSV2 AHR = 12.60, 95% CI: 2.13 to 21.87; Neisseria gonorrhoeae AHR = 6.82, 95% CI: 2.13 to 21.87] and in Durban (prevalent HSV2 AHR = 1.64, 95% CI: 1.07 to 2.51; N. gonorrhoeae AHR = 4.40, 95% CI: 2.07 to 9.39). In Durban, having multiple partners (adjusted odds ratio (AOR) = 1.78 95% CI: 1.11 to 2.85) and sex although a partner was under the influence of alcohol/drugs (AOR = 1.51 95% CI: 1.05 to 2.16) significantly increased risk, whereas in Johannesburg, sexual debut <16 years (AOR = 2.60 95% CI: 1.30 to 5.17) was a strong predictor of HIV acquisition. DISCUSSION: Important differences were seen in drivers of HIV incidence at the 3 study locations. Results from this analysis imply that targeted HIV programing could have a large impact on incident HIV infection in women, and that the most effective approach will likely vary based on knowledge of the local situation/epidemiology. PMID- 21654503 TI - Epidemiological impact of tenofovir gel on the HIV epidemic in South Africa. AB - BACKGROUND: Tenofovir gel, an antiretroviral-based vaginal microbicide, reduced HIV acquisition by 39% in women in a recent randomized controlled clinical trial in South Africa. METHODS: To inform policy, we used a dynamical model of HIV transmission, calibrated to the epidemic in South Africa, to determine the population-level impact of this microbicide on HIV incidence, prevalence, and deaths and to evaluate its cost-effectiveness. RESULTS: If women use tenofovir gel in 80% or more of sexual encounters (high coverage), it could avert 2.33 (0.12 to 4.63) million new infections and save 1.30 (0.07 to 2.42) million lives and if used in 25% of sexual encounters (low coverage), it could avert 0.50 (0.04 to 0.77) million new infections and save 0.29 (0.02 to 0.44) million deaths, over the next 20 years. At US $0.50 per application, the cost per infection averted at low coverage is US $2392 (US $562 to US $4222) and the cost per disability adjusted life year saved is US $104 (US $27 to US $181); at high coverage the costs are about 30% less. CONCLUSIONS: Over 20 years, the use of tenofovir gel in South Africa could avert up to 2 million new infections and 1 million AIDS deaths. Even with low rates of gel use, it is highly cost-effective and compares favorably with other control methods. This female-controlled prevention method could have a significant impact on the epidemic of HIV in South Africa. Programs should aim to achieve gel use in more than 25% of sexual encounters to significantly alter the course of the epidemic. PMID- 21654504 TI - Management of acute cardiac failure by intracoronary administration of levosimendan. AB - Acute cardiac failure caused by myocardial infarction or inadequate cardioprotection during heart surgery is associated with increased mortality and morbidity. Levosimendan is a new drug used in heart failure though it is limited by the systemic hypotension, which develops with intravenous administration. Intracoronary (IC) administration however should affect systemic circulation less while maintaining the beneficial cardiac effects of the drug. We herewith report the results from the first such clinical series. Levosimendan was administered IC in 33 consecutive patients who developed cardiogenic shock during heart surgery and were unable to wean off cardiopulmonary bypass despite maximal support. Preadministration/postadministration coronary graft flows, hemodynamic parameters, left ventricular function, and metabolic requirements were measured and compared. Levosimendan significantly increased graft flows and improved hemodynamic parameters. Systolic blood pressure (93 +/- 26.4 vs. 106 +/- 18.2 mm Hg, P < 0.05) and cardiac index (2.0 +/- 0.5 vs. 3.1 +/- 0.2, P < 0.001) were increased, whereas systemic vascular resistance (1470.7 +/- 114 vs. 1195.8 +/- 112, P < 0.01) was reduced. Better myocardial perfusion improved metabolic requirements, with myocardial oxygen extraction and glucose uptake increasing by 72% and 74%, respectively, whereas lactate production was reduced by 64%. Echocardiography demonstrated additional ventricular segment recruitment. Therefore, IC Levosimendan administration in acute heart failure is safe and efficacious producing improved cardiac function without significant detrimental hypotension. PMID- 21654505 TI - Endogenous kappa-opioid peptide mediates the cardioprotection induced by ischemic postconditioning. AB - The aim of this study was to investigate the underlying mechanism that dynorphin, an endogenous kappa opioid receptor (kappa-OR) agonist, triggers antiapoptotic effect of postconditioning (Postcon). In addition to vehicle treatment, Sprague Dawley rats (n = 6) underwent a 30-minute left anterior descending occlusion followed by 2 hours of reperfusion with or without a Postcon stimulus. The selective kappa-OR antagonist nor-binaltorphimine (Nor-BNI) was administered intravenously 5 minutes before reperfusion. Infarct size was determined by using 2,3,5-triphenyltetrazolium chloride staining. Blood plasma concentrations of creatine kinase (CK) and lactate dehydrogenase (LDH) and myocardial caspase-3 activity were analyzed spectrophotometrically. Myocardial apoptosis was analyzed by the detection of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling. Immunoreactive dynorphin in blood serum and myocardium was measured by means of an antigen-competitive enzyme linked immunosorbent assay. Infarction size, caspase-3 activity, apoptotic index, and CK and LDH levels were significantly higher in the ischemic/reperfusion group than in the vehicle group (P < 0.01). Postcon significantly reduced infarction size, caspase-3 activity, apoptotic index, CK and LDH levels (P < 0.01 vs. ischemic/reperfusion). Dynorphin content significantly increased after Postcon (P < 0.01). All the effects described above were abolished by Nor-BNI, with the exception of dynorphin content. We found that cardiac protection and antiapoptotic effect of Postcon is mediated by the activation of kappa-OR. Effect of Postcon is mediated, at least partially, by enhanced dynorphin expression. PMID- 21654506 TI - Effects of creatine supplementation in Rett syndrome: a randomized, placebo controlled trial. AB - OBJECTIVE: To evaluate the effects of creatine monohydrate (CMH) supplementation on global DNA methylation and disease-specific clinical symptoms in female patients with Rett syndrome (RTT). METHODS: Double-blind, randomized, placebo controlled crossover trial of female patients with RTT. Participants received 200 mg/kg of either CMH or placebo daily for 6 months and switched following a 4-week washout period. Primary endpoints were change in global DNA methylation and in a RTT-specific symptom score as defined by medical history and clinical evaluation with Rett Syndrome Motor and Behavioral Assessment. Secondary endpoints were changes in biochemical markers of methionine metabolism. RESULTS: Eighteen female patients aged 3 to 25 years with clinically diagnosed typical RTT and MECP2 mutation at clinical Stages III or IV were studied. CMH supplementation resulted in a statistically significant increase of global methylation by 0.11 (95% confidence interval 0.03-0.19, p = .009) compared with placebo. Total and subscores of Rett Syndrome Motor and Behavioral Assessment tended to improve but without statistical significance. CONCLUSION: CMH supplementation increases global DNA methylation statistically significantly. Scores were lower for creatine than for placebo reflecting clinical improvement but not reaching statistical significance. Biochemical variables of methionine-homocysteine remethylation are unaffected. Multicenter studies are urgently warranted to evaluate the long-term effects of CMH supplementation in an optimally homogenous RTT population over a prolonged period. PMID- 21654508 TI - Comorbid ADHD and anxiety affect social skills group intervention treatment efficacy in children with autism spectrum disorders. AB - OBJECTIVE: To assess the influence of psychiatric comorbidity on social skill treatment outcomes for children with autism spectrum disorders (ASDs). METHODS: A community sample of 83 children (74 males, 9 females) with an ASD (mean age = 9.5 yr; SD = 1.2) and common comorbid disorders participated in 10-week social skills training groups. The first 5 weeks of the group focused on conversation skills and the second 5 weeks focused on social problem solving skills. A concurrent parent group was also included in the treatment. Social skills were assessed using the Social Skills Rating System. Ratings were completed by parents at pre- and posttreatment time periods. RESULTS: Children with ASD and children with an ASD and comorbid anxiety disorder improved in their parent reported social skills. Children with ASD and comorbid attention deficit/hyperactivity disorder failed to improve. CONCLUSION: Psychiatric comorbidity affects social skill treatment gains in the ASD population. PMID- 21654509 TI - Priorities for early childhood development in low-income countries. AB - The remarkable progress in reducing child mortality in low-income countries is now accompanied with a rapidly expanding population of child survivors and increased life expectancy. However, many have special health care needs in the early foundational years for optimal health and educational and vocational status. Investment in early childhood development (ECD) is therefore crucial but likely to be constrained by lack of adequate resources making priority-setting inevitable. A review of current ECD approaches in sub-Saharan Africa and South Asia shows that concerted multidisciplinary and cross-sectoral initiatives targeted at children with developmental disabilities across all crucial domains of ECD and guided by available evidence on optimal timing for interventions are urgently required. This focus would necessitate appropriate national ECD policies, modifications to the current global ECD programs in the developing world, and a more active collaboration between pediatricians and other related service providers. PMID- 21654511 TI - Lower corneal hysteresis is associated with more rapid glaucomatous visual field progression. AB - AIM: We investigated the correlation between central corneal thickness (CCT) and corneal hysteresis (CH) and their relationship with the rate of visual field (VF) change. METHODS: Glaucoma patients who underwent complete ophthalmic examination and tonometry using both the Goldmann applanation tonometer and the Ocular Response Analyzer were prospectively enrolled. Only eyes with >=5 SITA Standard 24-2 VF tests were included. Automated pointwise linear regression analysis was used to determine VF progression. One hundred fifty-three eyes (153 patients; mean age, 61.3 +/- 14.0 y; mean number of VF, 8.5 +/- 3.4; mean follow-up time, 5.3 +/- 2.0 y) met the enrollment criteria. RESULTS: The mean global rate of VF change was -0.34 +/- 0.7 dB/y. Twenty-five eyes (16%) reached a progression endpoint. Progressing eyes had lower CCT (525.0 +/- 34.2 vs 542.3 +/- 3 8.5 MUm, P=0.04) and lower CH (7.5 +/- 1.4 vs 9.0 +/- 1.8 mm Hg, P<0.01) compared with nonprogressing eyes. CH and CCT correlated significantly (r=0.33, P<0.01). By multivariate analysis, peak intraocular pressure [odds ratio (OR)=1.13 per mm Hg higher, P<0.01], age (OR=1.57 per decade older, P=0.03), and CH (OR=1.55 per mm Hg lower, P<0.01) remained statistically significant. CONCLUSIONS: Corneal biomechanical and physical properties, such as CH and CCT, are highly correlated and associated with VF progression. As CH may describe corneal properties more completely than thickness alone, it may be a parameter that is better associated with progression. PMID- 21654512 TI - The glaucomatous process and the evolving definition of glaucoma. PMID- 21654510 TI - Detection of progressive retinal nerve fiber layer thickness loss with optical coherence tomography using 4 criteria for functional progression. AB - PURPOSE: To compare the rates of retinal nerve fiber layer (RNFL) thickness loss using optical coherence tomography (OCT) in progressing versus nonprogressing eyes using 4 methods to define functional progression. METHODS: Normal and glaucomatous eyes with >=3 years of follow up were prospectively enrolled. Standard automated perimetry (Swedish Interactive Threshold Algorithm Standard 24 2) and OCT (Stratus OCT, Carl Zeiss Meditec, Dublin, CA) imaging were performed every 6 months in glaucomatous eyes. OCT imaging was performed annually in normal eyes. Functional progression was determined using early manifest glaucoma trial criterion, visual field index (VFI), Progressor software, and the 3-omitting method. RESULTS: Seventy-six eyes (46 glaucoma and 30 normal) of 38 patients were enrolled with a mean follow-up of 43.9 +/- 5.02 months (range: 36 to 48 mo). Eleven eyes progressed using Progressor criterion, 5 eyes using VFI, 2 eyes using the 3-omitting method, and 2 eyes using Early Manifest Glaucoma Trial criterion. The annual rate of average RNFL loss (MUm/y) was significantly greater (P<0.05) in progressing versus nonprogressing eyes using Progressor (-1.0 +/- 1.3 vs. 0.02 +/- 1.6), VFI (-2.1 +/- 1.1 vs. -0.002 +/- 1.4), and the 3-omitting method (-2.2 +/- 0.2 vs. -0.1 +/- 1.5). Mean rate (MUm/y) of average and superior RNFL thickness change was similar (P>0.05) in nonprogressing glaucomatous eyes compared with normal eyes. Using linear mixed-effect models, mean (P<0.001) and peak (P=0.01) intraocular pressure were significantly associated with rate of average RNFL atrophy in glaucomatous eyes. CONCLUSIONS: Despite differences in criteria used to judge functional progression, eyes with standard automated perimetry progression have significantly greater rates of RNFL loss measured using OCT compared with nonprogressing eyes. PMID- 21654513 TI - Change in intraocular pressure measurement after myopic LASEK: a study evaluating goldmann, pascal and applanation resonance tonometry. AB - PURPOSE: To prospectively evaluate 3 tonometry methods--the gold standard, Goldmann applanation tonometry, a new method, Pascal dynamic contour tonometry (PDCT), and a method under development, applanation resonance tonometry (ART)- with respect to intraocular pressure (IOP) measurements before, 3 and 6 months after laser-assisted subepithelial keratectomy (LASEK). MATERIALS AND METHODS: One randomly assigned eye of each of 53 healthy individuals, who underwent LASEK surgery for myopia was studied. Visual acuity, central corneal thickness, corneal curvature, and IOP were measured at each visit. Six IOP measurements/methods with 5 minutes pause between methods were performed. RESULTS: All tonometry methods measured a significantly lower IOP after LASEK correction by a mean of -3.1 diopters. The IOP reduction was largest after 6 months for Goldmann applanation tonometry (-1.7 +/- 1.8 mm Hg) followed by ARTstat (-1.2 +/- 1.5 mm Hg), PDCT ( 1.1 +/- 1.6 mm Hg), and ARTdyn (-1.0 +/- 1.5 mm Hg). The reduction of IOP did not differ significantly between different methods (P=0.11). There was a significant further reduction of measured IOP for PDCT between 3 and 6 months (-0.5 +/- 1.0 mm Hg). Uncorrected visual acuity improved significantly between 3 and 6 months postoperatively from 1.32 +/- 0.28 to 1.43 +/- 0.27. CONCLUSIONS: All tonometry methods measured a significant, but low, reduction of IOP 3 and 6 months after LASEK. Further change in visual acuity and IOP measurements between 3 and 6 months suggest a still ongoing postoperative process. PMID- 21654514 TI - Agreement between spectral domain optical coherence tomography and retinal nerve fiber layer photography in chinese. AB - PURPOSE: To compare spectral domain optical coherence tomography (OCT) and fundus photography to identify localized retinal nerve fiber layer defects (RNFLD) in Chinese patients with early-to-medium advanced glaucoma. METHODS: Thirty-nine patients (48 eyes) with localized RNFLDs by fundus photography and 48 age-matched control individuals were included into the study. The individuals underwent spectral domain OCT of the retinal nerve layer. In OCT, a localized RNFLD was defined as a dipping of the retinal nerve fiber layer thickness curve into the red-colored band of the graph, measured at a peripapillary circle with a diameter of 3.46 mm. RESULTS: In the 48 eyes of the study group, 63 localized RNFLDs were seen on the fundus photographs. On the OCTs, 58 of these 63 localized RNFLDs were detected, whereas 5 defects were not detected. Two localized RNFLDs seen on the OCTs were not found on the corresponding fundus photographs. The resulting sensitivity and specificity of OCT for detecting localized RNFLDs were 92% and 96%, respectively. The overall agreement rate between both methods was 94% (90/96), and the kappa value was 0.90 (P<0.001). The results of both techniques correlated with each other for the determination of the location (Pearson correlation coefficient (r)=0.99; P<0.001) and the width of the localized RNFLDs (201 +/- 123 degrees vs. 207 +/- 115 degrees; r=0.93; P<0.001). CONCLUSIONS: Spectral domain OCT as compared with examiner-performed assessment of conventional fundus photographs is capable of detecting and measuring localized retinal nerve fiber layer defects with a relatively high diagnostic precision. PMID- 21654515 TI - Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: effect of multiple B-scan averaging on RNFL measurement. AB - PURPOSE: To determine the effect of multiple B-scan averaging on retinal nerve fiber layer (RNFL) thickness measurement taken with a spectral-domain optical coherence tomographer (OCT). METHODS: Twenty-five normal individuals and 29 patients with glaucoma were examined. One eye was selected randomly of each participant for circumpapillary RNFL scanning by the Spectralis OCT (Heidelberg Engineering, Heidelberg, GmbH, Dossenheim, Germany). Three sets of OCT image series comprising 2, 8, and 16 consecutive B-scans were obtained in the same visit. After multiple B-scan averaging, the respective global and sectoral (superonasal, nasal, inferonasal, inferotemporal, temporal, and superotemporal) RNFL thicknesses were compared with linear mixed modeling and analyzed for RNFL measurement variability. RESULTS: There was no RNFL segmentation failure in all the scans. No significant differences were found in global or sectoral RNFL thicknesses among the image series averaged with different number of B-scan except for the inferonasal sector in the glaucoma group (P=0.036). The intraclass correlation coefficients were all >0.971 and the coefficients of variation were all below 4.33% for both sectoral and global RNFL thicknesses. No significant differences in the image quality score were detected among the image series (P>=0.141). CONCLUSIONS: Although multiple B-scan averaging is commonly applied to enhance visualization of the retinal layers in OCT images, it may not have a significant impact on global and sectoral RNFL thicknesses measured by the Spectralis OCT. PMID- 21654516 TI - Central corneal thickness in Chinese subjects with primary angle closure glaucoma. AB - PURPOSE: To characterize central corneal thickness (CCT) in Chinese eyes with primary angle closure glaucoma (PACG). METHODS: CCT was measured by ultrasound pachymetry in PACG eyes and compared with primary open-angle glaucoma (POAG) eyes. POAG eyes were further subdivided into high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) for analysis. PACG eyes had glaucomatous optic neuropathy and visual field loss, an angle in which at least 180 degrees of angle in which the posterior trabecular meshwork was not visible, and raised intraocular pressure (IOP) and/or peripheral anterior synechiae. Both HTG (IOP >21 mm Hg) and NTG (IOP consistently <21 mm Hg) eyes had glaucomatous optic neuropathy with compatible visual field defects and open angles. Further comparison was made with CCT data of 1067 normal subjects previously enrolled in a population-based study. RESULTS: We enrolled 154 patients with PACG and 300 with POAG. Mean age of PACG patients was 68.1+/-8.3 years compared with 71.1+/ 12.4 years in POAG patients (P=0.002). There was no difference in mean CCT of PACG eyes (541.28+/-33.95 MUm) and POAG eyes (539.28+/-34.84 MUm, P=0.56) or normal eyes of control subjects (536.74+/-31.08 MUm) (P=0.07). However, mean CCT of NTG eyes (535.23+/-36.10 MUm) was significantly lower than that of HTG eyes (543.44+/-33.10 MUm, P=0.04), and HTG eyes had thicker CCT than normal eyes (P=0.01). CONCLUSIONS: PACG eyes had similar CCT as those with POAG or normal eyes in Chinese subjects. PMID- 21654517 TI - An antibody-based multifaceted approach targeting the human transferrin receptor for the treatment of B-cell malignancies. AB - We previously developed an antibody-avidin fusion protein (ch128.1Av) targeting the human transferrin receptor 1 (TfR1, also known as CD71), which demonstrates direct in vitro cytotoxicity against malignant hematopoietic cells. This cytotoxicity is attributed to its ability to decrease the level of TfR1 leading to lethal iron deprivation. We now report that ch128.1Av shows the ability to bind the Fcgamma receptors and the complement component C1q, suggesting that it is capable of eliciting Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity. In addition, in 2 disseminated multiple myeloma xenograft mouse models, we show that a single dose of ch128.1Av results in significant antitumor activity, including long-term survival. It is interesting to note that the parental antibody without avidin (ch128.1) also shows remarkable in vivo anticancer activity despite its limited in vitro cytotoxicity. Finally, we demonstrate that ch128.1Av is not toxic to pluripotent hematopoietic progenitor cells using the long-term cell-initiating culture assay suggesting that these important progenitors would be preserved in different therapeutic approaches, including the in vitro purging of cancer cells for autologous transplantation and in vivo passive immunotherapy. Our results suggest that ch128.1Av and ch128.1 may be effective in the therapy of human multiple myeloma and potentially other hematopoietic malignancies. PMID- 21654518 TI - Requirement of the acquired immune system in successful cancer chemotherapy with cis-diamminedichloroplatinum (II) in a syngeneic mouse tumor transplantation model. AB - We examined the involvement of acquired immune response in the therapeutic effect of systemic tumor chemotherapy with cis-diamminedichloroplatinum (II) (cis-DDP) using a mouse syngeneic cancer transplantation model. The therapeutic effect observed in BALB/c mice was negligible in athymic BALB/c mice. The therapeutic effect became obvious when athymic mice were immunologically reconstituted with splenocytes containing CD4 T cells of BALB/c mice. The BALB/c mice in which tumor chemotherapy was successful exhibited cell line-specific tumor immunity to the second tumor transplantation. Splenocytes of these mice exhibited cell line specific cytotoxicity. After systemic cis-DDP treatment, an increase in apoptotic cells and macrophage infiltration was observed in the tumor mass. In the same lesion, an increase in the levels of high-mobility group box protein and its intracellular translocation from the nucleus to the cytoplasm were observed. In a chase study on the infiltrated macrophage with labeled tumor cells, the translocation of tumor cell components to regional lymph nodes was observed after the chemotherapy. The peripheral monocytosis induced by administrations of monocyte colony-stimulating factor augmented the therapeutic efficacy of cis-DDP treatment. These indicate that the phagocytosis of apoptotic tumor cells exhibiting the adjuvant protein by infiltrated macrophages and the subsequent antigen presentation by the macrophages to T cells take place, and that the acquired immune response to the tumor cells as the consequence plays an essential role in the therapeutic effect of cis-DDP. PMID- 21654519 TI - In vitro comparison of three different chimeric receptor-modified effector T-cell populations for leukemia cell therapy. AB - The identification of the optimal T-cell effector subtype is a crucial issue for adoptive cell therapy with chimeric receptor-modified T cells. The ideal T cell population must be able to home toward tumor site, exert prolonged antitumoral activity, and display minimal toxicity against normal tissues. Therefore, we characterized the in vitro antitumoral properties of three effector T-cell populations: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs), cytokine-induced killer (CIK) cells, and gamma9delta2 T (GDT) cells, after transduction with a chimeric receptor specific for the CD33 antigen, broadly expressed on acute myeloid leukemia cells. EBV-CTLs, CIK, and GDT cells were generated and transduced with high efficiency with a retroviral vector coding for an anti-CD33-zeta chimeric receptor without alterations of their native phenotype. Anti-CD33-zeta chimeric receptor-redirected T cells displayed analogous in vitro chemotactic activity toward CXCL12. In addition, anti-CD33 zeta chimeric receptor-expressing EBV-CTLs, CIK, and GDT cells showed potent and similar cytotoxicity against several CD33+ leukemic targets both in short-term 4 hours-51chromium-release assays (mean killing vs primary leukemic cells at effector:target ratio of 5:1; 50%, 61%, and 50% for EBV-CTLs, CIK, and GDT cells, respectively) and in long-term assays, where they were cocultured with leukemic cells for 6 days on stromal mesenchymal cells (mean survival of primary leukemic cells at effector:target ratio of 1:100; 18%, 16%, and 29% for EBV-CTLs, CIK, and GDT cells, respectively). Moreover, all effector cells acquired consistent capability to proliferate in vitro after contact with CD33+ cells and to release high and comparable levels of immunostimulatory cytokines, while secreting similar low amount of immunoregulatory cytokines as the unmanipulated counterpart. Our results indicate that expression of an anti-CD33-zeta chimeric receptor potently and similarly increase the antileukemic functions of different effector T-cell subtypes, underlying the impossibility to identify a more potent T-cell population through in vitro analysis, and consistently with recent observations that have emerged from clinical trials with chimeric receptor modified T cells, suggesting the need to perform such type of studies in the human setting. PMID- 21654520 TI - Tumor-infiltrating cytotoxic T lymphocytes as independent prognostic factor in epithelial ovarian cancer with wilms tumor protein 1 overexpression. AB - Immune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we related Wilms tumor protein 1 (WT1) overexpression, a well-established immunotherapeutic target, to clinicopathological characteristics, immunological parameters, and survival in primary EOC. WT1 overexpression was evaluated in primary EOC tissue of 270 patients by immunohistochemistry on tissue microarrays (TMAs). Clinicopathological characteristics, follow-up, and data on infiltration of CD8+ cytotoxic T lymphocytes (CTLs), FoxP3+ regulatory T lymphocytes (Tregs), major histocompatibility complex (MHC) class I, and II molecule expression, were derived from a previously published dataset. WT1 overexpression was defined as positive immunostaining for WT1. WT1 overexpression, present in 56.3% of EOC, was associated with infiltration of Tregs [odds ratio (OR), 2.7; 95% confidence interval (95% CI), 1.6-4.7; P<0.001] and up-regulation of MHC class II (OR, 2.2; 95% CI, 1.2-4.1; P=0.014). Advanced stage (OR, 4.0; 95% CI, 1.9-8.6; P<0.001) and serous histology (OR, 6.7; 95% CI, 3.2-13.6; P<0.001) were independent predictors of WT1 overexpressing EOC. High number of CTL was an independent prognostic factor for progression-free survival (hazard ratio, 0.5; 95% CI, 0.3-0.8; P=0.006) in WT1 overexpressing EOC. As WT1 overexpressing EOC is associated with CTL and Treg infiltration next to MHC class II up-regulation, future clinical trials should evaluate the combination of therapeutic WT1 vaccines with strategies depleting Tregs and/or up-regulating MHC class I, in an attempt to enhance clinical efficacy in EOC patients. PMID- 21654521 TI - A phase 2 trial of bevacizumab and high-dose interferon alpha 2B in metastatic melanoma. AB - Bevacizumab is a humanized recombinant monoclonal antibody that neutralizes vascular endothelial growth factor, an agent with proangiogenic effects in melanoma. Interferon alpha (IFN-alpha) has antiangiogenic properties through its ability to downregulate basic-fibroblast growth factor levels. We hypothesized that the coadministration of these agents would lead to tumor regression. Patients with metastatic melanoma received bevacizumab 15 mg/kg intravenously on day 1 of the 2-week cycle. IFN-alpha was administered thrice weekly at 5 MU/m subcutaneously during cycle 1 and was increased to 10 MU/m during cycle 2. Patients were restaged every 6 cycles. Patients with stable disease or a response continued with therapy. Baseline serum vascular endothelial growth factor and fibroblast growth factor were measured. Twenty-five patients were accrued. Mean age was 58.4 years. Eleven patients required IFN-alpha dose reductions due to toxicity. Common grade 3 toxicities associated with IFN-alpha included fatigue and myalgia. Bevacizumab administration was associated with grade 2-3 proteinuria in 6 patients. Grade 4 adverse events were pulmonary embolus (1), myocardial infarction (1), and stroke (1). Six patients had a partial response, and 5 patients exhibited stable disease that lasted more than 24 weeks (range: 30 to 122 wk). Median progression-free survival and overall survival were 4.8 and 17 months, respectively. Significantly lower fibroblast growth factor levels were observed in patients with a partial response compared to those with stable or progressive disease (P=0.040). Administration of bevacizumab with IFN led to a clinical response in 24% of patients with stage IV melanoma and stabilization of disease in another 20% of patients. This regimen has activity in advanced melanoma. PMID- 21654522 TI - Cancer testis antigen, ropporin, is a potential target for multiple myeloma immunotherapy. AB - Despite recent improvements in standard pharmacologic treatments of multiple myeloma (MM), immunotherapy may prove to be more effective due to its higher specificity and lower toxicity. A novel cancer/testis antigen, ropporin, is a testis-specific protein localized in the sperm flagella. Comparing ropporin expression in healthy and MM samples, we did not detect ropporin expression in the normal tissues, but positive signals were found in 44% of the MM primary samples. The immunogenicity of ropporin was confirmed by the presence of specific antibodies detected by enzyme-linked immunosorbent assay in patients' serum. Our results show that ropporin is a novel cancer/testis antigen for MM. Except for in the testis, an immune privileged site, ropporin was not expressed in normal tissues, but was present in MM cell lines and patients' samples. Noteworthy, we show for the first time that ropporin was present at the cell surface of MM plasma cells. We suggest that ropporin is a promising target for MM immunotherapy, as we were able to generate human leukocyte antigen class I restricted cytotoxic lymphocytes able to kill autologous MM cells. PMID- 21654523 TI - Retinal ganglion cell layer volumetric assessment by spectral-domain optical coherence tomography in multiple sclerosis: application of a high-precision manual estimation technique. AB - BACKGROUND: Neuronal loss in the retina has been demonstrated pathologically in eyes of patients with multiple sclerosis (MS). In vivo, MS eyes have reduced total macular volumes by optical coherence tomography (OCT). Using a high resolution spectral-domain OCT, this pilot study used a manual method to measure ganglion cell layer (GCL) volumes and to determine the relation of these volumes to visual function in MS eyes. METHODS: Sixteen eyes of 8 patients with MS and 8 eyes of 5 disease-free control participants were studied using fast macular OCT scans performed with Spectralis OCT (Heidelberg Engineering). Visual function tests of low-contrast letter acuity and high-contrast visual acuity were administered. RESULTS: MS patient eyes had significantly lower GCL volumes than the control eyes (P < 0.001 vs controls, generalized estimating equation regression models accounting for age and within-patient intereye correlations). Within the MS group, eyes with a history of optic neuritis (ON, n = 4) had significantly lower GCL volumes than MS eyes with no ON history (P < 0.001). In contrast to measures of high-contrast visual acuity (P = 0.14), decreased GCL volumes were associated with worse performance on low-contrast letter acuity testing (P = 0.003). CONCLUSIONS: This pilot study has characterized thinning of the GCL in MS patient eyes, particularly in those with a history of acute ON, which corresponded to a reduced performance on low-contrast letter acuity testing. Studies utilizing computerized segmentation algorithms will continue to facilitate the detection of GCL loss on a larger scale and provide important information in vivo on the role and timing of neuronal vs axonal loss in MS eyes. PMID- 21654524 TI - Sagittal plane deformity in bicondylar tibial plateau fractures. AB - OBJECTIVE: To evaluate the prevalence and magnitude of sagittal plane deformity in bicondylar tibial plateau fractures. DESIGN: Retrospective radiographic review. SETTING: Two Level I trauma centers. MAIN OUTCOME MEASUREMENT: Sagittal inclination of the medial and lateral plateau measured in relation to the longitudinal axis of the tibia using computed tomographic reconstruction images. PATIENTS: Seventy-four patients (mean age, 49 years; range, 16-82 years; 64% male) with acute bicondylar tibial plateau fractures (Orthopaedic Trauma Association 41C, Schatzker VI) treated from October 2006 to July 2009. RESULTS: The average sagittal plane angulation of the lateral plateau was 9.8 degrees posteriorly (range, 17 degrees anteriorly to 37 degrees posteriorly). The medial plateau was angulated 4.1 degrees posteriorly on average (range, 16 degrees anteriorly to 31 degrees posteriorly). Forty-two lateral plateaus were angulated more than 5 degrees from the "normal" anatomic slope (defined as 5 degrees of posterior tibial slope). Of these, 76% were angulated posteriorly. Forty-three (58%) of the medial plateaus were angulated greater than 5 degrees from normal, of which only 47% were inclined posteriorly (P = 0.019 compared with lateral plateaus). In 68% of patients, the difference between medial and lateral plateaus was greater than 5 degrees ; the average intercondylar slope difference was 9 degrees (range, 0 degrees -31 degrees ; P < 0.001). Spanning external fixation did not affect the slope of either the medial or lateral tibial plateau. Intraobserver and interobserver correlations were high for both the medial and lateral plateaus (r > 0.81, P < 0.01). CONCLUSIONS: Considerable sagittal plane deformity exists in the majority of bicondylar tibial plateau fractures. The lateral plateau has a higher propensity for sagittal angulation and tends to have increased posterior slope. Most patients have a substantial difference between the lateral and medial plateau slopes. The identification of this deformity allows for accurate preoperative planning and specific reduction maneuvers to restore anatomic alignment. PMID- 21654525 TI - Nonoperative treatment of proximal humerus fractures: a systematic review. AB - BACKGROUND: Proximal humerus fractures are common in the setting of osteopenia and osteoporosis and can often be treated nonoperatively. There are few studies that evaluate the long-term outcomes of nonoperative treatment of these fractures. We performed a systematic review of the literature to examine the results of nonoperative treatment of proximal humerus fractures. METHODS: The PubMed search engine and EMBASE database were used. Inclusion criteria were: 1) proximal humerus fractures resulting from trauma; 2) age older than 18 years; 3) more than 15 patients in the study; 4) greater than 1 year follow-up; 5) at least one relevant functional outcome score; and 6) a quality outcome score of at least a 5 of 10 according to previously published scoring system. RESULTS: We identified 12 studies that included 650 patients with a mean age of 65.0 years (range, 51-75 years) and a mean follow-up of 45.7 months (range, 12-120 months). There were 317 one-part fractures, 165 two-part fractures, 137 three-part fractures, and 31 four-part fractures. The rate of radiographic union was 98% and the complication rate 13%. The average range of motion reported in five studies was 139 degrees forward flexion, 48 degrees external rotation, and 52 degrees internal rotation. The average Constant score reported in six studies was 74 (range, 55-81). Varus malunion was the most common complication reported, whereas avascular necrosis was uncommon (13 cases). CONCLUSIONS: We conclude that our systematic review of the literature on the nonoperative treatment of proximal humerus fractures demonstrates high rates of radiographic healing, good functional outcomes, and a modest complication rate. PMID- 21654526 TI - Fractures of the calcaneal tuberosity treated with suture fixation through bone tunnels. AB - Fractures of the calcaneal tuberosity, although rare, present a challenge for the treating surgeon. The goal of treatment is restoration of function of the gastrocnemius-soleus complex and the Achilles tendon. These fractures often occur in diabetics and elderly osteoporotic patients and therefore fixation of the displaced fragment is difficult. Displaced fractures, if not recognized and promptly reduced, often result in secondary soft tissue compromise. Often, the fragment is a small shell of osteoporotic bone, which is less than optimal for bony fixation. We present our technique for surgical fixation of calcaneal tuberosity fractures using a suture placed through bone tunnels in the calcaneal body. This technique is used by itself for smaller fragments or supplemented with screw fixation for larger fragments. PMID- 21654527 TI - Blast-induced lower extremity fractures with arterial injury: prevalence and risk factors for amputation after initial limb-preserving treatment. AB - OBJECTIVES: The purpose of this study is to determine the rate of late (secondary) amputation and to identify risk factors for amputation in injuries that were initially treated with limb preservation on the battlefield. METHODS: A retrospective review at our institution identified 24 consecutive patients with 26 blast-induced open fractures distal to the joint that had associated arterial injuries. All injuries were initially cared for on the battlefield and during the evacuation chain of care with limb preservation protocols. All definitive orthopaedic care was provided by a single fellowship-trained orthopaedic trauma surgeon at a tertiary care stateside facility. Injury factors were analyzed based on radiographic and chart review to determine associations with amputation. RESULTS: Twenty of 26 injured limbs received an amputation for a total amputation rate of 76.9% (95% confidence interval, 57.9-88.9%). Fourteen limbs received early amputation before limb salvage attempts. Six of the 12 limbs that received limb salvage underwent late amputation. CONCLUSIONS: The rate of amputation in severe blast-induced extremity fractures combined with an arterial injury initially treated with limb preservation on the battlefield and before transfer to the definitive military treatment facility is extremely high. Blast-injured lower limbs with a combined severe bony and soft tissue injury should be carefully assessed when arterial injury is present because they may require early amputation during initial surgical care on the battlefield. PMID- 21654528 TI - The greater trochanter-head contact method: a cadaveric study with a new technique for the intraoperative control of rotation of femoral fractures. AB - OBJECTIVE: To describe a new method for femoral rotational alignment during intramedullary nail insertion using the profile of the greater trochanter and its relation to the femoral head. METHODS: Radiologically, the line that represents the posterior border of the greater trochanter comes in contact with the femoral head contour during external rotation. The degree of rotation to achieve this contact was measured on both lower extremities of 15 whole fresh-frozen cadavers and seven dried human femora using a standard image intensifier. Computed tomography was used in the dried femora to assess the femoral anteversion angle, the length of the femoral neck, and the neck-shaft angle. RESULTS: The side difference of the greater trochanter-head contact angle was 6 degrees or less in 14 of 15 whole fresh-frozen cadavers. Regarding the dried human femora, this angle had a strong positive correlation with femoral neck anteversion angle (r = 0.9), whereas no statistically significant correlation could be detected with the neck length or the neck-shaft angle. CONCLUSION: Our described method is simple to execute because it depends on a definite point of measurement. Furthermore, an angle is recorded for each extremity, which enables us to estimate the amount of the rotational difference. This method does not depend on special views, especially at the hip, but only a direct anteroposterior view with gradual internal rotation of the image intensifier. PMID- 21654529 TI - A comprehensive approach to fragility fractures. AB - To address the cause of fragility fractures, an understanding of the determinants of bone strength is needed. Identifying patients at increased fracture risk should take into account bone quantity, quality, and turnover. Postmenopausal osteoporosis remains the most common derangement of bone strength; however, decreased bone strength can also result from secondary causes of osteoporosis. In order to properly manage patients with fragility fractures, assessment should include a focused medical history and physical examination, proper laboratory investigation, dual-energy x-ray absorptiometry screening, and, if necessary, use of the fracture risk assessment tool (FRAX). Treatment options will include nonpharmacologic treatment such as calcium and vitamin D and pharmacologic treatment with antiresorptive or anabolic agents to prevent future fractures. Bisphosphonates remain the standard treatment for osteoporosis. Concerns of oversuppression of bone turnover on long-term bisphosphonate treatment can be addressed with a drug holiday depending on the patient's fracture risk. An anabolic agent such as teriparatide is a powerful tool for the prevention of fragility fractures and should be reserved for patients at high risk for fracture, such as those with declining bone mineral density despite bisphosphonate treatment. Careful evaluation of all patients with a fragility fracture will enable the orthopaedic surgeon to identify the cause of fracture and implement a treatment plan that can prevent subsequent fractures in this vulnerable population. PMID- 21654530 TI - Lengthening of the femur over an existing intramedullary nail. AB - Leg length discrepancies can occur despite successful union of femur fractures after intramedullary nailing (IMN). Often, the leg length discrepancy can result in significant disability to the patient, altered gait biomechanics, pelvic obliquity, and pain. Therefore, a successful clinical result for such deformities after IMN involves addressing the leg length inequality. Femoral reconstruction with an osteotomy around an existing intramedullary nail was introduced to address axial deformity correction and limb lengthening without changing or removing a previously inserted IMN. This technique uses the principles of lengthening over an IMN. The presence of the nail has minimized the time needed for the external fixator because the nail supports the regenerate bone or osteotomy during the consolidation phase. With this technique, surgery is minimized by avoiding the need for exchange nailing. PMID- 21654531 TI - The use of cervical vertebrae plates for cortical substitution in posterior wall acetabular fractures. AB - We report a new technique for operative fixation of posterior wall acetabular fractures that require cortical substitution. This technique uses cervical vertebrae plates that are H-shaped as an alternative to the combination of standard locking or nonlocking pelvic reconstruction plates and cortical substitution plates, ie, spring plates. We believe this technique provides a more robust structural support with the plate acting as a cortical substitute in comminuted fracture patterns. Compared with pelvic reconstruction plates, cervical vertebrae plates are almost twice as wide. Additionally, the plate configuration allows more screws per unit length compared with pelvic reconstruction plates, potentially providing more points of fixation. Finally, cost comparison of the two plates shows the cervical vertebrae plates to be less expensive than standard pelvic reconstruction plates. Our series of 23 consecutive patients shows outcomes similar to the published literature for standard pelvic reconstruction plates, and initial results show no early hardware failure. PMID- 21654532 TI - The use of a T-plate as "spring plates" for small comminuted posterior wall fragments. AB - In the treatment of posterior wall fractures of the acetabulum, a modified distal radius T-plate can be substituted for one third tubular spring plates for fixation of thin, small, or comminuted posterior wall fragments. This technique is described as well as a case series of 33 patients with various posterior wall acetabular fractures. PMID- 21654533 TI - Effect of postactivation potentiation on swimming starts in international sprint swimmers. AB - The aim of this study was to investigate the effects of postactivation potentiation (PAP) on swim start performance (time to 15 m) in a group of international sprint swimmers. Nine international sprint swimmers (7 men and 2 women) volunteered and gave informed consent for this study, which was approved by the university ethics committee. Initially, swimmers performed a countermovement jump (CMJ) on a portable force platform (FP) at baseline and at the following time points ~15 seconds, 4, 8, 12, and 16 minutes after a PAP stimulus (1 set of 3 repetitions at 87% 1 repetition maximum [RM]) to individually determine the recovery time required to observe enhanced muscle performance. On 2 additional days, swimmers performed a swim start to 15 m under 50-m freestyle race conditions, which was preceded by either their individualized race specific warm-up or a PAP stimulus (1 set of 3 repetitions at 87% 1RM). Both trials were recorded on 2 cameras operating at 50 Hz with camera 1 located at the start and camera 2 at the 15-m mark. Peak vertical force (PVF) and peak horizontal force (PHF) were measured during all swim starts from a portable FP placed on top of the swim block. A repeated measures analysis of variance revealed a significant time effect with regard to power output (PO) (F = 20.963, p < 0.01) and jump height (JH) (F = 14.634, p < 0.01) with a paired comparison indicating a significant increase in PO and JH after 8 minutes of recovery from the PAP stimulus. There was a significant increase in both PHF and PVF after the PAP stimulus compared to the swim-specific warm-up during the swim start (PHF 770 +/- 228 vs. 814 +/- 263 N, p = 0.018; PVF: 1,462 +/- 280 vs. 1,518 +/- 311 N, p = 0.038); however, time to 15 m was the same when both starts were compared (7.1 +/ 0.8 vs. 7.1 +/- 0.8 seconds, p = 0.447). The results from this study indicate that muscle performance during a CMJ is enhanced after a PAP stimulus providing adequate recovery (~8 minutes) is given between the 2 activities. In addition, this study demonstrated that swimmers performed equally well in terms of time to 15 m when a PAP stimulus was compared to their individualized race specific warm up and indicates that PAP may be a useful addition to a warm-up protocol before races. However, more research is required to fully understand the role PAP plays in swim performance. PMID- 21654534 TI - Embryology and imaging review of aortic arch anomalies. AB - Congenital malformations of the thoracic aorta can be discovered on chest radiographs when associated with symptoms or found incidentally. We review the imaging anatomy and associations of many of the aortic arch malformations that can be encountered in adults and highlight key points with regard to their treatment and prognoses. An understanding of the normal and abnormal embryologic development of the aortic arch, with knowledge of their imaging features, may be important for improving diagnostic accuracy and patient care. PMID- 21654535 TI - History of the vertebral venous plexus and the significant contributions of Breschet and Batson. AB - Before the 18th century, the vertebral venous plexus (VVP) received scant mention, had no clinical relevance, and was largely ignored by anatomists, most likely because of its location and nondistensible nature. Gilbert Breschet in 1819 provided the first detailed anatomic description of the VVP, describing it as a large plexiform valveless network of vertebral veins consisting of 3 interconnecting divisions and spanning the entire spinal column with connections to the cranial dural sinuses distributed in a longitudinal pattern, running parallel to and communicating with the venae cavae, and having multiple interconnections. More than a century passed before any work of significance on the VVP was noted. In 1940, Oscar V. Batson reported the true functionality of the VVP by proving the continuity of the prostatic venous plexus with the VVP and proposed this route as the most plausible explanation for the distribution of prostate metastatic disease. With his seminal work, Batson reclassified the human venous system to consist of the caval, pulmonary, portal, and vertebral divisions. Further advances in imaging technology confirmed Batson's results. Today, the VVP is considered part of the cerebrospinal venous system, which is regarded as a unique, large-capacitance, valveless plexiform venous network in which flow is bidirectional that plays an important role in the regulation of intracranial pressure with changes in posture and in venous outflow from the brain, whereas in disease states, it provides a potential route for the spread of tumor, infection, or emboli. PMID- 21654536 TI - Intraoperative high-field magnetic resonance imaging combined with fiber tract neuronavigation-guided resection of cerebral lesions involving optic radiation. AB - BACKGROUND: Intraoperative magnetic resonance imaging (iMRI) combined with optic radiation neuronavigation may be safer for resection of cerebral lesions involving the optic radiation. OBJECTIVE: To investigate whether iMRI combined with optic radiation neuronavigation can help maximize tumor resection while protecting the patient's visual field. METHODS: Forty-four patients with cerebral tumors adjacent to the optic radiation were enrolled in the study. The reconstructed optic radiations were observed so that a reasonable surgical plan could be developed. During the surgery, microscope-based fiber tract neuronavigation was routinely implemented. The lesion location (lateral or not to the optic radiation) and course of the optic radiation (stretched or not) were categorized, and their relationships to the visual field defect were determined. RESULTS: Analysis of the visible relationship between the optic radiation and the lesion led to a change in surgical approach in 6 patients (14%). The mean tumor residual rate for glioma patients was 5.3% (n = 36) and 0% for patients with nonglioma lesions (n = 8). Intraoperative MRI and fiber tract neuronavigation increased the average size of resection (first and last iMRI scanning, 88.3% vs 95.7%; P < .01). Visual fields after surgery improved in 5 cases (11.4%), exhibited no change in 36 cases (81.8%), and were aggravated in 3 cases (6.8%). CONCLUSION: Diffusion tensor imaging information was helpful in surgical planning. When iMRI was combined with fiber tract neuronavigation, the resection rate of brain lesions involving the optic radiation was increased in most patients without harming the patients' visual fields. PMID- 21654537 TI - Multiple splenic artery aneurysms resulting in infarction of the spleen and regional portal hypertension. PMID- 21654539 TI - Statin use and the risk of pancreatic cancer: a population-based case-control study. AB - OBJECTIVES: The aim of this study was to investigate whether the use of statins was associated with pancreatic cancer risk. METHODS: We conducted a population based case-control study in Taiwan. Data were retrospectively collected from the Taiwan National health Insurance Research Database. Cases consisted of all patients who were 50 years or older and had a first-time diagnosis of pancreatic cancer for the period between 2003 and 2008. The control subjects were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multiple logistic regression. RESULTS: We examined 190 pancreatic cancer cases and 760 control subjects. The unadjusted OR for any statin prescription was 1.07 (95% CI, 0.72-2.06), and the adjusted OR was 0.87 (95% CI, 0.56-1.36). Compared with no use of statins, the adjusted ORs were 1.06 (95% CI, 0.61-1.85) for the group having been prescribed statins with cumulative defined daily doses less than 114.33 and 0.71 (95% CI, 0.39-1.30) for the group with cumulative statin use of 114.33 defined daily doses or more. CONCLUSIONS: This study does not provide support for a beneficial association between usage of statin and pancreatic cancer. PMID- 21654538 TI - Weight loss precedes cancer-specific symptoms in pancreatic cancer-associated diabetes mellitus. AB - OBJECTIVES: New-onset diabetes mellitus (DM) may herald pancreatic cancer (PaC). We determined whether changes in body weight distinguished PaC-associated DM (PaCDM) from type 2 DM. METHODS: Among Olmsted County residents, we identified 29 PaCDM and 43 type 2 DM subjects who had serial fasting blood glucose measurements, new-onset DM, and no cancer-specific symptoms at DM onset. We compared body weight (kg) and fasting blood glucose (mg/dL) at DM onset, 1 to 2 years before and at index date in the 2 groups. RESULTS: Fasting blood glucose values were similar before and at the onset of DM. Before onset of DM, PaCDM and type 2 DM subjects had similar body weight (P = 0.80). However, at onset of DM, 59% of PaCDM subjects lost weight versus 30% of type 2 DM subjects (P = 0.02). At onset of DM, 56% of type 2 DM subjects gained weight versus 31% of PaCDM subjects (P = 0.04). By index date, PaCDM subjects lost more weight than type 2 DM subjects did (8.3 +/- 8.3 vs 0.8 +/- 4.8 kg, P < 0.01). CONCLUSIONS: Although new onset primary type 2 DM is typically associated with weight gain, weight loss frequently precedes onset of PaCDM. The paradoxical development of diabetes in the face of ongoing weight loss may be an important clue to understanding the pathogenesis of PaCDM. PMID- 21654540 TI - Target-specific agents imaging ectopic and orthotopic human pancreatic cancer xenografts. AB - OBJECTIVES: This study aimed to develop target-specific binding agents for in vitro and in vivo imaging of human pancreatic cancer. METHODS: A monoclonal neutrophil gelatinase-associated lipocalin (NGAL)-specific antibody and a peptide specific for matrix metalloproteinase (MMP) were labeled with a near-infrared dye for in vitro and in vivo imaging studies. Fluorescence or confocal microscopy was used to determine antibody or peptide binding and internalization of agents into human AsPC-1, Panc-1, and MiaPaCa pancreatic cancer cell lines and in mice bearing ectopic or orthotopic pancreatic tumor transplants. RESULTS: Both the NGAL-specific antibody and MMP peptide bound to pancreatic cancer cells with high specificity; most NGAL-specific antibody localized to the cytosol. In vivo imaging results demonstrated high signal intensity of both agents bound to the tumor. The average tumortr-to-background ratio of antibody and peptide was 1.29 and 2.86, respectively. Signal was also detectable in the liver, kidneys, and bladder. CONCLUSIONS: Both NGAL-specific antibody and MMP peptide bound to cancer cells, and the labeled antibody was internalized. These results demonstrate that both agents can be used to enhance detection of human pancreatic cancer xenografts. However, the biodistribution patterns of these agents might limit their use in research and clinical practice. PMID- 21654542 TI - Sex-dependent effects of high-fat-diet feeding on rat pancreas oxidative stress. AB - OBJECTIVES: The objective of the study was to investigate whether sex differences in oxidative stress-associated insulin resistance previously reported in rats could be attributed to a possible sex dimorphism in pancreas redox status. METHODS: Fifteen-month-old male and female Wistar rats were fed a control diet or a high-fat diet for 14 weeks. Serum glucose, lipids, and hormone levels were measured. Insulin immunohistochemistry and morphometric analysis of islets were performed. Pancreas triglyceride content, oxidative damage, and antioxidant enzymatic activities were determined. Lipoprotein lipase, hormone-sensitive lipase, and uncoupling protein 2 (UCP2) levels were also measured. RESULTS: Male rats showed a more marked insulin resistance profile than females. In control female rats, pancreas Mn-superoxide dismutase activity and UCP2 levels were higher, and oxidative damage was lower compared with males. High-fat-diet feeding decreased pancreas triglyceride content in female rats and UCP2 levels in male rats. High-fat-diet female rats showed larger islets than both their control and sex counterparts. CONCLUSIONS: These results confirm the existence of a sex dimorphism in pancreas oxidative status in both control and high-fat-diet feeding situations, with female rats showing higher protection against oxidative stress, thus maintaining pancreatic function and contributing to a lower risk of insulin resistance. PMID- 21654541 TI - Aberrant expressions of AP-2alpha splice variants in pancreatic cancer. AB - OBJECTIVES: The present study was conducted to evaluate the expression and function of AP-2alpha isoforms in pancreatic ductal adenocarcinoma. METHODS: The expression of AP-2alpha was evaluated at the RNA level by reverse transcription polymerase chain reaction and at the protein level by Western blotting and immunofluorescence. Its function as a transcription factor was evaluated in transient transfection experiments: DNA binding properties by electromobility shift assay and transactivation capabilities by luciferase assay. RESULTS: Multiple alternative splicing events of AP-2alpha messenger occurred in all human pancreatic cancer cell lines, including a novel isoform, termed variant 6, which was not present in HeLa cells. At the protein level, except for 1 cell line, all pancreatic cancer cell lines expressed high nuclear levels of AP-2alpha. We also showed that AP-2alpha expressed by the pancreatic cancer cell lines could bind its cognate recognition site and activate transcription. However, variant 6, although not able to activate transcription, did not act in a dominant negative manner when cotransfected with the full-length protein. CONCLUSIONS: Multiple isoforms of AP-2alpha are highly expressed in pancreatic cancer cell lines including a new isoform, AP-2alpha variant 6, which seems to be pancreatic cancer specific and is deprived of transcriptional activity. PMID- 21654543 TI - Molecular basis of P2-receptor-mediated calcium signaling in activated pancreatic stellate cells. AB - OBJECTIVES: There is growing evidence that extracellular nucleotide-induced signaling confers to fibrogenesis in liver and pancreas. Pancreatic stellate cells (PSC) are the most important cell type in pancreatic fibrosis. P2 purine and pyrimidine receptors, again, are pivotal mediators of inflammatory and profibrogenic signals. Our aim was to elucidate the underlying signaling components in activated PSC. METHODS: We performed expression analysis of calcium ion (Ca(2+)) signaling components and monitored real-time intracellular Ca(2+) responses to nucleotides in rat PSC. RESULTS: Adenosine monophosphate, adenosine diphosphate, and adenosine-5'-triphosphate elicited detectable rises in intracellular Ca(2+) concentrations. Stimulation of PSC by ATP led to intracellular Ca signals mediated through both P2X and P2Y receptors. Whereas uridine triphosphate-mediated Ca(2+) signals were generated by activation of P2Y receptors only, uridine diphosphate stimulated P2X receptors as well. Of the phospholipase C (PLC)/inositol-1,4,5-trisphosphate pathway, all PLC-facilitating Galpha subunits were present in activated cells as were all 3 inositol-1,4,5 trisphosphate receptor isoforms. In addition, transcripts of PLC-beta and PLC delta isoforms were also strongly detectable. CONCLUSIONS: Activated PSC feature a plethora of elements from the Ca signaling toolkit and functionally express a subset of P2 nucleotide receptors. Purines and pyrimidines elicit robust intracellular Ca(2+) signals likely contributing to the fibrogenetic potential of these cells. PMID- 21654544 TI - The presence of IGHG1 in human pancreatic carcinomas is associated with immune evasion mechanisms. AB - OBJECTIVES: To investigate the expression of Iggamma-1 chain C region (IGHG1) in human pancreatic carcinomas and determine the biological function of IGHG1 expression in immune evasion mechanisms. METHODS: Comparative proteomic analysis was used to detect the differential expression of IGHG1 in human pancreatic cancer tissues versus adjacent noncancerous tissues, followed by confirmatory tests including quantitative real-time reverse transcription-polymerase chain reaction, Western blot analysis, immunohistochemistry, and immunofluorescence. A murine pancreatic tumor model was established by transplantation of IGHG1 overexpressing Panc02 cells. The cytotoxic responses of natural killer (NK) cells were assessed with a lactate dehydrogenase release assay. RESULTS: Iggamma-1 chain C region was found to be present in human pancreatic cancer tissues but nearly absent or expressed lower in adjacent noncancerous tissues. In the murine pancreatic tumor model, the tumor growth was significantly accelerated from day 12 to 20 after tumor injection, and the survival time of animals was decreased. Blockage of IGHG1 led to retarded tumor growth and improved survival. The cytotoxicity assay revealed that IGHG1 downregulated the cytotoxic activity of NK cells through inhibition of antibody-dependent cellular cytotoxicity function. CONCLUSIONS: The presence of IGHG1 in pancreatic cancer cells might constitute an important element responsible for tumor cell proliferation and immune evasion mechanisms. PMID- 21654545 TI - Estimation of physiologic ability and surgical stress score does not predict immediate outcome after pancreatic surgery. AB - OBJECTIVE: The Estimation of Physiologic Ability and Surgical Stress score was designed to predict postoperative morbidity and mortality in general surgery. Our study aims to evaluate its use and accuracy in estimating postoperative outcome after elective pancreatic surgery. METHODS: Between 2002 and 2007, approximately 304 patients requiring pancreatic resection at our institution were recorded prospectively and evaluated retrospectively. The patients' preoperative risk score, surgical stress score (SSS), and comprehensive risk score (CRS) were calculated and compared with the severity of postoperative morbidity, where mortality was regarded as the most severe postoperative complication. RESULTS: Observed and predicted mortality rates were 2.9% and 2.0%, respectively. Mean CRS was higher in patients who died than in patients that survived, but this difference was not statistically significant (P = 0.20). Preoperative risk score, SSS, and CRS did not differ between patients with and without complications (preoperative risk score: P = 0.32; SSS: P = 0.22; CRS: P = 0.13). Estimation of Physiologic Ability and Surgical Stress particularly underpredicted morbidity in patients with a CRS between 0.0 and less than 0.5. CONCLUSIONS: The Estimation of Physiologic Ability and Surgical Stress scoring system is an ineffective predictor of complications after pancreatic resection. Further refinements to the score calculation are warranted to provide accurate prediction of immediate surgical outcome after pancreatic surgery. PMID- 21654546 TI - Characteristics of Invasive Staphylococcus aureus in United Kingdom Neonatal Units. AB - BACKGROUND: In industrialized countries, Staphylococcus aureus (SA) is a leading cause of late-onset neonatal sepsis. METHODS: Culture-proven episodes were identified prospectively from neonatal units participating in the neonatal infection surveillance network. Demographic, risk factor, and outcome data were collected. RESULTS: Between 2004 and 2009, there were 117 episodes of SA infections (including 8 methicillin-resistant SA) in 116 infants from 13 units. The median gestational age and birth-weight were 27 weeks (90% <= 37 weeks, 85% <= 32 weeks) and 850 g (90% <= 2500 g), respectively. The overall incidence was 0.6 per 1000 live births and 23/1000 in infants <1500 g. Most episodes (94%) occurred more than 48 hours after birth (late onset). There were 7 early-onset episodes (< 48 hours) (median gestational age, 38.5 weeks), all due to methicillin-susceptible SA. At the time of culture, 67 of 95 (71%) infants were receiving respiratory support and 47 of 94 (50%) had a central line in situ. The majority of infants had nonspecific clinical features although evidence of focal infection (skin, soft tissue, bone, joint, or pneumonia) was ultimately seen in 41 of 91 (45%). There were 18 deaths, 4 (all late onset) directly due to methicillin-susceptible SA sepsis (4.4%). CONCLUSIONS: SA is the second most common pathogen causing late-onset neonatal infections in this neonatal network. Infants who weigh < 1500 g in intensive care settings are the most vulnerable group. Clinical signs are not sufficiently distinctive to allow targeted therapy, suggesting that an antistaphylococcal agent should be part of empiric therapy for late-onset sepsis in premature infants. PMID- 21654547 TI - Severe human herpesvirus 6-associated encephalopathy in three children: analysis of cytokine profiles and the carnitine palmitoyltransferase 2 gene. AB - Three children developed severe encephalopathy associated with human herpesvirus 6 infection. Magnetic resonance imaging of the brain showed either basal ganglia involvement or diffusion abnormalities in the cerebral white matter. Coagulopathy with hypercytokinemia was observed in 2 patients. One demonstrated thermolabile variation in carnitine palmitoyltransferase 2. These results suggest a heterogeneous pathogenic mechanism in encephalopathy associated with human herpesvirus 6 infection. PMID- 21654549 TI - Differential regulation of protein synthesis and mTOR signaling in skeletal muscle and visceral tissues of neonatal pigs after a meal. AB - Protein synthesis (PS) increases after a meal in neonates, but the time course of the changes in PS in different tissues after a meal is unknown. We aimed to evaluate the changes in tissue PS, mammalian target of rapamycin complex 1 (mTORC1) activation, and proportion of ribosomal protein (rp) mRNAs in polysomes over 4 h after a bolus meal in neonatal pigs (n = 6/group; 5- to 7-d-old). The results show a more sustained increase in PS in glycolytic compared with mixed fiber type muscles and no changes in oxidative muscles. PS increased in liver, jejunum, and pancreas but not in kidney and heart. Feeding did not affect AMP activated protein kinase or RAS-related GTP binding B activation. Phosphorylation of tuberous sclerosis complex 2, proline-rich Akt substrate of 40 kD, mTOR, eukaryotic initiation factor 4E binding protein, and rp S6 kinase 1 increased in all tissues after feeding. The proportion of mRNAs encoding rp S4 and S8 in liver polysomes increased within 30 min postfeeding. These results suggest that feeding stimulates mTORC1 signaling in muscle and viscera, but mTORC1 activation alone is not sufficient to stimulate PS in all tissues. PMID- 21654548 TI - The burden of invasive early-onset neonatal sepsis in the United States, 2005 2008. AB - BACKGROUND: Sepsis in the first 3 days of life is a leading cause of morbidity and mortality among infants. Group B Streptococcus (GBS), historically the primary cause of early-onset sepsis (EOS), has declined through widespread use of intrapartum chemoprophylaxis. We estimated the national burden of invasive EOS cases and deaths in the era of GBS prevention. METHODS: Population-based surveillance for invasive EOS was conducted in 4 of the Centers for Disease Control and Prevention's Active Bacterial Core surveillance sites from 2005 to 2008. We calculated incidence using state and national live birth files. Estimates of the national number of cases and deaths were calculated, standardizing by race and gestational age. RESULTS: Active Bacterial Core surveillance identified 658 cases of EOS; 72 (10.9%) were fatal. Overall incidence remained stable during the 3 years (2005: 0.77 cases/1000 live births; 2008: 0.76 cases/1000 live births). GBS (~ 38%) was the most commonly reported pathogen followed by Escherichia coli (~ 24%). Black preterm infants had the highest incidence (5.14 cases/1000 live births) and case fatality (24.4%). Nonblack term infants had the lowest incidence (0.40 cases/1000 live births) and case fatality (1.6%). The estimated national annual burden of EOS was approximately 3320 cases (95% confidence interval [CI]: 3060-3580), including 390 deaths (95% CI: 300-490). Among preterm infants, 1570 cases (95% CI: 1400-1770; 47.3% of the overall) and 360 deaths (95% CI: 280-460; 92.3% of the overall) occurred annually. CONCLUSIONS: The burden of invasive EOS remains substantial in the era of GBS prevention and disproportionately affects preterm and black infants. Identification of strategies to prevent preterm births is needed to reduce the neonatal sepsis burden. PMID- 21654550 TI - Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia-ischemia in newborn pigs. AB - Newborn piglets exposed to acute hypoxia-ischemia (HI) received i.v. cannabidiol (HI + CBD) or vehicle (HI + VEH). In HI + VEH, 72 h post-HI brain activity as assessed by amplitude-integrated EEG (aEEG) had only recovered to 42 +/- 9% of baseline, near-infrared spectroscopy (NIRS) parameters remained lower than normal, and neurobehavioral performance was abnormal (27.8 +/- 2.3 points, normal 36). In the brain, there were fewer normal and more pyknotic neurons, while astrocytes were less numerous and swollen. Cerebrospinal fluid concentration of neuronal-specific enolase (NSE) and S100beta protein and brain tissue percentage of TNFalpha(+) cells were all higher. In contrast, in HI + CBD, aEEG had recovered to 86 +/- 5%, NIRS parameters increased, and the neurobehavioral score normalized (34.3 +/- 1.4 points). HI induced histological changes, and NSE and S100beta concentration and TNFalpha(+) cell increases were suppressed by CBD. In conclusion, post-HI administration of CBD protects neurons and astrocytes, leading to histological, functional, biochemical, and neurobehavioral improvements. PMID- 21654551 TI - Optical detection of the brachial plexus for peripheral nerve blocks: an in vivo swine study. AB - BACKGROUND AND OBJECTIVES: Accurate identification of nerves is critical to ensure safe and effective delivery of regional anesthesia during peripheral nerve blocks. Nerve stimulation is commonly used, but it is not perfect. Even when nerve stimulation is performed in conjunction with ultrasound guidance, determining when the needle tip is at the nerve target region can be challenging. In this in vivo pilot study, we investigated whether close proximity to the brachial plexus and penetration of the axillary artery can be identified with optical reflectance spectroscopy, using a custom needle stylet with integrated optical fibers. METHODS: Ultrasound-guided insertions to place the needle tip near the brachial plexus at the axillary level were performed at multiple locations in 2 swine, with the stylet positioned in the cannula of a 20-gauge stimulation needle. During each insertion, optical reflectance spectra were acquired with the needle tip in skeletal muscle, at the surface of muscle fascia, and at the nerve target region; confirmation of the final needle position was provided by nerve stimulation. In addition, an insertion to the lumen of the axillary artery was performed in a third swine. Differences in the spectra were quantified with lipid and hemoglobin parameters that provide contrast for optical absorption by the respective chromophores. RESULTS: The transition of the needle tip from skeletal muscle to the nerve target region was associated with higher lipid parameter values (P < 0.001) and lower hemoglobin parameter values (P < 0.001). The transition of the needle tip from muscle fascia to the nerve target region was associated with higher lipid parameter values (P = 0.001). Intraluminal access of the axillary artery was associated with an elevated hemoglobin parameter. CONCLUSIONS: Spectroscopic information obtained with the optical needle is distinct from nerve stimulation and complementary to ultrasound imaging, and it could potentially allow for reliable identification of the injection site during peripheral nerve blocks. PMID- 21654552 TI - Suprascapular nerve block: a narrative review. AB - Suprascapular nerve blockade (SSNB) is a simple and safe technique for providing relief from various types of shoulder pain, including rheumatologic disorders, cancer, and trauma pain, and postoperative pain due to shoulder arthroscopy. Posterior, superior, and anterior approaches may be used, the most common being the posterior. Recently, an ultrasound-guided approach has been described. In this review, the basic anatomy of the suprascapular nerve will be described. The different techniques of SSNB and indications for SSNB will be discussed. The complications of SSNB and outcomes of SSNB on the management of acute and chronic shoulder pain will be reviewed. PMID- 21654553 TI - Developing effective web-based regional anesthesia education: a randomized study evaluating case-based versus non-case-based module design. AB - BACKGROUND AND OBJECTIVES: Little is known about the use of Web-based education in regional anesthesia training. Benefits of Web-based education include the ability to standardize learning material quality and content, build appropriate learning progressions, use interactive multimedia technologies, and individualize delivery of course materials. The goals of this investigation were (1) to determine whether module design influences regional anesthesia knowledge acquisition, (2) to characterize learner preference patterns among anesthesia residents, and (3) to determine whether learner preferences play a role in knowledge acquisition. Direct comparison of knowledge assessments, learning styles, and learner preferences will be made between an interactive case-based and a traditional textbook-style module design. METHODS: Forty-three Mayo Clinic anesthesiology residents completed 2 online modules, a knowledge pretest, posttest, an Index of Learning Styles assessment, and a participant satisfaction survey. Interscalene and lumbar plexus regional techniques were selected as the learning content for 4 Web modules constructed using the Blackboard Vista coursework application. One traditional textbook-style module and 1 interactive case-based module were designed for each of the interscalene and lumbar plexus techniques. RESULTS: Participants scored higher on the postmodule knowledge assessment for both of the interscalene and lumbar plexus modules. Postmodule knowledge performance scores were independent of both module design (interactive case-based versus traditional textbook style) and learning style preferences. However, nearly all participants reported a preference for Web-based learning and believe that it should be used in anesthesia resident education. Participants did not feel that Web-base learning should replace the current lecture-based curriculum. CONCLUSIONS: All residents scored higher on the postmodule knowledge assessment, but this improvement was independent of the module design and individual learning styles. Although residents believe that online learning should be used in anesthesia training, the results of this study do not demonstrate improved learning or justify the time and expense of developing complex case-based training modules. While there may be practical benefits of Web based education, educators in regional anesthesia should be cautious about developing curricula based on learner preference data. PMID- 21654554 TI - Postsurgical inflammatory neuropathy. AB - OBJECTIVE: Perioperative nerve injuries are devastating complications that are commonly attributed to a variety of patient, surgical, or anesthetic factors. Well-documented causes of postsurgical neuropathy include nerve compression, stretch, contusion, or transection, which can occur following surgical trauma or patient positioning. Potential anesthetic causes of perioperative nerve injury include mechanical trauma, local anesthetic toxicity, and ischemic injury. We present a case of a diffuse, bilateral neurologic deficit of unclear etiology in a patient who underwent a combined neuraxial-general anesthetic for bilateral total hip arthroplasty. CASE REPORT: A 17-year old boy with end-stage Legg Perthes disease presented with severe lower-extremity neuropathy of both legs following bilateral total hip arthroplasty under combined epidural-general anesthesia. A thorough workup excluded potentially devastating and treatable causes, including epidural hematoma or abscess and surgical bleeding or trauma. A neurology consultation and further testing (electromyography, nerve biopsy) resulted in a diagnosis of postsurgical inflammatory neuropathy. Treatment with prolonged, high-dose corticosteroids was undertaken, and although the patient's symptoms improved, he continues to have significant neurologic deficits 8 months after surgery. CONCLUSIONS: Perioperative nerve deficits not readily explained by direct surgical or anesthesia-related causes should prompt early neurologic consultation to seek alternative etiologies such as postsurgical inflammatory neuropathy. Although this condition is poorly understood, it is believed to be an idiopathic immune-mediated response to a physiologic stress (eg, surgery, regional block) and is treated with prolonged, high-dose corticosteroids. Because suppression of the immune system with high-dose steroids may result in improved neurologic outcome, it is essential that surgeons and anesthesiologists are aware of this condition so that treatment is not delayed. PMID- 21654555 TI - Do diagnostic blocks have beneficial effects on pain processing? AB - BACKGROUND AND OBJECTIVES: Diagnostic blocks of cervical zygapophysial joints have been used as part of the management strategy for patients with chronic neck pain. Little information is available regarding the sensory processing changes that occur after these common procedures. In a hypothesis-generating prospective study, the pressure-pain thresholds, electrical pain thresholds, and descending inhibitory modulation response using the conditioned pain modulation paradigm are described for 9 patients with cervical zygapophysial joint pain that underwent successful comparative diagnostic blocks. METHODS: The study was designed as a prospective cross-sectional study in 9 patients with cervical zygapophysial joint pain with positive comparative diagnostic blocks using lidocaine and bupivacaine. Each patient underwent baseline Quantitative Sensory Testing (QST) measurement (QST 1) after inclusion. Subsequent QST measurements (QST 2 and 3) were performed only after comparative blocks proved positive and only after the neck pain returned after each diagnostic block. RESULTS: Despite the return of their neck pain after the local anesthetic agents wore off, the patients exhibited (1) less focal pressure hyperalgesia, (2) generalized electrical hypoalgesia, and (3) significantly reduced conditioned pain modulation responses. CONCLUSIONS: Our preliminary evidence suggests that the perturbations to the sensory processing system from effective diagnostic blocks affect the tonic inhibitory system in a positive manner. Conditioned pain modulation, however, needs to be interpreted in the context of altered pain thresholds, and future studies should aim to investigate the shift in the nociceptive balance between facilitatory and inhibitory control after therapeutic interventions. PMID- 21654556 TI - GITR gene deletion and GITR-FC soluble protein administration inhibit multiple organ failure induced by zymosan. AB - Multiple organ dysfunction syndrome (MODS) is a systemic inflammatory event that can result in organ damage, failure, and high risk of mortality. The aim of this study was to evaluate the possible role of glucocorticoid-induced TNFR-related (GITR) on zymosan-induced MODS. Mice were allocated into one GITR knockout (GITR KO) and two GITR wild-type (GITR-WT) experimental groups. All the animals were treated with zymosan (500 mg/kg, suspended in saline solution, i.p.), and animals of one GITR-WT group received GITR-Fc (6.25 MUg/mouse; 3 h after zymosan injection) by mini-osmotic pump. Moreover, three control groups were performed (one GITR-KO and two GITR-WT experimental groups), administering saline instead of zymosan and treating one of the GITR-WT group with GITR-Fc (6.25 MUg/mouse; 3 h after saline injection) by mini-osmotic pump. A number of inflammatory parameters such as edema formation, histological damage, adhesion molecules expression, neutrophil infiltration, proinflammatory cytokines, nitrotyrosine, and iNOS production are significantly reduced in GITR-KO as compared with GITR-WT mice as well as in GITR-WT mice treated with GITR-Fc. We here show that GITR plays a role in the modulation of experimental MODS. In particular, we show that genetic inhibition of GITR expression, in GITR-KO mice, or administration of soluble GITR-Fc receptor in GITR-WT mice, reduces inflammation, organ tissue damage, and mortality. Results, while confirming the proinflammatory role of GITR, extend our observations indicating that GITR plays a role in zymosan induced inflammation and MODS. PMID- 21654557 TI - Polymyxin B-immobilized fiber column hemoperfusion therapy for septic shock. AB - Endotoxin, an outer membrane component of gram-negative bacteria, plays an important role in the pathogenesis of septic shock. Endotoxin adsorption therapy by polymyxin B-immobilized fiber column hemoperfusion (PMX) has been used for the treatment of septic shock patients in Japan since 1994. The covalent binding of polymyxin B onto the surface of the polystyrene-based carrier fiber in PMX inactivates the endotoxin in the blood without exerting toxicity. This study was performed as a systematic review to evaluate the efficacy and mechanism of PMX treatment in patients with septic shock. The PubMed database and references from identified articles were used to search and review the literature relating to the efficacy and mechanism of PMX treatment in patients with septic shock. Polymyxin B-immobilized fiber column hemoperfusion adsorbed monocytes, activated neutrophils, and anandamide, as well as endotoxin through direct covalent bond, hydrophobic and ionic interactions, and hydrodynamics, and reduced the blood concentrations of inflammatory cytokines, plasminogen activator inhibitor 1 and adhesion molecules. Polymyxin B-immobilized fiber column hemoperfusion increased blood pressure and reduced the dosage requirements for vasopressive/inotropic agents. The meta-analysis showed that PMX treatment had beneficial effects on the hemodynamics, pulmonary oxygenation, and mortality. These beneficial effects may be attributable to the direct adsorption of endotoxin, monocytes, activated neutrophils, and anandamide, as well as indirect decrease in inflammatory cytokines and other mediators. Polymyxin B-immobilized fiber column hemoperfusion treatment has additional effects on reducing endothelial damage, proapoptotic activity, and immunosuppression. Further studies will be needed to confirm the efficacy and mechanism of PMX treatment in septic shock. PMID- 21654558 TI - Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia. AB - Mesenchymal stem cells (MSCs) possess immunomodulatory properties and may curtail the inflammatory response that characterizes sepsis and other systemic inflammatory states. We aimed to determine whether intravenous infusion of MSCs is associated with reduced inflammation and improved myocardial function in a rat model of endotoxemia. Adult Sprague-Dawley rats were administered saline (vehicle) or LPS (5 mg/kg) via tail vein injection. Treatments, either vehicle or 2 * 10(6) MSCs, were infused 1 h later via tail vein. Animals were randomly assigned to the following groups: (a) vehicle + vehicle (control; n = 6), (b) LPS + vehicle (n = 6), or (c) LPS + MSCs (n = 6). Six hours after induction of endotoxemia, left ventricular ejection fraction (EF) and fractional shortening (FS) was assessed via parasternal short-axis M-mode echocardiography. Hearts and serum were collected for determination of cytokine levels via enzyme-linked immunosorbent assay. Animals injected with LPS + vehicle exhibited depressed cardiac function as indicated by a 26% and 37% reduction in EF and FS from baseline, respectively. Treatment with MSCs was associated with improved cardiac function compared with vehicle treatment as indicated by a reduction in EF and FS of only 10% and 17%, respectively (P < 0.05). Myocardial levels of TNF-alpha, IL 1beta, and IL-6 were elevated in LPS-treated animals versus control. Similarly, serum levels of IL-1beta, IL-6, and IL-10 were increased in LPS-treated animals. Treatment with MSCs, however, was associated with significant reductions in serum levels of IL-1beta and IL-6 and in myocardial levels of TNF-alpha, IL-1beta, and IL-6. In addition, treatment with MSCs was associated with a further increase in serum IL-10. Infusion of MSCs modulates the systemic inflammatory response and is associated with improved cardiac function during endotoxemia. PMID- 21654559 TI - Vascular and extravascular volume expansion of dobutamine and norepinephrine in normovolemic sheep. AB - In low-flow states, such as circulatory shock, both fluids and catecholamines are often coadministered. We have previously found that adrenergic agents alter volume expansion after a fluid bolus. The present study tested the volume expansion properties of dobutamine and norepinephrine in sheep treated with (series 1) and without (series 2) a fluid bolus. Series 1 (n = 6 per group): no drug (control), dobutamine (10 MUg x kg(-1) x min), or norepinephrine (1.0 MUg x kg(-1) x min(-1)) was begun 30 min before a 24-mL x kg(-1), 20-min, 0.9% NaCl bolus. The effect of drug and fluid on plasma volume (DeltaPV), urinary output (UOP), and extravascular volume (DeltaEVV) was determined. Series 2: Identical protocol but no fluid bolus. Series 1: the fluid bolus resulted in a peak and sustained DeltaPV expansion. Norepinephrine (7.5 +/- 0.9 mL x kg(-1)) and dobutamine (9.5 +/- 1.1 mL x kg(-1)) significantly increased DeltaPV compared with control (3.8 +/- 1.1 mL x kg(-1)). Cumulative UOP was reduced by dobutamine (3.8 +/- 1.4 mL x kg) compared with norepinephrine (25.1 +/- 3.9 mL x kg(-1)) and control (16.9 +/- 4.0 mL x kg(-1)). Norepinephrine increased DeltaPV, while reducing DeltaEVV after bolus. Series 2: DeltaPV was unchanged in the control group. Dobutamine and norepinephrine increased DeltaPV over time, 5.1 +/- 0.5 and 4.0 +/- 0.5 mL x kg(-1), respectively. At study end, UOP was lowest in dobutamine. Norepinephrine resulted in loss of DeltaEVV fluid. data suggest a novel role for adrenergic receptors in regulating vascular and EVV expansion. beta-Adrenergic agonists enhance vascular volume expansion, whereas alpha adrenergic agonists eliminate extravascular fluid. PMID- 21654560 TI - Intraventricular hemorrhage secondary to intranidal aneurysm rupture-successful management by arteriovenous malformation embolization followed by intraventricular tissue plasminogen activator: case report. AB - BACKGROUND AND IMPORTANCE: Intraventricular hemorrhage related to arteriovenous malformation (AVM) rupture is associated with significant morbidity and mortality. Intraventricular tissue plasminogen activator (tPA) has been used to treat spontaneous intraventricular hemorrhage. We demonstrate the successful application of endovascular occlusion to seal the rupture site of an AVM followed by intraventricular tPA. CLINICAL PRESENTATION: A 32-year-old woman presented with a right frontoparietal parasagittal AVM abutting the motor cortex. The AVM was diagnosed when the patient was 13 years old, and she initially underwent conservative management. At the age of 30, the patient suffered an intracranial hemorrhage, leaving her with left hemiparesis. After rehabilitation, the patient regained ambulation; however, she remained spastic and hyperreflexic on the left side. Two years after her major hemorrhage, she presented for elective treatment of her AVM. The patient was advised to undergo staged embolization before surgical resection of her AVM. The initial embolization was uneventful. A second embolization was complicated by intraventricular hemorrhage and coma. The patient was treated with placement of an external ventricular drain followed by embolization of intranidal aneurysm. After embolization of the intranidal aneurysm the ruptured, the patient was treated with intraventricular tPA. The patient had rapid clearance of the intraventricular hemorrhage and significant improvement in her neurological examination, following commands 24 hours later and returning almost to baseline. CONCLUSION: This case demonstrates the feasibility of treating AVM-related intraventricular hemorrhage with tPA if the rupture source can be confidently sealed interventionally. This strategy can be lifesaving but needs further study to ensure its safety. PMID- 21654562 TI - Surgical approach and safety of spinal cord stem cell transplantation. PMID- 21654567 TI - Neuromodulation of the locus coeruleus: a key to controlling wakefulness. PMID- 21654568 TI - Red light, green light: start/stop signals in nigrostriatal circuits. PMID- 21654569 TI - Is it time to abandon warfarin and embrace oral direct thrombin inhibitors to prevent stroke in patients with atrial fibrillation? PMID- 21654570 TI - Insights into pediatric concussions from a novel repeat traumatic brain injury mouse model. PMID- 21654571 TI - Physician employment: it will work this time. PMID- 21654572 TI - Better early than never: vertebroplasty for acute compression fractures effective. PMID- 21654573 TI - Epidermal growth factor receptor vaccination for glioblastoma multiforme. PMID- 21654575 TI - Advances in the treatment and outcome of brainstem cavernous malformation surgery: a single-center case series of 300 surgically treated patients. AB - BACKGROUND: Brainstem cavernous malformations (BSCMs) are relatively uncommon, low-flow vascular lesions. Because of their relative rarity, relatively little data on their natural history and on the efficacy and durability of their treatment. OBJECTIVE: To evaluate the long-term durability of surgical treatment of BSCMs and to document patient outcomes and clinical complications. METHODS: The charts of all patients undergoing surgical treatment of BSCM between 1985 and 2009 were reviewed retrospectively. The study population consisted of 300 patients who had surgery for BSCM. Forty patients were under 19 years of age at surgery; pediatric BSCMs have been reported separately. Patient demographics, lesion characteristics, surgical approaches, and patient outcomes were examined. RESULTS: The study population consisted of 260 adult patients with a female-to male ratio of 1.5 and mean age of 41.8 years. Of the 260 patients, 252 presented with a clinical or radiographic history of hemorrhage. The mean follow-up in 240 patients was 51 months. The mean Glasgow Outcome Scale on admission, at discharge, and at last follow-up was 4.4, 4.2, and 4.6. Postoperatively, 137 patients (53%) developed new or worsening neurological symptoms. Permanent new deficits remained in 93 patients 3(36%). There were perioperative complications in 74 patients (28%); tracheostomy, feeding tube placement, and cerebrospinal fluid leakage were most common. Eighteen patients (6.9%) experienced 20 rehemorrhages. Twelve patients required reoperation for residual/recurrent BSCM. The overall annual risk of postoperative rehemorrhage was 2%/patient. CONCLUSION: Although BSCM surgery has significant associated risks, including perioperative complications, new neurological deficits, and death, most patients have favorable outcomes. Overall, surgery markedly improved the risk of rehemorrhage and related symptoms and should be considered in patients with accessible lesions. PMID- 21654576 TI - Synthetic routes and biological evaluation of largazole and its analogues as potent histone deacetylase inhibitors. AB - Natural products with interesting biological properties and structural diversity have often served as valuable lead drug candidates for the treatment of various human diseases. Largazole, isolated from the marine cyanobacterium Symploca sp. has exhibited potent inhibitory activity against many cancer cell lines. Besides, it shows remarkable selectivity between transformed and nontransformed cells, which is the main disadvantage of other antitumor natural products such as paclitaxel and actinomycin D. Due to its potential as a potent and selective anticancer drug candidate, a great deal of attention has been focused on largazole and its analogues. It is the aim of this review to highlight synthetic aspects of largazole and its analogues as well as their preliminary structure activity relationship studies. PMID- 21654577 TI - The 2-(triphenylsilyl)ethoxycarbonyl-("Tpseoc"-) group: a new silicon-based, fluoride cleavable oxycarbonyl protecting group highly orthogonal to the Boc-, Fmoc- and Cbz-groups. AB - Starting from 2-(triphenylsilyl)ethanol a new oxycarbonyl protecting group cleavable by fluoride ion induced Peterson-elimination has been developed. Known 2-(triphenylsilyl)ethanol has been prepared from commercially available triphenylvinyl-silane by a hydroboration-oxidation sequence using the sterically hindered borane reagent 9-BBN. The silyl alcohol was subsequently transformed into its chloroformate, imidazolylcarboxylic acid ester and p-nitrophenyl carbonate and used in standard protocols for the formation of carbamates and carbonates. The Tpseoc group proved to be highly resistant against acidic conditions applied in removal of tert-butyl esters and the t-Boc-group. It also withstood catalytic hydrogenation, treatment with morpholine, methylhydrazine and Pd-reagents/allyl-scavanger combinations, conditions required to cleave Cbz-, Fmoc-, phthalimide- and Alloc-groups. The Tpseoc-group is cleaved upon treatment with TBAF/CsF at 0 degrees C or r.t. with cleavage times reaching from. PMID- 21654578 TI - Monasnicotinates A-D, four new pyridine alkaloids from the fungal strain Monascus pilosus BCRC 38093. AB - Four new pyridine derivatives, monasnicotinates A-D (1-4) were isolated from the red yeast rice of Monascus pilosus BCRC 38093. Their structures were elucidated on the basis of physicochemical evidence, in-depth NMR spectroscopic analysis, and high-resolution mass spectrometry. Their inhibitory effects on NO production was also evaluated. PMID- 21654579 TI - Antioxidant capacity and phenolic content of Caesalpinia pyramidalis Tul. and Sapium glandulosum (L.) Morong from Northeastern Brazil. AB - The aims of this study were to quantify the phenolic content and evaluate the antioxidant potential of extracts from the bark and leaves of C. pyramidalis and S. glandulosum. The total phenolic content (TPC) and total tannin content (TTC) were determined using the Folin-Ciocalteu method, and the total flavonoids content (TFC) was measured via complexation with aluminum chloride. The antioxidant activity was evaluated with DPPH (2.2-diphenyl-1-picrylhydrazyl) and FIC (ferrous ion chelating) assays. The TPC ranged between 135.55 +/- 9.85 and 459.79 +/- 11.65 tannic acid equivalents (TAE) in mg/g material (mg TAE/g). The leaves of both species contained high levels of tannins and flavonoids. The crude ethanol extracts (CEE) from the bark of C. pyramidalis showed high antioxidant activity when compared to ascorbic acid and rutin, whereas the CEE from the leaves was more efficient in chelating ferrous ions. C. pyramidalis had very high phenolic content and anti-radical activity, which indicates a need for further studies aimed at the purification and identification of compounds responsible for the antioxidant activity. PMID- 21654580 TI - Design and synthesis of a dual linker for solid phase synthesis of oleanolic acid derivatives. AB - A hydrophilic amino-terminated poly(ethylene glycol)-type dual linker for solid phase synthesis of oleanolic acid derivatives using trityl chloride resin was designed and synthesized for the first time. Model reactions in both liquid and solid phase were performed to show the feasibility of its selective cleavage at two different sites. The biological assay results indicated that the long and flexible alkyl ether functionality in the linker is less likely to be critical for the binding event. Following the successful solid-phase synthesis of model compounds, the potential of this dual linker in reaction monitoring and target identification is deemed worthy of further study. PMID- 21654581 TI - Synthesis and antimicrobial activity of some novel 5-alkyl-6-substituted uracils and related derivatives. AB - 6-chloro-5-ethyl-, n-propyl- and isopropyluracils 5a-c were efficiently prepared from the corresponding 5-alkybarbituric acids 3a-c via treatment with phosphorus oxychloride and N,N-dimethylaniline to yield the corresponding 5-alkyl-2,4,6 trichloro-pyrimidines 4a-c, which were selectively hydrolyzed by heating in 10% aqueous sodium hydroxide for 30 minutes. The reaction of compounds 5a-c with 1 substituted piperazines yielded the corresponding 5-alkyl-6-(4-substituted-1 piperazinyl)uracils 6a-j. The target 8-alkyltetrazolo[1,5-f]pyrimidine-5,7(3H,6H) diones 7a-c were prepared via the reaction of 5a-c with sodium azide. Compounds 6a-j and 7a-c were tested for in vitro activities against a panel of Gram positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compound 6h displayed potent broad-spectrum antibacterial activity, while compound 6b showed moderate activity against the Gram-positive bacteria. All the tested compounds were practically inactive against Candida albicans. PMID- 21654582 TI - Biologically important eremophilane sesquiterpenes from alaska cedar heartwood essential oil and their semi-synthetic derivatives. AB - The essential oil of Alaska cedar heartwood is known to contain compounds which contribute to the remarkable durability of this species. While previous research has identified several compounds, a complete description of this oil has not been undertaken. In this research a profile of the oil is given in which the major components are identified by GC, isolation and spectroscopic techniques. The major components of the steam distilled essential oil were identified as nootkatin, nootkatone, valencene, nootaktene, carvacrol, methyl carvacrol, nootkatol (2), and eremophil-1(10),11-dien-13-ol (3). The last two compounds were isolated for the first time from Alaska cedar in this research. The absolute stereochemistry at C-2 of nootkatol was shown to have the (S) configuration using the Mosher ester method. Assignment of stereochemistry for valencene-13-ol (3) was established by synthesis from valencene (6). Finally, two related sesquiterpenoids were synthesized from nootkatone and valencene. These sesquiterpenoids were nootkatone-1,10-11,12-diepoxide (5) and valencene-13 aldehyde (4), respectively. PMID- 21654583 TI - Global complacency in the face of HIV/AIDS: the worst infection. PMID- 21654584 TI - Cuba's national HIV/AIDS program. PMID- 21654585 TI - HIV detection in Cuba: role and results of the National Laboratory Network. PMID- 21654586 TI - The human dimension of AIDS in Cuba: Jorge Perez MD MS, Director, Pedro Kouri Tropical Medicine Institute. Interviewed by Gail Reed. AB - Except for the people living with the disease, no others have so immersed themselves in Cuba's world of HIV/AIDS as Dr Jorge Perez. It is a world of Cuban returnees from Angola's war against apartheid South Africa, gay and bisexual men, housewives, transactional sex workers, rebellious teenagers, and infected surgeons and scientists-a cultural kaleidoscope reflecting all the faces of AIDS. To more than one international author, he is simply "Cuba's AIDS doctor." Speaking to his patients at the Pedro Kouri Tropical Medicine Institute in Havana, it is easy to see why, but also to appreciate the courage, compassion, and persistent search for new knowledge that characterize the Institute's staff as a whole. Dr Perez's story-now told in two books based on his diaries-is not his alone. MEDICC Review held two interview sessions with Jorge Perez just days apart at the beginning of April: one before and one after his designation as the new Director of the Tropical Medicine Institute, where he previously served as Deputy Director and Chief of Hospital Services. More than strictly medical matters, the conversation turned to the human dimension of HIV/AIDS, the depth to which it has touched many directly and affected Cuban society as a whole, and the challenges ahead for Cuba's flagship institution for research and treatment of infectious diseases. PMID- 21654587 TI - Antiretroviral therapy adherence in persons with HIV/AIDS in Cuba. AB - INTRODUCTION Cuba has an HIV prevalence of 0.1% in the population aged 15 to 49 years, very low despite increased incidence in recent years. In 2001, domestically-produced generic antiretroviral therapy was introduced and there has been complete coverage since 2003. In 2006, 1986 people with HIV/AIDS were receiving ART; by 2009, that figure reached 5034. Adherence to antiretroviral therapy is fundamental: nonadherence leads to treatment failure, development of resistance, progression to AIDS, and death. OBJECTIVE Measure levels of treatment adherence and its predictive factors in persons with HIV/AIDS receiving antiretroviral therapy in 2006 in Cuba. METHODS A cross-sectional study was carried out in 2006 of Cuban HIV-positive individuals receiving antiretroviral therapy. A sample size of 876 was calculated using two-stage sampling (first by strata, and then by simple random sampling in each stratum). An anonymous structured questionnaire was administered to participants. Reporting of doses taken on each of the three days and in the week preceding the survey was recoded into five categories. Participants were considered highly adherent if they reported taking >=95.0% of their medication as prescribed. Reasons for nonadherence were described and logistic regression modeling used to develop hypotheses on associations between high adherence and its predictive factors. RESULTS Interviews were obtained with 847 individuals, 70.6% of whom self reported high adherence. There were no significant differences between highly adherent and less adherent patients with regard to sex, place of residence, treatment setting, time of diagnosis, or length of treatment. Variables associated with high adherence were communication with the specialist physician, change in treatment, memory, self-efficacy, as well as commitment to and opinions about treatment. CONCLUSIONS In Cuba, where treatment is free of charge to patients, adherence is good. Treatment adherence might be improved by achieving a closer doctor-patient relationship; taking measures to motivate patients and promote self-efficacy and commitment to treatment; publicizing treatment outcomes; and providing assistance to patients to help them remember their medication schedule. Further studies are required to determine current adherence levels; and longitudinal research to determine adherence over time. PMID- 21654588 TI - Drug-resistant HIV-1 in Cuban children and their seropositive mothers. AB - INTRODUCTION The use of highly active antiretroviral therapy has reduced progression to AIDS and increased survival among seropositive persons; yet, appearance of resistant viruses may jeopardize these benefits. In Cuba, HIV mainly affects adults; at the end of 2009 of the 41 children infected, 25 were still alive; of these, 22 were under antiretroviral treatment. Until now, nothing was known about HIV-1 antiviral resistance and viral subtypes in the pediatric population in Cuba. OBJECTIVE This study aims to identify presence of antiretroviral-resistant HIV-1 strains in Cuban children and their mothers, and to provide a phylogenetic characterization and comparison of pol gene sequences in the same. METHODS Plasma samples were collected from 22 children and their mothers, all HIV-1-infected, from 2004 through 2009. Reverse transcription polymerase chain reaction was used to amplify the pol gene fragment coding for HIV protease and reverse transcriptase enzymes; this was then sequenced and subjected to phylogenetic analysis of HIV subtypes and recombinant forms to compare sequences between mothers and children. HIV mutations conferring antiretroviral resistance were determined. RESULTS Viral amplification was achieved in samples from 11 children and 8 mothers. Subtypes detected were: CRF19_cpx in five children, subtype B in three, CRF18_cpx in two, and subtype C in one child. In all mother-child pairs, samples were grouped within the same viral subtype in the phylogenetic tree. One mother was under treatment and five children had been treated before the sample was collected. In viruses amplified from samples of children under treatment, resistance was most frequently found to lamivudine (3 cases) and nevirapine (4 cases). Two untreated children carried resistant viruses possibly acquired from their mothers. CONCLUSIONS This is the first study to describe HIV-1 antiviral resistance in the pediatric population in Cuba; it also identified viral subtypes infecting the mother-child pairs studied. We recommend antiretroviral resistance assays before initiating treatment in pregnant seropositive women and their newborns. PMID- 21654589 TI - Occult hepatitis B in Cuban HIV patients. AB - INTRODUCTION Co-infections between hepatitis B and HIV viruses are frequent due to their similar epidemiological characteristics. Worldwide, hepatitis B infection is one of the main causes of hepatocellular carcinoma and cirrhosis. In Cuba as elsewhere, prevalences of hepatitis B and hepatitis C viral infections are higher in persons with HIV. These hepatitis viruses act as opportunistic infections in persons with HIV. In other contexts, persons with HIV have been found to be at higher risk for occult hepatitis B, defined as the presence in serum or plasma of hepatitis B virus DNA and antibodies to its core antigen, in the absence of hepatitis B surface antigen. OBJECTIVES Describe occult hepatitis B prevalence in Cuban HIV-positive patients and explore possible associations with their clinical characteristics. METHODS A total of 325 serum samples from patients positive for HIV and negative for hepatitis B surface antigen were studied, divided into two groups, Group 1, negative for hepatitis C virus; and Group 2, positive for hepatitis C virus. Exposure to hepatitis B was determined by testing for hepatitis B core antigen; samples positive for hepatitis B core antigen were then examined for presence of antibodies to hepatitis B surface antigen. Both determinations were done by ultramicroELISA. In samples positive for hepatitis B core antigen with levels of antibodies to hepatitis B surface antigen of <50 IU/L, real-time polymerase chain reaction was used to detect hepatitis B DNA and its presence examined in relation to several clinical variables. All data were obtained from patients' clinical records. RESULTS In the hepatitis-C-negative group, 27.9% (68/243) of serum samples tested were positive for hepatitis B core antigen. In the hepatitis-C-positive group, 37.8% (31/82) were positive for hepatitis B core antigen. Total hepatitis B virus exposure prevalence was 30.4% (99/325); 54.5% (54/99) showing low immunity (hepatitis B virus surface antigen <50 IU/L) and 24% of these (13/54), occult hepatitis. There was no statistically significant association between hepatitis B virus DNA and any of the clinical variables studied. CONCLUSIONS Low-immunity HIV-positive persons in our study were exposed to hepatitis B virus. Diagnosis of occult hepatitis B infection is frequent in these patients. This study suggests that diagnostic protocols for persons with HIV and without hepatitis B surface antigen should include testing for hepatitis B core antigen, with positive results followed by molecular techniques to detect occult hepatitis B. This study makes a useful contribution to prevention and control of hepatitis B in Cuba. PMID- 21654590 TI - Raising HIV/AIDS awareness through Cuba's Memorias project. AB - As long as there is no cure for AIDS, the only effective means of containing its spread is prevention, primarily through public education. Cuba's AIDS Prevention Group is a community-based organization whose main purpose is to support the National HIV/AIDS Program's prevention and education efforts. The Group's Memorias Project uses the creation and display of memorial quilts to put a human face on AIDS statistics and stimulate public reflection on issues related to the disease and society. PMID- 21654591 TI - Prevalence of febrile syndromes in dengue surveillance, havana city, 2007. AB - OBJECTIVE: Determine point prevalence of febrile syndromes and compare with prevalence reported by habitual clinical and seroepidemiologic dengue surveillance system in Havana City. METHODS: In October 2007, a descriptive, cross-sectional study was carried out in a representative sample, calculating prevalences of febrile syndromes and undifferentiated febrile syndromes. Chi square analysis was used for rate comparisons. RESULTS: Point prevalences of febrile syndromes and undifferentiated febrile syndromes were 352.6 and 144.2 times greater, respectively, than those reported by the habitual clinical and seroepidemiologic dengue surveillance system; these differences were statistically significant (p < 0.001). CONCLUSIONS: Point prevalence of febrile syndromes was far greater than prevalence reported by the habitual clinical and seroepidemiologic dengue surveillance system, an indication of underreporting. PMID- 21654592 TI - Ergo-anthropometrics: joining fit to fat to predict cardiovascular risk. PMID- 21654593 TI - Descriptive study about congruence in wheelchair prescription. AB - AIM: Wheelchair prescription is relevant in the prevention of muscular joint pathology, and to facilitate autonomy and the patient's social life. However, in order to reach this goal, respecting the standards with a client-centred approach is essential. Congruence between user ability and wheelchair characteristics by making wheelchairs more "user friendly" can improve patient independence, facilitate integration into society and improve the patient's quality of life. The purpose of this study was to analyse congruence of wheelchair use by our patients, through the consideration of specific recommendations related to each subject's individual clinical situation. The second aim of the paper was to improve wheelchair prescriptions, by identifying the most frequent mistakes in the prescription and construction of wheelchairs. DESIGN: Observational study, outpatient. POPULATION: One hundred-fifty wheelchair users (average age 46.7+/ 17.3) were analysed and described at 16.2+/-8.5 years from the onset of their disability. The subjects were 80 males and 70 females. RESULTS: Sixty-eight percent of the wheelchairs were not suitable for the patients, while 32% were suitable. We reported the incidence of non-congruence with respect to each wheelchair part. CONCLUSION: After finding a correlation between the prescription sources and suitability, the authors suggested that wheelchair prescriptions should be carried out in specialized departments, or that physician competences, and collaboration between physicians and technicians must be improved. Our data indicates the necessity to pay more attention to wheelchair prescription while considering ergonomic fitting to the individual. CLINICAL REHABILITATION IMPACT: Identifying the most frequent mistakes in the prescription and construction of wheelchairs in this paper could help to make more appropriate prescriptions. PMID- 21654594 TI - "Wearing two hats": when a physician has a family member admitted to ICU. PMID- 21654595 TI - Can lactate levels and vasopressors use predict outcome in out-of-hospital cardiac arrest survivors? PMID- 21654596 TI - Staged laparoscopic-assisted endorectal pull-through for long segment Hirschprung's disease and total colonic aganglionosis. AB - AIM: Recently laparoscopic endorectal pull-through (LERPT) has been widely performed for treatment of Hirschsprung's disease (HD) as a one stage procedure. In long segment aganglionosis (LSA) and in case of total colonic aganglionosis (TCA) a staged procedure can be preferred. The authors report their experience in the staged LERPT for LSA and TCA. METHODS: In the last five years we treated 4 infants (3 male, 1 female) with LSA and TCA. The mean age at presentation was 40 days (2-110 days). In 3 patients we performed in the first step rectal biopsies, multiple laparoscopic biopsies and stoma. In one case - presenting as small bowel obstruction - we performed an emergency laparotomy for ileostomy and biopsies of the bowel. Histology showed 2 left colon aganglionosis (LCA) and 2 TCA. The LERPT was performed at a main age of 10 months. After stoma closure the LERPT was performed according to Georgeson's technique. RESULTS: There were no intraoperative complications. The patient with previous laparotomy needed conversion because of the abdominal adhesions. The two infants with LCA had preoperative and recurrent postoperative enterocolitis. In one case a successful posterior anorectal myectomy was performed. At follow up the children present constipation. The patient with TCA undergoing to LERPT presents a good frequency of defecation. CONCLUSION: Our experience, although on limited series, shows that staged minimally invasive surgical treatment can be safely performed in the LSA and TCA, but conversion can be necessary especially in case of previous laparotomy. PMID- 21654597 TI - Diverse genotypical features and impacts on clinical course and severity of cystic fibrosis: early childhood experience. AB - AIM: Very little is known about the relationship between genotype and phenotype of cystic fibrosis (CF) from the Turkish children. The aim of the study was to analyze the genotype and phenotype of 24 children with CF and to investigate the correlation between type of mutation in cystic fibrosis transmembrane conductance regulator (CFTR) protein gene and clinical manifestation of the disease. METHODS: Patients were evaluated retrospectively and prospectively. History, clinical findings, sweat test and mutation analysis were used for the definitive diagnosis of CF. Phenotypical features of 24 cases were evaluated according to clinical findings. We compared the clinical phenotype and age at diagnosis, genotypic features. A total of 36 mutations were analyzed by polymerase chain reaction (PCR) and reverse hybridization methods. Statistical analysis was done by using chi2, Fisher exact and Pearson correlation tests. RESULTS: The mean age of the cases that were admitted to our out-patient clinic was 5.3+/-4 years. The median age of diagnosis was three months. Parents were consanguineous in 37.5% of cases and loss of a sibling at one year of age was stated in a quarter. The most frequent symptom was recurrent diarrhoea (79.2%) and there was severe growth retardation in 12 (50%) and pseudo-Bartter (PB) syndrome in 11 of the cases. The incidence of PB was higher in cases that were diagnosed at one year of age. Out of 18 cases with mutation analysis, nine (50%) were positive for DF508 mutation, and four cases were homozygous out of nine cases. Two separate mutations were determined in two cases with severe clinical picture. The incidence of respiratory tract infection during the admission was lower in DF508 positive cases (P=0.016). There was no statistically significant relation between DF508 positivity and diarrhea, severe growth retardation and PB (P>0.05). The other mutations that were determined in our patients were rarely seen mutations such as 3120+1 G-A, R347P, 1677delTA, 2789+5G-A, 2183AA-G, and R1066C. CONCLUSION: DF508 mutation rates in our cases diagnosed in early childhood were higher than the rates reported previously in Turkish children. The definition of molecular defect in CFTR gene has an impact on verifying the diagnosis and decreasing morbidity and mortality. An adequately large sample size is needed to evaluate the mutation profiles and genotype-phenotype characteristics in our country. PMID- 21654598 TI - Efficacy of complex herbal compound of Echinacea angustifolia (Imoviral(r) Junior) in recurrent upper respiratory tract infections during pediatric age: preliminary results. AB - AIM: Among pediatric population the recurrent upper respiratory tract infections are very common. Several phytotherapies are been proposed as support therapies and, in particular, the efficacy of Echinacea angustifolia is controversial. This paper presents an evaluation of a new herbal compound in the treatment of recurrent upper respiratory tract infections in a pediatric cohort. METHODS: An immunostimulant herbal compound of Echinacea angustifolia, Arabinogalactan, Acerola (Vitamin C), Beta- Glucan e Zinc (Imoviral(r) Junior) was given to 37 children affected by recurrent pharyngotonsillitis or otitis media. RESULTS: The mean number of inflammatory episodes (i.e. tonsillitis or otitis media) during 6 months before treatment was 3+/-2.19, during the 6 months following treatment initiation it was 1+/-0.93 (P=0.04). After the complete treatment, 77% of children reported an improvement of chronic inflammatory in frequency of acute episodes. The total score of a questionnaire about life quality is improved (P=0.04). Finally, none collateral effects was occurred. CONCLUSION: The herbal compound of echinacea, beta-glucan, vitamin c, arabinoglactan and zinc (Imoviral(r) Junior) can improve the quality of life in pediatric patients affected by recurrent pharyngotonsillitis and otitis media without contralateral effects. PMID- 21654599 TI - Emerging biosignature of brain function and intervention in pediatric bipolar disorder. AB - Pediatric bipolar disorder (PBD) is a complex illness with a chronic course, requiring multiple medications over the longitudinal course of illness, with limited recovery and high relapse rate. Beyond the placebo controlled trials of monotherapy, there is an increased need to understand how each medication influences regions of affective and cognitive circuitry function by normalization or deployment of alternative circuitry regions. Functional studies are beginning to unravel the improved function in the fronto-limbic and fronto-temporal affective circuitry, and based on the paradigm administered, also in the interfacing cognitive fronto-striato-temporo-parietal regions. Treatment studies illustrated a pattern of improvement in functional activity consistently among the affective ventrolateral and medial prefrontal regions, and variably in the cognitive dorsolateral prefrontal cortex. While there is decreased activity in amygdala with treatment for mania or depression among patients with PBD, there appears to be residual increased amygdala activity regardless of response, relative to healthy controls, suggesting a trait-like abnormality. Parallel biochemical abnormalities in magnetic resonance spectroscopic studies and fronto limbic activity in magnetic resonance imaging studies of brain function at baseline provide maiden data on predicting outcome. This preliminary cohort of studies that probed the hypothesized circuitries underlying specific symptom constructs, coupled with futuristic paradigms and analytic methods, serve as a guidepost to generate the next generation of studies and build on the emerging biosignature towards specific treatment targets for personalized medicine in PBD. PMID- 21654600 TI - Early preventive interventions for adolescents exposed to a potentially traumatic event. AB - The development and evaluation of early preventative interventions for individuals exposed to a potentially traumatic event (PTE) have been increasing in number and sophistication over the last decade. Evaluation of early interventions for individuals who are symptomatic several weeks after exposure to a PTE have been effective in preventing the development of chronic post-traumatic stress disorder (PTSD). However, there has been little research demonstrating effectiveness of immediate interventions. In addition, there are not specific early interventions targeted toward the adolescent age group. While providers of early interventions should initiate contact with the family as whole, they may need to decide whether to employ a model that was developed for both children and adolescents or for adults depending on the particular needs of the adolescent. This review will examine a range of issues regarding the meaning, timing and effectiveness of early interventions after a PTE and will cover models for all age groups as well as models designed for immediate crisis intervention as well as for those individuals who are symptomatic and distressed in the early post traumatic period. The rapid growth in the formulation and research of early intervention models and the success of certain models in the prevention of chronic PTSD are promising developments for establishing an evidence base of cost effective preventative early interventions. PMID- 21654601 TI - [Epilepsy genetics and genetic epilepsies]. AB - During the last two decades, the molecular revolution in medicine has had a strong impact in the field of epilepsies. The quest for epilepsy-genes has been focused mainly on large mendelian pedigrees. This approach has allowed the identification of new causative genes and has provided new information about the pathogenesis of many epilepsy syndromes. Neverthless, the clinical implication of this information still has a relatively little impact on the genetic counselling for most of the syndromes. PMID- 21654602 TI - Cleft lips and palates: the roles of specialists. AB - Cleft lips and cleft palates are among the most common of birth defects and if left untreated can lead to serious medical and concurrent speech and language problems. However, while the consequences of cleft lips and palates can be severe and long-lasting, these can be averted by medical intervention, especially if it is done as early as possible. This paper explores the various options for surgical, medical, dental, and speech and audiological management of cleft of the secondary palates in children with Apert's syndrome and the ways in which these interventions can help children with these particular birth defects. PMID- 21654603 TI - Persistent pulmonary hypertension of the newborn refractory to inhaled nitric oxide and prostacyclin, responsive to neuromuscular blockade. AB - Neonatal pulmonary hypertension refractory to high frequency ventilation (HFOV) and inhaled nitric oxide (iNO) is an occasional occurrence. We report a full-term neonate with severe pulmonary hypertension unresponsive to the treatment with HFOV and iNO, later associated with prostacyclin, who rapidly improved after the addition of vecuronium, a neuromuscular blocker. PMID- 21654604 TI - Ectopic thymus presenting as neck mass in a neonate: a case report. AB - Neck masses are rare in newborns and can represent a big challenge for the paediatric surgeons. Different histological types are reported in the recent literature; while 80% of neck masses are benign, the pediatric surgeon is often called upon to assist in the evaluation, diagnosis and treatment. A two-month old baby was evaluated for an asymptomatic left sided cervical mass, presented at birth, which slowly increased in size. A magnetic resonance imaging scan was performed, with evidence of capsulated solid neck mass, lateral to the sternocleidomastoid muscle, not including the major vassel structures of the neck. The patient underwent surgical excision in the criteria to define the histology of the mass. A well capsulated mass was detected at surgery. At histology, an ectopic cervical thymus tissue was reported. The ectopic cervical thymus is an uncommon entity with only 91 cases reported; only nine occurred in infants, two in the neonatal period. According to the authors, in case of enlarging solid neck mass with unclear imaging or clinical data, complete surgical resection is the only and safe procedure to perform. PMID- 21654605 TI - Importance of a critical reading of neuropsychological testing. AB - Neuropsychological testing has become an important part of the diagnostic tools available to assess children's functioning. Tests are routinely use to establish diagnosis, measure patient's impairment and drive rehabilitation. The authors present the clinical case of a eight-year-old girl, sent to our Child Neuropsychiatry and Rehabilitation Unit for a suspected Specific Learning Disorder. Peculiar findings regarding attention and reading ability became evident during the initial evaluation; a mistaken diagnosis of dyslexia was avoided by carefully examining her global functioning (in particular sight, as she suffered from hyperopia but more importantly she had an insufficient control of vertical saccadic movements) and the strategies she used during testing. This constitutes a good example of the need to take into consideration the patient as a whole during any assessment, including neuropsychological testing. PMID- 21654606 TI - [Sex ratio in the offspring of pregnant women with polycystic ovary syndrome: effect of different phenotypes]. AB - AIM: The aim of this paper was to investigate the sex ratio in the offspring of pregnant patients with polycystic ovary syndrome (PCOS). METHODS: Analysis of 70 pregnant patients with PCOS who achieve a pregnancy without any kind of treatment, and having as controls 63 healthy pregnant women without any feature of PCOS. RESULTS: No significant difference in sex ratio was detected between PCOS and controls, even if it resulted significantly different in the full-blown and non-PCO phenotypes. CONCLUSION: The PCOS phenotypes influenced the sex ratio in the offspring, suggesting that environmental factors could play a role in determination of the offspring gender. PMID- 21654607 TI - Minilaparotomic myomectomy for large symptomatic uterine myomas: a prospective study. AB - AIM: The aim of this paper was to evaluate the feasibility, morbidity, and reproductive performance of fertile women undergoing minilaparotomic myomectomy for large uterine myomas. METHODS: Ninety-nine consecutive women with symptomatic myomas underwent myomectomy through a skin incision <=8 cm. Operative, postoperative and reproductive data were prospectively collected. RESULTS: Median (range) age and Body Mass Index (BMI) were 37 years (23-44) and 23 (18-43), respectively. Median (range) myoma diameter was 7 cm (4-20), and the median number of myomas removed was 1 (range 1-31). Myomas were intramural in 76 (76%) cases. Median incision length was 7 cm (range 4-13) and median duration of surgery was 70 min (range 40-180). Operative time and length of skin incision were not correlated with the progressive number of interventions. An incision larger than 8 cm was necessary in 7 (7%) patients and the length of incision was significantly correlated with the diameter of the largest myoma (P<0.01). The feasibility of minilaparotomy was significantly reduced when the diameter of the largest myoma was >12 cm (P<0.05). Operative time was significantly longer in patients having >1 myoma (P<0.05). Three (3%) patients underwent blood transfusion. Median (range) postoperative stay was 2 days (range 2-12). Fever occurred in 8 (8%) patients, and wound complications in 5 (5%). CONCLUSION: Myomectomy by minilaparotomy is a feasible procedure in more than 90% of unselected patients with large symptomatic myomas. Feasibility is questionable when the myoma is >12 cm. This technique is a mini-invasive option to treat patients with large and multiple myomas. PMID- 21654608 TI - Congenital defects in assisted reproductive technology pregnancies. AB - AIM: The aim of this study was to evaluate the prevalence and kind of congenital malformations in assisted reproductive technology (ART) pregnancies. METHODS: This study included pregnancies conceived by in-vitro fertilization (IVF) or intra cytoplasmic sperm injection (ICSI), evaluated in a referral center for prenatal diagnosis between January 2008 and December 2009. The control group included all the pregnancies examined in the same centre during in the same period of time. A computerized database was used to retrospectively identify the two study groups. RESULTS: The study evaluated 225 IVF or ICSI pregnancies (88 IVF and 137 ICSI). A congenital malformation was diagnosed in 13 pregnancies and the malformation rate was 5.8%. The number of malformed fetuses was similar in the ICSI (5.8%) or the IVF (5.7%) pregnancies. The anatomic districts more frequently involved by malformations were the encephalic one (38.5%) and the limbs (23.1%). In the control group, represented by 5,884 pregnancies, the malformation rate was 2.7%; encephalic (22.2%), urogenital (18.4%), cardiac (13.9%) CONCLUSION: In our experience on congenital defects in ART pregnancies, the encephalic district and the limbs are more frequently involved by fetal malformation. No significant difference was observed in the malformation prevalence between the IVF and the ICSI pregnancies. PMID- 21654609 TI - [Psychic aspects of the premenstrual dysphoric disorders. New therapeutic strategies: our experience with Vitex agnus castus]. AB - AIM: The premenstrual dysphoric disorder (PMDD) is one of the main problems of the premenstrual phase. It consists of symptoms that sometimes invalidate the scope of employment, social and psycho-affective of patients, requiring thus a diagnostic and therapeutic approach as detailed and accurate as possible. The therapeutic strategies available for this disease are many, but recently the emphasis has been on Vitex agnus castus (VAC), considered by many as evidence drug of choice for both PMS and for the PMDD, being with satisfactory therapeutic properties and small side effects. METHODS AND RESULTS: Our study evaluated a group of patients suffering from PMDD and the clinical efficacy of treatment with VAC (and compared the effectiveness of the results of a more homogeneous group of patients treated with fluoxetine). CONCLUSION: This study confirms the data reported in the literature regarding the effectiveness of VAC therapy with no side effects. PMID- 21654610 TI - Innovations in conservative endometriosis treatment: an updated review. AB - Endometriosis is a common, benign and chronic gynecological disorder. It is also an estrogen-dependent disorder that can result in intractable dysmenorrhea, heavy and/or irregular periods, painful bowel movements and urination during menstruation and infertility and ultimatively in repeated surgeries. Although surgery to remove endometriotic lesions is effective in relieving endometriosis associated pain, recurrence rates are high and many women require continuous medical therapy to control symptoms. Symptom relief with palliation of pain and optimization of the quality of life should be the main aim of the medical therapy. Different pharmacologic treatment options are currently available. The most widely exerted medical therapy for endometriosis involves gonadotropin releasing hormone (GnRH) agonists and oral contraceptives. Also progestogens and androgen derivates are used. New treatment options that are currently under investigation are selective progestogen receptor modulators (SPRMs), aromatase inhibitors (AI), GnRH- antagonists, cyclooxygenase (COX)-2 inhibitors, angiogenesis disruptor's und immune modulators. Although these new agents are promising, further confirmation in randomized clinical trials is required. PMID- 21654611 TI - The role of neoadjuvant chemotherapy in the management of primary breast cancer. AB - Neoadjuvant chemotherapy for primary breast cancer is the gold standard in the treatment of locally advanced, inoperable breast cancer, but based on a large body of evidence has become a standard treatment option for patients with operable disease, who are clear candidates for adjuvant chemotherapy. Neoadjuvant chemotherapy aims at reducing mortality and improving surgical options and offers an in vivo chemosensitivity testing at the same time. It is the ideal setting for clinical and translational research. Administering chemotherapy before surgery raises some important issues concerning the choice of specific treatment regimens as well as the management of the axilla and postoperative radiotherapy. A reliable high quality diagnostic and pathological work-up is mandatory for an ideal tailoring of neoadjuvant chemotherapy. This review gives an outline of the state-of-the-art management of primary breast cancer in the setting of neoadjuvant chemotherapy. PMID- 21654612 TI - Selective estrogen receptor modulators: the future in menopausal treatment. AB - The results of hormone therapy (HT) studies have changed the perception of HT benefits and risks. Selective estrogen receptor modulators (SERMs) represent drugs with a tissue-specific estrogen receptor agonist/antagonist activity and they are an alternative to HT. Each SERM stimulates and blocks different genes with different biological responses. Established SERMs or second generation are tamoxifen and raloxifene. Both SERMs have positive effects on breast, bone and lipids, but with an increased risk for venous thromboembolism and hot flushes. None of these SERMs has shown a preventive effect on non-vertebral fractures. At present, there is a new generation of SERMs (third generation: bazedoxifene, lasofoxifene and ospemifene) which has completed phase III clinical trials and has been submitted to the Health Regulatory Authorities for approval. A new concept, tissue selective estrogen complex (TSEC), has the potential to demonstrate the benefits of SERMs along with the additional benefits of estrogens. A long road to the ideal SERM still remains, but new SERMs represent an attractive new menopause treatment. PMID- 21654613 TI - Role of chemotherapy in epithelial ovarian cancer. AB - Despite the fact the standard-of-care primary chemotherapy strategy in epithelial ovarian cancer has undergone very limited changes over the past decade there have been important advances in treatment outcomes resulting from data generated in evidence-based trials that has modified the paradigm for second-line disease management. Recently reported data suggest novel classes of agents, including anti-angiogenic drugs and PARP inhibitors may add to the established utility of standard cytotoxic chemotherapy. PMID- 21654614 TI - Pharmacological profile of estrogens in oral contraception. AB - The synthetic estrogen ethinylestradiol (EE)given by mouth is stable and yields satisfactory results in terms of ovulation inhibition and effects on the endometrium. It increases however the risk especially for venous thrombotic events and to a lesser degree also arterial thrombosis. Therefore research focused on diminuition of the EE dosage and the development of a different estrogen component in oral contraceptives, specifically an estrogen occurring during physiological processes in the female body. Two estrogens emerge: 17beta Estradiol is the most potent natural estrogen and it is the major estrogen secreted by the ovaries. Estetrol is a human sex steroid (15 alpha hydroxyestriol) which is only produced during pregnancy by the fetal liver. The pharmacolokinetic and pharmacodynamic properties of these estrogens are compared to those of EE (absorption, metabolization, bioavailability etc.) and the clinical profile is described as far it is known from a limited number of studies. PMID- 21654615 TI - [Selective estrogen receptor modulators: focus on bazedoxifene]. AB - Prevention of osteopenia/osteoporosis in postmenopausal patients can reduce fracture risk. In this view, the use of Selective Estrogen Receptor Modulators (SERMs) appear to be important in managing this condition. Bazedoxifene Acetate (BZA) is a third-generation SERM that showed to protect bone mass in postmenopausal women with osteopenia, and to reduce vertebral fracture risk in osteoporotic postmenopausal women; moreover, BZA decreased the non-vertebral fracture risk in a subgroup of patients at high-risk for fracture in comparison to placebo. BZA showed no stimulating effects on endometrium and breast. BZA can be a valid option in management of osteopenia/osteoporosis in postmenopause. PMID- 21654616 TI - Short-term effects of high-intensity laser therapy versus ultrasound therapy in the treatment of low back pain: a randomized controlled trial. AB - BACKGROUND: Low back pain (LBP) is a common musculoskeletal disorder that is highly prevalent in the general population. Management of this pathology includes numerous interventions depending on pain severity: analgesic, nonsteroidal anti inflammatory drugs, steroid injections. However, the effect size and duration of symptom relief are limited. Physical therapy (ultrasound [US], laser therapy, manual therapy, interferential current therapy, Back School, aerobic work, therapeutic aquatic exercise acupuncture) have been reported often with mixed results. AIM: To evaluate the short-term effectiveness of high-intensity laser therapy (HILT) versus ultrasound (US) therapy in the treatment of LBP. DESIGN: Randomized clinical trial. SETTING: University hospital. POPULATION: Thirty patients with LBP were randomly assigned to a HILT group or a US therapy group. METHODS: Study participants received fifteen treatment sessions of HILT or US therapy over a period of three consecutive weeks (five days/week). RESULTS: For the 30 study participants there were no between-group differences at baseline in Visual Analogic Scale (VAS) and Oswestry Low Back Pain Disability Questionnaire (OLBPDQ) scores. At the end of the 3-week intervention, participants in the HILT group showed a significantly greater decrease in pain (measured by the VAS) and an improvement of related disability (measured by the OLBPDQ) compared with the group treated with US therapy. CONCLUSION: Our findings obtained after 15 treatment sessions with the experimental protocol suggested greater effectiveness of HILT than of US therapy in the treatment of LBP, proposing HILT as a promising new therapeutic option into the rehabilitation of LBP. PMID- 21654617 TI - Core elements of physiotherapy in cerebral palsy children: proposal for a trial checklist. AB - BACKGROUND: Currently international literature describes physiotherapy in cerebral palsy (CP) children only in generic terms (traditional / standard / background / routine). AIM: The aim of this study is to create a checklist capable of describing the different modalities employed in physiotherapeutic treatment by means of a non-bias, common, universal, standardised language. DESIGN: A preliminary checklist was outlined by a group of physiotherapists specialised in child rehabilitation. SETTING: For its experimentation, several physiotherapists from various paediatric units from all over Italy with different methodological approaches and backgrounds, were involved. METHODS: Using the interpretative model, proposed by Ferrari et al., and through collective analysis and discussion of clinical videos, the core elements were progressively selected and codified. A reliability study was then carried out by eight expert physiotherapists using an inter-rate agreement model. RESULTS: The checklist analyses therapeutic proposals of CP rehabilitation through the description of settings, exercises and facilitations and consists of items and variables which codify all possible physiotherapeutic interventions. It is accompanied by written explanations, demonstrative videos, caregiver interviews and descriptions of applied environmental adaptations. All checklist items obtained a high level of agreement (according to Cohen's kappa coefficient), revealing that the checklist is clearly and easily interpretable. CONCLUSION: The checklist should facilitate interaction and communication between specialists and families, and lead to comparable research studies and scientific advances. CLINICAL REHABILITATION IMPACT: The main value is to be able to correlate therapeutic results with core elements of adopted physiotherapy. PMID- 21654618 TI - Electrode positioning and montage in transcranial direct current stimulation. AB - Transcranial direct current stimulation (tDCS) is a technique that has been intensively investigated in the past decade as this method offers a non-invasive and safe alternative to change cortical excitability. The effects of one session of tDCS can last for several minutes, and its effects depend on polarity of stimulation, such as that cathodal stimulation induces a decrease in cortical excitability, and anodal stimulation induces an increase in cortical excitability that may last beyond the duration of stimulation. These effects have been explored in cognitive neuroscience and also clinically in a variety of neuropsychiatric disorders--especially when applied over several consecutive sessions. One area that has been attracting attention of neuroscientists and clinicians is the use of tDCS for modulation of pain-related neural networks. Modulation of two main cortical areas in pain research has been explored: primary motor cortex and dorsolateral prefrontal cortex. Due to the critical role of electrode montage, in this article, we show different alternatives for electrode placement for tDCS clinical trials on pain; discussing advantages and disadvantages of each method of stimulation. PMID- 21654619 TI - Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. AB - Mitochondrial membrane potential (DeltaPsim) is critical for maintaining the physiological function of the respiratory chain to generate ATP. A significant loss of DeltaPsim renders cells depleted of energy with subsequent death. Reactive oxygen species (ROS) are important signaling molecules, but their accumulation in pathological conditions leads to oxidative stress. The two major sources of ROS in cells are environmental toxins and the process of oxidative phosphorylation. Mitochondrial dysfunction and oxidative stress have been implicated in the pathophysiology of many diseases; therefore, the ability to determine DeltaPsim and ROS can provide important clues about the physiological status of the cell and the function of the mitochondria. Several fluorescent probes (Rhodamine 123, TMRM, TMRE, JC-1) can be used to determine Deltapsim in a variety of cell types, and many fluorescence indicators (Dihydroethidium, Dihydrorhodamine 123, H(2;)DCF-DA) can be used to determine ROS. Nearly all of the available fluorescence probes used to assess DeltaPsim or ROS are single wavelength indicators, which increase or decrease their fluorescence intensity proportional to a stimulus that increases or decreases the levels of DeltaPsim or ROS. Thus, it is imperative to measure the fluorescence intensity of these probes at the baseline level and after the application of a specific stimulus. This allows one to determine the percentage of change in fluorescence intensity between the baseline level and a stimulus. This change in fluorescence intensity reflects the change in relative levels of DeltaPsim or ROS. In this video, we demonstrate how to apply the fluorescence indicator, TMRM, in rat cortical neurons to determine the percentage change in TMRM fluorescence intensity between the baseline level and after applying FCCP, a mitochondrial uncoupler. The lower levels of TMRM fluorescence resulting from FCCP treatment reflect the depolarization of mitochondrial membrane potential. We also show how to apply the fluorescence probe H(2)DCF-DA to assess the level of ROS in cortical neurons, first at baseline and then after application of H(2)O(2). This protocol (with minor modifications) can be also used to determine changes in ?Psim and ROS in different cell types and in neurons isolated from other brain regions. PMID- 21654620 TI - Coherence between brain cortical function and neurocognitive performance during changed gravity conditions. AB - Previous studies of cognitive, mental and/or motor processes during short-, medium- and long-term weightlessness have only been descriptive in nature, and focused on psychological aspects. Until now, objective observation of neurophysiological parameters has not been carried out--undoubtedly because the technical and methodological means have not been available--, investigations into the neurophysiological effects of weightlessness are in their infancy (Schneider et al. 2008). While imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) would be hardly applicable in space, the non invasive near-infrared spectroscopy (NIRS) technique represents a method of mapping hemodynamic processes in the brain in real time that is both relatively inexpensive and that can be employed even under extreme conditions. The combination with electroencephalography (EEG) opens up the possibility of following the electrocortical processes under changing gravity conditions with a finer temporal resolution as well as with deeper localization, for instance with electrotomography (LORETA). Previous studies showed an increase of beta frequency activity under normal gravity conditions and a decrease under weightlessness conditions during a parabolic flight (Schneider et al. 2008a+b). Tilt studies revealed different changes in brain function, which let suggest, that changes in parabolic flight might reflect emotional processes rather than hemodynamic changes. However, it is still unclear whether these are effects of changed gravity or hemodynamic changes within the brain. Combining EEG/LORETA and NIRS should for the first time make it possible to map the effect of weightlessness and reduced gravity on both hemodynamic and electrophysiological processes in the brain. Initially, this is to be done as part of a feasibility study during a parabolic flight. Afterwards, it is also planned to use both techniques during medium- and long-term space flight. It can be assumed that the long-term redistribution of the blood volume and the associated increase in the supply of oxygen to the brain will lead to changes in the central nervous system that are also responsible for anaemic processes, and which can in turn reduce performance (De Santo et al. 2005), which means that they could be crucial for the success and safety of a mission (Genik et al. 2005, Ellis 2000). Depending on these results, it will be necessary to develop and employ extensive countermeasures. Initial results for the MARS500 study suggest that, in addition to their significance in the context of the cardiovascular and locomotor systems, sport and physical activity can play a part in improving neurocognitive parameters. Before this can be fully established, however, it seems necessary to learn more about the influence of changing gravity conditions on neurophysiological processes and associated neurocognitive impairment. PMID- 21654621 TI - Trichuris muris infection: a model of type 2 immunity and inflammation in the gut. AB - Trichuris muris is a natural pathogen of mice and is biologically and antigenically similar to species of Trichuris that infect humans and livestock. Infective eggs are given by oral gavage, hatch in the distal small intestine, invade the intestinal epithelial cells (IECs) that line the crypts of the cecum and proximal colon and upon maturation the worms release eggs into the environment. This model is a powerful tool to examine factors that control CD4(+) T helper (Th) cell activation as well as changes in the intestinal epithelium. The immune response that occurs in resistant inbred strains, such as C57BL/6 and BALB/c, is characterized by Th2 polarized cytokines (IL-4, IL-5 and IL-13) and expulsion of worms while Th1-associated cytokines (IL-12, IL-18, IFN-gamma) promote chronic infections in genetically susceptible AKR/J mice. Th2 cytokines promote physiological changes in the intestinal microenvironment including rapid turnover of IECs, goblet cell differentiation, recruitment and changes in epithelial permeability and smooth muscle contraction, all of which have been implicated in worm expulsion. Here we detail a protocol for propagating Trichuris muris eggs which can be used in subsequent experiments. We also provide a sample experimental harvest with suggestions for post-infection analysis. Overall, this protocol will provide researchers with the basic tools to perform a Trichuris muris mouse infection model which can be used to address questions pertaining to Th proclivity in the gastrointestinal tract as well as immune effector functions of IECs. PMID- 21654622 TI - A simple and efficient method to isolate macrophages from mixed primary cultures of adult liver cells. AB - Kupffer cells are liver-specific resident macrophages and play an important role in the physiological and pathological functions of the liver. Although the isolation methods of liver macrophages have been well-described, most of these methods require sophisticated equipment, such as a centrifugal elutriator and technical skills. Here, we provide a novel method to obtain liver macrophages in sufficient number and purity from mixed primary cultures of adult rat liver cells, as schematically illustrated in Figure 1. After dissociation of the liver cells by two-step perfusion method, a fraction mostly composed of parenchymal hepatocytes is prepared and seeded into T75 tissue culture flasks with culture medium composed of DMEM and 10% FCS. Parenchymal hepatocytes lose the epithelial cell morphology within a few days in culture, degenerate or transform into fibroblast-like cells (Figure 2). As the culture proceeds, around day 6, phase contrast-bright, round macrophage-like cells start to proliferate on the fibroblastic cell sheet (Figure 2). The growth of the macrophage-like cells continue and reach to maximum levels around day 12, covering the cell sheet on the flask surface. By shaking of the culture flasks, macrophages are readily suspended into the culture medium. Subsequent transfer and short incubation in plastic dishes result in selective adhesion of macrophages (Figure 3), where as other contaminating cells remain suspended. After several rinses with PBS, attached macrophages are harvested. More than 10(6) cells can be harvested repeatedly from the same T75 tissue culture flask at two to three day intervals for more than two weeks (Figure 3). The purities of the isolated macrophages were 95 to 99%, as evaluated by flow cytometry or immunocytochemistry with rat macrophage-specific antibodies (Figure 4). The isolated cells show active phagocytosis of polystylene beads (Figure 5), proliferative response to recombinant GM-CSF, secretion of inflammatory/anti-inflammatory cytokines upon stimulation with LPS, and formation of multinucleated giant cells. In conclusion, we provide a simple and efficient method to obtain liver macrophages in sufficient number and purity without complex equipment and skills. This method might be applicable to other mammalian species. PMID- 21654623 TI - Generation of neural stem cells from discarded human fetal cortical tissue. AB - Neural stem cells (NSCs) reside along the ventricular zone neuroepithelium during the development of the cortical plate. These early progenitors ultimately give rise to intermediate progenitors and later, the various neuronal and glial cell subtypes that form the cerebral cortex. The capacity to generate and expand human NSCs (so called neurospheres) from discarded normal fetal tissue provides a means with which to directly study the functional aspects of normal human NSC development. This approach can also be directed toward the generation of NSCs from known neurological disorders, thereby affording the opportunity to identify disease processes that alter progenitor proliferation, migration and differentiation. We have focused on identifying pathological mechanisms in human Down syndrome NSCs that might contribute to the accelerated Alzheimer's disease phenotype. Neither in vivo nor in vitro mouse models can replicate the identical repertoire of genes located on human chromosome 21. Here we use a simple and reliable method to isolate Down syndrome NSCs from aborted human fetal cortices and grow them in culture. The methodology provides specific aspects of harvesting the tissue, dissection with limited anatomical landmarks, cell sorting, plating and passaging of human NSCs. We also provide some basic protocols for inducing differentiation of human NSCs into more selective cell subtypes. PMID- 21654624 TI - Vibrodissociation of neurons from rodent brain slices to study synaptic transmission and image presynaptic terminals. AB - Mechanical dissociation of neurons from the central nervous system has the advantage that presynaptic boutons remain attached to the isolated neuron of interest. This allows for examination of synaptic transmission under conditions where the extracellular and postsynaptic intracellular environments can be well controlled. A vibration-based technique without the use of proteases, known as vibrodissociation, is the most popular technique for mechanical isolation. A micropipette, with the tip fire-polished to the shape of a small ball, is placed into a brain slice made from a P1-P21 rodent. The micropipette is vibrated parallel to the slice surface and lowered through the slice thickness resulting in the liberation of isolated neurons. The isolated neurons are ready for study within a few minutes of vibrodissociation. This technique has advantages over the use of primary neuronal cultures, brain slices and enzymatically isolated neurons including: rapid production of viable, relatively mature neurons suitable for electrophysiological and imaging studies; superior control of the extracellular environment free from the influence of neighboring cells; suitability for well controlled pharmacological experiments using rapid drug application and total cell superfusion; and improved space-clamp in whole-cell recordings relative to neurons in slice or cell culture preparations. This preparation can be used to examine synaptic physiology, pharmacology, modulation and plasticity. Real-time imaging of both pre- and postsynaptic elements in the living cells and boutons is also possible using vibrodissociated neurons. Characterization of the molecular constituents of pre- and postsynaptic elements can also be achieved with immunological and imaging-based approaches. PMID- 21654625 TI - Transmembrane domain oligomerization propensity determined by ToxR assay. AB - The oversimplified view of protein transmembrane domains as merely anchors in phospholipid bilayers has long since been disproven. In many cases membrane spanning proteins have evolved highly sophisticated mechanisms of action. One way in which membrane proteins can modulate their structures and functions is by direct and specific contact of hydrophobic helices, forming structured transmembrane oligomers. Much recent work has focused on the distribution of amino acids preferentially found in the membrane environment in comparison to aqueous solution and the different intermolecular forces that drive protein association. Nevertheless, studies of molecular recognition at the transmembrane domain of proteins still lags behind those of water-soluble regions. A major hurdle remains: despite the remarkable specificity and affinity that transmembrane oligomerization can achieve, direct measurement of their association is challenging. Traditional methodologies applied to the study of integral membrane protein function can be hampered by the inherent insolubility of the sequences under examination. Biophysical insights gained from studying synthetic peptides representing transmembrane domains can provide useful structural insight. However, the biological relevance of the detergent micellar or liposome systems used in these studies to mimic cellular membranes is often questioned; do peptides adopt a native-like structure under these conditions and does their functional behaviour truly reflect the mode of action within a native membrane? In order to study the interactions of transmembrane sequences in natural phospholipid bilayers, the Langosch lab developed ToxR transcriptional reporter assays. The transmembrane domain of interest is expressed as a chimeric protein with maltose binding protein for location to the periplasm and ToxR to provide a report of the level of oligomerization (Figure 1). In the last decade, several other groups (e.g. Engelman, DeGrado, Shai) further optimized and applied this ToxR reporter assay. The various ToxR assays have become a gold standard to test protein-protein interactions in cell membranes. We herein demonstrate a typical experimental operation conducted in our laboratory that primarily follows protocols developed by Langosch. This generally applicable method is useful for the analysis of transmembrane domain self-association in E. coli, where beta galactosidase production is used to assess the TMD oligomerization propensity. Upon TMD-induced dimerization, ToxR binds to the ctx promoter causing up regulation of the LacZ gene for beta-galactosidase. A colorimetric readout is obtained by addition of ONPG to lyzed cells. Hydrolytic cleavage of ONPG by beta galactosidase results in the production of the light absorbing species o nitrophenolate (ONP) (Figure 2). PMID- 21654626 TI - Polarized translocation of fluorescent proteins in Xenopus ectoderm in response to Wnt signaling. AB - Cell polarity is a fundamental property of eukaryotic cells that is dynamically regulated by both intrinsic and extrinsic factors during embryonic development. One of the signaling pathways involved in this regulation is the Wnt pathway, which is used many times during embryogenesis and critical for human disease. Multiple molecular components of this pathway coordinately regulate signaling in a spatially-restricted manner, but the underlying mechanisms are not fully understood. Xenopus embryonic epithelial cells is an excellent system to study subcellular localization of various signaling proteins. Fluorescent fusion proteins are expressed in Xenopus embryos by RNA microinjection, ectodermal explants are prepared and protein localization is evaluated by epifluorescence. In this experimental protocol we describe how subcellular localization of Diversin, a cytoplasmic protein that has been implicated in signaling and cell polarity determination is visualized in Xenopus ectodermal cells to study Wnt signal transduction. Coexpression of a Wnt ligand or a Frizzled receptor alters the distribution of Diversin fused with red fluorescent protein, RFP, and recruits it to the cell membrane in a polarized fashion. This ex vivo protocol should be a useful addition to in vitro studies of cultured mammalian cells, in which spatial control of signaling differs from that of the intact tissue and is much more difficult to analyze. PMID- 21654627 TI - Live-cell imaging of sensory organ precursor cells in intact Drosophila pupae. AB - Since the discovery of Green Fluorescent Protein (GFP), there has been a revolutionary change in the use of live-cell imaging as a tool for understanding fundamental biological mechanisms. Striking progress has been particularly evident in Drosophila, whose extensive toolkit of mutants and transgenic lines provides a convenient model to study evolutionarily-conserved developmental and cell biological mechanisms. We are interested in understanding the mechanisms that control cell fate specification in the adult peripheral nervous system (PNS) in Drosophila. Bristles that cover the head, thorax, abdomen, legs and wings of the adult fly are individual mechanosensory organs, and have been studied as a model system for understanding mechanisms of Notch-dependent cell fate decisions. Sensory organ precursor (SOP) cells of the microchaetes (or small bristles), are distributed throughout the epithelium of the pupal thorax, and are specified during the first 12 hours after the onset of pupariation. After specification, the SOP cells begin to divide, segregating the cell fate determinant Numb to one daughter cell during mitosis. Numb functions as a cell-autonomous inhibitor of the Notch signaling pathway. Here, we show a method to follow protein dynamics in SOP cell and its progeny within the intact pupal thorax using a combination of tissue-specific Gal4 drivers and GFP-tagged fusion proteins. This technique has the advantage over fixed tissue or cultured explants because it allows us to follow the entire development of an organ from specification of the neural precursor to growth and terminal differentiation of the organ. We can therefore directly correlate changes in cell behavior to changes in terminal differentiation. Moreover, we can combine the live imaging technique with mosaic analysis with a repressible cell marker (MARCM) system to assess the dynamics of tagged proteins in mitotic SOPs under mutant or wildtype conditions. Using this technique, we and others have revealed novel insights into regulation of asymmetric cell division and the control of Notch signaling activation in SOP cells (examples include references 1-6, 7, 8). PMID- 21654628 TI - Generation of multivirus-specific T cells to prevent/treat viral infections after allogeneic hematopoietic stem cell transplant. AB - Viral infections cause morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We and others have successfully generated and infused T-cells specific for Epstein Barr virus (EBV), cytomegalovirus (CMV) and Adenovirus (Adv) using monocytes and EBV-transformed lymphoblastoid cell (EBV LCL) gene-modified with an adenovirus vector as antigen presenting cells (APCs). As few as 2x10(5)/kg trivirus-specific cytotoxic T lymphocytes (CTL) proliferated by several logs after infusion and appeared to prevent and treat even severe viral disease resistant to other available therapies. The broader implementation of this encouraging approach is limited by high production costs, complexity of manufacture and the prolonged time (4-6 weeks for EBV-LCL generation, and 4-8 weeks for CTL manufacture--total 10-14 weeks) for preparation. To overcome these limitations we have developed a new, GMP-compliant CTL production protocol. First, in place of adenovectors to stimulate T-cells we use dendritic cells (DCs) nucleofected with DNA plasmids encoding LMP2, EBNA1 and BZLF1 (EBV), Hexon and Penton (Adv), and pp65 and IE1 (CMV) as antigen-presenting cells. These APCs reactivate T cells specific for all the stimulating antigens. Second, culture of activated T-cells in the presence of IL-4 (1,000 U/ml) and IL-7 (10 ng/ml) increases and sustains the repertoire and frequency of specific T cells in our lines. Third, we have used a new, gas permeable culture device (G-Rex) that promotes the expansion and survival of large cell numbers after a single stimulation, thus removing the requirement for EBV-LCLs and reducing technician intervention. By implementing these changes we can now produce multispecific CTL targeting EBV, CMV, and Adv at a cost per 10(6) cells that is reduced by >90%, and in just 10 days rather than 10 weeks using an approach that may be extended to additional protective viral antigens. Our FDA-approved approach should be of value for prophylactic and treatment applications for high risk allogeneic HSCT recipients. PMID- 21654629 TI - Solid plate-based dietary restriction in Caenorhabditis elegans. AB - Reduction of food intake without malnutrition or starvation is known to increase lifespan and delay the onset of various age-related diseases in a wide range of species, including mammals. It also causes a decrease in body weight and fertility, as well as lower levels of plasma glucose, insulin, and IGF-1 in these animals. This treatment is often referred to as dietary restriction (DR) or caloric restriction (CR). The nematode Caenorhabditis elegans has emerged as an important model organism for studying the biology of aging. Both environmental and genetic manipulations have been used to model DR and have shown to extend lifespan in C. elegans. However, many of the reported DR studies in C. elegans were done by propagating animals in liquid media, while most of the genetic studies in the aging field were done on the standard solid agar in petri plates. Here we present a DR protocol using standard solid NGM agar-based plate with killed bacteria. PMID- 21654630 TI - Bidirectional association between depression and obesity in middle-aged and older women. AB - OBJECTIVE: Although it has been hypothesized that the depression-obesity relation is bidirectional, few studies have addressed this hypothesis in a prospective setting. We aimed to examine the bidirectional relationship in middle-aged and elderly women. SUBJECTS: A total of 65 955 women aged 54-79 years in the Nurses' Health Study were prospectively followed from 1996 to 2006 with updated information on body weight, depression status and various covariates every 2 years. Depression was defined as self-report of physician-diagnosed depression and/or antidepressant use. Obesity was defined as a BMI >=30.0 kg m(-2). The first three waves (1996-2000) were used as the baseline period and the last three waves (2002-2006) were used as the follow-up period. RESULTS: After adjusting for baseline age, physical activity, comorbidities, BMI and other covariates, depression at the baseline period was associated with an increased risk of obesity at the follow-up period in all women (multivariate-adjusted odds ratio (OR), 1.38; 95% confidence interval (95% CI), 1.24-1.53) and baseline non-obese women (OR, 1.51; 95% CI, 1.36-1.67). In the opposite direction, after adjusting for baseline age, physical activity, comorbidities, depression status and other covariates, obese women at baseline had a moderately increased risk of depression at the follow-up period compared with normal-weight women (OR, 1.11; 95% CI, 1.03 1.18), and this association was similar for new onset of depression (OR for obese versus normal weight women, 1.10; 95% CI, 1.02-1.20). CONCLUSIONS: Our results suggest a bidirectional association between depression and obesity in middle-aged and elderly women. Future studies are needed to confirm our findings in different populations, and investigate the potential mechanisms underlying this association. Our results underscore the importance of early detection and proper behavioral modifications to lower the burden of both conditions. PMID- 21654631 TI - Longer sleep duration associates with lower adiposity gain in adult short sleepers. AB - The objective of this longitudinal, observational study was to verify whether a favorable change in sleep duration over 6 years could impact objective indicators of adiposity in adults aged 18-64 years. Short-duration sleepers (<=6 h per day; n=43) at baseline were divided into two groups: (i) those who increased their sleep duration to a 'healthy' length of 7-8 h per day at year 6 (mean increase: 1.52+/-0.66 h per day; n=23); and (ii) those who maintained their short sleep duration habits (mean change: -0.11+/-0.38 h per day; n=20). Adult individuals who reported sleeping 7-8 h per day at both baseline and year 6 (n=173) were used as a control group. Change in adiposity indicators for each sleep-duration group was compared by analysis of covariance. We observed that the two short-sleep duration groups had similar baseline characteristics. However, short-duration sleepers who maintained their short sleep duration experienced a greater increase in body mass index (BMI) (difference: 1.1+/-0.36 kg m(-2), P<0.05) and fat mass (difference: 2.4+/-0.64 kg, P<0.05) over the 6-year follow-up period than short duration sleepers who increased their sleep duration, even after adjustment for relevant covariates. We did not observe any significant difference in adiposity changes between the control group and short-duration sleepers who increased their sleep duration. This study suggests for the first time that shifting sleep duration from a short to a healthier length is associated with an attenuation of fat mass gain. PMID- 21654632 TI - An infrequent molecular ruler controls flagellar hook length in Salmonella enterica. AB - The bacterial flagellum consists of a long external filament connected to a membrane-embedded basal body at the cell surface by a short curved structure called the hook. In Salmonella enterica, the hook extends 55 nm from the cell surface. FliK, a secreted molecular ruler, controls hook length. Upon hook completion, FliK induces a secretion-specificity switch to filament-type substrate secretion. Here, we demonstrate that an infrequent ruler mechanism determines hook length. FliK is intermittently secreted during hook polymerization. The probability of the specificity switch is an increasing function of hook length. By uncoupling hook polymerization from FliK expression, we illustrate that FliK secretion immediately triggers the specificity switch in hooks greater than the physiological length. The experimental data display excellent agreement with a mathematical model of the infrequent ruler hypothesis. Merodiploid bacteria expressing simultaneously short and long ruler variants displayed hook-length control by the short ruler, further supporting the infrequent ruler model. Finally, the velocity of FliK secretion determines the probability of a productive FliK interaction with the secretion apparatus to change secretion substrate specificity. PMID- 21654633 TI - Neither IL-17A mRNA nor IL-17A protein are detectable in Langerhans cell histiocytosis lesions. AB - Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions including CD207(+)/CD1a(+) dendritic cells that can result in significant morbidity and mortality. The etiology of LCH remains speculative, and neoplastic and inflammatory origins have been debated for decades. A recent study identified abundant interleukin-17 (IL-17A) protein in dendritic cells in LCH lesions as well as in plasma from patients with active disease. Furthermore, it identified dendritic cells as a novel source of IL-17A expression. However, subsequent studies from our research group failed to identify any IL-17A gene expression from CD207(+) dendritic cells or CD3(+) T cells in LCH lesions. In this study, further investigation once again fails to identify any cells in LCH lesions with IL-17A gene expression. Furthermore, IL-17A antigen is undetectable in LCH lesion lysates with western blotting, immunoprecipitation, spectral analysis, and enzyme-linked immunosorbent assay (ELISA). Western blots, immunoprecipitation, and ELISA experiments also demonstrate that antibodies used in original studies that established the IL-17A hypothesis for pathogenesis of LCH recognize nonspecific proteins. We conclude that evidence for IL-17A as a significant factor in LCH remains inadequate and clinical trials targeting IL-17A remain unjustified. PMID- 21654634 TI - Single-particle tracking as a quantitative microscopy-based approach to unravel cell entry mechanisms of viruses and pharmaceutical nanoparticles. AB - Highly sensitive fluorescence microscopy techniques allow single nanoparticles to be tracked during their uptake into living cells with high temporal and spatial resolution. From analysis of the trajectories, random motion can be discriminated from active transport and the average transport velocity and/or diffusion coefficient determined. Such an analysis provides important information regarding the uptake pathway and location of viruses and nanoparticles. In this review, we give an introduction into single-particle tracking (SPT) and determination of the mean-squared displacement. We also give an overview of recent advances in SPT. These include millisecond alternating-laser excitation for removal of spectral crosstalk, alternating wide-field (WF), and total internal reflection fluorescence (TIRF) microscopy for sensitive experiments at the plasma membrane and three-dimensional tracking strategies. Throughout the review, we highlight recent advances regarding the entry (and egress) of natural and artificial viruses obtained via SPT. PMID- 21654635 TI - Determination of nanoparticle size distribution together with density or molecular weight by 2D analytical ultracentrifugation. AB - Nanoparticles are finding many research and industrial applications, yet their characterization remains a challenge. Their cores are often polydisperse and coated by a stabilizing shell that varies in size and composition. No single technique can characterize both the size distribution and the nature of the shell. Advances in analytical ultracentrifugation allow for the extraction of the sedimentation (s) and diffusion coefficients (D). Here we report an approach to transform the s and D distributions of nanoparticles in solution into precise molecular weight (M), density (rho(P)) and particle diameter (d(p)) distributions. M for mixtures of discrete nanocrystals is found within 4% of the known quantities. The accuracy and the density information we achieve on nanoparticles are unparalleled. A single experimental run is sufficient for full nanoparticle characterization, without the need for standards or other auxiliary measurements. We believe that our method is of general applicability and we discuss its limitations. PMID- 21654636 TI - Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sites. AB - A role for PrP in the toxic effect of oligomeric forms of Abeta, implicated in Alzheimer's disease (AD), has been suggested but remains controversial. Here we show that PrP is required for the plasticity-impairing effects of ex vivo material from human AD brain and that standardized Abeta-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity in a PrP dependent manner. We screened a panel of anti-PrP antibodies for their ability to disrupt the ADDL-PrP interaction. Antibodies directed to the principal PrP/Abeta binding site and to PrP helix-1, were able to block Abeta binding to PrP suggesting that the toxic Abeta species are of relatively high molecular mass and/or may bind multiple PrP molecules. Two representative and extensively characterized monoclonal antibodies directed to these regions, ICSM-35 and ICSM 18, were shown to block the Abeta-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination. PMID- 21654637 TI - Origami-like unfolding of hydro-actuated ice plant seed capsules. AB - Actuated plant materials are a source of inspiration for the design of adaptive materials and structures that are responsive to specific external stimuli. Hydro responsive, metabolism-independent plant movements are particularly fascinating, because the extracted concepts are more amenable to transfer into engineering than those dependent on cellular activity. Here we investigate the structural and compositional basis of a sophisticated plant movement mechanism--the hydration dependent unfolding of ice plant seed capsules. This reversible origami-like folding pattern proceeds via a cooperative flexing-and-packing mechanism actuated by a swellable cellulose layer filling specialized plant cells. Swelling is translated into a bidirectional organ movement through simple geometric constraints embedded in the hierarchical architecture of the ice plant valves. Extracted principles from this reliable and reversible actuated movement have relevance to the emerging field of 'programmable matter' with applications as far reaching as the design of satellites and artificial muscles. PMID- 21654638 TI - MicroRNA122 is a key regulator of alpha-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma. AB - alpha-fetoprotein (AFP) is not only a widely used biomarker in hepatocellular carcinoma (HCC) surveillance, but is also clinically recognized as linked with aggressive tumour behaviour. Here we show that deregulation of microRNA122, a liver-specific microRNA, is a cause of both AFP elevation and a more biologically aggressive phenotype in HCC. We identify CUX1, a direct target of microRNA122, as a common central mediator of these two effects. Using liver tissues from transgenic mice in which microRNA122 is functionally silenced, an orthotopic xenograft tumour model, and human clinical samples, we further demonstrate that a microRNA122/CUX1/microRNA214/ZBTB20 pathway regulates AFP expression. We also show that the microRNA122/CUX1/RhoA pathway regulates the aggressive characteristics of tumours. We conclude that microRNA122 and associated signalling proteins may represent viable therapeutic targets, and that serum AFP levels in HCC patients may be a surrogate marker for deregulated intracellular microRNA122 signalling pathways in HCC tissues. PMID- 21654639 TI - A synthetic icosahedral DNA-based host-cargo complex for functional in vivo imaging. AB - The encapsulation of molecular cargo within well-defined supramolecular architectures is highly challenging. Synthetic hosts are desirable because of their well-defined nature and addressability. Encapsulation of biomacromolecules within synthetic hosts is especially challenging because of the former's large size, sensitive nature, retention of functionality post-encapsulation and demonstration of control over the cargo. Here we encapsulate a fluorescent biopolymer that functions as a pH reporter within synthetic, DNA-based icosahedral host without molecular recognition between host and cargo. Only those cells bearing receptors for the DNA casing of the host-cargo complex engulf it. We show that the encapsulated cargo is therefore uptaken cell specifically in Caenorhabditis elegans. Retention of functionality of the encapsulated cargo is quantitatively demonstrated by spatially mapping pH changes associated with endosomal maturation within the coelomocytes of C. elegans. This is the first demonstration of functionality and emergent behaviour of a synthetic host-cargo complex in vivo. PMID- 21654640 TI - An autonomous DNA nanomachine maps spatiotemporal pH changes in a multicellular living organism. AB - Structural DNA nanotechnology seeks to build synthetic molecular machinery from DNA. DNA nanomachines are artificially designed assemblies that switch between defined conformations in response to an external cue. Though it has proved possible to create DNA machines and rudimentary walkers, the function of such autonomous DNA-based molecular devices has not yet been achieved inside living organisms. Here we demonstrate the operation of a pH-triggered DNA nanomachine inside the nematode Caenorhabditis elegans. The nanomachine uses fluorescence resonance energy transfer to effectively map spatiotemporal pH changes associated with endocytosis in wild type as well as mutant worms, demonstrating autonomous function within the organismal milieu in a variety of genetic backgrounds. From this first demonstration of the independent functionality of a DNA nanomachine in vivo, we observe that rationally designed DNA-based molecular devices retain their in vitro functionality with quantitative precision. This positions DNA nanodevices as exciting and powerful tools to interrogate complex biological phenomena. PMID- 21654642 TI - The dose makes the poison. PMID- 21654641 TI - Developmental correspondence between action prediction and motor ability in early infancy. AB - How do infants understand the goals of others' actions? It has been proposed that action-understanding results from a mechanism whereby an observed action is mapped onto the observer's own motor representation of that action. However, direct evidence of the matching process in early infancy is difficult to find. Here we show the developmental correspondence between action prediction and motor ability by comparing gazing and grasping responses to interesting objects in 4- to 10-month-old infants and adults. The onset of infants' ability to predict the goal of others' action was found to be synchronized with the onset of their own ability to perform that action. Moreover, there was correspondence relationship between action-prediction ability and motor ability of same action. Our findings indicate that the ability to predict others' action goals requires a corresponding motor ability, providing ontogenetic evidence for a direct matching process by a mirror neuron system. PMID- 21654644 TI - News: Putting a damper on nanoresonators. PMID- 21654645 TI - In vitro studies: Ups and downs of cellular uptake. PMID- 21654646 TI - Covalent organic frameworks: Growing honeycombs on graphene. PMID- 21654647 TI - Nanoscale optics: Random resolution. PMID- 21654648 TI - The sequence is dead: long live the genome. PMID- 21654649 TI - First cystic fibrosis drug advances towards approval. PMID- 21654650 TI - Pfizer's JAK inhibitor sails through phase 3 in rheumatoid arthritis. PMID- 21654652 TI - Debate re-ignites on contribution of public research to drug development. PMID- 21654655 TI - Chinese vaccine developers gain WHO imprimatur. PMID- 21654659 TI - Spat over IMI funding and intellectual property. PMID- 21654660 TI - Raising hairs. PMID- 21654661 TI - Intranasal delivery to the brain. PMID- 21654662 TI - Quantitative analysis demonstrates most transcription factors require only simple models of specificity. PMID- 21654663 TI - Jury remains out on simple models of transcription factor specificity. PMID- 21654664 TI - US attitudes toward human embryonic stem cell research. PMID- 21654665 TI - Recurrent copy number variations in human induced pluripotent stem cells. PMID- 21654666 TI - Is silence still golden? Mapping the RNAi patent landscape. PMID- 21654668 TI - MicroRNAs and reprogramming. PMID- 21654669 TI - Human peptidome display. PMID- 21654670 TI - Molecular evolution picks up the PACE. PMID- 21654672 TI - Assessing the impact of China's Thousand Talents Program on life sciences innovation. PMID- 21654673 TI - PREDICT: a method for inferring novel drug indications with application to personalized medicine. AB - Inferring potential drug indications, for either novel or approved drugs, is a key step in drug development. Previous computational methods in this domain have focused on either drug repositioning or matching drug and disease gene expression profiles. Here, we present a novel method for the large-scale prediction of drug indications (PREDICT) that can handle both approved drugs and novel molecules. Our method is based on the observation that similar drugs are indicated for similar diseases, and utilizes multiple drug-drug and disease-disease similarity measures for the prediction task. On cross-validation, it obtains high specificity and sensitivity (AUC=0.9) in predicting drug indications, surpassing existing methods. We validate our predictions by their overlap with drug indications that are currently under clinical trials, and by their agreement with tissue-specific expression information on the drug targets. We further show that disease-specific genetic signatures can be used to accurately predict drug indications for new diseases (AUC=0.92). This lays the computational foundation for future personalized drug treatments, where gene expression signatures from individual patients would replace the disease-specific signatures. PMID- 21654674 TI - RNA sequencing reveals two major classes of gene expression levels in metazoan cells. AB - The expression level of a gene is often used as a proxy for determining whether the protein or RNA product is functional in a cell or tissue. Therefore, it is of fundamental importance to understand the global distribution of gene expression levels, and to be able to interpret it mechanistically and functionally. Here we use RNA sequencing (RNA-seq) of mouse Th2 cells, coupled with a range of other techniques, to show that all genes can be separated, based on their expression abundance, into two distinct groups: one group comprised of lowly expressed and putatively non-functional mRNAs, and the other of highly expressed mRNAs with active chromatin marks at their promoters. These observations are confirmed in many other microarray and RNA-seq data sets of metazoan cell types. PMID- 21654675 TI - Increasing rates of cervical cancer in young women in England: an analysis of national data 1982-2006. AB - BACKGROUND: In England, cervical cancer is the second most common cancer in women aged under 35 years. Overall incidence of cervical cancer has decreased since the introduction of the national screening programme in 1988 but recent trends of incidence in young women have not been studied in detail. METHODS: Information on 71,511 incident cases of cervical cancer in England, 1982-2006, in 20-79-year olds was extracted from a national cancer registration database. Changes in incidence were analysed by age group, time period and birth cohort. Poisson regression was used to estimate annual percentage change (APC). RESULTS: Overall incidence, during 1982-2006, fell significantly from 213 to 112 per million person years. However, in 20-29-year-olds, after an initial fall, incidence increased significantly during 1992-2006, (APC 2.16). In 30-39-year-olds incidence stabilised during the latter part of the study period. The pattern was most marked in the North East, Yorkshire and the Humber and East Midlands regions. Birth cohorts that were initially called for screening between 60-64 and 35-39 years of age show an incidence peak soon after the age of presumed first screen, whereas younger birth cohorts show a peak at about 35 years of age. Incidence in the 1977-1981 birth cohort has increased relative to that among women born between 1962 and 1976. CONCLUSION: These results have implications for cervical screening, human papilloma virus vaccination and other public health interventions targeting young people. PMID- 21654676 TI - D-glucuronyl C5-epimerase suppresses small-cell lung cancer cell proliferation in vitro and tumour growth in vivo. AB - BACKGROUND: D-Glucuronyl C5-epimerase (GLCE) is a key enzyme involved in the biosynthesis of heparan sulphate proteoglycans, which has an important role in cell-cell and cell-matrix interactions and signalling. Decreased GLCE expression in human breast tumours and its anti-proliferative effects in breast cancer cells suggest that it may be a candidate tumour-suppressor gene. The aim of this study was to investigate the involvement of GLCE in lung carcinogenesis. METHODS: D Glucuronyl C5-epimerase expression in different lung cancer cell lines was determined and the gene was ectopically re-expressed in U2020 small-cell lung cancer cells. Cellular proliferation in vitro and tumour growth in vivo were then examined. RESULTS: Ectopic re-expression of GLCE in U2020 cells did not affect cell viability but did influence morphology. Cellular proliferation in vitro and tumour formation in vivo were both suppressed. These effects were mediated via downregulation of several pro-angiogenic growth factors and their receptors, including VEGF-A, TGFB1, FGFR2, PDGF-A and PDGF-B, and TNFa and its receptors. Expression of matrix metalloproteinase2, MTA1, PLAU, TIMP3, S100A4, SERPINE1 and TWIST1 was also downregulated. CONCLUSION: The anti-tumour effects associated with ectopic GLCE re-expression suggest that it may be a potential tumour suppressor gene and a possible target for lung cancer diagnosis and treatment. PMID- 21654677 TI - Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis. AB - BACKGROUND: Meta-analyses of the published literature indicate that about 9% of gastric cancers contain Epstein-Barr virus (EBV), with consistent and significant differences by sex and anatomic subsite. This study aimed to identify additional determinants of EBV positivity and their joint effects. METHODS: From 15 international populations with consistent laboratory testing for EBV, we pooled individual-level data for 5081 gastric cancer cases including information on age, sex, subsite, histologic type, diagnostic stage, geographic region, and period of diagnosis. First, we combined population-specific EBV prevalence estimates using random effects meta-analysis. We then aggregated individual-level data to estimate odds ratios of EBV positivity in relation to all variables, accounting for within-population clustering. RESULTS: In unadjusted analyses, EBV positivity was significantly higher in males, young subjects, non-antral subsites, diffuse type histology, and in studies from the Americas. Multivariable analyses confirmed significant associations with histology and region. Sex interacted with age (P=0.003) and subsite (P=0.002) such that male predominance decreased with age for both subsites. The positivity of EBV was not significantly associated with either stage or time period. CONCLUSION: Aggregating individual-level data provides additional information over meta-analyses. Distinguishing histologic and geographic features as well as interactions among age, sex, and subsite further support classification of EBV-associated gastric cancer as a distinct aetiologic entity. PMID- 21654678 TI - A seven-gene prognostic model for platinum-treated ovarian carcinomas. AB - BACKGROUND: Prognosis of ovarian carcinoma is poor, heterogeneous, and not accurately predicted by histoclinical features. We analysed gene expression profiles of ovarian carcinomas to identify a multigene expression model associated with survival after platinum-based therapy. METHODS: Data from 401 ovarian carcinoma samples were analysed. The learning set included 35 cases profiled using whole-genome DNA chips. The validation set included 366 cases from five independent public data sets. RESULTS: Whole-genome unsupervised analysis could not distinguish poor from good prognosis samples. By supervised analysis, we built a seven-gene optimal prognostic model (OPM) out of 94 genes identified as associated with progression-free survival. Using the OPM, we could classify patients in two groups with different overall survival (OS) not only in the learning set, but also in the validation set. Five-year OS was 57 and 27% for the predicted 'Favourable' and 'Unfavourable' classes, respectively. In multivariate analysis, the OPM outperformed the individual current prognostic factors, both in the learning and the validation sets, and added independent prognostic information. CONCLUSION: We defined a seven-gene model associated with outcome in 401 ovarian carcinomas. Prospective studies are warranted to confirm its prognostic value, and explore its potential ability for better tailoring systemic therapies in advanced-stage tumours. PMID- 21654679 TI - Epstein-Barr virus microRNAs and lung cancer. AB - BACKGROUND: We conducted the first analysis of viral microRNAs (miRNAs) in lung cancer, with a focus on Epstein-Barr virus (EBV). METHODS: We evaluated viral miRs with a two-channel oligo-array targeting mature, anti-sense miRNAs in 290 cases. In 48 cases, we compared microarray and real-time quantitative PCR (qPCR) expression for three EBV miRNAs. We tested for EBV DNA, RNA, and protein in tumour tissue from six cases with and six cases without strong qPCR-based evidence of EBV miRNAs. RESULTS: The EBV miRNAs strongly differentiated between adenocarcinoma and squamous cell carcinoma using the microarray (P<0.01 for 9 out of 16 EBV miRNAs). However, microarray and qPCR measurements of BART1, BART2, and BHRF1-3 expression were not significantly correlated (P=0.53, 0.94, and 0.47, respectively). Although qPCR provided substantial evidence of EBV miRNAs in 7 out of 48 cases, only 1 of these 7 cases had detectable EBV DNA in tumour tissue. None had detectable EBV RNA or protein by histochemical stains. CONCLUSION: In a comprehensive evaluation of EBV miRNA, DNA, RNA, and protein in lung cancer, we found little evidence of EBV in lung tumour tissue. Discrepancies between microarray- and qPCR-based strategies highlight the difficulty of validating molecular markers of disease. Our results do not support a role of EBV in lung cancer. PMID- 21654680 TI - How to minimise the effect of tumour cell content in detection of aberrant genetic markers in neuroblastoma. AB - BACKGROUND: Clinical heterogeneity reflects the complexity of genetic events associated with neuroblastoma (NB). To identify the status of all described genetic loci with possible prognostic interest, high-throughput approaches have been used, but only with tumour cell content >60%. In some tumours, necrotic, haemorrhagic and/or calcification areas influence the low amount of neuroblasts. We evaluated the effect of tumour cell content in the detection of relevant aberrant genetic markers (AGM) diagnosed by fluorescence in situ hybridisation (FISH) on tissue microarrays (TMA) in NB. METHODS: Two hundred and thirty-three MYCN non-amplified primary NB included in 12 TMAs were analysed. RESULTS: Presence of AGM reduced event-free survival (EFS) (P=0.004) as well as overall survival (OS) (P=0.004) of patients in the whole cohort. There were no differences in prognostic impact of presence of AGM according to tumour cell content. CONCLUSION: We propose the use of FISH to diagnose AGM of all NB samples having the above-mentioned areas to determine patient risk. PMID- 21654681 TI - Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) remains by far the major cause of cancer related death in the Western world in both men and women. The majority of patients will be diagnosed with metastatic disease, and chemotherapy doublets remain the cornerstone of treatment for these patients. However, chemotherapy has a minimal impact on long-term survival and prognosis remains poor for these patients. Further improvement in treatment is likely to require incorporation of novel targeted therapies. Among these agents, inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated significant activity in the first-, second- or third-line treatment of NSCLC. The purpose of current paper is to present the evidence for using several proposed molecular biomarkers as a tool for selection of NSCLC patients for anti-EGFR treatment. According to current data, EGFR mutation status appears to be the strongest predictor for the selection of NSCLC patients to first-line treatment with EGFR tyrosine kinase inhibitors vs chemotherapy. Use of other biomarkers remains investigational. PMID- 21654682 TI - Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a meta-analysis. AB - BACKGROUND: Prostate-specific antigen (PSA) screening has low specificity. Assessment of methylation status in body fluids may complement PSA screening if the test has high specificity. METHOD: The purpose of this study was to conduct a meta-analysis of the sensitivity and specificity for prostate cancer detection of glutathione-s-transferase-pi (GSTP1) methylation in body fluids (plasma, serum, whole blood, urine, ejaculate, and prostatic secretions). We conducted a comprehensive literature search on Medline (Pubmed). We included studies if they met all four of the following criteria: (1) measurement of DNA methylation in body fluids; (2) a case-control or case-only design; (3) publication in an English journal; and (4) adult subjects. Reviewers conducted data extraction independently using a standardised protocol. Twenty-two studies were finally included in this paper. Primer sequences and methylation method in each study were summarised and evaluated using meta-analyses. This paper represents a unique cross-disciplinary approach to molecular epidemiology. RESULTS: The pooled specificity of GSTP1 promoter methylation measured in plasma, serum, and urine samples from negative-biopsy controls was 0.89 (95% CI, 0.80-0.95). Stratified analyses consistently showed a high specificity across different sample types and methylation methods (include both primer sequences and location). The pooled sensitivity was 0.52 (95% CI, 0.40-0.64). CONCLUSIONS: The pooled specificity of GSTP1 promoter methylation measures in plasma, serum, and urine was excellent and much higher than the specificity of PSA. The sensitivity of GSTP1 was modest, no higher than that of PSA. These results suggest that measurement of GSTP1 promoter methylation in plasma, serum, or urine samples may complement PSA screening for prostate cancer diagnosis. PMID- 21654683 TI - A promoting early presentation intervention increases breast cancer awareness in older women after 2 years: a randomised controlled trial. AB - BACKGROUND: We have developed the Promoting Early Presentation (PEP) Intervention to equip older women with the knowledge, skills, confidence and motivation to present promptly with breast symptoms, and thereby improve survival from breast cancer. The PEP Intervention consists of a 10-min interaction between a radiographer and an older woman, supported by a booklet. Our previous report showed that at 1 year, the PEP intervention increased the proportion who were breast cancer aware compared with usual care. METHODS: We randomised 867 women aged 67-70 years attending for their final routine appointment on the National Health Service Breast Screening Programme to receive the PEP Intervention, a booklet alone or usual care. The primary outcome was breast cancer awareness measured using a validated questionnaire asking about knowledge of breast cancer symptoms, knowledge that the risk of breast cancer increases with age and breast checking behaviour. RESULTS: At 2 years, the PEP Intervention increased the proportion who were breast cancer aware compared with usual care (21 vs 6%; odds ratio 8.1, 95% confidence interval 2.7-25.0). CONCLUSIONS: The uniquely large and sustained effect of the PEP Intervention on breast cancer awareness increases the likelihood that a woman will present promptly should she develop breast cancer symptoms up to many years later. PMID- 21654684 TI - Tumour-suppressor microRNAs let-7 and mir-101 target the proto-oncogene MYCN and inhibit cell proliferation in MYCN-amplified neuroblastoma. AB - BACKGROUND: MicroRNAs (miRNAs) regulate expression of many cancer-related genes through posttranscriptional repression of their mRNAs. In this study we investigate the proto-oncogene MYCN as a target for miRNA regulation. METHODS: A luciferase reporter assay was used to investigate software-predicted miRNA target sites in the 3'-untranslated region (3'UTR) of MYCN. The miRNAs were overexpressed in cell lines by transfection of miRNA mimics or miRNA-expressing plasmids. Mutation of the target sites was used to validate MYCN 3'UTR as a direct target of several miRNAs. To measure miRNA-mediated suppression of endogenous N-myc protein, inhibition of proliferation and inhibition of clonogenic growth, miRNAs were overexpressed in a MYCN-amplified neuroblastoma cell line. RESULTS: The results from this study show that MYCN is targeted by several miRNAs. In addition to the previously shown mir-34a/c, we experimentally validate mir-449, mir-19a/b, mir-29a/b/c, mir-101 and let-7e/mir-202 as direct MYCN-targeting miRNAs. These miRNAs were able to suppress endogenous N-myc protein in a MYCN-amplified neuroblastoma cell line. The let-7e and mir-202 were strong negative regulators of MYCN expression. The mir-101 and the let-7 family miRNAs let-7e and mir-202 inhibited proliferation and clonogenic growth when overexpressed in Kelly cells. CONCLUSION: The tumour-suppressor miRNAs let-7 and mir-101 target MYCN and inhibit proliferation and clonogenic growth of MYCN amplified neuroblastoma cells. PMID- 21654685 TI - HOXC11-SRC-1 regulation of S100beta in cutaneous melanoma: new targets for the kinase inhibitor dasatinib. AB - BACKGROUND: Cutaneous melanoma is an aggressive disease. S100beta is an established biomarker of disease progression; however, the mechanism of its regulation in melanoma is undefined. METHODS: Expression of HOXC11 and SRC-1 was examined by immunohistochemistry and immunofluorescence. Molecular and cellular techniques were used to investigate regulation of S100beta, including, western blot, qPCR, ChIP and migration assays. RESULTS: Expression levels of the transcription factor HOXC11 and its coactivator SRC-1 were significantly elevated in malignant melanoma in comparison with benign nevi (P<0.001 and P=0.017, respectively, n=80), and expression of HOXC11 and SRC-1 in the malignant tissue associated with each other (P<0.001). HOXC11 recruitment to the promoter of S100beta was observed in the primary melanoma cell line SKMel28. S100beta expression was found to be dependant on both HOXC11 and SRC-1. Treatment with the Src/Abl inhibitor, dasatinib, reduced HOXC11-SRC-1 interaction and prevented recruitment of HOXC11 to the S100beta promoter. Dasatinib inhibited both mRNA and protein levels of S100beta and reduced migration of the metastatic cell line MeWo. CONCLUSION: We have defined a signalling mechanism regulating S100beta in melanoma, which can be modulated by dasatinib. Profiling patients for expression of key markers of this network has the potential to increase the efficacy of dasatinib treatment. PMID- 21654686 TI - A systematic review to establish the frequency of cyclooxygenase-2 expression in normal breast epithelium, ductal carcinoma in situ, microinvasive carcinoma of the breast and invasive breast cancer. AB - BACKGROUND: Epidemiological studies have suggested a protective effect of cyclooxygenase (COX)-inhibiting non-steroidal anti-inflammatory drugs in breast cancer risk and disease progression. We performed a systematic review to evaluate the frequency of COX-2 expression in normal breast epithelium, ductal carcinoma in situ of breast (DCIS), DCIS-adjoining invasive breast cancer, microinvasive carcinoma of the breast (MICB) and invasive breast cancer. METHODS: Literature searches were carried out on MEDLINE, EMBASE and Web of Science from their commencement until September 2010. Primary studies examining COX-2 expression by immunohistochemistry methodology were included. Meta-analyses were carried out using random effects models for individual study estimates of COX-2 expression and pooled to give an overall estimate. RESULTS: The pooled prevalences (95% confidence intervals) of COX-2 expressions were 53% (44-61) in DCIS studies and 42% (36-49) in the invasive breast cancer studies. There were too few studies involving normal breast epithelium, DCIS-adjoining invasive breast cancer and MICB to conduct meta-analyses. CONCLUSION: The findings from our meta-analyses have shown similar COX-2 expression in DCIS and invasive breast cancer. This may suggest the involvement of COX-2 in early carcinogenesis. Further studies of COX 2 expression in DCIS are required to investigate the use of COX-2 as a potential drug target for prevention of disease progression in DCIS. PMID- 21654687 TI - Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT. AB - BACKGROUND: Women at high ovarian cancer risk, especially those with mutations in BRCA1/BRCA2, are encouraged to undergo bilateral risk-reducing salpingo oophorectomy (BRRSPO) prior to the natural menopause. The decision to use HRT to cover the period of oestrogen deprivation up to 50 years of age is difficult because of balancing the considerations of breast cancer risk, bone and cardiovascular health. METHODS: We reviewed by questionnaire 289 women after BRRSPO aged <=48 years because of high ovarian cancer risk; 212 (73%) of women responded. RESULTS: Previous HRT users (n=67) had significantly worse endocrine symptom scores than 67 current users (P=0.006). A total of 123 (58%) of women had >=24 months of oestrogen deprivation <50 years with 78 (37%) never taking HRT. Bone density (DXA) evaluations were available on 119 (56%) women: bone loss with a T score of <=-1.0 was present in 5 out of 31 (16%) women with no period of oestrogen deprivation <50 years compared with 37 out of 78 (47%) of those with >=24 months of oestrogen deprivation (P=0.03). INTERPRETATION: Women undergoing BRRSPO <50 years should be counselled concerning the risks/benefits of HRT, taking into consideration the benefits on symptoms, bone health and cardiovascular health, and that the risks of breast cancer from oestrogen-only HRT appear to be relatively small. PMID- 21654688 TI - A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer. AB - BACKGROUND: Infusional fluorouracil/leucovorin (FU/LV) plus irinotecan (FOLFIRI) is one of the standard first-line options for patients with metastatic colorectal cancer (mCRC). Irinotecan is converted into 7-ethyl-10-hydroxycamptothecin (SN 38) by a carboxylsterase and metabolised through uridine diphosphate glucuronosyl transferase (UGT1A1). The UGT1A1*28 allele has been associated with the risk of developing severe toxicities. The present trial was designed to define the maximum tolerated dose according to UGT1A1 genotype. This report focuses on the results of tolerance to different escalated doses of FOLFIRI first-line of chemotherapy. PATIENTS AND METHODS: Patients undergoing first-line treatment for mCRC and eligible for treatment with FOLFIRI were classified according to UGT1A1 genotype. A total of 94 patients were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 180 mg m(-2) for the *1/*1, 110 mg m(-2) for the *1/*28 and 90 mg m(-2) for the *28/*28 genotypes. RESULTS: The dose of irinotecan was escalated to 450 mg m(-2) in patients with the *1/*1 genotype, to 390 mg m(-2) in those with the *1/*28 genotype and to 150 mg m(-2) in those with the *28/*28 genotype. Neutropenia and diarrhoea were the most common grade 3 or 4 toxicities. CONCLUSIONS: Our results demonstrated that the recommended dose of 180 mg m(-2) for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated for patients with the UGT1A1 *1/*1 and *1/*28 genotypes. The maximum tolerable dose (MTD) in patients with a high-risk UGT1A1 *28/*28 genotype is 30% lower than the standard dose of 180 mg m(-2). PMID- 21654689 TI - Serum antibodies to the HPV16 proteome as biomarkers for head and neck cancer. AB - BACKGROUND: Human papillomavirus (HPV) type 16 is associated with oropharyngeal carcinomas (OPC). Antibodies (Abs) to HPV16 E6 and E7 oncoproteins have been detected in patient sera; however, Abs to other early HPV-derived proteins have not been well explored. METHODS: Antibodies to the HPV16 proteome were quantified using a novel multiplexed bead assay, using C-terminal GST-fusion proteins captured onto Luminex beads. Sera were obtained from untreated patients with OPC (N=40), partners of patients with HPV16+ OPC (N=11), and healthy controls (N=50). RESULTS: Oropharyngeal carcinomas patients with known virus-like capsid particle+ Abs had elevated serum Abs to HPV16 E1, E2, E4, E6, and E7, and L1 antibody levels, but not E5. The ratios of specific median fluorescence intensity to p21 GST compared with controls were E1: 50.7 vs 2.1; E4: 14.6 vs 1.3; E6: 11.3 vs 2.4; E7: 43.1 vs 2.6; and L1: 10.3 vs 2.6 (each P<=0.01). In a validation cohort, HPV16 E1, E2, and E7 antibody levels were significantly elevated compared with healthy control samples (P<=0.02) and partners of OPC patients (P<=0.01). CONCLUSION: Patients with HPV16+ OPC have detectable Abs to E1, E2, and E7 proteins, which are potential biomarkers for HPV-associated OPC. PMID- 21654696 TI - Protein therapy using heme-oxygenase-1 fused to a polyarginine transduction domain attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. AB - A sequence of 11 consecutive arginine residues (11R) is one of the best protein transduction domains for introducing proteins into cell membranes. Heme-oxygenase 1 (HO-1) is involved in heme catabolism and reduces the contractile effect of hemoglobin after subarachnoid hemorrhage (SAH). Therefore, we constructed 11R fused HO-1 protein to achieve successful transduction of the protein into the cerebral arteries and examined the therapeutic effect of the 11R-HO-1 protein for cerebral vasospasm (CV) after SAH. We injected the 11R-HO-1 protein into the cisterna magna of male rats and, several hours after the injection, performed immunofluorescence staining and western blotting analysis of the rat basilar arteries (BAs) to determine transduction efficacy. We also assessed intraarterial HO-1 activity as cGMP (cyclic guanosine 3', 5'-cyclic monophosphate) accumulation in SAH and determined whether protein transduction of 11R-HO-1 quantified the therapeutic effect in a rat double-hemorrhage model of SAH. The BAs expressed significantly more HO-1 in the group injected with 11R-HO-1 (3.56+/-0.54 (11R-HO 1) versus control (saline)), and transduction of 11R-HO-1 resulted in higher activity (>3.25-fold) in rat BAs with SAH. Moreover, the results of the rat double-hemorrhage model showed that the 11R-HO-1 protein significantly attenuated CV after SAH (317.59+/-23.48 MUm (11R-HO-1) versus 270.08+/-14.66 MUm (11R-fused enhanced green fluorescent protein), 252.05+/-13.95 MUm (saline), P<0.01). PMID- 21654698 TI - Labeled acetate as a marker of astrocytic metabolism. AB - Astrocytes have various important roles in brain physiology. To further elucidate the details of astrocytic functions under normal and pathological states, astrocyte-specific measurements are mandatory. For studying brain energy metabolism, the use of the astrocyte-specific energy substrate acetate has proven to be of great value. Since the first applications of labeled acetate for brain studies about 50 years ago, numerous methodologies have been developed and employed in compartment-specific investigations of brain metabolism. Here, we provide an overview of these different methodological approaches and review studies employing acetate labeled with the most commonly used carbon isotopes. PMID- 21654697 TI - Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia--an ultrasound and MRI study. AB - Transcranial Doppler is a widely used noninvasive technique for assessing cerebral artery blood flow. All previous high altitude studies assessing cerebral blood flow (CBF) in the field that have used Doppler to measure arterial blood velocity have assumed vessel diameter to not alter. Here, we report two studies that demonstrate this is not the case. First, we report the highest recorded study of CBF (7,950 m on Everest) and demonstrate that above 5,300 m, middle cerebral artery (MCA) diameter increases (n=24 at 5,300 m, 14 at 6,400 m, and 5 at 7,950 m). Mean MCA diameter at sea level was 5.30 mm, at 5,300 m was 5.23 mm, at 6,400 m was 6.66 mm, and at 7,950 m was 9.34 mm (P<0.001 for change between 5,300 and 7,950 m). The dilatation at 7,950 m reversed with oxygen. Second, we confirm this dilatation by demonstrating the same effect (and correlating it with ultrasound) during hypoxia (FiO(2)=12% for 3 hours) in a 3-T magnetic resonance imaging study at sea level (n=7). From these results, we conclude that it cannot be assumed that cerebral artery diameter is constant, especially during alterations of inspired oxygen partial pressure, and that transcranial 2D ultrasound is a technique that can be used at the bedside or in the remote setting to assess MCA caliber. PMID- 21654700 TI - Effect of multiple micronutrient-fortified food on mild morbidity and clinical symptoms in Zambian infants: results from a randomised controlled trial. AB - BACKGROUND/OBJECTIVES: We aimed to assess the effects on mild morbidity of a richly micronutrient-fortified complementary/replacement food given to Zambian infants aged 6-18 months. Previous results (The Chilenje Infant Growth, Nutrition and Infection Study Team, 2010) showed an increase in the rate of hospital referral for pneumonia in the same cohort. SUBJECT/METHODS: A total of 743 six month-old healthy Zambian infants were randomised to receive either a richly or a basal micronutrient-fortified porridge for 12 months. Mild morbidity was defined as an illness that did not cause death or require hospitalisation and was diagnosed on clinical examination at scheduled visits. RESULTS: There was no evidence of an effect of trial arm on overall mild morbidity during the study (odds ratio (OR)=1.04, 95% confidence interval (CI)=0.90, 1.20, P=0.62). Infants in the richly fortified arm had significantly more visits in which they were diagnosed with lower respiratory tract infections/pneumonia (OR=1.65, 95% CI=1.06, 2.59, P=0.03) and fewer visits in which a diagnosis of urinary tract infection was made (OR=0.43, 95% CI=0.21, 0.87, P=0.02). Maternally reported symptoms were similar between trial arms. CONCLUSION: Compared with the basal diet, the richly micronutrient-fortified food was associated with more episodes of lower respiratory infections/pneumonia diagnosed at scheduled visits, which reinforces our previously reported findings of a higher incidence in hospital referral for pneumonia. PMID- 21654699 TI - Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability. AB - The cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) is an important factor determining the functional state of blood-brain barrier (BBB) endothelial cells but little is known on the effect of dynamic [Ca(2+)](i) changes on BBB function. We applied different agonists that trigger [Ca(2+)](i) oscillations and determined the involvement of connexin channels and subsequent effects on endothelial permeability in immortalized and primary brain endothelial cells. The inflammatory peptide bradykinin (BK) triggered [Ca(2+)](i) oscillations and increased endothelial permeability. The latter was prevented by buffering [Ca(2+)](i) with BAPTA, indicating that [Ca(2+)](i) oscillations are crucial in the permeability changes. Bradykinin-triggered [Ca(2+)](i) oscillations were inhibited by interfering with connexin channels, making use of carbenoxolone, Gap27, a peptide blocker of connexin channels, and Cx37/43 knockdown. Gap27 inhibition of the oscillations was rapid (within minutes) and work with connexin hemichannel-permeable dyes indicated hemichannel opening and purinergic signaling in response to stimulation with BK. Moreover, Gap27 inhibited the BK-triggered endothelial permeability increase in in vitro and in vivo experiments. By contrast, [Ca(2+)](i) oscillations provoked by exposure to adenosine 5' triphosphate (ATP) were not affected by carbenoxolone or Gap27 and ATP did not disturb endothelial permeability. We conclude that interfering with endothelial connexin hemichannels is a novel approach to limiting BBB-permeability alterations. PMID- 21654701 TI - A diet rich in oat bran improves blood lipids and hemostatic factors, and reduces apparent energy digestibility in young healthy volunteers. AB - BACKGROUND/OBJECTIVES: Oat bran shows cholesterol-lowering properties, but its effects on other cardiovascular risk markers are less frequently investigated. This study examined the effects of oat bran on blood lipids, hemostatic factors and energy utilization. SUBJECTS/METHODS: A double-blind, randomized crossover study in 24 adults (age 25.2+/-2.7 years; body mass index: 24.9+/-2.9 kg/m2), who completed two 2-week dietary intervention periods: low-fiber diet (control) or an oat bran (control +102 g oat bran/day) diet. Fasting blood samples were drawn before and after each period, and 3-day fecal samples were collected during the last week of each period. RESULTS: Total cholesterol decreased by 14% during the oat bran period compared with 4% during the control period (P<0.001). Non-high density lipoprotein (HDL) cholesterol decreased by 16% in the oat bran period compared with 3% in the control period (P<0.01), as did total triacylglycerol (21 vs 10%, P<0.05) and very-low-density lipoprotein triacylglycerol 33 vs 9%, P<0.01). Plasminogen activator inhibitor-1 (PAI-1) and factor VII (fVII) levels decreased more during consumption of oat bran compared with the control period (PAI-1: 30 vs 2.3%, P<0.01; fVII: 15 vs 7.6%, <0.001). Fecal volume and dry matter were greater when consuming the oat bran diet compared with the control (P<0.001), and energy excretion was increased by 37% (1014 vs 638 kJ/day, P<0.001); however, changes in body weight did not differ (oat bran:-0.3+/-0.5 kg; control: 0.0+/-0.7 kg). CONCLUSIONS: Addition of oat bran (6 g soluble fiber/day) to a low-fiber diet lowered total and non-HDL cholesterol, as well as hemostatic factors, and may affect energy balance through reduced energy utilization. PMID- 21654703 TI - Evolution: three major steps to a mammalian brain. PMID- 21654704 TI - Autism: converging pathways. PMID- 21654705 TI - Tinkering with nature. PMID- 21654702 TI - Dietary fiber intake and risk of cardiovascular disease in the Japanese population: the Japan Public Health Center-based study cohort. AB - BACKGROUND/OBJECTIVES: There has been no study with regard to the association between dietary fibers and the incidence of stroke and coronary heart disease (CHD) in Asia. We investigated the association between dietary fiber and the risk of cardiovascular disease (CVD), which we defined as stroke or CHD, in a Japanese population. SUBJECTS/METHODS: We studied 86 387 Japanese subjects (age 45-65 years, without CVD or cancer in 1995 as Cohort I and in 1998 as Cohort II) and used a self-administered questionnaire to follow-up the participants until the end of 2004. Dietary fiber intake was estimated from food-frequency questionnaires comprising 138 food items. RESULTS: After 899 141 person-years of follow-up, we documented the incidence of 2553 strokes and 684 cases of CHD. Multivariable-adjusted hazard ratios (95% confidence intervals (CIs)) of CVD for the third to fifth quintiles of total fiber were 0.79 (0.63-0.99), 0.70 (0.54 0.89) and 0.65 (0.48-0.87) in women, respectively, compared with the lowest quintile. Total fiber intake was inversely associated with the incidence of stroke, either cerebral infarction or intracerebral hemorrhage in women. The results for insoluble fiber in women were similar to those for total fiber, whereas those for soluble fiber were weak. An inverse association of total fiber with CVD was observed primarily in non-smokers (P for trend=0.045 and 0.001) and not in smokers (probability values for interaction between total fiber and smoking were 0.06 and 0.01 in men and women, respectively). CONCLUSIONS: Higher total dietary fiber was associated with reduced risk of CVD in Japanese non smokers. PMID- 21654706 TI - Non-coding RNA: A new molecular pathway for TP53. PMID- 21654708 TI - Overweight or obesity during midlife is associated with late-life dementia. PMID- 21654707 TI - Autophagy: TFEB perfects multitasking. PMID- 21654709 TI - RAPID MRI analysis may speed up selection for tPA therapy. PMID- 21654710 TI - Stem cells reveal mechanisms of myotonic dystrophy type 1. PMID- 21654711 TI - MRI may predict the onset of Alzheimer disease. PMID- 21654712 TI - High levels of maternal vitamin D may be protective against multiple sclerosis. PMID- 21654713 TI - ROR blockers inhibit T(H)17 cells. PMID- 21654714 TI - miR-34b-a novel plasma marker for Huntington disease? PMID- 21654715 TI - Multiple sclerosis: HLA-DRB1 genotypes linked to the risk of developing neutralizing antibodies to recombinant IFN-beta during therapy. PMID- 21654716 TI - Epilepsy: Efficacy of epilepsy surgery: what are the questions today? AB - Consistent with previous findings, two recent studies of temporal lobectomy from Kerala, India demonstrate that early seizure recurrence bodes poorly for long term seizure control, and that relapse following drug discontinuation affects one third of patients. Key questions in the field now concern advanced preoperative and intraoperative techniques for improving surgical outcomes. PMID- 21654718 TI - Universal GFR determination based on two time points during plasma iohexol disappearance. AB - An optimal measurement of glomerular filtration rate (GFR) should minimize the number of blood draws, and reduce procedural invasiveness and the burden to study personnel and cost, without sacrificing accuracy. Equations have been proposed to calculate GFR from the slow compartment separately for adults and children. To develop a universal equation, we used 1347 GFR measurements from two diverse groups consisting of 527 men in the Multicenter AIDS Cohort Study and 514 children in the Chronic Kidney Disease in Children cohort. Both studies used nearly identical two-compartment (fast and slow) protocols to measure GFR. To estimate the fast component from markers of body size and of the slow component, we used standard linear regression methods with the log-transformed fast area as the dependent variable. The fast area could be accurately estimated from body surface area by a simple parameter (6.4/body surface area) with no residual dependence on the slow area or other markers of body size. Our equation measures only the slow iohexol plasma disappearance curve with as few as two time points and was normalized to 1.73 m2 body surface area. It is of the form: GFR=slowGFR/[1+0.12(slowGFR/100)]. In a random sample utilizing a third of the patients for validation, there was excellent agreement between the calculated and measured GFR with low root mean square errors being 4.6 and 1.5 ml/min per 1.73 m2 for adults and children, respectively. Thus, our proposed simple equation, developed in a combined patient group with a broad range of GFRs, may be applied universally and is independent of the injected amount of iohexol. PMID- 21654717 TI - Autoimmune myopathies: autoantibodies, phenotypes and pathogenesis. AB - The different autoimmune myopathies-for example, dermatomyositis, polymyositis, and immune-mediated necrotizing myopathies (IMNM)-have unique muscle biopsy findings, but they also share specific clinical features, such as proximal muscle weakness and elevated serum levels of muscle enzymes. Furthermore, around 60% of patients with autoimmune myopathy have been shown to have a myositis-specific autoantibody, each of which is associated with a distinct clinical phenotype. The typical clinical presentations of the autoimmune myopathies are reviewed here, and the different myositis-specific autoantibodies, including the anti-synthetase antibodies, dermatomyositis-associated antibodies, and IMNM-associated antibodies, are discussed in detail. This Review also focuses on a newly recognized form of IMNM that is associated with statin use and the production of autoantibodies that recognize 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the pharmacological target of statins. The contribution of interferon signaling to the development of dermatomyositis and the potential link between malignancies and the initiation of autoimmune myopathies are also assessed. PMID- 21654719 TI - Cognitive-behavioral therapy for sleep disturbance decreases inflammatory cytokines and oxidative stress in hemodialysis patients. AB - Sleep disturbance is common in dialysis patients and is associated with the development of enhanced inflammatory responses. Cognitive-behavioral therapy is effective for sleep disturbance and reduces inflammation experienced by peritoneal dialysis patients; however, this has not been studied in hemodialysis patients. To determine whether alleviation of sleep disturbance in hemodialysis patients also leads to less inflammation, we conducted a randomized controlled interventional study of 72 sleep-disturbed hemodialysis patients. Within this patient cohort, 37 received tri-weekly cognitive-behavioral therapy lasting 6 weeks and the remaining 35, who received sleep hygiene education, served as controls. The adjusted post-trial primary outcome scores of the Pittsburgh Sleep Quality Index, the Fatigue Severity Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory were all significantly improved from baseline by therapy compared with the control group. The post-trial secondary outcomes of high sensitive C-reactive protein, IL-18, and oxidized low-density lipoprotein levels significantly declined with cognitive-behavioral therapy in comparison with the control group. Thus, our results suggest that cognitive-behavioral therapy is effective for correcting disorganized sleep patterns, and for reducing inflammation and oxidative stress in hemodialysis patients. PMID- 21654720 TI - Myeloproliferative neoplasms cause glomerulopathy. AB - Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders that can produce an undefined glomerulopathy. To better characterize the glomerular disease associated with myeloproliferative neoplasms, we evaluated features of 11 patients with myeloproliferative neoplasm-related glomerulopathy that included 8 patients with primary myelofibrosis, and 1 each with chronic myelogenous leukemia, polycythemia vera, and essential thrombocythemia. Indications for biopsy were nephrotic-range proteinuria (nephrotic syndrome in four) and chronic renal insufficiency. The mean time from diagnosis of the neoplasms to biopsy was 7.2 years. Histologically, mesangial sclerosis and hypercellularity were seen in all 11 cases, segmental sclerosis in 8, features of chronic thrombotic microangiopathy in 9, and intracapillary hematopoietic cells in 4. On follow-up, seven patients had persistent renal dysfunction and four progressed to end-stage renal disease (ESRD). Thus, glomerulopathy appears to be a late complication of myeloproliferative neoplasms, particularly primary myelofibrosis, with guarded prognosis. Greater awareness of this entity and larger studies are needed to define possible therapies. PMID- 21654721 TI - The rediscovery of uromodulin (Tamm-Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease. AB - Uromodulin (Tamm-Horsfall protein) is the most abundant protein excreted in the urine under physiological conditions. It is exclusively produced in the kidney and secreted into the urine via proteolytic cleavage. Its biological function is still not fully understood. Uromodulin has been linked to water/electrolyte balance and to kidney innate immunity. Also, studies in knockout mice demonstrated that it has a protective role against urinary tract infections and renal stone formation. Mutations in the gene encoding uromodulin lead to rare autosomal dominant diseases, collectively referred to as uromodulin-associated kidney diseases. They are characterized by progressive tubulointerstitial damage, impaired urinary concentrating ability, hyperuricemia, renal cysts, and progressive renal failure. Novel in vivo studies point at intracellular accumulation of mutant uromodulin as a key primary event in the disease pathogenesis. Recently, genome-wide association studies identified uromodulin as a risk factor for chronic kidney disease (CKD) and hypertension, and suggested that the level of uromodulin in the urine could represent a useful biomarker for the development of CKD. In this review, we summarize these recent investigations, ranging from invalidation studies in mouse to Mendelian disorders and genome-wide associations, which led to a rediscovery of uromodulin and boosted the scientific and clinical interest for this long discovered molecule. PMID- 21654722 TI - Clinical utility gene card for: haemophilia A. PMID- 21654723 TI - An atlas of tissue-specific conserved coexpression for functional annotation and disease gene prediction. AB - Gene coexpression relationships that are phylogenetically conserved between human and mouse have been shown to provide important clues about gene function that can be efficiently used to identify promising candidate genes for human hereditary disorders. In the past, such approaches have considered mostly generic gene expression profiles that cover multiple tissues and organs. The individual genes of multicellular organisms, however, can participate in different transcriptional programs, operating at scales as different as single-cell types, tissues, organs, body regions or the entire organism. Therefore, systematic analysis of tissue specific coexpression could be, in principle, a very powerful strategy to dissect those functional relationships among genes that emerge only in particular tissues or organs. In this report, we show that, in fact, conserved coexpression as determined from tissue-specific and condition-specific data sets can predict many functional relationships that are not detected by analyzing heterogeneous microarray data sets. More importantly, we find that, when combined with disease networks, the simultaneous use of both generic (multi-tissue) and tissue-specific conserved coexpression allows a more efficient prediction of human disease genes than the use of generic conserved coexpression alone. Using this strategy, we were able to identify high-probability candidates for 238 orphan disease loci. We provide proof of concept that this combined use of generic and tissue-specific conserved coexpression can be very useful to prioritize the mutational candidates obtained from deep-sequencing projects, even in the case of genetic disorders as heterogeneous as XLMR. PMID- 21654724 TI - Clinical utility gene card for: Aarskog-Scott syndrome (faciogenital dysplasia). PMID- 21654725 TI - Gene and genetic diagnostic method patent claims: a comparison under current European and US patent law. AB - The paper focuses on the fundamental debate that is going on in Europe and the United States about whether genes and genetic diagnostic methods are to be regarded as inventions or subject matter eligible for patent protection, or whether they are discoveries or principles of nature and thus excluded from patentability. The study further explores some possible scenarios of American influences on European patent applications with respect to genetic diagnostic methods. Our analysis points out that patent eligibility for genes and genetic diagnostic methods, as discussed in the United States in the Association of Molecular Pathology versus US Patent and Trademark Office decision, is based on a different reasoning compared with the European Patent Convention. PMID- 21654726 TI - Renal coloboma syndrome. AB - Renal coloboma syndrome (RCS), also called papillorenal syndrome, is an autosomal dominant condition characterized by optic nerve dysplasia and renal hypodysplasia. The eye anomalies consist of a wide and sometimes excavated dysplastic optic disc with the emergence of the retinal vessels from the periphery of the disc, frequently called optic nerve coloboma or morning glory anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst and pigmentary macular dysplasia. The kidney abnormalities consist of small and abnormally formed kidneys known as renal hypodysplasia. Histologically, kidneys exhibit fewer than the normal number of glomeruli and these glomeruli are enlarged, a finding called oligomeganephronia. Consequences of the ocular malformations include decreased visual acuity and retinal detachment. Consequences of the renal hypodysplasia include hypertension, proteinuria and renal insufficiency that frequently progresses to end-stage kidney disease. High frequency hearing loss has been reported. Autosomal dominant mutations in PAX2 can be identified in nearly half of all patients with clinical findings suggestive of RCS, however, the majority of published cases have mutations in PAX2, thus biasing the known information about the phenotype. PMID- 21654727 TI - Duplication at chromosome 2q31.1-q31.2 in a family presenting syndactyly and nystagmus. AB - HOXD genes encode transcription factors involved in the antero-posterior patterning of the limb bud and in the specification of fingers. During the embryo development, HOXD genes are expressed, following a spatio-temporal colinearity that involves at least three regions, centrometric and telomeric to this cluster. Here, we describe a father and a daughter presenting a 3-4 hand bilateral syndactyly associated with a nystagmus. Array-comparative genomic hybridisation showed a 3.8 Mb duplication at 2q31.1-q31.2, comprising 27 genes including the entire HOXD cluster. We performed expression studies in lymphoblasts by reverse transcription-PCR and observed an HOXD13 and HOXD10 overexpression, whereas the HOXD12 expression was decreased. HOXD13 and HOXD10 overexpression, associated with a misregulation of at least HOXD12, may therefore induce the syndactyly. Deletions of the HOXD cluster and its regulatory sequences induce hand malformations and, particularly, finger anomalies. Recently, smaller duplications of the same region have been reported in association with a mesomelic dysplasia, type Kantaputra. We discuss the variable phenotypes associated with such 2q duplications. PMID- 21654728 TI - Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene. AB - We report on three hydropic fetuses of 17, 22 and 25 gestational weeks from three distinct families presenting with Desbuquois dysplasia type 1. All fetuses showed brachymelia and characteristic dysmorphic features. X-ray studies revealed delta shaped extraphalangeal bones and disease-specific prominence of the lesser trochanter, varying in severity with fetal age. Early lethal manifestation of the disorder was reflected in lung hypoplasia and in early death of similarly affected siblings in cases 1 and 2. All families were German Caucasians by descent. Sequence analysis of the CANT1 gene revealed two frameshift mutations, c.228_229insC and c.277_278delCT, in homozygous and compound heterozygous configuration, respectively, and a homozygously novel missense mutation, c.336C>A (p.D112E), located within a highly conserved region of exon 2. Haplotype analyses by high-resolution single-nucleotide polymorphism array showed that the haplotype associated with c.228_229insC may be traced to a single founder in the German population. PMID- 21654729 TI - Haploinsufficiency of ANKRD11 causes mild cognitive impairment, short stature and minor dysmorphisms. PMID- 21654730 TI - Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes. AB - ART is suspected to generate increased imprinting errors in the lineage. Following an intra cytoplasmic sperm injection (ICSI) procedure, a certain number of embryos fail to develop normally and imprinting disorders may be associated to the developmental failure. To evaluate this hypothesis, we analysed the methylation profile of H19DMR, a paternally imprinting control region, in high graded blastocysts, in embryos showing developmental anomalies, in the matching sperm and in oocytes of the concerned couples when they were available. Significant hypomethylation of the paternal allele was observed in half of the embryos, independently of the stage at which they were arrested (morula, compacted morula, pre blastocyst or BC-graded blastocysts). Conversely, some embryos showed significant methylation on the maternal allele, whereas few others showed both hypomethylation of the paternal allele and abnormal methylation of the maternal allele. The matching sperm at the origin of the embryos exhibited normal methylated H19 patterns. Thus, hypomethylation of the paternal allele in the embryos does not seem inherited from the sperm but likely reflects instability of the imprint during the demethylating process, which occurred in the early embryo. Analysis of a few oocytes suggests that the defect in erasure of the paternal imprint in the maternal germ line may be responsible for the residual methylation of the maternal allele in some embryos. None of these imprinting alterations could be related to a particular stage of developmental arrest; compared with high-grade blastocysts, embryos with developmental failure are more likely to have abnormal imprinting at H19 (P<0.05). PMID- 21654731 TI - Mosaics and moles. AB - Hydatidiform mole (HM) is an abnormal human pregnancy, where the placenta presents with vesicular swelling of the chorionic villi. A fetus is either not present, or malformed and not viable. Most moles are diploid androgenetic as if one spermatozoon fertilized an empty oocyte, or triploid with one maternal and two paternal chromosome sets as if two spermatozoa fertilized a normal oocyte. However, diploid moles with both paternal and maternal markers of the nuclear genome have been reported. Among 162 consecutively collected diploid moles, we have earlier found indications of both maternal and paternal genomes in 11. In the present study, we have performed detailed analysis of DNA-markers in tissue and single cells from these 11 HMs. In 3/11, we identified one biparental cell population only, whereas in 8/11, we demonstrated mosaicism: one biparental cell population and one androgenetic cell population. One mosaic mole was followed by persistent trophoblastic disease (PTD). In seven of the mosaics, one spermatozoon appeared to have contributed to the genomes of both cell types. Our observations make it likely that mosaic conceptuses, encompassing an androgenetic cell population, result from various postzygotic abnormalities, including paternal pronuclear duplication, asymmetric cytokinesis, and postzygotic diploidization. This corroborates the suggestion that fertilization of an empty egg is not mandatory for the creation of an androgenetic cell population. Future studies of mosaic conceptuses may disclose details about fertilization, early cell divisions and differentiation. Apparently, only a minority of diploid moles with both paternal and maternal markers are 'genuine' diploid biparental moles (DiBiparHMs). PMID- 21654732 TI - A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. AB - Linkage testing using Affymetrix 6.0 SNP Arrays mapped the disease locus in TCD G, an Irish family with autosomal dominant retinitis pigmentosa (adRP), to an 8.8 Mb region on 1p31. Of 50 known genes in the region, 11 candidates, including RPE65 and PDE4B, were sequenced using di-deoxy capillary electrophoresis. Simultaneously, a subset of family members was analyzed using Agilent SureSelect All Exome capture, followed by sequencing on an Illumina GAIIx platform. Candidate gene and exome sequencing resulted in the identification of an Asp477Gly mutation in exon 13 of the RPE65 gene tracking with the disease in TCD G. All coding exons of genes not sequenced to sufficient depth by next generation sequencing were sequenced by di-deoxy sequencing. No other potential disease causing variants were found to segregate with disease in TCD-G. The Asp477Gly mutation was not present in Irish controls, but was found in a second Irish family provisionally diagnosed with choroideremia, bringing the combined maximum two-point LOD score to 5.3. Mutations in RPE65 are a known cause of recessive Leber congenital amaurosis (LCA) and recessive RP, but no dominant mutations have been reported. Protein modeling suggests that the Asp477Gly mutation may destabilize protein folding, and mutant RPE65 protein migrates marginally faster on SDS-PAGE, compared with wild type. Gene therapy for LCA patients with RPE65 mutations has shown great promise, raising the possibility of related therapies for dominant-acting mutations in this gene. PMID- 21654733 TI - Moderation of adult depression by a polymorphism in the FKBP5 gene and childhood physical abuse in the general population. AB - Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic-pituitary-adrenal axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid-receptor sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childhood abuse with rs1360780 in predicting adult depression. In all, 2157 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and Childhood Trauma Questionnaire. The DSM-IV diagnosis of major depressive disorder (MDD) was assessed by interview. Genotypes of rs1360780 were taken from the Affymetrix Human SNP Array 6.0. Significant interaction (p=0.006) of physical abuse with the TT genotype of rs1360780 was found increasing the BDI-II score to 17.4 (95% confidence interval (CI)=12.0-22.9) compared with 10.0 (8.2-11.7) in exposed CC/CT carriers. Likewise, the adjusted odds ratio for MDD in exposed TT carriers was 8.2 (95% CI=1.9-35.0) compared with 1.3 (0.8-2.3) in exposed subjects with CC/CT genotypes. Relative excess risk due to interaction (RERI) analyses confirmed a significant additive interaction effect (RERI=6.8; 95% CI=0.64-33.7; p<0.05). In explorative analyses, the most severe degree of sexual and emotional abuse also yielded significant interaction effects (p<0.05). This study revealed interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression. Given the large effect sizes, rs1360780 could be included into prediction models for depression in individuals exposed to childhood abuse. PMID- 21654734 TI - The metabotropic glutamate 2/3 receptor agonist LY379268 blocked nicotine-induced increases in nucleus accumbens shell dopamine only in the presence of a nicotine associated context in rats. AB - The metabotropic glutamate 2/3 (mGlu2/3) receptor agonist LY379268 ([-]-2-oxa-4 aminobicyclo [3.1.0] hexane-4,6-dicarboxylate) attenuates both nicotine self administration and cue-induced nicotine seeking in rats. In this study, the effects of LY379268 (1 mg/kg) or saline pretreatment on nicotine-induced increases in nucleus accumbens (NAcc) shell dopamine were evaluated using in vivo microdialysis under different experimental conditions: (i) nicotine (0.4 mg/kg, base) was experimenter-administered subcutaneously to nicotine-naive rats; (ii) nicotine was experimenter-administered either subcutaneously (0.4 mg/kg) or by a single experimenter-administered infusion (0.06 mg/kg, base) in rats with a history of nicotine self-administration (nicotine experienced) in the absence of a nicotine-associated context (ie, context and cues associated with nicotine self administration); (iii) nicotine (0.06 mg/kg) was self-administered or experimenter-administered in nicotine-experienced rats in the presence of a nicotine-associated context. In saline-pretreated nicotine-naive and nicotine experienced rats, nicotine increased NAcc shell dopamine regardless of the context used for testing. Interestingly, LY379268 pretreatment blocked nicotine induced increases in NAcc shell dopamine in nicotine-experienced rats only when tested in the presence of a nicotine-associated context. LY379268 did not block nicotine-induced increases in NAcc shell dopamine in nicotine-naive or experienced rats tested in the absence of a nicotine-associated context. These intriguing findings suggest that activation of mGlu2/3 receptors negatively modulates the combined effects of nicotine and nicotine-associated contexts/cues on NAcc dopamine. Thus, these data highlight a critical role for mGlu2/3 receptors in context/cue-induced drug-seeking behavior and suggest a neurochemical mechanism by which mGlu2/3 receptor agonists may promote smoking cessation by preventing relapse induced by the combination of nicotine and nicotine-associated contexts and cues. PMID- 21654735 TI - Abnormal medial prefrontal cortex resting-state connectivity in bipolar disorder and schizophrenia. AB - Bipolar disorder and schizophrenia overlap in symptoms and may share some underlying neural substrates. The medial prefrontal cortex (MPFC) may have a crucial role in the psychophysiology of both these disorders. In this study, we examined the functional connectivity between MPFC and other brain regions in bipolar disorder and schizophrenia using resting-state functional magnetic resonance imaging (fMRI). Resting-state fMRI data were collected from 14 patients with bipolar disorder, 16 patients with schizophrenia, and 15 healthy control subjects. Functional connectivity maps from the MPFC were computed for each subject and compared across the three groups. The three groups showed distinctive patterns of functional connectivity between MPFC and anterior insula, and between MPFC and ventral lateral prefrontal cortex (VLPFC). The bipolar disorder group exhibited positive correlations between MPFC and insula, and between MPFC and VLPFC, whereas the control group exhibited anticorrelations between these regions. The schizophrenia group did not exhibit any resting-state correlation or anticorrelation between the MPFC and the VLPFC or insula. In contrast, neither patient group exhibited the significant anticorrelation between dorsal lateral prefrontal cortex (DLPFC) and MPFC that was exhibited by the control group. The decoupling of DLPFC with MPFC in bipolar disorder and schizophrenia is consistent with the impaired executive functioning seen in these disorders. Functional connectivity between MPFC and insula/VLPFC distinguished bipolar disorder from schizophrenia, and may reflect differences in the affective disturbances typical of each illness. PMID- 21654736 TI - MU-Opioid receptor coupling to Galpha(o) plays an important role in opioid antinociception. AB - Opioid analgesics elicit their effects via activation of the mu-opioid receptor (MOR), a G protein-coupled receptor known to interact with Galpha(i/o)-type G proteins. Work in vitro has suggested that MOR couples preferentially to the abundant brain Galpha(i/o) isoform, Galpha(o). However, studies in vivo evaluating morphine-mediated antinociception have not supported these findings. The aim of the present work was to evaluate the contribution of Galpha(o) to MOR dependent signaling by measuring both antinociceptive and biochemical endpoints in a Galpha(o) null transgenic mouse strain. Male wild-type and Galpha(o) heterozygous null (Galpha(o) +/-) mice were tested for opioid antinociception in the hot plate test or the warm-water tail withdrawal test as measures of supraspinal or spinal antinociception, respectively. Reduction in Galpha(o) levels attenuated the supraspinal antinociception produced by morphine, methadone, and nalbuphine, with the magnitude of suppression dependent on agonist efficacy. This was explained by a reduction in both high-affinity MOR expression and MOR agonist-stimulated G protein activation in whole brain homogenates from Galpha(o) +/- and Galpha(o) homozygous null (Galpha(o)-/-) mice, compared with wild-type littermates. On the other hand, morphine spinal antinociception was not different between Galpha(o) +/- and wild-type mice and high-affinity MOR expression was unchanged in spinal cord tissue. However, the action of the partial agonist nalbuphine was compromised, showing that reduction in Galpha(o) protein does decrease spinal antinociception, but suggesting a higher Galpha(o) protein reserve. These results provide the first in vivo evidence that Galpha(o) contributes to maximally efficient MOR signaling and antinociception. PMID- 21654737 TI - Evidence for the role of histamine H3 receptor in alcohol consumption and alcohol reward in mice. AB - Recent research suggests that histamine H3 receptor (H3R) antagonism may diminish motivational aspects of alcohol dependence. We studied the role of H3Rs in alcohol-related behaviors using H3R knockout (KO) mice and ligands. H3R KO mice consumed less alcohol than wild-type (WT) mice in a two-bottle free-choice test and in a 'drinking in the dark' model. H3R antagonist ciproxifan suppressed and H3R agonist immepip increased alcohol drinking in C57BL/6J mice. Impairment in reward mechanisms in H3R KO mice was confirmed by the lack of alcohol-evoked conditioned place preference. Plasma alcohol concentrations of H3R KO and WT mice were similar. There were no marked differences in brain biogenic amine levels in H3R KO mice compared with the control animals after alcohol drinking. In conclusion, the findings of this study provide evidence for the role of H3R receptor in alcohol-related behaviors, especially in alcohol drinking and alcohol reward. Thus, targeting H3Rs with a specific antagonist might be a potential means to treat alcoholism in the future. PMID- 21654738 TI - Cross-disorder analysis of bipolar risk genes: further evidence of DGKH as a risk gene for bipolar disorder, but also unipolar depression and adult ADHD. AB - Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65-243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH. PMID- 21654739 TI - Critical role of peripheral actions of intravenous nicotine in mediating its central effects. AB - In addition to its direct action on central neurons, nicotine (NIC) activates multiple nicotinic acetylcholine receptors localized on afferent terminals of sensory nerves at the sites of its administration. Although the activation of these receptors is important in mediating the primary sensory and cardiovascular effects of NIC, their role in triggering and maintaining the neural effects of NIC remains unclear. Using high-speed electroencephalography (EEG) and electromyography (EMG) recordings in freely moving rats, we showed that NIC at low intravenous (i.v.) doses (10-30 MUg/kg) induced rapid, strong, and prolonged EEG desynchronization both in the cortex and ventral tegmental area (with decreases in alpha and robust increases in beta and gamma frequencies) and neck EMG activation that began during the injection (~5 s). EEG and EMG effects of NIC were drastically reduced by pre-treatment with hexamethonium, a peripherally acting NIC antagonist, and the immediate EEG effects of NIC were strongly inhibited during urethane anesthesia. Although NIC pyrrolidine methiodide, a quaternary NIC analog that cannot enter the brain, also induced rapid EEG desynchronization, its effects were much shorter and weaker than those of NIC. Therefore, NIC by acting on peripheral nicotinic receptors provides a major contribution to its rapid, excitatory effects following i.v. administration. Since this action creates a sensory signal that rapidly reaches the brain via neural pathways and precedes the slower and more prolonged direct actions of NIC on brain cells, it could have a major role in associative learning and changes in the behavioral and physiological effects of NIC following its repeated use. PMID- 21654740 TI - The reduction of R1, a novel repressor protein for monoamine oxidase A, in major depressive disorder. AB - The novel transcriptional repressor protein, R1 (JPO2/CDCA7L/RAM2), inhibits monoamine oxidase A (MAO A) gene expression and influences cell proliferation and survival. MAO A is implicated in several neuropsychiatric illnesses and highly elevated in major depressive disorder (MDD); however, whether R1 is involved in these disorders is unknown. This study evaluates the role of R1 in depressed subjects either untreated or treated with antidepressant drugs. R1 protein levels were determined in the postmortem prefrontal cortex of 18 untreated MDD subjects and 12 medicated MDD subjects compared with 18 matched psychiatrically normal control subjects. Western blot analysis showed that R1 was significantly decreased by 37.5% (p<0.005) in untreated MDD subjects. The R1 level in medicated MDD subjects was also significantly lower (by 30%; p<0.05) compared with control subjects, but was not significantly different compared with untreated MDD subjects. Interestingly, the reduction in R1 was significantly correlated with an increase (approximately 40%; p<0.05) in MAO A protein levels within the MDD groups compared with controls. Consistent with the change in MAO A protein expression, the MAO A catalytic activity was significantly greater in both MDD groups compared with controls. These results suggest that reduced R1 may lead to elevated MAO A levels in untreated and treated MDD subjects; moreover, the reduction of R1 has been implicated in apoptotic cell death and apoptosis has also been observed in the brains of MDD subjects. Therefore, modulation of R1 levels may provide a new therapeutic target in the development of more effective strategies to treat MDD. PMID- 21654741 TI - Biomarkers for the prediction of type 2 diabetes and cardiovascular disease. AB - Risk prediction for type 2 diabetes (T2D) and cardiovascular disease (CVD) remains suboptimal even after the introduction of global risk assessment by various scores. This has prompted the search for additional biomarkers. A variety of blood biomarkers representing various pathophysiological pathways of insulin resistance and atherosclerosis, as well as markers of subclinical disease and genetic markers, have been investigated. This review provides an overview of studies assessing the clinical utility of various biomarkers on the basis of hypothesis-driven selection as well as hypothesis-free approaches from novel " omics" technologies. So far, the assessment of genotypes and of several candidate biomarkers from blood has resulted in only small improvements in the accuracy of prediction of CVD and T2D over and above that predicted on the basis of established risk factors. Integrated approaches, combining biomarkers from genomics, transcriptomics, proteomics, and metabolomics, as well as serial measurements of biomarkers, are required to make a complete assessment of the potential clinical usefulness of biomarkers for risk prediction of cardiometabolic disease. PMID- 21654742 TI - New drug targets for the treatment of obesity. AB - There is a huge void in the current pharmacological treatment options for obesity. This gap is surprising given the high prevalence and associated costs of obesity. Many factors have prevented active drug development, including the poor safety and efficacy of earlier antiobesity drugs. However, there are now several compelling targets on the horizon. The new generation of antiobesity drugs offers hope for the management of obesity, but no single agent is likely to be a panacea. Rather, obesity will need to be managed like many other chronic diseases, with combination therapies and long-term treatment in order to achieve sustained success. New targets have arisen as more research has been performed to understand the complex circuitry that controls energy homeostasis. The goal of this review is to discuss the latest pharmacological agents and strategies that are under development and that may eventually be used for the treatment of obesity. PMID- 21654743 TI - The obesity paradox in heart failure: accepting reality and making rational decisions. PMID- 21654746 TI - De novo cardiomyocytes from within the activated adult heart after injury. AB - A significant bottleneck in cardiovascular regenerative medicine is the identification of a viable source of stem/progenitor cells that could contribute new muscle after ischaemic heart disease and acute myocardial infarction. A therapeutic ideal--relative to cell transplantation--would be to stimulate a resident source, thus avoiding the caveats of limited graft survival, restricted homing to the site of injury and host immune rejection. Here we demonstrate in mice that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. We reveal a novel genetic label of the activated adult progenitors via re-expression of a key embryonic epicardial gene, Wilm's tumour 1 (Wt1), through priming by thymosin beta4, a peptide previously shown to restore vascular potential to adult epicardium-derived progenitor cells with injury. Cumulative evidence indicates an epicardial origin of the progenitor population, and embryonic reprogramming results in the mobilization of this population and concomitant differentiation to give rise to de novo cardiomyocytes. Cell transplantation confirmed a progenitor source and chromosome painting of labelled donor cells revealed transdifferentiation to a myocyte fate in the absence of cell fusion. Derived cardiomyocytes are shown here to structurally and functionally integrate with resident muscle; as such, stimulation of this adult progenitor pool represents a significant step towards resident-cell-based therapy in human ischaemic heart disease. PMID- 21654747 TI - Hydrogen-poor superluminous stellar explosions. AB - Supernovae are stellar explosions driven by gravitational or thermonuclear energy that is observed as electromagnetic radiation emitted over weeks or more. In all known supernovae, this radiation comes from internal energy deposited in the outflowing ejecta by one or more of the following processes: radioactive decay of freshly synthesized elements (typically (56)Ni), the explosion shock in the envelope of a supergiant star, and interaction between the debris and slowly moving, hydrogen-rich circumstellar material. Here we report observations of a class of luminous supernovae whose properties cannot be explained by any of these processes. The class includes four new supernovae that we have discovered and two previously unexplained events (SN 2005ap and SCP 06F6) that we can now identify as members of the same class. These supernovae are all about ten times brighter than most type Ia supernova, do not show any trace of hydrogen, emit significant ultraviolet flux for extended periods of time and have late-time decay rates that are inconsistent with radioactivity. Our data require that the observed radiation be emitted by hydrogen-free material distributed over a large radius (~10(15) centimetres) and expanding at high speeds (>10(4) kilometres per second). These long-lived, ultraviolet-luminous events can be observed out to redshifts z > 4. PMID- 21654748 TI - CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. AB - Macrophages, which are abundant in the tumour microenvironment, enhance malignancy. At metastatic sites, a distinct population of metastasis-associated macrophages promotes the extravasation, seeding and persistent growth of tumour cells. Here we define the origin of these macrophages by showing that Gr1 positive inflammatory monocytes are preferentially recruited to pulmonary metastases but not to primary mammary tumours in mice. This process also occurs for human inflammatory monocytes in pulmonary metastases of human breast cancer cells. The recruitment of these inflammatory monocytes, which express CCR2 (the receptor for chemokine CCL2), as well as the subsequent recruitment of metastasis associated macrophages and their interaction with metastasizing tumour cells, is dependent on CCL2 synthesized by both the tumour and the stroma. Inhibition of CCL2-CCR2 signalling blocks the recruitment of inflammatory monocytes, inhibits metastasis in vivo and prolongs the survival of tumour-bearing mice. Depletion of tumour-cell-derived CCL2 also inhibits metastatic seeding. Inflammatory monocytes promote the extravasation of tumour cells in a process that requires monocyte derived vascular endothelial growth factor. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer. Our data provide the mechanistic link between these two clinical associations and indicate new therapeutic targets for treating metastatic breast cancer. PMID- 21654749 TI - X-ray illumination of the ejecta of supernova 1987A. AB - When a massive star explodes as a supernova, substantial amounts of radioactive elements--primarily (56)Ni, (57)Ni and (44)Ti--are produced. After the initial flash of light from shock heating, the fading light emitted by the supernova is due to the decay of these elements. However, after decades, the energy powering a supernova remnant comes from the shock interaction between the ejecta and the surrounding medium. The transition to this phase has hitherto not been observed: supernovae occur too infrequently in the Milky Way to provide a young example, and extragalactic supernovae are generally too faint and too small. Here we report observations that show this transition in the supernova SN 1987A in the Large Magellanic Cloud. From 1994 to 2001, the ejecta faded owing to radioactive decay of (44)Ti as predicted. Then the flux started to increase, more than doubling by the end of 2009. We show that this increase is the result of heat deposited by X-rays produced as the ejecta interacts with the surrounding material. In time, the X-rays will penetrate farther into the ejecta, enabling us to analyse the structure and chemistry of the vanished star. PMID- 21654750 TI - MicroRNAs 103 and 107 regulate insulin sensitivity. AB - Defects in insulin signalling are among the most common and earliest defects that predispose an individual to the development of type 2 diabetes. MicroRNAs have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism. However, the direct regulation of insulin sensitivity by microRNAs in vivo has not been demonstrated. Here we show that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR 103/107. We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity. PMID- 21654751 TI - Sodium intake in men and potassium intake in women determine the prevalence of metabolic syndrome in Japanese hypertensive patients: OMEGA Study. AB - Dietary intake affects hypertension and metabolic syndrome (MS) and their management. In Japanese hypertensive patients, little evidence exists regarding the relation between diet and MS. A self-administered lifestyle questionnaire was completed by each patient at the baseline. Three dietary scores were calculated for each patient: sodium intake, potassium intake and soybean/fish intake. The relationships between dietary scores and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were analyzed by multiple regression analysis. The relation between dietary intake of sodium, potassium and soybean/fish, and the presence of MS was evaluated by the Mantel-Haenszel test. A total of 9585 hypertensive patients (mean age, 64.9 years; women, 51.4%) were included in this sub-analysis. High sodium intake was significantly related to increased SBP (P=0.0003) and DBP (P=0.0130). Low potassium intake was significantly related to increased SBP (P=0.0057) and DBP (P=0.0005). Low soybean/fish intake was significantly related to increased SBP (P=0.0133). A significantly higher prevalence of MS was found in men in the highest quartile of sodium intake compared with the lower quartiles (P=0.0026) and in women in the lowest quartile of potassium intake compared with the higher quartiles (P=0.0038). A clear relation between dietary habits and blood pressure was found in Japanese hypertensive patients using a patient-administered questionnaire. Sodium and potassium intake affect MS prevalence. Dietary changes are warranted within hypertension treatment strategies. PMID- 21654752 TI - Evaluating risk factors in hypertension screening in children and adolescent. PMID- 21654753 TI - Decreased circulating endothelial progenitor cell levels and function in essential hypertensive patients with electrocardiographic left ventricular hypertrophy. AB - The aim of this study was to explore the role of circulating endothelial progenitor cells (EPCs) and endothelial apoptotic microparticles in hypertensive patients with and without electrocardiographic left ventricular hypertrophy (LVH). Flow cytometry was used to assess endothelial cell apoptosis and circulating EPC level by quantification of circulating EPC markers (defined as CD34(+)CD133(+), CD34(+)KDR(+)) and endothelial apoptotic microparticles (defined as CD31(+)/annexin V(+)) in peripheral blood samples. The LVH was defined by ECG with the Cornell voltage criteria. In total, 128 hypertensive patients (83 men and 45 women, aged 59+/-14 years) were enrolled in this study, in which 107 patients (84%) showed no electrocardiographic evidence of LVH, and 21 patients (16%) fulfilled the LVH criteria by ECG. There were no significant differences in basic characteristics between the two groups, but hypertensive patients with LVH had a higher urine albumin excretion rate than those without LVH (P=0.027). Furthermore, hypertensive patients with LVH were shown to have decreased circulating EPC numbers (all P<0.05) and adhesive function compared with those without LVH (LVH vs. no LVH: 14+/-6 vs. 30+/-6 cells per high-power field, P<0.001). Increased numbers of endothelial apoptotic microparticles were noted in hypertensive patients with LVH (4.2+/-4.9 vs. 2.4+/-3.4%, P=0.115), although the difference was not significant. This study showed that essential hypertensive patients with electrocardiographic LVH evidence have decreased circulating EPC numbers and adhesive function compared with those without LVH. These findings may explain the pathogenetic processes that link hypertensive LVH and endothelial injury in cardiovascular disease. PMID- 21654754 TI - Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling. AB - Angiotensin II (Ang II) is essential for endothelial progenitor cells (EPCs) function as Ang-II-induced oxidative stress causes senescence of EPCs and endothelial dysfunction and Ang II type 1 receptor blockers increase EPCs. Moreover, EPCs activity is dependent on nitric oxide (NO) and heme oxygenase (HO) 1 as these correlate with EPCs senescence and are reduced in hypertensives. Bartter's/Gitelman's syndrome patients (BS/GS), have increased Ang II yet normo/hypotension along with blunted Ang II signaling, reduced oxidative stress, increased NO and HO-1, thus presenting a unique system to explore EPC biology and its relationship with vascular clinical and biochemical correlates. Circulating EPCs, NO-dependent vasodilation (flow-mediated dilation (FMD)) and HO-1 gene expression were characterized in 10 BS/GS patients and in 10 normotensive subjects. EPCs defined by cell surface antigens CD34+kinase-insert domain receptor (KDR+), CD133+KDR+ and CD133+CD34+KDR+ cells were quantitiated via direct three-color flow-cytometry analysis, HO-1 gene expression by reverse transcription-PCR and FMD by B-mode echo scan of the right brachial artery. Correlation analysis was carried out regarding FMD and EPCs, FMD and HO-1 and EPCs and HO-1. In BS/GS, CD34+KDR+ cell numbers did not differ from controls while CD133+KDR+ and CD133+CD34+KDR+ cell numbers were higher. HO-1 gene expression, as well as FMD, was higher in BS/GS compared with controls. Both CD133+KDR+ and CD133+CD34+KDR+ strongly correlated with both FMD and HO-1. FMD and HO-1 were also strongly correlated. These results document in a human system that EPC numbers and specific populations are related to important clinical and biochemical factors involved in cardiovascular (CV) status and reaffirm the utility of BS/GS patients as a useful system to investigate EPC's role(s) in the pathophysiology of cardiovascular remodeling in humans. PMID- 21654755 TI - Additive antioxidative effects of azelnidipine on angiotensin receptor blocker olmesartan treatment for type 2 diabetic patients with albuminuria. AB - The present study aimed to determine whether either of two calcium channel blockers affected urinary albumin excretion or urinary levels of 8-hydroxy-2' deoxyguanosine (8-OHdG) and liver-type fatty acid-binding protein (L-FABP) in hypertensive diabetic patients with chronic kidney disease (CKD) who were already being treated with maximum doses of the angiotensin II receptor blocker olmesartan. We conducted an open-label, randomized, parallel-controlled study on type 2 diabetic patients with stable glycemic control who were receiving fixed doses of antidiabetic agents. The patients received either 8 mg per day azelnidipine, which was increased up to 16 mg per day (azelnidipine group; n=34), or 2.5 mg per day amlodipine, which was increased up to 5 mg per day (amlodipine group; n=33), over a 24-week period. Mean systolic and diastolic blood pressure decreased significantly in both groups, but there was no significant difference between the two groups at the end of the study. Serum creatinine levels and estimated glomerular filtration rate did not differ significantly between the two groups, whereas the urinary albumin/creatinine ratio and 8-OHdG and L-FABP levels decreased significantly in the azelnidipine group compared with the amlodipine group. Plasma aldosterone level was significantly decreased in the azelnidipine group, and its changes correlated significantly with those of urinary 8-OHdG and L-FABP. Our results suggest that the addition of azelnidipine to the maximal recommended dose of olmesartan was more effective in reducing albuminuria and oxidant stress in hypertensive diabetic patients with CKD than the addition of amlodipine. PMID- 21654756 TI - The clinical value of apex beat and electrocardiography for the detection of left ventricular hypertrophy from the standpoint of the distance factors from the heart to the chest wall: a multislice CT study. AB - The aim of this study was to investigate the clinical value of the apex beat and two ECG voltage criteria in the detection of left ventricular hypertrophy (LVH) while considering two distances, from the heart to the inner chest wall and to the chest surface, measured by using multislice CT (MSCT). The study population consisted of 151 patients clinically judged as requiring MSCT angiography. The apex beat was palpated with patients in the supine. Sokolow-Lyon voltage and Cornell voltage to detect LVH were determined. The pattern of sustained or double apical impulse and Cornell voltage had higher specificity as an indicator of LVH than Sokolow-Lyon voltage. Furthermore, the distance to the inner chest wall was negatively correlated with left ventricular end-diastolic volume and mass. Contrarily, the distance to the chest surface was correlated with the body mass index. Multivariate analyses revealed that the pattern of sustained or double apical impulse showed a stronger association with the distance to the inner chest wall than to the chest surface, but Sokolow-Lyon voltage was associated with the distance to the chest surface. Among the screening tests for excluding patients with LVH, Cornell voltage or the apex beat would be better than Sokolow-Lyon voltage because these are less dependent on body size and have higher specificity. PMID- 21654757 TI - The electromotive force of MnAs nanoparticles. PMID- 21654758 TI - Cyberwarfare challenge. PMID- 21654759 TI - Second chances. PMID- 21654760 TI - Misspent energy. PMID- 21654761 TI - Beware of gifts that come at too great a cost. PMID- 21654773 TI - Fukushima deep in hot water. PMID- 21654774 TI - A healthier Japan. Interview by David Cyranoski. PMID- 21654775 TI - Microbe outbreak panics Europe. PMID- 21654776 TI - US research facilities anticipate budget gloom. PMID- 21654777 TI - Hungarian natural history under threat. PMID- 21654778 TI - Whistle-blower claims his accusations cost him his job. PMID- 21654779 TI - Computer security: Is this the start of cyberwarfare? PMID- 21654780 TI - Evolution: Darwin's city. PMID- 21654781 TI - Save our soils. PMID- 21654782 TI - Don't judge species on their origins. PMID- 21654787 TI - Slovenian scientists reward mentors. PMID- 21654788 TI - NIH: FDA key for speed and safety. PMID- 21654789 TI - NIH: translation centre bridges a gap. PMID- 21654790 TI - EU innovation must benefit society. PMID- 21654791 TI - Complex systems: Unzipping Zipf's law. PMID- 21654792 TI - Stem cells: iPS cells under attack. PMID- 21654793 TI - Epidemiology: How common is autism? PMID- 21654795 TI - Physical chemistry: Water's wafer-thin surface. PMID- 21654796 TI - Neuroscience: Flies race to a safe place. PMID- 21654797 TI - Quantum physics: How to catch a wave. PMID- 21654798 TI - DNA repair: Cyclin D1 multitasks. PMID- 21654799 TI - Role of YAP/TAZ in mechanotransduction. AB - Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment. PMID- 21654800 TI - Direct measurement of the quantum wavefunction. AB - The wavefunction is the complex distribution used to completely describe a quantum system, and is central to quantum theory. But despite its fundamental role, it is typically introduced as an abstract element of the theory with no explicit definition. Rather, physicists come to a working understanding of the wavefunction through its use to calculate measurement outcome probabilities by way of the Born rule. At present, the wavefunction is determined through tomographic methods, which estimate the wavefunction most consistent with a diverse collection of measurements. The indirectness of these methods compounds the problem of defining the wavefunction. Here we show that the wavefunction can be measured directly by the sequential measurement of two complementary variables of the system. The crux of our method is that the first measurement is performed in a gentle way through weak measurement, so as not to invalidate the second. The result is that the real and imaginary components of the wavefunction appear directly on our measurement apparatus. We give an experimental example by directly measuring the transverse spatial wavefunction of a single photon, a task not previously realized by any method. We show that the concept is universal, being applicable to other degrees of freedom of the photon, such as polarization or frequency, and to other quantum systems--for example, electron spins, SQUIDs (superconducting quantum interference devices) and trapped ions. Consequently, this method gives the wavefunction a straightforward and general definition in terms of a specific set of experimental operations. We expect it to expand the range of quantum systems that can be characterized and to initiate new avenues in fundamental quantum theory. PMID- 21654801 TI - Hydrogen bonding at the water surface revealed by isotopic dilution spectroscopy. AB - The air-water interface is perhaps the most common liquid interface. It covers more than 70 per cent of the Earth's surface and strongly affects atmospheric, aerosol and environmental chemistry. The air-water interface has also attracted much interest as a model system that allows rigorous tests of theory, with one fundamental question being just how thin it is. Theoretical studies have suggested a surprisingly short 'healing length' of about 3 angstroms (1 A = 0.1 nm), with the bulk-phase properties of water recovered within the top few monolayers. However, direct experimental evidence has been elusive owing to the difficulty of depth-profiling the liquid surface on the angstrom scale. Most physical, chemical and biological properties of water, such as viscosity, solvation, wetting and the hydrophobic effect, are determined by its hydrogen bond network. This can be probed by observing the lineshape of the OH-stretch mode, the frequency shift of which is related to the hydrogen-bond strength. Here we report a combined experimental and theoretical study of the air-water interface using surface-selective heterodyne-detected vibrational sum frequency spectroscopy to focus on the 'free OD' transition found only in the topmost water layer. By using deuterated water and isotopic dilution to reveal the vibrational coupling mechanism, we find that the free OD stretch is affected only by intramolecular coupling to the stretching of the other OD group on the same molecule. The other OD stretch frequency indicates the strength of one of the first hydrogen bonds encountered at the surface; this is the donor hydrogen bond of the water molecule straddling the interface, which we find to be only slightly weaker than bulk-phase water hydrogen bonds. We infer from this observation a remarkably fast onset of bulk-phase behaviour on crossing from the air into the water phase. PMID- 21654802 TI - Irregular tropical glacier retreat over the Holocene epoch driven by progressive warming. AB - The causes and timing of tropical glacier fluctuations during the Holocene epoch (10,000 years ago to present) are poorly understood. Yet constraining their sensitivity to changes in climate is important, as these glaciers are both sensitive indicators of climate change and serve as water reservoirs for highland regions. Studies have so far documented extra-tropical glacier fluctuations, but in the tropics, glacier-climate relationships are insufficiently understood. Here we present a (10)Be chronology for the past 11,000 years (11 kyr), using 57 moraines from the Bolivian Telata glacier (in the Cordillera Real mountain range). This chronology indicates that Telata glacier retreated irregularly. A rapid and strong melting from the maximum extent occurred from 10.8 +/- 0.9 to 8.5 +/- 0.4 kyr ago, followed by a slower retreat until the Little Ice Age, about 200 years ago. A dramatic increase in the rate of retreat occurred over the twentieth century. A glacier-climate model indicates that, relative to modern climate, annual mean temperature for the Telata glacier region was -3.3 +/- 0.8 degrees C cooler at 11 kyr ago and remained -2.1 +/- 0.8 degrees C cooler until the end of the Little Ice Age. We suggest that long-term warming of the eastern tropical Pacific and increased atmospheric temperature in response to enhanced austral summer insolation were the main drivers for the long-term Holocene retreat of glaciers in the southern tropics. PMID- 21654803 TI - Visual place learning in Drosophila melanogaster. AB - The ability of insects to learn and navigate to specific locations in the environment has fascinated naturalists for decades. The impressive navigational abilities of ants, bees, wasps and other insects demonstrate that insects are capable of visual place learning, but little is known about the underlying neural circuits that mediate these behaviours. Drosophila melanogaster (common fruit fly) is a powerful model organism for dissecting the neural circuitry underlying complex behaviours, from sensory perception to learning and memory. Drosophila can identify and remember visual features such as size, colour and contour orientation. However, the extent to which they use vision to recall specific locations remains unclear. Here we describe a visual place learning platform and demonstrate that Drosophila are capable of forming and retaining visual place memories to guide selective navigation. By targeted genetic silencing of small subsets of cells in the Drosophila brain, we show that neurons in the ellipsoid body, but not in the mushroom bodies, are necessary for visual place learning. Together, these studies reveal distinct neuroanatomical substrates for spatial versus non-spatial learning, and establish Drosophila as a powerful model for the study of spatial memories. PMID- 21654804 TI - A genetically humanized mouse model for hepatitis C virus infection. AB - Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo. PMID- 21654805 TI - In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. AB - Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T(reg)) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T(reg) cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T(reg) cells seem to participate in creating a localized zone where HSPCs reside and where T(reg) cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack. PMID- 21654806 TI - A somitic Wnt16/Notch pathway specifies haematopoietic stem cells. AB - Haematopoietic stem cells (HSCs) are a self-renewing population of cells that continuously replenish all blood and immune cells during the lifetime of an individual. HSCs are used clinically to treat a wide array of diseases, including acute leukaemias and congenital blood disorders, but obtaining suitable numbers of cells and finding immune-compatible donors remain serious problems. These difficulties have led to an interest in the conversion of embryonic stem cells or induced pluripotent stem cells into HSCs, which is not possible using current methodologies. To accomplish this goal, it is critical to understand the native mechanisms involved in the specification of HSCs during embryonic development. Here we demonstrate in zebrafish that Wnt16 controls a novel genetic regulatory network required for HSC specification. Non-canonical signalling by Wnt16 is required for somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), and these ligands are, in turn, required for the establishment of definitive haematopoiesis. Notch signalling downstream of Dlc and Dld is earlier than, and distinct from, known cell-autonomous requirements for Notch, strongly suggesting that novel Notch-dependent relay signal(s) induce the first HSCs in parallel to other established pathways. Our results demonstrate that somite specific gene expression is required for the production of haemogenic endothelium. PMID- 21654807 TI - Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1. AB - Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the transgenic expression of three transcription factors collectively called OSK: Oct3/4 (also called Pou5f1), Sox2 and Klf4. However, the conversion to iPSCs is inefficient. The proto-oncogene Myc enhances the efficiency of iPSC generation by OSK but it also increases the tumorigenicity of the resulting iPSCs. Here we show that the Gli-like transcription factor Glis1 (Glis family zinc finger 1) markedly enhances the generation of iPSCs from both mouse and human fibroblasts when it is expressed together with OSK. Mouse iPSCs generated using this combination of transcription factors can form germline-competent chimaeras. Glis1 is enriched in unfertilized oocytes and in embryos at the one-cell stage. DNA microarray analyses show that Glis1 promotes multiple pro-reprogramming pathways, including Myc, Nanog, Lin28, Wnt, Essrb and the mesenchymal-epithelial transition. These results therefore show that Glis1 effectively promotes the direct reprogramming of somatic cells during iPSC generation. PMID- 21654811 TI - Sexual function and health-related quality of life following anterior vaginal wall surgery for stress urinary incontinence and pelvic organ prolapse. AB - To assess female sexual function (FSF) and health-related quality of life (HRQOL) following anterior vaginal wall surgeries for stress urinary incontinence (SUI) and pelvic organ prolapse (POP). The retrospective study consisted of 116 patients. Chinese translations of the modified Lemack Questionnaire (not validated) and Pelvic Floor Distress Inventory-Short Form 20 were used to assess FSF and HRQOL, 3 months pre-operatively and 12-24 months (mean 16.8 months) post operatively. Sixty-one (52.6%, 29 in SUI group and 32 in POP group) of patients were sexually active before and after the operation. Overall, 12 (19.7%, six in SUI group and six in POP group) reported an improvement in overall intercourse satisfaction, 21 (34.4%, 8 in the SUI and 13 in the POP group) were decreased and 28 (45.9%, 15 in SUI group and 13 in POP group) were unchanged. Incidence of coital incontinence decreased significantly in SUI group. Frequency of intercourse decreased, vaginal dryness and pain due to it and asymptomatic vaginal narrowing increased significantly, following the surgery in POP group. There were no statistically significant differences in the frequency of intercourse in SUI group, patients' perception of intercourse, frequency of orgasm and the importance of sex life in both groups. Partner discomfort remained unchanged. HRQOL improved significantly after the operation in both groups. There was no association between HRQOL and FSF in the post-operative period. In most patients, overall FSF did not impaired. All trans-anterior vaginal wall surgery positively impacted on the patients' HRQOL. A prospective study with validated questionnaire is necessary in future. PMID- 21654808 TI - A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers. AB - Cyclin D1 is a component of the core cell cycle machinery. Abnormally high levels of cyclin D1 are detected in many human cancer types. To elucidate the molecular functions of cyclin D1 in human cancers, we performed a proteomic screen for cyclin D1 protein partners in several types of human tumours. Analyses of cyclin D1 interactors revealed a network of DNA repair proteins, including RAD51, a recombinase that drives the homologous recombination process. We found that cyclin D1 directly binds RAD51, and that cyclin D1-RAD51 interaction is induced by radiation. Like RAD51, cyclin D1 is recruited to DNA damage sites in a BRCA2 dependent fashion. Reduction of cyclin D1 levels in human cancer cells impaired recruitment of RAD51 to damaged DNA, impeded the homologous recombination mediated DNA repair, and increased sensitivity of cells to radiation in vitro and in vivo. This effect was seen in cancer cells lacking the retinoblastoma protein, which do not require D-cyclins for proliferation. These findings reveal an unexpected function of a core cell cycle protein in DNA repair and suggest that targeting cyclin D1 may be beneficial also in retinoblastoma-negative cancers which are currently thought to be unaffected by cyclin D1 inhibition. PMID- 21654812 TI - Ultrastructural features and possible functional role of kit-positive interstitial cells in the guinea pig corpus cavernosum. AB - The objective of the present study was to identify kit-positive interstitial cells (ICs) in guinea pig corpus cavernosum and examine their relationships with adjacent smooth muscle cells (SMCs) and intramural nerves. In addition, we investigated the possible involvement of ICs in nitric oxide (NO)-mediated relaxation of corpus cavernosum smooth muscle (CCSM). ICs were identified by their immunoreactivity to the kit receptor, a cell surface marker encoded by c kit proto-oncogene and specific for interstitial cells of Cajal. ICs were abundantly distributed in guinea pig corporal tissues. Ultrastructural investigation by conventional transmission electron microscopy revealed the ultrastructural features of ICs and gap junctions located between ICs and adjacent SMCs, furthermore, a close contact between ICs and intramural nerves for the first time. Western blot analysis of purified ICs by fluorescence-activated cell sorting revealed coexpression of soluble guanylate cyclase (sGC)alpha1, sGCbeta1 and kit receptor tyrosine kinase protein in them. These observations imply that ICs express the NO-sensitive sGC molecule and may be involved in the NO-mediated relaxation of CCSM in the guinea pig corpus cavernosum. PMID- 21654813 TI - Experience with intracavernous injection in the treatment of erectile dysfunction after radical prostatectomy: dose considerations. AB - We sought to identify factors influencing dose maintenance of intracavernous (IC) injection among patients with ED following radical prostatectomy. A total of 93 patients underwent prostatectomy and received IC treatment for ED, including PGE1 single therapy (n=53) and triple therapy (n=40). In the PGE1-only group, the maintenance dosage was significantly correlated with preoperative sexual function and nerve sparing (NS) (P<0.05). For example, the maintenance dose among patients with no, unilateral and bilateral NS was 10.8 +/- 6.6 MUg (0.54 +/- 0.33 ml), 10.8 +/- 3.8 MUg (0.54 +/- 0.19 ml) and 6.4 +/- 4.6 MUg (0.32 +/- 0.23 ml), respectively. In terms of preoperative sexual function, the maintenance dose among non-ED versus ED patients was 0.38 +/- 0.25 ml (7.6 +/- 5.0 MUg) and 0.59 +/- 0.31 ml (11.8 +/- 6.2 MUg), respectively. No significant correlation was observed between the maintenance dose and NS or preoperative sexual function among the triple-therapy patients or between the maintenance dose and age, body mass index, systemic diseases and initiation of ED treatment among all patients (P>0.05). Thus, maintenance dose of PGE1 therapy could be partly determined by NS status and prior ED of patients. PMID- 21654814 TI - Early insertion of inflatable prosthesis for intractable ischemic priapism: our experience and review of the literature. AB - A cohort of 20 patients with delayed priapism who underwent treatment at the Emergency Department of our academic referral centers between January 2002 and April 2010 was studied. Of these, 16 cases suffered from a low-flow priapism. A total of 6 cases were managed non-surgically, 10 required shunt surgery, and of these 5 were treated by early penile prosthesis surgery. Prostheses were easily implanted in all patients with a mean operative time of 94 min. No intraoperative complications and no infection were registered. All patients with an inflatable prosthesis complained a reduction in penile sensibility that lasted 3 months. All patients were satisfied with the results of surgery (International Index of Erectile Function Questionnaire-5, Q5 mean value 4), and all were successfully engaging in satisfactory sexual intercourses. No significant loss of penile length, neither apical erosion nor extrusion was recorded. Early insertion of a penile prosthesis is a simple and safe procedure in patients with ischemic priapism, which failed to respond to conservative management. Early insertion of a prosthesis helps to maintain adequate penile length, resolve priapism and, in the long term, it results in high satisfaction rates. PMID- 21654815 TI - Relationship between penile fracture and Peyronie's disease: a prospective study. AB - Peyronie's disease is postulated to be initiated by repetitive minor traumas to the fully or partially erect penis. We investigated Peyronie's disease prospectively in cases treated for penile fracture (PF) within the last 20 years. Medical records of 63 cases treated for PFs were reviewed. Subjects were required to self-assess their current penile morphologies and sexual functions. Penile nodules and Peyronie's plaques were also evaluated with physical examination, ultrasonography and magnetic resonance imaging (MRI), and penile curvatures with auto-photography, and sexual function with international erectile function index (IIEF). Of the 63 cases (mean age 37 years), 46 who had mean follow-up of 63 months were re-evaluated. The mean IIEF-5 score was 23.2+/-3.1. Painful erections (n=5), penile nodules (n=5) and also penile curvatures <20 degrees (n=2) were investigated. No Peyronie's plaque was palpated in any of the cases. Ultrasound and MRI showed fibrotic nodules of 5 mm in diameter, which extended into the subtunical area in the rupture site in 54% of the cases, although any thickening and Peyronie's plaque were not found in the tunica albuginea and intracavernosal septum of the cases examined. In PF patients treated surgically, the erectile function and penile morphology were preserved. In our cases PFs did not induce the development of Peyronie's disease. PMID- 21654816 TI - Tumour suppression: Shedding light on degradation. PMID- 21654817 TI - Cancer metabolism: feed it forward. PMID- 21654819 TI - Impact of polyplex micelles installed with cyclic RGD peptide as ligand on gene delivery to vascular lesions. AB - Gene therapy is expected to open a new strategy for the treatment of refractory vascular diseases, so the development of appropriate gene vectors for vascular lesions is needed. To realize this requirement with a non-viral approach, cyclo(RGDfK) peptide (cRGD) was introduced to block copolymer, poly(ethylene glycol)-block-polycation carrying ethylenediamine units (PEG-PAsp(DET)). cRGD recognizes alpha(v)beta(3) and alpha(v)beta(5) integrins, which are abundantly expressed in vascular lesions. cRGD-conjugated PEG-PAsp(DET) (cRGD-PEG-PAsp(DET)) formed polyplex micelles through complexation with plasmid DNA (pDNA) and the cRGD-PEG-PAsp(DET) micelles achieved significantly more efficient gene expression and cellular uptake as compared with PEG-PAsp(DET) micelles in endothelial cells and vascular smooth muscle cells. Intracellular tracking of pDNA showed that cRGD PEG-PAsp(DET) micelles were internalized via caveolae-mediated endocytosis, which is associated with a pathway avoiding lysosomal degradation and that, PEG PAsp(DET) micelles were transported to acidic endosomes and lysosomes via clathrin-mediated endocytosis. Further, in vivo evaluation in rat carotid artery with a neointimal lesion revealed that cRGD-PEG-PAsp(DET) micelles realized sustained gene expression, whereas PEG-PAsp(DET) micelles facilitated rapid, but transient gene expression. These findings suggest that introduction of cRGD to polyplex micelles might create novel and useful functions for gene transfer and contribute to the establishment of efficient gene therapy for vascular diseases. PMID- 21654820 TI - Successful target cell transduction of capsid-engineered rAAV vectors requires clathrin-dependent endocytosis. AB - Cell surface targeting of recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to modify AAV's natural tropism. As modification of the capsid surface is likely to affect the mechanism of vector internalization and consequently the vector's intracellular fate, we investigated early steps in cell transduction of rAAV capsid insertion mutants. Mutants displaying peptides with neutral overall charge at position 587 transduced cells independently of AAV2's primary receptor heparan sulfate proteoglycan (HSPG), whereas mutants carrying positively charged insertions were capable of HSPG binding with affinities correlating with their net positive charge. Whereas rAAV2 is internalized via an HSPG- and clathrin-dependent pathway, HSPG-binding mutants used a clathrin- and caveolin-independent mechanism. Surprisingly, although this pathway was as efficient in mediating vector entry as the one used by rAAV2, successful cell transduction was hampered at a post-entry step, presumably caused by inefficient endosomal escape. In contrast, HSPG-independent, clathrin-dependent internalization used by non-HSPG-binding mutants correlated with efficient nuclear delivery of vector genomes and robust transgene expression. These findings indicate that cell surface targeting strategies should direct uptake of rAAV targeting vectors to clathrin-mediated endocytosis, the naturally evolved entry route of AAV, to promote successful intracellular processing and re targeting of rAAV's tropism. PMID- 21654818 TI - SWI/SNF nucleosome remodellers and cancer. AB - SWI/SNF chromatin remodelling complexes use the energy of ATP hydrolysis to remodel nucleosomes and to modulate transcription. Growing evidence indicates that these complexes have a widespread role in tumour suppression, as inactivating mutations in several SWI/SNF subunits have recently been identified at a high frequency in a variety of cancers. However, the mechanisms by which mutations in these complexes drive tumorigenesis are unclear. In this Review we discuss the contributions of SWI/SNF mutations to cancer formation, examine their normal functions and discuss opportunities for novel therapeutic interventions for SWI/SNF-mutant cancers. PMID- 21654821 TI - Rescue administration of a helper-dependent adenovirus vector with long-term efficacy in dogs with glycogen storage disease type Ia. AB - Glycogen storage disease type Ia (GSD-Ia) stems from glucose-6-phosphatase (G6Pase) deficiency and causes hypoglycemia, hepatomegaly, hypercholesterolemia and lactic acidemia. Three dogs with GSD-Ia were initially treated with a helper dependent adenovirus encoding a human G6Pase transgene (HDAd-cG6Pase serotype 5) on postnatal day 3. Unlike untreated dogs with GSD-Ia, all three dogs initially maintained normal blood glucose levels. After 6-22 months, vector-treated dogs developed hypoglycemia, anorexia and lethargy, suggesting that the HDAd-cG6Pase serotype 5 vector had lost efficacy. Liver biopsies collected at this time revealed significantly elevated hepatic G6Pase activity and reduced glycogen content, when compared with affected dogs treated only by frequent feeding. Subsequently, the HDAd-cG6Pase serotype 2 vector was administered to two dogs, and hypoglycemia was reversed; however, renal dysfunction and recurrent hypoglycemia complicated their management. Administration of a serotype 2 HDAd vector prolonged survival in one GSD-Ia dog to 12 months of age and 36 months of age in the other, but the persistence of long-term complications limited HDAd vectors in the canine model for GSD-Ia. PMID- 21654823 TI - Elastin-like polypeptide matrices for enhancing adeno-associated virus-mediated gene delivery to human neural stem cells. AB - The successful development of efficient and safe gene delivery vectors continues to be a major obstacle to gene delivery in stem cells. In this study, we have developed an elastin-like polypeptide (ELP)-mediated adeno-associated virus (AAV) delivery system for transducing fibroblasts and human neural stem cells (hNSCs). AAVs have significant promise as therapeutic vectors because of their safety and potential for use in gene targeting in stem cell research. ELP has been recently employed as a biologically inspired 'smart' biomaterial that exhibits an inverse temperature phase transition, thereby demonstrating promise as a novel drug carrier. The ELP that was investigated in this study was composed of a repetitive penta-peptide with [Val-Pro-Gly-Val-Gly]. A novel AAV variant, AAV r3.45, which was previously engineered by directed evolution to enhance transduction in rat NSCs, was nonspecifically immobilized onto ELPs that were adsorbed beforehand on a tissue culture polystyrene surface (TCPS). The presence of different ELP quantities on the TCPS led to variations in surface morphology, roughness and wettability, which were ultimately key factors in the modulation of cellular transduction. Importantly, with substantially reduced viral quantities compared with bolus delivery, ELP-mediated AAV delivery significantly enhanced delivery efficiency in fibroblasts and hNSCs, which have great potential for use in tissue engineering applications and neurodegenerative disorder treatments, respectively. The enhancement of cellular transduction in stem cells, as well as the feasibility of ELPs for utilization in three-dimensional scaffolds, will contribute to the advancement of gene therapy for stem cell research and tissue regenerative medicine. PMID- 21654825 TI - Synchrotron phase-contrast X-ray imaging reveals fluid dosing dynamics for gene transfer into mouse airways. AB - Although airway gene transfer research in mouse models relies on bolus fluid dosing into the nose or trachea, the dynamics and immediate fate of delivered gene transfer agents are poorly understood. In particular, this is because there are no in vivo methods able to accurately visualize the movement of fluid in small airways of intact animals. Using synchrotron phase-contrast X-ray imaging, we show that the fate of surrogate fluid doses delivered into live mouse airways can now be accurately and non-invasively monitored with high spatial and temporal resolution. This new imaging approach can help explain the non-homogenous distributions of gene expression observed in nasal airway gene transfer studies, suggests that substantial dose losses may occur at deliver into mouse trachea via immediate retrograde fluid motion and shows the influence of the speed of bolus delivery on the relative targeting of conducting and deeper lung airways. These findings provide insight into some of the factors that can influence gene expression in vivo, and this method provides a new approach to documenting and analyzing dose delivery in small-animal models. PMID- 21654824 TI - Jaagsiekte sheep retrovirus pseudotyped lentiviral vector-mediated gene transfer to fetal ovine lung. AB - Viral vector-mediated gene transfer to the postnatal respiratory epithelium has, in general, been of low efficiency due to physical and immunological barriers, non-apical location of cellular receptors critical for viral uptake and limited transduction of resident stem/progenitor cells. These obstacles may be overcome using a prenatal strategy. In this study, HIV-1-based lentiviral vectors (LVs) pseudotyped with the envelope glycoproteins of Jaagsiekte sheep retrovirus (JSRV LV), baculovirus GP64 (GP64-LV), Ebola Zaire-LV or vesicular stomatitis virus (VSVg-LV) and the adeno-associated virus-2/6.2 (AAV2/6.2) were compared for in utero transfer of a green fluorescent protein (GFP) reporter gene to ovine lung epithelium between days 65 and 78 of gestation. GFP expression was examined on day 85 or 136 of gestation (term is ~145 days). The percentage of the respiratory epithelial cells expressing GFP in fetal sheep that received the JSRV-LV (3.18 * 10(8)-6.85 * 10(9) viral particles per fetus) was 24.6+/-0.9% at 3 weeks postinjection (day 85) and 29.9+/-4.8% at 10 weeks postinjection (day 136). Expression was limited to the surface epithelium lining fetal airways <100 MUm internal diameter. Fetal airways were amenable to VSVg-LV transduction, although the percentage of epithelial expression was low (6.6+/-0.6%) at 1 week postinjection. GP64-LV, Ebola Zaire-LV and AAV2/6.2 failed to transduce the fetal ovine lung under these conditions. These data demonstrate that prenatal lung gene transfer with LV engineered to target apical surface receptors can provide sustained and high levels of transgene expression and support the therapeutic potential of prenatal gene transfer for the treatment of congenital lung diseases. PMID- 21654826 TI - Limiting the consumption of sugar sweetened beverages in Mexico's obesogenic environment: a qualitative policy review and stakeholder analysis. AB - Mexico is building a legal framework to address its childhood obesity epidemic. Sugar sweetened beverages (SSB) in the school environment represent a major policy challenge. We addressed the following questions: What barriers inhibit political attention to SSB and childhood obesity? What political instruments, international and national, exist to guide agenda setting in Mexico? What opportunities exist for policy adoption? We conducted a systematic review of international and national legal instruments concerned with SSB consumption. We traced process, conducting interviews with key informants. Thematic analysis helped us identify barriers and opportunities for public health interventions. We found 11 national policy instruments, but detected implementation gaps and weak fiscal policies on SSB consumption in schools: limited drinking water infrastructure, SSB industry interests, and regulatory ambiguities addressing reduction of sugar in beverages. Public policy should target marketing practices and taxation. The school environment remains a promising target for policy. Access to safe drinking water must complement comprehensive and multi-sector policy approaches to reduce access to SSB. PMID- 21654827 TI - Timing the multiple cell death pathways initiated by Rose Bengal acetate photodynamic therapy. AB - Rose Bengal acetate photodynamic therapy (RBAc-PDT) induced multiple cell death pathways in HeLa cells through ROS and ER stress. Indeed, apoptosis was the first preferred mechanism of death, and it was triggered by at least four different pathways, whose independent temporal activation ensures cell killing when one or several of the pathways are inactivated. Apoptosis occurred as early as 1 h after PDT through activation of intrinsic pathways, followed by activation of extrinsic, caspase-12-dependent and caspase-independent pathways, and by autophagy. The onset of the different apoptotic pathways and autophagy, that in our system had a pro-death role, was timed by determining the levels of caspases 9, 8, 3 and 12; Bcl-2 family; Hsp70; LC3B; GRP78 and phospho-eIF2alpha proteins. Interestingly, inhibition of one pathway, that is, caspase-9 (Z-LEHD-FMK), caspase-8 (Z-IETD-FMK), pan-caspases (Z-VAD-FMK), autophagy (3-MA) and necrosis (Nec-1), did not impair the activation of the others, suggesting that the independent onset of the different apoptotic pathways and autophagy did not occur in a subordinated manner. Altogether, our data indicate RBAc as a powerful photosensitiser that induces a prolonged cytotoxicity and time-related cell death onset by signals originating from or converging on almost all intracellular organelles. The fact that cancer cells can die through different mechanisms is a relevant clue in the choice and design of anticancer PDT. PMID- 21654828 TI - Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. AB - The major cellular event in the development and progression of liver fibrosis is the activation of hepatic stellate cells (HSCs). Activated HSCs proliferate and produce excess collagen, leading to accumulation of scar matrix and fibrotic liver. As such, the induction of activated HSC death has been proposed as a means to achieve resolution of liver fibrosis. Here we demonstrate that cannabidiol (CBD), a major non-psychoactive component of the plant Cannabis sativa, induces apoptosis in activated HSCs through a cannabinoid receptor-independent mechanism. CBD elicits an endoplasmic reticulum (ER) stress response, characterized by changes in ER morphology and the initiation of RNA-dependent protein kinase-like ER kinase-, activating transcription factor-6-, and inositol-requiring ER-to nucleus signal kinase-1 (IRE1)-mediated signaling cascades. Furthermore, CBD induces downstream activation of the pro-apoptotic IRE1/ASK1/c-Jun N-terminal kinase pathway, leading to HSC death. Importantly, we show that this mechanism of CBD-induced ER stress-mediated apoptosis is specific to activated HSCs, as it occurs in activated human and rat HSC lines, and in primary in vivo-activated mouse HSCs, but not in quiescent HSCs or primary hepatocytes from rat. Finally, we provide evidence that the elevated basal level of ER stress in activated HSCs has a role in their susceptibility to the pro-apoptotic effect of CBD. We propose that CBD, by selectively inducing death of activated HSCs, represents a potential therapeutic agent for the treatment of liver fibrosis. PMID- 21654829 TI - Role of TRAIL and the pro-apoptotic Bcl-2 homolog Bim in acetaminophen-induced liver damage. AB - Acetaminophen (N-acetyl-para-aminophenol (APAP), paracetamol) is a commonly used analgesic and antipyretic agent. Although considered safe at therapeutic doses, accidental or intentional overdose causes acute liver failure characterized by centrilobular hepatic necrosis with high morbidity and mortality. Although many molecular aspects of APAP-induced cell death have been described, no conclusive mechanism has been proposed. We recently identified TNF-related apoptosis inducing ligand (TRAIL) and c-Jun kinase (JNK)-dependent activation of the pro apoptotic Bcl-2 homolog Bim as an important apoptosis amplification pathway in hepatocytes. In this study, we, thus, investigated the role of TRAIL, c-JNK and Bim in APAP-induced liver damage. Our results demonstrate that TRAIL strongly synergizes with APAP in inducing cell death in hepatocyte-like cells lines and primary hepatocyte. Furthermore, we found that APAP strongly induces the expression of Bim in a c-JNK-dependent manner. Consequently, TRAIL- or Bim deficient mice were substantially protected from APAP-induced liver damage. This study identifies the TRAIL-JNK-Bim axis as a novel target in the treatment of APAP-induced liver damage and substantiates its general role in hepatocyte death. PMID- 21654830 TI - Psoriasis in a nationwide cohort study of patients with celiac disease. AB - Earlier studies on the association between celiac disease (CD) and psoriasis show contradictory results. The purpose of this study was to assess the risk of psoriasis in patients with biopsy-verified CD. Through 28 pathology departments in Sweden, we identified individuals with CD diagnosed between 1969 and 2008 (Marsh 3: villous atrophy; n = 28,958 unique individuals). We then used Cox regression to compare individuals with CD with 143,910 sex- and age-matched controls regarding their risk of psoriasis. CD was a risk factor for future psoriasis (hazard ratio (HR) = 1.72; 95% confidence interval (CI) = 1.54-1.92; during follow-up, 401 individuals with CD and 1,139 controls had a diagnosis of psoriasis). The absolute risk of future psoriasis in patients with CD was 135/100,000 person-years (excess risk = 57/100,000). In all, 42% of all psoriasis in patients with CD could be attributed to the underlying CD. Moreover, in children we saw a positive association between CD and psoriasis (HR = 2.05; 95% CI = 1.62-2.60). The association between CD and psoriasis seems to be independent of a temporal relationship, as we also found a positive association between CD and psoriasis before CD diagnosis (odds ratio = 1.91; 95% CI = 1.58-2.31). In conclusion, individuals with CD were at increased risk of psoriasis both before and after CD diagnosis. PMID- 21654831 TI - Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A producing cells and are found in lesional skin. AB - Psoriasis is an autoimmune-related chronic inflammatory skin disease that is strongly associated with IL-23 and T helper-17 (Th17) effector cytokines. In addition, CD4+CD25(high) regulatory T-cell (Treg) function appeared to be impaired in psoriasis. CD4+CD25(high)Foxp3+ Tregs are typically considered inhibitors of autoimmune responses. However, under proinflammatory conditions, Tregs can differentiate into inflammation-associated Th17 cells--a paradigm shift, with as yet largely unknown consequences for human disease initiation or progression. Th17 cells are highly proinflammatory T cells that are characterized by IL-17A and IL-22 production and expression of the transcription factor retinoic acid-related orphan receptor gammat (RORgammat). We here show that Tregs of patients with severe psoriasis, as compared with those of healthy controls, have an enhanced propensity to differentiate into IL-17A-producing cells on ex vivo stimulation. This enhanced Treg differentiation was linked to unexpectedly high RORgammat levels and enhanced loss of Foxp3. Notably, IL-23 boosted this Treg differentiation process particularly in patients with psoriasis but less so in controls. IL-23 further reduced Foxp3 expression while leaving the high RORgammat levels unaffected. The histone/protein deacetylase inhibitor, Trichostatin-A, prevented Th17 differentiation of Tregs in psoriasis patients. Importantly, IL-17A+/Foxp3+/CD4+ triple-positive cells were present in skin lesions of patients with severe psoriasis. These data stress the clinical relevance of Treg differentiation for the perpetuation of chronic inflammatory disease and may pave novel ways for immunotherapy. PMID- 21654832 TI - Polo-like kinase 1 is a potential therapeutic target in human melanoma. AB - Exploration of the human melanoma cell-cycle pathway can lead to identification of new therapeutic targets. By gene set enrichment analysis, we identified the cell-cycle pathway and its member polo-like kinase 1 (Plk-1) to be significantly overexpressed in primary melanomas and in melanoma metastases. In vitro expression of Plk-1 was peaked at the G2/M phase of the cell cycle. Plk-1 knockdown/inhibition led to induction of apoptosis, which was caspase-3/8 dependent and p53-independent, and involved BID and Bcl-2 proteins. Comparative genomic hybridization/single-nucleotide polymorphism arrays showed no genetic alteration in the Plk-1 locus. Previous suggestions and significant enrichment of the mitogen-activated protein kinase (MAPK) signaling pathway pointed to potential regulation of Plk-1 by MAPK signaling. Inhibition of this pathway resulted in decreased Plk-1 expression as a consequence of G1 cell-cycle arrest rather than direct regulation of Plk-1. Inhibition of MAPK and Plk-1 had an additive effect on reduced cell viability. This study shows that in human melanoma, Plk-1 expression is dynamically regulated during the cell cycle, knockdown of Plk-1 leads to apoptotic cell death, and that a combination of Plk-1 and MAPK inhibition has an additive effect on melanoma cell viability. We conclude that combined inhibition of Plk-1 and MAPK could be a potentially attractive strategy in melanoma therapy. PMID- 21654833 TI - Transcriptional inhibition of hypertrophic scars by a gene silencer, pyrrole imidazole polyamide, targeting the TGF-beta1 promoter. AB - Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. We examined the effects of a transforming growth factor (TGF)-beta1-targeted PI polyamide (Polyamide) on hypertrophic skin scars in rats. Hypertrophic scars were created dorsally in rats by incisions. FITC-labeled Polyamide was injected to investigate its distribution in the skin. Expression of TGF-beta1, connective tissue growth factor (CTGF), collagen type1, and fibronectin mRNAs was evaluated by reverse transcription PCR analysis. The extent of fibrosis and the expression of TGF-beta1 were evaluated histologically and immunohistochemically. Polyamide was distributed in almost all nuclei of skin cells. Expression of TGF-beta1 mRNA reached a peak at 3 days after skin incision. Expression of CTGF and extracellular matrix mRNAs was increased continuously even after the peak induction of TGF-beta1 mRNA. Injection of Polyamide completely inhibited both the development of scars and the induction of growth factors and extracellular matrix mRNAs. The treatment also markedly inhibited fibrotic changes and reduced the numbers of vimentin-positive spindle-shaped fibroblasts. Injection of Polyamide also reduced established hypertrophic scars in rats. Thus, TGF-beta1-targeted PI polyamide should be a feasible gene silencer for hypertrophic scars and keloids. PMID- 21654834 TI - Dacarbazine promotes stromal remodeling and lymphocyte infiltration in cutaneous melanoma lesions. AB - Dacarbazine (DTIC) is the standard first-line drug for advanced stage melanoma, but it induces objective clinical responses in only 15% of patients. This study was designed to identify molecular changes specifically induced by treatment in chemo-sensitive lesions. Using global transcriptome analysis and immunohistochemistry, we analyzed cutaneous metastases resected from patients with melanoma before and after DTIC treatment. The treatment induced similar functional changes in different lesions from the same patient. Stromal and immune response-related genes were the most frequently upregulated, particularly in lesions that responded to treatment by stabilizing or regressing. T-cell infiltration and enhanced major histocompatibility complex class II expression were observed in a subset of patients. Stable, chemo-sensitive lesions exhibited activation of genetic programs related to extracellular matrix remodeling, including increased expression of secreted protein acidic and rich in cysteine (SPARC) by tumor cells. These events were associated with local response to treatment and with superior survival in our group of patients. In contrast, SPARC expression was downregulated in lesions resistant to DTIC. Thus, chemotherapy drugs originally selected for their direct cytotoxicity to tumor cells may also influence disease progression by inducing changes in the tumor microenvironment. PMID- 21654835 TI - Resolution of psoriasis by a leukocyte-targeting bacterial protein in a humanized mouse model. AB - Psoriasis is a very common chronic skin disease, affecting 2-3% of the world's population or more than 125 million individuals worldwide. The characteristic lesion of psoriasis is due to rapid proliferation and shortened transition of keratinocytes through the epidermis. Proinflammatory white blood cells (WBCs) migrate into the psoriatic plaques, and the pathogenic cytokine environment causes the changes in keratinocyte proliferation and differentiation. Enhanced migration of WBCs is due to the upregulation and activation of adhesion molecules such as leukocyte function antigen-1 (LFA-1), which binds intercellular adhesion molecule-1 (ICAM-1) on endothelial cells. Targeting LFA-1 and preventing interaction with ICAM-1 has proven an effective strategy for treating psoriasis. We show here that a natural leukocyte-targeting bacterial protein (leukotoxin (LtxA)) that binds LFA-1 can inhibit proliferation of activated WBCs from psoriasis patients and demonstrates significant therapeutic efficacy in a psoriasis xenograft transplantation model. In ex vivo studies, LtxA preferentially targeted proinflammatory WBC subtypes, including activated CD25(+) T cells and CD14(+)CD16(+) monocytes. LFA-1 has been shown to have a significant role in the pathogenesis of numerous autoimmune and inflammatory diseases, and we propose that LtxA may be a highly effective agent for treating these diseases. PMID- 21654836 TI - Impaired keratinocyte proliferative and clonogenic potential in transgenic mice overexpressing 14-3-3sigma in the epidermis. AB - The 14-3-3 protein family controls diverse biochemical processes through interaction with phosphorylated consensus sequences in protein targets. Its epithelial specific member, 14-3-3sigma, also known as stratifin, is highly expressed in differentiated keratinocytes, and in vitro evidence indicates that 14-3-3sigma downregulation leads to keratinocyte immortalization. To define the role of 14-3-3sigma in skin homeostasis in vivo, we generated transgenic mice overexpressing 14-3-3sigma in proliferating keratinocytes of the epidermis and hair follicle. Transgenic animals show decreased epidermal thickness and hair follicle density associated with reduced number of proliferating keratinocytes and decreased levels of keratins 14, 5, and 15. Primary keratinocytes isolated from transgenic mice manifest reduced proliferation and migration. Moreover, clonogenicity assessment and label-retaining analysis reveal a reduction in keratinocyte progenitor cell number in transgenic mice. Response to IGF-1 is strongly impaired in cultured transgenic keratinocytes compared with wild-type cells. Consistently, activation of phosphoinositol 3-kinase (PI3K), AKT, and Rac1, all IGF-1 downstream mediators, is reduced. Our results demonstrate that 14 3-3sigma controls the in vivo epidermal proliferation-differentiation switch by reducing proliferative potential and forcing keratinocytes to exit the cell cycle, and that this effect associates with inhibition of the IGF-1 pathway. PMID- 21654837 TI - Infliximab infusions for Netherton syndrome: sustained clinical improvement correlates with a reduction of thymic stromal lymphopoietin levels in the skin. PMID- 21654838 TI - From cancer stem cells to tumor maintenance in melanoma. AB - The utility of different models to identify cancer stem cells continues to be a subject of intense debate. Here, we summarize recent efforts to characterize intra-tumoral heterogeneity of melanoma and delineate key questions for future studies. Within a developing or already established tumor microenvironment, we propose that continuous tumor maintenance is assured by specific sub-populations whose phenotype is not static but instead is dynamically regulated. These small and temporarily distinct sub-populations likely have critical roles in tumor progression. They are important therapeutic targets, but only in the context of combination therapies, that also eliminate the bulk of the tumor. PMID- 21654839 TI - Loss of PTEN expression by dermal fibroblasts causes skin fibrosis. AB - Fibrosis represents a common pathway leading to organ failure and death in many diseases and has no effective therapy. Dysregulated repair and excessive tissue scarring provides a unifying mechanism for pathological fibrosis. The protein phosphatase and tensin homolog (PTEN) acts to dephosphorylate proteins, which promotes tissue repair and thus could be a key fibrogenic mediator. To test this hypothesis, we first showed that PTEN expression was reduced in skin fibroblasts from patients with the fibrotic autoimmune disease diffuse systemic sclerosis (dSSc). To evaluate whether this deficiency could be sufficient for fibrogenesis in vivo, we deleted PTEN in adult mouse fibroblasts. Compared with littermate control mice, loss of PTEN resulted in a 3-fold increase in dermal thickness due to excess deposition of collagen. PTEN-deleted fibroblasts showed elevated Akt phosphorylation and increased expression of connective tissue growth factor (CTGF/CCN2). Selective inhibition of the phosphatidylinositol 3-kinase/Akt pathway reduced the overexpression of collagen and CCN2 by PTEN-deficient fibroblasts. Overexpression of PTEN reduced the overexpression of type I collagen and CCN2 by dSSc fibroblasts. Thus, PTEN appears to be a potential in vivo master regulator of fibrogenesis; PTEN agonists may represent anti-fibrotic treatments. PMID- 21654840 TI - Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin. AB - Caspase-14 is a protease that is mainly expressed in suprabasal epidermal layers and activated during keratinocyte cornification. Caspase-14-deficient mice display reduced epidermal barrier function and increased sensitivity to UVB radiation. In these mice, profilaggrin, a protein with a pivotal role in skin barrier function, is processed correctly to its functional filaggrin (FLG) repeat unit, but proteolytic FLG fragments accumulate in the epidermis. In wild-type stratum corneum, FLG is degraded into free amino acids, some of which contribute to generation of the natural moisturizing factors (NMFs) that maintain epidermal hydration. We found that caspase-14 cleaves the FLG repeat unit and identified two caspase-14 cleavage sites. These results indicate that accumulation of FLG fragments in caspase-14(-/-) mice is due to a defect in the terminal FLG degradation pathway. Consequently, we show that the defective FLG degradation in caspase-14-deficient skin results in substantial reduction in the amount of NMFs, such as urocanic acid and pyrrolidone carboxylic acid. Taken together, we identified caspase-14 as a crucial protease in FLG catabolism. PMID- 21654841 TI - An intracytoplasmic IL-10 receptor variant permits rapid reduction in STAT3 activation. AB - Within the interleukin-10 receptor 1 (IL10R1) gene, two common variants are associated with certain diseases: single-nucleotide polymorphism 3 (SNP3), a serine-138 to glycine mutation is in linkage disequilibrium with SNP4, a glycine 330 to arginine mutation, both of which are considered loss-of-function alleles. However, the molecular consequence of G330R is unknown. We investigated possible roles of G330R on the dynamics of IL10R1 surface expression and signal transducer and activator of transduction (STAT) phosphorylation. HeLa cells expressing the respective IL10R1 haplotype were stimulated with IL-10. Significant reduction of IL10R1 surface expression was observed after ligand binding. Receptor expression remained low on continuous incubation with IL-10. In contrast, when treated with an IL-10 pulse, IL10R1 surface expression returned to its resting state within 3 9 h irrespective of the haplotype. STAT3 was rapidly phosphorylated both in cells with wild-type (WT) or variant IL10R1, and maintained phosphorylated when cells were cultured with IL-10. On IL-10 pulse, however, STAT3 phosphorylation declined rapidly in cells expressing IL10R1-G330R but not IL10R1-WT or S138G. Similar dynamics were observed with STAT1 phosphorylation at Tyr701. No differences in janus kinase 1 (JAK1) activation were observed in cells with WT or variant IL10R1. Our results indicate that IL10R1-G330R does not alter surface expression but duration of STAT phosphorylation, indicating that the position of G330 is important in stabilizing the STAT signal. PMID- 21654842 TI - Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations. AB - C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus and increased susceptibility to bacterial infections. However, the clinical symptoms may vary. For long, the molecular basis of C1q deficiency was ascribed to only six different mutations. In the present report, we describe five new patients with C1q deficiency, present the 12 causative mutations described till now and review the clinical spectrum of symptoms found in patients with C1q deficiency. With the results presented here, confirmed C1q deficiency is reported in 64 patients from at least 38 families. PMID- 21654843 TI - The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles. AB - The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1(*)0801-DQA1(*)0401/DQB1(*)0402 (DR8 DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-A(g7). Similar to HLA-DQ8 and H-2 I-A(g7), HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8- or I-A(g7) ligands, and several diabetes-specific peptides associated with DQ8 or I-A(g7) could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes. PMID- 21654844 TI - Genome-wide association study of severity in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome. PMID- 21654845 TI - FoxP3 interacts with linker histone H1.5 to modulate gene expression and program Treg cell activity. AB - The forkhead box transcription factor FoxP3 controls the development and function of CD4+CD25+ regulatory T (Treg) cell. FoxP3 modulates gene expression in Treg cells by multiple epigenetic mechanisms that are not clearly defined. We identified FoxP3-interacting proteins in human T cells by co immunoprecipitation/MS. We discovered that FoxP3 interacted with linker histone H1.5 via the leucine zipper (LZ) domain. Two independent IPEX patient-derived single residue mutations in the LZ of FoxP3 both abrogated its interaction with H1.5. Functionally, FoxP3 and H1.5 cooperatively repressed interleukin-2 (IL-2) expression in human T cells; and silencing of H1.5 expression inhibited the ability of FoxP3 to suppress IL-2 expression. We show that FoxP3 specifically enhanced H1.5 association at the IL-2 promoter, but reduce its association at the CTLA4 promoter, correlated with higher or lower histone acetylation of the respective promoters. Finally, silencing of H1.5 expression in human Treg cells impaired the Treg function to suppress target T cells. We conclude that FoxP3 interacts with H1.5 to alter its binding to target genes to modulate their expression and to program Treg function. PMID- 21654847 TI - A novel fungal family of oligopeptide transporters identified by functional metatranscriptomics of soil eukaryotes. AB - Functional environmental genomics has the potential to identify novel biological functions that the systematic sequencing of microbial genomes or environmental DNA may fail to uncover. We targeted the functions expressed by soil eukaryotes using a metatranscriptomic approach based on the use of soil-extracted polyadenylated messenger RNA to construct environmental complementary DNA expression libraries. Functional complementation of a yeast mutant defective in di/tripeptide uptake identified a novel family of oligopeptide transporters expressed by fungi. This family has a patchy distribution in the Basidiomycota and Ascomycota and is present in the genome of a Saccharomyces cerevisiae wine strain. High throughput phenotyping of yeast mutants expressing two environmental transporters showed that they both displayed broad substrate specificity and could transport more than 60-80 dipeptides. When expressed in Xenopus oocytes one environmental transporter induced currents upon dipeptide addition, suggesting proton-coupled co-transport of dipeptides. This transporter was also able to transport specifically cysteine. Deletion of the two copies of the corresponding gene family members in the genome of the wine yeast strain severely reduced the number of dipeptides that it could assimilate. These results demonstrate that these genes are functional and can be used by fungi to efficiently scavenge the numerous, low concentration, oligopeptides continuously generated in soils by proteolysis. PMID- 21654846 TI - SNP-based analysis of the HLA locus in Japanese multiple sclerosis patients. AB - Although several major histocompatibility complex (MHC)-wide single-nucleotide polymorphism (SNP) studies have been performed in populations of European descent, none have been performed in Asian populations. The objective of this study was to identify human leukocyte antigen (HLA) loci associated with multiple sclerosis (MS) in a Japanese population genotyped for 3534 MHC region SNPs. Using a logistic regression model, two SNPs (MHC Class III SNP rs422951 in the NOTCH4 gene and MHC Class II SNP rs3997849, susceptible alleles A and G, respectively) were independently associated with MS susceptibility (204 patients; 280 controls), two (MHC Class II SNP rs660895 and MHC Class I SNP rs2269704 in the NRM gene, susceptible alleles G and G, respectively) with aquaporin-4- (AQP4-) MS susceptibility (149 patients; 280 controls) and a single SNP (MHC Class II SNP rs1694112, susceptible allele G) was significant when contrasting AQP4+ against AQP4- patients. Haplotype analysis revealed a large susceptible association, likely DRB1*04 or a locus included in the DRB1*04 haplotype, with AQP4- MS, which excluded DRB1*15:01. This study is the largest study of the HLA's contribution to MS in Japanese individuals. PMID- 21654848 TI - Transcriptional response of the photoheterotrophic marine bacterium Dinoroseobacter shibae to changing light regimes. AB - Bacterial aerobic anoxygenic photosynthesis (AAP) is an important mechanism of energy generation in aquatic habitats, accounting for up to 5% of the surface ocean's photosynthetic electron transport. We used Dinoroseobacter shibae, a representative of the globally abundant marine Roseobacter clade, as a model organism to study the transcriptional response of a photoheterotrophic bacterium to changing light regimes. Continuous cultivation of D. shibae in a chemostat in combination with time series microarray analysis was used in order to identify gene-regulatory patterns after switching from dark to light and vice versa. The change from heterotrophic growth in the dark to photoheterotrophic growth in the light was accompanied by a strong but transient activation of a broad stress response to the formation of singlet oxygen, an immediate downregulation of photosynthesis-related genes, fine-tuning of the expression of ETC components, as well as upregulation of the transcriptional and translational apparatus. Furthermore, our data suggest that D. shibae might use the 3-hydroxypropionate cycle for CO(2) fixation. Analysis of the transcriptome dynamics after switching from light to dark showed relatively small changes and a delayed activation of photosynthesis gene expression, indicating that, except for light other signals must be involved in their regulation. Providing the first analysis of AAP on the level of transcriptome dynamics, our data allow the formulation of testable hypotheses on the cellular processes affected by AAP and the mechanisms involved in light- and stress-related gene regulation. PMID- 21654849 TI - Cultivation of methanogenic community from subseafloor sediments using a continuous-flow bioreactor. AB - Microbial methanogenesis in subseafloor sediments is a key process in the carbon cycle on the Earth. However, the cultivation-dependent evidences have been poorly demonstrated. Here we report the cultivation of a methanogenic microbial consortium from subseafloor sediments using a continuous-flow-type bioreactor with polyurethane sponges as microbial habitats, called down-flow hanging sponge (DHS) reactor. We anaerobically incubated methane-rich core sediments collected from off Shimokita Peninsula, Japan, for 826 days in the reactor at 10 degrees C. Synthetic seawater supplemented with glucose, yeast extract, acetate and propionate as potential energy sources was provided into the reactor. After 289 days of operation, microbiological methane production became evident. Fluorescence in situ hybridization analysis revealed the presence of metabolically active microbial cells with various morphologies in the reactor. DNA- and RNA-based phylogenetic analyses targeting 16S rRNA indicated the successful growth of phylogenetically diverse microbial components during cultivation in the reactor. Most of the phylotypes in the reactor, once it made methane, were more closely related to culture sequences than to the subsurface environmental sequence. Potentially methanogenic phylotypes related to the genera Methanobacterium, Methanococcoides and Methanosarcina were predominantly detected concomitantly with methane production, while uncultured archaeal phylotypes were also detected. Using the methanogenic community enrichment as subsequent inocula, traditional batch-type cultivations led to the successful isolation of several anaerobic microbes including those methanogens. Our results substantiate that the DHS bioreactor is a useful system for the enrichment of numerous fastidious microbes from subseafloor sediments and will enable the physiological and ecological characterization of pure cultures of previously uncultivated subseafloor microbial life. PMID- 21654851 TI - The association between aortic augmentation index and cardiovascular risk factors in a large unselected population. AB - The augmentation index (AIx) is a measure of systemic arterial stiffness, and previous studies have demonstrated an association between AIx and risk factors of cardiovascular disease (CVD). However, there is limited knowledge about the age and gender differences of the observed associations. Therefore, the aim of the present study is to examine the association's consistency at different ages and to see if the associations are the same in men and women. This study is based on 3432 subjects from The Copenhagen City Heart Study, a prospective epidemiological survey of a representative population in Denmark. All subjects had AIx measured non-invasively by the SphygmoCor device (SphygmoCor, West Ryde, Australia). To analyse the association between AIx and CVD risk factors multiple linear regression analyses were used stratified by gender and age. The main determinants of AIx were age, heart rate, height and systolic blood pressure in both age groups with few gender differences. Associations between AIx and cardiovascular risk factors further differed by age: In young subjects AIx was associated with cholesterol, high-sensitive C-reactive protein, current smoking, low weight, poor education and physical inactivity, whereas in subjects above age 60 AIx was associated with weight and current smoking in men. We found a modest association between AIx and traditional CVD risk factors and the association attenuated in subjects >60 years. Further longitudinal studies are needed to determine whether AIx is primarily a marker of CVD in younger subjects. PMID- 21654850 TI - Resistant hypertension, obstructive sleep apnoea and aldosterone. AB - Obstructive sleep apnoea (OSA) and hypertension commonly coexist. Observational studies indicate that untreated OSA is strongly associated with an increased risk of prevalent hypertension, whereas prospective studies of normotensive cohorts suggest that OSA may increase the risk of incident hypertension. Randomized evaluations of continuous positive airway pressure (CPAP) indicate an overall modest effect on blood pressure (BP). Determining why OSA is so strongly linked to having hypertension in cross-sectional studies, but yet CPAP therapy has limited BP benefit needs further exploration. The CPAP studies do, however, indicate a wide variation in the BP effects of CPAP, with some patients manifesting a large antihypertensive benefit such that a meaningful BP effect can be anticipated in some individuals. OSA is particularly common in patients with resistant hypertension (RHTN). The reason for this high prevalence of OSA is not fully explained, but data suggest that it may be related to the high occurrence of hyperaldosteronism in patients with RHTN. In patients with RHTN, it has been shown that aldosterone levels correlate with severity of OSA and that blockade of aldosterone reduces the severity of OSA. Overall, these findings are consistent with aldosterone excess contributing to worsening of underlying OSA. We hypothesize that aldosterone excess worsens OSA by promoting accumulation of fluid within the neck, which then contributes to increased upper airway resistance. PMID- 21654852 TI - White blood cell subsets are associated with carotid intima-media thickness and pulse wave velocity in an older Chinese population: the Guangzhou Biobank Cohort Study. AB - Cross-sectional associations between white blood cell (WBC) count, lymphocyte and granulocyte numbers, and carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (PWV) were examined in a novel older Chinese community sample. A total of 817 men and 760 women from a sub-study of the Guangzhou Biobank Cohort Study had a full blood count measured by an automated hematology analyzer, carotid IMT by B-mode ultrasonography and brachial-ankle PWV by a non invasive automatic waveform analyzer. Following adjustment for confounders, WBC count (beta=0.07, P<0.001) and granulocyte (beta=0.07, P<0.001) number were significantly positively related to PWV, but not lymphocyte number. Similarly, WBC count (beta=0.08, P=0.03), lymphocyte (beta=0.08, P=0.002) and granulocyte (beta=0.03, P=0.04) number were significantly positively associated with carotid IMT, but only the association with lymphocyte count survived correction for other cardiovascular risk factors. In conclusion, higher WBC, particularly lymphocyte and granulocyte, count could be used, respectively, as markers of cardiovascular disease risk, measured through indicators of atherosclerosis and arterial stiffness. The associations for WBC count previously observed by others were likely driven by higher granulocytes; an index of systemic inflammation. PMID- 21654853 TI - Socioeconomic position is positively associated with blood pressure dipping among African-American adults: the Jackson Heart Study. AB - BACKGROUND: Blunted nocturnal blood pressure (NBP) dipping is a significant predictor of cardiovascular events. Lower socioeconomic position (SEP) may be an important predictor of NBP dipping, especially in African Americans (AA). However, the determinants of NBP dipping are not fully understood. METHODS: The cross-sectional associations of individual and neighborhood SEP with NBP dipping, assessed by 24-h ambulatory BP monitoring, were examined among 837 AA adults (Mean age: 59.2 +/- 10.7 years; 69.2% women), after adjustment for age, sex, hypertension status, body mass index (BMI), health behaviors, office, and 24-h systolic BP (SBP). RESULTS: The mean hourly SBP was consistently lower among participants in the highest category of individual income compared to those in the lowest category, and these differences were most pronounced during sleeping hours. The odds of NBP dipping (defined as >10% decline in the mean asleep SBP compared to the mean awake SBP) increased by 31% (95% confidence interval: 13 53%) and 18% (95% confidence interval: 0-39%) for each s.d. increase in income and years of education, respectively, after multivariable adjustment. CONCLUSIONS: NBP dipping is patterned by income and education in AA adults even after accounting for known risk factors. These results suggest that low SEP is a risk factor for insufficient NBP dipping in AA. PMID- 21654854 TI - Alcohol intake and atherosclerotic risk factors in normotensive and prehypertensive men. AB - BACKGROUND: The purpose of this study was to determine whether relationships between alcohol intake and atherosclerotic risk factors were different in normotensive and prehypertensive persons. METHODS: Japanese men aged 35-60 years who showed normal blood pressure (n = 4,778) or prehypertension (n = 9,728) without any drug therapy for hypertension were divided into non, light (<22 g ethanol/day), heavy (>= 22 and < 44 g ethanol/day) and very heavy (>= 44 g ethanol/day) drinkers. RESULTS: In subjects with prehypertension, body mass index (BMI) and waist circumference were significantly lower and smaller, respectively, in light, heavy and very heavy drinkers than in nondrinkers. In subjects with normal blood pressure, BMI was significantly lower in light and heavy drinkers but not in very heavy drinkers than in nondrinkers, and waist circumference was not significantly different in non, light and heavy drinkers and was significantly larger in very heavy drinkers than in nondrinkers. Both in the prehypertensive and normotensive groups, compared with nondrinkers, hemoglobin A(1C) and low-density lipoprotein (LDL) cholesterol were significantly lower and high-density lipoprotein (HDL) cholesterol was significantly higher in light, heavy and very heavy drinkers, and log-converted triglycerides was significantly higher in very heavy drinkers. CONCLUSIONS: The association of alcohol intake with a lower occurrence of obesity is stronger in prehypertensives than in normotensives, while the associations of alcohol intake with lower occurrences of hyperglycemia and abnormal cholesterol profile, such as lowered HDL cholesterol and elevated LDL cholesterol, and a higher occurrence of elevated triglycerides are similar in normotensive and prehypertensive persons. PMID- 21654855 TI - Maternal age during pregnancy is associated with third trimester blood pressure level: the generation R study. AB - BACKGROUND: We hypothesized that hemodynamic adaptations related to pregnancy and ageing might be associated with differences in blood pressure levels during pregnancy between younger and older women. This might partly explain the increased risk of gestational hypertensive disorders with advanced maternal age. We examined the associations of maternal age with systolic and diastolic blood pressure in each trimester of pregnancy and the risks of gestational hypertensive disorders. METHODS: The study was conducted among 8,623 women participating in a population-based prospective cohort study from early pregnancy onwards. Age was assessed at enrolment. Blood pressure was measured in each trimester. Information about gestational hypertensive disorders was available from medical records. RESULTS: In second and third trimester, older maternal age was associated with lower systolic blood pressure (-0.9 mm Hg (95% confidence interval: -1.4, -0.3) and -0.6 mm Hg (95% confidence interval: -1.1, -0.02) per additional 10 maternal years, respectively). Older maternal age was associated with higher third trimester diastolic blood pressure (0.5 mm Hg (95% confidence interval: 0.04, 0.9) per additional 10 maternal years). Maternal age was associated with pregnancy-induced hypertension among overweight and obese women. CONCLUSION: Older maternal age is associated with lower second and third trimester systolic blood pressure, but higher third trimester diastolic blood pressure. These blood pressure differences seem to be small and within the physiological range. Maternal age is not consistently associated with the risks of gestational hypertensive disorders. Maternal body mass index might influence the association between maternal age and the risk of pregnancy-induced hypertension. PMID- 21654857 TI - Association between a thyroid hormone receptor-alpha gene polymorphism and blood pressure but not with coronary heart disease risk. AB - BACKGROUND: Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor beta whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-alpha (TR-alpha) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-alpha (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk. METHODS: We analyzed the associations between five THRA polymorphisms and (i) BP level in two population-based studies (MONICA Lille n = 1,155; MONICA Toulouse n = 1,170) and (ii) the risk of CHD in two case-control studies (Lille CHD n = 558 cases/568 controls; PRIME n = 527 cases/584 controls). RESULTS: Individuals carrying the rs939348 T allele had higher systolic BP (~+1.3 mm Hg) than CC individuals in both the MONICA Lille (P = 0.02) and Toulouse (P = 0.03) studies. The odds ratio (OR) for hypertension was 1.25 (P = 0.02) in the combined sample. Concerning the CHD risk, no significant association could be detected. CONCLUSIONS: For the first time, our study showed associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension but not with CHD, although we admit that the statistical power available to study any relationship with CHD was very limited. Further larger association studies are needed to confirm our findings. PMID- 21654856 TI - Interactions of genetic variants with physical activity are associated with blood pressure in Chinese: the GenSalt study. AB - BACKGROUND: Blood pressure (BP) homeostasis involves complex interactions among genetic and nongenetic factors, providing major challenges to dissection of the genetic components that influence BP and hypertension. In this study, we examine the effects of interaction of genetic variants with physical activity on BP in a relatively genetically homogenous cohort of rural Chinese villagers. METHODS: Generalized estimating equations analysis was used to test for associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with variants in 24 genes in BP pathways (196 single-nucleotide polymorphisms (SNPs)) among 3,142 Chinese participants divided according to physical activity (active vs. inactive groups). RESULTS: In the physically active group, two SNPs in NR3C2 were significantly associated with lower SBP, and a SNP in SCNN1B was significantly associated with lower SBP and DBP. In the physically inactive group, a SNP in APLNR was associated with lower SBP, a SNP in GNB3 (guanine nucleotide binding protein, beta polypeptide 3) was associated with higher SBP and DBP, and a SNP in BDKRB2 (bradykinin receptor B2) was associated with lower DBP. Cumulative effects in carriers of minor alleles of these SNPs showed reductions of SBP and DBP as large as 8 and 5 mm Hg, respectively, in the active individuals compared to inactive individuals carrying the same number of minor alleles. CONCLUSIONS: We found that physical activity modifies the effects of genetic variants on BP. However, our results also show that active individuals with specific genotypes always have lower BP than inactive individuals with the same genotypes, demonstrating the overall beneficial effects of physical activity on BP. PMID- 21654858 TI - Impact of home blood pressure telemonitoring and blood pressure control: a meta analysis of randomized controlled studies. AB - BACKGROUND: Home blood pressure telemonitoring figures among the possible solutions that could help improve blood pressure control of hypertensive patients. To summarize the effectiveness of home blood pressure telemonitoring on blood pressure control from randomized, controlled studies. METHODS: Electronic databases were searched for publications in English, reporting on randomized trials of home blood pressure telemonitoring vs. usual care. Outcome measures were office or ambulatory blood pressure changes, rate of blood pressure control, and number of antihypertensive drugs used by patients. A random effects model was applied. RESULTS: Twelve studies met inclusion criteria. A high level of heterogeneity was found among studies for all the variables explored. Office blood pressure was reduced significantly more in patients randomized to home telemonitoring (systolic: 5.64 (95% confidence interval: 7.92, 3.36) mm Hg; diastolic: 2.78 (3.93, 1.62) mm Hg; 11 comparisons, n = 4,389). The effect on ambulatory blood pressure was smaller than on office blood pressure (systolic: 2.28 (4.32, 0.24); diastolic: 1.38 (3.55, +0.79) mm Hg; 3 comparisons, n = 655). The relative risk of blood pressure normalization (<140/90 mm Hg nondiabetics and <130/80 mm Hg diabetics) in the telemonitoring vs. the usual care group was 1.31 (1.06, 1.62) (5 comparisons, n = 2,432 subjects). Use of telemonitoring was associated with a significantly increased use of antihypertensive medications (+0.22 (+0.02, +0.43), 5 comparisons, n = 1,991). CONCLUSIONS: Home blood pressure telemonitoring may represent a useful tool to improve blood pressure control. However, heterogeneity of published studies suggests that well designed, large-scale, randomized, controlled studies are still needed to demonstrate the clinical usefulness of this technique. PMID- 21654859 TI - Association between central elastic artery stiffness and cerebral perfusion in deep subcortical gray and white matter. AB - BACKGROUND: Central elastic artery stiffness can increase vascular resistance and induce hypertrophic remodeling of cerebral arterioles and, in turn, may increase the risk of cerebral hypoperfusion. In this study, we examined whether central artery stiffness was directly associated with cerebral perfusion. METHODS: Thirty five adults (15 men and 20 women; 49 +/- 7 years) were studied. Central artery stiffness was determined by carotid-femoral pulse wave velocity (cfPWV). Regional cerebral perfusion in deep subcortical white and gray matter was measured using arterial spin labeling (ASL). RESULTS: Participants were divided into two groups created by a median split of pooled subjects (median cfPWV = 1,090 cm/s). The group with high cfPWV showed significantly lower cerebral perfusion in frontal (29.9 +/- 3.6 vs. 50.7 +/- 3.7 ml/100 g/min, P = 0.001) and parietal (33.4 +/- 6.0 vs. 57.5 +/- 5.7 ml/100 g/min, P < 0.01) white matter and hippocampus (44.4 +/- 4.4 vs. 60.1 +/- 6.1 ml/100 g/min, P = 0.04) than the low cfPWV group. Simple correlation analysis revealed that cfPWV is significantly associated with cerebral perfusion in frontal (r = -0.64, P < 0.001) and parietal (r = -0.36, P = 0.03) white matter. Multiple linear regression analysis further indicated that 11% of the variability in frontal white matter perfusion (DeltaR(2) = 0.11, P = 0.03) is explained by cfPWV (beta = -0.54, P = 0.03), independent of age, sex, race, heart rate, blood pressure, and cardiovascular medication. CONCLUSIONS: Central elastic artery stiffness is inversely and significantly associated with cerebral perfusion in deep subcortical frontal white matter, independent of potential confounding factors. PMID- 21654860 TI - [The Director of Public Health personality]. PMID- 21654861 TI - Predictors of nursing student success in an Italian school of Nursing. AB - Aims of the study was To define predictor factors of academic success of student in an Italian Nursing School. The recent introduction of the first level nursing education at university in Italy primed many changes processes and required to think new methods and contents. The study was descriptive and retrospective. The setting is an Italian School of Nursing. It was considered a sample constituted by 2 three years. Academic success was defined such as the capability of the student to finish formative pathway in three years with a final mark >90/110. An half of sample (53.7%, 66/123) finished the studies in three years. Variables that more influenced academic success were age, nationality, admission mark, evaluations obtained in professionals and tutorship formative activity. To know factors influenced academic success provides some indications that should be useful to define "at risk" students for which to plan formative pathways and specific supports. PMID- 21654862 TI - Results from the monitoring of pesticide residues in fruits and vegetables marketed in Piedmont (Italy), 2000-2008. AB - The Regional Agency for Public Health in Piedmont (Italy) analyzed pesticide residue levels (more than 190 pesticides) from 2000 to 2008 in 4.078 fruit samples, 2.869 vegetable samples from conventional agriculture, and 428 fruit and vegetable samples (2004-2007) from organic agriculture. Residues above the maximum residue levels were found in 4% of the fruit samples, in 2% of the vegetable samples, and in 2% of samples from organic farming. The main purpose of the present work was to evaluate the opportunity to start specific procedures of risk management and prevention strategies along the production chain and the official control. PMID- 21654863 TI - [Economic class syndrome: epidemiological features and preventive measures]. AB - The term "economic class syndrome" is generally used to describe the occurrence of venous thromboembolism (VTE) in travelers after long-distance airline travel in economic class. However, cases of VTE have also been reported in business class travelers and in subjects exposed to prolonged periods of immobilization while using other forms of transportation such as automobile, train, and bus. VTE manifests with deep vein thrombosis and pulmonary embolism but may also present with less severe, reversible manifestations such as headache, vertigo, and respiratory symptoms. Epidemiological studies have shown that the risk of VTE doubles following airline travel lasting longer than four hours. The risk of VTE increases with increased duration of air travel even in the presence of multiple stop-overs. In subjects with known risk factors, incidence of VTE depends on the degree of risk (low, medium, high) and on the duration of the flight. The main factor leading to VTE is prolonged immobilization and the pathogenesis is based on Virchow's triad: venous stasis, vessel wall injury, and hypercoagulability of blood. Specific characteristics of airline travel such as jet lag, low air quality and dehydration may increase the risk of VTE with respect to other forms of travel. This article discusses epidemiological aspects and pathogenesis of travel-related VTE and prophylactic measures that should be undertaken. PMID- 21654864 TI - [Economic and health impact of the use of coal as an energy source]. PMID- 21654865 TI - [In memory of Bruno Angelillo]. PMID- 21654866 TI - [The history of cholera in the Puglia region (Italy), 1836-1994]. AB - Historians and epidemiologists agree that seven pandemics of cholera have occurred from 1817 to the present time. However they do not always agree on the date of onset and extinction of several of the pandemics. Cholera appeared for the first time in Europe and therefore in Italy in the first half of the 19th century. In this context, the population of the Puglia region (Italy) was first affected by cholera starting in 1836, during the second pandemic, and then again during the following pandemics and in more recent local outbreaks in 1973 and 1994. This article describes the impact of the disease in the Puglia region, not only in terms of morbidity and mortality but also in terms of collective behaviour and public health interventions. Information was obtained from documents held by the State Archives of the city of Bari and from local documents. This historical analysis highlights the great progress made in this Region in terms of environmental rehabilitation and control of infectious diseases. PMID- 21654867 TI - [Vaccination against measles, mumps and rubella in a Roma people camp in Rome, Italy]. AB - The immunization strategy aimed to the elimination of Measles and the prevention of Congenital Rubella failed to reach the planned objectives in Europe; in Italy the renewed National Elimination Plan (PNEMoRc 2010-2015) has been recently approved. The evaluation of a preventive intervention to avoid the spread of measles in a Roma people camp confirm the importance of specific vaccination in high risk populations, like nomads, in which low coverage rates are responsible for the maintenance of the disease. PMID- 21654869 TI - Reducing Adverse Self-Medication Behaviors in Older Adults with Hypertension: Results of an e-health Clinical Efficacy Trial. AB - A randomized controlled efficacy trial targeting older adults with hypertension (age 60 and over) provided an e-health, tailored intervention with the "next generation" of the Personal Education Program (PEP-NG). Eleven primary care practices with advanced practice registered nurse (APRN) providers participated. Participants (N = 160) were randomly assigned by the PEP-NG (accessed via a wireless touchscreen tablet computer) to either control (entailing data collection and four routine APRN visits) or tailored intervention (involving PEP NG intervention and four focused APRN visits) group. Compared to patients in the control group, patients receiving the PEP-NG e-health intervention achieved significant increases in both self-medication knowledge and self-efficacy measures, with large effect sizes. Among patients not at BP targets upon entry to the study, therapy intensification in controls (increased antihypertensive dose and/or an additional antihypertensive) was significant (p = .001) with an odds ratio of 21.27 in the control compared to the intervention group. Among patients not at BP targets on visit 1, there was a significant declining linear trend in proportion of the intervention group taking NSAIDs 21-31 days/month (p = 0.008). Satisfaction with the PEP-NG and the APRN provider relationship was high in both groups. These results suggest that the PEP-NG e-health intervention in primary care practices is effective in increasing knowledge and self-efficacy, as well as improving behavior regarding adverse self-medication practices among older adults with hypertension. PMID- 21654870 TI - Nondrug-related aspect of treating Ekbom disease, formerly known as restless legs syndrome. AB - Ekbom disease (EKD), formerly known as restless legs syndrome (RLS) has affected and bothered many people over the centuries. It is one of the most prevalent neurological disorders in Europe and North-America, affecting about 10% of the population. The main characteristics are the strong urge to move, accompanied or caused by uncomfortable, sometimes even distressing, paresthesia of the legs, described as a "creeping, tugging, pulling" feeling. The symptoms often become worse as the day progresses, leading to sleep disturbances or sleep deprivation, which leads to decreased alertness and daytime functions. Numerous studies have been conducted assessing the efficacy of dopaminergic drugs, opioids, and other pharmacologic agents in alleviating EKD symptoms. However, there is also a growing body of evidence demonstrating the effectiveness of nonpharmacologic treatments including life style changes, physical activity programs, pneumatic compression, massage, near-infrared light therapy, and complementary therapies. The working mechanisms behind these alternatives are diverse. Some increase blood flow to the legs, therefore reducing tissue hypoxia; some introduce an afferent counter stimulus to the cortex and with that "close the gate" for aberrant nerve stimulations; some increase dopamine and nitric oxide and therefore augment bio available neurotransmitters; and some generate endorphins producing an analgesic effect. The advantages of these treatments compared with pharmacologic agents include less or no side effects, no danger of augmentation, and less cost. PMID- 21654871 TI - The role of asenapine in the treatment of manic or mixed states associated with bipolar I disorder. AB - BACKGROUND: Bipolar disorders (BD) are of particular public health significance as they are prevalent, severe and disabling, and often associated with elevated risks of premature mortality. The aim of this concise overview is to investigate the role of asenapine in the treatment of manic and mixed states associated with BD type 1 disorder. METHOD: MedLine, Excerpta Medica and PsycINFO searches were performed to identify papers in English published over the past 7 years. Search terms were "asenapine", "manic" OR "mixed states", "bipolar I disorder". Subjects included in this study suffered from BD type 1 disorder. RESULTS: To date, only four studies of asenapine for the treatment of manic or mixed episodes associated with BD type 1 have been published. CONCLUSION: Research indicates that asenapine is generally well-tolerated, and that asenapine is efficacious and not inferior to olanzapine in the treatment of mixed or manic episodes associated with BD type 1 in the short-term and long-term. PMID- 21654872 TI - Physician perception of clinical improvement in children with attention deficit/hyperactivity disorder: a post hoc comparison of lisdexamfetamine dimesylate and mixed amphetamine salts extended release in a crossover analog classroom study. AB - OBJECTIVE: To assess effects of lisdexamfetamine dimesylate (LDX) and mixed amphetamine salts extended release (MAS XR) on symptom improvement in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover analog-classroom environment was conducted. The primary efficacy outcome was the deportment subscale of the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP-D) rating scale. The secondary efficacy outcome was the investigator-rated Clinical Global Impressions-Improvement (CGI-I), a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), which assesses improvement over time from baseline. McNemar test was used to compare participants' responses to LDX and MAS XR on CGI-I scores dichotomized into 1 (very much improved) vs all other response scores (2 to 7) in a 2 * 2 table. RESULTS: Fifty-two children (aged 6 to 12 years) were enrolled, titrated, and randomized; 50 completed the study. Investigators rated 74% of LDX participants as either very much improved or much improved on the CGI-I scale relative to 72% of MAS XR participants and 18% of placebo participants. Of the 50 children who completed the study, 32% of LDX participants were very much improved vs 16% of MAS XR, and 2% of placebo participants relative to baseline. McNemar test indicated that 10 participants were very much improved with LDX, but not MAS XR; 2 participants were very much improved with MAS XR, but not LDX; 6 participants were very much improved with both, while 32 were not very much improved with either. Analysis showed that LDX had a significantly higher number of children with a very much improved score on the CGI-I than MAS XR (P = 0.0386). CONCLUSION: Treatment of children with LDX resulted in a higher number of participants with a very much improved score on the CGI-I than treatment with MAS XR or placebo. PMID- 21654874 TI - Recurrent major depression, ataxia, and cardiomyopathy: association with a novel POLG mutation? AB - At present, more than 100 disease mutations in mitochondrial DNA polymerase gamma (POLG) have been indentified that are causally related to an array of neuropsychiatric diseases affecting multiple systems. Both autosomal recessive and autosomal dominant forms can be delineated, the latter being associated with Parkinsonism and depressive or psychotic syndromes. In this report, a middle-aged female patient with recurrent major depression with melancholic features, slowly progressive gait instability, and dilated cardiomyopathy is described. Detailed diagnostic evaluation was performed to elucidate the supposed relationship between ataxia, cardiomyopathy, and major depression with melancholia. After extensive genetic and metabolic investigation, a nucleotide substitution c.2207 A >G in the POLG gene resulting in amino acid change Asn 736Ser in exon 13 was demonstrated. This mutation was considered to be compatible with a mitochondrial disorder and implicated in the pathophysiology of the neuropsychiatric syndrome. It is concluded that this novel POLG mutation forms the most parsimonious etiological explanation for the here-described combination of ataxia, major depression, and cardiomyopathy. Therefore, in patients with a complex neuropsychiatric presentation, extensive diagnostic analysis is warranted, including the search for mitochondriopathies, in order to avoid unnecessary delay of adequate treatment. PMID- 21654873 TI - Risk factors for the development of depression in patients with hepatitis C taking interferon-alpha. AB - Interferon-alpha, currently used for the treatment of hepatitis C, is associated with a substantially elevated risk of depression. However, not everyone who takes this drug becomes depressed, so it is important to understand what particular factors may make some individuals more 'at risk' of developing depression than others. Currently there is no consensus as to why interferon-induced depression occurs and the range of putative risk factors is wide and diverse. The identification of risk factors prior to treatment may allow identification of patients who will become depressed on interferon, allowing the possibility of improved treatment support and rates of treatment adherence. Here, we consolidate and review the literature on risk factors, and we discuss the potential confounds within the research examined in order to better isolate the risk factors that may be important in the development of depression in these patients and which might help predict patients likely to become depressed on treatment. We suggest that interactions between psychobehavioral, genetic, and biological risk factors are of particular importance in the occurrence of depression in patients with hepatitis C taking interferon-alpha. PMID- 21654875 TI - Once-daily pramipexole for the treatment of early and advanced idiopathic Parkinson's disease: implications for patients. AB - Immediate-release (IR) pramipexole is indicated for the symptomatic treatment of idiopathic Parkinson's disease (PD), either alone (without levodopa) or in combination with levodopa, that is, during the entire progress of disease up to the advanced stage. It is also currently indicated for the treatment of moderate to-severe primary restless legs syndrome (RLS). An extended-release (ER) formulation of pramipexole has been developed to allow a once-daily formulation and to provide more stable dopaminergic stimulation. This review summarized the pharmacokinetic profile of pramipexole for both the IR and ER formulations, and discussed the role of pramipexole in the management of early and advanced PD. The introduction of a once-daily formulation of pramipexole poses significant potential advantages for patients and this is reflected by relatively stable plasma levels. The most obvious benefit is convenience of use and better adherence to treatment schedule. Additional advantages may be represented by the opportunity to provide continuous drug delivery in a fashion that could potentially help minimize dyskinesia risk if the drug is used early in the disease course. PMID- 21654876 TI - Primary malignant melanoma of the uterine cervix treated with ultraradical surgery: a case report. AB - Primary melanomas of the uterine cervix are rare tumors with no more than 60 cases reported in the world literature. Poor prognosis is considered for the neoplasia itself as well as for diagnostic tardiness. There is no standard treatment; however, radical surgery is the treatment cornerstone. Our aim was to present the case of a 34-year-old woman with a primary malignant melanoma in the uterine cervix with affectation of the posterior face of the vagina without metastasis. Total infraelevator pelvic exenteration and adjuvant radiotherapy was performed. The patient was under surveillance for 8 years of followup without evidence of local or distant disease. The majority of case reports found suggests radical hysterectomy as the treatment indicated for these patients. Notwithstanding this, survival is very short when patients are treated in this manner. Based on our results and on those reported in the literature, we propose initial treatment with total pelvic exenteration as optimal management for this neoplasia in its initial form. PMID- 21654877 TI - Elevated levels of CXC chemokine connective tissue activating peptide (CTAP)-III in lung cancer patients. AB - Despite advances in treatments, lung cancer has been the leading cause of cancer related deaths in the United States for the past several decades. Recent findings from the National Lung Screening Trial reveal that low-dose helical computed tomography (CT) scan screening of high-risk individuals reduces lung cancer mortality. This suggests that early detection is of key importance to improving patient outcome. However, of those screened with CT scans, 25% had positive scans that require further follow-up studies which often involve more radiation exposure and invasive tests to reduce false positive results. The purpose of this study was to identify candidate plasma biomarkers to aid in diagnosis of lung cancer in at-risk individuals. We found increased expression of the CXC chemokine connective tissue-activating peptide (CTAP)-III from plasma specimens of lung cancer patients compared to at-risk control subjects. Identification of the peptide was confirmed by the addition of an anti-NAP-2 antibody that recognizes CTAP-III and NAP-2. We also quantified and verified the increased levels of plasma CTAP-III with ELISA in patients with lung cancer (mean +/- SD, 1859 +/- 1219 ng/mL) compared to controls (698 +/- 434 ng/mL; P<0.001). Our findings demonstrate elevated plasma levels of CTAP-III occur in lung cancer patients. Further studies are required to determine if this chemokine could be utilized in a blood-based biomarker panel for the diagnosis of lung cancer. PMID- 21654878 TI - Configuration and rearrangement of the human GAGE gene clusters. AB - The GAGE protein is detected only in cancer and in testis and is expressed from a cluster of nearly identical gene copies on the X-chromosome. We determined the lengths of these GAGE gene clusters from human families, identical twins, and in clinical samples from cancer patients. The GAGE cluster lengths proved to be highly heterogeneous, ranging from 13 to 39 gene copies, with an average content of 20 GAGE genes per cluster. Low levels of mei-otic rearrangement in families and mitotic rearrangement in adult solid tumors are detectable. Analysis of Rothmund -Thomson syndrome (RTS) kindreds and probands showed GAGE cluster inheritance and stability indistinguishable from that found in non-RTS individuals. These observations support the concept of evolutionarily rapid rearrangement of clustered repetitive sequences in the human genome. PMID- 21654879 TI - The roles of EZH2 in cell lineage commitment. AB - Enhancer of zeste homolog 2 (EZH2), a catalytic component of polycomb repressive complex 2 (PRC2), epigenetically regulates chromatin structure and gene expressions through tri-methylation at histone H3K27 and recruitment of DNA methyltransferases for gene silencing. Despite extensive studies of the role of EZH2 in cancer progression and malignancy, increasing evidence also suggest that EZH2 plays a critical role in stem cells renewal, maintenance, and differentiation into specific cell lineages. Here, we review the updated information regarding how EZH2 contributes to stem cell maintenance, cell lineage determination, including myogenesis, adipogenesis, osteogenesis, neurogenesis, hematopoiesis, lymphopoiesis, epidermal differentiation and hepatogenesis, and how EZH2 is regulated by phosphorylation and microRNAs in these processes. PMID- 21654880 TI - Emerging tactical strategies for fighting the war on cancer based on the genetic landscape. AB - Although it is well-established that cancer is driven by genetic mutations resulting in the acquisition of onco-genes and the loss of tumor suppressors, until recently many of the genomic details remained obscure. As a result of recent high-throughput DNA sequencing, basic insights into the spectrum of protein coding mutations in many cancers are now known. These findings provide an unprecedented framework of understanding and present new avenues for diagnosis, treatment, and prevention of cancer. In this article we discuss several high impact areas of global sequencing projects including developing drugs that specifically target cancer cells, creating personalized tools for better treatment and monitoring, and developing pre-symptomatic diagnostic tests. Capitalizing on these and other advances represent a new turning point in the war on cancer. PMID- 21654881 TI - Lipotoxicity in HepG2 cells triggered by free fatty acids. AB - The goal of this study was to investigate the lipid accumulation and lipotoxicity of free fatty acids (FFAs) induced in HepG2 cells. HepG2 cells were co-incubated with various concentrations of FFAs for 24h and the intracellular lipid contents were observed by Oil Red O and Nile Red staining methods. The lipotoxicity of HepG2 cells were then detected by Hoechest 33342/PI, Annexin V-FITC/PI double staining and 3-(4,5-dimethylthiazol-2-yl)-2,5-di phenyltetrazolium bromide (MTT) experiment tests. The experiments showed a lipid accumulation and lipotoxicity by increasing FFA concentration gradients. Through cell morphological observation and quantitative analysis, FFAs have shown to increase in a dose-dependent manner compared with the control group. The data collected from hoechst 33342/PI, annexin V-FITC/PI double staining and also MTT experiments showed that cell apoptosis and necrosis significantly increased with increasing FFA concentrations. Apoptosis was not obvious in the 1 mM FFAs-treated group compared to the other two groups. In a certain concentration range, FFAs induced intracellular lipid accumulation and lipotoxicity of HepG2 cells in a dose dependent manner. PMID- 21654882 TI - Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. AB - Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatment remain challenging issues. Carfilzomib is a novel, well tolerated, irreversible proteasome inhibitor with minimal neurotoxicity. Carfilzomib demonstrates promising activity in myeloma patients who are refractory to bortezomib and immunomodulatory agents. This review focuses on the pharmacology, safety, and efficacy of carfilzomib for the treatment of multiple myeloma in bortezomib-naive and bortezomib-exposed populations. PMID- 21654883 TI - Predictive factors of success in selective laser trabeculoplasty (SLT) treatment. AB - PURPOSE: Glaucoma is a progressive optic neuropathy that may lead to blindness. Reducing intraocular pressure (IOP) is the only known treatment to slow progression in glaucoma. IOP can be reduced by pharmaceutical treatment, laser and surgery. The aim of the present study was to assess predictive factors of success after selective laser trabeculoplasty (SLT) treatment. METHODS: We used a retrospective chart review of eyes that underwent SLT between January 1, 2005 and December 31, 2005. The dependent variable was time to failure after SLT treatment. Failure after SLT was defined as any changes in the medical treatment, and/or a new SLT treatment was performed and/or the patient was sent for surgery. All patients were treated with 90 degrees SLT. A multivariate regression analysis was performed to assess correlation between time to failure after SLT and age, gender, IOP before treatment, number of medications used, SLT number, amount of spots, laser energy used, grade of angle, pigmentation and diagnosis. RESULTS: 120 eyes of 120 patients were identified. The average time to failure after SLT was 18 months. The predictive factors identified were: age, IOP before SLT and dose. CONCLUSION: Predictive factors identified in our study were high baseline IOP, age and amount of laser energy used. Our study confirms previous results about baseline IOP as a predictive factor. PMID- 21654884 TI - Trehalose: an intriguing disaccharide with potential for medical application in ophthalmology. AB - Trehalose is a naturally occurring disaccharide comprised of two molecules of glucose. The sugar is widespread in many species of plants and animals, where its function appears to be to protect cells against desiccation, but is not found in mammals. Trehalose has the ability to protect cellular membranes and labile proteins against damage and denaturation as a result of desiccation and oxidative stress. Trehalose appears to be the most effective sugar for protection against desiccation. Although the exact mechanism by which trehalose protects labile macromolecules and lipid membranes is unknown, credible hypotheses do exist. As well as being used in large quantities in the food industry, trehalose is used in the biopharmaceutical preservation of labile protein drugs and in the cryopreservation of human cells. Trehalose is under investigation for a number of medical applications, including the treatment of Huntington's chorea and Alzheimer's disease. Recent studies have shown that trehalose can also prevent damage to mammalian eyes caused by desiccation and oxidative insult. These unique properties of trehalose have thus prompted its investigation as a component in treatment for dry eye syndrome. This interesting and unique disaccharide appears to have properties which may be exploited in ophthalmology and other disease states. PMID- 21654885 TI - Congenital intrascleral cyst. AB - Congenital intrascleral cysts are rare. They are mostly located at the limbus with corneal involvement. We report a case of a 30-month-old boy with a bulber conjunctival cyst noticed at birth. The lesion enlarged over the following months but did not involve the cornea. During surgery the cyst proved to be intrascleral and a complete excision was carried out. The remaining defect was repaired with banked fascia lata. The histopathology revealed a scleral cyst wall lined by nonkeratinizing squamous epithelium with no goblet cells. We conclude that congenital intrascleral epithelial cysts are rare but should be considered in differential diagnosis of external eye cystic lesions. In our case, early excision and repair with fascia lata led to an uncomplicated postoperative course of 6 years. PMID- 21654886 TI - Review of hydroxypropyl cellulose ophthalmic inserts for treatment of dry eye. AB - Dry eye syndrome is a prevalent disease that affects visual acuity, activities of daily living, and quality of life. A number of contributory factors affect the severity of dry eye syndrome, including autoimmune disease, environmental surroundings, contact lens use, hormonal changes, anatomical features, chronic inflammation, infections, and iatrogenic factors, such as medications or surgery. Symptoms may include intermittent or constant blurry vision, discomfort, burning, foreign body sensation, hyperemia, dryness, and photophobia. The severity of dry eye syndrome can range from very mild disease to extremely severe cases with vision-threatening consequences. A variety of dry eye treatment modalities exist to address the different causes, symptoms, and consequences of ocular surface disease, including artificial tears, lubricating gels, ophthalmic inserts, anti inflammatory drops, and surgical procedures. In this paper, an assortment of literature pertaining to the treatment of dry eye syndrome, in particular hydroxypropyl cellulose ophthalmic inserts, is reviewed. These inserts can be used effectively as monotherapy, or in conjunction with other therapies, and should be considered in the treatment of dry eye syndrome. PMID- 21654887 TI - Age-related macular degeneration. AB - CLINICAL QUESTION: Is there any new knowledge about the pathogenesis and treatment of age-related macular degeneration (AMD)? RESULTS: We now understand better the biochemical and pathological pathways involved in the genesis of AMD. Treatment of exudative AMD is based on intravitreal injection of new antivascular endothelial growth factor drugs for which there does not yet exist a unique recognized strategy of administration. No therapies are actually available for atrophic AMD, despite some experimental new pharmacological approaches. IMPLEMENTATION: strategy of administration, safety of intravitreal injection. PMID- 21654888 TI - Densiron 68 as an intraocular tamponade for complex inferior retinal detachments. AB - INTRODUCTION: Densiron((r)) 68 is a high-density liquid used to tamponade inferior retinal detachments. We present a case series of 12 patients treated with Densiron as an intraocular tamponade agent. METHODS: A retrospective analysis of 12 eyes in 12 patients was carried out. The primary endpoint was anatomic reattachment of the retina following removal of Densiron oil. RESULTS: All patients had inferior detachments; 33% had associated proliferative vitreoretinopathy (PVR). Densiron was utilized as a primary agent in five patients (42%); the remaining patients had prior unsuccessful surgery for retinal reattachment, including pars plana vitrectomy, cryotherapy, laser, encirclement, gas (C3F8 or C2F6), or silicone oil. Eleven patients (91%) had successful reattachment of the retina at 3 months following removal of Densiron; one patient had extensive PVR, total retinal detachment, preretinal macula fibrosis, and chronic hypotony, and surgical intervention was unsuccessful. Six patients (50%) had raised intraocular pressure (IOP), resolving in the majority of cases following Densiron removal; two patients had long-term raised IOP requiring topical or surgical therapy. Of the six phakic patients, 50% developed significant cataract in the operated eye. Of those with successful retinal reattachment, visual outcome was variable, with 36% patients gaining two to four lines on Snellen, 27% remaining objectively the same, and 36% losing one to two lines. CONCLUSION: The anatomic success rate is high (91%) in patients requiring Densiron tamponade for inferior retinal detachments with or without evidence of PVR either as a primary or secondary intervention. A common complication is raised IOP; however, this most often resolves following removal of the oil. PMID- 21654889 TI - Presumed bilateral branch retinal vein occlusions secondary to antiepileptic agents. AB - A 61-year-old man presented to the ophthalmology department having developed bilateral branch retinal vein occlusions. Baseline blood tests revealed no abnormality; however, subsequent investigations showed a raised plasma homocysteine (HC) level. The patient has been treated for refractory epilepsy for a number of years. Although antiepileptic medications have been shown to reduce folate levels and result in a raised HC level, this has not previously been shown to be to a level causing a retinal vascular event. PMID- 21654890 TI - Macular laser photocoagulation guided by spectral-domain optical coherence tomography versus fluorescein angiography for diabetic macular edema. AB - BACKGROUND: The aim of this study was to compare the efficacy of spectral-domain optical coherence tomography (SD-OCT) and fluorescein angiography (FA) in the guidance of macular laser photocoagulation for diabetic macular edema. METHODS: This was a prospective interventional clinical comparative pilot study. Forty eyes from 24 consecutive patients with diabetic macular edema were allocated to receive laser photocoagulation guided by SD-OCT or FA. Best-corrected visual acuity (BCVA), central macular thickness, and retinal volume were assessed at baseline and two months after treatment. RESULTS: Subjects treated using FA guided laser improved BCVA from the logarithm of the minimum angle of resolution (logMAR) 0.52 +/- 0.2 to 0.37 +/- 0.2 (P < 0.001), and decreased mean central macular thickness from 397.25 +/- 139.1 to 333.50 +/- 105.7 MUm (P < 0.001) and retinal volume from 12.61 +/- 1.6 to 10.94 +/- 1.4 mm(3) (P < 0.001). Subjects treated using SD-OCT guided laser had improved BCVA from 0.48 +/- 0.2 to 0.33 +/- 0.2 logMAR (P < 0.001), and decreased mean central macular thickness from 425.90 +/- 149.6 to 353.4 +/- 140 MUm (P < 0.001) and retinal volume from 12.38 +/- 2.1 to 11.53 +/- 1.1 mm(3) (P < 0.001). No significant differences between the groups were found in two-month BCVA (P = 0.505), two-month central macular thickness (P = 0.660), or two-month retinal volume (P = 0.582). CONCLUSION: The short-term results of this pilot study suggest that SD-OCT is a safe and effective technique and could be considered as a valid alternative to FA in the guidance of macular laser photocoagulation treatment for diabetic macular edema. PMID- 21654891 TI - Severe anterior uveitis associated with idiopathic dacryoadenitis in diabetes mellitus patient. AB - A 38-year-old woman with diabetes mellitus complained of acute visual loss in the left eye (20/200) and swollen left upper eyelid. Slit lamp examination of the left eye revealed ciliary injection, posterior synechia iritis, numerous inflammatory cells, and fibrin exudates in the anterior chamber. T1-weighted enhanced magnetic resonance imaging demonstrated left lacrimal gland enhancement with inflammatory spread to the left anterior ocular segment. Blood examination showed increased blood sugar but the other components were within normal limits. The patient was treated with steroid pulse therapy (methylprednisolone 1 g/day * 3 days) under a blood sugar control regimen in consultation with an endocrinologist, after which additional peribulbar injection of triamcinolone acetonide (40 mg) was performed. Resolution of the anterior uveitis and the dacryoadenitis was obtained after 2 months and there was no recurrence 1 year after the therapy. This is a rare case of severe anterior uveitis caused by idiopathic dacryoadenitis in a patient with diabetes mellitus. PMID- 21654894 TI - Catalyzing Social Support for Breast Cancer Patients. AB - Social support is a critical, yet underutilized resource when undergoing cancer care. Underutilization occurs in two conditions: (a) when patients fail to seek out information, material assistance, and emotional support from family and friends or (b) when family and friends fail to meet the individualized needs and preferences of patients. Social networks are most effective when kept up to date on the patient's status, yet updating everyone takes effort that patients cannot always put in. To improve this situation, we describe the results of our participatory design activities with breast cancer patients. During this process, we uncovered the information a social network needs to stay informed as well as a host of barriers to social support that technology could help break down. Our resulting prototype, built using Facebook Connect, includes explicit features to reduce these barriers and thus, promote the healthy outcomes associated with strong social support. PMID- 21654895 TI - Transforming Clinic Environments into Information Workspaces for Patients. AB - Although clinic environments are a primary location for exchanging information with clinicians, patients experience these spaces as harsh environments to access, use, exchange, and manage information. In this paper, we present results from an ethnographic-inspired study of breast cancer patients actively interacting with information in clinic environments. Through observations and interviews, we observed information interactions in awkward physical positions; inefficient use of existing clinical space; separation of patients from their information and lack of support for collaborative document viewing. These factors compromised patients' abilities to manage their information work when they experienced bursts of information exchange, lack of advance information, fragmented attention, and heightened stress in clinic environments. To overcome these challenges, we identify formative strategies to focus attention, encourage collaboration, and improve communication in clinical settings. PMID- 21654896 TI - Hypericum brasiliense plant extract neutralizes some biological effects of Bothrops jararaca snake venom. AB - Alternative treatments for snake bite are currently being extensively studied, and plant metabolites are considered good candidates for such purpose. Here, the ability of a crude ethanolic extract of Hypericum brasiliense plant in neutralizing Bothrops jararaca snake venom was investigated by in vitro (coagulation, hemolysis or proteolysis) and in vivo (hemorrhage, lethality and edema) biological assays. We describe for the first time the ability of H. brasiliense extracts to inhibit some pharmacological effects of a Brazilian snake venom. Inhibitory assays were performed by incubating B. jararaca venom with H. brasiliense extracts for 30min at room temperature before the assays were performed. The results showed that H. brasiliense extracts impaired lethality, edema, hemorrhage, hemolysis, proteolysis as well as fibrinogen or plasma clotting induced by B. jararaca venom. This indicates that H. brasiliense extracts can provide promising agents to treat B. jararaca envenomation. PMID- 21654898 TI - Towards a new crown indicator: an empirical analysis. AB - We present an empirical comparison between two normalization mechanisms for citation-based indicators of research performance. These mechanisms aim to normalize citation counts for the field and the year in which a publication was published. One mechanism is applied in the current so-called crown indicator of our institute. The other mechanism is applied in the new crown indicator that our institute is currently exploring. We find that at high aggregation levels, such as at the level of large research institutions or at the level of countries, the differences between the two mechanisms are very small. At lower aggregation levels, such as at the level of research groups or at the level of journals, the differences between the two mechanisms are somewhat larger. We pay special attention to the way in which recent publications are handled. These publications typically have very low citation counts and should therefore be handled with special care. PMID- 21654897 TI - Characterization of intraocular pressure responses of the Tibetan monkey (Macaca thibetana). AB - PURPOSE: To characterize the effects of circadian rhythm, feeding time, age, general anesthesia, and ocular hypotensive compounds on intraocular pressure (IOP) of the Tibetan monkey (Macaca thibetana). METHODS: Tibetan monkeys were trained for IOP measurement with the TonoVet(r) rebound tonometer without sedation or anesthesia. Their circadian IOP fluctuation was monitored every 3 h. Effects of changing the feeding time, general anesthesia, age (2-3 year-old versus 8-15 year-old animals), and various pharmacological agents, such as travoprost, timolol, naphazoline and spiradoline, on IOP were also evaluated. RESULTS: After behavioral training, conscious Tibetan monkeys were receptive to IOP measurement. The lowest and highest IOP values in a circadian cycle were recorded at 3:00 AM (19.8+/-0.4 mmHg, mean+/-SEM, n=12) and noon (29.3+/-0.9 mmHg), respectively. Changing the feeding time from 11:30 AM to 12:30 PM lowered the noon IOP to 25.1+/-1.2 mmHg. General anesthesia lowered IOP in these monkeys, while IOP of young and mature animals were similar. Three hours after topical ocular administration, travoprost reduced IOP by 5.2+/-0.6 mmHg (n=6, p<0.001), and timolol reduced IOP by 2.8+/-0.7 mmHg (p<0.05). Naphazoline and spiradoline lowered IOP by 4.8 mmHg and 2.5 mmHg (both p<0.001), respectively, 2 h after drug administration. CONCLUSIONS: The circadian IOP fluctuation in conscious Tibetan monkeys and their responses to travoprost, timolol, and other experimental conditions are similar to other primates. These monkeys appear to be a suitable model for glaucoma research. PMID- 21654899 TI - EPR Study of Iron Ion Complexes in Human Blood. AB - Electronic states of iron ion complexes in human blood from patients with melanoma have been investigated by electron paramagnetic resonance (EPR). The measurements were performed at liquid nitrogen temperature (77 K) on an X-band EPR spectrometer. Numerous types of iron paramagnetic centers have been identified. In several kinds of protein complexes exemplified by methemoglobin, transferrin or ferritin, various forms of trivalent iron have been found. Three groups of patients with typical EPR spectra have been individualized. These groups differed in types and concentration of paramagnetic centers in peripheral blood. A good correlation has been found between the EPR results, the total iron ion complexes concentration and transferrin saturation. PMID- 21654900 TI - Improvement of quality of reporting in randomised controlled trials to prevent hypotension after spinal anaesthesia for caesarean section. AB - Hypotension is a frequent complication of spinal anaesthesia for caesarean section and can threaten the well-being of the unborn child. Numerous randomised controlled trials (RCTs) dealt with measures to prevent hypotension. The aim of this study was to determine the reporting quality of RCTs using the Consolidated Standards of Reporting Trials (CONSORT) statement since low quality can lend false credibility to a study and overestimate the effect of an intervention. We performed a systematic literature search in PubMed to identify relevant RCTs in a pre-CONSORT period (1990-1994) and a post-CONSORT period (2004-2008). A comparative evaluation was done between the two periods, and the trials were assessed for compliance with each of the 22 CONSORT items. A total of 37 RCTs was identified. The CONSORT score increased significantly (p < 0.05) from 66.7% (+/ 12.5%) in the pre-CONSORT period to 87.4% (+/-6.9%) in the post-CONSORT period. A statistically significant improvement was found for eight items, including randomization, blinding and intention-to-treat analysis. The CONSORT score in the post-CONSORT era was fairly good, also in comparison to other medical fields. In the post-CONSORT era, reporting of important items improved, in particular in the domains that are crucial to avoid bias and to improve internal validity. Use of CONSORT should be encouraged in order to keep or even improve the reporting quality. PMID- 21654901 TI - Group Composition of Guinea Baboons (Papio papio) at a Water Place Suggests a Fluid Social Organization. AB - Baboon social systems are among the most studied in primates. Solid knowledge of the hamadryas and savannah baboon systems has accumulated, leading to a dichotomic view of baboon social systems. Hamadryas baboons live in multilayered troops based on 1-male units whereas savannah baboons live in multimale multifemale groups based on a network of related females. Less attention has been paid to their West African congenerics, the Guinea baboons, Papio papio. To fill this gap, in 2007 we initiated a long-term study of a baboon troop ranging in the Niokolo Koba National Park in southeastern Senegal. Earlier studies suggested a tendency for a multilayered social system in Guinea baboons, similar to the hamadryas baboon organization. Therefore, as a first approach to analyzing variability in party size and composition, we observed members of the troop crossing an open area from a fixed point for 3 mo during the dry and wet seasons. We counted individuals and recorded changes in composition of both arriving and departing parties. Party size and composition were highly variable on both a daily and a seasonal basis; 45.9% of the arriving parties changed in composition while crossing the open area, either splitting into smaller parties or fusing into larger ones, suggesting a fluid organization. Our data support the existence of neither a hamadryas baboon-like multilayered social organization nor a stable medium-sized multimale multifemale group as in savannah baboons. In light of our data we may need to revise the dichotomic view of baboon social systems and include space for greater variability of their social systems. PMID- 21654903 TI - Clinical implementation of the hysteroscopic morcellator for removal of intrauterine myomas and polyps. A retrospective descriptive study. AB - The aim of this study is to report our experience with a novel technique, the hysteroscopic morcellator (HM), for removal of intrauterine myomas and polyps. We performed a retrospective study on 315 women undergoing operative hysteroscopy with the HM in our university-affiliated teaching hospital. We collected data on installation and operating times, fluid deficit, peri- and postoperative complications. In 37 patients undergoing myomectomy with the HM, mean installation time was 8.7 min, mean operating time, 18.2 min, and median fluid deficit, 440 mL. Three out of 37 HM procedures were converted to resectoscopy, related to a type 2 myoma. In 278 patients, mean installation and operating times for polypectomy with the HM were 7.3 min and 6.6 min, respectively. All procedures were uneventful. Implementation of the HM for removal of type 0 and 1 myomas <=3 cm, and removal of polyps appears safe and effective. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10397 010-0627-7) contains supplementary material, which is available to authorized users. PMID- 21654902 TI - Strategies for the Use of Fallback Foods in Apes. AB - Researchers have suggested that fallback foods (FBFs) shape primate food processing adaptations, whereas preferred foods drive harvesting adaptations, and that the dietary importance of FBFs is central in determining the expression of a variety of traits. We examine these hypotheses in extant apes. First, we compare the nature and dietary importance of FBFs used by each taxon. FBF importance appears greatest in gorillas, followed by chimpanzees and siamangs, and least in orangutans and gibbons (bonobos are difficult to place). Next, we compare 20 traits among taxa to assess whether the relative expression of traits expected for consumption of FBFs matches their observed dietary importance. Trait manifestation generally conforms to predictions based on dietary importance of FBFs. However, some departures from predictions exist, particularly for orang utans, which express relatively more food harvesting and processing traits predicted for consuming large amounts of FBFs than expected based on observed dietary importance. This is probably due to the chemical, mechanical, and phenological properties of the apes' main FBFs, in particular high importance of figs for chimpanzees and hylobatids, compared to use of bark and leaves-plus figs in at least some Sumatran populations-by orang-utans. This may have permitted more specialized harvesting adaptations in chimpanzees and hylobatids, and required enhanced processing adaptations in orang-utans. Possible intercontinental differences in the availability and quality of preferred and FBFs may also be important. Our analysis supports previous hypotheses suggesting a critical influence of the dietary importance and quality of FBFs on ape ecology and, consequently, evolution. PMID- 21654904 TI - Lipoprotein associated phospholipase A(2): role in atherosclerosis and utility as a biomarker for cardiovascular risk. AB - Atherosclerosis and its clinical manifestations are widely prevalent throughout the world. Atherogenesis is highly complex and modulated by numerous genetic and environmental risk factors. A large body of basic scientific and clinical research supports the conclusion that inflammation plays a significant role in atherogenesis along the entire continuum of its progression. Inflammation adversely impacts intravascular lipid handling and metabolism, resulting in the development of macrophage foam cell, fatty streak, and atheromatous plaque formation. Given the enormous human and economic cost of myocardial infarction, ischemic stroke, peripheral arterial disease and amputation, and premature death and disability, considerable effort is being committed to refining our ability to correctly identify patients at heightened risk for atherosclerotic vascular disease and acute cardiovascular events so that they can be treated earlier and more aggressively. Serum markers of inflammation have emerged as an important component of risk factor burden. Lipoprotein-associated phospholipase A2 (Lp PLA(2)) potentiates intravascular inflammation and atherosclerosis. A variety of epidemiologic studies support the utility of Lp-PLA(2) measurements for estimating and further refining cardiovascular disease risk. Drug therapies to inhibit Lp-PLA(2) are in development and show considerable promise, including darapladib, a specific molecular inhibitor of the enzyme. In addition to substantially inhibiting Lp-PLA(2) activity, darapladib reduces progression of the necrotic core volume of human coronary artery atheromatous plaque. The growing body of evidence points to an important role and utility for Lp-PLA(2) testing in preventive and personalized clinical medicine. PMID- 21654905 TI - The Effect of Contraceptive Knowledge on Fertility: The Roles of Mass Media and Social Networks. AB - This study examines the effect of contraceptive knowledge on fertility during the period when Taiwan's family planning programs were in effect. This study contributes to previous studies by directly measuring individual's contraceptive knowledge and fertility, as well as applying an instrumental variable approach to gauge the effect of contraceptive knowledge on fertility. The results indicate that mass media and social networks play important roles in disseminating contraceptive knowledge. This study finds that women transform their knowledge into behavior-that is, contraceptive knowledge reduces fertility, no matter which fertility metric is measured (life-time fertility or probability of giving birth). PMID- 21654906 TI - Physical Constraints on the Evolution of Cooperation. AB - The evolution of psychological adaptations for cooperation is still puzzling due to a tendency to frame social interaction in mathematical and game-theoretical terms, without systematically examining its causal structure and underlying mechanisms. Complementarily, empirical approaches to cooperation tend to focus on isolated components of mechanisms without sufficiently indicating how different components are combined into a single mechanism and different mechanisms fit into a single organism. An alternative approach to the evolution of cooperation is proposed, starting from a description of basic physical properties of individuals and their environment, and the limited physical or mechanistic possibilities to generate adaptive responses to those properties. This approach reveals that some forms of symmetrical cooperation do not require mechanisms "specifically designed for" benefiting others, whereas effective helping requires a specific mechanism that relatively unconditionally and persistently responds to the vulnerability of other individuals. Unraveling the causal structure of different types of other benefiting shows that a mechanism for asymmetrical helping may considerably improve symmetrical cooperation through properties such as tolerance, patience, and the human capacity to experience a wide variety of moral emotions. The proposed mechanistic approach to cooperation provides the mathematical/game theoretical approach with realistic assumptions about psychological adaptations, and helps to integrate the scattered facts about mechanisms gathered by the empirical approach. It also helps to build bridges between the two approaches by providing a common language for thinking about psychological mechanisms. PMID- 21654907 TI - The State Socialist Mortality Syndrome. AB - Death rates for working-age men in European state socialist countries deviated from general improvements in survival observed in the rest of Europe during the 20th century. The magnitude of structural labor force changes across countries correlates with lagged increases in death rates for men in the working ages. This pattern is consistent with a hypothesis that hyper-development of heavy industry and stagnation (even contraction) of the service sector created anomic conditions leading to unhealthy lifestyles and self-destructive behavior among men moving from primary-sector to secondary-sector occupations. Occupational contrasts within countries similarly show concentration of rising male death rates among blue collar workers. Collapse of state socialist systems produced rapid corrections in labor force structure after 1990, again correlated with a fading of the state socialist mortality syndrome in following decades. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11113 010-9192-z) contains supplementary material, which is available to authorized users. PMID- 21654908 TI - Update on the Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Virus Infection. AB - Chronic hepatitis B virus infection is an important cause of liver-related morbidity and mortality, with hepatocellular carcinoma being the most life threatening complication. Because of the highly variable clinical course of the disease, enormous research efforts have been made with the aim of revealing the factors in the natural history that are relevant to hepatocarcinogenesis. These include epidemiological studies of predisposing risk groups, viral studies of mutations within the hepatitis B viral genome, and clinical correlation of these risk factors in predicting the likelihood of development of hepatocellular cancer in susceptible hosts. This update addresses these risks, with emphasis on the latest research relevant to hepatocarcinogenesis. PMID- 21654909 TI - Combination Therapy for Chronic Hepatitis B: Current Indications. AB - Hepatitis B infection remains a major public health problem globally and in the United States, with significant use of healthcare resources. Several therapeutic agents active against viral and host targets are currently available for its treatment. The success of combination therapy in HIV infection, which has similarities to hepatitis B in both therapeutic targets and treatment options, stimulated studies on the efficacy and safety of various combinations of available drugs in the treatment of hepatitis B infection. In this review, we analyze the current role of combination therapy in chronic hepatitis B infection. PMID- 21654910 TI - Radionuclide Imaging of Viable Myocardium: Is it Underutilized? AB - Coronary artery disease is the major cause of heart failure in North America. Viability assessment is important as it aims to identify patients who stand to benefit from coronary revascularization. Radionuclide modalities currently used in the assessment of viability include (201)Tl SPECT, (99m)Tc-based SPECT imaging, and (18)F-fluorodexoyglucose ((18)F-FDG)-PET imaging. Different advances have been made in the last year to improve the sensitivity and specificity of these modalities. In addition, the optimum amount of viable (yet dysfunctional) myocardium is important to identify in patients, as a risk-benefit ratio must be considered. Patients with predominantly viable/hibernating myocardium can benefit from revascularization from a mortality and morbidity standpoint. However, in patients with minimal viability (predominantly scarred myocardium), revascularization risk may certainly be too high to justify revascularization without expected benefit. Understanding different radionuclide modalities and new developments in the assessment of viability in ischemic heart failure patients is the focus of this discussion. PMID- 21654911 TI - Noninvasive Markers of Hepatic Fibrosis in Chronic Hepatitis B. AB - A serum biomarker (FibroTest; Biopredictive, Paris, France; FibroSure; LabCorp, Burlington, USA) and liver stiffness measurement (LSM) by Fibroscan (Echosens, Paris, France) have been extensively validated in chronic hepatitis C. This review updates the clinical validation of serum biomarkers and LSM in patients with chronic hepatitis B (CHB). One meta-analysis combined all published studies and another used a database combining FibroTest individual data. Sensitivity analysis assessed the impact of several factors, including authors' independence, length of biopsy, ethnicity, hepatitis B early antigen status, viral load, and alanine aminotransferase value. Only two biomarkers had several validations: FibroTest (8 studies, 1,842 patients), and Fibroscan (5 studies, 618 patients). For the diagnosis of advanced fibrosis, the standardized area under the receiver operating curve was 0.84 (0.79-0.86) for FibroTest and 0.89 (0.83-0.96) for LSM, without significant difference. No significant factors of variability were identified for FibroTest's performance. In conclusion, FibroTest and LSM were the most validated biomarkers of fibrosis in CHB. However, the reliability of Fibroscan must be better assessed. PMID- 21654913 TI - Are Underlying Assumptions of Current Animal Models of Human Stroke Correct: from STAIRs to High Hurdles? AB - Animal models of acute ischemic stroke have been criticized for failing to translate to human stroke. Nevertheless, animal models are necessary to improve our understanding of stroke pathophysiology and to guide the development of new stroke therapies. The rabbit embolic clot model is one animal model that has led to an effective therapy in human acute ischemic stroke, namely tissue plasminogen activator (tPA). We propose that potential compounds that demonstrate efficacy in non-rabbit animal models of acute ischemic stroke should also be tested in the rabbit embolic blood clot model and, where appropriate, compared to tPA prior to investigation in humans. Furthermore, the use of anesthesia needs to be considered as a major confounder in animal models of acute ischemic stroke, and death should be included as an outcome measure in animal stroke studies. These steps, along with the current STAIRs recommendations, may improve the successful translation of experimental therapies to clinical stroke treatments. PMID- 21654914 TI - The Old Ladies of the Seed Harvester ant Pogonomyrmex Rugosus: Foraging Performed by Two Groups of Workers. AB - We examined temporal polyethism in Pogonomyrmex rugosus, predicting a pattern of decreasing age from foragers to nest maintenance workers to individuals that were recruited to harvest a temporary food source. Nest maintenance workers were younger than foragers, as indicated by their heavier mass and lower mandibular wear. In contrast, recruited foragers were similar in mass to foragers but they displayed higher mandibular wear, suggesting that they were at least as old as foragers. Longevity estimates for marked individuals of these two latter task groups showed mixed results. Higher mandibular wear of recruited foragers suggests that they did not follow the normal sequence for temporal polyethism, but rather that they functioned as seed-millers, which should more quickly abrade their dentition. This would be the first demonstration of specialist milling individuals in a monomorphic seed-harvester ant. PMID- 21654912 TI - The Complexity of Vascular and Non-Vascular Complications of Diabetes: The Hong Kong Diabetes Registry. AB - Diabetes is a complex disease characterized by chronic hyperglycemia and multiple phenotypes. In 1995, we used a doctor-nurse-clerk team and structured protocol to establish the Hong Kong Diabetes Registry in a quality improvement program. By 2009, we had accrued 2616 clinical events in 9588 Chinese type 2 diabetic patients with a follow-up duration of 6 years. The detailed phenotypes at enrollment and follow-up medications have allowed us to develop a series of risk equations to predict multiple endpoints with high sensitivity and specificity. In this prospective database, we were able to validate findings from clinical trials in real practice, confirm close links between cardiovascular and renal disease, and demonstrate the emerging importance of cancer as a leading cause of death. In addition to serving as a tool for risk stratification and quality assurance, ongoing data analysis of the registry also reveals secular changes in disease patterns and identifies unmet needs. PMID- 21654915 TI - Aboriginal Children and Their Caregivers Living with Low Income: Outcomes from a Two-Generation Preschool Program. AB - The development of preschool children of Aboriginal heritage is jeopardized by the inter-generational transmission of risk that has created, and continues to create, social disadvantage. Early intervention programs are intended to mitigate the impact of social disadvantage. Yet, evidence of the effectiveness of these programs for children of Aboriginal heritage is limited. The purpose of this study was to examine the effects of a two-generation, multi-cultural preschool program on 45 children of Aboriginal heritage and their caregivers. We used a single-group, pretest (program intake)/posttest (program exit) design with follow up when the children were 7 years old. We used an observational measure of child receptive language (Peabody Picture Vocabulary Test-III) and caregiver-reported measures of child development (Nipissing District Developmental Screen), risk for child maltreatment (Adult-Adolescent Parenting Inventory; AAPI), parenting stress (Parenting Stress Index; PSI), self-esteem (Rosenberg Self-Esteem scale; RSE), and life skills (Community Life Skills scale; CLS). Using paired t-tests we found statistically significant increases in child receptive language scores between intake and exit, and repeated-measures ANOVA showed that these improvements were maintained up to age 7 years. For caregivers, Pearson's correlations demonstrated that risk for child maltreatment, parenting stress, self-esteem, and life skills were stable over time. Results of this study suggest that children of Aboriginal heritage can benefit from participation in a two-generation, multi-cultural preschool program. Their caregivers may have received greater benefit if issues of intergenerational transmission of the negative influences of residential schools were addressed as part of programming. PMID- 21654916 TI - Social Support and Neighborhood Stressors Among African American Youth: Networks and Relations to Self-Worth. AB - Although neighborhood stressors have a negative impact on youth, and social support can play a protective role, it is unclear what types and sources of social support may contribute to positive outcomes among at-risk youth. We examined the influences of neighborhood disadvantage and social support on global self-worth among low-income, urban African American youth, both concurrently and longitudinally. We examined social support from both a structural and functional perspective, and tested the main-effects and the stress-buffering models of social support. Participants included 82-130 youth, in 6th-8th grade, who completed self-report measures. Network support results suggest participants received emotional, tangible, and informational support most often from mothers and other female relatives, with friends, fathers, and teachers also playing important roles. Model testing accounted for neighborhood stressors and support from various sources, revealing support from close friends was associated with concurrent self-worth; whereas, parent support predicted self-worth longitudinally, above and beyond initial levels of self-worth. The findings provide evidence for the main-effects model of social support and not the stress buffering model. Our findings illustrate the importance of extended family networks and the types of support that youth rely upon in African American impoverished communities, as well as how support contributes to global self worth. Implications and suggestions for future research and intervention are discussed. PMID- 21654917 TI - Perceptions and Practices of Stimulating Children's Cognitive Development Among Moroccan Immigrant Mothers. AB - We explored the perceptions of children's cognitive development among Moroccan Arabic and Berber immigrant mothers who cannot read, who are less educated, middle educated or highly educated in the Netherlands. A series of in-depth interviews was conducted with 22 mothers with young children (mean age = 5 years and 6 months). Qualitative data analyses revealed five major themes that are of significant importance to these mothers: moral attitudes, social values and religiousness; conversation, reading and playing as stimulating activities; importance attached to education; parental expectations; attributions of school success. The parental perceptions about the cognitive development of young children differed according to their own educational level. Mothers who cannot read and mothers with less education emphasized the development of moral, social and religious values for strengthening the cultural identity of their children. This sense of identity would enable them to function within their own cultural group and help them to perform well at school. School success was attributed in large part to a combination of the efforts of the child and the school. Middle and highly educated mothers, on the other hand, valued scholastic development and attributed school success to their own efforts and to the kind of support the child received. The ethnic background of the parents, whether Arabic or Berber, did not make a difference in the perceptions. PMID- 21654918 TI - In-Home Training for Fathers of Children with Autism: A Follow up Study and Evaluation of Four Individual Training Components. AB - Literature regarding fathers of children with autism remains sparse, and because mothers are the more common intervening parent, few training methods have focused on fathers. Thus, we sought to evaluate effects of in-home training directed at fathers and their ability to train mothers in the same manner in which they were trained. Fathers were taught four skills commonly associated with in-home training interventions for parents of children with autism: following the child's lead, imitation with animation, commenting on the child, and expectant waiting. Father skills were evaluated twice a week for 12 weeks during videotaped in-home father-child play sessions. Analyses included visual inspection of graphed data and statistical analyses of father skill acquisition, mother skill acquisition, and child behaviors with both parents. A multivariate repeated measures analysis of 18 dyads revealed significant increases in frequencies of fathers' imitation with animation, expectant waiting, and commenting on the child. Child initiating rates increased significantly as did frequencies of child non-speech vocalizations. Analysis of mothers revealed significant increases in frequencies of imitation with animation, expectant waiting, and following the child's lead. Child behaviors had similar results for father and mother sessions. Findings are consistent with those from our first study indicating that fathers can effectively implement skills that promote father-child social interactions and that children respond positively to this approach. PMID- 21654919 TI - New Strategies for Combining Mindfulness with Integrative Cognitive Behavioral Therapy for the Treatment of Generalized Anxiety Disorder. AB - Generalized anxiety disorder (GAD) severely impacts social functioning, distress levels, and utilization of medical care compared with that of other major psychiatric disorders. Neither pharmacological nor psychotherapy interventions have adequately controlled cardinal symptoms of GAD: pervasive excessive anxiety and uncontrollable worry. Research has established cognitive behavioral therapy (CBT) as the most effective psychotherapy for controlling GAD; however, outcomes remain at only 50% reduction, with high relapse rates. Mindfulness has been integrated with CBT to treat people suffering from numerous psychiatric disorders, with mindfulness based stress reduction (MBSR) being the most researched. Preliminary evidence supports MBSR's potential for controlling GAD symptoms and key researchers suggest mindfulness practices possess key elements for treating GAD. Classical mindfulness (CM) differs significantly from MBSR and possesses unique potentials for directly targeting process and state GAD symptoms inadequately treated by CBT. This article introduces the theory and practice of CM, its differences from MBSR, and a critical review of MBSR and CBT treatments for GAD. CM strategies designed to complement CBT targeting cardinal GAD symptoms are outlined with a case study illustrating its use. PMID- 21654920 TI - An attempt to control Cameraria ohridella using an attract-and-kill technique. AB - This study estimates the efficacy of an attract-and-kill (A&K) technique to control the horse chestnut leaf miner, Cameraria ohridella Deschka and Dimic (Lepidoptera, Gracillariidae), an invasive insect pest of the horse chestnut, Aesculus hippocastanum L. (Hippocastanaceae). The A&K formulation was dispensed as 50 MUl droplets of paste-like matrix, containing C. ohridella sex pheromone, (8E,10Z)-tetradeca-8,10-dienal (85% + pure; 0.16% w/w) and a fast acting contact toxicant, pyrocides (94% pure; 6% w/w), applied directly to the bark of the trees. It was tested in 2003 at rates of 30 and 45 droplets/tree at the Ostrobramska site and at rates of 30, 60 and 90 droplets/tree at the Woloska site in Warsaw, Poland, for the first insect generation. A set of untreated plots (0 droplets/tree) was established at each site as well. The treatment efficacy was estimated using two indices: (1) moth catches in pheromone traps and (2) the number of mines per leaf. Trap catches were significantly higher in the untreated plots than in the treated plots regardless of the application rate in all sites. However, there were no significant differences in leaf damage amongst all plots on each site. At the "Lazienki Krolewskie" park the attractiveness of two types of pheromone sources were compared: traps were baited with rubber septum lures or with A&K droplets. The catches of C. ohridella in traps baited with lures were lower than captures in A&K droplet-baited traps, but the difference was not significant. Possible reasons for the low efficacy of the A&K method in management of C. ohridella and reducing leaf damage are discussed. PMID- 21654921 TI - A comparative study of biodegradation of vinyl acetate by environmental strains. AB - Four Gram-negative strains, E3_2001, EC1_2004, EC3_3502 and EC2_3502, previously isolated from soil samples, were subjected to comparative studies in order to select the best vinyl acetate degrader for waste gas treatment. Comparison of biochemical and physiological tests as well as the results of fatty acids analyses were comparable with the results of 16S rRNA gene sequence analyses. The isolated strains were identified as Pseudomonas putida EC3_2001, Pseudomonas putida EC1_2004, Achromobacter xylosoxidans EC3_3502 and Agrobacterium sp. EC2_3502 strains. Two additional strains, Pseudomonas fluorescens PCM 2123 and Stenotrophomonas malthophilia KB2, were used as controls. All described strains were able to use vinyl acetate as the only source of carbon and energy under aerobic as well as oxygen deficiency conditions. Esterase, alcohol dehydrogenase and aldehyde dehydrogenase were involved in vinyl acetate decomposition under aerobic conditions. Shorter degradation times of vinyl acetate were associated with accumulation of acetic acid, acetaldehyde and ethanol as intermediates in the culture fluids of EC3_2001 and KB2 strains. Complete aerobic degradation of vinyl acetate combined with a low increase in biomass was observed for EC3_2001 and EC1_2004 strains. In conclusion, P. putida EC1_2004 is proposed as the best vinyl acetate degrader for future waste gas treatment in trickle-bed bioreactors. PMID- 21654922 TI - A 9-year study of shigellosis in Northeast Malaysia: Antimicrobial susceptibility and shifting species dominance. AB - AIMS: In Malaysia, Shigella spp. is the third most common bacterial agent responsible for childhood diarrhoea. This study was conducted to determine the prevalence and antimicrobial susceptibility patterns of Shigella spp. isolated from patients admitted to the Hospital Universiti Sains Malaysia from January 2001 to December 2009. SUBJECTS AND METHODS: A hospital-based retrospective study was used. Stool samples from patients were cultured using a standard culture method. Shigella spp. isolates were identified by biochemical and serological methods, and the antimicrobial susceptibility pattern was evaluated using the Kirby-Bauer disc-diffusion method. RESULTS: A total of 138 Shigella spp. were isolated from a total of 14,830 routine stool specimens, yielding an isolation rate of 0.93% that corresponded to 9.99% of the 1,381 bacterial pathogens isolated. Of these isolates, S. sonnei was the predominant species, followed by S. flexneri and S. boydii. Seasonal variation was noticed, and no significant differences were detected in the demographic data for S. flexneri and S. sonnei. The susceptibility of all isolated Shigella strains was tested against seven antibiotics. Ceftriaxone (99.1%), ciprofloxacin (98.4%), and nalidixic acid (93.8%) were effective against the Shigella strains, whereas tetracycline and trimethoprim-sulfamethoxazole exhibited high frequencies of resistance (58.4% and 53.8%, respectively). CONCLUSION: This study is important for public health education aimed at reducing the morbidity and mortality associated with Shigella spp. infection. Our results also will be helpful for paediatricians and microbiologists in the selection of appropriate antibiotics for the management of diarrhoea. PMID- 21654923 TI - Next generation therapies change the landscape in melanoma. AB - Melanoma is among the leading causes of years of life lost due to cancer. Current chemotherapy and cytokine-based immunotherapy approaches benefit only a small percentage of patients with advanced disease. However, the recent discovery of mutations in the gene encoding the serine-threonine kinase B-RAF (BRAF) raises the possibility that oncogene-targeted therapy may provide a new point of vulnerability. In parallel, a deeper understanding of the molecular mechanisms underlying antitumor T-cell activation and tolerance has provided a basis for developing therapies targeted against these processes. Results from an early phase trial with a BRAF inhibitor and a phase III trial with a novel agent that activates T cells have radically altered the prospects for improving outcomes for patients with this historically treatment-refractory disease. PMID- 21654924 TI - Natural killer cell-based therapies. AB - Allotransplantation of natural killer (NK) cells has been shown to be a key factor in the control and cure of at least some hematologic diseases, such as acute myeloid leukemia or pediatric acute lymphocytic leukemia. These results support the idea that stimulation of NK cells could be an important therapeutic tool in many diseases, and several such approaches are now in clinical trials, sometimes with conflicting results. In parallel, recent advances in the understanding of the molecular mechanisms governing NK-cell maturation and activity show that NK-cell effector functions are controlled by complex mechanisms that must be taken into account for optimal design of therapeutic protocols. We review here innovative protocols based on allotransplantation, use of NK-cell therapies, and use of newly available drug candidates targeting NK cell receptors, in the light of fundamental new data on NK-cell biology. PMID- 21654925 TI - The role of blood flow in determining the sites of atherosclerotic plaques. AB - Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells along the inner walls of arteries, and is an underlying cause of cardiovascular disease. Atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow, which exerts low/oscillatory shear stress on the vessel wall. This mechanical environment alters endothelial cell physiology by enhancing inflammatory activation. In contrast, regions of the arterial tree that are exposed to uniform, unidirectional blood flow and experience high shear stress are protected from inflammation and lesion development. Shear stress is sensed by the endothelium via mechanoreceptors and is subsequently transduced into biochemical signals resulting in modulation of proinflammatory signaling pathways. In this article, we address the molecular mechanisms behind the spatial localization of vascular inflammation and atherosclerosis, with particular focus on studies by our own group of two key proinflammatory signaling pathways, the mitogen-activated protein kinase pathway and the nuclear factor-kappa-B pathway. PMID- 21654926 TI - MicroRNAs in cardiovascular disease. AB - Rapid and accurate diagnosis of heart attacks-and the assessment of damage-are critical for improving coronary care. Mature microRNAs (miRNAs) are abundant, easily measured, and relatively stable in blood plasma. If they prove indicative of disease states, miRNAs measured from peripheral blood may be a particularly attractive source for routine clinical assessments. PMID- 21654927 TI - Clostridium difficile--a moving target. AB - Clostridium difficile has been recognized as a pathogen in humans for over 40 years, but in the past decade the incidence has increased and, more importantly, the clinical presentation and consequences have become more serious, with increased morbidity and mortality. The emergence of a new, more pathogenic strain, BI/NAP1/027, has driven these shifts. Treatment of this disease has been with two antibiotics, metronidazole and vancomycin, but increasing recurrence, not uncommon with C. difficile infections, has prompted research into several alternative therapies. These include a new class of antibiotic (fidaxomicin), a monoclonal antibody, a vaccine, and most recently a biotherapeutic (which, in this case, is a nontoxin-producing strain of C. difficile). The future management of C. difficile infection will probably require a combination of these approaches once we have the data from ongoing studies. PMID- 21654928 TI - Superficial siderosis in cerebral amyloid angiopathy. PMID- 21654929 TI - Molar tooth sign with ataxia and see-saw nystagmus (Joubert syndrome). PMID- 21654930 TI - Single-fiber EMG: A review. PMID- 21654931 TI - Ode to epileptologists! PMID- 21654932 TI - Tumor Cell Selective Cytotoxicity and Apoptosis Induction by an Herbal Preparation from Brucea javanica. AB - The plant Brucea javanica has shown impressive efficacy for treating various diseases including cancer. However, the mechanism by which B. javanica acts is poorly understood. We have established tissue culture assays to study the effects of B. javanica on cervical and several other cancer cells. Our results demonstrated that the aqueous extract from B. javanica is selectively toxic to cancer cells. Induction of apoptosis by B. javanica appears to be a possible mechanism by which it kills cancer cells. Interestingly, a significant increase of p53 protein level was observed in these apoptotic cells. Our studies indicated that both p53-dependent and p53-independent activities contributed to herb induced cell death. These results imply that further studies with B. javanica may lead to the development of novel anti-cancer drugs. PMID- 21654933 TI - CARBON AND NITROGEN STORAGE IN SOIL AND LITTER OF SOUTHERN CALIFORNIAN SEMI-ARID SHRUBLANDS. AB - Semi-arid shrublands of southern California, including chaparral and coastal sage, are found in widely varying elevation and microclimatic regimes and are subjected to disturbance such as fire and atmospheric N deposition that have the capacity to alter soil and litter C and N storage. Here we present a case study where soil and litter C and N were measured over 19 months in post-fire chaparral and mature coastal sage stands to assess whether differences in soil and litter C and N between these diverse shrublands could be attributed to differences in elevation, stand age, rainfall, and/or estimated N deposition exposure. Our results indicate that atmospheric N deposition exposure, either alone or in conjunction with other environmental variables (elevation, rainfall, and/or stand age), was the most frequent predictor of the spatial pattern in the soil and litter N and C variables observed. These results are consistent with those reported for high-elevation coniferous forests arrayed along an N deposition gradient in southern California, suggesting that N deposition may affect the soil N and C storage of semiarid shrublands and woodlands in a qualitatively similar manner. PMID- 21654934 TI - Progress in electron-multiplying CCD (EMCCD) based, high-resolution, high sensitivity x-ray detector for fluoroscopy and radiography. AB - A new high-resolution, high-sensitivity, low-noise x-ray detector based on EMCCDs has been developed. The EMCCD detector module consists of a 1kx1k, 8MUm pixel EMCCD camera coupled to a CsI(Tl) scintillating phosphor via a fiber optic taper (FOT). Multiple modules can be used to provide the desired field-of-view (FOV). The detector is capable of acquisitions over 30fps. The EMCCD's variable gain of up to 2000x for the pixel signal enables high sensitivity for fluoroscopic applications. With a 3:1 FOT, the detector can operate with a 144MUm effective pixel size, comparable to current flat-panel detectors. Higher resolutions of 96 and 48MUm pixel size can also be achieved with various binning modes. The detector MTFs and DQEs were calculated using a linear-systems analysis. The zero frequency DQE was calculated to be 59% at 74 kVp. The DQE for the 144MUm pixel size was shown to exhibit quantum-noise limited behavior down to ~0.1MUR using a conservative 30x gain. At this low exposure, gains above 30x showed limited improvements in DQE suggesting such increased gains may not be necessary. For operation down to 48MUm pixel sizes, the detector instrumentation noise equivalent exposure (INEE), defined as the exposure where the instrumentation noise equals the quantum-noise, was <0.1MUR for a 20x gain. This new technology may provide improvements over current flat-panel detectors for applications such as fluoroscopy and angiography requiring high frame rates, resolution, dynamic range and sensitivity while maintaining essentially no lag and very low INEE. Initial images from a prototype detector are also presented. PMID- 21654935 TI - Listening to Brain Microcircuits for Interfacing With External World-Progress in Wireless Implantable Microelectronic Neuroengineering Devices: Experimental systems are described for electrical recording in the brain using multiple microelectrodes and short range implantable or wearable broadcasting units. AB - Acquiring neural signals at high spatial and temporal resolution directly from brain microcircuits and decoding their activity to interpret commands and/or prior planning activity, such as motion of an arm or a leg, is a prime goal of modern neurotechnology. Its practical aims include assistive devices for subjects whose normal neural information pathways are not functioning due to physical damage or disease. On the fundamental side, researchers are striving to decipher the code of multiple neural microcircuits which collectively make up nature's amazing computing machine, the brain. By implanting biocompatible neural sensor probes directly into the brain, in the form of microelectrode arrays, it is now possible to extract information from interacting populations of neural cells with spatial and temporal resolution at the single cell level. With parallel advances in application of statistical and mathematical techniques tools for deciphering the neural code, extracted populations or correlated neurons, significant understanding has been achieved of those brain commands that control, e.g., the motion of an arm in a primate (monkey or a human subject). These developments are accelerating the work on neural prosthetics where brain derived signals may be employed to bypass, e.g., an injured spinal cord. One key element in achieving the goals for practical and versatile neural prostheses is the development of fully implantable wireless microelectronic "brain-interfaces" within the body, a point of special emphasis of this paper. PMID- 21654936 TI - Academic potential among African American adolescents in juvenile detention centers: Implications for reentry to school. AB - The study explores Black adolescent detainees academic potential and motivation to return to school to inform best practices and policies for juvenile reentry to educational settings. Adolescent detainees (N = 1,576) who were recruited from one male and one female youth detention facility, responded to surveys that assessed post-detention educational plans, as well as social and emotional characteristics, and criminal history. Multivariate analysis techniques were used to compare factors across race and gender, and plot linear relationships between key indicators of academic potential with associate factors. Findings revealed that youth were more likely to evince academic potential when they had a healthy level of self-esteem, adequate future goal orientation, positive mood, family and community involvement, fewer traumatic events, and less delinquent activity. PMID- 21654937 TI - Program to Improve Prescribing of Primarily Renally Cleared Oral Medications in Older Veteran Community Living Center Patients. PMID- 21654938 TI - The impact of voting on tax payments. AB - This study examines whether participating in governmental decisions influences taxpayers' cooperation. The results of experiment 1 show that participants tend to contribute more when they can vote on different rules for a public good game. Experiment 2 reveals that tax payments are lowest in a tax simulation when participants benefit from tax payments and can not vote. However, when the participants did not benefit from tax payments, voting had no impact and cooperation was about the same as when participants benefited and could vote. Furthermore, voting increases procedural fairness and trust mediates the effect of procedural fairness on tax payments. PMID- 21654939 TI - Domestic violence: "What's love got to do with it?". PMID- 21654940 TI - Adenoviral keratoconjunctivitis. AB - Acute epibulbar infections in humans are one of the most frequently diagnosed eye diseases. The majority of these are thought to be caused by the adenovirus. This review focuses on the features of the human adenovirus eye diseases, mode of transmission, signs and symptoms, available interventions, and preventive measures. It is concluded that infection control is still widely accepted to be the key to the management of human adenovirus infection in order to prevent the spread, individual suffering and economic damage. PMID- 21654941 TI - Clinical and Epidemiological Characteristics of Pituitary Tumours using a Web based Pituitary Tumour Registry in Oman. AB - OBJECTIVE: From a recently instituted web-based pituitary tumour registry at Sultan Qaboos University Hospital, Oman, this study explores the results of comprehensive clinical evaluation, hormonal levels, radiological evidence of pituitary mass lesion using magnetic resonance (MRI) and the different treatment modalities. METHODS: All patients who were diagnosed with pituitary mass tumours in our tertiary care endocrinology clinic between January 1998 and February 2006 were registered in the Oman pituitary tumour registry. Two physicians performed hospital chart review and data entry. RESULTS: A total of 160 entries were made into the pituitary tumour registry. The overall mean age of the cohort was 32 +/ 12 years (age range 8-73 years). The majority of registrations were female (n=114; 71%). There were 81 patients with non-functioning adenomas (50.6%), 59 with prolactinoma (36.9%) eight with acromegaly (5%), seven with craniopharyngioma (4.4%), four with Cushing's disease (2.5%) and one with sarcoidosis (0.6%). Sub-group analyses were done only for the subjects with the 3 most prevalent pituitary tumours (non-functioning adenomas, prolactinomas, and acromegaly). The most prevalent symptoms are amenorrhea-galactorrhea (n=55; 37%), headache (n=31; 21%) and fatigue (n=23; 16%). The most common treatment modality was medical (n=58; 39%), followed by observation (n=56; 38%), surgery (n=31; 21%) and surgery plus medical (n=3; 2%). None of the patients in this registry are recorded to have died. CONCLUSION: To our knowledge, this is the first pituitary tumour registry in the Arabian Gulf countries using a web-based programme. This tumour registry will enable us to characterize clinical and the epidemiological features of pituitary tumours in the Sultanate of Oman. PMID- 21654942 TI - Prevalence and Correlates of Neural Tube Defect in South West Iran: Retrospective analysis. AB - OBJECTIVE: In view of the large number of pregnancies complicated by neural tube defect (NTD) in Khuzestan, south west Iran, this study assesses the prevalence of NTD and its ecological and social factors. METHODS: This is a retrospective study, based on medical documents using an analytic assessment of NTDs in pregnant women attending the Jundi Shapur University hospitals in Ahvaz from 21 March 2002 to 20 March 2004. RESULTS: The total number of pregnant women was 13,262 and 56 pregnancies were complicated with NTD. A large number of the infants with NTDs were female (70%) and the most common anomaly was anencephaly. The prevalence was 4.2 in 1,000 births. The percentage in primigravida was 42.6% and in multigravida 57.4%. The main risk factor for NTD was age of the mother, those between 21 and 30 being the most affected. Consanguinity is the second risk factor with 31% of couples who were close relatives. Other socio-demographic factors were also significant. CONCLUSION: This retrospective study confirms clinical observation that pregnancies complicated by NTD in Khuzestan are common. There are various ecological and social factors that correlate with the prevalence of NTD. PMID- 21654943 TI - Prevalence and Clinical Features of Blastocystis hominis Infection among Patients in Sebha, Libya. AB - OBJECTIVE: To determine the prevalence and seasonal variation, and to assess the clinical manifestations and treatment of blastocystosis in Libyan patients. METHODS: Three thousand six hundred and forty five stool samples were screened for Blastocystis hominis using normal saline and iodine solution preparations. The clinical features of 108 patients were described, in whom B. hominis was the only parasite isolated. Fifty symptomatic patients were treated with 1500 mg metronidazole daily for 7 days and their stools were re-investigated for B. hominis. RESULTS: B. hominis was found in 969 (26.58 %) of 3645 stool specimens examined. The infection of B. hominis was significantly more (p < 0.05) in summer than in winter over a three year period. In a prospective study of 108 patients, the most common symptoms with stools positive only for B. hominis were diarrhoea (84.94 %), abdominal pain (66.66 %), flatulence (17.20 %) and vomiting (16.12 %). High concentration of B. hominis cells were found more in symptomatic patients than asymptomatic ones (9.20 cells per 40 X field versus 4.06 respectively) with statistically significant differences (p < 0.001). Patients with B. hominis responded to metronidazole and were fully cured after 7 days. CONCLUSION: The occurrence of B. hominis infections in outpatients are probably related to weather conditions, with the suggestion that the hot, dry weather of the Sebha region favors the development and transmission of this organism. B. hominis infections might have a role in some pathological conditions, resulting in gastrointestinal symptoms. PMID- 21654944 TI - The role of computed tomography in blunt abdominal trauma. AB - OBJECTIVE: To determine the utility of the computed tomography (CT) scan in blunt abdominal trauma and to compare it with operative findings or clinical outcomes. METHODS: A retrospective analysis based on existing, diagnostic CT scan reports taken during a 5 year period from 245 consecutive patients with blunt abdominal trauma. Percentages and types of trauma identified were based on CT scan findings. Recorded data included age, sex, type of injuries and scan results. The CT findings were compared and correlated with the operative findings, or clinical follow-up in conservatively managed cases. RESULTS: Of the total of 245 patients, 113 (46%) underwent surgery. One hundred and thirty two (54%) patients were conservatively managed. There were 12 (4.9%) deaths. Hemoperitoneum were detected in 170 patients. All 52 patients with small hemoperitoneum on CT scan were conservatively managed and all 22 patients with large hemoperitoneum required surgical exploration. There were 95 splenic, 63 renal, 48 hepatic and 13 pancreatic injuries. Twenty one patients had bowel injuries. Five patients had vascular injuries. Twenty three patients had multi-organ injuries. Organ injuries were graded using the OIS (Organ Injury Scale) guidelines. CONCLUSION: In conjunction with close clinical monitoring, CT was reliable in the evaluation of blunt abdominal trauma in a selected group of patients, with overall sensitivity of 97% and specificity of about 95%. Positive predictive value 82% and negative predictive value 100%. PMID- 21654945 TI - Pharmacologic prophylaxis and treatment of venous thromboembolism after knee arthroplasty. AB - OBJECTIVE: The objective of this study was to evaluate the efficacy of unfractionated heparin, warfarin and low molecular weight heparins (LMWH) used for the prevention of venous thromboembolism in arthroplastic surgery of the knee joint. METHODS: In this prospective study from August 2002 to November 2004, 60 patients were included and divided into three groups with equal numbers, with each group receiving different treatment protocol. Postoperatively, the occurrence of symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) was recorded during the first 30 days after surgery and at a routine follow-up visit. RESULTS: A significantly lower prevalence of DVT and PE was found in patients using warfarin and LMWH as prophylaxis in comparison with patients using unfractionated heparin. CONCLUSION: Warfarin and low molecular weight heparins are more beneficial and effective than unfractionated heparin for DVT and PE prophylaxis in arthroplastic knee surgeries. PMID- 21654946 TI - The Relationship between Hysteroscopy, Endometrial Biopsy and The Results of Transvaginal Sonography in Assessing Endometrial Polyps. AB - OBJECTIVE: Transvaginal Sonography (TVS) is being used in the investigation of postmenopausal bleeding (PMB). The bleeding could be the result of a number of factors; endometrial polyps are one of the common findings in these patients. The aim was to compare the findings of TVS and hysteroscopy to determine the sensitivity of each method in detecting endometrial polyps. METHODS: This was a retrospective study, designed to investigate the sensitivity and specificity of transvaginal sonography in the detection of endometrial polyps. This study was conducted from July 1992 to July 1999 and identified from the record 37 patients with PMB referred for transvaginal sonography, hysteroscopy and biopsy investigations. RESULTS: Thirty-seven patients with PMB were scanned using TVS and hysteroscopy. The result was not specific or sensitive when using TVS alone. TVS showed 13.52 % sensitivity, hysteroscopy/biopsy showed 100% sensitivity. TVS p>0.06 was not significant. CONCLUSION: Using TVS alone to diagnose polyps in PMB patients is not sensitive, especially when the polyps are smaller than 6 mm. If it is combined with hysterscopy, the reliability and s sensitivity are significantly improved. PMID- 21654947 TI - Pulmonary Infarction: A rare case of adrenal carcinoma. AB - A case report of unsuspected adrenal carcinoma with pulmonary artery obstruction in a young girl who was admitted with recurrent episodes of hypotension is presented. Computed tomography (CT) scans demonstrated a large right adrenal mass extending into the inferior vena cava (IVC), right atrium, right ventricle and right pulmonary artery. There are many case reports in literature documenting IVC and right atrial thrombus in patients with adrenal carcinoma. To our knowledge, this is the first case report specifically documenting pulmonary infarction secondary to tumour extension into the pulmonary artery. PMID- 21654949 TI - Double inferior vena cava. PMID- 21654948 TI - Ovarian Vein Thrombophlebitis: An unusual cause of postpartum fever and abdominal pain. AB - Ovarian vein thrombophlebitis is an uncommon, but potentially serious, complication of complicated deliveries. Prolonged rupture of membranes prior to delivery is a pre-disposing factor. We report a case of a patient with prolonged ruptured membranes, who developed right ovarian vein thrombophlebitis. The patient was managed medically and responded favourably to treatment. PMID- 21654950 TI - Molecular imaging: bridging imaging and biology. PMID- 21654951 TI - Care of diabetic retinopathy patients in oman. PMID- 21654952 TI - Qualitative research and its uses in health care. AB - Although relatively uncommon in health care research, qualitative research is now receiving recognition and is increasingly used in health care research with social and cultural dimensions. Unlike quantitative research, which is deductive and tends to analyze phenomena in terms of trends and frequencies, qualitative research seeks to determine the meaning of a phenomenon through description. It aims to develop concepts that aid in the understanding of natural phenomena with emphasis on the meaning, experiences and views of the participants. Differences among qualitative researchers exist on matters of ontology, epistemology, data collection methods and methods of evaluation. The aim of this article is not to act as a practical guide on how to conduct qualitative research, but is an attempt to give an introduction to qualitative research methods and their use in health-related research. PMID- 21654953 TI - Screening of Patients with Snoring and Obstructive Sleep Apnoea using Heart Rate Variability Indices. AB - OBJECTIVE: Snoring and obstructive sleep apnea (OSA) are common disorders. Snoring associated with excessive daytime sleepiness is the most prevalent symptoms of OSA. Heart rate variability (HRV) is altered in patients with OSA and the degree of alteration may be linked to the severity of OSA. Alterations in HRV in 24 hour tachograms have recently been used in screening OSA patients. Autonomic components causing HRV can be reliably studied using spectral analysis techniques involving fast Fourier transformation (FFT). METHODS: Twenty-three subjects, 13 with severe OSA and 10 controls matched for age and body mass index, were selected from patients who had undergone polysomnography (PSG) for snoring at Sultan Qaboos University Hospital, Oman. A 24- hour electrocardiogram (ECG) Holter recording was done at home, starting at 10am. Spectral analysis of ECG from sleep Holter and PSG recordings was analysed using fast Fourier transformation (FFT). RESULTS: The ECG RR intervals of snorers with OSA were significantly shorter than in snorers without OSA (p<0.01). The low frequency (LF) spectral densities of HRV from polysomnography and Holter were significantly higher in OSA patients than in snorers, (p< 0.0001). The power spectral density of the high frequency bands was similar in the two groups. The overnight ECG Holter accurately identified all 13 snorers with severe OSA. CONCLUSION: The spectral power of the LF band obtained using FFT of sleep HRV from Holter tachograms may be a useful and cost effective test in identifying snorers with severe OSA. PMID- 21654954 TI - Outcome as a measure of quality of care in oncology: experience at sultan qaboos university hospital, oman. AB - OBJECTIVES: Measurement of outcomes is increasingly employed as an indicator of the quality of clinical care. The most commonly measured outcome in many clinical studies, especially in oncology, still remains the overall survival rate. Sultan Qaboos University Hospital (SQUH), Oman, is striving for excellence through quality management. In seeking continual improvement, quality measurement exercises have been initiated throughout the Hospital. We present the overall survival rate of four of the ten most common cancers diagnosed in Oman. METHODS: The cancers included non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), breast cancer, and stomach cancer. The studies were all retrospective and had been conducted previously. For present purposes, only the overall survival was compared with studies both from the region, and with bench-mark studies. RESULTS: For NHL, with a median follow-up of 8 months, the 2-year overall survival rate was 64%; 90% for low risk, 55% for intermediate risk, and 15% for high risk groups. For HL, the 5-year overall survival rate was 64%; 76% for low risk and 42% for high risk. For breast cancer, the 5-year survival rate was 67%; percentages were 88%, 75% and 59% for Groups I, II, and III respectively. For gastric cancer, the 5-year survival rate was 16.5 %; 24% for the non-metastatic group. CONCLUSION: The outcome of patients with early stages and fewer adverse prognostic factors is comparable to what has been reported in the international literature; however, the outcome is inferior for patients presenting with advanced stage disease and several adverse prognostic factors. PMID- 21654955 TI - Prevalence and Determinants of Waterpipe Tobacco Use among Adolescents in Oman. AB - OBJECTIVE: To assess the prevalence and determinants of waterpipe use among school-going adolescents in Oman. METHODS: A cross-sectional, school-based study was conducted in 2003 involving 9 regions of Oman, as part of the Global Youth Tobacco Survey. Participants were requested to complete an anonymous questionnaire containing demographic characteristics, current and previous use of waterpipe tobacco, attitudes towards cigarette smoking, parents' and friends' cigarette smoking habits. Proportions were used to calculate prevalence rates and logistic regression analysis to obtain odds ratio (OR) and 95% confidence interval (CI). RESULTS: 1,962 students participated of whom 1,005 (51.2%) were males. Eighty-eight percent were between 13 and 16 years of age. Five hundred and twenty-two (26.6%) reported ever smoking waterpipe tobacco while 189 (9.6%) were current users. Among males, 155 (15.5%) were current users while among females only 24 (2.6%) smoked currently. Study participants were more likely to use waterpipe if they had a parent or friend who smoked cigarettes. Adolescents were, however, less likely to use waterpipe tobacco if they believed that cigarette smoking was harmful to health. Students who were receiving 500 Baisas (US$ 1.3) or more per day pocket money were more likely to use waterpipe tobacco compared to those receiving less (OR 3.3, 95% CI 2.3 to 4.6). In multivariate analysis, the OR for males being a smoker of waterpipe tobacco compared to females was 4.46 (95% CI, 2.38 to 8.35); while the OR for most or all friends smoking cigarettes compared to non-smoking was OR 5.65 (95% CI 2.87 to 11.13). Study participants who perceived smoking as harmful to health were less likely to use waterpipe tobacco compared to those who did not believe smoking was harmful (OR 0.31, 95% CI 0.29 to 0.92) and those receiving 500 Baisas or more (OR 2.2, 95% CI 1.5 to 3.2). CONCLUSION: Waterpipe smoking among Omani adolescents is an emerging public health concern. Efforts to prevent adolescent smoking should be designed with knowledge of associated factors of such behaviour and should include all forms of tobacco. PMID- 21654956 TI - Some Risk Factors for Coronary Heart Disease among Omani Males: A matched case control study. AB - OBJECTIVES: Evaluation of some of the leading risk factors for coronary heart disease (CHD) among males in Oman. METHODS: We conducted a hospital-based pair wise matched case-control study among Omani CHD patients admitted in the Sultan Qaboos University Hospital and the Royal Hospital located in Muscat, Oman. The cases were matched with an equal number of controls in respect of age and hospital. The information was collected from the cases and controls based on an interview and review of the medical records of the admitted CHD patients. The odds ratios (ORs) were estimated under univariate as well as multivariate situations using conditional multiple binary logistic regression model. RESULTS: The analysis revealed that 74 percent of the cases were of angina pectoris. The majority of the cases (96%) were above 40 years of age. The prevalence of sedentary life style was predominant (88.0%). Hypertension, diabetes, family history of CHD and a sedentary occupation were the most significant risk factors for the development of the disease. The estimated values of the adjusted ORs were found to be 9.98, 2.74, 28.19 and 3.00 respectively (p<0.05). CONCLUSION: Individuals with hypertension, diabetes mellitus, a family history of CHD and with sedentary occupations are to be considered at high risk of developing CHD. Such individuals should be provided with appropriate health education along with close monitoring for symptoms and signs of CHD. PMID- 21654957 TI - Efficacy and safety of selective laser trabeculoplasty as a primary procedure for controlling intraocular pressure in primary open angle glaucoma and ocular hypertensive patients. AB - OBJECTIVE: Assessment of the potential efficacy and safety of selective laser trabeculoplasty (SLT) as a primary therapeutic modality for lowering the intraocular pressure (IOP) in high tension open angle glaucoma (OAG) and ocular hypertensive patients (OHT). METHODS: Twenty five patients (35 eyes) were enrolled in this prospective interventional longitudinal clinical study, undertaken during the period January 2005 to October 2006. All the laser procedures were done in the Oyoon Eye Center in Cairo, Egypt. Informed consent was taken from the patients after explanation of the procedure. Eighteen patients (25 eyes) had mild to moderate high tension open angle glaucoma, and there were 7 ocular hypertensive patients (10 eyes). Participants underwent selective laser trabeculoplasty (SLT) 180 degrees and followed up over a period of 12 months to assess the intraocular pressure lowering effect after SLT. Possible complications of the procedure were reported. RESULTS: The intraocular pressure (mean +/- standard deviation [StDev]) decreased from baseline pre-operative value of 26.78+/-3.13 mm Hg to 19.34+/-1.89 mm Hg 12 months after SLT (p<0.001). The average reduction in intraocular pressure (IOP) was 7.44 mm Hg (95% confidence interval 6.45 - 8.41 mm Hg). By the end of the follow up period (12 months), 62.9% of cases (22 eyes) showed IOP decrease by >= 30% from the baseline value, and 77.1% of cases (27 eyes) showed IOP decrease by >= 25% of baseline IOP. CONCLUSION: Selective laser trabeculoplasty is an effective IOP lowering modality. It can be used as a primary treatment for open angle glaucoma and ocular hypertensive patients. If the minimal side effects reported are considered, it can be concluded that SLT has a potential safety to be used as primary alternative treatment for open angle glaucoma and ocular hypertensive patients. PMID- 21654958 TI - Haemoglobinopathies encountered at Khoula Hospital, Oman: A retrospective study. AB - OBJECTIVE: The objective of this study was to find out the frequency of abnormal haemoglobins (Hb) in patients referred to Khoula Hospital, Oman and compare the data from other studies by assessing a large number of patients. METHODS: The results of 27,403 patients, either admitted to Khoula Hospital or referred to it from different health centres during the 4 years of the study from January 2001 till December 2004, were analysed for haemoglobinopathies. The laboratory methods used for detection of abnormal haemoglobins were sickle cell solubility test and haemoglobin electrophoresis. RESULTS: The frequency of sickle cell trait was 7.5%, sickle cell disease 0.46% and other Hb variants were 0.102%. The results correlate well with that of the National Genetic Blood Disorder Survey carried out by the research and studies department, Ministry of Health, Sultanate of Oman, during a 4 year period from January 2001 till December 2004. CONCLUSION: This retrospective study demonstrates the high prevalence of haemoglobinopathies among the studied group of patients. More attention to the importance of health education and genetic counselling is required for the prevention of this public health problem in the country. PMID- 21654959 TI - Insulinoma: a rare cause of a common metabolic disorder - hypoglycaemia. AB - We describe the first patient diagnosed with an insulinoma in Oman and successfully managed with a distal laparoscopic pancreatectomy. The importance of obtaining a good history from the patient and/or his family is stressed. All patients with loss of consciousness must have a Reflow check carried out and, if hypoglycaemic, this should be documented in the laboratory and a simultaneous serum sample stored for measurement of insulin, C-peptide proinsulin and sulphonylurea levels, if subsequently indicated. If magnetic resonance imaging fails to locate the tumour, endoscopic ultrasound of the pancreas, or indium 111 labelled octreotide scanning is indicated if the patient's hypoglycaemia has previously responded to treatment with octreotide. PMID- 21654960 TI - Intraorbital foreign body: clinical presentation, radiological appearance and management. AB - Intraorbital foreign bodies usually occur after a high velocity injury such as gunshot or industrial accidents; more rarely they occur following trivial trauma. A retained foreign body can give rise to serious complications, the most devastating of which is loss of the eye. This retrospective, interventional case report reviews the clinical features, radiological appearance and surgical management of two patients who presented at Sultan Qaboos University Hospital, Oman with intraorbital foreign bodies. Details of ocular history, preoperative ocular examination findings including visual acuity, surgical procedure and subsequent management were noted. The two patients, aged 10 years and 9 years old respectively, sustained orbital trauma with sharp objects. Both patients were found to have intraorbital foreign bodies that were documented clearly by computed tomography (CT) scans of the orbit. The first patient presented straight after injury, had no ocular involvement, underwent immediate surgical exploration and ended up with full recovery. The second patient presented to us after a delay of 4 days, and was found to have endophthalmitis. This patient ultimately lost all visual function in the affected eye. A CT scan is the modality of choice for orbital foreign body detection and localization. Early surgical exploration and foreign body extraction greatly influence the visual prognosis and final outcome. PMID- 21654961 TI - Graves' Disease following Interferon Therapy for Chronic Hepatitis C Infection. AB - We describe the first case of Graves' disease occurring at Sultan Qaboos University Hospital, Oman, in a patient who was under treatment with interferon alfa for HCV infection. INF-alpha is now being widely used to treat patients with a variety of disorders including infection with hepatitis C virus. Clinical thyroid disease, hypo and hyperthyroidism can occur in up to 15% of patients. We emphasize the need for thyroid function screening before and during therapy to identify patients early in the course of their disease.. PMID- 21654962 TI - Tc-99m tetrofosmin scintimammography for the detection of recurrent breast cancer in a patient with equivocal mammography study. AB - This is a case report describing a patient at Sultan Qaboos University Hospital, Oman, with recurrent local breast cancer and axillary lymph node metastasis. The cancer was detected with (99)Tc-(m) tetrofosmin scintimammography after an equivocal mammography study. PMID- 21654963 TI - A case of castor bean poisoning. AB - Castor beans, sometimes used in traditional therapies, contain ricin one of the most toxic substances known. It may cause an acute and potentially fatal gastroenteritis in addition to neurological and ophthalmological lesions. Poisoning may also lead to delayed visceral damages; however, the latter is quite rare. The toxicity is dose related and depends on the amount of castor beans ingested. There is no specific treatment and symptomatic management to reduce the load of the toxin needs to be initiated quickly and early when a case of poisoning is suspected so that serious complications will be avoided. Increasing the awareness of the population to the dangers of ricin would be a way to avoid the utilisation of castor seeds in traditional therapies. Here we are reporting a case of mild poisoning after ingestion of a single castor bean. The patient, who presented at Nizwa Hospital, Oman, fortunately recovered completely as the ingested dose was quite small. PMID- 21654964 TI - Washing Machine Injuries of the Upper Extremity: Case reports with a review of the literature. AB - Washing machines are part of every household and there are various reports of upper extremity injuries due to inadequate safety precautions while operating the machine. Most of the injuries occur when an attempt is made to remove the clothes from the machine and the hand gets caught in the spinning machine. The presentation can vary from minor soft tissue injuries to a mangled upper extremity. The chance of neurovascular damage resulting in compartment syndrome is very high. The author reports three cases of washing machine injuries to draw attention to this not so uncommon injury. The relevant literature is also considered. PMID- 21654965 TI - Prenatal MRI image of a fetus with semilobar holoprosencephaly. PMID- 21654966 TI - Re: Our Efforts are Reflected in Our Health. PMID- 21654967 TI - Models in complimentary medicine. PMID- 21654968 TI - Neurohemodynamic correlates of 'OM' chanting: A pilot functional magnetic resonance imaging study. AB - BACKGROUND: A sensation of vibration is experienced during audible 'OM' chanting. This has the potential for vagus nerve stimulation through its auricular branches and the effects on the brain thereof. The neurohemodynamic correlates of 'OM' chanting are yet to be explored. MATERIALS AND METHODS: Using functional Magnetic Resonance Imaging (fMRI), the neurohemodynamic correlates of audible 'OM' chanting were examined in right-handed healthy volunteers (n=12; nine men). The 'OM' chanting condition was compared with pronunciation of "ssss" as well as a rest state. fMRI analysis was done using Statistical Parametric Mapping 5 (SPM5). RESULTS: In this study, significant deactivation was observed bilaterally during 'OM' chanting in comparison to the resting brain state in bilateral orbitofrontal, anterior cingulate, parahippocampal gyri, thalami and hippocampi. The right amygdala too demonstrated significant deactivation. No significant activation was observed during 'OM' chanting. In contrast, neither activation nor deactivation occurred in these brain regions during the comparative task - namely the 'ssss' pronunciation condition. CONCLUSION: The neurohemodynamic correlates of 'OM' chanting indicate limbic deactivation. As similar observations have been recorded with vagus nerve stimulation treatment used in depression and epilepsy, the study findings argue for a potential role of this 'OM' chanting in clinical practice. PMID- 21654969 TI - Effect of yoga on mental health: Comparative study between young and senior subjects in Japan. AB - BACKGROUND: Japan has a large number of senior citizens. Yoga can be wisely applied in old age care. There is no any age restriction to practice yoga. The effect may differ by age. There is a need to study the mechanism of action of yoga with respect to age. AIM: This study was conducted in Japan to find the effect of yoga on mental health between young and senior people. MATERIALS AND METHODS: Twenty-five normal healthy volunteers of both sexes were divided into two groups according to age. Fifteen participants of the age group between 65 to 75 years and 10 participants of the age group between 20 to 30 years were selected. This study was approved by the ethical committee of Kawasaki University of Medical Welfare. Selected individuals were subjected to 90 min of yoga classes once or twice a week for a month. Salivary amylase activity was assessed before and after yoga practice. State Trait Anxiety Inventory (STAI) was given before yoga on the first day and after one month of practice to assess the change in State anxiety and Trait anxiety. RESULTS: Senior group - Salivary amylase activity decreased from 111.2+/-42.7 to 83.48+/-39.5 kU/L [average+/-standard deviation]. Younger group - Salivary amylase activity reduced from 60.74+/-31.8 to 42.39+/-24 kU/L. Senior group - State anxiety score decreased from 41.13 +/ 8.43 to 30.8+/-6.49, Trait anxiety score reduced from 45.66+/-7.5 to 40.73+/-8.3. Younger group - State anxiety score reduced from 38.7+/-4.8 to 30.8+/-4.1,Trait anxiety score reduced from 46.2+/-7.9 to 42.9+/-9.1. Changes were statistically significant with P<0.05. CONCLUSION: Decrease in Salivary amylase activity may be due to reduction in sympathetic response. Reduction in State and Trait anxiety score signifies that yoga has both immediate as well as long-term effect on anxiety reduction. Thus yoga helps to improve the mental health in both the groups. PMID- 21654970 TI - Effect of integrated yogic practices on positive and negative emotions in healthy adults. AB - BACKGROUND: Studies on affective wellbeing have shown the beneficial role of positive emotions on cognitive processing and the harmful role of negative emotions on coping, stress and health status. Studies have shown that yoga practices reduce anxiety and depression and improve wellbeing. OBJECTIVE: The aims of the study were to, (i) examine the safety and feasibility of conducting a weeklong free yoga camp, and (ii) assess its impact on the negative and positive affect in normal healthy volunteers. MATERIALS AND METHODS: In this open-arm study450 participants were taught integrated yoga module. It included asanas, pranayama, relaxation, notional correction and devotional sessions. Assessment was carried out on the first and last day of the camp, using a modified version of Positive Affect Negative Affect Scale (PANAS). It has ten questions each to measure positive (PA) and negative affect (NA). Nine questions have been added which are referred as other positive affect (OPA) and other negative affect (ONA) domains. RESULTS: Three hundred and twelve sets of pre-post data were analyzed. There was an increase in PA of PANAS by 13% (P<0.001, Wilcoxon's signed rank test) and OPA by 17% (P<0.001). The NA reduced by 47% (P<0.001) and ONA by 48% (P<0.001). CONCLUSION: It is feasible and safe to conduct a weeklong yoga camp in an urban setting, and integrated yoga practices can reduce the negative affect and increase the positive affect within one week. PMID- 21654971 TI - Impact of Yoga Nidra on psychological general wellbeing in patients with menstrual irregularities: A randomized controlled trial. AB - BACKGROUND: Yogic relaxation therapy (Yoga Nidra) has been effectively prescribed in conjunction with other medical and yogic procedures in the management of severe psychosomatic diseases, including cancer, bronchial asthma, colitis, peptic ulcer and menstrual irregularities. AIM OF THE STUDY: To assess the impact of Yoga Nidra on psychological problems in patients with menstrual disorders. MATERIALS AND METHODS: Patients were recruited from the Department of Obstetrics and Gynecology, C.S.M. Medical University (erstwhile KGMU), Lucknow, Uttar Pradesh, India. A total of 150 female subjects were randomly divided into two groups: 1) group of 75 subjects (with yogic intervention) and 2) a control group of 75 subjects (without yogic intervention). Assessment of psychological general wellbeing (tool) was used for all the subjects Assessment of psychological general well being (tool) was used for all the subjects (Cases and controls). This assessment was done twice first time in the beginning (baseline) and then after six months. RESULTS: Anxiety decreased significantly (P<0.003) and depression decreased significantly (P<0.01) in the Yoga group. Positive wellbeing and general health improved significantly (P<0.02), and vitality improved significantly (P<0.01) after six months of Yoga therapy (Yoga Nidra) in the Yoga group compared with the control group. CONCLUSION: The current findings suggest that patients with menstrual irregularities having psychological problems improved significantly in the areas of their wellbeing, anxiety and depression by learning and applying a program based on Yogic intervention (Yoga Nidra). PMID- 21654972 TI - Effect of integrated yoga practices on immune responses in examination stress - A preliminary study. AB - BACKGROUND: Stress is often associated with an increased occurrence of autonomic, cardiovascular, and immune system pathology. This study was done to evaluate the impact of stress on psychological, physiological parameters, and immune system during medical term -academic examination and the effect of yoga practices on the same. MATERIALS AND METHODS: The study was carried out on sixty first-year MBBS students randomly assigned to yoga group and control group (30 each). The yoga group underwent integrated yoga practices for 35 minutes daily in the presence of trained yoga teacher for 12 weeks. Control group did not undergo any kind of yoga practice or stress management. Physiological parameters like heart rate, respiratory rate, and blood pressure were measured. Global Assessment of Recent Stress Scale and Spielbergers State Anxiety score were assessed at baseline and during the examination. Serum cortisol levels, IL-4, and IFN-gamma levels were determined by enzyme-linked immunosorbent assay technique. RESULT: In the yoga group, no significant difference was observed in physiological parameters during the examination stress, whereas in the control group, a significant increase was observed. Likewise, the indicators of psychological stress showed highly significant difference in control group compared with significant difference in yoga group. During the examination, the increase in serum cortical and decrease in serum IFN-gamma in yoga group was less significant (P<0.01) than in the control group (P<0.001). Both the groups demonstrated an increase in serum IL-4 levels, the changes being insignificant for the duration of the study. CONCLUSION: Yoga resists the autonomic changes and impairment of cellular immunity seen in examination stress. PMID- 21654973 TI - The importance of spirituality in supportive care. AB - BACKGROUND: It has been shown that the pineal gland plays a fundamental role in mediating either the spiritual perception or the anticancer immunity by stimulating the endogenous production of anticancer cytokine interleukin (IL)-2. OBJECTIVE: The present study was performed to evaluate the impact of a spiritual approach consisting of Kriya Yoga program alone or in association with melatonin (MLT) or low-dose IL-2 plus MLT on the survival time in a group of metastatic cancer patients with life expectancy less than 1 year. MATERIALS AND METHODS: A case-control study was carried out in 240 patients (M/F: 146/94; median age: 62 years, range: 34-71, suffering from non-small-cell lung cancer or gastrointestinal tumors) who were subdivided into 6 groups of 40 patients, treated with supportive care alone as a control group, supportive care plus Yoga, MLT alone, MLT plus Yoga, inteleukin-2 plus MLT, or IL-2 plus MLT plus Yoga. RESULTS: The best results in terms of increased survival time were obtained by the association between neuroimmunotherapy with MLT plus IL-2 and Yoga program (2 years), which was significantly longer with respect to that achieved by supportive care alone, Yoga alone, or IL-2 plus MLT alone (1 year). CONCLUSIONS: This study would suggest that a spiritual therapeutic approach may improve the survival time of untreatable metastatic solid tumor patients. PMID- 21654974 TI - Yoga and lipid profile. PMID- 21654975 TI - Psychophysiological techniques and energy medicine. PMID- 21654976 TI - Tobacco use among medical students and surrogate control of tobacco in India. PMID- 21654977 TI - Pandemic influenza - Indian experience. PMID- 21654978 TI - A study on habits of tobacco use among medical and non-medical students of Kolkata. AB - BACKGROUND: Age-old practice "using tobacco" is a well known major global concern as it victimizes all its lovers by a host of chronic noncommunicable diseases including cancer; all develop very slowly and silently, and can cause premature death. OBJECTIVES: To assess the pattern of tobacco use among the medical and nonmedical college students. MATERIALS AND METHODS: A cross-sectional descriptive study was carried out in Kolkata collecting anonymous data from 515 medical and 349 nonmedical college students of two medical and two general colleges, selected randomly. RESULT: Overall prevalence of tobacco use (18.3% vs 43.6%) and smoking (14.9% vs 40.7%) were significantly less in medical subjects, both across the sex and years of study. Lower rate of tobacco adoption at college level, higher quitting rate, correct knowledge regarding uselessness of filter attached with cigarette, and ill-effects of tobacco consumption were observed among medical participants. More nonmedical subjects were increasingly smoking compared to medical students. Filter-tipped cigarette was the top choice, and smoking was more prevalent mode of use among the nonmedical participants, most (62.3%) of whom were mild users. Curiosity was the top influencing factor for the initiation of tobacco use and two-third users wanted to quit. CONCLUSION: Although the mortal habits was comparatively less among medical students, the medical environment seemed to fail to curb the dreadful practice totally. Thereby it can be recommended that active behavior-changing communication is required for all sections of the society to tear out the social root of the problem instead of unimpressive vague health warnings in vogue. PMID- 21654979 TI - Clinico-epidemiological features of the hospitalized patients with 2009 pandemic influenza A (H1N1) virus infection in Saurashtra region, India (September, 2009 to February, 2010). AB - BACKGROUND: The first case of 2009 pandemic influenza A (H1N1) virus infection in India was reported in May, 2009 and in Saurashtra region in August, 2009. We describe the clinico-epidemiological characteristics of patients who were hospitalized with 2009 influenza A (H1N1) infection in Saurashtra region. MATERIALS AND METHODS: From September, 2009 to February, 2010, we observed 274 persons infected with 2009 influenza A (H1N1) virus who were admitted in different hospitals in Rajkot city. Real-time reverse-transcriptase-polymerase chain-reaction (RT-PCR) testing was used to confirm infection; the clinico epidemiological features of the disease were closely monitored. RESULTS: Of 274 patients, median age was 29.5 years, and 51.5% were males. Only 1.1% patients had recent travel history to infected region. Median time of five days was observed from onset of illness to influenza A (H1N1) diagnosis, while median time of six days reported for hospital stay. All admitted patients received oseltamivir drug, but only 16.1% received it within two days of onset of illness. One fourth of admitted patients were expired. The most common symptoms were cough (96.7%), fever (92%), sore throat and shortness of breathing, and coexisting conditions including diabetes mellitus (9.9%), hypertension (8.8%), chronic pulmonary diseases (5.5%) and pregnancy (5.5%) (P<0.05). Pneumonia was reported in 93% patients with chest radiography. CONCLUSION: We have demonstrated that infection related illness affects both children and adults with survival of 74% patients. The median time from onset of illness to virus detection with use of real-time RT PCR is five days. Pregnancy is found as a significant (P<0.05) risk factor for severe disease. PMID- 21654980 TI - Increased sensitivity of sputum microscopy with sodium hypochlorite concentration technique: A practical experience at RNTCP center. AB - BACKGROUND: In revised national tuberculosis control program (RNTCP), microscopic examination of sputum for AFB plays an important role in the initial diagnosis of tuberculosis. Bacillary concentration after decontamination and liquefaction by 5% sodium hypochlorite is useful in providing increased sensitivity and safety for handling of specimen. MATERIALS AND METHODS: In this cross-sectional, prospective study, carried out at NKP Salve Institute of Medical Sciences and RC, Nagpur, patients were included according to RNTCP criteria. One set of smears was made according to the RNTCP guidelines while another set was prepared by concentration after decontamination with 5% sodium hypochlorite. Both set of smears were stained according to RNTCP method and were screened by two observers separately to remove observer's bias and graded according to the RNTCP guidelines. A total of 591 sputum samples from 219 patients were included in the study with 168 males (76.71%) and 51 females (23.28%). RESULTS: A total of 77 samples (13.02%) from 34 patients were positive by routine method whereas by concentration method 119 samples (20.13%) from 49 patients were found positive diagnosing 15 additional patients. This rise of 7.11% in sputum positivity over routine is highly significant (P=0.001021, chi(2)=10.78) with 44.11% increase in diagnosed cases. CONCLUSION: There is a statistically significant rise in smear positive cases after concentration with 5% sodium hypochlorite solution. Considering its low cost, decontaminating and liquefaction properties with better sensitivity, this method is safe and can be of vital importance; at least for smear negative cases. PMID- 21654981 TI - Role of sputum examination for acid fast bacilli in tuberculous pleural effusion. AB - BACKGROUND: Sputum for acid fast bacilli (AFB) is seldom looked for in the etiological diagnosis of tuberculous pleural effusion usually due to the absence of any parenchymal lesion radiologically, but presence of tubercle bacilli in sputum may have important epidemiological and therapeutic implication. AIMS: This study aims to evaluate the role of sputum examination for AFB in the patients of tuberculous pleural effusion with no apparent lung parenchymal lesion radiologically. SETTINGS AND DESIGN: Forty-five consecutive indoor patients of suspected tuberculous pleural effusion having no apparent lung parenchymal lesion on chest radiography were selected for our study. It was a prospective and observational study conducted over a period of 1 year. MATERIALS AND METHODS: After confirming the etiology of pleural effusion as tuberculous by biochemical, cytological, histopahtological, and microbiological tests, emphasis was given on sputum examination for AFB by smear examination and culture for Mycobacterium tuberculosis. RESULTS: Sputum was bacteriologically (smear and /or culture) positive for tuberculosis in 10 out of 30 cases (33.33%) in which tuberculous etiology was confirmed by histology and /or bacteriology (definite tuberculosis). No sputum AFB (smear and culture) was found in 15 cases of probable tuberculosis where tuberculous etiology was established by indirect methods like Adenosine de aminase level more than 40 unit/l and other relevant investigations. Over all, sputum was bacteriologically smear and/or culture positive in 10 out of 45 cases (22.22%). CONCLUSION: Careful and thorough sputum examination in cases of tuberculous pleural effusion may help as a diagnostic tool and it has therapeutic and epidemiological implications. PMID- 21654982 TI - Pulmonary zygomycosis: A clinicopathological study. AB - BACKGROUND AND OBJECTIVE: Zygomycosis is an emerging infection worldwide. Pulmonary zygomycosis (PZ) is uncommon with only few reported series from India. MATERIALS AND METHODS: All cases of PZ diagnosed on histopathology between 1995 and 2008 were included. Clinical and imageological findings were noted in all cases. Routine hematoxylin and eosin-stained sections were studied to assess the pathology; Gomori's methenamine silver (GMS), periodic acid Schiff were done for delineating fungal morphology. Culture reports were collected wherever available. Treatment and outcome details were noted. RESULTS: Seven patients were diagnosed with PZ during the study period, which included six males and one female patient. Six of these had diabetes mellitus (DM) and one patient was on chemotherapy for the treatment of Hodgkin's lymphoma. Fever and cough were the most common presenting features. Consolidation with or without cavitation was seen in six patients and lung abscess with fungal ball in one patient. All six patients with DM had upper lobe involvement and four had multiple lesions. Histological sections revealed necrotizing inflammation, hemorrhagic infarcts and angioinvasion. Culture was available in two patients, which grew Rhizopus oryzae. Five patients succumbed to disease and remaining two were lost to follow-up. CONCLUSION: Diabetes mellitus is the most common predisposing factor for PZ and carries high mortality. PMID- 21654983 TI - Evaluation of mucociliary clearance among women using biomass and clean fuel in a periurban area of Chennai: A preliminary study. AB - BACKGROUND: Nasal mucociliary clearance (NMC) plays a crucial role in the defense of the airways against inhaled substances and is affected by various factors. The effect of particulate matter on NMC in women using biomass fuel has not been well studied. AIM: This cross-sectional study was conducted to assess the NMC time in biomass fuel users and compare it with that of clean fuel users. MATERIALS AND METHODS: NMC time and Peak Expiratory Flow Rate (PEFR) were determined in women of age ranging from 18 to 45 years using biomass fuel (n=30) and clean fuel (n=30). The time taken to perceive the sweet taste, following placement of saccharin 1 cm behind the anterior end of inferior turbinate was recorded as NMC time. PEFR was measured using mini-Wright peak flow meter. Comparison between groups was analyzed using t-test and ANOVA in R statistical software. RESULTS: NMC time was significantly prolonged in biomass fuel users (765.8 +/- 378.16 s) in comparison to clean fuel users (545.4 +/- 215.55 s). PEFR was significantly reduced (319.3 l/min) in biomass fuel users compared to clean fuel users (371.7 l/min). Women from lower socioeconomic status, lower literacy status, older undernourished women and women cooking for>15 years had prolonged Saccharin Transit Time (STT) and reduced PEFR. CONCLUSIONS: This study highlights the effects of indoor air pollution on respiratory defense mechanism. This simple noninvasive, inexpensive, screening test can be used as an early indicator of respiratory damage caused by exposure to air pollutants. PMID- 21654984 TI - An insight into the swine-influenza A (H1N1) virus infection in humans. AB - WHO declares on June 11, 2009, that H1N1 (Swine-influenza A) is pandemic. There have been nearly 30,000 confirmed H1N1 cases across 74 countries. The reports have shown sharp increase in the number of infections reported in recent days from Chile, Japan, and the UK, and other parts of the world, with the most dramatic increase recorded in Australia where more than 1200 cases were reported in a very short duration. As per the latest report of the Ministry of Health and Family Welfare, death from swine flu has reached to 1235. Around 12,3397 people have been tested in India as on February 1, 2010. In India, 23.3% of people who have tested for swine flu are found suffering from swine flu. Also around 4% of people who have tested positive for swine flu have died and could not be saved in India. The New York Times has reported that this is the first flu for being pandemic in the last 41 years. This article enlightens the brief review about the swine influenza virus, its modes of spread, and prevention measures. The aim of this article is to bring awareness in general and know the consequences of the infection. PMID- 21654986 TI - Noninvasive ventilation in acute respiratory failure due to H1N1 influenza. AB - We present a case of severe H1N1 influenza with hypoxemic acute respiratory failure necessitating mechanical ventilation benefited from noninvasive positive pressure ventilation (NIPPV). The NIPPV may be of great use in treating patients with H1N1-related acute respiratory distress syndrome in a resource poor setting or when invasive ventilator is unavailable. PMID- 21654985 TI - Recent trends in pulmonary arterial hypertension. AB - Pulmonary hypertension is a serious and unrelenting pulmonary vascular disorder that affects the functional quality of patients and significantly decreases their life span. If diagnosed early, with the number of new therapeutic options that are available, a better quality of life can be provided for a protracted length of time. It is likely that the available treatment will change the natural course of the disease and perhaps prolong survival. As symptoms are often subtle in the early stages of the disease it is imperative that physicians are aware of the manifestations of this condition. A thorough investigation of patients suspected of this condition is essential so that appropriate treatment can be initiated promptly. The routine workup of a patient suspected to have pulmonary hypertension could easily be carried out in any well-equipped peripheral hospital in many affluent and advanced countries. However, it must be mentioned that in some less advanced countries the necessary work up can only be done in major teaching hospitals. Both pulmonologists and cardiologists should be aware of the pathophysiology of pulmonary arterial hypertension, the workup and the treatment options that are available. Patients with refractory pulmonary hypertension should be referred to these research centers for enrolment into any ongoing drug trials as well as for evaluation for heart-lung, single lung, or double lung transplantation. This paper is primarily aimed at pulmonologists and cardiologists taking care of these patients. Unless indicated otherwise this paper mainly deals with WHO group 1 pulmonary hypertension which is designated pulmonary arterial hypertension. Extensive review of the literature spanning the last 30 years was made through Medline using titles such as primary pulmonary hypertension, pulmonary arterial hypertension, secondary pulmonary hypertension, and pulmonary vascular diseases. PMID- 21654987 TI - Diffuse alveolar hemorrhage in Wegener's granulomatosis. AB - Diffuse alveolar hemorrhage is a life-threatening though rare manifestation of Wegener's granulomatosis (WG). An active diagnostic workup, intensive observation, and aggressive immunosuppressive treatment are cornerstones of the management. The treatment modalities available for such complications are pulse cyclophosphamide therapy with steroids. We report here a case of WG with diffuse alveolar hemorrhage as the first manifestation of the disease in life that responded to steroids and cyclophosphamide. PMID- 21654989 TI - Isoniazid-induced alopecia. AB - Isoniazid is a safe and very effective antituberculosis drug. Antimitotic agents routinely cause alopecia. Drug-induced alopecia is usually reversible upon withdrawal of the drug. Isoniazid, thiacetazone and ethionamide are the antituberculosis drugs which have been associated with alopecia. Isoniazid induced alopecia was observed in one case and confirmed by the finding that hair growth resumed when drug removed from the regimen. PMID- 21654988 TI - Development of bilateral chylothorax in a younger female secondary to tuberculosis. AB - Chylothorax is a rare clinical entity characterized by a milky white aspirate with increased triglyceride levels. The commonest etiology is malignancy and trauma, and bilateral chylothorax, secondary to tuberculosis, is an extremely rare cause, as observed in the present case. PMID- 21654990 TI - A case of squamous cell carcinoma of lung presenting with paraneoplastic type of acanthosis nigricans. AB - A 70-years-old male presented with blackening of both hands and face for last six months which was progressive and attended dermatology outpatients department. Dermatologist opined the skin lesions as acanthosis nigricans. He was referred to our department to evaluate for any underlying internal malignancy as he was a smoker. His chest X-ray revealed right sided hilar prominence with a mid zone cavity with fluid level. Fibreoptic bronchoscopy was done, there was one ulcerative growth in right middle lobe bronchus. Biopsy from the ulcer revealed probable squamous cell carcinoma. CT scan of thorax was also done and CT guided FNAC of Rt lung lesion yielded non small cell carcinoma. His skin lesions were also biopsied and diagnosis of acanthosis nigricans was confirmed. Here we report a case of acanthosis nigricans associated with non-small cell cancer of lung. PMID- 21654991 TI - Cause of seizures: Lungs, not the brain. AB - Hyponatremia is a common electrolyte abnormality but is usually asymptomatic and is often neglected. We present case of a 22-year-old diabetic male who presented with generalized tonic clonic seizures which was later found to be a consequence of hyponatremia. Further investigation unravels the presence of SIADH which was eventually found to be due to the consolidation of the left lingual lobe of lung. This case emphasizes the need for a thorough workup to identify the etiology of hyponatremia as it may unmask a treatable entity. PMID- 21654992 TI - Congenital lobar emphysema in an adult. AB - Congenital lobar emphysema (CLE) is a clinico-radiological diagnosis, seen usually by four-six weeks of age (50% of patients) and rarely (<5% of patients) after the age of six months. Here, we report a young male with gradual onset of mild exertional breathlessness and physical examination revealing the features of right sided pneumothorax. X-ray of chest, with subsequent CT of chest, leads to the diagnosis of CLE. The pulmonary function tests, bronchoscopic examination and alpha(1)-antitrypsin level are normal. Patient is managed conservatively. PMID- 21654993 TI - Radiological presentation of patients of pulmonary tuberculosis with diabetes mellitus. PMID- 21654994 TI - Radiographic findings in tuberculous diabetic patients. PMID- 21654995 TI - Bronchopleurocutaneous fistula in absence of empyema: A rare presentation of pulmonary tuberculosis. PMID- 21654996 TI - A rare presentation of empyema necessitatis. PMID- 21654997 TI - Extrapulmonary tuberculosis and HIV. PMID- 21654998 TI - Three cases of ARDS: An emerging complication of Plasmodium vivax malaria - Queries? PMID- 21654999 TI - Erythema multiforme due to antitubercular drugs. PMID- 21655000 TI - Video-assisted thoracic surgery and thoracic empyema. PMID- 21655001 TI - Authors' reply. PMID- 21655002 TI - Shoulder instability in the middle-aged and elderly patients: Pathology and surgical implications. PMID- 21655003 TI - Shoulder dislocation in patients older than 60 years of age. AB - PURPOSE: Recurrent anterior shoulder dislocation in elderly patients is a little studied condition. The goal of this paper is to clarify the role of associated injuries with respect to loss of function and recurrence of dislocation. MATERIALS AND METHODS: We have conducted a retrospective, descriptive study on 29 patients older than 60 years at the moment they suffered their first dislocation episode. All patients were assessed clinically (Constant test) and by imaging testing (X-ray, MRI). RESULTS: Nine (31.03%) out of 29 patients had a recurrent dislocation. Four of them required reconstructive surgery to maintain joint stability. Injury to the anterior support (anterior labrum, anterior glenoid rim) showed a statistically significant relation to the recurrence of dislocations. The occurrence or non-occurrence of a rotator cuff tear does have an impact on the shoulder function. The degree of rotator cuff involvement on the coronal plane does not significantly affect the shoulder's functional outcome. The tear extension on the sagittal plane does cause impairment on the Constant test. CONCLUSIONS: Labrum and/or anterior glenoid involvement should be suspected in elderly patients presenting with recurrent shoulder dislocation. Recurrence is due to an injury in the anterior support or both (anterior and posterior), even though shoulder function gets impaired when a rotation cuff tear occurs with anterior extension on the sagittal plane. Evidence level: IV Case series. PMID- 21655004 TI - Giant benign nodular hidradenoma of the shoulder: A rare tumor in orthopedic practice. AB - A clear cell hidradenoma is a rare dermal tumor, which is believed to originate from the apical portion of the sweat glands. The usual size reported is 5-30 mm. It is generally found in the head, face, and upper extremity regions. This lesion has not been reported to be large enough to impinge a joint range of motion. Hence, its description in the orthopedic literature is extremely rare. We present a giant benign nodular hidradenoma presenting as painful restriction of the right shoulder joint in a 35-year-old male. PMID- 21655005 TI - Elastofibroma dorsi: A soft tissue masquerade. AB - Elastofibroma dorsi (ED) is a soft tissue tumor found in the subscapular region. The pathogenesis of ED is unclear, but may involve a regenerative or reactive hyperproliferation due to mechanical microtrauma. Magnetic resonance imaging (MRI) is preferred to diagnose ED and complete excision is curative. When bilateral, subscapular masses are identified in the elderly patient and MRI characteristics are typical, biopsy and excision can be avoided. Symptomatic EDs should be excised, and recurrence is rare. Three hundred and thirty cases of ED have been reported since 1980. Fourteen case series and 43 isolated case reports involved 263 women and 67 men (F:M ratio = 3.9:1), with a mean age of 62 years (range 6-94 years). Bilateral ED was present in 164 patients and unilateral ED in 157. The reported prevalence in the elderly population ranges from a minimum of 2% to a maximum of 24%. PMID- 21655006 TI - True congenital dislocation of shoulder: A case report and review of the literature. AB - The dislocation of a shoulder joint in infancy is extremely rare and is usually the result of traumatic birth injuries, a sequel to brachial plexus injury, or a true congenital dislocation of shoulder. With more advanced obstetric care, the incidence of first two types has drastically decreased. We report a case of true congenital dislocation of shoulder, second of its kind, in a child who was delivered by cesarean section thereby negating any influence of trauma. We report the case because of its rarity, and review the available literature on this topic. We also discuss the management options when encountered with such a rare case scenario. PMID- 21655007 TI - Anesthesia for thymectomy. PMID- 21655008 TI - A comparative study of efficacy of esmolol and fentanyl for pressure attenuation during laryngoscopy and endotracheal intubation. AB - OBJECTIVE: To compare the effectiveness of single bolus dose of esmolol or fentanyl in attenuating the hemodynamic responses during laryngoscopy and endotracheal intubation. METHODS: Ninety adult ASA I and ASA II patients were included in the study who underwent elective surgical procedures. Patients were divided into three groups. Group C (control) receiving 10 ml normal saline, group E (esmolol) receiving bolus dose of esmolol 2 mg/kg and group F (fentanyl) receiving bolus dose of fentanyl 2 ug/kg intravenously slowly. Study drug was injected 3 min before induction of anesthesia. Heart rate, systemic arterial pressure and ECG were recorded as baseline and after administration of study drug at intubation and 15 min thereafter. RESULTS: Reading of heart rate, blood pressure and rate pressure product were compared with baseline and among each group. The rise in heart rate was minimal in esmolol group and was highly significant. Also the rate pressure product at the time of intubation was minimal and was statistically significant rate 15 min thereafter in group E. CONCLUSION: Esmolol 2 mg/kg as a bolus done proved to be effective in attenuating rises in heart rate following laryngoscopy and intubation while the rise in blood pressure was suppressed but not abolished by bolus dose of esmolol. PMID- 21655009 TI - Airway management in patients with maxillofacial trauma - A retrospective study of 177 cases. AB - BACKGROUND: Airway management in maxillofacial injuries presents with a unique set of problems. Compromised airway is still a challenge to the anesthesiologist in spite of all modalities available. Maxillofacial injuries are the result of high-velocity trauma arising from road traffic accidents, sport injuries, falls and gunshot wounds. Any flaw in airway management may lead to grave morbidity and mortality in prehospital or hospital settings and as well as for reconstruction of fractures subsequently. METHODS: One hundred and seventy-seven patients of maxillofacial injuries, operated over a period of one and half years during July 2008 to December 2009 in Al-Nahdha hospital were reviewed. All patients were reviewed in depth with age related type of injury, etiology and techniques of difficult airway management. RESULTS: The major etiology of injuries were road traffic accidents (67%) followed by sport (15%) and fall (15%). Majority of patients were young in the age group of 11-30 years (71 %). Fracture mandible (53%) was the most common injury, followed by fracture maxilla (21%), fracture zygoma (19%) and pan-facial fractures (6%). Maxillofacial injuries compromise mask ventilation and difficult airway due to facial fractures, tissue edema and deranged anatomy. Shared airway with the surgeon needs special attention due to restrictions imposed during surgery. Several methods available for securing the airway, both decision-making and performance, are important in such circumstances. Airway secured by nasal intubation with direct visualization of vocal cords was the most common (57%), followed by oral intubation (17%). Other methods like tracheostomy and blind nasal intubation was avoided by fiberoptic bronchoscopic nasal intubation in 26% of patients. CONCLUSION: The results of this study indicated that surgically securing the airway by tracheostomy should be revised compared to other available methods. In the era of rigid fixation of fractures and the possibility of leaving the patient without wiring an open mouth and alternative techniques like fiberoptic bronchoscopic intubation, it is unnecessary to carry out tracheostomy for securing the airway as frequently as in the past. PMID- 21655010 TI - A retrospective study of the outcome of cesarean section for women with severe pre-eclampsia in a third world setting. AB - OBJECTIVE: To compare the outcome of subarachnoid block (spinal anesthesia) and general anesthesia in Cesarean delivery for women with severe pre-eclampsia. METHODS: A retrospective study of women with severe pre-eclampsia requiring Cesarean section from January 2005 to June 2009 was carried out. Maternal age, parity, gestational age at delivery, booking status, Apgar scores, maternal and perinatal mortality of the sub-arachnoid block group were compared with those of general anesthesia group using chi(2), Student t-test and Fischer exact test. RESULTS: There were no significant difference between the two groups in overall maternal mortality (5.4% vs. 11.9%, P=0.5) and perinatal mortality (2.7% vs. 11.9%, P=0.15). The general anesthesia group had significantly more birth asphyxia than the spinal group (55.9% vs. 27.0%, P=0.0006). CONCLUSION: There was no significant difference in the maternal and perinatal mortality outcome of cesarean delivery between women with severe pre-eclampsia who had regional anesthesia and those that had general anesthesia. There was significantly higher proportion of birth asphyxia in babies of women who received general anesthesia. PMID- 21655011 TI - Palonosetron: A novel approach to control postoperative nausea and vomiting in day care surgery. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the complications which hamper the successful implementation of day care surgical procedure in spite of the availability of so many antiemetic drugs and regimens for its prevention. The aim was to compare the prophylactic effects of intravenously (IV) administered ondansetron and palonosetron on PONV prevention in patients undergoing laparoscopic gynecological surgery under general anesthesia. METHODS: A prospective double-blind study comprised of 60 ASAI/II female patients between the age group of 25 and 40 years was carried out in the Departments of Anesthesiology and Obstetrics and Gynecology of our institute. Patients were randomly divided into two groups of 30 patients each in a double-blind manner. Group I received 8 mg of inj. ondansetron IV while group II received inj. palonosetron 0.075 mg IV 5 minutes before the induction of anesthesia. The need for rescue antiemetics, episodes of PONV and other side effects were observed for 6 hours in the postanesthesia care unit and thereafter complaints were received on phone after the discharge. At the end of study, results were compiled and statistical data was subjected to statistical analysis using Student two-tailed 't' and chi(2) test and value of P<0.05 was considered significant. RESULTS: The demographical profile of the patients was comparable. Twenty and 13.33% of the patients in group I had nausea and vomiting episodes postoperatively as compared to 6.67% and 3.33%, respectively, in group II which was statistically significant (P<0.05). Twenty percent of the patients in group I experienced significant post op headache as compared to 6.67% in group II. The mean rescue dose of antiemetic was significantly higher (10.6 mg) in the group I as compared to group II (6.4 mg) (P=0.036). The rest of parameters were comparable and statistically nonsignificant. CONCLUSIONS: Palonosetron is a comparatively better drug to prevent the PONV in patients undergoing day care surgical procedures as compared to ondansetron as it has got a prolonged duration of action and favorable side effects profile. PMID- 21655012 TI - Anesthesia for patients undergoing transsternal thymectomy for juvenile myasthenia gravis. AB - BACKGROUND: Juvenile myasthenia gravis (JMG) is the rare form of myasthenia gravis presenting in childhood and adolescence. When medical management fails, thymectomy is offered for these patients. Complete resection of the thymus is best achieved through transsternal thymectomy. Anesthetic management of patients with JMG is challenging, particularly in regards to the goals of postoperative pain control, respiratory function, and extubation. METHODS: We retrospectively reviewed the medical records of 13 patients, ranging in age from 6 to 22 years, who underwent transsternal thymectomy for JMG. Information on patient demographics, characteristics of their disease and treatment, anesthetic management, and postoperative course were collected. RESULTS: All patients had undergone multiple treatment modalities and presented for surgery because of inadequate symptom control with medical management. As expected for a pediatric population, anesthesia induction was age dependent. 40% of the patients underwent an inhalation induction and 60% underwent an intravenous induction. Anesthesia was maintained with a low-dose inhalation agent in all patients, supplemented in 84% of patients with a remifentanil infusion, and in 69% of patients with an epidural infusion. Muscle relaxants were avoided in all patients. With this regimen, 92% of patients could be extubated successfully in the operating room. CONCLUSION: We found that avoidance of muscle relaxants and use of remifentanil with a low-dose hypnotic agent provided a stable intraoperative course, facilitated rapid emergence, and allowed early extubation in patients with JMG undergoing transsternal thymectomy. Epidural analgesia reduced the need for intra and postoperative intravenous opioids and did not have an adverse effect on respiratory strength. PMID- 21655013 TI - Evaluation of analgesic effects of intrathecal clonidine along with bupivacaine in cesarean section. AB - AIMS AND CONTEXT: The objective of the present study was to evaluate the analgesic and adverse effects of intrathecal clonidine with hyperbaric bupivacaine in spinal anesthesia. SETTINGS AND DESIGN: Randomized single blind trial. METHODS: 210 ASA I-II pregnant females undergoing emergency cesarean section were randomized in a single-blind fashion to one of the three groups. In group I (n=70) patients received 12.5 mg of 0.5% hyperbaric bupivacaine intrathecally. In group II (n=70) patients received intrathecal mixture of 0.5% hyperbaric bupivacaine (8 mg) and clonidine 50 MUg. In group III (n=70), patients received 0.5% hyperbaric bupivacaine (10 mg) intrathecally along with 50 MUg of clonidine. STATISTICAL ANALYSIS USED: Groups were compared using one-way ANOVA with the Bonferroni multiple comparison post hoc test. The proportion of adverse events was compared using the chi-square test (chi(2) =57.2410). RESULTS: On adding 50 MUg clonidine, we were able to reduce intrathecal dose of bupivacaine for cesarean section to 8 mg. Patients receiving intrathecal clonidine along with bupivacaine had significantly long lasting analgesia with lower bupivacaine dose [246.21+/-5.15 min. (group II) vs 146.0+/-4.55 min (group I), P=0.021; 95% confidence interval: 238.01-257.40, group II and 134.99-157.0 group I]. CONCLUSIONS: Addition of intrathecal clonidine causes some sedation in the postoperative period, but it provides adequate analgesia and motor paralysis at lower dose of bupivacaine. It also significantly prolongs postoperative pain relief. PMID- 21655014 TI - Dexmedetomidine versus propofol for sedation in patients undergoing vitreoretinal surgery under sub-Tenon's anesthesia. AB - PURPOSE: The purpose of this study was to evaluate the hemodynamic, respiratory effects, the recovery profile, surgeons, and patients satisfaction with dexmedetomidine sedation compared with those of propofol sedation in patients undergoing vitreoretinal surgery under sub-Tenon's anesthesia. METHODS: Sixty patients were enrolled in this prospective, single-blind, randomized study. The patients were divided into two groups to receive either dexmedetomidine (group D) or propofol (group P). Sedation level was titrated to a Ramsay sedation scale (RSS) of 3. Hemodynamic and respiratory effects, postoperative recovery time, analgesic effects, surgeons and patients satisfaction were assessed. RESULTS: Both groups provided a similar significant reduction in heart rate and mean arterial pressure compared with baseline values. The respiratory rate values of the dexmedetomidine group were significantly higher than those in the propofol group. The oxygen saturation values of the dexmedetomidine group were significantly higher than those of the propofol group. The expired CO(2) was similar in both groups. Postoperatively, the time to achieve an Aldrete score of 10 was similar in both groups. Dexmedetomidine patients have significantly lower visual analog scale for pain than propofol patients. The surgeon satisfaction with patients' sedation was similar for both groups. The patients' satisfaction was higher in the dexmedetomidine group. CONCLUSION: Dexmedetomidine at similar sedation levels with propofol was associated with equivalent hemodynamic effects, maintaining an adequate respiratory function, similar time of discharge from PACU, better analgesic properties, similar surgeon's satisfaction, and higher patient's satisfaction. Thus, dexmedetomidine may prove to be a valuable adjuvant for sedation in patients undergoing vitreoretinal surgery under sub-Tenon's anesthesia. PMID- 21655015 TI - Efficacy of ultrasound-guided obturator nerve block in transurethral surgery. AB - BACKGROUND: During transurethral resection surgery (TUR), accidental stimulation of the obturator nerve can cause violent adductor contraction, leading to serious intraoperative complications. General anesthesia with muscle relaxation is currently the preferred technique for TUR surgery. Spinal anesthesia combined with obturator nerve block has also been used for TUR surgery in geriatric population. Blind, anatomical methods for identifying the obturator nerve are often unsatisfactory. Therefore, we conducted this prospective study to validate the efficacy of ultrasound-guided obturator nerve block (USONB) during TUR procedures. METHODS: Eighteen male patients undergoing TURP surgery under spinal anesthesia were included in the study. Bilateral USONB with maximum 20 ml of 1% lidocaine per patient was performed. An independent observer was present to monitor any adduction movements during the operation and to record patient and surgeon satisfactions. RESULTS: In all patients, obturator nerve was visualized from the first attempt, requiring an average of 4.3 min for blocking of each side. USONB was successful (97.2%) in preventing an adductor spasm in all except one patient. Patient's and surgeon's satisfaction were appropriate. In all patients, adductor muscle strength recovered fully within 2 h following the surgical procedure. CONCLUSIONS: USONB is safe and effective during TUR surgery. It provides optimal intra-and postoperative conditions. PMID- 21655016 TI - Combined parecoxib and I.V. paracetamol provides additional analgesic effect with better postoperative satisfaction in patients undergoing anterior cruciate ligament reconstruction. AB - BACKGROUND: Adequacy of postoperative analgesia is one of the most important factors that determine early hospital discharge and patients' ability to resume their normal activities postoperatively. The optimal non-opioid analgesic technique for postoperative pain management would reduce pain and enhance patient satisfaction, and it also facilitates earlier mobilization and rehabilitation by reducing pain-related complications after surgery. The aim of this study was to evaluate the analgesic efficacy of intravenous paracetamol and parecoxib when used alone, or in combination. METHODS: Sixty American Society of Anesthesiology (ASA) physical status I and II adult patients who were scheduled for anterior cruciate ligament reconstruction were included in this study. Patients were allocated into three groups: group I patients received 1g intravenous paracetamol after induction and another 1 g 4 h later, group II received 40 mg parecoxib after induction, while group III received combination of both drugs (paracetamol 1 g and parecoxib 40 mg). Pain during rest and mobility was assessed in the immediate postoperative period, 2 h and 8 h successively using visual analog scale (VAS). Patient satisfaction was rated according to satisfaction score. RESULTS: Total morphine requirements were lower in group III patients (6.9+/-2.7 mg) in comparison to group I patients (12.6+/-3.6 mg) or group II patients (9.8+/ 2.8 mg). The least VAS scores were recorded during knee movement (3.8+/-1.1) in group III patients compared to group I (6.0+/-1.8) and group II patients (4.8+/ 1.9). Eight hours postoperatively, group III patients were more satisfied regarding the postoperative pain management. CONCLUSION: Combination of intravenous paracetamol and parecoxib provided better analgesia and higher patient satisfaction than each drug when used separately. PMID- 21655017 TI - Comparative study of attenuation of the pain caused by propofol intravenous injection, by granisetron, magnesium sulfate and nitroglycerine. AB - BACKGROUND: Propofol has the disadvantage of causing pain or discomfort on injection. The aim of the study was to assess the efficacy of pretreatment with various drugs to alleviate the propofol injection pain. METHODS: One hundred American Society of Anesthesiology (ASA) I and II adults, scheduled for various elective surgical procedures under general anesthesia (GA), were included in the study. They were randomly divided into four groups having 25 patients in each group. Group A received pretreatment with intravenous (i.v.) magnesium sulfate, group B received i.v. granisetron, group C received i.v. nitroglycerine and group D was the control group. One-fourth of the total calculated induction dose of propofol was administered over a period of 5 seconds. The patients were asked about the pain on injection. The intensity of pain was assessed using verbal response. A score of 0-3 which corresponds to no, mild, moderate and severe pain was recorded. RESULTS: All the three drugs reduced the incidence and intensity of pain on propofol injection but the order of efficacy in attenuation of pain on the propofol injection was granisetron > nitroglycerine > magnesium sulfate > control. CONCLUSION: Granisetron was the most effective followed by nitroglycerine and magnesium sulfate in attenuating pain on propofol intravenous injection. PMID- 21655018 TI - Effect of magnesium infusion on thoracic epidural analgesia. AB - INTRODUCTION: Patients of lung volume reduction surgery (LVRS) having an ASA status III or more are likely to be further downgraded by surgery to critical levels of pulmonary function. AIM: To compare the efficacy of thoracic epidural block with (0.125%) bupivacaine, fentanyl combination and (0.125%) bupivacaine, fentanyl combination with adjunctive intravenous magnesium infusion for the relief of postoperative pain in patients undergoing LVRS. METHODS: Patients were operated under general anesthesia. Thirty minutes before the anticipated completion of skin closure in both groups, (Group A and Group B) 7 ml of (0.125%) bupivacaine calculated as 1.5 ml/thoracic segment space for achieving analgesia in dermatomes of T4, T5, T6, T7, and T8 segments, along with fentanyl 50 MUg (0.5 ml), was administered through the catheter, activating the epidural block, and the time was noted. Thereafter, in patients of Group A, magnesium sulfate injection 30 mg/kg i.v. bolus was followed by infusion of magnesium sulfate at 10 mg/kg/hr and continued up to 24 hours. Group B was treated as control. RESULTS AND ANALYSIS: A significant increase in the mean and maximum duration of analgesia in Group A in comparison with Group B (P<0.05) was observed. Total epidural dose of fentanyl and bupivacaine required in Group A was significantly lower in comparison with Group B in 24 hours. DISCUSSION: Requirement of total doses of local anesthetics along with opioids could be minimized by magnesium infusion; therefore, the further downgradation of patients of LVRS may be prevented. CONCLUSION: Intravenous magnesium can prolong opioid-induced analgesia while minimizing nausea, pruritus, and somnolence. PMID- 21655019 TI - A clinical comparison of etomidate-lipuro, propofol and admixture at induction. AB - OBJECTIVE: The purpose of this study was to compare etomidate-lipuro and propofol and 50%, (1:1) admixture of these agents at induction with special reference to injection pain, hemodynamic changes, and myoclonus. METHODS: Ninety patients were assigned at random to three groups in which induction was performed with either etomidate-lipuro, propofol or etomidate-lipuro-propofol admixture. After monitorization with bispectral index (BIS) all agents were given with infusion with a perfuser at a constant rate of 200 ml/min till the BIS values decreased to 40. Blood pressure and heart rate were measured every 30 s at this period. Patients were asked for pain at the injection site and observed visually for myoclonus. The time BIS values decreased to 40 (BIS 40 time) and total amounts of induction doses were measured. RESULTS: BIS 40 time measurements were P > E > PE (199.4 +/- 40.9, 176.9 +/- 31.6, 163.5 +/- 20.6 s). The hemodynamic (systolic, diastolic and mean blood pressures, heart rate) changes were minimal in group PE than other two groups (P = 0.017). The intensity of myoclonus was graded as mild in 9, moderate in 12, and severe in 5 patients in the group E (76.3%). Myoclonus was not observed in group PE and group P. There were no injection pain in group PE as the incidence were (83.8%) in group P and in (63.2%) group E. CONCLUSION: Incidence of hemodynamic changes, myoclonus, and injection pain is significantly lower in group PE. BIS 40 times is least in group PE. We concluded that 1:1 admixture of etomidate-lipuro and propofol is a valuable agent for induction. PMID- 21655020 TI - Evaluating ranitidine, pantoprazole and placebo on gastric pH in elective surgery. AB - BACKGROUND AND AIM: Concern about the grim nature of postoperative acid aspiration syndrome grew among the anesthesiologist over the years warranting the need for pre-emptive intervention. The aim of the study is to compare the effects of preoperative oral ranitidine versus pantoprazole given in regulating gastric pH in elective surgery. METHODS: This prospective, parallel group, controlled, randomized, single-blind study was conducted at a tertiary care postgraduate teaching institute at Kolkata, involving 120 participants of either sex, aged 18 60 years of American Society of Anesthesiologists physical status I and II, who were scheduled for elective surgery under general anesthesia lasting for more than 2 h. The participants were divided into three groups. In group A (n=40) participants received placebo tablet, in group B (n=40) participants received ranitidine tablet while in group C (n=40), participants received pantoprazole tablet and their gastric pH estimated serially. RESULTS: The participants in the three groups were comparable in terms of age, sex, body weight, duration of surgery and type of surgery distribution. In regard to changes in gastric pH trends, there was no statistically significant difference between serial pH values in group A (Friedman test; P>0.05) and group C participants. (P>0.05). However, the mean preoperative gastric pH values (7.140+/-.7652) were significantly lower than mean pH values (7.253+/-.7514) after 2 h postoperatively in group B participants (P<0.05). CONCLUSION: From the observations and analyses of the present study, it can be inferred that ranitidine is more effective than pantoprazole to raise the gastric pH for prevention of aspiration pneumonitis. PMID- 21655021 TI - Reported survival with severe mixed acidosis and hyperlactemia after toluene poisoning. AB - Lactic acidosis is a recognized complication of the inhalant abuse such as toluene, especially in patients with renal insufficiency. We report a case of severe metabolic acidosis and hyperlactemia due to toluene sniffing. The favorable outcome, despite extremely poor clinical symptoms, signs, laboratory and radiological findings, was unexpected. Specific aspects of the clinical course are addressed. Toluene sniffing should be considered in evaluating sever metabolic acidosis. Favorable outcome could be achieved with early diagnosis and proper interventions. PMID- 21655022 TI - Continuous positive airway pressure ventilation during whole lung lavage for treatment of alveolar proteinosis -A case report and review of literature. AB - Pulmonary alveolar proteinosis (PAP) is a rare disease that affects young population usually in the age group of 20-40 years, characterized by the deposition of lipoproteinacious material in the alveoli secondary to abnormal processing of surfactant by macrophages. We report a case of a 15-year-old female who had history of cough with sputum for 3 days along with fever. She was seen in another hospital and was treated as a case of pneumonia where she received antibiotic but with no improvement. Computerized tomography (CT) chest showed diffuse interlobular septal thickening in the background of ground glass opacity giving a picture of crazy paving pattern which was consistent with the diagnosis of PAP. The patient was scheduled to undergo, first right-sided whole lung lavage (WLL) under general anesthesia. Endobronchial intubation using left sided 37 Fr double lumen tube. Continuous positive airway pressure (CPAP) as described in our previously published report was connected to the right lumen of the endobronchial tube. CPAP ventilation was used during the suctioning of lavage fluid phase in order to improve oxygenation. WLL was done using 5 L of warm heparinized saline (500 i.u/litre). The same procedure was repeated on the left side using 6 L of heparinized normal saline solution. In conclusion, anesthesia in alveolar proteinosis for patients undergoing WLL is challenging to the anesthesiologist. It requires meticulous preoperative preparation with antibiotics, mucolytics and chest physiotherapy. Also it requires careful intraoperative monitoring and proper oxygenation especially during the suctioning phase of the lavaged fluid. With this second case report of successful anesthetic management using the modified CPAP system we recommend with confidence the application of CPAP ventilation to improve oxygenation during WLL. PMID- 21655023 TI - Delayed recovery due to exaggerated acid, base and electrolyte imbalance in prolonged laparoscopic repair of diaphragmatic hernia. AB - The acid, base and electrolyte changes are usually observed in the perioperative settings. We report a case of prolonged laparoscopic repair of left-sided diaphragmatic hernia which involved a lot of tissue handling and fluid replacement leading to acid, base and electrolyte imbalance. A 42-year-old male underwent prolonged laparoscopic repair under general anesthesia. Intraoperatively, surgeon reported that contents of hernia includes bowel along with mesentery, spleen and lot of fatty tissue The blood loss was about 2 L which was replaced with 1 L of colloid and 7.5 L of lactated ringer. Near the end of surgery arterial blood gas analysis revealed metabolic acidosis, hyperkalemia, and hypocalcemia leading to delayed recovery. We conclude prolonged laparoscopic surgery involving lot of tissue handling including gut and fat should be monitored for acid, base, electrolyte imbalance and corrected timely to have uneventful rapid recovery. PMID- 21655024 TI - Anesthetic and airway management of a child with a large upper-lip hemangioma. AB - An 11-month-old male child weighing 8 kg was brought to the plastic surgery out patient department by his parents with chief complaints of sudden increase in size of a swelling over the upper lip and difficulty in feeding for the last 7 days. It was diagnosed as a case of hemangioma of the upper lip. All the routine and special investigations including coagulation profile of the child were normal. The child was planned for ablation of feeding vessels along with intralesional steroid injection. Airway management of the child posed the challenge for us as the size and site of the lesion carried the risk of difficult intubation and possible risk of extensive hemorrhage. All the requisite equipment for difficult airway management was made ready. We were able to intubate the child with miller number-2 blade from the left angle of mouth without putting much pressure on the swelling. The surgical and postoperative period was uneventful and the child was discharged the next day to be followed up after 2 weeks. PMID- 21655025 TI - Intubation with Airtraq laryngoscope in a morbidly obese patient. AB - In the present study, we report a case of successful endotracheal intubation using Airtraq(TM) Laryngoscope (AQL) in a morbidly obese patient. A 35-year-old woman, morbidly obese (weight, 105 kg; height, 160 cm; BMI, 41 kg/m(2)), known hypertensive and diabetic, was admitted in the operating room for total abdominal hysterectomy under general anesthesia. The preoperative airway assessment anticipated both difficult bag-mask ventilation and intubation. Tracheal intubation using AQL was attempted after induction with propofol and relaxation with succinylcholine. Successful tracheal intubation was accomplished within 12 seconds of insertion of AQL into the oral cavity. The minimal hemodynamic response during this maneuver was advantageous in our patient. PMID- 21655026 TI - Anesthetic management of a child with Apert syndrome. AB - In this paper, the authors describe an anesthetic technique for a child with Apert syndrome, presenting to the operating room for a syndactyly separation. The anesthetic approach is innovative for the clinic and is a combination of intravenous anesthesia and two regional techniques (axillary block and transversus abdominis plane block, respectively). They were performed under ultrasound guidance and provided analgesia in the two body regions, which were to be operated. PMID- 21655027 TI - Inadvertent intrathecal injection of tranexamic acid. AB - Some factors have been identified as contributing to medical errors such as labels, appearance, and location of ampules. In this case report, inadvertent intrathecal injection of 80 mg tranexamic acid was followed by severe pain in the back and the gluteal region, myoclonus on lower extremities and agitation. General anesthesia was induced to complete surgery. At the end of anesthesia, patient developed polymyoclonus and seizures needing supportive care of the hemodynamic, and respiratory systems. He developed ventricular tachycardia treated with Cordarone infusion. The patient's condition progressively improved to full recovery 2 days after. Confusion between hyperbaric bupivacaine and tranexamic acid was due to similarities in appearance between both ampules. PMID- 21655028 TI - Cardiac arrest after anesthetic management in a patient with hereditary sensory autonomic neuropathy type IV. AB - Hereditary sensory autonomic neuropathy type IV is a rare disorder with an autosomal recessive transmission and characterized by self-mutilation due to a lack in pain and heat sensation. Recurrent hyperpyrexia and anhydrosis are seen in patients as a result of a lack of sweat gland innervation. Self-mutilation and insensitivity to pain result in orthopedic complications and patients undergone recurrent surgical interventions with anesthesia. However, these patients are prone to perioperative complications such as hyperthermia, hypothermia, and cardiac complications like bradycardia and hypotension. We report a 5-year-old boy with hereditary sensory autonomic neuropathy type IV, developing hyperpyrexia and cardiac arrest after anesthesia. PMID- 21655029 TI - Symptomatic sinus bradycardia: A rare adverse effect of intravenous ondansetron. AB - Ondansetron is a serotonin receptor antagonist which has been used frequently to reduce the incidence of post-operative nausea and vomiting in laparoscopic surgery. It has become very popular drug for the prevention of post-operative nausea and vomiting due to its superiority in-terms of efficacy as well as lack of side effects and drug interactions. Although cardiovascular adverse effects of this drug are rare, we found a case of symptomatic sinus bradycardia in a 43-year old female patient, going for laparoscopic cholecystectomy, who developed the same after she was given intravenous ondansetron in operation theater during premedication. Hence, we report this case, as the rare possibility of encountering bradycardia effect after intravenous administration of ondansetron should be born in mind. PMID- 21655030 TI - Anesthetic management of a patient with sickle beta thalassemia. AB - Sickle cell disease is a congenital condition and its most common clinical manifestation is anemia due to chronic hemolysis. Persistent and accelerated hemolysis associated with multiple transfusions is a recognized risk factor for the development of cholelithiasis. The occurrence of gallstones is one of the most important manifestations of sickle cell disease in the digestive tract. Most gallstones are pigmented and characteristically occur at younger ages and the prevalence of cholelithiasis increases progressively with age, affecting 50% of young adults. Cholecystectomy is the most common surgical procedure performed in sickle cell disease patients. Anesthesia in this population of patients for major surgeries deserves special attention due to various complications particularly silent infarctions of end organs are common. We are reporting a 14-year-old girl diagnosed with sickle cell anemia and beta(+) thalassemia with cholelithiasis went for cholecystectomy under general anesthesia. Although the patient has both beta(+) thalassemia and sickle cell disease component, the latter is of more concern for anesthesia. PMID- 21655031 TI - Mismatched transfusion of 8 AB0-incompatible units of packed red blood cells in a patient with acute intermittent porphyria. AB - We report on a patient with acute intermittent porphyria, who received 8 AB0 incompatible units of packed red blood cells in an emergency situation. She never showed any signs of severe intravascular haemolysis. The patient died after four weeks because of a multi-organ failure caused from the malpractice of the porphyria. The problems of bedside testing, mixing field reaction, fresh frozen plasma and molecular-genetic determination of bloodgroup were discussed. PMID- 21655032 TI - An unusual cause of post-operative orbital edema in a child after general anesthesia. AB - We present an unusual ocular complication during the perioperative period, bilateral orbital edema in an otherwise healthy child after an outpatient surgical procedure. Ocular complications under general anesthesia remain a rare event. When periorbital edema is present, the appropriate work-up includes ruling out the potential for an allergic event by reviewing the medications administered and serum tryptase testing. Ophthalmology consultation should be considered to exclude pathology native to the eye itself. An allergist may assist in confirming a diagnosis and for allergic testing, if indicated. In our patient, the eventual diagnosis of exclusion was that of a localized reaction to the cellophane-based eye tape. PMID- 21655033 TI - Pseudo loss of resistance in epidural space localization: A complication of subcutaneous emphysema or simply a faulty technique. PMID- 21655034 TI - Novel technique in difficult percutaneous tracheostomy. PMID- 21655035 TI - Life-threatening arrhythmias due to faulty microdebrider during nasal sinus surgery. PMID- 21655036 TI - Use of heat and moisture exchanger in intubated patients reduces the blockage in gas sampling tube of the mass spectrometer. PMID- 21655037 TI - Oxygen desaturation following methylene blue injection: Not always spurious. PMID- 21655038 TI - Intraocular lens power calculation using IOLMaster and various formulas in short eyes. AB - PURPOSE: To evaluate the predictability of intraocular lens (IOL) power calculations using the IOLMaster and four different IOL power calculation formulas (Haigis, Hoffer Q, SRK II, and SRK/T) for cataract surgery in eyes with a short axial length (AL). METHODS: The present study was a retrospective comparative analysis which included 25 eyes with an AL shorter than 22.0 mm that underwent uneventful phacoemulsification with IOL implantation from July 2007 to December 2008 at Seoul National University Boramae Hospital. Preoperative AL and keratometric power were measured by the IOLMaster, and power of the implanted IOL was determined using Haigis, Hoffer Q, SRK II, and SRK/T formulas. Postoperative refractive errors two months after surgery were measured using automatic refracto keratometry (Nidek) and were compared with the predicted postoperative power. The mean absolute error (MAE) was defined as the average of the absolute value of the difference between actual and predicted spherical equivalences of postoperative refractive error. RESULTS: The MAE was smallest with the Haigis formula (0.37 +/- 0.26 diopter [D]), followed by those of SRK/T (0.53 +/- 0.25 D), SRK II (0.56 +/- 0.20 D), and Hoffer Q (0.62 +/- 0.16 D) in 25 eyes with an AL shorter than 22.0 mm. The proportion with an absolute error (AE) of less than 1 D was greatest in the Haigis formula (96%), followed by those in the SRK II (88%), SRK-T (84%), and Hoffer Q (80%). CONCLUSIONS: The MAE was less than 0.7 D and the proportion of AE less than 1 D was more than 80% in all formulas. The IOL power calculation using the Haigis formula showed the best results for postoperative power prediction in short eyes. PMID- 21655039 TI - Comparison of the short-term effects of intravitreal triamcinolone acetonide and bevacizumab injection for diabetic macular edema. AB - PURPOSE: To compare the short-term effects of intravitreal triamcinolone acetonide (IVTA) with those of intravitreal bevacizumab (IVB) injection for diabetic macular edema (DME). METHODS: The present retrospective, comparative case study included 58 eyes of 35 consecutive patients (IVTA group, 20 eyes; IVB group, 38 eyes) with DME. IVTA (4 mg) or IVB (1.25 mg) injection was performed under local anesthesia. The effects of injection for DME were evaluated using best-corrected visual acuity (BCVA), central macular thickness (CMT) by optical coherence tomography and intraocular pressure (IOP) by applanation tonometer. Patients underwent eye examinations, including BCVA, CMT, and IOP at pre injection, 2, 4, and 8 weeks after injection. RESULTS: BCVA (logarithm of the minimum angle of resolution) +/- SD at pre-injection, 2, 4, and 8 weeks after injection was 0.67 +/- 0.40, 0.56 +/- 0.35 (p = 0.033), 0.55 +/- 0.33 (p = 0.041), and 0.43 +/- 0.31 (p = 0.001) in the IVTA group and 0.51 +/- 0.31, 0.42 +/- 0.26 (p = 0.003), 0.43 +/- 0.32 (p = 0.001), and 0.43 +/- 0.27 (p = 0.015) in the IVB group, respectively. CMT (um) +/- SD at pre-injection, 2, 4, and 8 weeks after injection was 400.4 +/- 94.9, 332.8 +/- 47.4 (p = 0.002), 287.5 +/- 49.1 (p = 0.007), and 282.5 +/- 49.6 (p = 0.043) in the IVTA group and 372.6 +/- 99.5, 323.2 +/- 72.4 (p = 0.077), 360.9 +/- 50.3 (p = 0.668), 368.2 +/- 88.6 (p = 0.830) in the IVB group, respectively. CONCLUSIONS: The effects of IVTA for BCVA were more favorable than were those of IVB and were consistent throughout the eight weeks after injection. IVTA significantly reduced CMT during the eight weeks after injection, while IVB did not. PMID- 21655040 TI - Multifocal electroretinogram findings after intravitreal bevacizumab injection in choroidal neovascularization of age-related macular degeneration. AB - PURPOSE: To evaluate the changes in multifocal electroretinogram (mfERG) and optical coherence tomography (OCT) after intravitreal bevacizumab injection in the treatment of age-related macular degeneration (AMD). METHODS: Twenty-one eyes with choroidal neovascularization secondary to AMD were studied before and after intravitreal bevacizumab injection for best corrected visual acuity (BCVA), OCT, and mfERG. RESULTS: The BCVA improved, while central macular thickness and total macular volume in OCT decreased after intravitreal bevacizumab injection (p = 0.03, 0.01, and 0.01, respectively). In mfERG, the amplitude of P1, and implicit time of P1 and N1 indicated a statistically significant improvement of retinal response after intravitreal bevacizumab injection. CONCLUSIONS: There is a potential role for mfERG in evaluating the effect on retinal function of intravitreal bevacizumab injection. PMID- 21655041 TI - Comparison of retinal nerve fiber layer thickness between Stratus and Spectralis OCT. AB - PURPOSE: To compare the peripapillary retinal nerve fiber layer (RNFL) thickness of normal patients and those with various glaucoma diseases by time domain (Stratus) and spectral domain (Spectralis) optical coherence tomography (OCT). METHODS: The RNFL thickness as measured by the Stratus and Spectral OCT was compared (paired t-test). The relationship and agreement of RNFL thickness between the two OCT modalities were evaluated by Pearson correlation, Bland Altman plot, and area under the receiver operating characteristic curve. RESULTS: Two-hundred seventeen eyes of 217 patients, including twenty-four normal eyes, ninety-one glaucoma suspects, seventy-six normal tension glaucoma cases, and twenty-six primary open angle glaucoma cases (POAG) were analyzed. The peripapillary RNFL thicknesses as measured by Stratus OCT were significantly greater than those measured by Spectralis OCT. However, in quadrant comparisons, the temporal RNFL thickness obtained using Stratus OCT were significantly less than those obtained using Spectralis OCT. Correlations between RNFL parameters were strong (Pearson correlation coefficient for mean RNFL thickness = 0.88); a high degree of correlation was found in the POAG group. Bland-Altman plotting demonstrated that agreement in the temporal quadrant was greater than any other quadrant. CONCLUSIONS: Both OCT systems were highly correlated and demonstrated strong agreement. However, absolute measurements of peripapillary RNFL thickness differed between Stratus OCT and Spectralis OCT. Thus, measurements with these instruments should not be considered interchangeable. The temporal quadrant was the only sector where RNFL thickness as measured by Spectralis OCT was greater than by Stratus OCT; this demonstrated greater agreement than other sectors. PMID- 21655042 TI - Quantitative analysis of optic disc color. AB - PURPOSE: To evaluate the reproducibility of ImageJ software in analyzing the color of the optic disc. METHODS: One hundred twelve normal participants (56 males and 56 females) were enrolled in this study. The image of the optic disc was taken using Kowa digital disc photo-graphy, and the gray scales of the nasal rim (NR), brightest cupping center (BCC) and largest inferior retinal vein (IRV) were calculated using histogram in ImageJ. Three different observers calculated the gray scales three separate times. Reproducibility was assessed using the interclass correlation coefficient (ICC). RESULTS: The mean age of the participants was 50.6 years old (range, 11 to 82 years). The mean gray scales of the nasal rim were 91.81, 94.91, and 93.24; those of the brightest cupping center were 174.84, 179.94, and 177.76; and those of the largest inferior retinal vein were 61.85, 53.48, and 56.73 for observers 1, 2, and 3, respectively. Inter observer reproducibility for NR, BCC and IRV was considered good based upon ICC values of 0.944, 0.860, and 0.789 for observers 1, 2, and 3, respectively. Significant age-related differences between the values of the brightest cupping center were noted, and the gray scale score was decreased in the older participants (p < 0.001). CONCLUSIONS: The gray scale of the brightest cupping center diminished with age. ImageJ can be a useful objective tool with high reproducibility in the analysis of optic disc color. PMID- 21655043 TI - Comparison of fibrin glue and sutures for conjunctival wound closure in strabismus surgery. AB - PURPOSE: To evaluate and compare the efficacy and tolerance of fibrin glue and sutures for closing conjunctival wounds in strabismus surgery. METHODS: In a prospective trial, we performed strabismus surgery using limbal incisions. Conjunctival wounds were closed with fibrin glue in 20 eyes of 20 patients (fibrin group) and 8-0 polyglactin suture in 20 eyes of 20 patients (suture group). Postoperative pain, tearing, and inflammation were compared at 1 day, 1 week, 3 weeks, and 6 weeks after surgery. Conjunctival incision healing was also investigated. RESULTS: One day and one week post-operatively, pain and tearing scores were lower in the fibrin group (p = 0.000, respectively). Mean surgery time was significantly shorter in the fibrin (48 +/- 5 minutes) than the suture group (63 +/- 7 minutes) (p = 0.000). Inflammation was significantly more severe in the suture group until 3 weeks postoperative (p = 0.000, respectively), but conjunctival healing did not differ between the groups. Hyperemia appeared more prominent in the fibrin group 3 and 6 weeks after surgery (p = 0.087 and 0.000, respectively). Two eyes in the fibrin group showed conjunctival gaps of more than 2 mm, which closed spontaneously by three weeks after surgery. No allergic reactions or infections developed. CONCLUSIONS: Fibrin glue proved to be as effective as sutures in closing conjunctival wounds. It provides more comfortable early postoperative courses and might be considered as an alternative to sutures in strabismus surgery. PMID- 21655044 TI - Effectiveness of home-based pencil push-ups (HBPP) for patients with symptomatic convergence insufficiency. AB - PURPOSE: To report the effectiveness of home-based pencil push-ups (HBPP) therapy for patients with symptomatic convergence insufficiency. METHODS: Data was collected prospectively on 16 patients who were diagnosed with convergence insufficiency beginning in January 2009. The study group was composed of ten male and six female patients. The duration of symptoms, refractive error, distant and near deviation angles, and near point of convergence (NPC) prior to and after 12 weeks of HBPP therapy were measured in all patients. RESULTS: The mean age of the patients was 19.3 years. The mean deviation angle of exophoria was 3 prism diopters (PD) at distant and 11.2 PD at near. The mean value of NPC prior to HBPP therapy was 36.3 cm; however, the near point of accommodation was within the normal range. After 12 weeks of HBPP therapy, the mean deviation angle of exophoria decreased to orthophoric at distant and 4 PD at near. The mean value of NPC decreased to 14.4 cm. CONCLUSIONS: Twelve weeks of HBPP therapy appears to be an easy, cost-free and effective therapy for patients with symptomatic convergence insufficiency. PMID- 21655045 TI - Intravenously administered anti-recoverin antibody alone does not pass through the blood-retinal barrier. AB - PURPOSE: Cancer-associated retinopathy is a paraneoplastic retinal degeneration which may primarily result from auto-immune mediated apoptosis. It has been hypothesized that high titer of auto-antibodies are able to cross the blood retinal barrier (BRB) and to enter retinal cells to activate apoptotic pathway which has been already well-established. However, it still remains to be elucidated whether auto-antibodies could cross BRB in the retina. Herein, we demonstrated that intravenously administrated anti-recoverin antibodies could not pass through BRB and not lead to retinal cell death. METHODS: Anti-recoverin antibody was intravenously injected to C57BL/6 mice, which were sacrificed 1 and 7 days to obtain eye. Vascular endothelial growth factor was intravitreally injected to induce BRB breakdown, which was confirmed by fluorescein angiography and western blotting for zonula occludens (ZO)-1, ZO-2 and occludin. To investigate the location of anti-recoverin antibody in the retina, immunofluorescein was performed. The retinal toxicity of intravenous anti recoverin antibody was evaluated by histological examination and transferase mediated dUTP nick-end labeling. Immunofluorescein staining for glial fibrillary acidic protein was done to address glial activation as well. RESULTS: Intravenously administrated anti-recoverin antibodies were exclusively distributed on retinal vessels which were co-localized with CD31, and led to neither increase of glial fibrillary acidic protein expression, as an indicator of retinal stress, nor apoptotic retinal cell death. Moreover, even in the condition of vascular endothelial growth factor-induced BRB breakdown, anti recoverin antibodies could not migrate across BRB and still remained on retinal vessels without retinal cytotoxicity. CONCLUSIONS: Our results suggest that high titer of intravascular anti-recoverin antibodies could not penetrate into the retina by themselves, and BRB breakdown mediated by dysregulation of tight junction might not be sufficient to allow anti-recoverin antibodies to pass through BRB. PMID- 21655046 TI - Mechanisms of apoptosis on human lens epithelium after ultraviolet light exposure. AB - PURPOSE: The purpose of this study is to understand the mechanism of apoptosis occurring on a cultured human lens epithelial cell line after exposure to ultraviolet (UV) light. We intended to confirm the presence of cellular toxicity and apoptosis and to reveal the roles of p53, caspase 3 and NOXA in these processes. METHODS: Cells were irradiated with an ultraviolet lamp. Cellular toxicity was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hoechst staining and fluorescent anti-caspase 3 antibodies were used for apoptosis investigation. The quantities of p53, caspase 3, and NOXA were measured by Western blotting for to investigate the apoptosis pathway. RESULTS: Cellular toxicity on the human lens epithelium markedly increased with time after UV exposure. On Hoechst staining, we found that apoptosis also remarkably increased after exposure to ultraviolet light, compared with a control group. In the immunochemical study using anti-caspase 3 antibodies, active caspase 3 significantly increased after exposure to ultraviolet light. On Western blotting, p53 decreased, while caspase 3 and NOXA increased. CONCLUSIONS: Exposure of cultured human lens epithelial cell lines to ultraviolet light induces apoptosis, which promotes the expression of NOXA and caspase 3 increases without increasing p53. This may suggest that UV induced apoptosis is caused by a p53-independent pathway in human lens epithelial cells. PMID- 21655047 TI - A case of crystalline keratopathy in monoclonal gammopathy of undetermined significance (MGUS). AB - A 62-year-old female visited our clinic with progressively decreased vision in both eyes beginning 12 years prior. Idiopathic corneal opacity in all layers of the cornea was found in both eyes. One year later, we performed penetrating keratoplasty on the undiagnosed right eye. During post-surgical follow-up, corneal edema and stromal opacity recurred, and penetrating keratoplasty was performed two more times. The patient's total serum protein level, which had previously been normal, was elevated prior to the final surgery. She was diagnosed with monoclonal gammopathy of undetermined significance. We made a final diagnosis of monoclonal gammopathy-associated crystalline keratopathy after corneal biopsy. Monoclonal gammopathy-associated crystalline keratopathy is difficult to diagnose and may lead to severe visual loss. A systemic work-up, including serologic tests like serum protein or cholesterol levels, is needed in patients with unexplainable corneal opacity. PMID- 21655048 TI - Conventional Epi-LASIK and lamellar epithelial debridement in myopic patients with dermatologic keloids. AB - We report the outcome of conventional epipolis laser in situ keratomileusis (Epi LASIK, flap-on) and lamellar epithelial debridement (LED; Epi-LASIK, flap-off) in myopic patients with dermatologic keloids. Three patients, who were all noted to be susceptible to keloid scarring, received conventional Epi-LASIK in their right eyes and LED in their left eyes. The patients were followed-up for 6 to 21 months after their surgeries, and the outcomes were then evaluated. In case 1, the preoperative spherical equivalent (SE) was -6.5 diopters (D) in the right eye (OD) and -6.25 D in the left eye (OS). At 21 months postoperatively, the uncorrected visual acuity (UCVA) was 20 / 12.5 in both eyes. In case 2, the preoperative SE was -5.25 (OD) / -6.00 (OS). After six months, the postoperative UCVA was 20 / 12.5 in both eyes. In case 3, the preoperative SE was -4.5 (OD) / 2.0 (OS). The UCVA at the six-month follow-up was 20 / 12.5 in both eyes. No adverse events, including corneal haze, occurred in any of the patients. All three of our patients reported excellent visual outcomes following both conventional Epi-LASIK and LED, despite their histories of keloid formation. The present cases suggest that both Epi-LASIK and LED may be safe and effective techniques for myopic patients with dermatologic keloids. PMID- 21655049 TI - Neurotrophic corneal ulcer development following cataract surgery with a limbal relaxing incision. AB - A 60-year-old man with bilateral corneal opacity underwent cataract extraction surgery involving the use of a limbal relaxing incision in his left eye. He had lower lid ectropion and lagophthalmos in both eyes. Eleven days after the surgery, a slit-lamp examination revealed a neurotrophic corneal ulcer with a punch-out epithelial defect and rolled edges at the center of the pre-existing corneal opacity. The patient was treated with sodium hyaluronate, autologous serum, and oral doxycycline. Six weeks after the surgery an improvement in corneal sensation was observed and the neurotrophic corneal ulcer subsequently healed over the course of one year. In this report, we present a case of neurotrophic keratitis that occurred after performing cataract surgery concurrent with a limbal relaxing incision. As such, we suggest that limbal relaxing incisions should be performed cautiously in patients with causative risk factors for corneal hypesthesia. PMID- 21655050 TI - Acute-onset bilateral myopia and ciliochoroidal effusion induced by hydrochlorothiazide. AB - The authors experienced two cases of hydrochlorothiazide (HCTZ)-induced acute onset bilateral myopia and shallowing of the anterior chambers. Two middle-aged women taking HCTZ, a sulfa derivative, visited our clinic complaining of acute bilateral visual deterioration. Both had good visual acuity without corrective lenses before taking HCTZ. A complete ophthalmologic examination revealed bilateral myopic shift, intraocular pressure elevation, shallowing of the anterior chambers, choroidal effusions, radiating retinal folds, and conjunctival chemosis. Approximately one week after HCTZ discontinuance, all ocular changes disappeared completely. Physicians should be aware of the adverse ocular effects of HCTZ and should manage patients accordingly. PMID- 21655051 TI - A case of intravitreal bevacizumab injection for the treatment of choroidal neovascularization in angioid streaks. AB - A 56-year-old Korean woman presented with decreased visual acuity of the right eye. She had a history of two photodynamic therapy treatments for choroidal neovascularization (CNV) due to angioid streaks in her left eye with central scarring and low visual acuity. She was diagnosed with subfoveal CNV due to angioid streaks in her right eye and treated with six intravitreal bevacizumab (1.25 mg / 0.05 mL) injections over one year. Best corrected visual acuity improved from 20 / 125 at baseline to 20 / 50 at the final visit. The area of CNV had changed into a fibrotic scar by the final visit, and fluorescein angiography and indocyanine green angiography revealed no evidence of leakage. Optical coherence tomography showed that central macular thickness decreased from 311 um at baseline to 203 um with complete resolution of subretinal and intraretinal fluid at the final visit. Intravitreal bevacizumab for CNV associated with angioid streaks prevented the progression of disease and resulted in the improvement of visual acuity after one year of follow-up in our patient. PMID- 21655052 TI - Short-term clinical observation of acute retinal pigment epitheliitis using spectral-domain optical coherence tomography. AB - We investigated the case of a young man with blurred vision in his left eye. His visual acuity was slightly decreased, and ophthalmoscopy disclosed a gray-white lesion in the macula. He had no systemic or ocular history. On the visual field test, the threshold sensitivity was decreased in the corresponding region. Spectral domain optical coherence tomography (OCT) demonstrated a disruption in the photoreceptor inner and outer segment (IS/OS) junction and undulation of the retinal pigment epithelium (RPE) with backscattering. We re-examined the patient after two weeks and after three months without any treatment. Visual acuity and visual field results were gradually normalized, and OCT demonstrated the recovery of continuity in the photoreceptor IS/OS junction, as well as decreased RPE irregularity with minimal backscattering. We used spectral domain OCT instead of time domain OCT (OCT3) so that we could provide better image resolution of the acute retinal pigment epitheliitis (ARPE). Finally, we observed recovery of the functional and anatomical changes in the ARPE patient with a resolution of the condition within three months following the initial examination, using OCT and visual field tests. PMID- 21655053 TI - The genetic basis of panic disorder. AB - Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene gene and gene-environment interactions, and pharmacogenetic studies are needed. PMID- 21655054 TI - Estimation of nationwide vaccination coverage and comparison of interview and telephone survey methodology for estimating vaccination status. AB - This study compared interview and telephone surveys to select the better method for regularly estimating nationwide vaccination coverage rates in Korea. Interview surveys using multi-stage cluster sampling and telephone surveys using stratified random sampling were conducted. Nationwide coverage rates were estimated in subjects with vaccination cards in the interview survey. The interview survey relative to the telephone survey showed a higher response rate, lower missing rate, higher validity and a less difference in vaccination coverage rates between card owners and non-owners. Primary vaccination coverage rate was greater than 90% except for the fourth dose of DTaP (diphtheria/tetanus/pertussis), the third dose of polio, and the third dose of Japanese B encephalitis (JBE). The DTaP4: Polio3: MMR1 fully vaccination rate was 62.0% and BCG1:HepB3:DTaP4:Polio3:MMR1 was 59.5%. For age-appropriate vaccination, the coverage rate was 50%-80%. We concluded that the interview survey was better than the telephone survey. These results can be applied to countries with incomplete registry and decreasing rates of landline telephone coverage due to increased cell phone usage and countries. Among mandatory vaccines, efforts to increase vaccination rate for the fourth dose of DTaP, the third dose of polio, JBE and regular vaccinations at recommended periods should be conducted in Korea. PMID- 21655055 TI - Effects of intronic and exonic polymorphisms of paraoxonase 1 (PON1) gene on serum PON1 activity in a Korean population. AB - Paraoxonase 1 (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces lipid peroxide accumulation, and PON1 genetic polymorphisms in the coding region modulate serum PON1 activity. In this study, we investigated the association between 3 polymorphisms of PON1 located in intron 5 (17899insdelTT and 17974CT) and exon 6 (192QR) and serum PON1 activity. The genetic polymorphisms and serum activity of PON1 were analyzed in 153 healthy Koreans by using a direct sequencing assay and spectrophotometric method, respectively. A significant linkage disequilibrium (LD) was observed between all tested single nucleotide polymorphisms, with the strongest LD observed between 17899insdelTT and 192QR (D' = 0.984). The 17899insdelTT, 17974CT and 192QR genetic polymorphisms were associated with significant differences in serum paraoxonase activity. In multiple regression analyses, smoking, triglyceride level, high density lipoprotein (HDL) level, and the 17899insdelTT and 192QR genetic polymorphisms were significant determinants of serum paraoxonase activity, while age, smoking, triglyceride level, HDL level, and the 192QR genetic polymorphism were significant determinants of serum arylesterase activity. These results suggest that although the 192QR genetic polymorphism in the coding region of PON1 is primarily associated with serum PON1 activity, the intronic polymorphisms are also involved in serum PON1 activity, and this association may be mediated by LD. PMID- 21655057 TI - Norovirus infections in asymptomatic food handlers in elementary schools without norovirus outbreaks in some regions of Incheon, Korea. AB - Norovirus (NV) has caused large outbreaks of gastroenteritis in schools. Studies of NV epidemiology in schools related to NV outbreaks have been frequently reported. However, reports of that in schools without outbreaks are not found. Presently, NV molecular epidemiology surveillance was carried out in asymptomatic food handlers working at nonoutbreak elementary schools in Incheon, Korea, in March, April and December, 2009. NV prevalence was examined by real-time reverse transcription-PCR (RT-PCR) and the positive products were re-evaluated by conventional RT-PCR for sequencing. Fecal samples (n = 776) were collected from 776 food handlers in 60 schools. NV was detected in 26 of them (3.4%). Of these, 17 (65%) were positive for NV GII and 10 (38%) were positive for NV GI. Of the 26 samples, 19 were positive by conventional RT-PCR. Sequencing of these 19 strains revealed GII/4 (n = 5), GI/6 (n = 3), GI/14 (n = 2), GII/8 (n = 2), GI/2 (n = 2), GI/10 (n = 1), GII/1 (n = 1), GII/3 (n = 1), GII/7 (n = 1), and GII/16 (n = 1). In this survey, the food handler population unrelated to NV outbreaks was found to normally contain asymptomatic carriers of NV. The excretion of NV from asymptomatic food handlers should be an infection source of NV outbreaks. PMID- 21655056 TI - Mesenchymal stem cells improve wound healing in vivo via early activation of matrix metalloproteinase-9 and vascular endothelial growth factor. AB - We investigated the effects of mesenchymal stem cells (MSCs) on wound healing using a three-dimensional (3D) collagen gel scaffold. Three circular full thickness skin defects were created on the back of Sprague-Dawley rats. One site was covered with a 3D collagen gel containing 2 * 10(6) MSCs (MSCs+/3D collagen+). Another site was replaced with a 3D collagen gel without MSCs and the third site was left empty. The wound size was significantly reduced in the MSCs+/3D collagen+ sites. MSCs+/3D collagen+ sites exhibited the most neovascularization. FISH showed that Y-chromosome possessing cells were found within the dermis of MSCs+/3D collagen+ sites. Gelatin zymography revealed that the most intense expression of MMP-9 was detected early in the MSCs+/3D collagen+ sites. Our results indicate that MSCs upregulate the early expression of MMP-9 which induces the early mobilization of VEGF. Thus, MSCs appear to accelerate significantly wound healing via early activation of MMP-9 and VEGF. PMID- 21655058 TI - Determination of malignant and invasive predictors in branch duct type intraductal papillary mucinous neoplasms of the pancreas: a suggested scoring formula. AB - Prediction of malignancy or invasiveness of branch duct type intraductal papillary mucinous neoplasm (Br-IPMN) is difficult, and proper treatment strategy has not been well established. The authors investigated the characteristics of Br IPMN and explored its malignancy or invasiveness predicting factors to suggest a scoring formula for predicting pathologic results. From 1994 to 2008, 237 patients who were diagnosed as Br-IPMN at 11 tertiary referral centers in Korea were retrospectively reviewed. The patients' mean age was 63.1 +/- 9.2 yr. One hundred ninty-eight (83.5%) patients had nonmalignant IPMN (81 adenoma, 117 borderline atypia), and 39 (16.5%) had malignant IPMN (13 carcinoma in situ, 26 invasive carcinoma). Cyst size and mural nodule were malignancy determining factors by multivariate analysis. Elevated CEA, cyst size and mural nodule were factors determining invasiveness by multivariate analysis. Using the regression coefficient for significant predictors on multivariate analysis, we constructed a malignancy-predicting scoring formula: 22.4 (mural nodule [0 or 1]) + 0.5 (cyst size [mm]). In invasive IPMN, the formula was expressed as invasiveness predicting score = 36.6 (mural nodule [0 or 1]) + 32.2 (elevated serum CEA [0 or 1]) + 0.6 (cyst size [mm]). Here we present a scoring formula for prediction of malignancy or invasiveness of Br-IPMN which can be used to determine a proper treatment strategy. PMID- 21655059 TI - Morphine attenuates endothelial cell adhesion molecules induced by the supernatant of LPS-stimulated colon cancer cells. AB - A large reservoir of bacterial lipopolysaccharide (LPS) is available in the colon and this could promote colon cancer metastasis by enhancing tumor cell adhesion, intravasation, and extravasation. Furthermore, adhesion molecules like ICAM-1, VCAM-1, and E-selectin play important roles in the adhesion of tumor cells to endothelium. This study was designed to determine whether morphine can attenuate the expressions of adhesion molecules up-regulated by the supernatant of LPS stimulated HCT 116 colon cancer cells (LPS-Sup). In this study, we divided to three groups by cell-growth medium of human umbilical vascular endothelial cells (HUVECs): the control group was incubated in growth factor-free endothelial medium, the Sup group was incubated in the supernatant of HCT 116 cells (Sup), and the LPS-Sup group was incubated in LPS-Sup. To observe effect of morphine to the adhesion molecules expressions in the LPS-Sup group, we co-treated morphine with LPS or added it to LPS-Sup. Adhesion molecule expressions on HUVECs in all three groups were measured during incubation period. Consquentially, ICAM-1, VCAM 1, and E-selectin expressions on HUVECs were significantly lower when morphine was co-treated with LPS than not co-treated. Thus, we suggest that morphine affects the expressions of adhesion molecules primarily by attenuating LPS stimuli on tumor cells. PMID- 21655060 TI - Relationship between chronic kidney disease and risk of coronary heart disease in Korean men. AB - There have been many epidemiological researches of chronic kidney disease (CKD), accompanied by an increase in the incidence of coronary heart disease (CHD). However, as far as we know, little research has been done to examine the extent of the relationship between CKD and CHD as estimated by Framingham risk score (FRS) in Korean men. CKD was defined as either proteinuria or an eGFR of < 60 mL/min per 1.73 m(2). The FRS has been used to predict the 10-yr risk of coronary events and usually divided into three levels of risk < 10% (low), 10%-19% (intermediate) and >= 20% (high). We defined FRS >= 10% as more-than-a-moderate CHD risk group and FRS >= 20% as a high CHD risk group, respectively. After adjusting for covariates, multivariable-adjusted logistic regression analyses showed a strong statistical significant relationship between CKD and high risk of CHD (adjusted OR, 1.95 [95% CI, 1.32-2.87]). Dipstick urinalysis and eGFR can be readily measured in most clinical settings. The measurement of kidney function may represent a relatively inexpensive and efficient way to identify individuals at higher risk for CHD. PMID- 21655061 TI - Carcinoembryonic antigen level can be overestimated in metabolic syndrome. AB - Carcinoembryonic antigen (CEA) levels can be affected by many factors and metabolic syndrome is also a candidate. This study examined the relationship between CEA levels and metabolic syndrome using the data of 32,897 healthy Koreans. Fecal occult blood tests were also performed. Subjects with colorectal carcinoma were excluded. Subjects were classified by their smoking status, metabolic syndrome and its components. Prevalence of metabolic syndrome and its all components showed a significant increase according to the quartile of serum CEA concentration (P < 0.001). Increased numbers of metabolic syndrome components showed a positive association with CEA levels (P-trend < 0.001). The odds ratios for the highest CEA quartile vs the lowest serum CEA quartile significantly increased in the presence of metabolic syndrome and its components. After adjusting for age, gender and smoking status, metabolic syndrome, low high density lipoprotein cholesterol and elevated blood pressure had higher odds ratios (OR) of the highest CEA quartile compared with the lowest serum CEA quartile (OR = 1.125, 95% CI = 1.030 to 1.222, P = 0.009; OR = 1.296, 95% CI = 1.195 to 1.405, P < 0.001; OR = 1.334, 95% CI = 1.229 to 1.448, P < 0.001, respectively). These results indicate that metabolic syndrome is associated with CEA value, which may lead to a misunderstanding of the CEA levels. PMID- 21655062 TI - Effect of aspirin on the expression of hepatocyte NF-kappaB and serum TNF-alpha in streptozotocin-induced type 2 diabetic rats. AB - Aspirin is a kind of anti-inflammatory drug and may be used to reverse hyperglycemia, hyperinsulinemia, and dyslipidemia by improving insulin resistance. We hypothesized that aspirin improves insulin resistance in type 2 diabetes by inhibiting hepatic nuclear factor kappa-beta (NF-kappaB) activation and serum tumor necrosis factor-alpha (TNF-alpha). Adult male Wistar rats were randomly divided into four groups: control, untreated diabetic, diabetic treated with metformin (100 mg/kg/day), and diabetic treated with aspirin (120 mg/kg/day). Diabetes was induced by high-fat feeding and a low dose of streptozotocin (30 mg/kg). After treatment, plasma glucose, insulin, lipids, free fatty acids (FFAs) concentrations and serum TNF-alpha were determined. The expression of NF-kappaB in hepatocytes was analyzed by immunohistochemistry and western blot. The results showed administration of aspirin caused no significant lowering in fasting glucose level but significant reduction of hepatic NF-kappaB expression and serum TNF-alpha level with improved insulin resistance compared to the diabetic group. The relevant analysis showed positive correlation between the expression of homeostasis model assessment-insulin resistance (HOMA-IR) and NF kappaB (r = 0.799, P < 0.01); HOMA-IR and serum TNF-alpha (r = 0.790, P < 0.01). It is concluded that aspirin improves insulin resistance by inhibiting hepatic NF kappaB activation and TNF-alpha level in streptozotocin-induced type 2 diabetic rats. PMID- 21655063 TI - Impact of visceral adiposity measured by abdominal computed tomography on pulmonary function. AB - Although an inverse relationship between abdominal adiposity and pulmonary function has been suggested, direct measurement of abdominal adipose tissue has rarely been attempted. Our object is to determine the impact of abdominal adiposity on pulmonary function by directly measuring abdominal adipose tissue with abdominal computed tomography (CT). In this cross-sectional study, we included never-smokers between the ages of 18 and 85 yr, who had undergone spirometry and abdominal adipose tissue analysis with CT scans during November 1, 2005 to October 31, 2009 as part of the comprehensive health examination. Among a total of 3,469 participants, 890 (25.7%) were male. The mean body mass index and waist circumference among males and females were 24.6 kg/m(2) and 87.8 cm and 23.0 kg/m(2) and 83.0 cm, respectively. Although total adipose tissue (TAT) of the abdomen in males (269.1 cm(2)) was similar to that in females (273.6 cm(2)), the ratio of visceral adipose tissue (VAT)/subcutaneous adipose tissue (SAT) was different; 0.99 in males and 0.50 in females. In males, TAT, SAT, and VAT were inversely associated with the absolute value of forced vital capacity (FVC), and TAT and VAT were inversely associated with forced expiratory volume in one second (FEV(1)). However, in females, TAT and VAT, but not SAT, were inversely associated with absolute FVC and FEV(1) values. In conclusion, the amount of abdominal adipose tissue directly measured using CT is inversely associated with lung function. PMID- 21655064 TI - Effects of scutellarin on MUC5AC mucin production induced by human neutrophil elastase or interleukin 13 on airway epithelial cells. AB - Scutellarin is a flavonoid extracted from a traditional Chinese herb, Erigeron breviscapus. The present study investigated the effect of scutellarin on MUC5AC mucin production and the possible mechanism. Human bronchial epithelial 16 (HBE16) cells were pretreated with scutellarin for 60 min, and then exposed to human neutrophil elastase (HNE) or interleukin (IL)-13 for 12 hr. RT-PCR and ELISA were performed to measure the amount of MUC5AC mucin production. The results showed that scutellarin inhibited MUC5AC expression both in mRNA and protein level induced by HNE in a concentration-dependent manner. However, scutellarin failed to inhibit MUC5AC mucin production induced by IL-13. To investigate the intracellular mechanisms associated with the effect of scutellarin on MUC5AC mucin production, western blotting was carried out to examine the phosphorylation of protein kinase C (PKC), signal transducer and activator of transcription 6 (STAT6) and extracellular signal-regulated kinase 1/2 (ERK1/2). The phosphorylation of PKC and ERK1/2 was attenuated after treatment with scutellarin, whereas STAT6 was not significantly affected. Therefore, it is suggested that scutellarin down-regulates MUC5AC mucin production on HBE16 cells via ERK-dependent and PKC-dependent pathways. PMID- 21655066 TI - Seroepidemiology of hepatitis A in Korea: changes over the past 30 years. AB - This study aimed to assess the immune status of the Korean population against hepatitis A virus (HAV). Residual serum samples from 2008 to 2010 were collected from diagnostic laboratories and a total of 1,872 samples were analyzed. Anti-HAV seroprevalence was 57.3% in subjects aged 1-4 yr, 69.8% at 5-9 yr and decreased to 38.8% at 10-14 yr, 13.0% at 15-19 yr, and 11.7% at 20-29 yr. Seroprevalence increased with increasing age: 52.2% at 30-39 yr, 83.2% at 40-49 yr, 81.4% at 50 59 yr, 93.2% at 60-69 yr, and 95.1% at 70-79 yr. The most susceptible age group consisted of subjects aged 10-29 yr, especially those aged 20-29 yr. This pattern is markedly different from that in the past 3 decades, where the most susceptible group had consisted of children aged less than 10 yr and almost all subjects aged more than 20 yr had developed anti-HAV antibodies. Because of improvements in hygiene and introduction of hepatitis A vaccine, the age demographic of the susceptible population has shifted. These data are important for creating new prevention measures, including vaccination policies, to prevent and control outbreaks of hepatitis A in Korea. PMID- 21655065 TI - Efficacy of levofloxacin and rifaximin based quadruple therapy in Helicobacter pylori associated gastroduodenal disease: a double-blind, randomized controlled trial. AB - The aim of this study was to evaluate the efficacy of levofloxacin and rifaximin based quadruple regimen as first-line treatment for Helicobacter pylori infection. A prospectively randomized, double-blinded, parallel group, comparative study was performed. Three hundred consecutive H. pylori positive patients were randomized to receive: omeprazole, amoxicillin, clarithromycin (OAC); omeprazole, amoxicillin, levofloxacin (OAL); and omeprazole, amoxicillin, levofloxacin, rifaximin (OAL-R). The eradication rates in the intention to treat (ITT) and per protocol (PP) analyses were: OAC, 77.8% and 85.6%; OAL, 65.3% and 73.6%; and OAL-R, 74.5% and 80.2%. The eradication rate achieved with OAC was higher than with OAL on the ITT (P = 0.05) and PP analysis (P = 0.04). OAL-R regimen was not inferior to OAC. The frequency of moderate to severe adverse effects was significantly higher in OAC treatment group. Especially, diarrhea was most common complaint, and there was a significantly low rate of moderate to severe diarrhea with the rifaximin containing regimen. In conclusion, the levofloxacin and rifaximin based regimen comes up to the standard triple therapy, but has a limited efficacy in a Korean cohort. The rifaximin containing regimen has a very high safety profile for H. pylori eradication therapy. PMID- 21655067 TI - Association of serum retinol binding protein 4 with adiposity and pubertal development in Korean children and adolescents. AB - Retinol binding protein 4 (RBP4) has been postulated to provide a new link between obesity and insulin resistance. We aimed to assess the relationship between serum RBP4 and insulin resistance by investigating serum RBP4 levels in children and adolescents according to degree of obesity and pubertal stage. A total of 103 (30 lean, 39 overweight, 34 obese) were evaluated for serum RBP4, adiponectin, insulin, glucose and lipid profiles. RBP4 levels of obese and overweight groups were higher than those of lean group. RBP4 level was higher in pubertal group than in prepubertal group. RBP4 was positively correlated with age, height, weight, body mass index (BMI), abdominal circumference, systolic blood pressure, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol and triglyceride, and inversely with adiponectin. In the multiple linear regression analysis, RBP4 was found to be independently associated with pubertal stage, BMI and triglyceride but not with HOMA-IR. In conclusion, serum RBP4 level is related with degree of adiposity and pubertal development. The association of RBP4 with insulin resistance is supposed to be secondary to the relation between RBP4 and adipose tissue in children and adolescents. PMID- 21655068 TI - Effects of level of consciousness on urodynamic procedure in female cats. AB - Urodynamic evaluation is an invasive and uncomfortable procedure that can cause physical distress and is difficult to perform in uncooperative patients. The aim of this study was to evaluate the effects of consciousness on urodynamic evaluation in an animal model. Repeated cystometry, electromyogram, and measurement of serum cortisol concentrations were performed in female cats under conscious (CON), conscious sedation (CS) and deep anesthesia (DA) conditions. Urodynamic evaluation showed that there were no statistical differences in maximum detrusor pressure or bladder capacity observed among the three conditions. Under the DA condition, but not the CON and CS conditions, bladder contraction was accompanied by an un-relaxed anal sphincter. Residue urine volume significantly increased in the DA condition compared to the CON and CS conditions. The levels of serum cortisol significantly increased after performing urodynamic evaluation under the CON condition, whereas these levels were not significantly increased under the CS and DA conditions. This study showed that conscious sedation has no adverse effects on the urodynamic variables, and that it significantly reduces distress in cats undergoing the examination. These results may provide novel insights for performing urodynamic studies in uncooperative patients. PMID- 21655069 TI - Prostate volume has prognostic value only in pathologic T2 radical prostatectomy specimens. AB - The objective of this study was to evaluate the prognostic roles of the prostate volume, tumor volume, and tumor percentage as a function of the pathologic T stage in radical prostatectomy specimens. This study included 259 patients who underwent radical prostatectomy between 2005 and 2010. The mean follow-up period was 41.2 months. In all of the specimens, prostate volume (P = 0.021), the Gleason score (P = 0.035), and seminal vesicle invasion (P = 0.012) were independent predictors of biochemical recurrence (BCR). In the T2 group, multivariate analysis showed that the BCR was significantly associated with prostate specific antigen (PSA) (P = 0.028), a lower prostate volume (P = 0.004), and the Gleason score (P = 0.040). The Kaplan-Meier survival curve showed that a smaller prostate volume was significantly associated with a greater risk of BCR (< 30 vs >= 30 mL; P = 0.010). In the T3 group, patients with seminal vesicle invasion had a significantly shorter mean BCR-free survival (P = 0.030). In this study, tumor volume and tumor percentage did not predict BCR. Notably, a lower prostate volume is an independent predictor for BCR only in the organ-confined radical prostatectomy specimens. But, prostate volume could not predict BCR in most locally advanced tumors. PMID- 21655070 TI - Spinal cord injury markedly altered protein expression patterns in the affected rat urinary bladder during healing stages. AB - The influence of spinal cord injury (SCI) on protein expression in the rat urinary bladder was assessed by proteomic analysis at different time intervals post-injury. After contusion SCI between T9 and T10, bladder tissues were processed by 2-DE and MALDI-TOF/MS at 6 hr to 28 days after SCI to identify proteins involved in the healing process of SCI-induced neurogenic bladder. Approximately 1,000 spots from the bladder of SCI and sham groups were visualized and identified. At one day after SCI, the expression levels of three protein were increased, and seven spots were down-regulated, including heat shock protein 27 (Hsp27) and heat shock protein 20 (Hsp20). Fifteen spots such as S100-A11 were differentially expressed seven days post-injury, and seven proteins including transgelin had altered expression patterns 28 days after injury. Of the proteins with altered expression levels, transgelin, S100-A11, Hsp27 and Hsp20 were continuously and variably expressed throughout the entire post-SCI recovery of the bladder. The identified proteins at each time point belong to eight functional categories. The altered expression patterns identified by 2-DE of transgelin and S100-A11 were verified by Western blot. Transgelin and protein S100-A11 may be candidates for protein biomarkers in the bladder healing process after SCI. PMID- 21655071 TI - Waldenstrom macroglobulinemia with CD5+ expression presented as cryoglobulinemic glomerulonephropathy: a case report. AB - Waldenstrom macroglobulinemia (WM) is a B-cell lymphoproliferative disorder associated with bone marrow involvement of lymphoplasmacytic lymphoma (LPL) and an IgM monoclonal gammopathy. Generally B-lymphocytes in LPL do not express CD5 that is important for differential diagnosis of B-cell lymphoproliferative disorders. In WM, various renal diseases and type I cryoglobulinemia are well described separately, but cryoglobulinemic glomerulonephropathy is very rarely reported. A 61-yr-old woman complained of generalized edema, cyanosis of the extremities in cold weather, visual disturbance, and pancytopenia. Bone marrow and renal biopsy showed CD5+ expressing B-cells and cryoglobulinemic glomerulonephropathy. With the diagnosis of WM, she received cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and got complete remission. Here, we report a rare case of WM associated with unusual expression of CD5+ B-lymphocytes and cryoglobulinemic glomerulonephropathy, and emphasize the importance of the clinical features in differentiating CD5+ B-cell lymphoproliferative disorders. PMID- 21655072 TI - Lineage switch at relapse of childhood acute leukemia: a report of four cases. AB - Lineage switch in acute leukemia is an uncommon event at relapse, and therefore rarely reported in the literature. Here, we have described the clinical laboratory features of four cases in which the cell lineage switched from acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML). One patient was initially diagnosed with B-ALL, switched to T-ALL at the first relapse, and eventually, AML at the second relapse. A lineage switch represented either relapse of the original clone with heterogeneity at the morphologic level or emergence of a new leukemic clone. Further sequential phenotypic and cytogenetic studies may yield valuable insights into the mechanisms of leukemic recurrence, with possible implications for treatment selection. PMID- 21655073 TI - Synchronous ectopic pancreatoblastoma in a child: a case report. AB - Pancreatoblastoma is a rare primary pancreatic neoplasm of children that may arise in any portion of the pancreas. We report a case of a 3-yr-old boy who presented to with abdominal pain our hospital and a progressive bulge in his right abdomen. Biochemical evaluation and serum levels of tumoral markers were within reference limits. On the computed tomography, two tumors were found. One located in the head of the pancreas; however, a laparotomy revealed that the head of pancreas was compressed but normal. The other was in the left abdomen near the spleen and the tail of the pancreas. The diagnosis of two synchronous pancreatoblastoma originating from the omentum was confirmed by pathology. Therefore, a pancreatoblastoma should be considered when a large well-defined, lobulated, and heterogeneous mass is identified in the pancreas of children. In addition, an ectopic pancreatoblastoma should be considered when identified within or near the ectopic pancreatic tissue. PMID- 21655074 TI - Refractory hypertension and isosexual pseudoprecocious puberty associated with renin-secreting ovarian steroid cell tumor in a girl. AB - Steroid cell tumor, not otherwise specified (NOS), are rare ovarian tumor, in addition, it is more rare in children. The majority of these tumors produce several steroid hormones, particularly testosterone. Estrogen also secreted by steroid cell tumor, NOS, but it is uncommon. Furthermore, hypertension is an infrequent sign in steroid cell tumor, NOS. An 8.5-yr-old girl with hypertension and frequent vaginal spotting visited at our clinic. On laboratory evaluation, secondary hypertension due to an elevated plasma renin level and isosexual pseudoprecocious puberty was diagnosed. Right solid ovarian mass was detected in radiologic tests. She underwent a right ooporectomy and it revealed renin and progesterone receptor positive steroid cell tumor, NOS. After operation, her blood pressure returned to normal level and vaginal bleeding disappeared. Even though this case is very rare, when hypertension coincides with virilization or feminization, a renin-secreting ovarian steroid cell tumor, NOS, should be considered. PMID- 21655075 TI - Clinical application of 7.0 T magnetic resonance images in Gamma Knife radiosurgery for a patient with brain metastases. AB - In the study we assessed the distortion of 7.0 T magnetic resonance (MR) images in reference to 1.5 T MR images in the radiosurgery of metastatic brain tumors. Radiosurgery with Gamma Knife Perfexion was performed for the treatment of a 54 yr-old female patient with multiple brain metastases by the co-registered images of the 7.0 T and 1.5 T magnetic resonance images (MRI). There was no significant discrepancy in the positions of anterior and posterior commissures as well as the locations of four metastatic brain tumors in the co-registered images between 7.0 T and 1.5 T MRI with better visualization of the anatomical details in 7.0 T MR images. This study demonstrates for the first time that 7.0 T MR images can be safely utilized in Perfexion Gamma Knife radiosurgery for the treatment of metastatic brain tumors. Furthermore 7.0 T MR images provide better visualization of brain tumors without image distortion in comparison to 1.5 T MR images. PMID- 21655076 TI - Atypical supernumerary phantom limb and phantom limb pain in two patients with pontine hemorrhage. AB - Phantom limbs are usually observed after amputation of extremities. In patients after a stroke, a similar but rarely occurring phenomenon consisting of the patient experiencing the presence of an additional limb has been described. This phenomenon, generally called supernumerary phantom limb (SPL), may be caused by lesions in the right or left cerebral hemisphere, but has been predominantly reported in patients who have had a right hemispheric stroke. We report two cases of atypical SPL and phantom limb pain (PLP) after pontine hemorrhage. The patients were treated conservatively and their symptoms lasted more than 1 month. This is the first report of SPLs after left pontine hemorrhage, and phantom perception and pain lasted longer than those in previously observed cases. Our results indicate that SPL may be more common than reported; therefore, thorough examinations are essential for the care of stroke patients. PMID- 21655077 TI - Letter to the editor: acute effects of intravenous administration of pamidronate in patients with osteoporosis. PMID- 21655079 TI - Epistasis between beneficial mutations and the phenotype-to-fitness Map for a ssDNA virus. AB - Epistatic interactions between genes and individual mutations are major determinants of the evolutionary properties of genetic systems and have therefore been well documented, but few quantitative data exist on epistatic interactions between beneficial mutations, presumably because such mutations are so much rarer than deleterious ones. We explored epistasis for beneficial mutations by constructing genotypes with pairs of mutations that had been previously identified as beneficial to the ssDNA bacteriophage ID11 and by measuring the effects of these mutations alone and in combination. We constructed 18 of the 36 possible double mutants for the nine available beneficial mutations. We found that epistatic interactions between beneficial mutations were all antagonistic the effects of the double mutations were less than the sums of the effects of their component single mutations. We found a number of cases of decompensatory interactions, an extreme form of antagonistic epistasis in which the second mutation is actually deleterious in the presence of the first. In the vast majority of cases, recombination uniting two beneficial mutations into the same genome would not be favored by selection, as the recombinant could not outcompete its constituent single mutations. In an attempt to understand these results, we developed a simple model in which the phenotypic effects of mutations are completely additive and epistatic interactions arise as a result of the form of the phenotype-to-fitness mapping. We found that a model with an intermediate phenotypic optimum and additive phenotypic effects provided a good explanation for our data and the observed patterns of epistatic interactions. PMID- 21655080 TI - DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. AB - Nonhomologous end-joining (NHEJ) is the primary DNA repair pathway thought to underlie chromosomal translocations and other genomic rearrangements in somatic cells. The canonical NHEJ pathway, including DNA ligase IV (Lig4), suppresses genomic instability and chromosomal translocations, leading to the notion that a poorly defined, alternative NHEJ (alt-NHEJ) pathway generates these rearrangements. Here, we investigate the DNA ligase requirement of chromosomal translocation formation in mouse cells. Mammals have two other DNA ligases, Lig1 and Lig3, in addition to Lig4. As deletion of Lig3 results in cellular lethality due to its requirement in mitochondria, we used recently developed cell lines deficient in nuclear Lig3 but rescued for mitochondrial DNA ligase activity. Further, zinc finger endonucleases were used to generate DNA breaks at endogenous loci to induce translocations. Unlike with Lig4 deficiency, which causes an increase in translocation frequency, translocations are reduced in frequency in the absence of Lig3. Residual translocations in Lig3-deficient cells do not show a bias toward use of pre-existing microhomology at the breakpoint junctions, unlike either wild-type or Lig4-deficient cells, consistent with the notion that alt-NHEJ is impaired with Lig3 loss. By contrast, Lig1 depletion in otherwise wild-type cells does not reduce translocations or affect microhomology use. However, translocations are further reduced in Lig3-deficient cells upon Lig1 knockdown, suggesting the existence of two alt-NHEJ pathways, one that is biased toward microhomology use and requires Lig3 and a back-up pathway which does not depend on microhomology and utilizes Lig1. PMID- 21655081 TI - Genomic prevalence of heterochromatic H3K9me2 and transcription do not discriminate pluripotent from terminally differentiated cells. AB - Cellular differentiation entails reprogramming of the transcriptome from a pluripotent to a unipotent fate. This process was suggested to coincide with a global increase of repressive heterochromatin, which results in a reduction of transcriptional plasticity and potential. Here we report the dynamics of the transcriptome and an abundant heterochromatic histone modification, dimethylation of histone H3 at lysine 9 (H3K9me2), during neuronal differentiation of embryonic stem cells. In contrast to the prevailing model, we find H3K9me2 to occupy over 50% of chromosomal regions already in stem cells. Marked are most genomic regions that are devoid of transcription and a subgroup of histone modifications. Importantly, no global increase occurs during differentiation, but discrete local changes of H3K9me2 particularly at genic regions can be detected. Mirroring the cell fate change, many genes show altered expression upon differentiation. Quantitative sequencing of transcripts demonstrates however that the total number of active genes is equal between stem cells and several tested differentiated cell types. Together, these findings reveal high prevalence of a heterochromatic mark in stem cells and challenge the model of low abundance of epigenetic repression and resulting global basal level transcription in stem cells. This suggests that cellular differentiation entails local rather than global changes in epigenetic repression and transcriptional activity. PMID- 21655082 TI - Revisiting heterochromatin in embryonic stem cells. PMID- 21655084 TI - Distinct functional constraints partition sequence conservation in a cis regulatory element. AB - Different functional constraints contribute to different evolutionary rates across genomes. To understand why some sequences evolve faster than others in a single cis-regulatory locus, we investigated function and evolutionary dynamics of the promoter of the Caenorhabditis elegans unc-47 gene. We found that this promoter consists of two distinct domains. The proximal promoter is conserved and is largely sufficient to direct appropriate spatial expression. The distal promoter displays little if any conservation between several closely related nematodes. Despite this divergence, sequences from all species confer robustness of expression, arguing that this function does not require substantial sequence conservation. We showed that even unrelated sequences have the ability to promote robust expression. A prominent feature shared by all of these robustness promoting sequences is an AT-enriched nucleotide composition consistent with nucleosome depletion. Because general sequence composition can be maintained despite sequence turnover, our results explain how different functional constraints can lead to vastly disparate rates of sequence divergence within a promoter. PMID- 21655083 TI - Mammalian BTBD12 (SLX4) protects against genomic instability during mammalian spermatogenesis. AB - The mammalian ortholog of yeast Slx4, BTBD12, is an ATM substrate that functions as a scaffold for various DNA repair activities. Mutations of human BTBD12 have been reported in a new sub-type of Fanconi anemia patients. Recent studies have implicated the fly and worm orthologs, MUS312 and HIM-18, in the regulation of meiotic crossovers arising from double-strand break (DSB) initiating events and also in genome stability prior to meiosis. Using a Btbd12 mutant mouse, we analyzed the role of BTBD12 in mammalian gametogenesis. BTBD12 localizes to pre meiotic spermatogonia and to meiotic spermatocytes in wildtype males. Btbd12 mutant mice have less than 15% normal spermatozoa and are subfertile. Loss of BTBD12 during embryogenesis results in impaired primordial germ cell proliferation and increased apoptosis, which reduces the spermatogonial pool in the early postnatal testis. During prophase I, DSBs initiate normally in Btbd12 mutant animals. However, DSB repair is delayed or impeded, resulting in persistent gammaH2AX and RAD51, and the choice of repair pathway may be altered, resulting in elevated MLH1/MLH3 focus numbers at pachynema. The result is an increase in apoptosis through prophase I and beyond. Unlike yeast Slx4, therefore, BTBD12 appears to function in meiotic prophase I, possibly during the recombination events that lead to the production of crossovers. In line with its expected regulation by ATM kinase, BTBD12 protein is reduced in the testis of Atm(-/-) males, and Btbd12 mutant mice exhibit increased genomic instability in the form of elevated blood cell micronucleus formation similar to that seen in Atm(-/-) males. Taken together, these data indicate that BTBD12 functions throughout gametogenesis to maintain genome stability, possibly by co-ordinating repair processes and/or by linking DNA repair events to the cell cycle via ATM. PMID- 21655085 TI - FGF signaling regulates the number of posterior taste papillae by controlling progenitor field size. AB - The sense of taste is fundamental to our ability to ingest nutritious substances and to detect and avoid potentially toxic ones. Sensory taste buds are housed in papillae that develop from epithelial placodes. Three distinct types of gustatory papillae reside on the rodent tongue: small fungiform papillae are found in the anterior tongue, whereas the posterior tongue contains the larger foliate papillae and a single midline circumvallate papilla (CVP). Despite the great variation in the number of CVPs in mammals, its importance in taste function, and its status as the largest of the taste papillae, very little is known about the development of this structure. Here, we report that a balance between Sprouty (Spry) genes and Fgf10, which respectively antagonize and activate receptor tyrosine kinase (RTK) signaling, regulates the number of CVPs. Deletion of Spry2 alone resulted in duplication of the CVP as a result of an increase in the size of the placode progenitor field, and Spry1(-/-);Spry2(-/-) embryos had multiple CVPs, demonstrating the redundancy of Sprouty genes in regulating the progenitor field size. By contrast, deletion of Fgf10 led to absence of the CVP, identifying FGF10 as the first inductive, mesenchyme-derived factor for taste papillae. Our results provide the first demonstration of the role of epithelial-mesenchymal FGF signaling in taste papilla development, indicate that regulation of the progenitor field size by FGF signaling is a critical determinant of papilla number, and suggest that the great variation in CVP number among mammalian species may be linked to levels of signaling by the FGF pathway. PMID- 21655086 TI - Nuclear accumulation of stress response mRNAs contributes to the neurodegeneration caused by Fragile X premutation rCGG repeats. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in Fragile X premutation carriers. Previous studies found that Fragile X rCGG repeats are sufficient to cause neurodegeneration and that the rCGG repeat-binding proteins Pur alpha and hnRNP A2/B1 can modulate rCGG-mediated neuronal toxicity. To explore the role of Pur alpha in rCGG-mediated neurodegeneration further, we took a proteomic approach and identified more than 100 proteins that interact with Pur alpha. Of particular interest is Rm62, the Drosophila ortholog of p68 RNA helicase, which could modulate rCGG-mediated neurodegeneration. Here we show that rCGG repeats decreased the expression of Rm62 posttranscriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional mRNAs involved in stress and immune responses. Together these findings suggest that abnormal nuclear accumulation of these mRNAs, likely as a result of impaired nuclear export, could contribute to FXTAS pathogenesis. PMID- 21655087 TI - Chk2 and p53 are haploinsufficient with dependent and independent functions to eliminate cells after telomere loss. AB - The mechanisms that cells use to monitor telomere integrity, and the array of responses that may be induced, are not fully defined. To date there have been no studies in animals describing the ability of cells to survive and contribute to adult organs following telomere loss. We developed assays to monitor the ability of somatic cells to proliferate and differentiate after telomere loss. Here we show that p53 and Chk2 limit the growth and differentiation of cells that lose a telomere. Furthermore, our results show that two copies of the genes encoding p53 and Chk2 are required for the cell to mount a rapid wildtype response to a missing telomere. Finally, our results show that, while Chk2 functions by activating the p53-dependent apoptotic cascade, Chk2 also functions independently of p53 to limit survival. In spite of these mechanisms to eliminate cells that have lost a telomere, we find that such cells can make a substantial contribution to differentiated adult tissues. PMID- 21655088 TI - Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. AB - CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositide phosphatase FIG4/SAC3. Affected individuals are compound heterozygotes carrying the missense allele FIG4-I41T in combination with a null allele. Analysis using the yeast two-hybrid system demonstrated that the I41T mutation impairs interaction of FIG4 with the scaffold protein VAC14. The critical role of this interaction was confirmed by the demonstration of loss of FIG4 protein in VAC14 null mice. We developed a mouse model of CMT4J by expressing a Fig4-I41T cDNA transgene on the Fig4 null background. Expression of the mutant transcript at a level 5 * higher than endogenous Fig4 completely rescued lethality, whereas 2 * expression gave only partial rescue, providing a model of the human disease. The level of FIG4-I41T protein in transgenic tissues is only 2% of that predicted by the transcript level, as a consequence of the protein instability caused by impaired interaction of the mutant protein with VAC14. Analysis of patient fibroblasts demonstrated a comparably low level of mutant I41T protein. The abundance of FIG4-I41T protein in cultured cells is increased by treatment with the proteasome inhibitor MG-132. The data demonstrate that FIG4-I41T is a hypomorphic allele encoding a protein that is unstable in vivo. Expression of FIG4-I41T protein at 10% of normal level is sufficient for long-term survival, suggesting that patients with CMT4J could be treated by increased production or stabilization of the mutant protein. The transgenic model will be useful for testing in vivo interventions to increase the abundance of the mutant protein. PMID- 21655090 TI - CorE from Myxococcus xanthus is a copper-dependent RNA polymerase sigma factor. AB - The dual toxicity/essentiality of copper forces cells to maintain a tightly regulated homeostasis for this metal in all living organisms, from bacteria to humans. Consequently, many genes have previously been reported to participate in copper detoxification in bacteria. Myxococcus xanthus, a prokaryote, encodes many proteins involved in copper homeostasis that are differentially regulated by this metal. A sigma factor of the ECF (extracytoplasmic function) family, CorE, has been found to regulate the expression of the multicopper oxidase cuoB, the P1B type ATPases copA and copB, and a gene encoding a protein with a heavy-metal associated domain. Characterization of CorE has revealed that it requires copper to bind DNA in vitro. Genes regulated by CorE exhibit a characteristic expression profile, with a peak at 2 h after copper addition. Expression rapidly decreases thereafter to basal levels, although the metal is still present in the medium, indicating that the activity of CorE is modulated by a process of activation and inactivation. The use of monovalent and divalent metals to mimic Cu(I) and Cu(II), respectively, and of additives that favor the formation of the two redox states of this metal, has revealed that CorE is activated by Cu(II) and inactivated by Cu(I). The activation/inactivation properties of CorE reside in a Cys-rich domain located at the C terminus of the protein. Point mutations at these residues have allowed the identification of several Cys involved in the activation and inactivation of CorE. Based on these data, along with comparative genomic studies, a new group of ECF sigma factors is proposed, which not only clearly differs mechanistically from the other sigma factors so far characterized, but also from other metal regulators. PMID- 21655089 TI - Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. AB - Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93*10(-10)) and BMP2 (rs4813802, P = 4.65*10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33*10(-8)) and rs11632715 (P = 2.30*10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases. PMID- 21655091 TI - Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-Fos expression in breast cancer cells. AB - Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and this activity has been linked to the repression of a limited number of target genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) analysis to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 breast cancer cells. Results showed that PADI4 is enriched in gene promoter regions near transcription start sites (TSSs); and, surprisingly, this pattern of binding is primarily associated with actively transcribed genes. Computational analysis found potential binding sites for Elk 1, a member of the ETS oncogene family, to be highly enriched around PADI4 binding sites; and coimmunoprecipitation analysis then confirmed that Elk-1 physically associates with PADI4. To better understand how PADI4 may facilitate gene transactivation, we then show that PADI4 interacts with Elk-1 at the c-Fos promoter and that, following Epidermal Growth Factor (EGF) stimulation, PADI4 catalytic activity facilitates Elk-1 phosphorylation, histone H4 acetylation, and c-Fos transcriptional activation. These results define a novel role for PADI4 as a transcription factor co-activator. PMID- 21655093 TI - N-acetylglucosamine 6-phosphate deacetylase (nagA) is required for N-acetyl glucosamine assimilation in Gluconacetobacter xylinus. AB - Metabolic pathways for amino sugars (N-acetylglucosamine; GlcNAc and glucosamine; Gln) are essential and remain largely conserved in all three kingdoms of life, i.e., microbes, plants and animals. Upon uptake, in the cytoplasm these amino sugars undergo phosphorylation by phosphokinases and subsequently deacetylation by the enzyme N-acetylglucosamine 6-phosphate deacetylase (nagA) to yield glucosamine-6-phosphate and acetate, the first committed step for both GlcNAc assimilation and amino-sugar-nucleotides biosynthesis. Here we report the cloning of a DNA fragment encoding a partial nagA gene and its implications with regard to amino sugar metabolism in the cellulose producing bacterium Glucoacetobacter xylinus (formally known as Acetobacter xylinum). For this purpose, nagA was disrupted by inserting tetracycline resistant gene (nagA::tet(r); named as DeltanagA) via homologous recombination. When compared to glucose fed conditions, the UDP-GlcNAc synthesis and bacterial growth (due to lack of GlcNAc utilization) was completely inhibited in nagA mutants. Interestingly, that inhibition occured without compromising cellulose production efficiency and its molecular composition under GlcNAc fed conditions. We conclude that nagA plays an essential role for GlcNAc assimilation by G. xylinus thus is required for the growth and survival for the bacterium in presence of GlcNAc as carbon source. Additionally, G. xylinus appears to possess the same molecular machinery for UDP-GlcNAc biosynthesis from GlcNAc precursors as other related bacterial species. PMID- 21655094 TI - EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. AB - Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer. PMID- 21655095 TI - Structure collisions between interacting proteins. AB - Protein-protein interactions take place at defined binding interfaces. One protein may bind two or more proteins at different interfaces at the same time. So far it has been commonly accepted that non-overlapping interfaces allow a given protein to bind other proteins simultaneously while no collisions occur between the binding protein structures. To test this assumption, we performed a comprehensive analysis of structural protein interactions to detect potential collisions. Our results did not indicate cases of biologically relevant collisions in the Protein Data Bank of protein structures. However, we discovered a number of collisions that originate from alternative protein conformations or quaternary structures due to different experimental conditions. PMID- 21655096 TI - Genome-wide profiling of H3K56 acetylation and transcription factor binding sites in human adipocytes. AB - The growing epidemic of obesity and metabolic diseases calls for a better understanding of adipocyte biology. The regulation of transcription in adipocytes is particularly important, as it is a target for several therapeutic approaches. Transcriptional outcomes are influenced by both histone modifications and transcription factor binding. Although the epigenetic states and binding sites of several important transcription factors have been profiled in the mouse 3T3-L1 cell line, such data are lacking in human adipocytes. In this study, we identified H3K56 acetylation sites in human adipocytes derived from mesenchymal stem cells. H3K56 is acetylated by CBP and p300, and deacetylated by SIRT1, all are proteins with important roles in diabetes and insulin signaling. We found that while almost half of the genome shows signs of H3K56 acetylation, the highest level of H3K56 acetylation is associated with transcription factors and proteins in the adipokine signaling and Type II Diabetes pathways. In order to discover the transcription factors that recruit acetyltransferases and deacetylases to sites of H3K56 acetylation, we analyzed DNA sequences near H3K56 acetylated regions and found that the E2F recognition sequence was enriched. Using chromatin immunoprecipitation followed by high-throughput sequencing, we confirmed that genes bound by E2F4, as well as those by HSF-1 and C/EBPalpha, have higher than expected levels of H3K56 acetylation, and that the transcription factor binding sites and acetylation sites are often adjacent but rarely overlap. We also discovered a significant difference between bound targets of C/EBPalpha in 3T3-L1 and human adipocytes, highlighting the need to construct species specific epigenetic and transcription factor binding site maps. This is the first genome-wide profile of H3K56 acetylation, E2F4, C/EBPalpha and HSF-1 binding in human adipocytes, and will serve as an important resource for better understanding adipocyte transcriptional regulation. PMID- 21655098 TI - EGb761, a Ginkgo biloba extract, is effective against atherosclerosis in vitro, and in a rat model of type 2 diabetes. AB - BACKGROUND: EGb761, a standardized Ginkgo biloba extract, has antioxidant and antiplatelet aggregation and thus might protect against atherosclerosis. However, molecular and functional properties of EGb761 and its major subcomponents have not been well characterized. We investigated the effect of EGb761 and its major subcomponents (bilobalide, kaemferol, and quercetin) on preventing atherosclerosis in vitro, and in a rat model of type 2 diabetes. METHODS AND RESULTS: EGb761 (100 and 200 mg/kg) or normal saline (control) were administered to Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, for 6 weeks (from 3 weeks before to 3 weeks after carotid artery injury). Immunohistochemical staining was performed to investigate cell proliferation and apoptosis in the injured arteries. Cell migration, caspase-3 activity and DNA fragmentation, monocyte adhesion, and ICAM-1/VCAM-1 levels were explored in vitro. Treatment with EGb761 dose-dependently reduced intima-media ratio, proliferation of vascular smooth muscle cells (VSMCs) and induced greater apoptosis than the controls. Proliferation and migration of VSMCs in vitro were also decreased by the treatment of EGb761. Glucose homeostasis and circulating adiponectin levels were improved, and plasma hsCRP concentrations were decreased in the treatment groups. Caspase-3 activity and DNA fragmentation increased while monocyte adhesion and ICAM-1/VCAM-1 levels decreased significantly. Among subcomponents of EGb761, kaemferol and quercetin reduced VSMC migration and increased caspase activity. CONCLUSIONS: EGb761 has a protective role in the development of atherosclerosis and is a potential therapeutic agent for preventing atherosclerosis. PMID- 21655097 TI - WHO 2010 guidelines for prevention of mother-to-child HIV transmission in Zimbabwe: modeling clinical outcomes in infants and mothers. AB - BACKGROUND: The Zimbabwean national prevention of mother-to-child HIV transmission (PMTCT) program provided primarily single-dose nevirapine (sdNVP) from 2002-2009 and is currently replacing sdNVP with more effective antiretroviral (ARV) regimens. METHODS: Published HIV and PMTCT models, with local trial and programmatic data, were used to simulate a cohort of HIV infected, pregnant/breastfeeding women in Zimbabwe (mean age 24.0 years, mean CD4 451 cells/uL). We compared five PMTCT regimens at a fixed level of PMTCT medication uptake: 1) no antenatal ARVs (comparator); 2) sdNVP; 3) WHO 2010 guidelines using "Option A" (zidovudine during pregnancy/infant NVP during breastfeeding for women without advanced HIV disease; lifelong 3-drug antiretroviral therapy (ART) for women with advanced disease); 4) WHO "Option B" (ART during pregnancy/breastfeeding without advanced disease; lifelong ART with advanced disease); and 5) "Option B+:" lifelong ART for all pregnant/breastfeeding, HIV-infected women. Pediatric (4-6 week and 18-month infection risk, 2-year survival) and maternal (2- and 5-year survival, life expectancy from delivery) outcomes were projected. RESULTS: Eighteen-month pediatric infection risks ranged from 25.8% (no antenatal ARVs) to 10.9% (Options B/B+). Although maternal short-term outcomes (2- and 5-year survival) varied only slightly by regimen, maternal life expectancy was reduced after receipt of sdNVP (13.8 years) or Option B (13.9 years) compared to no antenatal ARVs (14.0 years), Option A (14.0 years), or Option B+ (14.5 years). CONCLUSIONS: Replacement of sdNVP with currently recommended regimens for PMTCT (WHO Options A, B, or B+) is necessary to reduce infant HIV infection risk in Zimbabwe. The planned transition to Option A may also improve both pediatric and maternal outcomes. PMID- 21655099 TI - Evagination of cells controls bio-silica formation and maturation during spicule formation in sponges. AB - The enzymatic-silicatein mediated formation of the skeletal elements, the spicules of siliceous sponges starts intracellularly and is completed extracellularly. With Suberites domuncula we show that the axial growth of the spicules proceeds in three phases: (I) formation of an axial canal; (II) evagination of a cell process into the axial canal, and (III) assembly of the axial filament composed of silicatein. During these phases the core part of the spicule is synthesized. Silicatein and its substrate silicate are stored in silicasomes, found both inside and outside of the cellular extension within the axial canal, as well as all around the spicule. The membranes of the silicasomes are interspersed by pores of ~ 2 nm that are likely associated with aquaporin channels which are implicated in the hardening of the initial bio-silica products formed by silicatein. We can summarize the sequence of events that govern spicule formation as follows: differential GENETIC READOUT (of silicatein) -> FRACTAL ASSOCIATION of the silicateins -> EVAGINATION of cells by hydro-mechanical forces into the axial canal -> and finally PROCESSIVE BIO-SILICA POLYCONDENSATION around the axial canal. We termed this process, occurring sequentially or in parallel, BIO-INORGANIC SELF-ORGANIZATION. PMID- 21655100 TI - A novel labeling approach identifies three stability levels of acetylcholine receptors in the mouse neuromuscular junction in vivo. AB - BACKGROUND: The turnover of acetylcholine receptors at the neuromuscular junction is regulated in an activity-dependent manner. Upon denervation and under various other pathological conditions, receptor half-life is decreased. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate a novel approach to follow the kinetics of acetylcholine receptor lifetimes upon pulse labeling of mouse muscles with 125I-alpha-bungarotoxin in vivo. In contrast to previous assays where residual activity was measured ex vivo, in our setup the same animals are used throughout the whole measurement period, thereby permitting a dramatic reduction of animal numbers at increased data quality. We identified three stability levels of acetylcholine receptors depending on the presence or absence of innervation: one pool of receptors with a long half-life of ~13 days, a second with an intermediate half-life of ~8 days, and a third with a short half-life of ~1 day. Data were highly reproducible from animal to animal and followed simple exponential terms. The principal outcomes of these measurements were reproduced by an optical pulse-labeling assay introduced recently. CONCLUSIONS/SIGNIFICANCE: A novel assay to determine kinetics of acetylcholine receptor turnover with small animal numbers is presented. Our data show that nerve activity acts on muscle acetylcholine receptor stability by at least two different means, one shifting receptor lifetime from short to intermediate and another, which further increases receptor stability to a long lifetime. We hypothesize on possible molecular mechanisms. PMID- 21655101 TI - The stature of boys is inversely correlated to the levels of their sertoli cell hormones: do the testes restrain the maturation of boys? AB - The testes of preadolescent boys appear to be dormant, as they produce only trace levels of testosterone. However, they release supra-adult levels of Mullerian Inhibiting Substance (MIS, anti-Mullerian hormone) and lesser levels of inhibin B (InhB), for unknown reasons. Boys have a variable rate of maturation, which on average is slower than girls. The height of children relative to their parents is an index of their maturity. We report here that a boy's level of MIS and InhB is stable over time and negatively correlates with his height and his height relative to his parent's height. This suggests that boy's with high levels of MIS and InhB are short because they are immature, rather than because they are destined to be short men. The levels of MIS and InhB in the boys did not correlate with known hormonal modulators of growth, and were additive with age and the growth hormone/IGF1 axis as predictors of a boy's height. If MIS and InhB were causal regulators of maturity, then the inter-boy differences in the levels of these hormone produces variation in maturation equivalent to 18-months of development. MIS and InhB may thus account for most of the variation in the rate of male development. If boys lacked these hormones, then an average 5-year-old boy would be over 5 cm taller than age-matched girls, making boys almost as dimorphic as men, for height. This indicates that boys have a high growth potential that is initially suppressed by their testes. The concept of the childhood testes suppressing an adult male feature appears paradoxical. However, the growth of children requires intergenerational transfer of nutrients. Consequently, the MIS/InhB slowing of male growth may have been historically advantageous, as it would minimizes any sex bias in the maternal cost of early child rearing. PMID- 21655102 TI - Quick and clean cloning: a ligation-independent cloning strategy for selective cloning of specific PCR products from non-specific mixes. AB - We have developed an efficient strategy for cloning of PCR products that contain an unknown region flanked by a known sequence. As with ligation-independent cloning, the strategy is based on homology between sequences present in both the vector and the insert. However, in contrast to ligation-independent cloning, the cloning vector has homology with only one of the two primers used for amplification of the insert. The other side of the linearized cloning vector has homology with a sequence present in the insert, but nested and non-overlapping with the gene-specific primer used for amplification. Since only specific products contain this sequence, but none of the non-specific products, only specific products can be cloned. Cloning is performed using a one-step reaction that only requires incubation for 10 minutes at room temperature in the presence of T4 DNA polymerase to generate single-stranded extensions at the ends of the vector and insert. The reaction mix is then directly transformed into E. coli where the annealed vector-insert complex is repaired and ligated. We have tested this method, which we call quick and clean cloning (QC cloning), for cloning of the variable regions of immunoglobulins expressed in non-Hodgkin lymphoma tumor samples. This method can also be applied to identify the flanking sequence of DNA elements such as T-DNA or transposon insertions, or be used for cloning of any PCR product with high specificity. PMID- 21655103 TI - Inflammatory gene regulatory networks in amnion cells following cytokine stimulation: translational systems approach to modeling human parturition. AB - A majority of the studies examining the molecular regulation of human labor have been conducted using single gene approaches. While the technology to produce multi-dimensional datasets is readily available, the means for facile analysis of such data are limited. The objective of this study was to develop a systems approach to infer regulatory mechanisms governing global gene expression in cytokine-challenged cells in vitro, and to apply these methods to predict gene regulatory networks (GRNs) in intrauterine tissues during term parturition. To this end, microarray analysis was applied to human amnion mesenchymal cells (AMCs) stimulated with interleukin-1beta, and differentially expressed transcripts were subjected to hierarchical clustering, temporal expression profiling, and motif enrichment analysis, from which a GRN was constructed. These methods were then applied to fetal membrane specimens collected in the absence or presence of spontaneous term labor. Analysis of cytokine-responsive genes in AMCs revealed a sterile immune response signature, with promoters enriched in response elements for several inflammation-associated transcription factors. In comparison to the fetal membrane dataset, there were 34 genes commonly upregulated, many of which were part of an acute inflammation gene expression signature. Binding motifs for nuclear factor-kappaB were prominent in the gene interaction and regulatory networks for both datasets; however, we found little evidence to support the utilization of pathogen-associated molecular pattern (PAMP) signaling. The tissue specimens were also enriched for transcripts governed by hypoxia-inducible factor. The approach presented here provides an uncomplicated means to infer global relationships among gene clusters involved in cellular responses to labor-associated signals. PMID- 21655104 TI - Impact of birth weight and early infant weight gain on insulin resistance and associated cardiovascular risk factors in adolescence. AB - BACKGROUND: Low birth weight followed by accelerated weight gain during early childhood has been associated with adverse metabolic and cardiovascular outcomes later in life. The aim of this study was to examine the impact of early infant weight gain on glucose metabolism and cardiovascular risk factors in adolescence and to study if the effect differed between adolescents born small for gestational age (SGA) vs. appropriate for gestational age (AGA). METHODOLOGY/PRINCIPAL FINDINGS: Data from 30 SGA and 57 AGA healthy young Danish adolescents were analysed. They had a mean age of 17.6 years and all were born at term. Data on early infant weight gain from birth to three months as well as from birth to one year were available in the majority of subjects. In adolescence, glucose metabolism was assessed by a simplified intravenous glucose tolerance test and body composition was assessed by dual-energy X-ray absorptiometry. Blood pressures as well as plasma concentrations of triglycerides and cholesterol were measured. Early infant weight gain from birth to three months was positively associated with the fasting insulin concentration, HOMA-IR, basal lipid levels and systolic blood pressure at 17 years. There was a differential effect of postnatal weight gain on HOMA-IR in AGA and SGA participants (P for interaction = 0.03). No significant associations were seen between postnatal weight gain and body composition or parameters of glucose metabolism assessed by the simplified intravenous glucose tolerance test. In subgroup analysis, all associations with early infant weight gain were absent in the AGA group, but the associations with basal insulin and HOMA-IR were still present in the SGA group. CONCLUSION: This study suggests that accelerated growth during the first three months of life may confer an increased risk of later metabolic disturbances--particularly of glucose metabolism--in individuals born SGA. PMID- 21655106 TI - Structural and mechanistic studies of measles virus illuminate paramyxovirus entry. AB - Measles virus (MeV), a member of the paramyxovirus family of enveloped RNA viruses and one of the most infectious viral pathogens identified, accounts for major pediatric morbidity and mortality worldwide although coordinated efforts to achieve global measles control are in place. Target cell entry is mediated by two viral envelope glycoproteins, the attachment (H) and fusion (F) proteins, which form a complex that achieves merger of the envelope with target cell membranes. Despite continually expanding knowledge of the entry strategies employed by enveloped viruses, our molecular insight into the organization of functional paramyxovirus fusion complexes and the mechanisms by which the receptor binding by the attachment protein triggers the required conformational rearrangements of the fusion protein remain incomplete. Recently reported crystal structures of the MeV attachment protein in complex with its cellular receptors CD46 or SLAM and newly developed functional assays have now illuminated some of the fundamental principles that govern cell entry by this archetype member of the paramyxovirus family. Here, we review these advances in our molecular understanding of MeV entry in the context of diverse entry strategies employed by other members of the paramyxovirus family. PMID- 21655107 TI - Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis. AB - Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology. PMID- 21655108 TI - Endemic dengue associated with the co-circulation of multiple viral lineages and localized density-dependent transmission. AB - Dengue is one of the most important infectious diseases of humans and has spread throughout much of the tropical and subtropical world. Despite this widespread dispersal, the determinants of dengue transmission in endemic populations are not well understood, although essential for virus control. To address this issue we performed a phylogeographic analysis of 751 complete genome sequences of dengue 1 virus (DENV-1) sampled from both rural (Dong Thap) and urban (Ho Chi Minh City) populations in southern Viet Nam during the period 2003-2008. We show that DENV-1 in Viet Nam exhibits strong spatial clustering, with likely importation from Cambodia on multiple occasions. Notably, multiple lineages of DENV-1 co circulated in Ho Chi Minh City. That these lineages emerged at approximately the same time and dispersed over similar spatial regions suggests that they are of broadly equivalent fitness. We also observed an important relationship between the density of the human host population and the dispersion rate of dengue, such that DENV-1 tends to move from urban to rural populations, and that densely populated regions within Ho Chi Minh City act as major transmission foci. Despite these fluid dynamics, the dispersion rates of DENV-1 are relatively low, particularly in Ho Chi Minh City where the virus moves less than an average of 20 km/year. These low rates suggest a major role for mosquito-mediated dispersal, such that DENV-1 does not need to move great distances to infect a new host when there are abundant susceptibles, and imply that control measures should be directed toward the most densely populated urban environments. PMID- 21655109 TI - Passively administered pooled human immunoglobulins exert IL-10 dependent anti inflammatory effects that protect against fatal HSV encephalitis. AB - HSV-1 is the leading cause of sporadic encephalitis in humans. HSV infection of susceptible 129S6 mice results in fatal encephalitis (HSE) caused by massive inflammatory brainstem lesions comprising monocytes and neutrophils. During infection with pathogenic microorganisms or autoimmune disease, IgGs induce proinflammatory responses and recruit innate effector cells. In contrast, high dose intravenous immunoglobulins (IVIG) are an effective treatment for various autoimmune and inflammatory diseases because of potent anti-inflammatory effects stemming in part from sialylated IgGs (sIgG) present at 1-3% in IVIG. We investigated the ability of IVIG to prevent fatal HSE when given 24 h post infection. We discovered a novel anti-inflammatory pathway mediated by low-dose IVIG that protected 129S6 mice from fatal HSE by modulating CNS inflammation independently of HSV specific antibodies or sIgG. IVIG suppressed CNS infiltration by pathogenic CD11b(+) Ly6C(high) monocytes and inhibited their spontaneous degranulation in vitro. FcgammaRIIb expression was required for IVIG mediated suppression of CNS infiltration by CD45(+) Ly6C(low) monocytes but not for inhibiting development of Ly6C(high) monocytes. IVIG increased accumulation of T cells in the CNS, and the non-sIgG fraction induced a dramatic expansion of FoxP3(+) CD4(+) T regulatory cells (Tregs) and FoxP3(-) ICOS(+) CD4(+) T cells in peripheral lymphoid organs. Tregs purified from HSV infected IVIG treated, but not control, mice protected adoptively transferred mice from fatal HSE. IL-10, produced by the ICOS(+) CD4(+) T cells that accumulated in the CNS of IVIG treated, but not control mice, was essential for induction of protective anti inflammatory responses. Our results significantly enhance understanding of IVIG's anti-inflammatory and immunomodulatory capabilities by revealing a novel sIgG independent anti-inflammatory pathway responsible for induction of regulatory T cells that secrete the immunosuppressive cytokine IL-10 and further reveal the therapeutic potential of IVIG for treating viral induced inflammatory diseases. PMID- 21655110 TI - A freeze frame view of vesicular stomatitis virus transcription defines a minimal length of RNA for 5' processing. AB - The RNA synthesis machinery of vesicular stomatitis virus (VSV) comprises the genomic RNA encapsidated by the viral nucleocapsid protein (N) and associated with the RNA dependent RNA polymerase, the viral components of which are a large protein (L) and an accessory phosphoprotein (P). The 241 kDa L protein contains all the enzymatic activities necessary for synthesis of the viral mRNAs, including capping, cap methylation and polyadenylation. Those RNA processing reactions are intimately coordinated with nucleotide polymerization such that failure to cap results in termination of transcription and failure to methylate can result in hyper polyadenylation. The mRNA processing reactions thus serve as a critical check point in viral RNA synthesis which may control the synthesis of incorrectly modified RNAs. Here, we report the length at which viral transcripts first gain access to the capping machinery during synthesis. By reconstitution of transcription in vitro with highly purified recombinant polymerase and engineered templates in which we omitted sites for incorporation of UTP, we found that transcripts that were 30-nucleotides in length were uncapped, whereas those that were 31-nucleotides in length contained a cap structure. The minimal RNA length required for mRNA cap addition was also sufficient for methylation since the 31 nucleotide long transcripts were methylated at both ribose-2'-O and guanine-N-7 positions. This work provides insights into the spatial relationship between the active sites for the RNA dependent RNA polymerase and polyribonucleotidyltransferase responsible for capping of the viral RNA. We combine the present findings with our recently described electron microscopic structure of the VSV polymerase and propose a model of how the spatial arrangement of the capping activities of L may influence nucleotide polymerization. PMID- 21655111 TI - Superdominant right coronary artery with absent left circumflex artery. AB - Noninvasive imaging of coronary artery disease is rapidly replacing angiography as the first line of investigation. Multislice CT is the non-invasive modality of choice for imaging coronary artery disease and provides high speed with good spatial resolution. CT coronary angiography in addition to detecting and characterising atherosclerotic coronary artery disease is also a good imaging tool for evaluating anomalies of coronary arteries. Superdominant right coronary artery with absent left circumflex artery is one such rare coronary artery anomaly which is well evaluated with multislice CT angiography. The authors report one such case of superdominant right coronary artery with absent left circumflex artery imaged with 64-slice MDCT. PMID- 21655112 TI - Superselective embolisation for control of intractable epistaxis from maxillary artery injury. AB - Traumatic intractable epistaxis following fractures of the facial and base of skull rarely may be life-threatening. Common sites of injury are the internal carotid and maxillary artery. When conventional methods of arresting haemorrhage fail, the choices are then an open arterial ligation or superselective embolisation. This paper presents a patient with life-threatening epistaxis from a Le Fort type II fracture. Angiography revealed a maxillary artery injury in which superselective embolisation was performed and the haemorrhage was successfully arrested. A literature review of this technique is discussed, including its advantages and the relationship of the internal maxillary artery to facial fractures. PMID- 21655113 TI - Image-guided facet joint injection. AB - Chronic spine pain poses a peculiar diagnostic and therapeutic challenge due to multiple pain sources, overlapping clinical features and nonspecific radiological findings. Facet joint injection is an interventional pain management tool for facet-related spinal pain that can be effectively administered by a radiologist. This technique is the gold standard for identifying facet joints as the source of spinal pain. The major indications for facet injections include strong clinical suspicion of the facet syndrome, focal tenderness over the facet joints, low back pain with normal radiological findings, post-laminectomy syndrome with no evidence of arachnoiditis or recurrent disc disease, and persistent low back pain after spinal fusion. The contraindications are more ancillary, with none being absolute. Like any synovial joint degeneration, inflammation and injury can lead to pain on motion, initiating a vicious cycle of physical deconditioning, irritation of facet innervations and muscle spasm. Image-guided injection of local anesthetic and steroid into or around the facet joint aims to break this vicious cycle and thereby provide pain relief. This outpatient procedure has high diagnostic accuracy, safety and reproducibility but the therapeutic outcome is variable. PMID- 21655115 TI - Imaging overutilisation: Is enough being done globally? PMID- 21655114 TI - Potential targets for molecular imaging of apoptosis resistance in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers, which is mainly a concern in Southeast Asia. Apoptosis resistance in HCC is one of the significant factors for hepatocarcinogenesis and tumour progression. Recent advances of apoptosis resistance mechanisms in HCC could serve as potential targets for molecular imaging, which would be of considerable value to explore the molecular processes involved in HCC progression and to evaluate responses of certain anti-HCC therapies. Disruptions in the balance of anti-apoptotic and pro apoptotic processes have been found to be involved in apoptosis resistance in HCC. Loss of response to death receptors, transformation of growth factor-beta induced apoptosis, upregulation of anti-apoptotic Bcl-2 subgroup, as well as downregulation of pro-apoptotic Bax subgroup and BH3-only subgroup, are associated with apoptosis resistance in HCC. Mutation of p53 gene, dysregulation of NF-kappaB and survivin are also of interest because of their contribution to HCC development. In this review, the aim is to identify potential targets for molecular imaging of apoptosis resistance in HCC. PMID- 21655116 TI - Echocontrast cystosonography versus micturating cystourethrography in the detection of vesicoureteric reflux. AB - PURPOSE: To compare echocontrast cystosonography (ECS) using in-vivo agitated saline with fluoroscopic micturating cystourethrography (MCU) in the detection and grading of vesicoureteric reflux (VUR). MATERIALS AND METHODS: This was a prospective study of 25 children, who had MCU between 2007 and 2009. ECS was performed and findings documented prior to MCU. Baseline renal and bladder sonograms were obtained. The bladder was filled with normal saline followed by introduction of 10-20 mls of air to generate microbubbles. Detection of VUR was based on two sonographic criteria: (1) presence of microbubbles in the pelvicaliceal system (PCS), and (2) increase in dilatation of the PCS. VUR was graded as (1) Grade I: microbubbles seen in ureter only; (2) Grade II: microbubbles seen in non-dilated PCS; and (3) Grade III-V: microbubbles seen in dilated PCS. The ECS findings were compared using MCU as the gold standard. RESULTS: Of the 50 kidney-ureter (K-U) units studied, ECS detected 9 of 10 K-U units with VUR on MCU. ECS did not detect a Grade II VUR. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value for criterion 1 was 90%, 87.5%, 88%, 64.3% and 97%, respectively, compared to criterion 2 which was 70%, 90%, 86%, 64% and 92%, respectively. The grading of VUR was similar on both ECS and MCU except for one case. CONCLUSION: ECS using agitated saline was a sensitive technique for the detection of VUR. ECS grading was comparable with MCU grading of VUR. PMID- 21655117 TI - The surgical management of obesity with emphasis on the role of post operative imaging. AB - The role of surgery in the morbidly obese is becoming more prominent. There are a variety of surgical approaches which can be used and radiology plays a crucial role in post operative follow up, particularly in the management of complications. Many general radiologists remain unfamiliar with both the normal and abnormal appearances after bariatric surgery and this pictorial review aims to bridge this gap. PMID- 21655119 TI - Chemical analysis of nutritional content of prickly pads (Opuntia ficus indica) at varied ages in an organic harvest. AB - Opuntia ficus indica, also known as prickly pads, are an important part of the human diet and are also used as forage for livestock. This is an interesting vegetable due the environmental conditions in which it grows and its resistance to climatic extremes; however, little is known about its nutritional properties, especially in the later stages of maturity. The objective of this study was to determine the composition of organic prickly pads (Opuntia ficus indica) at differing stages of growth maturity. Chemical proximate analysis and mineral constituent analysis at different maturation stages were carried out in this investigation. As a result, older prickly pads were found to be an important source of nutritional components such as calcium. PMID- 21655118 TI - A cost-effectiveness analysis of India's 2008 prohibition of smoking in public places in Gujarat. AB - Tobacco smoking and exposure to secondhand tobacco smoke are associated with disability and premature mortality in low and middle-income countries. The aim of this study was to assess the cost-effectiveness of implementing India's Prohibition of Smoking in Public Places Rules in the state of Gujarat, compared to implementation of a complete smoking ban. Using standard cost-effectiveness analysis methods, the cost of implementing the alternatives was evaluated against the years of life saved and cases of acute myocardial infarction averted by reductions in smoking prevalence and secondhand smoke exposure. After one year, it is estimated that a complete smoking ban in Gujarat would avert 17,000 additional heart attacks and gain 438,000 life years (LY). A complete ban is highly cost-effective when key variables including legislation effectiveness were varied in the sensitivity analyses. Without including medical treatment costs averted, the cost-effectiveness ratio ranges from $2 to $112 per LY gained and $37 to $386 per acute myocardial infarction averted. Implementing a complete smoking ban would be a cost saving alternative to the current partial legislation in terms of reducing tobacco-attributable disease in Gujarat. PMID- 21655120 TI - Receiving an alcohol enquiry from a physician in routine health care in Sweden: a population-based study of gender differences and predictors. AB - Research has shown that the provision of brief interventions in the health care system is effective for reducing hazardous drinking. Using a telephone administered questionnaire, this study provides a population-based investigation on the extent to which physicians address patients' alcohol habits in the Swedish health care system, whether there are gender differences in the extent to which patients receive questions about alcohol, and predictors for receiving such questions. Data were obtained from monthly telephone surveys with around 72,000 people in 2006-2009. Having received an alcohol enquiry was defined as having been asked about one's drinking habits by a physician in any health care visit in the last 12 months. Fourteen percent of the total population had received an alcohol enquiry, but there were considerable gender differences: for hazardous drinkers, 13% of the women and 17% of the men had received an alcohol enquiry; among those with sensible alcohol consumption, 10% of women and 15% of men had received an alcohol enquiry. Patients were more likely to have received an alcohol enquiry if they had self-reported alcohol-related problems, were hazardous drinkers and/or daily smokers. Some of the alcohol enquiry predictors differed by gender; social class was an important predictor for women but not for men. PMID- 21655121 TI - Feeling healthy? A survey of physical and psychological wellbeing of students from seven universities in the UK. AB - University students' physical and psychological health and wellbeing are important and comprise many variables. This study assessed perceived health status in addition to a range of physical and psychological wellbeing indicators of 3,706 undergraduate students from seven universities in England, Wales and Northern Ireland. We compared differences in these variables across males and females, and across the participating universities. The data was collected in 2007-2008. A self-administered questionnaire assessed socio-demographic information (e.g., gender, age), self-reported physical and psychological health data, as well as questions on health awareness, health service use, social support, burdens and stressors and university study related questions. While females generally reported more health problems and psychological burdens, male students felt that they received/had fewer persons to depend on for social support. The comparisons of health and wellbeing variables across the different universities suggested some evidence of 'clustering' of the variables under study, whereby favourable situations would be exhibited by a cluster of the variables that is encountered at some universities; and conversely, the clustering of less favourable variables as exhibited at other universities. We conclude that the level of health complaints and psychological problems/burdens is relatively high and calls for increased awareness of university administrators, leaders and policy makers to the health and well-being needs of their students. The observed clustering effects also indicated the need for local (university-specific) health and wellbeing profiles as basis and guidance for relevant health promotion programmes at universities. PMID- 21655122 TI - Cross-sectional analysis of the utility of pulmonary function tests in predicting emphysema in ever-smokers. AB - Emphysema is largely an under-diagnosed medical condition that can exist in smokers in the absence of airway obstruction. We aimed to determine the sensitivity and specificity of pulmonary function tests (PFTs) in assessing emphysema using quantitative CT scans as the reference standard. We enrolled 224 ever-smokers (current or former) over the age of 40. CT of thorax was used to quantify the low attenuation area (% emphysema), and to measure the standardized airway wall thickness. PFTs were used individually and in combination to predict their ability to discriminate radiographic emphysema. Significant emphysema (>7%) was detected in 122 (54%) subjects. Twenty six (21%) emphysema subjects had no evidence of airflow obstruction (FEV(1)/FVC ratio <70%), while all subjects with >23% emphysema showed airflow obstruction. The sensitivity and specificity of spirometry for detecting radiographic emphysema were 79% and 75%, respectively. Standardized airway wall thickness was increased in subjects with airflow obstruction, but did not correlate with emphysema severity. In this cohort of lifetime ever-smokers, PFTs alone were inadequate for diagnosing emphysema. Airway wall thickness quantified by CT morphometry was associated with airflow limitation, but not with emphysema indicating that the heterogeneous nature of lung disease in smokers may represent distinct phenotypes. PMID- 21655123 TI - AGRICOH: a consortium of agricultural cohorts. AB - AGRICOH is a recently formed consortium of agricultural cohort studies involving 22 cohorts from nine countries in five continents: South Africa (1), Canada (3), Costa Rica (2), USA (6), Republic of Korea (1), New Zealand (2), Denmark (1), France (3) and Norway (3). The aim of AGRICOH, initiated by the US National Cancer Institute (NCI) and coordinated by the International Agency for Research on Cancer (IARC), is to promote and sustain collaboration and pooling of data to investigate the association between a wide range of agricultural exposures and a wide range of health outcomes, with a particular focus on associations that cannot easily be addressed in individual studies because of rare exposures (e.g., use of infrequently applied chemicals) or relatively rare outcomes (e.g., certain types of cancer, neurologic and auto-immune diseases). To facilitate future projects the need for data harmonization of selected variables is required and is underway. Altogether, AGRICOH provides excellent opportunities for studying cancer, respiratory, neurologic, and auto-immune diseases as well as reproductive and allergic disorders, injuries and overall mortality in association with a wide array of exposures, prominent among these the application of pesticides. PMID- 21655124 TI - Source reduction behavior as an independent measurement of the impact of a public health education campaign in an integrated vector management program for the Asian tiger mosquito. AB - The goal of this study was to evaluate the effectiveness of a public health educational campaign to reduce backyard mosquito-larval habitats. Three communities each, within two New Jersey counties, were randomly selected to receive: (1) both education and mosquito control, (2) education only, and (3) no education or mosquito control. Four separate educational events included a 5-day elementary school curriculum in the spring, and three door to door distributions of educational brochures. Before and after each educational event, the numbers of mosquito-larval container habitats were counted in 50 randomly selected homes per study area. Container surveys allowed us to measure source reduction behavior. Although we saw reductions in container habitats in sites receiving education, they were not significantly different from the control. Our results suggest that traditional passive means of public education, which were often considered the gold standard for mosquito control programs, are not sufficient to motivate residents to reduce backyard mosquito-larval habitats. PMID- 21655125 TI - Spatial multicriteria decision analysis of flood risks in aging-dam management in China: a framework and case study. AB - Approximately 30,000 dams in China are aging and are considered to be high-level risks. Developing a framework for analyzing spatial multicriteria flood risk is crucial to ranking management scenarios for these dams, especially in densely populated areas. Based on the theories of spatial multicriteria decision analysis, this report generalizes a framework consisting of scenario definition, problem structuring, criteria construction, spatial quantification of criteria, criteria weighting, decision rules, sensitivity analyses, and scenario appraisal. The framework is presented in detail by using a case study to rank dam rehabilitation, decommissioning and existing-condition scenarios. The results show that there was a serious inundation, and that a dam rehabilitation scenario could reduce the multicriteria flood risk by 0.25 in the most affected areas; this indicates a mean risk decrease of less than 23%. Although increased risk (<0.20) was found for some residential and commercial buildings, if the dam were to be decommissioned, the mean risk would not be greater than the current existing risk, indicating that the dam rehabilitation scenario had a higher rank for decreasing the flood risk than the decommissioning scenario, but that dam rehabilitation alone might be of little help in abating flood risk. With adjustments and improvement to the specific methods (according to the circumstances and available data) this framework may be applied to other sites. PMID- 21655126 TI - Biomarkers of immunotoxicity for environmental and public health research. AB - The immune response plays an important role in the pathophysiology of numerous diseases including asthma, autoimmunity and cancer. Application of biomarkers of immunotoxicity in epidemiology studies and human clinical trials can improve our understanding of the mechanisms that underlie the associations between environmental exposures and development of these immune-mediated diseases. Immunological biomarkers currently used in environmental health studies include detection of key components of innate and adaptive immunity (e.g., complement, immunoglobulin and cell subsets) as well as functional responses and activation of key immune cells. The use of high-throughput assays, including flow cytometry, Luminex, and Multi-spot cytokine detection methods can further provide quantitative analysis of immune effects. Due to the complexity and redundancy of the immune response, an integrated assessment of several components of the immune responses is needed. The rapidly expanding field of immunoinformatics will also aid in the synthesis of the vast amount of data being generated. This review discusses and provides examples of how the identification and development of immunological biomarkers for use in studies of environmental exposures and immune mediated disorders can be achieved. PMID- 21655127 TI - Pesticide exposure, safety issues, and risk assessment indicators. AB - Pesticides are widely used in agricultural production to prevent or control pests, diseases, weeds, and other plant pathogens in an effort to reduce or eliminate yield losses and maintain high product quality. Although pesticides are developed through very strict regulation processes to function with reasonable certainty and minimal impact on human health and the environment, serious concerns have been raised about health risks resulting from occupational exposure and from residues in food and drinking water. Occupational exposure to pesticides often occurs in the case of agricultural workers in open fields and greenhouses, workers in the pesticide industry, and exterminators of house pests. Exposure of the general population to pesticides occurs primarily through eating food and drinking water contaminated with pesticide residues, whereas substantial exposure can also occur in or around the home. Regarding the adverse effects on the environment (water, soil and air contamination from leaching, runoff, and spray drift, as well as the detrimental effects on wildlife, fish, plants, and other non-target organisms), many of these effects depend on the toxicity of the pesticide, the measures taken during its application, the dosage applied, the adsorption on soil colloids, the weather conditions prevailing after application, and how long the pesticide persists in the environment. Therefore, the risk assessment of the impact of pesticides either on human health or on the environment is not an easy and particularly accurate process because of differences in the periods and levels of exposure, the types of pesticides used (regarding toxicity and persistence), and the environmental characteristics of the areas where pesticides are usually applied. Also, the number of the criteria used and the method of their implementation to assess the adverse effects of pesticides on human health could affect risk assessment and would possibly affect the characterization of the already approved pesticides and the approval of the new compounds in the near future. Thus, new tools or techniques with greater reliability than those already existing are needed to predict the potential hazards of pesticides and thus contribute to reduction of the adverse effects on human health and the environment. On the other hand, the implementation of alternative cropping systems that are less dependent on pesticides, the development of new pesticides with novel modes of action and improved safety profiles, and the improvement of the already used pesticide formulations towards safer formulations (e.g., microcapsule suspensions) could reduce the adverse effects of farming and particularly the toxic effects of pesticides. In addition, the use of appropriate and well-maintained spraying equipment along with taking all precautions that are required in all stages of pesticide handling could minimize human exposure to pesticides and their potential adverse effects on the environment. PMID- 21655128 TI - A geostatistical approach to assess the spatial association between indoor radon concentration, geological features and building characteristics: the case of Lombardy, Northern Italy. AB - Radon is a natural gas known to be the main contributor to natural background radiation exposure and second to smoking, a major leading cause of lung cancer. The main source of radon is the soil, but the gas can enter buildings in many different ways and reach high indoor concentrations. Monitoring surveys have been promoted in many countries in order to assess the exposure of people to radon. In this paper, two complementary aspects are investigated. Firstly, we mapped indoor radon concentration in a large and inhomogeneous region using a geostatistical approach which borrows strength from the geologic nature of the soil. Secondly, knowing that geologic and anthropogenic factors, such as building characteristics, can foster the gas to flow into a building or protect against this, we evaluated these effects through a multiple regression model which takes into account the spatial correlation of the data. This allows us to rank different building typologies, identified by architectonic and geological characteristics, according to their proneness to radon. Our results suggest the opportunity to differentiate construction requirements in a large and inhomogeneous area, as the one considered in this paper, according to different places and provide a method to identify those dwellings which should be monitored more carefully. PMID- 21655129 TI - Playing it safe: assessing cumulative impact and social vulnerability through an environmental justice screening method in the South Coast Air Basin, California. AB - Regulatory agencies, including the U.S. Environmental Protection Agency (US EPA) and state authorities like the California Air Resources Board (CARB), have sought to address the concerns of environmental justice (EJ) advocates who argue that chemical-by-chemical and source-specific assessments of potential health risks of environmental hazards do not reflect the multiple environmental and social stressors faced by vulnerable communities. We propose an Environmental Justice Screening Method (EJSM) as a relatively simple, flexible and transparent way to examine the relative rank of cumulative impacts and social vulnerability within metropolitan regions and determine environmental justice areas based on more than simply the demographics of income and race. We specifically organize 23 indicator metrics into three categories: (1) hazard proximity and land use; (2) air pollution exposure and estimated health risk; and (3) social and health vulnerability. For hazard proximity, the EJSM uses GIS analysis to create a base map by intersecting land use data with census block polygons, and calculates hazard proximity measures based on locations within various buffer distances. These proximity metrics are then summarized to the census tract level where they are combined with tract centroid-based estimates of pollution exposure and health risk and socio-economic status (SES) measures. The result is a cumulative impacts (CI) score for ranking neighborhoods within regions that can inform diverse stakeholders seeking to identify local areas that might need targeted regulatory strategies to address environmental justice concerns. PMID- 21655130 TI - The environmental and economic sustainability of carbon capture and storage. AB - For carbon capture and storage (CCS) to be a truly effective option in our efforts to mitigate climate change, it must be sustainable. That means that CCS must deliver consistent environmental and social benefits which exceed its costs of capital, energy and operation; it must be protective of the environment and human health over the long term; and it must be suitable for deployment on a significant scale. CCS is one of the more expensive and technically challenging carbon emissions abatement options available, and CCS must first and foremost be considered in the context of the other things that can be done to reduce emissions, as a part of an overall optimally efficient, sustainable and economic mitigation plan. This elevates the analysis beyond a simple comparison of the cost per tonne of CO(2) abated--there are inherent tradeoffs with a range of other factors (such as water, NOx, SOx, biodiversity, energy, and human health and safety, among others) which must also be considered if we are to achieve truly sustainable mitigation. The full life-cycle cost of CCS must be considered in the context of the overall social, environmental and economic benefits which it creates, and the costs associated with environmental and social risks it presents. Such analysis reveals that all CCS is not created equal. There is a wide range of technological options available which can be used in a variety of industries and applications-indeed CCS is not applicable to every industry. Stationary fossil-fuel powered energy and large scale petroleum industry operations are two examples of industries which could benefit from CCS. Capturing and geo-sequestering CO(2) entrained in natural gas can be economic and sustainable at relatively low carbon prices, and in many jurisdictions makes financial sense for operators to deploy now, if suitable secure disposal reservoirs are available close by. Retrofitting existing coal-fired power plants, however, is more expensive and technically challenging, and the economic sustainability of post-combustion capture retrofit needs to be compared on a portfolio basis to the relative overall net benefit of CCS on new-build plants, where energy efficiency can be optimised as a first step, and locations can be selected with sequestration sites in mind. Examples from the natural gas processing, liquefied natural gas (LNG), and coal-fired power generation sectors, illustrate that there is currently a wide range of financial costs for CCS, depending on how and where it is applied, but equally, environmental and social benefits of emissions reduction can be considerable. Some CCS applications are far more economic and sustainable than others. CCS must be considered in the context of the other things that a business can do to eliminate emissions, such as far-reaching efforts to improve energy efficiency. PMID- 21655131 TI - Quantitative analysis of tremors in welders. AB - BACKGROUND: Workers chronically exposed to manganese in welding fumes may develop an extra-pyramidal syndrome with postural and action tremors. OBJECTIVES: To determine the utility of tremor analysis in distinguishing tremors among workers exposed to welding fumes, patients with Idiopathic Parkinson's Disease (IPD) and Essential Tremor (ET). METHODS: Retrospective study of recorded tremor in subjects from academic Movement Disorders Clinics and Welders. Quantitative tremor analysis was performed and associated with clinical status. RESULTS: Postural tremor intensity was increased in Welders and ET and was associated with visibly greater amplitude of tremor with arms extended. Mean center frequencies (Cf) of welders and patients with ET were significantly higher than the mean Cf of PD subjects. Although both the welders and the ET group exhibited a higher Cf with arms extended, welders could be distinguished from the ET subjects by a significantly lower Cf of the rest tremor than that measured in ET subjects. CONCLUSIONS: In the context of an appropriate exposure history and neurological examination, tremor analysis may be useful in the diagnosis of manganese-related extra-pyramidal manifestations. PMID- 21655132 TI - Release of nitrogen and phosphorus from poultry litter amended with acidified biochar. AB - Application of poultry litter (PL) to soil may lead to nitrogen (N) losses through ammonia (NH(3)) volatilization and to potential contamination of surface runoff with PL-derived phosphorus (P). Amending litter with acidified biochar may minimize these problems by decreasing litter pH and by retaining litter-derived P, respectively. This study evaluated the effect of acidified biochars from pine chips (PC) and peanut hulls (PH) on NH(3) losses and inorganic N and P released from surface-applied or incorporated PL. Poultry litter with or without acidified biochars was surface-applied or incorporated into the soil and incubated for 21 d. Volatilized NH(3) was determined by trapping it in acid. Inorganic N and P were determined by leaching the soil with 0.01 M of CaCl(2) during the study and by extracting it with 1 M KCl after incubation. Acidified biochars reduced NH(3) losses by 58 to 63% with surface-applied PL, and by 56 to 60% with incorporated PL. Except for PH biochar, which caused a small increase in leached NH(4) (+)-N with incorporated PL, acidified biochars had no effect on leached or KCl extractable inorganic N and P from surface-applied or incorporated PL. These results suggest that acidified biochars may decrease NH(3) losses from PL but may not reduce the potential for P loss in surface runoff from soils receiving PL. PMID- 21655134 TI - Restaurant and bar owners' exposure to secondhand smoke and attitudes regarding smoking bans in five Chinese cities. AB - Despite the great progress made towards smoke-free environments, only 9% of countries worldwide mandate smoke-free restaurants and bars. Smoking was generally not regulated in restaurants and bars in China before 2008. This study was designed to examine the public attitudes towards banning smoking in these places in China. A convenience sample of 814 restaurants and bars was selected in five Chinese cities and all owners of these venues were interviewed in person by questionnaire in 2007. Eighty six percent of current nonsmoking subjects had at least one-day exposure to secondhand smoke (SHS) at work in the past week. Only 51% of subjects knew SHS could cause heart disease. Only 17% and 11% of subjects supported prohibiting smoking completely in restaurants and in bars, respectively, while their support for restricting smoking to designated areas was much higher. Fifty three percent of subjects were willing to prohibit or restrict smoking in their own venues. Of those unwilling to do so, 82% thought smoking bans would reduce revenue, and 63% thought indoor air quality depended on ventilation rather than smoking bans. These results showed that there was support for smoking bans among restaurant or bar owners in China despite some knowledge gaps. To facilitate smoking bans in restaurants and bars, it is important to promote health education on specific hazards of SHS, provide country-specific evidence on smoking bans and hospitality revenues, and disseminate information that restricting smoking and ventilation alone cannot eliminate SHS hazards. PMID- 21655133 TI - Does secondhand smoke affect the development of dental caries in children? A systematic review. AB - This review evaluated evidence of the relationship between secondhand smoke (SHS) and dental caries in children in epidemiological studies. Relevant literature was searched and screened, and the methodological quality was assessed. The search yielded 42 citations. High-quality studies including one cohort format and 14 case-control format studies were selected. Early childhood caries was examined in 11 studies. The independent association of SHS was significant in 10 studies, and the strength was mostly weak to moderate. One study did not select SHS as a significant variable. Three studies reported decreases in the risk of previous exposure, and the association was not significant. Dose-response relationships were evident in five studies. Permanent teeth were examined in seven studies. Five studies reported significant associations, which were mostly weak. The risk of previous exposure remained similar to that of current exposure, and a dose response relationship was not evident in one study. The overall evidence for the causal association in early childhood caries is possible regarding epidemiological studies, and the evidence of permanent teeth and the effect of maternal smoking during pregnancy were insufficient. The results warrant further studies of deciduous teeth using a cohort format and basic studies regarding the underlying mechanism. PMID- 21655135 TI - Arsenic in soils and forages from poultry litter-amended pastures. AB - In regions of concentrated poultry production, poultry litter (PL) that contains significant quantities of trace elements is commonly surface-applied to pastures at high levels over multiple years. This study examined the effect of long-term applications of PL on soil concentrations of arsenic (As), copper (Cu), Zinc (Zn), and the uptake of these elements by bermuda grass grown on Cecil (well drained) and Sedgefield (somewhat poorly-drained) soils. The results showed that concentrations of As, Cu, and Zn in soils that had received surface-applied PL over a 14-year period were significantly greater than untreated soil at 0-2.5 and 2.5-7.5 cm depths. However, the levels were well below the USEPA loading limits established for municipal biosolids. Arsenic fractionation showed that concentrations of all As fractions were significantly greater in PL-amended soils compared to untreated soils at 0-2.5 and 2.5-7.5 cm depths. The residual fraction was the predominant form of As in all soils. The water-soluble and NaHCO(3) associated As were only 2% of the total As. Significant differences were found in concentrations of these trace elements and phosphorus (P) in forage from PL amended soils compared to that in untreated plots. The concentrations of Cu, Zn, As, and P were significantly greater in forage from Sedgefield amended soil compared to Cecil soil, but were in all cases below levels of environmental concern. PMID- 21655137 TI - Screening of oomycete fungi for their potential role in reducing the biting midge (Diptera: Ceratopogonidae) larval populations in Hervey Bay, Queensland, Australia. AB - Biting midges are globally distributed pests causing significant economic losses and transmitting arbovirus diseases to both animals and humans. Current biological and chemical control strategies for biting midge target destruction of adult forms, but strategies directed at immature stages of the insect have yet to be explored in Australia. In the present study, coastal waters of Hervey Bay region in Queensland, Australia were screened to detect the habitats of biting midge at immature stages. These results were then correlated to local environmental conditions and naturally occurring entomopathogenic fungal flora, in particular the Oomycete fungi, to determine their reducing effect on insect immature stages in the search for biological control agents in the region. The dominant species of biting midge found within this study was Culicoides subimmaculatus occuring between mean high water neaps and mean high water spring tide levels. Within this intertidal zone, the presence of C. subimmaculatus larvae was found to be influenced by both sediment size and distance from shore. Halophytophthora isolates colonized both dead and alive pupae. However, the association was found to be surface colonization rather than invasion causing the death of the host. Lack of aggressive oomycete fungal antagonists towards midge larvae might correlate with increased incidences of biting midge infestations in the region. PMID- 21655136 TI - Outcomes and cost-effectiveness of two nicotine replacement treatment delivery models for a tobacco quitline. AB - Many tobacco cessation quitlines provide nicotine replacement therapy (NRT) in the U.S. but consensus is lacking regarding the best shipping protocol or NRT amounts. We evaluated the impact of the Minnesota QUITPLAN((r)) Helpline's shift from distributing NRT using a single eight-week shipment to a two-shipment protocol. For this observational study, the eight week single-shipment cohort (n = 247) received eight weeks of NRT (patches or gum) at once, while the split shipment cohort (n = 160) received five weeks of NRT (n = 94), followed by an additional three weeks of NRT if callers continued with counseling (n = 66). Patient satisfaction, retention, quit rates, and cost associated with the three groups were compared. A higher proportion of those receiving eight weeks of NRT, whether in one or two shipments, reported that the helpline was "very helpful" (77.2% of the single-shipment group; 81.1% of the two-shipment group) than those receiving five weeks of NRT (57.8% of the one-shipment group) (p = 0.004). Callers in the eight week two-shipment group completed significantly more calls (3.0) than callers in the five week one-shipment group (2.4) or eight week single shipment group (1.7) (p < 0.001). Using both responder and intent-to-treat calculations, there were no significant differences in 30-day point prevalence abstinence at seven months among the three protocol groups even when controlling for demographic and tobacco use characteristics, and treatment group protocol. The mean cost per caller was greater for the single-shipment phase than the split shipment phase ($350 vs. $326) due to the savings associated with not sending a second shipment to some participants. Assuming no difference in abstinence rates resulting from the protocol change, cost-per-quit was lowest for the five week one-shipment group ($1,155), and lower for the combined split-shipment cohort ($1,242) than for the single-shipment cohort ($1,350). Results of this evaluation indicate that while satisfaction rates increase among those receiving more counseling and NRT, quit rates do not, even when controlling for demographic and tobacco use characteristics. PMID- 21655138 TI - The positive environmental contribution of jarosite by retaining lead in acid mine drainage areas. AB - Jarosite, KFe(3)(SO(4))(2)(OH)(6), is a secondary iron sulphate often found in acid mine drainage (AMD) environments, particularly in mining wastes from polymetallic sulphide ore deposits. Despite the negative environmental connotation usually ascribed to secondary sulphate minerals due to the release of hazardous elements to aquifers and soils, jarosite acts as an efficient remover and immobilizer of such metals, particularly lead. The mineral chemistry of jarosite is reviewed and the results of a Fe K-edge XANES (X-Ray Absorption Near Edge Structure) study of K-, Na- and Pb-jarosite are described and discussed within the context of the abandoned old mines of Sao Domingos and Aljustrel located in southern Portugal, in the Iberian Pyrite Belt (IPB). PMID- 21655139 TI - Cigarette taxes and smoking participation: evidence from recent tax increases in Canada. AB - Using the Canadian National Population Health Survey and the recent tax variation across Canadian provinces, this paper examines the impact of cigarette taxes on smoking participation. Consistent with the literature, we find evidence of a heterogeneous response to cigarette taxes among different groups of smokers. Contrary to most studies, we find that the middle age group-which constitutes the largest fraction of smokers in our sample-is largely unresponsive to taxes. While cigarette taxes remain popular with policy makers as an anti-smoking measure, identifying the socio-demographic characteristics of smokers who respond differentially to tax increase will help in designing appropriate supplementary measures to reduce smoking. PMID- 21655140 TI - Heavy drinking is associated with poor blood pressure control in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. AB - Alcohol intake has been shown to have a J-shaped association with blood pressure (BP). However, this association has not been examined in mixed race populations or in people with diabetes where tighter blood pressure control is recommended. Participants in the REGARDS study who were 45 years or older (n = 30,239) were included. Medical history (including self-reported alcohol intake) was collected by telephone while blood collection and clinical measurements were done during an in-home visit. We defined diabetes as use of medications and/or fasting glucose >= 126 mg/dL and hypertension as use of blood pressure lowering medications and/or BP >= 140/90 mmHg or BP >= 130/80 mmHg in people with diabetes. After adjustment for confounders, heavy drinking was associated with an increased odds of hypertension (OR = 1.59; 95% CI = 1.37, 1.87). Diabetes and gender significantly modified (interaction P < 0.05 for both) the association between alcohol use and hypertension, although heavy drinking remained associated with increased odds of hypertension in sub-group analyses. We did not observe the previously described J-shaped relationship in any sub-group except white females. These data suggest heavy alcohol consumption is associated with poor BP control and that heavy drinkers may want to consider limiting alcohol intake in order to manage hypertension. PMID- 21655141 TI - Evaluating pharmacokinetic and pharmacodynamic interactions with computational models in supporting cumulative risk assessment. AB - Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture by other chemical(s), resulting in a change in the toxicity from that predicted from the summation of the effects of the single chemicals using dose additivity. In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult. The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures. Further, PK models can be developed to describe mechanisms of action and tissue responses. In this article, PBPK/PD modeling efforts conducted to investigate chemical interactions at the PK and PD levels are reviewed to demonstrate the use of this predictive modeling framework in assessing health risks associated with exposures to complex chemical mixtures. PMID- 21655143 TI - The evaluation for alterations of DOM components from upstream to downstream flow of rivers in Toyama (Japan) using three-dimensional excitation-emission matrix fluorescence spectroscopy. AB - The dissolved organic matter (DOM) is one of the important factors for controlling water quality. The behavior and constitutions of DOM is related to the risk of human health because it is able to directly or indirectly affect the behavior, speciation and toxicity of various environmental pollutants. However, it is not easy to know the contents of DOM components without using various complicated and time consuming analytical methods because DOM is a complex mixture and usually exists at low concentration. Here, we describe the fluorescence properties of DOM components in water samples collected from four rivers in Toyama, Japan by means of the three-dimensional excitation-emission matrix (3DEEM) fluorescence spectroscopy. In order to evaluate the alterations of DOM components in each of the river during the flow from upstream to downstream, the patterns of relative fluorescence intensity (RFI) at six peaks which are originated from fluorophores including humic-like and protein-like components were investigated. The changes in the patterns of RFI values at each of the peak and the concentration of dissolved organic carbon (DOC) for each river water sample were discussed in connection with the differences of land use managements and basic water quality parameters, such as pH, EC, turbidity, Fe(3+), T-N, NO(3) N, T-P, PO(4)-P, chlorophyll a, DOC and N/P ratio. The DOC concentrations in the water samples collected from these rivers were relatively low (0.63-1.16 mg/L). Two main peaks which have a strong RFI value expressed a positive correlation with the DOC concentration (r = 0.557, 0.535). However, the correlations between the RFI values for other four peaks and the DOC concentration were below 0.287. The alterations of DOM components during the flow of a river from upstream to downstream were investigated from the changes in the patterns of RFI values for six fluorescent peaks. It was clarified that the great increase of RFI values in peak A and peak T from river water located in urban area showed high concentration of PO(4)-P and Fe(3+), and low N/P ratio due to the high biological activities. The values of fluorescence index (FIX) and biological index (BIX) were as high as 1.60 and 0.72, respectively. PMID- 21655144 TI - How do price minimizing behaviors impact smoking cessation? Findings from the International Tobacco Control (ITC) Four Country Survey. AB - This paper examines how price minimizing behaviors impact efforts to stop smoking. Data on 4,988 participants from the International Tobacco Control Policy Evaluation (ITC) Four-Country Survey who were smokers at baseline (wave 5) and interviewed at a 1 year follow-up were used. We examined whether price minimizing behaviors at baseline predicted: (1) cessation, (2) quit attempts, and (3) successful quit attempts at one year follow up using multivariate logistic regression modeling. A subset analysis included 3,387 participants who were current smokers at waves 5 and 6 and were followed through wave 7 to explore effects of changing purchase patterns on cessation. Statistical tests for interaction were performed to examine the joint effect of SES and price/tax avoidance behaviors on cessation outcomes. Smokers who engaged in any price/tax avoidance behaviors were 28% less likely to report cessation. Persons using low/untaxed sources were less likely to quit at follow up, those purchasing cartons were less likely to make quit attempts and quit, and those using discount cigarettes were less likely to succeed, conditional on making attempts. Respondents who utilized multiple behaviors simultaneously were less likely to make quit attempts and to succeed. SES did not modify the effects of price minimizing behaviors on cessation outcomes. The data from this paper indicate that the availability of lower priced cigarette alternatives may attenuate public health efforts aimed at to reduce reducing smoking prevalence through price and tax increases among all SES groups. PMID- 21655145 TI - Temporal and spatial pore water pressure distribution surrounding a vertical landfill leachate recirculation well. AB - Addition of liquids into landfilled waste can result in an increase in pore water pressure, and this in turn may increase concerns with respect to geotechnical stability of the landfilled waste mass. While the impact of vertical well leachate recirculation on landfill pore water pressures has been mathematically modeled, measurements of these systems in operating landfills have not been reported. Pressure readings from vibrating wire piezometers placed in the waste surrounding a liquids addition well at a full-scale operating landfill in Florida were recorded over a 2-year period. Prior to the addition of liquids, measured pore pressures were found to increase with landfill depth, an indication of gas pressure increase and decreasing waste permeability with depth. When liquid addition commenced, piezometers located closer to either the leachate injection well or the landfill surface responded more rapidly to leachate addition relative to those far from the well and those at deeper locations. After liquid addition stopped, measured pore pressures did not immediately drop, but slowly decreased with time. Despite the large pressures present at the bottom of the liquid addition well, much smaller pressures were measured in the surrounding waste. The spatial variation of the pressures recorded in this study suggests that waste permeability is anisotropic and decreases with depth. PMID- 21655142 TI - Protein-energy wasting and mortality in chronic kidney disease. AB - Protein-energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with an increased death risk from cardiovascular diseases. However, while even minor renal dysfunction is an independent predictor of adverse cardiovascular prognosis, PEW becomes clinically manifest at an advanced stage, early before or during the dialytic stage. Mechanisms causing loss of muscle protein and fat are complex and not always associated with anorexia, but are linked to several abnormalities that stimulate protein degradation and/or decrease protein synthesis. In addition, data from experimental CKD indicate that uremia specifically blunts the regenerative potential in skeletal muscle, by acting on muscle stem cells. In this discussion recent findings regarding the mechanisms responsible for malnutrition and the increase in cardiovascular risk in CKD patients are discussed. During the course of CKD, the loss of kidney excretory and metabolic functions proceed together with the activation of pathways of endothelial damage, inflammation, acidosis, alterations in insulin signaling and anorexia which are likely to orchestrate net protein catabolism and the PEW syndrome. PMID- 21655146 TI - Comparing distributions of environmental outcomes for regulatory environmental justice analysis. AB - Economists have long been interested in measuring distributional impacts of policy interventions. As environmental justice (EJ) emerged as an ethical issue in the 1970s, the academic literature has provided statistical analyses of the incidence and causes of various environmental outcomes as they relate to race, income, and other demographic variables. In the context of regulatory impacts, however, there is a lack of consensus regarding what information is relevant for EJ analysis, and how best to present it. This paper helps frame the discussion by suggesting a set of questions fundamental to regulatory EJ analysis, reviewing past approaches to quantifying distributional equity, and discussing the potential for adapting existing tools to the regulatory context. PMID- 21655147 TI - Review of pesticide urinary biomarker measurements from selected US EPA children's observational exposure studies. AB - Children are exposed to a wide variety of pesticides originating from both outdoor and indoor sources. Several studies were conducted or funded by the EPA over the past decade to investigate children's exposure to organophosphate and pyrethroid pesticides and the factors that impact their exposures. Urinary metabolite concentration measurements from these studies are consolidated here to identify trends, spatial and temporal patterns, and areas where further research is required. Namely, concentrations of the metabolites of chlorpyrifos (3,5,6 trichloro-2-pyridinol or TCPy), diazinon (2-isopropyl-6-methyl-4-pyrimidinol or IMP), and permethrin (3-phenoxybenzoic acid or 3-PBA) are presented. Information on the kinetic parameters describing absorption and elimination in humans is also presented to aid in interpretation. Metabolite concentrations varied more dramatically across studies for 3-PBA and IMP than for TCPy, with TCPy concentrations about an order of magnitude higher than the 3-PBA concentrations. Temporal variability was high for all metabolites with urinary 3-PBA concentrations slightly more consistent over time than the TCPy concentrations. Urinary biomarker levels provided only limited evidence of applications. The observed relationships between urinary metabolite levels and estimates of pesticide intake may be affected by differences in the contribution of each exposure route to total intake, which may vary with exposure intensity and across individuals. PMID- 21655148 TI - A multicentre open-label safety and efficacy study of tetrodotoxin for cancer pain. AB - BACKGROUND: Cancer pain is highly prevalent, and existing treatments are often insufficient to provide adequate relief. OBJECTIVES: We assessed the long-term safety and efficacy of subcutaneous tetrodotoxin treatment in reducing the intensity of chronic cancer-related pain. METHODS: In this multicentre open-label longitudinal trial, 30 MUg tetrodotoxin was administered subcutaneously twice daily for 4 days in a heterogeneous cohort of patients with persistent pain despite opioids and other analgesics. "Responder" was defined as a mean reduction of 30% or more in pain intensity from baseline; and "clinical responder" as some pain reduction, but less than 30%, plus agreement on the part of both the patient and the physician that a meaningful analgesic response to treatment had occurred. RESULTS: Of 45 patients who entered the longitudinal trial, 41 had sufficient data for analysis. Of all 45 patients, 21 (47%) met the criteria for "responder" [16 patients (36%)] or "clinical responder" [5 patients (11%)]. Onset of pain relief was typically cumulative over days, and after administration ended, the analgesic effect subsided over the course of a few weeks. No evidence of loss of analgesic effect was observed during subsequent treatments (2526 patient-days in total and a maximum of 400 days in 1 patient). One patient withdrew from the study because of adverse events. Toxicity was usually mild (82%) or moderate (13%), and remained so through subsequent treatment cycles, with no evidence of cumulative toxicity or tolerance. CONCLUSIONS: Long-term treatment with tetrodotoxin is associated with acceptable toxicity and, in a substantial minority of patients, resulted in a sustained analgesic effect. Further study of tetrodotoxin for moderate-to-severe cancer pain is warranted. PMID- 21655149 TI - O. Harold Warwick: Canada's first medical oncologist. AB - O. Harold Warwick graduated in medicine from McGill University as a gold medalist and Rhodes Scholar in 1940. After World War II, he started postgraduate training in Montreal, and in 1946, he began studying the newly described drug treatment of cancer in London, England. There he carried out the first study of nitrogen mustard in a group of adult patients with a non-hematologic solid tumour, lung cancer. After a brief period of practice in Montreal, he moved in 1948 to Toronto, where he became executive director of the Canadian Cancer Society and the National Cancer Institute of Canada. Simultaneously, he joined the staff of Toronto General Hospital and its Radiotherapy Institute, where he became the first physician-oncologist to provide medical care and administer anticancer drugs in a Canadian cancer centre. In 1958, the new Princess Margaret Hospital opened in Toronto; Warwick became its first chief physician, responsible for clinical drug trials. Here he carried out his best known clinical study-the use of vinblastine sulphate in patients with Hodgkin lymphoma. From 1961 to 1971, he served as dean and then vice-president Health Sciences at the University of Western Ontario. He returned to the practice of medical oncology from 1972 to 1980 at the London Cancer Clinic, after which he had a long and productive retirement. He died in October 2009. Although the specialty was not named until the latter years of his career, Harold Warwick satisfied all the criteria for and was undoubtedly Canada's first medical oncologist. PMID- 21655150 TI - Cord stem-cell transplantation in Ontario: do we need a public bank? AB - It has been 21 years since the first successful use of umbilical cord blood as a source of donor cells for hematopoietic stem cell transplantation (HSCT). Over those years, cord blood transplantation (CBT) has shown marked success as an effective modality in the treatment of children and adults with hematologic malignancies, marrow failure, immunodeficiency, hemoglobinopathy, and inherited metabolic diseases. Furthermore, transplantation without full human leukocyte antigen (HLA) matching is possible and, despite a lower incidence of graft-versus host disease, graft-versus-leukemia effect is preserved. More than 20,000 cbts have been performed worldwide. Ontario is the most populated province in Canada, and its cbt numbers have increased dramatically in recent years, but most of the umbilical cord blood units are purchased from unrelated international registries. There is no public cord bank in Ontario, but there is a private cord banking option, and notably, Ontario has the largest number of live births in Canada [approximately 40% of all Canadian live births per year occur in Ontario (Statistics Canada, 2007)]. In this brief review, the pros and cons of private and public cord banking and the feasibility of starting an Ontario public cord bank are discussed. PMID- 21655152 TI - Defining the elements for successful implementation of a small-city radiotherapy department. AB - AIMS: Distributed delivery models for cancer care have been introduced to bring care closer to home and to provide better access to cancer patients needing radiotherapy. Very little work has been done to demonstrate the elements critical for success in a non-centralized approach. The present study set out to identify the elements that are important for implementing radiotherapy away from large cities. METHODS AND RESULTS: This qualitative research project consisted of two separate components. In the first component, structured interviews were conducted with 5 external experts. Input on the expert responses was then sought from internal leaders in medical physics, radiation therapy, and radiation oncology. Those interviews were used to develop a proposed template of the elements needed in a small-city department. We tested the validity of all elements by surveying staff members from the radiation treatment program in Calgary, leading to a definition of the resources needed for the proposed department in Lethbridge. Seventy-five staff members contributed to the survey. CONCLUSIONS: Qualitative research methods allowed us to define important elements for a small-city radiotherapy department and to validate those elements with a large cohort of staff working in a tertiary centre. This work has influenced the planning of a small-city department in Lethbridge, emphasizing the importance of the elements identified to the service planners. We await the completion of the construction project and the opening of the centre so that we can re-evaluate the importance of the identified elements in actual practice. We recommend such an approach to jurisdictions that are considering devolved radiotherapy. PMID- 21655151 TI - Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme. AB - Recommendation 1: Multidisciplinary ApproachTo optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions.Recommendation 2: ImagingThe standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.Recommendation 3: Pseudo-progressionProgression observed by mri after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained.Recommendation 4: Repeat SurgerySurgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient's quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.Recommendation 5: Re irradiationRe-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.Recommendation 6: Systemic TherapyClinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or anti-angiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established. PMID- 21655153 TI - Impact of tumour volume on the potential efficacy of therapeutic vaccines. AB - With the recent approval by the U.S. Food and Drug Administration of the first therapeutic vaccine for cancer, the long-awaited goal of harnessing a patient's immune system to attack cancer through this modality is finally realized. However, as researchers in the field of cancer immunotherapy continue to perform randomized definitive studies, much remains to be learned about potential surrogate endpoints and appropriate patient populations for therapeutic vaccines. The present review addresses available data from clinical trials of immunotherapeutic agents relevant to the selection of appropriate patient populations. We believe that the weight of evidence supports the use of immunotherapy earlier in the disease course and in patients with less aggressive disease, and that the relevant findings have important implications for the design of clinical trials with therapeutic vaccines. PMID- 21655154 TI - Radiotherapy for steroid-resistant laryngeal Rosai-Dorfman disease. AB - Rosai-Dorfman disease is a rare lymphoproliferative disorder that can have nodal and extranodal manifestations. In the absence of established guidelines for the management of this condition, various therapeutic modalities are used, including radiotherapy. Radiation dosages and fractionation schedules have not been reported in all instances. We present a case in which glottic and subglottic Rosai-Dorfman lesions causing airway obstruction in a frail steroid-refractory patient were put into complete remission using radiotherapy. The lesions responded transiently to a course of prednisone, but responded completely to external-beam radiation, with minimal side effects to the patient. PMID- 21655155 TI - Uptake of novel medical therapies in the general population. PMID- 21655156 TI - Digital necrosis induced by erlotinib treatment in metastatic adenocarcinoma of the lung. PMID- 21655157 TI - Pan-Canadian initiatives in colorectal cancer screening: adopting knowledge translation tools to accelerate uptake and impact. AB - BACKGROUND: Despite the positive conclusions of several randomized controlled trials and the publication of national recommendations on colorectal cancer (crc) screening, uptake remained low. The inauguration of the National Colorectal Cancer Screening Network in 2007, the same year that the first screening program was announced in Canada, provided an opportunity for integrated knowledge translation to accelerate the processes of program implementation and screening uptake. AIM: Two primary aims were identified. The first focused on means to monitor the effects of various implementation plans in delivering high-quality population-based crc screening. The second focused on identifying and addressing knowledge gaps that may impair screening participation. METHOD: The methods used are described in the context of the knowledge-to-action cycle and demonstrate that the initiative itself dictates the point in the cycle at which to start. RESULTS: The identified need to monitor various implementation plans resulted in the shared development of a quality determinants document. All programs committed to designing data collection so that core components could be measured and compared; 6 operating programs have conducted the first data collection, which will allow for monitoring and for new knowledge creation as the process develops further. The knowledge gap identification project started with new knowledge creation, which identified a higher-than-expected willingness of Canadians to discuss crc screening with physicians, but a low level of understanding of screening as a wellness-related behaviour. Knowledge translation interventions have been developed with the stakeholders to address those gaps, and ongoing surveys to be carried out later in 2011 will help to gauge progress in the understanding and acceptance of crc screening by the population. CONCLUSIONS: A national network that engaged all programs, policymakers, experts, and lay representatives successfully used knowledge translation principles to enhance the trajectory of crc screening in Canada. PMID- 21655158 TI - Real-world experience with adjuvant fec-d chemotherapy in four Ontario regional cancer centres. AB - BACKGROUND: The efficacy of adjuvant chemotherapy with fec-d (5-fluorouracil epirubicin-cyclophosphamide followed by docetaxel) is superior to that with fec 100 alone in women with early-stage breast cancer. As the use of fec-d increased in clinical practice, health care providers anecdotally noted higher-than expected toxicity rates and frequent early treatment discontinuations because of toxicity. In the present study, we compared the rates of serious adverse events in patients who received adjuvant fec-d chemotherapy in routine clinical practice with the rates reported in the pacs-01 trial. METHODS: We retrospectively reviewed all patients prescribed adjuvant fec-d for early-stage breast cancer at 4 regional cancer centres in Ontario. Information was collected from electronic and paper charts by a physician investigator from each centre. Data were analyzed using chi-square tests, independent samples t-tests, one-way analysis of variance, and univariate regression. RESULTS: The 671 electronic and paper patient records reviewed showed a median patient age of 52.2 years, 229 patients (34.1%) with N0 disease, 508 patients (75.7%) with estrogen or progesterone receptor-positive disease (or both), and 113 patients (26%) with her2/neu overexpressing breast cancer. Febrile neutropenia occurred in 152 patients (22.7%), most frequently at cycle 4, coincident with the initiation of docetaxel [78/152 (51.3%)]. Primary prophylaxis with hematopoietic growth factor support was used in 235 patients (35%), and the rate of febrile neutropenia was significantly lower in those who received prophylaxis than in those who did not [15/235 (6.4%) vs. 137/436 (31.4%); p < 0.001; risk ratio: 0.20]. CONCLUSIONS: In routine clinical practice, treatment with fec-d is associated with a higher-than expected rate of febrile neutropenia, in light of which, primary prophylaxis with growth factor should be considered, per international guidelines. Adoption based on clinical trial reports of new therapies into mainstream practice must be done carefully and with scrutiny. PMID- 21655159 TI - Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer. AB - Non-small-cell lung cancer (nsclc) has the highest prevalence of all types of lung cancer, which is the second most common cancer and the leading cause of cancer-related mortality in Canada. The need for more effective and less toxic treatment options for nsclc has led to the development of agents targeting the epidermal growth factor receptor (egfr)-mediated signalling pathway, such as egfr tyrosine kinase inhibitors (egfr-tkis). Although egfr-tkis are less toxic than traditional anti-neoplastic agents, they are commonly associated with acneiform like rash and diarrhea. This review summarizes the clinical presentation and causes of egfr-tki-induced rash and diarrhea, and presents strategies for effective assessment, monitoring, and treatment of these adverse effects. Strategies to improve the management of egfr-tki-related adverse events should improve clinical outcomes, compliance, and quality of life in patients with advanced nsclc. PMID- 21655160 TI - Eyelash trichomegaly secondary to panitumumab therapy. PMID- 21655162 TI - Retraction notice. PMID- 21655161 TI - E-nephrology. AB - Diagnosis of renal diseases is often delayed owing to the scarcity of trained physicians, lack of facilities, and shortage of funds limits effective management, particularly when it comes to the red zone of renal replacement therapy. The Internetis expected to open up a myriad resource of knowledge and applications for academicians, researchers and clinicians alike in all health care professions across the globe. Also, the Internet has grown rapidly over the years and will inevitably expand even more. Evolving technologies offer modern applications for information management, communications with multimedia and virtual reality. Now, these innovative technologies have opened up newer possibilities for nephrologists. As Internet is serving as a backbone for these modern technologies, it is an utmost necessity to use and refine Internet applications for future nephrologists. Increasingly easy access to Internet has dramatically reduced barriers in sharing of information among basic and clinical nephrologists. Considering the growing scope for nephrologists in the use of Internet, it is necessary to understand Internet as a source of information and backbone of modern application. This review illustrates expanding roles of the Internet for the nephrologists and provides ready to use compilation of useful academic, research, clinical resources and is expected to introduce, stimulate and guide nephrologists into the realm of the world wide web. It also investigates how Internet is supporting in growth and development of the field of nephrology and present and future scopes of Internet as a tool for professionals involved in this area as well as information about biological sciences, and it also gives information about societies in various continents working in field of nephrology and the links useful for clinicians and research scientists. PMID- 21655163 TI - Collapsing glomerulopathy in renal allograft biopsies: A study of nine cases. AB - Collapsing glomerulopathy (CG) is considered to be a distinct clinicopathologic pattern of proliferative podocyte injury. The clinical significance of CG in renal allograft biopsies is yet not clear due to the scant data on the occurrence of CG in renal transplant recipients. We identified nine cases of CG in allograft biopsies over a period of 2 years. Detailed clinical information, including follow-up data, was collected and histopathological analysis performed. All the nine patients were males with a mean age at diagnosis of 32.4+/-11.2 years. The median posttransplantation duration at diagnosis of CG as 52 (range 12-98) months. All the patients presented with severe proteinuria and graft dysfunction. Histological analysis showed a median number of 8 glomeruli. The collapse of the glomerular tuft with visceral epithelial cell hyperplasia involved median of 2 glomeruli (range 1-4). At the last follow-up (mean duration 6 months), four patients had graft failure (return to dialysis) while four had functioning grafts. One patient was lost to follow-up. This series emphasizes the importance of this rare glomerular pathology as an important cause of graft dysfunction that may lead to allograft failure. PMID- 21655164 TI - Medical and non-medical factors that affect voluntary living-related kidney donation: A single-center study. AB - The aim was to evaluate the patients with chronic kidney disease stage 5 (CKD 5) and their prospective renal transplant donors with regard to their renal replacement choices, and to assess the medical and non-medical factors that affect living-related renal donor selection. Over 24 months, consecutive patients with CKD 5 and their relatives were interviewed at presentation. Reasons for the choice of modality were analyzed; the prospective recipients and their donors were again interviewed separately and the medical and nonmedical factors that affected the donor selection were determined. A total of 1257 patients were enrolled. Conservative therapy, maintenance dialysis, and renal transplantation were chosen by 513 (40.8%), 320 (25.5%), and 424 (33.7%) patients, respectively. Only socioeconomic status affected the modality chosen. The age, gender, and donor availability did not emerge as significant factors. Patients or donors were likely to withdraw from transplant evaluation due to the absence of a voluntary donor, presence of a male donor, coercion not to donate, and the absence of reimbursement. The commonest cause of rejection of a donor was blood group incompatibility (45.8%), followed by diabetes mellitus (DM) or risk of DM (24%), renal disease (5.9%), hypertension (5.5%), and persistent cross-match positivity (5.1%). To improve donation rates, the donor's spouse should be involved in the early stages of donor evaluation, financial support for the recipient has to be improved, and the apprehensions about complications of nephrectomy among the donors need to be alleyed. Male donors are at increased risk of leaving the program in the evaluation phase. PMID- 21655165 TI - Oxidative stress and its association with cardiovascular disease in chronic renal failure patients. AB - Cardiovascular disease (CVD) is responsible for the majority of deaths in chronic renal failure (CRF). Oxidative stress plays a key role in pathogenesis of atherosclerosis and CVD, which is promoted by the production of reactive oxygen species (ROS) and impaired antioxidant enzymes. These ROS react with nitric oxide (NO) to produce cytotoxic reactive nitrogen species that cause oxidative injury to the endothelium. This study evaluated biomarkers of oxidative stress, NOx (total NO(2) and NO(3)), and superoxide dismutase (SOD) enzyme in normal control and CRF patients as case group and correlated their association with CVD. This cross sectional study involved 173 CRF patients on different modes of treatment (hemodialysis, continuous ambulatory peritoneal dialysis (CAPD), and predialysis). Of these, 74 had CVD. The control group consisted of 33 healthy subjects who had no history of CRF and CVD. Both NOx and SOD levels were significantly lower (P<0.05, P<0.001, respectively) in the case group. Comparing between CRF patients with and without CVD, SOD level was found to be significantly lower in CRF patients with CVD (P<0.05). Logistic regression analysis showed significant association of CVD event with age, male gender, diabetes, SOD level, and lipid profile in CRF patients. Oxidative stress occurs in the CRF patients with or without CVD. This study found that NOx and SOD levels were reduced in all CRF patients with or without CVD. However, it was noted that the levels of these biomarkers of oxidative stress were significantly lower in CRF patients with CVD compared with CRF patients without CVD. Therefore, these oxidative stress markers maybe contributing factors in the pathogenesis of CVD in patients with CRF. PMID- 21655166 TI - Association of angiotensin-converting enzyme gene I/D polymorphism with steroid responsiveness in childhood nephrotic syndrome. AB - The aim of the study was to study the distribution of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, and its association with steroid responsiveness in children with idiopathic nephrotic syndrome (INS). One hundred twenty-five children with INS were classified into two groups: steroid sensitive nephrotic syndrome (SSNS: n = 90) and steroid-resistant nephrotic syndrome (SRNS: n=35). The control group consisted of 150 unrelated healthy children. Genomic DNA was extracted from peripheral leucocytes by the standard salting-out method. ACE genotyping was performed and ACE genotypes DD, ID, and II were compared between different groups. The frequency distribution of the DD genotype was significantly increased in children with INS compared to control subjects (P = 0.0012) while the difference was not significant (P = 0.071) between SSNS and control subjects. The frequency distribution of the DD genotype was significantly high in the SRNS group compared to control subjects (P < 0.0001). The distribution of the DD genotype was high in SRNS compared to SSNS group patients (P = 0.016). In conclusion, the presence of the DD genotype may predict risk for steroid resistance in childhood INS. PMID- 21655167 TI - Clinico-microbiological profile of urinary tract infection in south India. AB - The knowledge of etiology and antibiotic resistance pattern of the organisms causing urinary tract infection is essential. This study was taken up to determine the presentation and risk factors associated with community-acquired urinary tract infection (CA-UTI). The distribution of bacterial strains isolated from these patients and their resistance pattern were also studied. This multidisciplinary prospective observational study was conducted in M. S. Ramaiah Hospital, Bangalore, between January and December, 2008. Patients who had CA-UTI confirmed by positive urine culture reports were included in the study. Statistical analysis was done using the SPSS version 16. Symptomatology and others risk factors for CA-UTI were studied in these patients and the causative organisms and their resistance patterns were recorded. Of the total 510 patients included, 57% belonged to the elderly age group (50-79 years). Fever and dysuria were the most common clinical presentation, but were not specific in predicting CA-UTI. Escherichia coli (66.9%) was the most common organism causing CA-UTIs with extended spectrum beta lactamase (ESBL) resistance seen in nearly two-thirds of these cases (42.2%). The organisms recorded least resistance against carbapenems (3.9%). A high resistance rate was seen for fluoroquinolones (74.1%). In conclusion, a high rate of ESBL-positive organisms and their resistance to commonly used antibiotics brings a concern for future options in treating these conditions. PMID- 21655168 TI - Role of free radicals and antioxidant status in childhood nephrotic syndrome. AB - Nephrotic syndrome (NS) is characterized by heavy proteinuria and hypoalbuminuria. Reactive oxygen species (ROS) seem to play an important role in the etiopathogenesis of proteinuria in NS. This study aims to evaluate the potential role of reactive oxygen species in pathogenesis of NS by estimating the levels of oxidants and antioxidants in children with NS. Thirty patients of NS and thirty age, sex-matched healthy subjects, were selected for the study. As compared to healthy controls, the levels of serum lipid peroxide were significantly elevated while levels of nitric oxide, erythrocyte-superoxide dismutase activity, levels of vitamin C, albumin and total antioxidant capacity were significantly reduced in nephrotic patients. The levels of uric acid and bilirubin were significantly increased in children with NS as compared to controls. There was no significant difference in vitamin E level between patients and controls. It can be concluded that increased ROS generation and decreased antioxidant defense may be related to the pathogenesis of proteinuria in NS. PMID- 21655169 TI - Effective use of polymyxin B hemoperfusion in septic shock complicated by urosepsis. AB - Direct hemoperfusion using polymyxin B-immobilized fiber (PMX-DHP) is an established treatment method for septic shock caused by Gram-negative infections. Here we report one instance in which PMX-DHP therapy has been used successfully in a patient with septic shock from urosepsis. After antibiotic therapy, direct hemoperfusion using polymyxin B helped in cardiovascular stability. The patient recovered from the shock within a few days after treatment with polymyxin-B hemoperfusion. As far as we are aware, this is the first reported case of effective treatment of urosepsis complicated by septic shock using PMX-DHP therapy in India. PMID- 21655170 TI - NK/T-cell lymphoma in a renal transplant recipient and review of literature. AB - T-cell lymphomas, particularly NK/T-cell lymphomas are rare post transplantation malignancies. Only a few cases have been described. These tumors behave aggressively and the outcome is poor. We present here a case of NK/T-cell lymphoma who presented to us with an orbital swelling 9 years after renal transplantation, along with the review of literature. To the best of our knowledge, this is the first case of NK/T-cell lymphoma post-renal transplantation reported from India. PMID- 21655171 TI - Bilateral quadriceps tendon rupture as the presenting manifestation of chronic kidney disease. AB - Bilateral painful knees with loss of extension in a patient with chronic kidney disease (CKD) may be due to spontaneous quadriceps tendon rupture. This rare complication is usually seen in patients on long term dialysis. We present a case of bilateral spontaneous quadriceps tendon rupture demonstrated by magnetic resonance imaging in a 20-year-old woman who on evaluation was found to have CKD. PMID- 21655172 TI - Collagenofibrotic glomerulopathy - Case report with review of literature. AB - Collagenofibrotic glomerulopathy is a rare, idiopathic glomerular disease characterized by abnormal accumulation of type III collagen fibrils within the mesangial matrix and subendothelial space and a marked increase in serum type III procollagen peptide levels. Proteinuria (commonest feature), edema, hypertension, and occasional progression to end-stage renal disease are the various features of this disease. The etiology and pathogenesis remain elusive. There have been reports of the disease running in the family, suggesting the possibility of genetic transmission. We report two cases of this rare entity. PMID- 21655173 TI - An unusual case of bilateral renal enlargement due to primary renal lymphoma. AB - Primary renal lymphoma is an uncommon variant of extranodal non-Hodgkin's lymphoma. Manifestations are usually nonspecific hematuria, fever, flank pain, and renal insufficiency. Pathological data are scanty; few reports indicate it has a very poor prognosis. We describe a child with bilateral symmetrically palpable kidneys, low-grade pyrexia, and arthralgia. Clinically, diagnosis was missed partly due to the fact that bilateral large renal tumors commonly produce asymmetric renal swelling, renal dysfunction, and hematuria which were absent in this case and partly due to rarity of the condition. However, radiological investigations combined with renal histology helped in establishing diagnosis in the present case. PMID- 21655174 TI - Successful treatment of critically ill chronic kidney disease patient with multi organ dysfunction associated with H1N1 infection. AB - Chronic kidney disease (CKD) patients are at higher risk of H1N1 influenza A infection and associated complications. To our knowledge, this is the first case report of a febrile CKD patient with multi-organ dysfunction and associated H1N1 virus infection successfully treated with oseltamivir, hemodialysis, and mechanical ventilation. Oseltamivir is safe, effective, and well tolerated in our CKD patient. PMID- 21655175 TI - An unusual case of abdominal wall bleeding after renal allograft biopsy. AB - We report an unusual case of a enlarging anterior abdominal wall hematoma after percutaneous biopsy of a renal allograft. Angiography-directed embolization of the vessels filling the pseudoaneurysm was done and followed up with surgical exploration of the hematoma. In order to avoid this complication, Color Doppler evaluation of the overlying abdominal wall is suggested to look for significant vessels before the biopsy procedure. PMID- 21655176 TI - Hypokalemia induced rhabdomyolysis. PMID- 21655177 TI - Percutaneous nephrostomy under ultrasound guidance. PMID- 21655178 TI - Iron status in ESRD patients. PMID- 21655179 TI - Chronic kidney disease, immunosuppression and tuberculin test sensitivity. PMID- 21655180 TI - A case of emphysematous cystitis: Timely recognition is the key. PMID- 21655181 TI - Drosophila Ge-1 promotes P body formation and oskar mRNA localization. AB - mRNA localization coupled with translational control is a widespread and conserved strategy that allows the localized production of proteins within eukaryotic cells. In Drosophila, oskar (osk) mRNA localization and translation at the posterior pole of the oocyte are essential for proper patterning of the embryo. Several P body components are involved in osk mRNA localization and translational repression, suggesting a link between P bodies and osk RNPs. In cultured mammalian cells, Ge-1 protein is required for P body formation. Combining genetic, biochemical and immunohistochemical approaches, we show that, in vivo, Drosophila Ge-1 (dGe-1) is an essential gene encoding a P body component that promotes formation of these structures in the germline. dGe-1 partially colocalizes with osk mRNA and is required for osk RNP integrity. Our analysis reveals that although under normal conditions dGe-1 function is not essential for osk mRNA localization, it becomes critical when other components of the localization machinery, such as staufen, Drosophila decapping protein 1 and barentsz are limiting. Our findings suggest an important role of dGe-1 in optimization of the osk mRNA localization process required for patterning the Drosophila embryo. PMID- 21655182 TI - Caterpillars and fungal pathogens: two co-occurring parasites of an ant-plant mutualism. AB - In mutualisms, each interacting species obtains resources from its partner that it would obtain less efficiently if alone, and so derives a net fitness benefit. In exchange for shelter (domatia) and food, mutualistic plant-ants protect their host myrmecophytes from herbivores, encroaching vines and fungal pathogens. Although selective filters enable myrmecophytes to host those ant species most favorable to their fitness, some insects can by-pass these filters, exploiting the rewards supplied whilst providing nothing in return. This is the case in French Guiana for Cecropia obtusa (Cecropiaceae) as Pseudocabima guianalis caterpillars (Lepidoptera, Pyralidae) can colonize saplings before the installation of their mutualistic Azteca ants. The caterpillars shelter in the domatia and feed on food bodies (FBs) whose production increases as a result. They delay colonization by ants by weaving a silk shield above the youngest trichilium, where the FBs are produced, blocking access to them. This probable temporal priority effect also allows female moths to lay new eggs on trees that already shelter caterpillars, and so to occupy the niche longer and exploit Cecropia resources before colonization by ants. However, once incipient ant colonies are able to develop, they prevent further colonization by the caterpillars. Although no higher herbivory rates were noted, these caterpillars are ineffective in protecting their host trees from a pathogenic fungus, Fusarium moniliforme (Deuteromycetes), that develops on the trichilium in the absence of mutualistic ants. Therefore, the Cecropia treelets can be parasitized by two often overlooked species: the caterpillars that shelter in the domatia and feed on FBs, delaying colonization by mutualistic ants, and the fungal pathogen that develops on old trichilia. The cost of greater FB production plus the presence of the pathogenic fungus likely affect tree growth. PMID- 21655183 TI - BIM-mediated AKT phosphorylation is a key modulator of arsenic trioxide-induced apoptosis in cisplatin-sensitive and -resistant ovarian cancer cells. AB - BACKGROUND: Chemo-resistance to cisplatin-centered cancer therapy is a major obstacle to the effective treatment of human ovarian cancer. Previous reports indicated that arsenic trioxide (ATO) induces cell apoptosis in both drug sensitive and -resistant ovarian cancer cells. PRINCIPAL FINDINGS: In this study, we determined the molecular mechanism of ATO-induced apoptosis in ovarian cancer cells. Our data demonstrated that ATO induced cell apoptosis by decreasing levels of phosphorylated AKT (p-AKT) and activating caspase-3 and caspase-9. Importantly, BIM played a critical role in ATO-induced apoptosis. The inhibition of BIM expression prevented AKT dephosphorylation and inhibited caspase-3 activation during cell apoptosis. However, surprisingly, gene silencing of AKT or FOXO3A had little effect on BIM expression and phosphorylation. Moreover, the activation of caspase-3 by ATO treatment improved AKT dephosphorylation, not only by cleaving the regulatory A subunit of protein phosphatase 2A (PP2A), but also by increasing its activation. Furthermore, our data indicated that the c-Jun N terminal kinases (JNK) pathway is involved in the regulation of BIM expression. CONCLUSIONS: We demonstrated the roles of BIM in ATO-induced apoptosis and the molecular mechanisms of BIM expression regulated by ATO during ovarian cancer cell apoptosis. Our findings suggest that BIM plays an important role in regulating p-AKT by activating caspase-3 and that BIM mediates the level of AKT phosphorylation to determine the threshold for overcoming cisplatin resistance in ovarian cancer cells. PMID- 21655184 TI - A simple, versatile and sensitive cell-based assay for prions from various species. AB - Detection and quantification of prion infectivity is a crucial step for various fundamental and applied aspects of prion research. Identification of cell lines highly sensitive to prion infection led to the development of cell-based titration procedures aiming at replacing animal bioassays, usually performed in mice or hamsters. However, most of these cell lines are only permissive to mouse adapted prions strains and do not allow titration of prions from other species. In this study, we show that epithelial RK13, a cell line permissive to mouse and bank vole prion strains and to natural prion agents from sheep and cervids, enables a robust and sensitive detection of mouse and ovine-derived prions. Importantly, the cell culture work is strongly reduced as the RK13 cell assay procedure designed here does not require subcultivation of the inoculated cultures. We also show that prions effectively bind to culture plastic vessel and are quantitatively detected by the cell assay. The possibility to easily quantify a wider range of prions, including rodent experimental strains but also natural agents from sheep and cervids, should prompt the spread of cell assays for routine prion titration and lead to valuable information in fundamental and applied studies. PMID- 21655185 TI - MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes. AB - Gliomas such as oligodendrogliomas (ODG) and glioblastomas (GBM) are brain tumours with different clinical outcomes. Histology-based classification of these tumour types is often difficult. Therefore the first aim of this study was to gain microRNA data that can be used as reliable signatures of oligodendrogliomas and glioblastomas. We investigated the levels of 282 microRNAs using membrane array hybridisation and real-time PCR in ODG, GBM and control brain tissues. In comparison to these control tissues, 26 deregulated microRNAs were identified in tumours and the tissue levels of seven microRNAs (miR-21, miR-128, miR-132, miR 134, miR-155, miR-210 and miR-409-5p) appropriately discriminated oligodendrogliomas from glioblastomas. Genomic, epigenomic and host gene expression studies were conducted to investigate the mechanisms involved in these deregulations. Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs. We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression. Moreover, MDH1, the target of several deregulated microRNAs, is repressed in glioblastomas, making an intramitochondrial-NAD reduction mediated by the mitochondrial aspartate-malate shuttle unlikely. Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets. PMID- 21655187 TI - Spatially explicit analysis of metal transfer to biota: influence of soil contamination and landscape. AB - Concepts and developments for a new field in ecotoxicology, referred to as "landscape ecotoxicology," were proposed in the 1990s; however, to date, few studies have been developed in this emergent field. In fact, there is a strong interest in developing this area, both for renewing the concepts and tools used in ecotoxicology as well as for responding to practical issues, such as risk assessment. The aim of this study was to investigate the spatial heterogeneity of metal bioaccumulation in animals in order to identify the role of spatially explicit factors, such as landscape as well as total and extractable metal concentrations in soils. Over a smelter-impacted area, we studied the accumulation of trace metals (TMs: Cd, Pb and Zn) in invertebrates (the grove snail Cepaea sp and the glass snail Oxychilus draparnaudi) and vertebrates (the bank vole Myodes glareolus and the greater white-toothed shrew Crocidura russula). Total and CaCl(2)-extractable concentrations of TMs were measured in soils from woody patches where the animals were captured. TM concentrations in animals exhibited a high spatial heterogeneity. They increased with soil pollution and were better explained by total rather than CaCl(2)-extractable TM concentrations, except in Cepaea sp. TM levels in animals and their variations along the pollution gradient were modulated by the landscape, and this influence was species and metal specific. Median soil metal concentrations (predicted by universal kriging) were calculated in buffers of increasing size and were related to bioaccumulation. The spatial scale at which TM concentrations in animals and soils showed the strongest correlations varied between metals, species and landscapes. The potential underlying mechanisms of landscape influence (community functioning, behaviour, etc.) are discussed. Present results highlight the need for the further development of landscape ecotoxicology and multi-scale approaches, which would enhance our understanding of pollutant transfer and effects in ecosystems. PMID- 21655186 TI - Trends of the major porin gene (ompF) evolution: insight from the genus Yersinia. AB - OmpF is one of the major general porins of Enterobacteriaceae that belongs to the first line of bacterial defense and interactions with the biotic as well as abiotic environments. Porins are surface exposed and their structures strongly reflect the history of multiple interactions with the environmental challenges. Unfortunately, little is known on diversity of porin genes of Enterobacteriaceae and the genus Yersinia especially. We analyzed the sequences of the ompF gene from 73 Yersinia strains covering 14 known species. The phylogenetic analysis placed most of the Yersinia strains in the same line assigned by 16S rDNA-gyrB tree. Very high congruence in the tree topologies was observed for Y. enterocolitica, Y. kristensenii, Y. ruckeri, indicating that intragenic recombination in these species had no effect on the ompF gene. A significant level of intra- and interspecies recombination was found for Y. aleksiciae, Y. intermedia and Y. mollaretii. Our analysis shows that the ompF gene of Yersinia has evolved with nonrandom mutational rate under purifying selection. However, several surface loops in the OmpF porin contain positively selected sites, which very likely reflect adaptive diversification Yersinia to their ecological niches. To our knowledge, this is a first investigation of diversity of the porin gene covering the whole genus of the family Enterobacteriaceae. This study demonstrates that recombination and positive selection both contribute to evolution of ompF, but the relative contribution of these evolutionary forces are different among Yersinia species. PMID- 21655188 TI - Heme oxygenase-1 deletion affects stress erythropoiesis. AB - BACKGROUND: Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis. METHODOLOGY/PRINCIPAL FINDINGS: We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-alpha. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF alpha; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations. CONCLUSIONS/SIGNIFICANCE: As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases. PMID- 21655189 TI - 4D super-resolution microscopy with conventional fluorophores and single wavelength excitation in optically thick cells and tissues. AB - BACKGROUND: Optical super-resolution imaging of fluorescently stained biological samples is rapidly becoming an important tool to investigate protein distribution at the molecular scale. It is therefore important to develop practical super resolution methods that allow capturing the full three-dimensional nature of biological systems and also can visualize multiple protein species in the same sample. METHODOLOGY/PRINCIPAL FINDINGS: We show that the use of a combination of conventional near-infrared dyes, such as Alexa 647, Alexa 680 and Alexa 750, all excited with a 671 nm diode laser, enables 3D multi-colour super-resolution imaging of complex biological samples. Optically thick samples, including human tissue sections, cardiac rat myocytes and densely grown neuronal cultures were imaged with lateral resolutions of ~15 nm (std. dev.) while reducing marker cross talk to <1%. Using astigmatism an axial resolution of ~65 nm (std. dev.) was routinely achieved. The number of marker species that can be distinguished depends on the mean photon number of single molecule events. With the typical photon yields from Alexa 680 of ~2000 up to 5 markers may in principle be resolved with <2% crosstalk. CONCLUSIONS/SIGNIFICANCE: Our approach is based entirely on the use of conventional, commercially available markers and requires only a single laser. It provides a very straightforward way to investigate biological samples at the nanometre scale and should help establish practical 4D super-resolution microscopy as a routine research tool in many laboratories. PMID- 21655190 TI - Establishment of a transgenic zebrafish line for superficial skin ablation and functional validation of apoptosis modulators in vivo. AB - BACKGROUND: Zebrafish skin is composed of enveloping and basal layers which form a first-line defense system against pathogens. Zebrafish epidermis contains ionocytes and mucous cells that aid secretion of acid/ions or mucous through skin. Previous studies demonstrated that fish skin is extremely sensitive to external stimuli. However, little is known about the molecular mechanisms that modulate skin cell apoptosis in zebrafish. METHODOLOGY/PRINCIPAL FINDINGS: This study aimed to create a platform to conduct conditional skin ablation and determine if it is possible to attenuate apoptotic stimuli by overexpressing potential apoptosis modulating genes in the skin of live animals. A transgenic zebrafish line of Tg(krt4:NTR-hKikGR)(cy17) (killer line), which can conditionally trigger apoptosis in superficial skin cells, was first established. When the killer line was incubated with the prodrug metrodinazole, the superficial skin displayed extensive apoptosis as judged by detection of massive TUNEL- and active caspase 3-positive signals. Great reductions in NTR-hKikGR(+) fluorescent signals accompanied epidermal cell apoptosis. This indicated that NTR hKikGR(+) signal fluorescence can be utilized to evaluate apoptotic events in vivo. After removal of metrodinazole, the skin integrity progressively recovered and NTR-hKikGR(+) fluorescent signals gradually restored. In contrast, either crossing the killer line with testing lines or transiently injecting the killer line with testing vectors that expressed human constitutive active Akt1, mouse constitutive active Stat3, or HPV16 E6 element displayed apoptosis-resistant phenotypes to cytotoxic metrodinazole as judged by the loss of reduction in NTR hKikGR(+) fluorescent signaling. CONCLUSION/SIGNIFICANCE: The killer/testing line binary system established in the current study demonstrates a nitroreductase/metrodinazole system that can be utilized to conditionally perform skin ablation in a real-time manner, and provides a valuable tool to visualize and quantify the anti-apoptotic potential of interesting target genes in vivo. The current work identifies a potential use for transgenic zebrafish as a high throughput platform to validate potential apoptosis modulators in vivo. PMID- 21655191 TI - Genes of the unfolded protein response pathway harbor risk alleles for primary open angle glaucoma. AB - The statistical power of genome-wide association (GWA) studies to detect risk alleles for human diseases is limited by the unfavorable ratio of SNPs to study subjects. This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status. However, GWA approaches fall short when many rare alleles may give rise to a common disease, or when the number of subjects that can be recruited is limited. Here, we demonstrate that this multiple testing problem can be overcome by a comparative genomics approach in which an initial genome-wide screen in a genetically amenable model organism is used to identify human orthologues that may harbor risk alleles for adult-onset primary open angle glaucoma (POAG). Glaucoma is a major cause of blindness, which affects over 60 million people worldwide. Several genes have been associated with juvenile onset glaucoma, but genetic factors that predispose to adult onset primary open angle glaucoma (POAG) remain largely unknown. Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC). We selected 16 orthologous genes with 62 polymorphic markers and identified in two independent human populations two genes of the UPR that harbor POAG risk alleles, BIRC6 and PDIA5. Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention. PMID- 21655192 TI - Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult. AB - Glutathione (GSH), the major endogenous antioxidant produced by cells, can modulate the activity of N-methyl-D-aspartate receptors (NMDARs) through its reducing functions. During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain. Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR dependent long-term potentiation (LTP), a form of synaptic plasticity thought to represent a cellular model for memory. Here we show that orally supplementing aged mice with N-acetylcysteine, a precursor for the formation of glutathione, reverses the L-type calcium channel-dependent LTP seen in aged animals to NMDAR dependent LTP. In addition, introducing glutathione in the intrapipette solution during whole-cell recordings restores LTP obtained in whole-cell conditions in the aged hippocampus. We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP. PMID- 21655193 TI - A fear-inducing odor alters PER2 and c-Fos expression in brain regions involved in fear memory. AB - Evidence demonstrates that rodents learn to associate a foot shock with time of day, indicating the formation of a fear related time-stamp memory, even in the absence of a functioning SCN. In addition, mice acquire and retain fear memory better during the early day compared to the early night. This type of memory may be regulated by circadian pacemakers outside of the SCN. As a first step in testing the hypothesis that clock genes are involved in the formation of a time stamp fear memory, we exposed one group of mice to fox feces derived odor (TMT) at ZT 0 and one group at ZT 12 for 4 successive days. A separate group with no exposure to TMT was also included as a control. Animals were sacrificed one day after the last exposure to TMT, and PER2 and c-Fos protein were quantified in the SCN, amygdala, hippocampus, and piriform cortex. Exposure to TMT had a strong effect at ZT 0, decreasing PER2 expression at this time point in most regions except the SCN, and reversing the normal rhythm of PER2 expression in the amygdala and piriform cortex. These changes were accompanied by increased c-Fos expression at ZT0. In contrast, exposure to TMT at ZT 12 abolished the rhythm of PER2 expression in the amygdala. In addition, increased c-Fos expression at ZT 12 was only detected in the central nucleus of the amygdala in the TMT12 group. TMT exposure at either time point did not affect PER2 or c-Fos in the SCN, indicating that under a light-dark cycle, the SCN rhythm is stable in the presence of repeated exposure to a fear-inducing stimulus. Taken together, these results indicate that entrainment to a fear-inducing stimulus leads to changes in PER2 and c-Fos expression that are detected 24 hours following the last exposure to TMT, indicating entrainment of endogenous oscillators in these regions. The observed effects on PER2 expression and c-Fos were stronger during the early day than during the early night, possibly to prepare appropriate systems at ZT 0 to respond to a fear-inducing stimulus. PMID- 21655194 TI - Spag16, an axonemal central apparatus gene, encodes a male germ cell nuclear speckle protein that regulates SPAG16 mRNA expression. AB - Spag16 is the murine orthologue of Chlamydomonas reinhardtii PF20, a protein known to be essential to the structure and function of the "9+2" axoneme. In Chlamydomonas, the PF20 gene encodes a single protein present in the central pair of the axoneme. Loss of PF20 prevents central pair assembly/integrity and results in flagellar paralysis. Here we demonstrate that the murine Spag16 gene encodes two proteins: 71 kDa SPAG16L, which is found in all murine cells with motile cilia or flagella, and 35 kDa SPAG16S, representing the C terminus of SPAG16L, which is expressed only in male germ cells, and is predominantly found in specific regions within the nucleus that also contain SC35, a known marker of nuclear speckles enriched in pre-mRNA splicing factors. SPAG16S expression precedes expression of SPAG16L. Mice homozygous for a knockout of SPAG16L alone are infertile, but show no abnormalities in spermatogenesis. Mice chimeric for a mutation deleting the transcripts for both SPAG16L and SPAG16S have a profound defect in spermatogenesis. We show here that transduction of SPAG16S into cultured dispersed mouse male germ cells and BEAS-2B human bronchial epithelial cells increases SPAG16L expression, but has no effect on the expression of several other axoneme components. We also demonstrate that the Spag16L promoter shows increased activity in the presence of SPAG16S. The distinct nuclear localization of SPAG16S and its ability to modulate Spag16L mRNA expression suggest that SPAG16S plays an important role in the gene expression machinery of male germ cells. This is a unique example of a highly conserved axonemal protein gene that encodes two protein products with different functions. PMID- 21655195 TI - The motivational salience of infant faces is similar for men and women. AB - Infant facial features are thought to be powerful elicitors of caregiving behaviour. It has been widely assumed that men and women respond in different ways to those features, such as a large forehead and eyes and round protruding cheeks, colloquially described as 'cute'. We investigated experimentally potential differences using measures of both conscious appraisal ('liking') and behavioural responsivity ('wanting') to real world infant and adult faces in 71 non-parents. Overall, women gave significantly higher 'liking' ratings for infant faces (but not adult faces) compared to men. However, this difference was not seen in the 'wanting' task, where we measured the willingness of men and women to key-press to increase or decrease viewing duration of an infant face. Further analysis of sensitivity to cuteness, categorising infants by degree of infantile features, revealed that both men and women showed a graded significant increase in both positive attractiveness ratings and viewing times to the 'cutest' infants. We suggest that infant faces may have similar motivational salience to men and women, despite gender idiosyncrasies in their conscious appraisal. PMID- 21655196 TI - Three-armed trials including placebo and no-treatment groups may be subject to publication bias: systematic review. AB - BACKGROUND: It has been argued that placebos may not have important clinical impacts in general. However, there is increasing evidence of a publication bias among trials published in journals. Therefore, we explored the potential for publication bias in randomized trials with active treatment, placebo, and no treatment groups. METHODS: Three-armed randomized trials of acupuncture, acupoint stimulation, and transcutaneous electrical stimulation were obtained from electronic databases. Effect sizes between treatment and placebo groups were calculated for treatment effect, and effect sizes between placebo and no treatment groups were calculated for placebo effect. All data were then analyzed for publication bias. RESULTS: For the treatment effect, small trials with fewer than 100 patients per arm showed more benefits than large trials with at least 100 patients per arm in acupuncture and acupoint stimulation. For the placebo effect, no differences were found between large and small trials. Further analyses showed that the treatment effect in acupuncture and acupoint stimulation may be subject to publication bias because study design and any known factors of heterogeneity were not associated with the small study effects. In the simulation, the magnitude of the placebo effect was smaller than that calculated after considering publication bias. CONCLUSIONS: Randomized three-armed trials, which are necessary for estimating the placebo effect, may be subject to publication bias. If the magnitude of the placebo effect is assessed in an intervention, the potential for publication bias should be investigated using data related to the treatment effect. PMID- 21655197 TI - Scaling behavior of human locomotor activity amplitude: association with bipolar disorder. AB - Scale invariance is a feature of complex biological systems, and abnormality of multi-scale behaviour may serve as an indicator of pathology. The hypothalamic suprachiasmatic nucleus (SCN) is a major node in central neural networks responsible for regulating multi-scale behaviour in measures of human locomotor activity. SCN also is implicated in the pathophysiology of bipolar disorder (BD) or manic-depressive illness, a severe, episodic disorder of mood, cognition and behaviour. Here, we investigated scaling behaviour in actigraphically recorded human motility data for potential indicators of BD, particularly its manic phase. A proposed index of scaling behaviour (Vulnerability Index [VI]) derived from such data distinguished between: [i] healthy subjects at high versus low risk of mood disorders; [ii] currently clinically stable BD patients versus matched controls; and [iii] among clinical states in BD patients. PMID- 21655198 TI - CXCR7 protein expression in human adult brain and differentiated neurons. AB - BACKGROUND: CXCR7 and CXCR4 are receptors for the chemokine CXCL12, which is involved in essential functions of the immune and nervous systems. Although CXCR7 transcripts are widely expressed throughout the central nervous system, little is known about its protein distribution and function in the adult brain. To evaluate its potential involvement in CXCL12/CXCR4 signaling in differentiated neurons, we studied CXCR7 protein expression in human brain and cultured neurons. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemistry and RT-PCR analyses of cortex and hippocampus from control and HIV-positive subjects provided the first evidence of CXCR7 protein expression in human adult neurons, under normal and pathological conditions. Furthermore, confocal microscopy and binding assays in cultured neurons show that CXCR7 protein is mainly located into cytoplasm, while little to no protein expression is found on neuronal plasma membrane. Interestingly, specific CXCR7 ligands that inhibit CXCL12 binding to CXCR7 do not alter CXCR4-activated survival signaling (pERK/pAkt) in rat cortical neurons. Neuronal CXCR7 co-localizes to some extent with the endoplasmic reticulum marker ERp29, but not with early/late endosome markers. Additionally, large areas of overlap are detected in the intracellular pattern of CXCR7 and CXCR4 expression. CONCLUSIONS/SIGNIFICANCE: Overall, these results implicate CXCR4 as the main CXCL12 signaling receptor on the surface of differentiated neurons and suggest that CXCR7 may interact with CXCR4 at the intracellular level, possibly affecting CXCR4 trafficking and/or coupling to other proteins. PMID- 21655199 TI - Increased insensible water loss contributes to aging related dehydration. AB - Dehydration with aging is attributed to decreased urine concentrating ability and thirst. We further investigated by comparing urine concentration and water balance in 3, 18 and 27 month old mice, consuming equal amounts of water. During water restriction, 3 month old mice concentrate their urine sufficiently to maintain water balance (stable weight). 18 month old mice concentrate their urine as well, but still lose weight (negative water balance). 27 month old mice do not concentrate their urine as well and lose even more weight than the 18 month old mice, indicating a larger negative water balance. Negative water balance in older mice is accompanied by increased vasopressin excretion, providing further evidence of dehydration. All 3 groups maintain water balance while consuming only the water in gel food containing 56% water. However, both older groups excrete a smaller volume of urine of higher osmolality, indicating greater extra urinary water loss. Since their feces also contain less water, the excess water lost by the older mice apparently is through other routes, presumably insensible loss through the respiratory tract and skin. The greater insensible water loss occurs at an earlier age (18 months) than decreased urine concentrating ability (27 months). We propose that insensible water loss through skin and respiration increases with age, making a major contribution to aging related dehydration. PMID- 21655200 TI - Mouse transcobalamin has features resembling both human transcobalamin and haptocorrin. AB - In humans, the cobalamin (Cbl) -binding protein transcobalamin (TC) transports Cbl from the intestine and into all the cells of the body, whereas the glycoprotein haptocorrin (HC), which is present in both blood and exocrine secretions, is able to bind also corrinoids other than Cbl. The aim of this study is to explore the expression of the Cbl-binding protein HC as well as TC in mice. BLAST analysis showed no homologous gene coding for HC in mice. Submaxillary glands and serum displayed one protein capable of binding Cbl. This Cbl-binding protein was purified from 300 submaxillary glands by affinity chromatography. Subsequent sequencing identified the protein as TC. Further characterization in terms of glycosylation status and binding specificity to the Cbl-analogue cobinamide revealed that mouse TC does not bind Concanavalin A sepharose (like human TC), but is capable of binding cobinamide (like human HC). Antibodies raised against mouse TC identified the protein in secretory cells of the submaxillary gland and in the ducts of the mammary gland, i.e. at locations where HC is also found in humans. Analysis of the TC-mRNA level showed a high TC transcript level in these glands and also in the kidney. By precipitation to insolubilised antibodies against mouse TC, we also showed that >97% of the Cbl binding capacity and >98% of the Cbl were precipitated in serum. This indicates that TC is the only Cbl-binding protein in the mouse circulation. Our data show that TC but not HC is present in the mouse. Mouse TC is observed in tissues where humans express TC and/or HC. Mouse TC has features in common with both human TC and HC. Our results suggest that the Cbl-binding proteins present in the circulation and exocrine glands may vary amongst species. PMID- 21655203 TI - Detecting Coevolution of Functionally Related Proteins for Automated Protein Annotation. AB - Sequence similarity based protein clustering methods organize proteins into families of similar sequences, a task that continues to be critical for automated protein characterization. However, many protein families cannot be automatically characterized further because little is known about the function of any protein in a family of similar sequences. We present a novel phylogenetic profile comparison (PPC) method called Automated Protein Annotation by Coordinate Evolution (APACE) that facilitates the automated characterization of proteins beyond their homology to other similar sequences. Our method implements a new approach for the normalization of similarity scores among multiple species and automates the characterization of proteins by their patterns of co-evolution with other proteins that do not necessarily share a similar sequence. We demonstrate that our method is able to recapitulate the topology of the latest, unresolved, composite deep eukaryotic phylogeny and is able to quantify the as yet unresolved branch lengths. We further demonstrate that our method is able to detect more functionally related proteins, given the same starting data, than existing methods. Finally, we demonstrate that our method can be successfully applied to much larger comparative genomic problem instances where existing methods often fail. PMID- 21655204 TI - Vocal cord palsy: An uncommon presenting feature of myasthenia gravis. AB - Vocal cord palsy can have myriad causes. Unilateral vocal cord palsy is common and frequently asymptomatic. Trauma, head, neck and mediastinal tumors as well as cerebrovascular accidents have been implicated in causing unilateral vocal cord palsy. Viral neuronitis accounts for most idiopathic cases. Bilateral vocal cord palsy, on the other hand, is much less common and is a potentially life threatening condition. Myasthenia gravis, an autoimmune disorder caused by antibodies targeting the post-synaptic acetylcholine receptor, has been infrequently implicated in its causation. We report here a case of bilateral vocal cord palsy developing in a 68-year-old man with no prior history of myasthenia gravis 2 months after he was operated on for diverticulitis of the large intestine. Delay in considering the diagnosis led to endotracheal intubation and prolonged mechanical ventilation with attendant complications. Our case adds to the existing literature implicating myasthenia gravis as an infrequent cause of bilateral vocal cord palsy. Our case is unusual as, in our patient, acute-onset respiratory distress and stridor due to bilateral vocal cord palsy was the first manifestation of a myasthenic syndrome. PMID- 21655205 TI - Carcinoma of gall bladder presenting as dermatomyositis. AB - Cancer-related muscle diseases are usually paraneoplastic disorders. Dermatomyositis (DM) is a type of inflammatory myopathy that is strongly associated with a broad range of malignant disorders. The malignancy can occur before, concomitantly or after the onset of myositis. The malignancies most commonly associated with DM are carcinomas of ovary, lung, stomach, colorectal and pancreas, as well as non-Hodgkin's lymphoma. An association of DM with carcinoma of the gall bladder (GB) is extremely rare with only two previously reported cases in the literature. We report a case of carcinoma of GB with DM as the paraneoplastic manifestation. PMID- 21655206 TI - Macroglossia associated with 271 bp deletion in exon 50 of dystrophin gene. AB - Macroglossia is rare in patients of Duchenne muscular dystrophy (DMD), and its occurrence without any endocrinologic abnormality, seizures or an abnormal karyotype is even rarer. We describe a patient of DMD with isolated macroglossia with 271 bp deletion in exon 50 of the dystrophin gene and speculate a relationship in this regard. PMID- 21655207 TI - Kleine-Levine syndrome in an adolescent female and response to modafinil. AB - Kleine-Levine Syndrome (KLS) is a disorder characterized by a triad of periodic hypersomnia, hyperphagia, and hypersexuality. KLS, although more common in young males, it has also been seen in females. Treatment options available for its management include mood stabilisers like lithium, stimulants like amphetamines, antidepressants and other options including electroconvulsive therapy. Modafinil is one of the new stimulant medications approved for narcolepsy. Herein, we report a young female with KLS and showing favorable response to modafinil. More data is required to establish the effectiveness of modafinil in this syndrome. PMID- 21655208 TI - Mcleod syndrome: Report of an Indian family with phenotypic heterogeneity. AB - The present report deals with the clinical phenomenology of three members (brothers) of one family with McLeod syndrome (MLS). In two, the clinical pictures were of choreiform disorders with amyotrophy, which were found to be neurogenic in origin by detailed electrophysiological study. The index case had peripheral acanthocytosis; immunohematological and molecular genetic studies confirmed diagnosis of MLS. However, one brother only had a slowly progressive motor neuron disease like picture but no abnormal movement disorder. He had peripheral acanthocytes as well. The inheritance seems to be X-linked recessive in nature. The affected family members exhibited much phenotypic heterogeneity. This appears to be the first report of MLS from India. PMID- 21655209 TI - A case of disseminated neurocysticercosis. PMID- 21655210 TI - Superficial siderosis. PMID- 21655211 TI - Axelrod's metanorm games on networks. AB - Metanorms is a mechanism proposed to promote cooperation in social dilemmas. Recent experimental results show that network structures that underlie social interactions influence the emergence of norms that promote cooperation. We generalize Axelrod's analysis of metanorms dynamics to interactions unfolding on networks through simulation and mathematical modeling. Network topology strongly influences the effectiveness of the metanorms mechanism in establishing cooperation. In particular, we find that average degree, clustering coefficient and the average number of triplets per node play key roles in sustaining or collapsing cooperation. PMID- 21655212 TI - Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy. AB - BACKGROUND: Podocyte injury and subsequent excretion in urine play a crucial role in the pathogenesis and progression of diabetic nephropathy (DN). Quantification of messenger RNA (mRNA) expression in urinary sediment by real-time PCR is emerging as a noninvasive method of screening DN-associated biomarkers. We hypothesized that the urinary mRNA profile of podocyte-associated molecules may provide important clinical insight into the different stages of diabetic nephropathy. METHODS: DN patients (N = 51) and healthy controls (N = 13) were enrolled in this study. DN patients were divided into a normoalbuminuria group (UAE<30 mg/g, n = 17), a microalbuminuria group (UAE 30~300 mg/g, n = 15), and a macroalbuminuria group (UAE>300 mg/g, n = 19), according to their urinary albumin excretion (UAE). Relative mRNA abundance of synaptopodin, podocalyxin, CD2-AP, alpha-actin4, and podocin were quantified, and correlations between target mRNAs and clinical parameters were examined. RESULTS: The urinary mRNA levels of all genes studied were significantly higher in the DN group compared with controls (p<0.05), and mRNA levels increased with DN progression. Urinary mRNA levels of all target genes positively correlated with both UAE and BUN. The expression of podocalyxin, CD2-AP, alpha-actin4, and podocin mRNA correlated with serum creatinine (r = 0.457, p = 0.001; r = 0.329, p = 0.01; r = 0.286, p = 0.021; r = 0.357, p = 0.006, respectively). Furthermore, podocalyxin mRNA was found to negatively correlate with eGFR (r = -0.349, p = 0.01). CONCLUSION: The urinary mRNA profiles of synaptopodin, podocalyxin, CD2-AP, alpha-actin4, and podocin were found to increase with the progression of DN, which suggested that quantification of podocyte-associated molecules will be useful biomarkers of DN. PMID- 21655213 TI - Abnormal dosage compensation of reporter genes driven by the Drosophila glass multiple reporter (GMR) enhancer-promoter. AB - In Drosophila melanogaster the male specific lethal (MSL) complex is required for upregulation of expression of most X-linked genes in males, thereby achieving X chromosome dosage compensation. The MSL complex is highly enriched across most active X-linked genes with a bias towards the 3' end. Previous studies have shown that gene transcription facilitates MSL complex binding but the type of promoter did not appear to be important. We have made the surprising observation that genes driven by the glass multiple reporter (GMR) enhancer-promoter are not dosage compensated at X-linked sites. The GMR promoter is active in all cells in, and posterior to, the morphogenetic furrow of the developing eye disc. Using phiC31 integrase-mediated targeted integration, we measured expression of lacZ reporter genes driven by either the GMR or armadillo (arm) promoters at each of three X-linked sites. At all sites, the arm-lacZ reporter gene was dosage compensated but GMR-lacZ was not. We have investigated why GMR-driven genes are not dosage compensated. Earlier or constitutive expression of GMR-lacZ did not affect the level of compensation. Neither did proximity to a strong MSL binding site. However, replacement of the hsp70 minimal promoter with a minimal promoter from the X-linked 6-Phosphogluconate dehydrogenase gene did restore partial dosage compensation. Similarly, insertion of binding sites for the GAGA and DREF factors upstream of the GMR promoter led to significantly higher lacZ expression in males than females. GAGA and DREF have been implicated to play a role in dosage compensation. We conclude that the gene promoter can affect MSL complex mediated upregulation and dosage compensation. Further, it appears that the nature of the basal promoter and the presence of binding sites for specific factors influence the ability of a gene promoter to respond to the MSL complex. PMID- 21655214 TI - Nicotinic acid receptor abnormalities in human skin cancer: implications for a role in epidermal differentiation. AB - BACKGROUND: Chronic UV skin exposure leads to epidermal differentiation defects in humans that can be largely restored by pharmacological doses of nicotinic acid. Nicotinic acid has been identified as a ligand for the human G-protein coupled receptors GPR109A and GPR109B that signal through G(i)-mediated inhibition of adenylyl cyclase. We have examined the expression, cellular distribution, and functionality of GPR109A/B in human skin and skin derived epidermal cells. RESULTS: Nicotinic acid increases epidermal differentiation in photodamaged human skin as judged by the terminal differentiation markers caspase 14 and filaggrin. Both GPR109A and GPR109B genes are transcribed in human skin and in epidermal keratinocytes, but expression in dermal fibroblasts is below limits of detection. Receptor transcripts are greatly over-expressed in squamous cell cancers. Receptor protein in normal skin is prominent from the basal through granular layers of the epidermis, with cellular localization more dispersive in the basal layer but predominantly localized at the plasma membrane in more differentiated epidermal layers. In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional G(i)-mediated signaling. In contrast, in a squamous cell carcinoma derived cell line, receptor protein shows a more diffuse cellular localization and the receptors are nearly non-functional. CONCLUSIONS: The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role(s) of nicotinic acid receptors in human skin homeostasis. PMID- 21655215 TI - Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRgamma in skeletal muscle. AB - BACKGROUND: Retinoid X receptor (RXR) gamma is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXRgamma in skeletal muscle (RXRgamma mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism. METHODOLOGY/PRINCIPAL FINDINGS: RXRgamma mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXRgamma mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXRgamma mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXRgamma and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXRgamma mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXRgamma and PPARdelta resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXRgamma overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs. CONCLUSIONS/SIGNIFICANCE: Systemic glucose metabolism was increased in transgenic mice overexpressing RXRgamma. The enhanced glucose tolerance in RXRgamma mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXRgamma expression may be a novel therapeutic strategy against type 2 diabetes. PMID- 21655216 TI - Environmental and climatic determinants of molecular diversity and genetic population structure in a coenagrionid damselfly. AB - Identifying environmental factors that structure intraspecific genetic diversity is of interest for both habitat preservation and biodiversity conservation. Recent advances in statistical and geographical genetics make it possible to investigate how environmental factors affect geographic organisation and population structure of molecular genetic diversity within species. Here we present a study on a common and wide ranging insect, the blue tailed damselfly Ischnuraelegans, which has been the target of many ecological and evolutionary studies. We addressed the following questions: (i) Is the population structure affected by longitudinal or latitudinal gradients?; (ii) Do geographic boundaries limit gene flow?; (iii) Does geographic distance affect connectivity and is there a signature of past bottlenecks?; (iv) Is there evidence of a recent range expansion and (vi) what is the effect of geography and climatic factors on population structure? We found low to moderate genetic sub-structuring between populations (mean F(ST) = 0.06, D(est) = 0.12), and an effect of longitude, but not latitude, on genetic diversity. No significant effects of geographic boundaries (e.g. water bodies) were found. F(ST)-and D(est)-values increased with geographic distance; however, there was no evidence for recent bottlenecks. Finally, we did not detect any molecular signatures of range expansions or an effect of geographic suitability, although local precipitation had a strong effect on genetic differentiation. The population structure of this small insect has probably been shaped by ecological factors that are correlated with longitudinal gradients, geographic distances, and local precipitation. The relatively weak global population structure and high degree of genetic variation within populations suggest that I. elegans has high dispersal ability, which is consistent with this species being an effective and early coloniser of new habitats. PMID- 21655217 TI - Ecdysteroid-dependent expression of the tweedle and peroxidase genes during adult cuticle formation in the honey bee, Apis mellifera. AB - Cuticle renewal is a complex biological process that depends on the cross talk between hormone levels and gene expression. This study characterized the expression of two genes encoding cuticle proteins sharing the four conserved amino acid blocks of the Tweedle family, AmelTwdl1 and AmelTwdl2, and a gene encoding a cuticle peroxidase containing the Animal haem peroxidase domain, Ampxd, in the honey bee. Gene sequencing and annotation validated the formerly predicted tweedle genes, and revealed a novel gene, Ampxd, in the honey bee genome. Expression of these genes was studied in the context of the ecdysteroid coordinated pupal-to-adult molt, and in different tissues. Higher transcript levels were detected in the integument after the ecdysteroid peak that induces apolysis, coinciding with the synthesis and deposition of the adult exoskeleton and its early differentiation. The effect of this hormone was confirmed in vivo by tying a ligature between the thorax and abdomen of early pupae to prevent the abdominal integument from coming in contact with ecdysteroids released from the prothoracic gland. This procedure impaired the natural increase in transcript levels in the abdominal integument. Both tweedle genes were expressed at higher levels in the empty gut than in the thoracic integument and trachea of pharate adults. In contrast, Ampxd transcripts were found in higher levels in the thoracic integument and trachea than in the gut. Together, the data strongly suggest that these three genes play roles in ecdysteroid-dependent exoskeleton construction and differentiation and also point to a possible role for the two tweedle genes in the formation of the cuticle (peritrophic membrane) that internally lines the gut. PMID- 21655218 TI - Endogenous synthesis of n-3 polyunsaturated fatty acids in Fat-1 mice is associated with increased mammary gland and liver syndecan-1. AB - Long chain n-3 PUFA have been shown to have chemopreventive properties against breast cancer through various mechanisms. One pathway, studied in human breast cancer cell lines, involves upregulation of the proteoglycan, syndecan-1 (SDC-1) by n-3 PUFA-enriched LDL. Using Fat-1 mice that are able to convert n-6 to n-3 PUFA, we tested whether SDC-1 level in vivo is elevated in mammary glands due to endogenously synthesized rather than LDL-derived n-3 PUFA. Female Fat-1 and wild type (wt) mice were fed an n-6 PUFA- enriched diet for 7 weeks. Fatty acid analysis of plasma lipoproteins showed that total n-6 PUFA reflected dietary intake similarly in both genotypes (VLDL, 36.2+/-2.2 and 40.9+/-3.9; LDL, 49.0+/ 3.3 and 48.1+/-2.0; HDL, 54.6+/-1.2 and 58.2+/-1.3, mean +/- SEM percent of total fatty acids for Fat-1 and wt animals respectively). Lipoprotein percent n-3 PUFA was also similar between groups. However, phospholipids and triglycerides extracted from mammary and liver tissues demonstrated significantly higher n-3 PUFA and a corresponding decrease in the ratio n-6/n-3 PUFA in Fat-1 compared to wt mice. This was accompanied by higher SDC-1 in mammary glands and livers of Fat 1 mice, thus demonstrating that endogenously synthesized n-3 PUFA may upregulate SDC-1 in the presence of high dietary n-6 PUFA. PMID- 21655219 TI - Knockdown of midgut genes by dsRNA-transgenic plant-mediated RNA interference in the hemipteran insect Nilaparvata lugens. AB - BACKGROUND: RNA interference (RNAi) is a powerful technique for functional genomics research in insects. Transgenic plants producing double-stranded RNA (dsRNA) directed against insect genes have been reported for lepidopteran and coleopteran insects, showing potential for field-level control of insect pests, but this has not been reported for other insect orders. METHODOLOGY/PRINCIPAL FINDINGS: The Hemipteran insect brown planthopper (Nilaparvata lugens Stal) is a typical phloem sap feeder specific to rice (Oryza sativa L.). To analyze the potential of exploiting RNAi-mediated effects in this insect, we identified genes (Nlsid-1 and Nlaub) encoding proteins that might be involved in the RNAi pathway in N. lugens. Both genes are expressed ubiquitously in nymphs and adult insects. Three genes (the hexose transporter gene NlHT1, the carboxypeptidase gene Nlcar and the trypsin-like serine protease gene Nltry) that are highly expressed in the N. lugens midgut were isolated and used to develop dsRNA constructs for transforming rice. RNA blot analysis showed that the dsRNAs were transcribed and some of them were processed to siRNAs in the transgenic lines. When nymphs were fed on rice plants expressing dsRNA, levels of transcripts of the targeted genes in the midgut were reduced; however, lethal phenotypic effects after dsRNA feeding were not observed. CONCLUSIONS: Our study shows that genes for the RNAi pathway (Nlsid-1 and Nlaub) are present in N. lugens. When insects were fed on rice plant materials expressing dsRNAs, RNA interference was triggered and the target genes transcript levels were suppressed. The gene knockdown technique described here may prove to be a valuable tool for further investigations in N. lugens. The results demonstrate the potential of dsRNA-mediated RNAi for field level control of planthoppers, but appropriate target genes must be selected when designing the dsRNA-transgenic plants. PMID- 21655221 TI - Conservation genetics of a critically endangered limpet genus and rediscovery of an extinct species. AB - BACKGROUND: A third of all known freshwater mollusk extinctions worldwide have occurred within a single medium-sized American drainage. The Mobile River Basin (MRB) of Alabama, a global hotspot of temperate freshwater biodiversity, was intensively industrialized during the 20(th) century, driving 47 of its 139 endemic mollusk species to extinction. These include the ancylinid limpet Rhodacmea filosa, currently classified as extinct (IUCN Red List), a member of a critically endangered southeastern North American genus reduced to a single known extant population (of R. elatior) in the MRB. METHODOLOGY/PRINCIPAL FINDINGS: We document here the tripling of known extant populations of this North American limpet genus with the rediscovery of enduring Rhodacmea filosa in a MRB tributary and of R. elatior in its type locality: the Green River, Kentucky, an Ohio River Basin (ORB) tributary. Rhodacmea species are diagnosed using untested conchological traits and we reassessed their systematic and conservation status across both basins using morphometric and genetic characters. Our data corroborated the taxonomic validity of Rhodacmea filosa and we inferred a within MRB cladogenic origin from a common ancestor bearing the R. elatior shell phenotype. The geographically-isolated MRB and ORB R. elatior populations formed a cryptic species complex: although overlapping morphometrically, they exhibited a pronounced phylogenetic disjunction that greatly exceeded that of within-MRB R. elatior and R. filosa sister species. CONCLUSIONS/SIGNIFICANCE: Rhodacmea filosa, the type species of the genus, is not extinct. It persists in a Coosa River tributary and morphometric and phylogenetic analyses confirm its taxonomic validity. All three surviving populations of the genus Rhodacmea merit specific status. They collectively contain all known survivors of a phylogenetically highly distinctive North American endemic genus and therefore represent a concentrated fraction of continental freshwater gastropod biodiversity. We recommend the establishment of a proactive targeted conservation program that may include their captive propagation and reintroduction. PMID- 21655220 TI - Snapshot of the eukaryotic gene expression in muskoxen rumen--a metatranscriptomic approach. AB - BACKGROUND: Herbivores rely on digestive tract lignocellulolytic microorganisms, including bacteria, fungi and protozoa, to derive energy and carbon from plant cell wall polysaccharides. Culture independent metagenomic studies have been used to reveal the genetic content of the bacterial species within gut microbiomes. However, the nature of the genes encoded by eukaryotic protozoa and fungi within these environments has not been explored using metagenomic or metatranscriptomic approaches. METHODOLOGY/PRINCIPAL FINDINGS: In this study, a metatranscriptomic approach was used to investigate the functional diversity of the eukaryotic microorganisms within the rumen of muskoxen (Ovibos moschatus), with a focus on plant cell wall degrading enzymes. Polyadenylated RNA (mRNA) was sequenced on the Illumina Genome Analyzer II system and 2.8 gigabases of sequences were obtained and 59129 contigs assembled. Plant cell wall degrading enzyme modules including glycoside hydrolases, carbohydrate esterases and polysaccharide lyases were identified from over 2500 contigs. These included a number of glycoside hydrolase family 6 (GH6), GH48 and swollenin modules, which have rarely been described in previous gut metagenomic studies. CONCLUSIONS/SIGNIFICANCE: The muskoxen rumen metatranscriptome demonstrates a much higher percentage of cellulase enzyme discovery and an 8.7x higher rate of total carbohydrate active enzyme discovery per gigabase of sequence than previous rumen metagenomes. This study provides a snapshot of eukaryotic gene expression in the muskoxen rumen, and identifies a number of candidate genes coding for potentially valuable lignocellulolytic enzymes. PMID- 21655222 TI - Dual organism transcriptomics of airway epithelial cells interacting with conidia of Aspergillus fumigatus. AB - BACKGROUND: Given the complex nature of the responses that can occur in host pathogen interactions, dual transcriptomics offers a powerful method of elucidating these interactions during infection. The gene expression patterns of Aspergillus fumigatus conidia or host cells have been reported in a number of previous studies, but each focused on only one of the interacting organisms. In the present study, we profiled simultaneously the transcriptional response of both A. fumigatus and human airway epithelial cells (AECs). METHODOLOGY: 16HBE14o transformed bronchial epithelial cells were incubated with A. fumigatus conidia at 37 degrees C for 6 hours, followed by genome-wide transcriptome analysis using human and fungal microarrays. Differentially expressed gene lists were generated from the microarrays, from which biologically relevant themes were identified. Human and fungal candidate genes were selected for validation, using RT-qPCR, in both 16HBE14o- cells and primary AECs co-cultured with conidia. PRINCIPAL FINDINGS: We report that ontologies related to the innate immune response are activated by co-incubation with A. fumigatus condia, and interleukin-6 (IL-6) was confirmed to be up-regulated in primary AECs via RT-qPCR. Concomitantly, A. fumigatus was found to up-regulate fungal pathways involved in iron acquisition, vacuolar acidification, and formate dehydrogenase activity. CONCLUSION: To our knowledge, this is the first study to apply a dual organism transcriptomics approach to interactions of A. fumigatus conidia and human airway epithelial cells. The up-regulation of IL-6 by epithelia and simultaneous activation of several pathways by fungal conidia warrants further investigation as we seek to better understand this interaction in both health and disease. The cellular response of the airway epithelium to A. fumigatus is important to understand if we are to improve host-pathogen outcomes. PMID- 21655223 TI - Subcellular localization of SUN2 is regulated by lamin A and Rab5. AB - SUN2 is an inner nuclear membrane protein with a conserved Sad1/UNC-84 homology SUN-domain at the C-terminus. Intriguingly, SUN2 has also been reported to interact with Rab5, which localizes in early endosomes. To clarify the dual subcellular localization of SUN2, we investigated its localization in lamin A/C deficient cells rescued with lamin A or lamin C isoform, and in HeLa cells transfected with Rab5 or its mutants. We found that expression of lamin A but not lamin C partly restored the nuclear envelope localization of SUN2. SUN2 was redistributed to endosomes upon overexpression of Rab5, but remained on the nuclear envelope when the SUN domain was deleted. To explore the physiological function of SUN2 in vesicle trafficking and endocytosis, we demonstrated the colocalization of endogenous SUN2 and Rab5. Moreover, overexpression of SUN2 stimulated the uptake of transferrin while suppression of SUN2 expression attenuated the process. These findings support a role of SUN2 in endocytosis. PMID- 21655224 TI - The strength and timing of the mitochondrial bottleneck in salmon suggests a conserved mechanism in vertebrates. AB - In most species mitochondrial DNA (mtDNA) is inherited maternally in an apparently clonal fashion, although how this is achieved remains uncertain. Population genetic studies show not only that individuals can harbor more than one type of mtDNA (heteroplasmy) but that heteroplasmy is common and widespread across a diversity of taxa. Females harboring a mixture of mtDNAs may transmit varying proportions of each mtDNA type (haplotype) to their offspring. However, mtDNA variants are also observed to segregate rapidly between generations despite the high mtDNA copy number in the oocyte, which suggests a genetic bottleneck acts during mtDNA transmission. Understanding the size and timing of this bottleneck is important for interpreting population genetic relationships and for predicting the inheritance of mtDNA based disease, but despite its importance the underlying mechanisms remain unclear. Empirical studies, restricted to mice, have shown that the mtDNA bottleneck could act either at embryogenesis, oogenesis or both. To investigate whether the size and timing of the mitochondrial bottleneck is conserved between distant vertebrates, we measured the genetic variance in mtDNA heteroplasmy at three developmental stages (female, ova and fry) in chinook salmon and applied a new mathematical model to estimate the number of segregating units (N(e)) of the mitochondrial bottleneck between each stage. Using these data we estimate values for mtDNA Ne of 88.3 for oogenesis, and 80.3 for embryogenesis. Our results confirm the presence of a mitochondrial bottleneck in fish, and show that segregation of mtDNA variation is effectively complete by the end of oogenesis. Considering the extensive differences in reproductive physiology between fish and mammals, our results suggest the mechanism underlying the mtDNA bottleneck is conserved in these distant vertebrates both in terms of it magnitude and timing. This finding may lead to improvements in our understanding of mitochondrial disorders and population interpretations using mtDNA data. PMID- 21655225 TI - Matrix recruitment and calcium sequestration for spatial specific otoconia development. AB - Otoconia are bio-crystals anchored to the macular sensory epithelium of the utricle and saccule in the inner ear for motion sensing and bodily balance. Otoconia dislocation, degeneration and ectopic calcification can have detrimental effects on balance and vertigo/dizziness, yet the mechanism underlying otoconia formation is not fully understood. In this study, we show that selected matrix components are recruited to form the crystal matrix and sequester Ca(2+) for spatial specific formation of otoconia. Specifically, otoconin-90 (Oc90) binds otolin through both domains (TH and C1q) of otolin, but full-length otolin shows the strongest interaction. These proteins have much higher expression levels in the utricle and saccule than other inner ear epithelial tissues in mice. In vivo, the presence of Oc90 in wildtype (wt) mice leads to an enrichment of Ca(2+) in the luminal matrices of the utricle and saccule, whereas absence of Oc90 in the null mice leads to drastically reduced matrix-Ca(2+). In vitro, either Oc90 or otolin can increase the propensity of extracellular matrix to calcify in cell culture, and co-expression has a synergistic effect on calcification. Molecular modeling and sequence analysis predict structural features that may underlie the interaction and Ca(2+)-sequestering ability of these proteins. Together, the data provide a mechanism for the otoconial matrix assembly and the role of this matrix in accumulating micro-environmental Ca(2+) for efficient CaCO(3) crystallization, thus uncover a critical process governing spatial specific otoconia formation. PMID- 21655227 TI - Identification of novel schizophrenia loci by homozygosity mapping using DNA microarray analysis. AB - The recent development of high-resolution DNA microarrays, in which hundreds of thousands of single nucleotide polymorphisms (SNPs) are genotyped, enables the rapid identification of susceptibility genes for complex diseases. Clusters of these SNPs may show runs of homozygosity (ROHs) that can be analyzed for association with disease. An analysis of patients whose parents were first cousins enables the search for autozygous segments in their offspring. Here, using the Affymetrix(r) Genome-Wide Human SNP Array 5.0 to determine ROHs, we genotyped 9 individuals with schizophrenia (SCZ) whose parents were first cousins. We identified overlapping ROHs on chromosomes 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 19, 20, and 21 in at least 3 individuals. Only the locus on chromosome 5 has been reported previously. The ROHs on chromosome 5q23.3-q31.1 include the candidate genes histidine triad nucleotide binding protein 1 (HINT1) and acyl-CoA synthetase long-chain family member 6 (ACSL6). Other overlapping ROHs may contain novel rare recessive variants that affect SCZ specifically in our samples, given the highly heterozygous nature of SCZ. Analysis of patients whose parents are first cousins may provide new insights for the genetic analysis of psychiatric diseases. PMID- 21655226 TI - Efficient targeting of head and neck squamous cell carcinoma by systemic administration of a dual uPA and MMP-activated engineered anthrax toxin. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although considerable progress has been made in elucidating the etiology of the disease, the prognosis for individuals diagnosed with HNSCC remains poor, underscoring the need for development of additional treatment modalities. HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both. Here we explored the use of an intercomplementing anthrax toxin that requires combined cell surface uPA and MMP activities for cellular intoxication and specifically targets the ERK/MAPK pathway for the treatment of HNSCC. We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis. Interestingly, the human HNSCC cell lines were insensitive to the intercomplementing toxin when cultured ex vivo, suggesting that either the toxin targets the tumor-supporting stromal cell compartment or that the tumor cell requirement for ERK/MAPK signaling differs in vivo and ex vivo. This intercomplementing toxin warrants further investigation as an anti-HNSCC agent. PMID- 21655228 TI - Heterologous overexpression and mutagenesis of the human bile salt export pump (ABCB11) using DREAM (Directed REcombination-Assisted Mutagenesis). AB - Homologous recombination in Saccharomyces cerevisiae is a well-studied process. Here, we describe a yeast-recombination-based approach to construct and mutate plasmids containing the cDNA of the human bile salt export pump (BSEP) that has been shown to be unstable in E. coli. Using this approach, we constructed the necessary plasmids for a heterologous overexpression of BSEP in the yeast Pichia pastoris. We then applied a new site-directed mutagenesis method, DREAM (Directed REcombination-Assisted Mutagenesis) that completely bypasses E. coli by using S. cerevisiae as the plasmid host with high mutagenesis efficiency. Finally, we show how to apply this strategy to unstable non-yeast plasmids by rapidly turning an existing mammalian BSEP expression construct into a S. cerevisiae-compatible plasmid and analyzing the impact of a BSEP mutation in several mammalian cell lines. PMID- 21655229 TI - High-throughput sequencing of six bamboo chloroplast genomes: phylogenetic implications for temperate woody bamboos (Poaceae: Bambusoideae). AB - BACKGROUND: Bambusoideae is the only subfamily that contains woody members in the grass family, Poaceae. In phylogenetic analyses, Bambusoideae, Pooideae and Ehrhartoideae formed the BEP clade, yet the internal relationships of this clade are controversial. The distinctive life history (infrequent flowering and predominance of asexual reproduction) of woody bamboos makes them an interesting but taxonomically difficult group. Phylogenetic analyses based on large DNA fragments could only provide a moderate resolution of woody bamboo relationships, although a robust phylogenetic tree is needed to elucidate their evolutionary history. Phylogenomics is an alternative choice for resolving difficult phylogenies. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the complete nucleotide sequences of six woody bamboo chloroplast (cp) genomes using Illumina sequencing. These genomes are similar to those of other grasses and rather conservative in evolution. We constructed a phylogeny of Poaceae from 24 complete cp genomes including 21 grass species. Within the BEP clade, we found strong support for a sister relationship between Bambusoideae and Pooideae. In a substantial improvement over prior studies, all six nodes within Bambusoideae were supported with >=0.95 posterior probability from Bayesian inference and 5/6 nodes resolved with 100% bootstrap support in maximum parsimony and maximum likelihood analyses. We found that repeats in the cp genome could provide phylogenetic information, while caution is needed when using indels in phylogenetic analyses based on few selected genes. We also identified relatively rapidly evolving cp genome regions that have the potential to be used for further phylogenetic study in Bambusoideae. CONCLUSIONS/SIGNIFICANCE: The cp genome of Bambusoideae evolved slowly, and phylogenomics based on whole cp genome could be used to resolve major relationships within the subfamily. The difficulty in resolving the diversification among three clades of temperate woody bamboos, even with complete cp genome sequences, suggests that these lineages may have diverged very rapidly. PMID- 21655230 TI - The production of extracellular proteins is regulated by ribonuclease III via two different pathways in Staphylococcus aureus. AB - Staphylococcus aureus ribonuclease III belongs to the enzyme family known to degrade double-stranded RNAs. It has previously been reported that RNase III cannot influence cell growth but regulates virulence gene expression in S. aureus. Here we constructed an RNase III inactivation mutant (Deltarnc) from S. aureus 8325-4. It was found that the extracellular proteins of Deltarnc were decreased. Furthermore, we explored how RNase III regulated the production of the extracellular proteins in S. aureus. We found during the lag phase of the bacterial growth cycle RNase III could influence the extracellular protein secretion via regulating the expression of secY2, one component of accessory secretory (sec) pathway. After S. aureus cells grew to exponential phase, RNase III can regulate the expression of extracellular proteins by affecting the level of RNAIII. Further investigation showed that the mRNA stability of secY2 and RNAIII was affected by RNase III. Our results suggest that RNase III could regulate the pathogenicity of S. aureus by influencing the level of extracellular proteins via two different ways respectively at different growth phases. PMID- 21655231 TI - NAD(P)H: quinone oxidoreductase 1 deficiency conjoint with marginal vitamin C deficiency causes cigarette smoke induced myelodysplastic syndromes. AB - BACKGROUND: The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs. METHODOLOGY AND PRINCIPAL FINDINGS: Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective. CONCLUSIONS AND SIGNIFICANCE: CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS. PMID- 21655232 TI - Famous faces demand attention due to reduced inhibitory processing. AB - People have particular difficulty ignoring distractors that depict faces. This phenomenon has been attributed to the high level of biological significance that faces carry. The current study aimed to elucidate the mechanism by which faces gain processing priority. We used a focused attention paradigm that tracks the influence of a distractor over time and provides a measure of inhibitory processing. Upright famous faces served as test stimuli and inverted versions of the faces as well as upright non-face objects served as control stimuli. The results revealed that although all of the stimuli elicited similar levels of distraction, only inverted distractor faces and non-face objects elicited inhibitory effects. The lack of inhibitory effects for upright famous faces provides novel evidence that reduced inhibitory processing underlies the mandatory nature of face processing. PMID- 21655233 TI - Vaccination with Plasmodium knowlesi AMA1 formulated in the novel adjuvant co vaccine HTTM protects against blood-stage challenge in rhesus macaques. AB - Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading blood stage vaccine candidate. Plasmodium knowlesi AMA1 (PkAMA1) was produced and purified using similar methodology as for clinical grade PfAMA1 yielding a pure, conformational intact protein. Combined with the adjuvant CoVaccine HTTM, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model. Six rhesus monkeys were vaccinated with PkAMA1 and a control group of 6 were vaccinated with PfAMA1. A total of 50 ug AMA1 was administered intramuscularly three times at 4 week intervals. One of six rhesus monkeys vaccinated with PkAMA1 was able to control parasitaemia, upon blood stage challenge with P. knowlesi H-strain. Four out of the remaining five showed a delay in parasite onset that correlated with functional antibody titres. In the PfAMA1 vaccinated control group, five out of six animals had to be treated with antimalarials 8 days after challenge; one animal did not become patent during the challenge period. Following a rest period, animals were boosted and challenged again. Four of the six rhesus monkeys vaccinated with PkAMA1 were able to control the parasitaemia, one had a delayed onset of parasitaemia and one animal was not protected, while all control animals required treatment. To confirm that the control of parasitaemia was AMA1-related, animals were allowed to recover, boosted and re-challenged with P. knowlesi Nuri strain. All control animals had to be treated with antimalarials by day 8, while five out of six PkAMA1 vaccinated animals were able to control parasitaemia. This study shows that: i) Yeast-expressed PkAMA1 can protect against blood stage challenge; ii) Functional antibody levels as measured by GIA correlated inversely with the day of onset and iii) GIA IC(50) values correlated with estimated in vivo growth rates. PMID- 21655235 TI - Comparative metaproteomic analysis on consecutively Rehmannia glutinosa monocultured rhizosphere soil. AB - BACKGROUND: The consecutive monoculture for most of medicinal plants, such as Rehmannia glutinosa, results in a significant reduction in the yield and quality. There is an urgent need to study for the sustainable development of Chinese herbaceous medicine. METHODOLOGY/PRINCIPAL FINDINGS: Comparative metaproteomics of rhizosphere soil was developed and used to analyze the underlying mechanism of the consecutive monoculture problems of R. glutinosa. The 2D-gel patterns of protein spots for the soil samples showed a strong matrix dependency. Among the spots, 103 spots with high resolution and repeatability were randomly selected and successfully identified by MALDI TOF-TOF MS for a rhizosphere soil metaproteomic profile analysis. These proteins originating from plants and microorganisms play important roles in nutrient cycles and energy flow in rhizospheric soil ecosystem. They function in protein, nucleotide and secondary metabolisms, signal transduction and resistance. Comparative metaproteomics analysis revealed 33 differentially expressed protein spots in rhizosphere soil in response to increasing years of monoculture. Among them, plant proteins related to carbon and nitrogen metabolism and stress response, were mostly up regulated except a down-regulated protein (glutathione S-transferase) involving detoxification. The phenylalanine ammonia-lyase was believed to participate in the phenylpropanoid metabolism as shown with a considerable increase in total phenolic acid content with increasing years of monoculture. Microbial proteins related to protein metabolism and cell wall biosynthesis, were up-regulated except a down-regulated protein (geranylgeranyl pyrophosphate synthase) functioning in diterpenoid synthesis. The results suggest that the consecutive monoculture of R. glutinosa changes the soil microbial ecology due to the exudates accumulation, as a result, the nutrient cycles are affected, leading to the retardation of plant growth and development. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated the interactions among plant, soil and microflora in the proteomic level are crucial for the productivity and quality of R. glutinosa in consecutive monoculture system. PMID- 21655234 TI - Pirt, a TRPV1 modulator, is required for histamine-dependent and -independent itch. AB - Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt(-/ ) mice exhibit deficits in cellular and behavioral responses to various itch inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways. PMID- 21655236 TI - Biochemical comparison of Anopheles gambiae and human NADPH P450 reductases reveals different 2'-5'-ADP and FMN binding traits. AB - NADPH-cytochrome P450 oxidoreductase (CPR) plays a central role in chemical detoxification and insecticide resistance in Anopheles gambiae, the major vector for malaria. Anopheles gambiae CPR (AgCPR) was initially expressed in Eschericia coli but failed to bind 2',5'-ADP Sepharose. To investigate this unusual trait, we expressed and purified a truncated histidine-tagged version for side-by-side comparisons with human CPR. Close functional similarities were found with respect to the steady state kinetics of cytochrome c reduction, with rates (k(cat)) of 105 s(-1) and 88 s(-1), respectively, for mosquito and human CPR. However, the inhibitory effects of 2',5'-ADP on activity were different; the IC(50) value of AgCPR for 2',5'-ADP was significantly higher (6-10 fold) than human CPR (hCPR) in both phosphate and phosphate-free buffer, indicative of a decrease in affinity for 2',5'-ADP. This was confirmed by isothermal titration calorimetry where binding of 2',5'-ADP to AgCPR (K(d) = 410+/-18 nM) was ~10 fold weaker than human CPR (K(d) = 38 nM). Characterisation of the individual AgFMN binding domain revealed much weaker binding of FMN (K(d) = 83+/-2.0 nM) than the equivalent human domain (K(d) = 23+/-0.9 nM). Furthermore, AgCPR was an order of magnitude more sensitive than hCPR to the reductase inhibitor diphenyliodonium chloride (IC(50) = 28 uM+/-2 and 361+/-31 uM respectively). Taken together, these results reveal unusual biochemical differences between mosquito CPR and the human form in the binding of small molecules that may aid the development of 'smart' insecticides and synergists that selectively target mosquito CPR. PMID- 21655237 TI - Comparison of mortality following hospitalisation for isolated head injury in England and Wales, and Victoria, Australia. AB - BACKGROUND: Traumatic brain injury (TBI) remains a leading cause of death and disability. The National Institute for Health and Clinical Excellence (NICE) guidelines recommend transfer of severe TBI cases to neurosurgical centres, irrespective of the need for neurosurgery. This observational study investigated the risk-adjusted mortality of isolated TBI admissions in England/Wales, and Victoria, Australia, and the impact of neurosurgical centre management on outcomes. METHODS: Isolated TBI admissions (>15 years, July 2005-June 2006) were extracted from the hospital discharge datasets for both jurisdictions. Severe isolated TBI (AIS severity >3) admissions were provided by the Trauma Audit and Research Network (TARN) and Victorian State Trauma Registry (VSTR) for England/Wales, and Victoria, respectively. Multivariable logistic regression was used to compare risk-adjusted mortality between jurisdictions. FINDINGS: Mortality was 12% (749/6256) in England/Wales and 9% (91/1048) in Victoria for isolated TBI admissions. Adjusted odds of death in England/Wales were higher compared to Victoria overall (OR 2.0, 95% CI: 1.6, 2.5), and for cases <65 years (OR 2.36, 95% CI: 1.51, 3.69). For severe TBI, mortality was 23% (133/575) for TARN and 20% (68/346) for VSTR, with 72% of TARN and 86% of VSTR cases managed at a neurosurgical centre. The adjusted mortality odds for severe TBI cases in TARN were higher compared to the VSTR (OR 1.45, 95% CI: 0.96, 2.19), but particularly for cases <65 years (OR 2.04, 95% CI: 1.07, 3.90). Neurosurgical centre management modified the effect overall (OR 1.12, 95% CI: 0.73, 1.74) and for cases <65 years (OR 1.53, 95% CI: 0.77, 3.03). CONCLUSION: The risk-adjusted odds of mortality for all isolated TBI admissions, and severe TBI cases, were higher in England/Wales when compared to Victoria. The lower percentage of cases managed at neurosurgical centres in England and Wales was an explanatory factor, supporting the changes made to the NICE guidelines. PMID- 21655238 TI - The congenital cataract-linked G61C mutation destabilizes gammaD-crystallin and promotes non-native aggregation. AB - gammaD-crystallin is one of the major structural proteins in human eye lens. The solubility and stability of gammaD-crystallin play a crucial role in maintaining the optical properties of the lens during the life span of an individual. Previous study has shown that the inherited mutation G61C results in autosomal dominant congenital cataract. In this research, we studied the effects of the G61C mutation on gammaD-crystallin structure, stability and aggregation via biophysical methods. CD, intrinsic and extrinsic fluorescence spectroscopy indicated that the G61C mutation did not affect the native structure of gammaD crystallin. The stability of gammaD-crystallin against heat- or GdnHCl-induced denaturation was significantly decreased by the mutation, while no influence was observed on the acid-induced unfolding. The mutation mainly affected the transition from the native state to the intermediate but not that from the intermediate to the unfolded or aggregated states. At high temperatures, both proteins were able to form aggregates, and the aggregation of the mutant was much more serious than the wild type protein at the same temperature. At body temperature and acidic conditions, the mutant was more prone to form amyloid-like fibrils. The aggregation-prone property of the mutant was not altered by the addition of reductive reagent. These results suggested that the decrease in protein stability followed by aggregation-prone property might be the major cause in the hereditary cataract induced by the G61C mutation. PMID- 21655239 TI - Gap junctions and epileptic seizures--two sides of the same coin? AB - Electrical synapses (gap junctions) play a pivotal role in the synchronization of neuronal ensembles which also makes them likely agonists of pathological brain activity. Although large body of experimental data and theoretical considerations indicate that coupling neurons by electrical synapses promotes synchronous activity (and thus is potentially epileptogenic), some recent evidence questions the hypothesis of gap junctions being among purely epileptogenic factors. In particular, an expression of inter-neuronal gap junctions is often found to be higher after the experimentally induced seizures than before. Here we used a computational modeling approach to address the role of neuronal gap junctions in shaping the stability of a network to perturbations that are often associated with the onset of epileptic seizures. We show that under some circumstances, the addition of gap junctions can increase the dynamical stability of a network and thus suppress the collective electrical activity associated with seizures. This implies that the experimentally observed post-seizure additions of gap junctions could serve to prevent further escalations, suggesting furthermore that they are a consequence of an adaptive response of the neuronal network to the pathological activity. However, if the seizures are strong and persistent, our model predicts the existence of a critical tipping point after which additional gap junctions no longer suppress but strongly facilitate the escalation of epileptic seizures. Our results thus reveal a complex role of electrical coupling in relation to epileptiform events. Which dynamic scenario (seizure suppression or seizure escalation) is ultimately adopted by the network depends critically on the strength and duration of seizures, in turn emphasizing the importance of temporal and causal aspects when linking gap junctions with epilepsy. PMID- 21655240 TI - Construction of chimeric dual-chain avidin by tandem fusion of the related avidins. AB - BACKGROUND: Avidin is a chicken egg-white protein with high affinity to vitamin H, also known as D-biotin. Many applications in life science research are based on this strong interaction. Avidin is a homotetrameric protein, which promotes its modification to symmetrical entities. Dual-chain avidin, a genetically engineered avidin form, has two circularly permuted chicken avidin monomers that are tandem-fused into one polypeptide chain. This form of avidin enables independent modification of the two domains, including the two biotin-binding pockets; however, decreased yields in protein production, compared to wt avidin, and complicated genetic manipulation of two highly similar DNA sequences in the tandem gene have limited the use of dual-chain avidin in biotechnological applications. PRINCIPAL FINDINGS: To overcome challenges associated with the original dual-chain avidin, we developed chimeric dual-chain avidin, which is a tandem fusion of avidin and avidin-related protein 4 (AVR4), another member of the chicken avidin gene family. We observed an increase in protein production and better thermal stability, compared with the original dual-chain avidin. Additionally, PCR amplification of the hybrid gene was more efficient, thus enabling more convenient and straightforward modification of the dual-chain avidin. When studied closer, the generated chimeric dual-chain avidin showed biphasic biotin dissociation. SIGNIFICANCE: The improved dual-chain avidin introduced here increases its potential for future applications. This molecule offers a valuable base for developing bi-functional avidin tools for bioseparation, carrier proteins, and nanoscale adapters. Additionally, this strategy could be helpful when generating hetero-oligomers from other oligomeric proteins with high structural similarity. PMID- 21655242 TI - The persistence of African swine fever virus in field-infected Ornithodoros erraticus during the ASF endemic period in Portugal. AB - African swine fever (ASF) is an important disease of pigs and outbreaks of ASF have occurred in Europe on multiple occasions. To explore the period for which the European soft tick species Ornithodoros erraticus (Acari: Argasidae) is able to act as a reservoir of African swine fever virus (ASFV) after infected hosts are removed, we collected specimens from farms in the provinces of Alentejo and Algarve in Portugal during the endemic period and tested them subsequently using cell culture and experimental infection. We show that ticks from previously infected farms may contain infectious virus for at least five years and three months after the removal of infectious hosts. Furthermore, in two cases infectious virus was successfully isolated from ticks on restocked farms that had not yet suffered a re-emergence of disease. Experimental transmission to pigs was demonstrated in batches tested up to 380 days after an outbreak. These results clarify the epidemiological role of O. erraticus ticks in the persistence of ASFV in the field, provide additional evidence to support its role in the re-emergence of a sporadic outbreak of ASF in Portugal in 1999 and suggest that the current quarantine legislation and restocking advice when these ticks are present on the pig farm premises is appropriate. PMID- 21655241 TI - A comparative assessment of non-laboratory-based versus commonly used laboratory based cardiovascular disease risk scores in the NHANES III population. AB - BACKGROUND: National and international primary CVD risk screening guidelines focus on using total CVD risk scores. Recently, we developed a non-laboratory based CVD risk score (inputs: age, sex, smoking, diabetes, systolic blood pressure, treatment of hypertension, body-mass index), which can assess risk faster and at lower costs compared to laboratory-based scores (inputs include cholesterol values). We aimed to assess the exchangeability of the non-laboratory based risk score to four commonly used laboratory-based scores (Framingham CVD [2008, 1991 versions], and Systematic COronary Risk Evaluation [SCORE] for low and high risk settings) in an external validation population. METHODS AND FINDINGS: Analyses were based on individual-level, score-specific rankings of risk for adults in the Third National Health and Nutrition Examination Survey (NHANES III) aged 25-74 years, without history of CVD or cancer (n = 5,999). Risk characterization agreement was based on overlap in dichotomous risk characterization (thresholds of 10-year risk >10-20%) and Spearman rank correlation. Risk discrimination was assessed using receiver operator characteristic curve analysis (10-year CVD death outcome). Risk characterization agreement ranged from 91.9-95.7% and 94.2-95.1% with Spearman correlation ranges of 0.957-0.980 and 0.946-0.970 for men and women, respectively. In men, c statistics for the non-laboratory-based, Framingham (2008, 1991), and SCORE (high, low) functions were 0.782, 0.776, 0.781, 0.785, and 0.785, with p-values for differences relative to the non-laboratory-based score of 0.44, 0.89, 0.68 and 0.65, respectively. In women, the corresponding c-statistics were 0.809, 0.834, 0.821, 0.792, and 0.792, with corresponding p-values of 0.04, 0.34, 0.11 and 0.09, respectively. CONCLUSIONS: Every score discriminated risk of CVD death well, and there was high agreement in risk characterization between non laboratory-based and laboratory-based risk scores, which suggests that the non laboratory-based score can be a useful proxy for Framingham or SCORE functions in resource-limited settings. Future external validation studies can assess whether the sex-specific risk discrimination results hold in other populations. PMID- 21655243 TI - Enhanced in vitro refolding of fibroblast growth factor 15 with the assistance of SUMO fusion partner. AB - Fibroblast growth factor 15 (Fgf15) is the mouse orthologue of human FGF19. Fgf15 is highly expressed in the ileum and functions as an endocrine signal to regulate liver function, including bile acid synthesis, hepatocyte proliferation and insulin sensitivity. In order to fully understand the function of Fgf15, methods are needed to produce pure Fgf15 protein in the prokaryotic system. However, when expressed in Escherichia coli (E. coli), the recombinant Fgf15 protein was insoluble and found only in inclusion bodies. In the current study, we report a method to produce recombinant Fgf15 protein in E. coli through the use of small ubiquitin-related modifier (SUMO) fusion tag. Even though the SUMO has been shown to strongly improve protein solubility and expression levels, our studies suggest that the SUMO does not improve Fgf15 protein solubility. Instead, proper refolding of Fgf15 protein was achieved when Fgf15 was expressed as a partner protein of the fusion tag SUMO, followed by in vitro dialysis refolding. After refolding, the N-terminal SUMO tag was cleaved from the recombinant Fgf15 fusion protein by ScUlp1 (Ubiquitin-Like Protein-Specific Protease 1 from S. cerevisiae). With or without the SUMO tag, the refolded Fgf15 protein was biologically active, as revealed by its ability to reduce hepatic Cyp7a1 mRNA levels in mice. In addition, recombinant Fgf15 protein suppressed Cyp7a1 mRNA levels in a dose-dependent manner. In summary, we have developed a successful method to express functional Fgf15 protein in prokaryotic cells. PMID- 21655244 TI - Complete genome sequence of Treponema paraluiscuniculi, strain Cuniculi A: the loss of infectivity to humans is associated with genome decay. AB - Treponema paraluiscuniculi is the causative agent of rabbit venereal spirochetosis. It is not infectious to humans, although its genome structure is very closely related to other pathogenic Treponema species including Treponema pallidum subspecies pallidum, the etiological agent of syphilis. In this study, the genome sequence of Treponema paraluiscuniculi, strain Cuniculi A, was determined by a combination of several high-throughput sequencing strategies. Whereas the overall size (1,133,390 bp), arrangement, and gene content of the Cuniculi A genome closely resembled those of the T. pallidum genome, the T. paraluiscuniculi genome contained a markedly higher number of pseudogenes and gene fragments (51). In addition to pseudogenes, 33 divergent genes were also found in the T. paraluiscuniculi genome. A set of 32 (out of 84) affected genes encoded proteins of known or predicted function in the Nichols genome. These proteins included virulence factors, gene regulators and components of DNA repair and recombination. The majority (52 or 61.9%) of the Cuniculi A pseudogenes and divergent genes were of unknown function. Our results indicate that T. paraluiscuniculi has evolved from a T. pallidum-like ancestor and adapted to a specialized host-associated niche (rabbits) during loss of infectivity to humans. The genes that are inactivated or altered in T. paraluiscuniculi are candidates for virulence factors important in the infectivity and pathogenesis of T. pallidum subspecies. PMID- 21655245 TI - Emergence and persistence of minor drug-resistant HIV-1 variants in Ugandan women after nevirapine single-dose prophylaxis. AB - BACKGROUND: Nevirapine (NVP) single-dose is still a widely used antiretroviral prophylaxis for the prevention of vertical HIV-1 transmission in resource-limited settings. However, the main disadvantage of the Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) NVP is the rapid selection of NVP-resistant virus with negative implications for subsequent NNRTI-based long-term antiretroviral therapy (ART). Here, we analysed the emergence of drug-resistant HIV-1 including minor variants in the early phase after NVP single-dose prophylaxis and the persistence of drug-resistant virus over time. METHODS AND FINDINGS: NVP resistant HIV-1 harbouring the K103N and/or Y181C resistance mutations in the HIV 1 reverse transcriptase gene was measured from 1 week up to 18 months after NVP single-dose prophylaxis in 29 Ugandan women using allele-specific PCR assays capable of detecting drug-resistant variants representing less than 1% of the whole viral population. In total, drug-resistant HIV-1 was identified in 18/29 (62%) women; rates increased from 18% to 38% and 44% at week 1, 2, 6, respectively, and decreased to 18%, 25%, 13% and 4% at month 3, 6, 12 and 18, respectively. The proportion of NVP-resistant virus of the total viral population was significantly higher in women infected with subtype D (median 40.5%) as compared to subtype A (median 1.3%; p = 0.032, Mann-Whitney U test). 33% of resistant virus was not detectable at week 2 but was for the first time measurable 6-12 weeks after NVP single-dose prophylaxis. Three (10%) women harboured resistant virus in proportions >10% still at month 6. CONCLUSIONS: Current WHO guidelines recommend an additional postnatal intake of AZT and 3TC for one week to avoid NVP resistance formation. Our findings indicate that a 1 week medication might be too short to impede the emergence of NVP resistance in a substantial proportion of women. Furthermore, subsequent NNRTI-based ART should not be started earlier than 12 months after NVP single-dose prophylaxis. PMID- 21655247 TI - Phylogenetic relationships in Pterodroma petrels are obscured by recent secondary contact and hybridization. AB - The classification of petrels (Pterodroma spp.) from Round Island, near Mauritius in the Indian Ocean, has confounded researchers since their discovery in 1948. In this study we investigate the relationships between Round Island petrels and their closest relatives using evidence from mitochondrial DNA sequence data and ectoparasites. Far from providing clear delimitation of species boundaries, our results reveal that hybridization among species on Round Island has led to genetic leakage between populations from different ocean basins. The most common species on the island, Pterodroma arminjoniana, appears to be hybridizing with two rarer species (P. heraldica and P. neglecta), subverting the reproductive isolation of all three and allowing gene flow. P. heraldica and P. neglecta breed sympatrically in the Pacific Ocean, where P. arminjoniana is absent, but no record of hybridization between these two exists and they remain phenotypically distinct. The breakdown of species boundaries in Round Island petrels followed environmental change (deforestation and changes in species composition due to hunting) within their overlapping ranges. Such multi-species interactions have implications not only for conservation, but also for our understanding of the processes of evolutionary diversification and speciation. PMID- 21655246 TI - Transcriptional and post-transcriptional mechanisms for oncogenic overexpression of ether a go-go K+ channel. AB - The human ether-a-go-go-1 (h-eag1) K(+) channel is expressed in a variety of cell lines derived from human malignant tumors and in clinical samples of several different cancers, but is otherwise absent in normal tissues. It was found to be necessary for cell cycle progression and tumorigenesis. Specific inhibition of h eag1 expression leads to inhibition of tumor cell proliferation. We report here that h-eag1 expression is controlled by the p53-miR-34-E2F1 pathway through a negative feed-forward mechanism. We first established E2F1 as a transactivator of h-eag1 gene through characterizing its promoter region. We then revealed that miR 34, a known transcriptional target of p53, is an important negative regulator of h-eag1 through dual mechanisms by directly repressing h-eag1 at the post transcriptional level and indirectly silencing h-eag1 at the transcriptional level via repressing E2F1. There is a strong inverse relationship between the expression levels of miR-34 and h-eag1 protein. H-eag1antisense antagonized the growth-stimulating effects and the upregulation of h-eag1 expression in SHSY5Y cells, induced by knockdown of miR-34, E2F1 overexpression, or inhibition of p53 activity. Therefore, p53 negatively regulates h-eag1 expression by a negative feed-forward mechanism through the p53-miR-34-E2F1 pathway. Inactivation of p53 activity, as is the case in many cancers, can thus cause oncogenic overexpression of h-eag1 by relieving the negative feed-forward regulation. These findings not only help us understand the molecular mechanisms for oncogenic overexpression of h-eag1 in tumorigenesis but also uncover the cell-cycle regulation through the p53-miR-34-E2F1-h-eag1 pathway. Moreover, these findings place h-eag1 in the p53 miR-34-E2F1-h-eag1 pathway with h-eag as a terminal effecter component and with miR-34 (and E2F1) as a linker between p53 and h-eag1. Our study therefore fills the gap between p53 pathway and its cellular function mediated by h-eag1. PMID- 21655248 TI - Patterns of coral disease across the Hawaiian archipelago: relating disease to environment. AB - In Hawaii, coral reefs occur across a gradient of biological (host abundance), climatic (sea surface temperature anomalies) and anthropogenic conditions from the human-impacted reefs of the main Hawaiian Islands (MHI) to the pristine reefs of the northwestern Hawaiian Islands (NWHI). Coral disease surveys were conducted at 142 sites from across the Archipelago and disease patterns examined. Twelve diseases were recorded from three coral genera (Porites, Montipora, Acropora) with Porites having the highest prevalence. Porites growth anomalies (PorGAs) were significantly more prevalent within and indicative of reefs in the MHI and Porites trematodiasis (PorTrm) was significantly more prevalent within and indicative of reefs in the NWHI. Porites tissue loss syndrome (PorTLS) was also important in driving regional differences but that relationship was less clear. These results highlight the importance of understanding disease ecology when interpreting patterns of disease occurrence. PorTrm is caused by a parasitic flatworm that utilizes multiple hosts during its life cycle (fish, mollusk and coral). All three hosts must be present for the disease to occur and higher host abundance leads to higher disease prevalence. Thus, a high prevalence of PorTrm on Hawaiian reefs would be an indicator of a healthy coral reef ecosystem. In contrast, the high occurrence of PorGAs within the MHI suggests that PorGAs are related, directly or indirectly, to some environmental co-factor associated with increased human population sizes. Focusing on the three indicator diseases (PorGAs, PorTrm, PorTLS) we used statistical modeling to examine the underlying associations between disease prevalence and 14 different predictor variables (biotic and abiotic). All three diseases showed positive associations with host abundance and negative associations with thermal stress. The association with human population density differed among disease states with PorGAs showing a positive and PorTrm showing a negative association, but no significant explanatory power was offered for PorTLS. PMID- 21655249 TI - The membrane bound LRR lipoprotein Slr, and the cell wall-anchored M1 protein from Streptococcus pyogenes both interact with type I collagen. AB - Streptococcus pyogenes is an important human pathogen and surface structures allow it to adhere to, colonize and invade the human host. Proteins containing leucine rich repeats (LRR) have been identified in mammals, viruses, archaea and several bacterial species. The LRRs are often involved in protein-protein interaction, are typically 20-30 amino acids long and the defining feature of the LRR motif is an 11-residue sequence LxxLxLxxNxL (x being any amino acid). The streptococcal leucine rich (Slr) protein is a hypothetical lipoprotein that has been shown to be involved in virulence, but at present no ligands for Slr have been identified. We could establish that Slr is a membrane attached horseshoe shaped lipoprotein by homology modeling, signal peptidase II inhibition, electron microscopy (of bacteria and purified protein) and immunoblotting. Based on our previous knowledge of LRR proteins we hypothesized that Slr could mediate binding to collagen. We could show by surface plasmon resonance that recombinant Slr and purified M1 protein bind with high affinity to collagen I. Isogenic slr mutant strain (MB1) and emm1 mutant strain (MC25) had reduced binding to collagen type I as shown by slot blot and surface plasmon resonance. Electron microscopy using gold labeled Slr showed multiple binding sites to collagen I, both to the monomeric and the fibrillar structure, and most binding occurred in the overlap region of the collagen I fibril. In conclusion, we show that Slr is an abundant membrane bound lipoprotein that is co-expressed on the surface with M1, and that both these proteins are involved in recruiting collagen type I to the bacterial surface. This underlines the importance of S. pyogenes interaction with extracellular matrix molecules, especially since both Slr and M1 have been shown to be virulence factors. PMID- 21655250 TI - In situ prior proliferation of CD4+ CCR6+ regulatory T cells facilitated by TGF beta secreting DCs is crucial for their enrichment and suppression in tumor immunity. AB - BACKGROUND: CD4(+)CD25(+) regulatory T cells (Tregs), a heterogeneous population, were enrichment in tumor mass and played an important role in modulating anti tumor immunity. Recently, we reported a Treg subset, CCR6(+) Tregs but not CCR6( )Tregs, were enriched in tumor mass and closely related to poor prognosis of breast cancer patients. However, the underlying mechanism remains elusive. Here, we carefully evaluate the enrichment of CCR6(+)Tregs in tumor mass during progression of breast cancer and explore its possible mechanism. METHODOLOGY/PRINCIPAL FINDINGS: The frequency of CCR6(+)Tregs in tumor infiltrating lymphocytes (TILs ) was analyzed at early stage and at late stage of tumor in a murine breast cancer model by FACS respectively. The expansion of CCR6(+)Tregs and their CCR6(-) counterpart in tumor mass were determined by BrdU incorporation assay. The effect and its possible mechanism of tumor-resident antigen presenting cells (APCs) on the proliferation of CCR6(+)Tregs also were evaluated. The role of local expansion of CCR6(+)Tregs in their enrichment and suppression in vivo also was evaluated in adoptive cell transfer assay. We found that the prior enrichment of CCR6(+)Tregs but not CCR6(-)Tregs in tumor mass during progression of murine breast cancer, which was dependent on the dominant proliferation of CCR6(+) Tregs in situ. Further study demonstrated that tumor resident DCs triggered the proliferation of CCR6(+)Treg cells in TGF-beta dependent manner. Adoptive transfer of CCR6(+)Tregs was found to potently inhibit the function of CD8(+)T cells in vivo, which was dependent on their proliferation and subsequently enrichment in tumor mass. CONCLUSIONS/SIGNIFICANCE: Our finding suggested that CCR6(+) Tregs, a distinct subset of Tregs, exert its predominant suppressive role in tumor immunity through prior in situ expansion, which might ultimately provide helpful thoughts for the designing of Treg-based immunotherapy for tumor in the future. PMID- 21655251 TI - Evolution of hsp70 gene expression: a role for changes in AT-richness within promoters. AB - In disparate organisms adaptation to thermal stress has been linked to changes in the expression of genes encoding heat-shock proteins (Hsp). The underlying genetics, however, remain elusive. We show here that two AT-rich sequence elements in the promoter region of the hsp70 gene of the fly Liriomyza sativae that are absent in the congeneric species, Liriomyza huidobrensis, have marked cis-regulatory consequences. We studied the cis-regulatory consequences of these elements (called ATRS1 and ATRS2) by measuring the constitutive and heat-shock induced luciferase luminescence that they drive in cells transfected with constructs carrying them modified, deleted, or intact, in the hsp70 promoter fused to the luciferase gene. The elements affected expression level markedly and in different ways: Deleting ATRS1 augmented both the constitutive and the heat shock-induced luminescence, suggesting that this element represses transcription. Interestingly, replacing the element with random sequences of the same length and A+T content delivered the wild-type luminescence pattern, proving that the element's high A+T content is crucial for its effects. Deleting ATRS2 decreased luminescence dramatically and almost abolished heat-shock inducibility and so did replacing the element with random sequences matching the element's length and A+T content, suggesting that ATRS2's effects on transcription and heat-shock inducibility involve a common mechanism requiring at least in part the element's specific primary structure. Finally, constitutive and heat-shock luminescence were reduced strongly when two putative binding sites for the Zeste transcription factor identified within ATRS2 were altered through site-directed mutagenesis, and the heat-shock-induced luminescence increased when Zeste was over-expressed, indicating that Zeste participates in the effects mapped to ATRS2 at least in part. AT-rich sequences are common in promoters and our results suggest that they should play important roles in regulatory evolution since they can affect expression markedly and constrain promoter DNA in at least two different ways. PMID- 21655253 TI - A collaborative brain-computer interface for improving human performance. AB - Electroencephalogram (EEG) based brain-computer interfaces (BCI) have been studied since the 1970s. Currently, the main focus of BCI research lies on the clinical use, which aims to provide a new communication channel to patients with motor disabilities to improve their quality of life. However, the BCI technology can also be used to improve human performance for normal healthy users. Although this application has been proposed for a long time, little progress has been made in real-world practices due to technical limits of EEG. To overcome the bottleneck of low single-user BCI performance, this study proposes a collaborative paradigm to improve overall BCI performance by integrating information from multiple users. To test the feasibility of a collaborative BCI, this study quantitatively compares the classification accuracies of collaborative and single-user BCI applied to the EEG data collected from 20 subjects in a movement-planning experiment. This study also explores three different methods for fusing and analyzing EEG data from multiple subjects: (1) Event-related potentials (ERP) averaging, (2) Feature concatenating, and (3) Voting. In a demonstration system using the Voting method, the classification accuracy of predicting movement directions (reaching left vs. reaching right) was enhanced substantially from 66% to 80%, 88%, 93%, and 95% as the numbers of subjects increased from 1 to 5, 10, 15, and 20, respectively. Furthermore, the decision of reaching direction could be made around 100-250 ms earlier than the subject's actual motor response by decoding the ERP activities arising mainly from the posterior parietal cortex (PPC), which are related to the processing of visuomotor transmission. Taken together, these results suggest that a collaborative BCI can effectively fuse brain activities of a group of people to improve the overall performance of natural human behavior. PMID- 21655252 TI - Phenotypic characterization of HIV-specific CD8+ T cells during early and chronic infant HIV-1 infection. AB - Although CD8(+) T cells play an important role in the containment of adult HIV-1 replication, their role in infant HIV-1 infection is not as well understood. Impaired HIV-specific CD8(+) T cell responses may underlie the persistently high viral loads observed in infants. We examined the frequency and phenotype of infant HIV-specific CD8(+) T cells in 7 HIV-infected antiretroviral therapy-naive infants during the first 2 years of life, using class I HLA tetramers and IFN gamma-ELISPOT. The frequency (0.088-3.9% of CD3(+)CD8(+) cells) and phenotype (CD27(+)CD28(-), CD45RA(+/-), CD57(+/-), HLA-DR(+), CD95(+)) of infant HIV specific CD8(+) T cells were similar to reports in adults undergoing early infection. Unlike adults, at 23-24 months post-infection a high frequency of HIV specific CD8(+) T cells expressed HLA-DR (mean 80%, range 68-85%) and CD95 (mean 88%, range 79-96%), suggesting sustained activation and vulnerability to apoptosis. Despite comparable expansion of HIV-specific CD8(+) T cells of a similar phenotype to adults during early infection, infant T cells failed to contain HIV-1 replication, and remained persistently activated and vulnerable to apoptosis during chronic infection. PMID- 21655254 TI - Identification of novel Clostridium perfringens type E strains that carry an iota toxin plasmid with a functional enterotoxin gene. AB - Clostridium perfringens enterotoxin (CPE) is a major virulence factor for human gastrointestinal diseases, such as food poisoning and antibiotic associated diarrhea. The CPE-encoding gene (cpe) can be chromosomal or plasmid-borne. Recent development of conventional PCR cpe-genotyping assays makes it possible to identify cpe location (chromosomal or plasmid) in type A isolates. Initial studies for developing cpe genotyping assays indicated that all cpe-positive strains isolated from sickened patients were typable by cpe-genotypes, but surveys of C. perfringens environmental strains or strains from feces of healthy people suggested that this assay might not be useful for some cpe-carrying type A isolates. In the current study, a pulsed-field gel electrophoresis Southern blot assay showed that four cpe-genotype untypable isolates carried their cpe gene on a plasmid of ~65 kb. Complete sequence analysis of the ~65 kb variant cpe carrying plasmid revealed no intact IS elements and a disrupted cytosine methyltransferase (dcm) gene. More importantly, this plasmid contains a conjugative transfer region, a variant cpe gene and variant iota toxin genes. The toxin genes encoded by this plasmid are expressed based upon the results of RT PCR assays. The ~65 kb plasmid is closely related to the pCPF4969 cpe plasmid of type A isolates. MLST analyses indicated these isolates belong to a unique cluster of C. perfringens. Overall, these isolates carrying a variant functional cpe gene and iota toxin genes represent unique type E strains. PMID- 21655255 TI - VX hydrolysis by human serum paraoxonase 1: a comparison of experimental and computational results. AB - Human Serum paraoxonase 1 (HuPON1) is an enzyme that has been shown to hydrolyze a variety of chemicals including the nerve agent VX. While wildtype HuPON1 does not exhibit sufficient activity against VX to be used as an in vivo countermeasure, it has been suggested that increasing HuPON1's organophosphorous hydrolase activity by one or two orders of magnitude would make the enzyme suitable for this purpose. The binding interaction between HuPON1 and VX has recently been modeled, but the mechanism for VX hydrolysis is still unknown. In this study, we created a transition state model for VX hydrolysis (VX(ts)) in water using quantum mechanical/molecular mechanical simulations, and docked the transition state model to 22 experimentally characterized HuPON1 variants using AutoDock Vina. The HuPON1-VX(ts) complexes were grouped by reaction mechanism using a novel clustering procedure. The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX. The analysis showed that only conformations which have the attacking hydroxyl group of VX(ts) coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results. The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX. PMID- 21655256 TI - RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family. AB - BACKGROUND: Whole exome sequencing provides a labor-saving and direct means of genetic diagnosis of hereditary disorders in which the pathogenic gene harbors a large cohort of exons. We set out to demonstrate a suitable example of genetic diagnosis of MEN 2A/FMTC (multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma) using this approach. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced the whole exome of six individuals from a large Chinese MEN2A/FMTC pedigree to identify the variants of the RET (REarranged during Transfection) protooncogene and followed this by validation. Then prophylactic or surgical thyroidectomy with modified or level VI lymph node dissection and adrenalectomy were performed for the carriers. The cases were closely followed up. Massively parallel sequencing revealed four missense mutations of RET. We unexpectedly discovered that the proband's daughter with MEN 2A-related MTC presented a novel p.C634Y/V292M/R67H/R982C compound mutation, due to the involvement of p.C634Y in the proband with MEN 2A and p.V292M/R67H/R982C in the proband's husband with FMTC. In the maternal origin, p.C634Y caused bilateral MTC in all 5 cases and bilateral pheochromocytoma in 2 of the 5; the earliest onset age was 28 years. In the paternal origin, one of the six p.V292M/R67H/R982C carriers presented bilateral MTC (70 years old), one only had bilateral C-cell hyperplasia (44 years), two had bilateral multi-nodules (46 and 48 years) and two showed no abnormality (22 and 19 years). CONCLUSIONS/SIGNIFICANCE: The results confirmed the successful clinical utility of whole exome sequencing, and our data suggested that the p.C634Y/V292M/R67H/R982C mutation of RET exhibited a more aggressive clinical phenotype than p.C634Y or p.V292M/R67H/R982C, while p.V292M/R67H/R982C presented a relatively milder pathogenicity of MTC and likely predisposed to FMTC. PMID- 21655257 TI - Seasonality of human leptospirosis in Reunion Island (Indian Ocean) and its association with meteorological data. AB - BACKGROUND: Leptospirosis is a disease which occurs worldwide but particularly affects tropical areas. Transmission of the disease is dependent on its excretion by reservoir animals and the presence of moist environment which allows the survival of the bacteria. METHODS AND FINDINGS: A retrospective study was undertaken to describe seasonal patterns of human leptospirosis cases reported by the Centre National de References des Leptospiroses (CNRL, Pasteur Institute, Paris) between 1998 and 2008, to determine if there was an association between the occurrence of diagnosed cases and rainfall, temperature and global solar radiation (GSR). Meteorological data were recorded in the town of Saint-Benoit (Meteo France "Beaufonds-Miria" station), located on the windward (East) coast. Time-series analysis was used to identify the variables that best described and predicted the occurrence of cases of leptospirosis on the island. Six hundred and thirteen cases were reported during the 11-year study period, and 359 cases (58.56%) were diagnosed between February and May. A significant correlation was identified between the number of cases in a given month and the associated cumulated rainfall as well as the mean monthly temperature recorded 2 months prior to diagnosis (r = 0.28 and r = 0.23 respectively). The predictive model includes the number of cases of leptospirosis recorded 1 month prior to diagnosis (b = 0.193), the cumulated monthly rainfall recorded 2 months prior to diagnosis (b = 0.145), the average monthly temperature recorded 0 month prior to diagnosis (b = 3.836), and the average monthly GSR recorded 0 month prior to diagnosis (b = -1.293). CONCLUSIONS: Leptospirosis has a seasonal distribution in Reunion Island. Meteorological data can be used to predict the occurrence of the disease and our statistical model can help to implement seasonal prevention measures. PMID- 21655258 TI - The molecular subtype classification is a determinant of sentinel node positivity in early breast carcinoma. AB - INTRODUCTION: Several authors have underscored a strong relation between the molecular subtypes and the axillary status of breast cancer patients. The aim of our work was to decipher the interaction between this classification and the probability of a positive sentinel node biopsy. MATERIALS AND METHODS: Our dataset consisted of a total number of 2654 early-stage breast cancer patients. Patients treated at first by conservative breast surgery plus sentinel node biopsies were selected. A multivariate logistic regression model was trained and validated. Interaction covariate between ER and HER2 markers was a forced input of this model. The performance of the multivariate model in the training and the two validation sets was analyzed in terms of discrimination and calibration. Probability of axillary metastasis was detailed for each molecular subtype. RESULTS: The interaction covariate between ER and HER2 status was a stronger predictor (p = 0.0031) of positive sentinel node biopsy than the ER status by itself (p = 0.016). A multivariate model to determine the probability of sentinel node positivity was defined with the following variables; tumour size, lympho vascular invasion, molecular subtypes and age at diagnosis. This model showed similar results in terms of discrimination (AUC = 0.72/0.73/0.72) and calibration (HL p = 0.28/0.05/0.11) in the training and validation sets. The interaction between molecular subtypes, tumour size and sentinel nodes status was approximated. DISCUSSION: We showed that biologically-driven analyses are able to build new models with higher performance in terms of breast cancer axillary status prediction. The molecular subtype classification strongly interacts with the axillary and distant metastasis process. PMID- 21655259 TI - Variability in pediatric infectious disease consultants' recommendations for management of community-acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia (CAP) is a common childhood infection. CAP complications, such as parapneumonic empyema (PPE), are increasing and are frequently caused by antibiotic-resistant organisms. No clinical guidelines currently exist for management of pediatric CAP and no published data exist about variations in antibiotic prescribing patterns. Our objectives were to describe variation in CAP clinical management for hospitalized children by pediatric infectious disease consultants and to examine associations between recommended antibiotic regimens and local antibiotic resistance levels. METHODS: We surveyed pediatric members of the Emerging Infections Network, which consists of 259 pediatric infectious disease physicians. Participants responded regarding their recommended empiric antibiotic regimens for hospitalized children with CAP with and without PPE and their recommendations for duration of therapy. Participants also provided information about the prevalence of penicillin non-susceptible S. pneumoniae and methicillin-resistant S. aureus (MRSA) in their community. RESULTS: We received 148 responses (57%). For uncomplicated CAP, respondents were divided between recommending beta-lactams alone (55%) versus beta-lactams in combination with another class (40%). For PPE, most recommended a combination of a beta-lactam plus an anti-MRSA agent, however, they were divided between clindamycin (44%) and vancomycin (57%). The relationship between reported antibiotic resistance and empiric regimen was mixed. We found no relationship between aminopenicillin use and prevalence of penicillin non-suscepetible S. pneumoniae or clindamycin use and clindamycin resistance, however, respondents were more likely to recommend an anti-MRSA agent when MRSA prevalence increased. CONCLUSIONS: Substantial variability exists in recommendations for CAP management. Development of clinical guidelines via antimicrobial stewardship programs and dissemination of data about local antibiotic resistance patterns represent opportunities to improve care. PMID- 21655260 TI - Psychophysiological markers of vulnerability to psychopathology in men with an extra X chromosome (XXY). AB - Studying genetically defined syndromes associated with increased risk for psychopathology may help in understanding neurodevelopmental mechanisms related to risk for psychopathology. Klinefelter syndrome (47,XXY) is one of the most common sex chromosomal aneuploidies (1 in 650 male births) and associated with increased vulnerability for psychopathology, including psychotic symptoms. Yet, it remains unknown whether this increased risk is associated with underlying psychophysiological mechanisms that are typically deficient in individuals with psychotic disorders. The present study assessed three "classic" psychophysiological markers of psychosis in Klinefelter syndrome (KS): smooth pursuit eye movements (SPEM), prepulse inhibition (PPI) and P50 suppression. Fourteen adults with KS and 15 non-clinical adults participated in the study. Data on SPEM (reflecting visuo-motor control) as well as PPI and P50 suppression (reflecting sensory gating) were collected. Dysfunctions in SPEM were observed in individuals with KS, with less smooth pursuit as expressed in lower position gain. Also, reduced sensory gating in individuals with KS was suggested by significantly reduced prepulse inhibition of the startle response (PPI) (effect size 1.6). No abnormalities were found in suppression of the P50 (effect size 0.6). We speculate that impairments in these psychophysiological mechanisms may reflect core brain dysfunctions that may also mediate the described increased vulnerability for psychotic symptoms in KS. Although speculative, such deficit specific, rather than disorder specific, psychophysiological dysfunctions in KS might convey vulnerability to other types of psychopathology as well. As KS already can be diagnosed prenatally, the predictive value of childhood impairments in prepulse inhibition and smooth pursuit for development of psychopathology later in life could be assessed. In sum, studying individuals with KS may prove to be an avenue of research leading to new hypotheses and insights into "at risk" pathways to psychopathology. PMID- 21655261 TI - Alteration in superoxide dismutase 1 causes oxidative stress and p38 MAPK activation following RVFV infection. AB - Rift Valley fever (RVF) is a zoonotic disease caused by Rift Valley fever virus (RVFV). RVFV is a category A pathogen that belongs to the genus Phlebovirus, family Bunyaviridae. Understanding early host events to an infectious exposure to RVFV will be of significant use in the development of effective therapeutics that not only control pathogen multiplication, but also contribute to cell survival. In this study, we have carried out infections of human cells with a vaccine strain (MP12) and virulent strain (ZH501) of RVFV and determined host responses to viral infection. We demonstrate that the cellular antioxidant enzyme superoxide dismutase 1 (SOD1) displays altered abundances at early time points following exposure to the virus. We show that the enzyme is down regulated in cases of both a virulent (ZH501) and a vaccine strain (MP12) exposure. Our data demonstrates that the down regulation of SOD1 is likely to be due to post transcriptional processes and may be related to up regulation of TNFalpha following infection. We also provide evidence for extensive oxidative stress in the MP12 infected cells. Concomitantly, there is an increase in the activation of the p38 MAPK stress response, which our earlier published study demonstrated to be an essential cell survival strategy. Our data suggests that the viral anti apoptotic protein NSm may play a role in the regulation of the cellular p38 MAPK response. Alterations in the host protein SOD1 following RVFV infection appears to be an early event that occurs in multiple cell types. Activation of the cellular stress response p38 MAPK pathway can be observed in all cell types tested. Our data implies that maintaining oxidative homeostasis in the infected cells may play an important role in improving survival of infected cells. PMID- 21655262 TI - Identification of antifreeze proteins and their functional residues by support vector machine and genetic algorithms based on n-peptide compositions. AB - For the first time, multiple sets of n-peptide compositions from antifreeze protein (AFP) sequences of various cold-adapted fish and insects were analyzed using support vector machine and genetic algorithms. The identification of AFPs is difficult because they exist as evolutionarily divergent types, and because their sequences and structures are present in limited numbers in currently available databases. Our results reveal that it is feasible to identify the shared sequential features among the various structural types of AFPs. Moreover, we were able to identify residues involved in ice binding without requiring knowledge of the three-dimensional structures of these AFPs. This approach should be useful for genomic and proteomic studies involving cold-adapted organisms. PMID- 21655263 TI - Repression of mitochondrial translation, respiration and a metabolic cycle regulated gene, SLF1, by the yeast Pumilio-family protein Puf3p. AB - Synthesis and assembly of the mitochondrial oxidative phosphorylation (OXPHOS) system requires genes located both in the nuclear and mitochondrial genomes, but how gene expression is coordinated between these two compartments is not fully understood. One level of control is through regulated expression mitochondrial ribosomal proteins and other factors required for mitochondrial translation and OXPHOS assembly, which are all products of nuclear genes that are subsequently imported into mitochondria. Interestingly, this cadre of genes in budding yeast has in common a 3'-UTR element that is bound by the Pumilio family protein, Puf3p, and is coordinately regulated under many conditions, including during the yeast metabolic cycle. Multiple functions have been assigned to Puf3p, including promoting mRNA degradation, localizing nucleus-encoded mitochondrial transcripts to the outer mitochondrial membrane, and facilitating mitochondria-cytoskeletal interactions and motility. Here we show that Puf3p has a general repressive effect on mitochondrial OXPHOS abundance, translation, and respiration that does not involve changes in overall mitochondrial biogenesis and largely independent of TORC1-mitochondrial signaling. We also identified the cytoplasmic translation factor Slf1p as yeast metabolic cycle-regulated gene that is repressed by Puf3p at the post-transcriptional level and promotes respiration and extension of yeast chronological life span when over-expressed. Altogether, these results should facilitate future studies on which of the many functions of Puf3p is most relevant for regulating mitochondrial gene expression and the role of nuclear mitochondrial communication in aging and longevity. PMID- 21655264 TI - Colocalization of 14-3-3 proteins with SOD1 in Lewy body-like hyaline inclusions in familial amyotrophic lateral sclerosis cases and the animal model. AB - BACKGROUND AND PURPOSE: Cu/Zn superoxide dismutase (SOD1) is a major component of Lewy body-like hyaline inclusion (LBHI) found in the postmortem tissue of SOD1 linked familial amyotrophic lateral sclerosis (FALS) patients. In our recent studies, 14-3-3 proteins have been found in the ubiquitinated inclusions inside the anterior horn cells of spinal cords with sporadic amyotrophic lateral sclerosis (ALS). To further investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical analysis of 14-3-3 proteins and compared their distributions with those of SOD1 in FALS patients and SOD1-overexpressing mice. METHODS: We examined the postmortem brains and the spinal cords of three FALS cases (A4V SOD1 mutant). Transgenic mice expressing the G93A mutant human SOD1 (mutant SOD1-Tg mice), transgenic mice expressing the wild-type human SOD1 (wild type SOD1-Tg mice), and non-Tg wild-type mice were also subjected to the immunohistochemical analysis. RESULTS: In all the FALS patients, LBHIs were observed in the cytoplasm of the anterior horn cells, and these inclusions were immunopositive intensely for pan 14-3-3, 14-3-3beta, and 14-3-3gamma. In the mutant SOD1-Tg mice, a high degree of immunoreactivity for misfolded SOD1 (C4F6) was observed in the cytoplasm, with an even greater degree of immunoreactivity present in the cytoplasmic aggregates of the anterior horn cells in the lumbar spinal cord. Furthermore, we have found increased 14-3-3beta and 14-3-3gamma immunoreactivities in the mutant SOD1-Tg mice. Double immunofluorescent staining showed that C4F6 and 14-3-3 proteins were partially co-localized in the spinal cord with FALS and the mutant SOD1-Tg mice. In comparison, the wild-type SOD1-Tg and non-Tg wild-type mice showed no or faint immunoreactivity for C4F6 and 14-3-3 proteins (pan 14-3-3, 14-3-3beta, and 14-3-3gamma) in any neuronal compartments. DISCUSSION: These results suggest that 14-3-3 proteins may be associated with the formation of SOD1-containing inclusions, in FALS patients and the mutant SOD1-Tg mice. PMID- 21655265 TI - Immunolocalization of influenza A virus and markers of inflammation in the human Parkinson's disease brain. AB - Although much is known regarding the molecular mechanisms leading to neuronal cell loss in Parkinson's disease (PD), the initiating event has not been identified. Prevailing theories including a chemical insult or infectious agent have been postulated as possible triggers, leading to neuroinflammation. We present immunohistochemical data indicating the presence of influenza A virus within the substantia nigra pars compacta (SNpc) from postmortem PD brain sections. Influenza A virus labeling was identified within neuromelanin granules as well as on tissue macrophages in the SNpc. Further supporting a role for neuroinflammation in PD was the identification of T-lymphocytes that colocalized with an antibody to caspase-cleaved Beclin-1 within the SNpc. The presence of influenza A virus together with macrophages and T-lymphocytes may contribute to the neuroinflammation associated with this disease. PMID- 21655266 TI - Taming membranes: functional immobilization of biological membranes in hydrogels. AB - Single molecule studies on membrane proteins embedded in their native environment are hampered by the intrinsic difficulty of immobilizing elastic and sensitive biological membranes without interfering with protein activity. Here, we present hydrogels composed of nano-scaled fibers as a generally applicable tool to immobilize biological membrane vesicles of various size and lipid composition. Importantly, membrane proteins immobilized in the hydrogel as well as soluble proteins are fully active. The triggered opening of the mechanosensitive channel of large conductance (MscL) reconstituted in giant unilamellar vesicles (GUVs) was followed in time on single GUVs. Thus, kinetic studies of vectorial transport processes across biological membranes can be assessed on single, hydrogel immobilized, GUVs. Furthermore, protein translocation activity by the membrane embedded protein conducting channel of bacteria, SecYEG, in association with the soluble motor protein SecA was quantitatively assessed in bulk and at the single vesicle level in the hydrogel. This technique provides a new way to investigate membrane proteins in their native environment at the single molecule level by means of fluorescence microscopy. PMID- 21655267 TI - Transcription factors E2A, FOXO1 and FOXP1 regulate recombination activating gene expression in cancer cells. AB - It has long been accepted that immunoglobulins (Igs) were produced by B lymphoid cells only. Recently Igs have been found to be expressed in various human cancer cells and promote tumor growth. Recombination activating gene 1 (RAG1) and RAG2, which are essential enzymes for initiating variable-diversity-joining segment recombination, have also been found to be expressed in cancer cells. However, the mechanism of RAG activation in these cancer cells has not been elucidated. Here, we investigated the regulatory mechanism of RAG expression in four human cancer cell lines by analyzing transcription factors that induce RAG activation in B cells. By RT-PCR, Western blot and immunofluorescence, we found that transcription factors E2A, FOXO1 and FOXP1 were expressed and localized to the nuclei of these cancer cells. Over-expression of E2A, FOXO1 or Foxp1 increased RAG expression, while RNA interference of E2A, FOXO1 or FOXP1 decreased RAG expression in the cancer cells. Chromatin immunoprecipitation experiments showed acetylation of RAG enhancer (Erag) and E2A, FOXO1 or FOXP1 were bound to Erag in vivo. These results indicate that in these cancer cells the transcription factors E2A, FOXO1 and FOXP1 regulate RAG expression, which initiates Ig gene rearrangement much in the way similar to B lymphocytes. PMID- 21655268 TI - Exendin-4 improves blood glucose control in both young and aging normal non diabetic mice, possible contribution of beta cell independent effects. AB - AIMS: Type 2 diabetes is highly prevalent in the elderly population. Glucagon like Peptide-1 mimetic such as exendin-4 augments post-prandial insulin secretion. However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied. In this study, we examined the glucose regulatory effects of exendin-4 in mice with different ages. METHODS: We treated 3-month and 20 to 22-month old C57/DBA mice with 10 nM/kg exendin-4 for 10 days with measurements of blood glucose and body weight. We performed OGTT and ITT to evaluate the glucose response and insulin sensitivity. Islet morphology and beta cell mass were measured by immuno-staining and beta cell proliferation was evaluated by BrdU incorporation and PCNA staining. Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment. RESULTS: Exendin-4 treatment improved glycemic control in both 3-month and 20 to 22-month old mice. In both groups of mice, the blood glucose lowering effect was independent of beta cell function as indicated by unchanged beta cell proliferation, insulin secretion or beta cell mass. Moreover, we found that exendin-4 treatment increased hepatic AKT and FOXO1 phosphorylation and inhibited glucose-6-phosphotase (G6P) and Phosphoenolpyruvate carboxykinase (PEPCK) expression in young mice, but this effect was attenuated in aging mice while the insulin sensitivity showed no change in the young group but significantly improved in aging mice. CONCLUSION: Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging. We further showed that although there was slight difference in the glucose modulating mechanism of exendin-4 therapy in young and aged mice, the improved glucose control seemed uncorrelated with increased beta cell mass or insulin secretion. PMID- 21655269 TI - Success rate of split-thickness skin grafting of chronic venous leg ulcers depends on the presence of Pseudomonas aeruginosa: a retrospective study. AB - The last years of research have proposed that bacteria might be involved in and contribute to the lack of healing of chronic wounds. Especially it seems that Pseudomonas aeruginosa play a crucial role in the healing. At Copenhagen Wound Healing Centre it was for many years clinical suspected that once chronic venous leg ulcers were colonized (weeks or months preoperatively) by P. aeruginosa, the success rate of skin grafting deteriorated despite aggressive treatment. To investigate this, a retrospective study was performed on the clinical outcome of 82 consecutive patients with chronic venous leg ulcers on 91 extremities, from the 1(st) of March 2005 until the 31(st) of August 2006. This was achieved by analysing the microbiology, demographic data, smoking and drinking habits, diabetes, renal impairment, co-morbidities, approximated size and age of the wounds, immunosuppressive treatment and complicating factors on the clinical outcome of each patient. The results were evaluated using a Student T-test for continuous parameters, chi-square test for categorical parameters and a logistic regression analysis to predict healing after 12 weeks. The analysis revealed that only 33,3% of ulcers with P. aeruginosa, isolated at least once from 12 weeks prior, to or during surgery, were healed (98% or more) by week 12 follow-up, while 73,1% of ulcers without P. aeruginosa were so by the same time (p = 0.001). Smoking also significantly suppressed the outcome at the 12-week follow-up. Subsequently, a logistic regression analysis was carried out leaving P. aeruginosa as the only predictor left in the model (p = 0.001). This study supports our hypothesis that P. aeruginosa in chronic venous leg ulcers, despite treatment, has considerable impact on partial take or rejection of split thickness skin grafts. PMID- 21655270 TI - Activation of methanogenesis in arid biological soil crusts despite the presence of oxygen. AB - Methanogenesis is traditionally thought to occur only in highly reduced, anoxic environments. Wetland and rice field soils are well known sources for atmospheric methane, while aerated soils are considered sinks. Although methanogens have been detected in low numbers in some aerated, and even in desert soils, it remains unclear whether they are active under natural oxic conditions, such as in biological soil crusts (BSCs) of arid regions. To answer this question we carried out a factorial experiment using microcosms under simulated natural conditions. The BSC on top of an arid soil was incubated under moist conditions in all possible combinations of flooding and drainage, light and dark, air and nitrogen headspace. In the light, oxygen was produced by photosynthesis. Methane production was detected in all microcosms, but rates were much lower when oxygen was present. In addition, the delta(13)C of the methane differed between the oxic/oxygenic and anoxic microcosms. While under anoxic conditions methane was mainly produced from acetate, it was almost entirely produced from H(2)/CO(2) under oxic/oxygenic conditions. Only two genera of methanogens were identified in the BSC-Methanosarcina and Methanocella; their abundance and activity in transcribing the mcrA gene (coding for methyl-CoM reductase) was higher under anoxic than oxic/oxygenic conditions, respectively. Both methanogens also actively transcribed the oxygen detoxifying gene catalase. Since methanotrophs were not detectable in the BSC, all the methane produced was released into the atmosphere. Our findings point to a formerly unknown participation of desert soils in the global methane cycle. PMID- 21655271 TI - Evidence for a role of srGAP3 in the positioning of commissural axons within the ventrolateral funiculus of the mouse spinal cord. AB - Slit-Robo signaling guides commissural axons away from the floor-plate of the spinal cord and into the longitudinal axis after crossing the midline. In this study we have evaluated the role of the Slit-Robo GTPase activating protein 3 (srGAP3) in commissural axon guidance using a knockout (KO) mouse model. Co immunoprecipitation experiments confirmed that srGAP3 interacts with the Slit receptors Robo1 and Robo2 and immunohistochemistry studies showed that srGAP3 co localises with Robo1 in the ventral and lateral funiculus and with Robo2 in the lateral funiculus. Stalling axons have been reported in the floor-plate of Slit and Robo mutant spinal cords but our axon tracing experiments revealed no dorsal commissural axon stalling in the floor plate of the srGAP3 KO mouse. Interestingly we observed a significant thickening of the ventral funiculus and a thinning of the lateral funiculus in the srGAP3 KO spinal cord, which has also recently been reported in the Robo2 KO. However, axons in the enlarged ventral funiculus of the srGAP3 KO are Robo1 positive but do not express Robo2, indicating that the thickening of the ventral funiculus in the srGAP3 KO is not a Robo2 mediated effect. We suggest a role for srGAP3 in the lateral positioning of post crossing axons within the ventrolateral funiculus. PMID- 21655272 TI - Oct4-induced reprogramming is required for adult brain neural stem cell differentiation into midbrain dopaminergic neurons. AB - Neural stem cells (NSCs) lose their competency to generate region-specific neuronal populations at an early stage during embryonic brain development. Here we investigated whether epigenetic modifications can reverse the regional restriction of mouse adult brain subventricular zone (SVZ) NSCs. Using a variety of chemicals that interfere with DNA methylation and histone acetylation, we showed that such epigenetic modifications increased neuronal differentiation but did not enable specific regional patterning, such as midbrain dopaminergic (DA) neuron generation. Only after Oct-4 overexpression did adult NSCs acquire a pluripotent state that allowed differentiation into midbrain DA neurons. DA neurons derived from Oct4-reprogrammed NSCs improved behavioural motor deficits in a rat model of Parkinson's disease (PD) upon intrastriatal transplantation. Here we report for the first time the successful differentiation of SVZ adult NSCs into functional region-specific midbrain DA neurons, by means of Oct-4 induced pluripotency. PMID- 21655273 TI - Inflammation triggers emergency granulopoiesis through a density-dependent feedback mechanism. AB - Normally, neutrophil pools are maintained by homeostatic mechanisms that require the transcription factor C/EBPalpha. Inflammation, however, induces neutrophilia through a distinct pathway of "emergency" granulopoiesis that is dependent on C/EBPbeta. Here, we show in mice that alum triggers emergency granulopoiesis through the IL-1RI-dependent induction of G-CSF. G-CSF/G-CSF-R neutralization impairs proliferative responses of hematopoietic stem and progenitor cells (HSPC) to alum, but also abrogates the acute mobilization of BM neutrophils, raising the possibility that HSPC responses to inflammation are an indirect result of the exhaustion of BM neutrophil stores. The induction of neutropenia, via depletion with Gr-1 mAb or myeloid-specific ablation of Mcl-1, elicits G-CSF via an IL-1RI independent pathway, stimulating granulopoietic responses indistinguishable from those induced by adjuvant. Notably, C/EBPbeta, thought to be necessary for enhanced generative capacity of BM, is dispensable for increased proliferation of HSPC to alum or neutropenia, but plays a role in terminal neutrophil differentiation during granulopoietic recovery. We conclude that alum elicits a transient increase in G-CSF production via IL-1RI for the mobilization of BM neutrophils, but density-dependent feedback sustains G-CSF for accelerated granulopoiesis. PMID- 21655274 TI - Plasma corticosterone activates SGK1 and induces morphological changes in oligodendrocytes in corpus callosum. AB - Repeated stressful events are known to be associated with onset of depression. Further, stress activates the hypothalamic-pituitary-adrenocortical (HPA) system by elevating plasma cortisol levels. However, little is known about the related downstream molecular pathway. In this study, by using repeated water-immersion and restraint stress (WIRS) as a stressor for mice, we attempted to elucidate the molecular pathway induced by elevated plasma corticosterone levels. We observed the following effects both, in vivo and in vitro: (1) repeated exposure to WIRS activates the 3-phosphoinositide-dependent protein kinase (PDK1)-serum glucocorticoid regulated kinase (SGK1)-N-myc downstream-regulated gene 1 (NDRG1) adhesion molecule (i.e., N-cadherin, alpha-catenin, and beta-catenin) stabilization pathway via an increase in plasma corticosterone levels; (2) the activation of this signaling pathway induces morphological changes in oligodendrocytes; and (3) after recovery from chronic stress, the abnormal arborization of oligodendrocytes and depression-like symptoms return to the control levels. Our data strongly suggest that these abnornalities of oligodendrocytes are possibly related to depression-like symptoms. PMID- 21655275 TI - Neonicotinoid insecticide imidacloprid causes outbreaks of spider mites on elm trees in urban landscapes. AB - BACKGROUND: Attempts to eradicate alien arthropods often require pesticide applications. An effort to remove an alien beetle from Central Park in New York City, USA, resulted in widespread treatments of trees with the neonicotinoid insecticide imidacloprid. Imidacloprid's systemic activity and mode of entry via roots or trunk injections reduce risk of environmental contamination and limit exposure of non-target organisms to pesticide residues. However, unexpected outbreaks of a formerly innocuous herbivore, Tetranychus schoenei (Acari: Tetranychidae), followed imidacloprid applications to elms in Central Park. This undesirable outcome necessitated an assessment of imidacloprid's impact on communities of arthropods, its effects on predators, and enhancement of the performance of T. schoenei. METHODOLOGY/PRINCIPAL FINDINGS: By sampling arthropods in elm canopies over three years in two locations, we document changes in the structure of communities following applications of imidacloprid. Differences in community structure were mostly attributable to increases in the abundance of T. schoenei on elms treated with imidacloprid. In laboratory experiments, predators of T. schoenei were poisoned through ingestion of prey exposed to imidacloprid. Imidacloprid's proclivity to elevate fecundity of T. schoenei also contributed to their elevated densities on treated elms. CONCLUSIONS/SIGNIFICANCE: This is the first study to report the effects of pesticide applications on the arthropod communities in urban landscapes and demonstrate that imidacloprid increases spider mite fecundity through a plant mediated mechanism. Laboratory experiments provide evidence that imidacloprid debilitates insect predators of spider mites suggesting that relaxation of top down regulation combined with enhanced reproduction promoted a non-target herbivore to pest status. With global commerce accelerating the incidence of arthropod invasions, prophylactic applications of pesticides play a major role in eradication attempts. Widespread use of neonicotinoid insecticides, however, can disrupt ecosystems tipping the ecological balance in favor of herbivores and creating pest outbreaks. PMID- 21655276 TI - Potential use of a serpin from Arabidopsis for pest control. AB - Although genetically modified (GM) plants expressing toxins from Bacillus thuringiensis (Bt) protect agricultural crops against lepidopteran and coleopteran pests, field-evolved resistance to Bt toxins has been reported for populations of several lepidopteran species. Moreover, some important agricultural pests, like phloem-feeding insects, are not susceptible to Bt crops. Complementary pest control strategies are therefore necessary to assure that the benefits provided by those insect-resistant transgenic plants are not compromised and to target those pests that are not susceptible. Experimental GM plants producing plant protease inhibitors have been shown to confer resistance against a wide range of agricultural pests. In this study we assessed the potential of AtSerpin1, a serpin from Arabidopsis thaliana (L). Heynh., for pest control. In vitro assays were conducted with a wide range of pests that rely mainly on either serine or cysteine proteases for digestion and also with three non-target organisms occurring in agricultural crops. AtSerpin1 inhibited proteases from all pest and non-target species assayed. Subsequently, the cotton leafworm Spodoptera littoralis Boisduval and the pea aphid Acyrthosiphon pisum (Harris) were fed on artificial diets containing AtSerpin1, and S. littoralis was also fed on transgenic Arabidopsis plants overproducing AtSerpin1. AtSerpin1 supplied in the artificial diet or by transgenic plants reduced the growth of S. littoralis larvae by 65% and 38%, respectively, relative to controls. Nymphs of A. pisum exposed to diets containing AtSerpin1 suffered high mortality levels (LC(50) = 637 ug ml(-1)). The results indicate that AtSerpin1 is a good candidate for exploitation in pest control. PMID- 21655277 TI - Subliminal semantic priming in speech. AB - Numerous studies have reported subliminal repetition and semantic priming in the visual modality. We transferred this paradigm to the auditory modality. Prime awareness was manipulated by a reduction of sound intensity level. Uncategorized prime words (according to a post-test) were followed by semantically related, unrelated, or repeated target words (presented without intensity reduction) and participants performed a lexical decision task (LDT). Participants with slower reaction times in the LDT showed semantic priming (faster reaction times for semantically related compared to unrelated targets) and negative repetition priming (slower reaction times for repeated compared to semantically related targets). This is the first report of semantic priming in the auditory modality without conscious categorization of the prime. PMID- 21655278 TI - Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear. METHODOLOGY/PRINCIPAL FINDINGS: Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells. CONCLUSIONS/SIGNIFICANCE: Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation. PMID- 21655279 TI - The essential functions of NEDD8 are mediated via distinct surface regions, and not by polyneddylation in Schizosaccharomyces pombe. AB - The ubiquitin-like protein NEDD8 is highly conserved in eukaryotes, from man to Schizosaccharomyces pombe. NEDD8 conjugation to cullin proteins is a prerequisite for cullin based E3 ubiquitin ligase activity, and essential for S. pombe viability. Here, we have performed alanine scanning mutagenesis of all conserved surface residues and show that the majority of essential residues were located around the hydrophobic patch and the C-terminus. However, we further identified essential residues not previously reported to be involved in ubiquitin ligase regulation that importantly do not prevent Ned8p conjugation. We also find that mutation of all conserved lysine residues in Ned8p, did not affect yeast viability, suggesting that mono-neddylation is sufficient for yeast viability under most conditions. PMID- 21655281 TI - Decreased heart rate variability in HIV positive patients receiving antiretroviral therapy: importance of blood glucose and cholesterol. AB - The presence of autonomic dysfunction in HIV patients is largely unknown. Early studies found autonomic dysfunction in patients with AIDS. Antiretroviral combination therapy (ART) has dramatically changed the course of the disease and improved prognosis and decreased morbidity. AIM: To evaluate whether autonomic dysfunction is present in an ART treated HIV population and if so to identify factors of importance. METHODS: HIV patients receiving ART for at least 12 months (n = 97) and an age-matched control group of healthy volunteers (n = 52) were included. All were non-diabetic and had never received medication for hypertension. Following a 10 min resting period a 15 min ECG recording was performed. Heart-rate variability (HRV) analysis was performed in accordance with current guidelines and data reported as mean [interquartile range]. RESULTS: Mean normal-to-normal (NN) and total HRV measured as standard deviation of normal-to normal (SDNN) was lower in HIV patients compared to controls (905 vs. 982 ms; p<0.001 and 48 vs. 54 ms; p = 0.028, respectively). No differences were found between the groups in parasympathetic activity measured as square root of the mean squared difference of successive NN-intervals (RMSSD) or the percent of differences between adjacent NN intervals greater than 50 ms (pNN50). In the HIV positives, haemoglobin A1c correlated inversely with SDNN, RMSSD and pNN50 (p<0.05). Total cholesterol and LDL-C correlated inversely with RMSSD and pNN50 (p<0.05). Neither HIV duration, HIV-RNA, CD4 cell count nor CD4 nadir correlated with time or phase domain HRV variables. CONCLUSIONS: Moderate autonomic dysfunction is present in HIV positives patients even with suppressed viral load due to ART. The dysfunction is correlated with HbA1c and hypercholesterolemia but not to duration of HIV or whether the patients were receiving protease inhibitors as part of the ART regime. PMID- 21655280 TI - Mir-34a is upregulated during liver regeneration in rats and is associated with the suppression of hepatocyte proliferation. AB - BACKGROUND: MicroRNAs are a class of small regulatory RNAs that modulate a variety of biological processes, including cellular differentiation, apoptosis, metabolism and proliferation. This study aims to explore the effect of miR-34a in hepatocyte proliferation and its potential role in liver regeneration termination. METHODOLOGY/PRINCIPAL FINDING: MiR-34a was highly induced after partial hepatectomy. Overexpression of miR-34a in BRL-3A cells could significantly inhibit cell proliferation and down-regulate the expression of inhibin betaB (INHBB) and Met. In BRL-3A cells, INHBB was identified as a direct target of miR-34a by luciferase reporter assay. More importantly, INHBB siRNA significantly repressed cell proliferation. A decrease of INHBB and Met was detected in regenerating liver. CONCLUSION/SIGNIFICANCE: MiR-34a expression was upregulated during the late phase of liver regeneration. MiR-34a-mediated regulation of INHBB and Met may collectively contribute to the suppression of hepatocyte proliferation. PMID- 21655282 TI - A successful crayfish invader is capable of facultative parthenogenesis: a novel reproductive mode in decapod crustaceans. AB - Biological invasions are impacting biota worldwide, and explaining why some taxa tend to become invasive is of major scientific interest. North American crayfish species, particularly of the family Cambaridae, are prominent invaders in freshwaters, defying the "tens rule" which states that only a minority of species introduced to new regions become established, and only a minority of those become invasive and pests. So far, success of cambarid invaders has largely been attributed to rapid maturation, high reproductive output, aggressiveness, and tolerance to pollution. We provide experimental evidence that females of one cambarid species particularly widespread in Europe, the spiny-cheek crayfish Orconectes limosus, are capable of facultative parthenogenesis. Such reproductive mode has never before been recognized in decapods, the most diverse crustacean order. As shown by analysis of seven microsatellite loci, crayfish females kept physically separated from males produced genetically homogeneous offspring identical with maternal individuals; this suggests they reproduced by apomixis, unlike those females which mated with males and had a diverse offspring. Further research is needed to clarify what environmental conditions are necessary for a switch to parthenogenesis in O. limosus, and what role it plays in natural crayfish populations. However, if such reproductive plasticity is present in other cambarid crayfish species, it may contribute to the overwhelming invasive success of this group. PMID- 21655283 TI - Positive regulation by GABA(B)R1 subunit of leptin expression through gene transactivation in adipocytes. AB - BACKGROUND: The view that gamma-aminobutyric acid (GABA) plays a functional role in non-neuronal tissues, in addition to an inhibitory neurotransmitter role in the mammalian central nervous system, is prevailing, while little attention has been paid to GABAergic signaling machineries expressed by adipocytes to date. In this study, we attempted to demonstrate the possible functional expression of GABAergic signaling machineries by adipocytes. METHODOLOGY/PRINCIPAL FINDINGS: GABA(B) receptor 1 (GABA(B)R1) subunit was constitutively expressed by mouse embryonic fibroblasts differentiated into adipocytes and adipocytic 3T3-L1 cells in culture, as well as mouse white adipose tissue, with no responsiveness to GABA(B)R ligands. However, no prominent expression was seen with mRNA for GABA(B)R2 subunit required for heteromeric orchestration of the functional GABA(B)R by any adipocytic cells and tissues. Leptin mRNA expression was significantly and selectively decreased in adipose tissue and embryonic fibroblasts, along with drastically reduced plasma leptin levels, in GABA(B)R1 null mice than in wild-type mice. Knockdown by siRNA of GABA(B)R1 subunit led to significant decreases in leptin promoter activity and leptin mRNA levels in 3T3 L1 cells. CONCLUSIONS/SIGNIFICANCE: Our results indicate that GABA(B)R1 subunit is constitutively expressed by adipocytes to primarily regulate leptin expression at the transcriptional level through a mechanism not relevant to the function as a partner of heterodimeric assembly to the functional GABA(B)R. PMID- 21655284 TI - Evaluation of combined LED-fluorescence microscopy and bleach sedimentation for diagnosis of tuberculosis at peripheral health service level. AB - BACKGROUND: Sputum microscopy is the only diagnostic for tuberculosis (TB) available at peripheral levels of health service in resource-poor countries. Its sensitivity is reduced in high HIV-prevalence settings. Sodium hypochlorite (NaOCl) specimen sedimentation prior microscopy and light-emitting diode (LED) fluorescence microscopy (FM) can individually improve performance of microscopy. This study aimed to evaluate the performance of combined LED-FM and NaOCl sputum sedimentation for TB detection at peripheral level of health services. METHODS: A prospective study was conducted in an urban health clinic in Nairobi, Kenya. Three sputum specimens were collected over 2 days from consecutive TB suspects. Smears were prepared and stained with auramine O and Ziehl-Neelsen (ZN) methods. Bleach (3.5%) was added to the remaining specimen before overnight sedimentation at room temperature. Auramine O staining was performed on smears of sediment. A 4(th) specimen was collected for TB culture. Auramine smears were read under the same microscope as used for ZN smears, but equipped with the LED FluoLEDTM fluorescence illuminator. RESULTS: 497 patients were included, and 1394 specimens collected. The yield of positive specimen was significantly increased after NaOCl sedimentation (24.9%) compared to direct LED-FM (20.6%) and direct ZN (20.3%). In detecting smear-positive patients, sensitivity was 78.5% for LED-FM after NaOCl sedimentation compared to 73.2% and 72.0% for direct LED-FM (P = 0.06) and direct ZN (P = 0.06), respectively. Specificity was 87.8% for LED-FM after NaOCl sedimentation compared to 96.7% and 95.9% for direct LED-FM (P<0.01) and direct ZN (P<0.01), respectively. Inter-reading agreement (kappa = 0.7) and technicians' acceptability were good. CONCLUSION: NaOCl sedimentation did not improve the performance of LED-FM in the diagnosis of pulmonary TB at peripheral health service level. PMID- 21655285 TI - The use of carcasses for the analysis of cetacean population genetic structure: a comparative study in two dolphin species. AB - Advances in molecular techniques have enabled the study of genetic diversity and population structure in many different contexts. Studies that assess the genetic structure of cetacean populations often use biopsy samples from free-ranging individuals and tissue samples from stranded animals or individuals that became entangled in fishery or aquaculture equipment. This leads to the question of how representative the location of a stranded or entangled animal is with respect to its natural range, and whether similar results would be obtained when comparing carcass samples with samples from free-ranging individuals in studies of population structure. Here we use tissue samples from carcasses of dolphins that stranded or died as a result of bycatch in South Australia to investigate spatial population structure in two species: coastal bottlenose (Tursiops sp.) and short beaked common dolphins (Delphinus delphis). We compare these results with those previously obtained from biopsy sampled free-ranging dolphins in the same area to test whether carcass samples yield similar patterns of genetic variability and population structure. Data from dolphin carcasses were gathered using seven microsatellite markers and a fragment of the mitochondrial DNA control region. Analyses based on carcass samples alone failed to detect genetic structure in Tursiops sp., a species previously shown to exhibit restricted dispersal and moderate genetic differentiation across a small spatial scale in this region. However, genetic structure was correctly inferred in D. delphis, a species previously shown to have reduced genetic structure over a similar geographic area. We propose that in the absence of corroborating data, and when population structure is assessed over relatively small spatial scales, the sole use of carcasses may lead to an underestimate of genetic differentiation. This can lead to a failure in identifying management units for conservation. Therefore, this risk should be carefully assessed when planning population genetic studies of cetaceans. PMID- 21655286 TI - Remodeling of monoplanar Purkinje cell dendrites during cerebellar circuit formation. AB - Dendrite arborization patterns are critical determinants of neuronal connectivity and integration. Planar and highly branched dendrites of the cerebellar Purkinje cell receive specific topographical projections from two major afferent pathways; a single climbing fiber axon from the inferior olive that extend along Purkinje dendrites, and parallel fiber axons of granule cells that contact vertically to the plane of dendrites. It has been believed that murine Purkinje cell dendrites extend in a single parasagittal plane in the molecular layer after the cell polarity is determined during the early postnatal development. By three dimensional confocal analysis of growing Purkinje cells, we observed that mouse Purkinje cells underwent dynamic dendritic remodeling during circuit maturation in the third postnatal week. After dendrites were polarized and flattened in the early second postnatal week, dendritic arbors gradually expanded in multiple sagittal planes in the molecular layer by intensive growth and branching by the third postnatal week. Dendrites then became confined to a single plane in the fourth postnatal week. Multiplanar Purkinje cells in the third week were often associated by ectopic climbing fibers innervating nearby Purkinje cells in distinct sagittal planes. The mature monoplanar arborization was disrupted in mutant mice with abnormal Purkinje cell connectivity and motor discoordination. The dendrite remodeling was also impaired by pharmacological disruption of normal afferent activity during the second or third postnatal week. Our results suggest that the monoplanar arborization of Purkinje cells is coupled with functional development of the cerebellar circuitry. PMID- 21655287 TI - Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751)(SL) mice. AB - BACKGROUND: NADPH oxidase is implicated in neurotoxic microglial activation and the progressive nature of Alzheimer's Disease (AD). Here, we test the ability of two NADPH oxidase inhibitors, apocynin and dextromethorphan (DM), to reduce learning deficits and neuropathology in transgenic mice overexpressing human amyloid precursor protein with the Swedish and London mutations (hAPP(751)(SL)). METHODS: Four month old hAPP(751)(SL) mice were treated daily with saline, 15 mg/kg DM, 7.5 mg/kg DM, or 10 mg/kg apocynin by gavage for four months. RESULTS: Only hAPP(751)(SL) mice treated with apocynin showed reduced plaque size and a reduction in the number of cortical microglia, when compared to the saline treated group. Analysis of whole brain homogenates from all treatments tested (saline, DM, and apocynin) demonstrated low levels of TNFalpha, protein nitration, lipid peroxidation, and NADPH oxidase activation, indicating a low level of neuroinflammation and oxidative stress in hAPP(751)(SL) mice at 8 months of age that was not significantly affected by any drug treatment. Despite in vitro analyses demonstrating that apocynin and DM ameliorate Abeta-induced extracellular superoxide production and neurotoxicity, both DM and apocynin failed to significantly affect learning and memory tasks or synaptic density in hAPP(751)(SL) mice. To discern how apocynin was affecting plaque levels (plaque load) and microglial number in vivo, in vitro analysis of microglia was performed, revealing no apocynin effects on beta-amyloid (Abeta) phagocytosis, microglial proliferation, or microglial survival. CONCLUSIONS: Together, this study suggests that while hAPP(751)(SL) mice show increases in microglial number and plaque load, they fail to exhibit elevated markers of neuroinflammation consistent with AD at 8 months of age, which may be a limitation of this animal model. Despite absence of clear neuroinflammation, apocynin was still able to reduce both plaque size and microglial number, suggesting that apocynin may have additional therapeutic effects independent of anti-inflammatory characteristics. PMID- 21655288 TI - Automated analysis of craniofacial morphology using magnetic resonance images. AB - Quantitative analysis of craniofacial morphology is of interest to scholars working in a wide variety of disciplines, such as anthropology, developmental biology, and medicine. T1-weighted (anatomical) magnetic resonance images (MRI) provide excellent contrast between soft tissues. Given its three-dimensional nature, MRI represents an ideal imaging modality for the analysis of craniofacial structure in living individuals. Here we describe how T1-weighted MR images, acquired to examine brain anatomy, can also be used to analyze facial features. Using a sample of typically developing adolescents from the Saguenay Youth Study (N = 597; 292 male, 305 female, ages: 12 to 18 years), we quantified inter individual variations in craniofacial structure in two ways. First, we adapted existing nonlinear registration-based morphological techniques to generate iteratively a group-wise population average of craniofacial features. The nonlinear transformations were used to map the craniofacial structure of each individual to the population average. Using voxel-wise measures of expansion and contraction, we then examined the effects of sex and age on inter-individual variations in facial features. Second, we employed a landmark-based approach to quantify variations in face surfaces. This approach involves: (a) placing 56 landmarks (forehead, nose, lips, jaw-line, cheekbones, and eyes) on a surface representation of the MRI-based group average; (b) warping the landmarks to the individual faces using the inverse nonlinear transformation estimated for each person; and (3) using a principal components analysis (PCA) of the warped landmarks to identify facial features (i.e. clusters of landmarks) that vary in our sample in a correlated fashion. As with the voxel-wise analysis of the deformation fields, we examined the effects of sex and age on the PCA-derived spatial relationships between facial features. Both methods demonstrated significant sexual dimorphism in craniofacial structure in areas such as the chin, mandible, lips, and nose. PMID- 21655289 TI - CD34+ cells represent highly functional endothelial progenitor cells in murine bone marrow. AB - BACKGROUND: Endothelial progenitor cells (EPCs) were shown to have angiogenic potential contributing to neovascularization. However, a clear definition of mouse EPCs by cell surface markers still remains elusive. We hypothesized that CD34 could be used for identification and isolation of functional EPCs from mouse bone marrow. METHODOLOGY/PRINCIPAL FINDINGS: CD34(+) cells, c-Kit(+)/Sca 1(+)/Lin(-) (KSL) cells, c-Kit(+)/Lin(-) (KL) cells and Sca-1(+)/Lin(-) (SL) cells were isolated from mouse bone marrow mononuclear cells (BMMNCs) using fluorescent activated cell sorting. EPC colony forming capacity and differentiation capacity into endothelial lineage were examined in the cells. Although CD34(+) cells showed the lowest EPC colony forming activity, CD34(+) cells exhibited under endothelial culture conditions a more adherent phenotype compared with the others, demonstrating the highest mRNA expression levels of endothelial markers vWF, VE-cadherin, and Flk-1. Furthermore, a dramatic increase in immediate recruitment of cells to the myocardium following myocardial infarction and systemic cell injection was observed for CD34(+) cells comparing with others, which could be explained by the highest mRNA expression levels of key homing-related molecules Integrin beta2 and CXCR4 in CD34(+) cells. Cell retention and incorporation into the vasculature of the ischemic myocardium was also markedly increased in the CD34(+) cell-injected group, giving a possible explanation for significant reduction in fibrosis area, significant increase in neovascularization and the best cardiac functional recovery in this group in comparison with the others. CONCLUSION: These findings suggest that mouse CD34(+) cells may represent a functional EPC population in bone marrow, which could benefit the investigation of therapeutic EPC biology. PMID- 21655290 TI - CovR-controlled global regulation of gene expression in Streptococcus mutans. AB - CovR/S is a two-component signal transduction system (TCS) that controls the expression of various virulence related genes in many streptococci. However, in the dental pathogen Streptococcus mutans, the response regulator CovR appears to be an orphan since the cognate sensor kinase CovS is absent. In this study, we explored the global transcriptional regulation by CovR in S. mutans. Comparison of the transcriptome profiles of the wild-type strain UA159 with its isogenic covR deleted strain IBS10 indicated that at least 128 genes (~6.5% of the genome) were differentially regulated. Among these genes, 69 were down regulated, while 59 were up regulated in the IBS10 strain. The S. mutans CovR regulon included competence genes, virulence related genes, and genes encoded within two genomic islands (GI). Genes encoded by the GI TnSmu2 were found to be dramatically reduced in IBS10, while genes encoded by the GI TnSmu1 were up regulated in the mutant. The microarray data were further confirmed by real-time RT-PCR analyses. Furthermore, direct regulation of some of the differentially expressed genes was demonstrated by electrophoretic mobility shift assays using purified CovR protein. A proteomic study was also carried out that showed a general perturbation of protein expression in the mutant strain. Our results indicate that CovR truly plays a significant role in the regulation of several virulence related traits in this pathogenic streptococcus. PMID- 21655291 TI - MALDI-TOF mass spectrometry is a fast and reliable platform for identification and ecological studies of species from family Rhizobiaceae. AB - Family Rhizobiaceae includes fast growing bacteria currently arranged into three genera, Rhizobium, Ensifer and Shinella, that contain pathogenic, symbiotic and saprophytic species. The identification of these species is not possible on the basis of physiological or biochemical traits and should be based on sequencing of several genes. Therefore alternative methods are necessary for rapid and reliable identification of members from family Rhizobiaceae. In this work we evaluated the suitability of Matrix-Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF MS) for this purpose. Firstly, we evaluated the capability of this methodology to differentiate among species of family Rhizobiaceae including those closely related and then we extended the database of MALDI Biotyper 2.0 including the type strains of 56 species from genera Rhizobium, Ensifer and Shinella. Secondly, we evaluated the identification potential of this methodology by using several strains isolated from different sources previously identified on the basis of their rrs, recA and atpD gene sequences. The 100% of these strains were correctly identified showing that MALDI TOF MS is an excellent tool for identification of fast growing rhizobia applicable to large populations of isolates in ecological and taxonomic studies. PMID- 21655292 TI - A template-dependent dislocation mechanism potentiates K65R reverse transcriptase mutation development in subtype C variants of HIV-1. AB - Numerous studies have suggested that the K65R reverse transcriptase (RT) mutation develops more readily in subtype C than subtype B HIV-1. We recently showed that this discrepancy lies partly in the subtype C template coding sequence that predisposes RT to pause at the site of K65R mutagenesis. However, the mechanism underlying this observation and the elevated rates of K65R development remained unknown. Here, we report that DNA synthesis performed with subtype C templates consistently produced more K65R-containing transcripts than subtype B templates, regardless of the subtype-origin of the RT enzymes employed. These findings confirm that the mechanism involved is template-specific and RT-independent. In addition, a pattern of DNA synthesis characteristic of site-specific primer/template slippage and dislocation was only observed with the subtype C sequence. Analysis of RNA secondary structure suggested that the latter was unlikely to impact on K65R development between subtypes and that Streisinger strand slippage during DNA synthesis at the homopolymeric nucleotide stretch of the subtype C K65 region might occur, resulting in misalignment of the primer and template. Consequently, slippage would lead to a deletion of the middle adenine of codon K65 and the production of a -1 frameshift mutation, which upon dislocation and realignment of the primer and template, would lead to development of the K65R mutation. These findings provide additional mechanistic evidence for the facilitated development of the K65R mutation in subtype C HIV-1. PMID- 21655293 TI - Bacterial surface appendages strongly impact nanomechanical and electrokinetic properties of Escherichia coli cells subjected to osmotic stress. AB - The physicochemical properties and dynamics of bacterial envelope, play a major role in bacterial activity. In this study, the morphological, nanomechanical and electrohydrodynamic properties of Escherichia coli K-12 mutant cells were thoroughly investigated as a function of bulk medium ionic strength using atomic force microscopy (AFM) and electrokinetics (electrophoresis). Bacteria were differing according to genetic alterations controlling the production of different surface appendages (short and rigid Ag43 adhesins, longer and more flexible type 1 fimbriae and F pilus). From the analysis of the spatially resolved force curves, it is shown that cells elasticity and turgor pressure are not only depending on bulk salt concentration but also on the presence/absence and nature of surface appendage. In 1 mM KNO(3), cells without appendages or cells surrounded by Ag43 exhibit large Young moduli and turgor pressures (~700 900 kPa and ~100-300 kPa respectively). Under similar ionic strength condition, a dramatic ~50% to ~70% decrease of these nanomechanical parameters was evidenced for cells with appendages. Qualitatively, such dependence of nanomechanical behavior on surface organization remains when increasing medium salt content to 100 mM, even though, quantitatively, differences are marked to a much smaller extent. Additionally, for a given surface appendage, the magnitude of the nanomechanical parameters decreases significantly when increasing bulk salt concentration. This effect is ascribed to a bacterial exoosmotic water loss resulting in a combined contraction of bacterial cytoplasm together with an electrostatically-driven shrinkage of the surface appendages. The former process is demonstrated upon AFM analysis, while the latter, inaccessible upon AFM imaging, is inferred from electrophoretic data interpreted according to advanced soft particle electrokinetic theory. Altogether, AFM and electrokinetic results clearly demonstrate the intimate relationship between structure/flexibility and charge of bacterial envelope and propensity of bacterium and surface appendages to contract under hypertonic conditions. PMID- 21655294 TI - Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice. AB - Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory. PMID- 21655295 TI - Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2-mediated granulomatous lung inflammation. AB - Previous epidemiological studies in humans and experimental studies in animals indicate that survivors of severe sepsis exhibit deficiencies in the activation and effector function of immune cells. In particular, CD4+ T lymphocytes can exhibit reduced proliferative capacity and improper cytokine responses following sepsis. To further investigate the cell-intrinsic defects of CD4+ T cells following sepsis, splenic CD4+ T cells from sham surgery and post-septic mice were transferred into lymphopenic mice. These recipient mice were then subjected to both TH1-(purified protein derivative) and TH2-(Schistosoma mansoni egg antigen) driven models of granulomatous lung inflammation. Post-septic CD4+ T cells mediated smaller TH1 and larger TH2 lung granulomas as compared to mice receiving CD4+ T cells from sham surgery donors. However, cytokine production by lymph node cells in antigen restimulation assays indicated increased pan-specific cytokine expression by post-septic CD4+ T cell recipient mice in both TH1 and TH2 granuloma models. These include increased production of T(H)2 cytokines in TH1 inflammation, and increased production of T(H)1 cytokines in TH2 inflammation. These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression. PMID- 21655296 TI - Circulating vascular progenitor cells and central arterial stiffness in polycystic ovary syndrome. AB - OBJECTIVE: Subjects with Polycystic ovarian syndrome (PCOS) are at increased risk of Type 2 diabetes mellitus (T2DM). The mechanism of this enhanced risk is unclear. Circulating vascular progenitor cells (VPC) are immature bone marrow derived cells capable of differentiating into mature endothelial cells. VPC number/function and central arterial stiffness predict cardio-metabolic disease in at-risk populations. DESIGN: We studied VPC and arterial stiffness measures in non-obese PCOS subjects as compared to age and body mass index (BMI) matched healthy controls in a cross-sectional study. METHODS: Fourteen subjects with PCOS and 12 controls of similar age, BMI (all <30 kg/m(2)) and metabolic profile were studied. VPC number and in vitro function were studied by flow cytometry and tube formation assays respectively. Augmentation index (AIx), a measure of central arterial stiffness, and central (aortic) blood pressures (BP) were measured by applanation tonometry. RESULTS: Subjects with PCOS had a reduced number, mean+/ SEM, of circulating CD34(+)133(+) VPCs (317.5+/-51.0 vs. 558.3+/-101.2, p = 0.03) and impaired in vitro tube formation (completed tube area 1.0+/-0.06 vs. 1.2+/ 0.05*10(6) um(2) p = 0.02). PCOS subjects had significantly higher AIx (18.4+/ 1.9% vs. 4.9+/-2.0%) and this difference remained significant even after adjustments for age, BMI and smoking (p = 0.003) in multivariate analyses. Central systolic and pulse pressure were higher in PCOS subjects but these differences were not statistically significant after adjustment for age. Brachial systolic and pulse pressures were similar. VPC number/function and arterial stiffness or BP measures were not correlated. CONCLUSIONS: Non-obese PCOS is characterized by a reduced VPC number, impaired VPC function and increased central arterial stiffness. These changes in novel vascular risk markers may explain the enhanced risk of T2DM and CVD in PCOS. PMID- 21655298 TI - Activation of the parieto-premotor network is associated with vivid motor imagery -a parametric FMRI study. AB - The present study examined the neural basis of vivid motor imagery with parametrical functional magnetic resonance imaging. 22 participants performed motor imagery (MI) of six different right-hand movements that differed in terms of pointing accuracy needs and object involvement, i.e., either none, two big or two small squares had to be pointed at in alternation either with or without an object grasped with the fingers. After each imagery trial, they rated the perceived vividness of motor imagery on a 7-point scale. Results showed that increased perceived imagery vividness was parametrically associated with increasing neural activation within the left putamen, the left premotor cortex (PMC), the posterior parietal cortex of the left hemisphere, the left primary motor cortex, the left somatosensory cortex, and the left cerebellum. Within the right hemisphere, activation was found within the right cerebellum, the right putamen, and the right PMC. It is concluded that the perceived vividness of MI is parametrically associated with neural activity within sensorimotor areas. The results corroborate the hypothesis that MI is an outcome of neural computations based on movement representations located within motor areas. PMID- 21655297 TI - Early and late postnatal myocardial and vascular changes in a protein restriction rat model of intrauterine growth restriction. AB - Intrauterine growth restriction (IUGR) is a risk factor for cardiovascular disease in later life. Early structural and functional changes in the cardiovascular system after IUGR may contribute to its pathogenesis. We tested the hypothesis that IUGR leads to primary myocardial and vascular alterations before the onset of hypertension. A rat IUGR model of maternal protein restriction during gestation was used. Dams were fed low protein (LP; casein 8.4%) or isocaloric normal protein diet (NP; casein 17.2%). The offspring was reduced to six males per litter. Immunohistochemical and real-time PCR analyses were performed in myocardial and vascular tissue of neonates and animals at day 70 of life. In the aortas of newborn IUGR rats expression of connective tissue growth factor (CTGF) was induced 3.2-fold. At day 70 of life, the expression of collagen I was increased 5.6-fold in aortas of IUGR rats. In the hearts of neonate IUGR rats, cell proliferation was more prominent compared to controls. At day 70 the expression of osteopontin was induced 7.2-fold. A 3- to 7-fold increase in the expression of the profibrotic cytokines TGF-beta and CTGF as well as of microfibrillar matrix molecules was observed. The myocardial expression and deposition of collagens was more prominent in IUGR animals compared to controls at day 70. In the low-protein diet model, IUGR leads to changes in the expression patterns of profibrotic genes and discrete structural abnormalities of vessels and hearts in adolescence, but, with the exception of CTGF, not as early as at the time of birth. Invasive and non-invasive blood pressure measurements confirmed that IUGR rats were normotensive at the time point investigated and that the changes observed occurred independently of an increased blood pressure. Hence, altered matrix composition of the vascular wall and the myocardium may predispose IUGR animals to cardiovascular disease later in life. PMID- 21655299 TI - Social determinants of smoking in low- and middle-income countries: results from the World Health Survey. AB - INTRODUCTION: Tobacco smoking is a leading cause of premature death and disability, and over 80% of the world's smokers live in low- or middle-income countries. The objective of this study is to assess demographic and socioeconomic determinants of current smoking in low- and middle-income countries. METHODS: We used data, from the World Health Survey in 48 low-income and middle-income countries, to explore the impact of demographic and socioeconomic factors on the current smoking status of respondents. The data from these surveys provided information on 213,807 respondents aged 18 years or above that were divided into 4 pooled datasets according to their sex and country income group. The overall proportion of current smokers, as well as the proportion by each relevant demographic and socioeconomic determinant, was calculated within each of the pooled datasets, and multivariable logistic regression was used to assess the association between current smoking and these determinants. RESULTS: The odds of smoking were not equal in all demographic or socioeconomic groups. Some factors were fairly stable across the four datasets studied: for example, individuals were more likely to smoke if they had little or no education, regardless of if they were male or female, or lived in a low or a middle income country. Nevertheless, other factors, notably age and wealth, showed a differential effect on smoking by sex or country income level. While women in the low-income country group were twice as likely to smoke if they were in the lowest wealth quintile compared with the highest, the association was absent in the middle-income country group. CONCLUSION: Information on how smoking is distributed among low- or middle-income countries will allow policy makers to tailor future policies, and target the most vulnerable populations. PMID- 21655300 TI - Association of short tandem repeat polymorphism in the promoter of prostate cancer antigen 3 gene with the risk of prostate cancer. AB - BACKGROUND: PCA3 (prostate cancer antigen 3) gene is one of the most prostate cancer-specific genes at present. Consequently, the prostate-specific expression and the sharp up-regulation of PCA3 mRNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In our study, we evaluated whether there is polymorphism in PCA3 promoter region and also assess the association of the polymorphism with prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: We designed a specific primer set to screen the promoter of PCA3 gene by polymerase chain reaction (PCR)-based cloning and sequencing with the DNA extracted from peripheral blood samples of prostate cancer (PCa) cases (n = 186) and healthy control cases (n = 135). Genotype specific risks were estimated as odds ratios (ORs) with associated 95% confidence intervals (CIs) by chi-square test. Possible deviation of the genotype frequencies from controls and PCa cases expected under Hardy-Weinberg equilibrium was assessed by the chi-square test. Short tandem repeat polymorphism of TAAA was found in the promoter region of PCA3 gene, five polymorphisms and eight genotypes were identified. The eight genotypes were divided into three groups: <=10TAAA, 11TAAA, >=12TAAA. The group 11TAAA and >=12TAAA were associated with higher relative risk for prostate cancer than group <=10TAAA (OR = 1.76, 95%CI = 1.07 2.89[for group 11TAAA]; OR = 5.28, 95%CI = 1.76-15.89[for group >=12TAAA]). CONCLUSIONS/SIGNIFICANCE: The presence of the (TAAA)n short tandem repeat polymorphisms in the PCA3 promoter region may be a risk factor for prostate cancer in the Chinese population. PMID- 21655301 TI - Tsetse immune system maturation requires the presence of obligate symbionts in larvae. AB - Beneficial microbial symbionts serve important functions within their hosts, including dietary supplementation and maintenance of immune system homeostasis. Little is known about the mechanisms that enable these bacteria to induce specific host phenotypes during development and into adulthood. Here we used the tsetse fly, Glossina morsitans, and its obligate mutualist, Wigglesworthia glossinidia, to investigate the co-evolutionary adaptations that influence the development of host physiological processes. Wigglesworthia is maternally transmitted to tsetse's intrauterine larvae through milk gland secretions. We can produce flies that lack Wigglesworthia (Gmm(Wgm-) yet retain their other symbiotic microbes. Such offspring give rise to adults that exhibit a largely normal phenotype, with the exception being that they are reproductively sterile. Our results indicate that when reared under normal environmental conditions Gmm(Wgm-) adults are also immuno-compromised and highly susceptible to hemocoelic E. coli infections while age-matched wild-type individuals are refractory. Adults that lack Wigglesworthia during larval development exhibit exceptionally compromised cellular and humoral immune responses following microbial challenge, including reduced expression of genes that encode antimicrobial peptides (cecropin and attacin), hemocyte-mediated processes (thioester-containing proteins 2 and 4 and prophenoloxidase), and signal-mediating molecules (inducible nitric oxide synthase). Furthermore, Gmm(Wgm-) adults harbor a reduced population of sessile and circulating hemocytes, a phenomenon that likely results from a significant decrease in larval expression of serpent and lozenge, both of which are associated with the process of early hemocyte differentiation. Our results demonstrate that Wigglesworthia must be present during the development of immature progeny in order for the immune system to function properly in adult tsetse. This phenomenon provides evidence of yet another important physiological adaptation that further anchors the obligate symbiosis between tsetse and Wigglesworthia. PMID- 21655302 TI - N-terminal acetylation inhibits protein targeting to the endoplasmic reticulum. AB - Amino-terminal acetylation is probably the most common protein modification in eukaryotes with as many as 50%-80% of proteins reportedly altered in this way. Here we report a systematic analysis of the predicted N-terminal processing of cytosolic proteins versus those destined to be sorted to the secretory pathway. While cytosolic proteins were profoundly biased in favour of processing, we found an equal and opposite bias against such modification for secretory proteins. Mutations in secretory signal sequences that led to their acetylation resulted in mis-sorting to the cytosol in a manner that was dependent upon the N-terminal processing machinery. Hence N-terminal acetylation represents an early determining step in the cellular sorting of nascent polypeptides that appears to be conserved across a wide range of species. PMID- 21655303 TI - Lutzomyia longipalpis saliva or salivary protein LJM19 protects against Leishmania braziliensis and the saliva of its vector, Lutzomyia intermedia. AB - BACKGROUND: Leishmania transmission occurs in the presence of insect saliva. Immunity to Phlebotomus papatasi or Lutzomyia longipalpis saliva or salivary components confers protection against an infection by Leishmania in the presence of the homologous saliva. However, immunization with Lutzomyia intermedia saliva did not protect mice against Leishmania braziliensis plus Lu. intermedia saliva. In the present study, we have studied whether the immunization with Lu. longipalpis saliva or a DNA plasmid coding for LJM19 salivary protein would be protective against L. braziliensis infection in the presence of Lu. intermedia saliva, the natural vector for L. braziliensis. METHODOLOGY/PRINCIPAL FINDINGS: Immunization with Lu. longipalpis saliva or with LJM19 DNA plasmid induced a Delayed-Type Hypersensitivity (DTH) response against Lu. longipalpis as well as against a Lu. intermedia saliva challenge. Immunized and unimmunized control hamsters were then intradermally infected in the ears with L. braziliensis in the presence of Lu. longipalpis or Lu. intermedia saliva. Animals immunized with Lu. longipalpis saliva exhibited smaller lesion sizes as well as reduced disease burdens both at lesion site and in the draining lymph nodes. These alterations were associated with a significant decrease in the expression levels of IL-10 and TGF-beta. Animals immunized with LJM19 DNA plasmid presented similar findings in protection and immune response and additionally increased IFN-gamma expression. CONCLUSIONS/SIGNIFICANCE: Immunization with Lu. longipalpis saliva or with a DNA plasmid coding LJM19 salivary protein induced protection in hamsters challenged with L. braziliensis plus Lu. intermedia saliva. These findings point out an important role of immune response against saliva components, suggesting the possibility to develop a vaccine using a single component of Lu. longipalpis saliva to generate protection against different species of Leishmania, even those transmitted by a different vector. PMID- 21655304 TI - First Colombian multicentric newborn screening for congenital toxoplasmosis. AB - AIMS: To determine the incidence of congenital toxoplasmosis in Colombian newborns from 19 hospital or maternal child health services from seven different cities of five natural geographic regions (Caribbean, Central, Andean, Amazonia and Eastern). MATERIALS AND METHODS: We collected 15,333 samples from umbilical cord blood between the period of March 2009 to May 2010 in 19 different hospitals and maternal-child health services from seven different cities. We applied an IgM ELISA assay (Vircell, Spain) to determine the frequency of IgM anti Toxoplasma. The results in blood cord samples were confirmed either by western blot and repeated ELISA IgM assay. In a sub-sample of 1,613 children that were negative by the anti-Toxoplasma IgM assay, the frequency of specific anti-Toxoplasma IgA by the ISAGA assay was determined. All children with positive samples by IgM, IgA, clinical diagnosis or treatment during pregnancy were recalled for confirmatory tests after day 10 of life. RESULTS: 61 positive samples for specific IgM (0.39%) and 9 positives for IgA (0.5%) were found. 143 questionnaires were positive for a clinical diagnosis or treatment for toxoplasmosis during pregnancy. 109 out of the 218 children that had some of the criteria for postnatal confirmatory tests were followed. Congenital toxoplasmosis infection was confirmed in 15 children: 7 were symptomatic, and three of them died before the first month of life (20% of lethality). A significant correlation was found between a high incidence of markers for congenital toxoplasmosis and higher mean annual rainfall for the city. CONCLUSIONS: Incidence for congenital toxoplasmosis is significantly different between hospitals or maternal child health services from different cities in Colombia. Mean annual rainfall was correlated with incidence of congenital toxoplasmosis. PMID- 21655305 TI - Tsetse flies rely on symbiotic Wigglesworthia for immune system development. PMID- 21655306 TI - Vector competence of the tick Ixodes ricinus for transmission of Bartonella birtlesii. AB - Bartonella spp. are facultative intracellular vector-borne bacteria associated with several emerging diseases in humans and animals all over the world. The potential for involvement of ticks in transmission of Bartonella spp. has been heartily debated for many years. However, most of the data supporting bartonellae transmission by ticks come from molecular and serological epidemiological surveys in humans and animals providing only indirect evidences without a direct proof of tick vector competence for transmission of bartonellae. We used a murine model to assess the vector competence of Ixodes ricinus for Bartonella birtlesii. Larval and nymphal I. ricinus were fed on a B. birtlesii-infected mouse. The nymphs successfully transmitted B. birtlesii to naive mice as bacteria were recovered from both the mouse blood and liver at seven and 16 days after tick bites. The female adults successfully emitted the bacteria into uninfected blood after three or more days of tick attachment, when fed via membrane feeding system. Histochemical staining showed the presence of bacteria in salivary glands and muscle tissues of partially engorged adult ticks, which had molted from the infected nymphs. These results confirm the vector competence of I. ricinus for B. birtlesii and represent the first in vivo demonstration of a Bartonella sp. transmission by ticks. Consequently, bartonelloses should be now included in the differential diagnosis for patients exposed to tick bites. PMID- 21655307 TI - The early clinical features of dengue in adults: challenges for early clinical diagnosis. AB - BACKGROUND: The emergence of dengue throughout the tropical world is affecting an increasing proportion of adult cases. The clinical features of dengue in different age groups have not been well examined, especially in the context of early clinical diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: We structured a prospective study of adults (>= 18 years of age) presenting with acute febrile illness within 72 hours from illness onset upon informed consent. Patients were followed up over a 3-4 week period to determine the clinical outcome. A total of 2,129 adults were enrolled in the study, of which 250 (11.7%) had dengue. Differences in the rates of dengue-associated symptoms resulted in high sensitivities when the WHO 1997 or 2009 classification schemes for probable dengue fever were applied to the cohort. However, when the cases were stratified into age groups, fewer older adults reported symptoms such as myalgia, arthralgia, retro-orbital pain and mucosal bleeding, resulting in reduced sensitivity of the WHO classification schemes. On the other hand, the risks of severe dengue and hospitalization were not diminished in older adults, indicating that this group of patients can benefit from early diagnosis, especially when an antiviral drug becomes available. Our data also suggests that older adults who present with fever and leukopenia should be tested for dengue, even in the absence of other symptoms. CONCLUSION: Early clinical diagnosis based on previously defined symptoms that are associated with dengue, even when used in the schematics of both the WHO 1997 and 2009 classifications, is difficult in older adults. PMID- 21655308 TI - Inconsistent protective efficacy and marked polymorphism limits the value of Schistosoma japonicum tetraspanin-2 as a vaccine target. AB - BACKGROUND: Schistosoma mansoni tetraspanin 2 (Sm-TSP-2) has been shown to be strongly recognized by IgG1 and IgG3 antibodies from individuals putatively resistant to schistosome infection, but not chronically infected people, and to induce high levels of protection against challenge infection in the murine model of schistosomiasis. Amplification by PCR of homologous sequences from male and female S. japonicum worms showed the presence of 7 different clusters or subclasses of S. japonicum TSP-2. We determined the protective efficacy of one subclass - Sj-TSP-2e. METHODOLOGY/PRINCIPAL FINDINGS: Following the alignment of 211 cDNAs, we identified 7 clusters encoding S. japonicum TSP-2 (Sj-TSP-2) based on sequence variation in the large extracellular loop (LEL) region with differing frequency of transcription in male and female worms. Quantitative PCR analysis revealed elevated expression of Sj-TSP-2 in adult worms compared with other life cycle stages. We expressed in E. coli the LEL region of one of the clusters which exhibited a high frequency of transcription in female worms, and showed the purified recombinant protein (Sj-TSP-2e) was recognised by 43.1% of sera obtained from confirmed schistosomiasis japonica patients. Vaccination of mice with the recombinant protein induced high levels of IgG1 and IgG2 antibodies, but no consistent protective efficacy against challenge infection was elicited in three independent trials. CONCLUSIONS/SIGNIFICANCE: The highly polymorphic nature of the Sj-TSP-2 gene at the transcriptional level may limit the value of Sj-TSP-2 as a target for future S. japonicum vaccine development. PMID- 21655309 TI - Towards a functional understanding of protein N-terminal acetylation. AB - Protein N-terminal acetylation is a major modification of eukaryotic proteins. Its functional implications include regulation of protein-protein interactions and targeting to membranes, as demonstrated by studies of a handful of proteins. Fifty years after its discovery, a potential general function of the N-terminal acetyl group carried by thousands of unique proteins remains enigmatic. However, recent functional data suggest roles for N-terminal acetylation as a degradation signal and as a determining factor for preventing protein targeting to the secretory pathway, thus highlighting N-terminal acetylation as a major determinant for the life and death of proteins. These contributions represent new and intriguing hypotheses that will guide the research in the years to come. PMID- 21655311 TI - Phylomemetics--evolutionary analysis beyond the gene. AB - Genes are propagated by error-prone copying, and the resulting variation provides the basis for phylogenetic reconstruction of evolutionary relationships. Horizontal gene transfer may be superimposed on a tree-like evolutionary pattern, with some relationships better depicted as networks. The copying of manuscripts by scribes is very similar to the replication of genes, and phylogenetic inference programs can be used directly for reconstructing the copying history of different versions of a manuscript text. Phylogenetic methods have also been used for some time to analyse the evolution of languages and the development of physical cultural artefacts. These studies can help to answer a range of anthropological questions. We propose the adoption of the term "phylomemetics" for phylogenetic analysis of reproducing non-genetic elements. PMID- 21655310 TI - Multiple Crimean-Congo hemorrhagic fever virus strains are associated with disease outbreaks in Sudan, 2008-2009. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) activity has recently been detected in the Kordufan region of Sudan. Since 2008, several sporadic cases and nosocomial outbreaks associated with high case-fatality have been reported in villages and rural hospitals in the region. PRINCIPAL FINDINGS: In the present study, we describe a cluster of cases occurring in June 2009 in Dunkop village, Abyei District, South Kordufan, Sudan. Seven CCHF cases were involved in the outbreak; however, clinical specimens could be collected from only two patients, both of whom were confirmed as acute CCHF cases using CCHF-specific reverse transcriptase polymerase chain reaction (RT-PCR). Phylogenetic analysis of the complete S, M, and L segment sequences places the Abyei strain of CCHF virus in Group III, a virus group containing strains from various countries across Africa, including Sudan, South Africa, Mauritania, and Nigeria. The Abyei strain detected in 2009 is genetically distinct from the recently described 2008 Sudanese CCHF virus strains (Al-fulah 3 and 4), and the Abyei strain S and L segments closely match those of CCHF virus strain ArD39554 from Mauritania. CONCLUSIONS: The present investigation illustrates that multiple CCHF virus lineages are circulating in the Kordufan region of Sudan and are associated with recent outbreaks of the disease occurring during 2008-2009. PMID- 21655312 TI - Loxosceles gaucho venom-induced acute kidney injury--in vivo and in vitro studies. AB - BACKGROUND: Accidents caused by Loxosceles spider may cause severe systemic reactions, including acute kidney injury (AKI). There are few experimental studies assessing Loxosceles venom effects on kidney function in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In order to test Loxosceles gaucho venom (LV) nephrotoxicity and to assess some of the possible mechanisms of renal injury, rats were studied up to 60 minutes after LV 0.24 mg/kg or saline IV injection (control). LV caused a sharp and significant drop in glomerular filtration rate, renal blood flow and urinary output and increased renal vascular resistance, without changing blood pressure. Venom infusion increased significantly serum creatine kinase and aspartate aminotransferase. In the LV group renal histology analysis found acute epithelial tubular cells degenerative changes, presence of cell debris and detached epithelial cells in tubular lumen without glomerular or vascular changes. Immunohistochemistry disclosed renal deposition of myoglobin and hemoglobin. LV did not cause injury to a suspension of fresh proximal tubules isolated from rats. CONCLUSIONS/SIGNIFICANCE: Loxosceles gaucho venom injection caused early AKI, which occurred without blood pressure variation. Changes in glomerular function occurred likely due to renal vasoconstriction and rhabdomyolysis. Direct nephrotoxicity could not be demonstrated in vitro. The development of a consistent model of Loxosceles venom-induced AKI and a better understanding of the mechanisms involved in the renal injury may allow more efficient ways to prevent or attenuate the systemic injury after Loxosceles bite. PMID- 21655313 TI - Foxp3 and IL-10 expression correlates with parasite burden in lesional tissues of post kala azar dermal leishmaniasis (PKDL) patients. AB - BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL), a sequel to visceral leishamaniasis (VL) in 5-15% cases, constitutes a parasite reservoir important in disease transmission. The precise immunological cause of PKDL outcome remains obscure. However, overlapping counter regulatory responses with elevated IFN gamma and IL-10 are reported. METHODOLOGY/PRINCIPAL FINDINGS: Present study deals with ex-vivo mRNA and protein analysis of natural regulatory T cells (nTreg) markers (Foxp3, CD25 and CTLA-4) and IL-10 levels in lesion tissues of PKDL patients at pre and post treatment stages. In addition, correlation of nTreg markers and IL-10 with parasite load in tissue lesions was investigated. mRNA levels of nTreg markers and IL-10 were found significantly elevated in pre treatment PKDL cases compared to controls (Foxp3, P = 0.0009; CD25 & CTLA-4, P<0.0001; IL-10, P<0.0001), and were restored after treatment. Analysis of nTreg cell markers and IL-10 in different clinical manifestations of disease revealed elevated levels in nodular lesions compared to macules/papules. Further, Foxp3, CD25 and IL-10 mRNA levels directly correlated with parasite load in lesions tissues. CONCLUSION/SIGNIFICANCE: Data demonstrated accumulation of nTreg cells in infected tissue and a correlation of both IL-10 and nTreg levels with parasite burden suggesting their role in disease severity in PKDL. PMID- 21655314 TI - Let's be straight up about the alcohol industry. PMID- 21655315 TI - Threshold haemoglobin levels and the prognosis of stable coronary disease: two new cohorts and a systematic review and meta-analysis. AB - BACKGROUND: Low haemoglobin concentration has been associated with adverse prognosis in patients with angina and myocardial infarction (MI), but the strength and shape of the association and the presence of any threshold has not been precisely evaluated. METHODS AND FINDINGS: A retrospective cohort study was carried out using the UK General Practice Research Database. 20,131 people with a new diagnosis of stable angina and no previous acute coronary syndrome, and 14,171 people with first MI who survived for at least 7 days were followed up for a mean of 3.2 years. Using semi-parametric Cox regression and multiple adjustment, there was evidence of threshold haemoglobin values below which mortality increased in a graded continuous fashion. For men with MI, the threshold value was 13.5 g/dl (95% confidence interval [CI] 13.2-13.9); the 29.5% of patients with haemoglobin below this threshold had an associated hazard ratio for mortality of 2.00 (95% CI 1.76-2.29) compared to those with haemoglobin values in the lowest risk range. Women tended to have lower threshold haemoglobin values (e.g, for MI 12.8 g/dl; 95% CI 12.1-13.5) but the shape and strength of association did not differ between the genders, nor between patients with angina and MI. We did a systematic review and meta-analysis that identified ten previously published studies, reporting a total of only 1,127 endpoints, but none evaluated thresholds of risk. CONCLUSIONS: There is an association between low haemoglobin concentration and increased mortality. A large proportion of patients with coronary disease have haemoglobin concentrations below the thresholds of risk defined here. Intervention trials would clarify whether increasing the haemoglobin concentration reduces mortality. PMID- 21655316 TI - The transit phase of migration: circulation of malaria and its multidrug resistant forms in Africa. PMID- 21655317 TI - The impact of retail-sector delivery of artemether-lumefantrine on malaria treatment of children under five in Kenya: a cluster randomized controlled trial. AB - BACKGROUND: It has been proposed that artemisinin-based combination therapy (ACT) be subsidised in the private sector in order to improve affordability and access. This study in western Kenya aimed to evaluate the impact of providing subsidized artemether-lumefantrine (AL) through retail providers on the coverage of prompt, effective antimalarial treatment for febrile children aged 3-59 months. METHODS AND FINDINGS: We used a cluster-randomized, controlled design with nine control and nine intervention sublocations, equally distributed across three districts in western Kenya. Cross-sectional household surveys were conducted before and after the delivery of the intervention. The intervention comprised provision of subsidized packs of paediatric ACT to retail outlets, training of retail outlet staff, and community awareness activities. The primary outcome was defined as the proportion of children aged 3-59 months reporting fever in the past 2 weeks who started treatment with AL on the same day or following day of fever onset. Data were collected using structured questionnaires and analyzed based on cluster level summaries, comparing control to intervention arms, while adjusting for other covariates. Data were collected on 2,749 children in the target age group at baseline and 2,662 at follow-up. 29% of children experienced fever within 2 weeks before the interview. At follow-up, the percentage of children receiving AL on the day of fever or the following day had risen by 14.6% points in the control arm (from 5.3% [standard deviation (SD): 3.2%] to 19.9% [SD: 10.0%]) and 40.2% points in the intervention arm (from 4.7% [SD: 3.4%] to 44.9% [SD: 11.7%]). The percentage of children receiving AL was significantly greater in the intervention arm at follow-up, with a difference between the arms of 25.0% points (95% confidence interval [CI]: 14.1%, 35.9%; unadjusted p = 0.0002, adjusted p = 0.0001). No significant differences were observed between arms in the proportion of caregivers who sought treatment for their child's fever by source, or in the child's adherence to AL. CONCLUSIONS: Subsidizing ACT in the retail sector can significantly increase ACT coverage for reported fevers in rural areas. Further research is needed on the impact and cost-effectiveness of such subsidy programmes at a national scale. TRIAL REGISTRATION: Current Controlled Trials ISRCTN59275137 and Kenya Pharmacy and Poisons Board Ethical Committee for Clinical Trials PPB/ECCT/08/07. PMID- 21655318 TI - Maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study. AB - BACKGROUND: Infections during pregnancy have the potential to adversely impact birth outcomes. We evaluated the association between receipt of inactivated influenza vaccine during pregnancy and prematurity and small for gestational age (SGA) births. METHODS AND FINDINGS: We conducted a cohort analysis of surveillance data from the Georgia (United States) Pregnancy Risk Assessment Monitoring System. Among 4,326 live births between 1 June 2004 and 30 September 2006, maternal influenza vaccine information was available for 4,168 (96.3%). The primary intervention evaluated in this study was receipt of influenza vaccine during any trimester of pregnancy. The main outcome measures were prematurity (gestational age at birth <37 wk) and SGA (birth weight <10th percentile for gestational age). Infants who were born during the putative influenza season (1 October-31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature compared to infants of unvaccinated mothers born in the same period (adjusted odds ratio [OR] = 0.60; 95% CI, 0.38 0.94). The magnitude of association between maternal influenza vaccine receipt and reduced likelihood of prematurity increased during the period of at least local influenza activity (adjusted OR = 0.44; 95% CI, 0.26-0.73) and was greatest during the widespread influenza activity period (adjusted OR = 0.28; 95% CI, 0.11 0.74). Compared with newborns of unvaccinated women, newborns of vaccinated mothers had 69% lower odds of being SGA (adjusted OR = 0.31; 95% CI, 0.13-0.75) during the period of widespread influenza activity. The adjusted and unadjusted ORs were not significant for the pre-influenza activity period. CONCLUSIONS: This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth. PMID- 21655319 TI - Confidence interval based parameter estimation--a new SOCR applet and activity. AB - Many scientific investigations depend on obtaining data-driven, accurate, robust and computationally-tractable parameter estimates. In the face of unavoidable intrinsic variability, there are different algorithmic approaches, prior assumptions and fundamental principles for computing point and interval estimates. Efficient and reliable parameter estimation is critical in making inference about observable experiments, summarizing process characteristics and prediction of experimental behaviors. In this manuscript, we demonstrate simulation, construction, validation and interpretation of confidence intervals, under various assumptions, using the interactive web-based tools provided by the Statistics Online Computational Resource (http://www.SOCR.ucla.edu). Specifically, we present confidence interval examples for population means, with known or unknown population standard deviation; population variance; population proportion (exact and approximate), as well as confidence intervals based on bootstrapping or the asymptotic properties of the maximum likelihood estimates. Like all SOCR resources, these confidence interval resources may be openly accessed via an Internet-connected Java-enabled browser. The SOCR confidence interval applet enables the user to empirically explore and investigate the effects of the confidence-level, the sample-size and parameter of interest on the corresponding confidence interval. Two applications of the new interval estimation computational library are presented. The first one is a simulation of confidence interval estimating the US unemployment rate and the second application demonstrates the computations of point and interval estimates of hippocampal surface complexity for Alzheimers disease patients, mild cognitive impairment subjects and asymptomatic controls. PMID- 21655320 TI - A novel SERRS sandwich-hybridization assay to detect specific DNA target. AB - In this study, we have applied Surface Enhanced Resonance Raman Scattering (SERRS) technology to the specific detection of DNA. We present an innovative SERRS sandwich-hybridization assay that allows specific DNA detection without any enzymatic amplification, such as is the case with Polymerase Chain Reaction (PCR). In some substrates, such as ancient or processed remains, enzymatic amplification fails due to DNA alteration (degradation, chemical modification) or to the presence of inhibitors. Consequently, the development of a non-enzymatic method, allowing specific DNA detection, could avoid long, expensive and inconclusive amplification trials. Here, we report the proof of concept of a SERRS sandwich-hybridization assay that leads to the detection of a specific chamois DNA. This SERRS assay reveals its potential as a non-enzymatic alternative technology to DNA amplification methods (particularly the PCR method) with several applications for species detection. As the amount and type of damage highly depend on the preservation conditions, the present SERRS assay would enlarge the range of samples suitable for DNA analysis and ultimately would provide exciting new opportunities for the investigation of ancient DNA in the fields of evolutionary biology and molecular ecology, and of altered DNA in food frauds detection and forensics. PMID- 21655321 TI - Technical variability is greater than biological variability in a microarray experiment but both are outweighed by changes induced by stimulation. AB - INTRODUCTION: A central issue in the design of microarray-based analysis of global gene expression is that variability resulting from experimental processes may obscure changes resulting from the effect being investigated. This study quantified the variability in gene expression at each level of a typical in vitro stimulation experiment using human peripheral blood mononuclear cells (PBMC). The primary objective was to determine the magnitude of biological and technical variability relative to the effect being investigated, namely gene expression changes resulting from stimulation with lipopolysaccharide (LPS). METHODS AND RESULTS: Human PBMC were stimulated in vitro with LPS, with replication at 5 levels: 5 subjects each on 2 separate days with technical replication of LPS stimulation, amplification and hybridisation. RNA from samples stimulated with LPS and unstimulated samples were hybridised against common reference RNA on oligonucleotide microarrays. There was a closer correlation in gene expression between replicate hybridisations (0.86-0.93) than between different subjects (0.66-0.78). Deconstruction of the variability at each level of the experimental process showed that technical variability (standard deviation (SD) 0.16) was greater than biological variability (SD 0.06), although both were low (SD<0.1 for all individual components). There was variability in gene expression both at baseline and after stimulation with LPS and proportion of cell subsets in PBMC was likely partly responsible for this. However, gene expression changes after stimulation with LPS were much greater than the variability from any source, either individually or combined. CONCLUSIONS: Variability in gene expression was very low and likely to improve further as technical advances are made. The finding that stimulation with LPS has a markedly greater effect on gene expression than the degree of variability provides confidence that microarray based studies can be used to detect changes in gene expression of biological interest in infectious diseases. PMID- 21655322 TI - Alcohol exposure decreases CREB binding protein expression and histone acetylation in the developing cerebellum. AB - BACKGROUND: Fetal alcohol exposure affects 1 in 100 children making it the leading cause of mental retardation in the US. It has long been known that alcohol affects cerebellum development and function. However, the underlying molecular mechanism is unclear. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that CREB binding protein (CBP) is widely expressed in granule and Purkinje neurons of the developing cerebellar cortex of naive rats. We also show that exposure to ethanol during the 3(rd) trimester-equivalent of human pregnancy reduces CBP levels. CBP is a histone acetyltransferase, a component of the epigenetic mechanism controlling neuronal gene expression. We further demonstrate that the acetylation of both histone H3 and H4 is reduced in the cerebellum of ethanol-treated rats. CONCLUSIONS/SIGNIFICANCE: These findings indicate that ethanol exposure decreases the expression and function of CBP in the developing cerebellum. This effect of ethanol may be responsible for the motor coordination deficits that characterize fetal alcohol spectrum disorders. PMID- 21655323 TI - A compendium of canine normal tissue gene expression. AB - BACKGROUND: Our understanding of disease is increasingly informed by changes in gene expression between normal and abnormal tissues. The release of the canine genome sequence in 2005 provided an opportunity to better understand human health and disease using the dog as clinically relevant model. Accordingly, we now present the first genome-wide, canine normal tissue gene expression compendium with corresponding human cross-species analysis. METHODOLOGY/PRINCIPAL FINDINGS: The Affymetrix platform was utilized to catalogue gene expression signatures of 10 normal canine tissues including: liver, kidney, heart, lung, cerebrum, lymph node, spleen, jejunum, pancreas and skeletal muscle. The quality of the database was assessed in several ways. Organ defining gene sets were identified for each tissue and functional enrichment analysis revealed themes consistent with known physio-anatomic functions for each organ. In addition, a comparison of orthologous gene expression between matched canine and human normal tissues uncovered remarkable similarity. To demonstrate the utility of this dataset, novel canine gene annotations were established based on comparative analysis of dog and human tissue selective gene expression and manual curation of canine probeset mapping. Public access, using infrastructure identical to that currently in use for human normal tissues, has been established and allows for additional comparisons across species. CONCLUSIONS/SIGNIFICANCE: These data advance our understanding of the canine genome through a comprehensive analysis of gene expression in a diverse set of tissues, contributing to improved functional annotation that has been lacking. Importantly, it will be used to inform future studies of disease in the dog as a model for human translational research and provides a novel resource to the community at large. PMID- 21655324 TI - Spread of extensively drug-resistant tuberculosis in KwaZulu-Natal province, South Africa. AB - BACKGROUND: In 2005 a cluster of 53 HIV-infected patients with extensively drug resistant tuberculosis (XDR-TB) was detected in the Msinga sub-district, the catchment area for the Church of Scotland Hospital (CoSH) in Tugela Ferry, in KwaZulu-Natal province (KZN), South Africa. KZN is divided into 11 healthcare districts. We sought to determine the distribution of XDR TB cases in the province in relation to population density. METHODS: In this cross-sectional study, the KZN tuberculosis laboratory database was analysed. Results of all patients with a sputum culture positive for Mycobacterium tuberculosis from January 2006 to June 2007 were included. Drug-susceptibility test results for isoniazid, rifampicin, ethambutol, streptomycin, kanamycin and ofloxacin were available for all patients as well as the location of the hospital where their clinical diagnosis was made. FINDINGS: In total, 20858 patients attending one of 73 hospitals or their adjacent clinics had cultures positive for M. tuberculosis. Of these, 4170 (20%) were MDR-TB cases. Four hundred and forty three (11%) of the MDR tuberculosis cases displayed the XDR tuberculosis susceptibility profile. Only 1429 (34%) of the MDR-TB patients were seen at the provincial referral hospital for treatment. The proportion of XDR-TB amongst culture-confirmed cases was highest in the Msinga sub-district (19.6%), followed by the remaining part of the Umzinyati district (5.9%) and the other 10 districts (1.1%). The number of hospitals with at least one XDR-TB case increased from 18 (25%) to 58 (80%) during the study period. INTERPRETATION: XDR-TB is present throughout KZN. More than 65% of all diagnosed MDR-TB cases, including XDR-TB patients, were left untreated and likely remained in the community as a source of infection. PMID- 21655325 TI - Non-parametric change-point method for differential gene expression detection. AB - BACKGROUND: We proposed a non-parametric method, named Non-Parametric Change Point Statistic (NPCPS for short), by using a single equation for detecting differential gene expression (DGE) in microarray data. NPCPS is based on the change point theory to provide effective DGE detecting ability. METHODOLOGY: NPCPS used the data distribution of the normal samples as input, and detects DGE in the cancer samples by locating the change point of gene expression profile. An estimate of the change point position generated by NPCPS enables the identification of the samples containing DGE. Monte Carlo simulation and ROC study were applied to examine the detecting accuracy of NPCPS, and the experiment on real microarray data of breast cancer was carried out to compare NPCPS with other methods. CONCLUSIONS: Simulation study indicated that NPCPS was more effective for detecting DGE in cancer subset compared with five parametric methods and one non-parametric method. When there were more than 8 cancer samples containing DGE, the type I error of NPCPS was below 0.01. Experiment results showed both good accuracy and reliability of NPCPS. Out of the 30 top genes ranked by using NPCPS, 16 genes were reported as relevant to cancer. Correlations between the detecting result of NPCPS and the compared methods were less than 0.05, while between the other methods the values were from 0.20 to 0.84. This indicates that NPCPS is working on different features and thus provides DGE identification from a distinct perspective comparing with the other mean or median based methods. PMID- 21655326 TI - Recombinant trimeric HA protein immunogenicity of H5N1 avian influenza viruses and their combined use with inactivated or adenovirus vaccines. AB - BACKGROUND: The highly pathogenic avian influenza (HPAI) H5N1 virus continues to cause disease in poultry and humans. The hemagglutinin (HA) envelope protein is the primary target for subunit vaccine development. METHODOLOGY/PRINCIPAL FINDINGS: We used baculovirus-insect cell expression to obtain trimeric recombinant HA (rHA) proteins from two HPAI H5N1 viruses. We investigated trimeric rHA protein immunogenicity in mice via immunizations, and found that the highest levels of neutralizing antibodies resulted from coupling with a PELC/CpG adjuvant. We also found that the combined use of trimeric rHA proteins with (a) an inactivated H5N1 vaccine virus, or (b) a recombinant adenovirus encoding full length HA sequences for prime-boost immunization, further improved antibody responses against homologous and heterologous H5N1 virus strains. Data from cross clade prime-boost immunization regimens indicate that sequential immunization with different clade HA antigens increased antibody responses in terms of total IgG level and neutralizing antibody titers. CONCLUSION/SIGNIFICANCE: Our findings suggest that the use of trimeric rHA in prime-boost vaccine regimens represents an alternative strategy for recombinant H5N1 vaccine development. PMID- 21655327 TI - Diversity in the reproductive modes of European Daphnia pulicaria deviates from the geographical parthenogenesis. AB - BACKGROUND: Multiple transitions to obligate parthenogenesis have occurred in the Daphnia pulex complex in North America. These newly formed asexual lineages are differentially distributed being found predominantly at high latitudes. This conforms to the rule of geographical parthenogenesis postulating prevalence of asexuals at high latitudes and altitudes. While the reproductive mode of high latitude populations is relatively well studied, little is known about the reproduction mode in high altitudes. This study aimed to assess the reproductive mode of Daphnia pulicaria, a species of the D. pulex complex, from high altitude lakes in Europe. METHODOLOGY/PRINCIPAL FINDINGS: Variation at eight microsatellite loci revealed that D. pulicaria from the High Tatra Mountains (HTM) had low genotype richness and showed excess of heterozygotes and significant deviations from Hardy-Weinberg expectations, and was thus congruent with reproduction by obligate parthenogenesis. By contrast, populations from the Pyrenees (Pyr) were generally in Hardy-Weinberg equilibrium and had higher genotypic richness, suggesting that they are cyclic parthenogens. Four lakes from lowland areas (LLaP) had populations with an uncertain or mixed breeding mode. All D. pulicaria had mtDNA ND5 haplotypes of the European D. pulicaria lineage. Pyr were distinct from LLaP and HTM at the ND5 gene. By contrast, HTM shared two haplotypes with LLaP and one with Pyr. Principal Coordinate Analysis of the microsatellite data revealed clear genetic differentiation into three groups. HTM isolates were intermediate to Pyr and LLaP, congruent with a hybrid origin. CONCLUSION/SIGNIFICANCE: Inferred transitions to obligate parthenogenesis have occurred only in HTM, most likely as a result of hybridizations. In contrast to North American populations, these transitions do not appear to involve meiosis suppressor genes and have not been accompanied by polyploidy. The absence of obligate parthenogenesis in Pyr, an environment highly similar to the HTM, may be due to the lack of opportunities for hybridization. PMID- 21655328 TI - Design, synthesis, and characterization of a highly effective Hog1 inhibitor: a powerful tool for analyzing MAP kinase signaling in yeast. AB - The Saccharomyces cerevisiae High-Osmolarity Glycerol (HOG) pathway is a conserved mitogen-activated protein kinase (MAPK) signal transduction system that often serves as a model to analyze systems level properties of MAPK signaling. Hog1, the MAPK of the HOG-pathway, can be activated by various environmental cues and it controls transcription, translation, transport, and cell cycle adaptations in response to stress conditions. A powerful means to study signaling in living cells is to use kinase inhibitors; however, no inhibitor targeting wild-type Hog1 exists to date. Herein, we describe the design, synthesis, and biological application of small molecule inhibitors that are cell-permeable, fast-acting, and highly efficient against wild-type Hog1. These compounds are potent inhibitors of Hog1 kinase activity both in vitro and in vivo. Next, we use these novel inhibitors to pinpoint the time of Hog1 action during recovery from G(1) checkpoint arrest, providing further evidence for a specific role of Hog1 in regulating cell cycle resumption during arsenite stress. Hence, we describe a novel tool for chemical genetic analysis of MAPK signaling and provide novel insights into Hog1 action. PMID- 21655329 TI - Involvement of a Toxoplasma gondii chromatin remodeling complex ortholog in developmental regulation. AB - The asexual cycle of the parasite Toxoplasma gondii has two developmental stages: a rapidly replicating form called a tachyzoite and a slow growing cyst form called a bradyzoite. While the importance of ATP-independent histone modifications for gene regulation in T. gondii have been demonstrated, ATP dependent chromatin remodeling pathways have not been examined. In this study we characterized C9, an insertional mutant showing reduced expression of bradyzoite differentiation marker BAG1, in cultured human fibroblasts. This mutant contains an insertion in the gene encoding TgRSC8, which is homologous to the Saccharomyces cerevisiae proteins Rsc8p (remodel the structure of chromatin complex subunit 8) and Swi3p (switch/sucrose non-fermentable [SWI/SNF]) of ATP dependent chromatin-remodeling complexes. In the C9 mutant, TgRSC8 is the downstream open reading frame on a dicistronic transcript. Though protein was expressed from the downstream gene of the dicistron, TgRSC8 levels were decreased in C9 from those of wild-type parasites, as determined by western immunoblot and flow cytometry. As TgRSC8 localized to the parasite nucleus, we postulated a role in gene regulation. Transcript levels of several markers were assessed by quantitative PCR to test this hypothesis. The C9 mutant displayed reduced steady state transcript levels of bradyzoite-induced genes BAG1, LDH2, SUSA1, and ENO1, all of which were significantly increased with addition of TgRSC8 to the mutant. Transcript levels of some bradyzoite markers were unaltered in C9, or unable to be increased by complementation with TgRSC8, indicating multiple pathways control bradyzoite-upregulated genes. Together, these data suggest a role for TgRSC8 in control of bradyzoite-upregulated gene expression. Thus chromatin remodeling, by both ATP-independent and dependent mechanisms, is an important mode of gene regulation during stage differentiation in parasites. PMID- 21655330 TI - Coreceptor and cytokine concentrations may not explain differences in disease progression observed in HIV-1 clade A and D infected Ugandans. AB - BACKGROUND: The use of cellular coreceptors and modulation of cytokine concentrations by HIV to establish a productive infection is well documented. However, it is unknown whether the expression of these proteins affects the course of HIV clade A and D disease, reported to have different progression rates. METHODOLOGY/PRINCIPAL FINDINGS: We investigated whether the number of CD4(+) T-cells expressing CCR5 or CXCR4, the density of these coreceptors and concentrations of specific immune proteins linked to HIV pathogenesis vary between individuals infected with HIV clade A or D. We undertook additional analyses stratifying participants by early (CD4>500 cells/ul) or late (CD4<200 cells/ul) disease stage. Whole blood samples were taken from 50 HIV-1 infected individuals drawn from cohorts in rural south-west Uganda. Late stage participants had less than half the number of CD4(+)/CCR5(+) T-cells (p = 0.0113) and 5.6 times fewer CD4(+)/CXCR4(+) cells (p<0.0001) than early stage participants. There was also a statistically significant difference in the density of CXCR4 on CD4(+) cells between clade A and D infected early stage participants (142 [A] vs 84 [D]; p = 0.0146). Across all participants we observed significantly higher concentration of Th(1) cytokines compared to Th(2) (66.4 vs 23.8 pg/ml; p<0.0001). Plasma concentrations of IFNgamma and IL-2 were 1.8 and 2.4 fold lower respectively in Late-D infected participants compared to Late-A participants. MIP-1beta levels also decreased from 118.0 pg/ml to 47.1 pg/ml (p = 0.0396) as HIV disease progressed. CONCLUSIONS/SIGNIFICANCE: We observed specific alterations in the abundance of CD4(+)/CCR5(+) and CD4(+)/CXCR4(+) T-cells, and concentrations of immune proteins across different HIV clades and as infection progresses. Our results suggest that these changes are unlikely to explain the observed differences in disease progression between subtype A and D infections. However, our observations further the understanding of the natural progression of non-clade B HIV infection and how the virus adapts to exploit the host environment. PMID- 21655331 TI - Dynamic micro-Hall detection of superparamagnetic beads in a microfluidic channel. AB - We report integration of an InAs quantum well micro-Hall magnetic sensor with microfluidics and real-time detection of moving superparamagnetic beads. Beads moving within and around the Hall cross area result in positive and negative Hall voltage signals respectively. Relative magnitudes and polarities of the signals measured for a random distribution of immobilized beads over the sensor are in good agreement with calculated values and explain consistently the shape of the dynamic signal. PMID- 21655332 TI - Molecular insights into Parkinson's disease. AB - Parkinson's disease is a neurodegenerative movement disorder characterized by loss of midbrain dopaminergic neurons leading to motor abnormalities and autonomic dysfunctions. Despite intensive research, the etiology of Parkinson's disease remains poorly understood leaving us with no effective therapeutic options. However, the recent identification of genes linked to heritable forms of Parkinson's disease has revolutionized research in the field and has begun to provide new clues to disease pathogenesis. Here we discuss these recent genetic advances and highlight their significance in our quest to better understand common underlying disease mechanisms that will help us identify innovative neuroprotective therapies for Parkinson's disease. PMID- 21655333 TI - New tools in membrane protein determination. AB - The determination of membrane structures presents the structural biologist with many challenges; however, the last two years have seen major advances in our ability to resolve these structures at atomic resolution. My goal here is to summarize some of the most recent advances that have enhanced our prospects for understanding membrane proteins at the level of atomic structure. PMID- 21655335 TI - Medulloblastoma: advances and challenges. AB - Medulloblastoma, a cancer of the posterior fossa, is the most common malignant brain tumor in children. Although 80% of patients with average-risk medulloblastoma are cured, their quality of life is often compromised by treatment-related side effects. Recently, molecular and genomic studies have shown medulloblastoma to be a heterogeneous disease made up of distinct disease subtypes. The importance of this finding is that response to therapy appears to be subtype-specific. Nevertheless, most patients are still treated according to risk stratification methods based on the clinically defined presence or absence of disseminated disease, which take no account of these newly defined subtypes. The potential, however, to vastly reduce therapy-mediated toxicity to patients with tumor subtypes that have good outcomes, while improving therapy through targeting for the poor responders, is now palpable. Critical to this effort will be the ongoing refinement of our understanding of medulloblastoma subgroups at the molecular level and the development of mouse models that faithfully recapitulate tumor subtypes. PMID- 21655334 TI - Laminar fate specification in the cerebral cortex. AB - The cerebral cortex is composed of hundreds of different types of neurons, which underlie its ability to perform highly complex neural processes. How this astonishing cell diversity is generated during development constitutes a major challenge in developmental neurosciences, with important implications for neurological diseases. Here we review some recent and exciting advances in this field, from the description of the cellular processes at the origin of cortical neuron diversity, to the dissection of the molecular logic underlying fate selection in cortical neurons. PMID- 21655336 TI - Checkpoint recovery in cells: how a molecular understanding can help in the fight against cancer. AB - Dysregulation of the cell cycle is the underlying mechanism of neoplasia. Healthy cells prevent propagation of DNA mutations to progeny by activation of cellular checkpoints, which allows time for DNA repair. On the other hand, activation of the DNA damage response is also the general principle of many current cancer treatments. Thus, recent advances in understanding how checkpoints in the cell cycle work at the molecular level open the door to new approaches to antitumor therapy. PMID- 21655337 TI - Physics, biology and the right chemistry. AB - Joint studies that involve biologists and physicists are becoming more frequent and have contributed to the identification and understanding of physical parameters underlying key biological processes. Here, we illustrate the main findings resulting from a 10-year collaboration between a cell biologist and an experimental physicist, both interested in the mechanisms of intracellular transport and membrane dynamics in eukaryotic cells. PMID- 21655338 TI - Epigenetic changes in cancer. AB - Interest in epigenetics is now booming in all the biomedical fields. Initially, interest was sparked within the field of cancer research with the finding of global DNA hypomethylation events in the 1980s, followed by the CpG island hypermethylation of tumor suppressor genes in the 1990s and the approval of DNA demethylating drugs and histone deactylase inhibitors in the 2000s. For transformed cells, the arena is also expanding to include the wide spectrum of histone modification changes and the interaction with noncoding RNAs. What lies ahead is even more exciting, with the imminent completion of many human cancer epigenomes that will form the basis of better biomarkers and epigenetic drugs. PMID- 21655339 TI - High-response intrauterine insemination cycles converted to low-cost in vitro fertilization. AB - BACKGROUND: There is a trend to cancel intrauterine insemination (IUI) in women with a high response. The aim of this study was to evaluate the efficacy of low cost in vitro fertilization (IVF) in high-response IUI cycles in comparison with conventional IVF. METHODS AND MATERIALS: A total of 46 women were included in the study. Group A (study group) included 23 women with hyper-response to IUI cycles who were converted to IVF. They received oral letrozole 2.5 mg twice daily from days 3-7 of the menstrual cycle, along with 75 International Units (IU) of recombinant follicle-stimulating hormone on days 3 and 8. Group B (control group) underwent conventional IVF, and received downregulation with a gonadotrophin releasing hormone agonist followed by stimulation with recombinant follicle stimulating hormone 150-300 IU/day. Ovulation was triggered by 10,000 IU of human chorionic gonadotrophin, followed by IVF and embryo transfer. The primary outcome measure analyzed was pregnancy rates in both groups. RESULTS: The study group received a significantly lower (P = 0.001) total dose of follicle-stimulating hormone and had significantly (P = 0.002) decreased levels of terminal estradiol. Although the pregnancy rate (30.43% in the study group versus 39.13% in the conventional group) per stimulated cycle was higher in the conventional IVF group, the miscarriage rate (study group 4.34% versus conventional group 13.04%) was also higher, and hence the take-home baby rate (study group 26.08% versus conventional group 30.43%) was more or less similar in both the groups. CONCLUSION: IVF can be offered to women having a high response to IUI cycles with good pregnancy rates and at low cost compared with use of a conventional protocol, and therefore can be considered more patient-friendly in selected cases. PMID- 21655341 TI - Management of type 2 diabetes mellitus in the elderly: role of the pharmacist in a multidisciplinary health care team. AB - Intensive glycemic control using insulin therapy may be appropriate for many healthy older adults to reduce premature mortality and morbidity, improve quality of life, and reduce health care costs. However, frail elderly people are more prone to develop complications from hypoglycemia, such as confusion and dementia. Overall, older persons with type 2 diabetes mellitus are at greater risk of death from cardiovascular disease (CVD) than from intermittent hyperglycemia; therefore, diabetes management should always include CVD prevention and treatment in this patient population. Pharmacists can provide a comprehensive medication review with subsequent recommendations to individualize therapy based on medical and cognitive status. As part of the patient's health care team, pharmacists can provide continuity of care and communication with other members of the patient's health care team. In addition, pharmacists can act as educators and patient advocates and establish patient-specific goals to increase medication effectiveness, adherence to a medication regimen, and minimize the likelihood of adverse events. PMID- 21655340 TI - Clinical features and multidisciplinary approaches to dementia care. AB - Dementia is a clinical syndrome of widespread progressive deterioration of cognitive abilities and normal daily functioning. These cognitive and behavioral impairments pose considerable challenges to individuals with dementia, along with their family members and caregivers. Four primary dementia classifications have been defined according to clinical and research criteria: 1) Alzheimer's disease; 2) vascular dementias; 3) frontotemporal dementias; and 4) dementia with Lewy bodies/Parkinson's disease dementia. The cumulative efforts of multidisciplinary healthcare teams have advanced our understanding of dementia beyond basic descriptions, towards a more complete elucidation of risk factors, clinical symptoms, and neuropathological correlates. The characterization of disease subtypes has facilitated targeted management strategies, advanced treatments, and symptomatic care for individuals affected by dementia. This review briefly summarizes the current state of knowledge and directions of dementia research and clinical practice. We provide a description of the risk factors, clinical presentation, and differential diagnosis of dementia. A summary of multidisciplinary team approaches to dementia care is outlined, including management strategies for the treatment of cognitive impairments, functional deficits, and behavioral and psychological symptoms of dementia. The needs of individuals with dementia are extensive, often requiring care beyond traditional bounds of medical practice, including pharmacologic and non-pharmacologic management interventions. Finally, advanced research on the early prodromal phase of dementia is reviewed, with a focus on change-point models, trajectories of cognitive change, and threshold models of pathological burden. Future research goals are outlined, with a call to action for social policy initiatives that promote preventive lifestyle behaviors, and healthcare programs that will support the growing number of individuals affected by dementia. PMID- 21655342 TI - Plantar fasciitis - to jab or to support? A systematic review of the current best evidence. AB - BACKGROUND: Plantar fasciitis is a common condition routinely managed by podiatrists in the community and is widely treated conservatively. Two commonly used treatments for plantar fasciitis are customized functional foot orthoses and corticosteroid injections. While common to clinical practice, the evidence base underpinning these treatment strategies is unknown. Therefore, the aim of this systematic review was to assess the effectiveness and safety of customized functional foot orthoses and corticosteroid injections in the treatment of plantar fasciitis. METHODS: A systematic literature search was conducted. Experimental studies, in English, from 1998 to 2010 were accepted for inclusion in this review. The PEDro quality assessment tool and the National Health and Medical Research Council's hierarchy of evidence were used to assess the quality of the included studies. RESULTS: Six randomized controlled trials which met the selection criteria were included in this review. Four reported on customized functional foot orthoses and 2 on corticosteroid injections. Current best available evidence highlights that both customized functional foot orthoses and corticosteroid injections can lead to a decrease in pain associated with plantar fasciitis. Additionally, customized functional foot orthoses may also provide an additional benefit in terms of increased functional ability in patients with plantar fasciitis. Corticosteroid injections may have side effects, especially pain (from the injection). CONCLUSION: Both customized functional foot orthoses and corticosteroid injections can lead to reduction in pain associated with plantar fasciitis. While customized functional foot orthoses may increase the functional outcomes in patients with plantar fasciitis, corticosteroid injections may have side effects (especially pain as a result of the injection), which may limit its acceptability. PMID- 21655343 TI - Construct validity of the Moral Development Scale for Professionals (MDSP). AB - The aim of this study was to investigate the construct validity of the Moral Development Scale for Professionals (MDSP) using structural equation modeling. The instrument is a 12-item self-report instrument, developed in the Scandinavian cultural context and based on Kohlberg's theory. A hypothesized simplex structure model underlying the MDSP was tested through structural equation modeling. Validity was also tested as the proportion of respondents older than 20 years that reached the highest moral level, which according to the theory should be small. A convenience sample of 339 nursing students with a mean age of 25.3 years participated. Results confirmed the simplex model structure, indicating that MDSP reflects a moral construct empirically organized from low to high. A minority of respondents >20 years of age (13.5%) scored more than 80% on the highest moral level. The findings support the construct validity of the MDSP and the stages and levels in Kohlberg's theory. PMID- 21655344 TI - Long-term safety and tolerability of open-label aripiprazole augmentation of antidepressant therapy in major depressive disorder. AB - BACKGROUND: Effective management of major depressive disorder often includes the long-term use of multiple medications, and the longer-term utility and safety of adjunctive aripiprazole has not been evaluated in a controlled setting. PATIENTS AND METHODS: Patients (n = 706) completing one of two 14-week double-blind studies of aripiprazole augmentation, as well as de novo patients (n = 296) nonresponsive to current antidepressant therapy, were enrolled in this open-label study. Patients received open-label aripiprazole for up to 52 weeks. RESULTS: Open-label treatment was completed by 323 patients (32.2%). At endpoint (n = 987), the mean dose of aripiprazole was 10.1 mg/day. Common (>15% of patients) spontaneously reported adverse events were akathisia (26.2%), fatigue (18.0%), and weight gain (17.1%). The incidence of serious adverse events was 4.0%. Four spontaneous reports of possible tardive dyskinesia were submitted (0.4%); all resolved within 45 days of drug discontinuation. Mean weight change was 4.4 kg; 36.6% experienced >=7% increase in weight from baseline (observed case analysis, n = 303). No clinically relevant changes in other metabolic parameters were seen. At the end of open-label treatment, 221 patients (69.7%) had a Clinical Global Impression-Severity of Illness score of 1 (not at all ill) or 2 (borderline ill). CONCLUSION: Long-term adjunctive aripiprazole therapy was well tolerated with an acceptable long-term safety and tolerability profile in patients with major depressive disorder who had not responded to treatment with one or more antidepressant therapies. Clinically significant weight gain was observed in about one-third of patients. Overall, the adverse event profile was consistent with that reported in the short-term trials and readily managed clinically. PMID- 21655345 TI - Aripiprazole for the maintenance treatment of bipolar disorder: a review of available evidence. AB - We aimed to review and synthesize results reporting on the maintenance efficacy of Aripiprazole in adults with bipolar I disorder. Aripiprazole is FDA approved for the acute and maintenance treatment of bipolar I disorder. Aripiprazole's efficacy during the long-term treatment of bipolar disorder is supported by extension of acute phase studies and long-term (ie, 100-week) double-blind placebo controlled recurrence prevention registration trials. Aripiprazole is not established as efficacious in the acute or maintenance treatment of bipolar depression. Moreover, aripiprazole's efficacy during the acute or maintenance phase of bipolar II disorder has not been sufficiently studied. Aripiprazole has a relatively lower hazard for metabolic disruption and change in body composition when compared to other atypical agents (eg, olanzapine, quetiapine). Moreover, aripiprazole has minimal propensity for sedation, somnolence and prolactin elevation. Aripiprazole is associated with extrapyramidal side effects, notably akathisia, which in most cases is not severe or treatment limiting. Future research vistas are to explore aripiprazole's efficacy in bipolar subgroups; recurrence prevention of bipolar depression; and in combination with other mood stabilizing agents. PMID- 21655346 TI - Role of sublingual asenapine in treatment of schizophrenia. AB - Asenapine tablets are a new option for the treatment of schizophrenia. Sublingual administration is essential because bioavailability if ingested is less than 2%. Efficacy is supported by acute and long-term randomized controlled studies conducted by the manufacturer, with asenapine 5 mg twice daily evidencing superiority over placebo in six-week studies of acute schizophrenia, and flexibly dosed asenapine (modal dose 10 mg twice daily) superior to placebo in a 26-week maintenance of response study. Tolerability advantages over some second generation antipsychotics, such as olanzapine, include a relatively favorable weight and metabolic profile, as demonstrated in a 52-week randomized, head-to head, double-blind clinical trial. Although dose-related extrapyramidal symptoms and akathisia can be present, the frequency of these effects is lower than that for haloperidol and risperidone. Somnolence may also occur, and appears to be somewhat dose-dependent when examining rates of this among patients receiving asenapine for schizophrenia and bipolar disorder. Prolactin elevation can occur, but at a rate lower than that observed for haloperidol or risperidone. Unique to asenapine is the possibility of oral hypoesthesia, occurring in about 5% of participants in the clinical trials. Obstacles to the use of asenapine are the recommendations for twice-daily dosing and the need to avoid food or liquids for 10 minutes after administration, although the bioavailability is only minimally reduced if food or liquids are avoided for only two minutes. PMID- 21655348 TI - New antipoverty drugs, vaccines, and diagnostics: a research agenda for the US President's Global Health Initiative (GHI). PMID- 21655347 TI - Effect of BMAP-28 antimicrobial peptides on Leishmania major promastigote and amastigote growth: role of leishmanolysin in parasite survival. AB - BACKGROUND: Protozoan parasites, such as Leishmania, still pose an enormous public health problem in many countries throughout the world. Current measures are outdated and have some associated drug resistance, prompting the search into novel therapies. Several innovative approaches are under investigation, including the utilization of host defence peptides (HDPs) as emerging anti-parasitic therapies. HDPs are characterised by their small size, amphipathic nature and cationicity, which induce permeabilization of cell membranes, whilst modulating the immune response of the host. Recently, members of the cathelicidin family of HDPs have demonstrated significant antimicrobial activities against various parasites including Leishmania. The cathelicidin bovine myeloid antimicrobial peptide 28 (BMAP-28) has broad antimicrobial activities and confers protection in animal models of bacterial infection or sepsis. We tested the effectiveness of the use of BMAP-28 and two of its isomers the D-amino acid form (D-BMAP-28) and the retro-inverso form (RI-BMAP-28), as anti-leishmanial agents against the promastigote and amastigote intracellular Leishmania major lifecycle stages. METHODOLOGY/PRINCIPAL FINDINGS: An MTS viability assay was utilized to show the potent antiparasitic activity of BMAP-28 and its protease resistant isomers against L. major promastigotes in vitro. Cell membrane permeability assays, caspase 3/7, Tunel assays and morphologic studies suggested that this was a late stage apoptotic cell death with early osmotic cell lysis caused by the antimicrobial peptides. Furthermore, BMAP-28 and its isomers demonstrated anti leishmanial activities against intracellular amastigotes within a macrophage infection model. CONCLUSIONS/SIGNIFICANCE: Interestingly, D-BMAP-28 appears to be the most potent antiparasitic of the three isomers against wild type L. major promastigotes and amastigotes. These exciting results suggest that BMAP-28 and its protease resistant isomers have significant therapeutic potential as novel anti-leishmanials. PMID- 21655349 TI - The prevalence of blinding trachoma in northern states of Sudan. AB - BACKGROUND: Despite historical evidence of blinding trachoma, there have been no widespread contemporary surveys of trachoma prevalence in the northern states of Sudan. We aimed to conduct district-level surveys in this vast region in order to map the extent of the problem and estimate the need for trachoma control interventions to eliminate blinding trachoma. METHODS AND FINDINGS: Separate, population based cross-sectional surveys were conducted in 88 localities (districts) in 12 northern states of Sudan between 2006 and 2010. Two-stage cluster random sampling with probability proportional to size was used to select the sample. Trachoma grading was done using the WHO simplified grading system. Key prevalence indicators were trachomatous inflammation-follicular (TF) in children aged 1-9 years and trachomatous trichiasis (TT) in adults aged 15 years and above. The sample comprised 1,260 clusters from which 25,624 households were surveyed. A total of 106,697 participants (81.6% response rate) were examined for trachoma signs. TF prevalence was above 10% in three districts and between 5% and 9% in 11 districts. TT prevalence among adults was above 1% in 20 districts (which included the three districts with TF prevalence >10%). The overall number of people with TT in the population was estimated to be 31,072 (lower and upper bounds = 26,125-36,955). CONCLUSION: Trachoma mapping is complete in the northern states of Sudan except for the Darfur States. The survey findings will facilitate programme planning and inform deployment of resources for elimination of trachoma from the northern states of Sudan by 2015, in accordance with the Sudan Federal Ministry of Health (FMOH) objectives. PMID- 21655350 TI - Meeting cholera's challenge to Haiti and the world: a joint statement on cholera prevention and care. PMID- 21655352 TI - Research and capacity building for control of neglected tropical diseases: the need for a different approach. PMID- 21655351 TI - Regulatory T cells phenotype in different clinical forms of Chagas' disease. AB - CD25(High) CD4+ regulatory T cells (Treg cells) have been described as key players in immune regulation, preventing infection-induced immune pathology and limiting collateral tissue damage caused by vigorous anti-parasite immune response. In this review, we summarize data obtained by the investigation of Treg cells in different clinical forms of Chagas' disease. Ex vivo immunophenotyping of whole blood, as well as after stimulation with Trypanosoma cruzi antigens, demonstrated that individuals in the indeterminate (IND) clinical form of the disease have a higher frequency of Treg cells, suggesting that an expansion of those cells could be beneficial, possibly by limiting strong cytotoxic activity and tissue damage. Additional analysis demonstrated an activated status of Treg cells based on low expression of CD62L and high expression of CD40L, CD69, and CD54 by cells from all chagasic patients after T. cruzi antigenic stimulation. Moreover, there was an increase in the frequency of the population of Foxp3+ CD25(High)CD4+ cells that was also IL-10+ in the IND group, whereas in the cardiac (CARD) group, there was an increase in the percentage of Foxp3+ CD25(High) CD4+ cells that expressed CTLA-4. These data suggest that IL-10 produced by Treg cells is effective in controlling disease development in IND patients. However, in CARD patients, the same regulatory mechanism, mediated by IL-10 and CTLA-4 expression is unlikely to be sufficient to control the progression of the disease. These data suggest that Treg cells may play an important role in controlling the immune response in Chagas' disease and the balance between regulatory and effector T cells may be important for the progression and development of the disease. Additional detailed analysis of the mechanisms on how these cells are activated and exert their function will certainly give insights for the rational design of procedure to achieve the appropriate balance between protection and pathology during parasite infections. PMID- 21655353 TI - Clonal differences between Non-Typhoidal Salmonella (NTS) recovered from children and animals living in close contact in the Gambia. AB - BACKGROUND: Non-Typhoidal Salmonella (NTS) is an important cause of invasive bacterial disease and associated with mortality in Africa. However, little is known about the environmental reservoirs and predominant modes of transmission. Our study aimed to study the role of domestic animals in the transmission of NTS to humans in rural area of The Gambia. METHODOLOGY: Human NTS isolates were obtained through an active population-based case-control surveillance study designated to determine the aetiology and epidemiology of enteric infections covering 27,567 Gambian children less than five years of age in the surveillance area. Fourteen children infected with NTS were traced back to their family compounds and anal swabs collected from 210 domestic animals present in their households. Identified NTSs were serotyped and genotyped by multi-locus sequencing typing. PRINCIPAL FINDINGS: NTS was identified from 21/210 animal sources in the households of the 14 infected children. Chickens carried NTS more frequently than sheep and goats; 66.6%, 28.6% and 4.8% respectively. The most common NTS serovars were S. Colindale in humans (21.42%) and S. Poona in animals (14.28%). MLST on the 35 NTS revealed four new alleles and 24 sequence types (ST) of which 18 (75%) STs were novel. There was no overlap in serovars or genotypes of NTS recovered from humans or animal sources in the same household. CONCLUSION: Our results do not support the hypothesis that humans and animals in close contact in the same household carry genotypically similar Salmonella serovars. These findings form an important baseline for future studies of transmission of NTS in humans and animals in Africa. PMID- 21655354 TI - Matrix metalloproteinase-9 genetic variation and primary angle closure glaucoma in a Caucasian population. AB - PURPOSE: To investigate the association between genetic variation at the matrix metalloproteinase-9 (MMP9) locus and primary angle closure glaucoma (PACG) in an Australian Caucasian population. METHODS: A total of 107 Australian patients with PACG and 288 age and sex-matched controls were included in the current study. Tag single nucleotide polymorphisms (SNPs) were selected and genotyped to cover the majority of common variation within MMP9. Allele, genotype and haplotype association analyses were conducted using PLINK. RESULTS: Two SNPs from MMP9, rs3918249 and rs17576 were significantly associated under the allelic model with p values of 0.006 for both SNPs. In addition, haplotype analysis revealed a protective haplotype TACGG to be significantly more frequent in controls (69%) than in PACG cases (59%), with p=0.006. CONCLUSIONS: This study demonstrates an association between MMP9 SNPs rs3918249 and rs17576 and PACG in the Australian population, suggesting MMP9 may be involved in the pathogenesis of this blinding disease. Further replication will be helpful in confirming this finding before future clinical translation. PMID- 21655355 TI - Mutations in the beta-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa. AB - PURPOSE: This study was designed to identify pathogenic mutations causing autosomal recessive retinitis pigmentosa (RP) in consanguineous Pakistani families. METHODS: Two consanguineous families affected with autosomal recessive RP were identified from the Punjab Province of Pakistan. All affected individuals underwent a thorough ophthalmologic examination. Blood samples were collected, and genomic DNAs were extracted. Exclusion analysis was completed, and two-point LOD scores were calculated. Bidirectional sequencing of the beta subunit of phosphodiesterase 6 (PDE6beta) was completed. RESULTS: During exclusion analyses both families localized to chromosome 4p, harboring PDE6beta, a gene previously associated with autosomal recessive RP. Sequencing of PDE6beta identified missense mutations: c.1655G>A (p.R552Q) and c.1160C>T (p.P387L) in families PKRP161 and PKRP183, respectively. Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6beta protein. CONCLUSIONS: These results strongly suggest that mutations in PDE6beta are responsible for the disease phenotype in the consanguineous Pakistani families. PMID- 21655356 TI - Serum levels of Th17-related cytokines in Behcet disease patients after cataract surgery. AB - PURPOSE: To investigate the profile of T-helper type 17 (Th17) cell-related cytokines (interleukin-23 [IL-23], IL-27, IL-17 and interferon-gamma [IFN-gamma]) in postoperative inflammation in patients with Behcet disease (BD) after cataract surgery. METHODS: Serum was collected from seven BD patients with complicated cataract, and from nine controls with uncomplicated cataract, before cataract surgery, and again 1, 7, 30, and 90 days after surgery. In addition, aqueous humor was collected at commencement of surgery. The protein levels of IL-23, IL 27, IL-17, and IFN-gamma in the serum and in the aqueous humor were measured by an enzyme-linked immunosorbent assay. A laser flare-cell photometer was used to quantify intraocular inflammation. RESULTS: Serum IL-23, IL-27, and IFN-gamma levels were significantly increased after cataract surgery in the BD versus the control patients. In the BD patients, serum levels of IFN-gamma and IL-27 correlated strongly with aqueous flare values and cell counts. Remarkably, the levels of serum IL-27 were significantly associated with serum IFN-gamma levels in BD patients (r=0.796; p=0.002). CONCLUSIONS: Our data indicates that serum IFN gamma and IL-27 levels are significantly elevated in BD versus control patients and are strongly associated with post-operative intraocular inflammation. PMID- 21655357 TI - Genetic networks in the mouse retina: growth associated protein 43 and phosphatase tensin homolog network. AB - PURPOSE: The present study examines the structure and covariance of endogenous variation in gene expression across the recently expanded family of C57BL/6J (B) X DBA/2J (D) Recombinant Inbred (BXD RI) strains of mice. This work is accompanied by a highly interactive database that can be used to generate and test specific hypotheses. For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten). METHODS: The Hamilton Eye Institute (HEI) Retina Database within GeneNetwork features the data analysis of 346 Illumina Sentrix BeadChip Arrays (mouse whole genome-6 version 2). Eighty strains of mice are presented, including 75 BXD RI strains, the parental strains (C57BL/6J and DBA/2J), the reciprocal crosses, and the BALB/cByJ mice. Independent biologic samples for at least two animals from each gender were obtained with a narrow age range (48 to 118 days). Total RNA was prepared followed by the production of biotinylated cRNAs, which were pipetted into the Mouse WG-6V2 arrays. The data was globally normalized with rank invariant and stabilization (2z+8). RESULTS: The HEI Retina Database is located on the GeneNetwork website. The database was used to extract unique transcriptome signatures for specific cell types in the retina (retinal pigment epithelial, amacrine, and retinal ganglion cells). Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database. Bioinformatic tools located within GeneNetwork in conjunction with the HEI Retina Database were used to identify the unique signature Quantitative Trait Loci (QTLs) for Gap43 and Pten on chromosomes 1, 2, 12, 15, 16, and 19. Gap43 and Pten possess networks that are similar to ganglion cell networks that may be associated with axonal growth in the mouse retina. This network involves high correlations of transcription factors (SRY sex determining region Y-box 2 [Sox2], paired box gene 6 [Pax6], and neurogenic differentiation 1 [Neurod1]), and genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), as well as an inhibitor of DNA binding (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein [Id2]). Furthermore, we identified the potential upstream modifiers on chromosome 2 (teashirt zinc finger homeobox 2 [Tshz2], RNA export 1 homolog [Rae1] and basic helix-loop-helix domain contatining, class B4 [Bhlhb4]) on chromosome 15 (RAB, member of RAS oncogene family-like 2a [Rabl2a], phosphomannomutase 1 [Pmm1], copine VIII [Cpne8], and fibulin 1 [Fbln1]). CONCLUSIONS: The endogenous variation in mRNA levels among BXD RI strains can be used to explore and test expression networks underlying variation in retina structure, function, and disease susceptibility. The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina. PMID- 21655358 TI - Insulin, insulin-like growth factor-1, insulin receptor, and insulin-like growth factor-1 receptor expression in the chick eye and their regulation with imposed myopic or hyperopic defocus. AB - PURPOSE: Insulin stimulates eye growth in chicks and this effect is greatly enhanced if the retinal image is degraded by the defocus of either sign. However, it is unclear whether the insulin receptor (IR) is expressed at all in the chicken retina in animals 1-2 weeks post-hatching. We have investigated IR expression and whether IR transcript abundance varies in the fundal layers. To elucidate the possible role of insulin and insulin-like growth factor (IGF)-1 signaling in eye growth regulation, mRNA (mRNA) levels were measured for insulin, IGF-1, IR, and IGF-1 receptor (IGF-1R) during imposed negative or positive defocus. METHODS: Chicks were treated binocularly with positive or negative spectacle lenses for 4 or 24 h, or they remained untreated (n=6, for each treatment group). Northern blot analyses were performed to screen for transcription variants in the different fundal layers of untreated animals. Real time PCR was used to quantify IR, IGF-1R, IGF-1, and insulin mRNA levels in the different fundal layers of the chick eye in the three treatment groups. RESULTS: IR mRNA was found in all the studied tissues, although there is evidence of tissue-specific transcript variations. Three major transcripts were detected for IR. The brain, retina, and choroid showed the longest transcript (4.3 kb), which was not present in the liver. Nevertheless, the liver and brain showed a second transcript (2.6 kb) not present in the retina and choroid. A short transcript (1.3 kb) was the predominant form in the liver and choroid, and it seems to be present in the retinal pigment epithelium (RPE) and sclera as well. In the retina, no significant gene expression changes were found when defocus was imposed. Interestingly, in the RPE, both IR and IGF-1R were already downregulated after short periods (4 h) of positive lens wear. In contrast, IR and IGF-1R were upregulated in the choroid and fibrous sclera during treatment with negative, but not positive, lenses. CONCLUSIONS: Differences observed in the IR transcript length in different tissues suggest possibly different functions. The differential regulation of IR and IGF-1R in the RPE, choroid, and fibrous sclera is consistent with their involvement in a signaling cascade for emmetropization. PMID- 21655359 TI - Comparison of telomere length and association with progenitor cell markers in lacrimal gland between Sjogren syndrome and non-Sjogren syndrome dry eye patients. AB - PURPOSE: Indicators of aging such as disruption of telomeric function due to shortening may be more frequent in dysfunctional lacrimal gland. The aims of this study were to 1) determine the viability of quantitative fluorescence in situ hybridization of telomeres (telo-FISH) for the assessment of telomere length in lacrimal gland in Sjogren and non- Sjogren syndrome patients; and 2) investigate the relationship between progenitor cell markers and telomere length in both groups. METHODS: Quantitative fluorescence in situ hybridization with a peptide nucleic acid probe complementary to the telomere repeat sequence was performed on frozen sections from human lacrimal gland tissues. The mean fluorescence intensity of telomere spots was automatically quantified by image analysis as relative telomere length in lacrimal gland epithelial cells. Immunostaining for p63, nucleostemin, ATP-binding cassette, sub-family G, member 2 (ABCG2), and nestin was also performed. RESULTS: Telomere intensity in the Sjogren syndrome group (6,785.0+/-455) was significantly lower than that in the non-Sjogren syndrome group (7,494.7+/-477; p=0.02). Among the samples from the non-Sjogren syndrome group, immunostaining revealed that p63 was expressed in 1-3 acinar cells in each acinar unit and continuously in the basal layer of duct cells. In contrast, in the Sjogren syndrome group, p63 and nucleostemin showed a lower level of expression. ABCG2 was expressed in acinar cells in both sjogren and non Sjogren syndrome. CONCLUSIONS: The results of this study indicate that 1) telo FISH is a viable method of assessing telomere length in lacrimal gland, and 2) telomere length in Sjogren syndrome is shorter and associated with lower levels of expression of p63 and nucleostemin than in non-Sjogren syndrome. PMID- 21655360 TI - Sequence analysis of MYOC and CYP1B1 in a Chinese pedigree of primary open-angle glaucoma. AB - PURPOSE: To analyze two candidate genes, trabecular meshwork inducible glucocorticoid response (MYOC/TIGR) and human dioxin-inducible cytochrome P450 (CYP1B1), in a Chinese pedigree of primary open-angle glaucoma. METHODS: In a three-generation family containing 14 members, four of them were patients with primary open-angle glaucoma, one was a glaucoma suspect, and the rest were asymptomatic. All members of the family underwent complete ophthalmologic examinations. Exons of MYOC and CYP1B1 were amplified by polymerase chain reaction, sequenced, and compared with a reference database. RESULTS: Elevated intraocular pressure and impaired visual field were found in all patients. One MYOC heterozygous mutation G367R, in exon 3 was identified in four patients and the suspect, but not in the rest of the family members. Meanwhile, four single nucleotide polymorphisms in MYOC and CYP1B1 genes were found. CONCLUSIONS: Although the G367R mutation of MYOC, which causes primary open-angle glaucoma in the form of autosomal dominant inheritance, has been reported in some other ethnicities, it was found in Chinese pedigree for the first time. PMID- 21655361 TI - PAX6 gene analysis in irido-fundal coloboma. AB - PURPOSE: To screen the paired box gene 6 (PAX6) gene in irido-fundal coloboma. METHODS: The entire coding region of PAX6 including intron-exon boundaries was amplified from cases (n=30) and controls (n=30). All sequences were analyzed against the ensemble sequence (ENSG00000007372) for PAX6. RESULTS: DNA sequence analysis of patients and controls revealed a total of three nucleotide changes (g.31815391Cytosine>Thymine; Glycine72Glycine and g.31812215Thymine>Guanine) of which one was neutral/synonymous change and the remaining two were intronic changes. Of these 3 changes, 2 were novel and one was already reported change. All these changes were non-pathogenic, according to in silico analysis. CONCLUSIONS: In our study no pathogenic PAX6 mutation were identified. This suggests involvement of other coloboma genes. This study expands the SNP spectrum of PAX6, only rare variations which are not causative have been found. Since this is a pilot study in the north Indian population, results should be confirmed in different populations by similar studies. Familial cases are required for determining the underlying genetic loci accounting for this clinical phenotype and may lead to better understanding of disease pathogenesis. PMID- 21655363 TI - A research agenda for appearance changes due to breast cancer treatment. AB - Breast cancer is one of the most prevalent forms of cancer in the US. It is estimated that more than 180,000 American women will be diagnosed with invasive breast cancer in 2008. Fortunately, the survival rate is relatively high and continually increasing due to improved detection techniques and treatment methods. However, maintaining quality of life is a factor often under emphasized for breast cancer survivors. Breast cancer treatments are invasive and can lead to deformation of the breast. Breast reconstruction is important for restoring the survivor's appearance. However, more work is needed to develop technologies for quantifying surgical outcomes and understanding women's perceptions of changes in their appearance. A method for objectively measuring breast anatomy is needed in order to help both the breast cancer survivors and their surgeons take expected changes to the survivor's appearance into account when considering various treatment options. In the future, augmented reality tools could help surgeons reconstruct a survivor's breasts to match her preferences as much as possible. PMID- 21655362 TI - Identification of three prominin homologs and characterization of their messenger RNA expression in Xenopus laevis tissues. AB - PURPOSE: Prominin is a family of pentaspan transmembrane glycoproteins. They are expressed in various types of cells, including many stem/progenitor cells. Prominin-1 plays an important role in generating and maintaining the structure of the photoreceptors. In this study, we identified three prominin homologs in Xenopus laevis, a model animal widely used in vision research, and characterized their messenger RNA (mRNA) expression in selected tissues of this frog. METHODS: Reverse-transcription PCR (RT-PCR) and rapid amplification of cDNA ends (RACE) were used to isolate cDNAs of prominin homologs. Semiquantitative RT-PCR was used to measure the relative expression levels of mRNAs of the three prominin homologs in four X. laevis tissues, specifically those of the retina, brain, testis, and kidney. Sequences of prominin homologs were analyzed with bioinformatic software. RESULTS: We isolated cDNAs of three prominin homologs from X. laevis tissues and compared their sequences with previously described prominin-1, 2, and 3 sequences from other species using phylogenetic analysis. Two of these homologs are likely to be the X. laevis orthologs of mammalian prominin-1 and 2, respectively, while the third homolog is likely to be the X. laevis ortholog of prominin-3, which was only found in nonmammalian vertebrates and the platypus. We identified alternatively spliced exons in mRNAs of all three prominin homologs. Similar to mammalian prominin-1, we found that exons 26b, 27, and 28a of the X. laevis prominin-1 gene are alternatively spliced, and that the splice isoforms of mRNA show tissue-specific expression profiles. We found that prominin-1 was the most abundant homolog expressed in the retina, brain, and testis, while prominin-3 was the most abundant homolog in the kidney. The expression level of prominin-2 was the lowest of the three prominin homologs in all four examined tissues of this frog. CONCLUSIONS: Our results suggest that the mRNAs of prominin homologs are expressed in many tissues of X. laevis, but differ in their expression levels and mRNA splicing. Prominin-1 is the most abundant of the three prominin homologs expressed in the frog retina. PMID- 21655364 TI - Computer-aided detection of breast cancer - have all bases been covered? AB - The use of computer-aided detection (CAD) systems in mammography has been the subject of intense research for many years. These systems have been developed with the aim of helping radiologists to detect signs of breast cancer. However, the effectiveness of CAD systems in practice has sparked recent debate. In this commentary, we argue that computer-aided detection will become an increasingly important tool for radiologists in the early detection of breast cancer, but there are some important issues that need to be given greater focus in designing CAD systems if they are to reach their full potential. PMID- 21655366 TI - Rethinking breast self-examinations: are we asking the right questions? PMID- 21655365 TI - Podosomes and Invadopodia: Related structures with Common Protein Components that May Promote Breast Cancer Cellular Invasion. AB - A rate-limiting step in breast cancer progression is acquisition of the invasive phenotype, which can precede metastasis. Expression of cell-surface proteases at the leading edge of a migrating cell provides cells with a mechanism to cross tissue barriers. A newly appreciated mechanism that may be relevant for breast cancer cell invasion is the formation of invadopodia, well-defined structures that project from the ventral membrane and promote degradation of the extracellular matrix, allowing the cell to cross a tissue barrier. Recently, there has been some controversy and discussion as to whether invadopodia, which are associated with carcinoma cells, are related to a similar structure called podosomes, which are associated with normal cells. Invadopodia and podosomes share many common characteristics, including a similar size, shape, subcellular localization and an ability to promote invasion. These two structures also share many common protein components, which we outline herein. It has been speculated that podosomes may be precursors to invadopodia and by extension both structures may be relevant to cancer cell invasion. Here, we compare and contrast the protein components of invadopodia and podosomes and discuss a potential role for these proteins and the evidence that supports a role for invadopodia and podosomes in breast cancer invasion. PMID- 21655367 TI - In search of breast cancer culprits: suspecting the suspected and the unsuspected. AB - I would like to welcome breast cancer research community to the first editorial of our newest journal "Breast Cancer: Basic and Clinical Research". In pursuit of breast cancer culprits, we have come a long way since the early 90's when the first breast cancer susceptibility gene BRCA1 was mapped and cloned. In the past few years, several new loci associated with the various degree of breast cancer risk have been identified using "Candidate Gene Association Study (CGAS) and Genome-Wide Association Study (GWAS)" approaches. This editorial is meant to quickly glance over recent findings of these population-based association studies. PMID- 21655368 TI - Reversed Expression of the JAK/STAT Pathway Related Proteins Prolactin Receptor and STAT5a in Normal and Abnormal Breast Epithelial Cells. AB - The JAK/STAT pathway is important for cellular metabolism. One component, STAT5a, is activated in the breast upon prolactin to prolactin receptor (PRLR) binding facilitating the transcription of genes involved in lobule development. STAT5a was previously found to be expressed in most normal breast epithelial cells but not in many in situ or invasive carcinomas except secretory carcinomas which retain STAT5a expression. This report examines the JAK/STAT pathway in the breast through the detection of PRLR and STAT5a. Fifty breast tissues, including benign secretory change, microglandular adenosis, usual and atypical hyperplasia and in situ and invasive ductal carcinoma both usual and secretory, were obtained from the files of the Armed Forces Institute of Pathology. Sections were immunostained with antibodies to PRLR and STAT5a. PRLR was minimally detected on the surface of a few normal breast epithelial cells whereas STAT5a was greatly expressed in over 80% of normal cell nuclei. PRLR was also minimally detected in secretory carcinomas expressing STAT5a. However, the opposite pattern was seen in breast carcinomas lacking STAT5a expression. PRLR was abundantly expressed in these cells. This reversed expression may indicate a JAK/STAT pathway disturbance that could play a role in the initiation or maintenance of an abnormal breast phenotype. PMID- 21655369 TI - The reality in the surveillance of breast cancer survivors-results of a patient survey. AB - BACKGROUND: International guidelines for the surveillance of breast cancer patients recommend a minimized clinical follow-up including routine history and physical examination and regularly scheduled mammograms. However, the abandonment of scheduled follow-up examinations in breast cancer survivors remains a contradiction to established follow-up guidelines for other solid tumours. PATIENTS AND METHODS: We report the patients' view on the basis of a survey performed in two separate geographical areas in Germany. The questionnaires were sent out to 2.658 patients with a history of breast cancer. RESULTS: A total of 801 patients (30.1%) responded to the questionnaire. The results of the survey can be summarized in two major categories: First, necessity for surveillance was affirmed by a majority (>95%), and 47.8% of the organized patients answered that there was a need for more intensive diagnostic effort during follow-up. The main expectation from an intensified follow-up was the increased feeling of security as expressed by >80% of the women. Second, the present survey indicates that most of the regularly scheduled follow-up visits were expanded using extensive laboratory and imaging procedures exceeding the quantity of examinations recommended in the present follow-up guidelines. CONCLUSION: Despite the fact that only one third of the patients responded to the questionnaire, the survey indicates that a majority of physicians who treated these patients still do not accept the present follow-up guidelines. To some extent this may be explained by the observation that patients and possibly also their doctors trust that intensified follow-up increases diagnostic security and survival. Since considerable changes in the treatment options of breast cancer have been made during the last decades a new trial of investigations in follow-up is warranted. PMID- 21655370 TI - G-Protein Inwardly Rectifying Potassium Channel 1 (GIRK1) Knockdown Decreases Beta-Adrenergic, MAP Kinase and Akt Signaling in the MDA-MB-453 Breast Cancer Cell Line. AB - Previous data from our laboratory have indicated that there is a functional link between the beta-adrenergic receptor signaling pathway and the G-protein inwardly rectifying potassium channel (GIRK1) in breast cancer cell lines and that these pathways are involved in growth regulation of these cells. To determine functionality, MDA-MB-453 breast cancer cells were stimulated with ethanol, known to open GIRK channels. Decreased GIRK1 protein levels were seen after treatment with 0.12% ethanol. In addition, serum-free media completely inhibited GIRK1 protein expression. This data indicates that there are functional GIRK channels in breast cancer cells and that these channels are involved in cellular signaling. In the present research, to further define the signaling pathways involved, we performed RNA interference (siRNA) studies. Three stealth siRNA constructs were made starting at bases 1104, 1315, and 1490 of the GIRK1 sequence. These constructs were transfected into MDA-MB-453 cells, and both RNA and protein were isolated. GIRK1, beta(2)-adrenergic and 18S control levels were determined using real-time PCR 24 hours after transfection. All three constructs decreased GIRK1 mRNA levels. However, beta(2) mRNA levels were unchanged by the GIRK1 knockdown. GIRK1 protein levels were also reduced by the knockdown, and this knockdown led to decreases in beta-adrenergic, MAP kinase and Akt signaling. PMID- 21655372 TI - A decade of change: an institutional experience with breast surgery in 1995 and 2005. AB - INTRODUCTION: With the adoption of routine screening mammography, breast cancers are being diagnosed at earlier stages, with DCIS now accouting for 22.5% of all newly diagnosed breast cancers. This has been attributed to both increased breast cancer awareness and improvements in breast imaging techniques. How have these changes, including the increased use of image-guided sampling techniques, influenced the clinical practice of breast surgery? METHODS: The institutional pathology database was queried for all breast surgeries, including breast reconstruction, performed in 1995 and 2005. Cosmetic procedures were excluded. The results were analysed utilizing the Chi-square test. RESULTS: Surgical indications changed during 10-year study period, with an increase in preoperatively diagnosed cancers undergoing definitive surgical management. ADH, and to a lesser extent, ALH, became indications for surgical excision. Fewer surgical biopsies were performed for indeterminate abnormalities on breast imaging, due to the introduction of stereotactic large core biopsy. While the rate of benign breast biopsies remained constant, there was a higher percentage of precancerous and DCIS cases in 2005. The overall rate of mastectomy decreased from 36.8% in 1995 to 14.5% in 2005. With the increase in sentinel node procedures, the rate of ALND dropped from 18.3% to 13.7%. Accompanying the increased recognition of early-stage cancers, the rate of positive ALND also decreased, from 43.3% to 25.0%. CONCLUSIONS: While the rate of benign breast biopsies has remained constant over a recent 10-year period, fewer diagnostic surgical image-guided biopsies were performed in 2005. A greater percentage of patients with breast cancer or preinvasive disease have these diagnoses determined before surgery. More preinvasive and Stage 0 cancers are undergoing surgical management. Earlier stage invasive cancers are being detected, reflected by the lower incidence of axillary nodal metastases. PMID- 21655371 TI - Comparison and identification of estrogen-receptor related gene expression profiles in breast cancer of different ethnic origins. AB - The interactions between genetic variants in estrogen receptor (ER) have been identified to be associated with an increased risk of breast cancer. Available evidence indicates that genetic variance within a population plays a crucial role in the occurrence of breast cancer. Thus, the comparison and identification of ER related gene expression profiles in breast cancer of different ethnic origins could be useful for the development of genetic variant cancer therapy. In this study, we performed microarray experiment to measure the gene expression profiles of 59 Taiwanese breast cancer patients; and through comparative bioinformatics analysis against published U.K. datasets, we revealed estrogen-receptor (ER) related gene expression between Taiwanese and British patients. In addition, SNP databases and statistical analysis were used to elucidate the SNPs associated with ER status. Our microarray results indicate that the expression pattern of the 65 genes in ER+ patients was dissimilar from that of the ER- patients. Seventeen mutually exclusive genes in ER-related breast cancer of the two populations with more than one statistically significant SNP in genotype and allele frequency were identified. These 17 genes and their related SNPs may be important in population-specific ER regulation of breast cancer. This study provides a global and feasible approach to study population-unique SNPs in breast cancer of different ethnic origins. PMID- 21655373 TI - The MUC1 Cytoplasmic Tail and Tandem Repeat Domains Contribute to Mammary Oncogenesis in FVB Mice. AB - BACKGROUND: Though the importance of the transmembrane mucin MUC1 in mammary oncogenesis has long been recognized, the relative contributions of the cytoplasmic tail and tandem repeat domains are poorly understood. METHODS: To address this, mouse models of mammary carcinogenesis were created expressing full length, cytoplasmic tail-deleted, or tandem repeat-deleted MUC1 constructs. RESULTS: Overexpression of full-length MUC1 resulted in tumor formation in young mice (<=12 months); however, loss of either the cytoplasmic tail or the tandem repeat domain abrogated this oncogenic capacity. Aged mice in all strains developed late-onset mammary tumors similar to those previously described for the FVB background. CONCLUSIONS: This study is the first spontaneous cancer model to address the relative importance of the cytoplasmic tail and tandem repeat domains to MUC1-driven mammary oncogenesis, and suggests that both of these domains are essential for tumor formation. PMID- 21655374 TI - The Cell Surface Estrogen Receptor, G Protein- Coupled Receptor 30 (GPR30), is Markedly Down Regulated During Breast Tumorigenesis. AB - BACKGROUND: GPR30 is a cell surface estrogen receptor that has been shown to mediate a number of non-genomic rapid effects of estrogen and appear to balance the signaling of estrogen and growth factors. In addition, progestins appear to use GPR30 for their actions. Therefore, GPR30 could play a critical role in hormonal regulation of breast epithelial cell integrity. Deregulation of the events mediated by GPR30 could contribute to tumorigenesis. METHODS: To understand the role of GPR30 in the deregulation of estrogen signaling processes during breast carcinogenesis, we have undertaken this study to investigate its expression at mRNA levels in tumor tissues and their matched normal tissues. We compared its expression at mRNA levels by RT quantitative real-time PCR relative to GAPDH in ERalpha"-positive (n = 54) and ERalpha"-negative (n = 45) breast cancer tissues to their matched normal tissues. RESULTS: We report here, for the first time, that GPR30 mRNA levels were significantly down-regulated in cancer tissues in comparison with their matched normal tissues (p < 0.0001 by two sided paired t-test). The GPR30 expression levels were significantly lower in tumor tissues from patients (n = 29) who had lymph node metastasis in comparison with tumors from patients (n = 53) who were negative for lymph node metastasis (two sample t-test, p < 0.02), but no association was found with ERalpha, PR and other tumor characteristics. CONCLUSIONS: Down-regulation of GPR30 could contribute to breast tumorigenesis and lymph node metastasis. PMID- 21655375 TI - Circumareolar mastopexy with multiple glandular plications for symmetry of the contra-lateral breast, in patients undergoing breast reconstruction with prosthesis. Experience on 50 cases. AB - 4 years experience on 50 cases using the Elliott's technique for symmetrization of the contra-lateral breast in patients undergoing breast reconstruction with an anatomical prosthesis is presented in this paper.The Elliott's technique with its double superior and horizontal plication is a suitable and long-lasting procedure for patients with small-moderate ptotic breast and elastic skin, who wish to have a simple procedure and an immediate result with minimal scars. PMID- 21655376 TI - Tumor microvasculature: endothelial leakiness and endothelial pore size distribution in a breast cancer model. AB - Tumor endothelial leakiness is quantified in a rat mammary adenocarcinoma model using dynamic contrast enhancement MRI and contrast agents of widely varying sizes. The contrast agents were constructed to be of globular configuration and have their uptake rate into tumor interstitium be driven by the same diffusion process and limited only by the availability of endothelial pores of passable size. It was observed that the endothelial pore distribution has a steep power law dependence on size, r(-) (beta), with an exponent of -4.1. The model of large pore dominance in tumor leakiness as reported in some earlier investigation with fluorescent probes and optical chamber methods is rejected for this tumor model and a number of other tumor types including chemically induced tumors. This steep power law dependence on size is also consistent with observations on human breast cancer. PMID- 21655377 TI - Descriptive analysis of pitch volume in southeastern conference baseball pitchers. AB - BACKGROUND: Representative data on typical pitch volume for collegiate pitchers functioning in their specific roles is sparse and is needed for training specificity. OBJECTIVE: To report pitch volumes in Division I collegiate pitchers. The authors hypothesize that pitcher role will result in different pitch volumes. METHODS: Pitchers from twelve Division I collegiate baseball teams pitch volume during the 2009 baseball season was retrospectively reviewed through each team's website. The number of pitches and innings pitched for each pitcher were recorded. Pitchers were categorized based on their role as "Starter-only" (n=15), "Reliever-only" (n=76), or "Combined Starter/Reliever" (n=94) and compared using ANOVA. RESULTS: "Starter-only" pitchers threw the most pitches (97+/-10) and pitched the most innings (6.0+/-1.0) per appearance (p=<.001). "Combined Starter/Reliever" functioning as a starter threw significantly more pitches (68+/-19) and pitched more innings (4.0+/-1.3) per appearance compared to "Combined Starter/Reliever" functioning as a reliever and "Reliever-only" pitchers (p=<.001). The cumulative volume during a 13 week regular season revealed that "Starter-only" pitchers threw significantly more total pitches (1204+/-387) compared to "Combined Starter/Reliever" pitchers (613+/-182) who threw significantly more than "Reliever-only" pitchers (254+/-77) (P<.001). DISCUSSION: Pitcher's specific roles and representative volumes should be used to design training and rehabilitation programs. Comparison of this data to reported adolescent pitch volumes reveal that adolescent pitch volume per appearance approaches collegiate levels. CONCLUSIONS: Collegiate pitcher roles dictate their throwing volume. Starter-only pitchers (8%) throw the greatest cumulative number of pitches and should be trained differently than the majority of college pitchers (92%) who function primarily as a reliever or in combination starter/reliever roles that on average only requires approximately 40 pitches per appearance. PMID- 21655378 TI - Reliability and exploration of the side-lying thoraco-lumbar rotation measurement (strm). AB - STUDY DESIGN: Clinical Measurement, Reliability, Descriptive Study OBJECTIVES: To establish intrarater and interrater reliability of the Side-lying Thoraco-lumbar Rotation Measurement (STRM) and to explore frequencies and magnitude of rotational differences that exist in various musculoskeletal conditions. BACKGROUND: Limitation in thoracic rotation could lead to increased motion at adjacent areas (i.e., shoulders and low back). This could potentially lead to excessive strain and subsequent injury from repetitive stress. Currently, there is no well-established method to reliably measure and objectively quantify thoraco-lumbar spine rotation. METHODS: Intrarater reliability was assessed by a single investigator performing three STRM measurements on 10 participants on two consecutive days. Interrater reliability was assessed by two independent examiners, performing the STRM on 30 participants. Reliability was assessed using the intraclass correlation coefficient (ICC) statistic. To explore the incidence and magnitude of side-to-side thoraco-lumbar rotation differences, the STRM was measured on 156 participants of various musculoskeletal conditions. RESULTS: The intrarater reliability of the STRM was excellent (ICC=.94). The interrater reliability was good (ICC=.88). Fifty four percent of the sample exhibited greater than a 10% side-to-side difference in the STRM while twenty percent exhibited greater than a 20% side-to-side difference. CONCLUSION: The STRM can be used as a reliable and objective method to quantify thoraco-lumbar spine rotation. It also appears that a large percentage of patients with varied musculoskeletal complaints may have greater than a 10-20% asymmetry in spinal rotational movement. Future research is needed to determine the clinical applicability and relevance of these findings. LEVEL OF EVIDENCE: 4. PMID- 21655379 TI - The reliability, minimal detectable change and construct validity of a clinical measurement for identifying posterior shoulder tightness. AB - PURPOSE/BACKGROUND: Posterior shoulder tightness (PST) has been implicated in the etiology of numerous shoulder disorders. Therefore, clinicians and researchers must have a reliable and valid method for quantifying PST. The purpose of this study was to investigate the interrater reliability, minimal detectable change at the 90% confidence interval (MDC(90)) and construct validity of an inclinometric measurement designed to quantify PST. METHODS: Two investigators each performed sidelying PST measurements on the non-dominant shoulder of 45 asymptomatic participants in a blinded repeated measures design. Upon completion of the PST measurements, one rater assessed active internal and external rotation for the validity component of the investigation. RESULTS: Interrater reliability using an intraclass correlation coefficient (ICC) model 2,k was good (ICC 5 0.90). The MDC(90) indicated that a change of greater than or equal to 9 degrees would be required to be 90% certain that a change in the measurement would not be the result of inter-trial variability or measurement error. Construct validity was evaluated using active internal rotation for convergence and external rotation for discrimination. Construct validity was supported by a good to excellent relationship between PST and internal rotation (r 5 0.88) and by an inverse relationship between PST and external rotation (r 5 20.07). CONCLUSION: The sidelying procedure described in this investigation appears to be a reliable and valid means for quantifying PST when strict measurement protocols are adhered to. An advantage of this procedure lies in the ability to control scapular position to ensure motion is limited to the glenohumeral joint. Moreover, the use of inclinometry provides an absolute angle of tightness that may be used for intersubject comparison, documenting change, and to determine reference values. Clinicians and researchers should consider the MDC values presented when interpreting change values during subsequent measurement sessions. PMID- 21655380 TI - The use of acetic Acid iontophoresis in the management of a soft tissue injury. AB - BACKGROUND: Contusions are common injuries that occur in athletics. If repeated, complications like myositis ossificans can occur. This case describes the examination and treatment of an athlete with an acute soft tissue injury. OBJECTIVE: To describe the treatment approach used with a hockey player who sustained a soft tissue injury in his upper extremity. CASE DESCRIPTION: A 19 year old male sustained a soft tissue injury to his upper arm while playing hockey. The athlete complained of pain rated a 2-3 out of 10. He had a well circumscribed, firm, 8 by 5 centimeter palpable mass present along the lateral arm, and was able to passively flex his elbow from 56 degrees to 135 degrees , demonstrating a 56 degrees loss of elbow extension. Functionally, he was able to perform most activities of daily living, but he was unable to play hockey. Over 29 days, the athlete was treated one time with pulsed ultrasound and ice and nine times with iontophoresis using a 2% acetic acid solution. Additionally, the athlete performed pain-free active range of motion exercises for the elbow. OUTCOME: Following treatment, the athlete's pain resolved, the palpable mass disappeared, and his passive range of motion at the elbow was 0 degrees to 135 degrees . Most importantly, the athlete was able to resume playing hockey. DISCUSSION: Acetic acid iontophoresis may be a successful intervention for soft tissue injuries of the upper extremity. In this case, it appeared helpful in decreasing the athlete's impairments and contributed to quicker resumption of all functional activities in less time than previously reported in the literature using traditional treatment interventions. PMID- 21655381 TI - Diagnosis of an ulnar collateral ligament tear using musculoskeletal ultrasound in a collegiate baseball pitcher: a case report. AB - OBJECTIVE: To demonstrate a comparative diagnostic approach between magnetic resonance imaging (MRI) and musculoskeletal ultrasound for detecting UCL trauma of the elbow in a collegiate baseball pitcher. BACKGROUND: A 19 year-old male baseball pitcher with no previous history of an elbow injury presented with left medial elbow pain after experiencing a popping sensation during a bull pen throwing session. Patient initially demonstrated palpable tenderness directly over the UCL and a positive milking maneuver. Minimal swelling and no observable discoloration were noted upon examination. Diagnostic ultrasound was utilized to assess the elbow anatomical structures. The differential diagnosis included medial epicondylitis, flexor pronator muscle strain, ulnar collateral ligament tear TREATMENT: Initial treatment was conservative while preparing for a ligament reconstruction. Goals included pain control, restoration of range of motion, and reduction of inflammation. UNIQUENESS: Accurate diagnosis of UCL disruption was made using dynamic diagnostic musculoskeletal ultrasound despite a negative MRI. The ability to accurately identify the injury contributed to the timeliness of the appropriate surgical intervention and the facilitation of a timely and successful rehabilitation program. CONCLUSIONS: Dynamic musculoskeletal ultrasound may offer an effective option for diagnosing UCL tears of the elbow. Diagnostic musculoskeletal ultrasound is an affordable, accessible, and portable option that provides a clinician with real-time information and accurate observations in the hands of a skilled operator. Diagnostic musculoskeletal ultrasound may play an increased role as a diagnostic tool in the sports medicine community. PMID- 21655383 TI - Thoracic rotation measurement techniques: clinical commentary. AB - A number of sporting and daily activities involve rotation of the spine. The ability to quantify motion of the spine in a clinical setting usually relies on the use of a device to measure angles (goniometer or inclinometer) or visual assessment. Standardized measurement criteria exist for measuring rotation at the cervical and lumbar spine. Little has been written regarding established methods for measuring thoracic spine rotation. Thoracic rotation may be measured in a seated position, half-kneeling position, or quadruped position. Steps should be taken to minimize motion of surrounding segments such as the shoulder and hips, which may improve measurement accuracy. Key words: inclinometer, goniometer, range of motion. PMID- 21655382 TI - Understanding and preventing acl injuries: current biomechanical and epidemiologic considerations - update 2010. AB - This invited clinical commentary summarizes the current state of knowledge in the area of prevention of anterior cruciate ligament (ACL) injuries. ACL injuries occur with a four to six fold greater incidence in female compared to male athletes playing the same high risk sports. The combination of increased risk of ACL injury and a 10-fold increase in sports participation since the enactment of Title IX in 1972 has led to an almost epidemic rise in ACL injuries in female athletes. Examination of the mechanisms responsible for this sex disparity in ACL rupture accelerated in the last two decades. A summary of these findings and a synthesis and framework for understanding the results of the intense investigation of this research are detailed herein. This clinical commentary focuses on the current understanding, identification and interventional targeting of the primary neuromuscular and biomechanical risk factors associated with the ACL injury mechanism in high-risk individuals. PMID- 21655384 TI - Incorporating kettlebells into a lower extremity sports rehabilitation program. AB - The primary goal of a sports rehabilitation program is to return the injured athlete back to competition as quickly and as safely as possible. Sports physical therapists utilize a variety of exercise equipment to help an athlete restore function after an injury. An injured athlete's therapeutic exercise program frequently includes the prescription of functional strengthening and power exercises during the later stages of rehabilitation. One piece of exercise equipment, the kettlebell, has gained popularity for its ability to allow the user to perform functional power exercises. The unique exercises that can be performed with kettlebells may have utility in sports physical therapy practice. This clinical suggestion outlines the clinical rationale for the inclusion of kettlebell exercises when rehabilitating an athlete with a lower extremity injury. PMID- 21655385 TI - Adhesive capsulitis: use the evidence to integrate your interventions. AB - Frozen shoulder syndrome, clinically known as adhesive capsulitis, is a painful and debilitating condition affecting up to 5% of the population. Adhesive capsulitis is considered fibrosis of the glenohumeral joint capsule with a chronic inflammatory response. Patients experience pain, limited range of motion, and disability generally lasting anywhere from 1 to 24 months. The purpose of this clinical suggestion is to review the pathophysiolgy of adhesive capsulitis and discuss physical therapy interventions which are supported by evidence, thereby enhancing evidence-based practice. PMID- 21655386 TI - Mode of administration bias. PMID- 21655387 TI - Treatment of a female collegiate rower with costochondritis: a case report. AB - Rib injuries are common in collegiate rowing. The purpose of this case report is to provide insight into examination, evaluation, and treatment of persistent costochondritis in an elite athlete as well as propose an explanation for chronic dysfunction. The case involved a 21 year old female collegiate rower with multiple episodes of costochondritis over a 1-year period of time. Symptoms were localized to the left third costosternal junction and bilaterally at the fourth costosternal junction with moderate swelling. Initial interventions were directed at the costosternal joint, but only mild, temporary relief of symptoms was attained. Reexamination findings included hypomobility of the upper thoracic spine, costovertebral joints, and lateral ribs. Interventions included postural exercises and manual therapies directed at the lateral and posterior rib structures to improve rib and thoracic spine mobility. Over a 3-week time period pain experienced throughout the day had subsided (visual analog scale - VAS 0/10). She was able to resume running and elliptical aerobic training with minimal discomfort (VAS 2/10) and began to reintegrate into collegiate rowing. Examination of the lateral ribs, cervical and thoracic spine should be part of the comprehensive evaluation of costochondritis. Addressing posterior hypomobility may have allowed for a more thorough recovery in this case study. PMID- 21655388 TI - Clinimetrics corner: the many faces of selection bias. AB - Selection bias, also known as susceptibility bias in an intervention study or spectrum bias in a diagnostic accuracy study, is present throughout clinically applicable evidence in various forms. Selection bias implies that the intervention or diagnostic test has been studied in a less representative sample population, which can lead to inflated overall effect sizes and/or inaccurate findings. Within the literature, there are over 40 forms of selection bias that can influence the external validity of results. Recognition of selection bias is essential in the translation of evidence into effective clinical practice. This clinimetrics corner outlines the major biases that readers encounter and discusses key examples regarding pertinent orthopedic and manual therapy literature. PMID- 21655389 TI - Thoracic outlet syndrome: a controversial clinical condition. Part 1: anatomy, and clinical examination/diagnosis. AB - Thoracic outlet syndrome (TOS) is a frequently overlooked peripheral nerve compression or tension event that creates difficulties for the clinician regarding diagnosis and management. Investigators have categorized this condition as vascular versus neurogenic, where vascular TOS can be subcategorized as either arterial or venous and neurogenic TOS can subcategorized as either true or disputed. The thoracic outlet anatomical container presents with several key regional components, each capable of compromising the neurovascular structures coursing within. Bony and soft tissue abnormalities, along with mechanical dysfunctions, may contribute to neurovascular compromise. Diagnosing TOS can be challenging because the symptoms vary greatly amongst patients with the disorder, thus lending to other conditions including a double crush syndrome. A careful history and thorough clinical examination are the most important components in establishing the diagnosis of TOS. Specific clinical tests, whose accuracy has been documented, can be used to support a clinical diagnosis, especially when a cluster of positive tests are witnessed. PMID- 21655390 TI - Limited clinical reasoning skills used by novice physiotherapists when involved in the assessment and management of patients with shoulder problems: a qualitative study. AB - The aim of this study was to explore the clinical reasoning process used by novice physical therapists in specific patient problems. Nine physical therapists in the UK with limited experience of managing musculoskeletal problems were included. Semi-structured interviews were conducted on how novice physical therapists would assess and manage a patient with a shoulder problem; interviews were transcribed and analyzed using framework analysis. To be included as a final theme at least 50% of participants had to mention that theme. A large number of items (n = 93) were excluded as fewer than 50% of participants referred to each item. Included items related to seven main themes: history (16), physical exam (13), investigations (1), diagnostic reasoning (1), clinical reasoning process (diagnostic pathway) (3), clinical reasoning process (management pathway) (5) and treatment options (1). Items mostly related to information gathering, although there was some use of hypothetico-deductive clinical reasoning there appeared to be limited understanding of the clinical implications of data gathered, and clinical reasoning through use of pattern recognition was minimal. Major weaknesses were apparent in the clinical reasoning skills of these novice therapists compared to previous reports of expert clinical reasoning, indicating areas for development in the education of student and junior physical therapists. PMID- 21655391 TI - Application of a classification system and description of a combined manual therapy intervention: a case with low back related leg pain. AB - Low back pain and leg pain commonly occur together. Multiple factors can cause low back related leg pain; therefore, identification of the source of symptoms is required in order to develop an appropriate intervention program. The patient in this case presented with low back and leg pain. A patho-mechanism based classification is described in combination with the patient's subjective and objective examination findings to guide treatment. The patient's symptoms improved marginally with intervention addressing primarily the musculoskeletal impairments and with intervention addressing primarily the neurodynamic impairments. Full functional improvements were attained with a manual therapy intervention directed at both mechanisms simultaneously. The approach described in this case address a mixed pathology utilizing passive accessory and passive physiological lumbar mobilizations in combination with lower extremity neurodynamic mobilization. The patient reported complete resolution of symptoms after a total of seven visits over a period of 6 weeks. While specific guidelines do not yet exist for treatment based on the classification approach utilized, this case report provides an example of manual therapy to address low back related leg pain of mixed pathology. PMID- 21655392 TI - Symptom localization tests in the cervical spine: a descriptive study using imaging verification. AB - The concept of isolation of a movement to a single specific spinal segment by blocking/stabilization is considered useful and important during both examination and treatment. This descriptive study endeavoured to determine whether a typical manual stabilizing procedure changes movement patterns in the cervical spine. Lateral radiographs were taken of five volunteers in active/assisted extension with and without manual fixation grasping with the thumb and fingers around the dorsal aspect of the neck at the level of the vertebral arch. Vertebral angular differences between the fixated and non-fixated movements were measured for intra rater and inter-rater reliability using an intraclass correlation coefficient (ICC) and analyzed for differences using a student t-test. Intraclass correlation coefficient values for intra-rater reliability were fair to moderate whereas inter-rater reliability was excellent. Although not statistically significant, the results showed that in relation to the active extension, the vertebra above the fixated vertebrae moved slightly less (mean = -0.08 degrees ; SD = 2.55) as did the vertebrae two levels above fixation (mean = -0.11 degrees ; SD = 2.13). Movements of the vertebrae below the fixation and two levels below the fixation were also reduced (mean = -1.09 degrees ; SD = 2.07) and (mean = -0.65 degrees ; SD = 1.85) respectively. The results suggest the possibility of a three-point bending of the spinal column during fixation and symptom localization during fixation may be a product of soft tissue tension and/or pressure from the fixating fingers. Further research is necessary, including a design that allows consistency among all participants which is appropriately powered. PMID- 21655393 TI - The reliability of clinical judgments and criteria associated with mechanisms based classifications of pain in patients with low back pain disorders: a preliminary reliability study. AB - Mechanisms-based classifications of pain have been advocated for their potential to aid understanding of clinical presentations of pain and improve clinical outcomes. However, the reliability of mechanisms-based classifications of pain and the clinical criteria upon which such classifications are based are not known. The purpose of this investigation was to assess the inter- and intra examiner reliability of clinical judgments associated with: (i) mechanisms-based classifications of pain; and (ii) the identification and interpretation of individual symptoms and signs from a Delphi-derived expert consensus list of clinical criteria associated with mechanisms-based classifications of pain in patients with low back (+/-leg) pain disorders. The inter- and intra-examiner reliability of an examination protocol performed by two physiotherapists on two separate cohorts of 40 patients was assessed. Data were analysed using kappa and percentage of agreement values. Inter- and intra-examiner agreement associated with clinicians' mechanisms-based classifications of low back (+/-leg) pain was 'substantial' (kappa = 0.77; 95% confidence interval (CI): 0.57-0.96; % agreement = 87.5) and 'almost perfect' (kappa = 0.96; 95% CI: 0.92-1.00; % agreement = 92.5), respectively. Sixty-eight and 95% of items on the clinical criteria checklist demonstrated clinically acceptable (kappa ? 0.61 or % agreement ? 80%) inter- and intra-examiner reliability, respectively. The results of this study provide preliminary evidence supporting the reliability of clinical judgments associated with mechanisms-based classifications of pain in patients with low back (+/-leg) pain disorders. The reliability of mechanisms-based classifications of pain should be investigated using larger samples of patients and multiple independent examiners. PMID- 21655394 TI - The role and position of passive intervertebral motion assessment within clinical reasoning and decision-making in manual physical therapy: a qualitative interview study. AB - Passive intervertebral motion (PIVM) assessment is a characterizing skill of manual physical therapists (MPTs) and is important for judgments about impairments in spinal joint function. It is unknown as to why and how MPTs use this mobility testing of spinal motion segments within their clinical reasoning and decision-making. This qualitative study aimed to explore and understand the role and position of PIVM assessment within the manual diagnostic process. Eight semistructured individual interviews with expert MPTs and three subsequent group interviews using manual physical therapy consultation platforms were conducted. Line-by-line coding was performed on the transcribed data, and final main themes were identified from subcategories. Three researchers were involved in the analysis process. Four themes emerged from the data: contextuality, consistency, impairment orientedness, and subjectivity. These themes were interrelated and linked to concepts of professionalism and clinical reasoning. MPTs used PIVM assessment within a multidimensional, biopsychosocial framework incorporating clinical data relating to mechanical dysfunction as well as to personal factors while applying various clinical reasoning strategies. Interpretation of PIVM assessment and subsequent decisions on manipulative treatment were strongly rooted within practitioners' practical knowledge. This study has identified the specific role and position of PIVM assessment as related to other clinical findings within clinical reasoning and decision-making in manual physical therapy in The Netherlands. We recommend future research in manual diagnostics to account for the multivariable character of physical examination of the spine. PMID- 21655395 TI - Pharmacy students' test-taking motivation-effort on a low-stakes standardized test. AB - OBJECTIVE: To measure third-year pharmacy students' level of motivation while completing the Pharmacy Curriculum Outcomes Assessment (PCOA) administered as a low-stakes test to better understand use of the PCOA as a measure of student content knowledge. METHODS: Student motivation was manipulated through an incentive (ie, personal letter from the dean) and a process of statistical motivation filtering. Data were analyzed to determine any differences between the experimental and control groups in PCOA test performance, motivation to perform well, and test performance after filtering for low motivation-effort. RESULTS: Incentivizing students diminished the need for filtering PCOA scores for low effort. Where filtering was used, performance scores improved, providing a more realistic measure of aggregate student performance. CONCLUSIONS: To ensure that PCOA scores are an accurate reflection of student knowledge, incentivizing and/or filtering for low motivation-effort among pharmacy students should be considered fundamental best practice when the PCOA is administered as a low-stakes test. PMID- 21655396 TI - Clinical pharmacy consultations provided by American and Kenyan pharmacy students during an acute care advanced pharmacy practice experience. AB - OBJECTIVE: To compare the clinical consultations provided by American and Kenyan pharmacy students in an acute care setting in a developing country. METHODS: The documented pharmacy consultation recommendations made by American and Kenyan pharmacy students during patient care rounds on an advanced pharmacy practice experience at a referral hospital in Kenya were reviewed and classified according to type of intervention and therapeutic area. RESULTS: The Kenyan students documented more interventions than American students (16.7 vs. 12.0 interventions/day) and provided significantly more consultations regarding human immunodeficiency virus (HIV) and antibiotics. The top area of consultations provided by American students was cardiovascular diseases. CONCLUSIONS: American and Kenyan pharmacy students successfully providing clinical pharmacy consultations in a resource-constrained, acute-care practice setting suggests an important role for pharmacy students in the reconciliation of prescriber orders with medication administration records and in providing drug information. PMID- 21655397 TI - Assessment of pharmacy students' communication competence using the Roter Interaction Analysis System during objective structured clinical examinations. AB - OBJECTIVE: To determine the value of using the Roter Interaction Analysis System during objective structured clinical examinations (OSCEs) to assess pharmacy students' communication competence. METHODS: As pharmacy students completed a clinical OSCE involving an interview with a simulated patient, 3 experts used a global rating scale to assess students' overall performance in the interview, and both the student's and patient's languages were coded using the Roter Interaction Analysis System (RIAS). The coders recorded the number of utterances (ie, units of spoken language) in each RIAS category. Correlations between the raters' scores and the number and types of utterances were examined. RESULTS: There was a significant correlation between students' global rating scores on the OSCE and the number of utterances in the RIAS socio-emotional category but not the RIAS business category. CONCLUSIONS: The RIAS proved to be a useful tool for assessing the socio-emotional aspect of students' interview skills. PMID- 21655398 TI - A shared assignment to integrate pharmaceutics and pharmacy practice course concepts. AB - OBJECTIVE: To demonstrate for first-year pharmacy students the relevance of pharmaceutics course content to pharmacy practice by implementing a joint, integrated assignment in both courses and assessing its impact. DESIGN: Medication errors and patient safety issues relevant to ophthalmic and otic formulations were selected as the assignment topic. A homework assignment based on a mock court case involving a patient who was given an inappropriate formulation because of a pharmacist's medication error was given to students. The scenario was followed by essay and calculation questions linking physical pharmacy concepts with patient safety recommendations. ASSESSMENT: Students' average score on the crossover assignment was 88.7%. Minute papers completed before and after the assignment showed improvement in student learning. Students' scores on examination questions related to the assignment topic were significantly higher than the previous year's students' performance on similar questions. In a survey conducted at the end of the semester, 91% of students indicated that the assignment helped them relate the covered topics to future practice, and 98% agreed that the assignment emphasized the importance of the pharmaceutics in professional practice. CONCLUSION: A crossover assignment was an effective means of demonstrating the connection between specific pharmaceutics concepts and practice applications to pharmacy students. PMID- 21655399 TI - Refinement of strengths instruction in a pharmacy curriculum over eight years. AB - OBJECTIVE: To develop, refine, and integrate introductory-level strengths instruction within a doctor of pharmacy (PharmD) curriculum. DESIGN: Over 8 years, student pharmacists completed the StrengthsFinder assessment tool and identified their top 5 Signature Themes (talents). They then participated in either Web-based learning modules or live workshops designed to facilitate professional development. ASSESSMENT: Students preferred the live instruction over Web-based learning modules. Post-instruction evaluations demonstrated that students discussed their Signature Themes with peers, preceptors, and family members. Pharmacists working with students in strengths-related activities reported that the students applied the information in the practice setting. Both pharmacists and students recommended that this material be required for all students. CONCLUSIONS: Identifying a role in pharmacy that aligns with one's personal talents is critical for the success of pharmacy graduates. Strengths instruction is an important component of professional and career development, and can aid in identifying roles. PMID- 21655400 TI - Learning bridge tool to improve student learning, preceptor training, and faculty teamwork. AB - OBJECTIVES: To implement a Learning Bridge tool to improve educational outcomes for pharmacy students as well as for preceptors and faculty members. DESIGN: Pharmacy faculty members collaborated to write 9 case-based assignments that first-year pharmacy (P1) students worked with preceptors to complete while at experiential sites. ASSESSMENT: Students, faculty members, and preceptors were surveyed about their perceptions of the Learning Bridge process. As in our pilot study,(1) the Learning Bridge process promoted student learning. Additionally, the Learning Bridge assignments familiarized preceptors with the school's P1 curriculum and its content. Faculty teamwork also was increased through collaborating on the assignments. CONCLUSIONS: The Learning Bridge assignments provided a compelling learning environment and benefited students, preceptors, and faculty members. PMID- 21655401 TI - Murkiness in the channels of distribution of pharmaceuticals. PMID- 21655402 TI - Personalized medicine: are we preparing our students for the knowledge revolution? PMID- 21655403 TI - Medication therapy management training using case studies and the MirixaPro platform. AB - OBJECTIVE: To implement and assess a medication therapy management (MTM) training program for pharmacy students using the MirixaPro (Mirixa Corporation, Reston, VA) platform and case studies. DESIGN: Students received lectures introducing MTM and were given a demonstration of the MirixaPro platform. They were divided into teams and assigned cases and times to interview patients portrayed by faculty members. Using the MirixaPro system, students performed 2 comprehensive medication reviews during the semester, recording the patient's current medications, indications, side effects, allergies, health conditions, and laboratory test recommendations and developed a personal medication record and medication action plan. ASSESSMENT: Based on a rubric with a rating scale of 0 10, campus and distance pathway students received mean scores ranging from 6.3 7.4 for their performance on the second MTM exercise, an increase of 47%-54% over the first MTM exercise. In qualitative assessments, the majority of students believed that their confidence in providing MTM was enhanced by the activity, while faculty members recognized the advantage of using MirixaPro, which allowed students to experience what is required in processing a pharmacist led, billable MTM encounter. CONCLUSIONS: Use of the MirixaPro system and patient cases provides students with a "hands-on" experience that may encourage them to promote MTM during their APPEs and provide MTM services as practicing pharmacists. PMID- 21655404 TI - Professional technical standards in colleges and schools of pharmacy. AB - OBJECTIVE: To determine the prevalence, characteristics, and use of professional technical standards among colleges and schools of pharmacy accredited by the Accreditation Council for Pharmacy Education (ACPE). METHODS: The Web site of every college and school of pharmacy accredited by ACPE was searched to identify information regarding the availability, content, and use of technical standards and to obtain demographic information. RESULTS: Information was obtained from all of the 114 colleges and schools of pharmacy and 67 (59%) had technical standards in place. Common themes for technical standards were: observation; communication; motor; intellectual, conceptual, integrative and quantitative abilities; and behavioral and social attributes. Of those colleges and schools with technical standards, 61 (91%) had standards that addressed all 5 of these themes and 34 (51%) specified that the technical standards were used in their admission, progression, and graduation procedures. CONCLUSION: More than half of the colleges and schools of pharmacy examined in this study have technical standards; however, 41% have yet to develop and implement them. Colleges and schools of pharmacy looking for guidance in technical standards development could use the technical standards themes identified in this study. PMID- 21655405 TI - Assessment of the pharmacogenomics educational needs of pharmacists. AB - OBJECTIVES: To evaluate the self-perceived knowledge and confidence of inpatient and outpatient pharmacists in applying pharmacogenomics information to clinical practice. METHODS: A 19-question multiple-choice, electronic needs-assessment survey instrument was distributed to 480 inpatient and outpatient pharmacists in a large, academic, multi-campus healthcare system. RESULTS: The survey response rate was 64% (303). Most respondents (85%) agreed that pharmacists should be required to be knowledgeable about pharmacogenomics, and 65% agreed that pharmacists should be capable of providing information on the appropriate use of pharmacogenomics testing. Sixty-three percent felt they could not accurately apply the results of pharmacogenomics tests to drug-therapy selection, dosing, or monitoring. CONCLUSION: Pharmacists believe pharmacogenomics knowledge is important to the profession, but they lack the knowledge and self-confidence to act on the results of pharmacogenomics testing and may benefit from pharmacogenomics education. PMID- 21655406 TI - Liability and litigation risks for colleges and schools of pharmacy. AB - The potential for legal liability involving faculty members and students in higher education settings is a topic that warrants serious attention by administrators. Specific areas identified as high risk include dismissal of a faculty member, denial of tenure, misappropriation of grant-funding, intellectual property conflicts, Family and Medical Leave Act (FMLA) issues, sexual harassment, student suspension, disabilities, and student privacy issues. Examples of litigation in the higher-education setting are presented, along with a list of online resources for additional information. It is important for higher education administrators, faculty members, staff members, and students to recognize the currently accepted legal rights and responsibilities associated with these high-risk areas. PMID- 21655407 TI - Role-reversal exercise with Deaf Strong Hospital to teach communication competency and cultural awareness. AB - OBJECTIVE: To implement a role-reversal exercise to increase first-year pharmacy students' awareness of communication barriers in the health care setting, especially for deaf and hard-of-hearing patients. DESIGN: Volunteers from the local deaf community conducted Deaf Strong Hospital, a role-reversal exercise in which students were the "patients." Students navigated through a reception area, encounter with a physician, and having a prescription filled at a pharmacy without receiving or using any spoken language. ASSESSMENT: A debriefing session was held in which small groups of students had the opportunity to ask questions of a panel of deaf and hard-of-hearing volunteers. On a survey administered to assess students' learning, 97% agreed or strongly agreed that the experience would likely impact their attitudes and behavior in future interactions with patients who did not speak English. CONCLUSIONS: The role-reversal exercise was an effective method of teaching students that the delivery of health care is dependent on adequate communication between health care providers and the patient. PMID- 21655408 TI - Elective course in acute care using online learning and patient simulation. AB - OBJECTIVE: To enhance students' knowledge of and critical-thinking skills in the management of acutely ill patients using online independent learning partnered with high-fidelity patient simulation sessions. DESIGN: Students enrolled in the Acute Care Simulation watched 10 weekly Web-based video presentations on various critical care and advanced cardiovascular pharmacotherapy topics. After completing each online module, all students participated in groups in patient care simulation exercises in which they prepared a pharmacotherapeutic plan for the patient, recommended this plan to the patient's physician, and completed a debriefing session with the facilitator. ASSESSMENT: Students completed a pretest and posttest before and after each simulation exercise, as well as midterm and final evaluations and a satisfaction survey. Pharmacy students significantly improved their scores on 9 of the 10 tests (p <= 0.05). Students' performance on the final evaluation improved compared with performance on the midterm evaluation. Overall, students were satisfied with the unique dual approach to learning and enjoyed the realistic patient-care environment that the simulation laboratory provided. CONCLUSION: Participation in an elective course that combined self-directed Web-based learning and hands-on patient simulation exercises increased pharmacy students' knowledge and critical-thinking skills in acute care. PMID- 21655409 TI - Concept mapping to evaluate an undergraduate pharmacy curriculum. AB - OBJECTIVES: To explore a pharmacy school curriculum for opportunities for student engagement and to determine how these might shape student identity as pharmacists. METHODS: The learning aims and objectives and methods of assessment from the curriculum of a bachelor of pharmacy (BPharm) program were collected and a concept map was generated. The concept map was interpreted using Barnett and Coates' curricular domains of knowing, acting and being. RESULTS: The key concepts within the intended curriculum that were identified from the concept map were drugs, pharmacy, understanding, practice, and skills. Concepts such as patient and consumer, which would indicate a patient-centered approach to the curriculum, were limited. The main form of assessment used in the curriculum was multiple-choice and short-answer examinations. CONCLUSION: There was an emphasis in the curriculum on student acquisition of knowledge and this was reinforced by the use of theoretical examinations. The content of the curriculum was drug centered rather than patient-centered and the emergence of students' identity as pharmacists may be fragmented as a result. PMID- 21655410 TI - The role of colleges and schools of pharmacy in the advent of Healthy People 2020. AB - As the need for more experiential sites increases, colleges and schools of pharmacy should consider innovative and strategic approaches to expansion including adding programs that would address the target areas emphasized by Healthy People 2020. Healthy People 2020 encompasses the following areas: adolescent health, early and middle childhood, genomics, global health, health information technology, healthcare-associated infections, hearing and other sensory or communicating disorders (ear, nose, throat-voice, speech and language), weight status, older adults, quality of life and well-being, and social determinants of health. Academic leaders should consider what role exists for pharmacy practice in these areas and focus future program and curriculum development on Healthy People 2020 topic areas. PMID- 21655411 TI - Inclusion of black box warnings in the curriculum: a topic of global significance in patient care and management. PMID- 21655412 TI - Educational renaissance: a student's viewpoint. PMID- 21655413 TI - Clinical pharmacy education in China. PMID- 21655414 TI - Research and pharmaceutical progress. PMID- 21655415 TI - What can we do in our locality to acquaint the public with the service pharmacy renders? PMID- 21655416 TI - The lost art of the clinical examination: an overemphasis on clinical special tests. PMID- 21655417 TI - Studies of quality and impact in clinical diagnosis and decision-making. PMID- 21655418 TI - Lumbar instability: an evolving and challenging concept. AB - Identification and management of chronic lumbar spine instability is a clinical challenge for manual physical therapists. Chronic lumbar instability is presented as a term that can encompass two types of lumbar instability: mechanical (radiographic) and functional (clinical) instability (FLI). The components of mechanical and FLI are presented relative to the development of a physical therapy diagnosis and management. The purpose of this paper is to review the historical framework of chronic lumbar spine instability from a physical therapy perspective and to summarize current research relative to clinical diagnosis in physical therapy. PMID- 21655419 TI - Reproducibility of global three-dimensional motion during manual atlanto-axial rotation mobilization: an in vitro study. AB - The reproducibility of the three-dimensional (3D) kinematic aspects of motion coupling patterns during manual mobilizing techniques is still a debatable matter. The present in vitro study analysed segmental 3D motion of the atlanto axial joint during manual axial rotation mobilization. Twenty fresh frozen human cervical specimens were studied in a test-retest situation with two examiners. The specimens were manually mobilized using three different techniques: (1) a regional mobilization technique of the cervical spine; (2) a segmental mobilization technique of the atlas with manual fixation of the axis; and (3) a segmental mobilization of the atlas on the axis applying a locking technique. Segmental atlanto-axial kinematics was registered with a Zebris CMS-20 ultrasound based tracking system. The Euclidian norm was used as a representation of overall 3D motion. The results indicated good reproducibility (mean intraclass correlation coefficient, ICC: 0.87). Intraobserver reproducibility was slightly higher (mean ICC: 0.91; range: 0.76-0.99) than interobserver reproducibility (mean ICC: 0.85; range: 0.56-0.98) (P < 0.05). The total range of motion expressed as the Euclidean norm of 3D motion components was a parameter with good reproducibility in the study of segmental kinematics of manual atlanto-axial mobilization. Although previous studies have demonstrated poor inter-rater reliability of manual examination and mobilization of segmental motion components, the results of the present study shed a new and more positive light on the reproducibility of techniques for manual mobilization of the upper cervical spine. PMID- 21655420 TI - Evidence-based treatment for ankle injuries: a clinical perspective. AB - The most common ankle injuries are ankle sprain and ankle fracture. This review discusses treatments for ankle sprain (including the management of the acute sprain and chronic instability) and ankle fracture, using evidence from recent systematic reviews and randomized controlled trials. After ankle sprain, there is evidence for the use of functional support and non-steroidal anti-inflammatory drugs. There is weak evidence suggesting that the use of manual therapy may lead to positive short-term effects. Electro-physical agents do not appear to enhance outcomes and are not recommended. Exercise may reduce the occurrence of recurrent ankle sprains and may be effective in managing chronic ankle instability. After surgical fixation for ankle fracture, an early introduction of activity, administered via early weight-bearing or exercise during the immobilization period, may lead to better outcomes. However, the use of a brace or orthosis to enable exercise during the immobilization period may also lead to a higher rate of adverse events, suggesting that this treatment regimen needs to be applied judiciously. After the immobilization period, the focus of treatment for ankle fracture should be on a progressive exercise program. PMID- 21655421 TI - The effect of tibio-femoral traction mobilization on passive knee flexion motion impairment and pain: a case series. AB - The purpose of this case series was to explore the effects of tibio-femoral (TF) manual traction on pain and passive range of motion (PROM) in individuals with unilateral motion impairment and pain in knee flexion. Thirteen participants volunteered for the study. All participants received 6 minutes of TF traction mobilization applied at end-range passive knee flexion. PROM measurements were taken before the intervention and after 2, 4, and 6 minutes of TF joint traction. Pain was measured using a visual analog scale with the TF joint at rest, at end range passive knee flexion, during the application of joint traction, and immediately post-treatment. There were significant differences in PROM after 2 and 4 minutes of traction, with no significance noted after 4 minutes. A significant change in knee flexion of 25.9 degrees , which exceeded the MDC(95,) was found when comparing PROM measurements pre- to final intervention. While pain did not change significantly over time, pain levels did change significantly during each treatment session. Pain significantly increased when the participant's knee was passively flexed to end range; it was reduced, although not significantly, during traction mobilization; and it significantly decreased following traction. This case series supports TF joint traction as a means of stretching shortened articular and periarticular tissues without increasing reported levels of pain during or after treatment. In addition, this is the first study documenting the temporal aspects of treatment effectiveness in motion restoration. PMID- 21655422 TI - The efficacy of an integrated neuromuscular inhibition technique on upper trapezius trigger points in subjects with non-specific neck pain: a randomized controlled trial. AB - Currently, large levels of practice variability exist regarding the clinical deactivation of trigger points. Manual physical therapy has been identified as a potential means of resolving active trigger points; however, to date the ideal treatment approach has yet to be elucidated. The purpose of this clinical trial was to compare the effects of two manual treatment regimens on individuals with upper trapezius trigger points. Sixty patients, 19-38 years of age with non specific neck pain and upper trapezius trigger points, were randomized into one of two, 4 week physical therapy programs. One group received muscle energy techniques while the second group received an integrated neuromuscular inhibition technique (INIT) consisting of muscle energy techniques, ischemic compression, and strain-counterstrain (SCS). Outcomes including a visual analog pain scale (VAS), the neck disability index (NDI), and lateral cervical flexion range of motion (ROM) were collected at baseline, 2 and 4 weeks after the initiation of therapy. Results revealed large pre-post-effect sizes within the INIT group (Cohen's d = 0.97, 0.94 and 0.97). Additionally, significantly greater improvements in pain and neck disability and lateral cervical flexion ROM were detected in favor of the INIT group (0.29-0.57, 0.57-1.12 and 0.29-0.57) at a 95% CI respectively. The findings of this study indicate the potential benefit of an integrated approach in deactivating upper trapezius trigger points. Further research should be performed to investigate the long-term benefits of the current treatment approach. PMID- 21655423 TI - The development of a clinical decision making algorithm for detection of osteoporotic vertebral compression fracture or wedge deformity. AB - The clinical diagnosis of an osteoporotic vertebral compression fracture (OVCF) is challenging and requires detailed assessment using comprehensive imaging methods. Further complicating matter is that the clinical sequelae associated with OVCF typically involves asymptomatic findings and variable pain patterns. The purpose of this study was to identify clinical characteristics and assessment findings that were associated with a diagnosis of OVCF. The study evaluated routine clinical findings in over 1400 subjects seen at an adult spine surgery clinic for thoracolumbar spine-related conditions within the years 2005-2009. All patients underwent a standardized clinical examination that included a self report, observational, physical examination and imaging assessment. The diagnosis of OVCF was made after assessment of radiographic findings in sagittal alignment, vertebral body compression, and spinal canal dimensions. Data from the patient history and observational findings were then statistically analyzed and compared between those patients with a diagnosis of OVCF and those with an alternative diagnosis. Based on the results, a diagnostic support tool was created to predict the likelihood of OVCF. The most diagnostic combination included a cluster of: (1) age > 52 years; (2) no presence of leg pain; (3) body mass index ? 22; (4) does not exercise regularly; and (5) female gender. A finding of two of five positive tests or less demonstrated high sensitivity of 0.95 (95% CI = 0.83 0.99) and low negative likelihood ratio of 0.16 (95% CI = 0.04-0.51), providing moderate value to rule out OVCF. Four of five yielded a positive likelihood ratio (LR+) of 9.6 (95% CI = 3.7-14.9) providing moderate value in ruling in the diagnosis of OVCF. Further validation is necessary prospectively to determine the value of these findings on a disparate sample of patients in other unique environments. PMID- 21655424 TI - Is soft tissue massage an effective treatment for mechanical shoulder pain? A study protocol. AB - Very little research has been conducted into the effectiveness of soft tissue massage as an intervention for the treatment of mechanical shoulder pain. Studies that have been conducted suffer from methodological issues, poor long-term follow up and have conflicting results. The aim of this study, therefore, is to provide treating clinicians with improved evidence regarding the effectiveness of soft tissue massage for shoulder pain of local mechanical origin. Participants referred to the trial with mechanical shoulder pain will be assessed for range of motion, functional ability, and pain by a blinded assessor. Participants will then be randomly allocated to either an exercise-only group or an exercise and soft tissue massage group. Both groups will receive seven treatment sessions from a physical therapist over a period of 4 weeks. One week after the cessation of treatment, all participants will be reassessed by the same blinded assessor. Three months after cessation of treatment, subjects will again be reassessed. The primary outcome will be pain measured on a visual analogue scale (VAS) 1 week following the cessation of treatment. Secondary analyses will be pain at 3 months, the descriptive and present pain index sections of the short form McGill pain questionnaire, patient specific functional scale, and percentage improvement in pain scores and range of motion at 1 week following the cessation of treatment and at 3 month follow-up. Analysis of data will be carried out by a statistician who is blinded to group membership. Primary analyses will by intention-to-treat. PMID- 21655425 TI - To prevent neurodegeneration: HDAC6 uses different strategies for different challenges. AB - Neurodegenerative diseases are characterized by progressive dysfunction and death of neurons in specific areas of the nervous system. Loss of neurons is often associated with multiple stresses such as abnormal aggregation of misfolded proteins, deficiency of protein degradation system, mitochondrial dysfunction and excessive oxidative products. HDAC6 has recently been suggested to be an integral factor that copes with these stresses. In this mini-review, we summarize our current understanding of how HDAC6 promotes inclusion formation, facilitates autophagic degradation of protein aggregates and dysfunctional mitochondria. Finally, the possibility for HDAC6 to be a potential preventional and therapeutical target of some neurodegenerative diseases is put forward. PMID- 21655426 TI - Emerging roles for MAP kinases in agrin signaling. AB - Information between neurons and the target cells they innervate passes through sites of functional contact called synapses. How synapses form and are altered by sensory or cognitive experience is central to understand nervous system function. Studies of synapse formation and plasticity have concentrated on a few "model" synapses. The vertebrate neuromuscular junction (NMJ), the synapse between a motoneuron in the spinal cord and a skeletal muscle fiber, is one such model synapse. The extracellular matrix proteoglycan agrin plays an essential organizing role at the NMJ. Agrin is also present at some synapses in the brain and in other organs in the periphery, but its function outside the NMJ is unclear. The core signaling pathway for agrin at the NMJ, which is still incompletely defined, includes molecules specifically involved in this cascade and molecules used in other signaling pathways in many cells. Mitogen-activated protein kinases (MAPKs) are evolutionarily conserved components of intracellular signaling modules that control a myriad of cellular processes. This article reviews emerging evidence that suggests that MAPKs are involved in agrin signaling at the NMJ and in the putative functions of agrin in the formation of a subset of synapses in the brain. PMID- 21655427 TI - The Nucleolinus: A disappearing, forgotten and (maybe) misnamed organelle. AB - It is common knowledge that many of the cell components we study today were discovered more than a century ago. Some have been renamed due to a newer understanding of their physiology or composition, and in some cases the old terminology is abandoned. However, it is unusual to find a structure that has not been renamed but simply forgotten. This appears to be the case for the nucleolinus, discovered at least 150 years ago and studied by Agassiz, Haekel, Montgomery and others until it virtually dropped from the literature in the early 1970s. The nucleolinus was thought to have a role in cell division, but with little knowledge of its composition and no molecular markers (until recently) available for its study, we do not know if the nucleolinus is a ubiquitous structure or an antiquated descriptor. This brief article relates most of what we know about the nucleolinus and where to find more information. Our growing knowledge concerning the role of the closely allied nucleolus in cell cycle regulation suggests that renewed study of the nucleolinus will yield important information about the biogenesis and evolution of the cell division apparatus. PMID- 21655429 TI - Indispensable roles of mammalian Cbl family proteins as negative regulators of protein tyrosine kinase signaling: Insights from in vivo models. AB - All higher eukaryotes utilize protein tyrosine kinases (PTKs) as molecular switches to control a variety of cellular signals. Notably, many PTKs have been identified as proto-oncogenes whose aberrant expression, mutations or co-option by pathogens can lead to human malignancies. Thus, it is obvious that PTK functions must be precisely regulated in order to maintain homeostasis of an organism. Investigations over the past fifteen years have revealed that members of the Cbl family proteins can serve as negative regulators of PTK signaling, and biochemical and cell biological studies have unraveled the mechanistic basis of this regulation. Yet, it is only recently that the field has begun to appreciate the real significance of this novel regulatory apparatus in shaping PTK-mediated signaling in organismic contexts and in human diseases. Here, we discuss recent progress in murine models that are beginning to provide insights into the critical roles of Cbl proteins in physiological pathways, with important implications in understanding how aberrations of Cbl proteins contribute to oncogenesis. PMID- 21655430 TI - The society of our "out of Africa" ancestors (I): The migrant warriors that colonized the world. AB - The "out of Africa" hypothesis proposes that a small group of Homo sapiens left Africa 80,000 years ago, spreading the mitochondrial haplotype L3 throughout the Earth.1-10 Little effort has been made to try to reconstruct the society and culture of the tribe that left Africa to populate the rest of the world.1 Here, I find that hunter-gatherers that belong to mitochondrial haplotypes L0, L1 and L2 do not have a culture of ritualized fights. In contrast to this, almost all L3 derived hunter-gatherers have a more belligerent culture that includes ritualized fights such as wrestling, stick fights or headhunting expeditions. This appears to be independent of their environment because ritualized fights occur in all climates, from the tropics to the arctic. There is also a correlation between mitochondrial haplotypes and warfare propensity or the use of murder and suicide to resolve conflicts. The data implicate that the original human population outside Africa is descended from only two closely related sub-branches that practiced ritual fighting and had a higher propensity towards warfare and the use of murder for conflict resolution. This warfare culture may have given the out of Africa migrants a competitive advantage to colonize the world. But it could also have crucially influenced the subsequent history of The Earth. In the future, it would be interesting to see how we could further reconstruct the society and culture of the "Out of Africa Tribe." PMID- 21655428 TI - Evolution of glycosaminoglycans: Comparative biochemical study. AB - Glycosaminoglycans, a major component of the extracellular matrix molecules in animal tissues, play important roles in various physiological events. Glycosaminoglycans are found in not only vertebrates but also many invertebrates, implying a conserved function in the animal kingdom. Here, we discuss the analysis of glycosaminoglycans in 11 invertebrate phyla focusing on structure as well as physiological functions elucidated in model organisms. Various sulfated structures of heparan sulfate are widely distributed from very primitive organisms to humans, indicating an involvement in fundamental biological processes. By contrast, chondroitin/dermatan sulfate from lower organisms is limited in its structural complexity and often associated with a particular function. The presence of hyaluronic acid outside of vertebrates has been reported only in a mollusk. PMID- 21655431 TI - The expression of SPARC in human tumors is consistent with its role during cell competition. AB - In Drosophila, the elimination of viable but suboptimal cells is mediated by cell competition, ensuring that these cells do not accumulate during development. In addition, certain genes such as the Drosophila homologue of human c-myc (dmyc) are able to transform cells into supercompetitors, which eliminate neighboring wild-type cells by apoptosis and overproliferate leaving total cell numbers unchanged. We have recently identified Drosophila SPARC as an early marker transcriptionally upregulated in loser cells that provides a transient protection by inhibiting caspase activation in outcompeted cells. Here, we explore whether the expression of SPARC in human tumors is consistent with a role for cell competition during human cancer and find that, consistent with the existence of competitive interactions between cancer and normal cells, SPARC is upregulated at the tumor-host boundaries in several types of human cancer. PMID- 21655432 TI - Studies of novel interactions between Nck and VAV SH3 domains. AB - Following T-cell antigen receptor (TCR) engagement, a multi-molecular complex consisting of SLP-76, Nck and VAV1 is formed and recruited to the T-cell antigen presenting-cell (APC) interaction site. This complex is crucial for the regulation of the actin machinery. The molecules Nck (an adaptor) and VAV1 (a GEF for small G-proteins) were previously shown to bind SLP-76. Using high-resolution imaging techniques, together with gene silencing and biochemical analysis, we studied the dynamics of this signaling complex formation. We recently showed that VAV1 and Nck can bind each other independently of SLP-76. This direct interaction is mediated by the binding of the Nck C-terminal SH3 domain and the VAV1 N terminal SH3 domain. This interaction contributes to the cooperative nature of the complex formation. This observation was confirmed in functional studies: disruption of the Nck-VAV1 interaction strongly inhibited actin polymerization. Here, we show that Nck-VAV1 interaction is not required for Ca(2+) mobilization, since a point mutation in the VAV1 N-terminal SH3 domain, which prevents the direct interaction between Nck and VAV1, has no effect on Ca(2+) flux and minimal effects on ZAP-70, LAT or PLCgamma1 phosphorylation. PMID- 21655433 TI - Yeast dynamin implicated in endocytic scission and the disassembly of endocytic components. AB - The yeast dynamin-related GTPase Vps1 has been implicated in a range of cellular functions including vacuolar protein sorting, protein trafficking, organization of peroxisome and endocytosis.1,2 Vps1 is present at endocytic sites and may be directly involved in endocytic vesicle invagination through its membrane tubulating activity. Here, evidence supporting the functional link between Vps1 and the yeast amphiphysin Rvs167 in vesicle invagination is discussed. Though the disassembly of endocytic factors from pinched-off endocytic vesicles appears to be tightly regulated in a spatiotemporal manner, we are far from having complete understanding of the underlying mechanism. In this study, we provide evidence that Vps1 plays a role in the uncoating of endocytic proteins from post internalized vesicles, based on the observation of a quick disassembly of two endocytic coat proteins Ent1 and Ent2 in cells lacking Vps1. PMID- 21655434 TI - How does a protein with dual mitotic spindle and extracellular matrix receptor functions affect tumor susceptibility and progression? AB - The mechanisms responsible for the oncogenic effects of the hyaluronan (HA) receptor and mitotic spindle binding protein, RHAMM, are poorly understood. On one hand, extracellular RHAMM interacts with HA and cellsurface receptors such as CD44 to coordinately activate the MAPK/ERK1,2 pathway, thus contributing to the spread and proliferation of tumor cells. On the other hand, intracellular RHAMM decorates mitotic spindles and is necessary for spindle formation and progression through G2/M and overexpression or loss of RHAMM can result in multipole spindles and chromosome missegregation. The deregulation of these intracellular functions could lead to genomic instability and fuel tumor progression. This suggests that both extracellular and intracellular RHAMM can promote tumor progression. Intracellular RHAMM can bind directly to ERK1 to form complexes with ERK2, MEK1 and ERK1,2 substrates, and we present a model whereby RHAMM's function is as a scaffold protein, controlling activation and targeting of ERK1,2 to specific substrates. PMID- 21655435 TI - Calcium signaling components in the human pathogen: Cryptococcus neoformans. AB - Calcium signaling through calmodulin and the phosphatase calcineurin are required for key events of the biology of the human pathogen Cryptococcus neoformans, including mating, morphogenesis, growth at 37 degrees C and virulence. In a recent work we described the functional characterization of a new component of this calcium signaling network: the vacuolar calcium exchanger Vcx1. This transporter is involved in calcium tolerance and virulence in C. neoformans. Two other uncharacterized calcium transporters which are putative orthologs of Saccharomyces cerevisiae PMC1 (a vacuolar calcium ATPase) and PMR1 (a Golgi calcium ATPase) are also functional in C. neoformans. No ortholog of CRZ1, the target of calcineurin in other fungi, has been identified in C. neoformans, indicating a high complexity in cryptococcal calcium-related pathways. Future studies are necessary for the complete understanding of calcium signaling regulation in C. neoformans. PMID- 21655436 TI - Simplify, simplify: Lifestyle and compact genome of the body louse provide a unique functional genomics opportunity. AB - The body louse, with its recently sequenced genome, is now primed to serve as a powerful model organism for addressing fundamental questions relating to how insects interact with their environment. One characteristic of the body louse that facilitates this research is the size of its genome-the smallest insect genome sequenced to date. This diminutive genome must nonetheless control an organism that senses and responds to its environment, reacting to threats of corporal and genomic integrity. Additionally, the body louse transmits several important human diseases compared to its very close relative, the head louse, which does not. Therefore, these two organisms comprise an excellent model system for studying molecular mechanisms associated with vector competence. To understand more fully the development of vector/pathogen interactions, we have developed an in vitro bioassay system and determined that the body louse genome appears to contain the genes necessary for RNAi. The body louse will therefore be useful for determining the set of conditions permissive to the evolution of vector competence. PMID- 21655437 TI - Nature and nurture: A step towards investigating their interactions in the wild. AB - The debate about the relative importance of nature versus nurture has been around for decades, but despite this, there has been very little evidence about how these might in fact interact to drive evolution in the wild. Recently, the identification of a comparable methodology for analyzing both genetic and social effects of phenotypic variation revealed that fitness variation in a free-living population of dolphin was driven by a strong social and genetic interaction. This study not only provides evidence that nature and nurture do interact to drive phenotypic evolution but also represents a step towards partitioning the effects of genetic, social, environmental factors and their multiway interactions to better understand phenotypic evolution in the wild. PMID- 21655438 TI - Legionella pneumophila infection is enhanced in a RacH-null mutant of Dictyostelium. AB - Recently we reported that Dictyostelium cells ingest Legionella pneumophila by macropinocytosis, whereas other bacteria, such as Escherichia coli, Mycobacterium avium, Neisseria meningitidis or Salmonella typhimurium, are taken up by phagocytosis.1 In contrast to phagocytosis, macropinocytosis is partially inhibited by PI3K or PTEN inactivation, whereas both processes are sensitive to PLC inhibition. Independently from reduced uptake, L. pneumophila proliferates more efficiently in PI3K-null than in wild-type cells. PI3K inactivation also neutralizes resistance to infection conferred by constitutively expressing the endo-lysosomal iron transporter Nramp1. We have shown this to be due to altered recruitment of the V-H(+) ATPase, but not Nramp1, in the Legionella-containing vacuole (LCV) early during infection.1 As further evidence for impaired LCV acidification we examine here the effects of disrupting the small G protein RacH on Legionella infection. PMID- 21655439 TI - A new twist on plasma membrane repair. AB - Cells in multicellular organisms are under constant mechanical stress, and often the plasma membrane (PM) is compromised. Fortunately, there is a vigorous repair mechanism that rapidly (within seconds) reseals the wound site by fusion with an internal membrane patch. Downstream events, remodeling of the injury site and forming replacement PM, must be carried out quickly (within minutes) if a cell is to survive multiple sequential injuries. The repertoire of proteins required to repair breaks (the PM repairome) is one of the major unknowns in this area of research. As an initial approach to defining the PM repairome, a cell surface biotinylation protocol was developed to identify intracellular proteins that become exposed at the site of reversible PM injury. It is likely that at least some of these proteins are important mediators of repair. These initial studies led to a surprising finding, namely the identification of some nuclear and endoplasmic reticulum resident proteins transiently exposed at the surface of cells that ultimately recovered from PM damage. Thus, in reversible mechanical damage to the PM, underlying cellular structures may also be injured, and will also require mechanisms for repair. Other proteins at wound sites were previously identified docking partners for pathogenic bacteria and viruses (vimentin and nucleolin), or found to be upregulated and exposed on the surface of cancer cells (nucleolin and nucleophosmin-1). The new information from these studies may lead to development of novel antimicrobial and antineoplastic drugs. PMID- 21655440 TI - The hematopoietic stem cell polarization and migration: A dynamic link between RhoA signaling pathway, microtubule network and ganglioside-based membrane microdomains. AB - The polarization and migration of eukaryotic cells are fundamental processes for the development and maintenance of a tissue. These aspects gain especial interest when it comes to stem and progenitor cells in the way that their manipulation might open new avenues in regenerative therapy. In recent years, novel biological facets of migrating hematopoietic stem cells were revealed by several groups, including ours. Among these features, the polarization of their membranous (proteins and lipids) and cytoplasmic constituents, which leads to the formation of a specialized sub-cellular structure located at the rear pole-the uropod-has gained increasing interest. In a new study we have demonstrated that such phenomena involve a coordinated mechanism between Rho GTPase signaling and the microtubule network. Specifically, our results based on the use of synthetic inhibitors and RNA interference suggest that the activity of RhoA and its effector ROCK I is indispensable for cell polarization and the active reorganization of microtubules that are required for migration. PMID- 21655441 TI - Revisiting the ERK/Src cortactin switch. AB - The filamentous (F)-actin regulatory protein cortactin plays an important role in tumor cell movement and invasion by promoting and stabilizing actin related protein (Arp)2/3-mediated actin networks necessary for plasma membrane protrusion. Cortactin is a substrate for ERK1/2 and Src family kinases, with previous in vitro findings demonstrating ERK1/2 phosphorylation of cortactin as a positive and Src phosphorylation as a negative regulatory event in promoting Arp2/3 activation through neuronal Wiskott Aldrich Syndrome protein (N-WASp). Evidence for this regulatory cortactin "switch" in cells has been hampered due to the lack of phosphorylation-specific antibodies that recognize ERK1/2 phosphorylated cortactin. Our findings with phosphorylation-specific antibodies against these ERK1/2 sites (pS405 and pS418) indicate that cortactin can be co phosphorylated at 405/418 and tyrosine residues targeted by Src family tyrosine kinases. These results indicate that the ERK/Src cortactin switch is not the sole mechanism by which ERK1/2 and tyrosine phosphorylation events regulate cortactin function in cell systems. PMID- 21655442 TI - Linking LIMK1 deficiency to hyperacusis and progressive hearing loss in individuals with Williams syndrome. AB - Williams syndrome (a.k.a. Williams-Beuren Syndrome) is a multisystem disorder caused by the hemizygous deletion of a 1.6 Mb region at 7q11.23 encompassing about 26 genes, including that encoding LIM kinase 1 (LIMK1). Individuals with Williams Syndrome manifest hyperacusis and progressive hearing loss, and hyperacusis early onset suggests that it could be associated with one of the deleted genes. Based on our results about the critical role of LIM kinases in the regulation of the motile responses of cochlear outer hair cells (OHC) and cochlear amplification, we propose here that a reduced expression of LIMK1 in OHC would be the major underlying cause of the hyperacusis and progressive hearing loss observed in patients with Williams Syndrome. Moreover, we propose a novel model of gain-control for cochlear amplification based on LIMK-mediated regulation of OHC's slow motility. PMID- 21655443 TI - Readdressing synaptic pruning theory for schizophrenia: Combination of brain imaging and cell biology. AB - Disturbance in the synapse has been suggested in the pathology of schizophrenia, especially through examination of autopsied brains from patients with the disease. Nonetheless, it has been unclear whether and how such disturbance is associated with the onset and progression of the disease in young adulthood. Some studies with magnetic resonance spectroscopy (MRS) have suggested that overpruning of dendritic spines may occur in the prodromal and early stages of schizophrenia. In addition, our recent study indicates that DISC1, a promising risk factor for schizophrenia, has a crucial role in the maintenance of the dendritic spine in association with activation of the NMDA-type glutamate receptor.1 Disturbance of spine maintenance can be linked to aberrant synaptic pruning during postnatal brain maturation. Biological studies with genetic models may provide us with an opportunity to validate experimentally the synaptic pruning theory for schizophrenia. An integrative strategy of brain imaging and cell biology may be a promising approach to address a key biological question for mental illnesses. PMID- 21655444 TI - On the water lapping of felines and the water running of lizards: A unifying physical perspective. AB - We consider two biological phenomena taking place at the air-water interface: the water lapping of felines and the water running of lizards. Although seemingly disparate motions, we show that they are intimately linked by their underlying hydrodynamics and belong to a broader class of processes called Froude mechanisms. We describe how both felines and lizards exploit inertia to defeat gravity, and discuss water lapping and water running in the broader context of water exit and water entry, respectively. PMID- 21655445 TI - Experience-dependent plasticity in visual cortex: Dendritic spines and visual responsiveness. AB - To determine the relationship between synaptic structural changes and cortical function, we recently published a study where we imaged dendritic spines using two-photon in vivo microscopy while monitoring network activity in the visual cortex using intrinsic signal imaging. By manipulating cortical activity levels by dark-rearing mice and re-exposing them to light, we found a close inverse correspondence between dendritic spine structural dynamics and visually evoked cortical function on a timescale of days. Light exposure following dark-rearing slowly increased visually evoked cortical processing and stabilized dendritic spine structure, an effect partially mimicked by diazepam injections in dark reared mice suggesting that this slow recovery is mediated by inhibitory signaling. Surprisingly, very brief (2 h) periods of light exposure led to an NMDA-dependent rapid reorganization of cortical networks with an early emergence of visually-evoked cortical activation and enhanced spine dynamics. Here we further explore the relationship between spine morphology and visual function. PMID- 21655446 TI - A role for microglia in synaptic plasticity? AB - Remodeling of brain circuits, including the formation, modification and elimination of synaptic structures, occurs throughout life as animals adapt to their environment. Until very recently, known mechanisms for experience-dependent synaptic plasticity had placed neurons and their structural interactions with astrocytes in the spotlight. However microglia, the immune cells of the brain, are very active even in the absence of pathological insults and their processes periodically contact dendritic spines and axon terminals in vivo.1-3 This intriguing behavior prompted us to explore, using electron microscopy and two photon in vivo imaging in the primary visual cortex of juvenile mice, a possible role for quiescent microglia in the modification of synaptic structures.4 Our work uncovered subtle changes in the behavior of microglia during manipulations of visual experience including regulation of perisynaptic extracellular spaces, contact with subsets of structurally dynamic and transient dendritic spines, and phagocytic engulfment of intact synapses. Based on these results, here we further discuss three means of synapse modification or elimination that could be mediated by microglia in the context of normal experience-dependent plasticity. PMID- 21655447 TI - Eph signaling regulates gliotransmitter release. AB - Astrocytes have been recently identified as important components of the tripartite synaptic complex. There is growing evidence that astrocytes regulate synaptic functions, in part, through the release of gliotransmitters. In a recent study, we have demonstrated that ephrinB3 could stimulate astrocytic release of D serine through activation of EphB3 and EphA4 receptors. Eph receptors regulate this response by inducing the dephosphorylation of PKCalpha and activation of serine racemase to convert L-serine to D-serine. We now investigated whether ephrinB3 would increase the release of glutamine, which is also synthesized from serine and play important roles in regulating synaptic responses. Using HPLC, we observed an enhanced release of L/D-serine and glutamine from cultured astrocytes following ephrinB1 and/or ephrinB3 stimulation. In the absence of EphB3 and EphA4, ephrinB3-enhanced release of L/D-serine and glutamine was not observed. These studies provide evidence that Eph receptors may play broader roles in regulating gliotransmitter release from astrocytes, which could have important implications on synaptic transmission, and learning and memory processes. PMID- 21655448 TI - Working memory for braille is shaped by experience. AB - Tactile working memory was found to be more developed in completely blind (congenital and acquired) than in semi-sighted subjects, indicating that experience plays a crucial role in shaping working memory. A model of working memory, adapted from the classical model proposed by Baddeley and Hitch1 and Baddeley2 is presented where the connection strengths of a highly cross-modal network are altered through experience. PMID- 21655449 TI - Systems biomechanics of centrosome positioning: A conserved complexity. AB - Positioning of centrosomes within cells determines the directionality of cell division, as well as directionality of cellular activities in the interphase. This brief review focuses on similarities (and differences) of centrosome positioning during early divisions in the Caenorhabditis embryo and during the interaction of T lymphocytes with other cells in the course of immune response. In the study of the two phenomena, a synergy of experimentation and numerical mechanical analysis has recently been achieved. The picture that emerges from these studies is one in which simple physical forces under the constraints of the basic cell structure lead to complex, "life-like" mechanical behavior. This behavior includes instability of equilibria, irreversibility of structural transitions and multidimensional, multiperiodic oscillations. This new picture of cell mechanics may form an interesting paradigm for future research. PMID- 21655450 TI - Prestin and high frequency hearing in mammals. AB - Recent evidence indicates that the evolution of ultrasonic hearing in echolocating bats and cetaceans has involved adaptive amino acid replacements in the cochlear gene prestin. A substantial number of these changes have occurred in parallel in both groups, suggesting that particular amino acid residues might confer greater auditory sensitivity to high frequencies. Here we review some of these findings, and consider whether similar signatures of prestin protein sequence evolution also occur in mammals that possess high frequency hearing for passive localization and conversely, whether this gene has undergone less change in mammals that lack high frequency hearing. PMID- 21655451 TI - Vacuolar trafficking and Candida albicans pathogenesis. AB - The vacuole is likely to play a variety of roles in supporting host colonization and infection by pathogenic species of fungi. In the human pathogen Candida albicans, the vacuole undergoes dynamic morphological shifts during the production of the tissue invasive hyphal form, and this organelle is required for virulence. Recent efforts in my lab have focused on defining which vacuolar trafficking pathways are required for C. albicans hyphal growth and pathogenesis. Our results indicate that there are several distinct trafficking routes between the Golgi apparatus and vacuole. However, there is a large degree of functional overlap between each with respect to their roles in hyphal growth and virulence. Herein we consider these results and propose that during hyphal growth, specific trafficking routes maybe less important than the aggregate vacuolar trafficking capacity. PMID- 21655452 TI - Dissecting protein interactions during cytokinesis. AB - Appropriate assembly and constriction of the acto-myosin based contractile ring is essential for the final separation of the two daughter cells in mitosis. This is orchestrated by the small GTPase Rho as well as convergent signals from the prior events of mitosis. Contractile ring assembly requires the physical interaction of structural proteins like the microtubules of the central spindle, motor proteins and Rho activators. These and the interaction of newly localised proteins downstream of active Rho are essential for stability of the contractile ring and its proper constriction. Here, we discuss our recent findings that reveal a complex network of protein interactions during the early stages of cytokinesis. This includes evidence for a direct interaction between Polo Kinase and RacGAP50C as well as unpublished data suggesting other interactions of interest within the contractile ring. PMID- 21655453 TI - The relationship between lower extremity closed kinetic chain strength & sagittal plane landing kinematics in female athletes. AB - BACKGROUND: Female athletes continue to injure their anterior cruciate ligaments at a greater rate than males in comparable sports. During landing activities, females exhibit several different kinematic and kinetic traits when compared to their male counterparts including decreased knee flexion angles as well as decreased lower extremity (LE) strength. While open kinetic chain strength measures have not been related to landing kinematics, given the closer replication of movement patterns that occur during closed kinetic chain (CKC) activity, it is possible that lower extremity strength if measured in this fashion will be related to landing kinematics. PURPOSE: To determine if unilateral isometric CKC lower extremity (LE) strength was related to sagittal plane tibiofemoral kinematics during a single leg landing task in competitive female athletes. We hypothesized females who demonstrated lesser CKC LE strength would exhibit decreased sagittal plane angles during landing. METHODS: 20 competitive female athletes (age = 16.0 +/- 1.8 yrs; height = 166.5 +/- 8.3 cm; weight = 59.7 +/- 10.2 kg) completed CKC LE strength testing followed by 5 unilateral drop landings on the dominant LE during one test session at an outpatient physical therapy clinic. Closed kinetic chain LE strength was measured on a computerized leg press with an integrated load cell while sagittal plane tibiofemoral kinematics were quantified with an electrogoniometer. RESULTS: No significant relationships between absolute or normalized isometric CKC strength and sagittal plane landing kinematics were identified. CONCLUSIONS: Closed kinetic chain lower extremity isometric strength tested at 25 degrees of knee flexion is not related to sagittal plane landing kinematics in adolescent competitive female athletes. LEVELS OF EVIDENCE: Analytic, Observational. PMID- 21655454 TI - Physical therapy intervention for a former power lifter after arthroscopic microfracture procedure for grade iv glenohumeral chondral defects. AB - BACKGROUND: Power lifting places the shoulder complex at risk for injury. Microfracture is a relatively new procedure for chondral defects of the glenohumeral joint and is not well described in the literature. OBJECTIVES: The purpose of this case report is to describe the post-operative rehabilitation used with a power lifter who underwent a microfracture procedure to address glenoid and humeral chondral defects, debridement of type I superior labral anterior posterior lesion, and a subacromial decompression. CASE DESCRIPTION: The patient was a 46 year-old male who was evaluated nine weeks status-post arthroscopic microfracture procedure for glenoid and humeral chondral defects, debridement of superior labral anterior-posterior (SLAP) lesion, and subacromial decompression. Rehabilitation consisted of postural education, manual therapy, rotator cuff and scapular strengthening, dynamic stabilization, weightbearing exercises, and weight training over nine weeks (24 sessions). Lifting modifications were addressed. OUTCOMES: Results of the QuickDASH indicate that activities of daily living (ADLs), work, and sports modules all improved significantly, and the patient was able to return to recreational power lifting with limited discomfort or restrictions. DISCUSSION: A structured post-operative physical therapy treatment program allowed this patient to return to recreational power lifting while restoring independent function for work-related activities and ADLs. PMID- 21655456 TI - Utilization of sonography and a stress device in the assessment of partial tears of the ulnar collateral ligament in throwers. AB - The non-invasive assessment of medial elbow pain in throwers can be challenging. Valgus stress transmitted to the elbow during the late cocking and acceleration phases of the throwing motion can result in injury to the medial ligamentous structures of the elbow, bony surfaces, and common tendon of the forearm flexors. The utilization of musculoskeletal (MSK) ultrasound in combination with the Telos Stress Device (TSD) (Austin & Associates Fallston, MD) can be an alternate quick assessment when radiography is not be available. PMID- 21655455 TI - The role and implementation of eccentric training in athletic rehabilitation: tendinopathy, hamstring strains, and acl reconstruction. AB - The benefits and proposed physiological mechanisms of eccentric exercise have previously been elucidated and eccentric exercise has been used for well over seventy years. Traditionally, eccentric exercise has been used as a regular component of strength training. However, in recent years, eccentric exercise has been used in rehabilitation to manage a host of conditions. Of note, there is evidence in the literature supporting eccentric exercise for the rehabilitation of tendinopathies, muscle strains, and in anterior cruciate ligament (ACL) rehabilitation. The purpose of this Clinical Commentary is to discuss the physiologic mechanism of eccentric exercise as well as to review the literature regarding the utilization of eccentric training during rehabilitation. A secondary purpose of this commentary is to provide the reader with a framework for the implementation of eccentric training during rehabilitation of tendinopathies, muscle strains, and after ACL reconstruction. PMID- 21655457 TI - Shoulder muscle imbalance and subacromial impingement syndrome in overhead athletes. AB - Subacromial impingement is a frequent and painful condition among athletes, particularly those involved in overhead sports such as baseball and swimming. There are generally two types of subacromial impingement: structural and functional. While structural impingement is caused by a physical loss of area in the subacromial space due to bony growth or inflammation, functional impingement is a relative loss of subacromial space secondary to altered scapulohumeral mechanics resulting from glenohumeral instability and muscle imbalance. The purpose of this review is to describe the role of muscle imbalance in subacromial impingement in order to guide sports physical therapy evaluation and interventions. PMID- 21655458 TI - Invited clinical suggestion: "on the sidelines"- emergency care basics for the sports physical therapist. AB - An integral part of the responsibilities of the sports physical therapist is emergency care that is provided on the sidelines and courtside during athletic events. Often times, the sports physical therapist is the "most medical" individual present at athletic events, especially at high school, middle school, and club level events. The sports physical therapist is looked upon to provide appropriate care in the event of an injury to or sudden illness of an athlete, or in the event of an unexpected medical emergency that arises in members of the coaching staff, officials, and fans. PMID- 21655460 TI - Skin tumors in childhood. AB - BACKGROUND: Dermatologists, paediatricians, and general practitioners are often consulted by worried parents for the evaluation of a cutaneous tumor. METHODS: Selective literature review. RESULTS: Only 1-2% of skin tumors excised in children turn out to be malignant when examined histologically. Warning signs of malignancy include rapid growth, firm consistency, diameter exceeding 3 cm, ulceration, a non-movable mass, and presence in the neonatal period. The more common malignant skin tumors in adults-basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma-are very rare in childhood. Congenital melanocytic nevi and sebaceous nevi bear a lower malignant potential than previously believed; nevertheless, their excision is often indicated. A Spitz nevus can mimic a melanoma both clinically and histologically. Some benign skin tumors of childhood tend to regress spontaneously within a few years but may cause complications at particular locations and when multiple. For infantile hemangiomas requiring systemic treatment because of imminent obstruction or ulceration, propranolol seems to have a far more favorable risk-benefit ratio than corticosteroids. CONCLUSION: Physicians need specialized knowledge in order to decide whether a skin tumor in a child should be excised, non-surgically treated, or further evaluated, or whether it can be safely left untreated because of the likelihood of spontaneous remission. PMID- 21655459 TI - Bariatric surgery. AB - BACKGROUND: Bariatric surgery has increased in numbers, but the treatment of morbid obesity in Germany still needs improvement. The new interdisciplinary S3 guideline provides information on the appropriate indications, procedures, techniques, and follow-up care. METHODS: Systematic review of the literature, classification of the evidence, graded recommendations, and interdisciplinary consensus-building. RESULTS: Bariatric surgery is a component of the multimodal treatment of obesity, which consists of multidisciplinary evaluation and diagnosis, conservative and surgical treatments, and lifelong follow-up care. The current guideline extends the BMI-based spectrum of indications that was previously proposed (BMI greater than 40 kg/m(2), or greater than 35 kg/m(2)with secondary diseases) by eliminating age limits, as well as most of the contraindications. A prerequisite for surgery is that a structured, conservative weight-loss program has failed or is considered to be futile. Type 2 diabetes is now considered an independent indication under clinical study conditions for patients whose BMI is less than 35 kg/m(2) (metabolic surgery). The standard laparoscopic techniques are gastric banding, gastric bypass, sleeve gastrectomy, and biliopancreatic diversion. The choice of procedure is based on knowledge of the results, long-term effects, complications, and individual circumstances. Structured lifelong follow-up should be provided and should, in particular, prevent metabolic deficiencies. CONCLUSION: The guideline contains recommendations based on the scientific evidence and on a consensus of experts from multiple disciplines about the indications for bariatric surgery, the choice of procedure, techniques, and follow-up care. It should be broadly implemented to improve patient care in this field. PMID- 21655461 TI - Correspondence (letter to the editor): Bioimpedance analysis. PMID- 21655462 TI - Correspondence (letter to the editor): Not hungry today. PMID- 21655463 TI - Correspondence (letter to the editor): Treatment principles for decubitus ulcers. PMID- 21655464 TI - Correspondence (reply): In Reply. PMID- 21655465 TI - Correspondence (letter to the editor): Computed tomography was omitted. PMID- 21655466 TI - Correspondence (letter to the editor): Incidence of jaw necrosis is markedly higher. PMID- 21655467 TI - Correspondence (letter to the editor): Nuclear medicine offers therapeutic options for multiple bone metastases. PMID- 21655468 TI - Correspondence (letter to the editor): Additional remarks. PMID- 21655469 TI - Correspondence (reply): In reply. PMID- 21655471 TI - Ocean-bottom krill sex. AB - For the first time the entire sequence of the mating behaviour of Antarctic krill (Euphausia superba) in the wild is captured on underwater video. This footage also provides evidence that mating can take place near the seafloor at depths of 400-700 m. This observation challenges the generally accepted concept of the pelagic lifestyle of krill. The mating behaviour observed most closely resembles the mating behaviour reported for a decapod shrimp (Penaeus). The implications of the new observation are also discussed. PMID- 21655470 TI - Combined stress effect of pH and temperature narrows the niche width of flagellates in acid mining lakes. AB - Strains of the green alga Chlamydomonas acidophila and two chrysomonads, Ochromonas spp., isolated from each of two similar acid mining lakes (AMLs) with extremely low pH (~2.6) were investigated to consider a possible synergistic stress effect of low pH and unfavourable temperature. We measured flagellate growth rates over a combination of four pH (2.5, 3.5, 5.0 and 7.0) and three temperatures (10, 17.5 and 25 degrees C) in the laboratory. Our hypothesis was that, under highly acidic conditions (pH <3), an obligate acidophil species (C. acidophila) would be less sensitive to the combined stress of pH and temperature than acidotolerant species (Ochromonas spp.). We expected that the difference of the fundamental vs. realized pH niche would be greater in the latter. Another chrysomonad, Poterioochromonas malhamensis strain DS, served as a reference for a closely related neutrophil species. Surprisingly, C. acidophila did not survive temperatures >27 degrees C. The lowest temperature tested reduced growth rates of all three chrysomonad strains significantly. Since all chrysomonads were tolerant to high temperature, growth rate of one Ochromonas spp. strain was measured exemplarily at 35 degrees C. Only at this high temperature was the realized pH niche significantly narrowed. We also recorded significant intraspecific differences within the C. acidophila strains from the two AML, illustrating that the niche width of a species is broader than that of individual clones. PMID- 21655472 TI - [Sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer]. AB - The indication of neoadjuvant chemotherapy has been recently extended; it is now applied not only in locally advanced breast cancer but in primarily resecable tumours as well, in order to promote breast conservation. Based on recent clinical results, the reconsideration of traditional lymph node dissection in axillary staging is timely in patients receiving neoadjuvant chemotherapy. Precise axillary staging needs surgical removal of lymph nodes. Based on prospective randomised trials, sentinel lymph node biopsy appears to be appropriate for axillary staging even in tumours requiring neoadjuvant treatment. The extended indication of sentinel lymph node biopsy raises several questions and problems. In the present paper the authors review the results and possible limitations of sentinel lymph node biopsy in relation to neoadjuvant chemotherapy. PMID- 21655473 TI - [Conformal stereotactic radiosurgery therapy: plan evaluation methods and results]. AB - The purpose of our study was the objective evaluation of micro-multileaf collimator (mMLC)-based stereotactic radiosurgery treatment plans. Forty-seven patients, 71 lesions received static beam conformal stereotactic radiosurgery treatment in our institute between November 2005 and June 2008. Target volume and organs at risk were outlined on a MRI-CT image fusion basis. BrainSCAN 5.31 system (BrainLAB AG, Heimstetten, Germany) was used for treatment planning, Elekta Presice TS linear accelerator (Elekta Oncology Systems Ltd, Crawley, UK) and BrainLAB m3 mMLC were used for treatment delivery. An invasive head frame, mounted to the treatment table, was used with four screws for patient head fixation. Treatment plans were analysed with objective parameters, such as conformal index (COIN), homogeneity index (HI), coverage index (CI) and healthy tissue relative overdose factor (HTOF) tools. x2 tests were performed between COIN, HI and the geometrical parameters of the target volume (lesion volume - LV, lesion-organ distance - LOD, lesion deformity index - LDI). Mean value of COIN, HI, HTOF and CI was 0.52 (SD 0.13), 1.16 (SD 0.1), 0.88 (SD 0.53), and 0.94 (SD 0.11), respectively. COIN significantly correlated with (p<0.001 in all three cases), while HI was independent of LV, LOD, LDI (p=0.94; 0.14 and 0.72). COIN is similar, HTOF is less than data from the literature. According to our results geometrical parameters of the target volume (size, location, deformation) significantly influence the COIN, but they have no effect on HI. PMID- 21655474 TI - [Main treatment and preventive measures for hand-foot syndrome, a dermatologic side effect of cancer therapy]. AB - Hand-foot syndrome is a highly unpleasant adverse reaction caused by treatment protocols containing capecitabine (an orally administered drug), docetaxel, liposomal doxorubicin infusions or continuously infused 5-fluorouracil. It affects the skin of the palms and soles manifesting characteristic symptoms like erythema, inflammation, dysesthesia, pain, thickening, desquamation and cracking of the skin that may progress to cause wounds and ulceration, negatively influencing quality of life, psychological state and belief in recovery, which often result in the need of permanent or temporary interruption of the oncologic treatment and are potential sources of danger to the completion of the therapy. Adequate provision of the syndrome is of particular importance since a decline in adherence due to adverse events endangers precise maintenance of the self sufficient oral treatment at home. Early recognition of symptoms, regular oncologic checkups and patient education on how to prevent or soothe the unpleasant skin toxicities could ensure a more successful treatment. PMID- 21655475 TI - [Effect of KRAS mutation status on the efficiency of Avastin therapy of colorectal cancer]. AB - Anti-angiogenic therapy became a standard care of advanced colorectal cancer. Since the most frequent genetic alteration of colorectal cancer is KRAS mutation we have analyzed its effect on the efficacy of Avastin treatment. Since 2008 we have determined the KRAS status of 575 patients with colorectal carcinoma using a sensitive screening method and sequencing. In our database the frequency of KRAS mutation in colorectal cancer is 37% (codon 12: 31% followed by codon 13: 6%). We have examined the effect of KRAS status on the efficacy of Avastin treatment in 35 patients. Progression-free survival of KRAS mutant patients was highly similar to that of wild-type patients using log-rank test (9.2+/-5.5 months versus 8.7+/ 5.7 months, respectively). Our data support those observations that KRAS status of colorectal cancer does not interfere with the efficacy of Avastin treatment. PMID- 21655476 TI - [Examination of ERCC1 expression in lung cancer patients treated with platinum based chemotherapy]. AB - Platinum-based chemotherapies are widely used in the treatment of lung cancer. However, little is known about their effect in the expression of certain tissue biomarkers. We have studied the ERCC1 (excision repair cross-complementation group 1) expression in tissue samples of patients treated with neoadjuvant chemotherapy. Fifty lung cancer tissue blocks of 25 patients (15 males, 10 females) were studied. They included 25 bronchoscopic biopsies (14 squamous cell carcinomas and 11 adenocarcinomas) together with their corresponding surgical biopsies after neoadjuvant chemotherapy. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues to study the expression of ERCC1. Staining scores (0-300) were calculated by multiplying the percentage of positive tumor cells (0-100) by the staining intensity (0-3). All but one bronchosopic squamous cell carcinoma tissues (13/14) expressed ERCC1. Four of these cases became negative after neoadjuvant therapy, and in 8 cases the level of expression decreased. In the adenocarcinoma group all but one bronchosopic tissues (10/11) expressed ERCC1. Six of these cases became negative after neoadjuvant therapy, and in 4 cases the level of expression decreased. Comparison of staining scores before and after chemotherapy revealed more pronounced decrease in adenocarcinomas and in female patients. There was no newly expressed ERCC1 positive case in the surgical biopsy group. The results of the present study suggest that platinum-based chemotherapy affects the expression of tissue biomarker (ERCC1) which may have predictive value, and probably induces a selection of tumor cells with more aggressive phenotype. This knowledge might be of importance when designing treatment protocols for non-small cell lung cancer patients. PMID- 21655477 TI - [Complex assessment of late side effects affecting quality of life - the "Debrecen model"]. AB - As the outcome of childhood cancer improved substantially during the last 3 decades, the attitude of pediatric oncology has changed from "cure at any cost" to "cure at least cost". We investigated factors affecting quality of life in long-term survivors of childhood cancer in the in- and outpatient clinics of the Department of Pediatric Hematology-oncology, Institute of Pediatrics, Medical and Health Science Center, Debrecen. As a part of a comprehensive follow-up care program, we focused our attention on nephrotoxicity, osteoporosis and on cardiovascular morbidity. For long-term survivors of childhood cancer sensitive and cost-effective diagnostic algorithms were developed that can help in guiding secondary and tertiary prevention programs, in addition to assessing accurately the condition of patients. We found that anti-cancer treatments, including some of the supportive interventions, have adverse effects on glomerular (10%) and tubular functions (37%), impair the balance of bone resorption and formation (69%) and increase the frequency of cardiovascular risk factors (62%) in a significant proportion of patients. Our data confirm and extend the findings of other investigators and cooperative groups. In conclusion, we consider it important that the treatment plans of high-risk patients with cancer should be aimed at preserving the anticancer potential of therapy, without enhancing the frequency and severity of complications. The presented "Debrecen model" may help in achieving this goal and in increasing quality of life of long-term survivors of childhood cancer. PMID- 21655478 TI - A leg to stand on. AB - Learning about mental health at medical school was all about lists. I scribbled lists down the margins of my lecture pads: the DSM-IV criteria for depression and schizophrenia, the side effects of the atypical antipsychotics, the assessment of suicide risk. Lists can be vital in recognising the conditions that need treatment to prevent significant morbidity. In some cases, the right treatment can be lifesaving. However, in the messy mix that is general practice, lists are only part of the equation. In my practice I see many patients who are distressed by psychological symptoms that don't meet the DSM-IV criteria for a specific diagnosis. In these cases, the real challenge is to find ways to help the patient find meaning and a way through the mess. PMID- 21655479 TI - Antidepressant use. AB - The recent 2009-2010 National Prescribing Service (NPS) Evaluation Report(1) used Pharmaceutical Benefits Scheme (PBS) prescribing data to examine antidepressant prescribing. The report stated that general practitioner antidepressant prescribing in 2007-2009 was lower than expected due to NPS interventions. This article tests this statement using 12 years of nationally representative BEACH data, which includes data on antidepressants prescribed by GPs - not just those subsidised through the PBS. PMID- 21655480 TI - Mental health risk assessment - a guide for GPs. AB - BACKGROUND Risk assessment of patients in general practice is a challenging area of clinical practice. Competing interests of managing patient wishes, consideration of duty to warn others and invoking the Mental Health Act while practising in a medicolegally accountable manner can be difficult. OBJECTIVE This article summarises the risk assessment of patients with possible mental disorders and provides suggestions regarding measures that may be undertaken to manage risk in psychiatric emergencies. DISCUSSION The evidence of effectiveness for risk assessment interventions in acute settings is limited. While it is not possible for general practitioners to predict the future, and particularly to predict fatal outcomes, they can be expected to meet a standard of care that identifies those at risk and provide an acceptable clinical response. PMID- 21655481 TI - Anxiety disorders - assessment and management in general practice. AB - BACKGROUND: Anxiety is a normal physiological response to a threat. Anxiety disorders occur when this normal physiological response is associated with high levels of autonomic arousal, erroneous cognitions and dysfunctional coping strategies. Anxiety disorders are highly prevalent and present commonly to general practice. Anxiety disorders are often comorbid with other psychiatric and medical disorders and may be associated with significant morbidity. OBJECTIVE: This article describes the diagnosis, assessment and management of anxiety disorders in the general practice setting. DISCUSSION: Assessment in patients presenting with anxiety symptoms involves excluding a medical cause, identifying features of specific anxiety disorders as well as other coexisting psychiatric disorders, and assessing the degree of distress. Management options include psychoeducation, psychological treatments (particularly cognitive behaviour therapy) and pharmacological treatments. Patients with a diagnosis of an anxiety disorder can access Medicare funded psychological care under a number of Australian government initiatives. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors are the first line pharmacological agents used to treat anxiety disorders. Regular review is vital to monitor for clinical improvement and more complex presentations may require specialist psychological or psychiatric referral. PMID- 21655482 TI - Managing borderline personality disorder and substance use - an integrated approach. AB - BACKGROUND: Although substance use is a common feature of borderline personality disorder, regular use is associated with greater levels of psychosocial impairment, psychopathology, self harm and suicidal behaviour and leads to poorer treatment outcomes. Management of co-occurring substance use disorder and borderline personality disorder within primary care is further compounded by negative attitudes and practices in responding to people with these conditions, which can lead to a fractured patient-doctor relationship. OBJECTIVE: This article provides an overview of how the general practitioner can provide effective support for patients with co-occurring borderline personality disorder and substance use disorder, including approaches to assessment and treatment, the therapeutic relationship, referral pathways and managing risk and chronic suicidality. DISCUSSION: Despite the complexities associated with this population, GPs are ideally placed to engage patients with co-occurring borderline personality disorder and substance use disorder in a long term therapeutic relationship, while also ensuring timely referral to other key services and health professionals. To provide the most effective responses to this patient group, GPs need to understand borderline personality disorder and its relationship to substance use, develop an 'explanatory framework' for challenging behaviours, implement mechanisms for reflective practice to manage negative countertransference, as well as learn skills to respond adequately to behaviours which jeopardise treatment retention. PMID- 21655483 TI - Anxiety and depression - online resources and management tools. AB - BACKGROUND: There are significant unmet needs for psychological interventions for anxiety and depression in the population. e-health resources complement existing services by providing high quality information, symptom prevention, management interventions and peer support. OBJECTIVE: This article discusses e-health anxiety and depression resources offered by Australian providers and the ways in which general practitioners can assist their patients in accessing the diverse range of available resources. DISCUSSION: After appropriate diagnostic assessment, and as an adjunct to treatment according to best evidence based practice, GPs may consider referring patients to online information, support and assessment sites and/or prevention or treatment programs. People experiencing anxiety and depression are particularly likely to seek information online and may also value peer support online. There is now good evidence that symptom prevention and management programs can be effective in adults. Evaluation of programs for children and adolescents has also been encouraging. Current and future research will clarify the role of delivery factors such as therapist support that may influence effectiveness in clinical settings. PMID- 21655484 TI - Urodynamics. AB - Urodynamics is the study of lower urinary tract function and how this relates to a patient's urinary symptoms. The aim is to reproduce the patient's lower urinary tract symptoms to provide a pathophysiological explanation and to guide treatment. This article, and the accompanying patient information, focus particularly on invasive urodynamic studies. PMID- 21655485 TI - Patient information - urodynamic study. AB - A urodynamic study checks how your bladder works by taking pressure readings using computerised equipment. 'Fluoroscopic' means that X-rays are taken at the same time to give an outline of your bladder and urethra (the tube that allows urine to pass from the bladder to the outside). PMID- 21655486 TI - Bennett fracture dislocation - review and management. AB - BACKGROUND: Bennett fracture dislocation is an intra-articular fracture of the base of the first metacarpal with resultant dislocation of the first carpometacarpal joint. The fracture is unstable, and with inadequate treatment leads to osteoarthritis, weakness and/or loss of function of the first carpometacarpal joint. OBJECTIVE: This article reviews the current literature on Bennett fracture and describes the clinical assessment and management of a Bennett fracture. DISCUSSION: Bennett fractures usually result from falling on an extended or abducted thumb or an impact onto a clenched fist. The patient presents with pain and loss of function of the first carpometacarpal joint. Management can involve closed reduction, with or without percutaneous Kirschner wire fixation, or open reduction and internal fixation, with adequate reduction and the maintenance of reduction being the key to a successful outcome. Due to the difficulty of management it is recommended that patients be referred to a specialist hand surgeon. PMID- 21655487 TI - Combination antidepressants - use by GPs and psychiatrists. AB - BACKGROUND: Current treatment of depression fails to achieve remission in 50% of patients. Combinations of two antidepressants are used by some Australian psychiatrists. OBJECTIVE: This article investigates the pros and cons of combination antidepressant therapy and provides suggestions for when to consider their use, which combinations to choose, and how to introduce combination antidepressant therapies. DISCUSSION: Combining two antidepressants is a controversial strategy, with supporters and critics arguing its efficacy and safety from opposing perspectives. The use of combination antidepressant therapies may facilitate remission from depression. However, there is limited evidence supporting these treatments, and safety concerns are often cited. There is some support for combination therapies in selected cases from international bodies. After considering risks and benefits on a case-by-case basis, careful use of selected combination antidepressant therapy may be one of a range of effective treatments for some individuals suffering from depression. PMID- 21655488 TI - Women who smoke - A review of the evidence. AB - BACKGROUND: Women who smoke are at significantly greater risk of developing a smoking related disease than men. They are also at risk of pregnancy related complications due to smoking and have more difficulty quitting. There are important gender differences in smoking behaviour that have implications for the quitting process. Advice to female smokers should take these factors into account and support should be tailored to their needs. OBJECTIVE: This article presents a summary of the evidence and a range of gender specific strategies that general practitioners can use to optimise the support they give to female smokers. DISCUSSION: Women may need more intensive behavioural and pharmacological support when quitting. Particular emphasis should be placed on addressing stress, social support, smoking cues and concerns about weight gain. Nicotine replacement therapy is less effective in women. However, it is still useful if used in adequate doses and can be used in pregnancy if the woman is unlikely to quit without it. Varenicline and bupropion are not approved in pregnancy or in lactation. PMID- 21655489 TI - Ruffled wound suturing - closing wounds with sides of unequal lengths. AB - Wounds that have sides of unequal length can be closed using a simple traditional dressmaker's 'ruffle pattern'. This technique has the potential to reduce the need to correct 'dog ears' (standing cones), by excising Burrow triangles. PMID- 21655490 TI - Research on a shoestring. AB - The recent reaction from the scientific community to the proposed $400 million cut to the National Health and Medical Research Council (NHMRC) budget highlights the importance of adequate funding for research. While there has been significant growth in research dollars in recent years, as a percentage of gross domestic product it has remained the same for over a decade. PMID- 21655491 TI - Patient initiated aggression - prevalence and impact for general practice staff. AB - BACKGROUND: Patient initiated aggression toward general practice staff can cause distress among staff, however, it is unknown how frequently practice staff experience patient aggression in the workplace. The aim of this study is to determine the national prevalence of patient aggression toward general practice staff. METHOD: A clustered cross sectional survey involving general practice staff working in Australia. RESULTS: A questionnaire was posted to 1109 general practices nationally and 217 questionnaires were completed and returned (19.6% response rate). It was found that verbal aggression is commonly experienced by practice staff, particularly receptionists, whereas physical aggression is infrequent. Staff working in larger practices experience more verbal aggression and property damage or theft and it was reported that verbal aggression has a greater impact on staff wellbeing than physical aggression. DISCUSSION: This study provides some national evidence of the prevalence of patient aggression toward general practice staff. This may inform the development of policy and procedures. PMID- 21655492 TI - Folic acid in pregnancy - is there a link with childhood asthma or wheeze? AB - BACKGROUND: Folic acid supplementation has an established role in early pregnancy for preventing neural tube defects. However, there is controversy over a possible link between late pregnancy folic acid supplementation and childhood asthma. OBJECTIVE: To review the evidence exploring the association between maternal folate exposure in pregnancy and childhood asthma or wheeze. RESULTS: Four relevant observational studies were identified. Two found statistically significant associations between childhood asthma and late (but not early) pregnancy maternal folic acid exposure. Another found a statistically significant association between childhood wheeze and early (but not late) pregnancy maternal folic acid exposure. A fourth study found little association between maternal dietary folate in pregnancy and infantile wheeze. DISCUSSION: The currently available evidence regarding an association between folate in pregnancy and childhood asthma or wheeze is conflicting. We offer suggestions for discussing the potential risk with patients and recommend further research on this subject be conducted. PMID- 21655493 TI - Response rates in GP surveys - trialling two recruitment strategies. AB - BACKGROUND: This study aimed to examine the efficacy of two strategies for improving general practitioner response to a survey. A secondary aim was to assess GPs' self reported preferred mode of survey administration. METHODS: This study aimed to examine the efficacy of two strategies for improving general practitioner response to a survey. A secondary aim was to assess GPs' self reported preferred mode of survey administration. RESULTS: Of the 1666 GPs sampled, 52 were ineligible and 500 completed the survey. The response rates obtained in the trial of standard research group letterhead invitations alone (25.8%) versus division of general practice cover letter (32.5%) were not statistically significantly different; nor were the response rates obtained in the trial of a telephone reminder call. When asked about preferred mode of survey administration, 81.1% of respondents nominated mailed survey. DISCUSSION: The study failed to identify strategies to improve GP participation in the survey. This survey found no basis for supporting electronic GPs surveys. PMID- 21655494 TI - Electronic care plans and medicolegal liability. AB - BACKGROUND: Government policy encourages the use of care plans in general practice, and developments in information technology have the potential to facilitate their use via a shared electronic care plan. Sharing a comprehensive set of patient data raises privacy issues and questions about the nature and extent of potential liability. METHODS: A round table discussion was held with participants purposively selected for expertise in their fields. RESULTS: Consensus stressed the privacy dangers inherent in the creation of a shared electronic care plan accessible by multiple treating professionals and a private sector intermediary information technology provider, and the difficulties in ensuring appropriate informed consent is provided by patients. DISCUSSION: As the use of shared electronic care plans increases in Australia, new legal and ethical issues may emerge which need to be understood and addressed if general practitioners and other healthcare team members are to be able to participate with confidence. PMID- 21655495 TI - Recommending vaccination - general practice intervention with new parents. AB - BACKGROUND: Parents can be the source of vaccine preventable diseases that their children contract. The vaccination status of parents may not be readily available, and uptake rates are affected by factors such as complexity of vaccination schedules, personal perception of risks, and physician recommendation. METHODS: Parents at eight general practices in North Queensland had immunisation histories recorded and vaccine recommendations made when they brought in their infants for vaccination. They were followed up by practice nurses after 2 months. This article describes parental immunisation status at eight general practices and examines whether parents in these clinics acted on recommendations for vaccination. RESULTS: Vaccination was recommended for 66.1% of parents. Of these parents, 53% complied, resulting in improved up-to-date vaccination status from 33.9-68.9% (p<0.0001). DISCUSSION: Taking an immunisation history from parents and recommending specific vaccinations to them is likely to be a worthwhile intervention to add to general practice consultations for childhood vaccinations. Trialling this intervention in a broader cross section of general practices would be a useful next step. PMID- 21655496 TI - Explaining the unexplainable - crafting explanatory frameworks for medically unexplained symptoms. AB - BACKGROUND: Patients with multiple medically unexplained symptoms are common in general practice. Comorbid depression, anxiety, substance abuse and significant psychosocial stressors are common. It can be challenging to find a balance between excluding and treating organic causes and overinvestigating and overtreating. OBJECTIVE: This article provides the general practitioner with a suggested framework for explaining multiple medically unexplained symptoms to patients. DISCUSSION: An adequate explanation of the problem is important. General practitioners can use a number of explanatory models, including reassurance, somatisation and narrative techniques. Sometimes a solution to a specific problem is available and may involve referral to other health professionals. In many cases the more important management strategy may be to provide supportive care by being with the sufferer and acknowledging the suffering, without succumbing to the urge to fix the problem. General practitioners have a unique role in supporting patients who cope with symptoms, but without a clear medical diagnosis. PMID- 21655497 TI - How to complete a death certificate - a guide for GPs. AB - This article discusses some questions that frequently arise in general practice with regard to the completion of death certificates. PMID- 21655498 TI - Emergency management of acute on chronic liver disease. AB - Chronic liver disease is becoming more common in the UK. There has been much media coverage due to recent change in licensing laws and celebrity figures suffering from cirrhosis. This review highlights the common complications of cirrhosis that frequently present to the acute physician, focussing on initial presentation and subsequent management, based on the current best available evidence. PMID- 21655499 TI - Management of acute complications associated with sickle cell disease. AB - Sickle cell disease is the commonest haemoglobinopathy within the United Kingdom. Although the majority of patients will present to hospitals within major cities, this is not invariably the case. It is therefore important that all physicians on acute medical take are familiar with the acute management of sickle cell disease. This review encompasses the initial management which is subdivided into analgesia, investigations and supportive care. In addition the more severe complications of sickle cell, including the acute chest syndrome and stroke are covered. It should be remembered that close collaboration is required with the haematology department, particularly in those patients with respiratory distress or stroke, so that prompt arrangements can be made if exchange transfusion is required. PMID- 21655500 TI - Psoas abscess: diagnosis and treatment. AB - Psoas abscess is an uncommon presentation on the acute medical take. However recognition and appropriate treatment is essential. This review is designed to highlight the clinical features, microbiology, diagnostic tests and treatment for this condition. In order to illustrate some of the pitfalls and complexities in the management of psoas abscess we have included a case history of a patient who was recently treated in our department. PMID- 21655501 TI - Cerebrospinal Fluid analysis in Suspected Subarachnoid Haemorrhage. AB - Aneurysmal subarachnoid haemorrhage (SAH) is an acute life-threatening neurological disorder. A delay in diagnosis can lead to substantial and avoidable morbidity and mortality. It is important to identify patients with SAH promptly, to enable specialist referral to neurosurgical centres. This review aims to provide an up-to-date practical guide concerning the interpretation of spinal fluid results in patients with suspected SAH. PMID- 21655502 TI - Picture quiz. AB - A 38 year old male presented with worsening breathlessness and cough for 6 months duration. He was treated in the community with salbutamol and steroid inhaler by GP for suspected asthma but with no benefit. He presented to the emergency department complaining of further worsening breathlessness. His initial ECG (Figure 1) was abnormal. Subsequent CT scan of the chest was arranged (Figure 2, 3). PMID- 21655503 TI - Spontaneous splenic rupture in a patient with pneumonia and sepsis. AB - We present the case of a patient who presented with evidence of pneumonia, sepsis and anaemia but no significant abdominal signs. A routine abdominal ultrasound scan revealed evidence of spontaneous splenic rupture. He underwent splenectomy but passed away subsequently from respiratory complications. The many associations of spontaneous splenic rupture are discussed. The diagnosis should be considered in any patient presenting with shock and non-specific abdominal signs and in those with pre-existing conditions known to cause splenomegaly. PMID- 21655504 TI - A challenging case of malignant hypercalcaemia. AB - The investigation and management of patients presenting with hypercalcaemia is not always straightforward. We describe the case of a middleaged man presenting with severe symptomatic hypercalcaemia. The difficulties encountered here - in striving for biochemical and symptom control, and in establishing a definite diagnosis - are fortunately rare. The case illustrates the range of options in the treatment of severe hypercalcaemia, and highlights the use of haemodialysis in treatmentresistant cases. PMID- 21655505 TI - Abstracts from the Society for Acute Medicine: Spring meeting. AB - We have successfully been running with a Consultant presence in day-time (0900 1700) in the admissions area for a number of years. The recent NCEPOD report - an Acute Problem, criticised the lack of Consultant input into care of patients being transferred to Critical care areas out of hours. The DoH Hospital at Night project has suggested extending the normal working day into the twilight shift. PMID- 21655506 TI - Cardiac Arrhythmias - Part II: Broad Complex Tachycardia. AB - The acute management of the patient presenting with a broad complex tachycardia is a daunting clinical challenge. A broad complex tachycardia may be ventricular or supraventricular in origin and the ability to interpret correctly the 12-lead electrocardiogram is of critical importance in this differentiation. Broad complex tachycardia should be assumed to be ventricular in origin unless there is compelling clinical and electrocardiographic evidence to the contrary. This article focuses on the immediate diagnosis and management of broad complex tachycardia. In view of the broadening indications for implantation of cardioverterdefibrillator devices (ICD) in the management of ventricular arrhythmias, an approach to the ICD patient presenting to the accident and emergency department with recurrent device discharges is discussed. PMID- 21655507 TI - Pyrexia of unknown origin. AB - Classical pyrexia of unknown origin (PUO), defined as fever of >38 degrees C on several occasions for greater than three weeks despite investigation in hospital (>3 days) or out of hospital (>2 visits), is an uncommon but challenging problem. The incidence and aetiology vary according to the geographic region, the age structure of the population, and the immune status of the patient; alternative definitions of PUO exist for immune compromised individuals. Preliminary investigations should be determined by detailed history and repeated examination. Biopsy of abnormal tissues should be performed early. If uncertainty persists, abdominal computerised tomography (CT), radiolabeled white cell scans, and the Duke endocarditis criteria carry the highest diagnostic yield. Blind bone marrow biopsy is probably only useful in immunocompromised patients. PMID- 21655508 TI - Non-invasive ventilation for acute respiratory failure. AB - Non-invasive ventilation has become an increasingly utilised tool for the treatment of acute respiratory failure. Potential benefits include a decreased incidence of intubation, duration of hospital stay and mortality. Non-invasive ventilation is also being used more and more outside the intensive care environment. Successful use of non invasive ventilation involves knowledge of its indications, contraindications and limitations, and appropriate patient selection. This article reviews these issues as well as the practical application of non invasive ventilation in the acute setting. PMID- 21655509 TI - Acute urinary tract infections. AB - Urinary tract infections remain a significant cause of morbidity throughout the globe. Proper understanding of the disease is extremely important for appropriate management. Recent studies have helped to define the population groups at risk for these infections, as well as the most cost-effective management strategies. This article will discuss aspects of initial diagnosis and subsequent management of different high risk groups. PMID- 21655510 TI - Picture Quiz: An unusual cause of headache. AB - A sixty-six year old lady was admitted after describing two 'vacant' episodes with collapse. She had also complained of chronic fronto-occipital headache and more than 10kg weight loss over the preceding three month period. She denied any gastrointestinal, respiratory or cardiac symptoms. She was a non-smoker and did not drink alcohol regularly. She had a past history of hypertension and hypothyroidism for which she was taking ramipril and thyroxine. On examination she appeared cachexic, but no other abnormality was detected. PMID- 21655511 TI - Cellulitis or charcot neuropathy in diabetes? AB - Cellulitis of the lower limb is a common presentation in patients with diabetes. We report a case illustrating how Charcot neuropathy can be overlooked because of its resemblance to cellulitis. PMID- 21655512 TI - Sudden Hemiplegia in a young patient. AB - Stroke is more common in older patients; when it occurs in younger persons the causes may be slightly different. If adequately investigated, a cause can be ascertained in significant proportion of younger patients with stroke. Dissection of the internal carotid artery is an important cause of stroke in this age group and probably accounts for about 20% of cases. An association with elevated plasma homocysteine has been previously reported. We report a case of spontaneous internal carotid artery dissection associated with raised plasma homocysteine in a twenty-two year old, previously healthy man. PMID- 21655513 TI - The Evolving Role of the Acute Assessment Unit - from inpatient to outpatient care. AB - Acute Assessment Units (AAUs) have been developed to meet the demand for emergency care. Traditionally, AAUs have been an admission route to secondary care but the role is now evolving to assessment. AAUs are complex and have many interactions both in hospitals and the community. The effective functioning of an AAU requires excellent clinical leadership, appropriate facilities, timely access to diagnostics and input from the multi-disciplinary team. Increasingly, AAUs will have to develop services which are not dependent on using hospital beds. A variety of emergency medical presentations can, with the appropriate resources, be delivered in an out-patient setting. PMID- 21655514 TI - Picture Quiz: An unusual cause of headache - Answers. AB - Leptomenigeal Carcinomatosis (LC) affects approximately 5% of patients with cancer, either as a presenting sign or as a late complication Improvements in neuro imaging and increased awareness of the condition have led to the condition being diagnosed with increasing frequency. LC is thought to result from the multifocal seeding of malignant cells via the cerebro spinal fluid (CSF). PMID- 21655515 TI - Acute Abdominal Pain for the General Physician - who, when and how to refer to the on-call surgeon. AB - Patients with abdominal pain are most frequently referred to the on-call surgical team, but there are occasions when physicians may be required to assess, investigate or treat such patients. This article aims to equip non-surgeons with the skills to undertake an appropriate initial assessment and consider the most appropriate selection, timing and mode of referral to the surgical team. PMID- 21655516 TI - The management of acute pericarditis. AB - Acute pericarditis is usually a benign self-limiting condition, often of unexplained or viral aetiology, involving inflammation of the pericardial layers. It is often part of the differential diagnosis in patients admitted with acute chest pain and can be confused with acute myocardial infarction, acute pulmonary embolism and pleurisy. Occasionally it can result in cardiac tamponade and, if associated with myocarditis, in heart failure. This article sets out how to diagnose acute pericarditis, the common underlying causes, the possible treatment options and outcomes. PMID- 21655517 TI - Cardiac Arrhythmias - Part III Narrow Complex Tachycardia. AB - Narrow complex tachycardia usually refers to an abnormality of cardiac rhythm involving the tissues of the sinus node, atrial tissue, the atrioventricular node or an accessory atrioventricular communication. Although atrial fibrillation is the most common supraventricular arrhythmia, the term "supraventricular tachycardia" conventionally refers to the group of rhythm disturbances encompassing sinus tachycardia (appropriate and inappropriate), atrial tachycardia, atrial flutter, atrioventricular nodal reciprocating tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT) including the Wolff Parkinson White syndrome (WPW). Atrial fibrillation is beyond the scope of this article which focuses on the diagnosis and acute management of the patient presenting with one of these common causes of a regular, narrow complex tachycardia. PMID- 21655518 TI - Myxoedema coma. AB - Myxoedema coma is a rare and extreme presentation of hypothyroidism. It has a poor prognosis due to multisystem decompensation, and demands prompt but careful management in a high-dependency / intensive care setting. Early recognition of hypercapnia, hyponatraemia, and sepsis are especially important. Treatment should begin on suspicion of the diagnosis and can be life-saving. Intravenous thyroid hormone replacement is required at first, with steroid cover, although the optimum dose regimen remains unclear. PMID- 21655519 TI - Picture Quiz: Abdominal Pain in a patient receiving low molecular weight heparin. AB - A 63 year old lady with known ischaemic heart disease was admitted to hospital with cardiac sounding chest pain. Blood pressure was 161/80 on admission, and full examination was unremarkable. ECG showed ischaemic changes in the inferior leads, and a diagnosis of unstable angina was made. Troponin I was undetectable. She was treated with subcutaneous Enoxaparin 1.5mg/kg and an intravenous nitrate infusion. Her pain settled the following day, allowing the nitrate infusion to be weaned off, although the Enoxaparin treatment was continued, pending a cardiology opinion. On the third day after admission she collapsed on the ward with a blood pressure of 95/59mmHg; examination revealed lower abdominal tenderness with a mass in the right iliac fossa. Blood tests showed that her haemoglobin had dropped by 5 grams/decilitre,she underwent urgent abdominal ultrasound followed by CT. PMID- 21655520 TI - Amiodarone - induced pulmonary nodules mimiking metastatic lung disease - investigation by somatostatin radio peptide scanning. AB - A 61 year old former paramedic presented to A&E complaining of palpitations. He was found to be in atrial fibrillation, which reverted spontaneously to sinus rhythm. A chest x-ray taken at that time showed multiple pulmonary nodules consistent with metastatic malignancy (Figure 1). In the past he had been treated with amiodarone 200mg daily for 6 years following a previous diagnosis of atrial fibrillation, which had been attributed to alcoholic cardiomyopathy. He had discontinued the drug 8 months earlier, after self diagnosing hypotension and bradycardia. A previous chest x-ray, taken before starting amiodarone, was normal. PMID- 21655521 TI - Deep vein thrombosis assessment clinic: Evaluation of a new working practice. AB - Suspected deep vein thrombosis (DVT) is a common reason for medical referral to hospital. We evaluated our new approach to assessment of DVT using combined automated strain gauge plethysmography and pretest probability score in comparison with venous ultrasonography in 100 consecutive patients with suspected DVT referred to the nurse-led clinic. The combined plethysmography and pretest probability score produced a negative predictive value of 99%, positive predictive value 53%, sensitivity 94% and specificity 83% for detection of a DVT. We conclude that our new working practice for DVT assessment is both safe and cost effective and can lead to a reduction in venous ultrasonography of approximately 70%. PMID- 21655522 TI - Should physicians manage hip fractures? AB - Elderly People with hip fractures are among the most frail and medically complex of all hospital inpatients. In one sense, the fracture itself is merely a marker of frailty, and many of these patients would have found themselves on an acute medical ward if they had not broken a bone. Despite this, many centres still expect the orthopaedic team to manage these cases with only token input from physicians. This article explores other models of care for elderly hip fracture patients and looks at the evidence base to support the proposition that physicians should be managing hip fractures. PMID- 21655523 TI - Controversies in the management of life threatening asthma. AB - Asthma has a complex aetiology with many precipitating factors leading to a final common pathway of airway inflammation and bronchospasm. Patients with asthma are at risk of developing acute exacerbations. A subgroup of these patients develop severe exacerbations. This review will focus on some of the issues in the management of adults with life threatening asthma that remain controversial. PMID- 21655524 TI - Picture quiz (answer). AB - Subcutaneous low molecular weight heparins are widely used in hospitalised patients for the treatment of DVT, pulmonary embolism and acute coronary syndromes, as well as for thromboprophylaxis. Rectus sheath hematoma is a recognised, but sometimes misdiagnosed, complication of treatment with anticoagulant therapy,1 including full and prophylactic doses of low molecular weight heparin. PMID- 21655525 TI - Acute management and investigation of seizures. AB - This article summarises the management of different situations in which patients present to the acute medical service with seizures. It covers the management of single attacks of loss of consciousness, multiple seizures and status epilepticus in patients with and without known epilepsy. The importance of a good history and witness account where there is a diagnostic issue is stressed. In the case of multiple seizures and status epilepticus, the investigation of the cause of the attacks as well as their acute management is reviewed. PMID- 21655526 TI - Management of acute ischaemic stroke. AB - National audits of stroke care in the UK have repeatedly shown deficiencies in basic care. The key to good care is prompt thorough assessment, investigation and management of physiological parameters i.e blood pressure, glycaemia, temperature and oxygenation. Three interventions are of proven benefit in acute ischaemic stroke: admission to an organised stroke service, early aspirin and intravenous thrombolysis. The use of multidisciplinary guidelines and education and audit around these improves care. PMID- 21655527 TI - Recognition and early management of acute liver failure. AB - Acute liver failure (ALF) is a rare but frequently devastating condition, with the potential to disable virtually every organ and system in the body. However, if it is recognised swiftly, and if its specific complications are managed actively, a good outcome can be achieved, especially in the young. The first hours are crucial in stabilising the patient, optimising metabolic and cardiovascular parameters, and reducing the risk of permanent neurological injury or brain death. Simultaneous liason with a specialist unit will allow a planned, safe transfer and access to definitive treatment such as liver transplantation, should the patient require it. This review highlights the clinical and laboratory features of ALF, emphasises aspects of early treatment which will aid short term survival, and makes recommendations concerning safe transfer to a liver unit. Information is also given to aid early counselling of relatives and next of kin. PMID- 21655528 TI - Emergency management of phaeochromocytoma. AB - Phaeochromocytomas are catecholamine secreting tumours associated with unpredictable patterns of hypertension. A variety of forms of investigation are available for detecting hypersecretion of catecholamines or their metabolites. Recent developments in the biochemical diagnosis, localisation and management of phaeochromocytoma and its associated crisis are reviewed. PMID- 21655529 TI - Picture Quiz (questions). AB - A 75-year-old man was referred to hospital with a 24 hour history of severe neck pain, associated with fever, rigors and mild confusion. The pain radiated into his arms and was exacerbated by neck movements. Eight days prior to admission he had developed loose stools for 3 days. There was no history of trauma, and no other features of meningism. He gave a past history of ischemic heart disease and atrial fibrillation for which he was taking warfarin. Examination revealed a pyrexia of 38.3 degrees C. There was tenderness over the cervical spine but no other positive findings. Neurological examination was unremarkable. PMID- 21655530 TI - An unusual cause of meningitis. AB - A 57 year old man patient presented with fever and frontal headache. He had a background history of sero-positive rheumatoid arthritis which was well controlled on immunomodulatory disease modifying anti-rheumatoid drugs (DMARDS) including methotrexate and lef lunomide. Six months earlier he had returned from Massachussetts in the USA after a one year period of residence there. On examination his vital signs were within normal limits and he was afebrile with a temperature of 36.1oC. His left elbow joint was warm, tender and swollen; examination was otherwise normal. PMID- 21655531 TI - Making Sense of the Chest X-ray, a hands-on Dr Paul Jenkins, Hodder Arnold Press 2005. AB - The chest radiograph is one of the most challenging images to interpret reliably, yet accurate film reading can be very rewarding professionally and can significantly improve patient management. These skills are important for all professionals working in acute medicine and acquiring them requires a comprehensive book collection and a wide experience but above all a good teacher. PMID- 21655532 TI - Picture Quiz (answers). AB - The MRI scan reveals a shallow anterior epidural abscess at C5 / C6 level without cord compression. The recent history of diarrhea is suggestive of salmonella enteritidis. PMID- 21655533 TI - Contrast-enhanced ultrasonography represents a very good method in the assessment of liver masses. PMID- 21655534 TI - Contrast enhanced ultrasound for the diagnosis of liver hemangiomas in clinical practice. AB - BACKGROUND AND AIM: Contrast enhanced ultrasound (CEUS) has a well established place in the characterization of focal liver lesions (FLL). The aim of this paper was to evaluate the usefulness of CEUS in the assessment of liver hemangiomas. MATERIAL AND METHOD: We included in a prospective study all the CEUS examinations performed during a 13 months period for the evaluation of de novo FLL, using a Siemens Acuson S2000TM Ultrasound System, following an intravenous bolus of 2.4 ml SonoVue(r) CEUS was considered conclusive for hemangioma if a typical pattern was present following contrast (centripetal fill in during the arterial phase, hyperenhanced lesion during venous and late phases). RESULTS: During September 2009 - October 2010, 413 CEUS examinations were performed in our department for the evaluation of de novo FLL. Out of the 413 cases, based on standard ultrasound, 43 were suspected hemangiomas, 125 were uncharacteristic lesions and 245 were suspected for other types of lesions (metastases, focal nodular hyperplasias, hepatocellular carcinomas etc). Out of the 413 de novo FLL, 64 cases (15.5%) were diagnosed as hemangiomas by CEUS (typical CEUS pattern). MRI diagnosed 7 additional hemangiomas in inconclusive CEUS cases, so 90.1% (64/71) of the hemangiomas were diagnosed by CEUS alone. Out of the 125 uncharacteristic lesions on standard ultrasound, 29 cases were diagnosed after CEUS as hemangiomas. Thus, CEUS diagnosed additional 40.8% (29/71) hemangiomas as compared to standard ultrasound, without the need of more expensive imaging methods. CONCLUSION: CEUS is a reliable method for the diagnosis of hemangiomas, also allowing a precise characterization of FLL. This method diagnosed additional 40% hemangiomas in comparison with standard ultrasound (for atypical ultrasound hemangiomas) and finally, CEUS diagnosed correctly 90% of this type of lesions, all with typical enhancement pattern according to the EFSUMB guidelines. PMID- 21655535 TI - The value of contrast enhanced ultrasound in the evaluation of the nature of portal vein thrombosis. AB - Portal vein thrombosis (PVT) is a relatively common complication in patients with liver cirrhosis and hepatocellular carcinoma, but might also occur in the absence of liver disease. Ultrasound (US) is the first imaging method used for assessing PVT. THE PURPOSE: To evaluate the utility of contrast-enhanced ultrasound (CEUS) for the differentiation between benign and malignant PVT. MATERIALS AND METHODS: from October 2009 to October 2010, 38 PVTs were evaluated by means of ultrasound (standard, Doppler and CEUS). 29 PVT were in patients with liver cirrhosis and 9 in subjects without liver cirrhosis. RESULTS: 15 of 38 patients (39.5%) had benign PVT and 23 patients (60.5%) had malignant PVT. Results of CEUS examination were conclusive in 37/38 (97.2%) of the examinations for PVT, allowing the differentiation between benign and malignant thrombosis. When the result was inconclusive, another imaging method was performed (MRI). CONCLUSION: CEUS is a very good method for the evaluation of benign or malignant nature of portal vein thrombosis. PMID- 21655536 TI - Contrast enhanced ultrasound for the characterization of hepatocellular carcinoma. AB - AIM: Contrast-Enhanced Ultrasound (CEUS) is an imaging method that can discriminate between hepatocellular carcinoma (HCC) and other liver lesions. The purpose of this study is to present our experience concerning the use of CEUS in the characterization of HCCs. MATERIAL AND METHOD: We included in our study all the patients evaluated in our Department from September 2009 to October 2010, with focal liver lesions (FLLs) on abdominal ultrasound (US) that were diagnosed as HCCs after CEUS examination, also patients with chronic liver disease with focal liver lesions highly suspected to be HCCs but with an inconclusive pattern on CEUS. One hundred patients with 148 HCCs were included. The enhancement pattern of the nodules was evaluated according to the 2008 EFSUMB Guidelines. Nodules displaying arterial hyperenhancement with "washout" in the portal/venous phase on CEUS were considered diagnostic for HCC. Nodules considered indeterminate after CEUS were evaluated by contrast-enhanced CT or MRI for diagnosis. RESULTS: Among the 100 patients included, 96 were patients with chronic liver disease and 4 were patients without known liver disease. 71 patients had a solitary nodule, 16 patients had two nodules and 13 patients had three or more nodules. 112 HCCs had a typical enhancement pattern and 36 nodules were considered indeterminate after CEUS and were sent to CT/ MRI for diagnosis. CONCLUSIONS: 75.7% of the studied liver nodules were diagnosed by CEUS as HCCs, thus CEUS is an easy method, convenient to perform, avoiding other expensive examinations. PMID- 21655537 TI - Accuracy of modern ultrasonographic techniques in the follow up of patients with superficial bladder carcinoma. AB - PURPOSE: The present study was carried out to establish the accuracy of modern ultrasonographic techniques in the follow up of patients with superficial bladder carcinoma and to evaluate the patients tolerability of cystoscopy. METHODS: Thirty-three patients with a history of superficial bladder carcinoma under active surveillance were initially examined using transabdominal ultrasound followed in the same day by cystoscopy. RESULTS: Fourteen out of the 33 subjects were found to have bladder carcinoma recurrence on cystoscopy. In 11 cases (78.57%) US accurately diagnosed the bladder carcinoma. Two out of the 3 patients in which, the US examination failed to clearly diagnose bladder carcinoma, were found with a tumor smaller than 3 mm while, in the remaining patient the tumor was located in the inner part of a diverticula. The sensitivity of modern ultrasonographic techniques in the diagnosis of bladder cancer recurrence was 78.5%, the specificity 100%, the positive predictive value 100% and the negative predictive value 86.3%. Regarding the patient tolerability for cystoscopy, 17 patients (51.5%) reported excessive discomfort-low tolerability, 9 (27.2%) moderate discomfort-intermediate tolerability and 7 (21.2%) reported no discomfort-high tolerability. CONCLUSION: The technological evolution has rendered ultrasonography more accurate in the diagnosis of bladder carcinoma and thus it can be incorporated in the follow up schedule of patients with superficial bladder carcinoma. PMID- 21655538 TI - The evaluation of 20 MHz ultrasonography, computed tomography scans as compared to direct microscopy for periodontal system assessment. AB - AIM: To identify by ultrasonography (DermaScan C, Cortex Technology1) the reference points necessary to monitor the horizontal bone resorbtion and to assess the accuracy of the measurements by comparing with Cone Beam Computed Tomography images, having direct microscopic section measurements as a gold standard. MATERIAL AND METHODS: We performed the examinations on the lingual side of the alveolar bone of 4 pig mandibles. We tried to identify the enamel-cementum junction, the root, the periodontal space at the appearance of the tooth from the alveolar bone, the edge of cortical bone at its coronary limit (in order to assess the horizontal bone resorption). We measured the distance between the enamel-cementum junction and the coronal edge of cortical bone. RESULTS: There was a strong positive correlation between the alveolar bone level measured with the 3 techniques. Correlation parametric R2 tests were statistically significant for DermaScan measurements compared to microscopy ones (p<0.0001). Linear regression showed statistically significant correlations for alveolar bone level measurements made by CBCT compared to microscopy (p<0.05). CONCLUSIONS: The cementum-enamel junction may be identified on ultrasonic images with high accuracy according to the tooth anatomical convexities, therefore this method can be used for monitoring the periodontium. PMID- 21655539 TI - Arterial stiffness and carotid intima-media thickness in HIV infected patients. AB - BACKGROUND: Cardiovascular disease is an increasing cause of morbidity and mortality in HIV-infected patients. The increased cardiovascular risk is linked to traditional risk factors for atherosclerosis but also, to HIV infection itself which can damage the arterial wall and the antiretroviral therapy (ART) implicated in metabolic disturbances. The aim of our study was to identify the effects of HIV and ART on carotid artery intima-media thickness (C-IMT) and on arterial stiffness, parameters which are used for the evaluation of cardiovascular risk. PATIENTS AND METHODS: A cross-sectional case-control study of 63 HIV-infected patients (56 exposed to ART, 7 ART naive) and 36 controls matched for age and sex was performed. C-IMT, and arterial stiffness were measured ultrasonographically using an ALOKA ProSound alpha 10 echo-device. Parameters of arterial stiffness were measured at the common carotid and brachial arteries. RESULTS: HIV-infected patients had a greater C-IMT than controls (p<0.01). There were significant differences regarding arterial stiffness parameters in HIV infected patients compared to controls, and between the groups of patients with different types of ART, especially at the level of carotid artery. Patients with HIV infection had reduced carotid compliance compared to controls (p<0.01). Patients exposed to reverse transcriptase inhibitort (RTI), had increased beta stiffness index (p=0.01) and carotid PWV (p=0.02) and reduced carotid compliance (p<0.01) compared to controls. CONCLUSIONS: HIV infection and ARV treatment is associated with increased C-IMT, and an increase in the arterial stiffness of the large arteries. These vascular modifications are possible causes of increased cardiovascular risk observed in HIV infected patients. PMID- 21655540 TI - Factors that influence the correlation of acoustic radiation force impulse (ARFI), elastography with liver fibrosis. AB - AIM: To establish the influence of different factors on the correlation between liver stiffness (LS) measurements by ARFI and liver fibrosis, evaluated by liver biopsy (LB). We assessed the following factors: the success rate (SR) and interquartile range (IQR) interval, the place where ARFI was performed, liver steatosis, the quality of the specimen obtained by LB. METHODS: We studied 471 patients: 82 with LB, 82 healthy volunteers and 307 with cirrhosis. We performed 10 valid ARFI measurements, a median value was calculated, expressed in meters/second. RESULTS: Valid measurements were not obtained in 11 patients. There was a direct, strong, correlation (r=0.694) between ARFI and fibrosis (p<0.0001). There were no statistically significant differences between the mean ARFI values obtained in segments V vs. VIII (p=0.89). Considering the IQR and SR, the correlation of ARFI with fibrosis was: for IQR<30% and SR >= 60%: r=0.722 and for IQR>30% and/or SR <= 60%: r=0.268 (p=0.0001). The quality of the liver specimen (2-3 cm long vs. >3 cm) did not influence the correlation of ARFI with fibrosis. CONCLUSIONS: To obtain the best correlation between ARFI and fibrosis, IQR must be <30% and SR >= 60%. These technical parameters must be introduced to improve the ARFI value for LS evaluation. PMID- 21655541 TI - Applications of Doppler ultrasound during labor. AB - The information provided by Doppler ultrasound examination during labor permits the understanding of the mechanisms regarding the physiology and pathophysiology of feto-placental exchange and the fetal adaptive systems. There are certain technical difficulties related to intrapartum Doppler ultrasound examination. The investigated sites are the uterine arteries, umbilical arteries, fetal circulation. In diastole, when intrauterine pressure exceeds maternal diastolic pressure, the perfusion pressure of the uterine artery blood flow is no longer present. A progressive decrease in the diastolic component is seen along with an increase in intrauterine pressure from 10 to 60 mmHg. During premature birth or preeclampsia, there are particular changes in the uterine blood flow. A remarkable stability of the umbilical resistance index is found during labor, which shows the permanent presence of feto-placental exchange. Certain correlations can be established between fetal heart rate changes in labor and Doppler ultrasound aspects at the level of umbilical arteries. Doppler examination confirms the concept of reduced cerebral blood flow by the compression of the fetal skull as a cause of decelerations occurring during labor. The decision regarding the extraction of the fetus can only be made by correlating the results of Doppler ultrasound with the other paraclinical methods for the monitoring of the intrapartum fetal status. PMID- 21655542 TI - Contrast enhanced ultrasound of kidneys. Pictorial essay. AB - Contrast-enhanced ultrasound has entered the imaging mainstream in the last few years. It is a safe technique with exquisite temporal and spatial resolution and is especially useful for evaluating focal renal mass lesions in patients with renal impairment when iodinated or gadolinium contrast agents are contraindicated. The purpose of this manuscript is to briefly describe our technique, show the normal renal haemodynamics of ultrasound contrast agent and demonstrate a spectrum of renal masses and possible pitfalls. PMID- 21655543 TI - Parathyroid cyst, a rare cause of cystic cervical lesion. Case report. AB - Parathyroid cyst is a very rare abnormality. The diagnosis can be made based on ultrasound and the analysis of the aspirated cystic fluid for parathyroid hormone (PTH). We report the case of a nonfunctional parathyroid cyst in a 50-year-old female patient with an anterior neck mass. The patient was complaining of pain in the anterior cervical region, dysphagia, dyspnea and dysphonia started three weeks previously. Ultrasound demonstrated an anechoic and avascular lesion located in the left lobe of the thyroid. Fine needle aspiration (FNA) revealed a clear, colorless and watery cystic fluid, that showed a high concentration of parathyroid hormone (PTH) in both the native and the diluted content of the cyst, while serum PTH was normal, indicating a nonfunctional parathyroid cyst. The patient was in remission by percutaneous aspiration and there was no relapse of the parathyroid cyst after one-year follow-up. PMID- 21655544 TI - Imaging findings after fascial injection of tetanus vaccine. AB - Adverse reactions to vaccines vary from mild to fatal. Local reactions are often due to hypersensitivity to the adjuvant substances in the vaccine. This case report aims at illustrating the imaging findings of a fascial injection of the tetanus vaccine. A 14 year-old boy, vaccinated 6 months previously presented with a mass lesion in the left deltoid area. Magnetic resonance imaging and ultrasonographic evaluations were performed and the findings were characteristic for fascial granuloma. The histopathologic examination confirmed the diagnosis. In our knowledge, this is the first case of granuloma post intrafascial injection of tetanus vaccine which was MRI and ultrasonographic evaluated and histopathologicly confirmed. PMID- 21655545 TI - Posttraumatic gastric wall hematoma in a patient under anticoagulant therapy. Case report and literature review. AB - We report the clinical observation of a 58-year old patient who presented with upper abdominal pain and a small ecchymosis located in the umbilical area. Personal history of the patient revealed ischemic heart disease and chronic atrial fibrillation. He was under treatment with oral anticoagulants (coumarins). The clinical data and especially the imaging investigations led to a diagnosis of gastric wall hematoma, possibly occurring post-traumatically in a patient under anticoagulant treatment. A conservative therapeutic approach was adopted and ultrasound surveillance. After 6 months the gastric parietal collection manifested complete resorption, spontaneously. In relation to the case presentation, we also discuss some issues on the frequency, diagnosis and therapeutic attitude in this rare complication of anticoagulant therapy. PMID- 21655546 TI - Ultrasonography of the eye and orbit. AB - Ultrasonography (US) is, quite often, the first imaging modality used in eye and orbit assessment. The indications of ophthalmic US cover a wide range of disease where direct clinical assessment is impossible or of little value. Doppler US enhances the ability to assess blood flow in the main arteries and veins. In order to take full advantage of all the possibilities US has to offer the examiner thorough knowledge of the examination technique and normal US anatomy of the eye and orbit is required. This paper reviews the basics of the examination technique and ultrasound anatomy of the eye and orbit. PMID- 21655548 TI - Answer to quiz vol 13, no. 1. Small part tumors in a 37-year old woman. Malignant melanoma of the right lumbar region with "in transit" metastases. PMID- 21655551 TI - Electron-deficient 1- and 2-azabuta-1,3-dienes: a comprehensive survey of their synthesis and reactivity. AB - Electron-deficient 1- and 2-azabuta-1,3-dienes are reagents intrinsically able to provide a wide range of cyclic and acyclic N-containing building blocks. Depending on their substitution, they behave as dienes for Diels-Alder reactions, as partners for [4+1], [3+2], [2+2]-cycloadditions, for aziridinations and as electrophiles for 1,2 and 1,4-additions. Nowadays, they are a very versatile family of compounds, despite their usual instability and complex reactivity. Four decades of research in this challenging area are reviewed in this critical review: their synthetic aspects and their reactivity towards a wide range of dienophiles, dipoles and nucleophiles are described as well. The introduction focuses on their electronic properties in order to get a clear picture of their reactivity (190 references). PMID- 21655552 TI - Topochemical approach to efficiently produce main-chain poly(bile acid)s with high molecular weights. AB - Based on a topochemical approach, a strategy for efficiently producing main-chain poly(bile acid)s in the solid state was developed. This strategy allows for facile and scalable synthesis of main-chain poly(bile acid)s not only with high molecular weights, but also with quantitative conversions and yields. PMID- 21655553 TI - Living/controlled free radical copolymerization of chlorotrifluoroethene and butyl vinyl ether under 60Co gamma-ray irradiation in the presence of S-benzyl O ethyl dithiocarbonate. AB - Living/controlled free radical copolymerization of chlorotrifluoroethene and butyl vinyl ether has been successfully achieved at room temperature under (60)Co gamma-ray irradiation in the presence of S-benzyl O-ethyl dithiocarbonate. The alternating and block copolymers have been obtained with well-defined molecular weights and narrow molecular weight distributions. PMID- 21655554 TI - Binaphthyl platform as starting materials for the preparation of electron rich benzo[g,h,i]perylenes. Application to molecular architectures based on amino benzo[g,h,i]perylenes and carborane combinations. AB - Valuable amino benzo[g,h,i]perylenes have been obtained through a one pot electrophilic aromatic substitution--Scholl reaction sequence. Novel molecular architectures combining 3D-o-carborane and planar amino benzo[g,h,i]perylene units are described. Photophysical properties of amino benzo[g,h,i]perylene and the carborane-appended derivatives are discussed. PMID- 21655555 TI - Room temperature synthesis of protonated layered titanate sheets using peroxo titanium carbonate complex solution. AB - We report the synthesis of peroxo titanium carbonate complex solution as a novel water-soluble precursor for the direct synthesis of layered protonated titanate at room temperature. The synthesized titanates showed excellent removal capacity for Pb(2+) and methylene blue. Based on experimental observations, a probable mechanism for the formation of protonated layered dititanate sheets is also discussed. PMID- 21655556 TI - Integrated and diffusion-based micro-injectors for open access cell assays. AB - Currently, most microfluidic devices are fabricated with embedded micro-channels and other elements in a close form with outward connections. Although much functionality has been demonstrated and a large number of applications have been developed, they are not easy for routine operation in biology laboratories where most in vitro cell processing still relies on the use of culture dishes, glass slides, multi-well plates, tubes, pipettes, etc. We report here an open access device which consists of an array of isolated micro-channels plated on a large culture surface, each of them having tiny nozzles for localized drug delivery. In a diffusion dominant regime, steady gradients of molecule concentration could be obtained and varied by changing the flow rate inside the micro-channels. As assay examples, cell staining and drug-induced cell apoptosis were demonstrated, showing fast cell responses in close proximity of the nozzles. PMID- 21655557 TI - A ruthenium catalyst yielding crosslinked polyethylene. AB - A ruthenium phosphane aryl sulfonate was found to be an efficient catalyst for the polymerization of ethene. Surprisingly, the resulting polyethylene is crosslinked. PMID- 21655558 TI - Spin Seebeck coefficient of a molecular spin pump. AB - Within a generalized version of previously considered model of a molecular spin pump controlled by an external electric field [J. Fransson and M. Galperin, Phys. Rev. B, 2010, 81, 075311] we discuss thermal properties of such spintronic devices. The spin Seebeck coefficient of a molecular spin pump is introduced, and several possible definitions of a nonequilibrium Seebeck coefficient are discussed. The influence of inelastic effects in spin transport on its thermospintronic characteristics are demonstrated within numerical examples. PMID- 21655563 TI - The effect of leaving group on mechanistic preference in phosphate monoester hydrolysis. AB - We present 2-dimensional potential energy surfaces and optimised transition states (TS) for water attack on a series of substituted phosphate monoester monoanions at the DFT level of theory, comparing a standard 6-31++g(d,p) basis set with a larger triple-zeta (augmented cc-pVTZ) basis set. Small fluorinated model compounds are used to simulate increasing leaving group stability without adding further geometrical complexity to the system. We demonstrate that whilst changing the leaving group causes little qualitative change in the potential energy surfaces (with the exception of the system with the most electron withdrawing leaving group, CF(3)O(-), in which the associative pathway changes from a stepwise A(N) + D(N) pathway to a concerted A(N)D(N) pathway), there is a quantitative change in relative gas-phase and solution barriers for the two competing pathways. In line with previous studies, in the case of OCH(3), the barriers for the associative and dissociative pathways are similar in solution, and the two pathways are equally viable and indistinguishable in solution. However, significantly increasing the stability of the leaving group (decreasing proton affinity, PA) results in the progressive favouring of a stepwise dissociative, D(N) + A(N), mechanism over associative mechanisms. PMID- 21655564 TI - Electrospun nanofibers as sorbent material for solid phase extraction. AB - Electrospinning has emerged as the most versatile technique for nanofiber fabrication. Owing to their large surface area to volume ratio, electrospun nanofibers have the potential to serve as a good sorbent material for solid phase extraction (SPE) based techniques. The ability to incorporate a variety of functionalities prior or post-electrospinning presents a platform to tune the sorbents for specific applications. It is the aim of this contribution to highlight some of the recent developments that harness the great potential of electrospun nanofibers as sorbents for SPE. The review discusses the various ways in which the electrospinning technique addresses two important parameters for sorbent material, which are sorptive capacity and selectivity. It concludes by presenting and discussing the potential for development of SPE format technology and configurations based on electrospun nanofibers. PMID- 21655565 TI - Self-assembly of manganese oxide nanoparticles and hollow spheres. Catalytic activity in carbon monoxide oxidation. AB - Reactions between MnSO(4) and KMnO(4) in the presence of carboxylic acids provide a facile, one-pot route to nanostructured manganese oxides with high surface areas. Acetic and propionic acid induce formation of hierarchical nanosphere morphologies whereas butyric acid promotes assembly of hollow spheres. The materials are active catalysts for CO oxidation. PMID- 21655567 TI - Nanostructure changes in protic ionic liquids (PILs) through adding solutes and mixing PILs. AB - The effect of adding primary n-alcohols with aliphatic chains and hexane on the nanostructure of a series of 14 protic ionic liquids (PILs) was explored using small and wide angle X-ray scattering (SAXS and WAXS). PILs were investigated with primary, secondary and tertiary ammonium cations containing different alkyl chain lengths, with and without hydroxyl substitution of the alkyl chain. Formate or nitrate anions were paired with these cations. The PILs which had no identified intermediate range order between 5-16 A had very low solubilities of the solutes. The other PILs, which had non-polar domains present, were mostly miscible with the primary alcohols of ethanol, propanol and butanol. When the alkyl chain length of the alcohols was similar to the PILs then the alcohols co partitioned with the alkylammonium cation components of the PILs and caused either an increase or decrease in the size of the non-polar domains, depending on whether the alcohol chain length was longer or shorter than that of the cation in the PIL respectively. For ethylammonium nitrate (EAN) with propanol or butanol and propylammonium nitrate (PAN) with butanol, the difference between the alcohol chain length and the alkyl chain length was too great to lead to a modified nanostructure, and instead large aggregates were present. The solubility of hexane in the alkylammonium nitrate PILs had a very strong correlation to the alkyl chain length. The addition of hexane had very little effect on the non polar domain sizes, which was attributed to it not being orientated in alignment with the alkylammonium cations in the non-polar domains. Lastly, seven binary PIL PIL solution series were investigated using SAXS and WAXS to show how the nanostructure of these systems can be fine tuned to control the size and structure of the non-polar domains. PMID- 21655566 TI - Lithium cation enhances anion binding in a tripodal phosphine oxide-based ditopic receptor. AB - A tripodal ditopic receptor presents H-bond donors and a phosphine oxide to potential guests. In the idealized binding conformation, an endohedral P=O functionality provides enhanced halide binding in the presence of lithium with the greatest DeltaDeltaG degrees observed for bromide, while minimal changes in K(a) are observed in the presence of sodium. PMID- 21655568 TI - Reaction of SO4- with an oligomer of poly(sodium styrene sulfonate). Probing the mechanism of damage to fuel cell membranes. AB - Clarification of the mechanism of degradation of model compounds for polymers used in polymer electrolyte fuel cells may identify intermediates that propagate damage; such knowledge can be used to improve the lifetime of fuel cell membranes, a central issue to continued progress in fuel cell technology. In proton-exchange membranes based on poly(styrene sulfonic acid), hydroxycyclohexadienyl radicals are formed after reaction with HO and thought to decay to short-lived radical cations at low pH. To clarify subsequent reactions, we generated radical cations by reaction of SO(4)(-) with oligomers of poly(styrene sulfonic acid) (MW ~ 1100 Da). At 295 K, this reaction proceeds with k = (4.5 +/- 0.6) * 10(8) M(-1) s(-1), both at pH 2.4 and 3.4, and yields benzyl radicals with an estimated yield of <=60% relative to [SO(4)(-)]. The radical cation is too short-lived to be observed: based on a benzyl radical yield of 60%, a lower limit of k > 6.8 * 10(5) s(-1) for the intramolecular transformation of the aromatic radical cation of the oligomer to a benzyl radical is deduced. Our results show that formation of the benzyl radical, an important precursor in the breakdown of the polymer, is irreversible. PMID- 21655569 TI - MU-XAFS of a single particle of a practical NiO(x)/Ce2Zr2O(y) catalyst. AB - MU-XAFS analysis using an X-ray MU-beam (1000 nm (h) * 800 nm (v)) was successfully carried out on a single particle of a practical catalyst NiO(x)/Ce(2)Zr(2)O(y) (0 <=x<= 1, 7 <=y<= 8). The oxidation state and local coordination structure of the NiO(x)/Ce(2)Zr(2)O(y) particle were characterized by Ni K-edge MU-XANES and MU-EXAFS, which showed the catalytically active and inactive phases of a single catalyst particle. PMID- 21655570 TI - Synthesis, structure and catalytic properties of CNN pincer palladium(II) and ruthenium(II) complexes with N-substituted-2-aminomethyl-6-phenylpyridines. AB - N-substituted-2-aminomethyl-6-phenylpyridines 2a-c have been easily prepared from commercially available 6-bromo-2-picolinaldehyde in two steps. Reaction of 2a-c with PdCl(2) in toluene in the presence of triethylamine gave the CNN pincer Pd(II) complexes 3a-c in 18-28% yields. The CNN pincer Ru(II) complex 5 containing a Ru-NHR functionality could be obtained in a 71% yield by treatment of 2c with a Ru(II) precursor instead of PdCl(2). Additionally, the related CNN pincer Ru(II) complex 7 containing a Ru-NH(2) functionality has been synthesized by the reaction of 2-aminomethyl-6-phenylpyridine with the same Ru(II) precursor in a 68% yield. All the new compounds were characterized by elemental analysis (MS for ligands), (1)H, (13)C NMR, (31)P{(1)H} NMR (for Ru complexes) and IR spectra. Molecular structures of Pd complex 3c as well as Ru complexes 5 and 7 have been determined by X-ray single-crystal diffraction. The obtained Pd complexes 3a-c were effective catalysts for the allylation of aldehydes as well as for three-component allylation of aldehydes, arylamines and allyltributyltin and their activity was found to be much higher than a related NCN Pd(II) pincer in the allylation of aldehyde. On the other hand, the two new CNN pincer Ru(II) complexes 5 and 7 displayed excellent catalytic activity in the transfer hydrogenation of ketones in refluxing 2-propanol with the latter being much more active. The final TOF values were up to 4510 h(-1) with 0.01 mol% of 5 and 220,800 h(-1) with 0.005 mol% of 7, respectively. PMID- 21655571 TI - Structural phase transitions and magnetic order in SrTcO3. AB - The structure of the perovskite SrTcO(3) has been investigated using both synchrotron X-ray and neutron powder diffraction. At room temperature SrTcO(3) is orthorhombic as a consequence of cooperative tilting of the corner sharing TcO(6) octahedra. The tilts are sequentially removed as the sample is heated with the oxide displaying the sequence of structres Pnma->Imma->I4/mcm->Pm 3m. Neutron powder diffraction data collected in the temperature range 4-1023 K indicate that SrTcO(3) has G-type antiferromagnetic structure, in which each Tc moment is antiparallel to its six nearest neighbours, below ~1000 K. The magnetic structure is collinear antiferromagnetic with the technetium moments parallel to c-axis and can be described by the propagation vector k = [0,0,0] and the basis vector (0,0,A(z)). The same magnetic structure is observed in each of the four crystal structures. PMID- 21655572 TI - Polycyclic aromatic hydrocarbons and trace metal contamination of coastal sediment and biota from Togo. AB - The state of contamination of tropical environments, particularly in Africa, remains a relatively under explored subject. Here, we determined polycyclic aromatic hydrocarbon (PAH) and trace metal concentrations in coastal sediment and biota samples (fish and mussels) from Togo (West Africa). In the sediments, the ?21 PAH concentrations ranged from <4 ng g(-1) to 257 ng g(-1), averaging 92 ng g(-1). Concentration ratios of low molecular weight PAHs (2-3 rings) versus high molecular weight PAHs (>=4 rings) were always lower than 1 (ranging from 0.08 to 0.46) indicating that high molecular weight PAHs were dominant in all sediment samples, and that PAHs originated mainly from anthropogenic combustion activities. The sediments were also analyzed for major elements and a total of 15 trace metals, which were found in elevated concentrations. The calculated enrichment factor (EF) values relative to the Earth's crust show that the contamination is extremely severe for Cd (EF = 191), severe for Cr (EF = 18) and U (EF = 17.8), moderately severe for Zr (EF = 8.8), for Ni (EF = 6.8), Sr (EF = 5.9) and Ba (EF = 5.4), and moderate for V (EF = 3.6) and Zn (EF = 3.4). Sediments sampled in areas affected by the dumping of phosphorite mine tailings showed particularly high concentrations of trace metals. Overall, concentrations of both PAHs and trace metals in sediment tend to increase from the coastline to the open sea (2 km offshore). This is attributable to the increasingly finer texture of coastal sediment found offshore, which has a terrigenous origin and appears loaded with various contaminants through adsorption processes. Such high loads of trace metals were also found in the biota (fish and mussels). The ratio of measured trace metal concentrations in biota to threshold limits set by the World Health Organization herein defined as relative health factor (RHF) was high. Average RHF values in fish were highest for Se (470), As (250), Ag (97), Ni (78), Mn (63), Fe (53), Pb (36), Cd (10), and Cr (7) while lowest for Cu (0.08) and Zn (0.03). Cd and Al did not bioaccumulate in the analyzed fish species. In mussels, the RHF values were highest for Fe (9,108), As (295), Pb (276), Se (273), Mn (186), Ni (71), Ag (70), Cd (14), and Cu (4). PMID- 21655573 TI - Supercritical synthesis and characterization of SWNT-based one dimensional nanomaterials. AB - The present study developed a novel, fast and efficient method to synthesize one dimensional nanotube-based materials via supercritical reactions and supercritical fluids. It was proved that supercritical organic fluids were good media to take materials into the nanocavity, not only as solvents but also as reaction agents. Different kinds of metals (Ni, Cu, Ag) and fullerenes (C(60), C(70), C(78), C(84), Gd@C(82), Er@C(82), Ho@C(82), Y@C(82)) were successfully inserted into nanotubes with small diameters by this technique, with various supercritical fluids such as C(2)H(5)OH, CH(3)OH or C(6)H(5)CH(3). The filling rates were proved to be more than 90%. The high filling efficiency and the properties of the as-generated materials were characterized by TEM, Raman, EDS and XPS. In principle, this technique can be applied to construct new types of nanomaterials, if we choose the appropriate supercritical reaction and fluid in the CNTs. PMID- 21655574 TI - Hydroxylation of DHEA, androstenediol and epiandrosterone by Mortierella isabellina AM212. Evidence indicating that both constitutive and inducible hydroxylases catalyze 7alpha- as well as 7beta-hydroxylations of 5-ene substrates. AB - The course of transformation of DHEA, androstenediol and epiandrosterone in Mortierella isabellina AM212 culture was investigated. The mentioned substrates underwent effective hydroxylation; 5-ene substrates--DHEA and androstenediol- were transformed into a mixture of 7alpha- and 7beta- allyl alcohols, while epiandrosterone was converted into 7alpha- (mainly), 11alpha- and 9alpha- monohydroxy derivatives. Ketoconazole and cycloheximide inhibition studies suggest the presence of constitutive and substrate-induced hydroxylases in M. isabellina. On the basis of time course analysis of the hydroxylation of DHEA and androstenediol, the oxidation of allyl C(7)-H(alpha) and C(7)-H(beta) bonds by the same enzyme is a reasonable assumption. PMID- 21655575 TI - Putting the 'N' in ACENE: pyrazinacenes and their structural relatives. AB - Acenes have emerged as an important class of organic electronic material. Related heteroatom-substituted compounds, or heteroacenes, introduce an important means for modulating properties and improving materials' stability. In this perspective, we will review the historical origins of the heteroacenes and discuss recent progress in the field of acene and related compounds containing fused 1,4-diazabenzene units, i.e. pyrazine, also known as the 'pyrazinacenes'. We focus not only on the types of materials that have been prepared but also on their chemical and physical properties, including synthetic procedures, electronic properties, self-assembly characteristics, and we also introduce some of the computational studies aimed at understanding the more unusual behaviours of this group of compounds, such as protic tautomerism and aromaticity/antiaromaticity. PMID- 21655576 TI - Enantioselective synthesis of pyranonaphthoquinone antibiotics using a CBS reduction/cross-metathesis/oxa-Michael strategy. AB - The enantioselective syntheses of deoxydihydrokalafungin (5), cis deoxydihydrokalafungin (6) and deoxykalafungin (7) are reported. The strategy was based on 4 key reactions: (1) CBS reduction of prochiral ketone 10 to introduce chirality at C-1, (2) radical allylation of quinone 9a, (3) cross-metathesis of dimethoxynaphthalene 13 with methyl acrylate, and (4) intramolecular oxa-Michael addition of alcohol 8 to form the core naphthopyran ring system. This novel approach delivers naphthopyrans possessing the natural trans-stereochemistry observed in the pyranonaphthoquinone family of antibiotics. PMID- 21655577 TI - Surprising luminescent properties of the polyphosphates Ln(PO3)3:Eu (Ln = Y, Gd, Lu). AB - The optical emission properties of the lanthanoid catena-polyphosphates Ln(PO(3))(3) (Ln = Y, Gd, Lu) doped with europium were investigated. Incommensurately modulated beta-Y(PO(3))(3):Eu (super space group Cc (0|0.364|0)0) and Gd(PO(3))(3):Eu (space group I2/a) show the usual emission characteristics of Eu(3+), while in Lu(PO(3))(3):Eu (space group Cc) the europium is unprecedentedly partially reduced to the divalent state, as proven by both a broad emission band at 406 nm excited at 279 nm and an EPR spectroscopic investigation. (151)Eu-Mossbauer spectroscopy showed that only a very small part of the europium is reduced in Lu(PO(3))(3):Eu. An explanation for this unusual behaviour is given. PMID- 21655578 TI - Coumarin phosphorescence observed with N^N Pt(II) bisacetylide complex and its applications for luminescent oxygen sensing and triplet-triplet-annihilation based upconversion. AB - A dbbpy platinum(II) bis(coumarin acetylide) complex (Pt-1, dbbpy = 4,4'-di-tert butyl-2,2'-bipyridine) was prepared. Pt-1 shows intense absorption in the visible region (lambda(abs) = 412 nm, epsilon = 3.23 * 10(4) M(-1) cm(-1)) compared to the model complex dbbpy Pt(II) bis(phenylacetylide) (Pt-2, lambda(abs) = 424 nm, epsilon = 8.8 * 10(3) M(-1) cm(-1)). Room temperature phosphorescence was observed for Pt-1 ((3)IL, tau(P) = 2.52 MUs, lambda(em) = 624 nm, Phi(P) = 2.6%) and the emissive triplet excited state was assigned as mainly intraligand triplet excited state ((3)IL), proved by 77 K steady state emission, nanosecond time resolved transient absorption spectroscopy and DFT calculations. Complex Pt-1 was used for phosphorescent oxygen sensing and the sensitivity (Stern-Volmer quenching constant K(SV) = 0.012 Torr(-1)) is 12-fold of the model complex Pt-2 (K(SV) = 0.001 Torr(-1)). Pt-1 was also used as triplet sensitizer for triplet triplet-annihilation based upconversion, upconversion quantum yield Phi(UC) up to 14.1% was observed, vs. 8.9% for the model complex Pt-2. PMID- 21655579 TI - The influence of volume fractions on the phase behaviors of linear A(BC)(n)BA' multiblock terpolymers. AB - The phase behaviors of A(BC)(n)BA' linear multiblock terpolymers are investigated using the pseudo-spectral method of self-consistent field theory by varying the volume fractions of different blocks. The relative stability among the lamellae in-lamellae structures with different BC internal layers is tuned by the volume fraction of the two long tails. A larger A volume fraction favors the formation of structures with fewer BC thin layers. When the volume fraction of A is increased further, a hierarchical cylinder phase can be formed because of the effect of the spontaneous curvature and vice versa. The separation between B and C significantly reduces the phase regime of the cylinder, especially for the case of small A volume fraction. PMID- 21655580 TI - Nickel(II)-catalyzed diastereoselective [3+2] cycloaddition of N-tosyl-aziridines and aldehydes via selective carbon-carbon bond cleavage. AB - An efficient and mild Ni(ClO(4))(2)-catalyzed [3+2] cycloaddition of N tosylaziridines and aldehydes via C-C bond cleavage was developed. The cycloaddition reaction proceeds with high diastereoselectivity and regioselectivity leading to highly substituted 1,3-oxazolidines. Notably, this novel reaction can be easily expanded to gram level scale and the thermal conditions cannot achieve the same transformation. PMID- 21655581 TI - Conjugated polymer nanoparticles hybridized with the peptide aptamer. AB - A peptide aptamer, which was originally identified by affinity screening for hyperbranched poly(phenylene vinylene) (hypPPV), functioned as an excellent dispersant for hypPPV nanoparticle formation. PMID- 21655582 TI - Synthesis of fullerene@gold core-shell nanostructures. AB - A "direct encapsulation" method was developed for the synthesis of highly stable water-soluble fullerene@gold core-shell nanostructures, with gold nanoshells showing either closed or porous morphology. This gold nano-shell coating formed a "nano-oven", capable of decomposing encapsulated fullerene molecules rapidly when irradiated by laser. We envisaged this being a useful tool for chemical reactions as well as a novel scaffold for nano-material synthesis. PMID- 21655583 TI - 2,2'-Bipyridinyl carboranes as B,N,N-ligands in cyclometallated complexes of platinum(II). AB - Novel B,N,N-cyclometallated Pt(II) complexes of 2,2'-bipyridin-6-yl carboranes exhibit absorption and emission similar to relative Pt(II) complexes of aromatic C,N,N-ligands: the same transitions but lower intensities. DFT calculations suggest the former emits from the (3)MLCT state while for the latter the mixed (3)ICT-MLCT transitions should be considered. PMID- 21655584 TI - 9G DNAChip: a platform for the efficient detection of proteins. AB - According to the proposed DAGON method, the CRP and PSA antigens with the concentrations of 1 pg ml(-1) to 10 pg ml(-1) range can be easily differentiated in the buffer matrix. Moreover, it is for the first time that the multiple antigens with the concentrations of 1 pg ml(-1) and 0.1 pg ml(-1) can be detected in the mixture of the proteins without an amplification technique. PMID- 21655585 TI - Iridium-catalysed condensation of alcohols and amines as a method for aminosugar synthesis. AB - Primary carbohydrate amines at primary and secondary carbons are alkylated by alcohols in the presence of [Cp*IrCl(2)](2). When primary carbohydrate alcohols are used as the coupling partners and in the presence of Cs(2)CO(3), amine-linked pseudodisaccharides are obtained. Secondary carbohydrate alcohols are unaffected under these conditions, which allows regioselective reactions. PMID- 21655586 TI - A miniature capillary breakup extensional rheometer by electrostatically assisted generation of liquid filaments. AB - A micromachined chip capable of generating liquid microfilaments has been developed for a miniature version of the Capillary Breakup Extensional Rheometer (CaBER(r)). The proposed system is exceptionally simple and compact because liquid samples are actuated by voltages administered on-chip, which therefore requires only electrical connections (rather than a linear motor, an integral part of the CaBER(r)). Since chip features are photolithographically defined, the miniature rheometer can handle sub-microlitre samples. Following the CaBER(r), we show that a commercial LED micrometer effectively measures diameters of filaments generated by the electrowetting-on-dielectric (EWOD) forces. Since negligible electric fields are sustained within the liquid far away from the measurement region, the applied EWOD voltage does not influence tested material properties. Through breakup experiments using a wide range of Newtonian and complex fluids (e.g., glycerol, xanthan gum, dilute polystyrene, and dilute solutions of various molecular weight polyethylene oxide) we demonstrate a versatile testing platform for scarce and precious samples such as biochemical fluids and novel materials. Measured Newtonian and complex dynamics agree well with published theories and experiments. PMID- 21655587 TI - Trends in water monomer adsorption and dissociation on flat insulating surfaces. AB - The interaction of water with solid surfaces is key to a wide variety of industrial and natural processes. However, the basic principles that dictate how stable and in which state (intact or dissociated) water will be on a given surface are not fully understood. Towards this end, we have used density functional theory to examine water monomer adsorption on the (001) surfaces of a broad range of alkaline earth oxides, alkaline earth sulfides, alkali fluorides, and alkali chlorides. Some interesting general conclusions are arrived at: (i) on all the surfaces considered only a few specific adsorption structures are favoured; (ii) water becomes more stable upon descending the oxide and fluoride series but does not vary much upon going down the chloride and sulfide series; (iii) water is stabilised both by an increase in the lattice constant, which facilitates hydrogen bonding to the substrate, and by the flexibility of the substrate. These are also factors that favour water dissociation. We hope that this study is of some value in better understanding the surface science of water in general, and in assisting in the interpretation and design of future experiments. PMID- 21655588 TI - Recent advances in Sonogashira reactions. AB - The coupling of aryl or vinyl halides with terminal acetylenes catalysed by palladium and other transition metals, commonly termed as Sonogashira cross coupling reaction, is one of the most important and widely used sp(2)-sp carbon carbon bond formation reactions in organic synthesis, frequently employed in the synthesis of natural products, biologically active molecules, heterocycles, molecular electronics, dendrimers and conjugated polymers or nanostructures. This critical review focuses on developments in the Sonogashira reaction achieved in recent years concerning catalysts, reaction conditions and substrates (352 references). PMID- 21655589 TI - A lab-on-a-chip for rapid blood separation and quantification of hematocrit and serum analytes. AB - In this work, a new lab-on-a-chip for rapid analysis of low volume blood samples was designed, fabricated and demonstrated for integration of serum separation, hematocrit evaluation, and protein quantitation. Blood separation was achieved using microchannel flow-based separation. A novel method for evaluating hematocrit from microfluidic flow-separated blood samples was developed using gray scale analysis of a point-and-shoot digital photograph of separated blood in a micochannel. Protein quantitation was subsequently performed in a high surface area-to-volume ratio microfluidic chemiluminescent immunoassay using cell depleted serum produced by microfluidic flow-based separation of whole blood samples. All three steps were achieved in a single microchannel with separation of blood samples and hematocrit evaluation in less than 1 min, and protein quantitation in 5 min. PMID- 21655590 TI - Chirality transfer from chiral solvents and its memory in an azobenzene derivative exhibiting photo-switchable racemization. AB - The transfer and dynamic fixation of chirality in cyclic azobenzenes using R-(+) 1-phenylethylalcohol (R-PEA) and S-(-)-1-phenylethylalcohol (S-PEA) as solvents or additives are investigated. The cyclic azobenzenes used in this study carry a 1,5-dioxynaphthalene moiety as rotating unit, connected to the photoisomerizing (E-Z) azobenzene unit with spacers of varying lengths. With suitable lengths of the spacers the molecules exhibit stable enantiomers originated from the element of planar chirality in the E form due to the stopped rotation of the rotor, while in the Z form the allowed rotation results in racemization. The CD spectra of racemic compounds in the E form in chiral solvents were inert or almost negligible before irradiation, while 366 nm irradiation causing E-Z photoisomerization resulted in induction of clear CD bands. The thermal or photochemical reverse Z-E isomerization causes a change in the CD spectra to new ones which are reasonably matching with the spectra of the pure enantiomers recorded in non-chiral solvents. The obtained new CD spectra are maintained even in a racemic solvent system attained by the dilution with an equal amount of chiral solvent of opposite stereostructure. These results indicate that the chirality is transferred from the chiral solvents or additives to the racemizing Z form of cyclic azobenzene and it is fixed in the non-racemizing E form. The molecule without racemization in both E and Z forms did not show any significant induced CD bands irrespective of E-Z isomerizations. The molecule showing racemization in E and Z forms just shows the non-fixed induced CD. The property of photo-switchable racemization is necessary for the effective transfer and temporal fixation of the chirality in this type of chirality sensors. PMID- 21655591 TI - Differences in actinide metal-ligand orbital interactions: comparison of U(IV) and Pu(IV) beta-ketoiminate N,O donor complexes. AB - Syntheses and characterization of UCl(2)((Ar)acnac)(2), UI(2)((Ar)acnac)(2), and PuI(2)((Ar)acnac)(2) are reported ((Ar)acnac denotes a bis-phenyl beta ketoiminate ligand where Ar = 3,5-(t)Bu(2)C(6)H(3)). Structural analyses and computations show significant metal-ligand orbital interaction differences in U(IV) vs. Pu(IV) bonding. PMID- 21655592 TI - Linking optical and electrical small amplitude perturbation techniques for dynamic performance characterization of dye solar cells. AB - This paper unifies the analytical models used widely but thus far mostly separately for electrical and optical small amplitude perturbation measurements of nanostructured electrochemical dye solar cells (DSC): electrochemical impedance spectroscopy (EIS), intensity-modulated photocurrent spectroscopy (IMPS) and intensity-modulated photovoltage spectroscopy (IMVS). The models are linked by expressing the kinetic boundary condition used for solving the time dependent continuity equation of electrons in IMPS and IMVS analysis in terms of the series and parallel impedance components found in the complete equivalent circuit impedance model of DSC. As a result, analytical expressions are derived for potentiostatic IMPS and galvanostatic IMVS transfer functions of complete DSCs that are applicable at any operating point along the solar cell current voltage (IV) curve. In agreement with the theory, impedance spectrum calculated as a ratio of IMVS and IMPS transfer functions measured near the maximum power point matches exactly with the impedance spectrum measured directly with EIS. Consequently, both IMPS-IMVS and EIS yield equal estimates for the electron diffusion length. The role of the chemical capacitance of the nanostructured semiconductor photoelectrode in the interpretation of the so-called RC attenuation of the IMPS response is clarified, as well as the capacitive frequency dispersion in IMPS and IMVS. PMID- 21655593 TI - Why not consider a spherical protein? Implications of backbone hydrogen bonding for protein structure and function. AB - The intrinsic ability of protein structures to exhibit the geometric features required for molecular function in the absence of evolution is examined in the context of three systems: the reference set of real, single domain protein structures, a library of computationally generated, compact homopolypeptides, artificial structures with protein-like secondary structural elements, and quasi spherical random proteins packed at the same density as proteins but lacking backbone secondary structure and hydrogen bonding. Without any evolutionary selection, the library of artificial structures has similar backbone hydrogen bonding, global shape, surface to volume ratio and statistically significant structural matches to real protein global structures. Moreover, these artificial structures have native like ligand binding cavities, and a tiny subset has interfacial geometries consistent with native-like protein-protein interactions and DNA binding. In contrast, the quasi-spherical random proteins, being devoid of secondary structure, have a lower surface to volume ratio and lack ligand binding pockets and intermolecular interaction interfaces. Surprisingly, these quasi-spherical random proteins exhibit protein like distributions of virtual bond angles and almost all have a statistically significant structural match to real protein structures. This implies that it is local chain stiffness, even without backbone hydrogen bonding, and compactness that give rise to the likely completeness of the library solved single domain protein structures. These studies also suggest that the packing of secondary structural elements generates the requisite geometry for intermolecular binding. Thus, backbone hydrogen bonding plays an important role not only in protein structure but also in protein function. Such ability to bind biological molecules is an inherent feature of protein structure; if combined with appropriate protein sequences, it could provide the non-zero background probability for low-level function that evolution requires for selection to occur. PMID- 21655602 TI - Rapid separation and identification of the subtypes of swine and equine influenza A viruses by electromigration techniques with UV and fluorometric detection. AB - Influenza A is viral disease, which is a cause of yearly epidemics and, potentially, pandemics. The conventional techniques used today are equipment demanding, time-consuming and laborious. Recently, we have confirmed that the capillary isoelectric focusing is a suitable fast alternative for the verifying of virus purity. In the wide pH gradient of pH range 2.0-7.5 the isoelectric points for subtypes of equine (H3N8) and swine (H1N2) influenza A viruses were determined approximately as 6.6 and 6.5, respectively. In this contribution we have verified these findings using different isolates of different viral subtypes of swine influenza, H1N1, H1N2, and of equine influenza, H3N8, H7N7, which were separated by capillary zone electrophoresis (CZE) and capillary isoelectric focusing (CIEF) in the narrow pH gradient pH range from 6.0 to 7.0. It was found that the isoelectric points of different isolates and subtypes of equine and swine influenza are almost independent of their origin. The electromigration velocities of subtypes of equine or swine influenza viruses were dependent on the antigenic subtypes of their surface glycoproteins. The detection sensitivity of the influenza viruses labeled by the fluorescent non-ionogenic tenside based on poly(ethylene glycol)pyrenebutanoate for fluorometric detection was increased and down to ten labeled viruses were detected. The isoelectric points of the native and labeled equine and swine influenza A viruses and their subtypes do not differ. According to our experiments these methods appear to be useful for the fast preliminary differentiation of influenza viruses in future. PMID- 21655603 TI - Mobilization and plant accumulation of prometryne in soil by two different sources of organic matter. AB - Prometryne is a selective herbicide of the s-triazine chemical family. Due to its weak absorption onto soil, it readily leaches down through the soil and contaminates underground water. Application of organic manure to soil has become a widespread practice as a disposal strategy to improve soil properties. In this study, we demonstrated the effect of pig manure compost (PMC) and lake-bed sludge (SL) on the sorption/desorption, mobility and bioavailability of prometryne in soil using comprehensive analysis approaches. Downward movement of prometryne was monitored in the packed soil column. Addition of PMC or SL decreased considerably the mobility and total concentration of prometryne in the soil leachate. Bioavailability analyses with wheat plants revealed that addition of the organic matter reduced accumulation of prometryne in tissues and increased plant elongation and biomass. These results indicate that the organic amendments are effective in modifying adsorption and mobility of the pesticide in soil. PMID- 21655604 TI - Micro-droplet detection and characterization using thermal responses. AB - We suggest a novel method to detect droplets and determine the protein content of droplets in microfluidic system using the 3omega method, which is a powerful tool to easily detect thermal response changes with a simple device. By measuring the thermal response of droplets and a carrying flow in real time, water droplets in an oleic acid carrying flow can be detected, and the concentration of bovine serum albumin in droplets can be estimated. This method is expected to increase the practicality and power of droplet-based microfluidic systems. PMID- 21655605 TI - New solid-phase-nanoscavenger for the analytical enrichment of mercury from water. AB - A nanoscavenger of mercaptopropyl-modified silica microparticles has been developed for the determination of trace levels of mercury(II) in water. The synthesis of silica microparticles nanoscavengers is carried out by modification of pre-formed silica particles with mercaptopropyltrimethoxysilane or by incorporating the thiol modification agent during the growth of the silica particles. The silica nanoscavengers were characterized by SEM, TGA, particle analyzer, IR and the parameters influencing the extraction and recovery phases of the preconcentration process were performed by AAS. The results show that careful choice of particle size and surface characteristics produce a new mercapto-silica nanoscavenger that disperses in water as a quasi-stable sol. This permits the facile recovery of the mercury-loaded nanoscavenger particles. No agitation is required during the mercury extraction as the dispersion is maintained by Brownian motion and slow gravitational sedimentation. The technique overcomes a number of problems, such as cross-contamination and decreases in mercury concentration during sample transportation to the laboratory. Recovery achieved reaches >97 +/- 4% over a wide range of preconcentration factors. At a preconcentration factor of 50 the limit of detection (3sigma) was 0.19 ng mL(-1). The method is environmentally friendly as only 300 mg of mercapto-nanoscavenger is used, no organic solvent is required for the extraction and the experiment is performed without the need for manual or mechanical agitation. PMID- 21655606 TI - Gold nanoparticles generated through "green route" bind Hg2+ with a concomitant blue shift in plasmon absorption peak. AB - We discuss here a quick, simple, economic and ecofriendly method through a completely green route for the selective detection of Hg(2+) in aqueous samples. Here we exploited the ability of chitosan to generate gold nanoparticles and subsequently to act as a stabilizer for the formed nanoparticles. When chitosan stabilized gold nanoparticles (CH-Au NPs) are interacted with Hg(2+) a blue shift for its localized surface plasmon resonance absorbance (LSPR) band is observed. The blue shift is reasoned to be due to the formation of a thin layer of mercury over gold. A concentration as low as 0.01 ppm to a maximum of 100 ppm Hg(2+) can be detected based on this blue shift of the CH-Au NPs. While all other reported methods demand complex reaction steps and costly chemicals, the method we reported here is a simple, rapid and selective approach for the detection of Hg(2+). Our results also show that the CH-Au NPs have excellent selectivity to Hg(2+) over common cations namely, Pb(2+), Cd(2+), Mn(2+), Fe(2+), Ag(1+), Ce(4+), Ni(2+), and Cu(2+). PMID- 21655607 TI - A novel electrochemiluminescence aptasensor for protein based on a sensitive N (aminobutyl)-N-ethylisoluminol-functionalized gold nanoprobe. AB - A novel electrochemiluminescence (ECL) aptasensor for platelet-derived growth factor B chain (PDGF-BB) assay was developed by assembling N-(aminobutyl)-N ethylisoluminol functionalized gold nanoparticles (ABEI-AuNPs) with aptamers as nanoprobes. In the protocol, the biotinylated aptamer capture probes were first immobilized on a streptavidin coated gold nanoparticle (AuNPs) modified electrode, afterwards, the target PDGF-BB and the ABEI-AuNPs tagged aptamer signal probe were successively attached to the modified electrode by virtue of the dimer structure of PDGF-BB to fabricate a "sandwich" conjugate modified electrode, i.e. an aptasensor. ECL measurement was carried out with a double-step potential in carbonate buffer solution containing H(2)O(2). The aptasensor showed high sensitivity and selectivity toward PDGF-BB and specificity toward PDGF-BB aptamer. The detection limit was as low as 2.7 * 10(-14) M. In this work, the ABEI-AuNPs synthesized by a simple seed growth method have been successfully used as aptamer labels, which greatly amplified the ECL signal by binding numbers of ABEI molecules on the surface of AuNPs. The ABEI-AuNPs signal amplification is superior to other reported signal amplification strategies based on aptamer related polymerase chain reaction or functionalized nanoparticles in simplicity, stability, labeling property and practical applicability. And the ABEI-AuNPs based nanoprobe is more sensitive than the luminol functionalized AuNPs based nanoprobe. Moreover, such an ultra-sensitive and low-cost assay can be accomplished with a simple and fast procedure by using a simple ECL instrumentation. The aptasensor was also applied for the detection of PDGF-BB in human serum samples, showing great application potential. Given these advantages, the ECL aptasensor is well suited for the direct, sensitive and rapid detection of protein in complex clinical samples. PMID- 21655608 TI - Synthesis of cost-effective porous polyimides and their gas storage properties. AB - Porous polyimide (PI) networks with surface area up to 660 m(2) g(-1) were synthesized by planar structure monomers without detrimental catalysts. PMID- 21655609 TI - Fabrication of a well ordered microspheres film for efficient antibacterial activity. AB - Using the porphyrin molecule TEOP, highly ordered films of TEOP spheres were fabricated through a convenient and efficient in situ self-assembly approach. The diameter of the spheres can be adjusted by tuning the temperature. The well ordered film of TEOP spheres can be used to efficiently kill gram-negative bacteria under visible light. PMID- 21655610 TI - Highly enantioselective yttrium(III)-catalyzed Friedel-Crafts alkylation of beta trichloro(trifluoro)methyl aryl enones with indoles. AB - An efficient yttrium(III)-catalyzed highly enantioselective Friedel-Crafts alkylation of beta-trichloro(trifluoro)methyl aryl enones is described. The reaction delivered a series of functionalized indoles with a chiral tertiary carbon center bearing a trichloro(trifluoro)methyl group in excellent results (up to 96% ee and 99% yield) under mild conditions. PMID- 21655611 TI - Supramolecular assembly of graphene with functionalized poly(fluorene-alt phenylene): the role of the anthraquinone pendant groups. AB - Hybrid materials composed of graphene and conjugated poly(fluorene-alt-phenylene) endowed with redox-active anthraquinone moieties are prepared. Remarkable changes in the electronic properties of the polymer are observed. Effective interactions among the pendant anthraquinone and graphene, likely due to pi-pi stacking, are confirmed. PMID- 21655613 TI - Enhanced diffusion of pollutants by self-propulsion. AB - Current environmental models mostly account for the passive participation of pollutants in their environmental propagation. Here we demonstrate the paradigm changing concept that pollutants can propagate themselves with a rate that is greater than the rate for standard molecular diffusion by five orders of magnitude. PMID- 21655612 TI - Closely adjacent gold nanoparticles linked by chemisorption of neutral rhodamine 123 molecules providing enormous SERS intensity. AB - Addition of neutral R123 molecules (10(-7) M) to an as-prepared gold nanoparticles (AuNPs) suspension generated flocculates that are a small number of closely adjacent particles. Formation of AuNP flocculates was evidenced by the coupled localized plasmon peak at 720-750 nm. The AuNP flocculates provided pronounced SERS spectra of adsorbed neutral R123 molecules (SERS-A) as anticipated by FDTD (Finite Difference Time Domain) simulations. The observed SERS spectra are significantly different from those of cationic R123(+) molecules (SERS-B), which electrostatically adsorbed on Cl(-)-treated AuNPs. The difference is not simply due to deprotonation but reflects a distinct difference in adsorption nature between neutral R123 and cationic R123(+) molecules. Indeed neutral R123 molecules exclusively gave an Au-N stretching band at 202 cm(-1), showing the chemisorption on Au surfaces through lone pair electrons at the amino groups. The different adsorption nature is further evidenced by the observation that cationic R123(+) molecules adsorbed on as-prepared (without NaCl addition) AuNP flocculates gave both SERS-A and SERS-B spectra. Thus, the cationic R123(+) molecules form the flocculates both by chemisorption and electrostatic adsorption owing to modest surface charge on as-prepared AuNPs. PMID- 21655614 TI - A novel Mn-containing conducting metallopolymer obtained by electropolymerization in aqueous solution of a tetranuclear oxo-bridged manganese complex. AB - The [Mn(4)(IV)O(5)(terpy)(4)(H(2)O)(2)](6+) complex shows great potential for electrode modification by electropolymerization using cyclic voltammetry. The electropolymerization mechanism was based on the electron transfer between dx(2) y(2) orbitals of the metallic center and ppi orbital of the ligand. PMID- 21655615 TI - Bioassay for assessing cell stress in the vicinity of radio-frequency irradiating antennas. AB - The 24 h exposure of water plants (etiolated duckweed) to RF-EMF between 7.8 V m( 1) and 1.8 V m(-1), generated by AM 1.287 MHz transmitting antennas, resulted in alanine accumulation in the plant cells, a phenomenon we have previously shown to be a universal stress signal. The magnitude of the effect corresponds qualitatively to the level of RF-EMF exposure. In the presence of 10 mM vitamin C, alanine accumulation is completely suppressed, suggesting the involvement of free radicals in the process. A unique biological connection has thus been made between exposure to RF-EMF and cell stress, in the vicinity of RF transmitting antennas. This simple test, which lasts only 24 h, constitutes a useful bioassay for the quick detection of biological cell stress caused in the vicinity of RF irradiating antennas. PMID- 21655616 TI - Community exposure to arsenic in the Mekong river delta, Southern Vietnam. AB - We examined the daily inorganic arsenic (i-As) intake from drinking water and rice in 45 households (75 individuals) in the An Giang province, Southern Vietnam. The daily i-As intake ranged from 28-102 MUg d(-1), equivalent to the daily dose of 0.6-1.9 MUg d(-1) kg((body wt))(-1). Increased As concentrations were observed in human hair in the study location. Approximately 67% (n = 44), 42% (n = 28), and 15% (n = 10) of the hair samples had As levels exceeding 1, 3, and 10 MUg g(-1), respectively. The total As concentrations in female and male hair correlated well with the total daily i-As intake. Measurement of As concentrations in the hair of people who were consuming or had previously consumed As from contaminated sources may help predict the onset of negative health effects. We suggested an application of the Bayes's theorem to calculate the probability that an individual in a population will acquire a negative health effect, given that the concentration of arsenic in the subject's hair has been determined. PMID- 21655617 TI - Microfluidic array cytometer based on refractive optical tweezers for parallel trapping, imaging and sorting of individual cells. AB - Analysis of genetic and functional variability in populations of living cells requires experimental techniques capable of monitoring cellular processes such as cell signaling of many single cells in parallel while offering the possibility to sort interesting cell phenotypes for further investigations. Although flow cytometry is able to sequentially probe and sort thousands of cells per second, dynamic processes cannot be experimentally accessed on single cells due to the sub-second sampling time. Cellular dynamics can be measured by image cytometry of surface-immobilized cells, however, cell sorting is complicated under these conditions due to cell attachment. We here developed a cytometric tool based on refractive multiple optical tweezers combined with microfluidics and optical microscopy. We demonstrate contact-free immobilization of more than 200 yeast cells into a high-density array of optical traps in a microfluidic chip. The cell array could be moved to specific locations of the chip enabling us to expose in a controlled manner the cells to reagents and to analyze the responses of individual cells in a highly parallel format using fluorescence microscopy. We further established a method to sort single cells within the microfluidic device using an additional steerable optical trap. Ratiometric fluorescence imaging of intracellular pH of trapped yeast cells allowed us on the one hand to measure the effect of the trapping laser on the cells' viability and on the other hand to probe the dynamic response of the cells upon glucose sensing. PMID- 21655618 TI - A novel beta-loop scaffold of phage-displayed peptides for highly specific affinities. AB - Loop peptides stabilized by two beta-strands were used as a scaffold for a phage displayed peptide library. Affinity-based screening for insulin provided peptides, which showed affinity constants of 10(5) M(-1) order for insulin over 100 times greater than their affinity for the structurally similar insulin-like growth factor 1. The results suggested that the scaffold offers a powerful tool for generating and screening peptides as ligands for drugs and biologics. PMID- 21655619 TI - Novel cerium-tungsten mixed oxide catalyst for the selective catalytic reduction of NO(x) with NH3. AB - A novel Ce-W mixed oxide catalyst prepared by homogeneous precipitation method presented nearly 100% NO(x) conversion in a wide temperature range from 250 to 425 degrees C for the selective catalytic reduction of NO(x) with NH(3) under an extremely high GHSV of 500,000 h(-1). PMID- 21655620 TI - UV radiation simultaneously affects phototrophy and phagotrophy in nanoflagellate dominated phytoplankton from an Andean shallow lake. AB - Mixotrophic nanoflagellates, that combine photosynthesis and phagotrophy, are important members of planktonic food webs in many aquatic environments depending on the balance among the different carbon and energy sources. We carried out field sampling and laboratory experiments with natural nanoflagellate assemblages from an Andean North-Patagonian lake exposing them or not to UVR, and measuring photosynthetic parameters and bacterivory. The effect of different light treatments on the photosynthetic efficiency was studied by the non-invasive, pulse amplitude-modulated (PAM) fluorescence technique, and bacterivory was assessed with fluorescently labeled bacteria (FLB). Mixotrophic nanoflagellates were clearly dominant (up to 90% of total phytoplankton and 88% of total nanoflagellate abundance), and in the experiments labeled bacteria were observed in more than 75% of mixotrophic cells. These results support the idea that these phytoflagellates were never entirely photosynthetic. The high light : phosphorus ratio and the high C : N : P ratio suggest a strong nutrient limitation towards P. Our results show that both functions, photosynthesis and bacteria ingestion, were simultaneously reduced by the same level of UVR. We estimated that UVR exposure of mixotrophic nanoflagellates reduced photosystem II activity between 23% and 31% while ingestion rates were reduced between 23% and 28%. Therefore, our results suggest that the different cell functions could be concurrently impacted by UVR, implying that patterns and rates of C transfer would be substantially altered in the microbial food web. PMID- 21655621 TI - Complexes of the antitumoral drugs Doxorubicin and Sabarubicin with telomeric G quadruplex in basket conformation: ground and excited state properties. AB - We studied the binding of two anthracycline drugs, Doxorubicin and Sabarubicin, to a model telomeric sequence 5'-d[GGG(TTAGGG)(3)]-3' (21-mer), assuming the basket G-quadruplex (G4) conformation in Na(+)-rich aqueous solution. We used an approach that combines spectroscopic and microcalorimetric techniques to obtain information about ground and excited state properties of the most stable complexes. Both drugs bind to the 21-mer in basket conformation and complexes of 1:1 and 2:1 drug : 21-mer stoichiometry coexist in solution. Binding constants were determined from fluorescence and isothermal titration calorimetry experiments. For both drugs association is driven by enthalpy and disfavoured by entropy in the case of two sequential binding events to different sites. The drug fluorescence is completely quenched in the 1:1 complex, most likely by electron transfer from the guanine system to the anthraquinone moiety, while part of the emission survives in the 2:1 complex. Circular dichroism (CD) of the individual complexes is dominated by the G-quadruplex signal in the UV and by the anthracycline signal in the near-UV and Vis region. The experimental CD spectra combined with conformational calculations at MM level and quantum mechanical calculation of the rotational strength of the electronic transitions afforded information on the binding geometries. PMID- 21655622 TI - The centrality of PBGD expression levels on ALA-PDT efficacy. AB - Successful 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) is dependent on efficient porphyrin synthesis in the inflicted cancer tissue, which is regulated by several enzymes. Irradiation of the tumor excites the light sensitive porphyrins and results in ROS production and cell death. In this study we investigated the effect of the expression levels of two main enzymes in heme biosynthesis, ALA dehydratase (ALAD) and porphobilinogen deaminase (PBGD), on the capacity of K562 cells to undergo cell death following ALA-PDT. We manipulated PBGD and ALAD expression levels by shRNAs and PBGD overexpressing plasmid. PBGD down-regulation induced an elevation in ALAD activity, while overexpression of PBGD reduced ALAD activity, indicating a novel regulation feedback of PBGD on ALAD activity. This feedback mechanism enabled partial PpIX synthesis under PBGD silencing, whereas ALAD silencing reduced PpIX production to a minimum. ALA-PDT efficacy was directly correlated to PpIX levels. Thus, only ALAD-silenced cells were not affected by ALA+ irradiation, while following PBGD silencing, the accumulated PpIX, though decreased, was sufficient for successful ALA-PDT. The alterations in ALAD activity level initiated by changes in PBGD expression indicates PBGD's central role in heme synthesis. This enables efficient ALA-PDT, even when PBGD is not fully active. Conversely, ALAD loss resulted in reduced PpIX synthesis and consequently failure in ALA-PDT, due to the absence of compensation mechanism for ALAD. PMID- 21655623 TI - Role of entropy in supramolecular photochirogenesis: enantiodifferentiating photoisomerization of cyclooctenes in chiral sensitizer-immobilized MCM-41 cavities. AB - To examine the effects of confinement, or low-entropy environments, we employed the mesoporous silicate MCM-41 modified with optically active benzenetetracarboxylates as chiral reaction media to effect the enantiodifferentiating photoisomerization of (Z)-cyclooctene and (Z,Z)-1,5 cyclooctadiene. The ee of the (E)-isomer produced and its temperature dependence behavior in MCM-41 were completely different from those observed in homogeneous solutions. Immobilizing the sensitizer in MCM-41 reduced the contribution of the entropy factor. PMID- 21655624 TI - Pt nanoworms: creation of a bumpy surface on one-dimensional (1D) Pt nanowires with the assistance of surfactants embedded in mesochannels. AB - A new type of platinum nanowire with a bumpy surface "Pt nanoworm" is electrochemically synthesized in mesochannels of mesoporous silica films with the assistance of a nonionic surfactant (C(16)EO(8)). PMID- 21655625 TI - Thiourea isosteres as anion receptors and transmembrane transporters. AB - Compounds containing cyanoguanidine and 3-amino-1,2,4-benzothiadiazine-1,1 dioxide have been studied as anion receptors and transporters. Significant affinity for oxo-anions was observed in organic solution and the receptors were found to function as transmembrane chloride/nitrate antiporters with transport rates enhanced in the presence of valinomycin-K(+) complex. PMID- 21655626 TI - Highly plasmon-enhanced upconversion emissions from Au@beta-NaYF4:Yb,Tm hybrid nanostructures. AB - Unselectively enhanced multicolour upconversion (UC) emissions and low pumping threshold were achieved in Au@beta-NaYF(4):Yb,Tm hybrid nanostructures. This demonstrates that the plasmon field enhancement effect is the main reason for the improved UC emission efficiency. PMID- 21655627 TI - Template synthesis of ordered macroporous hydroxyapatite bioceramics. AB - Hydroxyapatite has found wide application in bone tissue engineering. Here we use a macroporous carbon template to generate highly ordered macroporous hydroxyapatite bioceramics composed of close-packed hollow spherical pores with interconnected channels. The template has advantages for the preparation of ordered materials. PMID- 21655628 TI - Monitoring biochemical reactions using Y-cut quartz thermal sensors. AB - In this paper, we present a micromachined Y-cut quartz resonator based thermal sensor array which is configured with a reaction chamber that is physically separated but located in close proximity to the resonator for sensitive calorimetric biosensing applications. The coupling of heat from the reaction chamber to the quartz resonator is achieved via radiation and conduction through ambient gas. The sensor was packaged onto a 300 MUm thick stainless plate with an opening in the middle. The sensor array was aligned to the opening and mounted from the underside of the plate. A reaction chamber designed for performing (bio)chemical reactions was used in the measurements. This configuration of the sensor allows for a very robust sensing platform with no fouling of the sensor surface or degradation in its performance metrics. Impedance-based tracking of resonance frequency was used for chemical, enzymatic, and cellular activity measurements. The sensor described has an impedance sensitivity of 852 Omega degrees C(-1) or a frequency sensitivity of 7.32 kHz degrees C(-1) for the 91 MHz resonator used in this work. Results on exothermic reaction between hydrochloric acid and ammonium hydroxide, the hydrolysis reaction of urea by urease and the catalytic reaction of glucose with glucose dehydrogenase are reported. From the signal to noise ratio analysis of the glucose sensor, <10 MUM glucose sensitivity could be obtained improving the detection limit by a factor of 250 in comparison to our previous work using thermopile sensors. Finally, calcium ionophore induced cellular activity was measured in pancreatic cancer cells using the sensor. PMID- 21655629 TI - Insights on the photomagnetism in copper octacyanomolybdates. AB - High level ab initio calculations on the photoinduced high-spin molecule [Mo(CN)(2)(CN-Cu(tris(2-aminoethyl)amine)(6)](8+) are reported. The calculations indicate that the mechanism of the photoinduced transformation from a paramagnetic to a ferromagnetic state involves a local Mo d-d transition followed by the deformation of the coordination sphere from dodecahedron to square antiprism. Subsequently, Mo loses a ligand and becomes seven coordinated in a pentagonal bipyramid coordination. The resulting Mo(IV)(S = 1) ion interacts ferromagnetically with the five remaining Cu(II) ions through the cyanide bridges. The estimated coupling is about +50 K and the resulting magnetic susceptibility curve resembles the experimental one taking into account that part of the sample is magnetically deactivated during the measurement. The calculated potential energy profile along the linear interpolated reaction coordinate shows a small barrier for the reverse reaction in agreement with the thermal reversibility of the photoinduced state. Moreover, we find that the reverse reaction can be induced by light. PMID- 21655630 TI - Artificial photosynthesis on a chip: microfluidic cofactor regeneration and photoenzymatic synthesis under visible light. AB - We present a microfluidic artificial photosynthetic platform that incorporates quantum dots and redox enzymes for photoenzymatic synthesis of fine chemicals under visible light. Similar to natural photosynthesis, photochemical cofactor regeneration takes place in the light-dependent reaction zone, which is then coupled with the light-independent, enzymatic synthesis in the downstream of the microchannel. PMID- 21655631 TI - Molecularly imprinted solid-phase extraction of matrine from radix Sophorae tonkinensis. AB - In the study, molecularly imprinted polymers (MIPs) with special molecular recognition properties of matrine (MAT) were prepared in our lab, using melamine urea-formaldehyde (MUF) as the functional monomer and matrine as the template. An equilibrium binding experiment was performed to investigate the binding ability of the MIPs, and indicated that the MIPs had a high adsorption and good elution ability to the target molecule MAT, when the template/functional monomer ratio (T/M) was 5 mg g(-1). Scatchard analysis and isothermal equilibrium adsorption indicated that only one kind of binding site had existed in the MAT-imprinted polymers with its dissociation constants estimated to be 3.31 * 10(-4) mol L(-1) (200-400 mesh (inch(-1))) and 6.83 * 10(-4) mol L(-1) (over 400 mesh (inch(-1))) depending on the mesh of the MIPs. MAT purification and elution experiments were carried out using MIPs as the solid-phase extraction (MISPE) sorbent, and acetone, water, and chloroform as the elution solvents. The results demonstrated that MIPs achieved their highest adsorption capability after treatment with alkaline solution, while acetone was the most efficient elution solvent. Then, a crude extraction of matrine in radix Sophorae tonkinensis was performed using these MIPs as the separation medium. The results showed that MIPs had a high MAT selectivity, and the amount of matrine content obtained by MISPE was 1.4-fold to that obtained by liquid-liquid extraction. PMID- 21655632 TI - Encoded peptide libraries and the discovery of new cell binding ligands. AB - Cells over-expressing integrins or CCR6 were incubated on a DNA microarray, pre hybridized with a 10,000 member PNA-encoded peptide library allowing novel cell specific ligands for integrins and CCR6 to be identified. PMID- 21655633 TI - Lithium-doped MOF impregnated with lithium-coated fullerenes: a hydrogen storage route for high gravimetric and volumetric uptakes at ambient temperatures. AB - We theoretically demonstrated that by the impregnation of Li-decorated IRMOF-10 with Li-coated C(60), the hydrogen storage capacity is improved to be 6.3 wt% and 42 g L(-1) at 100 bar and 243 K. Both the gravimetric and volumetric hydrogen uptakes reach the 2015 DOE target at near ambient conditions. PMID- 21655634 TI - Dendrimers and miktoarm polymers based multivalent nanocarriers for efficient and targeted drug delivery. AB - The delivery of biologically active agents to the desired site in the body and intracellular organelles is still a big challenge despite efforts made for more than five decades. With the elaboration of synthetic methodologies to branched and hyperbranched macromolecules such as miktoarm stars and dendrimers, the focus has shifted to nanocarriers able to release and direct drug molecules to a desired location in a controlled manner. We present here recent developments in the field of targeted drug delivery with a focus on two specific macromolecular nanocarriers, dendrimers and miktoarm stars, and provide examples of these nanocarriers tested in different biological systems. A particular attraction of miktoarm stars is their versatility in achieving superior drug loading within their self-assembled structures. Advantages of dendrimers over linear polymers are that the former provide a platform for development of multivalent and multifunctional nanoconjugates, in addition to their ability to accommodate a large number of molecules inside, or at their surfaces. PMID- 21655635 TI - Highly selective, sensitive and quantitative detection of Hg2+ in aqueous medium under broad pH range. AB - Amidothiourea linked acridinedione derivatives selectively detect Hg(2+) in unbuffered aqueous solution under broad pH range with both single- and two-photon excitation. The observed linear fluorescence intensity change allows the quantitative detection of Hg(2+) in the concentration range of 22 nM-0.33 MUM with the lower detection limit of 2 nM. PMID- 21655636 TI - Molecular tectonics: design of enantiomerically pure helical tubular crystals with controlled channel size and orientation. AB - The combination of four enantiomerically pure organic tectons composed of a rigid chiral backbone bearing two terminal pyridyl coordinating sites with ZnSiF(6) behaving as an infinite pillar leads to the formation of tubular 2-D enantiomerically pure helical channels with controlled size and orientation. PMID- 21655637 TI - Efficient aerobic oxidative synthesis of 2-aryl quinazolines via benzyl C-H bond amination catalyzed by 4-hydroxy-TEMPO. AB - A novel and efficient aerobic protocol for the oxidative synthesis of 2-aryl quinazolines via benzyl C-H bond amination by a one-pot reaction of arylmethanamines with 2-aminobenzoketones and 2-aminobenzaldehydes has been carried out using the 4-hydroxy-TEMPO radical as the catalyst, without any metals or additives. PMID- 21655638 TI - Inkjet-like printing of single-cells. AB - Cell sorting and separation techniques are essential tools for cell biology research and for many diagnostic and therapeutic applications. For many of these applications, it is imperative that heterogeneous populations of cells are segregated according to their cell type and that individual cells can be isolated and analysed. We present a novel technique to isolate single cells encapsulated in a picolitre sized droplet that are then deposited by inkjet-like printing at defined locations for downstream genomic analysis. The single-cell-manipulator (SCM) developed for this purpose consists of a dispenser chip to print cells contained in a free flying droplet, a computer vision system to detect single cells inside the dispenser chip prior to printing, and appropriate automation equipment to print single-cells onto defined locations on a substrate. This technique is spatially dynamic, enabling cell printing on a wide range of commonly used substrates such as microscope slides, membranes and microtiter plates. Demonstration experiments performed using the SCM resulted in a printing efficiency of 87% for polystyrene microbeads of 10 MUm size. When the SCM was applied to a cervical cancer cell line (HeLa), a printing efficiency of 87% was observed and a post-SCM cell viability rate of 75% was achieved. PMID- 21655639 TI - New mediators of vascular damage in dialysed patients. AB - Cardiovascular events are the main causes of mortality in dialysed patients. Traditional risk factors such as hypertension, aging, smoking, diabetes, and abnormal lipid metabolism does not fully explain the high frequency of cardiovascular disease in renal patients, indicating that some other distinct pathogenesis may be involved. Vascular calcification have been associated with high cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. It is an active process that resembles osteogenesis, regulated by bone proteins and osteoblast-like cells. Elements involved in the pathogenesis are: the risk factors that initiates the process, the promoters released and overexpressed and the dysregulation of the inhibitor factors of extraskeletal calcifications. Although researches in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in vascular calcification, many questions remain unanswered. PMID- 21655640 TI - Colorectal cancer and the 7th revision of the TNM staging system: review of changes and suggestions for uniform pathologic reporting. AB - Colorectal cancer (CRC) is a neoplastic disease with a continuously growing incidence in Romania and throughout the world. Although the surgery remains the first line treatment for most of the cases, newly discovered targeted molecular therapies - effective for some patients, but with various side effects and significant financial burden for the national health systems - requires not only stratification of patients in prognostic groups but also evaluation of some non anatomic factors with major impact on the prognosis and therapeutic strategy. The AJCC/UICC TNM staging system, in his 7th revision, effective for cases diagnosed on or after January 1, 2010, responds to these needs. On the other hand, the role of the pathologist is increasing in terms of workload and amount of information to be included in the pathology report in order to deliver a personalized diagnosis. There are concerns worldwide regarding relevance, validity and completeness of pathologic reporting of CRC in the absence of a uniform reporting format. Therefore, suggestions for a standardized pathology report of CRC are made, based on TNM 7 and recent, up-to-date conclusive published data. PMID- 21655641 TI - Evaluation of proliferation potential in thyroid normo-/hypofunctioning and hyperfunctioning nodules. AB - INTRODUCTION: Thyroid follicular adenomas (FA) and adenomatous thyroid nodules (AN) - lesions that are frequently found in areas with iodine deficiency, can be normo-/hypofunctioning (scintigraphically cold - SCN) or hyperfunctioning (scintigraphically hot - SHN) nodules. AIM: Evaluation of proliferation potential in thyroid nodules on tissue samples obtained at surgery from euthyroid patients clinically diagnosed with SCN and from patients with thyroid hyperfunction and SHN. MATERIALS AND METHODS: We investigated the proliferation activity estimated by assessing PCNA and Ki-67 proliferation markers in 20 SCN (eight FA and 12 AN) and 16 toxic nodules (six hyperfunctioning FA and 10 toxic multinodular goiters), on formalin-fixed and paraffin-embedded tissue samples, 4-5 MUm thick; we used the immunohistochemical technique in LSAB system (DAB visualization) with anti PCNA (PC10) and anti-Ki-67 (MIB-1) monoclonal antibodies. For each case, we calculated the proliferation index PI-PCNA and PI-Ki-67. The dates were statistically evaluated using the t-unpaired test. RESULTS: We observed a higher PI-PCNA in thyroid nodules than in the normal surrounding thyroid tissue, with statistically significant values for FA (14.3% vs. 3.8%; p<0.029) and also for AN (8.36% vs. 1.24%; p<0.001). The mean PI-Ki-67 in nodules vs. surrounding thyroid tissue was 1.64% vs. 1.10% in FA (p<0.35) and 1.07% vs. 0.51% in AN (p>0.05). We also noted: (1) significantly higher PI-PCNA values (p < 0.01) in FA (14.03%) than in AN (8.36%), as compared to statistically insignificant values for Ki-67 (1.64% vs. 1.07%; p>0.05); (2) increased proliferation rate (p<0.01) in thyroid nodules with aspects of lymphocytic thyroiditis (LT) (PI-Ki-67 was 1.21%) as compared to nodules without LT (PI-Ki-67 was 0.12%); (3) a mean PI-PCNA of 8.5% and PI-Ki-67 of 4.61% in toxic thyroid nodules (TTN) vs. 3.01% and 1.5% in normal surrounding thyroid, respectively. CONCLUSIONS: The clinical expression of SCN is the consequence of increased thyrocyte proliferation in the nodules; the increased proliferative potential of TTN thyrocytes is a common feature of nodules, independent of their histopathological characteristics. PMID- 21655642 TI - Histopathological and immunohistochemical features of gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. Major advances in their definition and classification and the understanding of their molecular mechanisms have recently been made. These advances have become a model of targeted therapy in oncology. The diagnosis of GISTs relies on histological arguments - proliferation of spindle cells, seldom of epithelioid cells or both spindle and epithelioid cells and on immunohistochemical arguments - expression of CD117 usually associated with CD34 expression. The evaluation of the prognosis is essential and based on a simple algorithm using two prognostic parameters, tumor size and mitotic index. The aim of this paper is a complex histopathological assessment, using both classic and modern (immunohistochemistry) techniques, of the GISTs comprised in the study. GISTs occur mainly in older adults (median age 60-69 years), anywhere along the gastrointestinal tract but also retroperitoneal. Most of them were nodular (75%), tumor necrosis and mucosal ulceration being the most frequent encountered secondary alterations; these modifications proved to be significantly correlated with large tumor size and high malignancy. Immunohistochemical evaluation revealed that 77 (97%) cases of GISTs presented a positive reaction for CD117, 50 (63%) cases were positive for CD34, 19 (24%) were positive for SMA and only 10 (13%) were positive for S100. Immunohistochemical evaluation remains an important tool of pathology in the diagnosis of GISTs, in the differential diagnosis from other gastrointestinal mesenchymal tumors and represents the gold standard for diagnosis of these tumors and an eligibility criterion for imatinib therapy. PMID- 21655643 TI - Pulmonary venous compartment of the airways circulation. AB - Bronchial circulation has three components: a systemic arterial component represented by the bronchial arteries; a pulmonary venous component represented by the pulmonary veins; and a systemic venous component represented by the bronchial veins. We have used vascular casting, microscope dissection coupled with tracers and light microscopy to define the detailed anatomy of the pulmonary venous compartment of the bronchial circulation. We have found that the extrapulmonary drainage territory of the pulmonary veins correlate with the forming pattern of the right superior pulmonary vein. In the case of a large apical venous trunk, pulmonary veins drain the venous blood of the main bronchia, terminal portion of the trachea and of the tracheobronchial lymph nodes. In the case of the systemic venous drainage of the extrapulmonary airways, we constantly found a pulmonary component which drains the venous blood from the subcarinal lymph nodes and the medial side of the main bronchia. PMID- 21655644 TI - Stage pT3a of renal clear cell carcinoma: do tumors with sinus fat involvement behave the same as those with perinephric fat involvement? AB - INTRODUCTION: In this report, we review our series of patients with pT3a clear cell renal carcinoma (CCRC) and comment on their outcome. MATERIALS AND METHODS: We have reviewed 260 cases of CCRC operated in the Mostoles General Hospital, Madrid, between 2000 and 2004. We have found 30 cases with pT3a tumors. Eleven of them were invading the perinephric fat, nine were invading the renal sinus fat and ten were pT3a locally but showed metastasis at the moment of diagnosis (cM1, TNM stage IV). We have analyzed the prognostic influence of histopathological parameters (vascular invasion, size, Fuhrman grade) and also immunohistochemical ones (p53, cyclin D1, proliferation index with Ki67, bcl-2 and vascular density with CD34). RESULTS: Only six of 10 patients with perinephric fat involvement died of disease compared with all the patients with sinus fat involvement, suggesting a worse prognosis for the latter. However, this difference did not reach statistical significance, probably due to the small number of cases. Of all the clinical, histological and immunohistochemical factors analyzed, only cyclin D1 was a strong indicator of worse prognosis in pT3a CCRC (p=0.02). We could not show any statistically significant relation between vascular density and prognosis. Vascular invasion was the only histological parameter that showed a trend toward significance (p=0.09). CONCLUSIONS: Sinus fat involvement might be underestimated in some series. A protocol for nephrectomy specimen handling could improve the detection rate of sinus fat involvement and allow the performance of randomized prospective studies to determine whether these tumors behave similarly. PMID- 21655645 TI - Diabetes mellitus type 1 induces dark neuron formation in the dentate gyrus: a study by Gallyas' method and transmission electron microscopy. AB - BACKGROUND: Diabetes mellitus type 1 is a chronic endogenous stressor. We investigated the effects of a diabetes mellitus type 1 on dark neuron formation in granular layer of dentate gyrus. MATERIALS AND METHODS: Diabetes was induced by a single intraperitoneal (IP) injection of streptozotocin (STZ) at a dose of 60 mg/kg dissolved in saline. Control animals were received only saline. In the end of eight weeks, the brains were removed and hippocampi studied by Gallyas' method and transmission electron microscopy. RESULTS: The comparison between the rate of dark neurons in diabetic group (223 +/- 25) and of control (5.75 +/- 4.34) showed significant level of difference (p<0.05). Ultrastructurally dark neurons showed apoptotic death criteria namely: dark and electron dense appearance, chromatin condensation, margination and clumping. CONCLUSIONS: Present results suggest that STZ-induced diabetes accelerates dark neuron formation with apoptotic criteria in granule layer of dentate gyrus. PMID- 21655646 TI - The diagnostic value of VEGF expression in the renal parenchyma tumors. AB - Tumor angiogenesis emerged as an important concept in cancer therapy over two decades ago, and was extensively studied by the discovery of VEGF family members. VEGF, also known as vascular permeability factor, is a generic name for VEGF-A, which is one of the members involved in angiogenesis. VEGF is the most important angiogenic factor, with significant effects on tumor angiogenesis. Tumor expression of VEGF was not the first angiogenesis indicator, but a growing number of studies have demonstrated that VEGF could be a prognostic factor, independent even from microvascular density, which is increased by its expression. Renal parenchyma tumors are a heterogeneous group of malignancies, difficult to classify or monitor, which prompts for the assessment of novel markers useful for the investigation of tumor histogenesis or prognostic assessment. VEGF expression in renal parenchyma tumors is poorly studied, with most of the articles published so far focusing on antiangiogenic usage in renal carcinoma therapy. The aim of this study is to detect the expression pattern of VEGF in renal parenchyma tumors by immunohistochemistry. PMID- 21655647 TI - Alterations in expression of cartilage-specific genes for aggrecan and collagen type II in osteoarthritis. AB - PURPOSE: Osteoarthritis is characterized by a progressive degradation of cartilage structure and function. This study tests the hypothesis that disease severity is characterized by alterations in expression of cartilage-specific genes for aggrecan and collagen type II. EXPERIMENTAL DESIGN: Cartilage, discarded from six subjects undergoing knee replacement, was subdivided into homogeneous portions by the surgeon according to the Outerbridge classification. For four subjects, it was possible to separate the tissue into two or three fractions with different disease severity. Portions of each sample were prepared either for histological analysis and ranking according to the Mankin system or for RNA extraction. Quantitative, competitive RT-PCR assays were used for measurement of mRNA for aggrecan, collagen type II, and glyceraldehyde-3 phosphate dehydrogenase. Clinical grading was correlated with histological score (Spearman r=0.60, p=0.043). RESULTS: There was a striking decrease in expression of aggrecan and collagen II that was correlated with increase in the grade in regions of cartilage within an individual subject. In the series of 12 samples, there was an inverse correlation between aggrecan expression and osteoarthritis grade (Spearman r=-0.59, p=0.042). CONCLUSIONS: In conclusion, there was an inverse relationship between regional disease severity in osteoarthritis and expression of aggrecan. Use of quantitative, competitive RT-PCR is practical for assessment of chondrocyte gene signatures. PMID- 21655648 TI - Practical value of the complex analysis of sentinel lymph nodes in colorectal carcinomas. AB - BACKGROUND: Despite modern factors, which seem to predict outcome, lymph node (LN) status remain the main prognostic factor, which also shows the need for complex oncotherapy in colorectal carcinomas (CRC). Sentinel lymph nodes (SLNs) mapping is a very controversial method, which can increase the number of identified LN. MATERIALS AND METHODS: In 28 patients who underwent surgical intervention between December 2009 and December 2010, we performed in vivo SLNs mapping followed by ex vivo examination at 1, 10, and 48 hours. All blue nodes were separately included. In cases without LN metastases (pN0) five multilevel sections and immunohistochemical stain with cytokeratin 20 were performed in SLNs. RESULTS: Two cases were excluded because they were in pT4 stage. In one case the diameter of lymph nodes was about 10 mm and we obtained a false negative result (negative SLNs with positivity in the non-SLNs). From the other 25 cases, 13 do not presented LN metastases or micrometastases, nine had metastases only in the SLNs and the other three in both SLNs and non-SLNs. Mean identified number of LNs was 15. The blue dye intensity increased after formalin fixation and some nodes with metastases were blue stained only after 10 hours. CONCLUSIONS: SLNs mapping is a simple and inexpensive technique, which can improve the management of CRC. All in vivo and ex vivo blue LNs should be considered SLNs. Ultrastaging of SLNs is an expensive method, with uncertain results. High diameter of LNs seems to be an exclusion criterion for SLNs mapping. PMID- 21655649 TI - Could stored blood transfusions (SBT) alter the mechanisms implied in wound healing, in burned patients? AB - Several years ago, researchers reported several complications produced after blood transfusions such as transfusion reactions, the transmission of a variety of infectious agents, etc. Recently, many authors appreciate that the stored blood transfusions (SBT) create an important damage for patients' life, because of oxygen metabolism disturbances, induced earlier, after three repeated transfusions and maintained longtime after. Our study proposed to note the consequences of SBT on wound healing, in burned patients, who were submitted to skin grafting and remained in hospital for a long period. We tried estimate the pathophysiological mechanisms implied in microcirculation's failure, microvascular systemic deficiency and death. RESULTS: Critically patients receiving SBT repeated frequently (six times/monthly for skin grafting) have an oscillatory outcomes depending by the reactivity of their biological terrain, as reflected by a several parameters we have measured. CONCLUSIONS: SBT administered as a restrictive transfusions to the patients with hemoglobin values <8 g% and hematocrit <35% has good effects on wound healing evolution. PMID- 21655650 TI - Distribution of sympathetic fiber areas in the sensory nerves of forearm: an immunohistochemical study in cadavers. AB - PURPOSE: Secondary to peripheral nerve injuries, involvement of sympathetic fibers complications such as Complex Regional Pain Syndrome (CRPS) have been reported. There are no reports available in the distribution of the sympathetic fibers/areas of sensory nerves in the forearm. MATERIALS AND METHODS: The present study aim is an attempt to find the distribution of sympathetic fibers in the anterior branch of medial antebrachial cutaneous nerve of forearm (AMACN), lateral antebrachial cutaneous nerve of forearm (LACN) and superficial branch of radial nerve (SBRN) at cubital fossae. We have studied on 17 fresh human cadaveric AMACN, LACN and SRBN samples. Frozen sections of these nerves were processed by immunohistochemical (tyrosine hydroxylase) method for sympathetic fibers. RESULTS: Sympathetic fibers area (Asym) was found to be more in SBRN when compared to AMACN and LACN. The comparison of the sympathetic index (SI = sympathetic fibers area / total fascicular area of the nerve) between AMACN and LACN (p-value < 0.001), AMACN and SBRN (p-value <0.001), LACN and SBRN (p-value < 0.001) were statistically significant. Sympathetic index (SI) for SBRN was more when compared to AMACN and LACN. SBRN had maximum percentage (5.16%) of Asym when compared with LACN and AMACN. CONCLUSIONS: Sympathetic fibers area (Asym), sympathetic index (SI) and percentage of sympathetic fibers area (Asym %) were found to be more in SBRN when compared with AMACN and LACN. These results of the study might help to explain sympathetic system-related diseases in the area of distribution of AMACN, LACN and SBRN. PMID- 21655651 TI - CD105/Ki67 double immunostaining expression in liver metastasis from colon carcinoma. AB - The liver is the most common and critical site for the development of colon cancer metastases. Tumor angiogenesis in liver metastasis from colon carcinoma is a controversial subject. Liver microenvironment, immunophenotypical and morphological particularities of hepatic vessels are only few aspects, which establish difficulties in quantification of tumor vascularisation from liver metastasis. The aim of this work is to study the distribution of CD105 positive vessels and the proliferation rate of endothelial cells from liver metastasis of colon carcinoma based on double immunostaining CD105/Ki67. In liver metastasis from well-differentiated adenocarcinoma we found a high number of CD105+/Ki67- vessels. On the other hand, in liver metastasis from poorly differentiated adenocarcinoma we noticed rare CD105+/Ki67+ vessels. It is hypothesized that neoangiogenesis of liver metastasis is performed through intussusceptive mechanism rather than sprouting and could be supported by the presence of kissing phenomenon, CD105 positive transcapillary pillars and the absence of endothelial cells proliferation in this vessels. We conclude that in liver metastasis principal mechanism of neovascularisation formation is based on intussusception. PMID- 21655652 TI - The arthroscopy-histological criterion link in the result's estimation of the endoscopic treatment by resection of the knee's meniscus lesions. AB - The authors present the results of a statistical, clinical, imaging X-ray and optical microscopic studies of some lesions of knee's meniscus, the arthroscopy allowing this structure's biopsy during the endoscopic procedures of resection. These histological criterions are very important estimation factors of long-term results of these techniques, often the microstructure looking different to the appearing normal macroscopic aspect. PMID- 21655653 TI - Morphologic, morphometrical and histochemical proprieties of the costal cartilage in children with pectus excavatum. AB - Pectus excavatum (PE) is the most frequent anterior chest deformity occurring in approximately one of 1000 live births. Despite the excellent achievements in the treatment of the disease, the etiology of PE is yet to be clarified. It is believed that the cause for PE is an intrinsic costal cartilage abnormality leading to an overgrowth of the cartilage, which pushes the sternum backward. Several histological studies revealed contradictory results and failed to identify a clear structural abnormality of the costal cartilage responsible for the apparition of PE. In this article, we focused on identifying the microscopic disturbances of the costal cartilage in patients with PE. We obtained cartilage samples from 29 children with PE and 18 control cartilage samples. The samples were subjected to morphologic, morphometrical and histochemical assess. The results indicate a young, immature pattern of the cartilage matrix with a normal cell/matrix ratio. These results sustain the theory that the cause of PE is to be found inside the costal cartilage and the most plausible cause is a global overgrowth of the costal cartilage. PMID- 21655654 TI - Endometrial carcinomas: correlation between ER, PR, Ki67 status and histopathological prognostic parameters. AB - We present a retrospective histopathological study that included a total of 22 endometrial carcinomas, from patients that were operated in the Obstetrics and Gynecology Clinics of the Emergency County Hospital of Craiova. This current study investigates these cases in order to assess the prognostic value of the correlations between the expression of estrogen and progesterone receptors, Ki67 expression and the histological stage, tumor stage, the degree of myometrial and vascular invasion. The study showed that estrogen and progesterone positive receptors correlate significantly with early stage and well differentiated tumors. The invasion of more than half the thickness of the myometrium and the vascular invasion were associated with decreased expression of the analyzed receptors and an increased proliferation index. PMID- 21655655 TI - Power Doppler sonography, a non-invasive method of assessment of the synovial inflammation in patients with early rheumatoid arthritis. AB - OBJECTIVE: To detect synovitis is important in both the diagnosis and outcome assessment of early rheumatoid arthritis. This study was meant to assess the validity and reproducibility of ultrasonography (US) as a mean of detection for the knee synovitis, by comparing US findings with clinical examination and histopathological findings in synovial membrane. METHODS: The study group included 65 patients with early rheumatoid arthritis - below 12 months from the debut, naive for DMARDs, in whom demographic data - gender, age, disease duration, the number of tender and swollen joints, HAQ score (Health Assessment Questionnaire) and serum samples for CRP, RF, anti-CCP2 antibodies (ELISA, QUANTA LiteTM, CCP IgG, INOVA Diagnostics Inc, USA), VEGF (ELISA, VEGF2, DRG International, IRC, USA) determination were recorded. Disease Activity Score for 28 joints (DAS28) was calculated. PDS signal was scored from 0 to 3 according to the overall expression of PDS findings at the knees. A sample of synovial tissue was obtained in 35 patients during the arthroscopy, and the vascularisation of the synovial tissue was evaluated by immunohistochemistry and was analyzed qualitatively by a pathologist who was unaware of the PDS findings. Written, informed consent was obtained from each patient before entering the study. They all had active synovitis of the knee, ultrasonographically confirmed, with the identification of the target biopsy sites. The study was approved by the Ethics Committee of the University of Medicine and Pharmacy of Craiova. RESULTS: Angiogenesis was evaluated and quantified by immunohistochemical evaluation of synovial VEGF, one of the most specific endothelial growing factors, that proved to correlate significantly with the serum levels of VEGF, DAS28 as well as with the power Doppler sonography (PDS) score. CONCLUSIONS: The statistical analysis of the data showed that PDS could be used as non-invasive marker with predictive value regarding synovial inflammation and disease progression in early forms of the disease as well as a useful method in the assessment of the therapeutic response. PMID- 21655656 TI - Relationship between sperm chromatin status and ICSI outcome in men with obstructive azoospermia and unexplained infertile normozoospermia. AB - This study was done to evaluate the effect of sperm source on chromatin integrity and ICSI outcomes. One hundred and thirteen samples containing epididymal aspirates of 57 obstructive azoospermic men and 56-ejaculated semen of normozoospermic men were included in this study. Sperm chromatin status was evaluated by Chromomycin A3 (CMA3), Aniline Blue (AB) and Toluidine Blue (TB). Fertilization rate and embryo quality were recorded. In epididymal group the percentage of sperms stained with AB, CMA3 and TB were significantly higher compared to ejaculate group while fertilization rate (60.6% vs. 74.04%) was significantly lower. However, embryo quality was not significantly different between two groups. In addition, abnormal sperm chromatin condensation and DNA fragmentation were not correlated with fertilization rate and embryo quality. Our results highlight the role of epididymis in sperm maturation and confirm that ICSI using ejaculated sperm is the gold standard for treatment of infertile men. PMID- 21655657 TI - P16, c-erbB2 and Ki67 immunoexpression in urothelial carcinomas of the bladder. AB - The study included a total of 28 cases of urothelial carcinomas, which were analyzed histopathologically and immunohistochemically using anti-human p16, c erbB2 and Ki67 antibodies and the LSAB/HRP work system. Histopathological analysis revealed the presence of urothelial carcinomas with different degrees of differentiation and invasion in the lamina propria or muscularis propria. The immunostain for p16, c-erbB2 and Ki67 was present at the nuclear and cytoplasmic level, respectively at membrane and nuclear level. Immunoreactions had quantified values, which were statistically correlated with the degree of differentiation in case of c-erbB2 or depth of invasion for p16. Tumor activity status and the risk of progression of bladder urothelial carcinomas can be assessed objectively using the antibody panel consisting of p16, c-erbB2 and Ki67. PMID- 21655658 TI - Age assessment from mandible: comparison of radiographic and histologic methods. AB - Age assessment is an integral and important aspect of forensic odontology. The use of long bones and teeth has been documented since decades. The aim of this study was to use both radiographic and histologic methods of age estimation and to determine which method gives a near actual age. Orthopantomograph (OPG) was used to study the radiographic changes and ground sections were made for histologic study. Of the various parameters studied, we concluded that the histologic parameters recorded ages, which were closer to the actual age. Of the histologic parameters, two to three parameters when combined were still better. PMID- 21655659 TI - Identification of different subtypes of breast cancer using tissue microarray. AB - Breast cancer may be classified into luminal A, luminal B, HER2+/ER-, basal-like and normal-like subtypes based on gene expression profiling or immunohistochemical (IHC) characteristics. The main aim of the present study was to classify breast cancer into molecular subtypes based on immunohistochemistry findings and correlate the subtypes with clinicopathological factors. Two hundred and seventeen primary breast carcinomas tumor tissues were immunostained for ER, PR, HER2, CK5/6, EGFR, CK8/18, p53 and Ki67 using tissue microarray technique. All subtypes were significantly associated with Malay ethnic background (p=0.035) compared to other racial origins. The most common subtypes of breast cancers were luminal A and was significantly associated with low histological grade (p<0.000) and p53 negativity (p=0.003) compared to HER2+/ER-, basal-like and normal-like subtypes with high histological grade (p<0.000) and p53 positivity (p=0.003). Luminal B subtype had the smallest mean tumor size (p=0.009) and also the highest mean number of lymph nodes positive (p=0.032) compared to other subtypes. All markers except EGFR and Ki67 were significantly associated with the subtypes. The most common histological type was infiltrating ductal carcinoma, NOS. Majority of basal-like subtype showed comedo-type necrosis (68.8%) and infiltrative margin (81.3%). Our studies suggest that IHC can be used to identify the different subtypes of breast cancer and all subtypes were significantly associated with race, mean tumor size, mean number of lymph node positive, histological grade and all immunohistochemical markers except EGFR and Ki67. PMID- 21655660 TI - Malignant melanoma of nasal cavity. AB - INTRODUCTION: Malignant melanoma rarely develops in the mucous membranes. Statistical data indicate that rhinosinusal mucosal melanoma was reported in less than 1% of all melanic tumors and in 2-8% of all cancers developed in the nasal fossae and sinuses. Due to reduce and non-specific symptoms and a high degree of invasion away, patients come for a medical expertise in advanced stages of the disease, which is leading to a poor prognosis. The average five-year survival is 20-30%. PATIENT AND METHODS: We present the case of a 65-year-old female patient coming from a rural environment, hospitalized for unilateral nasal obstruction and nasal mucosal changes of a blackish appearance on all of the walls. RESULTS: The endoscopic examination revealed a matter and of a blackish appearance nasal mucosa along the whole length of the left nasal cavity (septum, turbinates, floor, ceiling). Presumptive diagnosis of melanoma led to the excision of inferior and middle turbinate mucosa, floor and ceiling mucosa and the excision of the nasal septum, keeping the columella and the posterior portion. Histopathological and mostly immunohistochemical exams confirmed the diagnosis of malignant melanoma. To determine the phenotype of tumor cells, it was evaluated their immunostaining for HMB-45, Melan-A, S-100, vimentin, cyclin D1 and CD44 markers. The patient followed oncologic treatment and radiochemotherapy, presenting a favorable evolution with the absence of loco-regional recurrence or distant metastasis 24 months postoperatively. PMID- 21655661 TI - Cardiac allograft vasculopathy in adult human recipients: a case series of seven patients and review of literature. AB - BACKGROUND: Chronic rejection (CR) also called cardiac allograft vasculopathy (CAV) is, besides infections and malignant tumors, the leading cause of death during the late period of post-heart transplant. PATIENTS AND METHODS: In this paper, we present a series of seven cases with chronic post-transplant cardiac rejection in the light of our experience related to histopathological aspects, difficulties in diagnosing and survival time. RESULTS: Our study comprises patients whose ages ranked at the time of transplant between 33 and 58 years, with a mean age of 47.71 years, the ratio between men and women being 6:1. Chronic rejection - cardiac allograft vasculopathy occurred in all seven patients comprised in this study, the earliest in the second year post-transplant (three patients), followed by the third year (one patient), the seventh and eighth year (one patient) and the latest survival period being over 11 years (one patient). Four out of the seven patients with chronic rejection events were preceded by episodes of acute cellular rejection. The most convincing indirect evidence of chronic rejection in endomyocardial biopsies were: ischemic events of the myocardiocytes and impaired microvascular network because of perivascular and interstitial fibrosis. CONCLUSIONS: Our study shows that the most important morphological factors correlated with the manifestation of chronic rejection were the episodes of acute cellular rejection or perivascular and interstitial fibrosis, these injuries also being indirect signs mainly detectable at the level of endomyocardial biopsies. PMID- 21655662 TI - A rare variant of internal anatomy of a third mandibular molar: a case report. AB - The several anatomical variations existing in the root canal system may contribute to failure of the root canal therapy. Knowledge of the internal dental morphology is a complex and extremely important point for planning and performing endodontic therapy. This paper reports the case of a left mandibular third molar that presented only one dental conical root and only one aberrant radicular canal with an initial annular portion situated in the coronar third of the root and a linear portion at the level of the other two thirds of the dental root, which opened through an apical foramen. Root canal therapy and case management are described. Features like wide crown access, adequate illumination and use of exploring files where important for successful completion of the endodontic treatment. The treatment was performed through conventional methods. This clinical case constitutes a rare anatomical variant of internal radicular morphology. PMID- 21655663 TI - Anatomical variations of the hepatic portal vein associated with incomplete celiac trunk. AB - An association of two anatomical variations was revealed in a 65-year-old male cadaver: the first variation concerns the forming of the trunk of the hepatic portal vein, while the second concerns the branches of the celiac trunk. In this case, the inferior and superior mesenteric veins form a common trunk that is further united with the splenic vein and gives rise to the hepatic portal vein. At the same time, the existence of an incomplete (branched) celiac trunk was revealed, the hepatosplenic trunk from which the common hepatic artery and the splenic artery arise; the left gastric artery arises separately at 0.5 cm superolaterally from the origin of the celiac trunk. Familiarity with this anatomical variation provides useful information for abdominal surgery procedures. PMID- 21655664 TI - Massive cortico-subcortical ischemic stroke with a consecutive hemorrhagic event: a case report. AB - BACKGROUND: We report a case of a 78-year-old woman with a large cerebral infarction probably due to athermanous embolism following atrial fibrillation. CASE DESCRIPTION: The patient, known with atrial fibrillation, high blood pressure and heart failure, complained of headache and motor impairment on the left side of the body. CT imaging revealed a subacute ischemic lesion in the right fronto-occipital lobes, and an old ischemic lesion in the right fronto parietal lobes. Anticoagulant treatment was conducted with careful monitoring of the coagulability status. After almost three weeks, suddenly the patient became comatose and died shortly after. Macroscopic and microscopic examination confirmed the cortico-subcortical ischemic lesions, but also identified a fresh hemorrhagic site in pons, distant from the initial lesion sites. An immunohistochemical study identified blood vessels in the ischemic sites completely isolated from any glial support. CONCLUSIONS: This is a rare case of a large cerebral infarction with a pontine hemorrhagic event. PMID- 21655665 TI - Chondrosarcoma of the upper end of the femur. AB - Chondrosarcoma is a malignant tumor that produces cartilage matrix. Occurs in the fourth to sixth decades and has a male to female ratio of 2/1. It is most common in the long bones and on the surface of the pelvis. The authors present a case of chondrosarcoma of the upper end of the femur of a 50-year-old female patient who has come in our Department of Orthopedics and Traumatology two month ago, complaining of severe and persistent pain in the left hip joint and presenting limitation of adduction movement, limitation of internal-external rotation movements, and also could not be able to do thigh flexion on the abdomen. The woman presented a four-month history of persistent and severe pain, not assigned at anti-inflammatory drugs. Laboratory tests not had shown any significance. On radiographies and magnetic nuclear resonance the lesion was shown very clear, deciding for biopsy. The tumor had been large surgical excised with safe limits. Histopathology indicated the histological feature as a differentiated chondrosarcoma, grade III. Our patient has started the chemotherapy and radiation. PMID- 21655666 TI - Rhino-cerebral zygomycosis after allogeneic transplant: case report and literature review. AB - The proportion of patients with hematological malignancies (HM) who develop rare invasive fungal infections (IFI) has increased worldwide over the past few decades. Zygomycosis is an opportunistic fungal infection, which begins in the nose and paranasal sinuses due to inhalation of fungal spores. Rhino-cerebral zygomycosis is the most common form of the disease, it typically develops in diabetic or immunocompromised patients and presents as an acute fulminate infection, which is often lethal. We report a case of rhino-cerebral zygomycosis in an allotransplanted patient to emphasize early diagnosis and treatment of this potentially fatal fungal infection. We discuss different risk factors, specific diagnosis procedures and review the current concepts in management of zygomycosis. PMID- 21655667 TI - The unexpected evolution of a case of diffuse large B-cell non-Hodgkin lymphoma. AB - The diffuse large B-cell lymphoma (DLBCL) represents the most common type of aggressive non-Hodgkin's lymphoma with a heterogeneous morphology, biology and clinical presentation. Gene expression profiling studies identified three distinct molecular subtypes of DLCBL arisen from B-cells at different stages of differentiation: germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, primary mediastinal B-cell lymphoma (PMBL). The most relevant oncogenic pathways in diffuse large B-cell lymphoma are: deregulated B-cell receptor/proliferation signaling, BCL6 and NF-kB constitutive expression, defects in apoptosis and neoangiogenesis. The treatment of DLBCL has been completely modified in the last ten years by combination of anti-CD20 monoclonal antibody (rituximab) and CHOP chemotherapy, which is now the first line therapy. In the last years, there have been reported several cases of progressive multifocal leukoencephalopathy (PML) at patients with rheumatoid arthritis treated with rituximab. Progressive multifocal leukoencephalopathy is possible as an adverse reaction to rituximab at patients treated with R-CHOP for diffuse large B-cell lymphoma. PMID- 21655668 TI - A unique case with splitting of the median nerve by the ulnar artery. AB - Variations of the median nerve and ulnar artery have been well documented in the literature. In the present case, splitting of the median nerve by the ulnar artery is presented. Our literature searches revealed that there was no article, to our knowledge, describing such splitting. We think that this variation should be kept in mind during surgical and diagnostic procedures. PMID- 21655669 TI - Holoprosencephaly sequence. AB - Holoprosencephaly (HPE) sequence is a rare spectrum of cerebral and facial malformations resulting from incomplete division of the embryonic forebrain into distinct lateral cerebral hemisphere. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. A subtype of HPE called middle inter hemispheric variant (MIHF) has been also reported. The etiology is heterogeneous: teratogens, chromosomal abnormalities and single gene mutations can be involved. Holoprosencephaly results in early morbidity and mortality with a reduced survival beyond neonatal period. The disorder is estimated to occur in 1/16,000 live births. This case report presents a male new born diagnosed with holoprosencephaly, accompanied by median cleft palate, absent nasal bones and chromosomal abnormalities. PMID- 21655670 TI - Bilateral incomplete discoid lateral meniscus in a 14 weeks fetus: a case report and review of literature. AB - Discoid lateral meniscus is a rare condition that unilateral is more common than bilateral, here we report a case of bilateral discoid lateral meniscus which was observed in the knee joints of a female fetal cadaver of 14 weeks gestation (92 mm crown-rump length). It was an incomplete type of discoid meniscus, occupying about three fourth of the tibial plateau area. The embryological basis of this anomaly is discussed with emphasize on its clinical implications. This finding support the opinion that discoid lateral meniscus as a true congenital malformation that is not found in normal development. PMID- 21655671 TI - Factor VII activating protease. Single nucleotide polymorphisms light the way. AB - Factor VII activating protease (FSAP) is a circulating serine protease with high homology to fibrinolytic enzymes. A role in the regulation of coagulation and fibrinolysis is suspected based on in vitro studies demonstrating activation of FVII or pro-urokinase plasminogen activator (uPA). However, considering the paucity of any studies in animal models or any correlative studies in humans the role of FSAP in haemostasis remains unclear. In relation to vascular remodeling processes or inflammation it has been convincingly shown that FSAP interacts with growth factors as well as protease activated receptors (PAR). Against this sparse background there are a plethora of studies which have investigated the linkage of single nucleotide polymorphisms (SNP) in the FSAP gene (HABP2) to various diseases. The G534E SNP of FSAP is associated with a low proteolytic activity due to an amino acid exchange in the protease domain. This and other SNPs have been linked to carotid stenosis, stroke as well as thrombosis in the elderly and plaque calcification. These SNP analyses indicate an important role for FSAP in the regulation of the haemostasis system as well as fibroproliferative inflammatory processes. PMID- 21655672 TI - Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. AB - It was the objective of this study to quantify the effects of rivaroxaban administration on global coagulation parameters associated with routine clinical procedures, we collected plasma samples from patients undergoing major orthopaedic surgery receiving rivaroxaban at various time points after drug administration. Forty-seven patients received rivaroxaban (10 mg daily) for venous thromboembolism prophylaxis. Blood samples were collected at four different time points: A) before surgery; B) before drug administration at day 4 5 after surgery (steady state of rivaroxaban); C) 2 hours (h) after drug administration and D) 12 h after drug administration. The prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), antithrombin (AT) level, fibrinogen level by Clauss method (FibC), and derived fibrinogen (dFIB) level were assessed with various reagents. At 2 h after rivaroxaban administration, the PT and aPTT clotting times were significantly prolonged to different extents up to 1.4 fold, whereas 12 h after drug administration, no significant effect was observed. Rivaroxaban administration had no influence on the TT or the FibC concentration. The dFIB assay was differentially affected by rivaroxaban when different reagents were tested. The AT assay dependent on thrombin activity was not influenced by rivaroxaban, whereas the AT levels dependent on factor Xa activity were significantly increased by rivaroxaban. Clinicians should be aware of the time-dependent influence of rivaroxaban on factor Xa-dependent routine coagulation assays. Therefore, routine coagulation parameters should be assessed directly before drug administration to keep the interaction of rivaroxaban low. PMID- 21655673 TI - Platelet factor XIII gene expression and embolic propensity in atrial fibrillation. AB - Nearly 15% of patients with non-valvular atrial fibrillation (NVAF) have left atrial appendage thrombus (LAAT) by transesophageal echocardiography (TEE) and yet the annual stroke rate averages 5%. The aim of this study was to identify variables influencing embolic propensity of LAAT. Platelet RNA was extracted from platelet-rich regions within formalin-fixed, paraffin-embedded specimens obtained from NVAF patients during cardiac surgery (26 LAAT from 23 patients) or peripheral embolectomy (51 thrombi from 41 patients). Platelet RNA was also assessed from whole blood from 40 NVAF patients. Expression of six platelet predominate genes: H2A histone family, A1 domain of factor XIII, integrin alpha2bbeta3; glycoprotein IX, platelet factor 4, glycoprotein Ib, was performed using TaqMan MGB-probe based quantitative real-time polymerase chain reaction. Platelet factor XIII subunit A gene expression was significantly lower in embolised compared to non-embolised thrombi as determined by normalised cycle threshold values (4.0 +/- 1.2 v 2.8 +/- 1.8, p=0.02). Expression of other genes did not differ by embolic status. In conclusion, RNA extracted from formalin fixed, paraffin-embedded platelet-rich tissues can be used for analysis of platelet-predominate gene expression. Variable factor XIII gene expression in thrombi generated during NVAF may in part explain the propensity to embolisation. PMID- 21655674 TI - Haemostatic profiles assessed by thromboelastography in patients with end-stage renal disease. AB - Patients with end-stage renal disease (ESRD) have abnormalities in the cellular and plasmatic systems regulating blood homeostasis, which may contribute to their risk for thrombotic and bleeding complications. However, their relative contributions in this population are poorly understood. The aim of this study was to evaluate the distribution of enzymatic and cellular abnormalities in ESRD patients on haemodialysis as assessed by thromboelastography (TEG(r)). Whole blood samples were analysed by TEG in ESRD patients (n=70) and in a control group (n=70) of subjects with coronary artery disease. Profiles were constructed considering the maximum amplitude (MA), a marker of platelet function, and reaction time (R), a marker of thrombin generation, values. R values were higher in ESRD patients compared with the control group (8.2 +/- 2.8 vs. 5.7 +/- 1.9 minutes [min], p <0.0001), while there were no differences in MA (66.7 +/- 8.1 vs. 66.2 +/- 6.6 mm, p=0.562). Normal manufacturer defined coagulation (2-8 min) and aggregation (51-69 mm) parameters were present in 31% of ESRD patients compared with 56% of controls (p=0.006). A hypocoagulable status was observed in 42.9% of ESRD patients compared with 8.9% in the control group (p<0.0001). There were no differences in platelet function, which showed a hyperaggregable status in 41.4% versus 35.7% of cases (p=0.603). Abnormalities in both parameters were observed in 15.7% of ESRD patients versus 1.4% in the control group (p= 0.004), which were more common among older patients (p= 0.005). In conclusion, patients with ESRD have an elevated prevalence of abnormal haemostatic profiles, which may contribute to their elevated risk of bleeding and thrombotic complications. PMID- 21655675 TI - The in vitro effect of the new antithrombotic drug candidate ALX-0081 on blood samples of patients undergoing percutaneous coronary intervention. AB - Compound ALX-0081 is a bivalent humanised Nanobody(r) that binds the A1-domain of von Willebrand factor (VWF) with high affinity. Consequently, it can block the interaction between VWF and its platelet-receptor-glycoprotein Ib, which leads inevitably to formation of arterial thrombi. It was the objective of this study to assess the in vitro effects of ALX-0081 on platelet adhesion and aggregation in coronary artery disease (CAD) patients to determine the optimal concentration of ALX-0081 and the effect of co-medication. We included nine CAD patients, who were scheduled for elective percutaneous coronary intervention (PCI), and 11 healthy volunteers. At admission all patients received aspirin, clopidogrel and heparin. Blood was drawn 24 hours (h) before and 1 h after start of the PCI procedure and was subsequently spiked with different concentrations of ALX-0081 or buffer. The efficacy of ALX-0081 was assessed by in vitro experiments: flow chamber experiments, ristocetin-induced platelet aggregation (RIPA), and the platelet function analyser (PFA-100TM). VWF levels in CAD patients were significantly higher than in healthy controls. During PCI VWF levels did not rise. In all in vitro experiments, ALX-0081 led to complete inhibition of platelet adhesion and aggregation. However, the required effective concentration was higher in patients than in controls and was related to plasma VWF levels. In conclusion, ALX-0081 is able to completely inhibit in vitro platelet adhesion and aggregation in CAD patients scheduled for elective PCI. The efficacy of ALX-0081 is not influenced by PCI or co-medication. However, due to higher VWF levels in CAD patients a higher effective concentration of ALX-0081 was required than in healthy individuals. PMID- 21655676 TI - Platelets regulate CD4+ T-cell differentiation via multiple chemokines in humans. AB - Atherosclerosis is an inflammatory and thrombotic disease. Both platelets and lymphocytes play important roles in atherogenesis. However, information on their interaction is limited. We therefore studied how platelets regulate CD4+ T cell activation and differentiation. Human CD4+ T cells and autologous platelets were co-cultured. Platelets concentration-dependently enhanced anti-CD3/CD28-induced IFNgamma production by CD4+ T cells, but attenuated their proliferation. Abrogation of heterotypic cell-cell contact partially reversed the enhancement, and supernatant from activated platelets partially mimicked the enhancement, suggesting that platelets exert their effects via both soluble mediators and direct cell-cell contact. Platelets enhanced the production of IL-10 and cytokines characteristic for type 1 T helper (TH1) (IFNgamma/TNFalpha) and TH17 (IL-17) cells, but influenced TH2 cytokines (IL-4/IL-5) little. The cytokine responses were accompanied by enhanced TH1/TH17/TReg differentiation. Using neutralising antibodies and recombinant PF4, RANTES, and TGFbeta, we found that platelet-derived PF4 and RANTES enhanced both pro- and anti-inflammatory cytokine production, whilst recombinant TGFbeta enhanced IL-10 but not TNFalpha production. In conclusion, platelets enhance the differentiation and cytokine production of anti-CD3/CD28-stimulated CD4+ T cells via both multiple chemokines and direct cell-cell contact. Our study provides new insights into the cross-talk between thrombosis and adaptive immunity, and indicates that platelets can enhance T-effector cell development. PMID- 21655677 TI - Early determination of clopidogrel responsiveness by platelet reactivity indexidentifies patients at risk for cardiovascular events after myocardial infarction. AB - While acute myocardial infarction (MI) is associated with impaired clopidogrel responsiveness, systematic evaluation is lacking due to the inability of functional aggregation-based assays to analyse clopidogrel responsiveness in the presence of glycoprotein IIb/IIIa inhibitors. Using the P2Y12-specific, non aggregation-based platelet-reactivity-index (PRI) we assessed clopidogrel responsiveness in patients with acute MI. Clopidogrel responsiveness was determined 24 hours (h) after loading with 600 mg clopidogrel in 54 patients with acute MI admitted for coronary intervention. A PRI >50% was considered as suboptimal inhibition. Overall response in MI patients was suboptimal with a median PRI of 58%. Diabetes, low high-density lipoprotein and pre-hospital clopidogrel loading were associated with impaired clopidogrel responsiveness. Patients loaded at first medical contact had a significantly weaker platelet inhibition by clopidogrel after 24 h (PRI 63%) compared to those loaded peri interventionally (PRI 54%, p=0.014). Clinical outcome was assessed as a combination of cardiac death, non-fatal MI, stent thrombosis, ischaemic stroke, and urgent target vessel revascularisation after 12 months. The pre-selected cut off of PRI <=50% yielded a sensitivity of 87% at a specificity of 26%, whereas a PRI <=57% determined by receiver-operating characteristics (ROC)-analysis yielded a sensitivity of 80% at a specificity of 56% (event rate: PRI <=57%: 12.0%; PRI >57%: 41.4%, p=0.0136). In conclusion, PRI detects clopidogrel responsiveness in acute MI patients requiring glycoprotein IIb/IIIa antagonism; and impaired clopidogrel responsiveness predisposes to clinical events. Pre-hospital clopidogrel loading was associated with impaired response and more adverse events challenging the concept of earliest oral clopidogrel loading in MI patients. PMID- 21655678 TI - Arterial and venous thrombosis and prothrombotic fibrin clot phenotype in a Polish family with type 1 antithrombin deficiency (antithrombin Krakow). PMID- 21655680 TI - A cascade of thromboembolic processes in a patient with paroxysmal nocturnal haemoglobinuria terminated by treatment with eculizumab. PMID- 21655679 TI - Longer legs are associated with greater risk of incident venous thromboembolism independent of total body height. The Longitudinal Study of Thromboembolism Etiology (LITE). AB - Several studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesised that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus torso length. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height, we standardised leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 years. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modelled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs. PMID- 21655681 TI - Platelet function following trauma. A multiple electrode aggregometry study. AB - Platelets play a central role in coagulation. Currently, information on platelet function following trauma is limited. We performed a retrospective analysis of patients admitted to the emergency room (ER) at the AUVA Trauma Centre, Salzburg, after sustaining traumatic injury. Immediately after admission to the ER, blood was drawn for blood cell counts, standard coagulation tests, and platelet function testing. Platelet function was assessed by multiplate electrode aggregometry (MEA) using adenosine diphosphate (ADPtest), collagen (COLtest) and thrombin receptor activating peptide-6 (TRAPtest) as activators. The thromboelastometric platelet component, measuring the contribution of platelets to the elasticity of the whole-blood clot, was assessed using the ROTEM device. The study included 163 patients, 79.7% were male, and the median age was 43 years. The median injury severity score was 18. Twenty patients (12.3%) died. Median platelet count was significantly lower among non-survivors than survivors (181,000/MUl vs. 212,000/MUl; p=0.01). Although platelet function defects were relatively minor, significant differences between survivors and non-survivors were observed in the ADPtest (94 vs. 79 U; p=0.0019), TRAPtest (136 vs. 115 U; p<0.0001), and platelet component (134 vs.103 MCEEXTEM - MCEFIBTEM; p=0.0012). Aggregometry values below the normal range for ADPtest and TRAPtest were significantly more frequent in non-survivors than in survivors (p=0.0017 and p=0.0002, respectively). Minor decreases in platelet function upon admission to the ER were a sign of coagulopathy accompanying increased mortality in patients with trauma. Further studies are warranted to confirm these results and investigate the role of platelet function in trauma haemostatic management. PMID- 21655682 TI - Massive muscle haematoma three months after starting vitamin K antagonist therapy for deep-vein thrombosis in an antithrombin deficient patient: another case of factor IX propeptide mutation. PMID- 21655683 TI - Self-testing and self-management of oral anticoagulation therapy in children. AB - Children and adolescents on oral anticoagulation therapy (OAT) present special challenges in terms of rapid fluctuations in International Normalised Ratio (INR) values, interruption in daily life due to frequent hospital/doctor visits, and difficulties and pain in the performance of venepuncture. Optimised management of OAT improves the quality of treatment, potentially accomplished by new methods such as patient self-testing (PST) and patient self-management (PSM). A review was performed, identifying 11 trials with children and adolescents. All studies had different methodological problems, predominantly by being non-randomised trials. A total of 284 patients were included with a mean follow-up of 22 months, finding a time within therapeutic INR target range between 63% and 84%. The coagulometers used for estimating the INR values were found to have sufficient precision and accuracy for clinical use, but external quality control is probably advisable. It can be concluded that PST and PSM are at least as good treatment options as conventional management in highly selected children. Larger studies, preferably randomised, controlled trials using clinical endpoints, are obviously needed in order to elucidate whether these new regimens of treatment are superior to conventional management of oral anticoagulation therapy. PMID- 21655684 TI - Severity of viral coinfection in hospitalized infants with respiratory syncytial virus infection. AB - OBJECTIVE: To compare the severity of single respiratory syncytial virus (RSV) infections with that of coinfections. METHODS: A historical cohort was studied, including hospitalized infants with acute RSV infection. Nasopharyngeal aspirate samples were collected from all patients to detect eight respiratory viruses using molecular biology techniques. The following outcomes were analyzed: duration of hospitalization and of oxygen therapy, intensive care unit admission and need of mechanical ventilation. Results were adjusted for confounding factors (prematurity, age and breastfeeding). RESULTS: A hundred and seventy six infants with bronchiolitis and/or pneumonia were included in the study. Their median age was 4.5 months. A hundred and twenty one had single RSV infection and 55 had coinfections (24 RSV + adenovirus, 16 RSV + human metapneumovirus and 15 other less frequent viral associations). The four severity outcomes under study were similar in the group with single RSV infection and in the coinfection groups, independently of what virus was associated with RSV. CONCLUSION: Virus coinfections do not seem to affect the prognosis of hospitalized infants with acute RSV infection. PMID- 21655686 TI - Factors associated with HIV/AIDS treatment dropouts in a special care unit in the City of Rio de Janeiro, RJ, Brazil. AB - OBJECTIVE: This study aimed to identify factors associated with the health care of patients with HIV/AIDS who drop out. METHODS: The study was developed in a specialized health care unit of a University hospital in Rio de Janeiro, Brazil, considering a stratified sample of adult patients including all dropout cases (155) and 44.0% of 790 cases under regular follow-up. Bivariate analyses were used to identify associations between health care dropout and demographic, socioeconomic and clinical variables. Logistic and Cox regression models were used to identify the independent effects of the explanatory variables on risk for dropout, in the latter by incorporating information on the outcome over time. RESULTS: Patients were, on average, 35 years old, predominantly males (66.4%) and of a low socioeconomic level (45.0%). In both models, health care dropout was consistently associated with being unemployed or having an unstable job, using illicit drugs and having psychiatric background--positive association; and with age, having AIDS, and having used multiple antiretroviral regimens--negative association. In the logistic regression, dropping out was also positively associated with time between diagnosis and the first outpatient visit, while in the Cox model, the hazard for dropping out was positively associated with being single, and negatively associated with a higher educational level. CONCLUSIONS: The results of this work allow for the identification of HIV/AIDS patients more likely to drop out from health care. PMID- 21655685 TI - Systematic follow-up of hyperbilirubinemia in neonates with a gestational age of 35 to 37 weeks. AB - OBJECTIVES: To determine the outcomes of an intervention for follow-up of bilirubinemia in the first week of life in a cohort of newborn infants with gestational ages between 35 0/7 and 37 6/7 weeks and to determine risk factors for readmission for phototherapy (total bilirubin > 18 mg/dL). METHODS: Retrospective cohort study carried out at a public teaching hospital. Neonates underwent periodic monitoring of total bilirubin levels (measured in plasma or by transcutaneous device) before and after discharge to assess the need for phototherapy. A systematic approach, based on risk percentiles of a bilirubin reference curve, was employed. RESULTS: The study sample comprised 392 neonates. Only one outpatient visit was required in 61.7% of newborns. Peak total bilirubin was >= 20 mg/dL in 34 neonates (8.7%), and reached 25-30 mg/dL in three (0.8%). Phototherapy was indicated after discharge in 74 neonates (18.9%). Weight loss between birth and first follow-up visit and total bilirubin above the 40th percentile at discharge were risk factors for requiring phototherapy. Total bilirubin above the 95th percentile at discharge was associated with greater risk of readmission (RR = 49.5 [6.6-370.3]). Weight loss between discharge and first follow-up visit was the sole independent clinical predictor (RR = 1.16 [1.04 1.17]). CONCLUSION: Systematic follow-up during the first week of life was effective in preventing dangerous hyperbilirubinemia. Encouraging breastfeeding and discharging neonates only after weight loss has been stabilized may prevent readmission due to hyperbilirubinemia. PMID- 21655687 TI - Nutritional Status of the adult population in the Bolsa Familia Program in Curitiba, State of Parana, Brazil. AB - INTRODUCTION: The Bolsa Familia Program is the largest program of conditional cash transfer in Brazil, and its major goal is to reverse the current food insecurity. In spite of that, there are few studies that show the development of nutritional status for this population. OBJECTIVE: This study aimed to describe the nutritional status of the adult population enrolled in the Bolsa Familia program, in the municipality of Curitiba, PR. METHODS: This is a cross-sectional, population-based study, performed in the health districts of the city of Curitiba, Parana, in the period from July 2006 to July 2007. We interviewed 747 adults, 18 years of age and over, of both sexes, living in the catchment area of the basic healthcare units in the city. To assess the nutritional status of this population, we measured weight (kg), height (cm), and waist circumference (WC) and calculated the body mass index. They were asked about age, marital status, occupation, number of household members, origin, and years of schooling. The association between excessive weight, waist circumference and sociodemographic co variables was assessed by unconditional logistic regression. RESULTS: About 40% of the population was considered of normal weight and 27.1% obese, according to BMI standards. Analyzing waist circumference data, 48.2% have measures that show a much greater risk for developing cardiovascular disease. Significant statistical association occurred between BMI increase and age (OR = 2.16; CI 95%: 1.57-2.96), sex (OR = 0.57; CI 95%: 0.33-0.97) and marital status (OR = 1.40; CI 95%: 1.03-1.88). A significant association was observed between waist circumference and age (OR = 2.93; IC 95%: 2.13-4.02) and sex. CONCLUSION: Most of the population presented excessive weight and abdominal fat, risks for cardiovascular diseases. The results point towards the need to build and implement regional diet public policies. PMID- 21655688 TI - Family focus and community orientation in tuberculosis control. AB - This study aimed to describe tuberculosis control actions in the context of Family Health Teams, regarding the dimensions family focus and community orientation. A cross-sectional evaluative research was carried out in 2008, with 84 healthcare workers. The Primary Care Assessment Tool was used, validated and adapted to assess tuberculosis care in Brazil. Respondents answered each question according to a pre-determined scale, (Likert's scale) ranging from zero to five. Data were tabulated using the Statistical Package for the Social Sciences software and were analyzed according to frequency and median. In the first dimension, outcomes revealed that 67.9% of health workers evaluate contact cases with diagnostic tests; 63.1% use radiology tests; 64.3% include the household to face the disease; 77.4% identify risk factors; 41.7% interface with other sectors to find solutions for the identified problems. In the second dimension, 73.8% of them perform case search; 40.5% provide inputs for sputum collection; 50% take educational actions in the community; 14.3% recognize social participation in tuberculosis control. Therefore, the efficiency of such services requires taking actions that give special attention to family and community, and the development of skills to create new spaces for professionals to act and to strengthen the interface with other sectors of society. PMID- 21655689 TI - [Prevalence and factors associated with Posttraumatic Stress Disorder (PTSD) in emergency workers: a systematic literature review]. AB - OBJECTIVE: To identify the prevalence of Posttraumatic Stress Disorder (PTSD) in emergency workers and determine the factors associated with outcomes. METHODS: Seven databases were consulted (Medline via Pubmed, PsycINFO, LILACS, SciELO, BDENF, DISASTERS, and MEDCARIB) between September 10 and 25, 2009. The search only included articles published in Portuguese, English or Spanish between 2004 and 2009. The key-words involved terms related to emergency services/workers, Posttraumatic stress disorder, working conditions, and occupational health. Quantitative observational studies on PTSD prevalence and determinant or associated factors regarding the health of firefighters, emergency ambulance personnel, Red Cross workers, and medical emergency workers were included. Studies using samples unrelated to the purposes of this review (police officers, volunteers and emergency workers' children) or that did not include PTSD symptoms as the dependent variable in at least one of the objectives of the study were excluded. RESULTS: 30 articles were selected by reading the titles and abstracts. 17 complete articles were reviewed and analyzed. Studies adopted different research designs, instruments and diagnostic criteria for statistical analysis. The prevalence of the disease ranged from absence of reported cases to a rate of 38.5%. Socio-demographic, biological and psychological characteristics, morbidity, exposure to occupational and non-occupational traumatic events, and work and job features were associated with the prevalence of PTSD in emergency workers. CONCLUSION: Individual and contextual variables are considered as factors associated with PTSD, which explains the multidimensional nature of the outcome studied. PMID- 21655690 TI - Multiple causes of death related to cerebrovascular diseases in the State of Parana, Brazil. AB - OBJECTIVE: To identify associated causes and the number of causes on death certificates that reported cerebrovascular diseases as the underlying cause among residents of the State of Parana, in Brazil. METHODS: Mortality data in 2004 were obtained on the Datasus website. The population was selected by the TabWin program and multiple causes were processed by the Multiple Causes of Death Tabulator program. RESULTS: The mean number of causes listed on death certificates was 2.92 for women and 2.97 for men. Most people who died (74.8%) were aged 65 or older. Among the major causes associated with cerebrovascular disease deaths were respiratory diseases (37.9%), hypertensive diseases (37.5%), and symptoms, signs and abnormal clinical and laboratory tests (32.3%). FINAL CONSIDERATIONS: There was a relative improvement in the quality of mortality data regarding the number of causes registered. Hypertension as a major associated cause suggests the need for its control in the fight against mortality caused by cerebrovascular disease. Studies with multiple causes should be encouraged, taking into account all causes listed on death certificates, many of which are overlooked in mortality studies that only use the underlying cause of death. PMID- 21655691 TI - Physician satisfaction with care to cardiovascular diseases in the municipalities of Minas Gerais: Cardiosatis-TEAM Scale. AB - OBJECTIVE: To evaluate psychometric validity and reliability properties of the CARDIOSATIS-Team scale and measure physician satisfaction before and after the implementation of the project. This scale was designed to evaluate physician satisfaction with the healthcare delivered for cardiovascular diseases in cities that participate in a telemedicine system. METHODS: The scale was applied in 82 cities of Minas Gerais, before and after the implementation of a telecardiology system. The analysis of the psychometric properties of CARDIOSATIS-Team scale included: construct validity using factorial analysis; internal consistency reliability using Cronbach's Alpha; Pearson's correlation between items; Spearman's correlation between domains and global scale and; discriminant analysis. RESULTS: The factor analysis of the principal components extracted two factors that explained 66.5% of the variance in satisfaction scores: healthcare delivery and diagnosis structure and satisfaction with the care delivered. Cronbach's Alfa for internal consistency reliability of the scale showed values of 0.92 for the global scale and up to 0.84 for factors. Inter-factor and inter scale correlations were adequate, showing values of 0.59 to 0.89 and 0.73 to 0.85, respectively. The scale was able to distinguish the two moments of its application (before and after intervention), showing high satisfaction for most items measured afterwards (p < 0.05). CONCLUSIONS: We can conclude based on the present study that the telemedicine system improved provider satisfaction and that the CARDIOSATIS-Team scale is a good tool to evaluate provider satisfaction with care delivered for CVD. Its appropriate characteristics in terms of validity and internal consistency reliability justify its utilization in other studies. PMID- 21655692 TI - [Utilization of generics in an area covered by a family health unit in a southern Brazilian city]. AB - The objective of the study was to estimate the prevalence of generics and their associated factors in a population of adults aged 20 to 59 years. The sample consisted of 374 individuals from the catchment area of a Family Health Unit in Ponta Grossa, PR, Brazil. Data were collected in home interviews. Study variables were divided into 3 groups: sociodemographic, health status and the use of health services. The chi-square test was used for statistical analysis. The prevalence of generics was 9.9%. Of those interviewed, 96.5% claimed to know about generic drugs, 64.3% believed they had the same quality as brand-name drugs and 88.9% reported they were cheaper. The most commonly-used groups of drugs were those for the nervous system and those for the cardiovascular system. After univariate analysis, the following factors were found to be statistically significant: economic status, employment status, health insurance, presence of chronic disease, medical consultation in the previous three months and hospitalization within the previous 12 months. The low prevalence of the use of generic drugs emphasizes the fact that stronger policies are needed to make generics available to the public, especially through the Family Health Strategy, since it is the studied population's principal form of access to these medications. PMID- 21655693 TI - Quality of life, physical and mental health of physicians: a self-evaluation by graduates from the Botucatu Medical School--UNESP. AB - OBJECTIVE: This paper aimed to analyze self-evaluations in terms of quality of life (QoL), physical health (PH) and mental health (MH) of ex-medical students from a Brazilian public university, correlating these outcomes with demographic data and several professional aspects. METHODS: a cross-sectional study with a target population of all students graduated from the Botucatu School of Medicine (UNIFESP--Sao Paulo State University) between 1968 and 2005. A self-administered questionnaire, which could be answered by regular mail or internet, was used. RESULTS: From the 2,864 questionnaires that were sent by mail, 1,224 (45%) were answered and sent back. Good or very good QoL, PH and MH were reported by 67.8%, 78.8% and 84.5% of participants, respectively. In the final logistic regression model, positive QoL was associated with good PH and MH, regular attendance to scientific meetings, enough leisure time, and professional satisfaction. Good or very good PH was independently associated with positive QoL and MH, higher income level, regular physical activities, and never having smoked. Positive MH remained associated with professional satisfaction, enough leisure time, and positive evaluation of both QoL and PH. CONCLUSIONS: Among medical doctors graduated from Sao Paulo State University, PH and MH were inseparable aspects, which were also related to the self-evaluation of QoL. Good habits, such as regular practice of physical exercise, enough leisure time, and not smoking were associated with positive health in general and should be encouraged. Professional satisfaction had an important impact on the emotional well-being of participants. PMID- 21655694 TI - [Impact of osteomuscular symptoms on the quality of life of teachers]. AB - The aim of this study was to determine the impact of osteomuscular symptoms on the quality of life of public school teachers in Natal, Brazil. This is a descriptive-analytical study with a cross-sectional design, comprising a sample of 242 teachers. The WHOQOL-brief was used to assess quality of life and the Nordic questionnaire for osteomuscular symptoms. Descriptive statistical procedures and Mann-Whitney test were used in data analysis, with the significance level set at 5%. The prevalence of the aforementioned symptoms among the subjects investigated was 63.2%, considering the seven days before data collection. All quality of life domains were compromised in the group of teachers who presented osteomuscular symptoms, when compared to the asymptomatic group. The physical, psychological, social and environmental domains all had p-values smaller than 0.001. Thus, the presence of osteomuscular symptoms showed a strong statistical correlation with lower quality of life of teachers from the basic education system of Natal, Brazil. PMID- 21655695 TI - Auditory vocal analysis and factors associated with voice disorders among teachers. AB - Teachers are professionals who demand much of their voices and, consequently, present a high risk of developing vocal disorders during the course of employment. OBJECTIVE: To identify factors associated with vocal disorders among teachers. METHOD: An exploratory cross-sectional study, which investigated 476 teachers in primary and secondary schools in the city of Salvador, Bahia. Teachers answered a questionnaire and were submitted to auditory vocal analysis. The GRBAS was used for the diagnosis of vocal disorders. RESULTS: The study population comprised 82.8% women, teachers with an average age of 40.7 years, teachers with higher education (88.4%), with an average workday of 38 hours per week, average 11.5 years of professional practice and average monthly income of R$1.817.18. The prevalence of voice disorders was 53.6%. (255 teachers). The bivariate analysis showed statistically significant associations between vocal disorders and age above 40 years (PR = 1.83; 95% CI; 1.27-2.64), family history of dysphonia (PR = 1.72; 95% CI; 1.06-2.80), over 20 hours of weekly working hours (PR = 1.66; 95% CI; 1.09-2.52) and presence of chalk dust in the classroom (PR = 1.70; 95% CI; 1.14-2.53). CONCLUSION: The study concluded that teachers, 40 years old and over, with a family history of dysphonia, working over 20 hours weekly, and teaching in classrooms with chalk dust are more likely to develop voice disorders than others. PMID- 21655696 TI - Factors associated with central obesity in adults from Florianopolis, Santa Catarina: a population based-study. AB - OBJECTIVE: To estimate the prevalence of central obesity and its association with socio-demographic factors and health-related behaviors among adults from Florianopolis, State of Santa Catarina, Southern Brazil. METHODS: A cross sectional population-based study was carried out in a sample of 1,720 adults between 20 to 59 years of age, residents in the urban area of the city. The outcome was the central obesity which was defined as a waist-height ratio > 0.50. Unadjusted and adjusted models were performed by using Poisson regression allowing estimation of the Prevalence Ratio (PR). All analyses were stratified by sex. RESULTS: The prevalence of central obesity was 50.5% (95% CI: 46.6-54.4) among men and 38.9% (95% CI 34.4-43.5) among women. In the adjusted analysis, central higher prevalence of obesity was observed in women aged 50 to 59 years and those who were living with a partner; lower prevalences were observed among women with > 12 years of study (PR: 0.63; 95% CI: 0.47-0.85) and among those with higher income (PR: 0.64; 95% CI: 0.47-0.86). Among men, a higher prevalence of central obesity was associated with ages 50 to 59 years and among those who were living with a partner, while a lower prevalence was identified in those in the highest income group. CONCLUSION: The prevalence of central obesity was high in the population studied. Demographic and socioeconomic factors were strongly associated with central obesity in both sexes. The knowledge of factors associated with central obesity may help the implementation of health interventions in order to prevent this core issue in Public Health. PMID- 21655697 TI - Severe maternal morbidity and near misses in a regional reference hospital. AB - OBJECTIVE: To investigate severe maternal morbidity/near misses in a tertiary public maternity in the state of Rio de Janeiro, using different identification criteria. METHODS: This is a cross-sectional study, performed in a regional reference hospital between June and October 2009, on severe maternal morbidity/near miss cases identified from the log books of the maternity hospital and review of medical records. This study focused on women who, during pregnancy, delivery, or the postpartum period, showed no clinical symptoms compatible with the defining criteria for severe maternal morbidity/near miss of Waterstone et al, Mantel et al. and the World Health Organization (WHO). RESULTS: Among the 1,544 admissions during the period studied, 89 women with severe maternal morbidity were identified, considering all criteria. The occurrence of severe maternal morbidity/near misses ranged from 81.4 to 9.4 per 1,000 live births (LB), depending on the criterion used. The mortality rate was 3.2%, reaching 23% in the WHO criteria. Only 40% of these women had more than six prenatal visits and 10% did not have any visit at all. The most common markers found were severe preeclampsia, followed by severe hemorrhage, ICU admissions, HELLP syndrome, and eclampsia. There were three maternal deaths with a MMR = 280/100.000 LB and one late death. The WHO criterion showed greater specificity, identifying more severe cases, while the Waterstone criterion was more sensitive. CONCLUSIONS: The study of severe maternal morbidity/near misses in a regional reference hospital can contribute to the knowledge of this event's magnitude, as well as to identify its most frequent characteristics and clinical conditions, being essential for dealing with maternal morbidity and mortality. PMID- 21655698 TI - [Profile and process of the care provided to high-risk newborns in southern Brazil]. AB - OBJECTIVE: To describe newborns at risk and check the process of care provided by the High Risk Newborn Surveillance Program in Maringa-PR. METHODS: Data were collected from medical records and monitoring sheets of a stratified sample consisting of 505 newborns at risk, born in 2007. Maternal and neonatal care were analyzed descriptively using Statistica 7.1 software. RESULTS: The program only considered biological risks as inclusion criteria, whether they appeared alone (63.2%) or associated (36.8%). Regarding mothers, 71.5% were adults, 78.2% had > 8 years of schooling, 57.2% were single parents, 55.3% had an unpaid occupation, 69.5% had > 6 prenatal visits, 87.3% had a single baby, and 65.4% had a C section. Regarding newborns at risk, 51% were male, 50.3% had low birth weight, 51.5% were full term, 95.8% without congenital anomalies, and 90.3% with 5th minute scores > 7. Regarding care provided to children at risk, 69.5% were accompanied by the Program, 71% of the medical records were located, for 82.6% there were no home visits, 8.9% received > 12 medical consultations, 33.1% had not received any guidance, 5.8% were hospitalized, 18.7% were weighed > 12 times, and 19.8% presented full immunization records. CONCLUSION: It is necessary to reorganize primary care to ensure integral care and for ongoing monitoring of the bio-psychosocial development and growth of children at risk. PMID- 21655699 TI - Emergence of the first permanent molar in 5-6-year-old children: implications from a longitudinal analysis for occlusal caries prevention. AB - The timing of tooth emergence is of considerable importance in the planning of prevention of occlusal caries. OBJECTIVE: The aim was to estimate the trends of emergence of the first permanent molars in girls and boys between 5-6 years of age, since more children are included in the first grade after Brazilian elementary education has been extended from eight to nine years of duration. METHODS: Dental spaces of 497 children aged 60 months or older were examined four times by a calibrated dentist (kappa > 0.97) during 18 months in a longitudinal study. The first permanent molar was considered emerged when any tooth surface could be reached by a ball point probe. Participants' age was measured in months; 95% confidence intervals were obtained for prevalence and incidence values for each sex in three age groups--60.0 to 65.9; 66.0 to 71.9; 72.0 to 77.9 months. Incidence rate ratios were estimated by Poisson regression analysis. RESULTS: The majority of children from 66.0 to 71.9 months and 72.0 to 77.9 months presented at least one emerged permanent molar. For each three children in the 66.0-71.9 month group, at least one had all four permanent molars emerged. CONCLUSION: The emergence trends observed justify the need for specific protection and surveillance measures for occlusal caries prevention. PMID- 21655700 TI - [Prevalence of idiopathic scoliosis and associated variables in schoolchildren of elementary public schools in Cuiaba, state of Mato Grosso, 2002]. AB - OBJECTIVE: To estimate the prevalence of idiopathic scoliosis and its associated factors in schoolchildren of elementary public schools. METHODS: Cross sectional two-phase study, the first of which in classrooms. Those considered Adams positive were invited for the second phase, which consisted of an interview for associated factors and a scoliosis exam. Those with a confirmed test in the second phase were submitted to x-rays for scoliosis and other factors. To estimate the prevalence, curves with > 5 and > 10 Cobb degrees were used as cut off. RESULTS: In the first phase, 382 students were counted as Adams positive; of these 210 came for the second phase, 142 of which with a confirmed test. Using a chi-square test to compare the variables age, sex and color of the lost group (n = 172) to the group that accepted the invitation (n = 210), no statistical significance was observed, allowing statistical inference for the sample studied (n = 3,105). The estimated prevalence of scoliosis in the sample studied was 5.3% for curves > 5 Cobb degrees and 2.2% for curves > 10 Cobb degrees. Thoracic curves were observed in 44.8%, Risser grade 1 in 97.4%, and vertebral rotation degree I in 3.2%. Statistical significance was observed (p < 0.05) for the association of scoliosis with: physical activity, hump, and flexibility of the spine to the right. CONCLUSION: The estimated prevalence of scoliosis in our study is comparable to those from other studies. However, its diagnosis and follow-up are important to health promotion and to the prevention of more severe disorders. PMID- 21655701 TI - Validity of 5-year-old children's oral hygiene pattern referred by mothers. AB - OBJECTIVE: To determine the validity of oral hygiene questions for children, as commonly used in epidemiological studies, and assess their validity by family income and mother's education. METHODS: A subsample of 1122 children from the 2004 Pelotas Birth Cohort, Southern Brazil (who had participated in a 2009 oral health study) was analyzed. The children received dental examinations, and their mothers were interviewed at home. The gold standard for oral hygiene was the Simplified Oral Hygiene Index; from its total score, the outcome was dichotomized into the absence (total score = 0) or presence (total score >= 1) of dental plaque. The mothers answered questions related to their child's oral hygiene, including daily toothbrushing, toothbrushing before sleeping and the combination of the two (oral hygiene). These responses were dichotomized into regular and irregular. The validity was determined by calculating the percentages and respective 95% confidence intervals for sensitivity, specificity, positive predictive value and negative predictive value. RESULTS: The overall prevalence of dental plaque was 37.0%. The following sensitivities, specificities, positive predictive values and negative predictive values were observed: 29.6%, 82.5%, 49.8% and 66.6%, respectively, for irregular daily toothbrushing; 41.8%, 64.6%, 40.9% and 65.5%, respectively, for irregular toothbrushing before sleeping; and 48.8%, 60.8%, 42.2% and 67.0%, respectively, for irregular oral hygiene. The validity of the oral hygiene reporting varied across different levels of family income and mother's education. The sensitivity and positive predictive values were higher among children with lower incomes and less educated mothers, while opposite associations were observed for specificity and negative predictive value. CONCLUSIONS: Oral hygiene questions answered by mothers of five year-old children are not an appropriate substitute for direct oral hygiene assessment by the clinical examination of dental plaque. PMID- 21655702 TI - Factors associated with intimate partner physical violence among health service users. AB - OBJECTIVE: To estimate the prevalence of intimate partner violence against women and identify factors associated. METHODS: Cross-sectional study comprising 504 women aged 15 to 49 years users of five primary care clinics in a municipality in the state of Sao Paulo, Southeastern Brazil, in 2008. Face-to-face interviews were carried out using a questionnaire consisting of 119 questions on sociodemographic information, reproductive health, perceptions of gender roles in the marital relationship and experience of violence. Univariate and multiple regression analyses were performed. RESULTS: More than a third of the women reported intimate partner violence. In the multiple regression analysis factors predisposing to violence included living in rental housing, sexual abuse during childhood, the partner's experience of physical violence during childhood, alcohol and drug use by the woman and her partner, and woman's perception of her partner's temperament. CONCLUSIONS: The factors identified produced a predictive model that can be used to assess a woman's risk of experiencing intimate partner violence. PMID- 21655703 TI - A revised version of the Healthy Eating Index for the Brazilian population. AB - The revised version of the Brazilian Healthy Eating Index is an indicator of dietary quality developed according to current nutritional recommendations. Dietary data were obtained from a population-based survey, the 2003 Inquerito de Saude e Alimentacao (ISA - Health and Diet Survey)-Capital. The Revised Index consists of 12 components: nine food groups included in the 2006 Brazilian Dietary Guidelines, in which daily portions are expressed in terms of energy density; two nutrients (sodium and saturated fats), and SoFAAS (calories from solid fat, alcohol and added sugar). The Revised Brazilian Healthy Eating Index allows for the measurement of dietary risk factors for chronic diseases, evaluating and monitoring the diet at both individual and population levels. PMID- 21655704 TI - Social contextual factors contributing to child and adolescent labor: an ecological analysis. AB - OBJECTIVE: To examine the relationship between social contextual factors and child and adolescent labor. METHODS: Population-based cohort study carried out with 2,512 families living in 23 subareas of a large urban city in Brazil from 2000 to 2002. A random one-stage cluster sampling was used to select families. Data were obtained through individual household interviews using questionnaires. The annual cumulative incidence of child and adolescent labor was estimated for each district. New child and adolescent labor cases were those who had their first job over the two-year follow-up. The annual cumulative incidence of child and adolescent labor was the response variable and predictors were contextual factors such as lack of social support, social deprivation, unstructured family, perceived violence, poor school quality, poor environment conditions, and poor public services. Pearson's correlation and multiple linear regression were used to assess the associations. RESULTS: There were selected 943 families corresponding to 1,326 non-working children and adolescents aged 8 to 17 years. Lack of social support, social deprivation, perceived violence were all positively and individually associated with the annual cumulative incidence of child and adolescent labor. In the multiple linear regression model, however, only lack of social support and perceived violence in the neighborhood were positively associated to child and adolescent labor. No effect was found for poor school quality, poor environment conditions, poor public services or unstructured family. CONCLUSIONS: Poverty reduction programs can reduce the contextual factors associated with child and adolescent labor. Violence reduction programs and strengthening social support at the community level may contribute to reduce CAL. PMID- 21655705 TI - Mechanisms of RON-mediated epithelial-mesenchymal transition in MDCK cells through the MAPK pathway. AB - The epithelial-mesenchymal transition (EMT) is involved in neoplastic metastasis, and the RON protein may be involved. In the present study, we determined the role and the mechanisms of action of RON in EMT in Madin-Darby canine kidney (MDCK) cells by Western blot and cell migration analysis. Activation of RON by macrophage stimulating protein (MSP) results in cell migration and initiates changes in the morphology of RON-cDNA-transfected MDCK cells. The absence of E cadherin, the presence of vimentin and an increase in Snail were observed in RE7 cells, which were derived from MDCK cells transfected with wt-RON, compared with MDCK cells. Stimulation of RE7 cells with MSP resulted in increased migration (about 69% of the wounded areas were covered) as well as increased activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and glycogen synthase kinase 3beta (GSK-3beta; the percent of the activation ratio was 143.6/599.8% and 512.4%, respectively), which could be inhibited with an individual chemical inhibitor PD98059 (50 MUM) specific to MAPK/ERK kinase (the percent inhibition was 98.9 and 81.2%, respectively). Thus, the results indicated that RON protein could mediate EMT in MDCK cells via the Erk1/2 pathway. Furthermore, GSK-3beta regulates the function of Snail in controlling EMT by this pathway. PMID- 21655706 TI - Breaking bad news during prenatal care: a challenge to be tackled. AB - Communicating an unfavorable diagnosis during prenatal care is a growing challenge in clinical practice, as more and more tests are being performed to screen for the main conditions affecting the pregnant woman and her fetus. The way patients receive and subsequently deal with bad news is directly influenced by how the news is communicated by the attending physician. Unfortunately, physicians receive little or no training in communicating bad news, and they generally feel quite uncomfortable about doing so. Although many physicians consider the saying that "there's no good way to break bad news" to be the truth, the maxim does not reflect the true picture. The scope of this article is to discuss, in light of the scientific literature and the experience of fetal medicine services, some recommendations that can help to deal with these difficult moments and improve patient care for the remainder of the pregnancy. PMID- 21655707 TI - Prenatal care policies: when the "outcome is unexpected". PMID- 21655708 TI - Beyond words and science: contributions to a debate. PMID- 21655710 TI - [Aesthetic surgery, medical discourse and health]. AB - The increase in plastic surgery interventions in Brazil and the growth of the beauty industry, as well as care of the body and corporal enhancement, are part of a broader process of medical and aesthetic preoccupation with health. According to the Brazilian Plastic Surgery Association there has been a substantial increase in the number of plastic surgery procedures in Brazil. Every year, approximately 350,000 aesthetic surgical interventions are performed in the country. Our work investigated the construction of meaning and value, the use of aesthetic parameters in this construction and how those meanings are appropriated and treated by those representatives of the medical profession who work in the body transformation process, namely plastic surgeons. In this respect, an analysis of the pronouncements and discourse posted on the Brazilian Plastic Surgery Association website was conducted, as it is the regulatory body of the field and is responsible for training professionals and supervising the sector. Analysis of the official content of the website page posted on September 26, 2005 was the basis for this research. PMID- 21655712 TI - [Work in health: sanitary surveillance of drugstores in Salvador (state of Bahia, Brazil)]. AB - A drugstore is an establishment of interest in health, from which medication is dispensed, namely the therapeutic technology most broadly used in the practice of medicine. The scope of this study is to describe and analyze the sanitary surveillance of drugstores. Based on the theory of working processes in healthcare, a case study was conducted on the sanitary surveillance of drugstores in Salvador (Bahia, Brazil), examining 2 analytical categories: agents and activities. Data were collected through observation, analysis of documents and interviews, and QSR N Vivo software was used for data processing. Personnel of the surveillance service were found to have varied professional and educational backgrounds, with limited experience in the sanitary surveillance of drugstores, and insufficient technical training for the performance of the tasks assigned. Deficiencies of a managerial nature were detected in the service. Its operation is primarily focused on granting drugstore licenses, prioritizing attendance to spontaneous demand, thereby configuring a technological model of intervention based on sanitary inspection. The findings revealed a need for updating the service and the adoption of technologies to enhance control of risk, given that technological evolution provides drugs that are increasingly more potent, with a concomitant rise in levels risk. PMID- 21655711 TI - [Nutritional intervention program associated with physical activity: discourse of obese elderly women]. AB - Obesity is a complex nutritional problem with social and psychological dimensions, which affects individuals of all ages. In addition to presenting risk factors for some diseases, obesity may interfere with the quality of life of the elderly. This qualitative study of an exploratory nature investigated the discourse of obese elderly women regarding their participation in a nutritional intervention program associated with physical activity. Eighteen obese elderly women attending Centers of Reference and Citizenship in the city of Joao Pessoa, state of Paraiba, Brazil were enlisted in the study. Interviews using a series of questions that addressed the core issue pertaining to the scope of the study was the technique used for data collection. The data obtained were analyzed by the collective subject discourse (CSD) technique. The following central ideas emerged from CSD: changes in lifestyle, in eating habits, in health and in self-esteem. The core ideas reflected the value attributed to the aforesaid program for promotion of health of the group of elderly women who participated in the study. It is hoped that this research might elicit further investigation in the area of health of the elderly. PMID- 21655713 TI - [Men and conjugal violence: an analysis of Brazilian studies]. AB - This study consisted of a qualitative analysis of 54 Brazilian texts about men and conjugal violence related to research or intervention activities. Initially, the material was divided up according to the topics under scrutiny, the main focus and the type of text. Analysis and synthesis of the main considerations of the texts, based on the thematic points revealed, was then carried out. This included the different approaches to the problem, the magnitude of conjugal violence, the attitudes of men vis-a-vis violence and interventions and/or policies towards male aggressors. The parameter for the analysis was the national and international debate seeking to overcome the controversy surrounding the definition of the problem as "gender violence" or conjugal violence," essentially fostering the hypothesis of various types of violent conjugal relationships. It was concluded that the unanimous outcome of the study was to view the problem as a gender relationship issue. Lastly, it was argued that the choice of the best approach between the poles of the controversy requires further investigation using qualitative methodologies together with players from different classes and social backgrounds. With respect to further intervention, it was considered necessary to examine a broad gamut of alternatives emphasizing the singular nature of the cases. PMID- 21655714 TI - [Family planning: significance for women of reproductive age]. AB - The study sought to comprehend the significance of family planning from the standpoint of women of reproductive age and identify their perceptions about the care received and the partner's participation in the decisions about the use of contraceptive methods. It is a descriptive study using a qualitative approach, conducted with 24 women who participated in the Family Planning program in a Basic Family Health Unit in Fortaleza, State of Ceara, Brazil, between August and October 2007. The information gleaned from interviews was recorded, organized into themes and analyzed on the basis of the concept of significance of symbolic interactionism. The results revealed three significant themes: the significance of family planning from the viewpoint of women of fertile age; interactions of women of fertile age in a family planning service; and male participation in family planning in terms of female significance. It was revealed that the significance of family planning for these women is related to avoiding pregnancy and according to values pertaining to their cultural, economic and social reality. The care is received in an isolated manner, without prioritizing women's needs and without input of an educational or empowerment stamp. PMID- 21655715 TI - [Distribution of body fat and breast cancer: a case-control study in the South of Brazil]. AB - The scope of this study is to verify the association between body fat distribution and breast cancer in women in the state of Rio Grande do Sul, Brazil. Case-control methodology was used in this study, in which 100 women with a histopathological diagnosis of breast cancer were compared to an out-patient control group (400 women) between January and October 2005. The anthropometric variables collected were: body mass (kg), height, waist circumference (WC), and hip circumference. No association was found between the body mass index (BMI) and the waist/hip ratio (WHR) with the occurrence of breast cancer. In relation to WC, it was observed that women with a high measurement (>= 88 cm) showed 2.08 times greater chance of developing the disease than those with normal or moderate measurements (< 80 cm-87 cm). When these women were grouped by (pre- and post-) menopausal state and anthropometric variables, only WC showed an adjusted OR association=3.15. The accumulation of fat in the upper part of the body (WC >= 88 cm) is a predisposing factor for breast cancer, especially in pre-menopausal women. PMID- 21655716 TI - [Prescribed and unprescribed drug use among pregnant patients attended by the Unified Health System in Santa Rosa (State of Rio Grande do Sul, Brazil)]. AB - In order to ascertain the use of prescribed and unprescribed drugs among pregnant patients of the Unified Health System (SUS), a descriptive study comprised of a sample of pregnant women was carried out in the city of Santa Rosa, State of Rio Grande do Sul, Brazil. Data were collected by means of structured interviews and consultation of patient records of pregnant women in the prenatal period. The prevalence of drug use was 90%, corresponding to an average of 4.1 drugs per pregnant woman, of which 83.6% were prescribed and 16.4% were self-medicated. Of this total, 17.5% of the drugs were included in fetal risk category C. The use of drugs during pregnancy is frequent and the majority of the pregnant women used one or more prescribed and unprescribed drugs during pregnancy. These data suggest the need for preventive measures to promote rational drug use during pregnancy. PMID- 21655717 TI - [Pap smear screening: sensations reported by nursing professionals when submitted to this test]. AB - This work sought to record the impressions of nursing assistants and technicians after submitting to Pap smear screening. This is a descriptive study using a qualitative approach conducted in September and October of 2006 with 35 employees of a public institution, which is a benchmark in gynecology in Fortaleza in the State of Ceara (Brazil). The data was collected through semi-structured interviews containing a recorded leading question and analyzed according to the methodological-theoretical reference of social phenomenology. The testimonials were separated in three groups: an exam that causes discomfort, fear and shame; an exam that causes anxiety about the results; and an exam that "makes me calm and relaxed". Despite the interviewees being part of an institution that cares for the prevention of cervical-uterine cancer in women, negative feelings about the Pap smear test were nonetheless reported. The conclusion reached is that it is important to stage educational campaigns emphasizing the importance of empowerment of patients in order to minimize these aspects. PMID- 21655718 TI - [Hormonal contraception: a comparison between patients of the private and public health network]. AB - The aim of this paper is to assess the profile of patients using hormonal contraceptives in the public health network and a comparison with the private health service, as well as the frequency of side effects and adherence to treatment. A cross-sectional study was conducted with 240 patients, namely 120 patients from the private health service and 120 patients from the public health network. The most commonly prescribed hormonal dosage on the private group (36.7%) was 15 or 20 micrograms of ethinyl estradiol (EE), associated with gestodene, desogestrel or levonorgestrel. On the other hand, the prescribed hormonal dosage in the public group was a combination of 30 micrograms of EE associated with gestodene, levonorgestrel or desogestrel (48.3%). There was no difference between the frequency of side effects in both groups surveyed (p>0.05). Meanwhile, adherence to treatment was higher in patients of the private group. The authors concluded that the most widely used contraceptive method was a low oral dose of ethinyl estradiol and there is no difference between the frequency of side effects. However, adherence to treatment was higher in the private group, which may be associated with social and cultural aspects of the patients surveyed. PMID- 21655719 TI - [Myths and beliefs surrounding breastfeeding]. AB - The scope of this work was to analyze the main myths and beliefs surrounding breastfeeding for the theoretical-practical perspective of the various studies extant in the literature. The studies were obtained by bibliographical surveys in the main databases (Medline, Lilacs, scielo), retrieved using the key words "Breastfeeding," "Weaning," "Myths" and "Beliefs" (and their versions in English and Spanish). Books, theories, dissertations and publications in international and national organs were also consulted. It was seen that over the centuries there have been doubts surrounding the correct form of suckling newborns based on concepts that include biological aspects and socio-cultural determinants. It was seen that various myths and beliefs surrounding suckling generate either feelings of guilt, anxiety, or feelings of trust and support in the breastfeeding mother with respect to her capacity to produce breast milk. In this respect, it is necessary for healthcare professionals to understand suckling from the maternal standpoint, dispelling myths and beliefs, altering outlooks, in such a way as to comprehend the various factors present in suckling, acting in a more effective way for prolongation and maintenance of breastfeeding. PMID- 21655720 TI - [Practice of abortion among teenagers: a study in ten schools of Maceio (AL, Brazil)]. AB - This is a cross-cut study that was carried out with the objective of investigating the causes through which adolescents have provoked abortion, relating it to age and the type of school attended. The sample was calculated by taking into account the number of hospital admissions for post-abortion curettage. A semi-structured and anonymous questionnaire was used as a research instrument which was applied in ten schools randomly chosen among all schools, of Maceio (Alagoas, Brazil), to reach 12-19 years old female teenagers. The data were assessed by the Epi Info Program making use of odds ratio and a relative risk to verify any association among variables and a confidence interval at 95%. At a sample of 2,592 adolescents, 559 (21.6%) had an active sexual life, 182 (7.0%) informed to have been pregnant and 149 (26.7%) to have aborted. The fear of the parents' reaction, age, lack of support of the partner and pregnancy rejection were the explanation to stimulate abortion. Fear was the most mentioned cause in both types of school. Abortion was more mentioned in public schools, being significant and protective the risk of aborting before the age of 15. The fear of the parents' reaction as a frequent cause suggests the necessity for additional studies on sexuality and communication between parents and children. PMID- 21655721 TI - [The relation between maternal breast feeding and non-nutritive sucking habits]. AB - This study sought to identify the type and duration of breastfeeding received by children and establish the association with non-nutritive suction habits. A retrospective, transversal study was conducted using a questionnaire given to 330 mothers or persons responsible for 3 to 6-year-old children registered in kindergartens in Aracatuba, State of Sao Paulo, after obtaining their free and informed consent. It was revealed that 86.4% of mothers breastfed their children. With respect to duration, only 33.4% of these mothers breastfed exclusively after 6 months. The average time of exclusive breastfeeding received by children was 3.84 months and complementary breastfeeding was 11.68 months. Of this total, 53.3% reported that their infants manifested non-nutritive suction habits and of these children, 70.45% were not exclusively breastfed for the first 6 months, there being a significant association between both (p<=0.05). Pacifier use was the most frequent habit (44.4%), showing a statistically significant association with breastfeeding time (p<0.0001). It was concluded that breastfeeding was practiced, albeit for a lesser duration than considered indispensable for the baby's development, there being an association between duration and type of breastfeeding and non-nutritive suction habits. PMID- 21655722 TI - [Repeated pregnancy among adolescents and social vulnerability in Rio de Janeiro (RJ, Brazil): data analysis of Information System on Live Births]. AB - Repeated pregnancy (RP) among adolescents is seldom researched in Brazil, even tough the debate on the reproductive rights is important for this extract of population. A transversal study was developed with data from the Declaration of Live Births of adolescent mothers, living in Rio de Janeiro (RJ, Brazil), in 2005. The aim was to estimate the magnitude and features associated with RP. Prevalence ratios (PR) of RP, with 95% confidence interval (CI) for selected variables, were estimated through log-binomial multivariate regression. Among 12,168 adolescents, a RP prevalence of 29.1% was identified and the principal factors associated were: age 15-19 anos (PR=5.42; RI 95% 3.72-7.81); not doing prenatal consultation (RP=2.36; CI 95% 2.16-2.58); educational status<4 anos (PR=1.48; CI 95% 1.25-1.76); housewife job (PR=1.8; CI 95% 1.57-2.15) or other (PR=1.9; CI 95%; 1.73-2.10). Giving birth by cesarean section and low birth weight were negatively associated to repeated pregnancy with RP equal to 0,94 (CI 95%; 0,86-0,99) and 0.69 (CI 95%; 0.62-0.77). The adolescents with RP had worst socioeconomic and assistance indicators than those on their first pregnancy. Specific social policies for adolescent mothers, in vulnerable situation, will enable them to have better conditions to exercise their reproductive rights. PMID- 21655723 TI - [Socioeconomic trends and differentials in mortality due to cervical cancer in the State of Parana (Brazil), 1980-2000]. AB - The scope of this paper is to discuss the evolution of mortality due to cervical cancer in the State of Parana, Brazil, between 1980 and 2000 and analyze the socioeconomic differentials in each region of the State. Mortality data were gathered from the System for Information on Mortality by age and town of residence. Age-adjusted death rates were calculated for 22 regions of the state in each year. Comparative analysis evaluated socioeconomic indicators associated with regions that showed either stationary or increasing mortality trends. Cervical cancer deaths increased in the state of Parana, with an annual percentage increase of 1.68% (1.20 to 2.17, 95% confidence interval). Most of the regions presented a stationary trend of cervical cancer deaths. The comparison of regions presenting an increasing trend indicated poorer socioeconomic indices for the former set: regions with an increase in cervical cancer mortality had a significantly higher illiteracy rate (p<0.001), percentage of individuals older than 15 years with less than 4 years schooling (p=0.001), and lower per-capita income (p=0.025) and human development index (p=0.023). An increasing mortality trend was thus observed throughout the State and areas with higher mortality rates had poorer socioeconomic indices. PMID- 21655724 TI - [Missed opportunities for cervical cancer prevention during prenatal care]. AB - Pregnancy constitutes an excellent opportunity for the prevention of cervical carcinoma since the gynecological examination is part of routine prenatal care. A transversal study was conducted in which a total of 445 postnatal women were interviewed using standardized questionnaires. The prevalence of an up-to-date cytopathological exam was 38.9% at the beginning of pregnancy, reaching 59.1% during the postnatal period (p>0.001). Postnatal women aged 19 years or less, non white, with less than 11 years schooling, family income of less than one minimum wage, sexually active at 15 years of age or less, with the beginning of prenatal care after the 1st trimester, and receiving prenatal care at healthcare units of the Unified Health System had a lower prevalence of cytopathological examination. Adjusted analysis revealed that the variables under study were not significantly associated with cytopathological coverage, though the incidence of prenatal care showed a prevalence ratio of 1.18 (95% CI: 0.98-1.42). The local health service proved ineffective, recvealing the need to increase cytopathological coverage and train health professionals regarding the importance of routine prenatal procedures. PMID- 21655725 TI - [Body image of women with breast cancer: a systematic review of literature]. AB - Women experience a major process of reshaping their body image when they deal with breast cancer. This article seeks to understand the relationship that breast cancer and its treatment have in the process of (re)construction of a woman's body image. The ultimate objective is to promote knowledge to train health professionals to become more aware of a woman's quality of life. A systematic review of the literature of scientific articles published between 2004 and 2009 available in three scientific databases was conducted and a total of 56 articles were reviewed and grouped into four thematic categories. There is a pressing need for further studies on the socio-cultural characteristics of women with breast cancer, the differences of (re)construction of body image of young and older women, and Brazilian publications about the personal experience and socio cultural context of women with breast cancer. PMID- 21655726 TI - [The use of apetite inhibitors by women: an insight based on the gender perspective]. AB - The scope of this study was to understand the motives that lead adult women to use appetite inhibitors and to establish, from a gender perspective, how these women relate to their own bodies. It was structured around the principles of qualitative research, and the methods of data collection were semi-structured interviews and direct observation. The informants were six women who used appetite inhibitors. The results indicated that images, publicity and social networks contribute significantly to the creation of new standards of physical appearance as well as lifestyles, which establish appearance (a slim body) and a happy marriage as the desired model. The slim body is represented as something able to alter the temperament of the individual, in other words a fat person is an unhappy person and a slim person is a happy person. The study shows that it is in the body per se that the social role destined for women is produced and reproduced. PMID- 21655727 TI - [Awareness about breast cancer and mammography in elderly women who frequent Daycare Centers in Sao Paulo (SP, Brazil)]. AB - Early detection at the initial stage of breast cancer through mammography is the best way of reducing morbidity and mortality rates. The scope of this study was to establish awareness about breast cancer and mammography among elderly women, if they take the exam and discover the reasons that lead them to take the exam or not. A cross-sectional and exploratory study was conducted with 98 elderly women in three Senior Citizen Daycare Centers in Sao Paulo. With respect to awareness of mammography as the exam used for early detection of breast cancer, 55% of the women answered that they knew. The majority of these women (77.6%) had taken the exam and 22.4% had never done so. The reasons most frequently cited for taking a mammography were concern with health (53.8%) and medical recommendation (38.5%). The reasons for not taking the exam were not having a medical recommendation (50%), conviction that they will never have the illness (23.1%), didn't feel symptoms (19.2%) and fear (7.7%). This study showed that the subject of "breast cancer" is well known by the women, however mammography needs to be explained better. The fact that there are elderly women who have never submitted to the exam reveals the ongoing need to stage educational campaigns about breast cancer and the early detection exams. PMID- 21655728 TI - [Functional incapacity among low-income elderly women]. AB - The scope of this study was to analyze the relationship between socio-demographic and health-related aspects and functional incapacity among low-income elderly women. This cross-sectional study involved a representative sample of 222 women with mean age of 70 years (+/- 7.27), in community groups in the city of Jequie, in the State of Bahia, Brazil. Anthropometric measurements were taken and interviews staged to examine the socio-demographic, physical and behavioral health variables. The statistical analysis was accomplished with a level of significance of p<0.05, with calculation of the respective odds ratio in the binary logistic regression, for analysis of hierarchically-grouped factors. The prevalence of functional incapacity was 46.8% and, by using hierarchical multivariate analysis, a significant association was detected with increased age, insufficient schooling, hospitalization, lack of physical exercise throughout life and alterations in the cognitive function. The characteristics identified that associated limitations in instrumental activities in daily life suggest a complex causal network in the determination of functional incapacity in low income elderly women. PMID- 21655729 TI - [Comprehensive care of pregnant adolescents in primary care]. AB - Prenatal adolescent care is characterized by technical actions seeking to provide assistance from the perspective of comprehensive care. The Community Health Agent Program/Family Health Program (PACS/PSF) is a strategy for implementing the changes envisaged, which motivated this scientific investigation. The scope of the research was to assess prenatal care to pregnant adolescents by health professionals of PACS/PSF and analyze it from the standpoint of comprehensive care. It is a qualitative study, with comprehensive care as its theoretical focus. It was conducted in PACS/PSF units in a city in the State of Bahia, and the subjects of study were the practitioners who treat pregnant adolescents. The empirical material was produced by means of semi-structured interviews and non participative observation in consultations and homecare visits and was analyzed using the speech analysis technique. This revealed that prenatal care for adolescents is provided using the biomedical model, where compliance with institutional protocols and routines takes precedence over considering the specific aspects of the adolescent. Thus it is far removed from comprehensive care, in that the practices are guided by ideological adherence to a model that fails to grant pregnant adolescents the opportunity to be treated as individuals. PMID- 21655730 TI - [The prevalence and factors associated with obesity in women attended at First Aid Units of the Unified Health System in southern Brazil]. AB - Obesity is currently one of the major epidemics, representing an important public health problem that is associated with an increase in chronic disease. The scope of this study is to investigate the prevalence of excess weight and obesity and associated factors in 20 to 59-year-old women attended at First Aid Units of the Unified Health System. Standardized interviews and anthropometric measurements were conducted with 440 women. Factors associated with the presence of excess weight/obesity were investigated using the Poisson model with robust variance. The prevalence of excess weight and obesity (64.3%) as well as central obesity (44.1%) in women attended at First Aid Units is higher than that in the population in general and is associated with an increased incidence of health problems. Insufficient physical activity (PR=1.44; 95% CI 1.24-1.66), a history of three pregnancies or more (PR=1.45; 95% CI 1.05-2.00), age above 50 (PR=1.34; 95% CI 1.00-1.82) and central obesity (PR=1.92; 95% CI 1.64-2.25) are associated with a higher prevalence of obesity. The implementation of public health polices focused on the prevention of obesity would undoubtedly have a major impact on primary prevention of chronic diseases in the female population. PMID- 21655731 TI - [Perceptions on the quality of services relating to women's healthcare]. AB - The scope of this work is to identify the characteristics relating to the quality of women's healthcare services from the perspective of the sanitary vigilance professionals (Visa) and women's healthcare coordinators (CSM) in the municipalities. It is a study with a qualitative approach that was carried out using semi-structured interviews. Three Brazilian state capitals were selected and three individuals in each capital were interviewed, namely a Visa healthcare service chief, as well as a technician, and a CSM coordinator. The content analysis technique was adopted to organize the data and the answers were grouped into the healthcare service evaluation topics based on Donabedian's model, i.e. structure, processes, and outcomes. Visa workers reported aspects related to the structure of health services, such as equipment and qualified human resources more frequently. The Visa chief mentioned aspects related to structure and processes, such as prioritization in attendance. The CWH coordinator examined all three categories, especially processes. Analysis of interviews points to a potential distortion in evaluation by results. The study highlights the need for joint action between the surveillance and assistance sectors to improve the quality of services. PMID- 21655732 TI - [Social support to pregnant adolescents: clarifying perceptions]. AB - This descriptive-exploratory study using a qualitative approach was undertaken to describe the perceptions of pregnant adolescents in relation to social support provided during pregnancy. Twelve adolescents in their first pregnancy who frequented the outpatient health service in Passo Fundo in the state of Rio Grande do Sul (Brazil) participated in the study. The data was obtained by semi structured interviews, genograms and ecomaps and was assessed by thematic analysis. It highlighted the need for support to overcome the fears and challenges of motherhood. The mothers and partners were perceived as the main sources of support in affective and material terms. Common sense knowledge prevailed in the information dimension and pregnancy as a mediator in the reconciliation with the father fulfilled the emotional dimension. The perception of the dimension of positive social interaction was blurred by self-imposed isolation. Thus the adolescent's perception of the social support received is clear in relation to the family nucleus and includes the people in the family circle. The network of care outside the family, including the healthcare services, is tenuous and generated the perception of psychosocial difficulties. This reveals the need for greater investment of primary healthcare professionals in the inclusion of first-time-pregnancy adolescents in social care groups, which ensure the healthy progress of the pregnancy. PMID- 21655734 TI - [Social support networks for elderly patients attended by Family Health teams]. AB - The aging process has specific aspects marked by the class of individuals and social groups as well as cultural, political, socio-economic and sanitary conditions of the collective groups. Social support systems are essential for meeting the specific needs of the elderly. The aim of this paper is to describe the socio-demographic profile and the social support networks of elderly patients served by the Family Health Strategy. It's a cross-sectional study with elderly patients living in Dourados, in the state of Mato Grosso do Sul (Brazil). Data were collected using a socio-demographic questionnaire and a Minimum Relationships Map for the Elderly (MMRI). Of the 503 elderly patients interviewed, 69% were female, 53.1% were illiterate, 58.3% earned less than one minimum salary and 82.9% lived with others. The MMRI showed that the family was the most important provider of care in all the dimensions assessed, but the elderly have their own small social networks. Elderly patients attended by the Family Health teams have low incomes and little formal education, and social support networks that are too small to meet their needs. PMID- 21655733 TI - Cadmium, environmental exposure, and health outcomes. AB - We provide an update of the issues surrounding health risk assessment of exposure to cadmium in food. Bioavailability of ingested cadmium has been confirmed in studies of persons with elevated dietary exposure, and the findings have been strengthened by the substantial amounts of cadmium accumulated in kidneys, eyes, and other tissues and organs of environmentally exposed individuals. We hypothesized that such accumulation results from the efficient absorption and systemic transport of cadmium, employing multiple transporters that are used for the body's acquisition of calcium, iron, zinc, and manganese. Adverse effects of cadmium on kidney and bone have been observed in environmentally exposed populations at frequencies higher than those predicted from models of exposure. Population data raise concerns about the validity of the current safe intake level that uses the kidney as the sole target in assessing the health risk from ingested cadmium. The data also question the validity of incorporating the default 5% absorption rate in the threshold-type risk assessment model, known as the provisional tolerable weekly intake (PTWI), to derive a safe intake level for cadmium. PMID- 21655735 TI - [Crack usage circuits in the downtown area of the city of Sao Paulo (SP, Brazil)]. AB - Although drug usage has been prevalent since the dawn of humankind, drug abuse has currently escalated alarmingly and can be characterized as a public health problem. The spread of "crack," a drug derived from cocaine paste, is worsening the situation by aggravating the social damages and harming the health of users. An ethnographic study was conducted in downtown Sao Paulo, SP (Brazil) in locations where crack is sold and used in order to establish the impact of the spread of this drug in the daily life of users. A field diary was used to record the observations and informal dialogues with the people who circulate in the location under scrutiny. The results of this study show the circuits covered by the users, their dynamics and the complex relationships with other social players, based on permanent tension, involving the practice of violence in which the users are both victims and perpetrators. The study also suggests the importance of other factors such as the history of the region in question, the public policies, economic questions and the lack of social investments and public health. It is suggested that the advanced degree of degradation of the region researched is not only the result of the people and activities practiced in the area, but also mainly of the urban process that led to such a social scenario. PMID- 21655736 TI - [The use of medication in the perception of users Hiperdia Program]. AB - This article discusses the question of access to medication as a social right, investigating how users registered in the Hiperdia program perceive their access to medication. To achieve this, the process of "medicalization" experienced by Brazilian society today was assessed, highlighting the influence that this process has on access to medication, prejudicing the achievement of universal and equalitarian access. Using a technique recommended by qualitative research, focal groups with Hiperdia users in the basic health service of Juiz de Fora, Minas Gerais, Brazil, were set up. The survey emphasizes the perception that these users have with respect to their rights related to essential medication. In this process, their beliefs, knowledge, attitudes, difficulties, fears, doubts and anxieties concerning the use of essential medication are investigated, as well as their viewpoints on the disease(s) they suffer from. Among the results obtained, it was revealed that the majority of the users of basic health units do not consider that they have rights and that access to medication as a constitutionally-assured social right is far from being implemented in the Brazilian public health service today. PMID- 21655737 TI - [The influence of the organizational structure on the internal controls of a foundation for cancer research, prevention and care in the interior of the state of Sao Paulo, Brazil]. AB - This work focuses on a discussion about the extent to which the level of organizational structure interferes in the internal control practices of non governmental organizations (NGOs), especially those related to health. The objective of this work was to observe the efficiency of the internal control tests applied within the organizational structure of the Foundation for Cancer Research, Prevention and Care, checking the reliability of the accounting records and operational controls. A case study in a third sector health organization was the chosen methodology. The case study involved company interviews and the analysis of confidential reports. After an evaluation of the organizational structure (of the relations between officials and volunteers) and the application of evaluation proceedings on the quality of the internal controls, the extent to which the organizational structure interferes with the internal control practices of the hospital was assessed. It was revealed that there are structured mechanisms of control in the institution, however the implementation of these controls is inadequately performed. It was further detected that the level of the organizational structure does indeed interfere in internal control practices at the entity. PMID- 21655738 TI - Validation study of a scale of life quality evaluation in a group of pediatric patients infected by HIV. AB - With the advent of potent antiretroviral therapy and the increase in life expectancy of pediatric patients infected with HIV, the quest for the promotion of enhanced quality of life should currently be the main focus in care of children with HIV/Aids. The scope of this study was to validate the Scale of Children's Quality of Life in a group of children infected with HIV receiving clinical care in Aids Service Units in Rio de Janeiro, Brazil. This scale consists of 26 questions and was tested on 100 children, with ages varying between 4 and 12, and their respective parents or guardians. Statistical analysis was conducted using canonical correlation and confidence interval analysis and the X2 test. The results showed that the cut-off point obtained was 49; the internal consistency with Cronbach's alpha was 0.73 for the children and 0.67 for parents or guardians. The response profile revealed marked satisfaction with aspects such as vacations and birthdays, though less satisfaction with items including hospitalization and playing alone. The conclusion was that the scale revealed satisfactory psychometric measurements, proving to be a reliable, consistent, valid and recommended instrument for measuring the quality of life of children infected with HIV. PMID- 21655739 TI - [Coliforms in the water supply of fast-food chains in the Metropolitan Region of Recife, in the state of Pernambuco (Brazil)]. AB - A guaranteed supply of clean drinking water in food outlets is a relevant subject for public health. The scope of this study was to assess the microbiological quality of 96 water samples of a network of fast-food stores in the city of Recife (state of Pernambuco, Brazil) and Metropolitan Area and to compare the results to the standards established by Brazilian Health Ministry decree no 518/2004. Every month, a double sample from one of the faucets in the food preparation area of the eight stores investigated was analyzed, totaling 96 samples over one year. The analyses followed the established methodology of American Public Health Association (APHA), in order to conduct the Presence Absence Test, considering the potability standard in pertinent legislation. Results revealed that 11.46% and 1.04% of samples contained water contaminated with total coliforms and thermotolerant coliforms, respectively. The quality of the water in the food establishments studied is thus a health hazard since a significant percentage of samples analyzed were inappropriate for human consumption in accordance with current legislation, which stipulates the absence of total coliforms and thermotolerant coliforms. PMID- 21655741 TI - Genomic instability in human actinic keratosis and squamous cell carcinoma. AB - OBJECTIVE: To compare the repetitive DNA patterns of human actinic keratoses and squamous cell carcinomas to determine the genetic alterations that are associated with malignant transformation. INTRODUCTION: Cancer cells are prone to genomic instability, which is often due to DNA polymerase slippage during the replication of repetitive DNA and to mutations in the DNA repair genes. The progression of benign actinic keratoses to malignant squamous cell carcinomas has been proposed by several authors. MATERIAL AND METHODS: Eight actinic keratoses and 24 squamous cell carcinomas (SCC), which were pair-matched to adjacent skin tissues and/or leucocytes, were studied. The presence of microsatellite instability (MSI) and the loss of heterozygosity (LOH) in chromosomes 6 and 9 were investigated using nine PCR primer pairs. Random Amplified Polymorphic DNA patterns were also evaluated using eight primers. RESULTS: MSI was detected in two (D6S251, D9S50) of the eight actinic keratosis patients. Among the 8 patients who had squamous cell carcinoma-I and provided informative results, a single patient exhibited two LOH (D6S251, D9S287) and two instances of MSI (D9S180, D9S280). Two LOH and one example of MSI (D6S251) were detected in three out of the 10 patients with squamous cell carcinoma-II. Among the four patients with squamous cell carcinoma III, one patient displayed three MSIs (D6S251, D6S252, and D9S180) and another patient exhibited an MSI (D9S280). The altered random amplified polymorphic DNA ranged from 70% actinic keratoses, 76% squamous cell carcinoma-I, and 90% squamous cell carcinoma-II, to 100% squamous cell carcinoma-III. DISCUSSION: The increased levels of alterations in the microsatellites, particularly in D6S251, and the random amplified polymorphic DNA fingerprints were statistically significant in squamous cell carcinomas, compared with actinic keratoses. CONCLUSION: The overall alterations that were observed in the repetitive DNA of actinic keratoses and squamous cell carcinomas indicate the presence of a spectrum of malignant progression. PMID- 21655742 TI - Glucose-dependent insulinotropic peptide receptor overexpression in adrenocortical hyperplasia in MEN1 syndrome without loss of heterozygosity at the 11q13 locus. AB - BACKGROUND: The molecular mechanisms involved in the genesis of the adrenocortical lesions seen in MEN1 syndrome (ACL-MEN1) remain poorly understood; loss of heterozygosity at 11q13 and somatic mutations of MEN1 are not usually found in these lesions. Thus, additional genes must be involved in MEN1 adrenocortical disorders. Overexpression of the glucose-dependent insulinotropic peptide receptor has been shown to promote adrenocortical tumorigenesis in a mice model and has also been associated with ACTH-independent Cushing syndrome in humans. However, to our knowledge, the status of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions in MEN1 has not been previously investigated. OBJECTIVE: To evaluate glucose-dependent insulinotropic peptide receptor expression in adrenocortical hyperplasia associated with MEN1 syndrome. MATERIALS/METHODS: Three adrenocortical tissue samples were obtained from patients with previously known MEN1 germline mutations and in whom the presence of a second molecular event (a new MEN1 somatic mutation or an 11q13 loss of heterozygosity) had been excluded. The expression of the glucose dependent insulinotropic peptide receptor was quantified by qPCR using the DDCT method, and b-actin was used as an endogenous control. RESULTS: The median of glucose-dependent insulinotropic peptide receptor expression in the adrenocortical lesions associated with MEN1 syndrome was 2.6-fold (range 1.2 to 4.8) higher than the normal adrenal controls (p = 0.02). CONCLUSION: The current study represents the first investigation of glucose-dependent insulinotropic peptide receptor expression in adrenocortical lesions without 11q13 loss of heterozygosity in MEN1 syndrome patients. Although we studied a limited number of cases of MEN1 adrenocortical lesions retrospectively, our preliminary data suggest an involvement of glucose-dependent insulinotropic peptide receptor overexpression in the etiology of adrenocortical hyperplasia. New prospective studies will be able to clarify the exact role of the glucose-dependent insulinotropic peptide receptor in the molecular pathogenesis of MEN1 adrenocortical lesions. PMID- 21655743 TI - The influence of intense intermittent versus moderate continuous exercise on postprandial lipemia. AB - INTRODUCTION: Postprandial lipemia is characterized by an increased concentration of circulating lipids after fat intake and is an independent risk factor for cardiovascular disease. Exercise is known to reduce postprandial lipemia and its negative clinical outcomes. OBJECTIVE: This study investigated the effect of intense intermittent versus moderate continuous exercise using the same energy expenditure in postprandial lipemia. MATERIALS AND METHODS: Twenty healthy men (aged 21.5 +/- 3.5 years) performed a random sequence of either rest or 500 Kcal tests separated by a minimum 48 h interval as follows: (a) no exercise (control), (b) intense intermittent exercise, or (c) moderate continuous exercise. Each test series was completed 30 min before ingestion of a high-fat meal (1 g fat/kg). Venous blood was collected before and at 1, 2, 3 and 4 hours after the high-fat meal. Postprandial lipemia was assessed using the area under the curve approach as well as a kinetic profile of mean lipid variables. Statistical significance was tested at the p<0.05 level. RESULTS: With both statistical approaches, intense intermittent and moderate continuous exercises were both effective in reducing postprandial triglycerides; however, only intense intermittent exercise reduced the levels of postprandial very low density lipoprotein. Intense intermittent and continuous exercise produced lower levels of insulinemia using the area under the curve analysis only. CONCLUSION: Intense intermittent or continuous exercise with an energy expenditure of 500 kcal completed 30 min before ingestion of high-fat meal reduced postprandial lipid levels to different levels in physically active men. Understanding these relevant differences will enable clinicians to provide the best exercise prescription for patients. PMID- 21655744 TI - Antimicrobial resistance and prevalence of resistance genes in intestinal Bacteroidales strains. AB - OBJECTIVE: This study examined the antimicrobial resistance profile and the prevalence of resistance genes in Bacteroides spp. and Parabacteroides distasonis strains isolated from children's intestinal microbiota. METHODS: The susceptibility of these bacteria to 10 antimicrobials was determined using an agar dilution method. beta-lactamase activity was assessed by hydrolysis of the chromogenic cephalosporin of 114 Bacteriodales strains isolated from the fecal samples of 39 children, and the presence of resistance genes was tested using a PCR assay. RESULTS: All strains were susceptible to imipenem and metronidazole. The following resistance rates were observed: amoxicillin (93%), amoxicillin/clavulanic acid (47.3%), ampicillin (96.4%), cephalexin (99%), cefoxitin (23%), penicillin (99%), clindamycin (34.2%) and tetracycline (53.5%). P-lactamase production was verified in 92% of the evaluated strains. The presence of the cfiA, cepA, ermF, tetQ and nim genes was observed in 62.3%, 76.3%, 27%, 79.8% and 7.8% of the strains, respectively. CONCLUSIONS: Our results indicate an increase in the resistance to several antibiotics in intestinal Bacteroides spp. and Parabacteroides distasonis and demonstrate that these microorganisms harbor antimicrobial resistance genes that may be transferred to other susceptible intestinal strains. PMID- 21655745 TI - Trends and predictors of changes in pulmonary function after treatment for pulmonary tuberculosis. AB - OBJECTIVES: The present study aimed to investigate the trends in changes in pulmonary function and the risk factors for pulmonary function deterioration in patients with pulmonary tuberculosis after completing treatment. INTRODUCTION: Patients usually have pulmonary function abnormalities after completing treatment for pulmonary tuberculosis. The time course for changes in pulmonary function and the risk factors for deterioration have not been well studied. METHODS: A total of 115 patients with 162 pulmonary function results were analyzed. We retrieved demographic and clinical data, radiographic scores, bacteriological data, and pulmonary function data. A generalized additive model with a locally weighted scatterplot smoothing technique was used to evaluate the trends in changes in pulmonary function. A generalized estimating equation model was used to determine the risk factors associated with deterioration of pulmonary function. RESULTS: The median interval between the end of anti-tuberculosis treatment and the pulmonary function test was 16 months (range: 0 to 112 months). The nadir of pulmonary function occurred approximately 18 months after the completion of the treatment. The risk factors associated with pulmonary function deterioration included smear-positive disease, extensive pulmonary involvement prior to anti tuberculosis treatment, prolonged anti-tuberculosis treatment, and reduced radiographic improvement after treatment. CONCLUSIONS: After the completion of anti-tuberculosis TB treatment, several risk factors predicted pulmonary function deterioration. For patients with significant respiratory symptoms and multiple risk factors, the pulmonary function test should be followed up to monitor the progression of functional impairment, especially within the first 18 months after the completion of anti-tuberculosis treatment. PMID- 21655746 TI - Eosinophilic esophagitis in patients with typical gastroesophageal reflux disease symptoms refractory to proton pump inhibitor. AB - BACKGROUND: TREATMEN The contribution of eosinophilic esophagitis (EoE) to refractory gastroesophageal reflux disease (GERD) remains unknown. When EoE and GERD overlap, the clinical, endoscopic and histological findings are nonspecific and cannot be used to distinguish between the two disorders. Limited data are available on this topic, and the interaction between EoE and GERD is a matter of debate. AIM: We have conducted a prospective study of adult patients with refractory GERD to evaluate the overlap of reflux and EoE. METHODS: Between July 2006 and June 2008, we consecutively and prospectively enrolled 130 male and female patients aged 18 to 70 years old who experienced persistent heartburn and/or regurgitation more than twice a week over the last 30 days while undergoing at least six consecutive weeks of omeprazole treatment (at least 40 mg once a day). The patients underwent an upper digestive endoscopy with esophageal biopsy, and intraepithelial eosinophils were counted after hematoxylin/eosin staining. The diagnosis of EoE was based on the presence of 20 or more eosinophils per high-power field (eo/HPF) in esophageal biopsies. RESULTS: Among the 103 studied patients, 79 (76.7%) were females. The patients had a mean age of 45.5 years and a median age of 47 years. Endoscopy was normal in 83.5% of patients, and erosive esophagitis was found in 12.6%. Only one patient presented lesions suggestive of EoE. Histological examination revealed >20 eo/HPF in this patient. CONCLUSION: Our results demonstrated a low prevalence of EoE among patients with refractory GERD undergoing omeprazole treatment. PMID- 21655747 TI - Does staged closure have a worse prognosis in gastroschisis? AB - INTRODUCTION: Correction of gastroschisis can be accomplished by primary or staged closure. There is, however, no consensus regarding the best approach or criteria to favor one method over the other has been established. OBJECTIVE: To compare the outcome of primary and staged closure in newborns with gastroschisis using intravesical pressure (IVP) as the decision criterion. PATIENTS & METHODS: We prospectively analyzed 45 newborns with gastroschisis. An IVP with a threshold of 20 cm H(2)O was used to indicate primary or staged closure, and the outcomes between the two methods were compared. RESULTS AND DISCUSSION: Newborns in whom primary closure was feasible were born at a lower gestational age. There was no significant difference in the frequency of complications, time to begin oral feeding, length of parenteral nutrition or length of hospital stay. Compared with previous reports, our data showed higher rates of prenatal diagnosis and cesarean delivery, a lower average birth weight, a higher rate of small gestational age babies and a more frequent association with intestinal atresia. Conversely, our data showed a lower rate of postoperative necrotizing enterocolitis and a lower average length of hospital stay. CONCLUSION: No significant difference was observed in the outcome of newborns who underwent primary closure or staged closure of gastroschisis when using an IVP below 20 cm H(2)O as the criterion for primary closure. PMID- 21655748 TI - Upper airway collapsibility evaluated by a negative expiratory pressure test in severe obstructive sleep apnea. AB - OBJECTIVES: To investigate the usefulness of measuring upper airway collapsibility with a negative expiratory pressure application as a screening test for severe obstructive sleep apnea (OSA). INTRODUCTION: OSA is a risk factor for cardiovascular disease, and it may have serious consequences. Its recognition may have important implications during the perioperative period. Increased upper airway collapsibility is one of the main determinants of OSA, and its evaluation could be useful for identifying this condition. METHODS: Severe OSA and normal subjects (24 in each group) were matched by body mass index and referred to our sleep laboratory. The subjects were enrolled in an overnight sleep study, and a diurnal negative expiratory pressure test was performed. Flow drop (DeltaV) and expiratory volume were measured in the first 0.2 s (V(0.2)) of the negative expiratory pressure test. RESULTS: DeltaV (%) and V(0.2) (%) values were statistically different between normal and OSA subjects. OSA patients showed a greater decrease in flow than normal subjects. In addition, severely OSA patients exhaled during the first 0.2 s of the negative expiratory pressure application was an average of only 11.2% of the inspired volume compared to 34.2% for the normal subjects. Analysis of the receiver operating characteristics showed that V(0.2) (%) and DeltaV (%) could accurately identify severe OSA in subjects with sensitivities of 95.8% and 91.7%, respectively, and specificities of 95.8% and 91.7%, respectively. CONCLUSIONS: V(0.2) (%) and DeltaV (%) are highly accurate parameters for detecting severe OSA. The pharyngeal collapsibility measurement, which uses negative expiratory pressure during wakefulness, is predictive of collapsibility during sleep. PMID- 21655749 TI - Predictive score for clinical complications during intra-hospital transports of infants treated in a neonatal unit. AB - OBJECTIVE: To develop and validate a predictive score for clinical complications during intra-hospital transport of infants treated in neonatal units. METHODS: This was a cross-sectional study nested in a prospective cohort of infants transported within a public university hospital from January 2001 to December 2008. Transports during even (n=301) and odd (n = 394) years were compared to develop and validate a predictive score. The points attributed to each score variable were derived from multiple logistic regression analysis. The predictive performance and the score calibration were analyzed by a receiver operating characteristic (ROC) curve and Hosmer-Lemeshow test, respectively. RESULTS: Infants with a mean gestational age of 35 +/- 4 weeks and a birth weight of 2457 +/- 841 g were studied. In the derivation cohort, clinical complications occurred in 74 (24.6%) transports. Logistic regression analysis identified five variables associated with these complications and assigned corresponding point values: gestation at birth [<28 weeks (6 pts); 28-34 weeks (3 pts); >34 weeks (2 pts)]; pre-transport temperature [<36.3 degrees Cor >37 degrees C(3pts); 36.3-37.0 degrees C (2 pts)]; underlying pathological condition [CNS malformation (4 pts); other (2 pts)]; transport destination [surgery (5 pts); magnetic resonance or computed tomography imaging (3 pts); other (2 pts)]; and pre-transport respiratory support [mechanical ventilation (8 pts); supplemental oxygen (7 pts); no oxygen (2 pts)]. For the derivation and validation cohorts, the areas under the ROC curve were 0.770 and 0.712, respectively. Expected and observed frequencies of complications were similar between the two cohorts. CONCLUSION: The predictive score developed and validated in this study presented adequate discriminative power and calibration. This score can help identify infants at risk of clinical complications during intra-hospital transports. PMID- 21655750 TI - The relationship between bisphosphonate use and demographic characteristics of male osteoporosis patients. AB - INTRODUCTION: This study aimed to investigate a number of demographic characteristics in males with osteoporosis (OP) treated with bisphosphonate and determine whether any of these measures could act as an effective indicator of medication persistence and compliance. MATERIAL AND METHOD: Among the patients with OP who applied to our clinic and were prescribed weekly oral bisphosphonate treatment, 89 patients over 50 years of age were included in this study. The demographic characteristics of these patients were evaluated. The number of medications used by the patients over the past 1 and 3 years were counted, and the persistence and compliance with bisphosphonate treatment was estimated. The patients were divided into two groups: fully compliant and noncompliant subjects. The two groups of patients were compared separately for 1 and 3 years while considering their demographic characteristics. RESULTS: The mean age of the 89 patients included in the study was 62.43 +/- 9.41 years. Comparisons among the studied demographic characteristics during the 1-year period of medication use indicated that the educational status of the fully compliant patients was higher. During the 3-year period of medication use, educational status was the only demographic characteristic that was determined to be significantly lower in the noncompliant patients than in the fully compliant group. CONCLUSION: Although deficiencies in medication persistence and compliance during osteoporosis treatment can lead to serious health and social problems in both genders, the causes of these deficiencies have not been thoroughly clarified. We suggest that the educational status of the patient may contribute to these deficiencies. PMID- 21655751 TI - Exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise are impaired in overweight/obese postmenopausal women. AB - OBJECTIVE: The purpose of this study was to compare the heart rate response to exercise and the exercise-induced improvements in muscle strength, cardiorespiratory fitness and heart rate response between normal-weight and overweight/obese postmenopausal women. METHODS: Sedentary women (n = 155) were divided into normal-weight (n = 79; BMI <25 kg/m(2); 58.3 +/- 8.6 years) and overweight/obese (n = 76; BMI >25 kg/m(2); 58.3 +/- 8.6 years) groups, and have their 1-repetition maximum strength (adjusted for body mass), cardiorespiratory fitness and heart rate response to a graded exercise test compared before and after 12 months of a three times-per-week exercise-training program. RESULTS: Overweight/obese women displayed decreased upper and lower extremity muscle strengths, decreased cardiorespiratory fitness, and lower peak and reserve heart rates compared to normal-weight women. After follow-up, both groups improved their upper (32.9% and 41.5% in normal-weight and overweight/obese women, respectively) and lower extremity(49.5% and 47.8% in normal-weight and overweight/obese women, respectively) muscle strength. However, only normal weight women improved their cardiorespiratory fitness (6.6%) and recovery heart rate (5 bpm). Resting, reserve and peak heart rates did not change in either group. CONCLUSIONS: Overweight/obese women displayed impaired heart rate response to exercise. Both groups improved muscle strength, but only normal-weight women improved cardiorespiratory fitness and heart rate response to exercise. These results suggest that exercise-induced improvements in cardiorespiratory fitness and heart rate response to exercise may be impaired in overweight/obese postmenopausal women. PMID- 21655752 TI - Role of psychiatric disorders and irritable bowel syndrome in asthma patients. AB - OBJECTIVES: The goals of the study were the following: 1) to determine the frequency of psychiatric disorders and irritable bowel syndrome in patients with asthma and 2) to compare the frequency of these disorders in patients with asthma to their frequency in healthy controls. INTRODUCTION: Patients with asthma have a higher frequency of irritable bowel syndrome and psychiatric disorders. METHODS: We evaluated 101 patients with bronchial asthma and 67 healthy subjects. All subjects completed the brief version of the Bowel Symptoms Questionnaire and a structured clinical interview for DSM-IV axis disorders (SCID-I/CV). RESULTS: There were 37 cases of irritable bowel syndrome in the group of 101 stable asthma patients (36.6%) and 12 cases in the group of 67 healthy subjects (17.9%) (p = 0.009). Irritable bowel syndrome comorbidity was not related to the severity of asthma (p = 0.15). Regardless of the presence of irritable bowel syndrome, psychiatric disorders in asthma patients (52/97; 53.6%) were more common than in the control group (22/63, 34.9%) (p = 0.02). Although psychiatric disorders were more common in asthma patients with irritable bowel syndrome (21/35, 60%) than in those without irritable bowel syndrome (31/62, 50%), the difference was not significant (p = 0.34). In asthma patients with irritable bowel syndrome and psychiatric disorders, the percentage of forced expiratory volume in 1 s (FEV(1)) was lower than it was in those with no comorbidities (p = 0.02). CONCLUSIONS: Both irritable bowel syndrome and psychiatric disorders were more common in asthma patients than in healthy controls. Psychiatric disorders were more common in asthma patients with irritable bowel syndrome than in those without irritable bowel syndrome, although the differences failed to reach statistical significance. In asthma patients with IBS and psychiatric disorders, FEV(1)s were significantly lower than in other asthma patients. It is important for clinicians to accurately recognize that these comorbid conditions are associated with additive functional impairment. PMID- 21655753 TI - Repeatability of the evaluation of systemic microvascular endothelial function using laser doppler perfusion monitoring: clinical and statistical implications. AB - OBJECTIVE: An awareness of the repeatability of biological measures is required to properly design and calculate sample sizes for longitudinal interventional studies. We investigated the day-to-day repeatability of measures of systemic microvascular reactivity using laser Doppler perfusion monitoring. METHODS: We performed laser Doppler perfusion monitoring in combination with skin iontophoresis using acetylcholine and sodium nitroprusside as well as post occlusive reactive and thermal hyperemia twice within two weeks. The repeatability was assessed by calculating the within-subject standard deviations, limits of agreement, typical errors and intra-class correlation coefficients between days 1 and 2. The ratio of the within-subject standard deviation to the mean values obtained on days 1 and 2 (within-subject standard deviation/GM) was used to determine the condition with the best repeatability. RESULTS: Twenty-four healthy subjects, aged 24.6 +/- 3.8 years, were recruited. The area under the curve of the vasodilatory response to post-occlusive reactivity showed marked variability (within-subject standard deviation/GM = 0.83), while the area under the curve for acetylcholine exhibited less variability (within-subject standard deviation/ GM = 0.52) and was comparable to the responses to sodium nitroprusside and thermal treatment (within-subject standard deviations/GM of 0.67 and 0.56, respectively). The area under the blood flow/time curve for vasodilation during acetylcholine administration required the smallest sample sizes, the area under the blood flow/time curve during post-occlusive reactivity required the largest sample sizes, and the area under the blood flow/time curves of vasodilation induced by sodium nitroprusside and thermal treatment required intermediate sizes. CONCLUSIONS: In view of the importance of random error related to the day to-day repeatability of laser Doppler perfusion monitoring, we propose an original and robust statistical methodology for use in designing prospective clinical studies. PMID- 21655754 TI - Evaluation of prognostic factors in stage IIA breast tumors and their correlation with mortality risk. AB - Breast tumors exhibit extensive molecular and clinical heterogeneity. One of the most utilized breast carcinoma classifications is based on its molecular aspects and subdivides breast cancer into five major groups based on the expression of certain genes. In this study, we evaluated which factors are important in determining a prognosis after 5 years of follow-up for patients with clinical stage IIA breast tumors. We took into consideration the different phenotypes (luminal A luminal B HER-2 overexpression, basal and triple-negative), various epithelial-mesenchymal (EMT) molecular markers and adhesion molecules (E cadherin, P-cadherin, N-cadherin, vimentin, twist snail and slug) and NOS-2, in addition to clinical and demographic data, tumor characteristics and treatment types. METHODS: The study population consisted of 82 patients with breast cancer. We analyzed eight molecular markers by immunohistochemistry on tissue microarrays containing breast tumor specimens from patients with ten years of follow-up, and we classified each tumor according to its estrogen receptor, progesterone receptor and HER-2 expression. We then placed the tumor into one of the above categories. RESULTS: The presence of several clinical and demographic factors, various histopathologies, treatment forms and several immunohistochemical markers were not associated with a worse prognosis for group IIA patients. The factors that were associated with a mortality risk were the triple-negative (odds ratio (OR) = 11.8, 95% confident interval (CI) = 2.0-70.3, P = 0.007) and basal (OR =18.4, 95% CI = 1.8-184.7, P= 0.013) phenotypic patterns. CONCLUSIONS: The EMT markers and NOS-2 were not mortality risk factors. Basal and triple-negative phenotypic patterns were related to a higher mortality risk in patients with stage IIA tumors. PMID- 21655755 TI - Physical activity attenuates neuropsychiatric disturbances and caregiver burden in patients with dementia. AB - INTRODUCTION: A significant benefit from physical activity has recently been described in some patients who suffer from neurodegenerative diseases. OBJECTIVE: To assess the effects of physical activity on neuropsychiatric disturbances in demented patients and on the mental burden of their caregivers. METHODS: Assisted by a public geriatric psychiatry clinical unit, we studied 59 patients with dementia. Patients were divided into three groups according to their diagnosis and level of physical activity. Data were assessed through a semi-structured interview. Patients were evaluated with the Neuropsychiatric Inventory, the Mini Sleep Questionnaire and the Baecke Questionnaire. The data were statistically analyzed using the Mann-Whitney U test and linear regression, with the level of significance set at 5%. RESULTS: Patients with Alzheimer's or vascular dementia who engaged in physical activity had fewer neuropsychiatric symptoms than those who did not. When compared to the control group, the caregivers of patients with vascular dementia who engaged in physical activity had a reduced burden. CONCLUSION: The regular practice of physical activity seems to contribute to a reduction in neuropsychiatric symptoms in dementia patients and to attenuate the burden of the caregivers of those patients. PMID- 21655756 TI - E-learning program for medical students in dermatology. AB - INTRODUCTION: Dermatological disorders are common in medical practice. In medical school, however, the time devoted to teaching dermatology is usually very limited. Therefore, online educational systems have increasingly been used in medical education settings to enhance exposure to dermatology. OBJECTIVE: The present study was designed to develop a e-learning program for medical students in dermatology and evaluate the impact of this program on learning. METHODS: This prospective study included second year medical students at the University of Technology and Science, Salvador, Brazil. All students attended discussion seminars and practical activities, and half of the students had adjunct online seminars (blended learning). Tests were given to all students before and after the courses, and test scores were evaluated. RESULTS: Students who participated in online discussions associated with face-to-face activities (blended learning) had significantly higher posttest scores (9.0 +/- 0.8) than those who only participated in classes (7.75+/-1.8, p <0.01). CONCLUSIONS: The results indicate that an associated online course might improve the learning of medical students in dermatology. PMID- 21655757 TI - Verbal fluency in Alzheimer's disease, Parkinson's disease, and major depression. AB - OBJECTIVE: To compare verbal fluency among Alzheimer's disease, Parkinson's disease, and major depression and to assess the sociodemographic and clinical factors associated with the disease severity. METHODS: Patients from an outpatient university center with a clinical diagnosis of Alzheimer's disease, Parkinson's disease or major depression were studied. Severity was staged using the Hoehn & Yahr scale, the Hamilton Depression scale and the Clinical Dementia Rating for Parkinson's disease, major depression, and Alzheimer's disease, respectively. All subjects were tested with the Mini-Mental State Examination, the digit span test, and the verbal fluency test (animals). We fit four types of regression models for the count variable: Poisson model, negative binomial model, zero-inflated Poisson model, and zero-inflated negative binomial model. RESULTS: The mean digit span and verbal fluency scores were lower in patients with Alzheimer's disease (n = 34) than in patients with major depression (n = 52) or Parkinson's disease (n = 17) (p<0.001). The average number of words listed was much lower for Alzheimer's disease patients (7.2 words) compared to the patients presenting with major depression (14.6 words) or Parkinson's disease (15.7 words) (KW test = 32.4; p<0.01). Major depression and Parkinson's disease groups listed 44% (ROM = 1.44) and 48% (ROM = 1.48) more words, respectively, compared to those patients with Alzheimer's disease; these results were independent of age, education, disease severity and attention. Independently of diagnosis, age, and education, severe disease showed a 26% (ROM = 0.74) reduction in the number of words listed when compared to mild cases. CONCLUSIONS: Verbal fluency provides a better characterization of Alzheimer's disease, major depression, and Parkinson's disease, even at later stages. PMID- 21655758 TI - Earthquake-related pelvic crush fracture vs. non-earthquake fracture on digital radiography and MDCT: a comparative study. AB - OBJECTIVE: To determine the features of earthquake-related pelvic crush fractures versus non-earthquake fractures with digital radiography and multidetector row computed tomography. METHODS: One hundred and sixty-seven survivors with pelvic crush fractures in the 2008 Sichuan earthquake were entered in our study as the earthquake-related group (139 underwent digital radiography, 28 underwent multidetector row computed tomography); 70 victims with non-earthquake pelvic fractures were enrolled into this study as the non-earthquake group (54 underwent digital radiography, 16 underwent multidetector row computed tomography). Data were reviewed retrospectively between groups, focusing on anatomic distributions, status of pelvic bone fractures, numbers of pelvic bones involved, and classification of pelvic ring fractures according to the Tile classification system. RESULTS: Pelvic fractures occurred more frequently in the pubis in the earthquake-related group than in the non-earthquake group (135/167, 81% vs. 48/70, 69%). In addition, comminuted fractures were more common in the earthquake related group than in the non-earthquake group (55/167, 33% vs. 10/70, 14%). Multiple fractures were less common in the earthquake-related group than in the non-earthquake group (81/167, 49% vs. 46/70, 66%). Regarding the classification of pelvic ring fractures, Type C predominantly composed of subtype C3 occurred more frequently (64/167, 38% vs. 12/70, 17%), and Type A was less common in the earthquake-related group than in the non-earthquake group (31/167, 19% vs. 23/70, 32%). All differences were statistically significant (p<0.05). No difference was found in Type B fractures between the groups (72/167, 43% vs. 35/70, 50%). CONCLUSION: Earthquake-related pelvic crush fractures can be characterized by a high incidence of pelvic fractures occurring in the pubis, comminuted fractures, and Type C fractures predominantly composed by subtype C3, despite a low incidence of multiple fractures. PMID- 21655759 TI - Functional outcomes of conservatively treated clavicle fractures. AB - OBJECTIVE: The main aim of the study was to analyze the outcomes of clavicle fractures in adults treated non-surgically and to evaluate the clinical effects of displacement, fracture patterns, fracture location, fracture comminution, shortening and fracture union on shoulder function. METHODS: Seventy clavicle fractures were non-surgically treated in the Orthopedics Department at the Tuanku Ja'afar General Hospital, a tertiary care hospital in Seremban, Malaysia, an average of six months after injury. The clavicle fractures were treated conservatively with an arm sling and a figure-eight splint for three weeks. No attempt was made to reduce displaced fractures, and the patients were allowed immediate free-shoulder mobilization, as tolerated. They were prospectively evaluated clinically and radiographically. Shoulder function was evaluated using the Constant scoring technique. RESULTS: There were statistically significant functional outcome impairments in non-surgically treated clavicle fractures that correlated with the fracture type (comminution), the fracture displacement (21 mm or more), shortening (15 mm or more) and the fracture union (malunion). CONCLUSION: This article reveals the need for surgical intervention to treat clavicle fractures and improve shoulder functional outcomes. PMID- 21655760 TI - A comparison between magnetic resonance angiography at 3 Teslas (time-of-flight and contrast-enhanced) and flat-panel digital subtraction angiography in the assessment of embolized brain aneurysms. AB - PURPOSE: To compare the time-of-flight and contrast-enhanced- magnetic resonance angiography techniques in a 3 Tesla magnetic resonance unit with digital subtraction angiography with the latest flat-panel technology and 3D reconstruction in the evaluation of embolized cerebral aneurysms. INTRODUCTION: Many embolized aneurysms are subject to a recurrence of intra-aneurismal filling. Traditionally, imaging surveillance of coiled aneurysms has consisted of repeated digital subtraction angiography. However, this method has a small but significant risk of neurological complications, and many authors have advocated the use of noninvasive imaging methods for the surveillance of embolized aneurysms. METHODS: Forty-three aneurysms in 30 patients were studied consecutively between November 2009 and May 2010. Two interventional neuroradiologists rated the time-of-flight magnetic resonance angiography, the contrast-enhanced-magnetic resonance angiography, and finally the digital subtraction angiography, first independently and then in consensus. The status of aneurysm occlusion was assessed according to the Raymond scale, which indicates the level of recanalization according to degrees: Class 1: excluded aneurysm; Class 2: persistence of a residual neck; Class 3: persistence of a residual aneurysm. The agreement among the analyses was assessed by applying the Kappa statistic. RESULTS: Inter-observer agreement was excellent for both methods (K = 0.93; 95 % CI: 0.84-1). Inter-technical agreement was almost perfect between time-of-flight-magnetic resonance angiography and digital subtraction angiography (K = 0.98; 95 % CI: 0.93-1) and between time-of flight-magnetic resonance angiography and contrast-enhanced-magnetic resonance angiography (K = 0.98; 95% CI: 0.93-1). Disagreement occurred in only one case (2.3%), which was classified as Class I by time-of-flight-magnetic resonance angiography and Class II by digital subtraction angiography. The agreement between contrast-enhanced-magnetic resonance angiography and digital subtraction angiography was perfect (K = 1; 95% CI: 1-1). In three patients, in-stent stenosis was identified by magnetic resonance angiography but not confirmed by digital subtraction angiography. CONCLUSION: Digital subtraction angiography and both 3T magnetic resonance angiography techniques have excellent reproducibility for the assessment of aneurysms embolized exclusively with coils. In those cases also treated with stent remodeling, digital subtraction angiography may still be necessary to confirm eventual parent artery stenosis, as identified by magnetic resonance angiography. PMID- 21655761 TI - Noninvasive measurement of cardiac performance in recovery from exercise in heart failure patients. AB - OBJECTIVE: To examine the association between cardiac performance during recovery and the severity of heart failure, as determined by clinical and cardiopulmonary exercise test responses. METHODS: As part of a retrospective cohort study, 46 heart failure patients and 13 normal subjects underwent cardiopulmonary exercise testing while cardiac output was measured using a noninvasive device. Cardiac output in recovery was expressed as the slope of a single exponential relationship between cardiac output and time; the recovery-time constant was assessed in relation to indices of cardiac function, along with clinical, functional, and cardiopulmonary exercise responses. RESULTS: The recovery time constant was delayed in patients with heart failure compared with normal subjects (296.7 +/- 238 vs. 110.1 +/-27 seconds, p <0.01), and the slope of the decline of cardiac output in recovery was steeper in normal subjects compared with heart failure patients (p<0.001). The slope of the decline in cardiac output recovery was inversely related to peak VO(2) (r = -0.72, p<0.001) and directly related to the VE/VCO(2) slope (r = 0.57, p,0.001). Heart failure patients with abnormal recovery time constants had lower peak VO(2), lower VO(2) at the ventilatory threshold, lower peak cardiac output, and a heightened VE/VCO(2) slope during exercise. CONCLUSIONS: Impaired cardiac output recovery kinetics can identify heart failure patients with more severe disease, lower exercise capacity, and inefficient ventilation. Estimating cardiac output in recovery from exercise may provide added insight into the cardiovascular status of patients with heart failure. PMID- 21655762 TI - Treatment of chronic periodontitis decreases serum prohepcidin levels in patients with chronic kidney disease. AB - OBJECTIVE: To determine the impact of periodontal treatment on serum levels of prohepcidin (the prohormone of hepcidin) and systemic inflammation markers, as well as correlations among these markers, in patients with chronic periodontitis and chronic kidney disease who were not undergoing dialysis. METHODS: We included 56 chronic periodontitis patients, 36 with chronic kidney disease and 20 without systemic diseases and with normal renal function (control group). Chronic kidney disease was defined as suggested by the clinical practice guidelines in the National Kidney Foundation. Chronic periodontitis was defined through clinical attachment level and by probing pocket depth, according to the American Association of Periodontology. The inflammatory markers ultrasensitive C-reactive protein, interleukin-6, and prohepcidin were evaluated before and 3 months after periodontal treatment. RESULTS: The efficacy of periodontal treatment was confirmed by the improvement in clinical parameters of chronic periodontitis in the control and chronic kidney disease groups. Periodontal treatment resulted in significant reductions in ultrasensitive C-reactive protein, interleukin-6 and serum prohepcidin levels in both groups. Moreover, in multivariate linear regression, the reduction in prohepcidin after periodontal treatment was significantly and independently associated with interleukin-6 levels in the control group. CONCLUSIONS: By inducing a decline in the systemic inflammatory response and a decrease in serum prohepcidin, successful periodontal treatment may represent an important means of ameliorating the inflammatory burden seen in patients with chronic kidney disease. TRIAL REGISTRATION: ISRCTN59866656. PMID- 21655763 TI - Enhancement of basolateral amygdaloid neuronal dendritic arborization following Bacopa monniera extract treatment in adult rats. AB - OBJECTIVE: In the ancient Indian system of medicine, Ayurveda, Bacopa monniera is classified as Medhya rasayana, which includes medicinal plants that rejuvenate intellect and memory. Here, we investigated the effect of a standardized extract of Bacopa monniera on the dendritic morphology of neurons in the basolateral amygdala, a region that is concerned with learning and memory. METHODS: The present study was conducted on 21/2-month-old Wistar rats. The rats were divided into 2-, 4- and 6-week treatment groups. Rats in each of these groups were further divided into 20 mg/kg, 40 mg/kg and 80 mg/kg dose groups (n = 8 for each dose). After the treatment period, treated rats and age-matched control rats were subjected to spatial learning (T-maze) and passive avoidance tests. Subsequently, these rats were killed by decapitation, the brains were removed, and the amygdaloid neurons were impregnated with silver nitrate (Golgi staining). Basolateral amygdaloid neurons were traced using camera lucida, and dendritic branching points (a measure of dendritic arborization) and dendritic intersections (a measure of dendritic length) were quantified. These data were compared with the data from the age-matched control rats. RESULTS: The results showed an improvement in spatial learning performance and enhanced memory retention in rats treated with Bacopa monniera extract. Furthermore, a significant increase in dendritic length and the number of dendritic branching points was observed along the length of the dendrites of the basolateral amygdaloid neurons of rats treated with 40 mg/kg and 80 mg/kg of Bacopa monniera (BM) for longer periods of time (i.e., 4 and 6 weeks). CONCLUSION: We conclude that constituents present in Bacopa monniera extract have neuronal dendritic growth-stimulating properties. PMID- 21655765 TI - A review of low-level air pollution and adverse effects on human health: implications for epidemiological studies and public policy. AB - The aim of this study was to review original scientific articles describing the relationship between atmospheric pollution and damage to human health. We also aimed to determine which of these studies mentioned public policy issues. Original articles relating to atmospheric pollution and human health published between 1995 and 2009 were retrieved from the PubMed database and analyzed. This study included only articles dealing with atmospheric pollutants resulting primarily from vehicle emissions. Three researchers were involved in the final selection of the studies, and the chosen articles were approved by at least two of the three researchers. Of the 84 non-Brazilian studies analyzed, 80 showed an association between atmospheric pollution and adverse effects on human health. Moreover, 66 showed evidence of adverse effects on human health, even at levels below the permitted emission standards. Three studies mentioned public policies aimed at changing emission standards. Similarly, the 29 selected Brazilian studies reported adverse associations with human health, and 27 showed evidence of adverse effects even at levels below the legally permitted emission standards. Of these studies, 16 mentioned public policies aimed at changing emission standards. Based on the Brazilian and non-Brazilian scientific studies that have been conducted, it can be concluded that, even under conditions that are compliant with Brazilian air quality standards, the concentration of atmospheric pollutants in Brazil can negatively affect human health. However, as little discussion of this topic has been generated, this finding demonstrates the need to incorporate epidemiological evidence into decisions regarding legal regulations and to discuss the public policy implications in epidemiological studies. PMID- 21655764 TI - Chronic treatment with the nitric oxide synthase inhibitor, L-NAME, attenuates estradiol-mediated improvement of learning and memory in ovariectomized rats. AB - INTRODUCTION: The role of ovarian hormones and nitric oxide in learning and memory has been widely investigated. OBJECTIVE: The present study was carried out to evaluate the effect of the nitric oxide synthase (NOS) inhibitor, N (G)-nitro L-arginine methyl ester (L-NAME), on the ability of estradiol to improve learning in OVX rats using the Morris water maze. METHODS: Forty rats were divided into five groups: (1) ovariectomized (OVX), (2) ovariectomized-estradiol (OVX-Est), (3) ovariectomized-L-NAME 10 (OVX-LN 10), (4) ovariectomized-L-NAME 50 (OVX-LN 50) and (5) ovariectomized-estradiol-L-NAME 50 (OVX-Est-LN 50). The animals in the OVX-Est group were treated with a weekly injection of estradiol valerate (2 mg/kg; i.m.). The OVX-LN 10 and OVX-LN 50 groups were treated with daily injections of 10 and 50 mg/kg L-NAME (i.p.), respectively. The animals in the OVX Est-LN 50 group received a weekly injection of estradiol valerate and a daily injection of 50 mg/kg L-NAME. After 8 weeks, all animals were tested in the Morris water maze. RESULTS: The animals in the OVX-Est group had a significantly lower latency in the maze than the OVX group (p<0.001). There was no significant difference in latency between the OVX-LN 10 and OVX-LN 50 groups in comparison with the OVX group. The latency in the OVX-Est-LN 50 group was significantly higher than that in the OVX-Est group (p<0.001). CONCLUSION: These results show that L-NAME treatment attenuated estradiol-mediated enhancement of spatial learning and memory in OVX rats, but it had no significant effect in OVX rats without estrogen, suggesting an interaction of nitric oxide and estradiol in these specific brain functions. PMID- 21655767 TI - Characteristics of chronically critically ill patients: comparing two definitions. PMID- 21655766 TI - An update on the clinical assessment of the infertile male. [corrected]. AB - Male infertility is directly or indirectly responsible for 60% of cases involving reproductive-age couples with fertility-related issues. Nevertheless, the evaluation of male infertility is often underestimated or postponed. A coordinated evaluation of the infertile male using standardized procedures improves both diagnostic precision and the results of subsequent management in terms of effectiveness, risk and costs. Recent advances in assisted reproductive techniques (ART) have made it possible to identify and overcome previously untreatable causes of male infertility. To properly utilize the available techniques and improve clinical results, it is of the utmost importance that patients are adequately diagnosed and evaluated. Ideally, this initial assessment should also be affordable and accessible. We describe the main aspects of male infertility evaluation in a practical manner to provide information on the judicious use of available diagnostic tools and to better determine the etiology of the most adequate treatment for the existing condition. PMID- 21655768 TI - Desmoid tumors of the chest wall: surgical challenges and possible risk factors. PMID- 21655769 TI - A comparison of the TruView EVO2 and macintosh laryngoscope blades. PMID- 21655770 TI - Auditory training and cognitive functioning in adult with traumatic brain injury. PMID- 21655771 TI - Acute treatment of uncompensated heart failure with 10% hypertonic saline and its subsequent effect on respiratory patterns. PMID- 21655772 TI - Occlusal force, electromyographic activity of masticatory muscles and mandibular flexure of subjects with different facial types. AB - OBJECTIVE: The aim of this study was to evaluate whether vertical facial patterns influence maximal occlusal force (MOF), masticatory muscle electromyographic (EMG) activity, and medial mandibular flexure (MMF). MATERIAL AND METHODS: Seventy-eight dentate subjects were divided into 3 groups by Ricketts's analysis: brachyfacial, mesofacial and dolychofacial. Maximum occlusal force in the molar region was bilaterally measured with a force transducer. The electromyographic activities of the masseter and anterior temporal muscles were recorded during maximal voluntary clenching. Medial mandibular flexure was calculated by subtracting the intermolar distance of maximum opening or protrusion from the distance in the rest position. The data were analyzed using ANOVA followed by Tukey's HSD test. The significance level was set at 5%. RESULTS: Data on maximum occlusal force showed that shorter faces had higher occlusal forces (P<0.0001). Brachyfacial subjects presented higher levels of masseter electromyographic activity and medial mandibular flexure, followed by the mesofacial and dolychofacial groups. Additionally, dolychofacial subjects showed significantly lower electromyographic temporalis activities (P<0.05). CONCLUSION: Within the limitations of the study, it may be concluded that maximum occlusal force, masticatory muscle activity and medial mandibular flexure were influenced by the vertical facial pattern. PMID- 21655774 TI - Evaluation of three instrumentation techniques at the precision of apical stop and apical sealing of obturation. AB - OBJECTIVE: The aim of this study was to investigate the ability of two NiTi rotary apical preparation techniques used with an electronic apex locator integrated endodontic motor and a manual technique to create an apical stop at a predetermined level (0.5 mm short of the apical foramen) in teeth with disrupted apical constriction, and to evaluate microleakage following obturation in such prepared teeth. MATERIAL AND METHODS: 85 intact human mandibular permanent incisors with single root canal were accessed and the apical constriction was disrupted using a #25 K-file. The teeth were embedded in alginate and instrumented to #40 using rotary Lightspeed or S-Apex techniques or stainless steel K-files. Distance between the apical foramen and the created apical stop was measured to an accuracy of 0.01 mm. In another set of instrumented teeth, root canals were obturated using gutta-percha and sealer, and leakage was tested at 1 week and 3 months using a fluid filtration device. RESULTS: All techniques performed slightly short of the predetermined level. Closest preparation to the predetermined level was with the manual technique and the farthest was with S Apex. A significant difference was found between the performances of these two techniques (p<0.05). Lightspeed ranked in between. Leakage was similar for all techniques at either period. However, all groups leaked significantly more at 3 months compared to 1 week (p<0.05). CONCLUSIONS: Despite statistically significant differences found among the techniques, deviations from the predetermined level were small and clinically acceptable for all techniques. Leakage following obturation was comparable in all groups. PMID- 21655773 TI - Evaluation of tissue reaction, cell viability and cytokine production induced by Sealapex Plus. AB - OBJECTIVE: The aim of this study was to investigate the effects of mineral trioxide aggregate (MTA), Sealapex, and a combination of Sealapex and MTA (Sealapex Plus) on the reaction of subcutaneous connective tissue of rats, and on cell viability and cytokine production in mouse fibroblasts. MATERIAL AND METHODS: The tissue reaction was carried out with dentin tubes containing the materials implanted in the dorsal connective tissue of rats. The histological analysis was performed after 7 and 30 days. Millipore culture plate inserts with polyethylene tubes filled with materials were placed into 24-well cell culture plates with mouse fibroblasts to evaluate the cell viability by MTT assay. ELISA assays were also performed after 24 h of exposure of the mouse fibroblasts to set material disks. RESULTS: Histopathologic examination showed Von Kossa-positive granules that were birefringent to polarized light for all the studied materials at the tube openings. No material inhibited the cell viability in the in vitro test. It was detected IL-6 production in all root-end filling materials. MTA and Sealapex Plus induced a slight raise of mean levels of IL-1beta. CONCLUSIONS: The results suggest that Sealapex Plus is biocompatible and stimulates the mineralization of the tissue. PMID- 21655777 TI - Nurses' professional training. PMID- 21655775 TI - Hydroxyapatite crystallinity does not affect the repair of critical size bone defects. AB - OBJECTIVE: The physicochemical properties of hydroxyapatite (HA) granules were observed to affect the biological behavior of graft materials. The aim of this work was to analyze the tissue response of two HA granules with different crystallinity and Ca/P ratio in vivo. MATERIAL AND METHODS: The HA granules were produced in the Biomaterials Laboratory (COPPE/UFRJ). The testing materials were HA granules presenting a Ca/P molar ratio of 1.60 and 28% crystallinity (HA-1), and a Ca/P molar ratio of 1.67 and 70% crystallinity (HA-2). Both HAs were implanted into a critical-size calvaria rat defects. RESULTS: To note, in the control group, the bone defects were filled with blood clot only. Descriptive and histomorphometric analyses after 1, 3, and 6 months postoperatively showed mild inflammatory infiltrate, mainly comprising macrophage-like and multinucleated giant cells, and an increase in the volume density of the fibrous tissues (p<0.05), which was in contrast to the similar volume density of the newly formed bone and biomaterials in relation to the control group. CONCLUSION: Thus, we concluded that HA-1 and HA-2 are biocompatible and non-degradable, and that crystallinity does not affect bone repair of critical size defects. PMID- 21655776 TI - Apical sealing of root canal fillings performed with five different endodontic sealers: analysis by fluid filtration. AB - OBJECTIVES: To evaluate the sealing ability of five root canal sealers, including two experimental cements (MBP and MTA-Obtura) using the fluid filtration method. MATERIAL AND METHODS: Teeth were divided into 5 study groups: G1-AH Plus; G2 Acroseal; G3Sealapex; G4-MBP; G5-MTA-Obtura; and two controls. Chemical mechanical preparation was performed with ProFile rotary nickel-titanium instruments 1 mm short of the apical foramen. The sealing ability was evaluated by fluid filtration at 15, 30, and 60 days. RESULTS: The statistical analysis showed significant difference between the materials at different periods (p<0.05). AH Plus and MBP had similar leakage values at 15 and 60 days, alternating with significant reduction at 30 days, while the other materials showed progressive increase in leakage values. Acroseal and Sealapex presented the best results at 15 days and the worst at 60 days. CONCLUSIONS: All sealers evaluated presented fluid leakage, with AH Plus and MBP showing the best results at the end of the experimental period. Acroseal, Sealapex, and MTA-Obtura presented increase in leakage values at longer observation periods. PMID- 21655778 TI - [Risk assessment for pressure ulcer in critical patients]. AB - Bedridden patients are in risk to developing pressure ulcers and represent a priority group to be studied to identify this condition. To reach this goal, specific instruments are used to assess this problem. The objective of this study was to analyze the risk factors to developing pressure ulcers in adult patients hospitalized in ICUs. This is a sectional analytical study, in which evaluations were performed on 140 patients, hospitalized in 22 ICUs, using the Braden scale. Results showed that patients hospitalized from 15 days or more showed some level of risk. The highest frequencies of pressure ulcers were found in patients in the following categories: sensorial perception (completely limited), moistness (constantly moist), mobility (completely immobilized), activity (bedridden), nutrition (adequate) and friction and shear (problem). In conclusion, the use of this scale is an important strategy when providing care to patients in intensive treatment. PMID- 21655779 TI - [Quality of life of caregivers of overweight or obese children and adolescents]. AB - This study evaluated the health-related quality of life (HRQL) of caregivers of overweight and obese children and adolescents. Three-hundred and sixty caregives of children and adolescents (ages ranging from 9 to 12 years) diagnosed with overweight (n=96; average age 11.1 years), obesity (n=62; average age 10.9 years) and eutrophy (n=202; average age 10.7 years), regular students of public and private schools in Uberlandia (Minas Gerais), were invited to answer The 36 item Short Form Questionnaire (SF-36). The scores obtained were compared according to the body mass index (BMI) of the children and adolescents, and no significant differences were found between caregivers of overweight, obese and etrophic children and adolescents. Hence, there is no harm to the HRQL of caregivers of overweight and obese children and adolescents. PMID- 21655780 TI - [Evaluation of pain intensity and vital signs in the cardiac surgery postoperative period]. AB - The objective of this study is to analyze the changes in vital signs of postoperative cardiac surgery patients, according to the referred pain intensity. This descriptive-exploratory study was performed using quantitative analysis to investigate 38 patients submitted to a first dressing change. The analysis of the data, measured before and after performing the nursing procedure, indicated that the manifestation of pain occurred at different levels. The main changes in vital signs referred to blood pressure. In conclusion, there is a relationship between pain intensity and vital signs, and the care that is delivered is indispensible to reestablishing the health state of the postoperative patient. PMID- 21655781 TI - [Basic human needs of nursing professional: situations of (dis)satisfaction at work]. AB - Care is associated with the nursing actions considering, above all, a group of needs of the nursing team. The objectives of this study were: to characterize situations of (dis) satisfaction of the nursing team at work and analyze their possible implications. Maslow's theory of basic human needs was used to understand the motivational factors, and a qualitative methodology was used applying quantitative techniques. The method consisted of participant observation with registers on a filed diary associated to the application of a questionnaire on 18 participants from the nursing team of a Public Hospital in Rio de Janeiro. The study indicates that the basic needs of the nursing team are compromised, especially safety and physiological needs, which are the most primary. The compromising of the subjects' primary needs implies health hazards and reduced work performance in hospital settings. PMID- 21655782 TI - [Cancer patients' knowledge about their legal rights]. AB - The study objectives were: to survey the knowledge that oncology patients have about their legal rights, to identify the most known rights, and verify their knowledge about the procedure for requesting it. A survey was performed applying a checklist instrument during an interview. Participants were 42 oncology patients who were undergoing chemotherapy and their relatives. Of all participants, 57% were female; 28% were between 61 and 70 years old; 62% had completed only primary education; 72% were married; 50% had a family income of 2.6 minimum salaries. 45% were unaware of the benefits; among the existing benefits, retirement was recognized by 23%; 33% stated the medical record as the most important document; 38% had access to the information through the media; 23% had not requested any benefits and 31% reported obtaining some kind of benefit. In conclusion, nurses should work effectively to disseminate the patients' rights, so that benefits are guaranteed and their condition as citizens is respected. PMID- 21655783 TI - [Attributes mobilized by nurses in family health: reaching performances when developing managerial competence]. AB - This exploratory-descriptive study was performed using a qualitative approach with the purpose to identify and analyze the attributes mobilized in work situations that characterize the performance of nurses in managerial competence in Family Health based on the concepts of dialogic competence. Data collection was performed through participant observation of the work performed by Family Health nurses in four units associated with the University of Sao Paulo in Ribeirao Preto - SP/Brazil, considering a typical workweek, with a total of 160 hours of observation. Through content analysis, using the thematic analysis technique, we identified five themes related to: supervision, teamwork, social control, work organization and planning. Results show there is a group of attributes mobilized by nurses which remains centered on work organization for individual health care with rare incursions for a systemized planning process. PMID- 21655784 TI - [Accessibility and content of electronic information about specialization courses in nursing administration]. AB - The objective of this descriptive study was to analyze the accessibility and the content of the information about Specialization Courses in Nursing Administration available on the websites of federal universities in Brazil. From September 2008 to April 2009, evaluations were performed on a total 19 courses that were available on the websites of the universities, regarding the level of access to information and the design of the curricula, in terms of the structure of the knowledge about Nursing Administration: Ideological and Theoretical Bases, Intervention Methods, and Resource Administration Practices. Results showed that, though we are currently in the era of the knowledge society, the electronic access to the teaching programs remain below the expectations in terms of the concepts of information and browsability. In terms of the design of the courses, it was observed that most are many times longer than the what s legally established as a minimum load of hours, and that there has been an appreciation towards studying the Ideological and Theoretical Bases in detriment to the Practices of Human Resources. PMID- 21655785 TI - [Work context assessment in intensive therapy units from the perspective of work psychodynamics]. AB - In view of the reorganization of working processes and changes in the profile of occupational illness, this article discusses on the occupational risks of falling ill among nurses working in Intensive Care Units (ICU). This exploratory, cross sectional, descriptive study was developed with a convenience sample of 44 subjects, workers at a private hospital. The Work Context Assessment Scale was used, which is composed of three factors. The results regarding the factor work organization indicated severe risks to the workers' health. Regarding the factor social-professional relationships the items showed moderate health risks. The assessment of the facto working conditions showed low risks to occupational health. The analysis was based on work psychodynamics, and on the criticism to the prevalence of the Taylor management model in nursing work. The study allowed for a better understanding of the subjectivity implied in nursing work and instigates to increase the focus of discussions on safety and occupational health to the context of the work organization. PMID- 21655786 TI - [Clinical and epidemiological aspects of burned patients hospitalized in a teaching hospital]. AB - The objectives of this study were to characterize burned patients according to epidemiological and clinical variables and identify the treatments, invasive procedures and complications. This is a retrospective, descriptive and quantitative study. The sample consisted of 138 burned patients hospitalized in a teaching hospital from January 2003 to December 2007, in Uberaba-MG. Of the 138 hospitalized patients, 98 (71.0%) were male, and the average age was 26.1 years. The average length of stay was 16.2 days; 93 (67.4%) of the burns were caused by accidents and the main cause (68; 49.3%) was an open flame. The average burned body surface was 20.8% and most (122; 88.4%) had second degree burns. The most common topic treatment (93; 67.4%) was silver sulfadiazine. Forty-seven (34.0%) patients had indwelling catheters; 30 (21.7%) underwent tissue transplantation, and 28 (20.3%) underwent debridement; the lesions in 14 (10.1%) patients became infected. PMID- 21655787 TI - [The working process of a neonatal intensive care unit]. AB - The objective of this study was to analyze the organization of the working process of a Neonatal Intensive Care Unit through the relationships established between the social actors present in the micropolitical space. This study used an unconventional methodology, adapted to a qualitative study. A case series study was adopted, whose trajectory was referred to as sentinel-trajectory, through which it was possible to detect noises that affected the quality of the care provided. The analysis of the flowchart revealed weaknesses of the contract network, problems regarind the registers and documentations, and errors in the health care process. PMID- 21655788 TI - [The difficulties of educating children with chronic illness in the hospital context]. AB - The objective of this qualitative study was to understand the perception that families of hospitalized children with chronic illness about their being away from the process of education. The empirical material was produced by means of interviews performed with families of hospitalized children with chronic illness. The data was analyzed based on the principles of thematic analysis. Among other aspects, the data showed the lack of systematized pedagogical actions in the studied hospital, in a way that the educational activities that were developed were seen as a moment of leisure. We understand that the hospital class is becoming an important health care technology for hospitalized children. Therefore, it requires support, especially from the Departments of Education, in terms of providing the necessary human resources, funding and materials. This is a pioneer study, capable of helping improve the quality of life of children with chronic illness. PMID- 21655789 TI - [An existential health care approach in hospital psychiatric nursing]. AB - The focus of Mental Health Care in Brazil has been on community psychiatric care services that replace the asylum model. However, individuals with mental disorders continue to shift between community services and psychiatric hospitals, besides becoming a target of the disciplinarization and violence that question the quality of the nursing care being delivered. The objective of this study is to understand the ontology of nursing care in psychiatric hospitalization. Participants were four individuals with mental disorders who attended a center for psychosocial care, who agreed to talk about their psychiatric hospitalization experience by means of a semi-directed interview. The subjects remembered about their psychiatric hospitalization and assigned meanings to it. Heidegger's Existential Analysis was used, and thus generated the Meaning Unit: Being-in-the world cared with impersonality; which allowed to unveil the phenomenon through Dasein's structure, and thus made it possible to outline the ontological care in nursing in psychiatric hospitals. PMID- 21655790 TI - [Religious beliefs, illness and death: family's perspectives in illness experience]. AB - The objectives of this study were to identify predominant themes in religion, illness and death in the life histories of families and examine the relationship between religion creeds, illness and death in the discourse of families that have an ill person. The theoretical framework used in this study was Symbolic Interactionism and the method was Oral History. Participants were seventeen families with nine different religions, who had experienced the death of a relative. Data analysis showed that following a religion is a relevant part of the lives of many families and cannot be neglected in the illness context. Results point to the importance of understanding the meaning that religion has to the families in the health-disease process, so nurses can work on the promotion of health. PMID- 21655791 TI - [Agreement between center of disease control and word health organization reference growth]. AB - The objective this study was to verify the agreement of the guidelines recommended by CDC and WHO to evaluate the nutritional state. This is a cross sectional study, which counted with the participation of 254 children of ages 3 to 11 months and 29 days from Sao Paulo and Ribeirao Preto, performed from June 2005 to July 2006. The anthropometric indexes were obtained using the software available on the CDC and WHO websites. The Kappa Test was used for nominal variables (length/age) and weighted-Kappa for ordinal variables (weight/length). It was found that there are differences between the CDC and WHO guidelines regarding the evaluation of child nutrition, with greater differences in the results for children of ages 3 to 6 months. PMID- 21655792 TI - [Hypothermia in the intraoperative period: can it be avoided?]. AB - The objective of this study was to identify what measures are taken to prevent hypothermia in the intraoperative period. This is a non-experimental, descriptive exploratory prospective study. To do this, a data collection instrument was developed, which was submitted to appearance and content validations. The sample consisted of 70 patients. The measure that was most commonly used in the operation room was the passive skin heating, such as using cotton sheets (11.4%) and bandaging the patient's lower limbs (14.3%). There was only one occurrence of active skin heating (1.4%). Results show there is a need to implement effective interventions to prevent hypothermia, and nurses play an important role in this context, as patient safety and avoiding complications due to the surgical anesthetic procedure are nursing care goals. PMID- 21655793 TI - [Mental health and solidary economy: the family in the inclusion through work]. AB - The Psychiatric Reform raises the issue of social inclusion through work from the perspective of Solidary Economy and family involvement. In city in the interior of Sao Paulo, a solidary enterprise of users of the Psychosocial Care Center was created. This qualitative study was performed with the following objective: to identify the composition and relationships of the families of members of the referred enterprise; to know the perception of the family members about inclusion of the users through work and the possibility of the family taking on a major role in this process. Interviews were performed using the genogram and ecomap of the Calgary Family Assessment Model as well as open questions about the families' perceptions, based on content analysis. Result show that most families are nuclear, headed by women. AMost users do not have and family conflicts and those who do refer having conflict with their parents. They recognize the importance of work as a space for creating meanings and new relationships and point at several forms for co-involvement to take place. PMID- 21655794 TI - [Communication between nursing students and patients with Aids]. AB - This study was performed with the purpose to analyze the communication between nursing students and patients with AIDS during peripheral venous puncture. Video recordings were made of six pairs (student-patient) while performing the venous puncture procedure in May 2009 at a day-hospital in Fortaleza-Ceara. As a group, four judges evaluated the interactions established between the pairs. The analyses were categorized in: Valuing technique over communication; Mask: a barriers to communication; Private space invasion; Interference of the environment in the communication. It was concluded that different factors increase the difficulty establishing an effective communication, especially the need for students to be trained about the importance of establishing communication during care, so as to promote humanized and individual care, in which sensitivity and empathy overlap fear and insecurity. PMID- 21655795 TI - [Affective bipolar disorder and ambivalence in relation to the drug treatment: analyzing the causal conditions]. AB - This study was performed with an aim to understand the conditions causing the ambivalence of the person with bipolar affective disorder (BAD) regarding following the drug treatment. A qualitative approach was used, with the Grounded Theory as the methodology framework, under the light of Symbolic Interactionism. Participants were 14 individuals with BAD who were being followed at an Outpatient Clinic for Mood Disorders of a university hospital and 14 relatives they indicated. Interviews and observation were the main forms of obtaining data. Results revealed three categories that described the referred causal conditions: experiencing the crises of the disorder; needing the drug; and living with the side effects of the drugs. It was found that there is a need to change the attitude of some health professionals from blaming the patient for interrupting the treatment to one of listening, valuing their symbolic and affective universe as well as the partnership in the treatment. PMID- 21655796 TI - [The family and the mental disturbance carrier: dynamics and their family relationship]. AB - This exploratory study was performed from September to November 2008, with six families of patients with mental disorders from a patients and family association in Curitiba. OBJECTIVES: to learn about the role of the family of patients with mental disorders, and to identify the family's perception of mental health - mental disorder, the patient with mental disorder and the mental health treatment. The data was obtained through Group Discussions and organized into thematic categories. It was found that the role of the family is to care, encourage, be there; mental health is the ability to establish relationships, perform activities without suffering; mental disorder is the opposite, in face of which the families feel helpless; hospitalization is seen as suffering, and the highlight is on the importance of the drug treatment. It is necessary to discuss on these issues with the families and prepare health professionals to meet these new health needs. PMID- 21655797 TI - [Translation and cultural adaptation of the brazilian version of Disabkids(r) Atopic Dermatits Module (ADM)]. AB - The objective of this study was to translate and make the cultural adaptation of the Brazilian version of the DISABKIDS(r) Atopic Dermatitis Module (ADM), an instrument used to measure the health-related quality of life of children and adolescents with atopic dermatitis. The instrument has 12 items answered using a Likert scale, with two versions: self and proxy. The study counted with a sample of 18 Brazilian children and adolescents with atopic dermatitis, of ages ranging between 8 and 18 years, and their respective parents or caregivers. The process involved the following steps of translation-back translation and semantic evaluation. The former revealed good acceptance of the translated version of the instrument, which participants considered having items of easy understanding. After completing the process of validation in the country, the instrument will become available to Brazilian researchers to measure health-related quality of life, as well as to compare results from Brazil to that of other cultures in which the instrument has already been validated. PMID- 21655798 TI - [The feelings of individuals with mental disorders undergoing psychosocial rehabilitation regarding recreational activities]. AB - Traditional therapies have the strength to control psychiatric symptoms, but do not offer the necessary conditions to maintain that control. Therefore, untraditional treatments may be used to help with that maintenance. The objective of this study was to survey the feelings that individuals with mental disorders experience while taking part in recreational activities. To do this, 10 users of a Psychosocial Care Center were interviewed after participating in 10 sessions of Recreational Activities Results showed the participants felt pleasure, tranquility, emotion and bonding. Thus, recreation can be considered an important activity in mental health care, as it has a positive effect on psychosocial rehabilitation. The participants showed very positive feelings, which suggest that recreational activities may be of great help in controlling symptoms hence increasing the patients' chances to maintain the symptoms of their disorders under control. PMID- 21655799 TI - [Playing in the waiting room of a children's outpatient clinic: the view of health professionals]. AB - The objective of this study was to understand, from the perspective of health professionals, the meaning of playing/toys in the waiting room of a children's outpatient clinic. Semi-structured interviews were performed with 11 workers. A quantitative analysis of the data was performed around two themes: acknowledging the importance of playing/toys and dealing with limitations. Playing is seen as a care strategy towards children, as it alleviates the waiting time in this environment, changes behavior in a positive way, and values the children's development process, besides improving the communication and interaction with health professionals. It is, however, necessary for the hospital to have adequate physical structure, allied to the health professionals and to the management team, which are sensitive regarding the inclusion of new care strategies, such as playing, with a view to humanize children's health care. PMID- 21655800 TI - [The experiences of relatives of children hospitalized in an emergency care service]. AB - Childhood is a phase that requires much attention from the family and the health service, because family members, besides depending on relatives, are vulnerable to the environment. The objective of this study was to describe the experiences of relatives of children hospitalized in an emergency care service, discuss on how those experiences affect the everyday life of the family and report the aspects that interfere in the nursing care. This descriptive study was performed using a qualitative approach, and was developed in a private emergency hospital. Interviews were performed with ten family members to obtain the data. The data was submitted to thematic analysis, and three categories were elaborated: experiences of the family member, changes in the everyday life of the family, the faith of the family and their closeness as facilitating agents. In conclusion, the person accompanying the patient goes thorough adaptations, whilst experiencing hospitalization, with changes to the routine of the family. However, because of the conflicts experienced by the family member, nursing should see them as a subject of the extended care. PMID- 21655801 TI - [Disclosure of aids diagnosis to children from the family members' perspective]. AB - This phenomenological study aimed at understanding how the care-giving family sees the disclosure of the AIDS diagnosis to the infected child, founded on the philosophy of Martin Buber. This study was performed at a teaching hospital in Porto Alegre, with seven family members of children with AIDS. Data collection was performed through phenomenological interviews and interpreted guided by hermeneutics. The dialogues for disclosing of the diagnosis to YOU child with AIDS show that this situation occurs in the experience lived by those caregivers and interferes in their existentiality, as it when they establish relationships with the other, in the world. The disclosing of the AIDS diagnosis to the child is a complex phenomenon that generates dialogues related to the everyday situations shared by the caregivers and the children. Further studies are needed on this theme that is constantly increasing in health services, which would take into consideration the dynamicity and singularity of the rumors taken by this epidemics in the Brazilian context. PMID- 21655802 TI - [Anxiety and depression among nursing professionals who work in surgical units]. AB - This descriptive, cross-sectional, correlational study was performed with the objective to evaluate anxiety and depression among nursing professionals working in Surgical Units. Participants were 211 nursing professionals from eleven hospitals of Londrina-Parana, Brazil. Data collection was performed between the months of April and November 2007, using a questionnaire for the socio demographic characterization of the professionals and the Hospital Anxiety and Depression Scale (HADS). Most participants were nursing aides (62.6%), female (86.7%), married (54.0%), and in average 40 years old. Overall, the workers average score for anxiety was 6.3 and 5.2 for depression in an interval from zero to 21. A statistically significant difference was found for the occurrence of anxiety for cases of holding two jobs and the type of institution (p<0.05) and for the occurrence of depression for cases of nurses holding two jobs (p<0.05). PMID- 21655803 TI - [The scientific nursing production about the clinic: an integrativa review]. AB - The objective of this study was to learn about the production of nursing knowledge in Brazil associated with the clinic theme. This is a qualitative study performed by means of an integrative review. Data collection was performed on the SciELO database using the keywords nursing and clinic, present in the abstracts of articles. It was found that the clinic is seen as an instrument used to establish connections between research and nursing care, having a constant movement of constructing and deconstructing knowledge and practices. The study results may contribute with the production of research and knowledge in nursing, providing elements to subsidize improvements in nursing care, in which there is an interaction between practice and biological and non-biological knowledge. PMID- 21655804 TI - [A nursing team's approach to users of a mental health emergency room]. AB - This qualitative exploratory study was conducted in 2008, at a Municipal Emergency Care Center in Curitiba. OBJECTIVE: to learn about the conception of the nursing team about emergencies in mental health, and analyze how the nursing team approaches users with mental disorders in cases of emergency. Participants were 6 nurses and 7 nursing technicians working in emergency and hospitalization. Data collection was performed using semi-structured interviews and organized into thematic categories. Participants considered psychiatric emergencies as situations that may threat their own lives or that of others. The emergency characteristics they mentioned were: aggressive and agitated behavior, suicide attempt and substance abuse. The first impression of the patient's behavior and an attempt to have conversation determine the conducts adopted by the professionals. They recognize their difficulty and lack of preparation to approach the patient. In conclusion, there is a need for permanent education on new services and for adjustments to existing services for care in this area. PMID- 21655805 TI - [Prevalence and comorbidity of pain and fatigue in women with breast cancer]. AB - This study analyzed the prevalence and comorbidity of pain and fatigue in women with breast cancer. This is a cross-sectional study using a non-probabilistic sample of 182 women following outpatient treatment for breast cancer, who were interviewed from July 2006 to March 2007. Fatigue was assessed using the Piper Fatigue Scale, and divided into two categories (scores 0.1-4.9 and >5-10). Pain was assessed by the 0-10 scale, and categorized the same way as fatigue. Fatigue occurred in 94 women (51.6%), and was >5 in 44 (46.8%) of the women. Pain occurred in 86 women (47.2%), with scores >5 in 50 (58.1%). Fatigue and pain were correlated (r=0.38, p=0.003) and the comorbidity fatigue and pain was 38.3%. Intense pain increased fatigue (p=0.089) and intense fatigue increased pain (p=0.016). Both data are new in our area, and confirm the existence of a cluster of symptoms and the harms resulting from that comorbidity. PMID- 21655806 TI - [Social companies and solidary economy: perspectives for the work inclusion of individuals with mental disorders]. AB - The psychiatric reform process requires the implementation of public policies that guarantee the work inclusion of individuals with mental disorders. To do this, work must be understood as a promoter of autonomy, emancipation and citizenship. The objective of this study is to reflect on the theoretical concepts related to social insertion through work, with the purpose of exploring the inclusion of individuals with mental disorders in the work market. The concepts social company and solidary economy where selected as fundamental for the study. In the social company, the subject is considered to be a social being, focusing on the development process towards emancipation. In solidary economy, the objective is to develop an economy that is more just, equal and solidary. Further discussions on these concepts should be developed to support the implementation of projects for social inclusion through work. PMID- 21655807 TI - [The importance of nursing care in managing complications related to fully implantable catheters]. AB - This is an experience report of a thirty-year-old female patient, diagnosed with recurrence of Acute Myeloid Leukemia, submitted to catheter implantation and presenting surgical wound necrosis. The following were used with success: collagenase, calcium alginate and oil lotion with essential fatty acids. It was found that the complications related to catheters are a great challenge in oncology nursing besides implying a delay in the oncological treatment. Making a correct decision as soon as possible is extremely important and avoids removing the catheter too soon. PMID- 21655808 TI - [Planning the hospital discharge of patients with diabetes: the construction of a proposal]. AB - The acute and chronic complications that patients with diabetes and their families have to deal with after hospital discharge may be a consequence of the deficiencies in the educational process across hospitalization and the formal preparation for discharge. The objective of this study is to present a proposal of the plan for hospital discharge of adult patients with diabetes. A literature review on the hospital discharge of the assessed population was performed, including articles published between 2004 and February 2009. Taking the literature into consideration, a flier was created to guide the discharge process. The flier lists the information that should be collected and worked with the patient during the first four days of hospitalization, considering their individual needs and the Ineffective self health management. The discharge must be inserted in the Nursing Process, as nurses have an essential role in identifying the needs of patients and their families. The flier helps to identify the patient's needs and the actions to be performed by the team. PMID- 21655809 TI - [The construction of a Project in adolescent maternity: an experience report]. AB - This article reports on the experience of a group of nursing faculty on the development of a project aimed at adolescent maternity with a view to prevent unwanted pregnancies. An additional proposal of the referred project is guiding adolescent mothers in terms of self-care, care with their babies, and encouraging exclusive breastfeeding. This would reduce the difficulties that those young mothers experience and, therefore, contribute with the maternal-child area. PMID- 21655810 TI - Dengue virus type 4 arrives in the state of Rio de Janeiro: a challenge for epidemiological surveillance and control. PMID- 21655811 TI - Regulatory elements involved in the post-transcriptional control of stage specific gene expression in Trypanosoma cruzi: a review. AB - Trypanosoma cruzi, a protozoan parasite that causes Chagas disease, exhibits unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes, RNA editing and trans-splicing. In the absence of mechanism controlling transcription initiation, organized subsets of T. cruzi genes must be post-transcriptionally co-regulated in response to extracellular signals. The mechanisms that regulate stage-specific gene expression in this parasite have become much clearer through sequencing its whole genome as well as performing various proteomic and microarray analyses, which have demonstrated that at least half of the T. cruzi genes are differentially regulated during its life cycle. In this review, we attempt to highlight the recent advances in characterising cis and trans-acting elements in the T. cruzi genome that are involved in its post-transcriptional regulatory machinery. PMID- 21655812 TI - Spoligotyping of clinical Mycobacterium tuberculosis isolates from the state of Minas Gerais, Brazil. AB - We performed spoligotyping on 114 strains of the Mycobacterium tuberculosis (Mtb) complex that had been isolated from patients in Minas Gerais Health Units during 2004. A total of 82/114 (72%) clinical isolates were clustered and 32/114 (28%) were unique. Seven shared types containing nine strains were newly created. A total of nine patterns corresponded to unreported orphan strains, as evaluated against all of the strains recorded in the SITVIT2 proprietary database in the Institut Pasteur de la Guadeloupe. The major clades were composed of isolates that belong to the following genotypes: Latin-America and Mediterranean (63/114, 55.3%) (the ill-defined T superfamily) (12/114, 10.5%), Haarlem (8/114, 7%), X clade (6/114, 5.3%), S clade (3/114, 2.6%) and the East-African Indian and Manu types, each with 1/114 (0.9%) isolates. A considerable number of strains (n = 20, 17.5%) showed patterns that did not fall within any of the previously described major clades. We conclude the bulk of tuberculosis (TB) (92/114, 80.7%) in our location is recent evolutionary strains that belong to the principal genetic groups 2/3. Further studies on epidemiology of TB are required to understand Mtb biodiversity and TB transmission in this region. PMID- 21655813 TI - Bat flies on phyllostomid hosts in the Cerrado region: component community, prevalence and intensity of parasitism. AB - Streblidae flies are specialised parasites of bat hosts, mainly phyllostomids. There is a high richness of streblids in the savannah-like Cerrado region; however, there is little quantitative data available in parasitological indices. Here, we describe the component community, prevalence and intensity of a streblid infestation on a phyllostomid bat assemblage in Serra da Bodoquena, a Cerrado region in Southwest Brazil. We conducted surveys by capturing and inspecting bat hosts during the seven-month period between October 2004-December 2005. All the ectoparasites found on the bats were collected in the field and then counted and identified in the laboratory. We captured 327 bats belonging to 13 species, of which eight species were parasitized by 17 species of streblids. Carollia perspicillata and Glossophaga soricina were infested with seven streblid species, whereas the other bat species were infested with four or fewer streblid species. Megistopoda proxima and Aspidoptera falcata flies were found on Sturnira lilium, and Trichobius joblingi was the most prevalent fly on C. perspicillata. Megistopoda aranea and Aspidoptera phyllostomatis were highly prevalent and had a high intensity of infestation on Artibeus planirostris. Overall comparisons of the available data suggest that the component communities of streblids vary more between the Cerrado and Atlantic Forest phytogeographical regions than between localities within the same phytogeographical region. PMID- 21655814 TI - Effect of CO2 and 1-octen-3-ol attractants for estimating species richness and the abundance of diurnal mosquitoes in the southeastern Atlantic forest, Brazil. AB - Studies have shown that both carbon dioxide (CO2) and octenol (1-octen-3-ol) are effective attractants for mosquitoes. The objective of the present study was to evaluate the attractiveness of 1-octen-3-ol and CO2 for diurnal mosquitoes in the southeastern Atlantic forest. A Latin square experimental design was employed with four treatments: CDC-light trap (CDC-LT), CDC-LT and 1-octen-3-ol, CDC-LT and CO2 and CDC-LT with 1-octen-3-ol and CO2. Results demonstrated that both CDC CO2 and CDC-CO2-1-octen-3-ol captured a greater number of mosquito species and specimens compared to CDC-1-octen-3-ol; CDC-LT was used as the control. Interestingly, Anopheles (Kerteszia) sp. was generally attracted to 1-octen-3-ol, whereas Aedes serratus was the most abundant species in all Latin square collections. This species was recently shown to be competent to transmit the yellow fever virus and may therefore play a role as a disease vector in rural areas of Brazil. PMID- 21655815 TI - Genetic and biological characterization of a densovirus isolate that affects dengue virus infection. AB - Brevidensoviruses have an encapsidated, single-stranded DNA genome that predominantly has a negative polarity. In recent years, they have received particular attention due to their potential role in the biological control of pathogenic arboviruses and to their unnoticed presence in cell cultures as contaminants. In addition, brevidensoviruses may also be useful as viral vectors. This study describes the first genetic and biological characterization of a mosquito densovirus that was isolated in Brazil; moreover, we examined the phylogenetic relationship between this isolate and the other brevidensoviruses. We further demonstrate that this densovirus has the potential to be used to biologically control dengue virus (DENV) infection with in vitro co-infection experiments. The present study provides evidence that this densovirus isolate is a fast-spreading virus that affects cell growth and DENV infection. PMID- 21655816 TI - Biological and genetic aspects of crosses between species of the genus Meccus (Hemiptera: Reduviidae Triatominae). AB - The degree of reproductive isolation between Meccus phyllosomus and the remaining five species of the genus Meccus, as well as between Meccus bassolsae and Meccus pallidipennis, Meccus longipennis and Meccus picturatus, was examined. Fertility and the segregation of morphological characteristics were examined in two generations of hybrids from crosses between these species. The percentage of couples with offspring (fertile) was high in the vast majority of sets of crosses, with the exception of that between ?M. phyllosomus and ?Meccus mazzottii. In sets of crosses involving M. bassolsae specimens, no first generation (F1) individuals were morphologically similar to M. bassolsae, but instead shared the morphology of the other parental species. A similar phenomenon was observed in most sets of crosses involving M. phyllosomus. These results indicated that different degrees of reproductive isolation exist among the species of Meccus involved in this study. The biological evidence obtained in this study does not support the proposal that M. bassolsae is a full species. It could indicate that, on the contrary, it should be considered a subspecies of a single polytypic species. The biological evidence does support the proposal that M. phyllosomus is a full species. PMID- 21655817 TI - Morphological and molecular description of Blastocrithidia cyrtomeni sp. nov. (Kinetoplastea: Trypanosomatidae) associated with Cyrtomenus bergi Froeschner (Hemiptera: Cydnidae) from Colombia. AB - A new trypanosomatid species, Blastocrithidia cyrtomeni, is herein described using morphological and molecular data. It was found parasitising the alimentary tract of the insect host Cyrtomenus bergi, a polyphagous pest. The morphology of B. cyrtomeni was investigated using light and transmission microscopy and molecular phylogeny was inferred from the sequences of spliced leader RNA (SL rRNA) - 5S rRNA gene repeats and the 18S small subunit (SSU) rRNA gene. Epimastigotes of variable size with straphanger cysts adhering to the middle of the flagellum were observed in the intestinal tract, hemolymph and Malpighian tubules. Kinetoplasts were always observed anterior to the nucleus. The ultrastructure of longitudinal sections of epimastigotes showed the flagellum arising laterally from a relatively shallow flagellar pocket near the kinetoplast. SL RNA and 5S rRNA gene repeats were positive in all cases, producing a 0.8-kb band. The amplicons were 797-803 bp long with > 98.5% identity, indicating that they originated from the same organism. According to the sequence analysis of the SL-5S rRNA gene repeats and the 18S SSU rRNA gene, B. cyrtomeni is different from all other known species or isolates of Trypanosomatidae. Both analyses indicate that among known species, it is most closely related to Blastocrithidia triatomae. PMID- 21655818 TI - Insights into the transcriptome of oenocytes from Aedes aegypti pupae. AB - Oenocytes are ectodermic cells present in the fat body of several insect species and these cells are considered to be analogous to the mammalian liver, based on their role in lipid storage, metabolism and secretion. Although oenocytes were identified over a century ago, little is known about their messenger RNA expression profiles. In this study, we investigated the transcriptome of Aedes aegypti oenocytes. We constructed a cDNA library from Ae. aegypti MOYO-R strain oenocytes collected from pupae and randomly sequenced 687 clones. After sequences editing and assembly, 326 high-quality contigs were generated. The most abundant transcripts identified corresponded to the cytochrome P450 superfamily, whose members have roles primarily related to detoxification and lipid metabolism. In addition, we identified 18 other transcripts with putative functions associated with lipid metabolism. One such transcript, a fatty acid synthase, is highly represented in the cDNA library of oenocytes. Moreover, oenocytes expressed several immunity-related genes and the majority of these genes were lysozymes. The transcriptional profile suggests that oenocytes play diverse roles, such as detoxification and lipid metabolism, and increase our understanding of the importance of oenocytes in Ae. aegypti homeostasis and immune competence. PMID- 21655819 TI - Human rhinovirus in the lower respiratory tract infections of young children and the possible involvement of a secondary respiratory viral agent. AB - Human rhinoviruses (HRV) are usually associated with mild respiratory symptoms in children. However, some studies have found that HRV can cause severe disease, especially when the patient is co-infected with a second virus. In this study, 532 nasopharyngeal aspirates (NPAs) were collected over a nine-year period from children at the Clinics Hospital of Uberlandia. The collected NPAs were then tested for HRV RNA using the reverse transcription-polymerase chain reaction. Eighty-three specimens from children diagnosed with lower respiratory tract illness (LRTI) were positive for HRV RNA and were then tested for the presence of eight other respiratory viruses. A second virus was detected in 37.3% (31/83) of the samples. The most frequent clinical diagnosis was bronchiolitis, followed by other LRTI and then pneumonia. The frequency of severe disease in children infected with more than one virus was not significantly different from the frequency of severe disease in children infected with HRV alone. Children infected with both HRV and parainfluenza virus (1.5 m.o.) were significantly younger than those infected by HRV alone (5.0 m.o.) (p = 0.0454). Overall, these results suggest that infection with a second virus does not lead to a higher frequency of severe syndromes in children presenting with LRTI. PMID- 21655820 TI - Efficiency of diagnostic biomarkers among colonic schistosomiasis Egyptian patients. AB - The schistosomal parasite plays a critical role in the development of malignant lesions in different organs. The pathogenesis of cancer is currently under intense investigation to identify reliable prognostic indices for disease detection. The objective of this paper is to evaluate certain biochemical parameters as diagnostic tools to efficiently differentiate between colonic carcinoma and colonic carcinoma associated with schistosomal infection among Egyptian patients. The parameters under investigation are interleukin 2 (IL-2), tumour necrosis factor alpha (TNF-alpha), carcinoembryonic antigen (CEA) levels, tissue telomerase, pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G-6 PD) and lactate dehydrogenase (LDH) enzyme activities. The results revealed a significant elevation in the level of the tumour markers IL-2, TNF-alpha and CEA as well as the activities of LDH, telomerase and G-6-PD among non-bilharzial and bilharzial colonic cancer groups, with a more potent effect in bilharzial infection-associated colonic cancer. A significant inhibition in PK activity was recorded in the same manner as compared to normal tissues. The efficacy of this biomarker was also evaluated through detecting sensitivity, specificity, negative and positive predictive values. In conclusion, schistosomal colonic carcinoma patients displayed more drastic changes in all parameters under investigation. The combination of the selected parameters succeeded in serving as biomarkers to differentiate between the two malignant types. PMID- 21655821 TI - Acute diarrhoea in a community cohort of children who received an oral rotavirus vaccine in Northeast Brazil. AB - Rotavirus is an important cause of childhood diarrhoea. A monovalent rotavirus vaccine (Rotarix(r)) was introduced into the Immunization Program of Brazil in 2006. In this study, we describe the incidence and burden of disease of rotavirus diarrhoea in two cohorts of children (vaccinated and unvaccinated). We followed two groups of 250 children under one year old, who were enrolled in December 2006 from a low-income residential area in Northeast Brazil. The children were monitored every two weeks for two years. Stool samples from children with diarrhoea were examined for the presence of rotavirus. Rotaviruses were genotyped using real time-polymerase chain reaction. The mean numbers of all-cause diarrhoea episodes/child (adjusted for age) in the first year were 0.87 and 0.84, in vaccinated and unvaccinated children, respectively. During the second year, the number of episodes/child decreased to 0.52 and 0.42. Only 16 (4.9%) of 330 stool samples were rotavirus-positive (10 vaccinated and 6 unvaccinated children) and only P[4]G2 rotaviruses were identified. All-cause diarrhoea episodes were more severe in unvaccinated children in the first year of age (p < 0.05), while vaccinated children had more severe episodes 18 months after vaccination. Rotavirus diarrhoea incidence was very low in both groups. PMID- 21655822 TI - Pauciconfibula patagonensis sp. nov. (Monogenea: Microcotylidae) parasitizing the horsefish, Congiopodus peruvianus (Pisces: Congiopodidae), from the Patagonian Shelf, Argentina. AB - Pauciconfibula patagonensis sp. nov. (Monogenea: Microcotylidae), parasite of gill filaments of the horsefish, Congiopodus peruvianus (Congiopodidae) collected in the Patagonian Shelf, Argentina, is described and illustrated. The new species is characterized by having intestinal caeca not confluent and entering into the haptor, vitelline follicles extending from the genital pore to near the posterior portion of haptor, two parallel rows each comprised of 16-20 microcotylid clamps in the haptor, 25-43 testes and a fusiform egg with one very long tangled polar filament. P. patagonensis is the only member of the genus known to parasitize a scorpaeniform host and represents the first record of a representative of this genus in the southern Atlantic Ocean. PMID- 21655823 TI - Epidemiology of fungal infections in liver transplant recipients: a six-year study of a large Brazilian liver transplantation centre. AB - Liver transplant seems to be an effective option to prolong survival in patients with end-stage liver disease, although it still can be followed by serious complications. Invasive fungal infections (ifi) are related to high rates of morbidity and mortality. The epidemiology of fungal infections in Brazilian liver transplant recipients is unknown. The aim of this observational and retrospective study was to determine the incidence and epidemiology of fungal infections in all patients who underwent liver transplantation at Albert Einstein Israeli Hospital between 2002-2007. A total of 596 liver transplants were performed in 540 patients. Overall, 77 fungal infections occurred in 68 (13%) patients. Among the 77 fungal infections, there were 40 IFI that occurred in 37 patients (7%). Candida and Aspergillus species were the most common etiologic agents. Candida species accounted for 82% of all fungal infections and for 67% of all IFI, while Aspergillus species accounted for 9% of all fungal infections and for 17% of all IFI. Non-albicans Candida species were the predominant Candida isolates. Invasive aspergillosis tended to occur earlier in the post-transplant period. These findings can contribute to improve antifungal prophylaxis and therapy practices in Brazilian centres. PMID- 21655824 TI - Multiple insecticide resistance in Aedes aegypti (Diptera: Culicidae) populations compromises the effectiveness of dengue vector control in French Guiana. AB - In French Guiana, pyrethroids and organophosphates have been used for many years against Aedes aegypti. We aimed to establish both the resistance level of Ae. aegypti and the ultra low volume spray efficacy to provide mosquito control services with practical information to implement vector control and resistance management. Resistance to deltamethrin and fenitrothion was observed. In addition, the profound loss of efficacy of AquaK'othrine(r) and the moderate loss of efficacy of Paluthion(r) 500 were recorded. Fenitrothion remained the most effective candidate for spatial application in French Guiana until its removal in December 2010. Further investigation of the mechanism of resistance to deltamethrin demonstrated the involvement of mixed-function oxidases and, to a lesser extent, of carboxylesterases. However, these observations alone cannot explain the level of insecticide resistance we observed during tube and cage tests. PMID- 21655825 TI - Diversity of sandflies (Psychodidae: Phlebotominae) captured in sandstone caves from Central Amazonia, Brazil. AB - In the present paper we describe the diversity of phlebotomine sandflies collected in three sandstone caves in the municipality of Presidente Figueiredo, state of Amazonas, Brazil. The phlebotomines were captured during 2006 with CDC light traps. Guano samples from inside the Gruta Refugio do Maruaga were collected to investigate the presence of immature specimens. A total of 2,160 adult phlebotomines representing 15 species were captured. Pintomyia pacae was the dominant species in Gruta dos Animais (1,723 specimens) and Gruta dos Lages (50 specimens) and Deanemyia maruaga new comb (280 specimens) was the dominant species in Gruta Refugio do Maruaga. A total of 18 guano samples were collected and seven of these samples included immature specimens. A total of 507 immature specimens were captured; 495 of these specimens were larvae and 12 were pupae. The presence of paca (Agouti paca) footprints near Gruta dos Animais and Gruta dos Lages suggests the association of Pi. pacae with this rodent. This finding may explain the abundance of Pi. pacae in these locations, while the species is relatively rare in the forest. Deanemyia maruaga is a cave species that uses guano to breed during its immature stages. Adult specimens of this species are apparently parthenogenetic and autogenous and represent the second record of parthenogenesis for the subfamily Phlebotominae. PMID- 21655826 TI - Carbon dioxide baited trap catches do not correlate with human landing collections of Anopheles aquasalis in Suriname. AB - Three types of carbon dioxide-baited traps, i.e., the Centers for Disease Control Miniature Light Trap without light, the BioGents (BG) Sentinel Mosquito Trap (BG Sentinel) and the Mosquito Magnet(r) Liberty Plus were compared with human landing collections in their efficiency in collecting Anopheles (Nyssorhynchus) aquasalis mosquitoes. Of 13,549 total mosquitoes collected, 1,019 (7.52%) were An. aquasalis. Large numbers of Culex spp were also collected, in particular with the (BG-Sentinel). The majority of An. aquasalis (83.8%) were collected by the human landing collection (HLC). None of the trap catches correlated with HLC in the number of An. aquasalis captured over time. The high efficiency of the HLC method indicates that this malaria vector was anthropophilic at this site, especially as carbon dioxide was insufficiently attractive as stand-alone bait. Traps using carbon dioxide in combination with human odorants may provide better results. PMID- 21655827 TI - Risk of dengue occurrence based on the capture of gravid Aedes aegypti females using MosquiTRAP. AB - We assessed the risk classification of dengue fever based on the capture of Aedes aegypti adults using MosquiTRAP, a type of sticky trap, in comparison with traditional larval infestation indices. A total of 27 MosquiTRAPs were installed, with one trap per block, and were inspected weekly between November 2008-February 2009. Infestation baseline data were obtained from a survey conducted prior to trap installation. The index generated by MosquiTRAP and house index (HI) classified the area "in alert situation". The set for risk of dengue occurrence proposed by the use of MosquiTRAP classify areas in the same way of the traditional HI. PMID- 21655828 TI - First report of the bla(OXA-58) gene in a clinical isolate of Acinetobacter baumannii in Rio de Janeiro, Brazil. AB - Carbapenemase production is an important mechanism of carbapenem resistance among nonfermentative Gram-negative isolates. This study aimed to report the detection of bla(OXA-58) gene in multiresistant clinical isolates of Acinetobacter baumannii recovered from inpatients in a public hospital. Polymerase chain reaction tests were performed to detect the bla(OXA-23-like), bla(OXA-24-like), bla(OXA-58-like) and bla(OXA-51-like) genes. The bla(OXA-58) and bla(OXA-23) genes were detected in one and three isolates, respectively. Sequencing of the bla(OXA-58-like) amplicon revealed 100% identity with the A. baumannii bla(OXA 58) gene listed in the GenBank database. This is the first report of an OXA-58 producing A. baumannii isolate in Rio de Janeiro, Brazil. PMID- 21655829 TI - Detection of human herpesvirus 7 infection in young children presenting with exanthema subitum. AB - In this study, we assessed the prevalence of human herpesvirus-7 (HHV-7) in 141 serum samples from children less than four years of age with exanthematic disease. All samples were negative for measles, rubella, dengue fever and parvovirus B19 infection. Testing for the presence of human herpesvirus-6 (HHV-6) specific high avidity IgG antibodies by indirect immunofluorescence assay (IFA) revealed two main groups: one composed of 57 patients with recent primary HHV-6 infection and another group of 68 patients showing signs of past HHV-6 infection. Another 16 samples had indeterminate primary HHV-6 infection, by both IgG IFA and IgM IFA. Serum samples were subjected to a nested polymerase chain reaction to detect the presence of HHV-7 DNA. Among patients with a recent primary HHV-6 infection, HHV-7 DNA was present in 1.7% of individuals; however, 5.8% of individuals tested positive for HHV-7 DNA in the group with past primary HHV-6 infection. Among the 16 samples with indeterminate diagnosis, 25% (4/16) had HHV 7 DNA (p < 0.002). We hypothesise that HHV-7 might be the agent that causes exanthema. However, a relationship between clinical manifestations and the detection of virus DNA does not always exist. Therefore, a careful interpretation is necessary to diagnose a primary infection or a virus-associated disease. In conclusion, we detected HHV-7 DNA in young children from the state of Rio de Janeiro, Brazil. PMID- 21655830 TI - Benzonidazole levels in blood vary with age in rats. AB - Benznidazole (Bz) exhibits toxic side effects in animal studies and clinical use. Reductive metabolism of Bz in liver microsomes modulates the duration of its chemotherapeutic effect and its toxicity. The rate of this metabolism depends on age and is less intense in newborns and youngsters than in adults. In the present study, we determined Bz blood levels in rats of different ages that received Bz intragastrically (100 mg/kg). We developed and validated a high-pressure liquid chromatography with UV detector method for determination of Bz levels in whole blood. Bz levels were significantly higher and persisted for longer periods of time in the blood of young rats when compared to that of adult animals. PMID- 21655831 TI - A rapid detection of multidrug-resistant Mycobacterium tuberculosis by a nitrate reductase assay on blood agar. AB - The susceptibility of 49 Mycobacterium tuberculosis clinical isolates to isoniazid (INH) and rifampisin (RIF) (28 multi-drug resistant-tuberculosis samples) was determined by a nitrate reductase assay (NRA) on blood agar. Agreement between the NRA and other testing methods was found to be 93.8% for both INH and RIF. The sensitivity, specificity, positive predictive value and negative predictive value for INH were 92.8%, 94.2%, 86.6% and 97%, respectively. The sensitivity, specificity, positive predictive value and negative predictive value for RIF were 90.4%, 96.4%, 95% and 93.1%. In conclusion, we show here that blood agar can be used effectively for the NRA test. PMID- 21655832 TI - Lutzomyia longipalpis in Uruguay: the first report and the potential of visceral leishmaniasis transmission. AB - Phlebotomine captures were performed in February 2010 in Salto (Salto department) and Bella Union-Cuarein (Artigas department), Uruguay. Bella Union is located across the Parana River from Monte Caseros, Argentina, where a focus of canine visceral leishmaniasis (VL) was reported in 2009. No VL cases have ever been recorded in Uruguay and the last reported capture of Phlebotominae was in 1932 (Lutzomyia cortelezzii and Lutzomyia gaminarai). Light traps were placed in peridomestic environments, and Lutzomyia longipalpis, the main vector of visceral leishmaniasis, was found in Salto and Bella Union. This is a first report of an area of potential VL transmission in Uruguay. Active and coordinated surveillance is required immediately the Uruguay-Argentina-Brazil border area. PMID- 21655833 TI - Can studies where subjects have different follow up times be analyzed through binomial regression? PMID- 21655834 TI - Dengue fever continues to challenge and to puzzle. PMID- 21655835 TI - [Uses of the concept of subjectivity in Public Health]. AB - This article analyzes the use of the concept of subjectivity in the public health field, associated with the historical and institutional conditions that demanded it. The main methodological strategy was a search in specific journals and reference books from the field. We identified three functions in the use of the concept of subjectivity, associating them primarily with external variables (trajectory in the health movement and institutionalization of the Unified National Health System - SUS) and secondarily with internal variables (logic of the theoretical/conceptual field). The functions discuss subjectivity as: (1) an element for conceiving the social action by political actors in the Health Reform project; (2) a strategy for problematizing health care and management as inter subjective practices; and (3) a substrate for the production of autonomy for individuals and collectives. In their external variables, the three functions are established as processes for building micro and macro policies for the consolidation of the SUS. PMID- 21655836 TI - [The (in)visibility of psychological family violence in childhood and adolescence]. AB - Psychological family violence in childhood and adolescence is still poorly studied, due to difficulties in its definition and detection. This article aims to examine how psychological family violence reported by children and adolescents has been addressed in academic studies, using a literature review (LILACS, MEDLINE, SciELO, PubMed, CAPES Portal, PsycINFO, and SCOPUS databases). Among 51 epidemiological studies, 16 articles met the review's objectives; some of the articles reported a high prevalence of such violence. The study showed that the issue has been studied more in the international literature than in Brazil, which has significantly increased its visibility in the last decade but still faces difficulties involving definition, conceptualization, and operationalization. Eliminating the invisibility of psychological violence in the family could help promote prevention of such violence and protection of children and adolescents. PMID- 21655837 TI - [Teenage pregnancy rates and socioeconomic characteristics of municipalities in Sao Paulo State, Southeast Brazil: a spatial analysis]. AB - Teenage pregnancy is a common public health problem worldwide. The objective of this ecological study was to investigate the spatial association between teenage pregnancy rates and socioeconomic characteristics of municipalities in Sao Paulo State, Southeast Brazil. We used a Bayesian model with a spatial distribution following a conditional autoregressive (CAR) form based on Markov Chain Monte Carlo algorithm. We used data from the Live Birth Information System (SINASC) and the Brazilian Institute of Geography and Statistics (IBGE). Early pregnancy was more frequent in municipalities with lower per capital gross domestic product (GDP), higher poverty rate, smaller population, lower human development index (HDI), and a higher percentage of individuals with State social vulnerability index of 5 or 6 (more vulnerable). The study demonstrates a significant association between teenage pregnancy and socioeconomic indicators. PMID- 21655838 TI - [Health services utilization by the adult population in Sao Leopoldo, Rio Grande do Sul State, Brazil: a cross-sectional study]. AB - The aim was to describe healthcare utilization by adults in a Brazilian city. The outcomes were medical appointments in the previous month and use of public (Unified National Health System - SUS) versus private healthcare services. A population-based cross-sectional study with 1,098 adults aged 20 years or over was carried out. No medical appointment in the previous month was reported by 623 persons (56.7%, 95%CI: 53.8-59.7). Of the 487 individuals who had consulted a physician, 51.2% used the public healthcare system, 26.9% private care, and 22% other services. Consultation was associated with female gender and older age. Individuals in the intermediate categories for income, schooling, and socioeconomic status consulted less than the corresponding high and low categories. The results suggest that the middle class in this city lacks the purchasing power to seek care in the private sector while also using public services less, thus generally seeking healthcare less frequently. PMID- 21655839 TI - [Life expectancy at birth: impact of variation in mortality by age group and cause of death in Campinas, Sao Paulo State, Brazil]. AB - This study investigated the impact of variation in mortality by age group and cause of death on gains in life expectancy at birth in the city of Campinas, Sao Paulo State, Brazil, in 1991, 2000, and 2005. Life tables were constructed. Pollard's method was used to estimate the contributions by age group and cause of death on gains in life expectancy. In 1991-2000, the age group that most contributed was 0-1 year (31.1% for males and 22.9% for females). In 2000-2005, 79% of the gain for males was the result of mortality improvements in the 15-44 year bracket. Cardiovascular diseases made the largest contribution in 1991-2000 (66.1% for males and 43.5% for females). A loss in longevity was seen in men (1.1 year) resulting from increased mortality from external causes. In 2000-2005, the substantial gain (2.3 year) in male life expectancy was due to a reduction in mortality from external causes. Neoplasms had a negative effect on the gain (0.11 year for males and 0.15 for females). These findings should help support public health policies to reduce mortality risks and increase life expectancy. PMID- 21655840 TI - [Factors associated with secondary breast cancer prevention in Maringa, Parana State, Brazil]. AB - This study analyzed the prevalence of secondary breast cancer prevention and associated factors in women 40 to 69 years of age in Maringa, Parana State, Brazil. Prevalence was 64.5% for breast self-examination, 71.5% for clinical examination, and 79% for mammography. The data suggest that age, schooling, ethnicity, socioeconomic status, religion, and prior hormone replacement therapy influenced the rates of the three types of examination. Preventive practices were significantly more common among women of higher socioeconomic status. Proper orientation and performance of preventive measures and tests should be at the reach of all women in the highest-risk age bracket, thereby decreasing late diagnosis and avoidable deaths and increasing the odds of curing breast cancer. PMID- 21655841 TI - [Identification of schistosomiasis risk areas using spatial analysis in Lauro de Freitas, Bahia State, Brazil]. AB - The spread of schistosomiasis mansoni defies efforts by Brazil's Unified National Health System, thus demonstrating the need to reassess endemic control programs in the country. The aim of this study was to demarcate geographic areas at risk of schistosomiasis in Lauro de Freitas, Bahia State, Brazil, and to establish the epidemiological and socioeconomic profile of the disease in this municipality (county). Kernel density estimator exploratory analysis was used for visual identification of areas at risk. Kulldorff & Nagarwalla's spatial analysis was used to obtain statistically significant clusters and to measure risk. These technologies identified four risk areas for schistosomiasis. Clusters identified within the risk areas were characterized by lower socioeconomic conditions. Multiple correspondence analyses showed a distinct profile for positive patients in the primary cluster. The techniques employed here represent an important methodological acquisition for tracking and controlling schistosomiasis in Lauro de Freitas. PMID- 21655842 TI - [Partial cross-cultural adaptation of the Aberrant Behavior Checklist (ABC) scale for analysis of patients with mental retardation]. AB - The aim of the ABC (Aberrant Behavior Checklist) is to evaluate the treatment response for aberrant behavior in patients with mental retardation. The aim of this study was to describe the partial cross-cultural adaptation of the ABC scale to Brazilian Portuguese. The process included conceptual and item equivalence, two translations (T1, T2) and their back-translations (R1, R2), evaluation of referential and general equivalence, expert evaluations, a pre-test, and elaboration of the final version. Conceptual and item equivalences of the ABC were considered pertinent to Brazilian culture. Semantic equivalence showed good correspondence between R1 items and ABC. Reasonable correspondence was obtained between ABC items and R2. All of the professors understood 94.8% of the items in the scale, while relatives understood 87.9%. The Brazilian Portuguese version of the ABC scale thus is available for use, with the appropriate conceptual, item, and semantic equivalence. PMID- 21655843 TI - [Use of diet sweeteners by adults in Pelotas, Rio Grande do Sul State, Brazil: a population-based study]. AB - This population-based study evaluated the use of diet sweeteners by adults (> 20 years) in Pelotas, Rio Grande do Sul State, Brazil. Data were collected from January to July 2010 (n = 2,732). Besides specific questions on diet sweeteners, demographic, socioeconomic, and health characteristics were recorded. Heterogeneity and linear trend chi-square tests were used for the statistical analysis. Prevalence of sweetener use was 19% (95%CI: 1.1-20.9), and was 3.7 times higher in elderly individuals as compared to 20-29-year-olds. Economic level and nutritional status were significantly associated with sweetener use. Nearly 98% of the sample used liquid sweeteners; the most frequently consumed (89.2%) were those containing saccharin or sodium cyclamate. Average intake was 10 drops of liquid sweetener or 1.5 sachets of powdered sweetener. Use of diet sweeteners was higher among women and the elderly. PMID- 21655844 TI - [Smoking among adolescents and young adults in Belo Horizonte, Minas Gerais State, Brazil: the influence of family setting and social group]. AB - The study aimed to estimate smoking prevalence in Belo Horizonte, Minas Gerais State, Brazil, and related risk factors among adolescents. We used data from the household survey conducted by the Brazilian National Cancer Institute (2002 2003). The following variables were analyzed: demographic data; physical activity; smoking; and alcohol consumption. The study included information on 630 adolescents (15-24 years of age) living in Belo Horizonte. Multivariate logistic regression analyses were carried out, with hierarchical entry of variables into the model and the generalized estimating equation (GEE) method. Overall smoking prevalence was 11.7%. The following factors were associated with smoking: alcohol consumption (OR = 20.6), older age (OR = 1.2), paternal smoking (OR = 4.0), sibling smoker (OR = 2.5), and best friend smoker (OR = 5.2). Smoking prevalence among adolescents was high, increasing with age and alcohol consumption. PMID- 21655845 TI - Cost-effectiveness of community health worker versus home-based guardians for directly observed treatment of tuberculosis in Vitoria, Espirito Santo State, Brazil. AB - The objective of this study was to compare the costs and outcomes associated with guardian-supervised directly observed treatment relative to the standard of care Directly Observed Therapy, Short Course (DOTS) provided by community health workers (CHW). New cases of culture-positive pulmonary tuberculosis (TB) treated in Vitoria, Espirito Santo State, Brazil, between January 2005 and December 2006 were interviewed and chose their preferred treatment strategy. Costs incurred by providers and patients (and patients' families) were estimated, and cost effectiveness was assessed by comparing costs per successfully treated patient. 130 patients were included in the study; 84 chose CHW-supervised DOTS and 46 chose guardian-supervised DOTS. 45 of 46 (98%) patients treated with guardian supervised DOTS were cured or completed treatment compared to 70/84 (83%) of the CHW-supervised patients (p = 0.01). Logistic regression showed only the strategy of supervision to be a significant association with treatment outcome, with guardian-supervised care strongly protective. Cost per patient treated with guardian-supervised DOTS was US$398, compared to US$548 for CHW-supervised DOTS. The guardian-supervised DOTS is an attractive option to complement CHW-supervised DOTS. PMID- 21655846 TI - [Factors associated with interruption of exclusive breastfeeding in low birth weight infants receiving primary care]. AB - This study aimed to identify factors associated with interruption of exclusive breastfeeding (EBF) in low birth weight infants receiving primary care. This was a cross-sectional study of 170 infants treated at primary care units on the urban periphery of Sao Paulo, Brazil. The sample included infants with birth weight <= 2,500g (including twins) and 5-minute Apgar >= 7, followed until the third month of life, and excluded infants/mothers with complications that would impede EBF, besides infant/maternal deaths. Data were collected from forms completed during consultations and patient records. Prevalence ratios were obtained by Poisson regression. The following factors were associated with interruption of EBF in the first three months of life: maternal age <= 18 years; informal employment (protective factor); alcohol intake during pregnancy; < 6 prenatal visits; multiple gestations; birth weight <= 2,000g; difficulty breastfeeding in the first month; complaints in breastfeeding during the first month; and use of pacifiers in the first two months. Prior knowledge of these factors can help plan measures and policies to increase EBF rates among low birth weight infants. PMID- 21655847 TI - [Critical issues for implementing oral health policy in the city of Salvador, Bahia State, Brazil]. AB - This study focuses on policy implementation by public organizations. This was a qualitative, exploratory case study focusing on Brazil's National Oral Health Policy, known as "Smiling Brazil", implemented in Salvador, the State capital of Bahia. The study aimed to identify factors that facilitated or hindered the policy's implementation, based on the public policy cycle and Carlos Matus' government triangle concept, for the period from 2004 to 2007. Data collection strategies included analysis of municipal documents, interviews with key informants, and direct observation of top management meetings at the Municipal Health Secretariat. The main factors that hindered implementation of the municipal oral health policy were the project's lack of specificity; lack of human resources; and lack of financial autonomy in the Municipal Health Secretariat. The study showed that the lack of connection between the variables comprising the government triangle raised obstacles to the implementation of oral health policy in Salvador. PMID- 21655848 TI - [Sleep, work, and study: sleep duration in working and non-working students]. AB - The aim of this study was to investigate the duration of sleep and associated factors in working and non-working students. Data were analyzed on the sleep-wake cycle in 863 teenage students in Sao Paulo, Brazil. Adjusted analyses were performed to compare sleep duration in working and non-working students. 18.4% of the group worked, and 52% of the working students slept eight hours or less per night. Prevalence of short sleep duration was higher in working students of both sexes (males, p = 0.017; females, p < 0.001). Working students showed short sleep duration in the analysis adjusted for socioeconomic status, but short sleep was more frequent in older adolescents (p = 0.004) and in lower (p = 0.001) and middle (p = 0.011) socioeconomic classes. Although more working students were in night school, in the model adjusted for gender and socioeconomic status, working students in afternoon courses showed higher prevalence of short sleep duration (PR = 2.53; 95%CI: 1.68-4.12). PMID- 21655849 TI - [Socio-demographic characteristics and prenatal and childbirth care in southern Brazil]. AB - This study aimed to compare prenatal and childbirth care received by teenagers and older mothers in Rio Grande, Rio Grande do Sul State, southern Brazil. From January 1st to December 31st 2007, all mothers were interviewed with a standardized questionnaire on the care they received. The chi-square test was used to compare proportions between adolescent and non-adolescent mothers. One fourth (516) of the infants were born to adolescent mothers. Compared to older mothers, teenagers showed lower rates of the following: completion of at least six prenatal visits (61% x 75%), initiation of prenatal care in the first trimester (58% x 77%), tetanus vaccination (81% x 85%), and completion of prenatal visits with the same health professional (70% x 78%). Meanwhile, teenage motherhood was associated with more: supplementation for iron deficiency (66% x 57%), use of forceps (11% x 6%), and episiotomy (86% x 66%). The findings show that teenage mothers received worse prenatal and childbirth care than older mothers. PMID- 21655850 TI - [Perceptions by patients and families towards treatment outcomes in mental health services]. AB - The need to evaluate treatment outcomes in mental health services from the user's perspective has been highlighted in the literature. The objective of this study was to compare the perceptions of patients and their families regarding treatment outcomes, in terms of perceived changes in the patient's life. The Perception of Change Scale was applied to 100 psychiatric patients that used public mental health services and 100 family members. The results showed a high percentage of agreement between patients' and families' perceptions of change on most items in the scale and on the open-ended questions. The results confirmed previous studies comparing patients' and families' satisfaction with other aspects of services. They also attest to the validity of patients' responses in the evaluation of treatment outcomes in mental health services. PMID- 21655851 TI - [Anemia in children 6 to 59 months of age and associated factors in Jordao, Acre State, Brazil]. AB - This study investigated anemia prevalence and associated factors using a cross sectional approach with 429 children 6 to 59 months of age in Jordao, Acre State, Brazil. Multiple Poisson regression in hierarchical models was used in the analysis. Overall anemia prevalence was 57.3% (95%CI: 52.5%-2.1%). Age under 24 months [prevalence ratio - PR (95%CI): 1.40 (1.09-1.74)], living in rural areas [PR: 1.23 (1.04-1.44)], households with 5-14 children [PR: 1.23 (1.04-1.44)], stunting [PR: 1.19 (1.01-1.39)], maternal anemia [PR: 1.18 (1.00-1.39)], and smoking during pregnancy [PR: 1.29 (1.09-1.53)] were associated with increased risk of anemia. Children of working mothers were at lower risk of anemia [PR: 0.78 (0.64-0.94)]. Anemia prevalence in childhood was found to be a serious public health problem in this municipality. Multi-sector prevention strategies should be implemented, addressing poverty and maternal-infant healthcare. PMID- 21655853 TI - Clinicopathological study of salivary gland tumors: an assessment of 303 patients. AB - Salivary gland neoplasms are remarkable for their histological diversity and several studies point to their varied occurrence in the population. Clinical aspects were histologically assessed to determine possible associations and define parameters to differentiate benign and malignant neoplasms. The case files of patients diagnosed with epithelial salivary gland tumors between 1989 and 2005 were reviewed. A majority (71%) of the 303 salivary gland tumors studied were benign and pleomorphic adenoma were found to be most common. Mean ages for patients with benign and malignant tumors were 49.2 and 58.5 years, respectively. A statistically significant difference between these tumors was observed for the following variables: mean age, tumor size and disease duration. A correlation was found between histological diagnosis and tumor consistency. The data presented here corroborate a number of previous studies and are therefore relevant in understanding the diverse characteristics exhibited by these tumors. PMID- 21655852 TI - [Prenatal care and management of hypertension in pregnant women in the public healthcare system in Rio de Janeiro, Brazil]. AB - The aim of this study was to assess the adequacy of prenatal care for pregnant women with hypertension as compared to those at low risk. Adequate management of hypertension and associated factors were also investigated. A cross-sectional study was conducted with 1,947 women, 187 of whom with hypertension, in public prenatal care units in Rio de Janeiro, Brazil, in 2007-2008. Demographic and socioeconomic data, obstetric history, and information on adequacy of prenatal care were collected using interviews and prenatal care cards. Adequacy of management of hypertension was evaluated according to performance of health professionals and health services and women's individual characteristics. Chi square and multivariate logistic regression were used to compare groups and identify factors associated with management of hypertension. Adequacy of prenatal care was 79% and did not differ between groups. Only 27% of pregnant women with hypertension received appropriate management, with poor professional performance. Hypertensive pregnant women with better prenatal care were those with previous neonatal deaths and/or stillbirths and those with 35 years of age and older. Despite adequate use of prenatal care, management of hypertension in pregnant women was inadequate. PMID- 21655854 TI - [Foreword]. PMID- 21655855 TI - [Management of hyperphosphatemia in CKD]. PMID- 21655856 TI - [Prevention and treatment of secondary hyperparathyroidism in CKD]. PMID- 21655857 TI - [Dialysate calcium concentration and hypercalcemia in CKD]. PMID- 21655858 TI - [Adynamic bone disease]. PMID- 21655859 TI - [Brazilian guidelines for bone and mineral disorders in CKD children]. PMID- 21655860 TI - [Aluminium intoxication in chronic kidney disease]. PMID- 21655861 TI - [Vascular calcification in CKD]. PMID- 21655862 TI - [Parathyroidectomy in CKD]. PMID- 21655863 TI - [Bone biopsy in chronic kidney disease]. PMID- 21655864 TI - [Guidelines for bone and mineral disorders after kidney transplantation]. PMID- 21655865 TI - [Hypoglycemia hypersinsulinemic of infancy]. AB - The hypoglycemia hyperinsulinemic of the infancy (HHI) is an emergency in the neonatal period. After a short period of fast the avid brain runs out of its main energy substrate. The authors overhaul the diagnosis of HH, not only in the neonatal period, but also in the late infant and in the adolescence. The aspects of the molecular alterations found in these cases, as well like the description of the main mutations are also approached. PMID- 21655866 TI - Ultrasonography compared to magnetic resonance imaging in thyroid-associated Graves' ophthalmopathy. AB - OBJECTIVE: To compare ultrasonography (US) to magnetic resonance imaging (MRI) and the clinical activity score (CAS) in Graves' ophthalmopathy. SUBJECTS AND METHODS: Nineteen patients underwent extraocular muscle thickness measurements by US and MRI, reflectivity by US and signal-intensity ratio by MRI. There were also twelve US control subjects. RESULTS: US median thicknesses were greater than in controls. Correlation was found between US and MRI in the median thickness of the left eye rectus medial muscle as well as between signal-intensity ratio (SIR) and thickness by US. An inverse correlation was found between reflectivity and SIR in the inferior and lateral rectus. On associating the tests for detecting activity the best results were obtained with CAS plus MRI (sensitivity 75%), and US and MRI (positive predictive value 77% and specificity 80%). CONCLUSION: CAS and US results showed poor correlation with MRI results suggesting that they cannot replace each other but when combined these methods can improve the evaluation of thyroid-associated ophthalmopathy. PMID- 21655867 TI - Body composition, metabolic syndrome and insulin resistance in type 1 diabetes mellitus. AB - OBJECTIVE: Our aim was to determine the relationship between body fat composition, metabolic syndrome (MS), and insulin resistance in type 1 diabetes (DM1). SUBJECTS AND METHODS: Forty-five DM1 women (36 +/- 9 years; body mass index 24.6 +/- 4.4 kg/m(2)) had body composition and insulin resistance determined by dual-energy X-ray absorptiometry and estimated glucose disposal ratio (eGDR), respectively. Twenty patients (45%) had MS according to World Health Organization (WHO) criteria. RESULTS: Women with DM1 and MS had increased central fat and lower eGDR than women without MS (41.9 +/- 2.0 vs. 33.7 +/- 1.8%; p = 0.004 and 4.99 +/- 0.40 vs. 8.37 +/- 0.39; p < 0.0001, respectively). Total body fat and peripheric fat were similar between the groups. Central fat negatively correlated with eGDR (r = -0.33; p = 0.03). CONCLUSION: Central fat deposition in young non-obese DM1 women was related to MS and insulin resistance. Thus, body fat composition analysis might be important to identify DM1 patients with increased metabolic risk. PMID- 21655868 TI - [Socioeconomic, demographic, nutritional, and physical activity factors in the glycemic control of adolescents with type 1 diabetes mellitus]. AB - OBJECTIVE: To identify the association of socioeconomic, demographic, nutritional and of physical activity factors in the glycemic control of adolescents with T1DM. SUBJECTS AND METHODS: Sectional study of 71 adolescents with type 1 diabetes. Socioeconomic, demographic and anthropometric data were obtained. The glycemic control was classified by the index of glycated hemoglobin (A1C). Four 24-hours recalls of food consumption and physical activity were applied. RESULTS: The A1C was inadequate for the majority of the adolescents. The low educational level of the caregivers influenced the inadequate glycemic control. Patients with lower insulin dose presented better glycemic control. The food consumption was high of fat and poor of carbohydrate. Most of the patients were sedentary. CONCLUSION: Factors related to education, insulin and food consumption influenced the glycemic control. PMID- 21655869 TI - Impaired functional and hemodynamic response to graded exercise testing and its recovery in patients with subclinical hyperthyroidism. AB - OBJECTIVE: To evaluate the functional and hemodynamic responses during exercise and its recovery in patients with subclinical hyperthyroidism (SCH). SUBJECTS AND METHODS: A cross-sectional study was carried out with 29 patients on TSH suppressive therapy with levothyroxine for thyroid carcinoma and 35 euthyroid subjects. All volunteers underwent a cardiopulmonary exercise testing on a treadmill and functional and hemodynamic variables were measured during exercise and its recovery. RESULTS: SCH patients showed impaired functional response to exercise, marked by lower values for oxygen consumption and exercise duration in addition to premature achievement of the anaerobic threshold. Heart-rate and blood pressure recovery immediately after exercise were slower among SCH patients when compared to euthyroid subjects. CONCLUSION: SCH is associated with impaired functional and hemodynamic responses during exercise and its recovery. PMID- 21655870 TI - Comparison of the hormonal responses to exhaustive incremental exercise in adolescent and young adult males. AB - OBJECTIVE: Evaluate hormonal responses to incremental-stage exercise (EX) test to exhaustion in adolescents. SUBJECTS AND METHODS: Adolescents were tested at 16 years of age in Tanner Stage 4 (TS4) and at 17 years of age in Tanner Stage 5 (TS5) (n = 6). Adults were tested at 21 +/- 1 y. (X +/- SD) (n = 4) and served as controls. Blood samples were taken at rest, at the end of each EX stage. RESULTS: Main effects for EX in cortisol (p < 0.01, increasing with each EX stage) and for subject group for testosterone (T) occurred (p < 0.01; TS4 < TS5, adults). Interaction effect of group by EX stage occurred for GH (p < 0.05). GH increased in response to EX in all groups, however, the magnitude of increase was significantly less for TS5 and adults than TS4. CONCLUSIONS: Differences in T and GH responses for TS4 than those for TS5 and adults reflect the differing maturation levels of the endocrine system between Tanner Stages. TS5 adolescents are more similar to young adults in hormonal responses to EX than are TS4 adolescents. PMID- 21655871 TI - Patients with familial non-medullary thyroid cancer have an outcome similar to that of patients with sporadic papillary thyroid tumors. AB - OBJECTIVE: The purpose of this study was to determine whether familial non medullary thyroid cancer (FNMTC) is more aggressive than sporadic thyroid cancer. SUBJECTS AND METHODS: We compared the clinical behavior and outcome of 16 subjects with FNMTC from 7 unrelated kindred with those observed in 160 subjects with sporadic PTC (SPTC) from our database. RESULTS: The only different baseline characteristics observed between both groups were: bilateral malignancy, 38% vs. 24%, respectively (p = 0.03), and lymph node metastasis, 56.2% vs. 39%, respectively (p = 0.01). Considering the outcome, in the FNMTC, 9 (56.2%) patients were rendered free of disease, one patient died from thyroid cancer (6%), and 6/16 (37.5%) had persistent disease. In the SPTC Group, 87 (54%) patients were considered free of disease, 11 (7%) died due to PTC, and 62 (38%) had persistent disease (p = ns). CONCLUSIONS: Despite the higher incidence of lymph node metastasis in FNMTC patients this situation seemed not to alter the compared outcome. PMID- 21655872 TI - [Cognitive dysfunction in patients with subclinical hypothyroidism]. AB - OBJECTIVE: Evaluate neuropsychological changes in patients with subclinical hypothyroidism (SH). SUBJECTS AND METHODS: Cross-sectional study comparing the results of the neuropsychological evaluation of 89 SH patients and 178 individuals without thyroid disease. The participants underwent the following neuropsychological assessment: Conner's Continuous Performance Test (CPT-II), Iowa Gambling Task, Stroop Test, Wisconsin Card Sorting Test (WCST), Verbal Fluency Test (semantic and phonologic categories) and Rey Auditory Verbal Learning Test. RESULTS: Among the neuropsychological tests, patients showed worse performance only in cognitive flexibility (WCST) and the ability to maintain sustained attention (omission errors on the CPT-II). CONCLUSIONS: These losses can cause detriments in the daily lives of patients, constituting potential treatment indications. PMID- 21655873 TI - Acute respiratory failure caused by neglected giant substernal nontoxic goiter. AB - Substernal goiter is usually defined as a goiter in which the thyroid mass has descended the plane of the thoracic inlet or if more than 50% of the thyroid mass is located below the thoracic inlet. Substernal goiters may be asymptomatic or may present with symptoms caused by compression of adjacent organs. Acute respiratory failure is rare in cases of substernal goiter. In cases of symptomatic substernal goiter the treatment is surgical by thyroidectomy. We present a rare case of a giant substernal nontoxic goiter which caused acute respiratory failure which was treated by urgent thyroidectomy through a T incision. PMID- 21655874 TI - [Extreme subcutaneous and intramuscular insulin resistance at type 1 diabetes mellitus]. AB - Insulin resistance signs reduced cellular response to this hormone and dysfunction of glucose transport to intracellular compartment. This phenomenon is associated to genetic factors and principally behavior factors correlating to obesity and its comorbidities, as type 2 diabetes mellitus, hypertension and dyslipidemia. However clinical factors of insulin resistance are still present at not obese type 1 diabetes in a known syndrome called type 1 diabetes mellitus with resistance to insulin administered subcutaneously and intramuscularly (DRIASM). This is a rare condition that consists into insulin resistance at subcutaneously and intramuscularly use and normal or near to normal sensitivity at intravenously way. Treatments until now proposed are ineffective and are related to frequent fails and complications. We report here two cases of DRIASM in 45 and 46 female patients that are different from others yet related because they have late diabetes type 1, sustained hyperglycemia associated to catabolic, microangiopathy and neuropathic complications without any ketoacidosis episode. The treatment vary from alternative ways for insulin infusion to inscription to a possible performance of pancreas transplantation like a experiment of definitive treatment. This report was approved by Research Ethic Committee from Sao Jose do Rio Preto medical school. PMID- 21655875 TI - II Guidelines for perioperative evaluation of the Brazilian Society of Cardiology. PMID- 21655876 TI - Vasculitides and eosinophils in endomyocardial biopsies as rejection predictors in heart transplantation. AB - BACKGROUND: The clinical significance of vasculitides, ischemic lesions, Quilty effect and the presence of eosinophils in endomyocardial biopsies of heart transplantation recipients with mild rejection has yet to be established. OBJECTIVE: To verify whether these histological findings observed in endomyocardial biopsies (eosinophils, vasculitides, Quilty effect and ischemic lesions) are capable of predicting acute graft rejection. METHODS: A total of 1,012 consecutive endomyocardial biopsies were reevaluated; of these, 939 were classified as OR or 1R according to the Nomenclature of the International Society of Heart and Lung Transplantation of 2005 and divided in two groups: (1) Predictive biopsies: those that preceded acute rejection; and (2) Nonpredictive biopsies: those that did not precede acute rejection. We compared the occurrence of the following histological findings: vasculitides, ischemic lesions, Quilty effect and eosinophils between the groups by uni- and multivariate analyses. RESULTS: The statistical analysis showed that the presence of severe vasculitides and eosinophils were the best predictors for future acute rejection, with the following odds ratios: 10.60 (95%CI: 3.62 - 31.06. p < 0.001) and 6.26 (95%CI: 3.16 - 12.43, p < 0.001). CONCLUSION: Severe vasculitides and eosinophils in myocardial biopsies are the main predictive factors of acute graft rejection post heart transplantation. PMID- 21655877 TI - Echocardiographic parameters of epicardial fat deposition and its relation to coronary artery disease. AB - BACKGROUND: Epicardial fat has been associated to the presence of significant coronary artery disease (CAD). However, the association of lipomatous infiltration of the atrial septum and fat infiltration of the right ventricle remains uncertain. None of these parameters has been thoroughly studied in Hispanic patients. OBJECTIVE: To determine the association between epicardial fat, lipomatous infiltration of the atrial septum and fat infiltration of the right ventricle with the presence of CAD. METHODS: Two hundred and fifty Hispanic patients (86 women and 164 men, mean age 61.5 +/- 8 vs 62 +/- 10 respectively), undergoing their first invasive coronary angiography (ICA) were studied. The day after the ICA, parameters of cardiac fat deposition were evaluated using 2D echocardiography. Clinical (age, sex, personal antecedents of smoking habit, hypertension and diabetes mellitus, as well as clinical presentation of CAD) and anthropometric (waist circumference and body mass index [BMI]) variables were also collected. RESULTS: Epicardial fat (OR 1.27 p = 0.009), as well as fat infiltration of the right ventricle (OR 2.94 p = 0.027), had a significant and independent association with the presence, but not the extent (p = 0.516) and clinical presentation (p = 0.153) of CAD. The extent of epicardial fat deposition showed a proportional and significant association (p = 0.001) with the presence of CAD. CONCLUSION: Epicardial fat and fat infiltration of the right ventricle were both significant and independent factors associated to the presence of CAD, which was proportionally increased according to the extent of cardiac fat deposition. PMID- 21655878 TI - Disseminated septic emboli, septic thrombosis of the vena cava and the common iliac and renal veins, and retroperitoneal abscess secondary to pyogenic spondylitis of the lumbar spine: a case report. PMID- 21655879 TI - Recurrent posterior dislocation of the hip treated with periacetabular osteotomy: a case report. PMID- 21655880 TI - Impaired wound-healing, local eczema, and chronic inflammation following titanium osteosynthesis in a nickel and cobalt-allergic patient: a case report and review of the literature. PMID- 21655881 TI - Patient safety climate among orthopaedic surgery residents. PMID- 21655882 TI - Evaluation of shoulder and elbow questions on the orthopaedic in-training examination as an instrument for enhancing examination preparation. PMID- 21655883 TI - Commentary on an article by Sunny Kim, PhD, et al.: "increase in outpatient knee arthroscopy in the United States: a comparison of National Surveys of Ambulatory Surgery, 1996 and 2006". PMID- 21655893 TI - Comparison of the low contact stress and press fit condylar rotating-platform mobile-bearing prostheses in total knee arthroplasty: a prospective randomized study. AB - BACKGROUND: To our knowledge, no study to date has compared the clinical results of posterior cruciate-sacrificing mobile-bearing total knee replacements with those of posterior-stabilized mobile-bearing total knee replacements in the same patients. The purpose of the present study was to compare the clinical and radiographic results of these two designs. We hypothesized that the results would be better for knees treated with the posterior-stabilized mobile-bearing prosthesis. METHODS: The present study consisted of a consecutive series of 107 female patients (mean age, 66.8 years) who underwent bilateral simultaneous total knee arthroplasty at the same surgical setting. All of these patients received a posterior cruciate-sacrificing mobile-bearing prosthesis in one knee and a posterior-stabilized mobile-bearing prosthesis in the contralateral knee. At the time of each follow-up (mean, 7.4 years; range, seven to 7.6 years), the patients were assessed clinically. RESULTS: The mean postoperative Knee Society knee score (96 compared with 97 points) and Hospital for Special Surgery knee score (93 compared with 94 points) were similar between the two groups. At the time of the latest follow-up, the average range of motion was 127.7 degrees (range, 70 degrees to 150 degrees ) in the knees with a posterior cruciate-sacrificing mobile-bearing prosthesis and 132.4 degrees (range, 90 degrees to 150 degrees ) in the knees with a posterior-stabilized mobile-bearing prosthesis. With a margin of error of the manual measurement of 5 degrees , this difference was not significant. The estimated survival rate was 97.2% (95% confidence interval, 91% to 99%) at seven years in the posterior-cruciate sacrificing mobile-bearing prosthesis group and 98.1% (95% confidence interval, 92% to 99%) at seven years in the posterior-stabilized mobile-bearing prosthesis group. CONCLUSIONS: After a minimum duration of follow-up of seven years, we found no significant differences between the two groups with regard to the clinical and radiographic results, including knee range of motion. PMID- 21655894 TI - Operative complications of combat-related transtibial amputations: a comparison of the modified burgess and modified Ertl tibiofibular synostosis techniques. AB - BACKGROUND: The complications of bone-bridging amputations remain ill defined. The purpose of this study was to compare the early and intermediate-term complications leading to reoperation between the modified Burgess and modified Ertl tibiofibular synostosis in combat-related transtibial amputations. METHODS: We conducted a retrospective review of consecutive, contemporaneous cohorts of thirty-seven modified Ertl bone-bridge and 100 modified Burgess combat-related transtibial amputations. The primary outcome measure was the need for reoperation following definitive closure. RESULTS: At a mean follow-up of two years (range, nine to forty-eight months), there was a 53% overall reoperation rate. The overall complications included infection (34%), neuroma excision (18%), heterotopic ossification excision (15%), myodesis failure (4%), and scar revision (7%). A significantly higher rate of overall complications (p = 0.008) was noted in the bone-bridge group. Additionally, there was an increased rate of noninfectious complications in the bone-bridge group (p = 0.02). A positive selection bias was also noted for performing bone-bridge amputations late (p = 0.0002) and outside the zone of injury (p < 0.0001). Bone-bridge-specific complications occurred in 32% of the modified Ertl group. Delayed union or nonunion of the synostosis (11%) and implant-related complications (27%) predominated. Three bone bridges were ultimately removed. CONCLUSIONS: Reoperations were needed at a significantly greater rate overall and for noninfectious complications following bone-bridge synostosis compared with modified Burgess transtibial amputations. Additionally, despite the positive selection bias favoring the bridge synostosis cohort, infection rates were not lower in that group. Detailed patient counseling and careful patient selection are indicated prior to performing modified Ertl amputations, particularly in the absence of convincing evidence regarding objective functional benefits from the procedure. PMID- 21655895 TI - Full-length spp24, but not its 18.5-kDa proteolytic fragment, inhibits bone healing in a rodent model of spine fusion. AB - BACKGROUND: Growth factors like bone morphogenetic protein (BMP) are used as bone graft substitutes to enhance bone growth in clinical situations. However, adverse reactions have been associated with BMP use. We developed a synthetic adjuvant therapy based on the sequence of a BMP-binding protein, secreted phosphoprotein 24 (spp24), which enhances the effects of BMPs and ameliorates the adverse reactions. Our hypothesis is that a natural proteolytic fragment of spp24 is identical to an osteogenic protein previously described independently by two investigators. To test this hypothesis, spp24 and a truncated form of spp24 were separately implanted with recombinant human BMP-2 (rhBMP-2) in a rodent model of spine fusion. METHODS: Two isoforms of spp24 were constructed with use of DNA recombinant technology. Spp24 with or without rhBMP-2 were added to collagen sponges and implanted bilaterally between L4 and L5 transverse processes. Radiographs were made biweekly, and spines were explanted after eight weeks. Gross evaluation, microquantitative computed tomography study, and histological analysis were performed to evaluate bone growth. RESULTS: Animals that received full-length spp24 and rhBMP-2 exhibited a complete obliteration of bone growth, while animals with the truncated form in combination with rhBMP-2 exhibited a mild inhibition to bone growth, with bone area measured from radiographs. Manual assessment and gross evaluation of all spines confirmed the results obtained from the bone-area measurements. Microquantitative computed tomography provided three dimensional visual images of representative specimens, while histological staining of spine tissue displayed cellular evidence of bone formation. CONCLUSIONS: Results from this investigation confirm that the various isoforms of spp24 affect the bone-healing activity of rhBMP-2 in the rat spine fusion model. Thus, proteolytic modification of this protein is a likely mechanism for the regulation of BMP availability in the physiological environment. Future studies will define the roles of these proteins in controlling the activity of BMPs and other members of the transforming growth factor-beta family of cytokines. This information will increase the understanding of normal bone-healing, allowing for the engineering of more effective orthopaedic treatment. PMID- 21655896 TI - Volumetric injury of the distal femoral physis during double-bundle ACL reconstruction in children: a three-dimensional study with use of magnetic resonance imaging. AB - BACKGROUND: Double-bundle anterior cruciate ligament (ACL) reconstruction was developed to produce a more "anatomic" reproduction of the anteromedial and posterolateral bundles of the ACL. The purpose of this study was to determine the volume of injury to the physis during double-bundle ACL reconstruction in children with open physes. METHODS: Magnetic resonance images (MRIs) of ten knees of children were converted into three-dimensional models. Computer-aided design/computer-aided manufacturing software placed drill-holes of 6, 7, 8, and 9 mm in diameter in these models, simulating tunnels in the femur used for anatomic double-bundle ACL reconstruction. Computer-aided design/computer-aided manufacturing software was used to calculate the total physeal volume and the volume of physis that was removed by creation of the tunnels. The ratio of the physeal volume that had been removed to the total physeal volume was subsequently determined. RESULTS: With use of 6, 7, 8, and 9-mm-diameter drill-holes in the femur, the average physeal volume removed, as a percentage of the total physeal volume, was 1.5%, 2.0%, 2.5%, and 2.9%, respectively, for the anteromedial tunnels; 2.2%, 2.9%, 3.6%, and 4.2% for the posterolateral tunnels; and 3.7%, 4.8%, 5.7%, and 6.5% for the anteromedial and posterolateral tunnels combined. The volume of physeal damage caused by the posterolateral drill-holes was greater than that produced by the anteromedial drill-holes in all subjects. CONCLUSIONS: Drill-hole placement during ACL reconstruction produces a zone of physeal injury. Double-bundle techniques substantially increase the volume of injury to the physis, which appears to increase the risk of abnormal growth in the distal femoral physis following this surgical procedure. PMID- 21655897 TI - Cementless total hip arthroplasty using the Spongiosa-I fully coated cancellous metal surface: a minimum twenty-year follow-up. AB - BACKGROUND: We present the results of cementless total hip arthroplasty performed with use of an anatomically adapted femoral stem and hemispherical cup with a fully coated Spongiosa-I metal surface, which was designed to achieve a surface similar to human cancellous bone. The purpose of the present retrospective case series was to determine the long-term outcomes of this hip arthroplasty system after a minimum of twenty years of follow-up. METHODS: Between 1983 and 1985, 209 consecutive total hip arthroplasty procedures (199 patients) were performed with use of the first-generation Spongiosa metal-surface chromium-cobalt total hip implant with an articulating surface consisting of a ceramic head and an ultra high-molecular-weight polyethylene liner. We report the clinical and radiographic outcomes, the rates of and reasons for revision, and the influence of sex and age on outcome and complications. RESULTS: At the time of the latest follow-up, twenty-seven patients had died and thirteen patients had been lost to follow-up; none of these forty patients had had revision surgery. The outcomes for 159 patients (169 prostheses) were reviewed. The mean duration of follow-up was 262 months (range, 242 to 275 months). There were nineteen revisions, including fourteen revisions of the femoral stem, two revisions of the acetabular cup, and three revisions of both components. The mean Harris hip score for patients who did not undergo revision surgery was 82 points. The probability of survival of both components at twenty years, with revision for any reason as the end point, was 97%. The probability of survival of the acetabular component was 98%, and the probability of survival of the femoral component only was 86%. The probability of component survival was significantly increased among older patients. CONCLUSIONS: The results of cementless hip arthroplasty with use of the first-generation Spongiosa implant were excellent at a minimum of twenty years of follow-up. The probability of survival of the acetabular component exceeded that of the femoral stem. PMID- 21655899 TI - Hounsfield units for assessing bone mineral density and strength: a tool for osteoporosis management. AB - BACKGROUND: Measurements obtained from clinical computed tomography examinations may yield information leading to the diagnosis of decreased bone mineral density, without added expense to the patient. The purpose of the present study was to determine if Hounsfield units, a standardized computed tomography attenuation coefficient, correlate with bone mineral density and compressive strength. METHODS: Twenty-five patients (including eighteen female and seven male patients with a mean age of 71.3 years) undergoing both lumbar spine dual x-ray absorptiometry scans and computed tomography imaging were evaluated to determine if Hounsfield units correlated with bone mineral density and T-scores. Normative data were generated from lumbar spine computed tomography examinations for eighty consecutive trauma patients and were stratified by age and sex. Separately, polyurethane foam blocks of varying densities were imaged with computed tomography and were subjected to mechanical testing to determine compressive strength. Compressive strength values and Hounsfield units were analyzed for correlation. RESULTS: Significant correlations were found between Hounsfield units and bone mineral density, age, and T-scores and between Hounsfield units and compressive strength (p < 0.001). CONCLUSIONS: Hounsfield units obtained from clinical computed tomography scans that are made for other purposes correlate with dual x-ray absorptiometry scores as well as compressive strengths based on osseous models and potentially provide an alternative method for determining regional bone mineral density at no additional cost to the patient. The information could conceivably be applied toward fracture risk assessment, diagnosis of osteoporosis, and early initiation of needed treatment. PMID- 21655898 TI - Comparison of the Paley method using chronological age with use of skeletal maturity for predicting mature limb length in children. AB - BACKGROUND: Treating patients with congenital or acquired limb-length inequality requires accurate estimations of limb length at skeletal maturity. There is controversy over the best indicator of maturity to be used for limb-length calculations. Paley popularized the multiplier method, in which chronological age is used, which has the virtue of simplicity but does not account for the wide variance in timing of the adolescent growth spurt. The purpose of this study was to determine whether the use of chronological age or the level of skeletal maturity provides more accurate limb-length predictions. METHODS: We identified patients with limb-length inequality, for whom scanograms had been obtained before and at maturity, and who had had no surgical procedures on their normal lower limb. Skeletal maturity was determined with use of the Greulich and Pyle atlas, Tanner-Whitehouse-3 method, and simplified stages described by Sanders et al. The length of the lower extremity was compared with the ultimate limb length and the actual multiplier (final limb length divided by current limb length) for each point in time. A linear model was used to determine the log-transformed multipliers for the level of skeletal maturity, and Paley's multipliers were used for chronological age. Residual standard errors were determined to compare the results of the methods. We also conducted piecewise linear regression on each of the methods and used the residual standard errors to rank their performance and cross-validated the results. RESULTS: We identified twenty-four patients (twelve girls and twelve boys) who met the study criteria. Most subjects had had multiple scanograms along with skeletal age radiographs (average, 4.5) at different ages. When all ages are considered, the Paley method had the best overall performance, with residual standard errors that were typically =5 cm. However, the Paley method did not perform best for subjects at stage-2 skeletal maturity or above; in those cases, skeletal-maturity-based predictions had residual standard errors of <2 cm. CONCLUSIONS: While the Paley method, which is based on chronological age, provides reasonable estimates of ultimate limb length for most patients, use of skeletal-maturity determinations appears to provide better predictions of mature limb length during adolescence. PMID- 21655900 TI - Modular prosthetic reconstruction of major bone defects of the distal end of the humerus. AB - BACKGROUND: Bone defects of the distal end of the humerus require complex reconstructions, for which standard prostheses may be insufficient. We investigated the outcomes of distal humeral reconstruction with use of a modular prosthesis. METHODS: Fifty-three elbows in fifty-two patients underwent reconstruction with a modular prosthesis (twelve total humeral replacements and forty-one distal humeral replacements) after tumor resection (thirty-eight elbows) or because of massive joint degeneration (fifteen elbows). In the tumor group, twenty-three patients (twenty-four elbows) had metastatic disease and fourteen had a primary tumor. Degenerative defects of the distal end of the humerus were caused by pseudarthrosis (six elbows), prosthetic failure (five), trauma (two), osteomyelitis (one), and supracondylar fracture (one). The mean duration of follow-up for all patients was twenty-eight months (median, thirteen months; range, one to 219 months). RESULTS: The mean Inglis-Pellicci score in the tumor group was 84 points, and the mean Musculoskeletal Tumor Society score was 78%. Patients with total humeral reconstruction had worse scores than those with distal humeral reconstruction. Twenty-four patients died of disease at a mean of thirteen months after surgery. Local tumor control was achieved in all patients. In the revision group, the mean Inglis-Pellicci score was 76 points. The Inglis Pellicci score was significantly better for patients in the tumor group. Eight patients (15%) had a deep periprosthetic infection, requiring amputation in one patient (2%) and prosthetic removal in two patients (4%). Four patients (8%) had the implants revised for aseptic loosening. CONCLUSIONS: Modular prostheses of the distal end of the humerus provide a stable reconstruction of the elbow with satisfactory function and disease control in patients with a tumor, but careful patient selection is required when the prostheses are used for revision surgery in patients without a tumor. PMID- 21655901 TI - Multimodal pain management after total joint arthroplasty. AB - Adequate postoperative pain control in patients who have undergone total joint arthroplasty allows faster rehabilitation and reduces the rate of postoperative complications. Multimodal pain management involves the introduction of adjunctive pain control methods in an attempt to control pain with less reliance on opioids and fewer side effects. Current research suggests that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and the associated cyclooxygenase type-2 (COX-2) inhibitors improve pain control in most cases. Nearly all multimodal pain management modalities have a safe side-effect profile when they are added to existing methods. The exception is the administration of DepoDur (extended release epidural morphine) to elderly or respiratory-compromised patients because of a potential for hypoxia and cardiopulmonary events. PMID- 21655902 TI - Adenosine-induced atrial tachycardia and multiple foci initiating atrial fibrillation eliminated by catheter ablation using a non-contact mapping system. AB - A 47-year-old male with both atrial tachycardia and atrial fibrillation underwent catheter ablation. During the procedure, rapid administration of adenosine triphosphate induced atrial tachycardia. A non-contact mapping system revealed a focal atrial tachycardia originating from the lateral right atrium, which was successfully ablated. Following the ablation of tachycardia, atrial fibrillation was induced by the injection of adenosine along with multiple extra pulmonary vein foci, which were eliminated by the application of radiofrequency under the guidance of a non-contact mapping system. PMID- 21655903 TI - Atypical giant cell arteritis predominantly involving intramural coronary arteries: a case showing refractory dialysis-related hypotension. AB - Giant cell arteritis involving intramural coronary artery branches is rare, and its clinical features remain poorly understood. We report a 56-year-old hemodialysed patient with a history of mitral valve replacement, who presented with "fever of unknown origin" and intractable hypotension. The antemortem diagnosis was very difficult and the autopsy revealed giant-cell-rich vasculitis in arteries in multiple organs. The heart was most severely involved, in which almost all of the intramural coronary artery branches were infiltrated by many multinucleated giant cells, macrophages, and lymphocytes with luminal narrowing, but the epicardial segments of the coronary arteries were spared. Superimposed on the preexisting valvular heart disease, the vasculitic lesions were thought to play a central role in severe cardiac dysfunction resulting in dialysis-related hypotension, which led to fatal non-occlusive mesenteric ischemia. This case highlights the possibility that giant cell arteritis of intramural coronary arteries could be an uncommon underlying cause of refractory dialysis-related hypotension. PMID- 21655904 TI - Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of high-sensitivity C-reactive protein in apparently healthy Japanese. AB - The aim of this study was to investigate the association between leukocyte subtype counts and hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia. Logistic regressions using hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia as a dependent variable and total leukocyte, basophil, eosinophil, neutrophil, lymphocyte, and monocyte counts as an independent variable were calculated adjusting for age, body mass index (BMI), high-sensitivity C-reactive protein (hs-CRP), smoking, drinking, and physical activity in apparently healthy Japanese men (1,803) and women (1,150). The odds ratio (OR) of hyper-LDL cholesterolemia for total leukocyte, eosinophil, and lymphocyte counts, the OR of hypertriglyceridemia for total leukocyte, eosinophil, neutrophil, and lymphocyte counts, and the OR of hypo-HDL cholesterolemia for total leukocyte, neutrophil, and lymphocyte counts were significant in men, and the OR of hyper-LDL cholesterolemia, for lymphocyte count, and the OR of hypo-HDL cholesterolemia for eosinophil count were significant in women. Lymphocyte count was significantly associated with hyper LDL cholesterolemia independently of hs-CRP in apparently healthy Japanese. PMID- 21655905 TI - Differentiation of malignant from benign heart and pericardial lesions using positron emission tomography and computed tomography. AB - OBJECTIVE: To assess the feasibility of (18)F-FDG PET-CT for the differentiation of malignancy from benign lesions of the heart and the pericardium. METHODS: A total of 23 cases (malignancy:benign = 13:10) with cardiac and pericardial lesions, confirmed by pathology or on clinical grounds, were analyzed in this study. All lesions were evaluated semi-quantitatively using maximum standard uptake values (SUV(max)) and SUV(max) lesion/blood, and the density of the heart and pericardium lesions and the relation with surrounding tissues were evaluated. The differences of SUV(max) and SUV(max) lesion/blood between benign and malignant lesions were analyzed by the Mann-Whitney test. Subsequently, the diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated for CT and PET-CT, respectively. RESULTS: The maximum SUV showed significant difference between malignancy (avg +/- SD 6.5) and benign (avg +/- SD 1.5) (Z = -3.601, P < .01), the SUV(max) lesion/blood of malignancy and benign were avg +/- SD 3.4 and avg +/ SD 0.9, respectively, also with a significant difference (Z = -3.600, P < .01). In this pilot study, the optimal cutoff value to separate benign vs malignant lesions of SUV(max) was 3.5-4.0 and the cutoff for SUV(max) lesion/blood was 1.3 2.0. The sensitivity, specificity, accuracy, PPV, and NPV of CT and PET-CT were 76.9%(10/13), 100.0%(10/10), 87.0%(20/23), 100.0%(10/10), 76.9%(10/13) and 100.0%(13/13), 90.0%(9/10), 95.7%(22/23), 92.9%(13/14), 100.0%(9/9), respectively. CONCLUSION: (18)F-FDG PET-CT appears promising for correctly differentiating benign vs malignant cardiac and pericardial lesions. PMID- 21655908 TI - Endonasal endoscopic resection of esthesioneuroblastoma: the Johns Hopkins Hospital experience and review of the literature. AB - Esthesioneuroblastoma is an uncommon malignant tumor originating in the upper nasal cavity. The surgical treatment for this tumor has traditionally been via an open craniofacial resection. Over the past decade, there has been tremendous development in endoscopic techniques. In this report, we performed a retrospective analysis of patients with esthesioneuroblastomas treated with a purely endonasal endoscopic approach and resection at the Johns Hopkins Hospital between January 2005 and April 2010. A total of eight patients with esthesioneuroblastoma, five men and three women, were identified. Six patients were treated for primary disease, and two were treated for tumor recurrence. The modified Kadish staging was A in one patient (12.5%), B in two patients (25%), C in four patients (50%), and D in one patient (12.5%). All patients had a complete resection with negative intraoperative margins. One patient had intraoperative hypertension; there were no perioperative complications. With a mean follow-up of over 27 months, all patients are without evidence of disease. In addition, we reviewed the literature and identified several overlapping case series of patients with esthesioneuroblastoma treated via a purely endoscopic technique. Our series adds to the growing experience of expanded endonasal endoscopic surgery in the treatment of skull base tumors including esthesioneuroblastoma. Longer follow-up on a larger number of patients is required to further demonstrate the utility of endoscopic approaches in the management of this malignancy. PMID- 21655907 TI - Lung cancers unrelated to smoking: characterized by single oncogene addiction? AB - Lung cancer is a major cause of cancer-related mortality worldwide. Currently, adenocarcinoma is its most common histological subtype in many countries. In contrast with small cell lung cancer or squamous cell carcinoma, lung adenocarcinoma often arises in never-smokers, especially in East Asian countries, as well as in smokers. Adenocarcinoma in never-smokers is associated with a lower incidence of genetic alterations (i.e., somatic mutations, loss of heterozygosity, and methylation) than in smokers. In addition, most adenocarcinomas in never-smokers harbor one of the proto-oncogene aberrations that occur in a mutually exclusive manner (EGFR mutation, KRAS mutation, HER2 mutations, or ALK translocation). It is of note that the proliferation and survival of lung cancer cells that harbor one of these oncogenic aberrations depend on the signaling from each aberrantly activated oncoprotein (oncogene addiction). Therefore, most adenocarcinomas in never-smokers can be effectively treated by molecularly targeted drugs that inhibit each oncoprotein. Moreover, from a pathological aspect, lung adenocarcinoma in never-smokers is characterized by terminal respiratory unit-type adenocarcinoma and a particular gene expression profile. Finally, epidemiological analyses have identified many candidate causes of lung cancer in never-smokers (genetic, environmental, and hormonal factors). The elucidation of the particular features of lung cancer unrelated to smoking and the development of new therapeutic modalities may reduce the mortality from lung cancers in the future. PMID- 21655909 TI - Histological and immunohistochemical evaluation of the peri-implant soft tissues around machined and acid-etched titanium healing abutments: a prospective randomised study. AB - A close spatial correlation has been described between the roughness of intraoral materials and the rate of bacterial colonisation. The aim of the present study in man was to conduct a comparative immunohistochemical evaluation of the inflammatory infiltrate, microvessel density, the nitric oxide synthases 1 and 3 and the vascular endothelial growth factor expression, the proliferative activity, and the B and T lymphocyte and histiocyte positivity in the peri implant soft tissues around machined and acid-etched titanium healing caps. Ten patients participated in this study. The patients were enrolled consecutively. All patients received dental implants left to heal in a non-submerged mode. Healing caps were inserted in all implants. Half of the implants were supplied randomly with machined caps of titanium (control), while the other half were provided randomly with acid-etched titanium caps (test). After a 6-month healing period, a gingival biopsy was performed with a circular scalpel around the healing caps of both groups. The inflammatory infiltrate was mostly present in test specimens. Their extension was much larger than that of the control samples. A higher number of T and B lymphocytes were observed in test specimens. Higher values of microvessel density and a higher expression of vascular endothelial growth factor intensity were observed in the test samples. Furthermore, the Ki 67, NOS1 and NOS3 expression was significantly higher in the test specimens. All these results showed that the tissues around test healing caps underwent a higher rate of restorative processes, most probably correlated to the higher inflammation processes observed in these tissues. PMID- 21655911 TI - Treatment of glioblastoma in "elderly" patients. AB - OPINION STATEMENT: The number of patients over 65 with newly diagnosed glioblastoma is anticipated to increase significantly in coming decades as a result of demographic shifts in the United States. Older patients with this disease have a significantly worse life expectancy compared with patients under 65. Mounting clinical evidence suggests that fit elderly patients with glioblastoma benefit from the addition of temozolomide to standard surgery and radiation. As a result, for healthy patients over 65 we recommend maximal surgical debulking followed by involved-field radiotherapy (60 Gy in 30 fractions) with concurrent temozolomide (75 mg/m(2)/day) and 6 months of adjuvant temozolomide (150-200 mg/m(2)/day for five consecutive days/month). Patients over 65 with newly diagnosed or recurrent glioblastoma should also be considered for inclusion in clinical trials. MGMT is a validated prognostic marker in patients over 65 and may be useful in clinical decision-making in frail elderly patients. Age alone should not be a factor in deciding how patients with newly diagnosed glioblastoma should be treated. PMID- 21655910 TI - Clinical performance of a light-cured denture base material compared to polymethylmethacrylate--a randomized clinical study. AB - The aim of this study was to evaluate the clinical long-term performance of a visible light-cured resin (VLCR) denture base material and to compare it to a well-established polymethylmethacrylate (PMMA)-based denture acrylic in a randomized split-mouth clinical long-term study. One hundred removable partial dentures in 90 patients, with at least two saddles each, were investigated. One saddle was made of VLCR, while the other was made of PMMA at random. Plaque adhesion, tissue reaction, and technical parameters of the dentures were assessed 6, 12, and 18 months after treatment. Statistical analysis was performed using the Wilcoxon rank-sum test. Though VLCR showed higher plaque adhesion than PMMA after 6, 12, and 18 months (p < 0.001), there were no important differences with regard to tissue reaction. Concerning plaque adhesion, surface quality with regard to the lower side, interfaces between denture acrylic and metal and the boundary between denture acrylic and denture tooth PMMA was rated higher than VLCR. The surface quality of the upper side of the denture saddles showed no significant differences (p > 0.05). Neither VLCR nor PMMA showed discoloration at any point in time (p > 0.05). It can be concluded that VLCR is a viable alternative for the production of removable dentures. Especially in patients with hypersensitivities to PMMA, VLCR is particularly suitable for clinical use. PMID- 21655912 TI - A LC-MS/MS method for concurrent determination of nicotine metabolites and role of CYP2A6 in nicotine metabolism in U937 macrophages: implications in oxidative stress in HIV + smokers. AB - Nicotine, the major constituent of tobacco, is predominantly metabolized by liver CYP2A6 into cotinine and many other compounds, including nicotine-derived nitrosamine ketone (NNK), which is known to cause oxidative stress. We have recently shown that CYP2A6 is highly expressed in U937 monocyte-derived macrophages. In this study we investigated the role of CYP2A6 in nicotine metabolism and oxidative stress in U937 macrophages. To study nicotine metabolism, we developed a highly sensitive LC-MS/MS method for simultaneous quantitative determination of nicotine, cotinine, and NNK. The LC-MS/MS analysis was carried out by multiple reaction monitoring mass transitions with m/z of 163.2/130.1, 177.4/98.3, and 208.4/122.1 for nicotine, cotinine, and NNK, respectively. The calibration curves were linear within 3.3-1028.1 ng/ml for nicotine and 0.3-652.6 ng/ml for cotinine and NNK. This novel method was then applied to quantify nicotine metabolites, cotinine and NNK, in nicotine-treated U937 macrophages. Cotinine and NNK initially formed at 30 min, followed by a peak at 2-3 h. The role of CYP2A6 in nicotine metabolism in U937 macrophages was further confirmed by using CYP2A6-selective inhibitor, tryptamine, which significantly decreased cotinine (70%) and completely inhibited NNK formations. Finally, we showed that nicotine-treated macrophages increase the formation of oxidant at 30-60 min, which is consistent with the initial formation of cotinine and NNK. In conclusion, we have developed a new LCMS/MS method for concurrent determination of nicotine metabolites and analyzed the role of CYP2A6 in nicotine metabolism and oxidative stress in U937 macrophages, which may have implications in viral replication among HIV + smokers. PMID- 21655914 TI - Faithful chaperones. AB - This review describes the properties of some rare eukaryotic chaperones that each assist in the folding of only one target protein. In particular, we describe (1) the tubulin cofactors, (2) p47, which assists in the folding of collagen, (3) alpha-hemoglobin stabilizing protein (AHSP), (4) the adenovirus L4-100 K protein, which is a chaperone of the major structural viral protein, hexon, and (5) HYPK, the huntingtin-interacting protein. These various-sized proteins (102-1,190 amino acids long) are all involved in the folding of oligomeric polypeptides but are otherwise functionally unique, as they each assist only one particular client. This raises a question regarding the biosynthetic cost of the high-level production of such chaperones. As the clients of faithful chaperones are all abundant proteins that are essential cellular or viral components, it is conceivable that this necessary metabolic expenditure withstood evolutionary pressure to minimize biosynthetic costs. Nevertheless, the complexity of the folding pathways in which these chaperones are involved results in error-prone processes. Several human disorders associated with these chaperones are discussed. PMID- 21655915 TI - Structural and functional relationships between photoreceptor tetraspanins and other superfamily members. AB - The two primary photoreceptor-specific tetraspanins are retinal degeneration slow (RDS) and rod outer segment membrane protein-1 (ROM-1). These proteins associate together to form different complexes necessary for the proper structure of the photoreceptor outer segment rim region. Mutations in RDS cause blinding retinal degenerative disease in both rods and cones by mechanisms that remain unknown. Tetraspanins are implicated in a variety of cellular processes and exert their function via the formation of tetraspanin-enriched microdomains. This review focuses on correlations between RDS and other members of the tetraspanin superfamily, particularly emphasizing protein structure, complex assembly, and post-translational modifications, with the goal of furthering our understanding of the structural and functional role of RDS and ROM-1 in outer segment morphogenesis and maintenance, and our understanding of the pathogenesis associated with RDS and ROM-1 mutations. PMID- 21655917 TI - Development of hemiasterlin derivatives as potential anticancer agents that inhibit tubulin polymerization and synergize with a stilbene tubulin inhibitor. AB - Hemiasterlins are cytotoxic tripeptides with antimicrotubule activity originally isolated from marine sponges. We have developed new hemiasterlin derivatives BF65 and BF78 that are highly potent to induce cancer cell death in the low nanomolar range. Examination of their mechanisms of cell cycle arrest and disruption of microtubules revealed an unusual characteristic in addition to anti-tubulin effect. Immunofluorescence staining revealed that A549 lung carcinoma cells treated with BF65 or BF78 exhibited both monopolar and multipolar mitotic spindles. Centrosomes were separated with short spindle microtubules in cells with multipolar spindles. In vitro tubulin polymerization assay confirmed that both BF65 and BF78 were highly potent to inhibit tubulin polymerization. These two compounds induced the formation of monoastral spindles suggesting that they might be inhibitors of mitotic kinesins such as KSP/Eg5. However, kinetic measurement of microtubule activated kinesin ATPase activity demonstrated that unlike the positive control monastrol, neither BF65 nor BF78 suppressed KSP/Eg5 activity. Hence the effect may be a variant form of tubulin inhibition. Similar to vinca alkaloids, BF compounds synergized with a colchicine site microtubule inhibitor stilbene 5c both in vitro and in vivo, which may provide a potential drug combination in the future clinical application. PMID- 21655916 TI - Organogenesis from stem cells in planta: multiple feedback loops integrating molecular and mechanical signals. AB - In multicellular organisms, the coordination of cell behaviors largely relies on biochemical and biophysical signals. Understanding how such signals control development is often challenging, because their distribution relies on the activity of individual cells and, in a feedback loop, on tissue behavior and geometry. This review focuses on one of the best-studied structures in biology, the shoot apical meristem (SAM). This tissue is responsible for the production of all the aerial parts of a plant. In the SAM, a population of stem cells continuously produces new cells that are incorporated in lateral organs, such as leaves, branches, and flowers. Organogenesis from stem cells involves a tight regulation of cell identity and patterning as well as large-scale morphogenetic events. The gene regulatory network controlling these processes is highly coordinated in space by various signals, such as plant hormones, peptides, intracellular mobile factors, and mechanical stresses. Many crosstalks and feedback loops interconnecting these pathways have emerged in the past 10 years. The plant hormone auxin and mechanical forces have received more attention recently and their role is more particularly detailed here. An integrated view of these signaling networks is also presented in order to help understanding how robust shape and patterning can emerge from these networks. PMID- 21655918 TI - Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks. AB - To explore the mechanism of action of foretinib (GSK1363089), an oral multi kinase inhibitor known to target MET, RON, AXL, and vascular endothelial growth factor receptors (VEGFRs), in gastric cancer, we evaluated the effects of the agent on cell growth and cell signaling in the following panel of gastric cancer cell lines: KATO-III, MKN-1, MKN-7, MKN-45, and MKN-74. Of these, only MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib. In MKN-45, 1 MUM of foretinib or PHA665752, another MET kinase inhibitor, inhibited phosphorylation of MET and downstream signaling molecules as expected. In KATO III, however, PHA665752 inhibited phosphorylation of MET independently of downstream molecules. Further, 1 MUM of foretinib or PD173074, a selective FGFR kinase inhibitor, inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III. We confirmed this novel activity of foretinib against FGFR2 in OCUM-2M, another FGFR2-amplified gastric cancer cell line. Using a phospho-receptor tyrosine kinase array, we found that foretinib inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. Knockdown of HER3 and FGFR3 in MKN-45 with siRNA resulted in the partial inhibition of cell signaling and cell growth. In conclusion, foretinib appears effective against gastric cancer cells harboring not only MET but also FGFR2 amplification, and exerts its inhibitory effects by blocking inter RTK signaling networks with MET or FGFR2 at their core. PMID- 21655920 TI - Ab initio study of MKr(n)2+(M = Cu, Ag, and Au, n = 1-6) clusters. AB - Quantum chemical calculations of the structures and stabilities of the title series at the CCSD(T) theoretical level are performed. Laplacian, electron density deformation, electron localization function and reduced density gradient analysis are investigated to explore the nature of the interaction. The results show that a covalent contribution occurs in the Kr-M(2+) bonding. PMID- 21655919 TI - Screening of well-established drugs targeting cancer metabolism: reproducibility of the efficacy of a highly effective drug combination in mice. AB - Alterations in metabolic pathways are known to characterize cancer. In order to suppress cancer growth, however, multiple proteins involved in these pathways have to be targeted simultaneously. We have developed a screening method to assess the best drug combination for cancer treatment based on targeting several factors implicated in tumor specific metabolism. Following a review of the literature, we identified those enzymes known to be deregulated in cancer and established a list of sixty-two drugs targeting them. These molecules are used routinely in clinical settings for diseases other than cancer. We screened a first library in vitro against four cell lines and then evaluated the most promising binary combinations in vivo against three murine syngeneic cancer models, (LL/2, Lewis lung carcinoma; B16-F10, melanoma; and MBT-2, bladder cancer). The optimum result was obtained using a combination of alpha-lipoic acid and hydroxycitrate (METABLOC(TM)). In this study, a third agent was added by in vivo evaluation of a large number of combinations. The addition of octreotide strongly reduced tumor development (T/C% value of 30.2 to 34.5%; P < 0.001) in the same models and prolonged animal survival (P < 0.001) as compared to cisplatin. These results were confirmed in a different laboratory setting using a human xenograft model (NCI-H69, small cell lung cancer). None of these three molecules are known to target DNA. The effectiveness of this combination in several animal models, as well as the low toxicity of these inexpensive drugs, emphasizes the necessity of rapidly setting up a clinical trial. PMID- 21655921 TI - Local hemostatic effect of cellulose tampons (Tampax) after stapled hemorrhoidopexy. PMID- 21655922 TI - Responses of male broiler chickens from two genetic groups to different stocking densities in a semi-arid subtropical environment. AB - The effects of stocking densities of 30, 35, 40 and 45 kg body weight (BW)/m(2) on the growth performance of Ross 308 and Hubbard broiler chickens were studied in a 49-day production period. Ross 308 was superior to Hubbard in weight gain and market weight and consumed more feed (p<0.05) but the strains did not differ significantly in feed efficiency, mortality rate and abdominal fatness. Overall, birds raised at stocking densities of 30, 35 and 40 kg BW/m(2) performed equally well in weight gain, feed consumption and 49-day live weight and outperformed those raised at 45 kg BW/m(2) (p<0.05). It is suggested that for profitable broiler production under tropical conditions Ross 308 and stocking density of 40 kg BW/m(2) be considered. PMID- 21655923 TI - Influence of sexually inactive bucks subjected to long photoperiod or testosterone on the induction of estrus in anovulatory goats. AB - The objective of this study was to evaluate the efficacy of treating sexually inactive bucks with artificial long photoperiod or testosterone on the induction of estrus in anovulatory grazing goats. A total of 91 multiparous mixed-breed anestrous goats were randomly assigned to one of three treatment groups: (1) joining with bucks subjected to 2.5 month of artificial long days (16 h of light/day; n=31), (2) joining with testosterone-treated bucks (n=30), and (3) joining with untreated bucks (control; n=30). There were no differences between the light-treated (100%) and testosterone-treated (93%) bucks in their ability to induce estrus in anovulatory does. On the other hand, none of the goats in contact with control bucks exhibited estrus. The interval from start of mating to estrus was shorter in goats with the light-treated bucks (37.9 +/- 4.8 h) compared with does in contact with testosterone-treated bucks (58.3 +/- 8.7 h). The overall pregnancy rate in goats joined with light-treated, testosterone treated and control bucks was 84%, 77% and 0%, respectively, with no difference (P>0.05) between the first two groups. Anogenital sniffing, approaches, mounting attempts, and mounts were highest (P<0.01) in light-treated bucks and lowest in control bucks. It was concluded that testosterone-treated bucks and long-day treated bucks were equally effective in synchronizing estrus in anovulatory goats and resulted in similar levels of fertility. Given that light-treated bucks are unviable in communal production systems of goats raised by resource-poor farmers, the sexual arousal of bucks with testosterone is a practical and reliable method to induce ovulation in anovulatory goats in pastoral goat systems in hot environments. PMID- 21655924 TI - p53 Binds to estrogen receptor 1 promoter in human breast cancer cells. AB - p53 is a tumor suppressor protein that regulates estrogen receptor 1 (ESR1) expression. To investigate the mechanism of ESR1 gene regulation by p53, chromatin immunoprecipitation was applied to assess the binding of p53, DNMT1, HDAC1 and MeCP2 to both silenced ESR1 promoter in MDA-MB-468 cells and active ESR1 promoter in MCF-7 breast cancer cells. The results of chromatin immunoprecipitation experiments showed that p53 protein binds to both unmethylated CpG island of the ESR1 promoter in the ER-positive MCF-7 and the hypermethylated ESR1 promoter in the ER-negative MDA-MB-468 cells. However, repression complex including DNMT1, HDAC1 and MeCP2 is only associated with silenced ESR1 in ER-negative MDA-MB-468 human breast cancer cells. In addition, ectopically expressed wild type p53 failed to reactivate the ESR1 gene in these cells. These results suggest that specific p53 mutations may contribute to loss of estrogen receptor alpha expression in breast tumors and also support the hypothesis that mutant p53 is likely to impact DNA methylation. PMID- 21655925 TI - Watchful waiting and active surveillance approach in patients with low risk localized prostatic cancer: an experience of out-patients clinic with 12-year follow-up. AB - In this study we evaluated the safety of expectant approach in the patients with low risk prostate cancer in the reality of community based out-patients clinics. 48 men were enrolled into the study. The inclusion criteria were age ranged from 60 to 75 years and the Epstein criteria for low risk prostate cancer. Patients were managed expectantly while curative treatment was offered when indicated. Initial and final Charlson comorbidity index (CCI) and BMI were assessed for all men. Patients' median follow-up was 81.1 +/- 29.1 years. During this study 41.7% of the patients chose active forms of treatment. Cancer was found in 20.8% (n-10) of our patients. Two first sessions of re-biopsy diagnosed 92% of T1c upgrading. Six men with CCI >=2 died from concomitant disease and no one died from PCa. Significant correlation was found between BMI and final CCI >=2 (p-0.001). Expectant approach can be considered as self alternative to active treatment model in selected group of patients with well differentiated PCa, however 20.8% of these patients are still at risk of having aggressive form of cancer. Expectant approach is particular beneficial for the patients with CCI 1-2 and high BMI. PMID- 21655926 TI - The effect of sleep restriction and psychological load on the diurnal metabolic changes in tryptamine-related compounds in human urine. AB - OBJECTIVE: The effect of a severely stressful situation (sleep restriction and psychological load) on the diurnal changes in novel tryptamine-related compounds (hydroxydiacetyltryptamine, sulphatoxymelatonin, and dihydromelatonin) was evaluated in human subjects for 16 days. METHODS: The subjects were allowed to sleep for 5 h on days three through 12 and for 8 h on the other days. On days three through 12, the subjects were asked to perform a psychological task. The first two and the last 4 days were viewed as control days. A performance test was administered to evaluate the extent of the subjects' fatigue. Total urine was sampled by collecting it into bottles three times a day [(1) during the sleeping period, (2) in the morning, and (3) in the afternoon]. Seven tryptamine-related compounds in urine were assayed using HPLC-fluorometry. RESULTS: The urine melatonin level was high at night and low during the day. In contrast, urinary levels of hydroxydiacetyltryptamine and sulphatoxydiacetyltryptamine were low at night and high during the day. Dihydromelatonin was undetectable in urine during the sleeping period. Sleep restriction and psychological load did not affect diurnal changes in urinary melatonin, hydroxydiacetyltryptamine, sulphatoxydiacetyltryptamine, or N-acetylserotonin levels. The concentrations of hydroxymelatonin and sulphatoxymelatonin in urine did not show diurnal changes and decreased gradually during the experimental days. A principal component analysis confirmed the diurnal changes and suggested two novel metabolic pathways: (1) N-acetylserotonin to sulphtoxydiacetyltryptamine via hydroxydiacetyltryptamine, and (2) melatonin to dihydromelatonin. CONCLUSION: Severely stressful situations did not affect diurnal changes in melatonin, hydroxydiacetyltryptamine, sulphatoxydiacetyltryptamine, or N-acetylserotonin levels in urine. PMID- 21655927 TI - Genetic variability and differentiation among populations of the Azorean endemic gymnosperm Juniperus brevifolia: baseline information for a conservation and restoration perspective. AB - The Azorean endemic gymnosperm Juniperus brevifolia (Seub.) Antoine is a top priority species for conservation in Macaronesia, based on its ecological significance in natural plant communities. To evaluate genetic variability and differentiation among J. brevifolia populations from the Azorean archipelago, we studied 15 ISSR and 15 RAPD markers in 178 individuals from 18 populations. The average number of polymorphic bands per population was 65 for both ISSR and RAPD. The majority of genetic variability was found within populations and among populations within islands, and this partitioning of variability was confirmed by AMOVA. The large majority of population pairwise F(ST) values were above 0.3 and below 0.6. The degree of population genetic differentiation in J. brevifolia was relatively high compared with other species, including Juniperus spp. The genetic differentiation among populations suggests that provenance should be considered when formulating augmentation or reintroduction strategies. PMID- 21655928 TI - Levels of HTNV-specific CD8+ T lymphocytes in PBMC from the patients with hemorrhagic fever with renal syndrome. AB - The pathogenesis of hemorrhagic fever with renal syndrome (HFRS) has not been fully clarified. Cell-mediated immunity appears to play a crucial role in the immune pathogenesis of HFRS. To explore the relationship between Hantaan (HTNV) specific CD8(+) T lymphocytes and the immune pathogenesis of HFRS, the levels of interferon gamma (IFN-gamma) secreted by HTNV-specific CD8(+) T lymphocytes were detected by flow cytometry in peripheral blood mononuclear cells. Levels of HTNV specific CD8(+) T lymphocytes in patients with HFRS were associated with different phases of HFRS. In fever phase, it was significantly elevated. The levels of HTNV-specific CD8(+) T lymphocytes in PBMC of patients with HFRS were negatively correlated with the levels of blood urea nitrogen and creatinine in plasma. The results show that the HTNV-specific CD8(+) T lymphocyte levels correlate with disease phases. Therefore, dynamic observation of these levels in patients with HFRS can help to judge the status of HFRS disease and to clarify the immune pathogenesis of HFRS. PMID- 21655929 TI - Inappropriate hospital admission: interaction between patient age and co morbidity. AB - The aim of the study is to determine the prevalence of inappropriate admission, and to identify the factors that influence appropriateness of hospital admission. Data were prospectively collected from all 345 consecutive patients admitted during the period of 1 month for acute hospital care at a 110-bed division of internal medicine using socio-demographic and medical information. Statistical analyses included chi2 tests, t tests, and logistic regression analyses. According to the European version of the Appropriateness Evaluation Protocol of hospital admission, 28.1% of medical admissions for acute care in the Central Hospital of Bolzano, Italy, have been classified as inappropriate. Factors that reduced appropriateness included female gender, age and chronic illness that are significantly associated with appropriateness of medical admission, whereas time of day or day of week of the emergency department (ED) visit does not influence appropriateness. In multiple logistic regression analyses, age and co-morbidity are not independently related to appropriateness, however, when tested for interaction, inappropriateness is significantly more frequent at a young age in the absence of co-morbidities, and, numerically most relevant, in elderly patients presenting with co-morbidities. In this evaluation of a single centre North Italian hospital admission, co-morbidity turns out to be an important age dependent determinant of appropriateness. Although in the young age group, co morbidity increases the likelihood of being appropriately admitted, the presence of chronic illness in the elderly increases the risk of inappropriate hospital use. PMID- 21655930 TI - Choosing a treatment for patients at the time a fracture is presented. AB - The occurrence of a fragility fracture is an opportunity to recognize osteoporosis and begin treatment to reduce the risk of another fracture. However, selecting the treatment may have an impact on the incident fracture and this requires careful consideration of the patient and the treatment choices. There is no consensus regarding the management of osteoporosis at the time of an incident fracture. This review will consider the treatment options after a fragility fracture. PMID- 21655931 TI - A review of osteoporosis diagnosis and treatment options in new and recently updated guidelines on case finding around the world. AB - Fracture rates are known to vary by more than an order of magnitude worldwide; therefore, a single approach cannot be universally applied to all countries. National considerations must reflect the burden of osteoporosis, available resources, the disease costs to the individual and society, and how these relate to competing health and other societal priorities. Recent developments in terms of diagnosis, fracture risk prediction, and therapeutic options have prompted many countries to review and update their clinical practice guidelines (CPGs) for the prevention and management of osteoporosis intended for use in primary care in the general adult population. This paper reviews recently updated CPGs from the following countries: Australia, Belgium, Canada, Germany, the United Kingdom, and the United States. PMID- 21655932 TI - The role of falls in fracture prediction. AB - Close to 75% of hip and non-hip fractures occur among seniors age 65 years and older. Notably, the primary risk factor for a hip fracture is a fall, and over 90% of all fractures occur after a fall. Thus, critical for the understanding and prevention of fractures at later age is their close relationship with muscle weakness and falling. In fact, antiresorptive treatment alone may not reduce fractures among individuals 80 years and older in the presence of nonskeletal risk factors for fractures despite an improvement in bone metabolism. This article will review the epidemiology of falls, and their importance in regard to fracture risk. Finally, fall prevention strategies and how these translate into fracture reduction are evaluated based on data from randomized controlled trials. PMID- 21655933 TI - Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats. AB - Previous studies indicated aging results in the significant cardiac function decreasing and myocardial apoptosis increasing in normal humans or rats. Additionally, animal experiments demonstrated aging increased myocardial ischemia / reperfusion (MI/R)-induced apoptosis. However, whether more myocardial apoptosis happen in the old acute myocardial infarction (AMI) patients is unclear. Reperfusion injury-induced apoptosis is an important cause of heart failure. This study determined the effect of aging upon myocardial apoptosis and cardiac function in patients suffering AMI. All enrolled AMI patients received percutaneous coronary intervention therapy. Volunteers and AMI patients were assigned to four groups: adult (age <65, n = 24) volunteers, elderly (age >=65, n = 21) volunteers, adult (age <65, n = 29) AMI patients, and elderly (age >=65, n = 36) AMI patients. Blood samples were obtained from all study participants. Plasma apoptotic markers (soluble form of Fas, tumor necrosis factor alpha, and interleukin 6) levels were determined. Cardiac function was evaluated with echocardiogram and Killip class. Due to lack of a direct apoptotic assay method in live human subjects, an additional animal experiment was performed. Both young (2 months) and old (24 months) rats were subjected to 30-min myocardial ischemia and 3 (for TUNEL/caspase activity apoptotic assay) or 24-h (for cardiac function determination) reperfusion. Compared to adult patients, the elderly patients manifested decreased cardiac function and increased plasma apoptotic marker levels significantly. The animal experiment results (cardiac function and plasma apoptotic markers assays) were consistent with the human result data. Animal TUNEL staining and caspase activity measurement revealed a higher myocardial apoptotic ratio in the older rat group. Aging exacerbated MI/R injury in humans and rats. Differential myocardial apoptosis may play a vital role in mediating the observed effects. PMID- 21655934 TI - Patient education methods to support quality of life and functional ability among patients with schizophrenia: a randomised clinical trial. AB - PURPOSE: The aim of this study was to estimate the effectiveness of patient education methods on quality of life and functional impairment of patients with schizophrenia. METHODS: A multicentre, randomized controlled trial was carried out in two psychiatric hospitals in Finland from March 2005 to October 2007. A total of 311 patients with a diagnosis of schizophrenia, schizotypal disorder or delusional disorder were randomly allocated to computer-based patient education (n = 100), conventional education with standard leaflets (n = 106) and standard treatment (n = 105). Participants were followed up 12 months later. Primary outcome was quality of life (Q-LES-Q-SF) and secondary outcome was functional disability (SDS). Analysis was performed by intention-to-treat. This study is registered, number ISRCTN74919979. RESULTS: Patients' global quality of life improved and functional disability decreased significantly in all education groups over the follow-up time. There were no significant differences between groups in these outcomes. CONCLUSIONS: In light of the findings there is no evidence to support a particular education method as the best way to improve patients' quality of life or improve functional ability. On the other hand, no intervention was found to be harmful. Thus computer-based patient education may be a suitable alternative for some patients. While information technology will be more widely used in societies, computer-based intervention may be beneficial for some patients with serious mental disorders. PMID- 21655935 TI - A miRNA-492 binding-site polymorphism in BSG (basigin) confers risk to psoriasis in central south Chinese population. AB - Psoriasis (PS; MIM#177900) is a chronic inflammatory immune-mediated skin disorder. Although the disease is believed to be caused by a combination of genetic, immunologic and environmental factors, its complete etiology has not been fully understood. Here, we focused on the BSG (MIM#109480), a member of the immunoglobulin superfamily expressed ubiquitously in circulating immune cell populations. We observed that the expression level of BSG in PBMCs was elevated in psoriasis patients. To understand the underlying mechanism for this change, we genotyped the rs8259 T>A SNP located in the 3'UTR of the BSG gene from 668 psoriasis patients and 1,143 healthy controls. The rs8259 T allele was associated with significantly decreased psoriasis susceptibility (OR = 0.758, 95% CI 0.638 0.901, p = 0.002). Interestingly, the rs8259 polymorphism was located in a seed region for miR-492 binding. The miR-492 was able to bind to the BSG 3'UTR sequence bearing the rs8259 T allele as assayed by luciferase reporter gene assay. The substitution of T with A abolished miR-492 binding. BSG protein expression in PBMCs from patients carrying the rs8259 AA genotype was significantly higher than in those from patients carrying the rs8259 TT genotype. Our study suggests that miR-492 may physiologically suppress BSG expression and the BSG rs8259 polymorphism is associated with decreased psoriasis susceptibility through affecting miR-492 binding. PMID- 21655936 TI - The single active X in human cells: evolutionary tinkering personified. AB - All mammals compensate for sex differences in numbers of X chromosomes by transcribing only a single X chromosome in cells of both sexes; however, they differ from one another in the details of the compensatory mechanisms. These species variations result from chance mutations, species differences in the staging of developmental events, and interactions between events that occur concurrently. Such variations, which have only recently been appreciated, do not interfere with the strategy of establishing a single active X, but they influence how it is carried out. In an overview of X dosage compensation in human cells, I point out the evolutionary variations. I also argue that it is the single active X that is chosen, rather than inactive ones. Further, I suggest that the initial events in the process-those that precede silencing of future inactive X chromosomes-include randomly choosing the future active X, most likely by repressing its XIST locus. PMID- 21655937 TI - Can bone quality be predicted accurately by Singh index in patients with rheumatoid arthritis? AB - The aim of this study was to evaluate Singh index as a simple and inexpensive means of estimation of bone quality in patients with rheumatoid arthritis. Singh index evaluation was made on digital pelvis radiographs in 50 consecutive patients by three observers. Bone mineral density T scores of the spine and left proximal femur were assessed using dual energy X-ray absorptiometry. Singh index was correlated with densitometry measurements after grouping the patients as normal, osteopenia and osteoporosis. Intra- and interobserver agreements were evaluated by kappa correlations. Sensitivity, specificity, positive and negative predictive values and likelihood ratio's of Singh index were calculated. Both intra- and interobserver agreements were 0.71 (range, 0.69 to 0.72) on average. Singh index proved highly sensitive for the diagnosis of osteopenia at the proximal femur (91%) and spine (90%), whereas the specificity of Singh index for identifying of osteoporosis at the femoral neck (93%) and spine (91%) was higher than sensitivity. Predictive values for osteoporosis at the proximal femur and spine were acceptable and positive likelihood ratios of Singh index for osteopenia and osteoporosis at the proximal femur were 2.4 and 10.1, respectively. Singh index can identify osteoporosis with a high specificity in patients with rheumatoid arthritis. However, the patients who are graded as osteopenia by the Singh index should undergo further evaluation with dual energy X-ray absorptiometry. PMID- 21655939 TI - Association between mannose-binding lectin and interleukin-1 receptor antagonist gene polymorphisms and recurrent vulvovaginal candidiasis. AB - OBJECTIVE: The influence of functional polymorphisms in the genes coding for mannose-binding lectin (MBL) and interleukin-1 receptor antagonist (IL-1ra) on recurrent vulvovaginal candidiasis (RVVC) were examined in an urban Brazilian population. METHODS: DNA was isolated from buccal swabs of 100 women with RVVC and 100 control women and tested by gene amplification for a single nucleotide polymorphism in codon 54 of the MBL2 gene and for a length polymorphism in intron 2 of the IL1RN gene. Genotype and allele frequencies were compared between groups. RESULTS: The frequency of the variant MBL2 B allele, associated with reduced circulating and vaginal MBL concentrations, was 27.0% in RVVC and 8.5% in control women (p < .0001). The MBL2 B,B genotype was present in 12% of RVVC patients and 1% of controls (p = .0025). The IL1RN 2 allele frequency, associated with the highest level of unopposed IL-1beta activity, was 24.0% in RVVC and 23.4% in controls. The IL1RN genotype distribution was also similar in both groups. CONCLUSION: Carriage of the MBL2 codon 54 polymorphism, but not the IL1RN length polymorphism, predisposes to RVVC in Brazilian women. PMID- 21655938 TI - Mechanisms of risk and resilience in military families: theoretical and empirical basis of a family-focused resilience enhancement program. AB - Recent studies have confirmed that repeated wartime deployment of a parent exacts a toll on military children and families and that the quality and functionality of familial relations is linked to force preservation and readiness. As a result, family-centered care has increasingly become a priority across the military health system. FOCUS (Families OverComing Under Stress), a family-centered, resilience-enhancing program developed by a team at UCLA and Harvard Schools of Medicine, is a primary initiative in this movement. In a large-scale implementation project initiated by the Bureau of Navy Medicine, FOCUS has been delivered to thousands of Navy, Marine, Navy Special Warfare, Army, and Air Force families since 2008. This article describes the theoretical and empirical foundation and rationale for FOCUS, which is rooted in a broad conception of family resilience. We review the literature on family resilience, noting that an important next step in building a clinically useful theory of family resilience is to move beyond developing broad "shopping lists" of risk indicators by proposing specific mechanisms of risk and resilience. Based on the literature, we propose five primary risk mechanisms for military families and common negative "chain reaction" pathways through which they undermine the resilience of families contending with wartime deployments and parental injury. In addition, we propose specific mechanisms that mobilize and enhance resilience in military families and that comprise central features of the FOCUS Program. We describe these resilience enhancing mechanisms in detail, followed by a discussion of the ways in which evaluation data from the program's first 2 years of operation supports the proposed model and the specified mechanisms of action. PMID- 21655940 TI - Violence committed against migrants in transit: experiences on the Northern Mexican border. AB - Thousands of Mexican and Central American migrants converge at the Mexico-United States border. Undocumented migrants in transit to the United States are vulnerable due to their lack of access to health care and legal assistance. This study attempts to provide evidence on the violent-related consequences that migration has on migrants. A mixed-method study was conducted between April 2006 May 2007 in shelters in Baja California, Mexicali and Tijuana, Mexico. 22 in depth interviews were performed and fifteen hundred and twelve migrants responded a questionnaire. Results from both in-depth interviews and the analysis of the quantitative data shows the different types of violence experiences by migrants which include threats, verbal abuse, and arbitrary detention based on ethnicity, as well as assaults, beatings and sexual violence. It is crucial to stress the importance and the need to evidence the condition in which migrants' transit to the US and to effectively respond to the violence they experience. PMID- 21655941 TI - Does transinstitutionalization explain the overrepresentation of people with serious mental illnesses in the criminal justice system? AB - Although there is broad consensus that people with serious mental illnesses (SMI) are overrepresented in correctional settings, there is less agreement about the policy trends that may have created this situation. Some researchers and policymakers posit a direct link between deinstitutionalization and increased rates of SMI in jails and prisons, a phenomenon described as transinstitutionalization. Others offer evidence that challenges this hypothesis and suggest that it may be a reductionist explanation. This paper reviews claims from both sides of the debate, and concludes that merely increasing access to state psychiatric hospital beds would likely not reduce the number of people with SMI in jails and prisons. A more nuanced approach is recommended for explaining why people with SMI become involved in the criminal justice system and why developing effective strategies to divert them out of jails and prisons and into community-based treatment is needed to improve both their mental health and criminal justice outcomes. PMID- 21655942 TI - Stressors and barriers to using mental health services among diverse groups of first-generation immigrants to the United States. AB - This study examined stressors and barriers to using mental health services among first-generation immigrants in San Jose, California. Focus groups for 30 immigrants from Cambodia, Eastern Europe, Iran, Iraq, Africa, and Vietnam were audio-recorded, translated and transcribed. Two researchers coded the data and identified themes pertaining to mental health stressors and barriers. Six primary stressors were identified: economic, discrimination, acculturation due to language differences, enculturation, parenting differences, and finding suitable employment. Primary barriers included: stigma, lack of a perceived norm in country of origin for using mental health services, competing cultural practices, lack of information, language barriers, and cost. A conceptual model is presented that may be used to inform the design and implementation of mental health services for this population. PMID- 21655943 TI - Metal chelation therapy in rheumathoid arthritis: a case report. Successful management of rheumathoid arthritis by metal chelation therapy. AB - Toxic metals are involved in the pathogenesis of some neurodegenerative and vascular diseases and are known to impair the immune system functions. We report here the case of a patient affected by heavy metal intoxication, who had developed an autoimmune disease. There was evidence of aluminium, cadmium and lead intoxication in a 63-year old Italian woman affected by rheumatoid arthritis (RA). We treated the patient with calcium disodium edetate (EDTA) once a week for a year in order to remove traces of heavy metal intoxication. Oxidative status profile was carried out at the beginning and after 6 months' EDTA chelation. At the end of the treatment, the patient did not show any signs of metal intoxication, RA symptoms and oxidative status improved. PMID- 21655944 TI - Microbial biosensors for organophosphate pesticides. AB - Organophosphates, amongst the most toxic substance known, are used widely in agriculture around the world. Their extensive use, however, has resulted in their occurrence in the water and food supply threatening humans and animals. Therefore, there is a need for determination of these neurotoxic compounds sensitively, selectively, and rapidly in the field. The present work is a brief review on the recent advancements in amperometric, potentiometric, and optical biosensors using genetically engineered microorganisms expressing organophosphate hydrolyzing enzyme intracellularly or anchored on the cell surface for the detection of organophosphate pesticides. The benefits and limitations associated with such microbial biosensors are delineated. PMID- 21655945 TI - SWI/SNF chromatin remodeling complex: a new cofactor in reprogramming. AB - Induced pluripotent stem (iPS) cells can be derived from somatic cells. Four key factors are required in this process including Oct4, Sox2, Klf4 and c-Myc. Ectopic expression of these four factors in somatic cells leads to reprogramming. Recent studies show that the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex plays critical roles in reprogramming of somatic cells and maintaining the pluripotency of stem cells. The possible mechanism is that SWI/SNF enhances the binding activity of reprogramming factors to pluripotent gene promoters and thus increases the reprogramming efficiency. Here, we review these recent advances and discuss how SWI/SNF plays a role in reprogramming. Understanding this mechanism will be helpful to find out the detail of reprogramming, which may provide a new therapy in medical science by generating patient-specific pluripotent stem cells. PMID- 21655946 TI - Basement membrane matrix (BME) has multiple uses with stem cells. AB - The utilization of basement membrane matrix has helped to overcome many of the obstacles associated with stem cell research. Initially, there were several problems with investigating stem cells, including difficult extraction from tissues, the need for feeder layers, poor survival, minimal proliferation, limited differentiation in vitro, and inadequate survival when injected or transplanted in vivo. Given that the basement membrane is the first extracellular matrix that is produced by the developing embryo, it was quickly identified as an important factor for modulating stem cell behavior, and since then, basement membrane extract (BME) has been successfully employed in numerous methods as a substratum in vitro and as a bioactive support in vivo to overcome many of these problems. A thin BME coating is sufficient to maintain an undifferentiated phenotype during embryonic stem cell expansion, while a thick BME hydrogel may be employed to induce stem cell differentiation. BME also promotes stem cell survival for in vivo applications and provides a physiological environment for evaluating stem cell co-culture with other cell types. The present article provides a concise review of current methodologies utilizing BME for stem cell research. PMID- 21655947 TI - In vitro and in vivo pathogenicity of Salmonella enteritidis clinical strains isolated from North America. AB - Salmonella enteritidis is a leading cause of food-borne gastroenteritis worldwide. In this study, 48 strains of S. enteritidis isolated from clinical cases of salmonellosis in North America were tested for their virulence associated traits including cell invasiveness, biofilm, motility, presence of a virulence plasmid, and virulence in orally challenged mice. The majority of strains exhibited high invasiveness (n = 45), whereas only few strains (n = 3) exhibited low invasiveness. All low-invasive strains (100%, 3/3) were biofilm negative, whereas the distribution of biofilm positive and negative phenotypes among high-invasive strains was 53.4% (24/45) and 46.6% (21/45), respectively. The in vitro cell invasiveness was not associated with biofilm formation (Fisher's exact test, P = 0.23) or the presence of a spvB gene, a marker for the virulence-associated plasmid (Fisher's exact test, P = 1). There was no correlation between cell invasiveness and motility (Spearman's rank test, r = 0.15; P = 0.27). Virulence testing in orally challenged mice revealed that the low-invasive strains were as virulent as high-invasive strains, indicating that in vitro cell invasiveness did not correlate with in vivo virulence. In conclusion, we show that despite phenotypic diversity among clinical strains of S. enteritidis, the majority of strains are highly invasive in vitro and in vivo. PMID- 21655949 TI - Eosinophilic gastrointestinal disorders (EGID) with peripheral eosinophilia: a retrospective review at Mayo Clinic. AB - BACKGROUND AND AIMS: Hypereosinophilic syndrome (HES) is defined by significant eosinophilia (>1,500 eos/MUl), which often leads to end-organ damage/dysfunction. It is unclear if the presence of significant peripheral eosinophilia (>1,500 eos/MUl) indicates a more aggressive form of eosinophilic gastrointestinal disorder (EGID). METHODS: A database query of the Mayo Clinic Rochester electronic records (1995-2008) was performed using several search terms for eosinophilic gastrointestinal disease, and 161 records were reviewed. Patients under 18 years age, those without Mayo-reviewed pathology specimens, those with eosinophilic esophagitis only, and/or those with evidence of secondary etiologies for GI eosinophilia were excluded. A total of 39 were found to have primary EGID. We compared individuals with biopsy-proven primary EGID based on whether they had significant peripheral eosinophilia (>=1,500 eos/MUl) (group A) or not (group B). RESULTS: Group A tended to have more atopy (A: 12/15; B: 11/24; p = 0.03) and more extensive segmental involvement of the GI tract (p = 0.001). None with available studies had evidence of cardiac (A: 7/15; B: 6/24) or bone marrow (A: 10/15; B: 6/24) involvement. The two thromboembolic events in group A after diagnosis did not translate to significantly greater risk (HR = infinity, p = 0.13; group A vs. B). Doses of initial (A: 40 mg/day; B: 55 mg/day; p = 0.17) and maintenance prednisone (A; 8.75 mg/day; B: 7.5 mg/day; p > 0.90) were similar. Group A was significantly more likely to need maintenance prednisone (77 vs. 8%, p = 0.001), with a median treatment duration of 52 weeks. Recurrence of symptoms (and peripheral eosinophilia) during prednisone taper was common in both groups. Prednisone-sparing agents (hydroxyurea, imatinib mesylate, interferon (IFN) alpha2b, anti-interleukin (IL-5) monoclonal antibody) were more commonly used in group A (73 vs. 8%; p < 0.0001). CONCLUSIONS: EGID with peripheral eosinophilia >=1,500/MUl is associated with atopy, greater GI segmental involvement, and uncertain risk of thrombosis. The common use of long-term steroids and variable responsiveness to nonsteroidal agents, particularly in group A, underscores the need for targeted therapies. PMID- 21655948 TI - Mechanisms linking nonalcoholic fatty liver disease with coronary artery disease. AB - The most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is coronary artery disease (CAD), not chronic liver disease. Fatty liver increases cardiovascular risk by classical (dyslipidemia, hypertension, diabetes) and by less conventional mechanisms. Common pathways involved in the pathogenesis of fatty liver and CAD includes hepatic insulin resistance and sub clinical inflammation. The hepatic insulin resistance state of fatty liver infiltration is characterized by increased FFA, which causes lipotoxicity and impairs endothelium dependent vasodilatation, increases oxidative stress, and has a cardio toxic effect. Additional metabolic risk factors include leptin, adiponectin, pro inflammatory cytokines [such as IL-6, C-reactive protein and plasminogen activator inhibitor-1 (PAI-1)], which together lead to increased oxidative stress and endothelial dysfunction, finally promoting coronary artery disease (CAD). When classical risk factors are superimposed on fatty liver accumulation, they may further increase the new metabolic risk factors, exacerbating CAD. The clinical implication is that patients with NAFLD are at higher risk (steatohepatitis, diabetes, obesity, atherogenic dyslipidemia) and should undergo periodic cardiovascular risk assessment including the Framingham score, cardiac effort test, and measurement of intimae-media thickening of the carotids arteries. This may improve risk stratification for CAD. PMID- 21655950 TI - Heterogeneous genetic associations of nucleotide sequence variants with bone mineral density by gender. AB - We examined genetic associations of previously identified sequence variants with bone mineral density and their heterogeneity by gender. Large-scale cohort data were used including a total of 8,419 subjects (4,034 males and 4,385 females) from the Korean Association REsource (KARE) cohort. Bone speed of sound (SOS) values were measured at distal radius or mid-shaft tibia by quantitative ultrasound. Genotypic associations of SOS were tested with each of nucleotide sequence variants identified by previous studies. The genetic association analysis revealed that 2 out of 11 nucleotide sequence variants were associated with SOS (rs1721400, rs7776725, P < 7.58 * 10(-4)). Further analysis with partitioning data by gender showed that the mid-shaft tibia phenotypes were associated with the rs1721400 and rs7776725 in females (P < 3.79 * 10(-4)), but not in males (P > 3.79 * 10(-4)). The current study suggested female-specific associations of rs1721400 and rs7776725 with bone mineral density and heterogeneity of genetic association by skeletal site measured for bone mineral density. PMID- 21655951 TI - Heterologous virus-induced gene silencing as a promising approach in plant functional genomics. AB - VIGS (virus induced gene silencing) is considered as a powerful genomics tool for characterizing the function of genes in a few closely related plant species. The investigations have been carried out mainly in order to test if a pre-existing VIGS vector can serve as an efficient tool for gene silencing in a diverse array of plant species. Another route of investigation has been the constructing of new viral vectors to act in their hosts. Our approach was the creation of a heterologous system in which silencing of endogenous genes was achieved by sequences isolated from evolutionary remote species. In this study, we showed that a TRV-based vector cloned with sequences from a gymnosperm, Taxus baccata L. silenced the endogenous phytoene desaturase in an angiosperm, N. benthamiana. Our results showed that inserts of between 390 and 724 bp isolated from a conserved fragment of the Taxus PDS led to silencing of its homolog in tobacco. The real time analysis indicated that the expression of PDS was reduced 2.1- to 4.0-fold in pTRV-TbPDS infected plants compared with buffer treated plants. Once the best insert is identified and the conditions are optimized for heterologous silencing by pTRV-TbPDS in tobacco, then we can test if TRV can serve as an efficient silencing vector in Taxus. This strategy could also be used to silence a diverse array of genes from a wide range of species which have no VIGS protocol. The results also showed that plants silenced heterologously by the VIGS system a minimally affected with respect to plant growth which may be ideal for studying the genes that their complete loss of function may lead to decrease of plant growth or plant death. PMID- 21655953 TI - Complete sequence and gene organization of the mitochondrial genome of scaly sided merganser (Mergus squamatus) and phylogeny of some Anatidae species. AB - The scaly-sided merganser (Mergus squamatus) is an endangered bird species on the IUCN Red List with the estimated global population of less than 2,500 individuals at present. In the present study, we studied the complete mitochondrial genome (mtDNA) and the phylogenetic of M. squamatus by PCR amplification and GenBank data. The genome was 16,595 bp in length and contained 37 genes (13 protein coding genes, two rRNAs, and 22 tRNAs) and a non-coding control region (D-loop). All protein-coding genes of M. squamatus mtDNA start with a typical ATG codon, except ND1, COI, and COII uses GTG as their initial codon. TAA, T- and TAG as the terminate codon occurred very commonly in the sequence. All tRNA genes can be folded into canonical cloverleaf secondary structure except for tRNA(Ser) (AGY) and tRNA(Leu) (CUN), which lose ''DHU'' arm. The genome sequences had been deposited in GenBank under accession number HQ833701. Based on the concatenated nucleotide sequences of mtDNA genes (Cyt b and D-loop), we reconstructed phylogenetic trees and discussed the phylogenetic relationships among ten Anatidae species. The results are different from the present classification, and we support Lophodytes cucullatus and Mergullus albellus to be members of the genus Mergus. PMID- 21655952 TI - Functional polymorphism of cyclooxygenase-2 gene (G-765C) in chronic obstructive pulmonary disease patients. AB - Cyclooxygenase two (COX-2) is an important enzyme metabolizing arachidonic acid. In contrast to constitutive cyclooxygenase one (COX-1), COX-2 is induced by proinflammatory factors. Polymorphism -765 G/C in COX-2-encoding gene promoter is associated with development of Alzheimer's disease, depression, carcinoma of the pancreas in smokers, breast cancer and rheumatoid arthritis. It is interesting whether the -765 G/C polymorphism in COX-2-encoding gene promoter can be associated with COPD, a disease which is inflammatory in character. It is highly probable as the breast and pancreas cancers, whose associations with the analyzed polymorphism have been studied, are smoking-dependent tumors. Additionally, tobacco smoke has been demonstrated to induce COX-2 in the lungs. The study group consisted of 122 COPD patients (48 females, 74 males). The control group consisted of 149 healthy nonsmoking subjects (83 females, 66 males). Polymerase chain reaction/restriction fragment length polymorphism was used for genotyping. A statistically significant difference in genotype distribution was observed as a result of the comparison between healthy subjects and patients with COPD. The distribution of alleles in both groups conformed with Hardy-Weinberg equilibrium. In the group of COPD patients, GG allele was found in 79 subjects, GC in 36, and CC in 7 subjects (F = 0.094, P = 0.296927); in the control group, 73 subjects had GG allele, 68--GC and 8--CC (F = 0.12728, P = 0.120265). The allele frequency revealed differences between those groups, attaining the level of statistical significance (chi(2) = 29.043, df = 2, P = 0.0000. The carriers of -765 G allele are at 1.53-fold higher risk of developing COPD. The presence of GG genotype does not increase significantly the risk of the disease. It is also noteworthy that the carriers of CC or GC genotypes are at significantly lower risk of developing COPD than the group of subjects with GG genotype. PMID- 21655954 TI - Effects of RhebL1 silencing on the mTOR pathway. AB - The insulin/Ras Homolog Enriched in Brain (Rheb)/Mammalian Target of Rapamycin (mTOR) pathway has been implicated in a variety of cancers. The activation of mTOR is regulated by a small G-protein, Rheb1. In mammalian systems there are two Rheb genes--Rheb1 and RhebL1 (Rheb2). The two genes show high sequence homology, however it has yet to be determined whether they are redundant in function. In this study the contribution of RhebL1 toward the mTOR pathway was investigated by transient gene silencing in three cell lines-HEK293, HeLa, and NIH3T3. Both Rheb1 and RhebL1 genes were silenced individually as well as in combination using eleven commercially synthesized siRNAs. Results from cross reactivity experiments showed the silencing of Rheb1 and RhebL1 to be highly specific for their target gene. This is the first report of its kind to examine the function of the endogenous Rheb genes using single and dual silencing. Phosphorylation of the mTOR effector S6 was not affected by RhebL1 silencing as it was by Rheb1 silencing, suggesting for the first time that RhebL1 may be impacting the mTOR pathway in a different manner than Rheb1. PMID- 21655955 TI - The complete mitochondrial genome sequences of Chelodina rugosa and Chelus fimbriata (Pleurodira: Chelidae): implications of a common absence of initiation sites (O(L)) in pleurodiran turtles. AB - Within the order Testudines, while phylogenetic analyses have been performed on the suborder Cryptodira with complete mitochondrial genomes (mitogenomes), mitogenomic information from another important suborder Pleurodira has been inadequate. In the present study, complete mitochondrial DNA (mtDNA) sequences of two chelid turtles Chelodina rugosa and Chelus fimbriata were firstly determined, the lengths of which were 16,582 and 16,661 bp respectively. As the typical vertebrate mitogenome, both mtDNAs consist of 13 protein coding genes, 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and a long noncoding region (control region, CR). However, the initiation sites for light-strand replication (O(L)), which has been identified in all reported Cryptodire mitogenomes, were not found in the putative position of the two chelid turtles and African helmeted turtle Pelomedusa subrufa. The results suggested that the absence of mitogenomic initiation sites (O(L)) could be a characteristic of Pleurodira. Phylogenetic relationships of chelid turtles and other turtles were reconstructed using the reported mitogenomes. Both maximum likelihood (ML) and Bayesian inference (BI) analyses suggested the monophyly of Pleurodira and Cryptodira as well as a sister group relationship between the two chelid turtles with strong statistical support. This phylogenetic framework was also utilized to estimate divergence dates among lineages using relaxed-clock methods combined with fossil evidence. Divergence estimates revealed that genus Chelodina diverged from genus Chelus in Late Cretaceous (~83 million years ago (mya)), and the time is consistent with the vicariance of the fragments which was caused by Gondwana split. PMID- 21655956 TI - Diversity of killer cell immunoglobulin-like receptor genes in Southern Turkey. AB - Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activating receptors expressed by natural killer (NK) cells and regulate NK cells' activity. KIR genes are highly polymorphic markers, characterized by a wide diversity, and can therefore be considered as good population genetic markers. The aim of this study was to determine KIR gene frequencies, ratios of haplotypes and genotypes in Southern Turkey and also to compare the data with other worldwide populations studied previously. The study group consisted of 200 non-related individuals from Southern Turkey. The percentage of each KIR gene in the population group was determined by direct counting. Differences between populations in the distribution of each KIR gene and genotype profile were estimated by two-tailed Fisher Exact test. The most frequent non-framework KIR genes detected in Southern Turkey population were: KIR 2DL1 (97%), KIR 3DL1 (91%), KIR 2DS4 (92%) and the pseudogene 2DP1 (96%). Fourty different genotypes were found in 200 subjects and AA1 genotype was the most frequent (27%). Among 40 different genotypes, ten of these were described for the first time in this study and were added to the database ( http://www.allelefrequencies.net ) numerized as genotype ID from 400 to 409. Gene frequencies and found genotypes demonstrated similarity of Southern Turkey's KIR repertoire with the KIR repertoires of Middle East and European population. High variability seen in KIR genome in this region is thought to be formed as a result of migration and settlement of different civilizations in this region and heterogenity formed in time. PMID- 21655957 TI - A novel salt-inducible gene SbSI-1 from Salicornia brachiata confers salt and desiccation tolerance in E. coli. AB - Salicornia brachiata is one of the extreme salt tolerant plants and grows luxuriantly in coastal areas. Previously we have reported isolation and characterization of ESTs from S. brachiata with large number of unknown gene sequences. Reverse Northern analysis showed upregulation and downregulation of few unknown genes in response to salinity. Some of these unknown genes were made full length and their functional analysis is being tested. In this study, we have selected a novel unknown salt inducible gene SbSI-1 (Salicornia brachiata salt inducible-1) for the functional validation. The SbSI-1 (Gen-Bank accession number JF 965339) was made full length and characterized in detail for its functional validation under desiccation and salinity. The SbSI-1 gene is 917 bp long, and contained 437 bp 3' UTR, and 480 bp ORF region encoding 159 amino acids protein with estimated molecular mass of 18.39 kDa and pI 8.58. The real time PCR analysis revealed high transcript expression in salt, desiccation, cold and heat stresses. However, the maximum expression was obtained by desiccation. The ORF region of SbSI-1 was cloned in pET28a vector and transformed in BL21 (DE3) E. coli cells. The SbSI-1 recombinant E. coli cells showed tolerance to desiccation and salinity stress compared to only vector in the presence of stress. PMID- 21655958 TI - Glypican-3, a novel prognostic marker of hepatocellular cancer, is related with postoperative metastasis and recurrence in hepatocellular cancer patients. AB - Metastasis/recurrence has been the most fundamental characteristic of hepatocellular cancer (HCC) and the ultimate cause of most HCC-related deaths. However, there are still a limited number of reliable tumor markers that can be used to predict the possibility of metastasis/recurrence in an HCC patient after operation. Recently, much evidence has shown that glypican-3 (GPC3) can be a useful tool to identify the early development of HCC, but little research has been done to test its usefulness as a prognostic marker related to post-operative metastasis/recurrence in HCC patients. In this study, the expression of GPC3 and its relationship with clinicopathological factors were determined by immunohistochemical analysis in 61 primary HCC patients. The potential prognostic value of GPC3 was investigated by comparing the survival time between HCC patients with high and low GPC3 expression. The results demonstrated that GPC3 expression was closely related with metastasis/recurrence in an HCC patient who can receive the operation. The risk of metastasis/recurrence after surgery in an HCC patient with high GPC3 expression was increased to 3.214 as compared to that of an HCC patient with low GPC3 expression. Survival analysis showed that HCC patients with high GPC3 expression had a significantly shorter overall survival time than HCC patients with low GPC3 expression (P=0.003). Further, multivariate analysis showed that GPC3 expression was a significant, independent prognostic parameter (P=0.030) for HCC patients. Overall, the study indicates that GPC3 might be a valuable marker closely related with prognosis and post-operative metastasis/recurrence in HCC patients. PMID- 21655959 TI - Peroxisomal localisation of the final steps of the mevalonic acid pathway in planta. AB - In plants, the mevalonic acid (MVA) pathway provides precursors for the formation of triterpenes, sesquiterpenes, phytosterols and primary metabolites important for cell integrity. Here, we have cloned the cDNA encoding enzymes catalysing the final three steps of the MVA pathway from Madagascar periwinkle (Catharanthus roseus), mevalonate kinase (MVK), 5-phosphomevalonate kinase (PMK) and mevalonate 5-diphosphate decarboxylase (MVD). These cDNA were shown to functionally complement MVA pathway deletion mutants in the yeast Saccharomyces cerevisiae. Transient transformations of C. roseus cells with yellow fluorescent protein (YFP)-fused constructs reveal that PMK and MVD are localised to the peroxisomes, while MVK was cytosolic. These compartmentalisation results were confirmed using the Arabidopsis thaliana MVK, PMK and MVD sequences fused to YFP. Based on these observations and the arguments raised here we conclude that the final steps of the plant MVA pathway are localised to the peroxisome. PMID- 21655960 TI - Effort-reward imbalance and depression among private practice physicians. AB - PURPOSE: Current private practice physicians provide medical services in a harsh economic situation. The effort-reward imbalance (ERI) model puts its emphasis on an imbalance between high efforts spent and low rewards received in occupational life. ERI model includes three different reward factors from task to organizational levels. We examined whether ERI in terms of low organizational reward (poor prospective and job insecurity) could be the most relevant and strongly associated with depression among private practice physicians. METHODS: This is a cross-sectional questionnaire study of 1,103 private practice physicians who were currently working in clinical settings and completed the data of exposure and outcome. The study questionnaire was mailed to all the physicians listed as members of a local branch of the Japan Medical Association (n = 3,441) between November and December 2008. Outcomes were prevalence of depression as measured by the Center for Epidemiologic Studies Depression Scale and adjusted odds ratios (OR) of depression with respect to ERI. RESULTS: Fifty-seven percent of physicians were exposed to ERI, and 18% of the physicians were depressed. Logistic regression analyses revealed that ERI was significantly associated with depression (OR and 95% confidence interval = 3.57; 2.43-5.26). ERI with regard to organizational reward was most prevalent (60%) and had the strongest association with depression (5.14; 3.36-7.92). CONCLUSION: Predominant prevalence of ERI in terms of organizational level low reward and strong associations between the ERI component and depression suggests that countermeasures from social perspective are crucial. PMID- 21655961 TI - Multiple immunoassay systems are negatively interfered by circulating cardiac troponin I autoantibodies. AB - Circulating cardiac troponin I (cTnI) autoantibodies have recently been detected in more and more patients with myocardial injury. In the present study, a total of 121 patients with acute myocardial infarction (AMI) were screened for cTnI autoantibodies using an indirect ELISA. Positive results were further confirmed by Western blot analysis. As a result, 13 autoantibody-positive sera were identified, in which cTnI values detected by different immunoassay systems are very different. Further evaluation revealed low recovery in one of the 13 samples with the Access 2 system (Beckman Coulter, 2^ generation), one low and one moderate recovery sample with Architect i2000 (Abbott), one low and two moderate with AxSYM (Abbott), two low and three moderate with Dimension Xpand (Dade Behring, 2^ generation), and four low and one moderate with Vidas (bioMerieux). Our work demonstrates that circulating cTnI autoantibodies occur in part of patients with AMI and, for the first time to our knowledge, shows that these autoantibodies can result in considerable negative interference in all the five commonly used cTnI immunoassay systems, which may lead to incorrect diagnoses and following treatments. The indirect ELISA established in our laboratory is suitable for a rapid preliminary screening for cTnI autoantibody in clinical work. PMID- 21655963 TI - Spontaneous subclavian artery rupture in neurofibromatosis type I. PMID- 21655962 TI - A small pontine infarct on DWI as a lesion responsible for wall-eyed bilateral internuclear ophthalmoplegia syndrome. AB - A 64-year-old man presented with alternating exotropia and bilateral medial longitudinal fasciculus (MLF) syndrome known as wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome. Diffusion-weighted imaging showed a small localized lesion in the median dorsal pons, and high-resolution T2-weighted imaging revealed slight left deviation of the lesion. A small penetrating artery was assumed to be occluded at the level of the MLF decussation. The median dorsal pons appears to be a location for the lesions causing WEBINO syndrome. PMID- 21655964 TI - Yield of head CT in the alcohol-intoxicated patient in the emergency department. AB - We aimed to determine the yield of positive head computed tomography (CT) findings among suspected alcohol-intoxicated patients presenting to the emergency department (ED). Our secondary aim was to determine if elderly intoxicated patients were more likely to have an intracranial injury. We identified patients suspected of alcohol intoxication who underwent CT scanning in the ED over a 4 year period. Pre-determined data elements including demographics, diagnosis, and disposition were extracted using a pre-formatted data sheet by blinded abstractors. "Positive" CT was defined as evidence of any type of intracranial hemorrhage. A total of 2,671 subjects with suspected alcohol intoxication and a head CT were identified. Fifty out of the 2,671 (1.9%) had a positive CT. Among CT scans of elderly (>=60 years of age) subjects, 15/555 (2.7%, 95% CI = 1.4 4.1%) were positive compared with 35/2,116 (1.7%, 95% CI = 1.1-2.2%) among those <60 years of age (p = 0.11). The yield of positive head CT among alcohol intoxicated patients was low, at 1.9%. An age cutoff of 60 years in this population did not predict a significantly higher positive rate. PMID- 21655965 TI - Radiologists' performance in the diagnosis of acute intestinal ischemia, using MDCT and specific CT findings, using a variety of CT protocols. AB - The aim of this study was to evaluate the performance of radiologists in the diagnosis of acute intestinal ischemia using specific multi-detector CT findings. The abdominal CT scans of 90 patients were retrospectively reviewed by three radiologists: an abdominal imaging specialist, an experienced general radiologist, and a senior resident. Forty-seven patients had surgically proven intestinal ischemia and comprised the case group, while 43 patients had no evidence of intestinal ischemia at surgery and comprised the control group. Images were reviewed in a random and blinded fashion. Radiologists' performance in diagnosing bowel ischemia from other bowel pathologies was evaluated. The sensitivity, specificity, and accuracy for diagnosing bowel ischemia were 89%, 67%, and 79% for the abdominal imager; 83%, 67%, and 76% for the general radiologist; and 66%, 83%, and 74% for the senior resident, respectively. The calculated kappa value for inter-observer agreement regarding the presence of bowel ischemia was 0.79. CT findings that significantly distinguished bowel ischemia from other bowel pathologies were decreased or absent bowel wall enhancement, filling defect in the superior mesenteric artery, small bowel pneumatosis, and gas in the portal veins or superior mesenteric vein. For most of these signs, there was good inter-observer agreement. Radiologists' performance in diagnosing bowel ischemia is good, but lower than previously reported since a significant amount of cases are evaluated using a suboptimal CT technique. Radiologists' experience and expertise have an important impact on their performance. PMID- 21655966 TI - CT findings in a mixed-type acute gastric volvulus. PMID- 21655967 TI - Public health policy, evidence, and causation: lessons from the studies on obesity. AB - The paper addresses the question of how different types of evidence ought to inform public health policy. By analysing case studies on obesity, the paper draws lessons about the different roles that different types of evidence play in setting up public health policies. More specifically, it is argued that evidence of difference-making supports considerations about 'what works for whom in what circumstances', and that evidence of mechanisms provides information about the 'causal pathways' to intervene upon. PMID- 21655968 TI - Rotational alignment in total knee arthroplasty: intraoperative inter- and intraobserver reliability of Whiteside's line. AB - INTRODUCTION: Proper rotational alignment is a critical step of total knee arthroplasty. For intraoperative determination of femoral rotation, Whiteside suggests a perpendicular line to the axis of the center of the trochlea and the intercondylar notch (Whiteside's line). METHOD: In a prospective clinical study, the intraoperative position of Whiteside's line was measured in 30 patients with the help of a navigation system. RESULTS: Whiteside's line was 2.1 degrees +/- 1.5 degrees externally rotated compared to a navigation based computer calculated preliminary AP axis of the femur. The intraobserver-reliability after 3 repeated measurements each was 1.6 degrees for the senior surgeon and 1.4 degrees for the junior surgeon (p = 0.598, p = 0.968). The interobserver reliability between the measurements by the senior and junior surgeon was 1.4 degrees (p = 0.547). CONCLUSION: Navigated intraoperative measurements of Whiteside's line showed a high inter- and intraobserver reliability. Considering the variability between Whiteside's line and the transepicondylar axis, intraoperative assessment of both the methods is recommended. PMID- 21655969 TI - A meta-analysis of the fixed-bearing and mobile-bearing prostheses in total knee arthroplasty. AB - INTRODUCTION: We asked whether the mobile-bearing knee prostheses could offer clinical and radiographic advantages over the fixed-bearing knee prostheses. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis to evaluate the validity of this theory. We searched PubMed, EMBASE, Ovid and the Cochrane Central Register of Controlled Trials from January 1979 to June 2010 for randomized controlled studies comparing the effect of fixed- and mobile-bearing prostheses in TKA. We assessed the methodological quality of the studies and abstracted the relevant data independently. RESULTS: 15 studies involving 1,950 knees were identified in this analysis. No statistically significant difference was present in terms of KSS, patient preference, radiolucent line around implant and prosthesis-related complications as compared to the fixed- and mobile-bearing knee design. CONCLUSIONS: Theoretically, mobile-bearing implant design could improve clinical and radiographic outcomes as being compared to fixed-bearing implant design, but the anticipated effectiveness has not been implemented in the current clinical practice at mid-term follow up. PMID- 21655970 TI - A simple and safe technique for performing single-port laparoscopic resection of appendiceal mucocele. AB - We report a new method of performing single-port laparoscopic surgery for appendiceal mucocele. The key points of our technique are placing a 3/4 circumferential skin incision with multiple radial splits on the confine of the umbilicus, use of a "home-made" multichannel port system, and trimming the skin incision straight through the confine of the umbilicus at the time of wound closure. A 65-year-old woman with appendiceal mucocele, 80 mm in diameter, successfully underwent ileocecal resection by this procedure. She remains in good health without any wound complications 8 months postoperatively. PMID- 21655971 TI - Monocyte/macrophages promote vasculogenesis in choroidal neovascularization in mice by stimulating SDF-1 expression in RPE cells. AB - BACKGROUND: Monocyte-macrophages play important roles in choroidal neovascularization (CNV); however, the mechanism is unclear. This study investigated the effects of monocyte depletion on laser-induced CNV in mice, especially the involvement of bone marrow-derived cells (BMCs) and underlying molecular mechanisms. METHODS: Clodronate-liposomes (lip) were used to deplete monocytes and their effect on retinal pigmental epithelium (RPE) cells, endothelial cells, and BMCs was analyzed. Green fluorescent protein (GFP) chimeric mice were developed by transplanting bone marrow cells from GFP transgenic mice to C57BL/6 J mice. CNV was induced by laser photocoagulation. Chimeric mice were intravenously treated with clodronate-lip, PBS-lip or PBS, 1 day before and after lasering. Histopathological and choroidal flatmount analysis were performed to measure CNV severity and BMCs recruitment. BMCs expression of endothelial cell marker CD31 and vascular smooth muscle cell marker alpha-SMA in CNV were detected by immunofluorescence. Expression of stromal cell-derived factor-1 (SDF-1) protein in vivo was detected by immunofluorescence as well as ELISA assay. SDF-1 was also examined by RT-PCR and ELISA in a human monocytes-RPE cells co-culturing system. RESULTS: No valid evidence for the toxicity of clodronate-lip was found. Depletion led to significant inhibition of CNV and BMCs recruitment into laser spots on days 3 and 14, reduced BMC expression of CD31 and alpha-SMA on day 14, and decreased expression of SDF-1 in vivo on day 3. SDF-1 was mostly within and around the RPE cells in the laser lesion. SDF-1 was dramatically up-regulated in RPE cells after co-culturing with monocytes. CONCLUSIONS: Monocytes may promote experimental CNV, especially BMC contribution in mice, by promoting SDF-1 production in RPE cells. PMID- 21655972 TI - Distinct mechanisms for delimiting expression of four Caenorhabditis elegans transcription factor genes encoding activators or repressors. AB - Regulatory transcription factors operate in networks, conferring biological robustness that makes dissection of such gene control processes difficult. The nematode Caenorhabditis elegans is a powerful molecular genetic system that allows the close scrutiny needed to understand these processes in an animal, in vivo. Strikingly lower levels of gene expression were observed when a gfp reporter was inserted into C. elegans transcription factor genes, in their broader genomic context, in comparison to when the reporter was fused to just the promoter regions. The lower level of expression is more consistent with endogenous levels of the gene products, based on independent protein and transcript assays. Through successive precise manipulations of the reporter fusion genes, elements essential for the lower level of expression were localised to the protein-coding region. With a closer focus on four transcription factor genes, the expression of both genes encoding transcriptional activators was found to be restricted by a post-transcriptional mechanism while expression of both genes encoding transcriptional repressors was delimited by transcriptional repression. An element through which the transcriptional repression acts for unc 4 was localised to a 30 base-pair region of a protein-encoding exon, with potentially wider implications for how homeobox genes operate. The hypothesis that the distinction in mechanisms delimiting expression of the two types of transcription factor genes, as observed here, may apply more widely is raised. This leads to observations concerning the implications of these different mechanisms on stochastic noise in gene expression and the consequent significance for developmental decisions in general. PMID- 21655973 TI - Endoscopic double-metallic stenting for malignant biliary and duodenal obstructions. AB - BACKGROUND: Endoscopic metallic stenting is a safe, effective treatment for malignant biliary obstructions, but can be technically difficult when combined malignant biliary and duodenal obstructions exist. Available duodenal metallic stents feature a tight mesh unsuitable for transpapillary biliary stenting. We evaluated the feasibility and usefulness of new endoscopic procedures for endoscopic double-stent placement in managing such obstructions. METHODS: The through-the-scope duodenal metallic stent has a central cross-wired, unfixed structure that allows insertion of the biliary stent through the mesh wall of a duodenal stent. Transpapillary endoscopic placement of a biliary stent was performed through the lumen of this duodenal stent. Endoscopic ultrasound (EUS) guided biliary drainage was performed successfully through the duodenal bulb after puncturing with a 19G needle. Biliary metallic stenting through the choledochoduodenal tract and effective drainage were achieved. CONCLUSIONS: Use of a combined endoscopic biliary and duodenal stent inserted through the mesh of the new duodenal metallic stent is feasible and effective in managing the aforementioned obstructions. EUS-guided biliary metal stenting is a therapeutic option for endoscopic management when a failed transpapillary approach through the lumen of the duodenal stent occurs. The continued development of endoscopic procedures and devices should resolve issues associated with complicated strictures. PMID- 21655974 TI - Preoperative biliary drainage for hilar cholangiocarcinoma: which stent should be selected? AB - The controversy over whether and how to perform preoperative biliary drainage (PBD) in patients with hilar cholangiocarcinoma (HCA) remains unsettled. Arguments against PBD before pancreatoduodenectomy have recently been gaining momentum. However, the complication-related mortality rate is as high as 10% for patients with HCA who have undergone major liver resection, and liver failure is a major cause of postoperative death. This suggests the need for PBD to treat jaundice in HCA patients scheduled for major surgical resection of the liver and that major surgery should be performed only after the recovery of hepatic function. No definite criteria or guidelines outlining indications for PBD are currently available. In patients with HCA, PBD may be performed by either percutaneous transhepatic biliary drainage (PTBD) or endoscopic biliary drainage (EBD). No consensus, however, has been reached regarding which drainage method is more appropriate. No reported study has compared the effectiveness of PTBD, endoscopic biliary stenting (EBS), and endoscopic nasobiliary drainage (ENBD) in patients with HCA. This review summarizes the results of our study comparing the three methods and outlines the preoperative endoscopic management of segmental cholangitis (SC) in HCA patients undergoing PBD. PMID- 21655975 TI - Microarray analysis of differentially expressed microRNAs in non-regressed and regressed bovine corpus luteum tissue; microRNA-378 may suppress luteal cell apoptosis by targeting the interferon gamma receptor 1 gene. AB - MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules that down regulate the expression of target genes in a sequence-dependent manner. Recent studies indicated that miRNAs are mechanistically involved in the regulation of the mammalian corpus luteum (CL). However, few studies have profiled the different miRNA expression patterns in bovine non-regressed and regressed CL. In this study, miRNA microarray was employed to investigate the different miRNA expression patterns in bovine CL. Among the 13 differentially expressed miRNAs, seven were preferentially expressed in non-regressed CL, while six miRNAs were more highly expressed in regressed CL. Real-time RT-PCR was used to validate the microarray results. Mir-378 miRNA, known to be associated with apoptosis, was 8.54-fold (P < 0.01) up-regulated in non-regressed CL, and the interferon gamma receptor 1 (IFNGR1) gene, which potentially plays a role in apoptosis of the luteal cell, was predicted to be the target of mir-378. The results of real-time RT-PCR of mir-378 and western blot analysis of the IFNGR1 protein at different stages of CL development showed that mir-378 decreased the expression of IFNGR1 protein but not IFNGR1 mRNA. Taken together, our data support a direct role for miRNA in apoptosis of bovine CL. PMID- 21655977 TI - Satisfactory urethral coitus in a patient with vaginal stenosis: case report. AB - Urethral coitus is a very rare sexual disorder seen in women either with intact or anomalous vagina such as vaginal agenesis or imperforate hymen. Only about 25 cases have been reported in the literature. We report a case of urethral coitus in a patient with surgically corrected ambiguous genitalia due to congenital adrenal hyperplasia. The patient had megalourethra and stenotic vaginal introitus. Megalourethra was corrected by plication technique. Correction of megalourethra with this technique has not been reported in literature up to now. To the best of our knowledge, the present case is the 26th of total cases with urethral coitus reported so far and the first case of urethral coitus associated with a stenotic vaginal introitus developing due to surgically corrected ambiguous genitalia. PMID- 21655978 TI - Obturator artery revisited. AB - INTRODUCTION AND HYPOTHESIS: The aim of this work is to analyse the variability of the obturator artery (oa), unify previous criteria and propose a simple classification for clinical use. METHODS: A sample of 119 adult human embalmed cadavers was used. Origin and course of the oa in relation with the external iliac artery, internal iliac artery and inferior epigastric artery were studied. Chi-squared and t test were used for statistical comparison, and p < 0.05 was considered significant. RESULTS: Based on the number of roots of origin, three different situations were observed. The oa shows a single origin (96.55%). The oa presents a double origin (3.02%), or the oa arises from three roots (0.43%). The first situation was subclassified into six types according to the oa origin. Equal vascular pattern in both hemi-pelvises was observed in 58.93%. CONCLUSIONS: Almost 31% of oa passes over the superior pubic ramus implying an increased risk during some procedures. PMID- 21655979 TI - Application of immobilized thrombin for production of S-thanatin expressed in Escherichia coli. AB - S-thanatin, a small antimicrobial peptide with 21 amino acid residues, was expressed as a fusion protein containing thrombin cleavage site in Escherichia coli BL21 (DE3). To reduce the production cost, immobilization of thrombin in polyacrylamide gel for cleavage was studied in this work. The immobilized thrombin exhibited excellent activity within wider ranges of pH value and temperature for reaction than free enzyme, and the residual activity could remain above 75% after ten times of usage. Tricine-SDS-PAGE result showed that the immobilized thrombin could cleave the S-thanatin fusion protein effectively. After cleavage, recombinant S-thanatin was purified by preparative reversed-phase high-performance liquid chromatography and mass spectrum showed that the molecular weight (2,448.86) was close to the theoretical value (2,448.98). After purification, about 7 mg of S-thanatin was obtained from 1 l of culture and the recombinant exhibited excellent bioactivity to E. coli ATCC 25922, with the minimum inhibitory concentration of 12 MUg/ml. The purification method could be applied to prepare other peptides with similar properties at low cost. PMID- 21655980 TI - Microbial metabolism and biotechnological production of D-allose. AB - D-allose has attracted a great deal of attention in recent years due to its many pharmaceutical activities, which include anti-cancer, anti-tumor, anti inflammatory, anti-oxidative, anti-hypertensive, cryoprotective, and immunosuppressant activities. D-allose has been produced from D-psicose using D allose-producing enzymes, including L-rhamnose isomerase, ribose-5-phosphate isomerase, and galactose-6-phosphate isomerase. In this article, the properties, applications, and metabolism of D-allose are described, and the biochemical properties of D-allose-producing enzymes and their D-allose production are reviewed and compared. Moreover, several methods for effective D-allose production are suggested herein. PMID- 21655981 TI - Molecular determinants of azo reduction activity in the strain Pseudomonas putida MET94. AB - Azo dyes are the major group of synthetic colourants used in industry and are serious environmental pollutants. In this study, Pseudomonas putida MET94 was selected from 48 bacterial strains on the basis of its superior ability to degrade a wide range of structurally diverse azo dyes. P. putida is a versatile microorganism with a well-recognised potential for biodegradation or bioremediation applications. P. putida MET94 removes, in 24 h and under anaerobic growing conditions, more than 80% of the majority of the structurally diverse azo dyes tested. Whole cell assays performed under anaerobic conditions revealed up to 90% decolourisation in dye wastewater bath models. The involvement of a FMN dependent NADPH: dye oxidoreductase in the decolourisation process was suggested by enzymatic measurements in cell crude extracts. The gene encoding a putative azoreductase was cloned from P. putida MET94 and expressed in Escherichia coli. The purified P. putida azoreductase is a 40 kDa homodimer with broad substrate specificity for azo dye reduction. The presence of dioxygen leads to the inhibition of the decolourisation activity in agreement with the results of cell cultures. The kinetic mechanism follows a ping-pong bi-bi reaction scheme and aromatic amine products were detected in stoichiometric amounts by high performance liquid chromatography. Overall, the results indicate that P. putida MET94 is a promising candidate for bioengineering studies aimed at generating more effective dye-reducing strains. PMID- 21655982 TI - Application of real-time PCR in the assessment of the toxic cyanobacterium Cylindrospermopsis raciborskii abundance and toxicological potential. AB - Cyanobacteria are prokaryotic photosynthetic microorganisms that pose a serious threat to aquatic environments because they are able to form blooms under eutrophic conditions and produce toxins. Cylindrospermopsis raciborskii is a planktonic heterocystous filamentous cyanobacterium initially assigned to the tropics but currently being found in more temperate regions such as Portugal, the southernmost record for this species in Europe. Cylindrospermopsin originally isolated from C. raciborskii is a cytotoxic alkaloid that affects the liver, kidney, and other organs. It has a great environmental impact associated with cattle mortality and human morbidity. Aiming in monitoring this cyanobacterium and its related toxin, a shallow pond located in the littoral center of Portugal, Vela Lake, used for agriculture and recreational purposes was monitored for a 2 year period. To accomplish this, we used the real-time PCR methodology in field samples to quantify the variation of specific genetic markers with primers previously described characterizing total cyanobacteria (16S rRNA), C. raciborskii (rpoC1), and cylindrospermopsin synthetase gene (pks). The results report the high abundance of both cyanobacteria and C. raciborskii in Vela Lake, with C. raciborskii representing 0.4% to 58% of the total cyanobacteria population. Cylindrospermopsin synthetase gene was detected in one of the samples. We believe that with the approach developed in this study, it will be possible to monitor C. raciborskii population dynamics and seasonal variation, as well as the potential toxin production in other aquatic environments. PMID- 21655983 TI - High-level production of poly (beta-L: -malic acid) with a new isolated Aureobasidium pullulans strain. AB - Poly (beta-L: -malic acid) (PMLA) is a water-soluble polyester with many attractive properties in chemical industry and medicine development. However, the low titer of PMLA in the available producer strains limits further industrialization efforts and restricts its many potential applications. In order to solve this problem, a new strain with the distinguished high productivity of PMLA was isolated from fresh plants samples. It was characterized as the candidate of Aureobasidium pullulans based on the morphology and phylogenetic analyses of the internal transcribed spacer sequences. After the optimization of culture conditions, the highest PMLA concentration (62.27 g l(-1)) could be achieved in the shake flask scale. In addition, the contribution of the carbon flux to exopolysaccharide (EPS) and PMLA could be regulated by the addition of CaCO3 in the medium. This high-level fermentation process was further scaled up in the 10 l benchtop fermentor with a high PMLA concentration (57.2 g l(-1)) and productivity (0.35 g l(-1) h(-1)), which are the highest level in all the literature. Finally, the suitable acid hydrolysis conditions of PMLA were also investigated with regard to the production of L: -malic acid, and the kinetics of PMLA acid hydrolysis was modeled to simulate the whole degradation process. The present work paved the road to produce this multifunctional biomaterial (PMLA) at industrial scale and promised one alternative method to produce L: -malic acid in the future. PMID- 21655984 TI - Characterization of the mannitol catabolic operon of Corynebacterium glutamicum. AB - Corynebacterium glutamicum encodes a mannitol catabolic operon, which comprises three genes: the DeoR-type repressor coding gene mtlR (sucR), an MFS transporter gene (mtlT), and a mannitol 2-dehydrogenase gene (mtlD). The mtlR gene is located upstream of the mtlTD genes in the opposite orientation. In spite of this, wild type C. glutamicum lacks the ability to utilize mannitol. This wild-type phenotype results from the genetic regulation of the genes coding for mannitol transport and catalytic proteins mediated by the autoregulated MtlR protein since mtlR mutants grow on mannitol as the sole carbon source. MtlR binds to sites near the mtlR (two sites) and mtlTD promoters (one site downstream of the promoter), with the consensus sequence 5'-TCTAACA-3' being required for its binding. The newly discovered operon comprises the three basic functional elements required for mannitol utilization: regulation, transport, and metabolism to fructose, further processed to the common intermediate of glycolysis fructose-6-phosphate. When relieved from MtlR repression, C. glutamicum, which lacks a functional fructokinase, excretes the fructose derived from mannitol and imports it by the fructose-specific PTS. In order to use mannitol from seaweed biomass hydrolysates as a carbon source for the production of useful commodity chemicals and materials, an overexpression system using the tac promoter was developed. For congruence with the operon, we propose to rename sucR as the mtlR gene. PMID- 21655985 TI - A combined approach of classical mutagenesis and rational metabolic engineering improves rapamycin biosynthesis and provides insights into methylmalonyl-CoA precursor supply pathway in Streptomyces hygroscopicus ATCC 29253. AB - Rapamycin is a macrocyclic polyketide with immunosuppressive, antifungal, and anticancer activity produced by Streptomyces hygroscopicus ATCC 29253. Rapamycin production by a mutant strain (UV2-2) induced by ultraviolet mutagenesis was improved by approximately 3.2-fold (23.6 mg/l) compared to that of the wild-type strain. The comparative analyses of gene expression and intracellular acyl-CoA pools between wild-type and the UV2-2 strains revealed that the increased production of rapamycin in UV2-2 was due to the prolonged expression of rapamycin biosynthetic genes, but a depletion of intracellular methylmalonyl-CoA limited the rapamycin biosynthesis of the UV2-2 strain. Therefore, three different metabolic pathways involved in the biosynthesis of methylmalonyl-CoA were evaluated to identify the effective precursor supply pathway that can support the high production of rapamycin: propionyl-CoA carboxylase (PCC), methylmalonyl-CoA mutase, and methylmalonyl-CoA ligase. Among them, only the PCC pathway along with supplementation of propionate was found to be effective for an increase in intracellular pool of methylmalonyl-CoA and rapamycin titers in UV2-2 strain (42.8 mg/l), indicating that the PCC pathway is a major methylmalonyl-CoA supply pathway in the rapamycin producer. These results demonstrated that the combined approach involving traditional mutagenesis and metabolic engineering could be successfully applied to the diagnosis of yield-limiting factors and the enhanced production of industrially and clinically important polyketide compounds. PMID- 21655986 TI - Overexpression and biochemical characterization of DagA from Streptomyces coelicolor A3(2): an endo-type beta-agarase producing neoagarotetraose and neoagarohexaose. AB - The DagA product of Streptomyces coelicolor is an agarase with a primary translation product (35 kDa) of 309 amino acids, including a 30-amino acid signal peptide. Although dagA expression in Streptomyces lividans under the control of its own set of promoters was previously reported, its enzymatic properties have never been elucidated. To develop an improved expression system for dagA, three types of strong promoters for the Streptomyces host were linked to dagA, and their efficiencies in DagA production were compared in S. lividans TK24. All of the transformants with dagA grew at improved rates and produced larger amounts of DagA in the modified R2YE medium containing 0.5% agar as the sole carbon source. Of the three transformants, the S. lividans TK24/pUWL201-DagA (ermE promoter) produced the highest agarase activity (A (540)=4.24), and even the S. lividans TK24/pHSEV1-DagA (tipA promoter) and S. lividans TK24/pWHM3-DagA (sprT promoter) produced higher agarase activity (A (540)=0.24 and 0.12, respectively) than the control (A (540)=0.01) in the modified R2YE medium. The mature form of DagA protein (32 kDa) was successfully purified by one-step affinity column chromatography by using agarose beads with excellent yield. The purified DagA was found to exhibit maximal agarase activity at 40 degrees C and pH 7.0. The K(m), V(max), and K(cat) values for agarose were 2.18 mg/ml (approximately 1.82 * 10( 5) M), 39.06 U/mg of protein, and 9.5 * 10(3)/s, respectively. Thin layer chromatography (TLC) analysis, matrix-assisted laser desorption/ionization-time of-flight (MALDI-TOF) mass spectrometry, and Fourier transform nuclear magnetic resonance (FT-NMR) spectrometry of the hydrolyzed products of agarose by DagA revealed that DagA is an endo-type beta-agarase that degrades agarose into neoagarotetraose and neoagarohexaose. PMID- 21655987 TI - Xylitol does not inhibit xylose fermentation by engineered Saccharomyces cerevisiae expressing xylA as severely as it inhibits xylose isomerase reaction in vitro. AB - Efficient fermentation of xylose, which is abundant in hydrolysates of lignocellulosic biomass, is essential for producing cellulosic biofuels economically. While heterologous expression of xylose isomerase in Saccharomyces cerevisiae has been proposed as a strategy to engineer this yeast for xylose fermentation, only a few xylose isomerase genes from fungi and bacteria have been functionally expressed in S. cerevisiae. We cloned two bacterial xylose isomerase genes from anaerobic bacteria (Bacteroides stercoris HJ-15 and Bifidobacterium longum MG1) and introduced them into S. cerevisiae. While the transformant with xylA from B. longum could not assimilate xylose, the transformant with xylA from B. stercoris was able to grow on xylose. This result suggests that the xylose isomerase (BsXI) from B. stercoris is functionally expressed in S. cerevisiae. The engineered S. cerevisiae strain with BsXI consumed xylose and produced ethanol with a good yield (0.31 g/g) under anaerobic conditions. Interestingly, significant amounts of xylitol (0.23 g xylitol/g xylose) were still accumulated during xylose fermentation even though the introduced BsXI might not cause redox imbalance. We investigated the potential inhibitory effects of the accumulated xylitol on xylose fermentation. Although xylitol inhibited in vitro BsXI activity significantly (K(I) = 5.1 +/- 1.15 mM), only small decreases (less than 10%) in xylose consumption and ethanol production rates were observed when xylitol was added into the fermentation medium. These results suggest that xylitol accumulation does not inhibit xylose fermentation by engineered S. cerevisiae expressing xylA as severely as it inhibits the xylose isomerase reaction in vitro. PMID- 21655988 TI - Species and material considerations in the formation and development of microalgal biofilms. AB - The development of microalgal biofilms has received very limited study despite its relevance in the design of photobioreactors where film growth may be advantageous for biomass separation or disadvantageous in fouling surfaces. Here, the effects of species selection, species control, and substrate properties on biofilms of Scenedesmus obliquus and Chlorella vulgaris were investigated. Experiments were conducted in batch culture and in continuous culture modes in a flow cell. Cell growth was monitored using confocal laser scanning microscopy and gravimetrically. Species selection and species control had significant effects on biofilm development. On non-sterile wastewater, C. vulgaris shifted from primarily planktonic (23.7% attachment) to primarily sessile (79.8% attachment) growth. The biofilms that developed in non-sterile conditions were thicker (52 +/ 19 MUm) than those grown in sterile conditions (7 +/- 6 MUm). By contrast, S. obliquus attained similar thicknesses (54 +/- 31 and 53 +/- 38 MUm) in both sterile and non-sterile conditions. Neither species was able to dominate a non sterile biofilm. The effect of substrate surface properties was minimal. Both species grew films of similar thickness (approximately 30 MUm for S. obliquus, < 10 MUm for C. vulgaris) on materials ranging from hydrophilic (glass) to hydrophobic (polytetrafluoroethylene). Surface roughness created by micropatterning the surface with 10 MUm grooves did not translate into long-term increases in biofilm thickness. The results indicate that species selection and control are more important than surface properties in the development of microalgal biofilms. PMID- 21655989 TI - The earwax-associated SNP c.538G>A (G180R) in ABCC11 is not associated with breast cancer risk in Europeans. AB - Genetic polymorphisms of human ABC-transporter genes have been suggested to modulate breast cancer risk in the general population. In particular ABCC11 (MRP8), which is highly expressed in breast cancer tissue and involved in the efflux of conjugated estrogen metabolites such as estrone-3-sulfate and estradiol 17beta-glucuronide, has recently been proposed as a potential risk factor for female breast cancer. The wet earwax-associated G-allele of the c.538G>A polymorphism was associated with an increased risk for breast cancer in Japanese women. In contrast, no evidence for such an association could be observed in Caucasian women. We aimed to confirm/refute the association of the c.538G>A variant in ABCC11 with breast cancer risk and/or histo-pathological tumor characteristics in an independent population-based breast cancer case-control study from Germany comprising 1021 cases and 1015 age-matched controls. No association for allele and genotype frequencies of the 538G>A variant in ABCB11 with breast cancer risk was found. Our data suggest that the c.538G>A variation in ABCC11 does not contribute to breast carcinogenesis in women of European descent. PMID- 21655990 TI - Evidence for biological effects of metformin in operable breast cancer: a pre operative, window-of-opportunity, randomized trial. AB - Metformin may reduce the incidence of breast cancer and enhance response to neoadjuvant chemotherapy in diabetic women. This trial examined the effects of metformin on Ki67 and gene expression in primary breast cancer. Non-diabetic women with operable invasive breast cancer received pre-operative metformin. A pilot cohort of eight patients had core biopsy of the cancer at presentation, a week later (without treatment; internal control), then following metformin 500-mg o.d. for 1 week increased to 1-g b.d. for a further week continued to surgery. A further 47 patients had core biopsy at diagnosis were randomized to metformin (the same dose regimen) or no drug, and 2 weeks later had core biopsy at surgery. Ki67 immunohistochemistry, transcriptome analysis on formalin-fixed paraffin embedded cores and serum insulin determination were performed blinded to treatment. Seven patients (7/32, 21.9%) receiving metformin withdrew because of gastrointestinal upset. The mean percentage of cells staining for Ki67 fell significantly following metformin treatment in both the pilot cohort (P = 0.041, paired t-test) and in the metformin arm (P = 0.027, Wilcoxon rank test) but was unchanged in the internal control or metformin control arms. Messenger RNA expression was significantly downregulated by metformin for PDE3B (phosphodiesterase 3B, cGMP-inhibited; a critical regulator of cAMP levels that affect activation of AMP-activated protein kinase, AMPK), confirmed by immunohistochemistry, SSR3, TP53 and CCDC14. By ingenuity pathway analysis, the tumour necrosis factor receptor 1 (TNFR1) signaling pathway was most affected by metformin: TGFB and MEKK were upregulated and cdc42 downregulated; mTOR and AMPK pathways were also affected. Gene set analysis additionally revealed that p53, BRCA1 and cell cycle pathways also had reduced expression following metformin. Mean serum insulin remained stable in patients receiving metformin but rose in control patients. This trial presents biomarker evidence for anti-proliferative effects of metformin in women with breast cancer and provides support for therapeutic trials of metformin. PMID- 21655991 TI - No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid. AB - PURPOSE: To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers. METHODS: In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1*1A/*1A genotype, seven with the *1B/*1B genotype, and five with the *15/*15 or *5/*15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography-tandem mass spectrometry. RESULTS: The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC(0-12)) in subjects with the SLCO1B1*1B/*1B genotype and in subjects with the SLCO1B1*15/*15 or *5/*15 genotype to the AUC(0-12) in subjects with the SLCO1B1*1A/*1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC(0-24) of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC(0-24) of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC(0-24) of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold (P < 0.05), respectively. CONCLUSIONS: Genetic polymorphism in SLCO1B1 does not affect pharmacokinetics of UDCA, suggesting that OATP1B1 is not rate-limiting to the hepatic uptake of therapeutic UDCA. Further studies are required to clarify the mechanisms by which UDCA increases the plasma concentrations of endogenous bile acids. PMID- 21655992 TI - Prescribed drugs and violence: a case/noncase study in the French PharmacoVigilance Database. AB - AIM: Our aim was to identify prescribed drugs associated with violent behaviours using the French PharmacoVigilance Database (FPVD). METHODS: All reports of adverse drug reactions (ADR) recorded in the FPVD between 1 January 1985 and 31 July 2008 and including the terms aggressiveness or violence were selected. We compared proportion of exposure to different drugs between cases (reports with violence) and noncases (other reports in the database). RESULTS: Among 537 cases, 56 were included (48 men, mean age 46 years). Misuse was observed in ten cases (18%). In 25 cases (44.6%), a previous psychiatric history was documented. Main drugs involved were nervous system (63.6%) followed by respiratory (7.8%), alimentary tract and metabolism (7.8%), dermatological (5.2%) and anti-infective (5.2%) agents. Case/noncase analysis found an association with dopaminergic agonists (pergolide, pramipexole, bromocriptine, piribedil), benzodiazepines (alprazolam, bromazepam) and serotoninergic antidepressants (taken as a whole), but not antipsychotics or antiepileptics. Association was also found with varenicline, isotretinoin, interferon alpha-2b, rimonabant, benfluorex, topiramate and antiviral drugs (ribavirin, efavirenz). CONCLUSION: Dopaminergic agonists, benzodiazepines and serotoninergic antidepressants are the main pharmacological classes able to induce aggressive behaviour. This study also emphasises the putative role of other drugs less known to be involved in such ADR. PMID- 21655993 TI - The impact of high-dose statin therapy on transendothelial neutrophil migration and serum cholesterol levels in healthy male volunteers. AB - RATIONALE: Cardiac surgery presents a risk to all major organs due to activation of the systemic inflammatory response. Patients referred for cardiac surgery are typically older, usually have comorbid conditions, and are thus at higher risk of postoperative multiorgan dysfunction. Patients demonstrating evidence of organ dysfunction require intensive postoperative management. Any means to predict and reduce the inflammatory response mounted postcardiac surgery could translate into a clinical benefit for the patient and reduce the length of stay in intensive care. OBJECTIVE: Statins are commonly used to prevent primary and secondary cardiovascular disease through their cholesterol-lowering effects. However, they have been shown to have anti-inflammatory properties, which may help reduce postoperative mortality and morbidity for patients undergoing cardiac surgery. The purpose of this study was to analyze the in vivo effects of high-dose atorvastatin (statin) on ex vivo neutrophil migration in healthy volunteers. METHODS: Thirteen healthy male volunteers consented and were placed on high-dose (40 mg) statin therapy for 2 weeks. At week 0 and week 2, full blood count, liver function, serum cholesterol and creatine kinase were assessed, as was neutrophil migration. RESULTS: Neutrophil migration of healthy volunteers was significantly reduced after 2 weeks of high-dose statin therapy (p = 0.002), as was serum cholesterol (p <0.001). There was no change in liver function during statin treatment. CONCLUSION: Statins have an established role as cholesterol-lowering agents, and this study demonstrates that they also potentially have an anti inflammatory effect in healthy male volunteers. PMID- 21655994 TI - Genetic analysis of resistance to septoria tritici blotch in the French winter wheat cultivars Balance and Apache. AB - The ascomycete Mycosphaerella graminicola is the causal agent of septoria tritici blotch (STB), one of the most destructive foliar diseases of bread and durum wheat globally, particularly in temperate humid areas. A screening of the French bread wheat cultivars Apache and Balance with 30 M. graminicola isolates revealed a pattern of resistant responses that suggested the presence of new genes for STB resistance. Quantitative trait loci (QTL) analysis of a doubled haploid (DH) population with five M. graminicola isolates in the seedling stage identified four QTLs on chromosomes 3AS, 1BS, 6DS and 7DS, and occasionally on 7DL. The QTL on chromosome 6DS flanked by SSR markers Xgpw5176 and Xgpw3087 is a novel QTL that now can be designated as Stb18. The QTLs on chromosomes 3AS and 1BS most likely represent Stb6 and Stb11, respectively, and the QTLs on chromosome 7DS are most probably identical with Stb4 and Stb5. However, the QTL identified on chromosome 7DL is expected to be a new Stb gene that still needs further characterization. Multiple isolates were used and show that not all isolates identify all QTLs, which clearly demonstrates the specificity in the M. graminicola-wheat pathosystem. QTL analyses were performed with various disease parameters. The development of asexual fructifications (pycnidia) in the characteristic necrotic blotches of STB, designated as parameter P, identified the maximum number of QTLs. All other parameters identified fewer but not different QTLs. The segregation of multiple QTLs in the Apache/Balance DH population enabled the identification of DH lines with single QTLs and multiple QTL combinations. Analyses of the marker data of these DH lines clearly demonstrated the positive effect of pyramiding QTLs to broaden resistance spectra as well as epistatic and additive interactions between these QTLs. Phenotyping of the Apache/Balance DH population in the field confirmed the presence of the QTLs that were identified in the seedling stage, but Stb18 was inconsistently expressed and might be particularly effective in young plants. In contrast, an additional QTL for STB resistance was identified on chromosome 2DS that is exclusively and consistently expressed in mature plants over locations and time, but it was also strongly related with earliness, tallness as well as resistance to Fusarium head blight. Although to date no Stb gene has been reported on chromosome 2D, the data provide evidence that this QTL is only indirectly related to STB resistance. This study shows that detailed genetic analysis of contemporary commercial bread wheat cultivars can unveil novel Stb genes that can be readily applied in marker-assisted breeding programs. PMID- 21655995 TI - A multiple-center phase II study of weekly docetaxel and oxaliplatin as first line treatment in patients with advanced gastric cancer. AB - BACKGROUND: Docetaxel and oxaliplatin are active agents for advanced gastric cancer (GC). The combination of these two drugs in a triweekly schedule is an active and attractive regimen for gastric cancer but with significant hematological toxicities. A multicenter phase II study was designed to establish an active regimen with good tolerability by using a weekly docetaxel-oxaliplatin (DO) combination in GC patients. METHODS: Eligible patients had histologically confirmed stage IV gastric cancer without previous palliative chemotherapy; age >=18 years; Eastern Cooperative Oncology Group (ECOG) performance status <=2; at least one measurable lesion; and adequate hematological, renal, and liver functions. All patients received premedications with dexamethasone and 5-HT3 antagonist before the chemotherapy. Docetaxel (Taxotere(r); Sanofi-Aventis) 30 mg/m(2) followed by oxaliplatin (Eloxatin(r); Sanofi-Aventis) 65 mg/m(2) were administered on days 1 and 8 of each 21-day cycle. Treatment continued until disease progression, intolerable toxicity, or consent withdrawal. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) version 3.0. Tumor responses were evaluated every 2 cycles by the Response Evaluation Criteria in Solid Tumors Guidelines. RESULTS: From May 2007 to December 2008, a total of 47 patients were enrolled. There were 8 females and 39 males with a median age of 57 years (range 26-76). Forty-three patients were evaluable for response. Two patients obtained a complete response (4.7%) and 12 patients had a partial response (27.9%), with an overall response rate of 32.6% (95% confidence interval [CI] 19.1-48.5); 20 patients experienced stable disease (46.5%), and the disease progressed in 9 patients (20.9%). Median time to disease progression was 4.2 months and median overall survival was 8.3 months. All 47 patients were assessable for toxicity. Major grade 3/4 hematological toxicities were anemia (5 patients, 10.6%), neutropenia (2 patients, 4.3%), and leukopenia (1 patient, 2.1%). The most common grade 3/4 non-hematological toxicities were fatigue (3 patients, 6.4%) and aspartate aminotransferase (AST) elevation in 3 patients (6.4%). CONCLUSIONS: The combination of weekly DO demonstrated a well tolerated profile with moderate activity in the treatment of advanced gastric cancer. Further studies of the combination together with a fluoropyrimidine are warranted. PMID- 21655996 TI - The double intramedullary cortical button fixation for distal biceps tendon repair. AB - PURPOSE: This study was designed to present the novel technique of intramedullary cortical button fixation for distal biceps tendon repair via a single-limited anterior portal. METHODS: To reattach the ruptured biceps tendon at the radial tuberosity, two Bicepsbutton(TM) (Arthrex, Naples, FL, USA) were intramedullary positioned to the anterior cortex. The surgical procedure is described in detail. This technique has been performed in a first series of 3 patients with acute distal biceps tendon ruptures. RESULTS: All patients were very satisfied after surgery and would undergo the same surgical procedure again. All patients regained full range of elbow motion with comparable strength of forearm supination and elbow flexion measured against the uninjured arm at 6 months of follow-up. No neurovascular complications have been occured. CONCLUSION: Double intramedullary cortical button repair has shown to be a safe and reliable fixation method for distal biceps tendon rupture in a small series of patients. Preliminary results are encouraging. PMID- 21655997 TI - Vascularity and histology of fetal labrum and chondrolabral junction: its relevance to chondrolabral detachment tears. AB - PURPOSE: Recently, acetabular labral tears were recognized as a source of hip pain. Most of these tears were found to be localized at the chondrolabral junction. The purpose of this study was to evaluate the chondrolabral junction in reference to its collagen fiber orientation and its vascularity, which might be used to explain the preponderance of labral tears. METHODS: Eighteen formalinized fetuses with a mean gestational age of 17 weeks (range: 11-24 weeks) were examined. The acetabuli were removed en bloc with the proximal femur for ease of orientation. The acetabuli were prepared and examined in four quadrants, namely, anterior, superior, posterior, and inferior. RESULTS: The staining pattern of the posteroinferior labrum was more dense than the anterosuperior labrum, due to its high collagen content. Collagen fibers in the posteroinferior quadrants were oriented perpendicularly to the chondrolabral junction, while those in the anterosuperior quadrants had a parallel oriented. Perpendicular collagen orientation and high collagen content may explain the stronger anchorage of the labrum to the bony acetabulum in posteroinferior quadrants. All of the vessels supplying the labrum originate from the capsular connective tissue and traverse the body of the labrum to reach the articular side. None of these vessels traverse the chondrolabral junction to reach the bony acetabulum. The total number of blood vessels was significantly higher in the capsular zone than in the articular zones. The number of blood vessels did not differ between the acetabular quadrants. CONCLUSIONS: In an effort to understand the chondrolabral junction tears, we can conclude that collagen content and fiber orientation may represent the histological basis for the predominance of tears at the anterosuperior region. PMID- 21655998 TI - Over-expression of HMG-CoA reductase and amorpha-4,11-diene synthase genes in Artemisia annua L. and its influence on artemisinin content. AB - Artemisinin, an endoperoxide sesquiterpene lactone, is a novel antimalarial natural product isolated from Artemisia annua L. plants. The low concentrations (0.01-1.1%) of this compound in A. annua L. plants is, however, a major constraint for commercialization of artemisinin-based combination therapies (ACTs) recommended by WHO for treating malaria caused by multidrug-resistant P. falciparum sp. In this context, in vivo yield improvement programs were undertaken by us. In the present study, HMG-Co A reductase gene (hmgr) from Catharanthus roseus (L) G. Don and amorpha-4,11-diene synthase (ads) gene from A. annua L. were over-expressed in A. annua L. plants to study their effects on artemisinin yields. The transgenic lines developed from putative transgenic regenerants were evaluated for integration and copy number of the transgenes using hptII gene probe, as it was a part of the expression cassette. The transgenic lines showed positive bands of hptII gene on Southern blots confirming the integration of transgenes. Some of the transgenic lines had single copy of the transgenes, while others had multiple copies. The expressions of hmgr and ads at the transcriptional level were also confirmed in each transgenic line employing RT-PCR assays. The HPLC analyses showed that the artemisinin contents were significantly increased in these transgenics. One of the transgenic lines, TR4, was found to contain 7.65-fold higher (1.73 mg/gDW) artemisinin than the non transgenic plant (W). The increased artemisinin levels were found to be correlated with HMG-Co A reductase and amorpha-4,11-diene synthase enzymatic activities in the biochemical analyses. PMID- 21655999 TI - [Neuroendocrine neoplasms of the appendix and colorectum]. AB - Appropriate diagnosis and treatment of neuroendocrine neoplasms (NENs) of the appendix and colorectum requires a detailed knowledge of their proper classification according to the updated WHO and TNM systems. The WHO classification distinguishes well differentiated NEN, the neuroendocrine tumors (G1 and G2 NETs), from the poorly differentiated carcinomas (G3 NECs). While NETs are common in the appendix and rectum, NECs occur predominantly in the colon. G1 appendiceal and rectal NETs of 1 cm in size or below that do not invade either the muscular wall or vessels bear almost no metastatic risk and can be treated by appendectomy or endoscopic resection. G2 appendiceal and rectal NETs larger than 1 cm in size in combination with other risk factors have an increased risk of metastasis and need to be treated more aggressively. NECs of the colon usually require chemotherapy in addition to resection. Today, most patients with NETs of the appendix and rectum have an excellent prognosis when these diagnostic and therapeutic guidelines are borne in mind. PMID- 21656000 TI - Application of physicochemical data for water-quality assessment of watercourses in the Gdansk Municipality (South Baltic coast). AB - The paper presents water-quality evaluation based on an 8-year monitoring programme in the Gdansk Municipality region, on the Southern coast of the Baltic Sea. The studies were carried out from 2000 to 2007 by surface water analysis at 15 various sites within eight watercourses. Sampling sites included rather urbanized or developed lands, farming fields and non-polluted city recreational areas such as parks and forests. Most of the watercourses were sampled monthly at two locations, one within the upper course of the watercourse and the other near its mouth. In all samples, eight parameters of water quality were determined: total suspended solids, dissolved oxygen, water temperature, oxygen saturation, 5 day biochemical oxygen demand, chemical oxygen demand, total phosphorus and total nitrogen concentration. Interpretation of the obtained results revealed that examination of those basic physicochemical parameters permits to discriminate initially watercourses with respect to level of water contamination. During the research, a large dataset was obtained and it was described by both basic statistical parameters and chemometric method of cluster analysis. The paper presents relations between analysed parameters and influence of land exploitation mode on water quality and describes variation of the results both in space and time. PMID- 21656001 TI - Longitudinal assessment of retinal structure and function reveals a rod-cone degeneration in a guinea pig model initially presented as night blind. AB - We have previously reported a naturally occurring retinopathy in a population of guinea pigs, where the affected animals presented a defect of the rod-mediated vision. The purpose of this study was to investigate if the mutants were affected with a stationary or degenerative retinopathy and to identify the cellular origin of this unique disorder. Electroretinogram (ERG) [postnatal day 1 (P1) to P450], light (LM) and electron microscopy (EM) [P5, P150, P450], and immunohistochemistry [P30, P150, P450] were evaluated from normal and mutant animals. Irrespective of age, the scotopic ERGs of mutants could only be evoked by bright flashes, and the resulting ERGs were of photopic waveform. Interestingly, the amplitude of the cone and the rod/cone a-waves was always of smaller amplitude in mutants, but this difference tended to decrease with age. In contrast, the b-waves were of larger amplitude than normal in photopic ERGs obtained prior to age 25 (days) and prior to age 10 for rod/cone ERGs. LM revealed, in mutants, an absence of the outer segment layer (OSL) with a reduction in the outer nuclear layer (ONL) thickness. EM disclosed the presence of cone outer segment (OS) while no rod OS could be evidenced. Immunohistochemistry revealed the presence of rhodopsin, both cone opsins as well as normal synaptophysin immunoreactivity. Finally, neither the retinal structure nor the function in the mutants achieved normal development. Results suggest that mutant animals are suffering from a degenerative retinal disorder that affects the structure and function of rods and cones. PMID- 21656002 TI - Reverse positional orientation in a neotropical orb-web spider, Verrucosa arenata. AB - Most orb-web spiders face downwards in the web. A downward orientation has been proposed to be the optimal strategy because spiders run faster downwards and thus can catch prey quicker. Consequently, orb-web spiders also extend their web in the lower part, leading to top-down web asymmetry. Since the majority of orb-web spiders face downwards, it has been difficult to test the effect of orientation on prey capture and web asymmetry. In this study, we explored the influence of reverse orientation on foraging efficiency and web asymmetry in Verrucosa arenata, a neotropical orb-web spider that faces upwards in the web. We show that reverse orientation does not imply reverse web asymmetry in this species. V. arenata spiders captured more prey in the lower part of the web but more prey per area on the upper part. The average running speeds of spiders did not differ between upward and downward running, but heavier spiders took longer to capture prey while running upwards. We discuss these findings in the context of foraging efficiency and web asymmetry. PMID- 21656003 TI - Genetic caste polymorphism and the evolution of polyandry in Atta leaf-cutting ants. AB - Multiple mating by females with different males (polyandry) is difficult to explain in many taxa because it carries significant costs to females, yet benefits are often hard to identify. Polyandry is a derived trait in social insects, the evolutionary origins of which remain unclear. One of several leading hypotheses for its evolution is that it improves division of labour by increasing intra-colonial genetic diversity. Division of labour is a key player in the ecological success of social insects, and in many successful species of ants is based on morphologically distinct castes of workers, each with their own task specialisations. Atta leaf-cutting ants exhibit one of the most extreme and complicated forms of morphologically specialised worker castes and have been reported to be polyandrous but with relatively low mating frequencies (~2.5 on average). Here, we show for the first time that there is a significant genetic influence on worker size in Atta colombica leaf-cutting ants. We also provide the first estimate of the mating frequency of Atta cephalotes (four matings) and, by analysing much higher within-colony sample sizes, find that Atta are more polyandrous than previously thought (approximately six to seven matings). The results show that high polyandry and a genetic influence on worker caste are present in both genera of leaf-cutting ants and add weight to the hypothesis that division of labour is a potential driver of the evolution of polyandry in this clade of ants. PMID- 21656004 TI - An individual and a sex odor signature in kittiwakes?: study of the semiochemical composition of preen secretion and preen down feathers. AB - The importance of olfaction in birds' social behavior has long been denied. Avian chemical signaling has thus been relatively unexplored. The black-legged kittiwake provides a particularly appropriate model for investigating this topic. Kittiwakes preferentially mate with genetically dissimilar individuals, but the cues used to assess genetic characteristics remain unknown. As in other vertebrates, their body odors may carry individual and sexual signatures thus potentially reliably signaling individual genetic makeup. Here, we test whether body odors in preen gland secretion and preen down feathers in kittiwakes may provide a sex and an individual signature. Using gas chromatography and mass spectrometry, we found that male and female odors differ quantitatively, suggesting that scent may be one of the multiple cues used by birds to discriminate between sexes. We further detected an individual signature in the volatile and nonvolatile fractions of preen secretion and preen down feathers. These results suggest that kittiwake body odor may function as a signal associated with mate recognition. It further suggests that preen odor might broadcast the genetic makeup of individuals, and could be used in mate choice to assess the genetic compatibility of potential mates. PMID- 21656005 TI - Do Scaphoideus titanus (Hemiptera: Cicadellidae) nymphs use vibrational communication? AB - Small Auchenorrhyncha use substrate-borne vibrations to communicate. Although this behaviour is well known in adult leafhoppers, so far no studies have been published on nymphs. Here we checked the occurrence of vibrational communication in Scaphoideus titanus (Hemiptera: Cicadellidae) nymphs as a possible explanation of their aggregative distributions on host plants. We studied possible vibratory emissions of isolated and grouped nymphs, as well as their behavioural responses to vibration stimuli that simulated presence of conspecifics, to disturbance noise, white noise and predator spiders. None of our synthetic stimuli or pre recorded substrate vibrations from nymphs elicited specific vibration responses and only those due to grooming or mechanical contacts of the insect with the leaf were recorded. Thus, S. titanus nymphs showed to not use species-specific vibrations neither for intra- nor interspecific communication and also did not produce alarm vibrations when facing potential predators. We conclude that their aggregative behaviour is independent from a vibrational communication. PMID- 21656006 TI - Detection of tetracycline and macrolide resistance determinants in Enterococci of animal and environmental origin using multiplex PCR. AB - An occurrence of resistance to tetracycline (TET) and erythromycin (ERY) was ascertained in 82 isolates of Enterococcus spp. of animal and environmental origin. Using E test, 33 isolates were resistant to TET and three isolates to ERY. Using polymerase chain reaction (PCR; single and multiplex), the TET determinants tet(M) and tet(L) were detected in 35 and 13 isolates, respectively. Twelve isolates carried both tet(M) and tet(L) genes. Eight isolates possessed ermB gene associated with ERY resistance. Multiplex PCR was shown to be a suitable method for simultaneous determination of all three resistance determinants that occurred most frequently in bacteria isolated from poultry. This study also demonstrates that gastrointestinal tract of broilers may be a reservoir of enterococci with acquired resistance to both TET and ERY that can be transferred to humans via food chain. PMID- 21656007 TI - Persistence in seasonally forced epidemiological models. AB - In this paper we address the persistence of a class of seasonally forced epidemiological models. We use an abstract theorem about persistence by Fonda. Five different examples of application are given. PMID- 21656008 TI - Periodic orbits near heteroclinic cycles in a cyclic replicator system. AB - A species is semelparous if every individual reproduces only once in its life and dies immediately after the reproduction. While the reproduction opportunity is unique per year and the individual's period from birth to reproduction is just n years, the individuals that reproduce in the ith year (modulo n) are called the ith year class, i = 1, 2, . . . , n. The dynamics of the n year-class system can be described by a differential equation system of Lotka-Volterra type. For the case n = 4, there is a heteroclinic cycle on the boundary as shown in previous works. In this paper, we focus on the case n = 4 and show the existence, growth and disappearance of periodic orbits near the heteroclinic cycle, which is a part of the conjecture by Diekmann and van Gils (SIAM J Appl Dyn Syst 8:1160-1189, 2009). By analyzing the Poincare map near the heteroclinic cycle and introducing a metric to measure the size of the periodic orbit, we show that (i) when the average competitive degree among subpopulations (year classes) in the system is weak, there exists an asymptotically stable periodic orbit near the heteroclinic cycle which is repelling; (ii) the periodic orbit grows in size when some competitive degree increases, and converges to the heteroclinic cycle when the average competitive degree tends to be strong; (iii) when the average competitive degree is strong, there is no periodic orbit near the heteroclinic cycle which becomes asymptotically stable. Our results provide explanations why periodic solutions expand and disappear and why all but one subpopulation go extinct. PMID- 21656009 TI - Exact and approximate distributions of protein and mRNA levels in the low-copy regime of gene expression. AB - Gene expression at the single-cell level incorporates reaction mechanisms which are intrinsically stochastic as they involve molecular species present at low copy numbers. The dynamics of these mechanisms can be described quantitatively using stochastic master-equation modelling; in this paper we study a generic gene expression model of this kind which explicitly includes the representations of the processes of transcription and translation. For this model we determine the generating function of the steady-state distribution of mRNA and protein counts and characterise the underlying probability law using a combination of analytic, asymptotic and numerical approaches, finding that the distribution may assume a number of qualitatively distinct forms. The results of the analysis are suitable for comparison with single-molecule resolution gene-expression data emerging from recent experimental studies. PMID- 21656010 TI - Adaptive conformational sampling based on replicas. AB - Computer simulations of biomolecules such as molecular dynamics simulations are limited by the time scale of conformational rearrangements. Several sampling techniques are available to search the multi-minima free energy landscape but most efficient, time-dependent methods do generally not produce a canonical ensemble. A sampling algorithm based on a self-regulating ladder of searching copies in the dihedral subspace is developped in this paper. The learning process using short- and long-term memory functions allows an efficient search in phase space while combining a deterministic dynamics and stochastic swaps with the searching copies conserves a canonical limit. The sampling efficiency and accuracy are indicated by comparing the ansatz with conventional molecular dynamics and replica exchange simulations. PMID- 21656011 TI - Pseudo-dermal sinus tract or spinal dermal-sinus-like stalk? PMID- 21656012 TI - Glioblastoma multiforme with very rapid growth and long-term survival in children: report of two cases and review of the literature. AB - Glioblastoma occurs rarely in pediatric patients (0.6-7.9% of all glioblastomas). Symptom duration is about 3-5 months prior to diagnosis with a dismal prognosis (median survival of 50 weeks). The authors describe two pediatric age patients with histopathologically confirmed glioblastoma multiforme whose lesions appeared within just 1 week of normal computed tomography scan and magnetic resonance imaging. Both patients had long-term survival (one of them 6 years and the other 3 years and 7 months) following tumor resection. The present report serially illustrates the very rapid development of glioblastoma in childhood and emphasizes the importance of serial neuroimaging as well as paying attention to sudden onset headaches in pediatric patients with inconclusive imaging findings. PMID- 21656013 TI - Space-time clustering in childhood nervous system tumors in the Region of Murcia, Spain, 1998-2009. AB - AIMS: The aims of this study are the following: first, to analyze incidence, trends, and survival of nervous system tumors in children under the age of 15 in the Region of Murcia, Spain, during the years 1998-2009 and second, to evaluate if certain environmental exposures may be involved in the etiology of childhood nervous system tumors. The study was performed on the spatial and temporo-spatial distribution of the observed cases. METHODS: The Environment and Pediatric Cancer in the Region of Murcia is an ongoing research project aimed at carefully collecting pediatric environmental history (PEH) and to use geographical information systems to map the incidence and to analyze the geographical distribution of pediatric cancer incidence in our region. Between 1998 and 2009, 125 patients were diagnosed with nervous system tumors. The spatial and temporal space clusters were evaluated using Kulldorff's statistics. Address at diagnosis was the main feature evaluated. RESULTS: The incidence (cases/million children) for central nervous system (CNS) tumors was 34.2, that for sympathetic nervous system tumors was 10.9, and that for retinoblastoma was 1.9. There was evidence of space clustering for medulloblastoma and space-time clustering for all tumors, CNS tumors, astrocytoma, and neuroblastoma. CONCLUSIONS: The incidence and survival for each type and subtype of nervous system tumors were within the reported values for the European region. There is evidence that spatial and spatial-temporal distribution in these cases is not random. The development of a careful PEH in these patients will help to reinforce geographical information system studies and to ascertain the importance of associated risk factors. PMID- 21656014 TI - Serodiagnosis of Helicobacter hepaticus infection in patients with liver and gastrointestinal diseases: western blot analysis and ELISA using a highly specific monoclonal antibody for H. hepaticus antigen. AB - BACKGROUND: Helicobacter hepaticus infection might be associated with liver and biliary tract diseases. To investigate its pathogenic role, the properties of anti-H. hepaticus serum antibody in patients with liver and diseases were elucidated. METHODS: Serum samples were collected from 166 patients-69 with liver diseases, 38 with upper gastrointestinal diseases, 17 with lower gastrointestinal diseases, 26 with biliary tract diseases, and 16 with pancreas diseases; 30 control sera were obtained from 30 healthy blood donors. Serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) and western blot using the new monoclonal antibody HR II-51. RESULTS: Anti-H. hepaticus serum antibody concentrations in patients with liver disease (n = 69) were significantly increased compared with those in other disease groups (p = 0.014 to <0.001). Particularly, liver cirrhosis (n = 19) showed a significantly higher antibody level compared with other liver diseases (n = 50, p = 0.005) and healthy donors (n = 30, p = 0.0005), as well as a higher seroprevalence (68.4%) compared with other liver diseases (p = 0.05) and healthy donors (p = 0.004). Furthermore, the ELISA value in liver cirrhosis (n = 19) was significantly higher than that in patients with hepatitis B virus (HBV)-and/or hepatitis C virus (HCV)-infected chronic hepatitis (n = 15) (0.389 +/- 0.084 vs. 0.350 +/- 0.084, p = 0.029). However, there was no relationship between the total immunoglobulin concentration and the anti-H. hepaticus antibody level in each liver disease (Spearman's rank correlation coefficient [rs] < 0.225). CONCLUSIONS: H. hepaticus infection might play a role in the development of liver diseases; in particular, it might increase the risk of the development of HBV- and/or HCV-infected liver diseases. PMID- 21656015 TI - Alteration in expression of hormone-related genes in wild emmer wheat roots associated with drought adaptation mechanisms. AB - Transcriptomic and metabolomic profiles were used to unravel drought adaptation mechanisms in wild emmer wheat (Triticum turgidum ssp. dicoccoides), the progenitor of cultivated wheat, by comparing the response to drought stress in roots of genotypes contrasting in drought tolerance. The differences between the drought resistant (R) and drought susceptible (S) genotypes were characterized mainly by shifts in expression of hormone-related genes (e.g., gibberellins, abscisic acid (ABA) and auxin), including biosynthesis, signalling and response; RNA binding; calcium (calmodulin, caleosin and annexin) and phosphatidylinositol signalling, in the R genotype. ABA content in the roots of the R genotype was higher in the well-watered treatment and increased in response to drought, while in the S genotype ABA was invariant. The metabolomic profiling revealed in the R genotype a higher accumulation of tricarboxylic acid cycle intermediates and drought-related metabolites, including glucose, trehalose, proline and glycine. The integration of transcriptomics and metabolomics results indicated that adaptation to drought included efficient regulation and signalling pathways leading to effective bio-energetic processes, carbon metabolism and cell homeostasis. In conclusion, mechanisms of drought tolerance were identified in roots of wild emmer wheat, supporting our previous studies on the potential of this genepool as a valuable source for novel candidate genes to improve drought tolerance in cultivated wheat. PMID- 21656016 TI - Validation of the Fiala multi-node thermophysiological model for UTCI application. AB - The important requirement that COST Action 730 demanded of the physiological model to be used for the Universal Thermal Climate Index (UTCI) was its capability of accurate simulation of human thermophysiological responses across a wide range of relevant environmental conditions, such as conditions corresponding to the selection of all habitable climates and their seasonal changes, and transient conditions representing the temporal variation of outdoor conditions. In the first part of this study, available heat budget/two-node models and multi node thermophysiological models were evaluated by direct comparison over a wide spectrum of climatic conditions. The UTCI-Fiala model predicted most reliably the average human thermal response, as shown by least deviations from physiologically plausible responses when compared to other models. In the second part of the study, this model was subjected to extensive validation using the results of human subject experiments for a range of relevant (steady-state and transient) environmental conditions. The UTCI-Fiala multi-node model proved its ability to predict adequately the human physiological response for a variety of moderate and extreme conditions represented in the COST 730 database. The mean skin and core temperatures were predicted with average root-mean-square deviations of 1.35 +/- 1.00 degrees C and 0.32 +/- 0.20 degrees C, respectively. PMID- 21656018 TI - PTH level but not 25 (OH) vitamin D level predicts bone loss rates in the elderly. AB - We assessed the impact of calciotropic hormones on bone loss in 195 elderly subjects. After a median follow up of 4 years, parathyroid hormone (PTH) correlated negatively with changes in bone mineral density (BMD) at all skeletal sites. After adjustment for potential predictors of bone loss in the elderly, PTH level alone explained 3% of the variance in BMD changes at the hip. INTRODUCTION: This study assessed the impact of calciotropic hormones on bone loss rates in an elderly population-based cohort of 195 ambulatory men and women, aged 65-85 years and followed up for a median of 4 years. METHODS: Calcium intake, serum calcium, and phosphorus were assessed at baseline. Serum creatinine was measured at follow up visit. The 25 (OH) vitamin D [25-OHD] and PTH were measured at baseline and at follow up. Bone mass at the lumbar spine, hip, forearm and total body, as well as body composition was measured at baseline and at follow up by dual energy X-ray absorptiometry. RESULTS: Mean 25-OHD level was 14.7 +/- 6.4 ng/ml and mean PTH level was 47.9 +/- 30.4 pg/ml. Age correlated negatively with percent changes in BMD at all skeletal sites (p < 0.05). Changes in body mass index (BMI) and in body composition correlated positively with BMD changes at all sites, except at the forearm. There was no correlation between 25-OHD and changes in BMD except at the trochanter (r = 0.19, p < 0.008). Conversely, PTH negatively correlated with changes in BMD at all skeletal sites (r = -0.14 to -0.27, p < 0.05). This correlation persisted after adjustment for age, changes in BMI, changes in fat mass and lean mass, serum creatinine, calcium intake, and 25-OHD levels. PTH level alone explained 3% of the variance in BMD changes at all hip subregions. CONCLUSIONS: Serum PTH, but not 25-OHD, predicted bone loss rates in the elderly. Thus, it is important to normalize PTH level when correcting hypovitaminosis D in the elderly. PMID- 21656019 TI - Use of health services among vineyard and winery workers in the North Willamette Valley, Oregon. AB - Although agricultural work is considered one of the most dangerous and physically demanding jobs, the majority of farmworkers remain vulnerable to disease and injury, while use of health services is limited. The present study analyzes the use of health care services among vineyard and winery workers in the North Willamette Valley, Oregon. Data from 513 foreign-born workers collected during the summer of 2009 by !Salud! Services, was used to test the influence of relevant predisposing and enabling factors of the Behavioral Model of Health Care Utilization among Vulnerable Populations. The majority of participants were males (87%) with an average age of 33 years. Over half of the workers were either married or living with a partner (54%) and had children living with them (58%). Very few spoke English (5%) and only a third had more than 6 years of formal education. Two-thirds of workers (65%) had a full time job and shared housing (67%). Only one of every five workers (19%) had health insurance. Multivariate analyses show that use of health services in the past 2 years is more likely among females, those who have children, have more than 6 years of education, work full time, are insured, and are currently attending school. This study provides further insight for health care provision initiatives to reduce the many barriers faced by farmworkers and their families. PMID- 21656020 TI - Health related quality of life in a rural area with low racial/ethnic density. AB - The purpose of this study was to compare the self-reported quality of life of racial/ethnic minorities and Caucasians living in a rural, northern New York county, where 94% of the population is Caucasian. Participants completed a 79 item survey online and in-person assessing health status, health-related quality of life, perceptions of health information, and health care access/use. Frequencies, Chi-Square, and ANOVA were used to analyze the results. A total of 1,039 surveys were completed. Racial/ethnic minorities earned significantly less income, F (1, 1031) = 29.306, P = .000, relied more on public health insurance, X ( 2 )(7, 1033) = 47.827, P = .000, were significantly less likely to see a doctor because of the cost, F(1,990) = 17.042, P = .000, and reported using health related services significantly less often when compared to Caucasians, F(1, 1032) = 17.051, P = .000. In terms of quality of life, while there were no significant differences in self-reported physical health, racial/ethnic minorities were more likely to feel sad/blue/depressed, F(1, 1031) = 7.193, P = .011 and worried/tense/anxious, F(1, 1031) = 5.550, P = .040. Findings from this study offer some initial evidence that, while perceived health status is generally good, rural racial/ethnic minorities residing in predominantly Caucasian rural areas may experience more mental health problems that are risk factors for chronic diseases. This coupled with lower use of health care services increases the need for culturally competent health programs and services for this population. PMID- 21656022 TI - Isolation of three important types of stem cells from the same samples of banked umbilical cord blood. AB - It is known that umbilical cord blood (UCB) is a rich source of stem cells with practical and ethical advantages. Three important types of stem cells which can be harvested from umbilical cord blood and used in disease treatment are hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs). Since these stem cells have shown enormous potential in regenerative medicine, numerous umbilical cord blood banks have been established. In this study, we examined the ability of banked UCB collected to produce three types of stem cells from the same samples with characteristics of HSCs, MSCs and EPCs. We were able to obtain homogeneous plastic rapidly-adherent cells (with characteristics of MSCs), slowly-adherent (with characteristics of EPCs) and non adherent cells (with characteristics of HSCs) from the mononuclear cell fractions of cryopreserved UCB. Using a protocol of 48 h supernatant transferring, we successfully isolated MSCs which expressed CD13, CD44 and CD90 while CD34, CD45 and CD133 negative, had typical fibroblast-like shape, and was able to differentiate into adipocytes; EPCs which were CD34, and CD90 positive, CD13, CD44, CD45 and CD133 negative, adherent with cobble-like shape; HSCs which formed colonies when cultured in MethoCult medium. PMID- 21656021 TI - The effect of hyperbaric oxygen treatment on aspiration pneumonia. AB - We have studied whether hyperbaric oxygen (HBO) prevents different pulmonary aspiration materials-induced lung injury in rats. The experiments were designed in 60 Sprague-Dawley rats, ranging in weight from 250 to 300 g, randomly allotted into one of six groups (n = 10): saline control, Biosorb Energy Plus (BIO), hydrochloric acid (HCl), saline + HBO treated, BIO + HBO treated, and HCl + HBO treated. Saline, BIO, HCl were injected into the lungs in a volume of 2 ml/kg. A total of seven HBO sessions were performed at 2,4 atm 100% oxygen for 90 min at 6 h intervals. Seven days later, rats were sacrificed, and both lungs in all groups were examined biochemically and histopathologically. Our findings show that HBO inhibits the inflammatory response reducing significantly (P < 0.05) peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudate, alveolar histiocytes, interstitial fibrosis, granuloma, and necrosis formation in different pulmonary aspiration models. Pulmonar aspiration significantly increased the tissue HP content, malondialdehyde (MDA) levels and decreased (P < 0.05) the antioxidant enzyme (SOD, GSH-Px) activities. HBO treatment significantly (P < 0.05) decreased the elevated tissue HP content, and MDA levels and prevented inhibition of SOD, and GSH-Px (P < 0.05) enzymes in the tissues. Furthermore, there is a significant reduction in the activity of inducible nitric oxide synthase, TUNEL and arise in the expression of surfactant protein D in lung tissue of different pulmonary aspiration models with HBO therapy. It was concluded that HBO treatment might be beneficial in lung injury, therefore, shows potential for clinical use. PMID- 21656023 TI - DHEA administration activates local bioactive androgen metabolism in cancellous site of tibia of ovariectomized rats. AB - It is not known whether local androgen metabolism is involved in the mechanisms underlying the dehydroepiandrosterone (DHEA) administration-induced improvement of bone mineral density (BMD) in an estrogen-deficiency state. The aim of the present study was to clarify whether DHEA administration would improve local androgen metabolism and BMD in cancellous site of tibia of ovariectomized (OVX) rats. Twenty-two female rats, 6 weeks old, were randomized into three groups: sham-operated rats, OVX control rats, and OVX rats that received DHEA treatment. DHEA was administered intraperitoneally at 20 mg/kg body weight for 8 weeks. The concentrations of free testosterone and dihydrotestosterone (DHT) in cancellous site of tibia did not change as a result of ovariectomy, while the DHT concentration increased following DHEA administration. We revealed that DHEA administration improved the reduction of 17beta- and 3beta-hydroxysteroid dehydrogenases and clearly reversed the reduction of 5alpha-reductase types 1 and 2 and androgen receptor in the cancellous site of tibia of OVX rats. DHEA administration suppressed estrogen deficiency relative to the decrease in the cancellous BMD, which was positively associated with local DHT concentration. These findings indicate that DHEA administration enhances local bioactive androgen metabolism in the cancellous tibia of young OVX rats, suggesting that local DHT may play a part in the DHEA administration-induced improvement of cancellous BMD. PMID- 21656025 TI - An unusual DMSA scan: answer. PMID- 21656024 TI - High mobility group box 1 is a novel substrate of dipeptidyl peptidase-IV. AB - AIMS/HYPOTHESIS: High mobility group box 1 (HMGB1) is a cytokine with a key role in tissue regeneration and angiogenesis. Previous studies have shown that topical application of HMGB1 to skin wounds of mouse models of diabetes enhanced vessel density and accelerated wound healing, suggesting that diabetes may affect endogenous HMGB1 functions. Dipeptidyl peptidase IV (DPP-IV/CD26) is a protease whose activity is increased in diabetes and whose inhibition improves glucose tolerance. Since HMGB1 contains potential DPP-IV cleavage sites, we determined whether HMGB1 may be a substrate for DPP-IV and whether DPP-IV-mediated cleavage may alter the biological activity of HMGB1. METHODS: Reversed phase HPLC, mass spectrometry and western blot analyses were performed to analyse and identify HMGB1 peptides generated following DPP-IV digestion. HMGB1 angiogenic functions in the presence of DPP-IV were evaluated in vitro and in vivo. HMGB1 protein was detected in the serum of type 2 diabetic patients before and after treatment with DPP-IV inhibitors. RESULTS: DPP-IV cleaved HMGB1 at its N-terminal region and affected its angiogenic functions. Specifically, DPP-IV inhibited HMGB1-induced endothelial cell migration and capillary-like structure formation, as well as HMGB1-mediated vascular network formation in Matrigel implants in mice. We had previously found that HMGB1 promoted endothelial cell migration through activation of extracellular regulated kinase signalling pathway. Here we showed that such an effect was abolished in the presence of DPP-IV. Finally, the N terminal truncated form of HMGB1 was detected in the serum of type 2 diabetic patients, in whom DPP-IV inhibitors enhanced the levels of full-length HMGB1. CONCLUSIONS/INTERPRETATION: DPP-IV cleaves HMGB1 and, via this mechanism, inhibits HMGB1 angiogenic activity. Treatment with DPP-IV inhibitors may enhance HMGB1 activity in diabetic patients, thereby improving angiogenesis in this condition. PMID- 21656026 TI - An unusual DMSA scan--question. PMID- 21656027 TI - The relationship between Bmi-1 and the epithelial-mesenchymal transition in lung squamous cell carcinoma. AB - This study aimed to investigate the expression of Bmi-1 in lung squamous cell carcinoma tissues and the relationship between Bmi-1 and the epithelial mesenchymal transition. RT-PCR and western blot analysis were performed to detect the expression of Bmi-1, E-cadherin, and Vimentin in 56 cases of lung squamous cell carcinoma tissues and adjacent normal tissues. The positive rates of Bmi-1, E-cadherin, and Vimentin mRNA expression in lung squamous cell carcinoma tissues were 73.2, 42.9, and 58.9%, respectively; compared to the expression of these genes in adjacent normal tissues (14.3, 75.0, and 28.6%), the differences were significant (P < 0.05). The expression of Bmi-1 in lung squamous cell carcinoma tissues showed a negative correlation with that of E-cadherin (r = -0.372, P = 0.005) and a positive correlation with that of Vimentin (r = 0.315, P = 0.02). The expression of Bmi-1 and Vimentin mRNA and protein in lung squamous cell carcinoma tissues was significantly higher than that in adjacent normal tissues (P < 0.05), and the expression of Bmi-1 and Vimentin in patients with lymph node and distal metastasis was significantly higher than that in patients without lymph node and distal metastasis (P < 0.05). The expression of E-cadherin mRNA and protein in lung squamous cell carcinoma tissues was significantly lower than that in adjacent normal tissues (P < 0.05), and the expression in patients with lymph node and distal metastasis was significantly lower than that in patients without lymph node and distal metastasis (P < 0.05). The expression of Bmi-1, E cadherin, and Vimentin was not associated with the patient's sex, age, tumor size or degree of tumor differentiation (P > 0.05). The increase in Bmi-1 expression was accompanied by the down-regulation of E-cadherin expression and up-regulation of Vimentin expression. Bmi-1 may be associated with the epithelial-mesenchymal transition in lung squamous cell carcinoma and the occurrence, invasion, and metastasis of lung squamous cell carcinoma. PMID- 21656028 TI - A potential role for the homeoprotein Hhex in hepatocellular carcinoma progression. AB - Hepatocellular carcinoma (HCC), the most common primary malignant tumor of the liver, often associated with the dysregulation of transcriptional pathways involved in cell growth and differentiation. The hematopoietically expressed homeobox protein (Hhex) is an important transcription factor throughout liver development and is essential to liver bud formation and hepatoblast differentiation. Here, we report a relationship between Hhex expression and HCC. First, adenovirus-mediated Hhex delivery into the hepatoma cell line, Hepa1-6, resulted in decreased expression of several proto-oncogenes (c-Jun and Bcl2), increased expression of some tumor suppressor genes (P53 and Rb), and enhanced expression of a cluster of hepatocytic and bile ductular markers. Second, Hhex expression significantly attenuated Hepa1-6 tumorigenicity in nude mice. Third, we report a correlation between Hhex expression and the differentiation state of human HCC. In 24 cases of clinical specimens, there was a significant difference in Hhex expression between poorly differentiated HCC and well-differentiated HCC (P < 0.001). Taken together, these results indicate that Hhex is a potential candidate molecular marker for HCC pathological evaluation, suggesting a need to evaluate Hhex as a potential target for therapeutic intervention. PMID- 21656029 TI - Hydraulic properties of fronds from palms of varying height and habitat. AB - Because palms grow in highly varying climates and reach considerable heights, they present a unique opportunity to evaluate how environment and plant size impact hydraulic function. We studied hydraulic properties of petioles from palms of varying height from three species: Iriartea deltoidea, a tropical rainforest species; Mauritia flexuosa, a tropical rainforest, swamp species; and Washingtonia robusta, a subtropical species. We measured leaf areas, petiole cross-sectional areas, specific conductivity (K(S)), petiole anatomical properties, vulnerability to embolism and leaf water potentials and calculated petiole Huber values and leaf-specific conductivities (K(L)). Leaf and petiole cross-sectional areas varied widely with height. However, hydraulic properties including Huber values, K(S) and K(L), remained constant. The two palmate species, M. flexuosa and W. robusta, had larger Huber values than I. deltoidea, a pinnately-compound species which exhibited the highest K(S). Metaxylem vessel diameters and vascular bundle densities varied with height in opposing patterns to maintain petiole conductivities. I. deltoidea and W. robusta petioles had similar P(50) values (the point at which 50% of hydraulic conductivity is lost) averaged over all crown heights, but W. robusta exhibited more negative P(50) values in taller palms. Comparison of P (50) values with transpiring midday leaf water potentials, as well as a double-dye staining experiment in a 1-m-tall palm, suggested that a fairly significant amount of embolisms were occurring and refilled on a diurnal basis. Therefore, across palms differing widely in height and growing environments, we found convergence in water transport per unit leaf area (K(L)) with individuals exhibiting differing strategies for achieving this. PMID- 21656030 TI - Elderly with autism: executive functions and memory. AB - Cognitive autism research is mainly focusing on children and young adults even though we know that autism is a life-long disorder and that healthy aging already has a strong impact on cognitive functioning. We compared the neuropsychological profile of 23 individuals with autism and 23 healthy controls (age range 51-83 years). Deficits were observed in attention, working memory, and fluency. Aging had a smaller impact on fluency in the high functioning autism (HFA) group than in the control group, while aging had a more profound effect on visual memory performance in the HFA group. Hence, we provide novel evidence that elderly with HFA have subtle neuropsychological deficits and that the developmental trajectories differ between elderly with and without HFA in particular cognitive domains. PMID- 21656031 TI - Chitosan/silk fibroin-based tissue-engineered graft seeded with adipose-derived stem cells enhances nerve regeneration in a rat model. AB - Sciatic nerve injury presents an ongoing challenge in reconstructive surgery. Local stem cell application has recently been suggested as a possible novel therapy. In the present study we evaluated the potential of a chitosan/silk fibroin scaffold serving as a delivery vehicle for adipose-derived stem cells and as a structural framework for the injured nerve regeneration. The cell-loaded scaffolds were used to regenerate rat sciatic nerve across a 10 mm surgically induced sciatic nerve injury. The functional nerve recovery was assessed by both walking track and histology analysis. Results showed that the reconstruction of the injured sciatic nerve had been significantly enhanced with restoration of nerve continuity and function recovery in the cell-loaded scaffold groups, and their target skeletal muscle had been extensively reinnervated. This study raises a potential possibility of using the newly developed nerve grafts as a promising alternative for nerve regeneration. PMID- 21656032 TI - Preparation of sulfonated porous carbon nanotubes/activated carbon composite beads and their adsorption of low density lipoprotein. AB - The high level of low density lipoprotein (LDL) in plasma is the main cause of atherosclerosis. Hemoperfusion is an ideal therapy to lower the level of LDL in human blood system while therapeutic effect is determined by the adsorbent. The adsorbent must have suitable pore structure and specific functional groups. Carbon nanotubes (CNTs) could be a new adsorbent material because CNTs have high specific surface area and they can be modified by a variety of functional groups. Porous carbon composite beads with the CNTs and phenolic resin mixture were synthesized by suspension polymerization, following with carbonization and steam activation. Then the porous composite beads were sulfonated with a sulfanilic acid anhydrous by diazotization and coupling reaction. The potential application of the sulfonated porous composite beads in adsorbing low density lipoprotein (LDL) from human serum was investigated. The results showed that the sulfonic acid groups on the composite beads could lower LDL levels greatly by electrostatic interaction with electropositive LDL. The higher 20-100 nm pore volume the composite beads had, the more LDL they could adsorb. The 20-100 nm pore volume was enhanced by adding more CNTs and improving CNTs dispersion (ultrasonic crushing). The sulfonated composite beads containing 45 wt% CNTs presented the highest adsorption capacity to LDL 10.46 mg/g, showing a good prospect as LDL adsorbent in hemoperfusion. PMID- 21656033 TI - Fabrication and characterization of bioactive composite coatings on Mg-Zn-Ca alloy by MAO/sol-gel. AB - High corrosion rate and accumulation of hydrogen gas upon degradation impede magnesium alloys' clinical application as implants. In this work, micro-arc oxidation (MAO) was used to fabricate a porous coating on magnesium alloys as an intermediate layer to enhance the bonding strength of propolis layer. Then the composite coatings were fabricated using sol-gel method by dipping sample into the solution containing propolis and polylactic acid at 40 degrees C. The corrosion resistance of the samples was determined based on potentiodynamic polarization experiments and immersion tests. Biocompatibility was designed by observing the attachment and growth of wharton's jelly-derived mesenchymal stem cells (WJCs) on substrates with MAO coating and substrates with composite coatings. The results showed that, compared with that of Mg-Zn-Ca alloy, the corrosion current density of the samples with composite coatings decreased from 5.37 * 10-5 to 1.10 * 10-6 A/cm2 and the corrosion potential increased by 240 mV. Composite coatings exhibit homogeneous corrosion behavior and can promote WJCs cell adhesion and proliferation. In the meantime, pH value was relatively stable during the immersion tests, which may be significant for cellular survival. In conclusion, our results indicate that composite coatings on Mg-Zn-Ca alloy fabricated by MAO/sol-gel method provide a new type bioactive material. PMID- 21656034 TI - Two genera of Aulacoscelinae beetles reflexively bleed azoxyglycosides found in their host cycads. AB - Aulacoscelinae beetles have an ancient relationship with cycads (Cycadophyta: Zamiaceae), which contain highly toxic azoxyglycoside (AZG) compounds. How these "primitive" leaf beetles deal with such host-derived compounds remains largely unknown. Collections were made of adult Aulacoscelis appendiculata from Zamia cf. elegantissima in Panama, A. vogti from Dioon edule in Mexico, and Janbechynea paradoxa from Zamia boliviana in Bolivia. Total AZG levels were quantified in both cycad leaves and adult beetles by high performance liquid chromatography (HPLC). On average, cycad leaves contained between 0.5-0.8% AZG (frozen weight, FW), while adult beetles feeding on the same leaves contained even higher levels of the compounds (average 0.9-1.5% FW). High AZG levels were isolated from reflex bleeding secreted at the leg joints when beetles were disturbed. Nuclear magnetic resonance and mass spectroscopy identified two AZGs, cycasin and macrozamin, in the reflex bleeding; this is the first account of potentially plant-derived compounds in secretions of the Aulacoscelinae. These data as well as the basal phylogenetic position of the Aulacoscelinae suggest that sequestration of plant secondary metabolites appeared early in leaf beetle evolution. PMID- 21656035 TI - Doxycycline attenuates peripheral inflammation in rat experimental autoimmune neuritis. AB - Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system and widely used animal model of human inflammatory demyelinating polyradiculoneuropathies. Doxycycline is a well-known antibiotic and has been reported to have neuroprotective and anti-inflammatory effects. Here we investigated the effects of doxycycline on rat EAN. Therapeutic treatment with doxycycline (40 mg/kg body weight daily from the Day 9 to Day 14 post immunization) significantly attenuated the severity of EAN, decreased inflammatory infiltration of macrophages, B- and T cells and demyelination in sciatic nerves of EAN rats. Pro-inflammatory molecules including matrixmetalloproteinase-9, inducible nitric oxide synthase and interleukin-17 were greatly decreased in sciatic nerves by administration of doxycycline as well. Taken together, our data showed that doxycycline could effectively suppress the peripheral inflammation to improve outcome of EAN, which suggests that doxycycline may be considered as a potential candidate of pharmacological treatment for neuropathies. PMID- 21656036 TI - Polymorphisms of presenilin-1 gene associate with dilated cardiomyopathy susceptibility. AB - Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. It is the third leading causes of heart failure and the most common cause of heart transplantation due to its ventricular dilatation and contractile dysfunction. Currently, four hypothesized pathogenic mechanisms have been proposed: genetic predisposition, persistent cardiotropic viral infection, autoimmunity, and cell apoptosis. Presenilin-1 gene has been previously found to be associated with cell apoptosis and cardiac development. To assess the role of presenilin-1 in DCM, we examined two single nucleotide polymorphisms (SNPs) in presenilin-1 gene, namely, rs1800844 and rs177415. A total of 282 DCM patients and 306 controls were included in the study, and all SNPs were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Compared with controls, the frequency of AA and AC genotypes and the A allele at SNP rs177415 were significantly increased in DCM patients. No difference of the SNP genotype and allele frequencies at SNP rs1800844 was detected between DCM and control groups. Unconditional logistic regression adjusting for type 2 diabetes, hyperlipidemia, cigarette smoking, and gender, confirmed the association between that SNP rs177415 of the presenilin-1 gene and the susceptibility of DCM (adjusted OR 1.300, 95% CI 1.013-1.669; P = 0.039). Our data indicate, for the first time, the association of the presenilin-1 gene SNPs with human DCM and the allele A at SNP rs177415 in presenilin-1 gene may increase the risk of DCM. PMID- 21656037 TI - [Trochanteric femoral fractures: anatomy, biomechanics and choice of implants]. AB - The objective of any surgical care of a trochanteric femoral fracture should be the achievement of a stable osteosynthesis that allows early full weight-bearing mobilisation of the patient, because long-term immobilisation soon becomes a vital threat to the affected patients who are usually elderly with correlating comorbidities. The anatomical references of the proximal femur and the structure of the hip joint contain some specifics that play an essential role in the incurrence of a trochanteric femoral fracture and the planning of the osteosynthesis as well. With reposition and fracture stabilisation particular importance must be attached to the collo-diaphyseal and the antetorsion angle so that they do not interfere with the functional interaction of the hip and knee joint. Uncomplex trochanteric fractures ordinarily stabilise sufficiently after reposition so that even an extramedullary implant can ensure full weight-bearing stability. With evermore distal fracture course and intertrochanteric comminution zone, rotational instability and pivot transfer of the fracture area to lateral and caudal are followed by an increase of the dislocating forces. These kinds of fractures (A2 and A3 according to the AO/ASIF classification) profit from an intramedullary and rotationally stable osteosynthesis. Basically primary total hip arthroplasty is a potential option for surgical care of a trochanteric fracture in elderly patients with relevant coxarthrosis. However this procedure can only be recommended in cases of a stable uncomplex fracture. The more the medial interlocking of the proximal femur is destroyed the more difficult it will be to primarily implant a total hip prosthesis with good offset and without a varus and rotational failure in the fracture zone.The current studies in the main show disadvantages due to increased complications in these patients, so that in cases of an unstable trochanteric fracture a primary osteosynthesis should be performed followed by total hip arthroplasty after fracture consolidation has occurred. PMID- 21656038 TI - Hypoxia-induced oxidative DNA damage links with higher level biological effects including specific growth rate in common carp, Cyprinus carpio L. AB - Both hypoxia and hyperoxia, albeit in different magnitude, are known stressors in the aquatic environment. Adopting an integrated approach, mirror carp (Cyprinus carpio L.), were exposed chronically (i.e. 30 days) to hypoxic (1.8 +/- 1.1 mg O(2) l(-1)) and hyperoxic (12.3 +/- 0.5 mg O(2) l(-1)) conditions and resultant biological responses or biomarkers were compared between these two treatments as well as with fish held under normoxic conditions (7.1 +/- 1.04 mg O(2) l(-1)). The biomarkers determined included the activities of glutathione peroxidase (GPx), measurement of oxidative DNA damage (using modified Comet assay employing bacterial enzymes: Fpg and Endo-III), haematological parameters, histopathological and ultrastructural examination of liver and gills. Specific growth rate (SGR) of the fish, as an important ecotoxicological parameter was also determined over the exposure period. The study suggested that while the levels of hepatic GPx were unaffected, there was a significant difference in activity in the blood plasma under different exposure conditions; the hyperoxic group showed increased GPx activity by approximately 37% compared to normoxic group and the hypoxic group showed a decrease by approximately 38% than the normoxic group. Interestingly, oxidative DNA damage was significantly higher in both hypoxic and hyperoxic by approximately 25% compared to normoxic conditions, Fpg showing enhanced level of damage compared to the Endo-III treatment (P < 0.001). The haematological parameters showed enhanced values under hypoxic conditions. Transmission electron microscopic (TEM) studies revealed damage to liver and gill tissues for both the treatments. Interestingly, SGR of fish was significantly lowered in hypoxic by approx. 30% compared to normoxic condition and this was found to be correlated with DNA damage (R = -0.82; P = 0.02). Taken together, these results indicate that prolonged exposure to both hypoxic and hyperoxic conditions induce oxidative stress responses at both DNA and tissue levels, and hypoxia can result in compensatory changes in haematological and growth parameters which could influence Darwinian fitness of the biota with wider ecological implications. PMID- 21656039 TI - Clinical aspects of familial forms of frontotemporal dementia associated with parkinsonism. AB - Frontotemporal dementia is the second most common dementia among people under the age of 65. Fifty percent of affected patients have an associated family history. Several pathogenic genes have been identified for frontotemporal dementia associated with parkinsonism, including microtubule-associated protein tau, progranulin, and chromatin modifying protein 2B, and fused in sarcoma. It has also been reported that frontotemporal dementia associated with parkinsonism can be linked to chromosome 9p. In addition, there are families with frontotemporal dementia associated with a parkinsonian phenotype but unknown genetic status. Some of these kindreds have been diagnosed clinically as familial progressive supranuclear palsy, hereditary diffuse leukoencephalopathy with axonal spheroids, "overlap" syndrome, and others. Clinical presentation of frontotemporal dementia associated with parkinsonism is variable at age of symptomatic disease onset, disease duration, symptoms, and their occurrence during the disease course. Clinically, it is often difficult to sort out the different genetic forms of frontotemporal dementia associated with parkinsonism. However, with available clinical genetic testing for known genes, the precise diagnosis can be accomplished in some cases. PMID- 21656040 TI - Transcriptional responses to flooding stress in roots including hypocotyl of soybean seedlings. AB - To understand the transcriptional responses to flooding stress in roots including hypocotyl of soybean seedlings, genome-wide changes in gene expression were analyzed using a soybean microarray chip containing 42,034 60-mer oligonucleotide probes. More than 6,000 of flooding-responsive genes in the roots including hypocotyl of soybean seedlings were identified. The transcriptional analysis showed that genes related to photosynthesis, glycolysis, Ser-Gly-Cys group amino acid synthesis, regulation of transcription, ubiquitin-mediated protein degradation and cell death were significantly up-regulated by flooding. Meanwhile, genes related to cell wall synthesis, secondary metabolism, metabolite transport, cell organization, chromatin structure synthesis, and degradation of aspartate family amino acid were significantly down-regulated. Comparison of the responses with other plants showed that genes encoding pyrophosphate dependent phosphofructokinase were down-regulated in flooded soybean seedlings, however, those in tolerant plants were up-regulated. Additionally, genes related to RNA processing and initiation of protein synthesis were not up-regulated in soybean, however, those in tolerant plants were up-regulated. Furthermore, we found that flooding-specific up-regulation of genes encoding small proteins which might have roles in acclimation to flooding. These results suggest that functional disorder of acclimative responses to flooding through transcriptional and post transcriptional regulations is involved in occurring flooding injury to soybean seedlings. PMID- 21656041 TI - Torpedoes in the cerebellar vermis in essential tremor cases vs. controls. AB - The study of the postmortem changes in essential tremor (ET) is in its infancy, although recent evidence points to a central role of the cerebellum, where Purkinje cell axonal swellings ("torpedoes") are significantly more common in ET than control brains. Yet, all existing studies have been confined to the cerebellar hemispheres, and whether there is a more widely distributed cerebellar problem is presently unknown. Our aims were to address whether: (1) ET cases have greater numbers of torpedoes in the vermis than controls, (2) there a correlation between the extent of vermal torpedo pathology and hemispheric torpedo pathology, and (3) vermal torpedo pathology is correlated with clinical features of the disease. A parasagittal neocerebellar block and a vermal block were harvested from 24 ET and 10 control brains. Paraffin sections (7 MUm) were stained with Luxol fast blue/hematoxylin and eosin, and torpedoes were quantified. All torpedo counts were corrected for Purkinje cell layer length. Vermal corrected torpedo count (VermTc) was higher in ET cases than controls (7.1+/-6.8 [median, 4.3] vs. 2.6+/-2.5 [median, 2]), p=0.002). The VermTc and the hemispheric corrected torpedo count (HemTc) were correlated with one another (Spearman's r=0.54, p=0.002). ET cases with neck, voice, and jaw tremors had the highest VermTc (p=0.046). The abundance of torpedoes in the ET brain is not confined to the ponto- or neocerebellum but is more broadly distributed, also involving the spino or paleocerebellum. These data further confirm the central role of the cerebellum in the underlying pathophysiology of this common neurological disorder. PMID- 21656042 TI - Plasma selenium, zinc, copper and lipid levels in postmenopausal Turkish women and their relation with osteoporosis. AB - It has been shown that the trace elements and lipids play role in the growth, development and maintenance of bones. We aimed to investigate serum selenium (Se), zinc (Zn), copper (Cu) and lipid (total cholesterol, triglyceride (TG), high density lipoprotein-cholesterol, low-density lipoprotein-cholesterol) levels in postmenopausal women with osteoporosis, osteopenia and in healthy controls, and to determine the relationship between Se, Zn, Cu and lipid parameters and bone mineral density (BMD). The study included 107 postmenopausal women; 35 healthy (group 1), 37 osteopenic (group 2) and 35 osteoporotic (group 3). The women in all three groups were carefully matched for body mass index (BMI). Serum concentrations of Se, Zn and Cu were measured by atomic absorption spectrophotometry. Plasma Se, Cu, Zn and lipid levels were similar in all groups (p > 0.05). When we combined the women in each of the three groups, and considered them as one group (n = 107) we found a positive correlation between BMI and lumbar vertebra BMD, femur neck BMD, femur total BMD; a positive correlation between TG and femur neck BMD, femur total BMD; a positive correlation between Zn and lumbar vertebra BMD (total T score) (p < 0.05). There was no correlation between Se, Cu, Zn, P and lipid parameters (p > 0.05). Although BMI has a positive effect on BMD, trace elements and lipids, except Zn and TG, did not directly and correlatively influence BMD. Further studies are needed to clarify the role and relationship of trace elements and lipid parameters in postmenopausal osteoporosis. PMID- 21656043 TI - Determination of multi-residue insecticides of organochlorine, organophosphorus, and pyrethroids in wheat. AB - The undesirable effects of green revolution include residues of extensively used pesticides in various food commodities. Several studies showed that pesticides could cause health problems. Keeping in view the problem of pesticide residues in various food commodities, the present study was conducted on domestic stored wheat as well as on imported wheat for the qualitative and quantitative analysis of organochlorine, organophosphorus and pyrethroids. Among the imported wheat, 22.5% samples were found contaminated by organophosphorus (chlorpyrifos 0.073 0.230 MUg/g, malathion 0.0419-0.1003 MUg/g) and pyrethroids (cypermethrin 0.1404 0.2005 MUg/g, permethrin 0.0140-0.0480 MUg/g) while in domestic wheat 6.7% samples were found contaminated by pyrethroids (deltamethrin 0.0650-1.2903 MUg/g) only. Method used for extraction and analysis of insecticides was validated both by recovery studies and inter laboratory comparison proficiency test. The method recovery results show that the average recovery of the fortified wheat samples was in the range of 73.77%-100.17% with the RSD in the range of 2.21-9.27 whereas, the Z-scores of the inter laboratory comparison proficiency test's result was less than 2. PMID- 21656044 TI - A 3D-CT scan study of the humeral and glenoid planes in 150 normal shoulders. AB - PURPOSE: The purpose of the study was to determine the normal three-dimensional relationship between the humeral and the glenoid plane of the individual patient. We measured the three-dimensional angle between the glenoid plane and the humeral plane (glenohumeral angle, degrees GH) and the angle between the plane of the scapula and the plane of the glenoid (glenoscapular angle, degrees GS) with the patient in a standardized position to the CT scan gantry. We hypothesized that a normal distribution with a small variation would exist for both angles. METHODS: A total of 150 conventional CT scans of normal shoulders from patients aged between 18 and 80 years were examined and three-dimensional reconstructions were derived from it. The descriptive statistics and the variability of degrees GH and degrees GS were determined. RESULTS: The mean degrees GH was 57.9 degrees , and the mean degrees GS was -3.77 degrees . The overall reliability of the measurement was good. Descriptive statistics of this study confirm the normal distribution and a narrow variation of both parameters. CONCLUSIONS: This is the first study to determine the normal 3D relationship between the humerus and the glenoid ( degrees GH). This new three-dimensional anatomical information of the normal glenohumeral relationship and glenoid can be used to distinguish normal from pathological anatomy, as well as alternative surgical guidance especially in bony deficient glenoids. Level of Evidence Level II Anatomical Study. PMID- 21656045 TI - Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype. AB - Adult-onset primary torsion dystonia (AOPTD) is an autosomal dominant disorder with markedly reduced penetrance. Sensory abnormalities are present in AOPTD and also in unaffected relatives, possibly indicating non-manifesting gene carriage (acting as an endophenotype). The temporal discrimination threshold (TDT) is the shortest time interval at which two stimuli are detected to be asynchronous. We aimed to compare the sensitivity and specificity of three different TDT tasks (visual, tactile and mixed/visual-tactile). We also aimed to examine the sensitivity of TDTs in different AOPTD phenotypes. To examine tasks, we tested TDT in 41 patients and 51 controls using visual (2 lights), tactile (non-painful electrical stimulation) and mixed (1 light, 1 electrical) stimuli. To investigate phenotypes, we examined 71 AOPTD patients (37 cervical dystonia, 14 writer's cramp, 9 blepharospasm, 11 spasmodic dysphonia) and 8 musician's dystonia patients. The upper limit of normal was defined as control mean +2.5 SD. In dystonia patients, the visual task detected abnormalities in 35/41 (85%), the tactile task in 35/41 (85%) and the mixed task in 26/41 (63%); the mixed task was less sensitive than the other two (p = 0.04). Specificity was 100% for the visual and tactile tasks. Abnormal TDTs were found in 36 of 37 (97.3%) cervical dystonia, 12 of 14 (85.7%) writer's cramp, 8 of 9 (88.8%) blepharospasm, 10 of 11 (90.1%) spasmodic dysphonia patients and 5 of 8 (62.5%) musicians. The visual and tactile tasks were found to be more sensitive than the mixed task. Temporal discrimination threshold results were comparable across common adult-onset primary torsion dystonia phenotypes, with lower sensitivity in the musicians. PMID- 21656046 TI - Artificial neural network posturography detects the transition of vestibular neuritis to phobic postural vertigo. PMID- 21656047 TI - The relationship between reproductive work and sociodemographic and psychosocial factors in regard to psychological distress in men and women in Spain. AB - Studies have shown that some sociodemographic factors, such as marital status, employment status or social class, can affect mental health in different ways for each gender. However, up until now, few research projects have tried to ascertain if the role that reproductive work or psychosocial factors play in mental health is different for men and women. The aim of this study is to assess the differences between men and women in terms of how reproductive work, sociodemographic and psychosocial factors are linked to psychological distress in Spain. A cross-sectional study of 29,478 male and female adults using data gathered for the Spanish National Health Survey 2006 was carried out. Psychological distress was measured using the GHQ-12. The independent variables analyzed were: sociodemographic, psychosocial (family functionality and functional social support) and those related to reproductive work (living with or being in charge of different types of people needing care and number of hours devoted to caregiver tasks). Different independent logistic regression models were developed for men and women. In general, with the exception of men who were more prone to psychological distress if they were signed off work for 3 months or more, no major differences were observed regarding the effect of sociodemographic and psychosocial characteristics on psychological distress. With regard to reproductive work, the likelihood of psychological distress doubles in both sexes when the person lives with someone who needs care. In women, a greater number of hours devoted to caring for another person is associated with an increase in distress. Men play a less frequent role in caregiving, but the impact on psychological distress is similar to that in women. Women experienced more psychological distress when they had to live with or be in charge of a disabled person or different types of persons needing care, while men were not affected by this. Major differences have been identified in terms of psychological distress in women and men in several aspects of reproductive work to date unexplored. PMID- 21656048 TI - Seasonal changes of macroinvertebrate communities in a stormwater wetland collecting pesticide runoff from a vineyard catchment (Alsace, France). AB - Agricultural land use may influence macroinvertebrate communities by way of pesticide contamination associated with agricultural runoff. However, information about the relation between runoff-related pesticides and communities of benthic macroinvertebrates in stormwater wetland that receive agricultural runoff does not currently exist. Here we show changes in macroinvertebrates communities of a stormwater wetland that collects pesticide-contaminated runoff from a vineyard catchment. Sixteen runoff-associated pesticides, including the insecticide flufenoxuron, were continuously quantified at the inlet of the stormwater wetland from April to September (period of pesticide application). In parallel, benthic macroinvertebrate communities, pesticide concentrations, and physicochemical parameters in the wetland were assessed twice a month. Twenty-eight contaminated runoffs ranging from 1.1 to 114 m3 entered the wetland during the study period. Flufenoxuron concentrations in runoff-suspended solids ranged from 1.5 to 18.5 MUg kg(-1) and reached 6 MUg kg(-1) in the wetland sediments. However, flufenoxuron could not be detected in water. The density, diversity, and abundance of macroinvertebrates largely varied over time. Redundancy and formal concept analyses showed that concentrations of flufenoxuron, vegetation cover, and flow conditions significantly determine the community structures of stormwater wetland macroinvertebrates. This study shows that flow conditions, vegetation cover, and runoff-related pesticides jointly affect communities of benthic macroinvertebrates in stormwater wetlands. PMID- 21656049 TI - Additional value of 16alpha-[18F]fluoro-17beta-oestradiol PET for differential diagnosis between uterine sarcoma and leiomyoma in patients with positive or equivocal findings on [18F]fluorodeoxyglucose PET. AB - PURPOSE: Pathological data suggest that the rate of oestrogen receptor (ER) expression in uterine sarcoma is significantly lower than in leiomyoma. The present study aimed to investigate whether ER expression using ER imaging agents for positron emission tomography (PET), of which the most successful has been 16alpha-[18F]-fluoro-17beta-oestradiol (FES), is able to add useful information to the differential diagnosis of uterine sarcoma and leiomyoma in patients with positive or equivocal findings on [18F]fluorodeoxyglucose (FDG) PET. METHODS: A total of 76 patients with suspected uterine sarcoma based on ultrasound and magnetic resonance imaging findings from 2007 to 2010 were enrolled. Twenty-four of the present patients were referred for FES PET because of FDG PET findings that showed equivocal or positive FDG uptake. PET images were quantitatively evaluated with reference to histopathological findings. Receiver-operating characteristic analysis was performed to determine the optimal cutoff value to differentiate uterine sarcoma and leiomyoma. RESULTS: Of the 24 patients, 11 had a final diagnosis of uterine sarcoma, while 13 had leiomyoma. The sensitivity, specificity and accuracy of an FDG to FES standardized uptake value (SUV) ratio greater than 2.0 were significantly higher using Cochran's Q test (p=0.024) when compared with FDG PET greater than 3.0 alone (90.9 vs 81.8%, 92.3 vs 84.6% and 91.3 vs 83.3%, respectively). CONCLUSION: Additional FES PET findings confirmed uterine sarcoma in 91.3% of a selected group of patients with equivocal or positive FDG uptake. PMID- 21656051 TI - Adjacent segment degenerative disease: is it due to disease progression or a fusion-associated phenomenon? Comparison between segments adjacent to the fused and non-fused segments. AB - INTRODUCTION: The purpose of this study was to determine whether fusion causes adjacent segment degeneration or whether degeneration is due to disease progression. MATERIALS AND METHODS: Eighty-seven patients that had undergone single level anterior cervical decompression and fusions with at least 5 years of follow-up were enrolled in this retrospective study. Segments adjacent to fusion levels (above or below) were allocated to group A, and all others were allocated to group B. Radiographic evaluations of adjacent level changes included assessments of; disc degenerative changes, anterior ossification formation, and segmental instability. The developments of new clinical symptoms were also evaluated. RESULTS: In group A, adjacent segment degenerative change developed in 28 segments (16%) and two cases (2%) developed new clinical symptoms. In group B, adjacent segment degenerative change developed in 10 segments (3%), and two cases (0.7%) also developed new clinical symptoms. Additional operations were performed in one patient in each group. CONCLUSION: Although, fusion per se can accelerate the severity of adjacent level degeneration, no significant difference was observed between adjacent and non-adjacent segments in terms of the incidence of symptomatic disease. The authors conclude that adjacent segment disease is more a result of the natural history of cervical spondylosis than the presence of fusion. PMID- 21656050 TI - Mechanisms and management of doxorubicin cardiotoxicity. AB - Doxorubicin is an effective anti-tumor agent with a cumulative dose-dependent cardiotoxicity. In addition to its principal toxic mechanisms involving iron and redox reactions, recent studies have described new mechanisms of doxorubicin induced cell death, including abnormal protein processing, hyper-activated innate immune responses, inhibition of neuregulin-1 (NRG1)/ErbB(HER) signalling, impaired progenitor cell renewal/cardiac repair, and decreased vasculogenesis. Although multiple mechanisms involved in doxorubicin cardiotoxicity have been studied, there is presently no clinically proven treatment established for doxorubicin cardiomyopathy. Iron chelator dexrazoxane, angiotensin converting enzyme (ACE) inhibitors, and beta-blockade have been proposed as potential preventive strategies for doxorubicin cardiotoxicity. Novel approaches such as anti-miR-146 or recombinant NRG1 to increase cardiomyocyte resistance to toxicity may be of interest in the future. PMID- 21656052 TI - Is spinal stenosis assessment dependent on slice orientation? A magnetic resonance imaging study. AB - INTRODUCTION: Lumbar spinal stenosis (LSS) treatment is based primarily on the clinical criteria providing that imaging confirms radiological stenosis. The radiological measurement more commonly used is the dural sac cross-sectional area (DSCA). It has been recently shown that grading stenosis based on the morphology of the dural sac as seen on axial T2 MRI images, better reflects severity of stenosis than DSCA and is of prognostic value. This radiological prospective study investigates the variability of surface measurements and morphological grading of stenosis for varying degrees of angulation of the T2 axial images relative to the disc space as observed in clinical practice. MATERIALS AND METHODS: Lumbar spine TSE T2 three-dimensional (3D) MRI sequences were obtained from 32 consecutive patients presenting with either suspected spinal stenosis or low back pain. Axial reconstructions using the OsiriX software at 0 degrees , 10 degrees , 20 degrees and 30 degrees relative to the disc space orientation were obtained for a total of 97 levels. For each level, DSCA was digitally measured and stenosis was graded according to the 4-point (A-D) morphological grading by two observers. RESULTS: A good interobserver agreement was found in grade evaluation of stenosis (k = 0.71). DSCA varied significantly as the slice orientation increased from 0 degrees to +10 degrees , +20 degrees and +30 degrees at each level examined (P < 0.0001) (-15 to +32% at 10 degrees , -24 to +143% at 20 degrees and -29 to +231% at 30 degrees of slice orientation). Stenosis definition based on the surface measurements changed in 39 out of the 97 levels studied, whereas the morphology grade was modified only in two levels (P < 0.01). DISCUSSION: The need to obtain continuous slices using the classical 2D MRI acquisition technique entails often at least a 10 degrees slice inclination relative to one of the studied discs. Even at this low angulation, we found a significantly statistical difference between surface changes and morphological grading change. In clinical practice, given the above findings, it might therefore not be necessary to align the axial cuts to each individual disc level which could be more time-consuming than obtaining a single series of axial cuts perpendicular to the middle of the lumbar spine or to the most stenotic level. In conclusion, morphological grading seems to offer an alternative means of assessing severity of spinal stenosis that is little affected by image acquisition technique. PMID- 21656053 TI - Changes in smoking behavior among college students following implementation of a strict campus smoking policy in Taiwan. AB - OBJECTIVES: To understand the perception and responses among college students to a strict campus smoking policy which was in accordance with a national law requiring complete prohibition indoors and permission to smoke in designated outdoor smoking areas only. METHODS: This study was conducted in the third to sixth month after the implementation of the revised Tobacco Hazard Prevention Act in Taiwan. In-depth interviews were conducted with 22 smokers who were second and third year students of a college in Taiwan. Thematic analysis was used to categorize ideas into concept themes. RESULTS: In interviews, most smokers revealed some modification in their smoking behavior and attitude: they sensed that smoking was unwelcome, reduced smoking in campus, thought about quitting, and tried to avoid exposing roommates in the dormitory. The reasons cited by the students for behavior change were grouped into four major themes: a changed smoking experience, change in social norm, the respect for law, and concern for others' health. CONCLUSIONS: Implementation of a strict smoking policy in college prompted smokers to markedly reduce smoking in campus. PMID- 21656054 TI - Alterations in architecture and metabolism induced by ultraviolet radiation-B in the carragenophyte Chondracanthus teedei (Rhodophyta, Gigartinales). AB - The in vivo effect of ultraviolet radiation-B (UVBR) in apical segments of Chondracanthus teedei was examined. Over a period of 7 days, the segments were cultivated and exposed to photosynthetically active radiation (PAR) at 80 MUmol photons m(-2) s(-1) and PAR + UVBR at 1.6 W m(-2) for 3 h per day. The samples were processed for electron microscopy and histochemistry; also was analyzed growth rates, mitochondrial activity, protein levels, content of photosynthetic pigments and photosynthetic performance. UVBR elicited increased cell wall thickness and accumulation of plastoglobuli, changes in mitochondrial organization and destruction of chloroplast internal organization. Compared to controls, algae exposed to PAR + UVBR showed a growth rate reduction of 55%. The content of photosynthetic pigments, including chlorophyll a and phycobiliproteins, decreased after exposure to PAR + UVBR. This result agrees with the decreased photosynthetic performance observed after exposing algae to PAR + UVBR. Irradiation also elicited increased activity of the antioxidant enzyme glutathione peroxidase and decreased mitochondrial NADH dehydrogenase activity, which correlated with the decreased protein content in plants exposed to PAR + UVBR. Taken together, these findings strongly indicate that UVBR negatively affects the architecture and metabolism of the carragenophyte C. teedei. PMID- 21656055 TI - Monitoring severe pre-eclampsia and eclampsia treatment in resource poor countries: skilled birth attendant perception of a new treatment and monitoring chart (LIVKAN chart). AB - The lack of easy to use protocols and monitoring charts in the management of pre eclampsia/eclampsia contribute to substandard care of women in resource poor settings. A treatment monitoring tool (LIVKAN chart) has been developed to improve the quality of care for these women. Based on feedback from skilled birth attendants (SBAs), a two page document which provides a visual record of the treatment and monitoring of women with severe pre-eclampsia/eclampsia over a 24 h period was developed. It also contains detailed treatment guidelines as well as a summary of the woman's treatment. A two page document on instructions for use of the chart was also developed. The chart design was evaluated by different level SBAs via a semi structured questionnaire. There was a 92% (109) response rate. About 30% (33) and 58% (63) of the respondents provided care to women in Primary Health Care and referral health care facilities respectively. Ninety eight percentage of respondents indicated that the chart would be of additional benefit in their care of women with pre-eclamptic/eclampsia. Seventy three percentage of respondents indicated that the chart would also be useful to lower health care facility SBAs. The design of the chart ensures that guidelines for managing/monitoring of patients are instantly available on a concise easy-to-use chart which confers added advantage over other chart designs. Having been evaluated by SBAs, acceptability and utilization in poor resource settings should be high. A study has been designed to evaluate the acceptability and effectiveness of this new monitoring chart in both BEOCs and CEOCs in two sub Saharan African countries. PMID- 21656056 TI - Teen motherhood and long-term health consequences. AB - The objective of this article is to examine the association of teen motherhood and long-term physical and mental health outcomes. The physical and mental health components (PCS and MCS) of the SF-12 Healthy Survey in the NLSY79 health module were used to assess long-term health outcomes of women who experienced teenage motherhood. Various familial, demographic, and environmental characteristics were indentified and controlled for that may have predicted teen motherhood and long term health outcomes. The two comparison groups for teen mothers were women who experienced teen-pregnancy only and women who were engaged in unprotected sexual activity as a teenage but did not experience pregnancy. Multivariate ordinary least squares regression was used for analysis. The average PCS and MCS for teen mothers was 49.91 and 50.89, respectively. Teen mothers exhibited poorer physical health later in life compared to all women as well as the comparison groups. When controlling for age, teen mothers had significantly lower PCS and MCS scores compared to all other women. Furthermore, when controlling for familial, demographic, and environmental characteristics, teen mothers exhibited significantly lower PCS and MCS scores. When comparing teen mothers to the two comparison groups, PCS was not statistically different although MCS was significantly lower in the teen-pregnancy group. Teen motherhood does lead to poorer physical health outcomes later in life. On the other hand, poorer mental health outcomes in later life may be attributed to the unmeasured factors leading to a teen pregnancy and not teen motherhood itself. Additional research needs to be conducted on the long-term consequences of teen motherhood. PMID- 21656057 TI - Exploring weathering: the relation of age to low birth weight among first generation and established United States-born Mexican-American women. AB - To determine the age-related patterns of low birth weight, preterm birth, and intrauterine growth retardation among first generation and established US-born Mexican-American mothers. We performed stratified analyses on an Illinois transgenerational dataset of Mexican-American infants (1989-1991) and their mothers (1956-1976) with appended U.S. census income information. In Cook County, Illinois established (second or higher generation) US-born Mexican-American women (N = 2,006) had a low birth weight (<2,500 g) rate of 6.2% compared to 4.8% for first generation US-born Mexican-American women (N = 1,450), RR = 1.3 (1.0-1.6). In both subgroups, low birth weight, preterm, and intrauterine growth retarded components rates did not increase with advancing maternal age. First generation 30-35 year old US-born Mexican-American women (N = 159) had a low birth weight rate of 3.1% compared to 4.2% for their teen counterparts (N = 386), RR = 0.8 (0.3-2.0). Established 30-35 year old US-born Mexican-American women (N = 330) had a low birth weight rate of 4.9% compared to 7.4% for their teen counterparts (N = 459), RR = 0.7 (0.4-1.2). There was no evidence of weathering among US-born Mexican-American mothers with a lifelong residence in lower income neighborhoods, with a general downward trend in low birth weight rates with increasing age until age 30-35. Rates of low birth weight, preterm birth, and intrauterine growth retardation do not increase with advancing age among first generation and established US-born 15-35 year old Mexican-American women. This trend persists among both generations of women with a lifelong residence in lower income neighborhoods. PMID- 21656059 TI - Negotiating authorship. PMID- 21656058 TI - Smoking cessation and relapse among pregnant African-American smokers in Washington, DC. AB - Smoking is the single most preventable cause of perinatal morbidity. This study examines smoking behaviors during pregnancy in a high risk population of African Americans. The study also examines risk factors associated with smoking behaviors and cessation in response to a cognitive behavioral therapy (CBT) intervention. This study is a secondary analysis of data from a randomized controlled trial addressing multiple risks during pregnancy. Five hundred African-American Washington, DC residents who reported smoking in the 6 months preceding pregnancy were randomized to a CBT intervention. Psycho-social and behavioral data were collected. Self-reported smoking and salivary cotinine levels were measured prenatally and postpartum to assess changes in smoking behavior. Comparisons were made between active smokers and those abstaining at baseline and follow-up in pregnancy and postpartum. Sixty percent of participants reported quitting spontaneously during pregnancy. In regression models, smoking at baseline was associated with older age, 40% diameter stenosis. Lipid laden neointima was defined as a region with marked signal attenuation and a diffuse border. Four (22.2%) of 18 patients with VLST had ruptured and lipid laden neointima inside DESs without uncovered or malapposed stent struts. In the remaining 14 patients who developed VLST without neointimal rupture, uncovered and malapposed struts were observed in nine and seven patients, respectively, and lipid-laden neointima in four patients. Lipid-laden neointima was more frequently observed in four patients with neointimal rupture than in 14 patients without neointimal rupture (100% vs. 28.6%, respectively, P = 0.023). Of 57 patients with neointimal hyperplasia, eight (14.0%) had lipid-laden neointima. Time to OCT study after DES implantation was significantly longer in the eight patients with lipid-laden neointima than in 49 patients without lipid-laden neointima (45.5 +/- 17.7 months vs. 11.7 +/- 7.2 months, respectively, P < 0.001). Lipid-laden neointima was detected in some patients with neointimal hyperplasia > 1 year after DES implantation. In addition to uncovered or malapposed struts, rupture of lipid-laden neointima inside DESs was identified in some patients with DES related VLST. PMID- 21656062 TI - Principles of hatchet-skin flap for repair of tissue defects on the cheek. AB - BACKGROUND: To date, cheek reconstruction remains a challenge for plastic surgeons. This report presents the authors' cheek reconstruction technique with different types of hatchet-skin flaps, which provides satisfactory results. METHODS: The cheek area was divided into three parts (P1, P2, and P3), with vertical lines passing through the medial and lateral canthus. Different types of hatchet-skin flaps were used to repair the tissue defects in each part. The study population consisted of 29 patients divided into three groups according to the location of the defect (G1, G2, and G3). Patient satisfaction was evaluated 1 year after the operation using a questionnaire concerning five important aspects: color match, texture match, scar visibility, morbidity, and function. RESULTS: The 29 patients (17 men and 12 women) ranged in age from 19 to 81 years. The sizes of the defects ranged from 1.5*1.5 to 2.5*3.5 cm. All the flaps survived. The patients' ages and defect sizes did not differ between the three groups. The mean rating of each evaluation was high in all three groups. The mean rating for scar visibility on a 5-point scale was significantly lower for G1 than for G3. CONCLUSION: The hatchet-skin flap procedure is a versatile technique for the repair of medium defects in the three parts of the cheek. The defects in each part of the cheek should be repaired separately depending on the characteristics of the natural lines. PMID- 21656063 TI - Carbon dioxide: maybe not the only one but an efficient and secure gas for treating local adiposities. PMID- 21656064 TI - Be the change: excerpts from the plenary address at the 41st National Council Mental Health and Addictions Conference, May 2, 2011. PMID- 21656065 TI - [Real-time feedback systems for improvement of resuscitation quality]. AB - The quality of chest compression is a determinant of survival after cardiac arrest. Therefore, the European Resuscitation Council (ERC) 2010 guidelines on resuscitation strongly focus on compression quality. Despite its impact on survival, observational studies have shown that chest compression quality is not reached by professional rescue teams. Real-time feedback devices for resuscitation are able to measure chest compression during an ongoing resuscitation attempt through a sternal sensor equipped with a motion and pressure detection system. In addition to the electrocardiograph (ECG) ventilation can be detected by transthoracic impedance monitoring. In cases of quality deviation, such as shallow chest compression depth or hyperventilation, feedback systems produce visual or acoustic alarms. Rescuers can thereby be supported and guided to the requested quality in chest compression and ventilation. Feedback technology is currently available both as a so-called stand alone device and as an integrated feature in a monitor/defibrillator unit. Multiple studies have demonstrated sustainable enhancement in the education of resuscitation due to the use of real-time feedback technology. There is evidence that real-time feedback for resuscitation combined with training and debriefing strategies can improve both resuscitation quality and patient survival. Chest compression quality is an independent predictor for survival in resuscitation and should therefore be measured and documented in further clinical multicenter trials. PMID- 21656066 TI - Laparoscopic versus open treatment for benign pancreatic insulinomas: an analysis of 89 cases. AB - BACKGROUND: The use of a laparoscopic approach in the treatment of insulinomas is increasing. This retrospective study aimed to evaluate the authors' experience with laparoscopic surgery for benign pancreatic insulinomas and to compare the results for a laparoscopic approach versus an open approach. METHODS: From January 2000 to December 2009, data were collected retrospectively from 89 patients who underwent resection of pancreatic insulinoma via either laparoscopy (n = 43) or laparotomy (n = 46). Clinical data, tumor features, and intra- and postoperative characteristics were analyzed. RESULTS: The operation time, blood loss, and complication rate did not differ significantly between the laparoscopic and open approach groups. In the laparoscopic group, the time required to achieve recovery of gastrointestinal function and postoperative oral intake was significantly shorter in the laparotomy group, as was the hospital stay. By the end of the follow-up period, 85 (95.5%) of the 89 patients were symptom free. CONCLUSIONS: Laparoscopic surgery is a safe procedure for patients with benign insulinomas. The complication rates are comparable with those for laparotomy procedures. Relative to open operations, laparoscopic pancreas operations are associated with a more rapid postoperative recovery. PMID- 21656067 TI - Robot-assisted parenchymal-sparing liver surgery including lesions located in the posterosuperior segments. AB - OBJECTIVE: The aim of the study is to describe techniques of robot-assisted parenchymal-sparing liver surgery. BACKGROUND: Laparoscopy provides the same oncologic outcomes as open liver resection and better early outcome. Limitations of laparoscopy remain resections in posterior and superior liver segments, frequently approached with laparoscopic right hepatectomy, bleeding from the section line, and prolonged operative times when a combined procedure is needed. METHODS: We retrospectively analyzed our series of robot-assisted liver resections between 2008 and September 2010 to evaluate whether robot assistance can overcome the limitations of laparoscopy. RESULTS: A total of 23 patients underwent robot-assisted liver resection for a total of 21 subsegmentectomies, 6 segmentectomies, 2 segmentectomies S6 + subsegmentectomies S7, 1 bisegmentectomy S2-3, and 2 pericystectomies. In ten cases (47.8%) liver nodules were located in the posterior and superior liver segments. In three cases the tumor was in contact with a main portal branch and in two cases with a hepatic vein. In one case the tumor had contact with both hepatic vein and portal branch. In the latter cases a no-margin resection was carried out. In 16 cases (65.5%) liver resection was associated with a concomitant procedure (10 laparoscopic colectomies, 1 robotic rectal resection, 3 laparoscopic radiofrequency ablations, and 2 extensive adhesiolyses). Mean operative time was 280 +/- 101 min, blood loss was 245 +/- 254 ml, and mean hospital stay was 8.9 +/- 9.4 days. Mortality was nil. One case of biliary leakage and two of intraoperative hemorrhage requiring transfusion were the main complications encountered. CONCLUSIONS: Robot assistance allows optimal access to all liver segments and facilitates parenchymal-sparing surgery also for lesions located in the posterosuperior segments or in contact with main liver vessels. PMID- 21656068 TI - Carbon dioxide insufflation during endoscopic retrograde cholangiopancreatography reduces bowel gas volume but does not affect visual analogue scale scores of suffering: a prospective, double-blind, randomized, controlled trial. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) and related procedures can cause abdominal pain and discomfort. Two clinical trials have indicated, using the visual analogue scale (VAS) score, that CO(2) insufflation during ERCP ameliorates the suffering of patients without complications, compared with air insufflation. However, differences in patient suffering between CO(2) and air insufflation after ERCP under deep conscious sedation have not been reported. We focused on the gas volume score (GVS) as an objective indicator of gas volume, and designed a multicenter, prospective, double-blind, randomized, controlled study with CO(2) and air insufflation during ERCP. METHODS: Between March 2010 and August 2010, 80 patients who required ERCP were enrolled and evenly randomized to receive CO(2) insufflation (CO(2) group) or air insufflation (air group). ERCP and related procedures were performed under deep conscious sedation with fentanyl citrate or pethidine and midazolam or diazepam. The GVS was evaluated as the primary endpoint in addition to the VAS score as the secondary endpoint. RESULTS: The GVS after ERCP and related procedures in the CO(2) group was significantly lower than that in the air group (0.14 +/- 0.06 vs. 0.31 +/- 0.11, P < 0.01), as well as the rate of increase in GVS ([GVS after - GVS before]/[GVS before ERCP and related procedures] * 100) (3.8 +/- 5.9 vs. 21 +/- 11.1%, P < 0.01). VAS scores 3 and 24 h after ERCP and related procedures were comparable between the CO(2) and air groups for abdominal pain, abdominal distension, and nausea. Additionally, VAS scores were not correlated with the GVS. CONCLUSIONS: CO(2) insufflation during ERCP reduces GVS (bowel gas volume) but not the VAS score of suffering compared with air insufflation. Deep and sufficient sedation during ERCP and related procedures is important for the palliation of patients' pain and discomfort. PMID- 21656069 TI - Minimizing hepatic trauma with a novel liver retraction method: a simple liver suspension using gauze suture. AB - BACKGROUND: Prolonged liver retraction during radical gastrectomy for adequate exposure of the hepatogastric ligament may lead to hepatic trauma. The authors offer a new minimally traumatic liver retraction method using a simple liver suspension with a gauze suture and compare it with the modified liver-puncture method. METHODS: This study retrospectively evaluated 92 patients who underwent the liver-suspension or liver-puncture method during gastric resections in 2010. Their clinical and operative characteristics were analyzed together with perioperative transaminases, and the two groups were compared. Patients with a history of liver disease, abnormal preoperative liver function test results, postoperative complications, or combined operations were excluded from the study. The liver-suspension method was performed using two 4 * 4-in. gauze pads threaded with a 2-0 Prolene suture, which were secured to the pars condensa with surgical clips and externally tied to suspend the liver toward the abdominal wall. RESULTS: Each liver retraction was completed without intraoperative complications. The patients in the liver-suspension group had more nonhepatic comorbidities than those in the liver-puncture group (P = 0.029). Other patient characteristics such as age, gender, and body mass index (BMI) did not differ between the two groups. No differences were found between the groups in terms of mean operative time (200.3 +/- 66.9 vs 214.9 +/- 74.4) or preoperative mean alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels. However, the patients in the liver-suspension group had significantly lower postoperative mean ALT levels (postoperative days 0, 1, 2, 3, and 5) and mean AST levels (postoperative days 0 and 1). CONCLUSION: Compared with the liver-puncture method, the authors' novel liver-suspension with suture-gauze technique is a safe and effective method for retracting the liver during laparoscopic and robotic upper abdominal surgeries. PMID- 21656070 TI - Major biliary complications in 2,714 cases of laparoscopic cholecystectomy without intraoperative cholangiography: a multicenter retrospective study. AB - BACKGROUND: The ongoing debate between routine and selective users of intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (LC) has not yet come to an end. Routine users argue that IOC decreases the rate of biliary complications such as bile duct injury, biliary leak and missed common bile duct (CBD) stones, a claim that selective users do not fully support. On the other hand, a third policy that was adopted by many other centers is performing LC without IOC. In this retrospective study, we are exploring the results of a relatively large multicenter series of LC without IOC regarding major biliary complications. METHODS: We performed a retrospective analysis of LC cases operated by experienced laparoscopic surgeons, without resorting to IOC, in four surgical units of university hospitals in Egypt during a 6-year period (January 2004 through December 2009). Excluded from the study were cases with positive predictors of CBD stones, namely, sonographically detected CBD dilatation and/or CBD stones, elevated bilirubin and/or alkaline phosphatase, persistent biliary pancreatitis, cholangitis, and those who had preoperative magnetic resonance cholangiography. RESULTS: Of the 2,955 cases of LC reviewed, 241 were excluded, leaving 2,714 cases enrolled in the study. Fifty-five cases (2%) were converted to open surgery. Five cases (0.18%) had major bile duct injuries requiring surgical repair. Postoperative bile leakage was encountered in seven cases (0.26%). Missed CBD stones were reported in six cases (0.22%). There was no perioperative mortality in the present study. CONCLUSION: LC can be performed safely without the use of IOC, with acceptable low rates of biliary complications provided that proper detection of patients with silent CBD stones is done and facilities for pre- and postoperative endoscopic retrograde cholangiopancreatography are available. PMID- 21656071 TI - Two-phase laparoscopic-assisted oesophago-gastrectomy: a single-unit experience of 111 consecutive cases and outcomes. AB - BACKGROUND: Minimal access surgery for oesophago-gastric cancer is topical and demanding, and approaches vary significantly. There is little data on the hybrid technique of laparoscopic-assisted two-phase oesophago-gastrectomy (LA2OG). Here we aim to review our experience, which exceeds 10 years, of this technique for oesophageal malignancy. METHODS: From June 1998 to May 2009, 111 patients underwent LA2OG. Patients included 84 men and 27 women with mean age 65 years (range 35-85 years). Retrospective analysis of indications, outcome, staging, complications and survival was performed. RESULTS: The majority of resections (96%) were performed for gastro-oesophageal junction or distal oesophageal pathology. Indications included adenocarcinoma (84.7%), squamous cell carcinoma (7.2%) and high-grade dysplasia (5.4%). Of patients, 67.6% received neoadjuvant chemotherapy. The median time for the laparoscopic phase was 207 min (range 105 600 min), and 420 min (range 210-780 min) overall. Estimated blood loss was 330 ml (range 100-1,200 ml). Median critical care and post-operative stays were 3 and 14 days, respectively. Over time, the radicality of surgery increased. From 1998 to 2001 median lymph node yield was 5, from 2002 to 2005 it was 12 nodes, and from 2006 to 2009 it was 28 nodes (p < 0.001). The overall complication rate was 38.7%, minor in 24.3%, with anastomotic leak rate of 5.5%. Median survival was 38.5 +/- 5.4 months. Thirty-day and in-hospital mortality were 1.8 and 2.7%, respectively. CONCLUSIONS: Two-stage laparoscopic-assisted oesophago-gastrectomy is a safe staged method of developing minimal access surgery for oesophago gastric cancer. This study provides a useful reference for comparison with other minimally invasive methods. PMID- 21656072 TI - Cost-efficiency of laparoscopic versus open colon surgery in a tertiary care center. AB - BACKGROUND: Real-world cost analysis of elective laparoscopic versus open colon resection in a tertiary Canadian teaching hospital was performed to evaluate the financial impact of minimally invasive surgery with the appointment of an experienced laparoscopic surgeon in a single-payer system. METHODS: A retrospective review of elective laparoscopic and open segmental colectomies (2005-2010) was performed. Combined cases and procedures performed for inpatients were excluded to minimize cost variation. The hospital case-costing system was used to calculate the hourly cost of operating room time and the daily hospital ward stay. The cost of disposable equipment was calculated manually. A cost minimization analysis was performed from the hospital perspective, which excludes physician payment. Cases were analyzed on an intention-to-treat basis. RESULTS: For this study, 470 right-side colectomies (322 open and 148 laparoscopic) and 266 left-side colectomies (181 open and 85 laparoscopic) were found to match the inclusion criteria. The operating room time was longer for the laparoscopic procedures than for the open procedures: 203.4 versus 173.4 min (P = 0.1) for right and extended right hemicolectomy (RC) and 287.4 versus 173.4 min (P = 0.009) for left and sigmoid colectomy (LC). This resulted in higher operating room costs: $4,094.10 versus $3312.11 for RC and $5,784.88 versus $4,582.55 for LC. The median hospital stay for an index admission was shorter for both sides: 5 days versus 8 days (P = 0.01) for RC and 4 days versus 6 days (P = 0.04). This resulted in lower ward costs: $4,556.07 versus $6,632.82 for RC and $3,297.24 versus $5,949.09 for LC. The cost of care per index admission after laparoscopic versus open resection was $10,097.93 versus $10,444.69 for RC and $11,067.72 versus. $11,146.56 for LC. The introduction of laparoscopic surgery has saved our institution $58,021.43 over 5 years. CONCLUSION: The reasons for observed differences in operating room time and length of hospital stay were uncontrolled and may be multifactorial. However, the results demonstrate that adopting a laparoscopic approach for elective colon surgery resulted in progressive financial savings. PMID- 21656073 TI - The LKB1 complex-AMPK pathway: the tree that hides the forest. AB - Initially identified as the Caenorhabditis elegans PAR-4 homologue, the serine threonine kinase LKB1 is conserved throughout evolution and ubiquitously expressed. In humans, LKB1 is causally linked to the Peutz-Jeghers syndrome and is one of the most commonly mutated genes in several cancers like lung and cervical carcinomas. These observations have led to classify LKB1 as tumour suppressor gene. Although, considerable dark zones remain, an impressive leap in the understanding of LKB1 functions has been done during the last decade. Role of LKB1 as a major actor of the AMPK/mTOR pathway connecting cellular metabolism, cell growth and tumorigenesis has been extensively studied probably to the detriment of other functions of equal importance. This review will discuss about LKB1 activity regulation, its effectors and clues on their involvement in cell polarity. PMID- 21656075 TI - Characterization of clonal vascular smooth muscle cell lines derived from young and old Fischer 344 rats. AB - A significant finding with aging humans (and aging animal models) is that blood vessels lose their ability to respond to beta-adrenergic receptor stimuli. Therefore, they produce less cyclic adenosine monophosphate (cAMP) and have decreased vasorelaxation with advancing age. This change likely contributes to hypertension, insufficient blood flow, and atherosclerosis. Our goal was to develop a vascular smooth muscle cell culture model that replicates the molecular and biochemical changes observed in blood vessels with advancing age. A clonal selection strategy was used to produce cell lines from 2-, 6-, 12-, and 24-month old male Fischer 344 rat aortae. Cultures were validated as smooth muscle cells with immunocytochemistry positive for alpha-actin and negative for von Willebrand factor VIII. Positive staining for G protein-coupled receptor kinase 2 indicated presence of this adrenergic receptor regulator. A total of n = 5 clones from n = 7 animals for each age group were initially analyzed for cAMP accumulation under three conditions: basal, isoproterenol stimulated, and forskolin stimulated. Results found that at passage 3, there was a significant reduction in cAMP accumulation to isoproterenol. However, this reduction disappeared by passage 6. Secondary analysis segregated clones into phenotypic age groups independent of donor animal age. Segregation identified n = 3 clones per group. At passage 3, the age-related change in the beta-adrenergic change was magnified. However, even with segregation, the adrenergic response was lost by passage 6. Our results show that early passaged clonal vascular smooth muscle cell cultures maintain their aging, adrenergic phenotype. Two separate strategies to identify age representative phenotypes into later passage were unsuccessful. PMID- 21656074 TI - Bioengineering the infarcted heart by applying bio-inspired materials. AB - Induction of cardiac muscle regeneration following myocardial infarction (MI) represents a major challenge in cardiovascular therapy, as the current clinical approaches are limited in their ability to regenerate a new muscle tissue and to replace infarcted myocardium. Here, we describe the conception of two strategies based on bio-inspired materials, aimed at myocardial repair after MI. In the first strategy, alginate biomaterial was designed with affinity-binding moieties, enabling the binding of heparin-binding proteins and their controlled presentation and release. The combined features of this unique alginate hydrogel, as a temporary extracellular matrix replacement and a depot for bio-molecules such as insulin-like growth factor-1 and hepatocyte growth factor, led to improvements in cardiac structure and function, as demonstrated by the biomaterial's abilities to thicken the scar and prevent left-ventricular remodeling and dilatation. Endogenous regeneration occurring at the infarct as manifested by the enhanced angiogenesis, cardiomyocyte proliferation, and appearance of cardiac-related stem cells is likely to have contributed to this. In the second strategy, phosphatidylserine (PS)-presenting liposomes were developed to mimic apoptotic cells bodies, specifically their capability of immunomodulating activated macrophages into anti-inflammatory state. In a rat model of acute MI, targeting of PS-presenting liposomes to infarct macrophages after injection via the femoral vein was demonstrated by magnetic resonance imaging. The treatment promoted angiogenesis, the preservation of small scars, and prevention of ventricular dilatation and remodeling. Collectively, the two bio-inspired material-based strategies presented herein represent unique and clinical accessible approaches for myocardial infarct repair. PMID- 21656076 TI - Additional copies of CBX2 in the genomes of males of mammals lacking SRY, the Amami spiny rat (Tokudaia osimensis) and the Tokunoshima spiny rat (Tokudaia tokunoshimensis). AB - Tokudaia osimensis (the Amami spiny rat) and Tokudaia tokunoshimensis (the Tokunoshima spiny rat) have a sex chromosome composition of XO/XO, no Y chromosome. The mammalian sex-determining gene, SRY, is also absent in these species, which indicates that these spiny rats exhibit a novel sex-determining mechanism that is independent of SRY. To identify a candidate gene that controls this mechanism, the copy numbers and chromosomal locations of 10 genes with important functions in gonadal differentiation were determined: ATRX, CBX2 (M33), DMRT1, FGF9, NR0B1 (DAX1), NR5A1 (Ad4BP/SF1), RSPO1, SOX9, WNT4, and WT1. Multiple bands were detected for NR0B1 in Southern blot analysis, which suggested the presence of multiple copies of the gene in the genomes of these two species. CBX2 was localized to two loci in both sexes of the two species by fluorescence in situ hybridization mapping: 3q24 and 6p11.2 in T. osimensis and 10q25-q26 and 14q12-q13.1 in T. tokunoshimensis. Quantification of copy numbers in the two species by quantitative real-time PCR indicated that there were two or three more copies of CBX2 per haploid genome in males (T. osimensis, n = 3; T. tokunoshimensis, n = 2) than in females (T. osimensis, n = 4; T. tokunoshimensis, n = 2), whereas NR0B1 was present as a single copy in both. The results suggest that additional copies of CBX2 in males might be involved in a novel sex determining mechanism in species that lack SRY. PMID- 21656077 TI - Tandem repeats on an eco-geographical scale: outcomes from the genome of Aegilops speltoides. AB - The chromosomal pattern of tandem repeat fractions of repetitive DNA is one of the most important characteristics of a species. In the present research, we aimed to detect and evaluate the level of intraspecific variability in the chromosomal distribution of species-specific Spelt 1 and Aegilops-Triticum specific Spelt 52 tandem repeats in Aegilops speltoides and in closely related diploid and polyploid species. There is a distinct eco-geographical gradient in Spelt 1 and Spelt 52 blocks abundance in Ae. speltoides. In marginal populations, the number of Spelt 1 chromosomal blocks could be 12-14 times lower than in the center of the species distribution. Also, in related diploid species, the abundance of Spelt 52 correlates with evolutionary proximity to Ae. speltoides. Finally, the B- and G-genomes of allopolyploid wheats have Spelt 1 chromosomal distribution patterns similar to those of the types of Ae. speltoides with poor and rich contents of Spelt 1, respectively. The observed changes in numbers of blocks of Spelt 1 and Spelt 52 tandem repeats along the eco-geographical gradient may due to their depletion in the marginal populations as a result of increased recombination frequency under stressful conditions. Alternatively, it may be accumulation of tandem repeats in conducive climatic/edaphic environments in the center of the species' geographical distribution. Anyway, we observe a bidirectional shift of repetitive DNA genomic patterns on the population level leading to the formation of population-specific chromosomal patterns of tandem repeats. The appearance of a new chromosomal pattern is considered an important factor in promoting the emergence of interbreeding barriers. PMID- 21656078 TI - The shunting of arachidonic acid metabolism to 5-lipoxygenase and cytochrome p450 epoxygenase antagonizes the anti-cancer effect of cyclooxygenase-2 inhibition in head and neck cancer cells. AB - BACKGROUND: It has recently been found that 5-lipoxygenase (5-LO) and cytochrome P450-2J2 (CYP2J2), molecules capable of arachidonic acid (AA) metabolism, might promote cancer cell viability through several mechanisms similar to those of cyclooxygenase-2 (COX-2). We found that not only COX-2 expression, but also the expression of 5-LO and CYP2J2 is up-regulated in head and neck squamous cell carcinoma (HNSCC) cell lines. From these observations, we hypothesized that AA metabolism by 5-LO and/or CYP2J2 may lower the efficacy of anti-cancer effect by COX-2 inhibition. METHODS AND RESULTS: Although COX-2 was highly expressed in all cell lines tested, COX-2-specific inhibition showed little growth-inhibitory effect in some cell lines. Inhibition of COX-2 resulted in increased production of LTB(4) and 14-15-DHET/EET, metabolites of 5-LO and CYP2J2, respectively. Combined knock-down of COX-2 and 5-LO or CYP2J2 by siRNA results in a decrease in cell proliferation and VEGF production. Furthermore, these results are dependent on 5-LO and CYP2J2 expression in cells. CONCLUSION: Therefore, combined inhibition of COX-2 and 5-LO or CYP2J2 may be one way to overcome low efficacy of single inhibition of COX-2 in cancer cells. In addition, combined therapies should be chosen based on the expression of members of other AA metabolism pathways. PMID- 21656079 TI - The effects of celebrity suicide on copycat suicide attempt: a multi-center observational study. AB - BACKGROUND: The effect of celebrity suicides on copycat suicide attempts is not well known. Our objective was to determine the association between celebrity suicide and copycat suicide attempts. METHODS: We conducted a retrospective multicenter observational time series analysis. Celebrity suicides were selected by an operational definition via three nationwide television news internet sites from January 2005 to December 2008. The reference week was defined as the week preceding date of suicide notification to the public. Then two pre-event weeks and four post-event weeks were analyzed for suicide attempts. We derived a prediction model for suicide attempt visits for each ED for these seven observational weeks using a General Additive Model with data from the National Emergency Department Information System (NEDIS) database. We calculated the mean excess visit (EV = observed visit - expected visit) and mean excess visit ratio (EVR = EV/expected visit). We tested the mean EV and EVR between reference weeks versus the observational weeks using independent t test and repeated measures ANOVA. RESULTS: Five celebrity suicides occurred during the study period. Total number of ED visits was 5,453,441 in the 85 EDs over the 4-year period, and suicide attempt or self-injury occurred in 27,605. The mean excess visit for each observational interval per ED was less than 0.1 during pre-event periods but increased to 0.695 in the second post-event week. EVs were significantly higher in the first to the third post-event weeks (p = 0.02, p < 0.01, p = 0.03, respectively) compared to reference week. The mean EVRs were significantly higher (=0.215) in the second post-week intervals compared with the reference week (p = 0.03). Mean EVs and mean EVRs showed significant increase in the post event period compared with the observational period (p = 0.001 in EV, p = 0.021 in EVR). CONCLUSION: From a prediction model using a 4-year nationwide ED database, ED visits for suicide attempts or self injury increased following the announcements of celebrity suicides. PMID- 21656080 TI - Modeling the effects of vaccination and treatment on pandemic influenza. AB - In this paper, we demonstrate the uses of some simple mathematical models for the study of disease dynamics in a pandemic situation with a focus on influenza. These models are employed to evaluate the effectiveness of various control programs via vaccination and antiviral treatment. We use susceptible-, infectious , recovered-type epidemic models consisting of ordinary differential equations. These models allow us to derive threshold conditions that can be used to assess the effectiveness of vaccine and drug use and to determine disease outcomes. Simulations are helpful for examining the potential consequences of control options under different scenarios. Particularly, results from models with constant parameters and models with time-dependent parameter functions are compared, demonstrating the significant differences in model outcomes. Results suggest that the effectiveness of vaccination and drug treatment can be very sensitive to factors including the time of introduction of the pathogen into the population, the beginning time of control programs, and the levels of control measures. More importantly, in some cases, the benefits of vaccination and antiviral use might be significantly compromised if these control programs are not designed appropriately. Mathematical models can be very useful for understanding the effects of various factors on the spread and control of infectious diseases. Particularly, the models can help identify potential adverse effects of vaccination and drug treatment in the case of pandemic influenza. PMID- 21656081 TI - Fusion of color Doppler and magnetic resonance images of the heart. AB - This study was designed to establish and analyze color Doppler and magnetic resonance fusion images of the heart, an approach for simultaneous testing of cardiac pathological alterations, performance, and hemodynamics. Ten volunteers were tested in this study. The echocardiographic images were produced by Philips IE33 system and the magnetic resonance images were generated from Philips 3.0-T system. The fusion application was implemented on MATLAB platform utilizing image processing technology. The fusion image was generated from the following steps: (1) color Doppler blood flow segmentation, (2) image registration of color Doppler and magnetic resonance imaging, and (3) image fusion of different image types. The fusion images of color Doppler blood flow and magnetic resonance images were implemented by MATLAB programming in our laboratory. Images and videos were displayed and saved as AVI and JPG. The present study shows that the method we have developed can be used to fuse color flow Doppler and magnetic resonance images of the heart. We believe that the method has the potential to: fill in information missing from the ultrasound or MRI alone, show structures outside the field of view of the ultrasound through MR imaging, and obtain complementary information through the fusion of the two imaging methods (structure from MRI and function from ultrasound). PMID- 21656082 TI - Site-specific tryptophan oxidation induced by autocatalytic reaction of polysorbate 20 in protein formulation. AB - PURPOSE: Tryptophan (Trp) oxidation leading to atypical degradation of a protein (Fab) formulated with polysorbate 20 (PS20) was investigated. Such atypical Trp oxidation was discussed in relation to a kinetic model that involves initiation of oxidizing free radical through an autocatalytic reaction. METHODS: Ion exchange chromatography and peptide mapping were used to determine Trp oxidation. Peroxides in PS20 and free radicals in Fab samples were detected by fluorometric assay and electron paramagnetic resonance (EPR), respectively. RESULTS: PS20 with increased peroxides level led to degradation of Fab stored at 30 degrees C. Degradation was characterized as Trp50 oxidation, which was not observed in a Fab variant where His31 was replaced. EPR peaks related to known spin adducts of 5,5 dimethylpyrroline N-oxide were detected in Fab exhibiting Trp oxidation, indicating free radicals were present. Trp oxidation of Fab observed in several drug product lots with different degradation rates fits an autocatalytic reaction model that involves free radicals. EDTA, catalase, and free tryptophan prevented oxidation. CONCLUSIONS: A metal-binding amino acid, His31, was responsible for Trp50 oxidation of Fab induced by peroxides in PS20 present in the protein formulation. Oxidation was induced by autocatalytic degradation of PS20 and could be inhibited by antioxidants. PMID- 21656084 TI - Massive portal venous air and pneumatosis intestinalis associated with cocaine induced mesenteric ischemia. AB - BACKGROUND: We report a 53-year-old female who presented to the emergency department in distress with an acute abdomen after recreational use of cocaine. DISCUSSION: The patient's computed tomography scan revealed extensive portal venous air with small-bowel pneumatosis intestinalis resulting from intestinal ischemia. Air could be seen throughout the superior mesenteric vein, portal vein, and hepatic portal venous distribution. The patient underwent extensive resuscitation and resection of small bowel requiring three operative interventions. A pertinent review of the literature of cocaine-induced small bowel ischemia is provided covering the pathophysiology, clinical findings, and epidemiology. CONCLUSION: Cocaine-induced mesenteric ischemia is a serious disease causing significant morbidity and mortality. Operative therapy is often required. PMID- 21656085 TI - Endoscopic mucosal resection of Barrett's esophagus and early esophageal cancer. PMID- 21656083 TI - Case files of the medical toxicology fellowship at Drexel University. Rhabdomyolysis and compartment syndrome following acute diphenhydramine overdose. PMID- 21656086 TI - Pyrosequence analysis of unamplified and whole genome amplified DNA from hydrocarbon-contaminated groundwater. AB - Pyrosequence data was used to analyze the composition and metabolic potential of a metagenome from a hydrocarbon-contaminated site. Unamplified and whole genome amplified (WGA) sequence data was compared from this source. According to MG RAST, an additional 2,742,252 bp of DNA was obtained with the WGA, indicating that WGA has the ability to generate a large amount of DNA from a small amount of starting sample. However, it was observed that WGA introduced a bias with respect to the distribution of the amplified DNA and the types of microbial populations that were accessed from the metagenome. The dominant order in the WGA metagenome was Flavobacteriales, whereas the unamplified metagenome was dominated by Actinomycetales as determined by RDPII and CARMA databases. According to the SEED database, the subsystems shown to be present for the individual metagenomes were associated with the metabolic potential that was expected to be present in the contaminated groundwater, such as the metabolism of aromatic compounds. A higher percentage (4.4) of genes associated with the metabolism of aromatic compounds was identified in the unamplified metagenome when compared to the WGA metagenome (0.66%). This could be attributed to the increased number of hydrocarbon degrading bacteria that had been accessed from this metagenome (Mycobacteria, Nocardia, Brevibacteria, Clavibacter, Rubrobacter, and Rhodoccocus). Therefore, it was possible to relate the taxonomic groups accessed to the contamination profile of the metagenome. By collating the sequencing data obtained pre- and post-amplification, this study provided insight regarding the survival strategies of microbial communities inhabiting contaminated environments. PMID- 21656088 TI - On the relation between the Eigen model and the asexual Wright-Fisher model. AB - We show that the Eigen model and the asexual Wright-Fisher model can be obtained as two different limit cases of a single stochastic model. This result is used to enlighten the mathematical similarities and differences among these two models.The two key concepts introduced with the Eigen model, the error threshold and the quasispecies, are not invalidated by these differences, so that they are naturally present also in population genetics models. According to this fact, we use the classical diploid mutation-selection equation and the single peak fitness approximation to obtain the error threshold for sexual diploids. Finally, we perform the same analysis in the asexual case and compare the results. PMID- 21656087 TI - Childhood abuse as a risk factor for sleep problems in adulthood: evidence from a U.S. national study. AB - BACKGROUND: Accumulating evidence indicates that stress impairs sleep quality. Few studies, however, have examined the extent to which early life stress can jeopardize sleep in adulthood. PURPOSE: Guided by a life course epidemiological perspective on health, this study examined associations between childhood abuse and adult sleep problems. METHODS: We used data from 835 respondents in the National Survey of Midlife Development in the United States (MIDUS). Self-report measures assessed the frequency of physical, emotional, and sexual abuse in childhood, as well as global and component indicators of sleep problems in adulthood. RESULTS: Having experienced all three types of childhood abuse-even infrequently-was associated with global sleep pathology, as well as specific types of sleep problems. Reports of both frequent physical and frequent emotional abuse-even in the absence of sexual abuse-were also associated with poor sleep. CONCLUSIONS: Childhood abuse is a risk factor for individuals' long-term sleep problems. PMID- 21656089 TI - Mars approach for global sensitivity analysis of differential equation models with applications to dynamics of influenza infection. AB - Differential equation models are widely used for the study of natural phenomena in many fields. The study usually involves unknown factors such as initial conditions and/or parameters. It is important to investigate the impact of unknown factors (parameters and initial conditions) on model outputs in order to better understand the system the model represents. Apportioning the uncertainty (variation) of output variables of a model according to the input factors is referred to as sensitivity analysis. In this paper, we focus on the global sensitivity analysis of ordinary differential equation (ODE) models over a time period using the multivariate adaptive regression spline (MARS) as a meta model based on the concept of the variance of conditional expectation (VCE). We suggest to evaluate the VCE analytically using the MARS model structure of univariate tensor-product functions which is more computationally efficient. Our simulation studies show that the MARS model approach performs very well and helps to significantly reduce the computational cost. We present an application example of sensitivity analysis of ODE models for influenza infection to further illustrate the usefulness of the proposed method. PMID- 21656090 TI - Comparison of MMP-3 levels in rheumatoid arthritis after treatment with tocilizumab or infliximab for 12 weeks. PMID- 21656091 TI - Effects of sevoflurane on voltage-gated sodium channel Na(v)1.8, Na(v)1.7, and Na(v)1.4 expressed in Xenopus oocytes. AB - Sevoflurane is widely used as a volatile anesthetic in clinical practice. However, its mechanism is still unclear. Recently, it has been reported that voltage-gated sodium channels have important roles in anesthetic mechanisms. Much attention has been paid to the effects of sevoflurane on voltage-dependent sodium channels. To elucidate this, we examined the effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 expressed in Xenopus oocytes. The effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 sodium channels were studied by an electrophysiology method using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes. Sevoflurane at 1.0 mM inhibited the voltage-gated sodium channels Na(v)1.8, Na(v)1.4, and Na(v)1.7, but sevoflurane (0.5 mM) had little effect. This inhibitory effect of 1 mM sevoflurane was completely abolished by pretreatment with protein kinase C (PKC) inhibitor, bisindolylmaleimide I. Sevoflurane appears to have inhibitory effects on Na(v)1.8, Na(v)1.4, and Na(v) 1.7 by PKC pathways. However, these sodium channels might not be related to the clinical anesthetic effects of sevoflurane. PMID- 21656092 TI - [Difference of opinion]. PMID- 21656093 TI - [Health care practice needs health services research: pros and cons of health services research from the perspective of health insurance funds]. AB - Health insurance funds need the results of health services research more than ever due to the socio-legal and socio-economic conditions currently prevailing. This should be possible by taking transparency and data protection into consideration, by cooperating with outside researchers while ensuring flexible use of routine data and if necessary gathering additional data, and by establishing links to epidemiological and registry data. It should become normative to clear the way for health insurance funds to regularly include this type of research in budget planning and to this end provide access to a suitable source of funds. In conclusion, it can simply be stated that it no longer suffices to effectively make a new clinically tested procedure, product, and service available because health insurance funds and their partners must know more precisely what this all accomplishes in practice. PMID- 21656094 TI - [Patient centeredness and decision-making in localised prostate cancer: possible fields of health services research in urology]. AB - BACKGROUND: Quality of care is essential for health services research. Therefore, our patients' preferences are of major importance and this can be illustrated by decision-making in localised prostate cancer. MATERIAL AND METHODS: A total of 349 patients reported on their preferred mode of decision-making, on their habits of information procurement, and on their feeling of being well informed. Moreover, we tried to objectify their actual knowledge. Their mean age was 63.0 years and mean PSA level 9.4 ng/ml. As 40% had a higher level of education we investigated possible influences of this feature by applying the chi-square test. RESULTS: Half of the patients preferred to share the treatment decision and 39% wanted to choose for themselves considering their physician's recommendation. The most important sources of information were treating physicians (88%) and the Internet (77%). All patients felt well informed and 94% knew their latest PSA count. Patients with a higher level of education had better knowledge of their clinical data and used the Internet more (84 vs 71%; p=0.007). CONCLUSIONS: Our patients actively take part in medical decision-making and thereby contribute significantly to everyday health care. Based on this aspect, the whole scope of urology is developed as a promising field of health services research. PMID- 21656095 TI - [Limits in health services research]. AB - Current limitations in health services research (HRS) in Germany are caused by issues of research funding, interest-driven commissioning, and restricted research conditions due to the structural and organizational context of the German health system. Methodological challenges arise in the validation and generalizability of routine data. There are substantial risks of bias in non controlled interventional studies. In order to overcome these limitations and to improve the standing and quality of HRS in Germany, political opinion leaders and stakeholders need to be provided with continuous information on the need and potential of HRS. Methodological standards are needed for the evaluation of routine data, and principles of evidence-based medicine must be applied in all research addressing the effectiveness of health care interventions. PMID- 21656096 TI - [Vesicoureteral reflux: diagnostics and therapy]. AB - The current management of vesicoureteral reflux (VUR) remains controversial. Recent well thought-out randomized studies on VUR in children have led to a debate on diagnostic and therapeutic algorithms. Individual parameters, such as age, gender, clinical course, renal function and scars, dysfunctional elimination syndrome and last but not least the compliance of the parents have gained in importance. Regarding recent data this article gives a summary of diagnostic steps and therapeutic management of VUR. PMID- 21656101 TI - Probing quadrupolar nuclei by solid-state NMR spectroscopy: recent advances. AB - Solid-state nuclear magnetic resonance (NMR) of quadrupolar nuclei has recently undergone remarkable development of capabilities for obtaining structural and dynamic information at the molecular level. This review summarizes the key achievements attained during the last couple of decades in solid-state NMR of both integer spin and half-integer spin quadrupolar nuclei. We provide a concise description of the first- and second-order quadrupolar interactions, and their effect on the static and magic angle spinning (MAS) spectra. Methods are explained for efficient excitation of single- and multiple-quantum coherences, and acquisition of spectra under low- and high-resolution conditions. Most of all, we present a coherent, comparative description of the high-resolution methods for half-integer quadrupolar nuclei, including double rotation (DOR), dynamic angle spinning (DAS), multiple-quantum magic angle spinning (MQMAS), and satellite transition magic angle spinning (STMAS). Also highlighted are methods for processing and analysis of the spectra. Finally, we review methods for probing the heteronuclear and homonuclear correlations between the quadrupolar nuclei and their quadrupolar or spin-1/2 neighbors. PMID- 21656102 TI - [Monoclonal antibody in the therapy of metastatic melanoma]. PMID- 21656103 TI - [72-year-old man with syncope and left hemiparesis]. AB - A 72-year-old man was admitted with left hemiparesis after a painless syncope with suspected ischemic stroke. So far he was a healthy man without any cardiovascular risk factors. A computed tomography scan of the head did not show any abnormal findings. In the clinical evaluation we revealed pulse deficits in the left-sided extremities and the blood pressure of the left arm was not measurable. The final diagnosis was an acute aortic dissection, beginning in the proximal portion of the ascending aorta, leading to the iliacal arteries. The patient was transferred and surgery was performed immediately with success. Painless acute aortic dissection presenting only with neurologic symptoms made the correct diagnosis extremely difficult. Correct diagnosis, however, is essential, otherwise thrombolytic therapy - indicated for acute-stage cerebral infarction - would have been performed, probably with a fatal outcome. PMID- 21656104 TI - Quantification of [18F]-FDG uptake in atherosclerotic plaque: impact of renal function. AB - OBJECTIVE: Impaired renal function causes both increased and prolonged tracer availability in the blood-pool which might result in increased tracer accumulation in atherosclerotic lesions. Therefore, the aim of this study was to investigate a possible correlation between the intensity of tracer uptake in atherosclerotic lesions and renal function. METHODS: Data from 50 [18F]-FDG scans were visually evaluated for tracer uptake in vessel wall alterations. Lesions were analyzed semiquantitatively by determining the blood-pool standardized uptake values (SUV(blood-pool)s), maximum SUVs (SUV(max)s), and the target-to background ratio (TBR). These parameters were tested for correlation with estimated glomerular filtration rate (eGFR), and cardiovascular risk factors. RESULTS: Both SUV(blood-pool)s (r(s) = -0.32, p = 0.03) and SUV(max)s for [18F] FDG (r(s) = -0.50, p < 0.0001) showed a significant negative correlation with eGFR. TBRs for [18F]-FDG demonstrated a significant positive correlation with eGFRs (r(s) = 0.21, p = 0.02). CONCLUSION: This study found that both intravascular tracer availability (SUV(blood-pool)) and intralesional tracer uptake (SUV(max)) are influenced by renal function. Calculation of TBR to account for that effect may result in overcorrection in case of [(18)F]-FDG. Renal insufficiency or subclinical changes in renal function have to be considered as a confounding factor in PET of atherosclerotic lesions. PMID- 21656105 TI - RETRACTED ARTICLE: Relationship between (18)F-FDG uptake on PET and various biologic molecular markers in benign pulmonary lesion: comparison with primary lung cancer. PMID- 21656106 TI - Supervisors' perception of the factors influencing the return to work of workers with common mental disorders. AB - INTRODUCTION: Over the last decade, common mental disorders have become an area of major concern in the field of work disability prevention due to the rising number of claims, costs, and impacts on quality of life. It has been shown that supervisory behavior influences return-to-work outcomes. This study aimed to investigate the perception held by supervisors involved in work disability management, of the factors facilitating or hindering the return to work of workers with common mental disorders. METHODS: This project consisted of an exploratory qualitative study. Semi-structured interviews were conducted of supervisors. All subjects had experience with the return to work of at least one worker who had been off work due to a common mental disorder (i.e., anxiety, mood or adjustment disorder). Content analysis of the transcripts was performed. RESULTS: A total of 11 supervisors from large and medium-sized companies participated in the project. Twenty-four factors that could hinder or facilitate the return-to-work process were found and classified into three main categories: factors related to the worker, work context, and return-to-work process. CONCLUSIONS: This study brought to light several factors influencing the return to work of workers with common mental disorders. Most of the supervisors interviewed were very open to finding ways to facilitate the return to work of these workers, but felt that the interventions used should take both their perspective and the constraints they face in the workplace into account. Subsequent studies on return to work should therefore focus equally on the individual and the workplace to ensure that the actions taken can be appropriately implemented and well received by all stakeholders, including supervisors, who are continually involved in front-line interventions. PMID- 21656107 TI - Characteristics of single-case designs used to assess intervention effects in 2008. AB - This article reports the results of a study that located, digitized, and coded all 809 single-case designs appearing in 113 studies in the year 2008 in 21 journals in a variety of fields in psychology and education. Coded variables included the specific kind of design, number of cases per study, number of outcomes, data points and phases per case, and autocorrelations for each case. Although studies of the effects of interventions are a minority in these journals, within that category, single-case designs are used more frequently than randomized or nonrandomized experiments. The modal study uses a multiple-baseline design with 20 data points for each of three or four cases, where the aim of the intervention is to increase the frequency of a desired behavior; but these characteristics vary widely over studies. The average autocorrelation is near to but significantly different from zero; but autocorrelations are significantly heterogeneous. The results have implications for the contributions of single-case designs to evidence-based practice and suggest a number of future research directions. PMID- 21656108 TI - [Treatment of disseminated granuloma annulare with anthralin]. AB - Granuloma annulare is a benign, often asymptomatic and self-limiting granulomatous skin disease. In cases of disseminated granuloma annulare, spontaneous regression is considerably less frequent than in localized forms so that therapy is often desired. Systemic treatments should always be assessed critically and reserved for patients who are severely affected and in whom treatment approaches with few side effects such as local application of anthralin do not suffice to achieve a satisfactory effect. PMID- 21656109 TI - [Environmental pollution and skin aging]. AB - Extrinsic skin aging is the skin aging process induced by environmental factors. The most prominent environmental factor leading to extrinsic skin aging is the sun; therefore extrinsic skin aging is also known as photoaging. However, numerous studies in recent years have shown that smoking leads to extrinsic skin aging. Further, very recently it has been shown, that environmental pollution by traffic is also associated with the occurrence of signs of extrinsic skin aging. Thus, in preventive skin aging strategies the long-term exposure towards air pollution by traffic must also be considered. PMID- 21656110 TI - [Uncommon cutaneous ulcerative and systemic sarcoidosis. Successful treatment with hydroxychloroquine and compression therapy]. AB - Sarcoidosis is a granulomatous multisystemic disease of unclear etiology, which can affect any organ. The cutaneous manifestations are variable, but ulcerative cutaneous sarcoidosis is very rare. One must rule out other granulomatous skin diseases, especially necrobiosis lipoidica. There is no standarized therapy; usually an interdisciplinary approach over years taking multiple side effects into consideration is needed. A 58-year-old woman with a long history of cutaneous, nodal and pulmonary sarcoidosis suddenly developed ulcerations within the disseminated skin lesions on her legs. The combination of systemic hydroxychloroquine and modern wound management lead to complete healing of the ulcers and a significant improvement in the remaining skin lesions. PMID- 21656112 TI - [Medical tumor therapy]. PMID- 21656113 TI - [Adjuvant systemic treatment of melanoma]. AB - Despite intensive clinical and research efforts during the last decades the prognosis for patients with stage IV melanoma still remains fatal. An efficient adjuvant treatment for patients with a high risk of relapse and metastases is one of the most urgent fields in clinical research. Systemic adjuvant chemotherapy was not beneficial in terms of relapse-free or overall survival improvement in several clinical trials. Treatment with IFN-alpha-2a and -2b treatment was the first and as yet only adjuvant therapy which has been proven to show a benefit in controlled studies and to gain approval in Germany in the indications for adjuvant therapy. Current clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon and on the other hand on testing new compounds, such as the CTLA4 inhibitor ipilimumab or a vaccination against the MAGE-A3 peptide. PMID- 21656115 TI - [Numerous pigmented lesions on sun-damaged skin. Where is the "wolf between the lambs"?]. AB - A 64-year-old patient presented with bronzed, sun-damaged skin presented with numerous light and dark brown macules, mainly with sharply demarcated with irregular borders, present. Dermatoscopy showed a faint, light and dark brown network, fingerprint-like structures and irregular, sharp, moth-eaten borders in most lesions. In contrast, one dark-brown and bluish, asymmetrical flat plaque on the patient's right arm showed blue-grey globules, blue ovoid structures and leaf like areas. Histology revealed a pigmented superficial basal cell carcinoma. Dermatoscopy allowed filtering out the malignant lesion easily despite the large number of solar lentigines and some melanocytic nevi because of the characteristic dermoscopic criteria and the "ugly duckling sign". PMID- 21656114 TI - [Systemic treatment of cutaneous lymphomas]. AB - The management of patients with primary cutaneous lymphomas requires first of all a diagnostic work-up in order to differentiate between patients with nodal non Hodgkin lymphomas with cutaneous manifestations and those with primary cutaneous lymphomas. In the latter an exact diagnosis of the type of cutaneous lymphoma has to be determined due to varying prognoses between the types of primary cutaneous lymphomas. In general, cutaneous lymphoma patients in early stages of disease can be treated successfully with skin-directed therapies. More advanced stages and some aggressive types like primary cutaneous diffuse large B-cell lymphoma, leg type or the leukemic variant of cutaneous T-cell lymphoma, the Sezary syndrome, require systemic treatment. The current recommendations regarding systemic therapy of patients with primary cutaneous lymphomas are reviewed. PMID- 21656116 TI - Newly developed back pain after subthalamic nucleus stimulation in Parkinson's disease. PMID- 21656117 TI - Middle turbinate vascularized flap for skull base reconstruction after an expanded endonasal approach. AB - INTRODUCTION: The expanded endonasal approaches to the skull base are modular approaches that arise from the sphenoidal sinus. The reconstructive techniques in these approaches are key to avoid postoperative complications. Available flaps for reconstruction include the pedicled nasoseptal flap, the transpterygoid temporoparietal fascia flap, and the posterior pedicle inferior turbinate flap (PPITF), among others. Recently, the middle turbinate flap has been described in a cadaveric study. We report our preliminary experience in the use of this middle turbinate vascularized flap for skull base reconstruction after expanded endonasal approaches. MATERIAL AND METHODS: Ten patients underwent reconstructive procedures with the mucoperiostial vascularized middle turbinate flap. Capability to cover the defect, closure success, operative time and complications related to the procedure are retrospectively analyzed. RESULTS: A satisfactory closure was obtained in all procedures, and there were no complications related to the technique. Required operative time was similar to the time employed for the nasoseptal flap. CONCLUSIONS: The vascularized middle turbinate flap is a reliable reconstructive technique for the reconstruction of moderate-sized skull base defects. It can be considered either as the first choice of closure or as an alternative to the nasoseptal flap when this is not available. Different flap combinations may facilitate skull base defect reconstruction. PMID- 21656118 TI - Effects of combining electrical stimulation with BDNF gene transfer on the regeneration of crushed rat sciatic nerve. AB - BACKGROUND AND AIMS: Various techniques have been investigated to enhance peripheral nerve regeneration including the application of low-intensity electrical stimulation (ES) and the administration of growth factors, especially brain-derived neurotrophic factor (BDNF). The purpose of this study was to investigate the effects of combining short-term (ES) and recombinant adenoviral vector-mediated BDNF (BDNF-Ad) transfer, in comparison to each sole modality, on peripheral nerve regeneration in a rat model with crush-injured sciatic nerve. METHODS: Sixty male Sprague-Dawley rats (250-300 g) were equally distributed into four groups; the control group, the ES group, the BDNF-Ad group, and the combination group (n = 15 each). A standard crush injury was introduced to the sciatic nerve. The control group received no treatment after injury, the ES group received 30 minutes of low-intensity ES, the BDNF-Ad group received an injection of recombinant BDNF-Ad (concentration = 10(11) pfu/MUl, 3 MUl/rat) after injury, and the combination group received both ES and BDNF-Ad. The rats were followed-up for 3 weeks. RESULTS: At the end of the follow-up period, the sciatic function index (ES =-39, BDNF-Ad =-38) and number of the retrogradely labeled sensory neurons were significantly increased in the ES group and the BDNF-Ad group (ES = 326, BDNF-Ad = 264), but not in the combined treatment group, compared to the control group (SFI = -53, retrogradely labeled neurons = 229). Axonal counts were highest in the ES group (7,208 axons), axonal densities in the BDNF group (10,598 axons/mm(2)), and the myelin thickness was greater in both groups as compared to the control group. The combined treatment group showed no signs of superior recovery compared to the other groups. CONCLUSIONS: Both the ES and the BDNF-Ad treatments were effective techniques enhancing the sciatic nerve regeneration following a crush injury in rats. Nevertheless, the combined treatment with ES and BDNF-Ad produces neither a synergistic effect nor an improvement in this injury model. PMID- 21656119 TI - Cerebral salt wasting syndrome in traumatic brain injury following therapeutic barbiturate coma. PMID- 21656120 TI - Physiological work demands of Spanish wildland firefighters during wildfire suppression. AB - PURPOSE: The aim of this study was to analyze the physiological demands and thermal strain of wildland firefighters during real wildfire suppression. METHODS: The response of core temperature and heart rate (HR) were analyzed in 200 wildland firefighters during wildfire suppression activities of different duration: <1 h (n = 52), 1-3 h (n = 70), 3-5 h (n = 44), and >5 h (n = 34). The exercise workload (TRIMP), the physiological strain index (PSI), and cumulative heat strain index (CHSI) were calculated using the time spent in different intensity zones, the HR, and core temperature. RESULTS: Mean HR was significantly higher (P < 0.05) in wildfires <1 h (133 +/- 2 bpm) and 1-3 h (128 +/- 1 bpm) versus 3-5 h (120 +/- 3 bpm) and >5 h (116 +/- 32 bpm). The time spent in higher intensity zones increased (P < 0.05) when wildfire duration increased. TRIMP accumulation increased with wildfire duration (54.9 +/- 3.2, 167.4 +/- 5.9, 296.0 +/- 8.3, 511.7 +/- 12.8 in <1, 1-3, 3-5, and >5 h, respectively). Neither core temperature (37.4 +/- 0.1 degrees C) nor PSI (4.5 +/- 0.2) were influenced by wildfire duration. The CHSI increased (p < 0.05) in the following order: <1 h (104 +/- 23), 1-3 h (1,396 +/- 275), 3-5 h (4,586 +/- 387), and >5 h (10,703 +/- 710). CONCLUSIONS: The results demonstrate the high work strain sustained by Spanish wildland firefighters during wildfire suppression. Both workload and CHSI increased with the wildfires duration although the pace of work was faster in wildfires of a shorter duration. PMID- 21656121 TI - Sampling of urinary cadmium: differences between 24-h urine and overnight spot urine sampling, and impact of adjustment for dilution. AB - PURPOSE: Urinary cadmium (U-Cd) sampling can be done either by 24-h urine or spot urine sampling, and adjustment for dilution is usually needed. The choice of sampling period and adjustment technique could, however, potentially induce bias. The aim of the study was to compare 24-h urine and spot urine sampling and two dilution adjustment techniques, when assessing U-Cd. METHODS: Separate 24-h urine (U24) and timed overnight spot urine (UON) samples were collected from 152 healthy kidney donors. U-Cd, creatinine concentration (U-Crea) and specific gravity (SG) were analysed. Differences between U24 and UON samples were tested using paired t test, and the effect of urinary flow rate (UF) was assessed by linear regression. RESULTS: The cadmium excretion rate (U-Cd/h) was lower in the UON than in U24 samples (mean 0.017 MUg/h vs. 0.021 MUg/h; p < 0.001). This decrease was found also for the creatinine-adjusted U-Cd (U-CdCrea) (mean 0.36 MUg/gC and 0.41 MUg/gC; p < 0.001). For U-Cd adjusted for specific gravity (U CdSG), the difference was reversed, but not statistically significant. The creatinine excretion rate (U-Crea/h) decreased at low UF, especially in the UON. CONCLUSIONS: Since U-Cd/h was lower in UON than in U24 samples, the former will underestimate the true Cd excretion. This was seen for U-CdCrea but not for U CdSG. However, it may be an advantage that the U-CdSG is similar, irrespective of sampling strategy. At low UF, U-CdCrea will be biased upwards. Whether U24 or UON samples adjusted for U-Crea or SG best reflect kidney-Cd is still unknown. PMID- 21656122 TI - An updated historical cohort mortality study of workers exposed to asbestos in a refitting shipyard, 1947-2007. AB - PURPOSE: To evaluate the long-term health effects of occupational asbestos exposure, an updated historical cohort mortality study of workers at a refitting shipyard was undertaken. METHODS: The cohort consisted of 249 male ship repair workers (90 laggers, 159 boiler repairers). To determine relative excess mortality, standardized mortality ratios (SMRs) were calculated using mortality rates among the Japanese male population. Mortality follow-up of study subjects was performed for the period from 1947 till the end of 2007. RESULTS: We identified the vital status of 87 (96.7%) laggers and 150 (94.3%) boiler repairers. Of these, 63 (72.4%) and 95 (63.3%), respectively, died. Laggers, who had handled asbestos materials directly, showed a significantly elevated SMR of 2.64 (95% confidence interval [CI]: 1.06-5.44) for lung cancer and 2.49 (95% CI: 1.36-4.18) for nonmalignant respiratory diseases. Boiler repairers, who had many opportunities for secondary exposure to asbestos and a few for direct exposure, showed no significant elevation in SMR for lung cancer but a significantly elevated SMR of 1.78 (95% CI: 1.06-2.81) for nonmalignant respiratory diseases. In an analysis according to duration of employment, there was a significantly elevated SMR of nonmalignant respiratory diseases in the longer working years group. Among workers from both jobs, no deaths caused by mesothelioma in addition to those in the original study were found and no subject died from larynx cancer. CONCLUSION: This updated study confirmed a significant excess of asbestos-related mortality from diseases such as lung cancer and nonmalignant respiratory diseases among workers in a refitting shipyard in Japan. PMID- 21656123 TI - Recovery intention: its association with fatigue in the working population. AB - PURPOSE: To investigate the association of the intention to recover from work with fatigue and its moderating effect on the link between occupational characteristics and fatigue. METHODS: Three hundred and eighty Austrian employees (nurses, teachers and administrative staff) participated in a survey assessing fatigue, the intention to create and engage in recovery activities and effort reward imbalance as a measure of job characteristics. Data were analysed by regression analysis. RESULTS: Recovery intention was negatively associated with fatigue. This association was especially pronounced under conditions of high effort-reward imbalance, thus suggesting a buffering effect. Effort-reward imbalance, in return, was positively related to prolonged fatigue, indicating that fatigue was partly work related in the present sample. CONCLUSIONS: Individuals differ in their intent to engage in recovery activities. Those high in recovery intention are less exhausted, especially under conditions of more demanding and less rewarding work characteristics. Thus, a promotion of recovery intentions could contribute to the prevention of work-related fatigue. PMID- 21656124 TI - Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome. AB - RATIONALE: Studies in the Fmr1 knockout (KO) mouse, a model of fragile X syndrome (FXS), suggest that excessive signaling through group I metabotropic glutamate receptors (mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role in the pathogenesis of FXS. Currently, no studies have assessed the effect of mGluR1 modulation on Fmr1 KO behavior, and there has not been an extensive behavioral analysis of mGluR5 manipulation in Fmr1 KO mice. OBJECTIVES: The goals for this study were to determine if pharmacologic blockade of mGluR1 may affect Fmr1 KO behavior as well as to expand on the current literature regarding pharmacologic blockade of mGluR5 on Fmr1 KO behavior. METHODS: Reduction of mGluR1 or mGluR5 activity was evaluated on a variety of behavioral assays in wild-type (WT) and Fmr1 KO mice through the use of antagonists: JNJ16259685 (JNJ, mGluR1 antagonist) and MPEP (mGluR5 antagonist). RESULTS: JNJ and MPEP decreased marble burying in both WT and Fmr1 KO mice without reductions in activity. Neither JNJ nor MPEP affected the prepulse inhibition in either WT or Fmr1 KO mice. JNJ did not affect Fmr1 KO motor coordination but did impair WT performance. MPEP improved a measure of motor learning in Fmr1 KO but not WT mice. While both JNJ and MPEP decreased the audiogenic seizures in the Fmr1 KO, MPEP completely abolished the manifestation of seizures. CONCLUSION: These data illustrate that, while the manipulation of either mGluR1 or mGluR5 can affect select behaviors in the Fmr1 KO, we observe greater effects upon mGluR5 reduction. PMID- 21656125 TI - Factors influencing the incidence of maxillofacial fractures. AB - PURPOSE: Maxillofacial injuries occur in a significant proportion of trauma patients. Trauma causes considerable economic expense due to procedural costs, the time a patient is off work, and the associated loss of income. For these reasons, it is an important health and economic issue. The aim of this study is to discuss the factors that may influence the incidence of maxillofacial fractures. As it is necessary to determine trends to help guide the development of new methods of injury prevention, preventative measures are also discussed. METHODS: An electronic search was undertaken in March 2011, including articles published between 1980 and 2011 with the terms "facial fractures" and "maxillofacial fractures" in the title. The texts of epidemiological studies were reviewed in order to identify factors that may influence the incidence of maxillofacial fractures. RESULTS: From the selected articles, ten factors were identified: age, gender, geographic region and cultural aspects, socioeconomic status, temporal and climatic influence, use of alcohol and drugs, compliance with road traffic legislation, domestic violence, osteoporosis, and etiology of the maxillofacial trauma. CONCLUSIONS: Care of injured patients should include not only management of the acute phase, but also combine preventive programs and interventional programs aimed at reducing the incidence of maxillofacial fractures. Therefore, there is a need to ensure strict compliance of traffic rules and regulations, implement improvement in automotive safety devices, organize prevention programs to minimize assaults, implement school education in alcohol abuse and handling potentially hostile situations (especially for men), improve protection during sporting activities, and legislate wearing of protective headgear in workers. Preventive strategies remain the cheapest way to reduce direct and indirect costs of the sequelae of trauma. Societal attitudes and behaviors must be modified before a significant reduction in the incidence of maxillofacial fractures will be seen. PMID- 21656127 TI - High-mobility group A1 proteins enhance the expression of the oncogenic miR-222 in lung cancer cells. AB - High-mobility group A1 (HMGA1) is a non-histone chromatin protein that has the ability to regulate the transcriptional activity of many genes. Overexpression of HMGA1 is associated with malignant cellular behavior in a range of human cancers but the underlying mechanism is largely unknown. Here we showed that in a cohort of non-small cell lung cancer (NSCLC) tumors, HMGA1 overexpression was immediately associated with enhanced expression of an oncogenic miRNA, namely, miR-222. Chromatin immunoprecipitation (CHIP) assay revealed that HMGA1 directly binds to the proximal promoter of miR-222 in NSCLC cells. We further showed that HMGA1 silencing reduced miR-222 transcriptional activity, whereas forced HMGA1 expression increased it, indicating that miR-222 is directly regulated by HMGA1. Based on in silico prediction, one of the putative targets of miR-222 is phosphatase 2A subunit B (PPP2R2A) which inhibits Akt phosphorylation (p-Akt). We demonstrated that miR-222 inhibited protein expression of PPP2R2A in NSCLC cells by directly interacting with its 3'-UTR region, leading to an obvious increase of p-Akt. HMGA1 silencing augmented PPP2R2A protein expression and inhibited Akt signaling, resulting in significantly retarded cell growth response to IGF-I. These results suggested that HMGA1 is a positive regulator of miR-222, and HMGA1 overexpression might contribute to dysregulation of Akt signaling in NSCLC. PMID- 21656126 TI - Neuroprotection by lomerizine, a prophylactic drug for migraine, against hydrogen peroxide-induced hippocampal neurotoxicity. AB - Migraine is one of the risk factor for ischemic stroke. The purpose of this study was to examine the effect of lomerizine, a prophylactic drug for migraine, on H(2)O(2)-induced cell death of hippocampal neurons. Cytosolic Ca(2+) concentration was measured using fura-2 as a Ca(2+) indicator. Cell death was estimated by trypan blue exclusion. In rat-cultured hippocampal neurons, the addition of H(2)O(2) induced biphasic Ca(2+) elevations and cell death. The H(2)O(2)-induced biphasic Ca(2+) elevations and cell death only occurred when extracellular Ca(2+) was present. The biphasic Ca(2+) elevation was mediated by Ca(2+) influx through the plasma membrane, but not Ca(2+) release from the intracellular Ca(2+) store. Both the early and late phases of H(2)O(2)-induced Ca(2+) influx were reduced by either a T- or L-type voltage-dependent Ca(2+) channel (VDCC) blocker, lomerizine. In fact, L-type VDCC (alpha(1C) subunit) and T-type VDCC (alpha(1G) subunit) mRNA were expressed in rat hippocampal neurons. Although an L-type VDCC blocker, nifedipine, partly suppressed the late phase of Ca(2+) influx in response to H(2)O(2), a T-type VDCC blocker, mibefradil, reduced both phases of Ca(2+) influx. Moreover, lomerizine and mibefradil strongly reduced H(2)O(2)-induced cell death, and nifedipine weakly reduced it. These findings suggest that the inhibition of H(2)O(2)-induced Ca(2+) influx through T type VDCC seems to be important in the protective effect of lomerizine against oxidative stress. It is possible that lomerizine may be a useful drug for prophylactic treatment of migraine, because migraine is a risk factor for ischemic stroke. PMID- 21656128 TI - 2-Methoxyestradiol-bis-sulfamate induces apoptosis and autophagy in a tumorigenic breast epithelial cell line. AB - In anticancer research where the focus is on finding agents that induces cell death while leaving non-tumorigenic cells less affected, a novel 2 methoxyestradiol derivative has come forth. 2-Methoxyestradiol-bis-sulfamate (2 MeOE2bisMATE) is a 2-methoxyestradiol derivative produced by bis-sulphamoylation, which possesses increased antiproliferative activity and biological availability. Several questions remain regarding the type of cell death mechanisms and possible induction of autophagy by 2-MeOE2bisMATE. The aim of this in vitro study was to investigate the cell death mechanisms exerted by 2-MeOE2bisMATE in an adenocarcinoma cell line (MCF-7) by analyzing its influence on cell growth, morphology, and possible induction of cell death. Spectrophotometry (crystal violet staining), transmission electron microscopy (TEM), light microscopy (hematoxylin and eosin staining), and fluorescent microscopy (Hoechst 33342, propidium iodide and acridine orange) were employed. Spectrophotometrical studies indicated that 2-MeOE2bisMATE decreased cell numbers to 75% in MCF-7 cells after 24 h and to 47% after 48 h of exposure. TEM demonstrated membrane blebbing, nuclear fragmentation, and chromatin condensation indicating the hallmarks of apoptosis. Light microscopy revealed the presence of several cells blocked in metaphase, and apoptotic cells were also observed. Fluorescent microscopy demonstrated increased lysosomal staining; suggesting the induction of autophagy. 2-MeOE2bisMATE shows therapeutic potential, as an, anticancer agent, and the investigation of the cell death mechanisms used by 2-MeOE2bisMATE, thus, warrants further investigation. PMID- 21656129 TI - Glutathione S-transferase variants as risk factor for essential hypertension in Italian patients. AB - Involvement of genetic polymorphisms in arterial hypertension has already been reported, including GST genes, with contrasting results. The present research evaluates the possible association between GST gene polymorphisms and essential hypertension (EH) in an Italian population sample. 193 hypertensive subjects and 210 healthy controls were recruited. Buccal cells were collected from each subject using an oral swab and DNA was extracted using the phenol:chloroform:isoamilic alcohol method. GST SNPs were determined using the PCR-RFLP method, while GST null polymorphisms were determined using a Multiplex PCR. Among GST polymorphisms, only the frequency of the GSTT1 null phenotype was significantly higher in hypertensive patients than in normotensive participants. GSTT1 null individuals were significantly associated with increased risk of hypertension [P < 0.001; adjusted OR 2.24 (1.43-3.50)]. In sex-based analysis, the risk was significantly higher in female hypertensives [P < 0.001; adjusted OR 3.25 (1.78-5.95)] but not in male subjects. This study analyzed all GST gene that, in other research, have been studied in relation to arterial hypertension and the GSTO polymorphisms, showing an association only with GSTT1. The results for the GSTO genes represent the first analysis of this GST class in relation to blood pressure regulation. The association between the GSTT1 null phenotype and EH was confirmed in the overall population and in women, but not in men. These data suggest that GSTT1 could be a sex-specific candidate gene for EH. PMID- 21656130 TI - Sinus pericranii: an overview and literature review of a rare cranial venous anomaly (a review of the existing literature with case examples). AB - Sinus pericranii is a rare vascular abnormality characterised by abnormal connections between the intra- and extracranial venous systems and is usually found in children. In most instances, a sinus pericranii presents as a soft scalp swelling that appears with the patient in the recumbent position and disappears in the erect position. We review two cases of sinus pericranii presented in adulthood and treated surgically with good outcomes. We have performed a search of the English literature using the PubMed database and reviewed the published cases to date to present an overview of this pathological entity. PMID- 21656132 TI - Pastoralists' perceptions of feed scarcity and livestock poisoning in southern rangelands, Ethiopia. AB - A survey was conducted between April and July 2007 to generate information on dry season feeding management and livestock poisoning in the southern rangelands of Ethiopia. A total of 119 pastoralists were interviewed using a semi-structured questionnaire. Moreover, additional information was obtained through informal discussions. The study revealed that pastoralists have rich knowledge of natural resource management and utilization and employ various strategies such as migration, collection of grasses and pods, and cutting branches to overcome feed scarcity during dry/drought periods. Migration of livestock and people to areas with better grazing is the widely used strategy. However, the implementation of this strategy is diminishing as a result of changes such as bush encroachment, expansion of settlements, and crop cultivation in dry-season grazing lands. The respondents also indicated the presence of poisonous plants in the rangeland, and about 20 such plants were identified by the respondents. Various species and classes of livestock are reported to be affected by toxic plants particularly in the dry and early rainy seasons when feed is in short supply. A more extensive survey is required to document all poisonous plants in the rangelands and to identify the major toxic principles in the different species. Future development interventions should consider the prevailing constraints and potentials of the rangelands with active participation of the pastoralists. PMID- 21656133 TI - Prevalence and species composition of ixodid ticks infesting horses in three agroecologies in central Oromia, Ethiopia. AB - A cross-sectional study was conducted to determine the species composition and prevalence of ixodid ticks infesting horses in three agroecological zones in central Ethiopia. For this purpose, a total of 1,168 horses were examined for tick infestation. An overall prevalence of 39.04% of tick infestation on horses was recorded. A total of 917 adult ticks were collected from infested horses. Amblyomma, Boophilus, Rhipicephalus, and Hyalomma genera with the respective prevalence of 3.2%, 1.8%, 29.2%, and 4.7% were identified. In the study, Rhipicephalus evertsi evertsi was encountered with the highest prevalence (15.8%) whereas Amblyomma gemma was with lowest prevalence (1.5%). From the highland, Hyalomma marginatum rufipes (3.1%), Hyalomma truncatum (1.0%), and Boophilus decoloratus (0.3%) were identified. From the midland, R. evertsi evertsi (27.5%), Rhipicephalus pulchellus (18%), Amblyomma variegatum (3.6%), B. decoloratus (2.8%), H. marginatum rufipes (2.6%), H. truncatum (1.8%), and A. gemma (1.5%) were identified. R. evertsi evertsi, 107 (27.5%), was with the highest prevalence in the midland. From the lowland, R. pulchellus (22.3%), R. evertsi evertsi (20%), H. truncatum (3.6%), A. gemma (3.1%), B. decoloratus (2.3%), H. marginatum rufipes (2.1%), and A. variegatum (1.5%) were identified. In the lowland, R. pulchellus, 87 (22.3%), was the most abundant tick species. The overall prevalence of tick infestation on horses was significantly (P<0.05) higher both in the midland, 225 (57.8%), and the lowland, 214 (54.87%), than the highland, 17 (4.4%). This suggests that horses in midland and lowland are at higher risk of tick infestation than those horses in the highland. Further studies on the role of ticks in transmission of diseases to equines and the importance of horses as alternative hosts in different parts of Ethiopia are needed. PMID- 21656131 TI - Cytokine networks in glioma. AB - Glioma is the most frequently occurring brain tumor, but the prognosis of patients with gliomas remains poor despite advances in surgery, radiotherapy, and chemotherapy. Therefore, great efforts have been made to develop improved therapeutic strategies. Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins that exert pleiotropic and redundant effects that promote the growth, differentiation, and activation of normal cells. Cytokines have either pro- or anti-inflammatory activity and immunosuppressive activity, depending on the microenvironment surrounding the tumor. The microenvironment consists of heterogeneous tumor cells, immune cells, and extracellular matrix. Modulation of the microenvironment by the tumor is essential for its growth and progress. Cytokine production acts as a means of communication in the tumor microenvironment. In this article, we review the cross-talk between cytokines in the tumor microenvironment and the cytokine therapies that have been used till date for glioma treatment. PMID- 21656134 TI - Primary intraosseous glomus tumor in a middle phalanx. PMID- 21656135 TI - Isolated femoral osseous megalymphatics with chylous reflux: case report and review of the literature. AB - We report here the clinical and imaging findings of marked dilatation of the intraosseous lymphatic vessels, "megalymphatics," with chylous reflux presenting with pain and extensive lytic changes in a femoral bone of a child. Multimodality imaging findings, including radiographs, magnetic resonance imaging, ultrasound, scintigraphy and percutaneous osseous lymphangiography are described. PMID- 21656136 TI - Use of the V-sign in the diagnosis of bucket-handle meniscal tear of the knee. AB - OBJECTIVE: Bucket-handle tear is a displaced vertical longitudinal tear of the meniscus. Several signs of the tear have been described on MRI but none in the axial plane. We propose to describe such a sign named the V-sign that is seen at the junction of the displaced fragment and the meniscus, which is in place. MATERIALS AND METHODS: MRI imaging of 25 surgically proven bucket-handle tears was reviewed for presence of the V-sign. Two control groups, one with normal menisci (n = 75) and one with surgically proven non-bucket-handle tears (n = 25), were also evaluated. Comparisons for presence or absence of the V-sign were performed among the three groups, and also for other commonly associated signs such as double PCL sign, double delta sign, and presence of ACL tear. Also, sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Among those with bucket-handle tear, 72% demonstrated the V sign while no participant in either control group had the V-sign (P <= 0.001). The V-sign occurred in 38% of those with double PCL sign, 55.6% with ACL tear, and 66.7% with double delta sign. The V-sign had higher sensitivity and negative predictive values than other signs related to bucket-handle tear. CONCLUSION: The V-sign, when seen on an axial plane image, is highly suggestive of bucket-handle tear. Our data suggest the benefit of using the V-sign for detecting bucket handle tears, perhaps even above other commonly used approaches. PMID- 21656137 TI - Advantages and challenges of increased antimicrobial copper use and copper mining. AB - Copper is a highly utilized metal for electrical, automotive, household objects, and more recently as an effective antimicrobial surface. Copper-containing solutions applied to fruits and vegetables can prevent bacterial and fungal infections. Bacteria, such as Salmonellae and Cronobacter sakazakii, often found in food contamination, are rapidly killed on contact with copper alloys. The antimicrobial effectiveness of copper alloys in the healthcare environment against bacteria causing hospital-acquired infections such as methicillin resistant Staphylococcus aureus (MRSA), Escherichia coli O157:H7, and Clostridium difficile has been described recently. The use of copper and copper-containing materials will continue to expand and may lead to an increase in copper mining and production. However, the copper mining and manufacturing industry and the consumer do not necessarily enjoy a favorable relationship. Open pit mining, copper mine tailings, leaching products, and deposits of toxic metals in the environment often raises concerns and sometimes public outrage. In addition, consumers may fear that copper alloys utilized as antimicrobial surfaces in food production will lead to copper toxicity in humans. Therefore, there is a need to mitigate some of the negative effects of increased copper use and copper mining. More thermo-tolerant, copper ion-resistant microorganisms could improve copper leaching and lessen copper groundwater contamination. Copper ion-resistant bacteria associated with plants might be useful in biostabilization and phytoremediation of copper-contaminated environments. In this review, recent progress in microbiological and biotechnological aspects of microorganisms in contact with copper will be presented and discussed, exploring their role in the improvement for the industries involved as well as providing better environmental outcomes. PMID- 21656139 TI - Expression of family 3 cellulose-binding module (CBM3) as an affinity tag for recombinant proteins in yeast. AB - Easy and low-cost protein purification methods for the mass production of commonly used enzymes that play important roles in biotechnology are in high demand. In this study, we developed a fast, low-cost recombinant protein purification system in the methylotrophic yeast Pichia pastoris using the family 3 cellulose-binding module (CBM3)-based affinity tag. The codon of the cbm3 gene from Clostridium thermocellum was optimized based on the codon usage of P. pastoris. The CBM3 tag was then fused with enhanced green fluorescent protein (CBM3-EGFP) or with inulinase and expressed in P. pastoris to demonstrate its ability to function as an affinity tag in a yeast expression system. We also examined the effects of glycosylation on the secreted CBM3-tag. The secreted wild type CBM3-EGFP was glycosylated; however, this had little influence on the adsorption of the fusion protein to the regenerated amorphous cellulose (RAC; maximum adsorption capacity of 319 mg/g). Two CBM3-EGFP mutants lacking glycosylation sites were also constructed. The three CBM3-EGFPs expressed in P. pastoris and the CBM3-EGFP expressed in Escherichia coli all had similar RAC adsorption capacity. To construct a tag-free recombinant protein purification system based on CBM3, a CBM3-intein-EGFP fusion protein was expressed in P. pastoris. This fusion protein was stably expressed and the self-cleavage of intein was efficiently induced by DTT or L: -cysteine. In this study, we were able to purify the recombinant fusion protein with high efficiency using both intein and direct fusion-based strategies. PMID- 21656138 TI - Development of a simple cultivation method for isolating hitherto-uncultured cellulase-producing microbes. AB - Although enrichment culture is typically employed to isolate cellulolytic microbes, this approach tends to favor fast-growing species and discriminates against all others. Therefore, efforts to prevent the overgrowth of fast-growing species are necessary to isolate novel cellulase-producing strains. In this study, we developed a simple culture method for isolating hitherto-uncultured microbes that possess cellulase activity, particularly exocellulase. In this method, the microbial source (a forest soil) was suspended in sterilized water and inoculated onto a mineral salts agar medium, which was then overlaid with filter paper to sandwich the microbial suspension between the agar surface and paper. The filter paper fibers served to immobilize the microbial cells and were the dominant carbon source. Following cultivation at 30 degrees C for 2 weeks, emerging colonies were isolated based on their morphology and were then subjected to phylogenetic and enzyme analyses. Using this method, 2,150 CFUs/g dry soil were obtained, and the ratio of fungal to bacterial isolates was approximately 4:1. Phylogenetic analyses revealed that most fungal and bacterial isolates belong to ten and two genera, respectively. Notably, all isolates possessed exocellulase activity, and several strains showed strong activity that was comparable to Trichoderma cellulase. Many isolates also exhibited cellulase and xylanase activity, and several strains possessed laccase activity. It is expected that the culture method described here will be useful for the isolation of hitherto-uncultured cellulolytic microbes and the identification of novel cellulases. PMID- 21656140 TI - 1,3-Propanediol production in a two-step process fermentation from renewable feedstock. AB - In this work, the production of 1,3-propanediol from glucose and molasses was studied in a two-step process using two recombinant microorganisms. The first step of the process is the conversion of glucose or other sugar into glycerol by the metabolic engineered Saccharomyces cerevisiae strain HC42 adapted to high (>200 g l(-1)) glucose concentrations. The second step, carried out in the same bioreactor, was performed by the engineered strain Clostridium acetobutylicum DG1 (pSPD5) that converts glycerol to 1,3-propanediol. This two-step strategy led to a flexible process, resulting in a 1,3-propanediol production and yield that depended on the initial sugar concentration. Below 56.2 g l(-1) of sugar concentration, cultivation on molasses or glucose showed no significant differences. However, at higher molasses concentrations, glycerol initially produced by yeast could not be totally converted into 1,3-propanediol by C. acetobutylicum and a lower 1,3-propanediol overall yield was observed. In our hand, the best results were obtained with an initial glucose concentration of 103 g l(-1), leading to a final 1,3-propanediol concentration of 25.5 g l(-1), a productivity of 0.16 g l(-1) h(-1) and 1,3-propanediol yields of 0.56 g g(-1) glycerol and 0.24 g g(-1) sugar, which is the highest value reported for a two step process. For an initial sugar concentration (from molasses) of 56.2 g l(-1), 27.4 g l(-1) of glycerol were produced, leading to 14.6 g l(-1) of 1.3 propanediol and similar values of productivity, 0.15 g l(-1) h(-1), and overall yield, 0.26 g g(-1) sugar. PMID- 21656141 TI - The secondary substrate binding site of the Pseudoalteromonas haloplanktis GH8 xylanase is relevant for activity on insoluble but not soluble substrates. AB - Previously, it has been demonstrated that the glycoside hydrolase family 8 xylanase from the psychrophylic bacterium Pseudoalteromonas haloplanktis (XPH) can bind substrate non-catalytically on the surface of its catalytic module. In the present study, the functional relevance of this secondary binding site (SBS) for the enzyme is investigated by site-directed mutagenesis and evaluation of activity and binding properties of mutant variants on a range of structurally different homoxylan and heteroxylan substrates. The SBS had an impact on the activity on insoluble substrates, whereas the activity on soluble substrates remained unaffected. Unexpectedly, the activity on a soluble oligomeric substrate was also affected for some mutants and results on a chromophoric polymeric model substrate were in contrast with the trends observed on the corresponding natural substrate. All in all, results show that the impact of the SBS on the activity of XPH is in part analogous to the functioning of some carbohydrate-binding modules in modular enzymes. PMID- 21656142 TI - Pancolitis during etanercept treatment of rheumatoid arthritis relapsing on the administration of further two TNF-alpha inhibitors. PMID- 21656143 TI - Improvement of cognitive function after a three-month pulmonary rehabilitation program for COPD patients. AB - The objective of the study was to evaluate the effect of multidisciplinary pulmonary rehabilitation program on cognitive function in COPD patients, adjusting for potential confounders (gender, age, tobacco consumption, and educational level). In this prospective study, 34 COPD patients were submitted to neuropsychological testing before and after a 3-month pulmonary rehabilitation program. A control group with 18 healthy subjects of similar age, sex, and educational status was used to compare the cognitive function of COPD patients and healthy subjects at baseline. The association between the rehabilitation and change on th scores of cognitive variables, adjusted for each covariate, was estimated by means of linear random-intercept regression models. At baseline, the COPD patients had worse cognitive function with regard to verbal learning, memory, subjective organization, and verbal processing in comparison to the healthy volunteers. The improvement in cognitive performance by the COPD patients was evidenced even after adjusting for the sociodemographic factors that could potentially interfere on cognitive function. Male gender and age less than 65 years old were associated to higher scores in verbal learning and memory at baseline and after the rehabilitation program. The clinical approach to COPD induced cognitive dysfunction should include participation in pulmonary rehabilitation programs. There were gender- and age-related differences in cognitive scores that persisted after rehabilitation. PMID- 21656144 TI - Adhesion molecules affected by treatment of lung cancer cells with epidermal growth factor. AB - Lung cancer is one of the leading causes of death in the world. Some tumor events are attributed to an important group of molecules (cadherins and integrins). We evaluated the interactions of cell adhesion molecules in cell lines from lung cancer. Two lung cancer cell lines were nonmetastatic (H358 and H441) and two were metastatic (H1299 and H292). All cell lines were treated with epidermal growth factor (EGF), and Western blot analysis was performed to assess the interactions between these proteins. The bronchoalveolar cells H358 showed the three analyzed proteins: E-cadherin, beta-catenin, and p120 catenin. The adenocarcinoma cells H441 did not present p120 catenin, and carcinoma cells did not show E-cadherin (H1299) or p120 catenin (H292). FAK (pTyr925) was dephosphorylated in adenocarcinoma cells H441, absent in carcinoma cells H1299, and upregulated in the other carcinoma cells H292. p130Cas showed no difference when the cell lines were treated with EGF for 30 min; it was absent in the metastatic carcinoma cells H1299. Paxillin was dephosphorylated in adenocarcinoma cells H441 and also absent in other metastatic carcinoma cells H292. Vinculin showed the same results, and talin was downregulated in adenocarcinoma cells H441 when the cells were treated with EGF. Rap1 was downregulated and PYK2 was upregulated in the same cell line. Our data help to comprehend the mechanism involved in cell migration to the blood and metastasis generation. In conclusion, the expression patterns of cell-cell adhesion were not affected by EGF treatment but it affected cell-extracellular matrix adhesion. PMID- 21656145 TI - High pregnancy intentions and missed opportunities for patient-provider communication about fertility in a South African cohort of HIV-positive women on antiretroviral therapy. AB - High fertility intentions amongst HIV-positive women have been reported elsewhere. Less is known about how clinical and HIV treatment characteristics correlate with fertility intentions. We use cross-sectional baseline data from a prospective cohort study to assess pregnancy intentions and patient-provider communication around fertility. Non-pregnant, HIV-positive women aged 18-35 on ART were recruited through convenience sampling at Johannesburg antiretroviral (ART) treatment facilities. Among the 850 women in this analysis, those on efavirenz had similar fertility intentions over the next year as women on nevirapine-based regimens (33% vs. 38%). In multivariate analysis, recent ART initiation was associated with higher current fertility intentions; there was no association with CD4 cell count. Forty-one percent of women had communicated with providers about future pregnancy options. Women on ART may choose to conceive at times that are sub-optimal for maternal, child and partner health outcomes and should be routinely counseled around safer pregnancy options. PMID- 21656146 TI - Improving participant understanding of informed consent in an HIV-prevention clinical trial: a comparison of methods. AB - Empirical research on informed consent has shown that study participants often do not fully understand consent information. This study assessed participant understanding of three mock consent approaches describing an HIV-prevention clinical trial in Lilongwe, Malawi prior to trial implementation. Pregnant women (n = 297) were systematically selected from antenatal-care waiting lines and sequentially allocated to receive an enhanced standard consent form (group 1), a context-specific consent form (group 2), or context-specific counseling cards (group 3). Understanding of research concepts and study procedures was assessed immediately postintervention and at 1-week follow-up. At postintervention, participants in groups 2 and 3 understood more about research concepts and study procedures compared with group 1. Group 3 participants also understood more about study procedures compared with group 2. At follow-up, participants in groups 2 and 3 continued to understand more about research concepts and study procedures. Context-specific approaches improved understanding of consent information in this study. PMID- 21656147 TI - Plasminogen K5 activates mitochondrial apoptosis pathway in endothelial cells by regulating Bak and Bcl-x(L) subcellular distribution. AB - Plasminogen Kringle 5(K5) is a proteolytic fragment of plasminogen, which displays potent anti-angiogenic activities. K5 has been shown to induce apoptosis in proliferating endothelial cells; however the exact mechanism has not been well explored. The present study was designed to elucidate the possible molecular mechanism of K5-induced endothelial cell apoptosis. Our results showed that K5 inhibited basic fibroblast growth factors activated in human umbilical vein endothelial cells (HUVECs), indicating proliferation in a dose-dependent manner and induced endothelial cell death via apoptosis. K5 exposure activated caspase 7, 8 and 9. These results suggested that both the intrinsic mitochondrial apoptosis pathway and extrinsic pathway might be involved in K5-induced apoptosis. K5 reduced mitochondrial membrane potential (MMP) of HUVECs, demonstrating mitochondrial depolarization in HUVECs. K5 increased the ratio of Bak to Bcl-x(L) on mitochondria, decreased the ratio in cytosol, and had no effect on the total amounts of these proteins. K5 also did not effect on Bax/Bcl 2 distribution. K5 increased the ratio of Bak to Bcl-x(L) on mitochondrial that resulted in mitochondrial depolarization, cytochrome c release and consequently the cleavage of caspase 9. These results suggested that K5 induces endothelial cell apoptosis at least in part via activating mitochondrial apoptosis pathway. The regulation of K5 on Bak and Bcl-x(L) distribution may play an important role in endothelial cell apoptosis. These results provide further insight into the anti-angiogenesis roles of K5 in angiogenesis-related ocular diseases and solid tumors. PMID- 21656148 TI - Singapore grouper iridovirus, a large DNA virus, induces nonapoptotic cell death by a cell type dependent fashion and evokes ERK signaling. AB - Virus induced cell death, including apoptosis and nonapoptotic cell death, plays a critical role in the pathogenesis of viral diseases. Singapore grouper iridovirus (SGIV), a novel iridovirus of genus Ranavirus, causes high mortality and heavy economic losses in grouper aquaculture. Here, using fluorescence microscopy, electron microscopy and biochemical assays, we found that SGIV infection in host (grouper spleen, EAGS) cells evoked nonapoptotic programmed cell death (PCD), characterized by appearance of cytoplasmic vacuoles and distended endoplasmic reticulum, in the absence of DNA fragmentation, apoptotic bodies and caspase activation. In contrast, SGIV induced typical apoptosis in non host (fathead minnow, FHM) cells, as evidenced by caspase activation and DNA fragmentation, suggesting that SGIV infection induced nonapoptotic cell death by a cell type dependent fashion. Furthermore, viral replication was essential for SGIV induced nonapoptotic cell death, but not for apoptosis. Notably, the disruption of mitochondrial transmembrane potential (DeltaPsim) and externalization of phosphatidylserine (PS) were not detected in EAGS cells but in FHM cells after SGIV infection. Moreover, the extracellular signal-regulated kinase (ERK) signaling was involved in SGIV infection induced nonapoptotic cell death and viral replication. This is a first demonstration of ERK-mediated nonapoptotic cell death induced by a DNA virus. These findings contribute to understanding the mechanisms of iridovirus pathogenesis. PMID- 21656149 TI - Biofeedback-assisted cardiovascular control in hypertensives exposed to emotional stress: a pilot study. AB - The study was aimed at examining the effect of a short Heart Rate-Biofeedback (HR BF) protocol on systolic (SBP) and diastolic (DBP) blood pressure levels and BP emotional reactivity. Twenty-four unmedicated outpatients with pre- and stage 1 hypertension, were randomly assigned to active treatment (BF-Training) or control (BP-Monitoring) group. Subjects in BF-Training Group underwent four BF sessions. Guided imagery of stressful events was introduced during sessions 3 and 4. Control participants self-monitored their BP at home for 4 weeks. Subjects in both groups performed an emotional Speech Test before and after the training (or monitoring) period. SBP and mean arterial pressure responses to the emotional Speech Test were significantly smaller after the BF-training than the BP monitoring. Moreover, clinic SBP and DBP were significantly reduced by about 10 mmHg in BF-Training Group, whereas they remained unchanged in control group. Self monitored BP decreased significantly in the active treatment group and not in control group. A short BF-training, including guided imagery of stressful events, was effective in reducing BP reactions to a psychosocial stressor. BP measured in the clinic, and self-monitored at home were also significantly reduced in the BF Training Group. HR-BF appears to be a suitable intervention for hypertensive patients, mostly when BP increase is associated with emotional activation. PMID- 21656150 TI - EEG biofeedback treatment improves certain attention and somatic symptoms in fibromyalgia: a pilot study. AB - Fibromyalgia (FMS) is a chronic, painful disorder often associated with measurable deficiencies in attention. Since EEG biofeedback (EEG-BF) has been used successfully to treat attention problems, we reasoned that this modality might be helpful in the treatment of attention problems in FMS. We also speculated that improvement in central nervous system (CNS) function might be accompanied by improvement in FMS somatic symptoms. We studied fifteen FMS patients with attention problems, demonstrated by visual and auditory continuous performance testing (CPT), while completing 40 or more EEG-BF sessions. Training consisted of a "SMR protocol" that augmented 12-15 Hz brainwaves (sensory motor rhythm; SMR), while simultaneously inhibiting 4-7 Hz brainwaves (theta) and 22-30 Hz brainwaves (high beta). Serial measurements of pain, fatigue, psychological distress, morning stiffness, and tenderness were also obtained. Sixty-three FMS patients who received standard medical care, but who did not receive EEG-BF, served as controls. Visual, but not auditory, attention improved significantly (P < 0.008). EEG-BF treated subjects also showed improvement in tenderness, pain and fatigue. Somatic symptoms did not change significantly in controls. Visual attention parameters and certain somatic features of FMS appear to improve with an EEG-BF SMR protocol. EEG-BF training in FMS deserves further study. PMID- 21656151 TI - The anti-botulism triterpenoid toosendanin elicits calcium increase and exocytosis in rat sensory neurons. AB - Toosendanin, a triterpenoid from Melia toosendan Sieb et Zucc, has been found before to be an effective anti-botulism agent, with a bi-phasic effect at both motor nerve endings and central synapse: an initial facilitation followed by prolonged depression. Initial facilitation may be due to activation of voltage dependent calcium channels plus inhibition of potassium channels, but the depression is not fully understood. Toosendanin has no effect on intracellular calcium or secretion in the non-excitable pancreatic acinar cells, ruling out general toosendanin inhibition of exocytosis. In this study, toosendanin effects on sensory neurons isolated from rat nodose ganglia were investigated. It was found that toosendanin stimulated increases in cytosolic calcium and neuronal exocytosis dose dependently. Experiments with membrane potential indicator bis (1,3-dibutylbarbituric acid)trimethine oxonol found that toosendanin hyperpolarized capsaicin-insensitive but depolarized capsaicin-sensitive neurons; high potassium-induced calcium increase was much smaller in hyperpolarizing neurons than in depolarizing neurons, whereas no difference was found for potassium-induced depolarization in these two types of neurons. In neurons showing spontaneous calcium oscillations, toosendanin increased the oscillatory amplitude but not frequency. Toosendanin-induced calcium increase was decreased in calcium-free buffer, by nifedipine, and by transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine. Simultaneous measurements of cytosolic and endoplasmic reticulum (ER) calcium showed an increase in cytosolic but a decrease in ER calcium, indicating that toosendanin triggered ER calcium release. These data together indicate that toosendanin modulates sensory neurons, but had opposite effects on membrane potential depending on the presence or absence of capsaicin receptor/TRPV 1 channel. PMID- 21656152 TI - Basic assessment of the older cancer patient. AB - Cancer is a disease of the elderly (median age 67 in the US), and this is a population with a variable health status. Therefore, treating the older half of the cancer population will present the challenge of not only addressing tumor diversity (the side often referred to in "personalized cancer care" discussions), but patient diversity as well as the interaction between these two heterogeneities. In that sense, geriatric oncology is the ultimate personalized cancer care. In this article, we will address the recent updates in the basic assessment of the patient's condition, and their implication for clinical and research use. The main progresses reported in the last couple of years pertain to geriatric screening tests, and to prediction of the tolerance to treatment. Some important data on the impact of comorbidities on cancer behavior have emerged, but the clinical implications of these data are still being sorted out. We recommend a two-step approach to the basic evaluation of the older cancer patient. First a short screening with a tested screening instrument. Then further work-up of the geriatric findings in parallel with the oncology work-up to define an integrated treatment plan. PMID- 21656153 TI - Treating prostate cancer in elderly men: how does aging affect the outcome? AB - OPINION STATEMENT: Prostate Cancer (PCa) is the second most common cancer in United States and remains the second leading cause of death in the Western world. Because the median age of diagnosis for men with prostate cancer is greater than 75 years, PCa can be considered a disease of the elderly. Several disease specific factors (e.g., stage, tumor grade, prostate-specific antigen (PSA) level) and patient-specific factors (e.g., age, co-morbidity, and functional status) need to be considered in the decision-making process. In an attempt to incorporate these important factors to select optimal treatment for older individuals, several decision models have been published, yet their utility in clinical practice remains poorly understood. Current guidelines for the management of patients with PCa do not make specific recommendations for the elderly. Clearly there is a need to improve our understanding of the complex interrelationships between old age, co-morbidities, and their impact on expected outcomes. PMID- 21656154 TI - Potential involvement of CCL23 in atherosclerotic lesion formation/progression by the enhancement of chemotaxis, adhesion molecule expression, and MMP-2 release from monocytes. AB - OBJECTIVE: CCL23 [Ckbeta8-1/myeloid progenitor inhibitory factor 1 (MPIF1)/macrophage inflammatory protein-3 (MIP3)], a member of the CC chemokine family, is involved in leukocyte trafficking, and implicated in inflammatory diseases. In the present study, we investigated the role of CCL23 in the development of human atherosclerosis, which is characterized by an inflammatory disease. METHODS: CCL23 transcripts were measured by reverse transcriptase polymerase chain reaction (RT-PCR) and CCL23 protein by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Expression of adhesion molecules was determined by flow cytometry, and matrix metalloproteinase-2 (MMP-2) levels by zymography. RESULTS: Proatherogenic factors such as oxidized low-density lipoprotein (oxLDL) and oxidative stress markedly enhanced CCL23 release from human THP-1 macrophages. CCL23 stimulated chemotaxis of human THP-1 monocytes in a dose-dependent manner and enhanced the expression of adhesion molecule CD11c, as well as release of MMP-2 from the THP-1 monocytes. Moreover, CCL23 expression at the mRNA level was significantly higher in human atherosclerotic lesions than in normal arteries, and CCL23 protein was co-expressed with CD68, a specific marker for macrophages. Circulating levels of plasma CCL23 were higher in atherosclerotic patients than in normal subjects. CONCLUSION: These findings suggest that CCL23 plays a role in the development of human atherosclerosis. CCL23 may be a useful target for the development of antiatherogenic agents. PMID- 21656155 TI - Calcium and copper transport ATPases: analogies and diversities in transduction and signaling mechanisms. AB - The calcium transport ATPase and the copper transport ATPase are members of the P ATPase family and retain an analogous catalytic mechanism for ATP utilization, including intermediate phosphoryl transfer to a conserved aspartyl residue, vectorial displacement of bound cation, and final hydrolytic cleavage of Pi. Both ATPases undergo protein conformational changes concomitant with catalytic events. Yet, the two ATPases are prototypes of different features with regard to transduction and signaling mechanisms. The calcium ATPase resides stably on membranes delimiting cellular compartments, acquires free Ca(2+) with high affinity on one side of the membrane, and releases the bound Ca(2+) on the other side of the membrane to yield a high free Ca(2+) gradient. These features are a basic requirement for cellular Ca(2+) signaling mechanisms. On the other hand, the copper ATPase acquires copper through exchange with donor proteins, and undergoes intracellular trafficking to deliver copper to acceptor proteins. In addition to the cation transport site and the conserved aspartate undergoing catalytic phosphorylation, the copper ATPase has copper binding regulatory sites on a unique N-terminal protein extension, and has also serine residues undergoing kinase assisted phosphorylation. These additional features are involved in the mechanism of copper ATPase intracellular trafficking which is required to deliver copper to plasma membranes for extrusion, and to the trans-Golgi network for incorporation into metalloproteins. Isoform specific glyocosylation contributes to stabilization of ATP7A copper ATPase in plasma membranes. PMID- 21656156 TI - Overcoming the production limitations of Photorhabdus temperata ssp. temperata strain K122 bioinsecticides in low-cost medium. AB - For low-cost production of Photorhabdus temperata ssp. temperata strain K122 bioinsecticide, a cheap complex medium was optimized. Diluted seawater was used as the source of micronutrients, especially sodium chloride, involved in the improvement of cell density, culturability and oral toxicity of the bacterium P. temperata against Ephestia kuehniella larvae. Thus, the new formulated medium was composed only of 10 g/l of soya bean meal, used as the carbon and nitrogen main source, mixed in sevenfold diluted seawater. At such conditions, several limitations of P. temperata bioinsecticide productions were shown to be overcome. The appearance of variants small colony polymorphism was completely avoided. Thus, the strain K122 was maintained at the primary form even after prolonged incubation. Moreover, the viable but nonculturable state was partially overcome, since the ability of P. temperata cells to form colonies on the solid medium was prolonged until 78 h of incubation. In addition, when cultured in the complex medium, P. temperata cells were produced at high cell density of 12 * 10(8) cells/ml and exhibited 81.48% improvement of oral toxicity compared to those produced in the optimized medium. With such medium, the large-scale bioinsecticides production into 3-l fully controlled fermenter improved the total cell counts, CFU counts and oral toxicity by 20, 5.81 and 16.73%, respectively. This should contribute to a significant reduction of production cost of highly potent P. temperata strain K122 cells, useful as a bioinsecticide. PMID- 21656157 TI - Cooperativity of adaptive and innate immunity: implications for cancer therapy. AB - The dichotomy of immunology into innate and adaptive immunity has created conceptual barriers in appreciating the intrinsic two-way interaction between immune cells. An emerging body of evidence in various models of immune rejection, including cancer, indicates an indispensable regulation of innate effector functions by adaptive immune cells. This bidirectional cooperativity in innate and adaptive immune functions has broad implications for immune responses in general and for regulating the tumor-associated inflammation that overrides the protective antitumor immunity. Mechanistic understanding of this two-way immune cross-talk could provide insights into novel strategies for designing better immunotherapy approaches against cancer and other diseases that normally defy immune control. PMID- 21656158 TI - Myxoma virus combined with rapamycin treatment enhances adoptive T cell therapy for murine melanoma brain tumors. AB - Adoptive transfer of tumor-specific T cells has shown some success for treating metastatic melanoma. We evaluated a novel strategy to improve adoptive therapy by administering both T cells and oncolytic myxoma virus to mice with syngeneic B16.SIY melanoma brain tumors. Adoptive transfer of activated CD8(+) 2C T cells that recognize SIY peptide doubled survival time, but SIY-negative tumors recurred. Myxoma virus killed B16.SIY cells in vitro, and intratumoral injection of virus led to selective and transient infection of the tumor. Virus treatment recruited innate immune cells to the tumor and induced IFNbeta production in the brain, resulting in limited oncolytic effects in vivo. To counter this, we evaluated the safety and efficacy of co-administering 2C T cells, myxoma virus, and either rapamycin or neutralizing antibodies against IFNbeta. Mice that received either triple combination therapy survived significantly longer with no apparent side effects, but eventually relapsed. Importantly, rapamycin treatment did not impair T cell-mediated tumor destruction, supporting the feasibility of combining adoptive immunotherapy and rapamycin-enhanced virotherapy. Myxoma virus may be a useful vector for transient delivery of therapeutic genes to a tumor to enhance T cell responses. PMID- 21656159 TI - Determination of mRNA expression of DMRT93B, vitellogenin, and cuticle 12 in Daphnia magna and their biomarker potential for endocrine disruption. AB - We explored the use of molecular genetic biomarkers for endocrine disruption in Daphnia magna after the exposure to fenoxycarb (FOC), a model juvenile hormone analog. For this purpose, the mRNA expression patterns of DMRT93B (DMRT, sex determination), cuticle 12 (CUT, molting), and vitellogenin (VTG, embryo development) were determined in D. magna. Furthermore, these results were compared with developmental abnormality and reproduction performance. The fold changes of CUT and VTG mRNA expression showed significant dose-response relationship with FOC exposure. Relative mRNA expressions of DMRT and CUT showed notable changes at as low as 1 ng/l FOC. After chronic exposure FOC significantly delayed the first day of reproduction and decreased the number of young and growth rate even at 10 ng/l FOC. A concentration-dependant trend in reproduction effect was also observed. Developmental abnormality such as poorly developed second antennae and curved or unextended shell spines were observed. These results suggest that the three mRNAs, i.e., DMRT, CUT, and VTG can be used as biomarkers of endocrine disrupting effects in D. magna. PMID- 21656161 TI - Influence of single-walled carbon nanotubes on microbial availability of phenanthrene in sediment. AB - Increasing production and use of single-walled carbon nanotubes (SWCNT) will inevitably lead to release of these nanoparticles to aquatic ecosystems. Similar to black carbon (BC) particles, SWCNT have a high affinity for hydrophobic organic contaminants (HOCs) and therefore the presence of SWCNT in sediment may lead to altered bioavailability of HOCs. We compared SWCNT with biochar and charcoal on their effect on the microbial degradability of 0.05 mg kg(-1) (14)C phenanthrene (PHE) by Mycobacterium vanbaalenii PYR-1 in two sediments with different organic carbon (OC) contents. When the amendment rate of SWCNT or BC was 1 mg g(-1), PHE mineralization was inhibited much more significantly by SWCNT than by either biochar or charcoal. After 360 h of incubation, the mineralized fraction of PHE in the presence of SWCNT was 59.5% of the non-amended control in the sediment with low OC content, and only 42.4% in the other sediment with a higher OC content. Analysis of the freely dissolved concentration (C (free)) using disposable polydimethylsiloxane (PDMS) fibers showed that SWCNT decreased C (free) by 85-95%, apparently due to preferential sorption of PHE to SWCNT particles that had a much larger specific surface area and pore volume than biochar or charcoal. However, pre-interaction of SWCNT with dissolved organic matter (peptone, tannic acid, and humic acid) led to attachment of polar functional groups and reduced surface area on SWCNT, resulting in decreased PHE sorption and an alleviated effect on PHE biodegradation in the order of peptone > tannic acid > humic acid. PMID- 21656160 TI - MAP kinase cell signaling pathway as biomarker of environmental pollution in the sponge Suberites domuncula. AB - In the present study, we analyzed the effects of two major pollutants of the environment, tributyltin (TBT) and water-accommodated fraction (WAF) of diesel oil, on MAP kinase activation, apoptosis induction and DNA damage, in the marine sponge Suberites domuncula. Our results clearly demonstrated a differential activation of the MAPKs depending on the chemicals tested. TBT induced the activation of p38 and JNK while diesel oil enhanced activation of both ERK and p38. The activation of MAPKs was observed after 1 h exposure and 6 and 24 h of recovery in seawater. In addition, DNA fragmentation, assessed by two techniques, the Fast micromethod((r)) and the TUNEL assay, was detected after sponges were treated with both chemicals. Moreover, the study of caspase 3/7 activity showed that apoptosis was induced and triggered with all concentrations of TBT but only at high diesel oil concentrations. After TBT exposure, a correlation was observed between JNK activation, caspase 3 activity and DNA damage while p38 activation followed the two latter parameters at high concentrations of diesel oil, suggesting that sponges enhanced a specific apoptotic pathway depending on the xenobiotic tested. This study demonstrated a high signal response by the sponge Suberites domuncula to the tested chemicals. Cell signaling pathway studies may thus be of use in water quality biomonitoring programs. PMID- 21656162 TI - Intake of whole-grain products and risk of prostate cancer among men in the Danish Diet, Cancer and Health cohort study. AB - OBJECTIVE: High intake of whole-grain products may protect against prostate cancer, but overall evidence is limited and inconclusive. The aim of the present study was to investigate the relationship between the intake of whole-grain products and risk of prostate cancer in a large prospective cohort. METHODS: A total of 26,691 men aged 50-64 years participated in the Diet, Cancer and Health cohort study and provided information about diet and potential prostate cancer risk factors. During a median follow-up of 12.4 years, we identified 1,081 prostate cancer cases. Associations between whole-grain product intake and prostate cancer incidence were analyzed using Cox's regression model. RESULTS: Overall, there was no association between total intake of whole-grain products and prostate cancer risk (adjusted incidence rate ratio per 50 g day(-1): 1.00 (95% confidence interval: 0.96, 1.05)) as well as between intake of the specific whole-grain products: whole-grain rye bread, whole-grain bread, and oatmeal, and risk of prostate cancer. No risk estimates did differ according to either stage or grade of disease. CONCLUSIONS: Results from this prospective study suggest that higher intakes of total or specific whole-grain products are not associated with risk of prostate cancer in a population of Danish middle-aged men. PMID- 21656163 TI - Television viewing time of colorectal cancer survivors is associated prospectively with quality of life. AB - OBJECTIVE: To examine prospective associations of television viewing time with quality of life, following a colorectal cancer diagnosis. METHODS: One thousand, nine hundred and sixty-six colorectal cancer survivors were recruited through the Queensland Cancer Registry. Interviews were conducted at 5, 12, 24, and 36 months post-diagnosis. Generalized linear mixed models estimated the effects of television viewing time on quality of life. RESULTS: Participants who watched >=5 h of television per day had a 16% lower total quality of life score than did participants reporting <=2 h per day. Deleterious associations of television viewing time were found with all quality of life subscales: functional well-being showed the strongest association (23% difference in quality of life scores between highest and lowest television viewing categories), and social well-being the weakest association (6% difference). Participants who increased their television viewing by one category (e.g., <=2 h, increasing to 3-4 h per day) had a proportional decrease of some 6% in their quality of life score (intra individual effect). CONCLUSIONS: The deleterious associations of television viewing time with quality of life were clinically significant and consistent over time. Decreasing sedentary behavior may be an important behavioral strategy to enhance the quality of life of cancer survivors. PMID- 21656164 TI - Cell-growth and migration inhibition of human mesothelioma cells induced by 3-O methylfunicone from Penicillium pinophilum and cisplatin. AB - Malignant pleural mesothelioma is a fatal malignancy linked to asbestos exposure. The main challenge for mesothelioma treatment is to go beyond the drug resistance, in particular against cisplatin (CDDP), one of the most used chemotherapeutic drug. 3-O-methylfunicone (OMF) is a metabolite produced by the fungus Penicillium pinophilum; its antiproliferative properties have been previously studied in vitro. Particularly, OMF is able to inhibit mesothelioma cell motility. To improve the effects of CDDP by-passing the resistance of mesothelioma cells to this drug, in the present study we investigated the combined treatment of OMF with CDDP respectively in an established mesothelioma cell line (NCI) and primary mesothelioma cells (Mest). As compared to the effect of single treatments, the combination of OMF and CDDP resulted in a stronger inhibition of NCI and Mest cell proliferation. OMF combination with CDDP was also able to affect the migratory ability of NCI and Mest cells by down-regulating alphav and beta5 expression and reducing metalloproteinase 2 (MMP-2) production. In addition, this association was effective in modulating VEGF gene expression. This finding highlights the possibility to use OMF and CDDP together to regulate angiogenesis and tumour progression in mesothelioma. PMID- 21656165 TI - Antioxidant and antimelanogenic behaviors of Paeonia suffruticosa. AB - Antioxidant properties of eight Paeonia suffruticosa (Ps) extracts (Ps-1 to Ps-8) were evaluated. The respective half maximally effective concentration (EC(50)) values of Ps-1 ~ 8 were 10.0, 9.8, 63.6, >100, 3.8, 85.1, 6.9, and 0.7 MUg/ml for 1,1-diphenyl-2-picrylhydrazyl radical (DPPH.) radical scavenging efficiency and 22.9, 11.4, 53.1, >100, 7.5, 97.6, 43.7, 4.2 MUg/ml for 2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS.(+)) radical scavenging capacity. The Ps-8 exhibited high free radical scavenging capacity, ion-chelating ability, reducing power, and inhibition of lipid peroxidation, which may have been attributable to its abundant phenolic and flavonoid content. In Hs68 and B16 cells treated with 100 MUg/ml Ps-1, Ps-3, Ps-4 and Ps-6, expressions of toxic activities were lower than those in cells treated with arbutin and ascorbic acid. The antimelanogenesis properties were also tested in B16 cells. Extract Ps-1, and particularly extract Ps-6, considerably inhibited cellular tyrosinase and 3,4-dihydroxyphenylalanine (DOPA) oxidase activity and also reduced melanin content in B16 cells by down-expression of melanocortin-1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related proteins-1 (TRP-1). The results suggest that P. suffruticosa extracts have antioxidant and antimelanogenesis activities with potential applications in cosmetic materials or food additives. PMID- 21656166 TI - Small bowel obstruction after antecolic antegastric laparoscopic Roux-en-Y gastric bypass without division of small bowel mesentery: a single-centre, 7-year review. AB - Reported incidence of small bowel obstruction (SBO) after laparoscopic Roux-en-Y gastric bypass varies between 1.5% and 3.5%. It has been suggested that the antecolic antegastric laparoscopic Roux-en-Y gastric bypass (AA-LRYGB) is associated with a low incidence of internal herniation (IH). Therefore we routinely did not close mesenteric defects. The records of 652 consecutive patients undergoing primary AA-LRYGB from January 2003 to December 2009 in a single institution were retrospectively reviewed to determine the incidence, etiology, clinical symptoms, radiologic diagnostic accuracy and operative outcomes of SBO. Of the 652 patients, 63 (9.6%) developed SBO. The majority (6.9%, 45 patients) had a SBO due to IH. In 41 (91%) cases, the IH was at the jejunojejunostomy (JJ), four cases had an IH at Petersen's space. Adhesions and ventral hernia were found in 14 (2.1%) and four (0.6%) cases, respectively. Twenty-nine out of 63 cases had negative computed tomography (CT) findings and IH was diagnosed on CT in only 33% (14/45) of patients with IH. All patients underwent diagnostic laparoscopy. No bowel resections had to be performed. In contrast to previous reports, a high incidence of SBO with a high rate of IH at the JJ site was found in our series. Accuracy of CT is low and diagnostic laparoscopy is mandatory when SBO is suspected. Since 2010 we have started closing the JJ site, and data on SBO are collected prospectively. We believe that closing of the mesenteric defects is a mandatory step, even in an AA-LRYGB. PMID- 21656167 TI - Serious spontaneous epistaxis and hypertension in hospitalized patients. AB - The aim of the study was to evaluate the role of hypertension in patients hospitalized for serious spontaneous epistaxis. This 6-year retrospective study was based on 219 patients hospitalized in a University Hospital ENT and Head and Neck surgery department for serious spontaneous epistaxis. The following parameters were recorded: length of hospital stay, history of hypertension, blood pressure (BP) recordings (on admission, during hospitalization and on discharge), epistaxis severity criteria, including medical and/or surgical management of epistaxis (blood transfusion depending on blood count, embolization, surgery), medications affecting clotting. Epistaxis was classified into two groups: serious and severe. No significant differences were observed between the two groups in terms of age, sex ratio, history of epistaxis and BP characteristics including history of hypertension, mean BP on admission, mean arterial pressure on discharge and number of patients in whom BP was difficult to control. Patients with more severe epistaxis had a similar exposure to anticoagulant and platelet antiaggregant medications as patients with less severe epistaxis. Overall, on univariate logistic regression analysis, no factors were independently associated with severity of epistaxis. The pathophysiology of serious spontaneous epistaxis remains to be unclear. It concerns elderly patients (>60-70 years old) with a history of hypertension in about 50% of cases. Serious spontaneous epistaxis may also be the presenting sign of underlying true hypertension in about 43% of patients with no history of hypertension. However, hypertension per se does not appear to be a statistically significant causal factor and/or a factor of severity of serious spontaneous epistaxis. PMID- 21656168 TI - Brain microvascular pericytes in health and disease. AB - Pericytes are located at periphery of the microvessel wall and wrap it with their processes. They communicate with other cells of the neurovascular unit by direct contact or through signaling pathways and regulate several important microcirculatory functions. These include development and maintenance of the blood-brain barrier (BBB), distribution of the capillary blood flow to match the local metabolic need of the nearby cells, and angiogenesis. Pericytes also exhibit phagocytic activity and may function as pluripotent stem cells. Increasing evidence suggests a role for pericytes in a wide range of CNS diseases. They appear to be vulnerable to oxygen and nitrogen radical toxicity and have been shown to contract during cerebral ischemia and remain contracted despite reopening of the occluded artery. This causes impaired re-flow and may diminish the benefit of re-canalization therapies in stroke patients. Hyperglycemia-induced dysfunction of the signaling pathways between pericytes and endothelia is thought to play an important role in diabetic retinopathy, a common cause of blindness. Amyloid deposits detected within degenerating pericytes in the brains of patients with Alzheimer's disease suggest that pericyte dysfunction may play a role in cerebral hypoperfusion and impaired amyloid beta-peptide clearance in Alzheimer's disease. This exciting possibility may reveal a novel temporal sequence of events in chronic neurodegeneration, in which microvascular dysfunction due to pericyte degeneration initiates secondary neurodegenerative changes. Identification of molecular mechanisms by which pericytes regulate BBB integrity in inflammatory conditions as well as in vasogenic brain edema may lead to new treatments. Pericytes may also take part in tissue repair and vascularization after CNS injury. In conclusion, although the evidence is just emerging and mostly preliminary, disclosing pericytes' role in the pathophysiology of CNS diseases may yield exciting developments and novel treatments. PMID- 21656169 TI - Inhibitory effects of TRPV1 blocker on UV-induced responses in the hairless mice. AB - The transient receptor potential vanilloid 1 (TRPV1) channel can be activated by vanilloids, exposure to ultraviolet (UV) irradiation, heat, or protons, and conditions that occur during tissue injury. In the present study, we investigated whether or not TRPV1-specific blocker, 5'-iodoresiniferatoxin (I-RTX), can reduce UV-induced matrix metalloproteinases (MMPs), pro-inflammatory cytokines, cyclooxygenase (COX)-2, and p53 expression in the skin of hairless mice. Our results showed that I-RTX inhibited UV-induced skin thickening, as measured by a caliper, or in hematoxylin and eosin (H&E)-stained sections. UV-induced mRNA and protein expression of MMP-13, MMP-9, MMP-3, and MMP-2 was significantly reduced by I-RTX. We also observed the inhibitory effects of I-RTX on UV-induced mRNA expression of the pro-inflammatory cytokines, interleukin (IL)-1beta, IL-2, IL-4, and tumor necrosis factor-alpha. UV-induced COX-2 and p53 protein expression was also significantly decreased by I-RTX. From the above results, we suggest that TRPV1-specific blocker, I-RTX, could prevent UV-induced skin responses, and provide new insight into development of effective therapeutic methods for photoaging. PMID- 21656170 TI - Late-onset vital complication after the Nuss procedure for pectus excavatum. AB - The Nuss procedure is the most popular technique for correction of pectus excavatum recently. Life-threatening complications associated with the procedure are very rare. We report a 13-year-old boy who developed late-onset bilateral hemothorax with hypovolemic shock 5 months after the Nuss procedure. In literature review, this is the first case of the late-onset life-threatening bilateral hemothorax with hypovolemic shock ever reported. PMID- 21656171 TI - The GINS complex from the thermophilic archaeon, Thermoplasma acidophilum may function as a homotetramer in DNA replication. AB - The eukaryotic GINS heterotetramer, consisting of Sld5, Psf1, Psf2, and Psf3, participates in "CMG complex" formation with mini-chromosome maintenance (MCM) and Cdc45 as a key component of a replicative helicase. There are only two homologs of the GINS proteins in Archaea, and these proteins, Gins51 and Gins23, form a heterotetrameric GINS with a 2:2 molar ratio. The Pyrococcus furiosus GINS stimulates the ATPase and helicase activities of its cognate MCM, whereas the Sulfolobus solfataricus GINS does not affect those activities of its cognate MCM, although the proteins bind each other. Intriguingly, Thermoplasma acidophilum, as well as many euryarchaea, have only one gene encoding the sequence homologous to that of archaeal Gins protein (Gins51) on the genome. In this study, we investigated the biochemical properties of the gene product (TaGins51). A gel filtration and electron microscopy revealed that TaGins51 forms a homotetramer. A physical interaction between TaGins51 and TaMcm was detected by a surface plasmon resonance analysis. Unexpectedly, TaGins51 inhibited the ATPase activity, but did not affect the helicase activity of its cognate MCM. These results suggest that another factor is required to form a stable helicase complex with MCM and GINS at the replication fork in T. acidophilum cells. PMID- 21656172 TI - Renal involvement in mitochondrial cytopathies. AB - Mitochondrial cytopathies constitute a group of rare diseases that are characterized by their frequent multisystemic involvement, extreme variability of phenotype and complex genetics. In children, renal involvement is frequent and probably underestimated. The most frequent renal symptom is a tubular defect that, in most severe forms, corresponds to a complete De Toni-Debre-Fanconi syndrome. Incomplete proximal tubular defects and other tubular diseases have also been reported. In rare cases, patients present with chronic tubulo interstitial nephritis or cystic renal diseases. Finally, a group of patients develop primarily a glomerular disease. These patients correspond to sporadic case reports or can be classified into two major defects, namely 3243 A>G tRNA(LEU) mutations and coenzyme Q10 biosynthesis defects. The latter group is particularly important because it represents the only treatable renal mitochondrial defect. In this Educational Review, the principal characteristics of these diseases and the main diagnostic approaches are summarized. PMID- 21656173 TI - Impact of gender on bladder cancer incidence, staging, and prognosis. AB - INTRODUCTION: While patient gender is an important factor in the clinical decision-making for the management of bladder cancer, there are minimal evidence based recommendations to guide health care professionals. Recent epidemiologic and translational research has shed some light on the complex relationship between gender and bladder cancer. Our aim was to review the literature on the effect of gender on bladder cancer incidence, biology, mortality, and treatment. METHODS: Using MEDLINE, we performed a search of the literature between January 1975 and April 2011. RESULTS: Although men are nearly 3-4 times more likely to develop bladder cancer than women, women present with more advanced disease and have worse survival. Recently, a number of population-based and multicenter collaborative studies have shown that female gender is associated with a significantly higher rate of cancer-specific recurrence and mortality after radical cystectomy. The disparity between genders is proposed to be the result of a differences exposure to carcinogens (i.e., tobacco and chemicals) as well as reflective of genetic, anatomic, hormonal, societal, and environmental factors. Explanations for the differential behavior of bladder cancer between genders include sex steroids and their receptors as well as inferior quality of care for women (inpatient length of stay, referral patterns, and surgical outcomes). CONCLUSIONS: It is imperative that health care practitioners and researchers from disparate disciplines collectively focus efforts to appropriately develop gender specific evidence-based guidelines for bladder cancer patients. We must strive to develop multidisciplinary collaborative efforts to provide tailored gender specific care for bladder cancer patients. PMID- 21656174 TI - Distribution profiles of nitroxide spin probes in human skin--a combined study using spatially resolved electron spin resonance spectroscopy and mass spectrometry. AB - Electron spin resonance spectroscopy and mass spectrometry are two analytical methods that are very rarely used in combination. In this paper, we will show that the methods complement one another in the example of the distribution of stable nitroxide radicals in human skin, including the spatial resolution of these distribution processes. There are many ESR investigations dealing with this subject, but unfortunately, they are all limited to the detection of paramagnetic species. The combination with MS allows the successful examination of the distribution profile of the main biotransformation product of the nitroxide radicals, the respective "ESR-silent" hydroxylamines. In order to maintain the biological state of the sample material as far as possible, atmospheric pressure matrix-assisted laser desorption/ionization with ion trap detection has been used for the mass spectrometric investigations. The results validate the former findings of the strong reduction of stable free radicals by biological material; moreover, the diamagnetic species formed during these processes have been identified. PMID- 21656175 TI - Development and validation of an HPLC-MS/MS method to quantify clopidogrel acyl glucuronide, clopidogrel acid metabolite, and clopidogrel in plasma samples avoiding analyte back-conversion. AB - A new sensitive and fast quantitative analytical method for the simultaneous determination of clopidogrel, its main metabolite clopidogrel carboxylic acid, and the newly described acyl glucuronide metabolite, in human plasma samples, is presented. The analytical procedures (plasma storage, handling, and extract storage in the autosampler) were optimized in order to avoid back-conversion; a known drawback in measurements of clopidogrel. Clopidogrel acyl glucuronide was confirmed as a major source of back-conversion to the parent drug in the presence of methanol, and thorough stability experiments were carried out to find the most appropriate conditions for an accurate analysis of clopidogrel and the two metabolites. The method was validated by assessing selectivity, sensitivity, linearity, accuracy, and precision for all three analytes, in accordance to Food and Drug Administration guidelines. Spiked quality controls in plasma as well as incurred samples were used to verify back-conversion in the selected conditions, with results meeting European Medicines Agency acceptance criteria (concentrations within 80-120% of the first reading). The method was then applied to a pharmacokinetic study, and for the first time, a pharmacokinetic curve of clopidogrel acyl glucuronide in human plasma is presented. The concentrations ranged up to 1,048.684 ng/mL, with a mean of 470.268 ng/mL, while clopidogrel had a mean C(max) of 1.348 ng/mL; these orders of magnitude show how much the back conversion of this metabolite may influence clopidogrel quantification if it is not properly controlled. PMID- 21656176 TI - A gas sensor based on Prussian blue film for the detection of chlorobenzene vapor. AB - A new resistance-type sensor based on Prussian blue film has been fabricated for the detection of chlorobenzene vapor. The effect of Prussian blue preparation conditions on the response of sensor was studied. The sensor exhibited good response and selectivity to chlorobenzene vapor. The sensor prepared with Fe(2)(SO(4))(3) at 298 K has response 8.5 at operating voltage of 10 V. The selectivity of the sensor to chlorobenzene against all other tested gases is exceeding almost by 5.6 times. The sensor showed linear response to chlorobenzene vapor in the concentration range of 24-169 ppm at room temperature and at a 10 V operating voltage. The response and recovery time of the sensor was about 18 and 12 s, respectively. Sensor stability test indicated the sensor had a good stability. Furthermore, seven real samples of chlorobenzene vapor was measured using the sensor. The relative error was in the range of about +/-1.3%. PMID- 21656177 TI - The emergence of multimodal imaging methods for real-time nanoscopy. PMID- 21656178 TI - Impact of diets with different proportions of linseed and sunflower oils on the growth, liver histology, immunological and chemical blood parameters, and proximate composition of pikeperch Sander lucioperca (L.). AB - The aim of the study was to determine the impact of applying different proportions of linseed (LO) and sunflower (SFO) oils in pikeperch diets on growth, histological changes in the liver, immunological and blood chemical parameters. The fish were fed isoenergetic and isoprotein feeds containing SFO (group 100SFO) or LO (group 100LO) in quantities of 67 g kg/feed, and a mixture of oils: 47 g SFO and 20 g LO kg/feed (group 70SFO/30LO) and 20 g SFO and 47 g LO kg/feed (group 30SFO/70LO). Dietary ratios of polyunsaturated fatty acids from the n-3 and n-6 series (n3/n6 index) were 0.36-2.15. Pikeperch were reared for 56 days in three replicates for each dietary treatment. Various dietary oils and ratios of n3/n6 did not impact fish growth, feed conversion ratio, viscerosomatic and hepatosomatic index, and size of the hepatocytes. Feeding the fish high quantities of LO and SO oils (groups 100LO and 100SFO) reduced the immunological response of the phagocytes and lymphocytes in the fish. Moreover, this resulted in significant differences among groups in the quantity of linolenic and linoleic acid in whole fish bodies, viscera, fillets, and livers. Various quantities of vegetable oils in the fish diets did not impact the quantity of arachidonic, eicosapentaenoic and docosahexaenoic acid in the fillets and livers. The immunological index and low quantities of linoleic acid in the fillets obtained in group 30SFO/70LO indicate that the n3/n6 dietary ratio of 1.35 was the most advantageous for feeding juvenile pikeperch feeds with vegetable oils. PMID- 21656180 TI - Serum vitamin D concentrations and unexplained elevation in ALT among US adults. PMID- 21656179 TI - Efficacy and tolerability of split-dose PEG compared with split-dose aqueous sodium phosphate for outpatient colonoscopy: a randomized, controlled trial. AB - BACKGROUND AND AIMS: Adequate bowel cleansing is essential for a high-quality, effective, and safe colonoscopy. The aims of this study were to compare the efficacy and tolerability of split-dose polyethylene glycol with aqueous sodium phosphate for outpatients who underwent scheduled colonoscopy. METHODS: In this prospective trial, 207 outpatients (aged between 18 and 65 years, with normal renal function, at low risk for renal damage) were randomized to receive split dose preparation of PEG (2 L/2 L) (N = 103) or NaP (45 mL/45 mL, 12 h apart) (N = 104) without strict diet restriction the day before colonoscopy. The bowel cleansing efficacy of preparations was rated according to the Ottawa scale and the patient tolerability was assessed using a patient questionnaire. RESULTS: There was no significant difference between the two groups for the mean total score using the Ottawa bowel preparation scale (P = 0.181). Significantly greater residual colonic fluid was observed in the split-dose PEG group (1.24 +/- 0.49) than in the NaP group (1.04 +/- 0.53) (P = 0.007). Patient compliance, preference, and acceptance of a two preparation regimen were similar with no significant differences (P = 0.095, P = 0.280 and P = 0.408, respectively). The overall incidence of adverse events was not significantly different between the two groups; however, the split-dose PEG group tended to have fewer adverse events (52/103 [50.5%], 66/104 [63.5%], P = 0.059) and had significantly less nausea and vomiting (P = 0.036). CONCLUSIONS: Split-dose PEG, compared with split-dose NaP, is associated with more residual colonic fluid, but produces equivalent colon cleansing efficacy and results in less nausea and vomiting, which might improve patient tolerability (clinical trial registration number NCT01229800). PMID- 21656181 TI - In PSC with colitis treated with UDCA, most colonic carcinomas develop in the first years after the start of treatment. AB - BACKGROUND: Patients with PSC and IBD have a high incidence of colonic carcinomas (CRC), and the annual incidence of CRC increases with duration of disease. UDCA treatment has been suggested to reduce colonic dysplasias and carcinomas. AIMS: The annual incidence of colorectal carcinomas after long-term UDCA treatment was studied. METHODS: Patients included in a prospective study on the outcome after ursodeoxycholic acid (UDCA) treatment were evaluated. RESULTS: A total of 120 of 171 PSC patients included had IBD (108 UC and 12 CD). All patients were treated with UDCA for a median time of 6.7 years. Seven patients with PSC and IBD developed a CRC yielding a prevalence of 5.8%. In years 0-3 (n = 120) after the start of UDCA, the annual incidence rate of CRC was 0.62/100 patient years; in years 3-6 (n = 93) it increased to 1.28 and decreased thereafter in years 6-9 (n = 67) to 1.17, then in years 9-12 (n = 42) to 0 and after >12 years (n = 24) it remained 0. In PSC with IBD, Kaplan-Meier estimate of CRC formation increased with time in the first years of treatment and reached a plateau after 9 years; after treatment for >= 9 years, no further CRC were observed. CONCLUSION: After the start of UDCA, the annual incidence of CRC increased up to 6 years and subsequently decreased. In PSC with IBD treated with UDCA, most colonic carcinomas develop in the first years after the start of treatment. PMID- 21656182 TI - Successful extracorporeal mature oocyte harvesting after laparoscopic oophorectomy following controlled ovarian hyperstimulation for the purpose of fertility preservation in a patient with borderline ovarian tumor. AB - PURPOSE: To report the successful extracorporeal recovery of mature oocytes after laparoscopic oophorectomy following ovarian hyperstimulation for the purpose of fertility preservation in a patient with recurrent serous borderline ovarian tumor. METHODS: A 25-year-old nulligravida woman presented with recurrence of a borderline serous adenocarcinoma in the right ovary after been treated conservatively with left oophorectomy for the same. RESULT(S): The patient underwent ovarian stimulation followed by a laparoscopic oophorectomy and ex-vivo retrieval of oocytes. Twenty two oocytes were recovered: fourteen metaphases II, two metaphases I, five prophases I and one degenerate. CONCLUSION(S): Mature oocytes were successfully retrieved ex-vivo from the hyperstimulated ovary recovered via laparoscopy. The procedure can be performed in a quick manner, with standard equipment, without damaging the ovary, the follicles or the oocytes, and without the risk of cancer cell spillage associated with the standard transvaginal oocyte retrieval if there is concern of ovarian surface/peritoneal metastatic disease. PMID- 21656183 TI - Rectal pocket syndrome following PPH and rectosigmoid resection. PMID- 21656184 TI - Nociceptin/orphanin FQ receptor-driven heterologous desensitization of the major HIV-1 co-receptor CXCR4. PMID- 21656185 TI - Detection and full genomic analysis of G6P[9] human rotavirus in Japan. AB - A rare genotype G6P[9] was identified in two human group A rotavirus strains designated as KF14 and KF17, that were detected in stool specimens from children with diarrhea in Japan. VP7 gene sequences of these two strains were identical and genetically closely related to G6 human rotavirus strains reported in European countries and the United States. To our knowledge, this is the first report of detection of a G6 human rotavirus in Japan. For further genetic analysis to elucidate the origin of the G6 rotavirus, nearly full-length sequences of all 11 RNA segments were determined for the KF17 strain. The complete genomic constellation of KF17 was determined as G6-P[9]-I2-R2-C2-M2-A3 N2-T3-E3-H3, a novel genotype constellation for human rotavirus. Phylogenetic analysis indicated that VP6, VP1-3, and NSP2 genes of KF17 clustered with bovine like G6 human strains and some animal strains into sub-lineages distinct from those of common DS-1-like G2 human rotaviruses. On the other hand, KF17 genes encoding VP4, NSP1, and NSP3-5 showed high sequence identities to the human G3P[9] strain AU-1, and clustered with AU-1 and some feline strains within the same lineage. These findings suggested that the G6P[9] human rotavirus detected in Japan may have occurred through reassortment among uncommon bovine-like human rotaviruses and human/feline AU-1-like rotaviruses. PMID- 21656186 TI - Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia. AB - Liver ischemia reperfusion injury is associated with both local damage to the hepatic vasculature and systemic inflammatory responses. CD39 is the dominant vascular endothelial cell ectonucleotidase and rapidly hydrolyses both adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate. These biochemical properties, in tandem with 5'-nucleotidases, generate adenosine and potentially illicit inflammatory vascular responses and thrombosis. We have evaluated the role of CD39 in total hepatic ischemia reperfusion injury (IRI). Wildtype mice, Cd39-hemizygous mice (+/-) and matched Cd39-null mice (-/-); (n = 25 per group) underwent 45 min of total warm ischemia with full inflow occlusion necessitating partial hepatectomy. Soluble nucleoside triphosphate diphosphohydrolase (NTPDases) or adenosine/amrinone were administered to wildtype (n = 6) and Cd39-null mice (n = 6) in order to study protective effects in vivo. Parameters of liver injury, systemic inflammation, hepatic ATP determinations by P(31)-NMR and parameters of lung injury were obtained. All wildtype mice survived up to 7 days with minimal biochemical disturbances and minor evidence for injury. In contrast, 64% of Cd39+/- and 84% of Cd39-null mice required euthanasia or died within 4 h post-reperfusion with liver damage and systemic inflammation associated with hypercytokinemia. Hepatic ATP depletion was pronounced in Cd39 null mice posthepatic IRI. Soluble NTPDase or adenosine administration protected Cd39-deficient mice from acute reperfusion injury. We conclude that CD39 is protective in hepatic IRI preventing local injury and systemic inflammation in an adenosine dependent manner. Our data indicate that vascular CD39 expression has an essential protective role in hepatic IRI. PMID- 21656187 TI - Fibrin glue does not improve the fixation of press-fitted cell-free collagen gel plugs in an ex vivo cartilage repair model. AB - PURPOSE: Adequate graft fixation over a certain time period is necessary for successful cartilage repair and permanent integration of the graft into the surrounding tissue. The aim of the present study was to test the primary stability of a new cell-free collagen gel plug (CaReS((r))-1S) with two different graft fixation techniques over a simulated early postoperative period. METHODS: Isolated chondral lesions (11 mm diameter by 6 mm deep) down to the subchondral bone plate were created on the medial femoral condyle in 40 porcine knee specimens. The collagen scaffolds were fixed in 20 knees each by press-fit only or by press-fit + fibrin glue. Each knee was then put through 2,000 cycles in an ex vivo continuous passive motion model. Before and after the 2,000 motions, standardized digital pictures of the grafts were taken. The area of worn surface as a percentage of the total collagen plug surface was evaluated using image analysis software. RESULTS: No total delamination of the scaffolds to leave an empty defect site was recorded in any of the knees. The two fixation techniques showed no significant difference in worn surface area after 2,000 cycles (P = n.s.). CONCLUSIONS: This study reveals that both the press-fit only and the press fit + fibrin glue technique provide similar, adequate, stability of a type I collagen plug in the described porcine model. In the clinical setting, this fact may be particularly important for implantation of arthroscopic grafts. PMID- 21656188 TI - Why perform an ACL augmentation? AB - PURPOSE: The objective of this article is to determine the importance of an intact anterior cruciate ligament (ACL) stump and its role in the clinical outcome of an ACL reconstruction. METHOD: A PubMed database search was conducted using the key words "anterior cruciate ligament healing" and "double-bundle structure". Articles concerning ACL healing, reconstruction, and rehabilitation were obtained. A total of 35 studies were incorporated in this article, and factors preset in the intact ACL stump were taken into consideration. RESULTS: Four factors were noted to be important in preserving the stump: protection in early rehabilitation, maintenance of vascular supply, preservation of proprioceptive receptors and may serve as reference for accurate tunnel placement. Also noted was the significance of the intact stump in the natural history, examination, and imaging of such injuries. CONCLUSION: This study provides a detailed justification in preserving ACL remnants and their vital role in surgical reconstruction of partial anterior cruciate ligament tears. PMID- 21656189 TI - Pain, affect and psychotic illness. PMID- 21656190 TI - Hotline update of clinical trials and registries presented at the 77th spring meeting of the German Society of Cardiology 2011. AB - This article provides information and commentaries on trials, which were presented during the Hotline Sessions at the 77th annual spring meeting of the German Society of Cardiology in Mannheim, Germany, from April 27 to 30, 2011. This article summarizes a number of important, novel clinical trials in the field of cardiovascular medicine. The comprehensive summaries have been generated from the oral presentation from the authors as previously reported [1] and should provide the readers with the most comprehensive information of relevant publications. The data were presented by leading experts in the field with relevant positions in the trials. PMID- 21656192 TI - Bacteria associated with the pinewood nematode Bursaphelenchus xylophilus collected in Portugal. AB - In this study, we report on the bacterial community associated with the pinewood nematode Bursaphelenchus xylophilus from symptomatic pine wilted trees, as well as from long-term preserved B. xylophilus laboratory collection specimens, emphasizing the close bacteria-nematode associations that may contribute to pine wilt disease development. PMID- 21656191 TI - Residual tumor after laser ablation of human non-small-cell lung cancer demonstrated by ex vivo staining: correlation with invasive temperature measurements. AB - OBJECT: Histology is the gold standard for confirming thermally induced necrosis. Generally, however, no specimen is obtained from thermal ablation therapy for pathological examination. The aim of this study was to provide evidence for the relationship between temperatures reached and resulting tissue coagulation during laser ablation in a near-physiological ex vivo lung tumor model by combining viability staining and direct temperature measurement. MATERIALS AND METHODS: In all, 17 human lung specimens with primary non-small-cell lung cancer (NSCLC) were examined in this study. Organs were resected with curative intent from patients of either gender (5 female, 12 male) with an average age of 65 years (51-78). Here, 11/17 specimens were subjected to interstitial laser thermal ablation in an ex vivo lung perfusion and ventilation model after surgery. A control group of 6/17 specimens was tested for viability without laser ablation. Tissue temperature was measured invasively in real-time during the ablation process using thermocouples. Afterwards, representative slices of all 17 specimens were tested for viability with triphenyltetrazolium chloride (TTC). Maximum tissue temperature Tmax[ degrees C] measured at a distance of 10 and 20 mm from the laser tip and time of temperature exposure were correlated with the diameter of the induced coagulation as ascertained with viability staining. CH evaluated the results. RESULTS: Mean maximum temperature was 75.9 degrees C +/- 14.4 degrees C at a distance of 10 mm from the laser tip and 50.3 degrees C +/- 14.6 degrees C at a distance of 20 mm, respectively. The mean distance between the coagulation margin and the laser tip was 17.8 mm +/- 7.3 mm. CONCLUSION: We found that coagulation size correlated positively with temperature. There was a clear trend towards the correlation of time over 44 degrees C and ablation depth. Maximum temperatures did not significantly correlate with coagulation size. Laser ablation of lung tumors using the IHLP (isolated human lung perfusion) model represents a possible method for evaluating ex vivo the interrelationships of temperature, time of temperature exposure, and resulting coagulation. PMID- 21656193 TI - Halomonas qijiaojingensis sp. nov. and Halomonas flava sp. nov., two moderately halophilic bacteria isolated from a salt lake. AB - Two moderately halophilic, Gram-negative, rod-shaped bacteria, designated YIM 93003(T) and YIM 94343(T), were isolated from a salt lake in Xinjiang province, north-west China. The two strains YIM 93003(T) and YIM 94343(T) grew at 20-40 degrees C, pH 6-9, 0.5-24% (w/v) NaCl and at 20-40 degrees C, pH 6-9, 0.5-23% (w/v) NaCl, respectively. No growth occurred in absence of NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strains YIM 93003(T) and YIM 94343(T) were phylogenetically affiliated to the genus Halomonas and exhibited sequence similarity of 97.5% and 97.4% to the type strain Halomonas anticariensis DSM 16096(T), respectively. The strains possessed chemotaxonomic markers that were consistent with their classification in the genus Halomonas (Q 9 as predominant respiratory quinine; C18:1omega7c, C16:0 and C16:1 omega7c/iso C15:02-OH as the major fatty acids). The DNA-DNA hybridization values for strains YIM 93003(T) and YIM 94343(T), YIM 93003(T) and DSM 16096(T), YIM 94343(T) and DSM 16096(T) were 38.1 +/- 3.0, 18.3 +/- 4.7, and 20.8 +/- 4.6%, respectively. The G+C contents of the strains YIM 93003(T) and YIM 94343(T) were 63.4 and 64.0 mol%, respectively. Based on comparative analysis of physiological, biochemical and chemotaxonomic data, including low DNA-DNA hybridization results, two novel species, Halomonas qijiaojingensis sp. nov., and Halomonas flava sp. nov., are proposed. The type strains are YIM 93003(T) (=CCTCC AB 208133(T) =KCTC 22228(T)) and YIM 94343(T) (=CCTCC AB 2010382(T) =KCTC 23356(T)), respectively. PMID- 21656194 TI - Fatal hemorrhagic pneumonia caused by Stenotrophomanas maltophilia in a patient with non-Hodgkin lymphoma. AB - Stenotrophomonas maltophilia is increasingly emerging as a multiresistant pathogen in the hospital environment. In immunosuppressed patients, this bacterium may cause severe infections associated with sepsis and multiple organ dysfunction. We report on a 57-year-old woman treated with intensive chemotherapy for non-Hodgkin lymphoma who developed severe neutropenia, hemorrhagic pneumonia, and acute respiratory failure, which led to her death within 36 h of onset of pneumonia. Postmortem examination revealed bilateral extensive intraalveolar hemorrhage associated with severe infection by the gram-negative bacterium Stenotrophomonas maltophilia. In vitro susceptibility testing showed resistance to carbapenem, cephalosporines and aminoglycosides, but sensitivity to minocycline, ciprofloxacin, levofloxacin, and trimethoprim/sulfamethoxazole (cotrimoxazole). Early diagnosis and adequate antibiotic treatment were difficult, as the clinical course was rapid and fulminant, and this bacterium is resistant to multiple antibiotics. To improve prognosis in such cases, it will be necessary to develop an effective prophylactic strategy for high-risk patients. PMID- 21656195 TI - Intravertebral neotrabecularization as an expression of focal load transfer by a keel-design lumbar total disc arthroplasty. AB - The aim of this study is to direct attention to the specific load transfer characteristics of keel-design total disc arthroplasty (TDA) implants that may be underreported. A variety of implants for lumbar TDA are available on the market. One of the main differences between the design types of lumbar TDA implants is whether they use a keel or small spikes/ridges in order to achieve primary stability. The consequences of such design features on load transfer have not been adequately discussed. We report and discuss a case in which new intravertebral bone trabecula have appeared after double-level implantation of a keel-based TDA. We think that the mid- and long-term follow-up radiographs of patients after TDA with keel-design implants should be examined for the presence or absence of such changes. Should our case turn out to be not a singular occurrence, this might have an impact on the design of future TDA implants. PMID- 21656196 TI - Implant survival and outcome after rotating-hinge total knee revision arthroplasty: a minimum 6-year follow-up. AB - INTRODUCTION: Data on long-time survival and clinical function of rotating hinge knee prostheses used in revision total knee arthroplasty (TKA) are scarce. METHOD: We evaluate the outcome of 42 revision TKA in 38 patients using the Endo model rotating hinge total knee prosthesis after a minimum of 6 years, with 10 year implant survival as our primary outcome measure. Only revision TKAs performed due to aseptic loosening were included, and the Swedish Knee Arthroplasty Register was consulted in order to ensure that patients unavailable for clinical follow-up had not been revised elsewhere. Mean follow-up was after 8.8 (6-18) years, mean age at revision surgery was 72 (55-88) years, and most patients had severe medical comorbidities (n = 31). RESULTS: At follow-up, four knees had been re-revised due to aseptic loosening, and five further knees underwent re-revision due to other reasons. With implant revision due to aseptic loosening as the endpoint, 10-year survival was 89.2%, and with implant revision due to any reason 10-year survival was 65.1%. 11 patients (13 knees) eligible for clinical follow-up were evaluated according to the Hospital for Special Surgery score (HSSS), the Knee Society scores (KSS), and by plain radiography. Mean HSSS was 67 (36-90), mean KSS-knee was 85 (73-96), and mean KSS-function was 29 (0 100). Radiography showed that no implant was in need of revision. CONCLUSION: Our results indicate that revision arthroplasty of the knee with this rotating hinge prosthesis can be performed with satisfactory or good results in an elderly population with severe comorbidities. PMID- 21656197 TI - Binaural unmasking of multi-channel stimuli in bilateral cochlear implant users. AB - Previous work suggests that bilateral cochlear implant users are sensitive to interaural cues if experimental speech processors are used to preserve accurate interaural information in the electrical stimulation pattern. Binaural unmasking occurs in adults and children when an interaural delay is applied to the envelope of a high-rate pulse train. Nevertheless, for speech perception, binaural unmasking benefits have not been demonstrated consistently, even with coordinated stimulation at both ears. The present study aimed at bridging the gap between basic psychophysical performance on binaural signal detection tasks on the one hand and binaural perception of speech in noise on the other hand. Therefore, binaural signal detection was expanded to multi-channel stimulation and biologically relevant interaural delays. A harmonic complex, consisting of three sinusoids (125, 250, and 375 Hz), was added to three 125-Hz-wide noise bands centered on the sinusoids. When an interaural delay of 700 MUs was introduced, an average BMLD of 3 dB was established. Outcomes are promising in view of real-life benefits. Future research should investigate the generalization of the observed benefits for signal detection to speech perception in everyday listening situations and determine the importance of coordination of bilateral speech processors and accentuation of envelope cues. PMID- 21656198 TI - Importance of residual myocardial ischemia after intervention in the genesis of cardiovascular events among patients with chronic coronary artery disease. AB - Recent randomized clinical trials support the strategy of ischemia-guided management for patients with stable ischemic heart disease. The application of serial testing to examine the efficacy of therapeutic intervention for ischemia suppression and to document the extent and severity of ischemia provides an important means to guide clinical decision making. This review provides a synopsis of available evidence on serial testing and meaningful thresholds for application of paired rest/stress myocardial perfusion single photon emission computed tomography imaging. PMID- 21656199 TI - Gaming industry employees' responses to responsible gambling training: a public health imperative. AB - Gaming industry employees work in settings that create personal health risks. They also have direct contact with customers who might engage in multiple risky activities (e.g., drinking, smoking, and gambling) and might need to facilitate help-seeking by patrons or co-workers who experience problems. Consequently, the empirical examination of the processes and procedures designed to prepare employees for such complex situations is a public health imperative. In the current study we describe an evaluation of the Casino, Inc. Play Responsibly responsible gaming program. We surveyed 217 employees prior to and 1 month after (n = 116) they completed a multimedia driven responsible gambling training program. We observed that employees improved their knowledge of responsible gambling concepts from baseline to follow-up. The Play Responsibly program was more successful in providing new knowledge than it was in correcting mistaken beliefs that existed prior to training. We conclude, generally, that Play Responsibly is associated with increases in employees' responsible gambling knowledge. PMID- 21656200 TI - Citation marketing and networking. AB - This is a comment on Thatje (Naturwissenschaften 97:237-239, 2010) The multiple faces of journal peer review, Naturwissenschaften, 97:237-239. PMID- 21656201 TI - Does contractility modulation have a role in the treatment of heart failure? AB - Cardiac resynchronization therapy (CRT) is an established therapy for patients with systolic dysfunction, QRS duration greater than 120 ms, and New York Heart Association (NYHA) class III or IV symptoms. However, most patients with heart failure have QRS duration below 120 ms and 30% or more of CRT recipients are nonresponders. Cardiac contractility modulation (CCM) signals are nonexcitatory electrical impulses applied during the absolute refractory period that are intended to enhance contractile strength independent of QRS duration. Myocardial biopsy studies suggest that modulation of protein phosphorylation and gene expression underlie the mechanisms by which CCM exerts its effects. Two prospective randomized studies have investigated the impact of CCM on exercise tolerance and quality of life in patients with chronic heart failure. These studies have included predominantly patients with NYHA class III heart failure with QRS duration below 130 ms. This review summarizes results of these clinical studies and outlines additional studies underway to further clarify the role of CCM in the treatment of heart failure. PMID- 21656202 TI - Sinonasal-type hemangiopericytoma of the nasal cavity and paranasal sinus. AB - Sinonasal-type hemangiopericytoma is a very rare disease. A 64-year-old man was admitted to our hospital because of nasal obstruction. Nasal endoscopy showed a polyp in the right nasal cavity. Imaging modalities including CT and MRI revealed polypoid tumors in the right nasal cavity and right sphenoid sinus. Excision of the tumors was performed. Macroscopically, the nasal tumor was reddish and focally cystic, and the tumor of the sphenoid sinus was reddish and solid. Microscopically, round and polygonal cells were seen to proliferate monotonously in a medullary fashion. Each tumor cell had a vesicular nucleus and amphophilic cytoplasm. The cellularity was high and mitotic figures were recognized in 6 per 10 high-power fields. Many thin-walled vessels were embedded within the tumor. No collagenization was recognized. A silver stain showed that fine argyrophilic fibers encased individual cells and a few cell nests. Mild invasion into the surrounding tissue was recognized in focal areas. The tumor showed focal cystic and hemorrhagic changes. Immunohistochemically, the tumor cells were positive for vimentin, bcl-2 and factor XIIIa, and negative for cytokeratins, epithelial membrane antigen, CD34, desmin, alpha-smooth muscle antigen, myoglobin, myogenin, CD31, KIT, p53 protein, CD99, and factor VIII-related antigen. Ki-67 labeling was 17%. The pathological diagnosis was low-grade malignant sinonasal-type hemangiopericytoma. The patient was followed up, but no recurrence has been seen 4 years after the operation. PMID- 21656203 TI - Extrapancreatic solid pseudopapillary tumor: case report and review of the literature. AB - A 22-year-old woman complained of abdominal discomfort. Ultrasonography, computed tomography, and an endocrinologic work-up revealed a 7-cm nonfunctional tumor at the left adrenal lesion. A transumbilical laparo-endoscopic single-site adrenalectomy was successfully completed in 166 min. The postoperative period was uneventful. The pathologic examination confirmed the solid pseudopapillary tumor occurred in the retroperitoneum. There are only five previous reports of extrapancreatic solid pseudopapillary tumors. In this case, the tumor was separated from the pancreas and no ectopic pancreas was histologically observed. To the best of our knowledge, this case is the first report of a solid pseudopapillary tumor of the retroperitoneum. PMID- 21656204 TI - Vitamin A deficiency-related retinopathy after bariatric surgery. PMID- 21656205 TI - Evaluation of p53 genotype on gene expression in the testis, liver, and heart from male C57BL/6 mice. AB - Our laboratory is conducting experiments designed to characterize the role of p53 in gene expression in the TSG-p53(r) mouse model. In the study reported here, gene expression levels in tissue derived from the testis, liver, and heart of male, 8-9 week old, p53 wild-type (WT), heterozygous (HET) or knockout (KO) mice were determined utilizing a targeted qPCR 84-gene array. The heart, liver and testis were selected because of the unique function and rate of cell division of each tissue. The genes on the arrays were categorized into three Functional Gene Groups, Apoptosis, Cell-Cycle and DNA Repair. Differences in expression of the functional groups were determined by multivariate analysis of variance (MANOVA) and significant (P < 0.05) differences in their expression were found among the heart, liver and testis. Further, the expression of the Functional Gene Groups in each of these tissues was also significantly affected by p53 genotype. These data indicate that gene expression in unperturbed tissue is influenced by the status of p53 genotype, and relates, at least partially, to the function of the tissue. PMID- 21656206 TI - The relationship between photoselective vaporization of the prostate and sexual function. AB - Although transurethral resection of the prostate remains the gold standard treatment of lower urinary tract symptoms that are refractory to medical therapy, photovaporization of the prostate (PVP) has become a popular alternative. Early PVP studies have been encouraging, but insufficient data exist regarding the effects of PVP on long-term sexual function. This article analyzes the published data and briefly reviews the literature. The studies on PVP are heterogeneous, and other than one that showed a decreased International Index of Erectile Function score after PVP, all the studies analyzed the population at large and did not focus on preoperatively potent patients. Further well-conducted and prospective studies are needed to confirm the impact of PVP on erectile function. PMID- 21656208 TI - Two cases of acute renal hemorrhage undergoing maintenance hemodialysis after concurrent administration of cinacalcet. AB - We report here a rare complication of renal hemorrhage in 2 male patients under treatment with long-term hemodialysis subsequent to the administration of the calcimemetic agent, cinacalcet hydrochloride. The patients presented with flank pain, peripheral hypereosinophilia and severe anemia. Computed tomography revealed a massive subcapsular hematoma on the kidney. Extensive coagulation analyses were within normal ranges. They had not been administered new medication for their complications during the 6 months prior to admission, except for cinacalcet (Case 1, 14 days; Case 2, 13 days). A drug lymphocyte stimulating test for cinacalcet was positive in both cases. Eight percent of the patients in our hospital who were administered cinacalcet presented with complication of renal hemorrhage. Based on these findings, the final diagnosis was renal hemorrhage due to cinacalcet. They were treated conservatively because both the size of the hematoma and anemia improved. To the best of our knowledge, this is the first report concerning renal hemorrhage. PMID- 21656209 TI - Estimated glomerular filtration rate in peritoneal dialysis practice. PMID- 21656210 TI - Effects of Schisandra sphenanthera extract on the blood concentration of tacrolimus in renal transplant recipients. PMID- 21656211 TI - Evaluation of limited sampling strategies for total and free prednisolone in adult kidney transplant recipients. AB - PURPOSE: The aims of this study were to evaluate the predictive performances of all previously derived limited sampling strategies (LSSs) for total prednisolone, and to derive LSSs for free prednisolone in an independent cohort of adult kidney transplant recipients. METHODS: Total and free prednisolone area under the concentration-time curve profiles from 0 to 12 hours post-dose (AUC(0-12)) were collected from 20 subjects. All previously published total prednisolone LSSs were identified from the literature. Free prednisolone LSSs were developed using multiple linear regression analyses. AUC predicted by each of the LSSs was compared with AUC(0-12). Median percentage prediction error (MPPE) and median absolute percentage prediction error (MAPE) were calculated to evaluate bias and imprecision. RESULTS: Total dose-adjusted prednisolone exposure varied 5-fold among study participants, while free dose-adjusted prednisolone exposure varied 3 fold. Correlation (r2) between total and free prednisolone AUC(0-12) was 0.79 (p = <0.0001) for the entire study cohort. This correlation was poorer in those early compared with late post-transplant (r2 = 0.42 (p = 0.04) versus r2 = 0.59 (p = 0.009) respectively). Ten previously published LSSs for total prednisolone and 15 derived LSSs for free prednisolone performed with acceptable levels of bias and imprecision (<15%). Of the free prednisolone LSSs, an equation incorporating 0.25-, 2- and 4-h concentrations showed the highest predictive power (AUC0-12 = -17.20 + 1.18 * C0.25 + 2.75 * C2 + 4.45 * C4; MPPE = 0.1%, MAPE = 4.6%). CONCLUSIONS: Wide between-subject variability in drug exposure suggests a role for TDM. LSSs can accurately estimate both total and free prednisolone AUC(0-12). However, given the poor correlation observed between the two parameters, our data suggest that free prednisolone LSSs may be preferable. PMID- 21656212 TI - Effects of codeine on pregnancy outcome: results from a large population-based cohort study. AB - BACKGROUND: Guidelines on codeine safety during pregnancy rely on small studies with inconsistent results, and associations between codeine use during pregnancy and increased risk of congenital malformations remain unsubstantiated. OBJECTIVES: Our objective was to analyze the effect of codeine on pregnancy outcome. METHODS: Pregnancy outcomes of 2,666 women who used codeine during pregnancy were compared with 65,316 women who used no opioids during pregnancy. Information on maternal sociodemographic and medical characteristics, potential confounders, and pregnancy outcome was obtained from The Norwegian Mother and Child Cohort Study [den norske Mor & barn-undersokelsen (MoBa)] data set and the Medical Birth Registry of Norway (MBRN) data set. The data sets were linked via the maternal personal identification number. Associations between codeine therapy and pregnancy outcomes were identified using logistic regression analyses. RESULTS: No significant differences were found in the survival rate [adjusted odds ratio (OR) 0.9, 95% confidence interval (CI) 0.6-1.5] or the congenital malformation rate (adjusted OR 0.9, 95% CI 0.8-1.1) between codeine-exposed and unexposed infants. Codeine use anytime during pregnancy was associated with planned Cesarean delivery (adjusted OR 1.4, 95% CI 1.2-1.7; P < 0.0001). Third trimester use was associated with acute Cesarean delivery (adjusted OR 1.5, 95% CI 1.3-1.8; P < 0.0001) and postpartum hemorrhage (adjusted OR 1.3, 95% CI 1.1 1.5; P < 0.0001). No significant associations with other adverse pregnancy outcomes were found. CONCLUSIONS: No effects of maternal codeine intake during pregnancy were observed on infant survival or congenital malformation rate. Our findings are reassuring; however, the association with acute Cesarean delivery and postpartum hemorrhage may justify a certain level of caution when administering codeine toward the end of pregnancy. PMID- 21656213 TI - Cognitively preserved MS patients demonstrate functional differences in processing neutral and emotional faces. AB - The ability to recognize emotional facial expressions is crucial to adequate social behavior. Previous studies have suggested deficits in emotion recognition in multiple sclerosis (MS). These deficits were accompanied by several confounders including cognitive or visual impairments, disease duration, and depression. In our study we used functional MRI (fMRI) to test for potential early adaptive changes in only mildly disabled MS patients performing an emotion recognition task including the facial expressions of the emotions anger, fear and disgust. Fifteen relapsing-remitting MS patients with a median Expanded Disability Status Scale (EDSS) score of 2 (range: 0-3.5) and 15 healthy controls (HC) matched for age, gender, and education underwent behavioral (BERT: behavioral emotion recognition test; BRB-N: Brief Repeatable Battery for neuropsychological tests, WCST: Wisconsin Card Sorting Test) and clinical assessments (BDI: Beck Depression Inventory). Conventional MRI at 3.0T served to assess whole-brain volume, white matter, gray matter, cerebrospinal fluid, and T2 lesion load; during fMRI, participants were confronted with neutral, scrambled, angry, disgusted, and fearful faces, and houses. In the absence of differences in cognitive performance and in the ability to accurately recognize distinct emotional facial expressions, MS patients demonstrated excess fMRI activations during facial recognition compared to HC. These differences concerned the posterior cingulate cortex (PCC) and precuneus for anger and disgust contrasted to neutral faces, and the occipital fusiform gyri and the anterior CC for neutral faces versus houses. This study provides first evidence for excess activation during processing of higher order visual stimuli of emotional content in the absence of emotional, visual or cognitive behavior abnormalities already in earlier stages of MS. PMID- 21656214 TI - Effects of plantar-flexor muscle fatigue on the magnitude and regularity of center-of-pressure fluctuations. AB - Control of bipedal posture is highly automatized but requires attentional investment, the amount of which varies between participants and with postural constraints, such as plantar-flexor muscle fatigue. Elevated attentional demands for standing with fatigued plantar flexors have been demonstrated using a stimulus-response reaction-time paradigm. Recently, a direct relation between the regularity of center-of-pressure (COP) fluctuations and the amount of attention invested in posture was proposed, according to which more regular COP fluctuations are expected with muscle fatigue than without. To study this prediction, we registered anterior-posterior COP fluctuations for bipedal stance with eyes closed prior to and after a plantar-flexor muscle fatiguing exercise protocol in 16 healthy young adults. We quantified the magnitude of COP fluctuations with conventional posturography and its regularity with sample entropy. The magnitude of COP fluctuations increased significantly with fatigued plantar flexors. In addition, more regular COP fluctuations were observed with fatigued plantar flexors, as evidenced by significantly lower sample entropy values. These findings corroborated our hypotheses. Moreover, COP regularity assisted in qualifying the change in sway magnitude with fatigue. Whereas increased sway is customary taken to reflect impaired postural control, we interpret it as a functional, but attention-demanding adaptation to the alteration of important posture-specific information. PMID- 21656215 TI - Modulation of the soleus H reflex by electrical subcortical stimuli in humans. AB - Over the past two decades, the H reflex has been used as a neural tool to assess the effect on the motoneuronal pool of conditioning volleys in supraspinal descending tracts elicited by transcranial magnetic stimulation (TMS) or auditory stimuli. However, mechanisms mediating such modulation are unclear. These hypothesized neural pathways are likely to be affected by single electrical stimulus applied through the electrodes implanted in the subthalamic nucleus for deep brain stimulation (sSTNDBS). To improve our knowledge on such mechanisms, we examined in 11 Parkinson's disease patients the effects of conditioning sSTNDBS applied contralateral and ipsilateral to the H reflex recording on the amplitude of the soleus H reflex, at interstimulus intervals (ISIs) between 0 and 110 ms. There was a significant main effect of the ISI (P<0.001) and of the sSTNDBS stimulation side (P=0.019) on the percentage change in the soleus H-reflex amplitude. Contralateral sSTNDBS modulation of the soleus H reflex resembles that of TMS in healthy subjects with two facilitation phases (at 5-20 ms and at 60 ms), while after ipsilateral sSTNDBS, there is only a single facilitation phase peaking up at 5 ms later than the first facilitation period observed with contralateral stimulation. These findings contribute to the discussion of the mechanisms underlying the excitability of the spinal alpha motoneuron pool and the modulation of the H reflex by supraspinal stimuli. PMID- 21656216 TI - Behavioral responses of trained squirrel and rhesus monkeys during oculomotor tasks. AB - The oculomotor system is the motor system of choice for many neuroscientists studying motor control and learning because of its simplicity, easy control of inputs (e.g., visual stimulation), and precise control and measurement of motor outputs (eye position). This is especially true in primates, which are easily trained to perform oculomotor tasks. Here we provide the first detailed characterization of the oculomotor performance of trained squirrel monkeys, primates used extensively in oculomotor physiology, during saccade and smooth pursuit tasks, and compare it to that of the rhesus macaque. We found that both primates have similar oculomotor behavior but the rhesus shows a larger oculomotor range, better performance for horizontal saccades above 10 degrees, and better horizontal smooth pursuit gain to target velocities above 15 deg/s. These results are important for interspecies comparisons and necessary when selecting the best stimuli to study motor control and motor learning in the oculomotor systems of these primates. PMID- 21656217 TI - The interplay of cue modality and response latency in brain areas supporting crossmodal motor preparation: an event-related fMRI study. AB - Crossmodal (auditory, visual) motor facilitation can be defined as a cue in one sensory modality eliciting speeded responses to targets in a different sensory modality. We used event-related functional magnetic resonance imaging (fMRI) to isolate brain activity underlying crossmodal motor preparation. Our predictions were that interactions between input modality and processes underlying response selection would be indexed by distinct spatiotemporal brain dynamics. A crossmodal response selection task was designed in which a central, nonspatial cue indicated the response rule (compatible or incompatible) to a lateralized target. Cues and targets appeared in auditory and visual modalities and were separated by a lengthy delay period in which cue-related brain activity could be dissociated. We found faster reaction times to auditory compared with visual cues. Next, we correlated brain activity with behavioural performance using multivariate spatiotemporal partial least squares. We identified a distinct, significant brain-behaviour pattern in which faster reaction times to auditory cues were correlated with higher blood oxygenation level-dependent percent signal change in medial visual, frontoparietal (inferior parietal lobule, superior frontal gyrus and premotor cortex) and subcortical (thalamus and cerebellum) areas. For visual cues, quicker responses were linked to greater activity in the same frontoparietal and subcortical but not medial visual areas. Our results show that both modality-dependent and modality-independent brain areas with different brain-behaviour relationships are implicated in crossmodal motor preparation. PMID- 21656218 TI - Self-other bodily merging in the context of synchronous but arbitrary-related multisensory inputs. AB - A debated issue in the multisensory literature concerns the relative contribution of bottom-up sensory components versus top-down cognitive elaborations in contributing to the rise and persistency of bodily illusion. Previous studies, for instance, have shown that simultaneity of sensory inputs and plausibility of the stimulated object play an important role in the rubber hand phenomenon, whereas violation of tactile expectancy does not disrupt the illusory feeling to own a fake hand. The present research examined this issue in the context of the "enfacement" phenomenon (i.e., self-other face-perception modification), using entirely arbitrary and non-ecological pairs of visual and tactile events. Visual and tactile stimulation was matched in terms of spatial location, but not linked by any previously learned associations, making temporal synchrony a critical binding factor. Participants received electro-tactile stimulations on their cheek, while they watched the face of a stranger illuminated on the cheek with a dot of white light. Synchronous (vs. asynchronous) stimulations yielded the enfacement effect. In addition, the stranger stimulated in synchrony was judged as more similar, physically and in terms of personality, and as closer to the self. These findings suggest that synchronous multisensory stimulation on the face can produce both perceptual and social binding, even in the absence of any previously learned associations between the stimulations. PMID- 21656219 TI - The rate of force development scaling factor (RFD-SF): protocol, reliability, and muscle comparisons. AB - Performing a set of isometric muscular contractions to varied amplitudes with instructions to generate force most rapidly reveals a strong linear relationship between peak forces (PF) achieved and corresponding peak rates of force development (RFD). The slope of this relationship, termed the RFD scaling factor (RFD-SF), quantifies the extent to which RFD scales with contraction amplitude. Such scaling allows relative invariance in the time required to reach PF regardless of contraction size. Considering the increasing use of this relationship to study quickness and consequences of slowness in older adults and movement disorders, our purpose was to further develop the protocol to measure RFD-SF. Fifteen adults (19-28 years) performed 125 rapid isometric contractions to a variety of force levels in elbow extensors, index finger abductors, and knee extensors, on 2 days. Data were used to determine (1) how the number of pulses affects computation of the RFD-SF, (2) day-to-day reliability of the RFD-SF, and (3) the nature of RFD-SF differences between diverse muscle groups. While sensitive to the number of pulses used in its computation (P<.05), RFD-SF was reliable when computed with >50 pulses (ICC>.7) and more so with 100-125 pulses (ICC=.8-.92). Despite differences in size and function across muscles, RFD-SF was generally similar (i.e., only 8.5% greater in elbow extensors than in index finger abductors and knee extensors; P=.049). Results support this protocol as a reliable means to assess how RFD scales with PF in rapid isometric contractions as well as a simple, non-invasive probe into neuromuscular health. PMID- 21656220 TI - An electrophysiological study of task demands on concreteness effects: evidence for dual coding theory. AB - We examined ERP responses during the generation of word associates or mental images in response to concrete and abstract concepts. Of interest were the predictions of dual coding theory (DCT), which proposes that processing lexical concepts depends on functionally independent but interconnected verbal and nonverbal systems. ERP responses were time-locked to either stimulus onset or response to compensate for potential latency differences across conditions. During word associate generation, but not mental imagery, concrete items elicited a greater N400 than abstract items. A concreteness effect emerged at a later time point during the mental imagery task. Data were also analyzed using time frequency analysis that investigated synchronization of neuronal populations over time during processing. Concrete words elicited an enhanced late going desynchronization of theta-band power (723-938 ms post stimulus onset) during associate generation. During mental imagery, abstract items elicited greater delta-band power from 800 to 1,000 ms following stimulus onset, theta-band power from 350 to 205 ms before response, and alpha-band power from 900 to 800 ms before response. Overall, the findings support DCT in suggesting that lexical concepts are not amodal and that concreteness effects are modulated by tasks that focus participants on verbal versus nonverbal, imagery-based knowledge. PMID- 21656221 TI - Evaluation of biocompatible dispersants for carbon nanotube toxicity tests. AB - Dispersion is one of the key obstacles to evaluating the in vitro and in vivo toxicity of carbon nanotubes (CNTs), as the aggregation or agglomeration of CNTs in culture media or vehicles complicates the interpretation of the toxicity test results. Thus, to test the dispersion of CNTs in biocompatible solutions, 5 known biocompatible dispersants were selected that are widely used for nanomaterial toxicity evaluation studies. Single-wall nanotubes (SWCNTs) and multi-wall nanotubes (MWCNTs) were both dispersed in these dispersants and their macrodispersion evaluated using a light absorbance method. The dispersion stability of the dispersed SWCNTs and MWCNTs was also evaluated for 16 weeks, plus the dispersants were tested for their innate toxicity using trypan blue dye exclusion, lactate dehydrogenase (LDH) leakage, and neutral red assays. All the dispersants were found to be biocompatible in the cytotoxicity tests when compared with a positive control of 2% Triton X-100. In the dispersion tests, 0.02, 0.1, and 0.5% MWCNTs and SWCNTs were diluted in the respective dispersants. Distilled water and dimethylsulfoxide (DMSO) both showed a poor macrodispersion of only 1-13% for the various CNT concentrations. In 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), the 0.02 and 0.1% MWCNTs showed a macrodispersion of 11 and 74%, respectively, while the 0.02 and 0.1% SWCNTs showed a macrodispersion of 15 and 16%, respectively. In 0.5% bovine serum albumin (BSA), the 0.02, 0.1, and 0.5% MWCNTs showed a very good macrodispersion of 32, 53, and 70%, respectively, yet the 0.02% SWCNTs only showed a macrodispersion of 17%. In 1% Tween 80, the 0.02-0.5% SWNCTs exhibited a good macrodispersion of 27-81%, whereas the 0.02-05% MWCNTs only showed a macrodispersion of 13-23%. The dispersion stability of the CNTs during 16 weeks was in the following descending order of BSA, Tween 80, DPPC, and DMSO for the MWCNTs and BSA, DPPC, Tween 80, and DMSO for the SWNCTs. Thus, appropriate dispersants are proposed according to the type of CNT, experiment concentration, and treatment duration. Also, it is suggested that the dispersibility, dispersion stability, and biocompatibility of the selected dispersant should all be confirmed before a toxicity evaluation. PMID- 21656222 TI - Evaluation of the cytotoxic and inflammatory potential of differentially shaped zinc oxide nanoparticles. AB - Zinc oxide (ZnO) nanoparticles have wide-ranging applications in a diverse array of industrial and consumer products, from ceramic manufacture and paint formulation to sunscreens and haircare products. Hence, it is imperative to rigorously characterize the health and safety aspects of human exposure to ZnO nanoparticles. This study therefore evaluated the cellular association, cytotoxic and inflammatory potential of spherical and sheet-shaped ZnO nanoparticles (of approximately the same specific surface area ~30 cm2/g) on mouse and human cell lines (RAW-264.7 and BEAS-2B respectively), as well as with primary cultures of mouse bone marrow-derived dendritic cells (DC). The WST-8 assay demonstrated dose dependent effects on the cytotoxicity of spherical and sheet-shaped ZnO nanoparticles on both RAW-264.7 and BEAS-2B cells, even though there was no significant effect of shape on the cytotoxicity of ZnO nanoparticles. There was however higher cellular association of spherical versus sheet-shaped ZnO nanoparticles. Measurement of reactive oxygen species (ROS) with the 2',7' dichlorfluorescein-diacetate (DCFH-DA) assay indicated up to 4-folds increase in ROS level upon exposure to ZnO nanoparticles, but there was again no significant difference between both ZnO nanoparticle shapes. Exposure of primary dendritic cells to ZnO nanoparticles upregulated expression of CD80 and CD86 (well-known markers of DC activation and maturation) and stimulated release of pro inflammatory cytokines--IL-6 and TNF-alpha, thus pointing to the potential of ZnO nanoparticles in inducing inflammation. Hence, our study indicated that ZnO nanoparticles can have potential detrimental effects on cells even at dosages where there are little or no observable cytotoxic effects. PMID- 21656223 TI - Use of the gammaH2AX assay for assessing the genotoxicity of bisphenol A and bisphenol F in human cell lines. AB - Bisphenol A (BPA) and bisphenol F (BPF) are widely used to manufacture plastics and epoxy resins. Both compounds have been shown to be present in the environment and are food contaminants, with, as a result, a low but chronic exposure of humans. However, the fate and possible bioactivation of these compounds at the level of human cell lines was not completely elucidated yet. In this study, we investigated the ability of human cells (intestinal cell line: LS174T, hepatoma cell line: HepG2, and renal cell line: ACHN) to biotransform BPA and BPF, and focused on the cytotoxicity and genotoxicity of these two bisphenols, through the use of a novel and efficient genotoxic assay based on the detection of histone H2AX phosphorylation. BPA and BPF were extensively metabolized in HepG2 and LS174T cell lines, with stronger biotransformation capabilities in intestinal cells than observed in liver cells. Both cell lines produced the glucuronide as well as the sulfate conjugates of BPA. Conversely, the ACHN cell line was found to be devoid of any metabolic capabilities for the two examined bisphenols. Cytotoxicity was tested for BPA, BPF, as well as one metabolite of BPF produced in vivo in rat, namely dihydroxybenzophenone (DHB). In the three cell lines used, we observed similar ranges of toxicity, with DHB being weakly cytotoxic, BPF exhibiting an intermediary cytotoxicity, and BPA being the most cytotoxic compound tested. BPA and DHB were not found to be genotoxic, whatever the cell line examined. BPF was clearly genotoxic in HepG2 cells. These results demonstrate that some human cell lines extensively metabolize bisphenols and establish the genotoxic potential of bisphenol F. PMID- 21656224 TI - Impaired bone formation and osteopenia in heterozygous beta(IVSII-654) knockin thalassemic mice. AB - beta-thalassemia caused by the C->T mutation at nucleotide 654 of the intron 2 (beta(IVSII-654)) results in aberrant splicing of beta-globin RNA, leading to an almost absence of beta-globin synthesis. Although trabecular and cortical bone loss was previously reported in beta-thalassemic mice with deletion of beta globin gene, the microscopic changes in trabecular structure in beta(IVSII-654) thalassemic mice remained elusive. Here, we investigated the macroscopic and microscopic bone changes in 12-week-old beta(IVSII-654) knockin thalassemic mice by dual-energy X-ray absorptiometry (DXA) and histomorphometric analysis, respectively. DXA revealed a decrease in bone mineral density in the lumbar vertebrae and tibial metaphysis, but not in the femoral diaphysis, suggesting that beta(IVSII-654) thalassemia predominantly led to osteopenia at the trabecular site, but not the cortical site. Further histomorphometric analysis of the tibial secondary spongiosa showed that trabecular bone volume was significantly decreased with the expansion of marrow cavity. Decreases in osteoblast surface, osteoid surface, mineral apposition rate, mineralizing surface, and mineralized volume were also observed. Moreover, trabecular bone resorption was markedly enhanced as indicated by increases in the osteoclast surface and eroded surface. It could be concluded that beta(IVSII-654) thalassemia impaired bone formation and enhanced bone resorption, thereby leading to osteopenia especially at the trabecular sites, such as the tibial metaphysis. PMID- 21656225 TI - In vitro and in vivo neo-cartilage formation by heterotopic chondrocytes seeded on PGA scaffolds. AB - Implantation of tissue-engineered heterotopic cartilage into joint cartilage defects might be an alternative approach to improve articular cartilage repair. Hence, the aim of this study was to characterize and compare the quality of tissue-engineered cartilage produced with heterotopic (auricular, nasoseptal and articular) chondrocytes seeded on polyglycolic acid (PGA) scaffolds in vitro and in vivo using the nude mice xenograft model. PGA scaffolds were seeded with porcine articular, auricular and nasoseptal chondrocytes using a dynamic culturing procedure. Constructs were pre-cultured 3 weeks in vitro before being implanted subcutaneously in nude mice for 1, 6 or 12 weeks, non-seeded scaffolds were implanted as controls. Heterotopic neo-cartilage quality was assessed using vitality assays, macroscopical and histological scoring systems. Neo-cartilage formation could be observed in vitro in all PGA associated heterotopic chondrocytes cultures and extracellular cartilage matrix (ECM) deposition increased in vivo. The 6 weeks in vivo incubation time point leads to more consistent results for all cartilage species, since at 12 weeks in vivo construct size reductions were higher compared with 6 weeks except for auricular chondrocytes PGA cultures. Some regressive histological changes could be observed in all constructs seeded with all chondrocytes subspecies such as cell-free ECM areas. Particularly, but not exclusively in nasoseptal chondrocytes PGA cultures, ossificated ECM areas appeared. Elastic fibers could not be detected within any neo-cartilage. The neo-cartilage quality did not significantly differ between articular and non-articular chondrocytes constructs. Whether tissue-engineered heterotopic neo-cartilage undergoes sufficient transformation, when implanted into joint cartilage defects requires further investigation. PMID- 21656226 TI - The role of nitric oxide in cellular response to hyperbaric conditions. AB - Nitric oxide (NO) acts as a regulator in cell proliferation and expression of growth factors and forms peroxynitrite (ONOO(-)) in oxidative conditions. The aim of the study was to investigate the role of NO in cellular response to hyperbaric oxygen (HBO). NO and nitrotyrosine (NT), biochemical marker for ONOO(-), cell proliferation and growth factors, were ex-vivo studied in cell cultures under HBO and normobaric (NOR) conditions. A549 (epithelial), L929 (fibroblast) and SVEC (endothelial) were exposed to 100% O(2), at P = 280 kPa for t = 60 min, once daily for five sessions. Cell proliferation was determined as the incorporation of bromodeoxyuridine (BrdU) into cells and NO as nitrates/nitrites (NO(3) (-)/ NO(2) (-)) Gries reaction product in cell culture supernatant (CCSP). NT, vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGFb1) were measured with enzyme-inked immunosorbent assay (ELISA) in CCSP. The time course of total NO was opposite to that of cell proliferation in HBO conditions, peaking after the second HBO session, while cell proliferation showed a reverse trend, minimizing at the same time, suggesting a reverse and transient anti-proliferative effect. Released growth factors were significantly increased in late HBO sessions. NT peaked after second treatment, indicating the formation of ONOO(-). In control cultures (NOR), proliferation rate was downward and no significant differences were found for the other parameters. In conclusion, the data suggested a key role for NO in the beneficial HBO action, depending on its concentration, which fluctuated with the time of HBO exposure and the activation of oxidant-antioxidant (REDOX) mechanisms, regardless of cell type. PMID- 21656227 TI - Fluid balance, thermal stress, and post exercise response in women's Islamic athletic clothing. AB - This study examined heat stress, heart rate (HR), fluid balance, micro environment temperature and humidity with Islamic athletic clothing (IC) compared to traditional soccer uniform (SC). Ratings of perceived exertion (RPE), session RPE (S-RPE), comfort, and cooling response were also examined. Female volunteers (N = 8) completed a treadmill [Formula: see text] test and then, in a randomized, counter-balanced order, two intermittent running bouts (45 min total) in a hot environment (30.0 degrees C WBGT) in IC and SC. Thereafter, participants sat for 40 min in the hot ambient environment. Repeated measures ANOVA revealed significantly greater micro-environment temperature (p = 0.02) (IC 33.3 +/- 3.2 degrees C, SC 32.0 +/- 2.8 degrees C) and humidity (p = 0.04) (IC 48.4 +/- 8.1%, SC 42.9 +/- 7.9%) in IC during the exercise trial but no difference in the 40-min recovery period for micro-environment temperature (p = 0.25) or humidity (p = 0.18). No significant difference (p > 0.05) was shown for core temperature (T (rec)) (IC 38.3 +/- 0.4 degrees C, SC 38.2 +/- 0.4 degrees C), HR (IC l54 +/- 28 beats min(-1), SC 151 +/- 26 beats min(-1)) or RPE (IC 4.7 +/- 2.1, SC 3.8 +/- 1.7) during the exercise trial or recovery period. Results from a paired t test revealed a significantly greater (p < 0.05) S-RPE (IC 5.8 +/- 1.2, SC 4.3 +/- 1.9), sweat loss (IC 1.4 +/- 0.4 L h(-1), SC 1.2 +/- 0.4 L h(-1)) and greater discomfort during the exercise and recovery period for the IC. IC clothing appears to have no detrimental effects on heat storage or heat strain during exercise or recovery. PMID- 21656228 TI - Effect of obesity and metabolic syndrome on hypoxic vasodilation. AB - This study was designed to test whether obese adults and adults with metabolic syndrome (MetSyn) exhibit altered hyperemic responses to hypoxia at rest and during forearm exercise when compared with lean controls. We hypothesized blood flow responses due to hypoxia would be lower in young obese subjects (n = 11, 24 +/- 2 years, BMI 36 +/- 2 kg m(-2)) and subjects with MetSyn (n = 8, 29 +/- 3 years BMI 39 +/- 2 kg m(-2)) when compared with lean adults (n = 13, 29 +/- 2 years, BMI 24 +/- 1 kg m(-2)). We measured forearm blood flow (FBF, Doppler Ultrasound) and arterial oxygen saturation (pulse oximetry) during rest and steady-state dynamic forearm exercise (20 contractions/min at 8 and 12 kg) under two conditions: normoxia (0.21 F(i)O(2), ~98% S(a)O(2)) and hypoxia (~0.10 F(i)O(2), 80% S(a)O(2)). Forearm vascular conductance (FVC) was calculated as FBF/mean arterial blood pressure. At rest, the percent change in FVC with hypoxia was greater in adults with MetSyn when compared with lean controls (p = 0.02); obese and lean adult responses were not statistically different. Exercise increased FVC from resting levels in all groups (p < 0.05). Hypoxia caused an additional increase in FVC (p < 0.05) that was not different between groups; responses to hypoxia were heterogeneous within and between groups. Reporting FVC responses as absolute or percent changes led to similar conclusions. These results suggest adults with MetSyn exhibit enhanced hypoxic vasodilation at rest. However, hypoxic responses during exercise in obese adults and adults with MetSyn were not statistically different when compared with lean adults. Individual hypoxic vasodilatory responses were variable, suggesting diversity in vascular control. PMID- 21656229 TI - No case of exercise-associated hyponatraemia in top male ultra-endurance cyclists: the 'Swiss Cycling Marathon'. AB - The prevalence of exercise-associated hyponatraemia (EAH) has been investigated in endurance athletes such as runners and Ironman triathletes, but not in ultra endurance road cyclists. We assessed fluid intake and changes in body mass, urine specific gravity and plasma sodium concentration ([Na(+)]) in 65 ultra-endurance road cyclists in a 720-km ultra-cycling marathon, the 'Swiss Cycling Marathon'. The cyclists lost 1.5 (1.7)% body mass (P < 0.01). No athlete developed EAH. Fluid intake was associated with the change in plasma [Na(+)] (r = -0.32, P < 0.05) and the change in body mass (r = -0.30, P < 0.05). The change in plasma [Na(+)] was related to post-race plasma [Na(+)] (r = 0.63, P < 0.0001). To conclude, ad libitum fluid intake in ultra-endurance cyclists in a single-stage ultra-endurance road cycling race showed no case of EAH. Future studies regarding drinking behaviour in different ultra-endurance disciplines might give insights into why the prevalence of EAH is different in the different disciplines. PMID- 21656230 TI - Metabolic and respiratory adaptations during intense exercise following long sprint training of short duration. AB - This study aimed to determine metabolic and respiratory adaptations during intense exercise and improvement of long-sprint performance following six sessions of long-sprint training. Nine subjects performed before and after training (1) a 300-m test, (2) an incremental exercise up to exhaustion to determine the velocity associated with maximal oxygen uptake (v-VO(2max)), (3) a 70-s constant exercise at intensity halfway between the v-VO(2max) and the velocity performed during the 300-m test, followed by a 60-min passive recovery to determine an individual blood lactate recovery curve fitted to the bi exponential time function: [Formula: see text], and blood metabolic and gas exchange responses. The training program consisted of 3-6 repetitions of 150-250 m interspersed with rest periods with a duration ratio superior or equal to 1:10, 3 days a week, for 2 weeks. After sprint training, reduced metabolic disturbances, characterized by a lower peak expired ventilation and carbon dioxide output, in addition to a reduced peak lactate (P < 0.05), was observed. Training also induced significant decrease in the net amount of lactate released at the beginning of recovery (P < 0.05), and significant decrease in the net lactate release rate (NLRR) (P < 0.05). Lastly, a significant improvement of the 300-m performance was observed after training. These results suggest that long sprint training of short durations was effective to rapidly prevent metabolic disturbances, with alterations in lactate accumulation and gas exchange, and improvement of the NLRR. Furthermore, only six long-sprint training sessions allow long-sprint performance improvement in active subjects. PMID- 21656231 TI - Cardiovascular responses to arm static exercise in men with thoracic spinal cord lesions. AB - Isometric muscle contraction (static exercise) induces circulatory response. Static exercise in individuals with thoracic spinal cord injury (TSCI) induces cardiovascular response and blood redistribution to the non-exercising muscles. The aim of our study was to determine the circulatory response during arm static exercise in individuals with TSCI and able-bodied (AB) controls. Mean blood pressure (MBP), heart rate (HR), cardiac output (CO), leg skin blood flow (SBF), and leg muscle blood flow (MBF) were recorded noninvasively, total peripheral resistance (TPR) was estimated by dividing MBP by CO, and hormonal changes were measured before, during and after static 35% maximal voluntary contraction (MVC) of the arm flexor muscles in seven male individuals with TSCI (T7-T11) and seven age-comparable AB control (32.2 +/- 7.6 and 31.0 +/- 4.7 years, respectively). The 35% MVC was similar in TSCI and AB individuals (107.3 +/- 28.2 and 101.0 +/- 22.5 N, respectively). HR, CO, MBP, TPR, SBF and MBF increased in both groups during arm static exercise. Plasma epinephrine concentration increased during arm static exercise in AB controls only (P < 0.05). Circulation to leg muscles was similar in TSCI and AB individuals and the lack of sympathetic vasoconstriction in the paralyzed leg area did not alter the cardiovascular responses during 35% MVC of arm static exercise. We conclude that sympathetic vasoconstriction in the resting leg area did not contribute to the pressor reflex during 35% MVC of arm static exercise. PMID- 21656232 TI - Monitoring changes in physical performance with heart rate measures in young soccer players. AB - The aim of the present study was to verify the validity of using exercise heart rate (HRex), HR recovery (HRR) and post-exercise HR variability (HRV) during and after a submaximal running test to predict changes in physical performance over an entire competitive season in highly trained young soccer players. Sixty-five complete data sets were analyzed comparing two consecutive testing sessions (3-4 months apart) collected on 46 players (age 15.1 +/- 1.5 years). Physical performance tests included a 5-min run at 9 km h(-1) followed by a seated 5-min recovery period to measure HRex, HRR and HRV, a counter movement jump, acceleration and maximal sprinting speed obtained during a 40-m sprint with 10-m splits, repeated-sprint performance and an incremental running test to estimate maximal cardiorespiratory function (end test velocity V (Vam-Eval)). Possible changes in physical performance were examined for the players presenting a substantial change in HR measures over two consecutive testing sessions (greater than 3, 13 and 10% for HRex, HRR and HRV, respectively). A decrease in HRex or increase in HRV was associated with likely improvements in V (Vam-Eval); opposite changes led to unclear changes in V (Vam-Eval). Moderate relationships were also found between individual changes in HRR and sprint [r = 0.39, 90% CL (0.07;0.64)] and repeated-sprint performance [r = -0.38 (-0.05;-0.64)]. To conclude, while monitoring HRex and HRV was effective in tracking improvements in V (Vam-Eval), changes in HRR were moderately associated with changes in (repeated-)sprint performance. The present data also question the use of HRex and HRV as systematic markers of physical performance decrements in youth soccer players. PMID- 21656233 TI - Emerging country pharmacology: a 10-year perspective from Naunyn-Schmiedeberg's Archives of Pharmacology. PMID- 21656234 TI - Retroaortic coronary artery: possible contraindication for device closure of atrial septal defect. PMID- 21656235 TI - Unmasking of neonatal renovascular hypertension by milrinone used for cardiac dysfunction. AB - A neonate initially presented with heart failure, with severe cardiac dysfunction confirmed by echocardiography, at 3 days of age. Blood pressure at presentation was in the high normal range. It was not until there was a rapid improvement of left-ventricular function on intravenous milrinone that the infant was noted to be hypertensive on day of life 7. It is noteworthy that milrinone, a drug with vasodilator and inotropic properties, paradoxically unmasked hypertension by rapidly improving left-ventricular function. Subsequent work-up showed the etiology of hypertension to be left renal artery stenosis. We present this case to alert clinicians to the rarer causes of left-ventricular dysfunction and to point out that its etiology, i.e., hypertension, may not be apparent until there is improvement in the systolic function of the left ventricle. PMID- 21656236 TI - Autologous right pulmonary artery tissue for repair of left pulmonary artery originating from left patent ductus arteriosus in a patient with tetralogy of Fallot and absent pulmonary valve. AB - Left pulmonary artery (PA) originating from patent ductus arteriosus is an exceptionally rare variant of tetralogy of Fallot with absent pulmonary valve. We described an alternative technique for the repair of discontinuous left PA with the use of the redundant pulmonary artery tissue as material for the conduit in a 3-year-old boy. PMID- 21656237 TI - Early NT-proBNP is able to predict spontaneous closure of patent ductus arteriosus in preterm neonates, but not the need of its treatment. AB - The objective of this study was to establish the potential utility of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the management of patent ductus arteriosus (PDA). This was a monocentric prospective blind study that was conducted in a referral neonatal intensive care unit. The patients were very low birth-weight/gestational-age neonates. Babies with cardiac congenital anomaly other than PDA, life-threatening congenital malformation, severe asphyxia at birth, persistent pulmonary hypertension, and death within the first week of life were excluded. Plasma NT-proBNP concentrations were determined on days 2, 4, and 7 of life. Echocardiography was performed on days 4 and 7. Results were blinded to clinicians. Only echographic results were available upon request. Thirty-one infants were included. NT-proBNP levels were significantly correlated to ductal size and to left atrial-to-aortic diameter ratio. The median NT-proBNP on both days 2 and 4 was significantly higher in neonates with later treated or persistent PDA. A level above 10.000 pg/mL at 48 h of age yielded a 100% positive and a 87% negative predictive value to exclude spontaneous ductal closure. However, no NT-proBNP threshold could predict which PDA would be judged necessary to treat. It was concluded that early low NT-proBNP values can be used as a reliable independent marker to predict spontaneous ductal closure in preterm neonates. Yet, high NT-proBNP levels should not be used to guide the decision to treat PDA, the risk being of treating many bystanding PDAs. PMID- 21656239 TI - Total anomalous pulmonary venous drainage complicated by tracheoesophageal fistula. AB - We provided emergency treatment to a 1-day-old neonate (1600 g) with tracheoesophageal fistula (gross classification, type C) and total anomalous pulmonary venous drainage (infracardiac type) complicated by pulmonary venous obstruction. Emergency surgery was required because the tracheoesophageal fistula would have caused respiratory failure. Here we report the perioperative management techniques we used, including the surgical strategy. PMID- 21656238 TI - Establishment of secondary iron overloaded mouse model: evaluation of cardiac function and analysis according to iron concentration. AB - Periodic blood transfusion can lead to secondary iron overload in patients with hematologic and oncologic diseases. Iron overload can result in iron deposition in heart tissue, which decreases cardiac function and can ultimately lead to death due to dilated cardiomyopathy and cardiac failure. In this study, we established murine model of secondary iron overload, studied the changes in cardiac function with echocardiography, and examined the histopathologic changes. Three experimental groups of the six week-old C57/BL mice (H-2(b)) were injected intraperitoneally with 10 mg of iron dextran daily 5 days a week for 2, 4, and 6 weeks. Cumulative doses of iron for the three experimental groups were 100, 200, and 300 mg, while the control groups were injected with the same amounts of phosphate-buffered saline. We studied the cardiac function under anesthesia with echocardiography using a GE Vivid7 Dimension system. Plasma iron levels and liver iron contents were measured. The hearts and livers were harvested and stained with H&E and Perls Prussian blue for iron, and the levels of iron deposit were examined. We assessed the cardiac measurements after adjustment for weight. On echocardiography, thicknesses of the interventricular septum and posterior ventricular wall (PS) during diastole showed correlation with the amount of iron deposit (P < 0.01). End-diastolic volume showed dilatation of the left ventricle in the 300 mg group (P < 0.01). Changes in the fractional shortening were not statistically significant (P = 0.07). Plasma iron levels and liver iron contents were increased proportionally according to the amount of iron loaded. The histopathologic findings of PS and liver showed higher grade of iron deposit proportional to the cumulated iron dose. In this study, we present an animal model which helps understand the cardiac function changes in patients with secondary iron overload due to repeated blood transfusions. Our results may help characterize the pathophysiologic features of cardiomyopathy in patients with secondary iron overload, and our model may be applied to in vivo iron-chelating therapy studies. PMID- 21656241 TI - A case study of infant health promotion and corporate marketing of milk substitutes. AB - The mismatch between the demand for, and supply of, health products has led to the increasing involvement of courts worldwide in health promotion and marketing. This study critically examines the implementation of one country's Milk Code within the framework of the International Code of Marketing of Breast-Milk Substitutes, and the efficacy of the judicial process in balancing corporate marketing and state regulatory objectives. Drawing upon the Philippine experience with its own Milk Code, it evaluates the capacities of courts to determine policy costs and risks against the benefits of delineating and containing corporate marketing strategies for milk substitutes and supplements. The study finds that the methodological and information-based challenges faced by courts in resolving multi-dimensional health issues may not be overcome without serious questions concerning the legitimacy of the judicial process itself. Despite the deficiencies of litigation and adjudication, the study notes the catalytic potential of a judicial decision in opening up vital policy space for future renegotiations among rival parties and interests. Third-party intervention is explored relative to this catalytic function. PMID- 21656240 TI - Interactions of uranyl ion with cytochrome b5 and its His39Ser variant as revealed by molecular simulation in combination with experimental methods. AB - The biological toxicity of uranyl ion (UO (2) (2+) ) lies in interacting with proteins and disrupting their native functions. The structural and functional consequences of UO (2) (2+) interacting with cytochrome b (5) (cyt b (5)), a small membrane heme protein, and its heme axial ligand His39Ser variant, cyt b (5) H39S, were investigated both experimentally and theoretically. In experiments, although cyt b (5) was only slightly affected, UO (2) (2+) binding to cyt b (5) H39S with a K (D) of 2.5 MUM resulted in obvious alteration of the heme active site, and led to a decrease in peroxidase activity. Theoretically, molecular simulation proposed a uranyl ion binding site for cyt b (5) at surface residues of Glu37 and Glu43, revealing both coordination and hydrogen bonding interactions. The information gained in this study provides insights into the mechanism of uranyl toxicity toward membrane protein at an atomic level. PMID- 21656242 TI - Mind over muscle: the role of gaze control, spatial cognition, and the quiet eye in motor expertise. AB - In the course of all motor behavior, the brain is limited in how much information it can process and act upon at a time. Performers must constantly decide where to look, what to attend to, and how to time fixated information with precisely controlled actions. The gaze can be directed to only one location at a time and information central to success must be selected from spatially complex environments, most often under severe time constraints. The coordination of these processes is explored in this Special issue in a number of motor tasks, including golf, soccer, law enforcement, and ballet. The papers describe the visual information and quiet eye characteristics that underlie the ability to make decisions under complex task conditions and the relationship between control of the gaze and task outcomes. With the attainment of motor expertise, measureable changes occur within the gaze, cognitive, and neural systems that are useful in training, rehabilitation, and the treatment of motor deficits. PMID- 21656243 TI - Autonomy, decisions, and free will. AB - Can humans make decisions? Can machines? What ethical questions arise from using robotics in the education of children? Or in elderly care? These were some of the topics of the interdisciplinary college (IK), which took place from the 25th of March to the 1st of April in Gunne, next to Lake Mohne. During this one-week spring school, more than 40 well-known lecturers from around the globe gave 170 participants an insight into a cornucopia of topics surrounding "autonomy, decisions, and free will". PMID- 21656244 TI - Impact of attenuation correction and gated acquisition in SPECT myocardial perfusion imaging: results of the multicentre SPAG (SPECT Attenuation Correction vs Gated) study. AB - PURPOSE: In clinical myocardial single photon emission computed tomography (SPECT), attenuation artefacts may cause a loss of specificity in the identification of diseased vessels that can be corrected by means of gated SPECT (GSPECT) acquisition or CT attenuation correction (AC). The purpose of this multicentre study was to assess the impact of GSPECT and AC on the diagnostic performance of myocardial scintigraphy, according to patient's sex, body mass index (BMI) and site of coronary artery disease (CAD). METHODS: We studied a group of 104 patients who underwent coronary angiography within 1 month before or after the SPECT study. Patients with a BMI>27 were considered "overweight". Attenuation-corrected and standard GSPECT early images were randomly interpreted by three readers blinded to the clinical data. RESULTS: In the whole group, GSPECT and AC showed a diagnostic accuracy of 86.5% (sensitivity 82%, specificity 93%) and 77% (sensitivity 75.4%, specificity 81.4%), respectively (p<0.05). In women, when anterior ischaemia was matched with CAD, AC failed to show any increase in specificity (AC 63.6% vs GSPECT 63.6%) with evident loss of sensitivity (AC 72.7% vs GSPECT 90.9%). AC significantly improved SPECT specificity in the identification of right CAD in overweight men (AC 100% vs GSPECT 66.7%, p<0.05). CONCLUSION: AC improved specificity in the evaluation of right CAD in overweight men. In the other evaluable subgroups specificity was not significantly affected while sensitivity was frequently reduced. PMID- 21656246 TI - Comparison of the myocardial blood flow response to regadenoson and dipyridamole: a quantitative analysis in patients referred for clinical 82Rb myocardial perfusion PET. AB - BACKGROUND: Regadenoson is a novel selective A2A adenosine receptor agonist, which is administered as an intravenous bolus at a fixed dose. It is currently not clear if the absolute flow increase in response to this fixed dose is a function of distribution volume in individual patients or if it is generally comparable to the previous standard agents dipyridamole or adenosine, which are dosed based on weight. We used quantitative analysis of clinical 82Rb PET/CT studies to obtain further insights. METHODS: A total of 104 subjects with normal clinical rest/stress 82Rb perfusion PET/CT were included in a retrospective analysis. To rule out confounding factors, none had evidence of prior cardiac disease, ischaemia or infarction, cardiomyopathy, diabetes with insulin use, calcium score>400, renal disease or other significant systemic disease. A group of 52 patients stressed with regadenoson were compared with a group of 52 patients stressed with dipyridamole before regadenoson became available. The groups were matched for clinical characteristics, risk factors and baseline haemodynamics. Myocardial blood flow (MBF) and myocardial flow reserve (MFR) were quantified using a previously validated retention model, after resampling of dynamic studies from list-mode 82Rb datasets. RESULTS: At rest, heart rate, blood pressure and MBF were comparable between the groups. Regadenoson resulted in a significantly higher heart rate (34+/-14 vs. 23+/-10 beats per minute increase from baseline; p<0.01) and rate-pressure product. Patients in the regadenoson group reported less severe symptoms and required less aminophylline. Stress MBF and MFR were not different between the groups (2.2+/-0.6 vs. 2.1+/-0.6 ml/min/g, p=0.39, and 2.9+/-0.8 vs. 2.8+/-0.7, p=0.31, respectively). In the regadenoson group, there was no correlation between stress flow or MFR and body weight or BMI. CONCLUSION: Despite its administration at a fixed dose, regadenoson results in an absolute increase in MBF which is comparable to that following dipyridamole administration and is independent of patient distribution volume. This further supports its usefulness as a clinical stress agent. PMID- 21656247 TI - Virulence regulator PrfA is essential for biofilm formation in Listeria monocytogenes but not in Listeria innocua. AB - The ability of the foodborne pathogen Listeria monocytogenes to develop biofilm in food-processing environment is a major concern for the food safety, because biofilms allow bacteria to better resist environmental stresses. PrfA is a key transcriptional activator that positively regulates most of the known listerial virulence gene expression. In order to explore the role of PrfA on Listeria biofilm development, we compared the abilities of biofilm formation by L. monocytogenes wild type strains (EGD and EGDe) and their prfA deletion mutants (EGD?prfA and EGDe?prfA), nonpathogenic Listeria innocua, as well as the recombinant strains that express constitutively active mutant PrfA (PrfA*) in L. innocua (LI-pERL3-prfA*) and in EGDe?prfA (EGDe?prfA-pERL3-prfA*) at 37 degrees C in brain heart infusion (BHI) medium using the polyvinyl chloride (PVC) microtiter plate assay and microscopic examination. Our results showed that the wild types of L. monocytogenes had strong abilities to develop biofilm with meshwork of bacterial aggregates, while biofilm with sparse small clumps were observed in L. innocua. The biofilm production of strains EGD?prfA and EGDe?prfA that lack funtional PrfA was reduced and could be recovered by the introduction of the PrfA*, however, the PrfA* had no impact on the biofilm forming ability of L. innocua. Our results suggest that PrfA plays a significant role in biofilm formation in L. monocytogenes but not in L. innocua, thus may reflect differences in the molecular mechanisms of biofilm formation by these two closely related species. PMID- 21656248 TI - Detection and characterization of pediocin PA-1/AcH like bacteriocin producing lactic acid bacteria. AB - Fifty-five bacteriocinogenic lactic acid bacteria (LAB) isolated from seven different sources. Eight isolates were found to produce pediocin PA-1 like bacteriocin as detected by pedB gene PCR and dot-blot hybridization. The culture filtrate (CF) activity of these isolates exhibited strong antilisterial, antibacterial activity against tested food-borne pathogens and LAB. The identification and genetic diversity among the selected LAB was performed by conventional morphological and molecular tools like RFLP, RAPD, and 16S rDNA gene sequencing. The isolates were identified as, 1 each of Pediococcus acidilactici Cb1, Lactobacillus plantarum Acr2, and Streptococcus equinus AC1, 2 were of P. pentosaceus Cb4 and R38, and other 3 were Enterococcus faecium Acr4, BL1, V3. Partial characterization of the bacteriocins revealed that the peptide was heat stable, active at acidic to alkaline pH, inactivated by proteolytic enzymes, and had molecular weight around 4.6 kDa and shared the properties of class IIa pediocin-family. The bacteriocin production at different temperatures, pH, and salt concentrations was studied to investigate the optimal condition for application of these isolates as a starter culture or as a biopreservative in either acidic or non-acidic foods. PMID- 21656249 TI - Cytogenetic effects induced by accelerated carbon ions with shielding. AB - Our work aims to understand the effects of shielding on the induction of biological damage by heavy charged particles and to compare the shielding effects of different materials at the same LET from two aspects: the biological effectiveness including or not including secondary particles emitted at large angles and the biological effectiveness at different angles with respect to the beam direction. We designed and conducted biological experiments to determine the biological effectiveness of 200 MeV/u carbon ions after traversing different shielding materials (Lucite and aluminium). Whole blood samples, which were either attached to the shielding material (48 mm Lucite or 29 mm aluminium)or positioned at 300 cm away from it at different angles with respect to the beam axis, were exposed to carbon ion beams. For comparison, whole blood samples were exposed directly to 200 MeV/u carbon ions. Chromosomal aberrations in lymphocytes were scored. The results indicated that the biological effectiveness per unit dose was not significantly changed by 48 mm Lucite or 29 mm aluminium, and no significant differences were observed in lymphocytes attached to the target and in lymphocytes positioned at a distance of 300 cm away from the target, at 0o angle of the beam axis. However, when plotted as a function of the number of ions hitting the shielding target, the curves are separated and the shield increases the effectiveness per unit ion. The frequency of chromosomal aberrations at tilted angles behind 29 mm Al and 48 mm Lucite was almost the same. These lesions were considered to be caused by secondary particles due to the passage of particles through the shielding materials. PMID- 21656250 TI - Long-term health and work outcomes of renal transplantation and patterns of work status during the end-stage renal disease trajectory. AB - INTRODUCTION: The aim of this study was to examine the health- and work outcomes of renal transplant recipients long-term after transplantation as well as the pattern of work status, work ability and disability benefits during the end-stage renal disease (ESRD) trajectory that precedes transplantation. METHODS: 34 transplant recipients completed interviews 3, 13 months and >6 years posttransplantation. Health status (SF-36), work ability (WAI), and fatigue (CIS) were assessed by questionnaires, clinical data were derived from medical charts, and data on functional limitations were extracted from the social security system database. The work status trajectory preceding transplantation was examined retrospectively. RESULTS: Of the 34 third wave transplant recipients, 29% were severely fatigued. Compared with the general working population, recipients experienced worse general health and less vitality. Non-working recipients had worse renal function and general health, and more limitations in physical functioning compared to working recipients. The WAI score indicated moderate work ability for 60% of the employed recipients. Although 67% were employed (45% parttime), 30% of those working still received some disability benefits. Social insurance physicians found variable levels of functional limitations. The mean work status trajectory showed more sickness absence and less work ability during dialysis, but after transplantation, both work status and work ability generally improved. CONCLUSIONS: Transplant recipients have a compromised health status which leads to functional limitations and disability. Although work status improved after transplantation, a substantial number of the transplant recipients received disability benefits. The negative health consequences of anti-rejection medications may play an important role in long-term work ability. These results indicate that a 'new' kidney has advantages over dialysis with respect to work, but does not necessarily leads to 'normal' work outcomes. PMID- 21656251 TI - Job acquisition for people with severe mental illness enrolled in supported employment programs: a theoretically grounded empirical study. AB - INTRODUCTION: The main purpose of this study was to test a conceptual model based on the theory of planned behaviour (TPB) to explain competitive job acquisition of people with severe mental disorders enrolled in supported employment programs. METHODS: Using a sample of 281 people with severe mental disorders participating in a prospective study design, the authors examined the contribution of the TPB in a model including clinical (e.g., severity of symptoms), psychosocial (e.g., self-esteem) and work related variables (e.g., length of time absent from the workplace) as predictors of job acquisition. Path analyses were used to test two conceptual models: (1) the model of job acquisition for people with mental illness adapted from the TPB, and (2) the extended TPB including clinical, psychosocial, and work related variables recognized in the literature as significant determinants of competitive employment. RESULTS: Findings revealed that both models presented good fit indices. In total, individual factors predicted 26% of the variance in job search behaviours (behavioural actions). However, client characteristics explained only 8% of variance in work outcomes, suggesting that environmental variables (e.g., stigma towards mental disorders) play an important role in predicting job acquisition. About 56% (N = 157) of our sample obtained competitive employment. CONCLUSION: Results suggest that employment specialists can be guided in their interventions by the concepts found in the extended model of work integration since most of these are modifiable, such as perceived barriers to employment, self-efficacy, and self-esteem. PMID- 21656252 TI - A participatory return-to-work program for temporary agency workers and unemployed workers sick-listed due to musculoskeletal disorders: a process evaluation alongside a randomized controlled trial. AB - INTRODUCTION: Beside (cost-)effectiveness, the feasibility of an intervention is important for successful implementation in daily practice. This study concerns the process evaluation of a newly developed participatory return-to-work (RTW) program for workers without an employment contract, sick-listed due to musculoskeletal disorders. The program consisted of a stepwise process, guided by an independent RTW coordinator, aimed at making a consensus-based RTW plan with the possibility of a temporary (therapeutic) workplace. The aims of this study were to describe the reach and extent of implementation of the new program, the satisfaction and experiences of all stakeholders, and the perceived barriers and facilitators for implementation of the program in daily practice. METHODS: Temporary agency workers and unemployed workers, sick-listed for 2-8 weeks due to musculoskeletal disorders were eligible for this study. Data were collected from the workers; their insurance physicians and labour experts at the Dutch Social Security Agency; RTW coordinators; and case managers from participating vocational rehabilitation agencies. Data collection took place using professionals' reports, standardized matrices, questionnaires at baseline and at 3-month follow-up, and group interviews with the professionals. RESULTS: Of the 79 workers who were allocated to the participatory RTW program group, 72 workers actually started with the intervention. Overall, implementation of the program was performed according to protocol. However, offering of suitable temporary workplaces was delayed with 44.5 days. Results showed satisfaction with the RTW coordinator among the workers and three quarters of the labour experts experienced a minor or major contribution of the presence of the RTW coordinator. Several barriers for implementation were identified, such as the administrative time-investment, unclear information about the program, no timely offering of temporary (therapeutic) workplaces, and the need for additional support in case of complex health problems. CONCLUSIONS: This study indicates overall feasibility for implementation of the participatory RTW program in daily practice. However, to overcome important barriers, more attention should be paid to improve timely offering of suitable temporary workplaces, to describe more clearly the program goals and the professional's roles, and to offer additional support for workers suffering from complex multi-causal health problems. TRIAL REGISTRATION: NTR1047. PMID- 21656253 TI - Injured workers' construction of expectations of return to work with sub-acute back pain: the role of perceived uncertainty. AB - INTRODUCTION: Little is known about the formation of expectations of return to work (RTW) from the perspective of injured workers with back injuries. This modified grounded theory study uses a biopsychosocial approach that considers the workers' complex social circumstances, to unpack the multidimensional construct of expectations of RTW from the injured worker's perspective. METHOD: Initial semi-structured interviews were conducted with 18 individuals with sub-acute back pain, who were off work between 3 and 6 months. Follow-up interviews were conducted with 7 participants for the purposes of member checking. The interview data was coded, compared and analyzed over the course of data collection, until saturation was reached. RESULTS: Data analysis revealed that expectations of return-to-work are constructed based on perceived uncertainty which subsumes five inter-related categories (1) perceived lack of control over the return-to-work process, (2) perceived lack of recognition by others of the impact of the injury, (3) perceived inability to perform the pre-injury job, (4) fear of re-injury, and (5) perceived need for workplace accommodations. Expectations, once formed, were influenced by the worker's experience of coping with perceived uncertainty. CONCLUSION: Perceived uncertainty plays a key role in injured workers' formation of expectations of return-to-work. Implications are discussed regarding how this perceived uncertainty plays a role in the development of (re)injury prevention and rehabilitation programs. The importance of further research on perceived uncertainty is presented, along with potential future research considerations. PMID- 21656254 TI - The impact of birth spacing on subsequent feto-infant outcomes among community enrollees of a federal healthy start project. AB - Numerous studies have shown an association between shorter birth intervals, and several adverse fetal outcomes, including low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA). However, there is little evidence on the effectiveness of interconception care on fetal outcomes associated with sub optimal interpregnancy interval (IPI). The purpose of this study is to examine the influence of the Federal Healthy Start's interconception care services on IPI and fetal growth outcomes. This is a retrospective cohort study used records from the Central Hillsborough Healthy Start program in Tampa, Florida linked to Florida vital statistics data covering the period 2002-2009. Only first and second pregnancies were considered, and interpregnancy interval (IPI), the exposure of interest, was categorized in months as 0-5, 6-17, 18-23, and >=24. The following feto-infant morbidities were considered as primary outcomes: LBW, PTB, and SGA. A composite variable coding the presence of any of the aforementioned adverse fetal events was also created. Multivariate logistic regression modeling was applied Overall, mothers with the shortest IPI (0-5 months: AOR = 1.39, 95% CI 1.23-1.56) and longest IPI (>=60 months: AOR = 1.13, 95% CI 1.03-1.23) were at a greater risk for adverse fetal growth outcomes, compared to the referent category (18-23 months). Our findings support the need for inter conception care that addresses IPI and delayed childbearing among women. PMID- 21656256 TI - Therapist training in empirically supported treatments: a review of evaluation methods for short- and long-term outcomes. AB - Therapist training efforts have been assessed using several outcomes. A model for evaluating therapist training in empirically supported treatments is presented, adapted from Kirkpatrick's (in: Craig and Bittel (eds.) Training and development handbook, 1967) training evaluation model. The adapted framework includes short term outcomes, such as reactions to training and changes in attitude, knowledge, or skills, and longer-term outcomes, such as changes in therapist behavior in practice or client outcomes. Evaluation methods for these outcomes are reviewed, with information on their validity, reliability, and feasibility. An agenda for further research to improve therapist training evaluation is presented, with discussion of how evaluation can inform other areas of the field. PMID- 21656255 TI - Modulation of connexin signaling by bacterial pathogens and their toxins. AB - Inherent to their pivotal tasks in the maintenance of cellular homeostasis, gap junctions, connexin hemichannels, and pannexin hemichannels are frequently involved in the dysregulation of this critical balance. The present paper specifically focuses on their roles in bacterial infection and disease. In particular, the reported biological outcome of clinically important bacteria including Escherichia coli, Shigella flexneri, Yersinia enterocolitica, Helicobacter pylori, Bordetella pertussis, Aggregatibacter actinomycetemcomitans, Pseudomonas aeruginosa, Citrobacter rodentium, Clostridium species, Streptococcus pneumoniae, and Staphylococcus aureus and their toxic products on connexin- and pannexin-related signaling in host cells is reviewed. Particular attention is paid to the underlying molecular mechanisms of these effects as well as to the actual biological relevance of these findings. PMID- 21656257 TI - Chromatin compaction in terminally differentiated avian blood cells: the role of linker histone H5 and non-histone protein MENT. AB - Chromatin has a tendency to shift from a relatively decondensed (active) to condensed (inactive) state during cell differentiation due to interactions of specific architectural and/or regulatory proteins with DNA. A promotion of chromatin folding in terminally differentiated avian blood cells requires the presence of either histone H5 in erythrocytes or non-histone protein, myeloid and erythroid nuclear termination stage-specific protein (MENT), in white blood cells (lymphocytes and granulocytes). These highly abundant proteins assist in folding of nucleosome arrays and self-association of chromatin fibers into compacted chromatin structures. Here, we briefly review structural aspects and molecular mode of action by which these unrelated proteins can spread condensed chromatin to form inactivated regions in the genome. PMID- 21656258 TI - Elevated depressive symptoms and incident stroke in Hispanic, African-American, and White older Americans. AB - Although depressive symptoms have been linked to stroke, most research has been in relatively ethnically homogeneous, predominantly white, samples. Using the United States based Health and Retirement Study, we compared the relationships between elevated depressive symptoms and incident first stroke for Hispanic, black, or white/other participants (N = 18,648) and estimated the corresponding Population Attributable Fractions. The prevalence of elevated depressive symptoms was higher in blacks (27%) and Hispanics (33%) than whites/others (18%). Elevated depressive symptoms prospectively predicted stroke risk in the whites/other group (HR = 1.53; 95% CI: 1.36-1.73) and among blacks (HR = 1.31; 95% CI: 1.05-1.65). The HR was similar but only marginally statistically significant among Hispanics (HR = 1.33; 95% CI: 0.92-1.91). The Population Attributable Fraction, indicating the percent of first strokes that would be prevented if the incident stroke rate in those with elevated depressive symptoms was the same as the rate for those without depressive symptoms, was 8.3% for whites/others, 7.8% for blacks, and 10.3% for Hispanics. PMID- 21656259 TI - Comment on: treatment of brain arteriovenous malformations by double arterial catheterization with simultaneous injection of Onyx: retrospective series of 17 patients: Abud DG, Riva R, Nakiri GS, Padovani F, Khawaldeh M, Mounayer C. AJNR Am J Neuroradiol. 2011;32:152-158. PMID- 21656260 TI - Acute contralateral submandibular sialadenitis as a complication of skull base surgery. PMID- 21656261 TI - Transpulmonary thermodilution in a pediatric patient with an intracardiac left-to right shunt. AB - Monitoring of cardiac output (CO) in the perioperative period and in seriously ill pediatric patients is of major importance for medical management. Hemodynamic monitoring, using transpulmonary thermodilution (TPTD) via a single thermal indicator injection, allows for measurements of CO, volumetric variables and extravascular lung water (EVLW). We describe and explain the influence of a left to-right shunt on TPTD curve characteristics and EVLW measurements in a young child undergoing a surgical atrial septal defect repair. We suggest that these specific changes in the TPTD curve and the overestimation of EVLW detected by current device, in absence of gas exchange abnormalities, could be indicators of existing circulatory shunts in pediatric patients. PMID- 21656262 TI - Genetic influence on bone mineral density in Korean twins and families: the healthy twin study. AB - Bone mineral density (BMD), a representative marker of osteoporosis risk, is found to be highly heritable in this Korean study, which is very consistent with the findings in Western populations. This finding strongly supports that genetic factors are significant determinants of osteoporosis risk along with individual biological and behavioral factors. INTRODUCTION: Although genetic factors are known to contribute significantly to variations in BMD in Western populations, such an association has not been fully evaluated in an Asian population. This study was conducted to determine the role of genetic factors on BMD in Korean population. METHODS: The study participants were 2,728 men and women consisting of 497 monozygotic (MZ) twin pairs, 119 dizygotic (DZ) twin pairs, and 1,496 first-degree relatives from the Healthy Twin Study. BMD was measured using dual energy X-ray absorptiometry. Quantitative genetic analysis based on a variance decomposition model was performed. RESULTS: Age and the measured covariates accounted for 17~61% of the variation in BMD, depending on the sites of measurement. After accounting for the covariate effects, the heritability of BMD at the whole body, thoracic and lumbar spine, whole ribs, whole pelvis, whole arms, and whole legs were 0.76, 0.72, 0.73, 0.71, 0.51, and 0.75, respectively. The pair-wise correlation of BMD was the highest within MZ twin pairs, followed by DZ twin pairs, sibling pairs, and parents-child pairs. Cross-trait correlation analysis revealed a positive genetic correlation between BMDs at different sites, ranging from 0.80 (arm and leg BMD) to 0.50 (pelvis and arm BMD). CONCLUSIONS: The high heritability of BMD in this Korean population similar to those found in Western populations and the significant common genetic basis between BMDs at different sites strongly supports a significant role of genetic determinants on the risk of osteoporosis. PMID- 21656263 TI - Multi-site bone ultrasound measurements in elderly women with and without previous hip fractures. AB - About 75% of patients suffering from osteoporosis are not diagnosed. This study describes a multi-site bone ultrasound method for osteoporosis diagnostics. In comparison with axial dual energy X-ray absorptiometry (DXA), the ultrasound method showed good diagnostic performance and could discriminate fracture subjects among elderly females. INTRODUCTION: Axial DXA, the gold standard diagnostic method for osteoporosis, predicts fractures only moderately. At present, no reliable diagnostic methods are available at the primary health care level. Here, a multi-site ultrasound method is proposed for osteoporosis diagnostics. METHODS: Thirty elderly women were examined using the ultrasound backscatter measurements in proximal femur, proximal radius, proximal and distal tibia in vivo. First, we predicted the areal bone mineral density (BMD) at femoral neck by ultrasound measurements in tibia combined with specific subject characteristics (density index, DI) and, second, we tested the ability of ultrasound backscatter measurements at proximal femur to discriminate between individuals with previously fractured hips from those without fractures. Areal BMD was determined by axial DXA. RESULTS: Combined ultrasound parameters, cortical thickness at distal and proximal tibia, with age and weight of the subject, provided a significant estimate of BMD(neck) (r = 0.86, p < 0.001, n = 30). When inserted into FRAX (World Health Organization fracture risk assessment tool), the DI indicated the same treatment proposal as the BMD(neck) with 86% sensitivity and 100% specificity. The receiver operating characteristic analyses, with a combination of ultrasound parameters and patient characteristics, discriminated fracture subjects from the controls similarly as the model combining BMD(neck) and patient characteristics. CONCLUSIONS: For the first time, ultrasound backscatter measurements of proximal femur were conducted in vivo. The results indicate that ultrasound parameters, combined with patient characteristics, may provide a means for osteoporosis diagnostics. PMID- 21656264 TI - Circulating osteocalcin level is associated with improved glucose tolerance, insulin secretion and sensitivity independent of the plasma adiponectin level. AB - In agreement with the results of animal studies, the plasma osteocalcin level is positively associated with improved glucose tolerance and insulin secretion and sensitivity. In addition, the plasma osteocalcin level is inversely associated with the development of diabetes; however, the plasma adiponectin level may not be involved in osteocalcin-mediated energy metabolism in humans. INTRODUCTION: Recent animal studies have suggested crosstalk between bone and energy metabolism through osteocalcin. The aims of this study were to determine whether or not osteocalcin is associated with the improved glucose tolerance and insulin secretion and sensitivity, and whether or not the association is dependent on the plasma adiponectin level in humans. METHODS: Four hundred twenty-five subjects, 19-82 years of age (mean age, 53 years), were enrolled. An oral glucose tolerance test (OGTT) and OGTT-based methods that were validated against the euglycemic clamp were determined. Total osteocalcin, leptin, and total adiponectin levels were measured. RESULTS: The plasma levels of total osteocalcin were significantly different between the normal glucose tolerance, pre-diabetes, and diabetes groups. The glucose levels and homeostasis model assessment insulin resistance values varied inversely with the osteocalcin tertiles, and OGTT-based insulin secretion (HOMA-B%, disposition index) and insulin sensitivity indices (Stumvoll's and OGIS indices) were increased with the tertiles. Although the plasma adiponectin level was positively correlated with the osteocalcin level, no changes in the association were noted between the plasma osteocalcin level and the glucose tolerance or insulin secretion and sensitivity indices after adjustment for the plasma adiponectin level. Based on multiple logistic regression analysis, the plasma osteocalcin level was inversely associated with the development of type 2 diabetes mellitus independent of age, gender, body mass index, and fasting plasma glucose and plasma adiponectin levels. CONCLUSIONS: Circulating osteocalcin level is associated with improved glucose tolerance and insulin secretion and sensitivity independent of the plasma adiponectin level in humans. PMID- 21656265 TI - Bone texture analysis of human femurs using a new device (BMATM) improves failure load prediction. AB - We measured bone texture parameters of excised human femurs with a new device (BMATM). We also measured bone mineral density by DXA and investigated the performance of these parameters in the prediction of failure load. Our results suggest that bone texture parameters improve failure load prediction when added to bone mineral density. INTRODUCTION: Bone mineral density (BMD) is a strong determinant of bone strength. However, nearly half of the fractures occur in patients with BMD which does not reach the osteoporotic threshold. In order to assess fracture risk properly, other factors are important to be taken into account such as clinical risk factors as well as macro- and microarchitecture of bone. Bone microarchitecture is usually assessed by high-resolution QCT, but this cannot be applied in routine clinical settings due to irradiation, cost and availability concerns. Texture analysis of bone has shown to be correlated to bone strength. METHODS: We used a new device to get digitized X-rays of 12 excised human femurs in order to measure bone texture parameters in three different regions of interest (ROIs). We investigated the performance of these parameters in the prediction of the failure load using biomechanical tests. Texture parameters measured were the fractal dimension (Hmean), the co-occurrence matrix, and the run length matrix. We also measured bone mineral density by DXA in the same ROIs as well as in standard DXA hip regions. RESULTS: The Spearman correlation coefficient between BMD and texture parameters measured in the same ROIs ranged from -0.05 (nonsignificant (NS)) to 0.57 (p = 0.003). There was no correlation between Hmean and co-occurrence matrix nor Hmean and run length matrix in the same ROI (r = -0.04 to 0.52, NS). Co-occurrence matrix and run length matrix in the same ROI were highly correlated (r = 0.90 to 0.99, p < 0.0001). Univariate analysis with the failure load revealed significant correlation only with BMD results, not texture parameters. Multiple regression analysis showed that the best predictors of failure load were BMD, Hmean, and run length matrix at the femoral neck, as well as age and sex, with an adjusted r (2) = 0.88. Added to femoral neck BMD, Hmean and run length matrix at the femoral neck (without the effect of age and sex) improved failure load prediction (compared to femoral neck BMD alone) from adjusted r (2) = 0.67 to adjusted r (2) = 0.84. CONCLUSION: Our results suggest that bone texture measurement improves failure load prediction when added to BMD. PMID- 21656266 TI - Epigenetic influences in the developmental origins of osteoporosis. AB - Osteoporosis is a major public health problem due to consequent fragility fractures; data from the UK suggest that up to 50% of women and 20% men aged 50 years will have an osteoporosis-related fracture in their remaining lifetime. Skeletal size and density increase from early embryogenesis through intrauterine, infant, childhood and adult life to reach a peak in the third to fourth decade. The peak bone mass achieved is a strong predictor of later osteoporosis risk. Epidemiological studies have demonstrated a positive relationship between early growth and later bone mass, both at peak and in later life, and also with reduced risk of hip fracture. Mother-offspring cohorts have allowed the elucidation of some of the specific factors in early life, such as maternal body build, lifestyle and 25(OH)-vitamin D status, which might be important. Most recently, the phenomenon of developmental plasticity, whereby a single genotype may give rise to different phenotypes depending on the prevailing environment, and the science of epigenetics have presented novel molecular mechanisms which may underlie previous observations. This review will give an overview of these latter developments in the context of the burden of osteoporosis and the wider data supporting the link between the early environment and bone health in later life. PMID- 21656268 TI - New synthesis--back to the future: new approaches and directions in chemical studies of coevolution. PMID- 21656267 TI - Use of molecular tools in identification of philometrid larvae in fishes: technical limitations parallel our poor assessment of their biodiversity. AB - The usefulness of the polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) and partial sequencing of the cytochrome oxidase I (COI) gene was tested regarding the utility of these techniques in unraveling philometrid life cycles and, in particular, to determine putative paratenic host species. Our focus was to study three species of philometrids commonly found in the estuaries of South Carolina: Philometroides paralichthydis and Philometra overstreeti from the southern flounder, Paralichthys lethostigma and Philometra carolinensis from the spotted seatrout, Cynoscion nebulosus. A total of 473 fish in 19 species known to be potential prey of the spotted seatrout and the southern flounder were dissected. Of all nematode larvae found in the mesenteries of 53 fish of 10 species, 21 specimens were determined to be philometrids using PCR. The use of PCR-RFLP allowed the identification of larvae of P. carolinensis and P. overstreeti in the freshwater goby, Ctenogobius shufeldti, and P. overstreeti in mummichog, Fundulus heteroclitus. However, 12 RFLP profiles could not be matched to control species, thus demonstrating the limitation of this technique in areas where diversity of philometrids is not well known and higher than anticipated. Similarly, COI procedures provided unknown sequences that did not match those of nine philometrid species used as controls. We concluded that although both techniques showed some usefulness and promise, at this point, however, they demonstrate the need of increasing our knowledge of marine and estuarine philometrid biodiversity. PMID- 21656269 TI - Cadmium is more toxic on volume bone mineral density than tissue bone mineral density. AB - It has been showed that Cd induces low areal bone mineral density, but we do not know the effect of Cd on cubic bone density. This study was aimed to investigate the effects of Cd on volumetric bone mineral density (VBMD) and tissue bone mineral density (TBMD) in male rats. Twenty-four Sprague-Dawley male rats were randomly divided into four groups that were given cadmium chloride by subcutaneous injection at doses of 0, 0.1, 0.5, and 1.5 mg/kg body weight for 8 weeks, respectively. Then, microcomputed tomography scanning was performed on the proximal tibia, and region of interest was reconstructed using microview software. The VBMD, bone volume fraction of rats treated with 1.5 mg Cd/kg, were significantly decreased compared to control (p < 0.01). The trabecular numbers of rats exposed to Cd were all significantly decreased relative to control (p < 0.05). The trabecular separation of rats treated with 1.5 mg Cd/kg was obviously increased compared to control (p < 0.01). However, Cd had no obvious influence on TBMD. Cd induced low VBMD but not TBMD; Cd effect on bone may be related with trabecular bone loss but not with trabecular bone demineralization. PMID- 21656270 TI - Prognostic significance of tumor location in high-grade non-muscle-invasive bladder cancer. AB - The management of high-grade (HG) non-muscle-invasive bladder cancer (NMIBC) continues to be a serious clinical problem. The role of many factors related to efficacy of Bacillus Calmette-Guerin (BCG), which is the most useful intravesical agent for these tumors, is still unknown. This study investigated the prognostic value of tumor location in high-grade non-muscle-invasive bladder cancer. Seventy four patients with HG non-muscle-invasive bladder cancer, without carcinoma in situ (CIS), were treated by transurethral resection of bladder tumor (TURBT). Twenty-eight patients received adjuvant BCG therapy after TURBT. The relation between tumor location and the recurrence capacity was estimated using a Cox regression model. Our results suggest that tumor location is an important prognostic factor for BCG-therapy response in patients with high-grade non-muscle invasive bladder cancer. Tumors in the bladder neck might have a higher risk of recurrence after intravesical immunotherapy. In addition, tumors in the lateral and posterior bladder walls might be at higher risk of recurrence when treated by TURBT alone. PMID- 21656271 TI - Automated analysis of protein expression and gene amplification within the same cells of paraffin-embedded tumour tissue. AB - BACKGROUND: The simultaneous detection of protein expression and gene copy number changes in patient samples, like paraffin-embedded tissue sections, is challenging since the procedures of immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH) negatively influence each other which often results in suboptimal staining. Therefore, we developed a novel automated algorithm based on relocation which allows subsequent detection of protein content and gene copy number changes within the same cell. METHODS: Paraffin-embedded tissue sections of colorectal cancers were stained for CD133 expression. IHC images were acquired and image coordinates recorded. Slides were subsequently hybridized with fluorescently labeled DNA probes. FISH images were taken at the previously recorded positions allowing for direct comparison of protein expression and gene copy number signals within the same cells/tissue areas. Relocation, acquisition of the IHC and FISH images, and enumeration of FISH signals in the immunophenotyped tumour areas were done in an automated fashion. RESULTS: Automated FISH analysis was performed on 13 different colon cancer samples that had been stained for CD133; each sample was scored for MYC, ZNF217 and Chromosome 6 in CD133 positive and negative glands. From the 13 cases four (31%) showed amplification for the MYC oncogene and seven of 13 (54%) cases were amplified for ZNF217. There was no significant difference between CD133 positive tumour and CD133 negative tumour cells. CONCLUSION: The technique and algorithm presented here enables an easy and reproducible combination of IHC and FISH based on a novel automated algorithm using relocation and automated spot counting. PMID- 21656272 TI - Long-term course of pain in breast cancer survivors: a 4-year longitudinal study. AB - After successful treatment of early breast cancer, many women still report pain symptoms, and attribute them to the previous illness or its treatment. However, knowledge about the long-term course of pain in breast cancer is limited. Baseline assessment included 3,088 women who received a breast cancer diagnosis on average 2 years prior to enrollment, and who completed typical medical treatments. After 4 years, a subsample of 2,160 recurrence-free women (70%) was re-assessed. The major outcome variable was the composite index for general pain symptoms. Over the 4-year course, a slight but significant increase in pain was reported. If only medical variables were examined, a triple interaction between surgery type, breast cancer stage, and time indicated that pain scores increased in most subgroups, while they decreased in stage II women after mastectomy and stage III women after lumpectomy. Using a regression analytical approach, psychological and other variables added significantly to the prediction of pain persistence. Regression analysis revealed that pain symptoms increased in those women taking tamoxifen at baseline, in those reporting depression at baseline or stressful life events during the first 12 months after enrollment. Exercise at baseline had a beneficial effect on pain recovery. The persistence or increase of pain symptoms in women surviving breast cancer is associated with some medical factors (surgery type, tamoxifen use), but also with psychological factors. Pain should be a standard outcome variable in the evaluation of cancer treatment programs. PMID- 21656273 TI - The hepatoprotective effect of coumarin and coumarin derivates on carbon tetrachloride-induced hepatic injury by antioxidative activities in rats. AB - Coumarins are a vast group of natural compounds and some of them possess antioxidant activities. The comparison of the antioxidant activity of some coumarins with various chemical molecular structure has not been investigated in previous studies. Therefore, this study was aimed to investigate the hepatoprotective effect against carbon tetrachloride (CCl(4)) -induced hepatic injury by coumarin (1,2-benzopyrone) and coumarin derivatives, esculetin (6,7 dihydroxycoumarin), scoparone (6,7-dimethoxycoumarin), and 4-methylumbelliferone (7-hyroxy-4-methyl) in male Sprague-Dawley rats. Product of lipid peroxidation, malondialdehyde (MDA), activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT) were evaluated for oxidative stress in hepatic injury. Gamma glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) were detected in plasma as a biomarker of hepatic injury. Significantly elevated levels of MDA and lowered levels of SOD and CAT activities were observed in liver of rats exposed to CCl(4), when compared to control values. Similarly, administration of CCl(4) increased LDH and GGT levels in serum. Pre-treatment of rats with esculetin (35 mg kg(-1), orally) and scoparone (35 mg kg(-1), orally) significantly prevented CCl(4)-induced decrease in MDA levels and increase in SOD and CAT, whereas 4 methylumbelliferone (35 mg kg(-1)) and coumarin (30 mg kg(-1)) had no effect against CCl(4)-induced rise in serum enzymes. Esculetin and scoparone also showed protective properties as was evidenced in reduced LDH and GGT levels in serum. The results of this study indicate that the chemical structures of coumarins play an important role in the prevention of oxidative stress. PMID- 21656274 TI - Probable gamma-aminobutyric acid involvement in bisphenol A effect at the hypothalamic level in adult male rats. AB - The aim of the present study was to investigate the effects of bisphenol A (BPA) on the neuroendocrine mechanism of control of the reproductive axis in adult male rats exposed to it during pre- and early postnatal periods. Wistar mated rats were treated with either 0.1% ethanol or BPA in their drinking water until their offspring were weaned at the age of 21 days. The estimated average dose of exposure to dams was approximately 2.5 mg/kg body weight per day of BPA. After 21 days, the pups were separated from the mother and sacrificed on 70 day of life. Gn-RH and gamma-aminobutyric acid (GABA) release from hypothalamic fragments was measured. LH, FSH, and testosterone concentrations were determined, and histological and morphometrical studies of testis were performed. Gn-RH release decreased significantly, while GABA serum levels were markedly increased by treatment. LH serum levels showed no changes, and FSH and testosterone levels decreased significantly. Histological studies showed abnormalities in the tubular organization of the germinal epithelium. The cytoarchitecture of germinal cells was apparently normal, and a reduction of the nuclear area of Leydig cells but not their number was observed. Taken all together, these results provide evidence of the effect caused by BPA on the adult male reproductive axis when exposed during pre- and postnatal period. Moreover, our findings suggest a probable GABA involvement in its effect at the hypothalamic level. PMID- 21656275 TI - Individualized volume CT dose index determined by cross-sectional area and mean density of the body to achieve uniform image noise of contrast-enhanced pediatric chest CT obtained at variable kV levels and with combined tube current modulation. AB - BACKGROUND: A practical body-size adaptive protocol providing uniform image noise at various kV levels is not available for pediatric CT. OBJECTIVE: To develop a practical contrast-enhanced pediatric chest CT protocol providing uniform image noise by using an individualized volume CT dose index (CTDIvol) determined by the cross-sectional area and density of the body at variable kV levels and with combined tube current modulation. MATERIALS AND METHODS: A total of 137 patients (mean age, 7.6 years) underwent contrast-enhanced pediatric chest CT based on body weight. From the CTDIvol, image noise, and area and mean density of the cross-section at the lung base in the weight-based group, the best fit equation was estimated with a very high correlation coefficient (gamma(2) = 0.86, P < 0.001). For the next study, 177 patients (mean age, 7.9 years; the CTDIvol group) underwent contrast-enhanced pediatric chest CT with the CTDIvol determined individually by the best fit equation. CTDIvol values on the dose report after CT scanning, noise differences from the target noise, areas, and mean densities were compared between these two groups. RESULTS: The CTDIvol values (mean +/- standard deviation, 1.6 +/- 0.7 mGy) and the noise differences from the target noise (1.1 +/- 0.9 HU) of the CTDIvol group were significantly lower than those of the weight-based group (2.0 +/- 1.0 mGy, 1.8 +/- 1.4 HU) (P < 0.001). In contrast, no statistically significant difference was found in area (317.0 +/- 136.8 cm(2) vs. 326.3 +/- 124.8 cm(2)), mean density (-212.9 +/- 53.1 HU vs. -221.1 +/- 56.3 HU), and image noise (13.8 +/- 2.3 vs. 13.6 +/- 1.7 HU) between the weight-based and the CTDIvol groups (P > 0.05). CONCLUSION: Contrast-enhanced pediatric chest CT with the CTDIvol determined individually by the cross-sectional area and density of the body provides more uniform noise and better dose adaptation to body habitus than does weight-based CT at variable kV levels and with combined tube current modulation. PMID- 21656276 TI - Paediatric radiology seen from Africa. Part I: providing diagnostic imaging to a young population. AB - Paediatric radiology requires dedicated equipment, specific precautions related to ionising radiation, and specialist knowledge. Developing countries face difficulties in providing adequate imaging services for children. In many African countries, children represent an increasing proportion of the population, and additional challenges follow from extreme living conditions, poverty, lack of parental care, and exposure to tuberculosis, HIV, pneumonia, diarrhoea and violent trauma. Imaging plays a critical role in the treatment of these children, but is expensive and difficult to provide. The World Health Organisation initiatives, of which the World Health Imaging System for Radiography (WHIS-RAD) unit is one result, needs to expand into other areas such as the provision of maintenance servicing. New initiatives by groups such as Rotary and the World Health Imaging Alliance to install WHIS-RAD units in developing countries and provide digital solutions, need support. Paediatric radiologists are needed to offer their services for reporting, consultation and quality assurance for free by way of teleradiology. Societies for paediatric radiology are needed to focus on providing a volunteer teleradiology reporting group, information on child safety for basic imaging, guidelines for investigations specific to the disease spectrum, and solutions for optimising imaging in children. PMID- 21656277 TI - Newly developed liquid-based cytology. TACASTM: cytological appearance and HPV testing using liquid-based sample. AB - Cell profiles determined by the thin-layer advanced cytology assay system (TACASTM), a liquid-based cytology technique newly developed in Japan, were analyzed in this study. Hybrid capture 2 (HC-2) was also performed using the liquid-based samples prepared by TACAS to ascertain its ability to detect human papillomavirus (HPV). Cell collection samples from uterine cervix were obtained from 359 patients and examined cytologically. A HC-2 assay for HPV was carried out in the cell specimens. All specimens were found to show background factors such as leukocytes. After excluding the 5 unsatisfactory cases from the total 354 cases, 82 cases (23.2%) were positive and 272 cases (76.8%) were negative for HPV. Cell specimens from 30 HPV-positive cases and 166 HPV-negative cases were subjected to 4 weeks of preservation at room temperature. Then, when subsequently re-assayed, 28 cases (93.3%) in the former group were found to be HPV positive and 164 cases (98.8%) in the latter group were found to be HPV negative. These results supported the excellent reproducibility of TACAS for HPV testing. A reasonable inference from the foregoing analysis is that TACAS may be distinguished from other liquid-based cytological approaches, such as ThinPrep and SurePath, in that it can retain the cell backgrounds. Furthermore, this study raises the possibility that cell specimens prepared using TACAS could be preserved for at least 4 weeks prior to carrying out a HC-2 assay for HPV. PMID- 21656279 TI - Streptococcus sanguinis adhesion on titanium rough surfaces: effect of shot blasting particles. AB - Dental implant failure is commonly associated to dental plaque formation. This problem starts with bacterial colonization on implant surface upon implantation. Early colonizers (such as Streptococcus sanguinis) play a key role on that process, because they attach directly to the surface and facilitate adhesion of later colonizers. Surface treatments have been focused to improve osseointegration, where shot-blasting is one of the most used. However the effects on bacterial adhesion on that sort of surfaces have not been elucidated at all. A methodological procedure to test bacterial adherence to titanium shot blasted surfaces (alumina and silicon carbide) by quantifying bacterial detached cells per area unit, was performed. In parallel, the surface properties of samples (i.e., roughness and surface energy), were analyzed in order to assess the relationship between surface treatment and bacterial adhesion. Rather than roughness, surface energy correlated to physicochemical properties of shot blasted particles appears as critical factors for S. sanguinis adherence to titanium surfaces. PMID- 21656278 TI - Genetic interactions between POB3 and the acetylation of newly synthesized histones. AB - Pob3p is an essential component of the S. cerevisiae FACT complex (yFACT). Several lines of evidence indicate that the yFACT complex plays an important role in chromatin assembly including the observation that the pob3 Q308K allele is synthetically lethal with an allele of histone H4 that prevents the diacetylation of newly synthesized molecules. We have analyzed the genetic interactions between the Q308K allele of POB3 and mutations in all of the sites of acetylation that have been identified on newly synthesized histones. Genetic interactions were observed between POB3 and sites of acetylation on the NH(2)-terminal tails of H3 and H4. For histone H3, lysine residues 14 and 23 were particularly important when POB3 activity is compromised. Surprisingly, synthetic defects observed when the pob3 Q308K allele was combined with mutations of H4 lysines 5 and 12, were not phenocopied by deletion of HAT1, which encodes the enzyme that is thought to generate this pattern of acetylation on H4. Genetic interactions were also observed between POB3 and sites of acetylation found in the core domain of newly synthesized histones H3 and H4. These include synthetic lethality with an allele of H4 lysine 91 that mimics constitutive acetylation. While the mutations that alter H4 lysines 5, 12 and 91 do not affect binding to Pob3p, mutation of histone H3 lysine 56 decreases the association of histones with Pob3p. These results support the model that the yFACT complex plays a central role in chromatin assembly pathways regulated by acetylation of newly synthesized histones. PMID- 21656280 TI - Formation of OTS self-assembled monolayers at chemically treated titanium surfaces. AB - Enhanced biocompatibility of titanium implants highly depends on the possibility of achieving high degrees of surface functionalization for a low immune response and/or enhanced mineralization of bioactive minerals, such as hydroxyapatite. In this respect, surface modification with Self Assembled Monolayers (SAMs) has a great potential in delivering artificial surfaces of improved biocompatibility. Herein, the effectiveness of common chemical pre-treatments, i.e. hydrogen peroxide (H(2)O(2)) and Piranha (H(2)SO(4) + H(2)O(2)), in facilitating surface decontamination and hydroxylation of titanium surfaces to promote further surface functionalization by SAMs is investigated. The quality of the octadecyltrichlorosilane (OTS) based SAM appeared to strongly depend upon the surface morphology, the density and nature of surface hydroxyl sites resulting from the oxidative pre-treatments. Contrary to common belief, no further hydroxylation of the titanium substrate was observed after the selected chemical pre-treatments, but the number of hydroxyl groups available on the surface was decreased as a result of the formation of a titanium oxide layer with a gel-type structure. Further examinations by atomic force microscopy, infrared spectroscopy and X-ray photoelectron spectroscopy also revealed that mild oxidizing conditions were sufficient to remove surface contamination without detrimental effects on surface hydroxylation state and surface roughness. Furthermore, the adsorption of the alkylsiloxane molecules forming the SAM film is believed to proceed through hydrolysis at surface acidic hydroxyl groups rather than randomly. This site dependent adsorption process has significant implications for further functionalization of titanium based implants. It also highlights the difficulty of achieving an OTS based SAM at the surface of titanium and question the quality of SAMs reported at titanium surfaces so far. PMID- 21656282 TI - Treating rheumatoid arthritis to target: an international initiative. PMID- 21656281 TI - Persistence of bacteria and phages in a chemostat. AB - The model of bacteriophage predation on bacteria in a chemostat formulated by Levin et al. (Am Nat 111:3-24, 1977) is generalized to include a distributed latent period, distributed viral progeny release from infected bacteria, unproductive adsorption of phages to infected cells, and possible nutrient uptake by infected cells. Indeed, two formulations of the model are given: a system of delay differential equations with infinite delay, and a more general infection age model that leads to a system of integro-differential equations. It is shown that the bacteria persist, and sharp conditions for persistence and extinction of phages are determined by the reproductive ratio for phage relative to the phage free equilibrium. A novel feature of our analysis is the use of the Laplace transform. PMID- 21656283 TI - Mechanisms and management of hypertension in pregnant women. AB - Hypertension is the most common medical disorder encountered during pregnancy. A recent report highlighted hypertensive disorders as one of the major causes of pregnancy-related maternal deaths in the United States. Significant advances in our understanding of preeclampsia, a form of hypertension unique to pregnancy, have occurred in recent years. The optimal timing and choice of therapy for hypertensive pregnancy disorders involves carefully weighing the risk-versus benefit ratio for each individual patient, with an overall goal of improving maternal and fetal outcomes. In this review, we summarize the mechanisms thought to be involved, review the current management guidelines for hypertensive pregnancy disorders as recommended by international guideline groups, and outline some newer perspectives on management. PMID- 21656284 TI - Homelessness among lesbian, gay, and bisexual youth: implications for subsequent internalizing and externalizing symptoms. AB - Although lesbian, gay, and bisexual (LGB) youth with a history of homelessness (running away or being evicted from their homes by parents) report more psychological symptoms than homeless heterosexual peers, it is unclear whether symptoms are due to homelessness, given the absence of a non-homeless comparison group. This study longitudinally investigates whether LGB youth with a history of homelessness report more subsequent psychological symptoms than non-homeless LGB youth and examines potential mediators of any such relationships. Of the 156 LGB youth interviewed (49% female; 78% non-White), 48% reported past homeless experiences. Homelessness was associated with subsequent symptoms of anxiety, depression, conduct problems, and substance abuse and to changes in symptoms over time even after controlling for childhood sexual abuse and early development of sexual orientation. Stressful life events, negative social relationships, and social support from friends mediated the relationships between homelessness and symptomatology. These findings suggest the need for interventions to reduce stress and enhance social support among LGB youth with a history of homelessness in order to reduce psychological symptoms. PMID- 21656286 TI - The cold war context of the golden jubilee, or, why we think of mendel as the father of genetics. AB - In September 1950, the Genetics Society of America (GSA) dedicated its annual meeting to a "Golden Jubilee of Genetics" that celebrated the 50th anniversary of the rediscovery of Mendel's work. This program, originally intended as a small ceremony attached to the coattails of the American Institute of Biological Sciences (AIBS) meeting, turned into a publicity juggernaut that generated coverage on Mendel and the accomplishments of Western genetics in countless newspapers and radio broadcasts. The Golden Jubilee merits historical attention as both an intriguing instance of scientific commemoration and as an early example of Cold War political theatre. Instead of condemning either Lysenko or Soviet genetics, the Golden Jubilee would celebrate Mendel - and, not coincidentally, the practical achievements in plant and animal breeding his work had made possible. The American geneticists' focus on the achievements of Western genetics as both practical and theoretical, international, and, above all, non ideological and non-controversial, was fully intended to demonstrate the success of the Western model of science to both the American public and scientists abroad at a key transition point in the Cold War. An implicit part of this article's argument, therefore, is the pervasive impact of the Cold War in unanticipated corners of postwar scientific culture. PMID- 21656287 TI - Michurinist Biology in the People's Republic of China, 1948-1956. AB - Michurinist biology was introduced to China in 1948; granted a state supported monopoly in 1952; and reduced to parity with western genetics from 1956. The Soviets exported it through the propaganda agencies Sino Soviet Friendship Association (SSFA) and VOKS (Cultural Relations with Foreign Countries). China's Ministry of Agriculture achieved broad public awareness and acceptance of Michurinist biology through a translation, publication, and Soviet guest speakers campaign - all managed by a team of agriculturalists led by Luo Tianyu, a veteran CCP (Communist Party) cadre. The campaign grew exponentially, but did not affect university or Chinese Academy of Sciences biology. Luo Tianyu's failed attempt to force Michurinist biology on a Beijing university triggered its second stage: monopoly status and a ban on "Mendelist-Morganist" biology in teaching, research, and publication. The CCP Central Committee supported this policy believing that Michurinst biology would increase agricultural production for the forthcoming first Five Year Plan; whereas, western genetics had no practical value. Michurinist biology flourished at all levels of education, research, and science literature; Western genetics was completely shut down. This only began to change when the CCP Central Committee became wary of China's dependency on Soviet technical expertise and failure to fully utilize that of China. Change was further promoted by significant attacks on Michurinist biology by Soviet and East German biologists. Soon, these developments informed China's "genetics question," which became a test case for larger questions about the definition of science and the relationship between scientists and the state. Under the guidance of Lu Dingyi's Central Committee Propaganda Department, the CCP eventually decided that, henceforth, science controversies would only be resolved by the science community; and that monopolies or ideological orthodoxies would not be imposed on science. At the same time, the CCP rescinded Michurinist biology's monopoly and the ban on western genetics. By the mid-1960s western genetics had successfully restored itself, largely due to the leadership of C. C. Tan, a former student of Dobzhansky. Michurinist biology's presence shrank and it became marginalized. PMID- 21656288 TI - [Junior ERUS: robot-assisted urology: from bedside surgeon to console surgeon]. PMID- 21656289 TI - Survival processing of faces. AB - The mnemonic benefit of rating words according to their relevance in a survival scenario is well documented (e.g., Nairne, Thompson, & Pandeirada, 2007). The present study examined whether the survival processing effect would extend to face stimuli. We tested this hypothesis in five experiments, using multiple survival and control scenarios, real and computer-generated face sets, within- and between-subjects designs, and several memory tests, as well as free recall of survival-relevant and survival-neutral attribute statements written about the person. Although the standard survival processing effect was obtained for survival-relevant and neutral attribute statements, the survival processing effect was not obtained for face memory across all experiments. These results identify an important boundary condition for survival processing benefits. PMID- 21656290 TI - Successful single lung transplantation from a dialysis-dependent donor. PMID- 21656291 TI - Mechanisms of cellular therapy in respiratory diseases. AB - PURPOSE: Stem cells present a variety of clinical implications in the lungs. According to their origin, these cells can be divided into embryonic and adult stem cells; however, due to the important ethical and safety limitations that are involved in the embryonic stem cell use, most studies have chosen to focus on adult stem cell therapy. This article aims to present and clarify the recent advances in the field of stem cell biology, as well as to highlight the effects of mesenchymal stem cell (MSC) therapy in the context of acute lung injury/acute respiratory distress syndrome and chronic disorders such as lung fibrosis and chronic obstructive pulmonary disease. METHODS: For this purpose, we performed a critical review of adult stem cell therapies, covering the main clinical and experimental studies published in Pubmed databases in the past 11 years. Different characteristics were extracted from these articles, such as: the experimental model, strain, cellular type and administration route used as well as the positive or negative effects obtained. RESULTS: There is evidence for beneficial effects of MSC on lung development, repair, and remodeling. The engraftment in the injured lung does not occur easily, but several studies report that paracrine factors can be effective in reducing inflammation and promoting tissue repair. MSC releases several growth factors and anti-inflammatory cytokines that regulate endothelial and epithelial permeability and reduce the severity of inflammation. CONCLUSION: A better understanding of the mechanisms that control cell division and differentiation, as well as of their paracrine effects, is required to enable the optimal use of bone marrow-derived stem cell therapy to treat human respiratory diseases. PMID- 21656292 TI - Palliative noninvasive ventilation in patients with acute respiratory failure. AB - Over the last two decades, the increasing use of noninvasive ventilation (NIV) has diminished the need for endotracheal ventilation, thus decreasing the rate of ventilation-induced complications. Thus, NIV has decreased both intubation rates and mortality rates in specific subsets of patients with acute respiratory failure (e.g., patients with hypercapnia, cardiogenic pulmonary edema, immune deficiencies, or post-transplantation acute respiratory failure). NIV is also increasingly used as a palliative strategy when endotracheal ventilation is deemed inappropriate. In this context, palliative NIV can either be administered to offer a chance for survival, or to alleviate the symptoms of respiratory distress in dying patients. The literature provides information from 10 studies published between 1992 and 2006, in which 458 patients received palliative NIV. The technique was feasible, usually well tolerated, and half of the patients survived. The objectives of this review article are to define palliative NIV, to delineate the place for palliative NIV among overall indications of NIV, and to define the contribution of NIV to the palliative strategies available for patients with acute respiratory failure. Potential benefits and harm from NIV in patients who are not eligible for endotracheal ventilation are discussed. The appropriateness of palliative NIV should be reported in a study that relies on both quantitative criteria (rate of palliative NIV use and mortality) and qualitative criteria (patient comfort, end-of-life process, family burden, and health-care provider satisfaction). PMID- 21656293 TI - Intrapulmonary percussive ventilation superimposed on spontaneous breathing: a physiological study in patients at risk for extubation failure. AB - PURPOSE: Intrapulmonary percussive ventilation (IPV) is a high-frequency ventilation modality that can be superimposed on spontaneous breathing. IPV may diminish respiratory muscle loading and help to mobilize secretions. The aim of this prospective study was to assess the short-term effects of IPV in patients at high risk for extubation failure who were receiving preventive non-invasive ventilation (NIV) after extubation. METHODS: Respiratory rate, work of breathing, and gas exchange were evaluated in 17 extubated patients during 20 min of IPV and 20 min of NIV delivered via a facial mask, separated by periods of spontaneous breathing. The pressure-support level during NIV was adjusted until tidal volume reached 6-8 ml/kg and positive end-expiratory pressure (PEEP) 4-5 cmH(2)O. For IPV, the pressurisation frequency was set at 250 cycles/min and driving pressure at 1.2 bar. The pressure-time product of the diaphragm (PTPdi/min) was measured using an oesophageal and gastric double-balloon catheter. RESULTS: Transdiaphragmatic pressure and PTPdi/min improved significantly (p < 0.01), from a median [25th-75th percentiles] of 264 [190-300] to 192 [152-221] cmH(2)O s/min with IPV and from 273 [212-397] to 176 [120-216] cmH(2)O s/min with NIV. Respiratory rate decreased significantly from 23 [19-27] to 22 [17-24] breaths/min for IPV and from 25 [19-28] to 20 [18-22] breaths/min for NIV (p < 0.01). Mean PaCO(2) decreased after NIV (from 46 [42-48] to 41 [36-42] mmHg, p < 0.01) but not after IPV. There was no noticeable effect on oxygenation. CONCLUSIONS: IPV is an interesting alternative to NIV in patients at risk for post-extubation respiratory failure. Both NIV and IPV diminished the respiratory rate and work of breathing, but IPV was less effective in improving alveolar ventilation. PMID- 21656294 TI - Metal contamination in select species of birds in Nilgiris district, Tamil Nadu, India. AB - Variation in metal contamination in six species of birds, namely the Cormorant (Phalacrocorax carbo), Cattle Egret (Bubulcus ibis), Little Egret (Egretta garzetta), Pond Heron (Ardeola grayii), Common Myna (Acridotheres tristis) and Jungle Babbler (Turdoides striatus) in Nilgiris district, Tamil Nadu, India. The accumulation of heavy metals differed among the species studied. On an average, Little Egret accumulated high concentrations of copper (53.31 +/- 23.19 ppm) followed by Cattle Egret (16.27 +/- 9.83 ppm) in liver. Of all the species, Jungle Babbler recorded the maximum concentrations (20.59 +/- 9.07 ppm) in muscle. The Pond Heron recorded the maximum concentration (35.38 +/- 11.14 ppm) in brain. On an average the maximum level was in the kidney of Common Myna (7.76 +/- 1.80 ppm). PMID- 21656295 TI - Validation of reference data on wisdom tooth mineralization and eruption for forensic age estimation in living persons. AB - Estimation of dental age is an important part of forensic age estimation in living persons. As the quality of the values given in population-specific reference studies has a great impact on the estimation, the aim of this study was to validate reference data for wisdom teeth mineralization and eruption of a German population concerning the diagnosis of the age limit of 18 years in persons with known age. Mineralization and eruption was evaluated in 307 orthopantomograms of Central European subjects aged 17.5-18.5 years. Dental age was estimated using reference data and compared to chronological age. Statistical methods were used to analyze the differences and to propose adjusted reference values. Estimation of dental age relying on mineralization resulted in overestimations of 2 years on average in 76% of the males and 82% of the females. Using eruption, all men and 75% of the women were overestimated by up to 7 years. The differences between estimated and chronological age in both men and women were associated with the mineralization and eruption stage, respectively. The higher the stage, the higher was the risk of overestimation. The mineralization stages up to stage E were associated with underestimations. Using the proposed adjusted reference values resulted in more accurate estimations of dental age. Validation of reference values for dental age estimation showed great overestimations resulting in high error rates with numerous persons being younger than the estimated dental age. Adjustments are proposed which reduce differences between estimated dental age and chronological age. PMID- 21656296 TI - A comparison of three established age estimation methods on an adult Spanish sample. AB - Most current methods for adult skeletal age-at-death estimation are based on American samples comprising individuals of European and African ancestry. Our limited understanding of population variability hampers our efforts to apply these techniques to various skeletal populations around the world, especially in global forensic contexts. Further, documented skeletal samples are rare, limiting our ability to test our techniques. The objective of this paper is to test three pelvic macroscopic methods [(1) Suchey-Brooks; (2) Lovejoy; and (3) Buckberry and Chamberlain] on a documented modern Spanish sample. These methods were selected because they are popular among Spanish anthropologists and because they never have been tested in a Spanish sample. The study sample consists of 80 individuals (55 males and 25 females) of known sex and age from the Valladolid collection. Results indicate that in all three methods, levels of bias and inaccuracy increase with age. The Lovejoy method performs poorly (27%) compared with Suchey Brooks (71%) and Buckberry and Chamberlain (86%). However, the levels of correlation between phases and chronological ages are low and comparable in the three methods (<0.395). The apparent accuracy of the Suchey-Brooks and Buckberry and Chamberlain methods is largely based on the broad width of the methods' estimated intervals. This study suggests that before systematic application of these three methodologies in Spanish populations, further statistical modeling and research into the covariance of chronological age with morphological change are necessary. Future methods should be developed specific to various world populations and should allow for both precision and flexibility in age estimation. PMID- 21656297 TI - Development and validation for identity testing of I-DNADuo, a combination of I DNA1 and a new multiplex system, I-DNA2. AB - The I-DNADuo multiplex system combination is composed of previously validated I DNA1 and a new short tandem repeat (STR) multiplex named I-DNA2 that analyses 11 STR loci plus amelogenin. I-DNADuo, with amplicon sizes ranging from 57 to 298 bp, is specifically designed to analyse amelogenin and 15 STR loci (ten of them plus amelogenin in duplicate), including all the STR loci of the CODIS, ISSL and ECL databases, and seven of the eight in GCL. The validation of I-DNADuo shows that it is a highly sensitive, robust multiplex system for obtaining individual genetic profiles and for detecting and preventing allelic dropouts. PMID- 21656298 TI - Blackberry virus E: an unusual flexivirus. AB - A virus, named blackberry virus E (BVE), was recently discovered in blackberries and characterized. The virus genome is 7,718 nt long, excluding the poly-A tail, contains five open reading frames (ORFs) and resembles that of flexiviruses. Phylogenetic analysis revealed relationships to allexiviruses, which are known to infect plants of the family Alliaceae. BVE lacks the 3'end-proximal ORF, which encodes a nucleotide-binding protein, a putative silencing suppressor in allexiviruses. The overall results of this study suggest that this virus is an atypical and as yet undescribed flexivirus that is closely related to allexiviruses. PMID- 21656299 TI - Sphagnum growth and ecophysiology during mire succession. AB - Sphagnum mosses are widespread in areas where mires exist and constitute a globally important carbon sink. Their ecophysiology is known to be related to the water level, but very little is currently known about the successional trend in Sphagnum. We hypothesized that moss species follow the known vascular plant growth strategy along the successional gradient (i.e., decrease in production and maximal photosynthesis while succession proceeds). To address this hypothesis, we studied links between the growth and related ecophysiological processes of Sphagnum mosses from a time-since-initiation chronosequence of five wetlands. We quantified the rates of increase in biomass and length of different Sphagnum species in relation to their CO(2) assimilation rates, their photosynthetic light reaction efficiencies, and their physiological states, as measured by the chlorophyll fluorescence method. In agreement with our hypothesis, increase in biomass and CO(2) exchange rate of Sphagnum mosses decreased along the successional gradient, following the tactics of more intensely studied vascular plants. Mosses at the young and old ends of the chronosequence showed indications of downregulation, measured as a low ratio between variable and maximum fluorescence (F(v)/F(m)). Our study divided the species into three groups; pioneer species, hollow species, and ombrotrophic hummock formers. The pioneer species S. fimbriatum is a ruderal plant that occurred at the first sites along the chronosequence, which were characterized by low stress but high disturbance. Hollow species are competitive plants that occurred at sites with low stress and low disturbance (i.e., in the wet depressions in the middle and at the old end of the chronosequence). Ombrotrophic hummock species are stress-tolerant plants that occurred at sites with high stress and low disturbance (i.e., at the old end of the chronosequence). The three groups along the mire successional gradient appeared to be somewhat analogous to the three primary strategies suggested by Grime. PMID- 21656300 TI - Herbivore resistance of invasive Fallopia species and their hybrids. AB - Hybridization has been proposed as a mechanism by which exotic plants can increase their invasiveness. By generating novel recombinants, hybridization may result in phenotypes that are better adapted to the new environment than their parental species. We experimentally assessed the resistance of five exotic Fallopia taxa, F. japonica var. japonica, F. sachalinensis and F. baldschuanica, the two hybrids F. * bohemica and F. * conollyana, and the common European plants Rumex obtusifolius and Taraxacum officinale to four native European herbivores, the slug Arion lusitanicus, the moth Noctua pronuba, the grasshopper Metrioptera roeselii and the beetle Gastrophysa viridula. Leaf area consumed and relative growth rate of the herbivores differed significantly between the Fallopia taxa and the native species, as well as among the Fallopia taxa, and was partly influenced by interspecific variation in leaf morphology and physiology. Fallopia japonica, the most abundant Fallopia taxon in Europe, showed the highest level of resistance against all herbivores tested. The level of resistance of the hybrids compared to that of their parental species varied depending on hybrid taxon and herbivore species. Genotypes of the hybrid F. * bohemica varied significantly in herbivore resistance, but no evidence was found that hybridization has generated novel recombinants that are inherently better defended against resident herbivores than their parental species, thereby increasing the hybrid's invasion success. In general, exotic Fallopia taxa showed higher levels of herbivore resistance than the two native plant species, suggesting that both parental and hybrid Fallopia taxa largely escape from herbivory in Europe. PMID- 21656301 TI - Systems of care: the story behind the numbers. AB - This article presents a brief description of a longitudinal study of system-level change, offers observations about what has been learned about the evolution of systems of care from the unique and qualified perspectives of the group of site visitors who gathered the data for the study, and identifies a set of issues that needs to be addressed to advance the system of care model in community based care of children and youth with behavioral health needs and their families. The article describes the system of care assessment portion of the national evaluation of the Federal Children's Mental Health Initiative and presents a brief summary of accumulated findings from the assessments conducted in communities funded in six successive waves of awards to provide context for the site visitors' observations and the authors' recommendations. The authors draw upon the expert observations of the site visitors, who represent many different disciplines and backgrounds, which suggest that, as a set of guiding principles, the system of care philosophy and approach seem to have become accepted standards of program practice and system operation in the funded sites, although implementation is uneven across principles and sites. The article concludes with the authors' identification of high-level system issues that must be addressed more effectively if systems of care are to come to scale. PMID- 21656302 TI - What a difference family-driven makes: stories of success and lessons learned. AB - Community Psychology's emphasis on citizen participation aligns with the nationwide children's mental health family movement and is clearly evident in communities that have made sustainable system changes. The national family movement has long advocated for the meaningful engagement of families and youth who are the focus population of the federal Children's Mental Health Initiative. Little rigorous research about the experience of families in leadership positions or of their impact on systems of care has been done. In the absence of scientifically acquired evidence, this article offers the reader a glimpse into the authority, influence and credibility earned by four family leaders as well as their impact on local system of care communities. Their stories occur in four distinct macro level arenas: governance, evaluation, legislative advocacy, and workforce development. In the end, common attributes emerge from their stories, providing anecdotal information useful to identifying the qualities of successful family leadership and their impact on sustainable macro level changes. PMID- 21656303 TI - Correlates of homeless episodes among indigenous people. AB - This study reports the correlates of homeless episodes among 873 Indigenous adults who are part of an ongoing longitudinal study on four reservations in the Northern Midwest and four Canadian First Nation reserves. Descriptive analyses depict differences between those who have and have not experienced an episode of homelessness in their lifetimes. Multivariate analyses assess factors associated with a history of homeless episodes at the time of their first interview and differentiate correlates of "near homelessness" (i.e., doubling up) and "homeless episodes" (periods of actual homelessness). Results show that individuals with a history of homeless episodes had significantly more individual and family health, mental health, and substance abuse problems. Periods of homelessness also were associated with financial problems. Among the female caretakers who experienced episodes of homelessness over the course of the study, the majority had been homeless at least once prior to the start of the study and approximately one fifth met criteria for lifetime alcohol dependence, drug abuse, or major depression. Family adversity during childhood was also common for women experiencing homelessness during the study. PMID- 21656304 TI - [Neuroendocrine colorectal tumors. Surgical and endoscopic treatment]. AB - The incidence of colorectal neuroendocrine tumors (NETs) is rising in developed countries primarily as a result of increased incidental detection by endoscopy and probably also due to a more adequate diagnosis according to the WHO classification. Less than 1% of colorectal NETs produce serotonin so that such tumors are practically never associated with a hormonal carcinoid syndrome. An exact clinico-pathological staging is of paramount importance for the therapeutic strategy and comprises the classification of the tumor type (well or poorly differentiated) and the assessment of established prognostic risk factors (depth of infiltration, vascular invasion, lymph node and distant metastases). Poorly differentiated colorectal NETs often present in an advanced, metastatic state, where surgical therapy is basically palliative. Well-differentiated tumors larger than 2 cm have a high risk of metastatic spread and should be treated as adenocarcinomas by radical oncological surgical resection. This applies to the majority of colon NETs. Tumors smaller than 1 cm, mainly locacted in the rectum, only rarely metastasize and are usually accessible for endoscopic treatment or transanal local surgery. Tumors between 1 and 2 cm in size have an uncertain prognosis and additional risk factors and co-morbidities of the patient have to be considered for a suitable, multidisciplinary therapeutic decision. PMID- 21656306 TI - Late onset Pott's paraplegia in patients with upper thoracic sharp kyphosis. AB - PURPOSE: The purpose of this study was to determine the clinical results of patients with late onset upper thoracic sharp Pott's kyphosis and to predict the prognosis for Pott's paraplegics. METHOD: The study included five patients who developed late onset upper thoracic (T1-T4) sharp Pott's kyphosis/kyphoscoliosis within a period from 19 to 37 years after the active disease was healed. The kyphosis angle of the patients ranged from 95 degrees to 105 degrees . Among them, three patients suffered onset of paraplegia ranging from 26 to 31 years after spinal tuberculosis was healed. The duration of neurological deterioration before surgery ranged from four to five years. All patients underwent decompressive surgery with an attempt to correct the curve. Neurological status was evaluated using the ASIA impairment classification and the motor score. RESULTS: Postoperatively, kyphosis correction ranged from 20 degrees to 30 degrees for five patients. No neurological deficit occurred in two patients with normal neurological status. Two ASIA D paraplegics remained unchanged after surgery and no further improvement was found at one year follow-up. One ASIA C paralysis deteriorated neurologically to ASIA B after surgery and persisted to a deterioration of neurological status at one year follow-up. CONCLUSION: Upper thoracic sharp Pott's kyphosis and neurological deficits occur progressively. The neurological recovery or improvement of Pott's paraplegics with upper thoracic severe sharp kyphosis results in poor prognosis after decompressive surgery. PMID- 21656307 TI - Distribution of SMI-32-immunoreactive neurons in the central auditory system of the rat. AB - SMI-32 antibody recognizes a non-phosphorylated epitope of neurofilament proteins, which are thought to be necessary for the maintenance of large neurons with highly myelinated processes. We investigated the distribution and quantity of SMI-32-immunoreactive(-ir) neurons in individual parts of the rat auditory system. SMI-32-ir neurons were present in all auditory structures; however, in most regions they constituted only a minority of all neurons (10-30%). In the cochlear nuclei, a higher occurrence of SMI-32-ir neurons was found in the ventral cochlear nucleus. Within the superior olivary complex, SMI-32-ir cells were particularly abundant in the medial nucleus of the trapezoid body (MNTB), the only auditory region where SMI-32-ir neurons constituted an absolute majority of all neurons. In the inferior colliculus, a region with the highest total number of neurons among the rat auditory subcortical structures, the percentage of SMI-32-ir cells was, in contrast to the MNTB, very low. In the medial geniculate body, SMI-32-ir neurons were prevalent in the ventral division. At the cortical level, SMI-32-ir neurons were found mainly in layers III, V and VI. Within the auditory cortex, it was possible to distinguish the Te1, Te2 and Te3 areas on the basis of the variable numerical density and volumes of SMI-32-ir neurons, especially when the pyramidal cells of layer V were taken into account. SMI-32-ir neurons apparently form a representative subpopulation of neurons in all parts of the rat central auditory system and may belong to both the inhibitory and excitatory systems, depending on the particular brain region. PMID- 21656305 TI - [Neuroendocrine tumors of the duodenum and pancreas. Surgical strategy]. AB - The incidence of neuroendocrine tumors (NET) has increased worldwide by 3-5 times over the last decades. This is mainly based on the broad use of imaging modalities such as computed tomography (CT) and endoscopic approaches. As a consequence many duodenal and pancreatic tumors are detected in an early stage resulting in an improved prognosis of these patients. Besides the measurement of serum chromogranin A and 5-hydroxy indolic acid measured in 24 h urine collection, CT, endosonographic ultrasound (EUS) and endoscopy are important diagnostic tools. About 20% of all patients with pancreatic and duodenal NETs are diagnosed because of specific symptoms. More than 95% of diagnosed NETs are sporadic tumors. Whenever possible these patients should be treated by resection. Benign neuroendocrine duodenal tumors up to 1 cm in size can be removed endoscopically. The endoscopic resection of larger tumors should be performed surgically. The therapy of hereditary NETs of the duodenum and the pancreas should be decided after interdisciplinary discussion. However, even these patients seem to benefit from resection. In case of metastatic disease debulking surgery should be considered if more than 90% of the tumor mass can be resected. In patients with extensive liver metastases but resectable primary NET, liver transplantation is a reasonable option. There is no consensus about adjuvant or neoadjuvant treatment of duodenal or pancreatic NETs. The therapy with everolimus or sunitinib in advanced tumor stages has shown promising results. The administration of somatostatin analogues or antacids is appropriate for symptom reduction. PMID- 21656308 TI - The effects of morphine-neostigmine and secretin provocation on pancreaticobiliary morphology in healthy subjects: a randomized, double-blind crossover study using serial MRCP. AB - BACKGROUND: Secretin-stimulated magnetic resonance cholangiopancreatography (MRCP) is used for the diagnosis of sphincter of Oddi dysfunction (SOD), but it does not correlate well with sphincter of Oddi manometry. Serial MRCP following morphine-neostigmine provocation may be of value in the assessment of SOD, but the effects of these pharmacological agents on pancreaticobiliary morphology in healthy subjects have not been studied. The aim of the present study was to use serial MRCP to characterize the effects of morphine-neostigmine and secretin provocation on serum pancreatic enzyme responses and pancreaticobiliary ductal morphology in healthy subjects. METHODS: Following a baseline scan and serum lipase and amylase assays, 10 healthy subjects were randomized in a double-blind manner to receive morphine (10 mg intramuscularly [IM]), neostigmine (1 mg IM) and saline (intravenously [IV]); OR saline (IM), saline (IM) and secretin (1 U/kg IV). A MRCP study was performed at 5, 30, 60, 90, 120, 150, and 180 min thereafter, with blood samples taken every 60 min for 4 h. Pancreatic duct (PD) diameter, visible PD length, common bile duct (CBD) diameter, and gallbladder volume were recorded. Crossover studies were performed 10 days later. RESULTS: Serum pancreatic enzyme concentrations were significantly greater (amylase, P = 0.003; lipase, P = 0.04) after morphine-neostigmine than after secretin. Following morphine-neostigmine and secretin provocation, the mean (SEM) percentage increase in PD diameter was 28.7 (7.2) versus 12.9 (3.3); P < 0.0001, and visible PD length was 49.4 (11.5) versus 28.1 (8.2); P < 0.0001, respectively. CONCLUSIONS: The effects of morphine-neostigmine were more pronounced than those of secretin in healthy subjects. The diagnostic utility of morphine-neostigmine stimulated serial MRCP for SOD merits further evaluation. PMID- 21656309 TI - Risk factors influencing postoperative outcomes of major hepatic resection of hepatocellular carcinoma for patients with underlying liver diseases. AB - BACKGROUND: Major hepatic resection of more than three segments in patients with hepatocellular carcinoma (HCC) is a high-risk operation, especially in patients with co-existing underlying liver diseases. The present study evaluated risk factors for postoperative morbidity and mortality after major hepatic resection in HCC patients with underlying liver diseases. METHODS: Perioperative data of 305 HCC patients with underlying liver diseases who underwent major hepatic resection were evaluated by univariate and multivariate analyses to identify risk factors for postoperative morbidity and mortality. RESULTS: The overall morbidity rate was 37.0% (n = 113), caused by pleural effusion (n = 56), ascites (n = 43), subphrenic effusion/infection (n = 23), hepatic dysfunction (n = 22), bile leakage (n = 10), respiratory infection (n = 7), incision infection (n = 7), intra-abdominal hemorrhage (n = 5), and others. The hospital mortality rate was 2.6% (n = 8), primarily caused by liver failure (4/8). Multivariate logistic regression analysis showed that preoperative platelet count <100 * 10(9)/l (P = 0.006), and increased intraoperative blood loss (>= 800 ml) (P = 0.008) were independent risk factors of postoperative morbidity, and that preoperative prothrombin time >14 s (P = 0.015) and preoperative platelet count <100 * 10(9)/l (P = 0.007) were independent risk factors for significant hospital mortality. CONCLUSIONS: Careful preoperative selection of patients in terms of the Child Pugh classification and decrease of intraoperative blood loss are important measures to reduce postoperative morbidity after major hepatic resection in HCC patients with underlying liver diseases. Moreover, we should be aware that preoperative platelet count is independently associated with postoperative morbidity and mortality for those patients following major hepatic resection. PMID- 21656310 TI - B7-h1 and a mathematical model for cytotoxic T cell and tumor cell interaction. AB - The surface protein B7-H1, also called PD-L1 and CD274, is found on carcinomas of the lung, ovary, colon, and melanomas but not on most normal tissues. B7-H1 has been experimentally determined to be an antiapoptotic receptor on cancer cells, where B7-H1-positive cancer cells have been shown to be immune resistant, and in vitro experiments and mouse models have shown that B7-H1-negative tumor cells are significantly more susceptible to being repressed by the immune system. We derive a new mathematical model for studying the interaction between cytotoxic T cells and tumor cells as affected by B7-H1. By integrating experimental data into the model, we isolate the parameters that control the dynamics and obtain insights on the mechanisms that control apoptosis. PMID- 21656311 TI - Differences between African American and White research volunteers in their attitudes, beliefs and knowledge regarding genetic testing for Alzheimer's disease. AB - Genetic susceptibility testing for common diseases is expanding, but little is known about race group differences in test perceptions. The purpose of this study was to examine differences between African Americans and Whites in knowledge, attitudes, and motivations regarding genetic susceptibility testing for Alzheimer's disease (AD). Before enrolling in an AD genetic testing research trial, 313 first-degree relatives of AD patients (20% African American; 71% female; mean age = 58 years) were surveyed regarding: (1) knowledge about genetics and AD risk; (2) concerns about developing AD; and (3) reasons for seeking testing. In comparison to Whites, African Americans were less knowledgeable about genetics and AD risk (p < .01) and less concerned about developing AD (p < .05), with lower levels of perceived disease risk (p = .04). The results suggest that African Americans and Whites differ notably in their knowledge, beliefs, and attitudes regarding genetic testing for AD. Additional research with more representative samples is needed to better understand these differences. PMID- 21656312 TI - Psychological and theological dynamics in an inpatient psychiatric chaplaincy group. AB - This article describes the structure and goals of chaplaincy groups in an inpatient psychiatric setting. The article also explores their therapeutic benefits for patients and offers a theological framework for thinking about the conversations that unfolded in these groups. The article focuses in particular on the value of discussion and reflection in a group setting, the significance of receiving and answering questions, and the experience of participating in a simple ritual to name hopes. PMID- 21656313 TI - Thromboembolic events are uncommon after open treatment of proximal humerus fractures using aspirin and compression devices. AB - BACKGROUND: Thromboembolic phenomena have long been recognized as a major cause of morbidity and mortality in hospitalized patients, especially those undergoing reconstructive surgery. We have been empirically treating patients with aspirin, early ambulation, and mechanoprophylaxis after operative management of proximal humerus fractures. However, we have not established the incidence of postoperative deep vein thrombosis and pulmonary embolism in this population. QUESTIONS/PURPOSES: We determined the incidence of deep vein thrombosis and pulmonary embolism in patients having surgery for displaced proximal humerus fractures treated with our thromboprophylactic regimen. PATIENTS AND METHODS: We prospectively followed 50 patients with proximal humerus fractures who underwent fixation with plate osteosynthesis (n = 40) or hemiarthroplasty (n = 10) between August 2005 and December 2008. Deep vein thrombosis prophylaxis consisted of oral enteric-coated aspirin, pneumatic calf compression pumps, and early ambulation in all patients unless medically contraindicated. Color-flow Doppler ultrasound of the affected arm and both lower extremities was performed at a mean of 14 days (range, 7-21 days) postoperatively to evaluate for deep vein thrombosis. All patients clinically suspected to have suffered a pulmonary embolism underwent a CT angiogram. RESULTS: We identified no patients with deep vein thrombosis or pulmonary embolism in this population. CONCLUSIONS: Deep vein thrombosis and pulmonary embolism are not uncommon after major reconstructive surgery about the shoulder in untreated patients. Our data suggest these events can be low after surgery for proximal humerus fractures followed by a thromboprophylactic regimen including aspirin, mechanical devices, and early mobilization. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21656314 TI - Endothelin-1 promotes osteosarcoma cell invasion and survival against cisplatin induced apoptosis. AB - BACKGROUND: Endothelin-1 (ET-1) participates in a wide range of cancer-relevant processes including cell proliferation, inhibition of apoptosis, matrix remodeling, bone deposition, and metastases. Although ET-1 reportedly promotes osteosarcoma (OS) cell invasion, suggesting an important role of ET-1 in OS metastasis, the role of ET-1 in OS remains unclear. QUESTION/PURPOSES: We asked whether (1) ET-1 expression is associated with the malignancy of OS, (2) ET-1 enhances the cell invasion ability of OS, and (3) ET-1 promotes OS cell survival against apoptotic stress. METHODS: We cultured primary OS specimens from 22 patients with Stages II (OS-II) and III (OS-III) in real-time quantitative RT-PCR and ELISA to compare ET-1 expression. We used Transwell((r)) cell invasion assays (in triplicate) to assess the invasion ability of cells in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We compared cell apoptosis rate among the cells treated with cisplatin in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We used OS cell line MG-63 in all experiments as a reference. RESULTS: Real-time quantitative RT-PCR and ELISA showed OS-III cells had greater ET-1 expression than OS-II cells at the mRNA and the secreted protein levels. Transwell((r)) cell invasion assays showed OS-III cells had a greater migrated cell number than OS-II cells, which could be abrogated by ET(A) receptor antagonist BQ123 (100 pmol/L), but not ET(B) receptor antagonist BQ788 (1 MUmol/L); exogenous ET-1 dose-dependently promoted OS cell migration, which could be inhibited by BQ123 (100 pmol/L). Cisplatin (10 nmol/L) induced less apoptosis in OS-III cells than in OS-II cells; exogenous ET-1 dose dependently promoted OS cell survival against cisplatin-induced apoptosis; both effects were reversed by BQ123 (1 MUmol/L), but not BQ788 (1 MUmol/L). CONCLUSIONS: Increased ET-1 expression appears to be associated with increased malignancy of OS. ET-1 promotes OS cell invasion and survival against cisplatin induced apoptosis through the ET(A) receptor. CLINICAL RELEVANCE: The ET-1/ET(A) pathway may represent an important target for treating OS, because blocking the ET(A) receptor with a selective antagonist can inhibit OS cell invasion and potentiate a chemotherapeutic agent's effect on OS. PMID- 21656315 TI - The Chitranjan Ranawat award: is neutral mechanical alignment normal for all patients? The concept of constitutional varus. AB - BACKGROUND: Most knee surgeons have believed during TKA neutral mechanical alignment should be restored. A number of patients may exist, however, for whom neutral mechanical alignment is abnormal. Patients with so-called "constitutional varus" knees have had varus alignment since they reached skeletal maturity. Restoring neutral alignment in these cases may in fact be abnormal and undesirable and would likely require some degree of medial soft tissue release to achieve neutral alignment. QUESTIONS/PURPOSES: We investigated what percentage of the normal population has constitutional varus knees and what are the contributing factors. SUBJECTS AND METHODS: We recruited a cohort of 250 asymptomatic adult volunteers between 20 and 27 years old for this cross sectional study. All volunteers had full-leg standing digital radiographs on which 19 alignment parameters were analyzed. The incidence of constitutional varus alignment was determined and contributing factors were analyzed using multivariate prediction models. RESULTS: Thirty-two percent of men and 17% of women had constitutional varus knees with a natural mechanical alignment of 3 degrees varus or more. Constitutional varus was associated with increased sports activity during growth, increased femoral varus bowing, an increased varus femoral neck-shaft angle, and an increased femoral anatomic mechanical angle. CONCLUSIONS: An important fraction of the normal population has a natural alignment at the end of growth of 3 degrees varus or more. This might be a consequence of Hueter-Volkmann's law. Restoration of mechanical alignment to neutral in these cases may not be desirable and would be unnatural for them. PMID- 21656316 TI - Surfactant-stabilized emulsion increases gentamicin elution from bone cement. AB - BACKGROUND: Liquid antimicrobial use for antimicrobial-loaded bone cement is limited because of decreased strength and small volume that can be loaded. Emulsifying the liquid antimicrobial into the monomer may address both issues. QUESTIONS/PURPOSES: We determined the effect of using a surfactant-stabilized emulsion on antimicrobial release, compressive strength, and porosity. METHODS: We made 144 standardized test cylinders from emulsified antimicrobial-loaded bone cement (three batches, 72 cylinders) and control antimicrobial-loaded bone cement made with antimicrobial powder (three batches, 72 cylinders). For each formulation, five specimens per batch (n = 15) were eluted in infinite sink conditions over 30 days for gentamicin delivery; five specimens per batch were axially compressed to failure after elution of 0, 1, and 30 days (n = 45); and two noneluted specimens and two gentamicin delivery specimens from each batch (n = 12) were examined under scanning electron microscopy for porosity. Antimicrobial release and compressive strength were compared across cement type and time using repeated-measures ANOVA. RESULTS: Emulsified antimicrobial-loaded bone cement released four times more antimicrobial than control. Compressive strength of emulsified antimicrobial-loaded bone cement was less than control before elution (58.1 versus 81.3 MPa) but did not decrease over time in elution. Compressive strength of control antimicrobial-loaded bone cement decreased over 30 days in elution (81.3 versus 73.9 MPa) but remained stronger than emulsified antimicrobial-loaded bone cement. Porosity was homogeneous, with pores ranging around 50 MUm. CONCLUSIONS: Emulsified antimicrobial-loaded bone cement has homogeneous porosity with increased drug release but a large loss of strength. CLINICAL RELEVANCE: Liquid antimicrobials are released from emulsified antimicrobial-loaded bone cement, but increased strength is needed before this method can be used for implant fixation. PMID- 21656318 TI - Laparoscopic removal of intravesical mesh following pelvic organ prolapse mesh surgery. AB - With the increasing popularity of mesh in prolapse surgery, complications such as intravesical mesh will arise more frequently. In three cases intravesical mesh was identified in the trigone of the bladder following laparoscopic mesh hysteropexy, open sacral colpopexy, and transvaginal mesh repair and presented 9 months to 7 years later with a variety of symptoms including recurrent urinary tract infections, suprapubic pain, and constant urinary leakage. Each underwent uncomplicated laparoscopic transvesical removal of intravesical mesh. Intravesical mesh can present years following index prolapse surgery and can develop despite the bladder integrity being documented as being intact at the initial surgery. The laparoscopic approach to the removal of intravesical mesh is feasible, minimally invasive, and a precise approach to this challenging complication. PMID- 21656317 TI - Insufficient acetabular version increases blood metal ion levels after metal-on metal hip resurfacing. AB - BACKGROUND: Many factors affect the blood metal ion levels after metal-on-metal (MOM) hip arthroplasty. The main surgically adjustable variable is the amount of coverage of the head provided by the cup which is a function of the inclination and version angles. However, most studies have used plain radiographs which have questionable precision and accuracy, particularly for version and large diameter metal heads; further, these studies do not simultaneously assess version and inclination. Thus the relationship between version and blood metal ions levels has not been resolved. QUESTIONS/PURPOSES: We determined whether cup inclination and version influence blood metal ion levels while adjusting for age at assessment, gender, body mass index, horizontal femoral offset, head size, manufacturer hip type, and Oxford hip score. PATIENTS AND METHODS: We prospectively followed 100 individuals (51 females, 49 males) with unilateral MOM hip resurfacing who underwent clinical assessment, CT scanning, and blood metal ion measurement. Multiple regression analysis was used to determine which variables were predictors of blood metal ion levels and to model the effect of these variables. RESULTS: Only cup inclination, version angles, and gender influenced blood cobalt or chromium levels. Cobalt and chromium levels positively correlated with inclination angle and negatively correlated with version angle. The effect of changes in version angle was less than for inclination angle. Based on our observations, we developed a formula to predict the effect of these parameters on metal ion levels. CONCLUSIONS: Our data suggest insufficient cup version can cause high blood metal ions after MOM hip arthroplasty. We were unable to show that excessive version caused high levels. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21656319 TI - Validation of the Wexner scale in women with fecal incontinence in a Turkish population. AB - INTRODUCTION AND HYPOTHESIS: The main aim of this study was to validate the Turkish translated version of the Wexner scale. METHODS: After establishing the test-retest reliability and internal consistency of the Turkish version of Wexner scale on 31 patients, total and subscale scores and anal manometric measurements of 60 participants were performed. Correlation between Wexner scale scores and manometric measurement values were analyzed and those values of patients with or without anal incontinence symptoms were compared. RESULTS: Of the 60 participants, 47 (78%) showed no signs or symptoms of anal incontinence. Wexner scale showed a high internal consistency (Cronbach's alpha = 0.816). Total and each subscale score of Wexner scale showed strong correlation with resting and maximal squeeze pressures and between each other (p < 0.005). The pressure values were significantly less in asymptomatic patients compared to patients with any degree of symptoms (p < 0.05). CONCLUSION: The Turkish translated version of the Wexner scale is a reliable, consistent, and valid instrument to evaluate anal functions in women with anal incontinence for Turkish speaking women. Total and subscale scores of the Wexner scale and anal manometric measurements showed significant correlation. PMID- 21656320 TI - Pelvic floor ultrasound in prolapse: what's in it for the surgeon? AB - Pelvic reconstructive surgeons have suspected for over a century that childbirth related trauma plays a major role in the aetiology of female pelvic organ prolapse. Modern imaging has recently allowed us to define and reliably diagnose some of this trauma. As a result, imaging is becoming increasingly important, since it allows us to identify patients at high risk of recurrence, and to define underlying problems rather than just surface anatomy. Ultrasound is the most appropriate form of imaging in urogynecology for reasons of cost, access and performance, and due to the fact that it provides information in real time. I will outline the main uses of this technology in pelvic reconstructive surgery and focus on areas in which the benefit to patients and clinicians is most evident. I will also try and give a perspective for the next 5 years, to consider how imaging may transform the way we deal with pelvic floor disorders. PMID- 21656321 TI - Anesthetic considerations in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome: a case series. AB - PURPOSE: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) is a rare inherited mitochondrial disorder associated with severe multiorgan pathology and stress-induced episodes of metabolic decompensation and lactic acidosis. The purpose of this case series is to review the medical records of patients with MELAS who underwent anesthetic care at the Mayo Clinic to observe their perioperative responses to anesthesia and to assess outcomes. PRINCIPAL FINDINGS: From September 1997 to October 2010, nine patients with MELAS were identified who underwent 20 general anesthetics, 12 prior to MELAS diagnosis. Debilitating neurologic symptoms involved eight patients, and three patients had substantial cardiac comorbidities. The patients tolerated commonly used anesthetics and muscle relaxants, including succinylcholine. Lactated Ringer's solution was used frequently. One patient was noted to have elevated postoperative serum lactate, but his serum lactate was chronically elevated. Metabolic acidosis was not observed in any patient. Hyponatremia and hyperkalemia, sometimes profound, were observed in seven patients, but these abnormalities also occurred at times remote from surgery. Two patients developed renal dysfunction following cardiac surgery and abdominal surgery for severe sepsis. CONCLUSION: The MELAS patients developed episodes of hyponatremia and hyperkalemia of variable severity unrelated to the timing of surgery, suggesting these patients are prone to major electrolyte disturbances. Given the propensity to develop acid-base disturbances and lactacidemia, it is prudent to review and normalize electrolyte abnormalities and to adjust the anesthetic plan accordingly. Fortunately, the limited data suggest that patients with MELAS tolerate commonly used anesthetic drugs well. PMID- 21656322 TI - [Risk stratification of progressive multifocal leukoencephalopathy under natalizumab: recommendations for JC virus serology]. PMID- 21656323 TI - A practical way to overcome the learning period of laparoscopic gastrectomy for gastric cancer. AB - BACKGROUND: Although laparoscopic gastrectomy is widely performed in patients with gastric cancer, it requires a learning period for surgeons. Few methods are known to reduce or overcome this learning period. We tested a method to reduce or overcome this learning period in the beginner surgeon. METHODS: Between April 2009 and March 2010, a total of 139 patients underwent laparoscopic gastrectomy by a beginner surgeon. During their training period of 6 months, the beginner had been the first assistant during 200 laparoscopic gastrectomies. To evaluate surgical outcomes as the surgeon started to perform laparoscopic gastrectomy, outcomes were assessed in 79 patients who underwent laparoscopic-assisted distal gastrectomy with extracorporeal gastroduodenostomy (LADG); the first 30 were performed by the surgeon and 49 were performed subsequently. Outcomes of LADG and totally laparoscopic distal gastrectomy with intracorporeal gastroduodenostomy (TLDG) were compared to evaluate the beginner's ability to adapt to intracorporeal reconstruction. The learning period was assessed by dividing patients who underwent LADG and TLDG into sequential groups of five each by time. RESULTS: No patient was converted to open surgery and none died. There were no significant differences between the first 30 patients and the next 49 who underwent LADG in surgical outcomes. The only significantly different outcome between LADG and TLDG was in operation time (95.9 min vs. 115.6 min, P < 0.001). There were no significant differences in mean operation times of sequential groups (LADG, P = 0.069; TLDG, P = 0.212). CONCLUSIONS: The beginning surgeon examined in this work obtained satisfactory surgical outcomes during the early period of performing laparoscopic gastrectomy. We speculate that participation in laparoscopic gastrectomy team of experts improved the beginner's surgical outcomes, suggesting that such participation may reduce or overcome the learning period of beginners. PMID- 21656324 TI - Endoscopic necrosectomy of pancreatic necrosis: a systematic review. AB - AIM: To review the current status of the novel technique of endoscopic necrosectomy in the management of pancreatic necrosis after acute pancreatitis. METHODS: Studies were identified by searching Medline, PubMed and Embase databases for articles from January 1990 to December 2009 using the keywords "acute pancreatitis", "pancreatic necrosis" and "endoscopy". Additional papers were identified by a manual search of the references from the key articles. Case series of fewer than five patients and case reports were excluded. RESULTS: Indications, techniques and outcomes of endoscopic necrosectomy were analysed. There were no randomised controlled trials identified. Ten case series were included in this analysis. There were a total of more than 1,100 endoscopic necrosectomy procedures in 260 patients with pancreatic necrosis. One hundred fifty-five were proven to be infected necrosis on culture. The overall mortality rate was 5%. The mean procedure-related morbidity rate was 27%. The rate of complete resolution of pancreatic necrosis with the endoscopic method alone was 76%. CONCLUSIONS: Endoscopic necrosectomy is a safe and effective treatment option in selected patients with pancreatic necrosis after acute pancreatitis. Future studies will be required to further define the selection criteria and the techniques for the endoscopic procedure. PMID- 21656325 TI - Intragastric balloon positioning and removal: sedation or general anesthesia? AB - BACKGROUND: Different anesthesiological techniques are currently used for intragastric balloon positioning and removal. The aim of this study is to compare different anesthesiological approaches for balloon positioning and removal in a large multicentric patient population. METHODS: Retrospective multicenter study was conducted. From May 2000 to April 2008, 3,824 patients underwent BIB((r)) placement [1,022 male/2,802 female; mean age 39.5 +/- 14.7 years, range 12-71 years; mean body mass index (BMI) 44.8 +/- 9.7 kg/m(2), range 28.0-79.1 kg/m(2); excess weight (EW) 59.1 +/- 29.8 kg, range 16-210 kg; %EW 89.3 +/- 31.7, range 21.4-262]. Patients were allocated to three groups according to anesthesiological technique used: conscious sedation (group A), deep sedation (group B), and general anesthesia (group C). Intragastric balloon was placed after diagnostic endoscopy and removed after 6 months. Both positioning and removal were done under different protocols. Conscious sedation was obtained with topical lidocaine spray, adding diazepam (0.05-0.1 mg/kg iv) or midazolam (0.03-0.05 mg/kg iv). Deep sedation was obtained with propofol alone or adding other drugs such as midazolam, meperidine/fentanyl or meperidine/fentanyl + midazolam. General anesthesia was obtained with midazolam premedication (0.01-0.02 mg/kg iv) followed by induction with propofol (1-1.5 mg/kg iv) + Norcuron (80 mcg/kg iv) + fentanyl (0.5-1 mcg/kg iv), and maintenance with propofol (50-150 MUg/kg/min) or sevorane. Oxygen saturation, hemodynamic stability, major anesthesiological complications and related mortality, patient satisfaction, time to return to autonomous walking, duration of procedure, and hospital stay were considered. RESULTS: Sedation-related mortality was absent. A significant number of patients with bronchoinhalation during balloon removal was observed with general anesthesia (P < 0.001). CONCLUSIONS: BIB positioning and removal should be performed under conscious sedation for patient safety and comfort, and technical success. PMID- 21656327 TI - High circulating levels of interleukin-18 binding protein indicate the severity of glomerular involvement in systemic lupus erythematosus. AB - In systemic lupus erythematosus (SLE), glomerular involvement often progresses with the activity of the disease. Immune complexes and abnormal secretion of cytokines are thought to be involved in the central mechanism of the development of lupus nephritis. We investigated serum levels of interleukin 18 (IL-18), a proinflammatory cytokine, and its natural antagonist IL-18 binding protein (IL-18 BP) in 45 patients with lupus nephritis. IL-18 levels were significantly increased in patients with Class II, Class III, and Class IV lupus nephritis compared with the level in a healthy control group. However, the levels stayed within the non-significant range in Class V. IL-18 BP levels were significantly increased in patients with Class III and Class IV lupus nephritis, in which histological activity and chronicity are severe. However, IL-18 BP levels stayed within the non-significant range in Class II and Class V, in which histological markers are mild. We also compared the levels of IL-18 and IL-18 BP in patients with and without glomerular infiltration of inflammatory cells. IL-18 was increased regardless of glomerular infiltration. However, IL-18 BP was increased only in patients with glomerular infiltration. These data suggest that IL-18 levels indicate the extent of the offending inflammatory response not only in the bloodstream but also in renal tissue, and that high IL-18 BP levels indicate the severity of existing glomerular injury. PMID- 21656326 TI - Curcumin attenuates aluminum-induced oxidative stress and mitochondrial dysfunction in rat brain. AB - Aluminum is neurotoxic both in animals and human beings primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondrial dysfunction is one such mechanism that has been implicated in the pathogenesis of neurodegenerative diseases like Alzheimer's disease. Aluminum toxicity is very closely related to Alzheimer's disease. We evaluated the potentials of curcumin, a known cytoprotectant, against neurotoxic consequences of aluminum that acts through a wide range of mechanisms. Curcumin has been reported to be an antioxidant, and it is this property that is widely held to be responsible for its protective effects in tissue. Aluminum was administered by oral gavage at a dose level of 100 mg/kg body wt/day for a period of 8 weeks. Curcumin was administered in conjunction with aluminum at a dose of 50 mg/kg of body wt i.p. for a period of 8 weeks on alternate days. The effects of different treatments were studied on oxidative phosphorylation and reduced glutathione of different regions of rat brain. The study indicates reduced activity of NADH dehydrogenase (complex I), succinic dehydrogenase (complex II), and cytochrome oxidize (Complex IV) in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. Curcumin supplementation to aluminum-treated rats was able to normalize significantly the activities of all the three mitochondrial complexes as well as reduced glutathione content in all the three regions of brain which were altered following aluminum treatment. We conclude that curcumin, by attenuating oxidative stress, as evident by hypoxia in histological observations and mitochondrial dysfunction holds a promise as an agent that can potentially reduce aluminum-induced adverse effects in brain. PMID- 21656328 TI - Triple-negative breast cancer with brain metastases: a comparison between basal like and non-basal-like biological subtypes. AB - The aim of this study was to divide the group of triple-negative breast cancer patients with brain metastases into basal-like and non-basal-like biological subtypes in order to compare clinical features and survival rates in those two groups. A comprehensive analysis of 111 consecutive triple-negative breast cancer patients with brain metastases treated in the years 2003-2009 was performed. In 75 patients, immunohistochemistry was used as a surrogate of microarray in order to evaluate the expression of three basal markers: cytokeratin 5/6 (CK 5/6), EGFR/HER1 and c-KIT. The basal-like (ER/PgR/HER2-negative, CK5/6positive and/or HER1-positive) and non-basal-like (ER/PgR/HER2-negative, CK5/6-negative, HER1 negative) subsets were selected. Clinical features and survivals were compared in both groups. In the group of 111 triple-negative breast cancer patients, median DFS, OS and survival from brain metastases were 20, 29 and 4 months, respectively. In 75 patients who were evaluable for basal markers, median DFS, OS and survival from brain metastases were 18, 26 and 3.2 months, respectively. In the basal-like subtype, the survival rates were 15, 26 and 3 months, respectively, and in the non-basal-like subtypes, they were 20, 30 and 2.8 months, respectively. No statistically significant differences in survivals were detected between the basal-like and non-basal-like biological subtypes. Factors influencing survival from brain metastases were: Karnofsky performance status (KPS), the status of extracranial disease and age. Biological markers differentiating triple-negative group into basal-like and non-basal-like subtype (CK 5/6, HER1, c-KIT) had no influence on survival. In patients with triple negative breast cancer and brain metastases, well-known clinical, but not molecular, features correlated with survival. PMID- 21656329 TI - Platine and cytarabine-based salvage treatment for primary central nervous system lymphoma. AB - The aim of this study was to evaluate the efficacy and toxicity of two chemotherapy regimens based on platinum and cytarabine in association with etoposide and methylprednisolone (ESHAP) or with dexamethasone (DHAP) with or without Rituximab (+/- R) in patients with refractory or a relapsed Primary Central Nervous System Lymphoma (PCNSL). All consecutive patients from two French centers with refractory or relapsed PCNSL treated with ESHAP/DHAP +/- R were included. We analyzed the overall response rate (ORR), toxicity and overall survival (OS) after salvage chemotherapy. Intensive chemotherapy and hematopoietic stem cell rescue (IC + HCR) was offered to patients less than 65 years of age and consisted of high-dose thiotepa, busulfan and cyclophosphamide. These results were compared with two previously reported series of PCNSL patients treated with the CYVE (high-dose cytarabine and etoposide) regimen at relapse. Twenty-two patients received a total of 60 DHAP/ESHAP cycles (median 3; range 1 5). The median age was 59 years. The ORR after salvage chemotherapy was 59%. Toxicity was mainly hematological, 18% of patients showing febrile neutropenia. There was no treatment-related death. ESHAP or DHAP regimens led to similar ORRs compared to the CYVE regimen in relapsed or refractory PCNSL, although they seemed less toxic. The therapeutic results of the ESHAP/DHAP regimens in relapsed or refractory PCNSL were also similar to those for relapsed systemic non Hodgkin's lymphomas (sNHL). Both chemotherapies, CYVE regimen and ESHAP/DHAP are treatment options to be considered in relapsed or refractory PCNSL, especially when IC + HCR is planned as a consolidation treatment. More efforts are still needed to improve the ORR at relapse. PMID- 21656330 TI - Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. AB - AIMS/HYPOTHESIS: Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake. METHODS: Eleven people with type 2 diabetes (49.5 +/- 2.5 years, BMI 33.6 +/- 1.2 kg/m(2), nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied. RESULTS: After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 +/- 0.4 to 5.9 +/- 0.4 mmol/l; p = 0.003). Insulin suppression of hepatic glucose output improved from 43 +/- 4% to 74 +/- 5% (p = 0.003 vs baseline; controls 68 +/- 5%). Hepatic triacylglycerol content fell from 12.8 +/- 2.4% in the diabetic group to 2.9 +/- 0.2% by week 8 (p = 0.003). The first-phase insulin response increased during the study period (0.19 +/- 0.02 to 0.46 +/- 0.07 nmol min(-1) m(-2); p < 0.001) and approached control values (0.62 +/- 0.15 nmol min(-1) m(-2); p = 0.42). Maximal insulin response became supranormal at 8 weeks (1.37 +/- 0.27 vs controls 1.15 +/- 0.18 nmol min(-1) m(-2)). Pancreatic triacylglycerol decreased from 8.0 +/- 1.6% to 6.2 +/- 1.1% (p = 0.03). CONCLUSIONS/INTERPRETATION: Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake. PMID- 21656331 TI - High-resolution spiral CT of the breast at very low dose: concept and feasibility considerations. AB - OBJECTIVE: Mammography, today's standard imaging approach, has deficits with respect to the superimposition of anatomical structures. Dedicated CT of the breast so far indicated that it can provide superior soft-tissue imaging, but that it still has significant limitations with respect to spatial resolution and dose. We have assessed novel dedicated breast CT technology. METHODS: Based on simulations and measurements we developed novel technology which uses direct conversion CdTe material and photon-counting electronics with 100 MUm detector element size for close to 100% dose efficiency. We assessed the potential for the imaging of microcalcifications of 100 to 200 MUm diameter and soft-tissue lesions of 1 to 5 mm diameter by simulations at dose levels between 1 and 6 mGy. RESULTS: Microcalcifications of 150 MUm and soft-tissue lesions of 2 mm diameter were found to be clearly detectable at an average glandular dose of 3 mGy. Separate displays are required for high-resolution microcalcification and for low resolution soft-tissue analysis. Total CT data acquisition time will be below 10 s. CONCLUSION: Dedicated breast CT may eventually provide comprehensive diagnostic assessment of microcalcifications and soft-tissue structures at dose levels equivalent to or below those of two-view screening mammography. PMID- 21656332 TI - Hypersexuality in a 28-year-old woman with rabies. AB - Unusual clinical presentations of rabies are well known. A case of rabies is reported in a 28-year-old female who presented with features of increased sexual desire and heightened sexual arousal without provocation. Health care providers should be aware that marked changes in sexual behavior may be related to infection due to rabies. PMID- 21656333 TI - Sexual orientation in men and avuncularity in Japan: implications for the kin selection hypothesis. AB - The kin selection hypothesis for male androphilia posits that genes for male androphilia can be maintained in the population if the fitness costs of not reproducing directly are offset by enhancing inclusive fitness. In theory, androphilic males can increase their inclusive fitness by directing altruistic behavior toward kin, which, in turn, allows kin to increase their reproductive success. Previous research conducted in Western countries (U.S., UK) has failed to find any support for this hypothesis. In contrast, research conducted in Samoa has provided repeated support for it. In light of these cross-cultural differences, we hypothesized that the development of elevated avuncular (i.e., altruistic uncle-like) tendencies in androphilic males may be contingent on a relatively collectivistic cultural context. To test this hypothesis, we compared data on the avuncular tendencies and altruistic tendencies toward non-kin children of childless androphilic and gynephilic men in Japan, a culture that is known to be relatively collectivistic. The results of this study furnished no evidence that androphilic Japanese men exhibited elevated avuncular tendencies compared to their gynephilic counterparts. Moreover, there was no evidence that androphilic men's avuncular tendencies were more optimally designed (i.e., were more dissociated from their altruistic tendencies toward non-kin children) compared to gynephilic men. If an adaptively designed avuncular male androphilic phenotype exists and its development is contingent on a particular social environment, then the research presented here suggests that a collectivistic cultural context is insufficient, in and of itself, for the expression of such a phenotype. PMID- 21656334 TI - Phellinus baumii ethyl acetate extract inhibits lipopolysaccharide-induced iNOS, COX-2, and proinflammatory cytokine expression in RAW264.7 cells. AB - Mushrooms are valuable sources of biologically active compounds possessing anticancer, antiplatelet, and anti-inflammatory properties. Phellinus baumii is a mushroom used in folk medicine for a variety of human diseases. However, its potential anti-inflammatory effect has remained unclear. Therefore, we studied the effect of P. baumii ethyl acetate extract (PBEAE) on inflammatory mediator and proinflammatory cytokine protein and/or mRNA expression levels using the nitric oxide (NO) assay, enzyme immunoassay (EIA), western blot, and reverse transcription polymerase chain reaction (RT-PCR) in lipopolysaccharide (LPS) stimulated macrophage like RAW264.7 cells. PBEAE markedly inhibited NO generation and prostaglandin E(2) (PGE(2)) synthesis in a concentration-dependent pattern without any cytotoxic effect at the concentration range used. PBEAE also suppressed inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression. In addition, LPS-induced iNOS and COX-2 mRNA expression levels were dose-dependently inhibited by PBEAE pretreatment. Furthermore, PBEAE attenuated the mRNA expression levels of proinflammatory cytokines, specifically interleukin (IL)-1beta, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF), in a concentration-dependent fashion. Our study suggests that P. baumii might exhibit anti-inflammatory properties by downregulating proinflammatory mediators. Thus, further study on compounds isolated from PBEAE is warranted to investigate the associated molecular mechanisms and identify the potential therapeutic targets. PMID- 21656335 TI - Coptisine inhibits RANKL-induced NF-kappaB phosphorylation in osteoclast precursors and suppresses function through the regulation of RANKL and OPG gene expression in osteoblastic cells. AB - Excessive receptor activator of NF-kappaB ligand (RANKL) signaling causes enhanced osteoclast formation and bone resorption. The downregulation of RANKL expression and its downstream signals may be an effective therapeutic approach to the treatment of bone loss diseases such as osteoporosis. Here, we found that coptisine, one of the isoquinoline alkaloids from Coptidis Rhizoma, exhibited inhibitory effects on osteoclastogenesis in vitro. Although coptisine has been studied for its antipyretic, antiphotooxidative, dampness dispelling, antidote, antinociceptive, and anti-inflammatory activities in vitro and in vivo, its effects on osteoclastogenesis have not been investigated. Therefore, we evaluated the effects of coptisine on osteoblastic cells as well as osteoclast precursors for osteoclastogenesis in vitro. The addition of coptisine to cocultures of mouse bone marrow cells and primary osteoblastic cells with 10(-8) M 1alpha,25(OH)(2)D(3) caused significant inhibition of osteoclast formation in a dose-dependent manner. Reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed that coptisine inhibited RANKL gene expression and stimulated the osteoprotegerin gene expression induced by 1alpha,25(OH)(2)D(3) in osteoblastic cells. Coptisine strongly inhibited RANKL-induced osteoclast formation when added during the early stage of bone marrow macrophage (BMM) cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. Among the RANK signaling pathways, coptisine inhibited NF-kappaB p65 phosphorylations, which are regulated in response to RANKL in BMMs. Coptisine also inhibited the RANKL-induced expression of NFATc1, which is a key transcription factor. In addition, 10 MUM coptisine significantly inhibited both the survival of mature osteoclasts and their pit-forming activity in cocultures. Thus, coptisine has potential for the treatment or prevention of several bone diseases characterized by excessive bone destruction. PMID- 21656336 TI - EQ-5D as a predictor of mortality and hospitalization in elderly people. AB - PURPOSE: The objective of this study was to assess whether the EQ-5D independently predicts all-cause mortality and first hospitalization in a generic elderly population and to evaluate the relationship between the EQ-5D "Class of problems," the EQ-5D index, the EQ-Visual Analogue Scale (EQ-VAS), and the number of hospitalizations occurring over a 2-year period. METHODS: The data were collected in a longitudinal study (over 5 years) conducted on 9,644 elderly people in northern Italy with 5,256 completed questionnaires returned. Multivariate Cox's proportional hazards models were used to assess the effect of the EQ-5D questionnaire on 12 and 24 month mortality and first hospitalization risk, controlling for sociodemographic and medical covariates. Multivariate Zero Inflated Poisson models were performed to test the association between the EQ-5D "Class of problems," the EQ-5D index and EQ-VAS and the number of hospitalizations over 2 years. RESULTS: The EQ-5D "Class of problems," EQ-5D index, and EQ-VAS were consistently associated with mortality and first hospitalization rates. The EQ-VAS was associated with the number of hospitalizations over 2 years, though the EQ-5D "Class of problems" and EQ-5D index were not. CONCLUSIONS: The EQ-5D questionnaire is a useful predictor of mortality and first hospitalization in a generic elderly population in Italy. This suggests that it would be a good instrument for evaluating the effect of social/medical actions in a population-based study. PMID- 21656337 TI - Experiencing virtual patients in clinical learning: a phenomenological study. AB - Computerised virtual patients (VPs) are increasingly being used in medical education. With more use of this technology, there is a need to increase the knowledge of students' experiences with VPs. The aim of the study was to elicit the nature of virtual patients in a clinical setting, taking the students' experience as a point of departure. Thirty-one students used VPs as a mandatory part of an early clinical rotation in rheumatology. Using the qualitative approach of phenomenology, we interviewed these students and then analysed data regarding their experiences of VPs as a learning activity. The result shows that students perceived VP activities in relation to actual patients, the clinical context and other learning activities. The VPs represented typical clinical cases which encouraged clinical reasoning and allowed for decision making. The students experienced the activities as integrating biomedical knowledge and clinical experience, providing structure that prepared for the unstructured clinical environment and patient encounters under unstressful conditions. However, the VPs were experienced as lacking the emotional interactivity and complexity of actual patients. Theoretical frameworks of clinical reasoning and experiential learning are suggested as foundations for further educational integration of VPs in the clinical environment. VP activities during clinical rotations provide experiences of clinical reality and allow students to solve problems actively. These features are dependent on VP technology but are also contingent on the surrounding environment. PMID- 21656338 TI - High doses of oxycodone-naloxone combination may provide poor analgesia. AB - Several studies have shown that an oxycodone/naloxone combination (ratio 2:1) provides analgesia and less constipation in non-cancer patients receiving relatively low doses of this formulation. A case report of a cancer patient who was receiving increasing doses of oxycodone with an unexpected declining analgesia is presented. The substitution with the same doses (240 mg/day) of regular controlled-release oxycodone was effective in regaining adequate analgesia. PMID- 21656340 TI - Abstracts of the 2011 International MASCC/ISOO (Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology) Symposium. June 23-25, 2011. Athens, Greece. PMID- 21656339 TI - Knowledge, beliefs, and concerns about opioids, palliative care, and homecare of advanced cancer patients: a nationwide survey in Japan. AB - PURPOSE: Patients' knowledge, beliefs, or concerns about opioids, palliative care, and homecare can be potential barriers to providing quality palliative care. The primary aim of this study was to clarify knowledge about opioids, beliefs about palliative care, and concerns about homecare in advanced cancer patients. METHODS: An anonymous questionnaire was sent to 1,619 outpatients with advanced cancer at 25 hospitals in four different regions of Japan. The respondents were asked to report their knowledge about opioids, beliefs about palliative care, and concerns about homecare, in addition to the levels of their sense of security regarding receiving cancer care in the region. RESULTS: A total of 925 responses were received. In total, 28% believed that opioids are addictive and/or shorten life; 52% believed that palliative care is only for terminally ill patients; 75% agreed that being taken care of at home puts a heavy burden on the family; and 61% agreed that home-visit services cannot respond to sudden changes in a patient's condition. Levels of patients' sense of security were significantly higher in those who agreed that "opioids can relieve most pain caused by cancer" "palliative care relieves pain and distress", "palliative care is provided along with chemotherapy and/or radiation therapy", and "pain can be alleviated as effectively through home-visit services as it can at the hospital", and those who disagreed with the statements that "home-visit services cannot respond to sudden changes in a patient's condition" and "being taken care of at home puts a burden on the family". CONCLUSIONS: Advanced cancer patients frequently had incorrect knowledge about opioids, a belief that palliative care is only for terminally ill patients, and concerns about homecare, especially the family burden and responses to sudden changes. Providing appropriate information about the safety of opioids, the availability of palliative care during the entire course of the disease, and realistic information about homecare is of marked importance to promote patients' sense of security. PMID- 21656341 TI - Lethal encephalitis caused by the Toscana virus in an elderly patient. PMID- 21656342 TI - Neurological features in adult Triple-A (Allgrove) syndrome. AB - Triple-A or Allgrove syndrome is a rare multisystem disease classically associated with esophageal achalasia, adrenal insufficiency and alacrima. Here, we describe the poorly understood neurological characteristics often associated with this condition, through the clinical and electrophysiological analysis of eight patients. All patients were genetically confirmed and had a mutation in the ALADIN gene. They all displayed a classical picture of Triple-A syndrome: all suffered from achalasia and alacrima and half of them from adrenal insufficiency. However, all harbored a neurological picture characterized by a recognizable pattern of peripheral neuropathy. Other neurological features included cognitive deficits, pyramidal syndrome, cerebellar dysfunction, dysautonomia, neuro ophthalmological signs and bulbar and facial symptoms. This neurological picture was prominent in all patients and misled the initial diagnosis in six of them, which had a late onset. We then review the previous neurological reports of this disease, to improve the understanding of this rare condition. Diagnosis of late onset Triple-A syndrome is difficult when the clinical picture is mainly neurological and when endocrine or gastrointestinal signs are minor. The characteristics of the peripheral neuropathy, among other neurological signs, can be of help. PMID- 21656343 TI - Frequent alternate muscle activity of plantar flexor synergists and muscle endurance during low-level static contractions as a function of ankle position. AB - We have investigated the appropriate joint angle for detecting frequent alternating activity in synergistic muscles and the relationship between muscle activation patterns and endurance during static low-level contractions. Eleven healthy men performed prolonged static plantar flexion of the ankle at 10% of the maximal voluntary contraction, with the ankle flexed at 100 degrees , 110 degrees , or 120 degrees , while seated with the right leg in full extension. The onset of muscle activation and/or inactivation was detected using quantitative analysis, and alternate activity among muscles was detected using a threshold criterion of *e or *1/e multiplied by the levels of mean electromyograms (EMG) calculated at 1-min intervals. Surface EMG revealed frequent alternations of activity among the lateral and medial gastrocnemius and soleus muscles at an ankle flexion of 110 degrees . The first alternation occurred after approximately 15 min of exercise. The number of alternations per hour was four- to sevenfold higher at 110 degrees than at 100 degrees or 120 degrees . Endurance was longest and shortest at 110 degrees and 120 degrees , respectively. These findings suggest that synergistic motor pools activated at a specific joint angle (110 degrees ) affect muscle endurance during static low-level fatiguing tasks. PMID- 21656345 TI - Social determinants and surveillance in the new millennium. PMID- 21656344 TI - Transitive inference in adults with autism spectrum disorders. AB - Individuals with autism spectrum disorders (ASDs) exhibit intact rote learning with impaired generalization. A transitive inference paradigm, involving training on four sequentially presented stimulus pairs containing overlapping items, with subsequent testing on two novel pairs, was used to investigate this pattern of learning in 27 young adults with ASDs and 31 matched neurotypical individuals (TYPs). On the basis of findings about memory and neuropathology, we hypothesized that individuals with ASDs would use a relational flexibility/conjunctive strategy reliant on an intact hippocampus, versus an associative strength/value transfer strategy requiring intact interactions between the prefrontal cortex and the striatum. Hypotheses were largely confirmed. ASDs demonstrated reduced interference from intervening pairs in early training; only TYPs formed a serial position curve by test; and ASDs exhibited impairments on the novel test pair consisting of end items with intact performance on the inner test pair. However, comparable serial position curves formed for both groups by the end of the first block. PMID- 21656346 TI - Screening for vancomycin-resistant enterococci: an efficient and economical laboratory-developed test. AB - A laboratory-developed test (Lab Assay), combining enrichment broth and real-time polymerase chain reaction (PCR) for vancomycin-resistant enterococci (VRE) screening, was developed and evaluated in this study. A total of 1,765 faecal or rectal swabs sent to the laboratory for VRE screening were investigated in parallel by Lab Assay and the Roche LightCycler VRE detection kit-based method. The diagnostic values for Lab Assay were as follows: 100% sensitivity, 79.92% specificity, 1.94% positive predictive value and 100% negative predictive value, which were comparable to the results from the LightCycler kit-based assay. The detection limit of Lab Assay was 10(0) to 10(1) colony-forming units (CFU)/ml of inoculum in broth for both VanA-type and VanB-type VRE. The PCR method developed in this study was approved to be applicable on both the Applied Biosystems 7500 Fast Real-Time PCR System and the LightCycler((r)) 480 Real-Time PCR System. The flexibility in choosing PCR systems makes it possible that the PCR assay could be fully compatible with the DNA extraction's platform, providing an integrated workflow. Furthermore, the material cost is saved at 7EUR per sample when Lab Assay replaces the commercial kit-based method in our routine screening for VRE. Therefore, the laboratory-developed broth-PCR method is an efficient and economical assay for VRE screening. PMID- 21656347 TI - Home-based exercise therapy in patients with ankylosing spondylitis: effects on pain, mobility, disease activity, quality of life, and respiratory functions. AB - The home-based exercise therapy recommended to the patients with ankylosing spondylitis (AS) is a simply applicable and cheap method. The aim of this study was to investigate the effects of home-based exercise therapy on pain, mobility, function, disease activity, quality of life, and respiratory functions in patients with AS. Eighty patients diagnosed with AS according to the modified New York criteria were included in the study. Home-based exercise program including range of motion, stretching, strengthening, posture, and respiratory exercises was practically demonstrated by a physiotherapist. A training and exercise manual booklet was given to all patients. Patients following home-based exercise program five times a week at least 30 min per session (exercise group) for 3 months were compared with those exercising less than five times a week (control group). Visual analog scale pain (VASp) values at baseline were significantly higher in the exercise group. The exercise group showed improvements in VASp, tragus-wall distance, morning stiffness, finger-floor distance, modified Schober's test, chest expansion, the Bath Ankylosing Spondylitis Disease Activity Index, the Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL), forced expiratory volume in first second, and forced vital capacity at third month. There was significant difference in ASQoL scores between the two groups in favor of the exercise group at third month. Regular home-based exercise therapy should be a part of main therapy in patients with AS. Physicians should recommend that patients with AS do exercise at least five times a week at least 30 min per session. PMID- 21656348 TI - [Musicians' medicine: a broad field]. PMID- 21656351 TI - Angiotensin II-mediated Nrf2 down-regulation: a potential causing factor for renal fibrosis? AB - Epithelial-mesenchymal transition (EMT), a phenotype conversion of epithelial cells to myofibroblasts, is closely related with pathogenesis of renal fibrosis. Although it has been known that angiotensin II (ATII) stimulates EMT process in various cell types, the precise molecular mechanisms had not been clearly demonstrated. In this issue, Kang et al. show that AII suppresses NF-E2-related factor 2 (Nrf2) signaling and enhances transforming growth factor-beta1's activity to induce EMT in renal epithelial cells (Kang et al., 2011). They suggest that ATII-mediated EMT stimulating effect may result from the increased oxidative stress via defect in Nrf2-antioxidant system. This report proposes a possible mechanism of ATII-mediated renal fibrosis. PMID- 21656352 TI - Overcoming metastatic melanoma with BRAF inhibitors. AB - Melanoma has the capacity to spread via the blood stream to the brain, and has been notoriously resistant to drug therapy. An activating mutation in the gene encoding BRAF is known to be responsible for half of melanomas. This article provides a review of GSK2118436 and PLX4032 as potential therapeutics for the treatment of melanomas by inhibiting oncogenic BRAF. PMID- 21656353 TI - Isolation of chemical constituents from the aerial parts of Verbascum thapsus and their antiangiogenic and antiproliferative activities. AB - Phytochemical investigation of Verbascum thapsus led to the isolation and identification of one new iridoid compound named verbathasin A, along with ten known compounds. The structure and relative stereochemistry of verbathasin A were elucidated by analysis of spectroscopic data. All the isolates except 10 deoxyeucommiol and ajugol were tested for antiangiogenic and antiproliferative activities, and compounds luteolin and 3-O-fucopyranosylsaikogenin F showed promising antiproliferative activities, with an obvious effect of inducing apoptosis of A549 lung cancer cells. PMID- 21656354 TI - Modiolide and pyrone derivatives from the sea fan-derived fungus Curvularia sp. PSU-F22. AB - Investigation of secondary metabolites from the sea fan-derived fungus Curvularia sp. PSU-F22 resulted in isolation of three new metabolites, curvulapyrone (1), curvulalide (2) and curvulalic acid (3) together with six known compounds, modiolides A (4) and B (5), pyrenolide A (6), stagonolide E (7), mycoepoxydiene (8), and deacetylmycoepoxydiene (9). Their antimicrobial activity against Staphylococcus aureus ATCC 25923, methicillin-resistant S. aureus and Microsporum gypseum SH-MU-4 were examined. PMID- 21656355 TI - Chemical constituents from Lobelia chinensis and their anti-virus and anti inflammatory bioactivities. AB - In total, forty six compounds, including the novel compound lobechine (1), were characterized from the methanol extracts of Lobelia chinensis. The chemical structures of known metabolites were identified by comparing their spectroscopic and physical data with compounds reported in the literature. The structure of lobechine (1) was comprehensively established with the aid of 1D and 2D NMR spectroscopic analyses. In addition, selected isolates were screened for their inhibition of HSV-1 replication, superoxide anion generation, and elastase release. Among the tested compounds, scoparone (10) exhibited significant inhibition of superoxide anion generation with IC(50) of 6.14 +/- 1.97 MUM and lobechine (1) exhibited moderate inhibition of elastase release with IC(50) of 25.01 +/- 6.95 MUM, respectively. PMID- 21656356 TI - A new cytotoxic coumarin, 7-[(E)-3',7'-dimethyl-6'-oxo-2',7'-octadienyl] oxy coumarin, from the leaves of Zanthoxylum schinifolium. AB - A new coumarin, 7-[(E)-3',7'-dimethyl-6'-oxo-2',7'-octadienyl]oxy coumarin (1), together with three known compounds, schinilenol (2), schinindiol (3) and 7-[(E) 7'-hydroxy-3',7'-dimethylocta-2',5'-dienyloxy]-coumarin (4) were isolated from the methylene chloride fraction of Z. schinifolium by normal and reverse phase column chromatographies. Their structures were determined on the basis of physical and spectroscopic evidences. Compound 1 (IC(50) 8.10 MUM) showed potent cytotoxicity compared to auraptene (IC(50) 55.36 MUM) against Jurkat T cells. The other isolated compounds 2 and 4 exhibited weak cytotoxicities. PMID- 21656357 TI - The conformation and CETP inhibitory activity of [10]-dehydrogingerdione isolated from Zingiber officinale. AB - In the course of searching for cholesteryl ester transfer protein (CETP) inhibitors from natural sources, a new type of CETP inhibitor, [10] dehydrogingerdione (1), was isolated from the extract of rhizomes of Zingiber officinale Roscoe. By NMR spectroscopic analysis of its (1)HNMR, (13)C-NMR, and (1)H-(1)H COSY, HMBC, HMQC and NOESY, more precise structure, compared with its originally proposed structures, of [10]-dehydrogingerdione has been elucidated. This active compound inhibited human plasma CETP with IC(50) values of 35 MUM. PMID- 21656358 TI - Design and characterization of colon-specific drug delivery system containing paracetamol microsponges. AB - The present work was aimed at designing microsponge based colon specific drug delivery system containing paracetamol. Eudragit S-100 based microsponges containing drug in varying amounts were prepared using quasi-emulsion solvent diffusion method. The microsponges were prepared by optimizing various process parameters. DSC and FTIR studies indicated compatibility of the drug in various formulations. Shape and surface morphology of the microsponges were examined using scanning electron microscopy. The formulations were subjected to in vitro release studies and the results were evaluated kinetically and statistically. The in vitro release data showed a bi-phasic pattern with an initial burst effect. In the first hour drug release from microsponges was found to be between 18-30%. The cumulative percent release at the end of 12(th) hour was noted to be between 74 98%. The release kinetics showed that the data followed Higuchi model and the main mechanism of drug release was diffusion. The colon specific tablets were prepared by compressing the microsponges followed by coating with pectin: hydroxypropylmethyl cellulose (HPMC) mixture. In vitro release studies exhibited that compression coated colon specific tablet formulations started releasing the drug at 6(th) hour corresponding to the arrival time at proximal colon. The study presents a new approach for colon specific drug delivery. PMID- 21656359 TI - High-performance liquid chromatographic determination and pharmacokinetic study of apigenin-7-O-beta-D-glucoside in rat plasma after intravenous administration. AB - The present study was designed to validate an analytical method based on HPLC for the quantitative measurement of the Apigenin-7-O-beta-D-glucoside (AGL) in rat plasma after intravenous administration. HPLC analysis was done using a C18 column, UV detection at 335 nm, and a mobile phase of methanol:0.2% phosphoric acid (1:1, v/v). Good linearity was observed over the range of 0.06-7.20 MUg/mL with a lower limit of quantication of 0.06 MUg/mL. The intra-and inter-day precision values were below 9.97%. No interference peaks or matrix effects were observed. The method was fully validated and successfully applied to a pharmacokinetic study of AGL. PMID- 21656360 TI - Roles of MgO release from polyethylene glycol 6000-based solid dispersions on microenvironmental pH, enhanced dissolution and reduced gastrointestinal damage of telmisartan. AB - The roles of magnesium oxide (MgO) release from solid dispersions (SDs) in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and water were investigated to elucidate the enhanced dissolution and reduced intestinal damages of telmisartan as a model drug. The polyethylene glycol 6000 (PEG 6000) was used to prepare the SDs. Three SDs were prepared: SD1 (PEG, MgO, TEL), SD2 (PEG 6000, TEL), SD3 (MgO, TEL). The physical mixture (PM) consisting of SD2 and MgO was also prepared. A binary SD without MgO (SD2) was also prepared for comparison in microenvironmental pH (pH(M)) modulation. The faster MgO released, the less control of pH(M) and the less enhanced dissolution of TEL were in consequences. SD3 increased dissolution in SIF and water (about 67%). Interestingly, ternary SD1 showed almost complete dissolution in all three media but dissolution of PM was the lowest due to the fast release of MgO and poor modulation of pH(M). MgO did not change the drug crystallinity but did have a strong molecular interaction with the drug. Additionally, the SD3-bearing tablet quickly increased pH(M) but then gradually decreased due to faster release of MgO while the SD1-bearing tablet gradually increased pH(M) at all fractional dimensions of the tablet by the MgO slowly released. The pH(M) of PM-bearing tablets was not varied as a function of time. Thus, the MgO-bearing SD1 also minimized gastrointestinal tissue damage caused by the model drug. PMID- 21656361 TI - Improving the solubility and bioavailability of dihydroartemisinin by solid dispersions and inclusion complexes. AB - Dihydroartemisinin (DHA) is a poorly water-soluble drug that displays low bioavailability after oral administration. Attempts have been made to improve the solubility of DHA. Yet, no information is available concerning improved bioavailability. This study aimed to improve the water solubility of DHA by two systems: solid dispersions with polyvinylpyrrolidone (PVPK30, PVPK25, PVPK15) and inclusion complexes with hydroxypropyl-beta-cyclodextrin (HPbetaCD), as well as improving the bioavailability of both systems. The phase transition of DHA with hydrophilic polymers was evaluated by X-ray diffraction (XRD) and differential scanning calorimetery (DSC). DHA became amorphous in DHA-HPbetaCD complexes and showed more amorphous behavior in XRD analyses with rise in molecular weight of PVP. Melting onset temperature of DHA decreased, while DSC thermograms revealed the peak area and enhanced enthalpy change (DH) in solid dispersions as well as inclusion complexes. DHA solubility was enhanced 84-fold in DHA-HPbetaCD complexes and 50-times in DHA-PVPK30. The improved solubility using the four polymers was in the following order: HPbetaCD > PVPK30 > PVPK25 > PVPK15. Values of area under curve (AUC) and half life (t(1/2)) of DHA-PVPK30 were highest followed by DHA-HPbetaCD, DHA-PVPK15 and DHA-PVPK25. V(d)/f of DHA-PVPK30 was 7 fold. DHA-HPbetaCD, DHA-PVPK15 and DHA-PVPK25 showed significantly different pharmacokinetic parameters compared with DHA solutions. The 95% confidence interval was meaningful in AUC and t(1/2). Pharmacokinetic parameters revealed that all four-test preparations were significantly more bioavailable than DHA alone. PMID- 21656362 TI - Effects of silymarin nanoemulsion against carbon tetrachloride-induced hepatic damage. AB - Silymarin is a complex mixture of four flavonolignan isomers (silybin, isosilybin, silydianin and silychristin) obtained from 'milk thistle' (Silybum marianum). This plant compound is used almost exclusively for hepatoprotection. Because of its low and poor oral bioavailability, silymarin was formulated as a nanoemulsion to increase its solubility (and so its oral bioavailability) as well as therapeutic activity. The present study assessed the hepatoprotective activity on Wistar rats by determining biochemical parameters and histopathological properties of the nanoemulsion formulation of silymarin against carbon tetrachloride (CCl(4))-induced hepatotoxicity. Hepatoprotective activity was evaluated by the activity of serum alkaline phosphatase, alanine transaminase and aspartate transaminase; antioxidative defence markers (concentration of reduced glutathione); oxidative stress parameter (thiobarbituric acid reactive substances) and liver histopathology. The nanoemulsion-treated group showed significant decreases in glutamate oxaloacetate transaminase, pyruvate transaminase, alkaline phosphotase, total bilirubin and tissue lipid peroxides and increased total protein, albumin, globulin and tissue glutathione as compared to toxicant. The results indicate an excellent potential of the nanoemulsion formulation for the reversal of CCl(4)-induced liver toxicity in rats as compared to standard silymarin. PMID- 21656363 TI - Solid state of CG-400549, a novel FabI inhibitor: characterization, dissolution, transformation. AB - The polymorphic and pseudopolymorphic forms of CG-400549, a novel FabI inhibitor with potent in vivo activity were prepared and characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and thermogravimetric analysis (TG). Seven crystal forms of CG-400549, one anhydrate and six solvates, have been isolated by recrystallization and the DSC and PXRD patterns of the seven crystal forms of CG-400549 were different respectively. The dissolution patterns of these seven crystal forms of CG-400549 were studied and they showed significant differences in the dissolution rate. After storage of 1 month at 0% RH (silica gel, 20 degrees C), 52% RH (saturated solution of Na(2)Cr(2)O(7)2H(2)O/20 degrees C) and 95% RH (saturated solution of Na(2)HPO(4)/20 degrees C), all crystal forms were not transformed. PMID- 21656364 TI - Inhibition of invasion and metastasis of MHCC97H cells by expression of snake venom cystatin through reduction of proteinases activity and epithelial mesenchymal transition. AB - Snake venom cystatin (sv-cystatin) is a member of the cystatin family of cysteine protease inhibitors. To further evaluate the possibility of sv-cystatin in cancer therapy, this study examined the effects of sv-cystatin on the invasion and metastasis of liver cancer cells (MHCC97H) in vitro and in vivo as well as the underlying mechanism. sv-cystatin cDNA was transfected into MHCC97H cells and the anti-invasion and antimetastasis effects of sv-cystatin were determined using migration and matrigel invasion assays and a lung-metastasis mice model. The results suggest that sv-cyst clone (sv-cystatin expression in MHCC97H cells) delayed the invasion and metastasis in vitro and in vivo compared to the parental, mock and si-sv-cyst clone cells (inhibited sv-cystatin expression by siRNA). The decreased activities of cathepsin B, MMP-2 and MMP-9 and EMT change index including higher E-cadherin, lower N-cadherin and decreased Twist activity were observed in the sv-cyst clone, which contributes to the change in invasion and metastasis ability of MHCC97H cells. This study provides evidence that expression of the sv-cystatin gene in MHCC97H cells inhibits tumor cell invasion and metastasis through the reduction of the proteinases activity and Epithelial Mesenchymal Transition (EMT), which might contribute to the anticancer research of the sv-cystatin protein. PMID- 21656365 TI - Induction of apoptosis by chelerythrine chloride through mitochondrial pathway and Bcl-2 family proteins in human hepatoma SMMC-7721 cell. AB - The objective of this study was to evaluate the antitumor activity of chelerythrine chloride (CHE) and investigate its potential apoptotic induction mechanism in SMMC-7721 cells. Our results suggested that the proliferation of SMMC-7721 cells was inhibited by CHE in a time and dose dependent manner, with a significant accumulation in S phase, and the cells exhibited typical apoptotic features. Moreover, CHE remarkably induced apoptosis by disruption of the mitochondrial membrane potential, release of Cyt-c, activation of caspase-3, and cleavage of poly-ADP-ribose polymerase in a dose dependent manner. Furthermore, the expression of Bcl-xl was downregulated while Bax and Bid expression was upregulated, and no variation was found for Bcl-2. These results indicated that CHE may play an important role in suppression of tumor growth by inducing apoptosis in human hepatoma cells via the activation of a mitochondrial pathway and regulating the expression of Bcl-2 family proteins. PMID- 21656366 TI - Comparative evaluation of the antioxidant effects of the natural vitamin C analog 2-O-beta-D-glucopyranosyl-L-ascorbic acid isolated from Goji berry fruit. AB - 2-O-beta-D-Glucopyranosyl-L-ascorbic acid (AA-2betaG) is a natural derivative of vitamin C (Lascorbic acid, AA) isolated from Goji berry (Lycium barbarum L.) fruit. We evaluated the antioxidant activities of AA-2betaG and AA using in vitro and in vivo model systems. In vitro radical scavenging assays demonstrated that AA-betaG was capable of scavenging 1,1-diphenyl-2-picryl-hydrazyl and hydroxyl peroxide and inhibiting H(2)O(2)-induced hemolysis better than AA. AA-2betaG and AA had similar hydroxyl radical scavenging capabilities, but AA-2betaG was incapable of scavenging superoxide anion radicals, and its capacity to scavenge nitrite (NO(2) (-)) was lower than that of AA. The overall in vitro reduction capability of AA-2betaG was also significantly lower than that of AA. Moreover, in vivo studies demonstrated that AA-2betaG was capable of protecting the liver against carbon tetrachloride-induced acute liver injury in mice. These results suggest that AA-2betaG is an important antioxidant component of Goji berry fruit, which may share similar but distinct antioxidant mechanistic properties with AA. This study furthers our understanding of the mechanisms of Goji berry fruit pharmacological activities on antiaging and antitumor properties as a traditional medicine and dietary supplement. PMID- 21656367 TI - Inhibition of UVA-mediated melanogenesis by ascorbic acid through modulation of antioxidant defense and nitric oxide system. AB - Ascorbic acid (AA) has been well known as a skin whitening agent, although attempts have been made to evaluate its protective role against ultraviolet (UV) induced skin hyperpigmentation or increased melanin production. While melanogenesis is a defense mechanism of the skin against UV irradiation, melanin overproduction may also contribute to melanoma initiation. UVA might play a role in melanogenesis through promoting oxidative stress, which occurs as the result of increased formation of oxidants and/or reactive nitrogen species (RNS) including nitric oxide (NO). Therefore, we investigated the antimelanogenic effect of AA (7.5-120 MUM) in association with its inhibitory effect on UVA induced oxidant formation, NO production through endothelial and inducible NO synthases (eNOS and iNOS) activation and impairment of antioxidant defense using G361 human melanoma cells. Our study demonstrated a comparable ability of AA with that of kojic acid, a well-known tyrosinase inhibitor in inhibiting mushroom tyrosinase. Melanin content was reduced by AA, but neither tyrosinase activity nor mRNA levels were reduced by AA at non-cytotoxic concentrations in UVA irradiated G361 cells. AA was shown to inhibit UVA-mediated catalase (CAT) inactivation, glutathione (GSH) depletion, oxidant formation and NO production through suppression of eNOS and iNOS mRNA. We report herein that AA can protect against UVA-dependent melanogenesis possibly through the improvement of antioxidant defense capacity and inhibition of NO production through down regulation of eNOS and iNOS mRNA. PMID- 21656368 TI - Mechanisms underlying the protective effect of eugenol in rats with acute doxorubicin cardiotoxicity. AB - The protective effect of eugenol and its possible mechanisms were investigated in rats with acute doxorubicin cardiotoxicity. Cardiac toxicity was induced by a single intraperitoneal injection of doxorubicin (20 mg/kg). Eugenol treatment (5 mg/kg/day, orally) was started 2 days before doxorubicin administration and continued for five consecutive days. Eugenol significantly reduced the elevated serum creatine kinase and lactate dehydrogenase levels, and restored the electrocardiographic disturbances resulted from doxorubicin administration. Also, eugenol reversed doxorubicin-induced deficits in the antioxidant defense mechanisms, decreased lipid peroxidation and attenuated the elevations in cytosolic Ca(2+) and nitric oxide levels in cardiac tissue. In addition, doxorubicin-induced cardiac tissue damage observed by histopathological examination was markedly ameliorated with eugenol. Immunohistochemical analysis revealed that eugenol prevented the doxorubicin-induced activation of caspase-3 in cardiomyocytes. The cardioprotective effect afforded by eugenol was not significantly inhibited by prior administration of capsazepine, the transient potential vanilloid receptor-1 antagonist. It was concluded that eugenol, through its antioxidant activity and its ability to reduce cardiac Ca(2+) accumulation and nitric oxide levels, is a potential candidate to protect against acute doxorubicin cardiotoxicity, a major and dose-limiting clinical problem. PMID- 21656369 TI - Suppression of Nrf2 signaling by angiotensin II in murine renal epithelial cells. AB - Angiotensin II (ATII), a physiologically active mediator of the renin-angiotensin system, has been shown to be associated with renal fibrosis pathophysiology. In our current study with murine renal epithelial TCMK-1 cells, ATII inhibited the expression of NF-E2-related factor 2 (Nrf2)-target antioxidant genes such as NAD(P)H: quinone oxidoreductase-1 and gamma-glutamate cysteine ligase (GCL). In accord to the reduced expression of GCL, a GSH biosynthesis enzyme, ATII treatment reduced intracellular GSH content and increased the levels of reactive oxygen species (ROS). While, there was no significant changes in nuclear protein levels of Nrf2 following ATII treatment, implying the potential alterations in the expression of partner proteins of Nrf2. Our measurement of Nrf2 partner bZIP transcription factors, including Bach1, small Maf proteins, and activating transcription factor 3 (ATF3) showed that the expression level for ATF3 was enhanced in ATII-treated TCMK cells. Presumably through ATII-induced oxidative stress, ATII treatment was found to enhance the inducible level of TGFbeta mediated alpha-smooth muscle actin (alpha-SMA) expression, which is one of molecular markers of renal fibrosis. In conclusion, our results indicate that ATII suppresses Nrf2-GSH signaling in murine renal epithelial cells. Elevated ROS levels in ATII exposed epithelial cells might be a causing factor contributing to renal fibrosis pathology. PMID- 21656370 TI - Interference of alpha-synuclein with cAMP/PKA-dependent CREB signaling for tyrosine hydroxylase gene expression in SK-N-BE(2)C cells. AB - Alpha-synuclein (alpha-SYN) is a small and highly conserved presynaptic protein that is implicated in both normal brain function and the pathogenesis of neurodegenerative diseases. Although the physiological function of alpha-SYN has not been fully evaluated, several lines of evidence suggest that it plays an important role in the regulation of dopamine homeostasis in the brain. Early studies have demonstrated that interaction of alpha-SYN and tyrosine hydroxylase (TH), a rate-limiting enzyme in dopamine synthesis, is functionally significant for dopaminergic neurotransmission and the pathophysiology of Parkinson's disease. In the present study, we would like to evaluate whether overexpression of wild-type or mutant alpha-SYN might affect cAMP/PKA-dependent TH activation in DA-producing SK-N-BE(2)C cells. Here we show that wild-type and mutant A30P and A53T alpha-SYN attenuate forskolin-induced TH up-regulation, but do not suppress TH basal expression in SK-N-BE(2)C cells. Forskolin-induced increase in TH promoter activity and CRE-dependent transcription are significantly suppressed in alpha-SYN-overexpressing cells. Alpha-SYN enters the nucleus, but does not bind to CREB or interfere with forskolin-induced CREB phosphorylation. These data indicate that elevated levels of alpha-SYN due to a specific disease or the normal aging process could be associated with dopaminergic neuronal dysfunction through interference with TH regulation. PMID- 21656371 TI - Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats. AB - Chlorogenic acid (5-O-caffeoylquinic acid, CA), a phenolic compound found ubiquitously in plants, has antidiabetic effect in diabetic animal models. In this study, we investigated the inhibitory effect of CA on diabetic cataractogenesis. We evaluated the aldose reductase (AR) activity during cataract development in 50% galactose-fed rats, an animal model of sugar cataract. Galactose-fed rats were treated orally with CA (10 and 50 mg/kg body weight) once a day for 2 weeks. In vehicle-treated galactose-fed rats, lens opacity was increased, and lens fiber swelling and membrane rupture were observed. In addition, AR protein was highly expressed in lens epithelial cells and lens cortical fibers of galactose-fed rats. However, CA inhibited the rat AR activity in vitro, and the administration of CA prevented the development of sugar cataract through the inhibition of AR activity. These observations suggest that CA is useful for the treatment of sugar cataract. PMID- 21656372 TI - Antiarthritic effect of lonicerin on Candida albicans arthritis in mice. AB - Fungal arthritis is a potentially serious disease resulting in rapid destruction of the joint. Among the various Candida species, Candida albicans is the most commonly associated with fungal arthritis. In the present study, we examined the effect of lonicerin, a flavonoid isolated from Lonicerae Flos, on an arthritis caused by C. albicans cell wall (CACW) in mice. To examine the effect, an emulsified mixture of CACW and complete Freund's adjuvant (CACW/CFA) was injected into BALB/c mice via hind footpad route on days -3, -2, and -1. On Day 0, mice with the swollen footpad received lonicerin at 1 or 2 mg/dose/time intraperitoneally 3 times every other day. The footpad-swelling was measured for 20 days. Results showed that the lonicerin treatment reduced the edema at all dose levels, and, furthermore, there was app. 54% edema reduction in animals given the 2 mg-dose at the peak (day 10) of septic arthritis (p < 0.05). Since the peak, the edema was reduced in similar rates. This antiarthritic activity appeared to be mediated by lonicerin's ability to suppress T cell proliferation, nitric oxide production from macrophages, and shift of cellular immunity from Th1 toward Th2-type responses, all of which are beneficial to treat arthritis. In addition, the flavonoid had anticandidal activity (p < 0.01). These data suggest that lonicerin alone, which has both anti-arthritic and antifungal activities, can result in a combination therapy for the treatment of fungal arthritis due to C. albicans infection. PMID- 21656373 TI - The stability of solitons in biomembranes and nerves. AB - We examine the stability of a class of solitons, obtained from a generalization of the Boussinesq equation, which have been proposed to be relevant for pulse propagation in biomembranes and nerves. These solitons are found to be stable with respect to small-amplitude fluctuations. They emerge naturally from non solitonic initial excitations and are robust in the presence of dissipation. Solitary waves pass through each other with only minor dissipation when their amplitude is small. Large-amplitude solitons fall apart into several pulses and small-amplitude noise upon collision when the maximum density of the membrane is limited by the density of the solid phase membrane. PMID- 21656374 TI - Measuring surface and bulk relaxation in glassy polymers. AB - We present a comprehensive study of gold nanoparticle embedding into polystyrene (PS) surfaces at temperatures ranging from T ( g ) + 8 K to T ( g ) - 83 K and times as long as 10(5) minutes. This range in times and temperatures allows the first concurrent observation of and differentiation between surface and bulk behavior in the 20 nm region nearest the free surface of the polymer film. Of particular importance is the temperature region near the bulk glass transition temperature where both surface and bulk processes can be measured. The results indicate that for the case of PS, enhanced surface mobility only exists at temperatures near or below the bulk T ( g ) value. The surface relaxation times are only weakly temperature dependent and near T ( g ), the enhanced mobility extends less than 10nm into the bulk of the film. The results suggest that both the concept of a "surface glass transition" and the use of glass transition temperatures to measure local mobility near interfaces may not universally apply to all polymers. The results can also be used to make a quantitative connection to molecular dynamics simulations of polymer films and surfaces. PMID- 21656375 TI - Concepts in projection-reconstruction. AB - The Achilles heel of conventional multidimensional NMR spectroscopy is the long duration of the measurements, set by the Nyquist sampling condition and the resolution requirements in the evolution dimensions. Projection-reconstruction solves this problem by radial sampling of the evolution-domain signals, relying on Bracewell's Fourier transform slice/projection theorem to generate a set of projections at different inclinations. Reconstruction is implemented by one of three possible deterministic back-projection schemes (additive, lowest-value, or algebraic), or by a statistical model-fitting program. For simplicity the treatment focuses principally on the three-dimensional case, and then extends the analysis to four dimensions. The concept of hyperdimensional spectroscopy is described for dealing with even higher dimensions. PMID- 21656376 TI - Visualization support for the planning of hepatic needle placement. AB - PURPOSE: Percutaneous image-guided interventions, such as radiofrequency ablation or biopsy, are using needle-shaped instruments which have to be inserted into a target area without penetrating any vital structure. The established planning workflow is based on viewing 2D slices of a pre-interventional CT or MR scan. However, access paths not parallel to the axial plane are often necessary. For such complicated cases, the planning process is challenging and time consuming if solely based on 2D slices. To overcome these limitations while keeping the well established workflow, we propose a visualization method that highlights less suited paths directly in the 2D visualizations with which the radiologist is familiar. METHODS: Based on a user defined target point and segmentation masks of relevant risk structures, a risk structure map is computed using GPU accelerated volume rendering and projected onto the 2D slices. This visualization supports the user in defining safe linear access paths by selecting a second point directly in the 2D image slices. RESULTS: In an evaluation for 20 liver radiofrequency ablation cases, 3 experienced radiologists stated for 55% of the cases that the visualization supported the access path choice. The visualization support was rated with an average mark of 2.2. For 2 of the 3 radiologists, a significant reduction of the planning duration by 54 and 50% was observed. CONCLUSIONS: The proposed visualization approach can both accelerate the access path planning for radiofrequency ablation in the liver and facilitate the differentiation between safer and less safe paths. PMID- 21656377 TI - KRAS assay selection: sensitivity and accuracy in clinical application. AB - KRAS mutation status is routinely tested before the administration of chemotherapeutic agents that target EGFR such as cetuximab and panitumumab. Various commercial assays to analyze KRAS mutational status are currently certified for in vitro diagnostic use. However, the differences in the operational characteristics of the different assays have not been investigated. Since different assays could be different in specificity, sensitivity and precision, studies to clarify the best option for an adequate determination of KRAS mutation status are necessary. Until a gold standard for testing KRAS mutation status is established, the treating physician must interpret the results of any given assay keeping this limitation in mind. PMID- 21656378 TI - RNASEL Asp541Glu and Arg462Gln polymorphisms in prostate cancer risk: evidences from a meta-analysis. AB - Epidemiological studies have evaluated the association between RNASEL Asp541Glu and Arg462Gln polymorphisms and prostate cancer (PCa) risk. However, the results remain inconclusive. To derive a more precise estimation of the association between RNASEL polymorphisms and PCa risk, we performed a meta-analysis based on nineteen case-control studies. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, we found that both Asp541Glu and Arg462Gln polymorphisms were not associated with PCa risk (for Asp541Glu polymorphism: Glu/Glu vs. Asp/Asp: OR 1.17, 95% CI: 0.95-1.45, P = 0.13; Glu/Asp vs. Asp/Asp: OR 1.02, 95% CI: 0.92-1.14, P = 0.70; for Arg462Gln polymorphism: Gln/Gln vs. Arg/Arg: OR 0.98, 95% CI: 0.88-1.08, P = 0.62; Gln/Arg vs. Arg/Arg: OR 0.97, 95% CI: 0.91-1.04, P = 0.53). The insignificant association was maintained in the dominant and the recessive genetic models. In subgroup analyses, the significant association was not detected in Caucasian populations. However, we found the significant association of RNASEL Asp541Glu polymorphism with sporadic PCa (Glu/Glu vs. Asp/Asp: OR 1.29, 95% CI: 1.04-1.59, P = 0.02; Glu/Asp vs. Asp/Asp: OR 1.24, 95% CI: 1.03-1.50, P = 0.03). In conclusion, we found that these RNASEL polymorphisms were not related to overall PCa risk, especially in Caucasians. However, in subgroup analyses we found a suggestion that RNASEL 541Gln allele might be a low-penetrent risk factor for sporadic PCa. PMID- 21656379 TI - Expression of Eph A molecules during swine embryo implantation. AB - Eph-Ephrin system can induce repulsive forces in cell migration and adhesion during embryonic development in various mammals. In this study, the attachment sites of swine endometrium during pregnancy were used and the physiological role of this system in the step of mammalian embryo implantation was estimated to investigate the involvement of the Eph-Ephrin system in swine embryo implantation. Real-time quantitative PCR indicated that mRNA expression of Eph A1 on endometrium increased extremely significantly around the implantation period (P < 0.01), while expression of Eph A2 and A4 decreased significantly during this period (P < 0.05). Immunostaining showed that protein expression of Eph A1, A2 and A4 in the endometrial stroma underlying the luminal epithelium was higher during mid-implantation compared with early or post-implantation. Western blotting examination demonstrated that protein expression of Eph A1, A2 and A4 at the attachment sites of swine endometrium increased from pregnancy day 13 to 18 (P < 0.01), and then decreased from pregnancy day 18 to 24 (P < 0.01). These findings suggest that the Eph-Ephrin A system might play an important role in regulating the swine contact between blastocysts and endometrium during embryo implantation. PMID- 21656380 TI - MiR-106a inhibits glioma cell growth by targeting E2F1 independent of p53 status. AB - MicroRNAs are single-stranded small non-coding RNA molecules which regulate mammalian cell growth, differentiation, and apoptosis by altering the expression of other genes and play a role in tumor genesis and progression. MiR-106a is upregulated in several types of malignancies and provides a pro-tumorigenic effect. However, its role in glioma is largely unknown. Our findings demonstrate that the low expression of miR-106a in human glioma specimens is significantly correlated with high levels of E2F1 protein and high-grade glioma. Here, we present the first evidence that miR-106a provides a tumor-suppressive effect via suppressing proliferation of and inducing apoptosis in human glioma cells. We further show that E2F1 is a direct functional target of miR-106a, suggesting that the effect of miR-106a on the glioma suppressive effect may result from inhibition of E2F1 via post-transcriptional regulation. In addition, our results reveal that miR-106a can increase p53 expression via E2F1 inhibition, whereas the effect of miR-106a on the proliferation of glioma cells is independent of p53 status. Further investigations will focus on the therapeutic use of miR-106a mediated antitumor effects in glioma. PMID- 21656382 TI - Anatomical considerations for safe scapular resection in snapping scapula syndrome. AB - BACKGROUND: The resection of the superomedial angle of the scapula in snapping scapula syndrome is associated with potential risk of injury to the suprascapular nerve. The aim of the present study was to determine the distance of site of resection on the upper border of the scapula from the suprascapular notch during arthroscopic resection of the superomedial angle using standard superior Bell's and medial portals at the middle of medial border. MATERIALS AND METHODS: The study was conducted on 92 intact dry adult scapulae of unknown sex. The junction of the medial two-thirds and the lateral one-third of an imaginary line joining the superomedial angle and the lateral margin of the acromion was marked as superior Bell's portal. The middle of the medial border was considered as the arthroscopic resection target. The site of resection on the upper border was found out with the help of these two points and other relevant measurements were also taken. RESULTS: The distance between the suprascapular notch and the lateral edge of resection on the upper border of the scapula was more than 10 mm in 85.9% cases and less than 10 mm in 14.1%. A statistically significant positive correlation was found between this distance and the distance between the superior angle and acromion angle of the scapula. CONCLUSION: Our study suggests that during arthroscopic resection using superior Bell's portal and medial portal, suprascapular notch hence the suprascapular nerve would have safe margin of more than 10 mm from the resection site on upper border in 85.9% cases and would be vulnerable to injury in 14% cases. The procedure would be safer in patients with a wider scapula. PMID- 21656381 TI - Thyrolingual trunk arising from the common carotid artery identified by three dimensional computed tomography angiography. AB - It is well-known that the branches of the external carotid artery (ECA) can show anatomical variation, but it is extremely rare that thyrolingual trunk originates from common carotid artery (CCA). Here we report a case of the thyrolingual trunk arising from the CCA on the right side in a 73-year-old female as revealed by three-dimensional computed tomography angiography for vascular mapping of the carotid vessels before head and neck microsurgical reconstruction. The thyrolingual trunk arose from the anterior surface of the right CCA, with an origin 14.5 mm (difference between the carotid bifurcation and upper border of the origin 12.7 mm) below the carotid bifurcation. The inner diameter of origin of the thyrolingual trunk was 3.5 mm, and the angle between the thyrolingual trunk and the CCA was 130 degrees . After a 10.2-mm course, the thyrolingual trunk divided into the superior thyroid artery (STA) and lingual artery (LA). The inner diameters of the origins of the STA and LA were 1.7 and 1.9 mm, respectively, and the angle between the branches was 94 degrees . It is important to recognize this anatomic variation of the branches of the ECA before the microsurgical reconstruction or super-selective intra-arterial chemotherapy for head and neck cancer. PMID- 21656385 TI - Discoloration of teeth from tetracyclines--even today? AB - The aim of this study was to examine whether brownish crown and root discoloration of wisdom teeth was related to treatment of acne with tetracyclines. For this purpose, 17 discolored third molars from nine patients were embedded without being decalcified, ground along the tooth axis, and examined using fluorescence microscopy. A thorough medical history served to determine the start and duration of any administration of tetracyclines. This confirmed the use of drugs against acne containing minocycline in all cases except one. The microscopic analyses of all teeth revealed intensely fluorescent bands in the dentin, which corresponded to the mineralization front at the time of tetracycline intake. More or less uniform discoloration of the entire crown was seen in association with treatment against acne prior to the completion of crown formation at the age of about 15 years. This uniform staining can be attributed to incorporation of minerals during ongoing maturation of the occlusal enamel, which is concomitant with the formation of the cervical crown regions. When acne was treated between 15 and 22 years of age, only the roots of the third molars displayed annular discolorations, which seemed to result from the incorporation of tetracyclines into dentin, while fine fluorescent incremental lines in root cementum were too thin to be apparent clinically. Three accidentally removed interradicular bony septa revealed that tetracyclines incorporated into alveolar bone remained there for about 2 years, but thereafter disappeared as a result of physiological remodelling. PMID- 21656386 TI - In vitro effect of chlorhexidine mouth rinses on polyspecies biofilms. AB - The aim of this study was to use the Zurich polyspecies biofilm model to compare the antimicrobial effects of chlorhexidine mouth rinses available on the Swiss market. As positive and negative controls, aqueous 0.15% CHX solution and water were used, respectively. In addition, Listerine(r) without CHX was tested. Biofilms in batch culture were grown in 24- well polystyrene tissue culture plates on hydroxyapatite discs in 70% mixed (1:1 diluted) unstimulated saliva and 30% complex culture medium. During the 64.5-hour culturing period, the biofilms were exposed to the test solutions for 1 minute twice a day on two subsequent days. Thereafter, the biofilms were dip-washed 3 times in physiological NaCl. Following the last exposure, the incubation of biofilms was continued for another 16 h. They were then harvested at 64.5 h. The dispersed biofilms were plated on 2 agar media. After incubation, colonies (CFU) were counted. All solutions containing CHX as well as Listerine (r) significantly reduced the number of microorganisms in biofilms. According to their efficacy, the mouth rinses were classified into 2 groups. The two Curasept ADS solutions, Parodentosan, and the Listerine(r) mouth rinse reduced the number of total CFU by 3 log10 steps. This seems sufficient for a long-lasting prophylactic application. The two PlakOut(r) mouth rinses and the CHX control fell into the other group, where the number of CFU was reduced by 7 log10 steps. These mouth rinses are predestined for short term therapeutic use. However, reversible side effects must be taken into account. It has thus far not been possible to formulate CHX products with effective ADS (Anti Discoloration System) additives without reducing antimicrobial activity. PMID- 21656387 TI - [Non-Hodgkin lymphoma of the mandible--a case report with differential diagnostic considerations]. AB - Approximately 5% of all malignant lesions are diagnosed as malignant lymphomas, of which 2-3% are localized in the head and neck region. After the squamous cell carcinoma and neoplasms of the salivary glands, malignant lymphomas represent the third most frequent malignant lesion in that region. Malignant lymphomas can be grouped into Hodgkin- and non- Hodgkin lymphomas (NHL) and subdivided into nodal (lymph nodes) and extranodal lymphomas. We present the case of an extranodal non Hodgkin lymphoma in the left mandible of a 47-year-old woman, who was referred to our department with an unclear swelling, which was supposed to be infectious. After clinical and radiological examination, a biopsy was taken and a CD20 and BCL-6 protein positive non-Hodgkin lymphoma of the large B-cell type (DLBCL) was diagnosed. The patient was treated primarily with immunochemotherapy (R-CHOP protocol) and refused to undergo a subsequent radiotherapy. The 18 months follow up showed a complete remission of the lymphoma. In this paper, the NHL in the oral and maxillofacial region is presented as a cause of unclear swelling. Important differential diagnostic conditions are discussed. PMID- 21656388 TI - A survey of Swiss swimming pool attendants' knowledge of first-aid treatment after lip and dental injuries. AB - SUMMARY: Although dental injuries are common occurrences at swimming pools, there are very few publications about them. The purpose of this study was to interview pool attendants at public swimming pools/bathing resorts in Switzerland on lip and dental injuries in 2007. The questions focussed on their knowledge of first aid, the frequency and accident site of lip and tooth trauma, as well as the storage medium for avulsed teeth. Questions were also asked about the presence of a "dental first-aid kit" and the poster on dental first aid. 606 public pools were contacted, and one pool attendant per pool was interviewed by telephone. 553 individuals participated; 53 declined to take part. The results show that in 2007, 40% of the interviewed pool attendants (n = 221) had witnessed at least one lip injury, and 36.9% (n = 204) at least one tooth trauma. At pools with slides, accidents were more frequent (p<0.001), and the waterslide was the most common accident site. The pool attendants provided satisfactory answers on their actions after lip and dental injuries. However, 68.7% could not adequately answer the questions on storage of avulsed teeth. Only 74 pool attendants had a dental first aid kit. Of these, only 68 used the kits as the storage medium for avulsed teeth. 59 pool attendants were in possession of the poster on dental first aid. Overall, it was shown that pool attendants who had a dental first-aid kit and a dental first aid poster gave better answers on how to handle tooth trauma. PMID- 21656389 TI - [All-ceramic restorations in the esthetic zone--the problem of choice]. AB - The restoration of anterior teeth even for the experienced practitioner remains a challenge. Although there are different full-ceramic materials available on the market, the reproduction of optical properties in natural teeth is not easy at all. In this article, the author presents a simplified classification of teeth to be restored, in relation to the optical properties of actual ceramic systems, which helps to make the natural reproduction more predictable. For the dentist it's important to know about the optical properties of the teeth to be restored and the ceramic material used. Without this, the clinical success of restorations in the anterior segment of may not be predictable at all. For implant retained and bridge-work there are additional parameters that need to be taken into consideration which are not addressed in this article. Ceramic materials with a high light transmission allow, in combination with adhesive bonding, the fabrication of esthetic restorations. High strength ceramics block the light more and therefore are not indicated for this type of reconstruction. They may be used to mask discolored substructures. The communication between dentist and lab technician plays an important role to be clinically successful. PMID- 21656390 TI - [Dental care of patients with organ transplants or prosthetic joints--a survey of specialty hospitals]. AB - The aim of the investigation was to collect information from specialized hospitals regarding dental care before and after organ transplantation or replacement of prosthetic joints. 50 transplantation centres and 100 orthopaedic hospitals in Germany were chosen. A questionnaire was used to elucidate the following aspects: Is a dental examination carried out preoperatively? When the patient is discharged, is he or she recommended to have antibiotic prophylaxis before dental treatment? If so, which antibiotic is recommended? The response rate was 56% (n = 28) for transplantation centres. 89% arranged a dental examination before the transplantation. 83% of those questioned recommend antibiotic prophylaxis before dental treatment: Amoxicillin was mentioned most frequently (36%). The response rate of the orthopaedic hospitals was 31% (n = 31). 3% of those questioned arranged a dental examination before insertion of an endoprothesis. 55% recommend antibiotic prophylaxis when dental treatment is to be carried out following the insertion of the endoprosthesis. Cephalosporine was most frequently mentioned (33%). It was not possible to identify a uniform recommendation regarding dental care before and after organ transplantation or replacement of prosthetic joints either for patients with an organ transplant or those having a prosthetic joint. PMID- 21656391 TI - Measuring educational outcomes. PMID- 21656392 TI - Analysis of AOA/ACGME accredited family medicine residency programs. AB - BACKGROUND AND OBJECTIVES: American Osteopathic Association (AOA) accreditation of Accreditation Council for Graduate Medical Education (ACGME) family medicine residency programs began in the early 1990s to increase the number of Osteopathic Graduate Medical Education (OGME) training positions in family medicine. Despite the rapid expansion of family medicine residencies accredited by both the AOA and the ACGME, little has been published about issues facing these programs. METHODS: We developed an Internet-based survey for osteopathic program directors of dual accredited family medicine residency programs in 2009. All 98 osteopathic family medicine program directors were surveyed, and 72 programs met the study's inclusion criteria of having graduated at least one class of dual-accredited residents. RESULTS: We received 56 responses (78%) to the survey. Sixty-four percent of study participants indicated that the primary benefit of dual accreditation was to attract more applicants who are US graduates. Sixty-six percent of respondents reported that less than 50% of their DO graduates take the ABFM board exam, citing cost as the primary reason. Additionally, 21% of study participants report that the annual cost of maintaining dual accreditation was greater than $20,000. CONCLUSIONS: A substantial number of osteopathic residents graduating from dual-accredited programs are not seeking board certification by the ABFM, but our study participants felt confident that their programs would maintain dual AOA-ACGME accreditation even if there was a significant increase in US MD applicants. PMID- 21656393 TI - The effect of simulation training on PALS skills among family medicine residents. AB - BACKGROUND AND OBJECTIVES: The Accreditation Council for Graduate Medical Education requires that family medicine residents receive structured skills training on pediatric advanced life support (PALS) and should learn procedures for medical emergencies in patients of all ages. Traditional methods of training family medicine residents in PALS is challenging given their limited clinical exposure to critically ill patients. The primary objective of this study was to assess the effect of a 2-hour PALS training session utilizing high-fidelity mannequins on residents' psychomotor skills performances. METHODS: Between February and June 2009, residents from two urban family medicine residency programs received training on four PALS procedures (bag-mask ventilation, tracheal intubation, intraosseous line placement, and cardiac rhythm assessment/defibrillation) at a university simulation center. Residents completed questionnaires to provide data on previous resuscitation training and experience. We collected self-confidence data and video recordings of residents performing the procedures before and after training. To assess retention at 6 months, we collected self-confidence data and video recordings of PGY-1 and PGY-2 residents performing the procedures. A blinded reviewer scored the video recordings. RESULTS: Forty-seven residents completed the study. The majority of residents (53.2%) had never performed any of the procedures on a real patient. Immediately following skills training, mean overall performance improved from 39.5% (+/- 11.5%) to 76.5% (+/- 10.4%), difference 37.0% (95% CI, 33.5%--40.6%). Bag-mask ventilation and intraosseous insertion skills remained above baseline at 6-month follow-up. CONCLUSIONS: Simulation training is beneficial for teaching PALS procedures to family medicine residents. PMID- 21656394 TI - Teaching medical error apologies: development of a multi-component intervention. AB - BACKGROUND AND OBJECTIVES: Apologizing is an important component in addressing medical errors; yet, offering apologies continues to challenge physicians. To address limitations of prior educational interventions, a multi-faceted, apologies intervention was developed to provide medical students with increasingly applied learning opportunities. METHODS: First-year medical students taking a professionalism course at the authors' Southeastern medical school in 2008 or 2009 were eligible for the study. Data from their assigned activities and a post-intervention survey were analyzed. RESULTS: A total of 384 students contributed study data; 57.8% were male, 58.6% white, 10.9% Asian-Indian, 10.9% Asian-Other, and 7.6% African-American. Seventy-four percent of students considered tasks as useful or extremely useful. Student confidence in providing effective apologies increased as well as their comfort in disclosing errors to a faculty member or patient. Perceived importance of apology skills similarly increased. Apologies written by female authors were rated higher in effectiveness by peers than apologies written by male authors. Apology evaluators adopting patient perspective were more critical than evaluators adopting peer perspective. No race differences were found. CONCLUSIONS: This intervention was perceived useful by students and demonstrated medium to large effect size changes in importance, confidence, and comfort around apology errors. The higher evaluations of apologies written by female authors as well as the lower evaluations by evaluators adopting patient perspective warrant further consideration. Additional research is also warranted on streamlining and implementing the intervention for other institutions and ultimately how actual student apology behaviors are later affected. PMID- 21656395 TI - Clinician knowledge about use of intrauterine devices in adolescents in South Carolina AHEC. AB - BACKGROUND AND OBJECTIVES: Intrauterine devices (IUDs) are recommended as first line choices for both nulliparous and parous adolescents by the American College of Obstetrics and Gynecology (ACOG). This study describes use of IUDs and knowledge regarding IUD use in adolescents in South Carolina family medicine residency programs. METHODS: Faculty and residents in South Carolina Area Health Education Consortium (SC AHEC) Family Medicine Residency Programs received an anonymous survey including questions about current use of IUDs and scenarios where they were asked whether they would recommend an IUD. Proportions were compared using chi-square or Fisher's Exact Test. Modified Wald method was utilized to calculate 95% confidence intervals. RESULTS: The survey response rate was 53.8% (n=133). Most respondents (78%) prescribed IUDs and 42% inserted them, but >= 90% reported only prescribing or inserting <= 10 yearly. In scenarios where IUD recommendation was appropriate, only 27% (95% CI: 20.2-35.2) recommended IUDs for a sexually active adolescent, whereas 60% (95% CI: 51.7 68.1) recommended use for a postpartum adolescent. For similar scenarios in non adolescents, a statistically significant higher proportion recommended IUDs, with 50% (95% CI: 42.0-58.7) recommending use in a 21-year-old nulliparous woman and 77% (95% CI: 68.8-83.1) in a breast-feeding mother. Women were more likely to recommend IUD use than men in non-adolescents, but not adolescents. There was no difference in recommendations by level of training. CONCLUSIONS: Knowledge regarding IUD use in nulliparous women and adolescents is limited in this sample of family physicians. Increasing appropriate IUD recommendations may increase IUD use and improve contraceptive counseling for adolescents. PMID- 21656396 TI - A brief instrument to measure patients' overall satisfaction with primary care physicians. AB - BACKGROUND AND OBJECTIVES: A brief and psychometrically sound scale to measure patients' overall satisfaction with their primary care physicians would be useful in studies where a longer instrument is impractical. The purpose of this study was to develop and examine the psychometrics of a brief instrument to measure patients' overall satisfaction with their primary care physicians. METHODS: Research participants included 535 outpatients (between 18--75 years old, 66% female) who completed a mailed survey that included 10 items for measuring overall satisfaction with their primary care physician who was named on the survey. Patients were also asked about their perceptions of physician empathy, preventive tests recommended by the physician (colonoscopy, mammogram, and prostate-specific antigen (PSA) for age and gender appropriate patients) and demographic information. RESULTS: Factor analysis of the patient satisfaction items resulted in one prominent component. Corrected item-total score correlations of the patient satisfaction scale ranged from 0.85 to 0.96; correlation between patient satisfaction scores and patient perception of physician empathy was 0.93, and correlation with recommending the physician to family and friends was 0.92. Criterion-related validity coefficients were mostly in the 0.80s and 0.90s. Patient satisfaction scores were significantly higher for those whose physicians recommended preventive tests (colonoscopy, mammogram, and PSA-compliance rates >.80). Cronbach's coefficient alpha for patient satisfaction scale was 0.98. CONCLUSIONS: Empirical evidence supported the validity and reliability of a brief patient satisfaction scale that has utility in the assessments of educational programs aimed at improving patient satisfaction, medical services, and patient outcomes in primary care settings. PMID- 21656397 TI - Do students falsify information in clinical notes? AB - BACKGROUND: If students report information in a post-encounter note that was allegedly not obtained from the patient, they may be suspected of serious professional misconduct, ie, deliberate falsification of patient data. Over reporting during a clinical assessment may result in accusations of cheating and even lead to failure of a high-stakes examination. Despite these serious implications, the prevalence and reasons for over-reporting are not clear. We investigated every detected incident of false reporting during our high-stakes clinical skills assessment (CSA) at the end of the third year. Of 73 alleged incidents, 69 were attributed to errors in standardized patient (SP) performance, note scoring, data management, or the design of cases or scoring instruments. The four instances of over-reporting by students were more compatible with mistakes and lack of specificity than deliberate falsification. We conclude that all potential sources of error must be excluded before over-reporting incidents are attributed to deliberate falsification of data by students. PMID- 21656398 TI - Student performance on smoking cessation counseling with standardized patients. AB - BACKGROUND AND OBJECTIVES: Gaps in medical school education exist for the leading preventable cause of morbidity and mortality in the United States--cigarette smoking. This report is on an innovative medical student curriculum of smoking cessation with a high-stakes required performance assessment during a third-year clerkship in family medicine addressing the following questions: (1) Can medical students consistently achieve high levels of performance providing smoking cessation advice with standardized patients and (2) Is the performance on standardized patients associated with other concurrent cognitive test performance on comprehensive topics relevant to family medicine? METHODS: From 1997--2002 (Cohort 1), 470 students completed a focused assessment with standardized patients on smoking cessation counseling. From 2003--2007, 277 students completed a revised, complex shared decision making assessment on smoking cessation with standardized patients. Associations between student performance on standardized patients and concurrent cognitive examinations were analyzed. RESULTS: High levels of student performance were sustained on standardized patients and were inconsistently associated with other concurrent (written and oral) cognitive examinations. CONCLUSIONS: These findings further substantiate a need for broadening the range of assessing medical student competency beyond cognitive evaluations alone. Medical students can consistently achieve high levels of smoking cessation counseling with standardized patients regardless of the complexity of approach or performance on other concurrent examinations. PMID- 21656399 TI - Optimistic bias about intimate partner violence among medical personnel. AB - BACKGROUND AND OBJECTIVES: The study seeks to contribute to the optimistic bias literature by studying the perceptual bias among medical personnel within the context of intimate partner violence (IPV). METHODS: A total of 316 medical students, residents, and nurses were surveyed. RESULTS: Care providers exhibit optimistic bias, believing they are less likely than others to become victims of intimate partner violence (IPV). Optimistic bias was related to age, third-person perception, and knowledge/expertise. CONCLUSIONS: From a screening standpoint, the finding suggests that care providers distance themselves from patients by believing they are less vulnerable to IPV, which could decrease screening or negatively impact the effectiveness of screening or the quality of patient care. This finding extends the literature, because it documents optimistic bias among medical personnel, whereas previous findings were limited to patients. PMID- 21656400 TI - The American Board of Family Medicine certification examination: a proxy for quality. PMID- 21656401 TI - "I know this must have been a difficult day for you:" personal care in a patient centered medical home. AB - In light of calls for a new model of care, family physicians are endeavoring to create a Patient-centered Medical Home. Yet, structures of care in themselves do not make a home; for the medical house to be a home requires physicians to demonstrate a personal touch that communicates caring to the patient. This essay describes one easily accomplished method by which to integrate personal care in a Patient-centered Medical Home. PMID- 21656402 TI - Being present. PMID- 21656403 TI - Relinquishing the truth. AB - In this essay, the author reflects on a case involving a client who presents to therapy asking for professional guidance as to whether she should tell her adult child of her true paternity. The child was the product of a paternal rape. The author explores the impact of this case on her thinking about truth as prerequisite to healing. PMID- 21656404 TI - Leadership for the future of family medicine: STFM's people and power. PMID- 21656405 TI - Portuguese version of the Geriatric Anxiety Inventory: transcultural adaptation and psychometric validation. AB - OBJECTIVES: The Geriatric Anxiety Inventory (GAI) is a recently developed anxiety instrument designed to assess the severity of anxiety symptoms across a range of presentations in older adults. In this study, the authors examined the validity of the Portuguese version of the GAI and assessed its psychometric properties. METHOD: A cross-sectional study was designed using a sample of 152 community dwelling older adults, and a geriatric psychiatric sample of outpatients with clinical diagnoses of depression (n = 32), anxiety disorders (n = 23), and early Alzheimer's disease (n = 10). RESULTS: The Portuguese version of the GAI required linguistic and transcultural adaptations, particularly on the somatic expressions of anxiety. It exhibited sound internal consistency and demonstrated good concurrent validity against the state half of the Spielberg State-Trait Anxiety Inventory, the Geriatric Depression Scale (GDS-30), and the General Health Questionnaire (GHQ-12). The optimal cut-off point to detect severe anxiety symptoms was 8/9, but no optimal cut-off point for Generalized Anxiety Disorder could be estimated. CONCLUSION: These findings provide initial evidence that the Portuguese version of the GAI is a valid and reliable measure for assessing late life anxiety and highlights the need for possible modifications of the instrument before being used in other languages and cultural groups. PMID- 21656406 TI - Association between components of family caregivers' sense of burden and types of paid care services provided in Japan. AB - OBJECTIVES: The aim was to identify significant relationships between the 21 components of caregivers' sense of burden in the Zarit Burden Interview and specific paid care services provided in Japan's long-term care insurance system. METHOD: We defined a service utilization level (SUL) that represents the amount of care services that caregivers were consuming. We calculated the ratios of people, among those with the same SUL value, whose sense of burden was weaker than a specific level. Finally, we conducted regression analysis and checked how this ratio varied compared to the change in SUL values. RESULTS: For 12 among 22 components, the use of paid care services in general were significantly and linearly related with a smaller number of people having the strongest sense of burden. Several pairs of burden components and care service types were identified indicating that the type of care services effectively alleviated that burden component. CONCLUSIONS: (1) Paid care services do relieve caregivers' sense of burden. (2) Measures to increase the ratio of people with the weakest sense of burden by encouraging the use of care services do not necessarily match those that decrease the ratio of people feeling the heaviest burden. (3) Policies that encourage caregivers to use more care services can be more effective if policy makers know which type of care service is related with a burden component. PMID- 21656407 TI - 'About as comfortable as a stranger putting their finger up your nose': speculation about the (extra)ordinary in gynaecological examinations. AB - In public health education, gynaecological examinations are presented as a routine and ordinary procedure. Medical research addressing women's reasons for screening reluctance emphasises underlying psychological categories of 'anxiety' and 'poor coping'. Minimal attention is paid to the effects of clinicians' interventions upon women's decision-making. Normalising promotes women's participation as speculum examinations are an essential part of many contemporary diagnostic and treatment procedures. In-depth email interviews were conducted with 26 women with diagnosis of either of the two commonest viral sexually transmitted infections, human papilloma virus and herpes simplex virus, and 12 sexual health clinicians. Data were analysed thematically. Findings indicate that women's screening compliance is influenced by clinicians' (in)attention to power relations, rapport-building, attentiveness to bodily (dis)comfort, technical skill and gender. Women's feedback is a valuable resource in devising interventions that may promote participation in examinations. PMID- 21656408 TI - 'It hurts, but I don't have a choice, I'm not working and I'm sick': decisions and experiences regarding abortion of women living with HIV in Cape Town, South Africa. AB - Research was conducted with 36 women living with HIV in Cape Town, South Africa, regarding their decision-making about, and experiences with, abortion of unwanted pregnancies in the public health sector. Abortion intentions and decisions were explored by investigating influencing factors; knowledge of abortion policy and public health sector services; and abortion perceptions and experiences. Findings reveal that many women face censure both for becoming pregnant and terminating a pregnancy, including by family, partners, community members and healthcare providers. Data suggest that abortion may be more stigmatised than HIV despite South Africa's liberal abortion law. Generally, however, study participants were satisfied with the abortion care received. Most would advise women living with HIV to think carefully about abortion, but to make a decision in their own best interests, including only seeking care early in pregnancy from an accredited clinic. Study implications include a need to integrate information and counselling on safe legal abortion within sexual and reproductive health services, especially in efforts to integrate sexual and reproductive health into HIV care, and to forge greater linkages between HIV and abortion services more generally to ensure continuity in follow-up of care for women. PMID- 21656409 TI - Girls want money, boys want virgins: the materiality of love amongst South African township youth in the context of HIV and AIDS. AB - How do young South Africans give meaning to love? In this paper we draw on findings from an interview study to examine the ways in which young Africans, aged 16 to 17 years in a poor township in KwaZulu-Natal province, express ideals of love and romance. Their claims to love we show are strategic advantages as they negotiate poverty and economic marginalisation. Girls' ideals of love are tied to their aspirations towards middle-class consumerism. Love becomes inseparable from the idealisation of men who provide. Upholding provider masculinity is a strategic means to claim money, fashionable clothes and prestige. Unlike girls, the boys' love investments were focused on farm girls from rural areas in South Africa. Farm girls were constructed as virgins with little investment in commodification. Farm girls are a strategic option through which boys' economic marginalisation experienced in the township girls is reconciled through an exalted masculinity. Love is produced by particular sets of economic and social circumstances through which gender inequalities are reproduced, and should be taken more seriously in working with young people to address gendered social environments and HIV risk. PMID- 21656410 TI - 'Good parents' strive to raise 'innocent daughters'. AB - This paper analyses the views of parents in a slum setting in Pakistan regarding the marriage preparedness of their daughters. Twenty-five parents participated in four gender-specific focus group discussions. Latent content analysis was used to explore parents' views and experiences with regard to their daughters' marriage and how they prepared them for it. The main theme identified was that 'good parents' strive to raise 'innocent daughters'. Three sub-themes contributing to the main theme were: a daughter-a responsibility and a burden; social and sexual innocence; and parents' roles in the preparation for marriage. The theme and the sub-themes together illustrate how parents saw themselves as responsible for raising 'innocent daughters' and arranging good marriages. Parents realised, though, that bringing up daughters for marriage required not only training in submissivness, but also building confidence and knowledge during their childhood. PMID- 21656411 TI - Reasoning and deciding PMTCT-adherence during pregnancy among women living with HIV in Kenya. AB - This study explores type identities among rural and urban slum women on antiretroviral therapies who become pregnant. Narrative structuring was chosen to develop type narratives that illustrate how rural and urban women handle their HIV-infection and how they reason and decide about PMTCT-adherence during pregnancy and childbirth. Women in rural areas described their lives as 'secure and family controlled'. This gave the women security and predictability in life, but also meant that it was difficult to keep secrets about HIV infection. For women in the urban slum area the narratives were a tale of the uncertain and hard to predict reality in the slum, but also about self-reliance and decisiveness. They portrayed themselves as 'vulnerable and striving to survive' thus managing a tough situation without long-term solutions. We conclude that pregnancy poses different social challenges in rural and urban areas affecting how women choose to manage their adherence to PMTCT, which is also affected by HIV stigma and lack of disclosure. PMID- 21656412 TI - Sexual contexts and the process of risk reduction. AB - Understanding the dynamics of sexual risks for HIV among men who have sex with men has been one of the ongoing challenges of HIV prevention. While the majority of HIV-prevention interventions target individual behaviour and decision making, multiple studies point to the importance of social context in shaping risk behaviour. Analysis of qualitative data from a study of men who have sex with men, drug use and sex found that sexual encounters were made up multiple contextual and interpersonal elements, which interacted to shape sexual practices and risk reduction strategies. Semi-structured interviews were conducted with 60 racially diverse men who have sex with men in NYC, recruited from multiple venues. The majority of respondents were gay-identified and half were 40 or older. Respondents described risk assessment and risk-reduction processes that develop throughout a sexual encounter, embedded in ongoing negotiations of sexual practices. Strategies of risk assessment and reduction draw on probability-based approaches to HIV prevention, presenting a challenge to health education. PMID- 21656413 TI - Exposure of the Irish population to PBDEs in food: consideration of parameter uncertainty and variability for risk assessment. AB - Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants used to retard the ignition and/or spread of fire. PBDEs are used in various consumer products, such as textiles, mattresses and TV screens. This study presents a chemical risk assessment for the Irish population based on exposure to PBDEs from food. Special regard is given to the influence of parameter uncertainty and variability on the margins of safety. To quantitatively model uncertainty and variability in concentration data and variability in consumer behavior, a hierarchical probabilistic model was constructed. This model was evaluated using a two-dimensional Monte Carlo simulation (2D-MCS) approach. By considering uncertainty and variability in concentration data, margins of safety (MOS) were derived that are lower by a factor of ~2 compared to MOS based on dose estimates that only consider variability. The lowest MOS is 7.5 * 10(4) for BDE-99, with impaired spermatogenesis as toxic endpoint. Assuming an MOS of 10(4) as acceptable, we conclude that there is no significant risk for human health through intake of contaminated food. To investigate whether additional measurements could improve the quality of dose estimates, the statistic "uncertainty-to-variability (UVR)" was developed. By applying the UVR to our dose estimates, we show that, in our case, the datasets contain little uncertainty and additional measurements would not significantly improve the quality of dose estimates. PMID- 21656414 TI - Disease-associated differences in religious cognition in patients with Parkinson's disease. AB - OBJECTIVE: We sought to establish whether patients with Parkinson's disease (PD) exhibit change in religiosity as a function of disease progression and asymmetry, medication regimens, mood dysfunction, sex, and age. METHOD: We assessed both controlled (conscious reflection) and automatic (semantic priming) modes of religiosity. In the main study, self-reported religiosity, cognitive, and clinical measures were assessed in 71 patients with midstage PD and 75 age matched controls with non-neurological chronic health conditions. To understand a potential mechanism associated with change in religiosity in PD patients, we supplemented the findings with pilot investigations. The pilot included 21 PD patients and utilized a different self-report measure than that of the main study and assessed automatic activation of religious concepts both on and off levodopa. RESULTS: The main study results demonstrated that PD patients consistently scored lower in five of six dimensions of religiosity. Multivariate linear regression demonstrated that self-reported religiosity was related to disease stage, asymmetry, and male gender. Results are discussed in the context of other neurologic correlates of religiosity. The pilot study on religious concept activation suggested that the mechanism is organic and hemisphere dependent. On/off drug testing confirmed these findings to be independent of medication effects. Gain/decay semantic modeling suggested that right and left forebrain pathways selectively mediated the time constant of gain and decay, respectively, for religious concepts. CONCLUSION: PD patients exhibit significant differences in both controlled and automatic access to religious concepts with mid/late stage, male, left-onset patients most impaired in access to religious cognition. The findings indicate that aspects of religious/spiritual cognition appear related to specific cerebral structures. PMID- 21656415 TI - Podophyllotoxin-derived insecticidal agents: part XIII--evaluation of insecticidal activity of podophyllotoxin derivatives against Brontispa longissima. AB - In an attempt to find the biorational insecticides for Brontispa longissima control, 12 podophyllotoxin (PPT) analogues were tested for their insecticidal activity against the fifth-instar larvae of B. longissima in vivo for the first time. Among all the tested compounds, especially compounds 6 and 8 showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia azedarach. The different insecticidal activity range of compounds 1-12 indicated that the variation of chemical structures in the PPT skeleton markedly affected the activity profiles of this compound class, and some important structure-activity relationship information has been revealed. Together, these preliminary results may be useful in guiding further modification of PPTs in the development of potential new insecticides. PMID- 21656416 TI - Antihaemorrhagic potentials of Fagonia cretica against Naja naja karachiensis (black Pakistan cobra) venom. AB - Plants have been extensively used as a remedy for the treatment of snake bites. The aim of this study was to determine the antivenom potentials of methanolic extract from the aerial parts (leaves and twigs) of Fagonia cretica L. on a haemorrhage induced by venom from Naja naja karachiensis. The haemorrhagic response of venom was dose dependent from 0.1 to 4.0 ug per 1.5 uL phosphate buffer saline (PBS) on vitelline veins of fertilised hens' eggs in their shells. The extract effectively eliminated and neutralised, in a dose-dependent manner, the haemorrhagic activity of snake venom. The minimum effective neutralising dose of F. cretica extract was found to be 15 ug per 1.5 uL PBS. The extract possesses potentials as haemorrhagic inhibitor against snake venom compared to the standard antiserum and various plants reported in the literature. This study also provides a scientific base for the use of F. cretica in traditional medicine for the treatment of snake bite. PMID- 21656417 TI - Antinociceptive activity of discretamine isolated from Duguetia moricandiana. AB - The phytochemical study of Duguetia moricandiana Mart. (Annonaceae) yielded the isolation of the alkaloid which was identified by spectral analysis as discretamine. The evaluation of antinociceptive activity carried out by the acetic acid-induced writhing, formalin and hot plate tests in mice, suggests a potent antinociceptive effect. Discretamine (5, 10 and 20 mg kg-1, i.p.) significantly reduced the number of writhes similarly at all doses tested and the number of paw licks during the first phase of formalin test when compared to control. The effect of discretamine on hot plate response provides a confirmation of its central effect. These results indicate antinociceptive properties of this alkaloid. PMID- 21656418 TI - Immunostimulatory and cytotoxic activities of Indigofera suffruticosa (Fabaceae). AB - One of the major disadvantages of the current cancer therapy is the suppression of the immune system. Brazilian flora is considered one of the most diverse in the world and many plants were found to contain active constituents that can be valuable sources of new drugs. The plant Indigofera suffruticosa was studied to determine its potential to stimulate the immune system and also to be effective against tumour cells. We investigated the effects of the alkaloidal fraction and the pure alkaloid indigo obtained from I. suffruticosa on macrophage activation by measuring nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha) production. Cytotoxic activity was also evaluated against the two tumour murine cells lines, LM2 (breast adenocarcinoma) and LP07 (lung adenocarcinoma). The alkaloidal fraction induced a high NO production and a moderated TNF-alpha release. The pure indigo demonstrated an elevated NO and TNF-alpha production. The fraction and the pure compound also exhibited cytotoxic activity against both adenocarcinoma cell lines and indigo showed the strongest cytotoxic activity with IC50 value of 0.89 ug mL-1 against LM2 and 1.44 ug mL-1 against LP07. Our results presented the immunostimulatory and cytotoxic activity of I. suffruticosa, enhancing macrophage function and therefore contributing to the host defence against tumours. PMID- 21656419 TI - Antioxidant, diuretic activities and polyphenol content of Stereospermum kunthianum Cham. (Bignoniaceae). AB - Stereospermum kunthianum was used for biological and phytochemical investigations. In biological studies, antioxidant activities were investigated with water, methanol and aqueous acetone extracts. Furthermore, the xanthine oxidase inhibitory activity and the diuretic activity of an aqueous acetone extract were evaluated. In the phytochemical investigations, the flavonoids and polyphenols were quantified spectrophotometrically in all extracts followed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis of an aqueous acetone extract. The 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing/antioxidant power (FRAP) and 2,2'-azinobis (3-ethylbenzoline-6 sulphonate (ABTS) methods have shown that the aqueous acetone extract presents the best antioxidant activities. This aqueous acetone extract was further proven to have interesting xanthine oxidase inhibitory activity, but only a weak diuretic activity. This aqueous acetone extract also possessed the highest phenolic and flavonoid contents. HPLC-MS analysis allowed identifying and quantifying, rutin, isoquercitrin, quercetin, hyperoside, quercitrin and luteolin and the glycosides of ferulic, sinapic p-coumaric acids and kaempferol, apigenin in aqueous-acetone extract. PMID- 21656420 TI - Cultural constructions of the concept of household in sample surveys. AB - We analyse the use of the concept of household in sample surveys, with evidence drawn from a review of survey definitions, a series of in-depth interviews with data producers and users, and a systematic study of recent literature. We consider the place of the concept within the discipline of demography, and demonstrate how its definition and use interact with cultural values and core concepts integral to the discipline. Focusing on Tanzania as a case study, we examine the diversity of factors that influence the construction of household level data from cross-sectional household surveys. Throughout the survey process, contrasting interpretations of the meaning of household and different motivations for using specific definitions of the term interact. This generates data and outputs with potential for undercounting, bias, and misrepresentations, with adverse effects on the quality of data used for monitoring development indicators. Some ways of improving data collection on households are proposed. PMID- 21656421 TI - [Economisation and privatisation in psychiatry and psychotherapy]. PMID- 21656422 TI - [Medical disorders in psychiatric patients]. PMID- 21656428 TI - [Oxygen in medicine]. PMID- 21656429 TI - [Papilledema]. PMID- 21656430 TI - [From gene therapy to the international IC3-D-classification: new aspects of corneal diseases]. PMID- 21656431 TI - [Viral vectors for gene delivery to corneal endothelial cells]. AB - BACKGROUND: Corneal endothelium is an interesting target for in vitro gene transfer strategies as it is readily accessible thanks to its anatomic structure as a monolayer and its direct contact to culture medium. Whereas the use of adenoviruses as viral vectors (carriers) to endothelial cells (EC) has been described as problematic as to its immunogenicity, lentiviruses and adeno associated viruses (AAV) are potent vectors for the transfer of genetic DNA into EC. Lentiviral vectors, developed on the basis of HI-viruses, can integrate the transferred gene into the host DNA and thus lead to a permanent protein expression. Evaluating apathogen alternatives to lentiviral vectors for humans, we herein compared non-integrating AAV to lentiviral gene transfer. MATERIALS AND METHODS: A comparison was made of the kinetics of expression of a green fluorescent protein after transduction using a lentiviral vector and AAV 2 / 2 in a murine EC line, human EC line and human primary cells (flow cytometry). A proof of principle experiment was conducted to demonstrate the function after lentiviral gene transfer of the anti-apoptotic gene Bcl-xL. RESULTS: The kinetics of protein expression after transduction of EC using a lentiviral or an AAV vector show fundamental differences. Contrary to gene transfer using AAV, a high expression of the reporter protein was readily detectable only hours after transduction using the lentiral vector. In addition, we could demonstrate distinct differences in protein expression characteristics between human and murine EC as well as human EC line and primary human EC. Function could be demonstrated by showing a significant reduction in apoptosis in both murine and human EC. CONCLUSION: AAV vectors are an alternative to lentiviral vectors for gene transfer to corneal EC. Given a cultivation time of donor corneas of up to 4 weeks before transplantation, translation to eye banking, e. g., to decrease apoptosis in corneal allografts, is conceivable. PMID- 21656432 TI - [Masquerade keratitis due to hereditary corneal disorders]. AB - Hereditary corneal disorders can show a unilateral corneal erosion for several days due to different morphological etiologies which may result in the misdiagnosis of bacterial or viral keratitis. In such a situation it is very important to examine the contralateral eye with regard to a possible corneal opacity. The slit lamp examination has to be performed with dilated pupil in direct and indirect illumination. Patient history including familial ocular problems and recurrent alternating ocular pain can be a hint for the correct diagnosis. Masquerade keratitis of hereditary corneal disorders can be distinguished in 3 main groups: (i) recurrent corneal erosion due to systemic hereditary disorders with corneal involvement; (ii) recurrent corneal erosion due to corneal dystrophies with dystrophy-specific corneal opacities; (iii) recurrent corneal erosion in childhood without dystrophy-specific corneal opacities (occurrence of dystrophy-specific corneal opacities in adults). The ocular pain which may last several days with third group of patients often occurs in the second half of night. The children's suffering is enormous and has a negative impact on the whole family. The wearing of therapeutic contact lenses during the night may considerably reduce the ocular pain. PMID- 21656433 TI - [Effect of various compositions of riboflavin eye drops on the intraoperative corneal thickness during UVA-cross-linking in keratoconus eyes]. AB - BACKGROUND: During the UVA-cross-linking treatment in keratoconus patients, the UVA rays are partially absorbed in the stroma of the riboflavin-loaded cornea. This effect protects the corneal endothelium from UVA irradiation damage. The intensity of UVA light reaching the endothelium is inversely correlated with corneal thickness. The common composition of riboflavin eye drops may lead to a marked reduction in corneal thickness increasing the risk of endothelial damage. PATIENTS AND METHODS: In a retrospective analysis of 23 UVA-cross-linking procedures on 23 patients we collected data about the pre-, intra- and postoperative corneal thickness (measured with ultrasound). Among these patients and depending on the preoperative state, 8 eyes received Medio Cross (TM) eye drops (group 1), 8 eyes received Medio Cross (TM) eye drops combined with riboflavin 0.1 %/methylhydroxypropylcellulose 1,5 %/NaCl 1.1 % (group 2) and 7 eyes received riboflavin 0.2 %/methylhydroxypropylcellulose 0.5 %/NaCl 0.7 % eye drops (group 3) before and during UVA irradiation. Data are presented as means +/ standard deviation. A comparison of the data was performed using (one-way) ANOVA. RESULTS: The mean corneal thickness at the end of the UVA cross-linking procedure was 67 +/- 9 % (means +/- standard deviation) of preoperative thickness in group 1, 118 +/- 14 % in group 2 and 140 +/- 23 % in group 3. The values in groups 2 and 3 were significantly different from those in the reference group 1. CONCLUSIONS: Our results show a strong variability of the postoperative corneal thickness using different standard compositions of riboflavin eye drops. Further studies are needed to find a composition of riboflavin eye drops ensuring a moderate increase in intraoperative corneal thickness to protect the corneal endothelium. PMID- 21656434 TI - [Application possibilities of modern thermography--first experience with the new Tomey TG 1000]. AB - Temperature is one of the fundamental characteristics of tissue metabolism and is certainly of major interest to investigate ocular physiology. Current instrumentation offers the potential to measure the ocular surface temperature (OST) with high accuracy and resolution. Potential applications of OST measurement may include any condition of the ocular surface. The present study gives a survey of the possible applications of thermography and describes our first experience with the new Tomey TG 1000. PMID- 21656435 TI - [Corneal riboflavin/UV-A collagen cross-linking (CXL) in keratoconus: two-year results]. AB - BACKGROUND: Photochemical collagen cross-linking with riboflavin and UV-A radiation (CXL) is reported to strengthen the cornea in keratoconus. This retrospective longitudinal study analyses the outcomes 2 years after CXL. METHODS: 46 eyes of 45 patients with keratoconus stadium 1 to 3 with disease progression confirmed by topography or patient history underwent CXL after corneal abrasion. Follow-up over 2 years included biomicroscopy, visual acuity, topography, pachymetry, and endothelial cell count. Changes were analysed with paired Student's t test or Wilcoxon signed-rank test. RESULTS: All patients showed initial haze (maximum 2 + ) and increase of epithelial surface irregularity resulting in temporarily reduced vision, but this resolved within 3 months. Medium visual acuity (logMAR) improved from 0.29 to 0.20 (p = 0.019, 12 months postop) or to 0.24 (p = 0.200; 24 months postop). This corresponds to an improvement (? 1 line) in 51 % of eyes, a loss of vision in 27 %. Mean maximum radius of curvature was reduced by 1.24 diopters (D) (95 % confidence interval 0.05 - 2.43; p = 0.042) in the first year, and reduced by 1.23 D (0.42 - 2.05; p = 0.004) at 2 years after CXL. Mean pachymetry showed a significant reduction of 23 um (p = 0.0004, 1 year postop), endothelial cell count showed no significant change. CONCLUSION: In spite of a temporary reduction in vision, long-term outcome showed recovery or increase in visual acuity in the majority of eyes. Topography data indicate a stabilisation of keratoconus after CXL. PMID- 21656436 TI - [Self-control in older adulthood: a German version of the delay discounting test by Kirby]. AB - Delay discounting procedures are used to assess self-control vs. impulsivity on a behavioural level. Such procedures include a presentation of a series of choices between smaller, immediate and larger, delayed rewards. The Delay Discounting Test (DDT) by Kirby is an elegant and relatively short procedure. A German DDT version was evaluated in a sample of 147 older and healthy individuals (60-94 years). The discounting rate is in the magnitude of the American version. Its consistency was very high. The largest correlation to external criteria was found for delay of gratification, but also for activation regulation, order, and impulsivity. Further, the discounting rate correlated with anxiety and negative affect, but not with depression and cognitive functioning. Criterion validity and reliability of the DDT could be confirmed. A comprehensive assessment of self control or impulsivity should include behavioural measures like the DDT besides self-report measures. PMID- 21656437 TI - [Criteria of sample recruiting in qualitative research]. PMID- 21656438 TI - [Insecure attachment--a developmental "missing link" to explain somatoform disorders?]. PMID- 21656439 TI - [Retrospective follow-up design in studying psychotherapeutic effectiveness- criteria and application]. AB - THEORY: Efficacy-studies have poor external validity for psychotherapy under practice conditions. One alternative is a retrospective follow-up design. Methodological criteria are defined and a study is presented. METHODS: 35 and 33 patients including their therapists were studied in a cross-validation design using retrospective assessments. RESULTS: Changes from beginning to end of therapy were reliable and reached medium to high effect sizes. During follow-up they remained stable. Participants did not differ in outcome, social and clinical characteristics from non-participants. DISCUSSION: The retrospective approach is a valid and viable tool to examine the effectiveness of psychotherapy under practice-conditions. It should be advanced in future by methodological improvements, e. g., by using standardized instruments, testing bigger samples, integrating more differentiated therapist ratings, and including more objective criteria. PMID- 21656440 TI - 527 fully endoscopic resections of vestibular schwannomas. AB - BACKGROUND: We report a series of 527 patients with unilateral vestibular schwannomas (VS) who underwent fully endoscopic resection of their tumors during the period of October, 2001 to July, 2010. Patients' outcomes were evaluated, with specific regard to hearing preservation, facial nerve function, postoperative complications and completeness of the resection. METHODS: The patient population consisted of 527 cases with unilateral VS(s); patients with neurofibromatosis type 2 (NFT2) were excluded from this study. Tumors ranged in size from 0.3-5.8 cm, most tumors were less than 4 cm in diameter (mean: 2.8 cm). Tumors were removed via 2.0 cm "keyhole" retrosigmoid craniotomies. RESULTS: Utilizing the fully endoscopic technique, 94% of tumors were completely removed; subtotal removal was performed in 6% of patients in an attempt to preserve their hearing. Anatomic preservation of the facial nerve was achieved in all of the patients. Functionally, measurable hearing (serviceable/some) was preserved in 57% of cases that had either "serviceable" or "some" hearing pre-operatively. There were no major neurological complications such as quadriparesis, hemiparesis, bacterial or aseptic meningitis, permanent lower cranial nerve deficits, or deaths. CONCLUSION: From our experience, we conclude that the endoscope is ideally suited for a minimally invasive approach for resection of vestibular schwannomas. PMID- 21656441 TI - Membranous structures affecting the success of endoscopic third ventriculostomy in adult aqueductus sylvii stenosis. AB - BACKGROUND: The purpose of the present study was to observe Liliequist's membrane (LM) and membranous structures located in the prepontine cistern via 3-Tesla magnetic resonance imaging (MRI) with 3D driven equilibrium radio frequency reset pulse (DRIVE) sequence and multiplanar reformat (MPR) images and to evaluate the success of endoscopic third ventriculostomy (ETV) by assessing these membranes in adult aqueduct stenosis. PATIENTS: 29 patients (17 female, 12 male) with primary aqueductus sylvii stenosis were included in the study. 19 patients were diagnosed as long-standing overt ventriculomegaly in adults (LOVA) and patients had severe ventriculomegaly, macrocephalus, and aqueduct stenosis on MR imaging. 10 patients were diagnosed as aqueduct stenosis presented with acute onset of hydrocephalus with symptoms of raised ICP. All patients in the study group were analyzed with conventional and cine MRI before and after treatment. We performed 3D DRIVE sequence and MPR at 3-T MR equipment to determine the membranous structures in 3 dimensions. We correlated the success of the procedure considering the preoperative, postoperative MRI and intraoperative images. RESULTS: 5 patients (26.3%) with LOVA and 2 patients (20%) with aqueduct stenosis, in total 7 patients (24.1%), did not respond to ETV. Cerebrospinal fluid (CSF) flow was blocked by membranous structures located in the prepontine cistern in 4 of 8 patients. In 2 patients, CSF through the stoma was blocked either by the LM or closed tuber cinerum. In 1 patient insufficient CSF flow was observed through the stoma and the LM accompanying prepontine membranes.Totally closed membranes were observed in the prepontine cistern in 5 patients (17.24%) according to the postoperative MRI. LM was verified in all patients intraoperatively that were also demonstrated in the preoperative MRI. CONCLUSION: 3D sequences with MPR may help to observe not only the LM but also other membranes located through the prepontine cistern, which may be the reason of failed ETV. PMID- 21656442 TI - Microvascular decompression for trigeminal neuralgia due to compression by the vertebral artery: report of 3 cases. AB - BACKGROUND: Trigeminal neuralgia elicited by the vertebral artery is unusual. According to a large trigeminal neuralgia series, only 4 of 1,404 (0.3%) consecutive patients with typical trigeminal neuralgia presented with vertebral artery compression. In such cases the vertebrobasilar system tends to be atherosclerotic, ectatic, and tortuous, requiring, in addition to an ordinary microvascular decompression method, technical modifications of this procedure. We report on 3 patients with trigeminal neuralgia due to compression by a tortuous vertebral artery. PATIENTS: All 3 patients underwent microvascular decompression via a small lateral suboccipital craniotomy. Operative exposure demonstrated that the root of the trigeminal nerve was compressed directly and stretched by a loop of the vertebral artery. The compression was successfully released by dislocation of the loop using Teflon (polytetrafluoroethene) slings. Immediately after the operation all 3 patients became pain-free. CONCLUSION: Among the surgical procedures used in microvascular decompression surgery, dislocation of the offending vessel with Teflon slings is a useful surgical technique to treat trigeminal neuralgia due to a tortuous vertebral artery. PMID- 21656443 TI - Recurrent intrahepatic dislocation of ventriculoperitoneal shunt. AB - BACKGROUND: Dislocation of ventriculoperitoneal (VP) shunt catheters is a well known complication after treatment of cerebrospinal fluid disorders; however, secondary perforation of the liver capsule by the catheter is exceptional. The literature on VP shunt complications involving the liver, their possible pathomechanisms and minimally invasive recovery strategies in reference to our own experience is reviewed. CASE REPORT: We present a patient who suffered penetration of the liver by the peritoneal catheter of her VP shunt. Causing intermittent epigastric pain, the shunt tip was found to have progressively dislocated into the liver, as documented by CT scans. A laparoscopic approach was indicated to recover the shunt. The peritoneal catheter was found to be covered by widespread adhesions, consistent with peritoneal fibrosis. After local adhesiolysis, it was successfully recovered without shunt dysfunction, hemorrhage of the liver, or biliary fistula. After 4 months, dislocation recurred with formation of a subdiaphragmatic pseudocapsule. Early formation of fibrosis was detected during laparoscopic revision surgery. Although bacterial smears from both laparoscopic surgeries did not show any pathological findings, the patient presented with an abscess in the Douglas pouch 4 months later. Coagulase-negative staphylococci were found on ultrasound-guided insertion of a pigtail catheter. The VP shunt had to be replaced by a ventriculoatrial shunt. The infection was treated successfully with piperacillin. The subsequent 6 months follow-up period was without adverse events. CONCLUSION: The treatment of choice in this exceptional case of intrahepatic shunt dislocation was laparoscopic recovery of the catheter. Laparoscopy allowed good visualization during adhesiolysis, immediate exclusion of hemorrhage or bile fistula at the puncture site, as well as function control and safe deposition of the shunt tip. Chronic infection as an underlying cause of peritoneal fibrosis has to be ruled out. PMID- 21656444 TI - Continuous subdural irrigation and drainage for intracranial subdural empyema in a 92-year-old woman. AB - INTRODUCTION: Intracranial subdural empyema (ISDE) is a life-threatening intracranial infection. Early and precise detection, timely surgery, and appropriate antibiotic therapy are the keys to a more favorable clinical outcome. Treatment is aimed at complete evacuation of the empyema and eradication of the source of infection. However, in the case of elderly patients or patients with poor health, doctors hesitate to perform open cranial surgery under general anesthesia; thus, the choice of appropriate surgical method is fraught with many limitations. CASE REPORT: We present a case of ISDE in a 92-year-old woman who was successfully treated with continuous irrigation of the subdural space with antibiotics and drainage through 2 burr holes for 1 week without any complications. CONCLUSION: Continuous subdural irrigation is useful for the evacuation of pus and eradication of the source of infection, thereby resulting in a favorable outcome, especially in elderly patients and patients with poor health. PMID- 21656445 TI - "Full moon" endoscopic sign in intraventricular neurocysticercosis. AB - INTRODUCTION: Despite improvements in sanitation, diagnosis and treatment, neurocysticercosis is still a public health problem in many countries. In symptomatic patients, there is a broad spectrum of clinical manifestations. When cysticerci are lodged in the ventricles or the subarachnoid space, the flow of cerebrospinal fluid can be obstructed and lead to hydrocephalus and intracranial hypertension. The endoscopic view may be useful as a diagnostic tool. PATIENTS: This report clearly shows a common endoscopic pattern in 4 selected patients with ventricular cysticercosis (2 third ventricle/2 lateral ventricle). The endoscopic view of the cysts in the ventricles resembles a "full moon". This analogy helped to identify the features of cysticerci with intact walls and the vesicular stage, malleable due to its cystic content and having an irregular surface, as evidence of the microscopic structure of the cyst wall in a cysticercus. CONCLUSIONS: This finding is not seen in other intraventricular cysts or tumors that can actually be considered as an additional diagnostic criterion among the definitive findings to establish the diagnosis of cysticercosis, since it involves direct endoscopic visualization of a cysticercus under histopathological demonstration. Additionally, the endoscopic approach can be used as primary treatment for these cases, following the minimally invasive approach principle. PMID- 21656446 TI - Endoscopic colloid cyst resection: technical note. AB - INTRODUCTION: Since the first reported endoscopic treatment of colloid cysts of the third ventricle by Powel et al. in 1983, several endoscopic techniques have been described. Therefore, the authors describe their technique of neuroendoscopic colloid cyst removal, developed during the last 16 years. TECHNIQUE: With the aid of the specially designed, no-through perforator, the colloid cyst is first partially evacuated to facilitate further dissection and mobilization. By intermittent gentle traction to mobilize the cyst out of the foramen of Monro, detachment from the tela choroidea is finally obtained, making total removal possible. CONCLUSIONS: With the described endoscopic technique, complete removal of colloid cysts is possible in almost 90 % of cases. PMID- 21656447 TI - Paraumbilical peritoneal incision using the little finger in shunt operations for hydrocephalus: technical note. AB - INTRODUCTION: The shunt operation remains the standard procedure for the treatment of hydrocephalus. We describe a simple minilaparotomy method that involves perforation of the peritoneum with the surgeon's little finger. TECHNIQUE: After placing a small paraumbilical incision at the skin and fascia, the little finger is introduced through the incision to perforate the pre peritoneal fat and peritoneum. The finger should be inserted at a 30-45 degrees angle to the horizontal plane to avoid injuring the underlying viscera and major blood vessels and to put sufficient shear force on the peritoneum. A catheter is inserted into the abdominal cavity after visual confirmation of proper perforation. CONCLUSION: As the paraumbilical wound is not noticeable postoperatively due to the presence of the natural umbilical skin fold, this method yields a cosmetically appealing result. PMID- 21656448 TI - Long constructs in the thoracic and lumbar spine with a minimally invasive technique. AB - BACKGROUND: Literature about long implants used together with a minimally invasive spine surgery (MISS) technique is scarce. Our objective is to contribute our surgical experience in this field and to specifically focus on several technical details. PATIENTS AND METHODS: A digitally-dissected canal along the paravertebral muscles was created linking the stab wounds on each side in relation with the pedicles to be cannulated. Screws were inserted following the percutaneous technique. Long rods were modelled, threaded through the extender sleeves along the paravertebral canal and pushed into the screw heads with the reduction forceps. When fusion was needed, the facet complex was decorticated with a drill. To insert a cross-link, a canal between the 2 rods was digitally created and the spinous process was drilled. RESULTS: 8 patients underwent surgery (age range: 25-77 years). Indications were postosteomyelitis kyphosis in 3 patients, bone tumor in 3, and spine fracture in 2. No blood transfusions were necessary during or after surgery. A cross-link was inserted in 2 patients. Posterolateral bone fusion was attempted in 4, but radiologically identifiable in none. In one patient a cantilever manoeuvre was done to correct kyphosis. Mean duration of surgery was 4 h. There were no clinical complications related to the operation or the hardware (mean follow-up of 7.14 months, range: 1-15 months). CONCLUSION: The application of MISS techniques can be broadened to long spinal constructs to assess fractures, tumors or deformity, especially in elderly or debilitated patients. Nevertheless, posterolateral fusion is still a challenge through these limited exposures. PMID- 21656449 TI - [Rate of influenza vaccination among medical staff working at a university hospital]. AB - BACKGROUND AND OBJEKTIVES: In 1988 the German Vaccination Board (STIKO) at the Robert-Koch-Institute (RKI) in Berlin, recommended that German health care workers should be vaccinated annually against influenza. Despite this, vaccination rates have remained low (20 %). Between January and March 2009 a study was performed at the University Clinical Centre in Essen to determine reasons for low influenza vaccination rates and to assess improvement strategies. METHODS: All employees and staff members of the University Hospital (n = 5349) were asked to fill in a questionnaire anonymously. The completed questionnaires were digitalized and the results analysed electronically. RESULTS: 1 670 of the 5 349 (31 %) questionnaires were found to be satisfactory for evaluation. The vaccination rate among this cohort was 29 %. Vaccination rates varied widely between different departments (4 - 71 %). The most common reason for not undergoing vaccination was "forgotten" (32 %). The second most common reason was the fear of side effects (30 %). Only 32 % of the employees stated that the quality of the information about influenza vaccination provided by their employer was "good" or "very good". CONCLUSION: The vaccination rate of 29 % among this group of health care workers was higher than the average (20 %) in German hospitals and highest among medical doctors. Strikingly enough employees of theoretic departments were vaccinated to a higher percentage than those providing nursing care and thus had more frequent contact to patients. A number of comparatively basic and inexpensive measures would be enough to increase vaccination rates significantly. PMID- 21656450 TI - [Does patient safety justify mandatory vaccinations?]. AB - BACKGROUND AND OBJECTIVES: Medical and dental students belong to a group of health care workers (HCWs) who are frequently exposed to patients with occupationally transmissible infectious diseases. Vaccinations are the most effective interventions to protect HCWs and patients from vaccine-preventable infectious diseases. Despite decades of effort to encourage HCWs to be immunized, vaccination levels (e. g. influenza) remain insufficient. METHODS: To assess the attitudes of German medical and dental students towards mandatory immunizations, an anonymous questionnaire was offered to medical and dental students of the University of Frankfurt/Main, Germany. Overall, 56.9 % (1823/3200) of all medical and dental students attended to the study. RESULTS: This study - so far the largest study done on this issue - showed that almost 88.5 % of the responding medical and dental students would accept mandatory vaccinations for HCWs. CONCLUSION: Contrary to the widespread concern that a vaccination requirement would cause resistance, our data support that mandatory vaccinations (at least for HCWs who care for immunocompromised patients) might be widely accepted. PMID- 21656451 TI - [Dementia in Whipple's disease?: relevance of infectious etiologies]. AB - HISTORY AND CLINICAL FINDINGS: A 69-year old patient who had been treated for joint pain over a long time was admitted because of weight loss and dementia. He was confused and cachectic with edema and skin hyperpigmentation. INVESTIGATIONS: Laboratory findings indicated chronic infection. Duodenal biopsy revealed Whipple's disease. The PCR of cerebrospinal fluid for Tropheryma whipplei was negative. TREATMENT AND COURSE: During treatment with ceftriaxon and intravenous fluid therapy the patient's mental state improved. However his motoric state remained insufficient. CONCLUSION: Whipple's disease should be considered in dementia, even more in previous "rheumatic symptoms", in order to avoid ineffective (immunosuppressive) treatment with unfortunate consequences. PMID- 21656452 TI - [Rare differential diagnosis of primary adrenal insufficiency: case 6/2011]. PMID- 21656453 TI - [Distinctive facial appearance in an 83-year-old man with dyspnea]. PMID- 21656454 TI - [Diagnostics and treatment in functional pancreatic neuroendocrine tumours]. AB - Pancreatic neuroendocrine tumours (PNET) are rare entities with an annual incidence of < 100,000. About 1 - 2 % of pancreatic neoplasias are neuroendocrine tumours. About one third of these tumours secrete biologically active substances that lead to development of specific clinical syndromes. PNET may occur sporadically or in association with hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN1). Among the functional PNET, insulinomas and gastrinomas are the most common entities. In contrast, vasoactive intetinale peptide (VIP)-secreting tumours, glucagonomas, serotonin-secreting carcinoid tumors, and tumours with secretion of ectopic hormones, such as calcitonin, are extremely rare. Once diagnosis has been established on the basis of clinical and laboratory findings, localization of the source of pathologic hormone secretion is warranted. Imaging methods frequently used for localization of PNET comprise anatomical imaging modalities, computed tomography, and magnetic resonance imaging, endoscopic ultrasound, selective arterial catheterization with hepatic venous sampling, DTPA-octreotid scintigraphy and DOTA-D-Phe(1)-Tyr(3)-octreotid positron emission tomography. Therapy is based on the specific tumour entity and the extent of the disease. In the majority of patients, even in the case of malignant disease, a surgical approach is warranted, eventually combined with a medical treatment. PMID- 21656455 TI - Safety and efficacy of a new non-foreshortening nitinol stent in malignant gastric outlet obstruction (DUONITI study): a prospective, multicenter study. AB - BACKGROUND AND STUDY AIMS: Gastric outlet obstruction (GOO) is a late complication of advanced gastric, periampullary, and duodenal malignancies. Palliation of obstruction is the primary aim of treatment in these patients. Self expandable metal stents have emerged as a promising treatment option. Our aim was to investigate the safety and efficacy of a new non-foreshortening nitinol duodenal stent. PATIENTS AND METHODS: A total of 52 patients with symptomatic malignant GOO were studied in this prospective multicenter cohort study. All patients received a D-Weave Niti-S duodenal stent (Taewoong Medical, Seoul, South Korea). Patients were followed up until withdrawal of informed consent or death. RESULTS: The cause of GOO was pancreatic cancer in the majority of patients (62%). The technical and clinical success rates were 96% and 77%, respectively. The GOO Scoring System score improved significantly (P < 0.0001) when the scores before stenting were compared with the mean scores until death. Median survival was 82 days and stent patency was observed in 75% for up to 190 days, accounting for death as a competing risk. In 13 patients (25%) stent dysfunction occurred (tumor ingrowth in 11, stent migration in two). Over time, the body mass index, the World Health Organization performance score, and the EuroQol visual analog scale revealed a not significant change (P = 0.52, P = 0.43, and P = 0.15, respectively), whereas the global health status improved significantly (P = 0.001). CONCLUSION: Placement of a new non-foreshortening nitinol enteral stent is safe and without major complications. This stent design produces significant relief of obstructive symptoms and improves quality of life in patients with incurable malignant GOO. PMID- 21656456 TI - A new large-caliber trocar for percutaneous endoscopic gastrostomy by the introducer technique in head and neck cancer patients. AB - BACKGROUND AND STUDY AIMS: In many patients, percutaneous endoscopic gastrostomy (PEG) can be limited by digestive tract stenosis. PEG placement using an introducer is the safest alternative for this group of patients, but the available devices are difficult to implement and require smaller-caliber tubes. The aim of this study was to evaluate the modification of an introducer technique device for PEG placement with regard to the following: procedure feasibility, possibility of using a 20-Fr balloon gastrostomy tube, tube-related function and problems, complications, procedure safety, and mortality. PATIENTS AND METHODS: Between March 2007 and February 2008, 30 consecutive patients with head and neck malignancies underwent introducer PEG placement with the modified device and gastropexy. Each patient was evaluated for 60 days after the procedure for the success of the procedure, infection, pain, complications, mortality, and problems with the procedure. RESULTS: The procedure was successful in all cases with no perioperative complications. No signs of stomal infection were observed using the combined infection score. The majority of patients experienced mild-to-moderate pain both in the immediate postoperative period and at 72 hours. One major early complication (3.3%) and two minor complications (6.7%) were observed. No procedure-related deaths occurred during the first 60 days after the procedure. CONCLUSION: The device modification for PEG using the introducer technique is feasible, safe, and efficient in outpatients with obstructive head and neck cancer. In this series, it allowed the use of a larger-caliber tube with low complication rates and no procedure-related mortality. PMID- 21656457 TI - Detection of gastric MALT lymphoma spreading to the small bowel by enteroscopy. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma is thought to be a multifocal disease with sometimes synchronous involvement of various mucosal structures. In this study we aimed to evaluate the potential involvement of the small bowel in patients suffering from gastric MALT lymphoma by analyzing the results of enteroscopy, a technique that allows easy and safe access to the small bowel with the potential for histological assessment of biopsy samples. We have retrospectively evaluated 347 enteroscopies and found nine patients with gastric MALT lymphoma who had undergone push enteroscopy with serial biopsies during staging. All patients tolerated enteroscopy without side effects, and no local complications occurred. In eight cases no evidence of duodenal or jejunal involvement was found macroscopically or by histological assessment of biopsies, while in one patient enteroscopy revealed jejunal MALT lymphoma infiltration with macroscopic accentuation of mucosal parts and consecutive histopathological verification more distal than 50 cm. This single-center retrospective analysis shows that enteroscopy can provide additional diagnostic information in patients with gastric MALT lymphoma, although the number of patients was small and only one out of nine patients showed hitherto undetected MALT lymphoma deposits. Further studies may quantify the additional diagnostic yield provided by this easy and safe endoscopic method. PMID- 21656459 TI - [Cyclic movement training versus conventional physiotherapy for rehabilitation of hemiparetic gait after stroke: a pilot study]. AB - BACKGROUND: Recovery of impaired motor functions following stroke is commonly incomplete in spite of intensive rehabilitation programmes. At 6 months following a stroke up to 60 % of affected individuals still suffer from permanent motor deficits, in particular hemiparetic gait, that are relevant for daily life. Novel innovative therapeutic strategies are needed to enhance the recovery of impaired gait function following stroke. METHOD: This pilot study has investigated the effectiveness of conventional physiotherapy in comparison to an apparative cyclic movement training over a period of 4 weeks to improve (i) power during a submaximal cyclic movement training of the lower limbs, (ii) cardiac fitness, (iii) balance and gait ability, and (iv) quality of life in stroke patients. RESULTS: In comparison to physiotherapy apparative cyclic movement training improved power, balance, cardiac fitness and quality of life to a greater extent. However, there was a statistically significant difference between both intervention groups only for balance but not for the other parameters assessed. CONCLUSION: The present pilot study should inspire future research with larger patient cohorts to allow appropriate judgement on the effectiveness of apparative cyclic movement training in stroke rehabilitation. PMID- 21656460 TI - [EYECUBE as 3D multimedia imaging in macular diagnostics]. AB - BACKGROUND: In the new generation of EYECUBE devices, the angiography image and the OCT are included in a 3D illustration as an integration. Other diagnostic procedures such as autofluorescence and ICG can also be correlated to the OCT. The aim was to precisely classify various two-dimensional findings in relation to each other. METHOD: The new generation of OCT devices enables imaging with a low incidence of motion artefacts with very good fundus image quality - and with that, permits a largely automatic classification. The feature enabling the integration of the EYECUBE was further developed with new software, so that not only the topographic image (red-free, autofluorescence) can be correlated to the Cirrus OCT, but also all other findings gathered within the same time frame can be correlated to each other. These were brightened and projected onto the cube surface in a defined interval. The imaging procedures can be selected in a menu toolbar. Topographic volumetry OCT images can be overlayed. The practical application of the new method was tested on patients with macular disorders. RESULTS: By lightening up the results from various diagnostic procedures, it is possible of late to directly compare pathologies to each other and to the OCT results. In all patients (n = 45 eyes) with good single-image quality, the automated integration into the EYECUBE was possible (to a great extent). The application is not dependent on a certain type of device used in the procedures performed. CONCLUSIONS: The increasing level of precision in imaging procedures and the handling of large data volumes has led to the possibility of examining each macular diagnostics procedure from the comparative perspective: imaging (photo) with perfusion (FLA, ICG) and morphology (OCT). The exclusion of motion artefacts and the reliable scan position in the course of the imaging process increases the informative value of OCT. PMID- 21656461 TI - [Clinical results after cataract surgery in patients with Behcet's disease]. AB - BACKGROUND: Behcet's disease is a systemic vasculitis disorder of unknown aetiology. Ocular involvement, especially with vasculitis, is detected in up to 80 % of the cases. Anterior segment involvement such as cataract is also seen in the follow-up of patients who are then treated surgically. In this study, we aimed to analyze the outcomes of cataract surgery in patients with Behcet's disease retrospectively. PATIENTS AND METHODS: The records of 9 patients (12 eyes) with Behcet's disease who underwent phacoemulsification with IOL implantation in 11 eyes and extracapsular cataract extraction (ECCE) with IOL implantation in one eye between June 2001 and September 2009 were evaluated retrospectively. The visual outcome and complications were analysed. RESULTS: The mean follow-up was 33.8 months (range 3 to 88 months). The mean preoperative LogMAR BCVA was 1.15 +/- 0.53 (95 % CI: 0.81 - 1.49) and increased to 0.36 +/- 0.32 (95 % CI: 0.15 - 0.56) at last medical visit (p < 0.001). The most frequent postoperative complication was posterior capsular opacification, which developed in 2 eyes (17 %). Other complications were mild fibrinous reaction in 1 eye (8 %). CONCLUSIONS: The outcomes of cataract surgery in patients with Behcet's disease were satisfactory. The great majority of the patients regained and retained a good visual outcome and had fewer postoperative complications. PMID- 21656462 TI - [COPD and Clinical Trials. Results of an expert meeting "Castles in the Air" 2010]. AB - Clinical trials in COPD patients aim at achieving progress in diagnosis and treatment. Study results should be applicable to a large number of patients. However, an analysis of the methods and design of current and previous trials reveals considerable room for improvement. COPD is a complex disease with different clinical phenotypes. Genetic factors need to be evaluated systematically to allow appropriate stratification of patients. Frequently used endpoints such as the FEV1 that had previously been considered reliable have shown limitations in recent trials. Thus, researchers now aim to identify new surrogate parameters that are related to the prognosis of the disease, e. g., composite endpoints and biomarkers. Physical activity and capacity are becoming increasingly important for the evaluation of disease progression. The focus of pharmaceutical development is long acting bronchodilators and new anti inflammatory drugs. The value of non-drug interventions will also be evaluated. PMID- 21656463 TI - [Marcello Malpighi (1628 - 1694) and the terms miliary and tubercle. A completion of hitherto existing historical terminology]. AB - Today Miliary Tuberculosis in Central Europe is a rare disease, quite often with resulting diagnostic uncertainty. The terms "miliary" and "tubercle" are outlined with their up to now accepted historical roots. An analysis of Marcello Malpighi's quite unknown post-mortem reports by the Italian author L. Munster reveals an earlier use of both terms than described till now. PMID- 21656464 TI - Repetitive arterial crisis of deep inferior epigastric perforator flap after mental stress: a case report. AB - The authors report a case of mental stress-induced repeatedly failing microsurgical flap. A 33-year-old female patient underwent a left breast reconstruction with deep inferior epigastric perforator flap. Repetitive arterial crisis occurred postoperatively, which eventually led to flap necrosis. In this case, there was clear correlation between the arterial crisis and mental factors. Mental stress may lead to arterial crisis. PMID- 21656465 TI - Elderly and prostate cancer screening. AB - PURPOSE: To discuss the issue of screening for prostate cancer in elderly individuals. The impact of life expectancy on the choice of treatment in both patients and health care providers has been investigated as well. MATERIALS AND METHODS: We identified studies published from 1990 onwards by searching the MEDLINE database of the National Library of Medicine. Initial search terms were "localized prostate cancer" and "early stage prostate cancer" combined with "elderly patients, life expectancy, palliative, curative, quality of life, watchful waiting, radical prostatectomy, brachytherapy, and external beam radiotherapy". RESULTS: Despite the decrease in prostate carcinoma-specific mortality, the use of prostate-specific antigen (PSA) has been shown to increase the prostate cancer detection rate with a shift to detection at earlier and less invasive pathological stages, overriding concerns about over-diagnosis and over treating. However, PSA screening is mainly offered to younger individuals, and older patients are more likely to have progressive disease and high-risk prostate cancer at diagnosis. Given that PSA screening diagnoses mainly curable, early prostate cancer, screening decision could be offered to otherwise healthy elderly patients who are likely to benefit from aggressive treatment. CONCLUSION: Prostate-specific antigen screening is not officially recommended and most scientific associations promote shared decision making. While PSA screening decision is currently based on physician's judgment, it is clear that a strict age cut-off of 75 years reduces over-screening, but also prohibits screening in healthy older men with a long life expectancy. PMID- 21656466 TI - Evidence-based urology: how does a randomized clinical trial achieve its designed goals? AB - PURPOSE: To discuss the methodological considerations of a standard and applicable randomized clinical trial (RCT). MATERIALS AND METHODS: Using a predefined strategy, we conducted systematic computerized search of the MEDLINE (1966 to 2011) and EMBASE (1980 to 2011) databases to identify all English language educational articles discussing the RCT methodological aspects. Full text versions of identified studies were reviewed in blinded fashion for key methodological and statistical characteristics. RESULTS: Randomized clinical trials in surgery are the highest level of the primary research evidence in evidence-based medicine. There is increasing demand for implementation of RCTs in urological daily practice. CONCLUSION: Randomized clinical trials' report should be absolutely clear, simple, and easy to understand with well-defined internal and external validity. Efforts should be made to design high quality RCTs in urology. There are substantial needs for urologists to their knowledge about RCT. PMID- 21656467 TI - The most important metabolic risk factors in recurrent urinary stone formers. AB - PURPOSE: To evaluate different urinary factors contributing to idiopathic calcium stone disease for determining appropriate medical treatments. MATERIALS AND METHODS: Two 24-hour urine samples were collected from 106 male recurrent idiopathic calcium stone formers and another 109 randomly selected men as the control group matching for age. RESULTS: Cases had significantly higher mean urine oxalate, calcium, uric acid, and chloride in comparison with the healthy controls (P < .001). After necessary adjustment, only mean urine levels of oxalate and uric acid were higher in stone formers than those in controls. The mean value of supersaturation for calcium oxalate was significantly higher in patients than the controls (P = .001); whereas supersaturation for calcium phosphate and uric acid did not reach statistical significance (P = .675 and P = .675, respectively). Hyperoxaluria and hypercalciuria were among the most frequent abnormalities. After categorizing urine parameter values into four quartiles, the risk of stone formation was found to increase as the urine calcium, oxalate, uric acid, chloride, and citrate rise. In contrast, the risk of stone formation decreased with the increase of urine potassium. CONCLUSION: Oxalate seems to play the most important role as urinary stone risk factor in our population followed by calcium and uric acid. In addition to the risk factors, it seems that supersaturation as the sum of all risk factors probably has a high predictive value. PMID- 21656468 TI - Laparoscopic extraperitoneal simple prostatectomy for benign prostate hyperplasia: a two-year experience. AB - PURPOSE: To evaluate the feasibility of laparoscopic simple prostatectomy for large volume prostates. MATERIALS AND METHODS: Between October 2007 and July 2009, laparoscopic simple prostatectomy was performed on 16 patients with the prostates over 80 mL. All the patients were operated with transvesical method. Peri-operative and 3rd postoperative month data were recorded and evaluated. RESULTS: The mean prostate volume was 147 mL (range, 80 to 200 mL). The mean operation time, blood loss, duration of hospitalization, and duration of drain placement was 133 minutes (range, 75 to 210 minutes), 134 cc (range, 50 to 300 cc), 3.9 days (range, 2 to 7 days), and 2.1 days (range, 2 to 3 days), respectively. Only one patient required blood transfusion due to postoperative bleeding and clot obstruction in the catheter lumen. Postoperative infection was not seen and recatheterization was not needed in any of the patients. All the patients' pathology reports were noted as benign. Pre-operative and postoperative International Prostate Symptom Score were 9.2 and 25.4, respectively. Maximum urinary flow rate was 4.0 mL/sec pre-operatively, but 24.7 mL/sec postoperatively. CONCLUSION: Laparoscopic simple prostatectomy is a feasible method with low morbidity and improved postoperative outcomes. PMID- 21656469 TI - Bowel preparation and peri-operative management for radical cystectomy in Turkey: Turkish Urooncology Association multicenter survey. AB - PURPOSE: To investigate the preferences and practice patterns of urooncologic surgeons in Turkey on bowel preparation and peri-operative management for radical cystectomy. MATERIALS AND METHODS: This study was conducted by Turkish Urooncology Association as a multicenter survey. Participants were asked to fill in questionnaires dispensed at annual oncologic meeting or using internet access to the website of Urooncology Association. The questionnaire consisted of multiple choice or open-ended questions related to frequency of cystectomy, surgical technique and type of diversion, bowel preparation protocol, nasogastric tube applications, antibiotic prophylaxis, and deep vein thrombosis prophylaxis. Collected data from the survey were presented descriptively. RESULTS: Forty-four questionnaires from 44 surgeons of different centers were evaluated. All participants answered that they always perform bowel preparation before cystectomy. Four participants reported that they had an experience of cystectomy without bowel preparation. Bowel preparation methods included long conservative methods, short enema protocols, and Golytely, but there were significant differences in application of each method. Of participants, 88.6% perform diversion by themselves whereas others ask help from a general surgeon. Antibiotic prophylaxis is preferred mostly by 2 agents using third-generation cephalosporins and metronidazole for a period of 5 days or more in the majority. Type, duration, and dosage of deep vein thrombosis prophylaxis differed among participants. CONCLUSION: There are significant individual differences in peri operative management of radical cystectomy, which render deficient and sometimes inadequate patient care. There is a need to establish standard protocols for bowel preparation and adequate peri-operative management for radical cystectomy. PMID- 21656470 TI - Is positron emission tomography reliable to predict post-chemotherapy retroperitoneal lymph node involvement in advanced germ cell tumors of the testis? AB - PURPOSE: To evaluate if 18 fluorodeoxyglucose positron emission tomography (18FDG PET) scan could identify post-chemotherapy retroperitoneal lymph node (RPLN) involvement in advanced germ cell tumors of the testis. MATERIALS AND METHODS: Between January 2005 and January 2009, 16 patients with advanced germ cell tumors of the testis underwent RPLN dissection (RPLND) following chemotherapy. Before RPLND, abdominal computed tomography (CT), magnetic resonance imaging (MRI), and 18FDG-PET were performed in all the patients. Findings on 18FDG-PET were compared with pathological evaluation of the removed lymphatic tissue. RESULTS: Both abdominal CT and MRI demonstrated retroperitoneal masses in all the patients following chemotherapy. Although PET did not demonstrate any activity in 8 patients, tumor was detected histopathologically. In 1 patient, 18FDG-PET demonstrated activity; however, no tumor was detected on pathology. Of the remaining 7 patients, 18FDG-PET findings were concordant with the histopathological findings. No activity was detected in 2 patients with no tumors whereas all 5 patients harboring viable tumor cells showed positive 18FDG-PET activity. In our study, sensitivity and specificity of 18FDG-PET in detecting RPLN involvement were detected to be 39% and 67%, respectively. CONCLUSION: 18FDG PET imaging does not seem to be a reliable method in detecting RPLN involvement in advanced germ cell tumors of the testis following chemotherapy. Therefore, we neither recommend routine use of 18FDG-PET scanning nor decide the treatment work up by solely relying on the 18FDG-PET findings in this patient group. PMID- 21656471 TI - General health and quality of life in patients with sexual dysfunctions. AB - PURPOSE: To study the general health and quality of life in patients with sexual dysfunctions. MATERIALS AND METHODS: One hundred and thirty-seven patients with diagnosis of a known sexual dysfunction (SD) were studied. A healthy group of 111 individuals matched for sex, education, and marital status were also selected as a control group. Both groups completed two questionnaires: General Health Questionnaire-28 (GHQ-28) and Personal Wellbeing Index- Adult (PWI-A). To analyze data, descriptive methods as well as student t test for independent groups were used. RESULTS: The mean scores for individuals suffering from SD were more than the control group in total GHQ scale and all its subscales. The mean scores in total PWI-A scale and most of its subscales for individuals suffering from SD were lower than the control group. Since the obtained t values (4.16 to 5.22) for all the comparisons done between the mean scores in GHQ for the two groups were higher than t value in the 't table' for df = 206 at alpha = 0.01 (2.58), differences obtained were significant. Since obtained t values (-2.03 to 4.65) for total quality of life and health, achievements, personal relationship, safety, and feeling part of community dimensions were higher than t value in the 't table' for df = 206 at alpha = 0.05 and alpha = 0.01 (1.96 and 2.58, respectively), differences obtained except for standard of living and future security were significant. CONCLUSION: Somatic, social, and mental measures for people having sexual dysfunctions (patient group) were lower than the control group. PMID- 21656472 TI - Triamcinolone injection following internal urethrotomy for treatment of urethral stricture. AB - PURPOSE: To investigate the success rate of internal urethrotomy when combined with corticosteroid injection in urethral scar tissue for treatment of urethral stricture. MATERIALS AND METHODS: We performed a double-blind, randomized, placebo-controlled study on 70 patients with urethral stricture, who underwent internal urethrotomy from June 2003 to July 2008. Patients were randomized into 2 groups; the experimental group (34 patients) who received triamcinolone acetonide injection and the control group (36 patients) that received an injection of sterile water after internal urethrotomy. Postoperative results were compared between two groups. RESULTS: In the experimental group, 1 (2.94%), 3 (8.82%), and 2 (5.8%) patients developed infection, bleeding, and extravasation, respectively, and recurrence was noted in 12 patients. In the control group, infection, bleeding, and extravasation occurred in 2 (5.55%), 3 (8.33%), and 2 (5.55%) patients, respectively, and stricture recurred in 15 patients. There were no significant differences in stricture location as well as its etiology between the two groups (P = .672 and P = .936, respectively). Complication and recurrence rates in experimental group were lower than the control group, but the difference was not statistically significant (P = .847 and P = .584, respectively). However, time to recurrence decreased significantly in experimental group (8.08 +/- 5.55 versus 3.6 +/- 1.59 months) (P < .05). In our study, we did not find any complications that could be attributed to the triamcinolone acetonide injections. CONCLUSION: It seems that steroid injection after internal urethrotomy is a safe method, which may delay the recurrence of urethral stricture. PMID- 21656473 TI - The lunar cycle: effects of full moon on renal colic. AB - PURPOSE: To evaluate renal colic frequency in different seasons and around full moon. MATERIALS AND METHODS: A total of 1481 patients with renal colic were studied retrospectively addressing days of a month both in solar and lunar calendar. RESULTS: The mean age of the patients was 57 +/- 13 years. Total admissions in summer was 613; of which 288 (41%), 199 (39%), and 126 (43%) were in years 2002, 2003, and 2004, respectively. The highest frequencies in solar calendar were on days 2 (56), 20 (63), and 27 (59) and the lowest were on days 6 (36), 22 (38), 26 (34), and 31 (31). We did not find any statistically significant association according to solar calendar (P = .3). In lunar calendar, most of the admissions were on day 15 (69) and the lowest rates were on days 1 (25) and 30 (26), which was statistically significant (P = .04). CONCLUSION: Renal colic frequency is not correlated with solar calendar, but its highest frequency in lunar calendar is in the middle of the month period. Although we found a correlation between full moon effect and renal tide, but this is a new window for further studies. PMID- 21656474 TI - Ligature versus transvenous endovenorrhaphy for closure of side-to-side arteriovenous fistula created for hemodialysis. AB - PURPOSE: To report a novel technique for arteriovenous fistula (AVF) closure in side-to-side fistulas. MATERIALS AND METHODS: One hundred and sixty-two patients with side-to-side AVFs, who were candidates for AVF closure, were randomly divided into two groups: group A (84 patients) who underwent AVF ligature and group B (78 patients) who underwent AVF closure using transvenous endovenorrhaphy technique. Both procedures were conducted by the same surgical team. The patients were followed up for 6 months. RESULTS: Of 124 patients with proximal AVFs, 65 (52%) subjects underwent ligation and 59 (42%) transvenous endovenorrhaphy. Of 38 patients with distal AVFs, half underwent ligation and for the remainder, transvenous endovenorrhaphy was done. Failure of AVF closure was detected in 28 (17%) patients; 25 (89.28%) were in group A and 3 (10.71%) were in group B. All of these recurrences were successfully treated by transvenous endovenorrhaphy technique. CONCLUSION: We claim that significant lower failure rate of transvenous endovenorrhaphy makes it the technique of choice, especially for side to-side AVFs. PMID- 21656475 TI - Double ureter and duplex system: a cadaver and radiological study. AB - PURPOSE: To study the prevalence of duplex system and double ureter in cadavers and intravenous pyelograms in Indian population. MATERIALS AND METHODS: Fifty cadavers were dissected and 50 intravenous pyelograms were examined on both (right and left) sides for the presence of duplex system and double ureter. RESULTS: One male cadaver aged 43 years showed complete double ureter and duplex system on the right side and incomplete double ureter and duplex system on the left side. Another male cadaver aged 56 years showed incomplete double ureter and duplex system only on the right side. An intravenous pyelogram of a 43-year-old man showed incomplete double ureter along with duplex system on the right side. CONCLUSION: Developmental anomalies of the kidney, ureter, and urinary bladder should be kept in mind and promptly detected before the manifestations of aforementioned complications increase the morbidity of the affected individuals. PMID- 21656476 TI - Laparoscopic repair of vesicouterine fistula: a brief report with review of literature. PMID- 21656477 TI - Spontaneous migration of a surgical clip following partial nephrectomy. PMID- 21656478 TI - Laparoscopic enucleation of leiomyoma of the urinary bladder: a case report and review of the literature. PMID- 21656479 TI - Endoscopic neo cystolithotripsy for multiple calculi in studer ileal neo bladder: a case report. PMID- 21656480 TI - Accidental rupture of hydrocele: a case report. PMID- 21656481 TI - Extragastrointestinal stromal tumor of the urinary bladder: a case report. PMID- 21656482 TI - Bladder amyloidosis mimicking carcinoma. PMID- 21656483 TI - Ureteral herniation with intermittent obstructive uropathy in a renal allograft recipient. PMID- 21656484 TI - [Current operative techniques and strategies in endocrine surgery]. AB - Technical advances and focusing on subsets modified endocrine surgery in the last ten years tremendously. There is on one side a clear trend towards minimal invasive approaches, first of all in the surgery of the adrenal glands, where the transperitoneal or retroperitoneal laparoscopic adrenalectomy has become the gold standard for tumors up to a size of 10 cm in diameter. But also in pancreatic endocrine surgery for small tumors localized in the pancreas tail and up to a certain extend in thyroid and parathyroid surgery, laparoscopic or video assisted techniques are used. On the other side more precise techniques allow a more complete and radical removal of endocrine tissue, especially in thyroid surgery. This article presents a summary of current operative techniques and strategies in endocrine surgery. PMID- 21656485 TI - [When and how to manage thyroid nodules?]. AB - Thyroid nodules are a very frequent finding in particular within the feminine population. Their prevalence increases with age and the vast majority (>95%) are benign and without dangerous consequences. A true cancer of the thyroid is rare. Following the discovery of a thyroid nodule by the patient himself or by the doctor, a relatively simple strategy should exclude the rare event of an underlying cancer. Thyroid ultrasound will confirm that the nodule is of thyroid origin. Furthermore, the ultrasound will measure the size of the nodule and reveal if other nodules or if suspicious lymph nodes are present. The next step is to measure the TSH level. If the TSH is normal, a fine needle aspiration is indicated for nodules larger than 1.0-1.5 centimetres. The choice between clinical follow up and a surgical thyroidectomy will be based upon the cytological analysis (hence the key role of an experimented pathologist in thyroid cytology). A thyroid scan is useless (except in case of hyperthyroidism with a low TSH). PMID- 21656486 TI - [Differentiated thyroid carcinoma--essential for the practitioner]. AB - Differentiated thyroid carcinoma (DCT) is a rare carcinoma (incidence 8 12/100,000) with an excellent prognosis (five year survival of papillary thyroid carcinoma 95%). The presenting symptom of DCT is most frequently an indolent thyroid nodule, often discovered by chance at the occasion of a routine clinical examination. Rarely, DCT presents with a fixed ipsilateral cervical lymph node enlargement or a newly developed hoarseness of the voice. Patients at risk are those who have had irradiation of the head or neck, those with rapid enlargement of a thyroid nodule or patients with rare familiar tumour syndromes. Treatment is most frequently accomplished with total thyroidectomy followed by radioiodine ablation with or without suppressive levothyroxine therapy. In special situations, several radioiodine therapies are needed. All patients need regular long term follow up by neck sonography, measurements of thyroglobuline levels and control of thyroid hormone replacement therapy. DCT may relapse many years (>10) after initial therapy. Patients should ideally be followed by specialized interdisclipinary centres. PMID- 21656487 TI - [Diagnosis and therapy of hyperthyreosis]. AB - Hyperthyreosis, diabetes and calcium disorders are frequent endocrine diseases that are often encountered by the primary care physician. The diagnosis of hyperthyreosis can be established by many different laboratory and analytical tests. However, the clinical context can often guide a specific diagnostic approach. Graves disease and toxic adenomas are the most frequent causes of hyperthyreosis. Diagnosis of Graves disease is most frequent between age 35 and 60 and about 10-20% of patients show already initially signs of endocrine orbithopathy. Measurement of thyroid stimulating immunoglobulins (TSI) is especially valuable in unclear cases. Toxic adenomas are always diagnosed by thyroid uptake studies. Rare causes of hyperthyreosis include thyreoiditis, which is characterized by transient hyperthyreosis (<2 months), and thyrotoxicosis factitia. Here, we discuss diagnosis and therapy of different causes of hyperthyreosis based on three clinical examples. PMID- 21656488 TI - [Pharmacotherapy of hyperthyreosis--adverse drug reactions]. AB - The antithyroid drugs mainly include thioimidazole (carbimazole, methimazole=thiamazole) and propylthiouracil. After absorption, carbimazole is rapidly metabolized to methimazole and thus switching between these two drugs should not be considered in case of side effects. Furthermore, in case of side effects, sometimes even cross reactions between thioimidazoles and propylthiouracil occur. Common and typical adverse reactions of antithyroid drugs include dose dependent hypothyroidism and thus thyroid function should be repeatedly checked while the patient is on antithyroid drugs. Furthermore, pruritus and rash may develop. In this case, one might try to switch from thioimidazoles to propylthiouracil or vice versa. Antithyroid drugs may cause mild dose dependent neutropenia or severe allergy-mediated agranulocytosis, which typically occurs during the first three months of treatment, has an incidence of 3 per 10,000 patients and cross reactivity between thioimidazoles to propylthiouracil may occur. Rarely, antithyroid drugs can cause aplastic anemia. Mainly propylthiouracil, but sometimes also methimazole may lead to an asymptomatic transient increase in liver enzymes or to severe, even lethal liver injury of cholestatic or hepatocellular pattern. Since propylthiouracil associated liver injury was observed increasingly among children and adolescent, it has been suggested to prefer thioimidazoles for these patients. Because of these potential serious adverse effects, physicians should advise patients to immediately seek medical help if they get a fever or sore throat or malaise, abdominal complaints or jaundice, respectively. Furthermore, arthralgias may develop in 1-5% of patients under both antithyroid drugs. Since arthralgias may be the first symptom of more serious immunologic side effects, it is recommended to stop the antithyroid drug in this case. Drug induced polyarthritis mainly develops during the first month of therapy, whereas ANCA-positive vasculitis is generally observed only after long term exposure to propylthiouracil or very rarely with the thioimidazoles. The teratogenic risk of the thioimidazoles is somewhat higher (Aplasia cutis congenita), that is why one generally recommends preferring propylthiouracil during pregnancy. During breast feeding both, thioimidazoles or propylthiouracil, may be administered. Nowadays, perchlorate is only used short term in case of latent hyperthyroidism before administering iodine-containing contrast agents. Therefore, the known side effects, which usually are only observed after long term treatment, are not an issue any more. PMID- 21656489 TI - [Amiodarone and thyroid]. AB - Amiodarone is a widely used antiarrythmic drug and can lead either to hypothyroidism or hyperthyroidism due to its molecular structure which is similar to levothyroxin. Amiodarone induced hypothyroidism can be treated easely with hormonal subsitution. Hyperthyroidism is more challenging. There exist two forms of amiodarone-induced Hyperthyroidism (AIT): AIT type 1 is directly related to the iodine compound of amiodarone and responds to thyreostatic therapy. Type 2 is a consequence of the direct toxicity of amiodarone to the thyroid gland and is treated primarily with glucocorticoids. However, this differentiation often is impossible in clinical settings and a pragmatic approach is needed. PMID- 21656490 TI - [Hypothyroidism]. AB - Hypothyroidism is one of the most frequent endocrine disorders affecting 4.6% of the adult population. 90% of the cases represent subclinical hypothyroidism, defined by increased serum TSH but normal free thyroxine (fT4) values. General screening for hypothyroidism is not recommended because of lack of benefits for the patients. Search for hypothyroidism should therefore focus on patients with symptoms and signs and/or those presenting risk factors for development of hypothyroidism (e.g., autoimmune disorders, thyroid injury, post partum state). Because of the lack of specificity of sings and symptoms of this frequent disorder the diagnosis is based on measurement of TSH or TSH and fT4 in case of conditions that may affect TSH values such as non-thyroidal illness, or medications. Whereas primary hypothyroidism is due to lack of function of the thyroid itself and easy recognized by increased serum TSH, mild forms of secondary hypothyroidism may be difficult to detect because of the lack of function of the pituitary and thus absence of the best indicator of thyroid function. Here measurement of fT4 and a clinical assessment are the cornerstones for diagnosis of secondary hypothyroidism and monitoring of its treatment. In case of subclinical hypothyroidism defined as increased TSH but fT4 still within the normal laboratory range a TSH value above 10 mU/l is regarded as indication for treatment. For values between 4 and 10 mU/l an individualized pragmatic treatment approach based on the presence of clinical sings of hypothyroidism may be justified. Some patients however should be treated regardless of their clinical symptoms including women in childbearing age who want to become pregnant, patients with goitre, and patients with history of Graves disease. Treatment of hypothyroidism is best done with thyroxine (T4) alone; combination therapy of thyroxine with the active compound T3 does not have any advantage. The required L-T4 dose for optimal substitution (TSH between 0.5 and 2.5 mU/l) is in the range of 1.6 ug/kg body weight per day. In young subjects the starting dose should be close to the required dose i.e., 75 to 100 ug, elder patients and those with ischemic heart disease should start with lower doses (25-50 ug). Pregnant women under L-T4 substitution should increase the dose by 25% as soon as pregnancy is diagnosed. PMID- 21656491 TI - [Primary hyperparathyroidism]. AB - Primary hyperparathyroidism is frequently an incidental finding in asymptomatic patients. Often the diagnosis of primary hyperparathyroidism is made in evaluation for osteoporosis, rarely in the context of hypercalcemic crisis, myopathy, kidney stones, nephrocalcinosis, and osteitis fibrosa. The most frequent cause for primary hyperparathyroidism is benign parathyroid adenoma, reminders have hyperplasia. Primary hyperparathyroidism is defined as hypercalcemia with inappropriately high parathyroid hormone levels. Surgery is the definitive treatment for patients with symptomatic primary hyperparathyroidism and asymptomatic patients, who meet one of the following criteria: serum calcium>0.25 mmol/L (1.0 mg/dl) above the accepted normal reference range, renal failure (GFR<60 ml/min) and presence of osteoporosis (T score<-2.5 or fracture). Parathyroidectomy should be performed by an experienced surgeon. As an alternative in inoperable patients or preoperatively in severe hypercalcemia cinacalcet successfully reduces calcium levels. In asymptomatic patients not meeting the above mentioned criteria serum calcium and creatinin levels should be measured once a year and DXA every two years, since 30% of the patients with asymptomatic primary hyperparathyroidism are progressive. PMID- 21656492 TI - [Hyponatremia]. AB - Hyponatremia is the most common electrolyte disorder in clinical practice and is associated with increased mortality in hospitalized patients. Sodium is the predominant extracellular cation and, together with its anion chloride, constitutes most of the osmoles in the extracellular space. In the presence of an intact thirst sensation, serum osmolality is set by the mechanisms of salt and water homeostasis to ~280-290 mOsm/kg. Hyponatremia results from excess of free water more often than from lack of salt. Free water clearance is regulated by the antidiuretic hormone and depends on adequate delivery of solute to the diluting segments of the nephron. Analysis of hyponatremia is best performed in a systematic manner, taking into account measured or calculated serum osmolality and the volume state as assessed clinically. Urinary osmolality and sodium concentration may facilitate the differential diagnosis. Therapy of hyponatremia should aim at correcting the underlying disorder. Only in severe, symptomatic hyponatremia should hypertonic saline be infused, in which case care should be taken to avoid complications such as osmotic demyelination. PMID- 21656493 TI - [Adrenal insufficiency--diagnosis and treatment in clinical practice]. AB - Adaequate stimulation of the hypothalamic-pituitary-adrenal axis (cortisol-axis) is essential for the adaptation of the human organism to stress and the preservation of homeostasis. Clinical and laboratory changes in adrenal insufficiency are often non-specific, therefore stimulation tests are needed in the assessment of the cortisol-axis. The most common cause of primary adrenal insufficiency is autoimmune adrenalitis (as part of the polyglandular autoimmune syndrome), while treatment with glucocorticoids is responsible for secondary adrenal insufficiency. Chronic adrenal insufficiency is reliably diagnosed by conventional or low-dose ACTH test. However, in the acute stage or in critically ill patients, cortisol deficiency is diagnosed on clinical grounds, namely hemodynamic instability and catecholamine resistance along with the results of the ACTH test. The dose of glucocorticoid replacement depends on body surface and has to be adjusted in stressful events. PMID- 21656494 TI - [Health risks of oral contraceptives]. AB - Oral contraceptives (OC) are either composed of a combination of an estrogen derivative (usually ethinly estradiol) and a progestogen, or they contain a progestogen only. OC are characterized by a high effectiveness and have a low failure rate if taken correctly. Most women tolerate OC relatively well, but adverse effects do occur which are driven by the estrogen dose as well as by the type of progestogen. The most frequently reported adverse effects are nausea or vomiting, breast tenderness, headache or inbalanced mood, but these unwanted side effects are often transient. The fear of weight gain of many OC users is not necessarily supported by data from studies which report relatively little differences in body mass index on average during OC use. Nevertheless, substantial weight gain can occur in individual women. The widely discussed fear of breast cancer is also not justified, and the risk of developing ovarian or endometrial cancer is reduced for women who use OC on a regular basis. Venous thromboembolism (VTE) is the adverse effect with the greatest potential for serious harm if pulmonary embolism develops. This rare, but potentially dangerous adverse effect of OC has been discussed emotionally for many years and keeps attracting a lot of public interest. VTE is rare in young women, but the VTE risk is increased two- to sixfold for OC users as compared to non-users. The VTE risk increases with increasing estrogen dose, is highest in the first year of use, and is higher for OC from the third generation (containing desogestrel, gestodene or norgestimate) than for OC from the second generation (containing levonorgestrel) or than for the progestogen-only pill. According to most studies, OC containing the progestogens drospirenone or cyproterone acetate are similar with regard to VTE risks than OC from the third generation. Individual genetic susceptibility affecting the clotting system plays a major role in the risk of developing VTE in combination with OC, and smoking is also an important contributing factor to an increased VTE risk for women using OC. It is important that doctors and pharmacists inform new users of OC about potential health risks of OC use, and that the personal and family history of previous health risks is assessed thoroughly in order to rule out that important and relevant contraindications are present when a women starts taking OC. PMID- 21656495 TI - [Perioperative cardiac risk management]. PMID- 21656496 TI - [Heart diseases]. PMID- 21656497 TI - [Comment on rule of thumb 14. Polymyalgia]. PMID- 21656498 TI - [Acute gastrointestinal bleeding - diagnosis with computed tomography]. AB - Computed tomography represents a fast, non-invasive and accurate imaging modality for the diagnosis of acute gastrointestinal bleeding by providing information about localization and source of bleeding. Owing to its robustness and wide availability, it has the potential to be the first line imaging test in patients with acute life-threatening bleeding, for helping in the planning of interventional or surgical procedures. PMID- 21656499 TI - [Adult syringomyelia - a syndrome of different origins]. AB - Syringomyelia describes an intra-medullary cyst in the spinal cord. In the adult patient, the pathology mostly results from Chiari-I-malformation or from severe spinal trauma. The clinical picture varies broadly, but symptoms often include pain and progressive neurologic deficits. During the clinical course, muscular atrophy and loss of pain and temperature sensation may develop in the affected region. Today, magnet resonance imaging helps to detect syringomyelia at an early stage. The interdisciplinary therapeutic approach includes an adequate pain treatment and physiotherapy, in selected cases a surgical intervention by an experienced surgeon. If not treated surgically, most symptomatic patients experience progressive neurologic deficits that may lead to severe paragplegia and chronic neuropathic pain. PMID- 21656500 TI - [Infectious endocarditis]. PMID- 21656501 TI - [Do elderly hypertensive patients benefit from drug therapy?]. PMID- 21656502 TI - [Alcohol, acid, vitamins and heart]. AB - We report on a 67-year-old male patient with chronic alcoholism, who presented with acute dyspnea, a strongly reduced left ventricular cardiac function and a severe lactic acidosis. In face of a low thiamine serum level and a rapid improvement after parenteral thiamine administration we were able to diagnose a Shoshin-Beriberi syndrome with cardiogenic shock and reversible dilated cardiomyopathy. The epidemiology, pathophysiology, clinics and treatment of the rare cardiac manifestation of this vitamine deficiency are discussed. PMID- 21656503 TI - [Irbesartan does not reduce the rate of cardiovascular events in patients with atrial fibrillation]. PMID- 21656504 TI - [Not Available]. PMID- 21656506 TI - [CME ultrasound diagnosis 40. Lymph node tuberculosis of the neck]. PMID- 21656509 TI - Hospital volume and surgical outcomes after elective hip/knee arthroplasty: a risk-adjusted analysis of a large regional database. AB - OBJECTIVE: To examine the relationship between hospital procedure volume and surgical outcomes following elective primary total hip arthroplasty/total knee arthroplasty (THA/TKA). METHODS: Using the Pennsylvania Health Care Cost Containment Council database, we identified all patients who underwent elective primary THA/TKA in Pennsylvania. Hospitals were categorized according to the annual volume of THA/TKA procedures, as follows: <=25, 26-100, 101-200, and >200. The 30-day complication rate and 30-day and 1-year mortality rates were assessed by logistic regression models, adjusted for age, sex, race, insurance type, hospital region, 3M All Patient Refined Diagnosis Related Group risk of mortality score, hospital teaching status, and bed count. RESULTS: In the THA and TKA cohorts, the mean age of the patients was 69 years, and 42.8% and 35%, respectively, were men. Compared with patients whose surgeries were performed at very-high-volume hospitals (>200 procedures/year), patients who underwent elective primary THA procedures at hospitals with a very low volume (<=25 procedures/year), a low volume (26-100 procedures/year), or a high volume (101 200 procedures/year) had higher multivariable-adjusted odds ratios (ORs) for venous thromboembolism (OR 2.0, 95% confidence interval [95% CI] 0.2-16.0), OR 3.4 [95% CI 1.4-8.0], and OR 1.1 [95% CI 0.3-3.7], respectively) and 1-year mortality (OR 2.1 [95% CI 1.2-3.6], OR 2.0 [95% CI 1.4-2.9], and OR 1.0 [95% CI 0.7-1.5], respectively). Among patients ages >=65 years who underwent elective primary TKA at very-low-volume, low-volume, and high-volume hospitals, the ORs for 1-year mortality were significantly higher (OR 0.6 [95% CI 0.2-2.1], OR 1.6 [95% CI 1.0-2.4], and OR 0.9 [95% CI 0.6-1.3], respectively), compared with very high-volume hospitals. CONCLUSION: Performance of elective primary THA and TKA surgeries in low-volume hospitals was associated with a higher risk of venous thromboembolism and mortality. Confounding due to unmeasured variables is possible. Modifiable system-based factors/processes should be targeted to reduce the number of complications associated with THA/TKA procedures. PMID- 21656511 TI - Inhibition or overactivation of AICDA to eliminate pathologic B cell clones? Comment on the article by Hsu et al. PMID- 21656512 TI - Preservation of kidneys from controlled donors after cardiac death. AB - BACKGROUND: Donation after cardiac death (DCD) expands the pool of donor kidneys, but is associated with warm ischaemic injury. Two methods are used to preserve kidneys from controlled DCD donors and reduce warm ischaemic injury: in situ preservation using a double-balloon triple-lumen catheter (DBTL) inserted via the femoral artery and direct cannulation of the aorta after rapid laparotomy. The aim of this study was to compare these two techniques. METHODS: This was a retrospective cohort study of 165 controlled DCD procedures in two regions in the Netherlands between 2000 and 2006. RESULTS: There were 102 donors in the DBTL group and 63 in the aortic group. In the aortic group the kidney discard rate was lower (4.8 versus 28.2 per cent; P < 0.001), and the warm (22 versus 27 min; P < 0.001) and the cold (19 versus 24 h; P < 0.001) ischaemia times were shorter than in the DBTL group. Risk factors for discard included preservation with the DBTL catheter (odds ratio (OR) 5.19, 95 per cent confidence interval 1.88 to 14.36; P = 0.001) and increasing donor age (1.05, 1.02 to 1.07; P < 0.001). Warm ischaemia time had a significant effect on graft failure (hazard ratio 1.04, 1.01 to 1.07; P = 0.009), and consequently graft survival was higher in the aortic cannulation group (86.2 per cent versus 76.8 per cent in the DBTL group at 1 year; P = 0.027). CONCLUSION: In this retrospective study, direct aortic cannulation appeared to be a better method to preserve controlled DCD kidneys. PMID- 21656513 TI - Outcome after partial hepatectomy for hepatocellular cancer within the Milan criteria. AB - BACKGROUND: There is a trend to offer liver transplantation to patients with hepatocellular carcinoma (HCC) with tumour status within the Milan criteria but with preserved liver function. This study aimed to evaluate the outcome of such patients following partial hepatectomy as primary treatment. METHODS: A retrospective analysis was performed on all adult patients with HCC and tumour status within the Milan criteria undergoing partial hepatectomy at a single centre from 1995 to 2008. Their outcomes were compared with those of similar patients having right-lobe living donor liver transplantation (LDLT) as primary treatment. RESULTS: A total of 408 patients with HCC were enrolled. Some 384 patients with a solitary tumour 5 cm or less in diameter had a better 5-year survival rate than 24 patients with oligonodular tumours (2-3 nodules, each 3 cm or less in size) (70.7 versus 46 per cent; P = 0.025). Multivariable analysis identified younger age (65 years or less), lack of postoperative complications, negative resection margin, absent microvascular invasion and non-cirrhotic liver as predictors of favourable overall survival. The 5-year survival rate of 287 younger patients with chronic liver disease and R0 hepatectomy was 72.8 per cent, comparable to that of 81 per cent in 50 similar patients treated by LDLT (P = 0.093). CONCLUSION: Partial hepatectomy for patients with HCC and tumour status within the Milan criteria achieved a satisfactory 5-year survival rate, particularly in younger patients with solitary tumours and R0 hepatectomy. Patients with oligonodular tumours have a worse survival and might benefit from liver transplantation. PMID- 21656514 TI - Complications associated with erythropoietin-stimulating agents in patients with metastatic breast cancer: a Surveillance, Epidemiology, and End Results-Medicare study. AB - BACKGROUND: The authors evaluated the patterns of use and the risk of thromboembolic events (TEE) associated with erythropoietin-stimulating agents (ESAs) in older patients with metastatic breast cancer who were receiving chemotherapy. METHODS: The study was retrospective and used the SEER-Medicare linked database. Stage IV breast cancer patients diagnosed from 1995-2005, treated with chemotherapy, >=66 years old, with full coverage of Medicare A and B were included. The World Health Organization's International Classification of Diseases (ICD-9) and the Healthcare Common Procedure Coding System (HCPCS) were used to identify the use of ESAs, chemotherapy, and complications of therapy. Analyses included descriptive statistics and logistic regression. RESULTS: Of 2266 women, 980 (43.3%) received ESAs, and 1286 (56.7%) did not. Patients diagnosed after 1999 or who received treatment with taxanes, anthracyclines, or vinorelbine were more likely to receive ESAs. Patients receiving ESAs had higher rates of stroke (18.5% vs 15.1%, P = .031); deep-vein thrombosis (DVT; 21.3% vs 14.4%, P<.001), other/unspecified thromboembolic event (TEE; 19.8% vs 14.7%, P = .001), and any clot (31.3% vs 23.4%, P<.0001). In multivariate analysis, patients receiving ESAs had increased risk for DVT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.05-1.75), and any clot (OR, 1.26; 95% CI, 1.02-1.57). A dose dependent effect was evident for stroke, DVT, other TEE, and any clot. CONCLUSIONS: In this cohort of patients, the use of ESAs increased the risk of TEEs, with a dose-dependent effect for stroke, DVT, other TEE, and any clot. The data show that among patients treated with chemotherapy and ESAs for metastatic breast cancer, TEEs are a common event. Therefore, caution is recommended when using these agents. PMID- 21656517 TI - Transcriptional regulation of organic anion transporting polypeptide SLCO4C1 as a new therapeutic modality to prevent chronic kidney disease. AB - Uremic toxins accumulate in patients with chronic kidney diseases (CKDs) and cause further progression of renal damage and cardiovascular diseases. Recently, it was reported that some of the organic anion transporting polypeptides (OATPs) and the organic anion transporters (OATs) are involved in the renal elimination of uremic toxins. SLCO4C1 is the only OATP expressed at the basolateral side of proximal tubular cells in human kidney, and it mediates the excretion of uremic toxins. The overexpression of human SLCO4C1 in rat kidney promotes the renal excretion of uremic toxins and reduces hypertension, cardiomegaly, and renal inflammation in renal failure. Statins induce SLCO4C1 expression thorough transcriptional factor Aryl hydrocarbon receptor through binding of the xenobiotic responsive element at its promoter region. The administration of statin in a rat renal failure model facilitated the elimination of uremic toxins and mitigated organ damage. In addition, metabolomic analysis of rat renal failure models and patients with CKD by capillary electrophoresis-mass spectrometry is a useful method for identifying new uremic solutes and explores surrogate biomarkers for detecting the progression of early stage CKD. PMID- 21656516 TI - Modeling structure-function relationships for diffusive drug transport in inert porous geopolymer matrices. AB - A unique structure-function relationship investigation of mechanically strong geopolymer drug delivery vehicles for sustained release of potent substances is presented. The effect of in-synthesis water content on geopolymer pore structure and diffusive drug transport is investigated. Scanning electron microscopy, N2 gas adsorption, mercury intrusion porosimetry, compression strength test, drug permeation, and release experiments are performed. Effective diffusion coefficients are measured and compared with corresponding theoretical values as derived from pore size distribution and connectivity via pore-network modeling. By solely varying the in-synthesis water content, mesoporous and mechanically strong geopolymers with porosities of 8%-45% are obtained. Effective diffusion coefficients of the model drugs Saccharin and Zolpidem are observed to span two orders of magnitude (~1.6-120 * 10(-8) cm(2) /s), comparing very well to theoretical estimations. The ability to predict drug permeation and release from geopolymers, and materials alike, allows future formulations to be tailored on a structural and chemical level for specific applications such as controlled drug delivery of highly potent substances. PMID- 21656515 TI - Myocilin, a glaucoma-associated protein, promotes cell migration through activation of integrin-focal adhesion kinase-serine/threonine kinase signaling pathway. AB - The MYOCILIN gene encodes a secreted glycoprotein which is highly expressed in eye drainage structures. Mutations in this gene may lead to juvenile open-angle glaucoma and adult onset primary open-angle glaucoma, one of the leading causes of irreversible blindness in the world. Functions of wild-type myocilin are still unclear. We have recently demonstrated that myocilin is a modulator of Wnt signaling and may affect actin cytoskeleton organization. Here we report that myocilin and its naturally occurring proteolytic fragments, similar to Wnt3a, are able to stimulate trabecular meshwork, NIH3T3, and FHL124 cell migration with the N-terminal proteolytic fragment of myocilin lacking the olfactomedin domain producing the highest stimulatory effect. Stimulation of cell migration occurs through activation of the integrin-focal adhesion kinase (FAK)-serine/threonine kinase (AKT) signaling pathway. Inhibition of FAK by siRNA reduced the stimulatory action of myocilin by threefold. Activation of several components of this signaling pathway was also demonstrated in the eyes of transgenic mice expressing elevated levels of myocilin in the eye drainage structures. These data extend the similarities between actions of myocilin and Wnt proteins acting through a beta-catenin-independent mechanism. The modification of the migratory ability of cells by myocilin may play a role in normal functioning of the eye anterior segment and its pathology including glaucoma. PMID- 21656518 TI - Complementary near-infrared and Raman chemical imaging of pharmaceutical thin films. AB - Complementary near-infrared (NIR) and Raman mapping techniques have been used to study the distribution of drug particles suspended in a polymeric film. The film configuration was used with the goal of maintaining a drug with a particle size of less than 10 um in a nonagglomerated form and to satisfy two commonly encountered pharmaceutical needs: enhanced dissolution rate of poorly soluble drugs and the content uniformity of drugs administered in low doses. A total of four film batches were prepared for this study using hydroxypropyl methylcellulose (HPMC) with griseofulvin as the active pharmaceutical ingredient. The NIR method analyzed a film area of 3 * 2.6 mm, whereas Raman mapping analyzed an area of 10 * 10 um, and every sample was analyzed by the two methods. The second derivative transform removed baseline variations in the NIR spectra and provided differentiation between the two components. NIR chemical imaging did not identify clusters larger than 0.05 mm. Raman analysis identified areas rich in griseofulvin or HPMC, which were used to develop a partial least squares discriminant analysis method to determine drug or polymer distribution throughout the film. PMID- 21656519 TI - How molecular interactions affect crystal morphology: the case of haloperidol. AB - The tableting behaviour of drugs can be dramatically affected by changes in the crystal habit of the drug molecule. Pharmaceutical companies are therefore interested in the morphology prediction as a possible tool to optimise the industrial process. Molecular mechanics calculations embedded in dedicated software together with X-ray diffraction analysis were used to enlighten the structural properties of 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4 fluorophenyl)butan-1-one-whose commercial name is haloperidol--an antipsychotic drug that contributed to the progress and revolution of psychiatric care. We defined, by means of X-ray powder diffraction, which--or how much--of the two crystallographic structures present in the Cambridge Crystallographic Database represents the commercial crystalline powder. Once the correct structure was selected, the whole structural analysis was carried out as a comparison with the already deposited structures. The available single crystal structure was used to model the X-ray powder diffraction pattern. The "real" structure was then optimised by means of molecular mechanics and the crystal morphology of the compounds was predicted with different computational methods. Analogies and differences among the different morphologies, together with the potential role of several solvents were used to try to bridge the gap between the molecular structure--that is, the atomic point of view--and the crystal habit. PMID- 21656520 TI - Molecular basis of chronopharmaceutics. AB - Many pathophysiological circumstances vary during 24 h periods. Many physiologic processes undergo biological rhythms, including the sleep-wake rhythm and metabolism. Disruptive effect in the 24 h variations can manifest as the emergence or exacerbation of pathological conditions. So, chronotherapeutics is gaining increasing interest in experimental biology, medicine, pharmacy, and drug delivery. This science and the plethora of information should be used intelligently for optimizing the effectiveness and safety of the drug, relying on the timing of drug intake. These chronopharmacological findings are affected by not only the pharmacodynamics but also pharmacokinetics of drugs. The mammalian circadian pacemaker is located in the suprachiasmatic nucleus. The molecular mechanisms are associated with Clock genes that control the circadian rhythms in physiology, pathology, and behavior. Clock controls several diseases such as metabolic syndrome, cancer, and so on. CLOCK mutation influences the expression of both rhythmic and nonrhythmic genes in wild-type tissues. These genotypic changes lead to phenotypic changes, affecting the drug pharmacokinetic and pharmacodynamic parameters. This review is intended to elaborate system regulating biological rhythms and the applicability in pharmaceutics from viewpoints of the intraindividual and interindividual variabilities of Clock genes. PMID- 21656521 TI - Spontaneous crystalline-to-amorphous phase transformation of organic or medicinal compounds in the presence of porous media, part 2: amorphization capacity and mechanisms of interaction. AB - Amorphization of crystalline compounds using mesoporous media is a promising technique to improve the solubility and dissolution rate of poorly soluble compounds. The objective of this paper is to determine the capacity of amorphization and understand the mechanisms of phase transformation. Commercial grades of mesoporous silicon dioxide (SiO(2)) samples (5- to 30-nm mean pore diameters) with either constant surface area or constant pore volume were used. The amorphization capacity of naphthalene was not proportional to either the surface area or the pore volume measured using adsorption chambers. Instead, the amorphization capacity correlated with surface curvature, that is, the smaller the pore diameter and the higher the surface curvature, the greater the amorphization capacity. The change in surface chemistry due to a highly curved surface may be responsible for the enhanced amorphization capacity as well. The amorphization of crystalline compounds was facilitated through capillary condensation, with the decrease in pore volume as the direct experimental evidence. The amorphization capacity was also enhanced by the dipole-dipole or dipole-induced dipole interaction, promoted by the hydroxyl groups on the surface of SiO(2). The enthalpy of vapor-solid condensation of crystalline compounds was a useful indicator to predict the rank order of amorphization capacity. PMID- 21656522 TI - Is surgical resection still the treatment of choice for early hepatocellular carcinoma? PMID- 21656523 TI - Treatment strategy for early hepatocellular carcinomas: comparison of radiofrequency ablation with or without transcatheter arterial chemoembolization and surgical resection. AB - BACKGROUND: The preferred choice between surgical treatment and radiofrequency ablation (RFA) for the treatment of small resectable hepatocellular [corrected] carcinoma (HCC) has become a subject for debate. METHODS: We compared the results of hepatic resection (n = 199) with those of RFA (n = 87), of which 69 patients were treated with transcatheter arterial chemoembolization followed by RFA, for 286 patients with 3 or fewer nodules, none of which exceeded 3 cm in diameter at Hiroshima University Hospital. RESULTS: In subgroup analysis of single HCC with tumor size exceeding 2 cm in Child-Pugh class A, the disease-free survival time was significantly longer in the surgical resection group than in the RFA group (P = 0.048). In the subgroups of a single and multiple HCC with tumor size <=2 cm in Child-Pugh class A, the overall and disease-free survival rates were almost the same for the surgical resection and RFA groups (P = 0.46 and 0.58, respectively, in single HCC, and P = 0.98 and 0.98, respectively, in multiple HCC). CONCLUSION: Surgical resection may provide better long-term disease-free survival than RFA in the subgroup of a single HCC exceeding 2 cm of Child-Pugh class A. PMID- 21656524 TI - The diagnostic value of circulating stanniocalcin-1 mRNA in non-small cell lung cancer. AB - BACKGROUND AND OBJECTIVES: Previous studies have suggested that the aberrant expression of Stanniocalcin-1 (STC1) occurs in tumor cells. In this study, we explored whether the circulating STC1 mRNA is a promising biomarker in the peripheral blood in patients with non-small cell lung cancer (NSCLC). METHODS: The level of circulating STC1 mRNA was determined with a sensitive quantitative real-time reverse transcription PCR assay. and the data were analyzed by the statistical methods of one-way ANOVA, Mann-Whitney-Wilcoxon U-Test, and Receiver operating characteristic (ROC) curve analysis. RESULTS: The level of circulating STC1 mRNA in patients with NSCLC was significantly higher than in patients with benign pulmonary disease (P < 0.001) or healthy volunteers (P < 0.001). Higher levels of circulating STC1 mRNA were associated with more advanced tumor stages and histological subtypes. Using a cutoff of 0.055, the sensitivity and specificity of STC1 mRNA levels to differentiate between patients with NSCLC and patients with benign pulmonary diseases was 66.7 and 90.9%, and it was 63.7 and 99.8% for patients with NSCLC and healthy volunteers, respectively. CONCLUSIONS: These findings support our hypothesis that circulating STC1 mRNA is a promising biomarker in the peripheral blood. PMID- 21656525 TI - Identification of high-risk stage II and stage III colorectal cancer by analysis of MMP-21 expression. AB - BACKGROUND: The expression of matrix metalloproteinase-21 (MMP-21) has been shown to be elevated in some solid tumor and thought to enhance tumor invasion and metastasis ability. In the present study, we investigated the expression of MMP 21 and its association with prognosis in stage II and III colorectal cancer. METHODS: MMP-21 expression was investigated in 286 cases of colorectal cancer by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of MMP-21 expression with clinicopathological characters and overall survival of patients with stage II and III colorectal cancer. RESULTS: MMP-21 expression was significantly higher in colorectal cancer, compared with that in normal epithelial tissue. And it also correlated with tumor invasion, lymph node metastasis, and distant metastasis of colorectal cancer. MMP-21 was also proved to be an independent prognostic factor in patients with stage II as well as stage III colorectal cancer. However, no correlations between MMP-21 expression and patients' age, sex, tumor location, or differentiation status were detected. CONCLUSION: These results suggested the potential role of MMP-21 in the invasion and metastasis process of human colorectal cancer. It could also be a novel molecular marker to predict prognosis of patients with stage II and stage III colorectal cancer. PMID- 21656526 TI - A meta-analysis of prospective randomized trials comparing minimally invasive and open distal gastrectomy for cancer. AB - Current literature suggests that minimally invasive distal gastrectomy (MIDG) may enhance post-operative recovery and decrease morbidity compared to open surgery (ODG) in patients with gastric cancer. A meta-analysis of six Prospective Randomized Trials comparing MIDG (343 patients) and ODG (323 patients) for gastric cancer was conducted. MIDG was associated with increased operative time, reduced blood loss and overall morbidity. There was not sufficient data to draw solid conclusions about the oncologic quality of MIDG. PMID- 21656527 TI - Hedgehog signaling protein expression and its association with prognostic parameters in prostate cancer: a retrospective study from the view point of new 2010 anatomic stage/prognostic groups. AB - BACKGROUND: The expression of Hedgehog (Hh) signaling pathway in prostate cancer is well-known but its clinicopathologic role has not been elucidated well. METHODS: Prostatectomy cases of prostate cancer (n=155) were prepared and assessed by clinicopathologic parameters including new 2010 anatomic stage/prognostic groups (ASPG) of prostate cancer. The expression of five Hh signaling proteins including Sonic hedgehog (Shh), Patched, Smoothened, and GLIoma-associated oncogene, in addition with Suppressor of fused (Su(fu)) were analyzed immunohistochemically. Real-time polymerase chain reaction was performed to assess the mRNA expression status. RESULTS: The expression of each Hh signaling protein was significantly correlated with poor prognostic parameters such as larger tumor size, high pretreatment prostate-specific antigen (PSA), high Gleason score, perineural invasion and new ASPG. Among Hh signaling proteins, Sonic hedgehog and Smoothened expressions tend to have a significantly higher risk of PSA recurrence (P<0.001 and P=0.011, respectively). Multivariate analysis proved Shh expression as independent prognostic factors of PSA recurrence along with Gleason score, ASPG, tumor volume, and pretreatment PSA. CONCLUSIONS: Hh signaling activity is significantly associated with worse prognostic parameters. Shh can be regarded as a poor prognostic factor for PSA recurrence. PMID- 21656528 TI - Pharmacodynamics of dietary phytochemical indoles I3C and DIM: Induction of Nrf2 mediated phase II drug metabolizing and antioxidant genes and synergism with isothiocyanates. AB - The antioxidant response element (ARE) is a critical regulatory element for the expression of many phase II drug metabolizing enzymes (DME), phase III transporters and antioxidant enzymes, mediated by the transcription factor Nrf2. The aim of this study was to examine the potential activation and synergism of Nrf2-ARE-mediated transcriptional activity between four common phytochemicals present in cruciferous vegetables; the indoles: indole-3-carbinol (I3C), 3,3' diindolylmethane (DIM); and the isothiocyanates (ITCs): phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). The cytotoxicity of the compounds was determined in a human liver hepatoma cell line (HepG2-C8). The combination index was calculated to assess the synergistic effects on the induction of ARE-mediated gene expressions. Quantitative real-time polymerase chain reaction (qPCR) was employed to measure the mRNA expressions of Nrf2 and Nrf2-mediated genes. I3C and DIM showed less cytotoxicity than SFN and PEITC. Compared with I3C, DIM was found to be a stronger inducer of ARE. Synergism was observed after combined treatments of 6.25 um I3C + 1 um SFN, 6.25 um I3C + 1 um PEITC and 6.25 um DIM + 1 um PEITC, while an additive effect was observed for 6.25 um DIM + 1 um SFN. Induction of endogenous Nrf2, phase II genes (GSTm2, UGT1A1 and NQO1) and antioxidant genes (HO-1 and SOD1) was also observed. In summary, the indole I3C or DIM alone could induce or syngergistically induce in combination with the ITCs SFN or PEITC, Nrf2 ARE-mediated gene expression, which could potentially enhance cancer chemopreventive activity. PMID- 21656529 TI - Amniopatch for iatrogenic rupture of the fetal membranes. AB - With the increased use of invasive fetal procedures, the number of women facing post-procedure membrane rupture is increasing. Here we review the use of platelets and fresh frozen plasma for sealing iatrogenic fetal membrane defects by describing the mechanisms of action of the amniopatch procedure as well as published experience. In cases of iatrogenic preterm pre-labour rupture of the membranes, amniopatch effectively seals the fetal membranes in over two-thirds of cases. There is a risk of 16% of in utero fetal death, which may occur at varying intervals from the procedure and often for unknown reasons. Amniopatch has also been used as a treatment of chorionic membrane separation. In summary, current experience suggests that in cases of early onset but persistent amniotic fluid leakage following an invasive fetal procedure, amniopatch is an option. PMID- 21656530 TI - Prenatal assessment and management of sacrococcygeal teratoma. AB - Sacrococcygeal teratoma (SCT) is one of the most common tumors in newborns with a birth prevalence of up to 1 in 21,700 births. Routine fetal anomaly screening programs allow for prenatal diagnosis in many cases. Fetal ultrasound with Doppler evaluation and more recently magnetic resonance imaging may be used to document the extent of the tumor as well as identifying the population at risk for serious fetal complications. Rapidly growing SCT and highly vascularized tumors are more likely to have hemodynamic repercussions. Fetal hydrops is usually considered as a poor prognostic marker and a potential indicator for fetal intervention. Newborns with SCT require stabilization prior to early surgical resection. In case of malignancy additional chemotherapy may be required. SCT may result in significant morbidity, either directly or as a consequence of surgical therapy. Careful postnatal follow-up is required for timely identification and treatment of complications as well as recurrence. This paper aims to review the perinatal management of this condition. PMID- 21656531 TI - Enantiomeric separation of D,L-tryptophan and D,L-kynurenine by HPLC using pre column fluorescence derivatization with R(-)-DBD-PyNCS. AB - The enantiomeric separation of D,L-tryptophan (Trp) and D,L-kynurenine (KYN) was investigated by high-performance liquid chromatography using pre-column fluorescence derivatization with a chiral fluorescent labeling reagent, R(-)-4-(3 isothiocyanatopyrrolidin-1-yl)-7- (N,N-dimethylaminosulfonyl)-2,1,3 benzoxadiazole [R(-)-DBD-PyNCS]. Using an octadecylsilica column, namely, an Inertsil ODS-3 column (250 x 2.0 mm; i.d., 3 MUm), four fluorescence peaks of D- and L-Trp as well as D- and L-KYN derivatized with R(-)-DBD-PyNCS were clearly observed, and their chemical structures were confirmed by HPLC-time-of-flight mass spectrometry. Simultaneous separation was achieved under the mobile phase condition of 1.5% acetic acid in H2O-CH3CN (60:40), and the separation factors of D,L-Trp and D,L-KYN derivatized with R(-)-DBD-PyNCS were 1.22 and 1.19, respectively. Fluorescence detection was carried out by setting the emission wavelength at 565 nm, and the excitation wavelength at 440 nm, and the detection limits were approximately 0.3-0.5 pmol (signal-to-noise ratio of 3). PMID- 21656532 TI - Rapid identification and evaluation of antioxidant compounds from extracts of Petasites japonicus by hyphenated-HPLC techniques. AB - Gradient HPLC coupled to Diode Array Detector (DAD), MS/MS and NMR was applied to the rapid structure determination of major compounds of methanol extracts from leaves and roots of Petasites japonicus. The relative antioxidant capacities of the compounds were evaluated by an HPLC system with post-column on-line antioxidant detection based on 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid radical scavenging. Six compounds were successfully separated on a reverse phase C(18) column and were identified as 5-caffeoylquinic acid (5-CQA), fukinolic acid (FA), 3,5-di-O-caffeoylquinic acid (3,5-DCQA), quercetin-3-O-(6" acetyl)-beta-glucopyranoside (QAG), 4,5-di-O-caffeoylquinic acid (4,5-DCQA) and kaempferol-3-O-(6"-acetyl)-beta-glucopyranoside (KAG) by MS/MS and (1)H NMR data. Among these compounds, those containing a caffeoyl moiety (5-CQA, FA, 3,5- and 4,5-DCQA) showed relatively strong radical scavenging capacity, with 3,5-DCQA having the greatest radical scavenging capacity in leaf (23.09% of total antioxidant capacity) and root (26.47%) extracts. The relative radical scavenging portion of QAG was only 3.41% in the leaves and KAG did not show any radical scavenging activity. These results demonstrate that the hyphenated HPLC techniques can be successfully applied to rapidly identify structures and evaluate antioxidant activities without prior purification of compounds from plant tissues of P. japonicus. PMID- 21656533 TI - Hydrophilic interaction chromatography-electrospray ionization tandem mass spectrometric analysis of anastrozole in human plasma and its application to a pharmacokinetic study. AB - A hydrophilic interaction chromatography-electrospray ionization tandem mass spectrometric method was developed for determination of anastrozole in human plasma. Anastrozole and irbesartan (internal standard) were extracted from human plasma with a mixture of dichloromethane and methyl tert-butyl ether (30:70, v/v). Analysis of the analytes was performed on a Luna HILIC column with the mobile phase of acetonitrile-10 m m ammonium formate (95:5, v/v) and detected by electrospray ionization tandem mass spectrometry in the selected reaction monitoring mode. The standard curve was linear (r(2) = 0.9992) over the concentration range of 0.10-50.0 ng/mL using 200 MUL of plasma sample. The coefficient of variation and relative error for intra- and inter-assay at four QC levels were 1.2-10.0% and -7.2-3.2%, respectively. The present method was applied successfully to the pharmacokinetic study of anastrozole after oral administration of 1 mg anastrozole tablet to healthy male volunteers. PMID- 21656534 TI - Sensitive, selective and rapid determination of bupropion and its major active metabolite, hydroxybupropion, in human plasma by LC-MS/MS: application to a bioequivalence study in healthy Indian subjects. AB - A sensitive, selective and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of bupropion (BUP) and its major active metabolite hydroxybupropion (HBUP) in human plasma. Separation of both the analytes and venlafaxine as internal standard (IS) from 50 MUL human plasma was carried out by solid-phase extraction. The chromatographic separation of the analytes was achieved on a Zorbax Eclipse XDB C(18) (150 * 4.6 mm, 5 um) analytical column using isocratic mobile phase consisting of 20 mm ammonium acetate-methanol (10:90, v/v), with a resolution factor of 3.5. The method was validated over a wide dynamic concentration range of 0.1-350 ng/mL for BUP and 0.1-600 ng/mL for HBUP. The matrix effect was assessed by post-column infusion and the mean process efficiency was 96.08 and 94.40% for BUP and HBUP, respectively. The method was successfully applied to a bioequivalence study of 150 mg BUP (test and reference) extended release tablet formulation in 12 healthy Indian male subjects under fed conditions. PMID- 21656535 TI - Quantification of paraquat in postmortem samples by gas chromatography-ion trap mass spectrometry and review of the literature. AB - Paraquat (PQ) is an herbicide implicated in numerous fatalities, mainly caused by voluntary ingestion. Several methods have been used to quantify PQ in plasma and urine samples of intoxicated humans as a predictor of clinical outcome. There is no validated method for the analysis of PQ in postmortem samples. Therefore, the aim of this study was to develop an analytical method, using gas chromatography ion trap mass spectrometry (GC-IT/MS) after solid-phase extraction, to quantify PQ in postmortem samples, namely in whole blood, urine, liver, lung and kidney, to cover the routes of distribution, accumulation and elimination of PQ. The method proved to be selective as there were no interferences of endogenous compounds with the same retention time as PQ and ethyl paraquat (internal standard). The regression analysis for PQ was linear in the range 0-10 ug/mL. The detection limits ranged from 0.0076 ug/mL for urine to 0.047 ug/mL for whole blood, and the recoveries were suitable for forensic analysis. The proposed GC IT/MS method provided an accurate and simple assay with adequate precision and recovery for the quantification of PQ in postmortem samples. The proof of applicability was performed in two fatal PQ intoxications. A review of the analytical methods for the determination of quaternary ammonium herbicides is also provided for a better understanding of the presently available techniques. PMID- 21656536 TI - Cell line misidentification: the case of the Chang liver cell line. PMID- 21656538 TI - Hepatocyte cytotoxicity is facilitated by asialoglycoprotein receptor. AB - It has been recently identified that hepatocytes can act as cytotoxic effectors and can kill contacted cells by way of CD95 ligand-CD95 and perforin-dependent pathways. However, it remained unknown whether hepatocyte-mediated cell killing is indiscriminant or is directed toward targets with particular cell surface characteristics, as well as whether hepatocytes have the capacity to directly eliminate contacted lymphocytes. In this study, we found that desialylation of surface glycoproteins significantly augments cell susceptibility to hepatocyte mediated killing. Using asialofetuin as a competitive ligand, and by silencing gene transcription with specific small interfering RNA, we found that the asialoglycoprotein receptor (ASGPR) is involved in hepatocyte recognition of cells predestined for killing, including activated autologous T lymphocytes. CONCLUSION: Hepatocytes are constitutively equipped in the molecular machinery capable of eliminating cells brought into contact with their surface in a manner that is reliant, at least in part, upon the recognition of terminally desialylated glycoproteins by hepatocyte ASGPR. The study adds a new dimension to the physiological role of hepatic ASGPR and provides further evidence that hepatocytes can actively contribute to intrahepatic immune regulation and moderation of the local inflammatory response. PMID- 21656539 TI - Childhood emotional abuse and eating symptoms in bulimic disorders: an examination of possible mediating variables. AB - OBJECTIVE: We sought to estimate prevalences of childhood emotional abuse (CEA) in bulimic and normal-eater control groups, and to replicate previous findings linking CEA to severity of eating symptoms in BN. We also examined potential mediators of the link between CEA and disordered eating. METHOD: Women diagnosed with a bulimic disorder (n = 176) and normal-eater women (n = 139) were assessed for childhood traumata, eating-disorder (ED) symptoms and psychopathological characteristics (ineffectiveness, perfectionism, depression, and affective instability) thought to be potential mediators of interest. RESULTS: CEA was more prevalent in the bulimic than in the nonbulimic group, and predicted severity of some eating-symptom indices. Ineffectiveness and affective instability both mediated relationships between CEA and selected ED symptoms. DISCUSSION: We found CEA to predict eating pathology through mediating effects of ineffectiveness and affective instability. CEA might influence severity of ED symptoms by impacting an individual's self-esteem and capacity for affect regulation. PMID- 21656540 TI - Differential associations between ovarian hormones and disordered eating symptoms across the menstrual cycle in women. AB - OBJECTIVE: We examined changes in drive for thinness, body dissatisfaction, and dietary restraint across the menstrual cycle and associations between these symptoms and ovarian hormones in two independent samples of women (N = 10 and 8 women, respectively) drawn from the community. METHOD: Daily self-report measures of disordered eating and negative affect were completed for 35-65 days. Daily saliva samples were assayed for estradiol and progesterone in Study 2 only. RESULTS: Levels of body dissatisfaction and drive for thinness were highest during the mid-luteal/pre-menstrual phases in both studies and were negatively associated with estradiol, and positively associated with progesterone. By contrast, dietary restraint showed less variation across the menstrual cycle and weaker associations with ovarian hormones. DISCUSSION: Differential associations between ovarian hormones and specific disordered eating symptoms point to distinct etiological processes within the broader construct of disordered eating. PMID- 21656541 TI - Mycobacterium chimaera causes tuberculosis-like infection in a male patient with anorexia nervosa. AB - Here we present a 27-year-old male patient--with a known prolonged history of anorexia nervosa (AN)--suffering from tuberculosis like infection. At the time he was admitted to clinical treatment, he had developed fever up to 40 degrees C and survived on a body mass index of 11.8. In this case, Mycobacterium chimaera, generally recognized for low pathogenicity, was identified as the causative agent. Remission from lung infection was achieved after antibiotic treatment according to laboratory susceptibility testing while earlier antituberculosis therapies had failed. Because of a large cavity in the upper left lung, surgical excision was necessary to prevent recurrence of lung infection. Moreover, stabilization of the patient general health problem needs to be supported by a lasting psychotherapy. PMID- 21656542 TI - Objective and subjective binge eating in underweight eating disorders: associated features and treatment outcome. AB - OBJECTIVE: To define the utility of the DSM-IV-TR definition of binge eating, as it applies to anorexia nervosa (AN) and underweight eating disorder not otherwise specified (ED-NOS). METHOD: We investigated the psychopathological features associated with bulimic episodes in 105 underweight individuals with eating disorders who reported regular objective bulimic episodes with or without subjective bulimic episodes (OBE group, n = 33), regular subjective bulimic episodes only (SBE group, n = 36) and neither objective nor subjective bulimic episodes (n = 36, no-RBE group). The Eating Disorder Examination (EDE), anxiety, depression, and personality tests were administered before and upon completion of inpatient cognitive behavior therapy (CBT) treatment 6 months later. RESULTS: Compared with the SBE group, OBE subjects had higher body mass index, and more frequent self-induced vomiting, while both OBE and SBE groups had more severe eating disorder psychopathology and lower self-directness than the no-RBE group. Dropout rates and outcomes in response to inpatient CBT were similar in the three groups. DISCUSSION: Despite a few significant differences at baseline, the similar outcome in response to CBT indicates that categorizing patients with underweight eating disorder on the basis of the type or frequency of bulimic episodes is of limited clinical utility. PMID- 21656543 TI - Synthesis and in-vitro antibacterial activity of 7-(3-aminopyrrolo[3,4-c]pyrazol 5(2H,4H,6H)-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives. AB - A series of novel 7-(3-aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-fluoro-4-oxo 1,4-dihydroquinoline-3-carboxylic acid derivatives was designed, synthesized and characterized by (1)H-NMR, MS and HRMS. These fluoroquinolones were evaluated for their in-vitro antibacterial activity against representative Gram-positive and Gram-negative strains. Generally, all of the target compounds display rather weak potency against the tested Gram-negative strains, but most of them exhibit good potency in inhibiting the growth of S. aureus including methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis including methicillin resistant S. epidermidis (MRSE) (MIC: 0.125-8 ug/mL). In particular, the compound 9g is 2 to 32 fold more potent than gemifloxacin (GM), moxifloxacin (MX), gatifloxacin (GT), and levofloxacin (LV) against S. pneumoniae 08-3, K. pneumoniae 09-23, and P. aeruginosa ATCC27853, 4 to 32 fold more potent than MX, GM, and LV against K. pneumoniae 09-21, and more active than or comparable to the four reference drugs against P. aeruginosa 09-32. PMID- 21656546 TI - Ma C. is arteriogenesis a blind alley? In a clinical view. J Cell Biochem 2010; DOI 10.1002/jcb.23001. PMID- 21656547 TI - Three-dimensional phase contrast angiography of the mouse aortic arch using spiral MRI. AB - Atherosclerosis is a complex disease whose spatial distribution is hypothesized to be influenced by the local hemodynamic environment. The use of transgenic mice provides a mechanism to study the relationship between hemodynamic forces, most notably wall shear stress (WSS), and the molecular factors that influence the disease process. Phase contrast MRI using rectilinear trajectories has been used to measure boundary conditions for use in computational fluid dynamic models. However, the unique flow environment of the mouse precludes use of standard imaging techniques in complex, curved flow regions such as the aortic arch. In this article, two-dimensional and three-dimensional spiral cine phase contrast sequences are presented that enable measurement of velocity profiles in curved regions of the mouse vasculature. WSS is calculated directly from the spatial velocity gradient, enabling WSS calculation with a minimal set of assumptions. In contrast to the outer radius of the aortic arch, the inner radius has a lower time-averaged longitudinal WSS (7.06 +/- 0.76 dyne/cm(2) vs. 18.86 +/- 1.27 dyne/cm(2) ; P < 0.01) and higher oscillatory shear index (0.14 +/- 0.01 vs. 0.08 +/- 0.01; P < 0.01). This finding is in agreement with humans, where WSS is lower and more oscillatory along the inner radius, an atheroprone region, than the outer radius, an atheroprotective region. PMID- 21656548 TI - Size-optimized 32-channel brain arrays for 3 T pediatric imaging. AB - Size-optimized 32-channel receive array coils were developed for five age groups, neonates, 6 months old, 1 year old, 4 years old, and 7 years old, and evaluated for pediatric brain imaging. The array consisted of overlapping circular surface coils laid out on a close-fitting coil-former. The two-section coil former design was obtained from surface contours of aligned three-dimensional MRI scans of each age group. Signal-to-noise ratio and noise amplification for parallel imaging were evaluated and compared to two coils routinely used for pediatric brain imaging; a commercially available 32-channel adult head coil and a pediatric sized birdcage coil. Phantom measurements using the neonate, 6-month-old, 1-year old, 4-year-old, and 7-year-old coils showed signal-to-noise ratio increases at all locations within the brain over the comparison coils. Within the brain cortex the five dedicated pediatric arrays increased signal-to-noise ratio by up to 3.6 , 3.0-, 2.6-, 2.3-, and 1.7-fold, respectively, compared to the 32-channel adult coil, as well as improved G-factor maps for accelerated imaging. This study suggests that a size-tailored approach can provide significant sensitivity gains for accelerated and unaccelerated pediatric brain imaging. PMID- 21656549 TI - Integrated Bloch-Siegert B1 mapping and multislice imaging of hyperpolarized 13C pyruvate and bicarbonate in the heart. AB - Hyperpolarization of (13) C labeled substrates via dynamic nuclear polarization has been used as a method to noninvasively study real-time metabolic processes occurring in vivo. In these studies, proper calibration of radiofrequency transmit power is required to efficiently observe rapidly decaying magnetization. Conventional transmit radiofrequency field (B1+) mapping methods rely on placing magnetization in a fixed, known state prior to imaging, making them unsuitable for imaging of hyperpolarized magnetization. Recently, a phase-based B(1) mapping method based on the Bloch-Siegert shift has been reported. This method uses a B(1) -dependent shift in the resonance frequency of nuclei in the presence of an off-resonance radiofrequency pulse. In this article, we investigate the feasibility of Bloch-Siegert B(1) mapping and observation of metabolism of hyperpolarized [1-13C] pyruvate in vivo, in a single injection. The technique is demonstrated with phantom experiments, and in normal rat and pigs in vivo. This method is anticipated to improve quantitative measurements of hyperpolarized (13) C metabolism in vivo by enabling accurate flip-angle corrections. This work demonstrates the use of Bloch-Siegert B(1) mapping under challenging out-of equilibrium imaging conditions. PMID- 21656550 TI - Evaluation of MRI resolution affecting trabecular bone parameters: determination of acceptable resolution. AB - The objective of this study is to evaluate the effect of MR image resolution on trabecular bone parameters and to determine the acceptable resolution that can be accurately analyzed to assess structural parameters. Ten distal femoral condyle specimens of 1 * 1 * 1 cm(3) were scanned with a 4.7-T Bruker BioSpec MRI scanner using a three-dimensional fast large-angle spin-echo sequence with various iso cubic voxels sizes (65, 130, 160, 196, 230, and 260 MUm). Otsu thresholding was applied to identify voxels containing bone. Conventional bone parameters, structural bone parameters, and skeleton-based local trabecular thickness (slTB.Th) were evaluated. The Bland-Altman method and correlation indicated that the conventional and structural bone parameters were preserved with an iso-cubic voxel size up to 230 MUm (r > 0.932 and r > 0.843, respectively). In addition, slTB.Th derived from the highest resolution images (65 MUm iso-cubic voxel size), correlated well (r > 0.833) with the values computed from lower resolution images, up to 230 MUm, which is twice typical human trabecular thickness range (100-150 MUm). The outcome of this study suggests that the various bone parameters were well preserved up to 230 MUm images. PMID- 21656552 TI - Time-efficient slab-selective water excitation for 3D MRI. AB - Spectral-Spatial (SPSP) radiofrequency pulses are simultaneously selective in both the spectral and spatial domains. To selectively excite water spins and exclude fat, the individual subpulses that make up a SPSP pulse must be short (<1 ms at 4 T). A short subpulse duration limits the sharpness of the spatial slabs that can be excited when using a traditional SPSP pulse design approach. In this manuscript, the authors present an algorithm for designing SPSP pulses with substantially reduced maximum B(1) amplitudes and specific absorption rates. The proposed algorithm alternates between iterative design of the radiofrequency waveform for a given gradient shape and minimum-time variable-rate selective excitation reshaping of the gradient waveform. This approach is shown to reduce peak B(1) amplitudes in iteratively designed SPSP pulses by an order of magnitude. Unlike the use of regularization to control peak B(1) or specific absorption rate, the proposed method does not comprise the quality of the excitation profile. To achieve high-quality profiles, it was necessary to design the radiofrequency pulses for a measured rather than ideal gradient waveform. Slab-selective water excitation pulses with durations of 4.1 and 9.2 ms (fractional transition widths of 0.14 and 0.073, respectively) are demonstrated at 4 T. PMID- 21656551 TI - In vivo determination of human breast fat composition by 1H magnetic resonance spectroscopy at 7 T. AB - The role of diet and fat consumption in the pathogenesis of breast cancer is an important subject. We report a method for noninvasive determination of lipid composition in human breast by proton magnetic resonance spectroscopy (MRS) at 7 T. Two respiratory-triggered TE-averaged stimulated echo acquisition mode (STEAM) acquisitions were performed on the adipose tissue of 10 healthy volunteers where the second acquisition had all gradients inverted. This acquisition protocol allows the suppression of modulation sidebands that complicate spectral analysis at the short TE(avg) = 24.5 ms. The entire acquisition takes ~10 min. Ten lipid peaks were typically resolved. T(1) and T(2) were also measured and used to correct the peak intensities. The calculated average lipid composition for saturated was 28.7 +/- 8.4%, monounsaturated, 48.5 +/- 7.9%, and polyunsaturated, 22.7 +/- 3.1%, in close agreement with reported values from subcutaneous adipose measurements. Intrasubject variability was 2.0, 1.6, and 3.6% for the saturated, monounsaturated, and polyunsaturated fractions, respectively. In conclusion, we have shown that a chemical analysis of lipids in breast tissue can be determined quite simply, quickly, and noninvasively by proton MRS at 7 T. PMID- 21656553 TI - Thalamus segmentation based on the local diffusion direction: a group study. AB - Fast and accurate segmentation of deep gray matter regions in the brain is important for clinical applications such as surgical planning for the placement of deep brain stimulation implants. Mapping anatomy from stereotactic atlases to patient data is problematic because of individual differences in subject anatomy that are not accounted for by commonly used atlases. We present a segmentation method for individual subject diffusion tensor MR data that is based on local diffusion information to identify subregions of the thalamus. We show the correspondence of our segmentation results to anatomy by comparison with stereotactic atlas data. Importantly, we verify the consistency of our segmentation by evaluating the method on 63 healthy volunteers. Our method is fast, reliable, and independent of any segmentation before the classification of regions within the thalamus. It should, therefore, be useful in clinical applications. PMID- 21656555 TI - Longitudinal inter- and intra-individual human brain metabolic quantification over 3 years with proton MR spectroscopy at 3 T. AB - The longitudinal repeatability of proton MR spectroscopy ((1) H-MRS) in the healthy human brain at high fields over long periods is not established. Therefore, we assessed the inter- and intra-subject repeatability of (1) H-MRS in an approach suited for diffuse pathologies in 10 individuals, at 3T, annually for 3 years. Spectra from 480 voxels over 360 cm(3) (~30%) of the brain, were individually phased, frequency-aligned, and summed into one average spectrum. This dramatically increases metabolites' signal-to-noise-ratios while maintaining narrow linewidths that improve quantification precision. The resulting concentrations of the N-acetylaspartate, creatine, choline, and myo-inositol are: 8.9 +/- 0.8, 5.9 +/- 0.6, 1.4 +/- 0.1, and 4.5 +/- 0.5 mM (mean +/- standard deviation). the inter-subject coefficients of variation are 8.7%, 10.2%, 10.7%, and 11.8%; and the longitudinal (intra-subject) coefficients of variation are lower still: 6.6%, 6.8%, 6.8%, and 10%, much better than the 35%, 44%, 55%, and 62% intra-voxel coefficients of variation. The biological and nonbiological components of the summed spectra coefficients of variation had similar contributions to the overall variance. PMID- 21656556 TI - Evaluation of a vessel-tracking-based technique for dynamic targeting in human liver. AB - The purpose of this study was to evaluate a novel vessel-tracking-based technique for tracking of human liver. The novelty of the proposed technique is that it measures the translation and deformation of a local tissue region based on the displacements of a set of vessels of interest instead of the entire organ. The position of the target point was estimated from the relative positions of the center-of-masses of the vessels, assuming that the topological relationship between the target point and center-of-masses is unchanged during breathing. To reduce inaccuracy due to the delay between vessel image acquisition and sonication, the near-future target position was predicted based on the vessel displacements in the images extracted from an image library acquired before the tracking stage. Experiments on healthy volunteers demonstrated that regardless of the respiratory condition, appropriate combinations of three center-of-masses from the vessels situated around the target-tissue position yielded an estimation error of less than 2 mm, which was significantly smaller than that obtained when using a single center-of-mass trio. The effect of the tracking delay was successfully compensated, with a prediction error of less than 3 mm, by using over four images selected from the image library. PMID- 21656554 TI - Automated detection and characterization of SPIO-labeled cells and capsules using magnetic field perturbations. AB - Understanding how individual cells behave inside living systems will help enable new diagnostic tools and cellular therapies. Superparamagnetic iron oxide particles can be used to label cells and theranostic capsules for noninvasive tracking using MRI. Contrast changes from superparamagnetic iron oxide are often subtle relative to intrinsic sources of contrast, presenting a detection challenge. Here, we describe a versatile postprocessing method, called Phase map cross-correlation Detection and Quantification (PDQ), that automatically identifies localized deposits of superparamagnetic iron oxide, estimating their volume magnetic susceptibility and magnetic moment. To demonstrate applicability, PDQ was used to detect and characterize superparamagnetic iron oxide-labeled magnetocapsules implanted in porcine liver and suspended in agarose gel. PDQ was also applied to mouse brains infiltrated by MPIO-labeled macrophages following traumatic brain injury; longitudinal, in vivo studies tracked individual MPIO clusters over 3 days, and tracked clusters were corroborated in ex vivo brain scans. Additionally, we applied PDQ to rat hearts infiltrated by MPIO-labeled macrophages in a transplant model of organ rejection. PDQ magnetic measurements were signal-to-noise ratio invariant for images with signal-to-noise ratio > 11. PDQ can be used with conventional gradient-echo pulse sequences, requiring no extra scan time. The method is useful for visualizing biodistribution of cells and theranostic magnetocapsules and for measuring their relative iron content. PMID- 21656558 TI - The influence of radial undersampling schemes on compressed sensing reconstruction in breast MRI. AB - Fast imaging applications in magnetic resonance imaging (MRI) frequently involve undersampling of k-space data to achieve the desired temporal resolution. However, high temporal resolution images generated from undersampled data suffer from aliasing artifacts. In radial k-space sampling, this manifests as undesirable streaks that obscure image detail. Compressed sensing reconstruction has been shown to reduce such streak artifacts, based on the assumption of image sparsity. Here, compressed sensing is implemented with three different radial sampling schemes (golden-angle, bit-reversed, and random sampling), which are compared over a range of spatiotemporal resolutions. The sampling methods are implemented in static scenarios where different undersampling patterns could be compared. Results from point spread function studies, simulations, phantom and in vivo experiments show that the choice of radial sampling pattern influences the quality of the final image reconstructed by the compressed sensing algorithm. While evenly undersampled radial trajectories are best for specific temporal resolutions, golden-angle radial sampling results in the least overall error when various temporal resolutions are considered. Reduced temporal fluctuations from aliasing artifacts in golden-angle sampling translates to improved compressed sensing reconstructions overall. PMID- 21656557 TI - Temporal SNR characteristics in segmented 3D-EPI at 7T. AB - Three-dimensional segmented echo planar imaging (3D-EPI) is a promising approach for high-resolution functional magnetic resonance imaging, as it provides an increased signal-to-noise ratio (SNR) at similar temporal resolution to traditional multislice 2D-EPI readouts. Recently, the 3D-EPI technique has become more frequently used and it is important to better understand its implications for fMRI. In this study, the temporal SNR characteristics of 3D-EPI with varying numbers of segments are studied. It is shown that, in humans, the temporal variance increases with the number of segments used to form the EPI acquisition and that for segmented acquisitions, the maximum available temporal SNR is reduced compared to single shot acquisitions. This reduction with increased segmentation is not found in phantom data and thus likely due to physiological processes. When operating in the thermal noise dominated regime, fMRI experiments with a motor task revealed that the 3D variant outperforms the 2D-EPI in terms of temporal SNR and sensitivity to detect activated brain regions. Thus, the theoretical SNR advantage of a segmented 3D-EPI sequence for fMRI only exists in a low SNR situation. However, other advantages of 3D-EPI, such as the application of parallel imaging techniques in two dimensions and the low specific absorption rate requirements, may encourage the use of the 3D-EPI sequence for fMRI in situations with higher SNR. PMID- 21656559 TI - Bleomycin-induced lung injury in mice investigated by MRI: model assessment for target analysis. AB - Magnetic resonance imaging (MRI) has been used to follow the course of bleomycin induced lung injury in mice and to investigate two knockout mouse lines with the aim of providing potential therapeutic targets. Bleomycin (0.25 mg/kg) was administered intranasally six times, once a day. MRI was carried out on spontaneously breathing animals up to day 70 after bleomycin. Neither cardiac nor respiratory gating was applied during image acquisition. A long lasting response following bleomycin has been detected by MRI in the lungs of male C57BL/6 mice. Histology showed that, from day 14-70 after bleomycin, fibrosis was the predominant component of the injury. Female C57BL/6 mice displayed a smaller response than males. Bleomycin-induced injury was significantly more pronounced in C57BL/6 than in Balb/C mice. MRI and histology demonstrated a protection against bleomycin insult in female heterozygous and male homozygous cancer Osaka thyroid kinase knockout animals. In contrast, no protection was seen in cadherin 11 knockout animals. In summary, MRI can quantify, in spontaneously breathing mice, bleomycin-induced lung injury. With the ability for repetitive measurements in the same animal, the technique is attractive for in vivo target analysis and compound profiling in this murine model. PMID- 21656560 TI - Influence of noise correlation in multiple-coil statistical models with sum of squares reconstruction. AB - Noise in the composite magnitude signal from multiple-coil systems is usually assumed to follow a noncentral chi distribution when sum of squares is used to combine images sensed at different coils. However, this is true only if the variance of noise is the same for all coils, and no correlation exists between them. We show how correlations may be obviated from this model if effective values are considered. This implies a reduced effective number of coils and an increased effective variance of noise. In addition, the effective variance of noise becomes signal-dependent. PMID- 21656561 TI - Quantification techniques to minimize the effects of native T1 variation and B1 inhomogeneity in dynamic contrast-enhanced MRI of the breast at 3 T. AB - The variation of the native T(1) (T(10)) of different tissues and B(1) transmission-field inhomogeneity at 3 T are major contributors of errors in the quantification of breast dynamic contrast-enhanced MRI. To address these issues, we have introduced new enhancement indices derived from saturation-recovery snapshot-FLASH (SRSF) images. The stability of the new indices, i.e., the SRSF enhancement factor (EF(SRSF)) and its simplified version (EF'(SRSF)) with respect to differences in T(10) and B(1) inhomogeneity was compared against a typical index used in breast dynamic contrast-enhanced MRI, i.e., the enhancement ratio (ER), by using computer simulations. Imaging experiments with Gd-DTPA-doped gel phantoms and a female volunteer were also performed. A lower error was observed in the new indices compared to enhancement ratio in the presence of typical T(10) variation and B(1) inhomogeneity. At changes of relaxation rate (DeltaR(1)) of 8 s(-1), the differences between a T(10) of 1266 and 566 ms are <1, 12, and 58%, respectively, for EF(SRSF), EF'(SRSF), and ER, whereas differences of 20, 8, and 51%, respectively, result from a 50% B(1) field reduction at the same DeltaR(1). These quantification techniques may be a solution to minimize the effect of T(10) variation and B(1) inhomogeneity on dynamic contrast-enhanced MRI of the breast at 3 T. PMID- 21656562 TI - Automatic coil selection for streak artifact reduction in radial MRI. AB - In radial MR imaging, streaking artifacts contaminating the entire field of view can arise from regions at the outer edges of the prescribed field of view. This can occur even when the Nyquist criterion is satisfied within the desired field of view. These artifacts become exacerbated when parts of the object lie in the superior/inferior regions of the scanner where the gradient strengths become weakened. When multiple coil arrays are used for signal reception, coils at the outer edges can be disabled before data acquisition to reduce the artifact levels. However, as the weakened gradient strengths near the edges often distort the object, causing the signal to become highly concentrated into a small region, the streaks are often not completely removed. Data from certain coils can also be excluded during reconstruction by visually inspecting the individual coil images, but this is impractical for routine use. In this work, a postprocessing method is proposed to automatically identify those coils whose images contain high levels of streaking for subsequent exclusion during reconstruction. The proposed method was demonstrated in vivo dynamic contrast enhanced MRI datasets acquired using a three-dimensional hybrid radial sequence. The results demonstrate that the proposed strategy substantially improves the image quality and show excellent agreement with images reconstructed with manually determined coil selection. PMID- 21656563 TI - Whole-heart coronary MR angiography with 2D self-navigated image reconstruction. AB - Several self-navigation techniques have been proposed to improve respiratory motion compensation in coronary MR angiography. In this work, we implemented a 2D self-navigation method by using the startup profiles of a whole-heart balanced Steady-state free precession sequence, which are primarily used to catalyze the magnetization towards the steady-state. To create 2D self-navigation images (2DSN), we added phase encoding gradients to the startup profiles. With this approach we calculated foot-head and left-right motion and performed retrospective translational motion correction. The 2DSN images were reconstructed from 10 startup profiles acquired at the beginning of each shot. Nine healthy subjects were scanned, and the proposed method was compared to a 1D self navigation (1DSN) method with foot-head correction only. Foot-head correction was also performed with the diaphragmatic 1D pencil beam navigator (1Dnav) using a tracking factor of 0.6. 2DSN shows improved motion correction compared to 1DSN and 1Dnav for all coronary arteries and all subjects for the investigated diaphragmatic gating window of 10 mm. The visualized vessel length of the right coronary artery could be significantly improved with a multiple targeted 2D self navigation approach, compared to 2DSN method. PMID- 21656564 TI - Arterial spin labeling angiography using a triple inversion recovery prepulse. AB - Arterial spin labeling is a well-known noninvasive angiography technique, which does not necessitate the use of a contrast agent. arterial spin labeling is still clinically underused because of several challenges: (1) long scan times because of the need for two acquisitions (labeled and nonlabeled datasets), (2) sensitivity to spatial misregistration because of the need for image subtraction, and (3) the need for precise planning and choice of an optimal inversion delay for best blood-to-background contrast. In this work, we propose a new arterial spin labeling method based on a triple-inversion-recovery sequence-arterial spin labeling. This approach exploits the ability of two nonselective inversion recovery prepulses to null the background signal over a wide range of T1 values, while maintaining the signal of labeled blood using a third slab selective inversion pulse. This technique therefore allows the acquisition of angiograms with a flexible inversion delay, easier planning procedure and no need for subtraction. PMID- 21656565 TI - Quantitative measurement of N-acetyl-aspartyl-glutamate at 3 T using TE-averaged PRESS spectroscopy and regularized lineshape deconvolution. AB - This article introduces regularized lineshape deconvolution in conjunction with TE-averaged PRESS spectroscopy to measure N-acetyl-aspartyl-glutamate (NAAG). Averaging different echo times suppressed the signals of multiplets from strongly coupled spin systems near 2 ppm; thus, minimizing the interfering signals to detect the acetyl proton signal of NAAG. Signal distortion was corrected by lineshape deconvolution, and Tikhonov regularization was introduced to reduce noise amplification arising from deconvolution; as a result, spectral resolution was enhanced without significantly sacrificing signal-to-noise ratio (SNR). This new approach was used to measure NAAG in the two regions of interest of healthy volunteers, dominated by gray matter and white matter, respectively. The acetyl proton signal of NAAG was directly quantified by fitting the deconvoluted spectra to a Voigt-lineshape spectral model function, yielding the NAAG-N-acetyl aspartate (NAA) ratios of 0.11+/-0.02 for the gray matter voxels (n=8) and 0.18+/ 0.02 for the white matter voxels (n=12). PMID- 21656566 TI - Reverse polarized inductive coupling to transmit and receive radiofrequency coil arrays. AB - In this study, the reverse polarization method is implemented using transmit and receive arrays to improve the visibility of the interventional devices. Linearly polarized signal sources--inductively and receptively coupled radiofrequency coils--are used in the experimental setups to demonstrate the ability of the method to separate these sources from a forward polarized anatomy signal. Two different applications of the reverse polarization method are presented here: (a) catheter tracking and (b) fiducial marker visualization, in both of which transmit and receive arrays are used. The performance of the reverse polarization method was further tested with phantom and volunteer studies, and the results proved the feasibility of this method with transmit and receive arrays. PMID- 21656568 TI - A mixed molecular modeling-robotics approach to investigate lipase large molecular motions. AB - Large-scale conformational rearrangement of a lid subdomain is a key event in the interfacial activation of many lipases. We present herein a study in which the large-scale "open-to-closed" movement of Burkholderia cepacia lipase lid has been simulated at the atomic level using a hybrid computational method. The two-stage approach combines path-planning algorithms originating from robotics and molecular mechanics methods. In the first stage, a path-planning approach is used to compute continuous and geometrically feasible pathways between two protein conformational states. Then, an energy minimization procedure using classical molecular mechanics is applied to intermediate conformations in the path. The main advantage of such a combination of methods is that only geometrically feasible solutions are prompted for energy calculation in explicit solvent, which allows the atomic-scale description of the transition pathway between two extreme conformations of B. cepacia lipase (BCL; open and closed states) within very short computing times (a few hours on a desktop computer). Of interest, computed pathways enable the description of intermediate conformations along the "open-to closed" conformational transition of BCL lid and the identification of bottlenecks during the lid closing. Furthermore, consideration of the solvent effect when computing the transition energy profiles provides valuable information regarding the feasibility and the spontaneity of the movement under the influence of the solvent environment. This new hybrid computational method turned out to be well-suited for investigating at an atomistic level large-scale conformational motion and at a qualitative level, the solvent effect on the energy profiles associated with the global motion. PMID- 21656567 TI - In vivo and ex vivo diffusion tensor imaging of cuprizone-induced demyelination in the mouse corpus callosum. AB - Diffusion tensor imaging has been widely used in studying rodent models of white matter diseases. In this study, we examined the differences between in vivo and ex vivo fractional anisotropy and diffusivity measurements in the mouse cuprizone model. In the control mouse corpus callosum, ex vivo diffusivities were significantly lower than in vivo measurements, but ex vivo fractional anisotropy values were not significantly different from in vivo fractional anisotropy values. With cuprizone induced demyelination and accompanying pathology in the corpus callosum, changes in in vivo and ex vivo fractional anisotropy and diffusivity measurements were not always in agreement. Our results suggest that ex vivo lambda(?) was a more reliable indicator of white matter demyelination than in vivo lambda(?) and in vivo lambda(||) was a more reliable indicator of axonal injury than ex vivo lambda(||) in this model. When comparing in vivo and ex vivo diffusion tensor imaging results of axon and myelin pathology in the rodent models, potential changes in tissue microstructures associated with perfusion fixation should be considered. PMID- 21656569 TI - NMR structure and dynamics of recombinant wild type and mutated jerdostatin, a selective inhibitor of integrin alpha1beta1. AB - NMR analysis of four recombinant jerdostatin molecules was assessed to define the structural basis of two naturally occurring gain-of-function events: C-terminal dipeptide processing and mutation of the active residue K21 to arginine. Removal of the highly mobile and a bulky C-terminal dipeptide produced pronounced chemical shift changes in the sequentially unconnected but spatially nearby alpha(1)beta(1) inhibitory loop. Analysis of chemical shift divergence and (15)N backbone relaxation dynamics indicated differences in motions in the picosecond to nanosecond time scale, and the higher T(2) rate of S25, S26, and H27 of rJerK21 point to a slowdown in the microsecond to millisecond motions of these residues when compared with rJerR21. The evidence presented in this article converges on the hypothesis that dynamic differences between the alpha(1)beta(1) recognition loops of rJerR21 and rJerK21 may influence the thermodynamics of their receptor recognition and binding. A decrease in the MUs-ms time scale may impair the binding affinity by reducing the rate of possible conformations that the rJerK21 can adopt in this time scale. PMID- 21656571 TI - Cover and spacer insertions: small nonhydrophobic accessories that assist protein oligomerization. AB - We investigated fragmental sequences that were inserted into proteins during long molecular evolution and relevant to the association of homo-oligomers. Seventeen insertions in 12 SCOP (structure classification of proteins) families were examined and were classified into large and small insertions. The large insertions are composed of interface-like residues and effectively increase the interface area. In contrast, small insertions are composed of the residues that are not commonly found at the interfaces and have a small interface area: their roles in the oligomerization process are unclear. We found that the small insertions were located in the middle of protein sequences and therefore must involve residues with strong turn and less interface-like propensities. From a structural viewpoint, small insertions were found to mask hydrophobic patches or act as spacers to fill cavities present at interfaces. The presence or absence of small insertions coincides with the annotated oligomeric states for homologs in the SwissProt database, and the calculation of the association scores predicts that small insertions contribute to the stability of oligomers. These results support the significant role of small, nonhydrophobic insertions in protein oligomerization. PMID- 21656570 TI - Trifluoperazine regulation of calmodulin binding to Fas: a computational study. AB - Death-inducing signaling complex (DISC) formation is a critical step in Fas mediated signaling for apoptosis. Previous experiments have demonstrated that the calmodulin (CaM) antagonist, trifluoperazine (TFP) regulates CaM-Fas binding and affects Fas-mediated DISC formation. In this study, we investigated the anti cooperative characteristics of TFP binding to CaM and the effect of TFP on the CaM-Fas interaction from both structural and thermodynamic perspectives using combined molecular dynamics simulations and binding free energy analyses. We studied the interactions of different numbers of TFP molecules with CaM and explored the effects of the resulting conformational changes in CaM on CaM-Fas binding. Results from these analyses showed that the number of TFP molecules bound to CaM directly influenced alpha-helix formation and hydrogen bond occupancy within the alpha-helices of CaM, contributing to the conformational and motion changes in CaM. These changes affected CaM binding to Fas, resulting in secondary structural changes in Fas and conformational and motion changes of Fas in CaM-Fas complexes, potentially perturbing the recruitment of Fas-associated death domain for DISC formation. The computational results from this study reveal the structural and molecular mechanisms that underlie the role of the CaM antagonist, TFP, in regulation of CaM-Fas binding and Fas-mediated DISC formation in a concentration-dependent manner. PMID- 21656572 TI - The gray area between synapse structure and function-Gray's synapse types I and II revisited. AB - On the basis of ultrastructural parameters, the concept was formulated that asymmetric Type I and symmetric Type II synapses are excitatory and inhibitory, respectively. This "functional Gray synapses concept" received strong support from the demonstration of the excitatory neurotransmitter glutamate in Type I synapses and of the inhibitory neurotransmitter gamma-aminobutyric acid in Type II synapses, and is still frequently used in modern literature. However, morphological and functional evidence has accumulated that the concept is less tenable. Typical features of synapses like shape and size of presynaptic vesicles and synaptic cleft and presence of a postsynaptic density (PsD) do not always fit the postulated (excitatory/inhibitory) function of Gray's synapses. Furthermore, synapse function depends on postsynaptic receptors and associated signal transduction mechanisms rather than on presynaptic morphology and neurotransmitter type. Moreover, the notion that many synapses are difficult to classify as either asymmetric or symmetric has cast doubt on the assumption that the presence of a PsD is a sign of excitatory synaptic transmission. In view of the morphological similarities of the PsD in asymmetric synapses with membrane junctional structures such as the zonula adherens and the desmosome, asymmetric synapses may play a role as links between the postsynaptic and presynaptic membrane, thus ensuring long-term maintenance of interneuronal communication. Symmetric synapses, on the other hand, might be sites of transient communication as takes place during development, learning, memory formation, and pathogenesis of brain disorders. Confirmation of this idea might help to return the functional Gray synapse concept its central place in neuroscience. PMID- 21656573 TI - Glycine receptor internalization by protein kinases activation. AB - Although glycine-induced currents in the central nervous system have been proven to be modulated by protein kinases A (PKA) and C (PKC), the mechanism is not well understood. In order to better comprehend the mechanism involved in this phenomenon, we tested the PKA and PKC activation effect on the specific [(3) H]glycine and [(3) H]strychnine binding to postsynaptic glycine receptor (GlyR) in intact rat retina. The specific binding constituted about 20% of the total radioligand binding. Kinetic analysis of the specific binding exhibited a sigmoidal behavior with three glycine and two strychnine binding sites and affinities of 212 nM for [(3) H]glycine and 50 nM for [(3) H]strychnine. Specific radioligand binding was decreased (60-85%) by PKA and PKC activation, an effect that was blocked by specific kinases inhibitors, as well as by cytochalasin D. GlyR expressed in the plasma membrane decreased about 50% in response to kinases activation, which was consistent with an increase of the receptor in the microsomal fraction when PKA was activated. Moreover, immunoprecipitation studies indicated that these kinases lead to a time-dependent receptor phosphorylation. Our results suggest that in retina, GlyR is cross-regulated by G protein-coupled receptors, activating PKA and PKC. PMID- 21656574 TI - Attenuation of inhibitory synaptic transmission by glial dysfunction in rat thalamus. AB - The thalamus serves as the obligatory gateway to the neocortex for sensory processing, and also serves as a pathway for corticocortical communication. In addition, the reciprocal synaptic connectivity between the thalamic reticular nucleus (TRN) and adjacent thalamic relay nuclei generates rhythmic activities similar to that observed during different arousal states and certain neurological conditions such as absence epilepsy. Epileptiform activity can arise from a variety of neural mechanisms, but in addition glia are thought to have an important role in such activities as well. Glia serve a central role in glutamine synthesis, a precursor for glutamate or GABA in nerve terminals. While alterations in glutamine shuttling from glia to neurons can influence GABA and glutamate neurotransmission; the consequences of such action on synaptic transmission and subsequent network activities within thalamic circuits is less understood. We investigated the consequences of altering glutamine transport on inhibitory transmission and intrathalamic activities using the in vitro thalamic slice preparation. Disruption of the glutamine shuttling by the neuronal glutamine transporter (system A transporter) antagonist, alpha (methylamino)isobutyric acid (MeAIB), or the selective gliotoxic drug, fluorocitric acid (Fc) dramatically decreased intrathalamic rhythmic activities. At the single cell level, MeAIB and Fc significantly attenuated electrically evoked inhibitory postsynaptic currents (eIPSCs) in thalamic relay neurons; however, miniature IPSCs were unaffected. These data indicate that glutamate glutamine shuttle is critical for sustaining thalamic synaptic transmission, and thereby alterations in this shuttle can influence intrathalamic rhythmic activities associated with absence epilepsy. PMID- 21656575 TI - Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma. AB - As a component of the MRN (MRE11/RAD50/NBS1) complex, NBS1 plays an important role in cellular response to DNA damage and the maintenance of chromosomal integrity. The NBS1 E185Q polymorphism (8360G>C, rs1805794) has been frequently studied in some cancers with discordant results, but its association with nasopharyngeal carcinoma (NPC) in Chinese population has not been investigated. Moreover, there is no report about the association between NBS1 3'UTR variant rs2735383 and the risk of NPC. A multiple center case-control analysis was performed to assess the association between NBS1 polymorphisms and NPC risk in Eastern and Southern Chinese population. The genotypes and haplotypes were determined in 1052 cases and 1168 controls and the associations with risk of NPC were estimated by logistic regression. Cell migration assays were performed in 24 well transwell chambers to detect the effects of NBS1 E185Q SNP on cell migration. We observed significant difference in genotype frequencies at the rs1805794 C/G site between cases and controls (P(trend) < 0.0001). The C allele increases the risk for invasive disease or metastatic disease, compared with G allele. More over, CNE-2 cells (NPC cell line) transfected with pcDNA-NBS1-185Q (8360CC) had significantly higher migration levels than those transfected with pcDNA-NBS1-185E (8360GG) (P = 0.024). These findings suggest that E185Q polymorphism in NBS1 may be a genetic modifier for the occurrence and aggression of NPC. PMID- 21656576 TI - Right-side and left-side colon cancer follow different pathways to relapse. AB - There is growing evidence that cancer of the ascending (right-side) colon is different from cancer of the descending (left-side) colon at the molecular level. Using microarray data from 102 right-side colon carcinomas and 95 left-side colon carcinomas we show that different pathways dominate progression to relapse in right-side and left-side colon cancer. Right-side tumors at a high risk for relapse exhibit elevated expression of cell cycle control genes and elevated Wnt signaling. On the other hand, relapse-prone left-side tumors show elevated expression of genes that promote stromal expansion and reduced expression of tumor suppressor genes that initiate Wnt signaling. Single gene prognostic biomarkers are found separately for right-side and left-side disease. In left side tumors with low expression levels of NADPH oxidase 4 (NOX4) the 5-yr relapse free survival probability is 0.89 95% CI (0.80-0.99), and in tumors with elevated NOX4 expression the probability is 0.51 95% CI (0.37-0.70). Right-side tumors with elevated expression levels of caudal type homeobox 2 (CDX2) have a 5-yr relapse-free survival probability of 0.88 95% CI (0.80-0.96), and those with low CDX2 expression have a corresponding probability of 0.39 95% CI (0.15-0.78). Both NOX4 and CDX2 are much less prognostic on the opposite sides. This newly identified role of NOX4 in colon cancer is further investigated using the SW620 lymph node metastasis colon adenocarcinoma cell line and RNA interference. We show that NOX4 is expressed in the SW620 cell line and that application of NOX4 siRNA causes a significant reduction in reactive oxidative species production. PMID- 21656577 TI - Association between fibroblast growth factor receptor 4 polymorphisms and risk of hepatocellular carcinoma. AB - Human fibroblast growth factor receptor 4 (FGFR4) polymorphisms have recently been shown to be associated with tumor progression of various types of cancer, including cancer of the breast, colon, and prostate and sarcoma. However, their association with hepatocellular carcinoma (HCC) is unknown. We evaluated the association of FGFR4 polymorphisms with risk of HCC in a study population with HCC and with/without hepatitis B virus (HBV) infection in East China. We genotyped four FGFR4 SNPs (rs351855, rs641101, rs376618, and rs31777) in 1,451 Chinese subjects, including 711 patients with HCC, 368 controls with HBV infection and 372 controls without HBV infection, using the TaqMan genotyping assay. Unconditional logistic regression analysis was performed to evaluate associations of genotypes of each SNP with HCC risk. For the rs351855 (Arg388) locus, we observed a reduced HCC risk associated with the T variant genotypes, particularly for those whose tumors with gross portal vein tumor thrombosis (gross PVTT) (OR = 0.66; 95% confidence interval, 95% CI = 0.46-0.95 for CT + TT). Such a protective effect was also observed for those with liver cirrhosis (OR = 0.42; 95% CI = 0.20-0.88 for CT + TT). Clearly the T allele was associated with these conditions. Our findings suggest that genetic polymorphism in FGFR4 may be a marker for risk of HCC with liver cirrhosis and gross PVTT in Chinese populations. PMID- 21656578 TI - Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck. AB - Both p53 tumor suppressor and murine double minute 2 (MDM2) oncoprotein are crucial in carcinogenesis. We hypothesized that MDM2 promoter single nucleotide polymorphisms (SNPs) SNP309 T > G, A2164G, and p53 codon 72 are associated with risk and age at onset of squamous cell carcinoma of head and neck (SCCHN). We genotyped these SNPs in a study of 1,083 Caucasian SCCHN cases and 1,090 cancer free controls. Although none of these SNPs individually had a significant effect on risk of SCCHN, nor did their combined putative risk genotypes (i.e., MDM2 SNP309 GT + GG, 2164 AA, and p53 codon 72 CC), we found that individuals with two to three risk genotypes had significantly increased risk of non-oropharyngeal cancer (OR = 1.42; 95% CI = 1.07-1.88). This increased risk was more pronounced among young subjects, men, smokers, and drinkers. In addition, female patients carrying the MDM2 SNP309 GT and GG genotypes showed a 3-yr (56.7 yr) and 9-yr (51.2 yr) earlier age at onset of non-oropharyngeal cancer (P(trend) = 0.007), respectively, compared with those carrying the TT genotype (60.1 yr). The youngest age (42.5 yr) at onset of non-oropharyngeal cancer was observed in female patients with the combined MDM2 SNP309 GG and p53 codon 72 CC genotypes. The findings suggest that MDM2 SNP309, A2164G, and p53 codon 72 SNPs may collectively contribute to non-oropharyngeal cancer risk and that MDM2 SNP309 individually or in combination with p53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. Further studies with large sample sizes are warranted to validate these results. PMID- 21656580 TI - Arene-anion based arginine-binding motif on a galactose scaffold: structure activity relationships of interactions with arginine-rich galectins. AB - Two series of C3-benzamido and O2-anion-substituted galactopyranosides were synthesized and studied as binders to arginine-rich proteins galectin-1, -3, -7, 8N (N-terminal domain), and -9N (N-terminal domain). The first series had a 4 methylbenzamide at C3 and the anionic O2-substituent was varied. The second series varied the 4-substituent of the C3-benzamide, whereas the anionic O2 substituent was kept as a sulfate. The influence of the O2-anion substituent correlated negatively with the oxygen charge density in case of galectin-1, -3, and -9N. In the second series, the electron-donating capacity of the 4 substituent of the C3-benzamides correlated positively with the magnitude of the affinity enhancement by the 2O-sulfate. PMID- 21656579 TI - A single-nucleotide polymorphism in tumor suppressor gene SEL1L as a predictive and prognostic marker for pancreatic ductal adenocarcinoma in Caucasians. AB - SEL1L is a putative tumor suppressor gene that is frequently down-regulated in pancreatic ductal adenocarcinoma (PDA). A single-nucleotide polymorphism (SNP) rs12435998 in intron3 of SEL1L has previously been reported to be associated with susceptibility to Alzheimer's disease. We hypothesized that this SNP may influence clinical outcomes of patients with PDA. We analyzed DNA samples from 497 Caucasian patients with pathologically confirmed primary PDA. Of these, 98 had been enrolled in a clinical trial of neoadjuvant chemo-radiotherapy and 77 of the 98 had subsequently undergone pancreaticoduodenectomy (PD). We performed Kaplan-Meier analysis to evaluate the correlation between different SNP genotypes and age at diagnosis, survival time after diagnosis, and survival time after PD. In nonsmokers, we found a significant difference in median age at diagnosis between variant genotypes (AG/GG) carriers and wild-type genotype (AA) carriers (58 vs. 62 yr; log-rank test, P = 0.017). Patients with variant genotypes also showed an increased hazard ratio (HR) of 1.45 [95% confidence interval (CI), 1.07 1.97] relative to wild-type genotype. Among the patients in the clinical trial, the variant genotypes carriers had a median post-PD survival time that was 34.7 months shorter than wild-type genotype carriers (log-rank test, P = 0.019; HR, 1.91; 95% CI, 1.09-3.34). Our results suggest that the rs12435998 SNP in SEL1L gene plays a role in modifying age at diagnosis of PDA in Caucasian nonsmokers. In addition, this SNP may serve as a prognostic marker in PDA patients who undergo the same or similar treatment as the clinical trials. PMID- 21656581 TI - A core-shell strategy for constructing a single-molecule junction. AB - Understanding the effects of intermolecular interactions on the charge-transport properties of metal/molecule/metal junctions is an important step towards using individual molecules as building blocks for electronic devices. This work reports a systematic electron-transport investigation on a series of "core-shell" structured oligo(phenylene ethynylene) (Gn-OPE) molecular wires. By using dendrimers of different generations as insulating "shells", the intermolecular pi pi interactions between the OPE "cores" can be precisely controlled in single component monolayers. Three techniques are used to evaluate the electron transport properties of the Au/Gn-OPE/Au molecular junctions, including crossed wire junction, scanning tunneling spectroscopy (STS), and scanning tunneling microscope (STM) break-junction techniques. The STM break-junction measurement reveals that the electron-transport pathways are strongly affected by the size of the side groups. When the side groups are small, electron transport could occur through three pathways, including through single-molecule junctions, double molecule junctions, and molecular bridges between adjacent molecules formed by aromatic pi-pi coupling. The dendrimer shells effectively prohibit the pi-pi coupling effect, but at the same time, very large dendrimer side groups may hinder the formation of Au-S bonds. A first-generation dendrimer acts as an optimal shell that only allows electron transport through the single-molecule junction pathway, and forbids the other undesired pathways. It is demonstrated that the dendrimer-based core-shell strategy allows the single-molecule conductance to be probed in a homogenous monolayer without the influence of intermolecular pi-pi interactions. PMID- 21656582 TI - In situ formed bifunctional primary amine-imine catalyst for asymmetric aldol reactions of alpha-keto esters. PMID- 21656583 TI - In situ growth of TiO2 in interlayers of expanded graphite for the fabrication of TiO2-graphene with enhanced photocatalytic activity. AB - We present a facile route for the preparation of TiO(2)-graphene composites by in situ growth of TiO(2) in the interlayer of inexpensive expanded graphite (EG) under solvothermal conditions. A vacuum-assisted technique combined with the use of a surfactant (cetyltrimethylammonium bromide) plays a key role in the fabrication of such composites. Firstly, the vacuum environment promotes full infusion of the initial solution containing Ti(OBu)(4) and the surfactant into the interlayers of EG. Subsequently, numerous TiO(2) nanoparticles uniformly grow in situ in the interlayers with the help of the surfactant, which facilitates the exfoliation of EG under the solvothermal conditions in ethanol, eventually forming TiO(2)-graphene composites. The as-prepared samples have been characterized by Raman and FTIR spectroscopies, SEM, TEM, AFM, and thermogravimetic analysis. It is shown that a large number of TiO(2) nanoparticles homogeneously cover the surface of high-quality graphene sheets. The graphene exhibits a multi-layered structure (5-7 layers). Notably, the TiO(2) graphene composite (only 30 wt % of which is TiO(2)) synthesized by subsequent thermal treatment at high temperature under nitrogen shows high photocatalytic activity in the degradation of phenol under visible and UV lights in comparison with bare Degussa P25. The enhanced photocatalytic performance is attributed to increased charge separation, improved light absorbance and light absorption width, and high adsorptivity for pollutants. PMID- 21656584 TI - Gold catalysis: domino reaction of en-diynes to highly substituted phenols. AB - By Sonogashira coupling of 1,7-heptadiynes and 1,8-octadiynes with 2-iodoallyl alcohols, various substrates that bear a 2-alkynylallyl alcohol moiety tethered to an additional alkyne were prepared in one step. Subjection to nitrogen acyclic carbene (NAC)/gold(I) catalysts delivered highly substituted phenols in an efficient domino reaction. Furan derivatives were formed as intermediates; this was proven by in situ NMR spectroscopy. The uncommon substitution pattern of these furans opens the way for a selective formation of phenols that contain the hydroxyl group in the meta position to the ring junction, which previously was not possible by gold-catalyzed furan-yne cyclization. Furthermore, interesting mechanistic insights were obtained by products derived from secondary allyl alcohols. In this case, in addition to the phenolic compounds, a ketone is formed by 1,2-alkyl shift. PMID- 21656585 TI - Yolk-shell gold nanoparticles as model materials for support-effect studies in heterogeneous catalysis: Au, @C and Au, @ZrO2 for CO oxidation as an example. AB - The use of nanostructured yolk-shell materials offers a way to discriminate support and particle-size effects for mechanistic studies in heterogeneous catalysis. Herein, gold yolk-shell materials have been synthesized and used as model catalysts for the investigation of support effects in CO oxidation. Carbon has been selected as catalytically inert support to study the intrinsic activity of the gold nanoparticles, and for comparison, zirconia has been used as oxidic support. Au, @C materials have been synthesized through nanocasting using two different nonporous-core@mesoporous-shell exotemplates: Au@SiO(2)@ZrO(2) and Au@SiO(2)@m-SiO(2). The catalytic activity of Au, @C with a gold core of about 14 nm has been evaluated and compared with Au, @ZrO(2) of the same gold core size. The strong positive effect of metal oxide as support material on the activity of gold has been proved. Additionally, size effects were investigated using carbon as support to determine only the contribution of the nanoparticle size on the catalytic activity of gold. Therefore, Au, @C with a gold core of about 7 nm was studied showing a less pronounced positive effect on the activity than the metal oxide support effect. PMID- 21656586 TI - A paradigm for solvent and temperature induced conformational changes. PMID- 21656587 TI - Substituent-controlled reactivity in the Nazarov cyclisation of allenyl vinyl ketones. AB - Alkyl substitution alpha to the ketone of an allenyl vinyl ketone enhances Nazarov reactivity by inhibiting alternative pathways involving the allene moiety and through electron donation and/or steric hindrance. This substitution pattern also accelerates Nazarov cyclisation by increasing the population of the reactive conformer and by stabilising the oxyallyl cation intermediate. Furthermore, alpha substitution by an alkyl group does not alter the regioselectivity of interrupted Nazarov reactions when the oxyallyl cation intermediate is intercepted by addition of an oxygen nucleophile, or by [4+3] cyclisation with acyclic dienes. The regioselectivity of the Nazarov process for allenyl vinyl ketones was determined to be a result of an electronic bias in the oxyallyl cation intermediate. Computational data are consistent with this observation. PMID- 21656588 TI - Oxidative esterification, thioesterification, and amidation of aldehydes by a two component organocatalyst system using a chiral N-heterocyclic carbene and redox active riboflavin. PMID- 21656589 TI - Expanding Mg-Zn hybrid chemistry: inorganic salt effects in addition reactions of organozinc reagents to trifluoroacetophenone and the implications for a synergistic lithium-magnesium-zinc activation. AB - Numerous organic transformations rely on organozinc compounds made through salt metathesis (exchange) reactions from organolithium or Grignard reagents with a suitable zinc precursor. By combining X-ray crystallography, NMR spectroscopy and DFT calculations, this study sheds new light on the constitution of the organometallic species involved in this important synthetic tool. Investigations into the metathesis reactions of equimolar amounts of Grignard reagents (RMgX) and ZnCl(2) in THF led to the isolation of novel magnesium-zinc hybrids, [{(thf)(2)Mg(MU-Cl)(3)ZnR}(2)] (R=Et, tBu, nBu or o-OMe-C(6)H(4)), which exhibit an unprecedented structural motif in mixed magnesium-zinc chemistry. Furthermore, theoretical modelling of the reaction of EtMgCl with ZnCl(2) reveals that formation of the mixed-metal compound is thermodynamically preferred to that of the expected homometallic products, RZnCl and MgCl(2). This study also assesses the alkylating ability of hybrid 3 towards the sensitive ketone trifluoroacetophenone, revealing a dramatic increase in the chemoselectivity of the reaction when LiCl is introduced as an additive. This observation, combined with recent related breakthroughs in synthesis, points towards the existence of a trilateral Li/Mg/Zn synergistic effect. PMID- 21656590 TI - Any old radical won't do: an EPR study of the selective excitation and quenching mechanisms of [Ru(bipy)3]2+ chemiluminescence and electrochemiluminescence. PMID- 21656591 TI - The O-O bonding in water oxidation: the electronic structure portrayal of a concerted oxygen atom-proton transfer pathway. PMID- 21656592 TI - A metal-free route to 2-aminooxazoles by taking advantage of the unique ring opening of benzoxazoles and oxadiazoles with secondary amines. PMID- 21656593 TI - Highly enantio- and diastereoselective synthesis of beta-methyl-gamma monofluoromethyl-substituted alcohols. AB - Enanatiopure beta-methyl-gamma-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)(2)AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity. PMID- 21656594 TI - Synthesis of polyaromatic hydrocarbons from bis(biaryl)diynes: large PAHs with low Clar sextets. PMID- 21656595 TI - Thermally induced multimicellar-aggregate-to-vesicle transition for a dentritic starch ester. PMID- 21656596 TI - A general cyclocarbonylation of aryl bromides and triflates with acetylenes: palladium-catalyzed synthesis of 3-alkylidenefuran-2-ones. PMID- 21656597 TI - Stability and electronic properties of imidazole-based mesoionic carbenes. PMID- 21656598 TI - In(OTf)3-catalyzed highly chemo- and regioselective head-to-tail heterodimerization of vinylarenes with 1,1-diarylethenes. PMID- 21656599 TI - Astragalosides rescue both cardiac function and sarcoplasmic reticulum Ca2+ transport in rats with chronic heart failure. AB - The study investigated the beneficial effects of astragalosides (AS) on cardiac performance in rats with chronic heart failure. Chronic heart failure was produced by left anterior descending coronary artery ligation, and the therapeutic efficacy of astragalosides at 10, 20 and 40 mg/kg was evaluated. Five weeks after the operation, cardiac function was deficient and sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity was significantly reduced. Moreover, SERCA mRNA decreased, while expression of the SERCA down-regulator phospholamban (PLB) was significantly increased. Phosphorylated phospholamban (P-PLB), the form that does not inhibit SERCA, was also reduced by chronic heart failure. Treatment with AS improved left ventricle function and cardiac structure, reversed the depression of SERCA activity, and increased P-PLB. These results suggest that the cardioprotective effect of AS may be due to the increase in P-PLB protein, which disinhibits SERCA activity. Rescue of sarcoplasmic reticulum Ca2+ cycling by astragalosides could normalize excitation-contraction coupling and improve overall cardiac function. PMID- 21656600 TI - Linseed oil: an investigation of its antiarthritic activity in experimental models. AB - Food sources rich in omega-3 fatty acids have been valued for their beneficial effect in the management of inflammatory disorders. The present study evaluates the antiarthritic and immunomodulatory activity of Linum usitatissimum fixed oil (LUFO) in experimental models. The LUFO produced a dose-dependent reduction in joint swelling and circulating TNF-alpha levels in both preventive and curative protocols of arthritis induced by complete Freund's adjuvant (CFA). Expression of TNF-R1 and Interleukin (IL) 6 proteins in the arthritic paw was also significantly reduced in the LUFO-treated animals. In the cotton pellet induced granuloma model, LUFO treatment significantly reduced the dry granuloma weight as compared with the control group. Results of our present study thus demonstrate the antiarthritic and disease modifying activity of LUFO. We believe that dietary incorporation of LUFO may be beneficial in the prevention and management of rheumatoid arthritis and other chronic inflammatory disorders. PMID- 21656601 TI - Antimycobacterial and synergistic effects of 18beta-glycyrrhetinic acid or glycyrrhetinic acid-30-piperazine in combination with isoniazid, rifampicin or streptomycin against Mycobacterium bovis. AB - 18beta-Glycyrrhetinic acid (18betaGA) is a major bioactive component of liquorice with known activity. In this study, we found that both 18betaGA and its derivative glycyrrhetinic acid-30-piperazine (PGA), have potent antimycobacterial properties against the drug-susceptible and drug-resistant Mycobacterium bovis. More importantly, they exhibited synergistic effects with the first-line drugs isoniazid (INH), rifampicin (RIF) and streptomycin (SM) against clinical M. bovis isolates, including drug-resistant strains. In combination with a subinhibitory concentration of 18betaGA, the minimum inhibitory concentrations (MICs) of the anti-tuberculosis agents decreased, ranging from 4- to 16-, 4- to 8- and 4- to 8 fold for INH (fractional inhibitory concentration index (FICI) 0.125-0.375), RIF (FICI 0.118-0.281) and SM (FICI 0.094-0.275), respectively. In the presence of PGA, MICs for the first-line agents resulted in a 4-16-fold decrease for INH (FICI 0.094-0.266, RIF (FICI 0.114-0.313) and SM (FICI 0.094-0.281). Additionally, the MICs of 18betaGA or PGA alone showed significant decreases ranging from 8- to 16-, 8- to 64- and 8- to 128-fold in the presence of INH, RIF and SM, respectively. These findings indicate that 18betaGA and its derivatives might serve as potential therapeutic compounds for future antimycobacterial drug development. PMID- 21656602 TI - Androgen-independent effects of Serenoa repens extract (Prostasan(r)) on prostatic epithelial cell proliferation and inflammation. AB - Extracts from Serenoa repens are widely used for the treatment of benign prostatic hyperplasia (BPH) and traditionally for prostatitis. In the present study we evaluated the biological effects of Serenoa repens extract (Prostasan(r)) on prostate cells beyond its known antiandrogenic actions. Prostasan(r) inhibited epidermal growth factor (EGF) and lipopolysaccharide (LPS) induced proliferation of the prostatic epithelial, androgen independent cell line PC-3. At effective concentrations of 50 ug/mL, Prostasan(r) partly displaced EGF from EGF receptor (EGFR) but fully blocked EGF-induced cell proliferation of PC-3 cells. Similarly, Prostasan(r) inhibited LPS-induced proliferation of PC-3 cells without affecting LPS activation of the NFKB pathway via toll-like receptor-4 (TLR-4). Additionally, Prostasan(r) reduced the constitutive secretion of monocyte chemotactic protein-1 (MCP-1), the LPS-induced secretion of IL-12 and inhibited MCP-1 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in the presence of LPS on PC-3 cells. Taken together, our results suggest that S. repens extracts, in addition to other reported effects on BPH development and prostatitis, inhibits EGF-dependent growth and proinflammatory responses of the prostate epithelial cells. PMID- 21656603 TI - Uncaria tomentosa aqueous-ethanol extract triggers an immunomodulation toward a Th2 cytokine profile. AB - Uncaria tomentosa (Willd.) DC (Rubiaceae) is a large woody vine that is native to the Amazon and Central American rainforests and is used widely in traditional medicine for its immunomodulatory and antiinflammatory activities. The present work used in vivo immunotoxic and in vitro immunomodulatory experiments to investigate the effects of a pentacyclic oxindole alkaloid extract from U. tomentosa bark on lymphocyte phenotype, Th1/Th2 cytokine production, cellular proliferation and cytotoxicity. For the in vivo immunotoxicity testing, BALB/c male mice were treated once a day with 125, 500 or 1250 mg/kg of U. tomentosa extract for 28 days. For the in vitro protocol, lymphocytes were cultured with 10 500 MUg/mg of the extract for 48 h. The extract increased the cellularity of splenic white pulp and the thymic medulla and increased the number of T helper lymphocytes and B lymphocytes. Also, a large stimulatory effect on lymphocyte viability was observed. However, mitogen-induced T lymphocyte proliferation was significantly inhibited at higher concentrations of U. tomentosa extract. Furthermore, an immunological polarization toward a Th2 cytokine profile was observed. These results suggest that the U. tomentosa aqueous-ethanol extract was not immunotoxic to mice and was able to modulate distinct patterns of the immune system in a dose-dependent manner. PMID- 21656604 TI - Tumor microenvironment in cancer treatment and metastasis. PMID- 21656605 TI - Rapid identification of calotropagenin glycosides using high-performance liquid chromatography electrospray ionisation tandem mass spectrometry. AB - INTRODUCTION: Cardiac glycosides in Calotropis procera have therapeutic use as inhibitors of Na+/K+-ATPase to regulate heart contractions. A large amount of research attention has been received by these compounds towards their identification and structural characterisation. In order to achieve rapid identification of cardiac glycosides in phytochemical extracts a liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed involving metal cationisation by post-column addition of alkali salts for the unambiguous determination of their molecular weights. OBJECTIVE: Identification of cardiac glycosides in Calotropis procera leaf extract. RESULTS: Calotropagenin and its 10 glycosides were unambiguously identified. The daughter ions at m/z 387, 369, 359, 351, 341 and 323 in their MS/MS spectra were attributed to the calotropagenin aglycone unit. CONCLUSION: High performance liquid chromatography in combination with electrospray ionization tandem mass spectrometry involving metal cationisation by post column addition of alkali salts was successfully utilised for the rapid identification of calotropagenin glycosides/derivatives in Calotropis procera extract. PMID- 21656606 TI - Improving food choices among Supplemental Nutrition Assistance Program recipients. AB - We used a principal-agent framework to examine the feasibility of two proposed modifications to the Supplemental Nutrition Assistance Program with the goal of encouraging healthier food choices among program participants. Specifically, we analyzed two types of contract: a restricted contract and an incentive contract. The restricted contract did not allow the purchase of unhealthy foods with program benefits, but compensated participants by increasing total benefits. The incentive contract provided increased benefits that varied according to the percentage of healthy foods purchased with program benefits. The theoretical results revealed the mechanisms for the two alternative contracts, the conditions under which each would be effective, and the key empirical questions to be examined for future policy analysis. PMID- 21656607 TI - The mini-mental adjustment to cancer scale: re-analysis of its psychometric properties in a sample of 160 mixed cancer patients. AB - BACKGROUND: The mini-Mental Adjustment to Cancer Scale is designed to assess psychological responses to cancer diagnosis and is widely used in research and clinical practice. Recent evidence demonstrates adequate convergent validity but inconsistent internal consistency and factor structure. This study aimed to provide a parsimonious factor structure with clinical utility. METHODS: Repeated measures data were collected from 160 cancer patients (mixed illness type) at diagnosis and 3-month follow-up. Principal axis factoring with oblimin rotation was used. The number of factors was decided using parallel analysis. The resultant factors were compared against the recommended five-factor structure on internal consistency (Cronbach's alpha) and test-retest reliability and convergent validity (Pearson's correlation). RESULTS: Parallel analysis suggested that a four-factor model optimally fits these data. Two of these-cognitive avoidance and fighting spirit-are equivalent to the original factor structure. Redistribution of the remaining items resulted in factors of cognitive distress and emotional distress. Internal consistency and test-retest reliability of the new four-factor structure are equivalent, but convergent validity is much improved overall when compared with a five-factor structure, with the exception of the fighting spirit factor. CONCLUSIONS: The revised four-factor structure represents a more psychometrically sound measure of psychological adjustment in the current dataset. Findings related to the larger cognitive distress factor are congruent with data from foreign-language validation studies. The brevity of this improved measure may make it easier to administer in the clinical setting. PMID- 21656609 TI - Brief report: evaluating the potential of putative pluripotent cells derived from human testis. AB - Human adult germline stem cells (haGSCs) were established from human testicular biopsies and were claimed to be pluripotent. Recently, the gene expression profile of haGSCs demonstrated that these cells presented with a fibroblast rather than a pluripotent identity. Nevertheless, haGSCs were reported to generate teratomas. In this report, we address this discrepancy. Instead of using haGSCs, which are no longer available for the stem cell community, we used a human testicular fibroblastic cell (hTFC) line that presents with a gene expression profile highly similar to that of haGSCs. Indeed, as shown by microarray analysis, the similarity between hTFCs and haGSCs is comparable to human embryonic stem cell (hESC) lines derived by different laboratories. We argue that the almost identical gene expression profile of hTFCs and haGSCs should result in a very similar if not identical differentiation potential. Strikingly, hTFCs were not able to generate teratomas after injection into nude mice. Instead, they formed a mesenchymal lesion that morphologically resembled the putative haGSC-derived teratomas reported previously. We conclude that haGSCs, which exhibit a profile similar to that of fibroblasts and could not generate teratomas, are not pluripotent. Future work will have to show if pluripotent cells can be derived from human testicular biopsies. Mouse work and certain testicular germ cell tumors indicate that this will be possible. PMID- 21656608 TI - Dura mater stimulates human adipose-derived stromal cells to undergo bone formation in mouse calvarial defects. AB - Human adipose-derived stromal cells (hASCs) have a proven capacity to aid in osseous repair of calvarial defects. However, the bone defect microenvironment necessary for osseous healing is not fully understood. In this study, we postulated that the cell-cell interaction between engrafted ASCs and host dura mater (DM) cells is critical for the healing of calvarial defects. hASCs were engrafted into critical sized calvarial mouse defects. The DM-hASC interaction was manipulated surgically by DM removal or by insertion of a semipermeable or nonpermeable membrane between DM and hASCs. Radiographic, histologic, and gene expression analyses were performed. Next, the hASC-DM interaction is assessed by conditioned media (CM) and coculture assays. Finally, bone morphogenetic protein (BMP) signaling from DM was investigated in vivo using novel BMP-2 and anti-BMP 2/4 slow releasing scaffolds. With intact DM, osseous healing occurs both from host DM and engrafted hASCs. Interference with the DM-hASC interaction dramatically reduced calvarial healing with abrogated BMP-2-Smad-1/5 signaling. Using CM and coculture assays, mouse DM cells stimulated hASC osteogenesis via BMP signaling. Through in vivo manipulation of the BMP-2 pathway, we found that BMP-2 plays an important role in DM stimulation of hASC osteogenesis in the context of calvarial bone healing. BMP-2 supplementation to a defect with disrupted DM allowed for bone formation in a nonhealing defect. DM is an osteogenic cell type that both participates in and stimulates osseous healing in a hASC-engrafted calvarial defect. Furthermore, DM-derived BMP-2 paracrine stimulation appears to play a key role for hASC mediated repair. PMID- 21656611 TI - Hydrogen rearrangement and ring cleavage reactions study of progesterone by triple quadrupole mass spectrometry and density functional theory. AB - The fragmentation mechanisms of progesterone have been studied by triple quadrupole tandem mass spectrometry (MSMS) and density functional theory (DFT). Mechanisms leading to major product ions are proposed. The data suggest that progesterone fragments preferentially via hydrogen and other rearrangements lead to neutral losses. These fragmentations are quite complex and are preceded by sigma-bond cleavages in most cases. Four major pathways for progesterone fragmentation are proposed involving: (1) cleavage of ring B at C9-C10, (2) cleavage of C6-C7 bond in ring B through m/z 191, (3) two types of cleavages of ring D, and (4) ketene elimination in ring A. Pathways (1)-(3) proceed via charge remote fragmentations while pathway (4) proceeds via charge-site initiated mechanism. The geometry of product ions in these pathways were optimized using DFT at the B3LYP/6-311G(d,p) level of theory from which the free energies of the pathways were calculated. The effect that the choice of basis sets and density functionals has on the results was tested by performing additional calculations using B3LYP/6-31G(d) and B3PW91/6-311G(d,p). PMID- 21656610 TI - Development and validation of LC-HRMS and GC-NICI-MS methods for stereoselective determination of MDMA and its phase I and II metabolites in human urine. AB - 3,4-Methylenedioxymethamphetamine (MDMA) is a racemic drug of abuse and its R- and S-enantiomers are known to differ in their dose-response curve. The S enantiomer was shown to be eliminated at a higher rate than the R-enantiomer most likely explained by stereoselective metabolism that was observed in various in vitro experiments. The aim of this work was the development and validation of methods for evaluating the stereoselective elimination of phase I and particularly phase II metabolites of MDMA in human urine. Urine samples were divided into three different methods. Method A allowed stereoselective determination of the 4-hydroxy-3-methoxymethamphetamine (HMMA) glucuronides and only achiral determination of the intact sulfate conjugates of HMMA and 3,4 dihydroxymethamphetamine (DHMA) after C18 solid-phase extraction by liquid chromatography-high-resolution mass spectrometry with electrospray ionization. Method B allowed the determination of the enantiomer ratios of DHMA and HMMA sulfate conjugates after selective enzymatic cleavage and chiral analysis of the corresponding deconjugated metabolites after chiral derivatization with S heptafluorobutyrylprolyl chloride using gas chromatography-mass spectrometry with negative-ion chemical ionization. Method C allowed the chiral determination of MDMA and its unconjugated metabolites using method B without sulfate cleavage. The validation process including specificity, recovery, matrix effects, process efficiency, accuracy and precision, stabilities and limits of quantification and detection showed that all methods were selective, sensitive, accurate and precise for all tested analytes. PMID- 21656613 TI - Development of a selective, sensitive, and reversible biosensor by the genetic incorporation of a metal-binding site into green fluorescent protein. PMID- 21656614 TI - Dramatically different conductivity properties of metal-organic framework polymorphs of Tl(TCNQ): an unexpected room-temperature crystal-to-crystal phase transition. PMID- 21656615 TI - Activation and deactivation of a chemical transformation by an electromagnetic field: evidence for specific microwave effects in the formation of Grignard reagents. PMID- 21656616 TI - High-contrast fluorescence imaging of tumors in vivo using nanoparticles of amphiphilic brush-like copolymers produced by ROMP. PMID- 21656617 TI - CO2 capture in amine-based aqueous solution: role of the gas-solution interface. PMID- 21656618 TI - Electric-induced enhancement and modulation of upconversion photoluminescence in epitaxial BaTiO3:Yb/Er thin films. PMID- 21656619 TI - Bio-orthogonal "double-click" chemistry based on multifunctional coatings. PMID- 21656620 TI - Allylic C-H alkylation of unactivated alpha-olefins: serial ligand catalysis resumed. PMID- 21656621 TI - The inherent competition between addition and substitution reactions of Br2 with benzene and arenes. PMID- 21656622 TI - Single pyramid magnets: Dy5 pyramids with slow magnetic relaxation to 40 K. PMID- 21656623 TI - Continuous-flow synthesis of 3,3-disubstituted oxindoles by a palladium-catalyzed alpha-arylation/alkylation sequence. PMID- 21656625 TI - Cryogenic magnetocaloric effect in a ferromagnetic molecular dimer. PMID- 21656624 TI - Synthesis and in vivo fate of zwitterionic near-infrared fluorophores. PMID- 21656631 TI - In vitro sortagging of an antibody fab fragment: overcoming unproductive reactions of sortase with water and lysine side chains. AB - Sortase A from Staphylococcus aureus attracts growing interest for its use in biotechnological protein modification. This enzyme binds to a short signal sequence at the C terminus of a target protein, cleaves it by formation of an acyl-enzyme intermediate, and subsequently attaches an oligoglycine with a peptide bond. In this work, we explored its usability for the modification of the L19 Fab fragment (specific for fibronectin ED-B), a promising candidate for antibody-based cancer therapy. The Fab fragment was expressed with a sortase signal sequence attached to its light chain, and was successfully modified with a fluorescent oligoglycine probe in good yield. Our interest focused on performance under conditions of limited oligoglycine concentrations. Two unproductive side reactions of sortase were observed. The first was hydrolysis of the acyl-enzyme intermediate; in the second, sortase accepted the epsilon-amino group of lysine as substrate, thereby resulting in polypeptide crosslinking. In case of the L19 Fab fragment, it led to the covalent connection of the heavy and light chains. Both side reactions were effectively suppressed by sufficient concentrations of the oligoglycine probe. PMID- 21656632 TI - Solvent exposure associated with single abasic sites alters the base sequence dependence of oxidation of guanine in DNA in GG sequence contexts. AB - The effect of exposure of guanine in double-stranded oligonucleotides to aqueous solvent during oxidation by one-electron oxidants was investigated by introducing single synthetic tetrahydrofuran-type abasic sites (Ab) either adjacent to or opposite tandem GG sequences. The selective oxidation of guanine was initiated by photoexcitation of the aromatic sensitizers riboflavin and a pyrene derivative, and by the relatively small negatively charged carbonate radical anion. The relative rates of oxidation of the 5'- and 3' side G in runs of 5'???GG??? (evaluated by standard hot alkali treatment of the damaged DNA strand followed by high resolution gel electrophoresis of the cleavage fragments) are markedly affected by adjacent abasic sites either on the same or opposite strand. For example, in fully double-stranded DNA or one with an Ab adjacent to the 5'-G, the 5'-G/3'-G damage ratio is >=4, but is inverted (<1.0) with the Ab adjacent to the 3'-G. These striking effects of Ab are attributed to the preferential localization of the "hole" on the most solvent-exposed guanine regardless of the size, charge, or reduction potential of the oxidizing species. PMID- 21656633 TI - Photocontrol of Peptide function: backbone cyclization strategy with photocleavable amino Acid. PMID- 21656634 TI - Detection of 5-hydroxymethylcytosine in DNA by transferring a keto-glucose by using T4 phage beta-glucosyltransferase. PMID- 21656635 TI - Structural analysis of an isolated cyclic tetrapeptide and its monohydrate by combined IR/UV spectroscopy. AB - Cyclopeptides are an important class of substances in nature, and their physiological effects are frequently based on the tendency to form bioactive conformations. Therefore the investigation of their structure yields an understanding of their functionalities. Mass-selective combined IR/UV spectroscopy in molecular beam experiments represents an ideal tool for structural analyses on isolated molecules in the gas phase, such as the investigated cyclo[L-Tyr(Me)-D-Pro](2) peptide and its complexes with water. Using the chosen spectroscopic method in combination with DFT calculations, an assignment of a structure with two intramolecular hydrogen bonds for the naked cyclopeptide is possible. For the monohydrated cluster two isomers have to be discussed: in one of them the water molecule is simply attached to the assigned monomer structure as hydrogen donor, whereas the second isomer can be characterized by a water molecule that is inserted into one of the intramolecular hydrogen bonds. PMID- 21656636 TI - Nanoparticle-electrode collision processes: the underpotential deposition of thallium on silver nanoparticles in aqueous solution. AB - The electrochemistry of collisions between metal nanoparticles (NPs) and electrode surfaces has been of recent interest with the development of anodic particle coulometry as a characterisation method. For the first time the underpotential deposition of metal ions from solution onto metal nanoparticles during collisions between the NPs and an inert electrode is reported. PMID- 21656637 TI - Molecular mechanism of uncaging CO2 from nitrophenylacetate provides general guidelines for improved ortho-nitrobenzyl cages. AB - Femtosecond spectroscopy and quantum chemical calculations provide detailed insights into the specificities of the uncaging mechanism of CO2 from ortho-, meta-, and para-nitrophenylacetate. The emerging general principles allow a rational design of improved ortho-nitrophenyl cages for chemical and biological applications. PMID- 21656638 TI - Packed to the rafters: filling up C60 with rare gas atoms. AB - How many rare gas atoms can be placed into a fullerene cage until the pressure becomes large enough to break the C(60) framework? The answer given by density functional and ab initio computations is surprising and underlines the high stability of this unique carbon structure. PMID- 21656639 TI - Prochloraz effects on biomarkers activity in zebrafish early life stages and adults. AB - Zebrafish early life stages (ELS) assays have been increasingly used to assess the toxicity of chemicals and waste waters, showing a great potential due to the wide variety of endpoints that can be incorporated in the test. Moreover, zebrafish ELS test have been proposed, mainly for ethical reasons, as a surrogate for tests with adults. In this work, the fungicide Prochloraz (PCZ) was used as a chemical model to compare sensitivities of embryos/larvae and adult zebrafish focusing on lethality and biomarkers as endpoints. Effects on embryo development were also assessed. Organization for economic cooperation and development (OECD) guidelines were followed and adapted to include the analyses of the biomarkers cholinesterase, glutathione S-transferase, and lactate dehydrogenase. The acute toxicity of PCZ for zebrafish ELS and adults seemed to be similar with 96 h-LC50 values of 8.5 and 4.6 mg/L, respectively. However, biomarkers were only responsive in larvae indicating a higher sensitivity of this life stage at sublethal level. PCZ also proved to be teratogenic: at intermediate concentrations effects on embryo development could be noticed, including spine deformations, edemas, lack of pigmentation, slower heart rate, and complete hatching failure. At the lowest concentrations, the more relevant effects (edemas and abnormal absorption of the yolk sac) were observed after hatching. The measurement of biomarkers in the zebrafish ELS assay seems to a useful tool in the detection of chemical effects showing higher sensitivity than adults. Further research should focus on the link between biomarkers responses in larvae and effects at later life stages of zebrafish. PMID- 21656640 TI - Assessment of reproductive biomarkers in three-spined stickleback (Gasterosteus aculeatus) from sewage effluent recipients. AB - The aim of this study was to examine the occurrence of endocrine disruption close to sewage treatment plant effluent discharges along the Finnish Baltic Sea coast using a set of reproductive biomarkers present in adult three-spined stickleback (Gasterosteus aculeatus). Possible variation and sensitivity of the biomarkers during an entire reproductive period were also examined. The analysis of vitellogenin (VTG) for estrogenic activity and spiggin for androgenic activity, together with histopathological analysis indicated that sticklebacks were exposed to estrogenic loads sufficient to cause inappropriate production of VTG and to disrupt normal testicular structure in adult male sticklebacks. No androgenic disruption was observed. The results emphasize the need of a combination of several reproductive biomarkers in fish and repeated sampling for the detection of potential endocrine modulating substances under field condition. PMID- 21656641 TI - Antioxidative and antigenotoxic effect of vitamin E against patulin cytotoxicity and genotoxicity in HepG2 cells. AB - Patulin (PAT) is a mycotoxin produced in fruits, mainly in apples, by certain species of Penicillium, Aspergillus, and Byssochlamys. It has been shown that PAT is cytotoxic, genotoxic, and mutagenic in different cell types. Several studies incriminate the oxidative stress as a mechanism of PAT-mediated toxicity. In this context, our aim was to investigate the protective role of Vitamin E (Vit E), an antioxidant agent, against PAT induced cytotoxicity and genotoxicity in cultured HepG2 cells. The obtained results showed that addition of Vit E in cells treated with PAT significantly reduce cell mortality induced by this toxin. In the same conditions, Vit E decreased the intracellular level of ROS, reduced PAT induced p53 expression, and reversed PAT induced DNA damage. In addition, Vit E prevented significantly the percentage of chromosome aberrations induced by PAT in HepG2 cells in a concentration dependant manner. These results suggest that Vit E, an exogenous antioxidant agent, plays an important role in defense against PAT induced cytotoxicity and genotoxicity, which confirms the involvement of oxidative stress in the induction of DNA damage by PAT in HepG2 cells. PMID- 21656642 TI - Catalase activity and innate immune response of Caenorhabditis elegans against the heavy metal toxin lead. AB - The heavy metal lead-induced oxidative stress on Caenorhabditis elegans was examined at the level of catalase activity and on innate immunity. Stress-induced C. elegans was exposed to Pseudomonas aeruginosa PA14::GFP for monitoring the impact at the physiological level. Role of catalase on the innate-immune responses of C. elegans was examined. PA14::GFP did not colonize lead pretreated C. elegans intestinal cells significantly compared to untreated controls, indicating stress-mediated upregulation of host-immunity. Semiquantitative PCR analyses of lead-exposed and PA14-infected C. elegans mRNA showed significant upregulation of candidate antimicrobial enzyme gene lys-7 after 24 h of exposures. Upregulation of metallothionein(mtl-1) when compared to mtl-2 in response to the lead suggesting active detoxification of metal by mtl-1. Exogenously provided Catalase (0.4-3.2 U) induced significant upregulation of lys 7 compared to controls. lys-7 upregulation during lead exposure was reconfirmed by real-time PCR. Confocal microscopy and fluorescence spectrophotometer analyses indicated that the lead pretreated C. elegans was significantly less colonized by PA14::GFP when compared to controls. Relative expression of ctl-1 and ctl-2 mRNA was measured using real time PCR and found to be regulated during lead exposures. Over all, the upregulation of antimicrobial gene expression appears to be correlated with the level of catalase during stress emphasizing their key roles in defensive mechanism(s). These results provide a link between the stress and related immune responses which can be explored in higher systems. PMID- 21656643 TI - Molecular mechanism of inflammatory response in mouse liver caused by exposure to CeCl3. AB - To investigate the molecular mechanism of inflammatory response in the mouse liver caused by exposure to CeCl3, we measured the liver indices, and cerium content, evaluated the liver histopathological section, detected serum biochemical parameters of liver function, and the immunoglobulin M (IgM) content, analyzed the liver mRNA and protein expression levels of Toll-like receptor 2, 4 (TLR2, TLR4), and inflammatory cytokines in liver using real-time quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that exposure to CeCl3 decreased body weight and caused cerium accumulation in the mouse liver and histopathological changes of liver (such as inflammatory cell infiltration). Furthermore, biochemical assays suggested that CeCl3 could promote the activities of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, lactate dehydrogenase, pseudocholinesterase, and leucine aminopeptidase, decrease serum IgM, upregulate the levels of TLR2, TLR4, nuclear factor-kappaB (NF-kappaB), NF-kappaBp52, NF kappaBp65, NF-kappaB-inducing kinase (NIK), IkappaB kinase alpha (IKK-alpha), IkappaB kinase beta (IKK-beta), and tumor necrosis factor-alpha (TNF-alpha) expression, and suppress NF-kappaB-inhibiting factor (IkappaB) and interleukin-2 (IL-2) expression in liver. Taken together, the inflammation of mice liver caused by exposure to CeCl3 might be closely associated with the alteration of inflammatory cytokine expressions in the mouse liver, the signal-transducing events happening in CeCl3-induced macrophages of liver sequentially might occur via activation of TLRs->TNF-alpha->NIK->IkappaB kinase (including IKK1, IKK2)->NF kappaB (including NF-kappaBP52, NF-kappaBP65)-> inflammation. PMID- 21656644 TI - Investigation of biochemical responses of Bacopa monnieri L. upon exposure to arsenate. AB - Widespread contamination of arsenic (As) is recognized as a global problem due to its well-known accumulation by edible and medicinal plants and associated health risks for the humans. In this study, phytotoxicity imposed upon exposure to arsenate [As(V); 0-250 MUM for 1-7 days] and ensuing biochemical responses were investigated in a medicinal herb Bacopa monnieri L. vis-a-vis As accumulation. Plants accumulated substantial amount of As (total 768 MUg g(-1) dw at 250 MUM As(V) after 7 days) with the maximum As retention being in roots (60%) followed by stem (23%) and leaves (17%). The level of cysteine and total nonprotein thiols (NP-SH) increased significantly at all exposure concentrations and durations. Besides, the level of metalloid binding ligands viz., glutathione (GSH) and phytochelatins (PCs) increased significantly at the studied concentrations [50 and 250 MUM As(V)] in both roots and leaves. The activities of various enzymes viz., arsenate reductase (AR), glutathione reductase (GR), superoxide dismutase (SOD), guaiacol peroxidase (GPX), ascorbate peroxidase (APX), and catalase (CAT) showed differential but coordinated stimulation in leaves and roots to help plants combat As toxicity up to moderate exposure concentrations (50 MUM). However, beyond 50 MUM, biomass production was found to decrease along with photosynthetic pigments and total soluble proteins, whereas lipid peroxidation increased. In conclusion, As accumulation potential of Bacopa may warrant its use as a phytoremediator but if Bacopa growing in contaminated areas is consumed by humans, it may prove to be toxic for health. PMID- 21656645 TI - Adverse influence of coumestrol on secretory function of bovine luteal cells in the first trimester of pregnancy. AB - Coumestrol is one of a few biologically active substances present in leguminous plants, which are widely used as fodder for ruminants. Depending on the doses, coumestrol acts on the reproductive processes as an estrogen-like factor or antiestrogen to evoke a decrease in ovulation frequency, elongation of estrous cycle duration. The aim of the current investigations was to study the influence of coumestrol on secretory function of luteal cells obtained from first trimester of pregnant cows. Luteal cells (2.5 * 10(5) /mL) from 3rd to 5th, 6th to 8th, and 9th to 12th week of pregnancy were preincubated for 24 h and incubated with coumestrol (1 * 10(-6) M) for successive 48 h and the medium concentrations of progesterone (P4), oxytocin (OT), prostaglandin (PG) E2 and F2alpha were determined. Moreover, the expression of mRNA for neurophysin-I/oxytocin (NP-I/OT; precursor of OT) and peptidyl-glycine-alpha-amidating mono-oxygenase (PGA, an enzyme responsible for post-translational OT synthesis) was determined after 8 h of treatment. Coumestrol did not affect P4 secretion but increased the secretion of OT from the cells collected at all stages of gestation studied. Hence, the ratio of P4 to OT was markedly decreased. Simultaneously, coumestrol increased the expression of NP-I/OT mRNA during 9th to 12th weeks of pregnancy, and mRNA for PGA during 3rd to 5th and 9th to 12th weeks of gestation. Furthermore, coumestrol decreased PGE2 secretion from luteal cells in all studied stages of pregnancy, while it affected PGF2alpha metabolite (PGFM) concentration only from week 3 to 5 of pregnancy. Obtained results suggest that coumestrol impairs secretory function of the corpus luteum (CL) and this way it can affect the maintenance of pregnancy in the cow. PMID- 21656646 TI - Multiwall carbon nano-onions induce DNA damage and apoptosis in human umbilical vein endothelial cells. AB - Growing evidence has indicated the potential adverse effects on cardiovascular system of some nanomaterials, including fullerenes. In this study, we have evaluated the biological effects of multiwall carbon nano-onions (MWCNOs) (average size of 31.2 nm, zeta potential of 1.6 mV) on human umbilical vein endothelial cells (HUVECs). It was found that MWCNOs exhibited a dose-dependent inhibitory effect on cell growth; EC50 was 44.12 MUg/mL. Thus, three concentrations were chosen (0.2, 1, and 5 MUg/mL) for further experiments. Flow cytometry analysis revealed that 1 and 5 MUg/mL MWCNOs could induce apoptosis in HUVECs, the apoptotic rates were 12% and 24% at 24 h after exposure. On the other hand, MWCNOs did not affect the cell cycle distribution during 24 h period. Using gammaH2AX foci formation as an indicator for DNA damage, it was shown that 5 MUg/mL MWCNOs can induce gammaH2AX foci formation in HUVECs at 6, 12, and 24 h after treatment, whereas 0.2 MUg/mL MWCNOs induced gammaH2AX foci formation only at 6 h after treatment. In addition, all three concentrations of MWCNOs induced the generation of reactive oxygen species (ROS), and inhibition of ROS generation can partially decrease the gammaH2AX foci formation induced by MWCNOs. Taken together, these data first suggested that MWCNOs can induce DNA damage and apoptosis in HUVECs, and that ROS might be involved in this process. PMID- 21656647 TI - Transcatheter aortic valve implantation: lessons from the learning curve of the first 270 high-risk patients. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a rapidly evolving strategy for therapy of aortic stenosis. We describe the effect of the learning curve from the first 270 high-risk patients in Vancouver, Canada. METHODS: Patients underwent TAVI by transfemoral (63%) or transapical (37%) routes using balloon expandable valves. The experience was divided into the first half (FH, patients 1-135) and second half (SH, patients 136-270). RESULTS: The mean age was 83.2 +/- 8 years (FH 83 +/- 12 vs. SH 81 +/- 7 years, P = 0.12). The mean Society of Thoracic Surgeons Score (STS) was 9.5% +/- 5.2%- FH 10.5 vs. SH 8.5% (P = 0.01). The overall procedural success rate in the FH was 92.6%, improving to 97.8% in the SH (P = 0.05). The transfemoral procedural success improved-FH 89.3% to SH 98.8% (P = 0.01). The transapical procedural success remained high-FH 98.0% to SH 96.1% (P = 0.53). The overall 30-day mortality was 9.6%, improving from FH 13.3% to SH 5.9% (P = 0.04). In the transfemoral cases, 30-day mortality decreased by 56% [10.7-4.7%, P = 0.14], and similarly in transapical cases [17.6 7.8%, P = 0.14]. In-hospital stroke occurred in 3.3% (FH 3.7% vs. SH 2.9%, P = 0.74). The overall need for a new permanent pacemaker was 5.9% (FH 5.9% vs. SH 5.9%, P = 1). The overall major vascular injury rate was 6.7% (FH 8.1% vs. SH 5.2%, P = 0.33). The overall incidence of coronary vessel occlusion was 1.1% (FH 1.5 % vs. SH 0.7%, P = 0.56). Device embolization or failure to cross the valve was rare and largely seen in the FH only. Procedural experience (>135 procedures) was an independent predictor of 30-day survival (HR: 6.7, 95% CI: 1.2-18.1, P = 0.03). CONCLUSION: TAVI outcomes improve with experience and device development. While overall complication rates are low, scope remains to further reduce procedural adverse events. PMID- 21656648 TI - Trans-apical aortic valve implantation complicated by left main occlusion. AB - Transcatheter aortic valve implantation (TAVI) is a highly effective procedure for selected patients who are at high risk for aortic valve replacement; however, the incidence of severe complications is still relevant. Coronary occlusion during TAVI is a life-threatening complication that requires immediate diagnosis and treatment. We report the case of an 87-years-old woman affected by severe aortic stenosis, symptomatic for refractory heart failure, who underwent urgent balloon aortic valvuloplasty and subsequent elective transapical aortic valve implantation. Valve deployment was complicated by cardiac arrest and hemodynamic collapse, and left main coronary artery occlusion was recognized and successfully recovered by balloon angioplasty and stent implantation. Patient is alive and well 6 months after procedure. PMID- 21656649 TI - Left main coronary artery stenting after cardiac arrest in an infant with William's syndrome. AB - A 6-month-old female with William's syndrome and biventricular outflow obstruction had a cardiac arrest due to myocardial ischemia soon after induction of anesthesia during cardiac catheterization. The patient was supported with extra corporeal membrane oxygenator (ECMO) and successful stenting of the left main coronary artery was performed as a rescue measure. This intervention allowed successful weaning from ECMO and subsequent discharge from the hospital. Coronary intervention in infants may be successfully performed in dire situations. PMID- 21656651 TI - 2010 International Consensus Conference on Liver Transplantation for Hepatocellular Carcinoma: texts of experts. PMID- 21656650 TI - Luminescence in Li2Sr2Al2PO4F9:Dy3+ - a novel nanophosphor. AB - Earlier research has revealed numerous advantages of the wet chemical method in reaction acceleration, yield improvement, enhanced photoluminescence properties and the evolution of new material phases. In the present study the novel nanophosphor Li(2)Sr(2)Al(2)PO(4)F(9):Dy(3+) was synthesized by a one-step wet chemical method. Formation of single-phase compounds was confirmed by X-ray diffraction (XRD) and characterized by photoluminescence (PL) and transmission electron microscopy (TEM) techniques. The average diameter of the particles was calculated from the TEM image as ca. 20 nm. The synthesized nanophosphor exhibited intense blue and yellow emissions at 482 and 575 nm, respectively, owing to the Dy(3+) ion, by Hg-free excitation at 387 nm, i.e. solid-state lighting excitation. The results obtained showed that phosphors have the potential for applications in the lamp industry. PMID- 21656652 TI - Transjugular intrahepatic portosystemic shunt for the treatment of sinusoidal obstruction syndrome in a liver transplant recipient and review of the literature. AB - Sinusoidal obstruction syndrome (SOS) is a rare, life-threatening clinical syndrome resulting from sinusoidal congestion, and it is characterized by hepatomegaly, ascites, weight gain, and jaundice. The frequency of this condition after liver transplantation (LT) is low, but when SOS is severe and refractory to medical therapy, the ultimate solution is retransplantation. We describe a patient with SOS after LT who was successfully treated by the placement of a transjugular intrahepatic portosystemic shunt (TIPS). Although information on this approach is scarce because of the low incidence of SOS in LT patients, we review the available literature on treating this condition with a TIPS. On the basis of the reported information and our patient's outcome, we suggest that prompt TIPS placement can be considered for SOS when medical treatment fails. Nonetheless, a formal assessment and prospective studies are needed to confidently indicate TIPS placement in this situation. PMID- 21656653 TI - What is the best staging system for hepatocellular carcinoma in the setting of liver transplantation? PMID- 21656654 TI - Region-specific challenges for minimizing endemic donor-transmitted infections. PMID- 21656655 TI - Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against hepatitis b virus recurrence after liver transplantation: a systematic review. AB - A combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogues (NUCs) is currently recommended as prophylaxis against the recurrence of hepatitis B virus (HBV) after liver transplantation (LT), but the optimal protocol is a matter of controversy. The aim of this study was the identification of factors associated with post-LT HBV recurrence in patients receiving HBIG and NUCs. We searched MEDLINE and PubMed for studies in English about the effectiveness of HBIG and NUCs [lamivudine (LAM) and/or adefovir dipivoxil (ADV)] against post-LT HBV recurrence (January 1998 to June 2010). Forty-six studies, which included 2162 HBV LT recipients, met the selection criteria. Patients receiving HBIG and LAM experienced HBV recurrence more frequently than patients receiving HBIG and ADV with or without LAM [6.1% (115/1889) versus 2.0% (3/152), P = 0.024], although they also were more frequently treated with indefinite HBIG prophylaxis (90% versus 57%, P < 0.001). For patients receiving HBIG and LAM, a lower frequency of HBV recurrence was associated with a high HBIG dosage (>=10,000 IU/day) versus a low HBIG dosage (<10,000 IU/day) during the first week after LT [3.2% (14/440) versus 6.5% (80/1233), P = 0.016], but the HBIG protocol had no impact on HBV recurrence in patients receiving HBIG and ADV. In conclusion, in comparison with the combination of HBIG and LAM, the combination of HBIG and ADV is associated with a lower rate of HBV recurrence after LT. Patients receiving HBIG and LAM should be given a high dosage of HBIG during the first week after LT, but a lower dosage can be used safely in patients receiving HBIG and ADV. Further studies with newer and more potent anti-HBV agents are definitely required. PMID- 21656656 TI - Patients' expectations and success criteria for liver transplantation. AB - Patient-reported outcomes are important to consider when the relative success of liver transplantation (LT) is being evaluated. Our primary objective was to examine the expectations for LT and the criteria for its success across 4 domains of functioning (pain, fatigue, emotional distress, and interference with daily activities) from the perspective of patients who were wait-listed for LT. One hundred four adult patients with a mean wait-list time of 16.5 +/- 13 months completed a semistructured interview with a modified version of the Patient Centered Outcomes Questionnaire (PCOQ). The patients reported moderate usual levels of pain, fatigue, emotional distress, and interference with daily activities (mean rating range = 3.8-6.2), and they attached great importance to improvements in these domains after LT (mean rating range = 7.3-8.0). Patients considered a mean reduction in pain of 33% to be a successful LT outcome. A reduction in fatigue of 56%, a reduction in emotional distress of 44%, and a reduction in interference with daily activities of 54% represented successful LT across these domains. Patients with more severe illness had higher expectations for fatigue (r = -0.30, P = 0.002) and interference with daily activities (r = 0.24, P = 0.015). Cluster and correlational analyses provided support for the validity of the PCOQ with LT patients. Our findings underscore the importance and value of using patient-centered assessments to better understand the ways in which patients prioritize LT outcomes and define transplantation success. Patient centered assessments have the potential to facilitate provider-patient communication by helping patients to prioritize their goals for LT and make informed choices on the basis of those priorities. PMID- 21656657 TI - Should we use living donor grafts for patients with hepatocellular carcinoma? Ethical considerations. PMID- 21656658 TI - Social barriers to listing for adult liver transplantation: their prevalence and association with program characteristics. AB - Social barriers to effective medical care are mandated to be routinely assessed as part of an evaluation for liver transplantation. This study explores how frequently liver transplant programs encounter these barriers in patients undergoing an evaluation and whether programs with higher proportions of Medicaid patients, historically disadvantaged minority patients, and rural patients encounter social barriers more frequently. A survey for assessing patient demographics and social barriers was electronically completed by representatives of 61 of 104 eligible US adult liver transplant programs (59%). Fifty-eight of the 61 programs identified themselves, and their characteristics were similar to those of all 104 US programs according to publicly available data from the Organ Procurement and Transplantation Network. Social barriers were reported to be encountered sometimes (10%-30%) or frequently (>30%) by the 61 programs as follows: inadequate or unstable health insurance (68.9% of the programs), a chaotic social environment (63.9%), a lack of a care partner (60.7%), an inability to obtain transportation (49.2%), a low educational level (36.1%), inadequate housing (23.0%), a language barrier (19.7%), no reliable way of contacting the patient (16.4%), difficulty in obtaining child care (11.5%), and food insecurity (8.2%). The frequencies of perceived social barriers did not differ significantly between programs reporting higher or lower proportions of Medicaid, minority, or rural patients. Our analysis suggests that program-level operational planning for addressing social barriers to transplant listing should be considered regardless of the proportions of Medicaid-insured, racial or ethnic minority, and rural patients in the population. PMID- 21656659 TI - Maternal influences on epigenetic programming of the developing hypothalamic pituitary-adrenal axis. AB - Parental and environmental factors during the prenatal and postnatal periods permanently affect the physiology and metabolism of offspring, potentially increasing disease risk later in life. Underlying mechanisms are being elucidated, and effects on a number of organs and metabolic pathways are likely involved. In this review, we consider effects on the developing hypothalamic pituitary-adrenal (HPA) axis, which may represent a common pathway for developmental programming. The focus is on prenatal and early postnatal development, during which the HPA axis may be programmed in a manner that affects health for a lifetime. Programming of the HPA axis involves, at least in part, epigenetic remodeling of chromatin, leading to alterations in the expression of genes in many organs and tissues involved in HPA activation and response, including the hippocampus and peripheral tissues. Examples of developmental epigenetic modifications affecting the HPA axis as well as target tissues are provided. PMID- 21656660 TI - Epigenomic reprogramming of the developing reproductive tract and disease susceptibility in adulthood. AB - During development, epigenetic programs are "installed" on the genome that direct differentiation and normal tissue and organ function in adulthood. Consequently, development is also a period of susceptibility to reprogramming of the epigenome. Developmental reprogramming occurs when an adverse stimulus or insult interrupts the proper "install" of epigenetic programs during development, reprogramming normal physiologic responses in such a way as to promote disease later in life. Some of the best examples of developmental reprogramming involve the reproductive tract, where early life exposures to environmental estrogens can increase susceptibility to benign and malignant tumors in adulthood including leiomyoma (fibroids), endometrial, and prostate cancer. Although specific mechanism(s) by which environmental estrogens reprogram the developing epigenome were unknown, both DNA and histone methylation were considered likely targets for epigenetic reprogramming. We have now identified a mechanism by which developmental exposures to environmental estrogens reprogram the epigenome by inducing inappropriate activation of nongenomic estrogen receptor (ER) signaling. Activation of nongenomic ER signaling via the phosphotidylinositol-3-kinase (PI3K) pathway activates the kinase AKT/PKB in the developing reproductive tract, which phosphorylates the histone lysine methyltransferase (HKMT) EZH2, the key "installer" of epigenetic histone H3 lysine 27 trimethylation (H3K27me3). AKT phosphorylation inactivates EZH2, decreasing levels of H3K27 methylation, a repressive mark that inhibits gene expression, in the developing uterus. As a result of this developmental reprogramming, many estrogen-responsive genes become hypersensitive to estrogen in adulthood, exhibiting elevated expression throughout the estrus cycle, and resulting in a "hyper-estrogenized" phenotype in the adult uterus that promotes development of hormone-dependent tumors. PMID- 21656661 TI - Microtia-anotia: a global review of prevalence rates. AB - BACKGROUND: There are few published studies on microtia-anotia frequency. METHODS: Using data from birth defects surveillance programs around the world, we conducted a systematic review on the frequency of microtia-anotia to further explore the differences in prevalence across countries. Ninety-two birth defects surveillance programs were evaluated with a total of 8917 cases of microtia anotia. We computed the prevalence per 10,000 births for each surveillance program for total cases of microtia-anotia (microtia types I to IV), microtia (types I to III), and anotia (type IV). Prevalence ratios were calculated by large geographic areas, race/ethnicity, and by surveillance methodologies. RESULTS: The overall prevalences were: microtia-anotia, 2.06 (confidence interval [CI], 2.02-2.10); microtia, 1.55 (CI, 1.50-1.60); and anotia 0.36 (CI, 0.34 0.38). Higher prevalences were observed for the Americas, Northern Europe and Asia, among Hispanics and Asians, and among active ascertainment and hospital based surveillance programs. CONCLUSIONS: We observed marked variation in the prevalence of microtia-anotia across surveillance programs and within countries. These results must be interpreted cautiously as this variability may be explained mainly by differences in surveillance methods. However, given the magnitude of some of the differences, other factors may also be involved. This study contributes to the knowledge of the prevalence of microtia-anotia by providing a critical analysis of the existing data. In addition, it supports the need for a coding system that allows complete phenotype characterization of microtia-anotia, including severity and laterality, as well as for further studies on the variation of its frequency related to race and ethnicity. PMID- 21656662 TI - May-Thurner syndrome. PMID- 21656663 TI - Multiparameter flow cytometric kinetics of phagocyte stimulus responses. PMID- 21656664 TI - Observations of cell size dynamics under osmotic stress. AB - Cultured mammalian cells [e.g., murine hybridomas, Chinese hamster ovary (CHO) cells] used to produce therapeutic and diagnostic proteins often exhibit increased specific productivity under osmotic stress. This increase in specific productivity is accompanied by a number of physiological changes, including cell size variation. Investigating the cell size variation of hyperosmotically stressed cultures may reveal, in part, the basis for increased specific productivity as well as an understanding of some of the cellular defense responses that occur under hyperosmotic conditions. The regulation of cell volume is a critical function maintained in animal cells. Although these cells are highly permeable to water, they are significantly less permeable to ionic solutes. Appropriate cell-water content is actively maintained in these cells by regulation of ion and osmolyte balances. Transport appropriate to extracellular conditions, leading to accrual or release of these species, is activated in response to acute cell volume changes. Osmotically induced regulatory volume increases (RVI) and regulatory volume decreases (RVD) are known to occur under a variety of conditions. We observed the time evolution of size variation in populations of two CHO cell lines under hyperosmotic conditions. Observations were made using multiple instruments, multiple cell lines, and multiple cell culture conditions. Size variation of CHO A1 was gauged by flow cytometry using an LSRII(r) flow cytometer while CHO B0 cells were quantified using a Cedex(r) cell analyzer. Hyperosmotic stress had a dose-dependent effect on the regulatory control of cell volume. Stressed cultures of CHO cells grown in suspension exhibited a shift in mean cell diameter. This shift in mean was not due to a change in the whole population, but rather to the emergence of distinct subpopulations of cells with larger cell diameters than those in the bulk of the population. PMID- 21656665 TI - Preparation and characterization of bioactive mesoporous calcium silicate-silk fibroin composite films. AB - Composite films of bioactive mesoporous calcium silicate (MCS)/silk fibroin (SF) and conventional calcium silicate (CS)/SF were fabricated by the solvent casting method, and the structures and properties of the composite films were characterized. Results of field emission scanning electron microscope (FESEM) indicated that MCS or CS was uniformly dispersed in the SF films. The measurements of the water contact angles suggested that the incorporation of either MCS or CS into SF could improve the hydrophilicity of the composite films, and the former was more effective than the later. The bioactivity of the composite films was evaluated by soaking in a simulated body fluid (SBF), and the formation of a hydroxycarbonate apatite (HCA) layer was determined by XRD and FT IR. The results showed that the MCS/SF composite films have significantly enhanced apatite-forming bioactivity compared with the CS/SF composite films owing to the highly specific surface area and pore volume of MCS. In vitro cell attachment and proliferation tests showed that the MCS/SF composite film was a good matrix for the growth of MG63 cells. Consequently, the MCS/SF composite film possessed excellent physicochemical and biological properties, indicating its potential application for bone tissue engineering by designing 3D scaffolds according to its corresponding composition. PMID- 21656666 TI - Pulmonary artery chemoembolization in a sheep model: Evaluation of performance and safety of irinotecan eluting beads (DEB-IRI). AB - The purpose of this study was to evaluate and compare plasma pharmacokinetics, lung tissue concentration, and the potential toxicity of drug eluting beads loaded with irinotecan (DEB-IRI) in a sheep pulmonary artery chemoembolization (PACE) model. Sheep (n = 24) were embolized with DEB-IRI loaded with different doses (0, 20, 50, or 100 mg). Direct pulmonary artery (PA) injections of irinotecan were also performed at two doses (50 or 100 mg; n = 4 sheep). Irinotecan was quantified in plasma and lung tissue (liquid chromatography fluorescence detection); pathological examination of lungs was performed 4 days or 4 weeks after PACE. Irinotecan was detected in the systemic circulation within a few minutes after PACE, for several hours in DEB-IRI 20 and DEB-IRI 50 groups, and for 24 hours for DEB-IRI 100. Both Cmax and AUC values increased significantly with dose (p = 0.0078 and p = 0.0008, respectively) after PACE. Cmax and AUC values were significantly reduced (by 80%, p = 0.0036, and by 50%, p = 0.0393, respectively) after PACE than after direct PA injection. Irinotecan was not detected in tissue 4 days after PACE. No sign of lung toxicity was observed, except a limited hemorrhagic angionecrosis seen 4 days after PACE with DEB-IRI 100. Inflammatory response on beads was moderate in all DEB-IRI groups. Compared to other routes of administration, DEB loaded with irinotecan at doses up to 100 mg was well tolerated. DEB loaded with 100 mg irinotecan seem a promising candidate for future PACE trials in patients. PMID- 21656667 TI - Synthesis and efficient hepatocyte targeting of galactosylated chitosan as a gene carrier in vitro and in vivo. AB - While chitosan (CS) has been researched widely as a non-viral vector, its usefulness has been limited by its low cell specificity and transfection efficiency. Therefore, we successfully synthesized galactosylated chitosan (GC) and complexed it with an enhanced green fluorescent protein plasmid (pIRES-EGFP) for transfection into cultured H22 cells (murine hepatic cancer cell line) using various GC/EGFP (N/P) charge ratios. Maximal gene transfection rates detected by flow cytometry occurred at an N/P ratio 5:1. Compared with those of lipofectin/EGFP and naked pIRES-EGFP, GC/EGFP complexes show a very efficient cell-selective transfection to hepatocytes. The MTT assay detected relatively low cytotoxicity in cells transfected with GC. A recombinant plasmid granulocyte macrophage colony-stimulating factor (GM-SCF) and interleukin (IL) 21 (pIRES/GM CSF-IL21) was successfully constructed and GC/GM-CSF-IL21 nanoparticles (average diameter, 82.1 nm) were administered via the tail vein of mice with liver metastasis of colon cancer model, for 5 consecutive days. The GC/GM-CSF-IL21 nanoparticles exhibited hepatocyte and passive tumor specificity, increased therapeutic efficacy compared to control groups, promoted leukocytes to aggregate in tumor tissues, and activated the cytotoxicity of natural killer (NK) cells and cytolytic T lymphocyte (CTL). Our results indicate that GC can be used in gene therapy to improve transfection efficiency and can be used as an immunological stimulant in vivo. PMID- 21656668 TI - Comparison of the impact of trans fatty acids from ruminant and industrial sources on surrogate markers of cholesterol homeostasis in healthy men. AB - SCOPE: Mechanisms by which trans fatty acids (TFA) from industrial (iTFA) and ruminant (rTFA) sources alter cholesterol homeostasis are virtually unknown. We compared the impact of dietary iTFA and rTFA on surrogate markers of cholesterol absorption (beta-sitosterol and campesterol) and synthesis (lathosterol) in healthy men. METHODS AND RESULTS: In a randomized, controlled double-blind crossover study, 38 healthy men consumed three experimental isoenergetic diets for 4 wk each. The three diets were (i) high in iTFA (10.2 g/2500 kcal), (ii) high in rTFA (10.2 g/2500 kcal) and (iii) control diet low in TFA from any source (2.2 g/2500 kcal). The sum of plasma beta-sitosterol and campesterol concentrations was significantly reduced after the iTFA diet compared with the control diet (-12%, p=0.050). The reduction in combined beta-sitosterol and campesterol levels was larger in magnitude after the rTFA diet (-29% versus the control diet and -20% versus the iTFA diet, p<0.0001). The TFA-rich diets had no impact on plasma lathosterol concentrations. CONCLUSIONS: Very high intakes of rTFA and iTFA decrease cholesterol absorption but have no impact on cholesterol synthesis. Consumption of rTFA reduces cholesterol absorption to a greater extent than iTFA, but this difference does not ultimately affect plasma cholesterol concentrations. PMID- 21656669 TI - Identification of hemocyanin as a novel non-cross-reactive allergen from the giant freshwater shrimp Macrobrachium rosenbergii. AB - SCOPE: Sensitization to giant freshwater shrimp Macrobrachium rosenbergii (Mr) was recently reported. However, the allergens have yet to be identified. This study aimed to identify and characterize a novel allergen of Mr shrimp. METHODS AND RESULTS: Extracted proteins were separated and purified by anion and in some experiments, size-exclusion chromatography. Serum IgE from shrimp allergic donors identified a candidate protein, which was characterized by LC-MS/MS. The specificity of IgE binding was tested using immunoblotting and inhibition ELISA. The IgE-binding profiles from 12 of 13 Mr allergic subjects that were pre incubated with an extract of Penaeus monodon showed residual binding to ~60-80 kDa proteins. The 60-80 kDa IgE-bound proteins were fractionated in the flow through of anion chromatography showing a high IgE reactivity. Peptides identified by LC-MS/MS showed the proteins closely match subunits of hemocyanin (Hcs). Purified Hcs from hemolymph markedly inhibited binding of IgE from sera of Mr allergic subjects to solid-phased Mr proteins in inhibition ELISA. CONCLUSION: Hcs were identified as heat-stable, non-cross-reactive, high-molecular-weight (MW) allergens from Mr shrimp. Since circulatory organs are not always removed during food preparation, high concentrations of Hcs may be present along with shrimp meat, which contains the known cross-reactive tropomyosin protein. PMID- 21656670 TI - Zinc deprivation inhibits extracellular matrix calcification through decreased synthesis of matrix proteins in osteoblasts. AB - SCOPE: Zinc is implicated as an activator for bone formation, however, its influence on bone calcification has not been reported. This study examined how zinc regulates the bone matrix calcification in osteoblasts. METHODS AND RESULTS: Two osteoblastic MC3T3-E1 cell subclones (SC 4 and SC 24 as high and low osteogenic differentiation, respectively) were cultured in normal osteogenic (OSM), Zinc deficient (Zn-, 1 MUM), or adequate (Zn+, 15 MUM) media up to 20 days. Cells (SC 4) were also supplemented with (50 MUg/mL) or no ascorbic acid (AA) in combination with Zinc treatment. Zn- decreased collagen synthesis and matrix accumulation. Although AA is essential for collagen formation, its supplementation could not compensate for Zinc deficiency-induced detrimental effects on extracellular matrix mineralization. Zn- also decreased the medium and cell layer alkaline phosphatase ALP activity. This decreased ALP activity might cause the decrease of Pi accumulation in response to Zn-, as measured by von Kossa staining. Ca deposition in cell layers, measured by Alizarin red S staining, was also decreased by Zn(-) . CONCLUSION: Our findings suggest that zinc deprivation inhibits extracellular matrix calcification in osteoblasts by decreasing the synthesis and activity of matrix proteins, type I collagen and ALP, and decreasing Ca and Pi accumulation. Therefore zinc deficiency can be considered as risk factor for poor extracellular matrix calcification. PMID- 21656671 TI - Affinity of vitamin E analogues for the ubiquinone complex II site correlates with their toxicity to cancer cells. AB - SCOPE: Vitamin E (VE) analogues, epitomised by the prototypic alpha-tocopheryl succinate (alpha-TOS), are potent anti-cancer agents. alpha-TOS has recently been shown to trigger apoptosis by targeting the ubiquinone (UbQ) binding site(s) of the mitochondrial complex II (CII) and to cause excessive production of reactive oxygen species. METHODS AND RESULTS: We have modelled, using two approaches, a range of VE analogues into the proximal UbQ (Q(p) ) binding site of CII. This study reveals that in both cases, the calculated interaction energies of individual VE analogues correlate (R(2) value >0.8) with their toxicity to cancer cells. CONCLUSION: These data further support the UbQ site(s) of CII as an important target determining the anti-cancer activity of VE analogues as well as other emerging anti-cancer drugs. PMID- 21656672 TI - Dicaffeoylquinic acids in Yerba mate (Ilex paraguariensis St. Hilaire) inhibit NF kappaB nucleus translocation in macrophages and induce apoptosis by activating caspases-8 and -3 in human colon cancer cells. AB - SCOPE: The biological functions of caffeoylquinic acid (CQA) derivatives from various plant sources have been partially elucidated. The objectives were to isolate and purify diCQAs from Yerba mate tea leaves and assess their anti inflammatory and anti-cancer capabilities in vitro and explore their mechanism of action. METHODS AND RESULTS: Methanol extracts of dried mate leaves were resolved by flash chromatography and further purified resulting in two fractions one containing 3,4- and 3,5-diCQAs and the other 4,5-diCQA with NMR-confirmed structures. Both fractions inhibited LPS-induced RAW 264.7 macrophage inflammation by suppressing nitric oxide/inducible nitric oxide and prostaglandin E(2) /cyclooxygenase-2 pathways through inhibiting nucleus translocation of Nuclear factor kappaB subunits, p50 and p65. The diCQA fractions inhibited Human colon cancer cells CRL-2577 (RKO) and HT-29 cell proliferation by inducing apoptosis in a time- and concentration-dependent manner, but did not affect the protein levels of p21, p27, p53, and Bax:Bcl-2 ratio in RKO cells. In HT-29 cells, however, the diCQA fractions increased Bax:Bcl-2 ratio. The diCQA fractions increased the activation of caspase-8 leading to cleavage of caspase-3 in both RKO and HT-29 colon cancer cells. CONCLUSION: The results suggest that diCQAs in Yerba mate could be potential anti-cancer agents and could mitigate other diseases also associated with inflammation. PMID- 21656673 TI - Direct manipulation of a single potassium channel gate with an atomic force microscope probe. AB - Ion channels are membrane proteins that regulate cell functions by controlling the ion permeability of cell membranes. An ion channel contains an ion-selective pore that permeates ions and a sensor that senses a specific stimulus such as ligand binding to regulate the permeability. The detailed molecular mechanisms of this regulation, or gating, are unknown. Gating is thought to occur from conformational changes in the sensor domain in response to the stimulus, which results in opening the gate to permit ion conduction. Using an atomic force microscope and artificial bilayer system, a mechanical stimulus is applied to a potassium channel, and its gating is monitored in real time. The channel-open probability increases greatly when pushing the cytoplasmic domain toward the membrane. This result shows that a mechanical stimulus at the cytoplasmic domain causes changes in the gating and is the first to show direct evidence of coupling between conformational changes in the cytoplasmic domain and channel gating. This novel technology has the potential to be a powerful tool for investigating the activation dynamics in channel proteins. PMID- 21656674 TI - Measurement of mass transfer during dip-pen nanolithography with phospholipids. AB - Dip-pen nanolithography (DPN) has been extensively used before for patterning surfaces; however a complete understanding of the ink transport mechanisms is still lacking. Moreover, quality control of the fabricated structures is a bottleneck in DPN fabrication, and one aspect of this is the quantification of the ink mass transfer to the substrate during the lithographic process. There is a demand for measuring the exact amount of molecules deposited on a surface by lithographic methods, especially for biological applications. This article demonstrates a quantitative method for measuring the amount of ink transferred onto the substrate in DPN with phospholipids by dynamic force spectroscopy. To achieve this, the harmonic oscillation of a microcantilever in an atomic force microscope is used, obtaining picogram mass sensitivity in the determination of mass deposition. PMID- 21656675 TI - Glyco-DNA-gold nanoparticles: lectin-mediated assembly and dual-stimuli response. PMID- 21656676 TI - Determination of sudan dyes in red wine and fruit juice using ionic liquid-based liquid-liquid microextraction and high-performance liquid chromatography. AB - The liquid-liquid microextraction (LLME) was developed for extracting sudan dyes from red wine and fruit juice. Room temperature ionic liquid was used as the extraction solvent. The target analytes were determined by high-performance liquid chromatography. The extraction parameters were optimized. The optimal conditions are as follows: volume of [C(6)MIM][PF(6)] 50 MUL; the extraction time 10 min; pH value of the sample solution 7.0; NaCl concentration in sample solution 5%. The extraction recoveries for the analytes in red wine and fruit samples are 86.79-108.28 and 68.54-85.66%, whereas RSDs are 1.42-5.12 and 1.43 6.19%, respectively. The limits of detection and quantification were 0.428 and 1.426 ng/mL for sudan I, 0.938 and 3.127 ng/mL for sudan II, 1.334 and 4.445 ng/mL for sudan III, 1.454 and 4.846 ng/mL for sudan IV, respectively. Compared with conventional liquid-liquid extraction (CLLE) and ultrasonic extraction (UE), when LLME was applied, the sample amount was less (LLME: 4 mL; CLLE: 10 mL; UE: 10 mL), the extraction time was shorter (LLME: 15 min; CLLE: 110 min; UE: 50 min) and the extraction solvent amount was less (LLME: 0.05 mL IL; CLLE: 15 mL hexane; UE: 20 mL hexane). The proposed method offers a simple, rapid and efficient sample preparation for determining sudan dyes in red wine and fruit juice samples. PMID- 21656677 TI - Determination of acetanilide herbicides in cereal crops using accelerated solvent extraction, solid-phase extraction and gas chromatography-electron capture detector. AB - A method was developed to determine eight acetanilide herbicides from cereal crops based on accelerated solvent extraction (ASE) and solid-phase extraction (SPE) followed by gas chromatography-electron capture detector (GC-ECD) analysis. During the ASE process, the effect of four parameters (temperature, static time, static cycles and solvent) on the extraction efficiency was considered and compared with shake-flask extraction method. After extraction with ASE, four SPE tubes (graphitic carbon black/primary secondary amine (GCB/PSA), GCB, Florisil and alumina-N) were assayed for comparison to obtain the best clean-up efficiency. The results show that GCB/PSA cartridge gave the best recoveries and cleanest chromatograms. The analytical process was validated by the analysis of spiked blank samples. Performance characteristics such as linearity, limit of detection (LOD), limit of quantitation (LOQ), precision and recovery were studied. At 0.05 mg/kg spiked level, recoveries and precision values for rice, wheat and maize were 82.3-115.8 and 1.1-13.6%, respectively. For all the herbicides, LOD and LOQ ranged from 0.8 to 1.7 MUg/kg and from 2.4 to 5.3 MUg/kg, respectively. The proposed analytical methodology was applied for the analysis of the targets in samples; only three herbicides, propyzamid, metolachlor and diflufenican, were detected in two samples. PMID- 21656678 TI - A high-resolution capillary isoelectric focusing method for the determination of therapeutic recombinant monoclonal antibody. AB - Capillary isoelectric focusing (CIEF) is a common choice for separation and analysis of the charge variants and impurities of therapeutic proteins. In this study, we developed a sensitive CIEF analysis method for determining the charge heterogeneity of therapeutic monoclonal antibody (mAb) using Beckman PA800 plus platform. The mixture of 5% Pharmalyte 8-10.5 and 1% Pharmalyte 3-10 was used to overcome the limitation of using single Pharmalyte 3-10 in detecting charge heterogeneity of basic mAb. This approach largely improved the resolution of the heterogeneous peaks. In addition, 3 M urea and 50 mM arginine (Arg) were used to improve the separation as solubilizer and cathodic stabilizer, respectively. Under optimized condition, both acidic and basic peaks of the mAb were separated well. Method qualification results showed good specificity, precision, and linearity within the concentration range of 0.03-0.20 mg/mL for mAb R1. The method was then used for C-terminal lysine (Lys) variants characterization and glycosylation profiles analysis. Furthermore, it also had a wide application in the clone screening process. The highly sensitive and repeatable results highlighted the wide application prospects of this method in biopharmaceutical industry. PMID- 21656679 TI - Determination of 2-ethylhexyl nitrate in diesel fuel. AB - The aim of this study was to develop and validate fast and easily applicable GC/MS assay for the quantification of the substance that increases cetane number in diesel fuel (2-ethylhexylnitrate, 2-EHN). These requirements were fulfilled best by a headspace GC-MS assay with negative chemical ionization with methane (HS-GC/MS). Chromatographic separation is achieved using a DB5-MS capillary column after the addition of known amount of internal standard (o-nitrotoluene). The limit of detection was 0.009% v/v for 2-EHN and the limit of quantification was 0.03% v/v. The HS-GC/MS method was applied for the quantification of cetane improver in spiked diesel fuel and real diesel fuel. The method is linear over the studied range (0.03-0.3%, v/v), with satisfactory intra- and inter-assay precision, and the relative standard deviations are lower than 10%. Good accuracy is achieved with bias <10% at all levels tested. PMID- 21656680 TI - MS-based glycomic strategies for probing the structural details of polylactosaminoglycan chain on N-glycans and glycoproteomic identification of its protein carriers. AB - Most MS-based glycomic and glycoproteomic analyses focus on identifying changes in terminal glyco-epitopes represented by sialylation and fucosylation at specific positions of the terminal N-acetyllactosamine units. Much less attention was accorded to the underlying linear or branched poly-N-acetyllactosamine extension from the N-glycan trimannosyl core other than a simple inference of its presence due to mass data and hence glycosyl compositional assignment. Using the EA.hy926 cell line derived from human umbilical vein endothelial cells (HUVEC), we have systematically investigated the MALDI- and ESI-MS-based methodologies for probing the structural details of endothelial polylactosaminoglycans at both MS and MS(2) levels in conjunction with the use of endo-beta-galactosidase to identify branching motifs and initiation sites. We showed that the polylactosaminoglycan chains on the N-glycans of EA.hy926 were less sialylated and fucosylated but more extended and branched than those of human umbilical vein endothelial cells, thus demonstrating a fundamental glycomic difference. For EA.hy926 that was investigated in more details, its polylactosaminoglycan chains were shown to be not restricted to extending from a specific antenna including the biologically important 6-arm position. Finally, experimental conditions for glycopeptide enrichment by tomato lectin were further optimized, which led to identification of over 40 candidate endothelial membrane protein carriers of polylactosaminoglycans by proteomic analysis. PMID- 21656681 TI - Comparative evaluation of label-free SINQ normalized spectral index quantitation in the central proteomics facilities pipeline. AB - Normalized spectral index quantification was recently presented as an accurate method of label-free quantitation, which improved spectral counting by incorporating the intensities of peptide MS/MS fragment ions into the calculation of protein abundance. We present SINQ, a tool implementing this method within the framework of existing analysis software, our freely available central proteomics facilities pipeline (CPFP). We demonstrate, using data sets of protein standards acquired on a variety of mass spectrometers, that SINQ can rapidly provide useful estimates of the absolute quantity of proteins present in a medium-complexity sample. In addition, relative quantitation of standard proteins spiked into a complex lysate background and run without pre-fractionation produces accurate results at amounts above 1 fmol on column. We compare quantitation performance to various precursor intensity- and identification-based methods, including the normalized spectral abundance factor (NSAF), exponentially modified protein abundance index (emPAI), MaxQuant, and Progenesis LC-MS. We anticipate that the SINQ tool will be a useful asset for core facilities and individual laboratories that wish to produce quantitative MS data, but lack the necessary manpower to routinely support more complicated software workflows. SINQ is freely available to obtain and use as part of the central proteomics facilities pipeline, which is released under an open-source license. PMID- 21656682 TI - Investigation of POPX2 phosphatase functions by comparative phosphoproteomic analysis. AB - Identifying the substrates and biochemical pathway regulated by phosphatases has always been more challenging than finding those regulated by kinases. Here, we report the use of phosphoproteomic methods to analyse the pathways regulated by POPX2 (partner of PIX 2) phosphatase. POPX2 is a serine/threonine phosphatase, found in many cancer types. The levels of the POPX2 have been found to be up regulated in the more invasive breast cancer cells compared with non-invasive ones. Our observations also suggest that POPX2 level is positively correlated with cell motility. Thus, finding substrates or pathways regulated by POPX2 will help to elucidate the regulatory mechanism of cancer cell motility and invasiveness. We have also developed and validated a protocol using electrostatic repulsion-hydrophilic interaction chromatography (ERLIC) to enrich the phosphopeptides followed by LC-MS/MS to allow comparison between the phosphoproteomes of control and POPX2 overexpressing cells. With this approach, we were able to identify a biochemical pathway through which POPX2 exerts its apparent cellular function: the regulation of activity of glycogen synthase kinase-3, which in turn modulates extracellular signal-regulated kinase and cell motility. PMID- 21656683 TI - Comparison between procedures using SDS for shotgun proteomic analyses of complex samples. AB - Filter-aided sample preparation (FASP) and a new sample preparation method using a modified commercial SDS removal spin column are quantitatively compared in terms of their performance for shotgun proteomic experiments in three complex proteomic samples: a Saccharomyces cerevisiae lysate (insoluble fraction), a Caenorhabditis elegans lysate (soluble fraction), and a human embryonic kidney cell line (HEK293T). The characteristics and total number of peptides and proteins identified are compared between the two procedures. The SDS spin column procedure affords a conservative fourfold improvement in throughput, is more reproducible, less expensive (i.e. requires less materials), and identifies between 30 and 107% more peptides at q<=0.01, than the FASP procedure. The peptides identified by SDS spin column are more hydrophobic than species identified by the FASP procedure as indicated by the distribution of GRAVY scores. Ultimately, these improvements correlate to as great as a 50% increase in protein identifications with two or more peptides. PMID- 21656684 TI - Effects of postmortem storage temperature on sea bass (Dicentrarchus labrax) muscle protein degradation: analysis by 2-D DIGE and MS. AB - Storage conditions are known to be important for postmortem deterioration of fish muscle, and temperature is one of the factors with the strongest impact on this process. In order to shed light on the influence of temperature on the status of sea bass (Dicentrarchus labrax) muscle proteins during postmortem storage, a 2-D DIGE and mass spectrometry study was performed on fish kept at either 1 or 18 degrees C for 5 days. As expected, the greatest alterations in sea bass filet protein composition were observed upon postmortem storage at 18 degrees C, with distinct changes appearing in the 2-D protein profile after 5 days of storage at this temperature. In particular, degradation of the myofibrillar protein myosin heavy chain and of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, among the most abundant muscle proteins, could be clearly observed upon storage at higher temperatures. Although to a lesser extent, however, several proteins were observed to vary in abundance also upon storage for 5 days at 1 degrees C. In particular, one of the most interesting observations was the rapid and significant decrease in the abundance of nucleoside diphosphate kinase B and phosphoglycerate mutase 2, which was observed also at low storage temperatures and appeared to be temperature-independent. The results of this study offer new knowledge on changes occurring in sea bass muscle proteins during postmortem storage at different temperatures and provide indications on protein degradation trends that might be useful for monitoring freshness of fish and quality of storage conditions. PMID- 21656685 TI - Patterned hydrogel substrates for cell culture with electrohydrodynamic jet printing. AB - Cells respond to and are directed by physiochemical cues in their microenvironment, including geometry and substrate stiffness. The development of substrates for cell culture with precisely controlled physiochemical characteristics has the potential to advance the understanding of cell biology considerably. In this communication, E-jet printing is introduced as a method for creating high-resolution protein patterns on substrates with controlled elasticity. It is the first application of E-jet printing on a soft surface. Protein spots as small as 5 um in diameter on polyacrylamide are demonstrated. The patterned hydrogels are shown to support cell attachment and spreading. Polyacrylamide substrates patterned by E-jet printing may be applied to further the study of cellular mechanobiology. PMID- 21656686 TI - Morphine-induced mu opioid receptor trafficking enhances reward yet prevents compulsive drug use. AB - Morphine, heroin and other commonly abused opioids induce little mu opioid receptor (MOR) trafficking compared to endogenous opioids. We utilized knock-in mice expressing a mutant recycling MOR (RMOR) that desensitizes and is internalized in response to morphine to show that facilitating MOR trafficking not only enhances morphine reward but, despite this, reduces the development of addiction-like behaviours. To demonstrate this, we developed a novel model of the transition from controlled to compulsive drug use that recapitulates many features of human addiction, including persistent drug seeking despite adverse consequences and a decreased preference for alternative rewards. These behaviours emerged spontaneously in wild-type but not RMOR mice, and their intensity predicted the reinstatement of morphine seeking after extended abstinence, while prior morphine intake did not. These results confirm previous findings in the rat that addiction can be dissociated from both reward and consumption. Most importantly, these results demonstrate that one can simultaneously reduce the 'addictiveness' of morphine and enhance its desirable effects by promoting agonist-induced MOR trafficking. PMID- 21656688 TI - Dynamic chirality determines critical roles for bioluminescence in symplectin dehydrocoelenterazine system. AB - Symplectin is a photoprotein containing the dehydrocoelenterazine (DCL) chromophore, which links to a cysteine residue through a covalent bond with the emission of blue light. This study focuses on the stereochemical process of the emerging stereogenic centers. Two isomeric fluorinated DCL analogs (2,4-diF- and 2,6-diF-DCL) were employed owing to their different bioluminescence activities, these being 200% and 20% compared to natural DCL, respectively. Each of these diF DCLs was found to exchange with the natural DCL in symplectin at pH 6.0. The emerging stereogenic carbons were racemic at the binding sites. Changing the pH of this storage form to the protein's optimum solubility pH (pH 7.8) resulted in 2,4-diF-DCL-bound symplectin luminescence, and the spent solutions were then analyzed and coelenteramide-390-CGLK-peptide and coelenteramine were detected after a peptidase digestion. The same analysis of the 2,6-diF-DCL-bound symplectin, on the other hand, afforded coelenteramine only but no coelenteramide. When the racemic storage diF-DCLs moved to the active site at pH 7.8, a change in the chirality with the 390-Cys residue resulted. Model experiments using L-cysteine-containing CGLK-peptide supported two diastereoisomers from each diF-DCL. The significant difference in the luminescence from these two chromophores is attributed to a plausible mechanism including the dynamically variable stereogenic center emerging at the storage and then the active site on the symplectin. It is concluded that such dynamic chirality plays a significant role in the symplectoteuthis bioluminescence. PMID- 21656689 TI - Platinum-acetylide polymers with higher dimensionality for organic solar cells. AB - A new series of platinum(II)-acetylide polymers P1-P3 containing thiophene triarylamine chromophores of different dimensions were synthesized and their electronic band structures, field-effect charge transport, and application in bulk heterojunction solar cells were evaluated. These materials are soluble in polar organic solvents and show strong absorptions in the solar spectra (with the highest absorption coefficient of 1.59*10(5) cm(-1) from thin films), thus rendering them excellent candidates for bulk heterojunction polymer solar cells. The spin-coated polymer thin films showed p-channel field-effect charge transport with hole mobilities of 1.90*10(-5) to 7.86*10(-5) cm(2) V(-1) s(-1) for P1-P3 and an improved charge carrier transport was found for P2 with higher molecular dimensionality than P1. The dependence of their photovoltaic properties and dimensionality was also investigated. Even if the polymers possess relatively high bandgaps and narrow absorption bandwidths, the highest power conversion efficiency of 2.24 % can be obtained based on blends of P3 with [6,6]phenyl-C(61) butyric acid methyl ester (PCBM) (1:5, w/w) under AM1.5 simulated solar illumination. The present work indicates that multidimensional polymers exhibit a better photovoltaic performance over the linear polymers under the same measurement conditions and can provide an attractive approach to developing highly efficient conjugated metallopolymers for efficient power generation. PMID- 21656687 TI - Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer. AB - Secretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole-genome data-mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal-type 1 (SPINK1) to be associated with poor survival in estrogen receptor-positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER- cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down-regulation of SPINK1 resulted in cell death. Further, SPINK1 overexpressing cells were resistant to drug-induced apoptosis due to reduced caspase-3 levels and high expression of Bcl2 and phospho Bcl2 proteins. Intriguingly, these anti-apoptotic effects of SPINK1 were abrogated by mutations of its protease inhibition domain. Thus, SPINK1 affects multiple aggressive properties in breast cancer: survival, invasiveness and chemoresistance. Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer. PMID- 21656690 TI - Isoxazol-5(4H)one derivatives as PTP1B inhibitors showing an anti-obesity effect. AB - In developing inhibitors of therapeutic target enzymes, significant time and effort are committed to the preparation of large numbers of compounds. In an effort to develop a potent inhibitor of protein tyrosine phosphatase (PTP) 1B as an anti-obesity and/or anti-diabetic agent, we constructed an isoxazolone chemical library by using a simplified procedure that circumvents tedious workup and purification steps. The 10*7 isoxazolone derivatives were synthesized by coupling the two halves of the target compounds. When mixed and heated in test tubes, the precursors produced the reaction products as precipitates. After brief washing, the products were pure enough to be used for enzymatic experiments. With the precursors for the coupling reactions prepared, the 10*7 library compounds could be prepared in a day by using the present protocol. The library compounds thus obtained were examined for their inhibitory activities against PTP1B. Among them, compound C3 was the most potent inhibitor of PTP1B with an IC(50) of 2.3 MUM. The in vivo effect of C3 was also examined in an obesity-prone mouse strain. Diet-induced obese (DIO)/diabetic mice were divided into two groups and each group was fed a high-fat diet (HFD) or HFD+C3 for four weeks. The group of C3-fed mice gained significantly less weight relative to the HFD-fed control group during the four weeks of the drug feeding period. In contrast to the anti-obesity effect of C3, no difference was observed in the glycemic control of the HFD and HFD+C3 mice groups. PMID- 21656691 TI - Oxyfold: a simple and efficient solid-supported reagent for disulfide bond formation. AB - The synthesis and use of novel polymer-supported reagents for disulfide bond formation is described. This family of supported reagents consists of a series of oxidized methionines grafted onto a solid support. Their cost and the simplicity of their preparation through N-carboxyanhydride polymerization on beads make them reactants of choice for the formation of disulfide bridges in peptides. PMID- 21656692 TI - Palladium(II)-catalyzed oxidative cascade cyclization reactions of anilides and anilines: scope and mechanistic investigations. AB - With Pd(OAc)(2)/pyridine as the catalyst system and molecular oxygen as a green oxidant, acrylanilides and N-allylanilines undergo oxidative cascade cyclization to form heterocyclic rings in high yields. This methodology is applicable to acrylanilides of different substitution patterns on olefinic units. Mechanistic studies revealed that cyclization of acrylanilides proceeded through an intramolecular syn-amidopalladation pathway. The reversible nature of amidopalladation serves as a "scavenging process" to prevent beta-hydride elimination from occurring halfway through the catalytic cycle, thus favoring the formation of cascade cyclization products. In addition, internal coordination between an sigma-alkylpalladium species and a tethered olefinic C=C double bond also appears to disfavor beta-hydride elimination. PMID- 21656693 TI - Unexpected formation of a trans-syn-fused linear triquinane from a trimethylenemethane (TMM)-diyl-mediated [2+3] cycloaddition reaction. PMID- 21656694 TI - Structure modulation of silica microspheres in bio-inspired silicification: effects of TEOS concentration. PMID- 21656695 TI - Hydrogenation of p-chloronitrobenzene over nanostructured-carbon-supported ruthenium catalysts. AB - Carbon nanotubes (CNTs) and carbon nanofibers (CNFs) have been used for the first time to support ruthenium nanoparticles for the hydrogenation of p chloronitrobenzene (p-CNB) to produce selectively p-chloroaniline. The preparation of well-dispersed ruthenium catalysts from the [Ru(3)(CO)(12)] precursor required activation of the purified supports by nitric acid oxidation. The supports, purified and functionalized, and the supported catalysts have been characterized by a range of techniques. The catalytic activity of these materials for the hydrogenation of p-CNB at 35 bar and 60 degrees C is shown to reach as high as 18 mol(p-CNB)g(Ru)(-1) h(-1), which is one order of magnitude higher than a commercial Ru/Al(2)O(3) catalyst. Selectivities between 92 and 94 % are systematically obtained, the major byproduct being aniline. PMID- 21656696 TI - Ru(II) -mediated hydrogen transfer from aqueous glycerol to CO2: from waste to value-added products. AB - Aqueous glycerol was used as the hydrogen source for the reduction of CO(2) to the hydrogen carrier formic acid in the presence of the catalyst [RuCl(2)(PPh(3))(3)]. All intermediates were identified and characterized. Glycerol was converted into glycolic acid, HO-CH(2)-COOH, that was identified by using (1)H and (13)C NMR spectroscopy. PMID- 21656697 TI - alpha,omega-Functionalized C19 monomers. PMID- 21656698 TI - Expression patterns of Ephs and ephrins throughout retinotectal development in Xenopus laevis. AB - The Eph family of receptor tyrosine kinases and their ligands the ephrins play an essential role in the targeting of retinal ganglion cell axons to topographically correct locations in the optic tectum during visual system development. The African claw-toed frog Xenopus laevis is a popular animal model for the study of retinotectal development because of its amenability to live imaging and electrophysiology. Its visual system undergoes protracted growth continuing beyond metamorphosis, yet little is known about ephrin and Eph expression patterns beyond stage 39 when retinal axons first arrive in the tectum. We used alkaline phosphatase fusion proteins of EphA3, ephrin-A5, EphB2, and ephrin-B1 as affinity probes to reveal the expression patterns of ephrin-As, EphAs, ephrin-Bs, and EphBs, respectively. Analysis of brains from stage 40 to adult frog revealed that ephrins and Eph receptors are expressed throughout development. As observed in other species, staining for ephrin-As displayed a high caudal to low rostral expression pattern across the tectum, roughly complementary to the expression of EphAs. In contrast with the prevailing model, EphBs were found to be expressed in the tectum in a high dorsal to low ventral gradient in young animals. In animals with induced binocular tectal innervation, ocular dominance bands of alternating input from the two eyes formed in the tectum; however, ephrin-A and EphA expression patterns were unmodulated and similar to those in normal frogs, confirming that the segregation of axons into eye-specific stripes is not the consequence of a respecification of molecular guidance cues in the tectum. PMID- 21656699 TI - Cancer nanotechnology research in the United States and China: cooperation to promote innovation. AB - The application of nanotechnology to cancer research is a promising area for US China cooperation. Cancer is a major public health burden in both countries, and progress in cancer nanotechnology research is increasing in several fields, including imaging, biomarker detection, and targeted drug delivery. The United States and China are international leaders in nanotechnology research, and have both launched national programs to support nanotechnology efforts in the recent past. The accelerating trend of co-authorship among US and Chinese nanotechnology researchers demonstrates that individual scientists already recognize the potential for cooperation, providing a strong platform for creating additional partnerships in pre-competitive research areas. Mechanisms that could help to enhance US-China cancer nanotechnology partnerships include: developing new programs for bi-directional training and exchange; convening workshops focused on specific scientific topics of high priority to both countries; and joint support of collaborative research projects by US and Chinese funders. In addition to the accelerating scientific progress, expanded cooperation will stimulate important dialog on regulatory, policy, and technical issues needed to lay the groundwork for US and Chinese scientists to move greater numbers of cancer nanotechnology applications into the clinic. PMID- 21656700 TI - GCT of proximal phalanx of ring finger: a case report. AB - Giant-cell tumor (GCT) of bone arising from phalanx of a finger is extremely rare. Rizzoli Orthopedic Institute in their study on 900 treated cases of GCT from 1947-1997 reported only 0.9% incidence of GCT in bones of the hand. There was no case of GCT of the phalanges in that series. We report here a case of GCT of bone arising from phalanx of finger because of its very unusual location. The tumor was diagnosed on the basis of fine-needle aspiration cytology and confirmed by histopathology. PMID- 21656701 TI - PCR study of a series of ASCUS cases HPV-positive by HCII. AB - Most guidelines currently recommend the testing of human papillomavirus (HPV) in ASCUS cases. The most used method for this purpose is Hybrid Capture II (HCII), but PCR techniques with GP5+/6+ primers can be also applied. Furthermore, the HCII high-risk probe test for detection of HPV shows cross-reactivity with low risk HPV. Although this cross-reactivity has been studied in screening populations, it has received little attention in ASCUS cases. To compare the performance of the HCII high-risk probe test and PCR for the detection of HPV in ASCUS cases. We randomly selected 83 ASCUS cases that were positive for high-risk HPV by HCII and applied the PCR test using MYO9-11 and GP5+/6+ primers to samples from these cases. Our results show cross-reactivity with low-risk HPV in 25.3% (21/83) of the HCII+ PCR+ cases. Regarding the follow-up our results emphasize the importance of HPV typing, especially for HPV 16 infection. We propose the use of PCR techniques using GP5+/6+ consensus primers for the screening of HPV in ASCUS. PMID- 21656702 TI - Extrinsic allergic alveolitis as an uncommon diagnostic pitfall in lung cytology. AB - House paints, the industrial products of toxic chemicals are known to be linked with severe respiratory disturbances especially in inadequately ventilated places. In this study, we aimed to report a biopsy-proven case of extrinsic allergic alveolitis (EAA) who presented with nonspecific respiratory symptoms 1 month after having her whole house interior painted. At CT scanning, we observed the ground glass opacities and the micronodular pattern typical for EAA and also a solid, consolidative lung area, highly suggestive of malignancy. The case initially was misinterpreted as a malignant tumor both radiologically and cytologically at CT-guided transthoracic fine needle aspiration biopsy. The final pathologic diagnosis was given as EAA on frozen section performed during thoracotomy operation. The patient received short-term steroid treatment and has been doing well for the last 7 months after her operation. As a conclusion, when assessing a cytologic material from a patient who has got a solid lung mass and also a history of chemical dye exposure, consolidative mass formation which is a rare form of EAA should always be kept in mind. Another final point is that the appropriate ventilation should be achieved if the exposure with the house paint chemicals is inevitable. PMID- 21656703 TI - Prolapsed fallopian tube: cytological findings in a ThinPrep liquid based cytology vaginal vault sample. AB - Fallopian tube prolapse through the vaginal vault after hysterectomy is a rare complication. The clinical diagnosis is difficult and the patient may undergo unnecessary treatment. A cytological diagnosis of tubal prolapse is rare. There are very few descriptions of the cytological appearances of prolapsed fallopian tube and to our knowledge, they have not been described in liquid based cytology preparations. The presence of classic columnar cells with cilia and sheets of cells with small granular uniform nuclei in an orderly arrangement are the diagnostic appearances of cells originating from the fallopian tube. We describe a case in which the cells had undergone squamous metaplasia with nuclear enlargement and increased nuclear to cytoplasmic ratios corresponding to reactive atypia but with fine and evenly distributed chromatin and smooth nuclear contours, which indicated their benign nature. In addition, in this case intracytoplasmic polymorphs and associated extracellular infiltrates of inflammatory cells are noted. The description of this case may help others to consider a cytological diagnosis of prolapsed fallopian tube, thus preventing repeated cauterisations of vault granulation tissue on one hand, and possibly excessive surgical treatment of a mistaken malignant lesion on the other. PMID- 21656704 TI - Slug regulates E-cadherin expression in metastatic adenocarcinoma cells isolated from pleural fluid. AB - Slug protein is a key regulator of epithelial-mesenchymal transition, but its expression in cancer is less well studied. To evaluate the expression of slug, E cadherin and vimentin in adenocarcinoma cells from malignant pleural effusions, we analyzed 121 malignant pleural fluid specimens. Twenty-eight nonmalignant pleural fluid specimens were analyzed as control. Besides clinical cytological diagnosis tests, immunofluorescence, immunocytochemistry and Western blotting methods were used. Results showed strong membrane staining of E-cadherin in adenocarcinoma cells from pleural fluid. Slug mainly showed nucleus staining. Cytoplasma positive of vimentin was found in adenocarcinoma cells isolated from pleural fluid. Slug, E-cadherin and vimentin expression was found in 43/121 (36%), 87/121 (72%) and 102/121 (84%) cases, respectively. Our data showed elevated levels of slug were accompanied by down regulation of E-cadherin and the expression of vimentin in adenocarcinoma cells. In addition, there was no relationship between slug expression and patient's age or gender or tumor site. Hyperplasia epithelium cells from nonmalignant pleural fluid were uniformly negative for E-cadherin and slug. In conclusion, the results demonstrated the inverse expression of slug and E-cadherin in the majority of malignant pleural fluid cases compared with nonmalignant pleural fluid. The slug protein may be helpful to access the prognosis of patients with pleural fluid. PMID- 21656706 TI - 2D format for screening bacterial cells at the throughput of flow cytometry. AB - We present a method for generating gel-based unordered 2D arrays of bacterial cells of a very high density, up to 10(5) cells per mm(2). Bacteria in a suspension are focused into a thin layer when the suspension and a dry gel matrix penetrate each other. Formation of a second gel from gel-forming components contained in the suspension results in immobilization of the cells. The immobilized cells stay alive and can repeatedly divide to produce microcolonies. The method provides for high-throughput screening and massively parallel analysis of individual cells in large populations, as well as for rapid isolation of rare clones. PMID- 21656705 TI - Uranium bioremediation in continuously fed upflow sand columns inoculated with anaerobic granules. AB - Reductive precipitation of soluble hexavalent uranium (U(VI)) to insoluble tetravalent uranium (U(IV)) containing minerals is one of the more promising approaches to uranium remediation. The objective of this study was to evaluate the long-term performance of methanogenic granules for the continuous treatment of U(VI). For this purpose, three sand-packed columns inoculated with anaerobic biofilm were operated with or without ethanol and one column was exposed to nitrate co-contamination. The columns were operated for 373 days and efficiently removed U (24 mg L(-1)) in excess of 99.8%. No long-term benefit of ethanol addition was observed, suggesting that endogenous substrates in the biofilm were sufficient to drive the reduction reactions. Nitrate addition was found to inhibit U(VI) reduction and cause re-oxidation of some U(IV) deposited in the column. Taken as a whole, the results indicate that methanogenic biofilms can be reliably applied in bioreactor technology for sustained U removal from groundwater. PMID- 21656708 TI - Secreted production of collagen-inspired gel-forming polymers with high thermal stability in Pichia pastoris. AB - Previously, we have shown that gel-forming triblock proteins, consisting of random coil middle blocks and trimer-forming (Pro-Gly-Pro)(9) end blocks, are efficiently produced and secreted by the yeast Pichia pastoris. These end blocks had a melting temperature (T(m)) of ~41 degrees C (at 1.1 mM of protein). The present work reveals that an increase of T(m) to ~74 degrees C, obtained by extension of the end blocks to (Pro-Gly-Pro)(16), resulted in a five times lower yield and partial endoproteolytic degradation of the protein. A possible cause could be that the higher thermostability of the longer (Pro-Gly-Pro)(16) trimers leads to a higher incidence of trimers in the cell, and that this disturbs secretion of the protein. Alternatively, the increased length of the proline-rich (Pro-Gly-Pro)(n) domain may negatively influence ribosomal translation, or may result in, for example, hydrophobic aggregation or membrane-active behavior owing to the greater number of closely placed proline residues. To discriminate between these possibilities, we studied the production of molecules with randomized end blocks that are unable to form triple helices. The codon- and amino acid composition of the genes and proteins, respectively, remained unchanged. As these nontrimerizing molecules were secreted intact and at high yield, we conclude that the impaired secretion and partial degradation of the triblock with (Pro-Gly Pro)(16) end blocks was triggered by the occurrence of intracellular triple helices. This degradation was overcome by using a yapsin 1 protease disruptant, and the intact secreted polymer was capable of forming self-supporting gels of high thermal stability. PMID- 21656707 TI - Osteogenic response to BMP-2 of hMSCs grown on apatite-coated scaffolds. AB - Osteoconductive materials play a critical role in promoting integration with surrounding bone tissue and resultant bone repair in vivo. However, the impact of 3D osteoconductive substrates coupled with soluble signals on progenitor cell differentiation is not clear. In this study, we investigated the influence of bone morphogenetic protein-2 (BMP-2) concentration on the osteogenic differentiation of human mesenchymal stem cells (hMSCs) when seeded in carbonated apatite-coated polymer scaffolds. Mineralized scaffolds were more hydrophilic and adsorbed more BMP-2 compared to non-mineralized scaffolds. Changes in alkaline phosphatase (ALP) activity within stimulated hMSCs were dependent on the dose of BMP-2 and the scaffold composition. We detected more cell-secreted calcium on mineralized scaffolds at all time points, and higher BMP-2 concentrations resulted in increased ALP and calcium levels. RUNX2 and IBSP gene expression within hMSCs was affected by both substrate and soluble signals, SP7 by soluble factors, and SPARC by substrate-mediated cues. The present data indicate that a combination of apatite and BMP-2 do not simply enhance the osteogenic response of hMSCs, but act through multiple pathways that may be both substrate- and growth factor-mediated. Thus, multiple signaling strategies will likely be necessary to achieve optimal bone regeneration. PMID- 21656709 TI - Dissolving carbon dioxide in high viscous substrates to accelerate biocatalytic reactions. AB - Solvent free biotransformation of polyglycerol-3 and lauric acid yields polyglycerol-3-laurate and water. This conversion can be catalyzed by Novozym 435. However, the performance is limited by the viscosity of polyglycerol as well as of polyglycerol-3-laurate. A decrease of viscosity by increasing reaction temperature is only possible in a certain temperature range because of the limited stability of the applied enzyme. By dissolving high dense carbon dioxide into the reaction system the viscosity could be reduced, keeping the temperature at an acceptable level at the same time. Thus the reaction rate was increased by a factor of 4 while working at a pressure of 280 bar and 60 degrees C. PMID- 21656710 TI - Down-regulation of CD81 tetraspanin in human cells producing retroviral-based particles: tailoring vector composition. AB - Retroviral-derived biopharmaceuticals (RV) target numerous therapeutic applications, from gene therapy to virus-like particle (rVLP)-based vaccines. During particle formation, beside the pseudotyped envelope proteins, RV can incorporate proteins derived from the virus producer cells (VPC). This may be detrimental by reducing the amounts of the pseudotyped envelope and/or by incorporating protein capable of inducing immune responses when non-human VPC are used. Manipulating the repertoire of VPC proteins integrated onto the vector structure is an underexplored territory and should provide valuable insights on potential targets to improve vector pharmacokinetic and pharmacodynamic properties. In this work, human HEK 293 cells producing retrovirus-like particles (rVLPs) and infectious RV vectors were used to prove the concept of customizing RV composition by manipulating cellular protein content. The tetraspanin CD81 was chosen since it is significantly incorporated in the RV membrane, conferring to the vector significant immunogenicity when used in mice. RNA interference mediated by shRNA lentiviral vector transduction was efficiently used to silence CD81 expression (up to 99%) and the rVLPs produced by knocked-down cells lack CD81. Silenced clones were analyzed for cell proliferation, morphological changes, susceptibility to oxidative stress conditions, and rVLP productivities. The results showed that the down-regulation of VPC proteins requires close monitoring for possible side effects on cellular production performance. Yet, they confirm that it is possible to change the composition of host-derived immunogens in RV by altering cellular protein content with no detriment for vector productivity and titers. This constitutes an important manipulation tool in vaccinology--by exploiting the potential adjuvant effect of VPC proteins or using them as fusion agents to other proteins of interest to be exposed on the vector membrane--and in gene therapy, by reducing the immunogenicity of RV-based vector and enhancing in vivo half-life. Such tools can also be applied to lentiviral or other enveloped viral vectors. PMID- 21656711 TI - Acceleration of neuronal precursors differentiation induced by substrate nanotopography. AB - Embryonic stem (ES) cell differentiation in specific cell lineages is a major issue in cell biology particularly in regenerative medicine. Differentiation is usually achieved by using biochemical factors and it is not clear whether mechanical properties of the substrate over which cells are grown can affect proliferation and differentiation. Therefore, we produced patterns in polydimethylsiloxane (PDMS) consisting of groove and pillar arrays of sub micrometric lateral resolution as substrates for cell cultures. We analyzed the effect of different nanostructures on differentiation of ES-derived neuronal precursors into neuronal lineage without adding biochemical factors. Neuronal precursors adhered on PDMS more effectively than on glass coverslips. We demonstrated that neuronal yield was enhanced by increasing pillars height from 35 to 400 nm. On higher pillar neuronal differentiation reaches ~80% 96 h after plating and the largest differentiation enhancement of pillars over flat PDMS was observed during the first 6 h of culture. We conclude that PDMS nanopillars accelerate and increase neuronal differentiation. PMID- 21656712 TI - Encapsulated mesenchymal stromal cells for in vivo transplantation. AB - Immunomodulatory human mesenchymal stromal cells (hMSC) have been incorporated into therapeutic protocols to treat secondary inflammatory responses post-spinal cord injury (SCI) in animal models. However, limitations with direct hMSC implantation approaches may prevent effective translation for therapeutic development of hMSC infusion into post-SCI treatment protocols. To circumvent these limitations, we investigated the efficacy of alginate microencapsulation in developing an implantable vehicle for hMSC delivery. Viability and secretory function were maintained within the encapsulated hMSC population, and hMSC secreted anti-inflammatory cytokines upon induction with the pro-inflammatory factors, TNF-alpha and IFN-gamma. Furthermore, encapsulated hMSC modulated inflammatory macrophage function both in vitro and in vivo, even in the absence of direct hMSC-macrophage cell contact and promoted the alternative M2 macrophage phenotype. In vitro, this was evident by a reduction in macrophage iNOS expression with a concomitant increase in CD206, a marker for M2 macrophages. Finally, Sprague-Dawley rat spinal cords were injured at vertebra T10 via a weight drop model (NYU model) and encapsulated hMSC were administered via lumbar puncture 24 h post-injury. Encapsulated hMSC localized primarily in the cauda equina of the spinal cord. Histological assessment of spinal cord tissue 7 days post-SCI indicated that as few as 5 * 10(4) encapsulated hMSC yielded increased numbers of CD206-expressing macrophages, consistent with our in vitro studies. The combined findings support the inclusion of immobilized hMSC in post-CNS trauma tissue protective therapy, and suggest that conversion of macrophages to the M2 subset is responsible, at least in part, for tissue protection. PMID- 21656713 TI - A novel planar flow cell for studies of biofilm heterogeneity and flow-biofilm interactions. AB - Biofilms are microbial communities growing on surfaces, and are ubiquitous in nature, in bioreactors, and in human infection. Coupling between physical, chemical, and biological processes is known to regulate the development of biofilms; however, current experimental systems do not provide sufficient control of environmental conditions to enable detailed investigations of these complex interactions. We developed a novel planar flow cell that supports biofilm growth under complex two-dimensional fluid flow conditions. This device provides precise control of flow conditions and can be used to create well-defined physical and chemical gradients that significantly affect biofilm heterogeneity. Moreover, the top and bottom of the flow chamber are transparent, so biofilm growth and flow conditions are fully observable using non-invasive confocal microscopy and high resolution video imaging. To demonstrate the capability of the device, we observed the growth of Pseudomonas aeruginosa biofilms under imposed flow gradients. We found a positive relationship between patterns of fluid velocity and biofilm biomass due to faster microbial growth under conditions of greater local nutrient influx, but this relationship eventually reversed because high hydrodynamic shear leads to the detachment of cells from the surface. These results reveal that flow gradients play a critical role in the development of biofilm communities. By providing new capability for observing biofilm growth, solute and particle transport, and net chemical transformations under user specified environmental gradients, this new planar flow cell system has broad utility for studies of environmental biotechnology and basic biofilm microbiology, as well as applications in bioreactor design, environmental engineering, biogeochemistry, geomicrobiology, and biomedical research. PMID- 21656714 TI - Surgical management of the duodenal manifestations of familial adenomatous polyposis. AB - BACKGROUND: Duodenal adenomas develop in patients with familial adenomatous polyposis, incurring a risk of carcinoma. When this risk is high, surgery is indicated. The choice of surgical treatment can be difficult as evidence-based data are lacking. METHODS: This is a systematic review of the literature on the non-medical management of duodenal lesions arising in the setting of familial adenomatous polyposis. Studies were identified through searching MEDLINE. Studies published between January 1965 and October 2009 were included. Data regarding number of subjects, complications, length of follow-up, recurrence rate and outcome were extracted. RESULTS: Transduodenal resection does not differ from an endoscopic approach in terms of recurrence. Ampullectomy has limited application as only papillary lesions are amenable to treatment in this manner. Duodenectomy with pancreas preservation is preferable to pancreaticoduodenectomy unless malignancy is present, or cannot be excluded. CONCLUSION: Surgery should be reserved for advanced or malignant polyps. PMID- 21656715 TI - Early results from a randomized trial of saphenous surgery with or without subfascial endoscopic perforator surgery in patients with a venous ulcer. AB - BACKGROUND: The aim was to clarify the role of incompetent perforators (IPs) in venous leg ulcers. This short-term report focused on safety, patient satisfaction and the fate of IPs after subfascial endoscopic perforator surgery (SEPS), or saphenous surgery alone. METHODS: Patients aged 30-78 years with an open or recently healed venous ulcer, and with an incompetent saphenous vein and IPs, were allocated randomly to saphenous surgery alone, or in combination with SEPS. A control duplex scan was performed 6-9 months after surgery, and clinical follow up was scheduled after 1 week, 3 and 12 months. A standard questionnaire was completed at each clinical visit. RESULTS: Seventy-five patients were enrolled; 37 had SEPS and 38 had saphenous surgery alone. SEPS prolonged the operation by a median of 15 min (P = 0.003). Duplex imaging revealed significantly more remaining IPs in the no-SEPS group (P < 0.001). Compared with the preoperative scan, significantly more legs were free from IPs in the SEPS group compared with the no-SEPS group (21 of 36 versus 7 of 37 respectively; P < 0.001). There were no other major outcome differences between the groups. CONCLUSION: There was no short-term clinical benefit from adding SEPS to saphenous surgery in patients with varicose ulcers and IPs, although SEPS reduced the number of perforators remaining after 1 year. PMID- 21656719 TI - Effect of abnormal screening mammogram on quality of life. AB - BACKGROUND: Screening for breast cancer reduces breast cancer-related mortality. Advantages of screening are explained clearly, but its disadvantages are underrepresented in consent folders. METHODS: In September 2002 a prospective, longitudinal study started concerning quality of life (QoL) in women with breast disease. Between September 2002 and January 2007, 385 women with an abnormal screening mammogram were included. Of these, 152 women were diagnosed with breast cancer (BC group) and 233 had a false-positive result (FP group). Questionnaires concerning anxiety (State and Trait Anxiety Inventory) and QoL (World Health Organization Quality of Life assessment instrument 100) were completed before diagnosis, and 1, 3, 6 and 12 months later. RESULTS: The BC group was significantly older (60.2 versus 57.3 years; P < 0.001); significantly more histological biopsies were needed in the FP group (P < 0.001). Almost 60 per cent of the FP group revisited the outpatient clinic in the first year. Trait anxiety had a profound influence on QoL. Women in the FP group with a high score on trait anxiety had lowest QoL on all measurements (P < 0.001). They also reported more feelings of anxiety compared with women in the FP group with a lower trait anxiety score, and women in the BC group with a low trait anxiety score (P < 0.001). CONCLUSION: Women with a false-positive diagnosis of screen-detected breast cancer had a low QoL and feelings of anxiety, especially when they scored high on trait anxiety. This effect lasted for at least 1 year. PMID- 21656717 TI - Multicentre evaluation of intraoperative molecular analysis of sentinel lymph nodes in breast carcinoma. AB - BACKGROUND: Ideally, intraoperative sentinel lymph node (SLN) analysis in breast cancer should be automated, have high concordance with extensive histopathology, and be applicable in any hospital setting. A prospective multicentre evaluation of the one-step nucleic acid amplification (OSNA) automated molecular diagnostic system of SLN analysis was undertaken. METHODS: Intraoperative examination of SLNs from 204 patients with breast cancer was performed by OSNA at four sites in the UK. Half of each SLN was assessed by OSNA (for cytokeratin 19 mRNA) and the remaining half was paraffin embedded for intensive histological examination at ten levels. Discordant cases were reanalysed by further molecular biological techniques and by additional histological examination of all remaining nodal material to ascertain whether the discordance was due to an uneven distribution of metastases, known as tissue allocation bias (TAB). RESULTS: After exclusion of samples affected by TAB, the overall concordance rate for OSNA versus histopathology was 96.0 per cent, with a sensitivity of 91.7 per cent and a specificity of 96.9 per cent. The median time to process a single SLN was 32 (range 22-97) min, and that for two nodes 42 (30-73) min. CONCLUSION: OSNA enables accurate automated intraoperative diagnosis and can be used successfully in different UK hospitals. When the SLN is shown to be positive, the patient can undergo immediate axillary clearance under the same anaesthetic rather than having a delayed second procedure. PMID- 21656721 TI - Long-term global quality of life in patients treated for colorectal liver metastases. AB - BACKGROUND: Surgical treatment of colorectal liver metastases has become increasingly aggressive. The influence of this more active surgical approach on patients' health-related quality of life (HRQoL) has hardly been evaluated. This study investigated the impact of surgical and systemic treatment on HRQoL in patients undergoing hepatic resection for colorectal metastases. METHODS: A total of 145 patients with colorectal liver metastases were entered prospectively into the study. Based on HRQoL values derived from the EuroQol-5D, health summary measures were calculated to express the overall impact on four distinct clinical states. The HRQoL instrument was used at baseline, 3 and 6 weeks after surgery, and every 3 months thereafter for up to 3 years. RESULTS: Patients showed a clear deterioration in HRQoL in the first weeks after surgery, followed by a recovery to baseline levels at 3 months after potentially curative surgery. In contrast, a sustained decline was noted when initial surgery for colorectal liver metastases was considered futile and palliative chemotherapy was started immediately. Three years after initial surgery, there were distinct differences in HRQoL between patients with or without recurrence. The latter group still had HRQoL scores at baseline levels, whereas patients with tumour recurrence showed a significant deterioration in HRQoL. Remarkably, there was no decline in HRQoL in patients with recurrent disease who could be treated by secondary surgical intervention. CONCLUSION: Superior overall HRQoL in the first 3 years after initial successful surgical intervention merits an aggressive surgical approach and intensive follow up to detect recurrence early. PMID- 21656723 TI - Multivisceral resection for primary locally advanced rectal carcinoma. AB - BACKGROUND: Pelvic multivisceral resection offers the possibility of cure in patients with locally advanced rectal cancer. This study assessed the clinical outcome and determinants of survival and local recurrence in patients undergoing multivisceral resection for clinical T4 primary rectal cancer. METHODS: This was a cohort study of consecutive multivisceral resections carried out in a single centre from 2000 to 2009. Determinants of local recurrence and survival were examined by means of Kaplan-Meier survival curves and Cox regression analysis. RESULTS: The study included 42 patients, with a median age of 62 (range 41-83) years, who underwent surgery with a median follow-up of 30 (range 2-102) months. Thirty-one patients had preoperative chemoradiotherapy. Seven patients had rectal resection with en bloc radical prostatectomy. The 30-day mortality rate was zero. Thirty-nine of the 42 patients had a negative circumferential resection margin. The 5-year overall survival rate for those who had complete resection was 48 per cent. Local recurrence was predicted by metastatic disease (P < 0.001) and nodal disease (P < 0.001), but not positive resection margins (P = 0.077). CONCLUSION: An aggressive surgical strategy with complete resection is predictive of long term survival in selected patients with T4a rectal carcinoma. With optimal treatment local recurrence is a sign of systemic disease. PMID- 21656724 TI - Long-term follow-up of patients with a painless inguinal hernia from a randomized clinical trial. AB - BACKGROUND: Up to one-third of patients with an inguinal hernia have no symptoms from the hernia. The aim of this study was to determine the long-term outcome of patients with a painless inguinal hernia randomized to observation or operation. METHODS: Some 160 men aged 55 years or more with a painless inguinal hernia were randomized to observation or operation between 2001 and 2003. All were invited to attend a research clinic at 6 and 12 months, and 5 years after randomization. Those unable to attend for clinical review were sent a questionnaire based on the clinical review pro forma. RESULTS: After a median follow-up of 7.5 (range 6.2 8.2) years, 42 men had died (19 in the observation and 23 in the operation group); 46 of the 80 men randomized to observation had conversion to operation. The estimated conversion rate (using the Kaplan-Meier method) for the observation group was 16 (95 per cent confidence interval 9 to 26) per cent at 1 year, 54 (42 to 66) per cent 5 years and 72 (59 to 84) per cent at 7.5 years. The main reason for conversion was pain in 33 men, and two presented with an acute hernia. Sixteen men developed a new primary contralateral inguinal hernia and three had recurrent hernias. There have been 90 inguinal hernia repairs in the 80 patients randomized to surgery compared with 56 in those randomized to observation. CONCLUSION: Most patients with a painless inguinal hernia develop symptoms over time. Surgical repair is recommended for medically fit patients with a painless inguinal hernia. PMID- 21656726 TI - Rectal washout and local recurrence of cancer after anterior resection (Br J Surg 2010 97 1589-1597). PMID- 21656727 TI - Single-incision laparoscopic right hemicolectomy (Br J Surg 2010; 97: 1881-1883). AB - The Editors welcome topical correspondence from readers relating to articles published in the Journal. Responses should be sent electronically via the BJS website (http://www.bjs.co.uk). All letters will be reviewed and, if approved, appear on the website. A selection of these will be edited and published in the Journal. Letters must be no more than 250 words in length. PMID- 21656730 TI - Meta-analysis of intraoperative povidone-iodine application to prevent surgical site infection (Br J Surg 2010; 97: 97 1603-1613). PMID- 21656731 TI - Rectum-conserving surgery in the era of chemoradiotherapy (Br J Surg 2010; 97: 1752-1764). PMID- 21656735 TI - Lung cancer a hot topic at AACR meeting: studies offer promise in detection, prevention, and personalized medicine. PMID- 21656736 TI - New insights into telomeres, stress, and cancer risk. PMID- 21656737 TI - Disparities in the application of adjuvant radiotherapy after breast-conserving surgery for early stage breast cancer: impact on overall survival. AB - BACKGROUND: Definitive local therapy of early stage breast cancer includes adjuvant radiotherapy after breast-conserving surgery (BCS). The authors analyzed factors that influence the receipt of radiotherapy therapy and their resultant impact on outcome. METHODS: Using data from the Kentucky Cancer Registry, the authors analyzed the rate of adjuvant radiotherapy for 11,914 women who underwent BCS as a primary surgical treatment for stage 0, I, or II breast cancer between 1998 and 2007. The authors assessed the probability of receiving radiotherapy by using multivariate logistic regression and measured impact on outcome by using Cox survival analysis. RESULTS: Overall, 66.2% of women received adjuvant radiotherapy for BCS over a 10-year period (annual rate range, 60.9%-70.1%). On multivariate analysis, the rate of receiving radiotherapy was drastically lower for women aged older than 70 years (vs younger) and rural Appalachian (vs non Appalachian) populations. The rate was modestly lower for African American (vs white) women, those with in situ (vs invasive) disease, and uninsured (vs insured) patients. Lack of radiotherapy was associated with an increased hazard ratio for death of 1.67 (95% CI, 1.508-1.851) on Cox survival analysis when age, stage, tumor size, grade, hormone receptors, smoking, and insurance were factored into the analysis. The 10-year overall survival for patients who received adjuvant radiotherapy versus BCS alone was 79.7% versus 67.6% (P < .0001). CONCLUSIONS: Despite widespread knowledge of the benefit of RT after BCS, the rate of undertreatment remains high, with significant disparities for elderly, rural, minority, and uninsured women. Multidisciplinary management strategies, including accelerated and hypofractionated radiation regimens, are needed to eliminate disparities and improve outcomes. PMID- 21656738 TI - Up-regulation and clinical significance of serine protease kallikrein 6 in colon cancer. AB - BACKGROUND: Kallikrein-related peptidase 6 (KLK6) encodes a trypsin-like serine protease that is up-regulated in several cancers, although the putative functions of KLK6 in cancer have not been elucidated. In the current study, overexpression of KLK6 was identified in colon cancer, and the possibility that KLK6 may be a suitable candidate as a tumor marker was examined. METHODS: Messenger RNA (mRNA) transcript levels and protein up-regulation of KLK6 in colon cancer tissues was examined using reverse transcriptase-polymerase chain reaction, immunohistochemistry, and clinicopathologic analyses. Cell proliferation, invasiveness, and antiapoptotic activity were determined in colon cancer cells that were transfected with small-interfering RNA (siRNA) of KLK6. RESULTS: KLK6 mRNA was up-regulated significantly in tumor tissues compared with nontumor regions. KLK6 protein was strongly expressed in adenocarcinomas but was not expressed in normal mucosa or in premalignant dysplastic lesions. Sera from patients with colon cancer revealed an increase in KLK6 secretion (0.25 MUg/mL; P = .031) compared with noncancer cells (0.19 MUg/mL). Clinicopathologic and immunohistochemical studies of 143 patients with colon cancer revealed a significant correlation between KLK6 expression and Dukes disease stage (P = .005). High KLK6 expression was associated significantly with shorter overall (P = .001) and recurrence-free survival (P = .001). The rates of proliferation and invasiveness were decreased by 50% in cells that were transfected with KLK6 siRNA. The overexpression of KLK6 led to decreased activity of the E-cadherin promoter. CONCLUSIONS: KLK6 was up-regulated significantly in tissues and sera from patients with colon cancer and was associated closely with a poor prognosis, suggesting that KLK6 may be used as a potential biomarker and a therapeutic target for colon cancer. PMID- 21656739 TI - A phase 2 trial of gemcitabine, 5-fluorouracil, and radiation therapy in locally advanced nonmetastatic pancreatic adenocarcinoma : cancer and Leukemia Group B (CALGB) 80003. AB - BACKGROUND: The purpose of this study was to assess the efficacy and safety of 5 fluorouracil (5FU) and gemcitabine administered concurrently with radiation in patients with locally advanced, nonmetastatic pancreatic cancer. METHODS: Eligible patients had histologically confirmed pancreatic adenocarcinoma deemed locally unresectable without evidence of metastatic disease. In addition, all patients underwent laparoscopy or laparotomy before study entry to rule out peritoneal carcinomatosis. Patients received radiation therapy (50.4 Gy) with concurrent infusional 5FU (200 mg/m(2) 5 days/week) and weekly gemcitabine (200 mg/m(2) ). After a 3-week break, patients received weekly gemcitabine at 1000 mg/m(2) for 3 of 4 weeks, for 4 cycles. The primary endpoint of the trial was the proportion of patients surviving 9 months from study entry. Secondary endpoints included objective tumor response, CA19-9 response, overall survival (OS) time to progression (TTP), and toxicity. RESULTS: Between November 2001 and October 2004, 81 patients were enrolled, 78 of whom were eligible for analysis. With a median follow-up of 55.2 months, the median OS was 12.2 months (95% confidence interval [CI], 10.9-14.9) and the median TTP was 10 months (95% CI, 6.4-12.0). An objective tumor response was seen in 19 patients (25%), and among 56 patients with an elevated CA19-9 at baseline, 29 (52%) had a sustained CA19-9 response. Overall, 41% of patients had grade 3 or greater treatment-related gastrointestinal adverse events. CONCLUSIONS: The combination of 5FU, gemcitabine, and radiation is well tolerated. Survival is comparable with the best results of other recent studies of 5FU and radiation or gemcitabine and radiation. PMID- 21656740 TI - Early hypofractionated salvage radiotherapy for postprostatectomy biochemical recurrence. AB - BACKGROUND: Postprostatectomy adjuvant or salvage radiotherapy, when using standard fractionation, requires 6.5 to 8 weeks of treatment. The authors report on the safety and efficacy of an expedited radiotherapy course for salvage prostate radiotherapy. METHODS: A total of 108 consecutive patients were treated with salvage radiation therapy to 65 grays (Gy) in 26 fractions of 2.5 Gy. Median follow-up was 32.4 months. Median presalvage prostate-specific antigen (PSA) was 0.44 (range, 0.05-9.50). Eighteen (17%) patients received androgen deprivation after surgery or concurrently with radiation. RESULTS: The actuarial freedom from biochemical failure for the entire group at 4 years was 67% +/- 5.3%. An identical 67% control rate was seen at 5 years for the first 50 enrolled patients, whose median follow-up was longer at 43 months. One acute grade 3 genitourinary toxicity occurred, with no acute grade 3 gastrointestinal and no late grade 3 toxicities observed. On univariate analysis, higher Gleason score (P = .006), PSA doubling time <=12 months (P = .03), perineural invasion (P = .06), and negative margins (P = .06) showed association with unsuccessful salvage. On multivariate analysis, higher Gleason score (P = .057) and negative margins (P = .088) retained an association with biochemical failure. CONCLUSIONS: Hypofractionated radiotherapy (65 Gy in 2.5 Gy fractions in about 5 weeks) reduces the length of treatment by from 1-1/2 to 3 weeks relative to other treatment schedules commonly used, produces low rates of toxicity, and demonstrates encouraging efficacy at 4 to 5 years. Hypofractionation may provide a convenient, resource-efficient, and well-tolerated salvage approach for the estimated 20,000 to 35,000 US men per year experiencing biochemical recurrence after prostatectomy. PMID- 21656741 TI - Progression-free survival as a predictor of overall survival in metastatic renal cell carcinoma treated with contemporary targeted therapy. AB - BACKGROUND: The majority of metastatic renal cell carcinoma (mRCC) clinical trials that examined targeted agents used progression-free survival (PFS) as the primary endpoint. Whether PFS can be used as a predictor of overall survival (OS) is unknown. METHODS: Patients from 12 cancer centers who received targeted therapy for mRCC were identified. Landmark analyses for progression at 3 months and 6 months after drug initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. RESULTS: In total, 1158 patients were included. The median follow-up was 30.6 months, the median age was 60 years, and the median Karnofsky performance status was 80%. For the entire cohort, the median PFS was 7.6 months, and the median OS was 19.7 months. In the landmark analysis, the median OS for patients who progressed at 3 months was 7.8 months compared with 23.6 months for patients who did not progress (log-rank test; P < .0001). Similarly, for patients who progressed at 6 months, the median OS was 8.6 months compared with 26 months for patients who did not progress (P < .0001). Compared with those who did not progress, for the patients who progressed at 3 months and at 6 months, the hazard ratios for death adjusted for adverse prognostic factors were 3.05 (95% confidence interval, 2.42-3.84) and 2.96 (95% confidence interval, 2.39-3.67), respectively. Similar results were demonstrated with landmark analyses at 9 months and at 12 months and in the bootstrap validation. Kendall tau rank correlation and a Fleischer model demonstrated a statistically significant dependent correlation. CONCLUSIONS: PFS at 3 months and at 6 months predicted OS, and the current results indicated that PFS may be a meaningful intermediate endpoint for OS in patients with mRCC who receive treatment with novel agents. PMID- 21656742 TI - Assessing gynecologic and breast cancer survivors' sexual health care needs. AB - BACKGROUND: The objective of this study was to identify patterns of interest in receiving care for sexual concerns among women who were survivors of gynecologic and breast cancers. METHODS: Survey and medical records data were collected from June 2008 to March 2009 from 261 gynecologic and breast cancer patients. Logistic regression was used to estimate the effect of age and months since treatment on interest in receiving sexual healthcare. RESULTS: The mean participant age was 55 years (range, 21-88 years). Only 7% of women had recently sought medical help for sexual issues, yet 41.6% were interested in receiving care. Greater than 30% responded that they would be likely to see a physician to address sexual matters, and 35% of all women were willing to be contacted if a formal program was offered. Compared with older women (aged >65 years), younger women (ages 18-47 years) were significantly more likely to report interest in receiving care to address sexual issues (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.14 7.54) and to see a physician to address sexual matters (OR, 4.51; 95% CI, 1.51 13.43), and they were more willing to be contacted for a formal program (adjusted OR [AOR], 5.00; 95% CI, 1.63-15.28). Compared with women who were currently in treatment, women who last received treatment >12 months previously were significantly more interested in receiving care (AOR, 2.02; 95% CI, 1.02-4.01) and were more willing to be contacted (AOR, 2.49; 95% CI, 1.18-5.26). CONCLUSIONS: Greater than 40% of survivors expressed interest in receiving sexual healthcare, but few had ever sought such care. The current results indicated that there is an unmet need for attention to sexual concerns among women with gynecologic and breast cancers. PMID- 21656743 TI - Correlation of LAPTM4B polymorphisms with cervical carcinoma. AB - BACKGROUND: Lysosome-associated protein transmembrane 4 beta (LAPTM4B), a novel oncoprotein, is overexpressed in several carcinomas. Previous studies revealed that LAPTM4B polymorphisms contribute to the risk of certain types of cancers. The purpose of this study was to investigate the association between different LAPTM4B alleles and the risk of cervical carcinoma. METHODS: A case-control analysis was performed in 317 patients with cervical cancer and 416 control subjects. Genomic DNA was extracted from peripheral blood lymphocytes in all participants. LAPTM4B genotypes were determined using polymerase chain reaction. Odds ratios and 95% confidence intervals (CIs) were computed using an unconditional logistic regression model. RESULTS: There was a significant difference (P<.001) in LAPTM4B*2 allele frequency between cervical cancer cases (35.8%) and controls (26.3%). There was also a significant difference in the overall genotypic distribution between patients and controls (P < .001). Using the LAPTM4B*1/1 genotype as a reference, we found that LAPTM4B allelic variation was associated with a significantly increased risk of cervical cancer, with adjusted odds ratios of 1.60 (95% CI, 1.15-2.22) and 2.12 (95% CI, 1.20-3.76) for the *1/2 and *2/2 genotype, respectively. Stratification analysis indicated that the association was more pronounced in younger subjects, smokers, premenopausal women, and women with more parities. Moreover, multiplicative joint effects were found between the *1/2 or *2/2 genotype and smoking. CONCLUSIONS: The findings of this study indicated that the LAPTM4B*2 allele might be a cervical cancer risk factor and may play an important role in genetic susceptibility to cervical cancer in the Chinese population. PMID- 21656744 TI - Satisfaction with ovarian carcinoma risk-reduction strategies among women at high risk for breast and ovarian carcinoma. AB - BACKGROUND: Women who are at high risk for breast and ovarian cancer have 2 major management options to reduce their risk of ovarian cancer: periodic screening (PS) or risk-reducing salpingo-oophorectomy (RRSO). Little is known regarding patient satisfaction levels with risk-reduction strategies. Thus, the authors sought to determine levels of patient satisfaction with PS versus RRSO and to identify factors that may influence satisfaction. METHODS: As part of a larger study, women who received testing for the breast cancer genes BRCA1 and BRCA2 were sent a follow-up questionnaire packet to explore issues related to cancer risk reduction. The authors report on the results from a variety of validated instruments, including the Satisfaction With Decision (SWD) scale, focused on the choice between PS and RRSO. RESULTS: In total, 544 surveys were mailed, and 313 responses were received (58%). The overall satisfaction rate among respondents was high. The median SWD score was significantly higher in the RRSO group compared with the PS group (P < .001). BRCA mutation carriers had higher median SWD scores regardless of management type (P = .01). Low satisfaction scores were associated with high levels of uncertainty and the perception that the decision between PS and RRSO was difficult to make (P = .001). Satisfaction was unrelated to demographics, clinical factors, or concerns of cancer risk. CONCLUSIONS: In the current study, the majority of women who were at high risk for breast and ovarian cancer were satisfied with their choice of risk-reduction strategy. Difficulty with decision making was associated with lower satisfaction levels. Improved education and support through the decision-making process may enhance overall levels of satisfaction. PMID- 21656746 TI - Activity of azacitidine in chronic myelomonocytic leukemia. AB - BACKGROUND: Hypomethylating drugs are useful in the management of myelodysplastic syndrome (MDS). Two of these drugs, azacitidine and decitabine, have received FDA approval for the treatment of MDS and chronic myelomonocytic leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS included only a small number of patients with CMML. The objective of this study was to evaluate the efficacy and safety of azacitidine in the treatment of CMML. METHODS: The records of thirty-eight patients diagnosed with CMML and treated with azacitidine at our institution were reviewed. Azacitidine was administered at 75 mg/m(2) /day for 7 days or 100 mg/m(2) /day for 5 days every 4 weeks. Patients who received at least 1 cycle of the drug were considered evaluable for response. RESULTS: Response was assessed by the modified International Working Group (IWG) criteria. The overall response rate was 39% (14 of 36); complete response (CR) rate was 11% (4 of 36); partial response (PR) rate was 3% (1 of 36); hematologic improvement (HI) was 25% (9 of 36). The median overall survival was 12 months. There was a statistically significant overall survival advantage in responders compared with nonresponders: 15.5 months versus 9 months, respectively (P = .04). Treatment was generally well tolerated. One of 2 patients had complete resolution of a skin rash that was due to monocytic infiltration. CONCLUSIONS: Azacitidine is active in the treatment of CMML. The therapy-associated toxicity is acceptable. Our results support further investigation of azacitidine in CMML, particularly in combination with other agents. PMID- 21656747 TI - Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. AB - BACKGROUND: In the AZA-001 trial, azacitidine (75 mg/m(2) /d subcutaneously for Days 1-7 of every 28-day cycle) demonstrated improved survival compared with conventional care regimens in patients with International Prognostic Scoring System-defined intermediate-2- or high-risk myelodysplastic syndrome and World Health Organization-defined acute myeloid leukemia with 20% to 30% bone marrow blasts. METHODS: This secondary analysis of the AZA-001 phase 3 study evaluated the time to first response and the potential benefit of continued azacitidine treatment beyond first response in responders. RESULTS: Overall, 91 of 179 patients achieved a response to azacitidine; responding patients received a median of 14 treatment cycles (range, 2-30). Median time to first response was 2 cycles (range, 1-16). Although 91% of first responses occurred by 6 cycles, continued azacitidine improved response category in 48% of patients. Best response was achieved by 92% of responders by 12 cycles. Median time from first response to best response was 3.5 cycles (95% confidence interval [CI], 3.0-6.0) in 30 patients who ultimately achieved a complete response, and 3.0 cycles (95% CI, 1.0-3.0) in 21 patients who achieved a partial response. CONCLUSIONS: Continued azacitidine therapy in responders was associated with a quantitative increase in response to a higher response category in 48% of patients, and therefore may enhance clinical benefit in patients with higher-risk MDS. PMID- 21656745 TI - Tristetraprolin regulates interleukin-6, which is correlated with tumor progression in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: Tumor-derived cytokines play a significant role in the progression of head and neck squamous cell carcinoma (HNSCC). Targeting proteins, such as tristetraprolin (TTP), that regulate multiple inflammatory cytokines may inhibit the progression of HNSCC. However, TTP's role in cancer is poorly understood. The goal of the current study was to determine whether TTP regulates inflammatory cytokines in patients with HNSCC. METHODS: TTP messenger RNA (mRNA) and protein expression were determined by quantitative real-time-polymerase chain reaction (Q RT-PCR) and Western blot analysis, respectively. mRNA stability and cytokine secretion were evaluated by quantitative RT-PCR and enzyme-linked immunoadsorbent assay, respectively, after overexpression or knockdown of TTP in HNSCC. HNSCC tissue microarrays were immunostained for interleukin-6 (IL-6) and TTP. RESULTS: TTP expression in HNSCC cell lines was found to be inversely correlated with the secretion of IL-6, vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE(2) )(.) Knockdown of TTP increased mRNA stability and the secretion of cytokines. Conversely, overexpression of TTP in HNSCC cells led to decreased secretion of IL-6, VEGF, and PGE(2) . Immunohistochemical staining of tissue microarrays for IL-6 demonstrated that staining intensity is prognostic for poor disease-specific survival (P = .023), tumor recurrence and development of second primary tumors (P = .014), and poor overall survival (P = .019). CONCLUSIONS: The results of the current study demonstrated that down-regulation of TTP in HNSCC enhances mRNA stability and promotes secretion of IL-6, VEGF, and PGE(2) . Furthermore, high IL-6 secretion in HNSCC tissue is a biomarker for poor prognosis. In as much as enhanced cytokine secretion is associated with poor prognosis, TTP may be a therapeutic target to reduce multiple cytokines concurrently in patients with HNSCC. PMID- 21656749 TI - A novel KIF5B-ALK variant in nonsmall cell lung cancer. AB - BACKGROUND: The anaplastic lymphoma kinase (ALK) gene is involved frequently in chromosomal translocations, resulting in fusion genes with different partners found in various lymphoproliferative conditions. It was recently reported in nonsmall cell lung cancer (NSCLC) that the fusion protein encoded by echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion gene conferred oncogenic properties. The objective of the current study was to identify other possible ALK fusion genes in NSCLC. METHODS: Immunohistochemical analysis was used to screen for aberrant ALK expression in primary NSCLC. The authors used 5' rapid amplification of complementary DNA ends to screen for potential, novel 5' fusion partners of ALK other than EML4-ALK. Reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization analyses were used to confirm the identity of 5' fusion partners. The genomic breakpoint was verified using genomic sequencing. Overexpression of the novel ALK fusion gene and variants 3a and 3b of EML4-ALK was performed to assess downstream signaling and functional effects. RESULTS: The authors identified a novel gene resulting from the fusion of kinesin family member 5B (KIF5B) exon 15 to ALK exon 20 in a primary lung adenocarcinoma. Western blot analysis of clinical tumor tissues revealed the expression of a protein whose size correlated with that of the predicted KIF5B-ALK. Overexpression of KIF5B-ALK in mammalian cells led to the activation of signal transducer and activator of transcription 3 and protein kinase B and to enhanced cell proliferation, migration, and invasion. CONCLUSIONS: The discovery of the novel KIF5B-ALK variant further consolidated the role of aberrant ALK signaling in lung carcinogenesis. PMID- 21656748 TI - Modeling the mortality reduction due to computed tomography screening for lung cancer. AB - BACKGROUND: The efficacy of computed tomography (CT) screening for lung cancer remains controversial because results from the National Lung Screening Trial are not yet available. In this study, the authors used data from a single-arm CT screening trial to estimate the mortality reduction using a modeling-based approach to construct a control comparison arm. METHODS: To estimate the potential lung cancer mortality reduction because of CT screening, a previously developed and validated model was applied to the screening trial to predict the number of lung cancer deaths in the absence of screening. By using age, gender, and smoking characteristics matching those of the trial participants, the model was used to simulate 5000 trials in the absence of CT screening to produce the expected number of lung cancer deaths along with 95% confidence intervals (95% CIs), while adjusting for healthy volunteer bias. RESULTS: There were 64 observed lung cancer deaths in the screening cohort (n = 7995), whereas the model predicted 117.7 deaths (95% CI, 98 deaths-139 deaths), indicating a mortality reduction of 45.6% (P < .001). When a more conservative healthy volunteer adjustment was applied, 111.3 lung cancer deaths were predicted (95% CI, 91 deaths-132 deaths), for a lung cancer-specific mortality reduction of 42.5% (P < .001). CONCLUSIONS: The results of the current study indicate that CT screening along with early stage treatment can reduce lung cancer-specific mortality. This mortality reduction is greatly influenced by the protocol of nodule follow-up and treatment, and the length of follow-up. PMID- 21656750 TI - Prognostic significance of RUNX3 expression in human melanoma. AB - BACKGROUND: RUNX3 is a tumor suppressor that plays important roles in cell proliferation, apoptosis, and metastasis. The authors investigated the role of RUNX3 in melanoma pathogenesis and analyzed the prognostic impact of RUNX3 expression in a large series of melanoma patients. METHODS: Two sets of tissue microarrays were constructed, including 440 cases of melanomas (202 for the training set and 238 for the validation set) and 88 cases of nevi (25 normal nevi and 63 dysplastic nevi). RUNX3 expression was evaluated by immunohistochemistry. RESULTS: Positive RUNX3 expression was observed in 56%, 54%, 33%, and 24% of the biopsies in normal nevi, dysplastic nevi, primary melanoma, and melanoma metastases, respectively. Significant differences for positive nuclear RUNX3 staining were observed between dysplastic nevi and primary melanomas (P = .002, chi-square test), between dysplastic nevi and melanoma metastases (P < .001, chi square test), and between primary melanoma and melanoma metastases (P = .045, chi square test). Loss of RUNX3 expression was correlated with a worse 5-year survival of melanoma patients in both training and validation sets. Furthermore, loss of RUNX3 expression was also correlated with a poor 5-year disease-specific survival in primary melanoma (P = .001) and metastatic melanoma patients (P = .008). Multivariate Cox regression analysis revealed that positive RUNX3 expression is an independent prognostic factor to predict melanoma patient outcome. CONCLUSIONS: Our findings indicate that RUNX3 plays an important role in melanoma pathogenesis and may serve as a promising prognostic marker for melanoma. PMID- 21656751 TI - Soft tissue sarcomas of the popliteal fossa: a single-institution retrospective review. AB - BACKGROUND: Soft tissue sarcomas (STSs) arising from the popliteal fossa present a challenge with regard to local control of primary tumors. Due to concerns of functional morbidity and neurovascular compromise, there is debate about what represents the best therapy for these patients. METHODS: We conducted a retrospective medical record review of patients treated at The University of Texas M. D. Anderson Cancer Center for STS of the popliteal fossa from 1990 to 2008. RESULTS: There were 47 eligible patients, 28 of whom were male and 19 of whom were female. Synovial sarcoma was the most common diagnosis, with 12 cases. Most patients had T2b tumors (31 patients; 66%). The median duration of follow-up was 3.8 years (range, 0.6-17.9 years). The 5- and 10-year overall survival rates were 63% and 51%, respectively. Metastasis at diagnosis was associated with poorer overall survival (5-year overall survival, 74% versus 13%; P<.001) and poorer recurrence-free survival (5-year recurrence-free survival, 51% versus 0%; P<.001) on univariate analysis. Radiation therapy improved local recurrence-free survival (5-year local recurrence-free survival, 56% versus 17%; P = .004), whereas a trend was observed for surgical margin status (P = .07). Tumor size and neurovascular involvement did not influence outcome. Twenty-two patients had recurrent disease, with 15 patients having local recurrence, and 16 patients died from progressive disease. CONCLUSIONS: Radiation therapy may play an important role in the treatment of popliteal fossa STS, but further study is needed to better define the best clinical application. Additional study is needed to re evaluate association of surgical margin status and outcome. PMID- 21656752 TI - Apoptosis induction through proteasome inhibitory activity of cucurbitacin D in human T-cell leukemia. AB - BACKGROUND: Human T-cell leukemia is an aggressive malignancy of T lymphocytes. T cell leukemia has a very poor prognosis, even with intensive chemotherapy, indicating the need for development of new drugs to treat the disease. Triterpenoid cucurbitacins have been shown to have antitumor activity, but the mechanism of this activity is not fully understood. METHODS: The effects of cucurbitacin D on the proliferation and apoptotic induction of T-cell leukemia cells using the Cell viability assay and Annexin V staining were evaluated. To investigate the mechanisms of apoptosis, antiapoptotic protein, NF-kappaB, and the proteasome activity of leukemia cells treated with cucurbitacin D were evaluated by Western blotting both in vitro and in vivo. RESULTS: In this study, cucurbitacin D was found to inhibit proliferation and to induce apoptosis of T cell leukemia cells. Constitutively activated NF-kappaB was inhibited by cucurbitacin D in the nucleus, which resulted in accumulation of NF-kappaB in the cytoplasm, leading to down-regulation of the expression of antiapoptotic proteins Bcl-xL and Bcl-2. Furthermore, cucurbitacin D induced the accumulation of inhibitor of NF-kappaB (IkappaB)alpha by inhibition of proteasome activity. Low doses of cucurbitacin D synergistically potentiated the antiproliferative effects of the histone deacetylase inhibitor VPA. Finally, the proapoptotic and proteasome inhibitory activities of cucurbitacin D also were demonstrated using SCID mice in an in vivo study. CONCLUSIONS: Cucurbitacin D induced apoptosis through suppression of proteasome activity both in vitro and in vivo, making cucurbitacin D a promising candidate for clinical applications in the treatment of T-cell leukemia. PMID- 21656753 TI - Higher population-based incidence rates of triple-negative breast cancer among young African-American women : Implications for breast cancer screening recommendations. AB - BACKGROUND: Differences in the breast cancer burden of African-American women compared with white American women are well documented. Recent controversies have emerged regarding age-appropriate mammographic screening guidelines, and these surveillance recommendations may influence future breast cancer disparities. The objective of the current study was to evaluate age-specific breast cancer stage distributions and incidence rates of triple-negative breast cancer (TNBC) in a population-based tumor registry. METHODS: The authors analyzed breast cancers from the California Cancer Registry (CCR) that were diagnosed between 1988 and 2006. The results were stratified by age and race/ethnicity, with white Americans identified as non-Hispanic whites (NHWs) and African Americans identified as non Hispanic blacks (NHBs). Breast cancer stage distributions and TNBC incidence rates also were analyzed. RESULTS: In total, 375,761 invasive breast cancers were evaluated (including 276,938 in NHWs and 21,681 in NHBs). NHBs and Hispanics tended to be younger than NHWs (median ages 57 years, 54 years, and 64 years, respectively). Lifetime incidence rates were higher for NHWs compared with NHBs and Hispanics; however, for women aged <44 years, incidence was highest among NHBs. NHBs also had higher incidence rates of stage III and IV disease and a higher incidence of TNBC in all age categories. CONCLUSIONS: Population-based data demonstrated that African-American women had a more advanced stage distribution for breast cancer compared with white American women and higher incidence rates for TNBC. These patterns were observed for women ages 40 to 49 years and for older women, and they suggest that mammographic screening for the early detection of breast cancer will be particularly relevant for younger African-American women. PMID- 21656755 TI - Studying cancer in minorities: a look at the numbers. AB - BACKGROUND: Inclusion of minorities is an important but challenging aspect of epidemiologic studies in the United States. One aspect of this challenge that has received little attention is the actual number of minorities with specific cancers. The authors aimed to understand how population characteristics affect the numbers of minority cancer cases in Surveillance, Epidemiology, and End Results (SEER) regions. METHODS: By using SEER data, the authors identified 6 cancers with higher incidence rates in racial and ethnic minorities and reviewed the annual number of cases of those cancers in SEER areas where there are large numbers of blacks, Hispanics, and Asians. The authors examined the age characteristics of the populations in SEER areas using data from the US Census. RESULTS: Although there are substantial numbers of cases for the most common cancers with higher incidence in blacks, their numbers are quite small for other cancers, <150 cases, and in many areas, <100 per year. Few registries have substantial numbers of Hispanics or Asians. As expected, the proportion of minority populations is lower in older age groups, whereas the proportion of non Hispanic whites is larger. CONCLUSIONS: Because of the sharp decline in minority populations associated with age and the high age-specific incidence rates of most cancers, the actual number of minority cases is quite small for several cancers. Thus, the inclusion of minority groups in studies of any but the most common cancers presents a challenge. PMID- 21656754 TI - Patient navigation for American Indians undergoing cancer treatment: utilization and impact on care delivery in a regional healthcare center. AB - BACKGROUND: A study was undertaken to assess patient navigation utilization and its impact on treatment interruptions and clinical trial enrollment among American Indian cancer patients. METHODS: Between February 2004 and September 2009, 332 American Indian cancer patients received patient navigation services throughout cancer treatment. The patient navigation program provided culturally competent navigators to assist patients with navigating cancer therapy, obtaining medications, insurance issues, communicating with medical providers, and travel and lodging logistics. Data on utilization and trial enrollment were prospectively collected. Data for a historical control group of 70 American Indian patients who did not receive patient navigation services were used to compare treatment interruptions among those undergoing patient navigation during curative radiation therapy (subgroup of 123 patients). RESULTS: The median number of contacts with a navigator was 12 (range, 1-119). The median time spent with the navigator at first contact was 40 minutes (range, 10-250 minutes), and it was 15 minutes for subsequent contacts. Patients treated with radiation therapy with curative intent who underwent patient navigation had fewer days of treatment interruption (mean, 1.7 days; 95% confidence interval [CI], 1.1-2.2 days) than historical controls who did not receive patient navigation services (mean, 4.9 days; 95% CI, 2.9-6.9 days). Of the 332 patients, 72 (22%; 95% CI, 17%-26%) were enrolled on a clinical treatment trial or cancer control protocol. CONCLUSIONS: Patient navigation was associated with fewer treatment interruptions and relatively high rates of clinical trial enrollment among American Indian cancer patients compared with national reports. PMID- 21656757 TI - Medical expenditures of adult cancer survivors aged <65 years in the United States. AB - BACKGROUND: To the authors' knowledge, this is the first study to provide national estimates of medical expenditures for all adult cancer survivors aged <65 years. Most studies of expenditures for cancer survivors in this age group have been based on the Medical Expenditure Panel Survey (MEPS) and were limited to "affected survivors." METHODS: MEPS expenditure data for 2001 to 2007 were linked to data identifying all survivors from the National Health Interview Survey (NHIS), which is the MEPS sampling frame. The sample was comprised of adults ages 25 to 64 years. Propensity-score matching was used to estimate the effects of cancer on average total and out-of-pocket expenditures for all services and separately for prescriptions. Probit models were used to estimate effects on the probability of exceeding different expenditure thresholds. RESULTS: Mean annual expenditures on all services in 2007 were $16,910 +/- $3911 for survivors who were newly diagnosed with cancer, $7992 +/- $972 for survivors who had been diagnosed in previous years, and $3303 +/- $103 for other adults. Fifty-three percent of survivors were not identified in MEPS but only by linking to NHIS. Expenditures for all survivors averaged approximately $9300 compared with $13,600 for "affected survivors." For previously diagnosed survivors, the increase in mean expenditures attributable to cancer was approximately $4000 to $5000 annually. On average, relatively little of the increase was paid out of pocket, but cancer nearly doubled the risk of high out-of-pocket expenditures. CONCLUSIONS: Previous MEPS analyses overstated average expenditures for all survivors. Nevertheless, the current results indicated that the increase in expenditures attributable to cancer is substantial, even for longer term survivors, and that cancer increases the relative risk of high out-of-pocket expenditures. PMID- 21656756 TI - Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children's Research Hospital OS99 trial. AB - BACKGROUND: The standard treatment of osteosarcoma includes cisplatin and high dose methotrexate (HDMTX); both agents exert significant toxicity, and HDMTX requires complex pharmacokinetic monitoring and leucovorin rescue. In the previous OS91 trial, the treatment of localized disease with carboplatin, ifosfamide, doxorubicin, and HDMTX yielded outcomes comparable to those of cisplatin-based regimens and caused less toxicity. To build on this experience, the authors conducted a multi-institutional trial (OS99) that evaluated the efficacy of carboplatin, ifosfamide, and doxorubicin without HDMTX in patients with newly diagnosed, localized, resectable osteosarcoma. METHODS: Treatment was comprised of 12 cycles of chemotherapy administered over 35 weeks: 3 cycles of carboplatin (dose targeted to area under the concentration-time curve of 8 mg/mL * min on Day 1) and ifosfamide (at a dose of 2.65 g/m(2) daily *3 days) and 1 cycle of doxorubicin (at a dose of 25 mg/m(2) daily *3 days) before surgical resection, followed by 2 additional cycles of the combination of carboplatin and ifosfamide and 3 cycles each of doxorubicin (25 mg/m(2) daily *2 days) combined with ifosfamide or carboplatin. RESULTS: A total of 72 eligible patients (median age, 13.4 years) were enrolled between May 1999 and May 2006. Forty of the 66 (60.6%) evaluable patients had good histologic responses (>90% tumor necrosis) to preoperative chemotherapy. The estimated 5-year event-free survival rate was 66.7% +/- 7.0% for the OS99 trial compared with 66.0% +/- 6.8% for the OS91 trial (P = .98). The estimated 5-year survival rate was 78.9% +/- 6.3% for the OS99 trial and 74.5% +/- 6.3% for the OS91 trial (P = .40). CONCLUSIONS: The regimen used in the OS99 trial was found to produce outcomes comparable to those of cisplatin-containing or HDMTX-containing regimens. This therapy offers a good alternative for patients, particularly those who demonstrate an intolerance of HDMTX, and for institutions that cannot provide pharmacokinetic monitoring for MTX. PMID- 21656758 TI - Outcomes of malignant tumors of the lacrimal apparatus: the University of Texas MD Anderson Cancer Center experience. AB - BACKGROUND: Malignant epithelial neoplasms of the lacrimal apparatus are rare and are typically treated with surgery and occasionally adjuvant radiation therapy (RT). The purpose of this study was to assess treatment outcomes by type of surgery (orbital exenteration vs eye-sparing surgery) and clarify the role of adjuvant RT for this rare disease. METHODS: Forty-six patients with malignant epithelial neoplasms of the lacrimal apparatus were treated at a single institution from 1945 through 2008. Twenty-seven patients (59%) were treated with orbital exenteration and 19 (41%) with eye-sparing surgery; 64% of the orbital exenteration group and 83% of the eye-sparing surgery group also received adjuvant RT (median dose, 60 grays). Median follow-up time for all patients was 38 months (range, 3-460 months). RESULTS: For the orbital exenteration and eye sparing surgery groups, the 5-year overall survival (OS) rates were 59% and 62%, and the 5-year disease-free survival (DFS) rates were 49% and 39%, respectively (P = .56, P = .35). Tumor status (T1-2 vs T3-4) was associated with OS (P = .02), and tumor size (<3.5 vs >3.5 cm) with DFS (P = .015). Median time to locoregional recurrence was 85 months for orbital exenteration, and 123 months for eye-sparing surgery. All patients who did not receive RT experienced local recurrence, and RT extended time to locoregional recurrence (median 460 vs 30 months, P = .009). Seven grade >=3 complications were experienced after adjuvant RT. CONCLUSIONS: For appropriately selected patients, an eye-sparing surgery for lacrimal apparatus tumors can achieve similar survival outcomes to those in patients treated with an orbital exenteration. Adjuvant RT should be considered for all patients presenting with these rare tumors. PMID- 21656759 TI - A note from history: landmarks in history of cancer, part 2. AB - Events that took place in medicine during the 15th, 16th, and 17th centuries signaled the end of the Dark Ages. The Renaissance movement, spreading from Italy across Europe, ended the religious and public prohibitions that had prevented progress in medicine. Pioneer physicians and surgeons who gave their attention to discoveries in anatomy, physiology, and chemistry established the foundations for tumor pathology, surgical oncology, and medical oncology. This review is a summary of their accomplishments. PMID- 21656761 TI - High-intensity focused ultrasound (HIFU) is not indicated for treatment of primary bone sarcomas. PMID- 21656762 TI - Alterations of sex-typical microanatomy: prenatal stress modifies the structure of medial preoptic area neurons in rats. AB - Prenatal stress disrupts normal sexual differentiation and behavior with concomitant alterations in brain development; however, its effects on the cytoarchitecture of neurons in the sexually dimorphic medial preoptic area (mPOA) of the hypothalamus is not known. Morphometric analysis of the mPOA of adult rats showed sex differences as neurons from control females had significantly greater numbers of basal dendritic branches and cumulative basal dendritic length as compared to control male neurons. Prenatal stress significantly altered these sexual dimorphisms, as prenatally stressed (P-S) males had increased measures of cell body area, perimeter, cumulative basal dendritic length, and branch point numbers as compared to control males. Prenatal stress also altered the cytoarchitecture in the female mPOA neurons as P-S female neurons had significantly greater measures for primary dendritic branch number and a trend towards significance for several additional measures as compared to control females. Therefore, there are significant effects of both sex and prenatal stress on neuronal architecture in the mPOA that may help to explain the well-documented alterations in reproductive behaviors observed in P-S animals. PMID- 21656763 TI - Maturation of shoaling behavior is accompanied by changes in the dopaminergic and serotoninergic systems in zebrafish. AB - The zebrafish has been one of the preferred vertebrate model organisms of developmental biology, and is becoming an important research tool for behavioral neuroscience and behavior genetics. A prominent feature of zebrafish is their strong shoaling tendency. Most recently, the first study investigating the development of shoaling in zebrafish demonstrated that a few days after hatching zebrafish do not shoal, but that shoaling tendency gradually increases during development. The current study investigates this phenomenon using the nearest neighbor distance, a measure most frequently employed for the quantification of shoal cohesion in fish. We demonstrate that shoal cohesion increases with age, while thigmotaxis, "wall hugging," does not show a consistent age-dependent change. The mechanisms underlying the maturation of shoaling are unknown. HPLC analysis of whole brain extracts finds the concentration of dopamine, DOPAC, serotonin, and 5-HIAA normalized to total brain protein weight to increase with age. Although the behavioral and neurochemical results are only correlative at this point, they may open a new avenue into the investigation of the mechanisms and development of social behavior in zebrafish. PMID- 21656764 TI - Handedness for grasping objects and declarative pointing: a longitudinal study. AB - It is still unclear whether infants become right-handed because of their left hemisphere specialization for language (through gestural communication for instance), whether they speak predominantly with their left hemisphere because of this hemisphere's superiority in controlling sequential actions which first results in right-handedness, or whether the two lateralization processes develop independently. To tackle this question, we followed 26 human infants from 8 to 20 months to evaluate the temporal relationship between the emergence of hand preference for grasping objects and for declarative pointing (communicative gesture). Our results show that when grasping and pointing are compared in similar conditions, with objects presented in several spatial positions, the tendency to use the right hand is significantly larger for pointing than for grasping, and both hand preferences are loosely correlated. This suggests that, at least at the age studied here, hand preferences for grasping and for declarative pointing develop relatively independently. PMID- 21656765 TI - Enhanced stress responses in adolescent versus adult rats exposed to cues of predation threat, and peer interaction as a predictor of adult defensiveness. AB - Development of the hypothalamic-pituitary-adrenal (HPA) axis is influenced by external factors during early life in mammals, which optimizes adult function for predicted conditions. We have hypothesized that adolescence represents a sensitive period for the development of some aspects of adult stress response regulation. This was based on prior work showing that repeated exposure of rats to a stressor across an adolescent period increases fearfulness in a novel environment in adulthood and results in lower levels of dopamine receptor subtype 2 protein in prefrontal cortex. Here, we further our investigation of both acute and long-term effects of repeated adolescent stressor exposure on physiological (i.e., corticosterone) and behavioral (i.e., defensive behavior) measures of stress responding in male and female rats. Furthermore, we compared outcomes with those following identical manipulations administered in early adulthood and found that animals exposed to cues of predation threat during adolescence showed the most robust defensive responses to a homotypic stressor encountered in adulthood. Peer interaction during control manipulation in adolescence was identified as an important individual characteristic mediating development of adult defensive strategies. PMID- 21656766 TI - Development of hand preference for object-directed actions and pointing gestures: a longitudinal study between 15 and 25 months of age. AB - The development of hand preferences for object-directed actions and pointing gestures was investigated in toddlers sampled bimonthly between 15 and 25 months of age. Language level was also assessed, in an attempt to examine the relationship between handedness and language development. Results did not reveal any changes over the study period in the mean Handedness Index of the whole sample, both for bimanual manipulative activities and pointing gestures. However, the categorization of participants as left-handers, right-handers, or non lateralized revealed that most of children presented nonlinear individual trajectories in the development of hand preference. Moreover, the only significant correlations observed between hand preferences for manipulation and pointing were negative correlations between the strength of hand preferences at 19 and 21 months of age, suggesting that manipulative actions and communicative gestures are controlled by different networks in the left cerebral hemisphere. These findings are discussed in relation to the development of speech-gesture links in infancy. PMID- 21656767 TI - Phase behavior of TPGS-PEG400/1450 systems and their application to liquid formulation: a formulation platform approach. AB - Vitamin E D-alpha-tocopheryl polyethylene glycol succinate (TPGS) and polyethylene glycol are common excipients used in both preclinical and commercial formulations. In this paper, the phase diagrams of TPGS and polyethylene glycol 400 (PEG 400) in the presence of either water or ethanol were constructed. The effect of water and ethanol on the cloud point temperature of TPGS-PEG 400 mixtures was investigated. In general, the cloud point temperature was reduced by the presence of either water or ethanol in the formulation. However, water was more effective in lowering the cloud point temperature than ethanol. Similarly, the phase diagram of TPGS-PEG 1450 was constructed. The cloud point temperature was observed to decrease with increasing TPGS concentration. It was found that TPGS and PEG 1450 could form a single phase when TPGS concentration was above 75%, based on differential scanning calorimetry, and FT-Raman analysis indicated that a vibration at 1330 cm(-1) disappeared in the melted single phase. In addition, a systematic melting point depression was observed for the mixtures of TPGS-PEG 1450. In the presence of Ibuprofen, a model compound, the cloud point temperature was also reduced. Finally, the extended Flory-Huggins theory for polymer solution was used to analyze the entropic and enthalpic contributions of water and ethanol to the free energy of mixing. PMID- 21656768 TI - Determination of the interaction between glimepiride and hyperbranched polymers in solid dispersions. AB - Solid dispersions of glimepiride, belonging to the sulfonylurea group of antidiabetic drugs, and poly(ester amide) hyperbranched polymers of different chemical compositions were prepared in order to improve glimepiride's poor water solubility. X-ray powder diffraction results show that glimepiride is in noncrystalline form, indicating that drug molecules are molecularly dispersed within the amorphous hyperbranched polymers. Nuclear magnetic resonance spectroscopy and Fourier transform-infrared spectroscopy results reveal the complex formation between the glimepiride drug and the particular hyperbranched polymer, which was confirmed also by quantum chemical calculations. The complex is stabilized by a hydrogen-bond interaction between the NH group of the sulfonylurea segment of glimepiride and the carbonyls of the amide and ester bonds of the hyperbranched polymers. The slightly acidic proton of the NH group of the sulfonylurea segment of glimepiride is also involved in an interaction with the tertiary amino functional groups of the hyperbranched polymer. As a consequence, the loading capacity is higher for the hyperbranched polymer with the tertiary amino groups. Owing to a complex formation between glimepiride and a particular hyperbranched polymer, glimepiride's water solubility and its dissolution rate are considerably improved relative to the pure glimepiride drug. PMID- 21656769 TI - In Focus: SCI BioResources young researchers--emerging young researchers in crop science. PMID- 21656770 TI - Efficiency of urease and nitrification inhibitors in reducing ammonia volatilization from diverse nitrogen fertilizers applied to different soil types and wheat straw mulching. AB - BACKGROUND: Some authors suggest that the absence of tillage in agricultural soils might have an influence on the efficiency of nitrogen applied in the soil surface. In this study we investigate the influence of no-tillage and soil characteristics on the efficiency of a urease inhibitor (N-(n butyl)thiophosphoric triamide, NBPT) and a nitrification inhibitor (diciandiamide, DCD) in decreasing ammonia volatilization from urea and ammonium nitrate (AN), respectively. RESULTS: The results indicate that ammonia volatilization in soils amended with urea was significantly higher than in those fertilized with AN. Likewise, the main soil factors affecting ammonia volatilization from urea are clay and sand soil contents. While clay impedes ammonia volatilization, sand favours it. The presence of organic residues on soil surface (no-tillage) tends to increase ammonia volatilization from urea, although this fact depended on soil type. The presence of NBPT in urea fertilizer significantly reduced soil ammonia volatilization. This action of NBPT was negatively affected by acid soil pH and favoured by soil clay content. CONCLUSION: The presence of organic residues on soil surface amended with urea increased ammonia volatilization, and was particularly high in sandy compared with clay soils. Application of NBPT reduced ammonia volatilization although its efficiency is reduced in acid soils. Concerning AN fertilization, there were no differences in ammonia volatilization with or without DCD in no-tillage soils. PMID- 21656771 TI - Influence of rootstock and cultivar on bioactive compounds in citrus peels. AB - BACKGROUND: Citrus fruits have a beneficial effect on human health because of their nutritional and antioxidant properties, and their consumption is associated with a decrease in the incidence of cardiovascular disease and reduced risk of certain cancers. Seven cultivars of mandarin and orange species from the Mediterranean area, grafted onto different rootstocks (Cleopatra mandarin and Troyer citrange), have been analysed. The influence of the rootstock on the content of bioactive compounds is discussed. RESULTS: In all citrus cultivars and rootstocks studied, hesperidin and narirutin flavonoids were the main flavanone glycosides identified, beta-cryptoxanthin and violaxanthin the most abundant carotenoids, limonene was the most abundant essential oil, calcium and potassium were the dominant macronutrients and, among the micronutrients, iron and boron represented the highest proportions. CONCLUSION: We have been found clear differences in the content of bioactive compounds for the different groups, in agreement with the Citrus classification. Although both mandarin and orange varieties showed similar tendencies concerning the majority of bioactive constituents, the proportion of the individual nutrients ranged among different cultivars and our results indicated differences between rootstocks although it would be necessary to carry out more analyses, and with the new rootstocks obtained from different breeding programmes, to elucidate conclusive values. PMID- 21656772 TI - The role of light in the regulation of ascorbate metabolism during berry development in the cultivated grapevine Vitis vinifera L. AB - BACKGROUND: The accumulation of L-ascorbate (Asc) in fruits is influenced by environmental factors including light quantity. Fruit exposure to ambient light is often reduced by the surrounding leaf canopy, and can be altered by cultivation practices. The influence of reduced sunlight exposure on the accumulation of Asc and its catabolites was investigated in field-grown berries of the cultivated grapevine Vitis vinifera L. cv. Shiraz. RESULTS: Growth under sunlight-eliminated conditions resulted in reduced berry fresh weight, chlorosis and a reduced total L-ascorbate pool size. The concentration of the Asc catabolite L-tartaric acid (TA) was reduced in berries grown without light. Conversely, concentrations of oxalic acid (OA), an alternative catabolite of Asc, and malic acid (MA), were unaffected by shading the berries during development. Brief and significant reductions in transcription of the Asc metabolic genes were observed in shade-grown berries after 4 weeks of dark acclimatisation whilst a key TA biosynthetic gene was not regulated by light. CONCLUSIONS: The results demonstrate that light-regulation of Asc and TA occurs only at brief stages of development and that OA and MA accumulation is light independent. Additionally, the comparable ratios of TA product to Asc precursor under both light regimes suggest that the diversion of Asc to TA is driven by factors that are not responsive to light. These findings suggest that an altered light regime is not the key to manipulating TA or MA levels in the harvested berry. PMID- 21656773 TI - Effect of steam cooking on the residual enzymatic activity of potatoes cv. Agria. AB - BACKGROUND: The aim of this work was to study the influence of steam cooking on pectin methylesterase (PME) and endogenous alpha- and beta-amylase activities in different tissues (cortex and pith) of raw and heat-treated potatoes cv. Agria. Three different cooking temperatures were chosen (55, 70 and 85 degrees C). For each cooking trial, time-temperature profiles were recorded and the degree of cooking was expressed in terms of cooking factor. RESULTS: Steam cooking contributed to significantly activate PME at 55 degrees C and to reduce its activity at the final processing temperature (85 degrees C), with the highest amount in the cortex (0.3745 +/- 0.0007 umol galacturonic acid (GA) g(-1) fresh weight (FW) min(-1) ) compared with the pith (0.2617 +/- 0.0012 umol GA g(-1) FW min(-1) ). The presence of heat-labile and heat-stable isoforms of PME in the considered potato tissues was also assumed. Heat treatment by steam resulted in a significant decrease in endogenous alpha- and beta-amylase activities in both tissues compared with the raw potato, though without complete deactivation. Starch-degrading enzymes were also found to be differently distributed in the raw tuber. CONCLUSION: Steam cooking affected in different ways the assessed residual enzymatic activity in the considered tissues of potatoes cv. Agria. Further research is needed to confirm the results obtained. PMID- 21656774 TI - Rheological properties and permeability of soy protein-stabilised emulsion gels made by acidification with glucono-delta-lactone. AB - BACKGROUND: Soy protein, an important efficient emulsifier, is widely used by the food industry for incorporation into milk, yogurts, ice cream, salad dressings, dessert products, etc. The objective of this study was to investigate the rheological and physical properties of soy protein-stabilised emulsion gels as affected by protein concentration and gelation temperature. RESULTS: The rheological properties and permeability were determined using oscillatory rheometry, permeability and whey separation. The modulus (G' and G"), fracture stress and fracture strain of acid-induced emulsion gels after 20 h of glucono delta-lactone addition depended strongly on soy protein concentration and gelation temperature. At increasing soy protein concentrations, acid-induced emulsion gels had shorter gelation times but higher storage moduli (G'), fracture stresses and strains. Increasing gelation temperature decreased the gelation time, G', fracture stresses and strains. Permeability and whey separation were significantly affected by the protein concentration and the gelation temperature. A significant positive correlation was observed between whey separation and permeability coefficient in emulsion gels formed at different temperatures. CONCLUSION: The rheological properties and permeability of soy protein-stabilised emulsion gels were significantly influenced by protein concentration and gelation temperature. PMID- 21656775 TI - Lighting the way to willow biomass production. AB - Biofuels produced from willow could help reduce our dependence on fossil fuels. To maximise yields per hectare light interception and utilisation of the plant canopy need to be optimised. Jennifer Cunniff and Marianna Cerasuolo explain how this target can be reached by integrating morphological field measurements and modelling techniques. PMID- 21656776 TI - Ageing-induced solubility loss in milk protein concentrate powder: effect of protein conformational modifications and interactions with water. AB - BACKGROUND: Protein conformational modifications and water-protein interactions are two major factors believed to induce instability of protein and eventually affect the solubility of milk protein concentrate (MPC) powder. To test these hypotheses, MPC was stored at different water activities (a(w) 0.0-0.85) and temperatures (25 and 45 degrees C) for up to 12 weeks. Samples were examined periodically to determine solubility, change in protein conformation by Fourier transform infrared (FTIR) spectroscopy and water status (interaction of water with the protein molecule/surface) by measuring the transverse relaxation time (T(2) ) with proton nuclear magnetic resonance ((1) H NMR). RESULTS: The solubility of MPC decreased significantly with ageing and this process was enhanced by increasing water activity (a(w) ) and temperature. Minor changes in protein secondary structure were observed with FTIR which indicated some degree of unfolding of protein molecules. The NMR T(2) results indicated the presence of three distinct populations of water molecules and the proton signal intensity and T(2) values of proton fractions varied with storage condition (humidity) and ageing. CONCLUSION: Results suggest that protein/protein interactions may be initiated by unfolding of protein molecules that eventually affects solubility. PMID- 21656777 TI - Effects of enzymatic action on the formation of theabrownin during solid state fermentation of Pu-erh tea. AB - BACKGROUND: Theabrownin (TB) is a main bioactive component in Pu-erh tea, and the total amount is between 100 and 140 g kg(-1). However, reports on the mechanism of formation of TB are sparse because it has a high molecular weight and complex composition. Hence, the mechanism of formation of TB in Pu-erh tea during solid state fermentation was investigated using an exogenous enzyme method. RESULTS: It was found that, in the presence of exogenous enzymes, the tea liquor prepared from the resulting leaves changed considerably in colour. In addition, the TB, total carbohydrate, polysaccharide, amino acid and protein contents were all increased, while the tea polyphenol content decreased sharply; the surfaces of leaves before fermentation appeared to be smooth and intact, and the structures of the cell, cellulose and lignin were complete, while after fermentation their surfaces were covered by microorganisms and the structures of the cells were largely disrupted. CONCLUSION: The enzymatic actions are closely related to the compositional changes occurring during Pu-erh tea manufacture, and its quality. Enzymes produced by microorganisms were found to be the main cause of TB formation during the fermentation of Pu-erh tea. PMID- 21656778 TI - Differences in two-dimensional gel electrophoresis patterns of skeletal muscle myosin light chain isoforms between Bos taurus, Sus scrofa and selected poultry species. AB - BACKGROUND: In this study the interspecies differences in two-dimensional electrophoresis patterns of skeletal muscle myosin light chain (MLC) isoforms between Bos taurus (cattle), Sus scrofa (pig), Gallus gallus (chicken), Meleagris gallopavo (turkey), Anas platyrhynchos (duck) and Anser anser (goose) were characterised on the basis of specific properties of MLCs associated with their structure and mobility in gel. RESULTS: Two-dimensional electrophoresis separations revealed species-specific differences in the molecular weight and pI of individual MLC isoforms (MLC1f, MLC2f and MLC3f). In the case of closely related animal species such as goose and duck or turkey and chicken, significant differences occurred in MLC1f. For MLC2f, differences between cattle and turkey and between pig and chicken were around 1 and 0.3 kDa respectively. It appeared from the comparison of amino acid sequences that even MLCs with only 2% difference in sequences have different electrophoretic mobilities. CONCLUSION: Interspecies differences in skeletal MLC isoforms appeared between cattle, pig, chicken, turkey, duck and goose. The slight changes observed in the course of the aging process confirmed that these proteins are relatively little susceptible to proteolytic enzymes during meat aging. PMID- 21656779 TI - Pulsed wave Doppler ultrasonography for the assessment of peripheral vasomotor response in an elderly population. AB - PURPOSE: To assess sympathetic vasomotor activity and its changes with age, using pulsed wave Doppler ultrasound. METHODS: We recruited 20 young adults (24-37 years old) and 20 older individuals (60-81 years old). Pulsed wave Doppler ultrasound was applied over the right radial artery to measure blood flow at rest and after a voluntary inspiratory cough eliciting sympathetic activation. The maximal (Vmax), minimal (Vmin), time-averaged (TAMaxV) blood flow velocity, and the pulsatility index (PI) were calculated and compared between groups. RESULTS: At rest, PI was similar in both groups but Vmax and TAMaxV were higher in the older group (p < 0.05). Vmax, Vmin, and TAMaxV decreased, and PI increased after inspiratory cough in both groups (p <= 0.001), but this increase was lower in the older group (p < 0.001). TAMaxV after coughing was higher in the older group (p < 0.05). Heart rate did not differ significantly within or between groups. CONCLUSIONS: The older group exhibited reduced vasomotor reactivity of the radial artery after sympathetic stimulus. Peripheral vasomotor response should be interpreted with caution in elderly populations. PMID- 21656780 TI - Value of contrast-enhanced sonography with micro flow imaging in the diagnosis of prostate cancer. AB - BACKGROUND: To evaluate the effectiveness of contrast-enhanced sonographic micro flow imaging (MFI) in the diagnosis of prostate cancer. METHODS: A total of 74 patients referred for prostate biopsy were prospectively evaluated with MFI. The abnormalities were categorized into four patterns: pattern 1: indistinct separation between the inner and outer gland; pattern 2: asymmetrical or focally increased enhancement in the outer gland; pattern 3: enhancement with focal defect; pattern 4: enhancement in the outer gland equal to that of the inner gland. The findings were correlated with Gleason scores. RESULTS: Prostate cancer was detected in 264 sites in 41 patients. The sensitivity, specificity, accuracy, and positive and negative predictive values for MFI were 81.1%, 84.3%, 83.3%, 68.6%, and 91.3%, respectively. Positive predictive values for the four patterns were 46.0 (pattern 1), 53.6 (pattern 2), 94.3 (pattern 3), and 95.4 (pattern 4). Gleason scores of cancers with patterns 3 (7.09) or 4 (7.51) were significantly higher than those with patterns 1 (6.17) or 2 (6.59) (p = 0.001, p = 0.005, p < 0.001, p < 0.001). CONCLUSIONS: Some MFI patterns had high positive predictive values and were associated with more aggressive cancers. This could be used to reduce the number of biopsy sites and detect clinically significant cancers. PMID- 21656781 TI - Imaging and assessment of placental function. AB - The placenta is the vital support organ for the developing fetus. This article reviews current ultrasound (US) methods of assessing placental function. The ability of ultrasound to detect placental pathology is discussed. Doppler technology to investigate the fetal, placental, and maternal circulations in both high-risk and uncomplicated pregnancies is discussed and the current literature on the value of three-dimensional power Doppler studies to assess placental volume and vascularization is also evaluated. The article highlights the need for further research into three-dimensional ultrasound and alternative methods of placental evaluation if progress is to be made in optimizing placental function assessment. PMID- 21656782 TI - Symptomatic plantar fibroma with a unique sonographic appearance. AB - We present a case of a solitary plantar fibroma with unique sonographic features with MRI and pathologic correlation. A 25-year-old woman presented with a left foot mass that interfered with her gait. Sonography demonstrated a well circumscribed, 32 mm * 27 mm * 14 mm subcutaneous mass with heterogeneous echogenicity. Unique sonographic characteristics included posterior acoustic enhancement, cystic components, and mild intratumoral hypervascularity. MRI confirmed the sonographic findings. Surgical excision was performed without complication. A pathologic diagnosis of fibroma with myxoid degeneration and cyst formation was made. PMID- 21656783 TI - Sonographic findings of a Bochdalek hernia: the importance of ring-down artifacts. AB - Bochdalek hernia is the most common congenital diaphragmatic hernia. It may be incidentally identified on CT. We report the sonographic findings in a case of Bochdalek hernia, which showed ring-down artifact posterior to the herniated intra-abdominal fat. PMID- 21656785 TI - Writing: there's no "app" for that. PMID- 21656784 TI - Testing a multi-group model of culturally competent behaviors among underrepresented nurse practitioners. AB - Diversifying the health professional workforce and enhancing cultural competence are recommended for decreasing health disparities. We tested a structural equation model of the predictors of culturally competent behaviors in a mailed survey of three groups of underrepresented nurse practitioners (n = 474). Our model had good fit and accounted for 29% of the variance in culturally competent behaviors. Life experiences with diversity had direct effects on awareness/sensitivity and behaviors, and diversity training had a direct effect on behaviors. Cultural awareness/sensitivity mediated the relationship between life experiences with diversity and culturally competent behaviors; all paths remained after controlling for covariates. For unique experiences that contribute to workplace diversity, life experiences with diversity, and diversity training are important for culturally competent behaviors. PMID- 21656786 TI - Validation of the multidimensional health locus of control scales for labor and delivery. AB - No current instrument assesses women's health locus of control beliefs in relation to childbirth. Form C of the Multidimensional Health Locus of Control Scales was used to develop items for a new instrument specific to labor and delivery (MHLC-LD). Psychometric analyses conducted with two independent samples of pregnant women supported a three-factor model of the new instrument, consisting of Internal, Powerful Others, and Chance subscales. Results revealed modest coefficient alphas (>.70) for the subscales and demonstrated construct validity in known group analyses. Future validation research will focus on improving the internal consistency reliability of the MHLC-LD, testing factorial invariance across demographic groups, and examining the relationships between obstetric risk, previous birth experiences, and beliefs about control over childbirth outcomes. PMID- 21656787 TI - A chirality-based metrics for free-energy calculations in biomolecular systems. AB - In this work, we exploit the chirality index introduced in (Pietropaolo et al., Proteins 2008, 70, 667) as an effective descriptor of the secondary structure of proteins to explore their complex free-energy landscape. We use the chirality index as an alternative metrics in the path collective variables (PCVs) framework and we show in the prototypical case of the C-terminal domain of immunoglobulin binding protein GB1 that relevant configurations can be efficiently sampled in combination with well-tempered metadynamics. While the projections of the configurations found onto a variety of different descriptors are fully consistent with previously reported calculations, this approach provides a unifying perspective of the folding mechanism which was not possible using metadynamics with the previous formulation of PCVs. PMID- 21656788 TI - Derivatives of molecular surface area and volume: simple and exact analytical formulas. AB - The computational effort of biomolecular simulations can be significantly reduced by means of implicit solvent models in which the energy generally contains a correction depending on the surface area and/or the volume of the molecule. In this article, we present simple derivation of exact, easy-to-use analytical formulas for these quantities and their derivatives with respect to atomic coordinates. In addition, we provide an efficient, linear-scaling algorithm for the construction of the power diagram required for practical implementation of these formulas. Our approach is implemented in a C++ header-only template library. PMID- 21656789 TI - CORAL: quantitative structure-activity relationship models for estimating toxicity of organic compounds in rats. AB - For six random splits, one-variable models of rat toxicity (minus decimal logarithm of the 50% lethal dose [pLD50], oral exposure) have been calculated with CORAL software (http://www.insilico.eu/coral/). The total number of considered compounds is 689. New additional global attributes of the simplified molecular input line entry system (SMILES) have been examined for improvement of the optimal SMILES-based descriptors. These global SMILES attributes are representing the presence of some chemical elements and different kinds of chemical bonds (double, triple, and stereochemical). The "classic" scheme of building up quantitative structure-property/activity relationships and the balance of correlations (BC) with the ideal slopes were compared. For all six random splits, best prediction takes place if the aforementioned BC along with the global SMILES attributes are included in the modeling process. The average statistical characteristics for the external test set are the following: n = 119 +/- 6.4, R(2) = 0.7371 +/- 0.013, and root mean square error = 0.360 +/- 0.037. PMID- 21656790 TI - Open fetal surgery for myelomeningocele. AB - Despite efforts at prevention through the use of preconception folic acid, spina bifida remains one of the most common congenital anomalies of the central nervous system that is compatible with life. It is, however, associated with a significant degree of lifelong morbidity. The development of open fetal surgery for myelomeningocele (MMC) has been a long process but one that serves as a model for how new procedures and technologies need to be properly evaluated before being brought into mainstream medical practice. Even so, risks and benefits need to be evaluated for each patient. The currently available studies have been carried out on a highly selected patient population where the fetal findings provided the maximum opportunity for benefit from prenatal closure of the MMC defect. There is the potential that as the surgery becomes more widely available, pressure will be brought to bear to perform surgery in cases where the likelihood for benefit is decreased and yet the risks are not. The only way to duplicate the results of the current studies is to follow the methodology and criteria that were used in the studies. This will mean that not every fetus with an MMC will be a candidate for in utero surgery. The balance of risk to benefit will continue to evolve as further technological advances are evaluated and more follow-up information is obtained. PMID- 21656791 TI - Novel application of the MSSCP method in biodiversity studies. AB - Analysis of 16S rRNA sequence diversity is widely performed for characterizing the biodiversity of microbial samples. The number of determined sequences has a considerable impact on complete results. Although the cost of mass sequencing is decreasing, it is often still too high for individual projects. We applied the multi-temperature single-strand conformational polymorphism (MSSCP) method to decrease the number of analysed sequences. This was a novel application of this method. As a control, the same sample was analysed using random sequencing. In this paper, we adapted the MSSCP technique for screening of unique sequences of the 16S rRNA gene library and bacterial strains isolated from biofilms growing on the walls of an ancient gold mine in Poland and determined whether the results obtained by both methods differed and whether random sequencing could be replaced by MSSCP. Although it was biased towards the detection of rare sequences in the samples, the qualitative results of MSSCP were not different than those of random sequencing. Unambiguous discrimination of unique clones and strains creates an opportunity to effectively estimate the biodiversity of natural communities, especially in populations which are numerous but species poor. PMID- 21656792 TI - Bio-control and plant growth promotion potential of siderophore producing endophytic Streptomyces from Azadirachta indica A. Juss. AB - Three endophytic actinomycetes strains recovered from surface sterilized root tissues of Azadirachta indica A. Juss. (Meliaceae), plants were selected through tests for their potential as bio-control and plant growth promoting agents. It was also observed that the seed treated with the spore suspension of three selected strains of Streptomyces, significantly promoted plant growth and antagonized the growth of Alternaria alternata, causal agent of early blight disease in tomato plant. It was observed that the three selected strains prolifically produce IAA and siderophores that play vital role in promotion of plant growth and in suppression of Alternaria alternata. Interestingly, Streptomyces strain AzR-051 produced the highest amount of IAA at 13.73 MUmol ml( 1) , compared to strains AzR-049 and AzR-010 9.22 MUmol ml(-1) and 10.43 MUmol ml(-1) respectively. It also produces siderophores higher than the other two strains. Thus these endophytic isolates have the potential as plant growth promoters as well as a bio-control agent, which is a useful trait for crop production in nutrient deficient soils. PMID- 21656793 TI - The response of filamentous fungus Rhizopus nigricans to flavonoids. AB - The saprophytic fungus Rhizopus nigricans constitutes a serious problem when thriving on gathered crops. The identification of any compounds, especially natural ones, that inhibit fungal growth, may therefore be important. During its life cycle, Rhizopus nigricans encounters many compounds, among them the flavonoids, plant secondary metabolites that are involved in plant defense against pathogenic microorganisms. Although not being a plant pathogen, Rhizopus nigricans may interact with these compounds in the same way as plant pathogens- in response to the fungitoxic effect of flavonoids the fungi transform them into less toxic metabolites. We have studied the interaction of R. nigricans with some flavonoids. Inhibition of hyphal spreading (from 3% to 100%) was observed by 300 MUM flavones, flavanones and isoflavones, irrespective of their basic structure, oxidized or reduced C-ring, and orientation of the B-ring. However, a hydrophobic A-ring was important for the toxicity. R. nigricans transformed some of the flavonoids into glucosylated products. Recognition of substrates for glucosylating enzyme(s) did not correlate with their fungitoxic effect but depended exclusively on the presence of a free -OH group in the flavonoid A-ring and of a hydrophobic B-ring. Although the fungus produced glucosyltransferase constitutively, an additional amount of the enzyme was induced by the substrate flavonoid. Moreover, effective detoxification was shown to require the presence of glucose. PMID- 21656794 TI - Rapid quantification and analysis of genetic diversity among Gordonia populations in foaming activated sludge plants. AB - Activated sludge plants, sporadically suffers malfunction due to the proliferation of filamentous bacteria mainly Gordonia and Microthrix species. Nested Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (nested PCR-RFLP) in combination with quantitative real-time PCR (q PCR) was applied to study the distribution of Gordonia in foaming samples. Samples of mixed liquor were collected from three full-scale activated sludge plants that were experiencing filamentous biological foaming. Partial sequencing of 16S rRNA genes revealed the dominance of Gordonia amarae (60-80%), Gordonia terrae (10%), Gordonia polyisoprenivorans (30-40%) and an unidentified Gordonia species (20 50%). Restriction enzyme analysis of the amplicons exhibited 87.14 to 99.6% similarity at interspecies level. The q PCR results showed that there was an average of 15.6% Gordonia 16S rRNA copies with respect to the total bacterial 16S rRNA gene in foaming sludge samples with the highest being 23.51% and lowest being 10.28%. The presence of Gordonia spp. in the foaming samples was observed throughout the year but was lower during winter and its presence was significantly higher in foaming samples, compared to Microthrix parvicella (r = 0.007, P < 5%). This approach could help to quantify and confirm the existence of genetically diverse indigenous Gordonia spp. in foaming samples and can be used as an indicator of forthcoming foaming incidents. PMID- 21656795 TI - Analysis of Aspergillus nidulans germination, initial growth and carbon source response by flow cytometry. AB - In this work, flow cytometry was utilized to analyze the initial vegetative growth of the model fungus Aspergillus nidulans as measured by the number of events increasing size and internal complexity. It was established the ideal parameters for the analysis of conidial populations, whose growth was followed after germination in glucose or sucrose. While glucose in culture increased growth several magnitudes in comparison to control cultures in saline, growth was less intense in cultures amended with sucrose. Results indicated that flow cytometry could be a useful tool to study fungal germination and initial growth since it allowed rapid identification of different populations by means of their increasing in size and granularity with good reproducibility and without the need for direct observation and count of individual cells. PMID- 21656796 TI - Phylogenetic-affiliation, antimicrobial potential and PKS gene sequence analysis of moderately halophilic Streptomyces sp. inhabiting an Indian saltpan. AB - A Gram-positive, moderately halophilic Streptomyces strain, designated JAJ06, was isolated from saltpan soil collected at Tuticorin, India, and subjected to a polyphasic characterization with an insight into their biotechnological importance. Growth characteristics and antimicrobial com-pound producing capabilities of Streptomyces sp. JAJ06 were observed on various International Streptomyces Project (ISP) media and production media. Optimum growth was observed on modified ISP 4 medium supplemented with 4% NaCl (w/v) at 29 degrees C incubated for 7 days. Maximum antibacterial compound production with good mycelial growth was observed on starch-yeast extract-peptone medium prepared with seawater (90%, v/v). The 16S rRNA gene based phylogenetic affiliation was determined by using various bioinformatics tools and the strain was identified as Streptomyces sp. JAJ06 with 99% sequence similarity to Streptomyces radiopugnans(T) . An antimicrobial assay of antimicrobial compound derived from Streptomyces sp. JAJ06 against a set of bacteria and a yeast strain revealed antimicrobial activity with significant minimal inhibitory concentrations. The potential antimicrobial compound produced by Streptomyces sp. JAJ06 was found to be polyketide in nature. Cloning and sequence analysis of 613-bp fragment of ketosynthase gene from the type-II polyketide operon revealed that Streptomyces sp. JAJ06 has the KSalpha gene with 91% sequence similarity to the type II polyketide synthase gene of Streptomyces peucetius. PMID- 21656797 TI - Starvation survival of Candida albicans in various water microcosms. AB - Candida is a major Human pathogen causing a variety of infections and can survive for extended period of time in aquatic environment including marine and fresh water. In this study we compared a colorimetric XTT assay to colony forming units (CFU) count to evaluate the survival potential of Candida albicans incubated in water microcosms. Our results showed that cells maintain cultivability within a long period followed by a decline in cultivability and a drop of plate counts to less than 20 cell ml(-1) after 150 days in tap water, 190 days in rain water and 200 days in seawater. In addition we noted that 10% of cells viability was reached after 150 days in seawater, 180 days in rain water and 210 days in tap water. Molecular method confirms the persistence of C. albicans cells in water during long time starvation period. PMID- 21656798 TI - Characterization of a hydrophobin of the ascomycete Paecilomyces farinosus. AB - The entomopathogenic ascomycete Paecilomyces farinosus (alternative name Isaria farinosa) synthesized a hydrophobin, irrespective of being grown in submerged or surface culture. The protein was extracted using trifluoroacetic acid and purified using preparative HPLC and SDS-PAGE. Partial sequences were obtained using ESI-MS/MS. The peptides were used as a start to apply a 'template switching oligo' protocol to elucidate the complete open reading frame of P. farinosus hydrophobin 1 (pfah1). The deduced protein sequence comprised 107 amino acids (10.7 kDa) including a 16 amino acid long hydrophobic signal peptide, showed a calculated pI of 4.56, and was interrupted by one intron. Phylogenetic analyses revealed relationships to hydrophobins of the ascomycetes Magnaporthe grisea and Metarhizium anisopliae. Based on solubility, hydropathy pattern and phylogeny PfaH1 was assigned to the class Ia hydrophobins. PMID- 21656799 TI - Purification, characterization and thermodynamics of antifungal protease from Streptomyces sp. A6. AB - A 20 kDa antifungal serine protease from Streptomyces sp. A6 was purified to 34.56 folds by gel permeation chromatography. The enzyme exhibited highest activity at neutral to near alka- line pH 7-9 and 55 degrees C. Neutral surfactant triton X-100 enhanced the activity by 4.12 fold. The protease activity also increased (109.9-119%) with increasing concentration of urea (2-8 mole/l). The enzyme was identified as serine protease with 67% similarity to SFase 2 of Streptomyces fradiae by MALDI-LC-MS/MS analysis. Determination of kinetic constants k(m) , V(max) , k(cat) and k(cat) /k(m) suggested higher affinity of enzyme for N-Suc-Ala-Ala-Val-Ala-p NA (synthetic substrate for chymotrypsin activity). The enzyme was highly stable at temperature prevailing under field conditions (40 degrees C) as apparent from K(d) and t(1/2) values, 0.0065 and 106.75 min, respectively and high DeltaG* and negative DeltaS * values, 87.17 KJ/mole and -126.95 J/mole, respectively. Thermal stability and increased activity of protease in presence of commonly used chemical fertilizer, urea, suggested its feasibility for agricultural applications. The present study is the first report on thermodynamic and kinetic properties of an antifungal protease from Streptomyces sp. A6. The study reflects potential of this enzyme for biocontrol of fungal plant pathogens. PMID- 21656800 TI - Isolation and characterization of arsenic resistant Geobacillus kaustophilus strain from geothermal soils. AB - A thermophilic, arsenate resistant bacterial strain was isolated from a geothermal field located in the area surrounding Monterotondo (Tuscany, Italy). Based on 16S rRNA gene analysis and recN comparisons the strain was identified as Geobacillus kaustophilus. Cells of the strain, designated A1, were rod-shaped, 2 3 MUm long and reacted negatively to Gram staining, despite its taxonomic classification as a Gram positive microorganism. Strain A1 is a thermophilic spore-forming bacterium, and grows optimally at pH 6.5 and 55 degrees C. An arsenate MIC of 80 mM was determined for strain A1, and the close relative G. kaustophilus DSM 7263(T) showed similar levels of arsenate resistance. These observations were consistent with the presence of arsenic detoxification genes in the genome of G. kaustophilus HTA426. Furthermore, strain A1 growth was not inhibited by 5 mM antimonite and 15 mM arsenite, the highest tested concentrations. This is the first description of arsenic resistance in a Geobacillus strain and supports the hypothesis that members of the genus may have a role in the biogeochemical cycling of arsenic. PMID- 21656801 TI - Culture-dependent and -independent molecular analysis of the bacterial community within uranium ore. AB - The bacterial community structure within a uranium ore was investigated using culture-dependent and -independent clone library analysis and denaturing gradient gel electrophoresis of 16S rRNA genes. The major aerobic heterotrophic bacteria were isolated and identified, and their resistance to uranium and other heavy metals was characterized. Together with near neutral pH, moderate organic carbon content, elevated U and other heavy metals (V, Ni, Mn, Cu, etc.), the ore showed high microbial counts and phylotype richness. The bacterial community mainly consisted of uncultured Proteobacteria, with the predominance of gamma - over beta - and alpha -subdivisions, along with Actinobacteria and Firmicutes. A phylogenetic study revealed that nearly one-third of the community was affiliated to as yet uncultured and unidentified bacteria having a closer relationship to Pseudomonas. Lineages of Burkholderiaceae and Moraxellaceae were relatively more abundant in the total community, while genera affiliated to Xanthomonadaceae and Microbacteriaceae and Exiguobacterium were detected in the culturable fraction. More than 50% of the bacterial isolates affiliated to Stenotrophomonas, Microbacterium, Acinetobacter, Pseudomonas and Enterobacter showed resistance to uranium and other heavy metals. The study showed for the first time that uranium ore harbors major bacterial groups related to organisms having a wide range of environmentally significant functional attributes, and the most abundant members are possibly new groups/taxa. These findings provide new insights into U-ore geomicrobiology that could be useful in biohydrometallurgy and bioremediation applications. PMID- 21656802 TI - Root colonization of a rice growth promoting strain of Enterobacter cloacae. AB - Enterobacter cloacae GS1 was isolated by in-planta enrichment of a rice rhizoplane bacterial community. It displayed strong seed adherence ability (2.5 * 10(5) cfu/seed) and colonized rice roots reaching up to 1.65 * 10(9) cfu/g of fresh root weight in a gnotobiotic root colonization system. E. cloacae GS1 was motile, able to solubilize tricalcium phosphate, and produced indole acetic acid like substances (15 MUg/ml). As an introduced bioinoculant in non-sterile soil, E. cloacae GS1 colonized rice roots and significantly improved the fresh weight, root length, shoot length, and nitrogen content in inoculated rice seedlings as compared to uninoculated controls. This isolate was tagged with green fluorescent protein and various stages of root colonization in gnotobiotic hydroponic environment and non-sterile soil environment were followed by fluorescence microscopy. Owing to its effective root colonizing ability and growth promoting potential, Enterobacter cloacae GS1 is a promising symbiotic bioinoculant for rice. PMID- 21656803 TI - Characterization of Beauveria bassiana MsW1 isolated from pine sawyers, Monochamus saltuarius. AB - Monochamus saltuarius is a vector for pine wilt disease that causes enormous damage to native pine trees in Korea. To develop a biological control method for this pine wilt disease vector, an entomopathogenic fungus was isolated from the cadaver of an adult M. saltuarius supporting fungal conidiation. This fungus was named MsW1 and identified as Beauveria bassiana by microscopic examination, PCR amplification using B. bassiana -specific primers and genetic sequencing of the ITS and EF1-alpha regions. Virulence tests against M. saltuarius were conducted with conidial suspensions (1 * 10(8) conidia/ml) of B. bassiana MsW1 in laboratory conditions. The median lethal times (LT(50)) of adults and larvae were 7.2 and 7 days, and 100% mortality was observed at 11 and 13 days after inoculation, respectively. This is the first characterization of B. bassiana from M. saltuarius. PMID- 21656804 TI - Rhamnolipid from Pseudomonas desmolyticum NCIM-2112 and its role in the degradation of Brown 3REL. AB - The biosurfactant produced by Pseudomonas desmolyticum NCIM 2112 (Pd 2112) was confirmed as rhamnolipid based on the formation of dark blue halos around the colonies in CTAB-methylene blue agar plates and the content of rhamnose sugar. The average yield of rhamnolipid was 0.398 g/l/day when grown on hexadecane as sole carbon source. Pd 2112 emulsification potential associated with cell free culture broth was stable for 72 h using various hydrocarbons and vegetable oils. Chemical structure of the biosurfactant was identified as mono-rhamnolipid (Rha C(6) -C(8) ) using HPTLC, fourier transform infrared spectroscopy, (1) H and (13) C NMR and gas chromatography-mass spectroscopy analysis. Pd 2112 mono-rhamnolipid (1 mg/ml) had increased permeabilization of Bacillus sp VUS NCIM 5342 and increased decolorization rate of textile dye Brown 3REL by 50%. Extracellular activities of lignin peroxidase and veratryl alcohol oxidase, enzymes involved in dye degradation, were significantly increased in the presence of mono-rhamnolipid by 324.52% and 100% respectively. Scanning electron micro-scopy observations revealed that rhamnolipid did not exert any disruptive action on Bacillus cells as compared to Tween 80. The mono-rhamnolipid of Pd 2112 has potential for its application in biodegradation of textile dyes. PMID- 21656805 TI - Caenorhabditis elegans as a model for studying Cronobacter sakazakii ATCC BAA-894 pathogenesis. AB - Cronobacter sakazakii is occasionally associated with food-borne illness seen in neonates and infants with weakened immune system. It can cause meningitis, local necrotizing enterocolitis and systemic bacteremia leading to infant mortality rates upto 33-80%. With the aim of investigating whether C. sakazakii is also a pathogen of the model organism C. elegans, we have performed killing assays and monitored the mortality of host fed with pathogen. C. elegans fed with C. sakazakii die over the course of several days, as a consequence of an accumulation of bacteria in the host intestine. Further, the rate of C. sakazakii mediated infection in C. elegans depends on the accumulation of the bacterial load inside the host. C. sakazakii killed C. elegans with an LT(50) (time for half to die) of 134 +/- 2.8 h in liquid assay conditions, whereas the mortality of C. elegans infected with C. sakazakii was less pronounced during solid assays. We found that 24 h of C. sakazakii infection is enough to cause gametogenesis defects and increased cell damage in intestinal tract of host. To monitor the immune regulations during C. sakazakii infection in C. elegans at molecular level, total RNA was isolated and few candidate genes (lys-7, clec-60 and clec 87) were kinetically analyzed by using the semi-quantitative RT-PCR. The level of expression of lys-7, clec-60 and clec-87 mRNAs isolated from C. elegans infected with C. sakazakii was significantly higher when compared to C. elegans exposed to E. coli OP50 control. This is the first report in which physiological changes and an induction of host immunity mediated antimicrobial genes by C. sakazakii are shown in C. elegans. PMID- 21656806 TI - Unusual occurrence of non carotenogenic strains of Dunaliella bardawil and Dunaliella parva in India. AB - Identification of green algal genus Dunaliella by conventional method is hard target since the strains vary morphologically and physiologically with conditions of growth. In this study, a total of nine different isolates of Dunaliella isolated from the salt pans of Tamil Nadu, India, were identified based on their morphology and cultural characteristics. In addition, the isolates were subjected to molecular identification using genus specific and species specific primers which distinguished the discrepancy in the conventional identification. This study evidently reported the first occurrence of non carotenogenic strains (a new variety) of D. bardawil and D. parva in India. PMID- 21656807 TI - Cellulases from psychrophilic microorganisms: a review. AB - Cellulases are hydrolytic enzymes that catalyze total hydrolysis of cellulose into sugars. Cellulases are produced by various groups of microorganisms and animals; however, psychrophiles are the ideal candidates for the production of enzymes active at low temperature and stable under alkaline conditions, in the presence of oxidants and detergents, which are in large demand as laundry additives. The cellulases from psychrophiles also find application in environmental bioremediation, food industry and molecular biology. Research work on cellulase has been done over the last six decades, but there is no exclusive review available on the cellulases from psychrophiles. This review is an attempt to fill this gap by providing all the relevant information exclusively for cellulases from psychrophiles, with a focus on the present status of knowledge on their activity, molecular characteristics, gene cloning, statistical experimental designs, crystal structure, and strategies for the improvement of psychrophilic cellulases. PMID- 21656808 TI - Detection of OXA-type carbapenemases and integrons among carbapenem-resistant Acinetobactor baumannii in a teaching hospital in China. AB - The increasing trend of carbapenem-resistance (CR) and multi-drug resistance (MDR) in A. baumannii worldwide has limited the therapeutic effectiveness of antibiotic therapy. The study was conducted to determine the prevalence of carbapenemases and integrons among the isolates of imipenem-resistant A. baumannii (IRAB). A total of 71 non-repetitive imipenem- resistant A. baumannii isolates were collected and tested for susceptibility to 17 antimicrobials. The modified Hodge test and EDTA-disc synergy test were performed for the screening of carbapenemases and metallo-beta -lactamases (MBLs) production, respectively. Isolates were then subjected to multiplex-PCR targeting genes encoding for OXA type carbapenemase, MBLs and integrases. Random amplified polymorphic DNA (RAPD) genotyping was performed to assess genetic relatedness. All isolates exhibited multi-drug resistant phenotype. Colistin was the most active antimicrobial agent tested. Seventy-one isolates (100%) demonstrated positive in the modified Hodge test. Thirty-nine isolates showed positive in the EDTA-disc synergy test, however, no MBL genes were detected. All strains possessed a bla(OXA-51) -like gene. The co-exis-tence of bla(OXA-51) -like/bla(OXA-23) -like/intI1, bla(OXA-51) -like/bla(OXA-23) -like, bla(OXA-51) -like/bla(OXA-24) -like was detected in 91.6% (n = 65), 5.6% (n = 4), 2.8% (n = 2), respectively. Analysis of the genetic con-text of bla(OXA-23) showed the presence of ISAba1 upstream of bla(OXA-23) . No ISAba1 was detected upstream of bla(OXA-51) . Two different gene cassettes were found in these strains, and a high prevalence of aacA4, aadA1 and catB8 genes was observed. RAPD of 71 isolates showed 7 genotypes. The strains were mainly recovered from patients in intensive care unit, neurosurgery and department of respiratory disease. These findings show that multi-drug resistance in A. baumannii is a common problem. This study also shows a high distribution of bla(OXA-23) -like and intI1 genes in imipenem-resistant A. baumannii isolates. The clonal spread played an important role in the increase of OXA-23 producing IRABs in the hospital environment. PMID- 21656809 TI - A study on significant microbial interaction leading to decolorization and degradation of textile dye Rubine 3GP. AB - The present study evaluates an obligatory interaction between the yeast Saccharomyces cerevisiae NCIM 3312 and the bacterium Pseudomonas sp. strain BCH3 for the biodegradation of the dye Rubin 3GP (R3GP). No significant degradation of R3GP was observed either by Saccharomyces cerevisiae NCIM 3312 or by Pseudomonas sp. strain BCH3, when both the cultures were tested individually under their respective optimum medium conditions. However, when both of them were allowed to intermingle with each other, R3GP was found to be degraded within 72 h, with a steady increase in beta -1,3-glucanase, chitinase and protease activity in the culture supernatant; indicating the possible role of Pseudomonas sp. strain BCH3 in cell wall lysis of S. cerevisiae NCIM 3312. The present study elucidates a rare microbial interaction where the bacterium Pseudomonas sp. strain BCH3 utilizes lysed yeast cells as the sole source of nutrients for its own growth and subsequently performs decolorization and degradation of R3GP. Enzymatic status showed involvement of various oxidoreductive enzymes like lignin peroxidase, laccase, DCIP reductase and azo reductase, indicating their role in decolorization and degradation of R3GP. Degradation was confirmed using HPLC, FTIR analysis and the biochemical pathway of degradation was elucidated by using GC-MS analysis. PMID- 21656810 TI - Diversity of protease-producing marine bacteria from sub-antarctic environments. AB - From seawater and the intestines of benthonic organisms collected from the Beagle Channel, Argentina, 230 marine bacteria were isolated. Cultivable bacteria were characterized and classified as psychrotolerant, whereas few isolates were psychrophiles. These isolates were capable of producing proteases at 4 and 15 degrees C under neutral (pH 7.0), alkaline (pH 10.0) and acidic (pH 4.5) conditions on different media, revealing 62, 33 and 22% producers at cold and 84, 47 and 33% producers at low temperatures, respectively. More protease-producing strains (67%) were detected when isolated from benthic invertebrates as compared to seawater (33%), with protease production under neutral conditions resulting in milk protein hydrolysis halos between 27 and 30 +/- 2 mm in diameter. Using sterile 0.22 MUm membrane filters, 29 isolates exhibiting extracellular protease activity were detected. These were grouped into six operational taxonomic units by restriction analysis and identified based on 16S rDNA as gamma-proteobacteria of the genera Pseudoalteromonas, Pseudomonas, Shewanella, Alteromonas, Aeromonas, and Serratia. Plasmids were found to be harbored by eight strains, mainly within the isolates from benthonic organisms. PMID- 21656811 TI - Wax ester-like compounds as biosurfactants produced by Dietzia maris from n alkane as a sole carbon source. AB - The hydrocarbon-degrading bacterium Dietzia maris WR-3 was isolated from a consortium comprising ammonia-oxidizing and denitrifying bacteria derived from marine sediments. Here, we examined biosurfactant production by strain WR-3 when cultured using several different carbon (D-glucose, n -decane, n -hexadecane, motor oil, olive oil, and rapeseed oil) and nitrogen (NH(4) )(2) SO(4) , NaNO(3) , yeast extract, and polypeptone) sources as growth substrates. Strain WR-3 was able to grow and reduce the surface tension of culture broth to 31+/-1.0 mN m(-1) when cultured using n -hexadecane and nitrate ions. The surface-active compounds produced by strain WR-3 were extracted and analyzed by thin layer chromatography. Moreover, the main components in the extract were further purified and subjected to gas chromatography/mass spectrometry (GC/MS). From the analysis, the surface active compounds were tentatively identified as wax ester-like compounds, which were synthesized from the degradation process of n -alkane. The production of surface-active compounds by strain WR-3 promoted attachment of cells to hydrocarbon droplets via increased cell hydrophobicity, thus allowing enhanced degradation of water immiscible substrates. As Dietzia spp. can grow and produce wax esters from the degradation process of hydrocarbons, these marine bacteria are potentially useful for the bioremediation of hydrocarbon-contaminated environments. PMID- 21656812 TI - Variation in biofilm formation among symbiotic and free-living strains of Vibrio fischeri. AB - Persistence and survival under various environmental stresses has been attributed to the capacity of most bacteria to form biofilms. In aquatic environments, the symbiotic bacterium Vibrio fischeri survives variable abiotic conditions during its free-living stage that dictates its ability to colonize the squid host. In the present study, the influence of different abiotic factors such as salt concentration, temperature, static/dynamic conditions, and carbon source availability were tested to determine whether biofilm formation occurred in 26 symbiotic and free-living V. fischeri strains. Statistical analysis indicate that most strains examined were strong biofilm producers under salinity concentrations that ranged between 1-5%, mesophilic temperatures (25-30 degrees C) and static conditions. Moreover, free-living strains are generally better biofilm formers than the symbiotically competent ones. Geographical location (strain origin) also correlated with biofilm formation. These findings provide evidence that abiotic growth conditions are important for determining whether mutualistic V. fischeri have the capacity to produce complex biofilms, allowing for increased competency and specificity during symbiosis. PMID- 21656813 TI - Fatty acid and hydrocarbon composition in tropical marine Shewanella amazonensis strain SB2B(T). AB - Shewanella amazonensis strain SB2B(T) is an isolate from shallow-water marine sediments derived from the Amazon River delta. This bacterium contained a long chain polyunsaturated hydrocarbon, all-cis -3,6,9,12,16,19,22,25,28 hentriacontanonaene (C31:9), constituting 1-2% of the total fatty acid methyl ester and hydrocarbon fraction, which was produced dependently of decreased growth temperature. Analysis of its cellular fatty acid composition demonstrated that isopentadecanoic acid was the major fatty acid component and that all the main monounsaturated fatty acids had straight chains with a cis configuration. However, monoenoic cyclopropyl fatty acids, which were previously reported to be present in this bacterium, were not detected by mass spectrometric analysis. The growth temperature affected the content of Delta9-cis -hexadecenoic [16:1(Delta9c)], palmitic, and heptadecanoic acids. These results suggest that C31:9, as well as 16:1(Delta9c) might be involved in adaptation to low temperature in S. amazonensis strain SB2B(T) . Our result suggests that polyunsaturated fatty acid synthase protein complex may be involved in synthesis of C31:9 but not in production of eicosapentaenoic acid. PMID- 21656814 TI - Mineralization of mono-nitrophenols by Bjerkandera adusta and Lentinus squarrosulus and their extracellular ligninolytic enzymes. AB - Nitroaromatic compounds constitute a major class of widely distributed environmental contaminants. Fifty fungal strains were screened for their potential to tolerance with 2-nitrophenol, 3-nitrophenol and 4-nitrophenol on solid medium supplemented with 2% malt extract (MEA). Growth rate (mm/day) was determined at three concentrations (0.25, 0.5 and 1 mM) of all the three nitrophenols. From the fifty fungal strains only Bjerkandera adusta and Lentinus squarrosulus were able to tolerate all the three nitrophenols (NPs). These white rot fungi (WRF) were chosen for liquid medium studies for the mineralization of mono-nitrophenols and ligninolytic enzyme activity at 0.25 mM concentration. Both varieties completely removed 2-NP and 3-NP while 4-NP was hard to mineralize. AAO (Aryl Alcohol Oxidase) is the main oxidase enzyme in B. adusta while laccase plays important role in L. squarrosulus. MnP (Manganese peroxidase) is the main peroxidase enzyme in both varieties. These fungal strains were capable to degrade nitrophenols and could be used for bioremediation applications on large scale. PMID- 21656815 TI - The cytotoxic early protein 77 of mycobacteriophage L5 interacts with MSMEG_3532, an L-serine dehydratase of Mycobacterium smegmatis. AB - Mycobacteriophage L5 is a temperate phage infecting a broad range of mycobacterial species. Upon induction of lytic growth, L5 rapidly switches off host protein synthesis. We have recently identified the mycobacteriophage L5 early protein gp77 as a host shut-off protein that acts growth inhibitory in the mycobacterial host when expressed through the corresponding phage promoter. Here we present data showing that this purified phage protein of unknown function specifically binds to protein MSMEG_3532 when incubated with cell lysates of Mycobacterium smegmatis. This interaction was confirmed by pull-down assays using purified MSMEG_3532 as bait which co-purified with gp77. The amino acid sequence of MSMEG_3532 is nearly identical to that of threonine dehydratases, serine dehydratases and an L-threo-3-hydroxyaspartate dehydratase. An enzymatic assay identified this host protein as a pyridoxal-5'-phosphate-dependent L-serine dehydratase (SdhA) which converts L-serine to pyruvate. This is the first biochemical characterization of a SdhA derived from mycobacteria. Though the addition of purified gp77 to the established in vitro assay had no influence on SdhA activity at a saturating L-serine concentration, the specific interaction of phage protein and dehydratase in vivo may well have a role in altering the amino acid pool or the products of amino acid metabolism in favour of phage maturation. PMID- 21656816 TI - Simultaneous analysis of foodborne pathogenic bacteria by an oligonucleotide microarray assay. AB - A rapid and accurate method for simultaneous identification of foodborne infectious pathogens was developed based on oligonucleotide microarray technology. The proposed identification method is based on PCR amplification of the target region of the groEL genes with degenerate primers, followed by the PCR products hybridization with oligonucleotide probes specific for species. The groEL gene amplification products of seventeen species of pathogenic bacteria were hybridized to the oligonucleotide array. Hybridization results were analyzed with digoxigenin-linked enzyme reaction. Results indicated that fifteen species of pathogenic bacteria showed high sensitivity and specificity for the oligonucleotide array, while two other species gave cross-reaction with the E. coli. Our results suggested that microarray analysis of foodborne infectious pathogens might be very useful for simultaneous identification of bacterial pathogens. The oligonucleotide array can also be applied to samples collected in clinical settings of foodborne infections. The superiority of oligonucleotide array over other tests lies on its rapidity, accuracy and efficiency in the diagnosis, treatment and control of foodborne infections. PMID- 21656817 TI - Screening and characterization of potential cadmium biosorbent Alcaligenes strain from industrial effluent. AB - Cadmium (Cd) is a heavy metal that is easily accumulated in the living organisms in connection with anthropogenic activities which may result in serious health problems. In the present study, five potential cadmium tolerant bacterial strains were isolated from industrial effluent with heavy metal contamination and were screened for biosorption potential with their active growth in different media. After growth in shake flasks containing mineral salt media and tryptone soya broth, cell pellet of AS-5 removed by centrifugation sequestered almost 98% and 69% of cadmium (a.i. 25 mg/l Cd) respectively. Other strains accumulated variable amounts of Cd. 16S rRNA gene sequence of AS-5 and its homology analysis using BLAST reveals its phylogenetic relationship with family beta-proteobacteriaceae and 98% homology with Alcaligenes sp., a facultative anaerobe. PMID- 21656818 TI - Comparative analysis of two types of methanol dehydrogenase from Methylophaga aminisulfidivorans MPT grown on methanol. AB - Two types of methanol dehydrogenase (MDH) were obtained from a novel marine methylotrophic bacterium, Methylophaga aminisulfidivorans MP(T), grown on methanol. Type I MDH consisted of two identical dimers of alpha (65.98 kDa) and beta (7.58 kDa) subunits organized to form the alpha(2)beta(2) tetramer. Type II MDH contained an additional MxaJ protein (27.86 kDa) and had more specific activity than type I MDH. The K(m) values of type I and II MDH for methanol under cytochrome c(L) reduction assay system were estimated to be 50.3 and 13.0 MUM, respectively, and the isoelectric points of type I and II MDH were determined to be 5.4 and 5.8, respectively. The average molar ratios of alpha:beta, alpha:MxaJ, and beta:MxaJ in type II MDH were approximately 1:0.99, 1:0.41 and 1:0.42, respectively. Based on these results, the original conformation of the MDH of M. aminisulfidivorans MP(T) is most likely the alpha(2)beta(2)-MxaJ complex. During purification, the lysozyme and freeze-thawing cell disruption method significantly increased the amount of type II MDH in the soluble fraction compared with strong physical disruption methods such as sonication and French Press. PMID- 21656819 TI - Characterization of a novel thioesterase (PtTE) from Phaeodactylum tricornutum. AB - The Phaeodactylum tricornutum (P. tricornutum) thioesterase PtTE was encoded by a 648 bp open reading frame. The deduced 216 amino acids showed no similarity with plant acyl-acyl carrier protein (ACP) thioesterases and bacterial thioesterases. Southern blot analysis revealed that one copy of PtTE was present in the P. tricornutum genome, and Real-time quantitative PCR showed that PtTE was up regulated upon nitrogen deprivation. Thioesterase activity of PtTE was established by heterologous expression of PtTE cDNA in Escherichia coli (E. coli) XL1-Blue and K27fadD88, a mutant strain of fatty acid beta-oxidation pathway. The substrate specificity of PtTE was determined by fatty acid profile analyses of the culture supernatant and membrane lipid of recombinant strains. Recombinant PtTE in E.coli enhanced total fatty acid content of XL1-Blue by 21%, and also changed the fatty acid compositions of membrane lipid and culture supernatant. These changes were directed predominantly towards C18:0 and C18:1 fatty acids. Overexpression of PtTE alone in P. tricornutum did not alter the fatty acid composition of P. tricornutum, but enhanced total fatty acid content by 72%. This novel thioesterase gene shows its potential in metabolic engineering for enhancing lipid yield of microalgae. This is so far the first report of thioesterase from eukaryotic microalgae. PMID- 21656820 TI - Surface colonization by Azospirillum brasilense SM in the indole-3-acetic acid dependent growth improvement of sorghum. AB - The key to improving plant productivity is successful bacterial-plant interaction in the rhizosphere that can be maintained in the environment. The results presented here confirm Azospirillum brasilense strain SM as a competent plant growth promoting bacterium over mid- and long-term associations with sorghum. This study establishes that plant growth can be directly correlated with the associated bacterium's indole-3-acetic acid (IAA) production capability as IAA over-expressing variants, SMp30 and SMDeltai3-6 fared better than the wild type strain. The auxin antagonist, p-chlorophenoxy isobutyric acid confirmed the role of bacterial IAA in plant growth promotion and verified the presence of larger amount of IAA available to the seeds on inoculation with IAA over-expressing mutants. Microscopic analysis identified the bacterial association at root tips, root-shoot junction and elongation zone and their surface colonizing nature. Scanning electron microscopy identified larger number of root hairs and extensive exopolysaccharide covering in comparison to untreated ones. In addition, vibroid shaped Azospirilla attached by means of fibrillar material were dispersed along the elongation zone. The notable difference with IAA over-expressing variants was enhanced number of root hairs. Thus, the variant strains may be more efficient surface colonizers of the sorghum root and used as superior bio-inoculants for improving plant productivity. PMID- 21656821 TI - Effect of carbon source on polysaccharide production by alginate-entrapped Aureobasidium pullulans ATCC 42023 cells. AB - The production of the exopolysaccharide pullulan using entrapped cells of the fungus Aureobasidium pullulans ATCC 42023 was investigated relative to carbon source. Fungal cells grown on glucose or sucrose as a carbon source were entrapped in calcium alginate beads and found to be capable of synthesizing the polysaccharide for two production cycles. Using 2.5% glucose or sucrose as a carbon source, productivity was 18.3 or 21.9 mg polysaccharide/g cells * h, respectively after the initial production cycle and decreased to 9.6 or 8.5 mg polysaccharide/g cells * h, respectively, after the second production cycle. Independent of carbon source, the entrapped fungal cells exhibited a higher yield during the initial cycle than the second production cycle while the entrapped ATCC 42023 cells elaborated a polysaccharide with a higher pullulan content during the second production cycle compared to the initial production cycle. PMID- 21656822 TI - Requirements for sulfur in cell density-independent induction of luminescence in Vibrio fischeri under nutrient-starved conditions. AB - Despite the universal requirement for sulfur in living organisms, it is not known whether the luminescence of Vibrio fischeri is sulfur-dependent and how sulfur affects the intensity of its luminescence. In this study, we investigated the requirement for sulfur in V. fischeri luminescence under nutrient-starved conditions. Full induction of V. fischeri luminescence required MgSO(4); in artificial seawater cultures that lacked sufficient MgSO(4), its luminescence was not fully induced. This induction of luminescence was not dependent on autoinduction because the cell density of V. fischeri did not reach the critical threshold concentration. In addition to MgSO(4), this cell density-independent luminescence was induced or maintained by nontoxic concentrations of l-cysteine, sulfate, sulfite, and thiosulfate. Moreover, the addition of N -3-oxo-hexanoyl homoserine lactone and N -octanoyl homoserine lactone, which are known autoinducers in V. fischeri, did not induce luminescence under these conditions. This result suggested that the underlying mechanism of luminescence may be different from the known autoinduction mechanism. PMID- 21656823 TI - Prokaryotic diversity of an active mud volcano in the Usu City of Xinjiang, China. AB - The Usu mud volcanoes are the largest group of terrestrial mud volcanoes in China. The volcanoes are located in a typical arid and semi-arid region, and the group consists of 36 erupting active mud volcanoes. In this study, the prokaryotic diversity and community structure in the sediment of an active mud volcano were investigated by constructing bacterial and archaeal clone libraries of the 16S rRNA gene. A total of 100 bacterial and 100 archaeal clones were analysed and found to comprise 11 and 7 distinct phylotypes, respectively. The bacterial phylotypes were classified into three phyla (Proteobacteria, Actinobacteria, and Fusobacteria). Of these, Proteobacteria were the most abundant bacterial group, with Deltaproteobacteria dominating the sediment community, and these were affiliated with the order Desulfuromonadales. The archaeal phylotypes were all closely related to uncultivated species, and the majority of the members were related to the orders Methanosarcinales and Halobacteriales of the Euryarchaeota originating from methane hydrate bearing or alkaline sediments. The rest of the archaeal phylotypes belonged to the phylum Crenarchaeota, with representatives from similar habitats. These results suggested that a large number of novel microbial groups and potential methanogenesis may exist in this unique ecosystem. PMID- 21656825 TI - Reduced glycosylation of alpha-dystroglycans on carcinoma cells contributes to formation of highly infiltrative histological patterns in prostate cancer. AB - BACKGROUND: alpha-Dystroglycan (DG) carries glycan chains that bind to laminin and thus function in homeostasis of not only skeletal muscle but also of various epithelial cells. Loss of glycosylation has been suggested to play important roles in tumor development, particularly in detachment and migration of carcinoma cells. We previously reported that glycosylation of alpha-DG, but not levels of alpha-DG core protein itself, is reduced in prostate carcinoma. In this study, we investigate the association between reduction of laminin-binding glycans on alpha DG and the degree of tumor cell differentiation and/or infiltrative properties, as assessed by the Gleason grading system. METHODS: Immunohistochemical analysis of 146 biopsy specimens of prostate adenocarcinoma with various Gleason scores was carried out employing IIH6 and 6C1 antibodies, which recognize laminin binding glycans on alpha-DG and alpha-DG core proteins, respectively. Double immunofluorescence staining was performed to evaluate colocalization of alpha-DG and laminin, and to determine which types of epithelial cells express laminin binding glycans on alpha-DG. RESULTS: Reduction of alpha-DG glycosylation, rather than loss of alpha-DG core protein, was correlated with higher Gleason patterns. Reduction was most conspicuous at the interface between carcinoma cells and the basement membrane. In addition, in non-neoplastic prostate glands, laminin binding glycans were expressed predominantly on the basolateral surface of basal cells. CONCLUSIONS: Reduced expression of laminin-binding glycans on alpha-DG may contribute to formation of highly infiltrative behavior of prostate carcinoma cells. Substantial reduction of laminin-binding glycans in carcinoma tissue could be partly ascribed to disappearance of pre-existing basal cells. PMID- 21656824 TI - An inducible model of abacterial prostatitis induces antigen specific inflammatory and proliferative changes in the murine prostate. AB - BACKGROUND: Prostatitis is a poorly understood disease and increasing evidence suggests inflammation is involved in other prostatic diseases including prostate cancer. METHODS: The ability of pre-activated CD8 T cells to induce prostatitis was examined by adoptive transfer of prostate antigen specific CD8 T cells into POET-3 mice or POET-3/Luc/Pten(-/+) mice. Characterization of the inflammatory response was determined by examining leukocyte infiltration by histological analysis, flow cytometry and by evaluating cytokine and chemokine levels in prostate tissue. The impact of inflammation on the prostate was evaluated by monitoring epithelial cell proliferation over time. RESULTS: Initiation of inflammation by ovalbumin specific CD8+ T cells (OT-I cells) resulted in development of acute prostatitis in the anterior, dorsolateral and ventral prostate of POET-3 and POET-3/Luc/Pten(-/+) mice. Acute prostatitis was characterized by recruitment of adoptively transferred OT-I cells and importantly, autologous CD4+ and CD8+ T cells, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). In concert with leukocyte infiltration elevated levels of pro-inflammatory cytokines and chemokines were observed. Inflammation also resulted in marked epithelial cell proliferation that was sustained up to 80 days post adoptive transfer of OT-I cells. CONCLUSIONS: The POET-3 model represents a novel mouse model to study both acute and chronic prostate inflammation in an antigen-specific system. Further, the POET-3 mouse model can be crossed with other genetic models of disease such as the C57/Luc/Pten(-/-) model of prostate cancer, allowing the impact of prostatitis on other prostatic diseases to be evaluated. PMID- 21656826 TI - Resistance to docetaxel-induced apoptosis in prostate cancer cells by p38/p53/p21 signaling. AB - BACKGROUND: Taxane chemotherapy is one of the few therapeutic options for men with castration-resistant prostate cancer. However, the working mechanisms are not fully understood. We aimed to investigate the possible molecular mechanism of apoptosis induced by taxanes in prostate cancer. METHODS: The human LNCaP cells (bearing wild-type p53), DU145 cells (bearing mutant p53) and PC3 cells (lacking p53) were used. The expression levels of protein were determined by Western blot and the mRNA levels were determined by reverse transcriptase PCR. The apoptosis was measured by propidium iodide (PI) staining and flow cytometric analysis. RESULTS: LNCaP cells are more resistant to docetaxel than DU145 and PC3 cells. Knocking down p53 by small interference RNA (siRNA) sensitizes LNCaP cells to docetaxel treatment. Docetaxel stabilizes p53 protein level and upregulates p21 in a p53-dependent manner in LNCaP cells. Docetaxel increases p38 phosphorylation in LNCaP cells. Treatment with p38-specific inhibitor SB203580 or knocking down p38 by siRNA significantly impaired the upregulation of p53 and p21 by docetaxel. Knocking down p38 or p21 sensitizes LNCaP cells to docetaxel treatment and the antiapoptotic effect of p21 can be reversed by p38 siRNA in LNCaP cells. CONCLUSIONS: Stimulation of the p38/p53/p21 signaling axis could be important for regulating the susceptibility towards docetaxel in prostate cancer. PMID- 21656827 TI - CYP17 gene polymorphisms and prostate cancer risk: a meta-analysis based on 38 independent studies. AB - BACKGROUND: The results of recent published studies focusing on CYP17 polymorphisms in prostate cancer (PCa) susceptibility are often conflicting. We performed a meta-analysis based on 38 independent studies to evaluate the association. METHODS: Data were collected from the following electronic databases: PubMed, Excerpta Medica Database, and Chinese Biomedical Literature Database, with the last report up to September 2010. Meta-analysis was conducted in a fixed/random effect model. RESULTS: Thirty-eight independent studies including 34,782 cases and 38,626 controls on the association of CYP17 gene polymorphisms with PCa risk in different ethnic groups were identified. The meta analysis was performed for five polymorphisms: rs743572 (A1/A2, 38 studies), rs6162 (C/T, 3 studies), rs619824 (C/A, 4 studies), rs2486758 (T/C, 4 studies), and rs10883782 (A/G, 4 studies). When all groups were pooled, we did not detect the association of rs743572 polymorphism with PCa risk. In the subgroup analysis, a significant association of rs743572 polymorphism and PCa was found in Black population (A2/A2 vs. A1/A1 + A2/A1: OR = 1.70, 95% CI = 1.08-2.69, P = 0.02), but not in Caucasian or Asian population. For other polymorphisms, we found that rs619824 polymorphism was associated with a significant decreased risk of PCa (A vs. C: OR = 0.95, 95% CI = 0.92-0.99, P = 0.01), and rs2486758 polymorphism was associated with a significant increased risk of PCa (C vs. T: OR = 1.07, 95% CI = 1.03-1.12, P = 0.002). CONCLUSION: This meta-analysis suggests that rs743572 polymorphism is associated with PCa risk in Black population, but not in Caucasian or Asian population. Moreover, our study suggests that rs619824 and rs2486758 polymorphisms are associated with PCa risk. PMID- 21656828 TI - Prostate-derived Ets transcription factor (PDEF) is a potential prognostic marker in patients with prostate cancer. AB - BACKGROUND: Reduced expression of prostate-derived Ets transcription factor (PDEF) leads to morphologic change as well as increased migration and invasiveness of prostate cancer cells. However, the clinical relevance of PDEF expression and its relationship to anti-apoptotic protein survivin is yet to be determined. METHODS: Tissue microarrays of 73 prostate carcinomas and their adjacent benign prostate tissue, as well as 50 benign prostates were evaluated for PDEF expression by immunohistochemistry. Results were confirmed in available tumor tissues using Western blot and RT-PCR. Expression of survivin in prostate carcinoma and benign tissues were determined using Western blot. Results and correlation with clinical data were statistically analyzed. RESULTS: Patients' specimens with low Gleason scores (GS < 5) expressed higher levels of PDEF protein and lower levels of survivin protein when compared with moderate-to-high GS tumors (GS > 6). Patients with PDEF-positive tumor survived significantly longer (P < 0.0001) than patients with PDEF-negative tumor, and the 8-year survival rate was 94% and 40%, respectively. PDEF expression was detected at the highest levels in benign tissues and was down-regulated or lost in 30 recently diagnosed prostate carcinomas. Re-expression of PDEF in prostate cancer cells inhibited survivin expression. Treatment of prostate cancer cells with methylseleninic acid resulted in restoration of PDEF expression, down-regulation of survivin, and inhibition of tumor cell growth when compared with untreated controls (P < 0.05). CONCLUSIONS: These studies demonstrated an inverse correlation between PDEF and survivin expression, and that up-regulation of PDEF was associated with a favorable prognosis in patients with clinically localized prostate cancer. PMID- 21656829 TI - Impact of prostate-specific antigen (PSA) nadir and time to PSA nadir on disease progression in prostate cancer treated with androgen-deprivation therapy. AB - BACKGROUND: The influence of PSA kinetics on the outcome of metastatic prostate cancer after androgen deprivation therapy (ADT) is not well understood. We evaluated the prognostic significance of PSA nadir and time to PSA nadir as well as their potential interactive effect on the progression of disease after ADT. METHODS: A total of 650 men with advanced or metastatic prostate cancer treated with ADT were studied. The prognostic significance of PSA nadir and time to PSA nadir on disease progression were analyzed using Kaplan-Meier analysis and the Cox regression model. RESULTS: We found that both PSA nadir and time to PSA nadir were independent and significant predictors of disease progression. Patients with higher PSA nadir (>=0.2 ng/ml) and shorter time to PSA nadir (<10 months) had significant shorter time to disease progression after adjusting for other covariates. The combined analyses showed a potential synergistic effect of these two variables on disease progression. Patient with higher PSA nadir and shorter time to PSA nadir had significantly higher risk for disease progression compared to those with lower PSA nadir and longer time to PSA nadir (Hazard Ratios (HR) = 3.11, P < 0.001). CONCLUSIONS: We concluded that both PSA nadir and time to PSA nadir are significant predictors of disease progression for prostate cancer patients receiving ADT. PMID- 21656830 TI - Reactivation of embryonic nodal signaling is associated with tumor progression and promotes the growth of prostate cancer cells. AB - BACKGROUND: Nodal is a member of the transforming growth factor beta (TGFbeta) superfamily that directs embryonic patterning and promotes the plasticity and tumorigenicity of tumor cells, but its role in the prostate is unknown. The goal of this study was to characterize the expression and function of Nodal in prostate cancer and determine whether, like other TGFbeta ligands, it modulates androgen receptor (AR) activity. METHODS: Nodal expression was investigated using immunohistochemistry of tissue microarrays and Western blots of prostate cell lines. The functional role of Nodal was examined using Matrigel and soft agar growth assays. Cross-talk between Nodal and AR signaling was assessed with luciferase reporter assays and expression of endogenous androgen regulated genes. RESULTS: Significantly increased Nodal expression was observed in cancer compared with benign prostate specimens. Nodal was only expressed by DU145 and PC3 cells. All cell lines expressed Nodal's co-receptor, Cripto-1, but lacked Lefty, a critical negative regulator of Nodal signaling. Recombinant human Nodal triggered downstream Smad2 phosphorylation in DU145 and LNCaP cells, and stable transfection of pre-pro-Nodal enhanced the growth of LNCaP cells in Matrigel and soft agar. Finally, Nodal attenuated AR signaling, reducing the activity of a PSA promoter construct in luciferase assays and down-regulating the endogenous expression of androgen regulated genes. CONCLUSIONS: An aberrant Nodal signaling pathway is re-expressed and functionally active in prostate cancer cells. PMID- 21656831 TI - Parathyroid hormone is not involved in prostate growth in patients with benign prostatic hyperplasia. AB - BACKGROUND: A recent population-based study reported that serum calcium and parathyroid hormone stimulate prostate growth. We evaluated whether serum PTH, vitamin D, and calcium levels correlate with prostate size, PSA levels, and obesity in Korean patients with histologically proven BPH. METHODS: Patients with histopathologically proven BPH who underwent transurethral resection of the prostate were enrolled (n = 289). Patients with PSA levels of >=3 ng/ml underwent multicore transrectal prostate biopsy before TURP to rule out prostate cancer. Patients with serum creatinine levels >1.4 mg/dl, PSA levels >20 ng/ml, and/or PTH levels <10 pg/ml were excluded. Correlations between serum parameters and clinical data were determined. After adjustment for potential confounders, including age and body mass index, multiple linear regression served to compute associations. RESULTS: The mean age, serum PSA level, PTH level, and prostate size were 68.13 +/- 7.15 years, 4.10 +/- 3.88 ng/ml, 24.33 +/- 12.52 pg/ml, and 44.27 +/- 24.15 g, respectively. Prostate size correlated positively with age (r = 0.209, P < 0.001) and PSA levels (r = 0.481, P < 0.001), and PSA levels correlated positively with age (r = 0.226, P < 0.001) and prostate size (r = 0.481, P < 0.001), but neither variable correlated with PTH, vitamin D, calcium levels, or BMI. Upon multiple adjusted linear regression analysis, prostate size correlated with BMI and serum PSA (both P < 0.001), and serum PSA levels correlated with BMI and prostate size (P = 0.007, P < 0.001, respectively), but neither variable correlated with PTH, vitamin D, or serum calcium levels. CONCLUSIONS: In Korean patients with histopathologically proven BPH, high PTH, vitamin D, and calcium levels do not stimulate prostate growth. PMID- 21656832 TI - Loss of EGFR induced autophagy sensitizes hormone refractory prostate cancer cells to adriamycin. AB - BACKGROUND: The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is over-expressed in advanced prostate cancer but tyrosine kinase inhibitors are not clinically effective in the treatment of prostate cancer. Recently it was found that EGFR in cancer cells has a kinase-independent pro survival function, preventing cells from undergoing autophagy. In the present study we investigated whether the anti-autophagic function of EGFR may contribute to resistance of hormone-refractory prostate cancer cells to chemotherapeutic induced apoptosis. METHODS: We first characterized the autophagic phenotype induced by knocking down EGFR in hormone refractory prostate cancer cells (PC 3MM2 and DU-145), then we tested whether loss of EGFR-induced autophagy could sensitize cancer cells to adriamycin. RESULTS: Using continuous live cell imaging techniques, we observed that knocking down EGFR lead to typical autophagic morphological/molecular changes, cell shrinkage without detachment, aggregation of microtubule-associated protein 1 light chain 3 (LC3) protein and absence of activation of apoptotic caspases 3/7. Loss of EGFR also increased the activity of calpain, which is pro-apoptotic. Knocking down EGFR, but not inhibiting its tyrosine kinase activity, significantly sensitized cells to adriamycin-induced apoptosis. Adriamycin-induced apoptosis could be inhibited by increased extracellular glucose level, suggesting intracellular glucose deficiency is a key mediator of the sensitization. The loss of EGFR induced autophagy and sensitization to adriamycin were also reproduced by using another hormone refractory prostate cancer cell line, Du145. CONCLUSION: Taken together, these data suggest that decreasing the expression level of EGFR protein, rather than inhibiting its tyrosine kinase activity, may enhance the efficiency of EGFR targeted therapy for prostate cancer. PMID- 21656833 TI - Long-term cryopreservation of pyramidalis muscle specimens as a source of striated muscle stem cells for treatment of post-prostatectomy stress urinary incontinence. AB - BACKGROUND: Stem-cell injection into the degenerated external urethral sphincter is a new treatment modality for stress urinary incontinence (SUI). We examined the possibility of long-term cryopreserved pyramidalis muscle (PM) specimens as a source of striated muscle stem cells for the treatment of post-prostatectomy SUI. METHODS: PM specimens were obtained from five male patients (mean age, 61-70 years) who underwent radical prostatectomy for prostate cancer. Specimens (volume, approximately 125 mm3 ) were obtained from the incisional edge, minced, and stored at -80 degrees C in a freezing medium (Cell Banker 1(r)). After 24-60 months, the specimens were thawed and directly incubated at 37 degrees C. Satellite cells were selectively cultured by magnetic affinity cell sorting using an anti-neural cell adhesion molecule (NCAM) antibody. Osteogenic and adipogenic differentiation were induced by bone morphogenic protein-7 (BMP-7) and gamma linolenic acid, respectively. RESULTS: NCAM-positive cells (>99% purity) were selectively cultured from all cryopreserved PM specimens and confirmed as being of striated muscle origin by the expression of desmin and MyoD. They fused and differentiated into multinucleated myotubes 7 days after incubation in a differentiation induction medium. Stimulation by BMP-7 and gamma-linolenic acid induced expression of alkaline phosphatase (osteoblast marker) and lipid deposition within the cytoplasm (adipocyte characteristic), respectively. CONCLUSIONS: Long-term cryopreserved PM specimens can be used to culture muscle stem cells. Therefore, this method may be utilized for SUI treatment when necessary. Moreover, complete remove of the prostate gland without fear of injury to the urethral sphincter may be possible in patients with apical cancer or T3 prostate cancer. PMID- 21656834 TI - TM4SF1, a novel primary androgen receptor target gene over-expressed in human prostate cancer and involved in cell migration. AB - BACKGROUND: The Androgen Receptor (AR) plays a key role in controlling prostate gland homeostasis and contributes to prostate carcinogenesis. The identification of its target genes should provide new candidates that may be implicated in cancer initiation and progression. METHODS: Transcriptomic experiments and chromatin immunoprecipitation were combined to identify direct androgen regulated genes. Real-time quantitative PCR (RT-qPCR) analyses were performed to measure TM4SF1 mRNA levels in prostate cancer and benign prostatic hyperplasia (BPH) specimens. Immunohistochemical methods were used to compare TM4SF1 protein expression profiles in the same cohort. A targeted siRNAs knockdown strategy was used, prior to wound healing assays, to analyze the role of TM4SF1 in cell migration in vitro. RESULTS: We demonstrate for the first time that TM4SF1 is a direct target gene of the AR, a transcription factor of the steroid nuclear receptor family. A functional androgen response element was identified in the promoter region of the gene. In addition, TM4SF1 mRNA expression was higher in cancer samples compared to BPH tissues. The TM4SF1 protein mediates cell motility of prostate cancer cells where it is predominantly localized in the cytoplasm, in contrast to its apical membrane localization in normal prostate epithelial cells. CONCLUSIONS: Our results reveal a novel function for TM4SF1 in AR signaling. The TM4SF1 mRNA expression is higher in prostate cancer tissues as compared to BPH samples. Inhibition of cell migration after targeted knockdown of TM4SF1 protein expression suggests its contribution to prostate cancer cell metastasis. PMID- 21656835 TI - Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth. AB - BACKGROUND: Interference of androgen receptor (AR) signaling is a target for prostate cancer (CaP) chemoprevention and treatment. We hypothesize that Zyflamend (ZYF) assert its anti-cancer effect by disrupting AR signaling. We also hypothesize that it may act synergistically with the anti-androgen bicalutimde to inhibit CaP cell growth. METHODS: Western blotting, ELISA and reporter assays were done to test ZYF on AR signaling. Semi-quantitative RT-PCR and AR half-life were also examined. Potential synergism between ZYF and bicalutimide were tested via cytotoxicity, colony formation assays, flow cytometry, and Western blotting in the human CAP line, LNCaP and 22RV1. RESULTS: ZYF reduced AR protein, mRNA and protein stability levels in LNCaPs. ZYF also reduced both full-length AR protein and truncated AR protein in the 22Rv1 cell line. Nkx3.1 and PSA were also reduced at the mRNA level. PSA promoter activity and secretion were lower after treatment of cells with ZYF. DHT induction of cell proliferation and AR responsiveness revealed reduction of AR, Nkx3.1, and PSA protein were demonstrated with ZYF treatment. Co-treatment with bicalutimide reducing cell growth, induced apoptosis, and reduced Bcl-2 and BclxL, caspase-3 and PARP. Co-treatment also reduced Nkx3.1 and PSA protein. CONCLUSIONS: These data indicate that ZYF suppresses cell growth mediated by AR signaling, and suggests that the co treatment with the anti-androgen bicalutimide and ZYF may be a promising approach for cancer therapy and may demonstrate the mechanism of action of ZYF. PMID- 21656836 TI - Claudin-4-targeted therapy using Clostridium perfringens enterotoxin for prostate cancer. AB - BACKGROUND: Clostridium perfringens enterotoxin (CPE) triggers lysis of epithelial cells through binding to tight-junction proteins claudin-3 (Cldn3) and Cldn4, which are over-expressed in prostate cancer. We investigated the potential of Cldn-targeted therapy using CPE. METHODS: We investigated the expression levels and subcellular localization of Cldn3 and Cldn4 in primary human prostate cancer tissues, human prostate cancer cell lines (22Rv1, DU145, and PC3) and normal human prostate epithelial cells (PrECs). Cytotoxic effects of CPE on these cells were examined by colorimetric assay. We studied whether knockdown of Cldn3 and/or Cldn4 expression using RNA interference influenced CPE-mediated cytotoxicity. The therapeutic effect of CPE was evaluated in PC3 xenografts in athymic mice. RESULTS: Cldn4 and Cldn3 were expressed in primary human prostate cancer tissues, 22Rv1, DU145, and PC3. Cldn4 protein was expressed in PrEC. Cldn4 was distributed along whole cell membranes of the cancer cell lines, whereas it was localized at tight junctions in PrEC. CPE-mediated cytotoxicity was greatly detected in PC3, but was hardly detectable in PrEC. Reduced expression of Cldn4, but not Cldn3, led to remarkable decreases of cytotoxicity in both PC3 and 22Rv1. The injection of CPE around PC3 xenografts significantly suppressed tumor growth. CONCLUSION: CPE-mediated cytotoxicity was observed in human prostate cancer cell lines, but barely detected in normal human PrECs. The cytotoxic effect depended not only on the expression level of Cldn4 protein but also on its subcellular localization. These results suggest that Cldn4-targeted therapy using CPE may be a new treatment for prostate cancer. PMID- 21656837 TI - Adenosine induces cell-cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines, LNcap-FGC-10, DU-145, and PC3. AB - BACKGROUND: Adenosine has been shown to inhibit cell growth and induce apoptosis in the several cancer cells via intrinsic and extrinsic pathway. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis in the DU-145, PC3, and LNcap-FGC10 human prostate cancer cells. METHODS: To observe cell viability and proliferation, MTT assay, cell counting, and BrdU assay were carried out in DU-145, PC3, and LNcap-FGC10 cells. Apoptosis was assessed with the analysis of cell cycle, Hoechst 33258 staining, propidium iodide and annexin-V staining, reactive oxygen species (ROS) formation, mitochondrial membrane potential (DeltaPsiM) measurement, caspase-3 activity assay, Bcl-2 and Bax protein expression. Moreover, the expression of adenosine receptors and the effects of adenosine receptor (A(1) , A(2a) , and A(3) ) antagonists were examined. RESULT: Adenosine significantly reduced cell proliferation in a dose-dependent manner in DU-145, PC3, and LNcap-FGC10 cell lines. Adenosine induced arrest in the cell-cycle progression in G0/G1 phase through Cdk4/cyclinD1-mediated pathway. Adenosine induced apoptosis, which was determined by morphological changes and increased sub-G1 population. Furthermore, increase of ROS, loss of MMP, activation of caspase-3, and down-regulation of Bcl 2 expression was observed. A(1) , A(2a) , A(2b) , and A(3) adenosine receptors mRNA are expressed in the cell lines. Moreover, adenosine-induced apoptosis was inhibited by MRS1220, A(3) adenosine receptor antagonist. CONCLUSION: Our results suggest that adenosine induced apoptosis in prostate cancer cells via the mitochondrial pathway and is related to the adenosine receptors. These data might suggest that adenosine could be used as an agent for the treatment of prostate cancer. PMID- 21656839 TI - Prevalence of musculoskeletal disorders and job exposure in Taiwan oyster shuckers. AB - BACKGROUND: Oyster shucking is characterized by long hours of static work, awkward working posture, and highly repetitive hand/wrist motion. The objectives of this study were to investigate the prevalence of musculoskeletal discomfort and kyphosis in oyster shuckers in Taiwan as well as the biomechanical features of oyster shucking. METHODS: The Chinese version of the Standardized Nordic Musculoskeletal Questionnaire was successfully collected from 234 oyster shuckers. The characteristics of workstation, hand/wrist motion angles, and muscular exertion in shucking oysters were recorded. Measurements to identify kyphosis were also taken from the subjects and a control group. RESULTS: Among the participated oyster shuckers, low back (75.2%), hand/wrist (60.3%), shoulder (44.0%), and elbow (27.8%) discomfort were reported most frequently. The prevalence of low back discomfort in oyster shuckers was higher than various groups of workers who need long hours of seated position. Those who worked on tables had fewer musculoskeletal complaints in shoulder and elbow (P < 0.05) than those not. Additionally, oyster shuckers were more prone to kyphosis than the general population (P < 0.001). CONCLUSIONS: Oyster shuckers are observed to have high prevalence of musculoskeletal discomfort and kyphosis. Introduction of ergonomic design to oyster shucking workshops is strongly suggested. PMID- 21656838 TI - Tobacco use among firefighters in the central United States. AB - BACKGROUND: This study provides a comprehensive, population-based examination of tobacco use among both career and volunteer firefighters. METHODS: Data are from a population-based cohort study of randomly selected career (N = 11) and volunteer (N = 13) departments comprised of 677 male firefighters. RESULTS: Unadjusted rates of smoking were 13.6% and 17.4% for career and volunteer firefighters, respectively. Smoking rates were less than a comparable occupational group (military personnel) and adult males in the states represented. Smokers were more likely to have been diagnosed with an anxiety disorder (OR = 5.8; P = 0.010), have an elevated CAGE alcohol problem score (OR = 2.9; P = 0.040), and more likely to report driving after drinking too much (OR = 4.5; P = 0.020) compared to never-smokers. Large percentages of career (18.4%) and volunteer (16.8%) firefighters used smokeless tobacco. CONCLUSIONS Smoking among firefighters is associated with other significant health and safety risks. High rates of smokeless tobacco use suggest that the fire service is an important target for intervention. Thus, despite strong statements against smoking by the fire service, the need to maintain high levels of health and fitness and relatively low smoking rates, a significant proportion of firefighters continue to use tobacco products. PMID- 21656840 TI - Flexible and conservative features of social systems in tufted capuchin monkeys: comparing the socioecology of Sapajus libidinosus and Sapajus nigritus. AB - Socioecological models assume that primates adapt their social behavior to ecological conditions, and predict that food availability and distribution, predation risk and risk of infanticide by males affect patterns of social organization, social structure and mating system of primates. However, adaptability and variation of social behavior may be constrained by conservative adaptations and by phylogenetic inertia. The comparative study of closely related species can help to identify the relative contribution of ecological and of genetic determinants to primate social systems. We compared ecological features and social behavior of two species of the genus Sapajus, S. nigritus in Carlos Botelho State Park, an area of Atlantic Forest in Sao Paulo state, and S. libidinosus in Fazenda Boa Vista, a semi-arid habitat in Piaui state, Brazil. S. libidinosus perceived higher predation risk and fed on clumped, high quality, and usurpable resources (fruits) all year round, whereas S. nigritus perceived lower predation risk and relied on evenly distributed, low-quality food sources (leaves) during periods of fruit shortage. As predicted by socioecology models, S. libidinosus females were philopatric and established linear and stable dominance hierarchies, coalitions, and grooming relationships. S. nigritus females competed less often, and could transfer between groups, which might explain the lack of coalitions and grooming bonds among them. Both populations presented similar group size and composition and the same polygynous mating system. The species differed from each other in accordance with differences in the characteristics of their main food sources, as predicted by socioecological models, suggesting that phylogenetic inertia does not constrain social relationships established among female Sapajus. The similarity in mating systems indicates that this element of the social system is not affected by ecological variables and thus, is a more conservative behavioral feature of the genus Sapajus. PMID- 21656841 TI - Structure elucidation of native N- and O-linked glycans by tandem mass spectrometry (tutorial). AB - Oligosaccharides play important roles in many biological processes. However, the structural elucidation of oligosaccharides remains a major challenge due to the complexities of their structures. Mass spectrometry provides a powerful method for determining oligosaccharide composition. Tandem mass spectrometry (MS) provides structural information with high sensitivity. Oligosaccharide structures differ from other polymers such as peptides because of the large number of linkage combinations and branching. This complexity makes the analysis of oligosaccharide unique from that of peptides. This tutorial addresses the issue of spectral interpretation of tandem MS under conditions of collision-induced dissociation (CID) and infrared multiphoton dissociation (IRMPD). The proper interpretation of tandem MS data can provide important structural information on different types of oligosaccharides including O- and N-linked. PMID- 21656842 TI - Mass spectrometric analysis of long-chain lipids. AB - Electrospray and matrix assisted laser desorption ionization generate abundant molecular ion species from all known lipids that have long chain fatty acyl groups esterified or amidated to many different polar headgroup features. Molecular ion species include both positive ions from proton addition [M+H](+) and negative ions from proton abstraction [M-H](-) as well as positive ions from alkali metal attachment and negative ions from acetate or chloride attachment. Collisional activation of both MALDI and ESI behave very similarly in that generated molecular species yield product ions that reveal many structural features of the fatty acyl lipids that can be detected in tandem mass spectrometric experiments. For many lipid species, collision induced dissociation of the positive [M+H](+) reveals information about the polar headgroup, while collision induced dissociation of the negative [M-H](-) provides information about the fatty acyl chain. The mechanisms of formation of many of these lipid product ions have been studied in detail and many established pathways are reviewed here. Specific examples of mass spectrometric behavior of several molecular species are presented, including fatty acids, triacylglycerol, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, ceramide, and sphingomeylin. PMID- 21656844 TI - Neurotensin regulates cortical glutamate transmission by modulating N-methyl-D aspartate receptor functional activity: an in vivo microdialysis study. AB - The aim of the present in vivo microdialysis study was to investigate whether the tridecapeptide neurotensin (NT) influences the N-methyl-D-aspartate (NMDA) receptor-mediated increase of cortical glutamate transmission in freely moving rats. Intracortical perfusion with NT influenced local extracellular glutamate levels in a bell-shaped, concentration-dependent manner. One hundred and three hundred nanomolar NT concentrations increased glutamate levels (151% +/- 7% and 124% +/- 3% of basal values, respectively). Higher (1,000 nM) and lower (10 nM) NT concentrations did not alter extracellular glutamate levels. The NT receptor antagonist SR48692 (100 nM) prevented the NT (100 nM)-induced increase in glutamate levels. NMDA (100 and 500 MUM) perfusion induced a concentration dependent increase in extracellular glutamate levels, the lower 10 MUM NMDA concentration being ineffective. When NT (10 nM, a concentration by itself ineffective) was added in combination with NMDA (100 MUM) to the perfusion medium, a significant greater increase in extracellular glutamate levels (169% +/ 7%) was observed with respect to the increase induced by NMDA (100 MUM) alone (139% +/- 4%). SR48692 (100 nM) counteracted the increase in glutamate levels induced by the treatment with NT (10 nM) plus NMDA (100 MUM). The enhancement of cortical glutamate levels induced by NMDA (100 and 500 MUM) was partially antagonized by the presence of SR48692, at a concentration (100 nM) that by itself was ineffective in modulating glutamate release. These findings indicate that NT plays a relevant role in the regulation of cortical glutamatergic transmission, especially by modulating the functional activity of cortical NMDA receptors. A possible role in glutamate-mediated neurotoxicity is suggested. PMID- 21656845 TI - Chronic isolation stress predisposes the frontal cortex but not the hippocampus to the potentially detrimental release of cytochrome c from mitochondria and the activation of caspase-3. AB - Mitochondria are central integrators and transducers of proapoptotic signals for neuronal apoptosis. The tumor suppressor protein p53 can trigger apoptosis independently of its transcriptional activity, through subcellular translocation of cytochrome c and caspase activation. To define better the proapoptotic role of p53 under various stress conditions, we investigated the protein levels of p53 and cytochrome c in mitochondrial and cytosolic fractions, as well as caspase-3 activation and apoptosis, in the prefrontal cortex and hippocampus of male Wistar rats subjected to acute, chronic, or combined stressors. Mitochondrial p53 can suppress the antioxidant enzyme MnSOD, so its activity was also determined. In the prefrontal cortex, but not in hippocampus, increased protein levels of p53 were found in mitochondria, leading to cytochrome c release into cytoplasm, activation of caspase-3, and apoptotic cell death following combined stressors. Decreased mitochondrial MnSOD activity following combined stressors in both brain structures indicated a state of oxidative stress. This suggests that chronic isolation stress compromises mitochondrial MnSOD activity in both the prefrontal cortex and the hippocampus but likely results in mitochondrial-triggered proapoptotic signaling mediated by a transcription-independent p53 mechanism only in the prefrontal cortex. Thus, our data demonstrate a tissue-specific (prefrontal cortex vs. hippocampus) response to applied stressors. PMID- 21656846 TI - Radiographic diagnosis of metabolic bone disease in captive bred mountain chicken frogs (Leptodactylus fallax). AB - Asymptomatic captive bred and wild-caught mountain chicken frogs (Leptodactylus fallax) were radiographed for evidence of metabolic bone disease (MBD). All 22 captive bred frogs had multiple folding fractures of long bones, decreased bone density, and cortical thinning, whereas none of the 11 wild-caught frogs had any radiographic evidence of MBD. These findings suggest that the nutritional requirements of L. fallax need to be examined for captive management purposes. PMID- 21656847 TI - Age class differences in the feeding behavior of captive Japanese macaques (Macaca fuscataia) in the forested and nonvegetated enclosure groups. AB - Age class differences in feeding behavior of primates are affected by many factors, including feeding competition, foraging skills, habitat type, food abundance and distribution, body mass, and food types. Two captive groups of Japanese macaques (Macaca fuscata), one housed in a forested enclosure and the other in a nonvegetated enclosure, were studied to examine the effect of environmental enrichment on age class differences in feeding behavior. Although there was no significant age class difference in time spent feeding on provisioned foods in either enclosure, the feeding rate (intake of unit food/minute) of adults consuming provisioned monkey chow was significantly higher than that of immatures in both enclosures, and was faster for both age groups in the nonvegetated than in the forested enclosure. Overall, feeding time was greatly extended for individuals of both age classes in the forested enclosure compared with their counterparts in the nonvegetated enclosure. Immatures in the forested enclosure utilized a significantly greater number of plant species and food items, exploiting many food items available among the terminal branches, and spent significantly more time feeding than adults. Perhaps constrained by larger body size, adults fed more often on the ground or middle height of the trees, likely reducing competition over plant food resources between adults and immatures. The natural vegetation played an important role in extending feeding time and segregating substrate use during feeding by adults and immatures. This study revealed the benefits concerning environmental enrichment of a naturally forested enclosure, which provides captive primates the opportunity to exhibit age class and species-typical feeding behaviors of importance for their dietary maintenance and general health. PMID- 21656848 TI - The effect of feeding enrichment methods on the behavior of captive Western lowland gorillas. AB - Three feeding enrichment treatments were tested in an outdoor yard used by six Western lowland gorillas (Gorilla gorilla gorilla). In "Yard-toss," forage was thrown by hand over one third of the yard. In "Set-up," forage and browse were hand-scattered throughout the yard. "Set-up Enriched" was similar with the addition of either a hay- and forage-filled feeder or forage-filled boomer ball(s) suspended from a climbing structure. Each treatment was presented on 5 d. Behavior was recorded for 30 min before (baseline) and 30 min after the start of each treatment. All treatments led to more foraging and less inactivity compared with baseline (P80.05), but Yard-toss was the least effective, likely because resources were clumped and monopolized by dominant animals. In Set-up Enriched, dominant animals had the greatest increase in foraging (P=0.03), partly because they generally monopolized the suspended items, but this allowed others to forage at ground level. This separation of the animals likely explains why Set-Up Enriched led to more foraging than all other treatments (P80.05). Findings show that for these hierarchical animals, enrichment resources are most effective when distributed widely, including vertically, and that enrichment strategies must take social structure into account. PMID- 21656849 TI - Quantifying intra-osseous growth of osteosarcoma in a murine model with radiographic analysis. AB - The orthotopic murine osteosarcoma model is an excellent representation of the human condition as mice develop rapid growth of 'primary' tumor with subsequent lung metastasis. Currently, monitoring tumor growth relies on measuring pulmonary metastases occurring four weeks post injection. Studies show that amputation of the tumor-bearing limb is required before pulmonary metastases are detectable due to rapid growth causing morbidity. Thus, a method measuring 'primary' tumor growth independent of metastasis is required. We hypothesized that serial radiography would allow for longitudinal quantification of 'primary' osteosarcoma growth and explored this idea by utilizing the tibial orthotopic model. Tumor growth was monitored weekly by radiography and calipers, and results were compared with uCT and histology. We found that radiographs demonstrate extra and intra-osseous tumor growth by displaying lytic and blastic lesions and the surrounding radio-opaque area enlarged significantly (p < 0.0001) allowing for quantification. Additionally, radiographs proved more precise than indirect caliper measurements (intra-observer error +/-6.64%: inter-observer error +/ 15.84%). Therefore, we determined that radiography provides accurate, longitudinal quantification of 'primary' osteosarcoma tumor that can be performed serially in the same mouse, does not require introduction of bioluminescence to the host or cell, and is more precise than the current caliper method. PMID- 21656850 TI - The effect of laterally wedged shoes on the loading of the medial knee compartment-in vivo measurements with instrumented knee implants. AB - A conventional method to unload the medial compartment of patients with gonarthrosis and thus to achieve pain reduction is the use of laterally wedged shoes. Our aim was to measure in vivo their effect on medial compartment loads using instrumented knee implants. Medial tibio-femoral contact forces were measured in six subjects with instrumented knee implants during walking with the following shoes: without wedge, with 5 and 10 mm wedges under the lateral sole, and with a laterally wedged insole (5 mm). Measurements were repeated with the shoes in combination with an ankle-stabilizing orthosis. Without orthosis, peak medial forces were reduced by only 1-4% on average. With orthosis, the average reduction was 2-7%. Highest reductions were generally observed with the 10 mm wedge, followed by the 5 mm wedge, and the 5 mm insole. Individual force reductions reached up to 15%. Medial force reductions while walking with wedged shoes were generally small. Due to high inter-individual differences, it seems that some patients might benefit from lateral wedges, whereas others might not. Further analyses of the individual kinematics will show which factors are most decisive for the reduction of medial compartment load. PMID- 21656851 TI - Clinical features, with video documentation, of the original familial lewy body parkinsonism caused by alpha-synuclein triplication (Iowa kindred). PMID- 21656852 TI - Tremor during movement correlates well with disability in people with essential tremor. AB - Essential tremor is the most common movement disorder, typically characterized by the presence of both postural and kinetic tremor of the hand. In recent studies, we described the effects of altering force and load conditions on tremor amplitude and power in people with essential tremor. In the same participants, we also measured tremor-related functional disability. In this article we report on the current study on correlations of measures of tremor severity with those of tremor-related functional disability. Twenty-one participants with essential tremor had tremor measured in their more tremorous hand. Power spectral and amplitude measures of tremor were calculated for each of 16 conditions: force tremor at 4 submaximal force levels, postural tremor in unloaded and 3 submaximal load conditions, and kinetic tremor in unloaded and 3 submaximal load conditions for each of concentric and eccentric contractions of the wrist extensors. Participants were rated on the hand items of the Fahn-Tolosa-Marin rating scale and timed on the unilateral hand tasks of the Test Evaluant la Performance des Membres superieurs des Personnes Agees. The most consistently high and significant correlations were found between kinetic tremor measures and the hand task scores and tremor-B scores (r = 0.548-0.780, P < .01). Postural tremor measures correlated with disability measures only in loaded conditions, most consistently with the hand task measures (r = 0.640-0.725, P < .01). Thus, measures of kinetic tremor and loaded postural tremor, but not unloaded postural tremor or force tremor, relate well to disability captured with dynamic tasks. PMID- 21656853 TI - Long-term efficacy and mortality in Parkinson's disease patients treated with subthalamic stimulation. AB - BACKGROUND: The objective of this study was to examine the clinical outcome and mortality of long-term deep brain stimulation of the subthalamic nucleus in advanced Parkinson's disease. METHODS: We included all 144 patients (mean age, 60.3 years; mean disease duration, 11.0 years) treated in our center from 2001 to 2007. RESULTS: Twelve months after surgery, the off-medication Unified Parkinson's Disease Rating Scale motor score was reduced by a mean of 53%, and the annual increase after surgery was 3.2 points. The daily dose of dopaminergic medication was reduced by a mean of 49% and increased only marginally during follow-up. Twelve of the 144 patients died in the study period, including 2 suicides (1.4%). Survival was 97% after 3 years and 90% after 5 years. CONCLUSIONS: The study confirms the stable efficacy of long-term subthalamic stimulation in selected patients with advanced Parkinson's disease. Throughout the study the patient characteristics at time of surgery changed, with less severe disease and shorter disease duration toward the end of the study period. PMID- 21656854 TI - SNARE protein expression in synaptic terminals and astrocytes in the adult hippocampus: a comparative analysis. AB - Several evidences suggest that astrocytes release small transmitter molecules, peptides, and protein factors via regulated exocytosis, implying that they function as specialized neurosecretory cells. However, very little is known about the molecular and functional properties of regulated secretion in astrocytes in the adult brain. Establishing these properties is central to the understanding of the communication mode(s) of these cells and their role(s) in the control of synaptic functions and of cerebral blood flow. In this study, we have set-up a high-resolution confocal microscopy approach to distinguish protein expression in astrocytic structures and neighboring synaptic terminals in adult brain tissue. This approach was applied to investigate the expression pattern of core SNARE proteins for vesicle fusion in the dentate gyrus and CA1 regions of the mouse hippocampus. Our comparative analysis shows that astrocytes abundantly express, in their cell body and main processes, all three protein partners necessary to form an operational SNARE complex but not in the same isoforms expressed in neighbouring synaptic terminals. Thus, SNAP25 and VAMP2 are absent from astrocytic processes and typically concentrated in terminals, while SNAP23 and VAMP3 have the opposite expression pattern. Syntaxin 1 is present in both synaptic terminals and astrocytes. These data support the view that astrocytes in the adult hippocampus can communicate via regulated exocytosis and also indicates that astrocytic exocytosis may differ in its properties from action potential dependent exocytosis at neuronal synapses, as it relies on a distinctive set of SNARE proteins. PMID- 21656855 TI - Schwann cells direct peripheral nerve regeneration through the Netrin-1 receptors, DCC and Unc5H2. AB - In the peripheral nervous system, Schwann cells (SCs) promote nerve regeneration by the secretion of trophic support molecules and the establishment of a supportive growth matrix. Elucidating factors that promote SC outgrowth following nerve injury is an important strategy for improving nerve regeneration. We identified the Netrin-1 receptors, Deleted in Colorectal Cancer (DCC) and Uncoordinated (Unc)5H2 as SC receptors that influence nerve regeneration by respectively promoting or inhibiting SC outgrowth. Significantly, we show both DCC and Unc5H2 receptors are distributed within SCs. In adult nerves, DCC is localized to the paranodes and Schmidt-Lantermann incisures of myelinating SCs, as well as along unmyelinated axons. After axotomy, DCC is prominently expressed in activated SCs at the regenerating nerve front. In contrast, Unc5H2 receptor is robustly distributed in myelinating SCs of the intact nerve and it is found at low levels in the SCs of the injury site. Local in vivo DCC siRNA mRNA knockdown at the growing tip of an injured nerve impaired SC activation and, in turn, significantly decreased axon regeneration. This forced DCC inhibition was associated with a dramatic reciprocal upregulation of Unc5H2 in the remaining SCs. Local Unc5H2 knockdown at the injury site, however, facilitated axon regrowth, indicating it has a role as an intrinsic brake to peripheral nerve regeneration. Our findings demonstrate that in adult peripheral nerves, SCs respond to DCC and Unc5H2 signaling, thereby promoting or hindering axon outgrowth and providing a novel mechanism for SC regulation during nerve regeneration. PMID- 21656857 TI - Morphological evidence for a transport of ribosomes from Schwann cells to regenerating axons. AB - Recently, we showed that Schwann cells transfer ribosomes to injured axons. Here, we demonstrate that Schwann cells transfer ribosomes to regenerating axons in vivo. For this, we used lentiviral vector-mediated expression of ribosomal protein L4 and eGFP to label ribosomes in Schwann cells. Two approaches were followed. First, we transduced Schwann cells in vivo in the distal trunk of the sciatic nerve after a nerve crush. Seven days after the crush, 12% of regenerating axons contained fluorescent ribosomes. Second, we transduced Schwann cells in vitro that were subsequently injected into an acellular nerve graft that was inserted into the sciatic nerve. Fluorescent ribosomes were detected in regenerating axons up to 8 weeks after graft insertion. Together, these data indicate that regenerating axons receive ribosomes from Schwann cells and, furthermore, that Schwann cells may support local axonal protein synthesis by transferring protein synthetic machinery and mRNAs to these axons. PMID- 21656858 TI - Reactive Zr(IV) and Hf(IV) butterfly peroxides on polyoxometalate surfaces: bridging the gap between homogeneous and heterogeneous catalysis. AB - At variance with previously known coordination compounds, the polyoxometalate (POM)-embedded Zr(IV) and Hf(IV) peroxides with formula: [M(2)(O(2))(2)(alpha XW(11)O(39))(2)](12-) (M=Zr(IV), X=Si (1), Ge (2); M=Hf(IV), X=Si (3)) and [M(6)(O(2))(6)(OH)(6)(gamma-SiW(10)O(36))(3)](18-) (M=Zr(IV) (4) or Hf(IV) (5)) are capable of oxygen transfer to suitable acceptors including sulfides and sulfoxides in water. Combined (1)H NMR and electrochemical studies allow monitoring of the reaction under both stoichiometric and catalytic conditions. The reactivity of peroxo-POMs 1-5 is compared on the basis of substrate conversion and kinetic. The results show that the reactivity of POMs 1-3 outperforms that of the trimeric derivatives 4 and 5 by two orders of magnitude. Reversible peroxidation of 1-3 occurs by H(2)O(2) addition to the spent catalysts, restoring oxidation rates and performance of the pristine system. The stability of 1-3 under catalytic regime has been confirmed by FT-IR, UV/Vis, and resonance Raman spectroscopy. The reaction scope has been extended to alcohols, leading to the corresponding carbonyl compounds with yields up to 99% under microwave (MW) irradiation. DFT calculations revealed that polyanions 1-3 have high-energy peroxo HOMOs, and a remarkable electron density localized on the peroxo sites as indicated by the calculated map of the electrostatic potential (MEP). This evidence suggests that the overall description of the oxygen-transfer mechanism should include possible protonation equilibria in water, favored for peroxo-POMs 1-3. PMID- 21656856 TI - CXCR2 signaling protects oligodendrocyte progenitor cells from IFN-gamma/CXCL10 mediated apoptosis. AB - Infiltration of activated lymphocytes into the central nervous system (CNS) is potentially harmful by damaging resident cells through release of cytokines. Among these is IFN-gamma that is secreted by activated natural killer (NK) cells and T lymphocytes and can exert a cytotoxic effect on resident glial populations including oligodendrocytes. Here we show that treatment of mouse oligodendrocyte progenitor cell (OPC)-enriched cultures with IFN-gamma resulted in a dose dependent increase in apoptosis. IFN-gamma-induced apoptosis is mediated, in part, through induction of the CXC chemokine ligand 10 (CXCL10; IP-10) from cultured OPCs. Treatment of OPCs with CXCL10 resulted in cell death in a concentration-dependent manner and IFN-gamma-treatment of CXCL10-/- OPCs resulted in >50% reduction in cell death. Further, treatment of CXCR3-/- OPC cultures with either IFN-gamma or CXCL10 resulted in reduced cell death supporting an important role for CXCL10 signaling in IFN-gamma-mediated OPC apoptosis. Data is also provided demonstrating that signaling through CXCR2 protects either IFN-gamma or CXCL10-treated OPC cultures from apoptosis and this effect is abolished in CXCR2 /- OPCs. CXCR2-mediated protection from apoptosis is associated with impaired cleavage of caspase 3 and elevated expression of the anti-apoptotic protein Bcl 2. These findings demonstrate a previously unappreciated role for CXCL10 in contributing to neuropathology by promoting oligodendrocyte apoptosis and emphasize the potential relevance in targeting CXCL10 in treating human demyelinating diseases including multiple sclerosis (MS). PMID- 21656859 TI - Stereodivergent ruthenium-catalyzed transfer semihydrogenation of diaryl alkynes. AB - [Ru(3)(CO)(12)]-catalyzed transfer semihydrogenation of various functionalized diaryl alkynes with N,N-dimethylformamide (DMF) and water as hydrogen source affords cis- and trans-stilbenes. The stereodivergent approach can be switched by the use of acetic (HOAc) or trifluoroacetic (TFA) acid as additives. The catalytic processes can be applied to the synthesis of analogues of natural products such as cis-combretastatin A-4 and trans-resveratrol. PMID- 21656860 TI - Controlled synthesis of noble metallic dimers and the influence of secondary metals on the catalytic activity. AB - To precisely discuss the influence of secondary metals on the whole nanosystem, two different types of Pd/Au dimers are constructed by reducing Au precursors with or without ascorbic acid. The number and size of gold nanoparticles attaching on larger Pd nanocrystals can be roughly controlled. Furthermore, based on electrocatalysis, we find that multidecorated dimers are generally more active than singly decorated ones. Meanwhile, the amount of Au precursor used in preparing multidecorated dimers is found to be very important to the catalytic activity of the as-prepared catalysts. The performance of the catalyst is enhanced with the increasing of Au precursor when the Au/Pd molar ratio is below 1:4, but hindered when the ratio climbs higher. Finally, this work provides a promising approach in forming hybrid nanocompositions to find an optimized amount of secondary metal, which is of significance in academic and economic fields. PMID- 21656861 TI - Coordination power adjustment of surface-regulating polymers for shaping gold polyhedral nanocrystals. AB - PVP (poly(vinyl pyrrolidone)) is a common polymer that behaves as a surface regulating agent that shapes metal nanocrystals in the polyol process. We have used different polymers containing tertiary amide groups, namely PVCL (poly(vinyl caprolactam)) and PDMAm (poly(N,N-dimethyl acrylamide)), for the synthesis of gold polyhedrons, including octahedrons, cuboctahedrons, cubes, and higher polygons, under the present polyol reaction conditions. The basicity and surface coordination power of the polymers are in the order of PVCL, PVP, and PDMAm. A correlation is observed between the coordination power of the polymers and the resulting gold nanocrystal size. Strong coordination and electron donation from the polymer functional groups to the gold surface restrict particle growth rates, which leads to small nanocrystals. The use of PVCL can yield gold polyhedral structures with small sizes, which cannot be achieved in the reactions with PVP. Simultaneous hydrolysis of the amide group in PDMAm leads to carboxylate functionality, which is very useful for generating chemical and bioconjugates through the formation of ester and amide bonds. PMID- 21656863 TI - Identification of a higher-order organozincate intermediate involved in Negishi cross-coupling reactions by mass spectrometry and NMR spectroscopy. AB - Negishi cross-coupling reactions were analyzed in solution by mass spectrometry and NMR spectroscopy to identify both the effect of LiBr as an additive as well as the purpose of 3-dimethyl-2-imidazolidinone (DMI) as a co-solvent. The results suggest that the main role of DMI is to facilitate a higher order bromozincate formation during the addition of LiBr. PMID- 21656862 TI - Intracellular protein labeling with prodrug-like probes using a mutant beta lactamase tag. AB - Intracellular protein labeling with small molecular probes that do not require a washing step for the removal of excess probe is greatly desired for real-time investigation of protein dynamics in living cells. Successful labeling of proteins on the cell membrane has been performed using mutant beta-lactamase tag (BL-tag) technology. In the present study, intracellular protein labeling with novel cell membrane permeable probes based on beta-lactam prodrugs is described. The prodrug-based probes quickly permeated the plasma membranes of living mammalian cells, and efficiently labeled intracellular proteins at low probe concentrations. Because these cell-permeable probes were activated only inside cells, simultaneous discriminative labeling of intracellular and cell surface BL tag fusion proteins was attained by using cell-permeable and impermeable probes. Thus, this technology enables adequate discrimination of the location of proteins labeled with the same protein tag, in conjunction with different color probes, by dual-color fluorescence. Moreover, the combination of BL-tag technology and the prodrug-based probes enabled the labeling of target proteins without requiring a washing step, owing to the efficient entry of probes into cells and the fast covalent labeling achieved with BL-tag technology after bioactivation. This prodrug-based probe design strategy for BL-tags provides a simple experimental procedure with application to cellular studies with the additional advantage of reduced stress to living cells. PMID- 21656864 TI - Asymmetric Mannich reaction of imines derived from aliphatic and aromatic aldehydes catalyzed by diarylprolinol silyl ether. PMID- 21656865 TI - Carbonyl coupling: defects and O2 make or break the essential reaction intermediate on titanium dioxide. PMID- 21656866 TI - Pulsed-wave tissue Doppler echocardiography for the analysis of fetal cardiac arrhythmias. AB - OBJECTIVES: Rhythm analysis of the fetal heart is hampered by the inability to routinely obtain electrocardiographic recordings of the fetus. Doppler studies of fetal cardiac tissue movements, assessing cardiac movements both qualitatively and quantitatively, have recently been described. We used a conventional high resolution ultrasound system to obtain rhythm data from pulsed-wave tissue Doppler signals of the fetal heart in normal cardiac rhythm and in a variety of fetal cardiac arrhythmias. METHODS: Fifty-five fetuses with normal (sinus) rhythm, 45 fetuses with rhythm disturbances and two neonates (one with arrhythmia and one with normal sinus rhythm) were studied. Using a conventional high resolution ultrasound system equipped for fetal studies, but without specific tissue Doppler hardware or software, we performed pulsed-wave tissue Doppler echocardiography (PW-TDE) of atrioventricular valve ring excursions to study the atrial and ventricular mechanical actions. In the neonates, electrocardiograms were also recorded. RESULTS: PW-TDE in normal fetuses shows a typical pattern of tissue motion parallel to the long axis of the heart and in the opposite direction to the blood flow, both in systole and diastole. This pattern is easily obtained from the tricuspid valve annulus in normal sinus rhythm and shows characteristic changes in various fetal arrhythmias. CONCLUSION: PW-TDE of atrioventricular valve annulus movement patterns may prove to be a valuable additional tool for assessing fetal cardiac arrhythmias. PMID- 21656867 TI - Three-dimensional ultrasonographic assessment of compression effect on urethra following tension-free vaginal tape and transobturator tape procedures. AB - OBJECTIVE: To compare the anatomical difference using three-dimensional (3D) ultrasound between the urethra at rest and during straining, in women who have undergone a tension-free vaginal tape (TVT) or TVT-obturator tape (TVT-O) procedure for stress urinary incontinence (SUI). METHODS: We reviewed retrospectively 48 women with SUI who had undergone either a TVT (n = 24) or a TVT-O (n = 24) procedure. All women underwent urinalysis, pelvic examination, pad test, 3D perineal ultrasonography and personal interview about urinary symptoms within 1 year after surgery. RESULTS: After both TVT and TVT-O procedures, the area and longest and shortest diameters of the hypoechoic core of the mid-urethra were significantly smaller during straining than during resting (P < 0.01). The distance between tape and urethra was similarly smaller during straining in both groups. Analysis of ultrasound measurements in women reporting success (n = 40) and those reporting failure (n = 8) of the procedure showed the area and longest and shortest diameters of the hypoechoic core of the mid-urethra to be significantly smaller during straining than during resting in both groups (P < 0.01). However, the shortest diameter of the proximal and distal urethra during straining were significantly smaller only in the successful group (P < 0.01). CONCLUSION: There are differences in urethral morphology during straining compared with during resting in women with TVT and those with TVT-O, regardless of tape procedure. A urethral compression effect of slings may have an important role in the continence mechanism. PMID- 21656868 TI - Comparison of transvaginal sonography and double-contrast barium enema for diagnosing deep infiltrating endometriosis of the posterior compartment. AB - OBJECTIVES: To compare the diagnostic accuracy of transvaginal sonography (TVS) and double-contrast barium enema (DCBE) in the preoperative detection of deep infiltrating endometriosis (DIE) of the posterior compartment. METHODS: This was a prospective study of 69 consecutive patients with results of pelvic examination or symptoms suggestive of DIE of the posterior compartment. TVS and DCBE were performed before surgery by two groups of physicians specialized in endometriosis, each blinded to the results of the other technique. Imaging data were compared with histopathologic analysis of the resected specimen (gold standard). Sensitivity, specificity, positive and negative predictive values and test accuracies were calculated for both imaging modalities. RESULTS: Sixty seven of the 69 women had a nodule of DIE confirmed at laparoscopy and histopathologic examination. TVS diagnosed DIE in 57 (85%) of these patients, while DCBE revealed the presence of the lesion in 24 (36%) women. For the diagnosis of posterior DIE, TVS and DCBE had, respectively, a sensitivity of 85% and 36%, specificity of 100% and 100%, positive predictive value of 100% and 100%, negative predictive value of 17% and 4% and accuracy of 85.5% and 38%. In patients with pure bowel DIE the sensitivity was 91% and 43%, specificity was 100% and 100%, positive predictive value was 100% and 100%, negative predictive value was 29% and 6% and accuracy was 91% and 45%, respectively. CONCLUSIONS: TVS has a much higher sensitivity than does DCBE in detecting the presence of posterior DIE and should thus be regarded as the imaging modality of choice when there is clinical suspicion of the disease. PMID- 21656869 TI - Identification and localization of the sperm CRISP family protein CiUrabin involved in gamete interaction in the ascidian Ciona intestinalis. AB - Ascidians are hermaphrodites, and most release sperm and eggs nearly simultaneously. Many species, including Halocynthia roretzi and Ciona intestinalis, are self-sterile. We previously reported that the interaction between a 12 EGF-like repeat-containing vitelline-coat (VC) protein, HrVC70, and a sperm GPI-anchored CRISP, HrUrabin, in lipid rafts plays a key role in self /nonself-recognizable gamete interaction in H. roretzi. On the other hand, we recently identified two pairs of polymorphic genes responsible for self incompatibility in C. intestinalis by positional cloning: The sperm polycystin 1 like receptors s-Themis-A/B and its fibrinogen-like ligand v-Themis-A/B on the VC. However, it is not known if the orthologs of HrVC70 and HrUrabin also participate in gamete interaction in C. intestinalis since they are from different orders. Here, we tested for a C. intestinalis ortholog (CiUrabin) of HrUrabin by searching the genome database and proteomes of sperm lipid rafts. The identified CiUrabin belongs to the CRISP family, with a PR domain and a GPI anchor-attachment site. CiUrabin appears to be specifically expressed in the testis and localized at the surface of the sperm head, as revealed by Northern blotting and immunocytochemistry, respectively. The specific interaction between CiVC57, a C. intestinalis ortholog of HrVC70, and CiUrabin was confirmed by Far Western analysis, similarly to the interaction between HrVC70 and HrUrabin. The molecular interaction between CiVC57 and CiUrabin may be involved in the primary binding of sperm to the VC prior to the allorecognition process, mediated by v Themis-A/B and s-Themis-A/B, during fertilization of C. intestinalis. PMID- 21656870 TI - Ca2+ signaling during maturation of cumulus-oocyte complex in mammals. AB - Under the influence of gonadotropins or growth factors, a close cooperation develops between cumulus cells and the oocyte that is implicated in transmitting signals involved in maintaining or releasing the meiotic arrest in the oocyte. While cyclic adenosine 5'-monophosphate (cAMP) is a key molecule in maintaining the meiotic arrest, calcium (Ca(2+)) may play a role in controlling either spontaneous or gonadotropin-induced oocyte maturation, possibly by modulating intracytoplasmic cAMP concentrations via Ca(2+)-sensitive adenylate cyclases. This review focuses on the mechanisms related to the origin of the Ca(2+) wave that travels from the cumulus cells to the oocyte, and discusses the source of variations affecting the dynamics of this wave. PMID- 21656871 TI - Aromatase is expressed and active in the rainbow trout oocyte during final oocyte maturation. AB - While it is generally well accepted that the ovarian follicular sites of estradiol-17beta (E2) synthesis are restricted to somatic cells, the possible contribution of the germinal compartment has received little or no attention in teleosts. In order to demonstrate the expression of ovarian aromatase in the oocyte, cyp19a1a mRNA was studied in ovarian follicles by in situ hybridization. In addition, the expression of cyp19a1a was studied in both somatic and germinal compartments of the ovarian follicle in rainbow trout (Oncorhynchus mykiss) during final oocyte maturation (i.e., maturational competence acquisition and subsequent meiosis resumption) by real-time PCR. The enzymatic activity of ovarian aromatase was also studied in both somatic and germinal compartments of the ovarian follicle. Finally, E2 levels were monitored in follicle-enclosed oocytes throughout the pre-ovulatory period. We were able to demonstrate a significant ovarian aromatase expression and activity in the late vitellogenic oocyte. Furthermore, a dramatic decrease in aromatase expression and activity occurs in the oocyte during late oogenesis, concomitantly with the trend observed in surrounding follicular layers. We also report an unexpected increase of E2 levels in the oocyte during the pre-ovulatory period. To our knowledge, these observations are reported for the first time in any teleost species. Together, our data support the hypothesis of the participation of the germinal compartment in follicular estrogen synthesis and a biological role of E2 during oocyte and/or early embryo development. PMID- 21656872 TI - Evidence for a virtual human analog of a rodent relational memory task: a study of aging and fMRI in young adults. AB - A radial maze concurrent spatial discrimination learning paradigm consisting of two stages was previously designed to assess the flexibility property of relational memory in mice, as a model of human declarative memory. Aged mice and young adult mice with damage to the hippocampus, learned accurately Stage 1 of the task which required them to learn a constant reward location in a specific set of arms (i.e., learning phase). In contrast, they were impaired relative to healthy young adult mice in a second stage when faced with rearrangements of the same arms (i.e., flexibility probes). This mnemonic inflexibility in Stage 2 is thought to derive from insufficient relational processing by the hippocampus during initial learning (Stage 1) which favors stimulus-response learning, a form of procedural learning. This was proposed as a model of the selective declarative and relational memory decline classically described in elderly people. As a first step to examine the validity of this model, we adapted this protocol to humans using a virtual radial-maze. (1) We showed that performance in the flexibility probes in young and older adults positively correlated with performance in a wayfinding task, suggesting that our paradigm assesses relational memory. (2) We demonstrated that older healthy participants displayed a deficit in the performance of the flexibility probes (Stage 2), similar to the one previously seen in aged mice. This was associated with a decline in the wayfinding task. (3) Our fMRI data in young adults confirmed that hippocampal activation during early discrimination learning in Stage 1 correlated with memory flexibility in Stage 2, whereas caudate nucleus activation in Stage 1 negatively correlated with subsequent flexibility. By enabling relational memory assessment in mice and humans, our radial-maze paradigm provides a valuable tool for translational research. PMID- 21656873 TI - Increased inhibition and enhancement of memory retrieval are associated with reduced hippocampal volume. AB - Putative control of encoding and retrieval processes have been linked to communication between the lateral prefrontal cortex (LPFC) and the hippocampus. Moreover, correlations between the LPFC (e.g., MFG) and hippocampus have predicted individuals' ability to inhibit memory retrieval. Anatomically, differences in volume of the hippocampus have been related to changes in long term episodic memories. Although the relationship between these ideas is clear, few studies have examined the association of how anatomy may affect the role of control over brain regions involved in distint memory processes. The current study sought to examine hippocampal volume and its relationship to LPFC control over the hippocampus. Using an automated cortical/subcortical segmentation technique (FIRST) on brain imaging gata from the Think/No-Think task, we show that hippocampal volume is associated to changes in both enhancement and inhibitory processes of memory retrival. PMID- 21656874 TI - Decoding representations of scenes in the medial temporal lobes. AB - Recent theoretical perspectives have suggested that the function of the human hippocampus, like its rodent counterpart, may be best characterized in terms of its information processing capacities. In this study, we use a combination of high-resolution functional magnetic resonance imaging, multivariate pattern analysis, and a simple decision making task, to test specific hypotheses concerning the role of the medial temporal lobe (MTL) in scene processing. We observed that while information that enabled two highly similar scenes to be distinguished was widely distributed throughout the MTL, more distinct scene representations were present in the hippocampus, consistent with its role in performing pattern separation. As well as viewing the two similar scenes, during scanning participants also viewed morphed scenes that spanned a continuum between the original two scenes. We found that patterns of hippocampal activity during morph trials, even when perceptual inputs were held entirely constant (i.e., in 50% morph trials), showed a robust relationship with participants' choices in the decision task. Our findings provide evidence for a specific computational role for the hippocampus in sustaining detailed representations of complex scenes, and shed new light on how the information processing capacities of the hippocampus may influence the decision making process. PMID- 21656876 TI - Chemistry with methane: concepts rather than recipes. AB - Four seemingly simple transformations related to the chemistry of methane will be addressed from mechanistic and conceptual points of view: 1) metal-mediated dehydrogenation to form metal carbene complexes, 2) the hydrogen-atom abstraction step in the oxidative dimerization of methane, 3) the mechanisms of the CH(4) >CH(3)OH conversion, and 4) the initial bond scission (C-H vs. O-H) as well as the rate-limiting step in the selective CH(3)OH->CH(2)O oxidation. State-of-the art gas-phase experiments, in conjunction with electronic-structure calculations, permit identification of the elementary reactions at a molecular level and thus allow us to unravel detailed mechanistic aspects. Where appropriate, these results are compared with findings from related studies in solution or on surfaces. PMID- 21656877 TI - Importance of ring puckering versus interstrand hydrogen bonds for the conformational stability of collagen. PMID- 21656875 TI - The POU transcription factor UNC-86 controls the timing and ventral guidance of Caenorhabditis elegans axon growth. AB - The in vivo mechanisms that coordinate the timing of axon growth and guidance are not well understood. In the Caenorhabditis elegans hermaphrodite specific neurons (HSNs), the lin-4 microRNA controls the stage of axon initiation independent of the UNC-40 and SAX-3 ventral guidance receptors. lin-4 loss-of-function mutants exhibit marked delays in axon outgrowth, while lin-4 overexpression leads to precocious growth in the L3 larval stage. Here, we show that loss of the POU transcription factor UNC-86 not only results in penetrant ventral axon growth defects in in the HSNs, but also causes processes to extend in the L1, three stages earlier than wild-type. This temporal shift is not dependent on UNC-40 or SAX-3, and does not require the presence of lin-4. We propose that unc-86(lf) HSN axons are misguided due to the temporal decoupling of axon initiation and ventral guidance responses. PMID- 21656878 TI - Biosensing platform based on fluorescence resonance energy transfer from upconverting nanocrystals to graphene oxide. PMID- 21656879 TI - The pentamethylcyclopentadienylsilicon(II) cation as a catalyst for the specific degradation of oligo(ethyleneglycol) diethers. PMID- 21656880 TI - Electrochemical signals of mitochondria: a new probe of their membrane properties. PMID- 21656882 TI - Synthesis of a palladium(IV) complex by oxidative addition of an aryl halide to palladium(II) and its use as precatalyst in a C-C coupling reaction. PMID- 21656881 TI - Alternative pathways for Heck intermediates: palladium-catalyzed oxyarylation of homoallylic alcohols. PMID- 21656884 TI - Hans-Dieter Arndt. PMID- 21656883 TI - Intramolecular pi-stacking interactions of bridged bis-p-phenylenediamine radical cations and diradical dications: charge-transfer versus spin-coupling. PMID- 21656885 TI - Kinetic control of one-pot trans-splicing reactions by using a wild-type and designed split intein. PMID- 21656889 TI - Fine tuning of a biological machine: DnaK gains improved chaperone activity by altered allosteric communication and substrate binding. AB - DnaK is a member of the Hsp70 family of molecular chaperones. This molecular machine couples the binding and hydrolysis of ATP to binding and release of substrate proteins. The switches that are involved in allosteric communication within this multidomain protein are mostly unknown. Previous insights were largely obtained by mutants, which displayed either wild-type activity or reduced folding assistance of substrate proteins. With a directed evolution approach for improved folding assistance we selected a DnaK variant characterized by a glycine to alanine substitution at position 384 (G384A); this resulted in a 2.5-fold higher chaperone activity in an in vitro DnaK-assisted firefly luciferase refolding assay. Quantitative biochemical characterization revealed several changes of key kinetic parameters compared to the wild type. Most pronounced is a 13-fold reduced rate constant for substrate release in the ATP-bound state, which we assume, in conjunction with the resulting increase in substrate affinity, to be related to improved chaperone activity. As the underlying mechanistic reason for this change we propose an altered interface of allosteric communication of mutant G384A, which is notably located at a hinge position between nucleotide and substrate binding domain. PMID- 21656887 TI - Abyssomicin biosynthesis: formation of an unusual polyketide, antibiotic-feeding studies and genetic analysis. PMID- 21656890 TI - Related (betaalpha)8-barrel proteins in histidine and tryptophan biosynthesis: a paradigm to study enzyme evolution. PMID- 21656891 TI - Defect-assisted covalent binding of graphene to an amorphous silica surface: a theoretical prediction. AB - We propose a mechanism for defect-assisted covalent binding of graphene to the surface of amorphous silica (a-SiO(2)) based on first-principles density functional calculations. Our calculations show that a dioxasilirane group (DOSG) on a-SiO(2) may react with graphene to form two Si-O-C linkages with a moderate activation barrier (~0.3 eV) and considerable exothermicity (~1.0 eV). We also examine DOSG formation via the adduction of molecular O(2) to a silylene center, which is an important surface defect in a-SiO(2) , and briefly discuss modifications in the electronic structure of graphene upon the DOSG-assisted chemical binding onto the a-SiO(2) surface. PMID- 21656892 TI - Changing the position of a bridged CH2 group at a fullerene cage surface in electrochemical synthesis: the case of C70 derivatives. AB - Electrochemical bridges: the electrochemical synthesis of bridged methylene derivatives of C(70) opens the route to the largest variety of such C(70) derivatives ever found. PMID- 21656893 TI - Triple resonance cross-polarization for more sensitive 13C MAS NMR spectroscopy of deuterated proteins. AB - Save the last WALTZ for me: the use of simultaneous proton and deuterium cross polarization for (13)C CPMAS NMR spectroscopy in highly deuterated proteins is discussed. The aim of the new method introduced herein, triple-resonance cross polarization, is to increase the sensitivity of the carbon-detected methods in such systems. PMID- 21656894 TI - Isolated gramicidin peptides probed by IR spectroscopy. AB - We report double-resonant IR/UV ion-dip spectroscopy of neutral gramicidin peptides in the gas phase. The IR spectra of gramicidin A and C, recorded in both the 1000 cm(-1) to 1800 cm(-1) and the 2700 to 3750 cm(-1) region, allow structural analysis. By studying this broad IR range, various local intramolecular interactions are probed, and complementary IR modes can be accessed. Ab initio quantum chemical calculations are used to support the interpretation of the experimental IR spectra. The comparison of the calculated frequencies with the experimental IR spectrum probed via the strong infrared absorptions of all the amide groups (NH stretch, C=O stretch and NH bend), shows evidence for a helical structure in the gas phase, which is similar to that in the condensed phase. Additionally, we show that to improve the spectral resolution when studying large neutral molecular structures of the size of gramicidin, the use of heavier carrier gas could be advantageous. PMID- 21656895 TI - Carbon monoxide oxidation on Pt single crystal electrodes: understanding the catalysis for low temperature fuel cells. AB - Herein the general concepts of fuel cells are discussed, with special attention to low temperature fuel cells working in alkaline media. Alkaline low temperature fuel cells could well be one of the energy sources in the next future. This technology has the potential to provide power to portable devices, transportation and stationary sectors. With the aim to solve the principal catalytic problems at the anode of low temperature fuel cells, a fundamental study of the mechanism and kinetics of carbon monoxide as well as water dissociation on stepped platinum surfaces in alkaline medium is discussed and compared with those in acidic media. Furthermore, cations involved as promoters for catalytic surface reactions are also considered. Therefore, the aim of the present work is not only to provide the new fundamental advances in the electrocatalysis field, but also to understand the reactions occurring at fuel cell catalysts, which may help to improve the fabrication of novel electrodes in order to enhance the performance and to decrease the cost of low temperature fuel cells. PMID- 21656896 TI - Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part 2: chemistry and biology of the cereal herbicide pinoxaden. AB - BACKGROUND: Pinoxaden is a new cereal herbicide that provides outstanding levels of post-emergence activity against a broad spectrum of grass weed species for worldwide selective use in both wheat and barley. RESULTS: Factors influencing activity and tolerance to pinoxaden were in part linked to distinct structural parts of the active ingredient. Three complementary contributions that decisively impact upon the herbicidal potency against grasses were identified: a preferred 2,6-diethyl-4-methyl aromatic substitution pattern, a dione area suitable for proherbicide formation and beneficial adjuvant effects. The uptake and translocation pattern of pinoxaden when coapplied with its tailored adjuvant were analysed by autoradiography, indicating extensive and rapid penetration, followed by effective distribution throughout the plant. Crop injury reduction on incorporation of the [1,4,5]oxadiazepane ring into the aryldione template was reinforced with safener technology. Comparative studies on the behaviour of pinoxaden applied either alone or in combination with the safener cloquintocet mexyl demonstrated that addition of the safener resulted in significant enhancement of metabolic degradation in wheat and barley, providing excellent crop tolerance and a substantial selectivity margin without adverse effects on weed control. CONCLUSION: The biological potential of pinoxaden and its active principle pinoxaden dione in terms of grass weed control and tolerance in cereals was fully exploited by inclusion of the safener cloquintocet-mexyl in the formulation in combination with a specific and tailor-made tank-mix adjuvant based on methylated rape seed oil. PMID- 21656897 TI - The phytotoxicity of natural tetramic acid derivatives. AB - Natural tetramic acid derivatives have attracted a great deal of interest of chemists because of their structural features and the broad range of biological activities. This paper focuses on five naturally occurring tetramic acid derivatives reported to have phytotoxicity and discusses their common structural characteristics. PMID- 21656898 TI - Esterase inhibition by synergists in the western flower thrips Frankliniella occidentalis. AB - BACKGROUND: Western flower thrips (WFT), Frankliniella occidentalis (Pergande), is among the most important crop pests in the south-eastern region of Spain. Its increasing resistance to insecticides constitutes a serious problem, and understanding the mechanisms involved is therefore of great interest. Use of synergists to inhibit the enzymes involved in insecticide detoxification is widely used to determine their responsibility for insecticide resistance. However, they do not always act as intended or expected, and caution must be exercised when interpreting synergist results. RESULTS: Laboratory-selected strains of WFT were used to analyse the effects of the synergists piperonyl butoxide (PBO), S,S,S-tributyl phosphorotrithioate (DEF) and methiocarb on total esterase activity. Significant differences were found, indicating esterase activity inhibition by DEF, a lower effect for methiocarb and a small inhibition of the activity by PBO. Esterase isoenzyme inhibition by these compounds showed a similar result; this assay revealed an extreme sensitivity of Triplet A (resistance-associated esterases) to DEF. In an in vivo assay carried out with these compounds at different incubation times, only DEF caused posterior in vitro esterase activity inhibition, with a maximum effect 1 h after treatment. CONCLUSION: In this work, only DEF shows true synergistic inhibition of WFT esterases. PMID- 21656899 TI - Semaphorin 3A expression in the colon of Hirschsprung disease. AB - BACKGROUND: Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon. The Semaphorin 3A (SEMA3A) gene is involved in the migration of enteric neural precursors (ENPs). To analyze the function of SEMA3A in HSCR, the SEMA3A expression in different colon segments in HSCR was examined. METHODS: The expression levels of SEMA3A in both ganglionic and aganglionic colon tissues of 32 patients with HSCR and in colon tissue of 5 newborn unaffected individuals were examined by real-time RT-PCR, Western-blot, and immunohistology. RESULTS: Comparison of SEMA3A expression levels between ganglionic and aganglionic tissues in HSCR revealed upregulation of SEMA3A expression in 43.75% (14/32) of the aganglionic colons. SEMA3A was expressed in the ganglion cells of the myenteric plexus, submucosa, as well as in the longitudinal and circular muscle layer of the normal colon of both unaffected newborns and patients with HSCR. In the aganglionic segment of patients with HSCR, SEMA3A was highly expressed in the circular muscle layer and was also detected in the submucosa and in the longitudinal muscles layer. The fluorescence intensity of SEMA3A in the circular muscle layer in the aganglionic segment was much higher than that in ganglionic segment (p < .001). CONCLUSION: SEMA3A expression was upregulated in the aganglionic smooth muscle layer of the colon in some patients with HSCR and our data suggest that increased SEMA3A expression may be a risk factor for HSCR pathology in a subset of patients. PMID- 21656900 TI - Do foreign- and U.S.-born mothers across racial/ethnic groups have a similar risk profile for selected sociodemographic and periconceptional factors? AB - BACKGROUND: We examined differences in selected pregnancy-related risk factors, including maternal sociodemographic characteristics, health-related conditions, and periconceptional behavioral factors, among foreign-born versus U.S.-born control mothers across race/ethnic groups. METHODS: We used data from the National Birth Defects Prevention Study, and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of the risk factors, for foreign-born Hispanic, non Hispanic white, non-Hispanic black, and Asian/Pacific Islander (API) mothers, compared to their U.S.-born counterparts. RESULTS: Across all race/ethnic groups, foreign-born mothers were older and had lower odds of obesity compared to their U.S.-born counterparts. With the exception of foreign-born black mothers, foreign born mothers from other race/ethnic groups had significantly lower odds of binge drinking during the periconceptional period. Compared to U.S.-born, foreign-born Hispanic mothers had twice the odds of gestational diabetes (OR = 2.23; 95% CI = 1.36-3.66). Certain health behaviors were less prevalent in foreign-born black mothers (e.g., folic acid use; OR = 0.54; 95% CI = 0.31-0.96) and foreign-born API mothers (e.g., cigarette smoking; OR = 0.10; 95% CI = 0.02-0.48). CONCLUSIONS: Significant differences in pregnancy related risk factors during the periconceptional period and throughout pregnancy were observed between maternal nativity groups and across race/ethnicity. Prevention efforts for both prepregnancy and after conception should be designed and delivered according to maternal nativity for each racial/ethnic group. PMID- 21656901 TI - Sinusoidal obstruction syndrome during induction therapy for acute lymphoblastic leukemia managed with N-acetyl Cysteine. PMID- 21656902 TI - Arsenic trioxide for the treatment of a relapsed acute promyelocytic leukemia with acute renal failure. PMID- 21656903 TI - No association between a common single nucleotide polymorphism, rs4141463, in the MACROD2 gene and autism spectrum disorder. AB - The Autism Genome Project (AGP) Consortium recently reported genome-wide significant association between autism and an intronic single nucleotide polymorphism marker, rs4141463, within the MACROD2 gene. In the present study we attempted to replicate this finding using an independent case-control design of 1,170 cases with autism spectrum disorder (ASD) (874 of which fulfilled narrow criteria for Autism (A)) from five centers within Europe (UK, Germany, the Netherlands, Italy, and Iceland), and 35,307 controls. The combined sample size gave us a non-centrality parameter (NCP) of 11.9, with 93% power to detect allelic association of rs4141463 at an alpha of 0.05 with odds ratio of 0.84 (the best odds ratio estimate of the AGP Consortium data), and for the narrow diagnosis of autism, an NCP of 8.9 and power of 85%. Our case-control data were analyzed for association, stratified by each center, and the summary statistics were combined using the meta-analysis program, GWAMA. This resulted in an odds ratio (OR) of 1.03 (95% CI 0.944-1.133), with a P-value of 0.5 for ASD and OR of 0.99 (95% CI 0.88-1.11) with P-value = 0.85 for the Autism (A) sub-group. Therefore, this study does not provide support for the reported association between rs4141463 and autism. PMID- 21656904 TI - Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations. AB - Catechol-O-methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine-induced paranoia (CIP) in African-American (AA) and European-American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family-controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (P = 0.05). In EAs, the best-known marker, rs4680 (Val158Met), was nominally significant in additive models (P = 0.03). SNP rs174696 also showed nominal significance in additive models (P = 0.02). We considered the three SNPs (rs737866-rs4680-rs174696) together in haplotype analysis in both family populations, using HBAT. The A-A-T haplotype was significantly associated with CIP in EAs (Z = 2.845; P = 0.0044, global P = 0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A-A-T haplotype was significantly associated to CIP in the AA unrelated population (P = 0.0015). Two haplotypes, A-G-C and A-A-C, were significant in the EA unrelated population (P = 0.001 and 0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family-controlled and unrelated-affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine. PMID- 21656905 TI - Primary role of multiparametric flow cytometry in the diagnostic work-up of indolent clonal mast cell disorders. AB - BACKGROUND: According to the World Health Organization (WHO) classification the diagnosis of systemic mastocytosis (SM) relies on bone marrow (BM) examination and is based on one major and four minor criteria. Herein, we used WHO criteria to compare flow cytometry (FC) with other available techniques in the diagnosis of SM after BM examination. METHODS: We analyzed a cohort of 95 patients with suspect SM. All patients underwent comprehensive BM examination by using cytology, immunohistochemistry, FC and molecular study for mutation of c-Kit and serum tryptase dosage. FC evaluation was based on a combination of monoclonal antibodies, specifically CD25/CD2/CD45/CD34/CD117. RESULTS: Seventy-four out of ninety-five patients were diagnosed with indolent SM (n = 59) or monoclonal mast cell activation syndrome (n = 15) because satisfying less than 3 minor criteria. Thirty-nine out of these seventy-four patients fulfilled the major histological criterion, whereas the presence of a minor criterion was assessed by FC, molecular study, cytology, and tryptase level in 70/74, 52/67, 56/74, and 42/74 patients, respectively. FC showed higher sensitivity than IHC in detection of CD25+ mast cells (MC) (92.9% vs. 73.8%; P = 0.019), especially in the absence of the major histological criterion (90.5% vs. 47.6%; P = 0.003). Moreover, CD2 expression was documented by FC and IHC in 97.1% and 35.3% of cases, respectively (P < 0.001). CONCLUSIONS: FC showed the best sensitivity for identifying abnormal MC compared to other techniques, especially in cases with low MC burden. Therefore, we hope for a major role of FC in the diagnostic work-up of clonal MC disorders. PMID- 21656906 TI - Mixed-valence nanoclusters: fast electron transfer in mixed-valence systems with a gold nanoparticle as the bridge. PMID- 21656907 TI - Optical properties of tipless gold nanopyramids. PMID- 21656908 TI - Orally active, antimetastatic, nontoxic diphenyl ether-derived carbamoylphosphonate matrix metalloproteinase inhibitors. AB - Seven 4-phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates (CPOs) bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors. The five lowest homologues [(CH2)2-6] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH2)7,8] lack inhibitory activity. The most potent homologues are those with (CH2)5,6; these two were evaluated for antimetastatic activity in a murine melanoma model and showed good potency both by oral and intraperitoneal administration without any toxic--including musculoskeletal--side effects. In contrast to the previously reported cis-ACCP, which was shown to inhibit MMP-2 for ~30 min, the new compounds inhibit MMP activity for the duration of measurement, lasting several hours. Pharmacokinetic evaluation revealed, on the one hand, low oral bioavailability; on the other hand, a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone. PMID- 21656909 TI - Mass spectrometric immunoassay of intact insulin and related variants for population proteomics studies. AB - PURPOSE: The purpose of the work presented herein was to develop a high throughput assay for the quantification of human insulin in plasma samples while simultaneously detecting, with high mass accuracy, any additional variant forms of insulin that might be present in each sample. EXPERIMENTAL DESIGN: A mass spectrometric immunoassay (MSIA) was designed in which anti-human insulin antibodies were immobilized to commercially available mass spectrometric immunoassay pipette tips and used to capture insulin and related protein variants from human plasma. RESULTS: Standard curves for insulin exhibited linearity (average R(2) for three days of analysis=0.99) and assay concentration limits of detection and limits of quantification for insulin were found to be 1 and 15 pM, respectively. Estimated coefficient of variations for inter-day experiments (n=3 days) were <8%. Simultaneously, the assay was shown to detect and identify insulin metabolites and synthetic insulin analogs (e.g. Lantus). Notably, insulin variants not known to exist in plasma were detected in diabetics. CONCLUSIONS AND CLINICAL RELEVANCE: This introductory study sets a foundation toward the screening of large populations to investigate insulin isoforms, isoform frequencies, and their quantification. PMID- 21656911 TI - Proteins in leaked amniotic fluid as biomarkers diagnostic for prelabor rupture of membranes. AB - PURPOSE: Early diagnosis of prelabor rupture of membranes (PROM) is essential to protect mother and fetus from intra-uterus infection and preterm birth. A simple and rapid bedside test would help clinicians confirm the diagnosis for early treatment. EXPERIMENTAL DESIGN: A protein array was used to screen cervical vaginal fluid (CVF) and amniotic fluid (AF) samples collected from normal and PROM pregnant women. Enzyme-linked immunosorbent assay was used to quantify two novel and potentially useful analytes, soluble intercellular adhesion molecule-1 (sICAM-1) and Axl receptor tyrosine kinase (Axl). RESULTS: The mean concentration of sICAM-1 and Axl was 85 and 482 times higher separately in 30 healthy AF samples than in 110 CVF samples of normal pregnancies. Comparing 110 CVF samples of PROM/Preterm PROM with 110 CVF samples of normal pregnancies, the diagnostic value for PROM was demonstrated by their high sensitivity and specificity (96.4 and 92.7%, respectively, for sICAM-1, and 92.4 and 90.4%, respectively, for Axl). CONCLUSIONS AND CLINICAL RELEVANCE: The results indicate that sICAM-1 and Axl in AF leaked to vagina are sensitive and specific biomarkers for the diagnosis of PROM. Furthermore, sICAM-1 or Axl can be developed into a rapid strip test for bedside use. PMID- 21656910 TI - A database of reaction monitoring mass spectrometry assays for elucidating therapeutic response in cancer. AB - PURPOSE: The Quantitative Assay Database (QuAD), http://proteome.moffitt.org/QUAD/, facilitates widespread implementation of quantitative mass spectrometry in cancer biology and clinical research through sharing of methods and reagents for monitoring protein expression and modification. EXPERIMENTAL DESIGN: Liquid chromatography coupled to multiple reaction monitoring (LC-MRM) mass spectrometry assays are developed using SDS PAGE fractionated lysates from cancer cell lines. Pathway maps created using GeneGO Metacore provide the biological relationships between proteins and illustrate concepts for multiplexed analysis; each protein can be selected to examine assay development at the protein and peptide levels. RESULTS: The coupling of SDS-PAGE and multiple reaction monitoring mass spectrometry screening has been used to detect 876 peptides from 218 cancer-related proteins in model systems including colon, lung, melanoma, leukemias, and myeloma, which has led to the development of 95 quantitative assays including stable-isotope-labeled peptide standards. Methods are published online and peptide standards are made available to the research community. Protein expression measurements for heat shock proteins, including a comparison with ELISA and monitoring response to the HSP90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), are used to illustrate the components of the QuAD and its potential utility. CONCLUSIONS AND CLINICAL RELEVANCE: This resource enables quantitative assessment of protein components of signaling pathways and biological processes and holds promise for systematic investigation of treatment responses in cancer. PMID- 21656914 TI - Dynamic regulation of aquaglyceroporin expression in erythrocyte cultures from cold- and warm-acclimated Cope's gray treefrog, Hyla chrysoscelis. AB - Cope's gray treefrog, Hyla chrysoscelis,is a freeze-tolerant anuran which accumulates and distributes glycerol as a cryoprotectant before freezing. We hypothesize that HC-3, an aquaglyceroporin member of the MIP family of water pores, may play an important role in the process of freeze tolerance by mediating transmembrane passage of glycerol and water during cold-acclimation. The objectives of this study were two-fold: to examine HC-3 protein abundance and cellular localization in erythrocytes from cold- and warm-acclimated frogs and to develop and characterize an erythrocyte cell culture system for examining HC-3 gene regulation. Compared with warm-acclimated frogs, erythrocytes from cold acclimated frogs had higher HC-3 protein expression and enhanced plasma membrane localization. Furthermore, erythrocytes from cold- and warm-acclimated frogs maintained in culture at 4 and 20 degrees C exhibited time- and temperature dependent regulation of HC-3 expression and an increase in the abundance of high molecular weight immunoreactive species within 24 hr of culture at 20 degrees C. Deglycosylation of erythrocyte proteins resulted in the disappearance of the high molecular weight species, indicating that HC-3 is post-translationally modified by N-linked glycosylation. Erythrocytes cultured in media containing glycerol also showed an increased abundance of the high molecular weight bands and enhanced plasma membrane localization of HC-3, suggesting a role for glycerol in regulating HC-3 subcellular trafficking. Thus, the development of this erythrocyte cell culture system from H. chrysoscelis opened an opportunity to study the properties of cells with changing expression of an aquaglyceroporin, HC 3, and to explore the factors regulating that expression. PMID- 21656913 TI - On-tissue identification of insulin: in situ reduction coupled with mass spectrometry imaging. AB - PURPOSE: The aim of this study was to use on-tissue reduction followed by MALDI MS imaging (MSI) to identify an m/z 5812.85 peak, which is over-expressed in healthy human pancreatic tissue compared with type one Diabetes (T1D) tissue. EXPERIMENTAL DESIGN: A major constraint of MALDI-MSI is identification of compounds with m/z >=4000. On-tissue reduction using tris (2-carboxyethyl) phosphine (TCEP) breaks the inter-domain disulphide bonds generating low molecular-weight peptides amenable to direct MS/MS analysis. Pancreatic tissues from healthy (n=4) and diabetic subjects (n=4) were profiled by MALDI-MSI with/without reduction. RESULTS: On-tissue reduction resulted in the loss of the over-expressed 5812.85 m/z peak and the simultaneous appearance of a 3430.664 m/z peak in healthy tissues. The latter peak presumably derived from the 5812.85 m/z peak was identified as the insulin B chain by MS/MS. MALDI-MSI images show that both the 5812.85 insulin peak before reduction and the 3430.664 peak after reduction co-localized with the healthy pancreatic islets. CONCLUSION AND CLINICAL RELEVANCE: On-tissue reduction followed by MALDI-MSI resulted in the identification of insulin and localization of pancreatic islets of langerhans. The approach will be useful in the future identification of novel therapeutic molecular targets to beta-cells lost during type one diabetes. PMID- 21656912 TI - Utility of formalin-fixed, paraffin-embedded liver biopsy specimens for global proteomic analysis in nonalcoholic steatohepatitis. AB - PURPOSE: To compare the proteomic profiles of formalin-fixed, paraffin-embedded (FFPE) liver biopsy material and matched frozen liver tissue from patients with nonalcoholic steatohepatitis (NASH). EXPERIMENTAL DESIGN: A label-free mass spectrometry-based approach was used to profile global protein expression in FFPE and frozen liver biopsy specimens from five patients with NASH. RESULTS: Eight hundred and sixty proteins were identified with >75% confidence: 225 common proteins were identified in both the FFPE and frozen tissues, and an additional 142 and 493 proteins were identified in the FFPE and frozen tissues, respectively. Functional analyses revealed a general, nonspecific reduction in the number of proteins identified in FFPE tissue compared with frozen tissue. No bias toward proteins located in any specific subcellular compartments or implicated in any particular biological functions was observed. The relative abundance of several proteins with functions relating to the pathogenesis of NASH (peroxiredoxin-1, fatty acid binding protein 1, fatty acid synthase, vimentin, catalase, and glutathione S-transferase A1) was similar in FFPE and frozen liver tissues. CONCLUSIONS AND CLINICAL RELEVANCE: FFPE liver biopsy material from NASH patients can be used for global proteomic analysis and biomarker identification studies, although a universal reduction in the number of identified proteins compared with frozen tissue is likely. PMID- 21656915 TI - Use of the one-minute preceptor as a teaching tool in the gross anatomy laboratory. AB - The one-minute preceptor (OMP) is a time-efficient technique used for teaching in busy clinical settings. It consists of five microskills: (1) get a commitment from the student, (2) probe for supporting evidence, (3) reinforce what was done right, (4) correct errors and fill in omissions, and (5) teach a general rule. It can also be used to address structure-identification questions in gross anatomy laboratory small-group settings. The OMP is an active learner-centered teaching approach that prepares students for a style of learning that they need to master in clinical settings, provides novice anatomy teachers with an efficient and effective teaching strategy, and moves anatomy learning beyond mere name tagging to active knowledge construction. PMID- 21656916 TI - Importance of adequate gross anatomy education: the impact of a structured pelvic anatomy course during gynecology fellowship. AB - Medical education underwent standardization at the turn of the 20th century and remained fairly consistent until recently. Incorporation of a patient-centered or case-based curriculum is believed to reinforce basic science concepts. One negative aspect is a reduction in hours spent with cadaveric dissection in the gross anatomy laboratory. For those entering a surgical career, limited anatomical exposure leaves knowledge deficits that must be corrected during further education during residency training. The benefit of providing formal anatomy education to residents and surgical fellows is described in the literature, specifically noting improvement in written test scores and surgical application. PMID- 21656917 TI - Attitudes to cadaveric organ donation in Irish preclinical medical students. AB - There is a worldwide shortage of organs for transplantation. It has been shown that the attitude of healthcare professionals can improve the rates of organ donation, and that educational programs aimed at improving both attitudes and knowledge base of professionals can have positive outcomes. Although there has been research carried out on this topic, there has been none in Ireland. Anatomy dissection can be a stressor to medical students-we investigate the attitudes of Irish students to organ donation and how they change with exposure to anatomy dissection. A questionnaire was administered to first year students in the School of Medicine in University College Dublin, Ireland, three times over a nine-week period at the commencement of classes in an academic year. The attitudes of the students were positive throughout regarding organ donation by a stranger, a family member, or themselves. There was, however, a significant decrease in support for the donation of a family member's organs in a minority of students. Irish students' attitudes to postmortem organ donation are positive and are not changed by exposure to the dissecting room. There is support for the donation of organs, and willingness among students to donate their own organs and support donation by family members. PMID- 21656918 TI - Student attitudes toward cadaveric dissection at a UK medical school. AB - A more humanistic approach toward dissection has emerged. However, student attitudes toward this approach are unknown and the influences on such attitudes are little understood. One hundred and fifty-six first-year medical students participated in a study examining firstly, attitudes toward the process of dissection and the personhood of the cadaver and secondly, the extent to which gender, anxiety, exposure to dissection, bereavement and prior experience of a dead body influenced these attitudes. Attitudes toward dissection were assessed by of levels of agreement toward eleven statements and by selection of adjectives describing possible feelings toward dissection. Students were asked about recent bereavement, whether they had seen a dead body prior to starting their course and exposure to dissection when completing the questionnaire. Validated instruments were used to measure disposition toward generalized anxiety (Hospital Anxiety and Depression Scale) and toward death anxiety (Collett-Lester Death Anxiety Scale). Between 60% and 94% of students held positive attitudes toward the process of dissection and over 70% of students selected 2 or fewer negative adjectives. Students' attitudes toward the personhood of the cadaver were more disparate. Disposition toward anxiety (particularly death anxiety), and exposure to dissection, influenced attitudes. Female gender and recent bereavement exerted a negative influence. Students with higher levels of anxiety experienced more negative feelings and those recently bereaved were less enthusiastic about dissection. Anticipation of dissection may be worse than reality. Sensitive preparation of students prior to entering the dissecting room for the first time may be beneficial. PMID- 21656919 TI - Identification of transcription factors perturbed by the synthesis of high levels of a foreign protein in yeast Saccharomyces cerevisiae. AB - For years, micro-organisms have been used for the industrial production of heterologous proteins. However, the production of foreign proteins causes undesirable problems for the host organism. The analysis of this phenomenon is desirable to improve the production of relevant proteins and so far no analysis of the effects of recombinant protein production on genetic regulation has been reported. In this work, network component analysis (NCA) was used to deduce transcription factor activities (TFAs) in a recombinant strain of Saccharomyces cerevisiae that produces a foreign protein, human superoxide dismutase (SOD) and compared the behavior of this yeast strain to the wild-type host to see the effect of the expression of the protein at the regulatory level. NCA identified a network of 817 genes regulated by 87 transcription factors (TFs). From the identified TFs, 45 show significant change in their activities at least in one of the three phases of diauxic growth (glucose, ethanol, and early stationary phase). The major effect of the expression of SOD on the activity of the TFs was observed in the early stationary phase with 34 of them perturbed in comparison with 12 on glucose and 20 on ethanol. These TFs cover the main functions of the cell, such as developmental processes, cell cycle, metabolism, and environmental response. Five of them are present in all growth phases: Hal9, Mac1, Oaf3, Stp1, and Urc2. In addition, TFA analysis corroborates the hypothesis that copper plays a key role as a stress factor and suggests that YJL206C, a TF with unknown function, could be related to Ace2, a cell cycle regulator. PMID- 21656921 TI - Finite dimensional structure of the GPI discharge in patients with Parkinson's disease. AB - Stochastic systems are infinitely dimensional and deterministic systems are low dimensional, while real systems lie somewhere between these two limit cases. If the calculation of a low (finite) dimension is in fact possible, one could conclude that the system under study is not purely random. In the present work we calculate the maximal Lyapunov exponent from interspike intervals time series recorded from the internal segment of the Globus Pallidusfrom patients with Parkinson's disease. We show the convergence of the maximal Lyapunov exponent at a dimension equal to 7 or 8, which is therefore our estimation of the embedding dimension for the system. For dimensions below 7 the observed behavior is what would be expected from a stochastic system or a complex system projecting onto lower dimensional spaces. The maximal Lyapunov exponent did not show any differences between tremor and akineto-rigid forms of the disease. However, it did decay with the value of motor Unified Parkinson's Disease Rating Scale -OFF scores. Patients with a more severe disease (higher UPDRS-OFF score) showed a lower value of the maximal Lyapunov exponent. Taken together, both indexes (the maximal Lyapunov exponent and the embedding dimension) remark the importance of taking into consideration the system's non-linear properties for a better understanding of the information transmission in the basal ganglia. PMID- 21656920 TI - Crystallization and liquid-liquid phase separation of monoclonal antibodies and fc-fusion proteins: screening results. AB - Crystallization holds the potential to be used for protein purification and low viscosity drug substance and drug product formulations. Twenty-two different proteins (20 monoclonal antibodies and two Fc-fusions) were examined to determine the breadth of applicability of crystallization to these therapeutic proteins. Vapor diffusion technique and an evaporative screening method were used to identify crystallization conditions using around a 100 initial conditions based on reagents that are generally regarded as safe (GRAS). Of 16 IgG2 s examined, at least four formed diffraction-quality crystals and four others formed crystal like particles. At least three of the IgG2 s that crystallized well were also crystallized under the same set of operating conditions using inexpensive GRAS reagents. The crystals were formed to high-yields in a few hours and were dissolved quickly without impacting product quality. Although only a fraction of the proteins examined crystallized, all exhibited liquid-liquid phase separation (LLPS), which could be used for their concentration or possibly purification. One of the Fc-fusions, for example, was concentrated by LLPS to a self-buffering solution at 150 g/L. Crystallization and LLPS in the salting-in region were shown to be feasible. PMID- 21656922 TI - Testing of information condensation in a model reverberating spiking neural network. AB - Information about external world is delivered to the brain in the form of structured in time spike trains. During further processing in higher areas, information is subjected to a certain condensation process, which results in formation of abstract conceptual images of external world, apparently, represented as certain uniform spiking activity partially independent on the input spike trains details. Possible physical mechanism of condensation at the level of individual neuron was discussed recently. In a reverberating spiking neural network, due to this mechanism the dynamics should settle down to the same uniform/ periodic activity in response to a set of various inputs. Since the same periodic activity may correspond to different input spike trains, we interpret this as possible candidate for information condensation mechanism in a network. Our purpose is to test this possibility in a network model consisting of five fully connected neurons, particularly, the influence of geometric size of the network, on its ability to condense information. Dynamics of 20 spiking neural networks of different geometric sizes are modelled by means of computer simulation. Each network was propelled into reverberating dynamics by applying various initial input spike trains. We run the dynamics until it becomes periodic. The Shannon's formula is used to calculate the amount of information in any input spike train and in any periodic state found. As a result, we obtain explicit estimate of the degree of information condensation in the networks, and conclude that it depends strongly on the net's geometric size. PMID- 21656923 TI - Application of recurrence quantification analysis for the automated identification of epileptic EEG signals. AB - Epilepsy is a common neurological disorder that is characterized by the recurrence of seizures. Electroencephalogram (EEG) signals are widely used to diagnose seizures. Because of the non-linear and dynamic nature of the EEG signals, it is difficult to effectively decipher the subtle changes in these signals by visual inspection and by using linear techniques. Therefore, non linear methods are being researched to analyze the EEG signals. In this work, we use the recorded EEG signals in Recurrence Plots (RP), and extract Recurrence Quantification Analysis (RQA) parameters from the RP in order to classify the EEG signals into normal, ictal, and interictal classes. Recurrence Plot (RP) is a graph that shows all the times at which a state of the dynamical system recurs. Studies have reported significantly different RQA parameters for the three classes. However, more studies are needed to develop classifiers that use these promising features and present good classification accuracy in differentiating the three types of EEG segments. Therefore, in this work, we have used ten RQA parameters to quantify the important features in the EEG signals.These features were fed to seven different classifiers: Support vector machine (SVM), Gaussian Mixture Model (GMM), Fuzzy Sugeno Classifier, K-Nearest Neighbor (KNN), Naive Bayes Classifier (NBC), Decision Tree (DT), and Radial Basis Probabilistic Neural Network (RBPNN). Our results show that the SVM classifier was able to identify the EEG class with an average efficiency of 95.6%, sensitivity and specificity of 98.9% and 97.8%, respectively. PMID- 21656924 TI - Nonlinear torque and air-to-fuel ratio control of spark ignition engines using neuro-sliding mode techniques. AB - This paper presents a new approach for the calibration and control of spark ignition engines using a combination of neural networks and sliding mode control technique. Two parallel neural networks are utilized to realize a neuro-sliding mode control (NSLMC) for self-learning control of automotive engines. The equivalent control and the corrective control terms are the outputs of the neural networks. Instead of using error backpropagation algorithm, the network weights of equivalent control are updated using the Levenberg-Marquardt algorithm. Moreover, a new approach is utilized to update the gain of corrective control. Both modifications of the NSLMC are aimed at improving the transient performance and speed of convergence. Using the data from a test vehicle with a V8 engine, we built neural network models for the engine torque (TRQ) and the air-to-fuel ratio (AFR) dynamics and developed NSLMC controllers to achieve tracking control. The goal of TRQ control and AFR control is to track the commanded values under various operating conditions. From simulation studies, the feasibility and efficiency of the approach are illustrated. For both control problems, excellent tracking performance has been achieved. PMID- 21656925 TI - Foreground detection in video sequences with probabilistic self-organizing maps. AB - Background modeling and foreground detection are key parts of any computer vision system. These problems have been addressed in literature with several probabilistic approaches based on mixture models. Here we propose a new kind of probabilistic background models which is based on probabilistic self-organising maps. This way, the background pixels are modeled with more flexibility. On the other hand, a statistical correlation measure is used to test the similarity among nearby pixels, so as to enhance the detection performance by providing a feedback to the process. Several well known benchmark videos have been used to assess the relative performance of our proposal with respect to traditional neural and non neural based methods, with favourable results, both qualitatively and quantitatively. A statistical analysis of the differences among methods demonstrates that our method is significantly better than its competitors. This way, a strong alternative to classical methods is presented. PMID- 21656926 TI - Generating balanced learning and test sets for function approximation problems. AB - In function approximation problems, one of the most common ways to evaluate a learning algorithm consists in partitioning the original data set (input/output data) into two sets: learning, used for building models, and test, applied for genuine out-of-sample evaluation. When the partition into learning and test sets does not take into account the variability and geometry of the original data, it might lead to non-balanced and unrepresentative learning and test sets and, thus, to wrong conclusions in the accuracy of the learning algorithm. How the partitioning is made is therefore a key issue and becomes more important when the data set is small due to the need of reducing the pessimistic effects caused by the removal of instances from the original data set. Thus, in this work, we propose a deterministic data mining approach for a distribution of a data set (input/output data) into two representative and balanced sets of roughly equal size taking the variability of the data set into consideration with the purpose of allowing both a fair evaluation of learning's accuracy and to make reproducible machine learning experiments usually based on random distributions. The sets are generated using a combination of a clustering procedure, especially suited for function approximation problems, and a distribution algorithm which distributes the data set into two sets within each cluster based on a nearest neighbor approach. In the experiments section, the performance of the proposed methodology is reported in a variety of situations through an ANOVA-based statistical study of the results. PMID- 21656927 TI - Ask the doctor. I have a feeling of fullness in my ears that won't go away. I think it has been diagnosed as something called eustachian tube dysfunction. I have been to several otolaryngologists. Nothing has worked. Suggestions? PMID- 21656928 TI - Recycling effort keeps hearts ticking. PMID- 21656929 TI - Exercise to strengthen heart and muscles best for diabetes. PMID- 21656930 TI - Ask the doctor. I have heard that one symptom of a stroke is "the worst headache you can imagine." I recently had a migraine that was so much more painful than previous ones that I worried it was a stroke. Is there any way to tell a migraine from a "stroke headache"? PMID- 21656931 TI - LDL cholesterol. New measurements of risk. PMID- 21656932 TI - Weight-loss surgery may help some with heart failure. PMID- 21656933 TI - Improving your health. 10 tips that can help. PMID- 21656934 TI - My dentist always asks if I grind my teeth because some of my teeth are unusually worn down. I'm pretty sure that I don't, but could I be doing it in my sleep? PMID- 21656935 TI - I've had heartburn problems. A recent endoscopy showed some inflammation in my esophagus. Now I'm taking a medication for it. How long will I have to take it? PMID- 21656936 TI - Incorporating cafe design principles into End-of-Life discussions: an innovative method for continuing education. AB - Cafe design provides an innovative method for conducting continuing education activities. This method was chosen to elicit meaningful conversation based on issues related to End-of-Life care. Cafe design principles incorporate the following: setting the context, creating hospitable space, exploring questions that matter, encouraging everyone's contributions, connecting diverse perspectives, listening together for insights, and sharing collective discoveries. Key discussion questions were identified from the End-of Life Nursing Education Consortium Core Curriculum. Questions were revised to incorporate the principles of appreciative inquiry, which encourage a shift from traditional methods of problem identification to creation of a positive vision. Participants rated the cafe design method as an effective way to share their ideas and to stimulate conversation. PMID- 21656937 TI - Correspondence: gated SPECT can detect abnormal RV structure or function. PMID- 21656938 TI - Response to vitamin D intake: from the Antarctic to the Institute of Medicine. PMID- 21656939 TI - Start-ups: In search of venture capital. PMID- 21656940 TI - Type 1 Brugada electrocardiogram pattern during complete left bundle-branch block due to right ventricular pacing. PMID- 21656941 TI - Oral health behavioral and social intervention research concepts and methods. PMID- 21656942 TI - What is a planning model? An introduction to PRECEDE-PROCEED. AB - Planning models exist at a macroscopic level; they serve as an organizing framework for an entire health promotion effort aimed at fostering reduction in a given disease. A particularly useful, widely applied, and easy-to-follow example of a planning model is the PRECEDE-PROCEED planning model (PPM). The PPM is very much an ecological approach to health promotion. The PPM is actually quite simple to understand once one realizes that it embodies two key aspects of intervention: a) planning, and (b) evaluation. The PPM guides the program planner to think logically about the desired end point and work "backwards" to achieve that goal. Through community participation, the planning process is broken down into objectives, step 3 sub-objectives, and step 4 sub-objectives. Conceptually, this approach to health promotion provides context to the use of theory, with theory being applied at the fourth step. This observation teaches a vital lesson, namely that program planning is larger and is a more comprehensive task compared to the subservient function of theory selection and application. PMID- 21656943 TI - Planning models are critical for facilitating the development, implementation, and evaluation of dental health promotion interventions. PMID- 21656944 TI - Planning models and theories: integrating components for addressing complex challenges. PMID- 21656945 TI - PRECEDE-PROCEED and the NIDA stage model: the value of a conceptual framework for intervention research. PMID- 21656946 TI - Five roles for using theory and evidence in the design and testing of behavior change interventions. AB - OBJECTIVE: The prevailing wisdom in the field of health-related behavior change is that well-designed and effective interventions are guided by theory. METHODS: Using the framework of intervention mapping, we describe and provide examples of how investigators can effectively select and use theory to design, test, and report interventions. RESULTS: We propose five roles for theory and evidence about theories: a) identification of behavior and determinants of behavior related to a specified health problem (i.e., the logic model of the problem); b) explication of a causal model that includes theoretical constructs for producing change in the behavior of interest (i.e., the logic model of change); c) selection of intervention methods and delivery of practical applications to achieve changes in health behavior; d) evaluation of the resulting intervention including theoretical mediating variables; and e) reporting of the active ingredients of the intervention together with the evaluation results. CONCLUSIONS: In problem-driven applied behavioral or social science, researchers use one or multiple theories, empiric evidence, and new research, both to assess a problem and to solve or prevent a problem. Furthermore, the theories for description of the problem may differ from the theories for its solution. In an applied approach, the main focus is on solving problems regarding health behavior change and improvement of health outcomes, and the criteria for success are formulated in terms of the problem rather than the theory. Resulting contributions to theory development may be quite useful, but they are peripheral to the problem-solving process. PMID- 21656947 TI - A new paradigm for behavior change. PMID- 21656948 TI - Injecting theory into the dental behavior intervention research process. PMID- 21656949 TI - The charge to advance theory and improve health outcomes. PMID- 21656950 TI - Statistical analysis for identifying mediating variables in public health dentistry interventions. AB - OBJECTIVE: This article provides an overview of statistical mediation analysis methods in the evaluation of public health dentistry interventions. METHODS AND RESULTS: First, reasons for conducting mediation analysis are outlined, followed by a discussion of the link between the mediation model and theoretical bases of interventions. Second, the basic statistical procedures in mediation analysis are presented. An example application to data from a hypothetical intervention is provided in Appendix A. Third, interpretation of the results from statistical mediation analysis is described along with additional information pertinent to identifying true mediation relations. CONCLUSIONS: Guidelines for describing mediation analyses in research articles related to public health dentistry intervention studies are outlined. PMID- 21656951 TI - Mediation in the development of early childhood caries. PMID- 21656952 TI - Be prepared: capitalizing on opportunities to advance theory and practice. PMID- 21656953 TI - Using mediation to identify mechanisms of change. PMID- 21656954 TI - The assessment, monitoring, and enhancement of treatment fidelity in public health clinical trials. AB - OBJECTIVES: To discuss methods of preservation of treatment fidelity in health behavior change trials conducted in public health contexts. METHODS: The treatment fidelity framework provided by the National Institutes of Health's Behavioral Change Consortium includes five domains of treatment fidelity (Study Design, Training, Delivery, Receipt, and Enactment). A measure of treatment fidelity was previously developed and validated using these categories. RESULTS: Strategies for assessment, monitoring, and enhancing treatment fidelity within each of the five treatment fidelity domains are discussed. The previously created measure of treatment fidelity is updated to include additional items on selecting providers, additional confounders, theory testing, and multicultural considerations. CONCLUSIONS: Implementation of a treatment fidelity plan may require extra staff time and costs. However, the economic and scientific costs of lack of attention to treatment fidelity are far greater than the costs of treatment fidelity implementation. Maintaining high levels of treatment fidelity with flexible adaptation according to setting, provider, and patient is the goal for public health trials. PMID- 21656955 TI - Fidelity in public health clinical trials: considering provider-participant relationship factors in community treatment settings. PMID- 21656956 TI - Maximizing treatment fidelity in public health clinical trials. PMID- 21656957 TI - The importance of monitoring and maximizing treatment fidelity in public health research. PMID- 21656958 TI - Qualitative methods to ensure acceptability of behavioral and social interventions to the target population. AB - OBJECTIVES: This paper introduces qualitative methods for assessing the acceptability of an intervention. METHODS: Acceptability refers to determining how well an intervention will be received by the target population and the extent to which the new intervention or its might meet the needs of the target population an d organizational setting. In this paper, we focus on two common qualitative methods for conducting acceptability research and their advantages and disadvantages: focus groups and interviews. RESULTS: We provide examples from our own research and other studies to demonstrate the use of these methods for conducting acceptability research and how one might adapt this approach for oral health research. DISCUSSION: We present emerging methods for conducting acceptability research, including the use of community-based participatory research, as well as the utility of conducting acceptability research for assessing the appropriateness of measures in intervention research. PMID- 21656959 TI - Enhancing the usefulness of results from economic evaluations of behavioral health interventions. PMID- 21656960 TI - Even the most sophisticated oral health interventions and technologies are of no help unless people accept and use them. PMID- 21656961 TI - Use of qualitative methods to ensure acceptability of interventions. PMID- 21656962 TI - A framework for implementing sustainable oral health promotion interventions. AB - The present paper addresses basic evaluation and procedural concepts that are involved in the process of implementing sustainable oral health behavioral and social interventions. It is part of a series of thematic articles describing cutting-edge methods for conducting oral health interventions research. Core components for effective intervention implementation are presented as part of a comprehensive model composed of four stages (training, adoption, implementation, and practice), along with sustaining influences involving preparation and maintenance. This model systematically addresses common barriers that can reduce innovation success and permanence. Special attention is given to the measurement and impact of organizational and related contextual influences across stages of the implementation process. Assessment tools and research strategies are recommended and illustrated based on evaluations of interventions implemented in addiction and mental health treatment systems. These tools and research strategies also hold promise for use within the National Institute of Dental and Craniofacial Research Practice-Based Research Networks, as well as other systems of oral health care delivery. PMID- 21656963 TI - Sustainable oral health interventions. PMID- 21656964 TI - Lasting change: sustaining improvements in oral health care. PMID- 21656965 TI - Advancing sustainability research: challenging existing paradigms. PMID- 21656966 TI - Overview of methods in economic analyses of behavioral interventions to promote oral health. AB - BACKGROUND: Broad adoption of interventions that prove effective in randomized clinical trials or comparative effectiveness research may depend to a great extent on their costs and cost-effectiveness (CE). Many studies of behavioral health interventions for oral health promotion and disease prevention lack robust economic assessments of costs and CE. OBJECTIVE: To describe methodologies employed to assess intervention costs, potential savings, net costs, CE, and the financial sustainability of behavioral health interventions to promote oral health. METHODS: We provide an overview of terminology and strategies for conducting economic evaluations of behavioral interventions to improve oral health based on the recommendations of the Panel of Cost-Effectiveness in Health and Medicine. To illustrate these approaches, we summarize methodologies and findings from a limited number of published studies. The strategies include methods for assessing intervention costs, potential savings, net costs, CE, and financial sustainability from various perspectives (e.g., health-care provider, health system, health payer, employer, society). Statistical methods for estimating short-term and long-term economic outcomes and for examining the sensitivity of economic outcomes to cost parameters are described. DISCUSSION: Through the use of established protocols for evaluating costs and savings, it is possible to assess and compare intervention costs, net costs, CE, and financial sustainability. The addition of economic outcomes to outcomes reflecting effectiveness, appropriateness, acceptability, and organizational sustainability strengthens evaluations of oral health interventions and increases the potential that those found to be successful in research settings will be disseminated more broadly. PMID- 21656967 TI - Economic context of employing behavioral interventions to improve oral health. PMID- 21656968 TI - Enhancing the usefulness of results from economic evaluations of behavioral health interventions. PMID- 21656969 TI - Behavioral and social intervention research at the National Institute of Dental and Craniofacial Research (NIDCR). PMID- 21656990 TI - [Community-associated MRSA: current status and molecular epidemiological perspective]. PMID- 21656991 TI - [City type MRSA infection]. PMID- 21656992 TI - [Hyperthermia. Modification of body temperature as clinical therapeutics]. AB - The application of heat or cold therapy is called thermotherapy Thermotherapy has been used since ancient times, Egyptians, Greeks and Romans used solar radiation or submersion in springs to apply heat and ice and snow for cold application. The first scientific references related to thermotherapy appear in late eighteenth century but the twentieth century when the introduction of new forms of deep heat therapy have expanded their capabilities and their operation with media surface more comfortable and effective. Thermotherapy although they require more experimentation to obtain a solid scientific proof that their use is raising great expectations in various fields such as oncology treatment, surgery neurology etc. In the surgical field thermal ablation has been used successfully in the treatment of various diseases, benign prostatic hyperplasia, liver and gynecological tumors, among others. In the field of oncology has been shown to improve outcomes diathermy applied in conjunction with chemo and radiation therapy Based on the literature review describing the main uses of the change in temperature as a therapeutic, the main indications for these techniques, as applicable, evidence of its benefits and complications arising from their use. PMID- 21656993 TI - [Czech perinatology in the future]. PMID- 21656994 TI - [Prognosis of the level of perinatal care in the Czech Republic in near future. I. Development of perinatal indicators in the Czech Republic]. AB - AIM OF THE STUDY: Prognosis of the development of perinatal care in the Czech Republic in near future. STUDY DESIGN: Nation-wide perinatal epidemiological study. SETTING: Institute for the Care of Mother and Child, Prague-Podoli. METHODS: Four basic conditions for prognosis: previous prognosis, current status (previous and actual nationwide perinatal data), current environment, and international data for comparison. RESULTS: Prognosis of the Czechoslovak Academy of Science from the beginning of eighties to lower perinatal mortality from 15/1000 to 10/1000 until the year 2000 was accomplished already in 1989. Prognosis of Scientific Board of the Czech Ministry of Health from 2004 analyzed in the first part the causes of improvement of perinatal mortality before and after 1990 and the reasons for increase of newborns under 2000 grams and cesarean sections in 90s. The second part of this prognosis predicted stagnation of perinatal mortality around 4/1000 until the year 2000 and postulated two alternatives for low birth-weight rate from 5.9% to a) 6.9% and b) 8.0% and cesarean section rates increase from 13.5% to a) 17% and b) 22%. This projection was based on previous two prognoses, on the data from the year 2000, and on the analysis of demographic and economic circumstances, and on the comparison of international perinatal data. According to the prognosis, the perinatal mortality decreased to 3.4/1000 in 2009, and the low birth-weight rate and cesarean section rate increased according to the alternative b). Increase of centralization of preterm newborns under 1500 grams and improvement of their birth-weight specific early neonatal mortality (the factors which played the main role in decrease of perinatal mortality before) have already stopped. In the situation of further increase of low birth-weight rate and further deterioration of other negative factors we could expect increase of perinatal mortality above 4/1000. CONCLUSION: According to the two previous prognoses we observed improvements of perinatal care. While the reserves for the continuing improvement (medical and organizational) are already exhausted and while the conditions for provision of care are worsening, we could expect worse perinatal results in terms of further increase of low birth-weight rate, increase of cesarean section rate, and elevation of perinatal mortality above 4/1000. PMID- 21656995 TI - [Prognosis of the level of perinatal care in the Czech Republic in near future II. From the World Health Organization point of view]. AB - AIM OF THE STUDY: Evaluation of performance according to Goals of the WHO Project Health for All 21 in the Czech Republic. STUDY DESIGN: Comparative study of the WHO recommendations and the situation in the Czech Republic. SETTING: Institute for the Care of Mother and Child, Prague-Podoli. METHODS: Comparison of completion of 4 out of 21 Goals of the WHO Project Health for All 21 related to perinatal care in the Czech Republic. RESULTS: After experience with the WHO Project HFA 2000 for Europe (introduced in late 70s) consisting of 38 goals for particular fields of medicine to be achieved by the end of 2000 (adapted in 1992), the WHO Project HFA 21 with 21 Goals to be achieved by 2020 was introduced. While in relation to the Project HFA 2000 the Czech Republic analyzed the situation in 1993 without application of individual goals into the health care system, in 2003 the group of experts prepared "Recommendation for achievements of the Goals" of the WHO Project HFA 21. In 4 goals related to perinatal care, the recommendation postulated the ways and timeline and responsibilities in effort to accomplish these tasks. The evaluation of achievements by the year 2009 is attached. In the Goal 3, related to indicators of perinatal care, we have accomplish the decrease of perinatal mortality and the Czech Republic got among countries with the best results. On contrary, we have observed increase of low birth-weight rate and increase of frequency of cesarean delivery, and increase of drug abuse among pregnant women. The legislature in the field of long-term follow-up of handicapped children was not prepared. In the Goal 15 the Czech Republic accomplished the introduction of functional organizational system of care. In the Goal 17, the financing of high level of care was underestimated. In the Goal 20, the health care policy was not prepared to fulfill the requirements of this Goal. CONCLUSION: Comparison of recommendation of the 4 goals of the WHO Project Health for All 21 related to perinatal care in the Czech Republic and the national recommendations was confronted with the results. While the improvements of indicators of level of care and introduction of organization of perinatal care were achieved, the lack of health care policy was the main deficiency of the system. PMID- 21656996 TI - [Prognosis of the level of perinatal care in the Czech Republic in near future III. From the current medicine point of view]. AB - AIM OF THE STUDY: Resolution of discrepancy between advances in medicine and limited resources. STUDY DESIGN: Evaluation of the international stand on this issue. METHODS: Comparison of international approaches and management in the Czech Republic. SETTING: Institute for the Care of Mother and Child, Prague Podoli. RESULTS: The aim of international projects "The Goals of Medicine" and "Social Determinants of Health" was to solve the discrepancy in between current advances in medicine and possibilities to introduce them in the environment of limited resources, coming predominantly from general medical insurance and partly from the government budget. These advances are on one hand the possibility to prolong life of several newborns who were to die before due to better diagnosis and treatment - this though drains substantial proportion of limited resources, on the other hand the improved and resources-demanding prevention measures can maintain good health status of numerous selected risk groups of the population. One of the recommendations of these projects was suggestion to governments to relay and interpret this information to general public this conflict and in discussions with care providers and consumers to balance such level of care which is available to all with respect to social equity. The extent of completion of recommendation of the two international projects and WHO HFA 21 Goals is the matter of summary discussion of all three parts of publication. It is also a base for prognosis of perinatal care level in the Czech Republic in near future. CONCLUSION: Two international projects suggested recommendations how to deal with disparity in between advances in medicine and limited resources. The stand of the Czech Republic on this issue is a matter of summary discussion to all three parts of this publication. It is also a basis for prognosis of level of perinatal care in the Czech Republic in near future. PMID- 21656997 TI - [Analysis of perinatological outcome of Slovak Republic in the years 2007-2009]. AB - OBJECTIVE: Analysis of perinatological outcome in Slovak Republic in the years 2007-2009. DESIGN: Epidemiological perinatological nation-wide. SETTINGS: 1st Department of Gynaecology and Obstetrics School of Medicine, Comenius University and University Hospital, Bratislava, Slovak Republic. METHODS: Retrospective analysis of some perinatological data from the years 2007-2009 available in database of expert for gynaecology and obstetrics Ministry of Health Slovak Republic. RESULTS: The number of maternity hospitals decreased from 63 to 57 in the years 2007-2009. Total number of deliveries increased from 51,146 to 56,094 and that of live births from 51,650 to 56,579 in this period. Perinatal mortality rate was 6.2, 6.6 and 6.0 per 1000 in the years 2007, 2008 and 2009 respectively. Caesarean section rate progressively increased from 24.1% to 27.4% in this period. Preterm deliveries rate ranged between 7.3% and 7.5% and that of multiple pregnancies 1.3% and 1.4%. Maternal mortality ratio increased from 8 to 25 per 100,000 live births. CONCLUSION: Perinatal mortality rate 6.0 per thousand is the best result of Slovak perinatological history. Caesarean rate frequency rapidly increased up to 27.4% in the year 2009. Centralisation of high-risk pregnancies, transfer "in utero" and prenatal detection of congenital malformations are still to be improved in Slovakia. PMID- 21656998 TI - [Perinatal indicators of the Zilina region in Slovak Republic during the period 2000-2009]. AB - OBJECTIVE: To provide health care providers, patients, and the general public the improvements and objective data outcomes in perinatal health care indicators for the Zilina district, northern part of Slovak republic. SETTING: Martin perinatology center (Department of Gynecology and Obstetrics, Department of Neonatology, Jessenius Medical Faculty, Commenius University, Martin, Slovak Republic). SUBJECT AND METHOD: Retrospective analysis of selected main perinatal outcomes for the period of 10 years (last decade) in the Zilina region. The comparison between the regional data and similar ones retrieved for the Slovak republic. RESULTS: During the analyzed period we have observed a significant decrease in perinatal mortality (PM) with lowest rate of 3.1 per thousand in year 2009 with the 4.13 per thousand decade average. The more favorable trend in PM drop was observed when analyzed separately from congenital disorders, which when compared to national rate decreased by 2.9 per thousand and by 1 per thousand when compared to crude PM in Zilina region for the year 2009. Furthermore, the sophisticated clinical management and improved technical equipment led to the decrease in other main perinatal indicators (e.g. decade average of frequency drop in preterm labors to 5.4%; early neonatal mortality to 2.14 per thousand; stillbirth rate drop to 0.327 per thousand, decrease in neonatal asfyxia rate with pH <7.15 to 0.01% in 2009 with decade average of 0.08% and increased proportion of in-utero transports with 5-years average of 90.9%). Contrary to that, there was revealed a doubling effect of cesarean section rate per observed period (15.7% vs. 32.9%). CONCLUSIONS: Our results showed that the symbiosis in organization of health care, basic and applied clinical research together with improved technical equipment and introducing the WHO guidelines into the obstetrical praxis has prepared the clinical background which led to the immense improvement in the perinatal outcomes in the northern part of Slovakia during the last decade. PMID- 21656999 TI - [Proteomics and biomarkers for detection of preterm labor: a systematic review]. AB - OBJECTIVE: To review the published articles about identification of biomarkers of spontaneous preterm birth using a proteomic approach and to create a list of potential biomarkers. DESIGN: Systematic review of literature. SETTING: Department of Obstetrics and Gynecology, Medical Faculty Charles University Hradec Kralove. METHODS: The following databases were accessed in search of relevant citation: MEDLINE, SCOPUS and PubMed. Totally 101 references were identified and relevant 37 abstracts were screened. As appropriated were pointed 16 studies. Finally, the data were extracted from five articles. CONCLUSION: The implementation of high-throughput technologies is necessary in the field of spontaneous preterm birth research. A compelling option is the use of proteomics in the area spontaneous preterm birth biomarkers identification in amniotic fluid, maternal serum/plasma, cervical-vaginal fluid and placental tissue. The data was extracted from published articles and a list of 72 proteins was created. PMID- 21657000 TI - [Innate immunity in pathogenesis of intraamniotic inflammation in pregnancies complicated by preterm premature rupture of membranes]. AB - OBJECTIVE: To give an overview about the role of the innate immunity in pathogenesis of intraamniotic inflammation in pregnancies complicated by preterm premature rupture of membranes. DESIGN: Review article. SETTING: Department of Clinical Immunology and Allergy, Faculty of Medicine and University Hospital in Hradec Kralove, Charles University in Prague. METHOD: An overview of recent published data. CONCLUSION: Immune system has an indisplaceable function throughout the successful pregnancy. Spontaneous labor is the result of many factors in which innate immunity playes a major role. The increased concentrations of proinflammatory markers (interleukin (IL)-1beta, IL-6, tumour necrosis factor alfa a IL-8) were found in amniotic fluid both in term and in preterm spontaneous delivery. These markers could be used for an early diagnosis of intraamnial infection/inflammation, which is the most common cause of preterm delivery (PTD) and preterm premature rupture of membranes (PPROM). The elevation of these markers could also better determine the patients with enhanced probability of PTD and PPROM. PMID- 21657001 TI - [Substitution of prenatal karyotyping with targeted QFPCR--cytogenetic residual risk assessment]. AB - OBJECTIVE: Molecular techniques focused on detection of common aneuploidies--FISH and QFPCR--provide a quick result in prenatal diagnosis. There is a trend to apply these rapid tests as 'stand-alone' tests which would lead to substantial economical savings. The purpose of the retrospective study is to determine the frequency of chromosomal aberrations (CA) which would be missed by this tool in particular indication groups--residual cytogenetic risk. DESIGN: Retrospective study. SETTING: Department of Medical Genetics and Foetal Medicine University Hospital Olomouc. METHOD: 5305 prenatal samples were examined and the frequency of QFPCR undetected CA (structural and rare aneuploidies) was observed. RESULTS: The residual risk in patients referred for abnormal results of current prenatal screening programs for Down syndrome or for maternal age, without any ultrasound (US) pathological findings, was 0.9%. It was 6.9% in the group where US pathological findings or family history of CA were present. CONCLUSION: The rapid test can replace karyotyping if there is a risk for CA based exclusively on abnormal results of current screening programes for Down syndrome or age related risk, providing that US is normal. PMID- 21657002 TI - [Use of psychoactive substances and risk sexual behavior]. AB - OBJECTIVE: Present influence of illicit drug and alcohol on risk sexual behavior of young women in Prague and Central Bohemia. DESIGN OF THE STUDY: Prospective study. SETTING: Department of Gynecology and Obstetrics, Teaching Hospital and 2nd Medical Faculty of Charles University in Prague. METHODS: The study participants were 400 sexual active women between 16 and 35 years of age living in Prague and Central Bohemia. All participants were asked via questionnaire illicit drugs and alcohol experience, number of sexual partners, sexual behavior and use condom. RESULTS: Women using illicit drugs or alcohol had higher number of sexual partners. 1/3 said that drinking or drug use has influenced their decisions about sex and sexual behavior and unprotected sex. CONCLUSION: Use of psychoactive substances including alcohol influence negative sexual behavior. Cause escalated sexual activity and promiscuity, more frequently have risk and unprotected sex. PMID- 21657003 TI - [Female sexual desire disorders--prevalence, classification and treatment possibilities]. AB - OBJECTIVE: Description of female Hypoactive Sexual Desire Disorder (HSDD) and its prevalence, information on possible ways of diagnosis, definition of models of female sexual behaviour, classification of female sexual dysfunctions and perspective on treatment possibilities. SUBJECT: Systematic review. SETTING: GONA, Private Sexuology Centre, Prague. SUBJECT AND METHODS: Current literature review. CONCLUSION: Low sexual desire is present in more than 40% of the female population. 10-16% of women report personal distress associated with low sexual desire and which is characteristic of HSDD. Standardized questionnaires are used for HSDD diagnosis. Current treatment modalities do not provide satisfactory results and require further research. PMID- 21657004 TI - [The effectiveness of recurrent stress urinary incontinence treatment after Burch colposuspension failure with transobturatory tape procedure]. AB - OBJECTIVE: To evaluate the safety and efficacy of the transobturatory tape (TOT) procedure in the treatment of female recurrent stress urinary incontinence after the Burch colposuspension failure. DESIGN: Retrospective clinical trial. SETTING: Obstetrics and Gynecology Department, Charles University, 2nd Medical School and Faculty Hospital Motol, Prague. METHODS: The group of fifteen women was treated for recurrent stress urinary incontinence with TOT procedure. Preoperative evaluation consisted of complete urogynecological examination. The cure rate and complications were determined in postoperative follow up 6 weeks and 12 months after the surgery. RESULTS: The mean age was 58.7 (46-64) years. Burch colposuspension was performed 6.4 (1-13) years before current TOT procedure. The cure rate in 12 month follow-up was 86.6% (13 of 15 patients), one patient was improved (6.7%). Postoperative complications occurred in 2 (13.4%) cases--one lower urinary tract infection and one overactive bladder symptomatology cured by anticholinergic therapy. CONCLUSION: The study showed that the TOT procedure is a safe and effective minimally invasive method in the treatment of recurrent stress urinary incontinence after Burch colposuspension. PMID- 21657005 TI - [Fatal course of neonatal citrobacter infection and its legal evaluation]. AB - OBJECTIVE: The article describes fatal course of citrobacter central nervous system infection in the neonates and the subsequent legal responsibility of the medical facility. SUBJECT: Case report with the review of a lawyer specialized in medical law. SETTING: Department of Obstetrics and Gynecology, Faculty of Health Studies, University of Pardubice, Pardubice, Faculty of Military Health Science, University of Defence, Hradec Kralove. CONCLUSION: The court granted plaintiff's claim has been fully paid by the insurance company, since it did not show the fault of the medical facility. Health injury was caused by operational activities and the right to compensation is in accordance with Section 420a of the Civil Code. PMID- 21657006 TI - [Ecological memory and its potential applications in ecology: a review]. AB - Ecological memory (EM) is defined as the capability of the past states or experiences of a community to influence the present or future ecological responses of the community. As a relatively new concept, EM has received considerable attention in the study of ecosystem structure and function, such as community succession, ecological restoration, biological invasion, and natural resource management. This review summarized the definition, components, and categories of EM, and discussed the possible mechanisms and affecting factors of EM. Also, the potential applications of EM were proposed, in order to further understand the mechanisms of community succession and to guide ecological restoration. PMID- 21657007 TI - [Vegetation above-ground biomass and its affecting factors in water/wind erosion crisscross region on Loess Plateau]. AB - Field investigations were conducted in Liudaogou small watershed in late September 2009 to study the differences of vegetation above-ground biomass, soil moisture content, and soil nutrient contents under different land use patterns, aimed to approach the vegetation above-ground biomass level and related affecting factors in typical small watershed in water/wind erosion crisscross region on Loess Plateau. The above-ground dry biomass of the main vegetations in Liudaogou was 177-2207 g x m(-2), and that in corn field, millet field, abandoned farmland, artificial grassland, natural grassland, and shrub land was 2097-2207, 518-775, 248-578, 280-545, 177-396, and 372-680 g x m(-2), respectively. The mean soil moisture content in 0-100 layer was the highest (14.2%) in farmlands and the lowest (10.9%) in shrub land. The coefficient of variation of soil moisture content was the greatest (26. 7% ) in abandoned farmland, indicating the strong spatial heterogeneity of soil moisture in this kind of farmland. The mean soil water storage was in the order of farmland > artificial grassland > natural grassland > shrub land. Soil dry layer was observed in alfalfa and caragana lands. There was a significant positive correlation (r = 0.639, P < 0.05) between above-ground dry biomass and 0-100 cm soil water storage, and also, a very significant positive correlation between above-ground fresh biomass and vegetation height. The above-ground biomass of the higher vegetations could potentially better control the wind and water erosion in the water/wind erosion crisscross region. Vegetation above-ground biomass was highly correlated with soil moisture and nutrient contents, but had no significant correlations with elevation, slope gradient, slope aspect, and soil bulk density. PMID- 21657008 TI - [Relationships between initial chemical composition of forest leaf litters and their decomposition rates in degraded red soil hilly region of Southern China]. AB - A pot experiment with litter bags was conducted to study the relationships between the initial chemical composition of 8 kind forest leaf litters and 4 kind mixed leaf litters and their decomposition rates in degraded red soil hilly region of Southern China. Comparing with needle-leaf litters, broad-leaf litters had significantly higher contents of N, P, K, and Mg, but significantly lower contents of lignin and C. The decomposition rates of test litters were significantly positively correlated with the litters initial contents of N, P, K, and Mg (P < 0.05), and negatively correlated with the initial contents of lignin and C as well as the lignin/N, lignin/P, and C/P ratios (P < 0. 05). The lignin content explained 54.3% of the variation in litter decomposition rates, being the key affecting factor. Litters C, N, and P contents also had close correlations with the decomposition rates, and together with lignin content, contributed 81.4% of the variation. It was suggested that in the process of vegetation restoration in degraded red soil hilly region of Southern China, introducing broad-leaf trees with lower lignin and higher N and P contents would benefit the acceleration of forest litters decomposition and the restoration of soil fertility. PMID- 21657009 TI - [Magnolia liliiflora whole-tree sap flow in response to multiple environmental variables in Beijing]. AB - In order to clarify the environmental factors affecting the water use of typical urban tree species Magnolia liliflora, an investigation was conducted on the responses of M. liliiflora whole-tree sap flow to the air temperature, air relative humidity, radiation, wind speed, soil temperature and water content, and precipitation in Beijing from April to October, 2008. The eight environmental factors affecting M. liliiflora whole-tree sap flow could be divided into three categories, i.e., evaporative demand index, soil index, and precipitation index. The evaporative demand index (air temperature, air relative humidity, total radiation, wind speed, and vapor pressure deficit) could explain 60% of the variation in the sap flow of individual trees, which presented S-type change trend, i.e., the sap flow reached an asymptote where higher light and evaporative demands could not cause sap flow to increase further. Soil index (soil temperature and water content) and precipitation index (precipitation amount) had little influence on the sap flow. PMID- 21657010 TI - [Spatiotemporal differentiation of construction land expansion in a typical town of south Jiangsu Province]. AB - Choosing Xinzhuang Town in south Jiangsu Province as study area, and by using 1980, 1991, 2001, and 2009 high-resolution remote sensing images and GIS spatial analysis technology, an integrated expansion degree index model was established based on the existing indicators of construction land expansion, and the general and spatiotemporal differentiation characteristics of construction land expansion in the Town in three time periods of 1980-2009 were quantitatively analyzed. In 1980-2009, with the acceleration of rural urbanization and industrialization, the area of construction land in the Town increased significantly by 19.24 km2, and especially in 2001-2009, the expanded area, expanded contribution rate, and expansion intensity reached the maximum. The construction land expansion had an obvious spatial differentiation characteristic. In 1980-1991, the newly increased construction land mainly concentrated in town area. After 1991, the focus of construction land gradually spread to the villages with developed industries. Most of the increased construction lands were converted from paddy field and dry land, accounting for 88.1% of the total increased area, while the contribution from other land types was relatively small. PMID- 21657011 TI - [Interaction between pest and fire disturbances in Huzhong area of Great Xing' an Mountains: long-term simulation]. AB - Forest pest and forest fire are the two major disturbances of forest ecosystem, and there exists definite interaction between the disturbances at large spatial and temporal scales. In this paper, the spatially intuitional landscape model (LANDIS) was adopted to simulate the long-term (300 years) interaction between forest pest and forest fire in Huzhong area of Great Xing' an Mountains. The results showed that pest disturbance decreased the fine fuel load, increased the coarse fuel load at the early (0-100 a) and middle (100-200 a) stages of simulation course, and decreased the fire frequency at the early and middle stages. The fire frequency under different forest pest disturbance scenarios was similar at the later stage (200-300 a) of simulation course. Pest disturbance decreased the fire intensity and fire risk class at the early and later stages, but increased the fire intensity and fire risk class at the middle stage. Fire suppression could increase the occurrence area of forest pest, and thus, it was suggested that forest managers should take appropriate measures to prevent insect pest, not solely with the focus on fire suppression but also adopting the forest fire management measures such as taking off coarse fuel and implementing prescribed fire to ensure the sustainable development of forest ecosystem. PMID- 21657012 TI - [137Cs profile distribution character and its implication for soil erosion on Karst slopes of northwest Guangxi]. AB - This paper studied the profile distribution characters of 137Cs and soil organic carbon (SOC) on the Karst slopes and in the fissures in typical peak-cluster depression in Northwest Guangxi, aimed to approach the applicability of 137Cs method on Karst slopes and the implication of 37Cs for the characteristics of slope soil erosion. In all test profiles, there was a significant correlation between 137Cs and SOC, indicating that both of them might have the same loss pathway. On the slopes under secondary forests, 137Cs mainly existed within the depth 0-24 cm. On the upper middle and middle slope sites, 137Cs had an exponential decrease with depth, indicating no or slight surface erosion; while on the foot slope site, the distribution pattern of 137Cs indicated severer erosion. On the slopes with cultivated lands, 137Cs distributed uniformly within the plough layer. In the upper middle and middle slopes profiles, 137Cs mainly existed in the depth around 15 cm and far less than the background value, indicating severe soil erosion; while in foot slope profiles, 137Cs was aggraded to the depth 45 cm. A discontinuous distribution of 137Cs in the profiles was detected on the foot slopes under secondary forests, on the upper middle and foot slopes of cultivated lands, and in the fissures, indicating that the soil particles on Karst slopes had a trend of losing with rainwater to the underground, but the loss quantity was negligible, compared with surface erosion. PMID- 21657013 TI - [Soil heterotrophic respiration and its sensitivity to soil temperature and moisture in Liquidambar formosana and Pinus massoniana forests in hilly areas of southeast Hubei Province, China]. AB - Field monitoring was conducted to study the annual dynamics of soil heterotrophic respiration and soil temperature and moisture in Liquidambar formosana and Pinus massoniana forests in hilly areas of southeast Hubei Province, China. At the same time, laboratory experiment was performed to study the heterotrophic respiration rate along soil profile, and the sensitivity of surface soil (0-5 cm) heterotrophic respiration to soil temperature and moisture. Then, a model was established to valuate the potential effects of warming change on the soil heterotrophic respiration in study area. In L. formosana and P. massoniana forests, the soil heterotrophic respiration rate in 0-5 cm layer was 2.39 and 2.62 times, and 2.01 and 2.94 times of that in 5-10 cm and 10-20 cm layers, respectively, illustrating that soil heterotrophic respiration mainly occurred in 0-5 cm surface layer. The temperature sensitivity factor (Q10) of soil heterotrophic respiration in 0-5 cm, 5-10 cm, and 10-20 cm layers was 2.10, 1.86, and 1.78 in L. formosana forest, and 1.86, 1.77, and 1.44 in P. massoniana forest, respectively. The relationship between surface soil heterotrophic respiration and temperature (T) well fitted exponential function R = alphaexp (beta3T), and that between surface soil heterotrophic respiration and moisture (W) well fitted quadratic function R = a+bW+cW2. Therefore, the relationship of surface soil heterotrophic respiration with soil temperature and moisture could be described by the model lnR = a+bW+cW2 +dT+eT2, which suggested that the response of soil heterotrophic respiration to soil moisture was depended on soil temperature, i.e., the sensitivity decreased with decreasing soil temperature. The calculation of the annual soil heterotrophic respiration rate in the two forests with the established model showed that the calculated respiration rate was a slightly higher in L. formosana forest but close to the measured one in P. massoniana forest, illustrating the applied importance of the model. Our results suggested that the soil heterotrophic respiration in the L. formosana and P. massoniana forests in hilly areas of southeast Hubei Province would have an obvious increase under the background of global warming. PMID- 21657014 TI - [Energy balance and evapotranspiration in broad-leaved Korean pine forest in Changbai Mountains]. AB - Based on the continuous measurements of an open-path eddy covariance system, this paper analyzed the characteristics of energy balance components and evapotranspiration in a broad-leaved Korean pine forest in Changbai Mountains in 2008, as well as the differences of energy balance components and evapotranspiration between growth season and dormant season. For the test forest, the year-round energy balance closure was 72%, being at a medium level, compared to the other studies in the Fluxnet community. The energy balance components had significant differences in their diurnal and seasonal variations. In growth season, turbulent energy exchange was dominated by upward latent heat flux, accounting for 66% of available energy; while in dormant season, the turbulent energy exchange was dominated by upward sensible heat flux, accounting for 63% of available energy. The accumulated annual evapotranspiration in the study site in 2008 was 484.7 mm, occupying 87% of the precipitation at the same time period (558.9 mm), which demonstrated that evapotranspiration was the main water loss item in temperate forests of northern China. PMID- 21657015 TI - [Soil heavy metals concentration in different type plantations in Harbin City]. AB - In order to understand the soil heavy metals characteristics in different type plantations in Harbin City, 0-10 cm and 10-30 cm soil samples were collected from eight mono-cultured plantations (Larix gmelinii, Pinus sylvestris var. mongolica, Pinus tabulaeformis var. mukdensis, Phellodendron amurense, Juglans mandshurica, Fraxinus mandshurica, Betula platyphylla, and Quercus mongolica) and one mixed plantation (P. sylvestris var. mongolica + F. mandshurica + Pinus koraiensis + P. amurense + B. platyphylla) established in the Urban Forestry Demonstration Research Base of Northeast Forestry University in the 1950s to analyze the concentrations of Cu, Zn, Cd, Ni, Pb, and As, and the comprehensive pollution index was used to assess the soil heavy metals pollution in the plantations, based on the background values of black soil in the City. There existed significant differences in the heavy metals concentration in the same soil layers among different type plantations. In the test plantations, the concentrations of soil heavy metals except As and Ni tended to decrease with soil depth. In the same soil layers, Zn had the highest concentration (62.29-126.35 mg x kg(-1)), while Cd had the lowest one (0.06-0.47 mg x kg(-1)). The abundance and accumulation tendency of test heavy metals in the plantations was in the order of Zn>Pb>Cu(Ni)> Ni(Cu)>As>Cd, and Cd>Pb>Zn>Cu>Ni>As, respectively. There existed positive correlations among soil Cu, Zn, Pb, and Cd concentrations in the plantations except F. mandshurica, and the concentrations of these four heavy metals in the plantations except F. mandshurica and Q. mongolica were positively correlated with soil organic matter, N, P, and K. The concentrations of soil Cd, Pb, Zn, and Cu were higher than the background values, suggesting the anthropogenic inputs; while those of Ni and As were similar to or lower than the background values, suggesting the origin from soil materials. The soil comprehensive pollution index of the plantations was decreased in the order of F. mandshurica > P. amurense > mixed plantation > J. mandshurica > P. sylvestris var. mongolica > P. tabulaeformis var. mukdensis > L. gmelinii >B. platyphylla > Q. mongolica. PMID- 21657016 TI - [Vegetation net primary productivity in Northeast China in 2000-2008: simulation and seasonal change]. AB - By using GLOPEM-CEVSA model, the spatiotemporal pattern and its affecting factors of the vegetation net primary productivity (NPP) in Northeast China in 2000-2008 were simulated, and, taking four forest ecosystem stations (Daxing' anling, Laoyeling, Liangshui and Changbai Mountains) as the cases, the seasonal changes and their main driving force of forest NPP in Northeast China were studied. In 2000-2008, the annual averaged vegetation NPP in the region was 445 g C x m(-2) x a(-1), being the highest in the areas from Changbai Mountains to Xiaoxing' anling Mountains and parts of Sanjiang Plain, followed by in the areas from Changbai Mountains to Liaohe River Plain, eastern Songnen Plain, Sanjiang Plain, and Daxing' anling Mountain, and the lowest in the sparse grass and desert areas in the west. Forest ecosystem had the highest annual averaged NPP, followed by shrub, cropland and grassland, and desert. In forest ecosystem, coniferous and broad-leaf mixed forests had the highest annual averaged NPP (722 g C x m(-2) x a(-1)), while deciduous needle-leaf forest had the lowest one (451 g C x m(-2) x a(-1)). During the study period, no significant inter-annual changes were observed in the forest NPP though it was higher in 2007 and 2008 probably due to the increased air temperature (1 degrees C-2 degrees C higher than that in other years). The beginning time of forest growth season in Northeast China advanced gradually from north to south, and the growth season became longer. PMID- 21657017 TI - [Effects of simulated nitrogen deposition on soil acid phosphomonoesterase activity and soil available phosphorus content in subtropical forests in Dinghushan Mountain]. AB - An in situ field experiment was conducted to study the effects of simulated nitrogen (N) deposition on soil acid phosphomonoesterase activity (APA) and soil available phosphorous (AP) content in Pinus massoniana forest (PF), coniferous and broad-leaved mixed forest (MF), and monsoon evergreen broad-leaved forest (MEBF) in Dinghushan Mountain. In PF and MF, three treatments were installed, i.e., CK (0 kg N x hm(-2) x a(-1)), low N (50 kg N x hm(-2) x a(-1)), and medium N (100 kg N x hm(-2) x a(-1)); in MEBF, four treatments were installed, i.e., CK, low N, medium N, and high N (150 kg N x hm(-2) x a(-1)). The soil APA and soil AP content decreased with soil depth. The soil APA was the highest in MEBF, while the AP content had no significant difference in the three forests. The effects of N addition on soil APA differed with forest types. In MEBF, the APA was the highest (19.52 micromol x g(-1) x h(-1)) in low N treatment; while in PF and MF, the APA was the highest (12.74 and 11.02 micromol x g(-1) x h(-1), respectively) in medium N treatment. In the three forests, soil AP content was the highest in low N treatment, but had no significant differences among the N treatments. There was a significant positive correlation between soil APA and soil AP content. PMID- 21657018 TI - [Spatiotemporal variations of aboveground biomass and leaf area index of typical grassland in tower flux footprint]. AB - By using cyclic sampling method, the aboveground biomass and leaf area index (LAI) of typical grassland in tower flux footprint were measured at three growth stages, i.e., early July (July 2-7), late July (July 20-26), and late August (Aug. 25-30), with their spatial patterns analyzed by geostatistics. At the three stages, the aboveground biomass of the grassland kept rising, while the LAI decreased after an initial increase. Both the two variables had good spatial autocorrelation, with similar spatial pattern and temporal evolution trend, and changed from stripe to patch. From early July to late August, the C0/(C0+C) of the aboveground biomass and LAI all decreased significantly, indicating that the spatial autocorrelation of the two variables changed from medium to high. The change ranges of the two variables gradually decreased, presenting the decrease of spatial continuity. The fractal dimension (D) also decreased gradually, suggesting the increase of spatial dependence. Topography and field management were the main factors affecting the spatial distribution of aboveground biomass and LAI, which induced the spatial variability of water and heat, and further, affected the grass growth. PMID- 21657019 TI - [Photosynthesis and transpiration characteristics of female and male Trichosanthes kirilowii Maxim individuals]. AB - A field research was conducted on the photosynthesis and transpiration characteristics of dioecious Trichosanthes kirilowii individuals at four key development stages. At vegetative growth stage, the photosynthesis rate, transpiration rate, stomatal conductance, and water use efficiency of male individuals were higher than those of female individuals, and hence, male individuals entered into reproductive growth stage 22 days earlier than female individuals. After entering into reproductive growth stage, male individuals had higher photosynthesis rate, transpiration rate, and stomatal conductance, but slightly lower water use efficiency than female individuals. As the female individuals started to reproductive growth, their photosynthesis rate and water use efficiency were significantly lower, while the transpiration rate and stomatal conductance were higher than those of the male individuals. The effects of climate factors on the growth and development of T. kirilowii mainly occurred at its vegetative growth and early reproductive growth stages, and weakened at later reproductive growth stages. Higher temperature and lower relative humidity benefited the growth and development of T. kirilowii, and illumination could enhance the photosynthesis rate of T. kirilowii, especially its male individuals. After entering into reproductive growth stage, the photosynthesis rate of male individuals increased significantly with increasing illumination, but that of female individuals only had a slight increase, and the transpiration rate of male individuals as well as the photosynthesis rate of female individuals all increased significantly with increasing temperature. PMID- 21657020 TI - [Effects of drought stress on physiological and biochemical parameters of Dahlia pinnata]. AB - Taking Dahlia pinnata 'Fenxishi' as test material, this paper studied its leaf physiological and biochemical responses to different degrees of drought stress and re-watering. With the increasing extent and duration of drought stress, the leaf relative water content, water potential, and chlorophyll content of D. pinnata 'Fenxishi' decreased significantly, leaf relative electric conductivity and malondialdehyde (MDA) content had a significant increase, plasma membrane was damaged, and massive ions were leaked out. The damage of plasma membrane was most serious under severe stress, and could not recover to the control level after re watering. The leaf soluble sugar and proline contents also increased significantly with increasing extent and duration of drought stress. Especially for proline content, it was increased significantly in the later period of moderate and severe stresses, suggesting its lower sensitivity to water deficit. The leaf soluble protein content had a trend of down-up-down, while the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) decreased after an initial increase. There were some differences in the responses of the three enzymes to drought stress and reactive oxygen, exhibiting their coordinating role. PMID- 21657021 TI - [Soil organic carbon content and its distribution pattern in Hangzhou Bay coastal wetlands]. AB - In this paper, the soil organic carbon (SOC) content and its distribution pattern in the natural intertidal zones and reclaimed wetlands of Hangzhou Bay were studied, aimed to explore the effects of vegetation succession, exotic species invasion, and reclamation on the SOC in costal wetlands of the Bay. In intertidal zones, the surface SOC content ranged from 4.41 to 8.58 g x kg(-1), with an average of 6.45 g x kg(-1), and differed significantly under different vegetations, with a tendency of under Phragmites australis (8.56 +/- 0.04 g x kg( 1)) > Spartina alterniflora (7.31 +/- 0.08 g x kg(-1)) > Scirpus mariqueter (5.48 +/- 0.29 g x kg(-1)) > mudflats (4.47 +/- 0.09 g x kg(-1)); in reclaimed wetlands, the surface SOC content was 7.46 +/- 0.25 g x kg(-1) in the 1960s, 1.96 +/- 0.46 g x kg(-1) in the 1980s, and 5.12 +/- 0.16 g x kg(-1) in 2003, showing a trend of increased after an initial decrease with increasing reclamation year. The SOC in the profiles all showed a decreasing trend from the surface to the bottom. The SOC in intertidal zones and reclaimed wetlands was significantly negatively correlated with soil pH, and positively correlated with soil total nitrogen (TN), suggesting a large reserve of organic nitrogen in TN. The correlation between SOC and soil C/N ratio was not obvious in intertidal zones, but significantly positive in reclaimed wetlands, indicating that reclamation affected soil C/N ratio to a certain extent. This study showed that in the intertidal zones, soil carbon sequestration capacity increased gradually with plant community succession. However, the invasion of exotic species Spartina alternflora might decrease the capacity of carbon sequestration in intertidal zones. It was also found that the changes of soil moisture content, particle composition, vegetation coverage, and reclamation history were the main factors affecting the SOC distribution in reclaimed wetlands. PMID- 21657022 TI - [Profile distribution of organic carbon and nitrogen in major soil types in the middle of Qilian Mountains]. AB - This paper studied the distribution patterns of organic carbon (OC), total nitrogen (TN), NH4+ -N, and NO3- -N in the profiles of brown calcic soil, grey cinnamon soil, chestnut soil, and alpine meadow soil in the middle of Qilian Mountains. In all test soils, the contents of OC, TN, NH4+ -N, and NO3- -N decreased with increasing soil depth, and the accumulation and decomposition of OC and various N forms differed with soil types. The average content of OC in different soil profiles changed from 14.01 to 41.17 g x kg(-1), and was in the order of grey cinnamon soil > alpine meadow soil > chestnut soil > brown calcic soil; the average content of TN changed from 1.28 to 2.73 g x kg(-1), with a sequence of alpine meadow soil > grey cinnamon soil > chestnut soil > brown calcic soil. The C/N ratio was from 11.33 to 19.22, with the order of grey cinnamon soil > chestnut soil > alpine meadow soil > brown calcic soil. NH4+ -N content changed from 5.80 to 8.40 mg x kg(-1), and was in the order of brown calcic soil > alpine meadow soil > chestnut soil > grey cinnamon soil; NO3- -N content changed from 6.57 to 15.11 mg x kg(-1), being in the order of chestnut soil > alpine meadow soil > brown calcic soil > grey cinnamon soil. The ratio of NO3- -N to NH4+ -N was 1.00-2.69, with the sequence of grey cinnamon soil > chestnut soil > alpine meadow soil > brown calcic soil. The OC and N contents in the same soil types differed significantly with the conditions of climate, vegetation, and topography (e. g. , slope aspect and slope position). Correlation analysis showed that there were highly significant nositive correlations between OC, TN, and NH4+ -N, but these three items had no significant positive correlations with NO3- -N. Furthermore, there were highly significant positive correlations between available K, NH4+ -N, and NO3- -N and between available P and OC, significant positive correlations between available P, TN, and NH4+ -N, but no significant correlations between pH, total K, and total P and OC and N. PMID- 21657023 TI - [Effects of nitrogen application and elevated atmospheric CO2 on electron transport and energy partitioning in flag leaf photosynthesis of wheat]. AB - Wheat (Triticum aestivum) plants were pot-cultured in open top chambers at the nitrogen application rate of 0 and 200 mg x kg(-1) soil and the atmospheric CO2 concentration of 400 and 760 micromol x mol(-1). Through the determination of flag leaf nitrogen and chlorophyll contents, photosynthetic rate (Pn)-intercellar CO2 concentration (Ci) response curve, and chlorophyll fluorescence parameters at heading stage, the photosynthetic electron transport rate and others were calculated, aimed to investigate the effects of nitrogen application and elevated atmospheric CO2 concentration on the photosynthetic energy partitioning in wheat flag leaves. Elevated atmospheric CO2 concentration decreased the leaf nitrogen and chlorophyll contents, compared with the ambient one, and the chlorophyll a/b ratio increased at the nitrogen application rate of 200 mg x kg(-1). With the application of nitrogen, no evident variations were observed in the maximal photochemical efficiency (Fv/Fm), maximal quantum yield under irradiance (Fv'/Fm') of PS II reaction center, photochemical fluorescence quenching coefficient (q(p)), and actual PS II efficiency under irradiance (phi(PS II) at elevated atmospheric CO2 concentration, and the total photosynthetic electron transport rate (J(F)) of PS II reaction center had no evident increase, though the non-photochemical fluorescence quenching coefficient (NPQ) decreased significantly. With no nitrogen application, the Fv'/Fm', psi(PS II), and NPQ at elevated atmospheric CO2 concentration decreased significantly, and the J(F) had a significant decrease though the Fv/Fm and q(p) did not vary remarkably. Nitrogen application increased the J(F) and photochemical electron transport rate (Jc); while elevated atmospheric CO2 concentration decreased the photorespiration electron transport rate (J0), Rubisco oxidation rate (V0), ratio of photorespiration to photochemical electron transport rate (J0/Jc) , and Rubisco oxidation/carboxylation rate (Vo/Vc), but increased the photochemical electron transport rate (Jc) and Rubisco carboxylation rate (Vc). It was concluded that elevated atmospheric CO2 concentration decreased the leaf nitrogen and chlorophyll contents, while nitrogen application increased the photosynthetic electron transport rate of PS II reaction center significantly, and promoted the photosynthetic electron flow towards photochemistry, making more photosynthetic electron take part in Rubisco carboxylation and leading to the significant increase of Pn. PMID- 21657024 TI - [Effects of asymmetric warming on the growth characteristics and yield components of winter wheat under free air temperature increased]. AB - In 2007-2009, a field warming experiment was performed in Nanjing of Jiangsu Province, China to investigate the effects of asymmetric warming (all-day warming, AW; daytime warming from 6:00 to 18:00, DW; and nighttime warming from 18:00 to 6:00, NW) on the growth and development of winter wheat under free air temperature increase (FATI). Asymmetric warming increased the effective tillers and decreased the ineffective tillers. In CK plot, the ineffective tillers were 2.6, 1.7 and 3.5 times of those in AW, DW and NW plots, while the effective tillers were decreased by 13.7%, 3.2%, and 0.5%, respectively. Asymmetric warming also increased the plant height, flag leaf area, and the total green leaf area and green leaf ratio at flowing stage. In treatments AW, DW, and NW, the plant height was increased by 5.6%, 4.5%, and 1.3%, flag leaf area increased by 45.7%, 39.4% and 26.1%, total green leaf area increased by 25.1%, 29.8%, and 17.3%, and green leaf ratio increased by 37.7%, 43.3%, and 38.7%, respectively, compared with CK. As for the yield components, the spikelet number per panicle and the filled grain number per panicle in treatments AW, DW and NW were increased by 4.1%, 5.7%, and 1.7%, and by 2.2%, 5.3%, and 2.6%, respectively. Though the grain/leaf ratio in treatments AW, DW, and NW was decreased by 15.3%, 8.5%, and 11.3%, the thousand-grain mass in the treatments was increased by 6.9%, 6.2% and 11.8%, and thus, the yield per unit was increased by 27.0%, 40.1%, and 18.3%, respectively, compared to the CK. Our results suggested that under anticipated warming, the winter wheat productivity in eastern China would be further enhanced. PMID- 21657025 TI - [Effects of coated controlled release urea combined with conventional urea on winter wheat growth and soil NO3- -N]. AB - Field experiments were conducted to study the effects of different dosages coated controlled release urea (PCU60, 60 d release duration) combined with conventional urea (U) used as basal on the winter wheat grain yield, nitrogen (N) recovery rate, and soil NO3- -N content, etc. Five treatments were installed, i.e., U (CK), 10% PCU60+90% U (PU1), 20% PCU60+80% U (PU2), 30% PCU60+70% U (PU3), and 40% PCU60+60% U (PU4). In the meantime, a comparative analysis was also carried out on the PCU60 N release characteristics under field condition and in 25 "C static water. At the same N dosage, all the test indices in treatment PU4 were significantly higher, with the grain yield, N recovery rate, total N accumulation amount, total tiller number and aboveground biomass at ripening stage, and economic benefit increased by 5.6%, 14.6%, 7.2%, 2.6%, 7.5%, and 984.3 yuan x hm( 2), respectively, compared with those in treatment U. The accumulation amount of NO3- -N in 0-100 cm soil layer in all treatments ranged in 39.70-49.93 kg x hm-2, and was the lowest (39.70 kg x hm(-2)) in treatment PU4. The N release pattern of PCU60 under field condition better fitted the N absorption characteristics of winter wheat. PMID- 21657026 TI - [Differences in water consumption characteristics and grain yield of different wheat cultivars]. AB - A field experiment with 10 wheat cultivars was conducted to study the water consumption characteristics at different growth stages and the differences in the grain yield of the cultivars. Three irrigation treatments were installed, i.e., no irrigation (W0), irrigation before sowing and at jointing stage (W1), and irrigation before sowing and at jointing and anthesis stages (W2), with irrigation amount 60 mm each time. Based on the cluster analysis with the parameters grain yield and water use efficiency (WUE) in the three treatments, the test ten cultivars could be divided into three groups, i.e., high yield and high WUE (Group I), high yield and medium WUE (Group II), and medium yield and low WUE (Group III). The average values of grain yield and WUE in each group were calculated to elucidate the water consumption characteristics of the three groups. In treatment W0, the total water consumption amount in the whole growth period, the water consumption amount from anthesis to maturing stages and its proportion to the total water consumption amount of Group I were lower than those of Group II and Group III, but the grain yield of Group I was the highest. In treatment W1, the water consumption amount from jointing to anthesis stages and its proportion to total water consumption amount of Group I were lower than those of Group II and Group III, but the water consumption amount from anthesis to maturing stages had no significant differences among Group I, Group II, and Group III. In treatment W2, the total soil water consumption amount, water consumption amount from jointing to anthesis stages and its proportion to total water consumption amount of Group I were lower than those of Group II and Group III, while the water consumption amount from anthesis to maturity stages and its proportion to total water consumption amount of both Group I and Group III were lower than those of Group II. In terms of high-yield and water-saving under the present experimental condition, it was implicated that the most appropriate cultivars might fall into the Group I with high yield and high WUE, and the most appropriate irrigation regime with high yield and low water consumption was treatment W1, i.e., irrigated 60 mm each time before sowing and at jointing stage. PMID- 21657027 TI - [Effects of high temperature on leaf photosynthetic characteristics and photosystem II photochemical activity of kernel-used apricot]. AB - In order to explore the photosynthetic adaption mechanisms of kernel-used apricot under high temperature stress, gas exchange technique and chlorophyll fluorescence transient technique (JIP-test) were adopted to study the leaf photosynthetic characteristics and photosystem II (PS II) photochemical activity of 4 year-old 'Chaoren' (Armeniaca vulgaris x sibirica) growing on Horqin sandy land at 25 degrees C, 30 degrees C, 40 degrees C, and 50 degrees C. Within a definite temperature range, and as the temperature increased, the 'Chaoren' could enhance its leaf photosynthetic pigments content and ratio to maintain the light absorption, transfer, and conversion, and thereby, to ensure the function of photosynthetic apparatus. However, when the temperature exceeded the physiological adjustment threshold of leaves, the chlorophyll began to be decomposed, net photosynthetic rate (Pn) declined obviously, and intercellular CO2 concentration (Ci) increased, indicating that the decline in photosynthesis was limited by mesophyll factor. At 40 degrees C, the density of PS II reaction centers per excited cross-section (RC/CS0) dropped distinctly; and at 50 degrees C, the K phase (Wk) and J phase (Vj) in the O-J-I-P chlorophyll fluorescence transients increased distinctly, indicating that high temperature damaged the oxygen-evolving complex (OEC), donor sides, and PS II reaction centers. In addition, the minimum chlorophyll fluorescence (F0) at 50 degrees C increased significantly by 1.26 times, compared with the control, and the maximum photochemical efficiency (Fv/Fm) and performance index (PI(ABS)) reduced to 37.9% and 10.3% of the control, respectively. High temperature injured the function of the donor and acceptor sides in the PS II of photosynthetic apparatus, leading to the decrease of photosynthetic efficiency, and being one of the main mechanisms for the damage of photosynthetic apparatus in kernel-used apricot leaves under high temperature stress. PMID- 21657028 TI - [Thermal dissipation pathway in cucumber seedling leaves under hypoxia stress]. AB - A water culture experiment was conducted to study the relationship between photosynthetic thermal dissipation and xanthophyll cycle in cucumber seedling leaves under hypoxia stress (the dissolved oxygen concentration in nutrient solution was 0.9-1.1 mg x L(-1)). Under the hypoxia stress, there was a significant decrease in the quantum yield of PS II photochemistry rate (phi(PS II)), net photosynthetic rate (Pn) under saturation light intensity, quanta yield (AQY), and maximal photochemical efficiency (Fv/Fm), suggesting that the photoinhibition of the seedling leaves was induced. Meanwhile, the thermal dissipation (NPQ) and the allocation of dissipation energy (D) by antenna increased, but the photochemical quenching apparent (q(p)) decreased, suggesting the enhancement of thermal dissipation in cucumber leaves under hypoxia stress. A positive correlation was observed between NPQ and xanthophyll de-epoxidation state (DEPS), and both of them were promoted by ascorbic acid (AsA) and inhibited by 1,4-dithiothreitol (DTT), suggesting that xanthophyll cycle was the major pathway of photosynthetic thermal dissipation in cucumber seedling leaves under hypoxia stress. PMID- 21657029 TI - [Effects of reduced nitrogen application on the yield, quality, and economic benefit of sugarcane intercropped with soybean]. AB - A two-factor field experiment of randomized block design was conducted in Guangzhou to investigate the effects of reduced nitrogen application on the yield, quality, and total biomass dynamic of sugarcane as well as the economic benefit of the sugarcane population under different sugarcane/soybean intercropping patterns. Neither N application nor intercropping pattern had significant effects on the yield and quality of sugarcane, and no significant differences were observed in the yield and quality of sugarcane among all treatments. The land equivalent ratio (LER) of sugarcane/soybean intercropping at different N application levels was from 1.36 to 2.12, suggesting that sugarcane/soybean intercropping had higher LER than monoculture sugarcane. The total dry matter (except root) of sugarcane in all treatments increased with plant growth, and the growth pattern fitted sigmoid function. At lower nitrogen application level, the eigenvalues of the dynamic dry matter accumulation model were more coordinative, compared with those at higher nitrogen application level, which meant that in the later case, sugarcane had an advanced peak growth time and shortened fast-growth duration, and thereby, its yield decreased. Therefore, it was possible to reasonably adjust nitrogen application level to improve the eigenvalues of the sugarcane dynamic dry matter accumulation model, and accordingly, to achieve high yield. The population economic benefit under sugarcane/soybean intercropping was 3.2%-26.3% higher at lower than at higher nitrogen application level, suggesting the increase of the economic benefit of sugarcane population under reduced nitrogen application. Among the treatments, 1:2 sugarcane/soybean intercropping had the best economic benefit. PMID- 21657030 TI - [Yield loss model and yield loss mechanism of high-yielding summer maize infected by Physoderma maydis]. AB - A total of 21 different disease-grading summer maize groups were formed by fixed point natural infection of maize brown spot in the field, and mass loss estimation models of single ear mass and 100-grain mass were constructed by stepwise regression with DPS software. The mass loss estimation models of single ear and 100-grain were Y = -4.012 + 0.377X1 - 0.228X2 + 0.694X3 - 0.144X4 and Y = -4.536 + 0.173X1 + 0.188X2 + 0.248X3 - 0.034X4, respectively, where Y was yield loss rate, X1 was the disease index at flowering stage, X2 was the disease index at pollination stage, X3 was the disease index at filling stage, and X4 was the disease index at dough stage. The measured relationships between the disease indices at different growth stages and the mass loss for single ear and 100-grain coincided well with the modeling results. Maize brown spot directly affected the net photosynthetic rate of ear height leaf and the activities of RuBP carboxylase and PEP carboxylase. The higher the disease-grade, the lower the net photosynthetic rate and the activities of the two enzymes were. PMID- 21657031 TI - [Microbial diversity in rhizosphere soil of transgenic Bt rice based on the characterization of phospholipids fatty acids]. AB - Taking non-transgenic parental rice as the control, and by using 13C pulse-chase labeling method coupled with phospholipid fatty acid (PLFA) analysis, this paper studied the effects of transgenic Bt rice on the microbial diversity in rhizosphere soil. The results showed that in the rhizosphere soils of transgenic Bt rice and its non-transgenic parent, saturated PLFAs and branched PLFAs were the main, followed by monounsaturated PLFAs, and polyunsaturated PLFAs. A significantly lower amount of Gram-positive bacterial PLFAs and a higher amount of Gram-negative bacterial PLFAs were observed in the rhizosphere soil of transgenic Bt rice at its seedling, booting, and heading stages, as compared with the control. In the whole growth period of rice, transgenic Bt gene had no significant effects on the fungal and actinomycete PLFAs in rhizosphere soil, and no significant difference was observed in the rhizosphere soil 13C-PLFA content between transgenic Bt rice and its non-transgenic parent. These findings indicated that the insertion of exogenous cry1Ab gene into rice only had temporary effects on the microbial community composition in the rhizosphere soil of rice. PMID- 21657032 TI - [Landscape ecological security pattern during urban expansion of Nanchong City]. AB - Based on the theory of landscape ecological security pattern and the RS and GIS techniques, this paper analyzed the distribution of ecological security grades in Nanchong City, taking six elements including terrain condition, flood hazard, soil erosion, vegetation cover, geological disaster, and biological protection as the ecological constraints (or determinants) of urban expansion. According to the minimum cumulative resistance model, the ecological corridors and ecological nodes were built to strengthen the space contact of ecological network, and, on the basis of the protection of ecological safety, the reasonable trend of urban expansion and the optimization of space layout were investigated. The results showed that the ecological security of Nanchong City was quite good, with the regions of low ecological security mainly distributed in the west suburban mountains and the downstream region of Jialing River in the south of the City. Ecological elements were the most important constraints for the future expansion of urban space. There were more spaces for the urban expansion in the southern and northern parts of Nanchong City. To develop satellite towns would be the best selection to guarantee the ecological security of the city. PMID- 21657033 TI - [Landscape spatial pattern of typical loess hilly-gully watershed based on ALOS imagery]. AB - Based on the ALOS satellite medium and high resolution images, seven landscape types closely related to the ecosystem restoration, farming, and living of Yan' gou watershed, a typical watershed in loess hilly-gully region, were interpreted. The landscape pattern and function of the watershed in 2007 were analyzed with the landscape indices of diversity and heterogeneity, and the landscape distribution suitability of the whole and parts of the watershed were evaluated, combined with the digital elevation model (DEM) data. The results showed that the dominant landscape types in the watershed were bush and forest, which were mainly distributed on the slopes with a gradient greater than 25 degrees. The patch fractal dimension of the watershed was 1.09, suggesting that the general landscape spatial pattern was stable. The area ratio of the three landscape functional types of eco-protection, product economy, and living service was 23:9:1. The suitability of the whole watershed landscape distribution was 0.76, suggesting that the overall landscape distribution was relatively reasonable. However, the land-use suitability of semi-shade slopes and of the areas with an altitude less than 900 m was lower, being 0.74 and 0.02, respectively. PMID- 21657034 TI - [Analysis on sustainable development of marine economy in Jiangsu Province based on marine ecological footprint correction model]. AB - Based on the theories and methods of ecological footprint, the concept of marine ecological footprint was proposed. According to the characteristics of marine environment in Jiangsu Province, five sub-models of marine ecological footprints, including fishery, transporation, marine engineering construction, marine energy, and tidal flat, were constructed. The equilibrium factors of the five marine types were determined by using improved entropy method, and the marine footprints and capacities in Jiangsu Province from 2000 to 2008 were calculated and analyzed. In 2000-2008, the marine ecology footprint per capita in Jiangsu Province increased nearly seven times, from 36.90 hm2 to 252.94 hm2, and the ecological capacity per capita grew steadily, from 105.01 hm2 to 185.49 hm2. In 2000, the marine environment in the Province was in a state of ecological surplus, and the marine economy was in a weak sustainable development state. Since 2004, the marine ecological environment deteriorated sharply, with ecological deficit up to 109660.5 hm2, and the sustainability of marine economy declined. The high ecological footprint of fishery was the main reason for the ecological deficit. Tidal flat was the important reserve resource for the sustainable development of marine economy in Jiangsu Province. PMID- 21657035 TI - [Coupling analysis of agro-ecolomic system in gully area of Loess Plateau in 1949 2008: a case study in Changwu County of Shaanxi Province]. AB - Based on the analysis of the coercing and dynamic evolution relationships between agro-economic system and agro-ecological system, and by using modified entropy method, the weight of each evaluation index for the agro-ecolomic system in Changwu County of Shaanxi Province was determined, and, by employing coupling degree model, the coupling processes of agro-ecolomic system in the gullyarea of Loess Plateau were investigated. From 1949 to 2008, the agro-ecolomic system in the County experienced three stages of "traditional extensive agriculture", "agricultural mechanization", and "agricultural pre-modernization". In corresponding to the implement of national macro policies, the coupling degree of the agro-ecolomic system reached two peaks standing for utmost increasing phase and three valleys standing for coordinate development phase. Periods 1955-1961 and 1984-1992 were the utmost increasing phases of the coupling degree; periods 1962-1965 and 1981-1983 were the rapid transition periods responding to the national-wide policies controlling; while periods 1949-1954 and 1966-1980 were the low-level coordinated development phases. Since 1993, the system had been in the harmonious phase by a spiral development. At present, the system had a potential risk of changing from the harmonious phase to the utmost development phase. Appropriate agricultural policies and better external environment could promote the stable development of the agro-ecolomic system on a harmonious level; otherwise, a retrogressive system might be expected. PMID- 21657036 TI - [Changes of China agricultural climate resources under the background of climate change. III. Spatiotemporal change characteristics of agricultural climate resources in Northwest Arid Area]. AB - By using the 1961-2007 daily weather data from 78 meteorological stations in Northwest Arid Area, this paper analyzed the spatiotemporal characteristics of agricultural climate resources, i.e., heat, light, and precipitation, in the area, both in the whole year and in temperature-defined growth seasons of chimonophilous and thermophilic crops. In 1961-2007, the mean annual temperature in the area had an increasing trend, and the climate tendency rate was 0.35 degrees C x (10 a)(-1). The accumulated temperature in temperature-defined growth seasons of both chimonophilous and thermophilic crops also had an increasing trend, and the climate tendency rate was 67 and 50 degrees C d x (10 a)(-1), respectively. The annual sunshine hours in most stations of the research area had an obvious decreasing trend, but the sunshine hours during the temperature defined growth seasons of chimonophilous and thermophilic crops had an increasing trend, except that in most regions of Xin-jiang and east Ningxia Plain. The annual reference evapotranspiration in most regions of the study area tended to decrease, while the reference evapotranspiration during temperature-defined growth seasons of chimonophilous and thermophilic crops tended to decrease in the west but increase in the east. Compared with that in 1961-1980, the precipitation both in the whole year and in temperature-defined growth seasons of chimonophilous and thermophilic crops in 1981-2007 increased, and the increment reduced progressively from the northwest to the southeast. PMID- 21657037 TI - [A long distance colonization event of Chinese endemic bat Myotis davidii]. AB - In order to reveal the population phylogenetic relationships and colonization history of Chinese endemic bat species Myotis davidii, a total of 126 samples from 14 populations in nationwide were collected in 2001-2009, taking the mitochondrial control region as the molecular marker. Based on the TCS network diagram of the mitochondrial DNA control region sequences, the 14 geographical populations were divided into three geographical regions, i.e., mid-east plain region, southwest plateau region, and south hills region. In the 53 haplotypes, the No. 14 in Zhejiang Province, No. 47 in Guizhou Province, and No. 50 in Guangdong Province were the ancestors in the three regions, respectively. Based on Geodis analysis, mismatch distribution analysis, and neutrality test, the population expansion events were found in mid-eastern plain region (76.12 and 79.17 ka BP) and southwest plateau (69.12 ka BP). In 61.24 ka BP, a long distance migration event originated from the southwest plateau region to the mid-east plain region occurred. The evidences of molecular biology, bionics, anatomy, and aerodynamics all revealed the long-distance migration capability of M. davidii. PMID- 21657038 TI - [Spatial pattern of Sitodiplosis mosellana and its egg parasitoids mixed population]. AB - Geostatistis methods were adopted to analyze the spatial pattern of Sitodiplosis mosellana (Diptera: Cecidomyiidae) at its different development periods and of its egg parasitoids mixed population (Tetrastichus sp. and Platygaster error; Hymoneptera: Eulophidae and Platygastridae). The aggregated spatial arrangements for S. mosellana cocoon, adult, and larva and for egg parasitoids mixed population could be well described by spherical model, spherical-exponential model, linear sill model, and spherical-exponential model, respectively. The spatial dependence range of S. mosellana cocoon, adult at initial emergence period, adult at peak emergence period, and larva, and of egg parasitoids mixed population was 53.6, 190.6, 154.1, 4.2 and 280.3 m, and the aggregation intensity was 30.5%, 95.6%, 96.3%, 14.9% and 95.3%, respectively. The simulated maps of the spatial distribution produced by Kriging model could intuitively analyze the dynamic changes of S. mosellana at its different development periods and of egg parasitoids mixed population from the two aspects of time and space. PMID- 21657039 TI - [Self-pollution in Ruditapes philippinarum bottom-cultured area of Zhuanghe coast]. AB - By using sediment trap and closed respirator, a year-round in situ investigation was made on the bio-deposition rate, ammonia excretion rate, and phosphate excretion rate in the Ruditapes philippinarum bottom-cultured area of Zhuanghe coast. The three test rates of R. philippinarum all showed obvious seasonal variability, with the bio-deposition rate ranged in 0.15-1.47 g x ind(-1) x d(-1) (annual average 0.61 g x ind(-1) x d(-1)), ammonia excretion rate ranged in 0.02 0.40 mg x ind(-1) x d(-1) (annual average 0.17 mg x ind(-1) x d(-1)), and phosphate excretion rate ranged in 0.01-0.39 mg x ind(-1) x d(-1)(annual average 0. 13 mg x ind(-1) x d(-1)). Based on these, it was estimated that the annual bio deposit production by the bottom-cultured R. philippinarum in Zhuanghe coast could reach as high as 5.46 x 10(7) t dry mass, amounting to 9.07 x 10(6) t organic matter (OM), 1.00 x 10(6) t organic carbon (OC), or 1.18 x 10(5) t organic nitrogen (ON), and the annual NH4+ -N and PO4(3-)-P productions were 1.49 x 10(4) t and 1.15 x 10(4) t, respectively. Our results suggested that for the large scale and high density bivalve culture in China coasts, the potential impacts of self-pollutants by filter-feeding bivalves on the environment should not be neglected. PMID- 21657040 TI - [Abundance distribution of virioplankton in Yangtze River estuary and its adjacent East China Sea in summer and winter]. AB - An investigation was made on the abundance distribution and its variation of virioplankton in the Yangtze River estuary and its adjacent East China Sea in summer 2006 and winter 2007. The virus direct count (VDC) was quantified by fluorescent microscopy. In summer 2006, the VDC was from 2.22 x 10(6) to 9.97 x 10(7) ind x m(-1), being higher in the surface sea water of B area (122.5 degrees 123.5 degrees E); in winter 2007, the VDC was from 1.99 x 10(6) to 2.66 x 10(7) ind x mh(-1), being higher in coastal A area (120.5 degrees-122.5 degrees E) and decreased from nearshore waters to offshore waters. In summer, the VDC had close relationships with bacteriaplankton biomass and chlorophylla concentration but less relationship with nutrients concentration (P > 0.05); in winter, the VDC was closely related to bacteriaplankton biomass and nutrients concentration but less related to chlorophyll-a concentration (P > 0.05). The abundance distribution pattern of virioplankton showed significant seasonal variability, with the VDC significantly larger in summer than in winter (P < 0.01), which was mainly decided by the distribution of the viral host, and partly by the nutrients concentration in wintertime. PMID- 21657041 TI - [Ecological effects of utilizing non-timber forest products]. AB - Non-timber forest products (NTFPs) include all plant materials other than timber, such as seeds, flowers, fruits, leaves, roots, bark, latex, resins, and other non wood plant parts. The significant role of NTFPs in improving local people's lives and forest biodiversity conservation has been widely accepted. However, many studies in past decades indicated that NTFPs utilization had various ecological effects on different levels, from plant individual and population to community and forest ecosystem, depending not only on the plant parts extracted and their biological or ecological attributes, but also on the harvest forms. This paper reviewed the research progress about the effects of the utilization of NTFPs from biological and ecological aspects, and discussed some research problems and research priorities. PMID- 21657042 TI - [Ecological relationships between Bursaphelenchus xylophilus and its companion microorganisms]. AB - Pine wood nematode Bursaphelenchus xylophilus is a notorious invasive species from North America, which can kill a large amount of pine trees and causes economic losses and ecosystem destruction. There is a close relationship and ecological interaction between B. xylophilus and its companion microorganisms. This paper listed the species of companion microorganisms, reviewed their important ecological roles in the propagation and pathogenicity of the nematode, and discussed the pine wilt disease from the viewpoint of microecosystem. The companion fungi can supply food for B. xylophilus, hold the cycle of second infection of the nematode, increase the proportions of dauer juveniles, and benefit the infection and distribution of B. xylophilus. The companion bacteria can enhance the pathogenicity of B. xylophilus, promote the propagation of the nematode, benefit the pinene degradation, and thereby, promote the adaptability of the nematode. PMID- 21657043 TI - [Recent advance in solidification/stabilization technology for the remediation of heavy metals-contaminated soil]. AB - Remediation of heavy metals-contaminated soil is still a difficulty and a hotspot of international research projects. At present, the technologies commonly adopted for the remediation of contaminated sites mainly include excavation, solidification/stabilization (S/S), soil washing, soil vapor extraction (SVE), thermal treatment, and bioremediation. Based on the S/S technical guidelines of Unite State Environmental Protection Agency (EPA) and United Kingdom Environment Agency (EA) and the domestic and foreign patents, this paper introduced the concepts of S/S and its development status at home and abroad, and discussed its future development directions. Solidification refers to a process that binds contaminated media with a reagent, changing the media's physical properties via increasing its compressive strength, decreasing its permeability, and encapsulating the contaminants to form a solid material. Stabilization refers to the process that involves a chemical reaction which reduces the leachability of a waste, chemically immobilizes the waste and reduces its solubility, making the waste become less harmful or less mobile. S/S technology includes cement solidification, lime pozzolanic solidification, plastic materials stabilization, vitrification, and regent-based stabilization. Stabilization (or immobilization) treatment processes convert contaminants to less mobile forms through chemical or thermal interactions. In stabilization technology, the aim of adding agents is to change the soil physical and chemical properties through pH control technology, redox potential technology, precipitation techniques, adsorption technology, and ion-exchange technology that change the existing forms of heavy metals in soil, and thus, reduce the heavy metals bioavailability and mobility. This review also discussed the S/S evaluation methods, highlighted the need to enhance S/S technology in the molecular bonding, soil polymers, and formulation of China's S/S technical guidelines. PMID- 21657044 TI - [Cropping patterns of Bupleurum chinense in semi-arid region of Loess Plateau]. AB - Field experiments were conducted to investigate the suitable cropping patterns of grain crops and medical plant Bupleurum chinense in the semi-arid region of the Loess Plateau. Three cropping patterns were designed, including corn-Bupleurum chinense intercropping (corn/Bupleurum chinense), wheat followed by soybean Bupleurum chinense intercropping (wheat-soybean/Bupleurum chinense), and sequential planting of Bupleurum chinense (wheat-Bupleurum chinense). Of the three patterns, wheat-soybean/Bupleurum chinense was the best in economic yields and ecological benefits. Among the cultivars (cv. Lingchuan, Zuoquan and Wanrong) of Bupleurum chinense tested, the cv. Wanrong originated from relatively high temperature region exhibited the highest yield, while the cv. Zuoquan originated from relatively low temperature region had the lowest one, indicating that introducing Bupleurum chinense cultivars from the areas with higher temperature to lower temperature areas could increase their yield. The cropping pattern of wheat-soybean/Bupleurum chinense was the most effective one, with the yield being 11.6% and 16.8% higher than that of corn/Bupleurum chinense and wheat-Bupleurum chinense, respectively. PMID- 21657045 TI - [Recent progress of hydrophilic interaction chromatography based oligosaccharides separation]. PMID- 21657046 TI - [Advances in miniaturization of chromatograph and detectors]. AB - The innovation design of miniaturization of chromatographic instruments, in combination with the progress in materials and opto-electron technologies, has led to the breakthrough in key chromatography techniques. The novel design of detectors has improved the sensitivity and reduced the consumptions of power and gases. The utilization of surface thermo ionization principle yields a detector of extremely high sensitivity and selectivity towards amines. The low cost, high performance integration and miniaturization of chromatograph will lead to high standard commercial instruments in the two or three coming years. These instruments will be applied for on-line or off-line monitoring in fields and laboratories. Important progresses on the developments of detectors and miniaturization of instruments are reviewed and commented in this paper. PMID- 21657047 TI - [Recent development for purification of active proteins from bovine pancreas with liquid chromatography]. AB - Many active proteins exist in bovine pancreas and some of them have become protein drugs for human heath. These protein drugs sourcing from bovine pancreas are also high-tech product having high economic benefit. In the modern biological technology, the preparation of most active protein products relies on various liquid chromatographic techniques. The recent development of extraction of the active proteins from bovine pancreas and their separations and purifications, mainly with chromatographic methods are reviewed in this paper. It would be expected to be helpful for the preparation and application of the active proteins from natural products. PMID- 21657048 TI - [Reversed-phase liquid chromatography with double gradient elution for the separation and mass spectrometric analysis of peptides]. AB - Highly effective separation of complex peptide mixture is a prerequisite for protein identification with high coverage in proteomics. Currently, peptide mixture is separated by two-dimensional liquid chromatography (2D-LC), ion exchange chromatography as the first dimension and reversed-phase chromatography as the second dimension, in Shotgun proteomics. Though the 2D-LC is now widely used, its separation efficiency still needs further improvement. In this work, the first dimensional separation was performed by the pH and organic solvent double-gradient elution. And then the two fractions, one from the early eluted section and the other from the later eluted section (with equal time intervals) were pooled and analyzed by MS/MS. The experimental results from the protein mixture of saccharomyces cerevisiae lysate showed that the separation by pH and organic solvent double-gradient elution, RP-HPLC-nanoRPLC coupled with MS/MS identified 567 more yeast protein groups (3 035 peptides) over strong cation exchange chromatography-nanoRPLC coupled with MS/MS. The pI values and relative molecular masses of identified peptides ranged from 3.42 to 12.01, and from 587.67 to 3 499.79, respectively. The pI values and relative molecular masses of identified proteins ranged from 3.82 to 12.19 and from 3 446.55 to 432 905, respectively. These results indicated that this new 2DLC-MS method has the advantages over the conventional Shotgun method, and were expected to be applied in the separation of complex samples for proteomic studies in the future. PMID- 21657049 TI - [Determination of five microcystins in water using liquid chromatography-diode array detection/ion trap mass spectrometry]. AB - A method for the determination of five microcystins (MCs) in water was established using liquid chromatography (LC)-diode array detection (DAD)/ion trap mass spectrometry (IT MS). The five MCs in water were enriched and purified by solid phase extraction, and determined by LC-DAD/IT MS. DAD was used for both qualitative and quantitative analysis, and IT MS was used for qualitative analysis only. Under the optimized conditions, the detection limits of 5 MCs in water were 0.1 microg/L. The average recoveries of the three spiked levels (0.2, 0.8 and 5 microg/L) were 52.2% - 115.2% with the relative standard deviations (RSDs) of 1.2% - 10.0%. This method uses UV absorption spectrum and MS spectrum in the qualitative and quantitative analysis, and can be applied in the determination of various MCs in both surface water and drinking water. PMID- 21657050 TI - [Determination of avermectin, diclazuril, toltrazuril and metabolite residues in pork by high performance liquid chromatography-tandem mass spectrometry]. AB - A method for the determination of avermectin, ivermectin, doramectin, moxidectin, eprinomectin, diclazuril, toltrazuril and its two metabolite residues in pork was developed using QuEChERS method with high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The sample was extracted with acetonitrile and purified through QuEChERS method using ODS as the sorbent. The target compounds were separated on a Venusil ASB C18 column (150 mm x 2.1 mm, 3.0 microm) and detected by HPLC-MS/MS. The linear ranges were 0.005 - 0.2 mg/L and the correlation coefficients were all above 0.990. The average recoveries and the relative standard deviations ranged from 73.2% to 91.5% and from 12% to 17% at the spiked levels of 0.005, 0.01 and 0.02 mg/kg for the 9 analytes in pork matrix. This method is reliable, and suitable for the determination of the residues of avermectin and related compounds in pork. PMID- 21657051 TI - [Determination of selenium species in food by high performance liquid chromatography with inductively coupled plasma mass spectrometry]. AB - An analytical method for selenium species of selenate (SeVI), selenite (SeIV), selenomethionine (SeMet), selenocystine (SeCys2 ) and selenoethionine (SeEt) was established using high performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC-ICP-MS). A Hamilton PRP X-100 reversed-phase anion exchange column (250 mm x 4.6 mm, 5 microm) with a 5 mmol/L citric acid buffer solution (pH 4.5, adjusted with 20% (v/ v) ammonia) as mobile phase was used for separation, and ICP-MS was used for detection. The five species were completely separated within 21 min. All the linear correlation coefficients of the five selenium species were greater than 0.999 5, and the detection limits of SeVI, SeIV, SeMet, SeCys2, SeEt were 0.4, 0.4, 5.6, 0.9 and 1.2 microg/L, respectively. The extraction procedure was studied for fresh mushroom and pork samples. For water-soluble selenium compounds, citric acid was a good extraction solution, and the recoveries were around 100% for inorganic selenium and in the range of 85.0% 95.3% for SeMet; but worse for SeCys2 and SeEt. As for the proteinase K, the recoveries of SeCys2 and SeEt were raised to the range of 79.9% -91.5%. The method has the advantages of simple operation and good accuracy, and can be used for the quantitative determination of the five selenium species in food. PMID- 21657052 TI - [Sample pretreatment for determination of chlorinated organic pollutants in plants by gas chromatography and gas chromatography-mass spectrometry]. AB - The sample pretreatment methods for the determination of chlorinated organic pollutants in plants by gas chromatography (GC) and GC-mass spectrometry (MS) were established. The homogeneous extraction was used to extract the chlorinated organic pollutants from plants. The main interferences in the co-extract from several kinds of plant samples were recognized. The sensitivity of the analysis on organochlorine pesticides and polychlorinated biphenyls (PCB) in plant samples was effectively improved. The removal efficiency of the interferences from the extract by gel permeation chromatography (GPC) and solid-phase extraction (SPE) was investigated. The impurities such as fatty acids and phenols can be cleaned up through a Carb/NH2 SPE column with 20 mL mixed solvent of hexane-ethyl acetate (8:2, v/v) in 3% toluene as the eluent, and the recoveries were higher than 74%. It was necessary to combine GPC with SPE as the clean-up method when the sample was determined by GC, and only the SPE as the clean-up method was used if a mass spectrometer was employed as a detector. The methods are rapid and sensitive, and can be used in the analysis of organic pollutant residues in plant samples efficiently. PMID- 21657053 TI - [Evaluations of poly(methyl methacrylate) bearing glucose pendant or cellobiose pendant in high performance liquid chromatography as polymeric chiral stationary phases]. AB - The glucopyranos units consisting of cyclodextrin and polysaccharide derivatives have been extensively used as chromatographic chiral stationary phases. The synthetic polymeric chiral stationary phases based on methyl methacrylate bearing glucose or cellobiose pendants for high performance liquid chromatography (HPLC) were prepared by radical polymerization. Fifteen racemic chiral compounds including alcohols, amines, amides and ketones, were resolved on the two chiral stationary phases using hexane-isopropanol (90/10, v/v), hexane-isopropanol triethylamine (90/10/0.2, v/v/v) or hexane-isopropanol-trifluoroacetic acid (90/ 10/0.2, v/v/v) as mobile phase, separately. The results showed that both chiral stationary phases possessed good enantioselectivity for most of the racemic alcohols and amines. A few amides and ketones could also be separated. There was some compensation of the chiral discriminating abilities between the two chiral stationary phases. This work indicates that polymers of mono- and disaccharide derivatives can soon become a very attractive new chiral stationary phase for HPLC. PMID- 21657054 TI - [Determination of sulfur amino acids in feedstuffs by high performance liquid chromatography coupled with pre-column derivatization]. AB - A method of quantitative analysis of sulfur amino acids in feedstuffs by high performance liquid chromatography coupled with pre-column derivatization was developed. Before the feedstuffs were hydrolyzed under acidic condition, the cystine and methionine in the feedstuffs were oxidized to cysteic acid and methionine sulfone respectively by performic acid, and then derivatized by 2,4 dinitrofluorobenzene. The separation was performed on an Elite AAK C18 column (250 mm x 4.6 mm, 5 microm) by the gradient elution of 0.05 mol/L sodium acetate and acetonitrile-water (50: 50, v/v) as the mobile phase with a flow rate of 1.2 mL/min at 31 degrees C. The detection wavelength was set at 360 nm. The linearities of cystine and methionine were good in the ranges of 0.4 - 16.0 mg/L and 0.7 - 29.6 mg/L with the correlation coefficients of 0.999 9 and 0.999 8, respectively. The quantification limits (S/N = 10) were 2.6 microg/kg, 3.1 microg/kg, and the recoveries were 100.28% - 102.00% and 105.72% - 107.89%, respectively. The method can be adapted to the accurate quantification of the sulfur amino acids in feedstuffs. PMID- 21657055 TI - [Simultaneous determination of chlormequat chloride and mepiquat chloride in plants by mobile phase ion chromatography]. AB - Ion-pair reagent was used as mobile phase for the simultaneous separation of chlormequat chloride and mepiquat chloride in plants. The rapid separation was performed on a Dionex IonPac NG1 guard column and a Dionex IonPac NS1 analytical column using 1.0 mL/min of the eluent mixture of 1.00 mmol/L nonafluoropentanoic acid (as ion-pair reagent) and 7% acetonitrile, and the detection was achieved by a suppressed conductivity detector. The method provided good resolution of the analyte peaks without any interference. The detection limits of chlormequat chloride and mepiquat chloride were 0.154 6 mg/L and 0.171 4 mg/L, respectively. The linear calibration curves were obtained in the range of 1 - 100 mg/L. The mean recoveries in the ranges of 96.06% - 104.6% for chlormequat chloride and 98.53% - 103.7% for mepiquat chloride were obtained in real samples. The method requires only simple sample preparation and the technique is suitable for routine quality control analysis. PMID- 21657056 TI - [Surface characterization of urushiol-titanium chelate polymers by inverse gas chromatography]. AB - Urushiol-titanium chelate polymer (UTP), the reaction product of urushiol with titanium compound, is a special eco-friendly polymer with excellent performances, such as strong acids-resistance, strong alkalis-resistance, salt solution resistance and several organic solvent-resistance. Inverse gas chromatography (IGC) was used to measure the dispersive component of surface free energy (gamma(s)d) and the Lewis acid-base parameters of UTP in this work. The gamma(s)d and the acid/base characters of UTP' surfaces were estimated by the retention time with different non-polar and polar probes at infinite dilution region. n Pentane (C5), n-hexane (C6), n-heptane (C7), n-octane (C8) and n-nonane (C9) were chosen as the non-polar probes to characterize the gamma(s)d. Trichloromethane (CHCl3), tetrahydrofuran (THF) and acetone were chosen as polar probes to detect the Lewis acid-base parameters. The specific free energy (deltaG(a)AB) and the enthalpy (deltaH(a)AB) of adsorption corresponding to acid-base surface interactions were determined. By correlating deltaH(a)AB with the donor and acceptor numbers of the probes, the acidic (K(a)) and the basic (K(b)) parameters of the samples were calculated. The results showed that the dispersive components of the free energy of UTP were 37.68, 33.53, 35.92, 24.01 and 31.32 mJ/m2 at 70, 80, 90, 100 and 110 degrees C, respectively. The Lewis acidic number K(a) of UTP was 0.185 3, and the Lewis basic number K(b) was 0.966 2. The results were of great importance to the study of the surface properties and the applications for urushiol-metal chelate polymers. PMID- 21657057 TI - [Separation of 1-phenyl-3-methyl-5-pyrazolone derivatives of traditional Chinese medicine oligosaccharides by capillary zone electrophoresis]. AB - A simple and practical capillary zone electrophoretic (CZE) method has been developed for the separation of traditional Chinese medicine oligosaccharides according to their relative molecular masses (M(r)). To optimize the conditions of the method, the concentration and pH value of the running buffer, and the applied voltage were evaluated. The optimized conditions were as follows: 1 phenyl-3-methyl-5-pyrazolone (PMP) derivatives of the oligosaccharides were separated with 50 mmol/L phosphate buffer (pH 2.5) as running buffer and the voltage was 15 kV. The detection was performed with an ultraviolet detector at 245 nm. An uncoated fused-silica capillary of 50 microm i. d. and 38/48 cm length (effective length/total length) was employed, and a hydrodynamic pressure injection (10 cm x 2 s) was applied. In order to examine the practicability of the method for the analysis of actual traditional Chinese medicine oligosaccharide samples, a complex sample consisting of some usual monosaccharides and oligosaccharides degraded from beta-cyclodextrin was separated under the electrophoretic conditions. And then, the method was applied to the analysis of the controlled degradation products of Indigowoad Root polysaccharide. The results indicated that the oligosaccharide sample could fully be separated from low to high M(r). This method is efficient and practical. In addition, the separation hypothesis of PMP derivatives of monosaccharides and oligosaccharides in pH 2.5 running buffer is also discussed, which would be helpful for us to understand the unusual migration of the PMP derivatives of rhamnose and mannose. PMID- 21657058 TI - [Determination of ginsenosides Rg1, Re and Rb1 in Panax quinquefolium by micellar electrokinetic capillary chromatography]. AB - The accurate assay of the three highly hydrophobic ginsenosides Rg1, Re and Rb1 in one injection plays a key role in assessing the quality of Panax quinquefolius. A micellar electrokinetic capillary chromatographic (MEKC) method was therefore developed for the simultaneous determination of ginsenosides Rg1, Re and Rb1 in Panax quinquefolium. The separation was carried out on an uncoated fused-silica capillary with 50 microm i. d. and 30 cm effective length (to the detector). The separation buffer was V (15 mmol/L Na2B4O7 + 30 mmol/L H3BO3 (pH 9.0) + 100 mmol/L dodecyl sulfate sodium salt (SDS) + 30 g/L polyethylene glycol (PEG) 35000): V (methanol): V (iso-propanol) = 2: 1:1. The separation voltage was 30 kV with hydrodynamic injection at 3. 448 kPa for 15 s. The detection wavelength was set at 214 nm. The factors such as the buffer concentration, the content of the organic solvent and buffer additives, which influenced the accurate analysis of ginsenosides, were investigated in detail. The samples were simply extracted twice by methanol-10 mmol/L SDS (1: 1, v/v). The limits of detection (LOD, S/N = 3) for Rg1, Re and Rb1 were 30, 40 and 30 mg/L, respectively. The limits of quantitation (LOQ, S/N = 9) were 90, 120 and 90 mg/L, respectively. The recoveries at the studied concentrations were between 87.4% and 95.2%. The established method was used for the determination of the certified reference material (CRM) of Rg1, Re and Rb1 in Panax quinquefolium. The results were in good agreement with those of the high performance liquid chromatographic (HPLC) method. The samples of Panax quinquefolium from Canada, United States and China were also analyzed separately and satisfactory results were obtained. PMID- 21657059 TI - [Determination of immunoglobulin G in mare colostrum by high-performance gel permeation chromatography]. AB - A direct high-performance gel permeation chromatographic (HPGPC) method for the determination of immunoglobulin G in mare colostrum was established. HPGPC separation was performed on a TOSOH TSK-G4000PW(XL) column (300 mm x 7.8 mm, 5 microm) with 0.05 mol/L phosphate buffer solution (pH 6.9) as the mobile phase at a flow rate of 0.8 mL/min, and the column temperature was maintained at 25 degrees C. The injection volume was 20 microL. At the detection wavelength of 280 nm, the linear range was from 0.2 to 3.0 g/L (r2 = 0.999 5) with a detection limit of 0.08 mg/L (S/N = 10). The recovery was 97.47% with a relative standard deviation (RSD) of 1.22%. The RSDs of the peak area of stability, accuracy and reproducibility for the established method were 2.86%, 1.62% and 1.82%, respectively. Mare milk was collected from Zhaosu (China), a complete collection was stored in an ice box, then sent to a laboratory and stored in a low temperature refrigerator. The whey milk was prepared by centrifugation two times at 12 000 r/min and 4 degrees C for 30 min. The whey protein was obtained from the middle layer. A 2 mL volume of the whey milk was mixed with 23 mL of mobile phase. The average contents of IgG were from 35.0 g/L to 50.0 g/L at the first lactation (2 h), and the average contents of IgG were from 2.0 g/L to 4.0 g/L after 72 h. The relatively simple analytical method was proved to be accurate and precise in its application to mare colostrum. PMID- 21657060 TI - [Separation of bases, phenols and pharmaceuticals on ionic liquid-modified silica stationary phase with pure water as mobile phase]. AB - N-methylimidazolium ionic liquid (IL) -modified silica was prepared with the reaction of 3-chloropropyl modified silica and N-methylimidazole using toluene as solvent. Based on the multiple interactions between N-methylimidazolium IL modified silica and analytes such as hydrophobic interaction, electrostatic attraction, repulsion interaction, hydrogen-bonding, etc., the bases (cytosine, thymine, 2-aminopyrimidine and 6-chloroguanine), phenols (m-aminophenol, resorcinol and m-nitrophenol) and three pharmaceuticals (moroxydine hydrochloride, acyclovir and cephalexin hydrate) were separated successfully with only pure water as the mobile phase. These chromatographic separations are environmental friendly, economical and convenient, without any organic solvent or buffer additive. The retention mechanism of these samples on the stationary phase was also investigated. PMID- 21657061 TI - [Determination of antioxidant residues in polymer food package using gas chromatography]. AB - A new method for the determination of antioxidants, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA) and tertiary butylhydroquinone (TBHQ) in plastic food package by gas chromatography-electron capture detection (ECD) was developed. The antioxidants were extracted by cyclohexane with ultrasonic extraction, separated by an HP-50 + chromatographic column (30 m x 0.53 mm x 1 microm) and quantified by external standard method with an ECD detector. The average recoveries of antioxidants were 88% -93%, 92% - 101% and 83% -97% for BHT, BHA and TBHQ, respectively, at the spiking levels of 3.00 - 10.0 mg/kg. The corresponding relative standard deviations (RSDs, n = 5) were 2.01% - 2.89%, 2.11% - 3.19% and 2.99% - 4.02%, respectively. The limits of detection (S/N = 3) were 0.5, 0.5 and 0.8 mg/kg for BHT, BHA and TBHQ, respectively. The proposed method has been applied to the analysis of 5 kinds of polymer food package. The results indicated that all the above antioxidants were found in the practical polymer food package samples. Plastic food package contained BHT and BHA with the concentrations varying from 6.3 to 7.8 mg/kg and rubber food package contained all the three antioxidants with the concentrations varying from 9.3 to 28.4 mg/kg. This method is accurate, sensitive, highly reproducible and suitable for the analysis of residual antioxidants in polymer food package. PMID- 21657062 TI - [Preparation of crocin from gardenia yellow pigment by slow rotary countercurrent chromatography]. AB - A method was established for the preparation of crocin from gardenia yellow pigment by slow rotary countercurrent chromatography (SRCCC). A two-phase solvent system consisting of methyl tert-butyl ether, n-butanol, acetonitrile and water (2 : 2. 5 : 1 : 5, v/v/v/v) was used. The upper phase was used as the stationary phase, and the lower phase as the mobile phase. By SRCCC elution, 2.47 g of crocin with a purity of 96.8% was obtained from 5 g of gardenia yellow pigment at a flow rate of 5 mL/min and a rotation speed of 50 r/min. The results indicated that SRCCC is a powerful technique for the purification of crocin from gardenia yellow pigment with high preparative capacity, high safety and high efficiency in resolution, and it is possible to prepare crocin at industrial level by SRCCC. PMID- 21657063 TI - [Hormesis and its application in medicinal plant growing]. AB - Hormesis describes the low-dose stimulation and high-dose inhibition phenomena for all kind lives under toxicity environment. This paper generalized hormesis of medicinal plant on grow and metabolite after introducing the concept and study state of hormesis and analyzing hormesis mechanism and its significance. It points out that hormesis can be well used for medicinal plants growth, including increasing the metabolise, giving a dereaction for cultivated field chosen, guiding the agriculture management during the cultivation and improving the anti stress. PMID- 21657064 TI - [Influence of nitrogen forms ratio on growth and photosynthetic characteristics in Prunella vulgaris]. AB - OBJECTIVE: The effects of different nitrogen forms on the growth and photosynthetic characteristics of Prunella vulgaris were observed. METHOD: Water culture experiments were carried out to observe the effects of NH4+: NO3- ratios(100:0, 75: 25, 50:50, 25:75, 0:100 in mmol x L(-1)) on the growth and photosynthetic characteristics of P. vulgaris. RESULT: The leaf area, fresh biomass and P(n) of these cultivars increased with the increasing of NH4(+) -N: NO3(-) -N ratios, and they were found to be the highest in 25: 75 NH4(+) -N: NO3) ) -N. However, they decreased with the increasing NH4(+) -N: NO3(-) -N ratio further. P. vulgaris had a minimum leaf area, biomass, chlorophyll content and P(n) in pure ammonium group. The biggest chlorophyll and carotenoid contents were found in the ratios of NH4(+) -N to NO3(-) -N of 50: 50. CONCLUSION: The results indicated that properly increasing nitrate proportion could promote the growth and photosynthesis of P. vulgaris. PMID- 21657065 TI - [Molecular identification of one Uncaria plant]. AB - OBJECTIVE: In order to identify a species of Uncaria, molecular phylogenetic analysis was carried out by using the rDNA ITS sequence as molecular marker. METHOD: Total DNA was extracted from the plant with modified CTAB method and thereby rDNA ITS regions were amplified with universally conserved primer. The rDNA ITS amplicon was characterized by cloning, sequencing, blasting in GenBank and phylogenetic analyses using PAUP by maximum parsimony (MP) criteria. RESULT: The rDNA ITS entire sequence of this species of Uncaria was 719 bp. The sequence is related to the U. sinensis available in GenBank and the similarity reaches 99.7%. CONCLUSION: Based on molecular biology methods of rDNA ITS region analysis, molecular identification is available in accurate classification on this species of Uncaria. PMID- 21657066 TI - [Analysis of genetic relationships of Pueraria thomsonii based on SRAP markers]. AB - OBJECTIVE: To determine the interspecies relationships of 18 Pueraria thomsonii cultivars in molecular level. METHOD: Eighteen P. thomsonii cultivars were evaluated by using sequence-related amplified polymorphism (SRAP) markers, with P. lobata and P. peduncularis as contrast species. Systematic relationships were constructed based on the UPGMA method by TREECONW software. RESULT: The results showed that 22 primer pairs produced 338 loci, out of which 216 were polymorphic, the percentage of polymorphic loci was 63.9%. An average of 15.4 loci and 9.8 polymorphic loci were generated by each pair of primers. Genetic distance was analyzed by TREECONW software. Genetic distance of 18 P. thomsonii were changed from 0.004 7 to 0.265 8, with an average of 0.316. Using cluster analysis (UPGMA) based on those polymorphism bands amplified with SRAP primers, the 22 cultivars were classified into three groups, groups 1 with 18 P. thomsonii, group 2 with 3 P. lobata, and group 3 with 1 P. peduncularis. Most of the P. thomsonii from the same region were not in the same group. CONCLUSION: SRAP markers could be a good marker for genetic relationship research in the P. thomsonii. PMID- 21657067 TI - [Diversity of endophytic fungi from Cistanche deserticola]. AB - To study the diversity of endophytic fungi community from Cistanche deserticola, samples were collected from two planting bases in Inner Mongolia and Ningxia autonomous regions separately in spring and autumn. As a result, 618 strains of endophytic fungi had been isolated from samples. It was identified that 453 of the strains which accounted for 73.30% were spore strains, respectively belonging to 24 genera, and Fusarium (25.89%) and Acremonium (16.99%) were determined as dominant species. Number and species of endophytic fungi from C. deserticola showed a great diversity, and the differences of parts, localities and seasons were demonstrated. PMID- 21657068 TI - [Establishment of induction and culture system for hairy roots of Psammosilene tunicoides]. AB - OBJECTIVE: To establish a culture system for Psammosilene tunicoides hairy roots, and provide technological aid for the large-scale production of P. tunicoides material. METHOD: The young leaves and stem segments of sterile plantlets were infected with ACCC10060 strain, and subsequently a culture system suitable for hairy roots growth was further established. RESULT: When explants were co cultured with ACCC10060 (A600 0.8) on B5 media containing 20 mg x L(-1) Acetosyringo (AS) for 48 h, the hairy roots could be successfully induced, and it could achieve a higher induction rate using young leaves as explants than that of stem segments. The transfected hairy roots possessed the ability of kanamycin resistance and growth on hormone-free media, and synthesis of opines. All above results demonstrated that the present hairy roots originated in the infection of P. tunicoides tissues by ACCC10060 strains. After 35 d culture in liquid hormone free MS (1/2 strength), the biomass of hairy roots increased 14.11 times (fresh weight) and 8. 39 times (dry weight), respectively, and the content of total saponins in hairy roots reached to 0.857% (DW), by contrast, it's only 0.388% and 0.217% in callus and seedlings respectively. CONCLUSION: Establishment of hairy roots culture of P. tunicoides provided a foundation for industrial production of active components from P. tunicoides culture. PMID- 21657069 TI - [Study on seed biological characteristics of Gentiana crassicaulis]. AB - OBJECTIVE: To study seed biological characteristics of Gentiana crassicaulis. METHOD: The samples were collected from five localities, and the morphological observation, germination test and viability TTC test were carried out. RESULT: The seed morphological characters of all samples were similar to each other. The viability of all samples was similar to each other, but the germination rate of wild seed was the highest in all samples after stored for 8 months. Also, the seed energy of wild seed and sample 2008XR02 was higher than other three samples. There was no obvious correlation between thousand seed weight and germination rate. CONCLUSION: The quality of wild seed and sample 2008XR02 was superior than that of the other three samples. The results can be used for basic data of in situ conservation and germplasm breeding of G. crassicaulis. PMID- 21657070 TI - [Seed germination characteristics of Gentiana rigescens]. AB - OBJECTIVE: To investigate the influences of temperature, lightness, storage method, storage time, and gibberellin on seed germination of Gentiana rigescens. METHOD: The germination rates of G. rigescens in different treatments were observed. RESULT AND CONCLUSION: The most suitable temperature for the seed germination was 25 degrees C, at which the germination rate was 76.33%. The effect of lightness on the seeds was significantly; the germination rate of the seed was very low. Under the natural condition, the best storage method was dry storage (within 6 months), which could promote the after-ripening of the seed. 100-1 000 mg x L(-1) gibberellic acid could significantly reduce the seed germination time, and 500 mg x L(-1) gibberellic acid increased the germination rate of the seed to 95.00%. PMID- 21657071 TI - [Analysis on changes of chemical compounds in different processed products of Euodiae fructus]. AB - OBJECTIVE: To study the relationship among processing methods and chemical compounds. METHOD: HPLC was used to compare the difference between pre and post processing. The main peaks in chromatogram were identified and divided into groups of chemical compounds. The contents of identified compounds and groups of chemical compounds were also analyzed. RESULT: The chromatographic peaks were divided into three groups of chemical compounds that were flavonoid glocosides, uinazoline alkaloids and bitter principle, indoloquinazoline alkaloids. The contents of flavonoid glocosides were reduced in each processed product, and that in hot-water processing product were the least. The contents of all three groups of chemical compounds were decreased in Coptidis Rhizoma processing products. The dissolving release of quinolones alkaloids were increased in wine, salt, Glycyrrhizae Radix et Rhizoma and ginger processing products. CONCLUSION: Different processing methods caused different changes of chemical compounds. PMID- 21657072 TI - [Effective constituents and kinetic model of microwave drying from shuxiong prescription]. AB - A mathematical model of microwave drying kinetics based on Fick's second diffusion law was established and and the influence of microwave drying on ferulic acid (FA) and hydrosafflower yellow A (HSYA) in Shuxiong prescription was studied. The proposed model has been verified by using experimental data from microwave drying of Shuxiong prescription. By increasing the microwave output power (500-650 W) and the sample amount (15-60 g), the diversion rate of FA and HSYA changed. In order to determine the kinetic parameters, the drying data were fifed to various models based on the ratios of differences between the initial and final moisture contents and equilibrium moisture content versus drying time. The activation energy was calculated using an exponential expression based on Arrhenius equation. The relationship between the drying rate constant and effective moisture diffusivity was also estimated, and it showed linear. PMID- 21657073 TI - [Optimization of the hydrolysis process for C21 steroidal glycoside of bai shou wu by acetic acid with multi-target orthogonal design]. AB - OBJECTIVE: To study the optimizal hydrolysis process for C21 steroidal glycoside of Bai Shou Wu by acetic acid. METHOD: The effects of acetic acid concentration, reaction temperature and reaction time had been investigated using orthogonal design and the contents of kidjoranin 3-O-beta-digitoxopyranoside, caudatin, kidjoranin 3-O-alpha-L-diginopyranosyl-(1 --> 4)-beta-cymaropyranoside and caudatin 3-O-beta-cymaropyranoside as response indexs were determined by the high performance liquid chromatography. RESULT: The factors influencing acetic extraction efficiency were as follows: A > B > C (A. reaction temperature; B. reaction time; C. acetic acid concentration). The optimal hydrolysis condition obtained was: refluxing for 6 hours with 5.0% dilute CH3COOH solution at 100 degrees C. CONCLUSION: The content of antitumor active ingredients under the optimum hydrolysis condition is raised obviously and has a great part in studying this antitumor drug. PMID- 21657074 TI - [Study on dispersivity of baicalin solid dispersion by vibrational spectrometry]. AB - OBJECTIVE: To study the dispersivity of baicalin solid dispersion by Raman spectrometry and infrared spectrometry in order to obtain a new and simple method in examining the dispersivity of solid dispersion. METHOD: Baicalin solid dispersion was prepared by solvent method. The Raman spectra, infrared spectra and X-ray powder diffraction patterns of crude baicalin, PVP K30, physical mixture, solid dispersion were acquired by Raman and Fourier transform infrared spectrometers and X-ray powder diffractometry. Then the spectra were compared with each other in order to find out the differences between baicalin solid dispersion and other materials. RESULT: The result of Raman spectrometry was that amorphous baicalin presented in the solid dispersion, which was in agreement with that of X-ray powder diffractometry. CONCLUSION: Raman spectrometry which is fast, direct and non-destructive is an ideal method for examining the dispersivity of solid dispersion. PMID- 21657075 TI - [Chemical constituents from aerial part of Atractylodes macrocephala]. AB - OBJECTIVE: To investigate the chemical constituents from the aerial part of Atractylodes macrocephala. METHOD: The constituents were isolated and purified by repeated column chromatography on silica gel, Sephadex LH-20 and ODS. Their structures were identified by physicochemical properties and spectrum analysis. RESULT: Fourteen compounds were isolated and identified as atractylenolide I-III (1-3), 2-[(2E) -3, 7-dimethyl-2, 6-octadienyl]-6-methyl-2, 5-cyclohexadiene-1, 4 dione(4), 2, 6-dimethoxyphenol (5), scopoletin (6), 4-methoxycinnamic acid (7), caffeic acid (8), ferulic acid (9) protocatechuic acid (10), 3-hydroxy-1-(4 hydroxy-3- methoxyphenyl) propan-1-one (11), dictamnoside A (12), syringin (13), D-mannitol (14). CONCLUSION: All the compounds were isolated from the aerial part of A. macrocephala for the first time and compounds 4, 5, 7-12, 14 were isolated from this species for the first time. PMID- 21657076 TI - [Flavonoids with special B-ring from Macrothelypteris viridifrons and their anti proliferative effects on tumor cell]. AB - OBJECTIVE: To study the chemical constituents of Macrothelypteris viridifrons and their anti-proliferative effects on tumor cell. METHOD: The compounds were isolated by column chromatography with silica gel, C18 reverse-phase silica gel, sephadex LH-20, and their structures were elucidated on the basis of physiochemical propertities and spectral analysis. The antitumor activities of all compounds were tested with MOLT4, Hep G2, A-549, MCF-7, HT-29, PC-3 tumor cell lines. RESULT: Five compounds were isolated and identified as protoapigenone (1), protoapigenin (2), protoapigenin-4'-O-beta-D-glucopyanoside (3), 5,7 dihydroxy-2-(1,2-isopropyldioxy-4-oxo-cyclohex-5-enyl) -chromen-4-one (4), 5,7 dihydroxy-2-(1-hydroxy-2,6-dimethoxy-cyclohex-4-oxo) -chromen-4-one (5), respectively. CONCLUSION: All compounds were obtained from this plant for the first time. Compounds 1, 4 and 5 showed strong anti-proliferative effects on six tumor cells, which were in concentration-dependent manner. PMID- 21657077 TI - [Simultaneous determination of seven nucleosides and nucleobases in aqueous extracts of Fritillaria taipaiensis by HPLC-DAD]. AB - OBJECTIVE: To develop a high performance liquid chromatography coupled with a photodiode array detector (HPLC-DAD) method for simultaneous determination of 7 nucleosides and nucleobases in Fritillaria taipaiensis. METHOD: The analyses were performed on an Agilent Zorbax-SB-Aq-C18 column (4.6 mm x 250 mm, 5 microm) eluted with water and methanol in gradient mode. The flow rate was 1.0 mL x min( 1). The detection wavelength was 260 nm. The temperature of sample manager was set at 25 degrees C, and the injection volume was 20 microL. RESULT: The investigated compounds including uracil, cytidine, uridine, guanosine, thymidine, adenosine and adenine were shown good linearity (r > or = 0.999 8) over the tested ranges. The average recoveries were within 96.96% - 103.5% with RSD < or = 3.8%. CONCLUSION: The accuracy, stability, repeatability and average recovery of the method are satisfying, and the seven nucleosides and nucleobases components in F. taipaiensis can be rapidly and accurately quantified by HPLC-DAD. This work provided helpful information for comprehensive quality evaluation of F. taipaiensis. PMID- 21657078 TI - [Simultaneous determination of six flavonoids in Apocynum venetum by HPLC]. AB - OBJECTIVE: To develop a high-performance liquid chromatography (HPLC) method for the simultaneous determination of rutin, hyperoside, isoquercetin, astragulin, quercetin, and kaempferol in Apocynum venetum and its extracts. METHOD: The separation was carried out on a Shim pack ODS (4.6 mm x 250 mm, 5 microm) colum eluted with in mobile phases of water containing 0.2% phosphoric acid and acetonitrile containing 0.2% phosphoric acid in acetonitrile gradient mode. The column temperature was 40 degrees C, and the flow rate was 1.0 mL x min(-1). The detection wavelength was set at 360 nm. RESULT: The good seperation of six flavonoids was achieved within 40 min, with the relative standard deviations (RSD) of intra- and inter-day precision < or = 2.0%. Calibration curves of rutin, hyperoside, isoquercetin, astragulin, quercetin, and kaempferol showed good linear relationship (R2 > 0.999 7, n = 6). The average recoveries of the six flavonoids were within 97.30% - 105.8% (RSD 2.6%). Three batches of A. venetum and 2 batches of its extracts were determined. CONCLUSION: The developed method is simple, accurate, and repeatable, and can be readily used as a powerful tool for the quality control of A. venetum and its extracts. PMID- 21657079 TI - [Determination of five iridoid glycosides in Phlomis younghusbandii by HPLC]. AB - OBJECTIVE: To develop an RP-HPLC method for the determination of five iridoid glycosides in Phlomis younghusbandii. METHOD: HPLC analysis was performed on a Symmetry C18 (4.6 mm x 150 mm, 5 microm, Waters) column eluted with acetonitrile (A) and water (B) in gradient elution. The gradient program was as follows: 0-5 min kept 7% A; 5-10 min changed to 12% A; 10-40 min kept 12% A. The flow rate was 1.0 mL x min(-1). The column temperature was 20 degrees and the detection wavelength was 235 nm. RESULT: The linear ranges of sesamoside, shanzhiside methyl ester, 7, 8-dehydropenstemoside, penstemoside and 8-O-acetylshanzhiside methyl ester were 0.050-0.650 (r = 0.999 3), 0.050-0.350 (r = 0.999 5), 0.040 0.280 (r = 0.999 4), 0.010-0.070 (r = 0.999 6), 0.040-0. 280 (r = 0.999 7) g x L( 1), respectively. The average recoveries (n = 6) of them were all between 96% and 104%, RSD < 5.0%. CONCLUSION: The method is simple, accurate, repeatable and stable, which can be used for quality control of P. younghusbandii. PMID- 21657080 TI - [Determination of mangiferin in rat plasma and aqueous humor by HPLC]. AB - A HPLC method was developed for the determination of mangiferin in rat plasma and aqueous humor. 4-Nitrophenol was used as internal standard. Analysis was performed on a Cosmosil ODS C18 analytical column (4.6 mm x 250 mm, 5 microm) with mobile phase consisting of methanol-water (40: 60) with 2% glacial acetic acid at a flow rate of 1.0 mL x min(-1). The calibration curve of mangiferin in rat plasma and aqueous humor showed excellent linear behaviors over the investigated concentration of 0. 50-250.00 mg x L(-1) in plasma and 0.10-10.00 mg x L(-1) in aqueous humor, respectively, and the correlation coefficients were all above 0.995 4. The intra-day and inter-day precisions for all samples were measured to be below 12%. The limit of quantitation was 0.10 mg x L(-1) and low enough for the determination of mangiferin in all samples. The validated method has been successfully applied to preliminary pharmacokinetics study of mangiferin in rat plasma and aqueous humor. PMID- 21657081 TI - [GC-MS analysis of essential oil from root of Angelica dahurica cv. Qibaizhi]. AB - OBJECTIVE: Essential oil from root of Angelica dahurica cv. Qibaizhi were studied. METHOD: Essential oil was extracted by water-steam distillation and analyzed by GC-MS. RESULT: Two hundreds and ninety chromatographic peaks were detected, among which 111 compounds have been identified. The contents of them made up 90.61% of the total essential oil. CONCLUSION: The main compounds in the essential oil were 3-carene (12.70%), beta-elemene (6.20%), beta-terpinene (3.53%), beta-myrcene (1.97%), gamma-elemene (1.82%), beta-phellandrene (1.65%), and beta-maaliene (1.61%), et al. In addition, suberosin (0.16%), a coumarins compound, was also determined. PMID- 21657082 TI - [Experimental study of relationship between effect of ginsenoside Rg1 to delay hematopoietic stem cell senescence and expression of p16(INK4a)]. AB - OBJECTIVE: To investigate the relation between the effect of ginsenoside Rg1 to delay hematopoietic stem cell senescence and the expression of p16(INK4a). The purpose is to provide the theory and experimental foundation for searching the methods of how to delay HSC senescence. METHOD: Sca-1 + HSC was isolated by magnetic cell sorting (MACS) and divided into five groups. The control group cells were routinely cultured, the aging group cells were induced aging by tert butylhydroperoxide( t-BHP, final concentration of 100 micromol x L(-1)) to establish the aging model, the Rg1 group cells were co-cutured with Rg1 (final concentration is 10 micromol x L(-1)). To Rg1 delay aging group, Sca-1 + HSC were established aging model after pretreatment of Rg1 (final concentration is 10 micromol x L(-1)). To Rg1 treat aging group, Sca-1 + HSC gave Rg1 (final concentration is 10 micromol x L(-1)) antiaging treatment after the aging model was established. The changes of cells observed by senescence-associated beta galactosidase (SA-beta-gal) staining, cell cycle analysis and culture of mixed hematopoietic progenitor cell were used to investigate the antiaging and delay aging effect of ginsenoside Rg1. The expression of senescence associated p16(INK4a) mRNA and p16(INK4a) protein was examined by RT-PCR and western blotting. RESULT: Compared with aging group, the percentage of positive cells expressed SA-beta-gal and cells in G1 phase decreased and the number of forming colony of mixed hematopoietic progenitor increased and it showed higher expression of p16(INK4a) mRNA and p16(INK4a) protein in Rg1 treat aging group and Rg1 delay aging group. Furthermore the percentage of positive cells expressed SA beta-gal, cells in G1 phase, the number of forming colony of mixed hematopoietic progenitor and the expression of p16(INK4a) mRNA and protein decreased in Rg1 delay aging group compared with Rg1 treat aging group. CONCLUSION: Rg1 can significantly delay and treat the senescence of Sca-1 + HSC. The effect of Rg1 delaying aging is better than treatment, p16(INK4a) may be play a key role in the antiaging effect of Rg1 to Sca-1 + HSC senescence induced by t-BHP. PMID- 21657083 TI - [Effect of different treating principles and formulas on expression of osteogenic factors in steroid-induced osteonecrosis of femoral head of chichen]. AB - OBJECTIVE: To investigate the effect of two treating principles and formulas, which are named 'invigorating spleen to remove phlem and promoting blood circulation to remove meridian obstruction' (Jianpi) and 'invigorate the kidney and promoting blood circulation to remove meridian obstruction' (Bushen), on the expression of osteogenic factors in steroid-induced osteonecrosis of the femoral head (SONFH), such as bone morphogenetic protein 2 (BMP2) and transforming growth factor beta1 (TGFbeta1) and Smads, as well as to explore and compare their mechanisms of prevention and treatment of SONFH. METHOD: Animal model of SONFH was established by injection with methylprednisolone in chest muscle on chickens. 48 SONFH chickens were randomly assigned to model, Jianpi and Bushen group. Another 16 normal chickens served as control group. At the 8th and 16th week, the expression of BMP2, TGFbeta1, Smad4 and Smad7 of bilateral femoral heads were detected with immunohistochemistry. RESULT: The expression of BMP2, TGFbeta1 and Smad4 decreased, and Smad7 increased significantly in model group compared with control group. The expression of BMP2, TGFbeta1, Smad4 increased and Smad7 decreased significantly in Jianpi group at the 8th week compared with model group, and the same changes in Bushen group at the 16th week. CONCLUSION: Both Jianpi and Bushen formulas exerted preventive and therapeutic activity on SONFH through regulating the expression of BMP2, TGFbeta1, Smad4 and Smad7 to promote bone repair. Notably Jianpi formula took effect earlier than Bushen formula PMID- 21657084 TI - [10-Hydroxycamptothecin aerosol treatment inhibits lung metastases in B16F10 melanoma mice models]. AB - OBJECTIVE: To estimate the effect of 10-hydroxycamptothecin (HCPT) to the melanoma lung metastasis mice models and the feasibility of aerosol delivery treatment for lung cancer therapy. METHOD: B16F10 melanoma lung metastasis mice models were made, and nodules number, inhibition rate, tumor area, mean nodules diameter and so on were investigated after the aerosol delivery treatment. Spleen index and thymus index were calculated at the end of the experiments. The change of body weight, physiological state and the lung tumor tissue in pathological histology were inspeated. RESULT: The total number of tumor lesions, weight of lungs and the area of lung metastasis of aerosol treatment group had significant difference comparing with normal group and control group. Mean nodules diameter had no significant difference comparing with control group. The spleen index of aerosol treatment group was decreased and thymus index was significantly decreased comparing with normal group and control group. During the treatment there are no obvious changes in physiological state. The lung cancer tissue of aerosol delivery treatment group was recovered in pathological histology. CONCLUSION: The results suggested that aerosol delivery of HCPT demonstrated powerful antitumor activity and was useful for melanoma lung metastasis by aerosol delivery treatment. PMID- 21657085 TI - [Effects of Ganoderma lucidum polysaccharides on advanced glycation end products and receptor of aorta pectoralis in T2DM rats]. AB - OBJECTIVE: To investigate the effects of Ganoderma lucidum polysaccharides (GLPs) on advanced glycation end products (AGEs) and the receptor (RAGE) of aorta pectoralis in the T2DM rats, and explore the protective mechanism of GLPs on the aorta pectoralis. METHOD: SD rats were fed with high-fat diet for 4 weeks and then were injected STZ (30 mg x kg(-1)) to induce the type 2 diabetic rats. Once the T2DM models were set successfully, rats were randomly divided into normal control group, diabetes model (DM) group, berberine (30 mg x kg(-1)) group, GLPs of low (GLPs-L), middle (GLPs-M) and high-dose (GLPs-H) group (GLPs were orally given 200, 400, 800 mg x kg(-1)). After 12 weeks' treatment, the content of fasting blood glucose and AGEs in serum were detected. The expressions of AGEs and RAGE in aortas pectoralis were measured both by immunohistochemistric assays and western-blot analysis. RESULT: Compared with DM group, the content of blood glucose and AGEs in serum were significantly decreased in GLPs-H group and GLPs-M group (P < 0.01). Compared with DM group, the expressions of AGEs and RAGE in aorta pectoralis were decreased in other groups, especially in GLPs-H group (P < 0. 01). CONCLUSION: GLPs could low blood glucose and protect aortas effectively. The mechanisms may be involved in down-regulation the expressions of AGEs and RAGE in aortal tissue. PMID- 21657086 TI - [Evaluation of vitro hepatotoxicity of monocrotaline by precision-cut liver slice technique]. AB - OBJECTIVE: To modify the empirical method of precision-cut liver slice technique, and study the hepatotoxicity of monocrotaline by this technique. METHOD: Liver slices were prepared by the domestic shaking slicer. The technique of precision cut liver slice was established by detecting MTT reduction used as the slice viability under different culture medium, thickness of slices, pH and culture temperature. After monocrotaline and liver slices co-culture for 6, 24 h, the slice viability, enzyme activity of GPT, GOT, LDH, GGT and protein concentration were detected by MTT reduction, enzyme kinetics method and BCA protein assay method, respectively. RESULT: When the thickness of slices was 200 microm and pH of medium was 6.8, culture temperature was 37 degrees C, BPM culture medium, the viability of slices could maintain on a steady level. LDH leakage was significantly increased and protein content was obviously decreased after monocrotaline co-culture for 24 h with final concentration 0.02, 0.1 and 0.5 g x L(-1). No statistically significant difference between control group and monocrotaline 3 dose groups was observed in the slice viability and the content of GPT, GOT, LDH, GGT and protein after monocrotaline co-culture for 6 h. CONCLUSION: The slice viability could retain 24 h in modified BPM medium surroundings; monocrotaline displayed liver toxicity in some degree after co culture for 24 hours in 0.02, 0.1 and 0.5 g x L(-1) concentration. PMID- 21657088 TI - [Research progress on current pharmacokinetic evaluation of Chinese herbal medicines]. AB - In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction. PMID- 21657087 TI - [Effect of oral scorpio and scolopendra powder on T-cell subsets in peripheral blood and intestine from rats with collagen induced arthritis]. AB - OBJECTIVE: To observe effect of oral scorpio and scolopendra powder on T-cell subsets in peripheral blood and intestine from rats with collagen induced arthritis (CIA). METHOD: 60 rats were randomly divided into 6 groups: normal control group, model control group, low-dose scorpio and scolopendra group, middle-dose scorpio and scolopendra group, high-dose scorpio and scolopendra group, and type II collagen group. Rat's rheumatoid arthritis was induced by collagen II (C II). Level of T-cell subsets from peripheral blood and intestine was measured by flow cytometry. RESULT: CD4+ T cellular level was obviously increased (P < 0.05 or P < 0.01) or kept increased tendency in peripheral blood and intestine from the model group compared with that of the normal group, while the ratio of CD4+/CD8+ in intestine was obviously descent but the contrary in peripheral blood (P < 0.05 or P < 0.01). CD4+, CD8+ T cellular level in intestine were obviously descent and the ratio of CD4+ /CD8+ increased in all treated groups when compared with in the model group (P < 0.05 or P < 0.01). However, CD4+ T cellular level and the ratio of CD4+/CD8+ in peripheral blood were remarkablely decreased. CONCLUSION: The mechanism that scorpio and scolopendra could treat rat's rheumatoid arthritis may be regulating balance of T-lymphocyte subsets in peripheral blood and intestine. PMID- 21657089 TI - [Research progress of anticarious Chinese herbal]. AB - Caries is a chronicly infectious disease which happens to the hard tissue of the teeth and is the most common dental disease of human. Many scholars have devoted to research anticarigenics drugs and the Chinese herbal was considerably concerned. The paper briefly introduces kinds of anticarigenics Chinese herbals, such as Turkish galls, TFA and Magnolia. PMID- 21657090 TI - [Vittorio Benussi and experimental psychoanalysis]. AB - This essay proposes to reconstruct the project of experimental psychoanalysis initiated by Vittorio Benussi in the Psychology Laboratory of the University of Padua between 1919 and 1927. For Benussi, the language of the unconscious never refers back to an experimental or psychoanalytical context, but always to a possible relationship between the two. From the contact between these perspectives, there emerges one of the most extreme attempts at knowledge of the mind: the "real psychic analysis." Here Benussi is at the core of the idea of measuring the psyche, and his style is aligned with the experimental psychopathology research conducted by E. Bleuler and C.G. Jung at Burgholzli, Zurich, with the assignment of the laboratory practice to areas precluded to the experimentalist. But the Freudian lexicon is not sufficient to explain the unconscious. Benussi summons new instruments to the center of his reflection: the "physiological unconscious," the "metric analysis of breathing," the "base sleep," and the "emotional functional autonomy." If the Benussian discourse places itself at the borderline between experimentation and depth psychology, it is within this limit that it expresses its theoretical peaks and its tragic conclusion. PMID- 21657091 TI - Molecular aspects of activation mechanisms of CF1. AB - The Ca2( +) -dependent ATPase activity of spinach chloroplast coupling factor 1 (CF1) is activated by treatment with dithiothreitol (DDT). If excess of this reagent is eliminated by gel filtration, an Eadie-Hofstee biphasic plot is obtained. These results are consistent with the existence of two active forms of the enzyme governed by the redox state. We have observed that SDS-polyacrylamide gel electrophoresis pattern is affected by the pretreatment of the samples under those two different conditions. Spontaneous activation of the samples, due to a limited proteolytic process, has also been detected. In this case the electrophoretic pattern was also affected. The protease implied in this process could be a cystein protease co-isolated with CF1. These observations suggest that limited proteolysis, as well as redox-induced changes, are involved in the physiological regulation of the enzyme. PMID- 21657092 TI - Re: Our healthcare "system"--what system?, by Lynn Nagle 23(4): 1-3. PMID- 21657093 TI - Exploring emerging trends in wound care. PMID- 21657094 TI - Continence coach: Product performance characteristics to protect skin integrity. PMID- 21657095 TI - Retrospective database review. PMID- 21657096 TI - [Quality assurance should be more precise]. PMID- 21657097 TI - [Conflict of interest and credibility]. PMID- 21657098 TI - [12th statewide diabetology symposium. Diabetes and gastroenterology. Hradec Kralove, 4 June 2010]. PMID- 21657099 TI - Homer and Herodotus to Egyptian medicine. AB - Egyptian medicine is the base of Greek medicine. Egyptian people and their medical knowledge are often mentioned in the Iliad and Odyssey of Homer (VIII sec. BCE). Many Greek doctors, such as Melampus, Asclepius as well as Hippocrates visited Egypt to study and understand medicine. This work intends to focus particularly on Homer, Herodotus and Plutarch's letters, where the importance of Egypt in religion, science and medicine is clear. Herodotus (484-420 BCE) in the second book of "The Histories" describes Egypt and the medical knowledge of its doctors. Plutarch (I-II sec CE) in "The virtues of Sparta" and "Life of Lycurgus", tells about an energy beverage, named nepenthe, made with drugs from Egypt. PMID- 21657100 TI - Ibn Abi Ussaibea "Oyoun aI-Anbaa Fi Tabaqat al-Attiba" a selected review of this Index of Physicians and their Works; (from early Greeks to his time in Egypt). AB - Muwaffaq-al-Deen abu-al-Abbas Ahmad ibn Abi Ussaibea (1203-1270) was born in Damascus. He started his brilliant career in his birth place then moved to Cairo where he worked and excelled for the rest of his life. His learning was intensified by the scholarly contacts of the intellectual leaders of the day. In this study we review The Index of Physicians-Oyoun al-Anbaa Fi Tabaqat al-Attiba- (Sources of Information in the Classes of Physicians) of ibn Abi Ussaibea.The biographies in this book do not just cover physicians only but also the learned people of his day whose knowledge and expertise covered medicine, astronomy, mathematics, philosophy, and botany. For this reason the book of ibn Abi Ussaibea represents an indispensable source of the scientific and philosophical achievements of the Arabic/Islamic civilization. PMID- 21657101 TI - Unique surgical tool as an iatromagic charm. AB - Papyri are writings made on special sheets made out of reeds grown on the banks of the river Nile. The Authors comment on the relationship between a ritual text and surgical therapy with an exploration of an ancient charm as recorded in a Greek written papyrus stored in the Medicea Laurenziana Library papyri collection. This charm was presumably intended to act apotropaically, rendering harmless the aggressive surgical tool by means of still keeping its therapeutic value and thereby affording healing protection. This ritual charm acts as a "therapeutic medium" to help the surgical procedure useful to cut or to excise the uvula. The surgical power of stafillotomos is linked to the protective power of the iatromagic charm, giving the chance to analyze ancient data and to suggest a possible shape of the original scalpel. PMID- 21657102 TI - Epidemic waves during Justinian's plague in the Byzantine Empire (6th-8th c. AD). AB - The aim of the present study is to collect the epidemic outbreaks and the epidemic waves of the bubonic plague of the Byzantine Empire during the first pandemic (541-751 AD). Human activities, such as trade and military movements have been speculated as underlying factors for the causation of the pandemic. Historical data combined with geographical spreading of the plague, allows an alternative speculation of suspicious enzootic areas in the Middle East. We conclude that the possible existence of enzootic areas in that region might have been responsible for the causation of the numerous outbreaks of the bubonic plague in the Eastern provinces of the Byzantine Empire during the 6th-8th century period. PMID- 21657103 TI - Egyptian imprints on Geto-Dacian magical medicine. AB - Several characteristics of Egyptian culture and civilization could be identified in prehistoric and ancient historic Geto-Dacian territories, belonging to modern Romania (Fig. 1). From early times, magic, religion and philosophy have been part of pre-scientific medicine. Therefore these aspects are to be tackled when speaking of medicine in mythological or legendary ages. Progress of ancient Geto Dacian medicine was principally ascribed to the interface of local civilizations with ancient Egypt, Greece and Rome. Such connections were well documented and understood in historic times and were mainly based on texts of renowned Greek and Roman historians. Egyptian impact upon Dacia, -the ancient name of today's Romania-, was often explained in terms of indirect Greek- or Roman-mediated influences.The Greek and then the Roman colonies on the Black sea shore, together with later Roman colonies in Dacia Felix, founded in the heart of Transylvania, enabled access for Romania to Mediterranean cultures, including that of Egypt. PMID- 21657104 TI - On "officinalis" the names of plants as one enduring history of therapeutic medicine. AB - The officina was the building, usually an out-building, in medieval monasteries where medical monks prepared medicaments and pharmaceutical preparations to heal the sick. Dried extracts, infusions, decoctions, tinctures and distillates were prepared therein. Often the officina was attached to the medicinal or herbal gardens, also enclosed within the monastery precinct. When Linnaeus invented the binomial system of nomenclature, he gave the specific name "officinalis", to dozens of herbs and plants whose medical use had been established in preceding millennia. In the 1735 (1st Edition) of his Systema Naturae, he acknowledged the historical traditions of healing by naming scores of plants with the species designator, "officinalis", as a generic qualifier. Literally "from the officina", the species name "officinalis" thus embodied the history of many centuries of medicinal use and health lore. PMID- 21657105 TI - Medicine and nursing in the Spanish Civil War: women who served in the health services of the International Brigades (1936-1939). AB - The outbreak of the Spanish Civil War in 1936 had repercussions throughout the world. Even though Western democracies had signed a Non-Intervention Agreement, thousands of foreign volunteers fought on the Republican side. This paper briefly summarizes the issues that directly led to the war, and focuses on the intervention of the International Brigades, the origins of the International Sanitary Service (ISS) and the role played by women at the ISS. These women implemented and collaborated in important and innovative procedures in military medicine, that we analyze below. PMID- 21657106 TI - The recognition of the remains of Francesco Petrarca (Petrarch), (1304-1374). AB - Francesco Petrarca, (Petrarch), the poet who sang of his love for Laura, died in Arqua, today Arqua Petrarca, in 1374, and according to sources, was buried in the parish church. In 1380 his remains were transferred into a monumental marble tomb in front of the church by his son-in-law, Francescuolo di Brossano. Throughout the centuries the tomb was reopened on several occasions and for various reasons: to steal some of the famous poet's bones, for safety reasons, and lastly, to carry out scientific research. In this article, we intend to discuss the various openings, focusing in particular on the findings of the most recent recognition in 2003. This investigation confirmed that the skeleton is indeed Petrarca's, with the notable exception of the skull fragments, which turn out to be attributable to a member of the female sex. Using primary sources, including several unpublished documents, we offer some thoughts on when and under what circumstances this substitution might have taken place. PMID- 21657107 TI - The new EPS: Epidemiology and Psychiatric Sciences. PMID- 21657108 TI - New perspectives of mental health service research. PMID- 21657109 TI - Monitoring service utilization of persons with mental disorders--a case for mapping pathways of care. AB - Routinely collected and reported indicators for health service utilization have traditionally been event/episode related and hospital centered. This is also the case for service utilization by persons with mental disorders, for whom national and international databases usually report rates of hospital discharges, mean length of stay for hospital episode and the like. Such event/episode-related indicators are of limited use for planning and improving services for persons with mental disorders. It is argued that new reporting systems are needed that allow the monitoring of the pathways of persons with mental disorders through the service system. It is shown how--owing to recent developments in techniques of 'pseudonymization' and the ever-increasing computer power for dealing with large volumes of patient data--such a system can be established and how it can contribute to analyzing empirically such mental health-care issues as 'heavy utilizers', 'revolving door psychiatry', 'continuity of care', 'de institutionalization' and the like. Results of a record linkage study for the total population of a federal state of Austria monitoring both psychiatric and non-psychiatric health service utilization are reported. Some unexpected findings include the high utilization of non-psychiatric services by patients discharged from a psychiatric hospital bed, results which could not have been found by psychiatric case registers which usually only monitor utilization of psychiatric services. PMID- 21657110 TI - European comparisons between mental health services. AB - When developing accessible, affordable and effective mental health systems, exchange of data between countries is an important moving force towards better mental health care. Unfortunately, health information systems in most countries are weak in the field of mental health, and comparability of data is low. Special international data collection exercises, such as the World Health Organization (WHO) Atlas Project and the WHO Baseline Project have provided valuable insights in the state of mental health systems in countries, but such single-standing data collections are not sustainable solutions. Improvements in routine data collection are urgently needed. The European Commission has initiated major improvements to ensure harmonized and comprehensive health data collection, by introducing the European Community Health Indicators set and the European Health Interview Survey. However, both of these initiatives lack strength in the field of mental health. The neglect of the need for relevant and valid comparable data on mental health systems is in conflict with the importance of mental health for European countries and the objectives of the 'Europe 2020' strategy. The need for valid and comparable mental health services data is today addressed only by single initiatives, such as the Organisation for Economic Co-operation and Development work to establish quality indicators for mental health care. Real leadership in developing harmonized mental health data across Europe is lacking. A European Mental Health Observatory is urgently needed to lead development and implementation of monitoring of mental health and mental health service provision in Europe. PMID- 21657111 TI - Economic context analysis in mental health care. Usability of health financing and cost of illness studies for international comparisons. AB - This paper discusses an integrated approach to mental health studies on Financing of Illness (FoI) and health accounting, Cost of Illness (CoI) and Burden of Disease (BoD). In order to expand the mental health policies, the following are suggested: (a) an international consensus on the standard scope, methods to collect and to analyse mental health data, as well as to report comparative information; (b) mathematical models are also to be validated and tested in an integrated approach, (c) a better knowledge transfer between clinicians and knowledge engineers, and between researchers and policy makers to translate economic analysis into practice and health planning. PMID- 21657112 TI - What are evidence-based treatment recommendations? AB - In recent years new methodologies for developing treatment recommendations that give consideration to evidence, values, preferences and feasibility issues have been developed. One of the most well-developed approaches is the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. This article briefly presents how this methodology may be employed to develop treatment recommendations that might constitute a permanent infrastructure between primary research and everyday clinical practice. PMID- 21657113 TI - Brain anatomy of major depression II. Focus on amygdala. AB - Here, we briefly summarize the most consistent structural magnetic resonance imaging (MRI) studies on amygdala in major depression and debate the effects of clinical variables on amygdalar morphology. PMID- 21657114 TI - Prevention and treatment of child and adolescent depression: challenges and opportunities. AB - OBJECTIVE: To examine the current theoretical rationale and empirical evidence for preventing and treating major depressive disorder in childhood and adolescence. METHODS: Selective review of recent controlled investigations on the efficacy and safety of preventive and treatment interventions. RESULTS: Even more than in adults, pediatric clinical trials in depression are dominated by symptomatic improvement with non-specific clinical contact (on average, 50% 'placebo response'). The additional benefit of specific psychotherapeutic or pharmacological treatment is on average modest. Antidepressant medication is effective in speeding up improvement, but more than a third of patients do not reach full remission even after prolonged treatment. The advantage of routinely combining medication with cognitive-behavioral therapy (CBT) is unclear. Depressed suicidal adolescents can benefit from CBT and medications. CBT can protect high-risk youths from developing a depressive episode. CONCLUSIONS: Effective interventions to prevent and treat depression in youth exist, but their therapeutic benefit appears to be, on average, small, possibly due to the clinical heterogeneity subsumed under the current diagnostic construct of depressive disorder. More specifically, targeted interventions tailored to individual clinical and biological characteristics may result in greater effectiveness and overall efficiency. PMID- 21657115 TI - Factor-structure of the Italian version of the Scale Of Prodromal Symptoms (SOPS): a comparison with the English version. AB - AIMS: The 19-item 'Scale Of Prodromal Symptoms' (SOPS) and its semi-structured interview, the Structured Interview for Prodromal Symptoms (SIPS), have been developed to assess prodromes of psychosis. We assessed psychometric properties of the Italian version of the instrument. METHODS: We collected socio-demographic and clinical data of 128 people seeking first-time psychiatric help in a large Roman area, either as outpatients at community facilities or as inpatients in psychiatric wards of two general hospitals. Participants were administered the Italian version of the SOPS and the 24-item Brief Psychiatric Rating Scale (BPRS). Data were analysed through Pearson's correlation and factorial analysis. RESULTS: The English and Italian SOPS versions showed similar psychometric properties and factorial structure. The best-fit model was trifactorial, explaining 90% of total variance, and roughly corresponding to the positive, negative, and general dimensions, with disorganisation spreading over the other dimensions. Compared with the BPRS, the Italian version of the SOPS showed construct validity and convergent validity. CONCLUSIONS: The factor-structure of the Italian version of the SOPS is similar to those of the English and Spanish versions, in that the factors emerged are the same (positive, negative, and general symptoms). The scale could be used to assess at-risk people in early intervention services. PMID- 21657116 TI - Recovered or dead? A Swedish study of 321 persons surveyed as severely mentally ill in 1995/96 but not so ten years later. AB - AIM: The aim was to follow-up a group of persons who were considered severely and persistently mentally ill (SMI) at the time of the 1995 Swedish mental health care reform but not so ten years later. METHODS: Surveys were conducted in 1995/96 and 2006 in an area of Sweden. Of 602 persons surveyed as SMI in 1995/96, 321 were not found to be so in a similar survey in 2006. These persons were followed up concerning death rates and causes, as well as concerning recovery and present care. Comparisons between subgroups were made using the results of interviews conducted in 1995/96. RESULTS: Nineteen percent of the persons considered SMI in 1995/96 were recovered in 2006 in the sense that they no longer were considered SMI. The only variable found to predict recovery was diagnosis. Half of the persons in the sample given a diagnosis of neurosis were recovered but only 6% of those given a diagnosis of psychosis. Death rates and death causes seemed to be in line with previous research. CONCLUSIONS: Relatively few persons were considered recovered after ten years. Most persons in the sample were still in contact with care and services. PMID- 21657117 TI - Effectiveness of continuity-of-care programs to reduce time in hospital in persons with schizophrenia. AB - AIMS: To assess the impact of the Continuity-of-Care Program (CCP; a clinical case management model) on hospital use of persons with schizophrenia in three Community Mental Health Services in Madrid (Spain). METHODS: Using data provided by the Psychiatric Case Register, we analyzed the use of hospitalization in 250 individuals before and after the date of inclusion in this program. RESULTS: During the first year after launching the program, there was a 40-69% reduction in the number of admissions, length of each hospital stay, proportion of admitted patients, total number of days in-hospital, proportion of patients visiting the emergency room, and emergency room visits. This drop was maintained over the subsequent 3 years of program functioning. CONCLUSIONS: These results encourage the development and implementation of such programs, even though more studies evaluating the effectiveness of these programs for other endpoints are needed. PMID- 21657118 TI - Employers' attitudes to people with mental health problems in the workplace in Britain: changes between 2006 and 2009. AB - AIM: This study examines whether there have been improvements in mental health related knowledge, attitudes and workplace practices among British employers between 2006 and 2009. METHOD: In 2006, the Shaw Trust surveyed 550 British employers. Telephone interviews ascertained their knowledge, attitudes and practices related to mental health in the workplace. This study compares their findings with a repeat survey of 500 employers in 2009. RESULTS: In 2006, 33% of employers reported that none of their employees would develop a mental health problem during their working lifetime, dropping to 7% in 2009. In both years, less than a third of companies had formal policies on stress and mental health. In 2006, 68% agreed they would be flexible in offering adjustments to someone with mental ill-health, rising to 87% in 2009. In 2006, 76% agreed that British industry needs more support to improving the way it deals with mental health in the workplace, increasing to 88% in 2009. CONCLUSIONS: While employers' mental health knowledge significantly improved and many offer 'reasonable adjustments', there is a need to formalise these arrangements and for further training and support. Resistance to the Equality Bill amendment banning pre-employment health questions, with exceptions, is predicted based on employers' preference for pre employment disclosure. PMID- 21657119 TI - A randomised controlled trial of assertive outreach vs. treatment as usual for black people with severe mental illness. AB - AIM: We aimed at testing whether an assertive outreach team (AOT) run by a Black voluntary organisation is more acceptable to Black people with severe mental illness. METHODS: A randomised controlled trial (RCT) of 83 Black (African, African Caribbean or Black British) patients with severe mental illness with treatment as usual (TAU) or Assertive Outreach (AO) by a non-statutory sector Black AOT. Frequency of admissions, duration of admissions, symptom severity and client satisfaction with clinical interventions were assessed. RESULTS: The mean length of admission at follow-up was not significantly different between the two groups (74.64 v. 64.51; mean difference= 10.13, 95% CI -2.86, 23.11, p= 0.125), neither was the mean number of admissions (1.32 v. 1.20; mean difference=0.13, 95% CI -0.18, 0.43, p = 0.401). Mean Brief Psychiatric Rating Scale (BPRS) ratings at 1-year follow-up were significantly lower in the AOT group than in the TAU group (56.34 v. 63.62; mean difference = 7.27, 95% CI 0.66, 13.88, p = 0.032), and people were significantly more satisfied with AOT 24/29 (83%) than the generic services: 4/26 (15%), p<0.001. CONCLUSIONS: While the AO service was highly culturally acceptable to Black people, there was no evidence that the provision of AOT reduces frequency or duration of hospital admission. PMID- 21657120 TI - Risk factors for postoperative depression in 150 subjects treated for drug resistant focal epilepsy. AB - OBJECTIVE: The primary goal was to identify risk factors for post-surgical depression in subjects operated on for drug-resistant epilepsy. Secondary goals were to confirm the high rate of depression in subjects suffering from epilepsy (prior to surgery) and to look for first post-surgical depressive episode. METHODS: Case series study of 150 subjects surgically treated for partial epilepsy (side of surgery: 72 right, 78 left; site of surgery: 97 Unilobar Temporal, 17 Unilobar Frontal, 14 Posterior, 22 Multilobar). All subjects routinely had three psychiatric evaluations: before surgery (baseline) and at 6 and 12 months after surgery. Psychiatric diagnoses were made according to DSM-IV TR criteria. Bivariate (Fisher exact test and Kruskal-Wallis rank sum test) and multivariate (logistic regression model fitting) analyses were performed. RESULTS: Thirty-three (22%) subjects had post-surgical depressive episodes, 31 of them in the first 6 months. Fourteen out of 33 experienced depression for the first time. Post-surgical depressive episodes are not associated with gender, outcome on seizures, side/site of surgical resection, histological diagnosis, psychiatric diagnoses other than depression. Depressive episodes before surgery and older age at surgery time are risk factors for post-surgical depression (p= 0.0001 and 0.01, respectively, at logistic regression analysis). No protective factors were identified. CONCLUSIONS: Our data show that lifetime depressive episodes and older age at surgery time are risk factors for postsurgery depression. Moreover, a prospective study could be useful in order to assess whether depression is really a consequence of surgery. PMID- 21657121 TI - Professor of computer-based restorative dentistry--an impulse for CAD/CAM? PMID- 21657122 TI - Full arch scans: conventional versus digital impressions--an in-vitro study. AB - The digital intraoral impression has become a central part of the CAD/CAM technique. The objective of the present study was to compare the accuracy (trueness and precision) of digital impressions of the full arch with that of conventional impressions on the in-vitro model. For this purpose, a master model was acquired with a new reference scanning process, the measuring trueness of which was +/- 4.1 microm and the precision +/- 2.5 microm. On the one hand, conventional impressions and then plaster models (n = 5) were produced from this master model, and on the other hand, digital impressions were made with the Cerec AC Bluecam and the Lava COS system (each n = 5). The plaster models were also scanned with the reference scanner. The available data records were superimposed and the differences determined. The deviation from the master model defines the trueness of the impression method. The deviations of the models among one another demonstrate the precision of the method. The trueness of the impressions was 55 +/- 21.8 microm in the conventional impression group, for digital impressions with Cerec Bluecam it was 49 +/- 14.2 microm and for digital impressions with Lava COS 40.3 +/- 14.1 microm. The precision was 61.3 +/- 17.9 microm for conventional impression with Impregum, 30.9 +/- 7.1 microm for digital impression with the Cerec Bluecam and 60.1 +/- 31.3 microm for digital impression with Lava COS. These in-vitro results show that accuracy of the digital impression is similar to that of the conventional impression. These results will have to be confirmed in further clinical studies. PMID- 21657123 TI - Comparison of computer generated occlusal surfaces with functionally waxed-on surfaces. AB - CAD/CAM methods are also being used ever more frequently to produce fully anatomical restorations. These automated, computer-assisted methods play an outstanding role in generating occlusal surfaces. This study examines whether such computer generated occlusal surfaces are comparable with those which an experienced dental technician functionally waxes-up in the individually controlled articulator. A comparison of the occlusal surfaces in twelve posterior teeth of eleven functionally healthy patients showed differences ranging from 380 to 530 pm related to the mean difference in volume between both types of occlusal surface. Furthermore, a mean pixel deviation of the superimposed occlusal surfaces of 5.12 +/- 1.951 microm (min: 2.49 microm, max: 9.16 microm) was observed. These deviations were found for both functionless surfaces and occlusal surface areas of the functional occlusion. Thus, comparable occlusal surfaces can be achieved with computer generated methods, but they do not quite achieve the result of functionally waxed-up occlusal surfaces in the individually programmed articulator. PMID- 21657124 TI - The impression-free Cerec multilayer bridge with the CAD-on method. AB - Two new developments extend the spectrum of the Cerec applications: Cerec Connect: The entire mandible and maxilla can be scanned, as well as their relationship to one another, with the intraoral scanner. Multilayer technique for up to four-unit fixed dental prostheses (FDPs): the CAD-on technique from Ivoclar is the latest procedure in which a zirconium oxide framework and a veneer structure of e.max-CAD are bonded together by ceramic. Intraoral data acquisition with Cerec-Connect, design with Cerec-inLab and fabrication of the three-unit FDP are described and illustrated with a clinical case, and further developments are suggested. PMID- 21657125 TI - Restoration of maxillary anterior esthetics using lava all-ceramic fixed dental prostheses. AB - The success of all-ceramic crowns and increased patient demand for metal-free, tooth-colored restorations has led to the development of many different restorative systems for all-ceramic fixed dental prostheses (FDPs). The most recent core materials for all-ceramic FDPs are the yttrium-tetragonal zirconia polycrystal (Y-TZP)-based materials. Yttrium oxide is a stabilizing oxide added to pure zirconia to stabilize it at room temperature and to generate a multiphase material known as partially stabilized zirconia. This exhibits very high flexural strength and fracture toughness along with good biocompatibility and excellent esthetics. This clinical report describes the use of the Lava All-ceramic system, based on Y-TZP, for the fabrication of two fixed dental prostheses (FDPs) in the maxillary anterior region of the patient, restoring both esthetics and function. PMID- 21657126 TI - Impression-free production techniques. AB - Digital acquisition of the clinical situation in the mouth seems much more logical than digitizing the impressions. Intraoral scanning systems are laser supported or video based. The retraction of the gingiva plays a special part in the accurate display of the preparation border. The working procedures in the dental practice and in the dental laboratory have been changed fundamentally by this new technology. Workable solutions are already available and rapid further developments can be expected in the near future. PMID- 21657127 TI - Grasping the spirit in nature: Anschauung in Orsted's epistemology of science and beauty. AB - The intersection between art, poetry, philosophy and science was the leitmotif which guided the lives and careers of romantic natural philosophers including that of the Danish natural philosopher, H. C. Orsted. A simple model of orsted's career would be one in which it was framed by two periods of philosophical speculation: the youth's curious and idealistic interest in new attractive thoughts and the experienced man's mature reflections at the end of his life. We suggest that a closer look at the epistemological aspects of his works on the theory of beauty reveals a connection between this late work and his early philosophical work including experimental philosophy, but also with the work in teaching and textbook writing, that lies in between. The latter includes Orsted's view on the application of mathematics in natural philosophy as well as his failed attempt at a genetic presentation of elementary geometry. PMID- 21657128 TI - Objectivity, abstraction, and the individual: the influence of Soren Kierkegaard on Paul Feyerabend. AB - This paper explores the influence of Soren Kierkegaard upon Paul Feyerabend by examining their common criticisms of totalising accounts of human nature. Both complained that philosophical and scientific theories of human nature which were methodologically committed to objectivity and abstraction failed to capture the richness of human experience. Kierkegaard and Feyerabend argued that philosophy and the science were threatening to become obstacles to human development by imposing abstract theories of human nature and reality which denied the complexities of both. In both cases, this took the form of asserting an 'existential' criterion for the assessment of philosophical and scientific theories. Kierkegaard also made remarks upon the inappropriateness of applying natural scientific methods to human beings which Feyerabend later expanded and developed in his criticisms of the inability of the 'scientific world-view' to accommodate the values necessary to a flourishing human life. I conclude by noting some differences between Kierkegaard and Feyerabend's positions and by affirming the value of existential criticisms of scientific knowledge. PMID- 21657129 TI - Founding a medical history museum in a medical school and questions encountered as medical historians. PMID- 21657130 TI - Physicians as diplomats in the Renaissance Republic of Dubrovnik (Ragusa). PMID- 21657131 TI - The National DNA Database on trial: engaging young people in South Wales with genetics. AB - While there has been research conducted on public views about ethical and social aspects of the National DNA Database (NDNAD), there is little which focuses on views of young people, in particular those whose details are held on the NDNAD. We describe an engagement activity developed in South Wales to engage young offenders with ethical and social issues surrounding the NDNAD--a Mock Trial--and how we facilitated the presentation of their views to policy makers. We discuss the successes and challenges we encountered with engaging young offenders, decisions that the young people reached about possible future policies for the NDNAD at the Mock Trial, and their contribution to the decision-making process. PMID- 21657132 TI - Public participation: democratic ideal or pragmatic tool? The cases of GM foods and functional foods. AB - Over recent decades, public participation initiatives have been employed across Europe often with a focus on science and technology issues. In the area of new food technologies most participation initiatives have centered on genetically modified foods. By contrast, in the area of functional foods--where significant EU legislation was recently passed--we have seen no initiatives towards public inclusion. This applies also for Denmark, the country which is the focus of this article. Based on an interview study with members of the Danish parliament the article examines why such considerable differences exist between initiatives to involve the public, and it challenges the role that public participation plays in Danish politics. The main claim made in the article is that although politicians argue for the value and relevance of public participation their willingness to initiate participatory processes is overruled by their concern with playing by the rules of the political game. PMID- 21657133 TI - Food labels as boundary objects: how consumers make sense of organic and functional foods. AB - This paper considers how consumers make sense of food labeling, drawing on a qualitative, empirical study in England. I look in detail at two examples of labeling: 1) food certified as produced by organic methods and 2) functional food claimed to be beneficial for human health, especially probiotic and cholesterol lowering products. I use the concept of "boundary objects" to demonstrate how such labels are intended to work between the worlds of food producers and food consumers and to show how information is not merely transferred as a "knowledge fix" to consumer ignorance. Rather, consumers drew on a binary of "raw" and "processed" food and familiarity with marketing in today's consumer culture to make sense of such labeling. PMID- 21657135 TI - Government management of two media-facilitated crises involving dioxin contamination of food. AB - Incidents become crises through a constant and intense public scrutiny facilitated by the media. Two incidents involving dioxin contamination of food led to crises in Belgium and the Republic of Ireland in 1999 and 2008, respectively. Thought to cause cancer in humans, dioxins reached the food supply in both incidents through the contamination of fat used for animal feed. The food and agricultural industries connected to each incident relied on crisis management activities of federal governments to limit adverse public reaction. Analysis of the management of the two crises by their respective federal governments, and a subsequent review of crisis management literature, led to the development of an effective crisis management model. Such a model, appropriately employed, may insulate industries associated with a crisis against damaged reputations and financial loss. PMID- 21657134 TI - The public understanding of nanotechnology in the food domain: the hidden role of views on science, technology, and nature. AB - In spite of great expectations about the potential of nanotechnology, this study shows that people are rather ambiguous and pessimistic about nanotechnology applications in the food domain. Our findings are drawn from a survey of public perceptions about nanotechnology food and nanotechnology food packaging (N = 752). Multinomial logistic regression analyses further reveal that knowledge about food risks and nanotechnology significantly influences people's views about nanotechnology food packaging. However, knowledge variables were unrelated to support for nanofood, suggesting that an increase in people's knowledge might not be sufficient to bridge the gap between the excitement some business leaders in the food sector have and the restraint of the public. Additionally, opposition to nanofood was not related to the use of heuristics but to trust in governmental agencies. Furthermore, the results indicate that public perceptions of nanoscience in the food domain significantly relate to views on science, technology, and nature. PMID- 21657136 TI - Foodborne microbial risks in the press: the framing of listeriosis in Canadian newspapers. AB - Outbreaks of foodborne illness generally receive abundant print media coverage. However, the framing of outbreaks and representations of foodborne pathogens in the media discourse are not necessarily homogeneous. Drawing on previous research on media coverage of emerging diseases and on the conceptual tools of framing theory, this paper explores the diversity of frames and representations used in the media coverage of two listeriosis outbreaks that occurred in Canada in fall 2008. In the dominant war against microbes frame, microbes are portrayed as posing serious risks that call for stringent control measures. This frame coexists with other frames which rather emphasize economic, ecosystem or nutrition issues and which are supported by representations of microbial risks that either mitigate these risks, present them as inevitable or as less serious than others. The implications of these observations for the public understanding of foodborne microbial risks are discussed. PMID- 21657137 TI - Students as vital participants in research projects. AB - Inclusion of research coursework into a medical technology or clinical laboratory science program is currently viewed as a mark of a good degree program. Examples of this type of coursework are evaluation of scientific papers, techniques of scientific writing, application and performance of statistical analysis and introduction to research ethics (e.g., Institutional Review Board approval process). While many programs have the ability to recruit experienced scientists into research mentorship of medical technology/clinical laboratory science students, it is recognized that not all programs have this ability. It is also recognized that clinical laboratorians are performing critical diagnostic tests and, in this capacity, have the ability to identify research projects that are necessary, evidence-based and timely. It is hereby proposed that clinical laboratorians take advantage of this innate ability and create rich teaching experiences for students by including them in performance of research projects. Because of the fact that students are armed with up-to-date knowledge, have willing and enthusiastic spirits and are highly motivated to learn, they are vital participants in research. The students receive an invaluable active learning experience and possibly a future job; the clinical laboratorians meet and possibly exceed the research and scholarship expectations of their institutions; and the scientific community benefits by the science being shared through publication in scientific journals. PMID- 21657138 TI - HbA1c does not always estimate average glucose. AB - Hemoglobin A1c (HbA1c) testing can be inaccurate in persons with elevated amounts of Hemoglobin F, or with abnormal hemoglobins found in sickle cell trait, HbC trait and HbE trait. These variants are more prevalent in African and Asian Americans, the same demographic that has an increased risk of diabetes. Variant hemoglobins might cause a false increase or decrease in HbAlc, depending on methodology and manufacturer. Case studies of two African American patients, one with and one without variant hemoglobins, are presented. The major methods used to assay HbAlc, immunoassay, HPLC and boronate affinity are described, and compared for their ability to detect variant hemoglobins. An algorithm is proposed to test new patients using the HPLC method to identify or rule out the presence of the most common variant hemoglobins. Patients with variant hemoglobins can subsequently be assigned to HbAlc methods proven to be accurate in the presence of those hemoglobins. PMID- 21657139 TI - Homozygous sickle cell anemia and secondary complications: a case study. AB - A 26-year-old African-American male presented with chest and back pain, fatigue and a history of the following: homozygous sickle cell anemia, pain crises, stroke, hip replacement following avascular necrosis of the femoral head, priapism, chronic transfusions, iron overload, hypertension, migraine headaches, port infections, depression and type II diabetes. PMID- 21657140 TI - Trypanosoma brucei infection in a HIV positive Ugandan male. AB - Human African Trypanosomiasis, or African Sleeping Sickness, is a parasitic infection caused by Trypanosoma brucei (gambiense or rhodesiense), and one of the declared neglected tropical diseases. Sleeping sickness has high fatality rates and is a continued threat in several African countries. We present characteristic clinical and microbiologic features of a fatal case of African Sleeping Sickness in an HIV-infected individual. PMID- 21657141 TI - Immunoglobulin light chain levels can be used to determine disease stage in children with juvenile idiopathic arthritis. AB - OBJECTIVE: Patients with some inflammatory diseases have been shown to have increased levels of immunoglobulin light chains. In this study, we measured the concentrations of immunoglobulin kappa and lambda light chains in sera of patients with juvenile idiopathic arthritis (JIA) (study group), familial mediterranean fever (FMF) (disease control group) and in healthy children. Our aim was to compare immunoglobulin light chain levels with other well-known markers of inflammation, such as the erythrocyte sedimentation rate (ESR) and the acute phase reactants (APRs), serum amyloid A (SAA) and C-reactive protein (CRP), to find out if immunoglobulin light chain determinations have any discriminating value in the follow-up of these patients. RESULTS: ESR, CRP, SAA, kappa and lambda chain levels and lambda/IgG ratio showed a statistically significant difference between active and remission stages in JIA patients. Kappa correlated very well with SAA and ESR in both stages. On the other hand, lambda correlated with SAA and ESR only in the remission period. There was no significant difference in kappa and lambda chain levels between active and remission stages in FMF patients. In addition, kappa and lambda chain concentrations showed no correlation with other markers of inflammation and immunoglobulin levels neither in entire FMF group nor in different subgroups with respect to clinical status. Immunoglobulin light chains kappa and lambda as well as levels of three markers of inflammation were found to be significantly higher in JIA patients who were in the active stage of disease when compared to data of healthy children CONCLUSION: Ig light chains especially kappa chain concentrations are helpful to determine disease stage in JIA patients but with our current data, they do not exhibit superiority to any of the classical tests for inflammation. PMID- 21657142 TI - Serum water analysis in normal pregnancy and preeclampsia. AB - Hemodilution and hemoconcentration affect hematology measurements and serum analyte concentrations but whether a given blood sample is hemodiluted or hemoconcentrated is frequently not known. Preeclampsia (PE) is a serious pregnancy complication and samples obtained from PE patients may be relatively hemoconcentrated when compared to those of normal pregnancy, where hemodilution is the norm. Laboratory test results may appear similar when values would differ if adjusted for hemodilution and hemoconcentration. We sought to determine if serum water (SW) content analysis can facilitate differentiation of the hemodilution of normal pregnancy from the hemoconcentration of PE, within the broader search of a clinical laboratory method to potentially correct for pregnancy-related, sample concentration variations. Serum samples from 59 non pregnant, 64 normal pregnant, 23 mild PE, and 8 severe PE patients were tested for SW content. The mean results in g/100g were as follows: 91.15, 91.86, 92.00, and 92.46 respectively. SW data were also compared with corresponding total protein (TP), serum albumin (SA), and hematocrit (HCT) results. The t-test was significant (p= <0.001) for TP, SA, HCT, and SW in group-by-group comparisons. SA and SW were significantly, inversely correlated in the normal pregnant and severe PE groups, while TP and SW were significantly, inversely correlated in all groups. Correlation coefficients were stronger in the pregnancy groups than the non-pregnant group. This study demonstrates differences in the SW content between: non-pregnant, normal pregnant, mild PE, and severe PE patient sera. PMID- 21657143 TI - Patient safety and the medical laboratory an introduction. PMID- 21657144 TI - Patient safety and the medical laboratory using the IOM aims. AB - Examining the quality of medical laboratory services using the perspective of the six IOM aims provides laboratory professionals with numerous opportunities to improve the quality of healthcare and validate the value of medical laboratory test information in improving patients' lives. This necessitates exploring the effects of other healthcare processes upon the TTP, as well as the affect laboratory test information and processes have upon other healthcare delivery processes. It requires using analytical approaches that value data collection, systematic process improvement models and lessons learned in other disciplines. PMID- 21657145 TI - Improving patient safety: lessons from other disciplines. AB - Other industries and certain healthcare specialties have employed a variety of methods to improve safety and quality of services. Techniques such as industry wide standardized collection and reporting of error data, standardization of practice through checklists, application of electronic health records, and simulator-based interdisciplinary training have improved outcomes in aviation, anesthesiology, and surgery. Although traditionally the clinical laboratory has concentrated on analytical performance, pre- and post-analytical aspects of laboratory services may also be improved through the application of these methods. PMID- 21657146 TI - Just culture-changing the environment of healthcare delivery. AB - Although errors cannot be totally eliminated, they can be reduced by adopting a system of accountability that requires employees to self-report errors in the interest of patient safety. Traditional laboratory accountability systems are based on a culture of blame, focusing on punishing individuals, and with little emphasis on learning lessons from the errors. Under a just culture laboratory accountability system, if factors in the environment or process contributed to an error, the individual should not be punished. Rather, they and the system can both identify improvements for processes so that this type of error does not reoccur. Using this approach, laboratory services can be made safer for current and future patients. PMID- 21657147 TI - Clinics in the "suitcase camp": nursing the migrants during the Great Depression, 1938-1941. PMID- 21657148 TI - Dysplasia in inflammatory bowel diseases. PMID- 21657149 TI - Dysplasia in ulcerative colitis: still a challenge. AB - As duration of inflammatory bowel disease (IBD), in particular ulcerative colitis (UC), is a major risk factor for the development of colorectal cancer (CRC), it is rational to propose a screening colonoscopy when the risk starts to increase, i.e., after 8-10 years from the onset of disease. If low-grade dysplasia is detected, the 9-fold increased risk of developing CRC reported in the most recent meta-analysis could reasonably be viewed as justification for colectomy even if some follow-up studies have shown a lower rate of CRC. A reasonable compromise could be to continue surveillance with extensive biopsy sampling at shorter (perhaps 3-6 month) intervals. If high grade dysplasia is present, the decision is easier, because the risk of concomitant CRC may be as high as one third, assuming that the biopsies were indeed obtained from flat mucosa and not from an adenoma. Total proctocolectomy with ileal pouch anal anastomosis (IPAA) has become the most commonly performed procedure for patients with ulcerative colitis requiring elective surgery for dysplasia. Nevertheless, a recent systematic review alerted that the risk of dysplasia in anal transition zone and rectal cuff in patients undergone to restorative proctocolectomy was remarkable, mainly in patients operated on for dysplasia or colorectal cancer. PMID- 21657150 TI - Pathology of dysplasia and cancer in inflammatory bowel disease. AB - In both Crohn's disease and ulcerative colitis, colorectal cancer (CRC) secondary prevention basically relies on the histology detection of dysplasia. In inflammatory bowel diseases (IBD) setting, dysplasia identifies the subgroup of patients eligible to a (more) strict surveillance program (or prophylactic colectomy). In the clinical practice, a number of issues might affect the benefit of the clinico-pathological surveillance of the IBD-dysplasia-patients: sampling errors, inconsistency in biopsy assessment, patients' drop-out, etc. Even in such a multifaceted context, evidence has been provided that surveillance of dysplasia is effective in reducing both CRC mortality and morbidity. This manuscript focuses on current issues concerning the histology assessment of the IBD associated dysplastic lesions. PMID- 21657152 TI - Evolving endoscopic technologies for the detection of dysplasia in inflammatory bowel diseases. AB - Patients with long-standing and extensive ulcerative colitis (UC) and colonic Chron's disease (CD) have an increased risk of CRC compared with the general population. Although no large controlled trials have proven that surveillance reduces mortality, cancer prevention in inflammatory bowel disease depends on the detection of dysplasia during scheduled surveillance colonoscopy and is widely recommended by gastroenterological associations. Dysplasia in IBD may occur in flat mucosa or in raised lesions (DALM) which have sometimes endoscopic features similar to adenoma (adenoma-like DALM). Recently, new endoscopic techniques to facilitate the distinction between dysplastic and actively inflamed or normal mucosa have been proposed. Chromoendoscopy significantly increases the sensitivity of detecting subtle dysplastic lesions and has emerged as the new standard of cancer surveillance in patients with IBD. Confocal laser endomicroscopy (CLE) is a novel technique that enables the endoscopist to obtain real time in vivo microscopic images of the gastrointestinal mucosa and can be used for targeting biopsies to relevant areas. CLE in conjunction with chromoendoscopy proved able to increase the diagnostic yield of dysplasia in ulcerative colitis and reduce the number of biopsies needed. The role of digital filtering technologies (virtual chromoendoscopy) and autofluorescence in IBD surveillance will be also discussed. PMID- 21657151 TI - Colonic carcinogenesis in IBD: molecular events. AB - Patients with ulcerative colitis (UC) and Crohn's disease (CD) are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. Several evidences suggest a causal link between chronic inflammation and the development of cancer in the gastrointestinal tract. In fact, patients with UC are exposed to repeated episodes of inflammation that predispose to various tumorigenic events and the sequence of these events are different from those that contribute to develop a sporadic colorectal cancer. In UC carcinogenesis the early events are represented by DNA methylation that produce an inhibition of onco-suppressor genes, mutation of p53, aneuploidy and microsatellite instability. Hypermethylation of tumor suppressors and DNA mismatch repair gene promoter regions, is an epigenetic mechanism of gene silencing that contributes to tumorigenesis and might represent the first step in inflammatory carcinogenesis. P53 is frequently mutated in the early stages of UC associated cancer, in 33-67% of patients with dysplasia and in 83-95% of UC related cancer patients. Moreover, aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC Finally, the inconsistency between the high cumulative rate of dysplasia in UC and the relatively lower incidence of invasive cancer raises the question about the mechanisms of immunosurveillance that may prevent malignant progression of neoplasm in the colon in most cases. Co stimulatory molecule CD80 up-regulation in colonic mucosa in UC dysplasia may be one of these mechanism. PMID- 21657153 TI - Surgery in presence of dysplasia in IBD. AB - Patients with longstanding ulcerative colitis (UC) and Crohn's disease have an increased risk of developing colorectal cancer. Dysplasia can be defined as neoplastic intraepithelial change, paralleling the location ofneoplasia, arising from chronic inflammation, divided in different grades from low to high grade. Different types of dysplasia have been described in UC such as "flat dysplasia", DALM or ALM. The management of dysplasia and cancer associated with UC has been strongly influenced by the considerable progress in the surgical treatment of the disease that has taken place in the last decades. The presence of dysplasia modifies the surgical attitude in sphincter-saving procedures such as ileorectal and ileoanal anastomosis where colonic mucosa is left in situ. With the stapled anastomosis few centimeters of colonic mucosa (1-2 cm) are left in site below ileo-anal anastomosis with a risk of malignant degeneration. The hand-sewn IPAA with mucosectomy reduces the risk of retained colonic mucosa below the anastomosis, but does not allow complete removal of columnar epithelium with its potential evolution to a malignant state. CONCLUSIONS: in case of preoperative diagnosis of dysplasia we strongly recommend an oncologic resection of the specimen with TME, ligation at the origin of all the vascular pedicles and a extended lymphadenectomy. PMID- 21657154 TI - Urgent surgery for sigmoid diverticulitis. Retrospective study of 118 patients. AB - OBJECTIVE: Aim of our study was to identij5 the risk factors for operative morbility and mortality after urgent surgery for complicated sigmoid diverticulitis. A further end point was define the adequate surgical approach in these patients. METHODS: Data fJom 118 patients who were admitted for emergency surgery between 2000 and 2009 for non-haemorrhagic complicated diverticulitis of the sigmoid colon were retrospectively evaluated and analysed. Operative options included resection with primary anastomoses (PA), Hartmann's procedure (HP) and colostomy. All operative complications were noted and potential risk factors listed. RESULTS: One hundred eighteen patients were enrolled in this study. Surgery for peritonitis was indicated for 102 patients and for intestinal obstruction in the remainder. Overall morbidity and mortality rates were 37.3% and 9.3%, respectively. Primary resection was performed on 113 patients (95.8%). Age greater than 70 years, diffuse peritonitis, Mannheim Peritonitis Index (MPI) above 18, and symptoms lasting longer than 24 hours are considered as independent risk factors for operative morbidity and mortality. DISCUSSION: Our results confirmed that while age older than 70 years and delaying treatment (>24h) are independent risk factors for operative morbidity and mortality, comorbidity is not. According to general guidelines, first target of surgery was to attempt a primary resection of the diseased colon (95.8% of our patients). In our series an high rate of Hartmann procedure (HP) in Hinchey's class 2 patients was observed. This unusually high number is explained by the rate (68.4%) of pelviperitonitis diagnosed in these patients. Extended pelvic peritonitis is generally defined as a local peritonitis (class 2 Hinchey), which is not accurate. Colonic resection in these cases would not completely remove peritoneal contamination and renders the indication for PA questionable. CONCLUSIONS: Emergency surgery for complicated diverticulitis is characterised by high rates of morbidity and mortality. Age greater than 70 years, symptoms lasting longer than 24 hours, MPI above 18, and diffuse peritonitis were significant predictors. Early eradication of septic focus is the main goal of surgery. Primary anastomosis is recommended only if sepsis is completely removed. PMID- 21657155 TI - ABCB5 in peripheral blood of a patient affected by multiple primary malignancies. AB - BACKGROUND: Multiple primary neoplasm malignancies syndrome (MPMN), is the presence of two or more abnormal growths of tissue, occurring simultaneously. Although the number of second malignancies is increasing, due to several factors, the presence of triple or quadruple malignancies is still very rare. PATIENT AND METHODS: We report a case of a 78-year-old man, with six primaries: a prostatic adenocarcinoma, breast cancer, two melanoma, a basal cell carcinoma, and a lymphoma in a four years period. RESULTS: The onset of MPMN is probably caused by a mutation of DNA repair genes, probably the TP53 gene. Common features of this syndrome are early rise and low tendency to metastatize. We reviewed the markers of staminality for various tumors: RNA expression of ALDH1, CD 133, and ABCB 5, extracted from the sentinel lymph node (SLN) and from the peripheral blood of the patient, was verified. CONCLUSION: People with multiple tumors represent a segment of the cancer-survivor population, which is continuously increasing (10%). Several genetic mutation can be involved in this kind of population. Our patient was positive for the expression of ABCB5, a marker for staminality of melanoma, in periphal blood. PMID- 21657156 TI - An uncommon association between parathyroid adenoma and Hodgkin disease. AB - The Authors refer their experience of a patient operated for adenoma of the inferior parathyroid of left lobe associated to a limphoadenopathy fom HD. Diagnostic and therapeutical approach are described. The literature of these last decades reports a single case with similar characteristics, but not with the same association. Numerous neoplasias associated more frequently with parathyroid adenoma are mentioned and the probable causes of this association. Although the associations with other affections of the hemolymphopoietic system are relatively frequent, the causes of the rarity of the association between parathiroid adenoma and HD remain unknown. PMID- 21657157 TI - Small cell carcinoma of the breast. Report of a case. AB - The recognition of undifferentiated forms of endocrine tumors in the extrapulmonary sites is considered as extremely infequent. Immunohistochemical patterns of this tumor are similar to small cell neuroendocrine cancer of the lung and as the pulmonary one, it is more aggressive than carcinoma without neuroendocrine differentiation. We report a case of a 68 years old woman with a primary small cell carcinoma of the breast gland presented as a palpable and mobile 2 cm mass, located in the upper outer quadrant of her right breast. It was treated with surgery and the diagnosis was made after surgical treatment, thanks to the immunohistochemical studies of tissue. PMID- 21657158 TI - Primary testicular plasmocytoma. AB - A case of Primary Testicular Plasmocytoma (PTP) in an 81-year-old man with a painless nodule in the left testis is reported. All possible pre-operative investigations were carried out, but the diagnosis of PTP was possible only after microscopic examination of the resected testis. PMID- 21657159 TI - Thrombosis of the superior mesenteric vein in association with hormonal contraceptive use. A case report and review of the literature. AB - INTRODUCTION: There are a number of reports in the literature which describe the association of venous thrombosis with oral contraceptives. Venous thrombosis is a rare form of mesenteric ischemia which may be lethal if not diagnosed and treated quickly. Although the non specificity of clinical signs do not always permit an early diagnosis. MATERIALS AND METHODS: The patient, aged 52, with a case history characterized by alteration of the alvus with occasional emission of blood, and abdominal pain. She referred with metrorrhagia of about one year, and was being treated with Ethynylestradiol/Gestodene. A CAT scan with contrast showed the signs of thrombosis in the superior mesenteric vein. The patient underwent surgical laparotomy. On opening the peritoneum we found a large tumefaction formed of conglobate iliac loops together with intense inflammation. A resection of the tumefaction was performed "en bloc". DISCUSSION: Pharmacological contraception remains in various cases as the only identified risk factor and there are reports which also censure a relationship of greater risk with increased hormonal doses and even reports of mesenteric venous thrombosis in patients taking triphasic drugs. Thus, we may state with near certainty, that a relationship between pharmacological contraceptives and mesenteric venous thrombosis exists and is probably more than a simple risk factor in contrast to that which exists for tobacco smoking and obesity. CONCLUSIONS: Before the prescription of contraceptive therapy the examination of risk factors is necessary, compiled preferably by hematochemical screening to exclude haematological and/or coagulative pathologies, and not deriding the use of non pharmalogical methods of contraception when possible. Considering the technological advancement of instrumentation (CAT scan, angiogram), even a diagnosis aimed at a suspected clinical history; starting from less invasive screening by ultrasonographic Doppler, might induce to a rapid intervention and thereby avoid sacrificing too much intestinal tissue if it is the case. PMID- 21657160 TI - Huge fibroid (g. 3.000) removed during cesarean section with uterus preservation. A case report. AB - Removal of a giant fibroid during a caesarean section is very rare. We report a case of multiple myomectomy among which a huge myomas (cm 22, weight 3.000 g) in a 44 years old nullipara at 38 weeks. A 10 cm long suprapubic transversal incision according to Pfannenstiel on spinal anaesthesia was done; a female baby weighing 2.285 g, with Apgar score 9/10 was born. Owing to the uterine hypotonia following foetal extraction, myomectomy with womb preservation was carried out. Postoperative course was regular for mother and newborn too. PMID- 21657161 TI - An uncommon association between skin lesions and LEOPARD syndrome affected an old patient. Case report. AB - LEOPARD syndrome (LS) is a rare inherited autosomal dominant disease with high penetrance and markedly variable expression characterized by a spectrum of somatic abnormalities. In 1971, Gorlin proposed the well-known acronym LEOPARD (lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of the genitalia, retardation of growth, deafness). The nature and clinical importance of cardiovascular phenotypes associated with LS remain uncertain, because few patients with the disease have undergone comprehensive cardiac evaluations. To date, 200 cases have been described and one review has been published. We emphasize that this case is exceptional insofar as life expectancy was longer than other LEOPARD syndrome cases described in previous reports; these have had an early mortality due to cardiopathies. The aim of our study is to report a rare case of a patient affected with LEOPARD syndrome, survived until 67 years with cutaneous associations never described in literature. PMID- 21657162 TI - Transdiaphragmatic blockage of the lymphatic may reduce bacterial translocation. AB - PURPOSE: Bacterial translocation is a spread of living and non-living bacteria and bacterial end-products, passing over the mucosal barrier distending mesenteric lymph nodes, blood and viscera. DuraSeal(polyglycolic acid glue) has adhesive power and it usually used in brain or spinal surgery. We aimed to show the barrier system effect using experiments, in which intraabdominal infection induced and translocation from diaphragm to thorax is researched. METHODS: We used 90 Wistar Albino male rats weighing 200-250 grams in our experiment. Laparotomy was performed to all groups. After laparotomy, intraperitoneal 1 cc physiological saline was given in Group I (control). 1 x 109 cfu/m/kg (colony forming unit/mililiter/kilograms) E. Coli was injected intraperitoneally in Group II. In Group III, DuraSeal (Confluent Surgical, Inc., Waltham, MA) was sprayed on the diaphragm. After waiting for approximately 2 minutes to see the barrier effect, 1 x 109 cfu/ml/kg E Coli was injected intraperitoneally. RESULTS: For the samples taken intraperitoneally, 100% breeding was determined in all groups except Group 1. While no positive staining was observed in the thoraxes of the rats in Group I and Group III at the first hour, the positive staining ratio in the Group II was 70%. The positivity ratio of Group II was 80% and the ratio was 50% in Group III at the third and sixth hours. Regarding hemoculture E Coli positivity, there was no proliferation in the hemoculture samples of Group I at all time periods, whereas it was positive in the other groups excluding the first hour. CONCLUSIONS: The synthetic hydrogel Duraseal, which was designed to prevent postoperative fibrosis and air leakage, was able to partially block the translocation of the bacteria to the thorax via lymphatic or directly. PMID- 21657163 TI - The effects of laparoscopic mesh fixation device on bone, costo-chondral junction and tendon site. AB - Osteitis pubis is one of the important complications of inguinal hernia repair surgery occurring with the placement of sutures through the periosteum. The aim of this study is to evaluate scintigraphic and histopathological alterations associated with the use of mesh fixation device on pelvic bone, cartilage and tendons in an experimental animal model. Twenty New-Zealand young male rabbits were used. A mesh fixation device was inserted at each animal's costa-chondral junction, superior anterior iliac crest, and achiles tendon. One week prior to the surgery and 16 weeks after the operation, scintigraphic evaluation was performed. Histopathological evaluation was performed at the end of study. No nuclear activity or pathological change was found at bone site (p > 0.05). Foreign body reaction was evident at the tendon and costa-chondral site (p = 0.001). In conclusion; the mesh fixation device leads to foreign body reaction in costa-chondral junction and tendon. It does not cause any nuclear activity increase. PMID- 21657164 TI - Sculpture in plastic surgery. PMID- 21657166 TI - Medicine-lite. PMID- 21657165 TI - Wannabes. PMID- 21657167 TI - Medical controversies: the great divides. PMID- 21657168 TI - Maryland legislator agrees with the legalization of medical marijuana. PMID- 21657169 TI - Controversies in treatment. The quality of medical care: a commentary. PMID- 21657170 TI - Controversies in traumatic brain injury. PMID- 21657171 TI - Controversies in concussion management: who should clear the athlete to return to play? PMID- 21657172 TI - Gender controversies in ischemic heart disease. PMID- 21657173 TI - Pharmaceutical drug development for women's health care: triumphs, disappointments, and market needs. PMID- 21657174 TI - Taking responsibility for one's health helps to run a financially sustainable health care system. PMID- 21657175 TI - Death by a thousand cuts. Why I opted out. PMID- 21657176 TI - Valuing your medical practice--Part 2: Understanding the components used to determine a fair and marketable price. PMID- 21657177 TI - Meaningful use: the glass half full. AB - Although there is only limited evidence that EMRs and centralized patient repositories will truly save money for the overall system, it is abundantly clear that electronic exchange of clinical and financial information will reduce doctor expenses and improve cash flow. Physicians who are interested in improving their practices' operations now have a new paradigm they can leverage to their advantage. PMID- 21657178 TI - MEDCHI, the Maryland State Medical Society 2011 legislative and regulatory agenda. PMID- 21657179 TI - Safe disposal of medicine update and prescription drug turn-in program. PMID- 21657180 TI - Common terms. PMID- 21657181 TI - Attempted semen collection using the massage technique in blue-fronted Amazon parrots (Amazona aestiva aestiva). AB - The purpose of this study was to establish a technique for collecting semen from blue-fronted Amazon parrots (Amazona aestiva aestiva) and to evaluate the samples that were collected. The massage method is the most common technique used to collect semen in birds and has been proven successful in several psittacine species; however, collection attempts in larger parrots have been unsatisfactory. Six blue-fronted Amazon parrot males, 3 paired with hens and 3 unpaired, were used in this study. The semen collection technique was revised to allow collection from individual birds by a single person. Semen collection was attempted from the 6 parrots on 52-56 occasions, which totaled 330 single attempts. Nineteen ejaculates were collected, and each bird produced at least 1 ejaculate that contained spermatozoa. Large ranges of sample volume (1-15.4 microL), sperm quality (motility = 2%-60%; live:dead ratio = 2:198 to 185:15), sperm concentration (0.79-3.3 x 10(6) sperm/mL), and contamination rate (0%-100%) were observed. Measured parameters did not appear to be significantly impacted by birds being paired or kept singly. Because of the relatively short acclimation period, the birds appeared to be sexually inactive for the majority of the study. Further research using sexually active birds will be necessary to determine standard spermatological parameters and verify the success of the methodology used here. PMID- 21657182 TI - Analysis of electrocardiographic parameters in helmeted guinea fowl (Numida meleagris). AB - The goal of this study was to describe normal electrocardiographic (ECG) patterns and values in conscious helmeted guinea fowl (Numida meleagris). Using 8 clinically healthy birds, 4 males and 4 females, standard bipolar and augmented unipolar limb lead ECGs were recorded. Wave forms were analyzed in all leads at 50 mm/s and at 10 mm = 1 mV to determine PR, QRS, ST, QT durations; the net QRS complex; and P and T amplitudes. The polarity of each wave form was tabulated in all leads. The mean electrical axis (MEA) for the frontal plane was calculated by using leads II and III. The mean (SD) heart rate calculated from the lead II was 338.4 +/- 19.0 beats/min. The P wave was predominantly positive in all leads. The dominant pattern of wave forms of the QRS complexes was RS in leads II, III, and aVF; R in lead I; QR in lead aVR; and qR in lead aVL. The T wave was predominantly positive in leads I, II, III, and aVF. The mean (SD) of the heart MEA was -60.2 degrees +/- 24.0 degrees. The ECG values and patterns tabulated in these clinically normal helmeted guinea fowl should provide a means of comparison to aid in the diagnosis of pathologic abnormalities in this species. PMID- 21657183 TI - Invalid measurement of plasma albumin using bromcresol green methodology in penguins (Spheniscus species). AB - The purpose of this study was to examine the validity of albumin determinations in penguin plasma by the bromcresol green (BCG) method and the gold standard of protein electrophoresis (EPH). Plasma from 96 clinically normal and abnormal penguins (Spheniscus species) was analyzed. The 2 methods did not yield equivalent results. The BCG method underestimated the albumin level in samples from normal patients (indicated by a normal albumin:globulin ratio) and overestimated the albumin level in samples from clinically abnormal penguins (indicated by a decreased albumin:globulin ratio). After EPH of plasma samples from clinically abnormal penguins samples was performed to separate albumin and globulin fractions, the globulins exhibited marked binding to the BCG dye. There were no significant differences between the variable reaction of paired serum and plasma samples when using the BCG method. These results demonstrated marked differences in the determination of albumin levels when using the BCG method and protein EPH. They further demonstrated that the BCG method can provide erroneous results, which have the potential to significantly impact clinical diagnosis and treatment. This study confirmed findings from previous studies in other avian species that the BCG method yields unreliable results in avian species. It is our conclusion that the BCG method, commonly found on automated analyzers in commercial laboratories and on point-of-care analyzers, should not be used to determine albumin concentration in avian samples. PMID- 21657184 TI - Plasma concentrations of fluconazole after a single oral dose and administration in drinking water in cockatiels (Nymphicus hollandicus). AB - Candidiasis frequently affects the oropharynx, esophagus, and crop of juvenile birds with immature immune systems and adult birds that have received long-term antibiotic treatment. Fluconazole is used extensively in human medicine to treat mucosal and invasive candidiasis and has been used in birds; however, there have been few pharmacokinetic studies in avian species to guide safe and effective treatment. The purpose of the present study was to investigate the disposition of fluconazole in cockatiels (Nymphicus hollandicus) after single oral dose administration and to determine if therapeutic plasma concentrations could be safely achieved by providing medicated water. Twenty-eight cockatiels were placed into 7 groups and were orally administered a 10 mg/kg fluconazole suspension. Blood samples were collected from each group for plasma fluconazole assay at serial time points. Fluconazole-medicated drinking water was prepared daily and offered to 15 cockatiels at a concentration of 100 mg/L for 8 days. Blood was collected for plasma fluconazole assay at 2 time points on days 3 and 7. When using naive averaged data in the single-dose study, pharmacokinetic parameters were similar for both compartmental and noncompartmental analyses. The elimination half-life of fluconazole was 19.01 hours, maximum plasma concentration was 4.94 microg/mL, time until maximal concentration was 3.42 hours, and the area under the plasma concentration versus time curve (AUC) was 149.28 h x microg/mL. Computer-simulated trough and peak plasma concentrations at steady-state after multiple doses of fluconazole at 10 mg/kg every 24 hours, 10 mg/kg every 48 hours, and 5 mg/kg every 24 hours were approximately 4.1-8.5 microg/mL, 1.2-6.0 microg/mL, and 2.0-4.3 microg/mL, respectively. Mean +/- SD plasma fluconazole concentrations for the 100 mg/L medicated water study at 0800 and 1600 hours on day 3 were 3.69 +/- 1.22 microg/mL (range, 1.73-5.26 microg/mL) and 4.17 +/- 1.96 microg/mL (range, 3.58-7.49 microg/mL), respectively, and at 0800 and 1600 hours on day 7 were 4.78 +/- 0.91 microg/mL (range, 2.62-6.11 microg/mL) and 6.61 +/- 1.67 microg/mL (range, 3.76-8.78 microg/ mL), respectively. Treatment with fluconazole administered orally at a dosage of 5 mg/kg once daily or 10 mg/kg every 48 hours or fluconazole administered in the drinking water at a concentration of 100 mg/L is predicted to maintain plasma concentrations in most cockatiels that exceed the minimum inhibitory concentration of 90% or therapeutic AUC:MIC of most strains of Candida albicans (by using susceptibility data from humans). The compounded oral suspension was stable for 14 days when stored at 5 degrees C (41 degree sF) and protected from light. PMID- 21657185 TI - Cardiomyopathy and right-sided congestive heart failure in a red-tailed hawk (Buteo jamaicensis). AB - A 15-year-old female red-tailed hawk (Buteo jamaicensis) was evaluated because of dyspnea, anorexia, and coelomic distension. Diagnostic imaging results confirmed severe coelomic effusion and revealed a markedly dilated right ventricle. The diagnosis was right-sided congestive heart failure. Results of measurements of vitamin E, selenium, lead, zinc, and cardiac troponin levels were normal or nondiagnostic. The hawk was treated with furosemide, antifungal and antimicrobial agents, and supplemental fluids and oxygen, but euthanasia was elected because of the poor prognosis and the practical difficulties associated with intensive case management. To our knowledge, this is the first described case of cardiomyopathy and congestive heart failure in a captive red-tailed hawk. PMID- 21657186 TI - Mycobacterium tuberculosis in a red-crowned parakeet (Cyanoramphus novaezelandiae). AB - An adult female red-crowned parakeet (Cyanoramphus novaezelandieae) was presented for necropsy and histopathologic evaluation. The bird had died after exhibiting lameness, weight loss, respiratory signs, and hemoptysis. Postmortem radiographs revealed lesions in the diaphysis of the left femur and soft-tissue opacities in the lungs. At necropsy, the muscles of the left femur were pale and swollen, white-yellow small nodules were visible in lungs and air sacs, and the liver and other coelomic organs appeared pale. On histologic examination, areas of necrosis in the lungs were extensively infiltrated with acid-fast positive bacilli surrounded by macrophages, epithelioid cells, and giant cells. Acid-fast bacilli were also present in the left leg muscle and in granulomas in the liver, kidneys, and intestine. Fungal hyphae associated with a Splendore-Hoeppli phenomenon were visible in the left leg muscle. Mycobacterium tuberculosis was confirmed by polymerase chain reaction testing performed on muscle samples. Results were indicative of infection with M tuberculosis complicated by mycotic myositis. The disease in avian species is of zoonotic importance, and infected birds may be a useful sentinel for human infection. PMID- 21657187 TI - Necrotic dermatitis in waterfowl associated with consumption of perennial rye grass (Lolium perenne). AB - Mute swans (Cygnus olor), whooper swans (Cygnus cygnus), and mixed-breed domestic geese (Anser anser domesticus) were presented for necrotic lesions on the feet, eyelids, and beak. Individuals from the same collection of birds had developed identical lesions during March-September of each of the previous 3 years. Vesicular and necrotic dermatitis involved only nonfeathered and nonpigmented areas of the integument. No abnormal clinical signs were seen on either carnivorous species or birds with pigmented skin from the same collection. The enclosure that housed the birds had been planted with perennial rye grass (Lolium perenne) 3 years previously. Based on the pathologic features and anatomic location of the lesions, the seasonal occurrence, the vegetation history of the enclosure, and the feeding behavior of the affected species, vesicular dermatitis resulting from photosensitization was the presumptive diagnosis. All affected birds recovered completely after the birds were removed from the enclosure, and no further clinical signs have been reported. PMID- 21657188 TI - Exotic animals: appropriately owned pets or inappropriately kept problems? PMID- 21657189 TI - What is your diagnosis? Whitish nodules in the oropharynx. PMID- 21657190 TI - Trickling filter and trickling filter-suspended growth process design and operation: a state-of-the-art review. AB - The modern trickling filter typically includes the following major components: (1) rotary distributors with speed control; (2) modular plastic media (typically cross-flow media unless the bioreactor is treating high-strength wastewater, which warrants the use of vertical-flow media); (3) a mechanical aeration system (that consists of air distribution piping and low-pressure fans); (4) influent/recirculation pump station; and (5) covers that aid in the uniform distribution of air and foul air containment (for odor control). Covers may be equipped with sprinklers that can spray in-plant washwater to cool the media during emergency shut down periods. Trickling filter mechanics are poorly understood. Consequently, there is a general lack of mechanistic mathematical models and design approaches, and the design and operation of trickling filter and trickling filter/suspended growth (TF/SG) processes is empirical. Some empirical trickling filter design criteria are described in this paper. Benefits inherent to the trickling filter process (when compared with activated sludge processes) include operational simplicity, resistance to toxic and shock loads, and low energy requirements. However, trickling filters are susceptible to nuisance conditions that are primarily caused by macro fauna. Process mechanical components dedicated to minimizing the accumulation of macro fauna such as filter flies, worms, and snail (shells) are now standard. Unfortunately, information on the selection and design of these process components is fragmented and has been poorly documented. The trickling filter/solids contact process is the most common TF/SG process. This paper summarizes state-of-the art design and operational practice for the modern trickling filter. Water Environ. PMID- 21657191 TI - Improving thermal dewatering characteristics of mechanically dewatered sludge: response surface analysis of combined lime-heat treatment. AB - In this study, disintegration of dewatered sludge (dry solids content [DS%] = 23 +/- 2) was studied to assess the possibility of enhancing the overall performance of a thermal dewatering processes. Powdered lime was used as an alkaline disintegrator. The combined effects of drying temperature, powdered lime dosage, and organic content on the thermal drying rate of dewatered sludge were investigated in a full-scale wastewater treatment plant. Effects of selected design parameters on the sludge drying rate were modeled using a response surface method. In addition, the possible interaction between lost on ignition and total organic carbon parameters also was investigated statistically. Specific resistance to filtration and free water contents of raw and disintegrated mixed sludge (DS% = 1.0 to 1.8) samples were compared statistically. The obtained results indicated that all of the selected design parameters have a significant effect on thermal dewatering characteristics, and the alkaline disintegration technique could remarkably improve thermal evaporation rate of dewatered sludge. These results are important because they could help to establish a sustainable sludge management model, which is critical in reducing environmental health risks. PMID- 21657192 TI - Temporal evolution of linear alkylbenzene sulfonates and heavy metals in sludge from wastewater treatment plant. AB - Five homologues of linear alkylbenzene sulfonates (LAS)-LAS C-10, LAS C-11, LAS C 12, and LAS C-13 and total LAS-were monitored during a one-year period in primary, secondary, and digested sludge to evaluate their presence and temporal evolution. Extraction of LAS was carried out using microwaves energy, and determination was performed using high-performance liquid chromatographic- fluorescence (HPLC-FL). The results showed that concentrations of total LAS were between 9 337 mg/kg(-1) dry matter for primary sludge and 33.3 mg/kg(-1)(DM) for secondary sludge. Concentrations of total LAS were greater than 2 113 mg/kg(-1) in primary and digested sludge and were less than 260 mg/kg(-) in secondary sludge. On the other hand, the highest concentrations of LAS in primary sludge were found in summer, probably because of lack of rain during those months. Concentrations tend to be constant throughout the year in digested sludge. In addition heavy metals also were analyzed. Heavy metals, including zinc, copper, nickel, lead, and chromium are persistent environmental contaminants that cannot be destroyed. Biomagnification through the food-chain and potential accumulation in human tissues can cause both human health and environmental concerns. Concern regarding total heavy metal content of sludge limits sludge recycling for use on agricultural lands. This paper presents a comparative study of wastewater sludge that are going to be used as fertilizer based on the requirements of legislation proposed in the European Union. This research found that concentrations of total LAS in digested sludge are higher than the limits established in the proposed new draft. PMID- 21657193 TI - Kinetics and reaction pathways of formaldehyde degradation using the UV-fenton method. AB - This study was based on the purpose of investigating the reaction rules of formaldehyde (HCHO) as an intermediate product in the degradation of many other organic wastewaters. The process conditions of UV-Fenton method for the degradation of the low concentrations of HCHO were studied in a batch photochemical reactor. The results showed that, when the original HCHO concentration was 30 mg/L, at an operating temperature of 23 degrees C, pH = 3, an H202 dosage of 68 mg/L, and an H2O2-to-Fe2+ mole ratio (H2O2:Fe2+) of 5, 91.89% of the HCHO was removed after 30 minutes. The degradation of HCHO in the UV-Fenton system was basically in accordance with the exponential decay. The kinetic study results showed that the reaction orders of HCHO, Fe2+, and H2O2 in the system were 1.054, 0.510, and 0.728, respectively, and the activation energy (Ea) was 9.85 kJ/mol. The comparison of UV/H2O2, Fenton, and UV-Fenton systems for the degradation of HCHO, and the results of iron catalyst tests showed that the mechanism of UV-Fenton on the degradation of HCHO was through a synergistic effect of Fe2+ and UV light to catalyze the decomposition of H2O2. The introduction of UV irradiation to the Fenton system largely increased the degradation rate of HCHO, mainly as a result of the accelerating effect on the formation of the Fe2+/Fe3+ cycle. The reaction products were analyzed by gas chromatography-mass spectrometry and a chemical oxygen demand (COD) analyzer. The effluent gases also were analyzed by gas chromatography. Based on those results, the reaction pathways of HCHO in the UV-Fenton system were proposed. The qualitative and quantitative analysis of the reaction products and the COD showed that the main intermediate product of the reaction was formic acid, and the further oxidation of it was the rate-limiting step for the degradation of HCHO. PMID- 21657194 TI - Distribution and mobilization of pollutants in the sediment of a constructed floating wetland used for treatment of combined sewer overflow events. AB - Sediments in combined sewer overflow treatment systems may exhibit elevated pollutant concentrations. Concentrations measured in the sediment of a floating treatment wetland ranged from 0.17 to 1.6 (cadmium), 28 to 142 (copper), 10 to 33 (chromium), 50 to 141 (manganese), 5 to 20 (nickel), 50 to 203 (lead), and 185 to 804 (zinc) mg/kg dry matter and 7.4 to 17 (iron), 2 to 8 (total nitrogen), and 1.3 to 4.4 (total phosphorus) g/kg dry matter. During overflow events, the entering water volumes can disturb the sediments. A greenhouse experiment was set up to evaluate the possible mobilization of pollutants through disturbation. The disturbation did not result in an increased mobilization of cadmium, copper, chromium, nickel, lead, zinc, nitrogen, phosphorus, and organic carbon towards the pore and surface water. Calcium concentrations in the surface water increased for all sediments, as a result of release from the exchangeable sediment pool and dissolution of carbonates. Geochemical speciation modeling indicated that, in the pore water, the free ion form was the most abundant for calcium, iron, manganese, cadmium, and nickel, with its fraction increasing with time. PMID- 21657195 TI - Effect of process parameters on greenhouse gas generation by wastewater treatment plants. AB - The effect of key process parameters on greenhouse gas (GHG) emission by wastewater treatment plants was evaluated, and the governing parameters that exhibited major effects on the overall on- and off-site GHG emissions were identified. This evaluation used aerobic, anaerobic, and hybrid anaerobic/aerobic treatment systems with food processing industry wastewater. The operating temperature of anaerobic sludge digester was identified to have the highest effect on GHG generation in the aerobic treatment system. The total GHG emissions of 2694 kg CO2e/d were increased by 72.5% with the increase of anaerobic sludge digester temperature from 20 to 40 degrees C. The operating temperature of the anaerobic reactor was the dominant controlling parameter in the anaerobic and hybrid treatment systems. Raising the anaerobic reactor's temperature from 25 to 40 degrees C increased the total GHG emissions from 5822 and 6617 kg CO2e/d by 105.6 and 96.5% in the anaerobic and hybrid treatment systems, respectively. PMID- 21657196 TI - Characteristics transformation of humic acid during ozonation and biofiltration treatment processes. AB - Characteristics transformation of humic acid extracted from natural water during the ozonation and biofiltration treatment processes was investigated based on the analyses of total organic carbon, UV absorbance, infrared spectroscopy, and gel permeation chromatography. With ozone doses of 1, 4, and 7 mg/L, high-molecular weight humic acid was cleaved into low-molecular-weight particles and accumulated at group 6 (molecular weight < or = 4000 g/mole) on the Sephadex G-75 (Pharmacia Fine Chemicals, Uppsala, Sweden) fraction. Furthermore, the molecular-size distribution of organic compounds by Sephadex G-25 was shifted from groups 2 (molecular weight = 4000 to 400 g/mole) and 3 (molecular weight = 400 to 180 g/mole) to groups 2, 3, and 4 (molecular weight < or = 180 g/mole) under ozone doses of 1 and 4 mg/L. An increased ozone dose destroyed functional groups C=C and C-O of aromatic and phenolic compounds and increased UV-insensitive biodegradable organic carbon for subsequent biofiltration. PMID- 21657197 TI - Effect of anaerobic HRT on biological phosphorus removal and the enrichment of phosphorus accumulating organisms. AB - The purpose of this research was to develop a better understanding of the dynamic effects of anaerobic hydraulic retention time (HRT) on both enhanced biological phosphorus removal (EBPR) performance and enrichment of phosphorus accumulating organisms (PAOs). The research was conducted using laboratory-scale sequencing batch reactors inoculated with mixed microbial consortia and fed real wastewater. Exposing microorganisms to extended anaerobic HRTs is not recommended for EBPR configured systems. In this research, however, longer anaerobic exposure did not negatively affect performance even if volatile fatty acids were depleted. Further, extended anaerobic HRTs may positively affect phosphorus removal through enhanced aerobic uptake. The EBPR consortia also appear to maintain reserve energetic capacity in the form of polyphosphate that can be used to survive and grow under variable operational and environmental conditions. Finally, the tested EBPR systems yield mixed microbial consortia enriched with PAOs (specifically Candidatus Accumulibacter phosphatis) at approximately 7.1 to 21.6% of the total population. PMID- 21657198 TI - Bacterial adhesion to metal oxide-coated surfaces in the presence of silicic acid. AB - This study investigated the effect of silicic acid to the adhesion of Bacillus subtilis to metal oxide-coated surfaces. The first sets of column experiments were conducted under various concentrations of silicic acid. The second and third experiments were performed under various concentrations of sulfate and nitrate to compare the results from silicic acid. Bacterial breakthrough curves were obtained by monitoring effluent, and mass recoveries were quantified from these curves. The results show that, at silicic acid concentrations between 0 and 0.2 mM, bacteria were negatively charged, while the charges of metal oxides were changed from positive to negative. Bacterial adhesion to metal oxide-coated surfaces decreased sharply with increasing silicic acid concentration (bacterial mass recovery increased from 11.5 to 82.2%), as a result of the hindrance effect of silicic acid adsorbed onto metal oxide-coated surfaces. Between 0.2 and 10 mM, both bacteria and metal oxides were negatively charged. Bacterial adhesion remained constant (mass recovery were 80.5 to 82.2%), despite the increasing silicic acid concentration, possibly as a result of the hindrance effect of polymerized silicic acid. That is, the bacterial approach to the metal oxide coated surfaces could be disturbed through steric hindrance of polymerized silicic acid, which compensates the potential enhancement effect from the electrical double layer compression. The results also illustrate that the effect of silicic acid on bacterial adhesion was greater than those of sulfate and nitrate. This study demonstrates that silicic acid can play a significant role in bacterial interaction with metal oxide-coated surfaces. PMID- 21657199 TI - Discussion of the capture and destruction of Escherichia coli from simulated urban runoff using conventional bioretention media and iron oxide-coated sand, L. Zhang, E. A. Seagren, A. P. Davis, J. S. Karns, 82, 701-714 (2010). PMID- 21657200 TI - CPMV-polyelectrolyte-templated gold nanoparticles. AB - The use of polyelectrolyte surface-modified Cowpea mosaic virus (CPMV) for the templated synthesis of narrowly dispersed gold nanoparticles is described. The cationic polyelectrolyte, poly(allylamine) hydrochloride (PAH), is electrostatically bound to the external surface of the virus capsid; the polyelectrolyte promotes the adsorption of anionic gold complexes, which are then easily reduced, under mild conditions, to form a metallic gold coating. As expected, the templated gold nanoparticles can be further modified with thiol reagents. In contrast, reaction of polyelectrolyte-modified CPMV (CPMV-PA) with preformed gold nanoparticles results in the self-assembly of large, hexagonally packed, tessellated-spheres. PMID- 21657202 TI - Synthesis and evaluation of 5-substituted 2'-deoxyuridine monophosphate analogues as inhibitors of flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. AB - A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 MUM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 MUM) and represents the first example of a selective mycobacterial FDTS inhibitor. PMID- 21657203 TI - Plasmon-assisted optofluidics. AB - We study the ability of a plasmonic structure under illumination to release heat and induce fluid convection at the nanoscale. We first introduce the unified formalism associated with this multidisciplinary problem combining optics, thermodynamics, and hydrodynamics. On this basis, numerical simulations were performed to compute the temperature field and velocity field evolutions of the surrounding fluid for a gold disk on glass while illuminated at its plasmon resonance. We show that the velocity amplitude of the surrounding fluid has a linear dependence on the structure temperature and a quadratic dependence on the structure size (for a given temperature). The fluid velocity remains negligible for single nanometer-sized plasmonic structures (<1 nm/s) due to a very low Reynolds number. However thermal-induced fluid convection can play a significant role when considering either micrometer-size structures or an assembly of nanostructures. PMID- 21657201 TI - Direct effects of carbon nanotubes on dendritic cells induce immune suppression upon pulmonary exposure. AB - Pharyngeal aspiration of single-walled carbon nanotubes (SWCNTs) caused inflammation, pulmonary damage, and an altered cytokine network in the lung. Local inflammatory response in vivo was accompanied by modified systemic immunity as documented by decreased proliferation of splenic T cells. Preincubation of naive T cells in vitro with SWCNT-treated dendritic cells reduced proliferation of T cells. Our data suggest that in vivo exposure to SWCNT modifies systemic immunity by modulating dendritic cell function. PMID- 21657204 TI - Analysis of affinity maps of membrane proteins on individual human embryonic stem cells. AB - The heterogeneity found in many cell types has greatly inspired research in single-cell gene and protein profiling for discovering the origin of heterogeneity and its role in cell fate decisions. Among the existing techniques to probe heterogeneity, atomic force microscopy (AFM) utilizes an antibody/ligand modified tip to explore the distribution of a target membrane protein on individual cells in their native environment. In this paper, we establish a practical model to analyze the data systematically, and attempt the quantification of membrane protein abundance on single cells by taking account issues, such as the level of nonspecific interaction, the probe resolution, and the reproducibility of detecting protein distribution. We demonstrated the application in examining the heterogeneous distribution and the local protein abundance of TRA-1-81 antigen on human embryonic stem (hES) cells at the subcellular level. Heterogeneity in TRA-1-81 expression was also detected at the single cell level, suggesting the presence of subpopulation cells within an undifferentiated hES cell colony. The method provides a platform to unveiling the correlation between heterogeneity of membrane proteins and cell development in a complex cell community. PMID- 21657205 TI - Polyelectrolyte-templated synthesis of bimetallic nanoparticles. AB - Bimetallic nanoparticles (NPs) are known to exhibit enhanced optical and catalytic properties that can be optimized by tailoring NP composition, size, and morphology. Galvanic deposition of a second metal onto a primary metal NP template is a versatile method for fabricating bimetallic NPs using a scalable, solution-based synthesis. We demonstrate that the galvanic displacement reaction pathway can be controlled through appropriate surface modification of the NP template. To synthesize bimetallic Au-Ag NPs, we used colloidal Ag NPs modified by layer-by-layer (LBL) assembled polyelectrolyte layers to template the reduction of HAuCl(4). NPs terminated with positively and negatively charged polyelectrolytes yield highly contrasting morphologies and Au surface concentrations. We propose that these charged surface layers control galvanic charge transfer by controlling nucleation and diffusion at the deposition front. This surface-directed synthetic strategy can be advantageously used to tailor both overall NP morphology and Au surface concentrations. PMID- 21657206 TI - Refined crystal structure and idealized structure of mixed-valent Eu4F5(CN2)2: transition possible. AB - The new europium fluoride carbodiimide Eu(4)F(5)(CN(2))(2) was synthesized by solid state reaction from mixtures of EuF(3) and Li(2)(CN(2)) at 700 degrees C. The crystal structure as refined by single crystal X-ray diffraction (P 42(1)c, no. 114, a = 16.053(1) A, c = 6.5150(6) A, Z = 8) reveals three crystallographically distinct [N?C?N](2-) ions in the structure of mixed-valent Eu(4)F(5)(CN(2))(2). The presence of one Eu(3+) and three Eu(2+) per formula unit Eu(4)F(5)(CN(2))(2) is confirmed by magnetic measurements and (151)Eu-Mossbauer spectroscopy. The arrangement of Eu ions and gravity centers of [NCN](2-) ions in the structure of Eu(4)F(5)(CN(2))(2) follow the motif formed by atoms in the CuAl(2)-type structure. A possible high-symmetry structure of Eu(4)F(5)(CN(2))(2) is discussed on the basis of a group-subgroup scheme. PMID- 21657207 TI - Cobalt complexes with "Click"-derived functional tripodal ligands: spin crossover and coordination ambivalence. AB - We demonstrate the use of a Cu(I) catalyzed "Click" reaction in the synthesis of novel ligands for spin crossover complexes. The reaction between azides and alkynes was used to synthesize the reported tripodal ligand tris[(1-benzyl-1H 1,2,3-triazol-4-yl)methyl]amine, TBTA, and the new ligands tris[(1-cyclohexyl-1H 1,2,3-triazol-4-yl)methyl]amine, TCTA, and tris[(1-n-butyl-1H-1,2,3-triazol-4 yl)methyl]amine, TBuTA. Reactions of TBTA with Co(ClO(4))(2) lead to complexes of the form [Co(TBTA)(CH(3)CN)(3)](ClO(4))(2), 1, and [Co(TBTA)(2)](ClO(4))(2), 2, where complex formation can be controlled by the metal/ligand ratio and the complexes 1 and 2 can be chemically and reversibly switched from one form to another in solution resulting in coordination ambivalence. The benzyl substituents of TBTA in 2 show intramolecular C-H-pi T-stacking that generates a chemical pressure to stabilize the low spin (LS) state at lower temperatures. The structural parameters of 2 are consistent with a Jahn-Teller active LS Co(II) (elongation) ion showing four short and two long bonds. 2 shows spin-crossover (SCO) behavior in the solid state and in solution with a high T(0) close to room temperature which is driven by the T-stacking. 1 remains high spin (HS) between 2 and 400 K. Reversible chemical switching is observed between 1 and 2 at room temperature, with an accompanying change in the spin state from HS to LS. The importance of the intramolecular T-stacking in driving the SCO behavior is proven by comparison with two analogous compounds that lack an aromatic substituent and remain HS down to very low temperatures. PMID- 21657208 TI - Synthesis, reactivity, and properties of N-fused porphyrin manganese(I) tricarbonyl complexes. AB - The reactions of N-fused tetraphenylporphyrin (NFTPP, 1a) and its 21-substituted derivatives, 21-Br-NFTPP (1b), 21-NO(2)-NFTPP (1c), and 21-Bz-NFTPP (1d), with Mn(CO)(5)Br gave the manganese(I) tricarbonyl complexes bearing N-fused tetraphenylporphyrinato ligands (2a-d), respectively, in 46-99% yields. The complexes were characterized by mass, IR, (1)H and (13)C NMR spectroscopy, and the final structural proof was evident from the X-ray crystallographic analysis for 2a. The crystals of 2a.CH(2)Cl(2) belong to the monoclinic space group P2(1)/n (#14), with a = 15.007(2) A, b = 12.5455(19) A, c = 21.150(3) A, beta = 102.227(4) degrees , and Z = 4. The lengths (A) of three manganese-nitrogen and three manganese-carbon bonds are inequivalent respectively [Mn-N(2), 2.007(2); Mn N(23), 2.033(2); Mn-N(24), 1.988(3); and Mn-CO, 1.798(4), 1.804(4), 1.841(3)], reflecting the asymmetric structure of the NFp ligand. The aromatic substitution reactions of 2a, such as nitration, formylation, and chlorination, proceeded without a loss of center metal to give the corresponding 21-nitro (2c), 21-formyl (2e), and 21-chloro (2f) derivatives, regioselectively. In the electrochemical measurements of 2, one reversible oxidation and two reversible reduction waves were observed. The redox potentials of 2 indicate the narrow energy gaps between the highest occupied molecular orbital and the lowest unoccupied molecular orbital (HOMO-LUMO) being consistent with the electronic absorption spectra that display the absorption edges over 1000 nm. Protonation occurred at the inner core nitrogen of 2a upon the addition of acids, which is inferred from the (1)H NMR spectra as well as theoretical calculations. By a treatment with amine N-oxides, demetalation of 2 proceeded to afford the corresponding NFP free-bases (1). PMID- 21657209 TI - Diblock glycopolymers promote colloidal stability of polyplexes and effective pDNA and siRNA delivery under physiological salt and serum conditions. AB - A series of glycopolymers composed of 2-deoxy-2-methacrylamido glucopyranose (MAG) and the primary amine-containing N-(2-aminoethyl) methacrylamide (AEMA) were synthesized via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. The colloidal stability of the polyplexes formed with three diblock glycopolymers and pDNA was assessed using dynamic light scattering, and the polyplexes were found to be stable against aggregation in the presence of salt and serum over the 4 h time period studied. Delivery experiments were performed in vitro to examine the cellular uptake, transfection efficiency, and cytotoxicity of the glycopolymer/pDNA polyplexes in cultured HeLa cells and the diblock copolymer with the shortest AEMA block was found to be the most effective. Additionally, the ability of the diblock glycopolymers to deliver siRNA to U-87 (glioblastoma) cells was screened, and the diblock copolymer with the longest AEMA block was found to have gene knockdown efficacy similar to Lipofectamine 2000. PMID- 21657210 TI - Biodistribution of amino-functionalized diamond nanoparticles. In vivo studies based on 18F radionuclide emission. AB - Nanoparticles have been proposed for several biomedical applications; however, in vivo biodistribution studies to confirm their potential are scarce. Nanodiamonds are carbon nanoparticles that have been recently proposed as a promising biomaterial. In this study, we labeled nanodiamonds with (18)F to study their in vivo biodistribution by positron emission tomography. Moreover, the impact on the biodistribution of their kinetic particle size and of the surfactant agents has been evaluated. Radiolabeled diamond nanoparticles accumulated mainly in the lung, spleen, and liver and were excreted into the urinary tract. The addition of surfactant agents did not lead to significant changes in this pattern, with the exception of a slight reduction in the urinary excretion rate. On the other hand, after filtration of the radiolabeled diamond nanoparticles to remove those with a larger kinetic size, the uptake in the lung and spleen was completely inhibited and significantly reduced in the liver. PMID- 21657211 TI - Flurbiprofen encapsulation using pluronic triblock copolymers. AB - Pulsed-field gradient stimulated-echo nuclear magnetic resonance (NMR) and surface tension measurements have been used to study the effect of drug addition on the micellization behavior of pluronic triblock copolymers (P103, P123, and L43). The addition of 0.6 wt% flurbiprofen to Pluronic P123 and P103 solutions reduced their cmc and promoted micellization. Also, a substantial increase in the hydrodynamic radius of Pluronic P103 from 5 to 10 nm was observed, along with an increased fraction of polymer micellized, demonstrating that the polymers solubilize this nonsteroidal anti-inflammatory drug. PMID- 21657212 TI - Membranes of vertically aligned superlong carbon nanotubes. AB - In the present work, we have developed a simple but effective method to prepare superlong vertically aligned carbon nanotubes (SLVA-CNT) and epoxy composite membranes, and we have demonstrated that various liquids, including water, hexane, and dodecane, can effectively pass through the SLVA-CNT membranes. These results were confirmed by molecular dynamics simulations. While the mechanical densification was used to further enhance the flow transport through the SLVA-CNT membranes, we developed in this study a magnetic-nanoparticle switching system to turn on and off the flow through the nanotube membrane by simply applying an alternating voltage. The methodologies developed in this study should have a significant implication to the development of various smart membranes for advanced intelligent systems. PMID- 21657214 TI - Structure-directing and template roles of aromatic molecules in the self-assembly formation process of 3D holmium-succinate MOFs. AB - Two new holmium-succinate frameworks have been synthesized by hydrolysis in situ of the succinylsalicylic acid under different hydrothermal conditions. Compound 1, [Ho(2)(C(4)H(4)O(4))(3)(H(2)O)(2)].0.33(C(7)H(6)O(3)), P i space group, has a novel structure composed by 1D-SBUs consisting of [HoO(9)] chains of polyhedra linked by the succinate ligands giving a 3D framework. Compound 2, [Ho(2)(C(4)H(4)O(4))(3)(H(2)O)(2)], also belonging to the P i space group, has a denser structure. The role of the in-situ-generated salicylic acid on formation of both structures is studied by means of a synthesis design methodology. A topological study of the new holmium succinate compounds in comparison with the previously reported 3D holmium-succinate framework is performed here. PMID- 21657215 TI - Metallic membranes with subwavelength complementary patterns: distinct substrates for surface-enhanced Raman scattering. AB - We present a detailed comparison of surface-enhanced Raman spectroscopy (SERS) signals from metallic nanoparticle arrays and their complementary hole arrays. Using an analytical model for local field enhancement, we show that the SERS enhancements of the hole arrays are closely related to their transmission spectra. This trend is experimentally confirmed and characterized by a cos(4 )theta dependence of the SERS signal on the excitation polarization angle theta. The particle arrays, on the other hand, exhibit quite different behavior because of the existence of considerable evanescent modes in the near field. Their maximal local field gains appear at wavelengths generally much larger than their localized surface plasmonic resonant wavelengths. PMID- 21657213 TI - Using microcontact printing of fibrinogen to control surface-induced platelet adhesion and activation. AB - The ability to promote or inhibit specific platelet-surface interactions in well controlled environments is crucial to studying fundamental adhesion and activation mechanisms. Here, microcontact printing was used to immobilize human fibrinogen covalently in the form of randomly placed, micrometer-sized islands at an overall surface coverage of 20, 50, or 85%. The nonprinted background region was blocked with covalently immobilized human albumin. Platelet adhesion and morphology on each substrate were assessed using combined differential interference and fluorescence microscopy. At 20% coverage, most of the fibrinogen surface features were small round islands, and platelet adhesion and spreading areas were limited by the position and the size of the islands. Platelet circularity, indicated the morphology was mostly rounded. At 50% coverage, some fibrinogen islands coalesced and platelet adhesion and spreading areas increased. Platelet morphology was controlled by the shape of underlying fibrinogen islands, leading to more irregular spreading. At 85% coverage, the fibrinogen pattern was completely interconnected and both platelet adhesion and the spreading area were significantly higher than at lower coverage. In addition, platelets also spread over the albumin regions, suggesting that after a critical surface density of fibrinogen ligands is reached, platelet spreading is no longer inhibited by albumin. Increasing the overall fibrinogen coverage resulted in higher activation levels defined by key morphological characteristics of the spreading platelet. PMID- 21657216 TI - The effects of substituent grafting on the interaction of pH-responsive polymers with phospholipid monolayers. AB - pH-responsive amphiphilic polymers with suitable graftings have demonstrated highly efficient cell membrane activity and hence are promising applicants for drug-delivery. Grafting the hydrophobic amino acid l-phenylalanine and the hydrophilic methoxy poly(ethylene glycol) amine onto the pendant carboxylic acid moieties of a linear polyamide, poly(l-lysine isophthalamide), can effectively modify the amphiphilicity and conformation of the amphiphilic polymers. Here, the interactions of these polymers with phospholipid monolayers adsorbed on mercury (Hg) electrodes have been studied. AC voltammetry (ACV), rapid cyclic voltammetry (RCV), and electrochemical impedance spectroscopy (EIS) have been applied to monitor phospholipid monolayer associations with different polymer concentrations under different pH values. The polymers interact reversibly with the monolayer shown by altering the monolayer capacitance and inhibiting the phospholipid reorientation in electric field. Polymer grafting enhances the pH-mediated conformational change of the polymers which in turn increases their phospholipid monolayer activity. The most significant monolayer interactions have been observed with the polymer grafted with hydrophobic l-phenylalanine. A low level of PEGylation of the backbone also increases the monolayer activity. The polymer/DOPC interactions have been represented with an impedance model, which takes account of the interaction giving rise to an increase in monolayer capacitance and inhomogeneity and a Debye type dielectric relaxation. The extent of penetration of the polymers into the monolayer is inversely related to the electrical resistance they give rise to during the Debye relaxation. The cell membrane activities of these amphiphilic polymers have been successfully mirrored in this supported DOPC monolayer system, isolating the key parameters for biomembrane activities and giving insight into the mechanism of the interactions. The conclusions from this study provide strategic directions in material design catering to different requirements in biomedical applications. PMID- 21657217 TI - Spontaneous imbibition in disordered porous solids: a theoretical study of helium in silica aerogels. AB - We present a theoretical study of spontaneous imbibition of liquid (4)He in silica aerogels focusing on the effect of porosity on the fluid dynamical behavior. We adopt a coarse-grained three-dimensional lattice-gas description like in previous studies of gas adsorption and capillary condensation and use a dynamical mean-field theory, assuming that capillary disorder predominates over permeability disorder as in recent phase-field models of spontaneous imbibition. Our results reveal a remarkable connection between imbibition and adsorption as also suggested by recent experiments. The imbibition front is always preceded by a precursor film, and the classical Lucas-Washburn ?t scaling law is generally recovered, although some deviations may exist at large porosity. Moreover, the interface roughening is modified by wetting and confinement effects. Our results suggest that the interpretation of the recent experiments should be revised. PMID- 21657218 TI - Cooperative calcium phosphate nucleation within collagen fibrils. AB - Although "chaperone molecules" rich in negatively charged residues (i.e., glutamic and aspartic acid) are known to play important roles in the biomineralization process, the precise mechanism by which type I collagen acquires intrafibrillar mineral via these chaperone molecules remains unknown. This study demonstrates a mechanism of cooperative nucleation in which three key components (collagen, chaperone molecules, and Ca(2+) and PO(4)(3-)) interact simultaneously. The mineralization of collagen under conditions in which collagen was exposed to pAsp, Ca(2+), and PO(4)(3-) simultaneously or pretreated with the chaperone molecule (in this case, poly(aspartic acid)) before any exposure to the mineralizing solution was compared to deduce the mineralization mechanism. Depending on the exact conditions, intrafibrillar mineral formation could be reduced or even eliminated through pretreatment with the chaperone molecule. Through the use of a fluorescently tagged polymer, it was determined that the adsorption of the chaperone molecule to the collagen surface retarded further adsorption of subsequent molecules, explaining the reduced mineralization rate in pretreated samples. This finding is significant because it indicates that chaperone molecules must interact simultaneously with the ions in solution and collagen for biomimetic mineralization to occur and that the rate of mineralization is highly dependent upon the interaction of collagen with its environment. PMID- 21657219 TI - Systematic modulation of a bichromic cyclometalated ruthenium(II) scaffold bearing a redox-active triphenylamine constituent. AB - The syntheses and physicochemical properties of nine bis-tridentate ruthenium(II) complexes containing one cyclometalating ligand furnished with terminal triphenylamine (TPA) substituents are reported. The structure of each complex conforms to a molecular scaffold formulated as [Ru(II)(TPA-2,5-thiophene pbpy)(Me(3)tctpy)] (pbpy = 6-phenyl-2,2'-bipyridine; Me(3)tctpy = trimethyl 4,4',4''-tricarboxylate-2,2':6',2''-terpyridine), where various electron-donating groups (EDGs) and electron-withdrawing groups (EWGs) are installed about the TPA unit and the anionic ring of the pbpy ligand. It is found that the redox chemistry of the Ru center and the TPA unit can be independently modulated by (i) placing EWGs (e.g., -CF(3)) or EDGs (e.g., -OMe) on the anionic ring of the pbpy ligand (substituted sites denoted as R(2) or R(3)) and/or (ii) installing electron-donating substituents (e.g., -H, -Me, -OMe) para to the amine of the TPA group (i.e., R(1)). The first oxidation potential is localized to the TPA unit when, for example, EDGs are placed at R(1) with EWGs at R(2) (e.g., the TPA(*+)/TPA(0) and Ru(III)/Ru(II) redox couples appear at +0.98 and +1.27 V vs NHE, respectively, when R(1) = -OMe and R(2) = -CF(3)). This situation is reversed when R(3) = EDG and R(1) = -H: TPA-based and metal-centered oxidation waves occur at +1.20 and +1.11 V vs NHE, respectively. The UV-vis spectrum for each complex is broad (e.g., absorption bands are extended from the UV region to beyond 800 nm in all cases) and intense (e.g., epsilon ~ 10(4) M(-1).cm(-1)) because of the overlapping intraligand charge-transfer and metal-to-ligand charge transfer transitions. The information derived from this study offers guiding principles for modulating the physicochemical properties of bichromic cyclometalated ruthenium(II) complexes. PMID- 21657220 TI - Magnetic systems with mixed carboxylate and azide bridges: slow relaxation in Co(II) metamagnet and spin frustration in Mn(II) compound. AB - Two coordination polymers formulated as [{[Co(2)(L)(N(3))(4)].2DMF}(n) (1) and [Mn(2)(L)(H(2)O)(0.5)(N(3))(8)](n) (2) (L = 1,4-bis(4-carboxylatopyridinium-1 methyl)benzene) were synthesized and structurally and magnetically characterized. In compound 1, the anionic uniform Co(II) chains with mixed (MU-EO-N(3))(2)(MU COO) triple bridges (EO = end-on) are cross-linked by the cationic bis(pyridinium) spacers to generate 2D coordination layers. It was demonstrated that the triple bridges mediate ferromagnetic coupling and that the compound represents a new example of the rare systems exhibiting the coexistence of antiferromagnetic ordering, metamagnetism, and slow magnetic dynamics. Compound 2 features the magnetic Delta-chain formed from isosceles triangular units with single MU-EE-N(3) and double (MU-EO-N(3))(MU-COO) bridges (EE = end-to-end). The Delta-chains are interlinked by long organic ligands into a 3D framework with novel net topology and 3-fold interpenetration. The magnetic properties of 2 indicate the presence of spin frustration characteristic of Delta-chains with antiferromagnetic interactions. PMID- 21657221 TI - Expression profiling and regulation of genes related to silkworm posterior silk gland development and fibroin synthesis. AB - The posterior silk gland (PSG) is the most important suborgan responsible for the synthesis and secretion of silk core fibroin proteins in silkworm. Here, we performed genome-scale expression profiling analysis of silkworm PSG at the fourth molting (M4) and at day 1 (V1), day 3 (V3), day 5 (V5), and wandering stage (W) of the fifth instar by microarray analysis with 22 987 probes. We found that the five genes of silk proteins secreted from PSG including fibroin heavy (H) and light (L) chains, P25, seroin 1, and seroin 2 basically showed obvious up regulation at V3 which lasted to V5, while slight down-regulation at W. The expression of translation-related genes including ribosomal proteins and translation initiation factors generally remained stable from M4 to V5, whereas it showed clear down-regulation at W. Clustering analysis of the 643 significantly differentially expressed transcripts revealed that 43 of the important genes including seroin 1 and sugar transporter protein had co expression patterns which were consistent with the rate changes of fibroin synthesis and PSG growth. Pathway analysis disclosed that the genes in different clusters might have co-regulations and direct interactions. These genes were supposed to be involved in the fibroin synthesis and secretion. The differential expression of several hormone-related genes also suggested their functions on the regulation of PSG development and fibroin synthesis. 2D gel-based proteomics and phosphoproteomics profiling revealed that the phosphorylated proteins accounted for no more than one-sixth of the total proteins at each stage, which was much lower than the level in normal eukaryotic cells. Changes in the phosphorylation status and levels of several proteins such as actin-depolymerizing factor 1 and enolase might be deeply involved in fibroin secretion and tissue development. Shotgun proteomic profiling combined with label-free quantification analysis on the PSG at V3, V5, and W revealed that many small heat shock proteins (sHSP) were specially expressed at W, which was substantially consistent with the results from 2-DE analysis, and implied the close correlations of sHSP with the physiological states of PSG at W. A majority of significantly up-regulated proteins at V5 were related to ribosome pathway, which was different from the microarray results, implying that the translation-level regulation of ribosomal proteins might be critical for fibroin synthesis. In contrast, the ubiquitin proteasome pathway related proteins appeared obviously up-regulated at W, suggesting that the programmed cell death process of PSG cells might be started before cocooning. PMID- 21657222 TI - Improved solid oxide fuel cell performance with nanostructured electrolytes. AB - Considerable attention has been focused on solid oxide fuel cells (SOFCs) due to their potential for providing clean and reliable electric power. However, the high operating temperatures of current SOFCs limit their adoption in mobile applications. To lower the SOFC operating temperature, we fabricated a corrugated thin-film electrolyte membrane by nanosphere lithography and atomic layer deposition to reduce the polarization and ohmic losses at low temperatures. The resulting micro-SOFC electrolyte membrane showed a hexagonal-pyramid array nanostructure and achieved a power density of 1.34 W/cm(2) at 500 degrees C. In the future, arrays of micro-SOFCs with high power density may enable a range of mobile and portable power applications. PMID- 21657223 TI - Singlet excited states of silicon-containing anions relevant to interstellar chemistry. AB - As the number of anions detected in the interstellar medium (ISM) increases, knowledge of their chemical properties is crucial in expanding our understanding of the chemistry of space. In this work we build on a previous study done in our group to examine the excited-state properties of five anions likely to exist in the ISM: SiCCN(-), CSiCN(-), CCSiN(-), SiCN(-), and SiNC(-). Our coupled cluster results indicate that SiCCN(-) and SiNC(-) possess dipole-bound singlet excited states while SiCCN(-) also has one valence state and CCSiN(-) potentially has two. Nearly all of the associated transition energies fall within the visible to near-IR region of the electromagnetic spectrum, making them applicable to the study of phenomena such as the diffuse interstellar bands. PMID- 21657224 TI - Guanylated diamines, triamines, and polyamines: chemistry and biological properties. PMID- 21657225 TI - A new dual-responsive organogel based on uracil-appended glycyrrhetinic acid. AB - A novel functional tweezer based on uracil-appended glycyrrhetinic acid with excellent gelation ability was synthesized, and the gel could transform to sol by F(-) and Hg(2+). PMID- 21657226 TI - Nonlocal behavior of an electron in the ring-opening of cyclobutene. AB - The nonlocal behavior of an electron in the ring-opening of cyclobutene is analyzed using the sharing amplitude and tools based thereupon. The sharing amplitude is a generalization of the absolute value squared of the wave function (a probability density according to the Born interpretation) to a measure that gives, for a single particle in a many particle system, both the relative phase of a wavelike quantity between any two space/spin points and a measure of the distribution of that quantity between those points. The sharing indices are related to the absolute value squared of the amplitude, thereby ensuring that the amplitude and the indices are consistent. To provide prototypical behavior of the sharing quantities in single and double bonds and to identify nonbonding and antibonding behavior, these tools are used to describe single electron behavior in ethane and ethylene, in the latter including separate sigma and pi contributions and two excited states. Similar analyses of the single and double carbon-carbon bonds in the reactant cyclobutene and in the product s-cis butadiene (a planar transition state allowing for sigma and pi separation) are carried out. Comparisons are made to the prototypical molecules. The sharing quantities in the locally stable forms of s-gauche-butadiene are then considered. A remnant of the bond that is broken in cyclobutene is found in a form that is consistent with a conrotatory ring-opening, a behavior suggested by Woodward and Hoffmann on the basis of the symmetry of the highest occupied molecular orbital in the product, but here without appeal to only that molecular orbital. Finally, the nonlocal behavior of an electron during the breaking and making of bonds in the reaction is discussed for several geometries along the reaction path. PMID- 21657227 TI - Integrated solid-phase synthesis and purification of PEGylated protein. AB - We describe an integrated method for solid-phase protein PEGylation and the purification of mono-PEGylated protein thus synthesized. Lysozyme was used as model protein in this study. Methoxy-polyethyleneglycol propionaldehyde (or m-PEG propionaldehyde) was first immobilized on a stack of microporous hydrophobic interaction membranes housed in a module. The membrane-bound m-PEG propionaldehyde was then contacted with lysozyme solution, which also contained sodium cyanoborohydride as a reducing agent. The PEGylated lysozyme thus synthesized remained attached to the membrane, whereas unreacted protein could easily be removed from the module. PEGylated protein was then eluted from the membrane in a partially purified form using salt-free buffer. Two separate steps were thus integrated into a single process: protein PEGylation, followed by purification of mono-PEGylated protein. This solid-phase method is likely to be suitable for PEGylating any protein because it is based on the immobilization of the activated PEG and not the protein being PEGylated. PMID- 21657228 TI - Formation of a strandlike polycatenane of icosahedral cages for reversible one dimensional encapsulation of guests. AB - Self-assembly of ZnCl(2) and the ligand 2,4,6-tris(4-pyridyl)pyridine (pytpy) in solution yields [(ZnCl(2))(12)(pytpy)(8)](n).xCHCl(3), a polycatenane consisting of a strand of mechanically interlocking icosahedral cages with an inner volume of more than 2700 A(3). This can be used to encapsulate guest molecules of appropriate size and polarity, forming a precisely defined three-dimensional array of solvent nanodroplets within the crystalline framework. The dynamic composition of these droplets was studied using quantitative solid-state NMR spectroscopy. PMID- 21657229 TI - Adsorption of sophorolipid biosurfactants on their own and mixed with sodium dodecyl benzene sulfonate, at the air/water interface. AB - The adsorption of the lactonic (LS) and acidic (AS) forms of sophorolipid and their mixtures with the anionic surfactant sodium dodecyl benzene sulfonate (LAS) has been measured at the air/water interface by neutron reflectivity, NR. The AS and LS sophorolipids adsorb with Langmuir-like adsorption isotherms. The more hydrophobic LS is more surface active than the AS, with a lower critical micellar concentration, CMC, and stronger surface adsorption, with an area/molecule ~70 A(2) compared with 85 A(2) for the AS. The acidic sophorolipid shows a maximum in its adsorption at the CMC which appears to be associated with a mixture of different isomeric forms. The binary LS/AS and LS/LAS mixtures show a strong surface partitioning in favor of the more surface active and hydrophobic LS component but are nevertheless consistent with ideal mixing at the interface. In contrast, the surface composition of the AS/LAS mixture is much closer to the solution composition, but the surface mixing is nonideal and can be accounted for by regular solution theory, RST. In the AS/LS/LAS ternary mixtures, the surface adsorption is dominated by the sophorolipid, and especially the LS component, in a way that is not consistent with the observations for the binary mixtures. The extreme partitioning in favor of the sophorolipid for the LAS/LS/AS (1:2) mixtures is attributed to a reduction in the packing constraints at the surface due to the AS component. Measurements of the surface structure reveal a compact monolayer for LS and a narrow solvent region for LS, LS/AS, and LS/LAS mixtures, consistent with the more hydrophobic nature of the LS component. The results highlight the importance of the relative packing constraints on the adsorption of multicomponent mixtures, and the impact of the lactonic form of the sophorolipid on the adsorption of the sophorolipid/LAS mixtures. PMID- 21657230 TI - Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study. AB - The hepatotoxicity of Troglitazone (TGZ) has been ascribed to the formation of reactive metabolites, and the primary reactive metabolite of TGZ has been confirmed to be an o-quinone methide. Oxidation of the chromane moiety is also known to produce quinone containing metabolites. Quantum chemical studies have been performed to analyze the possible reaction pathways for the metabolism of the TGZ side chain, 6-hydroxy-2,2,5,7,8-pentamethylchromane (HPMC). From this analysis, a new pathway including oxidation at the C13 and C14 atoms of HPMC has been proposed for the formation of o-quinone methide (M2), while oxidation at the hydroxyl group leads to the formation of the quinone metabolite (M7). o-Quinone methide reactive metabolites have been shown to be more electrophilic at the reactive methylene center using quantum chemically estimated parameters. PMID- 21657231 TI - Thermodynamics of hyperbranched poly(ethylenimine) with isobutyramide residues during phase transition: an insight into the molecular mechanism. AB - The thermodynamic behavior of hyperbranched poly(ethylenimine) with isobutyramide groups (HPEI-IBAm) during thermal-induced phase transition in water was investigated by turbidity measurement, calorimetric measurements (DSC), FT-IR, and dynamic light scattering (DLS). Both turbidity and calorimetric measurements indicated a recoverable phase transition with a small hysteresis. Detailed FT-IR investigation gave an insight into its molecular mechanism about detailed group interaction during the heating-cooling process. The second derivative and Gaussian fit were carried out to separate three components of nu(C?O): 1648, 1625, and 1600 cm(-1), which are assigned to C?O...D-N H-bonds, single and double H-bonded carbonyl groups with water molecules, respectively. Quantitative analysis of amide I groups indicates a better revival compared to PNIPAM. The isosbestic point determination and 2D correlation analysis together with dynamic light scattering were applied to draw out the mechanism. Thermosensitive HPEI IBAm dissolves in water exhibits small particles of ca. 3 nm at room temperature at first. As temperature increases, the polymer begins to shrink and water is driven out from the polymer. Finally, the polymer results in a hydrophobic sphere, which aggregates further for a relative stable state upon heating. Above LCST, C?O...D-N hydrogen bonds form with the disassociation of C?O...D(2)O, which helps in the dehydration of CH groups. Upon cooling, the driven force of the transition is the hydration of CH groups. Compared with linear-PNIPAM, the globule-like hyperbranched polymer has a high specific area which endows the groups with a high degree of freedom and more sufficient interaction with water. PMID- 21657232 TI - Synthesis and anion sensing of water-soluble metallomacrocycles. AB - The self-assembly of (TMEDA)Pd(NO(3))(2) or (TMEDA)Pt(NO(3))(2) (where TMEDA = N(1),N(1),N(2),N(2)-tetramethylethane-1,2-diamine) and anthracene- or ferrocene based diimidazole ligands (L(1-3)) in aqueous solution affords a series of positively charged [M(2)L(2)](4+) dimetallomacrocycles. Their structures were characterized by (1)H NMR and electrospray ionization mass spectrometry and in the cases of {[(TMEDA)Pd](2)L(1)(2)}(NO(3))(4) (1), {[(TMEDA)Pd](2)L(1)(2)}(PF(6))(4) (1a), and {[(TMEDA)Pd](2)L(3)(2)}(NO(3))(4) (4) by single-crystal X-ray diffraction analysis. Interestingly, the NMR spectra of 1 and 1a revealed that the difference of their structures, as confirmed by X-ray diffraction analysis, was that a NO(3)(-) of 1 was encapsulated inside the cavity of the basket-shaped metallomacrocycle by C-H...O hydrogen bonds, while PF(6)(-) of 1a was bound outside by C-H...F hydrogen bonds. The fluorescence titration experiment exhibited the formation of 1:1 host-guest complexation for anthracene based positively charged [M(2)L(2)](4+)-type metallomacrocycles with NO(3)(-). The interactions between metallomacrocycles and various anions were investigated via fluorescence titration and cyclic voltammetry studies, respectively. PMID- 21657233 TI - Reactivity of diaminogermylenes with ruthenium carbonyl: Ru3Ge3 and RuGe2 derivatives. AB - The nature of the products of the reactions of [Ru(3)(CO)(12)] with diaminogermylenes depends upon the volume and the cyclic or acyclic structure of the latter. Thus, the triruthenium cluster [Ru(3){MU Ge(NCH(2)CMe(3))(2)C(6)H(4)}(3)(CO)(9)], which has a planar Ru(3)Ge(3) core and an overall C(3h) symmetry, has been prepared in quantitative yield by treating [Ru(3)(CO)(12)] with an excess of the cyclic 1,3-bis(neo-pentyl)-2 germabenzimidazol-2-ylidene in toluene at 100 degrees C, but under analogous reaction conditions, the acyclic and bulkier Ge(HMDS)(2) (HMDS = N(SiMe(3))(2)) quantitatively leads to the mononuclear ruthenium(0) derivative [Ru{Ge(HMDS)(2)}(2)(CO)(3)]. Mixtures of products have been obtained from the reactions of [Ru(3)(CO)(12)] with the cyclic and very bulky 1,3-bis(tert-butyl)-2 germaimidazol-2-ylidene under various reaction conditions. The Ru(3)Ge(3) and RuGe(2) products reported in this paper are the first ruthenium complexes containing diaminogermylene ligands. PMID- 21657234 TI - Using SAXS to reveal the degree of bundling in the polysaccharide junction zones of microrheologically distinct pectin gels. AB - The results of microrheological studies carried out on ionotropic pectin gels, particularly the manifest power law behavior observed at high frequencies, indicate that by using different assembly conditions gels can be formed in which the elementary network strands have different stiffnesses. It has been hypothesized that these differences reflect different network architectures, the extreme cases of which might be described as (i) dimeric calcium-chelating junction-zones of limited extent, linked by considerably longer, flexible, single chain sections, or (ii) semiflexible bundles consisting of extensively aggregated dimeric junction zones that latterly become entangled and cross-linked. To test this hypothesis directly, microrheologically distinct pectin gels have been generated using different assembly modalities, in particular by using different concentrations of polymer and cross-linking ions and by contrasting the controlled-release of ions or ion-binding groups, and the resulting systems have been studied by small-angle X-ray scattering. The results straightforwardly reveal that gels that are clearly more semiflexible from a microrheological point of-view contain larger scattering entities than those with a more flexible character. Furthermore, a more detailed interpretation of the scattering data with the aid of molecular modeling suggests that for the gels formed here those with a semiflexible microrheological signature consist predominantly of network filaments consisting of four or more chains, whereas those with a more flexible signature are predominantly single-chain sections linked by dimeric associations with no more that a few percent of the chains bundled to any higher extent. The ability to generate differing network architectures from the same polymer that fulfill different functional requirements, either in vivo in the plant cell wall, where pectin plays a crucial structural and mechanical role, or in vitro in a myriad of applications, makes these biomimetic biopolymer networks of considerable interest. PMID- 21657235 TI - Role of water during the extrusion of substrates by the efflux transporter AcrB. AB - The major efflux system in Escherichia coli is the tripartite complex AcrAB-TolC. Its homotrimeric transporter AcrB is polyspecific and extrudes antibiotics out of the bacterium. This extrusion is performed via a functional rotation, in which each monomer assumes a particular conformation. In the present study, targeted molecular dynamics simulations have been employed to obtain a molecular level understanding of the transport process. A particular focus is put on the role of water molecules in this extrusion process. It is shown that the water flows from the binding pocket toward the exit gate in the extrusion step and helps the substrate to move along this path. These results are underpinned by a detailed analysis of the electrostatic interaction energy. Furthermore, the role of water for the polyspecificity of the transporter is discussed. PMID- 21657238 TI - Discrete dynamics of nanoparticle channelling in suspended graphene. AB - We have observed a previously undescribed stepwise oxidation of mono- and few layer suspended graphene by silver nanoparticles in situ at subnanometer scale in an environmental transmission electron microscope. Over the range of 600-850 K, we observe crystallographically oriented channelling with rates in the range 0.01 1 nm/s and calculate an activation energy of 0.557 +/- 0.016 eV. We present a discrete statistical model for this process and discuss the implications for accurate nanoscale patterning of nanoscale systems. PMID- 21657239 TI - Nanophotonic three-dimensional microscope. AB - Three-dimensional (3D) optical microscopy based on integral imaging techniques is limited mainly by diffraction effects and the pitch of the microlens array used to sample the specimen. We integrate nanotechnology to the integral imaging technique and demonstrate a nanophotonic 3D microscope, where a nanophotonic lens array is used to finely sample the specimen. The resolution limitation due to diffraction is reduced by capturing images before the diffraction effects predominate and hence overcomes the bottleneck of achieving high resolution in an integral imaging 3D microscope. PMID- 21657237 TI - Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits. AB - Glutamate cysteine ligase (GCL) deficiency is a rare autosomal recessive trait that compromises production of glutathione, a critical redox buffer and enzymatic cofactor. Patients have markedly reduced levels of erythrocyte glutathione, leading to hemolytic anemia and, in some cases, impaired neurological function. Human glutamate cysteine ligase is a heterodimer comprised of a catalytic subunit (GCLC) and a regulatory subunit (GCLM), which catalyzes the initial rate-limiting step in glutathione production. Four clinical missense mutations have been identified within GCLC: Arg127Cys, Pro158Leu, His370Leu, and Pro414Leu. Here, we have evaluated the impacts of these mutations on enzymatic function in vivo and in vitro to gain further insight into the pathology. Embryonic fibroblasts from GCLC null mice were transiently transfected with wild-type or mutant GCLC, and cellular glutathione levels were determined. The four mutant transfectants each had significantly lower levels of glutathione relative to that of the wild type, with the Pro414Leu mutant being most compromised. The contributions of the regulatory subunit to GCL activity were investigated using a Saccharomyces cerevisiae model system. Mutant GCLC alone could not complement a glutathione deficient strain and required the concurrent addition of GCLM to restore growth. Kinetic characterizations of the recombinant GCLC mutants indicated that the Arg127Cys, His370Leu, and Pro414Leu mutants have compromised enzymatic activity that can largely be rescued by the addition of GCLM. Interestingly, the Pro158Leu mutant has kinetic constants comparable to those of wild-type GCLC, suggesting that heterodimer formation is needed for stability in vivo. Strategies that promote heterodimer formation and persistence would be effective therapeutics for the treatment of GCL deficiency. PMID- 21657240 TI - A highly efficient type I beta-turn mimetic simulating an Asx-Pro-turn-like structure. AB - Asx-Pro-turns have been identified with high frequency in protein structures nucleating type I beta-turns. By bridging the amino acid side chain in position i with a nitrogen substituent in position i+2 by ring-closing olefin metathesis (RCM), peptide mimetics of type 1 could be developed. NMR based conformational investigations indicated a stable intramolecular H-bond constraining a U-turn conformation that was predicted to simulate a type I beta-turn. PMID- 21657241 TI - Enone-alkyne reductive coupling: a versatile entry to substituted pyrroles. AB - The reductive coupling of enones or enals with alkynes, followed by olefin oxidative cleavage and Paal-Knorr cyclization, provides a versatile entry to a variety of pyrrole frameworks. A number of limitations of alternate entries to the requisite 1,4-dicarbonyl intermediate are avoided. Classes of pyrroles that are accessible by this approach include 2,3-, 2,4-, 1,2,3-, 1,2,4-, 2,3,5-, and 1,2,3,5-substituted monocyclic pyrroles as well as a number of fused-ring polycyclic derivatives. PMID- 21657242 TI - Photochemical chlorination of graphene. AB - We report the covalent functionalization of graphene by photochemical chlorination. The gas-phase photochlorination of graphene, followed by the structural transformation of the C-C bonds from sp(2) to sp(3) configuration, could remove the conducting pi-bands and open up a band gap in graphene. X-ray photoelectron spectroscopy revealed that chlorine is grafted to the basal plane of graphene, with about 8 atom % chlorine coverage. Raman spectroscopy, atomic force microscopy, and transmission electron microscopy all indicated that the photochlorinated graphene is homogeneous and nondestructive. The resistance increases over 4 orders of magnitude and a band gap appears upon photochlorination, confirmed by electrical measurements. Moreover, localized photochlorination of graphene can facilitate chemical patterning, which may offer a feasible approach to the realization of all-graphene circuits. PMID- 21657243 TI - Asymmetric synthesis of (+)-mequitazine from quinine. AB - The first asymmetric synthesis of the antihistaminic drug mequitazine is reported. Our approach started from quinine, a Cinchona alkaloid, whose chiral information was exploited for setting up the stereogenic center of (+) mequitazine. PMID- 21657244 TI - Characterization of Arabidopsis Ca2+/H+ exchanger CAX3. AB - Plant calcium (Ca(2+)) gradients, millimolar levels in the vacuole and micromolar levels in the cytoplasm, are regulated in part by high-capacity vacuolar cation/H(+) exchangers (CAXs). Several CAX transporters, including CAX1, appear to contain an approximately 40-amino acid N-terminal regulatory region (NRR) that modulates transport through N-terminal autoinhibition. Deletion of the NRR from several CAXs (sCAX) enhances function in plant and yeast expression assays; however, to date, there are no functional assays for CAX3 (or sCAX3), which is 77% identical and 91% similar in sequence to CAX1. In this report, we create a series of truncations in the CAX3 NRR and demonstrate activation of CAX3 in both yeast and plants by truncating a large portion (up to 90 amino acids) of the NRR. Experiments with endomembrane-enriched vesicles isolated from yeast expressing activated CAX3 demonstrate that the gene encodes Ca(2+)/H(+) exchange with properties distinct from those of CAX1. The phenotypes produced by activated CAX3 expressing in transgenic tobacco lines are also distinct from those produced by sCAX1-expressing plants. These studies demonstrate shared and unique aspects of CAX1 and CAX3 transport and regulation. PMID- 21657245 TI - Enantioselective cyclization of 4-alkenoic acids via an oxidative allylic C-H esterification. AB - An enantioselective intramolecular oxidative cyclization of 4-alkenoic acids was developed. The reaction proceeded via a pi-allyl Pd intermediate generated by an allylic C-H activation to give gamma-lactone derivatives with moderate to good enantioselectivity. Spiro bis(isoxazoline) ligand, SPRIX, was indispensable for this asymmetric transformation. PMID- 21657246 TI - In vitro evaluation of antioxidant and anti-inflammatory properties of genistein modified hemodialysis membranes. AB - Genistein-modified poly(amide):poly(vinyl pyrrolidone) (PA:PVP/G) hemodialysis membranes have been fabricated by coagulation via solvent (dimethyl sulfoxide, DMSO)/nonsolvent (water) exchange. The antioxidant and anti-inflammatory properties of the unmodified PA:PVP membranes were evaluated in vitro using human blood. It was found that these unmodified PA:PVP membranes were noncytotoxic to peripheral blood mononuclear cells (PBMC) but raised intracellular reactive oxygen species (ROS) levels. Pure genistein (in DMSO solution) was not only nontoxic to PBMC, but also suppressed the ROS levels in a manner dependent on genistein dosage. A similar dose-dependent suppression of ROS was found in genistein-modified PA (i.e., PA/G) membranes. However, the PVP addition had little or no effect in the suppression of ROS levels for the ternary PA:PVP/G system; the membrane ROS suppression was largely controlled by the genistein dosage. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin (IL-6) in whole blood were measured by ex vivo stimulation with lipopolysaccharide (LPS). The unmodified PA:PVP membranes drastically increased the level of TNF-alpha; however, the concentration of IL 1beta and IL-6 remained almost the same. The PA/G membranes reduced the concentration of IL-1beta and TNF-alpha even at very low genistein loadings, but it required a higher genistein loading to realize a similar effect in the case of IL-6. Of particular importance is that the genistein-modified blend membranes (PA:PVP/G) showed greater suppression of the concentrations of all three cytokines (TNF-alpha, IL-1beta, and IL-6) in comparison with those of the PA/G membranes, signifying the role of PVP in the enhanced anti-inflammatory properties of these genistein-modified membranes. Ultraviolet-visible (UV-vis) spectroscopy was employed to quantify any genistein leaching during the in vitro testing. PMID- 21657247 TI - Combined gene and stem cell therapy for cutaneous wound healing. AB - In current medical practice, wound therapy remains a clinical challenge and much effort has been focused on the development of novel therapeutic approaches for wound treatment. Gene therapy, initially developed for treatment of congenital defects, represents a promising option for enhancing wound repair. In order to accelerate wound closure, genes encoding for growth factors or cytokines have shown the most potential. The majority of gene delivery systems are based on viral transfection, naked DNA application, high pressure injection, and liposomal vectors. Besides advances stemming from breakthroughs in recombinant growth factors and bioengineered skin, there has been a significant increase in the understanding of stem cell biology in the field of cutaneous wound healing. A variety of sources, such as bone marrow, umbilical cord blood, adipose tissue and skin/hair follicles, have been utilized to isolate stem cells and to modulate the healing response of acute and chronic wounds. Recent data have demonstrated the feasibility of autologous adult stem cell therapy in cutaneous repair and regeneration. Very recently, stem cell based skin engineering in conjunction with gene recombination, in which the stem cells act as both the seed cells and the vehicle for gene delivery to the wound site, represents the most attractive field for generating a regenerative strategy for wound therapy. The aim of this article is to discuss the use and the potential of these novel technologies in order to improve wound healing capacities. PMID- 21657249 TI - Charge saturation and neutral substitutions in halomethanes and their group 14 analogues. AB - A computational analysis of the charge distribution in halomethanes and their heavy analogues (MH(4-n)X(n): M = C, Si, Ge, Sn, Pb; X = F, Cl, Br, I) as a function of n uncovers a previously unidentified saturation limit for fluorides when M ? C. We examine the electron densities obtained at the CCSD, MP2(full), B3PW91, and HF levels of theory for 80 molecules for four different basis sets. A previously observed substituent independent charge at F in fluoromethanes is shown to be a move toward saturation that is restricted by the low polarizability of C. This limitation fades into irrelevance for the more polarizable M central atoms such that a genuine F saturation is realized in those cases. A conceptual model leads to a function of the form [q(M(n')) - q(M(n))] = a[chi(A') - chi(A)] + b that links the electronegativities (chi) of incoming and leaving atoms (e.g., A' = X and A = H for the halogenation of MH(4-n)X(n)) and the associated charge shift at M. We show that the phenomenon in which the charge at the central atom, q(M), is itself independent of n (e.g., at carbon in CH(4-n)Br(n)) is best described as an "M-neutral substitution"--not saturation. Implications of the observed X saturation and M-neutral substitutions for larger organic and inorganic halogenated molecules and polymeric materials are identified. PMID- 21657250 TI - Anomalous shape changes of silicon nanopillars by electrochemical lithiation. AB - Silicon is one of the most attractive anode materials for use in Li-ion batteries due to its ~10 times higher specific capacity than existing graphite anodes. However, up to 400% volume expansion during reaction with Li causes particle pulverization and fracture, which results in rapid capacity fading. Although Si nanomaterials have shown improvements in electrochemical performance, there is limited understanding of how volume expansion takes place. Here, we study the shape and volume changes of crystalline Si nanopillars with different orientations upon first lithiation and discover anomalous behavior. Upon lithiation, the initially circular cross sections of nanopillars with <100>, <110>, and <111> axial orientations expand into cross, ellipse, and hexagonal shapes, respectively. We explain this by identifying a high-speed lithium ion diffusion channel along the <110> direction, which causes preferential volume expansion along this direction. Surprisingly, the <111> and <100> nanopillars shrink in height after partial lithiation, while <110> nanopillars increase in height. The length contraction is suggested to be due to a collapse of the {111} planes early in the lithiation process. These results give new insight into the Si volume change process and could help in designing better battery anodes. PMID- 21657248 TI - A sequential strand-displacement strategy enables efficient six-step DNA templated synthesis. AB - We developed a sequential strand-displacement strategy for multistep DNA templated synthesis (DTS) and used it to mediate an efficient six-step DTS that proceeded in 35% overall yield (83% average yield per step). The efficiency of this approach and the fact that the final product remains linked to a DNA sequence that fully encodes its reaction history suggests its utility for the translation of DNA sequences into high-complexity synthetic libraries suitable for in vitro selection. PMID- 21657251 TI - Stoichiometric self-assembly of shape-persistent 2D complexes: a facile route to a symmetric supramacromolecular spoked wheel. AB - An approach to multicomponent coordination-driven self-assembly of the first terpyridine-based, shape-persistent, giant two-dimensional D(6h) supramacromolecular spoked wheel is reported. Mixing core T6, rim T3, and Zn(II) or Cd(II) ions in a stoichiometric ratio (1:6:12) permitted the selective generation of a highly symmetric spoked wheel in 94% isolated yield via geometric and thermodynamic control. The products were characterized by a combination of traveling-wave ion mobility mass spectrometry and NMR techniques together with TEM imaging, which agreed with computational simulations. PMID- 21657252 TI - Unique inclusion properties of crystalline powder p-tert-butylthiacalix[4]arene toward alcohols and carboxylic acids. AB - Powdery crystals of p-tert-butylthiacalix[4]arene (2) selectively include EtOH from 1:1 mixtures of MeOH-EtOH and EtOH-PrOH, and EtCO(2)H from HCO(2)H-EtCO(2)H. On the other hand, no acid is included from HCO(2)H-MeCO(2)H, even though MeCO(2)H is included from the neat acid. The origins of these phenomena are discussed based on X-ray analysis of inclusion crystals prepared separately by crystallization. PMID- 21657253 TI - Concise entry to both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one based on novel oxidative etherification: formal synthesis of (+)-sundiversifolide. AB - Both enantiomers of 8-oxabicyclo[3.2.1]oct-3-en-2-one (6) have been synthesized from 4-hydroxycyclohept-2-enone (3) on the basis of a novel oxidative cyclo etherification using PhI(OH)OTs (Koser's reagent). (-)-(1S,5R)-8 Oxabicyclo[3.2.1]oct-3-en-2-one [(-)-6, 95% ee] was expeditiously transformed to (+)-sundiversifolide (1). PMID- 21657254 TI - Helix stabilization of poly(ethylene glycol)-peptide conjugates. AB - Hybrid polymer-peptide conjugates offer the potential for incorporating biological function into synthetic materials. The secondary structure of short helical peptides, however, frequently becomes less stable when expressed independent of longer protein sequences or covalently linked with a conformationally disordered synthetic polymer. Recently, new amphipathic peptide poly(ethylene glycol) conjugates were introduced (Shu, J., et al. Biomacromolecules 2008, 9, 2011), which displayed enhanced peptide helicity upon polymer functionalization while retaining tertiary coiled-coil associations. We report here a molecular simulation study of peptide helix stabilization by conjugation with poly(ethylene glycol). The polymer oxygens are shown to favorably interact with the cationic lysine side chains, providing an alternate binding site that protects against disruption of the peptide hydrogen-bonds that stabilize the helical conformation. When the peptide lysine charges are neutralized or poly(ethylene glycol) is conjugated with polyalanine, the polymer exhibits a negligible effect on the secondary structure. We also observe the interactions of poly(ethylene glycol) with the amphipathic peptide lysines tends to segregate the polymer away from the nonpolar face of the helix, suggesting no disruption of the interactions that drive tertiary contacts between helicies. PMID- 21657255 TI - Metabolic profiling of strawberry grape ( Vitis * labruscana cv. 'Isabella') components by nuclear magnetic resonance (NMR) and evaluation of their antioxidant and antiproliferative properties. AB - In the assessment of the antioxidant properties of edible plants, the widely consumed Vitis * labruscana cv. 'Isabella', known in Italy as "fragola" (strawberry) grape, was of interest. Phenol and flavonoid contents of the methanolic extracts of peel, pulp, seed, leaf, and stalk components of the plant were determined. The metabolic profile of the extracts was performed by 1D and 2D NMR. Quantitative analysis, obtained in the presence of 0.01% of internal standard trimethylsilyl propionate, evidenced the presence of catechins in both stalk and seed extracts, whereas caffeic acid and quercetin were the main metabolites of the leaf extract. Furthermore, the extracts were tested for their radical scavenging and reducing capacities by measuring their capacity to scavenge DPPH(*) and ABTS(*+) and to reduce Fe(III) and Mo(VI) salts. The antioxidant efficacy of the extracts in cell-free systems and their antiproliferative activity toward HepG2 and A549 cells were also evaluated. Seed and stalk components are able to reduce by 39.6 and 40.6%, respectively, the amount of the metabolically active HepG2 cells after only 24 h of exposure. PMID- 21657256 TI - Computer simulations of structure-activity relationships for HERG channel blockers. AB - The hERG potassium channel is of major pharmaceutical importance, and its blockade by various compounds, potentially causing serious cardiac side effects, is a major problem in drug development. Despite the large amounts of existing biochemical data on blockade of hERG by drugs and druglike compounds, relatively little is known regarding the structural basis of binding of blockers to the channel. Here, we have used a recently developed homology model of hERG to conduct molecular docking experiments with a series of channel blockers, followed by molecular dynamics simulations of the complexes and evaluation of binding free energies with the linear interaction energy method. The calculations yield a remarkably good agreement with experimental binding affinities and allow for a rationalization of three-dimensional structure-activity relationships in terms of a number of key interactions. Two main interaction regions of the channel are thus identified with implications for further mutagenesis experiments and design of new compounds. PMID- 21657257 TI - Microstructure and surface properties of fibrous and ground cellulosic substrates. AB - Cotton and linen fibers were ground in a ball-mill, and the effect of grinding on the microstructure and surface properties of the fibers was determined by combining a couple of simple tests with powerful techniques of surface and structure analysis. Results clearly proved that the effect of grinding on cotton fiber was much less severe than on linen. For both fibers, the degree of polymerization reduced (by 14.5% and 30.5% for cotton and linen, respectively) with a simultaneous increase in copper number. The increased water sorption capacity of the ground substrates was in good agreement with the X-ray results, which proved a less perfect crystalline structure in the ground samples. Data from XPS and SEM-EDS methods revealed that the concentration of oxygen atoms (bonded especially in acetal and/or carbonyl groups) on the ground surfaces increased significantly, resulting in an increase in oxygen/carbon atomic ratio (XPS data: from 0.11 to 0.14 and from 0.16 to 0.29 for cotton and linen, respectively). Although grinding created new surfaces rich in O atoms, the probable higher energy of the surface could not be measured by IGC, most likely due to the limited adsorption of the n-alkane probes on the less perfect crystalline surfaces. PMID- 21657258 TI - Carbon nanotubes induce malignant transformation and tumorigenesis of human lung epithelial cells. AB - Carcinogenicity of carbon nanotubes is a major concern but has not been well addressed due to the lack of experimental models. Here, we show that chronic exposure to single-walled carbon nanotubes causes malignant transformation of human lung epithelial cells. The transformed cells induce tumorigenesis in mice and exhibit an apoptosis resistant phenotype characteristic of cancer cells. This study provides new evidence for carbon nanotube-induced carcinogenesis and indicates the potential role of p53 in the process. PMID- 21657259 TI - Optical modulation of molecular conductance. AB - A novel scanning probe microscope stage permits break junction measurements of single molecule conductance while the molecules are illuminated with visible light. We studied a porphyrin-fullerene dyad molecule designed to form a charge separated state on illumination. A significant fraction of illuminated molecules become more conductive, returning to a lower conductance in the dark, suggesting the formation of a long-lived charge separated state on the indium-tin oxide surface. Transient absorption spectra of these molecular layers are consistent with formation of a long-lived charge separated state, a finding with implications for the design of molecular photovoltaic devices. PMID- 21657260 TI - The influence of surface oxide on the growth of metal/semiconductor nanowires. AB - We report the critical effects of oxide on the growth of nanostructures through silicide formation. Under an in situ ultrahigh vacuum transmission electron microscope, it is observed from the conversion of Si nanowires into the metallic PtSi grains epitaxially through controlled reactions between lithographically defined Pt pads and Si nanowires. With oxide, instead of contact area, single crystal PtSi grains start forming either near the center between two adjacent pads or from the ends of Si nanowires, resulting in the heterostructure formation of Si/PtSi/Si. Without oxide, transformation from Si into PtSi begins at the contact area between them, resulting in the heterostructure formation of PtSi/Si/PtSi. The nanowire heterostructures have an atomically sharp interface with epitaxial relationships of Si(20-2)//PtSi(10-1) and Si[111]//PtSi[111]. Additionally, it has been observed that the existence of oxide significantly affects not only the growth position but also the growth behavior and the growth rate by two orders of magnitude. Molecular dynamics simulations have been performed to support our experimental results and the proposed growth mechanisms. In addition to fundamental science, the significance of the study matters for future processing techniques in nanotechnology and related applications as well. PMID- 21657261 TI - Thermodynamic and structural characterization of zwitterionic micelles of the membrane protein solubilizing amidosulfobetaine surfactants ASB-14 and ASB-16. AB - Surface tension and isothermal titration calorimetry (ITC) were used to determine the critical micelle concentration (cmc) of the zwitterionic amidosulfobetaine surfactants ASB-14 and ASB-16 (linear alkylamidopropyldimethylammoniopropanosulfonates) at 25 degrees C. The cmc and the heat of micellization were determined from 15 to 75 degrees C by ITC for both surfactants. The increase in temperature caused significant changes in the enthalpy and in the entropy of micellization, with small changes in the standard Gibbs energy (DeltaG(mic)), which is consistent to an enthalpy-entropy compensation with a compensatory temperature of 311 K (ASB-14) and 314 K (ASB 16). In the studied temperature range, the heat capacity of micellization (DeltaC(p)(mic)) was essentially constant. The experimental DeltaC(p)(mic) was lower than that expected if only hydrophobic interactions were considered, suggesting that polar interactions at the head groups are of significant importance in the thermodynamics of micelle formation by these surfactants. Indeed, a NMR NOESY spectrum showed NOEs that are improbable to occur within the same monomer, resulting from interactions at the polar head groups involving more than one monomer. The ITC and NMR results indicate a tilt in the polar headgroup favoring the polar interactions. We have also observed COSY correlations typical of dipolar interactions that could be recovered with the partial alignment of the molecule in solution, which results in an anisotropic tumbling. The anisotropy suggested an ellipsoidal shape of the micelles, which results in a positive magnetic susceptibility, and ultimately in orientation induced by the magnetic field. Such an ellipsoidal shape was confirmed from results obtained by SAXS experiments that revealed aggregation numbers of 108 and 168 for ASB-14 and ASB 16 micelles, respectively. This study characterizes an interesting micelle system that can be used in the study of membrane proteins by solution NMR spectroscopy. PMID- 21657262 TI - Solvation-induced sigma-complex structure formation in the gas phase: a revisit to the infrared spectroscopy of [C6H6-(CH3OH)2]+. AB - Structures of the [C(6)H(6)-(CH(3)OH)(2)](+) cluster cation are investigated with infrared (IR) spectroscopy. While the noncovalent type structure has been confirmed for the n = 1 cluster of [C(6)H(6)-(CH(3)OH)(n)](+), only contradictory interpretations have been given for the spectra of n = 2, in which significant changes have been observed with the Ar tagging. In the present study, we revisit IR spectroscopy of the n = 2 cluster from the viewpoint of the sigma-complex structure, which includes a covalent bond formation between the benzene and methanol moieties. The observed spectral range is extended to the lower-frequency region, and the spectrum is measured with and without Ar and N(2) tagging. A strongly hydrogen-bonded OH stretch band, which is characteristic to the sigma complex structure, is newly found with the tagging. The remarkable spectral changes with the tagging are interpreted by the competition between the sigma complex and noncovalent complex structures in the [C(6)H(6)-(CH(3)OH)(2)](+) system. This result shows that the microsolvation only with one methanol molecule can induce the sigma-complex structure formation. PMID- 21657264 TI - Study of dimethoxyethane/ethanol solutions. AB - The unusual properties of poly(ethyleneoxide) + alcohol mixtures were analyzed using a poly(ethylene oxide) monomer (1,2-dimethoxyethane) in ethanol solutions as a model. A collection of thermophysical measurements and computational studies, using density functional theory and classical molecular dynamics approaches, provide valuable information about the molecular-level structure of this mixture and on the interaction between 1,2-dimethoxyethane and ethanol molecules. Thermophysical measurements show remarkable deviations from ideality, which are related to the development of intermolecular hydrogen bonding between both molecules upon mixing and to the balance of homo- and heteroassociations. Density functional theory allows better characterization from energetic and structural viewpoints. In this work, the characteristics for the different 1,2 dimethoxyethane/ethanol hydrogen-bonding complexes are analyzed via atoms in a molecule and natural bond orbital methods. Classical molecular dynamics simulations are carried out for pure 1,2-dimethoxyethane and for mixtures in the whole composition range. Force field validation is done by comparison of predicted thermophysical properties with measured ones and through the analysis of 1,2-dimethoxyethane conformers. Structural features are inferred from the analysis of radial and distribution functions and their evolution with composition, together with the study of molecular distribution in the mixed fluids (microheterogeneities). Dynamic aspects of the mixtures' behavior are inferred from the calculated self-diffusion constants and mean square displacements. The whole study points to a highly structured fluid, whose structure is determined by the balance of the 1,2-dimethoxyethane disrupting effect on the ethanol hydrogen-bonding network and the appearance of microheterogeneities. PMID- 21657263 TI - Polymeric antimicrobial N-halamine epoxides. AB - A new N-halamine copolymer has been prepared, characterized, and evaluated for antimicrobial efficacy, stability toward hydrolyses, and stability toward UVA degradation when covalently bound to cellulose fibers. A copolymer of 3-chloro-2 hydroxypropylmethacrylate and glycidyl methacrylate was coated onto cotton, and, after curing, was treated with an aqueous solution containing the potassium salt of 5,5-dimethylhydantoin to form a coating which became antimicrobial upon exposure to househod bleach (sodium hypochlorite). The coating inactivated S. aureus and E. coli O157:H7 within minutes of contact time and was quite stable toward washing and UVA photodegradation. PMID- 21657265 TI - Efficient synthesis of 4,7-diamino substituted 1,10-phenanthroline-2,9 dicarboxamides. AB - A convenient and high-yielding multigram synthesis of the versatile intermediate 4,7-dichloro-1,10-phenanthroline-2,9-dicarboxylic acid is described. The intermediate is further efficiently derivatized to 4,7-diamino-1,10 phenanthroline-2,9-dicarboxamides with potential G-quadruplex stabilizing effects. PMID- 21657266 TI - Carbon-silicon and carbon-carbon bond formation by elimination reactions at metal N-heterocyclic carbene complexes. AB - Two functional groups can be delivered at once to organo-rare earth complexes, (L)MR(2) and (L)(2)MR (M = Sc, Y; L = ({1-C(NDippCH(2)CH(2)N)}CH(2)CMe(2)O), Dipp = 2,6-(i)Pr(2)-C(6)H(3); R = CH(2)SiMe(3), CH(2)CMe(3)), via the addition of E-X across the metal-carbene bond to form a zwitterionic imidazolinium-metal complex, (L(E))MR(2)X, where L(E) = {1-EC(NDippCH(2)CH(2)N)}CH(2)CMe(2)O, E is a p-block functional group such as SiR(3), PR(2), or SnR(3), and X is a halide. The "ate" complex (L(Li))ScR(3) is readily accessible and is best described as a Li carbene adduct, ({1-Li(THF)C(NDippCH(2)CH(2)N)}CH(2)CMe(2)O)Sc(CH(2)SiMe(3))(3), since structural characterization shows the alkoxide ligand bridging the two metals and the carbene Li-bound with the shortest yet recorded Li-C bond distance. This can be converted via lithium halide-eliminating salt metathesis reactions to alkylated or silylated imidazolinium derivatives, (L(E))ScR(3) (E = SiMe(3) or CPh(3)). All the E-functionalized imidazolinium complexes spontaneously eliminate functionalized hydrocarbyl compounds upon warming to room temperature or slightly above, forming new organic products ER, i.e., forming C-Si, C-P, and C-Sn bonds, and re-forming the inorganic metal carbene (L)MR(X) or (L)(2)MX complex, respectively. Warming the tris(alkyl) complexes (L(E))MR(3) forms organic products arising from C-C or C-Si bond formation, which appears to proceed via the same elimination route. Treatment of (L)(2)Sc(CH(2)SiMe(3)) with iodopentafluorobenzene results in the "reverse sense" addition, which upon thermolysis forms the metal aryl complex (L)(2)Sc(C(6)F(5)) and releases the iodoalkane Me(3)SiCH(2)I, again facilitated by the reversible functionalization of the N-heterocyclic carbene group in these tethered systems. PMID- 21657267 TI - Formation of superhydrophobic microspheres of poly(vinylidene fluoride- hexafluoropropylene)/graphene composite via gelation. AB - We report on the spontaneous formation of superhydrophobic poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP)/graphene composite microspheres with uniform size via gelation. When the suspension of PVDF-HFP/graphene (0.25 wt. % with respect to PVDF-HFP) in DMF adsorbs water vapor, it changes to a hybrid gel. A dried porous gel is obtained after solvent exchange and freeze drying. Morphology characterization shows that this hybrid gel is composed of PVDF HFP/graphene microspheres with a diameter of 8-10 MUm. In contrast, PVDF-HFP solution gives rise to a cellular microstructure following the same experimental procedures. We further elucidate the formation mechanism on the basis of the characterization by freeze fracture transmission electron microscopy, X-ray diffraction, and differential scanning calorimetry characterizations. Furthermore, contact angle measurements of water on PVDF-HFP/graphene indicates that the hydrophobic nature of PVDF-HFP combined with the micro/nanoscale hierarchical texture creates a superhydrophobic surface. Such superhydrophobic microspheres may have potential applications as water-repellent catalyst supporting materials. PMID- 21657268 TI - DNA electron injection interlayers for polymer light-emitting diodes. AB - Introduction of a DNA interlayer adjacent to an Al cathode in a polymer light emitting diode leads to lower turn-on voltages, higher luminance efficiencies, and characteristics comparable to those observed using a Ba electrode. The DNA serves to improve electron injection and also functions as a hole-blocking layer. The temporal characteristics of the devices are consistent with an interfacial dipole layer adjacent to the electrode being responsible for the reduction of the electron injection barrier. PMID- 21657269 TI - Membrane-based emitter for coupling microfluidics with ultrasensitive nanoelectrospray ionization-mass spectrometry. AB - An integrated poly(dimethylsiloxane) (PDMS) membrane-based microfluidic emitter for high-performance nanoelectrospray ionization mass spectrometry has been fabricated and evaluated. The ~100-MUm-thick emitter was created by cutting a PDMS membrane that protrudes beyond the bulk substrate. The reduced surface area at the emitter enhances the electric field and reduces wetting of the surface by the electrospray solvent. As such, the emitter enables highly stable electrosprays at flow rates as low as 10 nL/min and is compatible with electrospray solvents containing a large organic component (e.g., 90% methanol). This approach enables facile emitter construction and provides excellent stability, reproducibility, and sensitivity as well as compatibility with multilayer soft lithography. PMID- 21657270 TI - Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6 methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6 yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor. AB - We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6 difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo 1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385. PMID- 21657271 TI - Collateral sensitivity of multidrug-resistant cells to the orphan drug tiopronin. AB - A major challenge in the treatment of cancer is multidrug resistance (MDR) that develops during chemotherapy. Here we demonstrate that tiopronin (1), a thiol substituted N-propanoylglycine derivative, was selectively toxic to a series of cell lines expressing the drug efflux pump P-glycoprotein (P-gp, ABCB1) and MRP1 (ABCC1). Treatment of MDR cells with 1 led to instability of the ABCB1 mRNA and consequently a reduction in P-gp protein, despite functional assays demonstrating that tiopronin does not interact with P-gp. Long-term exposure of P-gp-expressing cells to 1 sensitized them to doxorubicin and paclitaxel, both P-gp substrates. Treatment of MRP1-overexpressing cells with tiopronin led to a significant reduction in MRP1 protein. Synthesis and screening of analogues of tiopronin demonstrated that the thiol functional group was essential for collateral sensitivity while substitution of the amino acid backbone altered but did not destroy specificity, pointing to future development of targeted analogues. PMID- 21657273 TI - Controlled formation of mass-selected Cu-Au core-shell cluster beams. AB - Synthesis of bimetallic clusters is a topic of accelerated interest; their physical and chemical properties are greatly dependent on their composition, size, and structure. The cluster beam technique is widely used for preparation of clusters. However, creating bimetallic clusters with well-controlled composition, size, and structure, especially for larger clusters (>100 atoms), is still a big challenge. Here we demonstrate that not only size and composition but also the structure of bimetallic clusters can be controlled by tuning aggregation parameters. PMID- 21657272 TI - Thiourea/proline derivative-catalyzed synthesis of tetrahydrofuran derivatives: a mechanistic view. AB - A thiourea/proline derivative-catalyzed synthesis of linear alpha-substituted tetrahydrofuran/pyran derivatives starting with lactol substrates is presented. This study demonstrates the utility and potential complications of using (thio)urea/proline cocatalysis as each of these catalysts is necessary to provide the observed reactivity, but a time-dependent decrease in enantioselectivity is observed. New mechanistic insights into (thio)urea/proline cocatalysis are presented. PMID- 21657274 TI - Discovery and mechanistic studies of a general air-promoted metal-catalyzed aerobic N-alkylation reaction of amides and amines with alcohols. AB - The thermodynamically unfavorable anaerobic dehydrogenative alcohol activation to aldehydes and hydridometal species is found to be the bottleneck in metal catalyzed N-alkylations due to a general and unnoticed catalyst deactivation by amines/amides. Thus, different from the anaerobic dehydrogenation process in borrowing hydrogen or hydrogen autotransfer reactions that require noble metal complexes or addition of capricious ligands for catalyst activation, the water producing, exothermic, metal-catalyzed aerobic alcohol oxidation is thermodynamically more favorable and the most effective and advantageous aldehyde generation protocol. This leads to a general and advantageous air-promoted metal catalyzed aerobic N-alkylation methodology that effectively uses many simpler, less expensive, more available, and ligand-free metal catalysts that were inactive under typical anaerobic borrowing hydrogen conditions, avoiding the use of preformed metal complexes and activating ligands and the exclusive requirement of inert atmosphere protection. This aerobic method is quite general in substrate scope and tolerates various amides, amines, and alcohols, revealing its potentially broad utilities and interests in academy and industry. In contrast to the commonly accepted borrowing hydrogen mechanism, based on a thorough mechanistic study and supported by the related literature background, a new mechanism analogous to the relay race game that has never been proposed in metal catalyzed N-alkylation reactions is presented. PMID- 21657275 TI - Anion conductive block poly(arylene ether)s: synthesis, properties, and application in alkaline fuel cells. AB - Anion conductive aromatic multiblock copolymers, poly(arylene ether)s containing quaternized ammonio-substituted fluorene groups, were synthesized via block copolycondensation of fluorene-containing (later hydrophilic) oligomers and linear hydrophobic oligomers, chloromethylation, quaternization, and ion-exchange reactions. The ammonio groups were selectively introduced onto the fluorene containing units. The quaternized multiblock copolymers (QPEs) produced ductile, transparent membranes. A well-controlled multiblock structure was responsible for the developed hydrophobic/hydrophilic phase separation and interconnected ion transporting pathway, as confirmed by scanning transmission electron microscopic (STEM) observation. The ionomer membranes showed considerably higher hydroxide ion conductivities, up to 144 mS/cm at 80 degrees C, than those of existing anion conductive ionomer membranes. The durabilities of the QPE membranes were evaluated under severe, accelerated-aging conditions, and minor degradation was recognized by (1)H NMR spectra. The QPE membrane retained high conductivity in hot water at 80 degrees C for 5000 h. A noble metal-free direct hydrazine fuel cell was operated with the QPE membrane at 80 degrees C. The maximum power density, 297 mW/cm(2), was achieved at a current density of 826 mA/cm(2). PMID- 21657276 TI - Diastereodivergent behavior of alkyl versus cyano allenylcuprates toward aldehydes: a key role for lithium. AB - The stereodivergent behavior of allenyl(cyano)- and allenyl(alkyl)cuprates toward aldehydes, providing a selective preparation of both syn- and anti homopropargylic alcohols, is described. This study, which combines both experimental and theoretical support, shows that the copper nontransferred "dummy ligand" controls the localization of the lithium cation with respect to the allenylcuprate moiety. As a consequence, Li(+) acts as a Lewis acid activator but also controls the diastereoselectivity during the addition of allenylcuprates onto aldehydes. The combined high selectivity, efficiency, and versatility of these cuprate compounds opens the way to new one-pot synthetic procedures, as illustrated by the combined Klein rearrangement/transmetalation methodology described herein. PMID- 21657278 TI - Other/miscellaneous. PMID- 21657280 TI - Other/miscellaneous. PMID- 21657281 TI - The unity of knowledge. PMID- 21657282 TI - Letters: Werner Stumm: Environmental chemist, teacher, and advocate. PMID- 21657283 TI - Technology Update: A pollution-preventing wrinkle in fabric finishing. PMID- 21657284 TI - Technology Update: Attempting to activate the market for coal waste. PMID- 21657286 TI - Pesticide mixtures more lethal to earthworms, study finds. PMID- 21657285 TI - "Take-back" directive threatens international trade. PMID- 21657287 TI - Risk-management software tool makes long-overdue debut. PMID- 21657288 TI - Synergistic effects of chemical mixtures and degradation byproducts not reflected in water quality standards, USGS finds. PMID- 21657290 TI - Other News: ACI + hydrated lime = 90% mercury reduction? PMID- 21657289 TI - Reducing mercury emissions in tandem with other pollutants cuts costs, EPA finds. PMID- 21657291 TI - Stumm and Morgan win Stockholm Water Prize. PMID- 21657292 TI - Belated acid rain report may trigger legislation, investigation. PMID- 21657293 TI - Is ailing U.S. environmental industry missing opportunities overseas? PMID- 21657295 TI - News Briefs: Federal regulations cost the typical family $7239 in 1998. PMID- 21657294 TI - News Briefs: The first geographically detailed estimate of the U.S. population's exposure to 148 hazardous air pollutants. PMID- 21657296 TI - News Briefs: Consumer use of water treatment devices and concern about water quality is increasing. PMID- 21657298 TI - News Briefs: Sprawl threatens six of the nation's 10 most endangered rivers. PMID- 21657297 TI - News Briefs: Most bottled water sold in the United States is exempt from Food and Drug Administration (FDA) regulations for water safety. PMID- 21657299 TI - News Briefs: Separation technologies have great potential for helping reduce process waste. PMID- 21657300 TI - News Briefs: More than one-fourth of the world's population will face "severe water scarcity" in the next 25 years. PMID- 21657301 TI - News Briefs: Calcium is an essential nutrient for tree growth and necessary for neutralizing acid rain, but calcium levels in forest soils have decreased. PMID- 21657302 TI - EPA Watch: Shortfalls projected for wastewater infrastructure. PMID- 21657303 TI - EPA Watch: Enforcement plan focuses on industrial compliance. PMID- 21657304 TI - EPA Watch: Drinking water systems expected to monitor MTBE. PMID- 21657305 TI - EPA Watch: Chemical risk management plans due this month. PMID- 21657306 TI - EPA Watch: USGS, EPA team up to monitor pesticides. PMID- 21657307 TI - Peer reviewed: megacities: sweet dreams or environmental nightmares? AB - Absent external financing mechanisms, megacity problems in developing nations may be insurmountable. PMID- 21657308 TI - Peer reviewed: creating multidisciplinary research opportunities. AB - A unifying framework model helps researchers to address the complexities of environmental problems. PMID- 21657319 TI - Research Watch: Toxic compound detection. PMID- 21657309 TI - Peer reviewed: the use of critical loads in environmental policy making: a critical appraisal. PMID- 21657321 TI - Buyer's Guide: Buyer's Guide. PMID- 21657320 TI - Online/In print: online/in print. PMID- 21657326 TI - Other/miscellaneous. PMID- 21657324 TI - PBDDs/Fs and PCDDs/Fs in the raw and clean flue gas during steady state and transient operation of a municipal waste combustor. AB - Concentrations of polybrominated dibenzo-p-dioxins, and -dibenzofurans (PBDDs/Fs) and polychlorinated dibenzo-p-dioxins, and -dibenzofurans (PCDDs/Fs), were determined in the pre- and post-air pollution control system (APCS) flue gas of a municipal waste combustor (MWC). Operational transients of the combustor were found to considerably increase levels of PBDDs/Fs and PCDDs/Fs compared to steady state operation, both for the raw and clean flue gas; SigmaPBDDs/Fs increased from 72.7 to 700 pg dscm(-1) in the raw, pre-APCS gas and from 1.45 to 9.53 pg dscm(-1) in the post-APCS flue gas; SigmaPCDDs/Fs increased from 240 to 960 ng dscm(-1) in the pre-APCS flue gas, and from 1.52 to 16.0 ng dscm(-1) in the post APCS flue gas. The homologue profile of PBDDs/Fs and PCDDs/Fs in the raw flue gas (steady state and transients) was dominated by hexa- and octa-isomers, while the clean flue gas homologue profile was enriched with tetra- and penta-isomers. The efficiency of the APCS for PBDD/F and PCDD/F removal was estimated as 98.5% and 98.7%, respectively. The cumulative TEQ(PCDD/F+PBDD/F) from the stack was dominated by PCDD/F: the TEQ of PBDD/F contributed less than 0.1% to total cumulative toxic equivalency of MWC stack emissions. PMID- 21657329 TI - Electronic preprint publications. PMID- 21657328 TI - Other/miscellaneous. PMID- 21657330 TI - Letters: Electronic reprints available. PMID- 21657331 TI - Letters: Animal kingdom confusion. PMID- 21657332 TI - Correction: correction. PMID- 21657334 TI - Letters: Geography lesson. PMID- 21657333 TI - Letters: Improved combustion? PMID- 21657335 TI - Technology Update: New sensor may widen monitoring capabilities. PMID- 21657337 TI - Power plants' TRI reports spur relative risk debate. PMID- 21657336 TI - Technology Update: Glowing sensors highlight contamination. PMID- 21657338 TI - Consensus on health risks from mercury exposure eludes federal agencies. PMID- 21657339 TI - Coral reef project aims to pinpoint hot spots. PMID- 21657340 TI - New research challenges fertilizer as cause of coral reef declines. PMID- 21657341 TI - NASA's flagship satellite will revolutionize study of climate change. PMID- 21657342 TI - News Briefs: To find out how the adoption of an environmental management system (EMS) changes a company's economic and environmental performance. PMID- 21657343 TI - News Briefs: There is no evidence that environmental regulations promote suburban sprawl. PMID- 21657344 TI - News Briefs: Climate change does not pose a serious threat to the U.S. insurance industry. PMID- 21657345 TI - News Briefs: Waterborne microbial pollutants that are not adequately addressed by regulations are a major source of health and economic problems. PMID- 21657346 TI - News Briefs: Federal activities cause roughly half the nonpoint pollution problems in three western states. PMID- 21657347 TI - News Briefs: Market forces will increasingly drive environmental progress, and environmental opportunities will drive strategic business planning. PMID- 21657348 TI - News Briefs: Federal subsidies undermine recycling. PMID- 21657349 TI - EPA Watch: PCB-cooled transformers listed in national database. PMID- 21657351 TI - EPA Watch: Pulp mills targeted by enforcement investigators. PMID- 21657350 TI - EPA Watch: Monitoring could offer ecological "report card". PMID- 21657353 TI - EPA Watch: Beachgoers warned about poor water quality. PMID- 21657352 TI - EPA Watch: New laboratory designed with environment in mind. PMID- 21657354 TI - View From the Administrator's Office. AB - At EPA, Carol Browner is committed to facilitating practical approaches that address major environmental issues. PMID- 21657355 TI - Peer reviewed: strategies for promoting a sustainable industrial ecology. AB - Businesses can improve operations by capitalizing on the collective knowledge of their human resources. PMID- 21657367 TI - Research Watch: Source apportionment. PMID- 21657380 TI - Research Watch: Approximation methods. PMID- 21657383 TI - Buyer's Guide: Buyer's Guide. PMID- 21657382 TI - Online/In print: online/in print. PMID- 21657390 TI - Other/miscellaneous. PMID- 21657388 TI - Other/miscellaneous. PMID- 21657391 TI - Progress? At what price? PMID- 21657392 TI - Study finding perchlorate in fertilizer rattles industry. PMID- 21657393 TI - Gulf dead zone grows, perplexes scientists. PMID- 21657394 TI - Water shortages loom; technology, creative approaches offer solutions. PMID- 21657396 TI - Health: Rapid, genetic-based test can identify human viruses in beach water. PMID- 21657395 TI - Phthalate standard endorsed by industry. PMID- 21657397 TI - Risk: U.K. proposes risk assessment based on genetic variations. PMID- 21657398 TI - Cacophony of comments stalls multiple chemical sensitivity report. PMID- 21657399 TI - EPA puts MTBE water degradation before air quality benefits. PMID- 21657400 TI - EPA moves to make corporations responsible for disposal of mountains of manure. PMID- 21657402 TI - NAFTA loophole threatens environmental legislation. PMID- 21657401 TI - Report on greening SUVs captures auto industry's attention. PMID- 21657403 TI - News Briefs: New studies on endocrine disrupters should be conducted to follow at risk subjects from conception through adulthood. PMID- 21657404 TI - News Briefs: Two-thirds of those who have held the highest ranking positions in EPA's pesticide program now work for the pesticide industry. PMID- 21657406 TI - News Briefs: Human error, the failure to recognize that certain regulations apply to facilities, is the root cause of environmental violations. PMID- 21657405 TI - News Briefs: Hydropower should not be promoted as green energy. PMID- 21657408 TI - News Briefs: Ireland's environment is under "increasing threat" from social and economic factors. PMID- 21657407 TI - News Briefs: Corporate executives are increasingly aware that urban sprawl hurts the bottom line. PMID- 21657410 TI - News Briefs: A higher degree of trust in government agencies, less press coverage, and less scientific knowledge may explain why Americans are more receptive than Europeans to genetically modified foods and crops. PMID- 21657409 TI - News Briefs: Herbicide-tolerant and insect-resistant crops do not always increase yields and lower pesticide applications. PMID- 21657412 TI - EPA Watch: Scientific evidence does not support TRI lead requirement, critics say. PMID- 21657414 TI - EPA Watch: States, EPA discuss compromise plan to halt lawsuit over NOX plan. PMID- 21657413 TI - EPA Watch: EPA's lax oversight adds to wetlands losses. PMID- 21657416 TI - Will bt-based pest resistance management plans work? AB - EPA is evolving its policies in reaction to widespread adoption of Bt crops and scientific uncertainties about impacts. PMID- 21657417 TI - Profiling the commission for environmental cooperation. AB - By facilitating cooperation and public participation, the organization is fostering conservation, protection, and enhancement of the North American environment. PMID- 21657419 TI - Promoting your environmental web site. AB - For just a modest investment of time and money, opportunities abound to increase site visibility on the Internet. PMID- 21657424 TI - Research Watch: Ozone disinfection byproducts. PMID- 21657438 TI - Research Watch: Pollutants in meat smoke. PMID- 21657443 TI - Online/In print: online/in print. PMID- 21657444 TI - Buyer's Guide: Buyer's Guide. PMID- 21657449 TI - Other/miscellaneous. PMID- 21657451 TI - Other/miscellaneous. PMID- 21657452 TI - Experiential learning. PMID- 21657453 TI - Technology Update: Wastewater-to-fertilizer process under investigation in major cities. PMID- 21657454 TI - U.N. Negotiations on POPs snag on malaria. PMID- 21657456 TI - EPA charts new course in draft cumulative risk assessment for pesticides. PMID- 21657455 TI - Climate: Understanding global water cycle is key to managing climate change, NRC reports. PMID- 21657457 TI - Long-dormant Clean Water Act provision strengthened. PMID- 21657459 TI - Monitoring technologies crucial for carbon sequestration. PMID- 21657458 TI - Mapping carbon content stored in world's forests. PMID- 21657460 TI - News Briefs: Genetically modified ingredients turned up in almost every bit of popular processed and fast food sampled. PMID- 21657462 TI - News Briefs: Without rapid technological innovation, growth in worldwide energy use could have "potentially disastrous" environmental consequences in the next century. PMID- 21657461 TI - News Briefs: Dependence-not depletion-should frame the debate on how and when to phase out global coal usage. PMID- 21657463 TI - News Briefs: Many visitors find dirtier air at summer vacation spots than in the cities they flee. PMID- 21657464 TI - News Briefs: Thanks to new technologies, biologically based industrial products are growing more popular. PMID- 21657465 TI - News Briefs: The United States could significantly reduce its carbon dioxide (CO2) emissions to well below its Kyoto Protocol requirements by 2010. PMID- 21657466 TI - News Briefs: Emissions from windshield washer fluid may contribute substantially to the formation of ground-level ozone in Canada. PMID- 21657467 TI - News Briefs: More than 25% of all chemical releases in North America during 1996 came from Texas, Ontario, Louisiana, and Ohio. PMID- 21657468 TI - EPA Watch: NRC urges efforts supporting particulate control plans. PMID- 21657469 TI - EPA Watch: Science getting its proper due in regulatory decision making? PMID- 21657470 TI - EPA Watch: DOE urges extension for refiners under sulfur proposal. PMID- 21657471 TI - EPA Watch: Mountaintop mining agreement disturbs environmentalists. PMID- 21657472 TI - Sustaining global fish stocks. AB - Despite conflicting views on harm from trawling and overfishing, experts agree that changes in fishing practices are necessary. PMID- 21657473 TI - Powering Tomorrow's Cars. AB - Partnerships and investments are driving fuel cell technology advances, and the move from prototype car to everyday use is on the horizon. PMID- 21657475 TI - Peer reviewed: environmental sleuth at work. AB - A combination of technical approaches and forensic tools can determine historic causes, timing, and impacts of site contamination. PMID- 21657484 TI - Research Watch: Extensive snowmobile pollution. PMID- 21657489 TI - Research Watch: Heavy metal accumulation. PMID- 21657500 TI - Other/miscellaneous. PMID- 21657502 TI - Other/miscellaneous. PMID- 21657503 TI - Errata: errata. PMID- 21657505 TI - ES&T in the new millennium. PMID- 21657504 TI - Letters: Industry not rattled. PMID- 21657506 TI - ES&T Europe: ES&T. PMID- 21657507 TI - Growing evidence of widespread GMO contamination. PMID- 21657508 TI - Overflowing sewers cause backlog of water problems. PMID- 21657509 TI - Honda's Insight is first hybrid vehicle to hit U.S. market. PMID- 21657510 TI - Energy: Fuel cells promise assured power for Postal Service. PMID- 21657511 TI - Energy: Ford opens first U.S. hydrogen fueling station. PMID- 21657512 TI - NRC supports mining law reforms advocated by Interior Secretary Babbitt. PMID- 21657514 TI - Uncertainties linked to water vapor's role in climate change. PMID- 21657513 TI - Emissions: Magnesium industry commits to reduce emissions of powerful greenhouse gas. PMID- 21657515 TI - News Briefs: Midwestern rain contains dangerous levels of mercury. PMID- 21657516 TI - News Briefs: Global environmental resources are reaching the crisis point. PMID- 21657517 TI - News Briefs: The European Union (EU) generated almost 28 million tons of hazardous waste in the mid 1990s. PMID- 21657519 TI - News Briefs: Worldwide electricity use will double by 2020. PMID- 21657518 TI - News Briefs: Habitat loss, invasive species, and overharvesting have put one of every eight plant species at risk of extinction worldwide. PMID- 21657520 TI - News Briefs: Children in the world's megacities are exposed to air pollution levels 2 to 8 times above the maximum World Health Organization exposure guideline. PMID- 21657521 TI - News Briefs: Millions of tax dollars subsidize corporate chicken and hog factories. PMID- 21657524 TI - EPA Watch: Pilot may lead utilities to control mercury. PMID- 21657526 TI - Can renewable energy survive deregulation? AB - Renewable energy use is on an upswing, but proponents worry that it will lose out in a strictly competitive energy market. PMID- 21657525 TI - EPA Watch: Ruling may allow Mass. To sell electric cars. PMID- 21657527 TI - Peer reviewed: update on environmental biosensors. AB - Scientific understanding and technological development are advancing, but commercialization, with a few exceptions, has been slow. PMID- 21657529 TI - Interview: establishing renewable energy markets. AB - Deutsche Shell AG board member Fritz convinced that there are profitable niches for renewable-energy technologies. PMID- 21657530 TI - Peer reviewed: facing the challenges of a service economy. AB - The environmental impacts of the large-and growing-service-based sector of the U.S. economy are poorly characterized. PMID- 21657531 TI - Technology Update: A wide variety of bugs can break down perchlorate. PMID- 21657534 TI - Research Watch: Chlorinated organic micropollutants. PMID- 21657539 TI - Research Watch: Atmospheric chemistry of MMT. PMID- 21657554 TI - Online/In print: online/in print. PMID- 21657556 TI - Buyer's Guide: Buyer's Guide. PMID- 21657557 TI - 1999 index: 1999 a-page index. PMID- 21657560 TI - A flow cytometry based oligotrophic pollutant exposure test to detect bacterial growth inhibition and cell injury. AB - Toxicity of chemical pollutants in aquatic environments is often addressed by assays that inquire reproductive inhibition of test microorganisms, such as algae or bacteria. Those tests, however, assess growth of populations as a whole via macroscopic methods such as culture turbidity or colony-forming units. Here we use flow cytometry to interrogate the fate of individual cells in low-density populations of the bacterium Pseudomonas fluorescens SV3 exposed or not under oligotrophic conditions to a number of common pollutants, some of which derive from oil contamination. Cells were stained at regular time intervals during the exposure assay with fluorescent dyes that detect membrane injury (i.e., live-dead assay). Reduction of population growth rates was observed upon toxicant insult and depended on the type of toxicant. Modeling and cell staining indicate that population growth rate decrease is a combined effect of an increased number of injured cells that may or may not multiply, and live cells dividing at normal growth rates. The oligotrophic assay concept presented here could be a useful complement for existing biomarker assays in compliance with new regulations on chemical effect studies or, more specifically, for judging recovery after exposure to fluctuating toxicant conditions. PMID- 21657564 TI - Other/miscellaneous. PMID- 21657562 TI - Other/miscellaneous. PMID- 21657565 TI - The new millennium. PMID- 21657566 TI - NIEHS eyes potential threats from Hurricane Floyd. PMID- 21657567 TI - Researchers point toward chiral chemistry as pollution cure. PMID- 21657568 TI - European Union bans phthalate softeners in baby toys. PMID- 21657569 TI - Flooded with U.S. hazardous waste imports, Canada rethinks its rules. PMID- 21657570 TI - Governments are a speed bump on the road to smart growth. PMID- 21657571 TI - Legislators, environmentalists, and states up in arms over anti-environmental rider. PMID- 21657572 TI - Scientists elucidate role elements play in eutrophication. PMID- 21657573 TI - Laureate extols genetic engineering's value for aiding hungry developing nations. PMID- 21657574 TI - UNEP Prize winner to study megacities in developing world. PMID- 21657575 TI - News Briefs: Eastern European countries may need 20 years or more to comply with all current environmental requirements. PMID- 21657576 TI - News Briefs: Water pricing based on full-cost recovery is still rare. PMID- 21657577 TI - News Briefs: Global warming might not cause the sea level to rise. PMID- 21657578 TI - News Briefs: Wind energy could generate 10% of the world's electricity by 2020. PMID- 21657579 TI - News Briefs: Breast cancer was linked with the use of lawn services, dry cleaning, and home pesticides. PMID- 21657581 TI - News Briefs: By 2025, Africa's sub-Saharan nations and territories may only be able to feed 40% of their projected population of 1 billion. PMID- 21657580 TI - News Briefs: Increased humidity due to global warming could become a major source of discomfort and stress. PMID- 21657582 TI - News Briefs: The Gulf of Mexico's oxygen starved dead zone could be shrunk. PMID- 21657585 TI - EPA Watch: GAO finds major shortcomings in drinking water research. PMID- 21657584 TI - EPA Watch: Chemicals used in children's products could receive closer scrutiny. PMID- 21657586 TI - EPA Watch: Fuel efficiency has slipped in favor of auto weight. PMID- 21657587 TI - EPA Watch: NRC studies wetlands mitigation techniques. PMID- 21657588 TI - EPA Watch: Showdown on environmental justice at U.S.-Mexican border. PMID- 21657589 TI - Peer reviewed: sediment management: deciding when to intervene. AB - Identification of cleanup options for contaminated sediment requires a solid mix of pragmatism and sound science. PMID- 21657591 TI - Peer reviewed: risk management should be about efficiency and equity. AB - A hybrid strategy that addresses both issues can be developed, and its feasability should be explored. PMID- 21657590 TI - Peer reviewed: the evolution of industrial ecology. AB - No longer focusing solely on technology, industrial ecology is beginning to address sustainability through metadisciplinary partnerships. PMID- 21657593 TI - Technology Update: Transmission technologies can decrease the environmental impact of deregulated electric power. PMID- 21657595 TI - Research Watch: Wet-weather flow. PMID- 21657594 TI - Technology Update: Detoxifying anti-NOX technology. PMID- 21657597 TI - Research Watch: Sulfur transport. PMID- 21657596 TI - Research Watch: Chlorinated hydrocarbon destruction. PMID- 21657599 TI - Research watch: u.s. Research. PMID- 21657598 TI - Research Watch: Bird health. PMID- 21657600 TI - Research Watch: Population interviews. PMID- 21657602 TI - Research Watch: Remediating oil spills. PMID- 21657601 TI - Research Watch: Organochlorine compounds. PMID- 21657604 TI - Research Watch: Photoestrogen research. PMID- 21657603 TI - Research Watch: Polyethylene combustion. PMID- 21657606 TI - Research Watch: Metals and nutrients. PMID- 21657605 TI - Research Watch: Impact of clouds. PMID- 21657608 TI - Research Watch: Water test alternative. PMID- 21657607 TI - Research Watch: Ozone standard. PMID- 21657609 TI - Research Watch: Elements in soils. PMID- 21657610 TI - Research Watch: Toxics identification. PMID- 21657612 TI - Research Watch: Air-surface exchange. PMID- 21657611 TI - Research Watch: Groundwater GIS. PMID- 21657613 TI - Research Watch: Cryptosporidium parvum transport. PMID- 21657615 TI - Research Watch: Incineration study. PMID- 21657614 TI - Research Watch: Lake quality. PMID- 21657616 TI - Online/In print: online/in print. PMID- 21657618 TI - Buyer's Guide: Buyer's Guide. PMID- 21657619 TI - 2000 advisory board: 2000 advisory board. PMID- 21657620 TI - Other/miscellaneous. PMID- 21657623 TI - Other/miscellaneous. PMID- 21657625 TI - Other/miscellaneous. PMID- 21657626 TI - How to thank our reviewers. PMID- 21657627 TI - Pollution monitoring should get personal, scientists say. PMID- 21657629 TI - Canada's water supply vulnerable to export pressures. PMID- 21657628 TI - Some ship emissions may help cool planet. PMID- 21657630 TI - Corps plan for water management met with opposition. PMID- 21657631 TI - Split United Nations vote slows fight to save fertile lands. PMID- 21657632 TI - Air Quality: Fuller accounting of ecological systems needed to quantify air quality benefits. PMID- 21657633 TI - European ban on use of surfactant alarms U.S. producers. PMID- 21657634 TI - Genetically modified trees sow seeds of growing conflict. PMID- 21657635 TI - European governments urged to consider environmental benchmarks. PMID- 21657636 TI - Health Assessment: Long-running diesel health assessment needs tweaking, EPA science advisors say. PMID- 21657637 TI - News Briefs: Nationwide efforts to reduce solid waste cut the amount of trash dumped in U.S. landfills by 23.3 million tons in 1996. PMID- 21657638 TI - News Briefs: There were more than 600,000 chemical accidents in the United States between 1987 and 1996. PMID- 21657639 TI - News Briefs: One billion tons of underwater sediments are sufficiently contaminated with toxic pollutants. PMID- 21657640 TI - News Briefs: Some of the world's poorest countries have significantly cut pollution. PMID- 21657641 TI - News Briefs: More than 12% of the prinitng and writing paper produced in the United States was projected to end up in catalogs in 1999. PMID- 21657642 TI - News Briefs: Environmental factors such as exposure to toxic substances and pollutants. PMID- 21657643 TI - News Briefs: California's public school buses rank among "the oldest and highest polluting in the nation". PMID- 21657645 TI - EPA Watch: Confusion over agreement confounds species protection efforts. PMID- 21657644 TI - News Briefs: Only 1% of conservation areas are protected from extractive activities in 10 key developing countries. PMID- 21657646 TI - EPA Watch: 2000 budget includes steady funding; policy orders. PMID- 21657647 TI - EPA Watch: PBT releases, including dioxin, will be captured on TRI reports. PMID- 21657648 TI - EPA Watch: Proposal to regulate large animal farms still under fire. PMID- 21657649 TI - Technology Update: Existing technologies can remove arsenic, but at a cost. PMID- 21657652 TI - Peer reviewed: continuing fire threat in southeast Asia. AB - Environmental harm could continue for years if vast numbers of underground coal and peat fires in the region are not suppressed. PMID- 21657650 TI - Assessing the environmental health of europe. AB - Protection of Europe's environmental health will depend heavily on successful management of its fast-growing industrial base. PMID- 21657653 TI - Restoring our rivers. AB - River ecosystems range in size from small streams to the vast Everglades. Leading ecologists view current efforts to restore and save these systems as flawed and too little too late. PMID- 21657675 TI - Research Watch: Controlling mercury emissions. PMID- 21657662 TI - Research Watch: Huge dioxin emission source. PMID- 21657676 TI - Online/In print: online/in print. PMID- 21657680 TI - Other/miscellaneous. PMID- 21657682 TI - Other/miscellaneous. PMID- 21657685 TI - Protecting our cultural heritage. PMID- 21657686 TI - Trash study creates a stir, but little action. PMID- 21657687 TI - Reconciling trade pacts with multilateral environmental agreements. PMID- 21657688 TI - Effects: Perchlorate's drag on frog development could contribute to population decline. PMID- 21657689 TI - Maglev trains race along an environmental track to reality. PMID- 21657690 TI - Breaching dams may save salmon, but the science remains an issue. PMID- 21657691 TI - European environmental groups press for court representation. PMID- 21657692 TI - Toxicity: Activists hope to raise the heat on EPA with publication of their own dioxin report. PMID- 21657693 TI - U.K. businesses propose greenhouse gas emissions trading scheme. PMID- 21657694 TI - Research: NSF charts new course for environmental research. PMID- 21657695 TI - U.S.-Canadian talks set to clear transboundary smog. PMID- 21657696 TI - Pollution: Toxic releases rise in Canada. PMID- 21657697 TI - News Briefs: The Internet could prevent 95 million metric tons of greenhouse gas emissions by 2008. PMID- 21657698 TI - News Briefs: Most soft toys sold in the United States still contail phthalates. PMID- 21657699 TI - News Briefs: Every living human now harbors 500 synthetic chemicals. PMID- 21657701 TI - News Briefs: Alternative-fuel bus purchases are on the rise. PMID- 21657700 TI - News Briefs: NOX levels in the United States increased 11% between 1970 and 1997. PMID- 21657703 TI - EPA Watch: Agency reassessing GM crop rules and regulations. PMID- 21657704 TI - EPA Watch: Clinton orders agencies to weave environmental priorities into U.S. trade policy. PMID- 21657705 TI - EPA Watch: EPA reviews New York City watershed management. PMID- 21657706 TI - EPA Watch: EPA, states win first court battle over stormwater program. PMID- 21657707 TI - Interview: biodiversity at the crossroads. AB - E. O. Wilson speaks out on the need for preserving biodiversity in science and technology's role in this endeavor. PMID- 21657709 TI - Going, going, gone? Plant species extinction in the 21st century. AB - Prospects for halting it or even slowing its rate are bleak, but perhaps not hopeless. PMID- 21657710 TI - Peer reviewed: evaluating impacts of hormonally active agents in the environment. AB - Information about endocrine disrupters is limited, with sparse data, few answers, great uncertainties, and a definite need for further research. PMID- 21657715 TI - Research Watch: Monitoring vehicle emissions. PMID- 21657711 TI - Technology Solutions: Driving desulfurization technology development. PMID- 21657723 TI - Research Watch: Lake Baikal pollution. PMID- 21657735 TI - Online/In print: online/in print. PMID- 21657740 TI - Other/miscellaneous. PMID- 21657742 TI - Other/miscellaneous. PMID- 21657743 TI - A word about ethics. PMID- 21657744 TI - Researchers point to incinerator emissions as a major source of atmospheric lead concentrations. PMID- 21657746 TI - New test advances understanding of fish-killing algae. PMID- 21657745 TI - Research priorities for fueling fuel cells called into question. PMID- 21657747 TI - EPA draft almost doubles safe dose of perchlorate in water. PMID- 21657748 TI - News Briefs: Policies creating incentives to reduce raw materials consumption will increase profits and protect the environment. PMID- 21657749 TI - News Briefs: Although a growing number of Americans consider environmental protection important. PMID- 21657750 TI - News Briefs: Deserts are expanding over 41% of the Earth's land area. PMID- 21657751 TI - News Briefs: Developing new environmental technologies is crucial to the U.S. economy. PMID- 21657752 TI - News Briefs: Prosecution of environmental crimes has fallen sharply. PMID- 21657753 TI - News Briefs: The Clinton administration has failed to make headway in reducing anthropogenic mercury emissions. PMID- 21657754 TI - News Briefs: If states hope to retain public ownership over coastal land. PMID- 21657755 TI - EPA Watch: Rule includes flexibility for handling remediation waste. PMID- 21657757 TI - Peer reviewed: promoting green chemistry initiatives. AB - Supported by a rapidly growing infrastructure, the field promises innovative solutions to pressing environmental problems. PMID- 21657758 TI - Addressing the Y2K Challenge. AB - Many organizations are unprepared to solve their "year 2000" problems on time. PMID- 21657760 TI - Peer reviewed: genetic engineering: the frontier of bioremediation. AB - New molecular tools and an improved understanding of biodegradative processes are slowly increasing prospects for successful technology deployment. PMID- 21657765 TI - Research Watch: Toxic metal cleanup. PMID- 21657761 TI - Technology Update: The future of coal power technology looks hotter. PMID- 21657780 TI - Research Watch: Contamination from incinerators. PMID- 21657785 TI - Buyer's Guide: Buyer's Guide. PMID- 21657784 TI - Online/In print: online/in print. PMID- 21657788 TI - Investigation of the persistence of nitroxynil residues in milk from lactating dairy cows by ultra performance liquid chromatography tandem mass spectrometry. AB - Nitroxynil is an anthelmintic used in the treatment of liver fluke. In this study, six dairy cows were treated during lactation with Trodax, a 34% solution containing nitroxynil as its N-ethylglucamine salt, indicated for the treatment of fascioliasis in cattle and sheep. Samples were collected twice daily for 16 days and later at weekly intervals up to 58 days post-treatment. Nitroxynil residues were extracted from milk samples using acetonitrile; magnesium sulfate and sodium chloride were added to induce liquid-liquid partitioning and purified by dispersive solid phase extraction for clean-up. Nitroxynil was determined by ultra performance liquid chromatography coupled to tandem mass spectrometry (UPLC MS/MS) in negative ionization mode. The limit of detection (CCalpha) of the method is 0.24 MUg/kg. Maximum concentration of nitroxynil in the samples was in the range of 688-1358 MUg/kg, with levels persisting for 58 days in four of the six lactating cows. Incurred nitroxynil samples were treated with sulfatase and beta-glucuronidase from Helix pomatia ; the results indicated the presence of glucuronide conjugates in samples at early withdrawal times. At later withdrawal times the concentration of free nitroxynil was lower than the concentration in the control samples, indicating potential degradation during enzymatic treatment. PMID- 21657789 TI - Cell compatible trimethoprim-decorated iron oxide nanoparticles bind dihydrofolate reductase for magnetically modulating focal adhesion of mammalian cells. AB - On the basis of the high affinity binding of trimethoprim (TMP) to Escherichia coli dihydrofolate reductase (eDHFR), TMP-decorated iron oxide nanoparticles bind to eDHFR with high affinity and specificity, which allows magnetic modulation of focal adhesion of mammalian cells adhered to a surface. Besides being the first example of nanoparticles that selectively bind to eDHFR, the biocompatibility of the conjugate of TMP-iron oxide nanoparticles renders a convenient and versatile platform for investigating the cellular responses to specific, mechanical perturbation of proteins via a magnetic force. PMID- 21657790 TI - Transparent cellulose films with high gas barrier properties fabricated from aqueous alkali/urea solutions. AB - Transparent and bendable regenerated cellulose films prepared from aqueous alkali (NaOH or LiOH)/urea (AU) solutions exhibit high oxygen barrier properties, which are superior to those of conventional cellophane, poly(vinylidene chloride), and poly(vinyl alcohol). Series of AU cellulose films are prepared from different cellulose sources (cotton linters, microcrystalline cellulose powder, and softwood bleached kraft pulp) for different dissolution and regeneration conditions. The oxygen permeabilities of these AU cellulose films vary widely from 0.003 to 0.03 mL MUm m(-2) day(-1) kPa(-1) at 0% relative humidity depending on the conditions used to prepare the films. The lowest oxygen permeability is achieved for the AU film prepared from 6 wt % cellulose solution by regeneration with acetone at 0 degrees C. The oxygen permeabilities of the AU cellulose films are negatively correlated with their densities, and AU films prepared from solutions with high cellulose concentrations by regeneration in a solvent at low temperatures generally have low oxygen permeabilities. The AU cellulose films are, therefore, promising biobased packaging materials with high-oxygen barrier properties. PMID- 21657791 TI - Inverse regulation in the metabolic genes pckA and metE revealed by proteomic analysis of the Salmonella RcsCDB regulon. AB - The RcsC, RcsD, and RcsB proteins compose a system used by enteric bacteria to sense envelope stress. Signal transmission occurs from the sensor RcsC to the transcriptional regulator RcsB. Accessory proteins, such as IgaA, are known to adjust the response level. In a previous transcriptomic study, we uncovered 85 genes differentially expressed in Salmonella enterica serovar Typhimurium igaA mutants. Here, we extended these observations to proteomics by performing differential isotope-coded protein labeling (ICPL) followed by liquid chromatography-electrospray ionization tandem mass spectrometry. Five-hundred five proteins were identified and quantified, with 75 of them displaying significant changes in response to alterations in the RcsCDB system. Divergent expression at the RNA and protein level was observed for the metabolic genes pckA and metE, involved in gluconeogenesis and methionine synthesis, respectively. When analyzed in diverse environmental conditions, including the intracellular niche of eukaryotic cells, inverse regulation was more evident for metE and in bacteria growing in defined minimal medium or to stationary phase. The RcsCDB system was also shown to repress the synthesis of the small RNA FnrS, previously reported to modulate metE expression. Collectively, these findings provide new insights into post-transcriptional regulatory mechanisms involving the RcsCDB system and its control over metabolic functions. PMID- 21657792 TI - Scandium arene inverted-sandwich complexes supported by a ferrocene diamide ligand. AB - The synthesis and characterization of the first scandium arene inverted-sandwich complexes supported by a ferrocene diamide ligand (NN(fc)) are reported. Through the use of (NN(fc))ScI(THF)(2) as a precursor and potassium graphite (KC(8)) as a reducing agent, the naphthalene and anthracene complexes [(NN(fc))Sc](2)(MU C(10)H(8)) and [(NN(fc))Sc](2)(MU-C(14)H(10)), respectively, were synthesized and isolated in moderate to high yields. Both molecular structures feature an inverted-sandwich geometry and exhibit short Fe-Sc distances. DFT calculations were employed to gain understanding of the electronic structures of these new scandium arene complexes. A variable-temperature NMR spectroscopic study of [(NN(fc))Sc](2)(MU-C(14)H(10)) indicated that two different structures are accessible in solution. Reactivity studies showed that the naphthalene complex [(NN(fc))Sc](2)(MU-C(10)H(8)) can be converted to the corresponding anthracene species [(NN(fc))Sc](2)(MU-C(14)H(10)) and that [(NN(fc))Sc](2)(MU-C(10)H(8)) can act as either a reductant or a proton acceptor. The reaction of [(NN(fc))Sc](2)(MU-C(10)H(8)) with excess pyridine led to a rare example of C-C bond formation between two pyridine rings at the para position. PMID- 21657793 TI - 3-(Hetero)aryl-4-indolylamino-alpha-tetralones by diastereoselective internal redox cyclization: an "azaenamine" conjugate addition. AB - (E)-3-(hetero)aryl-1-(2-((E)-(indolin-1-ylimino)methyl)phenyl)prop-2-en-1-ones 1 undergo 6-exo-trig cyclization reactions upon treatment with BF(3).Me(2)S in dichloromethane at low temperature to give the tetralones 10 in good yield. This cyclization process can be considered to be an intramolecular Michael-type addition which is accompanied by an internal redox reaction as the indoline fragment is oxidized to indole with simultaneous hydrogen shift to nitrogen atom N1 and the alpha-carbon atom of the Michael system. The reactions at the iminic centers take place via umpolung of the classical carbonyl reactivity. The reaction is diastereoselective and affords exclusively 3,4-disubstituted alpha tetralones 10 as trans-diastereomers. According to quantum chemical calculations the reactions take place under kinetic control with the trans-diastereomer being the kinetically favored product as it has the lower activation barrier compared to the cis-diastereomer. PMID- 21657795 TI - Components of complex lipid biosynthetic pathways in developing castor (Ricinus communis) seeds identified by MudPIT analysis of enriched endoplasmic reticulum. AB - Ricinoleic acid is a feedstock for nylon-11 (N11) synthesis which is currently obtained from castor (Ricinus communis) oil. Production of this fatty acid in a temperate oilseed crop is of great commercial interest, but the highest reported level in transgenic plant oils is 30%, below the 90% observed in castor and insufficient for commercial exploitation. To identify castor oil-biosynthetic enzymes and inform strategies to improve ricinoleic acid yields, we performed MudPIT analysis on endoplasmic reticulum (ER) purified from developing castor bean endosperm. Candidate enzymes for all steps of triacylglycerol synthesis were identified among 72 proteins in the data set related to complex-lipid metabolism. Previous reported proteomic data from oilseeds had not included any membrane bound enzyme that might incorporate ricinoleic acid into oil. Analysis of enriched ER enabled determination of which protein isoforms for these enzymes were in developing castor seed. To complement this data, quantitative RT-PCR experiments with castor seed and leaf RNA were performed for orthologues of Arabidopsis oil-synthetic enzymes, determining which were highly expressed in the seed. These data provide important information for further manipulation of ricinoleic acid content in oilseeds and peptide data for future quantification strategies. PMID- 21657794 TI - Escherichia coli processivity clamp beta from DNA polymerase III is dynamic in solution. AB - Escherichia coli DNA polymerase III is a highly processive replicase because of the presence of the beta clamp protein that tethers DNA polymerases to DNA. The beta clamp is a head-to-tail ring-shaped homodimer, in which each protomer contains three structurally similar domains. Although multiple studies have probed the functions of the beta clamp, a detailed understanding of the conformational dynamics of the beta clamp in solution is lacking. Here we used hydrogen exchange mass spectrometry to characterize the conformation and dynamics of the intact dimer beta clamp and a variant form (I272A/L273A) with a weakened ability to dimerize in solution. Our data indicate that the beta clamp is not a static closed ring but rather is dynamic in solution. The three domains exhibited different dynamics, though they share a highly similar tertiary structure. Domain I, which controls the opening of the clamp by dissociating from domain III, contained several highly flexible peptides that underwent partial cooperative unfolding (EX1 kinetics) with a half-life of ~4 h. The comparison between the beta monomer variant and the wild-type beta clamp showed that the beta monomer was more dynamic. In the monomer, partial unfolding was much faster and additional regions of domain III also underwent partial unfolding with a half life of ~1 h. Our results suggest that the delta subunit of the clamp loader may function as a "ring holder" to stabilize the transient opening of the beta clamp, rather than as a "ring opener". PMID- 21657796 TI - Theoretical study of magnetic properties of oxovanadium(IV) complex self assemblies with tetradentate Schiff base ligands. AB - The theoretical study of the magnetic properties of oxovanadium(IV) complex self assemblies with tetradentate Schiff base ligands is discussed on the basis of DFT calculations. Large negative spin densities are found on the axial oxygens of the various oxovanadium(IV) complexes. The relationship between the effective exchange parameters J(ab) and the geometrical parameters for these complexes was studied by changing the position of the neighboring molecules for the purpose of clarifying the mechanism of the ferromagnetic coupling. The intermolecular ferromagnetic interaction of the oxovanadium(IV) complexes with tetradentate Schiff base ligands is significantly affected by the formation of polymeric octahedral structures in the solid state. The overlap between the 2p orbitals of the axial oxygen and the 3d orbitals of the adjacent vanadium is effective for the ferromagnetic coupling. On the other hand, the effect of overlap between the vanadium 3d(xy) orbitals is too small to lead to magnetic coupling. It was revealed that the intermolecular ferromagnetic interaction of the polynuclear oxovanadium(IV) complexes is significantly affected by the spin polarization on the axial oxygen. PMID- 21657797 TI - Graphene patchwork. AB - Graphene oxide (GO) holds tremendous potential for large-area electronics, high strength and conducting fillers in composites, and high-surface-area electrodes for energy storage. Graphene oxide for such applications will require manufacturing methods that are industrially compatible but also preserve its unique properties. Recent work by Korkut et al. describes a promising new scheme for continuous processing of colloidal suspension of GO into tapes that are meters long and tens of micrometers thick. Tapes of restacked graphene sheets exhibit graphite-like mechanical robustness and electrical conductivity but retain the high surface area and flexibility of graphene. PMID- 21657798 TI - Atom-resolved evidence of anisotropic growth in ZnS nanotetrapods. AB - ZnS nanotetrapods were investigated by atom-resolved microscopy characterization and quantitative simulation. The octahedron core enclosed with Zn- and S terminated surfaces was verified. Four hexaprism-shaped arms were selectively grown from Zn-terminated surfaces of the core by alternately stacking zinc blende and wurtzite structures. The stacking order change at the core/arm interface is significant to activate the arm growth. The anisotropic growth mechanism was proposed and further proved by the synthesis of ZnS nanoparticles and nanobelts. PMID- 21657799 TI - Surface charge affects cellular uptake and intracellular trafficking of chitosan based nanoparticles. AB - Chitosan-based nanoparticles (NPs) are widely used in drug delivery, device-based therapy, tissue engineering, and medical imaging. In this aspect, a clear understanding of how physicochemical properties of these NPs affect the cytological response is in high demand. The objective of this study is to evaluate the effect of surface charge on cellular uptake profiles (rate and amount) and intracellular trafficking. We fabricate three kinds of NPs (~ 215 nm) with different surface charge via SPG membrane emulsification technique and deposition method. They possess uniform size as well as identical other physicochemical properties, minimizing any differences between the NPs except for surface charge. Moreover, we extend our research to eight cell lines, which could help to obtain a representative conclusion. Results show that the cellular uptake rate and amount are both positively correlated with the surface charge in all cell line. Subsequent intracellular trafficking indicates that some of positively charged NPs could escape from lysosome after being internalized and exhibit perinuclear localization, whereas the negatively and neutrally charged NPs prefer to colocalize with lysosome. These results are critical in building the knowledge base required to design chitosan-based NPs to be used efficiently and specifically. PMID- 21657800 TI - Complexation of lanthanides(III), americium(III), and uranium(VI) with bitopic N,O ligands: an experimental and theoretical study. AB - New functionalized terpyridine-diamide ligands were recently developed for the group actinide separation by solvent extraction. In order to acquire a better understanding of their coordination mode in solution, protonation and complexation of lanthanides(III), americium(III), and uranium(VI) with these bitopic N,O-bearing ligands were studied in homogeneous methanol/water conditions by experimental and theoretical approaches. UV-visible spectrophotometry was used to determine the protonation and stability constants of te-tpyda and dedp-tpyda. The conformations of free and protonated forms of te-tpyda were investigated using NMR and theoretical calculations. The introduction of amide functional groups on the terpyridine moiety improved the extracting properties of these new ligands by lowering their basicity and enhancing the stability of the corresponding 1:1 complexes with lanthanides(III). Coordination of these ligands was studied by density functional theory and molecular dynamics calculations, especially to evaluate potential participation of hard oxygen and soft nitrogen atoms in actinide coordination and to correlate with their affinity and selectivity. Two predominant inner-sphere coordination modes were found from the calculations: one mode where the cation is coordinated by the nitrogen atoms of the cavity and by the amide oxygen atoms and the other mode where the cation is only coordinated by the two amide oxygen atoms and by solvent molecules. Further simulations and analysis of UV-visible spectra using both coordination modes indicate that inner-sphere coordination with direct complexation of the three nitrogen and two oxygen atoms to the cation leads to the most likely species in a methanol/water solution. PMID- 21657801 TI - Cost benefit and cost effectiveness of antifungal prophylaxis in immunocompromised patients treated for haematological malignancies: reviewing the available evidence. AB - There has been a large increase in the incidence of invasive fungal infections (IFIs) over the past decades, largely because of the increasing size of the population at risk. One of the major risk groups for IFIs are patients with haematological malignancies treated with cytotoxic chemotherapy or undergoing haematopoietic stem cell transplantation. These IFIs are associated with high morbidity and mortality rates. Consequently, as the diagnosis of IFIs is difficult, antifungal prophylaxis is desirable in high-risk patients. Furthermore, as the economic impact of IFIs is also significant, it is important to assess the cost benefit and cost effectiveness of each prophylactic agent in order to aid decisions concerning which prophylactic agent provides the best value for limited healthcare resources. This article systematically reviews the available pharmacoeconomic evidence regarding antifungal prophylaxis in immunocompromised patients treated for haematological malignancies. Furthermore, specific points of interest concerning economic analyses of antifungal prophylaxis are briefly discussed. Considering the available evidence, antifungal prophylaxis in immunocompromised patients treated for haematological malignancies seems to be an intervention with favourable cost-benefit, cost-effectiveness and cost-saving potential. Furthermore, recently introduced antifungal agents seem to be attractive alternatives to fluconazole from a pharmacoeconomic point of view. However, due to wide heterogeneity in patient characteristics, underlying diseases, hospital settings and study methods in the included economic studies, as well as the lack of 'head-to-head' trials, it is difficult to find clear evidence of the economic advantages of a single prophylactic agent. Furthermore, we show that the results of cost-effectiveness analyses are highly dependent on several crucial factors that influence the baseline IFI incidence rates and, therefore, differ per patient population or region. PMID- 21657803 TI - Attenuation of rate of change in carotid intima-media thickness by lipid modifying drugs: impact on clinical outcomes. AB - Measurements of carotid intima-media thickness (CIMT) are widely used in clinical research as a measure of atherosclerosis. Many randomized controlled trials (RCTs) have been performed using the rate of change in CIMT as the primary endpoint to study the efficacy of lipid-modifying therapies. The main advantage of using CIMT over the use of cardiovascular events as a primary endpoint is the greater efficiency and feasibility. The underlying assumption for the use of CIMT in trials is that the rate of change in CIMT achieved by a therapy reflects a change in the risk for cardiovascular events. We therefore set out to assess the evidence showing whether the rate of change in CIMT induced by lipid-lowering therapies has an impact on clinical outcomes, by reviewing the available evidence based on a search of the PubMed database. Solid evidence from observational studies shows that increased CIMT relates to an increase in cardiovascular risk. RCTs consistently demonstrate that the annual rate of change in CIMT is favourably affected by lipid-modifying therapies. One study investigating the relationship between the rate of change in CIMT and clinical events has been published and showed a positive relationship between these two outcomes. A published meta-analysis based on pooled CIMT data from statin trials has shown a positive relationship between attenuated rate of change in CIMT after statin therapy and clinical outcomes. However, methodological issues question the validity of the meta-analytical approach. The consistent agreement between results from CIMT trials and event trials on the effects of lipid-modifying therapies, however, clearly supports the presence of a relationship between changes in CIMT and clinical endpoints. Therefore, although direct evidence is scarce, the data overall on whether the attenuation of rate of change in CIMT by lipid-lowering therapies impact on clinical outcomes are supportive. PMID- 21657802 TI - Influence of renin-angiotensin system gene polymorphisms on the risk of ST segment-elevation myocardial infarction and association with coronary artery disease risk factors. AB - BACKGROUND: Recent advances in molecular biology have made it possible to identify numerous polymorphisms of the renin-angiotensin system, which play an important role in the etiology of cardiovascular disease. OBJECTIVE: The aims of the study were (i) to assess the distribution of the angiotensin II type 1 receptor (AGTR1) gene 1166A/C polymorphism and two polymorphisms of the angiotensinogen (AGT) gene (Met235Thr and Thr174Met) in patients with ST-segment elevation myocardial infarction (STEMI) who underwent coronary angiography, compared with healthy volunteers; (ii) to determine if there was any correlation between these polymorphisms and risk of STEMI; and (iii) to assess the association of the examined polymorphisms with such classic cardiovascular risk factors as hypertension, diabetes mellitus, obesity (based on a body mass index >=25 kg/m2), smoking, dyslipidemia, and family history of cardiovascular disease. METHODS: A total of 100 patients (mean age 57 +/- 10 years [range 31-76 years]; 21% women) with diagnosed STEMI and a control group consisting of 95 healthy volunteers (mean age 38 +/- 11 years [range 17-60 years]; 20% women) were investigated for the AGTR1 1166A/C polymorphism and two variants of AGT (Met235Thr and Thr174Met). All patients received standard therapy for STEMI. RESULTS: There were significant differences in the distribution of genotypes and the AGT Met174 allele for AGT Thr174Met polymorphism between patients and healthy subjects (p < 0.05). The AGTR1 1166A/C polymorphism genotype frequencies were significantly different in patients with hypertension compared with normotensive individuals. Specifically, the AGTR1 1166 AA genotype was twice as common in patients with hypertension as in those without (67% vs 33%), while the AC and CC genotypes were found predominantly in normotensive patients (p = 0.0016). The variant 1166C allele was much more common in patients without hypertension (67%) than in patients with hypertension (33%; p = 0.0006). The variant AGT Thr235 allele was more common in patients without a family history of cardiovascular disease than in patients with this risk factor (p < 0.05). The odds ratio (OR) for STEMI in patients with the heterozygous AGT 174 Thr/Met genotype was increased to 1.884 (95% confidence interval [CI] 1.03, 3.446; p < 0.05), while the OR calculated for carriers of the AGT Met174 allele was 2.038 (95% CI 1.129, 3.68; p = 0.0182). Significant genotypic associations of combinations of renin angiotensin system gene polymorphisms in STEMI were not observed. CONCLUSIONS: The most powerful predictive value for STEMI was represented by the Thr/Met genotype and the Met174 allele of the AGT Thr174Met gene polymorphism. In our study, in contrast to observations reported by other authors, the AA genotype of the AGTR1 1166A/C gene polymorphism - much more than other genotypes - was associated with hypertension. PMID- 21657804 TI - Evaluation of prescriber responses to pharmacist recommendations communicated by fax in a medication therapy management program (MTMP). AB - BACKGROUND: As defined by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, medication therapy management programs (MTMPs) must be designed to decrease adverse drug events and improve patient outcomes by promoting appropriate medication use. WellPoint Inc. contracted with the pharmacist-run University of Arizona College of Pharmacy Medication Management Center (UA MMC) to provide a pilot telephone-based MTMP to approximately 5,000 high-risk beneficiaries from among its nearly 2 million Medicare prescription drug plan (PDP) beneficiaries. Eligibility for the program was determined by a minimum of 2 of 6 chronic diseases (dyslipidemia, cardiovascular disease, depression, diabetes mellitus, congestive heart failure, and chronic obstructive pulmonary disease; at least 1 of the latter 2 diseases must be present), at least 3 Part-D covered medications, and greater than $4,000 per year in predicted drug spending. In addition to these criteria, WellPoint Inc. used the Johns Hopkins adjusted clinical groups (ACG) predictive model to identify the high-risk beneficiaries to be enrolled in the program. Medication therapy reviews were conducted for these patients. If any medication-related problems (MRPs) were identified, the patient's prescribers were contacted via a fax communication with recommendation(s) to resolve these MRPs. The UA MMC fax interventions were categorized as cost saving, guideline adherence, or safety concerns. OBJECTIVES: To (a) determine prescriber responses to pharmacist-initiated recommendations in an MTMP for the 3 intervention categories, (b) compare prescriber responses between intervention categories, and (c) compare prescriber response by prescriber type (primary care physician [PCP] vs. specialist) within each intervention category. METHODS: A retrospective analysis of pharmacist-initiated interventions from August through December 2008 was performed using data collected from the UA MMC database. Data were collected on intervention category (cost saving, guideline adherence, or safety concerns), and responses of prescribers were recorded as either approval or decline (no response was considered decline). Prescriber specialty was identified from searching records of state medical boards. Logistic regression analyses with the robust variance option to adjust for correlation within prescribers were conducted to compare prescriber approval rates between and within intervention categories. Significance was assessed at alpha 0.05. RESULTS: Of 4,967 Medicare Part D beneficiaries determined to be MTMP-eligible, 4,277 beneficiaries (86.1%) were available for assessment (400 declined, 186 disenrolled, and 104 were deceased). Pharmacists initiated 1,548 valid medication recommendations (i.e., recommendations were excluded for deceased patients, incorrect prescribers, and where prescriber specialty was not identified). These recommendations for 1,174 beneficiaries (27.5% of those available) were faxed to prescribers requesting approval. Mean (SD) age for beneficiaries having recommendations was 72.9 (9.4) years, and the majority (57.6%) was female. By category of recommendation, 58.3% (n=902) were guideline adherence, 33.3% (n=515) were cost saving, and 8.5% (n=131) were safety concerns. Prescriber approval rates were 47.2% overall (n =731/1,548), 41.4% (n=373/902) for guideline adherence, 58.3% (n=300/515) for cost savings, and 44.3% (n=58/131) for safety concerns; 817 recommendations were not approved by prescribers (n= 255 [16.5%] denials and 562 no response [36.3%]). Prescriber approval was significantly higher for cost-saving interventions compared with guideline adherence interventions (odds ratio [OR]=1.98, 95% CI=1.56-2.51, P< 0.001) and compared with safety interventions (OR=1.76, 95% CI=1.19, 2.59, P=0.004); there was no significant difference in the prescriber approval rates for the interventions for safety versus guideline adherence. The overall approval rate was higher for PCPs (49.8%, n=525/1,054) versus specialists (41.7%, n=206/494; OR=1.39, 95% CI=1.08-1.78, P=0.011) and for the category for guideline adherence interventions (44.0% for PCPs vs. 35.9% for specialists; OR =1.40, 95% CI=1.01-1.95, P=0.044), but not for the other 2 intervention categories. CONCLUSIONS: Prescriber approval rates for pharmacist recommendations for drug therapy changes for MTMP beneficiaries were approximately 47% overall and higher for recommendations that involved cost savings compared with recommendations for safety concerns or guideline adherence. Compared with specialists, PCPs had higher approval rates for pharmacist recommendations overall and for the intervention category guideline adherence. PMID- 21657805 TI - Descriptive analysis of mail interventions with physicians and patients to improve adherence with antihypertensive and antidiabetic medications in a mixed model managed care organization of commercial and Medicare members. AB - BACKGROUND: Medication nonadherence is a major concern for many health care stakeholders. Improving medication adherence in health plan members who have both hypertension and diabetes is essential for the successful management of these chronic diseases, with anticipated outcomes in decreased health care utilization, all-cause mortality and cost. OBJECTIVE: To (a) identify patients who are potentially nonadherent to antidiabetic or antihypertensive agents within 1 managed care organization and (b) determine the relationship of rates of medication nonadherence with 2 mail intervention programs that involved quarterly medication-specific profiles of patients with potential nonadherence sent to primary care physicians (PCPs) and general medication adherence letters sent to patients with potential nonadherence. METHODS: The study sample consisted of commercial members, Medicare Advantage-Prescription Drug Plan (MA-PD) members and Medicare Prescription Drug Plan (PDP) members who filled prescriptions for antihypertensive and antidiabetic medications and utilized their managed care pharmacy benefit during each measurement quarter (3 months) in the 2-year study period. Nonadherence was defined as a medication possession ratio (MPR) less than 77.0% for 1 or more antihypertensives and/or antidiabetic medications for each standalone calendar quarter. The first intervention, letters to PCPs with patient specific medication profiles for 2008 Q2, began 6-8 weeks after 2008 Q2 and continued for each standalone calendar quarter through the end of the study period in 2010 Q1 (January 1, 2010, through March 31, 2010). We assumed that patient care was managed by PCPs for hypertension and diabetes treatment. The medication profile also included antihyperlipidemic medication claims information, but there was no adherence analysis performed for antihyperlipidemic medications. The second intervention, letters sent to potentially nonadherent patients, began 6-8 weeks after 2009 Q1 for patients with MPR less than 77% for 1 or more antidiabetic or antihypertensive medications in 2009 Q1 and continued for each standalone calendar quarter through the end of the study period in 2010 Q1. RESULTS: Because there were 2 different interventions, 2 baseline adherence rates were calculated, for 2008 Q2 for the PCP mailing and for 2009 Q1 for the patient mailing. Compared with the baseline nonadherence rate in 2008 Q2 (35.6%), a small increase in nonadherence was observed in 2008 Q3 (36.4%), following by 6 calendar quarters of lower rates of nonadherence with a 27.7% nonadherence rate in the last measurement period in 2010 Q1. Compared with the nonadherence rate of 30.8% in baseline 2 (2009 Q1), the patient mailings were associated with small increases in nonadherence to 31.4% in 2009 Q2 and 31.1% in 2009 Q3, respectively, followed by lower nonadherence rates in 2009 Q4 (29.2%) and 2010 Q1 (27.7%). CONCLUSIONS: A 2-part intervention that involved mailings to PCPs for patients with both diabetic and antihypertensive medications who were potentially nonadherent to at least 1 medication, followed 9 months later by a general mailing sent to these potentially nonadherent patients regarding medication adherence, was associated with apparent improvement. However, the effect of the 2 part intervention on medication nonadherence could not be isolated because of coincident disease management interventions in diabetes and hypertension during the 2-year study period. PMID- 21657806 TI - A comparison of daily average consumption (DACON) of oxycodone and oxymorphone long-acting oral tablets. AB - BACKGROUND: The utilization of high-potency opioids is an important component of chronic pain management, and appropriate utilization of these medicines is a common concern of payers. Two of the most commonly prescribed oral long-acting opioids, oxycodone controlled-release (CR) and oxymorphone extended-release (ER), are FDA-approved for twice-daily dosing, which equates to a theoretical average consumption (DACON) of 2 tablets per day. DACON values greater than 2 have budget and policy implications for managed care pharmacists. OBJECTIVES: To assess from the perspective of the pharmacy benefit decision maker the DACONs of oxycodone CR and oxymorphone ER. METHODS: The main outcome measure for the analysis was DACON. Pharmacy and medical claims data from a large commercially insured population (i3 InVision Data Mart database) were analyzed to identify patients with at least 1 pharmacy claim for either oxycodone CR or oxymorphone ER from July 1, 2007, to September 30, 2009. After an initial 30-day titration period, all subjects included in the study had 1 or more claims totaling at least a 90-day supply of either study drug during the subsequent 90 days (DACON measurement period). Patients were excluded if there was evidence of a switch from one to the other study opioid during the 90-day measurement period. There were no limitations on the use of other opioids, either short- or long-acting, during either the DACON measurement period or the previous 6 months (baseline period). In addition, patients were excluded if the enrollee was younger than 18 years old, pregnant, did not have continuous insurance coverage for the 6 months before and after the start of the 90-day DACON measurement, or were enrolled in an HMO plan. Bivariate analyses were performed with between-group differences in DACON values assessed using t-tests and Wilcoxon rank sum tests. Patient characteristics including age, sex, geographic location, and baseline Charlson Comorbidity Index (CCI) for each drug group were evaluated descriptively using either the Pearson chi-square test or t-test. Multivariate analyses were conducted using generalized linear models (GLM) to adjust for the observed heterogeneity among patients in the observational database. For the GLMs, the gamma distribution and log link function were chosen to account for non-normal distributions of DACON. Independent variables included study drug, tablet strengths, age, sex, CCI, the maximum days gap between prescription refills during the DACON measurement period, and other opioid medication use. Several sensitivity analyses were conducted to verify all findings. RESULTS: The final analyses were conducted on 6,567 oxycodone CR patients and 796 oxymorphone ER patients. The unadjusted DACON mean value for the highest strength of oxycodone CR 80 milligrams (mg) was 3.9, compared with 2.9 for oxymorphone ER 40 mg (P < 0.001); mean DACON values were 3.0 versus 2.4, respectively, for lower strengths (P < 0.001) and 3.1 versus 2.5 for all strengths (P < 0.001). After adjusting for age, sex, CCI, maximum gap days, and other opioid medication use, a risk-adjusted mean difference in DACON remained, with oxycodone CR patients receiving on average 0.6 tablets more per day than those dispensed oxymorphone ER (P < 0.001). The direction, magnitude, and statistical significance of these differences were essentially unchanged in sensitivity analyses. CONCLUSIONS: On average during a 90-day time period, patients taking oxymorphone ER consumed 0.6 fewer tablets per day than did patients taking oxycodone CR. Further research is necessary to see if this difference amounts to cost savings for health plans that provide prescription reimbursement for patients with chronic pain syndromes. PMID- 21657807 TI - How do seniors respond to 100% cost-sharing for prescription drugs? Quality of the evidence underlying opinions about the Medicare Part D coverage gap. AB - Popular press coverage of the Medicare Part D coverage gap is based largely on research conducted using retrospective analyses of administrative claims data. These datasets are incomplete because they lack information about methods of obtaining medication that are commonly used by seniors, including free samples, generic drug discount programs, over-the-counter substitution, and patient assistance programs. As a result, evidence about the effects of 100% cost sharing on seniors is limited and suboptimal. Although the current deficit of information about the coverage gap is not entirely unexpected because the Medicare Part D program is relatively new, reliance on claims-based analyses to inform questions that claims data cannot possibly address accurately has tended to mislead and politicize rather than produce constructive policy guidance. Numerous important health policy questions remain unaddressed. These questions are becoming especially important as optimal approaches to providing health care to seniors are the subject of an increasingly vigorous debate. PMID- 21657808 TI - Effects of cohort selection on the results of cost-effectiveness analysis of disease-modifying drugs for relapsing-remitting multiple sclerosis. AB - BACKGROUND: Decision-analytic cost-effectiveness models are used to determine the most cost-effective treatment option on the basis of the best available data. Guidelines for pharmacoeconomic model development indicate that models should be updated as new evidence becomes available. OBJECTIVE: To evaluate the appropriateness of the clinical data that were selected for Goldberg et al.'s 2009 model of cost-effectiveness in multiple sclerosis and calculate results based on a revised cohort selection method for intramuscular (IM) interferon (IFN) beta-1a. METHODS: The original model compared cost per relapse avoided for IM IFN beta-1a, subcutaneous (SC) IFN beta-1a, IFN beta-1b, and glatiramer acetate (GA) based on intent-to-treat (ITT) results from clinical trials. However, due to lower-than-expected subject dropout rates, the IM IFN beta-1a trial had sufficient statistical power to be terminated early and was subsequently found to have met its primary endpoint, time to sustained 1.0-point Expanded Disability Status Scale progression. Within the "all-patient"(ITT) cohort (n=301), approximately 43% of patients were followed for less than 2 years; 172 patients were followed for 2 years or more. In contrast, the proportions of patients followed for at least 2 years in the clinical trials of IFN beta-1b, SC IFN beta-1a, and GA were 92%, 90%, and 86%, respectively. To test the impact of data selection on the cost-effectiveness model results, we recreated the original model using both the all-patient and 2-year cohorts from the IM IFN beta-1a pivotal trial. We then compared our results with those of the original model. RESULTS: In the original model, costs per relapse avoided were $141,721 for IM IFN beta-1a, $80,589 for SC IFN beta-1a, $87,061 for SC IFN beta 1b, and $88,310 for GA. In the reanalysis using the 2-year completer data for IM IFN beta-1a, costs per relapse avoided were $77,980 for IM IFN beta-1a, $80,121 for SC IFN beta-1a, $86,572 for IFN beta-1b, and $87,767 for GA. The cost per relapse avoided for IM IFN beta-1a was approximately 45% lower than in the original analysis, whereas the recreated results for the other 3 therapies differed from the original results by less than 1%. Sensitivity analyses showed that the recreated model was robust and that the rank order of cost-effectiveness results was unaffected by changes to any univariate parameter. CONCLUSIONS: The current study highlights the importance of data selection in cost-effectiveness analyses. After limiting the pivotal trial data for IM IFN beta-1a to patients followed for at least 2 years, we found that IM IFN beta-1a was more cost effective than in the original analysis, while results for the other first-line disease-modifying drugs remained stable. PMID- 21657809 TI - Priority setting in primary health care: a framework for local catchments. AB - Managers and staff in primary health care partnerships in local catchments, particularly in regional areas, are periodically required to work collaboratively to set health priorities. Setting priorities involves making decisions about which health needs are most important and what programs will be funded to address them. There is no universally agreed set of decision-making rules for setting priorities. Dominant approaches prioritise health economics, and have favoured expert knowledge drawn from technical-rational methodologies rather than consumer involvement and community action. However, research reveals that setting priorities is a complex, value laden, contested process buffeted by competing objectives and political interests. As such, an interdisciplinary, collaborative approach is called for. Using reflective practice from a priority setting project for a primary care partnership in a local, regional catchment in Victoria, Australia, a conceptual framework for priority setting is presented that identifies 13 interconnected factors spanning economic, political, policy, epidemiological, moral, evidentiary and evaluative domains. This interdisciplinary framework extends current knowledge about the considerations and trade-offs in setting priorities among collaborating primary health care agencies. It offers a potentially valuable heuristic tool for healthcare decision makers in rural areas. PMID- 21657814 TI - Acute pulmonary and moderate cardiovascular responses of spontaneously hypertensive rats after exposure to single-wall carbon nanotubes. AB - As a novel kind of nanomaterial with wide potential applications, the adverse effects of carbon nanotubes (CNTs) have recently received significant attention after respiratory exposure. In this study, single-wall carbon nanotubes (SWCNTs) containing different metal contents were intratracheally instilled into lungs of spontaneously hypertensive rats. Pulmonary and cardiovascular system alterations were evaluated at 24 and 72 h post-instillation. Biomarkers of inflammation, oxidative stress and cell damage in the bronchoalveolar lavage fluid (BALF) were increased significantly 24 h post-exposure of SWCNTs. The increased endothelin-1 levels in BALF and plasma and angiotensin I-converting enzyme in plasma suggested endothelial dysfunction in the pulmonary circulation and peripheral vascular thrombosis. These findings suggest that respiratory exposure to SWCNTs can induce acute pulmonary and cardiovascular responses and individuals with existing cardiovascular diseases are very susceptible to SWCNTs exposure. The co-existence of metal residues in SWCNTs can aggravate the adverse effects. PMID- 21657816 TI - Fine-needle aspiration cytology of the breast. AB - Fine-needle aspiration cytology (FNAC) is an established, highly accurate, and cost-effective method for diagnosing lesions in different organs, including the breast. The method is minimally invasive without unwanted side effects. FNAC forms part of the triple assessment of breast lesions. Despite some shortcomings of the reporting categories, FNAC as part of the triple assessment has proved its value in describing the findings most accurately. The diagnostic impact depends on experience of the operator, quality of preparation, and diagnostic skills of the cytopathologist. The highest accuracy is achieved at centers with a multidisciplinary approach. FNAC is often palpation guided from palpable breast masses, whereas ultrasonography guidance is more widely used on nonpalpable lesions. Inadequate sampling with FNAC is particularly seen in collagenous lesions and in submitted specimens sampled by physicians lacking experience with the FNAC procedure. A diagnostic biopsy is recommended when FNAC provides scant material. FNAC is considered to be a safe method for screening purposes, although moderately less sensitive than core needle biopsy. FNAC is most accurate when experienced cytopathologists are available to assess the adequacy of the aspirated material and advise on additional aspirations for ancillary tests when needed. PMID- 21657817 TI - Multiple organ invasion by viruses: pathological characteristics in three fatal cases of the 2009 pandemic influenza A/H1N1. AB - To further understand the pathological characteristics of multiple organ involvement of the 2009 pandemic influenza A/H1N1 infection, tissues of bronchial mucosa, lung, myocardium, gastrocnemius, and liver from 3 patients with fatal A/H1N1 infections were investigated by light microscopy and transmission electron microscopy. In all 3 patients, bronchial mucosa showed necrotizing bronchiolitis, epithelial necrosis and desquamation, and squamous metaplasia, while lung consolidation or fibrosis was identified. Myocardium and gastrocnemius exhibited focal necrosis and fibrosis, surrounded by muscle cells showing features of cell damage. In liver, there was widespread fatty degeneration and necrosis, most often around the central lobular vein and portal area. Viral particles were found in all samples, frequently located in endothelium, epithelium, and muscle cells. The observations demonstrate that in fatal cases of A/H1N1 infection, viruses not only infect the respiratory system, but also engage in multiple organ invasions, causing pathologic changes. PMID- 21657818 TI - Clinicopathological characteristics of obesity-associated focal segmental glomerulosclerosis. AB - Obesity-related glomerulopathy (ORG) is a secondary form of focal segmental glomerulosclerosis (FSGS) occurring in obese patients with a body-mass index higher than 30 kg/m(2). It is typically manifested by nephrotic-range proteinuria without full nephrotic syndrome, and progressive renal insufficiency. Characteristic morphologic features include the consistent presence of glomerulomegaly, predominance of perihilar variant of FSGS, and the relatively mild fusion of visceral epithelial cell foot processes. The concept of podocyte depletion as a driver of the glomerular scarring in obesity-associated FSGS is well documented. The underlying mechanisms are likely to be related in part to the oxidative stress and the impairment of the integrity of the slit diaphragm and cell adhesion resulting mainly from angiotensin II and transforming growth factor-beta. These proapoptotic cytokines are upregulated in obesity in response to insulin resistance, compensatory hyperinsulinemia and glomerular hyperfiltration-hypertension mediated mechanical stress. This review is designed to discuss the clinicopathologic features of obesity-associated FSGS, with a focus on the podocyte injury, which is involved in the onset and progression of the glomerulosclerotic process. Ultrastructural glomerular lesions are documented. PMID- 21657819 TI - Ultrastructure of popliteal vein aneurysm. AB - The term aneurysm is used to indicate a permanent and irreversible localized vascular dilatation that involves all three layers of the blood vessel wall. It may develop in any part of the circulatory system, including veins, and its history, presentation, and management differ depending on the location. A venous aneurysm is defined as a solitary area of fusiform or saccular dilatation occurring in the course of a major vein or connected by a single channel to a major venous structure. The lower extremities are the most frequently affected, with the popliteal vein being the most common site. Although different theories have been advanced, the etiology of the disease remains uncertain. Mechanical stress and/or degenerative changes within the vein wall are believed to represent the most likely causes of venous aneurysm. To date, there are only a few publications dealing with the histological appearance of popliteal vein aneurysm, and no studies that specifically describe its ultrastructural details have been published to our knowledge. In an attempt to fill this gap and to provide better insights into the pathophysiological mechanisms possibly involved in aneurysmal venous disease, we describe the fine structure of popliteal vein wall and valve in health and disease using both scanning and transmission electron microscopy. PMID- 21657820 TI - Renal giant cytoplasmic inclusions in Chediak-Higashi syndrome: first ultrastructural demonstration in a human biopsy. AB - This report ultrastructurally illustrates the giant lysosome-related organelles in the various cellular components of a renal biopsy from a 10 year-old female affected by the Chediak-Higashi syndrome. Albeit similar observations have been made and reported in animal models of the syndrome, to the author's knowledge, this is the first illustration of the changes as demonstrated in a human renal biopsy. PMID- 21657821 TI - Ultrastructural descriptions of heterotypic aggregation between eosinophils and tumor cells in human gastric carcinomas. AB - A histological variant of gastric adenocarcinoma, characterized by an intense tumor-associated tissue eosinophilia (TATE), has been occasionally reported in the literature. The purpose of this ultrastructural study was to determine the interactions between frequently occurring eosinophils and tumor cells in gastric carcinoma characterized by TATE. Fresh tumor tissue of 92 gastric carcinomas was processed for both light and electron microscopic examination. Intense TATE was found in 7 out of 92 (7.6%) gastric carcinomas (6 of intestinal-type and 1 of diffuse-type). Electron microscopy, selectively performed in 7 cases with intense TATE, revealed eosinophils, singly or in groups, in contact with damaged or necrotic tumor cells. Activated eosinophils showing piecemeal degranulation were also found in intimate contact with viable tumor cells, characterized by plasma membrane caveolar invaginations. The authors regard this close morphological relationship as in vivo evidence for possible cross-talk between eosinophil and viable tumor cell, a conclusion that has already been drawn from experimental studies, but until now inadequately supported by ultrastructural observations in a human tumor. PMID- 21657822 TI - Comparison of selective laser trabeculoplasty success in patients treated with either prostaglandin or timolol/dorzolamide fixed combination. AB - PURPOSE: The purpose of this study was to compare the efficacy of selective laser trabeculoplasty (SLT) in eyes of patients with open-angle glaucoma receiving either a prostaglandin (PG) analog or a timolol/dorzolamide fixed combination (TDFC). METHODS: In this retrospective study, we analyzed 48 eyes of 35 patients who underwent SLT for open-angle glaucoma receiving either a PG analog (n=20) or a TDFC (n=28). Mean decrease in intraocular pressure (IOP) and success rates were compared between patients treated with PG and those treated with TDFC. Success was defined as an IOP reduction of at least 20% at postoperative 1 year. RESULTS: The mean decrease in IOP in eyes treated with PG and in eyes treated with TDFC were 4.1+/-3.1 and 4.6+/-3.5 at 1 week (P=0.579), 5.3+/-3.4 and 5.7+/-2.0 at 1 month (P=0.485), 5.2+/-3.1 and 5.5+/-2.5 at 3 months (P=0.271), 5.0+/-3.1 and 6.1+/-2.5 and at 6 months (P=0.044), and 4.7+/-3.1 and 6.5+/-2.9 at 1 year (P=0.017), respectively. The success rate at postoperative 1 year was 50.0% (standard deviation+/-16) in eyes receiving PG and 78.6% (standard deviation:+/ 11) in eyes receiving TDFC (P=0.041). CONCLUSION: This study shows that the SLT seems to be more effective in TDFC users than PG analog users. PMID- 21657823 TI - Design of built environments to accommodate mobility scooter users: part II. AB - PURPOSE.Accessibility standards for wheeled mobility devices currently use a 1.5 m turning circle, designed to accommodate manual wheelchairs. Scooters are less manoeuvrable than wheelchairs, so allowing a full turning circle would require too much space. Instead, we propose using a rectangle that provides space for a three-point turn. Here, we determine the area requirements of this approach. METHOD. For rectangular 'rooms' of varying aspect ratios, we measured the minimum dimensions in which two four-wheeled scooters (the Celebrity-X and Fortress 1700), which combine good outdoor performance with reasonable indoor manoeuvrability, could enter the space, perform a three-point turn and exit. Moveable Styrofoam walls defined each 'room', and a doorway was located either near the corner of the space or in the middle of one wall. 'Room' size was decreased until our expert driver could no longer perform the manoeuvre. RESULTS. Compared to the area required for a turning circle, 42-54% savings were achieved. Relative to existing requirements, 53-95% more space is required to accommodate the Celebrity-X; 173-223% increases are necessary for the Fortress-1700. CONCLUSIONS. When accommodating four-wheeled scooters, our proposed three-point turn definition would require more space than the current standards, but considerably less than if a full turning circle were used. PMID- 21657824 TI - Retrograde intrarenal surgery versus percutaneous nephrolithotomy in the management of lower-pole renal stones with a diameter of 15 to 20 mm. AB - PURPOSE: To compare the outcomes of percutaneous nephrolithotomy (PCNL) and retrograde intrarenal surgery (RIRS) for 15 to 20 mm lower-pole (LP) renal calculi by evaluating stone-free rates and associated complications. PATIENTS AND METHODS: The records of 79 patients who underwent either PCNL (n=42) or RIRS (n=37) by standard techniques for 15 to 20 mm LP renal calculi were reviewed retrospectively. RESULTS: In the PCNL group, the stone-free rate was 92.8% (39/42 patients); this rate increased to 97.6% after a second intervention (shockwave lithotripsy in one and RIRS in one). After a single RIRS procedure, 33 of 37 (89.2%) patients were completely stone free. Two patients needed an additional procedure (rigid ureteroscopy in one and RIRS in one), after which they were all completely stone free, resulting in an overall success rate of 94.6%. Two patients had asymptomatic residual fragments <7 mm in the LP of the kidney, and these patients had been followed with ultrasonography of the kidney. For complications, there were minimal differences in both procedures, except for hemorrhage (necessitated transfusion) in three patients who were treated with PCNL. The overall stone-free rates and complication rates for PCNL were higher, but the differences were not statistically significant. Operative time was significantly longer in the RIRS group, and postoperative hospital stay was significantly longer in PCNL group. CONCLUSION: PCNL and RIRS are safe and effective methods for medium-sized LP calculi. For selected patients, RIRS may represent an alternative therapy to PCNL, with acceptable efficacy and low morbidity. PMID- 21657825 TI - Open versus robot-assisted partial nephrectomy: effect on clinical outcome. AB - BACKGROUND AND PURPOSE: Robot-assisted partial nephrectomy (RPN) has emerged as a viable alternative to open partial nephrectomy (OPN) for small renal masses (SRMs). Comparative outcomes of RPN and OPN at a single institution were analyzed. PATIENTS AND METHODS: A retrospective review was performed to compare 69 RPNs with 234 OPNs between May 2003 and December 2010 at a single institution. Clinicopathologic variables, operative parameters, and renal functional outcomes were analyzed. RESULTS: There were no significant differences between the two cohorts (RPN vs OPN) with respect to patient age (P=0.609), sex (P=0.703), preoperative estimated glomerular filtration rate (eGFR, P=0.146), estimated blood loss (P=0.600), and tumor size (P=0.256). The mean operative time was longer in the RPN group (192 vs 142 min, P<0.001). The mean warm ischemia time was longer in the RPN cohort (22.99 vs 18.87 min, P<0.001), but there were no significant differences in the postoperative eGFR (P=0.162) and change in the eGFR (P=0.520). The length of hospitalization (6.2 vs 8.9 d, P<0.001) and use of postoperative analgesics (ketoprofen, 0.26 vs 0.88 ampules, P<0.001) were more favorable in the RPN cohort. The number of patients with positive surgical margins was 0 for the RPN and 6 for the OPN groups. The intraoperative complication rates were 4.35% and 4.27% in the RPN and OPN groups, respectively (P=0.999). The overall postoperative complication rates were 8.7% and 15.4% in the RPN and OPN groups, respectively (P=0.158). CONCLUSIONS: RPN is a viable option as a nephron-sparing surgical procedure for SRMs considering the perioperative parameters and postoperative renal function changes, in addition to the traditional benefits of the laparoscopic procedure. PMID- 21657826 TI - Change in biomechanical parameters after flap creation using the Intralase femtosecond laser and subsequent excimer laser ablation. AB - PURPOSE: This study aims to investigate the effect of both flap creation and laser ablation on corneal hysteresis (CH) and corneal resistance factor (CRF), as well as the inward applanation signal amplitude produced by the ocular response analyzer (ORA), immediately following each step of the LASIK procedure using the Intralase femtosecond laser for flap creation. METHODS: A total of 66 eyes of 35 subjects who underwent Intra-LASIK surgery were prospectively enrolled in this study. Changes in the CH, CRF, and amplitude of the first applanation peak (Peak 1) of the infrared signal were measured preoperatively, immediately after flap elevation and repositioning, as well as subsequent to laser ablation in all eyes. Repeated measures analysis of variance (ANOVA) was performed with a post-test of contrast variable profiles to investigate changes following each step of the procedure. RESULTS: The repeated measures ANOVA indicated a significant difference (p < 0.001) among the three time points for CH, CRF, and Peak 1. There was no significant change in CH (p = 0.20) or CRF (p = 0.57) after flap creation, but there was significant decrease in these parameters following laser ablation (p < 0.0001), when compared to values obtained pre-operatively. There was a significant decrease in Peak 1 both after flap creation (p < 0.0001) and after subsequent ablation (p < 0.0001), when compared to pre-operative ORA signal peak amplitudes. CONCLUSION: There is a well documented change in corneal biomechanical properties following a LASIK procedure. This study reveals that this change may be predominantly due to laser ablation. However, flap creation with the Intralase laser does produce a biomechanical consequence consistent with reduction of corneal stiffness, as measured by the reduced amplitude of Peak 1. CH and CRF do not fully characterize this change. PMID- 21657827 TI - In vivo monitoring of VEGF-induced retinal damage in the Kimba mouse model of retinal neovascularization. AB - PURPOSE: To monitor retinal and vascular changes associated with neovascularization, which were generated through photoreceptor-specific overexpression of human vascular endothelial growth factor (hVEGF), in transgenic trVEGF029 (Kimba) mice. MATERIALS AND METHODS: The Spectralis Heidelberg Retina Angiography and Optical Coherence Tomography (HRA+OCT) imaging device was used to track changes in the retina and retinal vasculature of Kimba mouse eyes (n = 32) and control C57Bl/6J mouse eyes (n = 20) at 4, 8, 12, 16, and 20 weeks of age. RESULTS: Retinal vascular leakage, focal dilated vessel, vessel tortuosity, attenuated vessel, venous beading, capillary dropout, retinal non-perfusion, neovascularization, and focal retinal detachment were observed in Kimba mouse eyes. Through track changes, we detected edema in the peripheral part of the retina of 2/32 Kimba mouse eyes examined. The retinae of the Kimba mice were significantly thinner than control mice retinae at all ages of the mice assessed (p < 0.01). CONCLUSIONS: In vivo monitoring of retinal vascular and neural retinal changes in the Kimba mice using the Spectralis HRA+OCT imaging device allowed us to assess and track VEGF-induced damages in great detail and in real time. Real-time monitoring of these changes can be used to study the interplay between VEGF overexpression and other molecular factors and to monitor dynamic retinal changes following therapeutic intervention. PMID- 21657828 TI - Stem Cells are mobilized from the bone marrow into the peripheral circulation in response to retinal pigment epithelium damage--a pathophysiological attempt to induce endogenous regeneration. AB - PURPOSE: Stem cell regeneration of damaged tissue has recently been reported in many different organs. Here, we investigated the mobilization of different stem/progenitor cell (SPC) populations into the peripheral blood (PB), their subsequent homing to the injured retina (IR) and contribution to its regeneration in a retinal pigment epithelium (RPE) damage model induced by sodium iodate (NaIO(3)). METHODS: Mobilization of SPCs was evaluated by flow cytometry. SPCs distribution in IR was assessed using bone marrow (BM)-derived GFP(+)Lin(-) cells transplanted intravenously into NaIO(3)-treated C57Bl/6 mice. The quantity of the chemokine SDF-1 in PB and IR was measured by ELISA and qRT-PCR, respectively. Apoptosis (TUNEL assay), cell proliferation (PCNA analysis) as well as functional retinal activity (electroretinogram) were examined at several time points after NaIO(3) administration. RESULTS: Mobilization of SPCs along with the highest cell proliferation and massive apoptosis within IR were observed on the third day after NaIO(3) administration. Similarly, donor GFP(+)Lin(-) cells were detected in the retina as soon as day 4 after NaIO(3) injection. Plasma levels of SDF-1 did not differ significantly in mice exposed to NaIO(3) compared to healthy controls, however mRNA for SDF-1 was overexpressed locally in IR. Functional retinal recovery was not achieved. CONCLUSION: Our study provides evidence that BM SPCs egress into PB and home to the injured retina, but are not capable of restoring its function. These results indicate that if the range of retinal destruction is profound, endogenous regeneration is ineffective and may ultimately require adjuvant therapeutic transplantation of specific SPCs subpopulations. PMID- 21657830 TI - Upper bonded retainers. AB - OBJECTIVE: To assess the frequency and type of upper bonded retainer failure and to identify possible predisposing factors. MATERIALS AND METHODS: The records of 466 consecutive patients with upper bonded retainers were analyzed retrospectively with respect to retainer failures and failure type as well as timing of failure, differences among operators, and the number of defects of the multibracket appliances (MB) prior to the retention period. RESULTS: A total of 58.2% of all patients experienced retainer failures. The average failure odds were 1.26 failures per retainer. The odds were highest for 3-3 retainers (1.37) and lowest for the 1-1 retainer (0.54). The detachment and total loss rates were significantly influenced by operator experience-both rates were lower for experienced practitioners. Total retainer losses occurred more frequently in case of previous MB defects, while retainer fractures were seen more frequently when the retainer included the canines. CONCLUSIONS: Upper bonded retainer failures are a frequent problem during the retention period (58.2% of patients). Less operator experience correlated with higher failure rates. An increased number of total retainer losses must also be expected with a decreasing number of bonding sites and in cases involving previous MB defects. PMID- 21657829 TI - Impact of orthodontic retainers on periodontal health status assessed by biomarkers in gingival crevicular fluid. AB - OBJECTIVE: To evaluate whether biomarkers of inflammation and periodontal remodeling are differentially expressed in the gingival crevicular fluid (GCF) of patients wearing different types of orthodontic retainers. MATERIALS AND METHODS: Thirty-one adult subjects (17 men and 14 women with an age range of 20 to 35 years) were allocated to three different groups. Group 1 consisted of 10 patients wearing fixed retainers, group 2 included 11 patients using lower removable retainers, and group 3 comprised 10 patients without retainers (control). Periodontal health assessment and GCF collection were carried out at two sites per subject: the lingual side of a central lower incisor and the lingual side of a lower second premolar. Aliquots from diluted GCF were screened for the presence of biomarkers using a microarray technique. RESULTS: Group 1 patients exhibited a higher percentage of sites with visible plaque in the incisor region than the other groups (P = .03); no differences were noted in gingival bleeding and probing depths. The median concentrations (pg/mL) of interferon-gamma and interleukin-10 were significantly higher in the premolar sites of patients in group 2 (P = .01 and P = .04, respectively), whereas the concentration of matrix metalloproteinase-9 was significantly higher at the incisors of patients wearing fixed retainers (P = .02). A significant difference between the two sites was seen only in group 2. CONCLUSIONS: The presence of different orthodontic retainers may promote specific alterations in the GCF composition. With retention periods potentially becoming longer, this finding may be of clinical significance. PMID- 21657831 TI - Intermittent posterior displacement of the rat mandible in the growth period affects the condylar cancellous bone. AB - OBJECTIVE: To examine whether intermittent posterior condylar displacement causes changes in cancellous bone in the mandibular condyle during the growth period. MATERIALS AND METHODS: Sixteen 5-week-old male Wistar rats were divided into experimental and control groups. In the experimental group, an appliance was attached to the maxillary incisors to induce posterior displacement of the condyles in the occluded condition. Untreated rats served as the control group. Animals were sacrificed at 14 days, and the condyles were removed to analyze the three-dimensional cancellous bone structure by microcomputed tomography (micro CT). Serial sagittal paraffin sections of the condyles were used for hematoxylin and eosin staining to investigate histomorphological changes and for tartrate resistant acid phosphatase (TRAP) staining to identify osteoclastic cells. RESULTS: Micro-CT analysis showed that in the experimental group, the bone volume fraction and the degree of anisotropy were significantly decreased compared with those in the control group in the anterior region of the condyle. Moreover, the number of TRAP-positive cells was significantly greater in the same region in the experimental group than in the control group. CONCLUSION: Intermittent posterior displacement of the mandible can cause region-specific changes in the profile and microarchitecture of the condylar cancellous bone. PMID- 21657832 TI - Calcein assay: a high-throughput method to assess P-gp inhibition. AB - Transporter mediated drug-drug interactions (tDDI) mediated by ABCB1 have been shown to be clinically relevant. Hence, the assessment of the ABCB1 tDDI potential early in the drug development process has gained interest. We have evaluated the Calcein assay as a means of assessing the ABCB1 tDDI that is amenable to high throughout and compared it with the monolayer efflux assay. We found the Calcein assay, when performed in K562MDR cells using the protocol originally published more sensitive than digoxin transport inhibition in MDCKII MDR1 cells. Application of the Calcein assay to cell lines containing different amounts of ABCB1, yielded IC(50) values that varied 10-100-fold. The differences observed for IC(50) values for the same compounds were in the following rank order: IC(50, MDCKII-MDR1) >IC(50, K562MDR)>IC(50, hCMEC/D3). Higher IC(50) values were obtained in cells with higher ABCB1 expression. The Calcein assay is a high-throughput alternative to digoxin transport inhibition as it appears to have a comparable selectivity but higher sensitivity than previously published digoxin transport inhibition in MDCKII-MDR1 cells. In addition, it can be performed in a barrier-specific manner highlighting the dependence of ABCB1 IC(50) values on different ABCB1 expression levels. PMID- 21657833 TI - Pharmacokinetic characterization of decursinol derived from Angelica gigas Nakai in rats. AB - Decursinol is a major coumarin derived from the roots of Angelica gigas and has various pharmacological effects against inflammation, angiogenesis, nociceptive pain and Alzheimer's disease. In vitro and in vivo studies were conducted to characterize the metabolism and pharmacokinetics of decursinol. Decursinol exhibited high stability to oxidative and glucuronic metabolism in human and rat liver microsomes. In Caco-2 cell monolayers, decursinol showed high permeability (>14 * 10(-6) cm/s) at all tested concentrations in the absorptive direction, which saturated at 100 MUM. Secretion increased in a concentration-dependent manner, with an efflux ratio of more than 2 at 50 MUM, indicating the participation of an active efflux transporter such as P-glycoprotein, multidrug resistance protein 2 or breast cancer resistance protein. The fraction of decursinol not bound to plasma proteins was 25-26% in the rat and 9-18% in humans. In human plasma, but not rat plasma, the percentage of unbound decursinol was concentration dependent. Following intravenous administration in rats, non linear elimination of decursinol was observed with K(m) and V(max) values of 2.1 MUg/mL and 2.5 mg.h(-1).kg(-1), respectively. Following oral administration, decursinol exhibited high oral bioavailability (>45%) and rapid absorption (T(max), 0.4-0.9 h) over the dose range studied. In addition, dose-dependent absorption and elimination were observed at 20 mg/kg. PMID- 21657834 TI - General parenting, childhood overweight and obesity-inducing behaviors: a review. AB - Despite emerging efforts to investigate the influence parents have on their children's weight status and related dietary and activity behaviors, reviews regarding the role of general parenting are lacking. We performed a systematic review regarding the relationship between general parenting and these weight related outcomes to guide observational research. In total, 36 studies were included. Discrepancies across studies were found, which may be explained by differences in conceptualization of parenting constructs. Overall, however, results suggest that children raised in authoritative homes ate more healthy, were more physically active and had lower BMI levels, compared to children who were raised with other styles (authoritarian, permissive/indulgent, uninvolved/neglectful). Findings of some moderation studies indicate that general parenting has a differential impact on children's weight-related outcomes, depending on child and parental characteristics. These findings underline the importance of acknowledging interactions between general parenting and both child and parent characteristics, as well as behavior-specific parenting practices. PMID- 21657835 TI - Intracranial pressure changes following traumatic brain injury in rats: lack of significant change in the absence of mass lesions or hypoxia. AB - Traumatic brain injury (TBI) often causes raised intracranial pressure (ICP), with >50% of all TBI- related deaths being associated with this increase in ICP. To date, there is no effective pharmacological treatment for TBI, partly because widely used animal models of TBI may not replicate many of the pathophysiological responses observed in humans, and particularly the ICP response. Generally, rodents are the animal of choice in neurotrauma research, and edema formation has been demonstrated in rat models; however, few studies in rats have specifically explored the effects of TBI on ICP. The aim of the current study was to investigate the ICP response of rats in two different, focal and diffuse, injury models of TBI. Adult male Sprague-Dawley rats were subjected to brain trauma by either lateral fluid percussion or impact-acceleration induced injury, in the presence or absence of secondary hypoxia. ICP, mean arterial blood pressure (MABP), and cerebral perfusion pressure (CPP) were monitored for 4 h after TBI. TBI alone or coupled with hypoxia did not result in any significant increase of ICP in rats unless there was an intracranial hemorrhage. At all other times, changes in CPP were the result of changes in MABP and not ICP. Our results suggest that rats may be able to compensate for the intracranial expansion associated with cerebral edema after TBI, and that they only develop a consistent post-traumatic increase in ICP in the presence of a mass lesion. Therefore, they are an inappropriate model for the investigation of ICP changes after TBI, and for the development of therapies targeting ICP. PMID- 21657836 TI - Cancer biomarkers, companion diagnostics and personalized oncology. PMID- 21657837 TI - The need for personalized therapy and companion diagnostics in prostate cancer. PMID- 21657838 TI - Prostate transglutaminase: a unique transglutaminase and its role in prostate cancer. AB - Prostate transglutaminase-4, also known as TGM4 or transglutaminase P, belongs to the prostate transglutaminase protein family, but is almost uniquely distributed in the prostate gland. Recent years have seen an expansion of interest in this enzyme, which is intriguingly expressed in prostate tissues and prostate cancer. In recent studies, the molecule has been found to have a diverse impact on prostate cancer cell growth, migration and invasiveness, and to be involved in the tumor-endothelial interaction and epithelial-mesenchymal transition, and has a wide interaction with other molecular complexes implicating it as a possible biomarker of aggressive versus nonaggressive cancer, as well as a therapeutic factor. This article reviews the recent progress and discusses the controversies and future directions in this exciting area of prostate cancer research. PMID- 21657839 TI - Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. AB - DNA sequence analysis has become a significant laboratory test in oncology, permitting treatment to become increasingly personalized for both solid tumors and hematologic malignancies. Traditional approaches to sequence analysis, including Sanger sequencing, pyrosequencing and allele-specific PCR, are now widely used to guide therapy for patients diagnosed with lung and colorectal cancer as well as for melanoma, sarcomas (e.g., gastrointestinal stromal tumors) and subtypes of leukemia and lymphoma. Traditional sequence analysis has been limited in bandwidth and throughput and as a result, has been focused exclusively on testing the most common aberrations in key genes or fully sequencing single genes. The massively parallel or next-generation sequencing (NGS) approach to DNA analysis holds a number of potential advantages over the traditional methods, including the ability to fully sequence large numbers of genes (hundreds to thousands) in a single test. Furthermore, NGS can simultaneously detect deletions, insertions, copy number alterations, translocations and exome-wide base substitutions (including known hot-spot mutations) in all known cancer related genes. However, significant challenges, particularly with respect to demands on expertise and infrastructure, will have to be overcome to translate NGS to the bedside of the cancer patient. Extensive computational expertise is required to bring NGS into clinical context, and a deep knowledge of cancer medicine and cancer biology will be required to generate truly useful, so-called 'clinically actionable' reports for clinicians. While NGS is on the cusp of being launched as a clinical test, it may be expected that the near future will continue to bring major advances in the technology that will lower the overall cost, speed up the turnaround time, increase the breadth of genome sequencing, and detect epigenetic markers and other important genomic parameters, while becoming applicable to smaller and smaller specimens, including circulating tumor cells and circulating free DNA in plasma. PMID- 21657840 TI - Update on HER2 testing for breast and upper gastrointestinal tract cancers. AB - With the regulatory approvals in Europe and the USA of trastuzumab-based anti HER2 targeted therapy for upper gastrointestinal cancers in 2010, HER2 testing has now become universal for newly diagnosed cases of both breast cancer and adenocarcinomas of esophagus, stomach and gastroesophageal origin. In the 12 years or more since the approval of trastuzumab for breast cancer, general refinements in approaches to HER2 testing, including a greater understanding of the implications of preanalytic factors impacting the test results and the application of standardization of reporting of HER2 test results, have taken place. There has also been continuing development in breast cancer with the introduction of new HER2 tests, including non-FISH tests, dimerization assays, phosphorylated HER2 receptor tests, mRNA-based tests, HER2 gene sequencing tests and the application of HER2 testing to circulating tumor cells. Most recently, the introduction of HER2 testing for upper gastrointentinal malignancies has emphasized the need for performing and interpreting slide-based assays in a manner unique to these specimens and not to apply the breast cancer testing protocols to esophageal and gastric adenocarcinomas. PMID- 21657841 TI - Biomarker-based selection of therapy for colorectal cancer. AB - Colorectal cancer (CRC) has been re-classified based on molecular analyses of various genes and proteins capable of separating morphologic types of tumors into molecular categories. The diagnosis and management of CRC has evolved with the discovery and validation of a wide variety of biomarkers designed to facilitate a personalized approach for the treatment of the disease. In addition, a number of new prognostic and predictive individual genes and proteins have been discovered that are designed to reflect the sensitivity and/or resistance of CRC to existing therapies. Multigene predictors have also been developed to predict the risk of relapse for intermediate-stage CRC after completion of surgical resection. Finally, a number of biomarkers have been proposed as specific predictors of chemotherapy and radiotherapy response and, in some instances, drug toxicity. In this article, a series of novel biomarkers are considered and compared with standard-of-care markers for their potential use as pharmacogenomic and pharmacogenetic predictors of disease outcome. PMID- 21657842 TI - Melanoma update: diagnostic and prognostic factors that can effectively shape and personalize management. AB - Routine light microscopy remains a powerful tool to diagnose, stage and prognose melanoma. Although it is very economical and efficient, it requires a significant level of expertise and, in difficult cases the final diagnosis is affected by subjective interpretation. Fortunately, new insights into the genomic aberrations characteristic of melanoma, coupled with ancillary studies, are further refining evaluation and management allowing for more confident diagnosis, more accurate staging and the selection of targeted therapy. In this article, we review the standard of care and new updates including four probe FISH, the 2009 American Joint Commission on Cancer staging of melanoma and mutant testing of melanoma, which will be crucial for targeted therapy of metastatic melanoma. PMID- 21657843 TI - Predictive value of anti-annexin V autoantibodies in the follow-up of vaso occlusive crisis associated with sickle cell disease. PMID- 21657844 TI - Beyond hematopoietic targets: the role of erythropoietin in diabetic wound healing. PMID- 21657848 TI - Nano-enabled biomarker discovery and detection. AB - The completion of the human genome project has led to intensified efforts toward comprehensive analysis of proteomes. New possibilities exist for efficient proteomic technologies. However, primary attention is given to the discovery of new predictive biomarker patterns. Understanding proteomes and, in particular, protein-mediated interactions underlying their complexity and diversity, is critical for the development of more reliable and robust diagnostic platforms, which are anticipated to enable personalized medicine. Of immediate relevance in this respect are those approaches that capitalize on the application of nanotechnology, which is seen as a powerful tool for the diagnosis of early-stage diseases. Here we highlight the current state of the field exemplified by recent nano-enabled technologies for biomarker discovery. PMID- 21657847 TI - Elevated plasma myeloperoxidase levels in relation to circulating inflammatory markers in coronary artery disease. AB - AIMS: Elevation of the leukocyte enzyme myeloperoxidase (MPO) in stable coronary artery disease (CAD) is controversial and its relationship with oxidized low density lipoprotein (ox-LDL) and nitrite/nitrate (NOx) levels in CAD patients has not been evaluated. Therefore, we sought to evaluate these relationships. MATERIALS & METHODS: This study included 50 stable CAD patients, 50 unstable CAD patients and 50 control subjects. Plasma MPO and ox-LDL levels were determined using enzyme immunoassay. Plasma NOx and other risk factors were also measured in the patients. RESULTS: Plasma MPO levels were higher in unstable CAD patients (71.2 +/- 19.6 ng/ml) than in stable CAD patients (34.5 +/- 6.8 ng/ml) and control subjects (23.0 +/- 3.6 ng/ml) (p < 0.001). Furthermore, plasma MPO was positively correlated with ox-LDL and negatively correlated with NOx levels (p < 0.05). CONCLUSION: Plasma MPO levels were elevated in CAD patients and its relation to CAD may be through the oxidation of LDL and reduction of NO levels. PMID- 21657849 TI - Developing a nonendoscopic screening test for Barrett's esophagus. AB - Barrett's esophagus (BE) arises as a complication of chronic gastro-esophageal reflux disease and is the precursor lesion for esophageal adenocarcinoma. The prevalence of esophageal adenocarcinoma has been increasing in Western countries and the overall prognosis from this cancer remains dismal. Surveillance for BE is highly controversial since although early cancer detection through surveillance programs benefits individuals, surveillance has not been proven to reduce population mortality from the disease. One factor contributing to this apparent paradox is that an estimated >80% cases of BE are undiagnosed and, therefore, do not have the benefit of surveillance. Some form of screening modality is required to achieve more comprehensive detection of BE, which in turn, may lead to early detection of cancerous lesions and early intervention in order to reduce progression to invasive and symptomatic cancer. The advent of endoscopic therapy makes this paradigm attractive. A number of methods could be considered for screening. These include a nonendoscopic sampling method using a Cytosponge that needs to be coupled with a biomarker to obtain required levels of sensitivity and specificity. For screening to be recommended consideration needs to be given to the point of delivery, cost and acceptability to patients. PMID- 21657852 TI - Continuing professional development for interprofessional teams supporting patients in healthcare decision making. AB - Healthcare professionals and organizations, policy makers, and the public are calling for safe and effective care that is centered on patients' needs, values, and preferences. The goals of interprofessional shared decision making and decision support are to help patients and professionals agree on choices that are effective, health promoting, realistic, and consonant with patients' and professionals' values and preferences. This requires collaboration among professionals and with patients and their family caregivers. Continuing professional development is urgently needed to help healthcare professionals acquire the knowledge, skills, and attitudes necessary to create and sustain a culture of collaboration. We describe a model that can be used to design, implement, and evaluate continuing education curricula in interprofessional shared decision making and decision support. This model aligns curricular goals, objectives, educational strategies, and evaluation instruments and strategies with desired learning and organizational outcomes. Educational leaders and researchers can institutionalize such curricula by linking them with quality improvement and patient safety initiatives. PMID- 21657854 TI - General practitioner-pharmacist interactions in professional pharmacy services. AB - Australian community pharmacies offer a range of professional pharmacy services (PPS) which include Home Medicines Review (HMR) and the Diabetes Medication Assistance Service (DMAS). The extent of interaction and collaboration between general practitioners (GPs) and pharmacists in the context of these services is unknown. Therefore, the aim of this study was to investigate (1) the nature and extent of interactions between GPs and community pharmacists and; (2) the factors that influence these interactions in the context of PPS. Individual semi structured face-to-face and telephone interviews were conducted with a purposive sample of 15 GPs and 15 pharmacists in rural and metropolitan areas of New South Wales, Australia. The results indicated that involvement in PPS resulted in a perceived increase in the level of interactions between the pharmacist and GP. Factors found which may influence collaborative behaviour in PPS include interactional, practitioner and environmental determinants. These factors are in line with what has previously been reported however, facilitators of collaboration in the primary care, PPS context included additional environmental factors such as the presence of rules and protocols, interprofessional continuing education and the availability of adequate remuneration. Attention to these environmental factors as well as the more established interactional and practitioner determinants will improve collaboration in PPS. PMID- 21657851 TI - Prevention of both neutrophil and monocyte recruitment promotes recovery after spinal cord injury. AB - Strategies that block infiltration of leukocytes into the injured spinal cord improve sparing of white matter and neurological recovery. In this article, we examine the dependency of recovery on hematogenous depletion of neutrophils and monocytes. Mice were depleted of neutrophils or monocytes by systemic administration of anti-Ly6G or clodronate-liposomes. A third group was depleted of both subsets. Neurological improvement, based on a battery of tests of performance, and white matter sparing, occurred only in animals depleted of both neutrophils and monocytes. We also attempted to define the nature of the environment that was favorable to recovery. Hemeoxygenase-1 and malondialdehyde, markers of oxidative stress and lipid peroxidation, respectively, were reduced to similar levels in animals depleted of both neutrophils and monocytes, or only monocytes, but remained elevated in the group only depleted of neutrophils. Matrix metalloproteinase-9, a protease involved in early damage, was most strongly reduced in animals depleted of both leukocyte subsets. Finally, disruption of the blood-spinal cord barrier and abnormal nonheme iron accumulation were reduced only in animals depleted of both neutrophils and monocytes. Together, these findings indicate cooperation between neutrophils and monocytes in mediating early pathogenesis in the contused spinal cord and defining long-term neurological recovery. PMID- 21657855 TI - Engaging with the global challenge. PMID- 21657857 TI - Urine drug screens: a double-edged sword. PMID- 21657858 TI - Opioid consumption in a tertiary hospital setting over an 8-year timeframe--a potential resource for tracking trends in pain management. AB - Opioid consumption by countries and health care organizations can be regarded as a marker of the quality of pain management. However, there are only limited data on opioid consumption in hospital settings. Objective and reliable data can be obtained by monitoring direct opioid consumption within a hospital, and then that data can be analyzed for identifying trends and directions to assist in guiding improved pain treatment within the hospital. This article tracks opioid consumption in a tertiary hospital over an 8-year period and by comparing the data to the consumption during the previous decade, it highlights trends and tendencies in the use of opioids as a potential indicator of pain management within this facility. PMID- 21657859 TI - Role of immediate-release morphine (MIR) in the treatment of predictable pain in radiotherapy. AB - Radiotherapy is crucial in the management of cancer patients in both the curative and palliative settings. However, patients often report pain both during positioning for, and execution of, radiotherapy and this may be a reason for interrupting the radiotherapy session. This observation is common even if the patient is undergoing baseline drug therapy for cancer pain. Recent data suggest that orally administrated immediate-release morphine (MIR) is able to reduce pain in patients with predictable pain. The authors tested a rescue dose of MIR 10 or 20 mg, 20 to 60 minutes before radiotherapy, to verify the effectiveness of MIR in this setting and also to assess the patient's ability to receive the full course of radiotherapy. One hundred forty consecutive patients were evaluated during radiotherapy treatment and visual analogue scale (VAS) and positioning VAS scores were assessed. All patients completed the course of scheduled radiotherapy and pain was well controlled, despite the fact that previous pharmacological treatment had not been able to completely control chronic cancer pain. These data strongly suggest a role for MIR pretreatment in patients with pain due to positioning during radiotherapy. PMID- 21657860 TI - Computational opioid prescribing: a novel application of clinical pharmacokinetics. AB - We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist prescribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety. PMID- 21657861 TI - Methylnaltrexone for opioid-induced constipation in patients with advanced illness: a 3-month open-label treatment extension study. AB - Methylnaltrexone is a methylated form of the mu-opioid antagonist naltrexone that blocks peripheral effects of opioids without affecting centrally mediated analgesia. The authors conducted a 3-month open-label extension trial of methylnaltrexone in patients with advanced illness and opioid-induced constipation (OIC). Following completion of a 2-week double-blind (DB) trial, 82 patients with OIC who did not respond to laxatives received subcutaneous (SC) methylnaltrexone as needed for up to 3 months. Patients received 0.15 mg/kg as a first dose, adjusted to 0.3 mg/kg or 0.075 mg/kg as needed (maximum of one dose per 24 hours). Mean laxation response (rescue-free bowel movement within 4 hours) rates (DB phase, months 1, 2, 3 open-label phase) were 45.3%, 45.5%, 57.7%, and 57.3%, respectively, for patients treated with DB methylnaltrexone and 10.8%, 48.3%, 47.6%, and 52.1%, respectively, for patients treated with DB placebo. Median time to laxation among responders was 45 minutes (range 0-4 hours) for all doses. Approximately 50% of patients reported improvement in constipation distress. Patient and investigator global clinical impression of change scores also improved. There were minimal changes in pain scores and opioid withdrawal symptoms. Adverse events included abdominal pain and nausea, mostly mild or moderate in severity. SC methylnaltrexone administered PRN (as needed) for up to 3 months continued to rapidly induce laxation in advanced illness patients with OIC. PMID- 21657862 TI - Chronic pain and surgery: a review of new insights from sensory testing. AB - Chronic pain is increasingly recognized as an undesirable outcome after surgery. Predicting risk of postoperative chronic pain, as well as chronic pain prevention or treatment, requires understanding of the processes underlying its development. Quantitative sensory testing research over the last decade has made it possible to start understanding the alterations in central pain processing associated with chronic pain and its development. Chronic pain syndromes are typically characterized by a pronociceptive state of pain processing, e.g., generalized hyperalgesia as a sign of supraspinal central sensitization and poor inhibitory or even facilitatory descending modulation. In the perioperative context, development and progression of chronic pain are accompanied by signs congruent with a shift towards a pronociceptive state. Preoperatively, hyperalgesia and poor descending inhibitory modulation appear to increase the risk of subsequent chronic pain. Postoperatively, abnormal persistence and spread of hyperalgesia, compatible with rostral neuraxial spread of central sensitization, are increasingly linked to the development and progression of chronic pain. These findings, which need further confirmation, suggest that perioperative quantitative sensory testing of pain sensitivity and pain modulation has the potential to become a valuable clinical tool for assessing risk of chronic pain development and for managing its prevention and treatment. PMID- 21657863 TI - Errors in managing postsurgical pediatric pain in Mexico. AB - Postoperative pain is a subjective symptom that has been extensively studied in adults, but only minimally in children. In children, use of low analgesic doses and failure to document the pain and its management are common concerns. In newborns and infants pain is difficult to interpret. This was a double-blind, prospective, multicenter observational study conducted in four public Mexican hospitals to identify analgesic use. One hundred subjects were enrolled at each institution and monitored for 24 to 48 hours following surgery. Data were collected on 152 girls and 248 boys ranging in age from newborns to 14 years. Nearly 300 (290) underwent major procedures; 110 had short stay surgery. The most common analgesics used were paracetamol and dipyrone at low doses. Less frequently ibuprofen or another anti-inflammatory was used. Many children received no analgesic, including 30 newborns, and others received only one or two analgesic doses. Fifteen burn patients received ketorolac. The occurrence and characteristics of the pain were poorly documented in all four hospitals. Postoperative pain causes suffering and can prolong hospital stays. Graphic pain intensity scales exist to evaluate pain, but use of them was not documented in medial records. Nurses and doctors in training did not have the skills needed to evaluate pain. The study revealed errors in pain management and fear among staff in using high doses of common analgesics. The study results document patterns of care in most Mexican hospitals today and indicate a need for pain management training for Mexican doctors and nurses. PMID- 21657864 TI - American Pain Foundation Position statement on access to pain care. PMID- 21657866 TI - A tale of two mothers. AB - This narrative describes the experience of the author's mother with pancreatic cancer from diagnosis to death. The author lives in the United States and his mother lived in India. Decisions about the type of care to seek, learning about palliative care, and the family's experience of seeking care at Pallium India are described. As a young Hindu boy in India, the author met Mother Theresa. He describes how her message of compassion to the young school boy became more clear and meaningful only after the loss of his mother when he appreciated the similar compassion shown by Mother Theresa and the staff of Pallium India. PMID- 21657865 TI - About the lecture by a physician. AB - As I had been lectured to by a physician about the dangers of morphine use in my child, I agonized over allowing its administration, which only prolonged my son's suffering. It is one of my biggest regrets upon looking back on Austin's time here on earth. A lack of education on the positive benefits of morphine actually increased the time of his suffering. It's still hard to digest. When Austin received morphine he did not stop breathing, die, or lose his personality as I had feared. Instead, he was able to regain some of the weight he had lost during his bouts with dystonia and spasticity and could enjoy life within reason. He could even smile again, something that I had not seen in a full month of his suffering in the hospital. He died at age 14, but not before enduring other periods of time dealing with horrific spasms. Austin's pain became unmanageable in February 2005 and I had to make the painful decision to withdraw nutrition and hydration in order to end his horrible suffering, as there was no cure for the disease he had and no end in sight for the pain. PMID- 21657867 TI - Venu's Story. AB - This is the story of a man in India who is among millions denied access to pain relief all over the developing world. He was in agonizing pain and pleaded to a doctor for pain relief, adding that he had not slept for several days. Not only was pain relief denied to him, but he was also insulted by a doctor with the words, "What do you want me to do? Sing a lullaby and rock you to sleep?" Even after a year, the patient says that he cannot help being angry with that doctor and cannot help feeling like wanting to stab him with a knife. We as health care professionals can add insult to injury by our behavior. We can be cruel not only by denying pain relief but also by refusing to feel and empathize. Why do health care professionals behave like that? Is it just callousness or is it a sense of helplessness from not knowing what to do when faced with pain and suffering? PMID- 21657870 TI - Postherpetic neuralgia. AB - Questions from patients about analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self advocates. The topic addressed in this issue is postherpetic neuralgia, symptoms, risk factors, and treatment. PMID- 21657888 TI - Higher metabolic risk with National Institutes of Health versus Rotterdam diagnostic criteria for polycystic ovarian syndrome in Turkish women. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disease with well established metabolic abnormalities in women of reproductive age. There are various diagnostic criteria to define and establish PCOS. However, data conflict regarding the optimal diagnostic criteria for PCOS and its metabolic consequences. We have evaluated the clinical, endocrine, and metabolic features between main PCOS phenotypes according to different diagnostic criteria. METHODS: In this prospective, case-control study, 175 consecutive women with PCOS, 41 ovulatory women with idiopathic hirsutism, and 109 healthy, nonhirsute, ovulatory controls were enrolled. The following diagnostic criteria were assessed: Hirsutism; ovulatory function; ovarian sonography; gonadotropin, testosterone, dehydroepiandrosterone (DHEA), 17-hydroxyprogesterone, fasting insulin, and lipid levels; oral glucose tolerance test; homeostasis model assessment for insulin resistance (HOMA-IR); body mass index (BMI); waist circumference; and the presence of metabolic syndrome. RESULTS: Of the 175 women meeting the Rotterdam criteria for PCOS, 121 (69%) had both androgen excess and ovulatory dysfunction, thus also meeting the National Institutes of Health (NIH) criteria. The other 54 (31%) had either androgen excess or ovulatory dysfunction. Women meeting the NIH criteria had the largest mean BMI, waist circumference, and HOMA-IR score; the highest mean testosterone, DHEA, triglyceride, and fasting insulin levels; the lowest mean progesterone level; and the greatest prevalence of insulin resistance (HOMA-IR score >3) among the groups. CONCLUSIONS: The NIH criteria identify women at high risk for insulin resistance and metabolic syndrome. The Rotterdam criteria include women who have less severe metabolic implications. PMID- 21657889 TI - An exploration of the attitudes and experiences of mothers in the United Kingdom who chose to breastfeed exclusively for 6 months postpartum. AB - BACKGROUND: Levels of exclusive breastfeeding are negligible in the United Kingdom despite World Health Organization recommendations to practice exclusive breastfeeding for the first 6 months postpartum. Although numerous studies have explored the reasons behind low levels of breastfeeding, few have examined the behaviors of women who do breastfeed successfully. However, understanding the influences upon the decision to breastfeed exclusively is important in supporting women to continue breastfeeding. METHODS: In the current study, 33 women with an infant 6-12 months old who exclusively breastfed for the first 6 months postpartum took part in an interview to explore their motivation and experiences while breastfeeding. The interview explored issues such as sources of support, difficulties, and familial and peer behavior. RESULTS: Mothers reported high levels of confidence and determination in their decision despite difficulties in reaching their goal and discussed a range of techniques they adopted to overcome issues faced. CONCLUSIONS: Ingrained and strong beliefs that their choice of feeding method was the normal and healthiest way to feed an infant enabled mothers to overcome problems and continue breastfeeding. PMID- 21657890 TI - Integrating routine lactation consultant support into a pediatric practice. AB - BACKGROUND: Although research shows that healthcare professionals' support improves breastfeeding duration, many physicians do not believe they have adequate time to address breastfeeding concerns during office visits. This study evaluated the impact of a pediatric practice's postnatal lactation consultant intervention. To improve breastfeeding support, the study practice changed policy and began using a lactation consultant overseen by a physician, to conduct the initial postpartum office visit for all breastfeeding infants. METHODS: A retrospective chart review was performed on consecutive newborns before (n = 166) and after (n = 184) implementation of the program. Feeding method was assessed at each well child visit during the infant's first 9 months. chi2 and logistic growth curve analyses were used to test the association between implementation status and non-formula feeding (NFF). RESULTS: Mothers and infants in 2007 and 2009 were similar with regard to type of insurance, parity, gestational age, multiple births, and cesarean sections. Overall, NFF improved after program implementation (odds ratio = 1.12, 95% confidence interval 1.02-1.23). In 2009, NFF rates at 2 months, 4 months, 6 months, and 9 months were greater than 2007 rates by 10%, 15%, 11%, and 9%, respectively. Logistic growth curve analysis indicated the difference across these time points was significant between 2007 and 2009. CONCLUSION: A routine post-discharge outpatient lactation visit coordinated within a primary care practice improved breastfeeding initiation and intensity. This effect was sustained for 9 months. PMID- 21657936 TI - Listeria monocytogenes serotypes 1/2c and 3c possess inlH. AB - To examine the serotype specificity of inlH, which encodes the virulence associated surface protein InlH related to the intracellular survival of Listeria monocytogenes in mice, the presence of inlH in 337 L. monocytogenes strains, representing 11 different serotypes, was studied. A total of 106 strains representing 3 serotypes and 14 pulsed-field gel electrophoresis (PFGE) types were positive for inlH by polymerase chain reaction. inlH was present in all 99 serotype 1/2c and 3 serotype 3c strains. Moreover, 4 out of 129 (3%) serotype 1/2a strains carried inlH. All 106 strains representing serotypes 1/2b, 3a, 3b, 4a, 4b, 4c, 4d, and 7 and 125 out of 129 (97%) serotype 1/2a strains were inlH negative. The coding sequences of the inlH genes of eight L. monocytogenes strains representing three serotypes and five PFGE types were identical. These results suggest that inlH is specifically present in serotype 1/2c, 3c, and a small fraction of 1/2a L. monocytogenes strains and exists as a single allele. PMID- 21657937 TI - Outbreak of Shiga-toxigenic Escherichia coli O157:H7 infections associated with rodeo attendance, Utah and Idaho, 2009. AB - OBJECTIVES: In summer 2009, the Utah Department of Health investigated an outbreak of Shiga-toxigenic Escherichia coli (STEC) O157:H7 (O157) illness associated with attendance at multiple rodeos. MATERIALS AND METHODS: Patients were interviewed regarding exposures during the week before illness onset. A ground beef traceback investigation was performed. Ground beef samples from patient homes and a grocery store were tested for STEC O157. Rodeo managers were interviewed regarding food vendors present and cattle used at the rodeos. Environmental samples were collected from rodeo grounds. Two-enzyme pulsed-field gel electrophoresis (PFGE) and multiple-locus variable-number tandem repeat analysis (MLVA) were performed on isolates. RESULTS: Fourteen patients with primary STEC O157 illness were reported in this outbreak. Isolates from all patients were indistinguishable by PFGE. Isolates from nine patients had identical MLVA patterns (main outbreak strain), and five had minor differences. Thirteen (93%) patients reported ground beef consumption during the week before illness onset. Results of the ground beef traceback investigation and ground beef sampling were negative. Of 12 primary patients asked specifically about rodeo attendance, all reported having attended a rodeo during the week before illness onset; four rodeos were mentioned. All four rodeos had used bulls from the same cattle supplier. An isolate of STEC O157 identified from a dirt sample collected from the bullpens of one of the attended rodeos was indistinguishable by PFGE and MLVA from the main outbreak strain. DISCUSSION: Recommendations were provided to rodeo management to keep livestock and manure separate from rodeo attendees. This is the first reported STEC O157 outbreak associated with attendance at multiple rodeos. Public health officials should be aware of the potential for rodeo associated STEC illness. PMID- 21657938 TI - Gilthead seabream (Sparus aurata) as carriers of SHV-12 and TEM-52 extended spectrum beta-lactamases-containing Escherichia coli isolates. AB - In recent years, bacterial resistance to beta-lactam antibiotics has risen dramatically in Escherichia coli isolated from animals that could pass through the food chain to humans. One hundred eighteen fecal samples of Sparus aurata were tested for extended-spectrum beta-lactamase (ESBL)-containing E. coli recovery. Susceptibility to 16 antimicrobial agents was performed by disk diffusion. ESBL-phenotypic detection was carried out by double-disk test, and the presence of genes encoding TEM, OXA, SHV, and CTX-M type beta-lactamases was studied by polymerase chain reaction and sequencing. The detection of other antimicrobial resistance mechanisms and phylogenetic groups was also performed in recovered isolates as well as their clonal diversity by pulsed-field gel electrophoresis. Five of the 118 fecal samples harbored ESBL-positive E. coli isolates (4.2%), and one isolate per sample was completely characterized. These five ESBL-positive E. coli isolates contained the bla(TEM-52) or bla(SHV-12) genes, as well as a variety of other resistance genes (cmlA, tetA, aadA, sul1, sul2, and sul3). Four isolates harbored class 1 integrons with the following gene cassettes in their variable region: dfrA1 + aadA1 (one isolate) and sat + psp + aadA2 (three isolates). Four unrelated pulsed-field gel electrophoresis patterns were identified among the five ESBL-positive isolates, and they were ascribed to phylogroups A and B1. The intestinal tract of S. aurata might constitute a reservoir of ESBL-producing E. coli isolates. PMID- 21657939 TI - Prospective and randomized comparison of two techniques of staple line reinforcement during open Roux-en-Y gastric bypass: oversewing and bioabsorbable Seamguard(r). AB - AIMS: Surgical staple line dehiscence usually leads to severe complications. Several techniques and materials have been used to reinforce this stapling and thus reduce the related complications. The objective was to compare safety of two types of anastomotic reinforcement in open gastric bypass. METHODS: A prospective, randomized study comparing an extraluminal suture, fibrin glue, and a nonpermanent buttressing material, Seamguard(r), for staple line reinforcement. Fibrin glue was excluded from the study and analysis after two leaks, requiring surgical reintervention, antibiotic therapy, and prolonged patient hospitalization. RESULTS: Twenty patients were assigned to the suture and Seamguard reinforcement groups. The groups were similar in terms of preoperative characteristics. No staple line dehiscence occurred in the two groups, whereas two cases of dehiscence occurred in the fibrin glue group. No mortality occurred and surgical time was statistically similar for both techniques. Seamguard made the surgery more expensive. CONCLUSION: In our service, staple line reinforcement in open bariatric surgery with oversewing or Seamguard was considered to be safe. Seamguard application was considered to be easier than oversewing, but more expensive. PMID- 21657940 TI - Endoscopic submucosal dissection for rectal neuroendocrine (carcinoid) tumors. AB - PURPOSE: Rectal neuroendocrine (carcinoid) tumors smaller than 1 cm without lymph node metastasis and confined within the submucosal layer (stage T1aN0) can be treated using endoscopic resection. The present study was aimed to assess the safety and efficacy of endoscopic submucosal dissection (ESD) for T1aN0 carcinoid tumors. PATIENTS AND METHODS: A total of 35 consecutive patients with a T1aN0 rectal carcinoid tumor were enrolled between March 2007 and December 2009. The study evaluated the histologically complete resection rate, procedure time, complications, and short-term oncological outcomes. RESULTS: The mean patient age was 49.0 years (range, 32-74 years), and there were 25 men and 10 women. The mean procedure time was 35.6 minutes (range, 7-82 minutes). All neoplasms were removed in one piece, and the histologically complete resection rate was 74.3% (26 cases including 5 cases showing no residual tumor). No post-ESD bleeding was observed. Abdominal computed tomography scans showed a perforation in 1 patient only, but that perforation was not associated with any peritonitis symptoms, and the patient was discharged on postprocedure day 3. One patient underwent radical surgery after ESD because of angiolymphatic invasion and positive resection margins, and the final pathology revealed no residual tumor or lymph node metastasis. No patient showed local recurrence or distant metastasis during a median follow-up of 25 months (range, 12-43 months). CONCLUSIONS: ESD is feasible and safe for treating T1aN0 rectal carcinoid tumors. Further studies are required to accurately determine long-term oncological outcomes. PMID- 21657941 TI - Pericardial cysts: an analysis of 12 cases. AB - BACKGROUND: Pericardial cysts are usually asymtomatic, benign, congenital mediastinal lesions but may also be acquired after cardiothoracic surgery. The purpose of the study was to evaluate surgical approach and results of our experience with pericardial cysts. PATIENTS AND METHODS: A total of 12 patients who had undergone surgical treatment for pericardial cyst between February 1999 and August 2010 were retrospectively evaluated. All patients were analyzed according to the symptoms, method for the diagnosis, cyst location, management, and outcomes. RESULTS: The mean age was 50.4+/-17 years (range, 23-68 years) with a female-to-male ratio of 8:4. Pericardial cyst were located in the right hemithorax in 8 (67%) patients and left hemithorax in 4 (33%) patients. The cysts were resected by thoracotomy in 4 (33%) patients and by video-assisted thoracic surgery in 8 (67%) patients. There was an excellent long-term follow-up with no morbidity or mortality. CONCLUSION: Videothoracoscopic surgical removal of pericardial cysts is an excellent surgical intervention without serious morbidity and mortality. PMID- 21657942 TI - Continuous ambulatory peritoneal dialysis after intra-abdominally placed synthetic mesh for ventral hernia repair. AB - BACKGROUND: We present a unique experience with a patient who had undergone continuous ambulatory peritoneal dialysis (CAPD) after laparoscopic repair of ventral incisional hernia (LRVIH) with an expanded polytetrafluoroethylene (e PTFE) mesh (DualMesh((r)); WL Gore) and who later suffered from multiple episodes of CAPD-related peritonitis without any signs of mesh infection. METHODS: A 48 year-old man with an open abdominal aortic reconstruction in 1994 for occlusive arterial disease presented with an incisional ventral hernia. He underwent LRVIH using an e-PTFE mesh of 30*20 cm. RESULTS: Postoperatively, he developed renal failure. For various reasons, the only therapeutic option was CAPD. A CAPD catheter was implanted via laparoscopy, taking care not to compromise the mesh that was completely covered with neoperitoneum. After 3 months of uneventful CAPD, he developed a bacterial peritonitis. Antibiotic treatment failed and the CAPD-catheter was removed. The mesh was left in place and the patient recovered. Later on another CAPD-catheter was implanted via laparoscopy and used for 10 months. Again he developed peritonitis from which he recovered after catheter removal. Mesh was left in place and remained uninfected, probably protected from intra-abdominal bacteria by the neoperitoneum. CONCLUSIONS: The risk of secondary infection of an intra-abdominal mesh seems to diminish largely after neoperitonealization of the mesh. CAPD seems possible in a patient with an intra abdominal mesh when it is covered with neoperitoneum. PMID- 21657943 TI - Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution. AB - The elucidation of the molecular basis of familial hypercholesterolemia (FH) by Brown and Goldstein about three decades ago provided the most convincing evidence for a causative relationship between a high plasma level of low-density lipoprotein (LDL) cholesterol and the conditions of atherosclerosis and premature atherosclerotic cardiovascular disease. Today, with a prevalence of about one in 500 individuals, FH remains the most common monogenic disorder of lipoprotein metabolism, and is mainly due to mutations in the LDL receptor (LDLR) gene that lead to the plasma accumulation of cholesterol ester-laden LDL particles. Another form of autosomal dominant hypercholesterolemia, familial defective apolipoprotein B-100, a genocopy of FH caused by defects in the APOB gene that lead to decreased clearance of LDL, is now established as a significant cause of coronary heart disease. Yet another form, due to mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, has been recently identified that similarly causes decreased clearance of LDL by novel mechanisms also involving the hepatic LDLR endocytotic pathway. Recent advances in molecular genotyping technology have yielded a staggering amount of detail about human genetic diversity at the single nucleotide level in both private and public databases including the International HapMap Consortium. This, as well as the availability of ancient human DNA from burial sites and the development of new statistical methods, now provide an unprecedented capacity to study human demography and the ability to examine the genealogical ties between ancient and modern people. The aim of this article is to review the epidemiology of FH, and to attempt to draw inferences from our knowledge at a DNA level of inherited hypercholesterolemia of contemporary people that may contribute to the understanding of human population history and adaptation that resulted in the massive demographic expansion following the adoption of agriculture in the Neolithic period. PMID- 21657944 TI - Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. AB - The brain is one of the major target organs of alcohol actions. Alcohol abuse can lead to alterations in brain structure and functions and, in some cases, to neurodegeneration. Cognitive deficits and alcohol dependence are highly damaging consequences of alcohol abuse. Clinical and experimental studies have demonstrated that the developing brain is particularly vulnerable to alcohol, and that drinking during gestation can lead to a range of physical, learning and behavioral defects (fetal alcohol spectrum disorders), with the most dramatic presentation corresponding to fetal alcohol syndrome. Recent findings also indicate that adolescence is a stage of brain maturation and that heavy drinking at this stage can have a negative impact on brain structure and functions causing important short- and long-term cognitive and behavioral consequences. The effects of alcohol on the brain are not uniform; some brain areas or cell populations are more vulnerable than others. The prefrontal cortex, the hippocampus, the cerebellum, the white matter and glial cells are particularly susceptible to the effects of ethanol. The molecular actions of alcohol on the brain are complex and involve numerous mechanisms and signaling pathways. Some of the mechanisms involved are common for the adult brain and for the developing brain, while others depend on the developmental stage. During brain ontogeny, alcohol causes irreversible alterations to the brain structure. It also impairs several molecular, neurochemical and cellular events taking place during normal brain development, including alterations in both gene expression regulation and the molecules involved in cell-cell interactions, interference with the mitogenic and growth factor response, enhancement of free radical formation and derangements of glial cell functions. However, in both adult and adolescent brains, alcohol damages specific brain areas through mechanisms involving excitotoxicity, free radical formation and neuroinflammatory damage resulting from activation of the innate immune system mediated by TLR4 receptors. Alcohol also acts on specific membrane proteins, such as neurotransmitter receptors (e.g. NMDA, GABA-A), ion channels (e.g. L-type Ca2+ channels, GIRKs), and signaling pathways (e.g. PKA and PKC signaling). These effects might underlie the wide variety of behavioral effects induced by ethanol drinking. The neuroadaptive changes affecting neurotransmission systems which are more sensitive to the acute effects of alcohol occur after long-term alcohol consumption. Alcohol-induced maladaptations in the dopaminergic mesolimbic system, abnormal plastic changes in the reward related brain areas and genetic and epigenetic factors may all contribute to alcohol reinforcement and alcohol addiction. This manuscript reviews the mechanisms by which ethanol impacts the adult and the developing brain, and causes both neural impairments and cognitive and behavioral dysfunctions. The identification and the understanding of the cellular and molecular mechanisms involved in ethanol toxicity might contribute to the development of treatments and/or therapeutic agents that could reduce or eliminate the deleterious effects of alcohol on the brain. PMID- 21657945 TI - Differential expression of the Wnt/beta-catenin pathway in the genital tubercle (GT) of fetal male rat following maternal exposure to di-n-butyl phthalate (DBP). AB - Di-n-butyl phthalate (DBP) is one of the most abundantly produced endocrine disruptors that leaches out from polyvinyl chloride plastics and can cause hypospadias in male rats during maternal exposure. The objective of this study was to first explore the roles of Wnt/beta-catenin pathway in the fetal rat genital tubercle (GT) following in-utero exposure to DBP. Timed-pregnant rats were given DBP by gastric intubation at a dose of 750 mg/kg body weight (bw)/day from gestation day (GD) 14 to GD18 to establish a rat model of hypospadias. On GD19, genital tubercle down-regulation of beta-catenin, Phospho-GSK-3beta, and up regulation of GSK-3beta (glycogen synthase kinase-3beta), NFkappaB in fetal male rats was observed by western blot analysis. beta-catenin was located in the urethral plate epithelium (UPE). Immunochemistry showed that the relative expression of beta-catenin decreased in the DBP-treated fetal rat GT compared to the normal control. These findings, for the first time, indicate that DBP may affect the development of GT by down-regulating the Wnt/beta-catenin pathway in fetal male rats. PMID- 21657946 TI - Investigational drugs in thrombotic thrombocytopenic purpura. AB - INTRODUCTION: Familial and acquired, idiopathic, thrombotic thrombocytopenic purpura (TTP) are life-threatening thrombotic microangiopathies characterized by thrombocytopenia and microangiopathic hemolytic anemia deriving from a deficiency of a disintegrin-like and metalloprotease with thrombospondin repeats (ADAMTS)13 activity induced by genetic defects or autoantibodies. Although the introduction of plasma exchange in 1991 made these conditions curable, many patients still die from TTP and improved therapeutic approaches are, therefore, required. AREAS COVERED: Based on recent progress in terms of etiology and pathogenesis of TTP, several innovative therapies have been proposed in the last few years. This review provides an overview of results obtained with the ?new? therapeutic options in the light of the ?old? treatments that have been already validated by clinical trials. EXPERT OPINION: Plasma exchange and steroids are still the most effective treatments for TTP, but several new therapeutic approaches promise to further improve the prognosis of affected patients. Immunosuppressants stronger than steroids are expected to inhibit the production of anti-ADAMTS13 autoantibodies in acquired forms when the standard approach fails to reach this goal. Moreover, new antithrombotic drugs are expected to reduce the risk of thrombosis during the period required for inhibiting the production of autoantibodies. Finally, the possibility of replacing the infusion of fresh frozen plasma with recombinant ADAMTS13 could further improve the prognosis of TTP, especially in subjects with familial forms. PMID- 21657947 TI - Synthesis and analgesic activity of some acetamide derivatives. AB - In the present study, some acetamide derivatives were synthesized and their potential analgesic activities were investigated. N-(benzothiazol-2-yl)-2-[(1 substituted-1H-tetrazol-5-yl)thio]acetamide derivatives were obtained by the nucleophilic substitution reaction of 2-chloro-N-(benzothiazole-2-yl)acetamides with appropriate tetrazol-5-thioles. The chemical structures of the compounds were elucidated by IR, 1H-NMR, 13C-NMR and FAB+-MS spectral data and elemental analyses. The prepared compounds were investigated for their potential analgesic properties against thermal, mechanical and chemical nociceptive stimuli using hot plate, tail-clip and acetic acid-induced writhing tests, respectively. The assessment of motor coordination was carried out using Rota-Rod test. Tested compounds applied at 100 mg/kg doses caused significant decrease in acetic acid induced writhing responses and increase in hot-plate and tail-clip latencies. None of the compounds exhibited destructive effect on motor coordination of the mice in Rota-Rod performance. PMID- 21657948 TI - Design, synthesis and SAR exploration of hybrid 4-chlorophenylthiazolyl-s triazine as potential antimicrobial agents. AB - Two novel series of hybrid class 4-chlorophenylthiazole-s-triazine were synthesized via nucleophilic substitution of 2,4,6-trichloro-1,3,5-triazine with distinguished alkenyl/alkyl/aryl/hetero alkyl-aryl amino and mercapto nucleophiles under nitrogen atmosphere. We identified that the spectrums of antibacterial activity of all tested compounds reveal promising and significant inhibition of gram-positive and gram-negative micro-organisms and the most active compounds, 31d and 32d, were found to be non-toxic in preliminary cytotoxicity assay. We also report that the Molinspiration and Osiris Property Explorer calculations have found a new lead 32d, which binds preferentially to the nuclear receptor to exhibit antibacterial potency. PMID- 21657949 TI - Comparative study of the effect of green and roasted water extracts of mate (Ilex paraguariensis) on glucosyltransferase activity of Streptococcus mutans. AB - Glucosyltransferase (GTF) plays an important role in the development of dental caries. This study was carried out to compare the efficiency of green mate (GM) and roasted mate (RM) water extracts, drinks rich in polyphenolic compounds consumed in the subtropical region of South America, on the extracellular GTF activity from Streptococcus mutans. The RM extract exhibited a greater inhibitory effect (IC50 of 10 mg/mL) despite presenting lower polyphenolic content. The kinetic analysis showed that there were significant differences (P < 0.05) between the extracts with respect to the values for K(m) and K(i), whereas the values for V(max) were the same, implying the competitive nature of GTF inhibition. GTF activity was also measured using selected polyphenols as inhibitors, and the most effective inhibitors were rutin and caffeoylshikimic acid. The characterization of the extracts by ESI-MS and UPLC-MS showed that the compounds formed during roasting, possibly shikimic acid derivatives and other unindentified compounds formed by the Maillard reaction, appeared to contribute to the inhibition of GTF activity. PMID- 21657950 TI - Synthesis of 5-aryl-6-cinnamoyl-7-methyl-flavanones as novel antioxidants and antihyperlipidemics. AB - An economical and efficient one-pot synthesis of a series of novel 5-aryl-6 cinnamoyl-7-methyl-flavanones has been developed by simple refluxing of cinnamoyl chalcones with NaOAc in aqueous ethanol in quantitative yields. These flavanones were screened for their in vitro antioxidant and in vivo antidyslipidemic activities. Among 24 compounds screened, four compounds 28, 29, 30, and 48 showed significant antidyslipidemic activities. However, out of all the compounds, only compound 28 exhibited significant antioxidant activity and other compounds showed moderate antioxidant activities. PMID- 21657952 TI - A complex karyotype masked a cryptic variant t(8;21)(q22;q22) in a child with acute myeloid leukemia. PMID- 21657953 TI - Hematological malignancies in human immunodeficiency virus-positive individuals in North India. PMID- 21657951 TI - Fluorine bearing sydnones with styryl ketone group: synthesis and their possible analgesic and anti-inflammatory activities. AB - In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone group 4-[1-oxo-3-(substituted aryl)-2 propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2a-i, was synthesized as better analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated at 100 mg?kg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice. Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine substitution. PMID- 21657954 TI - FcgammaRIIA and FcgammaRIIIA polymorphisms do not influence survival and response to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy in patients with diffuse large B-cell lymphoma. PMID- 21657955 TI - Hemophagocytic lymphohistiocytosis following differentiation syndrome in acute promyelocytic leukemia. PMID- 21657956 TI - Mantle cell lymphoma: curcumin nanodisks and possible new concepts on drug delivery for an incurable lymphoma. PMID- 21657957 TI - Inhibition of histone deacetylase 6 as a therapeutic strategy for acute lymphocytic leukemia. PMID- 21657958 TI - Vorinostat induced cellular stress disrupts the p38 mitogen activated protein kinase and extracellular signal regulated kinase pathways leading to apoptosis in Waldenstrom macroglobulinemia cells. AB - Histone deacetylases (HDACs) are aberrantly expressed, and inhibitors of HDACs induce apoptosis in lymphoplasmacytic cells (LPCs) in Waldenstrom macroglobulinemia (WM). The molecular profile by which these agents induce apoptosis in WM LPCs remains to be delineated. We examined the activity of the histone deacetylase inhibitor, vorinostat, and dissected its pro-apoptotic pathways in WM LPCs. Vorinostat induced apoptosis in WM cells through activating specific caspases at varying times. Inhibitors of apoptosis (IAPs) were down regulated after vorinostat treatment. Cellular stress induced in vorinostat treated WM cells was reflected by changes in the mitogen activated protein kinase (MAPK) pathways. Activated phospho-p38 MAPK was up-regulated at 12 h, while phospho-extracellular signal-regulated kinase (Erk) abruptly decreased at 24 h. Bortezomib did not augment vorinostat induced primary WM cell killing as reported in other B-cell disorders. These studies support that stress induced apoptosis in vorinostat-treated WM LPCs is mediated through disrupting the activity of the Erk and p38 MAPK pathways. PMID- 21657959 TI - Patient with ataxia telangiectasia who developed acute myeloid leukemia. PMID- 21657960 TI - Vaccination with immunoglobulin frame region-derived nonapeptide elicits cellular immune response against lymphoma in human leukocyte antigen-A2.1 transgenic mice. AB - The epitope in the frame region (FR) of the immunoglobulin heavy chain variable region (IgHV) is a potential target for lymphoma immunotherapy. Our previous work identified a FR-derived nonapeptide (QLVQSGAEV) capable of in vitro eliciting anti-lymphoma specific cytotoxic T lymphocytes (CTLs) in lymphocytes from human leukocyte antigen (HLA)-A2.1 donors. Here we used HLA-A2.1 transgenic mice and SCID (severe combined immunodeficiency) mice to confirm the ability of these specific CTLs against lymphomas. We immunized transgenic mice with nonapeptide conjugated to the adjuvant of PADRE (pan HLA DR-binding epitope). The specificity of the elicited CTLs from the immunized transgenic mice was identified by enzyme linked immunospot (ELISpot) assay and pentamer staining. The elicited CTLs specifically attacked lymphomas with surface IgHV1 in vitro. Adoptive transfer of the CTLs to SCID mice loaded with QLVQSGAEV(+)/HLA-A2.1(+) lymphoma cells effectively inhibited tumor growth. Our results indicate that the relatively constant epitope in the IgHV FR may be useful for immunotherapy of lymphomas with the same IgHV subfamily. PMID- 21657961 TI - Predictive factors for successful salvage high-dose therapy in patients with multiple myeloma relapsing after autologous blood stem cell transplantation. AB - For patients with relapsed or refractory multiple myeloma (MM) treated with a prior high-dose therapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT), the reapplication of HDT is a widely used salvage strategy. In this retrospective study, we report on 55 patients who were treated with salvage HDT at our institution. The conditioning regimen consisted of melphalan 200 mg/m(2) (27%), melphalan 140 mg/m(2) and busulfan 12 mg/kg body weight (40%), or melphalan 200 mg/m(2) and bortezomib 1.3 mg/m(2) (33%). Treatment-related mortality was 5% and response rates were as follows: 9% complete remission, 9% very good partial remission, 56% partial remission, 11% minimal response + stable disease, and 4% progressive disease (5% not assessable). Toxicity was moderate and the median event-free (EFS) and overall survival (OS) were 14 months and 52 months, respectively. The different conditioning regimens did not result in differences in terms of remission rates, EFS and OS, or toxicity. In multivariate analysis a duration of remission of more than 12 months after the first transplant was the only predictive factor for both EFS (p < 0.0001) and OS (p = 0.0001). In conclusion, salvage HDT followed by autologous PBSCT is an effective treatment option for patients with relapsed or refractory MM, while patients with an early relapse after their first transplant do not benefit from this treatment modality. PMID- 21657962 TI - Two different del(5q) clones in a patient with myelodysplastic syndrome. PMID- 21657963 TI - Polymorphisms in folate-related genes: impact on risk of adult acute lymphoblastic leukemia rather than pediatric in Han Chinese. AB - Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. An aberrant folate metabolism caused by a genetic polymorphism may lead to genomic instability and affect the susceptibility to malignancies including acute lymphoblastic leukemia (ALL). This study was designed to explore the correlation between the polymorphisms in folate-related genes and the risk of ALL in Han Chinese. The DNA was isolated from 231 patients with pediatric ALL, 130 patients with adult ALL, and 367 healthy subjects (as controls). Polymorphisms were examined for RFC1 80G > A, DHFR 19 bp del/ins and 317A > G, SHMT1 1420C > T, MTHFR 677C > T and 1298A > C, MTR 2756A > G, MTRR 66A > G, TYMS 3R/2R, MTHFD1 1958G > A, and ABCG2 421G > T using real-time polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (RFLP). The risk of adult ALL was increased by the RFC1 80AA variant (odds ratio [OR] = 2.09; 95% confidence interval [CI] 1.19-3.67) and MTRR 66GG variant (OR = 2.15; 95% CI 1.06 4.39) but reduced by the MTHFR 677TT variant (OR = 0.47; 95% CI 0.25-0.88), ABCG2 421GT variant (OR = 0.62; 95% CI 0.41-0.96), and ABCG2 421GT + TT variant (OR = 0.60; 95% CI 0.40-0.90). The increase in risk of adult ALL with the RFC1 80AA associated with the MTRR 66GG variant was even more significant (OR = 8.92; 95% CI 1.97-40.42). Furthermore, the MTHFR 677TT associated with the ABCG2 421GT + TT variant more significantly reduced the risk of adult ALL (OR = 0.32; 95% CI 0.12 0.85). However, all gene polymorphisms tested in this study failed to affect the pediatric ALL risk. Our study clearly demonstrates that polymorphisms in folate related genes only modulate the susceptibility to adult ALL, but not to pediatric ALL, in Han Chinese. PMID- 21657964 TI - High-dose methotrexate in patients with primary central nervous system lymphoma: does drug exposure really matter? PMID- 21657965 TI - Follicular lymphoma: still Six characters in search of an author? AB - Follicular lymphoma (FL) is regarded as a distinct entity in the literature as well as in the 2008 edition of the WHO classification of tumours of haematopoietic and lymphoid tissues. Nevertheless, there are still several issues that are matters of controversy such as the grading system or the exact biological location of grade 3B FL. This makes FL somewhat like the Six characters in search of an author of Pirandello's comedy. Here, we revise the morphology and pathobiology of FL by highlighting both the areas remaining critical and future perspectives. This review was inspired by the reappraisal of Professor Lennert's personal archive that represents a unique legacy for the entire scientific community. PMID- 21657966 TI - In vitro metabolism of dexamethasone cipecilate, a novel synthetic corticosteroid, in human liver and nasal mucosa. AB - Dexamethasone cipecilate (DX-CP, 9-fluoro-11beta,17,21-trihydroxy-16alpha methylpregna-1,4-diene-3,20-dione 21-cyclohexanecarboxylate 17 cyclopropanecarboxylate) is a novel synthetic corticosteroid used to treat allergic rhinitis. The pharmacological effect of DX-CP is considered to be mainly due to its active de-esterified metabolite (DX-17-CPC). To investigate the in vitro metabolism of DX-CP in human liver, DX-CP was incubated with human liver microsomes and S9. In addition, a metabolism study of DX-CP with human nasal mucosa was carried out in order to elucidate whether DX-17-CPC is formed in nasal mucosa, the site of action of DX-CP. DX-17-CPC was the major metabolite in both liver microsomes and S9. Two new epoxide metabolites, UK1 and UK2, were detected in liver S9, while only UK1 was detected in liver microsomes. This suggests that cytosol enzymes are responsible for the formation of UK2. In human nasal mucosa, DX-CP was mainly transformed into DX-17-CPC. By using recombinant human carboxylesterases (CESs), the reaction was shown to be catalyzed by CES2. These results provide the evidence that the active metabolite DX-17-CPC is the main contributor to the pharmacological action after the intranasal administration of DX-CP to humans. PMID- 21657967 TI - The disposition and metabolism of zibotentan (ZD4054): an oral-specific endothelin A receptor antagonist in mice, rats and dogs. AB - Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. Following oral and intravenous administration, zibotentan was slowly absorbed (maximal concentration at approximately 4 h) and rapidly excreted, with the majority being eliminated by 48 h. The main route of elimination was via the urine in dogs and female rats, but via the faeces in male rats and mice of both sexes. Zibotentan was moderately bound to plasma proteins of all species examined (55-95%), and widely distributed throughout all tissues with the highest concentrations seen in the organs of excretion. Zibotentan was moderately metabolised. Zibotentan was well absorbed, moderately bound to plasma proteins, widely distributed and excreted predominantly via the urine. PMID- 21657968 TI - CRP and leukocyte-count after lumbar spine surgery: fusion vs. nucleotomy. AB - BACKGROUND: Despite the fact that C-reactive protein (CRP) levels and white blood cell (WBC) count are routine blood chemistry parameters for the early assessment of wound infection after surgical procedures, little is known about the natural history of their serum values after major and minimally invasive spinal procedures. METHODS: Pre- and postoperative CRP serum levels and WBC count in 347 patients were retrospectively assessed after complication-free, single-level open posterior lumbar interlaminar fusion (PLIF) (n = 150) for disc degeneration and spinal stenosis and endoscopically assisted lumbar discectomy (n = 197) for herniated lumbar disc. Confounding variables such as overweight, ASA classification, arterial hypertension, diabetes mellitus, and perioperative antibiotics were recorded to evaluate their influence on the kinetics of CRP values and WBC count postoperatively. RESULTS: In both procedures, CRP peaked 2-3 days after surgery. The maximum CRP level was significantly higher after fusion: mean 127 (SD 57) (p < 0.001). A rapid fall in CRP within 4-6 days was observed for both groups, with almost normal values being reached after 14 days. Only BMI > 25 and long duration of surgery were associated with higher peak CRP values. WBC count did not show a typical and therefore interpretable profile. CONCLUSION: CRP is a predictable and responsive serum parameter in postoperative monitoring of inflammatory responses in patients undergoing spine surgery, whereas WBC kinetics is unspecific. We suggest that CRP could be measured on the day before surgery, on day 2 or 3 after surgery, and also between days 4 and 6, to aid in early detection of infectious complications. PMID- 21657969 TI - Treatment of shoulder sequelae in brachial plexus birth injury. AB - BACKGROUND: Many children with permanent brachial plexus birth injury (BPBI) develop shoulder problems, with subsequent joint deformity without treatment. We assessed the indications and outcome of shoulder operations for BPBI. PATIENTS AND METHODS: 31 BPBI patients who had undergone a shoulder operation in our hospital between March 2002 and December 2005 were included in the study. Relocation of the humeral head had been performed in 13 patients, external rotation osteotomy of the humerus in 5 patients, subscapular tendon lengthening in 5 patients, and teres major transposition in 8 patients. Subjective results were registered. Shoulder range of motion was measured, and function assessed according to the Mallet scale. Magnetic resonance imaging (MRI) was performed pre and postoperatively. Glenoscapular angle (GSA) and percentage of humeral head anterior to the middle of the glenoid fossa (PHHA) were measured. Congruency of the glenohumeral joint (GHJ) was estimated. The mean follow-up time was 3.8 (1.7 6.8) years. RESULTS: At follow-up, the subjective result was satisfactory in 30 of the 31 patients. There were 4 failures, which in retrospect were due to wrong choice of surgical method in 3 of these 4 patients. Mean increase in Mallet score was 5.5 after successful relocation, 1.4 after rotation osteotomy, 2.2 after subscapular tendon lengthening, and 3.1 after teres major transposition. Congruency of the shoulder joint improved in 10 of 13 patients who had undergone a relocation operation, with mean improvement in GSA of 33o and mean increase in PHHA of 25%. There were no substantial changes in congruency of the glenohumeral joint in patients treated with other operation types. INTERPRETATION: Restriction of the range of motion and malposition of the glenohumeral joint can be improved surgically in brachial plexus birth injury. Remodeling of the joint takes place after successful relocation of the humeral head in young patients. PMID- 21657970 TI - Locking plate osteosynthesis in displaced 4-part fractures of the proximal humerus. AB - BACKGROUND AND PURPOSE: There is considerable uncertainty about the optimal treatment of displaced 4-part fractures of the proximal humerus. Within the last decade, locking plate technology has been considered a breakthrough in the treatment of these complex injuries. METHODS: We systematically identified and reviewed clinical studies on the benefits and harms after osteosynthesis with locking plates in displaced 4-part fractures. RESULTS: We included 14 studies with 374 four-part fractures. There were 10 case series, 3 retrospective observational comparative studies, 1 prospective observational comparative study, and no randomized trials. Small studies with a high risk of bias precluded reliable estimates of functional outcome. High rates of complications (16-64%) and reoperations (11-27%) were reported. INTERPRETATION: The empirical foundation for the value of locking plates in displaced 4-part fractures of the proximal humerus is weak. We emphasize the need for well-conducted randomized trials and observational studies. PMID- 21657971 TI - Results of 189 wrist replacements. A report from the Norwegian Arthroplasty Register. AB - BACKGROUND AND PURPOSE: There is very little literature on the long-term outcome of wrist replacements. The Norwegian Arthroplasty Register has registered wrist replacements since 1994. We report on the total wrist replacements and their revision rates over a 16-year period. MATERIAL AND METHODS: 189 patients with 189 primary wrist replacements (90 Biax prostheses (80 of which were cementless), 23 cementless Elos prostheses, and 76 cementless Gibbon prostheses), operated during the period 1994-2009 were identified in the Norwegian Arthroplasty Register. Prosthesis survival was analyzed using Cox regression analyses. The 3 implant designs were compared and time trends were analyzed. RESULTS: The 5-year survival was 78% (95% CI: 70-85) and the 10-year survival was 71% (CI: 59-80). Prosthesis survival was 85% (CI: 78-93) at 5 years for the Biax prosthesis, 77% (CI: 30-90) at 4 years for the Gibbon prosthesis, and 57% (CI: 33-81) at 5 years for the Elos prosthesis. There was no statistically significant influence of age, diagnosis, or year of operation on the risk of revision, but females had a higher revision rate than males (RR = 3, CI: 1-7). The number of wrist replacements performed due to osteoarthritis increased with time, but no such change was apparent for inflammatory arthritis. INTERPRETATION: The survival of the total wrist arthroplasties studied was similar to that in other studies of wrist arthroplasties, but it was still not as good as that for most total knee and hip arthroplasties. However, a failed wrist arthroplasty still leaves the option of a well-functioning arthrodesis. PMID- 21657972 TI - Obesity in total hip arthroplasty--does it really matter? A meta-analysis. AB - BACKGROUND AND PURPOSE: Discussion persists as to whether obesity negatively influences the outcome of hip arthroplasty. We performed a meta-analysis with the primary research question of whether obesity has a negative effect on short- and long-term outcome of total hip arthroplasty. METHODS: We searched the literature and included studies comparing the outcome of hip arthroplasty in different weight groups. The methodology of the studies included was scored according to the Cochrane guidelines. We extracted and pooled the data. For continuous data, we calculated a weighted mean difference and for dichotomous variables we calculated a weighted odds ratio (OR). Heterogeneity was calculated using I(2) statistics. RESULTS: 15 studies were eligible for data extraction. In obese patients, dislocation of the hip (OR = 0.54, 95% CI: 0.38-0.75) (10 studies, n = 8,634), aseptic loosening (OR = 0.64, CI: 0.43-0.96) (6 studies, n = 5,137), infection (OR = 0.3, CI: 0.19-0.49) (10 studies, n = 7,500), and venous thromboembolism (OR = 0.56, CI: 0.32-0.98) (7 studies, n = 3,716) occurred more often. Concerning septic loosening and intraoperative fractures, no statistically significant differences were found, possibly due to low power. Subjective outcome measurements did not allow pooling because of high heterogeneity (I(2) = 68%). INTERPRETATION: Obesity appears to have a negative influence on the outcome of total hip replacement. PMID- 21657973 TI - Where did bone come from? AB - Bone is specific to vertebrates, and originated as mineralization around the basal membrane of the throat or skin, giving rise to tooth-like structures and protective shields in animals with a soft cartilage-like endoskeleton. A combination of fossil anatomy and genetic information from modern species has improved our understanding of the evolution of bone. Thus, even in man, there are still similarities in the molecular regulation of skin appendages and bone. This article gives a brief overview of the major milestones in skeletal evolution. Some molecular machineries involving members of core genetic networks and their interactions are described in the context of both old theories and modern genetic approaches. PMID- 21657974 TI - Outcome after surgery for metastatic spinal cord compression in 54 patients with prostate cancer. AB - BACKGROUND AND PURPOSE: The criteria for selecting patients who may benefit from surgery of spinal cord compression in metastatic prostate cancer are poorly defined. We therefore studied patients operated for metastatic spinal cord compression in order to evaluate outcome of surgery and to find predictors of survival. PATIENTS AND METHODS: We reviewed the records of 54 consecutive patients with metastatic prostate cancer who were operated for spinal cord compression at Umea University Hospital. The indication for surgery was neurological deficit due to spinal cord compression. 41 patients had hormone refractory cancer and 13 patients had previously untreated, hormone-naive prostate cancer. 29 patients were operated with posterior decompression only, and in 25 patients posterior decompression and stabilization was performed. RESULTS: Preoperatively, 6/54 of patients were able to walk. 1 month after surgery, 33 patients were walking, 15 were non-ambulatory, and 6 had died. Mortality rate was 11% at 1 month, 41% at 6 months, and 59% at 1 year. In the hormone-naive group, 8/13 patients were still alive with a median postoperative follow-up of 26 months. In the hormone-refractory group, median survival was 5 months. Patients with hormone-refractory disease and Karnofsky performance status (KPS) of <= 60% had median survival of 2.5 months, whereas those with KPS of 70% and KPS of >= 80% had a median survival of 7 months and 18 months, respectively (p < 0.001). Visceral metastases were present in 12/41 patients with hormone-refractory tumor at the time of spinal surgery, and their median survival was 4 months-as compared to 10 months in patients without visceral metastases (p = 0.003). Complications within 30 days of surgery occurred in 19/54 patients. INTERPRETATION: Our results indicate that patients with hormone-naive disease, and those with hormone refractory disease with good performance status and lacking visceral metastases, may be helped by surgery for metastatic spinal cord compression. PMID- 21657975 TI - Hydroxyapatite (HA) coating appears to be of benefit for implant durability of tibial components in primary total knee arthroplasty. AB - BACKGROUND: It is unclear whether there is a clinical benefit to adding hydroxyapatite (HA) coatings to total knee implants, especially with the tibial component, where failure of the implant more often occurs. A systematic review of the literature was undertaken to identify all prospective randomized trials for determining whether the overall clinical results (as a function of durability, function, and adverse events) favored HA-coated tibial components. METHODS: A comprehensive literature search was performed for the years 1990 to September 16, 2010. We restricted our search to randomized controlled trials involving participants receiving either an HA-coated tibia or other forms of tibial fixation. The primary outcome measures evaluated were durability, function, and acute adverse events. RESULTS: Data from 926 evaluable primary total knee implants in 14 studies were analyzed. Using an RSA definition for durability, HA coated tibial components (porous or press-fit) without screw fixation were less likely to be unstable at 2 years than porous and cemented metal-backed tibial components (RR = 0.58, 95% CI: 0.34-0.98; p = 0.04, I(2) = 39%, M-H random effects model). There was no significant difference in durability, as measured from revision and evaluated at 2 and 8-10 years, between groups. Also, functional status using different validated measures showed no significant difference at 2 and 5 years, no matter what measure was used. Lastly, there was no significant difference in adverse events. Limitations included small numbers of evaluable patients (<= 50) in 7 of the 14 trials identified, and a lack of "hard" evidence of durability with need for replacement (i.e. frank failure, pain, or loss of functionality). INTERPRETATION: In patients > 65 years of age, an HA-coated tibial implant may provide better durability than other forms of tibial fixation. Larger trials should be undertaken comparing the long-term durability, function, and adverse events of HA-coated implants with those of other porous-coated tibial implants in younger, more active OA patients. PMID- 21657977 TI - Interventions addressing general parenting to prevent or treat childhood obesity. AB - Observational studies increasingly emphasize the impact of general parenting on the development of childhood overweight and obesity. The aim of the current literature review was to provide an overview of interventions addressing general parenting in order to prevent or treat childhood obesity. Electronic literature databases were systematically searched for relevant studies. Seven studies were eligible for inclusion. The studies described four different general parenting programs, which were supplemented with lifestyle components (i.e., physical activity and nutrition). All studies showed significant small to moderate intervention effects on at least one weight-related outcome measure. The current review shows that despite the emerging observational evidence for the role of parenting in children's weight-related outcomes, few interventions have been developed that address general parenting in the prevention of childhood obesity. These interventions provide evidence that the promotion of authoritative parenting is an effective strategy for the prevention and management of childhood obesity. PMID- 21657976 TI - A scientific approach to optimal treatment of cruciate ligament injuries. PMID- 21657978 TI - Genetics of pre-pubertal growth: a longitudinal study of Japanese twins. AB - BACKGROUND: Genetic factors explain a major part of the variation of adult stature, but little is still known on the genetics of growth, especially in non Caucasian populations. AIM: To analyse the quantitative genetics of pre-pubertal growth in Japanese children. SUBJECTS AND METHODS: Data from birth until 11 years of age were collected on 349 complete twin pairs based on previously recorded height measures. The data were analysed using two different multivariate models by the Mx statistical package. RESULTS: No major sex differences were found and thus boys and girls were analysed together. Since 1 year of age, genetic factors explained from 42-71% and environmental factors shared by co-twins from 14-33% of the variation of height. Genetic continuity of height was high and 75% of the genetic variance was shared since 1 year of age. Environmental factors affecting height showed weaker correlations between early and late childhood than genetic factors. CONCLUSION: Growth from early to late childhood is largely regulated by the same set of genes. However, also environmental factors shared by co-twins are important for growth. Identifying specific environmental factors affecting growth has potentially important public health implications, even in an affluent society such as Japan. PMID- 21657980 TI - Sequence elements outside the catalytic core of natural hairpin ribozymes modulate the reactions differentially. AB - Abstract Hairpin ribozymes occur naturally only in the satellite RNAs of tobacco ringspot virus (TRsV), chicory yellow mottle virus (CYMoV) and arabis mosaic virus (ArMV). The catalytic centre of the predominantly studied sTRsV hairpin ribozyme, and of sArMV is organised around a four-way helical junction. We show here that sCYMoV features a five-way helical junction instead. Mutational analysis indicates that the fifth stem does not influence kinetic parameters of the sCYMoV hairpin ribozyme in vitro reactions, and therefore seems an appendix to that junction in the other ribozymes. We report further that all three ribozymes feature a three-way helical junction outside the catalytic core in stem A, with Watson-Crick complementarity to loop nucleotides in stem B. Kinetic analyses of cleavage and ligation reactions of several variants of the sTRsV and sCYMoV hairpin ribozymes in vitro show that the presence of this junction interferes with their reactions, particularly the ligation. We provide evidence that this is not due to a presumed interaction of the afore-mentioned elements in stems A and B. The evolutionary survival of this cis-inhibiting element seems rather to be caused by the coincidence of its position with that of the hammerhead ribozyme in the other RNA polarity. PMID- 21657981 TI - Morpholino knockdown of the ubiquitously expressed transmembrane serine protease TMPRSS4a in zebrafish embryos exhibits severe defects in organogenesis and cell adhesion. AB - Abstract Over the past years the members of the type II transmembrane serine protease (TTSP) family have emerged as new players in mammalian biology. TMPRSS4 (transmembrane protease/serine) is overexpressed in several human cancer tissues, promoting invasion, migration, and metastasis. However, the physiological function has not yet been elucidated. Here, we present morpholino knockdown studies targeting TMPRSS4a, a homolog of human TMPRSS4 in zebrafish embryos. By RT-PCR, we could demonstrate an expression of this protease already 5 h post fertilization, suggesting important functions in the early stages of embryonic development. Indeed, in vivo gene silencing caused severe defects in tissue development and cell differentiation including a disturbed skeletal muscle formation, a decelerated heartbeat, and a degenerated vascular system. Scanning electron microscopy revealed strong defects in epidermal skin organization, with clearly altered cell-cell contacts, resulting in the detachment of keratinocytes from the underneath tissue. The disturbed organogenesis in general is consistent with RT-PCR results which exhibited a ubiquitous expression of TMPRSS4a, predominantly in kidney, skin, heart, and gills. Our results demonstrate the importance of TMPRSS4a in tissue development and cell differentiation. Whether its proteolytic activity is directed towards adhesion molecules or leads to the activation of other proteases needs to be investigated further. PMID- 21657982 TI - Isolation of dipeptidyl peptidase IV (DP 4) isoforms from porcine kidney by preparative isoelectric focusing to improve crystallization. AB - Abstract In the present studies we resolved the post-translational microheterogeneity of purified porcine dipeptidyl peptidase IV (DP 4) from kidney cortex. Applying SDS-homogeneous DP 4 onto an analytical agarose isoelectric focusing (IEF) gel, pH 4-6, activity staining resulted in at least 17 isoforms between pH 4.8-6.0. These could be separated into fractions with only two to six isoforms by means of preparative liquid-phase IEF, using a Rotofor cell. Starting off with three parallel Rotofor runs under the same conditions at pH 5-6, the fractions were pooled according to the specific activity of DP 4, pH and analytical IEF profile, and further refractionated without any additional ampholytes. Since excessive dilution of ampholytes and proteins was kept to the minimum, a second refractionation step could be introduced, resulting in pH gradients between 0.022 and 0.028 pH increments per fraction. By performing two consecutive refractionation steps, the high resolution necessary for the separation of DP 4 isoforms could be achieved. This represents an alternative method if isolation of isoforms with similar pI's results in precipitation and denaturation in presence of a narrow pH range. Furthermore, it demonstrates that preparative IEF is a powerful tool to resolve post-translational microheterogeneity of a purified protein required for crystallization processing. PMID- 21657983 TI - The role of fibroblasts in self-assembled skeletal muscle. AB - Small facial skeletal muscles often have no autologous donor source to effect surgical reconstruction. Autologously derived muscles could be engineered for replacement tissue, but must be vascularized and innervated to be functional. As a critical step, engineered muscle must mimic the morphology, protein and gene expression, and function of native muscle. This study utilized a self-assembly process to engineer three-dimensional (3D) muscle from a statically strained muscle cell monolayer. Primary mouse myoblasts (PMMs) and mouse embryonic fibroblasts (MEFs) were separately proliferated and coseeded on a fibrin sheet with anchored sutures. Within 10 days of initiating PMM differentiation, the cell gel layer contracted, lifted, and rolled into a cylindrical 3D structure around the tendon-like suture anchors; the myotubes longitudinally aligned along the lines of tensile force. The objectives of this study were to characterize these engineered muscles and to elucidate the role of the fibroblasts in the self assembly process. Fibroblasts maintained myotube viability, mediated fibrin degradation, and assisted in muscle self-assembly. The optimal 1:1 PMM:MEF ratio resulted in tissue morphology remarkably similar to native muscle. Through gene and protein expression assays, the development and maturation of the engineered muscle tissue was demonstrated to recapitulate normal skeletal muscle development. PMID- 21657985 TI - The dose-dependent toxicological effects and potential perturbation on the neurotransmitter secretion in brain following intranasal instillation of copper nanoparticles. AB - Increasing production and application of metallic nanomaterials are likely to result in the release of these particles into the environment. These released nanoparticles may enter into the lungs and the central nervous system (CNS) directly through inhalation, which therefore poses a potential risk to human health. Herein, we focus on the systemic toxicity and potential influence on the neurotransmitter secretion of intranasally instilled copper nanoparticles (23.5 nm) at three different doses. Copper nanoparticle-exposed mice exhibit pathological lesions at different degrees in certain tissues and especially in lung tissue as revealed by histopathology and transmission electron microscopy (TEM) observations. Inductively-coupled plasma mass spectrometry (ICP-MS) results show that the liver, lung and olfactory bulb are the main tissues in which the copper concentrations increased significantly after exposure to a higher level of Cu nanoparticles (40 mg/kg of body weight). The secretion levels of various neurotransmitters changed as well in some brain regions, especially in the olfactory bulb. Our results indicate that the intranasally instilled copper nanoparticles not only cause the lesions where the copper accumulates, but also affect the neurotransmitter levels in the brain. PMID- 21657987 TI - Orthogonal recursive bisection as data decomposition strategy for massively parallel cardiac simulations. AB - We present the orthogonal recursive bisection algorithm that hierarchically segments the anatomical model structure into subvolumes that are distributed to cores. The anatomy is derived from the Visible Human Project, with electrophysiology based on the FitzHugh-Nagumo (FHN) and ten Tusscher (TT04) models with monodomain diffusion. Benchmark simulations with up to 16,384 and 32,768 cores on IBM Blue Gene/P and L supercomputers for both FHN and TT04 results show good load balancing with almost perfect speedup factors that are close to linear with the number of cores. Hence, strong scaling is demonstrated. With 32,768 cores, a 1000 ms simulation of full heart beat requires about 6.5 min of wall clock time for a simulation of the FHN model. For the largest machine partitions, the simulations execute at a rate of 0.548 s (BG/P) and 0.394 s (BG/L) of wall clock time per 1 ms of simulation time. To our knowledge, these simulations show strong scaling to substantially higher numbers of cores than reported previously for organ-level simulation of the heart, thus significantly reducing run times. The ability to reduce runtimes could play a critical role in enabling wider use of cardiac models in research and clinical applications. PMID- 21657988 TI - Validation of a new non-invasive blood pressure measurement method on mice via pulse wave propagation time measurement on a cuff. AB - In the present article, we describe the validation of a new non-invasive method for measuring blood pressure (BP) which also enables to determine the three BP values: systolic, diastolic and mean value. Our method is based on the pulse transit time (PTT) measurement along an artery directly at the BP cuff. The accuracy of this method was evaluated by comparison with the direct simultaneous measurement of blood pressure from 40 anesthetized female mice. Close correlation between the gained data from these two methods was observed. PMID- 21657989 TI - Middle ear of human and pig: a comparison of structures and mechanics. AB - INTRODUCTION: Animal studies are an essential method to evaluate implants for the middle ear prior to clinical studies. New Zealand rabbits, guinea pigs and chinchillas are, among other small mammals, well established animal models, but their auditory system is significantly smaller compared to human. Hence, the suitability of the domestic pig (sus scrofa domesticus) as a new animal model for research on the middle ear (ME), that would match the human in size, was investigated. METHODS: Thirty halved pig heads were obtained from the butcher and each middle ear was dissected. Using a digital light microscope, several anatomical magnitudes were determined for 24 specimens, namely the planar projected area of the tympanic membrane (TM), in relation to the stapes footplate as well as the dimensions and weight of the ossicles, in order to determine the effective lever ratios. Using normal and micro computed tomography (CT), six porcine temporal bones were scanned and the geometric data obtained were transferred into a finite element model (FEM) simulation of the porcine middle ear. The transfer function was determined and compared to those from humans determined by measurements and simulations, respectively. RESULTS: The anatomy investigated presented itself as highly comparable to that of the human. Differing from literature, no fourth ossicle could be found. The porcine dimensions and lever ratios determined match the humans far better than those of all established animal models. The obtained transfer function was congruent to the human one. This underlines the suitability of the pig as an animal model for middle ear implants. PMID- 21657990 TI - Effects of electric and magnetic loadings on bone surface remodeling: a model modification and simulation. AB - This paper presents a new modification to the previous model of bone surface remodeling under electric and magnetic loadings. For this study, the thermo electro-magneto-elastic model of bone surface remodeling is used. This model is modified by considering an important phenomenon occurring in living bone through its adaptation to external loadings called desensitization. In fact, bone cells lose their responsiveness and sensitivity to long-term external loadings, i.e., they become desensitized. Therefore, bone cells need a recovery period, during which they become resensitized. In this work, this phenomenon is considered in the original model. The effects of various electric and magnetic loading conditions, including various frequencies, waveforms and pulse duty cycles, are explored on the modified model and compared to the original model. The modified model is also searched for the optimal frequency and duty cycle, to obtain the best bone growth response under electromagnetic fields. The results of this paper show that the modified model is consistent with experimental observations. In addition, it is indicated that this modified model in contrast to the original model, is sensitive to frequency. It is shown that the optimal frequency of loading for the modified model is 1 Hertz (Hz), and the pulse duty cycles up to 50% are sufficient for bone remodeling to reach its maximum value. PMID- 21657991 TI - The role of LH in ovarian stimulation. AB - LH is a glycoprotein that plays a crucial role in folliculogenesis during the natural ovarian cycles. It has the same activity and shares receptors with hCG. However the use of LH in combination with FSH in controlled ovarian stimulation remains controversial. A practical approach concerning the usefulness of LH according to the endogenous level of LH is described herein. Specific groups of patients can benefit from ovarian stimulation with LH. New applications of LH/hCG activity are also discussed. PMID- 21657992 TI - Modeling follicle stimulating hormone levels in serum for controlled ovarian hyperstimulation III: improved gonadotropin administration. AB - BACKGROUND: A numerical model with two pharmacokinetic parameters (the rate of diffusion into the blood (tauin) and the rate of disappearance from the blood (tauout)) mimicks the slow changes of follicle stimulating hormone (FSH) seen in serum. It is often desired to change serum FSH levels more rapidly. Since the pharmacokinetic parameters cannot be changed in patients, we used the model to investigate changing the amount and timing of gonadotropin administration to change FSH levels in serum more rapidly. METHODS: Parameters defining the model were obtained as described previously [1]. The doses administered, and the timing of administration were individually specified. RESULTS: The rise of serum FSH was made more rapid by administering an initial injection larger than the subsequent injections. When a rapid decrease of serum FSH was desired, administration of the new, lower dose was delayed. CONCLUSION: Use of a model that simulates the serum levels of FSH during gonadotropin administration provided a framework for learning how to achieve the desired serum FSH levels more rapidly in patients. With knowledge of a particular patient's tauin and tauout, optimal FSH administration for that patient can be determined through modeling. PMID- 21657993 TI - Modeling Follicle Stimulating Hormone (FSH) levels in serum for controlled ovarian hyperstimulation II: the underlying mechanisms. AB - BACKGROUND: Serum levels of follicle stimulating hormone (FSH) in patients change slowly during repeated daily injections of gonadotropin, requiring several days to achieve stable values. Using a numerical (computer) model we mimicked the serum levels of FSH using two kinetic constants that describe biological phenomena: diffusion of FSH from the injection site into the blood (tauin) and disappearance of FSH from the blood by excretion/degradation (tauout). We investigated the effects of these two parameters on the FSH profiles seen in the model. METHODS: The parameters, tauin and tauout, were systematically changed to determine their effects on the delay from injection to the peak following a single injection (Tmax). Other values were investigated systematically during repeated daily injections. RESULTS: The model's parameters tauin and tout affected Tmax and several features of FSH level during daily injections of gonadotropin. These included the maximum level of FSH in the serum (relative to the level attained following the first injection), the rate of rise of peaks following injections after the first, and the shortening of the delay from injection to peak. CONCLUSION: Knowledge of tauin and tauout permits us to predict serum FSH levels and time course during daily injections of gonadotropin. PMID- 21657994 TI - Modeling follicle stimulating hormone levels in serum for controlled ovarian hyperstimulation I: comparing gonadotropin products. AB - BACKGROUND: Despite the dangers of gonadotropin administration, our understanding of serum levels of gonadotropins in our patients is poor. We created a mathematical model of gonadotropin administration in order to learn about the temporal profiles of Follicle Stimulating Hormone (FSH) levels in patients related to the doses of different gonadotropin products administered. METHODS: Model parameters for each product were determined from published pharmacokinetic information available from the manufacturers. RESULTS: For each product, serum levels of FSH rose then fell following a single injection of FSH. When a gonadotropin dose was injected repeatedly (daily), each injection resulted in a peak level of FSH that was higher than the level attained from the previous injection. Daily FSH peaks rose asymptotically, requiring 3-10 days to approach the maximum. The maximum averaged 3.5 times the peak of the first injection. Decline of FSH following the final injection required 3-10 days to approach the baseline. Time courses and peak values of FSH using different gonadotropin preparations varied widely. CONCLUSION: Knowledge of the slow changes of FSH that occur during modeled FSH administration will provide a framework for understanding the gonadotropin profiles that occur in patients during controlled ovarian hyperstimulation. PMID- 21657995 TI - Genetic profile of SNP(s) and ovulation induction. AB - Obtaining an adequate number of good quality oocytes while minimizing adverse drug reactions (ADRs) and cycle cancellation rates is considered the gold standard in controlled ovarian hyperstimulation (COH) for fertility treatment. Patients who undergo IVF/ICSI cycles tend to present with different responses to exogenous gonadotrophin administration. Research has shown that the secret probably lies in the various single nucleotide polymorhisms (SNPs) in their receptor genes. The decryption of human genome provided specialists with additional information in assessing and even predicting ovarian response to COH. In this context, the study of Pharmacogenomics, Pharmacogenetics and SNPs unravels as a promising field in optimizing fertility treatment. Several SNPs in FSH and estrogen receptor genes have been detected so far, but only three of them, one in FSH receptor and two in estrogen receptor genes have been associated with ovarian response to COH. It seems that the Asn/Ser variant of the FSH receptor functions more efficiently, while the Ser/Ser and Asn/Asn variants have a tendency to resist to FSH stimulation. With regards to estrogen receptor 1 (ESR1), the Pvull and the Xbal polymorphisms seem to be associated with differences in the response to ovarian stimulation, while the Rsal polymorphism in estrogen receptor 2 (ESR2) is currently under investigation. There exists evidence supporting the hypothesis that a set of genes, all related to the FSH hormone mechanism of action, may participate along with other factors to the control of ovarian response to FSH, thus a cautious interpretation of polymorphism detection results is considered mandatory. However, identifying potential genetic markers that could predict ovarian response and implementing them in routine screening tests for every woman entering an IVF/ICSI cycle, would be able to tailor fertility treatment to each patients needs thus maximizing the success rate and eliminating potential side-effects of fertility drugs. PMID- 21657996 TI - Possibilities and limits of ovarian reserve testing in ART. AB - Markers of ovarian reserve are associated with ovarian aging as they decline with chronologic age, and hence may predict stages of reproductive aging including the menopause transition. Assessment of ovarian reserve include measurement of serum follicle stimulating hormone (FSH), anti-M?llerian hormone (AMH), and inhibin-B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume also can have a role. The clomiphene citrate challenge test (CCCT), exogenous FSH ovarian reserve test (EFORT), and GnRH-agonist stimulation test (GAST) are dynamic methods that have been used in the past to assess ovarian reserve. In infertile women, ovarian reserve markers can be used to predict low and high oocyte yield and treatment failure in women undergoing in vitro fertilization. However the markers may have limitations when an in depth analysis of their accuracy, cost, convenience, and utility is performed. As ovarian reserve markers may permit the identification of both the extremes of ovarian stimulation, a possible role for their measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in the ovarian reserve testing before initiation of an IVF cycle and whether the ovarian reserve markers-determined strategy of ovarian stimulation for assisted conception may be associated to improved live birth rate. PMID- 21657997 TI - Significantly lower pregnancy rates in the presence of progesterone elevation in patients treated with GnRH antagonists and gonadotrophins: a systematic review and meta-analysis. AB - The current meta-analysis aimed to answer the following research question: is progesterone elevation on the day of hCG administration associated with the probability of clinical pregnancy in women undergoing ovarian stimulation for IVF using GnRH antagonists? A literature search in MEDLINE, EMBASE and CENTRAL electronic databases followed by extensive hand-searching from two independent reviewers was performed to identify relevant studies. Eventually five eligible studies (n=585 patients) were identified. No significant differences were present between patients with and those without progesterone elevation regarding female age, duration of stimulation and total dose of gonadotrophins required. However, patients with progesterone elevation were characterized by higher serum estradiol levels on the day of hCG administration (+956 pg/ml, 95% +248 to +1664, random effects model, p=0.008) and more COCs retrieved (+2.9, 95% CI +1.5 to +4.4, fixed effects model, p < 0.001). Progesterone elevation on the day of hCG administration was associated with a significantly decreased probability of clinical pregnancy per cycle (-9%, 95% CI -17 to -2, fixed model effects, p). In conclusion, in patients treated with GnRH antagonists and gonadotrophins, progesterone elevation on the day of hCG administration is significantly associated with a lower probability of clinical pregnancy. PMID- 21657998 TI - Ovarian stimulation: today and tomorrow. AB - In assisted reproductive technology, medications and ovarian stimulation play a crucial role. The availability of gonadotrophins and GnRH analogues has allowed the tailoring of several stimulation schemes. The two most commonly used gonadotrophin forms are urinary hMG and recombinant FSH in combination with GnRH agonists or GnRH antagonists. Cycles stimulate with recombinant FSH appear to have a higher risk of premature progesterone rise in the late follicular phase, if not triggered on time. Recently, corifollitropin alfa, a new long acting recombinant FSH was introduced which sustain multiple follicular growth for 7 days in women undergoing ovarian stimulation using GnRH antagonists. GnRH antagonist and agonist do have similar live birthrate. However, GnRH antagonists reduce significantly the risk of OHSS. Moreover, with the introduction of GnRH antagonists, it became possible to trigger ovulation with a bolus of a GnRH agonist as an alternative to hCG. The early OHSS is eliminated completely with the GnRH agonist trigger. However, due to an uncorrectable luteal phase deficiency, a poor clinical outcome is present, when GnRHa is used to trigger final oocyte maturation in IVF/ICSI antagonist protocols. Therefore, it has been suggested to cryopreserve the embryos and transfer in consecutive natural cycles. Future trials should aim to eliminate OHSS and multiple pregnancy rates by performing a single stimulation in a simplified corifolitropin alfa/GnRH antagonist cycle triggered by a GnRH agonist followed by Cryo-thawed SET in consecutive natural cycles. With this approach, the two major complications of COH for IVF could be eliminated without jeopardizing the outcome. PMID- 21657999 TI - Present and future of recombinant gonadotropins in reproductive medicine. AB - Pharmacological ovarian stimulation has a major role in reproductive medicine and has been used in anovulatory patients and in the induction of multifollicular development required for the procedures of assisted reproductive techniques (ART). Currently, gonadotropins are the most important tools to proceed with ovarian stimulation for all purposes, including ART and anovulation disorders, like hypogonadotropic hypogonadism and hypothalamic hypophyseal dysfunction. Gonadotropin preparations derived from human urine have been used clinically since the early 1960s and the first urine-derived preparation containing only FSH (urofollitropin) became available in 1983. More recently, the application of recombinant DNA technology has resulted in the development of recombinant FSH produced in mammalian cells. In the last period, LH became available by recombinant DNA technology and is now a new option for protocols of ovarian stimulation. Treatment with gonadotropins has been shown to be effective in males affected by hypogonadotropic hypogonadism. This success has resulted in attempts to utilize FSH therapy in oligozoospermic men, aimed at obtaining a quantitative increase in sperm count. The purpose of this review was to examine the pharmacological aspects and different clinical applications of recombinant gonadotropins (FSH, LH, hCG) in the treatment of female infertility in all its aspects and their use also in the treatment of male infertility. This review will trace these events, from the past through to the present, and conclude with a glance towards the future. PMID- 21658000 TI - ESR1, ESR2 and FSH receptor gene polymorphisms in combination: a useful genetic tool for the prediction of poor responders. AB - PURPOSE: Previous studies in humans concluded that a multigenic model including specific FSHR, ESR1 and ESR2 genotype patterns may partially explain the poor response to FSH. The aim of our study is to analyse three different loci polymorphisms in ESR1 Pvu II, ESR2 Rsa I and Ser680Asn FSH receptor gene- in a Greek population and their involvement in stimulation outcome and pregnancy rates. METHODS: Each locus was studied alone, and in combination with the others. We performed both restriction fragment length polymorphism analysis and real-time polymerase chain reaction. A total of 109 normally ovulating female patients underwent IVF or ICSI. RESULTS: Studying each locus alone, no significant results were drawn for ESR1 and ESR2 genes. Concerning the FSHR polymorphism, the women carrying the AA variant presented higher total amount of gonadotrophins used (P=0,048) and tended to have higher number of stimulation days (P=0,057). Considering the ESR1 and FSHR gene polymorphisms in combination, the TC/SA combination presents the highest number of pregnancies in poor responders group (3/4 pregnancies carried this genotype), in good responders group (4/12 pregnancies carried this genotype) and in the total population (10/26 pregnancies carried this genotype). Except the CC/AA combination, all other genotype combinations presented incidence of pregnancy, with TC/SA having the highest incidence. The CC/AA genotype presents the worst profile of ovulation induction, confirming a poor responder profile: the total amount of gonadotrophins used was highest in CC/AA group (P < 0,05). The peak E2, the number of follicles and of retrieved oocytes and the pregnancy rate were significantly lower (P < 0,05). This genotype combination seems to be over-presented in the poor responders group in a statistically significant way (P=0,038). Women with CC/AA combination have 1,5-2,4 times more risk to be poor responders in comparison with women that do not carry that combination. CONCLUSION: This study supports the hypothesis that a multigenic model, including the well studied ESR1 and FSHR genes is involved in the controlled ovarian stimulation outcome indicating that the CC/AA genotype presents the worst ovulation induction profile, while the TC/SA genotype presents the higher number of pregnancies in our population. PMID- 21658001 TI - Editorial: frontiers in ovarian stimulation. PMID- 21658002 TI - Recent patents of nanodevices for single cell immunological assays. AB - This review focuses on recent patents for the design and implementation of nanodevices to isolate and characterize single immune cells. Specifically, the most common categories of single cell assays were reviewed and new strategies were suggested to expand the capabilities of nanodevices further for the study of human immune disease. PMID- 21658003 TI - Binding affinities of vascular endothelial growth factor (VEGF) for heparin derived oligosaccharides. AB - Heparin and HS (heparan sulfate) exert their wide range of biological activities by interacting with extracellular protein ligands. Among these important protein ligands are various angiogenic growth factors and cytokines. HS binding to VEGF (vascular endothelial growth factor) regulates multiple aspects of vascular development and function through its specific interaction with HS. Many studies have focused on HS-derived or HS-mimicking structures for the characterization of VEGF165 interaction with HS. Using a heparinase 1-prepared small library of heparin-derived oligosaccharides ranging from hexasaccharide to octadecasaccharide, we systematically investigated the heparin-specific structural features required for VEGF binding. We report the apparent affinities for the association between the heparin-derived oligosaccharides with both VEGF165 and VEGF55, a peptide construct encompassing exclusively the heparin binding domain of VEGF165. An octasaccharide was the minimum size of oligosaccharide within the library to efficiently bind to both forms of VEGF and a tetradecasaccharide displayed an effective binding affinity to VEGF165 comparable to unfractionated heparin. The range of relative apparent binding affinities among VEGF and the panel of heparin-derived oligosaccharides demonstrate that the VEGF binding affinity likely depends on the specific structural features of these oligosaccharides, including their degree of sulfation, sugar-ring stereochemistry and conformation. Notably, the unique 3-O sulfo group found within the specific antithrombin binding site of heparin is not required for VEGF165 binding. These findings afford new insight into the inherent kinetics and affinities for VEGF association with heparin and heparin-derived oligosaccharides with key residue-specific modifications and may potentially benefit the future design of oligosaccharide-based anti-angiogenesis drugs. PMID- 21658004 TI - Altering the stability of the Cdc8 overlap region modulates the ability of this tropomyosin to bind co-operatively to actin and regulate myosin. AB - Tm (tropomyosin) is an evolutionarily conserved alpha-helical coiled-coil protein, dimers of which form end-to-end polymers capable of associating with and stabilizing actin filaments, and regulating myosin function. The fission yeast Schizosaccharomyces pombe possesses a single essential Tm, Cdc8, which can be acetylated on its N-terminal methionine residue to increase its affinity for actin and enhance its ability to regulate myosin function. We have designed and generated a number of novel Cdc8 mutant proteins with N-terminal substitutions to explore how stability of the Cdc8 overlap region affects the regulatory function of this Tm. By correlating the stability of each protein, its propensity to form stable polymers, its ability to associate with actin and to regulate myosin, we have shown that the stability of the N-terminal of the Cdc8 alpha-helix is crucial for Tm function. In addition we have identified a novel Cdc8 mutant with increased N-terminal stability, dimers of which are capable of forming Tm polymers significantly longer than the wild-type protein. This protein had a reduced affinity for actin with respect to wild-type, and was unable to regulate actomyosin interactions. The results of the present paper are consistent with acetylation providing a mechanism for modulating the formation and stability of Cdc8 polymers within the fission yeast cell. The data also provide evidence for a mechanism in which Tm dimers form end-to-end polymers on the actin filament, consistent with a co-operative model for Tm binding to actin. PMID- 21658005 TI - Mechanistic studies on the enzymatic processing of fluorinated methionine analogues by Trichomonas vaginalis methionine gamma-lyase. AB - TFM (L-trifluoromethionine), a potential prodrug, was reported to be toxic towards human pathogens that express MGL (L-methionine gamma-lyase; EC 4.4.1.11), a pyridoxal phosphate-containing enzyme that converts L-methionine into alpha oxobutyrate, ammonia and methyl mercaptan. It has been hypothesized that the extremely reactive thiocarbonyl difluoride is produced when the enzyme acts upon TFM, resulting in cellular toxicity. The potential application of the fluorinated thiomethyl group in other areas of biochemistry and medicinal chemistry requires additional studies. Therefore a detailed investigation of the theoretical and experimental chemistry and biochemistry of these fluorinated groups (CF3S- and CF2HS-) has been undertaken to trap and identify chemical intermediates produced by enzyme processing of molecules containing these fluorinated moieties. TvMGL (MGL from Trichomonas vaginalis) and a chemical model system of the reaction were utilized in order to investigate the cofactor-dependent activation of TFM and previously uninvestigated DFM (L-difluoromethionine). The differences in toxicity between TFM and DFM were evaluated against Escherichia coli expressing TvMGL1, as well as the intact human pathogen T. vaginalis. The relationship between the chemical structure of the reactive intermediates produced from the enzymatic processing of these analogues and their cellular toxicity are discussed. PMID- 21658006 TI - The oncogenetic role of microRNA-31 as a potential biomarker in oesophageal squamous cell carcinoma. AB - miR-31 (microRNA-31) is frequently altered in numerous cancers. The aim of the present study was to investigate the role of miR-31 in ESCC (oesophageal squamous cell carcinoma). We measured miR-31 in 45 paired ESCC tissues and 523 serum samples using real-time RT (reverse transcription)-PCR. The serum samples were divided into a discovery group (120 ESCCs and 121 normal controls), a validation group (81 ESCCs and 81 controls), and a final group comprising six other common tumours (colorectal, liver, cervical, breast, gastric and lung cancers; total n=120). A Mann-Whitney U test and Wilcoxon matched-pairs test were used for the statistics. miR-31 was up-regulated in 77.8% of the ESCC tissues. Serum miR-31 levels in ESCC patients were significantly higher than in normal controls (P<0.001). It yielded an ROC (receiver operating characteristic) AUC (area under the curve) of 0.902 [95% CI (confidence interval), 0.857-0.936] in the discovery group and a similar result in the validation group [ROC AUC, 0.888 (95% CI, 0.819 0.939)]. Patients with high-levels of serum miR-31 also had a poorer prognosis in relapse-free survival (P=0.001) and tumour-specific survival (P=0.005). In vitro studies showed that miR-31 promoted ESCC colony formation, migration and invasion. Luciferase reporter and Western blot assays confirmed that three tumour suppressor genes, namely EMP1 (epithelial membrane protein 1), KSR2 (kinase suppressor of ras 2) and RGS4 (regulator of G-protein signalling 4), were targeted by miR-31. We conclude that miR-31 plays oncogenetic functions and can serve as a potential diagnostic and prognostic biomarker for ESCC. PMID- 21658007 TI - TRALI-new challenges for histocompatibility and immunogenetics in transfusion medicine. AB - Antibodies against human leukocyte antigens (HLAs) have long been associated with transfusion-related acute lung injury (TRALI). In contrast to febrile transfusion reactions and refractoriness to platelet transfusions in immunized patients, the causative antibodies in TRALI are present in the transfused blood component, i.e. they are formed by the blood donor and not by the recipient. Consequently, blood components with high plasma volume are particularly associated with TRALI. In addition to antibodies against HLAs, antibodies directed against human neutrophil antigens (HNAs) present in the plasma of predominantly multiparous female blood donors can induce severe TRALI reactions. Especially, antibodies to HLA class II and HNA-3a antigens can induce severe or even fatal ALI in critically ill patients. Over the last decade, the clinical importance of TRALI as major cause for severe transfusion-related morbidities has led to the establishment of new guidelines aimed at preventing this condition, including routine testing for HLA and -HNA antibodies for plasma donors with a history of allogeneic sensitization. This, in turn, poses new challenges for close collaboration between blood transfusion centers and histocompatibility and immunogenetics laboratories, for sensitive and specific detection of the relevant antibodies. PMID- 21658008 TI - Nomenclature for factors of the HLA system, update March 2011. PMID- 21658009 TI - Characterization and polymorphic analysis of 4.5 kb genomic full-length HLA-C in the Chinese Han population. AB - This study used long-range polymerase chain reaction to sequence 4.5 or 4.3 kb of genomic DNA covering human leukocyte antigen C (HLA-C) and its flanks in 45 Chinese Han subjects to better characterize variation in the gene in a single population. Sequences of 35 HLA-C alleles were obtained from the population, including major alleles of 13 lineages of HLA-C. Four novel alleles, C*03:04:01:02, C*04:01:01:03, C*08:22, and C*17:01:01:02, were identified, and complete full-length sequences of 18 HLA-C alleles were obtained for the first time. All sequences herein reported also represent extensions through the promoter region and the 3'-untranslated region. Fourteen 5'-nucleotide sequences and 14 3'-nucleotide sequences were detected outside the coding region. In total, 316 single-nucleotide polymorphisms unequally distributed in HLA-C subregions were observed. In addition to exons 2 and 3, nucleotide variability was found to be particularly high in exon 5, which encodes the transmembrane region. The differentiation of the C*07 and C*17 lineages in this region accounts for the high variability. The congruence of phylogeny across most regions of the gene suggests that gene conversion or recombination has not markedly influenced divergence between lineages in the evolution of HLA-C. PMID- 21658010 TI - Scandinavian glutamine trial: a pragmatic multi-centre randomised clinical trial of intensive care unit patients. AB - BACKGROUND: Low plasma glutamine concentration is an independent prognostic factor for an unfavourable outcome in the intensive care unit (ICU). Intravenous (i.v.) supplementation with glutamine is reported to improve outcome. In a multi centric, double-blinded, controlled, randomised, pragmatic clinical trial of i.v. glutamine supplementation for ICU patients, we investigated outcomes regarding sequential organ failure assessment (SOFA) scores and mortality. The hypothesis was that the change in the SOFA score would be improved by glutamine supplementation. METHODS: Patients (n=413) given nutrition by an enteral and/or a parenteral route with the aim of providing full nutrition were included within 72 h after ICU admission. Glutamine was supplemented as i.v. l-alanyl-l-glutamine, 0.283 g glutamine/kg body weight/24 h for the entire ICU stay. Placebo was saline in identical bottles. All included patients were considered as intention-to-treat patients. Patients given supplementation for >3 days were considered as predetermined per protocol (PP) patients. RESULTS: There was a lower ICU mortality in the treatment arm as compared with the controls in the PP group, but not at 6 months. For change in the SOFA scores, no differences were seen, 1 (0,3) vs. 2 (0.4), P=0.792, for the glutamine group and the controls, respectively. CONCLUSION: In summary, a reduced ICU mortality was observed during i.v. glutamine supplementation in the PP group. The pragmatic design of the study makes the results representative for a broad range of ICU patients. PMID- 21658011 TI - The intensive care delirium screening checklist: translation and reliability testing in a Swedish ICU. AB - BACKGROUND: The view of delirium has changed considerably over the last decade, and delirium is now a very topical issue within the intensive care unit (ICU) setting. Delirium has proved to be common in critically ill patients and is manifested as acute changes in mental status with reduced cognitive ability, incoherent thought patterns, impaired consciousness, agitation and acute confusion. In order to be able to prevent, identify and alleviate problems related to delirium it is important that validated instruments for delirium screening are implemented and evaluated. The aim of this study was to translate the Intensive Care Delirium Screening Checklist (ICDSC) into Swedish and test the inter-rater reliability in a Swedish general ICU setting. METHODS: The study was carried out during 2009 in a general Swedish ICU. A translation of the scale from English into Swedish was made, including back-translation, critical review and pilot testing. A total of 49 paired ratings were carried out using the Swedish version of the ICDSC scale. The inter-rater reliability was tested using weighted kappa (kappa) statistics (linear weighting). RESULTS: The ICDSC scale was successfully translated into Swedish and the inter-rater reliability testing of the Swedish version resulted in a weighted k value of 0.92. CONCLUSION: The result of this study indicates that the Swedish version of the ICDSC scale has a very good inter-rater reliability. The high inter-rater reliability and the ease of administration make the ICDSC scale applicable for delirium screening in a Swedish ICU setting. PMID- 21658012 TI - Anaesthesia for endoscopic retrograde cholangiopancreatography. AB - Endoscopic Retrograde Cholangiopancreatography is used for both diagnostic and therapeutic purposes. It is relatively more complex than routine endoscopies and requires adequate patient sedation. Furthermore the patients often have co morbidities. This article provides an overview of various anaesthetic drugs and the type of anaesthesiological support. PMID- 21658013 TI - Heart rate variability: a diagnostic and prognostic tool in anesthesia and intensive care. AB - The autonomic nervous system (ANS) plays an important role in the human response to various internal and external stimuli, which can modify homeostasis, and exerts a tight control on essential functions such as circulation, respiration, thermoregulation and hormonal secretion. ANS dysfunction may complicate the perioperative course in the surgical patient undergoing anesthesia, increasing morbidity and mortality, and, therefore, it should be considered as an additional risk factor during pre-operative evaluation. Furthermore, ANS dysfunction may complicate the clinical course of critically ill patients admitted to intensive care units, in the case of trauma, sepsis, neurologic disorders and cardiovascular diseases, and its occurrence adversely affects the outcome. In the care of these patients, the assessment of autonomic function may provide useful information concerning pathophysiology, risk stratification, early prognosis prediction and treatment strategies. Given the role of ANS in the maintenance of systemic homeostasis, anesthesiologists and intensivists should recognize as critical the evaluation of ANS function. Measurement of heart rate variability (HRV) is an easily accessible window into autonomic activity. It is a low-cost, non-invasive and simple to perform method reflecting the balance of the ANS regulation of the heart rate and offers the opportunity to detect the presence of autonomic neuropathy complicating several illnesses. The present review provides anesthesiologists and intensivists with a comprehensive summary of the possible clinical implications of HRV measurements, suggesting that autonomic dysfunction testing could potentially represent a diagnostic and prognostic tool in the care of patients both in the perioperative setting as well as in the critical care arena. PMID- 21658014 TI - Effect of PEEP on regional ventilation during laparoscopic surgery monitored by electrical impedance tomography. AB - BACKGROUND: Anesthesia per se and pneumoperitoneum during laparoscopic surgery lead to atelectasis and impairment of oxygenation. We hypothesized that a ventilation with positive end-expiratory pressure (PEEP) during general anesthesia and laparoscopic surgery leads to a more homogeneous ventilation distribution as determined by electrical impedance tomography (EIT). Furthermore, we supposed that PEEP ventilation in lung-healthy patients would improve the parameters of oxygenation and respiratory compliance. METHODS: Thirty-two patients scheduled to undergo laparoscopic cholecystectomy were randomly assigned to be ventilated with ZEEP (0 cmH(2)O) or with PEEP (10 cmH(2)O) and a subsequent recruitment maneuver. Differences in regional ventilation were analyzed by the EIT-based center-of-ventilation index (COV), which quantifies the distribution of ventilation and indicates ventilation shifts. RESULTS: Higher amount of ventilation was examined in the dorsal parts of the lungs in the PEEP group. Throughout the application of PEEP, a lower shift of ventilation was found, whereas after the induction of anesthesia, a remarkable ventral shift of ventilation in ZEEP-ventilated patients (COV: ZEEP, 40.6 +/- 2.4%; PEEP, 46.5 +/- 3.5%; P<0.001) was observed. Compared with the PEEP group, ZEEP caused a ventral misalignment of ventilation during pneumoperitoneum (COV: ZEEP, 41.6 +/- 2.4%; PEEP, 44 +/- 2.7%; P=0.013). Throughout the study, there were significant differences in the parameters of oxygenation and respiratory compliance with improved values in PEEP-ventilated patients. CONCLUSION: The effect of anesthesia, pneumoperitoneum, and different PEEP levels can be evaluated by EIT based COV monitoring. An initial recruitment maneuver and a PEEP of 10 cmH(2)O preserved homogeneous regional ventilation during laparoscopic surgery in most, but not all, patients and improved oxygenation and respiratory compliance. PMID- 21658015 TI - Diagnostic accuracy of ultrasonography of optic nerve sheath diameter for detecting raised intracranial pressure. PMID- 21658016 TI - Instability in non-invasive haemoglobin measurement: a possible influence of oxygen administration. PMID- 21658018 TI - Cardiac displacement-induced hemodynamic instability during off-pump coronary artery bypass surgery and its predictors. AB - BACKGROUND: Emergent conversion to an on-pump procedure during an off-pump coronary artery bypass surgery (OPCAB) due to hemodynamic instability is associated with increased morbidity and mortality. The aim of this study was to evaluate the predictors of hemodynamic instability associated with mechanical heart displacement during OPCAB and the fate of these patients. METHODS: Data of 494 patients who underwent elective, isolated OPCAB between December 2006 and April 2010 were reviewed. Hemodynamic instability was defined as mixed venous oxygen saturation (SvO(2) ) <60% during grafting. Pre-operative variables including the presence of diastolic dysfunction and mitral regurgitation (MR) were evaluated for their predictive value for hemodynamic instability by logistic regression analysis. Outcome variables were also compared between patients who developed hemodynamic instability and those who did not. RESULTS: In univariate analysis, body mass index, diabetes mellitus, chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction, diastolic dysfunction, MR >= grade 1, higher creatinine and the use of diuretics were identified as risk factors. In multivariate analysis of these variables, COPD and creatinine remained as independent risk factors for hemodynamic instability. These patients also had significantly lower cardiac output and SvO(2) after sternum closure and a higher incidence of composite morbidity end points. CONCLUSION: COPD and pre operative creatinine level were identified as independent risk factors of mechanical heart displacement-induced hemodynamic instability during OPCAB. As these patients were associated with significantly lower SvO(2) even at the end of surgery and with adverse outcome, consideration may be given to initiate preemptive measures to increase SvO(2) before or during grafting. PMID- 21658019 TI - Early detection of the graft failure after pediatric liver transplantation: a Bergamo experience. AB - BACKGROUND: Effective indicators of the early graft failure after pediatric liver transplantation are currently a crucial question. The aim of this study was to analyze retrospectively laboratory parameters that may help anticipate an early graft loss (GL). METHODS: The 131 pediatric liver transplantations, performed in our hospital from January 2002 to December 2005, were reviewed. Post-operative laboratory parameters, collected in the first 36 h of the Paediatric Intensive Care Unit (PICU) stay, were analyzed for children with both graft survival and GL. Receiver operating characteristics analysis was used to identify the optimal cut-off for the laboratory parameters. Multivariate logistic regression analysis was used to calculate the adjusted risk of GL for the prognostic parameters identified. RESULTS: The mean age at transplant was 1.1 years. The two groups were comparable for all recipient and donor variables considered. Children with GL showed significantly higher levels of ammonia and transaminase at the admission to the PICU and higher levels of prothrombin time, creatinine, lactate and a lower level of platelets at the 36 h of PICU. The laboratory parameters over the cut-off value by the multivariate logistic regression identified all early thromboses earlier than Doppler ultrasound. CONCLUSIONS: This study suggests that routine blood tests may help to anticipate an early loss of liver grafts in children after transplantation and may improve our diagnostic investigation in the case of thrombosis suspicion. Further validation by a prospective study is needed to carefully assess the sensitivity and specificity of the identified criteria. PMID- 21658020 TI - Patients' participation in and evaluation of a follow-up program following intensive care. AB - BACKGROUND: Patients' difficulties following critical illness and the willingness of intensive care units (ICU) to take an expanded responsibility during the recovery period have led to the development of different follow-up programs. The aim of this study was to explore and describe patients' participation in and evaluation of a follow-up program at a nurse-led clinic (NLC). METHODS: Patients with a length of stay >=72 h, discharged from the ICU, participated in a follow up program based on three contacts, as a visit to the NLC, telephone contact, ward visit or as an indirect contact, during a 6-month period. A specially developed database recorded information regarding patients' participation and questionnaires were used to obtain patients' views of the follow-up program. RESULTS: Of 96 study patients, 51% visited the NLC once or twice. These patients were younger (P<0.001) and had lower Acute Physiology and Chronic Health Evaluation II (P=0.017) compared with those who did not visit the clinic. The most common reason for not visiting the clinic was not enough strength, chiefly physical. In the evaluation, patients answered that they received advice and information, an opportunity to talk, increased knowledge and re-evaluated memories and experiences from the ICU stay. Patients appreciated the follow-up and expressed gratitude to the competent and obliging staff. CONCLUSION: The current follow-up program, adjusted to individual patients' conditions and needs in terms of different types of contacts and continuity, was found to be of great value. Effects of the program other than the patient perspective are also relevant to evaluate. PMID- 21658021 TI - Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy. AB - BACKGROUND AND PURPOSE: Our previous studies demonstrated that a thiosemicarbazone iron chelator (di-2-pyridylketone-4,4-dimethyl-3 thiosemicarbazone; Dp44mT) possesses potent and selective anti-cancer activity but led to cardiotoxicity at non-optimal doses. In this study, we examined the in vivo anti-tumour efficacy and tolerability of a new-generation 2-benzoylpyridine thiosemicarbazone iron chelator (2-benzoylpyridine-4,4-dimethyl-3 thiosemicarbazone; Bp44mT) administered via the oral or i.v. routes. EXPERIMENTAL APPROACH: BpT chelators were tested in vitro against human lung cancer cells (DMS 53) and in vivo in DMS-53 tumour xenografts in mice. The toxicity of Bp44mT in vivo and its effects on the expression of iron-regulated molecules involved in growth and cell cycle control were investigated. KEY RESULTS: Administration of Bp44mT by either route resulted in marked dose-dependent inhibition of tumour growth. When administered at 50 mg.kg(-1) via oral gavage three times per week for 23 days, the net xenograft growth was inhibited by 75%, compared with vehicle treated mice. Toxicological examination showed reversible alterations including slight reduction of RBC count, with a decrease of liver and splenic iron levels, which confirmed iron chelation in vivo. Importantly, in contrast to Dp44mT, the chelator-treated mice did not show cardiac histological abnormalities. There was also no significant weight loss in mice, suggesting oral administration of Bp44mT was well tolerated. CONCLUSIONS AND IMPLICATIONS: This is the first study to show that Bp44mT can be given orally with potent anti-tumour efficacy. Oral administration of a novel and effective chemotherapeutic agent provides the benefits of convenience for chronic dosing regimens. PMID- 21658022 TI - Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti inflammatory and superoxide dismutase scavenging properties in A459 cells. AB - BACKGROUND AND PURPOSE: Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox-active nitroxide group. TEMPO-aspirin (TEMPO-ASA) and TEMPO indomethacin (TEMPO-IND) were synthesized and evaluated in the lung cancer cell line A549. EXPERIMENTAL APPROACHES: We evaluated physico-chemical properties of TEMPO-ASA and TEMPO-IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase-like properties was assayed by measuring cytochrome c reduction and anti-inflammatory effects were assayed by measuring production of prostaglandin E(2) (PGE(2) ) and leukotriene B(4) (LTB(4) ). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo. KEY RESULTS: MTD were: TEMPO (140 mg.kg(-1) ), ASA (100 mg.kg(-1) ), indomethacin (5 mg.kg(-1) ), TEMPO-ASA (100 mg.kg(-1) ) and TEMPO-IND (40 mg.kg(-1) ). While TEMPO-ASA was as well tolerated as ASA, TEMPO IND showed an eightfold improvement over indomethacin. TEMPO-IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO-ASA and TEMPO-IND inhibited production of PGE(2) and LTB(4) in A549 cells with maximum effects at 100 ug.mL(-1) or 10 ug.mL(-1) respectively. CONCLUSIONS AND IMPLICATIONS: The nitroxide-NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti-inflammatory effects, inhibiting cyclooxygenase and 5-lipoxygenase enzymes. These redox-modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID-associated toxicity. PMID- 21658024 TI - A holistic view of adenosine in the control of intestinal neuromuscular functions: the enteric 'purinome' concept. AB - Adenosine is involved in the modulation of enteric neuromuscular functions, operating a fine tuning of smooth muscle contractility, peristaltic reflex and transit. In this issue of the BJP, Zizzo et al. report novel findings on the expression of adenosine receptors in mouse duodenum, extending our knowledge of their involvement in the control of spontaneous and neurogenic intestinal motility. In this study, particular attention was paid to the differential activation of adenosine receptors, as a result of their interplay with regulatory systems, modulating the availability of endogenous adenosine in a compartmentalised manner. This evidence will contribute to the holistic evaluation of the role played by adenosine in the regulation of intestinal motility, in accordance with the novel concept of the enteric 'purinome'. This commentary discusses the role of the 'purinome' in the modulation of enteric neuromuscular activity, pointing out its involvement in the intestinal neuroplasticity associated with bowel dysmotility. PMID- 21658025 TI - The pharmacology of adrenomedullin 2/intermedin. AB - Adrenomedullin 2 (AM2) or intermedin is a member of the calcitonin gene-related peptide (CGRP)/calcitonin family of peptides and was discovered in 2004. Unlike other members of this family, no unique receptor has yet been identified for it. It is extensively distributed throughout the body. It causes hypotension when given peripherally, but when given into the CNS, it increases blood pressure and causes sympathetic activation. It also increases prolactin release, is anti diuretic and natriuretic and reduces food intake. Whilst its effects resemble those of AM, it is frequently more potent. Some characterization of AM2 has been done on molecularly defined receptors; the existing data suggest that it preferentially activates the AM(2) receptor formed from calcitonin receptor-like receptor and receptor activity modifying protein 3. On this complex, its potency is generally equivalent to that of AM. There is no known receptor-activity where it is more potent than AM. In tissues and in animals it is frequently antagonised by CGRP and AM antagonists; however, situations exist in which an AM2 response is maintained even in the presence of supramaximal concentrations of these antagonists. Thus, there is a partial mismatch between the pharmacology seen in tissues and that on cloned receptors. The only AM2 antagonists are peptide fragments, and these have limited selectivity. It remains unclear as to whether novel AM2 receptors exist or whether the mismatch in pharmacology can be explained by factors such as metabolism. PMID- 21658023 TI - Small lipid-binding proteins in regulating endothelial and vascular functions: focusing on adipocyte fatty acid binding protein and lipocalin-2. AB - Dysregulated production of adipokines from adipose tissue plays a critical role in the development of obesity-associated cardiovascular abnormalities. A group of adipokines, including adipocyte fatty acid binding protein (A-FABP) and lipocalin 2, possess specific lipid-binding activity and are up-regulated in obese human subjects and animal models. They act as lipid chaperones to promote lipotoxicity in endothelial cells and cause endothelial dysfunction under obese conditions. However, different small lipid-binding proteins modulate the development of vascular complications in distinctive manners, which are partly attributed to their specialized structural features and functionalities. By focusing on A-FABP and lipocalin-2, this review summarizes recent advances demonstrating the causative roles of these newly identified adipose tissue-derived lipid chaperones in obesity-related endothelial dysfunction and cardiovascular complications. The specific lipid-signalling mechanisms mediated by these two proteins are highlighted to support their specialized functions. In summary, A-FABP and lipocalin-2 represent potential therapeutic targets to design drugs for preventing vascular diseases associated with obesity. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. PMID- 21658026 TI - The effect of K201 on isolated working rabbit heart mechanical function during pharmacologically induced Ca2+ overload. AB - BACKGROUND AND PURPOSE: Reduced cardiac contractility has been associated with disrupted myocardial Ca(2+) signalling. The 1,4 benzothiazepine K201 (JTV-519) acts on several Ca(2+) handling proteins and improves cardiac contractility in vivo in a variety of animal models of myocardial dysfunction. However, it is unclear whether this improvement depends on the systemic effects of K201 or if K201 reverses the effects of Ca(2+) dysregulation, regardless of the cause. EXPERIMENTAL APPROACH: The effect of K201 on cardiac mechanical function was assessed in isolated working hearts from adult rabbits, using a ventricular pressure-volume catheter. In separate experiments, the effect of K201 was investigated in hearts following pharmacologically induced Ca(2+) overload using elevated extracellular [Ca(2+) ] ([Ca(2+) ](o) ) and beta-adrenoceptor stimulation. KEY RESULTS: K201 induced a concentration-dependent decline in systolic function (peak pressure, dP/dt(max) and preload recruitable stroke work), lusitropy (reduced dP/dt(min) and increased end diastolic pressure) and stroke volume, independent of decreased heart rate. In separate experiments, mechanical function in hearts exposed to 4.5 mmol.L(-1) [Ca(2+) ](o) and 150 nmol.L(-1) isoprenaline declined until cessation of aortic flow (in 6 out of 11 hearts). However, all hearts perfused with the addition of 1 umol.L(-1) K201 maintained aortic flow and demonstrated significantly improved peak systolic pressures, dP/dt(max) and dP/dt(min) . CONCLUSIONS AND IMPLICATIONS: K201 significantly improved mechanical function of the heart during Ca(2+) overload. This suggests that K201 can limit the detrimental effects of elevated intracellular Ca(2+) and exert beneficial effects on cardiac contractile function, independent of systemic effects previously observed in vivo. PMID- 21658027 TI - Plumbagin inhibits tumour angiogenesis and tumour growth through the Ras signalling pathway following activation of the VEGF receptor-2. AB - BACKGROUND AND PURPOSE: Angiogenesis-based therapy is an effective anti-tumour strategy and previous reports have shown some beneficial effects of a naturally occurring bioactive compound plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone). Here, we sought to determine the biological effects of plumbagin on signalling mechanisms during tumour angiogenesis. EXPERIMENTAL APPROACH: The effects of plumbagin were evaluated in various in vitro assays which utilised human umbilical vein endothelial cells (HUVEC) proliferation, migration and tube formation. Plumbagin was also evaluated in vivo using chicken embryo chorioallantoic membrane (CAM) and mouse corneal micropocket models., Human colon carcinoma and prostate cancer xenograft mouse models were used to evaluate the effects of plumbagin on angiogenesis. Immunofluorescence, GST pull-down and Western blotting were employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated Ras signalling pathways. KEY RESULTS: Plumbagin not only inhibited endothelial cell proliferation, migration and tube formation but also suppressed chicken chorioallantoic membrane neovascularzation and VEGF induced mouse corneal angiogenesis. Moreover, plumbagin suppressed tumour angiogenesis and tumour growth in human colon carcinoma and prostate cancer xenograft mouse models. At a molecular level, plumbagin blocked the Ras/Rac/cofilin and Ras/MEK signalling pathways mediated by VEGFR2 in HUVECs. CONCLUSIONS AND IMPLICATIONS: Plumbagin inhibited tumour angiogenesis and tumour growth by interference with the VEGFR2-mediated Ras signalling pathway in endothelial cells. Our findings demonstrate a molecular basis for the effects of plumbagin and suggest that this compound might have therapeutic ant-tumour effects. PMID- 21658029 TI - Diagnostic criteria for headache due to spontaneous intracranial hypotension: a perspective. AB - The clinical and radiographic manifestations of spontaneous intracranial hypotension are highly variable and many patients do not satisfy the 2004 International Classification of Headache Disorders criteria. We developed new diagnostic criteria for spontaneous intracranial hypotension based on cases we have seen reflecting the variable manifestations of the disorder. These criteria provide a basis for change when the classification criteria are next revised. The diagnostic criteria consist of A, orthostatic headache; B, the presence of at least one of the following: low opening pressure (<= 60 mm H(2) O), sustained improvement of symptoms after epidural blood patching, demonstration of an active spinal cerebrospinal fluid leak, cranial magnetic resonance imaging changes of intracranial hypotension (eg, brain sagging or pachymeningeal enhancement); C, no recent history of dural puncture; and D, not attributable to another disorder. PMID- 21658030 TI - The impact of locus of control and priming on the endowment effect. AB - This paper demonstrates the effects of different priming conditions on the endowment effect with respect to seller and buyer roles for individuals with different loci of control. Individuals with an external locus of control process information less rationally, and they are more susceptible to external influences. In addition, the literature reports that when individuals are making a purchasing decision, they tend to perceive the value of the product as being higher because of its utility aspect because decision makers search for reasons and arguments to justify their choices (Shafir 1993; Tversky & Griffin, 1991). Therefore, this study investigates the effects of different priming conditions (utilitarian priming vs. hedonic priming) on the endowment effect according to each type of locus of control (internal vs. external). The results showed that the endowment effect was larger when externals were exposed to utilitarian priming as opposed to hedonic priming. Finally, the implications of these findings and suggestions for future research are discussed. PMID- 21658028 TI - Are the pharmacology and physiology of alpha2 adrenoceptors determined by alpha2 heteroreceptors and autoreceptors respectively? AB - alpha(2)-Adrenoceptors are important mediators of physiological responses to the endogenous catecholamines noradrenaline and adrenaline. In addition, alpha(2) adrenoceptors are pharmacological targets for the treatment of hypertension, sympathetic overactivity and glaucoma. alpha(2)-Adrenoceptors are also targeted to induce sedation and analgesia in anaesthesia and intensive care. alpha(2) Adrenoceptors were first described as presynaptic receptors inhibiting the release of various transmitters from neurons in the central and peripheral nervous systems. In addition to these presynaptic neuronal receptors, alpha(2) adrenoceptors were also identified in many non-neuronal cell types of the body. Gene-targeting in mice provided a comprehensive assignment of the physiological and pharmacological functions of these receptors to specific alpha(2A)-, alpha(2B) - and alpha(2C)-adrenoceptor subtypes. However, the specific cell types and signalling pathways involved in these subtype-specific alpha(2)-adrenoceptor functions were largely unexplored until recently. This review summarizes recent findings from transgenic mouse models, which were generated to define the role of alpha(2)-adrenoceptors in adrenergic neurons, that is, alpha(2)-autoreceptors, versus alpha(2)-adrenoceptors in non-adrenergic neurons, termed alpha(2) heteroreceptors. alpha(2)-Autoreceptors are primarily required to limit release of noradrenaline from sympathetic nerves and adrenaline from adrenal chromaffin cells at rest. These receptors are desensitized upon chronic activation as it may for instance occur due to enhanced sympathetic activity during chronic heart failure. In contrast, pharmacological effects of acutely administered alpha(2) adrenoceptor agonist drugs essentially require alpha(2)-heteroreceptors in non adrenergic neurons, including analgesia, sedation, hypothermia and anaesthetic sparing as well as bradycardia and hypotension. Thus a clear picture has emerged of the significance of auto- versus heteroreceptors in mediating the physiological functions of alpha(2)-adrenoceptors and the pharmacological functions of alpha(2)-adrenoceptor agonist drugs respectively. PMID- 21658032 TI - Alloimmunization and granulocyte transfusion: a new study confirms old lessons. PMID- 21658033 TI - Residual risk of D alloimmunization: is it time to feel safe about platelets from D+ donors? PMID- 21658034 TI - Lipemic plasma: a renaissance. PMID- 21658035 TI - Transfusion medicine history illustrated: A historic picture: the first transfusion of citrated blood. PMID- 21658037 TI - Donation frequency of blood donors participating in a prospective cohort study of iron status. AB - BACKGROUND: Blood centers are interested in understanding determinants of frequent blood donation. We hypothesized that participation in uncompensated research could result in higher donation rates. STUDY DESIGN AND METHODS: Donation rates for 2425 subjects from six US blood centers enrolled in the Retrovirus Epidemiology Donor Study-II Donor Iron Status Evaluation Study were compared to those of nonenrolled donors (n = 202,383). Over 15 months, we compared mean donation rates and adjusted rate ratios (RRs) between enrolled and nonenrolled for three subgroups, first-time, reactivated, and frequent donors, and donation rates before and after the study enrollment period for frequent donors only. RESULTS: Enrolled donors had higher 15-month mean donation rates than nonenrolled donors (first-time, 1.21 [RR = 1.91]; reactivated, 1.68 [RR = 1.83]; frequent, 3.40 [RR = 1.12]). However, frequent donors donated at approximately the same rate after enrollment as they did before enrollment in the study (3.62 per 15 months [RR = 1.12]). CONCLUSION: Donors enrolled in the study donated at a higher rate than nonenrolled donors, but frequent donors remained consistent in their donation frequency both before and after enrollment. Although increased donation rates could have been causally related to study enrollment, we cannot rule out an enrollment bias whereby more committed donors were more likely to enroll in the study. PMID- 21658038 TI - A validation study of new cryopreservation bags for implementation in a blood and marrow transplant laboratory. AB - BACKGROUND: A new cryopreservation bag for hematopoietic cell transplantation requires validation as a safe alternative to the bag currently being used in the laboratory. STUDY DESIGN AND METHODS: The new bag was validated using both laboratory and clinical criteria. Laboratory validation proceeded using paired samples of mononuclear cells processed using standard procedures. Cells cryopreserved in the new and old bags were compared for viability, cell counts, CD34 enumeration, colony-forming unit assays, and bag integrity. After completion of laboratory investigations, engraftment with the new bags was followed and compared to historical engraftment using the old bags. RESULTS: There were no significant differences between the old and new bags detected using laboratory studies. Bag integrity was equivalent. The validation data suggested impaired cell function after cryopreservation in the new bags, but there were no significant differences in engraftment potential using either material. Days to engraftment was longer using the new bags, but statistical analysis revealed an association with CD34 dose and not with cryopreservation bag type. CONCLUSION: The new bags were noninferior to the old bags. A change in cryopreservation bag type may appear to affect cell function and potentially affect engraftment. Multiple analyses may be needed to understand the effect of cell processing changes. PMID- 21658039 TI - Use of cryopreserved autologous cells for extracorporeal photochemotherapy: clinical applications. AB - BACKGROUND: Using autologous cryopreserved mononuclear cells (MNCs) for extracorporeal photochemotherapy (ECP) offers several advantages, such as treating patients from geographically distant care centers or maintaining ECP schedule while dramatically reducing number of apheresis sessions. We previously reported that cryopreserved cells retain their immunomodulatory properties when exposed to UVA and psoralen. To date, there are no clinical data on the use of cryopreserved MNCs for ECP ("cryo-ECP"). CASE REPORTS: Three patients were treated by cryo-ECP for refractory dermatomyositis, juvenile localized scleroderma, and acute graft-versus-host disease. For the first two patients, cryo-ECP aimed to reduce the number of apheresis sessions. Each cell product was split into three equal fractions: one was infused, and the other two were frozen for later infusion. The third patient was referred to our center from a hospital 700 km away. Fifteen apheresis procedures were performed during his stay: 12 were immediately treated and infused while three were cryopreserved. After discharge, the three cryopreserved bags were thawed, ECP-treated, and then sent back to the patient. CONCLUSION: In all three patients, cryo-ECP was safe and feasible. These cases illustrate promising clinical applications of the technique, opening perspectives for making ECP much more acceptable to patients while extending its indications. PMID- 21658040 TI - The hemostatic efficacy of platelet components prepared with pathogen inactivation. PMID- 21658042 TI - Local DNA sequence determinants of FUT2 copy number variation. PMID- 21658043 TI - Clarify the negatives of the MIRASOL noninferiority trial. PMID- 21658045 TI - The effects of a phone call prompt on subsequent blood donation among first-time donors. AB - BACKGROUND: A strategy used by blood centers to retain donors is to place phone call reminders. However, among first-time donors, no studies have tested the effect of this strategy. This was the aim of this study among individuals who had recently given their first lifetime blood donation. STUDY DESIGN AND METHODS: A quasi-experimental study using a nonequivalent control group was adopted; participants in the control group were donors with blood types B+ and AB+, since these individuals are not phoned by the blood agency. A total of 1604 first-time donors aged 18 to 70 years from the province of Quebec, Canada, were assigned to the experimental (n = 870) or the control (n = 734) group. Participants in the experimental group were phoned a few days before they had a new opportunity to give blood while those in the control condition were not phoned. RESULTS: In the experimental condition, 48.3% of the donors attempted to give blood during the 12 month follow-up period compared to 38.0% in the control condition. The hazards of the first blood donation attempt among donors who were phoned were 32% higher compared to the hazards of those who were not phoned (p = 0.0004). CONCLUSION: The results of this study indicate that a first phone call reminder about the upcoming opportunity to give blood again has a significant positive effect on return rates among first-time donors. PMID- 21658046 TI - Transfusion requirements in obstetric patients with placenta accreta. AB - BACKGROUND: Providing transfusion support for patients with placenta accreta is a challenging task. There is no consensus on predelivery transfusion planning for these patients and the prevalence of massive transfusion is unknown. With little published experience, it is difficult to predict blood component usage accurately. Therefore, this retrospective study spanning 14 years quantified blood usage and clinical outcome in a group of patients with placenta accreta. STUDY DESIGN AND METHODS: A retrospective medical record review identified 66 patients with placenta accreta who presented for delivery. Data were extracted from the patients' medical records related to patient demographics, pathology diagnosis, blood component usage, operative course, and clinical outcome. Selected variables were analyzed for statistical association with total blood component usage. RESULTS: The range of blood component usage was 0 to 46 red blood cell (RBC) units, 0 to 48 random-donor platelet unit equivalents, 0 to 64 plasma units, and 0 to 30 cryoprecipitate units. The incidence of transfusion was 95% (mean RBC use, 10 +/- 9 units; median, 6.5 units), with 39% of patients requiring 10 or more RBC units and 11% requiring 20 or more RBC units. Blood component use did not differ significantly between the pathology-defined placenta accreta subtypes. Potential clinical laboratory variables that would predict increased blood component use were not identified. CONCLUSION: The delivery of patients with placenta accreta is a high-risk procedure that requires multidisciplinary planning and adequate resources to optimize outcome. Transfusion services should have a protocol for managing these cases that addresses preoperative blood component preparation and intraoperative management, should massive hemorrhage occur. PMID- 21658047 TI - Efficacy and cost-benefit analysis of risk-adaptive use of plerixafor for autologous hematopoietic progenitor cell mobilization. AB - BACKGROUND: Plerixafor (P) reduces mobilization failure rates but it is very expensive. For better utilization of P, we employed a risk-adaptive strategy of using it only in patients who are at high risk of mobilization failure, defined by peripheral blood (PB) CD34+ cell count of fewer than 10*10(6)/L after 4 days of filgrastim (F) alone. STUDY DESIGN AND METHODS: Herein, we present the results of efficacy and cost-benefit analysis of this risk-adaptive approach for hematopoietic progenitor cell (HPC) collection. All patients received daily F for 4 days, and P was added for those "at-risk" patients from Day 4 with apheresis commencing the following morning. F and P were continued daily for up to a maximum of 4 days or until more than 5*10(6) CD34+ cells/kg were collected. Forty two transplant-eligible patients underwent HPC mobilization. RESULTS: Eighteen patients mobilized with F alone and 24 patients required P with F. Two patients failed adequate HPC mobilization after F+P. Addition of P increased the PB CD34+ count by 6.8-fold with a mean yield of 4.9*10(6) CD34+ cells/kg. Decision analysis model estimated cost-effectiveness for this risk-adaptive approach of using P with savings of $19,300/patient. Engraftment after HPC infusion was similar among the patients regardless of mobilization regimens. CONCLUSION: These results suggest that addition of P to F based on a risk-adaptive strategy significantly reduces the frequency of mobilization failures and is also cost effective. PMID- 21658048 TI - Anti-D investigations in individuals expressing weak D Type 1 or weak D Type 2: allo- or autoantibodies? AB - BACKGROUND: Whether anti-D produced by individuals with a weak D phenotype are allo- or autoantibodies remains a matter of debate even though blood transfusion practice is impacted. The aim of our study was to determine the serologic features of anti-D in individuals expressing the most frequent weak D type in Caucasians that are weak D Type 1 or weak D Type 2, to assess whether anti-D were allo- or autoantibodies. STUDY DESIGN AND METHODS: Serologic D typing and molecular analysis enabled the including of 121 weak D Type 1 individuals and 99 weak D Type 2 individuals in our study. Serologic features of anti-D included autologous controls, direct antiglobulin test, elution, and titration of anti-D before and after adsorption of serum on autologous red blood cells (RBCs). RESULTS: Serologic D typing showed a variable reactivity of RBCs expressing weak D Type 1 or weak D Type 2 (4+ to 0). Anti-D was identified in six weak D Type 1 and six weak D Type 2 individuals, respectively. The serologic data were in favor of autoantibodies. CONCLUSION: A complete anti-D investigation in individuals with a D variant (weak D or partial D identified by molecular analysis) should be systematically performed before any valid conclusion on the nature of the antibody. Transfusing weak D Type 1 or weak D Type 2 patients with D+ RBC units should be recommended. Weak D Type 1 or weak D Type 2 pregnant women do not need anti-D immunoprophylaxis. PMID- 21658049 TI - Platelet transfusions in neonates: practices in the United States vary significantly from those in Austria, Germany, and Switzerland. AB - BACKGROUND: Thrombocytopenia affects 20% to 35% of patients admitted to neonatal intensive care units (NICUs). Platelet (PLT) transfusions are usually administered to neonates with thrombocytopenia at higher thresholds than those used for older children or adults, although there is a paucity of evidence to guide these decisions. STUDY DESIGN AND METHODS: In this study, we used a Web based survey to investigate the PLT transfusion thresholds used in Level 1 NICUs (equivalent to Level 3 in the US) in three European countries (Austria, Germany, and Switzerland [AUT/GER/SUI]). This survey was identical to the one that was previously sent to US neonatologists, thus allowing for a direct comparison of their responses to 11 case-based scenarios. RESULTS: In nine of the scenarios, AUT/GER/SUI neonatologists selected substantially lower PLT transfusion thresholds than US neonatologists (p < 0.0001). Transfusion thresholds were more similar when treating neonatal alloimmune thrombocytopenia and before invasive procedures. The clinical impact of these differences was estimated by extrapolating the AUT/GER/SUI versus the US answers to a cohort of neonates with a birth weight below 1000 g. This suggested that, in AUT/GER/SUI, these neonates would receive 167 PLT transfusions per 1000 infants, compared to 299 PLT transfusions in the United States. CONCLUSION: This first international comparative survey on PLT transfusion practice in neonates reveals substantially higher transfusion thresholds in the United States than in AUT/GER/SUI. Well designed clinical studies are needed to address the risks and/or benefits of these different approaches. PMID- 21658050 TI - Hemolytic transfusion reaction due to anti-IH. AB - BACKGROUND: Anti-IH is usually a clinically insignificant antibody that may complicate a serologic workup. However, it can occasionally cause hemolysis. We report a rare case of acute hemolysis caused by anti-IH. CASE REPORT: A 60-year old man with a long history of chronic myelomonocytic leukemia and anemia, blood group A, D+ was found to have an unidentified antibody on serologic workup. He received an A, D+ red blood cell (RBC) unit that was crossmatch compatible by immunoglobulin G indirect antiglobulin test and then experienced an acute hemolytic transfusion reaction with fever, hemoglobinuria, and acute renal failure. The antibody was later identified as an anti-IH with a wide thermal amplitude. The transfused RBCs were later typed as A(2). The patient was subsequently typed as an A(1) individual. The patient recovered completely from the effects of this reaction and was transfused with A(1) RBCs over the next few days with no adverse effect. CONCLUSION: Anti-IH, which is usually clinically insignificant and often found in A(1), B, and A(1) B individuals, can, on rare occasions, cause acute hemolytic transfusion reactions, especially when an A(2) unit is transfused to an A(1) patient. PMID- 21658051 TI - Stability of cryopreserved white blood cells (WBCs) prepared for donor WBC infusions. AB - BACKGROUND: White blood cells (WBCs) collected from hematopoietic stem cell transplant donors are often given to the recipient to speed immune recovery or treat disease relapse. The postthaw recovery and viability of cryopreserved donor WBCs, stored for as long as 7 years, were assessed. STUDY DESIGN AND METHODS: Total nucleated cell (TNC) cell recovery, CD3+ cell recovery, and TNC viability were measured in 311 clinical donor WBC products: 168 products were unmanipulated or minimally manipulated and 143 products were extensively manipulated. An additional 45 products were selected because they were stored for a longer duration; these were tested using both standard methods and global transcriptional analysis. All products were cryopreserved in 5% dimethyl sulfoxide (DMSO) plus 6% pentastarch and stored in liquid nitrogen. RESULTS: The mean duration of storage of the 311 products was 143 days. Their TNC recovery was 92 +/- 17%, CD3+ cell recovery was 76 +/- 19%, and the TNC viability was 84 +/- 6%. Duration of storage had no effect on TNC recovery, CD3+ cell recovery, or TNC viability of the 311 products. The mean duration of storage of the long-term stored products was 5.2 years; their TNC recovery (93 +/- 14%) and the TNC viability (78 +/- 13%) did not differ from the 311 products, but their CD3 cell recovery was greater (86 +/- 22%; p = 0.0042). Gene expression profiles of the long-term-stored products revealed no differences due to storage duration. CONCLUSIONS: Donor WBC products cryopreserved in 5% DMSO and 6% pentastarch can be stored in liquid nitrogen for at least 7 years. PMID- 21658052 TI - Nomenclature of metal allergens in contact dermatitis. PMID- 21658053 TI - Hand eczema guidelines based on the Danish guidelines for the diagnosis and treatment of hand eczema. AB - BACKGROUND: Classification of hand eczema has traditionally been based both on aetiology and clinical appearance. For 20% of cases, the aetiology is unknown. OBJECTIVES: To suggest a classification based on well-defined aetiology as well as on predefined clinical patterns and on the dynamics of hand eczema. METHODS: Literature studies and discussions among members of the Danish Contact Dermatitis Group. RESULTS: Criteria are given for the aetiological diagnoses of allergic contact dermatitis of the hands, irritant contact dermatitis of the hands, protein contact dermatitis of the hands, atopic hand eczema and aetiologically unclassifiable hand eczema. Six different clinical patterns are described and illustrated. Suggestions for general treatment principles are given. CONCLUSION: Operational guidelines for the diagnosis and treatment of hand eczema are described. PMID- 21658054 TI - Classification of hand eczema: clinical and aetiological types. Based on the guideline of the Danish Contact Dermatitis Group. AB - BACKGROUND: No generally accepted classification scheme for hand eczema exists. The Danish Contact Dermatitis Group recently developed a guideline defining common clinical types and providing criteria for aetiological types. OBJECTIVES: To test the concepts of this guideline in a group of hand eczema patients. METHODS: Seven hundred and ten hand eczema patients were included from seven dermatology clinics in Denmark. The hand eczema was classified into one of five clinical types, with standard photographs as reference. The severity was scored by the physician, who also made a final aetiological diagnosis. RESULTS: Irritant contact dermatitis was most frequent in chronic, dry fissured hand eczema (44.3%), pulpitis (41.7%), and nummular hand eczema (40.9%), whereas allergic contact dermatitis dominated in vesicular types of hand eczema, with recurrent (35%) and few (24.2%) eruptions. Hyperkeratotic palmar hand eczema was the only clinical type that constituted a distinct subgroup; it was found most frequently in older men and had the strongest relationship, although not significant, with non-specific dermatitis. CONCLUSIONS: The relationship between clinical type of hand eczema and aetiological diagnosis fitted with general experience, but no simple relationship was found. This emphasizes that patch testing and exposure analysis are mandatory. Hyperkeratotic palmar hand eczema was identified as a distinct clinical subtype. PMID- 21658055 TI - Fixed drug eruption caused by iodinated contrast media. PMID- 21658056 TI - A new entity: the neutrophilic fixed food eruption. PMID- 21658057 TI - Acrylates tooth and nail: coexistent allergic contact dermatitis caused by acrylates present in desensitizing dental swabs and artificial fingernails. PMID- 21658058 TI - Allergic contact dermatitis caused by Tinosorb(r) M. PMID- 21658059 TI - Contact dermatitis caused by chlorothalonil on imported roses: irritant or allergic reaction? PMID- 21658060 TI - Clinical work-up of a highly reactive nickel-allergic patient. PMID- 21658061 TI - Allergic contact dermatitis in a nurse caused by airborne rubber additives. PMID- 21658062 TI - A case of wheat-dependent exercise-induced anaphylaxis sensitized with hydrolysed wheat protein in a soap. PMID- 21658063 TI - Bullous allergic contact dermatitis caused by Critonia aromatisans. PMID- 21658064 TI - Interconversion between local lymph node assay EC3 units. PMID- 21658065 TI - Revision of the European standard for control of the EU nickel restriction--a probable improvement for European citizens. PMID- 21658066 TI - Palladium allergy prevalence is underestimated because of an inadequate test allergen. PMID- 21658068 TI - Api m 10, a genuine A. mellifera venom allergen, is clinically relevant but underrepresented in therapeutic extracts. AB - BACKGROUND: Generalized systemic reactions to stinging hymenoptera venom constitute a potentially fatal condition in venom-allergic individuals. Hence, the identification and characterization of all allergens is imperative for improvement of diagnosis and design of effective immunotherapeutic approaches. Our aim was the immunochemical characterization of the carbohydrate-rich protein Api m 10, an Apis mellifera venom component and putative allergen, with focus on the relevance of glycosylation. Furthermore, the presence of Api m 10 in honeybee venom (HBV) and licensed venom immunotherapy preparations was addressed. METHODS: Api m 10 was produced as soluble, aglycosylated protein in Escherichia coli and as differentially glycosylated protein providing a varying degree of fucosylation in insect cells. IgE reactivity and basophil activation of allergic patients were analyzed. For detection of Api m 10 in different venom preparations, a monoclonal human IgE antibody was generated. RESULTS: Both, the aglycosylated and the glycosylated variant of Api m 10 devoid of cross-reactive carbohydrate determinants (CCD), exhibited IgE reactivity with approximately 50% of HBV sensitized patients. A corresponding reactivity could be documented for the activation of basophils. Although the detection of the native protein in crude HBV suggested content comparable to other relevant allergens, three therapeutical HBV extracts lacked detectable amounts of this component. CONCLUSION: Api m 10 is a genuine allergen of A. mellifera venom with IgE sensitizing potential in a significant fraction of allergic patients independent of CCD reactivity. Thus, Api m 10 could become a key element for component-resolved diagnostic tests and improved immunotherapeutic approaches in hymenoptera venom allergy. PMID- 21658069 TI - Pubertal development timing in urban Chinese boys. AB - We describe current pubertal development in healthy urban Chinese boys. A cross sectional study of the pubertal development of 18,807 urban Chinese boys aged from 3.50 to 18.49years was conducted between 2003 and 2005. Testicular volume was evaluated with a Prader orchidometer. Pubic hair development was assessed according to the Tanner method. Data on spermarche were collected using the status quo method. Probit analysis was used to calculate the median age and 95% CI at different stages of testicular development, pubic hair development and spermarche. By age 9, 12.99% of the boys had a testicular volume of 4mL or greater. The median age of onset of puberty defined as the age at attainment of testicular volume of 4mL or greater was 10.55 (95% CI 10.27-10.79) years. The median age for onset of pubic hair development (PH(2) ) and spermarche was 12.78 (95%CI 12.67-12.89) years and 14.05 (95%CI 13.80-14.32) years, respectively. Pubertal onset in urban Chinese boys is earlier than currently used clinical norms but their pubic hair development occurs relatively late in comparison with the reported data from numerous other countries. There is also evidence of a secular trend towards an earlier age of spermarche since 1979 in Chinese urban boys. PMID- 21658071 TI - Effect of root canal curvature on the failure incidence of ProFile rotary Ni-Ti endodontic instruments. AB - AIM: To investigate the effect of root canal curvature on the failure incidence and fracture mechanism of ProFile rotary Ni-Ti endodontic instruments. METHODOLOGY: Three hundred mesial root canals of mandibular molars were instrumented using the ProFile system in a crown-down technique up to size 25 0.06 taper. Root canals were classified according to the angle and radius of curvature to: straight (group A: 0 + 10 degrees , radius 0 mm), moderately curved (group B: 30 +/- 10 degrees , radius 2 +/- 1 mm) and severely curved (group C: 60 +/- 10 degrees , radius 2 +/- 1 mm). After each use, instruments were cleaned ultrasonically and autoclaved. Instruments that prepared 20 root canals, fractured or were plastically deformed without fracture were retrieved and substituted. Kaplan-Meier estimator was used for survival analysis and post hoc test for determination of significant differences (a=0.05). All fractured instruments were subjected to fractographic analysis under SEM, and all used instruments were viewed under the metallographic microscope. RESULTS: Regardless of the size of instrument, fracture and overall failure were significantly more frequent (P<0.05) in group C. SEM examination of the fracture surfaces revealed mainly the characteristic pattern of ductile failure, whereas examination under the metallographic microscope revealed no sign of cracks. CONCLUSIONS: The abruptness of root canal curvature negatively affected the failure rate of ProFile rotary Ni-Ti instruments. The fractographic results confirmed that failure of Ni-Ti files was caused by a single overload during chemomechanical preparation. PMID- 21658072 TI - Failure analysis and survival rate of post and core restorations under cyclic loading. AB - AIM: To investigate in a laboratory setting the influence of (i) post material (ii) preparation design and (iii) luting agent on the survival probability of root filled teeth, restored with all-ceramic restorations. METHODOLOGY: The crowns of 80 extracted single-rooted human teeth were removed, and root canal treatment was performed including canal filling with Gutta-percha without sealer (crown-down-pressureless technique). The root fillings were removed and the root canal enlarged with a reamer up to size 110. Prefabricated zirconia (CeraPost) or glass-fibre-reinforced posts (DentinPost) were luted using either Ketac Cem or Panavia F 2.0. A core build-up was applied (Clearfil Photocore), and the teeth were prepared with or without a 2-mm ferrule design (n=10 per experimental group). The prepared teeth were scanned (Cerec 3D) and crowns fabricated. After luting of the crowns (Ketac Cem), teeth were subjected to thermocycling (*4000, 5 55 degrees C) and cyclic loading (1.5 million cycles, 90 N). After load cycling, the teeth were immersed in methyleneblue solution for 24 h and subsequently sectioned in three segments for a dye penetration test. Kaplan-Meyer analysis was performed to assess the survival probability followed by a Cox regression analysis (alpha=5%). RESULTS: Teeth prepared using the ferrule design as well as the teeth with DentinPosts exhibited a significantly higher survival probability (P<0.05). The luting agent was of minor importance (P>0.05). Most common failure was debonding of posts (CeraPost) and post fracture (DentinPost). The majority of the teeth showed dye penetration after cyclic loading. CONCLUSIONS: Post material and ferrule design were of paramount importance regarding the survival probability of the post and core restorations using pre-fabricated posts. DentinPosts showed superior results versus CeraPosts. PMID- 21658073 TI - Autotransplantation of an ectopic impacted premolar with sinus lift and allogenic bone graft. AB - AIM: This article presents a case report of autogenous tooth transplantation to a site which had insufficient bone volume using a sinus lift and allogenic bone graft. SUMMARY: An ectopic, fully impacted premolar tooth was autotransplanted from its ectopic impaction site into its original site, where there was insufficient recipient vertical bone volume because of sinus expansion. The deciduous tooth was extracted from the recipient site, and the sinus membrane detached and elevated via the alveolar socket. Allogenic bone grafting was performed, and the impacted premolar was transplanted into the prepared site. To improve adaptation, the recipient site was prepared using a rapid prototype tooth model, a replica tooth which allowed complete socket preparation in advanced of the actual removal of the donor tooth. The donor tooth was fixed with sutures and maintained for 17 days to allow physiologic movement. Root canal treatment was initiated 24 days after autotransplantation, and an intra-canal medicament was used for 4 months. Canal filling was completed 5 months after autotransplantation. There was no root resorption of the transplanted tooth, and the grafted bone was well preserved and had no signs of infection. KEY LEARNING POINTS: When the recipient bone volume is insufficient, autotransplantation can be preceded by bony augmentation. The preparation of the recipient tooth socket using a tooth replica from CBCT reduces the extra-oral time of the actual tooth and promotes better periodontal ligament healing. Careful evaluation of the pulp status of the donor tooth is important in advance of timely endodontic treatment. PMID- 21658074 TI - Use of cone-beam computed tomography to evaluate root and canal morphology of mandibular molars in Chinese individuals. AB - AIM: To evaluate the root canal configuration of permanent mandibular first and second molar teeth in a Chinese subpopulation using cone-beam computed tomography (CBCT). METHODOLOGY: Patients who required CBCT radiographic examinations as part of their routine examination, diagnosis and treatment planning, were enrolled. Cases where the anatomy was compromised by physiological or pathological processes and the original root canal morphology was not clear were excluded. A total of 389 healthy, untreated, fully developed mandibular molars in Chinese individuals were included. The following observations were recorded: (i) the number of roots and their morphology; (ii) the number of canals per root; (iii) the canal configuration; (iv) the frequency of distolingual roots in the mandibular first molars and (v) the frequency of C-shaped canals in the mandibular second molars. The root canal configurations were classified according to the method of Vertucci (Oral Surgery, Oral Medicine, and Oral Pathology58, 1984, 589). RESULTS: The majority of mandibular molars (70% of first molars, 76% of second molars) had two separate roots; however, three roots were identified in 29% of first molars. C-shaped roots occurred in 29% of second molars. Three canals were found in 56% of mandibular first molars and 43% had four canals. In the mandibular second molars, 46% had three canals and 38% had two canals. Most distal roots had a simple type I configuration, whereas mesial roots had more complex canal systems, with more than one canal. There were seven variants of the root canal morphology amongst the mandibular first molars and eight variants amongst the mandibular second molars, without considering the various root types. CONCLUSIONS: Three-rooted mandibular first molars and C-shaped mandibular second molars occurred frequently in this Chinese population. CBCT is an effective tool for the detection of additional distolingual roots and C-shaped roots/canals, and it is a valuable aid for dentists providing root canal treatment. PMID- 21658075 TI - Pulp pathosis in inlayed teeth of the ancient Mayas: a microcomputed tomography study. AB - AIM: To evaluate three-dimensionally, using microcomputed tomography (MUCT), the anatomical relationship between the cavity prepared to hold the inlay stone and the pulp chamber in the teeth of the ancient Maya. METHODOLOGY: Six well preserved teeth from Maya corpses found in an archaeological site in Guatemala (approximately 1600 year old) were selected and scanned using a high-resolution MUCT system (SkyScan 1174v2; SkyScan N.V., Kontich, Belgium). The sample comprised six maxillary teeth: two canines, one premolar, two central incisors and one lateral incisor. All teeth had one or two inlay stones on the buccal surface of the crown. Each specimen was scanned at an isotropic resolution of 22.5 MUm, a rotational step of 0.70 degrees , a rotational angle of 180 degrees and a 3.1-s exposure time, using a 1-mm-thick aluminium filter. Images of each specimen were reconstructed from apex to the crown with dedicated software (NRecon v1.6.1.5) in approximately 450 slices. CTan v1.11 and CTVol v2.1 were used for three-dimensional visualization and qualitative analysis of the external and internal anatomy of the teeth. RESULTS: The tooth modification in all samples was classified as type E1 (one stone on the buccal surface of the crown) or E2 (two stones on the buccal surface of the crown). In the canine teeth, the cavities created to insert the inlay stone did not reach the pulp chamber. Conversely, in the maxillary incisors, the cavities clearly perforated the pulp chamber resulting in massive internal inflammatory resorption or partial calcification of the pulp cavity. In the premolar tooth, a small perforation of the pulp chamber under the buccal cusp, without morphological alteration of the intraradicular dentine, was observed. CONCLUSIONS: Microcomputed tomography analysis of teeth of the ancient Maya civilization showed that the inlay cavities cut reached the pulp chamber in the maxillary incisors and premolar teeth, with the potential to cause pulp and periapical disease. PMID- 21658076 TI - Influence of pH changes on chlorine-containing endodontic irrigating solutions. AB - Chlorine-containing solutions are used for broad disinfection purposes. Water disinfection literature suggests that their disinfectant action depends on pH values as this will influence the available free chlorine forms. Hypochlorous acid (HOCl) has been suggested to have an antimicrobial effect around 80-100 times stronger than the hypochlorite ion. The aim of this paper was to review the influence of pH changes on the efficacy of chlorine-containing endodontic irrigating solutions. An electronic and hand search (articles published through to 2010, including 'in press' articles; English language; search terms 'root canal irrigants AND sodium hypochlorite or hypochlorous acid or superoxidized water or electrochemically activated solution'; 'antimicrobial action AND sodium hypochlorite or hypochlorous acid or superoxidized water or electrochemically activated solution'; 'tissue dissolution AND sodium hypochlorite or hypochlorous acid or superoxidized water or electrochemically activated solution'; 'smear layer AND sodium hypochlorite or hypochlorous acid or superoxidized water or electrochemically activated solution') was performed to identify publications that compared chlorine water solutions with different pH. Of 1304 publications identified, 20 were considered for inclusion in the review. The search resulted in the retrieval of articles studying sodium hypochlorite (NaOCl), superoxidized waters (SOW) and sodium dichloroisocyanurate (NaDCC). Regarding antimicrobial efficacy, the literature suggested that reducing the pH value of NaOCl to between 6 and 7.5 would lead to improved action; SOW was described as having a lower antimicrobial effect. The tissue dissolution activity NaOCl decreased when the pH reached values between 6 and 7.5; NaDCC and SOW had no clinically relevant tissue dissolution capability. Chlorine solutions of different characteristics appeared to have some cleaning efficacy although they should to be used in conjunction with chelating and/or detergent agents. PMID- 21658077 TI - Dissolving efficacy of eucalyptus and orange oil, xylol and chloroform solvents on different root canal sealers. AB - AIM: To evaluate the solubility of five root canal sealers in orange oil, eucalyptol, xylol and chloroform solvents. METHODOLOGY: The solubility of RoekoSeal, Sealer 26, Epiphany, Endomethasone and EZ-Fill sealers was assessed in orange oil, eucalyptol, xylol, chloroform and distilled water. Seventy-five samples of root canal sealers were prepared and then divided into five groups for immersion in solvent for 2, 5 or 10 min. The means of loss weight were determined for each material in each solvent at all immersion periods, and the values were compared by factorial analysis of variance (anova) and SNK multiple comparisons. RESULTS: In the orange and eucalyptus oil groups, there was no significant difference among RoekoSeal, Sealer26, Epiphany and EZ-Fill at the three immersion periods (P > 0.05). With xylol, no significant differences were found at 5 and 10 min (P > 0.05) for each root sealer. Orange and eucalyptus oil solvents were as effective as chloroform at 2 min in dissolving all the root sealers. CONCLUSIONS: Xylol was the most effective solvent followed by the chloroform and the essential oils (eucalyptol and orange oil). Orange oil behaved in a similar way to eucalyptus oil. PMID- 21658078 TI - Large eddy simulation of a stenosed artery using a femoral artery pulsatile flow profile. AB - Computational fluid dynamics simulation of stenosed arteries allows the analysis of quantities including wall shear stress, velocity, and pressure; detailed in vivo measurement is difficult yet the analysis of the fluid dynamics related to stenosis is important in understanding the likely causes and ongoing effects on the integrity of the vessel. In this study, a three-dimensional Large Eddy Simulation is conducted of a 50% occluded vessel, with a typical femoral artery profile used as the transient inlet conditions. The fluid is assumed to be homogenous, Newtonian and incompressible and the walls are assumed rigid. The stenosis is axisymmetric, however the three-dimensional study allows for a flow field that is not axisymmetric and results show significant three-dimensionality. High values of wall shear stress and oscillatory values of wall shear stress (varying in both space time) are observed. The results of the study give insight into the time-varying flow structures for a mildly stenosed artery and indicate that three-dimensional simulations may be important to gain a complete understanding of the flow field. PMID- 21658079 TI - Bead packing and release using flexible polydimethylsiloxane membrane for semi continuous biosensing. AB - The continuous or semi-continuous biosensing of systemic inflammatory responses is important both during and after cardiopulmonary bypass (CPB) procedures. A bead packing and release method, which is able repetitively to capture and release receptor-coated beads within microfluidic channels, is herein advanced for use in semi-continuous biosensing. The receptor-coated beads are compacted and concentrated at specific locations in the device using an elastomeric valve. This concentration creates a localized bioreactor in which the binding of the antigen with the functionalized beads can be made more effective. After the reaction and detection have taken place, the beads can be released and a new assay carried out. We demonstrated the operation of our device using streptavidin coated beads and biotin-4-fluorescein (B4F). The high sensitivity of the device allows it to detect a B4F concentration of 50 pg/mL after an incubation time of 5 min. We also tested our device in the semi-continuous immunoassay of interleukin (IL)-6, which is one of the proinflammatory cytokines. The assay demonstrated the linear dependence of the intensity of fluorescence at concentrations of IL-6 from 10 to 250 pg/mL, which is a physiologically important range for CPB procedures. PMID- 21658080 TI - Superior mesenteric artery mycotic aneurysm in patients with left ventricular assist device support and intravenous drug abuse. AB - Mycotic aneurysm of the superior mesenteric artery (SMA) is one of the complications associated with infective endocarditis. However, there are no previous case reports in the literature describing mycotic SMA aneurysm after left ventricular assist device (LVAD) implantation. We describe the case of a 31 year-old male diagnosed with congestive heart failure due to nonischemic dilated cardiomyopathy who underwent LVAD implantation for bridge to heart transplantation. The postoperative course was uneventful, and the patient was maintained on anticoagulation and antiplatelet therapy. There were no signs of pump failure or device-related infections. However, 7 months post-LVAD support, the patient complained of abdominal symptoms (nausea and vomiting) with low-grade fever. Computed tomography identified an aneurysmal change of the SMA (2.2 * 1.8 cm). There was no evidence of thrombus or septic vegetation inside the heart. Aneurysm and segmental small bowel resection was performed. Pathological study revealed typical findings of mycotic aneurysm with significant infiltration of inflammatory cells. The patient, however, expired due to concurrent brain hemorrhage. Postmortem study indicated no sign of pump thrombus or septic emboli inside the pump or inflow/outflow conduit. This case report presents a rare mycotic aneurysm that developed in the SMA after chronic LVAD support. PMID- 21658081 TI - Repair of bone defect in femoral condyle using microencapsulated chitosan, nanohydroxyapatite/collagen and poly(L-lactide)-based microsphere-scaffold delivery system. AB - Bone repair ability of microencapsulated chitosan, nanohydroxyapatite/collagen (nHAC), and poly(L-lactide) (PLLA)-based microsphere-scaffold delivery system was investigated in present research, with nHAC/PLLA composite scaffold as a control. Chitosan microspheres (CMs) encapsulated with bone morphogenetic protein-2 derived synthetic peptide were incorporated into nHAC and PLLA-based matrix via a thermally induced phase separation method, in which dioxane was used as the solvent for PLLA. Compared with the rapid release from CMs, the synthetic peptide was delivered from CMs/nHAC/PLLA microsphere-scaffold composite in a temporally controlled manner, depending on the degradation of both incorporated CMs and PLLA matrix. MC3T3-E1 osteoblastic cells were seeded into nHAC/PLLA and CMs/nHAC/PLLA scaffolds, respectively, and in vitro cytocompatibility was tested by scanning electron microscopy and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The results indicated that, with the appearance of CMs in microsphere-scaffold composite, the osteoblasts exhibit better morphology and proliferation ability. In vivo tissue compatibility was evaluated by transplanting the scaffolds into rabbit femoral condyles with a defect 6 mm in diameter. After implanting for 4, 8, and 12 weeks, respectively, radiographic and histological observation revealed that the CMs/nHAC/PLLA composite can accelerate the regeneration of cancellous bone defect as compared with the nHAC/PLLA scaffold. The results demonstrated that the CMs/nHAC/PLLA possesses better biocompatibility, which should be attributed to both the incorporated chitosan component and the encapsulated bioactive synthetic peptide. The promising CMs/nHAC/PLLA microsphere-scaffold composite can be used as delivery system for multiple bioactive factors or as inductive implant scaffold for bone regeneration. PMID- 21658082 TI - Tn916-like genetic elements: a diverse group of modular mobile elements conferring antibiotic resistance. AB - Antibiotic-resistant Gram-positive bacteria are responsible for morbidity and mortality in healthcare environments. Enterococcus faecium, Enterococcus faecalis, Staphylococcus aureus and Streptococcus pneumoniae can all exhibit clinically relevant multidrug resistance phenotypes due to acquired resistance genes on mobile genetic elements. It is possible that clinically relevant multidrug-resistant Clostridium difficile strains will appear in the future, as the organism is adept at acquiring mobile genetic elements (plasmids and transposons). Conjugative transposons of the Tn916/Tn1545 family, which carry major antibiotic resistance determinants, are transmissible between these different bacteria by a conjugative mechanism during which the elements are excised by a staggered cut from donor cells, converted to a circular form, transferred by cell-cell contact and inserted into recipient cells by a site specific recombinase. The ability of these conjugative transposons to acquire additional, clinically relevant antibiotic resistance genes importantly contributes to the emergence of multidrug resistance. PMID- 21658084 TI - Coordination of secondary metabolism and development in fungi: the velvet family of regulatory proteins. AB - Filamentous fungi produce a number of small bioactive molecules as part of their secondary metabolism ranging from benign antibiotics such as penicillin to threatening mycotoxins such as aflatoxin. Secondary metabolism can be linked to fungal developmental programs in response to various abiotic or biotic external triggers. The velvet family of regulatory proteins plays a key role in coordinating secondary metabolism and differentiation processes such as asexual or sexual sporulation and sclerotia or fruiting body formation. The velvet family shares a protein domain that is present in most parts of the fungal kingdom from chytrids to basidiomycetes. Most of the current knowledge derives from the model Aspergillus nidulans where VeA, the founding member of the protein family, was discovered almost half a century ago. Different members of the velvet protein family interact with each other and the nonvelvet protein LaeA, primarily in the nucleus. LaeA is a methyltransferase-domain protein that functions as a regulator of secondary metabolism and development. A comprehensive picture of the molecular interplay between the velvet domain protein family, LaeA and other nuclear regulatory proteins in response to various signal transduction pathway starts to emerge from a jigsaw puzzle of several recent studies. PMID- 21658086 TI - The essence of yeast quiescence. AB - Like all microorganisms, yeast cells spend most of their natural lifetime in a reversible, quiescent state that is primarily induced by limitation for essential nutrients. Substantial progress has been made in defining the features of quiescent cells and the nutrient-signaling pathways that shape these features. A view that emerges from the wealth of new data is that yeast cells dynamically configure the quiescent state in response to nutritional challenges by using a set of key nutrient-signaling pathways, which (1) regulate pathway-specific effectors, (2) converge on a few regulatory nodes that bundle multiple inputs to communicate unified, graded responses, and (3) mutually modulate their competences to transmit signals. Here, I present an overview of our current understanding of the architecture of these pathways, focusing on how the corresponding core signaling protein kinases (i.e. PKA, TORC1, Snf1, and Pho85) are wired to ensure an adequate response to nutrient starvation, which enables cells to tide over decades, if not centuries, of famine. PMID- 21658087 TI - Relation between bacterial activity in the surface microlayer and estuarine hydrodynamics. AB - Bacterial communities of the surface microlayer (SML) of the estuary Ria de Aveiro (Portugal) were characterized in terms of abundance and activity during a 2-year survey at two sites with distinct hydrodynamic properties (marine and brackish water zones). The hydrodynamic conditions were simulated using a bidimensional numerical model and related to the microbiological observations. The pattern of variation of bacterial biomass productivity (BBP) was distinct between the two sampling sites. At the outer site, BBP was significantly lower at the SML, whereas at the inner site, it was significantly enhanced at the SML. Although the total bacterial abundance was similar in the SML and underlying water (UW), the fraction of cells attached to particles was significantly higher at the SML (two to three times). The integration of microbiological results with environmental and hydrological variables shows that strong currents in the marine zone promote the vertical mixing, inhibiting the establishment of an SML bacterial community distinct from that of UW. In contrast, in the brackish water zone, lower current velocities provide conditions for enhancing the bacterial activity in the enriched SML. Estuarine dynamics influence the distribution and activity of microorganisms at the SML and in the water column, with anticipated impacts for the carbon cycle in the estuarine environment. PMID- 21658088 TI - Postnatal development of the rabbit caecal microbiota composition and activity. AB - This study describes the development of the rabbit caecum microbiota and its metabolic activities from the neonatal (day 2) until the subadult period (day 70). The caecal microbiota was analysed using 16S rRNA gene approaches coupled with capillary electrophoresis single-stranded conformation polymorphism (CE SSCP) and qPCR. At day 2, rabbits harboured population levels up to 8.4, 7.2 and 7.4 log(10) copy number g(-1) full caecum of the total bacteria, Bacteroides Prevotella and Firmicutes groups, respectively. These populations reached their maximum levels from day 14 for Firmicutes groups (10.8 log(10) copy number g(-1) caecal content) and day 21 (11.4 and 10.7 log(10) copy number g(-1) caecal content of the total bacteria and the Bacteroides-Prevotella group, respectively). The archaeal population could be detected only from day 7 onwards (5.5 log(10) copy number g(-1) full caecum) and reached its maximum level at day 35 (7.4 log(10) copy number g(-1) caecal content). Similarity analysis, diversity calculation and quantitative evaluation of the stability of bacterial community CE-SSCP profiles provided some evidence that the caecal microbiota develops progressively from a simple and unstable community after birth into a complex and climax community in subadult rabbits. Meanwhile, the microbial activity evolved with the progressive decrease of the propionate/butyrate ratio towards a rabbit specific value <1. PMID- 21658089 TI - Monitoring horizontal antibiotic resistance gene transfer in a colonic fermentation model. AB - The human microbiota is suggested to be a reservoir of antibiotic resistance (ABR) genes, which are exchangeable between transient colonizers and residing bacteria. In this study, the transfer of ABR genes from Enterococcus faecalis to Listeria monocytogenes and to commensal bacteria of the human gut microbiota was demonstrated in a colonic fermentation model. In the first fermentation, an E. faecalis donor harboring the marked 50-kb conjugative plasmid pRE25(*) and a chromosomal marker was co-immobilized with L. monocytogenes and infant feces. In this complex environment, the transfer of pRE25(*) to L. monocytogenes was observed. In a second fermentation, only the E. faecalis donor and feces were co immobilized. Enumeration of pRE25(*) and the donor strain by quantitative PCR revealed an increasing ratio of pRE25(*) to the donor throughout the 16-day fermentation, indicating the transfer of pRE25(*) . An Enterococcus avium transconjugant was isolated, demonstrating that ABR gene transfer to gut commensals occurred. Moreover, pRE25(*) was still functional in both the E. avium and the L. monocytogenes transconjugant and transmittable to other genera in filter mating experiments. Our study reveals that the transfer of a multiresistance plasmid to commensal bacteria in the presence of competing fecal microbiota occurs in a colonic model, suggesting that commensal bacteria contribute to the increasing prevalence of antibiotic-resistant bacteria. PMID- 21658085 TI - Profiling a killer, the development of Cryptococcus neoformans. AB - The ability of fungi to transition between unicellular and multicellular growth has a profound impact on our health and the economy. Many important fungal pathogens of humans, animals, and plants are dimorphic, and the ability to switch between morphological states has been associated with their virulence. Cryptococcus neoformans is a human fungal pathogen that causes life-threatening meningoencephalitis in immunocompromised and, in some cases, immunocompetent hosts. Cryptococcus neoformans grows vegetatively as a budding yeast and switches to hyphal growth during the sexual cycle, which is important in the study of cryptococcal pathogenicity because spores resulting from sexual development are infectious propagules and can colonize the lungs of a host. In addition, sexual reproduction contributes to the genotypic variability of Cryptococcus species, which may lead to increased fitness and virulence. Despite significant advances in our understanding of the mechanisms behind the development of C. neoformans, our knowledge is still incomplete. Recent studies have led to the emergence of many intriguing questions and hypotheses. In this review, we describe and discuss the most interesting aspects of C. neoformans development and address their impact on pathogenicity. PMID- 21658090 TI - Effects of selected root exudate components on soil bacterial communities. AB - Low-molecular-weight organic compounds in root exudates play a key role in plant microorganism interactions by influencing the structure and function of soil microbial communities. Model exudate solutions, based on organic acids (OAs) (quinic, lactic, maleic acids) and sugars (glucose, sucrose, fructose), previously identified in the rhizosphere of Pinus radiata, were applied to soil microcosms. Root exudate compound solutions stimulated soil dehydrogenase activity and the addition of OAs increased soil pH. The structure of active bacterial communities, based on reverse-transcribed 16S rRNA gene PCR, was assessed by denaturing gradient gel electrophoresis and PhyloChip microarrays. Bacterial taxon richness was greater in all treatments than that in control soil, with a wide range of taxa (88-1043) responding positively to exudate solutions and fewer (<24) responding negatively. OAs caused significantly greater increases than sugars in the detectable richness of the soil bacterial community and larger shifts of dominant taxa. The greater response of bacteria to OAs may be due to the higher amounts of added carbon, solubilization of soil organic matter or shifts in soil pH. Our results indicate that OAs play a significant role in shaping soil bacterial communities and this may therefore have a significant impact on plant growth. PMID- 21658083 TI - Population biology of Gram-positive pathogens: high-risk clones for dissemination of antibiotic resistance. AB - Infections caused by multiresistant Gram-positive bacteria represent a major health burden in the community as well as in hospitalized patients. Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium are well known pathogens of hospitalized patients, frequently linked with resistance against multiple antibiotics, compromising effective therapy. Streptococcus pneumoniae and Streptococcus pyogenes are important pathogens in the community and S. aureus has recently emerged as an important community-acquired pathogen. Population genetic studies reveal that recombination prevails as a driving force of genetic diversity in E. faecium, E. faecalis, S. pneumoniae and S. pyogenes, and thus, these species are weakly clonal. Although recombination has a relatively modest role driving the genetic variation of the core genome of S. aureus, the horizontal acquisition of resistance and virulence genes plays a key role in the emergence of new clinically relevant clones in this species. In this review, we discuss the population genetics of E. faecium, E. faecalis, S. pneumoniae, S. pyogenes and S. aureus. Knowledge of the population structure of these pathogens is not only highly relevant for (molecular) epidemiological research but also for identifying the genetic variation that underlies changes in clinical behaviour, to improve our understanding of the pathogenic behaviour of particular clones and to identify novel targets for vaccines or immunotherapy. PMID- 21658092 TI - Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database. PMID- 21658093 TI - Pharmacokinetics of two formulations of omeprazole administered through a gastrostomy tube in patients with severe neurodevelopmental problems. AB - AIMS: Omeprazole is often administered through a gastrostomy tube as either (i) a Multiple Unit Pellet System (MUPS(r)) tablet disintegrated in water (MUPS(r) formulation), or (ii) a suspension in 8.4% sodium bicarbonate (suspension formulation). This bioavailability study evaluates this practice in tube-fed patients with severe neurodevelopmental problems. METHODS: Nonblinded, two-phase cross-over trial. RESULTS: In seven of 10 patients, bioavailability was higher for the suspension formulation than for the MUPS(r) formulation. Median (90% confidence interval) area under the plasma concentration-time curve ratio (MUPS(r) over suspension) was 0.5 (0.06-2.37). CONCLUSIONS: In this population, omeprazole MUPS(r) formulation has no apparent advantage over the more easily administered suspension formulation. PMID- 21658091 TI - Effects of growth hormone replacement within the KIMS survey on estimated cardiovascular risk and predictors of risk reduction in patients with growth hormone deficiency. AB - OBJECTIVE: There is growing evidence for an increased cardiovascular (CV) risk in untreated growth hormone deficiency of adults (GHD). We aimed at estimating CV risk with established algorithms before and during GH replacement in GHD and in healthy controls and at identifying predictors of risk reduction. DESIGN: A prospective, nested case-control study. PATIENTS: We included 344 patients (44.7 +/- 14.9 years) from the German Pfizer (formerly Kabi) International Metabolic Database (KIMS) cohort and included a healthy sex- and age-matched control group from a primary care cohort. MEASUREMENTS: We calculated Framingham, Prospective Cardiovascular Munster Heart Study (PROCAM) and European Society of Cardiology (ESC) Score algorithms at all time points. In multivariate analyses, we analysed potential predictors of 2-year reduction in CV risk, defined as a higher than median reduction in risk. RESULTS: In KIMS, the estimated 10-year risks of CV events or CV mortality calculated with Framingham, PROCAM and ESC Score algorithms at baseline were 4.6%, 6.0% and 2.3%, respectively. These dropped to 2.4%, 4.8% and 0.8%, respectively, after 2 years of GH replacement (all P < 0.001 vs baseline) and returned to baseline levels after four years of GH replacement. In controls, the Framingham risk estimates were lower than in KIMS at baseline. All risk estimates increased during follow-up and were significantly higher than in KIMS after four years (all P < 0.01). In backward-selection models, high total cholesterol, low high-density lipoprotein (HDL) cholesterol and male sex were significant predictors of response in most scores. CONCLUSION: Two years of GH replacement decreased CV risk estimates approximately by half. Male sex, high total and low HDL cholesterol levels are potential predictors of good response. PMID- 21658094 TI - A critique of Rasch analysis using the Dyspnoea-12 as an illustrative example. AB - AIM: This paper is a report of a study of the application and critique of Rasch analysis to the development of the Dyspnoea-12 questionnaire; an instrument that measures breathlessness severity. BACKGROUND: The development of questionnaires has traditionally involved application of classical test theory. Rasch analysis has gained international momentum as a robust application of 'modern' psychometric testing for the development of new instruments and the refinement of existing ones. METHOD: A total of 358 patients [mean age 62 (sd = 8); chronic obstructive pulmonary disease = 123, interstitial lung disease = 129, heart failure = 106], responded to an initial list of 81 items (between May 2006 and February 2008). Hierarchical modelling reduced the list to 34 items. Rasch analysis was used to inform decisions about further item removal and fit to the unidimensional model. Rasch analysis included tests of item response appropriateness, item residual, differential item functioning (including gender and diagnosis) and unidimensionality. RESULTS: Twenty-two items failed to reach the requirements of the Rasch model and were removed. Reasons included high residuals and item bias associated with gender and diagnosis. The 12-items conformed to the Rasch unidimensional parameters (number of statistically significant t-tests 6.7%; confidence interval: 4.4-9.0%). CONCLUSION: We have presented the steps involved in reducing and refining a large item-set by identifying those items which possessed the most reliable measurement properties. The Dyspnoea-12 is reliable and simple to use and should find utility in both practice and research settings. We recommend that nurses consider Rasch analysis in the development of health-related questionnaires. PMID- 21658095 TI - Job demands, job resources and long-term sickness absence in the Danish eldercare services: a prospective analysis of register-based outcomes. AB - AIM: To investigate associations between psychosocial job demands, job resources and cases of registered long-term sickness absence among nursing staff in the eldercare services. BACKGROUND: Research has shown that psychosocial work environment exposures predict sickness absence in healthcare settings. However, only few studies have longitudinally investigated associations between specific job demands and job resources and risk of long-term sickness absence. METHODS: Questionnaire data were collected in 2004 and 2005 among all employees in the eldercare services in 35 Danish municipalities and were followed in a National register on payment of sickness absence compensation for a 1-year follow-up period (N = 7921). Three psychosocial job demands - emotional demands, quantitative demands and role conflicts - and three job resources - influence, quality of leadership and team climate - were investigated to predict risk of sickness absence for eight or more consecutive weeks in the follow-up period. Data were analysed using Cox proportional hazards model. RESULTS: A percentage of 6.5 of the respondents were absent for eight or more consecutive weeks during follow-up. The analyses showed that emotional demands, role conflicts, influence, quality of leadership and team climate were significantly associated with risk of long-term sickness absence. In an analysis with mutual adjustment for all job demands and job resources, influence constituted the strongest predictor of long term sickness absence (negative association). CONCLUSIONS: Job demands and job resources are significantly associated with risk of long-term sickness absence. Interventions aimed at improving the psychosocial work environment may, therefore, contribute towards preventing long-term sickness absence in the eldercare services. PMID- 21658096 TI - Coping and subjective burden in caregivers of older relatives: a quantitative systematic review. AB - AIM: This article is a report on a review of the effect of coping strategies on subjective burden in informal caregivers of older adults. BACKGROUND: Informal care has negative effects on caregivers' health, and subjective burden is one of these. It has been linked with other effects (e.g. anxiety and depression). Thus, greater prevention of subjective burden will mean increased prevention of these effects. To achieve this, identification of factors related to subjective burden is essential. DATA SOURCES: Electronic databases and manual searches of scientific journals. REVIEW METHODS: A quantitative systematic review was conducted including: (a) original studies (b) that related caregiver subjective burden to coping strategies compatible with the classifications of Lazarus & Folkman or Moos et al. (c) in informal caregivers of older relatives. The searches ranged from the first year included in each database until January 2010. After quality appraisal, ten studies were included; these, care-recipients living at home and having cognitive impairment. RESULTS: Four coping categories have been related to subjective burden: problem-focused, emotion-focused, approach and avoidance. Interesting results were only found for avoidance coping (positive association). In other categories, results were heterogeneous (problem-focused and approach) or we found few valid studies (emotion-focused). CONCLUSION: We found some evidence for a positive association between avoidance coping and subjective burden in home caregivers of older relatives with cognitive impairment. It is probable that avoidance coping either mediates or moderates the relationship between subjective burden and its outcomes, or that avoidance coping precedes subjective burden, which in turn leads to the coping outcomes. In both situations, avoidance coping is an ineffective coping. PMID- 21658097 TI - A survey evaluating nurses' perception and expectations towards the role of pharmacist in Pakistan's healthcare system. AB - AIM: This paper is a report of a study of nurses' perception towards the role of pharmacist in Pakistan healthcare setup. BACKGROUND: Collaborative care by the healthcare professionals has the potential to improve patient care, enhance patient safety and to reduce workload issues that cause burn out among healthcare professionals. DESIGN: A quantitative (cross-sectional) study design was adopted. METHOD: A sample of 458 nurses was selected from government hospitals of three cities of Punjab, Pakistan. The study took place from 10 January 2009 to 15 March 2009. RESULTS: Two hundred and sixty-six questionnaires were returned, giving the response rate of (58.07%). Three-fifths of the nurses reported that they had once a day interaction with the pharmacist. Seven-tenths of the nurses expected the pharmacist to take personal responsibility for resolving any drug-related problems. Moreover they appear to have high expectations of the pharmacist, almost nine-tenths regarded pharmacists as knowledgeable drug therapy experts, and almost two-thirds of the nurses emphasized on counselling of patient by the pharmacist. CONCLUSION: Nurses in Pakistan showed negative perception towards the role of pharmacist in healthcare setting. Although nurses considered pharmacist as a drug information expert but their expectation did not match their experience. A possible factor for this behaviour could be due to nurses' belief that incorporating the role of pharmacist in patient care, may decrease their worth and can result in intrusion into their duties. PMID- 21658098 TI - Addressing sexuality issues of women with gynaecological cancer: Chinese nurses' attitudes and practice. AB - AIM: This paper reports a study conducted to describe Chinese nurses' attitudes and practice in addressing the sexuality concerns of people with gynaecological cancer. BACKGROUND: Women with gynaecological cancer face numerous challenges to their sexuality. The importance of addressing sexuality concerns of people with cancer is emphasized by a growing body of literature in Western countries. METHODS: This is a descriptive and correlational study. An inventory was adopted to explore Chinese nurses' attitudes and practice related to sexuality care in nursing. Data were collected from December 2009 to February 2010. RESULTS: A sample of 202 nurses working in gynaecological units in China was recruited. Study results revealed that the majority (77.7%) held the attitude that 'sexuality is too private an issue to discuss with patients'. Only 34.2%'make time to discuss sexual concerns with patients'. Regression analysis revealed that nurse' marital status and hospital type in which they were working influenced their practice in sexuality care. Nurses' conservative attitudes towards sexuality, their prejudices about gynaecological cancer, the lack of availability of private environment, the lack of sexuality care training and the failure to include sexuality care in routine nursing care, were found to be factors that significantly influenced sexual care and nursing practice (adjusted R(2) = 0.542, P < 0.001). CONCLUSIONS: The study findings contribute to the understanding of Chinese nurses' attitudes and practice in addressing the sexuality concerns of people with gynaecological cancer. There is a need to increase Chinese nurses' awareness of their roles and the importance of equipping themselves with relevant skills in sexuality care in nursing practice. PMID- 21658099 TI - Causality, criticality, and reading words: distinct sources of fractal scaling in behavioral sequences. AB - The finding of fractal scaling (FS) in behavioral sequences has raised a debate on whether FS is a pervasive property of the cognitive system or is the result of specific processes. Inferences about the origins of properties in time sequences are causal. That is, as opposed to correlational inferences reflecting instantaneous symmetrical relations, causal inferences concern asymmetric relations lagged in time. Here, I integrate Granger-causality with inferences about FS. Four simulations illustrate that causal analyses can isolate distinct FS sources, whereas correlational techniques cannot. I then analyze three simultaneous sequences of responses from a database of word-naming trials. I find that two, or perhaps three, distinct sources account for the presence of FS in these sequences, but FS is not a general property of the system. This suggests that FS arises due to the properties of a limited number of identifiable psychological and/or neural processes. Finally, I reanalyze a previously published dataset of acoustic frequency spectra using the new tools. The causality/criticality combination introduced here offers a new important perspective in the study of cognition. PMID- 21658100 TI - Intrinsic fluctuations yield pervasive 1/f scaling: comment on Moscoso del Prado Martin (2011). PMID- 21658101 TI - The prevalence of mind-body dualism in early China. AB - We present the first large-scale, quantitative examination of mind and body concepts in a set of historical sources by measuring the predictions of folk mind body dualism against the surviving textual corpus of pre-Qin (pre-221 BCE) China. Our textual analysis found clear patterns in the historically evolving reference of the word xin (heart/heart-mind): It alone of the organs was regularly contrasted with the physical body, and during the Warring States period it became less associated with emotions and increasingly portrayed as the unique locus of "higher" cognitive abilities. We interpret this as a semantic shift toward a shared cognitive bias in response to a vast and rapid expansion of literacy. Our study helps test the proposed universality of folk dualism, adds a new quantitative approach to the methods used in the humanities, and opens up a new and valuable data source for cognitive scientists: the record of dead minds. PMID- 21658102 TI - A genome-wide polyketide synthase deletion library uncovers novel genetic links to polyketides and meroterpenoids in Aspergillus nidulans. AB - Fungi possess an advanced secondary metabolism that is regulated and coordinated in a complex manner depending on environmental challenges. To understand this complexity, a holistic approach is necessary. We initiated such an analysis in the important model fungus Aspergillus nidulans by systematically deleting all 32 individual genes encoding polyketide synthases. Wild-type and all mutant strains were challenged on different complex media to provoke induction of the secondary metabolism. Screening of the mutant library revealed direct genetic links to two austinol meroterpenoids and expanded the current understanding of the biosynthetic pathways leading to arugosins and violaceols. We expect that the library will be an important resource towards a systemic understanding of polyketide production in A. nidulans. PMID- 21658103 TI - Quorum-sensing autoinducer molecules produced by members of a multispecies biofilm promote horizontal gene transfer to Vibrio cholerae. AB - Vibrio cholerae, the causative agent of cholera and a natural inhabitant of aquatic environments, regulates numerous behaviors using a quorum-sensing (QS) system conserved among many members of the marine genus Vibrio. The Vibrio QS response is mediated by two extracellular autoinducer (AI) molecules: CAI-I, which is produced only by Vibrios, and AI-2, which is produced by many bacteria. In marine biofilms on chitinous surfaces, QS-proficient V. cholerae become naturally competent to take up extracellular DNA. Because the direct role of AIs in this environmental behavior had not been determined, we sought to define the contribution of CAI-1 and AI-2 in controlling transcription of the competence gene, comEA, and in DNA uptake. In this study we demonstrated that comEA transcription and the horizontal acquisition of DNA by V. cholerae are induced in response to purified CAI-1 and AI-2, and also by autoinducers derived from other Vibrios co-cultured with V. cholerae within a mixed-species biofilm. These results suggest that autoinducer communication within a consortium may promote DNA exchange among Vibrios, perhaps contributing to the evolution of these bacterial pathogens. PMID- 21658104 TI - Molecular basis of indole production catalyzed by tryptophanase in the genus Prevotella. AB - Indole is most commonly known as a diagnostic marker and a malodorous chemorepellent. More recently, it has been recognized that indole also functions as an extracellular signaling molecule that controls bacterial physiology and virulence. The gene (tnaA) for tryptophanase, which produces indole, ammonia, and pyruvate via beta-elimination of L-tryptophan, was cloned from Prevotella intermedia ATCC 25611 and recombinant TnaA was purified and enzymatically characterized. Analysis by reverse transcriptase-mediated PCR showed that the gene was not cotranscribed with flanking genes in P. intermedia. The results of gel-filtration chromatography suggested that P. intermedia TnaA forms homodimers, unlike other reported TnaA proteins. Recombinant TnaA exhibited a K(m) of 0.23 +/ 0.01 mM and k(cat) of 0.45 +/- 0.01 s(-1). Of 22 Prevotella species tested, detectable levels of indole were present in the culture supernatants of six, including P. intermedia. Southern hybridization showed that tnaA-positive signals were present in the genomic DNA from the six indole-producing strains, but not the other 16 strains tested. The indole-producing strains, with the exception of Prevotella micans, formed a phylogenetic cluster based on trees constructed using 16S rRNA gene sequences, which suggested that tnaA in P. micans might have been transferred from other Prevotella species relatively recently. PMID- 21658105 TI - Toxin-antitoxin (TA) systems are prevalent and transcribed in clinical isolates of Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. AB - The percentage of bacterial infections refractory to standard antibiotic treatments is steadily increasing. Among the most problematic hospital and community-acquired pathogens are methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PA). One novel strategy proposed for treating infections of multidrug-resistant bacteria is the activation of latent toxins of toxin-antitoxin (TA) protein complexes residing within bacteria; however, the prevalence and identity of TA systems in clinical isolates of MRSA and PA has not been defined. We isolated DNA from 78 MRSA and 42 PA clinical isolates and used PCR to probe for the presence of various TA loci. Our results showed that the genes for homologs of the mazEF TA system in MRSA and the relBE and higBA TA systems in PA were present in 100% of the respective strains. Additionally, reverse transcriptase PCR analysis revealed that these transcripts are produced in the clinical isolates. These results indicate that TA genes are prevalent and transcribed within MRSA and PA and suggest that activation of the toxin proteins could be an effective antibacterial strategy for these pathogens. PMID- 21658106 TI - Oxidative stress sensitivity of engineered Escherichia coli cells with a reduced genome. AB - The construction of engineered bacterial cells with a reduced genome allows the investigation of molecular mechanisms that may be cryptic in wild-type strains and derivatives. Previously, a large-scale combined deletion mutant of Escherichia coli that lacked 29.7% of the parental chromosome was constructed by combining large chromosome deletions. In this work, we improved the system for making markerless-chromosomal deletions and obtained mutants with a genome that lacked up to 38.9% of the parental chromosome. Although the large-scale deletion mutants possessed genes needed for resistance to oxidative stress, including superoxide dismutase, catalase, and RpoS, they were sensitive to menadione, which induces reactive oxygen species during stationary phase. Small genome size did not necessarily correlate with greater sensitivity to menadione as several mutants with large deletions were more resistant to menadione. The sensitivity to menadione depended on whether the mutants were grown aerobically or anaerobically, suggesting that the mechanism governing menadione resistance depended on the oxygen tension of the growth medium. Further analysis of the large-scale deletion mutants should help identify the regulatory networks that are important for cellular defense against oxidative stress. PMID- 21658107 TI - Development of a strain-specific real-time PCR assay for the detection and quantification of the biological control agent Fo47 in root tissues. AB - Being able to identify specifically a biological control agent at the strain level is not the only requirement set by regulations (EC)1107/2009, it is also necessary to study the interactions of the agent with the plant and the pathogen in the rhizosphere. Fo47 is a soil-borne strain of Fusarium oxysporum which has the capacity to protect several plant species against the pathogenic formae speciales of F. oxysporum inducing wilts. A strain-specific sequence characterized amplified region marker has been designed which makes it possible to distinguish Fo47 from other strains of F. oxysporum. In addition, a real-time PCR assay has been developed to quantify Fo47 in root tissues. The proposed assay has been validated by following the dynamics of root colonization of tomato plants grown in soil infested with Fo47. Results showed that with the method it is possible to quantify Fo47 in roots in the absence or presence of the pathogen and in the absence or in presence of the native microbial communities. PMID- 21658108 TI - Zero prevalence of Clostridium difficile in wild passerine birds in Europe. AB - Clostridium difficile is an important bacterial pathogen of humans and a variety of animal species, where it can cause significant medical problems. The major public health concern is the possibility of inapparent animal reservoirs of C. difficile and shedding of bacteria to noninfected individuals or populations, as well as being a source of food contamination. Migrating birds can be a key epizootiological factor for transmission and distribution of pathogens over a wide geographic range. Therefore, the purpose of this study was to investigate whether migrating passerine birds can be a source of spread of C. difficile along their migration routes. Cloacal samples were taken from 465 passerine birds during their migration south over the Alps. Selective enrichment was used for detection of C. difficile. Clostridium difficile was not isolated from any of the samples, which indicates that migrating passerine birds are unlikely to serve as a reservoir and a carrier of C. difficile. PMID- 21658109 TI - Neutrophil-derived resistin release induced by Aggregatibacter actinomycetemcomitans. AB - Resistin is an adipokine that induces insulin resistance in mice. In humans, resistin is not produced in adipocytes, but in various leukocytes instead, and it acts as a proinflammatory molecule. The present investigation demonstrated high levels of resistin in culture supernatants of neutrophils that are stimulated by a highly leukotoxic strain of Aggregatibacter actinomycetemcomitans. In contrast, the level of resistin was remarkably low when neutrophils were exposed to two other strains that produce minimal levels of leukotoxin and a further isogenic mutant strain incapable of producing leukotoxin. Pretreatment of neutrophils with a monoclonal antibody to CD18, beta chain of lymphocyte function-associated molecule 1 (LFA-1), or an Src family tyrosine kinase inhibitor before incubation with the highly leukotoxic strain inhibited the release of resistin. These results show that A. actinomycetemcomitans-expressed leukotoxin induces extracellular release of human neutrophil-derived resistin by interacting with LFA-1 on the surface of neutrophils and, consequently, activating Src family tyrosine kinases. PMID- 21658111 TI - Primary cutaneous actinomycosis caused by Actinomyces bovis in a patient with common variable immunodeficiency. AB - Actinomycosis is a chronic, suppurative granulomatous disease caused by the genus Actinomyces. This report is an interesting case of primary cutaneous actinomycosis (PCA) in a patient with common variable immunodeficiency (CVI) affecting the fingernails. The patient was successfully treated with penicillin G, cefazolin and metronidazole as well as surgical debridement of the infected tissues. In a 4-year follow-up period, no recurrence was observed. Primary cutaneous actinomycosis is a rare disease and the diagnosis needs a high index of clinical suspicion with attention to the history of skin implantation of the organism. PMID- 21658110 TI - Multicentric reticulohistiocytosis with elevated cytokine serum levels. AB - Multicentric reticulohistiocytosis (MRH) is an uncommon non-Langerhans cell histiocytosis of unknown etiology. It is a multisystem disorder characterised by a papulonodular skin eruption, mainly in the extensor surfaces, and destructive polyarthritis. Histologically, either cutaneous lesions or the synovium show a dense dermal infiltrate of histiocytes and multinucleated giant cells with an eosinophilic granular material in the cytoplasm. In the immunohistochemical analysis these cells stain positively with monocyte/macrophage markers (CD68 and CD45), as well as with certain cytokines (tumor necrosis factor-alpha, interleukin 1beta and interleukin 6). Moreover, recent reports suggest an osteoclastic nature of the infiltrating cells, as they stain strongly with osteoclast tissue lytic markers including tartrate-resistant acid phosphatase and cathepsin K. We report a case of MRH presenting with clinical features of dermatomyositis. Furthermore, the patient showed elevated cytokine serum levels that lowered after therapy. PMID- 21658112 TI - Subungual trichoadenoma showing differentiation toward follicular infundibulum. PMID- 21658113 TI - Azathioprine-induced pellagra. PMID- 21658114 TI - Case of juvenile localized scleroderma with joint sclerosis and Sjogren's syndrome in a child with precocious puberty. PMID- 21658115 TI - Risk factors for recurrence of scabies: a retrospective study of scabies patients in a long-term care hospital. AB - A considerable number of patients suffer recurrence of scabies. To elucidate risk factors for recurrence of scabies, we compared patients who experienced scabies recurrence and those who suffered scabies only once. We conducted a retrospective review of medical records of all scabies patients in a long-term care hospital for the elderly (300 beds; six wards) for a period of 42 months to determine frequency of scabies onsets, underlying diseases, history of treatment, and demographic data such as age and sex. One hundred and forty-eight patients and five hospital staff members suffered scabies during the 42-month study period. All staff members and 98 patients had no recurrence, while 50 patients experienced at least one recurrence of scabies. The cumulative number of scabies diagnoses was 228. The rates of scabies onset and recurrence were considerably different among wards. The dementia unit showed the highest rate of onset and recurrence. In addition to frequent exposure to infectious sources, problematic behavior, such as lying in other patients beds, might cause the high recurrence rate in dementia units. Higher serum total lymphocyte count and topical use of gamma-benzene hexachloride were associated with lower risk of scabies recurrence. Recurrence of scabies is not uncommon among elderly patients in institutional settings. Impaired immunity may be a risk factor for recurrence of scabies. Groups with a high onset rate of scabies pose a high likelihood of recurrence. Problematic behavior of demented patients may increase the risk of recurrence. Use of effective topical treatment may effectively prevent recurrence. PMID- 21658116 TI - Impact of lymph node metastases on serum level of melanoma inhibitory activity in stage III melanoma patients. AB - Melanoma patients in stage III have a considerable recurrence rate. The 10-year survival in this stage depends on the number and size of affected nodes. Currently, there is no optimal serum marker for early detection of relapse available. The goal of the study was to assess the utility of melanoma inhibitory activity (MIA) serum marker in the follow up and primary diagnosis of stage III melanoma patients. One hundred and thirty-eight melanoma patients in stage III at time of primary diagnosis were analyzed at time of primary diagnosis and during periodical routine follow up both for serum MIA using an enzyme-linked immunosorbent assay and for serum lactate dehydrogenase (LDH). Results were correlated with the positivity of the sentinel lymph node (SLN) and the number of lymph node metastases in the completion lymph node dissection at time of primary diagnosis. During follow up, the overall survival time was assessed using the Kaplan-Meier method in terms of elevated MIA (>12 ng/mL) values. Regarding SLN status, significant differences of MIA values (P = 0.024) and LDH (P = 0.007) were found, both within the normal cut-off. Having lymph node metastases in the completion lymph node dissection, significantly higher MIA values (12.55 ng/mL [+/-0.48], P < 0.0001) were found. In patients with three or more tumor-positive nodes, MIA values were significantly higher when compared to patients with one or two affected nodes (P = 0.024). In the routine follow-up, stage III patients with an MIA value of more than 12 ng/mL had a five times higher risk for developing recurrences (P < 0.0001). Patients with relapsing disease had a significantly (P < 0.0001) higher mean MIA value (13.76 ng/mL) compared to patients without relapse (7.52 ng/mL). The MIA serum marker can be helpful in patients undergoing lymph node dissection. Furthermore, during follow up, patients showing relapsing diseases can have an elevated MIA value. PMID- 21658117 TI - Two cases of recessive dystrophic epidermolysis bullosa diagnosed as severe generalized. AB - Recessive dystrophic epidermolysis bullosa (RDEB) is a congenital bullous disease resulting from defective anchoring fibrils at the dermal-epidermal junction and mutations in the type VII collagen gene. In this report, we describe two patients with severe generalized RDEB. Patient 1 was a 24-day-old male infant, and patient 2 was a 1-day-old female infant. Immunofluorescence microscopy demonstrated absence of type VII collagen labeling in a skin sample of patient 1, and reduced staining in patient 2. Electron microscopy revealed absence of anchoring fibrils below the lamina densa in patient 1, and reduced or rudimentary anchoring fibrils in patient 2. Mutation analyses of COL7A1 in these patients revealed heteroallelic recessive mutations which resulted in premature termination codons (PTC): 6573+1G>C in intron81 and 886del6ins14 in exon 7 in patient 1, and 6573+1G>C in intron81 and 4535insC in exon 44 in patient 2. Heteroallelic combinations of PTC mutation generally result in the severe generalized type. Patient 2 has developed a digital fusion at age 2, which is a typical manifestation of severe generalized RDEB. The RDEB subtype is considered to be determined based on comprehensive information, including analysis of alleles, protein expression, ultrastructure and clinical symptoms after growth. However, mutation analyses of COL7A1 can provide valuable information estimating a diagnosis in early infancy. PMID- 21658118 TI - The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula performs worse than the Modification of Diet in Renal Disease (MDRD) equation in estimating glomerular filtration rate in Type 2 diabetic chronic kidney disease. PMID- 21658120 TI - Differences in the implications of maternal lipids on fetal metabolism and growth between gestational diabetes mellitus and control pregnancies. AB - AIMS: To evaluate the potential contribution of maternal glucose and lipids to fetal metabolic variables and growth in pregnancies with normal glucose tolerance in comparison with pregnancies with well-controlled gestational diabetes previously reported by us. METHODS: In 190 pregnancies with normal oral glucose tolerance tests (controls), insulin, glucose and lipid components were determined in maternal and arterial cord blood serum. Birthweight and neonatal fat mass were obtained after delivery. Values were adjusted for maternal pre-pregnancy BMI, Caesarean section and gestational age. Measurements were compared with those of gestational diabetes previously reported. RESULTS: Maternal serum glucose, triacylglycerol, free fatty acid and cholesterol levels did not differ between control pregnancies and those with gestational diabetes, whereas insulin, homeostasis model assessment and glycerol values were significantly lower in the former (2.6 vs. 5.6 MUmol/l and 176 vs. 193 MUmol/l, respectively). In contrast, cord blood glucose and free fatty acids were significantly lower in control pregnancies than in those with gestational diabetes (3.9 vs. 4.4 mmol/l and 80.7 vs. 137 MUmol/l, respectively); the same was valid for insulin (0.03 vs. 0.05 nmol/l) and homeostasis model assessment (1.0 vs. 1.87). In control pregnancies, maternal serum glucose, free fatty acids and glycerol correlated with those in cord blood, but not with neonatal weight and fat mass, as seen for free fatty acids in those with gestational diabetes. The negative correlation between cord blood triacylglycerols and neonatal weight or fat mass previously reported in gestational diabetes could not be confirmed in control pregnancies, where all fetal lipids showed a positive correlation to neonatal anthropometrics. CONCLUSION: In normal pregnancies, in contrast to those with gestational diabetes, maternal lipids do not influence neonatal weight. Similar levels of maternal lipids in pregnancies with gestational diabetes and control pregnancies, but higher free fatty acids in the cord blood of those with gestational diabetes, indicate their enhanced placental transport and/or enhanced lipolysis as a result of decreased fetal insulin responsiveness. PMID- 21658119 TI - Neuropad: evaluation of three cut-off points of sudomotor dysfunction for early detection of polyneuropathy in recently diagnosed diabetes. AB - AIMS: To examine the sensitivity and specificity of three cut-off points of Neuropad for the diagnosis of distal symmetric polyneuropathy and small-fibre dysfunction in patients within the first year after diagnosis of diabetes. METHODS: Neuropad results were read at 10, 15 and 20 min and evaluated for diagnostic utility in distal symmetric polyneuropathy confirmed by electrophysiology and small-fibre dysfunction in 52 patients with Type 1 diabetes and 99 patients with Type 2 diabetes. RESULTS: The prevalence of distal symmetric polyneuropathy was 15.4% in Type 1 diabetes and 43.4% in Type 2 diabetes, while that of small-fibre dysfunction was 9.6 and 31.3%, respectively. Sensitivity of Neuropad for the diagnosis of distal symmetric polyneuropathy and small-fibre dysfunction was highest in Type 1 diabetes for the 10-min threshold reaching 87.5 and 80.0%, respectively, while it was modestly high in Type 2 diabetes at 65.1 and 67.7%, respectively. Specificity in both diabetes types was modest for the 10 min threshold (44.7-48.2%). It was highest for the 20-min threshold (83.8-89.3%) at the cost of poor sensitivity at 12.5-34.9%. Negative predictive values were relatively high for all three cut-off points in both types of diabetes (64.1 97.1%) at the cost of poor positive predictive values at 12.5-71.4%. CONCLUSIONS: In patients within the first year after diagnosis of diabetes, the 10-min cut-off for Neuropad provides a relatively high sensitivity and modest specificity for distal symmetric polyneuropathy and small-fibre dysfunction, rendering the test more suitable as a screening tool than the 15- and 20-min cut-offs. PMID- 21658121 TI - Low incidence of cardiovascular events in Japanese patients with Type 2 diabetes in primary care settings: a prospective cohort study (JDDM 20). AB - AIMS: To investigate whether a reduced incidence of cardiovascular disease in Type 2 diabetes can be achieved in a newly recruited cohort following the recently advanced concept of multifactorial treatment and followed in primary care settings as compared with earlier cohorts. METHODS: A prospective study was performed in primary care settings at multiple clinics nationwide in the Japan Diabetes Clinical Data Management (JDDM) study group. Subjects were 2984 patients with Type 2 diabetes without prevalent cardiovascular disease. The main outcome measure was the first event of non-fatal or fatal coronary heart disease, ischaemic stroke or peripheral artery disease, and the incidence was compared with other representative cohorts. RESULTS: There were 90 cardiovascular events over 10,827 person-years of follow-up with a dropout rate of 6%. The incidences (per 1000 person-years, 95% confidence interval) of composite, coronary heart disease, ischaemic stroke and peripheral artery disease in the JDDM study were 8.3 (6.6-10.0), 4.4 (3.2-5.6), 3.1 (2.1-4.2), and 0.7 (0.2-1.2), respectively. Each incidence was lowest in the JDDM study compared with other cohorts (P < 0.01 vs. each cohort). In the JDDM study, significant variables predictive of the occurrence of a cardiovascular event were age, duration of diabetes, HbA(1c), HDL cholesterol and urinary albumin. CONCLUSION: The novel finding of low cardiovascular disease occurrence in this study may be conferred by the feasibility at primary care settings for providing patients with Type 2 diabetes with favourable control of blood glucose, blood pressure and lipids, coupled with unique ethnicity/country factors. PMID- 21658122 TI - Effects of Nordic walking on health-related quality of life in overweight individuals with type 2 diabetes mellitus, impaired or normal glucose tolerance. AB - AIMS: To assess the effects of 4 months of increased physical activity on health related quality of life in overweight individuals with Type 2 diabetes mellitus, normal or impaired glucose tolerance. METHODS: We included 212 individuals without severe physical or cardiovascular impairments aged 61 (57-64) years, with BMI of 29 (27.5-32) kg/m2. Numbers are median (25th-75th percentile). Subjects were stratified based on normal glucose tolerance (n = 128), impaired glucose tolerance (n = 34) or Type 2 diabetes mellitus (n = 50). They were randomized into either a control group (n= 125), who maintained unaltered habitual lifestyle, or an exercise intervention group (n = 87), who were directed to engage in Nordic walking with walking poles, 5 h per week over 4 months. Self reported physical activity and health-related quality of life was assessed at the time of inclusion and after 4 months. RESULTS: Baseline health-related quality of life of this study cohort was similar to, or better than, an age- and sex-matched Swedish population sample, for 12 of 13 scales. Quality of sleep and BMI were improved for participants with normal glucose tolerance after 4 months of Nordic walking, with little or no musculoskeletal pain as compared with control subjects. No correlation was evident between improved quality of sleep and improved BMI. CONCLUSIONS: Quality of sleep improved in the group with normal glucose tolerance following 4 months of Nordic walking. BMI reduction did not account for this improvement. Nordic walking can be introduced in a primary health care setting as a low-cost mode of exercise that promotes weight loss and improved health satisfaction. PMID- 21658123 TI - Uric acid levels are associated with microvascular endothelial dysfunction in patients with Type 1 diabetes. AB - AIMS: Recent data identified uric acid as an independent risk factor for cardiovascular disease. The aim of the present study was to assess the association between uric acid and endothelial dysfunction in 57 patients with Type 1 diabetes and 53 healthy control subjects. METHODS: Microvascular endothelial function was evaluated using laser Doppler perfusion monitoring coupled with pharmacological (iontophoretic administration of acetylcholine and sodium nitroprusside) and physiological (post-occlusive reactive hyperaemia and thermal hyperaemia) stimuli. RESULTS: Uric acid was higher in subjects without diabetes than in those with diabetes (P = 0.03). Microvascular vasodilator response to acetylcholine was significantly reduced in Type 1 diabetes (P = 0.002) and was correlated to disease duration (r = -0.3, P = 0.01), triglyceride (r = -0.37, P = 0.005), insulin dose (r = -0.28, P = 0.03), fasting plasma glucose levels (r = -0.3, P = 0.02), HbA(1c) (r = -0.34, P = 0.001) and uric acid (r = -0.3, P = 0.005). On stepwise multivariate analysis, age, HbA(1c) and uric acid were the most important independent variables that were associated with the endothelium-dependent response in Type 1 diabetes (P = 0.02). CONCLUSIONS: Glycaemic control and uric acid in the normal range were the most important contributing factors to the decreasing endothelium-dependent responses associated with Type 1 diabetes. Consequently, uric acid could be a new potential marker of microvascular endothelial dysfunction in these patients. Further studies are required to explore the clinical relevance of the relationship between uric acid levels, oxidative stress and endothelial dysfunction in patients with Type 1 diabetes, as well as whether treatment with uric acid-lowering drugs for slight elevations in uric acid would benefit these patients. PMID- 21658125 TI - New International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: a retrospective study on pregnancy outcome. AB - AIMS: The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel recommends new criteria for diagnosing gestational diabetes. We evaluated the clinical and metabolic characteristics, and pregnancy outcome, in women previously classifiable as 'normal' according to the 4th International Workshop Conference on gestational diabetes criteria, but reclassified as 'abnormal' according to the new recommendations. METHODS: Using the new IADPSG criteria, 3953 pregnancies were retrospectively reclassified as 1815 women with normal glucose tolerance and 2138 with gestational diabetes, 112 (2.8%) of whom would have been classified as normal according to the older criteria. RESULTS: Of the 2138 women classified as abnormal by the new criteria, the 112 women now reclassified as abnormal were younger and had a lower pre pregnancy BMI than the 2026 women who had also been classified as abnormal by the previous criteria. The 100-g oral glucose tolerance test showed significantly higher glucose levels in these 112 women than in the 1815 women reclassified as normal (P < 0.0001). Caesarean section was significantly more frequent (P < 0.01) and the ponderal index for the newborn significantly higher in these reclassified women than in those classified as normal (P < 0.0001), and their basal glucose levels correlated significantly with the ponderal index (P < 0.05). CONCLUSION: The new criteria for diagnosing gestational diabetes identified a group of women previously classifiable as normal according to the 4th International Workshop Conference criteria, but revealing metabolic characteristics and pregnancy outcomes resembling those of women who would have been considered to have gestational diabetes by the previous criteria. PMID- 21658124 TI - Increment of 30-min post-challenge plasma glucose is associated with urine albumin excretion in men with normal glucose regulation. AB - AIMS: The overwhelming majority of subjects with normal glucose regulation have the highest plasma glucose concentration at 30 minutes during oral glucose tolerance. We aimed to examine the association between increment of 30-min post challenge glucose and albuminuria in participants with normal glucose regulation. METHODS: A population-based cross-sectional study was conducted in six communities in Shanghai between 2007 and 2008. A total of 3508 subjects with normal glucose regulation had complete data and were enrolled into the analysis. Among the selected subjects, only 1525 individuals (581 men, 944 women) were examined for their serum insulin levels. We assessed post-challenge blood glucose and insulin at 0, 30 and 120 min, urinary albumin and creatinine. The 30-min post challenge glucose increment (Delta) was calculated as 30-min post-challenge glucose minus fasting plasma glucose, and albumin/creatinine ratio was used to reflect urinary albumin excretion. RESULTS: Multivariable logistic regression analysis revealed that the Delta30-min post-challenge glucose was independently associated with increased albumin/creatinine ratio in men with normal glucose regulation (OR = 1.08, P = 0.025), but not in women. Furthermore, multivariable linear regression analysis revealed that early-phase glucose disposition index was the main factor responsible for Delta30-min post-challenge glucose and explained 14-20% of the variance of Delta30-min post-challenge glucose in the two subgroups (P < 0.05). Notably, men had higher Delta30-min post-challenge glucose and lower early-phase glucose disposition index than women (all P < 0.001). CONCLUSIONS: The 30-min post-challenge plasma glucose increment is associated with urine albumin excretion in men with normal glucose regulation. PMID- 21658126 TI - Telemedicine to improve glycaemic control: 3-year results from the Pro-Active Call Centre Treatment Support (PACCTS) trial. PMID- 21658127 TI - Conservation development practices, extent, and land-use effects in the United States. AB - Conservation development projects combine real-estate development with conservation of land and other natural resources. Thousands of such projects have been conducted in the United States and other countries through the involvement of private developers, landowners, land trusts, and government agencies. Previous research has demonstrated the potential value of conservation development for conserving species, ecological functions, and other resource values on private lands, especially when traditional sources of conservation funding are not available. Nevertheless, the aggregate extent and effects of conservation development were previously unknown. To address this gap, we estimated the extent and trends of conservation development in the United States and characterized its key attributes to understand its aggregate contribution to land-conservation and growth-management objectives. We interviewed representatives from land trusts, planning agencies, and development companies, searched the Internet for conservation development projects and programs, and compiled existing databases of conservation development projects. We collected data on 3884 projects encompassing 1.38 million ha. About 43% of the projects targeted the conservation of specific plant or animal species or ecological communities of conservation concern; 84% targeted the protection of native ecosystems representative of the project area; and 42% provided buffers to existing protected areas. The percentage of protected land in conservation development projects ranged from <40% to >99%, and the effects of these projects on natural resources differed widely. We estimate that conservation development projects have protected roughly 4 million ha of land in the United States and account for about 25% of private land conservation activity nationwide. PMID- 21658128 TI - Influence of care of domestic carnivores on their predation on vertebrates. AB - Domestic dogs (Canis familiaris) and cats (Felis catus) are the most abundant mammalian carnivores worldwide. Given that domestic carnivores rely on human provided food, their densities are usually independent of prey densities. Nevertheless, underfed pets may need to hunt to meet their energetic and nutritional requirements. We explored the effects of different levels of care (provision of food) of dogs and cats on their predation rates on wild vertebrates in 2 areas of southern Chile. We interviewed cat and dog owners and analyzed prey remains in scats of pets to examine how domestic dogs and cats were managed and to gather information on the wild vertebrates killed and harassed by pets. We used logistic regression to examine the association between pet care and the frequency of wild vertebrate remains in scats. The probability of a dog preying on vertebrates was higher for poorly fed than for adequately fed dogs (odds ratio = 3.7) and for poorly fed than for adequately fed cats (odds ratio = 4.7). Domestic dogs and cats preyed on most endemic and threatened mammals present in the study sites. Our results provide support for the hypothesis that the less care domestic animals receive from owners the higher the probability those animals will prey on wild vertebrates. PMID- 21658129 TI - Demographic effects of harvesting epiphytic bromeliads and an alternative approach to collection. AB - Hundreds of epiphytic bromeliads species are harvested from the wild for trade and for cultural uses, but little is known about the effects of this harvest. We assessed the potential demographic effects of harvesting from the wild on 2 epiphytic bromeliads: Tillandsia macdougallii, an atmospheric bromeliad (adsorbs water and nutrients directly from the atmosphere), and T. violaceae, a tank bromeliad (accumulates water and organic material between its leaves). We also examined an alternative to harvesting bromeliads from trees--the collection of fallen bromeliads from the forest floor. We censused populations of T. macdougallii each year from 2005 to 2010 and of T. violaceae from 2005 to 2008, in Oaxaca, Mexico. We also measured monthly fall rates of bromeliads over 1 year and monitored the survival of fallen bromeliads on the forest floor. The tank bromeliad had significantly higher rates of survival, reproduction, and stochastic population growth rates (lambda(s) ) than the atmospheric bromeliad, but lambda(s) for both species were <1, which suggests that the populations will decline even without harvest. Elasticity patterns differed between species, but in both, survival of large individuals had high elasticity values. No fallen bromeliads survived more than 1.5 years on the forest floor and the rate of bromeliad fall was comparable to current harvest rates. Low rates of population growth recorded for the species we studied and other epiphytic bromeliads and high elasticity values for the vital rates that were most affected by harvest suggest that commercial harvesting in the wild of these species is not sustainable. We propose the collection of fallen bromeliads as an ecologically and, potentially, economically viable alternative. PMID- 21658130 TI - Quantitative measurement of airborne cockroach allergen in New York City apartments. AB - We designed and tested a sampling and analysis system for quantitative measurement of airborne cockroach allergen with sufficient sensitivity for residential exposure assessment. Integrated 1-week airborne particle samples were collected at 10-15 LPM in 19 New York City apartments in which an asthmatic child who was allergic to cockroach allergen resided. Four simultaneous air samples were collected in each home: at heights of 0.3 and 1 m in the child's bedroom and in the kitchen. Extracts of air samples were analyzed by ELISA for the cockroach allergen Bla g2, modified by amplifying the colorimetric signal generated via use of AMPLI-Q detection system (DAKO Corporation, Carpinteria, CA, USA). Settled dust samples were quantified by conventional ELISA. Of the homes where cockroach allergen was detected in settled dust, Bla g2 also was detected in 87% and 93% of air samples in the bedroom and kitchen, respectively. Airborne Bla g2 levels were highly correlated within and between the bedroom and kitchen locations (P < 0.001). Expressed as picogram per cubic meter, the room average geometric mean for Bla g2 concentrations was 1.9 pg/m3 (95% CI 0.63, 4.57) and 3.8 pg/m3 (95% CI 1.35, 9.25) in bedrooms and kitchens, respectively. This method offers an attractive supplement to settled dust sampling for cockroach allergen exposure health studies. PRACTICAL IMPLICATIONS: Until now, cockroach allergen exposures have usually been assessed by collection and analysis of settled dust, on the assumption that airborne cockroach allergen cannot be reliably measured. In this study, a sensitive and quantitative method for measuring indoor airborne exposures to cockroach allergens involving a 7-day integrated total suspended particulate (TSP) sample collected at approximately 10-15 l/min was developed. Investigators are now empowered with an alternative exposure assessment method to supplement their studies and the understanding of allergen aerodynamics in the homes of children with asthma. We report airborne cockroach allergen in apartments, suggesting an ongoing burden of inhalation exposure. PMID- 21658131 TI - Anatomical variation of the posterior lumbar tributaries of the left renal vein in retroperitoneoscopic left living donor nephrectomy. AB - OBJECTIVES: To increase awareness of the anatomical variation of the posterior lumbar tributaries of the left renal vein in retroperitoneoscopic left living donor nephrectomy. METHODS: A total of 61 cases of retroperitoneoscopic left living donor nephrectomy were carried out from March 2008 to June 2010. The anatomical variations of the posterior lumbar tributaries of the left renal vein in these patients were noted. RESULTS: According to the variation of posterior lumbar tributaries, there were seven types in total, including five main types (accounts for 95.1%, 58/61 cases) and the type of reno-hemi-azygo-lumbar trunk (AZV; accounts for 16.4%, 10/61 cases). According to the number of posterior lumbar tributaries, no lumbar vein covers accounted for 16.4% (10/61 cases), one lumbar vein accounted for 47.5% (29/61 cases), two lumbar veins accounted for 32.8% (20/61 cases) and three lumbar veins accounted 3.3% (2/61 cases). According to the operation time during the process of managing posterior lumbar veins, it was type 4 (AZV) on which the surgeon spent the most time (P<0.05), and type 5 (no lumbar vein) on which the surgeon spent the least time (P<0.05). CONCLUSIONS: This is the first report of the anatomical variation of the posterior lumbar tributaries of the left renal vein in retroperitoneal laparoscopic left living donor nephrectomy. Detailed knowledge of these anatomical variations will undoubtedly help surgeons to avoid the potential risk of vein damage during nephrectomy and to obtain a longer renal artery for the following renal transplantation. PMID- 21658132 TI - Photodynamic diagnosis of positive margin during radical prostatectomy: preliminary experience with 5-aminolevulinic acid. AB - OBJECTIVES: To investigate the feasibility of intraoperative photodynamic diagnosis (PDD) by 5-aminolevulinic acid (ALA) for the identification of positive surgical margins (PSM) during retropubic radical prostatectomy (RRP) in patients with prostate cancer (PCa). METHODS: Intraoperative PDD was carried out in 16 patients with pathologically confirmed PCa by biopsy of the apex, or carrying >25% of probability of extraprostatic extension as defined by Japan PC Table. Before operation, 1.0 g of ALA was given orally. During open RRP, the resection margins inside the body were examined by PDD system with a fluorescence laparoscope. After their removal, 12 harvested prostates were divided and also investigated by PDD. Red fluorescent-positive lesions were biopsied and compared with the pathological result. RESULTS: All 16 patients were fluorescence-negative inside the body, and negative margins were pathologically confirmed during PDD. Among the 43 specimens of 12 cases obtained by biopsy under PDD, 11 specimens (25.6%) were pathologically diagnosed as malignant tissue (adenocarcinoma, 10 specimens; high grade prostatic intraepithelial neoplasia, 1 specimen) and 19 specimens (44.2%) were evaluated as positive fluorescence by PDD with a sensitivity of 81.8%, a specificity of 68.8% and a predictive accuracy of 72.1%. No side-effects were observed and the procedures were well tolerated. CONCLUSIONS: PDD mediated by ALA during RRP might be a feasible and safe modality for detection of surgical margins. Further prospective randomized studies with larger populations are required. PMID- 21658133 TI - Circumaortic renal vein tumor thrombus in renal cell carcinoma. PMID- 21658134 TI - Effects of a short-term increase in the nutritional plane before the mating period on metabolic and endocrine parameters, hepatic gene expression and reproduction in primiparous beef cows on grazing conditions. AB - Sixty-four spring-calved primiparous crossbred cows paired by calving date and body condition score (BCS) at calving were used to study the effect of a short term increase in the nutritional plane before the mating period on cow and calf performance, changes in metabolic and endocrine parameters and hepatic gene expression. At 48 +/- 10 days post-partum (onset of nutritional treatment = day 0), cows were assigned to two treatments during 23 days: control (grazing of native pastures; NP; n = 31) and increased nutritional plane (NP improved with Lotus subbiflorous cv Rincon; IP; n = 33). Cow body weight (BW), BCS and total protein and albumin concentrations increased while urea and non-esterified fatty acids levels decreased from the beginning of the nutritional treatment in both groups, indicating the animal positive energy balance as forage growth and availability of pastures increased during spring. In addition, cow BW and BCS, as well as calf average daily gain and BW, were greater in IP than in NP cows groups. Insulin concentrations were less in IP than in NP (1.37 vs. 2.25 +/- 0.26 MUU/ml) because insulin increased owing to nutritional treatment only in NP cows. Hepatic insulin receptor mRNA at day 23 tended to be 1.5-fold greater, while insulin growth factor binding protein-3 mRNA expression was 1.7-fold greater in NP than in IP cows. Reproductive responses were not affected by nutritional treatment, but days to initiation of ovarian ciclicity (108 +/- 10 days) were positively correlated with insulin concentrations. Grazing of improved NP for 23 days before the mating period did not improve cow reproductive performance but modified metabolic, endocrine and gene expression parameters, in agreement with greater nutrient and energy partitioning towards milk production, reflected in better calf performance. PMID- 21658135 TI - Serous fluid cytology of multicentric Castleman's disease and other lymphoproliferative disorders associated with Kaposi sarcoma-associated herpes virus: a review with case reports. AB - OBJECTIVE: The aim of this study is to describe and review the cytological features of Kaposi sarcoma-associated herpes virus (KSHV) related entities, such as multicentric Castleman's disease (MCD), plasmablastic-lymphoma (PBL) and primary effusion lymphoma (PEL), which all may present as body cavity effusions. Serous fluid cytology of MCD and PBL has not, to our knowledge, thus far been described. Although different in nature, MCD, PBL and PEL are characterized by similar morphological features. MATERIALS AND METHODS: Body cavity effusions from four different patients with previously known or unknown KSHV-related lymphoproliferations have been examined by routine cytology, immunocytochemistry (IC) and polymerase chain reaction (PCR). RESULTS: MCD, PBL and PEL are all characterized by increased cellularity, comprising mainly lymphoid and plasmacytoid cells with variable proportions of immunoblasts. Immunocytochemistry and PCR results show the MCD to be CD138 and KSHV positive, CD30 negative, IgM, IgH and lambda restricted but IgH polyclonal. PBL was CD138 positive, kappa restricted, weakly positive with VS38 and over 80% positive with MIB 1. PEL was CD45, EMA, CD138, KSHV, p53 and CD3 positive, CD20, EBV, CD30, CD2, CD4, ALK1, epithelial and mesothelial markers negative, and PCR monoclonal B-cell expanded (Ig-kappa bands). CONCLUSION: Cytological examination of effusions in KSHV related lymphoproliferative disorders may show similar morphological features but clonality studies and immunocytochemistry are very helpful in distinguishing between these rare benign and malignant lymphoproliferative diseases. PMID- 21658136 TI - Women's preferences regarding options for management of atypical, borderline or low-grade cervical cytological abnormalities: a review of the evidence. AB - OBJECTIVES: To review the evidence on women's preferences for and valuation of alternative management pathways following identification of low-grade cytological abnormalities as part of routine cervical cancer screening. The aim was to identify empirical studies evaluating women's preferences regarding alternative management pathways and to compare the impact of alternative elicitation methods on results. METHODS: A systematic review of the literature was conducted using the online bibliographic information service PubMed database. Empirical studies were identified that elicited general preferences, utilities or valuations based on willingness to pay (WTP) with respect to management of low-grade cytology results. Data were extracted on the methodology used and the empirical results. RESULTS: Where quality of life data were elicited directly from patients that were undergoing management of low-grade abnormalities utilizing direct elicitation techniques such as WTP, general preference questionnaires and the Euroqol, the studies tended towards a preference in favour of HPV testing (and colposcopy referral if HPV positive) rather than repeat cytology. In contrast, where studies included the general population and presented hypothetical scenarios of treatment pathways, and explicitly tried to incorporate assessment of process utility, the evidence indicated a slight tendency to favour repeat cytology. CONCLUSION: Consideration of patient preferences in the management of low-grade cytology is important for designing screening protocols. The reviewed studies indicate that potentially different conclusions may be drawn depending on the elicitation methodology and selection of participants in the research. PMID- 21658137 TI - Solitary fibrous tumour: a diagnostic challenge for the cytopathologist. AB - BACKGROUND: Solitary fibrous tumour (SFT) is an uncommon spindle cell tumour that can occur in a variety of locations. Cytological features of this tumour have only rarely been reported in the literature. We describe the cytomorphological features of SFT with an emphasis on diagnostic pitfalls. METHODS: We retrieved nine cases of histopathologically proven SFT. Three cases had sampling error with inadequate smears and, therefore, six cases with adequate cellularity were analysed for cytological findings. The cytomorphological features and the differential diagnoses on fine needle aspiration cytology (FNAC) are discussed. RESULTS: No definitive cyto-diagnosis of any of these cases was possible because of the morphological overlap with various soft tissue tumours and other tumour types. There was one false-positive case, in which the possibility of sarcoma was suggested due to the presence of scattered atypical cells. Cytologically, the smears from the SFTs showed spindle to plump cells embedded in metachromatically staining dense ropy collagen material. The cells usually had oval to spindle shaped nuclei, bland chromatin and wavy elongated pale staining cytoplasm. CONCLUSION: A diagnosis of SFT on cytology smears is challenging. Careful attention given to certain cytological features in an appropriate clinicoradiological setting and application of immunochemistry, including CD34 and CD99 immunostaining on cytological samples, can help in the diagnosis of SFT in some cases. It is important to consider cytological overlaps of this tumour in order to avoid false-negative or false-positive results. PMID- 21658138 TI - Human platelet antigen allele frequencies and new mutations on platelet glycoprotein genes in the Chinese Han population. AB - BACKGROUND AND OBJECTIVES: The frequencies of human platelet antigens (HPAs) vary between different populations. In this study, we determined the HPA allele frequencies in the Chinese Han population and identified situation of incompatibility possibly leading to alloimmunisation. METHODS: A total of 750 volunteer blood donors of the Chinese Han population were genotyped for HPA-1 to 17w systems. HPA genotyping was determined by polymerase chain reaction sequence based typing. RESULTS: Among the 17 HPA systems, the allele frequency is different from other populations. We noted the absence of HPA-7bw to HPA-14bw, HPA-16bw and HPA-17bw alleles in the population. The estimated incompatibility probabilities regarding platelet antigens 1 to 6w and 15 systems after transfusion of random donor platelet were from 0.004 to 0.373. Thirteen glycoprotein alleles were observed in the population. In addition, we identified 16 novel mutations on the glycoprotein genes separated from HPA polymorphisms, including GP1BA (517-525delAAC), ITGA2B (2722C>T and IVS26+85T>C), ITGA2 (1521C>T, 2474T>G and IVS20+10 G>C), ITGB3 (1476G>A, IVS10+19C>A, 1813G>A, IVS11+21G>A, IVS11+152A>G and IVS11-104T>C), GP1BB (IVS1-79G>A, IVS1-27C>T and 129G>A) and CD109 (2139A>G). Five of them could lead to amino acid deletion, substitution or premature stop codon in corresponding glycoprotein. CONCLUSIONS: There was a high degree of polymorphism of the membrane glycoprotein genes related to human platelet alloantigen-1 to -17w systems in the Chinese Han population. These data could have some impact on the diagnosis, prevention and treatment of alloimmune thrombocytopenia. PMID- 21658139 TI - Prevalence of immunoglobulin A deficiency in Chinese blood donors and evaluation of anaphylactic transfusion reaction risk. AB - OBJECTIVES/AIMS: We investigated the incidence of immunoglobulin A (IgA) deficiency in Chinese population. BACKGROUND: The frequency of IgA deficiency, defined as a serum IgA level of <0.05 mg dL(-1) , has been broadly studied in different ethnic groups. Individuals with IgA deficiency may form specific antibodies against IgA, which can cause an anaphylactic response when the patient receives an IgA-containing blood transfusion. METHODS: A sandwich enzyme-linked immunosorbent assay was performed to screen for IgA deficiency and particle gel immunoassay used for confirmation. IgA antibodies were further detected by the DiaMed anti-IgA test in IgA-deficient blood donors. RESULTS: Of the total 22,609 healthy blood donors screened, only seven cases were confirmed as having IgA deficiency (<0.05 mg dL(-1) ). Another seven cases displayed relative IgA deficiencies, with mean IgA concentrations ranging from 0.39 to 3.70 mg dL(-1) . Anti-IgA was identified in 2 of the 14 IgA-deficient blood donors whose IgA levels were <5 mg dL(-1) . Estimation of the theoretical risk for IgA anaphylactic transfusion reaction was 0.009%. CONCLUSION: The prevalence of IgA deficiency in Chinese is low. However, potential risks exist in performing blood transfusion to IgA-deficient persons, and measures should be taken to reduce IgA anaphylaxis. PMID- 21658140 TI - Impact of the removal of misleading terms on cigarette pack on smokers' beliefs about 'light/mild' cigarettes: cross-country comparisons. AB - AIM: This paper examines how smokers' beliefs about 'light/mild' cigarettes in Australia, Canada and the United Kingdom were affected by the removal of misleading 'light/mild' terms from packs. DESIGN, SETTING AND PARTICIPANTS: The data come from the first seven waves (2002-09) of the International Tobacco Control Policy Evaluation (ITC) Four-Country Survey, an annual cohort telephone survey of adult smokers in Canada, the United States, the United Kingdom and Australia (21 613 individual cases). 'Light' and 'mild' descriptors were removed in 2003 in the United Kingdom, in 2006 in Australia and in 2007 in Canada. We compare beliefs about 'light' cigarettes both before and after the bans, with those of smokers in the United States serving as the control condition. MEASURES: Smokers' beliefs about 'light' cigarettes were assessed using a set of statements rated on a five-point 'agree'-'disagree' scale. FINDINGS: The proportions of respondents reporting misperceptions about light cigarettes declined between 2002 and 2009 in all four countries. There were marked temporary reductions in reported misperceptions in the United Kingdom and Australia, but not in Canada, following the removal of 'light/mild' descriptors. CONCLUSIONS: Removal of 'light/mild' descriptors and tar, nicotine and carbon monoxide yield information from cigarette packs is insufficient to effectively eliminate false beliefs. The combination of alternative descriptors and design features that produce differences in taste strength and harshness, independent of actual intakes, are sufficient to produce or sustain the same misbeliefs. PMID- 21658141 TI - Genetic variants in the serotonin transporter influence the efficacy of bupropion and nortriptyline in smoking cessation. AB - AIMS: We investigated whether variants in the serotonin transporter gene (SLC6A4) influence smoking cessation rates using antidepressant therapy (i.e. bupropion and nortriptyline). DESIGN: Pharmacogenetic (secondary) analysis of a randomized, placebo-controlled efficacy trial of bupropion and nortriptyline for smoking cessation. SETTING: Single-centre study, Maastricht University, the Netherlands. PARTICIPANTS: A total of 214 of 255 (84%) current daily smokers participating in a randomized controlled efficacy trial. MEASUREMENTS: Subjects were genotyped for three functional variants in SLC6A4 (5-HTTLPR, STin2, rs25531). Primary outcome measures were prolonged abstinence from weeks 4-12, 4-26 and 4-52. Secondary outcome measures included 7-day point prevalence abstinence at weeks 4, 12, 26 and 52. FINDINGS: Carriers of the 5-HTTLPR high-activity L-variant had higher prolonged cessation rates with bupropion than placebo [odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.01-2.05, P = 0.04]. Combining the three variants resulted in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high-activity variants (bupropion: OR = 2.00, 95% CI =1.21-3.29, P = 0.01; nortriptyline: OR = 1.91, 95% CI = 1.02 3.56, P = 0.04). Similar results were found for point prevalence abstinence. CONCLUSIONS: Bupropion and nortriptyline seem to be more effective in smoking cessation among SLC6A4 high-activity variant carriers, probably by blocking the increased serotonin transporter activity, thereby increasing serotonin levels. Prospective studies have to assess if this can improve cessation rates when treatment is targeted at individuals based on their genotypes. PMID- 21658142 TI - Natural selection on a measure of parasite resistance varies across ages and environmental conditions in a wild mammal. AB - Parasites detrimentally affect host fitness, leading to expectations of positive selection on host parasite resistance. However, as immunity is costly, host fitness may be maximized at low, but nonzero, parasite infection intensities. These hypotheses are rarely tested on natural variation in free-living populations. We investigated selection on a measure of host parasite resistance in a naturally regulated Soay sheep population using a longitudinal data set and found negative correlations between parasite infection intensity and annual fitness in lambs, male yearlings and adult females. However, having accounted for confounding effects of body weight, the effect was only significant in lambs. Associations between fitness and parasite resistance were environment-dependent, being strong during low-mortality winters, but negligible during harsher high mortality winters. There was no evidence for stabilizing selection. Our findings reveal processes that may shape variation in parasite resistance in natural populations and illustrate the importance of accounting for correlated traits in selection analysis. PMID- 21658143 TI - Increased copulation duration before ejaculate transfer is associated with larger spermatophores, and male genital titillators, across bushcricket taxa. AB - Copulation duration varies considerably across species, but few comparative studies have examined factors that might underlie such variation. We examined the relationship between copulation duration (prior to spermatophore transfer), the complexity of titillators (sclerotized male genital contact structures), spermatophore mass and male body mass across 54 species of bushcricket. Using phylogenetic comparative analyses, we found that copulation duration was much longer in species with titillators than those without, but it was not longer in species with complex compared with simple titillators. A positive relationship was found between spermatophore size and copulation duration prior to ejaculate transfer, which supports the hypothesis that this represents a period of mate assessment. The slope of this relationship was steeper in species with simple rather than complex titillators. Although the data suggest that the presence of titillators is necessary to maintain long copulation prior to ejaculate transfer, mechanisms underlying this association remain unclear. PMID- 21658144 TI - Pilot study of influenza vaccine effectiveness in urban Australian children attending childcare. AB - BACKGROUND: Influenza outbreaks in the childcare setting are a significant cause of excess winter morbidity. This study explored methods of follow up and sample collection for a proposed randomised controlled trial of influenza vaccination in children attending childcare. METHODS: The study was conducted in four Sydney childcare centres during 2007. Healthy children aged 6-59 months eligible for vaccination were recruited in two centres, with another two acting as controls. Data on influenza-like illness (ILI: >=37.8 degrees C plus at least one respiratory symptom) occurrence were collected weekly. In those children with an ILI, parents were asked to collect nasal swabs and send via surface mail for viral polymerase chain reaction. Vaccine efficacy (VE) for ILI was estimated overall and for subgroups aged 6-23 and 24-59 months using the formula VE = 1 - relative risk (RR). RESULTS: Sixty-three per cent (151/238) of eligible children had parents give consent. Sixty-three children received influenza vaccine and 88 participated as controls. Of 26 specimens returned, a virus was detected in 18 (69%); none with influenza. Two symptomatic children had positive near-patient influenza tests in general practice (one a vaccine failure). The RR with 95% confidence interval in all children and those aged 6-23 months were less than one, 0.56 (0.32-1.02) and 0.46 (0.15-1.45), respectively. CONCLUSIONS: This study demonstrated the feasibility and utility of parent-collected and mailed respiratory specimens for VE research in the childcare setting. Two-thirds of parent-collected swabs proved positive for at least one virus. Finding ways to reduce reluctance of parents to submit samples could improve the representativeness of samples collected and the power of the study. No evidence was found for influenza VE, but point estimates were in the direction of protection. PMID- 21658145 TI - Complementary and alternative medicine in children attending gastroenterology clinics: usage patterns and reasons for use. AB - BACKGROUND: The use of complementary and alternative medicines (CAM) appears to be increasing. This cross-sectional study aimed to assess the use of CAM in children, investigate factors influencing their use and attitudes towards them and to contrast to previous usage patterns. METHODS: Parents of children attending gastroenterology outpatient clinics at a tertiary paediatric hospital completed a questionnaire providing details of CAM usage, awareness and attitudes. RESULTS: Sixty-nine percent of the 98 respondents were using or had used CAM (n= 66). Nutritional supplements (n= 37, 56% of CAM users) and probiotics (n= 33, 50%) were most commonly used. Most CAM users sought complementary therapy to help a chronic problem (n= 43, 69.4%) and had been referred by a friend or family member (n= 33, 53.2%). Self-reported well-being was associated with CAM use (P= 0.0009) and CAM were described as partially effective by 40 parents (67.8%). Forty-six parents (75.4%) expressed that they would use CAM again. Seventy-two respondents (80%) believed that doctors should support the use of CAM. CONCLUSION: Children attending this gastroenterology clinic are commonly given CAM. Awareness and acceptance of CAM by carers of children with gastroenterology conditions is high. PMID- 21658146 TI - Effect of warfarin on menstruation and menstrual management of the adolescent on warfarin. AB - AIM: The aim of this study was to review a consecutive cohort of adolescent females on warfarin to determine the effect of warfarin on menstruation, management options and their perceived efficacy. METHODS: All female patients on warfarin, over the age of 10 years, as of 31 August 2006, were identified using the Department of Haematology (Royal Children's Hospital) warfarin database. The presence of menorrhagia was defined by clinical indicators. RESULTS: Of 81 adolescent females on warfarin, 24 (30%) were referred to gynaecology due to a concern about heavy periods and one for anticipatory guidance, on the basis of impending menarche. In 18 cases (22% of the cohort), menorrhagia could be substantiated on the basis of clinical indicators. Nineteen patients required treatment for menorrhagia with the options for treatment being the combined oral contraceptive pill, subdermal hormone administrations, tranexamic acid and the progesterone-only contraceptive pill. Significant adolescent psychosocial stresses were identified in those adolescents taking warfarin. CONCLUSIONS: Adolescent females on warfarin commonly suffer from menorrhagia. Adolescent review of all teenage girls receiving warfarin therapy is indicated. PMID- 21658148 TI - Congenital adrenal hyperplasia: an Indian experience. AB - AIMS: Data regarding the presentation and course of patients with congenital adrenal hyperplasia (CAH) is scarce in South Asia. We aimed to fill that gap by collating our experience with CAH and comparing it with findings from few other centres around the world for pertinent differences. METHODS: We retrospectively analysed the records of 86 CAH patients seen at our tertiary care centre in Eastern-India from 1996 to 2010. RESULTS: Forty-five patients (52.3%) had classic disease and 41 (47.7%) had non-classic disease (NC CAH). In the classic CAH group, 18 (20.9%) had salt wasting CAH (SW CAH) while 27 (31.4%) had simple virilising disease (SV CAH). Ten (11.6%) had a 46,XY karyotype. Patients with SW CAH were diagnosed earlier in infancy at a median age of 0.5 year, than those with SV type, who were diagnosed at 9 years (P < 0.05). The NC CAH patients were diagnosed still later, at 20.4 years. In patients with SW CAH, boys were diagnosed at an earlier median age of 0.1 year than girls who were diagnosed at 6.4 years (P < 0.05). Sixteen girls (21% of the girls) underwent vaginoplasty of whom four required additional clitoroplasty. One girl needed bilateral laparoscopic adrenalectomy. One NC CAH patient had a successful assisted pregnancy. Hypothyroidism, found in seven (8.1%) was the commonest coexisting abnormality. CONCLUSION: The skewed male : female ratio suggested that a substantial proportion of males were being missed and consequently may die. Majority of the diagnosed patients (n= 55, 64%) have been lost to follow-up. Remaining patients could be reasonably controlled with standard therapy. PMID- 21658147 TI - Vincristine pharmacodynamics and pharmacogenetics in children with cancer: a limited-sampling, population modelling approach. AB - BACKGROUND: Vincristine is a key component of many childhood cancer treatment regimens. Pharmacodynamic parameters such as clinical efficacy and toxicity may be influenced by polymorphisms of CYP3A. AIM: The aim of this study was to document CYP3A5 genotype, vincristine pharmacokinetics (PK) and neurotoxicity profile for 50 children with cancer and determine whether, in a population of Australian children, the CYP3A5 genotype influenced the pharmacodynamics of vincristine as reflected by peripheral neurotoxicity. METHODS: Blood for PK analysis was collected after any single dose of vincristine and assayed using high performance liquid chromatography with tandem mass spectrometry detection. CYP3A5*3 and CYP3A5*6 genotype was determined using gel-electrophoresis or automated microfluidic electrophoresis. Neurotoxicity was determined by physical examination. RESULTS: The median age of children sampled was 6.5 years (range 1 16.25). Half the patients received concurrent corticosteroids for acute lymphoblastic leukaemia. Six patients (12%) had experienced grade 3 or 4 neurotoxicity. The median clearance, area under the curve and Cmax of vincristine was 482 mL/min/m(2) (range 132-698), 49.7 mcg/L.h (16.5-143.1) and 3.5 mcg/L (1.0 31.2), respectively. In contrast to prediction, all but three children were homozygous for wild-type CYP3A5*3. No CYP3A5*6 polymorphisms were identified. CONCLUSIONS: No correlation was identified between vincristine clearance, vincristine neurotoxicity, age, sex or concomitant steroid therapy. The limited sampling methodology proved acceptable to patients and families and would be suitable for larger scale studies including a wider range of genotypic variants and more detailed prospective evaluation of neurotoxicity. PMID- 21658149 TI - Does more protein in the first week of life change outcomes for very low birthweight babies? AB - BACKGROUND: Following publication of revised recommended nutrient intakes (RNI) for infants <1500 g, our intravenous nutrition (IVN) solutions were reformulated to deliver RNI in a restricted volume to ensure additional non-nutritional fluids did not detract from nutritional intake. An audit was performed to determine whether these changes achieved RNI and influenced growth, clinical or neurodevelopmental outcomes. METHODS: Two cohorts of 40 infants <1500 g were identified from a prospectively maintained database: babies born before and after reformulation of the IVN solutions. Data on nutritional intakes for the first 30 days of life, growth and clinical outcomes were collected. Neurodevelopmental outcomes at 18 months corrected age (CA) were obtained from a Bayley III assessment. Results are presented as mean +/- SD. RESULTS: The 'after' group received significantly less fluid (105 +/- 12 vs. 132 +/- 15 mL/kg/day, P < 0.001) but more protein (3.2 +/- 0.6 vs. 2.4 +/- 0.5 g/kg/day, P < 0.001) in the first week of life. There were no differences in clinical outcome, growth z scores at 4 weeks of age or neurodevelopmental outcome at 18 months CA between the 'before' and 'after' infants. Enteral protein intake in the first 2 weeks of life was positively associated with neurodevelopmental outcome (cognitive score r(2) = 0.13 P= 0.03, motor score r(2) = 0.27 P= 0.001). CONCLUSION: Although the new IVN regimen achieved intakes closer to RNI, there were no major effects on growth, clinical outcome or neurodevelopmental outcome at 18 months CA. Enteral protein intake in the first two weeks was positively associated with neurodevelopmental outcome, suggesting early enteral protein intake is important for optimal brain function. PMID- 21658150 TI - Stimulant medication in pre-school children in New South Wales. AB - AIMS: The aims of this study were: (i) to examine the annual treatment rate of children under 4 years from 1997 to 2006; (ii) to compare their treatment rate and attrition with that of children starting treatment at the modal age; (iii) to describe the clinical characteristics of children aged less than 4 years and their response to stimulant medication for the treatment of attention-deficit hyperactivity disorder. METHODS: Retrospective study of electronic prescription and authority records of the New South Wales Department of Health and a review of clinical reports. RESULTS: The annual treatment initiation rate for children under 4 years showed a progressive decline over the decade. In 2001, 13.6% of the children starting treatment were aged 7 years (modal age); those aged <4 years represented 1.1% of the total. There was no significant difference in attrition rate between these two groups. For those aged <4 years with clinical reports available (n= 235), oppositional behaviour and developmental problems were reported frequently (78 and 43%, respectively). Non-pharmacological interventions were implemented in 77% and non-stimulant medications were prescribed in 50%. For 76% of children, an improvement in behaviour was reported after stimulant therapy. CONCLUSIONS: Children treated with stimulant medication aged <4 years were a small subgroup with a high rate of co-morbidity. The majority were perceived to have a favourable response to stimulant medication. However, there was a disturbingly high rate of prescribing of other psychotropic medications of known toxicity and unproven efficacy. PMID- 21658151 TI - Health care reform, access to care, and dentistry. PMID- 21658152 TI - Evaluation of stress distribution in overdenture-retaining bar with different levels of vertical misfit. AB - PURPOSE: To evaluate the effects of different levels of vertical misfit between implant and bar framework on distribution of static stresses in an overdenture retaining bar system using finite element analysis. MATERIAL AND METHODS: A 3D finite element model (11,718 elements and 21,625 nodes) was created and included two titanium implants and a bar framework placed in the medial region of the anterior part of a severely reabsorbed-jaw. All materials were presumed to be linear elastic, homogenous, and isotropic. Mechanical simulation software (NEiNastran 9.0) was used, where displacements were applied on the end of the bar framework to simulate the closure of the vertical misfits (5, 25, 50, 100, 200, and 300 MUm) after tightening of the screws. Data were qualitatively evaluated using Von Mises stress given by the software. RESULTS: The models showed stress concentration in cortical bone, corresponding to the cervical part of the implant, and in cancellous bone, corresponding to the apical part of the implant; however, in these regions few changes were observed in stress to the misfits studied. While in the bar framework, retaining-screw neck, and implant platform, a considerable stress increase proportional to the misfit amplification was observed. CONCLUSIONS: The different levels of vertical misfit did not considerably influence the static stress levels in the peri-implant bone tissue; however, the mechanical components of the overdenture-retaining bar system are more sensitive to lack of passive fit. PMID- 21658154 TI - Helicobacter pylori may be involved in stroke pathophysiology by altering tumor necrosis factor-alpha and matrix metalloproteinases. PMID- 21658156 TI - Symptomatic liver injury (hepatotoxicity) associated with administration of complementary and alternative products (Ayurveda-AP-Mag Capsules((r))) in a beta interferon-treated multiple sclerosis patient. PMID- 21658157 TI - Letter to the editor concerning Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J. EFNS guideline on the treatment of tension-type headache- report of an EFNS task force. Eur J Neurol 2010; 17: 1318-1325. PMID- 21658158 TI - Comment from the EFNS Scientific Committee on the letter from Gunther Haag concerning Bendsten L et al. EFNS guideline on the treatment of tension-type headache--report of an EFNS task force. Eur J Neurol 2010; 17: 1318-1325. PMID- 21658161 TI - Sequential imaging analysis using MIBG scintigraphy revealed progressive degeneration of cardiac sympathetic nerve in Parkinson's disease. AB - BACKGROUND: Metaiodobenzylguanidine (MIBG) cardiac scintigraphy was used to differentiate Parkinson's disease (PD) with Lewy body pathology from other degenerative parkinsonisms. MIBG cardiac scintigraphy demonstrates the extent of degeneration of myocardial post-ganglionic sympathetic nerves in patients with PD. Because of its specificity for Lewy body (LB) pathology, MIBG scan might also be useful biomarker for the neurodegeneration attributed to PD. To estimate the utility of the imaging technique as a biomarker, we conducted sequential imaging analysis and power analysis. METHODS: Sixty-three patients who met the UK PD Society Brain Bank criteria were enrolled in this study. (123) I-MIBG myocardial scintigraphy was performed on all subjects, and the heart to mediastinum (H/M) ratio was calculated. A second imaging session was carried out after a mean interval of 268 days. RESULTS: Sequential imaging revealed a 2.9% decline of the H/M ratio from the baseline to the follow-up image, which reached statistical significance, but the power analysis showed that a relatively large number of patients would be required to demonstrate the neuroprotective effects of any therapy. CONCLUSIONS: Sequential imaging using (123) I-MIBG myocardial scintigraphy revealed progressive degeneration of the cardiac sympathetic nerve in 63 patients with PD. Although careful elimination of other disease conditions that damage the cardiac sympathetic nerve system is necessary, (123) I-MIBG myocardial scintigraphy may be a useful addition to clinical trials that intend to prove neuroprotection among patients with PD. PMID- 21658162 TI - Experiences with cerebrospinal fluid analysis in Dutch memory clinics. AB - BACKGROUND: Evidence on cerebrospinal fluid (CSF) analysis to demonstrate Alzheimer's disease has not yet been implemented in diagnostic guidelines. METHODS: We investigated the use of CSF analysis in a survey amongst all known memory clinics in the Netherlands, of which 85 of 113 (75.2%) responded. RESULTS: Sixty per cent of respondents used CSF analysis in 5% (median) of patients. The analysis almost always confirmed the working diagnosis in 68.4% and sometimes changed it in 28.2%. Complications occurred very infrequently (0%, median) and were mild. Reasons not to perform CSF analysis included the lack of clear recommendations in diagnostic guidelines. CONCLUSIONS: These results ask for a guideline update to clarify the use of CSF analysis as an add-on diagnostic method. PMID- 21658163 TI - Diagnosing narcolepsy with cataplexy on history alone: challenging the International Classification of Sleep Disorders (ICSD-2) criteria. AB - BACKGROUND AND PURPOSE: The second version of the International Classification of Sleep Disorders suggests narcolepsy with cataplexy can be diagnosed on history alone. PATIENTS: Five patients with a history supportive of narcolepsy/cataplexy. METHOD: Case review following clinical investigation. RESULTS: None of the five patients had a diagnosis of narcolepsy/cataplexy on the basis of objective testing using polysomnography (PSG) and multiple sleep latency testing (MSLT). CONCLUSION: PSG and MSLT should always be used in conjunction with a comprehensive history taken by an experienced sleep physician to support a diagnosis of narcolepsy with cataplexy and to exclude other conditions that may mimic narcolepsy. PMID- 21658164 TI - Abnormal expression of dysferlin in skeletal muscle and monocytes supports primary dysferlinopathy in patients with one mutated allele. AB - BACKGROUND: In some cases, a definitive confirmation of dysferlinopathy cannot be achieved by DNA test, because the mutation is detected in one allele only. PATIENTS AND METHODS: DYSFERLIN expression in skeletal muscle and peripheral blood monocytes (PBM) was studied by Western blot in two unrelated adult patients. The comparative C(T) method (DeltaDeltaC(T) ) was used to calculate relative changes in dysferlin mRNA determined from real-time quantitative PCR experiments. The dysferlin gene was studied by direct sequencing of cDNA and genomic DNA and by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis. RESULTS: A comparable severe reduction in dysferlin was demonstrated in both skeletal muscle and PBM. The expression of dysferlin mRNA was significantly reduced. A novel mutation in exon 47 (c.5289G>C) of the dysferlin gene in the heterozygous state, causing an amino acid change (p.Glu1763Asp), was detected in both patients. The MLPA analysis did not reveal any deletion or duplication. CONCLUSIONS: Dysferlin and/or dysferlin mRNA abnormalities are diagnostic for dysferlinopathy when mutational analysis detects a mutation in one allele only. Analysis of dysferlin mRNA can be helpful for distinguishing symptomatic heterozygotes from such patients. PMID- 21658166 TI - Mutations in coagulation factor XIII subunit A in severe factor XIII deficiency patients: five novel mutations detected. PMID- 21658165 TI - UKHCDO guidelines on the management of HCV in patients with hereditary bleeding disorders 2011. AB - Chronic HCV infection continues to be of significant clinical importance in patients with hereditary bleeding disorders. This guideline provides information on the recent advances in the investigation and treatment of HCV infection and gives GRADE system based recommendations on the management of the infection in this patient group. PMID- 21658167 TI - Rural surgeons' attitudes towards and usage of evidence-based medicine in rural surgical practice. AB - INTRODUCTION: Rural and remote surgical practice presents unique barriers to the uptake of the evidence-based medicine (EBM) paradigm. As medical and education institutions around Australia develop practices and support for EBM, there are growing questions about how EBM is situated in the rural and remote context. The Monash University Department of Surgery at Monash Medical Centre implemented a study to explore the current understandings, attitudes and practices of rural surgeons towards the EBM paradigm. METHODS: Descriptive survey of rural surgeons based in a tertiary care environment. RESULTS: The overall results of the survey demonstrate that: (1) rural surgeons have a good understanding of EBM; (2) EBM evidence is somewhat useful but not very important to clinical decision making; and (3) while rural surgeons are relatively confident in most sources listed, they are most confident in their own judgment and clinical practice guidelines, and least confident in telephone contact with colleagues. Rural surgeons' understanding, usage and confidence in EBM purports that rural surgeons have contradictory, ambivalent and complex views of the EBM paradigm and its place in rural surgical practice. DISCUSSION: Professional isolation and context specificity are important to consider when extending the EBM paradigm to rural surgical practice and understanding the EBM uptake in the rural surgery context. PMID- 21658169 TI - Abstracts of the Ninth International Conference on Bipolar Disorder. June 9-11, 2011. Pittsburgh, Pennsylvania, USA. PMID- 21658168 TI - Simple and efficient method for generation of induced pluripotent stem cells using piggyBac transposition of doxycycline-inducible factors and an EOS reporter system. AB - PiggyBac (PB) transposition of reprogramming factors (Oct3/4 (O), Sox2 (S), Klf4 (K) and c-Myc) is a safe, nonviral method for generating induced pluripotent stem cells (iPSCs). However, compared with retroviral methods, the reprogramming efficiency of the PB-mediated methods is relatively low. In this study, we describe a simple and efficient system for generating high-quality iPSCs by a single transfection of multiple plasmids that does not require the use of a virus, special instruments or skilled techniques. To improve reprogramming efficiency, we modified the components of the polycistronic 2A vectors used in this study and also investigated the combination of another reprogramming-related factor (L-Myc). By simultaneous transposition of multiple PB vectors containing an EOS (early transposon promoter and Oct3/4 and Sox2 enhancers) reporter and modified polycistronic doxycycline (Dox)-inducible factors, we reprogrammed mouse somatic cells with an efficiency higher than is usually obtained with retroviral methods and we established some iPSC lines that contributed highly to chimeras. By using the Dox-inducible system, we also showed that the appropriate elimination of exogenous-factor expression at appropriate time accelerated the induction of Oct3/4 when a combination of OKS and c-Myc vectors were used. PMID- 21658170 TI - A conserved archaeal pathway for tail-anchored membrane protein insertion. AB - Eukaryotic tail-anchored (TA) membrane proteins are inserted into the endoplasmic reticulum by a post-translational TRC40 pathway, but no comparable pathway is known in other domains of life. The crystal structure of an archaebacterial TRC40 sequence homolog bound to ADP*AlF(4) (-) reveals characteristic features of eukaryotic TRC40, including a zinc-mediated dimer and a large hydrophobic groove. Moreover, archaeal TRC40 interacts with the transmembrane domain of TA substrates and directs their membrane insertion. Thus, the TRC40 pathway is more broadly conserved than previously recognized. PMID- 21658171 TI - Regulation of Vps4 during MVB sorting and cytokinesis. AB - Multivesicular body (MVB) formation is the result of invagination and budding of the endosomal limiting membrane into its intralumenal space. These intralumenal vesicles (ILVs) contain a subset of endosomal transmembrane cargoes destined for degradation within the lysosome, the result of active selection during MVB sorting. Membrane bending and scission during ILV formation is topologically similar to cytokinesis in that both events require the abscission of a membrane neck that is oriented away from the cytoplasm. The endosomal sorting complexes required for transport (ESCRTs) represent cellular machinery whose function makes essential contributions to both of these processes. In particular, the AAA-ATPase Vps4 and its substrate ESCRT-III are key components that seem to execute the membrane abscission reaction. This review summarizes current knowledge about the Vps4-ESCRT-III system and discusses a model for how the recruitment of Vps4 to the different sites of function might be regulated. PMID- 21658172 TI - Comparative microbial diversity analyses of modern marine thrombolitic mats by barcoded pyrosequencing. AB - Thrombolites are unlaminated carbonate structures that form as a result of the metabolic interactions of complex microbial mat communities. Thrombolites have a long geological history; however, little is known regarding the microbes associated with modern structures. In this study, we use a barcoded 16S rRNA gene pyrosequencing approach coupled with morphological analysis to assess the bacterial, cyanobacterial and archaeal diversity associated with actively forming thrombolites found in Highborne Cay, Bahamas. Analyses revealed four distinct microbial mat communities referred to as black, beige, pink and button mats on the surfaces of the thrombolites. At a coarse phylogenetic resolution, the domain bacterial sequence libraries from the four mats were similar, with Proteobacteria and Cyanobacteria being the most abundant. At the finer resolution of the rRNA gene sequences, significant differences in community structure were observed, with dramatically different cyanobacterial communities. Of the four mat types, the button mats contained the highest diversity of Cyanobacteria, and were dominated by two sequence clusters with high similarity to the genus Dichothrix, an organism associated with the deposition of carbonate. Archaeal diversity was low, but varied in all mat types, and the archaeal community was predominately composed of members of the Thaumarchaeota and Euryarchaeota. The morphological and genetic data support the hypothesis that the four mat types are distinctive thrombolitic mat communities. PMID- 21658173 TI - Internalization, phagolysosomal biogenesis and killing of mycobacteria in enucleated epithelial cells. AB - Bacterial and parasitic intracellular pathogens or their secreted products have been shown to induce host cell transcriptional responses, which may benefit the host, favour the microorganism or be unrelated to the infection. In most instances, however, it is not known if the host cell nucleus is proximately required for the development of an intracellular infection. This information can be obtained by the infection of artificially enucleated host cells (cytoplasts). This model, although rather extensively used in studies of viral infection, has only been applied to few bacterial pathogens, which do not include Mycobacterium spp. Here, we investigate the internalization, phagosome biogenesis and survival of M. smegmatis in enucleated type II alveolar epithelial cells. Cytoplasts were infected with M. smegmatis, but the percentage of infection was significantly lower than that of nucleated cells. Scanning electron microscopy indicated that in both cells and cytoplasts, bacteria were internalized by a phagocytosis-like mechanism. Interestingly, phagosome fusion with lysosomes and mycobacterial killing were both more efficient in enucleated than in nucleated cells, a finding that may be correlated with the increased number of autophagic vesicles developed in cytoplasts. We provide evidence that although quantitative changes were observed, the full development of the infection, as well as mycobacterial killing did not require the presence of the host cell nucleus. PMID- 21658174 TI - Associations of endothelial dysfunction and arterial stiffness with intradialytic hypotension and hypertension. AB - Intradialytic hypotension and hypertension are both independently associated with mortality among persons with end-stage renal disease on hemodialysis. Endothelial dysfunction and arterial stiffness are two possible mechanisms underlying these phenomena, but their association with hemodynamic instability during dialysis has not been evaluated. Thirty patients were recruited from chronic dialysis units at San Francisco General Hospital and San Francisco Veterans Affairs Medical Center. Endothelial dysfunction was assessed with flow-mediated dilation of the brachial artery after upper arm occlusion. Arterial stiffness was assessed using carotid femoral pulse wave velocity measured by tonometry. Intradialytic hypotension and hypertension were defined as the average decrease in systolic blood pressure (SBP) over 1 week, as well as the frequency over 1 month of hypotension or hypertension. Every 5% decrease in flow-mediated dilation was associated with a 7.5 mmHg decrease in SBP after adjustment for phosphorus, body mass index, atherosclerosis, and ultrafiltration (P=0.02). Every 5 m/s increase in pulse wave velocity was associated with an 8 mmHg increase in SBP after adjustment for predialysis SBP and ultrafiltration (P=0.03). Over 1 month, every 5% lower flow mediated dilation was associated with a 10% higher frequency of hypotension (P=0.09), and every 5 m/s increase in pulse wave velocity was associated with an 15% higher frequency of hypertension (P=0.02). In a cross-sectional analysis of 30 dialysis patients, endothelial dysfunction and arterial stiffness were independently associated with intradialytic hypotension and intradialytic hypertension, respectively. Elucidating these potential mechanisms of hemodynamic instability during dialysis may facilitate development of treatment strategies specific to this pathophysiology. PMID- 21658176 TI - Plant hormones: metabolism, signaling and crosstalk. PMID- 21658175 TI - Retrospective study of traumatic dental injuries in primary teeth in a Brazilian specialized pediatric practice. AB - OBJECTIVE: To determine the prevalence of traumatic dental injuries (TDI) in children younger than 7 years and the effect of predisposing clinical factors on their occurrence. MATERIAL AND METHODS: Dental records of 2725 children younger than 7 years seen in a private pediatric dental clinic in Goiania, Brazil, from February 1993 to December 2008 were analyzed. A group of 150 children without traumatic injuries and with similar characteristics to those of the trauma group were used to study predisposing clinical factors as follows: lip coverage (adequate/inadequate), overbite (normal/negative/deep), and overjet (less or greater than 3 mm). Frequency distribution and a chi-square test were used for data analysis. The level of significance was set at 5%. RESULTS: Clinical and radiographic data of 412 injured deciduous teeth were found in 383 records. TDI prevalence was 11.9%, with no significant difference between sexes. The maxillary central incisors were the teeth most frequently affected (83.3%), and the most frequent type of injury was subluxation (35.1%). TDI was most prevalent in the 13 to-36-month age group (47.7%). Home (43.5%) was the main place of occurrence, followed by school (10.1%); falls (50.3%) were the most common cause, followed by collisions with objects (18.2%). The first examination or treatment occurred in the first 24 h in 46.5% of the cases. The analysis of the association of predisposing clinical factors with TDI revealed no differences in lip coverage; however, overjet >3 mm and deep and negative overbite were significantly associated with TDI. CONCLUSION: TDI in primary dentition should receive careful attention, particularly when it affects children younger than 3 years and in the presence of overjet, overbite, or both. PMID- 21658177 TI - Auxin-oxylipin crosstalk: relationship of antagonists. AB - Stephan Pollmann (Corresponding author) Phytohormones regulate a wide array of developmental processes throughout the life cycle of plants. Herein, the various plant hormones may interact additively, synergistically, or antagonistically. By their cooperation they create a delicate regulatory network whose net output largely depends on the action of specific phytohormone combinations rather than on the independent activities of separate hormones. While most classical studies of plant hormonal control have focused mainly on the action of single hormones or on the synergistic interaction of hormones in regulating various developmental processes, recent work is beginning to shed light on the crosstalk of nominally antagonistic plant hormones, such as gibberellins and auxins with oxylipins or abscisic acid. In this review, we summarize our current understanding of how two of the first sight antagonistic plant hormones, i.e. auxins and oxylipins, interact in controlling plant responses and development. PMID- 21658178 TI - Over-expression of WOX1 leads to defects in meristem development and polyamine homeostasis in Arabidopsis. AB - In plants, the meristem has to maintain a separate population of pluripotent cells that serve two main tasks, i.e., self-maintenance and organ initiation, which are separated spatially in meristem. Prior to our study, WUS and WUS-like WOX genes had been reported as essential for the development of the SAM. In this study, the consequences of gain of WOX1 function are described. Here we report the identification of an Arabidopsis gain-of-function mutant wox1-D, in which the expression level of the WOX1 (WUSCHEL HOMEOBOX 1) was elevated and subtle defects in meristem development were observed. The wox1-D mutant phenotype is dwarfed and slightly bushy, with a smaller shoot apex. The wox1-D mutant also produced small and dark green leaves, and exhibited a failure in anther dehiscence and male sterility. Molecular evidences showed that the transcription of the stem cell marker gene CLV3 was down-regulated in the meristem of wox1-D but accumulated in the other regions, i.e., in the root-hypocotyl junction and at the sites for lateral root initiation. The fact that the organ size and cell size in leaves of wox1-D are smaller than those in wild type suggests that cell expansion is possibly affected in order to have partially retarded the development of lateral organs, possibly through alteration of CLV3 expression pattern in the meristem. An S-adenosylmethionine decarboxylase (SAMDC) protein, SAMDC1, was found able to interact with WOX1 by yeast two-hybrid and pull-down assays in vitro. HPLC analysis revealed a significant reduction of polyamine content in wox1-D. Our results suggest that WOX1 plays an important role in meristem development in Arabidopsis, possibly via regulation of SAMDC activity and polyamine homeostasis, and/or by regulating CLV3 expression. PMID- 21658179 TI - The induction of mild hypothermia improves systolic function of the resuscitated porcine heart at no further sympathetic activation. AB - AIM: Mild hypothermia (MH) after cardiac arrest attenuates hypoxic brain injury and improves survival. As MH increases contractility in normal hearts, we hypothesized that MH improves cardiovascular function after cardiac arrest. METHODS: In 16 anaesthetized pigs (64 +/- 2 kg), ventricular fibrillation was induced electrically for 5 min. At 10 min after resuscitation and return of spontaneous circulation (ROSC), pigs were assigned to normothermia (NT, 38 degrees C, n = 8) or MH (33 degrees C, n = 8, intravascular cooling). RESULTS: At ROSC 6 h vs. baseline, heart rate (HR) was unchanged in NT, but decreased in MH. Cardiac output (CO, l min(-1)) decreased in MH (3.5 +/- 0.2 vs. 5.5 +/- 0.4, P < 0.05) more than in NT (4.8 +/- 0.4 vs. 5.7 +/- 0.4, P = ns). Mixed venous oxygen saturation decreased in NT (56 +/- 2 vs. 66 +/- 3%, P < 0.05), but remained constant in MH (64 +/- 2 vs. 65 +/- 2%) due to a 35% decrease of whole body oxygen consumption. Left ventricular (LV) dP/dt(max) (mmHg s(-1)) decreased in NT (1163 +/- 97 vs. 1665 +/- 134, P < 0.05), but was preserved in MH (1602 +/- 102 vs. 1603 +/- 96), whereas LV relaxation was profoundly slowed during MH. Pressure volume analysis confirmed improved LV systolic function during MH, but also demonstrated decreased LV end-diastolic distensibility, which was further potentiated by right atrial pacing at baseline HR. MH did not increase plasma catecholamine levels. Spectral analysis of heart rate variability revealed reduced sympathetic activation during MH. CONCLUSION: The induction of MH after cardiac resuscitation improves systolic myocardial function without further sympathetic activation. A reduced metabolism during MH outweighs a decreased CO and thereby acts favourably on systemic oxygen supply/demand balance. PMID- 21658181 TI - Summer and smiles all around. PMID- 21658182 TI - Qualitative and quantitative resistances to leaf rust finely mapped within two nucleotide-binding site leucine-rich repeat (NBS-LRR)-rich genomic regions of chromosome 19 in poplar. AB - * R(US) is a major dominant gene controlling quantitative resistance, inherited from Populus trichocarpa, whereas R(1) is a gene governing qualitative resistance, inherited from P. deltoides. * Here, we report a reiterative process of concomitant fine-scale genetic and physical mapping guided by the P. trichocarpa genome sequence. The high-resolution linkage maps were developed using a P. deltoides * P. trichocarpa progeny of 1415 individuals. R(US) and R(1) were mapped in a peritelomeric region of chromosome 19. Markers closely linked to R(US) were used to screen a bacterial artificial chromosome (BAC) library constructed from the P. trichocarpa parent, heterozygous at the locus R(US) . * Two local physical maps were developed, one encompassing the R(US) allele and the other spanning r(US) . The alignment of the two haplophysical maps showed structural differences between haplotypes. The genetic and physical maps were anchored to the genome sequence, revealing genome sequence misassembly. Finally, the R(US) locus was localized within a 0.8-cM interval, whereas R(1) was localized upstream of R(US) within a 1.1-cM interval. * The alignment of the genetic and physical maps with the local reorder of the chromosome 19 sequence indicated that R(US) and R(1) belonged to a genomic region rich in nucleotide binding site leucine-rich repeat (NBS-LRR) and serine threonine kinase (STK) genes. PMID- 21658180 TI - DNA barcoding of Canada's skates. AB - DNA-based identifications have been employed across broad taxonomic ranges and provide an especially useful tool in cases where external identification may be problematic. This study explored the utility of DNA barcoding in resolving skate species found in Atlantic Canadian waters. Most species were clearly resolved, expanding the utility for such identification on a taxonomically problematic group. Notably, one genus (Amblyraja) contained three of four species whose distributions do not overlap that could not be readily identified with this method. On the other hand, two common and partially sympatric species (Little and Winter skates) were readily identifiable. There were several instances of inconsistency between the voucher identification and the DNA sequence data. In some cases, these were at the intrageneric level among species acknowledged to be prone to misidentification. However, several instances of intergeneric discrepancies were also identified, suggesting either evidence of past introgressive hybridization or misidentification of vouchered specimens across broader taxonomic ranges. Such occurrences highlight the importance of retaining vouchered specimens for subsequent re-examination in the light of conflicting DNA evidence. PMID- 21658184 TI - Evolutionary ecology of plant-microbe interactions: soil microbial structure alters selection on plant traits. AB - * Below-ground microbial communities influence plant diversity, plant productivity, and plant community composition. Given these strong ecological effects, are interactions with below-ground microbes also important for understanding natural selection on plant traits? * Here, we manipulated below ground microbial communities and the soil moisture environment on replicated populations of Brassica rapa to examine how microbial community structure influences selection on plant traits and mediates plant responses to abiotic environmental stress. * In soils with experimentally simplified microbial communities, plants were smaller, had reduced chlorophyll content, produced fewer flowers, and were less fecund when compared with plant populations grown in association with more complex soil microbial communities. Selection on plant growth and phenological traits also was stronger when plants were grown in simplified, less diverse soil microbial communities, and these effects typically were consistent across soil moisture treatments. * Our results suggest that microbial community structure affects patterns of natural selection on plant traits. Thus, the below-ground microbial community can influence evolutionary processes, just as recent studies have demonstrated that microbial diversity can influence plant community and ecosystem processes. PMID- 21658183 TI - Phloem transport of arsenic species from flag leaf to grain during grain filling. AB - * Strategies to reduce arsenic (As) in rice grain, below concentrations that represent a serious human health concern, require that the mechanisms of As accumulation within grain be established. Therefore, retranslocation of As species from flag leaves into filling rice grain was investigated. * Arsenic species were delivered through cut flag leaves during grain fill. Spatial unloading within grains was investigated using synchrotron X-ray fluorescence (SXRF) microtomography. Additionally, the effect of germanic acid (a silicic acid analog) on grain As accumulation in arsenite-treated panicles was examined. * Dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) were extremely efficiently retranslocated from flag leaves to rice grain; arsenate was poorly retranslocated, and was rapidly reduced to arsenite within flag leaves; arsenite displayed no retranslocation. Within grains, DMA rapidly dispersed while MMA and inorganic As remained close to the entry point. Germanic acid addition did not affect grain As in arsenite-treated panicles. Three-dimensional SXRF microtomography gave further information on arsenite localization in the ovular vascular trace (OVT) of rice grains. * These results demonstrate that inorganic As is poorly remobilized, while organic species are readily remobilized, from leaves to grain. Stem translocation of inorganic As may not rely solely on silicic acid transporters. PMID- 21658185 TI - Where do youth learn about suicides on the Internet, and what influence does this have on suicidal ideation? AB - BACKGROUND: Young people are susceptible to suicidal behavior as a result of learning about the suicidal behavior of others. This study was designed to determine whether Internet sites, such as online news and social networking websites, expose young people to suicide stories that might increase suicide ideation. METHOD: We reinterviewed 719 young people ages 14 to 24 who had participated in a prior nationally representative survey. Respondents reported knowledge of persons they knew who had committed or attempted suicide as well as personal experiences of hopelessness and suicidal ideation on both occasions. On the second occasion one year later, they also reported use of various Internet platforms and how often they had been exposed to suicide stories on those sites, as well as from personal sources. Changes in ideation as a function of exposure to different sources of suicide stories were analyzed holding constant prior hopelessness and ideation. RESULTS: While traditional sources of information about suicide were most often cited (79% were from friends and family or newspapers), online sources were also quite common (59%). Social networking sites were frequently cited as sources, but these reports were not linked to increases in ideation. However, online discussion forums were both cited as sources and associated with increases in ideation. CONCLUSIONS: The Internet and especially social networking sites are important sources of suicide stories. However, discussion forums appear to be particularly associated with increases in suicidal ideation. Greater efforts should be undertaken to promote Internet sites directed to young people that enhance effective coping with hopelessness and suicidal ideation. PMID- 21658187 TI - Changes in behavioural trait integration following rapid ecotype divergence in an aquatic isopod. AB - Colonization of new habitats can relax selection pressures, and traits or trait combinations no longer selected for might become reduced or lost. We investigated behavioural differentiation and behavioural trait integration in the freshwater isopod Asellus aquaticus. This isopod has recently colonized a novel habitat and diverged into two ecotypes which encounter different predator faunas. We investigated sex-specific behavioural differences and phenotypic integration in three behavioural assays: (i) time to emerge (TE) from a shelter, (ii) activity and (iii) escape behaviour. General activity and escape behaviour differed between ecotypes. Furthermore, general activity and TE differed between sexes. Behavioural traits were more frequently correlated in the ancestral habitat, and phenotypic integration tended to be higher in this habitat as well. Our study suggests that different predator types, but also other ecological factors such as habitat matrices and population densities, might explain the differences in behavioural integration in these ecotypes. PMID- 21658188 TI - Populations with elevated mutation load do not benefit from the operation of sexual selection. AB - Theory predicts that if most mutations are deleterious to both overall fitness and condition-dependent traits affecting mating success, sexual selection will purge mutation load and increase nonsexual fitness. We explored this possibility with populations of mutagenized Drosophila melanogaster exhibiting elevated levels of deleterious variation and evolving in the presence or absence of male male competition and female choice. After 60 generations of experimental evolution, monogamous populations exhibited higher total reproductive output than polygamous populations. Parental environment also affected fitness measures - flies that evolved in the presence of sexual conflict showed reduced nonsexual fitness when their parents experienced a polygamous environment, indicating trans generational effects of male harassment and highlighting the importance of a common garden design. This cost of parental promiscuity was nearly absent in monogamous lines, providing evidence for the evolution of reduced sexual antagonism. There was no overall difference in egg-to-adult viability between selection regimes. If mutation load was reduced by the action of sexual selection in this experiment, the resultant gain in fitness was not sufficient to overcome the costs of sexual antagonism. PMID- 21658189 TI - Basal cold but not heat tolerance constrains plasticity among Drosophila species (Diptera: Drosophilidae). AB - Thermal tolerance and its plasticity are important for understanding ectotherm responses to climate change. However, it is unclear whether plasticity is traded off at the expense of basal thermal tolerance and whether plasticity is subject to phylogenetic constraints. Here, we investigated associations between basal thermal tolerance and acute plasticity thereof in laboratory-reared adult males of eighteen Drosophila species at low and high temperatures. We determined the high and low temperatures where 90% of flies are killed (ULT(90) and LLT(90) , respectively) and also the magnitude of plasticity of acute thermal pretreatments (i.e. rapid cold- and heat-hardening) using a standardized, species-specific approach for the induction of hardening responses. Regression analyses of survival variation were conducted in ordinary and phylogenetically informed approaches. Low-temperature pretreatments significantly improved LLT(90) in all species tested except for D. pseudoobscura, D. mojavensis and D. borealis. High temperature pretreatment only significantly increased ULT(90) in D. melanogaster, D. simulans, D. pseudoobscura and D. persimilis. LLT(90) was negatively correlated with low-temperature plasticity even after phylogeny was accounted for. No correlations were found between ULT(90) and LLT(90) or between ULT(90) and rapid heat-hardening (RHH) in ordinary regression approaches. However, after phylogenetic adjustment, there was a positive correlation between ULT(90) and RHH. These results suggest a trade-off between basal low-temperature tolerance and acute low-temperature plasticity, but at high temperatures, increased basal tolerance was accompanied by increased plasticity. Furthermore, high- and low temperature tolerances and their plasticity are clearly decoupled. These results are of broad significance to understanding how organisms respond to changes in habitat temperature and the degree to which they can adjust thermal sensitivity. PMID- 21658190 TI - Markers of autoreactivity, coagulation and angiogenesis in patients with nonallergic asthma. AB - BACKGROUND: Patients with nonallergic asthma frequently show autoreactivity as do subjects with chronic urticaria (CU). Activation of the coagulation cascade and hyper-expression of vascular endothelial growth factor (VEGF) were recently found in CU, and there is sparse evidence that the same may occur in asthma. OBJECTIVE: To investigate autoreactivity, activation of the coagulation cascade, and expression of VEGF in patients with nonallergic asthma. METHODS: Twenty-one adults with nonallergic asthma underwent autologous plasma skin test (APST) and the measurement of plasma levels of the prothrombin fragment F1+2, D-dimer, VEGF, and the inflammatory marker C-reactive protein (CRP). Twenty-one healthy sex- and age-matched subjects served as normal controls. RESULTS: The APST scored positive in 19 of 21 (90%) patients vs 0 controls. Mean fragment F1+2 plasma levels were significantly higher in patients with asthma (267 +/- 243 pM) than in controls (150 +/- 51 pM; P = 0.0001). Similarly, plasma levels of both D-dimer and VEGF were significantly higher in patients than in controls (D-dimer: 2364 +/- 1467 vs 1301 +/- 525 pM; P = 0.0001; VEGF: 1721 +/- 2566 vs 76 +/- 375 fM; P = 0.0001). A trend toward increased levels of F1+2, D-dimer, VEGF, and CRP was found in patients with a more severe disease according to GINA classification. CONCLUSION: Nonallergic asthma is characterized by autoreactivity as well as increased coagulation and angiogenesis markers, which are known to enhance vascular permeability. The presence of circulating vasoactive factors may be relevant to understand the disease pathophysiology and to detect novel therapeutic strategies in nonallergic asthma. PMID- 21658191 TI - Editor's choice. The problem with fetal monitoring. PMID- 21658192 TI - The effect of perinatal omega-3 fatty acid supplementation on inflammatory markers and allergic diseases: a systematic review. AB - BACKGROUND: Maternal supplementation with omega-3 polyunsaturated fatty acids (n 3 PUFA) may modulate immune responses and allergy in neonates and children. OBJECTIVE: To determine if n-3 PUFA supplementation during pregnancy and lactation reduces risk for childhood allergic disease. SEARCH STRATEGY: We searched Medline and all evidence-based medicine reviews for randomised controlled trials comparing the effects of n-3 PUFA and placebo supplementation during pregnancy and/or lactation on childhood allergic diseases and inflammatory cytokines. SELECTION CRITERIA: We included studies reporting on food allergy, response to the egg skin prick test (SPT), atopy and asthma in infancy and childhood as well as production of interleukin-13 and interferon-gamma, two cytokines involved in the pathogenesis of asthma. For assessment of inclusion, two authors reviewed all abstracts for suitability and independently extracted data. DATA COLLECTION AND ANALYSIS: Two-by-two tables were constructed and odds ratios (OR) were calculated for the outcomes: response to the SPT, food allergy, atopy and asthma in childhood. The assays differed so data on inflammatory markers were reported in narrative form. MAIN RESULTS: Five randomised controlled trials (n = 949) were included. n-3 PUFA supplementation during pregnancy reduced 12-month prevalence of positive egg SPT (two trials, 12/87 versus 32/100, OR 0.33, 95% CI 0.16, 0.70) and childhood asthma (two trials, 10/303 versus 17/179, OR 0.349, 95% CI 0.154, 0.788) and significantly reduced cord blood interleukin 13 levels. Supplementation during lactation did not prevent asthma, food allergy or atopy. CONCLUSION: n-3 PUFA supplementation during pregnancy decreases childhood asthma and response to SPT. PMID- 21658193 TI - Evaluation and impact of cardiotocography training programmes: a systematic review. AB - BACKGROUND: The interpretation and management of cardiotocography (CTG) tracings are often criticised in obstetric malpractice cases. As a consequence, regular CTG training has been recommended, even though little is known about the effect of CTG training. OBJECTIVES: To perform a systematic review of the existing literature on studies on CTG training in order to assess educational strategies, evaluation of training programmes, and impact of training programmes. SEARCH STRATEGY: The Medline database was searched to identify studies describing and/or evaluating CTG training programmes. The literature search resulted in 409 citations. SELECTION CRITERIA: Twenty studies describing and evaluating CTG training programmes were included. There was no restriction on study design. DATA COLLECTION AND ANALYSIS: Data regarding study design, study quality, educational strategies used for training in CTG interpretation and decision making, target groups, number of participants, methods used for evaluation, quality of evaluation, level of evaluation and results of training was extracted from 20 articles, and analysed using Kirkpatrick's four-level model for the evaluation of education. MAIN RESULTS: Training was associated with improvements on all Kirkpatrick levels, resulting in increased CTG knowledge and interpretive skills, higher interobserver agreement, better management of intrapartum CTG, and improved quality of care. Computer-based training (CBT) might be less time consuming than classroom teaching. Clinical skills seem to decrease faster than theoretical knowledge. AUTHOR'S CONCLUSIONS: Training can improve CTG competence and clinical practise. Further research on CBT, test-enhanced learning and long term retention, evaluation of training and impact on clinical outcomes is recommended. PMID- 21658194 TI - The role of individually targeted information to reduce anxiety before colposcopy: a randomised controlled trial. AB - OBJECTIVE: We investigated whether providing targeted information on an individual level by mail and by phone reduces anxiety in women referred to the colposcopy clinic. DESIGN: Randomised controlled trial. POPULATION: Women referred to the colposcopy clinic. METHODS: Between December 2007 and April 2010, 169 patients with abnormal smear results were randomised into two study arms. Group A received individually targeted information about the diagnosis and procedure by mail and phone. Group B received the standard folder about colposcopies alone. Patients were requested to fill out a questionnaire prior to their first colposcopy appointment. MAIN OUTCOME MEASURES: The questionnaire included the hospital anxiety and depression scale (HADS), and the Spielberger state-trait anxiety inventory (STAI), as well as a short self-administered questionnaire. RESULTS: Twenty women were excluded from further analyses after randomisation, leaving 149 women for evaluation. The median STAI state anxiety score was high (50.0), but there was no significant difference in median STAI state anxiety and HADS anxiety scores between both groups. However, knowledge about human papillomavirus and the colposcopy procedure did significantly increase in group A (P = 0.004). CONCLUSIONS: Anxiety levels before primary colposcopy are surprisingly high, and are not reduced following individually targeted information given before colposcopy. PMID- 21658195 TI - Maternal serum 25-hydroxyvitamin D levels at 11(+0) -13(+6) weeks in pregnant women with diabetes mellitus and in those with macrosomic neonates. AB - OBJECTIVE: To investigate whether maternal serum levels of 25-hydroxyvitamin D [25(OH)D] in the first trimester are altered in pregnant women with pre-existing type 2 diabetes, women who subsequently develop gestational diabetes mellitus (GDM) and women who deliver large for gestational age (LGA) neonates compared with normoglycaemic pregnant women who deliver an appropriate for gestational age (AGA) neonate. DESIGN: Case-control study. SETTING: Antenatal clinic. POPULATION: Singleton pregnancies at 11(+0) -13(+6) weeks, including 50 women with type 2 diabetes, 100 women who subsequently developed GDM, 50 nondiabetic women who subsequently delivered LGA neonates and 1000 nondiabetic controls who delivered AGA neonates. METHODS: Maternal serum total 25(OH)D levels were measured in the four groups of pregnancies. Multiple regression analysis in the controls was used to identify factors among maternal characteristics with a significant contribution to the levels of serum 25(OH)D, so that the values in all cases were expressed as a multiple of the median (MoM) in the controls. MAIN OUTCOME MEASURES: Comparison of MoM 25(OH)D in the four groups. RESULTS: In controls, significant independent contributions to the serum level of 25(OH)D were provided by maternal age, body mass index, smoking status, racial origin and season of sampling. The median and interquartile range (IQR) of serum 25(OH)D in the type 2 diabetes group (1.01; IQR, 0.68-1.47 MoM), GDM group (0.93; IQR, 0.67-1.23 MoM) and LGA group (0.97; IQR, 0.67-1.25 MoM) were not significantly different from those in the controls (0.99; IQR, 0.71-1.33 MoM) (overall P = 0.643). CONCLUSIONS: The first-trimester maternal serum level of 25(OH)D is not altered in women with type 2 diabetes, those who develop GDM or those who deliver LGA neonates. PMID- 21658196 TI - Abstracts Blair Bell Research Society. November 18-19, 2010. PMID- 21658197 TI - Administration of misoprostol by trained traditional birth attendants to prevent postpartum haemorrhage in home births in Pakistan: randomised placebo-controlled trial. PMID- 21658199 TI - A qualitative study of women's preferences for treatment of pelvic floor disorders. PMID- 21658201 TI - Risk of synechiae following uterine compression sutures. PMID- 21658203 TI - Routine indwelling catheterisation in caesarean section-there is still a role. PMID- 21658205 TI - Postpartum haemorrhage and postpartum urinary retention: could voiding be the best way of avoiding postpartum haemorrhage? PMID- 21658209 TI - Fibrocytes and the tissue niche in lung repair. AB - Human fibrocytes are bone marrow-derived mesenchymal progenitor cells that express a variety of markers related to leukocytes, hematopoietic stem cells and a diverse set of fibroblast phenotypes. Fibrocytes can be recruited from the circulation to the tissue where they further can differentiate and proliferate into various mesenchymal cell types depending on the tissue niche. This local tissue niche is important because it modulates the fibrocytes and coordinates their role in tissue behaviour and repair. However, plasticity of a niche may be co-opted in chronic airway diseases such as asthma, idiopathic pulmonary fibrosis and obliterative bronchiolitis. This review will therefore focus on a possible role of fibrocytes in pathological tissue repair processes in those diseases. PMID- 21658210 TI - Sequential injection chromatography with a miniaturized multi-channel fiber optic detector for separation and quantification of propranolol and hydrochlorothiazide. AB - BACKGROUND: Sequential injection chromatography (SIC) is a new alternative separation technology. It has some advantages over high performance liquid chromatography (HPLC) regarding simplicity, inexpensiveness, portability, ease of use, maintenance requirement and operation time. In contrast, SIC has had suffered from some limitations. RESULTS: The current work involves four achievements. (a) One of the limitations of SIC has been overcome. A higher pressure resistant selection valve with additional ports was installed in an SIC system. This development allows propelling solution without showing solution leakage. (b) A new inexpensive rapid and green method for the separation and quantification of propranolol (PRP) and hydrochlorothiazide (HTZ) in their formulations was optimized and validated. (c) A miniaturized multi-channel fiber optic detector was coupled with the newly developed SIC system to detect PRP and HTZ at 270 and 290 nm, respectively. This issue enhanced the sensitivity rather than using a single-channel detector. (d) A comparative study on the efficiency of the SIC method with that of previous HPLC methods was conducted. CONCLUSIONS: Besides the benefits of the instrumentation of SIC, the proposed method is rapider and more reagent-saving than previous HPLC methods. The total volume of consumed reagents and sample was 4.04 mL. The sample frequency was 22 samples/h. Other such analytical characters of the SIC method as resolution, peak symmetry, numbers of theoretical plates, linearity range, accuracy, precision and limits of detection and quantification recorded comparable results. PMID- 21658211 TI - Instrument development, data collection, and characteristics of practices, staff, and measures in the Improving Quality of Care in Diabetes (iQuaD) Study. AB - BACKGROUND: Type 2 diabetes is an increasingly prevalent chronic illness and an important cause of avoidable mortality. Patients are managed by the integrated activities of clinical and non-clinical members of primary care teams. This study aimed to: investigate theoretically-based organisational, team, and individual factors determining the multiple behaviours needed to manage diabetes; and identify multilevel determinants of different diabetes management behaviours and potential interventions to improve them. This paper describes the instrument development, study recruitment, characteristics of the study participating practices and their constituent healthcare professionals and administrative staff and reports descriptive analyses of the data collected. METHODS: The study was a predictive study over a 12-month period. Practices (N = 99) were recruited from within the UK Medical Research Council General Practice Research Framework. We identified six behaviours chosen to cover a range of clinical activities (prescribing, non-prescribing), reflect decisions that were not necessarily straightforward (controlling blood pressure that was above target despite other drug treatment), and reflect recommended best practice as described by national guidelines. Practice attributes and a wide range of individually reported measures were assessed at baseline; measures of clinical outcome were collected over the ensuing 12 months, and a number of proxy measures of behaviour were collected at baseline and at 12 months. Data were collected by telephone interview, postal questionnaire (organisational and clinical) to practice staff, postal questionnaire to patients, and by computer data extraction query. RESULTS: All 99 practices completed a telephone interview and responded to baseline questionnaires. The organisational questionnaire was completed by 931/1236 (75.3%) administrative staff, 423/529 (80.0%) primary care doctors, and 255/314 (81.2%) nurses. Clinical questionnaires were completed by 326/361 (90.3%) primary care doctors and 163/186 (87.6%) nurses. At a practice level, we achieved response rates of 100% from clinicians in 40 practices and > 80% from clinicians in 67 practices. All measures had satisfactory internal consistency (alpha coefficient range from 0.61 to 0.97; Pearson correlation coefficient (two item measures) 0.32 to 0.81); scores were generally consistent with good practice. Measures of behaviour showed relatively high rates of performance of the six behaviours, but with considerable variability within and across the behaviours and measures. DISCUSSION: We have assembled an unparalleled data set from clinicians reporting on their cognitions in relation to the performance of six clinical behaviours involved in the management of people with one chronic disease (diabetes mellitus), using a range of organisational and individual level measures as well as information on the structure of the practice teams and across a large number of UK primary care practices. We would welcome approaches from other researchers to collaborate on the analysis of this data. PMID- 21658212 TI - HIV seroprevalence and its effect on outcome of moderate to severe burn injuries: A Ugandan experience. AB - BACKGROUND: HIV infection in a patient with burn injuries complicates the care of both the patient and the treating burn team. This study was conducted to establish the prevalence of HIV among burn patients in our setting and to compare the outcome of these patients who are HIV positive with those who are HIV negative. METHODS: This was a prospective cohort study involving burn injury patients admitted to Mulago Hospital between November 2005 and February 2006. Patients were stratified into HIV positive (exposed) group and HIV-negative (unexposed) group. Data was collected using a pre-tested coded questionnaire and analyzed using SPSS statistical computer software version 11.5. RESULTS: Of the 130 patients included in the study, 17 (13.1%) patients tested HIV positive and this formed the study (exposed) group. The remaining 113 patients (86.9%) formed the control (unexposed) group. In the HIV positive group, females outnumbered males by a ratio of 1.4:1 and the mean age was 28.4 +/- 21.5 years (range 3 months-34 years). 64.7% of HIV positive patients reported to have risk factors for HIV infection. Of these, multiple sexual partners [Odds Ratio 8.44, 95% C.I. (3.87-143.23), P = 0.011] and alcoholism [Odds Ratio 8.34, 95% C.I. (5.76-17.82), P = 0.002] were found to be independently and significantly associated with increased risk to HIV infection. The mean CD4 count for HIV positive and HIV negative patients were 394 +/- 328 cells/MUL and 912 +/- 234 cells/MUL respectively which is statistically significant (P = 0.001). There was no difference in the bacteria cultured from the wounds of HIV positive and negative patients (P = 0.322). Patients with clinical signs of sepsis had lower CD4+ counts compared to patients without sepsis (P < 0.001). ). Skin grafting was carried out in 35.3% of HIV negative patients and 29.4% of HIV positive patients with no significant difference in skin graft take and the degree of healed burn on discharge was the same (P = 0.324). There was no significant difference in hospital stay between HIV positive and negative patients (P = 0.674). The overall mortality rate was 11.5%. Using multivariate logistic regression analysis, mortality rate was found to be independently and significantly related to the age of the patient, HIV positive with stigmata of AIDS, CD4 count, inhalation injury, %TBSA and severity of burn (p-value < 0.001). CONCLUSION: HIV infection is prevalent among burn injury patients in our setting and thus presents an occupational hazard to health care workers who care for these patients. All burn health care workers in this region need to practice universal precautions in order to reduce the risk of exposure to HIV infection and post-exposure prophylaxis should be emphasized. The outcome of burn injury in HIV infected patients is dependent upon multiple variables such as age of the patient, inhalation injury and %TBSA and not the HIV status alone. PMID- 21658213 TI - External review and validation of the Swedish national inpatient register. AB - BACKGROUND: The Swedish National Inpatient Register (IPR), also called the Hospital Discharge Register, is a principal source of data for numerous research projects. The IPR is part of the National Patient Register. The Swedish IPR was launched in 1964 (psychiatric diagnoses from 1973) but complete coverage did not begin until 1987. Currently, more than 99% of all somatic (including surgery) and psychiatric hospital discharges are registered in the IPR. A previous validation of the IPR by the National Board of Health and Welfare showed that 85-95% of all diagnoses in the IPR are valid. The current paper describes the history, structure, coverage and quality of the Swedish IPR. METHODS AND RESULTS: In January 2010, we searched the medical databases, Medline and HighWire, using the search algorithm "validat* (inpatient or hospital discharge) Sweden". We also contacted 218 members of the Swedish Society of Epidemiology and an additional 201 medical researchers to identify papers that had validated the IPR. In total, 132 papers were reviewed. The positive predictive value (PPV) was found to differ between diagnoses in the IPR, but is generally 85-95%. CONCLUSIONS: In conclusion, the validity of the Swedish IPR is high for many but not all diagnoses. The long follow-up makes the register particularly suitable for large scale population-based research, but for certain research areas the use of other health registers, such as the Swedish Cancer Register, may be more suitable. PMID- 21658214 TI - Managing depression in primary care: A meta-synthesis of qualitative and quantitative research from the UK to identify barriers and facilitators. AB - BACKGROUND: Current management in primary care of depression, with or without comorbid physical illness, has been found to be suboptimal. We therefore conducted a systematic review to identify clinician perceived barriers to and facilitators for good depression care. METHODS: We conducted a systematic literature search to identify qualitative and quantitative studies published in the UK since 2000 of GPs' and practice nurses' attitudes to the management of depression. We used principles from meta-ethnography to identify common and refuted themes across studies. RESULTS: We identified 7 qualitative and 10 quantitative studies; none concerned depression and co-morbid physical illness of any kind. The studies of managing patients with a primary diagnosis of depression indicated that GPs and PNs are unsure of the exact nature of the relationship between mood and social problems and of their role in managing it. Among some clinicians, ambivalent attitudes to working with depressed people, a lack of confidence, the use of a limited number of management options and a belief that a diagnosis of depression is stigmatising complicate the management of depression. CONCLUSIONS: Detection and management of depression is considered complex. In particular, primary care clinicians need guidance to address the social needs of depressed patients. It is not known whether the same issues are important when managing depressed people with co-morbid physical illness. PMID- 21658215 TI - Social validity of randomised controlled trials in health services research and intellectual disabilities: a qualitative exploration of stakeholder views. AB - BACKGROUND: Randomised controlled trials (RCTs) are the gold standard of evidence based practice in medicine but they have had limited influence in the field of intellectual disabilities. Previous literature suggests that participants and professionals have limited tolerance for this type of research methodology. However, it is not known how well service users, carers and other health professionals understand and accept the need for RCTs, and why it is important for individuals with intellectual disabilities to be included in this kind of research. METHODS: We examined individual perceptions of RCTs in 51 participants (18 carers, 6 service users and 27 professionals) using semi-structured interviews. A framework approach was adopted in the analysis of data. RESULTS: We found that participants had concerns about capacity and resource allocation but held positive views towards this type of research methodology. Understanding of the principles behind RCTs was poor amongst service users and a minority of carers, but mediated by previous exposure to research for professionals. CONCLUSIONS: The social validity of RCTs in intellectual disabilities may be compromised by lack of understanding of the design and the on-going concerns about obtaining informed consent especially in incapacitated adults. However, the overall finding that the need for this form of research was seen in a positive light suggests that there is a turning point in the perceptions of stakeholders working in intellectual disabilities services. We recommend that researchers include on-going education on RCT design during trials, tailoring it to all stakeholders with emphasis on strong service user and care involvement. This could be a pivotal element in improving acceptability of, and recruitment to RCTs. PMID- 21658218 TI - Psychological and social consequences among mothers suffering from perinatal loss: perspective from a low income country. AB - BACKGROUND: In developed countries, perinatal death is known to cause major emotional and social effects on mothers. However, little is known about these effects in low income countries which bear the brunt of perinatal mortality burden. This paper reports the impact of perinatal death on psychological status and social consequences among mothers in a rural area of Bangladesh. METHODS: A total of 476 women including 122 women with perinatal deaths were assessed with the Edinburgh Postnatal Depression Scale (EPDS-B) at 6 weeks and 6 months postpartum, and followed up for negative social consequences at 6 months postpartum. Trained female interviewers carried out structured interviews at women's home. RESULTS: Overall 43% (95% CI: 33.7-51.8%) of women with a perinatal loss at 6 weeks postpartum were depressed compared to 17% (95% CI: 13.7-21.9%) with healthy babies (p = < 0.001). Depression status were significantly associated with women reporting negative life changes such as worse relationships with their husband (adjusted OR = 3.89, 95% CI: 1.37-11.04) and feeling guilty (adjusted OR = 2.61, 95% CI: 1.22-5.63) following the results of their last pregnancy outcome after 6 months of childbirth. CONCLUSIONS: This study highlights the greatly increased vulnerability of women with perinatal death to experience negative psychological and social consequences. There is an urgent need to develop appropriate mental health care services for mothers with perinatal deaths in Bangladesh, including interventions to develop positive family support. PMID- 21658217 TI - Gyrodactylus salinae n. sp. (Platyhelminthes: Monogenea) infecting the south European toothcarp Aphanius fasciatus (Valenciennes) (Teleostei, Cyprinodontidae) from a hypersaline environment in Italy. AB - BACKGROUND: Historically, non-native species of Gambusia (Poeciliidae) have been used to control larval stages of the Asian tiger mosquito, Stegomyia albopicta Reinert, Harbach et Kitching, 2004 throughout Italy. The potential utility of indigenous populations of Aphanius fasciatus (Valenciennes) (Teleostei: Cyprinodontidae) as an appropriate alternative biological control is currently being explored. A sub-sample of ten fish collected from Cervia Saline, Italy (salinity 65 ppt; 30 degrees C) to assess their reproductive capability in captivity, harboured a moderate infection of Gyrodactylus von Nordmann, 1832 (Platyhelminthes, Monogenea). A subsequent morphological and molecular study identified this as being a new species. RESULTS: Gyrodactylus salinae n. sp. is described from the skin, fins and gills of A. fasciatus. Light and scanning electron microscopical (SEM) examination of the opisthaptoral armature and their comparison with all other recorded species suggested morphological similarities to Gyrodactylus rugiensoides Huyse et Volckaert, 2002 from Pomatoschistus minutus (Pallas). Features of the ventral bar, however, permit its discrimination from G. rugiensoides. Sequencing of the nuclear ribosomal DNA internal transcribed spacers 1 and 2 and the 5.8S rRNA gene and a comparison with all species listed in GenBank confirmed they are unique and represent a new species (most similar to Gyrodactylus anguillae Ergens, 1960, 8.3% pair-wise distance based on 5.8S+ITS2). This represents the first species of Gyrodactylus to be described from Aphanius and, to date, has the longest ITS1 (774 bp) sequenced from any Gyrodactylus. Additional sampling of Cervia Saline throughout the year, found G. salinae n. sp. to persist in conditions ranging from 35 ppt and 5 degrees C in December to 65 ppt and 30 degrees C in July, while in captivity a low level of infection was present, even in freshwater conditions (0 ppt). CONCLUSIONS: The ability of G. salinae n. sp. to tolerate a wide range of salinities and temperatures shows its potential to readily adapt to several environmental conditions. These findings, together with the fact that A. fasciatus is a protected species and is considered as a biological control organism, necessitate further studies on the ecology and virulence of G. salinae n. sp. PMID- 21658219 TI - Using e-mail recruitment and an online questionnaire to establish effect size: A worked example. AB - BACKGROUND: Sample size calculations require effect size estimations. Sometimes, effect size estimations and standard deviation may not be readily available, particularly if efficacy is unknown because the intervention is new or developing, or the trial targets a new population. In such cases, one way to estimate the effect size is to gather expert opinion. This paper reports the use of a simple strategy to gather expert opinion to estimate a suitable effect size to use in a sample size calculation. METHODS: Researchers involved in the design and analysis of clinical trials were identified at the University of Birmingham and via the MRC Hubs for Trials Methodology Research. An email invited them to participate.An online questionnaire was developed using the free online tool 'Survey Monkey(c)'. The questionnaire described an intervention, an electronic participant information sheet (e-PIS), which may increase recruitment rates to a trial. Respondents were asked how much they would need to see recruitment rates increased by, based on 90%. 70%, 50% and 30% baseline rates, (in a hypothetical study) before they would consider using an e-PIS in their research.Analyses comprised simple descriptive statistics. RESULTS: The invitation to participate was sent to 122 people; 7 responded to say they were not involved in trial design and could not complete the questionnaire, 64 attempted it, 26 failed to complete it. Thirty-eight people completed the questionnaire and were included in the analysis (response rate 33%; 38/115). Of those who completed the questionnaire 44.7% (17/38) were at the academic grade of research fellow 26.3% (10/38) senior research fellow, and 28.9% (11/38) professor. Dependent upon the baseline recruitment rates presented in the questionnaire, participants wanted recruitment rate to increase from 6.9% to 28.9% before they would consider using the intervention. CONCLUSIONS: This paper has shown that in situations where effect size estimations cannot be collected from previous research, opinions from researchers and trialists can be quickly and easily collected by conducting a simple study using email recruitment and an online questionnaire. The results collected from the survey were successfully used in sample size calculations for a PhD research study protocol. PMID- 21658216 TI - Biotechnological applications of recombinant single-domain antibody fragments. AB - BACKGROUND: Single-domain antibody fragments possess structural features, such as a small dimension, an elevated stability, and the singularity of recognizing epitopes non-accessible for conventional antibodies that make them interesting for several research and biotechnological applications. RESULTS: The discovery of the single-domain antibody's potentials has stimulated their use in an increasing variety of fields. The rapid accumulation of articles describing new applications and further developments of established approaches has made it, therefore, necessary to update the previous reviews with a new and more complete summary of the topic. CONCLUSIONS: Beside the necessary task of updating, this work analyses in detail some applicative aspects of the single-domain antibodies that have been overseen in the past, such as their efficacy in affinity chromatography, as co crystallization chaperones, protein aggregation controllers, enzyme activity tuners, and the specificities of the unconventional single-domain fragments. PMID- 21658220 TI - TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families. AB - BACKGROUND: The TRPV4 gene encodes a calcium-permeable ion-channel that is widely expressed, responds to many different stimuli and participates in an extraordinarily wide range of physiologic processes. Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK) and metatropic dysplasia (MD) are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. Recently, TRPV4 mutations have been found in patients diagnosed with these skeletal phenotypes. METHODS AND RESULTS: We critically analysed the clinical and radiographic data on 26 subjects from 21 families, all of whom had a clinical diagnosis of one of the conditions described above: 15 with MD; 9 with SMDK; and 2 with brachyolmia. We sequenced TRPV4 and identified 9 different mutations in 22 patients, 4 previously described, and 5 novel. There were 4 mutation-negative cases: one with MD and one with SMDK, both displaying atypical clinical and radiographic features for these diagnoses; and two with brachyolmia, who had isolated spine changes and no metaphyseal involvement. CONCLUSIONS: Our data suggest the TRPV4 skeletal dysplasias represent a continuum of severity with areas of phenotypic overlap, even within the same family. We propose that AD brachyolmia lies at the mildest end of this spectrum and, since all cases described with this diagnosis and TRPV4 mutations display metaphyseal changes, we suggest that it is not a distinct entity but represents the mildest phenotypic expression of SMDK. PMID- 21658221 TI - Health-related quality of life and physical recovery after a critical illness: a multi-centre randomised controlled trial of a home-based physical rehabilitation program. AB - INTRODUCTION: Significant physical sequelae exist for some survivors of a critical illness. There are, however, few studies that have examined specific interventions to improve their recovery, and none have tested a home-based physical rehabilitation program incorporating trainer visits to participants' homes. This study was designed to test the effect of an individualised eight-week home-based physical rehabilitation program on recovery. METHODS: A multi-centre randomised controlled trial design was used. Adult intensive care patients (length of stay of at least 48 hours and mechanically ventilated for 24 hours or more) were recruited from 12 Australian hospitals between 2005 and 2008. Graded, individualised endurance and strength training intervention was prescribed over eight weeks, with three physical trainer home visits, four follow-up phone calls, and supported by a printed exercise manual. The main outcome measures were blinded assessments of physical function; SF-36 physical function (PF) scale and six-minute walk test (6MWT), and health-related quality of life (SF-36) conducted at 1, 8 and 26 weeks after hospital discharge. RESULTS: Of the 195 participants randomised, 183, 173 and 161 completed the 1, 8 and 26 weeks assessments, respectively. Study groups were similar at Week 1 post-hospital; for the intervention and control groups respectively, mean norm-based PF scores were 27 and 29 and the 6MWT distance was 291 and 324 metres. Both groups experienced significant and clinically important improvements in PF scores and 6MWT distance at 8 weeks, which persisted at 26 weeks. Mixed model analysis showed no significant group effects (P = 0.84) or group by time interactions (P = 0.68) for PF. Similar results were found for 6MWT and the SF-36 summary scores. CONCLUSIONS: This individualised eight-week home-based physical rehabilitation program did not increase the underlying rate of recovery in this sample, with both groups of critically ill survivors improving their physical function over the 26 weeks of follow-up. Further research should explore improving effectiveness of the intervention by increasing exercise intensity and frequency, and identifying individuals who would benefit most from this intervention. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register ACTRN12605000166673. PMID- 21658222 TI - Impact of UGT2B7 His268Tyr polymorphism on the outcome of adjuvant epirubicin treatment in breast cancer. AB - INTRODUCTION: Epirubicin is a common adjuvant treatment for breast cancer. It is mainly eliminated after glucuronidation through uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7). The present study aimed to describe the impact of the UGT2B7(His268Tyr) polymorphism on invasive disease-free survival in breast cancer patients after epirubicin treatment. METHODS: This is a pharmacogenetic study based on samples collected from 745 breast cancer patients of the Austrian Tumor of breast tissue: Incidence, Genetics, and Environmental Risk factors (TIGER) cohort who did not present metastases at baseline. This cohort included 205 women with epirubicin-based combination chemotherapy, 113 patients having received chemotherapy without epirubicin and 427 patients having received no chemotherapy at all. Of the epirubicin-treated subgroup, 120 were subsequently treated with tamoxifen. For all women UGT2B7(His268Tyr) was genotyped. Invasive disease-free survival was assessed using Kaplan-Meier and Cox's proportional hazard regression analysis. RESULTS: Among the 205 epirubicin treated patients, carriers of two UGT2B7(268Tyr) alleles had a mean invasive disease-free survival of 8.6 (95% confidence interval (CI) 7.9 to 9.3) years as compared to 7.5 (95% CI 6.9 to 8.0) years in carriers of at least one UGT2B7(268His) allele (adjusted hazard ratio (HR) = 2.64 (95% CI 1.22 to 5.71); P = 0.014). In addition, the impact of the UGT2B7(His268Tyr) polymorphism became even more pronounced in patients subsequently treated with tamoxifen (adjusted HR = 5.22 (95% CI 1.67 to 26.04); P = 0.015) whereas no such difference in invasive disease-free survival was observed in patients not receiving epirubicin. CONCLUSIONS: Breast cancer patients carrying the UGT2B7(268Tyr/Tyr) genotype may benefit most from adjuvant epirubicin-based chemotherapy. These results warrant confirmation in further studies. PMID- 21658223 TI - The usefulness of magnetic resonance imaging of the hand and wrist in very early rheumatoid arthritis. AB - INTRODUCTION: Magnetic resonance imaging (MRI) was used to study the hand and wrist in very early rheumatoid arthritis (RA), and the results were compared with early and established disease. METHODS: Fifty-seven patients fulfilling the new American College of Rheumatology criteria for RA, 26 with very early RA (VERA), 18 with early RA (ERA), and 13 with established RA (ESTRA), (disease duration < 3 months, < 12 months, and > 12 months, respectively) were enrolled in the study. MRI of the dominant hand and wrist was performed by using fat-suppressed T2 weighted and plain and contrast-enhanced T1-weighted sequences. Evaluation of bone marrow edema, synovitis, and bone erosions was performed with the OMERACT RA MRI scoring system. RESULTS: Edema, erosions, and synovitis were present in VERA, and the prevalence was 100%, 96.15%, and 92.3%, respectively. Significant differences in edema and erosions were found between VERA and ESTRA (P < 0.05). No significant difference was found in synovitis. CONCLUSIONS: Edema, erosions, and synovitis are findings of very early RA. MRI, by detecting these lesions, may play an important role in the management of these patients. PMID- 21658224 TI - Effect of a 6-week dynamic neuromuscular training programme on ankle joint function: A Case report. AB - BACKGROUND: Ankle joint sprain and the subsequent development of chronic ankle instability (CAI) are commonly encountered by clinicians involved in the treatment and rehabilitation of musculoskeletal injuries. It has recently been advocated that ankle joint post-sprain rehabilitation protocols should incorporate dynamic neuromuscular training to enhance ankle joint sensorimotor capabilities. To date no studies have reported on the effects of dynamic neuromuscular training on ankle joint positioning during landing from a jump, which has been reported as one of the primary injury mechanisms for ankle joint sprain. This case report details the effects of a 6-week dynamic neuromuscular training programme on ankle joint function in an athlete with CAI. METHODS: The athlete took part in a progressive 6-week dynamic neuromuscular training programme which incorporated postural stability, strengthening, plyometric, and speed/agility drills. The outcome measures chosen to assess for interventional efficacy were: 1 Cumberland Ankle Instability Tool (CAIT) scores, 2 Star Excursion Balance Test (SEBT) reach distances, 3 ankle joint plantar flexion during drop landing and drop vertical jumping, and 4 ground reaction forces (GRFs) during walking. RESULTS: CAIT and SEBT scores improved following participation in the programme. The angle of ankle joint plantar flexion decreased at the point of initial contact during the drop landing and drop vertical jumping tasks, indicating that the ankle joint was in a less vulnerable position upon landing following participation in the programme. Furthermore, GRFs were reduced whilst walking post-intervention. CONCLUSIONS: The 6-week dynamic neuromuscular training programme improved parameters of ankle joint sensorimotor control in an athlete with CAI. Further research is now required in a larger cohort of subjects to determine the effects of neuromuscular training on ankle joint injury risk factors. PMID- 21658225 TI - Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients. AB - BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management. PMID- 21658226 TI - Comparative study of clinical grade human tolerogenic dendritic cells. AB - BACKGROUND: The use of tolerogenic DCs is a promising therapeutic strategy for transplantation and autoimmune disorders. Immunomodulatory DCs are primarily generated from monocytes (MDDCs) for in vitro experiments following protocols that fail to fulfil the strict regulatory rules of clinically applicable products. Here, we compared the efficacy of three different tolerance-inducing agents, dexamethasone, rapamycin and vitamin D3, on DC biology using GMP (Good Manufacturing Practice) or clinical grade reagents with the aim of defining their use for human cell therapy. METHODS: Tolerogenic MDDCs were generated by adding tolerogenic agents prior to the induction of maturation using TNF-alpha, IL-beta and PGE2. We evaluated the effects of each agent on viability, efficiency of differentiation, phenotype, cytokine secretion and stability, the stimulatory capacity of tol-DCs and the T-cell profiles induced. RESULTS: Differences relevant to therapeutic applicability were observed with the cellular products that were obtained. VitD3-induced tol-DCs exhibited a slightly reduced viability and yield compared to Dexa-and Rapa-tol-DCs. Phenotypically, while Dexa-and VitD3 tol-DCs were similar to immature DCs, Rapa-tol-DCs were not distinguishable from mature DCs. In addition, only Dexa-and moderately VitD3-tol-DCs exhibited IL-10 production. Interestingly, in all cases, the cytokine secretion profiles of tol DCs were not modified by a subsequent TLR stimulation with LPS, indicating that all products had stable phenotypes. Functionally, clearly reduced alloantigen T cell proliferation was induced by tol-DCs obtained using any of these agent. Also, total interferon-gamma (IFN-gamma) secretion by T cells stimulated with allogeneic tol-DCs was reduced in all three cases, but only T cells co-cultured with Rapa-tol-DCs showed impaired intracellular IFN-gamma production. In addition, Rapa-DCs promoted CD4+ CD127 low/negative CD25high and Foxp3+ T cells. CONCLUSIONS: Our results demonstrate contrasting influences of different clinical grade pharmacological agents on human tol-DC generation. This should be taken into account for decisions on the use of a specific agent for the appropriate cellular therapy in the context of a particular disease. PMID- 21658229 TI - Experiences of outreach workers in promoting smoking cessation to Bangladeshi and Pakistani men: longitudinal qualitative evaluation. AB - BACKGROUND: Despite having high smoking rates, there have been few tailored cessation programmes for male Bangladeshi and Pakistani smokers in the UK. We report on a qualitative evaluation of a community-based, outreach worker delivered, intervention that aimed to increase uptake of NHS smoking cessation services and tailor services to meet the needs of Bangladeshi and Pakistani men. METHODS: This was a longitudinal, qualitative study, nested within a phase II cluster randomised controlled trial of a complex intervention. We explored the perspectives and experiences of five outreach workers, two stop smoking service managers and a specialist stop smoking advisor. Data were collected through focus group discussions, weekly diaries, observations of management meetings, shadowing of outreach workers, and one-to-one interviews with outreach workers and their managers. Analysis was undertaken using a modified Framework approach. RESULTS: Outreach workers promoted cessation services by word of mouth on the streets, in health service premises, in local businesses and at a wide range of community events. They emphasised the reasons for cessation, especially health effects, financial implications, and the impact of smoking on the family. Many smokers agreed to be referred to cessation services, but few attended, this in part being explained by concerns about the relative inflexibility of existing service provision. Although outreach workers successfully expanded service reach, they faced the challenges of perceived lack of awareness of the health risks associated with smoking in older smokers and apathy in younger smokers. These were compounded by perceptions of "lip service" being given to their role by community organisations and tensions both amongst the outreach workers and with the wider management team. CONCLUSIONS: Outreach workers expanded reach of the service through taking it to diverse locations of relevance to Pakistani and Bangladeshi communities. The optimum method of outreach to retain and treat Bangladeshi and Pakistani smokers effectively in cessation programmes needs further development. PMID- 21658228 TI - ATA homozigosity in the IL-10 gene promoter is a risk factor for schizophrenia in Spanish females: a case control study. AB - BACKGROUND: Three IL-10 gene promoter single nucleotide polymorphisms -1082G > A, -819C > T and -592C > A and the haplotypes they define in Caucasians, GCC, ACC, ATA, associated with different IL-10 production rates, have been linked to schizophrenia in some populations with conflicting results. On the basis of the evidence of the sex-dependent effect of certain genes in many complex diseases, we conducted a sex-stratified case-control association study to verify the linkage of the IL-10 gene promoter SNPs and haplotypes with schizophrenia and the possible sex-specific genetic effect in a Spanish schizophrenic population. METHODS: 241 DSM-IV diagnosed Spanish schizophrenic patients and 435 ethnically matched controls were genotyped for -1082G > A and -592C > A SNPs. Chi squared tests were performed to assess for genetic association of alleles, genotypes and haplotypes with the disease. RESULTS: The -1082A allele (p = 0.027), A/A (p = 0.008) and ATA/ATA (p = 0.003) genotypes were significantly associated with schizophrenia in females while neither allelic nor genotypic frequencies reached statistical significance in the male population. CONCLUSIONS: Our results highlight the hypothesis of an imbalance towards an inflammatory syndrome as the immune abnormality of schizophrenia. Anyway, a better understanding of the involvement of the immune system would imply the search of immune abnormalities in endophenotypes in whose sex and ethnicity might be differential factors. It also reinforces the need of performing complex gene studies based on multiple cytokine SNPs, including anti and pro-inflammatory, to clarify the immune system abnormalities direction in the etiology of schizophrenia. PMID- 21658227 TI - The current status and future directions of myxoma virus, a master in immune evasion. AB - Myxoma virus (MYXV) gained importance throughout the twentieth century because of the use of the highly virulent Standard Laboratory Strain (SLS) by the Australian government in the attempt to control the feral Australian population of Oryctolagus cuniculus (European rabbit) and the subsequent illegal release of MYXV in Europe. In the European rabbit, MYXV causes a disease with an exceedingly high mortality rate, named myxomatosis, which is passively transmitted by biting arthropod vectors. MYXV still has a great impact on European rabbit populations around the world. In contrast, only a single cutaneous lesion, restricted to the point of inoculation, is seen in its natural long-term host, the South-American Sylvilagus brasiliensis and the North-American S. Bachmani. Apart from being detrimental for European rabbits, however, MYXV has also become of interest in human medicine in the last two decades for two reasons. Firstly, due to the strong immune suppressing effects of certain MYXV proteins, several secreted virus-encoded immunomodulators (e.g. Serp-1) are being developed to treat systemic inflammatory syndromes such as cardiovascular disease in humans. Secondly, due to the inherent ability of MYXV to infect a broad spectrum of human cancer cells, the live virus is also being developed as an oncolytic virotherapeutic to treat human cancer. In this review, an update will be given on the current status of MYXV in rabbits as well as its potential in human medicine in the twenty-first century. PMID- 21658230 TI - Modification of the loops in the ligand-binding site turns avidin into a steroid binding protein. AB - BACKGROUND: Engineered proteins, with non-immunoglobulin scaffolds, have become an important alternative to antibodies in many biotechnical and therapeutic applications. When compared to antibodies, tailored proteins may provide advantageous properties such as a smaller size or a more stable structure. RESULTS: Avidin is a widely used protein in biomedicine and biotechnology. To tailor the binding properties of avidin, we have designed a sequence-randomized avidin library with mutagenesis focused at the loop area of the binding site. Selection from the generated library led to the isolation of a steroid-binding avidin mutant (sbAvd-1) showing micromolar affinity towards testosterone (Kd ~ 9 MUM). Furthermore, a gene library based on the sbAvd-1 gene was created by randomizing the loop area between beta-strands 3 and 4. Phage display selection from this library led to the isolation of a steroid-binding protein with significantly decreased biotin binding affinity compared to sbAvd-1. Importantly, differential scanning calorimetry and analytical gel-filtration revealed that the high stability and the tetrameric structure were preserved in these engineered avidins. CONCLUSIONS: The high stability and structural properties of avidin make it an attractive molecule for the engineering of novel receptors. This methodology may allow the use of avidin as a universal scaffold in the development of novel receptors for small molecules. PMID- 21658231 TI - Screening for tuberculosis and prediction of disease in Portuguese healthcare workers. AB - INTRODUCTION: Results of systematic screening of healthcare workers (HCWs) for tuberculosis (TB) with the tuberculin skin test (TST) and interferon-gamma release assays (IGRA) in a Portuguese hospital from 2007 to 2010 are reported. METHODS: All HCWs are offered screening for TB. Screening is repeated depending on risk assessment. TST and QuantiFERON Gold In-Tube (QFT) are used simultaneously. X-ray is performed when TST is > 10 mm, IGRA is positive or typical symptoms exist. RESULTS: The cohort comprises 2,889 HCWs. TST and IGRA were positive in 29.5%, TST-positive but IGRA-negative results were apparent in 43.4%. Active TB was diagnosed in twelve HCWs - eight cases were detected during screening and four cases were predicted by IGRA as well as by TST. However, the progression rate in IGRA-positive was higher than in TST-positive HCWs (0.4% vs. 0.2%, p-value 0.06). CONCLUSIONS: The TB burden in this cohort was high (129.8 per 100,000 HCWs). However, the progression to active TB after a positive TST or positive IGRA was considerably lower than that reported in literature for close contacts in low-incidence countries. This may indicate that old LTBI prevails in these HCWs. PMID- 21658232 TI - Protocol for a systematic review of the effects of schools and school-environment interventions on health: evidence mapping and syntheses. AB - BACKGROUND: Schools may have important effects on students' and staff's health. Rather than treating schools merely as sites for health education, 'school environment' interventions treat schools as settings which influence health. Evidence concerning the effects of such interventions has not been recently synthesised. METHODS/DESIGN: Systematic review aiming to map and synthesise evidence on what theories and conceptual frameworks are most commonly used to inform school-environment interventions or explain school-level influences on health; what effects school-environment interventions have on health/health inequalities; how feasible and acceptable are school-environment interventions; what effects other school-level factors have on health; and through what processes school-level influences affect health.We will examine interventions aiming to promote health by modifying schools' physical, social or cultural environment via actions focused on school policies and practices relating to education, pastoral care and other aspects of schools beyond merely providing health education. Participants are staff and students age 4-18 years.We will review published research unrestricted by language, year or source. Searching will involve electronic databases including Embase, ERIC, PubMed, PsycInfo and Social Science Citation Index using natural-language phrases plus reference/citation checking.Stage 1 will map studies descriptively by focus and methods. Stage 2 will involve additional inclusion criteria, quality assessment and data extraction undertaken by two reviewers in parallel. Evidence will be synthesised narratively and statistically where appropriate (undertaking subgroup analyses and meta-regression and where no significant heterogeneity of effect sizes is found, pooling these to calculate a final effect size). DISCUSSION: We anticipate: finding a large number of studies missed by previous reviews; that non-intervention studies of school effects examine a greater breadth of determinants than are addressed by intervention studies; and that intervention effect estimates are greater than for school-based health curriculum interventions without school-environment components. PMID- 21658235 TI - Assessing causal relationships in genomics: From Bradford-Hill criteria to complex gene-environment interactions and directed acyclic graphs. AB - Observational studies of human health and disease (basic, clinical and epidemiological) are vulnerable to methodological problems -such as selection bias and confounding- that make causal inferences problematic. Gene-disease associations are no exception, as they are commonly investigated using observational designs. A rich body of knowledge exists in medicine and epidemiology on the assessment of causal relationships involving personal and environmental causes of disease; it includes seminal causal criteria developed by Austin Bradford Hill and more recently applied directed acyclic graphs (DAGs). However, such knowledge has seldom been applied to assess causal relationships in clinical genetics and genomics, even in studies aimed at making inferences relevant for human health. Conversely, incorporating genetic causal knowledge into clinical and epidemiological causal reasoning is still a largely unexplored area.As the contribution of genetics to the understanding of disease aetiology becomes more important, causal assessment of genetic and genomic evidence becomes fundamental. The method we develop in this paper provides a simple and rigorous first step towards this goal. The present paper is an example of integrative research, i.e., research that integrates knowledge, data, methods, techniques, and reasoning from multiple disciplines, approaches and levels of analysis to generate knowledge that no discipline alone may achieve. PMID- 21658234 TI - Translocation of signalling proteins to the plasma membrane revealed by a new bioluminescent procedure. AB - BACKGROUND: Activation by extracellular ligands of G protein-coupled (GPCRs) and tyrosine kinase receptors (RTKs), results in the generation of second messengers that in turn control specific cell functions. Further, modulation/amplification or inhibition of the initial signalling events, depend on the recruitment onto the plasma membrane of soluble protein effectors.High throughput methodologies to monitor quantitatively second messenger production, have been developed over the last years and are largely used to screen chemical libraries for drug development. On the contrary, no such high throughput methods are yet available for the other aspect of GPCRs regulation, i.e. protein translocation to the plasma membrane, despite the enormous interest of this phenomenon for the modulation of receptor downstream functions. Indeed, to date, the experimental procedures available are either inadequate or complex and expensive. RESULTS: Here we describe the development of a novel conceptual approach to the study of cytosolic proteins translocation to the inner surface of the plasma membrane. The basis of the technique consists in: i) generating chimeras between the protein of interests and the calcium (Ca2+)-sensitive, luminescent photo-protein, aequorin and ii) taking advantage of the large Ca2+concentration [Ca2+] difference between bulk cytosolic and the sub-plasma membrane rim. CONCLUSION: This approach, that keeps unaffected the translocation properties of the signalling protein, can in principle be applied to any protein that, upon activation, moves from the cytosol to the plasma membrane.Thus, not only the modulation of GPCRs and RTKs can be investigated in this way, but that of all other proteins that can be recruited to the plasma membrane also independently of receptor activation.Moreover, its automated version, which can provide information about the kinetics and concentration-dependence of the process, is also applicable to high throughput screening of drugs affecting the translocation process. PMID- 21658236 TI - Prevalence of thinness in children and adolescents in the Seychelles: comparison of two international growth references. AB - BACKGROUND: Thinness in children and adolescents is largely under studied, a contrast with abundant literature on under-nutrition in infants and on overweight in children and adolescents. The aim of this study is to compare the prevalence of thinness using two recently developed growth references, among children and adolescents living in the Seychelles, an economically rapidly developing country in the African region. METHODS: Weight and height were measured every year in all children of 4 grades (age range: 5 to 16 years) of all schools in the Seychelles as part of a routine school-based surveillance program. In this study we used data collected in 16,672 boys and 16,668 girls examined from 1998 to 2004. Thinness was estimated according to two growth references: i) an international survey (IS), defining three grades of thinness corresponding to a BMI of 18.5, 17.0 and 16.0 kg/m2 at age 18 and ii) the WHO reference, defined here as three categories of thinness (-1, -2 and -3 SD of BMI for age) with the second and third named "thinness" and "severe thinness", respectively. RESULTS: The prevalence of thinness was 21.4%, 6.4% and 2.0% based on the three IS cut-offs and 27.7%, 6.7% and 1.2% based on the WHO cut-offs. The prevalence of thinness categories tended to decrease according to age for both sexes for the IS reference and among girls for the WHO reference. CONCLUSION: The prevalence of the first category of thinness was larger with the WHO cut-offs than with the IS cut-offs while the prevalence of thinness of "grade 2" and thinness of "grade 3" (IS cut-offs) was similar to the prevalence of "thinness" and "severe thinness" (WHO cut-offs), respectively. PMID- 21658237 TI - Longitudinal molecular microbial analysis of influenza-like illness in New York City, May 2009 through May 2010. AB - BACKGROUND: We performed a longitudinal study of viral etiology in samples collected in New York City during May 2009 to May 2010 from outpatients with fever or respiratory disease symptoms in the context of a pilot respiratory virus surveillance system. METHODS: Samples were assessed for the presence of 13 viruses, including influenza A virus, by MassTag PCR. RESULTS: At least one virus was detected in 52% of 940 samples analyzed, with 3% showing co-infections. The most frequently detected agents were rhinoviruses and influenza A, all representing the 2009 pandemic H1N1 strain. The incidence of influenza H1N1 positive samples was highest in late spring 2009, followed by a decline in summer and early fall, when rhinovirus infections became predominant before H1N1 reemerged in winter. Our study also identified a focal outbreak of enterovirus 68 in the early fall of 2009. CONCLUSION: MassTag multiplex PCR affords opportunities to track the epidemiology of infectious diseases and may guide clinicians and public health practitioners in influenza-like illness and outbreak management. Nonetheless, a substantial proportion of influenza-like illness remains unexplained underscoring the need for additional platforms. PMID- 21658238 TI - Time series analysis of dengue incidence in Guadeloupe, French West Indies: forecasting models using climate variables as predictors. AB - BACKGROUND: During the last decades, dengue viruses have spread throughout the Americas region, with an increase in the number of severe forms of dengue. The surveillance system in Guadeloupe (French West Indies) is currently operational for the detection of early outbreaks of dengue. The goal of the study was to improve this surveillance system by assessing a modelling tool to predict the occurrence of dengue epidemics few months ahead and thus to help an efficient dengue control. METHODS: The Box-Jenkins approach allowed us to fit a Seasonal Autoregressive Integrated Moving Average (SARIMA) model of dengue incidence from 2000 to 2006 using clinical suspected cases. Then, this model was used for calculating dengue incidence for the year 2007 compared with observed data, using three different approaches: 1 year-ahead, 3 months-ahead and 1 month-ahead. Finally, we assessed the impact of meteorological variables (rainfall, temperature and relative humidity) on the prediction of dengue incidence and outbreaks, incorporating them in the model fitting the best. RESULTS: The 3 months-ahead approach was the most appropriate for an effective and operational public health response, and the most accurate (Root Mean Square Error, RMSE = 0.85). Relative humidity at lag-7 weeks, minimum temperature at lag-5 weeks and average temperature at lag-11 weeks were variables the most positively correlated to dengue incidence in Guadeloupe, meanwhile rainfall was not. The predictive power of SARIMA models was enhanced by the inclusion of climatic variables as external regressors to forecast the year 2007. Temperature significantly affected the model for better dengue incidence forecasting (p-value = 0.03 for minimum temperature lag-5, p-value = 0.02 for average temperature lag-11) but not humidity. Minimum temperature at lag-5 weeks was the best climatic variable for predicting dengue outbreaks (RMSE = 0.72). CONCLUSION: Temperature improves dengue outbreaks forecasts better than humidity and rainfall. SARIMA models using climatic data as independent variables could be easily incorporated into an early (3 months-ahead) and reliably monitoring system of dengue outbreaks. This approach which is practicable for a surveillance system has public health implications in helping the prediction of dengue epidemic and therefore the timely appropriate and efficient implementation of prevention activities. PMID- 21658233 TI - Critical care services and the H1N1 (2009) influenza epidemic in Australia and New Zealand in 2010: the impact of the second winter epidemic. AB - INTRODUCTION: During the first winter of exposure, the H1N1 2009 influenza virus placed considerable strain on intensive care unit (ICU) services in Australia and New Zealand (ANZ). We assessed the impact of the H1N1 2009 influenza virus on ICU services during the second (2010) winter, following the implementation of vaccination. METHODS: A prospective, cohort study was conducted in all ANZ ICUs during the southern hemisphere winter of 2010. Data on demographic and clinical characteristics, including vaccination status and outcomes, were collected. The characteristics of patients admitted during the 2010 and 2009 seasons were compared. RESULTS: From 1 June to 15 October 2010, there were 315 patients with confirmed influenza A, of whom 283 patients (90%) had H1N1 2009 (10.6 cases per million inhabitants; 95% confidence interval (CI), 9.4 to 11.9) which was an observed incidence of 33% of that in 2009 (P < 0.001). The maximum daily ICU occupancy was 2.4 beds (95% CI, 1.8 to 3) per million inhabitants in 2010 compared with 7.5 (95% CI, 6.5 to 8.6) in 2009, (P < 0.001). The onset of the epidemic in 2010 was delayed by five weeks compared with 2009. The clinical characteristics were similar in 2010 and 2009 with no difference in the age distribution, proportion of patients treated with mechanical ventilation, duration of ICU admission, or hospital mortality. Unlike 2009 the incidence of critical illness was significantly greater in New Zealand (18.8 cases per million inhabitants compared with 9 in Australia, P < 0.001). Of 170 patients with known vaccination status, 26 (15.3%) had been vaccinated against H1N1 2009. CONCLUSIONS: During the 2010 ANZ winter, the impact of H1N1 2009 on ICU services was still appreciable in Australia and substantial in New Zealand. Vaccination failure occurred. PMID- 21658239 TI - GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells. AB - BACKGROUND: Aromatase inhibitors (AI) that inhibit breast cancer cell growth by blocking estrogen synthesis have become the treatment of choice for post menopausal women with estrogen receptor positive (ER+) breast cancer. However, some patients display de novo or acquired resistance to AI. Interactions between estrogen and growth factor signaling pathways have been identified in estrogen responsive cells as one possible reason for acquisition of resistance. Our laboratory has characterized an autocrine growth factor overexpressed in invasive ductal carcinoma named PC-Cell Derived Growth Factor (GP88), also known as progranulin. In the present study, we investigated the role GP88 on the acquisition of resistance to letrozole in ER+ breast cancer cells METHODS: We used two aromatase overexpressing human breast cancer cell lines MCF-7-CA cells and AC1 cells and their letrozole resistant counterparts as study models. Effect of stimulating or inhibiting GP88 expression on proliferation, anchorage independent growth, survival and letrozole responsiveness was examined. RESULTS: GP88 induced cell proliferation and conferred letrozole resistance in a time- and dose-dependent fashion. Conversely, naturally letrozole resistant breast cancer cells displayed a 10-fold increase in GP88 expression when compared to letrozole sensitive cells. GP88 overexpression, or exogenous addition blocked the inhibitory effect of letrozole on proliferation, and stimulated survival and soft agar colony formation. In letrozole resistant cells, silencing GP88 by siRNA inhibited cell proliferation and restored their sensitivity to letrozole. CONCLUSION: Our findings provide information on the role of an alternate growth and survival factor on the acquisition of aromatase inhibitor resistance in ER+ breast cancer. PMID- 21658240 TI - Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT study. AB - INTRODUCTION: Enteral nutrition (EN) with eicosapentaenoic acid (EPA)/gamma linolenic acid (GLA) is recommended for mechanically ventilated patients with severe lung injury. EPA/GLA has anti-inflammatory benefits, as evidenced by its association with reduction in pulmonary inflammation, improvement in oxygenation and improved clinical outcomes in patients with severe forms of acute lung injury. This study was a prospective, multicenter, randomized, double-blinded, controlled trial designed to investigate whether EPA/GLA could have an effective role in the treatment of patients with early sepsis (systemic inflammatory response syndrome with confirmed or presumed infection and without any organ dysfunction) by reducing the progression of the disease to severe sepsis (sepsis associated with at least one organ failure) or septic shock (sepsis associated with hypotension despite adequate fluid resuscitation). Secondary outcomes included the development of individual organ failure, increased ICU and hospital length of stay, need for mechanical ventilation and 28-day all-cause mortality. METHODS: Randomization was concealed, and patients were allocated to receive, for seven days, either an EPA/GLA diet or an isocaloric, isonitrogenous control diet not enhanced with lipids. Patients were continuously tube-fed at a minimum of 75% of basal energy expenditure * 1.3. To evaluate the progression to severe sepsis and/or septic shock, daily screening for individual organ failure was performed. All clinical outcomes were recorded during a 28-day follow-up period. RESULTS: A total of 115 patients in the early stages of sepsis requiring EN were included, among whom 106 were considered evaluable. Intention-to-treat (ITT) analysis demonstrated that patients fed the EPA/GLA diet developed less severe sepsis and/or septic shock than patients fed the control diet (26.3% versus 50%, respectively; P = 0.0259), with similar results observed for the evaluable patients (26.4% versus 50.9% respectively; P = 0.0217). The ITT analysis demonstrated that patients in the study group developed cardiovascular failure (36.2% versus 21%, respectively; P = 0.0381) and respiratory failure (39.6% versus 24.6%, respectively; P = 0.0362) less often than the control group. Similarly, when considering only the evaluable patients, fewer patients developed cardiovascular failure (20.7% versus 37.7%, respectively; P = 0.03) and respiratory failure (26.4% versus 39.6%, respectively; P = 0.04). The percentage of patients fed the EPA/GLA diet requiring invasive mechanical ventilation was reduced compared with controls (ITT patients: 18.9% versus 33.9%, respectively; P = 0.394; evaluable patients: 17.5% versus 34.5%, respectively; P = 0.295). Patients nourished with the EPA/GLA diet remained in the ICU fewer days than the control population (ITT patients: 21.1 ICU-free days versus 14.7 ICU-free days, respectively; P < 0.0001; evaluable patients: 20.8 ICU-free days versus 14.3 ICU free days, respectively; P < 0.0001) and fewer days at the hospital (ITT patients: 19.5 hospital-free days versus 10.3 hospital-free days, respectively; P < 0.0001; evaluable patients: 19.1 hospital-free days versus 10.2 hospital-free days, respectively; P < 0.001) (all numbers expressed as means). No significant differences in 28-day all-cause mortality were observed (ITT patients: 26.2% EPA/GLA diet versus 27.6% control diet, respectively; P = 0.72; evaluable: 26.4 EPA/GLA diet versus 30.18 control diet, respectively; P = 0.79). CONCLUSIONS: These data suggest that EPA/GLA may play a beneficial role in the treatment of enterally fed patients in the early stages of sepsis without associated organ dysfunction by contributing to slowing the progression of sepsis-related organ dysfunction, especially with regard to cardiovascular and respiratory dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00981877. PMID- 21658241 TI - Structural mutants of dengue virus 2 transmembrane domains exhibit host-range phenotype. AB - BACKGROUND: There are over 700 known arboviruses and at least 80 immunologically distinct types that cause disease in humans. Arboviruses are transmitted among vertebrates by biting insects, chiefly mosquitoes and ticks. These viruses are widely distributed throughout the world, depending on the presence of appropriate hosts (birds, horses, domestic animals, humans) and vectors. Mosquito-borne arboviruses present some of the most important examples of emerging and resurgent diseases of global significance. METHODS: A strategy has been developed by which host-range mutants of Dengue virus can be constructed by generating deletions in the transmembrane domain (TMD) of the E glycoprotein. The host-range mutants produced and selected favored growth in the insect hosts. Mouse trials were conducted to determine if these mutants could initiate an immune response in an in vivo system. RESULTS: The DV2 E protein TMD defined as amino acids 452SWTMKILIGVIITWIG467 was found to contain specific residues which were required for the production of this host-range phenotype. Deletion mutants were found to be stable in vitro for 4 sequential passages in both host cell lines. The host range mutants elicited neutralizing antibody above that seen for wild-type virus in mice and warrant further testing in primates as potential vaccine candidates. CONCLUSIONS: Novel host-range mutants of DV2 were created that have preferential growth in insect cells and impaired infectivity in mammalian cells. This method for creating live, attenuated viral mutants that generate safe and effective immunity may be applied to many other insect-borne viral diseases for which no current effective therapies exist. PMID- 21658242 TI - Synergistic antimicrobial activity between pentacyclic triterpenoids and antibiotics against Staphylococcus aureus strains. AB - BACKGROUND: There has been considerable effort to discover plant-derived antibacterials against methicillin-resistant strains of Staphylococcus aureus (MRSA) which have developed resistance to most existing antibiotics, including the last line of defence, vancomycin. Pentacyclic triterpenoid, a biologically diverse plant-derived natural product, has been reported to show anti staphylococcal activities. The objective of this study is to evaluate the interaction between three pentacyclic triterpenoid and standard antibiotics (methicillin and vancomycin) against reference strains of Staphylococcus aureus. METHODS AND RESULTS: The activity of the standard antibiotics and compounds on reference methicillin-sensitive and resistant strains of S. aureus were determined using the macrodilution broth method. The minimum inhibitory concentration (MIC) of the compounds was compared with that of the standard antibiotics. The interaction between any two antimicrobial agents was estimated by calculating the fractional inhibitory concentration (FIC index) of the combination. The various combinations of antibiotics and compounds reduced the MIC to a range of 0.05 to 50%. CONCLUSION: Pentacyclic triterpenoids have shown anti-staphylococcal activities and although individually weaker than common antibiotics produced from bacteria and fungi, synergistically these compounds may use different mechanism of action or pathways to exert their antimicrobial effects, as implicated in the lowered MICs. Therefore, the use of current antibiotics could be maintained in their combination with plant-derived antibacterial agents as a therapeutic option in the treatment of S. aureus infections. PMID- 21658243 TI - The 'off-hour' effect in trauma care: a possible quality indicator with appealing characteristics. AB - A recent paper has drawn attention to the paucity of widely accepted quality indicators for trauma care. At the same time, several studies have measured whether mortality of trauma patients changes between normal working time and other parts of the day/week, i.e. the so-called 'off-hour' or 'weekend' effect. This measure has the characteristics to become an accepted quality indicator because it combines the advantages of both outcome and process indicators. As an outcome indicator it would not need validation, a procedure particularly difficult in trauma care where gathering scientific evidence is more difficult than in other disciplines. As a process indicator it would provide indications about where to intervene to improve quality. PMID- 21658244 TI - Gender difference and sex hormone production in rodent renal ischemia reperfusion injury and repair. AB - BACKGROUND: Several lines of evidence suggest a protective effect of female sex hormones in several organs subjected to ischemia-reperfusion injury. The aim of the study was to investigate sex hormone production in male rats after a renal ischemia-reperfusion sequence and analyze the influence of gender differences on tissue remodelling during the recovery process. METHOD: Age-matched sexually mature male and female rats were subjected to 60 min of renal unilateral ischemia by pedicle clamping with contralateral nephrectomy and followed for 1 or 5 days after reperfusion. Plasma creatinine, systemic testosterone, progesterone and estradiol levels were determined. Tubular injury, cell proliferation and inflammation, were evaluated as well as proliferating cell nuclear antigen, vimentin and translocator protein (TSPO) expressions by immunohistochemistry. RESULTS: After 1 and 5 days of reperfusion, plasma creatinine was significantly higher in males than in females, supporting the high mortality in this group. After reperfusion, plasma testosterone levels decreased whereas estradiol significantly increased in male rats. Alterations of renal function, associated with tubular injury and inflammation persisted during the 5 days post-ischemia reperfusion, and a significant improvement was observed in females at 5 days of reperfusion. Proliferating cell nuclear antigen and vimentin expression were upregulated in kidneys from males and attenuated in females, in parallel to injury development. TSPO expression was transiently increased in proximal tubules in male rats. CONCLUSIONS: After ischemia, renal function recovery and tissue injury is gender-dependent. These differences are associated with a modulation of sex hormone production and a modification of tissue remodeling and proliferative cell processes. PMID- 21658245 TI - Indigenous Knowledge of HIV/AIDS among High School students in Namibia. AB - BACKGROUND: The use of Indigenous Knowledge (IK) can help students to form schemas for interpreting local phenomena through the prism of what they already know. The formation of schemas related to HIV/AIDS risk perception and prevention is important for individuals to form local meanings of the HIV/AIDS epidemic. The objective of this study was to explore the indigenous names and symptoms of HIV/AIDS among High School students in Namibia METHODS: Focus group discussions were used to collect qualitative data on indigenous names and symptoms of HIV/AIDS from students in 18 secondary schools located in six education regions. Data were grouped into themes. RESULTS: People living with HIV/AIDS were called names meaning prostitute: ihule, butuku bwa sihule, and shikumbu. Names such askibutu bwa masapo (bone disease), katjumba (a young child), kakithi (disease), and shinangele (very thin person) were used to describe AIDS. Derogatory names like mbwa (dog), esingahogo (pretender), ekifi (disease), and shinyakwi noyana (useless person) were also used. Other terms connoted death (zeguru, heaven; omudimba, corpse), fear (simbandembande, fish eagle; katanga kamufifi, (hot ball), and subtle meaning using slang words such as 4 * 4, oondanda ne (four letters), desert soul, and mapilelo (an AIDS service organization). Typical (body wasting) and non-typical (big head, red eyes) symptoms of HIV were also revealed. CONCLUSIONS: The study determined students' IK of the names and symptoms of HIV/AIDS. Programmes to prevent/manage adolescent HIV infection and stigma may be strengthened if they take students' indigenous understandings of the disease on board. PMID- 21658246 TI - Pharmacokinetics study of bio-adhesive tablet of Panax notoginseng saponins. AB - Panax notoginseng saponin (PNS) is the main active gradient of Chinese traditional medicine Panax notoginseng. Although its prominent therapeutic efficacy has been demonstrated by various researchers, the broader application is restricted by the low bioavailability of PNS. This article aims to discuss PNS's plasma pharmacokinetics after oral administration of bio-adhesive tablet of PNS to beagle dogs and improve its bioavailability in comparison with normal tablet. The bio-adhesive tablet was prepared according to our previous patent, using chitosan as main excipient. A simple and sensitive LC-MS/MS combined with solid phase extraction (SPE) method for the analysis of PNS in dog's plasma was developed in our previous study, and was validated to apply in the pharmacokinetics study in this work. Three ingredients: Notoginsenoside R1 (R1), Ginsenoside Rg1 (Rg1) and Ginsenoside Rb1 (Rb1) (Figure 1), were chosen as indicators of PNS to analyze it in vivo. Statistically significant increase (P < 0.05) in pharmacokinetic parameters of PNS including AUC and Tmax for R1, Rg1 and Rb1, Cmax for R1 and Rb1, MRT for Rg1 were obtained after oral administration of bio-adhesive tablet of PNS comparing with its normal tablet. The formulation modification of using chitosan to prepare bio-adhesive tablet for oral administration is effective in improving the bioavailability of PNS, thereby enhancing its potential therapeutic effect and broadening its clinical application. PMID- 21658247 TI - Reduced cardiac output in imported Plasmodium falciparum malaria. AB - BACKGROUND: Volume substitution remains subject of controversy in the light of effusions and oedema potentially complicating this highly febrile disease. Understanding the role of myocardial and circulatory function appears to be essential for clinical management. In the present study, cardiac function and cardiac proteins have been assessed and correlated with parasitological and immunologic parameters in patients with imported Plasmodium falciparum malaria. METHODS: In a prospective case-control study, 28 patients with uncomplicated and complicated P. falciparum malaria were included and findings were compared with 26 healthy controls. Cardiac function parameters were assessed by an innovative non-invasive method based on the re-breathing technique. In addition, cardiac enzymes and pro- and anti-inflammatory cytokines were measured and assessed with respect to clinical symptoms and conditions of malaria. RESULTS: Cardiac index (CI) as a measurement of cardiac output (CO) was 21% lower in malaria patients than in healthy controls (2.7 l/min/m2 versus 3.4 l/min/m2; P < 0.001). In contrast, systemic vascular resistance index (SVRI) was increased by 29% (32.6 mmHg?m2/(l/min) versus 23.2 mmHg?m2/(l/min); P < 0.001). This correlated with increased cardiac proteins in patients versus controls: pro-BNP 139.3 pg/ml versus 60.4 pg/ml (P = 0.03), myoglobin 43.6 MUg/l versus 27.8 MUg/l (P = < 0.001). All measured cytokines were significantly increased in patients with malaria. CI, SVRI as well as cytokine levels did not correlate with blood parasite density. CONCLUSIONS: The results support previous reports suggesting impaired cardiac function contributing to clinical manifestations in P. falciparum malaria. Findings may be relevant for fluid management and should be further explored in endemic regions. PMID- 21658248 TI - Bactericidal activity of oxacillin and glycopeptides against Staphylococcus aureus in patients with endocarditis: looking for a relationship between tolerance and outcome. AB - BACKGROUND: There is no clear relationship between in vitro bactericidal activity tests and clinical outcome. We studied bactericidal activity of oxacillin, vancomycin and teicoplanin against Staphylococcus aureus isolates in patients with endocarditis and then we sought to determine if there was a relationship between in vitro bactericidal activity and clinical outcome. METHODS: Minimal bacteriostatic and minimal bactericidal concentrations were determined for Staphylococcus aureus strains isolated from patients with endocarditis following standardized methods. Medical records were reviewed retrospectively to collect data on antimicrobial susceptibility at admission, antimicrobial therapy, need for surgery, embolic events and outcome. RESULTS AND DISCUSSION: Sixty-two Staphylococcus aureus strains were studied in 62 patients with endocarditis. Overall, 91.9% definite, 21% methicillin resistant and 72.6% cured. Surgery was performed in 32.3% and embolic events were documented in 64.5%. Tolerance to oxacillin and teicoplanin was more common than vancomycin tolerance among methicillin susceptible Staphylococcus aureus. Among methicillin resistant Staphylococcus aureus teicoplanin was shown to have a higher rate of tolerance than vancomycin. No statistically significant differences on clinical outcome between oxacillin tolerant and oxacillin non tolerant Staphylococcus aureus infections were observed. Tolerance to oxacillin did not adversely affect clinical outcomes of patients with methicillin susceptible Staphylococcus aureus endocarditis treated with a combination of antimicrobials including oxacillin. The cure rate was significantly lower among patients with methicillin resistant Staphylococcus aureus endocarditis. CONCLUSIONS: In vitro bactericidal test results were not valid predictors of clinical outcome. Physicians need to use additional parameters when treating patients with staphylococcal endocarditis. PMID- 21658249 TI - Between forwarding and mentoring: a qualitative study of recommending medical doctors for international postdoctoral research positions. AB - BACKGROUND: Young scientists rarely have extensive international connections that could facilitate their mobility. They often rely on their doctoral supervisors and other senior academics, who use their networks to generate opportunities for young scientists to gain international experience and provide the initial trigger for an outward move. METHODS: To explore the process of informal recommending of young physicians from a small country for postdoctoral research positions in foreign countries, we conducted in-depth interviews with eight senior academics who acted as recommenders and eight physicians who, based on the recommendations of senior academics, spent at least a year working in a laboratory abroad. Interviews were transcribed and analyzed by using the framework approach. RESULTS: The findings showed that recommending can take four distinct forms: 1) forwarding information, 2) passive recommending, 3) active recommending, and 4) mentor recommending. These forms differ in their level of commitment and mutual trust among actors, and possible control over the success of the process. Two groups of recommendees--'naive' and 'experienced'--can be distinguished based on their previous scientific experience and research collaboration with the recommender. Crucial for the success of the process is an adequate preparation of recommendees' stay abroad, as well as their return and reintegration. The benefits of recommending extend beyond the individual participants to the scientific community and broader society of the sending country. CONCLUSIONS: With a sufficient level of commitment by the actors, informal recommending can be a part of or grow into an all-encompassing developmental relationship equal to mentoring. The importance of senior academics' informal contacts and recommendations in promoting junior scientists' mobility should be acknowledged and encouraged by the research institutions and universities, particularly in developing countries. PMID- 21658250 TI - Particulate matter air pollution causes oxidant-mediated increase in gut permeability in mice. AB - BACKGROUND: Exposure to particulate matter (PM) air pollution may be an important environmental factor leading to exacerbations of inflammatory illnesses in the GI tract. PM can gain access to the gastrointestinal (GI) tract via swallowing of air or secretions from the upper airways or mucociliary clearance of inhaled particles. METHODS: We measured PM-induced cell death and mitochondrial ROS generation in Caco-2 cells stably expressing oxidant sensitive GFP localized to mitochondria in the absence or presence of an antioxidant. C57BL/6 mice were exposed to a very high dose of urban PM from Washington, DC (200 MUg/mouse) or saline via gastric gavage and small bowel and colonic tissue were harvested for histologic evaluation, and RNA isolation up to 48 hours. Permeability to 4 kD dextran was measured at 48 hours. RESULTS: PM induced mitochondrial ROS generation and cell death in Caco-2 cells. PM also caused oxidant-dependent NF kappaB activation, disruption of tight junctions and increased permeability of Caco-2 monolayers. Mice exposed to PM had increased intestinal permeability compared with PBS treated mice. In the small bowel, colocalization of the tight junction protein, ZO-1 was lower in the PM treated animals. In the small bowel and colon, PM exposed mice had higher levels of IL-6 mRNA and reduced levels of ZO-1 mRNA. Increased apoptosis was observed in the colon of PM exposed mice. CONCLUSIONS: Exposure to high doses of urban PM causes oxidant dependent GI epithelial cell death, disruption of tight junction proteins, inflammation and increased permeability in the gut in vitro and in vivo. These PM-induced changes may contribute to exacerbations of inflammatory disorders of the gut. PMID- 21658251 TI - Learning alters theta amplitude, theta-gamma coupling and neuronal synchronization in inferotemporal cortex. AB - BACKGROUND: How oscillatory brain rhythms alone, or in combination, influence cortical information processing to support learning has yet to be fully established. Local field potential and multi-unit neuronal activity recordings were made from 64-electrode arrays in the inferotemporal cortex of conscious sheep during and after visual discrimination learning of face or object pairs. A neural network model has been developed to simulate and aid functional interpretation of learning-evoked changes. RESULTS: Following learning the amplitude of theta (4-8 Hz), but not gamma (30-70 Hz) oscillations was increased, as was the ratio of theta to gamma. Over 75% of electrodes showed significant coupling between theta phase and gamma amplitude (theta-nested gamma). The strength of this coupling was also increased following learning and this was not simply a consequence of increased theta amplitude. Actual discrimination performance was significantly correlated with theta and theta-gamma coupling changes. Neuronal activity was phase-locked with theta but learning had no effect on firing rates or the magnitude or latencies of visual evoked potentials during stimuli. The neural network model developed showed that a combination of fast and slow inhibitory interneurons could generate theta-nested gamma. By increasing N methyl-D-aspartate receptor sensitivity in the model similar changes were produced as in inferotemporal cortex after learning. The model showed that these changes could potentiate the firing of downstream neurons by a temporal desynchronization of excitatory neuron output without increasing the firing frequencies of the latter. This desynchronization effect was confirmed in IT neuronal activity following learning and its magnitude was correlated with discrimination performance. CONCLUSIONS: Face discrimination learning produces significant increases in both theta amplitude and the strength of theta-gamma coupling in the inferotemporal cortex which are correlated with behavioral performance. A network model which can reproduce these changes suggests that a key function of such learning-evoked alterations in theta and theta-nested gamma activity may be increased temporal desynchronization in neuronal firing leading to optimal timing of inputs to downstream neural networks potentiating their responses. In this way learning can produce potentiation in neural networks simply through altering the temporal pattern of their inputs. PMID- 21658252 TI - A hinged external fixator for complex elbow dislocations: a multicenter prospective cohort study. AB - BACKGROUND: Elbow dislocations can be classified as simple or complex. Simple dislocations are characterized by the absence of fractures, while complex dislocations are associated with fractures of the radial head, olecranon, or coronoid process. The majority of patients with these complex dislocations are treated with open reduction and internal fixation (ORIF), or arthroplasty in case of a non-reconstructable radial head fracture. If the elbow joint remains unstable after fracture fixation, a hinged elbow fixator can be applied. The fixator provides stability to the elbow joint, and allows for early mobilization. The latter may be important for preventing stiffness of the joint. The aim of this study is to determine the effect of early mobilization with a hinged external elbow fixator on clinical outcome in patients with complex elbow dislocations with residual instability following fracture fixation. METHODS/DESIGN: The design of the study will be a multicenter prospective cohort study of 30 patients who have sustained a complex elbow dislocation and are treated with a hinged elbow fixator following fracture fixation because of residual instability. Early active motion exercises within the limits of pain will be started immediately after surgery under supervision of a physical therapist. Outcome will be evaluated at regular intervals over the subsequent 12 months. The primary outcome is the Quick Disabilities of the Arm, Shoulder, and Hand score. The secondary outcome measures are the Mayo Elbow Performance Index, Oxford Elbow Score, pain level at both sides, range of motion of the elbow joint at both sides, radiographic healing of the fractures and formation of periarticular ossifications, rate of secondary interventions and complications, and health-related quality of life (Short-Form 36). DISCUSSION: The outcome of this study will yield quantitative data on the functional outcome in patients with a complex elbow dislocation and who are treated with ORIF and additional stabilization with a hinged elbow fixator. TRIAL REGISTRATION: The trial is registered at the Netherlands Trial Register (NTR1996). PMID- 21658253 TI - Implementing a quality improvement programme in palliative care in care homes: a qualitative study. AB - BACKGROUND: An increasing number of older people reach the end of life in care homes. The aim of this study is to explore the perceived benefits of, and barriers to, implementation of the Gold Standards Framework for Care Homes (GSFCH), a quality improvement programme in palliative care. METHODS: Nine care homes involved in the GSFCH took part. We conducted semi-structured interviews with nine care home managers, eight nurses, nine care assistants, eleven residents and seven of their family members. We used the Framework approach to qualitative analysis. The analysis was deductive based on the key tasks of the GSFCH, the 7Cs: communication, coordination, control of symptoms, continuity, continued learning, carer support, and care of the dying. This enabled us to consider benefits of, and barriers to, individual components of the programme, as well as of the programme as a whole. RESULTS: Perceived benefits of the GSFCH included: improved symptom control and team communication; finding helpful external support and expertise; increasing staff confidence; fostering residents' choice; and boosting the reputation of the home. Perceived barriers included: increased paperwork; lack of knowledge and understanding of end of life care; costs; and gaining the cooperation of GPs. Many of the tools and tasks in the GSFCH focus on improving communication. Participants described effective communication within the homes, and with external providers such as general practitioners and specialists in palliative care. However, many had experienced problems with general practitioners. Although staff described the benefits of supportive care registers, coding predicted stage of illness and advance care planning, which included improved communication, some felt the need for more experience of using these, and there were concerns about discussing death. CONCLUSIONS: Most of the barriers described by participants are relevant to other interventions to improve end of life care in care homes. There is a need to investigate the impact of quality improvement programmes in care homes, such as the GSFCH, on a wider range of outcomes for residents and their families, and to monitor the sustainability of any resulting improvements. It is also important to explore the impact of the different components of these complex interventions. PMID- 21658255 TI - The inpatient burden of abdominal and gynecological adhesiolysis in the US. AB - BACKGROUND: Adhesions are fibrous bands of scar tissue, often a result of surgery, that form between internal organs and tissues, joining them together abnormally. Postoperative adhesions frequently occur following abdominal surgery, and are associated with a large economic burden. This study examines the inpatient burden of adhesiolysis in the United States (i.e., number and rate of events, cost, length of stay [LOS]). METHODS: Hospital discharge data for patients with primary and secondary adhesiolysis were analyzed using the 2005 Healthcare Cost and Utilization Project's Nationwide Inpatient Sample. Procedures were aggregated by body system. RESULTS: We identified 351,777 adhesiolysis related hospitalizations: 23.2% for primary and 76.8% for secondary adhesiolysis. The average LOS was 7.8 days for primary adhesiolysis. We found that 967,332 days of care were attributed to adhesiolysis-related procedures, with inpatient expenditures totaling $2.3 billion ($1.4 billion for primary adhesiolysis; $926 million for secondary adhesiolysis). Hospitalizations for adhesiolysis increased steadily by age and were higher for women. Of secondary adhesiolysis procedures, 46.3% involved the female reproductive tract, resulting in 57,005 additional days of care and $220 million in attributable costs. CONCLUSIONS: Adhesiolysis remain an important surgical problem in the United States. Hospitalization for this condition leads to high direct surgical costs, which should be of interest to providers and payers. PMID- 21658254 TI - Chondroitin sulfates play a major role in breast cancer metastasis: a role for CSPG4 and CHST11 gene expression in forming surface P-selectin ligands in aggressive breast cancer cells. AB - INTRODUCTION: We have previously demonstrated that chondroitin sulfate glycosaminoglycans (CS-GAGs) on breast cancer cells function as P-selectin ligands. This study was performed to identify the carrier proteoglycan (PG) and the sulfotransferase gene involved in synthesis of the surface P-selectin reactive CS-GAGs in human breast cancer cells with high metastatic capacity, as well as to determine a direct role for CS-GAGs in metastatic spread. METHODS: Quantitative real-time PCR (qRT-PCR) and flow cytometry assays were used to detect the expression of genes involved in the sulfation and presentation of chondroitin in several human breast cancer cell lines. Transient transfection of the human breast cancer cell line MDA-MB-231 with the siRNAs for carbohydrate (chondroitin 4) sulfotransferase-11 (CHST11) and chondroitin sulfate proteoglycan 4 (CSPG4 ) was used to investigate the involvement of these genes in expression of surface P-selectin ligands. The expression of CSPG4 and CHST11 in 15 primary invasive breast cancer clinical specimens was assessed by qRT-PCR. The role of CS GAGs in metastasis was tested using the 4T1 murine mammary cell line (10 mice per group). RESULTS: The CHST11 gene was highly expressed in aggressive breast cancer cells but significantly less so in less aggressive breast cancer cell lines. A positive correlation was observed between the expression levels of CHST11 and P selectin binding to cells (P < 0.0001). Blocking the expression of CHST11 with siRNA inhibited CS-A expression and P-selectin binding to MDA-MB-231 cells. The carrier proteoglycan CSPG4 was highly expressed on the aggressive breast cancer cell lines and contributed to the P-selectin binding and CS-A expression. In addition, CSPG4 and CHST11 were over-expressed in tumor-containing clinical tissue specimens compared with normal tissues. Enzymatic removal of tumor-cell surface CS-GAGs significantly inhibited lung colonization of the 4T1 murine mammary cell line (P = 0.0002). CONCLUSIONS: Cell surface P-selectin binding depends on CHST11 gene expression. CSPG4 serves as a P-selectin ligand through its CS chain and participates in P-selectin binding to the highly metastatic breast cancer cells. Removal of CS-GAGs greatly reduces metastatic lung colonization by 4T1 cells. The data strongly indicate that CS-GAGs and their biosynthetic pathways are promising targets for the development of anti metastatic therapies. PMID- 21658256 TI - Physician privacy concerns when disclosing patient data for public health purposes during a pandemic influenza outbreak. AB - BACKGROUND: Privacy concerns by providers have been a barrier to disclosing patient information for public health purposes. This is the case even for mandated notifiable disease reporting. In the context of a pandemic it has been argued that the public good should supersede an individual's right to privacy. The precise nature of these provider privacy concerns, and whether they are diluted in the context of a pandemic are not known. Our objective was to understand the privacy barriers which could potentially influence family physicians' reporting of patient-level surveillance data to public health agencies during the Fall 2009 pandemic H1N1 influenza outbreak. METHODS: Thirty seven family doctors participated in a series of five focus groups between October 29-31 2009. They also completed a survey about the data they were willing to disclose to public health units. Descriptive statistics were used to summarize the amount of patient detail the participants were willing to disclose, factors that would facilitate data disclosure, and the consensus on those factors. The analysis of the qualitative data was based on grounded theory. RESULTS: The family doctors were reluctant to disclose patient data to public health units. This was due to concerns about the extent to which public health agencies are dependable to protect health information (trusting beliefs), and the possibility of loss due to disclosing health information (risk beliefs). We identified six specific actions that public health units can take which would affect these beliefs, and potentially increase the willingness to disclose patient information for public health purposes. CONCLUSIONS: The uncertainty surrounding a pandemic of a new strain of influenza has not changed the privacy concerns of physicians about disclosing patient data. It is important to address these concerns to ensure reliable reporting during future outbreaks. PMID- 21658257 TI - The SLC2A9 nonsynonymous Arg265His variant and gout: evidence for a population specific effect on severity. AB - INTRODUCTION: The C allele of the nonsynonymous Arg265His (rs3733591) variant of SLC2A9 confers risk for gout in Han Chinese, Solomon Island and Japanese samples, with a stronger role in tophaceous gout. There is no evidence for an association with gout in Caucasian populations. In the present study, we tested rs3733591 for association with gout in New Zealand (NZ) Maori, Pacific Island and Caucasian samples. METHODS: Rs3733591 was genotyped across gout patients (n = 229, 232 and 327 NZ Maori, Pacific Island and Caucasian samples, respectively) and non-gout controls (n = 343, 174 and 638 Maori, Pacific Island and Caucasian samples, respectively). Further Caucasian sample sets consisting of 67 cases and 4,712 controls as well as 153 cases and 6,969 controls were obtained from the Framingham Heart Study and the Atherosclerosis Risk in Communities study, respectively. The Polynesian samples were analyzed according to Eastern and Western Polynesian ancestry. RESULTS: No evidence for risk conferred by the C allele of rs3733591 with gout was found in the sample sets of NZ Maori (odd ratio (OR) = 0.98, P = 0.86), Eastern Polynesians (OR = 0.99, P = 0.92), Western Polynesians (OR = 1.16, P = 0.36) or combined Caucasians (OR = 1.15, P = 0.13). The C allele was significantly overrepresented in Maori tophaceous cases compared to cases without tophi (OR = 2.21, P = 0.008), but not in the other ancestral groupings. CONCLUSIONS: Noting that our study's power was limited for detecting weak genetic effects, we were unable to replicate associations of rs3733591 with gout in Eastern Polynesian, Western Polynesian and Caucasian samples. However, consistent with a previous study of Han Chinese and Solomon Island populations, our data suggest that rs3733591 could be a marker of severe gout in some populations. Our results also suggest that the effect of this variant is population-specific, further confirming population heterogeneity regarding the association of SLC2A9 with gout. PMID- 21658258 TI - Current measures of metabolic heterogeneity within cervical cancer do not predict disease outcome. AB - BACKGROUND: A previous study evaluated the intra-tumoral heterogeneity observed in the uptake of F-18 fluorodeoxyglucose (FDG) in pre-treatment positron emission tomography (PET) scans of cancers of the uterine cervix as an indicator of disease outcome. This was done via a novel statistic which ostensibly measured the spatial variations in intra-tumoral metabolic activity. In this work, we argue that statistic is intrinsically non-spatial, and that the apparent delineation between unsuccessfully- and successfully-treated patient groups via that statistic is spurious. METHODS: We first offer a straightforward mathematical demonstration of our argument. Next, we recapitulate an assiduous re analysis of the originally published data which was derived from FDG-PET imagery. Finally, we present the results of a principal component analysis of FDG-PET images similar to those previously analyzed. RESULTS: We find that the previously published measure of intra-tumoral heterogeneity is intrinsically non-spatial, and actually is only a surrogate for tumor volume. We also find that an optimized linear combination of more canonical heterogeneity quantifiers does not predict disease outcome. CONCLUSIONS: Current measures of intra-tumoral metabolic activity are not predictive of disease outcome as has been claimed previously. The implications of this finding are: clinical categorization of patients based upon these statistics is invalid; more sophisticated, and perhaps innately geometric, quantifications of metabolic activity are required for predicting disease outcome. PMID- 21658259 TI - Increasing Access to Subsidized Artemisinin-based Combination Therapy through Accredited Drug Dispensing Outlets in Tanzania. AB - BACKGROUND: In Tanzania, many people seek malaria treatment from retail drug sellers. The National Malaria Control Program identified the accredited drug dispensing outlet (ADDO) program as a private sector mechanism to supplement the distribution of subsidized artemisinin-based combination therapies (ACTs) from public facilities and increase access to the first-line antimalarial in rural and underserved areas. The ADDO program strengthens private sector pharmaceutical services by improving regulatory and supervisory support, dispenser training, and record keeping practices. METHODS: The government's pilot program made subsidized ACTs available through ADDOs in 10 districts in the Morogoro and Ruvuma regions, covering about 2.9 million people. The program established a supply of subsidized ACTs, created a price system with a cost recovery plan, developed a plan to distribute the subsidized products to the ADDOs, trained dispensers, and strengthened the adverse drug reactions reporting system. As part of the evaluation, 448 ADDO dispensers brought their records to central locations for analysis, representing nearly 70% of ADDOs operating in the two regions. ADDO drug register data were available from July 2007-June 2008 for Morogoro and from July 2007-September 2008 for Ruvuma. This intervention was implemented from 2007 2008. RESULTS: During the pilot, over 300,000 people received treatment for malaria at the 448 ADDOs. The percentage of ADDOs that dispensed at least one course of ACT rose from 26.2% during July-September 2007 to 72.6% during April June 2008. The number of malaria patients treated with ACTs gradually increased after the start of the pilot, while the use of non-ACT antimalarials declined; ACTs went from 3% of all antimalarials sold in July 2007 to 26% in June 2008. District-specific data showed substantial variation among the districts in ACT uptake through ADDOs, ranging from ACTs representing 10% of all antimalarial sales in Kilombero to 47% in Morogoro Rural. CONCLUSIONS: The intervention increased access to affordable ACTs for underserved populations. Indications are that antimalarial monotherapies are being "crowded out" of the market. Importantly, the transition to ACTs has been accomplished in an environment where the safety and efficacy of the drugs and the quality of services are being monitored and regulated. This paper presents a description of the pilot program implementation, results of the program evaluation, and a discussion of the challenges and recommendations that will be used to guide rollout of subsidized ACT in ADDOs in the rest of Tanzania and possibly in other countries. PMID- 21658260 TI - When masculinity interferes with women's treatment of HIV infection: a qualitative study about adherence to antiretroviral therapy in Zimbabwe. AB - BACKGROUND: Social constructions of masculinity have been shown to serve as an obstacle to men's access and adherence to antiretroviral therapies (ART). In the light of women's relative lack of power in many aspects of interpersonal relationships with men in many African settings, our objective is to explore how male denial of HIV/AIDS impacts on their female partners' ability to access and adhere to ART. METHODS: We conducted a qualitative case study involving thematic analysis of 37 individual interviews and five focus groups with a total of 53 male and female antiretroviral drug users and 25 healthcare providers in rural eastern Zimbabwe. RESULTS: Rooted in hegemonic notions of masculinity, men saw HIV/AIDS as a threat to their manhood and dignity and exhibited a profound fear of the disease. In the process of denying and avoiding their association with AIDS, many men undermine their wives' efforts to access and adhere to ART. Many women felt unable to disclose their HIV status to their husbands, forcing them to take their medication in secret, and act without a supportive treatment partner, which is widely accepted to be vitally important for adherence success. Some husbands, when discovering that their wives are on ART, deny them permission to take the drugs, or indeed steal the drugs for their own treatment. Men's avoidance of HIV also leaves many HIV-positive women feeling vulnerable to re infection as their husbands, in an attempt to demonstrate their manhood, are believed to continue engaging in HIV-risky behaviours. CONCLUSIONS: Hegemonic notions of masculinity can interfere with women's adherence to ART. It is important that those concerned with promoting effective treatment services recognise the gender and household dynamics that may prevent some women from successfully adhering to ART, and explore ways to work with both women and men to identify couples-based strategies to increase adherence to ART. PMID- 21658261 TI - A novel subtilase with NaCl-activated and oxidant-stable activity from Virgibacillus sp. SK37. AB - BACKGROUND: Microbial proteases are one of the most commercially valuable enzymes, of which the largest market share has been taken by subtilases or alkaline proteases of the Bacillus species. Despite a large amount of information on microbial proteases, a search for novel proteases with unique properties is still of interest for both basic and applied aspects of this highly complex class of enzymes. Oxidant stable proteases (OSPs) have been shown to have a wide application in the detergent and bleaching industries and recently have become one of the most attractive enzymes in various biotechnological applications. RESULTS: A gene encoding a novel member of the subtilase superfamily was isolated from Virgibacillus sp. SK37, a protease-producing bacterium isolated from Thai fish sauce fermentation. The gene was cloned by an activity-based screening of a genomic DNA expression library on Luria-Bertani (LB) agar plates containing 1 mM IPTG and 3% skim milk. Of the 100,000 clones screened, all six isolated positive clones comprised one overlapping open reading frame of 45% identity to the aprX gene from Bacillus species. This gene, designated aprX-sk37 was cloned into pET21d(+) and over-expressed in E. coli BL21(DE3). The enzyme product, designated AprX-SK37, was purified by an immobilized metal ion affinity chromatography to apparent homogeneity and characterized. The AprX-SK37 enzyme showed optimal catalytic conditions at pH 9.5 and 55 degrees C, based on the azocasein assay containing 5 mM CaCl2. Maximum catalytic activity was found at 1 M NaCl with residual activity of 30% at 3 M NaCl. Thermal stability of the enzyme was also enhanced by 1 M NaCl. The enzyme was absolutely calcium-dependent, with optimal concentration of CaCl2 at 15 mM. Inhibitory effects by phenylmethanesulfonyl fluoride and ethylenediaminetetraacetic acid indicated that this enzyme is a metal-dependent serine protease. The enzyme activity was sensitive towards reducing agents, urea, and SDS, but relatively stable up to 5% of H2O2. Phylogenetic analysis suggested that AprX-SK37 belongs to a novel family of the subtilase superfamily. We propose the name of this new family as alkaline serine protease-X (AprX). CONCLUSIONS: The stability towards H2O2 and moderately halo- and thermo-tolerant properties of the AprX-SK37 enzyme are attractive for various biotechnological applications. PMID- 21658262 TI - The challenges and opportunities of conducting a clinical trial in a low resource setting: the case of the Cameroon mobile phone SMS (CAMPS) trial, an investigator initiated trial. AB - Conducting clinical trials in developing countries often presents significant ethical, organisational, cultural and infrastructural challenges to researchers, pharmaceutical companies, sponsors and regulatory bodies. Globally, these regions are under-represented in research, yet this population stands to gain more from research in these settings as the burdens on health are greater than those in developed resourceful countries. However, developing countries also offer an attractive setting for clinical trials because they often have larger treatment naive populations with higher incidence rates of disease and more advanced stages. These factors can present a reduction in costs and time required to recruit patients. So, balance needs to be found where research can be encouraged and supported in order to bring maximum public health benefits to these communities. The difficulties with such trials arise from problems with obtaining valid informed consent, ethical compensation mechanisms for extremely poor populations, poor health infrastructure and considerable socio-economic and cultural divides. Ethical concerns with trials in developing countries have received attention, even though many other non-ethical issues may arise. Local investigator initiated trials also face a variety of difficulties that have not been adequately reported in literature. This paper uses the example of the Cameroon Mobile Phone SMS trial to describe in detail, the specific difficulties encountered in an investigator-initiated trial in a developing country. It highlights administrative, ethical, financial and staff related issues, proposes solutions and gives a list of additional documentation to ease the organisational process. PMID- 21658263 TI - Alkaline peroxide pretreatment of corn stover: effects of biomass, peroxide, and enzyme loading and composition on yields of glucose and xylose. AB - BACKGROUND: Pretreatment is a critical step in the conversion of lignocellulose to fermentable sugars. Although many pretreatment processes are currently under investigation, none of them are entirely satisfactory in regard to effectiveness, cost, or environmental impact. The use of hydrogen peroxide at pH 11.5 (alkaline hydrogen peroxide (AHP)) was shown by Gould and coworkers to be an effective pretreatment of grass stovers and other plant materials in the context of animal nutrition and ethanol production. Our earlier experiments indicated that AHP performed well when compared against two other alkaline pretreatments. Here, we explored several key parameters to test the potential of AHP for further improvement relevant to lignocellulosic ethanol production. RESULTS: The effects of biomass loading, hydrogen peroxide loading, residence time, and pH control were tested in combination with subsequent digestion with a commercial enzyme preparation, optimized mixtures of four commercial enzymes, or optimized synthetic mixtures of pure enzymes. AHP pretreatment was performed at room temperature (23 degrees C) and atmospheric pressure, and after AHP pretreatment the biomass was neutralized with HCl but not washed before enzyme digestion. Standard enzyme digestion conditions were 0.2% glucan loading, 15 mg protein/g glucan, and 48 h digestion at 50 degrees C. Higher pretreatment biomass loadings (10% to 20%) gave higher monomeric glucose (Glc) and xylose (Xyl) yields than the 2% loading used in earlier studies. An H2O2 loading of 0.25 g/g biomass was almost as effective as 0.5 g/g, but 0.125 g/g was significantly less effective. Optimized mixtures of four commercial enzymes substantially increased post-AHP pretreatment enzymatic hydrolysis yields at all H2O2 concentrations compared to any single commercial enzyme. At a pretreatment biomass loading of 10% and an H2O2 loading of 0.5 g/g biomass, an optimized commercial mixture at total protein loadings of 8 or 15 mg/g glucan gave monomeric Glc yields of 83% or 95%, respectively. Yields of Glc and Xyl after pretreatment at a low hydrogen peroxide loading (0.125 g H2O2/g biomass) could be improved by extending the pretreatment residence time to 48 h and readjusting the pH to 11.5 every 6 h during the pretreatment. A Glc yield of 77% was obtained using a pretreatment of 15% biomass loading, 0.125 g H2O2/g biomass, and 48 h with pH adjustment, followed by digestion with an optimized commercial enzyme mixture at an enzyme loading of 15 mg protein/g glucan. CONCLUSIONS: Alkaline peroxide is an effective pretreatment for corn stover. Particular advantages are the use of reagents with low environmental impact and avoidance of special reaction chambers. Reasonable yields of monomeric Glc can be obtained at an H2O2 concentration one-quarter of that used in previous AHP research. Additional improvements in the AHP process, such as peroxide stabilization, peroxide recycling, and improved pH control, could lead to further improvements in AHP pretreatment. PMID- 21658264 TI - Tracking progress towards equitable child survival in a Nicaraguan community: neonatal mortality challenges to meet the MDG 4. AB - BACKGROUND: Nicaragua has made progress in the reduction of the under-five mortality since 1980s. Data for the national trends indicate that this poor Central American country is on track to reach the Millennium Development Goal-4 by 2015. Despite this progress, neonatal mortality has not showed same progress. The aim of this study is to analyse trends and social differentials in neonatal and under-five mortality in a Nicaraguan community from 1970 to 2005. METHODS: Two linked community-based reproductive surveys in 1993 and 2002 followed by a health and demographic surveillance system providing information on all births and child deaths in urban and rural areas of Leon municipality, Nicaragua. A total of 49 972 live births were registered. RESULTS: A rapid reduction in under five mortality was observed during the late 1970s (from 103 deaths/1000 live births) and the 1980s, followed by a gradual decline to the level of 23 deaths/1000 live births in 2005. This community is on track for the Millennium Development Goal 4 for improved child survival. However, neonatal mortality increased lately in spite of a good coverage of skilled assistance at delivery. After some years in the 1990s with a very small gap in neonatal survival between children of mothers of different educational levels this divide is increasing. CONCLUSIONS: After the reduction of high under-five mortality that coincided with improved equity in survival in this Nicaraguan community, the current challenge is the neonatal mortality where questions of an equitable perinatal care of good quality must be addressed. PMID- 21658266 TI - Electromagnetic compatibility of implantable neurostimulators to RFID emitters. AB - BACKGROUND: The objective of this study is to investigate electromagnetic compatibility (EMC) of implantable neurostimulators with the emissions from radio frequency identification (RFID) emitters. METHODS: Six active implantable neurostimulators with lead systems were tested for susceptibility to electromagnetic fields generated by 22 RFID emitters. These medical devices have been approved for marketing in the U.S. for a number of intended uses that include: epilepsy, depression, incontinence, Parkinsonian tremor and pain relief. Each RFID emitter had one of the following carrier frequencies: 125 kHz, 134 kHz, 13.56 MHz, 433 MHz, 915 MHz and 2.45 GHz. RESULTS: The test results showed the output of one of the implantable neurostimulators was inhibited by 134 kHz RFID emitter at separation distances of 10 cm or less. The output of the same implantable neurostimulator was also inhibited by another 134 kHz RFID emitter at separation distances of 10 cm or less and also showed inconsistent pulsing rate at a separation distance of 15 cm. Both effects occurred during and lasted through out the duration of the exposure. CONCLUSIONS: The clinical significance of the effects was assessed by a clinician at the U.S. Food and Drug Administration. The effects were determined to be clinically significant only if they occurred for extended period of time. There were no observed effects from the other 5 implantable neurostimulators or during exposures from other RFID emitters. PMID- 21658265 TI - Heterologous expression of pathogen-specific genes ligA and ligB in the saprophyte Leptospira biflexa confers enhanced adhesion to cultured cells and fibronectin. AB - BACKGROUND: In comparison to other bacterial pathogens, our knowledge of the molecular basis of the pathogenesis of leptospirosis is extremely limited. An improved understanding of leptospiral pathogenetic mechanisms requires reliable tools for functional genetic analysis. Leptospiral immunoglobulin-like (Lig) proteins are surface proteins found in pathogenic Leptospira, but not in saprophytes. Here, we describe a system for heterologous expression of the Leptospira interrogans genes ligA and ligB in the saprophyte Leptospira biflexa serovar Patoc. RESULTS: The genes encoding LigA and LigB under the control of a constitutive spirochaetal promoter were inserted into the L. biflexa replicative plasmid. We were able to demonstrate expression and surface localization of LigA and LigB in L. biflexa. We found that the expression of the lig genes significantly enhanced the ability of transformed L. biflexa to adhere in vitro to extracellular matrix components and cultured cells, suggesting the involvement of Lig proteins in cell adhesion. CONCLUSIONS: This work reports a complete description of the system we have developed for heterologous expression of pathogen-specific proteins in the saprophytic L. biflexa. We show that expression of LigA and LigB proteins from the pathogen confers a virulence-associated phenotype on L. biflexa, namely adhesion to eukaryotic cells and fibronectin in vitro. This study indicates that L. biflexa can serve as a surrogate host to characterize the role of key virulence factors of the causative agent of leptospirosis. PMID- 21658267 TI - Do improvements in outreach, clinical, and family and community-based services predict improvements in child survival? An analysis of serial cross-sectional national surveys. AB - BACKGROUND: There are three main service delivery channels: clinical services, outreach, and family and community. To determine which delivery channels are associated with the greatest reductions in under-5 mortality rates (U5MR), we used data from sequential population-based surveys to examine the correlation between changes in coverage of clinical, outreach, and family and community services and in U5MR for 27 high-burden countries. METHODS: Household survey data were abstracted from serial surveys in 27 countries. Average annual changes (AAC) between the most recent and penultimate survey were calculated for under-five mortality rates and for 22 variables in the domains of clinical, outreach, and family- and community-based services. For all 27 countries and a subset of 19 African countries, we conducted principal component analysis to reduce the variables into a few components in each domain and applied linear regression to assess the correlation between changes in the principal components and changes in under-five mortality rates after controlling for multiple potential confounding factors. RESULTS: AAC in under 5-mortality varied from 6.6% in Nepal to -0.9% in Kenya, with six of the 19 African countries all experiencing less than a 1% decline in mortality. The strongest correlation with reductions in U5MR was observed for access to clinical services (all countries: p = 0.02, r2 = 0.58; 19 African countries p < 0.001, r2 = 0.67). For outreach activities, AAC U5MR was significantly correlated with antenatal care and family planning services, while AAC in immunization services showed no association. In the family- and community services domain, improvements in breastfeeding were associated with significant changes in mortality in the 30 countries but not in the African subset; while in the African countries, nutritional status improvements were associated with a significant decline in mortality. CONCLUSIONS: Our findings support the importance of increasing access to clinical services, certain outreach services and breastfeeding and, in Africa, of improving nutritional status. Integrated programs that emphasize these services may lead to substantial mortality declines. PMID- 21658268 TI - Population, behavioural and environmental drivers of malaria prevalence in the Democratic Republic of Congo. AB - BACKGROUND: Malaria is highly endemic in the Democratic Republic of Congo (DRC), but the limits and intensity of transmission within the country are unknown. It is important to discern these patterns as well as the drivers which may underlie them in order for effective prevention measures to be carried out. METHODS: By applying high-throughput PCR analyses on leftover dried blood spots from the 2007 Demographic and Health Survey (DHS) for the DRC, prevalence estimates were generated and ecological drivers of malaria were explored using spatial statistical analyses and multilevel modelling. RESULTS: Of the 7,746 respondents, 2268 (29.3%) were parasitaemic; prevalence ranged from 0-82% within geographically-defined survey clusters. Regional variation in these rates was mapped using the inverse-distance weighting spatial interpolation technique. Males were more likely to be parasitaemic than older people or females (p < 0.0001), while wealthier people were at a lower risk (p < 0.001). Increased community use of bed nets (p = 0.001) and community wealth (p < 0.05) were protective against malaria at the community level but not at the individual level. Paradoxically, the number of battle events since 1994 surrounding one's community was negatively associated with malaria risk (p < 0.0001). CONCLUSIONS: This research demonstrates the feasibility of using population-based behavioural and molecular surveillance in conjunction with DHS data and geographic methods to study endemic infectious diseases. This study provides the most accurate population-based estimates to date of where illness from malaria occurs in the DRC and what factors contribute to the estimated spatial patterns. This study suggests that spatial information and analyses can enable the DRC government to focus its control efforts against malaria. PMID- 21658269 TI - A Synchronous undifferentiated nasopharyngeal carcinoma and infiltrating ductal carcinoma of the breast successfully treated with induction chemotherapy followed by local control of both tumours: a case report. AB - BACKGROUND: Multiple primary cancers have a low incidence particularly when cancers are synchronous. Few cases of synchronous head and neck cancer and breast carcinoma are reported in the literature. CASE PRESENTATION: We report here an exceptional case of a 47 years old Moroccan woman presenting two synchronous cancers, the first in the nasopharynx and the second in the breast. The patient was treated successfully with a combined strategy associating chemotherapy, radiation therapy, and surgery. She remains disease free after 27 months of follow up. CONCLUSIONS: Treatment strategy in the case of multiple primary cancers remains controversial because of the variety of presentations; initial aggressive treatment reports good results. PMID- 21658270 TI - Functional characterization of human Cd33+ and Cd11b+ myeloid-derived suppressor cell subsets induced from peripheral blood mononuclear cells co-cultured with a diverse set of human tumor cell lines. AB - BACKGROUND: Tumor immune tolerance can derive from the recruitment of suppressor cell populations, including myeloid-derived suppressor cells (MDSC). In cancer patients, MDSC accumulation correlates with increased tumor burden, but the mechanisms of MDSC induction remain poorly understood. METHODS: This study examined the ability of human tumor cell lines to induce MDSC from healthy donor PBMC using in vitro co-culture methods. These human MDSC were then characterized for morphology, phenotype, gene expression, and function. RESULTS: Of over 100 tumor cell lines examined, 45 generated canonical CD33+HLA-DR(low)Lineage- MDSC, with high frequency of induction by cervical, ovarian, colorectal, renal cell, and head and neck carcinoma cell lines. CD33+ MDSC could be induced by cancer cell lines from all tumor types with the notable exception of those derived from breast cancer (0/9, regardless of hormone and HER2 status). Upon further examination, these and others with infrequent CD33+ MDSC generation were found to induce a second subset characterized as CD11b+CD33(low)HLA-DR(low)Lineage-. Gene and protein expression, antibody neutralization, and cytokine-induction studies determined that the induction of CD33+ MDSC depended upon over-expression of IL 1beta, IL-6, TNFalpha, VEGF, and GM-CSF, while CD11b+ MDSC induction correlated with over-expression of FLT3L and TGFbeta. Morphologically, both CD33+ and CD11b+ MDSC subsets appeared as immature myeloid cells and had significantly up regulated expression of iNOS, NADPH oxidase, and arginase-1 genes. Furthermore, increased expression of transcription factors HIF1alpha, STAT3, and C/EBPbeta distinguished MDSC from normal counterparts. CONCLUSIONS: These studies demonstrate the universal nature of MDSC induction by human solid tumors and characterize two distinct MDSC subsets: CD33+HLA-DR(low)HIF1alpha+/STAT3+ and CD11b+HLA-DR(low)C/EBPbeta+, which should enable the development of novel diagnostic and therapeutic reagents for cancer immunotherapy. PMID- 21658271 TI - Characterization of herpes simplex virus clinical isolate Y3369 as a glycoprotein G variant and its bearing on virus typing. AB - BACKGROUND: Herpes simplex viruses exist as two major serotypes, type 1 (HSV-1) and type 2 (HSV-2). Determination of type, either HSV-1 or HSV-2, is important in accurate diagnosis and clinical control of transmission. Several tests are available for typing HSV, including a monoclonal antibody specific for glycoprotein G and several PCR assays. FINDINGS: A clinical isolate was identified as herpes simplex virus, but tested negative for both HSV-1 and HSV-2 antigens using type-specific monoclonal antibody assays. The isolate was determined to be HSV-1 by PCR analysis. A mutation which likely caused the monoclonal antibody non-reactivity was found in glycoprotein G. Phylogenetic analysis revealed two groups of HSV, one with the mutation and one without. Three population studies examining mutations in HSV-1 glycoprotein G were analyzed by chi-squared test. To this point, the epitope which the monoclonal antibody recognizes was only found in HSV-1 isolates from human European populations (p < 0.0001). CONCLUSIONS: These findings suggest that the PCR-based methods for HSV typing may be more useful than the standard monoclonal antibody test in areas of the world where the variant in glycoprotein G is more prevalent. PMID- 21658272 TI - Children's health and parental socioeconomic factors: a population-based survey in Finland. AB - BACKGROUND: Socioeconomic inequalities in health are a global problem, not only among the adult population but also among children. However, studies concerning young children especially are rare. The aim of this study was to describe the health of Finnish children under 12 years of age, and the socioeconomic factors associated with health. The socioeconomic factors were parental education level, household net income, and working status. METHODS: A population-based survey among Finnish children aged under 12 years (n = 6,000) was conducted in spring 2007. A questionnaire was sent to parents, and a response rate of 67% was achieved. Each child's health was explored by asking a parent to report the child's health status on a 5-point Likert scale, current symptoms from a symptoms list, and current disease(s) diagnosed by a physician. The final three outcome measures were poor health, the prevalences of psychosomatic symptoms, and long term diseases. Data were analysed using Pearson's Chi-Square tests, and logistic regression analysis with 95% confidence intervals (CIs). P-values <= 0.05 were considered as statistically significant. RESULTS: In total, 3% of parents reported that their child's health status was poor. The prevalences of psychosomatic symptoms and long-term diseases were both 11%. The probability for poor health status was lowest among children aged 3-6 and 7-11 years, and for psychosomatic symptoms among 3-6-year-old children, whereas the odds ratios for long-term diseases was highest among children aged 7-11 years. Parental socioeconomic factors were not associated with the children's health. CONCLUSIONS: Most of the children were reported by their parent to have good health status, and approximately one tenth had experienced some psychosomatic symptoms or long-term diseases. Our study suggests that parental socioeconomic factors are not associated with the health of children aged under 12 years in Finland. PMID- 21658273 TI - Single nucleotide polymorphism discovery in elite North American potato germplasm. AB - BACKGROUND: Current breeding approaches in potato rely almost entirely on phenotypic evaluations; molecular markers, with the exception of a few linked to disease resistance traits, are not widely used. Large-scale sequence datasets generated primarily through Sanger Expressed Sequence Tag projects are available from a limited number of potato cultivars and access to next generation sequencing technologies permits rapid generation of sequence data for additional cultivars. When coupled with the advent of high throughput genotyping methods, an opportunity now exists for potato breeders to incorporate considerably more genotypic data into their decision-making. RESULTS: To identify a large number of Single Nucleotide Polymorphisms (SNPs) in elite potato germplasm, we sequenced normalized cDNA prepared from three commercial potato cultivars: 'Atlantic', 'Premier Russet' and 'Snowden'. For each cultivar, we generated 2 Gb of sequence which was assembled into a representative transcriptome of ~28-29 Mb for each cultivar. Using the Maq SNP filter that filters read depth, density, and quality, 575,340 SNPs were identified within these three cultivars. In parallel, 2,358 SNPs were identified within existing Sanger sequences for three additional cultivars, 'Bintje', 'Kennebec', and 'Shepody'. Using a stringent set of filters in conjunction with the potato reference genome, we identified 69,011 high confidence SNPs from these six cultivars for use in genotyping with the Infinium platform. Ninety-six of these SNPs were used with a BeadXpress assay to assess allelic diversity in a germplasm panel of 248 lines; 82 of the SNPs proved sufficiently informative for subsequent analyses. Within diverse North American germplasm, the chip processing market class was most distinct, clearly separated from all other market classes. The round white and russet market classes both include fresh market and processing cultivars. Nevertheless, the russet and round white market classes are more distant from each other than processing are from fresh market types within these two groups. CONCLUSIONS: The genotype data generated in this study, albeit limited in number, has revealed distinct relationships among the market classes of potato. The SNPs identified in this study will enable high-throughput genotyping of germplasm and populations, which in turn will enable more efficient marker-assisted breeding efforts in potato. PMID- 21658274 TI - A qualitative study of older adults' responses to sitting-time questions: do we get the information we want? AB - BACKGROUND: In the last decade, there has been increasing interest in the health effects of sedentary behavior, which is often assessed using self-report sitting time questions. The aim of this qualitative study was to document older adults' understanding of sitting-time questions from the International Physical Activity (PA) Questionnaire (IPAQ) and the PA Scale for the Elderly (PASE). METHODS: Australian community-dwelling adults aged 65+ years answered the IPAQ and PASE sitting questions in face-to-face semi-structured interviews. IPAQ uses one open ended question to assess sitting on a weekday in the last 7 days 'at work, at home, while doing coursework and during leisure time'; PASE uses a three-part closed question about daily leisure-time sitting in the last 7 days. Participants expressed their thoughts out loud while answering each question. They were then probed about their responses. Interviews were recorded, transcribed and coded into themes. RESULTS: Mean age of the 28 male and 27 female participants was 73 years (range 65-89). The most frequently reported activity was watching TV. For both questionnaires, many participants had difficulties understanding what activities to report. Some had difficulty understanding what activities should be classified as 'leisure-time sitting'. Some assumed they were being asked to only report activities provided as examples. Most reported activities they normally do, rather than those performed on a day in the previous week. Participants used a variety of strategies to select 'a day' for which they reported their sitting activities and to calculate sitting time on that day. Therefore, many different ways of estimating sitting time were used. Participants had particular difficulty reporting their daily sitting-time when their schedules were not consistent across days. Some participants declared the IPAQ sitting question too difficult to answer. CONCLUSION: The accuracy of older adults' self-reported sitting time is questionable given the challenges they have in answering sitting-time questions. Their responses to sitting-time questions may be more accurate if our recommendations for clarifying the sitting domains, providing examples relevant to older adults and suggesting strategies for formulating responses are incorporated. Future quantitative studies should include objective criterion measures to assess validity and reliability of these questions. PMID- 21658275 TI - High incidence of hepatitis B infection-associated cirrhosis and hepatocellular carcinoma in the Southeast Asian patients with portal vein thrombosis. AB - BACKGROUND: Portal vein thrombosis (PVT) is a rare condition associated with serious morbidity and mortality. The objective of this study was to determine the frequency, clinical presentations, and risk factors of PVT from the set of data firstly collected among the Southeast Asian population. METHODS: A retrospective study was undertaken to identify patients diagnosed with thrombosis of the portal system and other abdominal veins. The hospital medical records were retrieved based on the selected ICD-10 codes. Clinical presentations were collected and risk factors determined. RESULTS: From 2000-2009, 467 hospital charts with designated ICD-10 codes of I81, I82.2, I82.3, I82.8, I82.9, or K55.0 were identified. PVT (I81) was the most common thrombosis (194 cases, 41.54%). The majority of PVT patients were males (65%), older than 40 years (75%), and presented with abdominal distension/ascites (69%), splenomegaly (54.6%), and abdominal pain (50.5%). Overall, the predominant risk factor was hepatocellular carcinoma (HCC) (52.5%), followed by liver cirrhosis without cancer (9.3%), abdominal infection/inflammation (9.3%), cholangiocarcinoma (8.2%), and abdominal intervention (7.7%). In young patients, abdominal interventions including umbilical catheterization (23.1%) and hepatectomy (7.7%) were the most frequent risks whereas in older cases, primary hepatobiliary cancer and cirrhosis (78%) were the major risks. Liver metastases from other organs were infrequently found. Chronic hepatitis B virus (HBV) infection was the main etiology associated with cirrhosis/HCC leading to PVT in this cohort. A third of the older PVT patients (age >40) had HBV and very few carried hepatitis C virus (HCV) whereas none of the young PVT patients (age <20) had HBV or HCV. A variety of abdominal infections/inflammations were also found including liver abscess, splenic abscess, cholangitis, cholecystitis, pancreatitis, omphalitis, and abdominal tuberculosis. Single cases of systemic lymphangiomatosis and Klippel-Trenaunay vascular malformation syndrome were also identified. Other thrombophilic conditions such as myeloproliferative neoplasms, paroxysmal nocturnal hemoglobinuria, protein S deficiency, and anti-phospholipid syndrome were rarely encountered. CONCLUSION: HBV is the major risk of PVT in the Southeast Asian population. Several risk factors identified in this population have rarely been described and some are remarkably different from those reported in the West. Host and environmental factors may play a causal role in the initiation and development of PVT in various ethnicities and geographic locations. PMID- 21658276 TI - Changes of dendritic cells and fractalkine in type 2 diabetic patients with unstable angina pectoris: a preliminary report. AB - BACKGROUND: It has been shown that dendritic cells (DCs) and fractalkine play a role in accelerating progression of the inflamed atherosclerotic lesions and plaque rupture. We evaluated the numbers and functional changes of DCs and its subsets in human type 2 diabetes with or without unstable angina pectoris (UAP). METHODS: The study population consisted of 39 diabetic patients (DM:18 without CAD; DM + UAP: 21 with UAP), 18 non-diabetic UAP patients (UAP), and 15 healthy control (Normal). Peripheral blood DCs and its subsets were measured by three color flow cytometry. Serum levels of fractalkine, IL-12, and IFN-alpha were also measured. The functional status of the monocyte-derived DCs was analyzed by flow cytometry and allogeneic mixed T lymphocytes reaction. RESULTS: The percent and absolute numbers of DCs and mDC within the total leukocyte population was similar for Normal and DM, while significantly lower in DM + UAP. pDC numbers were not significantly altered. Serum fractalkine in DM + UAP was highest among the four groups (p = 0.04 vs. UAP, p = 0.0003 vs. DM, p < 0.0001 vs. Normal). Circulating mDC inversely correlated with serum fractalkine (r = -0.268, p = 0.01) level. Compared with DM and UAP, the costimulatory molecules CD86 and proliferation of T cells stimulated by DCs were significantly increased in DM + UAP group. CONCLUSIONS: Our study suggested that increases in the fractalkine level and the number and functional changes of blood DCs might contribute to diabetic coronary atherosclerosis and plaque destabilization. PMID- 21658277 TI - Endoscopic resection of duodenal bulb neuroendocrine tumor larger than 10 mm in diameter. AB - BACKGROUND: Endoscopic treatment for duodenal bulb neuroendocrine tumor larger than 10 mm is still controversial. This report presents four cases successfully treated with endosonography (EUS)-assisted endoscopic mucosal resection (EMR) procedure for duodenal bulb neuroendocrine tumor larger than 10 mm in diameter. METHODS: The case series of four patients diagnosed with neuroendocrine tumor from 2003 to 2008 were reviewed. EUS demonstrated well-defined hypoechoic tumors confined to the submucosal hyperechoic layer and the underlying hypoechoic muscularis propria was intact in all four patients. EMR were planned and performed for the duodenal bulb neuroendocrine tumors larger than 10 mm. RESULTS: En bloc resections with tumor free lateral and basal margins were accomplished using an endoscopic diathermic snare with forward-viewing instruments without any complications. Neither residual duodenal neuroendocrine tumors nor metastatic lesions were detected during the observation period ranging 19 to 78 months CONCLUSION: Duodenal bulb neuroendocrine, larger than 10 mm in diameter, can be treated by endoscopic procedure, after confirming that the tumor confined to the submucosal layer in EUS examination, and no lymph node involvement by abdominal CT and US. PMID- 21658278 TI - Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy. AB - BACKGROUND: Multiple system atrophy (MSA) is a sporadic disease. Its pathogenesis may involve multiple genetic and nongenetic factors, but its etiology remains largely unknown. We hypothesized that the genome of a patient with MSA would demonstrate copy number variations (CNVs) in the genes or genomic regions of interest. To identify genomic alterations increasing the risk for MSA, we examined a pair of monozygotic (MZ) twins discordant for the MSA phenotype and 32 patients with MSA. RESULTS: By whole-genome CNV analysis using a combination of CNV beadchip and comparative genomic hybridization (CGH)-based CNV microarrays followed by region-targeting, high-density, custom-made oligonucleotide tiling microarray analysis, we identified disease-specific copy number loss of the (Src homology 2 domain containing)-transforming protein 2 (SHC2) gene in the distal 350-kb subtelomeric region of 19p13.3 in the affected MZ twin and 10 of the 31 patients with MSA but not in 2 independent control populations (p = 1.04 * 10-8, odds ratio = 89.8, Pearson's chi-square test). CONCLUSIONS: Copy number loss of SHC2 strongly indicates a causal link to MSA. CNV analysis of phenotypically discordant MZ twins is a powerful tool for identifying disease-predisposing loci. Our results would enable the identification of novel diagnostic measure, therapeutic targets and better understanding of the etiology of MSA. PMID- 21658279 TI - A rapid, simple method for the genetic discrimination of intact Arabidopsis thaliana mutant seeds using metabolic profiling by direct analysis in real-time mass spectrometry. AB - BACKGROUND: Efficient high throughput screening systems of useful mutants are prerequisite for study of plant functional genomics and lots of application fields. Advance in such screening tools, thanks to the development of analytic instruments. Direct analysis in real-time (DART)-mass spectrometry (MS) by ionization of complex materials at atmospheric pressure is a rapid, simple, high resolution analytical technique. Here we describe a rapid, simple method for the genetic discrimination of intact Arabidopsis thaliana mutant seeds using metabolic profiling by DART-MS. RESULTS: To determine whether this DART-MS combined by multivariate analysis can perform genetic discrimination based on global metabolic profiling, intact Arabidopsis thaliana mutant seeds were subjected to DART-MS without any sample preparation. Partial least squares discriminant analysis (PLS-DA) of DART-MS spectral data from intact seeds classified 14 different lines of seeds into two distinct groups: Columbia (Col-0) and Landsberg erecta (Ler) ecotype backgrounds. A hierarchical dendrogram based on partial least squares-discriminant analysis (PLS-DA) subdivided the Col-0 ecotype into two groups: mutant lines harboring defects in the phenylpropanoid biosynthetic pathway and mutants without these defects. These results indicated that metabolic profiling with DART-MS could discriminate intact Arabidopsis seeds at least ecotype level and metabolic pathway level within same ecotype. CONCLUSION: The described DART-MS combined by multivariate analysis allows for rapid screening and metabolic characterization of lots of Arabidopsis mutant seeds without complex metabolic preparation steps. Moreover, potential novel metabolic markers can be detected and used to clarify the genetic relationship between Arabidopsis cultivars. Furthermore this technique can be applied to predict the novel gene function of metabolic mutants regardless of morphological phenotypes. PMID- 21658280 TI - First construction of infectious clone for newly emerging mutation porcine circovirus type 2 (PCV2) followed by comparison with PCV2a and PCV2b genotypes in biological characteristics in vitro. AB - BACKGROUND: Porcine circovirus type 2 (PCV2), the causative agent of postweaning multisystemic wasting syndrome (PMWS), is a serious economic problem in the swine industry. Different genotypes (PCV2a, PCV2b and PCV2d) of the virus are present in the clinical cases in China, and it is necessary to elucidate the pathogenic difference among different genotypes of PCV2. In this study, four strains of different genotypes were isolated, two were ordinary strains and another two were mutation strains, which there are one and two amino acids elongation in the capsid protein (Cap) of PCV2, respectively. Representative strains of different genotypes of the virus were constructed by infectious molecular clone and biological characterization of the rescued viruses were identified in vitro. RESULTS: Four PCV2 isolates (PCV2a/CL, PCV2b/YJ, PCV2b/JF and PCV2d/BDH) of different genotypes were isolated from the clinical cases of PMWS in China. Four infectious clones of PCV2 were constructed and the rescued viruses were harvested after transfection into PK15 cells. The rescued viruses were verified by nucleotide sequence analysis, morphology of the viruses and immunoperoxidase monolayer assay (IPMA). The rescued viruses propagated stably after consecutive incubation for more than ten passages, and virus propagation reached its peak 72h post infection (PI), and the virus titers were up to 105.7 TCID50/ml. By using neutralizing 1D2 monoclonal antibody (mAb) of PCV2, the antigen capture ELISA showed that only the PCV2a/rCL and PCV2b/rJF strains has immunoreactivity with the 1D2 mAb, however, another two rescued strains (PCV2b/rYJ and PCV2d/rBDH) do not, which indicated the antigenic difference among the rescued viruses of different genotypes. In addition, here is the first report of obtaining the newly emerging PCV2 with mutation in vitro by infectious molecular clone technology. CONCLUSIONS: Conclusions drawn from this study show that PCV2 has prevailing differences in genomic and ORF2 gene length and antigen in swine herds in China. Four representative clones for different genotypes were constructed and rescued, which will facilitate further studies on the pathogenic differences resulting from different subtypes of PCV2. PMID- 21658281 TI - GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease. AB - BACKGROUND: Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study. METHODS: Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls. RESULTS: Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 * 10(-7)), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 * 10(-8); Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 * 10(-4); OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 * 10(-2), OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 * 10(-3), OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 * 10(-3), OR = 1.13, 95% CI:1.042, 1.215). CONCLUSION: We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations. PMID- 21658282 TI - Melatonin receptor 1 B polymorphisms associated with the risk of gestational diabetes mellitus. AB - BACKGROUNDS: Two SNPs in melatonin receptor 1B gene, rs10830963 and rs1387153 showed significant associations with fasting plasma glucose levels and the risk of Type 2 Diabetes Mellitus (T2DM) in previous studies. Since T2DM and gestational diabetes mellitus (GDM) share similar characteristics, we suspected that the two genetic polymorphisms in MTNR1B may be associated with GDM, and conducted association studies between the polymorphisms and the disease. Furthermore, we also examined genetic effects of the two polymorphisms with various diabetes-related phenotypes. METHODS: A total of 1,918 subjects (928 GDM patients and 990 controls) were used for the study. Two MTNR1B polymorphisms were genotyped using TaqMan assay. The allele distributions of SNPs were evaluated by x2 models calculating odds ratios (ORs), 95% confidence intervals (CIs), and corresponding P values. Multiple regressions were used for association analyses of GDM-related traits. Finally, conditional analyses were also performed. RESULTS: We found significant associations between the two genetic variants and GDM, rs10830963, with a corrected P value of 0.0001, and rs1387153, with the corrected P value of 0.0008. In addition, we also found that the two SNPs were associated with various phenotypes such as homeostasis model assessment of beta cell function and fasting glucose levels. Further conditional analyses results suggested that rs10830963 might be more likely functional in case/control analysis, although not clear in GDM-related phenotype analyses. CONCLUSION: There have been studies that found associations between genetic variants of other genes and GDM, this is the first study that found significant associations between SNPs of MTNR1B and GDM. The genetic effects of two SNPs identified in this study would be helpful in understanding the insight of GDM and other diabetes-related disorders. PMID- 21658283 TI - Effect of guidewire on contribution of loss due to momentum change and viscous loss to the translesional pressure drop across coronary artery stenosis: an analytical approach. AB - BACKGROUND: Guidewire (GW) size and stenosis dimensions are the two major factors affecting the translesional pressure drop. Studying the combined effect of these parameters on the mean pressure drop (Deltap) across the stenosis is of high practical importance. METHODS: In this study, time averaged mass and momentum conservation equations are solved analytically to obtain pressure drop-flow, Deltap-Q, curves for three different percentage area blockages corresponding to moderate (64%), intermediate (80%), and severe (90%) stenoses. Stenosis is considered to be axisymmetric consisting of three different sections namely converging, throat, and diverging regions. Analytical expressions for pressure drop are obtained for each of these regions separately. Using this approach, effects of lesion length and GW insertion on the mean translesional pressure drop and its component (loss due to momentum change and viscous loss) are analyzed. RESULTS AND CONCLUSION: It is observed that for a given percent area stenosis (AS), increase in the throat length only increases the viscous loss. However, increase in the severity of stenosis and GW insertion increase both loss due to momentum change and viscous loss. GW insertion has greater contribution to the rise in viscous loss (increase by 2.14 and 2.72 times for 64% and 90% AS, respectively) than loss due to momentum change (1.34% increase for 64% AS and 25% decrease for 90% AS). It also alters the hyperemic pressure drop in moderate (48% increase) to intermediate (30% increase) stenoses significantly. However, in severe stenoses GW insertion has a negligible effect (0.5% increase) on hyperemic translesional pressure drop. It is also observed that pressure drop in a severe stenosis is less sensitive to lesion length variation (4% and 14% increase in Deltap for without and with GW, respectively) as compared to intermediate (10% and 30% increase in Deltap for without and with GW, respectively) and moderate stenoses (22% and 48% increase in Deltap for without and with GW, respectively). Based on the contribution of pressure drop components to the total translesional pressure drop, it is found that viscous losses are dominant in moderate stenoses, while in severe stenoses losses due to momentum changes are significant. It is also shown that this simple analytical solution can provide valuable information regarding interpretation of coronary diagnostic parameters such as fractional flow reserve (FFR). PMID- 21658284 TI - Genetic characterization, species differentiation and detection of Fasciola spp. by molecular approaches. AB - Liver flukes belonging to the genus Fasciola are among the causes of foodborne diseases of parasitic etiology. These parasites cause significant public health problems and substantial economic losses to the livestock industry. Therefore, it is important to definitively characterize the Fasciola species. Current phenotypic techniques fail to reflect the full extent of the diversity of Fasciola spp. In this respect, the use of molecular techniques to identify and differentiate Fasciola spp. offer considerable advantages. The advent of a variety of molecular genetic techniques also provides a powerful method to elucidate many aspects of Fasciola biology, epidemiology, and genetics. However, the discriminatory power of these molecular methods varies, as does the speed and ease of performance and cost. There is a need for the development of new methods to identify the mechanisms underpinning the origin and maintenance of genetic variation within and among Fasciola populations. The increasing application of the current and new methods will yield a much improved understanding of Fasciola epidemiology and evolution as well as more effective means of parasite control. Herein, we provide an overview of the molecular techniques that are being used for the genetic characterization, detection and genotyping of Fasciola spp.. PMID- 21658286 TI - Efficient virus-induced gene silencing in apple, pear and Japanese pear using Apple latent spherical virus vectors. AB - BACKGROUND: Virus-induced gene silencing (VIGS) is an effective technology for the analysis of gene functions in plants. Though there are many reports on virus vectors for VIGS in plants, no VIGS vectors available for Rosaceae fruit trees were reported so far. We present an effective VIGS system in apple, pear, and Japanese pear using Apple latent spherical virus (ALSV) vectors. RESULTS: Inoculation of ALSV vectors carrying a partial sequence of endogenous genes from apple [ribulose-1, 5-bisphosphate carboxylase small subunit (rbcS), alpha subunit of chloroplast chaperonin (CPN60a), elongation factor 1 alpha (EF-1a), or actin] to the cotyledons of seeds by a particle bombardment induced highly uniform knock down phenotypes of each gene on the true leaves of seedlings from 2~3 weeks after inoculation. These silencing phenotypes continued for several months. Northern blot and RT-PCR analyses of leaves infected with ALSV containing a fragment of rbcS gene showed that the levels of rbcS-mRNA drastically decreased in the infected apple and pear leaves, and, in reverse, rbcS-siRNAs were generated in the infected leaves. In addition, some of apple seedlings inoculated with ALSV vector carrying a partial sequence of a TERMINAL FLOWER 1 gene of apple (MdTFL1) showed precocious flowering which is expected as a knock-down phenotype of the silencing of MdTFL1 gene. CONCLUSIONS: The ALSV-based VIGS system developed have provides a valuable new addition to the tool box for functional genomics in apple, pear, and Japanese pear. PMID- 21658287 TI - Topics in machine learning for biomedical literature analysis and text retrieval. PMID- 21658288 TI - Building a biomedical tokenizer using the token lattice design pattern and the adapted Viterbi algorithm. AB - BACKGROUND: Tokenization is an important component of language processing yet there is no widely accepted tokenization method for English texts, including biomedical texts. Other than rule based techniques, tokenization in the biomedical domain has been regarded as a classification task. Biomedical classifier-based tokenizers either split or join textual objects through classification to form tokens. The idiosyncratic nature of each biomedical tokenizer's output complicates adoption and reuse. Furthermore, biomedical tokenizers generally lack guidance on how to apply an existing tokenizer to a new domain (subdomain). We identify and complete a novel tokenizer design pattern and suggest a systematic approach to tokenizer creation. We implement a tokenizer based on our design pattern that combines regular expressions and machine learning. Our machine learning approach differs from the previous split-join classification approaches. We evaluate our approach against three other tokenizers on the task of tokenizing biomedical text. RESULTS: Medpost and our adapted Viterbi tokenizer performed best with a 92.9% and 92.4% accuracy respectively. CONCLUSIONS: Our evaluation of our design pattern and guidelines supports our claim that the design pattern and guidelines are a viable approach to tokenizer construction (producing tokenizers matching leading custom-built tokenizers in a particular domain). Our evaluation also demonstrates that ambiguous tokenizations can be disambiguated through POS tagging. In doing so, POS tag sequences and training data have a significant impact on proper text tokenization. PMID- 21658285 TI - Advances in understanding and treating ADHD. AB - Attention deficit hyperactivity disorder (ADHD) is a neurocognitive behavioral developmental disorder most commonly seen in childhood and adolescence, which often extends to the adult years. Relative to a decade ago, there has been extensive research into understanding the factors underlying ADHD, leading to far more treatment options available for both adolescents and adults with this disorder. Novel stimulant formulations have made it possible to tailor treatment to the duration of efficacy required by patients, and to help mitigate the potential for abuse, misuse and diversion. Several new non-stimulant options have also emerged in the past few years. Among these, cognitive behavioral interventions have proven popular in the treatment of adult ADHD, especially within the adult population who cannot or will not use medications, along with the many medication-treated patients who continue to show residual disability. PMID- 21658289 TI - A system for de-identifying medical message board text. AB - There are millions of public posts to medical message boards by users seeking support and information on a wide range of medical conditions. It has been shown that these posts can be used to gain a greater understanding of patients' experiences and concerns. As investigators continue to explore large corpora of medical discussion board data for research purposes, protecting the privacy of the members of these online communities becomes an important challenge that needs to be met. Extant entity recognition methods used for more structured text are not sufficient because message posts present additional challenges: the posts contain many typographical errors, larger variety of possible names, terms and abbreviations specific to Internet posts or a particular message board, and mentions of the authors' personal lives. The main contribution of this paper is a system to de-identify the authors of message board posts automatically, taking into account the aforementioned challenges. We demonstrate our system on two different message board corpora, one on breast cancer and another on arthritis. We show that our approach significantly outperforms other publicly available named entity recognition and de-identification systems, which have been tuned for more structured text like operative reports, pathology reports, discharge summaries, or newswire. PMID- 21658291 TI - Collocation analysis for UMLS knowledge-based word sense disambiguation. AB - BACKGROUND: The effectiveness of knowledge-based word sense disambiguation (WSD) approaches depends in part on the information available in the reference knowledge resource. Off the shelf, these resources are not optimized for WSD and might lack terms to model the context properly. In addition, they might include noisy terms which contribute to false positives in the disambiguation results. METHODS: We analyzed some collocation types which could improve the performance of knowledge-based disambiguation methods. Collocations are obtained by extracting candidate collocations from MEDLINE and then assigning them to one of the senses of an ambiguous word. We performed this assignment either using semantic group profiles or a knowledge-based disambiguation method. In addition to collocations, we used second-order features from a previously implemented approach.Specifically, we measured the effect of these collocations in two knowledge-based WSD methods. The first method, AEC, uses the knowledge from the UMLS to collect examples from MEDLINE which are used to train a Naive Bayes approach. The second method, MRD, builds a profile for each candidate sense based on the UMLS and compares the profile to the context of the ambiguous word.We have used two WSD test sets which contain disambiguation cases which are mapped to UMLS concepts. The first one, the NLM WSD set, was developed manually by several domain experts and contains words with high frequency occurrence in MEDLINE. The second one, the MSH WSD set, was developed automatically using the MeSH indexing in MEDLINE. It contains a larger set of words and covers a larger number of UMLS semantic types. RESULTS: The results indicate an improvement after the use of collocations, although the approaches have different performance depending on the data set. In the NLM WSD set, the improvement is larger for the MRD disambiguation method using second-order features. Assignment of collocations to a candidate sense based on UMLS semantic group profiles is more effective in the AEC method.In the MSH WSD set, the increment in performance is modest for all the methods. Collocations combined with the MRD disambiguation method have the best performance. The MRD disambiguation method and second-order features provide an insignificant change in performance. The AEC disambiguation method gives a modest improvement in performance. Assignment of collocations to a candidate sense based on knowledge-based methods has better performance. CONCLUSIONS: Collocations improve the performance of knowledge-based disambiguation methods, although results vary depending on the test set and method used. Generally, the AEC method is sensitive to query drift. Using AEC, just a few selected terms provide a large improvement in disambiguation performance. The MRD method handles noisy terms better but requires a larger set of terms to improve performance. PMID- 21658290 TI - A context-blocks model for identifying clinical relationships in patient records. AB - BACKGROUND: Patient records contain valuable information regarding explanation of diagnosis, progression of disease, prescription and/or effectiveness of treatment, and more. Automatic recognition of clinically important concepts and the identification of relationships between those concepts in patient records are preliminary steps for many important applications in medical informatics, ranging from quality of care to hypothesis generation. METHODS: In this work we describe an approach that facilitates the automatic recognition of eight relationships defined between medical problems, treatments and tests. Unlike the traditional bag-of-words representation, in this work, we represent a relationship with a scheme of five distinct context-blocks determined by the position of concepts in the text. As a preliminary step to relationship recognition, and in order to provide an end-to-end system, we also addressed the automatic extraction of medical problems, treatments and tests. Our approach combined the outcome of a statistical model for concept recognition and simple natural language processing features in a conditional random fields model. A set of 826 patient records from the 4th i2b2 challenge was used for training and evaluating the system. RESULTS: Results show that our concept recognition system achieved an F-measure of 0.870 for exact span concept detection. Moreover the context-block representation of relationships was more successful (F-Measure = 0.775) at identifying relationships than bag-of-words (F-Measure = 0.402). Most importantly, the performance of the end-to-end system of relationship extraction using automatically extracted concepts (F-Measure = 0.704) was comparable to that obtained using manually annotated concepts (F-Measure = 0.711), and their difference was not statistically significant. CONCLUSIONS: We extracted important clinical relationships from text in an automated manner, starting with concept recognition, and ending with relationship identification. The advantage of the context-blocks representation scheme was the correct management of word position information, which may be critical in identifying certain relationships. Our results may serve as benchmark for comparison to other systems developed on i2b2 challenge data. Finally, our system may serve as a preliminary step for other discovery tasks in medical informatics. PMID- 21658292 TI - Improving a gold standard: treating human relevance judgments of MEDLINE document pairs. AB - Given prior human judgments of the condition of an object it is possible to use these judgments to make a maximal likelihood estimate of what future human judgments of the condition of that object will be. However, if one has a reasonably large collection of similar objects and the prior human judgments of a number of judges regarding the condition of each object in the collection, then it is possible to make predictions of future human judgments for the whole collection that are superior to the simple maximal likelihood estimate for each object in isolation. This is possible because the multiple judgments over the collection allow an analysis to determine the relative value of a judge as compared with the other judges in the group and this value can be used to augment or diminish a particular judge's influence in predicting future judgments. Here we study and compare five different methods for making such improved predictions and show that each is superior to simple maximal likelihood estimates. PMID- 21658293 TI - Machine learning with naturally labeled data for identifying abbreviation definitions. AB - BACKGROUND: The rapid growth of biomedical literature requires accurate text analysis and text processing tools. Detecting abbreviations and identifying their definitions is an important component of such tools. Most existing approaches for the abbreviation definition identification task employ rule-based methods. While achieving high precision, rule-based methods are limited to the rules defined and fail to capture many uncommon definition patterns. Supervised learning techniques, which offer more flexibility in detecting abbreviation definitions, have also been applied to the problem. However, they require manually labeled training data. METHODS: In this work, we develop a machine learning algorithm for abbreviation definition identification in text which makes use of what we term naturally labeled data. Positive training examples are naturally occurring potential abbreviation-definition pairs in text. Negative training examples are generated by randomly mixing potential abbreviations with unrelated potential definitions. The machine learner is trained to distinguish between these two sets of examples. Then, the learned feature weights are used to identify the abbreviation full form. This approach does not require manually labeled training data. RESULTS: We evaluate the performance of our algorithm on the Ab3P, BIOADI and Medstract corpora. Our system demonstrated results that compare favourably to the existing Ab3P and BIOADI systems. We achieve an F-measure of 91.36% on Ab3P corpus, and an F-measure of 87.13% on BIOADI corpus which are superior to the results reported by Ab3P and BIOADI systems. Moreover, we outperform these systems in terms of recall, which is one of our goals. PMID- 21658294 TI - A structural SVM approach for reference parsing. AB - BACKGROUND: Automated extraction of bibliographic data, such as article titles, author names, abstracts, and references is essential to the affordable creation of large citation databases. References, typically appearing at the end of journal articles, can also provide valuable information for extracting other bibliographic data. Therefore, parsing individual reference to extract author, title, journal, year, etc. is sometimes a necessary preprocessing step in building citation-indexing systems. The regular structure in references enables us to consider reference parsing a sequence learning problem and to study structural Support Vector Machine (structural SVM), a newly developed structured learning algorithm on parsing references. RESULTS: In this study, we implemented structural SVM and used two types of contextual features to compare structural SVM with conventional SVM. Both methods achieve above 98% token classification accuracy and above 95% overall chunk-level accuracy for reference parsing. We also compared SVM and structural SVM to Conditional Random Field (CRF). The experimental results show that structural SVM and CRF achieve similar accuracies at token- and chunk-levels. CONCLUSIONS: When only basic observation features are used for each token, structural SVM achieves higher performance compared to SVM since it utilizes the contextual label features. However, when the contextual observation features from neighboring tokens are combined, SVM performance improves greatly, and is close to that of structural SVM after adding the second order contextual observation features. The comparison of these two methods with CRF using the same set of binary features show that both structural SVM and CRF perform better than SVM, indicating their stronger sequence learning ability in reference parsing. PMID- 21658296 TI - Genomic and stem cell policy issues: more alike than different? PMID- 21658295 TI - Recent advances in the immunogenetics of idiopathic inflammatory myopathy. AB - This review summarizes the previous and current literature on the immunogenetics of idiopathic inflammatory myopathy (IIM) and updates the research progress that has been made over the past decade. A substantial part of the genetic risk for developing adult- and juvenile-onset IIM lies within the major histocompatibility complex (MHC), and a tight relationship exists between individual human leukocyte antigen alleles and specific serological subtypes, which in turn dictate clinical disease phenotypes. Multiple genetic regions outside of the MHC are increasingly being identified in conferring IIM disease susceptibility. We are still challenged with the task of studying a serologically and clinically heterogeneous disorder that is rarer by orders of magnitude than the likes of rheumatoid arthritis. An ongoing and internationally coordinated IIM genome-wide association study may provide further insights into IIM immunogenetics. PMID- 21658298 TI - Genome Medicine: stem cells, genomics and translational research. PMID- 21658297 TI - Epigenomics of human embryonic stem cells and induced pluripotent stem cells: insights into pluripotency and implications for disease. AB - Human pluripotent cells such as human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) and their in vitro differentiation models hold great promise for regenerative medicine as they provide both a model for investigating mechanisms underlying human development and disease and a potential source of replacement cells in cellular transplantation approaches. The remarkable developmental plasticity of pluripotent cells is reflected in their unique chromatin marking and organization patterns, or epigenomes. Pluripotent cell epigenomes must organize genetic information in a way that is compatible with both the maintenance of self-renewal programs and the retention of multilineage differentiation potential. In this review, we give a brief overview of the recent technological advances in genomics that are allowing scientists to characterize and compare epigenomes of different cell types at an unprecedented scale and resolution. We then discuss how utilizing these technologies for studies of hESCs has demonstrated that certain chromatin features, including bivalent promoters, poised enhancers, and unique DNA modification patterns, are particularly pervasive in hESCs compared with differentiated cell types. We outline these unique characteristics and discuss the extent to which they are recapitulated in iPSCs. Finally, we envision broad applications of epigenomics in characterizing the quality and differentiation potential of individual pluripotent lines, and we discuss how epigenomic profiling of regulatory elements in hESCs, iPSCs and their derivatives can improve our understanding of complex human diseases and their underlying genetic variants. PMID- 21658300 TI - Glaucoma. AB - INTRODUCTION: Glaucoma is characterised by progressive optic neuropathy and peripheral visual field loss. It affects 1% to 2% of white people aged over 40 years and accounts for 8% of new blind registrations in the UK. The main risk factor for glaucoma is raised intraocular pressure, but 40% of people with glaucoma have normal intraocular pressure and only 10% of people with raised intraocular pressure are at risk of optic-nerve damage. Glaucoma is more prevalent, presents earlier, and is more difficult to control in black people than in white populations. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for established primary open-angle glaucoma, ocular hypertension, or both? What are the effects of lowering intraocular pressure in people with normal tension glaucoma? What are the effects of treatment for acute angle-closure glaucoma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 12 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: laser trabeculoplasty (alone or plus topical medical treatment), topical medical treatments, and surgical trabeculectomy. PMID- 21658299 TI - Biomarkers in solid organ transplantation: establishing personalized transplantation medicine. AB - Technological advances in molecular and in silico research have enabled significant progress towards personalized transplantation medicine. It is now possible to conduct comprehensive biomarker development studies of transplant organ pathologies, correlating genomic, transcriptomic and proteomic information from donor and recipient with clinical and histological phenotypes. Translation of these advances to the clinical setting will allow assessment of an individual patient's risk of allograft damage or accommodation. Transplantation biomarkers are needed for active monitoring of immunosuppression, to reduce patient morbidity, and to improve long-term allograft function and life expectancy. Here, we highlight recent pre- and post-transplantation biomarkers of acute and chronic allograft damage or adaptation, focusing on peripheral blood-based methodologies for non-invasive application. We then critically discuss current findings with respect to their future application in routine clinical transplantation medicine. Complement-system-associated SNPs present potential biomarkers that may be used to indicate the baseline risk for allograft damage prior to transplantation. The detection of antibodies against novel, non-HLA, MICA antigens, and the expression of cytokine genes and proteins and cytotoxicity-related genes have been correlated with allograft damage and are potential post-transplantation biomarkers indicating allograft damage at the molecular level, although these do not have clinical relevance yet. Several multi-gene expression-based biomarker panels have been identified that accurately predicted graft accommodation in liver transplant recipients and may be developed into a predictive biomarker assay. PMID- 21658301 TI - Stroke management. AB - INTRODUCTION: Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents (calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists), specialised stroke care, systemic anticoagulation (heparinoids, specific thrombin inhibitors, low molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis. PMID- 21658302 TI - Pathogenesis and clinical approaches to anticonvulsant hypersensitivity syndrome: current state of knowledge. AB - Anticonvulsant hypersensitivity syndrome (AHS) is a rare, but severe and potentially fatal, adverse reaction that occurs in patients who are treated with commonly used older anticonvulsant drugs (phenytoin, carbamazepine and phenobarbital) and/or with some newer agents (lamotrigine). Paediatric patients are at an increased risk for the development of AHS for the higher incidence of seizure disorder in the first decade of life. Hypersensitivity reactions range from simple maculopapular skin eruptions to a severe life-threatening disorder. AHS is typically associated with the development of skin rash, fever and internal organ dysfunctions. Recent evidence suggests that AHS is the result of a chemotoxic and immunologically-mediated injury, characterized by skin and mucosal bioactivation of antiepileptic drugs and by major histocompatibility complex dependent clonal expansion of T cells. Early recognition of AHS and withdrawal of anticonvulsant therapy are essential for a successful outcome. In vivo and vitro tests can be helpful for the diagnosis that actually depends essentially on clinical recognition. PMID- 21658303 TI - Molecular approach by PCR is the best method to detect the presence of Chlamydia trachomatis and to define the true agent of ocular bacterial inflammation. AB - Chlamydia trachomatis (Ct) is an atypical agent for acute, subclinical and chronic conjunctivitis in developed countries, as stated by the International League against Trachoma. In order to evaluate the presence of Ct, from a total of 3,520 patients visiting the consulting room of the Eye Clinic of the University of Chieti, Italy from 2006-2008, we enrolled 171 patients affected by occasional mild, moderate or severe conjunctivitis in a three-arm prospective open study, using traditional analysis such as Immune Fluorescent Assay and Enzyme?Linked Fluorescent Assay (IFA and ELFA) and molecular analysis with Polymerase Chain Reaction (PCR) procedure for Ct DNA research (Ct DNA). At the same time, microbiological culture was carried out for common germs and mycetes. These patients were analyzed at different subsequent times. In the first arm (Group A) of 82 patients with IFA and ELFA only 10 people (12.2%) resulted positive to Ct infection with both methods. The presence of Ct was never alone, but always overlapped with contaminants, like corynebacteria, staphylococci, streptococci and colonbacteria, randomly distributed, while no growth of mycetes was observed. Of these positive patients, only one 47-year-old female, suffering from a moderate form of ocular chlamydial infection, showed serological conversion against this infection; furthermore, this female had also been suffering from reactive arthritis for sometime. In the second arm (Group B) of 89 patients, we carried out PCR for Ct detection: 82 (94.25%) were found positive to Ct ? DNA research, with common germ growth randomly associated, without sex or age prevalence, as in group A; no mycetes were found. The third arm (Group C) included 37 negative patients from Group A with severe or moderate chronic conjunctivitis, randomly recruited between relapsing cases, with the addition of the single previously positive seroconversion case, for a total of 38 patients, who were re-evaluated by PCR Ct-DNA analysis. All these patients, negative to IFA and ELFA, were positive to Ct-DNA analysis. These data indicate a higher rate of Ct infection in patients with severe or moderate chronic conjunctivitis, resistant to usual therapies even after eradication of common germs, thus showing the advantage of introducing this molecular technique of analysis in mild to severe chronic or recurrent conjunctivitis. PMID- 21658304 TI - Novel strategies for the development of a vaccine for Parietaria allergy. AB - Specific immunotherapy is a well established and clinically proved strategy to cure allergic reactions. The impressive boost of knowledge derived from DNA recombinant technology applied to this field allowed the identification, cloning and expression of several clinically relevant allergens. Recombinant allergens can be easily produced in a pure and reproducible way with immunological properties comparable to natural allergens and matching the requirements of pharmaceutical companies. Parietaria pollinosis is a major health problem in the Mediterranean basin with prolonged symptoms. In this review we will discuss the rational approaches to design hypoallergenic derivatives of the major allergens of this pollen, their immunological properties and possible clinical future implications. PMID- 21658306 TI - Paraquat- and rotenone-induced models of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder mainly characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta. In recent years, several new genes and environmental factors have been implicated in PD, and their impact on DA neuronal cell death is slowly emerging. However, PD etiology remains unknown, whereas its pathogenesis begins to be clarified as a multifactorial cascade of deleterious factors. Recent epidemiological studies have linked exposure to environmental agents, including pesticides, with an increased risk of developing the disease. As a result, over the last two decades the "environmental hypothesis" of PD has gained considerable interest. This speculates that agricultural chemicals in the environment, by producing selective dopaminergic cell death, can contribute to the development of the disease. However, a causal role for pesticides in the etiology of PD has yet to be definitively established. Importantly, most insights into PD pathogenesis came from investigations performed in experimental models of PD, especially those produced by neurotoxins. This review presents data obtained in our laboratories along with current views on the neurotoxic actions induced by the two most popular parkinsonian pesticide neurotoxins, namely paraquat and rotenone. Although confined to these two chemicals, mechanistic studies underlying dopaminergic cell death are of the utmost importance to identify new drug targets for the treatment of PD. PMID- 21658305 TI - Allergic inflammation: role of cytokines with special emphasis on IL-4. AB - This review examines recent articles on the relationship of cytokines to allergy and inflammation with particular emphasis on interleukin (IL)-4. The objective of this article is therefore to review published studies to identify cytokines consistently involved in allergic inflammation. Proinflammatory cytokines, including IL-4, IL-5, IL-13 and GM-CSF along with TNF-alpha play a role in allergen-induced airway leukocyte recruitment and these cytokines can be generated by T mast cells and other cells. In addition, IL-9, IL-25, IL-33, IL 17, IL-27 and IFN-gamma are deeply involved in the regulation of asthma. Blocking the effect of these proinflammatory cytokines might provide new therapeutic approaches for the control of allergy and inflammation. PMID- 21658308 TI - The effects of captopril on cardiac regression, blood pressure and bradykinin components in diabetic Wistar Kyoto rats. AB - The present study examined the left ventricular wall thickness (LVWT), total urinary kallikrein, total plasma kininogen and mean arterial blood pressure (MABP) in diabetic and non-diabetic Wistar Kyoto (WKY) rats. The MABP was significantly raised (P<0.01) in diabetic WKY rats compared to the respective controls. The LVWT was also significantly (P<0.01) increased in diabetic WKY rats than that of control WKY rats. The mean total urinary kallikrein level and the mean total plasma kininogen level were higher (P<0.01) in diabetic WKY rats, when these rats were treated with captopril (40 mg/kg and 80 mg/kg) against the mean value obtained from control WKY rats. In conclusion, this investigation suggests that diabetes induced in these rats can cause hypertension, increased LVWT and changes in the BK-forming components. Captopril treatment caused reduction in MABP, regression of LVWT and alterations in bradykinin (BK)-forming components. The possible significance of these observations is discussed. PMID- 21658307 TI - Anti-TNF-alpha antibody (infliximab) therapy supports the recovery of eNOS and VEGFR2 protein expression in endothelial cells. AB - The aim of this study is to investigate the effect of sera obtained from patients of Crohn's disease treated by anti-TNF-alpha antibody (Infliximab) on the expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor receptor-2 (VEGFR2) protein in human umbilical vein endothelial cells (HUVEC) cultured in vitro. HUVEC was cultured in the presence of sera derived from patients before and after treatment, or from healthy individuals. Effects of sera on the expression of eNOS and VEGFR2 were monitored by determination of mRNA and protein levels using real time quantitative PCR and Western blot analysis, respectively. The serum of Crohn's patients contained elevated levels of TNF-alpha (34+/-1.80 pg/mL), which resulted in a decrease in the protein level of eNOS in HUVEC with a simultaneous induction of VEGFR2. Infliximab treatment normalized the expression level of these proteins by decreasing TNF-alpha level, particularly in those cases when clinical healing was also recorded, and it also conferred restitution of the level of angiogenic cytokines. Results suggest that altered angiogenesis possibly contributes to the initiation and perpetuation of inflammatory processes in inflammatory bowel disease (IBD). Endothelial dysfunction, a selective feature of Crohn's disease is beneficially affected by intravascular TNF-alpha neutralization. PMID- 21658309 TI - Eugenolol and glyceryl-isoeugenol suppress LPS-induced iNOS expression by down regulating NF-kappaB AND AP-1 through inhibition of MAPKS and AKT/IkappaBalpha signaling pathways in macrophages. AB - Eugenol and isoeugenol, two components of clover oil, have been reported to possess several biomedical properties, such as anti-inflammatory, antimicrobial and antioxidant effects. This study aims to examine the anti-inflammatory effects of eugenol, isoeugenol and four of their derivatives on expression of inducible nitric oxide synthase (iNOS) activated by lipopolysaccharide (LPS) in mouse macrophages (RAW 264.7), and to investigate molecular mechanisms underlying these effects. We found that two derivatives, eugenolol and glyceryl-isoeugenol, had potent inhibitory effects on LPS-induced upregulation of nitrite levels, iNOS protein and iNOS mRNA. In addition, they both suppressed the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) induced by LPS. Moreover, they both attenuated the DNA binding of NF-kB and AP-1, phosphorylation of inhibitory kB-alpha (IkB-alpha), and nuclear translocation of p65 protein induced by LPS. Finally, we demonstrated that glyceryl-isoeugenol suppressed the phosphorylation of ERK1/2, JNK and p38 MAPK, whereas eugenolol suppressed the phosphorylation of ERK1/2 and p38 MAPK. Taken together, these results suggest that that eugenolol and glyceryl-isoeugenol suppress LPS-induced iNOS expression by down-regulating NF-kB and AP-1 through inhibition of MAPKs and Akt/IkB-alpha signaling pathways. Thus, this study implies that eugenolol and glyceryl-isoeugenol may provide therapeutic benefits for inflammatory diseases. PMID- 21658310 TI - Complement system and rheumatoid arthritis: relationships with autoantibodies, serological, clinical features, and anti-TNF treatment. AB - Autoantibodies (rheumatoid factor, RF; anti-citrullinated-protein antibodies, ACPA) and complement system are involved in rheumatoid arthritis (RA). ACPA and anti-TNF agents are capable of in vitro modulating complement activity. We investigated the relationships between complement, autoantibodies, and anti-TNF treatment in vivo. One-hundred fourteen RA patients (89F/25M), diagnosed according to 1987 ACR criteria, and 30 healthy controls were enrolled. Serological analysis included ESR, CRP, complement C3, C4 and CH50, RF and ACPA (ELISA, cut-off>20 U/ml). Split-products (SP) of C3 and B were studied by immunoelectrophoresis/counterimmunoelectrophoresis. Seventy-six patients started anti-TNF treatment and were studied at baseline and after 22 weeks. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. At baseline, RA patients showed significantly higher levels of C3 and C4 than controls (C3 127.9+/-26.5 vs 110+/-25 mg/dl, P=0.0012; C4 29.7+/-10.2 vs 22.7+/ 8.3mg/dl, P=0.0003). No differences in C3, C4 and CH50 levels were observed between ACPA+ (n=76) and ACPA- (n=38) patients. After 22 weeks of anti-TNF, C3, C4 and RF were significantly reduced (P<0.003, <0.005 and <0.04, respectively) and RF changes showed negative correlation with CH50. SP of C3 and B were observed neither at baseline nor after 22 weeks. DAS28 significantly improved after 22 weeks. Patients showing higher baseline C3 or lower reduction of C3 levels after 22 weeks had a worse EULAR outcome (X2=22.793, P<0.001). RF levels seem to correlate with complement CH50. The presence of high levels of C3 in RA patients may reflect a pro-inflammatory status and represent a negative prognostic factor for anti-TNF therapy. PMID- 21658311 TI - A pilot study evaluating the clinical and immunomodulatory effects of an orally administered extract of Dendrobium huoshanense in children with moderate to severe recalcitrant atopic dermatitis. AB - Atopic dermatitis (AD) is a common inflammatory skin disorder for which few safe and effective systemic treatments are available. To test the clinical and immunomodulatory effects of a crude polysaccharide fraction isolated from Dendrobium huoshanense for the treatment of AD, we conducted a pilot, uncontrolled case series study. Twenty-seven patients aged 4-18 years (mean?SD, 10.82+/-4.4) with AD that had not responded to topical therapy were treated with polysaccharide derived from D. huoshanense for 4 weeks and followed-up for another 4 weeks. Progression of AD was determined with the Lund-Browder chart for children, the Investigator's Global Atopic Dermatitis Assessment (IGADA), and the Scoring Atopic Dermatitis (SCORAD) at weeks 0, 2, 4, and 8. Serum levels of cytokines were evaluated. Safety was determined with laboratory and clinical tests. The lesion area, IGADA score, total SCORAD result, and score for sleeplessness decreased significantly from weeks 0 to 4, but did not change significantly between weeks 4 and 8. The scores for subjective symptoms and pruritus decreased significantly from week 0 to week 4 and increased significantly from week 4 to week 8. Serum levels of IL-5, IL-13, IFN-gamma, and TGF-beta1 decreased significantly between weeks 0 and 4 and between weeks 0 and 8. No significant difference in the levels of IL-10 was found. The polysaccharide from D. huoshanense reduced the levels of some cytokines associated with AD and had beneficial effects on symptoms. No serious adverse effects occurred when it was administered orally for 4 weeks. PMID- 21658312 TI - Evaluation of thyroid gland function in children with obstructive apnea hypopnea syndrome. AB - Patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and thyroid function abnormalities, such as hypothyroidism and Hashimoto's thyroiditis, usually have closely resembling clinical features. Differentiation between these disorders is made more difficult because hypothyroid patients are also at risk for secondary sleep-disordered breathing. The aim of our study is to evaluate the prevalence of thyroid function abnormalities in children with OSAHS. Forty-four children (15 females: 29 males), 2.5-14.5 (7.43+/-2.98) years old were studied with overnight polysomnography. Biochemical screening of thyroid gland function was also carried out. Patients were judged to have OSAHS based mainly on the evaluation of Apnea Hypopnea index per hour of sleep (AHI). 15/44 (34.1%) children had mild OSAHS, 17/44 (38.6%) moderate and 12/44 (27.3%) severe OSAHS. Hypothyroidism was recorded only in 5/44 (11.4%) and Hashimoto's thyroiditis in 3/44 (6.8%) of OSAHS patients. Two patients with hypothyroidism showed mild and three severe OSAHS, while from the 3 children with Hashimoto's thyroiditis one presented mild, one moderate and one severe degree of OSAHS. Although the majority of studies in bibliography worldwide do not consider necessary the systemic evaluation of thyroid gland function in patients with breathing disorders during sleep, it seems that in children this type of screening is required for the differential diagnosis between primary sleep apnea and hypothyroid sleep-disordered breathing in order to differentiate these two conditions. Therefore, the laboratory investigation of thyroid gland function could be considered necessary. PMID- 21658313 TI - Characteristics of patients with respiratory allergy in France and factors influencing immunotherapy prescription: a prospective observational study (REALIS). AB - To describe the sensitization profile of respiratory allergies in France, identifying factors influencing the prescription of allergen immunotherapy (AIT) [Transversal phase (T)], and assess treatment efficacy, tolerability, compliance and satisfaction [Longitudinal phase (L)]. French allergists (600) and pneumo allergists (600) were offered participation and asked to recruit the first 20 new patients with allergic rhinitis (AR) and/or asthma, consulting for a first time allergy check-up with skin prick-test (T), and 5 patients sensitized to pollens (skin test and/or specific IgE) for whom SLIT with pollens was prescribed (L). In the T phase, 2,714 patients were recruited by 169 specialists, mostly allergists (76.5%). The majority (98%) suffered from AR, alone (57.7%) or with asthma (40.3%) and 80.3% suffered from moderate-to-severe rhinitis, mostly persistent (65.8%). Asthma, when present, was mostly intermittent (63.7%) or mild persistent (20.1%). Sensitization to house dust mites was the most common (64.5%), followed by grass pollens (61.5%), tree pollens (41.6%) and cat danders (30.5%). Poly sensitization was seen in 73.6% of patients. AIT, mostly sublingual, was recommended in 55.6% of the patients, mostly (78.1%) because of insufficient control with symptomatic treatments. The overall impact of symptoms on QOL, positive skin test to grass pollens, ocular pruritus and/or nasal obstruction and moderate-to-severe rhinitis were significant predictors of SLIT prescription. Poly-sensitization or concomitant asthma were not seen as deterrents. Most patients consulting a specialist for allergy testing suffer from moderate-to severe rhinitis. Treatment in current practice includes immunotherapy in half of the patients, and follows ARIA recommendations. PMID- 21658314 TI - Intranasal flunisolide treatment in patients with non-allergic rhinitis. AB - Non-allergic rhinitis (NAR) is a heterogeneous disease, characterized by nasal hyperreactivity and inflammation. Its treatment is still debated, intranasal corticosteroids may be an option. The present study is aimed at evaluating the effect of the use of intranasal flunisolide in patients with NAR, considering both clinical and cytological parameters. Sixty patients were treated with intranasal flunisolide (30) or saline solution (30) for 8 weeks. Symptom severity, turbinate size, and inflammatory cell counts were assessed, before and after treatment. Intranasal flunisolide induced a significant reduction of symptoms, turbinate size, and cellular infiltrate. Thus, intranasal flunisolide might be a therapeutic option for NAR. PMID- 21658315 TI - Biological effects of low frequency high intensity ultrasound application on ex vivo human adipose tissue. AB - In the present work the effects of a new low frequency, high intensity ultrasound technology on human adipose tissue ex vivo were studied. In particular, we investigated the effects of both external and surgical ultrasound-irradiation (10 min) by evaluating, other than sample weight loss and fat release, also histological architecture alteration as well apoptosis induction. The influence of saline buffer tissue-infiltration on the effects of ultrasound irradiation was also examined. The results suggest that, in our experimental conditions, both transcutaneous and surgical ultrasound exposure caused a significant weight loss and fat release. This effect was more relevant when the ultrasound intensity was set at 100 % (~2.5 W/cm2, for external device; ~19-21 W/cm2, for surgical device) compared to 70 % (~1.8 W/cm2 for external device; ~13-14 W/cm2 for surgical device). Of note, the effectiveness of ultrasound was much higher when the tissue samples were previously infiltrated with saline buffer, in accordance with the knowledge that ultrasonic waves in aqueous solution better propagate with a consequently more efficient cavitation process. Moreover, the overall effects of ultrasound irradiation did not appear immediately after treatment but persisted over time, being significantly more relevant at 18 h from the end of ultrasound irradiation. Evaluation of histological characteristics of ultrasound-irradiated samples showed a clear alteration of adipose tissue architecture as well a prominent destruction of collagen fibers which were dependent on ultrasound intensity and most relevant in saline buffer-infiltrated samples. The structural changes of collagen bundles present between the lobules of fat cells were confirmed through scanning electron microscopy (SEM) which clearly demonstrated how ultrasound exposure induced a drastic reduction in the compactness of the adipose connective tissue and an irregular arrangement of the fibers with a consequent alteration in the spatial architecture. The analysis of the composition of lipids in the fat released from adipose tissue after ultrasound treatment with surgical device showed, in agreement with the level of adipocyte damage, a significant increase mainly of triglycerides and cholesterol. Finally, ultrasound exposure had been shown to induce apoptosis as shown by the appearance DNA fragmentation. Accordingly, ultrasound treatment led to down-modulation of procaspase-9 expression and an increased level of caspase-3 active form. PMID- 21658316 TI - Analysis of inflammatory and immune response biomarkers in sputum and exhaled breath condensate by a multi-parametric biochip array in cystic fibrosis. AB - Cystic Fibrosis (CF) lung disease is characterized by high levels of cytokines and chemokines in the airways, producing chronic inflammation. Non-invasive biomarkers, which are also specific for the inflammatory and immune responses, are urgently needed to identify exacerbations and evaluate therapeutic efficacy. The aim of this study is to evaluate the association of sputum and exhaled breath condensate (EBC) biomarker changes with clinical exacerbation and response to therapy. We studied the simultaneous presence and concentration of twelve cytokines and growth factors (EGF, IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-gamma, MCP-1, TNF-alpha and VEGF) by a multi-parametric biochip array in sputum and EBC of 24 CF patients before, after 6 and 15 days of therapy, and 15 days after the end of treatment for an acute exacerbation. Correlations with functional respiratory tests (FEV1, FVC) and the systemic marker C-reactive protein (CRP) were looked for. In sputum, before therapy, VEGF and IL-1beta levels positively correlated with the respiratory function and CRP. Sputum IL 1alpha, IL-1beta IL-4, IL-10, TNF-alpha, and VEGF significantly decreased, while EGF increased, during therapy. IL-8 and IL-4 levels negatively correlated with the respiratory function at 15 and 30 days from the start of therapy, respectively. IL-4, IL-6, IL-10 and TNF-alpha positively correlated with CRP during therapy. Although some EBC biomarkers correlated with respiratory function and CRP, no significant associations with these clinical parameters were found. Sputum IL-1beta and VEGF might be considered biomarkers of an acute exacerbation in CF patients. A panel of sputum cytokines and growth factors may better describe the response to intravenous antibiotic treatment of CF than one single systemic marker. PMID- 21658317 TI - Procalcitonin, C-reactive protein, interleukin-6, and soluble intercellular adhesion molecule-1 as markers of postoperative orthopaedic joint prosthesis infections. AB - There is a universally recognized need to identify new, reliable markers of inflammation that can aid in the rapid diagnosis of orthopaedic joint prosthesis infections (OJP-Is). Since prompt diagnosis is key to timely intervention in the course of infection, different molecules have been studied. In this study, we examined three groups of patients: those with prosthesis infection, those without infection, and a third group with previous infection in whom the infection had been cleared. Four presumed markers of infection were tested: procalcitonin (PCT); C-reactive protein (CRP); interleukin-6 (IL-6); and soluble intercellular adhesion molecule-1 (sICAM-1). The results showed that PCT cannot be considered as a good marker of periprosthetic infection as no statistically significant difference in serum PCT levels emerged between patients with infection and controls or patients without infection. In contrast, both sICAM-1 and CRP may be considered as good markers of infection, as measurement of their levels allowed us to distinguish between patients with and without infection, and between patients with infection and those with previous infection, since marker levels quickly returned to baseline values after clearance of the infection. IL-6 was found to be a good marker for inflammation, as it distinguished between patients with infection and the other groups. In the patients with previous infection, the IL-6 values remained high versus the controls but lower and with a statistically significant difference versus the patients with infection. Further studies are needed to determine the cut-off value of IL-6 between patients with infection and those with previous infection. PMID- 21658318 TI - Use of complementary and alternative medicine in children with recurrent acute otitis media in Italy. AB - Controlling environmental factors, chemoprophylaxis, immunoprophylaxis and surgery are considered possible means of preventing recurrent acute otitis media (RAOM), but there are no available data concerning the paediatric use of complementary and alternative medicine (CAM). We evaluated the uses of CAM (homeopathy and/or herbal medicine) as means of preventing AOM in children with a history of RAOM. Eight hundred and forty Italian children with RAOM (>=3 episodes in six months) aged 1-7 years were surveyed in 2009 using a face-to-face questionnaire, filled by parents or caregivers, that explored the prevalence, determinants, reasons, cost, and perceived safety and efficacy of CAM. About one half (46%) of the children used CAM, significantly more than the number who used immunoprophylaxis (influenza vaccine 15%; p<0.05), PCV-7 34%; p<0.05) or chemoprophylaxis (2%; p<0.001). Use of CAM in the family was the only important factor positively associated with the use of CAM in children (adjusted OR 7.94; 95% CI: 5.26-11.99). The main reasons for using CAM were a fear of the adverse effects of conventional medicine (40%) and to increase host defences (20%). CAM was widely seen as safe (95%) and highly effective (68%). CAM prescribers were paediatricians in 50.7% of cases; self-initiation was reported by 23% of respondents. CAM expenditure was between Euro 25 and Euro 50/month in 27.6% of cases and >= Euro 50/month in 16%. Children with RAOM should be considered among the categories of subjects likely to be using CAM. Together with the fact that paediatricians are the main prescribers, this is worrying because of the current lack of evidence regarding the efficacy, safety and cost-effectiveness of CAM in the prevention of RAOM. PMID- 21658319 TI - Inflammatory cells, cytokines and matrix metalloproteinases in amicrobial pustulosis of the folds and other neutrophilic dermatoses. AB - Amicrobial pustulosis of the folds (APF) is a rare cutaneous disease characterized by relapsing sterile pustules frequently associated with autoimmune disorders. Although APF pathophysiology is still undefined, scattered reports suggest involvement of neutrophils. The aim of the present study is to evaluate the role of the skin inflammatory infiltrate, selected multifunctional cytokines and effectors of tissue damage in APF and other neutrophilic dermatoses. We studied, by immunohistochemical methods, inflammatory cell markers (CD3, CD163, myeloperoxidase), cytokines (TNF-alpha, IL-8, IL-17), metalloproteinases (MMP-2, MMP-9) and vascular-endothelial-growth-factor (VEGF) in lesional skin from six patients with APF, 11 with pyoderma gangrenosum (PG), 7 with Sweet's syndrome, and in 20 normal skin samples. Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-alpha, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in APF, PG and Sweet's syndrome than in controls (p=0.0001). IL-8 was more expressed in PG than in APF (P=0.002) and Sweet's syndrome (p=0.001). In APF, MMP-9 reactivity was higher than in Sweet's syndrome (p=0.035), but less intense than in PG (p=0.020). Our study supports the role of proinflammatory cytokines/chemokines and MMPs as important effectors for the tissue damage in APF similarly to classic neutrophilic dermatoses. PMID- 21658320 TI - Prognostic implication of high risk human papillomavirus E6 and E7 mRNA in patients with intraepithelial lesions of the cervix in relationship to age. AB - Since the introduction of the cytological screening programs, a significant reduction in the incidence of cervical cancer has been achieved. Almost all of these cancers are related to high-risk (HR) Human Papillomavirus (HPV) cervical infections. However, the natural history of HPV infection seems to be different in younger patients, resulting in a higher rate of regression. There is, therefore, the need to identify HPV-related biomarkers in order to enhance the effectiveness of screening of high-risk cytological lesions, in particular in women over 35 years of age. This study aims to evaluate the prognostic value of the HR HPV E6 and E7 mRNA expression in women with intraepithelial lesions of the cervix, older or younger than 35 years of age. One hundred and eighty-four HR HPV DNA positive patients with a low squamous intraepithelial lesion (LSIL) were tested for mRNA expressions, included in an observational study, and evaluated at follow-up with standard cytology up to 24 months from the mRNA test. The frequency of HSIL/LSIL cytology in the older cohort of mRNA positive patients was significantly higher compared to mRNA-negative patients, both at 1 and 2 years of follow-up (Chi-square: p 0.007 and p 0.009), but this difference was not found in the younger cohort. According to our results, the E6/E7 mRNA test could be a biomarker for viral activity, useful in identifying patients at higher risk of abnormal cytology, and in implementing the management of HR HPV DNA-positive women over 35 years of age. PMID- 21658321 TI - Exhaled nitric oxide levels in children with chronic adenotonsillar disease. AB - Exhaled nitric oxide (eNO) is a highly reactive biological mediator that has recently been associated with chronic tonsillar disease in adults, but there are no published data concerning eNO levels in their pediatric counterparts. The aim of this study is to measure mean eNO levels in children with chronic adenotonsillitis or adenotonsillar hypertrophy, and assess the effects of potential confounding factors. Children aged 3-17 years were divided into three groups (chronic adenotonsillitis, adenotonsillar hypertrophy and controls). Their eNO levels were measured in accordance with the international guidelines, and their other clinical and anamnestic characteristics were recorded. The mean eNO level in the children with chronic adenotonsillitis was slightly higher than that in the other groups, but there was no statistically significant between-group difference. Age (p=0.009), allergy (p=0.05) and body mass index (p=0.03), but not the mean grade of adenoidal or tonsil hypertrophy, were all statistically related to mean eNO levels. These preliminary results indicate the lack of an increase in mean eNO levels in children with chronic adenotonsillar disease, with no substantial difference between children with chronic adenotonsillitis and those with adenotonsillar hypertrophy. PMID- 21658322 TI - Anti-laminin-1 antibodies in sera and follicular fluid of women with endometriosis undergoing in vitro fertilization. AB - There is increasing evidence that autoimmune phenomena, including auto-antibody production, may affect fertility in women with endometriosis. The aims of this study are to evaluate anti-laminin-1 antibody (aLN-1) presence in sera and in follicular fluids (FF) of women with endometriosis undergoing IVF and its impact on oocyte maturation and IVF outcome. aLN-1 were measured by a home-made enzyme linked immunosorbent assay in sera and FF obtained from 35 infertile women with endometriosis and in sera from 50 fertile controls and 27 infertile women without endometriosis (IWWE). aLN-1 serum levels were significantly higher in women with endometriosis in comparison with both fertile controls and IWWE (P<0.001 and P<0.05, respectively) and a positive correlation was found between serum- and FF aLN-1 (r=0.47, P=0.004). According to the cut-off (mean+3 SD of fertile controls), 31% of women with endometriosis were aLN-1 positive. Metaphase II oocyte counts showed inverse correlation with FF-aLN-1 levels (r=-0.549, P=0.0006). Ongoing pregnancy (i.e pregnancy progressing beyond the 12th week of gestation) occurred in 4/11 aLN-1 positive patients and in 7/24 aLN-1 negative with no significant difference (P=0.7). In conclusion, our results highlight that aLN-1 are increased in women with endometriosis and their presence in FF may affect oocyte maturation leading to a reduced fertility. However, aLN-1 seem to have no effect on IVF outcome. PMID- 21658324 TI - Immunogenicity of an interferon-beta1a product. AB - In order to determine whether Blastoferon(r), a biosimilar interferon (IFN)- beta 1a formulation, shares epitopes with other known IFN-beta products, a series of neutralization bioassays were performed with a set of well-characterized anti-IFN beta monoclonal antibodies and human sera (World Health Organization Reference Reagents). The bioassay was the interferon-induced inhibition of virus cytopathic effect on human cells in culture (EMC virus and A-549 cells). Computer-calculated results were reported as Tenfold Reduction Units (TRU)/ml. To further assess Blastoferon(r) immunogenicity, in vivo production of anti-IFN beta antibodies was determined in sera of patients included in the pharmacovigilance plan of Blastoferon(r) by the level of IFN- beta 1a binding antibodies (by enzyme immunoassay -EIA) and neutralizing antibodies (in the Wish-VSV system). The highly characterized neutralizing monoclonal antibodies A1 and A5 that bind to specific regions of the IFN- beta molecule reacted positively with the three beta 1a IFNs: Blastoferon(r), Rebif(r), and the IFN- beta WHO Second International Standard 00/572. As expected, the non-neutralizing monoclonal antibodies B4 and B7 did not neutralize any of the IFN- beta preparations. The commercially available monoclonal antibody B-02 reacted essentially equally with Rebif(r) and Blastoferon(r). The WHO Reference Reagent human serum anti-IFN- beta polyclonal antibody neutralized all the IFN- beta products, whereas the WHO Reference Reagent human serum anti-IFN-alpha polyclonal antibody G037-501-572 appropriately failed to react with any of the IFN- beta products. On the basis of in vitro reactivity with known, well-characterized monoclonal and polyclonal antibody preparations, Blastoferon(r) shares immunological determinants with other human interferon- beta products, especially IFN- beta 1a. In vivo antibodies were detected by EIA in 72.9% of 37 chronically treated multiple sclerosis patients, whereas neutralizing antibodies were found in 8.1% of them. Blastoferon(r) appears to have immunological characteristics comparable to other IFN- beta 1a products. PMID- 21658325 TI - Adenosine A2A receptor polymorphisms in Korean patients with systemic sclerosis. AB - Adenosine A2A receptor (ADORA2A) regulates inflammation, promotes tissue repair and collagen production by human dermal fibroblasts. We investigated the genetic polymorphisms of ADORA2A in susceptibility to systemic sclerosis (SSc). We genotyped 142 Korean SSc patients and 150 controls for polymorphisms of -1751A/C (rs5996696) and 1976C/T (rs5751876), to cover the promoter and all exon sequences of ADORA2A in Koreans, using TaqMan fluorogenic 5' nuclease assay and single base primer extension assay. Neither -1751A/C nor 1976C/T polymorphism showed difference in the distribution of alleles or genotypes between patients and controls with allele frequency of 89.9% v 91.0% for -1751A (p=0.64) and 56.5% v 54.0% for 1976C (p=0.55). Our findings suggest that the role of ADORA2A in SSc may not be genetically related. PMID- 21658323 TI - Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis. AB - Papillary urothelial neoplasia of low malignant potential (PUNLMP) recurs in approximately 35% of patients. Conventional histopathological assessment does not distinguish non-recurrent from recurrent PUNLMP. The aim of this study is to explore the differences in global histone acetylation and global DNA methylation between non-recurrent and recurrent PUNLMP. Acetylated histone H3 lysine 9 (AcH3K9) and 5-methylcytosine (5MeC) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). The total optical density of the nuclear staining was measured photometrically in at least 40 nuclei separately for the basal, intermediate and luminal positions in each case. Concerning the total optical density values for both acetylation and methylation, a decrease in staining is observed from non recurrent PUNLMP to recurrent PUNLMP, at all nuclear locations. For acetylation the mean value in non-recurrent PUNLMP, intermediate between NU and UC, is closer to the former than to latter. The mean value in recurrent PUNLMP is closer to UC than to NU. In NU, non-recurrent and recurrent PUNLMP, the acetylation to methylation ratio decreased from the nuclei in basal position to those in the surface, the average for the above groups being 1.491, 1.611 and 1.746, respectively. Setting the observed values for NU at each sampling location to unity, acetylation shows a steady decrease, the percentages of changes in this nuclear location compared to NU being -5% in non-recurrent PUNLMP, -15% in recurrent PUNLMP and -24% in UC. Concerning methylation, there is a slight increase in non-recurrent PUNLMP (+5%), a decrease in recurrent PUNLMP (-19%) followed by a sharp rise for the UC (+61%). In conclusion, there are differences in global histone acetylation and DNA methylation patterns between non-recurrent and recurrent PUNLMP. Further studies are needed to elucidate the complex interplay between chromatin structure, its modifications and recurrence of PUNLMP. PMID- 21658327 TI - Friday asthma crisis in the daughter of two bakers. AB - The prevalence of sesame food allergy continues to increase worldwide. The diagnostic tools to confirm such allergy include skin prick tests, specific IgEs and food challenge. We report the case of a 7-year-old girl who presented recurrent episodes of wheezing and dyspnoea. After performing skin tests and evaluating specific IgEs we hypothesised an allergy to sesame. Our patient actually benefitted from avoiding any contact with sesame and sesame seeds. We confirmed our diagnosis through an inhalation food challenge. Further, by reviewing her personal history, we suspect inhalation was the mechanism in which the girl became sensitised to sesame. PMID- 21658326 TI - Exaggerated imiquimod application site reactions in the context of systemic tumor necrosis factor-alpha inhibition: more than a coincidental occurrence? AB - Topical imiquimod and tumor necrosis factor (TNF)-alpha inhibitors have gained wide acceptance as safe and effective treatments for non-melanoma skin cancer (NMSC) and moderate to severe psoriasis, respectively. While mild to moderate application site reactions (ASRs) are a well-known and common phenomenon associated with imiquimod, the potential of TNF-alpha blockers to elicit cutaneous inflammatory reactions has only recently been recognized. We present two cases of severe, atypical ASRs which occurred during NMSC treatment with imiquimod in the context of infliximab administration for psoriasis, and consider the grounds supporting a non-fortuitous association. To date, no relation has ever been suggested between TNF-alpha inhibitors and increased susceptibility to developing exaggerated ASRs with imiquimod. We believe that this subject deserves further analysis; meanwhile, increased attention should be drawn to the possibility of this adverse interaction, as simultaneous treatment with TNF-alpha blockers and imiquimod is becoming increasingly frequent in daily practice. PMID- 21658329 TI - Ulerythema ophryogenes, a rare and often misdiagnosed syndrome: analysis of an idiopathic case. AB - Keratosis pilaris (KP) is a follicular hyperkeratosis disorder which is frequently detected in the adult population (44%), mostly in female adolescents (80%). It is a genetic autodominant dermatosis with variable penetrance, but no specific gene association has been determined, even though association to the presence of chromosome 18p deletion has been reported in some cases. We report the case of a 51-year-old Caucasian woman affected by keratosis pilaris gradually progressing with age and with a story of multiple abortions. Standard karyotype and CGH array analyses did not reveal any genetic abnormality. Virological analyses detected the presence of HPV 36 DNA inside the dorsum biopsy, leading to hypothesize its involvement in the evolution of the lesion. Clinical history and patient examination led the diagnosis of an idiopathic case of Ulerythema ophryogenes. The analysis of more cases could be useful to verify the involvement of cutaneous HPV in the progression of the clinical manifestation of the KP variants. PMID- 21658328 TI - Diagnostic failure of ciprofloxacin-induced spontaneous bilateral Achilles tendon rupture: case-report and medical-legal considerations. AB - Rare side-effects of fluoroquinolone therapy are tendinitis and tendon rupture. Many reports have demonstrated that the concomitant use of corticosteroids, in patients aged 60 years or older, increase the risk substantially. We present a case of spontaneous bilateral Achilles tendon rupture induced by ciprofloxacin and methylprednisolone. A 61-year-old woman was diagnosed with Bronchiolitis Obliterans with Organizing Pneumonia (BOOP) and was started on oral ciprofloxacin 500 mg twice daily for 3 weeks and on oral methylprednisolone 16 mg twice daily for 2 weeks. The diagnosis was made after doctors, rather than stop drug therapy and advise complete rest, had mistakenly prescribed for the woman to undergo physiotherapy and local NSAIDs, thus favoring the onset of tendon ruptures and resulting in surgical and legal implications. Inspired by this case, we also submit a brief review on professional liability in Orthopaedics. PMID- 21658330 TI - Platelet amyloid precursor protein isoform expression in Alzheimer's disease: evidence for peripheral marker. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by a progressive cognitive and memory decline. Among peripheral markers of AD, great interest has been focused on the amyloid precursor protein (APP). In this regard, platelets represent an important peripheral source of APP since it has been demonstrated that the three major isoforms, that are constituted of 770, 751 and 695 aa residues, are inserted in the membrane of resting platelets. APP 751 and APP 770 contain a Kunitz-type serine protease inhibitor domain (APP KPI) and APP 695 lacks this domain. To address this issue, we first examined the platelet APP isoform mRNAs prospectively as biomarker for the diagnosis of AD by means of real time quantitative PCR, and then evaluated the correlation between APP mRNA expression levels and cognitive impairment of enrolled subjects. Differential gene expression measurements in the AD patient group (n=18) revealed a significant up-regulation of APP TOT (1.52-fold), APP KPI (1.32-fold), APP 770 (1.33-fold) and APP 751 (1.26-fold) compared to controls (n=22). Moreover, a statistically significant positive correlation was found between APP mRNA levels (TOT, KPI, 770 and 751) and cognitive impairment. Since AD definitive diagnosis still relies on pathological evaluation at autopsy, the present results are consistent with the hypothesis that platelet APP could be considered a potential reliable peripheral marker for studying AD and could contribute to define a signature for the presence of AD pathology. PMID- 21658331 TI - Lactose intolerance in systemic nickel allergy syndrome. AB - Some patients affected by nickel-contact allergy present digestive symptoms in addition to systemic cutaneous manifestations, falling under the condition known as systemic nickel allergy syndrome (SNAS). A nickel-related pro-inflammatory status has been documented at intestinal mucosal level. The aim of the present study is to evaluate the prevalence of lactose intolerance in patients affected by SNAS compared to a healthy population. Consecutive patients affected by SNAS referring to our departments were enrolled. The control population consisted of healthy subjects without gastrointestinal symptoms. All subjects enrolled underwent lactose breath test under standard conditions. One hundred and seventy eight SNAS patients and 60 healthy controls were enrolled. Positivity of lactose breath test occurred in 74.7% of the SNAS group compared to 6.6% of the control group. Lactose intolerance is highly prevalent in our series of patients affected by SNAS. Based on our preliminary results, we can hypothesize that in SNAS patients, the nickel-induced pro-inflammatory status could temporarily impair the brush border enzymatic functions, resulting in hypolactasia. Further trials evaluating the effect of a nickel-low diet regimen on lactase activity, histological features and immunological pattern are needed. PMID- 21658332 TI - Cervical follicular dendritic cell sarcoma: a case report and review of the literature. AB - Follicular dendritic cell (FDC) sarcoma is a rare tumour with a low-to intermediate grade of malignancy. It frequently occurs in cervical, mediastinal and axillary lymph nodes. In approximately 30% of cases an extranodal localization has been reported (tonsils, oral cavity, mediastinum, liver, and spleen). Very little is known about possible treatment options and overall prognosis. This case reports a 66 year-old patient, who underwent surgical removal of a persistently enlarged right cervical lymph node. The histopathological examination revealed a spindle cell tumour with lymphocyte and plasma cell infiltrates. Neoplastic cells stained positive for CD21, CD23 and CD35, thus confirming the diagnosis of FDC sarcoma. The neoplasm recurred two years later and partial regression was achieved by IGEV rescue therapy. We briefly discuss clinical history, histopathological differential diagnosis and treatment options of FDC sarcoma. PMID- 21658333 TI - Erythema multiforme-like irritant contact dermatitis after application of an antiscabies treatment. AB - We describe the case of an irritant contact dermatitis due to an antiscabies treatment in a man who presented to our clinic with an important cutaneous reaction with many hemorrhagic, "target" erythema multiforme-like lesions, as the result of an acute toxic insult of the skin by permethrin 5%. This is a possible, but very uncommon symptom of non-eczematous contact dermatitis and an unusual drug causing the acute hypersensitivity reaction typical of erythema multiforme. PMID- 21658334 TI - Deep wound infection following pediatric scoliosis surgery: incidence and analysis of risk factors. AB - BACKGROUND: Deep wound infection after spinal surgery is a severe complication that often requires prolonged medical and surgical management. It can compromise the outcome of the deformity correction, especially in patients requiring surgical intervention with subsequent removal of implants. Ascertaining the incidence and risk factors leading to infection may help to prevent this problem. METHODS: We reviewed the hospital charts of all patients who underwent spinal deformity correction from 1996 to 2005. RESULTS: In all, 227 patients were identified (139 idiopathic, 57 neuromuscular, 8 syndromic, 6 congenital, 17 other); 191 patients were treated with posterior instrumentation and fusion, 11 with anterior-only procedures and 24 with combined anterior and posterior procedures. Final follow-up ranged from 1 to 9.5 years. Infection developed in 14 patients. The overall incidence of infection was 6.2%. Drainage and back pain were the most common presenting symptoms. The incidence of infection was higher among patients with nonidiopathic diagnoses (risk ratio [RR] 8.65, p < 0.001). Use of allograft bone was associated with a higher rate of infection (RR 9.66, p < 0.001) even when stratified by diagnosis (nonidiopathic diagnoses, RR 7.6, p = 0.012). Higher volume of instrumentation was also a risk factor for infection (p = 0.022). Coagulase-negative Staphyloccocus was the most commonly identified organism, followed by Propionibacterium acnes and Pseudomonas. CONCLUSION: Development of infection following scoliosis surgery was found to be associated with several risk factors, including a nonidiopathic diagnosis, the use of allograft and a higher volume of instrumentation. Preventative measures addressing these factors may decrease the rate of infection. PMID- 21658336 TI - Canadian clinical practice guidelines for acute and chronic rhinosinusitis. Executive summary. PMID- 21658337 TI - Canadian clinical practice guidelines for acute and chronic rhinosinusitis. AB - This document provides health care practitioners with information regarding the management of acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS) to enable them to better meet the needs of this patient population. These guidelines describe controversies in the management of acute bacterial rhinosinusitis (ABRS) and include recommendations that take into account changes in the bacteriologic landscape. Recent guidelines in ABRS have been released by American and European groups as recently as 2007, but these are either limited in their coverage of the subject of CRS, do not follow an evidence-based strategy, or omit relevant stakeholders in the development of guidelines and do not address the particulars of the Canadian health care environment.Advances in understanding the pathophysiology of CRS, along with the development of appropriate therapeutic strategies, have improved outcomes for patients with CRS. CRS now affects large numbers of patients globally, and primary care practitioners are confronted by this disease on a daily basis. Although initially considered a chronic bacterial infection, CRS is now recognized as having multiple distinct components (eg, infection, inflammation), which have led to changes in therapeutic approaches (eg, increased use of corticosteroids). The role of bacteria in the persistence of chronic infections and the roles of surgical and medical management are evolving. Although evidence is limited, guidance for managing patients with CRS would help practitioners less experienced in this area offer rational care. It is no longer reasonable to manage CRS as a prolonged version of ARS, but, rather, specific therapeutic strategies adapted to pathogenesis must be developed and diffused.Guidelines must take into account all available evidence and incorporate these in an unbiased fashion into management recommendations based on the quality of evidence, therapeutic benefit, and risks incurred. This document is focused on readability rather than completeness yet covers relevant information, offers summaries of areas where considerable evidence exists, and provides recommendations with an assessment of the strength of the evidence base and the degree of endorsement by the multidisciplinary expert group preparing the document.These guidelines have been copublished in both Allergy, Asthma, and Clinical Immunology and the Journal of Otolaryngology-Head and Neck Surgery. PMID- 21658341 TI - Bipolar disorder self-assessment. AB - Bipolar disorder is a complex condition that is difficult to diagnose and treat, and many patients with this illness are not receiving adequate care, particularly in the early stages of the disorder when effective treatment is most critical. Self-Assessment CME is an educational activity in which clinicians answer a series of multiple-choice questions to ascertain their current knowledge and practice in treating CNS disorders. After completing the self-assessment, clinicians have the opportunity to review correct answers, see how their colleagues responded, and receive recommendations for further reading. This Self Assessment CME activity focuses on recognizing and bridging gaps in knowledge pertaining to bipolar disorder recognition and treatment. PMID- 21658342 TI - Assessing adolescents using ADHD rating scales. AB - Children with ADHD will often continue to have the disorder through adolescence, although individual symptoms may lessen or change, so their symptoms will need to be reassessed over time. In addition, adolescence is a transitional period in which youths experience new tasks and developmental challenges that may reveal impairments due to ADHD that were not apparent earlier. Evaluating for ADHD can be complicated by the differing symptoms seen in adolescents compared with children and the difficulty in obtaining a longitudinal history of symptoms. Various rating scales are available that can help clinicians to evaluate symptom frequency and severity and establish impairment when diagnosing adolescents with ADHD. Rating scales are also useful for establishing a baseline for symptoms, delineating individual symptoms as treatment targets, and measuring treatment success in patients with ADHD. PMID- 21658343 TI - Treatment-resistant depression: prevalence, risk factors, and treatment strategies. AB - Full symptomatic remission is the optimal outcome for patients with major depression. Unfortunately, initial antidepressant efficacy is limited to partial response for many patients. Incomplete remission of depressive symptoms is associated with increased risk of relapse, decreased functioning in work and social settings, and increased risk of suicide. Factors that increase the likelihood of treatment resistance include chronicity, severe symptomatology, and comorbid illnesses. Strategies to manage patients who do not respond to an initial course of antidepressant medication include optimizing the dose, switching antidepressants, or adding adjunctive treatment (ie, psychotherapy or a second medication). Augmentation may be the preferred strategy for improving response if tolerability to the original agent is acceptable and the initial medication has had some beneficial effects. Tracking patients' depressive symptoms with standardized measurement tools during the course of treatment is necessary for identifying incomplete remission and providing appropriate treatment modification. PMID- 21658346 TI - Child murder and mental illness in parents: implications for psychiatrists. PMID- 21658347 TI - Work hours, sleep sufficiency, and prevalence of depression among full-time employees: a community-based cross-sectional study. AB - OBJECTIVE: Depression due to long work hours and sleep deprivation is a major occupational health concern. The extent to which work hours and sleep are associated with depression was investigated in employees of small- and medium scale businesses in the Japanese city of Yashio, Saitama, and in the Ohta ward of Tokyo, a suburb of Tokyo, controlling for various potential confounders. METHOD: In this cross-sectional study, a total of 2,643 full-time employees (1,928 men and 715 women), aged 18-79 years (mean = 45 years), in 296 small- and medium scale businesses were surveyed from August 2002 to December 2002 using a self administered questionnaire evaluating work hours, sleep status, and covariates including sociodemographic and socioeconomic factors, health behaviors, biological factors, medication usage, and occupational factors. Depression was assessed using the Center for Epidemiologic Studies Depression Scale. Prevalence of depression by work hours, sleep status, and covariates was analyzed by chi2 test. Risk of depression by work hours, sleep status, and both combined was estimated by multivariate logistic regression analysis. RESULTS: Participants working > 10 hours per day, sleeping < 6 hours per day, and reporting insufficient sleep were, respectively, 37%, 43%, and 97% more likely to be depressed than those working 6 to 8 hours per day, sleeping 6 to < 8 hours per day, and reporting sufficient sleep (P < .05). Participants working > 10 hours per day or > 8 to 10 hours per day with < 6 hours per day of sleep showed a 41% 169% higher prevalence of depression versus those working 6 to 8 hours per day with 6+ hours per day of sleep (P < .05). Participants reporting insufficient sleep in 3 work-hour categories (6 to 8, > 8 to 10, and > 10 hours per day) showed a 62%-179% increase in the prevalence of depression versus those working 6 to 8 hours per day and reporting sufficient sleep (P < .05). No significant effects on depression were found for subjects in any work-hour category with 6+ hours of sleep or with subjective sufficient sleep. CONCLUSIONS: Depression associated with long work hours is primarily a result of sleep deprivation. Greater attention should be paid to management of sleep deprivation to prevent workplace depression. PMID- 21658345 TI - Antidepressants and risks of suicide and suicide attempts: a 27-year observational study. AB - OBJECTIVE: The 2007 revision of the black box warning for suicidality with antidepressants states that patients of all ages who initiate antidepressants should be monitored for clinical worsening or suicidality. The objective of this study was to examine the association of antidepressants with suicide attempts and with suicide deaths. METHOD: A longitudinal, observational study of mood disorders with prospective assessments for up to 27 years was conducted at 5 US academic medical centers. The study sample included 757 participants who enrolled from 1979 to 1981 during an episode of mania, depression, or schizoaffective disorder, each based on Research Diagnostic Criteria. Unlike randomized controlled clinical trials of antidepressants, the analyses included participants with psychiatric and other medical comorbidity and those receiving acute or maintenance therapy, polypharmacy, or no psychopharmacologic treatment at all. Over follow-up, these participants had 6,716 time periods that were classified as either exposed to an antidepressant or not exposed. Propensity score-adjusted mixed-effects survival analyses were used to examine risk of suicide attempt or suicide, the primary outcome. RESULTS: The propensity model showed that antidepressant therapy was significantly more likely when participants' symptom severity was greater (odds ratio [OR] = 1.16; 95% CI, 1.12-1.21; z = 8.22; P < .001) or when it was worsening (OR = 1.69; 95% CI, 1.50-1.89; z = 9.02; P < .001). Quintile-stratified, propensity-adjusted safety analyses using mixed effects grouped-time survival models indicate that the risk of suicide attempts or suicides was reduced by 20% among participants taking antidepressants (hazard ratio, 0.80; 95% CI, 0.68-0.95; z = -2.54; P = .011). CONCLUSIONS: This longitudinal study of a broadly generalizable cohort found that, although those with more severe affective syndromes were more likely to initiate treatment, antidepressants were associated with a significant reduction in the risk of suicidal behavior. Nonetheless, we believe that clinicians must closely monitor patients when an antidepressant is initiated. PMID- 21658348 TI - Developments in pediatric psychopharmacology: focus on stimulants, antidepressants, and antipsychotics. AB - Most major psychiatric disorders have an onset in childhood or adolescence in a sizeable proportion of patients, and earlier onset disorders often have a severe and chronic course that can seriously disrupt sensitive developmental periods, with lifelong adverse consequences. Accordingly, psychopharmacologic treatments have been increasingly utilized in severely ill youth. However, the increased use of psychopharmacologic treatments in pediatric patients has also raised concerns regarding a potential overdiagnosis and overtreatment of youth, without adequate data regarding the pediatric efficacy and safety of psychotropic agents. Over the past decade, a remarkable number of pediatric randomized controlled trials have been completed, especially with psychostimulants, antidepressants, and antipsychotics. For these frequently used agents, effect sizes against placebo have typically been at least moderate, with most numbers-needed-to-treat well below 10 for response, indicating clinical significance as well. Nevertheless, data also point to a greater and/or different profile of susceptibility to adverse effects in pediatric compared to adult patients, as well as to a role for nonpharmacologic treatments, given alone or combined with pharmacotherapy, for many of the youth. Taken together, these results highlight the need for a careful assessment of the risk-benefit relationship of psychopharmacologic treatments in patients who cannot be managed sufficiently with nonpharmacologic interventions and for routine, proactive adverse effect monitoring and management. Although considerable progress has been made, there is still enormous need for additional data and funding of pediatric psychopharmacology trials. It is hoped that the field will acquire the necessary resources to propel pediatric clinical psychopharmacology to new levels of insight by linking it with, but not replacing it by, pharmacoepidemiologic and biomarker approaches and advances. PMID- 21658349 TI - Exercise as an augmentation treatment for nonremitted major depressive disorder: a randomized, parallel dose comparison. AB - OBJECTIVE: Most patients with major depressive disorder (MDD) require second-step treatments to achieve remission. The Treatment with Exercise Augmentation for Depression (TREAD) study was designed to test the efficacy of aerobic exercise as an augmentation treatment for MDD patients who had not remitted with antidepressant treatment. METHOD: Eligible participants in this randomized controlled trial were sedentary individuals (men and women aged 18-70 years) diagnosed with DSM-IV nonpsychotic MDD who had not remitted with selective serotonin reuptake inhibitor (SSRI) treatment. Participants were recruited through physician referrals and advertisements. A total of 126 participants were randomized to augmentation treatment with either 16 kcal per kg per week (KKW) or 4 KKW of exercise expenditure for 12 weeks while SSRI treatment was held constant. Supervised sessions were conducted at The Cooper Institute, Dallas, Texas, with additional home-based sessions as needed to fulfill the weekly exercise prescription. The primary outcome was remission (as determined by a score <= 12 on the Inventory of Depressive Symptomatology, Clinician-Rated). The study took place between August 2003 and August 2007. RESULTS: There were significant improvements over time for both groups combined (F1,121 = 39.9, P < .0001), without differential group effect (group effect: F1,134 = 3.2, P = .07; group-by-time effect: F1,119 = 3.8, P = .06). Adjusted remission rates at week 12 were 28.3% versus 15.5% for the 16-KKW and 4-KKW groups, respectively, leading to a number needed to treat (NNT) of 7.8 for 16 KKW versus 4 KKW. Men, regardless of family history of mental illness, and women without a family history of mental illness had higher remission rates by week 12 with higher-dose (women, 39.0%; men, 85.4%) than with lower-dose exercise (women, 5.6%; men, 0.1%) (women: t95 = 2.1, P = .04; men: t88 = 5.4, P < .0001) (NNT: women, 3.0; men, 1.2). CONCLUSIONS: There was a trend for higher remission rates in the higher-dose exercise group (P < .06), with a clinically meaningful NNT of 7.8 in favor of the high exercise dose. Significant differences between groups were found when the moderating effects of gender and family history of mental illness were taken into account and suggest that higher-dose exercise may be better for all men and for women without a family history of mental illness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00076258. PMID- 21658351 TI - The pharmacologic treatment of bipolar disorder. AB - Over the past half century, substantial clinical trial data have accumulated to guide clinical management of bipolar disorder, and 13 medications have gained US Food and Drug Administration approval for the treatment of mania or bipolar depression or the maintenance treatment of bipolar disorder. While the number of studies has grown and many controversies related to pharmacologic treatment of bipolar disorder are not yet resolved, the task of transforming the accumulated evidence into useful guidance for clinical practice becomes more manageable and less error prone by limiting consideration to the highest quality studies. Therefore, this article emphasizes points of relative clarity by highlighting findings supported by double-blind, placebo-controlled clinical trials with samples of at least 100 subjects. A MEDLINE search was conducted and augmented by a manual search of bibliographies, textbooks, and abstracts from recent scientific meetings for randomized controlled trials published in English between 1950 and April 2010 with at least 100 subjects. Keywords used in the search included randomized controlled trial, mania, hypomania, depression, relapse prevention, placebo, antidepressant, switch, and maintenance treatment of bipolar disorder. A paradigm for implementing evidence-based treatment is offered along with consideration of patterns emerging across clinical trials. PMID- 21658352 TI - Integrated medical care for patients with bipolar disorder: who will be the principal physician? PMID- 21658350 TI - Emotion dysregulation and negative affect: association with psychiatric symptoms. AB - OBJECTIVE: A growing body of research focuses on the development and correlates of emotion dysregulation, or deficits in the ability to regulate intense and shifting emotional states. Current models of psychopathology have incorporated the construct of emotion dysregulation, suggesting its unique and interactive contributions, along with childhood disruptive experiences and negative affect, in producing symptomatic distress. Some researchers have suggested that emotion dysregulation is simply a variant of high negative affect. The aim of this study was to assess the construct and incremental validity of self-reported emotion dysregulation over and above childhood trauma and negative affect in predicting a range of psychopathology. METHOD: Five hundred thirty individuals aged 18 to 77 years (62% female) were recruited from the waiting areas of the general medical and obstetric/gynecologic clinics in an urban public hospital in Atlanta, Georgia. Participants completed a battery of self-report measures obtained by interview, including the Childhood Trauma Questionnaire, the Positive and Negative Affect Schedule, and the Emotion Dysregulation Scale. Regression analyses examined the unique and incremental associations of these self-report measurements of childhood traumatic experiences, negative affect, and emotion dysregulation with concurrent structured interview-based measurements of psychiatric distress and history of self-destructive behaviors. These measures included the Clinician-Administered PTSD Scale, the Alcohol Use Disorders Identification Test, the Short Drug Abuse Screening Test, the Beck Depression Inventory, and the Global Adaptive Functioning Scale from the Longitudinal Interval Follow-Up Evaluation. The presented data were collected between 2005 and 2009. RESULTS: Regression models including age, gender, childhood trauma, negative affect, and emotion dysregulation were significantly (P <= .001) associated with each of the study's criterion variables, accounting for large portions of the variance in posttraumatic stress symptoms (R2 = 0.21), alcohol and drug abuse (R2 = 0.28 and 0.21, respectively), depression (R2 = 0.55), adaptive functioning (R2 = 0.14), and suicide history (omnibus chi2 = 74.80, P < .001). Emotion dysregulation added statistically significant (P < .01) incremental validity to each regression model (beta = 0.25, 0.34, 0.35, 0.34, and -0.18, and Wald = 24.43, respectively). CONCLUSIONS: Results support the conceptualization of emotion dysregulation as a distinct and clinically meaningful construct associated with psychiatric distress that is not reducible to negative affect. Emotion dysregulation is a key component in a range of psychiatric symptoms and disorders and a core target for psychopharmacologic and psychosocial treatment interventions. PMID- 21658353 TI - Voltage-gated potassium channel/LGI1 antibody-associated encephalopathy may cause brief psychotic disorder. PMID- 21658355 TI - Suicidal risk during antidepressant treatment. PMID- 21658356 TI - Does combat trauma cause a majority of PTSD symptoms in combat Veterans? PMID- 21658357 TI - Sleep and circadian rhythm disturbances in bipolar disorder: an urgent need for objective assessment and systematic follow-up. PMID- 21658359 TI - Comparative embryotoxicity of pulp mill extracts in rainbow trout (Oncorhynchus mykiss), American flagfish (Jordanella floridae) and Japanese medaka (Oryzias latipes). AB - This study evaluated the effects of Chilean pulp mill effluent extracts (untreated, primary and secondary treated pulp mill effluents), along with steroid standards (testosterone and 17beta-estradiol) and a wood extractive standard (beta-sitosterol) on developing post-fertilized fish embryos. Our study included a cold freshwater species, rainbow trout (Oncorhynchus mykiss), and two warm freshwater species American flagfish (Jordanella floridae) and Japanese medaka (Oryzias latipes). Embryotoxicity results included delay in time to hatch and decreased hatchability but no significant egg and larvae mortality was observed in the pulp mill extract exposed embryos. By contrast, significant early hatching and increased hatchability were observed in beta-sitosterol exposed embryos, along with high mortality of testosterone exposed embryos across species. Teratogenic responses were observed in medaka embryos in all treatments. Abnormalities were detected starting at development stages 19-20 (2-4 somite stages) and included optical deformities (micro-opthalmia, 1 or 2 eyes) and lack of development of brains and hearts. Additionally, phenotypic sex identification of surviving offspring found female-biased sex-ratios in all treatments except testosterone across species. Overall, our study indicated that Chilean pulp and paper mill extractives caused embryotoxicity (post-fertilized embryos) across species and irrespective of the effluent treatment. The effects were mainly associated with delayed time to hatch, decreased hatchability, and species specific teratogenesis. PMID- 21658360 TI - Biological effects of marine contaminated sediments on Sparus aurata juveniles. AB - Chemical analysis of the compounds present in sediment, although informative, often is not indicative of the downstream biological effects that these contaminants exert on resident aquatic organisms. More direct molecular methods are needed to determine if marine life is affected by exposure to sediments. In this study, we used an aquatic multi-species microarray and q-PCR to investigate the effects on gene expression in juvenile sea bream (Sparus aurata) of two contaminated sediments defined as sediment 1 and 2, respectively, from marine areas in Northern Italy. Both sediments affected gene expression as evidenced by aquatic multi-species microarray analysis and q-PCR. Exposure of S. aurata juveniles to sediment 1 and sediment 2 altered expression of genes that are biomarkers for endocrine disruption. There were differences between the effects of sediment 1 and sediment 2 on gene expression in S. aurata juveniles indicating that the chemicals in the two sediments had different physiological targets. These results suggest that the classification of sediment solely on the basis of specific chemical profiles is inadequate, and not a true indicator of its potential to cause harmful effects. Our data also indicate that integration of physiochemical analysis and bioassays for monitoring the downstream harmful effects on aquatic organisms are required to gain a complete understanding of the effects of sediment on aquatic life. PMID- 21658361 TI - Cloning, expression, purification and kinetics of trehalose-6-phosphate phosphatase of filarial parasite Brugia malayi. AB - The pleiotropic functions of disaccharide trehalose in the biology of nematodes and its absence from mammalian cells suggest that its biosynthesis may provide a useful target for developing novel nematicidal drugs. The trehalose-6-phosphate phosphatase (TPP), one of the enzymes of trehalose metabolism has not been characterized so far in nematodes except the free living nematode Caenorhabditis elegans where it's silencing results into lethal outcomes. This prompted us to clone and characterize Brugia malayi TPP in order to discover novel antifilarial drug target. The recombinant protein (Bm-TPP) was purified with apparent homogeneity on a metal ion column and it was found to possess high phosphatase activity with robust specificity for the substrate trehalose-6-phosphate. Bm-TPP was found to be a member of the HAD-like hydrolase super family II based on the conserved motifs required for catalytic reaction. The K(m) for substrate trehalose-6-phosphate was around 0.42 mM with pH optimum ~7.0 and the enzyme showed an almost absolute requirement for Mg(2+) as a metal ion. Bm-TPP was expressed in all the life-stages of B. malayi. In the absence of an effective macrofilaricidal agent and validated antifilarial drug target, Bm-TPP bodes well as a rational drug target against lymphatic filariasis. PMID- 21658362 TI - Quantification of protein-bound sodium dodecyl sulfate by Rhodamine B: a method for identification of kinetically stable proteins. AB - Sodium dodecyl sulfate (SDS) bound to proteins in solution could be estimated by passing through Extracti-Gel that removes free SDS followed by specific interaction of the fluorophore Rhodamine B with protein-bound SDS. The resulting fluorescence intensity is compared with a calibration curve. Whereas globular proteins respond to binding of 1.4 mg SDS/mg protein under native conditions, "kinetically stable" proteins that are otherwise resistant to denaturation due to structural integrity show a low level of SDS binding. Analysis of the circular dichroism spectrum shows that in spite of the low level of SDS binding to kinetically stable proteins under nondenaturing conditions, the detergent generates considerable secondary structure in these proteins. Because the low level of SDS binding is a general feature of kinetically stable proteins, the protocol may fulfill one of the criteria to classify a protein as kinetically stable. PMID- 21658363 TI - Interleukin-10 down-regulates oxLDL induced expression of scavenger receptor A and Bak-1 in macrophages derived from THP-1 cells. AB - Here, we investigated the therapeutic potential of IL-10 by testing its effects on oxLDL-induced lipoprotein uptake and apoptosis by flow cytometry in THP-1 derived macrophages. The mRNA and protein expressions of lipid scavenger receptors (SR-A, CD36) and apoptosis-related proteins (Bcl-2, Bak-1) were also detected. Co-incubation of oxLDL with IL-10 reduced DiI-oxLDL uptake by 16.1+/ 3.8%, 35.2+/-3.8% and 28.9+/-1.8% at 6, 12 and 24h of treatment, respectively. Furthermore, treatment with oxLDL for 24h enhanced the SR-A mRNA and protein expressions by 89.3+/-17.1% and 70.1+/-17.6%, respectively. IL-10 abrogated the oxLDL-induced SR-A mRNA expression by 50.2+/-3.9% and its protein by 45.6+/-1.9%. Meanwhile IL-10 had no effect on the oxLDL-induced increase of CD36 expression. IL-10 inhibited the oxLDL-induced cell apoptosis in a time-dependent manner by 17.3+/-3.3%, 36.4+/-2.8% and 31.0+/-4.3% at 6, 12 and 24h, respectively. OxLDL increased Bak-1 mRNA and protein expressions by 38.4+/-13.3% and 36.9+/-12.1%, respectively. However co-stimulation of oxLDL with IL-10 for 24h inhibited Bak-1 expression to 28.4+/-7.2% (mRNA) and 25.7+/-6.3% (protein). Meanwhile, IL-10 had no effect on the oxLDL-induced decrease of Bcl-2 expression. Our findings suggested that IL-10 reduced the oxLDL-induced lipoprotein uptake and apoptosis partly via down-regulating the oxLDL-induced expression of SR-A and Bak-1 in THP 1-derived macrophages. PMID- 21658364 TI - Genipin up-regulates heme oxygenase-1 via PI3-kinase-JNK1/2-Nrf2 signaling pathway to enhance the anti-inflammatory capacity in RAW264.7 macrophages. AB - Genipin, an aglycon of geniposide, has been reported to exhibit diverse pharmacological functions such as antitumor and anti-inflammatory effects. This study aimed to elucidate the anti-inflammatory mechanism of genipin, focusing particularly on the role of heme oxygenase-1 (HO-1), a potent anti-inflammatory enzyme. In RAW264.7 cells, genipin increased HO-1 expression and its enzyme activity via a NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. These effects were significantly inhibited by exposure to the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, or by expression of a dominant negative mutant of PI 3-kinase. Additional experiments showed that the activation of c-Jun NH(2)-terminal kinase 1/2 (JNK1/2) is required for genipin-induced phosphorylation and nuclear translocation of Nrf2 and antioxidant response element (ARE)-driven induction of HO-1, and acts as a downstream effector of PI 3-kinase. Furthermore, functional significance of HO-1 induction was revealed by genipin-mediated inhibition of lipopolysaccharide-stimulated inducible nitric oxide synthase expression or cyclooxygenase-2 promoter activity, the response was reversed by the blocking of HO-1 protein synthesis or HO-1 enzyme activity. Therefore, identification of PI 3-kinase-JNK1/2-Nrf2-linked signaling cascade in genipin-mediated HO-1 expression defines the signaling event that could participate in genipin-mediated anti-inflammatory response. PMID- 21658365 TI - Inhibition of proton pumping in membrane reconstituted bovine heart cytochrome c oxidase by zinc binding at the inner matrix side. AB - A study is presented on the effect of zinc binding at the matrix side, on the proton pump of purified liposome reconstituted bovine heart cytochrome c oxidase (COV). Internally trapped Zn(2+) resulted in 50% decoupling of the proton pump at level flow. Analysis of the pH dependence of inhibition by internal Zn(2+) of proton release in the oxidative and reductive phases of the catalytic cycle of cytochrome c oxidase indicates that Zn(2+) suppresses two of the four proton pumping steps in the cycle, those taking place when the 2 OH(-) produced in the reduction of O(2) at the binuclear center are protonated to 2 H(2)O. This decoupling effect could be associated with Zn(2+) induced conformational alteration of an acid/base cluster linked to heme a(3). PMID- 21658367 TI - Tissue factor dependent liver injury causes release of retinoid receptors (RXR alpha and RAR-alpha) as lipid droplets. AB - Hepatic stellate cells (HSC) store retinoids and upon activation differentiate into myofibroblast-like cells, a process whereby they lose their retinoid containing lipid droplets. We reported earlier, activation of tissue factor (TF) in our MCT/LPS hepatotoxicity model. We now report the involvement of TF in the release of retinoid receptors RAR-alpha and RXR-alpha as accumulated lipid droplet during monocrotaline/lipopolysaccharide (MCT/LPS)-liver injury. Constitutive expression of RAR-alpha was observed in HSCs and endothelial cells of bile duct and portal vein, while expression of RXR-alpha was observed in certain pericentral hepatocytes and HSCs. Administration of sub-toxic doses of MCT or LPS strongly increased TF and RXR-alpha but not RAR-alpha expressions in HSCs and hepatocytes. However MCT/LPS co-treatment showed insoluble droplets containing RAR-alpha and RXR-alpha in the vicinity of the necrotic areas. Blocking TF with TF antisense oligonucleotides (TF-AS ODN) led to normal hepatocyte expression of RXR-alpha and upregulated the expression of RAR-alpha in HSCs. This study shows clear evidence of in vivo release of RAR-alpha and RXR alpha as insoluble lipid droplets in liver injury. It is possible that these insoluble droplets of RAR-alpha and RXR-alpha could be used as markers for liver injury in general and activation of HSCs in particular. RXR-alpha appears to be a more sensitive than RAR-alpha as it was affected by even the subtoxic doses of MCT or LPS. The fact that TF-AS treatment not only down-regulated TF but also obliterated the release of RAR-alpha and RXR-alpha as insoluble lipid droplets in hepatocytes points towards TF being an important regulatory molecule for RAR alpha and RXR-alpha. PMID- 21658366 TI - Structure of the lipodepsipeptide syringomycin E in phospholipids and sodium dodecylsulphate micelle studied by circular dichroism, NMR spectroscopy and molecular dynamics. AB - Syringomycin E (SRE) is a member of a family of lipodepsipeptides that characterize the secondary metabolism of the plant-associated bacteria Pseudomonas syringae pv. syringae. It displays phytotoxic, antifungal and haemolytic activities, due to the membrane interaction and ion channel formation. To gain an insight into the conformation of SRE in the membrane environment, we studied the conformation of SRE bound to SDS micelle, a suitable model for the membrane-bound SRE. In fact, highly similar circular dichroism (CD) spectra were obtained for SRE bound to sodium dodecylsulphate (SDS) and to a phospholipid bilayer, indicating the conformational equivalence of SRE in these two media, at difference with the CD spectrum of SRE in water solution. The structure of SDS bound SRE was determined by NMR spectroscopy combined with molecular dynamics calculations in octane environment. The results of this study highlight the influence of the interaction with lipids in determining the three-dimensional structure of SRE and provide the basis for further investigations on structural determinants of syringomycin E-membrane interaction. PMID- 21658368 TI - Characterization of a putative cis-regulatory element that controls transcriptional activity of the pig uroplakin II gene promoter. AB - Uroplakin II (UPII) is a one of the integral membrane proteins synthesized as a major differentiation product of mammalian urothelium. UPII gene expression is bladder specific and differentiation dependent, but little is known about its transcription response elements and molecular mechanism. To identify the cis regulatory elements in the pig UPII (pUPII) gene promoter region, we constructed pUPII 5' upstream region deletion mutants and demonstrated that each of the deletion mutants participates in controlling the expression of the pUPII gene in human bladder carcinoma RT4 cells. We also identified a new core promoter region and putative negative cis-regulatory element within a minimal promoter region. In addition, we showed that hepatocyte nuclear factor 4 (HNF4) can directly bind in the pUPII core promoter (5F-1) region, which plays a critical role in controlling promoter activity. Transient cotransfection experiments showed that HNF4 positively regulates pUPII gene promoter activity. Thus, the binding element and its binding protein, HNF4 transcription factor, may be involved in the mechanism that specifically regulates pUPII gene transcription. PMID- 21658369 TI - Expression of the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) potentiates the effects of GnRH on gonadotropin subunit gene expression. AB - We examined the effect of the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) on gonadotropin-releasing hormone (GnRH)-induced gonadotropin subunit promoter activities using the LbetaT2 gonadotroph cell line. In mock transfected cells, GnRH-increased LHbeta and FSHbeta promoters up to 2.74 +/- 0.15-fold and 1.6 +/- 0.05-fold respectively. When cells were transfected with PAC1R, both LHbeta and FSHbeta promoter activities were further increased up to 6.1 +/- 0.87-fold and 2.22 +/- 0.43-fold following GnRH stimulation. ERK phosphorylation, serum response element (SRE) promoters, and cAMP response element (CRE) promoters stimulated by GnRH were also potentiated in the presence of increasing amounts of PAC1R. The EC50 values for LHbeta and FSHbeta gene transcription by GnRH were significantly decreased by overexpression of PAC1R. PACAP 6-38, a PACAP receptor antagonist, failed to reduce the effect of GnRH on gonadotropin promoter activities in PAC1R overexpressing cells, suggesting that the potentiation of the effects of GnRH by PAC1R expression was not related to an autocrine mechanism of PACAP produced in the gonadotrophs. Our current results show that the action of GnRH in the regulation of gonadotropin subunit expression is enhanced by the presence of PAC1Rs. PMID- 21658370 TI - The TCP4 transcription factor of Arabidopsis blocks cell division in yeast at G1 >S transition. AB - The TCP transcription factors control important aspects of plant development. Members of class I TCP proteins promote cell cycle by regulating genes directly involved in cell proliferation. In contrast, members of class II TCP proteins repress cell division. While it has been postulated that class II proteins induce differentiation signal, their exact role on cell cycle has not been studied. Here, we report that TCP4, a class II TCP protein from Arabidopsis that repress cell proliferation in developing leaves, inhibits cell division by blocking G1->S transition in budding yeast. Cells expressing TCP4 protein with increased transcriptional activity fail to progress beyond G1 phase. By analyzing global transcriptional status of these cells, we show that expression of a number of cell cycle genes is altered. The possible mechanism of G1->S arrest is discussed. PMID- 21658371 TI - Generation of a Slc39a8 hypomorph mouse: markedly decreased ZIP8 Zn2+/(HCO3-)2 transporter expression. AB - Previously this laboratory has identified the mouse Slc39a8 gene encoding the ZIP8 transporter, important in cadmium uptake. ZIP8 functions endogenously as a electroneutral Zn(2+)/(HCO(3)(-))(2) symporter, moving both ions into the cell. The overall physiological importance of ZIP8 remains unclear. Herein we describe generation of a mouse line carrying the Slc39a8(neo) allele, containing the Frt flanked neomycin-resistance (neo) mini-cassette in intron 3 and loxP sites in introns 3 and 6. Cre recombinase functions correctly in Escherichia coli and in adeno-Cre-infected mouse fetal fibroblasts, but does not function in the intact mouse for reasons not clear. Slc39a8(neo) is a hypomorphic allele, because Slc39a8(neo/neo) homozygotes exhibit dramatically decreased ZIP8 expression in embryo, fetus, and visceral yolk sac - in comparison to their littermate wild type controls. This ZIP8 hypomorph will be instrumental in studying developmental and in utero physiological functions of the ZIP8 transporter. PMID- 21658372 TI - Intracytoplasmic sperm injection induces transcriptome perturbation without any transgenerational effect. AB - Faithful transcriptome regulation is important in development and also crucial for applications in reproductive and regenerative medicine. Intracytoplasmic sperm injection (ICSI), one of the human assisted reproductive technologies (ART), has long raised concerns about its influence on development. No clear consensus has been reached, however, in spite of many cohort studies carried out in the last two decades on the children conceived by ICSI and/or in vitro fertilization (IVF). In this study, the pre- and postnatal effects of ICSI were assessed using comprehensive transcriptome and phenotypic analyses in mice under strict conditions. Here we demonstrate that, in contrast to IVF, ICSI induces distinct long-lasting transcriptome change that remains at the neonatal stage. Importantly, no remarkable differences were observed in the ICSI adults in either the gene expression or phenotypic profiles, and there was no indication of transmission to the next generation via natural mating. Our results suggest there are no lifelong or transgenerational effects of ICSI, but the ICSI effects during neonatal period remain to be evaluated. PMID- 21658373 TI - The cytostatic activity of NUC-3073, a phosphoramidate prodrug of 5-fluoro-2' deoxyuridine, is independent of activation by thymidine kinase and insensitive to degradation by phosphorolytic enzymes. AB - A novel phosphoramidate nucleotide prodrug of the anticancer nucleoside analogue 5-fluoro-2'-deoxyuridine (5-FdUrd) was synthesized and evaluated for its cytostatic activity. Whereas 5-FdUrd substantially lost its cytostatic potential in thymidine kinase (TK)-deficient murine leukaemia L1210 and human lymphocyte CEM cell cultures, NUC-3073 markedly kept its antiproliferative activity in TK deficient tumour cells, and thus is largely independent of intracellular TK activity to exert its cytostatic action. NUC-3073 was found to inhibit thymidylate synthase (TS) in the TK-deficient and wild-type cell lines at drug concentrations that correlated well with its cytostatic activity in these cells. NUC-3073 does not seem to be susceptible to inactivation by catabolic enzymes such as thymidine phosphorylase (TP) and uridine phosphorylase (UP). These findings are in line with our observations that 5-FdUrd, but not NUC-3073, substantially loses its cytostatic potential in the presence of TP-expressing mycoplasmas in the tumour cell cultures. Therefore, we propose NUC-3073 as a novel 5-FdUrd phosphoramidate prodrug that (i) may circumvent potential resistance mechanisms of tumour cells (e.g. decreased TK activity) and (ii) is not degraded by catabolic enzymes such as TP which is often upregulated in tumour cells or expressed in mycoplasma-infected tumour tissue. PMID- 21658374 TI - Targeting siglecs--a novel pharmacological strategy for immuno- and glycotherapy. AB - The immune system must be tightly held in check to avoid bystander tissue damage as well as autoreactivity caused by overwhelming immune reactions. A novel family of immunoregulatory, carbohydrate-binding receptors, the Siglecs (sialic acid binding immunoglobulin-like lectins), has received particular attention in light of their capacity to mediate cell death, anti-proliferative effects and to regulate a variety of cellular activities. Siglec receptors are mainly expressed on leukocytes in a cell type-specific and differentiation-dependent manner. Siglecs might potentially be exploited as targets of novel immune- and glycotherapeutics for cell-directed therapies in autoimmune and allergic diseases, as well as in haematologic malignancies. Here we present novel insights on structural and functional characteristics, expression patterns and evolutionary aspects of Siglecs and their ligands. Pharmacological strategies using Siglec agonistic cross-linking therapeutics, such as monoclonal or engineered antibodies, intravenous immunoglobulin (IVIG), or glycomimetics are discussed. Modulation of immune responses by targeting Siglecs using agonistic or antagonistic therapeutics may have important clinical implications and may pave the way for novel pharmacological avenues for the treatment of autoimmune and allergic diseases or for tumor immunotherapy. PMID- 21658375 TI - Gene expression suggests conserved mechanisms patterning the heads of insects and myriapods. AB - Segmentation, i.e. the subdivision of the body into serially homologous units, is one of the hallmarks of the arthropods. Arthropod segmentation is best understood in the fly Drosophila melanogaster. But different from the situation in most arthropods in this species all segments are formed from the early blastoderm (so called long-germ developmental mode). In most other arthropods only the anterior segments are formed in a similar way (so called short-germ developmental mode). Posterior segments are added one at a time or in pairs of two from a posterior segment addition zone. The segmentation mechanisms are not universally conserved among arthropods and only little is known about the genetic patterning of the anterior segments. Here we present the expression patterns of the insect head patterning gene orthologs hunchback (hb), orthodenticle (otd), buttonhead-like (btdl), collier (col), cap-n-collar (cnc) and crocodile (croc), and the trunk gap gene Kruppel (Kr) in the myriapod Glomeris marginata. Conserved expression of these genes in insects and a myriapod suggests that the anterior segmentation system may be conserved in at least these two classes of arthropods. This finding implies that the anterior patterning mechanism already existed in the last common ancestor of insects and myriapods. PMID- 21658377 TI - Functional potencies of dopamine agonists and antagonists at human dopamine D2 and D3 receptors. AB - We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (+/-)-7-hydroxy-N,N-di-n-propyl-2 aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia. PMID- 21658376 TI - Muscles in a mouse model of spinal muscular atrophy show profound defects in neuromuscular development even in the absence of failure in neuromuscular transmission or loss of motor neurons. AB - A mouse model of the devastating human disease "spinal muscular atrophy" (SMA) was used to investigate the severe muscle weakness and spasticity that precede the death of these animals near the end of the 2nd postnatal week. Counts of motor units to the soleus muscle as well as of axons in the soleus muscle nerve showed no loss of motor neurons. Similarly, neither immunostaining of neuromuscular junctions nor the measurement of the tension generated by nerve stimulation gave evidence of any significant impairment in neuromuscular transmission, even when animals were maintained up to 5days longer via a supplementary diet. However, the muscles were clearly weaker, generating less than half their normal tension. Weakness in 3 muscles examined in the study appears due to a severe but uniform reduction in muscle fiber size. The size reduction results from a failure of muscle fibers to grow during early postnatal development and, in soleus, to a reduction in number of fibers generated. Neuromuscular development is severely delayed in these mutant animals: expression of myosin heavy chain isoforms, the elimination of polyneuronal innervation, the maturation in the shape of the AChR plaque, the arrival of SCs at the junctions and their coverage of the nerve terminal, the development of junctional folds. Thus, if SMA in this particular mouse is a disease of motor neurons, it can act in a manner that does not result in their death or disconnection from their targets but nonetheless alters many aspects of neuromuscular development. PMID- 21658378 TI - Antidiabetic activity of gamma-sitosterol isolated from Lippia nodiflora L. in streptozotocin induced diabetic rats. AB - Lippia nodiflora L. (Verbenaceae) is a creeping perennial herb widely used in traditional system of medicine to treat ulcers, bronchitis and heart diseases; it also possesses antidiabetic property. In the present study, gamma-sitosterol isolated from Lippia nodiflora was screened for its antidiabetic property in streptozotocin (STZ) induced diabetic rats. Insulin secretion in response to glucose was evaluated in isolated rat islets. Oral administration of gamma sitosterol (20 mg/kg body weight) once daily for 21 days in STZ-induced diabetic rats resulted in a significant decrease in blood glucose and glycosylated hemoglobin with a significant increase in plasma insulin level, body weight and food intake. Furthermore gamma-sitosterol showed antihyperlipidemic activity as evidenced by significant decrease in serum total cholesterol, triglycerides and very low density lipoprotein-cholesterol levels coupled with elevation of high density lipoprotein-cholesterol levels in treated rats. A significant decrease in the activities of alanine aminotransaminase, aspartate aminotransaminase, alkaline phosphatase and acid phosphatase in gamma-sitosterol treated rats when compared to diabetic control rats indicated its protective role against liver damage. gamma-Sitosterol increased insulin secretion in response to glucose. Immunohistochemical study of pancreas also confirmed the biochemical findings. These results indicated that gamma-sitosterol, the compound isolated from L. nodiflora, possessed antihyperglycemic activity. PMID- 21658379 TI - Antipsychotic effects of N-desmethylclozapine on sensorimotor gating function in rats--possible involvement of activation of M(1) muscarinic receptors. AB - N-desmethylclozapine (NDMC), one of the major metabolites of clozapine, has been demonstrated to exhibit partial agonistic activity at M(1) muscarinic receptors in vitro. Behavioral effects of NDMC were examined to determine whether NDMC contributed to the antipsychotic effects of clozapine via activation of muscarinic receptors. Both NDMC (10-30 mg/kg) and its parent compound clozapine (3-10 mg/kg) antagonized the disruption of prepulse inhibition (PPI) caused by the indirect dopamine agonist methamphetamine (3 mg/kg) in rats. However, NDMC (30 mg/kg) did not increase plasma levels of prolactin in rats. The same dose ranges of NDMC antagonized the disruption of PPI caused by the N-methyl-D aspartate receptor antagonist ketamine (5 mg/kg) in rats. Furthermore, NDMC in the same dose ranges antagonized the disruption of PPI caused by the muscarinic receptor antagonist scopolamine (0.3 mg/kg) in rats. These findings suggest that NDMC has potent antipsychotic effects in animal models to examine sensorimotor gating function, and that NDMC may act through the activation of a muscarinic receptor for the treatment of schizophrenia. PMID- 21658380 TI - Possible involvement of beta-endorphin in docosahexaenoic acid-induced antinociception. AB - We have previously demonstrated that the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) has an antinociceptive effect on various pain stimuli in a naloxone-reversible manner. In the present study, the role of the endogenous opioid peptide beta-endorphin in DHA-induced antinociception was examined. DHA induced antinociception was abolished when mice were pretreated with the MU opioid receptor antagonist beta-funaltrexamine (beta-FNA) and the delta-opioid receptor antagonist naltrindole, but not by the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) in the acetic acid-induced writhing test. In the radioligand binding assay, DHA itself did not have affinity for MU- , delta- or kappa-opioid receptors. On the other hand, the pretreatment of anti-beta endorphin antiserum inhibited DHA-induced antinociception. Furthermore, the intracerebroventricular injection of DHA dose-dependently reduced writhing behavior, and this effect was inhibited by d-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH(2) (CTOP) and naltrindole, but not nor-BNI. beta-endorphin-induced antinociception was inhibited by the pretreatment of beta-FNA, but not naltrindole or nor-BNI, and its levels in plasma were increased by DHA treatment. These findings suggest that the induction of antinociception by DHA may partially involve the MU-opioid receptor via the release of beta-endorphin. PMID- 21658381 TI - Fusion of core pathways reveals a horizontal synergistic mechanism underlying combination therapy. AB - Combination therapies have recently been shown to be more effective than monotherapies that may provide synergistic effects in the treatment of stroke, but its selective mechanism still remains unclear. Based on the median-effect method, the combination therapy of jasminoidin and ursodeoxycholic acid had a synergic effect on reducing the infarct volume. The numbers of up- or down regulated genes by at least 1.5-fold in the vehicle, jasminoidin, ursodeoxycholic acid, and the combination of jasminoidin and ursodeoxycholic acid treatment groups were 228, 95, 136, and 101, respectively. According to clustering and principal component analysis, the pattern of gene expression in the combination group was similar to that of jasminoidin group rather than ursodeoxycholic acid group. Based on these nine top sequences in the combination group excluding four overlapping pathways (MAPK-ERK, Kitlg, Icam1-Ap1, and prolactin), the jasminoidin group had four (PRLR-STAT1, AcvR2-AcvR1B, ACVR1/2A-SMAD1, GHR-NF-kappaB) contributing pathways, and the ursodeoxycholic acid group had one (IL-6) contributing pathway. Based on the multiple-pathway-dependent comparison analysis (MPDCA), it may lead to the conclusion that jasminoidin possibly contributes more important pharmacological effect in the combined treatment as jasminoidin regulated 80% of the pathways that the combination group mediated. The study reveals a horizontal synergistic effect by optimizing the fusion of more pathways from the compounds with more contribution to the combination therapy. Rather than selecting compounds only based on experience in the past, this study would give a new insight into the systematic strategies for designing synergistic combination therapies. PMID- 21658382 TI - ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment. AB - Elisidepsin is a marine-derived anti-tumor agent with unique mechanism of action. It has been suggested to induce necrosis associated with severe membrane damage. Since indirect evidence points to the involvement of ErbB receptor tyrosine kinases and lipid rafts in the mechanism of action of elisidepsin, we investigated the effect of the drug on the distribution of ErbB proteins and systematically compared the elisidepsin sensitivity of cell lines overexpressing ErbB receptors. Stable expression of a single member of the ErbB family (ErbB1-3) or co-transfection of ErbB2 and ErbB3 did not modify the elisidepsin sensitivity of CHO and A431 cells. However, elisidepsin induced the redistribution of ErbB3 and two GPI-anchored proteins (transfected GPI-anchored eGFP and placental alkaline phosphatase) from the plasma membrane to intracellular vesicles without comparable effects on ErbB1 and ErbB2. Elisidepsin increased the binding of a conformational sensitive anti-ErbB3 antibody without modifying the binding of other ErbB2 or ErbB3 antibodies, and it decreased the homoassociation of both ErbB2 and ErbB3. We also found that elisidepsin decreased the fluorescence anisotropy of a membrane specific fluorescent probe and induced a blue shift in the emission spectrum of Laurdan pointing to significant changes in the order of the plasma membrane possibly associated with the formation of liquid ordered domains. Although the distribution of ErbB proteins is preferentially altered by elisidepsin, our data question their role in determining sensitivity to the drug. We assume that induction of liquid ordered domains is the primary action of elisidepsin leading to all the other observed changes. PMID- 21658383 TI - Apoptotic effect of imatinib on human colon adenocarcinoma cells: influence on actin cytoskeleton organization and cell migration. AB - Imatinib mesylate (STI571) is the first member of a new class of agents that act by inhibiting specific tyrosine kinases, rather than killing all rapidly dividing cells. This drug is usually used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. It was recognized to inhibit activity of kinases such as Bcr/Abl, platelet-derived growth factor receptor, and c-kit. These proteins play important roles in cell growth, motility, and survival. Therefore, studies on the biological effects of imatinib on different cellular models are very important. Human colon adenocarcinoma LS180 cell line was used in the studies presented. Cells were exposed to 0.1-100 MUM imatinib for 24 and 48 h. Dose-dependent decreases in cell viability and morphological changes were observed. Moreover, the apoptotic effect of imatinib (10 MUM, 50 MUM) after 24 h of exposure was demonstrated as evaluated by translocation of phosphatidylserine to external membrane leaflet and by increased activity of caspase-3. Special attention was focused on imatinib influence on actin cytoskeleton organization and migration ability of LS180 cells. Distinct alterations in actin cytoskeleton architecture occurred in response to drug treatment, accompanied by appearance of filamentous actin aggregates and decrease in actin polymerization state. These changes were correlated with remarkable decrease in cell migration capacity. In summary, our data clearly demonstrate that imatinib induces apoptosis and inhibits human colon adenocarcinoma cell migration. Therefore, this drug may have potential in colon cancer therapy in the future. PMID- 21658384 TI - Tailoring elastase inhibition with synthetic peptides. AB - Chronic wounds are the result of excessive amounts of tissue destructive proteases such as human neutrophil elastase (HNE). The high levels of this enzyme found on those types of wounds inactivate the endogenous inhibitor barrier thus, the search for new HNE inhibitors is required. This work presents two new HNE inhibitor peptides, which were synthesized based on the reactive-site loop of the Bowman-Birk inhibitor protein. The results obtained indicated that these new peptides are competitive inhibitors for HNE and, the inhibitory activity can be modulated by modifications introduced at the N- and C-terminal of the peptides. Furthermore, these peptides were also able to inhibit elastase from a human wound exudate while showing no cytotoxicity against human skin fibroblasts in vitro, greatly supporting their potential application in chronic wound treatment. PMID- 21658385 TI - Cyclohexanol analogues are positive modulators of GABA(A) receptor currents and act as general anaesthetics in vivo. AB - GABA(A) receptors meet all the pharmacological criteria required to be considered important general anaesthetic targets. In the following study, the modulatory effects of various commercially available and novel cyclohexanols were investigated on recombinant human gamma-aminobutyric acid (GABA(A), alpha(1)beta(2)gamma(2s)) receptors expressed in Xenopus oocytes, and compared to the modulatory effects on GABA currents observed with exposures to the intravenous anaesthetic agent, propofol. Submaximal EC(20) GABA currents were typically enhanced by co-applications of 3-300 MUM cyclohexanols. For instance, at 30 MUM 2,6-diisopropylcyclohexanol (a novel compound) GABA responses were increased ~3-fold (although similar enhancements were achieved at 3 MUM propofol). As regards rank order for modulation by the cyclohexanol analogues at 30 MUM, the % enhancements for 2,6-dimethylcyclohexanol~2,6 diethylcyclohexanol~2,6-diisopropylcyclohexanol~2,6-di-sec-butylcyclohexanol ?2,6 di-tert-butylcyclohexanol~4-tert-butylcyclohexanol>cyclohexanol~cyclopentanol~2 methylcyclohexanol. We further tested the potencies of the cyclohexanol analogues as general anaesthetics using a tadpole in vivo assay. Both 2,6 diisopropylcyclohexanol and 2,6-dimethylcyclohexanol were effective as anaesthetics with EC(50)s of 14.0 MUM and 13.1 MUM respectively, while other cyclohexanols with bulkier side chains were less potent. In conclusion, our data indicate that cyclohexanols are both positive modulators of GABA(A) receptors currents and anaesthetics. The positioning and size of the alkyl groups at the 2 and 6 positions on the cyclohexanol ring were critical determinants of activity. PMID- 21658386 TI - Inhibition of 20-HETE attenuates diabetes-induced decreases in retinal hemodynamics. AB - The mechanisms of early diabetes-induced decreases in retinal blood flow have yet to be fully determined. The aim of this study was to explore the hypothesis that 20-hydroxyeicosatetraenoic acid (20-HETE) plays a role in the early decrease of retinal hemodynamics in diabetic mice. 20-HETE has been implicated previously in the diabetes-enhanced vasoconstriction of mesenteric and renal vessels; however, its role in the diabetic retinal microcirculation has not been investigated. Diabetes was induced by multiple low-dose injections of streptozotocin (STZ; 50 mg/kg for 5 consecutive days), then ~2 weeks later the mice were administered daily intraperitoneal injections with or without the 20-HETE inhibitor HET0016 (2.5 mg/kg/day) for the following 2 weeks. Non-diabetic age-matched mice were included as controls. Intravital microscopy was used to obtain measurements of retinal vascular diameters and red blood cell (RBC) velocities for the feed arterioles and draining venules extending out of and into the optic disk. From these values, wall shear rates and blood flow rates were calculated. Diabetes induced approximately 30-40% decreases in RBC velocity, wall shear rate, and blood flow rate. These decreases were attenuated to 5-10% in the mice given HET0016. In summary, the 20-HETE inhibitor HET0016 is able to attenuate the retinal hemodynamic changes induced by diabetes. PMID- 21658387 TI - LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson's disease-associated mutations. AB - LRRK2 is the causal molecule for autosomal-dominant familial Parkinson's disease, although its true function, including its physiological substrates, remains unknown. Here, using in vitro kinase assay with recombinant proteins, we demonstrated for the first time that LRRK2 directly phosphorylates Akt1, a central molecule involved in signal transduction for cell survival and prevention of apoptosis. Ser473, one of two amino acids essential for Akt1 activation, was the target site for LRRK2. A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2. The disease-associated mutations, R1441C, G2019S, and I2020T, exhibited reduced interaction with, and phosphorylation of, Akt1, suggesting one possible mechanism for the neurodegeneration caused by LRRK2 mutations. PMID- 21658388 TI - Inhibitory mechanism of pure curcumin on Wilms' tumor 1 (WT1) gene expression through the PKCalpha signaling pathway in leukemic K562 cells. AB - The aim of this study was to investigate the inhibitory mechanism of pure curcumin on WT1 expression in leukemic K562 cells. Pure curcumin suppressed WT1 expression, independent of effects on protein degradation or WT1 mRNA stability. Chromatin immunoprecipitation and reporter gene assays indicate that pure curcumin treatment attenuates WT1 auto-regulation. Interestingly, PKCalpha inhibition mimicks the repressive effects of pure curcumin in K562 cells. Conversely, myristoylated PKCalpha over-expression increased WT1 expression and reversed the inhibitory effect of pure curcumin. Our study indicates that pure curcumin attenuates WT1 auto-regulatory function through inhibition of PKCalpha signaling in K562 cells. PMID- 21658389 TI - miR-198 inhibits migration and invasion of hepatocellular carcinoma cells by targeting the HGF/c-MET pathway. AB - Metastasis is the leading cause of death in patients with hepatocellular carcinoma (HCC) and microRNAs have been implicated to influence this process. Emerging evidence indicates that miR-198 is down-regulated in HCC compared to normal liver parenchyma, but the functional roles of miR-198 in HCC cells remains unexplored. Herein, we show that miR-198 directly targets c-MET via its 3'UTR. Forced expression of miR-198 decreased c-MET expression at both mRNA and protein levels and consequently diminished HGF induced phosphorylation of p44/42 MAPK in HCC cells. Forced expression of miR-198 inhibited HGF promotion of HCC cell migration and invasion in a c-MET dependent manner. In conclusion, we have identified miR-198 as a novel suppressor of HCC cell invasion by negative regulation of the HGF/c-MET pathway. PMID- 21658390 TI - Differential expression of PTHrP and its receptor in pituitary gland and gills in estradiol-treated gilthead sea bream (Sparus auratus, L.). AB - In the gilthead sea bream (Sparus auratus) 17beta-estradiol (E2) plays an important role in the synthesis of vitellogenin. During vitellogenesis, vitellogenin as a nutritional precursor protein is loaded with calcium, which requires elevated plasma calcium levels. This is accomplished via E2-dependent processes. Reports have shown that hypercalcemic effects of E2 are possibly mediated by another hypercalcemic factor, viz. parathyroid hormone related protein (PTHrP). To further investigate the possibility of PTHrP as a mediator of E2-induced hypercalcemia, we investigated the local expression levels of the pthrp mRNA and of the gene coding for the PTHrP receptor, PTH1R (pth1r) in two tissues involved in the calcium regulation (gills, pituitary gland) of the sea bream treated with E2. Compared to control, treatment with E2 resulted in: significantly increased total calcium and plasma PTHrP levels (P<0.01), a down regulation of pthrp mRNA in the pituitary gland (P<0.01), and up-regulation of expression levels for both pthrp and pth1r in the branchial system (P<0.05). These findings provide direct evidence for a mediating role of PTHrP in E2 induced hypercalcemia, and in addition support the idea for the presence of two independent systems, an endocrine pituitary PTHrP system and a peripheral paracrine branchial PTHrP system. PMID- 21658391 TI - Dynamic Interaction of Hsp90 with Its Client Protein p53. AB - Although the structure of the molecular chaperone Hsp90 has been extensively characterized by X-ray crystallography, the nature of the interactions between Hsp90 and its client proteins remains unclear. We present results from a series of spectroscopic studies that strongly suggest that these interactions are highly dynamic in solution. Extensive NMR assignments have been made for human Hsp90 through the use of specific isotopic labeling of one- and two-domain constructs. Sites of interaction of a client protein, the p53 DNA-binding domain, were then probed both by chemical shift mapping and by saturation transfer NMR spectroscopy. Specific spectroscopic changes were small and difficult to observe, but were reproducibly measured for residues over a wide area of the Hsp90 surface in the N-terminal, middle and C-terminal domains. A somewhat greater specificity, for the area close to the interface between the N-terminal and middle domains of Hsp90, was identified in saturation transfer experiments. These results are consistent with a highly dynamic and nonspecific interaction between Hsp90 and p53 DNA-binding domain in this chaperone-client system, which results in changes in the client protein structure that are detectable by spectroscopic and other methods. PMID- 21658393 TI - Flow-induced changes in pial artery compliance registered with a non-invasive method in rabbits. AB - AIM: This study was performed: 1) to assess the relationship between blood flow velocity in the internal carotid artery (CBF(ICA)) and pial artery pulsation (cc TQ) and 2) to evaluate flow-induced changes in pial artery compliance. METHODS: Experiments were performed on 10 crossbred male rabbits. Heart rate (HR), blood pressure (BP), left ventricle ejection fraction (LVEF), CBF(ICA), the systolic diastolic blood volume fraction in the brain circulation (CBF(SDF)) and cc-TQ were recorded after glucagon and acetazolamide administration. cc-TQ was measured with near-infrared transillumination back scattering sounding (NIR-T/BSS), LVEF and CBF(SDF) with gated scintigraphy and BP and CBF(ICA) with electromagnetic pressure and flow transducers, respectively. Doses of drugs were chosen to exert a haemodynamic effect but not change BP or intracranial pressure. RESULTS: Acetazolamide and glucagon evoked significant increases in cc-TQ, CBF(SDF), CBF(ICA), LVEF and HR. The following interdependencies were found: 1) changes after acetazolamide administration compared to baseline: CBF(SDF) vs. LVEF (r=0.73, p<0.05), cc-TQ vs. CBF(SDF) (r=-0.67, p<0.05), cc-TQ vs. LVEF (r=-0.76, p<0.05), 2) changes after glucagon administration compared to baseline: CBF(ICA) vs. BP (r=0.73, p<0.05), CBF(SDF) vs. LVEF (r=0.87, p<0.05), cc-TQ vs. HR (r=0.85, p<0.05), cc-TQ vs. CBF(ICA) (r=-0.74, p<0.05). CONCLUSION: In the absence of systemic BP changes, pial arteries are significantly affected by changes in CBF(ICA). Pial arteries counteract changes in CBF(ICA) and CBF(SDF). The ability of pial arteries to stabilise CBF(ICA) is impaired after acetazolamide administration. Changes in cardiac output directly affect the brain's microcirculation. NIR-T/BSS recordings allow for non-invasive assessment of changes in pial artery compliance. PMID- 21658392 TI - The crystal structure of the substrate-binding protein OpuBC from Bacillus subtilis in complex with choline. AB - Bacillus subtilis can synthesize the compatible solute glycine betaine as an osmoprotectant from an exogenous supply of the precursor choline. Import of choline is mediated by two osmotically inducible ABC transport systems: OpuB and OpuC. OpuC catalyzes the import of various osmoprotectants, whereas OpuB is highly specific for choline. OpuBC is the substrate-binding protein of the OpuB transporter, and we have analyzed the affinity of the OpuBC/choline complex by intrinsic tryptophan fluorescence and determined a K(d) value of about 30 MUM. The X-ray crystal structure of the OpuBC/choline complex was solved at a resolution of 1.6 A and revealed a fold typical of class II substrate-binding proteins. The positively charged trimethylammonium head group of choline is wedged into an aromatic cage formed by four tyrosine residues and is bound via cation-pi interactions. The hydroxyl group of choline protrudes out of this aromatic cage and makes a single interaction with residue Gln19. The substitution of this residue by Ala decreases choline binding affinity by approximately 15 fold. A water network stabilizes choline within its substrate-binding site and promotes indirect interactions between the two lobes of the OpuBC protein. Disruption of this intricate water network by site-directed mutagenesis of selected residues in OpuBC either strongly reduces choline binding affinity (between 18-fold and 25-fold) or abrogates ligand binding. The crystal structure of the OpuBC/choline complex provides a rational for the observed choline specificity of the OpuB ABC importer in vivo and explains its inability to catalyze the import of glycine betaine into osmotically stressed B. subtilis cells. PMID- 21658394 TI - Identification of differentially expressed genes in the livers of chronically i As-treated hamsters. AB - Inorganic arsenic (i-As) is a human carcinogen causing skin, lung, urinary bladder, liver and kidney tumors. Chronic exposure to this naturally occurring contaminant, mainly via drinking water, is a significant worldwide environmental health concern. To explore the molecular mechanisms of arsenic hepatic injury, a differential display polymerase chain reaction (DD-PCR) screening was undertaken to identify genes with distinct expression patterns between the liver of low i-As exposed and control animals. Golden Syrian hamsters (5-6 weeks of age) received drinking water containing 15 mg i-As/L as sodium arsenite, or unaltered water for 18 weeks. The in vivo MN test was carried out, and the frequency of micronucleated reticulocytes (MN-RETs) was scored as a measure of exposure and As related genotoxic/carcinogenic risk. A total of 68 differentially expressed bands were identified in our initial screen, 41 of which could be assigned to specific genes. Differential level of expression of a selected number of genes was verified using real-time RT-PCR with gene-specific primers. Arsenic-altered gene expression included genes related to stress response, cellular metabolism, cell cycle regulation, telomere maintenance, cell-cell communication and signal transduction. Significant differences of MN-RET were found between treated (8.70 +/- 0.02 MN/1000RETs) and control (2.5 +/- 0.70 MN/1000RETs) groups (P<0.001), demonstrating both the exposure and the i-As genotoxic/carcinogenic risk. Overall, this paper reveals some possible networks involved in hepatic arsenic related genotoxicity, carcinogenesis and diabetogenesis. Additional studies to explore further the potential implications of each candidate gene are of especial interest. The present work opens the door to new prospects for the study of i-As mechanisms taking place in the liver under chronic settings. PMID- 21658395 TI - Phenylbutyrate inhibits homologous recombination induced by camptothecin and methyl methanesulfonate. AB - Homologous recombination is accompanied by extensive changes to chromatin organization at the site of DNA damage. Some of these changes are mediated through acetylation/deacetylation of histones. Here, we show that recombinational repair of DNA damage induced by the anti-cancer drug camptothecin (CPT) and the alkylating agent methyl methanesulfonate (MMS) is blocked by sodium phenylbutyrate (PBA) in the budding yeast Saccharomyces cerevisiae. In particular, PBA suppresses CPT- and MMS-induced genetic recombination as well as DNA double-strand break repair during mating-type interconversion. Treatment with PBA is accompanied by a dramatic reduction in histone H4 lysine 8 acetylation. Live cell imaging of homologous recombination proteins indicates that repair of CPT-induced DNA damage is redirected to a non-recombinogenic pathway in the presence of PBA without loss in cell viability. In contrast, the suppression of MMS-induced recombination by PBA is accompanied by a dramatic loss in cell viability. Taken together, our results demonstrate that PBA inhibits DNA damage induced homologous recombination likely by mediating changes in chromatin acetylation. Moreover, the combination of PBA with genotoxic agents can lead to different cell fates depending on the type of DNA damage inflicted. PMID- 21658396 TI - Profiles of recent autobiographical memory retrieval in semantic dementia, behavioural-variant frontotemporal dementia, and Alzheimer's disease. AB - Episodic autobiographical memory (ABM) comprises recollection for events that are grounded within a specific spatiotemporal context, and usually accompanied by perceptual and emotional information. The neural substrates mediating ABM retrieval are those harbouring significant pathology in semantic dementia (SD) and behavioural-variant frontotemporal dementia (bvFTD), the most common subtypes of FTD. Relatively little is known, however, regarding the differential patterns of contextual details during episodic ABM retrieval across these dementia syndromes. This study investigated episodic ABM retrieval under free and probed recall conditions from 4 time periods with the aim to identify disease-specific profiles of episodic ABM contextual details. Episodic ABM was measured in 25 SD and 15 bvFTD patients and their performance contrasted to that of 17 Alzheimer's disease (AD) patients and 19 age-matched controls. Critically, SD patients showed relatively preserved recent ABM in comparison with remote epochs. In contrast, bvFTD and AD patients showed a reduced capacity to recall specific and contextually rich ABMs across all life epochs, in both free and probed recall conditions. Analyses of the recent period (last 12 months) provided evidence for different profiles of contextual episodic details recalled in dementia syndromes. Following probing, SD patients' recall deficits emanated exclusively from compromised Emotion/Thoughts and Spatiotemporal details. In contrast, bvFTD patients were significantly impaired across all categories of contextual details whereas AD patients showed deficits for Event and Emotion/Thoughts details only. As the largest study of ABM in FTD to date, these findings emphasise the differential impairment of recent ABM contextual details contingent on the underlying disease pathology. In addition, these results point towards the importance of investigating the constituent elements of emotion processing and strategic retrieval processes as potential variables mediating recent episodic ABM retrieval. PMID- 21658397 TI - Hemispheric specialisation in haptic processing. AB - This study investigated the organising principles of touch. We examined specialisations within the haptic system and their hemispheric distribution. Haptic processing consists of the integration of data from multiple sources to form a single percept. Previous research provides strong support for a hierarchical and functional distribution within haptic processing. We investigated hemispheric asymmetry in haptic discrimination of objects with differing textures and centres of mass. By analogy with vision it was hypothesised that participants would demonstrate a left-hand advantage for centre of mass discrimination (a 'global', presumed right hemisphere, judgement) and a right-hand advantage for surface texture judgements (a 'local', presumed left hemisphere discrimination). We found that left-handed participants showed these effects to a lesser degree than did the right-handers, consistent with the notion that left-handed people generally show weaker asymmetries in bimanual tasks. In a second experiment the effect of conflicting information on haptic percept formation was investigated. Following from the previous hypotheses it was predicted that participants would be more accurate with their right hands at judging conflicting surfaces. Contrary to predictions an advantage was demonstrated for the left hand for texture discrimination and for the right hand for centre of mass judgement. PMID- 21658398 TI - Leanness of Lou/C rats does not require higher thermogenic capacity of brown adipose tissue. AB - Lou/C rats, an inbred strain of Wistar origin, remain lean throughout life and therefore represent a remarkable model of obesity resistance. To date, the exact mechanisms responsible for the leanness of Lou/C rats remain unknown. The aim of the present study was to investigate whether the leanness of Lou/C rats relies on increased thermogenic capacities in brown adipose tissue (BAT). Results showed that although daily energy expenditure was higher in Lou/C than in Wistar rats, BAT thermogenic capacity was not enhanced in Lou/C rats kept at thermoneutrality as demonstrated by reduced thermogenic response to norepinephrine in vivo, similar oxidative activity of BAT isolated mitochondria in vitro, similar levels of UCP1 mRNA and lower abundance of UCP1 protein in interscapular BAT depots. Relative abundance of beta3-adrenergic receptor mRNA was lower in Lou/C BAT while that of GLUT4, FABP or CPT1 was not altered. Activity-related energy expenditure was however considerably increased at thermoneutrality as Lou/C rats demonstrated an impressively high spontaneous running activity in voluntary running wheels. Prolonged cold-exposure (4 degrees C) depressed the spontaneous running activity of Lou/C rats while BAT thermogenic capacity was increased as reflected by rises in BAT mass, oxidative activity and UCP1 expression. It is concluded that the leanness of Lou/C rats cannot be ascribed to higher thermogenic capacity of brown fat but rather to, at least in part, increased locomotor activity. BAT is not deficient in this rat strain as it can be stimulated by cold exposure when locomotor activity is reduced suggesting some substitution between these thermogenic processes. PMID- 21658399 TI - Sex and age differences in the impact of the forced swimming test on the levels of steroid hormones. AB - Compared with the adult disorder, depression in children exhibits differences in its neurobiology, particularly in the HPA axis regulation. The bases of such differences can be evaluated in animal models of depression. The objective of the present study was to determine age and sex differences of Wistar rats in the forced swimming test (FST). The influence of sex and age on corticosterone, estrogens and testosterone serum levels was also determined. Prepubertal rats showed immobility, swimming and climbing behaviors during the pre-test and test sessions. In addition, in the prepubertal animals, no sex differences were found during the pre-test and test sessions. Age comparisons indicated no differences in the female groups, however adult males exhibited more immobility and less swimming than young males, in both FST sessions. The young and female rats showed less immobility behavior and increased levels of estrogens after the FST. The present results indicate that the FST is an animal model suitable to evaluate depressive-like behaviors in prepubertal subjects and to explore behavioral changes related to neurodevelopment. PMID- 21658400 TI - Characterization of diffusion and duration of action of a new botulinum toxin type A formulation. AB - RT002, an injectable form of botulinum neurotoxin type A (BoNTA), comprised of a purified 150 kDa neurotoxin formulated in a novel formulation, is designed to limit the extent of diffusion and permit safe administration of longer acting doses. The aim of this study was to evaluate the degree of diffusion of RT002 in comparison to another commercially available BoNTA product, Botox(r) Cosmetic (OnabotulinumtoxinA, Allergan, Inc., Irvine, CA, USA), and establish the relative duration of effect for diffusion matched doses of the two BoNTA formulations using quantitative measurements in mice. Measurement of muscle paralysis by muscle force generation (MFG) in mice at the injected gastrocnemius muscles indicated that RT002 and Botox are equipotent. Measurements of MFG inhibition in an adjacent muscle, the tibialis anterior muscle, indicated significantly less diffusion for RT002 as compared to Botox. When RT002 and Botox were dosed using the established diffusion matched doses, RT002 treatment resulted in an extended duration of drug effect as compared to Botox by 58-100% as assessed by either partial or complete recovery endpoints. Use of a daily voluntary running activity model provided confirmation that the two BoNTA formulations are equipotent by daily running distance and further confirmed the diffusion matched dose ratio assessed by degree of drug effect on body weight gain. Using these diffusion matched doses, RT002 treatment resulted in an extended duration of drug effect as compared to Botox (100-126% increase in duration) as assessed by either partial or complete recovery endpoints. Use of this model provides further evidence that the RT002 formulation limits diffusion with equipotency and thereby may permit safe administration of higher and more efficacious doses. In summary, data from two murine models suggest that RT002 may represent a next generation of BoNTA drug formulation offering superior degree and duration of effect at the intended target while controlling the unwanted diffusion and accompanying adverse effects of BoNTA at neighboring muscles and distal systemic targets. PMID- 21658401 TI - Heminecrolysin, the first hemolytic dermonecrotic toxin purified from scorpion venom. AB - Envenomation caused by Hemiscorpius (H.) lepturus from Liochlidae family presents clinical features that have not been previously described for the Buthidae family scorpions. The most significant manifestations of H. lepturus envenomation are hemolysis and dermonecrosis which could lead in severe cases to renal, cardio respiratory failure, and death. In this study, we aimed to identify and characterize the protein(s) causing these effects. We have purified a 33 kDa protein from the venom of H. lepturus and named it Heminecrolysin. Tryptic digestion and MS/MS analysis of obtained peptides showed homology with previously described brown spider sphingomyelinases D. Functional characterization of Heminecrolysin indicated a sphingomyelinase D, a complement-dependent hemolysis properties and a dermonecrosis activity. Heminecrolysin displayed higher hemolytic activity to human erythrocytes (ED50 of 0.025 MUg/ml), a stronger inflammatory and dermonecrotic effects when injected intra-dermally to rabbit skins, while its efficiency to hydrolyze sphingomyelin seems weaker than other known spider dermonecrotic SMasesD (149 +/- 32.5 nmol/mg). Step of sensitization of human erythrocytes by Heminecrolysin was shown to be Mg2+ and Ca2+-independent while hemolysis step in the presence of complement required both bivalent ions. Heminecrolysin is the first hemolytic dermonecrotic toxin identified in venom other than spiders. Except in spider Loxosceles genus and some pathogenic strains of Corynebacteria, sphingomyelinase D activity is unknown in the animal kingdom. PMID- 21658402 TI - Ability of Lactobacillus casei and Lactobacillus reuteri to protect against oxidative stress in rats fed aflatoxins-contaminated diet. AB - Lactic acid bacteria (LAB) have been reported to remove mycotoxins from aqueous solutions through a binding process, which appears to be species and strain specific. The aim of the current study was to evaluate the protective role of Lactobacillus casei (L1) and Lactobacillus reuteri (L2) against aflatoxin (AFs) induced oxidative stress in rats. Sixty female Sprague-Dawley rats were divided into 6 groups including the control group and the groups treated with L1 or L2 (1 x 1011/ml) alone at a dose of 10 ml/kg b.w or plus AFs (3 mg/kg diet) for 4 weeks. At the end of the treatments, blood and tissue samples were collected for biochemical and histological studies. The results indicated that AFs alone induced a significant decrease in food intake and body weight and a significant increase in transaminase, alkaline phosphatase cholesterol, triglycerides, total lipids, creatinine, uric acid and nitric oxide in serum and lipid peroxidation in liver and kidney accompanied with a significant decrease in total antioxidant capacity. Treatments with L1 or L2 succeeded to induce a significant improvement in all the biochemical parameters and histological picture of the liver. Moreover, L2 was more effective than L1 and both can be used safely in functional foods. PMID- 21658403 TI - Perceptual learning to reduce sensory eye dominance beyond the focus of top-down visual attention. AB - Perceptual learning is an important means for the brain to maintain its agility in a dynamic environment. Top-down focal attention, which selects task-relevant stimuli against competing ones in the background, is known to control and select what is learned in adults. Still unknown, is whether the adult brain is able to learn highly visible information beyond the focus of top-down attention. If it is, we should be able to reveal a purely stimulus-driven perceptual learning occurring in functions that are largely determined by the early cortical level, where top-down attention modulation is weak. Such an automatic, stimulus-driven learning mechanism is commonly assumed to operate only in the juvenile brain. We performed perceptual training to reduce sensory eye dominance (SED), a function that taps on the eye-of-origin information represented in the early visual cortex. Two retinal locations were simultaneously stimulated with suprathreshold, dichoptic orthogonal gratings. At each location, monocular cueing triggered perception of the grating images of the weak eye and suppression of the strong eye. Observers attended only to one location and performed orientation discrimination of the gratings seen by the weak eye, while ignoring the highly visible gratings at the second, unattended, location. We found SED was not only reduced at the attended location, but also at the unattended location. Furthermore, other untrained visual functions mediated by higher cortical levels improved. An automatic, stimulus-driven learning mechanism causes synaptic alterations in the early cortical level, with a far-reaching impact on the later cortical levels. PMID- 21658405 TI - Overdiagnosis in breast cancer: design and methods of estimation in observational studies. AB - OBJECTIVES: In recent years observational epidemiological studies have been used to estimate overdiagnosis in breast cancer screening. These estimates vary widely. In this paper we present some of the methodological issues which explain the large variability of the reported findings. METHODS: Different types of observational studies were identified according to study design, definition of the population, adjustment for breast cancer risk and adjustment for lead time. RESULTS: The majority of observational studies that have estimated breast cancer overdiagnosis have analyzed temporal trends or geographical differences in breast cancer incidence. Estimates of overdiagnosis in a dynamic population vary widely, from 4% to 52%. Only a few studies have used the cohort approach and they found estimates varying from 1% to 5%. CONCLUSIONS: The cohort approach is preferable to the analysis of a dynamic population because it allows the follow-up of a group of women who have had the opportunity for screening and evaluates if there is sufficient follow-up after the last screen. PMID- 21658404 TI - Age-dependence of the optomechanical responses of ex vivo human lenses from India and the USA, and the force required to produce these in a lens stretcher: the similarity to in vivo disaccommodation. AB - The purpose of this study was to study the age-dependence of the optomechanical properties of human lenses during simulated disaccommodation in a mechanical lens stretcher, designed to determine accommodative forces as a function of stretch distance, to compare the results with in vivo disaccommodation and to examine whether differences exist between eyes harvested in the USA and India. Postmortem human eyes obtained in the USA (n=46, age=6-83 years) and India (n=91, age=1 day 85 years) were mounted in an optomechanical lens stretching system and dissected to expose the lens complete with its accommodating framework, including zonules, ciliary body, anterior vitreous and a segmented rim of sclera. Disaccommodation was simulated through radial stretching of the sectioned globe by 2mm in increments of 0.25 mm. The load, inner ciliary ring diameter, lens equatorial diameter, central thickness and power were measured at each step. Changes in these parameters were examined as a function of age, as were the dimension/load and power/load responses. Unstretched lens diameter and thickness increased over the whole age range examined and were indistinguishable from those of in vivo lenses as well as those of in vitro lenses freed from zonular attachments. Stretching increased the diameter and decreased the thickness in all lenses examined but the amount of change decreased with age. Unstretched lens power decreased with age and the accommodative amplitude decreased to zero by age 45 50. The load required to produce maximum stretch was independent of age (median 80 mN) whereas the change in lens diameter and power per unit load decreased significantly with age. The age related changes in the properties of human lenses, as observed in the lens stretching device, are similar to those observed in vivo and are consistent with the classical Helmholtz theory of accommodation. The response of lens diameter and power to disaccommodative (stretching) forces decreases with age, consistent with lens nuclear stiffening. PMID- 21658406 TI - The evidence base for breast cancer screening. AB - The history of breast cancer screening is littered with controversy. With 10 trials spanning 4 decades, we have a substantial body of evidence, but with different aims and flaws. Combined analysis of the intention-to-treat results gives an overall relative reduction in breast cancer mortality of 19% (95% CI 12% 26%), which, if adjusted for non-attendance gives an approximate 25% relative reduction for those who attend screening. However, given that 4% of all-cause mortality is due to breast cancer deaths, this translates into a less than 1% reduction in all-cause mortality. An emerging issue in interpretation is the improvements in treatment since these trials recruited women. Modern systemic therapy would have improved survival (models suggest between 12% and 21%) in both screened and non-screened groups, which would result in a lesser difference in absolute risk reduction from screening but probably a similar, or slightly smaller, relative risk reduction. However benefits and harms, particularly over diagnosis, need to balanced and differ by age-groups. The informed views of recipients of screening are needed to guide current and future policy on screening. PMID- 21658407 TI - Defense of zebrafish embryos against Streptococcus pneumoniae infection is dependent on the phagocytic activity of leukocytes. AB - Severe community acquired pneumonia caused by Streptococcus pneumoniae is the most common cause of death from infection in developing countries. Serotype specific conjugate vaccines have decreased the incidence of invasive infections, but at the same time, disease due to non-vaccine serotypes have increased. New insights into host immune mechanisms against pneumococcus may provide better treatment and prevention strategies. Zebrafish is an attractive vertebrate model for studying host immune responses and infection biology. Here we show that an intravenous challenge with pneumococcus infects zebrafish embryos leading to death in a dose dependent manner. Survival rates correlate with the bacterial burden in the embryos. The production of proinflammatory cytokines is induced in zebrafish after pneumococcal exposure. Importantly, morpholino treated embryos lacking either myeloid cells or the ability to phagocytose bacteria have lowered survival rates compared to wild type embryos after pneumococcal challenge. These data suggest that the survival of zebrafish embryos upon intravenous infection with S. pneumoniae is dependent on the clearance of the bacteria by phagocytosing cells. Additionally, we demonstrate that mutant pneumococci lacking known virulence factors are attenuated in the zebrafish model. Our data demonstrate that zebrafish embryos can be used for study innate immune responses as well as virulence determinants in pneumococcal infections. PMID- 21658408 TI - Interaction between eicosanoids and the complement system in salmonid fish. AB - Both eicosanoid generation and the complement system have long evolutionary histories predating the emergence of the vertebrates over 500 myr ago. This study investigated the interplay between these two systems in an example of a bony fish, the rainbow trout (Oncorhynchus mykiss). Specifically, it examined whether purified complement fragments including C3a-1 and zymosan-activated serum, stimulate the biosynthesis of any of these eicosanoids by trout macrophages. Incubation of macrophages with zymosan pre-incubated with normal trout serum resulted in the phagocytosis of such particles and the generation of both intra- and extra-cellularly located lipoxygenase and cyclooxygenase products. Both eicosanoid generation and phagocytosis levels were significantly elevated following incubation of zymosan in trout serum in comparison with heat inactivated (60 degrees C for 30 min) trout serum and saline alone. A combined mass spectrometry/high performance liquid chromatography approach was employed to conclusively demonstrate the presence of the cyclooxygenase product, prostaglandin E (PGE) in the culture supernatants of ionophore-challenged macrophages. Incubation of trout macrophages with zymosan-activated trout serum (i.e. no zymosan present) failed to stimulate PGE generation. Similarly, incubation of these cells for up to 60 min with C3a-1 (4 or 50 nM) failed to generate significant amounts of PGE or lipoxygenase products such as leukotriene B(4/5) or lipoxin A(4/5). Longer term (6 & 24h) incubation of macrophages with C3a-1 (4 nM) resulted in a time dependent increase in the generation of PGE but not leukotriene B in culture supernatants. No conclusive evidence that the increase in PGE generation was caused by changes in the expression of either cyclooxygenase-1 or -2 was found. PMID- 21658409 TI - Neuroprotection of alpha-synuclein under acute and chronic rotenone and maneb treatment is abolished by its familial Parkinson's disease mutations A30P, A53T and E46K. AB - alpha-Synuclein (alpha-Syn) plays a crucial role in the pathophysiology of Parkinson's disease (PD). alpha-Syn has been extensively studied in many neuronal cell-based PD models but has yielded mixed results. The objective of this study was to re-evaluate the dual cytotoxic/protective roles of alpha-Syn in dopaminergic SH-SY5Y cells. Stable SH-SY5Y cells overexpressing wild type or familial alpha-Syn mutants (A30P, E46K and A53T) were subjected to acute and chronic rotenone and maneb treatment. Compared with untransfected SH-SY5Y cells, wild type alpha-Syn attenuated rotenone and maneb-induced cell death along with an attenuation of toxin-induced mitochondrial membrane potential changes and Reactive Oxygen Species level, whereas the mutant alpha-Syn constructs exacerbated environmental toxins-induced cytotoxicity. After chronic treatment, wild type alpha-Syn but not the mutant variants was found to rescue cells from subsequent acute hydrogen peroxide insult. These results suggest that the fundamental property of wild type alpha-Syn may be protective, and such property may be lost by its familial PD mutations. PMID- 21658410 TI - Structural remodeling, trafficking and functions of glycosylphosphatidylinositol anchored proteins. AB - Glycosylphosphatidylinositol (GPI) is a glycolipid that is covalently attached to proteins as a post-translational modification. Such modification leads to the anchoring of the protein to the outer leaflet of the plasma membrane. Proteins that are decorated with GPIs have unique properties in terms of their physical nature. In particular, these proteins tend to accumulate in lipid rafts, which are critical for the functions and trafficking of GPI-anchored proteins (GPI APs). Recent studies mainly using mutant cells revealed that various structural remodeling reactions occur to GPIs present in GPI-APs as they are transported from the endoplasmic reticulum to the cell surface. This review examines the recent progress describing the mechanisms of structural remodeling of mammalian GPI-anchors, such as inositol deacylation, glycan remodeling and fatty acid remodeling, with particular focus on their trafficking and functions, as well as the pathogenesis involving GPI-APs and their deficiency. PMID- 21658411 TI - Enzyme-linked immunosorbent assays for alpha-synuclein with species and multimeric state specificities. AB - Abnormal intracellular deposition of aggregated alpha-synuclein is the characteristic feature of a number of neurological disorders, including Parkinson's disease (PD). Although alpha-synuclein is typically known as a cytosolic protein, a small amount is secreted by exocytosis in both monomeric and aggregated forms. The extracellular forms of alpha-synuclein in human body fluids, such as cerebrospinal fluid (CSF) and blood plasma, might be a diagnostic target for PD and related diseases. Here, we characterized a new set of monoclonal antibodies against alpha-synuclein, and using different combinations of antibodies, we established ELISA systems to specifically detect human alpha synuclein, mouse and human alpha-synuclein together, and multimeric forms of alpha-synuclein in biological samples. By employing the Tyramide signal amplification method, the sensitivity of the assay was significantly improved to detect a concentration as low as ~12.5 pg/ml. These assays might be useful tools for quantitative analysis of alpha-synuclein in various forms and with high sensitivity in diverse biological samples. PMID- 21658413 TI - Calcium signals: analysis in time and frequency domains. AB - Cytosolic calcium signals play important roles in processes such as cell growth and motility, synaptic communication and formation of neural circuitry. These signals have complex time courses and their quantitative analysis is not easily accomplished; in particular it may be difficult to evidence subtle differences in their temporal patterns. In this paper, we use wavelet analysis to extract information on the structure of [Formula: see text] oscillations. To this aim we have derived a set of indices by which different [Formula: see text] oscillatory patterns and their change in time can be extracted and quantitatively evaluated. This approach has been validated with examples of experimental recordings showing changes in oscillatory behavior in cells stimulated with a calcium-releasing agonist. PMID- 21658412 TI - Production of functional recombinant G-protein coupled receptors for heteromerization studies. AB - G-protein-coupled receptors (GPCRs) represent a diverse protein family of receptors that transduce signals from the extracellular surrounding to intracellular signaling molecules evoking various cellular responses. It is now widely accepted that GPCRs are expressed and function as dimers or most probably as oligomers of more than two receptor protomers. The heteromer has different biochemical and pharmacological characteristics from the monomers, which increases the functional responses of GPCRs. GPCRs are involved in many diseases, and are also the target of around half of all modern medicinal drugs. In the case of Parkinson's disease, a degenerative process caused by gradual disappearance of dopaminergic nigrostriatal neurons, it is suspected that the targets for treatment should be dopamine-receptor-containing heteromers. Technologies based on the use of fluorescent- or luminescent-fused receptors and adaptations of resonance energy transfer (RET) techniques have been useful in investigating the functional inter-relationships between receptors in a heteromer. In this study functional recombinant adenosine A(2A)-Rluc, dopamine D(2)-GFP(2) and histamine H(3)-YFP receptor fusion proteins were successfully cloned and characterized, producing the essential basis for heteromerization studies between these receptors. This might provide a better insight into their pharmacological and functional inter-relationships in the brain and enable the design and evaluation of new therapeutic strategies for Parkinson's disease. PMID- 21658414 TI - HLA-A*11 and novel associations in Malays and Chinese with systemic lupus erythematosus. AB - We investigated the association of the HLA genes in Malaysian patients with systemic lupus erythematosus (SLE) and their associations with the clinical manifestations in 160 SLE patients (99 Chinese and 61 Malays) and 107 healthy control individuals (58 Chinese and 49 Malays) were studied. Sequence specific primer amplification (PCR-SSP) phototyping techniques were used to analyse 25 HLA A allele groups, 31 HLA-DR allele groups and 9 HLA-DQ allele groups. Appreciable increases in allele frequencies of HLA-A*11, DRB1*0701, DRB1*1601-1606, DRB5*01 02 and DQB1*05, and decrease in HLA-DRB1*1101-1121, 1411, DRB1*1201-3, DRB1*1301 22, DRB3*0101, 0201, 0202, 0203, 0301 and DQB1*0301, 1304 in SLE patients compared with healthy control individuals. However, after Bonferroni correction (p(c)<0.05) only HLA-A*1101, 1102, DRB5*01-02, DQB1*05, DRB1*1201-3, DRB3*0101, 0201, 0202, 0203, 0301 and DQB1*0301, 0304 remained significant. Allele frequencies of DRB1*0701 and DRB4*0101101, 0102, 0103, DQB1*05, DRB1*1301-22, DRB3*0101, 0201, 0202, 0203, 0301 and DQB1*0301, 0304 were significantly increased in Malay SLE patients compared with healthy control individuals. In contrast, Chinese SLE patients had increased allele frequencies of DRB1*1601 1606, DQB1*05, DRB1*1201-3, DRB3*0101, 0201, 0202, 0203, 0301, DRB3*0101, 0201, 0202, 0203, 0301 and DQB1*0301, 0304 compared with healthy control individuals. HLA-A*6801-02 and DRB1*1601-1606 frequencies appeared elevated in a subset of patients with serositis and DRB1* 0401-1122 frequency was elevated in those displaying neurologic disorder. However, unequivocal evidence of these associations would require investigation of substantially larger cohorts. On the whole, our findings suggest that HLA allele associations with SLE are race specific in Malays and Chinese. PMID- 21658415 TI - Salience-based progression of visual attention. AB - Cognitive and computational models assume that visual attention is directed to the most salient stimulus in a given scene, and physiological models suggest the attribution of salience might depend on the extrageniculate pathway, involving the superior colliculus and pulvinar. Empirical findings support these models. Another assumption is that attention progresses from the most to the least salient item until a target is found. We have therefore attempted to investigate whether behavioral nasal-temporal hemifield asymmetries in healthy humans are present in the salience-based progression of attention. Hemispheric asymmetries have also been investigated. Healthy volunteers were presented with brief lateralized displays containing three stimuli of unequal sizes (one target and two distractors) and asked to make a judgment regarding the target. In each new trial, each of the three stimuli was chosen randomly with equal probability of being the target. The expected salience-based progression was found in both response times and accuracy. While no temporal-nasal asymmetries were found in accuracy for displays processed by the left hemisphere, a well-marked asymmetry was found for displays processed by the right hemisphere. The progression slope was quite steep for nasal displays and nil for temporal displays. A companion experiment replicated the results, another one ruled out any sensory interpretation of the results, and a last one ruled out the possibility that the results were due to saccadic eye movements. What distinguishes the two pathways is therefore not whether or not they generate salience, but the strength of the activity that differentiates the visual input. Furthermore, the involvement of the right extrageniculate pathway in the fineness of the perceptual analysis that follows orienting of attention seems to take place independently of the salience of the attended item. PMID- 21658416 TI - Origins of brain asymmetry: lateralization of odour memory recall in primitive Australian stingless bees. AB - Left-right antennal asymmetry has been reported in honeybees. We studied primitive social bees to investigate the evolutionary origins of the asymmetry. Three species of Australian native, stingless bees (Trigona carbonaria, Trigona hockingsi and Austroplebeia australis) were trained to discriminate two odours, lemon (+)/vanilla (-), using the Proboscis Extension Reflex (PER). Recall of the olfactory memory at 1h after training was better when the odour was presented on the right than on the left side of the bee. In contrast, recall at 5h after training was better when the odour was presented on the left than on the right side of the bee. An additional experiment with T. hockingsi bees, fed with sugar 1h before recall and tested at 5h, produced similar results, showing that the shift in lateralized recall was due to the lapse of time per se and not to changes in motivation to feed. Stingless bees show the same laterality as honeybees, suggesting that asymmetry evolved prior to the evolutionary divergence of these species. PMID- 21658417 TI - Cortical activity and children's rituals, habits and other repetitive behavior: a visual P300 study. AB - This study examines the link between children's repetitive, ritualistic, behavior and cortical brain activity. Twelve typically developing children between the ages of 6 and 12 years were administered two visual P300, oddball tasks with a 32 electrode electroencephalogram (EEG) system. One of the oddball tasks was specifically designed to reflect sensitivity to asymmetry, a phenomenon common in children and in a variety of disorders involving compulsive behavior. Parents completed the Childhood Routines Inventory. Children's repetitive, compulsive like behaviors were strongly associated with faster processing of an asymmetrical target stimulus, even when accounting for their P300 latencies on a control task. The research punctuates the continuity between observed brain-behavior links in clinical disorders such as OCD and autism spectrum disorders, and normative variants of repetitive behavior. PMID- 21658418 TI - Sensory tract abnormality in the chick model of spina bifida. AB - Spina bifida aperta (SBA) is an open neural tube defect that occurs during the embryonic period. We created SBA chicks by incising the roof plate of the neural tube in the embryo. The area of the dorsal funiculus was smaller in the SBA chicks than in the normal controls. Additionally, the SBA group had fewer nerve fibres in the dorsal funiculus than the normal controls. The pathway of the ascending sensory nerves was revealed by tracing the degenerated nerve fibres using osmification. We cut the sciatic nerve (L5) of the control and SBA chicks at the central end of the dorsal root ganglion 1 day after hatching and fixed the tissue 3 days later. Degenerated sensory nerve fibres were observed in the ipsilateral dorsal funiculus in the control chicks. In contrast, degenerated sensory nerve fibres were observed in the ipsilateral and contralateral dorsal, ventral and lateral funiculi of the spinal cord in the SBA chicks. Consequently, fewer sensory nerve fibres ascended to the thoracic dorsal funiculus in the SBA chicks than in the normal controls. This is the first report of abnormal changes in the ascending sensory nerve fibres in SBA. PMID- 21658419 TI - Distribution of Satb1 in the central nervous system of adult mice. AB - This study consists of a thorough immunohistochemical examination of the expression profile of the transcription factor Satb1 (special AT-rich sequence binding protein 1) in the adult mouse central nervous system (CNS). Satb1 positive neurons were abundant in the deep layers of the neocortex, subiculum, anterior olfactory nucleus, nucleus of diagonal band, anterior part of the basolateral amygdaloid nucleus, compact part of substantia nigra, ventral tegmental area, ventral and dorsal tegmental nuclei, laterodorsal tegmental nucleus, and medullary and spinal dorsal horns. Relatively smaller populations of Satb1-positive neurons were observed in the piriform cortex, hippocampus, other subnuclei of the amygdala, centrolateral thalamic nucleus, parafascicular thalamic nucleus, posterior hypothalamic area, ventral part of the premammillary nucleus, supramammillary nucleus, deep layers of the superior colliculus, dorsal raphe nucleus, nucleus of trapezoid body, superior periolivary nucleus and nucleus of lateral lemniscus, and parabrachial region. Double immunostaining showed that Satb1 was expressed in midbrain dopaminergic neurons, but not in cholinergic or serotonergic neurons. Satb1 expression was never observed in glial cells. This study presents a comprehensive overview of Satb1 expression in the CNS, and provides insights for investigating the role of Satb1 in the mature CNS. PMID- 21658420 TI - Appetitive behaviours of children attending obesity treatment. AB - Associations between appetite and adiposity have not been examined in clinical samples of obese children. The Children's Eating Behaviour Questionnaire (CEBQ) was used to compare appetite in community (n=406) and clinical (n=66) samples. Clear graded patterns were seen for food responsiveness and emotional overeating; levels increased with increasing BMI SDS and the clinical sample scored highest. The reverse was seen for satiety responsiveness/slowness in eating. Differences were not solely explained by weight differences, suggesting that the clinical sample had more pronounced 'obesogenic' appetitive traits. This could make adherence to dietary guidance difficult. PMID- 21658421 TI - Association of susceptibility to Takayasu arteritis in Chinese Han patients with HLA-DPB1. AB - Takayasu arteritis (TA) is a chronic large-vessel vasculitis of unknown etiology. Human leukocyte antigen (HLA) alleles play an important role in the development of TA. The association between HLA-DPB1 and TA in Chinese Han patients remains unclear. We examined the genotypes of 72 Chinese patients with TA and 180 healthy unrelated individuals who did not have any history of chronic disease. HLA-DPB1 genotypes were determined using polymerase chain reaction sequence-specific primer (PCR-SSP). The frequencies of DPB1*09 and DPB1*1701 among the TA patients were significant higher than among the controls. The mean age of the onset of TA in patients with DPB1*1701 alleles was significant earlier than the DPB1*1701 negative patients. Our results indicated that the HLA-DPB1*09 and DPB1*1701 alleles might increase the susceptibility to TA, and the individuals possessing DPB1*1701 had the earlier onset age of the disease. Further studies on the mechanism underlying are warranted. PMID- 21658422 TI - No evidence of association of the KLF12 gene with rheumatoid arthritis in Spanish and Dutch cohorts and a meta-analysis of published data. AB - The aim of the present study was to replicate the previously reported association of KLF12 gene polymorphisms with rheumatoid arthritis (RA). Two independent cohorts from Spain (1,360 RA patients and 1,520 controls) and the Netherlands (1,018 RA patients and 1,150 controls) were genotyped for KLF12 rs1887346 and rs9565072 single-nucleotide polymorphisms using a TaqMan 5'-allele discrimination assay. No evidence of association of RA with the minor T allele of rs9565072 (31.82% vs 33.73%; p = 0.14, odds ratios [OR] 0.92 [95% confidence interval (CI) 0.82-1.03]) or the minor A allele of rs1887346 polymorphism (21.60% vs 21.77%; p = 0.88, OR 0.99 [95% CI 0.87-1.13]) was observed in Spanish patients compared with healthy controls. This lack of association was also confirmed in the Dutch cohort: the minor T allele frequency of rs9565072 in Dutch RA patients was 35.34% versus 35.57% in controls; p = 0.87, OR 0.99 (95% CI 0.87-1.12); and the minor A allele frequency of rs1887346 in Dutch RA patients was 27.64% versus 28.17% in controls; p = 0.70, OR 0.97 (95% CI 0.85-1.12). A meta-analysis of published KLF12 gene association with RA revealed a pooled OR of 0.99 (95% CI 0.93-1.04) for rs1887346 and a pooled OR of 0.99 (95% CI 0.95-1.04) for rs9565072. In conclusion, our findings indicate that the KLF12 rs1887346 and rs9565072 polymorphisms do not play a relevant role in RA. PMID- 21658423 TI - Development of a tailored vaccine against challenge with very virulent infectious bursal disease virus of chickens using reverse genetics. AB - Due to the problems associated with traditional methods for infectious bursal disease virus (IBDV) vaccine development and the pressure of evolution and variation of very virulent strains, it is urgent to develop IBDV vaccine rapidly with novel approaches. Using reverse genetics, the aim of this study was to generate a tailored vaccine strain (rGtHLJVP2) with its VP2 gene similar to very virulent IBDV (vvIBDV) to prevent the prevalence of IBDV. Characteristics of rGtHLJVP2 were evaluated in both cell culture and SPF chickens. rGtHLJVP2 replicated well as its parental strain Gt in vitro and in vivo. Immunization of SPF chickens with rGtHLJVP2 resulted in comparable antibody titers against IBDV as that of the medium virulent live vaccine B87, which was significant higher than that of attenuated vaccine Gt. Challenge studies with 10(4)ELD(50) of prevalent homogeneous or heterogeneous vvIBDV revealed complete (100%) protection in the groups immunized with rGtHLJVP2. No significant clinical and pathological lesions were observed in chickens immunized with rGtHLJVP2. Our data demonstrated that rGtHLJVP2 could be used as a novel vaccine candidate for prevention against vvIBDV. PMID- 21658424 TI - Quantitative and subcellular localization analysis of the nuclear isoform dUTP pyrophosphatase in alkylating agent-induced cell responses. AB - Our previous proteome analysis showed that the nuclear isoform of dUTP pyrophosphatase (DUT-N) was identified in the culture medium of human amnion FL cells after exposure to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). These results suggest that DUT-N may be a potential early biomarker to assess the risk of alkylating agents exposure. DUT-N is one of the two isoforms of deoxyuridine triphosphate nucleotidohydrolase (dUTPase). Our current knowledge of DUT-N expression in human cells is very limited. In the current study, we first investigated the appearance of DUT-N in the culture medium of different human cell lines in response to a low concentration of MNNG exposure. We verified that the MNNG-induced appearance of DUT-N in the extracellular environment is cell-specific. Western blot analysis confirmed that the intracellular DUT-N changes responded to MNNG in a concentration-dependent and cell-specific manner. Furthermore, subcellular fraction experiments showed that 0.25MUM MNNG treatment dramatically increased the DUT-N expression levels in the cytoplasmic extracts prepared from both FL and HepG2 cells, increased DUT-N levels in nuclear extracts prepared from HepG2 cells, and decreased DUT-N levels in nuclear extracts from FL cells. Morphological studies using immunofluorescence showed that a low concentration of MNNG could alter the distribution of DUT-N in FL and HepG2 cells in different ways. Taken together, these studies indicate a role of DUT-N in alkylating agent-induced cell responses. PMID- 21658425 TI - Cysteinyl leukotrienes synthesis is involved in aristolochic acid I-induced apoptosis in renal proximal tubular epithelial cells. AB - Aristolochic acid I (AAI) is a primary nephrotoxin and carcinogen that is found in some Chinese herbal medicines, and AAI is responsible for the progression of aristolochic acid nephropathy. The membrane associated proteins in the eicosanoid and glutathione metabolism (MAPEG) superfamily are associated with cysteinyl leukotrienes (cysLTs) synthesis. The present study investigated whether cysLTs synthesis was involved in AAI-induced renal proximal tubular epithelial cell injury in LLC-PK1 cells. Based on MAPEG and related molecular events, the potential mechanisms of AAI-induced LLC-PK1 cell injury were explored. AAI triggered the mitochondrial/caspase apoptotic pathway in LLC-PK1 cells, which was indicated by an enhanced Bax/Bcl-2 ratio, loss of mitochondrial membrane potential, cytochrome C release, and caspase 3 activation. In addition, AAI induced cysLTs release was accompanied by selective upregulation of 5 lipoxygenase activating protein (FLAP) and microsomal glutathione S-transferase 3 (mGST3) in a concentration-dependent manner. The FLAP inhibitor MK866 significantly protected cells from AAI-induced apoptosis. Furthermore, activation of extracellular signal-regulated kinase (ERK) 1/2 and inhibition of phosphorylated p38-MAPK were demonstrated at the early phase of AAI treatment. Notably, the MEK/ERK inhibitor U0126 reversed AAI-induced apoptosis and reduced both FLAP, mGST3 and mitochondrial/caspase protein expression. Taken together, these findings suggest that cysLTs synthesis is involved in AAI-induced apoptosis via an ERK activation way. PMID- 21658426 TI - Several agents and pathways regulate lipolysis in adipocytes. AB - Adipose tissue is the only tissue capable of hydrolyzing its stores of triacylglycerol (TAG) and of mobilizing fatty acids and glycerol in the bloodstream so that they can be used by other tissues. The full hydrolysis of TAG depends on the activity of three enzymes, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoacylglycerol lipase, each of which possesses a distinct regulatory mechanism. Although more is known about HSL than about the other two enzymes, it has recently been shown that HLS and ATGL can be activated simultaneously, such that the mechanism that enables HSL to access the surface of lipid droplets also permits the stimulation of ATGL. The classical pathway of lipolysis activation in adipocytes is cAMP-dependent. The production of cAMP is modulated by G-protein-coupled receptors of the Gs/Gi family and cAMP degradation is regulated by phosphodiesterase. However, other pathways that activate TAG hydrolysis are currently under investigation. Lipolysis can also be started by G-protein-coupled receptors of the Gq family, through molecular mechanisms that involve phospholipase C, calmodulin and protein kinase C. There is also evidence that increased lipolytic activity in adipocytes occurs after stimulation of the mitogen-activated protein kinase pathway or after cGMP accumulation and activation of protein kinase G. Several agents contribute to the control of lipolysis in adipocytes by modulating the activity of HSL and ATGL. In this review, we have summarized the signalling pathways activated by several agents involved in the regulation of TAG hydrolysis in adipocytes. PMID- 21658427 TI - Calcium decoding mechanisms in plants. AB - Ca(2+) is a crucial second messenger that is involved in mediating responses to various biotic and abiotic environmental cues and in the regulation of many developmental processes in plants. Intracellular Ca(2+) signals are realized by spatially and temporally defined changes in Ca(2+) concentration that represent stimulus-specific Ca(2+) signatures. These Ca(2+) signatures are sensed, decoded and transmitted to downstream responses by a complex tool kit of Ca(2+) binding proteins that function as Ca(2+) sensors. Plants possess an extensive and complex array of such Ca(2+) sensors that convey the information presented in the Ca(2+) signatures into phosphorylation events, changes in protein-protein interactions or regulation of gene expression. Prominent Ca(2+) sensors like, Calmodulins (CaM), Calmodulin-like proteins (CMLs), calcium dependent protein kinases (CDPKs), Calcineurin B-like proteins (CBLs) and their interacting kinases (CIPKs) exist in complex gene families and form intricate signaling networks in plants that are capable of robust and flexible information processing. In this review we reflect on the recently gained knowledge about the mechanistic principles of these Ca(2+) sensors, their biochemical properties, physiological functions and newly identified targets proteins. These aspects will be discussed in the context of emerging functional principles that govern the information processing via these signaling modules. PMID- 21658428 TI - A more detailed picture of the interactions between virtual screening-derived hits and the DNA G-quadruplex: NMR, molecular modelling and ITC studies. AB - The growing amount of literature about G-quadruplex DNA clearly demonstrates that such a structure is no longer viewed as just a biophysical strangeness but it is instead being considered as an important target for the treatment of various human disorders such as cancers or venous thrombosis. In this scenario, with the aim of finding brand new molecular scaffolds able to interact with the groove of the DNA quadruplex [d(TGGGGT)](4), we recently performed a successful structure based virtual screening (VS) campaign. As a result, six molecules were found to be somehow groove binders. Herein, we report the results of novel NMR titration experiments of these VS-derived ligands with modified quadruplexes, namely [d(TGG(Br)GGT)](4) and [d(TGGGG(Br)T)](4). The novel NMR spectroscopy experiments combined with molecular modelling studies, allow for a more detailed picture of the interaction between each binder and the quadruplex DNA. Noteworthy, isothermal titration calorimetry (ITC) measurements on the above-mentioned compounds revealed that 2, 4, and 6 besides their relatively small dimensions bind the DNA quadruplex [d(TGGGGT)](4) with higher affinity than distamycin A, to the best of our knowledge, the most potent groove binder identified thus far. PMID- 21658429 TI - AMP-activated protein kinase activates neuropeptide Y neurons in the hypothalamic arcuate nucleus to increase food intake in rats. AB - AMP-activated protein kinase (AMPK) is an energy sensor that is activated by the increase of intracellular AMP:ATP ratio. AMPK in the hypothalamic arcuate nucleus (ARC) is activated during fasting and the activation of AMPK stimulates food intake. To clarify the pathway underlying AMPK-induced feeding, we monitored the activity of single ARC neurons by measuring cytosolic Ca(2+) concentration ([Ca(2+)](i)) with fura-2 fluorescence imaging. An AMPK activator, AICA-riboside (AICAR), at 200 MUM increased [Ca(2+)](i) in 24% of ARC neurons. AMPK and acetyl CoA carboxylase were phosphorylated in the neurons with [Ca(2+)](i) responses to AICAR. AICAR-induced [Ca(2+)](i) increases were inhibited by Ca(2+)-free condition but not by thapsigargin, suggesting that AICAR increases [Ca(2+)](i) through Ca(2+) influx from extracellular space. Among AICAR-responding ARC neurons, 38% were neuropeptide Y (NPY)-immunoreactive neurons while no proopiomelanocortin (POMC)-immunoreactive neuron was observed. Intracerebroventricular administration of AICAR increased food intake, and the AICAR-induced food intake was abolished by the co-administration of NPY Y1 receptor antagonist, 1229U91. These results indicate that the activation of AMPK leads to the activation of ARC NPY neurons through Ca(2+) influx, thereby causing NPY-dependent food intake. These mechanisms could be implicated in the stimulation of food intake by physiological orexigenic substances. PMID- 21658430 TI - Effects of lisuride hydrogen maleate on pericontusional tissue metabolism, brain edema formation, and contusion volume development after experimental traumatic brain injury in rats. AB - After traumatic brain injury (TBI), the primary insult is followed by a cascade of secondary events which lead to enlargement of the primary lesion and are potentially amenable to therapeutic intervention. Lisuride is a dopaminergic agonist with additional serotoninergic, adrenergic, and glutamate antagonistic properties. In lack of previous data on lisuride in TBI, and based on well documented changes of dopamine metabolism after TBI, we speculated that lisuride could provide neuroprotection in the acute and post-acute stage of controlled cortical impact (CCI) injury in rats. The effect of varying dosages of lisuride on physiological parameter was investigated. Cerebral microdialysis (CMD) was employed to provide a temporal profile of lactate, pyruvate, glucose and glutamate in the pericontusional brain tissue. Additionally, brain edema formation and the development of contusion volume were assessed. In this study, no effect of treatment was seen on physiological parameters or microdialysis profiling of tissue metabolites. Whereas posttraumatic increase in brain water content and an increase in contusion volume could be observed, there was no significant effect of treatment. Taken together, our results suggest that lisuride does not provide neuroprotection in the CCI model at the acute and subacute stages. Based on the available literature, however, it might be possible that dopamine agonists such as lisuride, respectively, improve outcome in terms of cognitive function in a chronic setting. PMID- 21658431 TI - Decreased expression of Bmal2 in patients with Parkinson's disease. AB - Bmal1 is one of the central regulators of the clock machinery. Recently, we examined the expression profile of Bmal1 in total leukocytes for a 12h duration during the evening, overnight, and the morning, in subjects with Parkinson's disease (PD) and healthy controls. The results indicate that the expression of Bmal1 is significantly lower in PD patients versus control subjects. However, it is still unclear whether other key regulators of the clock machinery, especially Bmal2, the paralog of Bmal1, are also expressed differently in PD. To address this issue, the expression profiles of Bmal2, Clock, and Dec1 were examined in the same samples using real-time RT-PCR assay. The results show a difference in the expression pattern of Bmal2, but not Clock and Dec1. The expression of Bmal2 is significantly lower in PD at 21:00 h (p=0.005) and 00:00 h (p=0.025). These results together with our previous findings suggest that the molecular clock in total leukocytes is disturbed in PD patients. PMID- 21658432 TI - Lesions of the dentate and interposed nuclei are associated with impaired prehension in cerebellar patients. AB - In a recent study using voxel based lesion symptom mapping (VLSM) in cerebellar patients following stroke we found associations of prehensile deficits to lesions of the cerebellar cortex and dentate nucleus (DN). Associations to lesions of the interposed nucleus (IN), which has been shown to contribute to prehension in monkeys, could not be established. One possible reason was that the IN was largely unaffected in the stroke patients. To further address the question of IN involvement in prehension we performed VLSM in patients with surgical cerebellar lesions (n=20), exhibiting high lesion overlap in the medial and intermediate cerebellum including the IN. Prehensile deficits were quantified by analyses of movement kinematics and finger forces. In the patient population prehensile deficits comprised lower movement velocity in reaching and increased lift-off time in grasping. These were associated with lesions of the intermediate and lateral cerebellar cortex together with their output nuclei. Specifically, IN lesions were linked to increased lift-off time in grasping and not to slower reaching movements. Thus, our data support IN contribution particularly for the fluent production of grip forces during dexterous prehension in humans. PMID- 21658433 TI - Time- and concentration-dependent activation of TRPA1 by hydrogen sulfide in rat DRG neurons. AB - Hydrogen sulfide (H(2)S) is considered as a gasotransmitter. Although several reports have shown that H(2)S stimulates sensory neurons, the primary targets of H(2)S remain controversial. We investigated the effects of H(2)S on cultured sensory neurons isolated from rat dorsal root ganglion (DRG) using Ca(2+) imaging and whole-cell voltage-clamp techniques. Brief (2 min) application of NaHS (1mM), a donor of H(2)S, evoked marked increases in intracellular Ca(2+) concentration ([Ca(2+)](i)) in a subset of DRG neurons. These neurons also responded to both capsaicin and mustard oil (MO), transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) agonists, respectively. The NaHS-evoked [Ca(2+)](i) increases were inhibited by a removal of external Ca(2+) and antagonists for TRPA1, but not for TRPV1 or voltage-dependent Ca(2+) channels. At -80 mV, NaHS evoked inward currents in MO-sensitive neurons, which were also inhibited by a TRPA1 antagonist. Even at lower concentration (<=1 MUM), the 10-min application of NaHS increased [Ca(2+)](i) in a time- and concentration-dependent manner. These results suggest that H(2)S stimulates sensory neurons via activation of TRPA1. Endogenous H(2)S may be involved in physiological processes through TRPA1. PMID- 21658434 TI - The multiple roles of amphiregulin in human cancer. AB - Amphiregulin (AREG) is one of the ligands of the epidermal growth factor receptor (EGFR). AREG plays a central role in mammary gland development and branching morphogenesis in organs and is expressed both in physiological and in cancerous tissues. Various studies have highlighted the functional role of AREG in several aspects of tumorigenesis, including self-sufficiency in generating growth signals, limitless replicative potential, tissue invasion and metastasis, angiogenesis, and resistance to apoptosis. The oncogenic activity of AREG has already been described in the most common human epithelial malignancies, such as lung, breast, colorectal, ovary and prostate carcinomas, as well as in some hematological and mesenchymal cancers. Furthermore, AREG is also involved in resistance to several cancer treatments. In this review, we describe the various roles of AREG in oncogenesis and discuss its translational potential, such as the development of anti-AREG treatments, based on AREG activity. In the last decade, independent groups have reported successful but sometimes contradictory results in relation to the potential of AREG to serve as a prognostic and/or predictive marker for oncology, especially with regard to anti-EGFR therapies. Thus, we also discuss the potential usefulness of using AREG as a therapeutic target and validated biomarker for predicting cancer outcomes or treatment efficacy. PMID- 21658435 TI - Administration of the 5-HT2C receptor antagonist SB-242084 into the nucleus accumbens blocks the expression of ethanol-induced behavioral sensitization in Albino Swiss mice. AB - Behavioral sensitization to the stimulating effect of ethanol (EtOH) or other drugs, which can be observed in mice as an increase in locomotor activity after repeated administration, has been associated with neuroadaptations within the dopaminergic mesolimbic pathway. In the nucleus accumbens (NAc), an afferent region of the mesolimbic pathway, dopamine (DA) release can be modulated by serotonergic 2C receptors (5-HT2CR). The aim of the present study was to evaluate the function of 5-HT2CR in the expression of EtOH-induced behavioral sensitization in Albino Swiss mice with various levels of sensitization to EtOH. In the four experiments that we performed, the mice were given saline or 2.2 g/kg EtOH daily for 21 days. Based on their locomotion on day 21, the EtOH-pretreated mice were assigned to one of two groups, highly sensitized or weakly sensitized to the stimulating effect of EtOH. In each experiment, 2 weeks after the 21-day treatment (withdrawal period), the mice were submitted to four pharmacological challenges of two drug treatments each. The mice in experiments 1 and 2 received two i.p. injections, whereas the mice in experiments 3 and 4 received an intra NAc administration followed by an i.p. injection. The challenges were: saline+saline; saline+EtOH; SB-242084 (a 5-HT2CR antagonist; 0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 MUg/side intra-NAc)+EtOH; and SB-242084 (0.5, 1.0 or 2.0 mg/kg i.p. or 1.0 or 2.0 MUg/side intra-NAc)+saline. At all tested doses, i.p. administration of SB-242084 did not affect the stimulating effect of EtOH in the highly sensitized mice. However, when delivered by intra-NAc administration, SB 242084 reduced (at 1.0 MUg/side) or completely blocked (at 2.0 MUg/side) the expression of EtOH-induced behavioral sensitization in the highly sensitized mice. These findings suggest that the expression of behavioral sensitization to the stimulating effect of EtOH depends on accumbal 5-HT2CR activity. PMID- 21658436 TI - Impact of deltamethrin exposure on mRNA expression levels of metallothionein A, B and cytochrome P450 1A in rainbow trout muscles. AB - Metallothioneins (MT) are widely utilized to identify specific responses to heavy metal pollution. In addition, there is evidence demonstrating that in vertebrates MT synthesis is stimulated by different endogenous and exogenous agents in particular compounds leading to production of ROS. Also, cytochrome P450 1A can enhance the generation of ROS. On this basis, MT and CYP 1A induction can be considered as biomarkers of oxidative stress. In the current study, we examined the influences of pesticide administration on the expression of MT-A, MT-B and CYP 1A. For this purpose, we produced muscle metallothionein-A, metallothionein-B and cytochrome P450 1A cDNAs and used quantitative RT-PCR to assay mRNAs in rainbow trout exposed to acute and long-term deltamethrin administration. We observed that deltamethrin exposure significantly (p<0.05) increased the expression levels of Cyp1A, MT-A and MT-B in a time dependent manner. Results of our study contributes to the identification of inducers of such biomarkers in addition to well known agents. PMID- 21658437 TI - Gene expression profile of terminal end buds in rat mammary glands exposed to diethylstilbestrol in neonatal period. AB - Diethlstilbestrol (DES) is a synthetic estrogen prescribed to several millions of pregnant women worldwide. The risk for breast cancer after age 40 in women prenatally exposed to DES has been reported; however, the precise mechanism of susceptibility to breast cancer remains to be resolved. We investigated the global gene expression profile of terminal end buds (TEBs), the target of carcinogen, in rat mammary glands neonatally exposed to a low- or high-dose DES at postnatal days (PND) 35 and 45, equivalent to the peripubertal stage in humans. In all groups, the number of TEBs gradually increased, peaked at PND35 and decreased at PND49. At PND35 and 49, the low-dose DES-treated group (low-DES group) showed the highest number of TEBs. In the low-DES group at PND35, beta casein, gamma-casein and whey acidic protein (WAP) mRNA expression increased 8.2 fold, 26.1-fold and 13.3-fold, respectively, whereas gamma-casein and WAP mRNA decreased 17.6-fold and 27.7-fold, respectively, at PND49. The most significant network revealed by Ingenuity Pathway Analysis (IPA) software showed the relevance of NF-kappaB in low-DES group. The present findings suggest that the deregulation of mammary gland differentiation and development-related genes could be induced and cause the increased number of terminal duct lobular units (TDLUs) in human mammary glands of DES daughters in a critical period of mammary gland development. PMID- 21658438 TI - Polyphyllin D, a steroidal saponin from Paris polyphylla, inhibits endothelial cell functions in vitro and angiogenesis in zebrafish embryos in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angiogenesis, the process of blood vessel formation, is critical to tumour growth. The importance of angiogenesis in tumour development has lead to the development of anti-angiogenic strategies to inhibit tumour growth. In this study, polyphyllin D (PD), an active component in Chinese herb, Paris polyphylla, was evaluated for its potential anti-angiogenic effects. MATERIALS AND METHODS: The inhibitory effects of PD on three important processes involved in angiogenesis, i.e. proliferation, migration and differentiation were examined using human microvascular endothelial cell line HMEC-1 by MTT assay, scratch assay and tube formation assay, respectively. Using zebrafish embryos as an animal model of angiogenesis, the anti-angiogenic effect of PD was further verified in vivo. RESULTS: PD suppressed the growth of HMEC-1 cells at 0.1-0.4 MUM without toxic effects. At 0.3 MUM and 0.4 MUM, PD significantly inhibited endothelial cell migration and capillary tube formation. About 70% of the zebrafish embryos showed defects in intersegmental vessel formation upon treatment with PD at concentrations of 0.156 MUM and 0.313 MUM. CONCLUSION: The anti-angiogenic effects of PD have been explored in the study which implied a potential therapeutic development of PD in cancer treatment. PMID- 21658439 TI - Pro-apoptotic and anticancer properties of Thapring - A Tibetan herbal formulation. AB - AIM OF THE STUDY: To evaluate the pro-apoptotic and anti-tumorigenic properties of Thapring - a Traditional Tibetan Medicine - in hepatoma cells and in a transgenic mouse model of hepatocellular carcinoma. MATERIAL AND METHODS: The pro apoptotic action and growth inhibition property of Thapring were assessed in Huh7, HepG2 and A549 cell lines using flow cytometry and MTT assay, respectively. Confocal microscopy for colocalization of cytochrome c and mitochondria was done using dsRed mitotracker in Huh7 cells. The activation of p38 MAP kinase and p53 pathway was evaluated by Western blotting. Serological studies for liver function, vascular endothelial growth factor and superoxide dismutase were assessed in the serum of X15-myc transgenic mice. Immuno-histochemical studies for Bcl2 and p21(Waf1) expression were also carried out in the liver section of the above mice. RESULTS: Treatment with Thapring inhibited proliferation and accumulation of hepatoma cells in G1 phase. There was increased cytochrome c release from mitochondria and decreased Bcl2 levels - the key markers of apoptotic cell death. Besides activation of p38 MAP kinase and increased p53 expression were also observed. Oral administration of Thapring in transgenic mice lowered serum VEGF levels and conferred hepatoprotection as evident from normal serum ALT levels. Further, immunohistochemical analysis of the liver samples revealed reduced expression of anti-apoptotic protein Bcl2 and over-expression of cell cycle regulator p21(Waf1). CONCLUSIONS: The ability of Thapring to impose growth arrest and trigger pro-apoptotic death in cell culture as well as ameliorative effects in vivo provides scientific basis for its usefulness as traditional medicine and its clinical application in adjunct/combination therapy along with other known anticancer drugs. PMID- 21658440 TI - Gastroprotective effect of standardized leaf extract from Argyreia speciosa on experimental gastric ulcers in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Argyreia speciosa (L.f), Sweet (Family Convolvulaceae) is used traditionally in Indian System of Medicine as aphrodisiac, rejuvenating agent, intellect promoting agent, brain tonic and in the therapy of hepatomegaly, diabetes and chronic ulcer. AIM OF THE STUDY: To study the gastroprotective effect of standardized butanol fraction of Argyreia speciosa leaf (ASE). MATERIALS AND METHODS: The butanol fraction of Argyreia speciosa leaf (ASE; 50, 100 and 200mg/kg body weight) was administered orally, twice daily for 5 days for prevention from Aspirin (ASP)-, ethanol (EtOH)-, cold restraint stress (CRS) - and pylorus ligation (PL)-induced ulcers. Estimation of antioxidant enzymes activity was carried out in CRS-induced ulcer model, and various gastric secretion parameters like volume of gastric juice, acid output, and pH value were estimated in PL-induced ulcer model. RESULT: ASE showed dose dependent ulcer protective effect in ASP 23.64-58.76% (p<0.01 to p<0.001), EtOH 15.45-58.45% (p<0.001), CRS 19.39-78.36% (p<0.001) and PL 19.67-69.04% (p<0.05 to p<0.01), respectively. The percentage of protection by standard drug ranitidine was 77.77-84.32% (p<0.01 to p<0.001) in various gastric ulcer models. The gastric wall mucus was significantly (p<0.001) enhanced by ASE and is regarded as the first line of defence against EtOH-induced gastric ulcers showing cytoprotective property. ASE showed a marginal decrease in volume, acid pepsin concentration and acid pepsin output. However, ASE reduced the ulcer index with significant decrease in LPO level (p<0.001), and SOD level (p<0.01 to p<0.001) as compared with CRS-induced group. A gradual and significant increase in CAT values were observed at 100 and 200mg/kg dose levels (p<0.01 to p<0.001). CONCLUSIONS: The results of our study revealed that Argyreia speciosa possess significant dose dependent gastroprotective activity, probably due to its free radical scavenging activity. PMID- 21658441 TI - Histological characterisation of the ethanol-induced microphthalmia phenotype in a chick embryo model system. AB - The eye is a sensitive indicator of the teratogenic effects of ethanol with ophthalmic defects such as microphthalmia frequently observed in FAS children. In this study, we have optimised the chick-embryo model system to investigate ethanol-induced ocular defects. Injection of 20% ethanol (125MUl) directly into the yolk sac of HH-stage 7 embryos resulted in an overall 30% incidence of eye anomalies including microphthalmia. Ocular measurements showed that this treatment regime caused a significant reduction in overall globe size. Histological examination of microphthalmic specimens revealed three subgroups: (1) all ocular structures developed but were significantly retarded compared to age matched controls, (2) the bi-layered optic cup developed but with no evidence of lens induction, and (3) the optic vesicle failed to invaginate but remained as a vesicular structure comprising of a single layer of retinal pigment cells with no evidence of a neuro-retinal cell layer or lens structure. Further analysis identified clusters of apoptotic bodies in the ventral telencephalon, a region responsible for the expression of important genes in ocular specification. These results support a growing body of evidence, indicating that ethanol targets inductive signals in early eye development involving lens formation and retinal ganglion cell differentiation. The possible involvement of Shh, Fgf8, Bmp4 and Pax6 is discussed in relation to these outcomes. PMID- 21658443 TI - Inhibition of Cu2+-mediated generation of reactive oxygen species by the small heat shock protein alphaB-crystallin: the relative contributions of the N- and C terminal domains. AB - Oxidative stress, Cu(2+) homeostasis, and small heat shock proteins (sHsp's) have important implications in several neurodegenerative diseases. The ubiquitous sHsp alphaB-crystallin is an oligomeric protein that binds Cu(2+). We have investigated the relative contributions of the N- and C-terminal (C-TDalphaB crystallin) domains of alphaB-crystallin to its Cu(2+)-binding and redox attenuation properties and mapped the Cu(2+)-binding regions. C-TDalphaB crystallin binds Cu(2+) with slightly less affinity and inhibits Cu(2+) catalyzed, ascorbate-mediated generation of ROS to a lesser extent than alphaB crystallin. [Cu(2+)]/[subunit] stoichiometries for redox attenuation by alphaB crystallin and C-TDalphaB-crystallin are 5 and 2, respectively. Both alphaB crystallin and C-TDalphaB-crystallin also inhibit the Fenton reaction of hydroxyl radical formation. Trypsinization of alphaB-crystallin bound to a Cu(2+)-NTA column and MALDI-TOF analysis of column-bound peptides yielded three peptides located in the N-terminal domain, and in-solution trypsinization of alphaB crystallin followed by Cu(2+)-NTA column chromatography identified four additional Cu(2+)-binding peptides located in the C-terminal domain. Thus, Cu(2+) binding regions are distributed in the N- and C-terminal domains. Small-angle X ray scattering and sedimentation-velocity measurements indicate quaternary structural changes in alphaB-crystallin upon Cu(2+) binding. Our study indicates that an oligomer of alphaB-crystallin can sequester a large number (~150) of Cu(2+) ions. It acts like a "Cu(2+) sponge," exhibits redox attenuation of Cu(2+), and has potential roles in Cu(2+) homeostasis and in preventing oxidative stress. PMID- 21658444 TI - Simplified method for the collection, storage, and comet assay analysis of DNA damage in whole blood. AB - Single-cell gel electrophoresis (comet assay) is one of the most common methods used to measure oxidatively damaged DNA in peripheral blood mononuclear cells (PBMC), as a biomarker of oxidative stress in vivo. However, storage, extraction, and assay workup of blood samples are associated with a risk of artifactual formation of damage. Previous reports using this approach to study DNA damage in PBMC have, for the most part, required the isolation of PBMC before immediate analysis or freezing in cryopreservative. This is very time-consuming and a significant drain on human resources. Here, we report the successful storage of whole blood in ~250 MUl volumes, at -80 degrees C, without cryopreservative, for up to 1 month without artifactual formation of DNA damage. Furthermore, this blood is amenable for direct use in both the alkaline and the enzyme-modified comet assay, without the need for prior isolation of PBMC. In contrast, storage of larger volumes (e.g., 5 ml) of whole blood leads to an increase in damage with longer term storage even at -80 degrees C, unless a cryopreservative is present. Our "small volume" approach may be suitable for archived blood samples, facilitating analysis of biobanks when prior isolation of PBMC has not been performed. PMID- 21658442 TI - Collateralized dorsal raphe nucleus projections: a mechanism for the integration of diverse functions during stress. AB - The midbrain dorsal raphe nucleus (DR) is the origin of the central serotonin (5 HT) system, a key neurotransmitter system that has been implicated in the expression of normal behaviors and in diverse psychiatric disorders, particularly affective disorders such as depression and anxiety. One link between the DR-5-HT system and affective disorders is exposure to stressors. Stress is a major risk factor for affective disorders, and stressors alter activity of DR neurons in an anatomically specific manner. Stress-induced changes in DR neuronal activity are transmitted to targets of the DR via ascending serotonergic projections, many of which collateralize to innervate multiple brain regions. Indeed, the collateralization of DR efferents allows for the coordination of diverse components of the stress response. This review will summarize our current understanding of the organization of the ascending DR system and its collateral projections. Using the neuropeptide corticotropin-releasing factor (CRF) system as an example of a stress-related initiator of DR activity, we will discuss how topographic specificity of afferent regulation of ascending DR circuits serves to coordinate activity in functionally diverse target regions under appropriate conditions. PMID- 21658445 TI - Early embryonic ethanol exposure impairs shoaling and the dopaminergic and serotoninergic systems in adult zebrafish. AB - Fetal alcohol syndrome (FAS) is a devastating disorder accompanied by numerous morphological and behavioral abnormalities. Human FAS has been modeled in laboratory animals including the zebrafish. Recently, embryonic exposure to low doses of ethanol has been shown to impair behavior without any gross morphological alterations in zebrafish. The exposed zebrafish showed reduced responses to animated conspecific images. The effect of embryonic ethanol exposure, however, has not been investigated in a real shoal and the potential mechanisms underlying the behavioral impairment are also unknown. Here we show that a 2h long immersion in 0.25% and 0.50% (vol/vol) alcohol at 24h post fertilization significantly increases the distance among members of freely swimming groups of zebrafish when measured at 70 days post fertilization. We also show that this impaired behavior is accompanied by reduced levels of dopamine, DOPAC, serotonin and 5HIAA as quantified by HPLC from whole brain extracts. Our results demonstrate that even very low concentrations of alcohol applied for a short period of time during the development of zebrafish can impair behavior and brain function. We argue that the observed behavioral impairment is not likely to be due to altered performance capabilities, e.g. motor function or perception, but possibly to social behavior itself. We also argue that our neurochemical data represent the first step towards understanding the mechanisms of this abnormality in zebrafish, which may lead to better modeling of, and ultimately perhaps better therapies for human FAS. PMID- 21658446 TI - Modulation of Nrf2 expression alters high glucose-induced oxidative stress and antioxidant gene expression in mouse mesangial cells. AB - Reactive oxygen species (ROS) play an important role in the pathogenesis of diabetic nephropathy. Nuclear factor erythroid 2-related factor 2 (Nrf2) can up regulate the expression of antioxidant genes and protect cells from oxidative damage. The current study is aimed at examining the effect of modulation of Nrf2 expression on high glucose-induced oxidative stress and Nrf2-targeting antioxidant expression in mouse mesangial cells. In this study, mouse mesangial cells were transiently transfected with Nrf2-plasmid or the Nrf2-specific siRNA. The high glucose-induced intracellular ROS, malondialdehyde, cell proliferation, and TGF-beta1 secretion were measured. The levels of Nrf2, heme oxygenase-1 (HO 1), gamma-glutamylcysteine synthethase (gamma-GCS) expression, and nuclear expression of Nrf2 in mouse mesangial cells were determined. We found that high glucose induced ROS and malondialdehyde generation in mouse mesangial cells. Induction of Nrf2 over-expression reduced the high glucose-induced ROS and malondialdehyde production, inhibited cell proliferation and TGF-beta1 secretion, accompanied by up-regulating the expressions of HO-1 and gamma-GCS in mouse mesangial cells. However, knockdown of Nrf2 expression displayed reverse effects in mouse mesangial cells. All these results indicated that Nrf2 and its downstream antioxidants, HO-1 and gamma-GCS, are negative regulators of high glucose-induced ROS-related mouse mesangial cell dysfunction. PMID- 21658447 TI - Apico-basal polarity in polycystic kidney disease epithelia. AB - Epithelial cell polarity is essential for the establishment and maintenance of morphological and functional asymmetries that underlie normal renal structure and function and are brought about by the appropriate delivery of growth factor receptors and ion and fluid transporters and channels to apical or basolateral cell membranes. The fundamental process of cellular polarization is established early during development and is controlled by sets of evolutionarily conserved proteins that integrate intrinsic and extrinsic polarity cues. Specialized structural domains between adjacent cells and cells with their matrix, termed adherens junctions (AJ) and focal adhesions (FA), respectively, are formed that contain specific components of multi-molecular complexes acting as sites to recruit proteins and to activate intracellular mechano-transduction pathways. Regulation of these processes results in tight spatio-temporal control of renal tubule growth and lumen diameter. Abnormalities in macromolecular polarization complexes lead to a variety of diseases in different organs, a common example of which is Polycystic Kidney Disease (PKD), where epithelial cysts replace normal renal tubules. Membrane protein polarity defects in Autosomal Dominant (AD) PKD include the mis-polarization of normally basolateral membrane proteins to apical, lumenal membranes, such as epidermal growth factor (EGFR/ErbB) receptors and Na(+)K(+)-ATPase-alpha1 subunit; mis-polarization of normally apical membrane proteins to basolateral membranes, including the Na(+)K(+)2Cl(-) (NKCC1) symporter; and the failure to traffic and insert proteins into membranes resulting in their intracellular accumulation, such as E-cadherin and the beta1 subunit of Na(+)K(+)-ATPase. Abnormalities in structural AJ, FA and polarity complexes in ADPKD epithelia include loss of E-cadherin, and focal adhesion kinase (FAK), MALS-3, Crb and Dlg complexes as well as disruptions in Rab/sec and syntaxin trafficking and membrane docking pathways. Since proper polarization of epithelial cells lining renal tubules is essential for normal kidney development and differentiation to prevent abnormal cystic dilation, interventions to reverse polarity defects to normal would offer therapeutic opportunities for PKD. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 21658448 TI - Investigating the barrier function of skin lipid models with varying compositions. AB - The lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the barrier function. The main lipid classes in stratum corneum are ceramides, cholesterol, and free fatty acids. In previous publications, a lipid model was presented, referred to as the stratum corneum substitute (SCS), that closely mimics the SC lipid organization and SC barrier function. In the present study, we use the SCS to study the effect of changes in lipid organization on the lipid barrier function using benzoic acid as permeation compound. First, in the SCS, we increased the level of one of the three major lipid classes keeping the ratio between the other lipid classes constant. An increased cholesterol level resulted in an increase in phase-separated cholesterol and a reduction in the permeability. An increase in ceramide or free fatty acid level resulted in the formation of additional phases, but had no significant influence on the permeability. We also examined models that mimic selected changes in lipid composition reported for dry or diseased skin. The SCS that mimics the composition in recessive X-linked ichthyosis skin displayed a twofold increase in permeability. This increase is possibly related to the formation of an additional, less ordered phase in this model. PMID- 21658449 TI - A novel nanomatrix system consisted of colloidal silica and pH-sensitive polymethylacrylate improves the oral bioavailability of fenofibrate. AB - A novel solid particle system with a nanomatrix structure and without surfactant for the oral delivery of insoluble drugs was prepared. This used a combination of pH-sensitive polymethylacrylate and nano-porous silica, in order to improve the drug absorption using only pharmaceutical excipients and a relative simple process. The in vitro drug dissolution and in vivo oral bioavailability of this formulation, using fenofibrate as the model drug, were compared with other reference formulations such as a suspension, micronized formulation or self microemulsion drug delivery system (SMEDDS). The supersaturation stabilizing effect of different polymers was evaluated and the physicochemical characterization of the optimal formulation was conducted by SEM, TEM, surface area analysis, DSC, and XRD. The optimized formulation prepared with polymethylacrylate (Eudragit(r)L100-55) and silica (Sylysia(r)350) markedly improved the drug dissolution compared with other reference preparations and displayed a comparative oral bioavailability to the SMEDDS. Fenofibrate existed in a molecular or amorphous state in the nanomatrix, and this state was maintained for up to 1year, without obvious changes in drug release and absorption. In conclusion, the nanomatrix formulation described here is a promising system to enhance the oral bioavailability of water-insoluble drugs. PMID- 21658450 TI - Insect natural products and processes: new treatments for human disease. AB - In this overview, some of the more significant recent developments in bioengineering natural products from insects with use or potential use in modern medicine are described, as well as in utilisation of insects as models for studying essential mammalian processes such as immune responses to pathogens. To date, insects have been relatively neglected as sources of modern drugs although they have provided valuable natural products, including honey and silk, for at least 4-7000 years, and have featured in folklore medicine for thousands of years. Particular examples of Insect Folk Medicines will briefly be described which have subsequently led through the application of molecular and bioengineering techniques to the development of bioactive compounds with great potential as pharmaceuticals in modern medicine. Insect products reviewed have been derived from honey, venom, silk, cantharidin, whole insect extracts, maggots, and blood-sucking arthropods. Drug activities detected include powerful antimicrobials against antibiotic-resistant bacteria and HIV, as well as anti cancer, anti-angiogenesis and anti-coagulant factors and wound healing agents. Finally, the many problems in developing these insect products as human therapeutic drugs are considered and the possible solutions emerging to these problems are described. PMID- 21658451 TI - p75(NTR) expression and nuclear localization of p75(NTR) intracellular domain in spiral ganglion Schwann cells following deafness correlate with cell proliferation. AB - Spiral ganglion Schwann cells (SGSCs) myelinate spiral ganglion neurons (SGNs) and represent a potential source of neurotrophic support for SGNs. Deafening due to loss of hair cells results in gradual degeneration and death of SGNs. Successful efforts to maintain or regenerate a functional auditory nerve may depend on a healthy population of SGSCs, yet the responses of SGSCs to neural injury remain largely unknown. Here we investigate the role of p75(NTR) in SGSC responses to gradual denervation. Following deafening, SGSCs in the osseous spiral lamina (OSL) and, subsequently, in Rosenthal's canal (RC) expressed elevated p75(NTR) compared to hearing controls. p75(NTR)-positive cells co labeled with S100 and RIP antibodies (Schwann cell markers), but not with anti neurofilament. The pattern of p75(NTR) expression mirrored the pattern of neural degeneration, beginning in the OSL of the cochlea base and later extending into the apex. SGSCs expressed sortilin, a p75(NTR) co-receptor for pro-neurotrophins. Both pro-nerve growth factor (pro-NGF) and pro-brain derived neurotrophic factor (proBDNF) induced apoptosis in cultured SGSCs. Deafened animals exhibited significantly higher levels of SGSC proliferation (as measured by BrdU uptake) compared to hearing animals while total Schwann cell density remained stable, suggesting a tight regulation of SGSC proliferation and cell death. SGSCs undergoing cell division lose p75(NTR) expression from the cell surface and demonstrate nuclear localization of the intracellular domain (ICD), raising the possibility that p75(NTR) cleavage and ICD nuclear localization regulate SGSC proliferation. These results suggest that p75(NTR) contributes to SGSC responses to deafening and neural degeneration. PMID- 21658452 TI - White shrimp Litopenaeus vannamei immersed in seawater containing Sargassum hemiphyllum var. chinense powder and its extract showed increased immunity and resistance against Vibrio alginolyticus and white spot syndrome virus. AB - This study was to examine the immune response of white shrimp Litopenaeus vannamei and its resistance against Vibrio alginolyticus and WSSV when shrimp received the Sargassum hemiphyllum var. chinense powder and its hot-water extract. Both powder and extract showed activation of prophenoloxidase and generation of superoxide anion in the shrimp in vitro. The haemocyte count, phenoloxidase (PO) activity, respiratory burst, and lysozyme activity were examined after the shrimp were immersed in seawater containing S. hemiphyllum var. chinense powder or its extract at 0, 100, 300, and 500 mg L-1 for 1, 3, and 5 h. These immune parameters of shrimp immersed in 300 and 500 mg L-1 powder, and 100 and 300 mg L-1 extract were significantly higher than those of control shrimp after 3 h, but slightly decreased after 5 h. In another experiment, shrimp immersed in seawater containing the powder or the extract at 0, 100, 300, and 500 mg L-1 after 3 h were challenged with V. alginolyticus at 8 * 105 colony-forming unit (cfu) shrimp-1, or challenged with WSSV at 1 * 105 copies shrimp-1, and then placed in seawater. Survival rate of shrimp immersed in 500 mg L-1 powder was significantly higher than that of control shrimp after 24-120 h in the V. alginolyticus-challenge test, and after 72 h in the WSSV-challenge test, respectively. Survival rate of shrimp immersed in 300 mg L-1 extract was significantly higher than that of control shrimp after 72-120 h in both V. alginolyticus-challenge and WSSV-challenge tests. It was concluded that the shrimp immersed in seawater containing the powder at 500 mg L-1, and the extract at 300 mg L-1 had increased immunity and resistance against V. alginolyticus infection, and the shrimp that received extract at 300 mg L-1 showed resistance against WSSV infection. PMID- 21658453 TI - Copper exposure affects hemocyte apoptosis and Perkinsus marinus infection in eastern oysters Crassostrea virginica (Gmelin). AB - Dermo disease in the eastern oyster (Crassostrea virginica) is caused by an intracellular protistan parasite Perkinsus marinus. The progression and outcome of this disease is determined by a complex interplay between the host's immunity and parasite's escape mechanisms, both of which can be influenced by environmental pollutants including heavy metals such as copper (Cu). The goal of the present study was to determine the effects of Cu on the levels of apoptosis (which can serve as an important host defense mechanism) in oyster immune cells (hemocytes) in vitro and in vivo as well as on the establishment of P. marinus infections in vivo. Surprisingly, Cu exerted opposing effects on apoptosis levels of hemocytes in vitro and in vivo, stimulating apoptosis in isolated hemocytes but suppressing it during Cu exposure of whole oysters. The mechanisms of this effect are presently unknown and may be related to the different bioavailability of the metal in vitro and in vivo. As expected, Cu accumulated in oyster soft tissues during in vitro exposure. Unexpectedly, this metal also strongly accumulated in hemolymph plasma which is classically considered isoionic with the surrounding seawater, likely reflecting the presence of soluble Cu-binding proteins in oyster plasma. Cu reduced growth of P. marinus in vitro and greatly reduced infection levels of hemocytes in vivo, presumably by direct toxic effects on the parasite. As a possible parasitic counterbalance, Cu accumulation in the hemocytes was reduced by P. marinus infection, although this reduction was not sufficient to prevent the parasiticidal effects of the heavy metal in vivo. This effect of Cu may be useful as a potential therapeutic against Dermo disease in aquaculture conditions. Overall, this study provides important new insights into the potential role of environmental metals in host-parasite relationships and disease dynamics in C. virginica. PMID- 21658454 TI - Isolation and identification of novel microRNAs from Marsupenaeus japonicus. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that function as regulators of gene expression. They play essential roles in various biological processes, such as development, differentiation and immune response. In this study, we identified 35 miRNAs from Marsupenaeus japonicus. Among them, fifteen miRNAs exhibited high homology to the known miRNAs from other arthropods, while the rest might represent novel miRNAs. We further showed a correlation of WSSV infection and the expression levels of 22 miRNAs. This is the first report to identify miRNAs from the shrimp. Our results extend the knowledge of the gene regulation of crustacean, providing clues for future researches of shrimp immunity against virus infection. PMID- 21658456 TI - A multi-resolution scheme for distortion-minimizing mapping between human subcortical structures based on geodesic construction on Riemannian manifolds. AB - In this paper, we deal with a subcortical surface registration problem. Subcortical structures including hippocampi and caudates have a small number of salient features such as heads and tails unlike cortical surfaces. Therefore, it is hard, if not impossible, to perform subcortical surface registration with only such features. It is also non-trivial for neuroanatomical experts to select landmarks consistently for subcortical surfaces of different subjects. We therefore present a landmark-free approach for subcortical surface registration by measuring the amount of mesh distortion between subcortical surfaces assuming that the surfaces are represented by meshes. The input meshes can be constructed using any surface modeling tool available in the public domain since our registration method is independent of a surface modeling process. Given the source and target surfaces together with their representing meshes, the vertex positions of the source mesh are iteratively displaced while preserving the underlying surface shape in order to minimize the distortion to the target mesh. By representing each surface mesh as a point on a high-dimensional Riemannian manifold, we define a distance metric on the manifold that measures the amount of distortion from a given source mesh to the target mesh, based on the notion of isometry while penalizing triangle flipping. Under this metric, we reduce the distortion minimization problem to the problem of constructing a geodesic curve from the moving source point to the fixed target point on the manifold while satisfying the shape-preserving constraint. We adopt a multi-resolution framework to solve the problem for distortion-minimizing mapping between the source and target meshes. We validate our registration scheme through several experiments: distance metric comparison, visual validation using real data, robustness test to mesh variations, feature alignment using anatomic landmarks, consistency with previous clinical findings, and comparison with a surface-based registration method, LDDMM-surface. PMID- 21658455 TI - Longitudinal diffusion tensor imaging and perfusion MRI investigation in a macaque model of neuro-AIDS: a preliminary study. AB - The Simian immunodeficiency virus (SIV) infected macaque model exhibits neuropathological symptoms similar to those of HIV(+) patients, and is ideal for studying cognitive impairment and neuropathological sequelae of disease in repeated measurements. The aim of this study is to use Diffusion Tensor Imaging (DTI) and perfusion MRI to longitudinally access the disease development in SIV infected monkeys under controlled conditions and to cross-validate our finding with MRI studies in HIV(+) patients. Three adult male pig-tailed macaques (Macaca nemestrina) were inoculated with the SIVsmmFGb virus. Blood was collected for enumeration of CD4+ and CD8+ T-cells. Serial time-sensitive high-resolution T(2)- weighted structural images, Cerebral Blood Flow (CBF) maps measured with the Continuous Arterial Spin Labeling (CASL) technique, and DTI images were obtained. Animals were sacrificed after 24 weeks. Cognitive behavioral tests were also carried out at each time point. Longitudinal changes in brain volume, CBF, and DTI in selected regions were analyzed statistically. In this study, CD4+ T-cell counts were found declined significantly after SIV infection in all macaques. No significant neurological behavior and brain volume changes were observed following virus inoculation. The CBF was found reduced in the caudate, inferior parietal cortex, and the prefrontal cortex. Fractional Anisotropy (FA) values in the whole brain and several Regions of Interest (ROIs) decreased significantly. These longitudinal changes in CBF and FA are correlated with CD4+ T-cell depletion and/or CD4:CD8 ratio. The MRI findings from this pilot study agree with previous results in HIV(+) patients. PMID- 21658458 TI - Systematic relationships of Oriental tiny frogs of the family Microhylidae (Amphibia, Anura) as revealed by mtDNA genealogy. AB - We estimated the genealogical relationships and assessed systematic relationships among 45 out of 89 named species and four unnamed taxa from 11 of 14 genera of the Oriental microhylids from 1767 bp sequences of the mitochondrial DNA genes 12S rRNA and 16S rRNA using maximum parsimony, maximum likelihood, and Bayesian inference methods. Monophyly was rejected for the subfamily Microhylinae, and our data reveal four well-supported clades whose relationships to each other are unresolved: (A) Microhyla, Calluella, and Glyphoglossus, (B) Chaperina, (C) Kaloula, Phrynella, and Metaphrynella, and (D) Micryletta. They were genetically as divergent from each other as from another Oriental subfamily Kalophryninae, and could be recognized as distinct subfamilies. Within Clade A, our data reveal three well-supported subclades whose relationships to each other are unresolved: (AI) Microhyla-I, (AII) Calluella and Glyphoglossus, and (AIII) Microhyla-II. Of the two enigmatic Malaysian genera, whose subfamilial placement has been undetermined, Phrynella was found to be the sister species of Metaphrynella in Clade C, whereas Gastrophrynoides was grouped in the Papua-Australian subfamily Asterophryinae. Currently recognized subgenera and species groups within Microhyla based on morphology were not supported phylogenetically, and require thorough reassessments. PMID- 21658457 TI - Atlas-based investigation of human brain tissue microstructural spatial heterogeneity and interplay between transverse relaxation time and radial diffusivity. AB - Microstructural metrics obtained using magnetic resonance imaging (MRI) such as transverse relaxation time and radial diffusivity have been used as in vivo markers of human brain tissue integrity. Considering the sensitivity of these parameters to some common biophysical contributors and their structural and spatial heterogeneity, we hypothesized that strong inter and intra-regional associations exist between these variables providing evidence to possible interplay between transverse relaxation time and radial diffusivity. To validate our hypothesis we obtained high resolution anatomical T1-weighted data and fused it with T2-relaxometry and diffusion tensor imaging (DTI) data on a cohort of healthy adults. The anatomical data were parcellated using FreeSurfer and then coaligned and fused with the T2 and DTI maps. Our data reveal some association between transverse relaxation and radial diffusivity that may help toward the interpretation and modeling of the biophysical contributors to the measured MRI metrics. PMID- 21658459 TI - Evaluation of a novel ECG lead placement method in telemetered freely moving cynomolgus monkeys: assessment of an intravascular biopotential lead. AB - INTRODUCTION: ECG is considered as a critical biomarker of cardiac safety pharmacology. ECG signal quality is essential for accurate interval quantification and automated arrhythmia detection. METHODS: We evaluated ECG signal quality over a 6 month period from 15 cynomolgus monkeys with radiotelemetry transmitters using biopotential leads where the negative lead was inserted in the jugular vein and advanced to the superior vena cava (intravascular lead) and the positive lead was placed on the diaphragm at the apex of the heart (diaphragmatic lead). Signal noise and signal-to-noise ratio from this implantation methodology were compared with signals obtained from animals with subcutaneous ECG lead. Macroscopic pathology and histopathology associated with the intravascular lead were evaluated at 6 months post implantation in six monkeys. RESULTS: The ECG morphology obtained with the intravascular/diaphragmatic lead placement was comparable to conventional subcutaneous ECG (emulating Lead II) but presented higher amplitudes (P-wave +50.0%; R-wave +30.0%). Signal noise showed a circadian cycle of changes in magnitude for subcutaneous ECG leads that was not observed with this method. The intravascular/diaphragmatic lead placement presented a higher signal-to-noise ratio than subcutaneous ECG leads. No macroscopic abnormality was observed to be associated with the intravascular lead. Mild thickening of the intima/subintima with mild intimal proliferation of the cranial vena cava surrounding the intravascular lead were noted at histopathological examination. DISCUSSION: The intravascular/diaphragmatic ECG lead placement in cynomolgus monkeys provided reduced signal noise and elevated P-QRS-T amplitudes. The intravascular lead was well tolerated and appeared suitable for chronically instrumented cardiovascular safety pharmacology studies. Further assessments would be warranted to evaluate the potential of this methodology in other species. PMID- 21658460 TI - Genomic aberrations and survival of patients with light-chain-only multiple myeloma undergoing autologous stem cell transplantation. AB - The majority of patients with multiple myeloma (MM) have intact immunoglobulin, but in a subset of patients (~15%), their tumors produce monoclonal light chains only (LCO). Although specific genomic aberrations have emerged as a major prognostic factor in MM, their incidence and prognostic impact on LCO myeloma patients are not clear. We therefore investigated a cohort of 86 LCO MM cases diagnosed and treated with autologous stem cell transplantation at our institution. Overall, genomic risk factors del(13q), del(17p), t(4;14), 1p loss, and 1q21 gain were detected by cytoplasmic fluorescence in situ hybridization (cIg-FISH) in 40.6%, 18.5%, 11.9%, 18.8%, and 25% of the cases, respectively. Patients with del(13q) and 1q gains had a significantly shorter overall survival (OS) (median 80.4 vs 56.2 months, P = .021; median 77.9 vs 26.9 months, P = .006, respectively) and shorter progression-free survival (PFS) (median 33.4 vs 15.8 months, P = .002; median 33.4 vs 19.1 months, P = .011, respectively) than those without the genetic abnormalities. In addition, 1p loss was significantly associated with shorter PFS (median 37.9 vs 18.2 months, P = .001). There was no significant difference in PFS or OS in patients with or without t(4;14) or del(17p). On multivariate analysis, del(13q) was an independent prognostic factor for PFS and OS. PMID- 21658462 TI - Diversity of response to Trypanosoma brucei gambiense infections in the Forecariah mangrove focus (Guinea): perspectives for a better control of sleeping sickness. AB - At a time when human African trypanosomiasis (HAT) elimination again seems a reachable goal in many parts of sub-Saharan Africa, it is becoming increasingly important to characterise the factors involved in disease resurgence or maintenance to develop sustainable control strategies. In this study conducted in the Forecariah mangrove focus in Guinea, HAT patients and serological suspects (SERO) were identified through mass screening of the population with the Card Agglutination Test for Trypanosomiasis (CATT) and were followed up for up to 2 years. Analysis of the samples collected during the follow-up of HAT patients and SERO was performed with PCR (TBR1/TBR2) and the trypanolysis serological test (TL) in order to clarify the role played by these individuals in the epidemiology of HAT. PCR positivity was higher in TL+ than in SERO TL- (50% vs. 18%, respectively). Whereas CATT plasma titres decreased both in treated HAT patients and SERO TL-, SERO TL+ maintained high CATT titres. Four out of 17 SERO TL+ developed HAT during the study. These results strongly suggest that SERO TL+ individuals are asymptomatic carriers. In the context where disease prevalence is sufficiently low, treating SERO TL+ individual may thus be of crucial importance in order to cut transmission. PMID- 21658461 TI - Malignancies after hematopoietic cell transplantation for primary immune deficiencies: a report from the Center for International Blood and Marrow Transplant Research. AB - We describe the incidence of malignancy in patients with primary immunodeficiency disorders (PIDD) following hematopoietic cell transplantation (HCT). From the Center for International Blood and Marrow Transplant Research, 2266 PIDD patients who had undergone allogeneic HCT between 1968 and 2003 were identified. Patient, disease, and transplant factors for development of malignancy were examined and pathology reports for reported malignancies reviewed independently by a pathologist for confirmation. The incidence of malignancy was highest for Wiskott Aldrich syndrome (3.3%), with an overall incidence of 2.3% for PIDD. Post-HCT malignancy was confirmed for 52 of 63 reported cases. Forty-five of 52 patients developed posttransplant lymphoproliferative disorders (PTLD) at a median of 3 months post-HCT. Of these, 26 had received T cell-depleted (TCD) bone marrow. Three patients who developed myelodysplastic syndrome had received TCD marrow and total body irradiation. Three patients developed a solid tumor. Patients with PIDD are at a relatively low risk of developing malignancies post-HCT compared with their historic risk of cancer. The most frequent malignancy or lymphoproliferative disorder was early-onset PTLD. As in other HCT recipients, TCD appears to correlate with PTLD development. Our results lend support to the hypothesis that immune reconstitution in PIDD following HCT leads to a decrease in cancer risk. PMID- 21658463 TI - Basophils in immune responses against helminths. AB - Basophils are a major source of IL-4 and IL-13, two key cytokines that orchestrate expulsion of gastrointestinal nematodes in different mouse models. Based on recent reports, this review discusses potential roles of basophils and other cells during early and late phases of the immune response against parasitic worms. PMID- 21658464 TI - Multiple loci variable number tandem repeat (VNTR) analysis (MLVA) of Mycobacterium leprae isolates amplified from European archaeological human remains with lepromatous leprosy. AB - Molecular typing methods based on polymorphisms in single nucleotides and short tandem repeat motifs have been developed as epidemiological typing tools for Mycobacterium leprae. We have used a variable number tandem repeat method based on three variable loci to identify strain variation in archaeological cases of lepromatous leprosy. The panel of polymorphic loci used revealed unique profiles in five cases of leprosy, including those with identical SNP type and subtype. These were also different from profiles of three previously studied lepromatous skeletons. Whilst examination with SNP typing provides evidence for disease origins, dissemination and phylogeny, tandem repeat typing may be useful for studying cases from within a defined area or community where SNP types may be identical due to geographical constraints. We envisage the technique may be useful in studying contemporaneous burials such as those associated with leprosaria and will prove invaluable in authentication of ancient DNA analyses. PMID- 21658465 TI - Estimating prognosis for survival after treatment of choroidal melanoma. AB - Choroidal melanoma is fatal in about 50% of patients. This is because of metastatic disease, which usually involves the liver. Kaplan-Meier survival curves based only on tumor size and extent do not give a true indication of prognosis. This is because the survival prognosis of choroidal melanoma correlates not only with clinical stage but also with histologic grade, genetic type, and competing causes of death. We have developed an online tool that predicts survival using all these data also taking normal life-expectancy into account. The estimated prognosis is accurate enough to be relevant to individual patients. Such personalized prognostication improves the well-being of patients having an excellent survival probability, not least because it spares them from unnecessary screening tests. Such screening can be targeted at high-risk patients, so that metastases are detected sooner, thereby enhancing any opportunities for treatment. Concerns about psychological harm have proved exaggerated. At least in Britain, patients want to know their prognosis, even if this is poor. The ability to select patients with a high risk of metastasis improves prospects for randomised studies evaluating systemic adjuvant therapy aimed at preventing or delaying metastatic disease. Furthermore, categorization of tissue samples according to survival prognosis enables laboratory studies to be undertaken without waiting many years for survival to be measured. As a result of advances in histologic and genetic studies, biopsy techniques and statistics, prognostication has become established as a routine procedure in our clinical practice, thereby enhancing the care of patients with uveal melanoma. PMID- 21658466 TI - A calcium-insensitive attenuated nitrosative stress response contributes significantly in the radioresistance of Sf9 insect cells. AB - Lepidopteran insects/insect cells display 50-100 times higher radioresistance than humans, and are evolutionarily closest to mammals amongst all radioresistant organisms known. Compared to mammalian cells, Lepidopteran cells (TN-368, Sf9) display more efficient antioxidant system and DNA repair and suffer considerably less radiation-induced DNA/cytogenetic damage and apoptosis. Recent studies indicate that a considerably lower radiation-induced oxidative stress may significantly reduce macromolecular damage in Lepidopteran cells. Since nitrosative stress contributes in radiation-induced cellular damage, we investigated its nature in the gamma-irradiated Sf9 cells (derived from Spodoptera frugiperda; order Lepidoptera; family Noctuidae) and compared with BMG 1 human cell line having significant NOS expression. Radiation induced considerably less ROS/RNS in Sf9 cells, which remained unchanged on treatment with NOS inhibitor l-NMMA. Surprisingly, growth of Sf9 cultures or irradiation could not induce NO or its metabolites, indicating negligible basal/radiation induced NOS activity that remained unchanged even after supplementation with arginine. Cytosolic calcium release following high-dose (1000-2000Gy at 61.1cGys( 1)) gamma-irradiation or H(2)O(2) (250MUM) treatment also failed to generate NO in Sf9 cells having high constitutive levels of calmodulin, whereas BMG-1 cells displayed considerable calcium-dependent NO generation even following 10Gy dose. These results strongly imply the lack of calcium-mediated NOS activity in Sf9 cells. Addition of exogenous NO from GSH-NO caused considerable increase in radiation-induced apoptosis, indicating significant contribution of constitutively attenuated nitrosative stress response into the radioresistance of Lepidopteran cells. Our study demonstrates for the first time that a calcium insensitive, attenuated nitrosative stress response may contribute significantly in the unusual radioresistance displayed by Lepidopteran insect cells. PMID- 21658467 TI - Follow-on drugs: how far should chemists look? AB - A major remark made by observers relates to the focus of the pharmaceutical industry on 'me-too' drugs rather than 'first-in-class' drugs, the latter are considered to be 'truly' innovative medicines. Although the subject is heavily debated, chemists in project teams around the globe are routinely following up compounds from competitors. An important strategic consideration is the degree of chemical modification of the original structure required for success. Here, we present an analysis of the DiMasi and Faden set of first-in-class and follow-on drug pairs (n=74); showing that 70% of them are structurally very similar, meaning that they are characterized by minimal structural variations. This highlights the fact that even simple atomic variations can cause drastic changes in molecular properties responsible for therapeutic advantages. PMID- 21658468 TI - Development and validation of a high-content screening in vitro micronucleus assay in CHO-k1 and HepG2 cells. AB - In the present study an automated image analysis assisted in vitro micronucleus assay was developed with the rodent cell line CHO-k1 and the human hepatoma cell line HepG2, which are both commonly used in regulatory genotoxicity assays. The HepG2 cell line was chosen because of the presence in these cells of a functionally active p53 protein, a functionally competent DNA-repair system, active enzymes for phase-I and -II metabolism, and an active Nrf2 electrophile responsive system. These properties may result in an assay with a high predictivity for in vivo genotoxicity. The assays with CHO-k1 and HepG2 cells were both evaluated by testing a set of compounds recommended by the European Centre for the Validation of Alternative Methods (ECVAM), among which are in vivo genotoxins and non-genotoxins. The CHO-k1 cell line showed a high sensitivity (percentage of genotoxic compounds that gave a positive result: 80%; 16/20) and specificity (percentage of non-genotoxic compounds that came out negative: 88%; 37/42). Although the sensitivity of the HepG2 cell line was lower (60%; 12/20), the specificity was high (88%; 37/42). These results were confirmed by testing an additional series of 16 genotoxic compounds. For both the CHO-k1 and the HepG2 cell line it was possible to size-classify micronuclei, enabling distinguishing aneugens from clastogens. It is concluded that two high-throughput micronucleus assays were developed that can detect genotoxic potential and allow differentiation between clastogens and aneugens. The performance scores of the CHO-k1 and HepG2 cell lines for in vivo genotoxicity were high. Application of these assays in the early discovery phase of drug development may prove to be a useful strategy to assess genotoxic potential at an early stage. PMID- 21658469 TI - WITHDRAWN: Comparative study of the karyotypes and electrophoretic patterns of Biomphalaria alexandrina and Bulinus truncatus and the ova of their corresponding trematode hosts. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.parint.2011.05.006. The duplicate article has therefore been withdrawn. PMID- 21658470 TI - Expression of common fluorescent reporters may modulate virulence for Mycobacterium marinum: dramatic attenuation results from Gfp over-expression. AB - Mycobacterium marinum is an established surrogate pathogen for Mycobacterium tuberculosis because of its strong conservation of thousands of orthologous genes, lower risk to researchers and similar pathology in fish. This pathogen causes TB-like chronic disease in a wide variety of fish species. As in human TB, the microbe grows within the host macrophages, can mount life-long chronic infections and produces granulomatous lesions in target organs. One of the fish species known to manifest chronic "fish TB" is the small laboratory fish, Japanese ricefish (medaka; Oryzias latipes). Our laboratory is currently characterizing the disease progression in medaka using fluorescent reporter systems that are introduced into engineered strains of M. marinum. While conducting these studies we observed differences in growth, plasmid stability, and virulence depending on which fluorescent reporter construct was present. Here, we describe large negative effects on virulence and organ colonization that occurred with a commonly used plasmid pG13, that expresses green fluorescent protein (Gfp). The studies presented here, indicate that Gfp over-expression was the basis for the reduced virulence in this reporter construct. We also show that these negative effects could be reversed by significantly reducing Gfp expression levels or by using low-expression constructs of Rfp. PMID- 21658472 TI - Functionalization of liposomes with ApoE-derived peptides at different density affects cellular uptake and drug transport across a blood-brain barrier model. AB - A promising strategy to enhance blood-brain barrier penetration by drugs is the functionalization of nanocarriers with uptake-facilitating ligands. We studied the cellular uptake, by cultured RBE4 brain capillary endothelial cells, of nanoliposomes (NLs) covalently coupled with monomer or tandem dimer of apolipoprotein E (ApoE)-derived peptides (residues 141-150), at various densities. NLs without functionalization did not show either relevant membrane accumulation or cellular uptake, as monitored by confocal microscopy and quantified by fluorescence-activated cell sorting. Functionalization with peptides mediated an efficient NLs uptake that increased with peptide density; NLs carrying monomeric peptide performed the best. Moreover, we studied the ability of ApoE-NLs to enhance the transport of a drug payload through a RBE4 cell monolayer. The permeability of a tritiated curcumin derivative was enhanced after its entrapment into ApoE-NLs, in particular those functionalized with the dimer (+83% with respect to free drug, P < 0.01). Thus, these NLs appear particularly suitable for implementing further strategies for drug brain targeting. PMID- 21658471 TI - Estrogens and selective estrogen receptor modulators regulate gene and protein expression in the mesenteric arteries. AB - Estrogen has both beneficial and detrimental effects on the cardiovascular system. Selective estrogen receptor modulators (SERMs) exhibit partial estrogen agonist/antagonist activity in estrogen target tissues. Gene targets of estrogen and SERMs in the vasculature are not well-known. Thus, the present study tested the hypothesis that estrogens (ethinyl estradiol, estradiol benzoate, and equilin) and SERMs (tamoxifen and raloxifene) cause differential gene and protein expression in the vasculature. DNA microarray and real-time RT-PCR were used to investigate gene expression in the mesenteric arteries of estrogen and SERM treated ovariectomized rats. The genes shown to be differentially expressed included stearoyl-CoA desaturase (SCD), soluble epoxide hydrolase (sEH), secreted frizzled related protein-4 (SFRP-4), insulin-like growth factor-1 (IGF-1), phospholipase A2 group 1B (PLA2-G1B), and fatty acid synthase (FAS). Western blot further confirmed the differential expression of sEH, SFRP-4, FAS, and SCD protein. These results reveal that estrogens and SERMs cause differential gene and protein expression in the mesenteric artery. Consequently, the use of these agents may be associated with a unique profile of functional and structural changes in the mesenteric arterial circulation. PMID- 21658473 TI - Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility. AB - The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein- and cell repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples of alternatives to PEGylation. We present a novel conceptual approach that includes virulence factors for the engineering of bioactive, immune system-evasive stealth nanocarriers. FROM THE CLINICAL EDITOR: The efficacy of nanocarrier-based drug-delivery systems is often dampened by the Mononuclear Phagocyte System (MPS). Current approaches to circumvent MPS rely on protein- and cell-repelling properties of inert hydrophilic polymers, including PEG. This paper discusses the full scope of the immunological and biochemical barriers along with selected examples of alternatives to PEGylation. PMID- 21658474 TI - PAMAM dendrimer-azithromycin conjugate nanodevices for the treatment of Chlamydia trachomatis infections. AB - Chlamydia trachomatis is an important bacterial pathogen known to be etiological in genital infections, as well as several serious disease sequelae, including inflammatory arthritis. Chlamydiae can persist in infection, making treatment with antibiotics such as azithromycin (AZ) a challenge. The authors explore the use of neutral generation-4 polyamidoamine (PAMAM) dendrimers as intracellular drug-delivery vehicles into chlamydial inclusions. Azithromycin was successfully conjugated with the dendrimers, and the conjugate (D-AZ) released ~ 90% of the drug over 16 hours. The conjugate readily entered both the Chlamydia-infected HEp 2 cells and the chlamydial inclusions. The conjugate was significantly better than free drug in preventing productive infections in the cells when added at the time of infection, and better in reducing the size and number of inclusions when added either 24 hours or 48 hours post infection. These studies show that dendrimers can deliver drugs efficiently to growing intracellular C. trachomatis, even if the organism is in the persistent form. FROM THE CLINICAL EDITOR: In this report, the use of polyamidoamine dendrimers as intracellular drug-delivery vehicles into chlamydial inclusions is investigated. This method results in efficient intracellular delivery of azithromycin to address chlamydia infection. PMID- 21658475 TI - Effects of aggregation and the surface properties of gold nanoparticles on cytotoxicity and cell growth. AB - The effect of gold nanoparticles (Au NPs) on cells remains open for investigation. Here we show that small Au NPs can be endocytosed by cells and form aggregates inside the cell, resulting in cytotoxicity. When the aggregates become too large to enter the cell and instead adhere onto the cell surface, however, the growth rate of HeLa cells increases. Printed patterns of Au NPs fabricated through inkjet printing technology were used to study the effects of Au NP aggregation on human cervical carcinoma (HeLa) cell activity. The growth of the HeLa cells was inhibited on the polymer-coated Au NPs but increased on the silicon substrate. On the uncoated Au NP surface, however, the HeLa cell growth rate was higher than that on the silicon substrate. Experiments with Escherichia coli cells showed a similar effect of the Au NPs. This phenomenon provides a new perspective for research on toxicity in nanoparticle biology. FROM THE CLINICAL EDITOR: Printed patterns of Au NPs fabricated through inkjet printing technology were used to study the effects of Au NP aggregation on human cervical carcinoma (HeLa) cell activity. Small Au NPs can be endocytosed by cells resulting in cytotoxicity; in contrast, large aggregates adhere onto the cell surface and increase the growth rate of HeLa cells. PMID- 21658476 TI - I-CAN SLEEP: rationale and design of a non-inferiority RCT of Mindfulness-based Stress Reduction and Cognitive Behavioral Therapy for the treatment of Insomnia in CANcer survivors. AB - Individuals with cancer are disproportionately affected by sleep disturbances, relative to the general population. These problems can be a consequence of the psychological, behavioral and physical effects of a cancer diagnosis and treatment. Sleep disturbances often persist for years and, when combined with already high levels of cancer-related distress, may place cancer survivors at a higher risk of future psychopathology, health problems and poorer quality of life. It is important to develop and evaluate treatments that comprehensively address the common symptom profiles experienced by cancer survivors. METHODS: This study is a randomized controlled non-inferiority trial comparing Cognitive Behavior Therapy for Insomnia (CBT-I; a known efficacious treatment) to Mindfulness-Based Stress Reduction (MBSR; a treatment with demonstrated potential). This design can efficiently compare these two treatments directly and determine whether MBSR performs to the same standard as CBT-I for the treatment of insomnia with additional benefits of reducing cancer-related distress. Participants are randomly assigned to an 8-week CBT-I or MBSR group. Sleep indices are measured using subjective (sleep diaries) and objective (actigraphy) assessment tools. The primary outcome is insomnia severity. Secondary outcomes include sleep quality, symptoms of stress, mood disturbance, mindfulness, and dysfunctional beliefs and attitudes toward sleep. Assessments are completed at three time periods: pre-treatment, post-treatment and at 3month follow up. CONCLUSIONS: Considering the high prevalence of distress and sleep disturbances in the cancer population, should MBSR produce sleep effects comparable to CBT-I, it may be more comprehensive - making it the treatment of choice for addressing cancer-related psychological sequelae. PMID- 21658477 TI - Three-dimensional bioactive glass implants fabricated by rapid prototyping based on CO(2) laser cladding. AB - Three-dimensional bioactive glass implants were produced by rapid prototyping based on laser cladding without using moulds. CO(2) laser radiation was employed to melt 45S5 and S520 bioactive glass particles and to deposit the material layer by layer following a desired geometry. Controlled thermal input and cooling rate by fine tuning of the processing parameters allowed the production of crack-free fully dense implants. Microstructural characterization revealed chemical composition stability, but crystallization during processing was extensive when 45S5 bioactive glass was used. Improved results were obtained using the S520 bioactive glass, which showed limited surface crystallization due to an expanded sintering window (the difference between the glass transition temperature and crystallization onset temperature). Ion release from the S520 implants in Tris buffer was similar to that of amorphous 45S5 bioactive glass prepared by casting in graphite moulds. Laser processed S520 scaffolds were not cytotoxic in vitro when osteoblast-like MC3T3-E1 cells were cultured with the dissolution products of the glasses; and the MC3T3-E1 cells attached and spread well when cultured on the surface of the materials. PMID- 21658478 TI - Biocompatibility of modified polyethersulfone membranes by blending an amphiphilic triblock co-polymer of poly(vinyl pyrrolidone)-b-poly(methyl methacrylate)-b-poly(vinyl pyrrolidone). AB - An amphiphilic triblock co-polymer of poly(vinyl pyrrolidone)-b-poly(methyl methacrylate)-b-poly(vinyl pyrrolidone) (PVP-b-PMMA-b-PVP) was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The block co-polymer can be directly blended with polyethersulfone (PES) using dimethylacetamide (DMAC) as the solvent to prepare flat sheet and hollow fiber membranes using a liquid-liquid phase separation technique. The PVP block formed a brush on the surface of the blended membrane, while the PMMA block mingled with the PES macromolecules, which endowed the membrane with permanent hydrophilicity. After adding the as-prepared block co-polymer the modified membranes showed lower protein (bovine serum albumin) adsorption, suppressed platelet adhesion, and a prolonged blood coagulation time, and thereby the blood compatibility was improved. Furthermore, the modified PES membranes showed good cytocompatibility, ultrafiltration and protein anti-fouling properties. These results suggest that surface modification of PES membranes by blending with the amphiphilic triblock co-polymer PVP-b-PMMA-b-PVP allows practical application of these membranes with good biocompatibility in the field of blood purification, such as hemodialysis and bioartificial liver support. PMID- 21658479 TI - Nanostructure and mineral composition of trabecular bone in the lateral femoral neck: implications for bone fragility in elderly women. AB - Despite interest in investigating age-related hip fractures, the determinants of decreased bone strength in advanced age are not clear enough. Hitherto it has been obscure how the aging process affects the femoral neck nanostructure and composition, particularly in the lateral subregion of the femoral neck, which is considered as a fracture-initiating site. The femoral bone samples used in this study were obtained at autopsy in 10 women without skeletal disease (five younger: aged 20-40 years, and five elderly: aged 73-94 years). Atomic force microscopy (AFM) was applied to explore the mineral grain size in situ in young vs. old trabecular bone samples from the lateral femoral neck. The chemical compositions of the samples were determined using inductively coupled plasma optical emission spectroscopy and direct current argon arc plasma optical emission spectrometry. Our AFM study revealed differences in trabecular bone nanostructure between young and elderly women. The mineral grain size in the trabeculae of the old women was larger than that in the young (median: 95 vs. 59nm), with a particular bimodal distribution: 45% were small grains (similar to the young) and the rest were larger. Since chemical analyses showed that levels of calcium and phosphorus were unchanged with age, our study suggests that during aging the existing bone mineral is reorganized and forms larger aggregates. Given the mechanical disadvantage of large-grained structures (decreased material strength), the observed nanostructural differences contribute to our understanding of the increased fragility of the lateral femoral neck in aged females. Moreover, increasing data on mineral grains in natural bone is essential for advancing calcium-phosphate ceramics for bone tissue replacement. PMID- 21658480 TI - In vivo degradation of low temperature calcium and magnesium phosphate ceramics in a heterotopic model. AB - Bone replacement using synthetic and degradable materials is desirable in various clinical conditions. Most applied commercial materials are based on hydroxyapatite, which is not chemically degradable under physiological conditions. Here we report the effect of a long-term intramuscular implantation regime on the dissolution of various low temperature calcium and magnesium phosphate ceramics in vivo. The specimens were analysed by consecutive radiographs, micro-computed tomography scans, compressive strength testing, scanning electron microscopy and X-ray diffractometry. After 15months in vivo, the investigated materials brushite (CaHPO(4).2H(2)O), newberyite (MgHPO(4).3H(2)O), struvite (MgNH(4)PO(4).6H(2)O) and hydroxyapatite (Ca(9)(PO(4))(5)HPO(4)OH) showed significant differences regarding changes of their characteristics. Struvite presented the highest loss of mechanical performance (95%), followed by newberyite (67%) and brushite (41%). This was accompanied by both a distinct extent of cement dissolution as well as changes of the phase composition of the retrieved cement implants. While the secondary phosphate phases (brushite, newberyite, struvite) completely dissolved, re precipitates of whitlockite and octacalcium phosphate were formed in either particulate or whisker-like morphology. Furthermore, for the first time the possibility of a macropore-free volume degradation mechanism of bioceramics was demonstrated. PMID- 21658481 TI - In silico analysis of accurate proteomics, complemented by selective isolation of peptides. AB - Protein identification by mass spectrometry is mainly based on MS/MS spectra and the accuracy of molecular mass determination. However, the high complexity and dynamic ranges for any species of proteomic samples, surpass the separation capacity and detection power of the most advanced multidimensional liquid chromatographs and mass spectrometers. Only a tiny portion of signals is selected for MS/MS experiments and a still considerable number of them do not provide reliable peptide identification. In this article, an in silico analysis for a novel methodology of peptides and proteins identification is described. The approach is based on mass accuracy, isoelectric point (pI), retention time (t(R)) and N-terminal amino acid determination as protein identification criteria regardless of high quality MS/MS spectra. When the methodology was combined with the selective isolation methods, the number of unique peptides and identified proteins increases. Finally, to demonstrate the feasibility of the methodology, an OFFGEL-LC-MS/MS experiment was also implemented. We compared the more reliable peptide identified with MS/MS information, and peptide identified with three experimental features (pI, t(R), molecular mass). Also, two theoretical assumptions from MS/MS identification (selective isolation of peptides and N terminal amino acid) were analyzed. Our results show that using the information provided by these features and selective isolation methods we could found the 93% of the high confidence protein identified by MS/MS with false-positive rate lower than 5%. PMID- 21658483 TI - Skeletal effects of bazedoxifene paired with conjugated estrogens in ovariectomized rats. AB - A novel approach to menopausal therapy is the tissue selective estrogen complex (TSEC) that partners bazedoxifene (BZA) with conjugated estrogens (CE). We examined the effects of daily treatment with BZA 0.3mg/kg, CE 2.5mg/kg, or combined BZA/CE (BZA 0.1, 0.3, or 1.0mg/kg with CE 2.5mg/kg) over 12months on bone mass, bone architecture and strength, and biochemical markers of bone turnover in ovariectomized (OVX) female Sprague-Dawley rats vs OVX control rats. Total cholesterol and uterine weights were also evaluated. All BZA/CE dose combinations prevented ovariectomy-induced increases in bone turnover and significantly increased bone mineral density (BMD) at the lumbar spine, proximal femur, and tibia compared with OVX controls. All BZA/CE doses evaluated also prevented many of the ovariectomy-induced changes of the static and dynamic parameters of the cortical compartment of the tibia and the cancellous compartment of the L1 and L2 vertebrae. All BZA/CE doses increased biomechanical strength at the lumbar spine (L4) compared with OVX animals. The co administration of BZA 0.3 and 1.0mg/kg/day with CE 2.5mg/kg/day showed a dose dependent reduction in uterine wet weight compared with administration of CE alone. All BZA/CE doses significantly lowered total cholesterol levels compared with OVX controls. In conclusion, 12months of treatment with BZA/CE in OVX rats effectively maintained BMD, bone microstructure, and bone quality; and the pairing of BZA with CE prevented CE-induced uterine stimulation. PMID- 21658484 TI - Acceleration of spinal fusion using COMP-angiopoietin 1 with allografting in a rat model. AB - INTRODUCTION: Allografting has become widely available for the elimination of morbidity due to autogenous bone grafting procedures for spinal fusion. Enhancement of stable bone formation could facilitate this procedure. COMP-Ang1 is a recombinant chimeric protein of angiopoietin-1 that induces angiogenesis and vascular enlargement. We investigated the osteogenic potential of COMP-Ang1 for spinal fusion with allograft based on the enhancement of angiogenesis. METHODS: Sixty Sprague-Dawley rats underwent bilateral posterior and posterolateral arthrodesis with allograft at L3-4 and L4-5. The animals were divided into three groups (n=20 each): (1) no treatment (sham group); (2) the bovine serum albumin impregnated collagen sponge group (BSA group); 3) the COMP-Ang1-impregnated collagen sponge group (COMP-Ang1 group). Animals were sacrificed at six weeks for evaluation of spinal fusion using manual palpation, radiographs, and biomechanical and histomorphometric assessments. Total RNA was prepared from the fusion site and analyzed for osteogenic marker protein expression using RT-PCR analysis. RESULTS: The fusion rates determined by manual palpation were 38.9% in the sham group, 42.1% in the BSA group, and 89.5% in the COMP-Ang1 group. Optical density of fusion masses in the COMP-Ang1 group was significantly higher than those in the sham and BSA groups (p<0.001). Total bone volume was significantly higher in the COMP-Ang1 group than in the sham and BSA groups (p<0.001). The mechanical strength was significantly greater in the COMP-Ang1 group than in the sham and BSA groups (p<0.01). Histologically, the fusion site of the COMP-Ang1 group showed a larger number of reactive bones compared with those in the BSA and sham groups. Immunostaining of endothelial cells for factor VIII revealed that COMP-Ang1 group showed higher levels of vascularity in the fusion site. Runt related transcription factor 2 and its target genes were significantly up regulated in the COMP-Ang1 group. CONCLUSIONS: COMP-Ang1 induced radiologically and histologically demonstrable active osteogenesis by promoting angiogenesis in spinal fusions. It was concluded that COMP-Ang1 enhances spinal fusion and hence the strength of the fusion. PMID- 21658485 TI - Primary care physicians perceptions and practices regarding fall prevention in adult's 65 years and over. AB - BACKGROUND: Falls are the leading cause of injury deaths and the most common cause of disability, premature nursing home admissions, medical costs, and hospitalizations among people 65 years and over. Interventions targeting multiple fall risk factors can reduce fall rates by 30-40%. Yet, national studies show that screening conducted by physicians for older adult falls is short of acceptable standards. Tri-County Health Department (TCHD) in Colorado conducted a study to examine fall prevention practices among primary care physicians in our jurisdiction. METHODS: TCHD randomly sampled primary care physicians (n=100) obtained from a statewide healthcare provider database and surveyed them about fall prevention screening practices and perceived barriers to screening. Data were examined using single and multiple logistic regression analysis. RESULTS: The response rate was 67.6%. Only 8% of responding physicians based their fall prevention practices on clinical guidelines from any recognized organizations. Frequently reported barriers included a lack of time during visits, more pressing issues, and a lack of educational materials. Physicians who did not accept Medicare (OR 0.163 [CI 0.03-0.84]) remained significantly less likely to refer patients for home safety assessments than those who did, on multivariate analysis. CONCLUSIONS: This study reveals certain physicians require targeted interventions to improve fall prevention practices and use of clinical guidelines. Recommendations include providing physicians with trainings, screening guides, educational materials, environmental/home safety checklists, and referral resources. PMID- 21658482 TI - One small step for Mot1; one giant leap for other Swi2/Snf2 enzymes? AB - The TATA-binding protein (TBP) is a major target for transcriptional regulation. Mot1, a Swi2/Snf2-related ATPase, dissociates TBP from DNA in an ATP dependent process. The experimental advantages of this relatively simple reaction have been exploited to learn more about how Swi2/Snf2 ATPases function biochemically. However, many unanswered questions remain and fundamental aspects of the Mot1 mechanism are still under debate. Here, we review the available data and integrate the results with structural and biochemical studies of related enzymes to derive a model for Mot1's catalytic action consistent with the broad literature on enzymes in this family. We propose that the Mot1 ATPase domain is tethered to TBP by a flexible, spring-like linker of alpha helical hairpins. The linker juxtaposes the ATPase domain such that it can engage duplex DNA on one side of the TBP-DNA complex. This allows the ATPase to employ short-range, nonprocessive ATP-driven DNA tracking to pull or push TBP off its DNA site. DNA translocation is a conserved property of ATPases in the broader enzyme family. As such, the model explains how a structurally and functionally conserved ATPase domain has been put to use in a very different context than other enzymes in the Swi2/Snf2 family. This article is part of a Special Issue entitled:Snf2/Swi2 ATPase structure and function. PMID- 21658486 TI - Quality of traffic flow on urban arterial streets and its relationship with safety. AB - The two-fluid model for vehicular traffic flow explains the traffic on arterials as a mix of stopped and running vehicles. It describes the relationship between the vehicles' running speed and the fraction of running vehicles. The two parameters of the model essentially represent 'free flow' travel time and level of interaction among vehicles, and may be used to evaluate urban roadway networks and urban corridors with partially limited access. These parameters are influenced by not only the roadway characteristics but also by behavioral aspects of driver population, e.g., aggressiveness. Two-fluid models are estimated for eight arterial corridors in Orlando, FL for this study. The parameters of the two fluid model were used to evaluate corridor level operations and the correlations of these parameters' with rates of crashes having different types/severity. Significant correlations were found between two-fluid parameters and rear-end and angle crash rates. Rate of severe crashes was also found to be significantly correlated with the model parameter signifying inter-vehicle interactions. While there is need for further analysis, the findings suggest that the two-fluid model parameters may have potential as surrogate measures for traffic safety on urban arterial streets. PMID- 21658488 TI - The link between built environment, pedestrian activity and pedestrian-vehicle collision occurrence at signalized intersections. AB - This paper studies the influence of built environment (BE) - including land use types, road network connectivity, transit supply and demographic characteristics on pedestrian activity and pedestrian-vehicle collision occurrence. For this purpose, a two-equation modeling framework is proposed to investigate the effect of built environment on both pedestrian activity and vehicle-pedestrian collision frequency at signalized intersections. Using accident data of ambulance services in the City of Montreal, the applicability of our framework is illustrated. Different model settings were attempted as part of a model sensitivity analysis. Among other results, it was found that the BE in the proximity of an intersection has a powerful association with pedestrian activity but a small direct effect on pedestrian-vehicle collision frequency. This suggests that the impact of BE is mainly mediated through pedestrian activity. In other words, strategies that encourage densification, mix of land uses and increase in transit supply will increase pedestrian activity and may indirectly, with no supplementary safety strategies, increase the total number of injured pedestrians. In accordance with previous research, the number of motor vehicles entering a particular intersection is the main determinant of collision frequency. Our results show that a 30% reduction in the traffic volume would reduce the total number of injured pedestrians by 35% and the average risk of pedestrian collision by 50% at the intersections under analysis. Major arterials are found to have a double negative effect on pedestrian safety. They are positively linked to traffic but negatively associated with pedestrian activity. The proposed framework is useful for the identification of effective pedestrian safety actions, the prediction of pedestrian volumes and the appropriate safety design of new urban developments that encourage walking. PMID- 21658487 TI - Contextual deprivation, daily travel and road traffic injuries among the young in the Rhone Departement (France). AB - This study investigated the effect of the socioeconomic level of the municipality of residence on personal injury road traffic accident risk among young persons of 10-24 years of age in the Rhone Departement. This effect was assessed by comparing incidences of injuries (n=2792 casualties) on the basis of three denominators: the resident population of young people, the number of users of each mode and the distances covered by each mode. The results are presented for each type of road users (pedestrians, car passengers, car drivers, motorised two wheeler riders, cyclists, public transport users). Young persons from deprived municipalities use motorised-two wheelers, bicycles and the car (as passengers and drivers) less frequently, they walk more and take public transports more often than those from other municipalities. When considering injury risk, motorised two wheeler injuries among adolescent males, for example, are significantly less frequent in deprived municipalities. But the motorised two wheeler riders as well as car passengers from deprived municipalities are characterized by an excess injury risk, whether the selected denominator is the number of users or the kilometres travelled by this mode. For the first time in France, this study has enabled a comparison of the effects of a contextual socioeconomic indicator (the type of municipality of residence, deprived, or not) on daily travel practices and injury incidences among the population, among the users of each mode and per km of travel. PMID- 21658489 TI - The influence of multiple goals on driving behavior: the case of safety, time saving, and fuel saving. AB - Due to the innate complexity of the task drivers have to manage multiple goals while driving and the importance of certain goals may vary over time leading to priority being given to different goals depending on the circumstances. This study aimed to investigate drivers' behavioral regulation while managing multiple goals during driving. To do so participants drove on urban and rural roads in a driving simulator while trying to manage fuel saving and time saving goals, besides the safety goals that are always present during driving. A between subjects design was used with one group of drivers managing two goals (safety and fuel saving) and another group managing three goals (safety, fuel saving, and time saving) while driving. Participants were provided continuous feedback on the fuel saving goal via a meter on the dashboard. The results indicate that even when a fuel saving or time saving goal is salient, safety goals are still given highest priority when interactions with other road users take place and when interacting with a traffic light. Additionally, performance on the fuel saving goal diminished for the group that had to manage fuel saving and time saving together. The theoretical implications for a goal hierarchy in driving tasks and practical implications for eco-driving are discussed. PMID- 21658490 TI - Factors influencing students' usage of school bus seat belts: an empirical analysis of the Alabama pilot project. AB - The Alabama State Department of Education and the Governor's Study Group on School Bus Seat Belts authorized and funded a research project to investigate the effects of lap-shoulder seat belts on Alabama school buses. This article performs an empirical analysis to address an important component of the study - factors that impact students' decisions about wearing seat belts or not on school buses. Discrete choice modeling framework is applied to quantify relative influences of various factors. To obtain the disaggregate level information on individual student's characteristics and trip properties, a new data collection protocol is developed. Eleven variables are investigated and eight of them are found to have significant impacts. They are age, gender, the home county of a student, a student's trip length, time of day, presence and active involvement of bus aide, and two levels of bus driver involvement. The resulting model fits the data well and reveals several trends that have been overlooked or underestimated in the literature. The model can also be used to predict the change of seat belt usage rate caused by the change of impact factors. This is helpful in identifying the most cost-effective ways to improve compliance rate, which is critical to bring the added safety benefit of seat belts into effect. This article is the first to quantify relative impacts of a range of variables using rigorous statistical modeling techniques. This study will contribute to the literature and provide valuable insights to the practice of school transportation management. PMID- 21658491 TI - Personality traits and executive functions related to on-road driving performance among older drivers. AB - The present study investigated how executive functions and personality traits are related with driving performance among older drivers. Forty-two participants aged 60 and over were recruited to complete a battery of cognitive tests, measures of personality traits and an on-road driving test. Significant correlations were found between poor driving performances and low scores on tests assessing shifting and updating functions. In addition, extraversion had a negative relation with driving performance and made the only contribution, among the psychological factors, to the prediction of driving performance. Finally, gender and age emerged as the best predictors of on-road driving performance. Gender, personality traits and executive functions should be taken into account when studying safety among older drivers. PMID- 21658492 TI - Do young novice drivers overestimate their driving skills more than experienced drivers? Different methods lead to different conclusions. AB - In this study we argue that drivers have to make an assessment of their own driving skills, in order to sufficiently adapt to their task demands in traffic. There are indications that drivers in general, but novice drivers in particular, overestimate their driving skills. However, study results differ on the subject of self-assessment of skills. The objectives of this paper are (1) to study whether novice drivers indeed overestimate their driving skills more than experienced drivers; and (2) to evaluate the influence of the method to measure self-assessment of skills (i.e. comparison to 'average' and 'peer' driver versus independent measures of own performance). The results show that the conclusion of whether novice drivers overestimate their driving skills is highly affected by the method chosen to measure self-assessment of skills. When drivers are asked to compare themselves to the average and peer driver, we can conclude that novice drivers are not as optimistic about their driving skills as has been reported in the past. They seem to recognize that they are not as skilled (yet) as the average driver. However, when comparing their self-assessment with their actual behaviour there are indications that they overestimate their driving skills. PMID- 21658493 TI - The statistical analysis of highway crash-injury severities: a review and assessment of methodological alternatives. AB - Reducing the severity of injuries resulting from motor-vehicle crashes has long been a primary emphasis of highway agencies and motor-vehicle manufacturers. While progress can be simply measured by the reduction in injury levels over time, insights into the effectiveness of injury-reduction technologies, policies, and regulations require a more detailed empirical assessment of the complex interactions that vehicle, roadway, and human factors have on resulting crash injury severities. Over the years, researchers have used a wide range of methodological tools to assess the impact of such factors on disaggregate-level injury-severity data, and recent methodological advances have enabled the development of sophisticated models capable of more precisely determining the influence of these factors. This paper summarizes the evolution of research and current thinking as it relates to the statistical analysis of motor-vehicle injury severities, and provides a discussion of future methodological directions. PMID- 21658494 TI - Injury severities of truck drivers in single- and multi-vehicle accidents on rural highways. AB - In adverse driving conditions, such as inclement weather and/or complex terrain, trucks are often involved in single-vehicle (SV) accidents in addition to multi vehicle (MV) accidents. Ten-year accident data involving trucks on rural highway from the Highway Safety Information System (HSIS) is studied to investigate the difference in driver-injury severity between SV and MV accidents by using mixed logit models. Injury severity from SV and MV accidents involving trucks on rural highways is modeled separately and their respective critical risk factors such as driver, vehicle, temporal, roadway, environmental and accident characteristics are evaluated. It is found that there exists substantial difference between the impacts from a variety of variables on the driver-injury severity in MV and SV accidents. By conducting the injury severity study for MV and SV accidents involving trucks separately, some new or more comprehensive observations, which have not been covered in the existing studies can be made. Estimation findings indicate that the snow road surface and light traffic indicators will be better modeled as random parameters in SV and MV models respectively. As a result, the complex interactions of various variables and the nature of truck-driver injury are able to be disclosed in a better way. Based on the improved understanding on the injury severity of truck drivers from truck-involved accidents, it is expected that more rational and effective injury prevention strategy may be developed for truck drivers under different driving conditions in the future. PMID- 21658495 TI - Pedestrian injury analysis with consideration of the selectivity bias in linked police-hospital data. AB - Evaluation of crash-related injuries by medical specialists in hospitals is believed to be more exact than rather a cursory evaluation made at the crash scene. Safety analysts sometimes reach for hospital data and use them in combination with the police crash data. One issue that needs to be addressed is the, so-called, selectivity (or selection) bias possible when data used in analysis are not coming from random sampling. If not properly addressed, this issue can lead to a considerable bias in both the model coefficient estimates and the model predictions. This paper investigates pedestrian injury severity factors using linked police-hospital data. A bivariate ordered probit model with sample selection is used to check for the presence of the selectivity bias and to account for it in the MAIS estimates on the Maximum Abbreviated Injury Scale (MAIS). The presence of the sample selection issue has been confirmed. The selectivity bias is considerable in predictions of low injury levels. The pedestrian injury analysis identified and estimated several severity factors, including pedestrian, road, and vehicle characteristics. Male and older pedestrians were found to be particularly exposed to severe injuries. Rural roads and high-speed urban roads appear to be more dangerous for pedestrians, particularly when crossing such roads. Crossing a road between intersections was found to be particularly dangerous behavior. The size and weight of the vehicle involved in a pedestrian crash were also found to have an effect on the pedestrian injury level. The relevant safety countermeasures that may improve pedestrian safety have been proposed. PMID- 21658496 TI - Repairing faulty scripts to reduce speeding behaviour in young drivers. AB - BACKGROUND: Young drivers under the age of 25 throughout the world continue to be over-represented in motor vehicle accidents (WHO, 2007). A contributing factor to a large number of these motor vehicle accidents is speeding. Reducing drivers' tendency to speed remains a challenge. In aviation, one method that has yielded positive results in terms of improving pilots' risk management behaviour involves engaging pilots cognitively in the task (Molesworth et al., 2006). This type of training is hypothesized to repair faulty cognitive structures known as scripts. Therefore, the main aim of the present research was to examine the utility of a training program where drivers are actively engaged following a driving episode by giving them personalised feedback in order to reduce their tendency to speed. METHOD: 58 young (16-24 years) motorists were divided into four groups. All participants completed both a 'training' session followed by a test session one week apart. Training consisted of either, reading three accident cases involving speeding, cases with rules associated with the offence, a simulated drive with personalised post-drive feedback regarding speeding and its legal ramifications or a card sorting task (control). The main dependent variables were percentage of distance speeding and frequency of zone violations during the simulated drive in the test session. RESULTS: A series of planned contrast analysis with family-wise error corrected at .017 revealed that receiving personalised feedback regarding speeding behaviour following a simulated drive significantly reduced speeding tendency in the test session, when compared to control. Reading case examples alone, or coupled with rules, appeared to have no impact on speeding behaviour, compared to control. CONCLUSION: The results suggest that training programs that actively engage individuals about a driving episode by providing them with personalised feedback may be effective in curbing young drivers' speeding behaviour. These results are discussed from a theoretical and applied perspective. PMID- 21658497 TI - Driver secondary tasks in Germany: using interviews to estimate prevalence. AB - Secondary tasks while driving are frequently found in different types of studies from all over the world. For a profound understanding of secondary tasks' impact on road safety it is essential to know in detail what kind of tasks drivers are doing in which situations. In contrast to costly observational studies, interviews may be a suitable access to these data if reporting biases are minimized. In 2009, 289 drivers were interviewed in face-to-face interviews on German motorway service areas as well as in the city of Braunschweig about their secondary task engagement in the last 30 min of driving. Five groups of drivers were examined: (1) truck drivers at the motorway (N=90), (2) car drivers on private trips at the motorway (N=71), (3) car drivers on business trips at the motorway (N=29), (4) car drivers on private trips in town (N=85), (5) car drivers on business trips in town (N=12). The pattern and frequency of engagement in secondary tasks differed between these groups. Overall, about 80% of all drivers conducted one to three secondary tasks. Thus, secondary task engagement is a serious issue in Germany and accident studies are needed to estimate drivers' risk. PMID- 21658498 TI - Personality subtypes of young moped drivers, their relationship to risk-taking behavior and involvement in road crashes in an Austrian sample. AB - OBJECTIVE: This study aimed to identify subtypes of young moped drivers and analyze how these subtypes are involved in risk preferences and road crashes. DESIGN: A group of Austrian teenage moped drivers (213, 28% girls) completed an online questionnaire about moped usage, injuries, driving style, inattention, impulsivity, and personality according to the Five-Factor Model of Personality and Cloninger's model of personality. RESULTS: A cluster analysis yielded four types of moped drivers. One type was characterized by a high level of neuroticism, the second type was characterized by a risky personality and a risky driving style, the third type had a more cautious driving style, and the fourth type was characterized by a risky personality and high levels on inattention and impulsivity. CONCLUSIONS: Our conclusions suggest that young moped drivers should not be perceived as a homogenous group, according to measures of injury prevention and intervention. PMID- 21658499 TI - The contribution of perceived parental and familial characteristics to attitudes toward accompanied driving among young drivers. AB - One of the main requirements of the graduated driving licensing system in Israel is that new drivers be accompanied by an experienced driver (usually one of their parents) for the first three months after receipt of their license. The current series of studies examined the associations between young drivers' attitudes toward accompanied driving (ATAD) and their perception of their parents' driving styles and parenting modes, as well as dynamic of their family. Young drivers completed questionnaires assessing their ATAD, and either perceived parental driving style (Study 1, n=100), perceived parenting style (Study 2, n=120), or perceived family dynamic (Study 3, n=254). The results indicated significant associations between the young drivers' ATAD of tension, relatedness, avoidance, disapproval, and anxiety, and their own perceptions of the characteristic driving styles of their parents (risky, anxious, angry, and careful). They also indicated significant relationship between youngsters' ATAD and their perceptions of their parents' parenting modes (responsive, demanding, and autonomy-granting). Finally, the results indicated significant negative associations between ATAD of tension, avoidance, disapproval, and anxiety, and family cohesion and adaptability, and a positive association between these two and relatedness. The results are discussed in respect to the relationship between the parental model and the young drivers' ATAD in particular, and risk management in general, and practical implications of these results are offered. PMID- 21658500 TI - A study on crashes related to visibility obstruction due to fog and smoke. AB - Research on weather effects has focused on snow- or rain-related crashes. However, there is a lack of understanding of crashes that occur during fog or smoke (FS). This study presents a comprehensive examination of FS-related crashes using crash data from Florida between 2003 and 2007. A two-stage research strategy was implemented (1) to examine FS-related crash characteristics with respect to temporal distribution, influential factors and crash types and (2) to estimate the effects of various factors on injury severity given that a FS related crash has occurred. The morning hours from December to February are the prevalent times for FS-related crashes. Compared to crashes under clear visibility conditions, FS-related crashes tend to result in more severe injuries and involve more vehicles. Head-on and rear-end crashes are the two most common crash types in terms of crash risk and severity. These crashes were more prevalent on high-speed roads, undivided roads, roads with no sidewalks and two lane rural roads. Moreover, FS-related crashes were more likely to occur at night without street lighting, leading to more severe injuries. PMID- 21658501 TI - The negative binomial-Lindley distribution as a tool for analyzing crash data characterized by a large amount of zeros. AB - The modeling of crash count data is a very important topic in highway safety. As documented in the literature, given the characteristics associated with crash data, transportation safety analysts have proposed a significant number of analysis tools, statistical methods and models for analyzing such data. Among the data issues, we find the one related to crash data which have a large amount of zeros and a long or heavy tail. It has been found that using this kind of dataset could lead to erroneous results or conclusions if the wrong statistical tools or methods are used. Thus, the purpose of this paper is to introduce a new distribution, known as the negative binomial-Lindley (NB-L), which has very recently been introduced for analyzing data characterized by a large number of zeros. The NB-L offers the advantage of being able to handle this kind of datasets, while still maintaining similar characteristics as the traditional negative binomial (NB). In other words, the NB-L is a two-parameter distribution and the long-term mean is never equal to zero. To examine this distribution, simulated and observed data were used. The results show that the NB-L can provide a better statistical fit than the traditional NB for datasets that contain a large amount of zeros. PMID- 21658502 TI - Applying the motorcyclist's perspective to improve car drivers' attitudes towards motorcyclists. AB - This study sought to provide a first crucial step in the direction of developing an intervention program aimed at improving safe attitudes and skills among car drivers towards motorcycles. We intended to improve drivers' attitudes towards motorcyclists by exposing them to demands that motorcyclists face on the road. Car drivers were exposed to hazard perception clips taken from a motorcyclist's perspective, and interactive hazards in a motorcycle simulator. Car hazard perception clips and a car simulator were used as control conditions. A questionnaire assessed participant knowledge and attitudes towards motorcyclists before and after the intervention. After the intervention participants had more empathic- and fewer negative-attitudes, as well as safer attitudes towards motorcyclists. Self-reported attitude-change suggested that the use of motorcycle hazard perception clips was more effective than the simulator, and the intervention was most effective for those car drivers who reported the most negative attitudes prior viewing the clips or riding the simulator. Providing car drivers with a perspective of the motorcyclist may prove to be a useful tool for promoting safer attitudes towards motorcyclists. PMID- 21658503 TI - Motor vehicle-bicycle crashes in Beijing: irregular maneuvers, crash patterns, and injury severity. AB - This research presents a comprehensive analysis of motor vehicle-bicycle crashes using 4 years of reported crash data (2004-2007) in Beijing. The interrelationship of irregular maneuvers, crash patterns and bicyclist injury severity are investigated by controlling for a variety of risk factors related to bicyclist demographics, roadway geometric design, road environment, etc. Results show that different irregular maneuvers are correlated with a number of risk factors at different roadway locations such as the bicyclist age and gender, weather and traffic condition. Furthermore, angle collisions are the leading pattern of motor vehicle-bicycle crashes, and different irregular maneuvers may lead to some specific crash patterns such as head-on or rear-end crashes. Orthokinetic scrape is more likely to result in running over bicyclists, which may lead to more severe injury. Moreover, bicyclist injury severity level could be elevated by specific crash patterns and risk factors including head-on and angle collisions, occurrence of running over bicyclists, night without streetlight, roads without median/division, higher speed limit, heavy vehicle involvement and older bicyclists. This study suggests installation of median, division between roadway and bikeway, and improvement of illumination on road segments. Reduced speed limit is also recommended at roadway locations with high bicycle traffic volume. Furthermore, it may be necessary to develop safety campaigns aimed at male, teenage and older bicyclists. PMID- 21658504 TI - The development and validation of a hazard perception test for use in driver licensing. AB - Drivers' hazard perception is the ability to identify dangerous situations on the road ahead. We detail the development and validation of a new computer-based hazard perception test to be used for driver licensing purposes in Queensland, Australia. We proposed five principles of effective hazard perception test creation, which we used to guide development of the test. In Study 1, the video based instructions for the test were found to be intelligible to non-native English-speakers with an effective English reading age of 10 years. In Study 2, experienced drivers were found to be faster at responding to hazards in the test than learner drivers (independent of simple reaction time or ability to use the response device), providing evidence for test validity. We found no evidence of gender, income, or educational differences in hazard perception scores. The results of both experiments confirm the efficacy of the five principles, and provide support for the validity of the QT-HPT and its suitability for use in the graduated driver licensing system. PMID- 21658505 TI - Driver distraction and driver inattention: definition, relationship and taxonomy. AB - There is accumulating evidence that driver distraction and driver inattention are leading causes of vehicle crashes and incidents. However, as applied psychological constructs, they have been inconsistently defined and the relationship between them remains unclear. In this paper, driver distraction and driver inattention are defined and a taxonomy is presented in which driver distraction is distinguished from other forms of driver inattention. The taxonomy and the definitions provided are intended (a) to provide a common framework for coding different forms of driver inattention as contributing factors in crashes and incidents, so that comparable estimates of their role as contributing factors can be made across different studies, and (b) to make it possible to more accurately interpret and compare, across studies, the research findings for a given form of driver inattention. PMID- 21658506 TI - Psychosocial safety climate as a lead indicator of workplace bullying and harassment, job resources, psychological health and employee engagement. AB - Psychosocial safety climate (PSC) is defined as shared perceptions of organizational policies, practices and procedures for the protection of worker psychological health and safety, that stem largely from management practices. PSC theory extends the Job Demands-Resources (JD-R) framework and proposes that organizational level PSC determines work conditions and subsequently, psychological health problems and work engagement. Our sample was derived from the Australian Workplace Barometer project and comprised 30 organizations, and 220 employees. As expected, hierarchical linear modeling showed that organizational PSC was negatively associated with workplace bullying and harassment (demands) and in turn psychological health problems (health impairment path). PSC was also positively associated with work rewards (resources) and in turn work engagement (motivational path). Accordingly, we found that PSC triggered both the health impairment and motivational pathways, thus justifying extending the JD-R model in a multilevel way. Further we found that PSC, as an organization-based resource, moderated the positive relationship between bullying/harassment and psychological health problems, and the negative relationship between bullying/harassment and engagement. The findings provide evidence for a multilevel model of PSC as a lead indicator of workplace psychosocial hazards (high demands, low resources), psychological health and employee engagement, and as a potential moderator of psychosocial hazard effects. PSC is therefore an efficient target for primary and secondary intervention. PMID- 21658507 TI - Gender differences in pedestrian rule compliance and visual search at signalized and unsignalized crossroads. AB - Male pedestrians are over-represented in road crashes. Among pedestrians, males violate more rules than females do. For now, it is not known whether gender differences in pedestrian behaviors only concern rule compliance. The objective of this study was to explore gender differences in pedestrian rule compliance and in gaze targets before and during crossing. 400 adult pedestrians were observed at two signalized and two unsignalized crossroads, using a taxonomic observation grid which detailed 13 behavioral categories before, during and after crossing. The results show that the temporal crossing compliance rate is lower among male pedestrians but spatial crossing compliance does not differ between genders. Furthermore, different gaze patterns emerge between genders before and during crossing, notably as women particularly focus on other pedestrians during these two periods whereas men focus on vehicles. Moreover, females' gazes vary with the type of crossroads, but males' gazes do not. Spatial crossing compliance and gaze targets are furthermore modulated by the crossroad configuration. These results are discussed in terms of pedestrian visual strategy and compliance. PMID- 21658508 TI - Socio-economic inequalities in mortality due to injuries in small areas of ten cities in Spain (MEDEA Project). AB - OBJECTIVES: To analyse socio-economic inequalities in mortality due to injuries among census tracts of ten Spanish cities by sex and age in the period 1996-2003. METHODS: This is a cross-sectional ecological study where the units of analysis are census tracts. The study population consisted of people residing in the cities during the period 1996-2003. For each census tract we obtained an index of socio-economic deprivation, and estimated standardized mortality ratios using hierarchical Bayesian models which take into account the spatial structure of the data. RESULTS: In the majority of the cities, the geographical pattern of total mortality from injuries is similar to that of the socio-economic deprivation index. There is an association between mortality due to injuries and the deprivation index in the majority of the cities which is more important among men and among those younger than 45 years. In these groups, traffic injuries and overdoses are the causes most often associated with deprivation in the cities. The percentage of excess mortality from injuries related to socio-economic deprivation is higher than 20% in the majority of the cities, the cause with the highest percentage being drug overdose. CONCLUSIONS: In most cities, there are socio-economic inequalities in mortality due to overdose and traffic injuries. In contrast, few cities have found association between suicide mortality and deprivation. Finally, no association was found between deprivation and deaths due to falls. Inequalities are higher in men and those under 45 years of age. These results highlight the importance of intra-urban inequalities in mortality due to injuries. PMID- 21658509 TI - Analysis of driver casualty risk for different work zone types. AB - Using driver casualty data from the Fatality Analysis Report System, this study examines driver casualty risk and investigates the risk contributing factors in the construction, maintenance and utility work zones. The multiple t-tests results show that the driver casualty risk is statistically different depending on the work zone type. Moreover, construction work zones have the largest driver casualty risk, followed by maintenance and utility work zones. Three separate logistic regression models are developed to predict driver casualty risk for the three work zone types because of their unique features. Finally, the effects of risk factors on driver casualty risk for each work zone type are examined and compared. For all three work zone types, five significant risk factors including road alignment, truck involvement, most harmful event, vehicle age and notification time are associated with increased driver casualty risk while traffic control devices and restraint use are associated with reduced driver casualty risk. However, one finding is that three risk factors (light condition, gender and day of week) exhibit opposing effects on the driver casualty risk in different types of work zones. This may largely be due to different work zone features and driver behavior in different types of work zones. PMID- 21658510 TI - Effects of higher-order driving skill training on young, inexperienced drivers' on-road driving performance. AB - The aim of the current study was to compare the effects of training in higher order driving skills (e.g., perceptual, motivational, insight) and vehicle handling skill training in relation to on-road driving performance, hazard perception, attitudes to risky driving and driver confidence levels in young, inexperienced drivers. Thirty-six young drivers (23 males and 13 females, average age 16.3 years), mostly on a restricted NZ driver licence, participated in a Driver Training Research camp. Participants were randomly allocated to one of three equally sized groups according to the type of driving skill training (5 days) they received: higher-order, vehicle handling or control (no training). Professional driver assessors conducted a comprehensive driving assessment before (Baseline) and after the training (Post Training). At both time points, participants also carried out a computerised hazard perception task, and completed self-report questionnaires to assess attitudes to risky driving and driver confidence. In terms of on road driving, the participants who received higher-order driving skill training showed a statistically significant improvement in relation to visual search and the composite driving measure. This was accompanied by an improvement in hazard perception, safer attitudes to close following and to dangerous overtaking and a decrease in driving related confidence. The participants who received vehicle handling skill training showed significant improvements in relation to their on-road direction control, speed choice and the composite driving score. However, this group showed no improvement in hazard perception, attitudes to risky driving or driver confidence. The findings will be discussed in the context of driver training as a viable crash prevention intervention in regard to young, inexperienced drivers. PMID- 21658511 TI - Personality, risk aversion and speeding: an empirical investigation. AB - Evidence suggests that in addition to demographics, there are strong relationships between facets of drivers' personality (e.g., aggression, thrill seeking, altruism), aversion to risk and driving behaviour, particularly speeding. However, evidence is muted by the reliance on self-reported driving behaviour, which is thought to not accurately reflect actual driving behaviour. This paper reports on a study of 133 drivers in Sydney, who were asked to complete a short survey to develop their personality and risk aversion profiles and self-reported speeding behaviour. A Global Positioning System (GPS) device was then installed in their vehicle for several weeks as part of a major investigation of driving behaviour from which empirical measures of speeding are derived. Among the most pertinent findings are: (1) the tendency for drivers to both under and over-estimate their propensity to speed, (2) significant heterogeneity in speeding with a small, but notable number of drivers exceeding the limit for more than 20 percent of the distance driven, (3) weak relationships between the personality/risk-aversion measures and actual speeding, and (4) the suggestion that different personality traits appear to influence behaviour in different situations both from self-reported and actual speeding behaviour. PMID- 21658512 TI - Fatal accidents at railway level crossings in Great Britain 1946-2009. AB - This paper investigates fatal accidents and fatalities at level crossings in Great Britain over the 64-year period 1946-2009. The numbers of fatal accidents and fatalities per year fell by about 65% in the first half of that period, but since then have remained more or less constant at about 11 fatal accidents and 12 fatalities per year. At the same time other types of railway fatalities have fallen, so level crossings represent a growing proportion of the total. Nevertheless, Britain's level crossing safety performance remains good by international standards. The paper classifies level crossings into three types: railway-controlled, automatic, and passive. The safety performance of the three types of crossings has been very different. Railway-controlled crossings are the best-performing crossing type, with falling fatal accident rates. Automatic crossings have higher accident rates per crossing than railway controlled or passive crossings, and the accident rates have not decreased. Passive crossings are by far the most numerous, but many have low usage by road users. Their fatal accident rate has remained remarkably constant over the whole period at about 0.9 fatal accidents per 1000 crossings per year. A principal reason why fatal accidents and fatalities have not fallen in the second half of the period as they did in the first half is the increase in the number of automatic crossings, replacing the safer railway controlled crossings on some public roads. However, it does not follow that this replacement was a mistake, because automatic crossings have advantages over controlled crossings in reducing delays to road users and in not needing staff. Based on the trends for each type of crossing and for pedestrian and non-pedestrian accidents separately, in 2009 a mean of about 5% of fatal accidents were at railway controlled crossings, 52% were at automatic crossings, and 43% were at passive crossings. Fatalities had similar proportions. About 60% of fatalities were to pedestrians. A simple comparison of automatic railway level crossings and signalised road intersections found that in 2005 the numbers of fatalities per 1000 crossings or intersections were similar. PMID- 21658513 TI - Distance between speed humps and pedestrian crossings: does it matter? AB - Speed humps are a common physical measure installed at pedestrian crossings to reduce vehicle speeds therefore improve the safety and mobility of pedestrians at the crossing. The aim of this study was to determine whether variations in distance between speed humps and pedestrian crossings contribute differently to the safety and mobility of pedestrians and cyclists, especially children and the elderly, and if so, how. Three sites in Sweden were studied, where vehicle speed measurements and video filming at the site resulted in manually coded, road user behaviour of 1972 pedestrians and cyclists. Road user behaviour at three test sites and two comparison sites equipped with speed cushion at distances of about 5m and 10 m from the pedestrian crossing, i.e. about one or two car lengths, were studied. As vehicle speeds were somewhat lower at the pedestrian crossing when the distance between the speed cushion to the pedestrian crossing was greater, and there were positive aspects regarding the mobility of the pedestrians and cyclists, a greater distance of about 10 m or two car lengths between the hump and the pedestrian crossing is suggested. The present study only covers speed cushions, but the same distance is also regarded as important when installing other types of physical measures to reduce vehicle speed. PMID- 21658514 TI - The effects of road-surface conditions, age, and gender on driver-injury severities. AB - Drivers' adaptation to weather-induced changes in roadway-surface conditions is a complex process that can potentially be influenced by many factors including age and gender. Using a mixed logit analysis, this research assesses the effects that age, gender, and other factors have on crash severities by considering single vehicle crashes that occurred on dry, wet, and snow/ice-covered roadway surfaces. With an extensive database of single-vehicle crashes from Indiana in 2007 and 2008, estimation results showed that there were substantial differences across age/gender groups under different roadway-surface conditions. For example, for all females and older males, the likelihood of severe injuries increased when crashes occurred on wet or snow/ice surfaces-but for male drivers under 45 years of age, the probability of severe injuries decreased on wet and snow/ice surfaces - relative to dry-surface crashes. This and many other significant differences among age and gender groups suggest that drivers perceive and react to pavement surface conditions in very different ways, and this has important safety implications. Furthermore, the empirical findings of this study highlight the value of considering subsets of data to unravel the complex relationships within crash-injury severity analysis. PMID- 21658515 TI - On factors related to car accidents on German Autobahn connectors. AB - We make an attempt to identify factors that explain accidents on German Autobahn connectors. To find these factors we perform an empirical study making use of count data models with fixed and random coefficients. The findings are based on a set of 197 ramps, which we classify into three distinct types of ramps. For these ramps, accident data is available for a period of 3 years (January 2003 until December 2005). The negative binomial model with some random coefficients proved to be an appropriate model in our cross-sectional setting for detecting factors that are related to accidents. The most significant variable is a measure of the average daily traffic. For geometric variables, not only continuous effects were found to be significant, but also threshold effects indicating the exceedance of certain values. PMID- 21658516 TI - Are rural older drivers subject to low-mileage bias? AB - Comparing exposure-based collision statistics between older drivers based on age alone erroneously assumes a linear relationship between exposure and collision frequency. Research has suggested that low-mileage drivers, of any age, tend to have higher exposure-based collision rates because the majority of their travel is typically on congested city streets with higher potential for collisions, referred to as "low-mileage bias". It is unclear whether it is appropriate to extend this perspective to rural older drivers, where it could be expected they would likely have very different travel habits than an urban older driver with equivalent annual mileage. Consequently, reliance on "low-mileage-bias" as an explanation for high collision rates among seniors would benefit from the distinction of the differences in the type of driving exposure between urban and rural drivers. This paper used the detailed driving exposure information obtained from a Global Positioning System (GPS) supported travel diary study to explore whether "low-mileage bias" exists for rural older drivers. Revealed behaviour from GPS travel diaries of a convenience sample of 60 rural drivers aged 54-92 years showed the proportion of travel on urban streets increased with self reported mileage and decreased with age. This finding is contrary to previous results where no distinction was made between urban and rural drivers. These results, combined with previous research showing the oldest rural drivers (81 years and older) have higher collision rates than their urban counterparts, suggests "low-mileage bias" may not exist in the rural context. It is possible the collision risk for the oldest rural drivers is understated, but further research is required. Self-reported mileage groups are a useful way to organize and analyze exposure and collision information, but age group analysis should not be excluded. PMID- 21658517 TI - Evaluating the effect of vehicle modification in reducing injuries from landmine blasts. An analysis of 2212 incidents and its application for humanitarian purposes. AB - INTRODUCTION: Anti-vehicle (AV) mines have been laid indiscriminately in conflict areas for the past 100 years. With an indeterminate life-span they continue to pose a significant threat to the civilian population, as well as restrict the movement of people, aid and goods to vulnerable populations. The aim of this study was to analyse unique casualty data from 2212 mine incidents to determine if simple vehicle modifications can reduce fatality and injury rates from mine explosions. METHOD: We analysed casualty data from the Rhodesian War (1972-1980), to assess the effects of basic vehicle modifications (V-shaped hull, increased ground clearance, widened axles, heavy vehicles and blast deflectors) on injury rates. A multinomial regression statistical model was developed for vehicle modifications and number of alterations to explore these effects. RESULTS: Incident data was available on 2212 vehicle mine incidents involving 16,456 people. The overall fatality rate was 3.3% (544/16,456) and the overall injury rate was 22.7% (3741/16,456). Explosions against mine-protected vehicles resulted in a fatality rate of 1.2% (150/12,919); occupants in unprotected vehicles sustained a fatality rate of 11.4% (395/3537). The injury rate in mine protected vehicles was 22.2% (2868/12,919) compared to 24.7% in unprotected vehicles (873/3537). Utilising a multinomial logistical-regression model, we show that each design feature significantly reduced fatality rate (from 45% in unprotected vehicles to 0.8% in protected vehicles); each of these designs had a cumulative effect in fatality reduction. In isolation, blast deflectors, whilst reducing fatality rates, increased injury rates. CONCLUSIONS: Our data clearly demonstrates that simple vehicle modifications can have a significant effect on reducing fatality and injury rates from AV mine explosions. Given that the modifications described were produced using commercially available vehicles with basic engineering requirements, we believe that similar processes could be employed in post-conflict environments in a cost-effective manner. PMID- 21658518 TI - Managing speed at school and playground zones. AB - Since speeding is one of the major causes of frequent and severe traffic accidents around school and playground areas, many jurisdictions have reduced the speed limits in these areas to protect children who may be at risk. This paper investigated the speed compliance, mean speed and 85th percentile speed at selected school and playground zones in the City of Calgary in Alberta. Our results showed that the mean speed was lower and the rate of compliance was higher in the school zone compared to the playground zone, 2 lane roads relative to 4 lane roads, roads with fencing, traffic control devices and the presence of speed display device or children, and zones that were longer (> 200 m). Accordingly, this study provided recommendations to improve the effectiveness of school and playground zone speed limits. PMID- 21658519 TI - Cognitive-behavior therapy for disaster-exposed youth with posttraumatic stress: results from a multiple-baseline examination. AB - Youth traumatized by natural disasters report high levels of posttraumatic stress such as symptoms of posttraumatic stress disorder, other anxiety disorders, and depression. Research suggests that cognitive behavioral therapies are promising interventions for symptom reduction; however, few cognitive behavioral treatments have been systematically tested in youth hurricane survivors. The current study provides an examination of the efficacy of an intervention manual designed specifically for hurricane-exposed youth (i.e., the StArT manual) using a partially nonconcurrent multiple baseline design. Youth ages 8-13 (n = 6) who met diagnostic criteria for posttraumatic stress disorder were provided the individual StArT treatment in their school. Youth were assessed at pretreatment, weekly during treatment, and at posttreatment. Results provide initial evidence for the efficacy of the StArT manual and suggest the feasibility of conducting the StArT manual in a school setting. The importance of large-scale tests of effectiveness and implementation of cognitive behavioral treatments in the wake of disaster among youth are discussed. PMID- 21658521 TI - Intolerance of uncertainty and decisions about delayed, probabilistic rewards. AB - Worry is the inflated concern about potential future threats and is a hallmark feature of generalized anxiety disorder. Previous theoretical work has suggested that worry may be a consequence of intolerance of uncertainty (IU). The current study seeks to explore the behavioral consequences of IU. Specifically, we examine how IU might be associated with aspects of reward-based decision making. We utilized a simple laboratory gambling task in which participants chose between small, low-probability rewards available immediately at the beginning of each trial and large, high-probability rewards only available after some variable delay. Results demonstrate that higher levels of intolerance of uncertainty were associated with a tendency to select the immediately available, but less valuable and less probable rewards. IU also predicted decision-makers' sensitivity to outcomes. We discuss the cognitive and affective mechanisms that are likely to underlie the observed decision-making behavior and the implications for anxiety disorders. PMID- 21658520 TI - A multilevel examination of interpartner intimate partner violence and psychological aggression reporting concordance. AB - Low concordance of reports across partners has consistently been observed when partners report the frequency of intimate partner violence (IPV) and psychological aggression (PA) in their relationship. Researchers have been unsuccessful in the quest to discover systematic biases across reporters, perhaps due to examining constructs that are not the source of bias (e.g., gender, victim/perpetrator status) or examining potentially fruitful constructs using underpowered statistics or erroneous conceptualizations (e.g., examining variables at a dyadic, rather than an individual, level). We used multilevel modeling with two samples (Ns = 88 and 164 couples) to examine husbands' and wives' relationship satisfaction as individual-level correlates of husband- and wife-perpetrated IPV and PA reporting concordance. Consistent with prior literature, low to moderate levels of agreement were observed, and gender and victim/perpetrator status were not consistently associated with reporting concordance. In contrast, for both husbands and wives, relationship satisfaction was associated with reporting concordance such that high relationship satisfaction was related to reporting less of one's partner's PA than the partner reported, whereas low relationship satisfaction was related to reporting more of one's partner's PA than the partner reported. A similar pattern of results emerged for the reporting of IPV, but results did not cross validate between samples. These findings suggest that relationship satisfaction may lead to either reluctance, or increased willingness, to attribute negative relationship events to partner behavior, potentially due to partner blame and relationship schemas. In addition, the influence of individual-level factors may be occluded when aggregated across partners to examine correlates of interpartner reporting concordance. PMID- 21658522 TI - Reality monitoring in patients with body dysmorphic disorder. AB - Patients with body dysmorphic disorder (BDD) typically have very poor insight into their disorder. Their conviction in their ugliness is often of delusional intensity. Reality monitoring is the ability to distinguish in memory between things that one has imagined and things that one has perceived. Deficits in reality monitoring have been associated with the development of other delusional beliefs. Therefore, in the present study we investigated whether individuals with BDD (n = 20) demonstrate impairments in reality monitoring relative to individuals with obsessive-compulsive disorder (OCD; n = 20) and healthy controls (n = 20). This hypothesized impairment might predispose people with BDD to confuse memories of how they imagine themselves to appear (i.e., ugly) with memories of how they actually appear (i.e., normal). All participants completed a memory task assessing reality-monitoring ability for verbal stimuli. The BDD patients did not exhibit a reality-monitoring deficit despite elevated levels of focal delusionality. The results suggest that impairments in reality monitoring do not contribute to the development or maintenance of appearance-related beliefs in BDD. PMID- 21658523 TI - Patient utilization of cognitive-behavioral therapy for OCD. AB - The current study examined utilization of cognitive-behavioral therapy (CBT) by individuals receiving treatment for obsessive-compulsive disorder (OCD). Participants were 202 adults with primary DSM-IV OCD who enrolled in a longitudinal, observational study of the course of OCD and completed 2 years of annual follow-up interviews using the Longitudinal Interval Follow-Up Evaluation. One hundred twenty participants reported that a mental health professional recommended CBT for their OCD symptoms at some point during the 2-year follow-up period. One quarter (n = 31) of these participants did not initiate CBT despite receiving a treatment recommendation. Thirty-one percent of the 89 participants who entered CBT endorsed dropping out of CBT prematurely and less than one third received an adequate "dose" of CBT sessions. Self-reported CBT drop-out rates were significantly greater than attrition rates reported in clinical trials using intensive schedules of exposure and ritual prevention (EX/RP). Perceived environmental barriers and fears regarding treatment participation were the most frequently endorsed reasons for not participating or dropping out of CBT. Despite its efficacy for OCD, many individuals with clinically significant symptoms fail to initiate CBT when recommended by a mental health professional, receive treatments that are less intensive than those used in clinical trials, or drop out of treatment prematurely. Financial costs of CBT, difficulty attending sessions, and fears regarding treatment are significant barriers to initiating and completing therapy. PMID- 21658524 TI - Parent training with high-risk immigrant chinese families: a pilot group randomized trial yielding practice-based evidence. AB - We studied the efficacy and implementation outcomes of a culturally responsive parent training (PT) program. Fifty-four Chinese American parents participated in a wait-list controlled group randomized trial (32 immediate treatment, 22 delayed treatment) of a 14-week intervention designed to address the needs of high-risk immigrant families. Parents were eligible for intervention if they were Chinese speaking immigrants referred from schools, community clinics, or child protective services with concerns about parenting or child behavior problems. Retention and engagement were high with 83% of families attending 10 or more sessions. Results revealed that the treatment was efficacious in reducing negative discipline, increasing positive parenting, and decreasing child externalizing and internalizing problems. Treatment effects were larger among families with higher levels of baseline behavior problems and lower levels of parenting stress. Further augmentation of PT to address immigrant parent stress may be warranted. Qualitative impressions from group leaders suggested that slower pacing and increased rehearsal of skills may improve efficacy for immigrant parents unfamiliar with skills introduced in PT. PMID- 21658525 TI - An examination of the relation between traumatic event exposure and panic relevant biological challenge responding among adolescents. AB - The current study uniquely extended research that has linked traumatic event exposure to panic-spectrum problems among adolescents. It was hypothesized that among 127 adolescents (age range: 10 to 17 years; M = 14.63, SD = 2.24), those who endorsed a history of traumatic event exposure would evidence significantly greater anxious and fearful reactivity to a well-established 3-min voluntary hyperventilation procedure compared to nonexposed individuals. Results were consistent with hypotheses, suggesting traumatic event exposure is associated with anxious and fearful reactivity to abrupt increases in bodily arousal among adolescents. Moreover, consistent with hypotheses, anxiety sensitivity significantly mediated the relations between traumatic event exposure and both self-reported panic symptoms and panic symptoms elicited by the challenge. Future prospective research is now needed to better understand temporal relations between traumatic event exposure and indices of panic and related vulnerability. PMID- 21658526 TI - Evaluation of a DVD-based self-help program in highly socially anxious individuals--pilot study. AB - High social anxiety is a risk factor for the incidence of social anxiety disorder (SAD). Early diagnosis and intervention may prevent more severe psychiatric courses. Self-help programs may be a convenient, accessible, and effective intervention. This study examined the efficacy of a newly developed self-help program for SAD in individuals with subthreshold social anxiety. A total of 24 highly socially anxious individuals were randomly assigned to a DVD-based self help program or to a wait-list control group. The self-help program is based on the cognitive model according to Clark and Wells (1995; adapted to German by Stangier, Clark, & Ehlers, 2006) and comprises eight sessions. ANOVAs based on an intention-to-treat model were used for data analyses. The self-help program was well accepted; just one person withdrew during the intervention. There were significant Time* Group interactions on all primary outcome measures. For the intervention group moderate to high within-groups effect sizes up to Cohen's d = 1.05 were obtained. Between-groups effect sizes ranged from 0.24 to 0.65 in favor of the active intervention. The newly developed DVD-based self-help program seems to be a promising intervention for highly socially anxious individuals as it reduces social anxiety symptoms. PMID- 21658527 TI - The alliance in a friendship coaching intervention for parents of children with ADHD. AB - The alliance between parent and therapist was observed in a group-based parent training intervention to improve social competency among children with attention deficit/hyperactivity disorder (ADHD). The intervention, called Parental Friendship Coaching (PFC), was delivered to 32 parents in small groups as part of a randomized clinical trial. PFC was delivered in eight, 90-minute sessions to parents; there was no child treatment component. Observed parent-therapist alliance recorded among 27 of the parents was measured using the Therapy Process Observational Coding System--Alliance scale (TPOCS-A; McLeod, 2005). Early alliance and change in alliance over time predicted improvements in several parenting behaviors and child outcomes, including peer sociometrics in a lab based playgroup. These preliminary findings lend support to the importance of examining the parent-therapist alliance in parent-training groups for youth social and behavioral problems. PMID- 21658529 TI - Assessing women's responses to sexual threat: validity of a virtual role-play procedure. AB - This study evaluated the validity of a role-play procedure that uses virtual reality technology to assess women's responses to sexual threat. Forty-eight female undergraduate students were randomly assigned to either a standard, face to-face role-play (RP) or a virtual role-play (VRP) of a sexually coercive situation. A multimethod assessment strategy was used to evaluate the efficacy of the role-play procedure in creating a realistic and immersive situation. Consistent with our hypotheses, women in the VRP condition exhibited greater negative affect and immersion than women in the RP condition. In addition, the level of assertive refusal in the VRP, but not the RP, condition differentiated between women with and without a prior history of sexual victimization. These findings provide evidence of the validity of a virtual role-play procedure for assessing women's responses in sexually threatening situations. PMID- 21658528 TI - Effectiveness of the Challenging Horizons After-School Program for young adolescents with ADHD. AB - There are no empirically supported psychosocial treatments for adolescents with attention-deficit hyperactivity disorder (ADHD). This study examined the treatment benefits of the Challenging Horizons Program (CHP), a psychosocial treatment program designed to address the impairment and symptoms associated with this disorder in young adolescents. In addition to evaluating social and academic functioning outcomes, two critical questions from previous studies pertaining to the timing, duration, and family involvement in treatment were addressed. Forty nine students recruited in two cohorts were randomly assigned to receive either the CHP or a community care condition. Outcomes suggested that students who received the CHP improved compared to students in the control condition on measures of symptoms and impairment. Implications related to timing, duration, and family involvement are reported, as well as recommendations for future studies. PMID- 21658530 TI - Perceived impact of socially anxious behaviors on individuals' lives in Western and East Asian countries. AB - The current study compared the predicted social and career impact of socially withdrawn and reticent behaviors among participants from Western and East Asian countries. Three hundred sixty-one college students from 5 Western countries and 455 students from 3 East Asian countries read hypothetical vignettes describing socially withdrawn and shy behaviors versus socially outgoing and confident behaviors. Participants then answered questions following each vignette indicating the extent to which they would expect the subject of the vignette to be socially liked and to succeed in their career. Participants also completed measures of their own social anxiety and quality of life. The results indicated significant vignette-by-country interactions in that the difference in perceived social and career impact between shy and outgoing vignettes was smaller among participants from East Asian countries than from Western countries. In addition, significant negative correlations were shown between personal level of shyness and experienced quality of life for participants from both groups of countries, but the size of this relationship was greater for participants from Western than East Asian countries. The results point to the more negative impact of withdrawn and socially reticent behaviors for people from Western countries relative to those from East Asia. PMID- 21658532 TI - Sudden gains in treatment-as-usual couple therapy for military veterans. AB - Previous studies of couple therapy have conceptualized change as a gradual process. However, there is growing evidence that, for many clients, the majority of gains in other treatment modalities are often achieved between just 2 sessions. Isolating the frequency, nature, and predictors of these sudden gains (SGs) in couple therapy can add to a growing understanding of how and why couple therapy works. In a sample of 67 couples receiving treatment-as-usual couple therapy in two Veterans Affairs hospitals, 25% of individuals experienced a SG in relationship satisfaction. The magnitude of these SGs were large (d=1.62) and fully explained the total pre-post change for individuals who experienced them. Individuals with SGs showed significantly greater satisfaction gains during therapy; however SGs were not related to relationship satisfaction or relationship status at 18-month follow-up. SGs were predicted by the content of the previous session, putative change mechanisms of communication, intimacy, and behavior, as well as the partner's SGs during the same period. Results suggest that SGs are an important component of change during couple therapy for some individuals, challenging the assumption of continuous change in previous studies. In addition, predictors of SGs were generally consistent with theoretical and empirical examinations of mechanisms of change in couple therapy. PMID- 21658533 TI - Motor inhibition, reflection impulsivity, and trait impulsivity in pathological skin picking. AB - Pathological skin picking (PSP) is often recognized as an impulse control disorder. The current study sought to investigate the relationship between PSP and different forms of impulsivity. University students that met criteria for PSP (n = 55) and university students without history of PSP (n = 55) answered a multidimensional impulsivity questionnaire (the UPPS Impulsive Behavior Scale) and completed 2 neurocognitive tasks that assess impulsivity (the Stop Signal Task and the Information Sampling Task). The PSP group scored significantly higher than the control group on the negative and positive urgency subscales of the UPPS, but the groups did not differ on other subscales or the neurocognitive tasks. Logistic regression demonstrated that the urgency scales added to the prediction of PSP after negative affect and other forms of impulsivity were adjusted for. The results indicate that PSP sufferers are characterized by emotion-based impulsivity and do not appear to be impulsive in other ways. PMID- 21658534 TI - Choosing among techniques for quantifying single-case intervention effectiveness. AB - If single-case experimental designs are to be used to establish guidelines for evidence-based interventions in clinical and educational settings, numerical values that reflect treatment effect sizes are required. The present study compares four recently developed procedures for quantifying the magnitude of intervention effect using data with known characteristics. Monte Carlo methods were used to generate AB designs data with potential confounding variables (serial dependence, linear and curvilinear trend, and heteroscedasticity between phases) and two types of treatment effect (level and slope change). The results suggest that data features are important for choosing the appropriate procedure and, thus, inspecting the graphed data visually is a necessary initial stage. In the presence of serial dependence or a change in data variability, the nonoverlap of all pairs (NAP) and the slope and level change (SLC) were the only techniques of the four examined that performed adequately. Introducing a data correction step in NAP renders it unaffected by linear trend, as is also the case for the percentage of nonoverlapping corrected data and SLC. The performance of these techniques indicates that professionals' judgments concerning treatment effectiveness can be readily complemented by both visual and statistical analyses. A flowchart to guide selection of techniques according to the data characteristics identified by visual inspection is provided. PMID- 21658531 TI - Exploring the association between emotional abuse and childhood borderline personality features: the moderating role of personality traits. AB - Most of the extant literature on borderline personality disorder has focused on the course, consequences, and correlates of this disorder among adults. However, little is known about childhood borderline personality (BP) features, or the factors associated with the emergence of BP pathology in childhood. A greater understanding of childhood BP features and associated risk factors has important implications for the development of primary and secondary prevention programs. The goal of the present study was to examine the interrelationships among two BP relevant traits (affective dysfunction and impulsivity), a BP-relevant environmental stressor (emotional abuse), and BP features in a sample of 225 children aged 11 to 14 years. Results provide support for the role of both trait vulnerabilities and environmental stressors in childhood BP features. Further, findings highlight the moderating role of affective dysfunction in the relationship between emotional abuse and childhood BP features. PMID- 21658535 TI - State-of-the art (Arnold) behavioral neuroendocrinology. PMID- 21658536 TI - Public Health Sans Frontieres. PMID- 21658537 TI - Public health challenges of the emerging HIV epidemic among men who have sex with men in China. AB - A large-scale national survey was conducted in 2008 across 61 cities throughout China, covering over 18,000 men who have sex with men (MSM). The prevalence of human immunodeficiency virus (HIV) was 4.9% and incidence ranged from 2.6 to 5.4 per 100 person-years. The prevalence of sexually transmitted diseases ranged from 2.0% to 29.9% among MSM in different parts of China. Syphilis status, recruitment of sexual partners mainly from gay saunas, duration of MSM experience, and unprotected sex with regular male sex partners and multiple male sex partners predicted HIV seroconversion. The prevalence of consistent condom use was low during anal sex, ranging from 29.4% to 37.3%. Within this context, this paper considers the factors surrounding HIV prevention activity, and identifies a number of public health challenges which need to be considered if optimum outcomes are to be achieved. HIV prevention targeting MSM is a delayed response. The high risk associated with gay saunas and the need for steady condom supply at these venues needs urgent consideration. In addition, approximately one-third of MSM in China reported bisexual behavior, which may be attributed to sociocultural reasons and stigma against MSM. Female sex partners of MSM are seldom aware of their exposure to high risk of HIV transmission. Finally, the primitive nature of non-government organizations for HIV prevention and issues around their sustainability pose another serious challenge for the future of HIV prevention campaigns targeting MSM in China. PMID- 21658538 TI - Total cost comparison of standard antenatal care with a weight gain restriction programme for obese pregnant women. AB - OBJECTIVE: To perform a cost comparison of a weight gain restriction programme for obese pregnant women with standard antenatal care, and to identify if there were differences in healthcare costs within the intervention group related to degree of gestational weight gain or degree of obesity at programme entry. STUDY DESIGN: A comparison of mean healthcare costs for participants of an intervention study at antenatal care clinics with controls in south-east Sweden. METHODS: In total, 155 women in an intervention group attempted to restrict their gestational weight gain to <7 kg. The control group comprised 193 women. Mean costs during pregnancy, delivery and the neonatal period were compared with the costs of standard care. Costs were converted from Swedish Kronor to Euros (?). RESULTS: Healthcare costs during pregnancy were lower in the intervention group. There was no significant difference in total healthcare costs (i.e. sum of costs during pregnancy, delivery and the neonatal period) between the intervention group and the control group. Within the intervention group, the subgroup that gained 4.5 9.5 kg had the lowest costs. The total cost, including intervention costs, was ? 1283 more per woman/infant in the intervention group compared with the control group (P=0.025). The degree of obesity at programme entry had no bearing on the outcome. CONCLUSIONS: The weight gain restriction programme for obese pregnant women was effective in restricting gestational weight gain to <7 kg, but had a higher total cost compared with standard antenatal care. PMID- 21658540 TI - Magnetic resonance imaging images in adult congenital heart disease. AB - The use of cardiac magnetic resonance imaging has become an indispensable tool for the evaluation of patients with congenital heart disease. With the emergence of several generations of congenital heart disease survivors, there are now as many adults with these conditions as children, and complications are the rule rather than the exception. It is increasingly important, therefore, that the general cardiology community becomes aware of these defects and potential pitfalls to avoid. Among its many uses, cardiac magnetic resonance can provide an assessment of right ventricular function, flow, pulmonary artery anatomy, and aortic visualization that are often important considerations in these patients. This review provides an introductory visual glimpse into the varied conditions encountered and clinical questions addressed in the field of adult congenital heart disease. PMID- 21658541 TI - Beyond myth: designing better sexual violence prevention. PMID- 21658543 TI - Updates and advances in sports medicine. Preface. PMID- 21658544 TI - The preparticipation physical examination: an update. AB - The evolution of the preparticipation physical examination (PPE) in the United States continues to advance. In May 2010, the fourth edition of the Preparticipation Physical Examination Evaluation (PPE-4) monograph was published. The monograph is a product reflecting the collaborative efforts of 6 author societies. This article provides a brief historical review of the PPE and then highlights the recent changes and updates contained in the PPE-4 monograph, including cardiovascular screening in athletes. New recommendations to include the PPE in all well-child care visits and the need to develop a nationwide standard for the PPE are discussed. PMID- 21658545 TI - Cardiovascular screening and the elite athlete: advances, concepts, controversies, and a view of the future. AB - This article addresses programmatic cardiovascular screening and evaluation of the elite athlete at the intercollegiate, national team, professional, and Olympic levels. Although much of this content may apply to high-school and recreational sports at large, it is not specifically designed to address athletes participating in all sports activities. PMID- 21658546 TI - Pulmonary disorders in athletes. AB - Exercise is rarely limited by pulmonary causes in normal individuals. Cardiac output and peripheral muscle disease are usually the limiting factors. Although minute ventilation rises steeply during exercise, normal individuals maintain a substantial breathing reserve. Exercise in patients, however, can be limited by pulmonary disorders. Acute pulmonary causes (exercise-induced bronchospasm, vocal cord dysfunction, exercise-induced anaphylaxis, and exercise-induced urticaria) or chronic disorders (obstructive and restrictive lung disorders) reduce exercise tolerance. Exercise testing has proved the mainstay for diagnosis and treatment of these disorders. PMID- 21658547 TI - Sickle cell considerations in athletes. AB - This article highlights the exertional-sickling collapse syndrome in athletes with sickle cell trait (SCT). It covers all aspects of this syndrome, including pathophysiology, new research on microcirculatory changes, clinical features, differential diagnosis, prevention, and treatment. Also covered in this article are other clinical concerns for athletes with SCT, including lumbar myonecrosis, splenic infarction, hematuria, hyposthenuria, and venous thromboembolism. The final section offers practical points on athletes with sickling hemoglobinopathies more serious than SCT. PMID- 21658548 TI - Advances in management of the female athlete triad and eating disorders. AB - Although there are numerous benefits to women from athletic participation, a complex combination of endocrine and metabolic factors exaggerates risk for a serious health concern: the female athlete triad. The purpose of this article is to provide updates on new issues related to the triad, specifically the relationship between athletic-associated amenorrhea and endothelial dysfunction-a potential fourth component to the triad that is a concern for future cardiovascular risk, public health issues, and athletic performance. Folic acid should be considered a potential safe and inexpensive therapeutic treatment to restore endothelial-dependent vasodilation. PMID- 21658549 TI - Infectious disease. AB - Athletes are susceptible to the same infections as the general population. However, special considerations often need to be taken into account when dealing with an athlete who has contracted an infectious disease. Health care providers need to consider how even common illnesses can affect an athlete's performance, the communicability of the illness to team members, and precautions/contraindications related to athletic participation. Recent advances in the prevention, diagnosis, and/or management of frequently encountered illnesses, as well as certain conditions that warrant special attention in the athletic setting, are discussed in detail. PMID- 21658550 TI - Attention-deficit hyperactivity disorder and the athlete: new advances and understanding. AB - Attention-deficit/hyperactivity disorder (ADHD) is a brain-based behavioral disorder with heterogeneous expression affecting quality of life. Some affected individuals may not experience obvious impairment until after arrival at college. The incidence of ADHD may be increased among athletes who participate at the elite level. Neurotransmitters involved in ADHD also are involved in central fatigue, and fatigue research using medications used to treat ADHD suggests that endurance performance and thermoregulation are affected in ways that may put athletes taking these medications at risk. More information is needed on the effect on exercise of long-term administration of ADHD medication. PMID- 21658551 TI - Psychiatric and neuropsychological issues in sports medicine. AB - This article reviews psychiatric/psychological issues in the athletic training room, including recognition of these issues and a framework for management. Because the majority of research has been conducted in college settings, most of the issues discussed are presented in the context of college sports, although the results generalize to other athletic arenas. Greater awareness of psychological issues, empirical research, and education about mental health issues in the sports medicine community are clearly needed. PMID- 21658552 TI - The athlete's pharmacy. AB - Athletes use a variety of substances for the treatment of pain, injury, common illnesses, or to gain an advantage in competition. A growing concern is that many young athletes may use potentially dangerous, but legal, medications without consulting health professionals. Physicians providing care for athletes should be aware of any medications that an athlete is taking and how these substances may interact with performance, exercise, environment, and other medicines. Moreover, it is vital that physicians are familiar with these medications so that athletes are properly educated on the potential benefits and/or risks, and how each substance may affect the body. PMID- 21658553 TI - The international athlete--advances in management of jet lag disorder and anti doping policy. AB - To perform at the highest level of international competition, athletes need to maximize rest during long travel, and expeditiously overcome the detrimental effects of "jet lag" (JL). The negative effects of JL may be alleviated by adopting a multimodality approach, including the judicious use of melatonin and other pharmacologic agents to aid re-entrainment and improve sleep characteristics. Strict compliance with anti-doping policy is pivotal before and during competition. There have been several recent updates regarding the use of selected medications, which mandate constant vigilance by sports medicine personnel to both evaluate drug efficacy and judiciously prescribe approved medications. It is critical that medical staff maintain familiarity and awareness on a continual basis to effectively educate athletes and support staff. PMID- 21658554 TI - Eating for performance: bringing science to the training table. AB - Despite many advances in nutritional knowledge and dietary practices, sports nutrition-associated issues, such as fatigue, loss of strength and stamina, loss of speed, and problems with weight management and inadequate energy intake, are common. Sound nutritional practices and well-designed patterns of eating are not awarded the same priority as training and many athletes fail to recognize that poor eating habits or suboptimal hydration choices may detract from athletic performance. Those who care for athletes and active individuals must take an active role in their nutritional well-being. This article reviews the present generally accepted principles for nutritional management in sport. PMID- 21658555 TI - [The future of vector-borne infections in France]. PMID- 21658556 TI - Syphilitic aortic regurgitation and ostial coronary occlusion. PMID- 21658557 TI - Teamwork and leadership in cardiopulmonary resuscitation. AB - Despite substantial efforts to make cardiopulmonary resuscitation (CPR) algorithms known to healthcare workers, the outcome of CPR has remained poor during the past decades. Resuscitation teams often deviate from algorithms of CPR. Emerging evidence suggests that in addition to technical skills of individual rescuers, human factors such as teamwork and leadership affect adherence to algorithms and hence the outcome of CPR. This review describes the state of the science linking team interactions to the performance of CPR. Because logistical barriers make controlled measurement of team interaction in the earliest moments of real-life resuscitations challenging, our review focuses mainly on high-fidelity human simulator studies. This technique allows in-depth investigation of complex human interactions using precise and reproducible methods. It also removes variability in the clinical parameters of resuscitation, thus letting researchers study human factors and team interactions without confounding by clinical variability from resuscitation to resuscitation. Research has shown that a prolonged process of team building and poor leadership behavior are associated with significant shortcomings in CPR. Teamwork and leadership training have been shown to improve subsequent team performance during resuscitation and have recently been included in guidelines for advanced life support courses. We propose that further studies on the effects of team interactions on performance of complex medical emergency interventions such as resuscitation are needed. Future efforts to better understand the influence of team factors (e.g., team member status, team hierarchy, handling of human errors), individual factors (e.g., sex differences, perceived stress), and external factors (e.g., equipment, algorithms, institutional characteristics) on team performance in resuscitation situations are critical to improve CPR performance and medical outcomes of patients. PMID- 21658558 TI - Prognostic value of the SYNTAX score in patients with acute coronary syndromes undergoing percutaneous coronary intervention: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial. AB - OBJECTIVES: We sought to investigate the predictive value of the SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score (SS) for risk assessment of 1 year clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention (PCI). BACKGROUND: In the SYNTAX trial, the SS was effective in risk-stratifying patients with left main and triple-vessel coronary disease, the majority of whom had stable ischemic heart disease. METHODS: The SS was determined in 2,627 patients with non-ST segment elevation acute coronary syndromes undergoing PCI in the angiographic substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial. Patients were stratified according to tertiles of the SS: <7 (n = 854), >= 7 and <13 (n = 825), and >= 13 (n = 948). RESULTS: Among patients in the first, second, and third SS tertiles, the 1-year rates of mortality were 1.5%, 1.6%, and 4.0%, respectively (p = 0.0005); the cardiac mortality rates were 0.2%, 0.9%, and 2.7%, respectively (p < 0.0001); the myocardial infarction (MI) rates were 6.3%, 8.3%, and 12.9%, respectively (p < 0.0001); and the target vessel revascularization (TVR) rates were 7.4%, 7.0%, and 9.8%, respectively (p = 0.02). By multivariable analysis, the SS was an independent predictor of 1-year death (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.01 to 1.07; p = 0.005), cardiac death (HR: 1.06, 95% CI: 1.03 to 1.09; p = 0.0002), MI (HR: 1.03, 95% CI: 1.02 to 1.05; p < 0.0001), and TVR (HR: 1.03, 95% CI: 1.02 to 1.05; p < 0.0001). The SS affected death, cardiac death, and MI both within the first 30 days after PCI and between 30 days and 1 year, whereas it affected TVR primarily within the first 30 days. The predictive value of an increased SS was consistent among multiple pre-specified subgroups. CONCLUSIONS: In patients with non-ST segment elevation acute coronary syndromes undergoing PCI, the SS is an independent predictor of the 1-year rates of death, cardiac death, MI, and TVR. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes [ACS]; NCT00093158). PMID- 21658559 TI - Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study. AB - OBJECTIVES: The purpose of this study was to assess whether: 1) very small increases in troponin T, measured by a new highly sensitive cardiac troponin T (hs-cTnT), may reflect ischemia without necrosis; and 2) serial changes can discriminate ischemia from other causes of cardiac troponin T (cTnT) release. BACKGROUND: A new hs-cTnT assay offers greater sensitivity than current assays. METHODS: Nineteen patients referred for diagnostic catheterization underwent cannulation of the coronary sinus (CS). Serial CS and peripheral plasma samples were obtained at multiple time points during and after incremental rapid atrial pacing. cTnT was quantified using both a standard and a pre-commercial highly sensitive assay. Ischemia was determined by the presence of significant coronary artery disease (CAD) and myocardial lactate release with pacing. RESULTS: cTnT concentrations in CS blood increased from a median of 6.8 pg/ml prior to pacing to 15.6 pg/ml 60 min after termination of rapid atrial pacing (p < 0.0001), changes that were mirrored at 180 min in peripheral blood (5.1 to 11.8 pg/ml, p < 0.0001). Although peripheral cTnT concentrations tended to be higher at 180 min following pacing for patients with CAD and lactate elution (n = 7) when compared with those without either marker (n = 5) (25.0 pg/ml vs. 10.2 pg/ml, p = 0.10), relative (1.7-fold vs. 5.2-fold) and absolute (6.8 pg/ml vs. 8.8 pg/ml, p = 0.50) changes were not different between groups. CONCLUSIONS: Brief periods of ischemia, without frank infarction, cause low-level cTnT release, and small increases are common after periods of increased myocardial work, even among patients without objective evidence of myocardial ischemia or obstructive CAD. Additional research is needed before hs-cTnT assays are widely adopted in the management of subjects with chest pain syndromes. PMID- 21658560 TI - Pathobiology of troponin elevations: do elevations occur with myocardial ischemia as well as necrosis? PMID- 21658561 TI - Isolated coronary artery bypass graft combined with bone marrow mononuclear cells delivered through a graft vessel for patients with previous myocardial infarction and chronic heart failure: a single-center, randomized, double-blind, placebo controlled clinical trial. AB - OBJECTIVES: This study aimed at examining the efficacy of bone marrow mononuclear cell (BMMNC) delivery through graft vessel for patients with a previous myocardial infarction (MI) and chronic heart failure during coronary artery bypass graft (CABG). BACKGROUND: Little evidence exists supporting the practice of BMMNC delivery through graft vessel for patients with a previous MI and chronic heart failure during CABG. METHODS: From November 2006 to June 2009, a randomized, placebo-controlled trial was conducted to test the efficacy and safety of CABG for multivessel coronary artery disease combined with autologous BMMNCs in patients with congestive heart failure due to severe ischemic cardiomyopathy. Sixty-five patients were recruited, and 60 patients remained in the final trial and were randomized to a CABG + BMMNC group (n = 31) and a placebo-control group (i.e., CABG-only group, n = 29). All patients discharged received a 6-month follow-up. Changes in left ventricular ejection fraction from baseline to 6-month follow-up, as examined by magnetic resonance imaging, were of primary interest. RESULTS: The overall baseline age was 59.5 +/- 9.2 years, and 6.7% were women. After a 6-month follow-up, compared with the placebo-control group, the CABG + BMMNC group had significant changes in left ventricular ejection fraction (p = 0.029), left ventricular end-systolic volume index (p = 0.017), and wall motion index score (p = 0.011). Also, the changes in the distance on the 6-min walking test as well as B-type natriuretic peptide were significantly greater in the CABG + BMMNC group than in the control group. CONCLUSIONS: In summary, patients with a previous MI and chronic heart failure could potentially benefit from isolated CABG (i.e., those who received CABG only) combined with BMMNCs delivered through a graft vessel. (Stem Cell Therapy to Improve Myocardial Function in Patients Undergoing Coronary Artery Bypass Grafting [CABG]; NCT00395811). PMID- 21658563 TI - Cardiac resynchronization therapy: antiarrhythmic or proarrhythmic? PMID- 21658562 TI - Reverse remodeling and the risk of ventricular tachyarrhythmias in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). AB - OBJECTIVES: We aimed to evaluate the relationship between echocardiographic response to cardiac resynchronization therapy (CRT) and the risk of subsequent ventricular tachyarrhythmias (VTAs). BACKGROUND: Current data regarding the effect of CRT on the risk of VTA are limited and conflicting. METHODS: The risk of a first appropriate implantable cardioverter-defibrillator (ICD) therapy for VTA (including ventricular tachycardia, ventricular fibrillation, and ventricular flutter) was compared between high- and low-echocardiographic responders to CRT defibrillator (CRT-D) therapy (defined as >= 25% and <25% reductions, respectively, in left ventricular end-systolic volume [LVESV] at 1 year compared with baseline) and ICD-only patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). RESULTS: The cumulative probability of a first VTA at 2 years after assessment of echocardiographic response was highest among low responders to CRT-D (28%), intermediate among ICD-only patients (21%), and lowest among high responders to CRT-D (12%), with p < 0.001 for the overall difference during follow-up. Multivariate analysis showed that high responders to CRT-D experienced a significant 55% reduction in the risk of VTA compared with ICD-only patients (p < 0.001), whereas the risk of VTA was not significantly different between low responders and ICD-only patients (hazard ratio [HR]: 1.26; p = 0.21). Consistently, assessment of response to CRT-D as a continuous measure showed that incremental 10% reductions in left ventricular end-systolic volume were associated with corresponding reductions in the risk of subsequent VTA (HR: 0.80; p < 0.001), VTA/death (HR: 0.79; p < 0.001), ventricular tachycardia (HR: 0.80; p < 0.001), and ventricular fibrillation/ventricular flutter (HR: 0.75; p = 0.044). CONCLUSIONS: In patients with left ventricular dysfunction enrolled in the MADIT CRT trial, reverse remodeling was associated with a significant reduction in the risk of subsequent life-threatening VTAs. (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271). PMID- 21658564 TI - Meta-analysis and systematic review of the long-term predictive value of assessment of coronary atherosclerosis by contrast-enhanced coronary computed tomography angiography. AB - OBJECTIVES: We conducted a systematic review and meta-analysis to determine the predictive value of findings of coronary computed tomography angiography for incident cardiovascular events. BACKGROUND: Initial studies indicate a prognostic value of the technique; however, the level of evidence as well as exact independent risk estimates remain unclear. METHODS: We searched PubMed, EMBASE, and the Cochrane Library through January 2010 for studies that followed up >= 100 subjects for >= 1 year and reported at >= 1 hazard ratio (HR) of interest. Risk estimates for the presence of significant coronary stenosis (primary endpoint; >= 50% diameter stenosis), left main coronary artery stenosis, each coronary stenosis, 3-vessel disease, any plaque, per coronary segment containing plaque, and noncalcified plaque were derived in random effect regression analysis, and causes of heterogeneity were determined in meta-regression analysis. RESULTS: We identified 11 eligible articles including 7,335 participants (age 59.1 +/- 2.6 years, 62.8% male) with suspected coronary artery disease. The presence of >= 1 significant coronary stenosis (9 studies, 3,670 participants, and 252 outcome events [6.8%] with 62% revascularizations) was associated with an annualized event rate of 11.9% (6.4% in studies excluding revascularization). The corresponding HR was 10.74 (98% confidence interval [CI]: 6.37 to 18.11) and 6.15 (95% CI: 3.22 to 11.74) in studies excluding revascularization. Adjustment for coronary calcification did not attenuate the prognostic significance (p = 0.79). The estimated HRs for left main stenosis, presence of plaque, and each coronary segment containing plaque were 6.64 (95% CI: 2.6 to 17.3), 4.51 (95% CI: 2.2 to 9.3), and 1.23 (95% CI: 1.17 to 1.29), respectively. CONCLUSIONS: Presence and extent of coronary artery disease on coronary computed tomography angiography are strong, independent predictors of cardiovascular events despite heterogeneity in endpoints, categorization of computed tomography findings, and study population. PMID- 21658565 TI - Late status of Fontan patients with persistent surgical fenestration. AB - OBJECTIVES: This study was undertaken to determine the effects of creating a systemic-to-pulmonary venous atrial-level communication (fenestration) at the time of the Fontan procedure on late outcomes. BACKGROUND: Fenestrations are frequently performed during Fontan procedures, but late consequences are not well described. METHODS: Patient characteristics were compared between those with and without surgical fenestration among 536 subjects (mean age 11.9 years) enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study. The status of the fenestration and the association of a currently patent fenestration with health status and measures of ventricular performance were investigated. RESULTS: Fenestration was performed in 361 patients (67%), and frequency differed by year and center (p < 0.001 for each). After adjustment for center, age at Fontan, year of Fontan, and prior superior cavopulmonary surgery, the fenestrated group had shorter length of Fontan hospital stay. At the time of cross-sectional testing 8 +/- 3 years after Fontan, the fenestration remained open in 19% of subjects. Among those with confirmed fenestration closure, 59% were by catheter intervention and 1% by surgical intervention, and 40% had apparent spontaneous closure. Compared with those without evidence of a fenestration, subjects with a current fenestration were taking more medications (p = 0.02) and had lower resting oxygen saturation (median 89% vs. 95%, p < 0.001). Functional health status, exercise performance, echocardiographic variables, prevalence of post Fontan stroke or thrombosis, and growth did not differ by current fenestration status. CONCLUSIONS: Surgical fenestration is associated with well-demonstrated early post-operative benefits. This cross-sectional study found few associations between a persistent fenestration and deleterious later outcomes. PMID- 21658566 TI - Sonic hedgehog-induced functional recovery after myocardial infarction is enhanced by AMD3100-mediated progenitor-cell mobilization. AB - OBJECTIVES: This study was designed to compare the effectiveness of Sonic hedgehog (Shh) gene transfer, AMD3100-induced progenitor-cell mobilization, and Shh-AMD3100 combination therapy for treatment of surgically induced myocardial infarction (MI) in mice. BACKGROUND: Shh gene transfer improves myocardial recovery by up-regulating angiogenic genes and enhancing the incorporation of bone marrow-derived progenitor cells (BMPCs) in infarcted myocardium. Here, we investigated whether the effectiveness of Shh gene therapy could be improved with AMD3100-induced progenitor-cell mobilization. METHODS: Gene expression and cell function were evaluated in cells cultured with medium collected from fibroblasts transfected with plasmids encoding human Shh (phShh). MI was induced in wild-type mice, in matrix metalloproteinase (MMP)-9 knockout mice, and in mice transplanted with bone marrow that expressed green-fluorescent protein. Mice were treated with 100 MUg of phShh (administered intramyocardially), 5 mg/kg of AMD3100 (administered subcutaneously), or both; cardiac function was evaluated echocardiographically, and fibrosis, capillary density, and BMPC incorporation were evaluated immunohistochemically. RESULTS: phShh increased vascular endothelial growth factor and stromal cell-derived factor 1 expression in fibroblasts; the medium from phShh-transfected fibroblasts increased endothelial cell migration and the migration, proliferation, and tube formation of BMPCs. Combination therapy enhanced cardiac functional recovery (i.e., left ventricular ejection fraction) in wild-type mice, but not in MMP-9 knockout mice, and was associated with less fibrosis, greater capillary density and smooth muscle containing vessel density, and enhanced BMPC incorporation. CONCLUSIONS: Combination therapy consisting of intramyocardial Shh gene transfer and AMD3100 induced progenitor-cell mobilization improves cardiac functional recovery after MI and is superior to either individual treatment for promoting therapeutic neovascularization. PMID- 21658567 TI - Myocarditis, pericarditis, and cardiac tamponade associated with Rocky Mountain spotted fever. PMID- 21658568 TI - Calcium score reclassification: how should baseline risk be measured? PMID- 21658570 TI - Nonrandomized data on drug-eluting stents compared with coronary bypass surgery caution with interpretation. PMID- 21658572 TI - Clinical, molecular, and genomic changes after left ventricular assist device implantation. PMID- 21658574 TI - Multiple personalities in the ventral tegmental area. AB - A small number of ventral tegmental area dopamine neurons engage in numerous and apparently contradictory functions--how can this be? A clue is provided by Lammel and colleagues in this issue of Neuron: some VTA dopamine neurons display synaptic plasticity in response to cocaine, and others in response to pain, and these populations are distinguished by their axonal projections and Ih. PMID- 21658575 TI - Solving the autism puzzle a few pieces at a time. AB - In this issue, a pair of studies (Levy et al. and Sanders et al.) identify several de novo copy-number variants that together account for 5%-8% of cases of simplex autism spectrum disorders. These studies suggest that several hundreds of loci are likely to contribute to the complex genetic heterogeneity of this group of disorders. An accompanying study in this issue (Gilman et al.), presents network analysis implicating these CNVs in neural processes related to synapse development, axon targeting, and neuron motility. PMID- 21658576 TI - VEGF shows its attractive side at the midline. AB - Vascular endothelial growth factor (VEGF) family members are best known for their powerful mitotic and angiogenic activities toward endothelial cells. Two independent studies in this issue of Neuron now provide compelling evidence that VEGF-A secreted at the CNS midline functions as an attractant for developing axons of spinal commissural neurons and contralaterally projecting retinal ganglion cells. PMID- 21658577 TI - Epigenetic mechanisms in cognition. AB - Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in postmitotic neurons as a means of consolidating and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an "epigenetic code" in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and we review the therapeutic potential of epigenetic treatments for the amelioration of these conditions. PMID- 21658579 TI - Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. AB - Despite being the most abundant synaptic vesicle membrane protein, the function of synaptophysin remains enigmatic. For example, synaptic transmission was reported to be completely normal in synaptophysin knockout mice; however, direct experiments to monitor the synaptic vesicle cycle have not been carried out. Here, using optical imaging and electrophysiological experiments, we demonstrate that synaptophysin is required for kinetically efficient endocytosis of synaptic vesicles in cultured hippocampal neurons. Truncation analysis revealed that distinct structural elements of synaptophysin differentially regulate vesicle retrieval during and after stimulation. Thus, synaptophysin regulates at least two phases of endocytosis to ensure vesicle availability during and after sustained neuronal activity. PMID- 21658578 TI - Seeking a spotless mind: extinction, deconsolidation, and erasure of fear memory. AB - Learning to contend with threats in the environment is essential to survival, but dysregulation of memories for traumatic events can lead to disabling psychopathology. Recent years have witnessed an impressive growth in our understanding of the neural systems and synaptic mechanisms underlying emotional memory formation. As a consequence, interest has emerged in developing strategies for suppressing, if not eliminating, fear memories. Here, I review recent work employing sophisticated behavioral, pharmacological, and molecular tools to target fear memories, placing these memories firmly behind the crosshairs of neurobiologically informed interventions. PMID- 21658580 TI - Projection-specific modulation of dopamine neuron synapses by aversive and rewarding stimuli. AB - Midbrain dopamine (DA) neurons are not homogeneous but differ in their molecular properties and responses to external stimuli. We examined whether the modulation of excitatory synapses on DA neurons by rewarding or aversive stimuli depends on the brain area to which these DA neurons project. We identified DA neuron subpopulations in slices after injection of "Retrobeads" into single target areas of adult mice and found differences in basal synaptic properties. Administration of cocaine selectively modified excitatory synapses on DA cells projecting to nucleus accumbens (NAc) medial shell while an aversive stimulus selectively modified synapses on DA cells projecting to medial prefrontal cortex. In contrast, synapses on DA neurons projecting to NAc lateral shell were modified by both rewarding and aversive stimuli, which presumably reflects saliency. These results suggest that the mesocorticolimbic DA system may be comprised of three anatomically distinct circuits, each modified by distinct aspects of motivationally relevant stimuli. PMID- 21658581 TI - Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. AB - We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 * 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1. PMID- 21658582 TI - Rare de novo and transmitted copy-number variation in autistic spectrum disorders. AB - To explore the genetic contribution to autistic spectrum disorders (ASDs), we have studied genomic copy-number variation in a large cohort of families with a single affected child and at least one unaffected sibling. We confirm a major contribution from de novo deletions and duplications but also find evidence of a role for inherited "ultrarare" duplications. Our results show that, relative to males, females have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers. By analysis of the proportion and number of recurrent loci, we set a lower bound for distinct target loci at several hundred. We find many new candidate regions, adding substantially to the list of potential gene targets, and confirm several loci previously observed. The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes but also suggest functional convergence. PMID- 21658583 TI - Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. AB - Identification of complex molecular networks underlying common human phenotypes is a major challenge of modern genetics. In this study, we develop a method for network-based analysis of genetic associations (NETBAG). We use NETBAG to identify a large biological network of genes affected by rare de novo CNVs in autism. The genes forming the network are primarily related to synapse development, axon targeting, and neuron motility. The identified network is strongly related to genes previously implicated in autism and intellectual disability phenotypes. Our results are also consistent with the hypothesis that significantly stronger functional perturbations are required to trigger the autistic phenotype in females compared to males. Overall, the presented analysis of de novo variants supports the hypothesis that perturbed synaptogenesis is at the heart of autism. More generally, our study provides proof of the principle that networks underlying complex human phenotypes can be identified by a network based functional analysis of rare genetic variants. PMID- 21658584 TI - Experience dictates stem cell fate in the adult hippocampus. AB - Adult hippocampal neurogenesis has been implicated in cognitive and emotional processes, as well as in response to antidepressant treatment. However, little is known about how the adult stem cell lineage contributes to hippocampal structure and function and how this process is modulated by the animal's experience. Here we perform an indelible lineage analysis and report that neural stem cells can produce expanding and persisting populations of not only neurons, but also stem cells in the adult hippocampus. Furthermore, the ratio of stem cells to neurons depends on experiences of the animal or the location of the stem cell. Surprisingly, social isolation facilitated accumulation of stem cells, but not neurons. These results show that neural stem cells accumulate in the adult hippocampus and that the stem cell-lineage relationship is under control of anatomic and experiential niches. Our findings suggest that, in the hippocampus, fate specification may act as a form of cellular plasticity for adapting to environmental changes. PMID- 21658585 TI - RNA-binding protein FXR2 regulates adult hippocampal neurogenesis by reducing Noggin expression. AB - In adult mammalian brains, neurogenesis persists in the subventricular zone of the lateral ventricles (SVZ) and the dentate gyrus (DG) of the hippocampus. Although evidence suggest that adult neurogenesis in these two regions is subjected to differential regulation, the underlying mechanism is unclear. Here, we show that the RNA-binding protein FXR2 specifically regulates DG neurogenesis by reducing the stability of Noggin mRNA. FXR2 deficiency leads to increased Noggin expression and subsequently reduced BMP signaling, which results in increased proliferation and altered fate specification of neural stem/progenitor cells in DG. In contrast, Noggin is not regulated by FXR2 in the SVZ, because Noggin expression is restricted to the ependymal cells of the lateral ventricles, where FXR2 is not expressed. Differential regulation of SVZ and DG stem cells by FXR2 may be a key component of the mechanism that governs the different neurogenic processes in these two adult germinal zones. PMID- 21658586 TI - Lhx6 and Lhx8 coordinately induce neuronal expression of Shh that controls the generation of interneuron progenitors. AB - Lhx6 and Lhx8 transcription factor coexpression in early-born MGE neurons is required to induce neuronal Shh expression. We provide evidence that these transcription factors regulate expression of a Shh enhancer in MGE neurons. Lhx6 and Lhx8 are also required to prevent Nkx2-1 expression in a subset of pallial interneurons. Shh function in early-born MGE neurons was determined by genetically eliminating Shh expression in the MGE mantle zone (MZ). This mutant had reduced SHH signaling in the overlying progenitor zone, which led to reduced Lhx6, Lhx8, and Nkx2-1 expression in the rostrodorsal MGE and a preferential reduction of late-born somatostatin(+) and parvalbumin(+) cortical interneurons. Thus, Lhx6 and Lhx8 regulate MGE development through autonomous and nonautonomous mechanisms, the latter by promoting Shh expression in MGE neurons, which in turn feeds forward to promote the developmental program of the rostrodorsal MGE. PMID- 21658587 TI - VEGF signaling through neuropilin 1 guides commissural axon crossing at the optic chiasm. AB - During development, the axons of retinal ganglion cell (RGC) neurons must decide whether to cross or avoid the midline at the optic chiasm to project to targets on both sides of the brain. By combining genetic analyses with in vitro assays, we show that neuropilin 1 (NRP1) promotes contralateral RGC projection in mammals. Unexpectedly, the NRP1 ligand involved is not an axon guidance cue of the class 3 semaphorin family, but VEGF164, the neuropilin-binding isoform of the classical vascular growth factor VEGF-A. VEGF164 is expressed at the chiasm midline and is required for normal contralateral growth in vivo. In outgrowth and growth cone turning assays, VEGF164 acts directly on NRP1-expressing contralateral RGCs to provide growth-promoting and chemoattractive signals. These findings have identified a permissive midline signal for axons at the chiasm midline and provide in vivo evidence that VEGF-A is an essential axon guidance cue. PMID- 21658589 TI - arouser reveals a role for synapse number in the regulation of ethanol sensitivity. AB - A reduced sensitivity to the sedating effects of alcohol is a characteristic associated with alcohol use disorders (AUDs). A genetic screen for ethanol sedation mutants in Drosophila identified arouser (aru), which functions in developing neurons to reduce ethanol sensitivity. Genetic evidence suggests that aru regulates ethanol sensitivity through its activation by Egfr/Erk signaling and its inhibition by PI3K/Akt signaling. The aru mutant also has an increased number of synaptic terminals in the larva and adult fly. Both the increased ethanol sensitivity and synapse number of the aru mutant are restored upon adult social isolation, suggesting a causal relationship between synapse number and ethanol sensitivity. We thus show that a developmental abnormality affecting synapse number and ethanol sensitivity is not permanent and can be reversed by manipulating the environment of the adult fly. PMID- 21658588 TI - VEGF mediates commissural axon chemoattraction through its receptor Flk1. AB - Growing axons are guided to their targets by attractive and repulsive cues. In the developing spinal cord, Netrin-1 and Shh guide commissural axons toward the midline. However, the combined inhibition of their activity in commissural axon turning assays does not completely abrogate turning toward floor plate tissue, suggesting that additional guidance cues are present. Here we show that the prototypic angiogenic factor VEGF is secreted by the floor plate and is a chemoattractant for commissural axons in vitro and in vivo. Inactivation of Vegf in the floor plate or of its receptor Flk1 in commissural neurons causes axon guidance defects, whereas Flk1 blockade inhibits turning of axons to VEGF in vitro. Similar to Shh and Netrin-1, VEGF-mediated commissural axon guidance requires the activity of Src family kinases. Our results identify VEGF and Flk1 as a novel ligand/receptor pair controlling commissural axon guidance. PMID- 21658590 TI - Desynchronization of multivesicular release enhances Purkinje cell output. AB - The release of neurotransmitter-filled vesicles after action potentials occurs with discrete time courses: submillisecond phasic release that can be desynchronized by activity followed by "delayed release" that persists for tens of milliseconds. Delayed release has a well-established role in synaptic integration, but it is not clear whether desynchronization of phasic release has physiological consequences. At the climbing fiber to Purkinje cell synapse, the synchronous fusion of multiple vesicles is critical for generating complex spikes. Here we show that stimulation at physiological frequencies drives the temporal dispersion of vesicles undergoing multivesicular release, resulting in a slowing of the EPSC on the millisecond timescale. Remarkably, these changes in EPSC kinetics robustly alter the Purkinje cell complex spike in a manner that promotes axonal propagation of individual spikelets. Thus, desynchronization of multivesicular release enhances the precise and efficient information transfer by complex spikes. PMID- 21658592 TI - Interleukin-8 production from human somatotroph adenoma cells is stimulated by interleukin-1beta and inhibited by growth hormone releasing hormone and somatostatin. AB - OBJECTIVE: Pituitary adenomas cause morbidity and mortality due to their localization and influence on pituitary hormone secretion. Although the pathogenesis of pituitary adenomas is unclear, studies have indicated that cytokines are involved. We investigated the role of cytokines, in particular interleukin (IL)-8, in the pathogenesis of growth hormone (GH) producing tumours. DESIGN: Human somatotroph adenoma tissue was obtained from patients undergoing surgery for acromegaly. The tissue underwent mechanical and enzymatic digestion, was washed, suspended and cultured in 24-chamber plates. After stimulation/inhibition supernatants were harvested. As control of growth hormone producing properties of the cultured cells, GH releasing hormone (GHRH) stimulated and somatostatin inhibited the GH response. RESULTS: The cultured adenoma cells released both IL-6 and IL-8 and the secretion was inhibited by GHRH and somatostatin. IL-1beta dose-dependently stimulated GH, IL-6 and IL-8 secretion. CONCLUSION: Using cultured primary somatotroph adenoma cells as a dynamic method, we found a consistent release not only of IL-6 as described previously, but also of IL-8. This finding could be important for reassessing a role of these cytokines in the pathogenesis of pituitary tumour growth and function, and thus form a basis for targeted therapy. In line with previous studies, our results further indicated a common physiological or pathophysiological reaction of endocrine cells to cytokine stimulation. PMID- 21658593 TI - Aging phenotype and its relationship with IGF-I gene promoter polymorphisms in elderly people living in Catalonia. AB - OBJECTIVES: Genetic variations in the Insulin/IGF-I genes pathway have been related to longevity, dementia, metabolic diseases and cancer. The purpose of the present study was to investigate the 192 bp allele of IGF-I gene promoter and its relationship with metabolic syndrome (MS) components, mental and nutritional state, muscle strength and functional capacity in an aged Spanish population. DESIGN: Population-based study (Mataro Ageing Study), including 292 subjects (144 men and 148 women, mean age 77.0+/-5.4). Anthropometric variables, lipid profile, glucose and blood pressure (BP) were measured; mental state (MMSE), nutritional state (MNA) and Barthel scale were performed, and were correlated to the presence of the 192 bp allele of IGF-1 gene promoter polymorphisms. RESULTS: MS (ATP-III criteria) was found in 49.5% (41.4% in men and 57.6% in women). The 192 bp allele of IGF-I gene promoter was distributed as: 41.9% homozygous, 44.3% heterozygous and 13.9% were non-carriers of this allele. A lower prevalence of metabolic syndrome was observed in homozygous (41.9% vs 54.9% in heterozygous+non-carriers, p=0.031). Mental state (MMSE), nutritional state (MNA) and Barthel scale were better in homozygous individuals compared to heterozygous and non-carriers (p=0.015, p=0.026 and 0.047, respectively). In men, MNA was better in homozygous with no differences in MMSE and Barthel scales. In homozygous women, BP was lower (p=0.009) and Barthel scale was better (p=0.05) with no differences in MMSE and MNA. CONCLUSION: Homozygosity for the 192 bp allele of the IGF-I gene polymorphism suggests a healthier aging condition, with less prevalence of cardiometabolic disturbances, and better mental, nutritional and functional state. PMID- 21658591 TI - Calcium-dependent isoforms of protein kinase C mediate posttetanic potentiation at the calyx of Held. AB - High-frequency stimulation leads to a transient increase in the amplitude of evoked synaptic transmission that is known as posttetanic potentiation (PTP). Here we examine the roles of the calcium-dependent protein kinase C isoforms PKCalpha and PKCbeta in PTP at the calyx of Held synapse. In PKCalpha/beta double knockouts, 80% of PTP is eliminated, whereas basal synaptic properties are unaffected. PKCalpha and PKCbeta produce PTP by increasing the size of the readily releasable pool of vesicles evoked by high-frequency stimulation and by increasing the fraction of this pool released by the first stimulus. PKCalpha and PKCbeta do not facilitate presynaptic calcium currents. The small PTP remaining in double knockouts is mediated partly by an increase in miniature excitatory postsynaptic current amplitude and partly by a mechanism involving myosin light chain kinase. These experiments establish that PKCalpha and PKCbeta are crucial for PTP and suggest that long-lasting presynaptic calcium increases produced by tetanic stimulation may activate these isoforms to produce PTP. PMID- 21658595 TI - Identifying the trigger of c-IAPs: structural and functional characterization of CARD-mediated modulation of ubiquitin ligase activity. AB - In this issue of Molecular Cell, Lopez et al. (2011) examine the caspase recruitment domain (CARD) of c-IAP1 to reveal an intriguing mechanism in which conformational changes of the CARD determine c-IAP1's ubiquitin ligase activity, with implications for regulation of cell proliferation and survival by the IAPs. PMID- 21658594 TI - Pituitary choriocarcinoma in an adolescent male: tumor-derived CG and GH delay diagnosis. AB - BACKGROUND: Primary intracranial germ cell tumors usually present in the first two decades of life, often with precocious puberty. The most common location is in the pineal gland; suprasellar germ cell tumors are rare. We present an additional case of a suprasellar choriocarcinoma producing GH, and review the literature. CASE: This French Canadian, 17 year-old male presented to the ER with a history of mild weight loss and an episode of syncope while hiking in Mexico, but with no other neurological symptoms. Puberty began at age 13 years (growth spurt: 15-16 years), and he attained an adult height within genetic target by age 16 years. Past medical history was negative except for myopia diagnosed during childhood. System review revealed increased thirst and nocturia. The mother was treated for an oligo-astrocytoma in 2007. Clinical examination showed a euthyroid, well-looking young man with 20 ml testicles. Endocrine evaluation revealed elevated testosterone, mildly elevated PRL, borderline low FT4, and decreased IGF-I, morning cortisol and urine osmolality; tumor markers were positive in serum and CSF (hCG>50 IU/L, AFP>10 ng/mL). A transphenoidal biopsy of a 4.5 cm, homogeneous, non-calcified, suprasellar mass was compatible with the diagnosis of choriocarcinoma and stained intensely for hCG and hGH, presumably the placental variant (GH-V) as previously found in vitro in choriocarcinoma cell lines. Combined chemotherapy and irradiation led to tumor regression and undetectable serum hCG to 36 months of follow-up. He is doing well with no evidence of tumor progression and is on complete hormone replacement therapy. CONCLUSIONS: Choriocarcinomas can have a hormonal profile that delays the development of symptoms, due to hCG stimulation of both the gonadal and thyroid axes. This report corroborates previous in vitro evidence that choriocarcinoma cells are able to make GH-V. To what extent the patient's tumor-derived GH contributed to his normal growth is not known. Prognosis for this intracranial neoplasm is very reserved, although combined radiotherapy and chemotherapy has been successful in our patient now 36 months post-diagnosis. PMID- 21658596 TI - GSK3 TIPping off p53 to unleash PUMA. AB - Knowledge about "life vs. death" decisions made by p53 after DNA damage is limited but critical to preventing side effects during therapeutic application and to improve anticancer activity. Here, Charvet et al. define a signaling network that explains the protective effects of cytokines on cells exposed to gamma-radiation. PMID- 21658597 TI - ATIA: a link between inflammation and hypoxia. AB - In this issue of Molecular Cell,Choksi et al. (2011) report the identification of an NF-kappaB-independent ATIA (anti-TNFalpha-induced apoptosis)-Thioredoxin 2 axis that inhibits TNFalpha- and hypoxia-induced apoptosis through elimination of excessive reactive oxygen species directly. PMID- 21658598 TI - A SirT'N repression for Notch. AB - Mulligan et al. (2011) show here that the NAD(+)-dependent SIRT1 (H4K16; H1K26) deacetylase acts in concert with the LSD1 (H3K4) demethylase to repress Notch induced transcription, thus coupling two distinct histone modifications at a key epigenetic switch for Notch target genes. PMID- 21658599 TI - The SirT3 divining rod points to oxidative stress. AB - Sirtuins are NAD(+) dependent deacetylases that counter aging and diseases of aging. Sirtuin research has focused on SirT1, which deacetylates transcription factors and cofactors in the nucleus. More recent findings highlight SirT3 as a mitochondrial sirtuin that regulates metabolism and oxidative stress. This review focuses on new data linking SirT3 to management of reactive oxygen species from mitochondria, which may have profound implications for aging and late-onset diseases. PMID- 21658600 TI - Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. AB - Activation of p53 by DNA damage results in either cell-cycle arrest, allowing DNA repair and cell survival, or induction of apoptosis. As these opposite outcomes are both mediated by p53 stabilization, additional mechanisms to determine this decision must exist. Here, we show that glycogen synthase kinase-3 (GSK-3) is required for the p53-mediated induction of the proapoptotic BH3 only-protein PUMA, an essential mediator of p53-induced apoptosis. Inhibition of GSK-3 protected from cell death induced by DNA damage and promoted increased long-term cell survival. We demonstrate that GSK-3 phosphorylates serine 86 of the p53 acetyltransferase Tip60. A Tip60(S86A) mutant was less active to induce p53 K120 acetylation, histone 4 acetylation, and expression of PUMA. Our data suggest that GSK-3 mediated Tip60S86 phosphorylation provides a link between PI3K signaling and the choice for or against apoptosis induction by p53. PMID- 21658601 TI - A HIF-1 target, ATIA, protects cells from apoptosis by modulating the mitochondrial thioredoxin, TRX2. AB - The regulation of apoptosis is critical for controlling tissue homeostasis and preventing tumor formation and growth. Reactive oxygen species (ROS) generation plays a key role in such regulation. Here, we describe a HIF-1 target, Vasn/ATIA (anti-TNFalpha-induced apoptosis), which protects cells against TNFalpha- and hypoxia-induced apoptosis. Through the generation of ATIA knockout mice, we show that ATIA protects cells from apoptosis through regulating the function of the mitochondrial antioxidant, thioredoxin-2, and ROS generation. ATIA is highly expressed in human glioblastoma, and ATIA knockdown in glioblastoma cells renders them sensitive to hypoxia-induced apoptosis. Therefore, ATIA is not only a HIF-1 target that regulates mitochondrial redox pathways but also a potentially diagnostic marker and therapeutic target in human glioblastoma. PMID- 21658602 TI - Dynamics of Cdk1 substrate specificity during the cell cycle. AB - Cdk specificity is determined by the intrinsic selectivity of the active site and by substrate docking sites on the cyclin subunit. There is a long-standing debate about the relative importance of these factors in the timing of Cdk1 substrate phosphorylation. We analyzed major budding yeast cyclins (the G1/S-cyclin Cln2, S cyclin Clb5, G2/M-cyclin Clb3, and M-cyclin Clb2) and found that the activity of Cdk1 toward the consensus motif increased gradually in the sequence Cln2-Clb5 Clb3-Clb2, in parallel with cell cycle progression. Further, we identified a docking element that compensates for the weak intrinsic specificity of Cln2 toward G1-specific targets. In addition, Cln2-Cdk1 showed distinct consensus site specificity, suggesting that cyclins do not merely activate Cdk1 but also modulate its active-site specificity. Finally, we identified several Cln2-, Clb3 , and Clb2-specific Cdk1 targets. We propose that robust timing and ordering of cell cycle events depend on gradual changes in the substrate specificity of Cdk1. PMID- 21658603 TI - Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation. AB - Multiple cyclin-dependent kinases (CDKs) control eukaryotic cell division, but assigning specific functions to individual CDKs remains a challenge. During the mammalian cell cycle, Cdk2 forms active complexes before Cdk1, but lack of Cdk2 protein does not block cell-cycle progression. To detect requirements and define functions for Cdk2 activity in human cells when normal expression levels are preserved, and nonphysiologic compensation by other CDKs is prevented, we replaced the wild-type kinase with a version sensitized to specific inhibition by bulky adenine analogs. The sensitizing mutation also impaired a noncatalytic function of Cdk2 in restricting assembly of cyclin A with Cdk1, but this defect could be corrected by both inhibitory and noninhibitory analogs. This allowed either chemical rescue or selective antagonism of Cdk2 activity in vivo, to uncover a requirement in cell proliferation, and nonredundant, rate-limiting roles in restriction point passage and S phase entry. PMID- 21658604 TI - The catalytic activity of Ubp6 enhances maturation of the proteasomal regulatory particle. AB - The 26S proteasome is a 2.5 MDa macromolecular machine responsible for targeted protein degradation. Recently, four chaperones were identified that promote the assembly of the 19S regulatory particle (RP). Here, we probe the dynamic architecture of the proteasome by applying quantitative proteomics and mass spectrometry (MS) of intact complexes to provide a detailed characterization of how Ubp6 assists this assembly process. Our MS data demonstrate stoichiometric binding of chaperones and Ubp6 to the basal part of the RP. Genetic interactions of Ubp6 with Hsm3, but not with the other chaperones, indicate a functional overlay with Hsm3. Our biochemical data identified Ubp6 as an additional member of the Hsm3 module. Deletions of ubp6 with hsm3 perturb 26S proteasome assembly, which we attribute to an accumulation of ubiquitylated substrates on these assembly precursors. We therefore propose that Ubp6 facilitates proteasomal assembly by clearing ubiquitylated substrates from assembly precursors by its deubiquitylating activity. PMID- 21658605 TI - SH3BP1, an exocyst-associated RhoGAP, inactivates Rac1 at the front to drive cell motility. AB - The coordination of the several pathways involved in cell motility is poorly understood. Here, we identify SH3BP1, belonging to the RhoGAP family, as a partner of the exocyst complex and establish a physical and functional link between two motility-driving pathways, the Ral/exocyst and Rac signaling pathways. We show that SH3BP1 localizes together with the exocyst to the leading edge of motile cells and that SH3BP1 regulates cell migration via its GAP activity upon Rac1. SH3BP1 loss of function induces abnormally high Rac1 activity at the front, as visualized by in vivo biosensors, and disorganized and instable protrusions, as revealed by cell morphodynamics analysis. Consistently, constitutively active Rac1 mimics the phenotype of SH3BP1 depletion: slow migration and aberrant cell morphodynamics. Our finding that SH3BP1 downregulates Rac1 at the motile-cell front indicates that Rac1 inactivation in this location, as well as its activation by GEF proteins, is a fundamental requirement for cell motility. PMID- 21658606 TI - The molecular basis of ABA-independent inhibition of PP2Cs by a subclass of PYL proteins. AB - PYR1/PYL/RCAR proteins (PYLs) are confirmed abscisic acid (ABA) receptors, which inhibit protein phosphatase 2C (PP2C) upon binding to ABA. Arabidopsis thaliana has 14 PYLs, yet their functional distinction remains unclear. Here, we report systematic biochemical characterization of PYLs. A subclass of PYLs, represented by PYL10, inhibited PP2C in the absence of any ligand. Crystal structures of PYL10, both in the free form and in the HAB1 (PP2C)-bound state, revealed the structural basis for its constitutive activity. Structural-guided biochemical analyses revealed that ABA-independent inhibition of PP2C requires the PYLs to exist in a monomeric state. In addition, the residues guarding the entrance to the ligand-binding pocket of these PYLs should be bulky and hydrophobic. Based on these principles, we were able to generate monomeric PYL2 variants that gained constitutive inhibitory effect on PP2Cs. These findings provide an important framework for understanding the complex regulation of ABA signaling by PYL proteins. PMID- 21658609 TI - Musculoskeletal therapy and global challenges. PMID- 21658607 TI - Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. AB - The molecular mechanism for how RISC and microRNAs selectively and reversibly regulate mRNA translation in response to receptor signaling is unknown but could provide a means for temporal and spatial control of translation. Here we show that miR-125a targeting PSD-95 mRNA allows reversible inhibition of translation and regulation by gp1 mGluR signaling. Inhibition of miR-125a increased PSD-95 levels in dendrites and altered dendritic spine morphology. Bidirectional control of PSD-95 expression depends on miR-125a and FMRP phosphorylation status. miR 125a levels at synapses and its association with AGO2 are reduced in Fmr1 KO. FMRP phosphorylation promotes the formation of an AGO2-miR-125a inhibitory complex on PSD-95 mRNA, whereas mGluR signaling of translation requires FMRP dephosphorylation and release of AGO2 from the mRNA. These findings reveal a mechanism whereby FMRP phosphorylation provides a reversible switch for AGO2 and microRNA to selectively regulate mRNA translation at synapses in response to receptor activation. PMID- 21658608 TI - MCM proteins are negative regulators of hypoxia-inducible factor 1. AB - MCM proteins are components of a DNA helicase that plays an essential role in DNA replication and cell proliferation. However, MCM proteins are present in excess relative to origins of replication, suggesting they may serve other functions. Decreased proliferation is a fundamental physiological response to hypoxia in many cell types, and hypoxia-inducible factor 1 (HIF-1) has been implicated in this process. Here, we demonstrate that multiple MCM proteins bind directly to the HIF-1alpha subunit and synergistically inhibit HIF-1 transcriptional activity via distinct O(2)-dependent mechanisms. MCM3 inhibits transactivation domain function, whereas MCM7 enhances HIF-1alpha ubiquitination and proteasomal degradation. HIF-1 activity decreases when quiescent cells re-enter the cell cycle, and this effect is MCM dependent. Exposure to hypoxia leads to MCM2-7 downregulation in diverse cell types. These studies reveal a function of MCM proteins apart from their DNA helicase activity and establish a direct link between HIF-1 and the cell-cycle machinery. PMID- 21658610 TI - Preface on follicular non-Hodgkin's lymphoma. PMID- 21658611 TI - Pathology, pathogenesis and molecular genetics of follicular NHL. AB - Follicular lymphoma (FL) is a germinal centre-derived indolent B-cell lymphoma representing the second most common Non Hodgkin lymphoma in the Western world. This chapter focuses on the pathology of FL and summarizes the current knowledge about genetic and molecular features that are relevant for the pathogenesis of this neoplasm. The translocation t(14;18) is present in approximately 90% of FL leading to the upregulation of the anti-apoptotic protein BCL2, that may constitute a promising molecular target for therapeutic approaches. FL lacking the t(14;18) also exist, and B-cells carrying the t(14;18) can be detected in a subset of healthy individuals. In addition to the t(14;18), secondary genetic alterations are present in most FL and, more recently, deeper insights into the methylation and microRNA expression patterns in the tumour cells have been gained. The tumour microenvironment appears to be particularly important for the biology and the clinical course of FL. PMID- 21658612 TI - Follicular lymphoma grade 3B. AB - Follicular lymphoma (FL) grade 3B (FL3B) is defined as FL with more than 15% centroblasts per high resolution field present as solid sheets. Coexistence with diffuse large B-cell lymphoma (DLBCL) is frequent. In contrast to other FL, FL3B frequently lack CD10 expression (approximately 50% of cases), show lower probability of BCL2 expression (69% positive) and increased TP53 expression (31% positive). The t(14;18) hallmark translocation of FL is present in only around 13% of FL3B. In contrast, translocations affecting the BCL6 locus in 3q27 are frequent (44%). Overall, FL3B in many features resembles DLBCL. The presence of a diffuse component in FL3B has been related to an unfavorable outcome except for pediatric FL3B that presents in 60% of the cases this DLBCL component. In this chapter we sought to review the present knowledge on morphological, cytogenetic and molecular features in FL3B. PMID- 21658614 TI - The microenvironment in follicular lymphoma. AB - It has become increasingly clear that proliferation and survival in FL is not only driven by genetic changes, but also and possibly even predominantly by the close interaction with the immune microenvironment and stromal cells. Based on in vitro studies and experimental models and supported by immunohistochemical studies in biopsy specimens of FL patients, classes of CD4+ T-cell populations including follicular helper T cells and regulatory T cells are now identified as major players to regulate the delicate balance of effector populations into a supportive microenvironment. These insights may thoroughly change the therapeutic approaches in FL and translate into programs that combine direct cytotoxic and indirect immunomodulatory aspects. PMID- 21658613 TI - Host genetics in follicular lymphoma. AB - The role of inherited (host) genetic susceptibility in the pathogenesis of follicular lymphoma (FL) is reviewed. First degree relatives of FL patients are at an increased risk of FL, suggesting a role for inherited factors. While there have been no linkage studies in FL families, candidate gene and genome-wide association studies have identified several risk loci which have been confirmed in independent studies. These include regions on 6p21.32-33 and TNF family members. Host genetics has also been hypothesized to influence treatment response, disease progression and overall survival. Early leads in FL prognosis include pathways that regulate immune function, antibody-dependent cellular cytotoxicity, chemotaxis, and one-carbon metabolism, although few of these associations have been independently confirmed. While the use of host genetics to identify individuals at high risk of FL or to predict FL treatment response and prognosis appears to be very promising, it is not yet ready for the clinic. PMID- 21658616 TI - Imaging in follicular NHL. AB - Imaging contributes to management of follicular lymphoma (FL) through guiding biopsy, determining disease stage and assessing therapeutic response. Molecular imaging with positron emission tomography (PET), especially when combined with computer tomography (PET/CT), is more accurate than conventional imaging and extends the role of imaging to lesion characterisation, including non-invasive assessment of high-grade transformation. There is strong data to support the use of FDG PET/CT for primary staging, resulting in significant management change. In patients with early stage follicular lymphoma (stage I or II), there is a clear role for PET/CT to avoid futile involved-field radiotherapy in patients with widespread disease and to optimise the treatment field in patients with confirmed localised disease. For restaging, use of PET/CT allows discrimination between scar tissue and viable tumour in residual masses. Molecular imaging is likely to play an increasing role in selection of patients for specific treatments and in prognostic stratification. PMID- 21658617 TI - Treatment strategies in limited stage follicular NHL. AB - Limited stage (I-II) follicular lymphoma is an uncommon entity, since most patients with this disease have generalized adenopathy (stage III) or bone marrow involvement (stage IV). Although patients who present with stage III-IV disease often are considered to be incurable, ~50% of patients with limited disease will enjoy long-term freedom-from progression, usually following treatment with radiation therapy. Relapse among these patients is uncommon after 10 years and exceedingly rare after 15 years. Radiation treatment is generally restricted to the involved nodal region(s) with modest (~5 cm.) extension proximally and distally. Radiation dose is generally 30 Gy, but may be boosted slightly (36 Gy total) in the presence of bulky disease. Randomized clinical trials have been insufficiently powered to define the value of any additional treatment beyond radiation therapy, although single arm studies suggest a benefit to the addition of chemotherapy. There have been no reported experiences with chemo-immunotherapy or radioimmunotherapy. Patients should be monitored during follow up to identify transformation to a more aggressive lymphoma. PMID- 21658615 TI - Transformation of follicular lymphoma. AB - Histological transformation of follicular lymphoma (FL) to a more aggressive non Hodgkin's lymphomas is a pivotal event in the natural history of FL and is associated with poor outcome. While commonly observed in clinical practice and despite multiple studies designed to address its pathogenesis, the biology of this process represents an enigma. In this chapter we present a state of the art review summarizing the definition of histologic transformation, its incidence, pathogenesis, clinical manifestations, treatment and outcome. Furthermore, we specifically emphasize gaps in our knowledge that should be addressed in future studies. PMID- 21658618 TI - Treatment strategies in advanced stage follicular lymphoma. AB - Although the introduction of anti-CD20 monoclonal antibodies has improved the outcome of patients with follicular lymphoma, a curative treatment is still not available. Many questions still remain to be answered: when should treatment be initiated? Is there an optimal first line treatment and can this treatment be individualized on the basis of prognostic markers? What is the best treatment strategy for relapsed follicular lymphoma and what is the place of the many novel agents? Should maintenance treatment be given to all patients and how? In the present review we will address these questions. PMID- 21658620 TI - Molecular engineering to improve antibodies' anti-lymphoma activity. AB - The human/mouse chimeric CD20 antibody rituximab has significantly improved the survival of lymphoma patients. However, translational research into pharmacology and effector mechanisms of rituximab has identified several limitations of this prototypic antibody. For example, humanized or fully human next-generation antibodies demonstrated reduced immunogenicity, which may translate into improved applicability in certain patient populations. Furthermore, novel technologies of antibody engineering offer the potential to tailor antibody effector functions. Here, glyco- or protein engineering of antibodies' Fc region has demonstrated promising activity in preclinical models. However, these novel molecules are still in early phases of clinical development, and data from on-going and future studies will determine whether promising preclinical results will indeed translate into improved drugs for the treatment of lymphoma patients. PMID- 21658621 TI - Novel antibodies against follicular non-Hodgkin's lymphoma. AB - The anti-CD20 monoclonal antibody rituximab has revolutionized the treatment of patients with follicular B-cell lymphoma. With the combination of chemotherapy and rituximab the overall survival rate has increased with approximately 30%. Unfortunately, there is resistance to rituximab with relapse of the disease in about 60% of the patients during the first five years of treatment and eventually in all patients. To this end, there is a need to develop improved anti-CD20 monoclonal antibodies and antibodies that target other attractive molecules expressed on the follicular lymphoma cell. This review describes the development and clinical achievements so far of next generation anti-CD20 and other antibodies in the treatment of follicular B-cell lymphoma. PMID- 21658622 TI - Marrow-ablative treatment and autologous stem cell transplantation in follicular NHL. AB - High-dose therapy followed by autologous stem cell transplantation is widely accepted as salvage therapy for patients with relapsed aggressive lymphoma. In the pre-rituximab era, autologous stem cell transplantation had also been increasingly applied as a consolidation treatment for patients with indolent lymphoma in second or subsequent remission whereas controversies have emerged concerning its role in first line therapy from several randomized trials. Broad development and amazing efficacy of monoclonal antibody-based combination therapies for de novo or relapsing follicular lymphoma patients render previous conclusions outdated and underline the critical need for further phase III trials. This review focuses on available data from pre-rituximab and rituximab eras to help clarifying the precise role and timing of autologous stem cell transplantation among the current armamentarium for follicular lymphoma treatment. PMID- 21658619 TI - Rituximab resistance. AB - Rituximab has become a ubiquitous component of treatment regimens for follicular non-Hodgkin lymphoma. Despite widespread clinical use, the mechanisms by which tumor cells resist rituximab-mediated destruction remain unclear. Rituximab relies in part on immune effector mechanisms for its antitumor effect, and thus resistance may be mediated not only by intrinsic tumor-cell alterations but also by the host immunological environment. In this article, we explore the mechanisms of action of rituximab, the incidence of rituximab resistance, and potential mechanisms of resistance. Finally, we discuss novel approaches to modulate the antibody, the tumor cell, and the host immunologic environment to overcome rituximab resistance. Further research into the mechanisms of rituximab resistance will be essential to improving the efficacy of anti-CD20 therapy in NHL, and may also pay dividends in the optimization of monoclonal antibody therapy across a wide range of diseases. PMID- 21658623 TI - Allogeneic stem cell transplantation in follicular lymphoma. AB - Myeloablative allogeneic transplantation in follicular lymphoma has been found to be particularly effective in patients with relapsed disease and an inadequate bone marrow reserve or massive bone marrow involvement. Allogeneic transplantation carries the promise of long-term disease control by graft-versus lymphoma immunity but is associated with a 30%-40% risk of transplant-related mortality. Nonmyeloablative stem cell transplantation exploits the graft-versus lymphoma effect without the attendant toxicity of myeloablative conditioning. The results of several recent reports suggest that it has a high likelihood of resulting in long-term disease-free survival in patients up to 70 years of age with a good performance status, chemotherapy-sensitive disease, and HLA-matched sibling donors. At The University of Texas MD Anderson Cancer Center, the standard NST conditioning regimen for patients with follicular lymphoma is fludarabine, cyclophosphamide, and rituximab. This regimen results in a transplantation-related mortality rate of 10%, and 85% of patients are alive without disease at 8 years. In this article, we discuss the current issues in NST for follicular lymphoma, including chemosensitivity, conditioning intensity, graft-versus-host disease, donor lymphocyte infusion's role, and ongoing strategies to treat refractory disease. PMID- 21658624 TI - Radioimmunotherapy in follicular lymphoma. AB - The exquisite sensitivity of haematological malignancies to targeted radiation make Radioimmunotherapy (RIT) a theoretically attractive therapeutic approach. Furthermore, impressive results initially achieved by the pioneers in this field and more recently in larger studies have demonstrated the high clinical activity of RIT in follicular NHL (FL). For more than a decade clinical RIT of FL has been dominated by targeting the CD20 antigen and a number of pivotal clinical studies have resulted in the approval by the US FDA (Food and Drug Administration) of two radioimmunconjugates, (131)I-tositumomab (Bexxar) and (90)Y-ibritumomab (Zevalin). (90)Y-ibritumomab tiuxetan was subsequently approved within the EU in 2004 and more recently in the EU and in the US as a front line "consolidation" treatment in follicular NHL. Recent data have demonstrated that fractionated radioimmunotherapy targeting CD22 with (90)Y-epratuzumab tetraxetan achieved a high degree of durable complete responses in relapsed/refractory NHL. Despite the fact that these RIT agents clearly have unique non-cross reactive mechanisms of action with proven high clinical efficacy in patients resistant to both chemotherapy and rituximab, they have not been widely adopted by haemato-oncology community to date. This chapter reviews the progress that has been made in the development of clinical radioimmunotherapy in follicular lymphoma and suggest some guidelines to use it appropriately in first-line but also in the increasing number of patients emerging who are rituximab-refractory. PMID- 21658625 TI - Translational development of vaccination strategies in follicular NHL. AB - Follicular lymphoma expresses a unique immunoglobulin molecule termed idiotype that has been used as a tumor-specific antigen for vaccine development. Early stage clinical studies revealed that vaccination consisting of keyhole limpet hemocyanin-conjugated lymphoma idiotype protein in combination with granulocyte macrophage colony-stimulating factor induced tumor-specific immune responses and molecular remission in patients with follicular lymphoma. Three double-blind, randomized, Phase III trials were conducted to further determine the clinical benefit of this vaccine therapy. Compared to the placebo, prolonged disease-free survival in vaccinated patients was concluded only in one study where all the patients enrolled in the trial already had complete remission from induction chemotherapy. Next generation idiotype vaccines are being developed with the focus on simplifying vaccine formulation and potentiating tumor-specific immunity. This category includes genetically modified idiotype single-chain DNA vaccine, liposome-encapsulated idiotype vaccine and dendritic cell vaccine. Although preclinical data supported the immunogenicity and therapeutic advantage of these new vaccines, their clinical benefits remain to be tested. Optimizing new generation idiotype vaccines may require combination with immune adjuvants that potentiate vaccine-induced antitumor immunity, have direct effects against tumor or block immune regulatory checkpoints. Moreover, identification of a universal follicular lymphoma antigen is important for future development of vaccine therapy against this disease. PMID- 21658626 TI - New agents in follicular lymphoma. AB - The follicular lymphomas are indolent diseases that are highly responsive to various combinations of standard chemotherapy drugs. Nevertheless, until recently, no regimen had improved patient outcome. The incorporation of effective and well-tolerated monoclonal antibodies, such as rituximab, into chemoimmunotherapeutic strategies provided the first evidence that survival of these patients could be prolonged. Nevertheless, follicular lymphoma remains incurable and characterized by recurrent relapses requiring additional treatment. An increasing number of effective drugs are now being evaluated either alone or in combinations including the chemotherapy drugs bendamustine and bortezomib. More targeted agents include monoclonal antibodies and their derivatives such as drug-antibody conjugates and small modular immunopharmaceuticals. Other agents inhibit various cellular pathways including those triggered by the B-cell receptor, including spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase, and other intracellular pathways such as the mammalian target of rapamycin (mTOR), PI3-kinase, and apoptosis, and drugs that target the tumor microenvironment, notably the immunomodulatory agent lenalidomide. The development of combinations of these agents should be based on scientific rationale with correlative studies to enhance our understanding of the mechanisms of action and resistance of the drugs and the biology of the tumor to further improve the outcome of patients with follicular lymphoma. PMID- 21658627 TI - Perspective of clinical research in follicular NHL: interaction between science and industry. AB - Despite advancements in the treatment of follicular lymphoma (FL), curative therapy remains an elusive unmet medical need. Improvements in progression-free survival result in new logistical and financial challenges to clinical investigation and drug development in this indolent disease. Surrogate endpoints that utilize imaging and sensitive markers of treatment effect may serve to address this problem. Additionally, alternative trial designs may help to bypass some of the logistical hurdles. PMID- 21658628 TI - EuroCareCF: working together to improve patient care and therapy development. PMID- 21658629 TI - Developing new products in cystic fibrosis: needs and obstacles for activities of small and middle-sized companies. AB - Small and middle-sized enterprises (SMEs) can make important contributions to medical progress through the development of new safe and effective drugs that address the greatest unmet needs of patients. Regulatory inconsistencies across agencies in various countries, however, remain major challenges in cystic fibrosis (CF) drug development. Clear and consistent treatment guidelines, well educated clinical trial sites, a patient registry and grant funding for early development programs are important success-factors for an efficient development process. SMEs developing products for CF need partners in the CF community to assist with disease education and awareness for ongoing clinical trials. SMEs should collaborate and communicate with the CF community in a legally compliant way to take a patient-centric approach to drug design, development and administration. Furthermore, they can help to develop educational tools and fund medical education activities to increase the understanding of the underlying defects and mechanisms of CF disease. PMID- 21658630 TI - Medical needs of cystic fibrosis patients and policies for fair co-operation between small and middle-sized companies and patient organizations. AB - BACKGROUND AND METHODS: Workpackage 4 of EuroCareCF brought together a group of small and middle-size companies (SMEs) with strong interest in drug development for cystic fibrosis (CF). The common interest of SMEs and patient organizations (PO) in mutually beneficial cooperation was assessed. This was achieved by identifying critical unmet medical needs of CF patients and by analyzing fields of cooperation between SMEs and POs. RESULTS: Over and above all, finding a cure for the disease is considered the most important unmet medical need by POs. However, preventing or slowing down any further deterioration of health and the alleviation of symptoms are also considered valuable objectives. Areas of co operation with SMEs include the preparation and conduct of clinical trials and co operation in the post-marketing authorization period. CONCLUSIONS: If a policy of transparency and respect for the independence of POs is applied, SMEs and POs can develop mutually beneficial and sustainable co-operation. PMID- 21658631 TI - Gene and cell therapy for cystic fibrosis: from bench to bedside. AB - Clinical trials in cystic fibrosis (CF) patients established proof-of-principle for transfer of the wild-type cystic fibrosis transmembrane conductance regulator (CFTR) gene to airway epithelial cells. However, the limited efficacy of gene transfer vectors as well as extra- and intracellular barriers have prevented the development of a gene therapy-based treatment for CF. Here, we review the use of new viral and nonviral gene therapy vectors, as well as human artificial chromosomes, to overcome barriers to successful CFTR expression. Pre-clinical studies will surely benefit from novel animal models, such as CF pigs and ferrets. Prenatal gene therapy is a potential alternative to gene transfer to fully developed lungs. However, unresolved issues, including the possibility of adverse effects on pre- and postnatal development, the risk of initiating oncogenic or degenerative processes and germ line transmission require further investigation. Finally, we discuss the therapeutic potential of stem cells for CF lung disease. PMID- 21658632 TI - Pharmacological therapy for cystic fibrosis: from bench to bedside. AB - With knowledge of the molecular behaviour of the cystic fibrosis transmembrane conductance regulator (CFTR), its physiological role and dysfunction in cystic fibrosis (CF), therapeutic strategies are now being developed that target the root cause of CF rather than disease symptoms. Here, we review progress towards the development of rational new therapies for CF. We highlight the discovery of small molecules that rescue the cell surface expression and defective channel gating of CF mutants, termed CFTR correctors and CFTR potentiators, respectively. We draw attention to alternative approaches to restore epithelial ion transport to CF epithelia, including inhibitors of the epithelial Na(+) channel (ENaC) and activators of the Ca(2+)-activated Cl(-) channel TMEM16A. The expertise required to translate small molecules identified in the laboratory to drugs for CF patients depends on our ability to coordinate drug development at an international level and our ability to provide pertinent biological information using suitable disease models. PMID- 21658633 TI - Antibiotic treatment of CF lung disease: from bench to bedside. AB - Chronic infection of the respiratory tract is a hallmark of cystic fibrosis (CF). Antibiotic treatment has been used as one of the mainstays of therapy and together with other treatment modalities has resulted in increased survival of CF patients. Increasing resistance of CF-specific pathogens to various classes of antibiotics explains the need for novel antibiotic strategies. This review focuses on the future development of new antibiotic therapies, including: (1) New targets, (2) novel antibiotic regimens in CF, (3) new antibiotics, and (4) other investigational therapies. In addition, we briefly summarize developments in the area of microbial diagnostics and discuss interactions between the complex pulmonary microflora. PMID- 21658634 TI - Mouse models of cystic fibrosis: phenotypic analysis and research applications. AB - Genetically modified mice have been studied for more than fifteen years as models of cystic fibrosis (CF). The large amount of experimental data generated illuminates the complex multi-organ pathology of CF and raises new questions relevant to human disease. CF mice have also been used to test experimental therapies prior to clinical trials. This review recapitulates the major phenotypic traits of CF mice and highlights important new findings including aberrant alveolar macrophages, bone and cartilage abnormalities and abnormal bioactive lipid metabolism. Novel data are presented on the intestinal and nasal physiology of F508del-CFTR CF mice backcrossed onto different genetic backgrounds. Caveats, and sources of variability including age, gender and animal husbandry, are discussed. Interspecies differences limit comparison of lung pathology in CF mice to the human disease. The recent development of genetically modified pigs and ferrets heralds the application of more advanced animal models to CF research and drug development. PMID- 21658635 TI - European cystic fibrosis bone mineralisation guidelines. AB - Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology. PMID- 21658636 TI - The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease. AB - Chronic lung disease remains the major cause of morbidity and mortality of cystic fibrosis (CF) patients. Cftr mutant mice developed severe intestinal obstruction, but did not exhibit the characteristic CF ion transport defects (i.e. deficient cAMP-dependent Cl(-) secretion and increased Na(+) absorption) in the lower airways, and failed to develop CF-like lung disease. These observations led to the generation of transgenic mice with airway-specific overexpression of the epithelial Na(+) channel (ENaC) as an alternative approach to mimic CF ion transport pathophysiology in the lung. Studies of the phenotype of betaENaC transgenic mice demonstrated that increased airway Na(+) absorption causes airway surface liquid (ASL) depletion, reduced mucus transport and a spontaneous CF-like lung disease with airway mucus obstruction and chronic airway inflammation. Here, we summarize approaches that can be applied for studies of the complex in vivo pathogenesis and preclinical evaluation of novel therapeutic strategies in this model of CF lung disease. PMID- 21658637 TI - Diversified harmony: supranational and domestic regulation of pediatric clinical trials in the European Union. AB - Over the past decades, considerable legislative effort has been made to facilitate and encourage clinical research in the European Union (EU). Hereby, specific attention has been paid to the urgent need to conduct research in minors. In this article, we will analyze the regulation that currently governs pediatric clinical research conduct at the supranational level of the EU and at the level of individual EU member states. Our analysis will focus on the way in which the national and supranational legal frameworks address five ethical issues that are specific to pediatric clinical research: (a) informed consent, (b) the necessity to conduct research in minor subjects, (c) the interests of the subject concerned, (d) the risks and burdens involved, and (e) the pediatric expertise of protocol review committees. We conclude by discussing the harmonization and diversification of the legal requirements that govern pediatric clinical research in the EU. PMID- 21658638 TI - Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients. AB - Complete or incomplete intestinal obstruction by viscid faecal material in the terminal ileum and proximal colon - distal intestinal obstruction syndrome (DIOS) - is a common complication in cystic fibrosis. Estimates of prevalence range from 5 to 12 episodes per 1000 patients per year in children, with higher rates reported in adults. DIOS is mainly seen in patients with pancreatic insufficiency, positive history of meconium ileus and previous episodes of DIOS. DIOS is being described with increasing frequency following organ transplantation. Diagnosis is based on suggestive symptoms with a right lower quadrant mass confirmed on X-ray. The main differential is chronic constipation. Treatment consists of rehydration combined with stool softening laxatives or gut lavage with balanced electrolyte solutions. Rapid fluid shifts have been described following osmotic agents. Avoiding dehydration and optimizing pancreatic enzyme dosage may reduce the chance of further episodes. Prophylactic laxative therapy is widely used, but is not evidence-based. PMID- 21658639 TI - Best practice guidance for the diagnosis and management of cystic fibrosis associated liver disease. AB - Approximately 5-10% of cystic fibrosis (CF) patients develop multilobular cirrhosis during the first decade of life. Most CF patients later develop signs of portal hypertension with complications, mainly variceal bleeding. Liver failure usually occurs later, after the paediatric age. Annual screening for liver disease is recommended to detect pre-symptomatic signs and initiate ursodeoxycholic acid therapy, which might halt disease progression. Liver disease should be considered if at least two of the following variables are present: abnormal physical examination, persistently abnormal liver function tests and pathological ultrasonography. If there is diagnostic doubt, a liver biopsy is indicated. All CF patients with liver disease need annual follow-up to evaluate the development of cirrhosis, portal hypertension or liver failure. Management should focus on nutrition, prevention of bleeding and variceal decompression. Deterioration of pulmonary function is an important consideration for liver transplantation, particularly in children with hepatic dysfunction or advanced portal hypertension. PMID- 21658640 TI - End of life care for patients with cystic fibrosis. AB - Palliative care is an approach that improves quality of life for patients and their families facing problems associated with a life-threatening illness. Care planning is particularly important in CF, where predicting a time of death is extremely difficult. The patient and family should receive realistic information about health status and further options of care. Particularly important is the explanation that treatment does not stop during the terminal phase of the disease, instead the primary aim is to alleviate unpleasant symptoms. More invasive end of life care is becoming the norm in patients awaiting lung transplantation. Terminal care should be organised in the place chosen by the patient and their family. Ideally terminal care should not end when the patient dies, instead psychological and spiritual support should continue to bereaved families. PMID- 21658641 TI - Guiding principles on how to manage relevant psychological aspects within a CF team: interdisciplinary approaches. AB - Managing CF can be emotionally and physically challenging for patients and their relatives. The disease and its treatment influence the ability to tackle normal tasks of daily living and unexpected life events. The context within which psychologists work varies according to different cultural backgrounds and their professional and theoretical memberships. The benchmarks presented here focus on four crucial issues: (i) identifying a common base of tools and theoretical reflections through suggested readings, (ii) interdisciplinary work within a CF team and its importance for both persons with CF and other healthcare professionals, (iii) the benefits of an eclectic approach utilising cognitive behavioural theories for specific psychological problems and, (iv) effective and evaluated transition programmes from paediatric to adult healthcare services. PMID- 21658642 TI - EuroCareCF: a mighty effort and a huge success. PMID- 21658644 TI - Guideline on the design and conduct of cystic fibrosis clinical trials: the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). AB - We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials. PMID- 21658645 TI - The implementation of standards of care in Europe: state of the art. AB - The care and condition of people with cystic fibrosis (CF) in 34 European countries is reported using data obtained from publications, registries and professionals providing CF patient care. Care and outcomes differ markedly between countries. Although the 2005 European standards of patient care publication was widely known, in many countries there were no specialized CF centres. In only a minority of countries was funding considered adequate and in some countries costs covered by patients compromised care. Only 15 countries had a national CF patient registry. Neonatal screening was routine in only 10 countries, but this included 59% of European infants. The initiatives of EuroCareCF Workpackage 1 to form networks for professionals working with CF patients are described. Suggestions for the future include at least one adequately staffed CF Centre in each country, improved funding, neonatal screening, national patient registries and the formation of national CF parent and patient organisations. PMID- 21658643 TI - New clinical diagnostic procedures for cystic fibrosis in Europe. AB - In the majority of cases, there is no difficulty in diagnosing Cystic Fibrosis (CF). However, there may be wide variation in signs and symptoms between individuals which encourage the scientific community to constantly improve the diagnostic tests available and develop better methods to come to a final diagnosis in patients with milder phenotypes. This paper is the result of discussions held at meetings of the European Cystic Fibrosis Society Diagnostic Network supported by EuroCareCF. CFTR bioassays in the nasal epithelium (nasal potential difference measurements) and the rectal mucosa (intestinal current measurements) are discussed in detail including efforts to standardize the techniques across Europe. New approaches to evaluate the sweat gland, future of genetic testing and methods on the horizon like CFTR expression in human leucocytes and erythrocytes are discussed briefly. PMID- 21658646 TI - Chronic Pseudomonas aeruginosa infection definition: EuroCareCF Working Group report. AB - Chronic pulmonary infection with P. aeruginosa develops in most patients with cystic fibrosis (CF); by adulthood 80% of patients are infected and chronic P. aeruginosa infection is the primary cause of increased morbidity and mortality in CF. Chronic infection is preceded by an intermittent stage of infection. The initial stage is characteristically followed by the gradual emergence of mucoid variants of the colonizing strains and a rise in anti-Pseudomonas antibodies. In addition to optimizing existing therapeutic strategies, effective new agents need to be identified. Studies in patients with CF are particularly challenging: the progressive nature of the disease and the wide variation in severity influence considerably the outcome of drug testing. A validated, universally accepted, and clinically useful classification of patients infected with P. aeruginosa, particularly those chronically infected, is needed that can be used as both a criterion for patient selection for clinical trials and as a study endpoint. PMID- 21658647 TI - Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials. AB - Pulmonary exacerbations represent a key outcome variable in clinical trials of cystic fibrosis (CF). As there is variation in the trigger for use of intravenous antibiotics compared to the use of oral antibiotics or new nebulised therapy for treatment of exacerbations, the consensus view is that use of intravenous antibiotics cannot be regarded as the key defining character for an exacerbation on its own. The consensus view is that the clinical need for additional treatment as indicated by a recent change in clinical parameters provides the best definition of an exacerbation. Which parameters to include as well as the problems associated with the use of scoring systems and symptom clusters are being discussed. PMID- 21658648 TI - Measuring health-related quality of life in clinical trials in cystic fibrosis. AB - The inclusion of health-related quality of life (HRQoL) as an outcome measure in cystic fibrosis (CF) clinical trials can supply important patient-reported information not captured by other endpoints. Both an appropriate HRQoL measure and sound methodology are required in order to draw valid inferences about treatments and HRQoL. This paper provides the current consensus of the HRQoL Outcomes Group. Particular consideration has been given to the appropriateness of measurement scales, the rationale for including specific domains as endpoints, the importance of considering baseline ceiling effects and the difficulties of data interpretation. Guidance is provided on HRQoL measurement in National and European CF clinical trials. PMID- 21658649 TI - Recommendations for the classification of diseases as CFTR-related disorders. AB - Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as "a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF". The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR RDs. PMID- 21658650 TI - Reduced-intensity allogeneic hematopoietic stem cell transplantation for multiple myeloma: a concise review. AB - Reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HSCT) can result in reliable donor engraftment, relatively low treatment-related mortality, and sustained remissions in the treatment of multiple myeloma. However, substantial cytoreduction pre-allografting is often necessary because of a variable graft-versus-myeloma effect. The use of RIC allogeneic HSCT immediately after autologous HSCT provides a temporal separation between tumor reduction by high-dose chemotherapy and the graft-versus-myeloma effect. There are currently a number of prospective trials attempting to address the issue of whether this strategy leads to decreases in relapse and/or improvement in overall survival as compared with double autologous transplants. Unfortunately, similar to autografting, relapse remains the major cause of treatment failure after RIC allogeneic HSCT. To improve treatment results with allografting, consideration should be given to incorporating immunomodulatory drugs and targeted treatments to enhance pretransplantation remission status, as posttransplantation maintenance therapy, or in combination with donor lymphocyte infusions for refractory or relapsed disease. Studies exploring these strategies are ongoing. PMID- 21658651 TI - High-dose therapy/autologous hematopoietic stem cell transplantation in relapsed or refractory marginal zone non-Hodgkin lymphoma. AB - The optimal therapy for patients who have relapsed or refractory marginal zone lymphoma has not been defined. We analyzed the clinical outcomes of 14 patients who had relapsed or refractory marginal zone lymphomas and underwent high-dose therapy/autologous hematopoietic stem cell transplantation (HDT/AHSCT) at the University of Nebraska from August 1992 to August 2008. The median age of patients was 48 years (range, 29 to 62 years). All patients had relapsed or refractory disease. There were three treatment-related deaths within 100 days of transplantation. With a median follow-up of 138 months, the median duration of failure-free survival is 108 months, and the median duration overall survival is 120 months. Only two patients have relapsed. Secondary malignancies were seen in three patients (myelodysplastic syndrome, n = 2; gastric carcinoma. n = 1). We conclude that HDT/AHSCT is feasible in patients who have relapsed/refractory marginal zone lymphomas. Approximately one- third of patients can achieve long term disease-free survival. PMID- 21658652 TI - Outcome of diffuse large B-Cell lymphoma in the United States has improved over time but racial disparities remain: review of SEER data. AB - BACKGROUND: Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) outcome in the United States has not been reported outside the context of clinical trials. PATIENTS AND METHODS: We reviewed the Surveillance, Epidemiology, and End Results (SEER) registry and compared survival trends among DLBCL patients from 1973 to 2004. RESULTS: We identified 59,728 patients (mean age, 63 years; 54.4% men, 86.7% white) and had staging information for 57%, including 30% early-stage (I/II) and 27% advanced-stage (III/IV). Median overall survival (OS) from 1973 to 1979, 1980 to 1989,1990 to 1999, and 2000 to 2004 was 15, 18, 20, and 47 months, respectively (P < .005). For the period from 2000 to 2004, 4-year OS was 46%. Outcome was better in white patients than in black (47 months versus 29 months) (P = .001). Median OS for patients younger than 60 years old was not reached versus 23 months for patients older than 60 years. CONCLUSION: The outcome of DLBCL in the United States has improved significantly in the era of monoclonal antibodies; however, racial disparities remain. PMID- 21658653 TI - Fluorodeoxyglucose-positron-emission tomography findings in mantle cell lymphoma. AB - OBJECTIVE: Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma with a propensity for extranodal involvement. The role of fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging in common types of lymphoma has been well-established. However, there is limited information in the literature about the utility of FDG-PET imaging in patients who have MCL. The aim of this study was to determine the role of FDG-PET imaging in assessment of disease activity in MCL compared with conventional imaging techniques such as computerized tomography/magnetic resonance imaging (CT/MRI). METHODS: FDG-PET images of 20 patients with MCL who were referred to our center for assessment of extent of disease were reviewed retrospectively. The FDG-PET findings were compared with those of CT/MRI and were correlated with clinical information, histopathology, and outcome. RESULTS: The diagnostic sensitivity for PET was 90% (17/19), and specificity was 100% (1/1). For CT/MRI, the sensitivity was 87% (14/16) and specificity was 50% (2/4). PET was better than CT/MRI in detecting nodal involvement. With respect to extranodal involvement, PET detected more cases of spleen involvement than CT/MRI. PET was equivalent to conventional imaging in detecting bowel involvement. CONCLUSIONS: PET imaging has a high sensitivity in detecting both nodal and extranodal involvement in patients who have MCL. Based on the available data in patients who had other subtypes of non Hodgkin lymphoma, the specificity of PET also appears to be superior to anatomic imaging techniques. FDG-PET imaging may prove to be the single most effective method for detection. PMID- 21658654 TI - Late afternoon dosing of plerixafor for stem cell mobilization: a practical solution. AB - BACKGROUND: Plerixafor was recently approved for stem cell mobilization in patients who have non-Hodgkin lymphoma or multiple myeloma. However, the use of late evening (10 PM) injections is inconvenient for patients and requires an after-hours infrastructure that may not be readily available. PATIENTS AND METHODS: Based on an earlier study showing prolonged mobilization of stem cells in patients given plerixafor plus granulocyte colony-stimulating factor (G-CSF), we administered plerixafor at 5 PM and performed apheresis approximately 15 hours later. Plerixafor was administered primarily to patients who either had failed previous mobilization or were at risk for poor mobilization because of previous therapy, especially lenalidomide in patients who had multiple myeloma. RESULTS: Of 48 patients, including 24 with myeloma and 24 with lymphoma, 47 had enough stem cells collected (> 2 * 10E6 CD34+ cells/kg) to proceed to transplant, including all 13 patients who had failed previous chemotherapy plus G-CSF mobilization and 18 patients treated with four cycles or more of lenalidomide. The day +1 post-plerixafor increment in circulating CD34+ cells was greatest in patients who had the highest preplerixafor CD34 count; however, in patients with preplerixafor CD34+ cell counts < 10/MUL (and who typically mobilize poorly), 83% of patients had enough stem cells collected to proceed to transplant. CONCLUSION: This study suggests that plerixafor is effective when given 15 hours before apheresis, even in a population at high risk for mobilization failure. A proposed cost-effective use of plerixafor is to administer it to patients who are inadequately mobilized with G-CSF alone or for salvage in patients who fail previous mobilization with chemotherapy plus G-CSF. PMID- 21658655 TI - External validation of newly proposed cytogenetic risk classification in patients who have myelodysplastic syndrome: a retrospective analysis at a single institution. AB - BACKGROUND: A newly proposed cytogenetic risk classification (NPCRC) has defined four risk groups including favorable, intermediate-1 (Int-1), intermediate-2 (Int 2) and unfavorable. The current study evaluated the prognostic power of the NPCRC in patients who have myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Between 1996 and 2007, 116 MDS patients receiving best supportive care were included in the analysis at the Samsung Medical Center, Seoul, Korea. RESULTS: According to the NPCRC, 3 patients had 5q-,1 patient had 12p-, 3 patients had 20q , 3 patients had -Y, patient had t(11)(q23), 55 patients were normal, 1 patient had +1q, 1 patient had 3q21/q26-abnormalities, 11 patients had +8, 14 patients had any other single, 8 patients had any other double, 2 patients had -7/7q-, 5 patients had three complex abnormalities, and 8 patients had more than three complex abnormalities. Also, 66 patients (57%) were favorable, 35 (30%) were Int 1, 9 (8%) were Int-2, and 6 (5%) were in the unfavorable subgroup. The median OS times were 23.8, 24.1, 13.0, and 9.1 months in the favorable, Int-1, Int-2 and unfavorable subgroups, respectively (P = .005, between favorable/Int-1 and Int 2/unfavorable risk group, hazard ratio 2.19, 95% confidence interval 1.25-3.84). CONCLUSION: In our study, the NPCRC seems to stratify patients according to their risk of death, especially between the unfavorable/Int-2 and Int-1/favorable risk groups. PMID- 21658656 TI - Molecular monitoring of imatinib in chronic myeloid leukemia patients in complete cytogenetic remission: does achievement of a stable major molecular response at any time point identify a privileged group of patients? A multicenter experience in Argentina and Uruguay. AB - BACKGROUND: Monitoring minimal residual disease (MRD) by real-time quantitative polymerase chain reaction (RT-PCR) in chronic myeloid leukemia (CML) patients is mandatory in the era of tyrosine kinase inhibitors. Achieving a major molecular response (MMR) at 12 and 18 months predicts a better progression and event-free survival. PATIENTS AND METHODS: The objective of this prospective, multicentric study was to evaluate MRD by standardized RT-PCR in 178 patients with chronic phase CML who were treated with imatinib at different institutions in Argentina and Uruguay and to determine if achievement of a stable MMR (BCR-ABL transcript levels < 0.1%) identifies a low-risk cytogenetic relapse group. The median age of the patients was 50 years, and 55% of them had received imatinib as first-line therapy. BCR-ABL transcript levels were measured after achievement of complete cytogenetic remission (CCyR) and at 6-month intervals. RESULTS: MMR was detected in 44% patients at the start of the study. This value increased to 79% at month 36 of evaluation. Complete molecular response (CMR) also increased from 24% to 52% of patients. Not achieving a stable MMR determined a higher risk of cytogenetic relapse (9% of MMR patients not achieving an MMR vs. 1% of patients who achieved MMR). Patients with sustained MMR had a significantly better cytogenetic relapse-free survival at 48 months (97% vs. 87%; P = .008) but showed no differences in overall survival. Patients who did not remain in CCyR changed treatment. CONCLUSIONS: A stable MMR is a strong predictor for a durable CCyR. Standardized molecular monitoring could replace cytogenetic analysis once CCyR is obtained. These results emphasize the validity and feasibility of molecular monitoring in all standardized medical centers of the world. PMID- 21658657 TI - Treatment of cutaneous lymphoid hyperplasia with the monoclonal anti-CD20 antibody rituximab. AB - B-cell lymphoproliferative disorders are a continuum from benign cutaneous lymphoid hyperplasia (CLH) or "pseudolymphoma" to primary cutaneous B-cell lymphoma (PCBCL). Historically, CLH was treated with a combination of antibiotics, topical or intralesional corticosteroids, and/or localized radiotherapy. Rituximab, a monoclonal antibody that targets the CD20 marker on B cells, is an effective and well-reported treatment for PCBCL. We review the pathogenesis and current treatments of B-cell lymphoproliferative disorders and assess the role of rituximab for potential therapy in the setting of refractory CLH. We describe a case of CLH that was treated with intralesional rituximab. The patient had notable clinical improvement over the treatment period with rituximab. Because of some persistent and recurrent erythematous areas, topical tacrolimus was initiated, with significant clinical improvement. There were no reported side effects. Management of CLH with intralesional rituximab has been described. The treatment presented in this report substantiates rituximab as a reasonable therapeutic option for refractory CLH after failure of several other widely accepted treatments. Treatment with intralesional rituximab should be reserved for patients with documented CD20(+) lesions. PMID- 21658658 TI - Regression of Hodgkin lymphoma after discontinuation of a tumor necrosis factor inhibitor for Crohn's disease: a case report and review of the literature. AB - Lymphoma is an increasingly recognized complication of tumor necrosis factor (TNF) inhibition for the treatment of autoimmune and inflammatory disease; the majority of these cases are non-Hodgkin lymphomas (NHL). The impact of withdrawing TNF inhibition therapy in cases of lymphoma is not well described. A woman with Crohn's disease (CD) was diagnosed with Hodgkin lymphoma (HL) and subsequently went into remission with standard chemotherapy. Her CD later worsened, requiring initiation of adalimumab, a TNF inhibitor. Ten months later, she was found to have recurrence of HL. When she opted against additional treatment for the lymphoma, the TNF inhibitor was discontinued. Three months later, the measurable sites of disease had completely regressed. It can be concluded that HL is a potential complication of treatment with TNF inhibitors. Withdrawal of immunosuppression may be a consideration for patients treated for lymphoproliferative disorders including HL. Maintenance of an intact immune system may be important for prevention of lymphoma relapse. Further understanding of this complex interaction will help clinicians determine in which patients these agents have a favorable risk-benefit ratio. PMID- 21658659 TI - Cytopenia, dysplasia, and monocytosis: a precursor to chronic myelomonocytic leukemia or a distinct subgroup? Case reports and review of literature. AB - Chronic myelomonocytic leukemia (CMML) consists of disorders with overlapping dysplastic and proliferative features. The diagnosis of CMML requires absolute monocytosis (> 1000/MUL) in addition to other criteria outlined by the World Health Organization (WHO) classification.(1) Monocytosis not reaching 1000/MUL has been observed in myelodysplastic syndrome (MDS) and presents a diagnostic challenge in classification especially if increases in leukocyte count occurring during disease shifts the monocyte count into the absolute range. We discuss the laboratory and clinical features of 3 patients with myelodysplasia and associated monocytosis. Absolute neutropenia was the dominant feature at presentation, with mild anemia, thrombocytopenia, monocytosis (as a percentage), multilineage dysplasia, and increased myeloblasts, consistent with a diagnosis of refractory anemia with excess blasts (RAEB). Absolute monocytosis fulfilling the diagnostic criteria for CMML developed over 6-8 months, prompting a change in diagnosis. Two of 3 patients had normal cytogenetic examinations. JAK2 V617F mutation was detected after transformation to CMML in 1 of them; in the other, a novel translocation t(5;12)(p13;q24) was observed at the time of progression to acute leukemia. The use of different diagnostic terminologies--MDS, dysplasia with reactive monocytosis, myeloproliferative, and myeloproliferative/myelodysplastic syndromes by different and even the same pathologists at different times created confusion among the clinicians and patients. The disease course in these 3 patients was characterized by better survival and prolonged time to progression to acute leukemia, than predicted based on the original diagnosis of RAEB, suggesting that MDS with monocytosis may represent a subgroup distinct from MDS or CMML. PMID- 21658661 TI - Traditional response interference effects from anticipated action outcomes: a response-effect compatibility paradigm. AB - An act as simple as pressing a button involves various stages of processing. Each stage of action production is susceptible to interference from competing representations/processes. For example, in the Simon Effect, interference arises from an incongruence between incidental spatial information and the spatial properties of intended action; in the flanker task, interference arises when visual targets and distracters are associated with different responses (response interference [RI]). Less interference arises in the flanker task when targets and distracters are different in appearance but associated with the same response (perceptual interference [PI]). Interference also stems from the automatic activation of representations associated with the anticipated effects of an action, response-effect (R-E) compatibility (e.g., the presence of a left pointing arrow after one presses a button on the right will increase interference in future trials). This has been explained by ideomotor theory-that the mental representation of anticipated action-effects are activated automatically by voluntary action and that such representations can cause facilitation or interference by automatically priming their associated action plans. To illuminate the nature of action production and provide additional support for ideomotor theory, we examined for the first time the effects of PI and RI in a new R-E compatibility paradigm. PMID- 21658660 TI - Complete response to thalidomide and dexamethasone in a patient with necrobiotic xanthogranuloma associated with monoclonal gammopathy: a case report and review of the literature. AB - Necrobiotic xanthogranuloma (NXG) was first described in 1980 by Kossard and Winkelmann in an article in which they discussed 8 patients with xanthomatous plaques who were noted to have monoclonal gammopathy, predominantly of the Ig(immunoglobulin)G-kappa type.(1) Since then more than 50 patients with this disorder have been described, with approximately 80% of them having an associated monoclonal gammopathy. We describe the first case, to our knowledge, of NXG with associated monoclonal gammopathy treated with thalidomide plus dexamethasone, achieving complete resolution of the skin lesions and sustaining response more than 3 years after treatment. PMID- 21658662 TI - [Descriptive analysis of cutaneous recurrence patterns in patients with melanoma]. AB - BACKGROUND AND OBJECTIVES: Few studies have addressed cutaneous recurrence of melanoma. The aim of this retrospective study was to analyze the characteristics and prognostic significance of the different patterns of cutaneous recurrence. MATERIAL AND METHODS: Patients diagnosed with melanoma between 1988 and 2008 at Hospital de Bellvitge, Barcelona, Spain and for whom data were available for at least 2 years of follow-up were included in the study. Local recurrence was defined as melanoma invasion of the skin adjacent to the scar left by excision of the primary tumor, regional metastasis or recurrence as metastasis restricted to the area drained by a regional lymph node station, and distant cutaneous metastasis as metastasis occurring outside this area. The relationship between cutaneous recurrence pattern and age, sex, primary tumor site, tumor subtype, Breslow depth, and ulceration was assessed. RESULTS: Eighty-five out of 1,080 patients (7.87%) had cutaneous recurrence. In 71 of those patients (83.53%; 27 men and 44 women; mean age, 60.68 years), this was the first indication of melanoma recurrence. Thirty-two patients had local recurrence, 32 regional metastasis, and 7 distant metastasis. Significant differences were observed in survival time from diagnosis of the primary tumor (P=.044) and from diagnosis of cutaneous recurrence (P<.001) according to the type of recurrence. CONCLUSIONS: Our results suggest that the pattern of cutaneous recurrence is prognostically significant and related to the site of the primary tumor given that the majority of local and regional recurrences occurred in primary tumors located on the lower limbs and head. PMID- 21658663 TI - Atrial remodeling, autonomic tone, and lifetime training hours in nonelite athletes. AB - Endurance athletes have an increased risk of developing atrial fibrillation (AF) at 40 to 50 years of age. Signal-averaged P-wave analysis has been used for identifying patients at risk for AF. We evaluated the impact of lifetime training hours on signal-averaged P-wave duration and modifying factors. Nonelite men athletes scheduled to participate in the 2010 Grand Prix of Bern, a 10-mile race, were invited. Four hundred ninety-two marathon and nonmarathon runners applied for participation, 70 were randomly selected, and 60 entered the final analysis. Subjects were stratified according to their lifetime training hours (average endurance and strength training hours per week * 52 * training years) in low (<1,500 hours), medium (1,500 to 4,500 hours), and high (>4,500 hours) training groups. Mean age was 42 +/- 7 years. From low to high training groups signal averaged P-wave duration increased from 131 +/- 6 to 142 +/- 13 ms (p = 0.026), and left atrial volume increased from 24.8 +/- 4.6 to 33.1 +/- 6.2 ml/m(2) (p = 0.001). Parasympathetic tone expressed as root of the mean squared differences of successive normal-to-normal intervals increased from 34 +/- 13 to 47 +/- 16 ms (p = 0.002), and premature atrial contractions increased from 6.1 +/- 7.4 to 10.8 +/ 7.7 per 24 hours (p = 0.026). Left ventricular mass increased from 100.7 +/- 9.0 to 117.1 +/- 18.2 g/m(2) (p = 0.002). Left ventricular systolic and diastolic function and blood pressure at rest were normal in all athletes and showed no differences among training groups. Four athletes (6.7%) had a history of paroxysmal AF, as did 1 athlete in the medium training group and 3 athletes in the high training group (p = 0.252). In conclusion, in nonelite men athletes lifetime training hours are associated with prolongation of signal-averaged P wave duration and an increase in left atrial volume. The altered left atrial substrate may facilitate occurrence of AF. Increased vagal tone and atrial ectopy may serve as modifying and triggering factors. PMID- 21658664 TI - Internal medicine residency directors perspectives on global health experiences. PMID- 21658665 TI - Adult immunizations: update on recommendations. AB - The Advisory Committee for Immunization Practices recommends universal influenza vaccination for 2010-2011. Older adults should be offered protection against herpes zoster, and younger adults should receive immunization against human papilloma virus and pertussis. Hepatitis B vaccination should be encouraged in non-immune adults. Recommendations also address vaccinations for tetanus/diphtheria, hepatitis A, pneumococcus, measles/mumps/rubella, and meningococcus. PMID- 21658666 TI - Modified thrombolytic therapy for massive pulmonary emboli. PMID- 21658667 TI - Women's lifestyle behaviors while trying to become pregnant: evidence supporting preconception guidance. AB - OBJECTIVE: We sought to prospectively measure women's daily cigarette, alcohol, and caffeine use, while attempting pregnancy in relation to intentions to change. STUDY DESIGN: This was a cohort comprising 90 women enrolled upon discontinuing contraception and followed up prospectively until pregnant. Women reported number of daily cigarettes, and alcoholic and caffeinated beverages for 459 menstrual cycles while attempting pregnancy. RESULTS: A significant mean reduction in daily caffeinated drinks (estimate [EST] = -0.52; 95% confidence interval [CI], -0.70 to -0.33) was observed when compared to baseline usage. Intention to change was associated with a reduction in caffeinated drinks (EST = -0.32; 95% CI, -0.64 to 0.00), and with alcohol and cigarette usage from the first menstrual cycle (EST = -0.15; 95% CI, -0.28 to -0.02 and EST = -1.65; 95% CI, -3.12 to -0.19, respectively). CONCLUSION: A reduction in daily caffeine intake while attempting pregnancy was observed, but not in alcohol or cigarette use, underscoring the need for preconception guidance. PMID- 21658668 TI - Genotyping of human papillomavirus in triaging of low-grade cervical cytology. AB - OBJECTIVE: The objective of the study was to evaluate whether typing of human papillomavirus (HPV) among women with low-grade cervical cytology can improve the ability to identify women with cervical cancer or cervical intraepithelial neoplasia grade III (CIN III or worse). STUDY DESIGN: A total of 1595 women with low-grade cervical cytology participating in a randomized implementation trial of HPV triaging using Hybrid Capture II were also HPV genotyped and CIN III or worse predictive values evaluated. RESULTS: HPV 16 was detected in 57% of cases with CIN III or worse but only among 24% of all tested women. Testing for the 3 HPV types with highest risk (HPV16/31/33) detected 77% of CIN III or worse, with 36% of women testing positive. Positivity for the other high-risk HPV types had a decreased risk for CIN III or worse. CONCLUSION: Different high-risk HPV types confer different risks for the presence of CIN III or worse, implying that HPV genotyping could be useful for the optimization of triaging strategies. PMID- 21658669 TI - Prenatal amphetamine exposure and birth outcomes: a systematic review and metaanalysis. AB - OBJECTIVE: The aim of this study was to systematically review the relationship between amphetamine exposure in pregnancy and birth outcomes. STUDY DESIGN: Electronic databases were searched to identify relevant studies. Data from included studies were extracted by 2 reviewers. Summary odds ratio (OR) and confidence intervals (CIs) were calculated using the random effects model. RESULTS: Ten studies were included. Significant increases in unadjusted risks of preterm birth (OR, 4.11; 95% CI, 3.05-5.55), low birthweight (OR, 3.97; 95% CI, 2.45-6.43), and small for gestational age (OR, 5.79; 95% CI, 1.39-24.06) were identified among women exposed to amphetamines in pregnancy. The mean birthweight was significantly lower among amphetamine-exposed pregnancies (mean difference, 279 g; 95% CI, -485 to -74 g). Two studies provided adjusted estimates on different outcomes, and their results were consistent with the findings from the unadjusted data. CONCLUSION: Amphetamine exposure in pregnancy is associated with adverse birth outcomes and should be identified by physicians providing antenatal care. PMID- 21658671 TI - Surgical management of radiation-induced angiosarcoma after breast conservation therapy. AB - BACKGROUND: Radiation-induced angiosarcoma (RA) is a well-recognized complication of breast conservation therapy (BCT). METHODS: Over a 12-year period, 14 patients with a median age of 68 years were identified retrospectively. The median latency from BCT to onset of RA was 81 months. The incomplete excision rate (complete histologic margin taken to be > 10 mm) was 46%. There was a significant difference in the size of the cutaneous defect between the complete and incomplete excision groups (412 vs 592 cm(2), respectively; P < .05), indicating more extensive disease in the latter group. RESULTS: The tumor recurred locally in 12 patients (92%). The median time to local recurrence (LR) in patients with incomplete excision was 3 versus 23 months in patients who had a complete excision. The median survival time for patients who underwent complete versus incomplete excision was 42 and 6 months, respectively. CONCLUSIONS: RA is a challenging condition, with a prolonged latency period and variable clinical progression. Incomplete excision of RA is a surrogate marker of aggressive disease and is associated with rapid LR and poor survival. PMID- 21658672 TI - Impact of laparoscopy simulator training on the technical skills of future surgeons in the operating room: a prospective study. AB - BACKGROUND: The efficacy of laparoscopy simulators remains controversial. METHODS: This was a comparative prospective study that evaluated the impact of simulator training on technical competence during a real surgical procedure. Residents were divided into 3 groups: the Mcgill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS) group, training on a simple simulator; LAP Mentor group, training on a virtual simulator; and control group. An initial evaluation was made by a validated score during a laparoscopic cholecystectomy. Each resident was then trained for 1 month. A second evaluation was then performed. RESULTS: Before/after scores were significantly improved in the MISTELS (P = .042) and LAP Mentor (P = .026) groups. It was not the case in the control group. There was a better progression in the MISTELS (P = .026) and LAP Mentor (P = .007) groups than in the control group. There was no significant difference between the MISTELS and LAP Mentor groups. CONCLUSIONS: Simulator training provides a more rapid acquisition of competence in surgical technique. PMID- 21658670 TI - Relationship of maternal vitamin D level with maternal and infant respiratory disease. AB - OBJECTIVE: The objective of the study was to investigate the association of maternal vitamin D and maternal asthma and infant respiratory infection severity. STUDY DESIGN: The study included cross-sectional analyses of 340 mother-infant dyads enrolled from September to May 2004-2008 during an infant viral respiratory infection. Maternal vitamin D levels were determined from enrollment blood specimens. At enrollment, we determined self-reported maternal asthma and infant respiratory infection severity using a bronchiolitis score. We assessed the association of maternal vitamin D levels and maternal asthma and infant bronchiolitis score in race-stratified multivariable regression models. RESULTS: The cohort was 70% white, 19% African American, and 21% had asthma. Overall, the median maternal vitamin D level was 20 ng/mL (interquartile range, 14-28). Among white women, a 14 ng/mL increase in vitamin D was associated with a decreased odds of asthma (adjusted odds ratio, 0.54; 95% confidence interval, 0.33-0.86). Maternal vitamin D was not associated with infant bronchiolitis score. CONCLUSION: Higher maternal vitamin D levels were associated with decreased odds of asthma. PMID- 21658673 TI - [Sirolimus-eluting stent displaced fracture: case report and review of the literature]. AB - Drug-eluting stents have greatly reduced the risk of in-stent restenosis compared to bare metal stents by inhibiting neointimal growth. However, they may carry some long-term risks, especially the risk of late stent thrombosis. Recently, several cases of drug-eluting stent fracture have been also reported. The mechanisms, the diagnosis, the clinical implications and the management of this new complication are not well-known. We report the observation of a new case of displaced, sirolimus drug-eluting stent fracture. To our knowledge, this is the first reported case in France. PMID- 21658674 TI - [The ambulatory care of the acute myocardial infarction in Quebec: description, classification and typology]. AB - OBJECTIVE: Description of ambulatory care of AMI, in Quebec population. DESIGN: A retrospective cohort study was designed to classify and propose a typology of ambulatory care. METHODS: The studied population was included in all 25 years and older inpatients residing in Quebec, whose admission were from January to December 2000. The principal variables were: the number of medical visits, the type of consulted physicians and the place of consultation. The secondary variables were: age, sex and the presence of a revascularization. RESULTS: A typology of ambulatory care was created from principal variables. Men, younger patients and receiving a revascularization in the index hospitalization were cared for by a specialist. PMID- 21658675 TI - Acromegaly and sleep apnea: cephalometric evaluations. AB - Lateral teleradiography is a standard and quick examination. It has enabled us to define differences as regards to the craniofacial morphology between 20 acromegalic patients and 20 control subjects. The height of the mandibular ramus (from the posterior condyle point to the gonion point) increases significantly with the acromegalic patient and the cranial base angle (basion-superior tuberculum sellae-M point) is more extended. As acromegalic patients are more subject to sleep apnea (30% prevailing), the relationship between the amount of sleep apnea and hypopnea (AHI) in an acromegalic patient and his bone, tissue and hormone factors has been researched, in order to act on the causes of sleep apnea. It has emerged that confronting craniofacial bones and soft tissues factors enables a good prediction of the apnea and hypopnea index. Of course, we can find again the potential action of growth hormone (GH) but only in fifth place in importance order. The tongue, which increases in volume with the GH impact, is in a too short "lingual enclosure" (reduced length of the mandibular horizontal branch). PMID- 21658676 TI - Effects of user age and target-expansion methods on target-acquisition tasks using a mouse. AB - Target expansion, i.e., the increase of target size according to cursor movement, can be a practical scheme to improve the usability of target-selection tasks using a mouse. This study examined the effects of different user age groups and target-expansion methods on target-acquisition tasks with grouped icons. Twenty eight subjects performed acquisition tasks under eight experimental conditions: combinations of four expansion areas (no, one-icon, fish-eye, and group expansion) and two expansion techniques (occlusion and push). Older users took longer to acquire targets than younger users; however, they showed no significant difference in accuracy. Target expansion did not substantially improve performance speed compared to the static condition. However, the error rate was lowest when group area was expanded with the push technique, and both age groups were most satisfied with one-icon area expansion with the occlusion technique. We suggest alternative guidelines in designing target-expansion schemes. PMID- 21658677 TI - Effect of sympathetic nervous activity on alveolar bone loss induced by occlusal hypofunction in rats. AB - OBJECTIVE: To elucidate the effect of sympathetic nervous activity on alveolar bone loss induced by occlusal hypofunction in rat molars. DESIGN: Occlusal hypofunction in the molar area was produced by attaching appliances to rat maxillary and mandibular incisors. In addition, a non-selective beta-adrenergic receptor antagonist, propranolol, was administered orally to rats in drinking water to pharmacologically suppress sympathetic nervous activity. After 1 week, alveolar bones in all groups were examined by micro-CT, histomorphometry and histology to determine their trabecular bone phenotypes and histological changes. RESULTS: The marrow spaces of the interradicular alveolar bone of rat mandibular first molars (M1) increased in the occlusal hypofunction group (Group H) but not in the control group (Group C), whilst these decreased in rats in the occlusal hypofunction group that were administered propranolol (Group HB). Bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) for interradicular alveolar bone in M1 in Group H were significantly lower than those in Group C, whereas those in Group HB remained as high as those in Group C. The number of TRAP-positive cells in Group H increased compared to that in Group C, whereas it significantly decreased in Group HB. CONCLUSIONS: These results suggest that sympathetic nervous activity may influence the alveolar bone loss induced by occlusal hypofunction. PMID- 21658678 TI - What is our knowledge of functioning and disability in hand conditions based on? AB - OBJECTIVES: To analyze the content of published studies on hand conditions using the International Classification of Functioning, Disability and Health (ICF) as a reference, and to highlight the most common aspects of functioning as well as those that deserve more consideration in research on hand conditions. DATA SOURCES: The MEDLINE, Embase, PsycINFO, CINAHL, and PEDro databases were searched for English language studies on hand conditions published between 1998 and 2008. STUDY SELECTION: The identified studies were reviewed by 2 persons independently. Studies reporting firsthand data of patients with diseases/injuries of the hand and with a minimum sample size of 10 patients were included. Reviews, overviews, meta-analyses, and psychometric studies were excluded. DATA EXTRACTION: Peer review strategy was conducted in the data extraction process. Data from a random sample of 15% of the included studies was extracted by 2 reviewers independently. DATA SYNTHESIS: The search identified 18,861 citations. A random sample of 2782 (15%) abstracts was reviewed, leading to the inclusion of 471 publications. Preliminary included publications were reviewed in full-text, resulting in the final inclusion of 188 studies. The information obtained from the included studies was linked to 127 different second-level ICF categories. Second-level categories most frequently addressed in the studies were: health services, systems, and policies; sensation of pain and structure of upper extremity; mobility of joint functions; and muscle power functions. CONCLUSIONS: The ICF provides a valuable reference to systematically analyze the content of published studies on hand conditions. Research activity needs to widen its focus on mental functions, further mobility functioning, self-care, and domestic life aspects, as well as environmental factors to encompass the impact of hand conditions on an individual's health. This would increase our knowledge on patients' needs and would help to ensure patient-oriented care. PMID- 21658679 TI - A brief history of postpolio syndrome in the United States. AB - This is an overview of the history of the late effects of polio in this country from 1980 to the present in the context of the broader and much longer history of acute poliomyelitis. Books, articles, conference proceedings, and other relevant historical resources that dealt with polio-related issues from January 1, 1980, through December 31, 2009, were reviewed. The mean number of articles published per year was calculated for 5-year intervals beginning in 1980; the number of postpolio support groups and polio-dedicated clinics was compiled from directories published annually by Post-Polio Health International at 5-year intervals from 1985 to 2010. Beginning in the mid-1980s, the number of articles published each year increased dramatically, peaking during the years 1995 to 1999 when a mean of 48.2 articles were published each year. This figure steadily declined over the next 14 years. Support groups and clinics showed a similar pattern of rise and fall, with a maximum of 298 support groups and 96 clinics in 1990 and a decline to 131 and 32, respectively, by 2010. During the 1980s and early 1990s, there was a period of optimism that energized research, clinical, and self-help initiatives. As the limits of these efforts became apparent during the late 1990s and early 2000s, resources and activities declined as the postpolio community continued to age and decrease in size. Regardless of these trends, there are still thousands of survivors who continue to require skilled physiatric management as they cope with advancing age and declining function. PMID- 21658680 TI - The impact of a stress induction task on tic frequencies in youth with Tourette Syndrome. AB - Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics. Tic fluctuations are common and thought to be attributable in part, to contextual variables. Stress is one such variable, but its effects and mechanism of action are poorly understood. The current study measured the effects of a stress induction task on tic frequencies during periods of suppression and non-suppression of tics. Ten youth with TS between the ages of 9 and 17 were exposed to four conditions in random sequence: free-to-tic baseline (BL), reinforced tic suppression (SUP), reinforced tic suppression plus a stress induction task (SUP + STRESS), and a stress induction task alone (STRESS). Tic frequencies did not differ during STRESS and BL. Tic frequencies were greater in SUP + STRESS than SUP. Stress may impact tics through disrupting suppression efforts. Clinically, results suggest that interventions designed to improve tic inhibition in the presence of acute stressors may be beneficial. PMID- 21658681 TI - The adaptive pattern of the auditory N1 peak revealed by standardized low resolution brain electromagnetic tomography. AB - The N1 peak in the late auditory evoked potential (LAEP) decreases in amplitude following stimulus repetition, displaying an adaptive pattern. The present study explored the functional neural substrates that may underlie the N1 adaptive pattern using standardized Low Resolution Electromagnetic Tomography (sLORETA). Fourteen young normal hearing (NH) listeners participated in the study. Tone bursts (80 dB SPL) were binaurally presented via insert earphones in trains of 10; the inter-stimulus interval was 0.7s and the inter-train interval was 15s. Current source density analysis was performed for the N1 evoked by the 1st, 2nd and 10th stimuli (S(1), S(2) and S(10)) at 3 different timeframes that corresponded to the latency ranges of the N1 waveform subcomponents (70-100, 100 130 and 130-160 ms). The data showed that S(1) activated broad regions in different cortical lobes and the activation was much smaller for S(2) and S(10). Response differences in the LAEP waveform and sLORETA were observed between S(1) and S(2), but not between the S(2) and S(10). The sLORETA comparison map between S(1) and S(2) responses showed that the activation was located in the parietal lobe for the 70-100 ms timeframe, the frontal and limbic lobes for the 100-130 ms timeframe, and the frontal lobe for the 130-160 ms timeframe. These sLORETA comparison results suggest a parieto-frontal network that might help to sensitize the brain to novel stimuli by filtering out repetitive and irrelevant stimuli. This study demonstrates that sLORETA may be useful for identifying generators of scalp-recorded event related potentials and for examining the physiological features of these generators. This technique could be especially useful for cortical source localization in individuals who cannot be examined with functional magnetic resonance imaging or magnetoencephalography (e.g., cochlear implant users). PMID- 21658682 TI - Transplantation of artificial neural construct partly improved spinal tissue repair and functional recovery in rats with spinal cord transection. AB - Delivery of cellular and/or trophic factors to the site of injury may promote neural repair or axonal regeneration and return of function after spinal cord injury. Engineered scaffolds provide a platform to deliver therapeutic cells and neurotrophic molecules. To explore therapeutic potential of engineered neural tissue, we generated an artificial neural construct in vitro, and transplanted this construct into a completely transected spinal cord of adult rats. Two months later, behavioral analysis showed that the locomotion recovery was significantly improved compared with control animals. Immunoreactivity against microtubule associated protein 2 (Map2) and postsynaptic density 95 (PSD95) demonstrated that grafted cells had a higher survival rate and were able to differentiate toward neuronal phenotype with ability to form synapse-like structure at the injury site; this was also observed under the electron microscope. Immunostaining of neurofilament-200 (NF-200) showed that the number of nerve fibers regrowing into the injury site in full treatment group was much higher than that seen in other groups. Furthermore, Nissl staining revealed that host neuron survival rate was significantly increased in rats with full treatments. However, there were no biotin dextran amine (BDA) anterograde tracing fibers crossing through the injury site, suggesting the limited ability of corticospinal tract axonal regeneration. Taken together, although our artificial neural construct permits grafted cells to differentiate into neuronal phenotype, synaptogenesis, axonal regeneration and partial locomotor function recovery, the limited capacity for corticospinal tract axonal regeneration may affect its potential therapy in spinal cord injury. PMID- 21658683 TI - Improving memory and decreasing cognitive impairment in Tg-APPswe/PSEN1dE9 mice with Abeta3-10 repeat fragment plasmid by reducing Abeta deposition and inflammatory response. AB - The present study aimed to investigate the effects of Abeta3-10 repeat fragment plasmid for the treatment of Tg-APPswe/PSEN1dE9 (Tg) mice. The plasmid pcDNA3.1 (Abeta3-10)10-CpG was constructed and intramuscularly injected into 12-month-old Tg mice. Through the use of behavioral tests, anti-Abeta antibody and Abeta assays, cytokine assay, Abeta deposition, and astrocytes analysis results demonstrated that Abeta3-10 repeat fragment plasmid exhibited immunogenicity and reduced memory impairment in Tg mice via clearance of cerebral Abeta deposition, without significant side effects. Abeta3-10 repeat fragment plasmid immunization reduced Th1 cell-mediated immunity, secretion of interferon-gamma, and stimulation to astrocytes. These data showed that the Abeta3-10 repeat fragment plasmid improved memory and decreased cognitive impairment in Tg mice by reducing Abeta deposition and inflammatory responses. PMID- 21658684 TI - CST-II's recognition domain for acceptor substrates in alpha-(2->8)-sialylations. AB - CST-II is a bacterial sialyltransferase known for its ability to perform alpha-(2 >8)-sialylations using GM(3) related trisaccharide substrates. Previously, we probed the enzyme's substrate specificity and developed an efficient synthesis for alpha-(2->8)-oligosialosides, and we suggested that CST-II could have a very small substrate recognition domain. Here we report our full studies on CST-II's recognition feature for acceptor substrates. The current study further demonstrates the versatility of CST-II in preparing complex oligosaccharides that contain alpha-(2->8)-oligosialyl moieties. PMID- 21658685 TI - RE: imaging of illicit drug use. PMID- 21658686 TI - Invasion of the innominate vein by a hydatid cyst. PMID- 21658687 TI - Phraseology of disk herniation: an unproductive debate. PMID- 21658688 TI - Does the insertion of a gel-based marker at stereotactic breast biopsy allow subsequent wire localizations to be carried out under ultrasound guidance? AB - AIM: To investigate whether the insertion of a gel-based marker at the time of stereotactic breast biopsy allows subsequent preoperative localization to be performed under ultrasound guidance. MATERIALS AND METHODS: One hundred consecutive women who underwent either a 10 G stereotactic vacuum-assisted breast biopsy or 14 G stereotactic core biopsy with marker placement, followed by wire localization and surgical excision were identified. All had mammographic abnormalities not initially visible with ultrasound. The method of preoperative localization was recorded and its success judged with reference to the wire position on the post-procedure films relative to the mammographic abnormality and the marker. Histopathology data were reviewed to ensure the lesion had been adequately excised. RESULTS: Eighty-three women (83%) had a successful ultrasound guided wire localization. Successful ultrasound-guided localization was more likely after stereotactic vacuum biopsy (86%) compared to stereotactic core biopsy (68%), although this did not quite reach statistical significance (p=0.06). CONCLUSION: The routine placement of a gel-based marker after stereotactic breast biopsy facilitates preoperative ultrasound-guided localization. PMID- 21658689 TI - A re-look at an old disease: a multimodality review on gout. AB - Gout, the most common form of microcrystalline arthropathy has always interested radiologists. The diagnosis of gout is primarily based on clinical and laboratory findings; however, it has well known and characteristic radiographic manifestations. Radiographs remain the examination of choice in the diagnosis of joint involvement. Plain radiographs are less sensitive to early changes in gout than other imaging techniques. Recently, magnetic resonance imaging (MRI), ultrasound (US), and computed tomography (CT) have demonstrated an increasing role in early diagnosis of gouty arthritis, for assessing the extent of soft tissue involvement and as problem-solving tools for diagnostically difficult cases. Cross-sectional imaging can also be used for guiding needle aspirations in patients with an acute attack of gout, which may simulate an infective process clinically. This pictorial review illustrates the main imaging features of gout on radiographs, MRI, CT, and ultrasound with the aim of helping the radiologist to make a confident diagnosis in radiographically typical cases and to serve as a problem-solving tool in cases that present a diagnostic dilemma. PMID- 21658690 TI - CT and CT angiography in massive haemoptysis with emphasis on pre-embolization assessment. AB - Massive haemoptysis is a respiratory emergency. Computed tomography angiography (CTA) can play a crucial role in assessing the cause and origin of the haemoptysis and directing the interventional radiologist prior to treatment. The bronchial arterial supply and to a lesser extent the non-bronchial systemic arterial supply are responsible for the majority of cases of massive haemoptysis, but uncommon causes of massive haemoptysis should be considered to avoid misdiagnosis and delayed treatment. Failure to assess the imaging appropriately prior to endovascular treatment may result in early recurrent massive haemoptysis or patient death. PMID- 21658691 TI - 64-section CT angiography in patients with critical limb ischaemia and severe claudication: comparison with digital subtractive angiography. AB - AIM: To assess the utility of 64 section multidetector computed tomography (MDCT) lower-limb angiography in the evaluation of patients with critical limb ischaemia (CLI) or severe intermittent claudication (IC) in grading disease before endovascular treatment. MATERIALS AND METHODS: Forty-one consecutive patients with CLI or severe IC were assessed using 64 section MDCT angiography. The MDCT examinations were compared with subsequent intra-arterial digital subtraction angiography (IADSA) examinations performed at the time of endovascular intervention. The MDCT and IADSA examinations were independently scrutinized by readers blinded to the results of the other imaging method. RESULTS: For arterial segments with haemodynamically significant disease (stenosis >=50%), the overall sensitivity, specificity, and accuracy of MDCT in patients with severe claudication and CLI was 99% (95% CI: 98-100%), 98% (95% CI: 97-100%) and 98% (95% CI: 97-99%), respectively. The positive predictive value (PPV) was 97% and the negative predictive value (NPV) was 99%. CONCLUSIONS: MDCT angiography is a useful tool in the assessment of patients with severe claudication and CLI and can be reliably used to grade disease severity and plan treatment. PMID- 21658692 TI - Dieulafoy lesions: rare but often overdiagnosed? Observations based upon a case of small bowel haemorrhage and a critical review of the literature. PMID- 21658693 TI - Predictors of good outcome in patients with refractory bipolar disorder after a drug or a drug and cognitive-behavioral treatment. AB - OBJECTIVE: The objective of the present research study was to analyze the variables involved in the favorable prognosis of patients with refractory bipolar disorder after a drug or a drug and cognitive-behavioral treatment. METHODS: A sample of 40 patients was divided into 2 groups: (1) combined drug plus psychoeducational and cognitive-behavioral treatment or (2) drug treatment only (control group). We used a multigroup design with repeated measures at different times (baseline, posttreatment, 6-month follow-up, and 12-month follow-up) to evaluate the following variables: age, sex, number of hospitalizations, type of treatment, mania (Young Mania Rating Scale, or YMRS) and depression (Beck Depression Index, or BDI) symptoms, subsyndromal symptoms (BDI >7; YMRS >6), global suffering index, general index of social ability, self-esteem (Rosenberg scale), inadaptation (inadaptation Scale), anxiety (State-Trait Anxiety Inventory), quality of life (Global Activity Functioning), and health (European Quality of Life Scale). We considered favorable prognosis for subjects without persistent affective symptoms (BDI <7; YMRS <6) and/or without relevant difficulties in adaptation (Inadaptation Scale <14) in a 12-month follow-up. RESULTS: A binary logistic regression showed that the type of treatment (combined therapy corresponded to better progression), the number of prior hospitalizations (fewer hospitalizations corresponded to better progression), and self-esteem (higher self-esteem corresponded to better prognosis) were statistically significant. CONCLUSIONS: The type of treatment, the number of prior hospitalizations, and the level of self-esteem were the most influencing factors for a favorable progression of refractory bipolar disorder. Differently from other studies, no significant influences of age, sex, subsyndromal symptoms, anxiety, and depression symptoms on the prognosis of refractory bipolar disorder were observed in our study. PMID- 21658695 TI - Pressure ulcer prevention, the state of the art: the contribution of Tom Defloor. PMID- 21658694 TI - Concordance between chart review and structured interview assessments of schizophrenic symptoms. AB - BACKGROUND: It is unclear whether direct structured interviews are able to capture the full range of psychopathology in schizophrenia, as is required in diagnostic assessments or clinical ratings. We examined agreement between symptom ratings derived from direct patient interviews and from review of casenotes. METHODS: The study sample comprised 1021 schizophrenic subjects collected as part of the Irish Case-Control Study of Schizophrenia. Diagnostic interviews used a modified version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Symptoms were rated by the interviewer. In addition, the Casenote Rating Scale was used to rate symptoms based on medical record information. For each negative and positive symptom, we calculated the Pearson correlation between the interview and the casenote rating. Using the mean of the interview and casenote rating for each symptom, exploratory factor analysis using Varimax rotation was performed. RESULTS: Three factors were extracted in factor analysis: positive, negative, and Schneiderian symptoms. The highest correlations between interview and casenote ratings were for negative symptoms, in which all symptoms were significantly correlated. Positive and Schneiderian symptoms were significantly correlated with the exception of thought insertion, thought withdrawal, voices speaking in sentences, and somatic hallucinations. Significant correlations were generally moderate (0.2-0.55). CONCLUSION: Most schizophrenic symptoms, especially negative symptoms, can be assessed by direct interviews as the sole source of information with moderate reliability. However, the presence of some Schneiderian and possibly less prevalent positive symptoms may be difficult to determine without a review of records, which may include longitudinal observations and information from multiple observers. PMID- 21658696 TI - Molecular dynamics simulations of pore formation dynamics during the rupture process of a phospholipid bilayer caused by high-speed equibiaxial stretching. AB - Rupture of a phospholipid bilayer under mechanical stresses is triggered by pore formation in an intact bilayer. To understand the molecular details of the dynamics of pore formation we perform molecular dynamics simulations of a phospholipid bilayer under two different equibiaxial stretching conditions: first, unsteady stretching with various stretching speeds in the range of 0.1 1.0m/s, and second, quasistatic stretching. We analyze (i) patterns of pore formation, (ii) the critical area where a pore forms, (iii) the deformation of the bilayer, and (iv) the apparent breaking force. With stretching, the bilayer deforms anisotropically due to lipid chain packing and water penetrating into the hydrophilic region of the bilayer, and when the area exceeds a critical value, water filled pore structure penetrating the bilayer forms and develops into a large pore, resulting in rupture. For a high stretching speed, small pores (multipore) can temporarily form in a small area. It has been statistically determined that the probability of the multipore formation, the critical areal strain, and the apparent breaking force increase with the stretching speed in the range of 0-50%, 0.8-2.0, and 250-400 pN, respectively. The results qualitatively agree with the experimental and other simulation results, and rationalize the leakage of hemoglobin from erythrocytes in shock wave experiments. PMID- 21658697 TI - Skin-fixed scapula trackers: a comparison of two dynamic methods across a range of calibration positions. AB - The aim of this study was to establish the optimal methodology for skin-fixed measurement of the scapula during dynamic movement. This was achieved by comparing an optimally positioned Scapula Tracker device (ST) to a previously described palpation device, taken as the true measure of scapular kinematics. These measurements were compared across a range of calibration positions, including the use of multiple calibration positions for a single movement, in order to establish an optimal calibration approach. Ten subjects' scapular motion was measured using this ST and a previously described Acromial Method (AM). The two datasets were compared at a standard, an optimal and a 'multiple' calibration position, thus allowing a direct comparison between two common skin-fixed methods to track the bony kinematics of the scapula across different calibration positions. A comparison was also made with a bone-fixed technique from the literature. At both the standard and optimal calibration positions the ST was shown to be the more accurate measure of internal rotation and posterior tilt, particularly above 100 degrees of humerothoracic elevation. The ST errors were found to be acceptable in relation to clinically important levels. Calibration positions have been shown to have a significant effect on the errors of both skin fixed measurement techniques and therefore the importance of correct calibration is highlighted. It has thus been shown that a ST can be used to accurately quantify scapular motion when appropriately calibrated for the range of motion being measured. PMID- 21658698 TI - Use of isopycnic plots in designing operations of supercritical fluid chromatography: II. The isopycnic plots and the selection of the operating pressure-temperature zone in supercritical fluid chromatography. AB - In SFC, the key chromatographic parameters, the retention factors and the column efficiency, strongly depend on the density of the mobile phase. This indicates that the isodensity or isopycnic plots, drawn on the pressure-temperature plane, can provide an effective tool to help analyzing how the chromatograms obtained in SFC evolve, when the experimental conditions, the inlet and outlet pressures and the column temperature, are changed. In a companion paper, we analyzed the role of density in controlling the physical properties of the mobile phase, which in turn controls solute retentions and column efficiencies. In this report, we analyze the operating conditions in SFC with reference to the isopycnic plots of carbon dioxide. This analysis clarifies the differences and similarities between the operating conditions selected in the subcritical zone and those located in the supercritical zone. It also sets out an operational map illustrating how retention factors vary with respect to the operating temperatures and pressures. This study is focused on the use of pure carbon dioxide as the mobile phase, but the same method of investigation is also applicable when the mobile phase contains a modifier. PMID- 21658699 TI - Anion exchange membranes based on semi-interpenetrating polymer network of quaternized chitosan and polystyrene. AB - Anion exchange membranes with semi-interpenetrating polymer network (semi-IPN) were prepared based on quaternized chitosan (QCS) and polystyrene (PS). The PS was synthesized by polymerization of styrene monomers in the emulsion of the QCS in an acetic acid aqueous solution under nitrogen atmosphere at elevated temperatures. The semi-IPN system was formed by post-cross-linking of the QCS. A hydroxyl ionic conductivity of 2.80*10(-2) S cm(-1) at 80 degrees C and a tensile stress at break of 20.0 MPa at room temperature were reached, respectively, by the semi-IPN membrane containing 21 wt.% of the PS. The durability of the semi IPN membrane in alkaline solutions was tested by monitoring the variation of the conductivity and the mechanical strength. The degradation of the conductivity at 80 degrees C was about 5% by immersing the membrane in a 1 mol L(-1) KOH solution at room temperature for 72 h and at 60 degrees C for 50 h, respectively. The tensile stress at break at room temperature could maintain about 20.0 MPa for the membrane soaking in a 10 mol L(-1) KOH solution at ambient temperature for more than 70 h. The water swelling of the semi-IPN membranes was discussed based on the stress relaxation model of polymer chains, and it obeyed the Schott's second order swelling kinetics. PMID- 21658700 TI - Variable on-demand release function of magnetoresponsive hybrid capsules. AB - Magnetoresponsive hybrid capsules formed with polyelectrolytes, amphiphile bilayers and Fe(3)O(4) nanoparticles were fabricated by a colloid-templating technique. Melamine-formaldehyde (MF) core particles with polyelectrolyte multilayer shell were prepared by layer-by-layer assembly. Fe(3)O(4) nanoparticles were additionally deposited on the capsular surface. Hollow capsules were obtained by the removal of the MF core particles. Amphiphile bilayer was finally coated on the obtained hollow capsules. The deposition amount of the Fe(3)O(4) nanoparticles is variable by changing the concentration of Fe(3)O(4) dispersion using for preparation of capsules. Encapsulated dyes were released on-demand by irradiation with an alternating magnetic field, due to a phase transition in the amphiphile membrane, induced by heating of the magnetic nanoparticles. The release rate of the hybrid capsules was controllable through controlling the deposition amount of Fe(3)O(4) nanoparticles on the capsules. PMID- 21658702 TI - Shear-induced coalescence of oil-in-water Pickering emulsions. AB - This work reports on coalescence in oil-in-water Pickering emulsions subjected to simple shear flow. The emulsions were stabilized by silanized fumed silica particles forming layers a few hundred nanometers thick around drops that are tens of micrometers in size. The drop size and particle concentration in the emulsions were fixed, while the salt concentration was varied to adjust the colloidal interactions between the drops and particles. At rest the oil drops do not coalesce. The susceptibility of the drops to orthokinetic coalescence was found to depend on the extent of particle flocculation in the attached particle layer. The evolution of the drop size with time and shear rate was consistent with phenomenological models used to describe the behavior of emulsions under shear. PMID- 21658701 TI - Supramolecular assembled nanogel made of mannan. AB - The supramolecular assembly of amphiphilic mannan, synthesized by the Michael addition of hydrophobic 1-hexadecanethiol to vinyl methacrylated mannan, originates in aqueous medium the formation of a nanogel, stabilized by hydrophobic interactions among alkyl chains. The critical aggregation concentration, calculated by fluorescence spectroscopy ranged between 0.002 and 0.01 mg/mL, depending on the polymer degree of substitution. The cryo-field emission scanning electron microscopy showed spherical macromolecular micelles with diameters between 100 and 500 nm. The dynamic light scattering analysis revealed a polydisperse colloidal system, with mean hydrodynamic diameter between 50 and 140 nm, depending on the polymer degree of substitution. The nanogel is negatively charged, stable over a 6 months storage period, and stable at pH 3-8, salt or urea solutions. Bovine serum albumin and curcumin were spontaneously incorporated in the nanogel, being stabilized by the hydrophobic domains, opening the possibility for future applications as potential delivery systems for therapeutic molecules. In vitro assays were carried out to characterize the biocompatibility of the nanogel. A toxic effect of mannan-C(16) was observed, specific to mouse macrophage-like cell line J774, not affecting mouse embryo fibroblast cell line 3T3 viability. PMID- 21658703 TI - The influence of acid demineralization on surface characteristics of black carbon and its sorption for pentachlorophenol. AB - Acid treatment is a routine demineralization process to obtain black carbon (BC), but there has been little systematic research about its influence on BC's characteristics. In this study, elemental analysis, SEM, FTIR, and Boehm titration were used to investigate that effect. Our results showed that the acid treatment had little influence on the sorption of fly ash and soot to pentachlorophenol (PCP), but it greatly increased the sorption of rice chars to PCP. There were two competing effects of acid demineralization on the adsorption capacity of BC. On one hand, it increased the amount of the acidic functional groups, which decreased the adsorption capacity. On the other hand, it increased the surface and pore volume of BC and caused the emergence of hidden carbon enclosed by minerals, which in turn increased the sorptivity significantly. Especially for rice chars (600 degrees C), after acid treatment, their surface area increased from 3.52 to 235 m(2) g(-1) and the sorption capacity coefficient increased from 2.12 to 4.10. PMID- 21658704 TI - Effect of chain length of self-assembled monolayers in dip-pen nanolithography using molecular dynamics simulations. AB - The pattern transfer mechanism of an alkanethiol self-assembled monolayer (SAM) with different chain lengths during the dip-pen nanolithography (DPN) process and pattern characterizations are studied using molecular dynamics (MD) simulations. The mechanisms of molecular transference, alkanethiol meniscus characteristics, surface adsorbed energy, transfer number, and pattern formation are evaluated during the DPN process at room temperature. The simulation results clearly show that the molecular transfer ability in DPN is strongly dependent on the chain length. Shorter molecules have significantly better transport and diffusion abilities between the meniscus and substrate surface, and the transport period can be maintained longer. The magnitude of adsorbed energy increases with chain length, so many more molecules can be transferred to the surface when shorter molecules are used. After deposition, the magnitude of the adsorbed area and pattern height decrease with increasing chain length. PMID- 21658705 TI - Effect of alkyl chain length, head group and nature of the surfactant on the hydrolysis of 1,3-benzoxazine-2,4-dione and its derivatives. AB - The alkaline hydrolysis of carsalam (2H-1,3-benzoxazine-2,4(3H)-dione), denoted as I, and its N-substituted derivatives i.e., N-methyl-1,3-benzoxazine-2,4-dione (II) and N-benzoyl-1,3-benzoxazine-2,4-dione (III) was studied spectrophotometrically at physiological temperature. The rate of hydrolysis was found to be independent on the substrate concentration. In case of I, the reaction was fractional order with respect to [OH(-)] while for II and III, reaction obeyed the first order kinetics. Effect of cationic surfactants with varying hydrophobic chains (cetyltrimethylammonium bromide, CTAB, tetradecyltrimethylammonium bromide, TTAB and dodecyltrimethylammonium bromide, DTAB) and with different head-group (cetyl pyridinium chloride, CPC) and anionic surfactant (sodium dodecyl sulfate, SDS) was also seen on the rate of alkaline hydrolysis of the carsalam and its derivatives. Cationic surfactants first catalyzed the rate of hydrolysis at lower concentrations followed by the inhibition at higher concentrations. The length of the alkyl chain had remarkable effect on the catalytic efficiency of the surfactants. Similarly N-substitution on substrate also increased the catalysis by micelles. The anionic surfactant SDS inhibited the rate of hydrolysis at all of the concentrations studied. The catalysis by cationic micelles followed by inhibition was treated in terms of the pseudophase ion-exchange model, while for the inhibition by SDS micelles the Menger-Portnoy model was used to fit the data. The effect of salts (NaCl, NaBr and (CH(3))(4)NBr) was also seen on the hydrolysis of II and it was found that all salts inhibited the rate of reaction. The inhibition follows the trend NaCl= 6 milliseconds). Under the conditions defined in this model that did not consider myocardial infarction, the presence of initial anteriorly oriented electrical forces was indicative of preserved conduction in the left bundle and of impaired conduction in LV working myocardium. CONCLUSION: The elucidation of the participation of working myocardium impairment in the intraventricular conduction delay in the LV could be of vital significance for the clinical management of patients with LBBB patterns, for example, indicated for resynchronization therapy. PMID- 21658711 TI - The evaluation of an electrocardiographic myocardial ischemia acuteness score to predict the amount of myocardial salvage achieved by early percutaneous coronary intervention Clinical validation with myocardial perfusion single photon emission computed tomography and cardiac magnetic resonance. AB - BACKGROUND: The time from symptom onset to reperfusion in acute myocardial infarction (MI) has been shown to be a poor predictor of patient outcome. Acute electrocardiographic (ECG) changes, however, have been shown useful for estimated acuteness of myocardial ischemia using the Anderson-Wilkins ECG ischemia acuteness score (AW-acuteness score). The aim was to study whether acute ischemic ECG changes can predict the amount of salvageable myocardium in patients with acute ST-elevation MI. METHODS: Thirty-eight patients treated with primary percutaneous coronary intervention for first-time ST-elevation MI were retrospectively enrolled. Myocardium at risk (MaR) was determined by myocardial perfusion single photon emission computed tomography acutely or by T2-weighted cardiac magnetic resonance after 1 week, at the same time when final MI size was determined by late gadolinium enhancement. Myocardial salvage was calculated as (MaR - MI size)/MaR and compared with AW-acuteness score and time from symptom onset to primary percutaneous coronary intervention. RESULTS: The AW-acuteness score correlated significantly with salvageable myocardium for right coronary artery (RCA) occlusions (r = -0.57; P = .02) but not for left anterior descending artery (LAD) occlusions (r = -0.04; P = .88). Time from symptom onset did not correlate with the amount of salvageable myocardium (LAD, r = 0.04 and P = .87; RCA, r = -0.40 and P = .13). CONCLUSIONS: There is a moderate correlation between AW-acuteness score and salvageable myocardium in patients with acute RCA occlusion but not in patients with LAD occlusion. PMID- 21658713 TI - National profile of children with Down syndrome: disease burden, access to care, and family impact. AB - OBJECTIVE: To measure the co-morbidities associated with Down syndrome compared with those in other children with special health care needs (CSHCN). Additionally, to examine reported access to care, family impact, and unmet needs for children with Down syndrome compared with other CSHCN. STUDY DESIGN: An analysis was conducted on the nationally representative 2005 to 2006 National Survey of Children with Special Health Care Needs. Bivariate analyses compared children with Down syndrome with all other CSHCN. Multivariate analyses examined the role of demographic, socioeconomic, and medical factors on measures of care receipt and family impact. RESULTS: An estimated 98,000 CSHCN have Down syndrome nationally. Compared with other CSHCN, children with Down syndrome had a greater number of co-morbid conditions, were more likely to have unmet needs, faced greater family impacts, and were less likely to have access to a medical home. These differences become more pronounced for children without insurance and from low socioeconomic status families. CONCLUSIONS: Children with Down syndrome disproportionately face greater disease burden, more negatively pronounced family impacts, and greater unmet needs than other CSHCN. Promoting medical homes at the practice level and use of those services by children with Down syndrome and other CSHCN may help mitigate these family impacts. PMID- 21658712 TI - Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. AB - OBJECTIVE: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities. STUDY DESIGN: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities. RESULTS: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1). CONCLUSION: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis. PMID- 21658714 TI - Cot-side electroencephalography monitoring is not clinically useful in the detection of mild neonatal hypoglycemia. AB - OBJECTIVES: To determine whether there is a relationship between electroencephalography patterns and hypoglycemia, by using simultaneous cot-side amplitude integrated electroencephalography (aEEG) and continuous interstitial glucose monitoring, and whether non-glucose cerebral fuels modified these patterns. STUDY DESIGN: Eligible babies were >= 32 weeks gestation, at risk for hypoglycemia, and admitted to the neonatal intensive care unit. Electrodes were placed in C3-P3, C4-P4 O1-O2 montages. A continuous interstitial glucose sensor was placed subcutaneously, and blood glucose was measured by using the glucose oxidase method. Non-glucose cerebral fuels were measured at study entry, exit, and during recognized hypoglycemia. RESULTS: A total of 101 babies were enrolled, with a median weight of 2179 g and gestation of 35 weeks. Twenty-four of the babies had aEEG recordings, and glucose concentrations were low (< 2.6 mM). There were 103 episodes of low glucose concentrations lasting 5 to 475 minutes, but no observable changes in aEEG variables. Plasma concentrations of lactate, beta hydroxybutyrate, and glycerol were low and did not alter during hypoglycemia. CONCLUSIONS: Cot-side aEEG was not useful for the detection of neurological changes during mild hypoglycemia. Plasma concentrations of non-glucose cerebral fuels were low and unlikely to provide substantial neuroprotection. PMID- 21658715 TI - Surfactant deficiency in transient tachypnea of the newborn. AB - OBJECTIVE: To evaluate surfactant production and function in term neonates with transient tachypnea of the newborn (TTN). STUDY DESIGN: Samples of gastric aspirates collected within 30 minutes of birth from 42 term newborns with gestational age >= 37 weeks (21 patients with TTN and 21 control subjects), delivered via elective cesarean delivery, were analyzed with lamellar body count and stable microbubble test. RESULTS: Results of lamellar body counts and stable microbubble tests were significantly lower in the TTN group than in control subjects (P = .004 and .013, respectively). Lamellar body counts were significantly lower in infants with TTN requiring oxygen for >= 24 hours after birth than in infants requiring oxygen for < 24 hours (P = .029). When the cutoff point was 48 hours, the stable microbubble count was significantly lower in the group requiring oxygen for >= 48 hours than in the group requiring oxygen for < 48 hours (P = .047). CONCLUSIONS: Term infants with TTN had low lamellar body counts associated with decreased surfactant function, suggesting that prolonged disease is associated with surfactant abnormalities. PMID- 21658716 TI - Evaluation of miglustat treatment in patients with type III mucopolysaccharidosis: a randomized, double-blind, placebo-controlled study. AB - OBJECTIVE: To evaluate the efficacy and safety of oral miglustat treatment in patients with mucopolysaccharidosis type III. The primary outcome was efficacy with improvement or stabilization in at least two domains of Vineland Adaptative Behavior Scales at 6 months. The secondary outcome measured the evolution of other cognitive tests at 12 months. The safety and tolerability were assessed throughout the study. STUDY DESIGN: This was a randomized, double-blind, placebo controlled, monocenter, institutional, phase IIb to III study. In case of efficacy at 6 months, the study would go on for another 6 months on an open design with all patients receiving miglustat. In the absence of efficacy at 6 months, the trial had to be continued for 6 more months with the initial design. RESULTS: After 6 months, efficacy was not superior in patients with miglustat. The independent review board confirmed continuing the study until 12 months. CONCLUSION: Miglustat treatment was not associated with any improvement/stabilization in behavior problems in patients with mucopolysaccharidosis type III. Miglustat has an acceptable safety profile. However, the study has confirmed that miglustat is able to pass through the blood brain barrier without significantly decreasing ganglioside levels. PMID- 21658717 TI - The impact of killing and injuring others on mental health symptoms among police officers. AB - This study examined the relationship between killing or seriously injuring someone in the line of duty and mental health symptoms in a sample of police officers (N = 400) who were first assessed during academy training and at five additional time points over three years. We found that nearly 10% of police officers reported having to kill or seriously injure someone in the line of duty in the first three years of police service. After controlling for demographics and exposure to life threat, killing or seriously injuring someone in the line of duty was significantly associated with PTSD symptoms (p < .01) and marginally associated with depression symptoms (p = .06). These results highlight the potential mental health impact of killing or seriously injuring someone in the line of duty. Greater attention to mental health services following these types of exposures can serve as a preventative measure for police officers who have been negatively impacted. PMID- 21658719 TI - Prediction of indocyanine green retention rate at 15 minutes by correlated liver function parameters before hepatectomy. AB - BACKGROUND: Indocyanine green retention rate at 15 min (ICGR15) is a useful marker of liver function in deciding on the extent of hepatectomy. To determine ICGR15 regardless of liver condition, we sought to establish a formula for converted ICGR15 based on conventional blood tests and technetium-99 m galactosyl human serum albumin ((99m)Tc-GSA) scintigraphy. MATERIALS AND METHODS: We measured liver function parameters, including ICGR15, in 307 patients, including 265 liver cancer patients without biliary obstruction (no obstruction group) and 42 with biliary obstruction (obstruction group). RESULTS: In the no obstruction group, multiple regression analysis identified blood pool clearance ratio (HH15), liver uptake ratio (LHL15) calculated by heart and liver activity between 3 and 15 min after injection of (99m)Tc-GSA, and serum hyaluronic acid as significant correlates (P < 0.05). The calculated converted ICGR15 was then equal to 0.02*HA + 0.276*(HH15*100)-0.501*(LHL15*100) + 41.41. The mean difference between actual and converted ICGR15 was significantly lower in the obstruction than in the no obstruction group (P = 0.031). A significantly larger proportion of patients of the obstruction group had lower converted ICGR15 than those of the no obstruction group (P = 0.045). CONCLUSION: The converted ICGR15 is useful for evaluating hepatic function in patients with biliary obstruction who plan to undergo major hepatectomy. PMID- 21658718 TI - EGFR inhibition fails to suppress vascular proliferation and tumor growth in a Ewing's sarcoma model. AB - BACKGROUND: Expression of epidermal growth factor receptor (EGFR), a potent regulator of cellular homeostasis, is associated with aggressive tumor behavior. The mechanism by which EGFR inhibition functions is unclear, with controversial results demonstrating an effect on the tumor cells, endothelial cells, or pericytes. EGFR activation has been linked to the expression of vascular endothelial growth factor (VEGF), a known mitogen of angiogenesis, but the relationship between these factors and their effect on tumor vessel development is vague. We hypothesized that using an EGFR inhibitor on a human Ewing's sarcoma model would inhibit tumor growth by suppressing vessel proliferation. METHODS: A cell proliferation assay was performed on the Ewing's sarcoma (SK-NEP-1) cell line. Tumor cells were implanted intrarenally in athymic mice. Animals received daily gavage with vehicle or gefitinib 1 wk following implantation. Mice (n = 12/cohort) were euthanized 6 wk following implantation. Remaining mice were maintained without treatment for 2 wk. Vascular changes were assessed by angiography and immunohistochemically. EGFR and vascular endothelial growth factor (VEGF) expression were quantified using quantitative polymerase chain reaction (qPCR). RESULTS: Gefitinib suppressed in vitro cell growth with an IC(50) = 1.36 MUM. Minimal tumor growth suppression was noted at 6 wk (6.01 +/- 1.2 g in control versus 4.61 +/- 0.9 g treated, P = 0.36). After cessation of gefitinib, tumor growth was increased in both groups (7.37 +/- 1.62 g versus 6.77 +/- 1.53 g, P = 0.79). Microvessel density was unchanged despite EGFR inhibition (161,000 +/- 16,000 pixels versus 135,000 +/- 18,000 pixels, P = 0.31). At 6 wk, the vascular maturity index was similar in both groups (3.63 +/- 1.12 versus 4.09 +/- 1.71, P = 0.83). A downward trend in EGFR expression (49% of control) and an upward trend in VEGF levels (50% of control) occurred in the treated group. CONCLUSIONS: EGFR expression was suppressed in cultured cells and xenograft tumors. Despite a cytotoxic effect on cell lines, gefitinib had little effect on tumor growth. No effects on the tumor vasculature were noted in the setting of EGFR suppression, suggesting that angiogenesis induced by SK-NEP-1 cells is refractory to EGFR inhibition. Interestingly, the resulting increase in VEGF expression following EGFR blockade, provides an alternative pro-angiogenic pathway promoting tumor survival. PMID- 21658720 TI - Chronology of the effect of massive small bowel resection and hepatocyte growth factor (HGF) on intestinal adaptation. AB - BACKGROUND: We previously demonstrated that hepatocyte growth factor (HGF) increases mucosal protein and DNA content at single time points during intestinal adaptation in rats. This study evaluates mucosal changes after massive small bowel resection (MSBR) and with the addition of IV HGF measured over the timeframe of intestinal adaptation. METHODS: Sixty adult female Sprague-Dawley rats were divided into three groups and underwent massive small bowel resection (MSBR), MSBR+HGF (intravenous 150 mg/kg/d), or sham operation (control). Five animals per group were sacrificed at 7, 14, 21, and 28 d. Ileal mucosa was harvested and DNA and protein extracted. DNA content (ug/mg mucosa) was measured at 260 nm and protein content (ug/mg mucosa) was measured using the Bradford assay. MIB-5 immunohistochemical staining was done to confirm that the increased DNA content was due to proliferation. Statistical analysis was by ANOVA with post hoc Tukey's HSD test. RESULTS: At 7 and 14 d, protein concentration was increased following HGF administration in comparison to MSBR alone and in control rats (P<0.05 and P<0.03, respectively). Mucosal DNA content in the MSBR-HGF rats was significantly increased over MSBR and control groups at 21 and 28 d (P<0.02 and P<0.004, respectively). MIB-5 immunohistochemical staining correlated with mucosal DNA content at 21 and 28 d (P<0.0005 and P<0.002, respectively). CONCLUSIONS: The mucosal response to MSBR for the period 7-14 d after surgery demonstrates that protein content is increased due to an emphasis on hypertrophy, whereas at 21-28 d hyperplasia is the primary change as demonstrated by the increase in DNA content. This response was enhanced by HGF. This is the first demonstration correlating the bimodal gene response during intestinal adaptation to the bimodal mucosal response. Also, this is the first demonstration of a biphasic response by the mucosa to HGF during intestinal adaptation. PMID- 21658721 TI - Hypercalcemic crisis in the era of targeted parathyroidectomy. AB - BACKGROUND: Hypercalcemic crisis patients are appropriately treated by expeditious parathyroidectomy. Previous studies have suggested that crisis patients may have lower operative success rates compared to non-crisis patients. This study reviews the outcomes for hypercalcemic crisis in the era of targeted parathyroid surgery. METHODS: The records of 839 patients with primary hyperparathyroidism who underwent parathyroidectomy at a single institution from 1993 to 2009 were reviewed. From this group, 34 patients were surgically treated for hypercalcemic crisis, defined as having signs and symptoms of acute calcium intoxication and serum calcium levels>=14 mg/dL. All patients underwent parathyroidectomy guided by preoperative localization studies and intra-operative PTH hormone monitoring (IPM). Pre- and postoperative symptoms and laboratory values and rates of operative failure and recurrence were compared to 805 patients without crisis. RESULTS: Mean preoperative serum calcium (15.8 versus 11.6 mg/dL) and parathyroid hormone (PTH) (719 versus 175 pg/mL) levels were significantly higher among patients presenting with hypercalcemic crisis (P<0.0001). Postoperatively, the mean calcium and PTH levels were similar (9.4 versus 9.4 mg/dL, P=0.7) and (82 versus 51 pg/mL, P=0.1), respectively. Alteration in mental status as a presenting symptom was significantly more prevalent among those in crisis (24% versus 3%, P<0.0001), as was pancreatitis (6% versus 0.2%, P=0.001). The crisis patients were more likely to have an ectopic gland in the mediastinum (15 versus 2%, P<0.0001), significantly larger glands (2.4 versus 1.8 cm, P=0.001), and parathyroid carcinoma (6% versus 0.3%, P=0.015). Crisis patients had similar rates of operative success 34/34 (100%), compared with 787/805 (97.8%) non-crisis patients (P=0.9). There was no difference in recurrence rates (3% versus 1.4%, P=0.3). Mean overall follow-up was 36 mo. CONCLUSION: Despite presenting with more ectopic glands and parathyroid cancer, crisis patients have similar parathyroidectomy success rates compared with non-crisis patients. The high rate of success in the era of targeted parathyroidectomy may be due to the widespread use of localization studies and IPM. PMID- 21658723 TI - Influence of biliary drainage on the repair of hepatic lesions in biliary fibrosis. AB - BACKGROUND: Bilioduodenal (BD) and biliojejunal (BJ) derivation induce enterobiliary reflux and bile stasis. Decompression of the excluded loop of the Roux-en-Y (BJD) was proposed to minimize these effects. The aim of this study was to compare the influence of these three modalities of biliary bypass on hepatic lesion repair in rats with secondary biliary fibrosis. MATERIALS AND METHODS: Rats with 15 d of biliary obstruction underwent BD, BJ, and BJD drainage and were compared with a group submitted to simulated operation (SO) and biliary obstruction (CBO). The serum values of total and fractional bilirubin, alkaline phosphatase (ALP), and aminotransferases (AST and ALT), as well as hepatobiliointestinal excretion determined with (99m)Tc-Disida, were used for comparison. In addition, we used morphometric analyses to estimate the mass of the hepatocytes, bile ducts, and liver fibrosis. We also counted hepatic stellate cells (SC). RESULTS: For each of the three modalities of biliary drainage, there were significant reductions in bilirubin, AST, ALP, and the number of SCs. The recovery of the estimated mass of all histologic components occurred only after BJ and BJD; in the BD group, the estimated hepatocyte mass was reduced compared with the SO group. The residual hepatic radioactivity of (99m)Tc-Disida was greater in the BJD group than in the SO group. CONCLUSIONS: The interposition of the jejunal loop between the biliary tree and the intestine may slow hepatobiliary clearance of radioactivity, even though it provides the resolution of cholestasis and is effective in recovering from hepatic lesions. PMID- 21658722 TI - Peritrocal and intraperitoneal ropivacaine for laparoscopic cholecystectomy: a prospective, randomized, double-blind controlled trial. AB - BACKGROUND: The goal of this study was to evaluate the effect of peritrocal, intraperitoneal, or combined peritrocal-intraperitoneal ropivacaine on the parietal, visceral, and shoulder tip pain after laparoscopic cholecystectomy. METHODS: Eighty patients were randomly assigned to four groups. Group A received peritrocal and intraperitoneal saline. Group B received peritrocal saline and intraperitoneal ropivacaine. Group C received peritrocal ropivacaine and intraperitoneal saline. Group D received peritrocal and intraperitoneal ropivacaine. The parietal, visceral, and shoulder tip pain were assessed at 2, 4, 8, 12, 24, and 48 h postoperatively using a visual analog scale (VAS). The frequency of the patient pushing the button of the PCA and fentanyl use were also recorded. RESULTS: In visceral pain, significantly lower VAS scores were observed in Group B from 2 to 4 h and in Group D from 2 to 8 h. In parietal pain, significantly lower VAS scores were observed in Group C from 4 to 24 h and in Group D from 2 to 12 h. In shoulder tip pain, significantly lower VAS scores were observed in Group B from 4 to 48 h and in Group D from 2 to 12 h. The fentanyl use and the frequency to push the button of the PCA were the highest in Group A and the lowest in Group D at every time point. CONCLUSIONS: We conclude that peritrocal infiltration of ropivacaine significantly decreases parietal pain and intraperitoneal instillation of ropivacaine significantly decreases the visceral and shoulder tip pain. Their effects are additive with respect to the total pain. PMID- 21658725 TI - DITPA, a thyroid hormone analog, reduces infarct size and attenuates the inflammatory response following myocardial ischemia. AB - BACKGROUND: Thyroid hormone can have positive effects on the cardiovascular system but its therapeutic potential is limited secondary to its adverse effects. DITPA (3,5-diiodothyroproprionic acid) is a synthetic thyroid hormone analog with positive inotropic effects similar to thyroid hormone but with minimal systemic effects. DITPA has previously been shown to reduce pathologic remodeling and improve cardiac output following myocardial infarction; however, few studies have examined the role of DITPA in determining infarct size or the early inflammatory response following myocardial ischemia. We examined the role of DITPA in the acute phase following infarction. MATERIALS AND METHODS: Mice were subjected to surgical induction of myocardial infarction and were then randomized to receive daily injections of DITPA or vehicle control. After 3 d, animals were sacrificed and infarct size was determined by H and E staining. Myocardial macrophage and neutrophil accumulation was determined by immunofluorescent staining. Immunoblotting and enzyme-linked immunosorbent assay (ELISA) were used to examine the levels of intercellular adhesion molecule-1 (ICAM-1), keratinocyte-derived chemokine (KC), monocyte chemoattractant protein (MCP-1), and interleukin 6 (IL 6) in homogenates from the ischemic tissue. RESULTS: Compared with vehicle control, DITPA treated animals had smaller infarcts (52.1%+/-5.7% versus 37.3%+/ 3.6%, P<0.05) and decreased macrophage (32+/-4 versus 14+/-1 cells/HPF, P<0.05, and neutrophil (14+/-2 versus 7+/-1 cells/HPF, P<0.05) accumulation. Myocardial ICAM-1, (2.37+/-0.4 versus 1.1+/-0.2, P<0.05), KC levels (33.32+/-12.4 pg/mg, versus 21.24+/-8.9 pg/mg, P<0.05), and IL-6 levels (112.3+/-78 pg/mg versus 37.3+/-25.9 pg/mg, P<0.05) were also reduced in the DITPA treated group, while MCP-1 levels were equivalent between groups. CONCLUSIONS: Treatment with DITPA attenuates the acute inflammatory response and reduces myocardial infarct size. The reduction in myocardial ICAM-1, KC, and IL-6 levels in the DITPA group was associated with a decrease in macrophage and neutrophil accumulation. PMID- 21658724 TI - Breast MRI utilization in older patients with newly diagnosed breast cancer. AB - BACKGROUND: Recently, use of advanced imaging modalities, such as MRI, has increased dramatically. One novel but still evolving use for MRI is in the diagnosis and clinical staging of newly diagnosed breast cancer patients. Compared with mammography, MRI is more sensitive, but less specific, and far more expensive. The purpose of this study is to examine the prevalence and predictors of MRI use for clinical staging in older women with newly diagnosed breast cancer. MATERIALS AND METHODS: SEER-Medicare data were used to identify incident breast cancer cases between 2003 and 2005. Outpatient Medicare claims data were queried for receipt of breast MRI. Multivariate logistic regression analyses were performed to examine associations between receiving MRI and patient demographics, clinical characteristics, and SEER region. RESULTS: A total of 46,824 patients with breast cancer met inclusion criteria. MRI use increased from 3.9% of women diagnosed in 2003 to 10.1% of women diagnosed in 2005. In the bivariate analyses race, urban/rural location, SEER region, poverty level, education level, stage, surgery type, and tumor size were all significantly associated with receipt of MRI. In the multivariate analysis, those who were younger, white, living in more metropolitan areas, and living in wealthier areas were more likely to receive MRI. There was substantial variability in odds of MRI among different SEER regions. CONCLUSIONS: Breast MRI for patients with newly diagnosed breast cancer in the SEER-Medicare population is increasingly common. Ongoing examination of the dissemination of technology is critical to understanding current practice patterns and to the development and implementation of future guidelines. PMID- 21658726 TI - Cardiac autonomic control in patients with myasthenia gravis and thymoma. AB - OBJECTIVE: To evaluate cardiac autonomic control in patients with myasthenia gravis (MG) and thymoma. MATERIALS AND METHODS: The study was performed on 21 patients with MG and thymoma and the same number of matched healthy volunteers. Standard cardiovascular reflex tests according to Ewing and baroreflex sensitivity (BRS) at rest was applied. Spectral analysis of heart rate variability (HRV) at rest was assessed using a 20-minute ECG recording (normalized low- and high-frequency bands-LFnu-RRI, HFnu-RRI and LF/HF-RRI) Time domain analysis of HRV was derived from 24-hour ECG monitoring. RESULTS: Overall autonomic score according to Ewing was significantly increased in patients with MG and thymoma (p<0.05), mostly due to parasympathetic dysfunction. Time-domain parameters representing the overall and long-term sympathetic activity of HRV did not differ significantly between the two groups (p>0.05), but there was a significant decrease in measures of the short-term vagal variations in HRV (p<0.01). HFnu-RRI was lower, while LFnu-RRI and LF/HF-RRI were higher in patients with MG and thymoma in comparison to healthy controls but these differences were not of statistical significance (p>0.05). BRS at rest was highly significantly reduced in patients group (p<0.01). CONCLUSIONS: Our results showed mainly parasympathetic cardiac impairment in patients with myasthenia gravis and thymoma. Since autonomic dysfunction may lead to cardiac conduction abnormalities and sudden death, the investigation of autonomic nervous system function in these patients may be significant in everyday clinical practice. PMID- 21658728 TI - Neuropsychological correlates of olfactory dysfunction in Parkinson's disease. AB - Olfactory impairment is a common early non-motor manifestation in Parkinson's disease that has garnered interest as a clinical biomarker for early "pre-motor" diagnosis and prediction of associated clinical phenotypes. Whether olfactory impairment correlates well with motor symptoms is not yet clear, and recent interest has focused on the relationship between hyposmia and other non-motor symptoms. In this paper, we will review emerging evidence for a relationship between hyposmia and neuropsychiatric manifestations, discussing the potential pathophysiology together with challenges and opportunities for future research. PMID- 21658729 TI - Bioaccumulation of trace metals in the submarine hydrothermal vent crab Xenograpsus testudinatus off Kueishan Island, Taiwan. AB - The concentrations of ten trace metals were determined in the gills, muscles, hepatopancreas, and exoskeleton tissues of Xenograpsus testudinatus that lives around shallow and acidic hydrothermal vents off Kueishan Island, northeastern Taiwan. The analytical results demonstrate that the metal concentrations vary significantly with the type of crab tissue. The concentrations of Al, Cd, Co, Cu, Fe, Ni, and Zn are highest in the gills, whereas the concentration of Mn is highest in the exoskeleton. Cr and Pb concentrations are similar across the different tissues. The enhanced accumulation of most metals in the gills suggests the metal accumulation via the respiration pathway rather than the uptake of food. The results also reveal that the distribution patterns of metals in tissues are similar in the hepatopancreas and muscles, but very different in both the gills and the exoskeleton, perhaps because of the different pathways of metal utilization in the different crab tissues. PMID- 21658727 TI - Quantitative differences in the immunomodulatory effects of Rebif and Avonex in IFN-beta 1a treated multiple sclerosis patients. AB - Interferon-beta (IFN-beta) is a current effective treatment for multiple sclerosis (MS) and exerts its therapeutic effects by down-modulating the systemic immune response and cytokine signaling. In clinical practice there are several formulations of interferon including a low dose of IFN-beta 1a formulation of 30 MUg IM once weekly (Avonex) and a high dose formulation of 44 MUg SC three times weekly (Rebif). Recent studies suggest that Rebif is more efficacious compared to Avonex in preventing relapses and decreasing MRI activity in relapsing remitting MS (RRMS) patients. This study examines whether there are quantitative gene expression changes in interferon-treated RRMS patients that can explain the difference in efficacy and side effects between Rebif and Avonex. Herein, RRMS patients were treated for three months with IFN-beta 1a and the levels of plasma cytokines and gene expression in peripheral blood mononuclear cells were examined. Thirty-two normal subjects were compared to thirty-two RRMS patients, of which ten were treated with Rebif and ten with Avonex. Rebif and Avonex both significantly and equally suppressed plasma TNF-alpha and IL-6 levels. Rebif suppressed IL-13 significantly more than Avonex. Rebif also significantly suppressed the levels of the chemokines CCL17 and RANTES, the protease ADAM8, and COX-2 at a higher degree compared to Avonex. The STAT1-inducible genes IP-10 and caspase 1 were significantly increased with Rebif compared to Avonex. In conclusion, the higher dosed, more frequently administered IFN-beta 1a Rebif when compared to IFN-beta 1a Avonex has more potent immunomodulatory effects. These quantitative results might relate to efficacy and side-effect profile of the two IFN-beta 1a formulations and provide prospective practical clinical tools to monitor treatment and adjust dosage. PMID- 21658731 TI - The extent and historical trend of metal pollution recorded in core sediments from the artificial Lake Shihwa, Korea. AB - The vertical distribution of trace metals in sediment cores was investigated to evaluate the extent and the historical record of metal pollution over 30 years in the artificial Lake Shihwa in Korea. A marked increase of trace metals after 1980 was observed due to the operation of two large industrial complexes and dike construction for a reclamation project. There was a decreasing trend of metal concentrations with the distance from the pollution source. The enrichment factor and pollution load index of the metals indicated that the metal pollution was mainly derived from Cu, Zn and Cd loads due to anthropogenic activities. The concentrations of Cr, Ni, Cu, Zn, As and Pb in the upper part of all core sediments exceeded the ERL criteria of NOAA. Our results indicate that inadequate planning and management of industrialization and a large reclamation project accomplished by dike construction have continued to strongly accelerate metal pollution in Lake Shihwa. PMID- 21658730 TI - Biomarker responses in pelagic and benthic fish over 1 year following the Hebei Spirit oil spill (Taean, Korea). AB - After the Hebei Spirit oil spill incident (7th December, 2007) in the west coast of Korea, contamination of biliary PAH metabolite and hepatic biomarkers in a pelagic and a benthic fish was monitored for 1 year. Concentrations of 16 PAHs and alkylated PAHs in fish muscle were highest (22.0 ng/g d.w. for 16 PAHs and 284 ng/g d.w. for alkylated PAHs) at 5 days after the spill and then decreased rapidly to background levels at 11 months after the spill. Fish from the oiled site had elevated biliary PAH metabolite concentrations immediately after the spill; these declined steadily in both species, but were still above reference site concentrations 2 months after the spill. Oiled-site fish showed hepatic CYP 1A induction whose trend closely followed those of biliary PAH metabolite concentrations, implying continuous exposure to PAHs. Brain acetylcholinesterase activity was not related to oil exposure. PMID- 21658732 TI - Evaluations of heavy metal pollution in sediment and Mullus barbatus from the Izmir Bay (Eastern Aegean) during 1997-2009. AB - Izmir Bay is one of the great natural bays of the Mediterranean. The surface sediment and fish samples were collected during 1997-2009. The sediment concentrations of inner bay showed significant enrichments during sampling periods. Outer and middle bays exhibited low levels of metal enrichments except the estuary of Gediz River. The concentrations were generally higher than the background levels from the Mediterranean and Aegean except Cd and Pb levels gradually decreased. Metal EF is used as an index to evaluate anthropogenic influences of metals in sediments. Maximum metal enrichment was found for Hg in the outer bay, while Pb indicated maximum enrichment in the middle-inner bays. Metal levels were evaluated in sediments in accordance with the numerical SQG of the USEPA. The levels of fish tissues were lower than the results reported from polluted areas of the Mediterranean. The highest BAFs were detected for Hg and Cd in fish. PMID- 21658733 TI - [Left atrial myxoma: the great simulator]. PMID- 21658734 TI - Dispensing synthetic green leaf volatiles in maize fields increases the release of sesquiterpenes by the plants, but has little effect on the attraction of pest and beneficial insects. AB - Maize plants respond to feeding by arthropod herbivores by producing a number of secondary plant compounds, including volatile organic compounds (VOCs). These herbivore-induced VOCs are not only known to attract natural enemies of the herbivores, but they may also prime inducible defences in neighbouring plants, resulting in stronger and faster defence responses in these VOC-exposed plants. Among the compounds that cause this priming effect, green leaf volatiles (GLVs) have received particular attention, as they are ubiquitous and rapidly emitted upon damage. In this study, we investigated their effects under realistic conditions by applying specially devised dispensers to release four synthetic GLVs at physiologically relevant concentrations in a series of experiments in maize fields. We compared the VOC emission of GLV-exposed maize plants to non exposed plants and monitored the attraction of herbivores and predators, as well as parasitism of the caterpillar Spodoptera frugiperda, the most common herbivore in the experimental maize fields. We found that maize plants that were exposed to GLVs emitted increased quantities of sesquiterpenes compared to non-exposed plants. In several replicates, herbivorous insects, such as adult Diabrotica beetles and S. frugiperda larvae, were observed more frequently in GLV-treated plots and caused more damage to GLV-exposed plants than to non-exposed plants. Parasitism of S. frugiperda was only weakly affected by GLVs and overall parasitism rates of S. frugiperda were similar in GLV-exposed and non-exposed plots. The effects on insect presence depended on the distance from the GLV dispensers at which the plants were located. The results are discussed in the context of strategies to improve biological control by enhancing plant-mediated attraction of natural enemies. PMID- 21658735 TI - Ethnic differences in the health of women prisoners. AB - OBJECTIVES: The numbers of female and ethnic minority prisoners in the UK are increasing. Despite recent policy initiatives to improve both prison healthcare and the status of women and ethnic minority groups, there are few data with which to inform service development. This is the first study in the UK to examine differences in subjective health status and health behaviours between Black and White female prisoners. STUDY DESIGN: Retrospective secondary analysis of data from the Health of Women in Prison Study by the University of Oxford. The latter was a longitudinal survey. METHODS: Participants were given a questionnaire containing the Short Form 36 (SF-36) and questions about cigarette smoking, alcohol consumption, illicit drug use, physical exercise, diet, imprisonment history and ethnicity. Data from Black and White participants were compared. Physical and mental component summary scores from the SF-36 were assessed using the independent t-test for means. Differences in health behaviours between the Black and White women were assessed using a paired samples t-test for continuous variables or Chi-squared test for categorical data. RESULTS: Black women were more likely to have stayed in full-time education for longer and to have been legally employed prior to imprisonment. The average length of their current sentence was significantly higher than that for White women. Black women scored higher in general health perception, but there were no other significant differences in subjective health status. Significantly fewer Black women smoked or drank to excess, or had used drugs in the 6 months prior to imprisonment. Black women ate more healthily, but were more likely to be overweight and to have higher blood pressure than their White counterparts. Both groups, however, demonstrated poor health and health behaviours overall. CONCLUSION: Black women entering prison are more likely to be educated, employed, drug free and, in some ways, healthier than White women. However, all the prisoners, regardless of ethnicity, had poorer levels of mental and physical health than the general population; thus, a need exists for researchers and policy makers alike to examine the health of these groups within and out of prison. PMID- 21658736 TI - Characterization of enterotoxigenic E. coli (ETEC), Shiga-toxin producing E. coli (STEC) and necrotoxigenic E. coli (NTEC) isolated from diarrhoeic Mediterranean water buffalo calves (Bubalus bubalis). AB - Two hundred and twenty Escherichia coli isolates from 314 Mediterranean water buffalo calves less than 4 weeks old affected by severe diarrhoea with a lethal outcome were characterized for the presence of the virulence factors LT, ST, Stx1, Stx2, haemolysins, intimin, CNF1, CNF2, CDT-I, CDT-II, CDT-III, CDT-IV, and F17-related fimbriae (F17a, F17b, F17c, F17d). The prevalence of ETEC, STEC and NTEC were 1.8%, 6.8% and 20.9%, respectively. The ETEC isolates were all LT positive and ST-negative. The STEC isolates were all Stx and intimin-positive, with Stx1 (80%) more frequent than Stx2 (27%). The NTEC isolates were all CNF and Hly-positive, with CNF2 (83%) more frequent than CNF1 (22%). Susceptibility assays to 11 antimicrobials displayed high rates of resistance (>30%) to antimicrobials tested. These data show that the most prevalent strains in diarrhoeic water buffalo calves were NTEC, mostly CNF2 and HlyA-positive, with strong associations CNF2/CDT-III and CNF2/F17c. PMID- 21658737 TI - Phylogenetic analysis of low pathogenicity H5N1 and H7N3 influenza A virus isolates recovered from sentinel, free flying, wild mallards at one study site during 2006. AB - From August 2 to October 11, 2006, clusters of low pathogenicity (LP) North American lineage H5N1 and H7N3 avian influenza A viruses (AIV), and other subtypes, were recovered from free-flying, resident, wild mallards used as sentinels at one site. The antigenic subtypes, pathogenicity potential, and Sanger sequencing of the isolates determined the H5N1 and H7N3 isolates were only recovered from samples collected on 8/2/2006 and 9/8/2006, respectively. However, subsequent efforts using next-generation sequencing (NGS) and additional Sanger sequencing found partial H7 segments in other HA-NA virus combinations on 8/2/2006, 9/8/2006 and 10/11/2006. It is well established that over larger geographic areas and years AIVs form transient genomic constellations; this sequential sampling data revealed that over a short period of time the dynamics of AIVs can be active and newer sequencing platforms increase recognition of mixed infections. Both findings provide further insight into the natural history of AIVs in natural reservoirs. PMID- 21658739 TI - Bioconcentration of ibuprofen in fathead minnow (Pimephales promelas) and channel catfish (Ictalurus punctatus). AB - Pharmaceutical products and their metabolites are being widely detected in aquatic environments and there is a growing interest in assessing potential risks of these substances to fish and other non-target species. Ibuprofen is one of the most commonly used analgesic drugs and no peer-reviewed laboratory studies have evaluated the tissue specific bioconcentration of ibuprofen in fish. In the current study, fathead minnow (Pimephales promelas) were exposed to 250 MUg L(-1) ibuprofen for 28 d followed by a 14 d depuration phase. In a minimized bioconcentration test design, channel catfish (Ictalurus punctatus) were exposed to 250 MUg L(-1) for a week and allowed to depurate for 7 d. Tissues were collected during uptake and depuration phases of each test and the corresponding proportional and kinetic bioconcentration factors (BCFs) were estimated. The results indicated that the BCF levels were very low (0.08-1.4) implying the lack of bioconcentration potential for ibuprofen in the two species. The highest accumulation of ibuprofen was observed in the catfish plasma as opposed to individual tissues. The minimized test design yielded similar bioconcentration results as those of the standard test and has potential for its use in screening approaches for pharmaceuticals and other classes of chemicals. PMID- 21658740 TI - Cyp35a2 gene expression is involved in toxicity of fenitrothion in the soil nematode Caenorhabditis elegans. AB - In this study, the effect of organophosphorous (OP) pesticide, fenitrothion (FT), on the non-target organism was investigated using the soil nematode, Caenorhabditis elegans. Toxicity was investigated on multiple biological levels, from organism to molecular levels, such as, immoblity, growth, fertility, development, acetyl cholinesterase (AChE) activity and stress-response gene expressions. FT may provoke serious consequences on the C. elegans population, as it induced significant developmental disturbance. As expected, FT exposure inhibits AChE activity of C. elegans. The increased expression of the cytochrome p450 family protein 35A2 (cyp35a2) gene was also observed in FT exposed worms. To experimentally demonstrate the relationships between organism-level effects and the cyp35a2 gene expression in FT-exposed C. elegans, the integration of the gene expression with biochemical-, and organism level endpoints were attempted using a C. elegans cyp35a2 RNA interference (RNAi) and cyp35a2 mutant (gk317). The 24 h EC50s of C. elegans on FT exposure were in the order of cyp35a2 RNAi in cyp35a2 mutant (gk317)>cyp35a2 mutant (gk317)>cyp35a2 RNAi in wildtype (N2)>wildtype (N2). The higher EC50 values of cyp35a2 RNAi and cyp35a2 mutant (gk317) compared to that of wildtype C. elegans strongly supported that cyp35a2 gene plays an important role in the toxicity of FT towards C. elegans. The experiments with cyp35a2 RNAi also indicated that the development disturbance and decreased AChE activity, which were observed in FT exposed wildtype C. elegans were significantly rescued in the cyp35a2 RNAi C. elegans. Overall results suggest that the cyp35a2 may be an important gene for exerting FT toxicity in C. elegans. PMID- 21658738 TI - Cowpox virus induces interleukin-10 both in vitro and in vivo. AB - Cowpox virus infection induces interleukin-10 (IL-10) production from mouse bone marrow-derived dendritic cells (BMDCs) or cells of the mouse macrophage line (RAW264.7) at about 1800 pg/ml, whereas infections with vaccinia virus (strains WR or MVA) induced much less IL-10. Similarly, in vivo, IL-10 levels in bronchoalveolar lavage fluids of mice infected with cowpox virus were significantly higher than those after vaccinia virus infection. However, after intranasal cowpox virus infection, although dendritic and T-cell accumulations in the lungs of IL-10 deficient mice were greater than those in wild-type mice, weight-loss and viral burdens were not significantly different. IL-10 deficient mice were more susceptible than wild-type mice to re-infection with cowpox virus even though titers of neutralizing antibodies and virus-specific CD8 T cells were similar between IL-10 deficient and wild-type mice. Greater bronchopneumonia in IL-10 deficient mice than wild-type mice suggests that IL-10 contributes to the suppression of immunopathology in the lungs. PMID- 21658741 TI - PCB accumulation and tissue distribution in cave salamander (Proteus anguinus anguinus, Amphibia, Urodela) in the polluted karstic hinterland of the Krupa River, Slovenia. AB - For over two decades, a manufacturer of electrical capacitors disposed of its waste within the karstic hinterland of the Krupa River (Slovenia) resulting in the surroundings becomming heavily polluted with PCB. Albeit the extent of the contamination has been known since 1983 and the Krupa River has become one of the most PCB polluted river in Europe, the effects on the cave fauna of the region remain unknown. The most famous cave dweller of the Krupa hinterland is the endemic cave salamander Proteus anguinus anguinus. In this study we determine the levels of PCB in the tissues of the Proteus and in river sediments. The total concentration of PCB in individual tissue samples from specimens of the Krupa spring was between 165.59 MUg g(-1) and 1560.20 MUg g(-1)dry wt, which is at least 28-times higher than those from an unpolluted site. The kidneys contained the lowest concentration, while the highest concentration was in subcutaneous fat and tissues with high lipid contents like visceral fat and liver. Total PCB concentrations in sediment samples from the Krupa River were between 5.47 and 59.20 MUg g(-1)dry wt showing that a high burden of PCB still remains in the region. The most abundant PCB congeners in all analyzed samples were di-ortho substituted (PCB #101, #118, #138 and #158), but higher proportion of mono-ortho PCB was present in sediments. The ability of Proteus to survive a high PCB loading in its environment and especially in its tissues is remarkable. Its partial elimination of low chlorinated and mono-ortho substituted congeners is also reported. PMID- 21658742 TI - Frequency, phenotype, and genotype of minute gastrointestinal stromal tumors in the stomach: an autopsy study. AB - Gastrointestinal stromal tumors are the most common mesenchymal tumors of the human digestive tract. Up to 85% of these tumors show somatic gain-of-function mutation of the receptor tyrosine kinase c-KIT gene. A recent study has shown a high frequency (22.5%) of minute gastrointestinal stromal tumors in stomachs examined during routine autopsies. The aims of our study were to confirm the previously reported incidence of gastric gastrointestinal stromal tumors in routine autopsies and to investigate their molecular alterations. Gastrointestinal stromal tumors were collected prospectively from 578 autopsies over an 18-month period. After recording the size and location of each lesion, representative tissue samples were processed for hematoxylin and eosin staining and immunohistochemically stained for CD117 and CD34. Microdissected DNA from all identified gastrointestinal stromal tumors was studied for c-KIT and platelet derived growth factor receptor alpha mutations. We identified 17 gastrointestinal stromal tumors in 578 consecutive autopsies (2.9%) located in the gastric body (47%) and fundus (47%). One tumor location was not recorded. All tumors were immunohistochemically positive for CD117 and CD34. DNA analysis showed c-KIT mutations in 11 cases. One platelet-derived growth factor receptor alpha mutation was found. The incidence of gastric minute gastrointestinal stromal tumors (2.9%) is higher than the reported clinical incidence. All are benign tumors, and most, including minute tumors, contain c-KIT mutations. This finding highlights the fact that c-KIT mutations are an early event in the evolution of gastrointestinal stromal tumors but are not sufficient per se for clinically relevant disease. PMID- 21658743 TI - Low-grade fibromyxoid sarcoma of the perineum with heterotopic ossification: case report and review of the literature. AB - Low-grade fibromyxoid sarcoma was first described more than 20 years ago. Subsequently, it was discovered to carry the recurrent chromosomal translocation t(7;16)(q33;p11) encoding a FUS-CREB3L2 fusion oncoprotein. Molecular tests for this pathognomonic gene fusion can confirm the identity of histologic variants (such as hyalinizing spindle cell tumor with giant rosettes) and suggest that some cases of sclerosing epithelioid fibrosarcoma may represent a high-grade version of this entity. We present a case of an ossifying tumor of the perineum that required an open biopsy and fluorescent in situ hybridization testing for FUS and CREB3L2 for diagnosis as a variant of low-grade fibromyxoid sarcoma. Subsequent excision revealed characteristic areas with collagen rosettes as well as foci of heterotopic ossification. Significant ossification, which is well documented in entities such as synovial sarcoma, ossifying fibromyxoid tumor, and extraskeletal osteosarcoma, has not been reported previously in low-grade fibromyxoid sarcoma. This case demonstrates the value of having a distinctive confirmatory molecular pathology test for diagnosis and expands our knowledge of the histologic variants possible in low-grade fibromyxoid sarcoma. PMID- 21658744 TI - Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as retroperitoneal fibrosis. AB - Retroperitoneal fibrosis is a rare fibroinflammatory condition involving the abdominal aorta, iliac vessels, and ureters that carries an association with several other autoimmune conditions. Most cases of retroperitoneal fibrosis are thought to be idiopathic. The disorder can affect all age groups but is most common in persons between the ages of 50 and 70 years. A subset of cases is associated with an underlying immunohematologic abnormality including lymphoma. We describe in this case report a highly unusual presentation of a young woman who died with a diagnosis of "idiopathic retroperitoneal fibrosis" based on multiple biopsy procedures. Postmortem examination, however, revealed disseminated anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. The clinical and histopathologic importance of this very unusual presentation of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with retroperitoneal fibrosis is discussed. PMID- 21658745 TI - Critical regions and spreading of runt-related transcription factor-3 C-phosphate G (CpG) island methylation in human salivary gland adenoid cystic carcinoma. AB - We investigated the spreading pattern of runt-related transcription factor-3 (RUNX3) C-phosphate-G (CpG) island (3478 base pairs) methylation in salivary gland adenoid cystic carcinoma. The methylation status of multiple regions within the runt-related transcription factor-3 promoter CpG island (3478 base pairs) was detected by real-time methylation-specific polymerase chain reaction, and the runt-related transcription factor-3 protein was detected with a Western blot in 19 salivary gland adenoid cystic carcinoma samples and the corresponding nonneoplastic salivary glands. The risk ratio between runt-related transcription factor-3 CpG island methylation and salivary gland adenoid cystic carcinoma progression was analyzed by the logistic analysis of variance model. A possible association between runt-related transcription factor-3 methylation, clinicopathologic parameters, and runt-related transcription factor-3 protein was analyzed. Hypermethylation initially occurs the most at the 5' region of runt related transcription factor-3 CpG island before spreading to the transcription start site. The extent of methylation was found to be the highest in region nos. 1 and 2 among the successive 10 regions, which extend from the 5' region to the transcription start site within the runt-related transcription factor-3 CpG island. The extent of methylation is lowest at the transcription start site, both in salivary gland adenoid cystic carcinoma and in normal salivary glands. No methylation in the transcription start site was found in normal salivary glands. Logistic analysis of variance model indicates that the transcription start site within the runt-related transcription factor-3 promoter CpG island is critical for gene silencing. Western blots revealed that levels of the runt-related transcription factor-3 protein in adenoid cystic carcinoma samples are significantly lower than those in normal salivary glands (P < .001). Methylation of the runt-related transcription factor-3 CpG island spreads the most from 5' region to the transcription start site in adenoid cystic carcinoma tissues, and the transcription start site may be a critical region for the runt-related transcription factor-3 methylation. The spreading pattern of the runt-related transcription factor-3 methylation may play an a role in the progression of adenoid cystic carcinoma. PMID- 21658746 TI - Bioaccumulation of As, Cd, Cr, Hg(II), and MeHg in killifish (Fundulus heteroclitus) from amphipod and worm prey. AB - Elevated metal levels in fish are a concern for the fish themselves, their predators, and possibly humans who consume contaminated seafood. Metal bioaccumulation models often rely on assimilation efficiencies (AEs) of ingested metals and loss rate constants after dietary exposure (k(ef)s). These models can be used to better understand processes regulating metal accumulation and can be used to make site-specific predictions of metal concentrations in animal tissues. Fish often consume a varied diet, and prey choice can influence these two parameters. We investigated the trophic transfer of As, Cd, Cr, Hg(II), and methylmercury (MeHg) from a benthic amphipod (Leptocheirus plumulosus) and an oligochaete (Lumbriculus variegatus) to killifish (Fundulus heteroclitus) using gamma-emitting radioisotopes. Except for MeHg, AEs varied between prey type. AEs were highest for MeHg (92%) and lowest for Cd (2.9-4.5%) and Cr (0.2-4%). Hg(II) showed the largest AE difference between prey type (14% amphipods, 24% worms). For Cd and Hg(II) k(ef)s were higher after consuming amphipods than consuming worms. Tissue distribution data shows that Cd and Hg(II) were mainly associated with the intestine, whereas As and MeHg were transported throughout the body. Calculated trophic transfer factors (TTFs) suggest that MeHg is likely to biomagnify at this trophic step at all ingestion rates, whereas As, Cd, Cr, and Hg(II) will not. Data collected in this study and others indicate that using one prey item to calculate AE and k(ef) could lead to an over- or underestimation of these parameters. PMID- 21658747 TI - Small-scale and household methods to remove arsenic from water for drinking purposes in Latin America. AB - Small-scale and household low-cost technologies to provide water free of arsenic for drinking purposes, suitable for isolated rural and periurban areas not connected to water networks in Latin America are described. Some of them are merely adaptation of conventional technologies already used at large and medium scale, but others are environmentally friendly emerging procedures that use local materials and resources of the affected zone. The technologies require simple and low-cost equipment that can be easily handled and maintained by the local population. The methods are based on the following processes: combination of coagulation/flocculation with adsorption, adsorption with geological and other low-cost natural materials, electrochemical technologies, biological methods including phytoremediation, use of zerovalent iron and photochemical processes. Examples of relevant research studies and developments in the region are given. In some cases, processes have been tested only at the laboratory level and there is not enough information about the costs. However, it is considered that the presented technologies constitute potential alternatives for arsenic removal in isolated rural and periurban localities of Latin America. Generation, handling and adequate disposal of residues should be taken into account in all cases. PMID- 21658748 TI - Nitrogen pollution and source identification in the Haicheng River basin in Northeast China. AB - A survey was conducted in the Haicheng River near Liaodong Bay to analyze the characteristics and sources of the in-stream nitrogen pollution throughout the year 2010. The results indicated that the total nitrogen (TN) concentrations in the river water all exceeded the GB3838-2002 standard for Class V guideline of 2.0 mg/l at all sampling sites during the sampling seasons. Ammoniacal nitrogen (NH3-N) dominated TN during the spring season, while nitrate nitrogen (NO3-N) dominated during the summer and autumn seasons. Different forms of nitrogen had significant seasonal variations (p<0.01 or p<0.05). Only NH3-N and NO3-N displayed distinct spatial differences at p<0.05 and p<0.001, respectively. Most forms of nitrogen were interrelated with physicochemical parameters during different seasons, displaying nitrification and denitrification processes that occurred in the river rather than seasonal biological demand. Based on the nitrogen parameters, the 30 sampling sites were divided into three clusters, by which the pollution sources from chemical nitrogen fertilizers, animal wastes, domestic sewage, and industrial wastewater were identified. Generally, the Haicheng River basin provided about 700tons of the annual TN flux, contributing to the eutrophication of the Liaodong Bay and Bohai Sea. PMID- 21658749 TI - Local international normalised ratio (INR) derivation simplified using the European concerted action on anticoagulation (ECAA) prothrombin time/INR line. PMID- 21658751 TI - Prognostic significance of the relative dose intensity of chemotherapy in primary treatment of epithelial ovarian cancer. AB - OBJECTIVE: Relative dose intensity (RDI) is the ratio of delivered dose intensity of chemotherapy to standard dose intensity. In this study, we sought to determine the prognostic significance of RDI in patients with epithelial ovarian cancer (EOC). METHODS: A retrospective analysis of chemotherapy naive patients treated between 2001 and 2008 with intravenous taxane and platinum was performed. RDI was calculated as the delivered dose intensity (total dose delivered/total time of therapy) divided by standard dose intensity calculated for each regimen and compared to progression-free survival (PFS). Multivariate recursive partitioning survival analysis was utilized. RESULTS: 138 EOC patients completed initial taxane/platinum-based chemotherapy following surgical cytoreduction. The most common reasons for dose delays and reductions were thrombocytopenia (38%) and neutropenia (31%). 24% of treatment delays were due to social reasons such as transportation constraints or scheduling conflicts. The average RDI was 90% (range, 24-126%). The mean PFS was 31 months (range, 3-117). Patients that achieved an RDI between 70% and 110% had a mean PFS of 32 months compared to 20 months in patients with an RDI of <70% or >110% (p=0.046). 14 patients (10%) had a RDI of <70%. CONCLUSIONS: RDI is a significant predictor of survival in patients with EOC. Effort should be made to achieve an RDI of at least 70%. Dose reductions and treatment delays could be minimized by utilizing prophylactic colony stimulating factors and educating patients about the importance of adhering to their treatment schedule. PMID- 21658750 TI - Certoparin versus UFH to prevent venous thromboembolic events in the very elderly patient: an analysis of the CERTIFY study. AB - INTRODUCTION: There is an exponential rise of thromboembolic risk with age because of co-morbidities, immobility and pharmacotherapy. We aimed to investigate the benefits and risks of heparin prophylaxis in very elderly patients >=80 years and the type of heparin used in a subgroup analysis of the CERTIFY trial. PATIENTS/METHODS: 3,239 patients were randomized to 3,000 U aXa o.d. certoparin or 5,000 IU t.i.d. unfractionated heparin (UFH) for 8-20 days. RESULTS: Patients >=80 years (n=1,365) were more likely to be female, had a lower mean bodyweight, were more frequently using antiplatelets and had a GFR below 30 ml/min/1.73 m(2) more often than patients <80 years (n=1,875). The combined endpoint of proximal DVT, symptomatic non-fatal PE and VTE related death was experience by 5.26% of patients >=80 years versus 3.51% in younger patients (OR 1.53; 95%CI 1.05-2.21; p=0.03). There were no significant differences in both minor (OR 1.11; 95%CI 0.75-1.62) and major (OR 2.53; 95%CI 0.93-6.86) bleeding risks. Certoparin and UFH were equally effective in reducing thromboembolic risk in either age group. The risk of any (OR 0.45; 95%CI 0.26-0.79) and minor bleeding (OR 0.42; 95%CI 0.23-0.78) was reduced with certoparin in the very elderly only. There were more adverse events in elderly patients (OR 1.26; 95%CI 1.1-1.46), but rates were otherwise comparable. CONCLUSIONS: The analysis confirmed the increased thromboembolic risk in very elderly patients, but demonstrated no increased bleeding risk. Certoparin and UFH were equally effective and safe with a reduced risk of minor bleeding complications with certoparin in the very elderly. PMID- 21658752 TI - A cohort study evaluating robotic versus laparotomy surgical outcomes of obese women with endometrial carcinoma. AB - OBJECTIVE: Minimally invasive surgery offers advantages for management of obese patients, but technical difficulty often deters its utilization. Compared to laparotomy, robotic surgery should allow comparable staging and improved surgical outcomes. Therefore, we evaluated outcomes in robotic and laparotomy cohorts of obese women with endometrial cancer at our institution. METHODS: Retrospective robotic and laparotomy cohorts of obese women (BMI >= 30 kg/m(2)) undergoing surgical management of primary endometrial cancer from March 2006 to March 2009 were formulated utilizing a computerized database. Patient demographics, operative statistics, peri-operative complications, and pathologic details were collected in an intent to treat analysis. Chi-square or Fisher's exact test and t test were used for statistical analysis. RESULTS: 73 women underwent robotic surgical management, 11% converted to laparotomy. Mean BMI (39.8 vs. 41.9, p=0.152), number of co-morbidities (2.49 vs. 2.62, p=0.690), number of previous surgeries (0.97 vs. 0.94, p=0.841), and lymphadenectomies performed (65.8% vs. 56.7%, p=0.227) were similar between cohorts. Total lymph nodes obtained were not statistically different between cohorts (8.01 vs. 7.24, p=0.505). Total operative time and room time was significantly longer for robotic surgery; however, estimated blood loss, the percentage of patients receiving transfusion, hospital length of stay, wound complications (4.1% vs. 20.2%, p=0.002) and other complications (9.6% vs. 29.8%, p=0.001) were improved for the robotic cohort. CONCLUSIONS: Robotic management of obese women with endometrial cancer yields acceptable staging results and improved surgical outcomes. Although operating time is longer, hospital time is shorter. Robotic surgery may be an ideal approach for these patients. PMID- 21658754 TI - Strange medication reactions. PMID- 21658753 TI - Functional ear (a)symmetry in brainstem neural activity relevant to encoding of voice pitch: a precursor for hemispheric specialization? AB - Pitch processing is lateralized to the right hemisphere; linguistic pitch is further mediated by left cortical areas. This experiment investigates whether ear asymmetries vary in brainstem representation of pitch depending on linguistic status. Brainstem frequency-following responses (FFRs) were elicited by monaural stimulation of the left and right ear of 15 native speakers of Mandarin Chinese using two synthetic speech stimuli that differ in linguistic status of tone. One represented a native lexical tone (Tone 2: T2); the other, T2', a nonnative variant in which the pitch contour was a mirror image of T2 with the same starting and ending frequencies. Two 40-ms portions of f(0) contours were selected in order to compare two regions (R1, early; R2 late) differing in pitch acceleration rate and perceptual saliency. In R2, linguistic status effects revealed that T2 exhibited a larger degree of FFR rightward ear asymmetry as reflected in f(0) amplitude relative to T2'. Relative to midline (ear asymmetry=0), the only ear asymmetry reaching significance was that favoring left ear stimulation elicited by T2'. By left- and right-ear stimulation separately, FFRs elicited by T2 were larger than T2' in the right ear only. Within T2', FFRs elicited by the earlier region were larger than the later in both ears. Within T2, no significant differences in FFRS were observed between regions in either ear. Collectively, these findings support the idea that origins of cortical processing preferences for perceptually-salient portions of pitch are rooted in early, preattentive stages of processing in the brainstem. PMID- 21658755 TI - Source and profile of paralytic shellfish poisoning toxins in shellfish in Daya Bay, South China Sea. AB - Changes in cell density and cyst flux of Alexandrium tamarense, paralytic shellfish poisoning (PSP) toxin contents in shellfishes, and environmental parameters were measured in two stations in Daya Bay, South China Sea from March 2005 to July 2006. Vegetative cells of A. tamarense occurred sporadically; however, they presented abundantly during the winter months. Meanwhile, cyst flux reached its maximum level just following the peak abundance of motile cells. The PSP contents in shellfish were generally low, but higher in winter with the maximum of 14,015 MUg STX equiv./kg. The majority of toxins were found in digestive glands, with a maximum of 66,227 MUg STX equiv./kg. There were significant positive relationships between toxin level and vegetative cell density and cyst flux. This indicates that vegetative cells and cysts of Alexandrium significantly influenced PSP level, and could be an important source of PSP toxins in shellfish during winter. PMID- 21658756 TI - Integrin-mediated adhesion and proliferation of human MSCs elicited by a hydroxyproline-lacking, collagen-like peptide. AB - In this study, we evaluated the competence of a rationally designed collagen-like peptide (CLP-Cys) sequence - containing the minimal essential Glycine-Glutamic acid-Arginine (GER) triplet but lacking the hydroxyproline residue - for supporting human mesenchymal stem cell (hMSC) adhesion, spreading and proliferation. Cellular responses to the CLP-Cys sequence were analyzed by conjugating the peptide to two different substrates - a hard, planar glass surface and a soft hyaluronic acid (HA) particle-based hydrogel. Integrin mediated cell spreading and adhesion were observed for hMSCs cultivated on the CLP-Cys functionalized surfaces, whereas on control surfaces lacking the peptide motif, cells either did not adhere or maintained a round morphology. On the glass surface, CLP-Cys-mediated spreading led to the formation of extended and well developed stress fibers composed of F-actin bundles and focal adhesion complexes while on the soft gel surface, less cytoskeletal reorganization organization was observed. The hMSCs proliferated significantly on the surfaces presenting CLP Cys, compared to the control surfaces lacking CLP-Cys. Competitive binding assay employing soluble CLP-Cys revealed a dose-dependent inhibition of hMSC adhesion to the CLP-Cys-presenting surfaces. Blocking the alpha(2)beta(1) receptor on hMSC also resulted in a reduction of cell adhesion on both types of CLP-Cys surfaces, confirming the affinity of CLP-Cys to alpha(2)beta(1) receptors. These results established the competence of the hydroxyproline-free CLP-Cys for eliciting integrin-mediated cellular responses including adhesion, spreading and proliferation. Thus, CLP-Cys-modified HA hydrogels are attractive candidates as bioactive scaffolds for tissue engineering applications. PMID- 21658758 TI - Simulation of the in vivo resorption rate of beta-tricalcium phosphate bone graft substitutes implanted in a sheep model. AB - A few years ago, a model was proposed to predict the effect of the pore architecture of a bone graft substitute on its cell-mediated resorption rate. The aim of the present study was to compare the predictions of the model with the in vivo resorption rate of four beta-tricalcium phosphate bone graft substitutes implanted in a sheep model. The simulation algorithm contained two main steps: (1) detection of the pores that could be accessed by blood vessels of 50 MUm in diameter, and (2) removal of one solid layer at the surface of these pores. This process was repeated until full resorption occurred. Since the pore architecture was complex, MUCT data and fuzzy imaging techniques were combined to reconstruct the precise bone graft substitute geometry and then image processing algorithms were developed to perform the resorption simulation steps. The proposed algorithm was verified by comparing its results with the analytical results of a simple geometry and experimental in-vivo data of beta-TCP bone substitutes with more complex geometry. An excellent correlation (r(2)>0.9 for all 4 bone graft substitutes) was found between simulation results and in-vivo data, suggesting that this resorption model could be used to (i) better understand the in vivo behavior of bone graft substitutes resorbed by cell-mediation, and (ii) optimize the pore architecture of a bone graft substitute, for example to maximize its resorption rate. PMID- 21658757 TI - Effects of ligands with different water solubilities on self-assembly and properties of targeted nanoparticles. AB - The engineering of drug-encapsulated targeted nanoparticles (NPs) has the potential to revolutionize drug therapy. A major challenge for the smooth translation of targeted NPs to the clinic has been developing methods for the prediction and optimization of the NP surface composition, especially when targeting ligands (TL) of different chemical properties are involved in the NP self-assembly process. Here we investigated the self-assembly and properties of two different targeted NPs decorated with two widely used TLs that have different water solubilities, and developed methods to characterize and optimize NP surface composition. We synthesized two different biofunctional polymers composed of poly(lactide-co-glycolide)-b-polyethyleneglycol-RGD (PLGA-PEG-RGD, high water solubility TL) and PLGA-PEG-Folate (low water solubility TL). Targeted NPs with different ligand densities were prepared by mixing TL-conjugated polymers with non-conjugated PLGA-PEG at different ratios through nanoprecipitation. The NP surface composition was quantified and the results revealed two distinct nanoparticle assembly behaviors: for the case of PLGA-PEG-RGD, nearly all RGD molecules conjugated to the polymer were found to be on the surface of the NPs. In contrast, only ~20% of the folate from PLGA-PEG-Folate was present on the NP surface while the rest remained presumably buried in the PLGA NP core due to hydrophobic interactions of PLGA and folate. Finally, in vitro phagocytosis and cell targeting of NPs were investigated, from which a window of NP formulations exhibiting minimum uptake by macrophages and maximum uptake by targeted cells was determined. These results underscore the impact that the ligand chemical properties have on the targeting capabilities of self-assembled targeted nanoparticles and provide an engineering strategy for improving their targeting specificity. PMID- 21658759 TI - Functionalized PEG hydrogels through reactive dip-coating for the formation of immunoactive barriers. AB - Influencing the host immune system via implantable cell-delivery devices has the potential to reduce inflammation at the transplant site and increase the likelihood of tissue acceptance. Towards this goal, an enzymatically-initiated, dip-coating technique is adapted to fabricate conformal hydrogel layers and to create immunoactive polymer coatings on cell-laden poly(ethylene glycol) (PEG) hydrogels. Glucose oxidase (GOx)-initiated dip coatings enable the rapid formation of uniform, PEG-based coatings on the surfaces of PEG hydrogels, with thicknesses up to 500 MUm where the thickness is proportional to the reaction time. Biofunctional coatings were fabricated by thiolating biomolecules that were subsequently covalently incorporated into the coating layer via thiol-acrylate copolymerization. The presence of these proteins was verified via fluorescent confocal microscopy and a modified ELISA, which indicated IgG concentrations as high as 13 +/- 1 ng/coated cm2 were achievable. Anti-Fas antibody, known to induce T cell apoptosis, was incorporated into coatings, with or without the addition of ICAM-1 to promote T cell interaction with the functionalized coating. Jurkat T cells were seeded atop functionalized coatings and the induction of apoptosis was measured as an indicator of coating bioactivity. After 48 h of interaction with the functionalized coatings, 61 +/- 9% of all cells were either apoptotic or dead, compared to only 18 +/- 5% of T cells on non-functionalized coatings. Finally, the cytocompatibility of the surface-initiated GOx coating process was confirmed by modifying gels with either encapsulated beta-cells or 3T3 fibroblasts within a gel that contained a PEG methacrylate coating. PMID- 21658760 TI - Reprogramming induced pluripotent stem cells in the absence of c-Myc for differentiation into hepatocyte-like cells. AB - Induced pluripotent stem cells (iPSCs) with four reprogramming factors (Oct 4/Sox2/Klf-4/c-Myc) have been shown to differentiate into hepatic lineages. However, it was unclear whether obviation of the c-Myc oncogene in iPSCs affected hepatic differentiation or inhibited in vivo tumor formation. In this study, we demonstrated that iPSCs without c-Myc had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) with biological functions. As detected using planar-radionuclide imaging and Hoechst labeling assays, these iPSCs and iPSC Heps tended to mobilize to the injured liver area in thioacetamide (TAA)-treated mice. Intravenous transplantation of both iPSCs and iPSC-Heps but not mouse embryonic fibroblasts (MEFs) reduced the hepatic necrotic area, improved liver functions, and rescued TAA-treated mice from lethal acute hepatic failure (AHF). In addition, microarray-based bioinformatics and quantitative RT-PCR showed high expression of antioxidant genes in iPSCs and iPSC-Heps compared to MEFs. In vivo and in vitro studies of NAC pretreatment confirmed that iPSCs and iPSC-Heps potentially suppressed ROS production and activated antioxidant enzymes in TAA injured livers. Six months after transplantation in TAA-treated mice, tumor formation was not seen in non-c-Myc iPSC grafts. Therefore, reprogramming adult somatic cells without c-Myc may prevent oxidative stress-induced damage and provide a safer alternative for hepatic regeneration in AHF. PMID- 21658761 TI - KALA-modified multi-layered nanoparticles as gene carriers for MHC class-I mediated antigen presentation for a DNA vaccine. AB - DNA vaccines are a new-generation vaccines that elicit an immunological response against a wide-variety of antigens with frequent mutations. However, an effective non-viral vector for genetically engineered DNA to dendritic cells is yet to be developed. We previously reported that an octaarginine (R8)-modified tetra lamellar multi-functional envelope-type nano device (R8-T-MEND) increases transfection efficiency in dendritic cell cultures (JAWS II). The critical structural elements of the R8-T-MEND are a DNA-polycation condensed core coated with two nuclear membrane-fusogenic inner envelopes, and two endosome-fusogenic outer envelopes. While the gene expression was drastically enhanced by R8-T-MEND, antigen presentation using an epitope-encoding plasmid DNA remains an obstacle for future non-viral vectors in DNA vaccinations. In the present study, we upgraded the function of R8-T-MEND by improving the membrane-fusion processes with endosome- and nuclear membranes by incorporating the KALA peptide, and by reducing the charge ratio (+/-), in an attempt to accelerate intra-nuclear decondensation. The resulting KALA-modified T-MEND (R8/KALA-T-MEND) showed an approximately 20-fold higher transgene expression compared with the conventional R8-T-MEND in JAWS II, and exceeded that of Lipofectamine PLUS, a commercially available transfection reagent. Furthermore, significant antigen presentation of a specific epitope (SIINFEKL) was observed for the R8/KALA-T-MEND but was not detected for the conventional T-MEND or Lipofectamine PLUS when an ovalbumin (OVA)-encoding plasmid DNA was transfected. It thus appears that the R8/KALA-T MEND has the potential for use as a vector in DNA vaccinations. PMID- 21658762 TI - A system for treating ischemic disease using human embryonic stem cell-derived endothelial cells without direct incorporation. AB - Despite studies on the use of human embryonic stem cell (hESC) derivatives to treat ischemic diseases, there are technical safety issues that have yet to be resolved. Herein, we sought to develop a method for using secreted angiogenic factors from hESC-derived endothelial cell derivatives (hESC-ECs), while avoiding direct cell incorporation, to reduce tumorigenesis or unidentified side effects of injected cells in vivo. Multicellular aggregation of hESC-ECs (MA-hESC-ECs) increases survivability, and encapsulation in Matrigel (EnMA-hESC-ECs) blocks the cells' in vivo migration. To examine the therapeutic effects of EnMA-hESC-ECs, we implanted both forms of hESC-ECs in a mouse model of hindlimb ischemia. Treatment with EnMA-hESC-ECs suppressed limb loss and tissue damage with no noticeable side effects, such as tumorigenesis or teratoma formation, and the Matrigel implant could be easily removed after the procedure. Thus, MA and the encapsulation system are effective techniques for utilizing humoral factors secreted by hESC derivatives that aid in the survivability and safety. We expect these results to contribute to the thriving stem cell field by improving the bioavailability of hESC derivatives for regenerative medicine. PMID- 21658763 TI - Well-defined, reversible disulfide cross-linked micelles for on-demand paclitaxel delivery. AB - To minimize premature release of drugs from their carriers during circulation in the blood stream, we have recently developed reversible disulfide cross-linked micelles (DCMs) that can be triggered to release drug at the tumor site or in cancer cells. We designed and synthesized thiolated linear-dendritic polymers (telodendrimers) by introducing cysteines to the dendritic oligo-lysine backbone of our previously reported telodendrimers comprised of linear polyethylene glycol (PEG) and a dendritic cluster of cholic acids. Reversibly cross-linked micelles were then prepared by the oxidization of thiol groups to disulfide bond in the core of micelles after the self-assembly of thiolated telodendrimers. The DCMs were spherical with a uniform size of 28 nm, and were able to load paclitaxel (PTX) in the core with superior loading capacity up to 35.5% (w/w, drug/micelle). Cross-linking of the micelles within the core reduced their apparent critical micelle concentration and greatly enhanced their stability in non-reductive physiological conditions as well as severe micelle-disrupting conditions. The release of PTX from the DCMs was significantly slower than that from non-cross linked micelles (NCMs), but can be gradually facilitated by increasing the concentration of reducing agent (glutathione) to an intracellular reductive level. The DCMs demonstrated a longer in vivo blood circulation time, less hemolytic activities, and superior toxicity profiles in nude mice, when compared to NCMs. DCMs were found to be able to preferentially accumulate at the tumor site in nude mice bearing SKOV-3 ovarian cancer xenograft. We also demonstrated that the disulfide cross-linked micellar formulation of PTX (PTX-DCMs) was more efficacious than both free drug and the non-cross-linked formulation of PTX at equivalent doses of PTX in the ovarian cancer xenograft mouse model. The anti tumor effect of PTX-DCMs can be further enhanced by triggering the release of PTX on-demand by the administration of the FDA approved reducing agent, N acetylcysteine, after PTX-DCMs have reached the tumor site. PMID- 21658765 TI - Activation of neuropeptide Y(2) receptors exerts an excitatory action on cardio respiratory variables in anaesthetized rats. AB - The respiratory effects of stimulation of NPYY(2) receptors were studied in spontaneously breathing rats that were either (i) neurally intact and subsequently bilaterally vagotomized in the neck, or (ii) neurally intact and subjected to supranodosal vagotomy or (iii) neurally intact treated with pharmacological blockade of NPY(1-2) receptors. Before neural interventions an intravenous (iv) bolus of the NPYY(2) receptor agonist NPY 13-36 (10 MUg/kg) increased breathing rate, tidal volume and mean arterial blood pressure (MAP). Section of the midcervical vagi abrogated NPY 13-36-evoked increase in respiratory rate but had no effect on augmented tidal volume, minute ventilation and blood pressure. Supranodosal vagotomy prevented the increase in tidal volume and slightly reduced the pressor response. Blockade of NPYY(2) receptor with intravenous doses of BIIE 0246 eliminated cardio-respiratory effects of NPY 13-36 injection. BMS 193885 - an antagonist of NPYY(1) receptor-was not effective in abrogating cardio-respiratory response. The present study showed that (i) NPY 13 36 induced stimulation of breathing results from activation of NPYY(2) receptors associated with pulmonary vagal afferentation; (ii) the increase in the frequency of breathing is mediated by midcervical vagi and augmentation of tidal volume relies on the intact supranodosal trunks (iii) the pressor response results from the excitation of NPYY(2) receptors outside of the vagal pathway. PMID- 21658764 TI - Promising cellular therapeutics for prevention or management of graft-versus-host disease (a review). AB - Graft-versus-host disease (GVHD) frequently occurs following allogeneic hematopoietic stem cell transplantation. The primary treatment for GVHD involves immune suppression by glucocorticoids. If patients become refractory to steroids, they have a poor prognosis. Therefore, there is a pressing need for alternative therapies to treat GVHD. Here, we review clinical data which demonstrate that a cellular therapy using mesenchymal stromal cells (MSCs) is safe and effective for GVHD. Since MSCs derived from bone marrow present certain limitations (such as time lag for expansion to clinical dose, expansion failure in vitro, painful and invasive bone marrow MSC isolation procedures), alternative sources of MSCs for cellular therapy are being sought. Here, we review data which support the notion that MSCs derived from Wharton's jelly (WJ) may be a safe and effective cellular therapy for GVHD. Many laboratories have investigated the immune properties of these discarded MSCs with an eye towards their potential use in cellular therapy. We also review data which support the notion that the licensing of MSCs (meaning the activation of MSCs by prior exposure to cytokines such as interferon-gamma) may enhance their effectiveness for treatment of GVHD. In conclusion, WJCs can be collected safely and painlessly from individuals at birth, similar to the collection of cord blood, and stored cryogenically for later clinical use. Therefore, WJCs should be tested as a second generation, off-the-shelf cell therapy for the prevention or treatment of immune disorders such as GVHD. PMID- 21658766 TI - Depletion of alloreactive T-cells in vitro using the proteasome inhibitor bortezomib preserves the immune response against pathogens. AB - Current graft-versus-host disease (GVHD) inhibition approaches lead to abrogation of pathogen-specific T-cell responses. We propose an approach to inhibit GVHD without hampering immunity against pathogens: in vitro depletion of alloreactive T cells with the preoteasome inhibitor bortezomib. We show that PBMCs stimulated with allogeneic cells and treated with bortezomib greatly reduce their ability to produce IFN-gamma when re-stimulated with the same allogeneic cells, but mainly preserve their ability to respond to citomegalovirus stimulation. Unlike in vivo administration of immunosuppressive drugs or other strategies of allodepletion, in vitro allodepletion with bortezomib maintains pathogen-specific T cells, representing a promising alternative for GVHD prophylaxis. PMID- 21658767 TI - Miniaturized flow cytometry-based BCR-ABL immunoassay in detecting leptomeningeal disease. AB - Despite central nervous system (CNS) prophylactic programs limit leptomeningeal involvement in acute lymphoblastic leukemia (ALL), it can still occur in a restricted percentage of cases. The exact risk rate remains still unknown, and several factors are associated with an increased probability to develop CNS involvement. Among them, Philadelphia (Ph)-positive genotype seems to play a relevant role. Recently, a flow cytometric assay to detect BCR-ABL protein has been developed, but little is known about its possible employment in leptomeningeal disease. Here, we show the miniaturized application of the original assay for BCR-ABL oncoprotein detection in cerebrospinal fluid (CSF) samples. PMID- 21658769 TI - Posterior fossa dermoid cyst with a sinus tract and restricted diffusion on MR imaging: value of structural imaging findings and signal characteristics. PMID- 21658768 TI - Haematological and cytogenetic responses after only 7 days of Lenalidomide in a patient with myelodysplastic syndrome and chromosome 5q deletion. PMID- 21658770 TI - Methylmercury levels and bioaccumulation in the aquatic food web of a highly mercury-contaminated reservoir. AB - The low Ebro River basin (NE Spain) represents a particular case of chronic and long-term mercury pollution due to the presence of an industrial waste (up to 436 MUg/g of Hg) coming from a chlor-alkali plant Albeit high total mercury (THg) levels have been previously described in several aquatic species from the surveyed area, methylmercury (MeHg) values in fish individuals have never been reported. Accordingly, in order to investigate bioaccumulation patterns at different levels of the aquatic food web of such polluted area, crayfish and various fish species, were analysed for THg and MeHg content. At the hot spot, THg mean values of crayfish muscle tissue and hepatopancreas were 10 and 15 times, respectively, greater than the local background level. Higher mean THg concentrations were detected in piscivorous (THg=0.848 +/- 0.476 MUg/g wet weight (ww); MeHg=0.672 +/- 0.364 MUg/g ww) than in non-piscivorous fish (THg=0.305 +/- 0.163 MUg/g ww; MeHg=0.278 +/- 0.239 MUg/g ww). Although these results indicated that THg in fish increased significantly with increasing trophic position, the percentage of the methylated form of Hg was not strongly influenced by differences in relative trophic position. This is an important finding, since the fraction of THg as MeHg in the top fish predator was unexpectedly lower than for other species of the aquatic food chain. Moreover, mean THg concentrations in piscivorous fish exceed the maximum level recommended for human consumption. From our findings, it is clear that for this specific polluted system, speciation becomes almost mandatory when risk assessment is based on MeHg, since single measurements of THg are inadequate and could lead to an over- or under-estimation of contamination levels. PMID- 21658771 TI - Evaluation of procalcitonin and CRP as sepsis markers in 74 consecutive patients admitted with prolonged febrile neutropenia. PMID- 21658772 TI - Mucosal Leishmania infantum leishmaniasis: specific pattern in a multicentre survey and historical cases. AB - OBJECTIVE: Leishmania infantum mucosally restricted leishmaniasis was rarely reported, so that diagnostic and treatment strategies remain debated. A long-term multicentric survey appeared thereby necessary. METHODS: Cases were prospectively collected over 12 years in 3 academic hospitals of Southern France. Predisposing factors, clinical findings, diagnostic procedures, treatment and outcome were compared to medical literature. RESULTS: Ten new cases and 40 historical reports were collected. Respectively 10/10 and 35/40 patients were adult males. Immunodeficiency was frequent (5/10 and 18/40). No previous cutaneous lesion was reported. Leishmaniasis affected mostly larynx (5/10 and 19/40), but also mouth (2/10 and 19/40) and nose (3/10 and 5/40). Lesions were highly polymorph. Mucosa histological examination provided respectively 1/10 and 2/40 false negative results, contrary to serum immunoblotting and PCR on mucosal biopsy. Although local response was always satisfactory even using topical treatment, subsequent visceral spreading was observed in 2/10 and 1/40 cases. CONCLUSION: L. infantum mucosally restricted leishmaniasis exhibits a specific pattern, marked by tropism for adult males, high clinical and histological polymorphism. Immunoblot screening and PCR confirmation of suspected lesions are necessary because of direct examination occasional false negative results. The risk of visceral spreading sustains systemic therapy. SUMMARY: Leishmania infantum mucosal leishmaniasis mostly affects adult males, half of them immunodeficient. Clinical and histological polymorphism makes the diagnosis difficult, stressing the need for immunoblot screening and mucosa PCR analysis of suspected cases. Possible visceralization sustains systemic therapy. PMID- 21658773 TI - Declining trend of HIV infection among the rural population of South India - a comparison of HIV prevalence in high risk and low risk groups. PMID- 21658774 TI - Reversible dementia in a patient with central nervous system escape of human immunodeficiency virus. AB - HIV-associated neurocognitive disorders (HAND) are a group of conditions ranging from asymptomatic neurocognitive impairment to disabling dementia. The clinical spectrum and pathogenesis of these disorders is changing in the era of highly active antiretroviral therapy (HAART). High levels of HIV may exist in the cerebrospinal fluid (CSF) of some patients despite suppression of serum viral loads by HAART. We report a case of a 51-year-old male with profound levels of HIV in the CSF despite low serum levels. Adjusting his HAART regimen based on HIV genotype susceptibility data and a CNS Penetrating Effectiveness (CPE) score resulted in a dramatic improvement in cognitive function. Progressive dementia in this context is a rare but emerging trend and may be reversible. PMID- 21658775 TI - Impact of stressful life events on the course of panic disorder in adults. AB - BACKGROUND: Panic disorder with/without agoraphobia (PD/PDA) is a prevalent anxiety disorder, associated with impairment in quality of life and functionality, as well as increased healthcare utilization. Extant research shows a relationship between stressful life events (SLEs) and the onset of panic attacks in adults who ultimately develop PD/PDA. However, limited attention has been paid to how SLEs might affect the severity of panic symptoms in individuals with PD/PDA. In this study, we examined the relationship between SLEs and panic symptom severity in adults with PD/PDA. METHODS: Four hundred-eighteen adults with PD/PDA from the Harvard/Brown Anxiety Research Program (HARP), a long-term prospective longitudinal observational multicenter study of adults with a current or past history of anxiety disorders were included in this study. We examined occurrence of SLEs and their impact on panic symptom severity 12-weeks pre- and post-SLE. RESULTS: A time-slope effect showed that participants had worsened panic symptoms over the course of the 12-weeks after family/friends/household and work SLEs. That is, their symptoms worsened progressively after the event, rather than immediately thereafter (i.e., significant symptom change within the same week of the event). LIMITATIONS: The sample may not be representative of the general population. CONCLUSIONS: These findings provide new insights into how SLEs affect panic symptoms in adults with PD/PDA in that household-related SLEs, such as serious family arguments, and work-related SLEs, such as being fired, put some adults at risk for worsened panic symptoms within 12-weeks of the event. PMID- 21658776 TI - The influence of stigma on first aid actions taken by young people for mental health problems in a close friend or family member: findings from an Australian national survey of youth. AB - BACKGROUND: Young people are an important source of first aid for mental health problems in people they are close to, but their first aid skills remain inadequate. Research into the factors that influence mental health first aid skills are required to reveal targets for improving these skills. This study examined the influence of stigma on first aid actions taken by young people to help someone close to them with a mental health problem. METHODS: Participants in a national telephone survey of Australian youth (aged 12-25 years) reported on their stigmatising attitudes based on one of three disorders in vignettes: depression, depression with alcohol misuse, and social phobia. At a two-year follow-up interview, they were asked if they knew a family member or close friend with a problem similar to the vignette character since the initial interview, and those who did reported on the actions taken to help the person. RESULTS: Of the 1520 participants interviewed at follow up, 507 reported knowing someone with a similar problem. Young people's stigmatising attitudes (weak-not-sick, social distance and dangerousness/unpredictability) influenced their first aid actions. LIMITATIONS: Social desirability could have affected the assessment of stigma, we could not assess the severity of the first aid recipient's problem or the benefit derived from the first aid provided, and the proportion of variance explained was modest. CONCLUSIONS: Reducing stigma may help to improve the first aid that people with mental health problems can receive from young people who are close to them. PMID- 21658777 TI - Timing, quantity and quality of stressful life events in childhood and preceding the first episode of bipolar disorder. AB - BACKGROUND: A large body of evidence supports the importance of genetic risk factors in bipolar disorder (BPD), but less is known about the role of stressful life events (SLE). This study assessed the role of SLE in childhood, adulthood and one year prior to first episodes of both depression and mania in BPD. METHODS: Three groups of 50 matched subjects each were assessed: patients with BPD, with borderline personality disorder (BLPD) and healthy controls. Structured clinical interviews were used for diagnoses. The Coddington Life Events Schedule and the Israel Psychiatric Epidemiology Research Interview Life Event Scale measured life events and were confirmed with a semi-structured interview for subjective experience for each SLE. RESULTS: In BPD, the total number of SLE was lower during childhood and higher in the year preceding the first depression compared to controls and the proportion of loss-related events in childhood was higher. In the year preceding the first depressive episode, BPD subjects had more total, negative uncontrolled and independent but not positive SLE. In the year preceding the first episode of mania, the total number of uncontrolled, negative SLE were higher in BPD, whereas positive and separation-related SLE were not. After the first episode, BPD subjects had less SLE than controls. CONCLUSIONS: Negative and loss-related SLE are common in BPD subjects, occur in the year preceding the first episodes of depression and mania and are less common in childhood or after the onset of the disorder. PMID- 21658778 TI - Genetic association between bipolar disorder and 524A>C (Leu133Ile) polymorphism of CNR2 gene, encoding for CB2 cannabinoid receptor. AB - INTRODUCTION: Several studies provided evidence that the endocannabinoid system (ECS) is involved in psychiatric diseases, like major depression, schizophrenia and bipolar disorder (BD), mainly focusing on CB1 cannabinoid receptor, and FAAH, the fatty acid amide hydrolase involved in endocannabinoid metabolism. In this study we investigated the possible association of BD with three missense SNPs, of the gene CNR2, encoding for CB2 cannabinoid receptor. METHODS: The possible association between BD and three CNR2 missense SNPs, namely rs2501432 (315A>G; Arg63Gln), rs41311993 (524C>A; Leu133Ile) and rs2229579 (1073C>T; Tyr316His), was investigated through a case-control study. Eighty patients and one hundred and sixty healthy subjects were recruited. Allele Specific Oligonucleotide (ASO)-PCR and restriction fragment length polymorphism (RFLP) methods were used for genotyping. RESULTS: A statistically significant association was found between BD and the CNR2 524C>A; Leu133Ile (P(chi(2)) = 0.001; OR = 4.74; 95% C.I. = 2.52 10.50) while no statistically significant difference between BD and control group was observed for the other two SNPs. CONCLUSION: Though further investigations are necessary to confirm this data, our results suggest that CB2 cannabinoid receptor may play a role in BD. PMID- 21658779 TI - A systematic review of psychometric assessment of self-harm risk in the emergency department. AB - BACKGROUND: Assessment of self harm risk is both a common and difficult task in emergency room settings. Psychometric measures have been developed to help with this assessment but it is uncertain how well these measures perform and which are clinically useful for assessment in this setting. METHOD: Two reviewers independently assessed studies for relevance, inclusion, and study quality. Included studies classified mostly adult patients at risk for self-harm treated in an ED. The outcome variables selected were recurrence of self-harm/suicidal ideation or hospitalization. Only cohort study designs with follow-up were eligible. RESULTS: From 556 potentially relevant abstracts, 12 studies were identified for inclusion in the review. Overall, the risk of bias was considered moderate to low in this review. Of the included studies reporting future self harm as an outcome measure, only the scales that are part of the Manchester self harm project, the Implicit Associations Test and the Violence and Suicide Assessment Form were found to successfully predict self harm. The four studies that assessed admission as an outcome utilized eight different actuarial methods. Of the scales assessed, six were found to be significant predictors of admission. LIMITATIONS: It was not possible to perform a meta-analysis with the studies detected and it is uncertain whether publication bias or selection bias within the reviewed studies affected the results. CONCLUSION: Overall, while many methods used in the ED to assess suicidal and parasuicidal patients have strong psychometric properties, there is little clinical evidence supporting their use. PMID- 21658781 TI - Psychobiology of borderline personality traits related to subtypes of eating disorders: a study of platelet MAO activity. AB - Increased and decreased levers of platelet monoamine oxidase (MAO) activity have been reported in patients with eating disorders, indicating abnormalities of the serotonin turnover. However, whether these findings are related to eating disorders or are rather reflecting the pathophysiology of borderline personality traits in these patients is still unknown. Platelet MAO activity and comorbid personality disorders were investigated in 72 patients with different subtypes of eating disorders (ED) and in a group of 28 healthy controls. ED patients comprised the following subtypes: 25 anorexia nervosa (AN) restrictive, 14 AN binge eating-purging (AN b-p), 3 anorexia nervosa not otherwise specified (AN NOS) and 30 bulimia nervosa (BN). Personality disorders and traits were assessed with the Structured Interview for Personality Disorders (SCID-II), the Zanarini Rating Scale for Borderline Personality Disorder, and the Barrat Impulsiveness Scale. Platelet MAO activity was significantly lower in ED patients with comorbid borderline personality disorder (BPD) than in ED without Borderline personality disorder (BDP). Platelet MAO activity was significantly and inversely correlated with the number and severity of BPD clinical features. In the subsample of patients with binge eating-purging symptoms (AN b-p, AN NOS and BN), platelet MAO activity was significantly lower in binge-purge patients with comorbid BPD than in binge-purge patients without BPD. The whole group of eating disorders had a significantly reduced lever of platelet MAO activity compared with the control group. The results suggest that low platelet MAO activity might characterize eating disorders with comorbid borderline personality traits, reflecting greater serotonin dysfunction in these patients. The role of decreased platelet MAO as an endophenotype with specific clinical manifestations should be explored in future studies. PMID- 21658780 TI - Does Attention Deficit Hyperactivity Disorder increase the risk of suicide attempts? AB - OBJECTIVE: To determine if Attention Deficit Hyperactivity Disorder (ADHD) is a risk factor for suicide attempts. METHODS: Data were drawn from the National Comorbidity Replication Survey (NCS-R), a nationally representative sample of adults (N=8098). RESULTS: Of the 365 adults with current ADHD, 16% attempted suicide. After controlling for the presence of comorbid disorders, logistic regression analyses revealed that the ADHD was not a not a strong predictor of suicide attempts; having one or more comorbid disorders was associated with fourfold to twelvefold elevated risk. LIMITATIONS: The small sample size of respondents with ADHD who attempted suicide significantly reduced the probability of determining which specific comorbid disorders were correlated with parasuicide. CONCLUSIONS: Early treatment of ADHD and comorbidity may reduce the risk of suicide attempts and improve its prognosis. PMID- 21658782 TI - Higher n-3 fatty acids are associated with more intense fenfluramine-induced ACTH and cortisol responses among cocaine-abusing men. AB - Preclinical studies have shown that diets supplemented with or deficient in n-3 polyunsaturated fatty acids (PUFAs) could influence serotonergic neurotransmission, but information about their effects on the serotonergic function of humans is scant. Therefore, simultaneous assessments of n-3 PUFAs and of the adrenocorticotropic hormone (ACTH) and cortisol responses to challenges with the serotonin (5-HT) probe d,l-fenfluramine (FEN) were performed in 25 cocaine-abusing men and 12 control subjects. Cocaine abusers were tested 18 days after their admission to a closed ward. ACTH and cortisol were measured in plasma samples collected on two testing days separated by 48 h following the random administration of 60 mg of FEN or placebo. Fatty acids were measured in the first test day samples. Patients' FEN-induced ACTH rises were significantly and positively correlated with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Patients' cortisol rises were positively and significantly correlated with EPA but not with DHA. There were no significant correlations between hormonal responses and pre-hospitalization cocaine use parameters. Control subjects' responses to FEN were not correlated with any PUFA. In conclusion, higher EPA and DHA levels were associated with a more intense FEN-induced ACTH response and higher EPA levels with a more intense cortisol response in cocaine-abusing men withdrawn from cocaine but not in control subjects. These findings support and expand existing evidence that EPA and DHA could influence 5-HT function in some human subgroups. PMID- 21658784 TI - Importance of understanding pre-analytical variability in biomarker development. PMID- 21658783 TI - A randomized, controlled, multi-center trial comparing the safety and efficacy of zotarolimus-eluting and paclitaxel-eluting stents in de novo lesions in coronary arteries: final results of the ZoMaxx II trial. AB - BACKGROUND/OBJECTIVES: The purpose of this prospective, randomized, single-blind controlled clinical trial was to compare the effectiveness of a zotarolimus eluting stent (ZoMaxxTM) with a paclitaxel-eluting coronary stent (TaxusTM Express(2)TM) in patients with angina pectoris and a single native coronary artery lesion between 10-28 mm in length and 2.5-3.75mm in diameter. METHODS: Patients were enrolled at 75 international institutions between June 2005 and November 2006. RESULTS: 1099 (1672 originally planned) patients received 557 ZoMaxx and 542 Taxus stents: cohorts were well-matched for diabetes (27% vs. 27%), reference vessel diameter (2.73 +/- 0.46mm vs. 2.74 +/- 0.45mm) and lesion length (14.8 +/- 6.7mm vs. 14.3 +/- 6.4mm). Nine month clinical and angiographic follow-up was available in 1052/1099 (96%) and 649/836 (78%) patients, respectively. The safety profiles for the two stents (myocardial infarction (MI), cardiac death and/or target vessel revascularization (TVR)) were similar (ZoMaxx 8.7% vs. Taxus 6.9%, p=NS). The primary endpoint of 9-month TVR occurred more frequently after treatment with ZoMaxx (6.8%) as compared with Taxus (4.2%), therefore the primary clinical endpoint was not met. However, the 9-month in segment late lumen loss for ZoMaxx (0.29 +/- 0.47mm) and Taxus (0.22 +/- 0.41mm, p=NS) were similar, thus satisfying the primary angiographic endpoint. Secondary endpoints of the rates of in-segment and in-stent binary restenosis were also similar (5.9% vs. 5.8%, 7.8% vs. 7.9%, respectively). CONCLUSIONS: At 9months, the ZoMaxx stent failed to achieve the primary endpoint of non-inferiority in TVR to the Taxus stent, but safety endpoints were equal between the two stent systems. PMID- 21658785 TI - Dilated cardiomyopathy with centronuclear myopathy in a young male. PMID- 21658786 TI - Can procalcitonin predict bone infection in people with diabetes with infected foot ulcers? A pilot study. AB - AIMS: The diagnosis of osteomyelitis is a key step of diabetic foot management. Previous studies showed that procalcitonin (PCT), a novel infection marker, is superior to conventional infection markers in the diagnosis of diabetic foot infection. This study aimed to investigate the serum levels of PCT and other conventional infection markers in diabetic persons with and without osteomyelitis. METHODS: Twenty-four patients (18 male, mean age: 61.9+/-10.8 years) with infected foot ulcers were prospectively enrolled. Clinical characteristics of the wounds were noted. Blood samples were obtained for biochemical analysis. Magnetic resonance imaging of the foot was performed in all patients to diagnose osteomyelitis. RESULTS: Osteomyelitis was found in 13 of 24 (54%) patients. PCT levels were 66.7+/-43.5 pg/ml in patients with osteomyelitis and 58.6+/-35.5 pg/ml in patients without osteomyelitis. The difference did not reach statistical significance (p=0.627). Erythrocyte sedimentation rate, but not C-reactive protein and white blood cell count, was found significantly higher in patients with osteomyelitis. CONCLUSION: In this group of patients, PCT failed to discriminate patients with bone infection. Erythrocyte sedimentation rate can be used as a marker of osteomyelitis in diabetic persons. PMID- 21658787 TI - Design, implementation and scaling up of the balanced scorecard for hospitals in Lebanon: policy coherence and application lessons for low and middle income countries. AB - OBJECTIVES: This paper describes the development and implementation of the first national hospital performance indicators in Lebanon including its institutionalization within existing policy framework and the initiation of independent governance structure for sustainability. METHODS: Guided by the Ontario Acute Care Balanced Scorecard framework, a step-wise approach was used. Guiding principles were non-punitive reporting, anonymity, voluntary participation, stakeholder involvement, consensus and feasibility. Modified Delphi technique was used, readiness assessment surveys in 52 hospitals were conducted, pilot testing and evaluation were completed in 14 hospitals. RESULTS: Initial balanced set of 21 indicators were selected. Findings showed wide variations in indicators' measurement in hospitals including formulas and tools. Barriers to measurement included lack of quality culture, physician resistance and resources. A gradual implementation strategy was developed and selected indicators were divided into two levels. Most piloted indicators proved to be valid, feasible and reliable. The initiative was linked to the national hospital accreditation system resulting in a balanced set of 40 indicators. An independent, not-for-profit, arm's-length organization was established. CONCLUSIONS: This is among the first attempts made in the East Mediterranean Region to adapt the BSC approach and translate the experience of its development to addresses local needs and contextual reality. PMID- 21658789 TI - Use of blue-green and chlorophyll fluorescence measurements for differentiation between nitrogen deficiency and pathogen infection in winter wheat. AB - In recent years, several sensor-based approaches have been established to early detect single plant stresses, but the challenge of discriminating between simultaneously occurring stressors still remains. Earlier studies on wheat plants strongly affected by pathogens and nitrogen deficiency indicated that chlorophyll fluorescence might be suited to distinguish between the two stressors. Nevertheless, there is lack of information on the pre-symptomatic detection of synchronized occurrence of slight N-deficiency and the early stages of pathogen infection. The usefulness of the blue, green, and yellow fluorescence signals in this context has not yet been explored. We hypothesized that differentiation between wheat plants' physiological reaction due to N-deficiency and leaf rust (Puccinia triticina) as well as N-deficiency and powdery mildew (Blumeria graminis f. sp. tritici) might be accomplished by means of UV laser-induced fluorescence spectral measurements between 370 and 620nm in addition to chlorophyll fluorescence (640-800nm). Plants were provided with either a normal or a modified Hoagland nutrient solution in order to induce a slight N deficit. Pathogen inoculation was carried out on the second fully developed leaf. Four experimental groups were evaluated: (a) N-full-supply [N+]; (b) N-deficiency [N ]; (c) N-full-supply+pathogen [N+/LR] or [N+/PM]; (d) N-deficiency+pathogen [N /LR] or [N-/PM]. The results revealed that, in addition to the amplitude ratio of R/FR fluorescence, B/G fluorescence also facilitated reliable and robust discrimination among the four experimental groups. The discrimination among the experimental groups was accomplished as early as one and two days after inoculation for powdery mildew and leaf rust infection, respectively. During the 3days evaluation period, the differences among the treatment groups became more evident. Moreover, several other amplitude ratios and half-bandwidth ratios proved to be suited to early detect fungal infection, irrespective of the nitrogen status of the plant. PMID- 21658788 TI - Tissue sampling in lung cancer: a review in light of the MERIT experience. AB - Lung cancer continues to present an enormous global burden of morbidity and mortality, despite an increasing therapeutic armamentarium of chemotherapy and targeted agents. Recent research efforts have been directed towards identifying predictors of response to treatment, in order to facilitate the selection of patients likely to obtain the greatest benefit from specific therapeutic interventions, with the ultimate goal of providing customized therapy. A strong scientific basis exists for the use of markers to identify patients who are most likely to respond to biological and targeted therapies, based on characteristics such as tumour genotype and histology. Biomarkers have the potential to aid in patient stratification (risk assessment), treatment-response identification (surrogate markers), or differential diagnosis (identifying individuals who are likely to respond well to specific therapies). Numerous trials have demonstrated correlations between molecular biomarkers and the outcome of treatment with targeted therapies such as epidermal growth factor inhibitor tyrosine-kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). The recently completed MarkER Identification Trial (MERIT) found some evidence of a link between the molecular profile of a tumour and the clinical response to erlotinib in patients with relapsed NSCLC. However, MERIT also highlighted the difficulties in obtaining adequate samples for the various procedures involved in genetic analyses in clinical trials. Routine clinical practice brings its own challenges relating to biopsy techniques and tissue availability and this has implications for the application of molecular analyses in treatment decision-making. Applying the lessons learned from tissue sampling and molecular testing in MERIT and other major NSCLC trials will be essential in paving the way for the routine use of biomarker analyses in clinical practice. PMID- 21658790 TI - [New treatments in vascular diseases other than age related macular degeneration]. AB - Recent multicenter randomized studies about persistent macular edema in venous occlusions provided us with interesting results. Until now, the standard of care treatment of macular edema due to branch vein occlusion remained grid laser in contrast with central vein occlusion where the absence of treatment was still recommended. Score, Geneva, Bravo and Cruise studies recently provided us with the following results. Score study found triamcinolone to be interesting to treat macular edema due to central vein occlusion but not from branch occlusion. Geneva study assessed the effect of a delivery system of dexamethasone to treat macular edema due to venous occlusion whatever the clinical form with an improvement of visual acuity. Cruise and Bravo studies assessed the effect of ranubizumab, which was found to improve the visual acuity of macular edema due to either central or branch vein occlusions. At this stage we need comparative studies to precise the indication of these different approaches that remain perhaps complementary of laser treatment. PMID- 21658791 TI - [Extraocular myositis and comparative pathology: two case reports in the dog]. AB - Two cases of extraocular myositis in dogs are reported in a golden retriever and an Australian shepherd. This condition is characterized by sudden bilateral exophthalmos, the absence of pain and third eyelid protrusion, orbital sonography showing the enlargement of extraocular muscles, and a quick response to systemic steroids at an anti-inflammatory dose. The literature review reports a breed predisposition in the golden retriever, mainly in females. Histopathologic evaluations confirm the inflammation of one or several extraocular muscles. Chronic disease was also described. Canine extraocular myositis shows some resemblance to Graves ophthalmopathy but can better be compared to idiopathic orbital myositis. Both disorders are probably the consequence of an immune dysfunction that still has to be discovered. PMID- 21658792 TI - [AMD: Future therapies]. AB - Many drugs are presently tested in the different types of age-related macular degeneration (AMD), i.e. geographic atrophy or exudative AMD. In atrophic AMD, drugs attempt to spare the photoreceptors and the retinal pigment epithelium to prevent the oxidative damages or to suppress the inflammation process. In exudative AMD, some drugs try to challenge the available anti-VEGF drugs but others try to improve the visual prognosis in targeting other mechanisms or cells involved in angiogenesis, such as pericytes. The present article aims to summarize the available data, given in scientific meetings or given by the companies. PMID- 21658793 TI - [Drusen of the optic nerve in children and bleeding complications]. PMID- 21658794 TI - [Therapeutics of primary open-angle glaucoma in Cotonou: a series of 224 cases]. AB - AIMS: To determine POAG features and evaluate topical management in Cotonou, Benin, in order to suggest therapeutic diagrams adapted to local therapeutic conditions. PATIENTS AND METHOD: This was a retrospective, longitudinal study with cross-sectional collection of data from subjects with POAG who were admitted to the CNHU and Bethesda Hospital ophthalmologic center in Cotonou, Benin, from 1st January 2007 to 31st December 2008. RESULTS: Visual acuity higher than 6/10 improved from the first consultation (47.3% on the right and 43.8% on the left) to the second (62.5% on the right and 62.9% on the left). All the patients had received a topical treatment with predominance of monotherapy (59.4%) at the first consultation. Beta-blockers were the most frequently prescribed, alone or in association. They reduced IOP by 12.8% in the right eye and 14.6% in the left eye. The prostaglandins were responsible for 26.2% and 27.8% of IOP reduction in the right and left eyes, respectively. Whatever the therapeutic diagram, IOP decreased from one consultation to another (p<0.0001). The IOP was higher than 21 mm Hg in the majority of the cases at the first consultation (62.5% in right eye, 63.4% in the left eye) and lower than 21 mm Hg (75.9% in the right eye, 74.6% in the left eye) at the second. Dual therapy (t=72.2) was more effective than monotherapy (t=52.3). CONCLUSION: The search for therapeutic effectiveness and better treatment observance should bring physicians to more indications of surgery. PMID- 21658795 TI - Integrating static and dynamic features of melanoma: the DynaMel algorithm. AB - BACKGROUND: Sequential digital dermatoscopy identifies dynamic changes in melanocytic lesions. However, no algorithm exists that systematically weights dynamic changes regarding their association with melanoma. OBJECTIVE: We sought to identify relevant dynamic changes and to integrate these into a novel diagnostic algorithm. METHODS: During follow-up (mean 44.28 months) of 688 patients at high risk, 675 pigmented lesions with prospectively documented dynamic changes were excised. The association between specific changes and melanoma was assessed. RESULTS: We detected 61 melanomas (38 invasive, median thickness 0.42 mm) with dynamic changes. Multivariate logistic regression analyses revealed a significant association between the diagnosis of melanoma and 5 dynamic criteria. According to the observed odds ratios we defined two dynamic major criteria (2 points each: asymmetric-multifocal enlargement and architectural change) and 3 dynamic minor criteria (1 point each: focal increase in pigmentation, focal decrease in pigmentation, and overall decrease in pigmentation when not accompanied by a lighter pigmentation of the adjacent skin). The DynaMel score was generated by addition of dynamic and 7-point checklist scores with a threshold for excision of 3 or more points. Including information about dynamic changes increased the sensitivity of the 7-point checklist from 47.5% (29 of 61 melanomas detected) to 77.1% (47 of 61 melanomas detected). The specificity slightly decreased from 99.0% to 98.1%. LIMITATIONS: Before broad application the DynaMel algorithm needs to be validated using data from a different prospective study. CONCLUSIONS: The DynaMel algorithm integrates a scoring system for dynamic dermatoscopic changes into the 7-point checklist for dermatoscopy and thereby increased the sensitivity of melanoma detection. PMID- 21658796 TI - A review of DRESS-associated myocarditis. AB - DRESS (drug rash with eosinophilia and systemic symptoms), also known as drug induced hypersensitivity syndrome, is a severe, systemic drug reaction most commonly associated with aromatic anticonvulsants and sulfonamides. Patients typically present with fever, facial edema, cervical lymphadenopathy and a morbilliform eruption, which may progress to erythroderma. Hematologic abnormalities are a hallmark of the condition, including eosinophilia and atypical lymphocytosis. Visceral organ involvement typically manifests as hepatic dysfunction but may include lymphadenopathy, nephritis, interstitial pneumonitis, and myocarditis. Five to ten percent of patients with DRESS die from systemic complications, making timely recognition and treatment essential to prevent life threatening manifestations. Myocarditis is a fatal and under-recognized manifestation of DRESS, which may occur long after the initial diagnosis. We review the literature of previously reported cases of DRESS and myocardial involvement, highlighting the presenting symptoms associated with cardiac involvement, treatments used, and the outcome for each patient. In addition, we offer an algorithm for early diagnosis, treatment, and subsequent monitoring of these patients. PMID- 21658797 TI - Characteristic purpura of the ears, vasculitis, and neutropenia--a potential public health epidemic associated with levamisole-adulterated cocaine. AB - BACKGROUND: Dermatologists at the University of California, San Francisco recently reported two patients in the online Journal of the American Academy of Dermatology with purpura presumably induced by levamisole in contaminated cocaine. Levamisole-induced vasculitis and neutropenia has been reported elsewhere in the United States and Canada. Up to 70% of cocaine in the United States could be contaminated. OBJECTIVE: We sought to describe similar cases of vasculitis associated with cocaine use. METHODS: This is a retrospective case series. RESULTS: We report 6 remarkably similar patients seen over just the past few months with retiform purpura on the body and tender purpuric eruptions, necrosis, and eschars of the ears after cocaine use in New York and California. All of these patients had positive perinuclear antineutrophil cytoplasmic antibody values and 3 of the 6 also had an associated neutropenia. Direct immunofluorescence studies suggested an immune complex-mediated vasculitis. LIMITATIONS: This case series is descriptive in nature and, because testing is not easily performed, we did not test for levamisole in the serum or blood to prove this is the causative agent. CONCLUSION: It appears the use of cocaine is associated with the peculiar clinical findings of ear purpura, retiform purpura of the trunk, and neutropenia. We believe this case series may represent the tip of the iceberg as a looming public health problem caused by levamisole. Although the direct causal relationship may be difficult to establish, the astute dermatologist or primary care physician should be able to recognize the characteristic skin lesions and should be wary of the potential development of agranulocytosis. PMID- 21658799 TI - Funnel plots and risk-adjusted count data adverse events. A limitation of indirect standardisation. AB - Reporting of hospital adverse event data is becoming increasingly mandated and this has motivated work on methods for the analysis and display of these data for groups of institutions. Currently, the method preferred by many workers is the funnel plot. Often, indirect standardisation is employed to produce these plots. It appears that, when used to display binary data such as surgical site infection or mortality data, the method is satisfactory. Increasingly, these data are risk adjusted. However, risk adjustment of these data usually involves individual patients undergoing the same or similar procedures and the method does not appear to mislead. However, when dealing with count data such as bacteraemias it appears that this method can mislead, particularly where methods for risk adjustment of these data are used. Information about the hospitals or units of interest rather than individual patients is employed. For example, one hospital may have plastic and cardiac surgery units in which bacteraemias occur infrequently whereas another may provide treatment for renal failure (including transplantation) and have a large haematology-oncology unit (also including transplantation), each of which would expect higher bacteraemia rates. Moreover, the hospitals and units within them may differ substantially in size. It is well known that indirect standardisation can give biased results when denominators differ substantially. We illustrate this difficulty with risk-adjusted bacteraemia data from the Queensland Health Centre for Healthcare Infection, Surveillance and Prevention (CHRISP) database. PMID- 21658800 TI - Nosocomial outbreak of Blastoschizomyces capitatus associated with contaminated milk in a haematological unit. AB - In July 2002, Blastoschizomyces capitatus was isolated from four neutropenic patients in a haematology unit. Two patients died due to disseminated infection while the other two had oropharyngeal colonisation. Nosocomial acquisition of the fungus was suspected and epidemiological and environmental studies were undertaken. To determine the potential source for the acquisition of the fungus, epidemiological relationships between the patients were investigated. We performed surveillance cultures on all patients and took environmental cultures of air, inanimate surfaces, food samples, blood products and chemotherapy drugs. No direct contact transmission between patients was found and B. capitatus was isolated only in vacuum flasks used for breakfast milk distribution. All isolates were compared by four independent molecular typing methods: pulsed-field gel electrophoresis, genomic DNA restriction endonuclease analysis, randomly amplified polymorphic DNA, and polymerase chain reaction fingerprinting using a single primer specific for one minisatellite or two microsatellite DNAs. Milk vacuum flasks and clinical strains were genetically indistinguishable by all typing techniques. Milk vacuum flasks were withdrawn from all hospital units and no further B. capitatus infection was detected. Our findings suggest that clonal dissemination of a single strain of B. capitatus from vacuum flasks used for milk distribution was responsible for this nosocomial outbreak in the haematological unit. PMID- 21658801 TI - Adsorption of prion and tissue proteins to surgical stainless steel surfaces and the efficacy of decontamination following dry and wet storage conditions. AB - Iatrogenic transmission of the infectious prion protein (PrP(Sc)) is a potential threat due to its resistance to many chemical and enzymatic decontamination protocols and its strong adhesive properties to stainless steel. The conditions in which surgical instruments are handled during and after surgery may affect the level of tissue protein, prion attachment and the efficacy of subsequent decontamination regimes. This study investigated the adhesion of tissue protein and prion-associated amyloid to surgical stainless steel with respect to time and various storage conditions, and the subsequent outcome on the efficacy of enzymatic cleaning chemistries. Surfaces were contaminated with ME7-infected brain homogenate and left to dry between 0 and 120 min at room temperature or 24 h, in dry or moist conditions. Residual contamination before and after cleaning was visualised using sensitive fluorescent staining and episcopic differential interference contrast/epifluorescence microscopy. Longer drying times increased both protein and prion amyloid adsorption and affected the efficacy of the cleaning chemistries tested. A moist environment post-contamination significantly reduced the attachment of both protein and prion amyloid to the surgical stainless steel surface. Maintaining moist conditions could potentially improve the subsequent decontamination of reusable surgical instruments, also reducing process time and cost. PMID- 21658803 TI - Trauma is occasionally a surgical disease: how can we best predict when? PMID- 21658802 TI - Validation and refinement of a rule to predict emergency intervention in adult trauma patients. AB - STUDY OBJECTIVE: Trauma centers use "secondary triage" to determine the necessity of trauma surgeon involvement. A clinical decision rule, which includes penetrating injury, an initial systolic blood pressure less than 100 mm Hg, or an initial pulse rate greater than 100 beats/min, was developed to predict which trauma patients require emergency operative intervention or emergency procedural intervention (cricothyroidotomy or thoracotomy) in the emergency department. Our goal was to validate this rule in an adult trauma population and to compare it with the American College of Surgeons' major resuscitation criteria. METHODS: We used Level I trauma center registry data from September 1, 1995, through November 30, 2008. Outcomes were confirmed with blinded abstractors. Sensitivity, specificity, and 95% confidence intervals (CIs) were calculated. RESULTS: Our patient sample included 20,872 individuals. The median Injury Severity Score was 9 (interquartile range 4 to 16), 15.3% of patients had penetrating injuries, 13.5% had a systolic blood pressure less than 100 mm Hg, and 32.5% had a pulse rate greater than 100 beats/min. Emergency operative intervention or procedural intervention was required in 1,099 patients (5.3%; 95% CI 5.0% to 5.6%). The sensitivities and specificities of the rule and the major resuscitation criteria for predicting emergency operative intervention or emergency procedural intervention were 95.6% (95% CI 94.3% to 96.8%) and 56.1% (95% CI 55.4% to 56.8%) and 85.5% (95% CI 83.3% to 87.5%) and 80.9% (95% CI 80.3% to 81.4%), respectively. CONCLUSION: This new rule was more sensitive for predicting the need for emergency operative intervention or emergency procedural intervention directly compared with the American College of Surgeons' major resuscitation criteria, which may improve the effectiveness and efficiency of trauma triage. PMID- 21658804 TI - Elective neck dissection for second primary after previous definitive radiotherapy. AB - PURPOSE: The aim of this study was to define the role of neck dissection during surgery for patients who have received elective nodal irradiation in the course of treatment for a prior squamous cell carcinoma of the head and neck (SCCHN) and are subsequently diagnosed with a second primary SCCHN. MATERIALS AND METHODS: We reviewed the medical records of 13 patients who received both definitive radiotherapy and elective nodal irradiation for T1-4 N0 M0 SCCHN of the oral cavity, oropharynx, hypopharynx, or larynx who then subsequently developed a metachronous T1-4 N0 M0 SCCHN primary at a new site. All second primary tumors were treated with surgery. Ten of the 13 patients also received an elective neck dissection (END) at that time: 7 unilateral and 3 bilateral. We report the outcomes for the patients in this series. RESULTS: One (8%) of 13 neck dissection specimens was positive in 1 (10%) of 10 patients. The 5-year outcomes were the following: local-regional control, 67%; local control, 77%; disease-free survival, 62%; overall survival, 38%; and cause-specific survival rate, 77%. Six patients experienced treatment-related complications of grade 2 or higher (per Common Terminology Criteria for Adverse Events, version 4). Complications occurred exclusively in patients who received an END. CONCLUSIONS: The risk of occult nodal disease may be low enough to justify omitting an END for a second primary SCCHN in selected patients while maintaining treatment efficacy and reducing patient morbidity. Larger studies on this subject are needed to further address this question. PMID- 21658805 TI - Topical sucralfate for pain after oral CO2 laser surgery: a prospective, randomized, controlled trial. AB - PURPOSE: The aim of this study was to assess the effect of topical sucralfate on postoperative pain scores and other secondary outcomes including the frequency and duration of analgesic use and postoperative bleeding episodes after CO(2) laser treatment of oral leukoplakia. PATIENTS AND METHODS: In this prospective trial, a total of 80 patients were randomized into the sucralfate group (n = 40) or the control group (n = 40). Postoperative pain scores, the frequency and duration of analgesic requirements, and postoperative wound bleeding episodes were compared between the 2 groups from the operative day to postoperative day 6. RESULTS: Patients in the sucralfate group experienced significantly less postoperative pain on postoperative days 1 and 2. Although there was no significant difference in frequency and duration of analgesic use between the 2 groups, a trend toward lower frequency and fewer days of analgesic use in the sucralfate group was observed. CONCLUSIONS: This study demonstrated the efficacy of topical sucralfate application in diminishing postoperative pain after CO(2) laser therapy for oral leukoplakia. Topical sucralfate can be considered a feasible adjuvant medication for the control of pain after CO(2) laser treatment of oral leukoplakia. PMID- 21658806 TI - The tough tracheoesophageal puncture. AB - EDUCATIONAL OBJECTIVE: At the conclusion of this presentation, the participants should be aware of the technique and success of in-office transnasal esophageal (TNE)-guided tracheoesophageal puncture (TEP) placement in patients who have failed prior attempts in the operating room or are not healthy enough to undergo general anesthesia. OBJECTIVES: The aim of this study was to demonstrate the technique of TEP, which can be completed safely in an office setting when patients are not able to undergo general anesthesia due to medical comorbities or have previously had an unsuccessful attempt at TEP placement in the operating room due to anatomical reasons. STUDY DESIGN: This study is a retrospective chart review from 2007 to 2011. METHODS: A total of 13 outpatient adults with a history of total laryngectomy presenting to the laryngology clinic for TEP after either failing prior placement in the operating room or not being able to undergo general anesthesia due to medical comorbities were identified. In-office TNE guided TEP placement was performed on all 13 patients. RESULTS: All subjects underwent successful TNE-guided TEP placement in the office. Complications included 1 possible false passage and 1 case of cellulitis. CONCLUSIONS: Patients who could not undergo TEP placement in the operating room due to poor exposure or medical comorbities were able to successfully undergo the procedure in an office setting with good results. PMID- 21658807 TI - Early death from papillary thyroid carcinoma. AB - PURPOSE: The natural history of papillary thyroid carcinoma (PTC) is characterized by a slow growth rate and an excellent prognosis at 20 and 30 years. However, there is a small subset of patients with poorer outcome. METHODS: Twenty patients who died of PTC within 10 years of diagnosis were studied to identify prognostic indicators and biological markers of early death. Findings were statistically compared with a previous review of all patients with PTC treated in the same institute and studies in the literature. RESULTS: The study group included 6 men and 14 women with a mean age of 65 years at diagnosis. Average tumor size was 3.6 cm; 16 patients had extracapsular extension. All tumor samples studied histologically stained poorly for p53, Ki67, and CD34. Regional metastases were present in half the patients, and distal metastases in all. All patients had an advanced disease stage (Tumor, Node, Metastases classification), and only 4 had a low score on the Metastases, Age, Completeness of resection, local Invasion, tumor Size risk stratification. Analysis of the findings against data in the literature for the whole population of patients with PTC, who had a considerably better survival (<8% mortality within 8-15 years vs 100% within 10 years in our sample), yielded significant differences for rates of extrathyroidal extension (P = .0001), regional metastases (P = .016), and distant metastases (P = .0001). CONCLUSION: Extrathyroid extension, late regional metastases, and distant metastases may be risk factors for early death from PTC. PMID- 21658808 TI - The use of robotics in otolaryngology-head and neck surgery: a systematic review. AB - BACKGROUND: Robotic surgery has become increasingly used due to its enhancement of visualization, precision, and articulation. It eliminates many of the problems encountered with conventional minimally invasive techniques and has been shown to result in reduced blood loss and complications. The rise in endoscopic procedures in otolaryngology-head and neck surgery, and associated difficulties, suggests that robotic surgery may have a role to play. OBJECTIVE OF REVIEW: To determine whether robotic surgery conveys any benefits compared to conventional minimally invasive approaches, specifically looking at precision, operative time, and visualization. TYPE OF REVIEW: A systematic review of the literature with a defined search strategy. SEARCH STRATEGY: Searches of MEDLINE, EMBASE and CENTRAL using strategy: ((robot* OR (robot*AND surgery)) AND (ent OR otolaryngology)) to November 2010. EVALUATION METHOD: Articles reviewed by authors and data compiled in tables for analysis. RESULTS: There were 33 references included in the study. Access and visualization were regularly mentioned as key benefits, though no objective data has been recorded in any study. Once initial setup difficulties were overcome, operative time was shown to decrease with robotic surgery, except in one controlled series of thyroid surgeries. Precision was also highlighted as an advantage, particularly in otological and skull base surgery. Postoperative outcomes were considered equivalent to or better than conventional surgery. Cost was the biggest drawback. CONCLUSIONS: The evidence base to date suggests there are benefits to robotic surgery in OHNS, particularly with regards to access, precision, and operative time but there is a lack of controlled, prospective studies with objective outcome measures. In addition, economic feasibility studies must be carried out before a robotic OHNS service is established. PMID- 21658809 TI - Hypopharyngeal cancer in a pregnant woman. AB - Cancer in pregnant women is a very difficult clinical condition that profoundly affects patients and their families, as well as the medical staff who provide their care. Diagnostic and therapeutic decisions must balance adequate treatment and fetal risk. In developed societies, cancer in pregnant women has become more common during the last 30 years because of an increase in the number of relatively older women who give birth. The most common malignancies in pregnant women are melanoma; lymphoma; leukemia; and breast, cervical, ovarian, gastrointestinal, and genitourinary cancers. Cancer of the head and neck in pregnant patients is very rare. In this article, we describe a rare case of advanced squamous cell carcinoma of the hypopharyngeal area in a young pregnant woman, and we discuss the diagnosis and treatment of cancers of the head and neck in pregnant patients. PMID- 21658810 TI - Room ventilation and the risk of airborne infection transmission in 3 health care settings within a large teaching hospital. AB - BACKGROUND: Room ventilation is a key determinant of airborne disease transmission. Despite this, ventilation guidelines in hospitals are not founded on robust scientific evidence related to the prevention of airborne transmission. METHODS: We sought to assess the effect of ventilation rates on influenza, tuberculosis, and rhinovirus infection risk within 3 distinct rooms in a major urban hospital: a lung function laboratory, an emergency department negative pressure isolation room, and an outpatient consultation room. Air-exchange rate measurements were performed in each room using CO2 as a tracer. The model developed by Gammaitoni and Nucci was used to estimate infection risk. RESULTS: Current outdoor air-exchange rates in the lung function laboratory and emergency department isolation room limited infection risks to 0.1%-3.6%. Influenza risk for individuals entering an outpatient consultation room after an infectious individual departed ranged from 3.6% to 20.7%, depending on the duration for which each person occupied the room. CONCLUSION: Given the absence of definitive ventilation guidelines for hospitals, air-exchange measurements combined with modeling afford a useful means of assessing, on a case-by-case basis, the suitability of room ventilation for preventing airborne disease transmission. PMID- 21658811 TI - Trial to control an outbreak of Panton-Valentine leukocidin-positive methicillin resistant Staphylococcus aureus at a boarding school in Japan. AB - BACKGROUND: Our retrospective investigation of methicillin-resistant Staphylococcus aureus (MRSA) infection at a hospital in Japan around 2007 suggested dissemination of community-associated MRSA (CA-MRSA) strains among healthy students in a Japanese boarding school, which frequently caused skin disease and exhibited the same antibiogram patterns. METHODS: Active surveillance of skin diseases for 6 months after May 2008, examination of MRSA carriage in selected high-risk groups, and investigation of their life circumstances, including environmental cultures, were conducted in the school. Furthermore, we strengthened hygiene practices and improved recognized risk factors from November 2008 and observed the occurrence of skin diseases and MRSA carriage rate for the evaluation of infection controls. RESULTS: We identified 21 patients with skin diseases in whom MRSA strains were isolated. MRSA colonization rates in 3 selected groups ranged from 7.6% to 36.6%. The rates of both skin disease and MRSA carriage decreased significantly after infection controls were introduced. Genetic analysis revealed a main dissemination of a PVL-positive SCCmec IVc clone (41/47 isolates in total), presenting as a different pulsed-field type than USA300. CONCLUSION: This first report of a PVL-positive CA-MRSA outbreak in Japan demonstrates systematic management of dissemination by conducting surveillance in a closed community. PMID- 21658812 TI - Hepatitis B outbreak associated with a hematology-oncology office practice in New Jersey, 2009. AB - BACKGROUND: Transmission of bloodborne pathogens due to breaches in infection control is becoming increasingly recognized as greater emphasis is placed on reducing health care-associated infections. Two women, aged 60 and 77 years, were diagnosed with acute hepatitis B virus (HBV) infection; both received chemotherapy at the same physician's office. Due to suspicion of health care associated HBV transmission, a multidisciplinary team initiated an investigation of the hematology-oncology office practice. METHODS: We performed an onsite inspection and environmental assessment, staff interviews, records review, and observation of staff practices. Patients who visited the office practice between January 1, 2006 and March 3, 2009 were advised to seek testing for bloodborne pathogens. Patients and medical providers were interviewed. Specimens from HBV infected patients were sent to the Centers for Disease Control and Prevention for HBV DNA testing and phylogenic analysis. RESULTS: Multiple breaches in infection control were identified, including deficient policies and procedures, improper hand hygiene, medication preparation in a blood processing area, common-use saline bags, and reuse of single-dose vials. The office practice was closed, and the physician's license was suspended. Out of 2,700 patients notified, test results were available for 1,394 (51.6%). Twenty-nine outbreak-associated HBV cases were identified. Specimens from 11 case-patients demonstrated 99.9%-100% nucleotide identity on phylogenetic analysis. CONCLUSION: Systematic breaches in infection control led to ongoing transmission of HBV infection among patients undergoing invasive procedures at the office practice. This investigation underscores the need for improved regulatory oversight of outpatient health care settings, improved infection control and injection safety education for health care providers, and the development of mechanisms for ongoing communication and cooperation among public health agencies. PMID- 21658813 TI - A pledge to hand hygiene commitment. PMID- 21658814 TI - [Comment to "Photodynamic diagnosis with hexaminolevulinate in Non-Muscle Invasive Bladder Cancer. Experience of the BLUE GROUP"]. PMID- 21658815 TI - [Therapeutic adherence. How difficult it is to comply!]. PMID- 21658816 TI - Osteopoikilosis: a major diagnostic problem solved by bone scintigraphy. AB - Osteopoikilosis (OPK) is a rare disease with an unknown etiology. Although a benign condition, it may lead to diagnostic problems when the patient undergoes diagnostic imaging of the skeletal system due to various reasons like malignancy. Herein, we report 2 cases with OPK causing difficulties in the final diagnosis of the cases which was resolved with the contribution of bone scintigraphy and clinical follow-up. PMID- 21658817 TI - [Prevalence of micrometastases and isolated tumor cells in the sentinel node at early stage breast cancer]. AB - AIM: To analyze the prevalence of isolated tumor cells (ITC) and micrometastases in the sentinel node of early stage breast cancer. MATERIAL AND METHODS: A total of 234 patients diagnosed of breast cancer, stages T1 or T2, with no axillary involvement detected by palpation or ultrasound-FNA, were studied. The sentinel node (SN) was identified by lymphoscintigraphy and removed in the operating room. Serial sections and immunohistochemical staining were then performed, classifying them as negative (SN-), negative with ITC (SN-ITC), positive with micrometastases (SN+mic) and positive with macrometastases (SN+mac). A complete axillary lymphadenectomy (CAL) was carried out in those cases with micro- or macrometastases, the former being classified as negative (CAL-), positive with micrometatases (CAL+mic), and positive with macrometastases (CAL+mac). The follow up ranged from 6-71 months. RESULTS: ITC were found in 12 patients (5.1%) and micrometastases in 24 (10.3%). Thus, a total of 36 patients were affected by some of these conditions (15.4%). In the group with micrometastases, the result of CAL was CAL- in 19/24 (79.1%), CAL+mic in 2 (8.3%) and CAL+mac in 3 (12.5%). No axillary recurrences have occurred up to date. CONCLUSIONS: ITC and micrometastases were found in the sentinel node in a significant percentage of patients in the early stages of breast cancer. The low percentage of further axillary invasion in the group of micrometastases may open up the possibility of avoiding CAL in favor of other adjuvant treatments (chemotherapy, radiotherapy). PMID- 21658818 TI - SPECT-CT with 67Ga-citrate in the management of spondylodiscitis. AB - Spondylodiscitis affects a small proportion of all patients with locomotor system infections, however its early diagnosis is important due to its potential morbidity. Magnetic resonance imaging is the diagnostic method of choice. Nonetheless, it has certain limitations and is not suitable for all patients. The conventional scintigraphic studies for evaluating spondylodiscitis are those performed with (99m)Tc-HDP and (67)Ga-citrate. However, their poor image resolution is a disadvantage of these techniques. The use of hybrid Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) improves detection of the disease by combining functional and anatomical images. We present 9 patients with suspicion of spondylodiscitis who underwent sequential bone scintigraphy with (99m)Tc-HDP and SPECT-CT with (67)Ga-citrate, with positive findings confirmed by clinical monitoring for at least 6 months. PMID- 21658819 TI - Model of music cognition and amusia. AB - INTRODUCTION: The study of the neural networks involved in music processing has received less attention than work researching the brain's language networks. For the last two decades there has been a growing interest in discovering the functional mechanisms of the musical brain and understanding those disorders in which brain regions linked with perception and production of music are damaged. DISCUSSION: Congenital and acquired musical deficits in their various forms (perception, execution, music-memory) are grouped together under the generic term amusia. In this selective review we present the "cutting edge" studies on the cognitive and neural processes implicated in music and the various forms of amusia. CONCLUSIONS: Musical processing requires a large cortico-subcortical network which is distributed throughout both cerebral hemispheres and the cerebellum. The analysis of healthy subjects using functional neuroimaging and examination of selective deficits (e.g., tone, rhythm, timbre, melodic contours) in patients will improve our knowledge of the mechanisms involved in musical processing and the latter's relationship with other cognitive processes. PMID- 21658820 TI - Whipple's disease: multiple systemic and neurological relapses. PMID- 21658821 TI - [Simultaneous carotid angioplasty and intracraneal thrombectomy in acute stroke]. PMID- 21658822 TI - Nurses learn caring theory by being co-researchers in a surgical setting. AB - This paper present findings from research on the following issues: How nurses from surgical unit learn a caring theory by being co-researchers in a research group. The aim was to describe the learning process of the nurses when they were co-researchers in a research group. The study has a qualitative design and a hermeneutical approach. Data were collected through interviews with seven registered nurses in hospital in mid Sweden. The study shows that nurses learn caring by listening to each other. Four sub-themes emerged through the interpretation: Nurses learn caring theory by listening to each other when they are; giving time to talk to one another, expressing their actions in words, sharing thoughts with others and allowing themselves to be touched by each other's stories. The new understanding highlights that learning in research groups can be understood as a learning process, where nurses listen to one another and thereby create an expression and meaning of their experiences through caring theory, while at the same time developing their profession. Nurses learn caring theory by being co-researchers in a research group. In order for this to happen, the research collaboration should be characterized by realism and engagement. PMID- 21658823 TI - Drugs and having babies: an exploration of how a specialist clinic meets the needs of chemically dependent pregnant women. AB - OBJECTIVES: to explore the extent to which a specialist clinic meets the needs of chemically dependent women. DESIGN: a critical ethnography informed by theorists such as Habermas and feminists' interpretation of Foucault. SETTING: a specialist antenatal clinic for chemically dependent pregnant women at a major metropolitan women's hospital in Melbourne, Australia. PARTICIPANTS: a purposive sample of twenty (20) chemically dependent pregnant women who attended the clinic. Data collection and analysis included three taped interviews (two preceding the birth and one post birth), observation of the interactions between the women and the clinic staff over a 25-month period and chart audits. FINDINGS: similar to other studies there were multiple factors influencing development and maintenance of chemical dependency in this group of women, including family instability, family history of drug and alcohol abuse, childhood sexual abuse, having a chemically dependent partner and having a dual diagnosis of both drug addiction and mental illness. Initially there was considerable variation between the women and the clinic staff's expectations with regard to attending for antenatal care and conforming to a set regime as the women struggled with the contradictions inherent in their lifestyle and that of the 'normal' expectant mother. Aspects of that struggle included their belief that their opinions and knowledge of their lives was largely ignored, leading to episodes of resistance. Several women alleged the clinics staff's relationship with them was influenced by a belief that the women were 'hopeless addicts in need of expert medical and midwifery care' and that the clinic staff exercised control in an authoritarian manner. However, as they explored possibilities for collaboration, they realised they could exercise power and work towards a more equal relationship with staff. The quality of relationships in most instances improved over time, and if not always strictly collaborative, was situated at various points along a continuum from minimal to full co-operation, with concomitant varying levels of success in terms of outcomes. It was often the attitude of individual staff members, particularly midwives, that was the key to the way in which the women responded to care. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: comprehensive history-taking and engaging women as early as possible in pregnancy; providing continuity of care - particularly midwife care - to assist in developing a collaborative approach to care; provision of an extended period of postnatal support to at least six months for those women able to parent their children was a key recommendation. PMID- 21658825 TI - Adequacy of dialysis clinic staffing and quality of care: a review of evidence and areas of needed research. AB - Improving the quality of care delivered to patients receiving in-center dialysis treatment remains a perpetual concern with stakeholders. Quality indicators traditionally have focused on such items as adequacy of dialysis, anemia management, patient survival, and, most recently, the percentage using arteriovenous fistulas. Largely overlooked in the quest for improvement has been adequate consideration of dialysis clinic staffing levels. Staffing is important because it has been identified as a structural measure of quality. With 326,671 (93.1%) of all dialysis patients receiving in-center treatments, this is a potentially critical issue. This article reviews evidence related to inadequacies in clinic staffing and how they may be contributing to suboptimal care and outcomes. Focusing on nephrologists, nurses, patient care technicians, dietitians, and social workers, this article suggests areas of needed research. PMID- 21658824 TI - In vitro assessments of reverse glenoid stability using displacement gages are misleading - recommendations for accurate measurements of interface micromotion. AB - BACKGROUND: Baseplate micromotion of the reverse shoulder glenoid component can lead to implant loosening. We hypothesized that a remotely positioned displacement gage measures elastic deformation of the system rather than actual micromotion at the implant/bone interface. METHODS: Reverse glenoid components were implanted into polyurethane blocks of 3 different densities. A 700 N compressive load was maintained and a vertical 700 N shear load was applied for 1000 cycles. In addition to the typical gage measurement, a digital image analysis of micromotion at the implant/block interface using high resolution cameras was performed. The measurements were validated on human specimens. A finite element model was implemented to study the isolated effect of block deformation on baseplate displacements. FINDINGS: With the gage, typically reported micromotions were measured. Two orders of magnitude lower micromotions were detected using interface image-based analysis. The finite element simulation showed that elastic deformation alone can cause micromotion magnitudes as measured with displacement gages. Polyurethane blocks of 20 and 15 lbs per cubic foot density best reproduced micromotions as measured on human specimens. INTERPRETATION: We found considerably less relative micromotion at the implant/bone interface than previously assumed. Gage measurements quantify elastic deformation and not true interface micromotion. High resolution digital imaging at the implant/bone interface is strongly recommended for an accurate assessment of reverse glenoid component micromotion. Tests should further adopt 20 or 15 pcf bone test surrogates. Further studies are required to identify the failure modes encountered in vivo, and a corresponding in vitro testing methodology can then be developed. PMID- 21658826 TI - Membranous nephropathy associated with IgG4-related disease. AB - Immunoglobulin G4 (IgG4)-related systemic disease is a rare condition characterized by high levels of circulating IgG4 and IgG4-positive plasma cell infiltrates in various organs, including the pancreas, salivary glands, biliary tract, liver, lung, and kidney. We describe a case of a 54-year-old man with IgG4 related systemic disease presenting with autoimmune pancreatitis and Mikulicz disease. Steroid therapy decreased circulating IgG4 levels and promoted regression of clinical signs. Thereafter, an increase in serum IgG4 values was followed by the occurrence of nephrotic-range proteinuria. Kidney biopsy showed membranous nephropathy with no IgG4-positive cell infiltrates. A search for circulating immune complexes was negative, and antibodies against M-type phospholipase A(2) receptor could not be detected. Western blot analyses identified circulating IgG3 reacting with superoxide dismutase 2. This case suggests that membranous nephropathy represents an additional renal manifestation of IgG4-related systemic disease, with a pathogenesis possibly associated with neoproduction of autoantibodies targeting podocyte antigen(s). PMID- 21658827 TI - Dietary omega-3 fatty acid, ratio of omega-6 to omega-3 intake, inflammation, and survival in long-term hemodialysis patients. AB - BACKGROUND: Mortality in long-term hemodialysis patients is high, mostly attributed to cardiovascular events, and may be related to chronic inflammation. We hypothesized that the anti-inflammatory benefits of higher dietary intake of omega-3 compared with omega-6 polyunsaturated fatty acids may modulate the inflammatory processes and decrease death risk. STUDY DESIGN: Prospective cohort study using linear and Cox proportional regressions. SETTING & PARTICIPANTS: 145 hemodialysis patients from 8 DaVita dialysis clinics in Southern California in 2001-2007. PREDICTORS: Intake of dietary omega-3 and ratio of omega-6 to omega-3 using 3-day food record supplemented by dietary interview. OUTCOMES: 1-year change in serum C-reactive protein (CRP) level and 6-year survival. RESULTS: Patients were aged 53 +/- 14 years (mean +/- SD) and included 43% women and 42% African Americans. Median dietary omega-3 intake, ratio of omega-6 to omega-3 intake, baseline serum CRP level, and change in CRP level over 1 year were 1.1 (25th-75th percentile, 0.8-1.6) g/d, 9.3 (25th-75th percentile, 7.6-11.3), 3.1 (25th-75th percentile, 0.8-6.8) mg/L, and +0.2 (25th-75th percentile, -0.4 to +0.8) mg/L, respectively. In regression models adjusted for case-mix, dietary calorie and fat intake, body mass index, and history of hypertension, each 1-unit higher ratio of omega-6 to omega-3 intake was associated with a 0.55-mg/L increase in serum CRP level (P = 0.03). In the fully adjusted model, death HRs for the first (1.7-<7.6), second (7.6-<9.3), third (9.3-<11.3), and fourth (11.3 17.4) quartiles of dietary omega-6 to omega-3 ratio were 0.39 (95% CI, 0.14 1.18), 0.30 (95% CI, 0.09-0.99), 0.67 (95% CI, 0.25-1.79), and 1.00 (reference), respectively (P for trend = 0.06). LIMITATIONS: 3-day food record may underestimate actual dietary fat intake at an individual level. CONCLUSIONS: Higher dietary omega-6 to omega-3 ratio appears to be associated with both worsening inflammation over time and a trend toward higher death risk in hemodialysis patients. Additional studies including interventional trials are needed to examine the association of dietary fatty acids with clinical outcomes in these patients. PMID- 21658828 TI - Health-related quality of life and clinical outcomes in kidney transplant recipients. AB - BACKGROUND: Health-related quality of life (HRQoL) is an important outcome measure in patients with chronic kidney disease. It also has been shown repeatedly to predict mortality in various patient populations. In a prospective cohort study, we assessed the association between HRQoL and long-term clinical outcome in kidney transplant recipients. STUDY DESIGN: Prospective prevalent cohort study. SETTING & PARTICIPANTS: We collected sociodemographic parameters, medical and transplant history, and laboratory data at baseline from 879 prevalent kidney transplant recipients (mean age, 49 +/- 13 [standard deviation] years; 58% men; and 17% with diabetes mellitus). PREDICTOR: We assessed HRQoL using the KDQoL-SF (Kidney Disease Quality of Life Short Form) questionnaire and assessed depressive symptoms using the Center for Epidemiologic Studies Depression Scale. OUTCOMES: All-cause mortality and death-censored transplant loss or death with functioning transplant. Cox regression models and semiparametric competing-risks regression analyses were used to measure associations between HRQoL scores and outcomes. RESULTS: Most examined HRQoL domains were associated with clinical outcome in unadjusted models. After adjusting for several important confounders, the 36-Item Short Form Health Survey (SF-36) Physical Composite Score and Physical Functioning and General Health Perception subscale scores remained independently associated with clinical outcomes. Every 10-point increase in SF-36 Physical Composite Score and Physical Functioning and General Health Perception scores was associated with 18% (HR, 0.82; 95% CI, 0.71-0.95), 11% (HR, 0.89; 95% CI, 0.84-0.94), and 7% lower risks of mortality (HR, 0.93; 95% CI, 0.88-1.00), respectively. LIMITATIONS: Single center study. CONCLUSIONS: We showed that the SF-36 Physical Composite Score and Physical Functioning and General Health Perception KDQoL-SF domain scores are associated independently with increased risk of mortality in kidney transplant patients. Regular assessment of HRQoL may be a useful tool to inform health care providers about the prognosis of kidney transplant recipients. Additional studies are needed to assess whether interventions aimed at improving HRQoL would improve clinical outcomes in this patient population. PMID- 21658829 TI - Racial and ethnic differences in the association of body mass index and survival in maintenance hemodialysis patients. AB - BACKGROUND: In maintenance hemodialysis (HD) patients, overweight and obesity are associated with survival advantages. Given the greater survival of maintenance HD patients who are minorities, we hypothesized that increased body mass index (BMI) is associated more strongly with lower mortality in blacks and Hispanics relative to non-Hispanic whites. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We examined a 6-year (2001-2007) cohort of 109,605 maintenance HD patients including 39,090 blacks, 17,417 Hispanics, and 53,098 non-Hispanic white maintenance HD outpatients from DaVita dialysis clinics. Cox proportional hazards models examined the association between BMI and survival. PREDICTORS: Race and BMI. OUTCOMES: All-cause mortality. RESULTS: Patients had a mean age of 62 +/- 15 (standard deviation) years and included 45% women and 45% patients with diabetes. Across 10 a priori-selected BMI categories (<18->=40 kg/m(2)), higher BMI was associated with greater survival in all 3 racial/ethnic groups. However, Hispanic and black patients experienced higher survival gains compared with non-Hispanic whites across higher BMI categories. Hispanics and blacks in the >=40-kg/m(2) category had the largest adjusted decrease in death HR with increasing BMI (0.57 [95% CI, 0.49-0.68] and 0.63 [95% CI, 0.58-0.70], respectively) compared with non Hispanic whites in the 23- to 25-kg/m(2) group (reference category). In linear models, although the inverse BMI-mortality association was observed for all subgroups, overall black maintenance HD patients showed the largest consistent decrease in death HR with increasing BMI. LIMITATIONS: Race and ethnicity categories were based on self-identified data. CONCLUSIONS: Whereas the survival advantage of high BMI is consistent across all racial/ethnic groups, black maintenance HD patients had the strongest and most consistent association of higher BMI with improved survival. PMID- 21658830 TI - Genetic diagnosis in consanguineous families with kidney disease by homozygosity mapping coupled with whole-exome sequencing. AB - BACKGROUND: Accurate diagnosis of the primary cause of an individual's kidney disease can be essential for proper management. Some kidney diseases have overlapping histopathologic features despite being caused by defects in different genes. In this report, we describe 2 consanguineous Saudi Arabian families in which individuals presented with kidney failure and mixed clinical and histologic features initially believed to be consistent with focal segmental glomerulosclerosis. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We studied members of 2 apparently unrelated families from Saudi Arabia with kidney disease. MEASUREMENTS: Whole-genome single-nucleotide polymorphism analysis followed by targeted isolation and sequencing of exons using genomic DNA samples from affected members of these families, followed by additional focused genotyping and sequence analysis. RESULTS: The 2 apparently unrelated families shared a region of homozygosity on chromosome 2q13. Exome sequence from affected individuals lacked sequence reads from the NPHP1 gene, which is located within this homozygous region. Additional polymerase chain reaction-based genotyping confirmed that affected individuals had NPHP1 deletions, rather than defects in a known focal segmental glomerulosclerosis-associated gene. LIMITATIONS: The methods used here may not result in a clear genetic diagnosis in many cases of apparent familial kidney disease. CONCLUSIONS: This analysis shows the power of new high-throughput genotyping and sequencing technologies to aid in the rapid genetic diagnosis of individuals with an inherited form of kidney disease. We believe it is likely that such tools may become useful clinical genetic tools and alter the manner in which diagnoses are made in nephrology. PMID- 21658831 TI - Hispanic immigrant women's perspective on healthy foods and the New York City retail food environment: A mixed-method study. AB - Much has been written about the role of dietary acculturation in the epidemic of obesity among Hispanic immigrants in the United States. Yet little is known about the role of beliefs and preferences in immigrants' dietary practices and their relationship to the retail food environment in which the practices occur. We conducted a mixed-methods convergence study of these issues. Twenty-eight foreign born Hispanic adult women, recruited from families enrolled in a childhood asthma study and mainly living in New York City took part in 60-90 min, semi-structured interviews regarding their dietary beliefs, preferences, and practices. The findings were then used to formulate hypotheses for analyses of food frequency questionnaire (FFQ) data collected from the 345 New York Hispanic women enrolled in the asthma study. Generalized estimating equations were used to determine whether characteristics of the retail food environment within 0.5 km of the home predicted diet, adjusting for individual and neighborhood socio-demographic characteristics. In the interviews, healthy food was rarely discussed in terms of nutritional content. Instead, considerations of freshness, as indicated by time since harvest or slaughter and thus local sourcing; purity, as indicated by the absence of preservatives and processing; and naturalness, as indicated by chemical free farming practices, were the primary axes around which healthy food was defined. Quantitative results were consistent with the qualitative findings: 1) the presence of a farmers' market within the home neighborhood was associated with consumption of more total servings per day of fruit, vegetables, and juice, and 2) the presence of a farmers' market and/or a livestock market was associated with consumption of more servings per day of meat. Proximity to supermarkets or medium-sized grocery stores was not associated with consumption. The results suggest that the availability of fresh produce and meat from local farms may influence diet among Hispanic women in urban neighborhoods. PMID- 21658832 TI - Does degree of asymmetry relate to performance? A reply to Boles and Barth. AB - In a recent critique Boles and Barth (2011) argue that their prior study investigating asymmetry/performance relationships (Boles, Barth, & Merrill, 2008) uncovered the "true" association (i.e., negative correlation) between lateralization of visual lexical processes and word recognition performance. They contend that our study reporting positive correlations of lexical asymmetry and reading performance (Chiarello et al., 2009) was flawed and hence inconclusive. In this response we address the two major objections raised by Boles and Barth (2011) regarding our selection of tasks and asymmetry measures. We conclude that the Boles and Barth principle of task purity is not relevant to the stated aims of our investigation, and that our linear regression method of measuring asymmetry is valid given the high level of accuracy for the tasks we reported. Because the aims of each investigation differed, we argue that it is unwise to attempt to fit each study into the framework favored by Boles and Barth (2011). PMID- 21658833 TI - Characterization of a mediastinal thymic seminoma using cardiac magnetic resonance. PMID- 21658834 TI - Impact of the use of an automated chest-compression device on airway management during out-of-hospital cardiopulmonary resuscitation: the PLAINT study. AB - INTRODUCTION: Automated chest-compression devices (ACCDs) have recently been proposed in the management of out-of-hospital cardiac arrest (cardiopulmonary resuscitation, CPR). During CPR, it is still unknown whether the ACCD or intubation is to be first implemented. Knowing the impact of an ACCD on intubation conditions could strongly contribute to determine the best sequence. Therefore, we undertook an experimental study on intubation conditions on a mannequin with or without the use of an ACCD. METHODS: Emergency physicians and nurses experienced in the field of cardiac-arrest management (including orotracheal intubation) were randomly assigned to three scenarios to intubate a mannequin: patient lying on the floor without an ACCD (group 1), patient lying on the floor with the ACCD switched off (group 2) or switched on (group 3). The primary end point was intubation time. Estimated intubation difficulty evaluated on a visual analogue scale (VAS), ranging from 0 (easy) to 100 (impossible), number of attempts, Cormack grade and dental traumatisms associated with the intubation procedure were secondary end points. RESULTS: A total of 44 operators performed the intubation. Times to intubation were 14 (11-22), 15 (10-21) and 18 (15-27)s for groups 1, 2 and 3, respectively. The VAS difficulties were 12 (5 25), 15 (10-25) and 15 (5-21), respectively. Intubation conditions did not differ between the 'without an ACCD group' and the 'switched-off ACCD group'. In the 'switched-on ACCD group', time to intubation was significantly increased in comparison with groups 1 and 2 with a median difference of 4 (1-10) and 3 (0-7)s, respectively. The VAS difficulty was also significantly increased in the 'switched-on ACCD group'. Other secondary end-point criteria did not differ between the three groups. CONCLUSION: Due to the major role of compression during CPR, we suggest that the ACCD should not be systematically switched off for routine intubation. PMID- 21658835 TI - Temporary endovascular balloon occlusion of the bilateral internal iliac arteries to control hemorrhage during laparoscopic-assisted vaginal hysterectomy for cervical myoma. AB - OBJECTIVE: To report our initial experience with temporary endovascular balloon occlusion of the bilateral internal iliac arteries to control hemorrhage during laparoscopic-assisted vaginal hysterectomy (LAVH) for cervical myoma. STUDY DESIGN: Thirteen patients with cervical myoma were treated by LAVH combined with temporary endovascular balloon occlusion of the bilateral internal iliac arteries from September 2008 to October 2010. Preoperative evaluation of cervical myoma was made by ultrasonography, magnetic resonance imaging and three-dimensional computerized tomographic angiography, and curative management was made by LAVH combined with temporary endovascular balloon occlusion of the bilateral internal iliac arteries. RESULTS: Nine patients with extracervical myoma and 4 patients with intracervical myoma were successfully managed by LAVH combined with temporary endovascular balloon occlusion of the bilateral internal iliac arteries. For extracervical myomas, the median extirpated uterine weight was 591 g (range 360-1010 g). Median duration required for placement of balloon occlusion catheter was 60 min (range 47-69 min). Median surgical duration was 98.5 min (range 77-149 min). Median duration of endovascular balloon occlusion of the bilateral internal iliac arteries was 66 min (range 42-98 min). The median estimated blood loss was 355 mL (range 50-1950 mL). For intracervical myomas, the median extirpated uterine weight was 513 g (range 302-710 g). Median duration required for placement of balloon occlusion catheter was 63 min (range 42-76 min). Median surgical duration was 96.5 min (range 92-100 min). Median duration of endovascular balloon occlusion of the bilateral internal iliac arteries was 49 min (range 44-60 min). The median estimated blood loss was 210 mL (range 150-650 mL). Transfusion of preoperatively donated autologous blood negated the need for bank blood. There were no major interventional radiological and surgical complications in the present case series. CONCLUSIONS: Temporary endovascular balloon occlusion of the bilateral internal iliac arteries is a feasible minimally invasive alternative to control hemorrhage during LAVH for cervical myoma. PMID- 21658836 TI - Current management of endometrial hyperplasia-a survey of United Kingdom consultant gynaecologists. AB - OBJECTIVE: To determine current practice for the management of endometrial hyperplasia. STUDY DESIGN: We carried out a web-based survey of all UK consultant gynaecologists, from the Royal College of Obstetricians and Gynaecologists (RCOG) database, to evaluate the current practice and to enquire whether a trial between oral progestogens and LNG-IUS for endometrial hyperplasia is required. RESULTS: We sent 1090 email invitations and 411 (37.7%) responded to this survey. In total, 338 consultant gynaecologists, who manage patients with endometrial hyperplasia, responded to all items of the survey. The oral progestogens (33.2%) and the LNG-IUS (52.1%) were the most popular choices for managing complex endometrial hyperplasia. The majority of the gynaecologists would explore two conservative choices before embarking into performing a hysterectomy for this condition (130, 52.6%). However, for atypical hyperplasia, the majority of the gynaecologists would perform a hysterectomy (273, 83.2%) and would only consider LNG-IUS or oral progestogens as a second or third option. Two hundred forty-four (72.2%) responded that an RCT for oral progestogens versus LNG-IUS for the management of endometrial hyperplasia is required. There were 171 (50.6%) gynaecologists that would be willing to randomise in such an RCT. CONCLUSION: Our survey shows that complex endometrial hyperplasia is managed conservatively in UK, with oral progestogens or LNG-IUS, and atypical endometrial hyperplasia is managed with hysterectomy. An RCT, between oral progestogens and LNG-IUS for endometrial hyperplasia, is required to identify the optimum therapy. PMID- 21658837 TI - Nitrogen potential recovery and concentration of ammonia from swine manure using electrodialysis coupled with air stripping. AB - The practice of intensive animal production in certain areas has resulted in excessive manure production for the available regional land base. Consequently, there is a need to develop treatment technologies to recover the valuable nutrients that manure contains so that the resulting product can be transported and used as fertilizer on agricultural land. The project presented here used electrodialysis in a dilution/concentration configuration to transfer the manure ammonia in the diluate solution by electromigration to an adjacent solution separated by an ion-exchange membrane under the driving force of an electrical potential. Then, air stripping from the electrodialysis-obtained concentrate solution without pH modification was used to isolate the ammonia in an acidic solution. An optimal process operating voltage of 17.5 V was first determined on the basis of current efficiency and total energy consumption. During the process, the swine manure pH varied from 8.5 to 8.2, values favourable for NH(4)(+) electromigration. Total ammonia nitrogen reached 21,352 mg/L in the concentrate solution, representing approximately seven times the concentration in the swine manure. Further increases in concentration were limited by water transfer from the diluate solution due to electroosmosis and osmosis. Applying vacuum to the concentrate reservoir was found to be more efficient than direct concentrate solution aeration for NH(3) recuperation in the acid trap, given that the ammonia recuperated under vacuum represented 14.5% of the theoretical value of the NH(3) present in the concentrate solution as compared to 6.2% for aeration. However, an excessively low concentrate solution pH (8.6-8.3) limited NH(3)volatilization toward the acid trap. These results suggest that the concentrate solution pH needs to be raised to promote the volatile NH(3) form of total ammonia nitrogen. PMID- 21658838 TI - Usefulness of cervical volume by three-dimensional ultrasound in identifying the risk for preterm birth. AB - This study was conducted to establish the relationship between three-dimensional (3-D) cervical volume and the risk of spontaneous preterm birth. A total of 391 asymptomatic women with singleton pregnancies were prospectively evaluated two dimensional cervical length and 3-D cervical volume at 20-24 weeks of gestation. We assessed the relationship between cervical factors and the risk for preterm birth before 36 weeks of gestation. Logistic regression analysis demonstrated that not only cervical length (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.88-0.99, p = 0.002), but also cervical volume (OR, 0.26; 95% CI, 0.11 0.61, p = 0.045) was independent predictor of preterm birth. A combined approach in which a gravida was regarded as positive with a short cervical length (<=28 mm) or a small cervical volume (<=20 cm(3)) had a sensitivity of 57.1% for preterm birth. Screening combining cervical length and volume may provide a better prediction of preterm birth. PMID- 21658839 TI - GreenLight HPS 120-W laser vaporization versus transurethral resection of the prostate for the treatment of lower urinary tract symptoms due to benign prostatic hyperplasia: a randomized clinical trial with 2-year follow-up. AB - BACKGROUND: High-level evidence to support the use of photoselective vaporization of the prostate (PVP) is limited. OBJECTIVE: Assess the efficacy and safety of GreenLight HPS 120-W laser PVP compared with transurethral resection of the prostate (TURP). DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was performed with 50 patients having lower urinary tract symptoms due to benign prostatic hyperplasia in each treatment arm. INTERVENTION: Random allocation to PVP or TURP. MEASUREMENTS: International Prostate Symptom Score (IPSS), quality of life (QoL), and changes in maximum flow rate (Qmax) were the main end points. Patients were evaluated at a follow-up time of 2 yr. Five patients were lost to follow-up. A last observation carried forward analysis was done. RESULTS AND LIMITATIONS: Both laser PVP and TURP resulted in the same IPPS reduction at 2 yr (-15.7 and -14.9, respectively; p=0.48) and in the same gain in Qmax (+14.5 ml/s and +13.1 ml/s, respectively; p=0.65). QoL was equivalent for both treatment modalities. These results were independent of prostate size, American Society of Anesthesiologists risk category, and prior indwelling catheter. No statistically significant differences were detected between arms in terms of complication rates. In the laser PVP group, three patients were readmitted to the hospital and two developed a urethral stricture. In the TURP group, two patients were readmitted, six developed a urethral stricture, and two developed bladder neck sclerosis. In-hospital stay and time to catheter removal were significantly shorter with PVP. Limitations are the potential lack of power to detect differences in the complications between groups and the lack of blindness due to the nature of the intervention. CONCLUSIONS: GreenLight HPS 120-W laser PVP is as effective as TURP for symptom reduction and improvement of QoL. No differences were seen in the response of storage and voiding symptoms. Laser PVP and TURP have the same complication rate. Length of stay is shorter for laser PVP group. PMID- 21658840 TI - Purified autoantibodies against glucose-regulated protein 78 (GRP78) promote apoptosis and decrease invasiveness of ovarian cancer cells. AB - Circulating glucose-regulated protein 78 (GRP78) autoantibodies represent potential biomarker of epithelial ovarian cancer. However there is relatively limited identification of these antibodies in response to ovarian cancer. Here, we were interested in characterization of these antibodies and into their role in tumor development. We first purified GRP78 autoantibodies from sera of patients with ovarian cancer, and then tested them on SKOV-3 ovarian cancer cell line. A decrease of invasion and an increase of H(2)O(2)-induced apoptosis of SKOV-3 cells were observed, suggesting their protective role against ovarian cancer cells. PMID- 21658841 TI - Astragalin heptaacetate-induced cell death in human leukemia cells is dependent on caspases and activates the MAPK pathway. AB - Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. Here we demonstrate that the flavonoid derivative astragalin heptaacetate (AHA) induces cell death. This was prevented by the non specific caspase inhibitors z-VAD-fmk and Q-VD-OPH, and reduced by the selective caspase-4 inhibitor z-LEVD-fmk. AHA-induced cell death was found to be: (i) associated with the release of cytochrome c, (ii) suppressed by the overexpression of Bcl-x(L), (iii) amplified by inhibition of extracellular signal regulated kinases (ERKs) 1/2 and c-jun NH(2)-terminal kinases/stress activated protein kinases (JNK/SAPK) signaling, and (iv) completely abrogated by the free radical scavenger N-acetyl-l-cysteine. PMID- 21658842 TI - Identification of C1qTNF-related protein 4 as a potential cytokine that stimulates the STAT3 and NF-kappaB pathways and promotes cell survival in human cancer cells. AB - The NF-kappaB and IL6/STAT3 pathways are major participants in tumor-promoting inflammation. C1qTNF related protein (CTRP) is a family with multiple physiological functions, but their involvement in tumor-promoting inflammation has received little attention. For the first time, we have identified CTRP4 as a novel secretary protein by N-terminal sequencing. Moreover, recombinant CTRP4 can effectively induce the activation of both NF-kappaB and IL6/STAT3 signaling pathways in the pattern similar to that of classical cytokine. By western blot analysis, we detected the upregulation of CTRP4 in response to IL6. Importantly, functional research revealed that CTRP4 could promote tumor cell survival and tumor resistance against apoptosis induced by chemotherapeutics. These results strongly suggest that CTRP4 is a novel tumor-promoting inflammatory regulator. Our findings might provide a meaningful indication for cancer research. PMID- 21658843 TI - Exposure of Hong Kong residents to PBDEs and their structural analogues through market fish consumption. AB - High concentrations of polybrominated diphenyl ethers (PBDEs) and their structural analogues (such as methoxylated (MeO) and hydroxylated (OH) PBDEs) had been observed in environmental samples and human tissues. This study evaluated the occurrence, potential source and human exposure of these organobrominated compounds via market fish consumption in Hong Kong. The contamination of 22 PBDEs, 7 MeO-BDEs, 15 OH-BDEs and 3 bromophenols (BRPs) were analyzed in 20 fish species (279 samples). The estimated daily intakes of PBDEs, MeO-BDEs, OH-BDEs and BRPs via fish consumption ranged from 4.4 to 14, 0.50 to 4.3, 0.02 to 0.43 and 0 to 0.21 ng/kg day for Hong Kong residents, respectively, based on 50(th) and 95(th) centile concentrations. BDE-47 and 99 were found to be the major PBDE congeners while 2'-MeO-BDE-68, 6-MeO-BDE-47 and 3-MeO-BDE-47 were the dominant MeO-BDEs. Concentrations of OH-BDEs and BRPs were 10-100-fold less than those of PBDEs, with small frequencies of detection (max 36.7%). Dietary intake of PBDEs via fish consumption by Hong Kong residents was greater than many developed countries, such as the USA, UK, Japan and Spain. To our knowledge, this is the first report to estimate the dietary intake of MeO/OH-BDEs and BRPs via fish consumption. Our results indicated that the toxicity potential of these compounds should not be neglected. PMID- 21658844 TI - Corpuscular oxidation in newborn crossbred calves naturally infected with Theileria annulata. AB - Erythrocytic lipid peroxidation has been implicated as a cause of anemia in Theileria annulata infection in cattle. The present study aimed to evaluate oxidative damage of membrane lipids and proteins in addition to hemoglobin (Hb) as three criterions of erythrocyte oxidation and their relation to erythrocyte deformability and anemia of newborn crossbred calves (Friesian * Egyptian Balady breed) naturally infected with T. annulata. Twenty-five T. annulata-infected calves (aged 20-30 days) along with 15 age matched healthy controls were used. Percentage of parasitemia varied from 12% to 63% (34.76 +/- 3.05%). In comparison to controls, infected calves showed increased levels (P<0.001) of lipid peroxidation (malondialdehyde; MDA, 52%) and protein oxidation (protein carbonyls; PCs, 132%) in erythrocyte membrane as well as increased values of Hb oxidation (methemoglobin; MetHb, 186%), corpuscular osmotic fragility (15.1%) and hemolysis (free Hb; 195.5%). Parasitemia was positively correlated with MDA (r=0.41, P=0.039), PCs (r=0.45, P=0.023) and MetHb (r=0.40, P=0.042). Also, percent of erythrocytic deformability (echinocytosis) was positively correlated with MDA (r=0.49, P=0.013) and PCs (r=0.63, P<0.001). On the other hand, erythrocytic packed cell volume was negatively correlated with MDA (r=-0.44, P=0.028), PCs (r=-0.72, P<0.001) and MetHb (r=-0.42, P=0.037). In conclusion, T. annulata infection is associated with a parasitic burden-dependant oxidative damage to the erythrocyte membrane protein and lipid contents in addition to Hb. This oxidative damage is linked to the morphological changes of the erythrocyte and may act as mechanisms contribute to pathogenesis of anemia in T. annulata infection in newborn calves. PMID- 21658846 TI - Sulfur amino acid metabolism limits the growth of children living in environments of poor sanitation. AB - Environmental enteropathy has been identified as a cause of poor growth in children living in low-income countries, but a mechanism has not been well defined. We suggest changes in sulfur amino acid metabolism can in part explain the poor growth and possibly the histological changes in the small bowel, which is the hallmark of environmental enteropathy. In environments of poor sanitation, where infection is common, we propose increased oxidative stress drives methionine metabolism toward cystathionine synthesis. This "cystathionine siphon" limits sulfur amino acids from participating in critical protein synthesis pathways. Increased expression of cystathionine beta-synthase (CBS) could be one mechanism, as lipopolysaccharide and TNFalpha increase activity of this enzyme in vivo. CBS catalyzes the first of two steps in the transsulfuration pathway that converts homocysteine to cysteine. As enterocytes are one of the most rapidly proliferating cells in the body, we suggest diminished translation might also be important in the barrier failure observed in environmental enteropathy. Identifying sulfur amino acid metabolism as a mechanism leading to poor growth provides a new testable hypothesis for the undernutrition observed in children living in settings of poor sanitation. PMID- 21658847 TI - Declining of spermatozoa viability in forensic practice: a consequence of environmental hazards? PMID- 21658845 TI - Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats. AB - Nearly 12% of US children are exposed to intense adverse experiences. Research has demonstrated that these experiences can negatively impact adult health, often resulting in psychopathology. Less attention, however, is given to the impact of childhood adverse experiences on childhood health and wellbeing. Using a rodent model of chronic juvenile stress (restraint 6 h daily from postnatal day 20 to 41), we report that chronic stress has significant immediate morbidities in both males and females during this developmental window. Specifically, we demonstrate that chronic juvenile stress produces depressive-like behavior and significant neuronal remodeling of brain regions likely involved in these behavioral alterations: the hippocampus, prefrontal cortex and amygdala. Chronically stressed males and females exhibit anhedonia, increased locomotion when exposed to novelty, and altered coping strategies when exposed to acute stress. Coincident with these behavioral changes, we report simplification of dendrites in the hippocampus and prefrontal cortex and concurrent hypertrophy of dendrites in the amygdala. Taken together, these results demonstrate that chronically stressed juveniles exhibit aberrant behavioral responses to acute challenges that occur in conjunction with stress-induced remodeling of brain regions intimately involved in regulating emotionality and stress reactivity. Further, the absence of sex differences in our reported stress responses, likely speaks to the decreased sensitivity of immature HPA regulating brain regions to sex hormones. PMID- 21658848 TI - Obesity and the brain. AB - The world-wide increase in obesity has markedly stimulated research on the possibility that its cause can be found the brain. However, this research has produced little that can be used to treat obesity. The reason for the limited success of this approach may be that it relies on the hypothesis that the brain controls behavior. We suggest that this hypothesis is an artefact of the powerful tools used in behavioral neuroscience and that the brain has a permissive rather than causal role in eating behavior. Drugs affecting brain function are largely ineffective in treating obesity and may remain ineffective. Instead, we hypothesize that humans need external support to control body weight because they have evolved to pay a high physical price for food and are able to eat large amounts of food without constraints when that price is minimal. Two randomized controlled trials verify the hypothesis that support on how to eat normally and how to feel a normal level of fullness by use of on-line, real time feedback on a computer screen enables under- as well as overweight patients to adjust their eating behavior and improve their health. PMID- 21658849 TI - The effects of a beta-agonist treatment, vitamin D3 supplementation and electrical stimulation on meat quality of feedlot steers. AB - In this study, 20 young steers received no beta-agonist (C), 100 animals all received zilpaterol hydrochloride (Z), with 1 group only receiving Z while the other 4 groups received zilpaterol and vitamin D3 at the following levels (IU/animal/day) and durations before slaughter: 7 million for 3 days (3D7M); 7 million for 6 days (6D7M); 7 million for 6 days with 7 days no supplementation (6D7M7N) and 1 million for 9 days (9D1M). Left carcass sides were electrically stimulated (ES) and the right side not stimulated (NES). Samples were aged for 3 or 14 days post mortem. Parameters included Warner-Bratzler shear force (WBSF), myofibril filament length, sarcomere length and calpastatin and calpain enzyme activity. Both ES and prolonged aging reduced WBSF (P<0.001). 6D7M, 6D7M7N and Z remained significantly tougher than C (P<0.001), while 3D7M and 9D1M improved WBSF under NES conditions. ES is more effective to alleviate beta-agonist induced toughness than high vitamin D3 supplements. PMID- 21658850 TI - Nutritional evaluation of the lipid fraction of feral wild boar (Sus scrofa scrofa) meat. AB - Consumer increasing demand for wild boar meat and scarceness of data on its lipid fraction justified this study. The psoas major muscle collected from 25 feral wild boars was used to quantify the total lipid, total cholesterol, fatty acid (FA) profile, and vitamin E homologues. Intramuscular fat and total cholesterol contents averaged 4.64 g/100g of meat and 56.9 mg/100g of meat, respectively. No differences were found in FA composition between groups, except for 20:5n-3 that was higher in youngsters. All groups presented small concentrations of rumenic acid in meat (CLA; 0.24% of total FA). FA profile showed considerable resemblance with pork, while the vitamin E profile is marked by high concentrations of both alpha- (17.4 +/- 3.3 MUg/g meat) and gamma-tocopherols (2.6 +/- 1.3 MUg/g meat) and by the presence of other vitamin E homologues not previously reported in wild boar meat. PMID- 21658852 TI - Supratentorial neurometabolic alterations in pediatric survivors of posterior fossa tumors. AB - PURPOSE: Therapy and tumor-related effects such as hypoperfusion, internal hydrocephalus, chemotherapy, and irradiation lead to significant motor and cognitive sequelae in pediatric posterior fossa tumor survivors. A distinct proportion of those factors related to the resulting late effects is hitherto poorly understood. This study aimed at separating the effects of neurotoxic factors on central nervous system metabolism by using H-1 MR spectroscopy to quantify cerebral metabolite concentrations in these patients in comparison to those in age-matched healthy peers. METHODS AND MATERIALS: Fifteen patients with World Health Organization (WHO) I pilocytic astrocytoma (PA) treated by resection only, 24 patients with WHO IV medulloblastoma (MB), who additionally received chemotherapy and craniospinal irradiation, and 43 healthy peers were investigated using single-volume H-1 MR spectroscopy of parietal white matter and gray matter. RESULTS: Concentrations of N-acetylaspartate (NAA) were significantly decreased in white matter (p < 0.0001) and gray matter (p < 0.0001) of MB patients and in gray matter (p = 0.005) of PA patients, compared to healthy peers. Decreased creatine concentrations in parietal gray matter correlated significantly with older age at diagnosis in both patient groups (MB patients, p = 0.009, r = 0.52; PA patients, p = 0.006, r = 0.7). Longer time periods since diagnosis were associated with lower NAA levels in white matter of PA patients (p = 0.008, r = 0.66). CONCLUSIONS: Differently decreased NAA concentrations were observed in both PA and MB groups of posterior fossa tumor patients. We conclude that this reflects a disturbance of the neurometabolic steady state of normal-appearing brain tissue due to the tumor itself and to the impact of surgery in both patient groups. Further incremental decreases of metabolite concentrations in MB patients may point to additional harm caused by irradiation and chemotherapy. The stronger decrease of NAA in MB patients may correspond to the additional damage of combined irradiation and chemotherapy on neuroaxonal cell viability and number. PMID- 21658851 TI - Retrospective analysis of outcome differences in preoperative concurrent chemoradiation with or without elective nodal irradiation for esophageal squamous cell carcinoma. AB - PURPOSE: To evaluate the efficacy and patterns of failure of elective nodal irradiation (ENI) in patients with esophageal squamous cell carcinoma (SCC) undergoing preoperative concurrent chemoradiation (CCRT) followed by radical surgery. METHODS AND MATERIALS: We retrospectively studied 118 patients with AJCC Stage II to III esophageal SCC undergoing preoperative CCRT (median, 36 Gy), followed by radical esophagectomy. Of them, 73 patients (62%) had ENI and 45 patients (38%) had no ENI. Patients with ENI received radiotherapy to either supraclavicular (n = 54) or celiac (n = 19) lymphatics. Fifty-six patients (57%) received chemotherapy with paclitaxel plus cisplatin. The 3-year progression-free survival, overall survival, and patterns of failure were analyzed. Distant nodal recurrence was classified into M1a and M1b regions. A separate analysis using matched cases was conducted. RESULTS: The median follow-up was 38 months. There were no differences in pathological complete response rate (p = 0.12), perioperative mortality rate (p = 0.48), or delayed Grade 3 or greater cardiopulmonary toxicities (p = 0.44), between the groups. More patients in the non-ENI group had M1a failure than in the ENI group, with 3-year rates of 11% and 3%, respectively (p = 0.05). However, the 3-year isolated distant nodal (M1a + M1b) failure rates were not different (ENI, 10%; non-ENI, 14%; p = 0.29). In multivariate analysis, pathological nodal status was the only independent prognostic factor associated with overall survival (hazard ratio = 1.78, p = 0.045). The 3-year overall survival and progression-free survival were 45% and 45%, respectively, in the ENI group, and 52% and 43%, respectively, in the non ENI group (p = 0.31 and 0.89, respectively). Matched cases analysis did not show a statistical difference in outcomes between the groups. CONCLUSIONS: ENI reduced the M1a failure rate but was not associated with improved outcomes in patients undergoing preoperative CCRT for esophageal SCC. Pathological nodal metastasis predicted poor outcome. PMID- 21658853 TI - Which is the optimal biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell lung cancer? A meta-analysis. AB - PURPOSE: To assess the relationship between biologically effective dose (BED) and efficacy of stereotactic body radiation therapy (SBRT) and to explore the optimal BED range for Stage I non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Eligible studies were identified on Medline, Embase, the Cochrane Library, and the proceedings of annual meetings through June 2010. According to the quartile of included studies, BED was divided into four dose groups: low (<83.2 Gy), medium (83.2-106 Gy), medium to high (106-146 Gy), high (>146 Gy). To obtain pooled estimates of overall survival (OS), cancer-specific survival (CSS), and local control rate (LCR), data were combined in a random effect model. Pooled estimates were corrected for the percentage of small tumors (<3 cm). RESULTS: Thirty-four observational studies with a total of 2,587 patients were included in the meta-analysis. Corrected pooled estimates of 2- or 3-year OS in the medium BED (76.1%, 63.5%) or the medium to high BED (68.3%, 63.2%) groups were higher than in the low (62.3%, 51.9%) or high groups (55.9%, 49.5%), respectively (p <= 0.004). Corrected 3-year CSS in the medium (79.5%), medium to high (80.6%), and high groups (90.0%) were higher than in the low group (70.1%, p = 0.016, 0.018, 0.001, respectively). CONCLUSION: The OS for the medium or medium to high BED groups were higher than those for the low or high BED group for SBRT in Stage I NSCLC. The medium or medium to high BED (range, 83.2-146 Gy) for SBRT may currently be more beneficial and reasonable in Stage I NSCLC. PMID- 21658854 TI - Induction gemcitabine and stereotactic body radiotherapy for locally advanced nonmetastatic pancreas cancer. AB - PURPOSE: Stereotactic body radiotherapy (SBRT) has been used successfully to treat patients with locally advanced pancreas cancer. However, many patients develop metastatic disease soon after diagnosis and may receive little benefit from such therapy. We therefore retrospectively analyzed a planned strategy of initial chemotherapy with restaging and then treatment for those patients with no evidence of metastatic progression with SBRT. METHODS AND MATERIALS: Forty-seven patients received gemcitabine (1,000 mg/m(2) per week for 3 weeks then 1 week off) until tolerance, at least six cycles, or progression. Patients without metastases after two cycles were treated with SBRT (tolerance-based dose of 24-36 Gy in 3 fractions) between the third and fourth cycles without interrupting the chemotherapy cycles. RESULTS: Eight of the 47 patients (17%) were found to have metastatic disease after two cycles of gemcitabine; the remaining 39 patients received SBRT. The median follow-up for survivors was 21 months (range, 6-36 months). The median overall survival for all patients who received SBRT was 20 months, and the median progression-free survival was 15 months. The local control rate was 85% (33 of 39 patients); and 54% of patients (21 of 39) developed metastases. Late Grade III toxicities such as GI bleeding and obstruction were observed in 9% (3/39) of patients. CONCLUSION: For patients with locally advanced pancreas cancer, this strategy uses local therapy for those who are most likely to benefit from it and spares those patients with early metastatic progression from treatment. SBRT delivers such local therapy safely with minimal interruption to systemic chemotherapy, thereby potentially improving the outcome in these patients. PMID- 21658855 TI - Concurrent chemoradiotherapy improves survival in patients with hypopharyngeal cancer. AB - PURPOSE: To retrospectively review our institutional experience with hypopharyngeal carcinoma with respect to treatment modality. METHODS AND MATERIALS: A total of 70 patients with hypopharyngeal cancer treated between 1999 and 2009 were analyzed for functional and survival outcomes. The treatments included surgery alone (n = 5), surgery followed by radiotherapy (RT) (n = 3), surgery followed by chemoradiotherapy (CRT) (n = 13), RT alone (n = 2), CRT alone (n = 22), induction chemotherapy followed by RT (n = 3), and induction chemotherapy followed by CRT (n = 22). RESULTS: The median follow-up was 18 months. The median overall survival and disease-free survival for all patients was 28.3 and 17.6 months, respectively. The 1- and 2-year local control rate for all patients was 87.1% and 80%. CRT, given either as primary therapy or in the adjuvant setting, improved overall survival and disease-free survival compared with patients not receiving CRT. The median overall survival and disease-free survival for patients treated with CRT was 36.7 and 17.6 months vs. 14.0 and 8.0 months, respectively (p < .01). Of the patients initially treated with an organ preserving approach, 4 (8.2%) required salvage laryngectomy for local recurrence or persistent disease; 8 (16.3%) and 12 (24.5%) patients were dependent on a percutaneous gastrostomy and tracheostomy tube, respectively. The 2-year laryngoesophageal dysfunction-free survival rate for patients treated with an organ-preserving approach was estimated at 31.7%. CONCLUSIONS: Concurrent CRT improves survival in patients with hypopharyngeal cancer. CRT given with conventional radiation techniques yields poor functional outcomes, and future efforts should be directed at determining the feasibility of pharyngeal-sparing intensity-modulated radiotherapy in patients with hypopharyngeal tumors. PMID- 21658856 TI - Modeling the risk of radiation-induced acute esophagitis for combined Washington University and RTOG trial 93-11 lung cancer patients. AB - PURPOSE: To construct a maximally predictive model of the risk of severe acute esophagitis (AE) for patients who receive definitive radiation therapy (RT) for non-small-cell lung cancer. METHODS AND MATERIALS: The dataset includes Washington University and RTOG 93-11 clinical trial data (events/patients: 120/374, WUSTL = 101/237, RTOG9311 = 19/137). Statistical model building was performed based on dosimetric and clinical parameters (patient age, sex, weight loss, pretreatment chemotherapy, concurrent chemotherapy, fraction size). A wide range of dose-volume parameters were extracted from dearchived treatment plans, including Dx, Vx, MOHx (mean of hottest x% volume), MOCx (mean of coldest x% volume), and gEUD (generalized equivalent uniform dose) values. RESULTS: The most significant single parameters for predicting acute esophagitis (RTOG Grade 2 or greater) were MOH85, mean esophagus dose (MED), and V30. A superior-inferior weighted dose-center position was derived but not found to be significant. Fraction size was found to be significant on univariate logistic analysis (Spearman R = 0.421, p < 0.00001) but not multivariate logistic modeling. Cross validation model building was used to determine that an optimal model size needed only two parameters (MOH85 and concurrent chemotherapy, robustly selected on bootstrap model-rebuilding). Mean esophagus dose (MED) is preferred instead of MOH85, as it gives nearly the same statistical performance and is easier to compute. AE risk is given as a logistic function of (0.0688 MED+1.50 ConChemo 3.13), where MED is in Gy and ConChemo is either 1 (yes) if concurrent chemotherapy was given, or 0 (no). This model correlates to the observed risk of AE with a Spearman coefficient of 0.629 (p < 0.000001). CONCLUSIONS: Multivariate statistical model building with cross-validation suggests that a two-variable logistic model based on mean dose and the use of concurrent chemotherapy robustly predicts acute esophagitis risk in combined-data WUSTL and RTOG 93-11 trial datasets. PMID- 21658857 TI - Use of implanted markers and interportal adjustment with real-time tracking radiotherapy system to reduce intrafraction prostate motion. AB - PURPOSE: Interportal adjustment was applied to patients with prostate cancer using three fiducial markers and two sets of fluoroscopy in a real-time tumor tracking radiotherapy (RTRT) system. The incidence of table position adjustment required to keep intrafractional uncertainty within 2.0 mm was investigated in this study. METHODS AND MATERIALS: The coordinates of the center of gravity of the three fiducial markers were measured at the start of every portal irradiation in intensity-modulated radiotherapy (IMRT) with seven ports. The table position was adjusted to the planned position if the discrepancy was larger than 2.0 mm in the anterior-posterior (AP), cranial-caudal (CC), or left-right (LR) directions. In total, we analyzed 4,541 observations in 20 patients who received 70 Gy in 30 fractions (7.6 times a day on average). RESULTS: The incidence of table position adjustment at 10 minutes from the initial setup of each treatment was 14.2%, 12.3%, and 5.0% of the observations in the AP, CC, and LR directions, respectively. The accumulated incidence of the table position adjustment was significantly higher at 10 minutes than at 2 minutes for AP (p = 0.0033) and CC (p = 0.0110) but not LR (p = 0.4296). An adjustment greater than 5 mm was required at least once in the treatment period in 11 (55%) patients. CONCLUSIONS: Interportal adjustment of table position was required in more than 10% of portal irradiations during the 10-minute period after initial setup to maintain treatment accuracy within 2.0 mm. PMID- 21658858 TI - Isolated diaphyseal fractures of the ulna. PMID- 21658859 TI - Solitary enchondroma of the phalanx. PMID- 21658860 TI - Dupuytren contracture. PMID- 21658861 TI - [Implication of platelet-activating factor receptor A224D mutation in susceptibility to relapsing-remitting multiple sclerosis: A Tunisian population study]. AB - AIM OF THE STUDY: Platelet-activating factor interacts with its specific receptor and mediates leucocytes transmigration into central nervous system and expression of HLA molecules on antigens-presenting cells. These features are the major characteristics of multiple sclerosis pathology. In the present study, we investigated the role of platelet-activating factor receptor A224 mutation in the susceptibility to relapsing-remitting form of MS in a Tunisian population. PATIENTS AND METHODS: Forty-seven multiple sclerosis patients and 72 healthy controls were genotyped for platelet-activating factor receptor A224D mutation using polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: We used three models of inheritance: the codominant, dominant and recessive models. Our results showed a predisposing effect of platelet activating factor receptor 224D variant on susceptibility to relapsing-remitting multiple sclerosis (30% vs 48.1%, OR [IC 95%]=2.04 [1.04-3.99], P=0.023). Our results were also consistent with a dominant model of inheritance when comparing mild genotype (AA) with carriers of one or two copies of mutant allele (AD+DD) (55.7% vs 31.9%, OR [IC 95%]=2.92 [1.34-6.81], P=0.006). No effect of this mutation was shown when considering the age at disease onset, disease severity or gender. CONCLUSION: This first study reports an implication of platelet activating factor receptor A224D mutation in the susceptibility to relapsing remitting multiple sclerosis in Tunisian population. Further studies will be necessary to confirm the dominant role of PAFR A224D mutation and to elucidate the effect of this mutation on platelet-activating factor/platelet-activating factor receptor pathways. PMID- 21658863 TI - Effects of stress and alcohol cues in men with and without problem gambling and alcohol use disorder. AB - BACKGROUND: Relapse is a serious challenge in problem gambling (PG), as it is in substance addiction. Stress and cues are implicated in relapse in both conditions. However, experimental research on motivational effects of stress in PG subjects is scant. This study examined subjective-motivational, cognitive and physiological effects of stress and alcohol cues in subjects with PG, alcohol use disorder (AD), co-occurring PG and AD (CO), and healthy controls (HC). METHODS: Fifty-two (12/clinical group; 16 HC) physically healthy men received stress in the form of 10-min uncontrollable noise (U-Noise vs. controllable noise; C-Noise) and cues (355 ml non-alcoholic 'placebo' beer; P-Beer vs. soft drink) under Separate or Combined conditions on two test sessions. Visual analogue scales assessed subjective effects. Emotional Stroop and Go/No-Go 'Shift' tasks assessed inhibitory control. Systolic blood pressure (SBP) indexed physiological reactivity. RESULTS: U-Noise and C-Noise increased desire for alcohol in all groups. U-Noise selectively inhibited desire to gamble in PG subjects. Both U Noise and C-Noise inhibited desire to gamble in CO subjects. Neither manipulation reliably altered cognitive performance. Compared to Neutral words, Alcohol words impaired Stroop color-naming in all groups except PG, which displayed relatively faster color-naming of Alcohol words (facilitation). U-Noise increased SBP relative to C-Noise in AD and HC groups. U-Noise plus P-Beer and U-Noise per se decreased SBP in PG and CO groups, respectively. CONCLUSIONS: Noise stress has opposite motivational and physiological effects in men with problem gambling vs. alcohol use disorder. A homeostatic process may explain the impact of stress in problem gamblers. PMID- 21658864 TI - Longitudinal investigation of the age-related bacterial diversity in the feces of commercial pigs. AB - The importance of bacteria in the gastrointestinal tracts of animals is widely acknowledged as important. However, very little is known about composition and distribution of the microbial population in lower intestinal tracts of animals. Because most bacterial species in pig intestines have not been cultured, it has been difficult to analyze bacterial diversity by conventional culture methods. Even with the development of culture independent 16S rRNA gene sequencing, the previous methods were slow and labor intensive. Therefore, high throughput pyrosequencing of 16S rDNA libraries was used in this study in order to explore the bacterial diversity of the pig feces. In our two trials, fecal samples from individual pigs were collected five times at 3-week intervals, and the 16S rRNA genes in the community DNAs from fecal samples were sequenced and analyzed. This longitudinal study design identified that microbial populations in the feces of the each pig continued to change as pigs aged. The variations of bacterial diversity of the animals were affected by less abundant bacterial components of the feces. These results help us to understand the age-related bacterial diversity in the commercial pig feces. PMID- 21658862 TI - Maternal risk factors predicting child physical characteristics and dysmorphology in fetal alcohol syndrome and partial fetal alcohol syndrome. AB - BACKGROUND: Previous research in South Africa revealed very high rates of fetal alcohol syndrome (FAS), of 46-89 per 1000 among young children. Maternal and child data from studies in this community summarize the multiple predictors of FAS and partial fetal alcohol syndrome (PFAS). METHOD: Sequential regression was employed to examine influences on child physical characteristics and dysmorphology from four categories of maternal traits: physical, demographic, childbearing, and drinking. Then, a structural equation model (SEM) was constructed to predict influences on child physical characteristics. RESULTS: Individual sequential regressions revealed that maternal drinking measures were the most powerful predictors of a child's physical anomalies (R2 = .30, p < .001), followed by maternal demographics (R2 = .24, p < .001), maternal physical characteristics (R2=.15, p < .001), and childbearing variables (R2 = .06, p < .001). The SEM utilized both individual variables and the four composite categories of maternal traits to predict a set of child physical characteristics, including a total dysmorphology score. As predicted, drinking behavior is a relatively strong predictor of child physical characteristics (beta = 0.61, p < .001), even when all other maternal risk variables are included; higher levels of drinking predict child physical anomalies. CONCLUSIONS: Overall, the SEM model explains 62% of the variance in child physical anomalies. As expected, drinking variables explain the most variance. But this highly controlled estimation of multiple effects also reveals a significant contribution played by maternal demographics and, to a lesser degree, maternal physical and childbearing variables. PMID- 21658865 TI - Multidrug-resistant extraintestinal pathogenic Escherichia coli of sequence type ST131 in animals and foods. AB - Multidrug-resistant Escherichia coli sequence type 131 (ST131) has recently emerged as a globally distributed cause of extraintestinal infections in humans. Diverse factors have been investigated as explanations for ST131's rapid and successful dissemination, including transmission through animal contact and consumption of food, as suggested by the detection of ST131 in a number of nonhuman species. For example, ST131 has recently been identified as a cause of clinical infection in companion animals and poultry, and both host groups have been confirmed as faecal carriers of ST131. Moreover, a high degree of similarity has been shown among certain ST131 isolates from humans, companion animals, and poultry based on resistance characteristics and genomic background and human and companion animal ST131 isolates tend to exhibit similar virulence genotypes. However, most ST131 isolates from poultry appear to possess specific virulence genes that are typically absent from human and companion animal isolates, including genes associated with avian pathogenic E. coli. Since the number of reported animal and food-associated ST131 isolates is quite small, the role of nonhuman host species in the emergence, dissemination, and transmission of ST131 to humans remains unclear. Nevertheless, given the profound public health importance of the emergent ST131 clonal group, even the limited available evidence indicates a pressing need for further careful study of this significant question. PMID- 21658866 TI - Intestinal and extra-intestinal pathogenicity of a bovine reassortant rotavirus in calves and piglets. AB - Despite the impact of bovine group A rotaviruses (GARVs) as economically important and zoonotic pathogens, there is a scarcity of data on cross-species pathogenicity and extra-intestinal spread of bovine reassortant GARVs. During the course of characterizing the genotypes of all 11 genomic segments of bovine GARVs isolated from diarrheic calves in South Korea, a unique G6P[7] reassortant GARV strain (KJ9-1) was isolated. The strain harbors five bovine-like gene segments (VP7: G6; VP6: I2; VP1: R2; VP3: M2; NSP2: N2, and NSP4: E2), five porcine-like gene segments (VP4: P[7]; NSP1: A1; NSP3: T1, and NSP5: H1), and one human-like gene segment (VP2: C2). To investigate if this reassortant strain possessed cross species pathogenicity in calves and piglets, and could induce viremia and extra intestinal spread in calves, colostrum-deprived calves and piglets were experimentally inoculated with the KJ9-1 strain. The KJ9-1 strain caused severe diarrhea in experimentally infected calves with extensive intestinal villous atrophy, but replicated without causing clinical symptoms in experimentally infected piglets. By SYBR Green real-time RT-PCR, viral RNA was detected in sera of the calves at post-inoculation day (PID) 1, reaching a peak at PID3, and then rapidly decreasing from PID4. In addition, viral RNA was detected in the mesenteric lymph node, lungs, liver, choroid plexus, and cerebrospinal fluid. An immunofluorescence assay confirmed viral replication in the extra-intestinal organs and tissues of virus-inoculated calves. The data indicates that the homologous/heterologous origin of the NSP4 gene segment (E2 genotype), may play a key role in the ability to cause diarrhea in calves and piglets. PMID- 21658867 TI - Waddlia, Parachlamydia and Chlamydiaceae in bovine abortion. AB - The etiology remains unknown in many cases of bovine abortion in Switzerland. Bacteria of the Chlamydiales order are known abortive agents, therefore cases of bovine abortion from three representative regions of Switzerland were investigated in this study. Particularly Chlamydiaceae as well as the Chlamydia like organisms Waddlia and Parachlamydia were of interest, especially because of their possible zoonotic potential. Placenta samples (n=343) were tested for these bacteria by different PCR-methods, immunohistochemistry and serology for Chlamydia abortus. Additionally an attempt for the isolation of Waddlia and Parachlamydia was made by co-cultivation in amoebae. In 67.3% of the 343 cases a necrotizing and/or purulent placentitis was found histologically. By real-time PCR, 0.9% (3/343) of the cases were positive for Waddlia, 13.4% (46/343) positive for Parachlamydia and 14.6% (50/343) positive or questionable positive for Chlamydiaceae. Of these samples, confirmation by immunohistochemistry was possible in 2/3 cases for Waddlia, 25/46 for Parachlamydia and 4/50 for Chlamydiaceae. Of the 50 cases positive or questionable positive for Chlamydiaceae, species-identification by ArrayTube Microarray or 16S rRNA PCR resulted in 41 cases positive for C. abortus whereas the presence of Chlamydia suis was confirmed in four and Chlamydia pecorum in one case. This study brought evidence for the importance of different members of Chlamydiales in different regions of Switzerland although Waddlia is not occurring in a high prevalence. On the other hand mixed infections with different Chlamydiales as well as with other abortigenic agents could be found. PMID- 21658868 TI - In vitro susceptibility of fluconazole-susceptible and -resistant isolates of Malassezia pachydermatis against azoles. AB - OBJECTIVES: The first aim of this study was to evaluate the in vitro efficacies of fluconazole, ketoconazole, itraconazole and voriconazole on M. pachydermatis growth inhibition. This study also evaluated M. pachydermatis azole cross resistance, comparing wild clinical isolates and the same isolates with in vitro induced fluconazole resistance. METHODS: Two techniques were used: (1) a broth microdilution method based on protocol M27-A3 from the Clinical and Laboratory Standards Institute to determine the minimum inhibitory concentration (MIC) and (2) the Fekete-Forgacs method to induce fluconazole resistance in vitro. The isolates were divided into two groups: group 1 included fluconazole-susceptible clinical isolates (n=30) and group 2 contained the same isolates with in vitro induced fluconazole resistance (n=30). RESULTS: The two groups exhibited differences in susceptibility (p<0.001). Group 1 isolates were susceptible to azoles: ketoconazole (MIC 0.01-1.0 MUg/mL), itraconazole (MIC 0.01-1.0 MUg/mL), voriconazole (MIC 0.01-4.0 MUg/mL), and fluconazole (MIC 0.01-4.0 MUg/mL). Group 2 isolates demonstrated a wider range of MICs to azoles: ITZ (MIC 0.06-64.0 MUg/mL), KTZ (MIC 0.25-32.0 MUg/mL), VRZ (MIC 2.0-128.0 MUg/mL), and FLZ (MIC 64.0-128.0 MUg/mL). CONCLUSIONS: It was shown that FLZ-resistant M. pachydermatis isolates exhibit cross-resistance to other azoles, reinforcing the importance of susceptibility tests as a guide for the therapeutic prescription of antifungals in medical and veterinary mycology. PMID- 21658869 TI - Laboratory markers of perinatal acidosis are poor predictors of neurodevelopmental impairment in very low birth weight infants. AB - BACKGROUND: In asphyxiated term and near-term infants, therapeutic hypothermia increases survival without neurologic morbidity, and extending this new treatment to preterm infants is being debated. AIMS: To investigate the association of low pH and base excess (BE) at birth or admission, as used as entry criteria in cooling trials, and evolving brain damage in preterm infants. STUDY DESIGN AND MEASUREMENTS: Rates of death and neurodevelopmental impairment at 12 and 20 months corrected age were assessed in a cohort of 1137 preterm infants with a gestational age <35 weeks and birth weight <1500 g in relation to severe perinatal acidosis (umbilical artery pH<=7.0, pH at admission <=7.0, BE at admission <=-16 mmol/l, lowest BE during first 12 h of life <=-16 mmol/l). RESULTS: Umbilical artery pH was not linked to death or neurodevelopmental impairment. There was only weak predictive power of pH or BE at admission for death (positive predictive values [PPV] 0.36/0.30, receiver operator characteristics [ROC] areas 0.591/0.701), and lowest 12-h BE for death or neurodevelopmental impairment at 12 or 20 months (PPV 0.29/0.30/0.27, ROC 0.720/0.656/0.658). CONCLUSION: In very preterm infants, there is little association between laboratory markers of severe perinatal acidosis and neurodevelopmental outcome at 12 or 20 months. PMID- 21658870 TI - Age estimation of bloodstains: a preliminary report based on aspartic acid racemization rate. AB - This study describes an innovative application of a well-established method of age determination. The conventional method of aspartic acid racemization (AAR) is based on estimation of the d-l-aspartic acid ratio in slow turnover tissues, such as tooth tissue, to reflect the age of an individual. This method has been recently applied to age estimation in forensic investigations, and is also widely used for archeological dating of fossils. We suggest that the aspartic acid racemization method could be applied to a significant, although unresolved, forensic issue: that of bloodstain dating. Standard kinetic experiments were used to describe the characteristics of the racemization reaction in bloodstains, which were then employed to estimate the age of various samples. The soluble protein fraction of a bloodstain produced a stronger correlation between elapsed time and d-aspartic acid content than total amino acid fractions. According to our preliminary results, the time lapse after the creation of a bloodstain can be determined ex vivo by measuring the extent of aspartic acid racemization. Our analysis highlights the need for further study into the preservation and composition of bloodstains to assist in further development of this pioneering application. PMID- 21658871 TI - Methods for the enhancement of fingermarks in blood. AB - Fingermarks formed in or by blood often require specific development techniques. This review examines techniques and materials that may be used to enhance and record fingermarks deposited in blood or fingermarks generated by blood contaminated papillary ridges. A large number of techniques are presented here and are discussed from a chemical as well as practical perspective. It is concluded that an optimized sequence of techniques targeting both latent (non bloody) and bloody fingermarks must be applied to detect and enhance the maximum number of marks, and therefore optimize the information content from exhibits that may bear marks in blood. PMID- 21658872 TI - Anatomic differences of the distal aorta with dilatation or aneurysm between patients from Asia and Europe as seen on CT imaging. AB - AIM: The hypothesis of this research is that there are differences in morphology of dilated and aneurysm changed infrarenal aorta between the patients from Europe and Asia that are important for endovascular treatment. Authors analyzed the morphologic differences of the infra-renal segment of abdominal aorta (a.a.) and the iliac arteries, common iliac artery (c.i.a.) between the Asians and Europeans examined by computed tomography (64 MD CT) from the point of the clinical use of the endovascular stent-graft. MATERIALS AND METHODS: The research was conducted simultaneously in Europe and in Asia and 60 patients with distal aorta aneurysm were included (30 of each ethnic origin). The examinations were conducted at the identical types of 64 MD CT equipment, and under same conditions of examination technique and post-processing. RESULTS: There were statistically significant differences in regard to important morphology criteria for a.a. and c.i.a. between patients with the aneurysm from Asia and the Europe. Analysis was preformed referring to the gender, age, body weight (BW), height, body mass index (BMI), body surface (SA index), and various diameters of a.a. and c.i.a. at several linear and transversal levels, angle and volume of the aneurysm. The biggest differences relate to the width of the central part of aneurysm of a.a. and the length and volume of c.i.a. CONCLUSION: There were statistically significant differences in regard to important morphology criteria for a.a. and c.i.a. between patients with the aneurysm from Asia and the Europe. PMID- 21658873 TI - A probe-based method for confirmation of methicillin-resistant Staphylococcus aureus and detection of Panton-Valentine leukocidin and tst virulence genes. AB - Probe-based detection of mecA, lukS/F-PV (Panton-Valentine leukocidin), and tst virulence genes in 435 isolates of Staphylococcus aureus had comparable sensitivity and specificity to end-point polymerase chain reaction as a reference standard. PMID- 21658874 TI - HBsAg blood screening and diagnosis: performance evaluation of the ARCHITECT HBsAg qualitative and ARCHITECT HBsAg qualitative confirmatory assays. AB - A low initial reactive rate for screening assays is important for time- and cost effective infectious disease testing. Therefore, the new ARCHITECT HBsAg Qualitative screening assay, in conjunction with the new ARCHITECT HBsAg Qualitative Confirmatory assay, was introduced. As the role of hepatitis B surface antigen (HBsAg) as surrogate marker for HBV resolution and the monitoring of drug effectiveness are becoming increasingly important, the established ARCHITECT HBsAg Quantitative assay remains available on the market. Precision, sensitivity, and specificity of the newly developed screening assay were in the range of established HBsAg assays. Seroconversion sensitivity was slightly superior compared to other commercially available assays. An initial reactive rate of 0.2% (without HBsAg-confirmed positive samples of 0.17%) for the ARCHITECT HBsAg Qualitative assay was observed. As the new screening assay is a 1 step assay format, the "high-dose hook effect" was investigated to assess the risk of false-negative results, but even very high positive HBsAg samples obtained signals clearly above the cutoff. PMID- 21658875 TI - Concurrent detection of herpes simplex and varicella-zoster viruses by polymerase chain reaction from the same anatomic location. AB - Herpes simplex virus (HSV) and varicella-zoster virus (VZV) may cause latent infection of the same peripheral nerve ganglia. However, there are no large studies addressing the frequency of concurrent HSV/VZV PCR positivity from the same anatomic location. In an eight-year retrospective study, we observed 1.3% dual positivity from dermal, genital, and oral mucosal sources. PMID- 21658876 TI - Molecular testing of respiratory swabs aids early recognition of meningococcal disease in children. AB - Early meningococcal disease (MD) diagnosis is difficult. We assessed rapid molecular testing of respiratory specimens. We performed genotyping of respiratory swabs, blood, and cerebrospinal fluid from children with suspected disease and nasal swabs (NSs) from matched controls. Thirty-nine of 104 suspected cases had confirmed disease. Four controls were carriers. Throat swab ctrA and porA testing for detection of disease gave a sensitivity of 81% (17/21), specificity of 100% (44/44), positive predictive value (PPV) of 100% (17/17), negative predictive value (NPV) of 92% (44/48), and relative risk of 12. NS ctrA and porA testing gave a sensitivity of 51% (20/39), specificity of 95% (62/65), PPV of 87% (20/23), NPV of 77% (62/81), and relative risk of 4. Including only the 86 NSs taken within 48 h of presentation, the results were sensitivity of 60% (18/30), specificity of 96% (54/56), PPV of 90% (18/20), NPV of 82% (54/66), and relative risk of 5. Swab type agreement was excellent (kappa 0.80, P < 0.001). There was exact phylogenetic agreement from different specimen sites for individuals. Carried genosubtypes were P1.7 and P1.21-7. Prehospital rapid molecular testing of easily obtained respiratory specimens could accelerate diagnosis of MD. PMID- 21658878 TI - Validation of the Dri-Dot Latex agglutination and IgM lateral flow assays for the diagnosis of typhoid fever in an Egyptian population. AB - Laboratory confirmation of typhoid fever is essential for appropriate medical treatment. Blood culture is a standard test for diagnosis of typhoid fever, but well-equipped diagnostic facilities to perform culture are seldom available in endemic areas. We retrospectively compared 2 diagnostic field tests, a latex agglutination Dri-Dot assay and an IgM Lateral Flow assay, to blood culture, in patients with clinically diagnosed typhoid fever. Sensitivity of the Dri-Dot was 71.4%, and specificity was 86.3% for samples collected at time of first diagnosis. Sensitivity and specificity of IgM Lateral Flow were 80% and 71.4%, respectively. A major limitation of these serologic tests is the limited sensitivity at the early stage of the disease. Performing both tests in parallel increased sensitivity to 84.3%, but decreased specificity to 70.5%. There was a trend towards improved diagnostic performance using either assay over a longer duration of illness. These rapid, point-of-care assays for typhoid fever provide easy-to-interpret results in typhoid-endemic countries and may be most useful in patients presenting 1 week after symptom onset. PMID- 21658877 TI - Comparison of molecular diagnostic methods for the detection of Acanthamoeba spp. from clinical specimens submitted for keratitis. AB - Acanthamoeba spp. are responsible for a significant annual number of keratitis (AK) cases leading to vision-threatening disease worldwide. Current methods rely on direct examination of specimens by microscopy and/or culture. The former lacks sensitivity and the latter suffers from a poor turnaround time. We undertook a comparison of all published molecular methods, evaluating performance characteristics such as analytical sensitivity, specificity, limit of detection (LOD), reproducibility, accuracy, and cost of test. The study population comprised 128 patients. Eligible specimens were tested prospectively between April 2007 and May 2010 by microscopy and/or culture. Eleven different specimen types were used including corneal scrapings (51.5%), corneal swab (17.9%), and contact lens material (10.9%). Results of 2 published gel-based polymerase chain reaction (PCR) and 2 published real-time quantitative (Q) PCR methods were compared in a blinded manner to direct microscopic examination and/or culture for the detection of Acanthamoeba in clinical specimens. QPCR (Riviere method) had the highest sensitivity at 89.3%, excellent accuracy using ROC analysis (AUC ~0.90), lowest LOD down to 0.1 organism per microliter, and superior linear correlation with parasite density (R(2) = 0.9965) when compared with microscopy, culture, and other molecular methods. Phylogenetic analysis using a sequence based typing method revealed that clinical isolates in this population with AK were genetically distinct from granulomatous amebic encephalitis or environmental isolates. The QPCR method was more expensive ($14.80) than traditional methods such as culture ($2.50) or microscopy ($2.50). However, 13 culture- and microscopy-negative specimens were positive by QPCR during the study period, suggesting that detection using QPCR may result in reduced complications and health care costs associated with misdiagnosed AK. PMID- 21658879 TI - Resolution of galactomannan antigenemia in a patient receiving oral voriconazole for chronic necrotizing pulmonary aspergillosis. AB - The serologic markers of the therapeutic response of chronic necrotizing pulmonary aspergillosis (CNPA) are rarely reported. Here, we describe the changes in galactomannan (GM) antigenemia in a patient receiving oral voriconazole for CNPA, in whom a resolution of GM antigenemia to a normal level was associated with clinical improvements. The serum GM index can be an adjunctive tool for the diagnosis and monitoring of the therapeutic response of CNPA. PMID- 21658880 TI - Acute flank pain with intra-abdominal cystic mass. PMID- 21658881 TI - How do you treat an abscess in the era of increased community-associated methicillin-resistant Staphylococcus aureus (MRSA)? AB - BACKGROUND: In the era of increased prevalence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), there have been a number of questions and several recent studies that address the clinical management of uncomplicated abscesses in the emergency department (ED). DISCUSSION: We examine the historical and clinical predictors for MRSA in patients with an uncomplicated abscess and review the evidence behind the use of wound cultures, decolonization, antibiotics, irrigation, and packing after incision and drainage. We found that current recommendations and treatment guidelines are often based on limited data, expert opinion, and anecdotal experience. CONCLUSION: In light of the data currently available, antibiotics and decolonization should be used selectively, not routinely, for treatment of most uncomplicated abscesses. Wound cultures are generally not necessary in the ED, and all patients should be given return precautions for worsening symptoms. PMID- 21658882 TI - Mass sociogenic illness initially reported as carbon monoxide poisoning. AB - BACKGROUND: Mass sociogenic illness (MSI) is a rare occurrence involving a constellation of physical signs and symptoms in a group of individuals that are exhibited subconsciously and have no corresponding organic etiology. OBJECTIVES: To describe an outbreak of MSI initially attributed to carbon monoxide (CO) poisoning. CASE REPORTS: While attending a church service, one child fainted, followed by another. This led to multiple individuals reporting a constellation of symptoms. A total of 22 individuals presented to emergency departments (EDs) with neurologic, gastrointestinal, and respiratory complaints. The onset of symptoms followed evacuation in most of these patients. Prehospital personnel obtained carboxyhemoglobin (COHb) levels with a portable oximeter device, identifying levels up to 19% in 6 patients; 17 were taken to a tertiary hospital with a hyperbaric oxygen chamber, and the other 5 to a local ED. All other attendees were asymptomatic. Within the 15-min transport time, all patients were asymptomatic and had normal physical examinations. The mean age of patients was 13 years; 7 were male and 10 were female. Venous blood gas identified normal COHb levels in all patients. Pulse oximetry in the ED was normal. Another handheld oximeter device in the ED found normal COHb and methemoglobin levels. CONCLUSION: Varying complaints with onset after removal from the church suggest MSI. The hazardous materials team reproduced the scenario and no toxic gases were detected. Escalation of symptoms and an increased number of persons being affected along with increasing ambulance presence are common in MSI. We suspect that field oximeter readings were either aberrant from an inexperienced operator or were false-positive COHb readings. Clinicians should consider MSI after mass outbreaks of illness, particularly with rapid onset, rapid resolution of symptoms, and normal physical examinations and laboratory analyses. However, the diagnosis of MSI should be entertained only after potential toxicologic etiologies have been excluded. PMID- 21658883 TI - Shared decision making: prostate cancer patients' appraisal of treatment alternatives and oncologists' eliciting and responding behavior, an explorative study. AB - OBJECTIVE: To assess clinicians' use of shared decision making (SDM) skills, enabling patient treatment evaluations (appraisals); and varieties of patient appraisals and clinicians' preceding and following utterances. METHODS: Two coders rated videotaped initial visits of 25 early-stage prostate cancer patients to their radiation oncologist. SDM skills were assessed using the Decision Analysis System for Oncology (DAS-O); appraisals and clinicians' utterances were labeled using qualitative methodology. RESULTS: Clinicians offered a treatment choice to 10 patients. They informed 15/25 about pros and 20/25 about cons of options. Patients expressed 67 appraisals (median/visit=2; range, 0-12). Half of appraisals were favorable and one-fourth was unfavorable toward treatment options. One-fifth referred to explicit tradeoffs. One-third of appraisals followed clinician requests; 58% followed clinician information. Clinicians approved almost half of appraisals. They contested, ignored or highlighted a minority. CONCLUSION: Clinicians infrequently offered patients a choice or explored appraisals. Most appraisals supported rather than challenged treatment options. Clinicians most often legitimized appraisals, thereby helping patients to feel good about the decision. Exploring appraisals may help patients in forming more stable preferences, thus benefiting patients in the long run. PRACTICE IMPLICATION: Clinicians should request patient appraisals and ascertain whether these seem well-informed before making treatment recommendations. PMID- 21658884 TI - Effect of carotid sinus nerve blockade on hemodynamic stability during carotid endarterectomy under local anesthesia. AB - OBJECTIVE: To find out whether routine carotid sinus nerve blockade with lidocaine during carotid endarterectomy under local anesthesia results in perioperative changes in blood pressure and heart rate. METHODS: This was a prospective, randomized, single-center study, conducted in a university hospital. A total of 120 patients undergoing carotid endarterectomy under local anesthesia were randomly assigned to three equal groups. Patients with previous carotid endarterectomy were excluded from the study. During the operation the carotid sinus area was infiltrated as follows: group 1 received 2 mL of 1% lidocaine; group 2 received 2 mL of 0.9% NaCl; and group 3 received no infiltration. The carotid sinus nerve was spared in all patients. Blood pressure and heart rate were invasively monitored during the operation and 12 hours postoperatively over the radial artery cannula. Preoperative values were calculated as a mean of three noninvasive measurements on the day before surgery. Data comprised of arterial blood pressures and heart rates from 32 time point measurements for each patient were analyzed. RESULTS: There was no significant difference among the groups regarding the mean arterial blood pressures and mean heart rates during the follow-up period. There was no significant difference among groups regarding the number of patients that required vasoactive therapy at any time of measurement. CONCLUSION: Routine infiltration of carotid sinus area with 1% lidocaine during carotid endarterectomy performed under local anesthesia has no significant impact on mean arterial blood pressure and heart rate during the operative procedure and the following 12 postoperative hours. PMID- 21658885 TI - First clinical trial of nitinol self-expanding everolimus-eluting stent implantation for peripheral arterial occlusive disease. AB - BACKGROUND: A novel self-expanding drug-eluting stent was designed to slowly release everolimus to prevent restenosis following peripheral arterial intervention. The purpose of the first-in-human Superficial Femoral Artery Treatment with Drug-Eluting Stents (STRIDES) trial was to evaluate the safety and efficacy of this device for the treatment of symptomatic superficial femoral and proximal popliteal arterial occlusive disease. METHODS AND RESULTS: One hundred four patients were enrolled at 11 European investigative centers in a prospective, nonrandomized, single-arm trial. The patients had severe symptomatic vascular disease, including a significant proportion of patients with critical limb ischemia (17%), diabetes (39%), and single-vessel outflow (26%). The mean lesion length was 9.0 +/- 4.3 cm. Ninety-nine percent of patients were available for 12-month follow-up, including duplex imaging in 90% and arteriography in 83%. Clinical improvement, defined as a sustained decrease in Rutherford-Becker clinical category, was achieved in 80% of patients. Primary patency (freedom from >=50% in-stent restenosis) was 94 +/- 2.3% and 68 +/- 4.6% at 6 and 12 months, respectively. Plain radiographic examination of 122 implanted devices at 12 months revealed no evidence for stent fracture. CONCLUSIONS: The everolimus eluting self-expanding nitinol stent can be successfully implanted in patients with severe peripheral arterial disease with favorable outcomes and clinical improvements observed in the majority of patients. PMID- 21658886 TI - Stent graft treatment for hemodialysis access aneurysms. AB - BACKGROUND: Aneurysms that develop in arteriovenous accesses as a result of repeated punctures are sometimes complicated by infection or ischemia causing sloughing of the overlying skin, which may endanger the access and risk major bleeding and other complications. Surgical revision may necessitate the temporary use of a central venous catheter until dialysis can be resumed via the access. We used stent grafts in selected patients for the exclusion of access aneurysms. METHODS: Twenty of 63 patients requiring access revision for complication of an aneurysm from February 2005 to December 2009 underwent ambulatory endovascular stent graft deployment. Indications included signs of impending rupture, questionable viability of overlying skin, pain, infection, and limitation of cannulation sites by the size or number of the aneurysms. Endovascular treatment always included angioplasty of associated outflow or central vein stenoses at the same ambulatory session. RESULTS: Twenty patients with complicated access aneurysms were treated by endovascular stent graft exclusion at an average of 4.8 +/- 4.3 years (range, 0.2 to 16.1 years) after access construction: nine graft pseudoaneurysms, nine native vein aneurysms, and two acute iatrogenic pseudoaneurysms. Six patients had skin erosion over the aneurysm, and 12 had painful aneurysms and clinical signs of compromised blood supply to the skin. Another two patients with an acute giant false aneurysm occurring during endovascular procedures were treated in the same interventional session by the stenting technique to control bleeding. All the aneurysms underwent endovascular exclusion without complications. Only one infected puncture site failed to heal within 2 months of stenting and was closed surgically 10 months later due to persistent localized graft infection, but with no further bleeding episodes. Only one aneurysm did not reabsorb within 3 months. Patients with painful skin ischemia had immediate pain relief. All patients also had stenosis in the draining veins necessitating additional percutaneous transluminal angioplasty. Only one patient required hospitalization (for intravenous antibiotic treatment of staphylococcal sepsis). No patients required a central catheter for hemodialysis. One access occluded due to cephalic arch stenosis in a noncompliant patient. Functional patency was 87% at 12 months, with a median follow-up of 15 months (range, 6.3 to 55.5 months). CONCLUSION: Endovascular treatment with stent grafts in complicated access aneurysms is a simple, safe and rapid ambulatory procedure that enables treatment of both the aneurysm and its accompanying draining vein stenosis. It enables continued cannulation of the existing access and avoids the use of central catheters. PMID- 21658888 TI - Carotid endarterectomy for treatment of in-stent restenosis. AB - In-stent restenosis (ISR) after carotid angioplasty and stenting is becoming evident as more patients undergo carotid stenting and duplex scan surveillance. While redo endovascular therapy has been immediately successful, recurrent stenosis remains a problem. The ideal management of ISR has not been determined. Three cases of symptomatic ISR that were successfully treated by standard carotid endarterectomy (CEA) with removal of the stent are reported herein. Current options for management of ISR are reviewed from the literature. PMID- 21658887 TI - Endovenous ablation of incompetent perforating veins is effective treatment for recalcitrant venous ulcers. AB - OBJECTIVES: Endovenous closure of incompetent saphenous veins has been reported to facilitate venous ulcer healing; however, there is little information about the effectiveness of perforator ablation (PA) in healing recalcitrant venous ulcers. We report our experience with PA with venous ulcers unresponsive to prolonged compression therapy. METHODS: Patients with nonhealing venous ulcers of >3 months' duration underwent duplex ultrasound to assess their lower extremity venous system for incompetence of superficial, perforating, and deep veins. Patients who had either no saphenous incompetence or persistent ulcers after saphenous ablation underwent PA of incompetent perforating veins >3 mm that demonstrated reflux; initial treatment was performed on the perforator vein adjacent to the ulcer with additional incompetent veins treated if ulcer healing failed. RESULTS: Seventy-five ulcers with 86 associated incompetent perforating veins were treated with PA in 45 patients with CEAP 6 recalcitrant venous ulcers. Treated incompetent perforator veins were located in the medial ankle (61%), calf (37%), and lateral ankle (2%). Initial success of PA, assessed by postprocedure duplex ultrasound, was 58%; repeat ablation was 90% successful and 71% had eventual successful perforator closure. No complications (skin necrosis, infection, or nerve injury) occurred. Failure of ulcer healing with successful perforator closure occurred in 10% and was due to intercurrent illness, patient noncompliance, and patient death due to unrelated causes. Of patients who healed their ulcers, the healing occurred at a mean of 138 days; an average PA of 1.5 incompetent veins per ulcer was required for healing. Ninety percent of ulcers healed when at least one perforator was closed; no ulcer healed without at least one perforator being closed. CONCLUSIONS: This experience demonstrates both the feasibility and effectiveness of PA for a selected group of patients with venous ulcers who fail conventional therapy with compression. PMID- 21658889 TI - Safety and feasibility of a novel transcervical access neuroprotection system for carotid artery stenting in the PROOF Study. AB - BACKGROUND: Randomized controlled trials have shown that periprocedural rates of stroke and death are higher with carotid artery stenting (CAS) than with carotid endarterectomy (CEA) in the treatment of carotid artery stenosis. Diffusion weighted magnetic resonance imaging (DW-MRI) has shown higher rates of clinically silent new ischemic brain lesions when CAS is performed as compared with CEA. The Silk Road Medical Embolic PROtectiOn System: First-In-Man (PROOF) Study is a single-arm first-in-man study using the MICHI Neuroprotection System (Silk Road Medical Inc, Sunnyvale, Calif), a novel transcervical access and cerebral embolic protection system. This system enables stent implantation under controlled blood flow reversal of the carotid artery, also known as Flow Altered Short Transcervical Carotid Artery Stenting (FAST-CAS). METHODS: Between March 2009 and February 2010, a total of 44 subjects were enrolled into the study. The primary composite endpoint was major stroke, myocardial infarction, or death within 30 days. Forty-three patients (97.7%) completed the study through the 30-day endpoint. One patient was lost to follow-up. In a subgroup of consecutive subjects, DW-MRI examinations were performed preprocedure and within 24 to 48 hours after the stent implantation. Blinded independent neuroradiologists reviewed all DW-MRI studies and confirmed the absence or presence of new ischemic brain lesions. RESULTS: All enrolled patients were successfully treated, and no major adverse events were seen through the follow-up period. Thirty-one subjects had DW-MRI examinations. Of these, five patients (16%) had evidence of new ischemic brain lesions but no clinical sequelae. Transient intolerance to reverse flow was reported in 9% of cases, but in all cases, a stent was successfully placed, and the intolerance was managed by minimizing the duration of reverse flow during the procedure. CONCLUSION: In this first-in-man experience, FAST-CAS using the MICHI Neuroprotection System was shown to be a safe and feasible method for carotid revascularization. DW-MRI findings suggest controlled reverse flow provides cerebral embolic protection similar to that seen with CEA. PMID- 21658890 TI - Temporary extra-anatomic brain perfusion followed by total rerouting of the supra aortic vessels for hybrid repair of a ruptured aortic arch aneurysm. AB - Hybrid repair of ruptured aortic arch repair has been proposed as a valuable approach. However, the presence of an anterior mediastinal hematoma must be carefully detected because of the inherent risk of rupture at sternotomy. We report the case of a patient presenting a ruptured aortic arch aneurysm with anterior rupture who underwent hybrid repair using a temporary extra-anatomic brain perfusion followed by total rerouting of the supra-aortic trunks. We propose this adjunctive technique as a means of allowing a safe endovascular exclusion of aortic arch lesions and avoiding the risk of acute and total aortic rupture in case of anterior rupture of aortic arch aneurysms. PMID- 21658891 TI - Tridirectional phase-contrast magnetic resonance velocity mapping depicts severe hemodynamic alterations in a patient with aortic dissection type Stanford B. AB - This report describes flow patterns derived by three-dimensional (3D) three directional velocity-encoded cine (VEC) magnetic resonance imaging (MRI), in a patient with chronic Stanford type B aortic dissection. Acquired 3D VEC MRI data illustrated an acceleration of blood flow through the primary entry toward the vessel wall of the false lumen, leading to disturbed intraluminal flow. Furthermore, accelerated blood flow was observed in the partially compressed true lumen. 3D VEC MRI data may be helpful to guide physicians for a more comprehensive preoperative and postoperative assessment of complex aortic pathologies. PMID- 21658892 TI - Alexis Carrel, Rene Leriche, Jean Kunlin, and the history of bypass surgery. PMID- 21658893 TI - Surgical thrombectomy for iliofemoral venous thrombosis revisited. PMID- 21658894 TI - Left subclavian artery coverage during thoracic endovascular aortic repair and risk of perioperative stroke or death. AB - INTRODUCTION: Left subclavian artery (LSA) coverage during thoracic endovascular aortic repair (TEVAR) is often necessary due to anatomic factors and is performed in to up to 40% of procedures. Despite the frequency of LSA coverage during TEVAR, reported associations with risk of periprocedural stroke or death are inconsistent in reported literature. We examined the 2005-2008 American College of Surgeons National Surgical Quality Improvement Program Participant Use Data file to determine associations between LSA coverage during TEVAR and risk of perioperative stroke or death. METHODS: Current procedural terminology (CPT) codes were used to identify patients undergoing TEVAR, LSA coverage, and subclavian revascularization. Patients undergoing coronary bypass, ascending aortic repair, abdominal aortic aneurysm repair, or nonvascular intra-abdominal procedures during the same operation were excluded. Perioperative stroke and mortality associations with LSA coverage were examined using logistic regression models for each outcome. Significance was assessed at alpha = 0.05, with univariable P < .05 required for multivariable model entry. RESULTS: Eight hundred forty-five TEVAR procedures were identified, of which 52 patients were excluded due to additional major procedures performed with TEVAR. Seven hundred thirty-three of the remaining 793 procedures included CPT codes indicating primary placement of an initial thoracic endograft and form the basis of this analysis. LSA coverage occurred in 279 procedures (38%). Thirty-day stroke and mortality rates were 5.7% and 7.0%, respectively. LSA coverage was associated with increased 30-day risk of stroke in multivariable modeling (odds ratio [OR], 2.17 95% confidence interval [CI], 1.13-4.14; P = .019). Other significant multivariable risk factors for stroke included proximal aortic cuff placement during TEVAR (OR, 2.58; 95% CI, 1.30-5.16; P = .007) and emergency procedure status (OR, 3.60; 95% CI, 1.87-6.94; P < .001). No significant association between LSA coverage and perioperative mortality was identified (univariable OR, 1.70; 95% CI, 0.98-2.93; P = .0578). CONCLUSION: LSA coverage during thoracic endovascular repair is associated with increased risk of perioperative stroke following TEVAR. Further evidence is needed to determine whether procedural modifications, including LSA revascularization, reduce the incidence of stroke associated with TEVAR. PMID- 21658895 TI - The influence of gender and aortic aneurysm size on eligibility for endovascular abdominal aortic aneurysm repair. AB - OBJECTIVES: The purpose of this study was to compare the eligibility of men and women with infrarenal abdominal aortic aneurysms (AAAs) for on-label endovascular aneurysm repair (EVAR) as part of the clinician-Food & Drug Administration (FDA) collaborative effort, the Characterization of Human Aortic Anatomy Project (CHAP). METHODS: Computed tomography (CT) scans with 3D reconstruction from a single institution obtained between July 1996 and December 2009, including standardized measurements by a blinded third-party (M2S, West Lebanon, NH) were examined. For inclusion, abdominal aortic aneurysm (AAA) had to be infrarenal, unrepaired, and >5 cm, or 4 cm to 5 cm if the orthogonal sac diameter was more than twice the aortic diameter at the renal level. Scans were included regardless of subsequent EVAR, open repair, or lack of treatment. One thousand sixty-three unique, unrepaired AAAs were analyzed. RESULTS: Neck length, diameter, and angulation differ for women (P < .001) even after adjustment for patient age and AAA size. EVAR eligibility based on device Instructions for Use (IFU) criterion is affected by gender. Neck length <15 mm was found in 47% of men and 63% of women. Neck angulation exceeding 60 degrees was found in 12% of men and 26% of women. Minimum iliac diameter of 6 mm was found in 35% of men and 55% of women. Only 32% of men and 12% of women met all three neck criterion and had iliac lumen diameters >6 mm. Logistic regression modeling shows that older patient age (odds ratio [OR], 0.84 per decade), increased aneurysm diameter (OR, 0.70 per cm), and female gender (OR, 0.4) are each independently associated with decreased odds of meeting all device IFU neck criterion (P < .05). EVAR eligibility by neck criterion does not decline significantly until AAA size exceeds 5.5 cm in women and 6.5 cm in men. CONCLUSION: Women are significantly less likely to meet device IFU criterion for EVAR. Aortic neck criteria and iliac access are important for men and women, but more women than men fail to meet IFU criterion. Devices that accommodate shorter infrarenal AAA neck length will have the greatest impact on expanding on-label EVAR regardless of gender. Lower profile devices and those that accommodate higher neck angulation are expected to expand EVAR eligibility further for women. EVAR eligibility is unlikely to be lost as AAAs enlarge to 5.5 cm in women and 6.5 cm in men. Observation of small AAAs until they reach the standard threshold size for repair should not compromise EVAR eligibility. PMID- 21658896 TI - Effect of type II endoleaks and antiplatelet therapy on abdominal aortic aneurysm shrinkage after endovascular repair. AB - OBJECTIVE: Endovascular repair of abdominal aortic aneurysm (EVAR) has been shown to be safe, and its use is increasing rapidly, but the long-term results of this procedure remain unclear. A decrease in the diameter of the aneurysm sac is considered to represent successful exclusion of the aneurysm from the circulation, but it has been reported that aneurysm shrinkage occurs in only about 60% of patients who have undergone EVAR. We analyzed several factors to determine whether they were related to aneurysm shrinkage after EVAR. METHODS: From March 2007 to January 2010, EVAR was performed in 65 patients, 58 of whom underwent an enhanced computerized tomographic evaluation 6 months after the procedure. One patient was found to have a type Ia endoleak and was excluded from the study. In the remaining 57 patients, univariate and multiple regression analyses were used to determine whether there was a relationship between aneurysm shrinkage and various patient characteristics, aneurysm dimensions, and procedural outcomes. Aneurysm shrinkage was defined as a decrease in diameter of at least 4 mm. RESULTS: On univariate analysis, a lack of aneurysm shrinkage by 7 days and 6 months after EVAR was significantly associated with hyperlipidemia, ongoing multiagent antiplatelet therapy with clopidogrel, ticlopidine, or cilostazol as well as aspirin, length of the proximal neck of the aneurysm, preprocedure maximum aneurysm diameter, and the presence of a type II endoleak. On multiple regression analysis, only multiagent antiplatelet therapy and type II endoleak were significantly related to a lack of aneurysm shrinkage 6 months after EVAR. Multiagent antiplatelet therapy and type II endoleak 6 months after EVAR were not significantly associated with each other. CONCLUSION: Patients with a persistent type II endoleak and patients undergoing multiagent antiplatelet therapy are at an increased risk of a lack of aneurysm shrinkage 6 months after EVAR. PMID- 21658897 TI - Association of internal rotation of the knee joint with recurrent subluxation of the lateral meniscus. AB - PURPOSE: To compare the arc of rotation of the knee joint at 90 degrees of flexion in control knee joints and those affected by recurrent subluxation of the lateral meniscus (RSLM), in determining whether rotatory instability of the knee joint is a risk factor for RSLM. METHODS: Knee joints were diagnosed with RSLM when there was a history of mechanical locking episodes and when subluxation of the lateral meniscus with the peripheral margin of the posterior segment moving anteriorly beyond the lateral femoral condyle was recognized on arthroscopy. In this study 288 knee joints in 270 subjects were evaluated. The joints were classified into a control group (252 joints), an RSLM group (24 joints), and a contralateral RSLM group (12 joints). The arcs of external and internal rotation at 90 degrees of flexion of the knee joint induced by 7 Nm of torque under non weight-bearing conditions were measured with a Biodex System 3 (Biodex Medical Systems, Shirley, NY). RESULTS: There were no significant differences in mean values of external rotation among the 3 groups. The mean values of internal rotation of both the RSLM and contralateral RSLM groups were significantly larger than that of the control group, by about 15 degrees (P < .0001). The mean value of internal rotation was slightly higher than that of external rotation in the RSLM and contralateral RSLM groups, although the mean value of internal rotation was smaller than that of external rotation by 10.1 degrees in the control group. CONCLUSIONS: RSLM was found to be strongly related to bilateral increase in the arc of internal rotation at 90 degrees of flexion of the knee joint, suggesting that internal rotatory instability of the flexed knee joint can be considered one of the risk factors for and diagnostic parameters of RSLM. LEVEL OF EVIDENCE: Level III, diagnostic study of nonconsecutive patients. PMID- 21658898 TI - Karyopherin alpha 2 (KPNA2) is associated with the natural resistance to Schistosoma japanicum infection in Microtus fortis. AB - Microtus fortis is a naturally vertebrate host resistant to Schistosoma japonicum infection. In order to understand the molecular mechanism and identify the molecules related to the natural resistance to S. japanicum infection of M. fortis, we screened a gene pool named gE76 by expression cloning and proved it to have high anti-schistosomula effects in our previous work. In this study we identified a clone named gE76.44. We found that the conditioned medium of pcDNA1.1-gE76.44 caused 14.0% schistosomula death rate in 96 h, which was significantly higher than that of negative control (P<0.05). The gE76.44 was sequenced and the full-length cDNA was 2008 bp with ORF of 1590bp encoding a polypeptide of 529 amino acid residues. Bioinformatics analysis indicated it was the homologue of karyopherin alpha 2 (KPNA2). To further confirm its anti schistosome activity, we inserted full length of Mf-KPNA2 (KPNA2 of M. fortis) gene into a retroviral expression vector pLXSN and packaged the recombinant virus with PA317 cells. Mice infected with S. japanicum cercariae were administrated by intravenous injection through tail vein and treated with pLXSN-KPNA2. Adult worms and egg reduction were counted after heart perfusion of mice 42 d after infection. We found that compared with the control, mice injected with Mf-KPNA2 had 39.42% worm burden reduction and 76.50% reduction in LEPG (liver eggs per gram) (P<0.01), indicating its anti-schistosome effect of Mf-KPNA2 in vivo. Taken together, the results suggested Mf-KPNA2 as a novel anti-schistosome molecule in vitro and in vivo. PMID- 21658899 TI - Effect of light-emitting diode (LED) therapy on the development of osteoarthritis (OA) in a rabbit model. AB - OBJECTIVE: The objective of this study was to evaluate whether light-emitting diodes (LEDs) could be effective in a noninvasive, therapeutic device for the treatment of osteoarthritic (OA) knee joints. DESIGN: Five weeks following the anterior cruciate ligament transection (ACLT) of mature New Zealand White rabbits, the animal knees were exposed to LED stimulation at intervals of 10 min/day, 5 days/week for 5 weeks in the experimental group (n=7). The device used high intensity red and infrared (IR) LEDs with a total amount of energy delivered to the skin of 2.4 J/cm(2). Animals were sacrificed at 9 weeks postoperatively. Femoral surface gross morphology was evaluated with a modified Outerbridge classification and mRNA expression of catabolic and anabolic markers from femoral condyle cartilage and synovial tissue was assessed using RT-PCR. A control group was harvested 9 weeks following untreated ACLT. RESULTS: Gross morphometry of the control group showed four Grade II, two Grade III and one Grade IV (average 2.6) condyles macroscopically. The experimental group showed two Grade I and five Grade II (average 1.7) (Table 1). mRNA expression of aggrecan in the cartilage showed no difference between the groups, however type II collagen expression increased in the experimental group compared with control. TNF-alpha expression was significantly decreased in the experimental group compared to control. CONCLUSIONS: There was general preservation of the articular surface and decreased levels of inflammation in the osteoarthritic joints with the application of LED therapy. This may provide potential application as a noninvasive treatment. PMID- 21658900 TI - Poppers dependence: the mask behind hypersexuality. PMID- 21658901 TI - "Fulminant" Behcet disease. PMID- 21658902 TI - Does lack of ST-segment resolution still have prognostic value 6 years after an acute myocardial infarction treated with coronary intervention? AB - BACKGROUND: Limited data exist in regard to the correlation between ST-segment resolution (STR) in patients treated with primary percutaneous coronary intervention (pPCI) and very late mortality. The aim of the study was to determine the correlation between STR and 6-year mortality in patients successfully treated with pPCI. METHODS: We prospectively studied a group of 303 patients who had sustained an acute myocardial infarction with ST-segment elevation and subsequently exhibited TIMI 3 flow after pPCI. The patients were analyzed in 2 groups according to STR. RESULTS: There were 222 patients (73.3%) with STR and 81 patients (26.7%) without it. The mean "pain-to-balloon" time was 4.3 +/- 2.1 hours in the former group vs 4.9 +/- 2.8 hours in the latter (P = 0.016). In total, 64 people (21%) died during the 6-year follow-up period: 37 (17%) showed STR and 28 (35%) did not (P < 0.001). In multivariate analysis, STR, ejection fraction, and maximum creatine kinase and creatine kinase-MB levels were all associated with death. Anterior myocardial infarction, "pain-to-balloon" time, and ejection fraction were all further associated with lack of STR. CONCLUSIONS: Lack of early STR is associated with significantly higher mortality rates after successful pPCI during a 6-year follow-up period. Absence of an early STR appears to identify patients who are less likely to benefit from the early restoration of infarct-affected artery, possibly due to microvascular damage. STR therefore appears to be a powerful prognostic marker for the occurrence of an acute myocardial infarction 6 years later. PMID- 21658903 TI - Chemical shift artifact on steady-state free precession cardiac magnetic resonance sequences as a result of lipomatous metaplasia: a novel finding in chronic myocardial infarctions. AB - BACKGROUND: Because balanced steady-state free precession (SSFP) sequences are opposed-phase gradient echo techniques, linear low signal due to chemical shift artefact is observed at fat-water interfaces. We observed that some patients with chronic myocardial infarctions had linear low signal along the inner myocardial wall in areas of infarction, which we postulated was due to chemical shift artefact, as a result of lipomatous metaplasia. The purpose of this retrospective review was to evaluate whether subendocardial low signal on SSFP, likely related to chemical shift artifact, could be used to identify chronic myocardial infarctions. METHODS: Of 128 patients who underwent cardiac magnetic resonance, 79 with myocardial infarctions were included in this retrospective study. RESULTS: Of the 79 patients, 35 (44%) demonstrated areas of linear subendocardial decreased signal. In 16 of those 35 (46%), the infarcts were confirmed as fatty by correlation with CT. In 29 of 35 (83%) of these patients, the infarcts were likely chronic based on fixed wall thinning to less than 4 mm. In 3 patients, chemical shift artifact due to lipomatous metaplasia was also confirmed with conventional in-phase and opposed-phase T1-weighted sequences. Subendocardial chemical shift artefacts were not seen in any of the 19 patients with known, acute infarcts included in this series. Aneurysms were more common when subendocardial chemical shift artefact was present (22 of 35), in comparison to patients who did not have this finding (10 of 44, P = 0.02). CONCLUSIONS: Identification of linear subendocardial chemical shift artefacts on SSFP sequences is a sign of lipomatous metaplasia in chronic myocardial infarcts and is associated with an increased incidence of ventricular aneurysms. PMID- 21658904 TI - Assisted reproductive technology and risk for autism spectrum disorder. AB - Epidemiologic studies on maternal and pregnancy risk factors for autism spectrum disorder (ASD), including use of assisted reproductive technology (ART), found conflicting results. This study included the following aims: to assess frequencies of ART in a large ASD group; to examine confounding birth and familial risk factors in the ASD with ART group; to examine possible relationships between ART and autism severity, adaptive skills and developmental trajectory. The study included 624 participants, 507 diagnosed with ASD. Autism severity and adaptive skills were assessed using standardized tests. Extensive medical, familial and developmental histories were obtained. The rate of ART in the ASD group was significantly higher (10.7%) than in a large Israeli population (3.06%). Parental age's distribution did not differ in both ASD groups, with and without ART. Although maternal age was more advanced in the ASD group, the frequency of ART in young mothers (<29 years) was still significantly high (8.7%). The frequencies of gestational age <36 weeks and low birth weight (<2500 g) in the ASD with ART singleton group and in the Israeli population were not significantly different. None of the ASD with ART group and 14.7% in the ASD without ART group had a relative with ASD. Autism severity, adaptive skills and developmental regression were not significantly different in the ASD with and without ART groups. This pilot study points to the role of assisted conception as a risk factor for ASD. However, this group of ASD with ART does not represent a separate clinical phenotype in ASD. PMID- 21658905 TI - Persistent storage capability impairs decision making in a biophysical network model. AB - Two long-standing questions in neuroscience concern the mechanisms underlying our abilities to make decisions and to store goal-relevant information in memory for seconds at a time. Recent experimental and theoretical advances suggest that NMDA receptors at intrinsic cortical synapses play an important role in both these functions. The long NMDA time constant is suggested to support persistent mnemonic activity by maintaining excitatory drive after the removal of a stimulus and to enable the slow integration of afferent information in the service of decisions. These findings have led to the hypothesis that the local circuit mechanisms underlying decisions must also furnish persistent storage of information. We use a local circuit cortical model of spiking neurons to test this hypothesis, controlling intrinsic drive by scaling NMDA conductance strength. Our simulations provide further evidence that persistent storage and decision making are supported by common mechanisms, but under biophysically realistic parameters, our model demonstrates that the processing requirements of persistent storage and decision making may be incompatible at the local circuit level. Parameters supporting persistent storage lead to strong dynamics that are at odds with slow integration, whereas weaker dynamics furnish the speed-accuracy trade-off common to psychometric data and decision theory. PMID- 21658906 TI - Decisional conflict and regret: consequences of surrogate decision making for the chronically critically ill. AB - Decisional conflict may predispose surrogate decision makers (SDMs) of the chronically critically ill (CCI) to making health care decisions that are not aligned with the patient's health care preferences and increase the SDM's likelihood of experiencing decision regret. This study establishes the relationship between decisional conflict and decision regret and offers insight on tailoring decision support interventions to the preferences of SDMs of CCI patients. PMID- 21658907 TI - Balancing interests of hospitals and nurse researchers: lessons learned. AB - While nurse researchers and administrators in health care organizations need to collaborate to understand the variables that affect nursing practice environments and patient care outcomes, there are inherent risks associated with these collaborations that require careful consideration. A team of academic and hospital researchers found that in studying the off-peak (nights and weekends) nursing environment using institutional ethnography, which involved interviews of nurses and administrators, the subject of the research was frequently the hospitals where these individuals worked. Although the individuals who participated in the research consented to be interviewed about their work, it was less clear how and to what extent the anonymity of their organizations could be maintained. The risks and benefits encountered suggest the need for a decision making process to be undertaken by collaborative research teams. This decision process and analysis can help ensure a fruitful research relationship that protects sensitive concerns of hospital entities while advancing our understanding of nursing practice environments and patient care outcomes. Important strategies include having all leaders and research team members discuss the agendas of all entities and individuals involved, including clearly delineating the roles, responsibilities, and contributions of all parties. In addition, any constraints or expectations of first right of review of publications needs to be negotiated from the outset. Collaborators need to review their agreements throughout the research process to avoid pitfalls that could adversely impact the relationships as well as the dissemination of knowledge gained. PMID- 21658908 TI - Dietary effect of folate-rich fermented milk produced by Streptococcus thermophilus strains on hemoglobin level. AB - OBJECTIVE: Folate, a water-soluble vitamin, functions as a carbon carrier in the formation of heme, the iron-containing non-protein portion of hemoglobin. Therefore, its deficiency leads to anemia. The objective of this study was to determine the dietary effects of folate-rich fermented milk produced by high folate-producing Streptococcus thermophilus strains (RD 102 and RD 104) on hemoglobin level using a murine model. METHODS: Thirty-two albino mice 30 +/- 10 d old were assigned to ingest a basal diet (i.e., a synthetic anemic diet, n = 8, group I, control 1), a basal diet with skim milk (n = 8, group II, control 2), a basal diet with fermented skim milk produced by folate plus RD 102 (n = 8, group III, test 1), and a basal diet with fermented skim milk produced by folate plus RD 104 (n = 8, group IV, test 2) in a 6-wk, double-blind, placebo-controlled study. Hemoglobin concentrations were estimated by the Drabkin-Austin cyanmethemoglobin method during the prefeeding (10 d), feeding (20 d), and postfeeding (10 d) trials, respectively. RESULTS: The results showed that the test groups (III and IV) receiving folate-rich fermented milks prepared using high-folate producing S. thermophilus strains showed a significant increase in hemoglobin level compared with the control groups (I and II). CONCLUSION: Folate rich fermented milks have the potential to significantly increase the hemoglobin level of blood. Hence, high-folate-producing S. thermophilus strains offer a novel natural approach to fortify dairy products with folate. PMID- 21658909 TI - Australian children are not consuming enough long-chain omega-3 polyunsaturated fatty acids for optimal health. AB - OBJECTIVES: To determine children's polyunsaturated fatty acid (PUFA) intakes, compare these with adequate intake and adjusted suggested dietary targets, and determine if intakes between children of different body weight and physical activity levels differed. METHODS: The necessary data files were obtained from the Australian Social Science Data Archive and were merged for 4486 children 2 to 16 y old, with physical activity data collected only for children 5 to 16 y old. RESULTS: The median (interquartile range) PUFA intakes at 2 to 3, 4 to 8, 9 to 13, and 14 to 16 y were 4.7 g (3.1-6.2), 6.0 g (4.4-8.1), 7.1 g (5.3-9.7), and 8.5 g (6.0-11.3), respectively, for linoleic acid; 0.75 g (0.57-1.0), 0.91 g (0.67-1.2), 1.02 g (0.73-1.42), and 1.15 g (0.81-1.62), respectively, for alpha linolenic acid; and 56 mg (29-104), 68 mg (37-128), 88 mg (46-159), and 98 mg (49 190), respectively, for long-chain (LC) omega-3 PUFAs. Most children met the adequate intakes for linoleic acid and alpha-linolenic acid, but only 50% to 60% of children met the adequate intake for LC omega-3 PUFAs. Furthermore, only 6% of children met the adjusted suggested dietary target for LC omega-3 PUFA per day. Comparison of LC omega-3 PUFA tertile intakes showed no differences in intakes in different weight categories and physical activity levels. CONCLUSION: Most Australian children are not consuming enough LC omega-3 PUFAs for optimal health. PMID- 21658910 TI - Immediate functional loading of provisional implants in the reconstructed atrophic maxilla: preliminary results of a prospective study after 6 months of loading with a provisional bridge. AB - Implant-prosthetic rehabilitation of atrophic maxillae remains a challenging problem. The aim of this paper is to describe a novel treatment for functional rehabilitation of the atrophic maxilla and to discuss preliminary results of this treatment protocol. A prospective pilot study was carried out in 10 patients who underwent bony reconstruction of atrophic maxillae under general anaesthesia, with autologous calvarial bone grafts and simultaneous placement of six provisional implants. The provisional implants were loaded with a provisional acrylic bridge 1 day after surgery. After 6 months, the provisional implants were removed and final implants were placed under local anaesthesia, again in an immediate loading concept with a provisional bridge, followed by a final bridge after another 6 months of healing. The bone grafts integrated well in all 10 patients without infectious complications. The prosthetic survival of the provisional bridge at the time of placing the implants was 100%. All final implants could be placed and immediately loaded with a second provisional bridge. Patient satisfaction was high due to limited postoperative inconvenience and immediate fixed prosthetic rehabilitation. The preliminary results of this pilot study demonstrate that this treatment protocol is a well tolerated treatment for patients with maxillary atrophy desiring dental rehabilitation. PMID- 21658911 TI - Congenital infantile fibromatosis of the cheek: report of a rare case and differential diagnosis. AB - Infantile fibromatosis is a benign tumour that consists of dense masses of fibroblasts and myofibroblasts with marked collagen production. Although it is a nonmetastasising tumour, it has significant potential for local invasion and recurrence and may be fatal because of its size and location. The authors report an unusual case of infantile fibromatosis of the cheek in an 8-month-old boy, present since birth. The patient underwent surgical treatment with tumour-free margins and the 6-month follow-up revealed no signs of recurrence. Infantile fibromatosis of the cheek is a very rare condition at this location, especially congenital cases. It should be considered in the differential diagnosis of congenital lesions in childhood. PMID- 21658912 TI - The role of concomitant mandibular fractures in disc displacement and development of TMJ ankylosis secondary to sagittal fractures of the mandibular condyle. PMID- 21658913 TI - Q8IYL2 is a candidate gene for the familial epilepsy syndrome of Partial Epilepsy with Pericentral Spikes (PEPS). AB - PURPOSE: Partial Epilepsy with Pericentral Spikes (PEPS) is a novel Mendelian idiopathic epilepsy with evidence of linkage to Chromosome 4p15. Our aim was to identify the causative mutation in this epilepsy syndrome. METHODS: We re annotated all 42 genes in the linked chromosomal region and sequenced all genes within the linked interval. All exons, intron-exon boundaries and untranslated regions were sequenced in the original pedigree, and novel changes segregating correctly were subjected to bioinformatic analysis. Quantitative polymerase chain reaction was performed to examine for potential copy number variation (CNV). RESULTS: 29 previously undescribed variants correctly segregating with the linked haplotype were identified. Bioinformatic analysis demonstrated that six variants were non-synonymous coding sequence polymorphisms, one of which, in Q8IYL2 (Gly400Ala), was found in neither Caucasian (n=243) and ancestry-matched Brazilian (n=180) control samples, nor subjects from the 1000 Genome Project. No gene duplications or deletions were identified in the linked region. DISCUSSION: We postulate that Q8IYL2 is a causative gene for PEPS, after exhaustive resequencing and bioinformatic analysis. The function of this gene is unknown, but it is expressed in brain tissue. PMID- 21658915 TI - Comparison of direct antimicrobial susceptibility testing methods for rapid analysis of bronchial secretion samples in ventilator-associated pneumonia. AB - Two hundred and fifty tracheal aspirates were subjected to direct antimicrobial susceptibility testing by disk diffusion, Etest and inoculation on antibiotic enriched MacConkey agar plates. Results were compared with those obtained using an automated system on microorganisms recovered from standard quantitative culture. A total of 255 microorganisms were isolated from 194 positive samples by the standard quantitative procedure. A total of 85.1%, 82.5% and 72.5% agreement between direct disk diffusion, Etest and antibiotic-enriched MacConkey agar plates, respectively, and the standard procedure was observed in 64 microorganisms obtained from monomicrobial cultures that corresponded to 240 individual microorganism-antimicrobial agent combinations. Three (1.3%) and four (1.7%) very major errors for direct disk diffusion and Etest methods were observed, respectively. The antibiotic-enriched MacConkey agar plate method compared with the standard procedure demonstrated an unacceptable rate of very major (6.7%) and major errors (14.2%). Clinical evaluation of direct susceptibility tests based on the speculative impact on clinical practice by guiding patient's early treatment, if all positive cultures corresponded to infection, was correct in 79.9% for the direct disk diffusion test, 77.8% for the direct Etest method and 68.0% for antibiotic-enriched MacConkey agar plates. Direct diffusion tests (Etest or disk diffusion) applied on respiratory samples are rapid techniques that provide results comparable with standard antimicrobial susceptibility testing in <24 h. PMID- 21658914 TI - Alcohol use disorders contribute to hippocampal and subcortical shape differences in schizophrenia. AB - BACKGROUND: Alcohol abuse and dependence have been reported to exacerbate the clinical course of schizophrenia. However, the neurobiological basis of this co morbid interaction is unknown. The aim of this study was to determine the relationship of co-morbid alcohol use disorder (AUD) with brain structure abnormalities in schizophrenia patients. METHODS: T1-weighted magnetic resonance images were collected from schizophrenia patients without a history of any substance use disorder (SCZ_0, n=35), schizophrenia patients with a history of AUD only (SCZ_AUD, n=16), and a healthy comparison group without a history of any substance use disorder (CON, n=56). Large-deformation, high-dimensional brain mapping was used to quantify the surface shapes of the hippocampus, thalamus, striatum, and globus pallidus in these subject groups. Analysis of variance was used to test for differences in surface shape measures among the groups. RESULTS: SCZ_AUD demonstrated the greatest severity of shape abnormalities in the hippocampus, thalamus, striatum, and globus pallidus as compared to SCZ_0 and CON. SCZ_AUD demonstrated a combination of exaggerated shape differences in regions where SCZ_0 also showed shape differences, and unique shape differences that were not observed in SCZ_0 or CON. CONCLUSIONS: Shape differences in schizophrenia were compounded by a history of co-morbid AUD. Future research is needed to determine whether these differences are simply additive or whether they are due to an interaction between the underlying neurobiology of schizophrenia and alcoholism. The consequences of such shape differences for the clinical course of schizophrenia are not yet understood. PMID- 21658916 TI - Outbreak of Salmonella enterica serotype Infantis producing ArmA 16S RNA methylase and CTX-M-15 extended-spectrum beta-lactamase in a neonatology ward in Constantine, Algeria. AB - Plasmid-mediated 16S rRNA methylases such as ArmA, which confer high levels of resistance to aminoglycosides, are increasingly reported in Enterobacteriaceae. This study investigated the molecular mechanism of beta-lactam and aminoglycoside resistance in extended-spectrum beta-lactamase (ESBL)-producing Salmonella enterica serotype Infantis isolated at the 53-bed neonatology ward of University Hospital Benabib in Constantine, Algeria. From September 2008 to January 2009, 200 S. enterica isolates were obtained from 138 patients (age range 8-80 months) hospitalised in the neonatology ward. Most isolates were from stool cultures, but also from two blood cultures and one gastric fluid. The isolates were multidrug resistant and produced TEM-1 and CTX-M-15 enzymes as well as the 16S RNA methylase ArmA. The armA, bla(CTX-M-15) and bla(TEM-1) genes were located on the same 140-kb self-transferable plasmid belonging to the IncL/M incompatibility group. All of the S. Infantis isolates belonged to a single clone. Increased infection control measures and thorough biodecontamination of the rooms led to control of the outbreak but did not eradicate the epidemic strain. This study further illustrates the global emergence of ArmA methylase and its frequent association with bla(CTX-M) genes. Spread of 16S RNA methylase determinants at the same level as bla(CTX-M) genes in Enterobacteriaceae may seriously compromise the efficacy of aminoglycosides for treating Gram-negative infections. PMID- 21658917 TI - A new meta-analytic method for neuroimaging studies that combines reported peak coordinates and statistical parametric maps. AB - Meta-analyses are essential to summarize the results of the growing number of neuroimaging studies in psychiatry, neurology and allied disciplines. Image-based meta-analyses use full image information (i.e. the statistical parametric maps) and well-established statistics, but images are rarely available making them highly unfeasible. Peak-probability meta-analyses such as activation likelihood estimation (ALE) or multilevel kernel density analysis (MKDA) are more feasible as they only need reported peak coordinates. Signed-differences methods, such as signed differential mapping (SDM) build upon the positive features of existing peak-probability methods and enable meta-analyses of studies comparing patients with controls. In this paper we present a new version of SDM, named Effect Size SDM (ES-SDM), which enables the combination of statistical parametric maps and peak coordinates and uses well-established statistics. We validated the new method by comparing the results of an ES-SDM meta-analysis of studies on the brain response to fearful faces with the results of a pooled analysis of the original individual data. The results showed that ES-SDM is a valid and reliable coordinate-based method, whose performance might be additionally increased by including statistical parametric maps. We anticipate that ES-SDM will be a helpful tool for researchers in the fields of psychiatry, neurology and allied disciplines. PMID- 21658918 TI - Examining cognitive biases in patients with delusions of reference. AB - Cognitive biases may not be seen in all subtypes of delusions, and might be more involved in the etiology of some delusional subtypes than others. A sample of patients with delusions of reference did not show the jumping to conclusions (JTC) bias. JTC appears to be more closely related to paranoia than referential delusions. PMID- 21658919 TI - [A rare etiology of recurrent hemarthrosis in children: synovial hemangioma]. PMID- 21658920 TI - [Foreign body ingestion in children: 105 case reports]. AB - The ingestion of a foreign body (FB) is one of the most frequent childhood accidents requiring urgent care depending on the type and localization. Coins are the most frequent, and disk battery ingestion can lead to a significant risk of complications. FB stagnation in the esophagus entails a major risk of perforation. This article reports a retrospective study of 105 cases of foreign body ingestion admitted to the pediatric gastroenterology unit between November 2002 and June 2010. The average age of these patients was 4 years with a 1.5 sex ratio. Ten patients were followed for esophagus stenosis; the others had no considerable pathological histories. The fibroscopy performed on 104 patients allowed us to visualize the foreign body in 96 cases (91.4%). In the 8 remaining cases, the FB was not found (it had already migrated in the digestive tract). Coins were the most frequent (64.7%). Endoscopic extraction removed 83 FBs (86.4%). In 11 cases, it was pushed towards the stomach, split up in 1 case, and surgery was necessary in only 1 case. The progress of child digestive fibroscopy has decreased both the morbidity related to the ingestion of foreign bodies and the use of surgery. Prevention should be based on educating the parents by informing them about the risk of this kind of accident. PMID- 21658921 TI - Primary excision margins and sentinel lymph node biopsy in clinically node negative melanoma of the trunk or extremities. PMID- 21658922 TI - Growth, size and age at maturity of the agile frog (Rana dalmatina) in an Iberian Peninsula population. AB - The mean age of a population of agile frogs (Rana dalmatina) from the Iberian Peninsula was estimated using mark and recapture and skeletochronology. Life history parameters, including growth rate, body length, age and size at maturity, sexual dimorphism and longevity, were studied. The regression between age and snout-vent length (SVL) was highly significant in both sexes. Males reached sexual maturity at two years of age, although sometimes they can reach it at only one year of age. The average SVL at maturity was 51.75 mm (standard error (SE)=0.71; n=45). Females reached sexual maturity at two years of age with an average SVL of 62.14 mm (SE=2.20; n=14). A subset of the female population reached sexual maturity at three years of age. Growth was rapid until sexual maturity was reached. There was an overlap of SVL between different age classes. Growth was continuous, fulfilling the conditions of Von Bertalanffy's model. The growth coefficient (K) was 0.840 in males and 0.625 in females. The maximum SVL was greater in females (73.00 mm) than in males (59.50mm). Sexual dimorphism was significantly biased towards females in all age classes. The maximum longevity observed was 6 years in females and 8 years in males. Management strategies for agile frogs should take into account factors such as these life-history characteristics. PMID- 21658923 TI - Functional differentiation of trailing and leading forelimbs during locomotion on the ground and on a horizontal branch in the European red squirrel (Sciurus vulgaris, Rodentia). AB - Mammalian locomotion is characterized by the frequent use of in-phase gaits in which the footfalls of the left and right fore- or hindlimbs are unevenly spaced in time. Although previous studies have identified a functional differentiation between the first limb (trailing limb) and the second limb (leading limb) to touch the ground during terrestrial locomotion, the influence of a horizontal branch on limb function has never been explored. To determine the functional differences between trailing and leading forelimbs during locomotion on the ground and on a horizontal branch, X-ray motion analysis and force measurements were carried out in two European red squirrels (Sciurus vulgaris, Rodentia). The differences observed between trailing and leading forelimbs were minimal during terrestrial locomotion, where both limbs fulfill two functions and go through a shock-absorbing phase followed by a generating phase. During locomotion on a horizontal branch, European red squirrels reduce speed and all substrate reaction forces transmitted may be due to the reduction of vertical oscillation of the center of mass. Further adjustments during locomotion on a horizontal branch differ significantly between trailing and leading forelimbs and include limb flexion, lead intervals, limb protraction and vertical displacement of the scapular pivot. Consequently, trailing and leading forelimbs perform different functions. Trailing forelimbs function primarily as shock-absorbing elements, whereas leading forelimbs are characterized by a high level of stiffness. This functional differentiation indicates that European red squirrels 'test' the substrate for stability with the trailing forelimb, while the leading forelimb responds to or counteracts swinging or snapping branches. PMID- 21658924 TI - Postnatal essential fatty acid deficiency in mice affects lipoproteins, hepatic lipids, fatty acids and mRNA expression. AB - We have previously reported that essential fatty acid deficiency (EFAD) during suckling in mice resulted in an adult lean phenotype and a resistance to diet induced obesity. We now hypothesized that postnatal EFAD would cause long-term effects on lipid metabolism. C57BL/6 mice were fed an EFAD or a control diet from the 16th day of gestation and throughout lactation. The pups were weaned to standard diet (STD) and at 15 weeks of age given either high fat diet (HFD) or STD. Lipoprotein profiles, hepatic lipids, fatty acids and mRNA expression were analyzed in 3-week-old and 25-week-old offspring. At weaning, the EFAD pups had higher cholesterol levels in both plasma and liver and 6-fold higher concentrations of hepatic cholesterol esters than control pups. Adult EFAD offspring had higher levels of hepatic cholesterol and linoleic acid, but lower levels of dihomo-gamma-linolenic acid and Pparg mRNA expression in the liver. In addition, HFD fed EFAD offspring had lower plasma total cholesterol, lower hepatic triglycerides and lower liver weight compared to controls fed HFD. In conclusion, early postnatal EFAD resulted in short-term alterations with increased hepatic cholesterol accumulation and long-term protection against diet induced liver steatosis and hypercholesterolemia. PMID- 21658925 TI - The role of the central arachidonic acid-thromboxane A2 cascade in cardiovascular regulation during hemorrhagic shock in rats. AB - The aim of the current study was to elucidate the underlying central mechanism(s) of the cardiovascular effects evoked by centrally injected melittin and arachidonic acid (AA) in hemorrhaged hypotensive condition, specifically, from central AA release from the cell membrane under the influence of phospholipase A(2) (PLA(2)) to central thromboxane A(2) (TXA(2)) signaling via the cyclooxygenase (COX) pathway. As the main control of the study, melittin (3 MUg) or AA (150 MUg) was injected intracerebroventricularly (i.c.v.) after the hemorrhage procedure, which was performed by withdrawing a total volume of 2.2 ml of blood/100g body weight over a period of 10 min. Both treatments generated a pressor response and abolished the hypotension-induced hemorrhage. Pretreatment with the PLA(2) inhibitor mepacrine (500 MUg; i.c.v.) completely blocked the pressor response to melittin in the hemorrhagic hypotensive state. Pretreatments with the nonselective COX inhibitor indomethacin (200 MUg; i.c.v.) or the TXA(2) synthesis inhibitor furegrelate (250 or 500 MUg; i.c.v.) were made to test the role of central COX activity and, subsequently, the TXA(2) signaling pathway in the melittin- or AA-mediated reversal of hemorrhagic hypotension. Indomethacin completely prevented the pressor response to melittin and AA in the hemorrhaged, hypotensive state, but furegrelate did so only partially. In conclusion, these findings suggest that central COX activity and, subsequently, the central TXA(2) signaling pathway, are, at least in part, involved in the melittin- or AA-induced reversal effect during hemorrhagic shock. PMID- 21658926 TI - Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. AB - Butyrate is a four-carbon short-chain fatty acid that improves colonic trophism. Although several studies have shown the benefits of butyrate enemas in ulcerative colitis (UC), studies using the oral route are rare in the literature. In the present study, we evaluated the effect of butyrate intake in the immune response associated to UC. For that, mice were fed control or butyrate (0.5% sodium butyrate) diets for 14 days. Acute UC was induced by dextran sulphate sodium (DSS, 2.5%), replacing drinking water. The results showed that, in UC animals, oral butyrate significantly improved trophism and reduced leukocyte (eosinophil and neutrophil) infiltration in the colon mucosa and improved the inflammatory profile (activated macrophage, B and T lymphocytes) in cecal lymph nodes. In the small intestine, although mucosa histology was similar among groups, DSS treatment reduced duodenal transforming growth factor-beta, increased interleukin 10 concentrations and increased memory T lymphocytes and dendritic cells in Peyer's patches. Butyrate supplementation was able to revert these alterations. When cecal butyrate concentration was analyzed in cecal content, it was still higher in the healthy animals receiving butyrate than in the UC+butyrate and control groups. In conclusion, our results show that oral administration of sodium butyrate improves mucosa lesion and attenuates the inflammatory profile of intestinal mucosa, local draining lymph nodes and Peyer's patches of DSS-induced UC. Our results also highlight the potential use of butyrate supplements as adjuvant in UC treatment. PMID- 21658927 TI - Circulating isoflavonoid levels in CD-1 mice: effect of oral versus subcutaneous delivery and frequency of administration. AB - The CD-1 mouse is a commonly used animal model to understand the biological effects of early-life exposure to soy isoflavones in infants. Most studies using CD-1 mice have administered isoflavones by daily subcutaneous injection, while infants receive oral feeds every few hours. The study objectives were to compare the total serum levels of genistein (GEN), daidzein (DAI) and the DAI metabolites equol and O-desmethyl-angolensin (O-DMA), after subcutaneous injection and oral dosing and to determine if frequency of oral administration results in different circulating levels of isoflavones using the CD-1 mouse model. From postnatal days 1 to 5, pups randomly received corn oil or soy isoflavones (total daily dose, 0.010 mg DAI+0.025 mg GEN) by subcutaneous injection once a day, orally once a day or orally every 4 hours. On postnatal day 5, 1 h posttreatment, mice were killed and serum was collected. Mice treated with soy isoflavones had higher (P<.05) serum GEN (female: 1895-3391 ng/ml and male: 483-578 ng/ml) and DAI (female: 850-1580 ng/ml and male: 248-322 ng/ml) concentrations versus control (5 20 ng/ml) mice, regardless of route or frequency of administration, and were similar among dosing strategies. Total serum concentrations of GEN and DAI were higher (P<.05) among females (GEN: 2714 +/- 393 ng/ml and DAI: 1205 +/- 164 ng/ml) than males (GEN: 521 +/- 439 ng/ml and DAI: 288 +/- 184 ng/ml) across treatment groups. Serum equol and O-DMA concentrations were negligible (<3 ng/ml) across groups. In conclusion, different routes of delivery and frequency of administration resulted in similar total serum levels of GEN, DAI equol or O DMA. PMID- 21658928 TI - Alpha-linolenic acid increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase 1 expression: evidence for a farnesoid-X-receptor mechanism of action. AB - Increased cholesterol efflux from macrophage-derived foam cells (MDFCs) is an important protective mechanism to decrease lipid load in the atherosclerotic plaque. Dietary alpha-linolenic acid (ALA), an omega-3 polyunsaturated fatty acid (PUFA), decreases circulating cholesterol, but its role in cholesterol efflux has not been extensively studied. Stearoyl CoA desaturase 1 (SCD1) is the rate limiting enzyme in the synthesis of monounsaturated fatty acids (MUFAs). Endogenous MUFAs are preferentially incorporated into triglycerides, phospholipids and cholesteryl ester, which are abundant in atherosclerotic plaque. This study investigated the mechanisms by which ALA regulated SCD1 and subsequent effect on cholesterol storage and transport in MDFCs. Small interfering RNA (siRNA) also was applied to modify SCD1 expression in foam cells. Alpha-linolenic acid treatment and SCD1 siRNA significantly decreased SCD1 expression in MDFCs. The reduction of SCD1 was accompanied with increased cholesterol efflux and decreased intracellular cholesterol storage within these cells. Alpha-linolenic acid activated the nuclear receptor farnesoid-X-receptor, which in turn increased its target gene small heterodimer partner (SHP) expression, and decreased liver-X-receptor dependent sterol regulatory element binding protein 1c transcription, ultimately resulting in repressed SCD1 expression. In conclusion, repression of SCD1 by ALA favorably increased cholesterol efflux and decreased cholesterol accumulation in foam cells. This may be one mechanism by which dietary omega-3 PUFAs promote atherosclerosis regression. PMID- 21658929 TI - Differential effect of the 5-HTT gene-linked polymorphic region on emotional eating during stress exposure following tryptophan challenge. AB - Stress and negative moods, which are thought to be partly mediated by reduced brain serotonin function, often increase emotional eating in dieting women (restrainers). Because the short (S) allele polymorphism in the serotonin transporter gene (5-HTTLPR) is associated with serotonin dysfunction, S allele compared to long (L) allele 5-HTTLPR genotypes may be more susceptible to stress induced emotional eating. Consequently, serotonin challenge via tryptophan (TRP) rich protein hydrolysate (TPH) may alleviate stress-induced emotional eating particularly in S/S allele carriers. We tested whether acute stress affects emotional eating in women with high or low dietary restraints depending on their 5-HTTLPR genotype and TPH intake. Nineteen female subjects who were homozygous for the short-allele 5-HTTLPR genotype (S'/S'=S/L(G), L(G)/L(G): restrainers vs. nonrestrainers) and 23 female subjects who were homozygous for the long-allele 5 HTTLPR genotype (L'/L'=L(A)/L(A): restrainers vs. nonrestrainers) were tested in a double-blind, placebo-controlled crossover study of stress-induced emotional eating following intake of TPH or a placebo. TPH intake significantly increased the plasma TRP/large neutral amino acid ratio (P<.0001) in the L'/L' group (70%) compared to the S'/S' group (30%). TPH reduced food intake in both groups, but in the L'/L' group, it also reduced stress-induced negative mood (P=.037) and the desire for sweet, high-fat foods (P=.011) regardless of dietary restraint. CONCLUSIONS: Since TPH caused a greater increase in the plasma TRP/large neutral amino acid ratio in the L'/L' group compared to S'/S' group, the exclusive beneficial effects of L'/L' genotype may be due to enhanced brain 5-HT function. PMID- 21658930 TI - Biological role of lutein in the light-induced retinal degeneration. AB - Lutein, a xanthophyll of a carotenoid, is anticipated as a therapeutic product to prevent human eye diseases. However, its biological mechanism is still unclear. Here, we show the molecular mechanism of lutein's effect to reduce photodamage of the retina. We analyzed the light-exposed retinas of Balb/c mice given lutein supplemented or normal diet. Visual function was measured by electroretinogram, and histological changes were observed. Immunohistochemical and immunoblot analyses were performed to analyze molecular mechanism. The reactive oxygen species induced in the retina was evaluated by fluorescent probes. In the mice after light exposure, reduction of a-wave and b-wave amplitudes in electroretinogram, indicating visual impairment, and thinning of the photoreceptor cell layer owing to apoptosis were both attenuated by lutein diet. Interestingly, gamma-H2AX, a marker for double-strand breaks (DSBs) in DNA, was up-regulated in the photoreceptor cells after light exposure, but this increase was attenuated by lutein diet, suggesting that DSBs caused by photodamage contributed to the photoreceptor cell death and that this change was suppressed by lutein. Moreover, the expression of eyes absent (EYA), which promotes DNA repair and cell survival, was significantly up-regulated with lutein diet in the light-exposed retina. Therefore, lutein induced EYA for DNA repair, which could suppress DNA damage and photoreceptor cell apoptosis. Lutein reduced light induced oxidative stress in the retina, which might contribute to promote DNA repair. The lutein-supplemented diet attenuated light-induced visual impairment by protecting the photoreceptor cells' DNA. PMID- 21658931 TI - A qualitative evaluation of a peer-implemented overdose response pilot project in Gejiu, China. AB - BACKGROUND: A harm reduction NGO in southern Yunnan operating an emergency overdose response hotline service successfully reversed 76 overdoses through the administration of naloxone in one of the first interventions of its kind in China. METHOD: To explore local understandings of risk factors related to overdose, assess ongoing barriers to overdose response, and solicit client input on how to further reduce opiate overdose mortality in Gejiu, the authors conducted qualitative interviews with 30 clients, including 15 individuals who received naloxone injections to reverse an overdose and 15 individuals who called the hotline in response to the overdose of a peer. RESULTS: Participants pointed to a number of local structural shifts in heroin use including the ageing of the opiate using population and drug mixing practises that contribute to the city's overdose toll. Concerns over medical professionals' willingness to treat drug users, protection of confidentiality, and financial costs associated with treatment frequently cause drug users to avoid contact with the city's emergency service providers. Participants suggest directly distributing naloxone to clients as one strategy to further reduce overdose mortality. CONCLUSION: The authors explore possible strategies, including targeted trainings and new partnerships with local hospitals, to further reduce opiate overdose mortality in this resource-poor setting. PMID- 21658932 TI - Mass balances and life cycle inventory of home composting of organic waste. AB - A comprehensive experimental setup with six single-family home composting units was monitored during 1 year. The composting units were fed with 2.6-3.5 kg organic household waste (OHW) per unit per week. All relevant consumptions and emissions of environmental relevance were addressed and a full life-cycle inventory (LCI) was established for the six home composting units. No water, electricity or fuel was used during composting, so the major environmental burdens were gaseous emissions to air and emissions via leachate. The loss of carbon (C) during composting was 63-77% in the six composting units. The carbon dioxide (CO(2)) and methane (CH(4)) emissions made up 51-95% and 0.3-3.9% respectively of the lost C. The total loss of nitrogen (N) during composting was 51-68% and the nitrous oxide (N(2)O) made up 2.8-6.3% of this loss. The NH(3) losses were very uncertain but small. The amount of leachate was 130 L Mg(-1) wet waste (ww) and the composition was similar to other leachate compositions from home composting (and centralised composting) reported in literature. The loss of heavy metals via leachate was negligible and the loss of C and N via leachate was very low (0.3-0.6% of the total loss of C and 1.3-3.0% of the total emitted N). Also the compost composition was within the typical ranges reported previously for home composting. The level of heavy metals in the compost produced was below all threshold values and the compost was thus suitable for use in private gardens. PMID- 21658933 TI - Learning and motivation in the human striatum. AB - The past decade has seen a dramatic change in our understanding of the role of the striatum in behavior. Early perspectives emphasized a role for the striatum in habitual learning of stimulus-response associations and sequences of actions. Recent advances from human neuroimaging research suggest a broader role for the striatum in motivated learning. New findings demonstrate that the striatum represents multiple learning signals and highlight the contribution of the striatum across many cognitive domains and contexts. Recent findings also emphasize interactions between the striatum and other specialized brain systems for learning. Together, these findings suggest that the striatum contributes to a distributed network that learns to select actions based on their predicted value in order to optimize behavior. PMID- 21658934 TI - Omission of excisional therapy is associated with an increased risk of invasive cervical cancer after cervical intraepithelial neoplasia III. AB - BACKGROUND: Using data from the population-based Geneva Cancer Registry we evaluated the risk of invasive cervical cancer following carcinoma in situ (CIS) or cervical intraepithelial neoplasia (CIN) III according to type of treatment. METHODS: Included in the study were all women diagnosed with CIS/CIN III in Geneva (Switzerland) between 1970 to 2002 (n=2658) and followed for invasive cervical cancer occurrence until 31st December 2008. We calculated age and period standardised incidence ratios (SIR) and multiadjusted hazard ratios (HR) of invasive cervical cancer by treatment groups. RESULTS: During follow-up, 17 women developed invasive cervical cancer, conferring a SIR of 5.1 (95% confidence intervals [CI] 3.0-8.1). The risk of cervical cancer was significantly increased until 10 years after diagnosis. The risk was highest for women >= 50 years (SIR=7.3, 95% CI: 2.7-15.8) and for women who did not undergo excisional treatment (SIR=25, 95% CI: 12.0-46.0). The multiadjusted HR of invasive cervical cancer for women who did not undergo surgical excisional treatment was 9.4 (95% CI: 2.8-32.2) compared with women who did. CONCLUSION: Women diagnosed with CIS/CIN III are at increased risk of developing invasive cervical cancer. This risk is particularly high for women who did not have excision of cervical lesions. PMID- 21658935 TI - The role of ipsilateral breast radiotherapy in management of occult primary breast cancer presenting as axillary lymphadenopathy. AB - AIM: To assess the role of ipsilateral breast radiotherapy (IBR) in women with occult primary breast cancer presenting with axillary metastases (OPBC). METHODS: Patients with axillary nodal metastases and histological diagnosis of breast cancer without palpable, mammographic or ultrasonographic evidence of a breast primary were identified from a prospectively maintained single institution database. Imaging, surgery, radiotherapy, recurrence and survival data were collected. Patients whose breast cancer primary was detected on MRI (but occult on clinical examination and other imaging) were excluded from the analyses of IBR and outcome, but were included in other exploratory analyses. RESULTS: Fifty-five patients were included between 1975 and 2009. Median follow up was 68 months. Twenty patients had breast magnetic resonance imaging (MRI) in addition to other imaging. A primary breast cancer was detected in 7 of these 20. 48/55 patients had no detectable breast primary. 35/48 patients (73%) were treated with radiotherapy to the conserved breast, and 13/48 (27%) with observation. Patients who had IBR had better 5 year local recurrence free survival (LRFS) (84% versus 34%, p<0.001), and relapse free survival (RFS) (64% versus 34%, p=0.05), but no difference in overall survival (OS) (84% versus 85%, p=0.2). There was no difference in 5 year LRFS (80% versus 90%: p=0.3) between patients who received radiation of 50 Gy in 25 fractions versus >=60 Gy. CONCLUSION: Patients with OPBC should be managed with IBR and breast conservation, or mastectomy. Our data suggest it is not necessary to irradiate the breast to more than 50 Gy in 25 fractions. PMID- 21658936 TI - Re-evaluating the role of palliative radiotherapy in malignant pleural mesothelioma. AB - PURPOSE: To determine the objective response rate of malignant pleural mesothelioma (MPM) to short course radiation therapy. METHODS: We reviewed the cases of 54 patients with advanced MPM who were treated with palliative radiotherapy according to a standardised institutional policy. Pre- and post treatment computed tomography scans were used to assess response. RESULTS: Fifty seven percent of patients reported some improvement in their symptoms following radiotherapy. The radiology response rate was 43% (22 patients had a partial response and 1 patient a complete response). Response to treatment was correlated with the European Organisation for Research and Treatment of Cancer (EORTC) prognostic index (p=0.001), performance status (p=0.02) and histological subtype (p=0.04). In the EORTC good prognosis group 56% of patients responded, compared with only 7% in the poor prognosis group (p=0.001). The median survivals from diagnosis and from the start of radiotherapy were 11.3 months and 5.2 months, respectively. Survival following treatment was correlated with the EORTC prognostic index (p<0.001), histological subtype (p<0.001), performance status (p=0.001), treatment response (p=0.002) and haemoglobin level (0.02). The EORTC good and poor prognostic groups had survivals of 7.1 and 2.1 months, respectively (p<0.001). Neither tumour volume nor stage were associated with prognosis. CONCLUSIONS: Palliative radiotherapy produces a response rate in MPM that is equivalent to chemotherapy. The EORTC prognostic index can be used to select patients who are most likely to benefit from this treatment. PMID- 21658937 TI - Management of metastatic castration-resistant prostate cancer after first-line docetaxel. AB - Although chemotherapy, based on docetaxel, is now established in the management of metastatic castration-resistant prostate cancer (mCRPC), until recently, there has been no treatment licensed for use in the second line in men whose disease progresses during or after docetaxel therapy. This article reviews the classes of agents that have shown potential in this setting, notably chemotherapy drugs, hormonal therapies, immunotherapies, anti-angiogenic drugs, and clusterin targeted therapy. PMID- 21658938 TI - Relationship between CCL5 and transforming growth factor-beta1 (TGFbeta1) in breast cancer. AB - PURPOSE: Investigate circulating CCL5 in breast cancer patients and healthy controls, along with gene expression levels in corresponding tumour tissue and isolated primary stromal cells. Hormonal control of CCL5, and a potential relationship with TGFbeta1, was also investigated. METHODS: Circulating levels of CCL5 and TGFbeta1 were measured in 102 breast cancer patients and 66 controls using ELISA. Gene expression levels (CCL5, CCR5, TGFbeta1, TGFbetaRII) were quantified in corresponding tumour tissue (n = 43), normal tissue (n = 16), and isolated tumour (n = 22) and normal (n = 3) stromal cells using RQ-PCR. CCL5 and circulating menstrual hormones (LH, FSH, Oestradiol, Progesterone) were analysed in serum samples from healthy, premenopausal volunteers (n = 60). RESULTS: TGFbeta1 was significantly higher in breast cancer patients (Mean(SEM) 27.4(0.9)ng/ml) compared to controls (14.9(0.9)ng/ml). CCL5 levels decreased in the transition from node negative (59.6(3.7)ng/ml) to node positive disease (40.5(6.3)ng/ml) and increased again as the number of positive lymph nodes increased (?3 positive 50.95(9.8)ng/ml). A significant positive correlation between circulating CCL5 and TGFbeta1 (r = 0.423, p<0.0001) was observed, and mirrored at the gene expression level in tumour tissue from the same patients (r = 0.44, p<0.001). CCL5, CCR5 and TGFbeta1 expression was significantly higher in tumour compared to normal breast tissue (p < 0.001). A significant negative correlation was observed between circulating CCL5, Oestradiol and Progesterone (r = -0.50, r = -0.39, respectively, p < 0.05). CONCLUSION: CCL5 expression is elevated in the tumour microenvironment. The data support a role for hormonal control of circulating CCL5 and also highlight a potentially important relationship between CCL5 and TGFbeta1 in breast cancer. PMID- 21658939 TI - Risk factors for metachronous contralateral breast cancer suggest two aetiological pathways. AB - Although many studies show an increased risk of metachronous contralateral breast cancer (CBC) in women with a positive family history and young age at diagnosis of the initial breast cancer, the aetiological pathways are still enigmatic. In a cohort of 8478 primary breast cancer patients diagnosed between 1975 and 2006, 558 cases of metachronous CBC were identified. Using multivariate Cox proportional hazards models, we analysed risk factors assessed at the time of the first primary tumour, including patient demographics, tumour characteristics and treatment among 4681 breast cancer patients for whom data on key variables were available. The analysis was performed separately in patients who developed CBC without and with prior recurrence(s). Risk of CBC without prior recurrent disease was increased by a positive family history [adjusted relative risk (RR) 2.8 (95% confidence interval (CI) 1.4-5.5)]; and decreased by endocrine treatment [RR 0.6 (95% CI 0.4-1.0)]. We found an increased risk of CBC with prior recurrent disease with younger age [RR 1.2 (95% CI 1.4-3.0)]; positive family history [RR 2.1 (95%CI 0.8-5.0)]; and extensive lymph node involvement [RR 2.0 (95% CI 1.2-3.6)]. Our results suggest that nodal status of the primary tumour may be as important a risk factor as family history or age, which indicates a high susceptibility to breast cancer or an impaired host defence mechanism. It may also imply that some CBCs are metastases from the first primary tumour, particularly in patients who present with recurrent disease before CBC. PMID- 21658940 TI - H2 production from fowl manure by low temperature catalytic gasification. AB - In the paper, H(2) rich gas produced from fowl manure (hen compost-HC) by low temperature catalytic gasification (LTCG) technology is addressed. The pyrolysis behaviors of the samples before and after weak acid pretreatment were investigated using thermal gravimetric analysis. Furthermore, the catalytic influence of HC char and HC ash on the decomposition of the nascent volatiles was determined. A catalytic role of the minerals contained in HC on its pyrolysis behavior was confirmed due to the high content of Ca. LTCG process promotes the complete decomposition of the manure volatiles and significantly increases H(2) yield and the total gas yield. An obvious catalytic effect of HC char and HC ash on the decomposition of the nascent volatiles is attributed to CaO contained in them. PMID- 21658941 TI - Exploration of antimicrobial and antioxidant potential of newly synthesized 2,3 disubstituted quinazoline-4(3H)-ones. AB - A series of 2-(chloromethyl)-3-(4-methyl-6-oxo-5-[(E)-phenyldiazenyl]-2-thioxo 5,6-dihydropyrimidine-1(2H)-yl)quinazoline-4(3H)-ones 9a-j was synthesized by treating 2-(chloroacetyl)amino benzoic acid with 3-amino-6-methyl-5-[(E) phenyldiazenyl]-2-thioxo-2,5-dihydropyrimidine-4(3H)-one 8a-j and was screened for in vitro antibacterial activities against a representative panel of Gram positive and Gram-negative bacteria. The compounds were synthesized in excellent yields and the structures were corroborated on the basis of IR, (1)H NMR, Mass and elemental analysis data. All the synthesized compounds elicited the potent inhibitory action against all the tested bacterial stains. Furthermore, in order to explore the antioxidant potential of newly synthesized compounds, the free radical scavenging activity measurement were performed by the 1,1-diphenyl-2 picryl-hydrazyl (DPPH) assay method. It is revealed from the antioxidant screening results that the compounds 9c and f manifested profound antioxidant potential. PMID- 21658942 TI - The soy isoflavone genistein blunts nuclear factor kappa-B, MAPKs and TNF-alpha activation and ameliorates muscle function and morphology in mdx mice. AB - Several lines of evidence suggest a detrimental role of the nuclear factor-kappaB (NF-kappaB) activation in the dystrophic process. We showed in previous studies that its inhibition through drugs with antioxidant properties, have beneficial effects in mdx mice. We tested whether genistein, a well-known isoflavone, inhibitor of NF-kappaB, MAPK and TNF-alpha and readily available for clinical use, could have a beneficial effect in mdx mice in comparison with methylprednisolone, the gold standard treatment for DMD patients. Five-week old mdx mice received for five weeks: genistein (daily or 3-times/week), methylprednisolone or vehicle. Genistein treatment: (1) increased forelimb strength and strength normalized to weight; (2) reduced serum creatine-kinase levels; (3) reduced markers of oxidative stress; (4) reduced muscle necrosis and enhanced regeneration. The positive results were more evident with the daily administration of genistein and were comparable to the effect of corticosteroids. Our data support the novel hypothesis that, as other more specific therapeutic approaches are still under development, this soy-derived compound is a promising option to be further investigated in dystrophic process. PMID- 21658944 TI - Regulatory mechanism controlling stomatal behavior conserved across 400 million years of land plant evolution. AB - Stomatal pores evolved more than 410 million years ago [1, 2] and allowed vascular plants to regulate transpirational water loss during the uptake of CO(2) for photosynthesis [3]. Here, we show that stomata on the sporophytes of the moss Physcomitrella patens [2] respond to environmental signals in a similar way to those of flowering plants [4] and that a homolog of a key signaling component in the vascular plant drought hormone abscisic acid (ABA) response [5] is involved in stomatal control in mosses. Cross-species complementation experiments reveal that the stomatal ABA response of a flowering plant (Arabidopsis thaliana) mutant, lacking the ABA-regulatory protein kinase OPEN STOMATA 1 (OST1) [6], is rescued by substitution with the moss P. patens homolog, PpOST1-1, which evolved more than 400 million years earlier. We further demonstrate through the targeted knockout of the PpOST1-1 gene in P. patens that its role in guard cell closure is conserved, with stomata of mutant mosses exhibiting a significantly attenuated ABA response. Our analyses indicate that core regulatory components involved in guard cell ABA signaling of flowering plants are operational in mosses and likely originated in the last common ancestor of these lineages more than 400 million years ago [7], prior to the evolution of ferns [8, 9]. PMID- 21658943 TI - Cohesion fatigue induces chromatid separation in cells delayed at metaphase. AB - BACKGROUND: Chromosome instability is thought to be a major contributor to cancer malignancy and birth defects. For balanced chromosome segregation in mitosis, kinetochores on sister chromatids bind and pull on microtubules emanating from opposite spindle poles. This tension contributes to the correction of improper kinetochore attachments and is opposed by the cohesin complex that holds the sister chromatids together. Normally, within minutes of alignment at the metaphase plate, chromatid cohesion is released, allowing each cohort of chromatids to move synchronously to opposite poles in anaphase, an event closely coordinated with mitotic exit. RESULTS: Here we show that during experimentally induced metaphase delay, spindle pulling forces can cause asynchronous chromatid separation, a phenomenon we term "cohesion fatigue." Cohesion fatigue is not blocked by inhibition of Plk1, a kinase essential for the "prophase pathway" of cohesin release from chromosomes, or by depletion of separase, the protease that normally drives chromatid separation at anaphase. Cohesion fatigue is inhibited by drug-induced depolymerization of mitotic spindle microtubules and by experimentally increasing the levels of cohesin on mitotic chromosomes. In cells undergoing cohesion fatigue, cohesin proteins remain associated with the separated chromatids. CONCLUSION: In cells arrested at metaphase, pulling forces originating from kinetochore-microtubule interactions can, with time, rupture normal sister chromatid cohesion. This cohesion fatigue, resulting in unscheduled chromatid separation in cells delayed at metaphase, constitutes a previously overlooked source for chromosome instability in mitosis and meiosis. PMID- 21658945 TI - Land plants acquired active stomatal control early in their evolutionary history. AB - Stomata are pores that regulate plant gas exchange [1]. They evolved more than 400 million years ago [2, 3], but the origin of their active physiological responses to endogenous and environmental cues is unclear [2-6]. Recent research suggests that the stomata of lycophytes and ferns lack pore closure responses to abscisic acid (ABA) and CO(2). This evidence led to the hypothesis that a fundamental transition from passive to active control of plant water balance occurred after the divergence of ferns 360 million years ago [7, 8]. Here we show that stomatal responses of the lycophyte Selaginella [9] to ABA and CO(2) are directly comparable to those of the flowering plant Arabidopsis [10]. Furthermore, we show that the underlying intracellular signaling pathways responsible for stomatal aperture control are similar in both basal and modern vascular plant lineages. Our evidence challenges the hypothesis that acquisition of active stomatal control of plant carbon and water balance represents a critical turning point in land plant evolution [7, 8]. Instead, we suggest that the critical evolutionary development is represented by the innovation of stomata themselves and that physiologically active stomatal control originated at least as far back as the emergence of the lycophytes (circa 420 million years ago) [11]. PMID- 21658946 TI - Cell plate restricted association of DRP1A and PIN proteins is required for cell polarity establishment in Arabidopsis. AB - The polarized transport of the phytohormone auxin [1], which is crucial for the regulation of different stages of plant development [2, 3], depends on the asymmetric plasma membrane distribution of the PIN-FORMED (PIN) auxin efflux carriers [4, 5]. The PIN polar localization results from clathrin-mediated endocytosis (CME) from the plasma membrane and subsequent polar recycling [6]. The Arabidopsis genome encodes two groups of dynamin-related proteins (DRPs) that show homology to mammalian dynamin-a protein required for fission of endocytic vesicles during CME [7, 8]. Here we show by coimmunoprecipitation (coIP), bimolecular fluorescence complementation (BiFC), and Forster resonance energy transfer (FRET) that members of the DRP1 group closely associate with PIN proteins at the cell plate. Localization and phenotypic analysis of novel drp1 mutants revealed a requirement for DRP1 function in correct PIN distribution and in auxin-mediated development. We propose that rapid and specific internalization of PIN proteins mediated by the DRP1 proteins and the associated CME machinery from the cell plate membranes during cytokinesis is an important mechanism for proper polar PIN positioning in interphase cells. PMID- 21658947 TI - Arabidopsis WIH1 and WIH2 genes act in the transition from somatic to reproductive cell fate. AB - BACKGROUND: Unlike animals, higher plants do not establish a germ line in embryo development but form haploid germ cells from diploid somatic cells late in their life cycle. However, despite its prime importance, little is known about how this transition is regulated. RESULTS: Here, we show that the WUSCHEL (WUS) gene, initially identified as a stem cell regulator in the shoot meristem, is required for megasporogenesis and thus ultimately for the formation of female generative cells. WUS functions in this process by indirectly activating the expression of the WINDHOSE1 (WIH1) and WIH2 genes that encode small peptides found in plants and fungi, but not in animals. WIH genes function together with the tetraspanin type protein TORNADO2 (TRN2)/EKEKO in promoting megasporogenesis. CONCLUSIONS: Together, our studies identify a pathway promoting germ cell formation from somatic precursor cells. PMID- 21658948 TI - The inositol 5-phosphatase dOCRL controls PI(4,5)P2 homeostasis and is necessary for cytokinesis. AB - During cytokinesis, constriction of an equatorial actomyosin ring physically separates the two daughter cells. At the cleavage furrow, the phosphoinositide PI(4,5)P2 plays an important role by recruiting and regulating essential proteins of the cytokinesis machinery [1]. Accordingly, perturbation of PI(4,5)P2 regulation leads to abortive furrowing and binucleation [2-4]. To determine how PI(4,5)P2 is regulated during cytokinesis, we individually knocked down each of the enzymes controlling the phosphoinositide (PIP) cycle in Drosophila. We show that depletion of the Drosophila ortholog of human oculocerebrorenal syndrome of Lowe 1 (OCRL1), an inositol 5-phosphatase mutated in the X-linked disorder oculocerebrorenal Lowe syndrome, triggers a high rate of cytokinesis failure. In absence of dOCRL, several essential components of the cleavage furrow were found to be incorrectly localized on giant cytoplasmic vacuoles rich in PI(4,5)P2 and in endocytic markers. We demonstrate that dOCRL is associated with endosomes and that it dephosphorylates PI(4,5)P2 on internal membranes to restrict this phosphoinositide at the plasma membrane and thereby regulates cleavage furrow formation and ingression. Identification of dOCRL as essential for cell division may be important to understand the molecular basis of the phenotypic manifestations of Lowe syndrome. PMID- 21658949 TI - Protected and threatened components of fish biodiversity in the Mediterranean sea. AB - The Mediterranean Sea (0.82% of the global oceanic surface) holds 4%-18% of all known marine species (~17,000), with a high proportion of endemism [1, 2]. This exceptional biodiversity is under severe threats [1] but benefits from a system of 100 marine protected areas (MPAs). Surprisingly, the spatial congruence of fish biodiversity hot spots with this MPA system and the areas of high fishing pressure has not been assessed. Moreover, evolutionary and functional breadth of species assemblages [3] has been largely overlooked in marine systems. Here we adopted a multifaceted approach to biodiversity by considering the species richness of total, endemic, and threatened coastal fish assemblages as well as their functional and phylogenetic diversity. We show that these fish biodiversity components are spatially mismatched. The MPA system covers a small surface of the Mediterranean (0.4%) and is spatially congruent with the hot spots of all taxonomic components of fish diversity. However, it misses hot spots of functional and phylogenetic diversity. In addition, hot spots of endemic species richness and phylogenetic diversity are spatially congruent with hot spots of fishery impact. Our results highlight that future conservation strategies and assessment efficiency of current reserve systems will need to be revisited after deconstructing the different components of biodiversity. PMID- 21658950 TI - A positive feedback loop involving Haspin and Aurora B promotes CPC accumulation at centromeres in mitosis. AB - Haspin phosphorylates histone H3 at Thr3 (H3T3ph) during mitosis [1, 2], providing a chromatin binding site for the chromosomal passenger complex (CPC) at centromeres to regulate chromosome segregation [3-5]. H3T3ph becomes increasingly focused at inner centromeres during prometaphase [1, 2], but little is known about how its level or location and the consequent chromosomal localization of the CPC are regulated. In addition, CPC binding to shugoshin proteins contributes to centromeric Aurora B localization [5, 6]. Recruitment of the shugoshins to centromeres requires the phosphorylation of histone H2A at Thr120 (H2AT120ph) by the kinetochore kinase Bub1 [7], but the molecular basis for the collaboration of this pathway with H3T3ph has been unclear. Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. We propose that Aurora B activity triggers a CPC-Haspin-H3T3ph feedback loop that promotes generation of H3T3ph on chromatin. We also provide evidence that the Bub1 shugoshin-CPC pathway supplies a signal that boosts the CPC-Haspin-H3T3ph feedback loop specifically at centromeres to produce the well-known accumulation of the CPC in these regions. PMID- 21658952 TI - Sparganosis mimicking an intramedullary tumor of the cervical cord. AB - Sparganosis is a rare parasitic infection caused by the migrating plerocercoid larva of the tapeworm Spirometra mansoni that rarely affects the central nervous system. When sparganosis involves the spinal cord, it often affects the thoracic area. Here we report a patient with sparganosis mimicking an intramedullary tumor of the cervical cord. A 51-year-old male presented with slowly progressive paresthesias in all extremities and left-sided motor weakness. MRI of the spinal cord revealed an enhancing lesion from C1 to C4 that was suggestive of an intramedullary tumor. The results of enzyme-linked immunosorbent assays of the cerebrospinal fluid were consistent with infection with Spirometra mansoni, and the larvae were surgically removed. Sparganosis may mimic an intramedullary tumor of the spinal cord and should be considered in the differential diagnosis of a cervical cord mass with an uncertain course. PMID- 21658953 TI - Acute tetraplegia and cardiac arrest following high cervical leptomeningeal metastasis of giant cell glioblastoma. AB - Giant cell glioblastoma multiforme (gcGBM) is an unusual subtype of high-grade glioma (grade IV, World Health Organization classification). We report a patient with a rare acute tetraplegia, followed by lethal cardiac arrest, who had undergone a prior resection of a supratentorial gcGBM. Neuroradiological workup revealed a large, high cervical compressive leptomeningeal mass consistent with a drop metastasis. Due to the possibility of a rapid clinical deterioration in patients with high cervical cord compression, the diagnosis of drop metastasis to the spine should be considered in patients with a previous history of supratentorial GBM who present with acute diffuse motor weakness. PMID- 21658951 TI - Clinical and laboratory features of patients with myophosphorylase deficiency (McArdle disease). AB - Mutations of PYGM, the gene encoding human myophosphorylase, produce a metabolic myopathy characterised by exercise intolerance and, in some patients, myoglobinuria. To illustrate the clinical and laboratory features of myophosphorylase deficiency, we describe 10 patients diagnosed in Auckland, New Zealand, between 1989 and 2009. We review the clinical, biochemical, and histologic features and the results of mutation analysis. All patients reported exercise intolerance since childhood or the teenage years, starting within minutes of moderate or intense exertion. The "second wind" phenomenon, or myoglobinuria, were each reported in about half the patients. The serum creatine kinase concentration was elevated in all patients where this had been measured. Muscle biopsies revealed subsarcolemmal vacuolation and histochemical absence of myophosphorylase. Analysis of PYGM showed mutations in all alleles, most commonly Arg49Ter or Gly204Ser. One patient harbored a novel mutation, Pro488Arg, predicted to seriously disrupt the tertiary structure of the enzyme. Myophosphorylase deficiency produces a fairly uniform set of symptoms, and consistent elevation of the serum creatine kinase concentration. The diagnosis can be confirmed in most patients by mutation analysis using a blood sample. PMID- 21658954 TI - Parkinson's disease in general practice: assessing knowledge, confidence and the potential role of education. AB - In the context of an ageing population, Australian general practitioners (GPs) will be asked increasingly to manage challenging neurodegenerative conditions such as Parkinson's disease (PD). This study sought to evaluate whether Australian GPs have been provided with sufficient training to effectively diagnose and manage PD, and to determine the extent to which a brief training seminar could improve knowledge and increase confidence. A baseline assessment was completed by 168 GPs in New South Wales and the Australian Capital Territory, and was re-administered following an educational seminar to 105 GPs. Australian GPs demonstrated significant knowledge gaps on the baseline assessment, scoring only 50% (standard deviation [SD] 15.5%). Post-seminar results showed significant improvement (p<0.001) to 71.5% (SD 15%). Although following the seminar the vast majority reported increased confidence, there were some differential benefits between metropolitan and regional practitioners. These findings emphasise the need for continuing education in relation to PD in primary health care. PMID- 21658955 TI - Papillary tumour of the pineal region. AB - Papillary tumour of the pineal region (PTRR) is one of the new tumour entities to be included in the latest World Health Organization classification of central nervous system tumours. We report two illustrative patients, a 25-year-old female who presented following a head injury sustained from a fall due to gait disturbances, and a 42-year-old man who presented with headaches. Histology of both cases showed distinct papillary growth patterns with lining of the papillae by multi-layered cuboidal to columnar cells, prominent perivascular rosette and focal true rosette formation. Immunohistochemistry exhibited strong cytokeratin immunoreactivity in addition to CD56, focal S100, glial fibrillary acidic protein and neuron specific enolase positivity which supported a diagnosis of PTPR in both patients. Postoperatively, both patients underwent courses of adjuvant radiation therapy. One patient reported local recurrence of the tumour 23 months after surgery. While PTPR may have been misdiagnosed in the past, clear and consistent characteristics are beginning to be elucidated in the published reports and literature, which have been reviewed. As a relatively new distinct clinicopathological entity, prognostic data are limited and guidelines for treatment protocols are still being investigated in view of its propensity for local recurrence. PMID- 21658956 TI - Serial spread of benign metastasizing leiomyoma to the thoracic spine. AB - Benign metastasizing leiomyoma (BML) is a rare condition due to a histologically benign smooth muscle tumour originating from a uterine leiomyoma. It rarely affects the spine to cause spinal cord compression. Here we report a patient with serial metastases to the thoracic spine causing neurological compromise. The rapid spread of BML in this patient illustrates an aggressive manifestation of a usually benign indolent tumour. PMID- 21658958 TI - Application of N-C- or C-N-directed sequential native chemical ligation to the preparation of CXCL14 analogs and their biological evaluation. AB - CXCL14 is a chemokine that exhibits chemoattractant activity for activated macrophages, immature dendric cells, natural killer cells, and epithelial tumor cells. Its potential role as a metabolic regulator has recently been disclosed. However, a complete understanding of its physiological roles remains elusive. This is partly due to the lack of appropriate CXCL14-based molecular probes to explore the biological functions of CXCL14. In this context, we have developed synthetic protocols that provide access to a wide variety of CXCL14 analogs. Two sequential native chemical ligation (NCL) protocols, which proceed in opposite directions, have been used to assemble CXCL14 analogs from peptide fragments. The first involved a conventional C-N-directed sequential NCL, and afforded wild-type CXCL14. The other used peptide thioacids in N-C-directed elongation, and yielded CXCL14 analogs with molecular diversity at the C-terminal fragment. The CXCL14 analogs prepared showed biological activity on human monocytic leukemia-derived THP-1 cells that was comparable to that of wild-type CXCL14. PMID- 21658957 TI - Synthesis of enantiomerically pure D- and L-bicyclo[3.1.0]hexenyl carbanucleosides and their antiviral evaluation. AB - Based upon the fact that L-nucleosides have been generally known to be less cytotoxic than D-counterparts, L-bicyclo[3.1.0]hexenyl carbanucleoside derivatives with a fixed north conformation were designed and synthesized by employing a novel synthetic strategy starting from (R)-epichlorohydrin in order to search for new anti-HIV agents with high potency and less cytotoxicity. A tandem alkylation, gamma-lactonization, a chemoselective reduction of ester in the presence of gamma-lactone functional group, a RCM reaction, and a Mitsunobu coupling reaction were used as key reactions. D-Counterpart nucleosides were also prepared according to the same synthetic method. Among the synthesized carbanucleosides, D-thymine nucleoside, D-2 and L-thymine nucleoside, L-2 exhibited excellent anti-HIV-1 and -2 activities, in MT-4 cells, which were higher than those of ddI, an anti-AIDS drug. Whereas D-2 exhibited high cytotoxicity in MT-4 cell lines, L-2 did not show any discernible cytotoxicity in all cell lines tested, reflecting that L-2 may be a good candidate for an anti AIDS drug. L-2 also showed weak anti-HSV-2 activity without cytotoxicity. However, none of the synthesized nucleosides exhibited antiviral activities against RNA viruses including coxsakie, influenza, corona and polio viruses, maybe due to their 2',3'-dideoxy structure. Potent antiviral effects of D-2 and L 2 indicate that nucleosides belonging to a class of D4Ns can be an excellent candidate for anti-DNA virus agents. This research strongly supports L nucleosides of a class of D4Ns to be a very promising candidate for antiviral agents due to its low cytotoxicity and a good antiviral activity. PMID- 21658959 TI - Synthesis and mechanistic studies of a mitomycin dimer containing an eight membered cyclic disulfide. AB - Dimeric DNA alkylating agents have drawn significant interest because these compounds are expected to provide at least two reactive sites and as a result, generate enhanced levels of DNA interstrand cross-link (DNA ISC) adducts compared to their monomeric agents. We report the synthesis and mechanistic studies of a novel mitomycin dimer, 7-N,7'-N'-(1",2"-dithiocanyl-3",8" dimethylenyl)bismitomycin C (8) connected by an eight-membered cyclic disulfide. Mitomycins require prior activation (i.e., transformation to a good electrophile) for DNA adduction and therefore, 8 was aimed to undergo facile nucleophilic activation and produce enhanced levels of DNA ISC. At the core of this function lies a cyclic disulfide in 8. It was expected that disulfide cleavage by an appropriate nucleophile would successively produce two thiols that may trigger activation of two mitomycin rings in a dimer through intramolecular cyclization to quinine rings. Compound 8 was synthesized from mitomycin A (1) and the key intermediate, cyclic disulfide (11), along with the reference diol mitomycin 7 N,7'-N'-(2",7"-dihydroxy-1",8"-octanediyl)bismitomycin C (23) which does not contain the disulfide unit. We found that 8 underwent significantly enhanced nucleophilic activation in the presence of Et(3)P compared with 23, and that the disulfide unit in 8 played a key role for the nucleophilic activation. Based on these findings, we proposed a mechanism for nucleophilic activation of 8. We further demonstrated that 8 generated much higher levels of DNA ISC (94%) compared with 23 (4%) and 2 (3%) in the presence of Et(3)P (and L-DTT) leading to the conclusion that 8 is more efficient for DNA ISC processes than 23 and 2 due to the role of disulfide unit. PMID- 21658960 TI - Design, synthesis and biological assessment of novel N-substituted 3 (phthalimidin-2-yl)-2,6-dioxopiperidines and 3-substituted 2,6-dioxopiperidines for TNF-alpha inhibitory activity. AB - Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11-14 and 3 substituted 2,6-dioxopiperidines 16 and 18 were synthesized as tumor necrosis factor-alpha (TNF-alpha) synthesis inhibitors. Synthesis involved utilization of a novel condensation approach, a one-pot reaction involving addition, iminium rearrangement and elimination, to generate the phthalimidine ring required for the creation of compounds 9-14. Agents were, thereafter, quantitatively assessed for their ability to suppress the synthesis on TNF-alpha in a lipopolysaccharide (LPS)-challenged mouse macrophage-like cellular screen, utilizing cultured RAW 264.7 cells. Whereas compounds 9, 14 and 16 exhibited potent TNF-alpha lowering activity, reducing TNF-alpha by up to 48% at 30 MUM, compounds 12, 17 and 18 presented moderate TNF-alpha inhibitory action. The TNF-alpha lowering properties of these analogs proved more potent than that of revlimid (3) and thalidomide (1). In particular, N-dithiophthalimidomethyl-3-(phthalimidin-2-yl)-2,6 dioxopiperidine 14 not only possessed the greatest potency of the analogs to reduce TNF-alpha synthesis, but achieved this with minor cellular toxicity at 30 MUM. The pharmacological focus of the presented compounds is towards the development of well-tolerated agents to ameliorate the neuroinflammation, that is, commonly associated with neurodegenerative disorders, epitomized by Alzheimer's disease and Parkinson's disease. PMID- 21658961 TI - Discovery of 4-[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo 1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]benzoic acid hydrochloride: a highly potent orally available CCR5 selective antagonist. AB - Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented. PMID- 21658962 TI - Synthesis and radiolabeling of chelator-RNA aptamer bioconjugates with copper-64 for targeted molecular imaging. AB - Ribonucleic acid (RNA) aptamers with high affinity and specificity for cancer specific cell-surface antigens are promising reagents for targeted molecular imaging of cancer using positron emission tomography (PET). For this application, aptamers must be conjugated to chelators capable of coordinating PET radionuclides (e.g., copper-64, (64)Cu) to enable radiolabeling for in vivo imaging of tumors. This study investigates the choice of chelator and radiolabeling parameters such as pH and temperature for the development of (64)Cu labeled RNA-based targeted agents for PET imaging. The characterization and optimization of labeling conditions are described for four chelator-aptamer complexes. Three commercially available bifunctional macrocyclic chelators (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid mono N-hydroxysuccinimide [DOTA-NHS]; S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid [p-SCN-Bn-NOTA]; and p-SCN-Bn-3,6,9,15-tetraazabicyclo [9.3.1]pentadeca 1(15),11,13-triene-3,6,9-triacetic acid [p-SCN-Bn-PCTA]), as well as the polyamino-macrocyclic diAmSar (3,6,10,13,16,19-hexaazabicyclo[6.6.6] icosane-1,8 diamine) were conjugated to A10-3.2, a RNA aptamer which has been shown to bind specifically to a prostate cancer-specific cell-surface antigen (PSMA). Although a commercial bifunctional version of diAmSar was not available, RNA conjugation with this chelator was achieved in a two-step reaction by the addition of a disuccinimidyl suberate linker. Radiolabeling parameters (e.g., pH, temperature, and time) for each chelator-RNA conjugate were assessed in order to optimize specific activity and RNA stability. Furthermore, the radiolabeled chelator coupled RNA aptamers were evaluated for binding specificity to their target antigen. In summary, key parameters were established for optimal radiolabeling of RNA aptamers for eventual PET imaging with (64)Cu. PMID- 21658963 TI - 5-alk(en)ylresorcinols as the major active components in wheat bran inhibit human colon cancer cell growth. AB - We and others have found that wheat bran oil is the active constituent in wheat bran for colon cancer prevention. However, the active components in wheat bran oil are still unknown. Using human colon cancer cells (HCT-116 and HT-29) as the guiding assays, we further purified the active components from wheat bran using column chromatography. In this study, we identified that a fraction containing 5 n-alk(en)ylresorcinols had the strongest inhibitory effect on the proliferation of human HCT-116 and HT-29 colon cancer cells. Further purification led to the identification of 14 5-alk(en)ylresorcinols. Among them, 7, (10'Z,13'Z,16'Z)-5 (nonadeca-10',13',16'-trienyl)resorcinol, is a novel compound and 5, 6, 9, 10, and 13 were purified as individual compounds for the first time. The identification and structural elucidation of these compounds were based on 1D and 2D NMR and tandem mass spectral analyses. All these compounds (1-14) except 10 were evaluated for growth inhibition of human colon cancer cell lines (HCT-116 and HT-29). Our results indicate that increasing the length of the side chain will diminish the inhibitory activity, and the existence of a double bond and a carbonyl group will strengthen such an activity. PMID- 21658964 TI - CVD TiC/alumina multilayer coatings grown on sapphire single crystals. AB - Multilayers of TiC/alpha-Al(2)O(3) consisting of three (1 MUm thick) alumina layers separated by thin (~ 10 nm) oxidized TiC layers have been deposited onto c , a- and r-surfaces of single crystals of alpha-Al(2)O(3) by chemical vapour deposition (CVD). The aim of this paper is to describe and compare the detailed microstructure of the different multilayer coatings by using transmission electron microscopy (TEM). The general microstructure of the alumina layers is very different when deposited onto different surfaces of alpha-Al(2)O(3) single crystal substrates. On the c- and a-surfaces the alumina layers grow evenly resulting in growth of single crystal layers of TiC and alumina throughout the coating. However, when deposited on the r-surface the alumina layers generally grow unevenly. No pores are observed within the alumina layers, while a small number of pores are found at the interfaces below the TiC layers. The TiC and alumina layers grow epitaxially on the c- and a-surface substrates. On the r surface, epitaxy is present only at some rare locations. The TiC layers were oxidized in situ for 2 min in CO(2)/H(2) prior to the alumina layer deposition. For all three samples chemical analyses show that the whole TiC layer is oxidized. On the c- and a-surfaces the TiC layer was oxidized to an fcc TiCO phase. On the r-surface the oxidation stage resulted in a transformation of the initially deposited fcc TiC to a monoclinic TiCO phase, which appears to be a modified TiO structure with a high carbon content. PMID- 21658965 TI - Does the pulse play an important role during pulsatile pulmonary perfusion. PMID- 21658966 TI - Primary graft failure - the stepchild of cardiac transplantation. PMID- 21658967 TI - Mid-term results of endoscopic mitral valve repair in combination with endocardial or epicardial ablation. AB - OBJECTIVE: Concomitant ablative therapy for atrial fibrillation can be effective at converting patients to normal sinus rhythm and at maintaining a regular rhythm for at least 5 years. We provide herein a comparison of an endocardial approach using Cryoablation with an epicardial approach using a suction-based RF ablation technology. METHODS: Between February 2004 and January 2009, 325 patients underwent an endoscopic mitral valve repair. Of those patients, 112 (35%) had a history of atrial fibrillation prior to the procedure, all of whom underwent a concomitant ablation procedure. The first group of 78 concomitant ablation patients underwent a left-sided endocardial ablation procedure using a Cryoablation device. The second group of 34 ablation patients underwent a left sided epicardial ablation procedure using an internally cooled monopolar RF device. No significant differences existed between groups in the preoperative data. All ablated patients were treated by the same Amiodarone protocol. Patients were followed for a minimum of 6 months for determining each ablated patient's rhythm, medication use, and overall health status. RESULTS: The AF-free rates of group I and group II patients were statistically equivalent for both ablation groups at all evaluation time points. None of the 112 patients treated with endoscopic mitral valve repair and ablative therapy experienced a specific patient injury attributable to ablation; no ablated patients died in hospital following the procedure; there were no esophageal perforations and no coronary artery stenosis due to the ablations in either ablation group. The rate of patients without AF was 74% in group I and 82% in group II in the 6-month follow up. The group I pacemaker implantation rate of 14% was significantly higher than non-ablated group (4.7%), but the group II rate of 5.9% observed did not differ significantly from the non-ablated group. CONCLUSIONS: It was shown with our results that one succeeds with the en bloc-ablation in treating patients with different kinds of atrial fibrillation with concurrent intervention in the mitral valve reliably and with a high rate. The combination of this procedure with endocardial interventional ablation technologies can possibly develop to a promising strategy in the hybrid therapy of the isolated chronic atrial fibrillation as a standalone procedure. PMID- 21658968 TI - Mantle cell lymphoma. AB - MCL is a well-characterized clinically aggressive lymphoma with a poor prognosis. Recent research findings have slightly improved the outcome of this neoplasm. The addition of rituximab to conventional chemotherapy has increased overall response rates, but it does not improve overall survival with respect to chemotherapy alone. The use of intensive frontline therapies including rituximab and consolidated by ASCT ameliorates response rate and prolongs progression-free survival, but any impact on survival remains to be proven. Furthermore, the optimal timing, cytoreductive regimen and conditioning regimen, and the clinical implications of achieving a disease remission even at molecular level remain to be elucidated. The development of targeted therapies as the consequence of better dissection of pathogenetic pathways in MCL might improve the outcome of conventional chemotherapy in most patients and spare the toxicity of intense therapy in a minority of MCL patients characterized by a relatively indolent disease. Patients not eligible for intensive regimens, such as hyperC-VAD, may be considered for less demanding therapies, such as the combination of rituximab either with CHOP or with purine analogues, or bendamustine. Allogeneic SCT can be an effective option for relapsed disease in patients who are fit enough and have a compatible donor. Maintenance rituximab may be considered after response to immunochemotherapy for relapsed disease, although there are currently no data to recommend this approach as the first-line strategy. As the optimal approach to the management of MCL is still evolving, it is critical that these patients be enrolled in clinical trials to identify better treatment options. PMID- 21658969 TI - Complications in oral and maxillofacial surgery: management of hemostasis and bleeding disorders in surgical procedures. AB - Oral and maxillofacial surgeons perform a wide variety of surgical procedures. One of the major complications of these various surgical techniques is uncontrolled bleeding. The best management of perioperative hemorrhage is prevention. This includes proper preoperative patient evaluation, knowledge of the various bleeding disorders, and the characterization of the correct methods of management. This article evaluates various causes of bleeding, and identifies both local and systemic and pathways. Considerations of treatment for patients with these various disorders are discussed regarding the best management options for adequate hemostasis. PMID- 21658970 TI - Increased interleukin-4 and decreased interferon-gamma levels in serum of children with asthma. AB - BACKGROUND AND PURPOSE: Immune and inflammatory responses, mediated by cytokines, play important roles in the pathophysiology of asthma. These responses are associated with over expression of T helper (Th)-2 cytokine, particularly interleukin (IL)-4 and IL-5, and decreased expression of Th-1 cytokine, IL-2 and IFN-gamma. We hypothesized that there would be an imbalance in the levels of circulating IL-4 and IFN-gamma in the asthmatic subjects. METHOD: We investigated serum levels of IL-4 and IFN-gamma among eighty children (18 steroid-naive, 30 steroid-treated children with asthma and 32 healthy controls) using commercially available ELISA kits. RESULTS: Serum level of IL-4 was significantly higher in steroid-naive group of asthmatic children compared to the healthy control subjects and was lower in steroid-treated group though the level was statistically not significant. In contrast, serum levels of IFN-gamma were significantly lower in both steroid-naive and steroid-treated groups of asthmatic children compared to healthy control subjects. CONCLUSION: The results of our study suggest that serum level of IL-4 may be elevated in concert with decreased level of IFN-gamma in asthma. Determination of serum levels of IL-4 and IFN-gamma may be a useful tool for understanding the disease processes in asthma. PMID- 21658971 TI - Comparing thought suppression and mindfulness as coping techniques for spider fear. AB - The current study compared thought suppression, focused attention (mindfulness) and unfocused attention as strategies for managing spider fear. Spider fearful participants were exposed to a strategy induction before completing a Behavioural Approach Test (BAT). The BAT is a 10 step measurement of how close participants are willing to move towards a spider. Participants were instructed to use what they learned in the pre-BAT induction to help them advance through the steps of the BAT. The results of the study indicated that participants given the thought suppression or the unfocused attention induction moved through significantly less steps of the BAT than did those given the focused attention (mindful) induction. Additionally, the thought suppression group felt significantly more anxious than the focused and unfocused attention groups following completion of the BAT. These results are discussed in terms of the impact of thought suppression on avoidance behaviour in phobias. PMID- 21658972 TI - Synesthetic colors are elicited by sound quality in Japanese synesthetes. AB - Determinants of synesthetic color choice for Japanese phonetic characters were studied in six Japanese synesthetes. The study used Hiragana and Katakana characters, which represent the same set of syllables although their visual forms are dissimilar. From a palette of 138 colors, synesthetes selected a color corresponding to each character. Results revealed that synesthetic color choices for Hiragana characters and those for their Katakana counterparts were remarkably consistent, indicating that color selection depended on character-related sounds and not visual form. This Hiragana-Katakana invariance cannot be regarded as the same phenomenon as letter case invariance, usually reported for English grapheme color synesthesia, because Hiragana and Katakana characters have different identities whereas upper and lower case letters have the same identity. This involvement of phonology suggests that cross-activation between an inducer (i.e., letter/character) brain region and that of the concurrent (i.e., color) area in grapheme-color synesthesia is mediated by higher order cortical processing areas. PMID- 21658973 TI - Strict glycemic control and mortality risk among US adults with type 2 diabetes. AB - OBJECTIVE: To assess the relationships between strict HbA1c levels and mortality risk among adults with type 2 diabetes by age, insulin therapy, and hypertension comorbidity. METHODS: Data of adult participants with type 2 diabetes from the third National Health and Nutrition Examination Survey (1988-1994) and its linked mortality file (with follow-up death up to 2000) were used. RESULTS: Having strict glycemic control (i.e., HbA1c <=6.5%) was associated with a lower risk of mortality (hazards ratio=0.69; 95% confidence interval=0.48-0.98). However, among those with strict glycemic control levels, statistically significant results were not found. CONCLUSION: Reaching strict glycemic control levels in the general US population with type 2 diabetes appears to be associated with lower mortality. Further research is needed as to how strict glycemic control affects certain diabetic groups. PMID- 21658974 TI - Crisis checklists for the operating room: development and pilot testing. AB - BACKGROUND: Because operating room crises are rare events, failure to adhere to critical management steps is common. We sought to develop and pilot a tool to improve adherence to lifesaving measures during operating room crises. STUDY DESIGN: We identified 12 of the most frequently occurring operating room crises and corresponding evidence-based metrics of essential care for each (46 total process measures). We developed checklists for each crisis based on a previously defined method, which included literature review, multidisciplinary expert consultation, and simulation. After development, 2 operating room teams (11 participants) were each exposed to 8 simulations with random assignment to checklist use or working from memory alone. Each team managed 4 simulations with a checklist available and 4 without. One of the primary outcomes measured through video review was failure to adhere to essential processes of care. Participants were surveyed for perceptions of checklist use and realism of the scenarios. RESULTS: Checklist use resulted in a 6-fold reduction in failure of adherence to critical steps in management for 8 scenarios with 2 pilot teams. These results held in multivariate analysis accounting for clustering within teams and adjusting for learning or fatigue effects (11 of 46 failures without the checklist vs 2 of 46 failures with the checklist; adjusted relative risk = 0.15, 95% CI, 0.04-0.60; p = 0.007). All participants rated the overall quality of the checklists and scenarios to be higher than average or excellent. CONCLUSIONS: Checklist use can improve safety and management in operating room crises. These findings warrant broader evaluation, including in clinical settings. PMID- 21658975 TI - Protection from endogenous perforin: glycans and the C terminus regulate exocytic trafficking in cytotoxic lymphocytes. AB - Cytotoxic lymphocyte-mediated apoptosis is dependent on the delivery of perforin to secretory granules and its ability to form calcium-dependent pores in the target cell after granule exocytosis. It is unclear how cytotoxic lymphocytes synthesize and store perforin without incurring damage or death. We discovered that the extreme C terminus of perforin was essential for rapid trafficking from the endoplasmic reticulum to the Golgi compartment. Substitution of the C terminal tryptophan residue resulted in retention of perforin in the ER followed by calcium-dependent toxic activity that eliminated host cells. We also found that N-linked glycosylation of perforin was critical for transport from the Golgi to secretory granules. Overall, an intact C terminus and N-linked glycosylation provide accurate and efficient export of perforin from the endoplasmic reticulum to the secretory granules and are critical for cytotoxic lymphocyte survival. PMID- 21658976 TI - Facile synthesis [5-(13)C-4-(2)H(2)]-L-glutamine for hyperpolarized MRS imaging of cancer cell metabolism. AB - RATIONALE AND OBJECTIVES: Recent reports suggest that cancer cells may use glutamine, instead of glucose, as an alternative source of metabolic energy. This suggests that hyperpolarized (13)C glutamine may be useful as a magnetic resonance spectroscopy (MRS) imaging agent for detecting changes in glutamine metabolism in cancerous cells or tissues. MATERIALS AND METHODS: Synthesis of [5 (13)C-4-(2)H(2)]-L-glutamine was accomplished through a seven-step synthetic pathway with a 44% overall yield. The introduction of two stable isotopes was performed by a NaB(2)H(4)-mixed anhydride reduction and K(13)CN-nuclophilic substitution, respectively. The desired [5-(13)C-4-(2)H(2)]-L-glutamine was successfully obtained by a one-pot reaction of deprotection and controlled cyanide hydrolysis. Hyperpolarized [5-(13)C-4-(2)H(2)]-L-glutamine samples were tested in human glioma cells (myc upregulated glia cells, SF188-Bcl-x(L)). MRS signals were obtained with a 9.4 Tesla 89-mm bore nuclear magnetic resonance spectrometer and a direct-detection multi-nuclear probe. RESULTS: The initial degree of polarization for [5-(13)C-4-(2)H(2)]-L-glutamine was ~5% and the initial (13)C signal to noise ratio was ~100:1. Glutamate was detected within seconds after the injection of hyperpolarized glutamine into the cells. The ratio of glutamate to glutamine was very high, indicating rapid conversion to glutamate. Similar cell uptake studies using [(3)H]-L-glutamine also demonstrated cell uptakes higher than that of [(18)F]fluorodeoxyglucose. CONCLUSION: We are reporting the first example of using specifically deuterated [5-(13)C-4-(2)H(2)] L-glutamine in conjunction with hyperpolarized MRS for studying "glutaminolysis" in proliferating tumor cells. PMID- 21658977 TI - Prognostic significance of positive surgical margins after radical prostatectomy among pT2 and pT3a prostate cancer. AB - OBJECTIVE: To investigate the prognostic significance of positive surgical margins (PSM)s among patients who underwent radical prostatectomy (RP) for pT2 and pT3a prostate cancer. PATIENTS AND METHODS: We reviewed the records of 658 patients who were revealed to have pT2 and pT3a prostate cancer after undergoing RP without neoadjuvant or adjuvant treatment. For our analysis, patients were subgrouped as the following: group 1: 406 (61.7%) with negative surgical margins (NSM)s and no extracapsular extension of tumor (ECE); group 2: 99 (15.0%) with PSMs and no ECE; group 3: 63 (9.6%) with NSMs and ECE; and group 4: 90 (13.7%) with PSMs and ECE. The effects of various variables on biochemical recurrence (BCR)-free survival were assessed via uni- and multivariate analyses. RESULTS: During median follow-up of 36 months, group 1 had significantly higher BCR-free survival compared with the other 3 groups (P < 0.001). However, no significant differences in BCR-free survivals were observed among the group 2, 3, and 4 (all P > 0.05). In multivariate analysis, PSM (P = 0.009) was observed to be significantly associated with BCR-free survival among groups 1 and 2 combined. Among groups 3 and 4, pathologic Gleason score (P = 0.002), but not PSM (P = 0.668), was the only significant predictor for BCR-free survival in multivariate analysis. CONCLUSIONS: According to our results, PSM is significantly associated with biochemical outcome after RP in pT2 prostate cancer. Meanwhile, patients with pT2 tumor and PSM appear to have comparable biochemical outcome compared with those with stage pT3a tumor independent of their marginal status. PMID- 21658978 TI - Insulin-like growth factor pathway: a link between androgen deprivation therapy (ADT), insulin resistance, and disease progression in patients with prostate cancer? AB - Androgen deprivation therapy (ADT) is standard of care for patients with metastatic hormone-sensitive prostate cancer (HSPC), yet through its induction of a hypogonadal state leads to metabolic perturbations, including insulin resistance (IR) and obesity. IR and obesity have been associated with an increased risk of progression to castrate-resistant prostate cancer (CRPC) and ultimately increased prostate cancer-specific mortality. On a molecular level, this association between obesity/IR and prostate cancer progression may be mediated by alterations in the insulin-like growth factor (IGF) axis, which has been shown to be up-regulated upon disease progression to CRPC. Targeting the IGF axis, either by anti-IGF therapy or via enhancement of peripheral insulin sensitivity, represents a viable therapeutic target in patients with prostate cancer. Using the development of IR and/or obesity may represent a clinically available biomarker that may predict those patients most likely to respond to such therapy, and warrants testing in future prospective clinical trials. PMID- 21658979 TI - Heart rate variability, sleep and sleep disorders. AB - Heart rate (HR) is modulated by the combined effects of the sympathetic and parasympathetic nervous systems. Therefore, measurement of changes in HR over time (heart rate variability or HRV) provides information about autonomic functioning. HRV has been used to identify high risk people, understand the autonomic components of different disorders and to evaluate the effect of different interventions, etc. Since the signal required to measure HRV is already being collected on the electrocardiogram (ECG) channel of the polysomnogram (PSG), collecting data for research on HRV and sleep is straightforward, but applications have been limited. As reviewed here, HRV has been applied to understand autonomic changes during different sleep stages. It has also been applied to understand the effect of sleep-disordered breathing, periodic limb movements and insomnia both during sleep and during the daytime. HRV has been successfully used to screen people for possible referral to a Sleep Lab. It has also been used to monitor the effects of continuous positive airway pressure (CPAP). A novel HRV measure, cardiopulmonary coupling (CPC) has been proposed for sleep quality. Evidence also suggests that HRV collected during a PSG can be used in risk stratification models, at least for older adults. Caveats for accurate interpretation of HRV are also presented. PMID- 21658980 TI - Quantitative Sensory Testing to assess the sensory characteristics of cancer induced bone pain after radiotherapy and potential clinical biomarkers of response. AB - BACKGROUND/AIMS: Radiotherapy (XRT) is the gold standard treatment for cancer induced bone pain (CIBP), but only 50% of patients achieve adequate pain relief within 6 weeks. No predictors of analgesic response to XRT are known. The aim of this preliminary study was to explore the effect of XRT on sensory changes in CIBP with a view to predicting response. METHODS: After ethics committee approval, patients with CIBP were assessed prior to and 4-6 weeks after palliative XRT. This included completion of the Brief Pain Inventory (BPI) and bedside Quantitative Sensory Testing (QST) measuring evoked sensations to quantified stimuli on the skin over the area of CIBP and a control site. RESULTS: Twenty-three patients were assessed pre and post XRT. Thirteen (57%) had an analgesic response (defined as >=30% reduction in total BPI). Those patients who had normalisation of abnormal warm sensation ("warm responders", n = 6) were different in that they had higher baseline functional BPI pain scores (median score (IQR) in warm responders = 43 (31.75-58) compared to 31 (12-39.5) in the remaining patients, p = 0.039), larger reductions in pain scores (median difference of 33.5 in total BPI, p = 0.027) and increased likelihood of resolution of sensitivity to pinprick. CONCLUSIONS: This is the first clinical study to demonstrate alterations in sensory responses in CIBP. Alterations in specific sensory characteristics seem to be associated with an increased likelihood of successful analgesia from palliative XRT. This supports the use of QST in further biomarker studies to predict response to therapy and aid clinical decision making. PMID- 21658982 TI - Merkel cell carcinosarcoma: Merkel cell carcinoma with embryonal rhabdomyosarcoma like component. AB - Merkel cell carcinoma is an uncommon primary neuroendocrine neoplasm of the skin that may exhibit divergent differentiation. However, rhabdomyosarcomatous differentiation has only been rarely described and takes the form of isolated rhabdomyoblasts. We describe a case of cutaneous Merkel cell carcinoma with biphasic morphology imparted by discrete patches of embryonal rhabdomyosarcoma like spindle cells alternating with islands of neuroendocrine small round cells, justifying a designation of "Merkel cell carcinosarcoma." The former component showed positive immunostaining for desmin and myogenin; and the later component, pan-cytokeratin, cytokeratin 20, synaptophysin, and chromogranin. The patient was an elderly man who presented with a temporal skin mass, and the biphasic morphology was evident in the recurrence and metastasis that developed 2 months after incomplete excision of the skin lesion. PMID- 21658981 TI - LipoxinA(4) induced antinociception and decreased expression of NF-kappaB and pro-inflammatory cytokines after chronic dorsal root ganglia compression in rats. AB - Inflammatory and immune responses following nerve injury have been shown to play an important role in neuropathic pain. Lipoxins are endogenous lipoxygenase derived eicosanoids performing protective roles in a range of pathophysiologic processes. Here, we examined the effects of intrathecal lipoxinA4 (LXA4) on NF kappaB activation and pro-inflammatory cytokine (TNF-alpha, IL-1beta and IL-6) expression in dorsal root ganglia (DRG) following chronic compression of DRG (CCD), a model of neuropathic pain. Daily intrathecal injection of vehicle or LXA4 (10 ng or 100 ng) was performed for three successive days post-CCD. CCD induced both mechanical allodynia and thermal hyperalgesia, and increased the expression of TNF-alpha, IL-1beta, IL-6 and NF-kappaB. Intrathecal injection of LXA4 prevented the development of neuropathic pain and inhibited NF-kappaB activation and pro-inflammatory cytokine upregulation in a dose-dependent manner. In this study, we have shown the strong protective effect of intrathecal LXA4 on the development of nociceptive behaviors induced by CCD and that these effects might be associated with its anti-inflammatory and pro-resolution properties. PMID- 21658983 TI - Isolated vaginal myeloid sarcoma in a 16-year-old girl. AB - Involvement of the female genital tract by myeloid sarcoma as the initial presentation is extremely uncommon, especially in the vagina. The lack of specific histologic features and the unusual location can be a diagnostic challenge to both the surgical pathologist and the clinician. The very few reported cases of myeloid sarcoma occurring in the vagina have been exclusively seen in adults. We report a 16-year-old girl who presented with a vaginal mass of 4 weeks duration. The initial clinical impression was a Bartholin cyst vs an abscess. However, because of persistence of the vaginal mass after a full course of antibiotic treatment, a biopsy was performed. Immunohistochemistry supported the diagnosis of myeloid sarcoma. Peripheral blood and bone marrow studies were normal. The patient received 4 cycles of chemotherapy and remained disease free 5 months from therapy completion. The clinical course, diagnostic workup, and differential diagnosis of our patient are discussed. Reported cases of myeloid sarcoma occurring in the vagina are reviewed and summarized. PMID- 21658984 TI - Validation of longitudinal DXA changes in body composition from pre- to mid adolescence using MRI as reference. AB - Dual-energy X-ray absorptiometry (DXA) has been used extensively for bone mineral density and body composition assessments. Surprisingly, the role of DXA in monitoring changes in children's body composition, using direct imaging methods such as magnetic resonance imaging (MRI) as reference, is still yet to be validated. We aimed at validating the use of DXA in monitoring change in the thigh lean soft tissue mass (LSTM) and fat mass (FM) when compared with thigh skeletal muscle mass (SM) and FM, measured using MRI as the reference standard, from childhood to midadolescence. At baseline, 22 healthy children (16 boys and 6 girls) aged 8-11yr were included, and then recalled at pubertal stage Tanner2 Tanner4. LSTM-DXA and FM-DXA of the mid-third femur and SM-MRI and FM-MRI of the same region were measured on the same day. The same protocol was repeated 26-48mo later. At baseline, DXA overestimated LSTM-DXA on average by 222g (95% confidence interval [CI]: 33-410g) with a concordance C-LSTM=0.576. FM-MRI and FM-DXA were not significantly different (95% CI=213 to 199g, the C-FM=0.907). At follow-up, change in LSTM-DXA and FM-DXA were not significantly different to change in SM MRI and FM-MRI, respectively (95% CI of the difference was -278 to 208g for LSTM, and -148 to 236g for FM). The coefficient of concordance between the 2 techniques was 0.88 for both LSTM and FM. This study validates the use of DXA in monitoring changes in LSTM and FM in children, confirming its significant potential in clinical and research roles in pediatric body composition. PMID- 21658985 TI - Effect of anterior tympanomeatal angle blunting on the middle ear transfer function using a finite element ear model. AB - The anterior tympanomeatal angle (ATA) blunting is clinically defined as a certain degree of the ATA obliteration due to excessive fibrous tissue formation, which is a relatively common complication of external auditory canal (EAC) related operations. The aim of this study was to examine the effect of ATA blunting on the middle ear transfer function using a finite element (FE) model. Results showed that the displacements at the tympanic membrane (TM), at the manubrium and at the stapes footplate, and also the ratio of stapes footplate velocity to the sound pressure in the EAC were decreased to various degrees from ATA blunting of Grades 1-4. This was more significant with TM thickening at the frequencies below 3.2kHz, particularly in Grades 3 and 4 when analyzing the anterior region of the TM. The phase differences of TM and stapes footplate increased with the ATA blunting from Grades 1 to 4 in relation to normal ATA. It is noteworthy that the vibration mode of the malleus does not show obvious change, compared to the displacement reduction at the TM with ATA blunting Grades 1-4. These results suggest that FE analysis of ATA blunting effect appears to be effective. PMID- 21658986 TI - A computational tool to support pre-operative planning of stentless aortic valve implant. AB - In some cases of aortic valve leaflet disease, the implant of a stentless biological prosthesis represents an excellent option for aortic valve replacement (AVR). In particular, if compared to more classical surgical approaches, it provides a more physiological hemodynamic performance and a minor trombogeneticity avoiding the use of anticoagulants. The clinical outcomes of AVR are strongly dependent on an appropriate choice of both prosthesis size and replacement technique, which are, at present, strictly related to surgeon's experience and skill. Therefore, also this treatment, like most reconstructive procedures in cardiac surgery, remains "more art than science". Nowadays computational methodologies represent a useful tool both to investigate the aortic valve behavior, in physiologic and pathologic conditions and to reproduce virtual post-operative scenarios. The present study aims at supporting the AVR procedure planning through a patient-specific Finite Element Analysis (FEA) of stentless valve implantation. Firstly, we perform FEA to simulate the prosthesis placement inside the patient-specific aortic root; then, we reproduce, again by means of FEA, the diastolic closure of the valve to evaluate both the coaptation and the stress/strain state. The simulation results prove that both the valve size and the anatomical asymmetry of the Valsalva sinuses affect the prosthesis placement procedure. PMID- 21658987 TI - Clinical relevance vs. statistical significance: Using neck outcomes in patients with temporomandibular disorders as an example. AB - Statistical significance has been used extensively to evaluate the results of research studies. Nevertheless, it offers only limited information to clinicians. The assessment of clinical relevance can facilitate the interpretation of the research results into clinical practice. The objective of this study was to explore different methods to evaluate the clinical relevance of the results using a cross-sectional study as an example comparing different neck outcomes between subjects with temporomandibular disorders and healthy controls. Subjects were compared for head and cervical posture, maximal cervical muscle strength, endurance of the cervical flexor and extensor muscles, and electromyographic activity of the cervical flexor muscles during the CranioCervical Flexion Test (CCFT). The evaluation of clinical relevance of the results was performed based on the effect size (ES), minimal important difference (MID), and clinical judgement. The results of this study show that it is possible to have statistical significance without having clinical relevance, to have both statistical significance and clinical relevance, to have clinical relevance without having statistical significance, or to have neither statistical significance nor clinical relevance. The evaluation of clinical relevance in clinical research is crucial to simplify the transfer of knowledge from research into practice. Clinical researchers should present the clinical relevance of their results. PMID- 21658988 TI - Assessment of the degree of pelvic tilt within a normal asymptomatic population. AB - In clinical practice the degree of pelvic tilt is commonly assessed because of its reported relationship to pelvic, spinal and lower limb pathologies. There is little normative data presented within the literature establishing typical findings within an asymptomatic population from which to make comparisons in pathological populations. The aim of this study was to report typical pelvic angle in an asymptomatic populations and also the degree of side-to-side asymmetry which might exist within the pelvis. Pelvic angle was measured by finding the angle from horizontal of a line between the anterior superior and posterior superior iliac spines of the ilium using a PALM palpation meter in 120 healthy subjects (65 males, 55 females) with a mean age of 23.8(2.1) years. 85% of males and 75% of females presented with an anterior pelvic tilt, 6% of males and 7% of females with a posterior tilt and 9% of males and 18% of females presented as neutral. There was significant difference in pelvic angle between sides for males (p = 0.002) but a non-significant difference between sides for females (p = 0.314). But the difference in angle for males between sides was less than the smallest detectable difference statistic found in the reliability study, so most likely to be due to measurement error. PMID- 21658989 TI - Understanding shoot branching by modelling form and function. AB - Shoot branching plays a pivotal role in the development of the aboveground plant structure. Therefore, to understand branching in relation to the environment, it is not only necessary to integrate the knowledge on mechanisms that regulate branching at multiple levels of biological organisation, but also to include plant structure explicitly. To this end, we propose the application of an established methodology called functional-structural plant modelling. PMID- 21658991 TI - Study on the interaction between torasemide and 12-tungstophosphoric acid by resonance Rayleigh scattering and resonance nonlinear scattering spectra and its analytical applications. AB - In pH 0.6-1.1 HCl-NaAc buffer solution, torasemide (TOR) reacted with TP to form a 3:1 ion-association complexes. As a result, not only the absorption spectra were changed, but also the intensities of resonance Rayleigh scattering (RRS), second-order scattering (SOS) and frequency doubling scattering (FDS) were enhanced greatly. The maximum RRS, SOS and FDS wavelengths were located at 370, 333, 776 nm, respectively. Under given conditions, the intensities of RRS, SOS and FDS were all directly proportional to the concentration of TOR. The detection limits of RRS, SOS and FDS were 0.7173 ng mL(-1), 7.007 ng mL(-1) and 10.90 ng mL(-1). The optimum conditions and the effects of coexisting substances on the reaction were investigated. The results showed that the method had good selectivity. Therefore, a highly sensitive, simple and quick method has been developed for the determination of TOR. The method can be applied satisfactorily to the determination of TOR in tablets and urine samples. PMID- 21658990 TI - The value of (18)F-FDG PET/CT for the detection of distant metastases in high risk patients with head and neck squamous cell carcinoma. AB - The aims of this study were to assess a cohort of patients with head and neck squamous cell carcinoma (HNSCC) for: (1) the prevalence of synchronous distant metastases (DM) as detected by the initial staging by using (18)F-FDG PET/CT, (2) the prevalence of metachronous DM, and (3) the validity of published risk factors with special emphasis on the maximum standardized uptake value (SUV max) for the prediction of DM. Two hundred and ninety nine patients with advanced HNSCC were included. Following risk factors at the time of diagnosis and during follow-up were analyzed: advanced T/N stage, poor histological differentiation, level IV/Vb lymph nodes, primary site in the larynx/hypopharynx, and SUV max. The prevalence of DM at initial staging and during follow-up was 10% and 11%, respectively. At initial staging, primary site in the larynx/hypopharynx and neck nodes in level IV/Vb, and during follow-up only level IV/Vb nodes achieved statistical significance. The sensitivity for (18)F-FDG PET/CT with regard to the detection of DM was 96.8%, the specificity 95.4%, the positive predictive value (PV) 69.8%, and the negative PV 99.6%. Patients without DM showed a significantly better overall survival (OS) than patients developing DM (p<0.001). There was no significant difference in OS with regard to the time of diagnosis of DM. The prevalence for synchronous and metachronous DM in advanced HNSCC is considerable. (18)F-FDG PET/CT is highly accurate for initial staging and follow-up. DM carries a bad prognosis regardless of the time of diagnosis. PMID- 21658992 TI - Theoretical studies on molecular structure and vibrational spectra of 8 hydroxyquinolinium picrate. AB - Quantum chemical calculations of geometrical structure and vibrational wavenumbers of 8-hydroxyquinolinium picrate (8-HQP) were carried out by ab initio HF and density functional (DFT/B3LYP) method with 6-31++G(dp) basis set. The calculated geometric parameters of 8-HQP are presented. A detailed interpretation of the infrared spectra of 8-hydroxyquinolinium picrate (8-HQP) are also reported. Theoretical molecular frontier orbital energies of the title compound have been calculated using the method mentioned above in order to understand this phenomenon in the context of molecular orbital picture. The molecular HOMOs and LUMOs generated via HF and B3LYP method have been outlined. PMID- 21658993 TI - Preparation, characterization and photoluminescence properties of BaB2O4: Eu3+ red phosphor. AB - A new red emitting BaB2O4: Eu3+ phosphor was synthesized by solid-state reaction method. X-ray powder diffraction (XRD) analysis confirmed the monoclinic formation of BaB2O4. Field-emission scanning electron-microscopy (FE-SEM) observation indicated that the microstructure of the phosphor consisted of irregular grains with heavy agglomerate phenomena. Upon excitation with 394 nm light, the BaB2O4: Eu3+ phosphor shows bright red emissions with the highest photoluminescence (PL) intensity at 611 nm due to 5D0->7F2 transitions of Eu3+ ions. The CIE chromaticity coordinates are calculated from the emission spectrum to be x=0.64, y=0.35. The effects of the Eu3+ concentration on the PL were investigated. The results showed that the optimum concentration of Eu3+ in BaB2O4 host is 6 mol% and the dipole-dipole interaction plays the major role in the mechanism of concentration quenching of Eu3+ in BaB2O4: Eu3+ phosphor. The effect of charge compensation on the emission intensity was also studied. The charge compensations of Li+, Na+ and K+ anions all increased the luminescent intensity of BaB2O4: Eu3+. K+ anion gave the best improvement to enhance the intensity of the emission, indicating K+ is the optimal charge compensator. All properties show that this phosphor could serve as a potential candidate for application as a red phosphor for NUV chip LED. PMID- 21658994 TI - A vibrational spectroscopic study of hydrated Fe(3+) hydroxyl-sulfates; polymorphic minerals butlerite and parabutlerite. AB - Raman and infrared spectra of two polymorphous minerals with the chemical formula Fe3+(SO4)(OH).2H2O, monoclinic butlerite and orthorhombic parabutlerite, are studied and the spectra assigned. Observed bands are attributed to the (SO4)2- stretching and bending vibrations, hydrogen bonded water molecules, stretching and bending vibrations of hydroxyl ions, water librational modes, Fe-O and Fe-OH stretching vibrations, Fe-OH bending vibrations and lattice vibrations. The O-H?O hydrogen bond lengths in the structures of both minerals are calculated from the wavenumbers of the stretching vibrations. One symmetrically distinct (SO4)2- unit in the structure of butlerite and two symmetrically distinct (SO4)2- units in the structure of parabutlerite are inferred from the Raman and infrared spectra. This conclusion agrees with the published crystal structures of both mineral phases. PMID- 21658995 TI - Amino acid components of lees in salmon fish sauce are tyrosine and phenylalanine. AB - We report that the lees in salmon fish sauce consist of Tyr and Phe. The concentration of free l-Tyr (2.0mM) was almost same as the saturated concentration (2.4mM) in water at 20 degrees C. This result shows that lees are formed by Tyr precipitation due to its saturation in the sauce. PMID- 21658996 TI - Rapid identification of Burkholderia pseudomallei and Burkholderia mallei by fluorescence in situ hybridization (FISH) from culture and paraffin-embedded tissue samples. AB - We evaluated newly developed probes for rapid identification of Burkholderia (B.) pseudomallei and B. mallei and differentiation from B. thailandensis by fluorescence in situ hybridization (FISH). FISH correctly identified 100% of the tested B. pseudomallei (11), B. mallei (11), and B. thailandensis (1) strains, excluded 100% of all tested negative controls (61), and allowed demonstration of B. pseudomallei infection in a paraffin-embedded spleen tissue sample of an experimentally infected mouse. PMID- 21658998 TI - What does sports injury research tell us? PMID- 21658997 TI - Secretome analysis of Aspergillus fumigatus reveals Asp-hemolysin as a major secreted protein. AB - Surface-associated and secreted proteins represent primarily exposed components of Aspergillus fumigatus during host infection. Several secreted proteins are known to be involved in defense mechanisms or immune evasion, thus, probably contributing to pathogenicity. Furthermore, several secreted antigens were identified as possible biomarkers for the verification of diseases caused by Aspergillus species. Nevertheless, there is only limited knowledge about the composition of the secretome and about molecular functions of particular proteins. To identify secreted proteins potentially essential for virulence, the core secretome of A. fumigatus grown in minimal medium was determined. Two dimensional gel electrophoretic separation and subsequent MALDI-TOF-MS/MS analyses resulted in the identification of 64 different proteins. Additionally, secretome analyses of A. fumigatus utilizing elastin, collagen or keratin as main carbon and nitrogen source were performed. Thereby, the alkaline serine protease Alp1 was identified as the most abundant protein and hence presumably represents an important protease during host infection. Interestingly, the Asp-hemolysin (Asp-HS), which belongs to the protein family of aegerolysins and which was often suggested to be involved in fungal virulence, was present in the secretome under all growth conditions tested. In addition, a second, non-secreted protein with an aegerolysin domain annotated as Asp-hemolysin-like (HS-like) protein can be found to be encoded in the genome of A. fumigatus. Generation and analysis of Asp-HS and HS-like deletion strains revealed no differences in phenotype compared to the corresponding wild-type strain. Furthermore, hemolysis and cytotoxicity was not altered in both single-deletion and double-deletion mutants lacking both aegerolysin genes. All mutant strains showed no attenuation in virulence in a mouse infection model for invasive pulmonary aspergillosis. Overall, this study provides a comprehensive analysis of secreted proteins of A. fumigatus and a detailed characterization of hemolysin mutants. PMID- 21658999 TI - Dependency in elderly people newly diagnosed with cancer--a mixed-method study. AB - PURPOSE: This study, based on data from an empirical investigation, combines quantitative and qualitative approaches in a mixed-method design to explore dependency in elderly people newly diagnosed with cancer. METHODS AND SAMPLE: 101 elderly people newly diagnosed with cancer were included in the quantitative part, with 16 in the qualitative part. A questionnaire concerning quality of life and dependency issues was developed. For the qualitative part, open-ended interviews were conducted to get closer to the experience of dependency. RESULTS: Combining the two methods was seen as complementary. Involvement of the patient in decision-making related to contact with the primary and secondary health-care systems is an important element in reducing the perception of dependency and maintaining the Quality of Life (QoL) of elderly cancer patients. A more precise intervention in this patient population can be achieved by assessing, Activities of Daily Living (ADL) in the elderly. Receiving assistance from children seems to increase perceived dependency and to affect QoL negatively. CONCLUSIONS: The results of this mixed-method study indicate that dependency had a negative influence on the elderly with cancer. Being dependent on others was experienced as deterioration. Fatigue represents a significant risk factor for decreased functional ability and is experienced as a reminder of being old and the situation as being out of control. Patients may benefit from health-care professionals acquiring a complete picture of dependency and cancer-related fatigue in the elderly through a systematic assessment, where for example, functional limitations related to fatigue can be determined. PMID- 21659000 TI - Optimising the lymphoma response criteria in the era of targeted therapy. PMID- 21659002 TI - Why RIDL is not SIT. AB - History teaches that sterile insect technique (SIT) is a feasible strategy for mosquito population suppression. Female killing (FK) technologies developed later theoretically had greater potential than SIT, but depended upon chromosomal translocations. Unfortunately these were genetically unstable. New transgenic strategies have been misinterpreted as a replacement for SIT. Instead these strategies provide a means to revisit FK. Conditional lethal mutations inserted into mosquito genomes allow for adjustment of the age of mortality, female specific lethality, bisexual lethality and manipulation of germline-specific gene expression. A recent Aedes aegypti case study demonstrates the viability of one of these new transgenic strategies. PMID- 21659001 TI - Focus on the ringleader: the role of AMA1 in apicomplexan invasion and replication. AB - Apicomplexan parasites exhibit an unusual mechanism of host cell penetration. A central player in this process is the protein apical membrane antigen 1 (AMA1). Although essential for invasion, the precise functional roles AMA1 plays have been unclear. Several recent studies have provided important functional insight into its role within the multiprotein complex that comprises the moving junction (MJ). Initially formed at the apical tip of the invading parasite, the MJ represents a ring-like region of contact between the surfaces of the invading parasite and the host cell as the invaginated host plasma membrane is forced inward by the penetrating parasite. This review discusses these and other recent insights into AMA1 with particular emphasis on studies conducted in Plasmodium and Toxoplasma. PMID- 21659003 TI - Diagnosis of human sleeping sickness: sense and sensitivity. AB - In 1997 the World Health Organization (WHO) advocated increased access to diagnosis and treatment, as well as reinforcement of surveillance, for the control of sleeping sickness (human African trypanosomiasis, HAT). This coincided with the end of decades of civil conflicts in several endemic regions and negotiation of a sustainable supply of 'free' curative drugs and, as a result, HAT is at its lowest level in 50 years. However, reported cases underestimate prevalence and downplay HAT when compared with data generated by advanced diagnostic capacity for human immunodeficiency virus (HIV), tuberculosis (TB) and malaria, and, because HAT case numbers fall between epidemics, diagnostics become less commercially appealing. Here recent trends in the development of diagnostics for sleeping sickness are considered and progress towards a much-needed sensitive, specific and affordable point-of-care diagnostic is assessed. PMID- 21659005 TI - Emergency commitment from nursing homes. AB - PURPOSE: The purpose of this study was to describe emergency commitment of residents from nursing homes and to discuss relevant policy issues. DESIGN AND METHODS: This study used statewide, archival emergency commitment data from July 2000 through June 2008. These data are created by entering data from paper emergency commitment initiation forms of law enforcement, mental health professionals, and judges submitted by facilities as required by Florida law. RESULTS: During the 1 year from July 2007 through June 2008 there were 898 residents of Florida nursing homes with a total of 1032 emergency commitments. Some individuals had more than one emergency commitment from a nursing home during the year, with 9% having between two and five emergency commitments. One third of the emergency commitments were for residents younger than 65. Some of these individuals also had substantial numbers of emergency commitments in the 7 years from July 2000 through June 2007. IMPLICATIONS: There are facility, client, and regulatory factors that can be addressed to reduce the inappropriate usage of emergency commitments in nursing homes. PMID- 21659006 TI - Prevalence of diabetes and the burden of comorbid conditions among elderly nursing home residents. AB - BACKGROUND: Although the reported prevalence of diabetes in nursing home residents varies greatly among studies, there remains a common trend: increasing prevalence. Diabetes in the elderly is often associated with the presence of multiple comorbid conditions. However, limited data exist regarding the characteristics, symptom severity, disease management, and outcomes of care for residents of nursing homes with diabetes. OBJECTIVE: Our aim was to estimate the prevalence of diabetes in a national sample of skilled nursing facility (SNF) residents over a 12-month period and to examine differences in the burden of comorbidities between elderly residents with and without diabetes, including prevalence and severity of comorbidities, pharmacotherapy associated with these conditions, and cost. METHODS: This was a multicenter, observational, medical utilization evaluation study in 23 geographically representative SNFs in the United States. Comorbidities, cognition, physical activity, utilization of health services, and medications were obtained from medical chart audits, minimum data set records, and prescription claims files. Chart abstraction was performed between June 2006 and March 2007. Residents eligible for inclusion in the prevalence analysis were aged >=65 years, did not receive hospice care, and were not in a persistent vegetative condition. RESULTS: A total of 2317 residents met the inclusion criteria and were included in the prevalence analysis; 761 (32.8%) had diabetes. Residents with a full minimum data set assessment within 12 months before chart abstraction (n = 2095) were included in the comorbid burden analysis. Compared with those without diabetes, a greater proportion of residents with diabetes were younger, male, Hispanic or African American, and were overweight or obese. Residents with diabetes had a greater comorbidity burden (Hierarchical Condition Category, 1.90 vs 1.58), including more prescribed medications for certain common comorbid conditions (including angiotensin converting enzyme inhibitors/angiotensin II receptor blockers [46% vs 24%], diuretics [44% vs 34%], statins [40% vs 18%], or antiplatelets/antithrombotics [43% vs 37%]), and experienced more hospitalizations (37% vs 18% at 6 months) than residents without diabetes. CONCLUSION: Nearly one third of elderly SNF residents had diabetes. These patients, compared with SNF residents without diabetes, had a greater comorbid burden, were prescribed more medications to treat these conditions, and had more hospitalizations. PMID- 21659007 TI - Comment on: Serial changes in inflammatory biomarkers after Roux-en-Y gastric bypass surgery. PMID- 21659008 TI - Direct electrochemistry of cytochrome c entrapped in agarose hydrogel in room temperature ionic liquids. AB - Direct electrochemistry of cytochrome c (cyt-c) entrapped in agarose hydrogel on gold electrode (Au), edge plane pyrolytic graphite electrode (EPPGE) and glassy carbon electrode (GC) in two room temperature ionic liquids was investigated. The effects of the addition of N,N-dimethylformamide (DMF) in the agarose-cyt-c film, water concentration in ionic liquids and exterior metal ions on the electrochemical behavior of cyt-c were monitored, and electrocatalytic properties of cyt-c were also done. Results showed that a good quasi-reversible redox behavior of cyt-c could be found after adding DMF in agarose-cyt-c film, and peak shape would not change after continuously scanning for 50 cycles. In addition, a certain amount of water in hydrophilic ionic liquids is necessary to maintain electrochemical activities of cyt-c, electrochemical performance of cyt-c is the best when the water content is 5.2% and 5.8% for 1-butyl-3-methylimidazolium bromide ([Bmim][Br]) and 1-butyl-3-methylimidazolium tetrafluoroborate([Bmim][BF(4)]) respectively. However, electrochemical activities of cyt-c are inhibited by exterior metal ions. Interestingly, cyt-c entrapped in agarose hydrogel on EPPGE and GC could catalyze the electroreduction of trichloroacetic acid (TCA) and tert-butyl hydroperoxide (t-BuOOH) in [Bmim][BF(4)], but could not in [Bmim][Br]. Reasons for above-mentioned differences of electrochemical properties of cyt-c in different ionic liquids were preliminarily discussed. PMID- 21659004 TI - Non-prescription antimicrobial use worldwide: a systematic review. AB - In much of the world antimicrobial drugs are sold without prescription or oversight by health-care professionals. The scale and effect of this practice is unknown. We systematically reviewed published works about non-prescription antimicrobials from 1970-2009, identifying 117 relevant articles. 35 community surveys from five continents showed that non-prescription use occurred worldwide and accounted for 19-100% of antimicrobial use outside of northern Europe and North America. Safety issues associated with non-prescription use included adverse drug reactions and masking of underlying infectious processes. Non prescription use was common for non-bacterial disease, and antituberculosis drugs were available in many areas. Antimicrobial-resistant bacteria are common in communities with frequent non-prescription use. In a few settings, control efforts that included regulation decreased antimicrobial use and resistance. Non prescription antimicrobial and antituberculosis use is common outside of North America and northern Europe and must be accounted for in public health efforts to reduce antimicrobial resistance. PMID- 21659009 TI - Modularity: Comment on "The emergence of modularity in biological systems" by Michael W. Deem. PMID- 21659010 TI - Radioresistance of glioma stem cells: intrinsic characteristic or property of the 'microenvironment-stem cell unit'? AB - There is increasing evidence that glioblastoma possess 'stem-like' cells, low concentrations of which can initiate a tumour. It has been proposed that these cells are radioresistant, and that this property contributes to the poor treatment outcomes of these tumours. In this paper we propose that radioresistance is not simply an intrinsic characteristic of glioma stem cells but a result of interactions between these cells and microenvironmental factors, i.e. the 'microenvironment - stem cell unit'. The critical role of the microenvironment, along with glioma stem cells, is supported directly or indirectly by the following observations: glioma stem cells have been shown to reside preferentially in specific niches, the characteristics of which are known to influence cellular responses to radiation; radiation modifies environmental factors; and, contrarily to the consistency of clinical data, in vitro experiments have reported a wide variety in the radiation response of these cells. The paper, therefore, focuses on the interaction between tumour stem cells and the microenvironment, analyzing how its various elements (endothelial cells, extracellular matrix, cytokines, nitric oxide, oxygen levels) are affected by radiation and how these might influence the response of tumour stem cells to radiation. Finally, we summarize the ongoing debate on the optimal culture conditions for glioma stem cells and the difficulties in designing assays that reliably characterize their radiation response. PMID- 21659011 TI - Dorsally displaced extra-articular distal radius fractures fixation: Dorsal IM nailing versus volar plating. A randomized controlled trial. AB - INTRODUCTION: Fractures of the distal radius are very common and mainly occur in the elderly. There has been an increasing use of locked volar plate fixations which report satisfactory results. However, some authors advocate the use of nail fixation. HYPOTHESIS: The aim of this study is to compare dorsal nail plate versus locked volar plate fixation in the treatment of distal radius fractures with dorsal tilt. MATERIALS AND METHODS: The mean age of the patients was over 50 years. The study included extra-articular distal radius fractures with posterior tilt. We conducted a prospective randomized study between December 2007 and February 2009 including a group of 16 patients treated with a dorsal nail fixation (group 1) and a group of 15 patients managed with a locked volar plate fixation (group II). We analyzed both the clinical results (complications, Range of motion [ROM], tightening strength, Disabilities of the Arm, Shoulder and Hand [DASH] and Mayo Clinic scores) and the radiographic results from A/P and lateral radiographs in the early postoperative period and at 6-month follow-up. RESULTS: ROM toward extension was better in the volar plating subgroup (group I, 42.5 degrees , group II, 57.5 degrees ; P<0.05). Pronation mobility was better in the dorsal nail subgroup (group I, 85 degrees ; group II, 80 degrees ; P<0.05). The locked volar plate fixation subgroup demonstrated a better recovery of the tightening strength as compared with the uninjured side (group I, 78%, group II, 90%, P=0.03). The DASH score was similar in both groups (group I, 22.09+/-22.9; group II, 20.62+/-20.3, P>0.05). The Mayo Clinic score was better in the locked volar plate fixation subgroup (group I, 65+/-13.4; group II, 85.6+/-19.2; P=0.002). Radiographic results were good in both groups, however anatomical reduction of the volar tilt was significantly better in group II (plate) when compared with the uninjured side. Moreover, we report on two cases of tendinous damages to the long extensor muscle of the thumb in the dorsal nail fixation subgroup despite the use of a minimally invasive implant. CONCLUSION: The management of distal radius fractures with locked volar plate fixation in active elderly patients has proved successful and leads to better results than nail fixation regarding both reduction quality and objective functional scores. LEVEL OF EVIDENCE: Level II, prospective, randomized of low-level. PMID- 21659013 TI - Primary cyst of the spleen presenting as a splenocolic fistula. PMID- 21659012 TI - Bone metabolism of residual ridge beneath the denture base of an RPD observed using NaF-PET/CT. AB - PATIENT: A 66-year-old woman, who had a bilateral free-end edentulous mandible and no experience with dentures, was examined for the chief complaint of masticatory dysfunction on left side of dental arch. A unilateral distal extension removable partial denture (RPD) replacing lower-left molars was selected. Tomographic images were obtained using Fluorine-18 NaF positron emission computerized tomography (NaF-PET)/computed tomography (CT) before the RPD use and at 1, 6, and 13 weeks after the RPD use to observe the metabolic changes in residual bone caused by the RPD use. PET standardized uptake values (SUVs) and CT values were calculated for lower-left edentulous site (test side) and lower-right edentulous site (control side). As a result, SUVs on the control side remained static after the RPD use, whereas those on the test side increased at 1 and 6 weeks after the RPD use and then decreased. However, CT images showed no obvious changes in the bone shape and structure beneath RPD, and CT values both on the control and test sides did not change either. DISCUSSION: This report shows that NaF-PET could detect bone metabolic changes soon after the RPD use, which cannot be detected by clinical X-rays. The SUV changes may be a mechanobiological reaction to the pressure due to the RPD use, and wearing of the RPD may increase the bone turnover beneath denture. CONCLUSION: This report demonstrates that wearing of an RPD increases bone turnover beneath denture immediately after the RPD use without clinically detectable changes in bone structure or volume. PMID- 21659014 TI - Abundant intraperitoneal bleeding after colonoscopy. PMID- 21659015 TI - Hepatitis B virus infection and pregnancy. AB - Pregnancy only mildly affects that natural progression of acute and chronic infection by the hepatitis B virus (HBV) but it does bring to light three important questions. Mother to child (vertical) transmission risk is best prevented by mandatory HBs antigen testing in all pregnant women in their second trimester and by systemic serovaccination of newborns of infected mothers. In mothers with high viral load, vertical infection in utero could be prevented by lamivudine, telbivudine or tenofovir treatment. Invasive obstetric or gynecological procedures (such as amniocentesis, forceps, etc.) do not seem to increase the risk of vertical infection. Breastfeeding is not contraindicated in maternal HBV infection after serovaccination of the newborn. This holds true for mothers on active treatment with tenofovir which is not absorbed into breast milk. When it comes to managing active antiviral treatment, in absence of virosuppression with lamivudine, tenofovir remains a logical step-up treatment; in absence of virosuppression with adefovir, tenofovir also remains a logical step-up choice as do tenofovir/emtricitabine combinations or lamivudine in absence of preexisting resistance which may have been induced during combination treatment of adefovir and lamivudine. In cases of effective virosuppression with treatment by analogues, lamivudine should be continued and entecavir should eventually be replaced by lamivudine, telbivudine or tenofovir; adefovir should be replaced by tenofovir or lamivudine in absence of resistance (which would require tenofovir therapy) or adefovir which would restrict lamivudine therapy. PMID- 21659016 TI - Multiphysics neuron model for cellular volume dynamics. AB - Even though cellular volume dynamics has been linked to cell apoptosis and intrinsic optical signals, there is no quantitative model for describing neuronal volume dynamics on the millisecond time scale. This study introduces a multiphysics neuron model, where the cell volume is a time-varying variable and multiple physical principles are combined to build governing equations. Using this model, we analyzed neuronal volume responses during excitation, which elucidated the variety of optical signals observed experimentally across the literature. Several physiological conditions were examined to investigate their effect on the pattern of volume response. In addition, we analyzed volume responses on a longer time scale with repetitive stimulation to study the characteristics of slow cell swelling. This multiscale analysis of the multiphysics model will provide not only a novel quantitative elucidation of physiologically important issues related with cellular volume dynamics but also a chance for further studies, such as the interesting possibility of inferring the balance of ion flux from plateau volume changes. PMID- 21659017 TI - The effects of electrode size and orientation on the sensitivity of myoelectric pattern recognition systems to electrode shift. AB - Myoelectric pattern recognition systems for prosthesis control are often studied in controlled laboratory settings, but obstacles remain to be addressed before they are clinically viable. One important obstacle is the difficulty of maintaining system usability with socket misalignment. Misalignment inevitably occurs during prosthesis donning and doffing, producing a shift in electrode contact locations. We investigated how the size of the electrode detection surface and the placement of electrode poles (electrode orientation) affected system robustness with electrode shift. Electrodes oriented parallel to muscle fibers outperformed electrodes oriented perpendicular to muscle fibers in both shift and no-shift conditions (p < 0.01). Another finding was the significant difference (p < 0.01) in performance for the direction of electrode shift. Shifts perpendicular to the muscle fibers reduced classification accuracy and real-time controllability much more than shifts parallel to the muscle fibers. Increasing the size of the electrode detection surface was found to help reduce classification accuracy sensitivity to electrode shifts in a direction perpendicular to the muscle fibers but did not improve the real-time controllability of the pattern recognition system. One clinically important result was that a combination of longitudinal and transverse electrodes yielded high controllability with and without electrode shift using only four physical electrode pole locations. PMID- 21659019 TI - Adaptive neural output feedback tracking control for a class of uncertain discrete-time nonlinear systems. AB - This brief studies an adaptive neural output feedback tracking control of uncertain nonlinear multi-input-multi-output (MIMO) systems in the discrete-time form. The considered MIMO systems are composed of n subsystems with the couplings of inputs and states among subsystems. In order to solve the noncausal problem and decouple the couplings, it needs to transform the systems into a predictor form. The higher order neural networks are utilized to approximate the desired controllers. By using Lyapunov analysis, it is proven that all the signals in the closed-loop system is the semi-globally uniformly ultimately bounded and the output errors converge to a compact set. In contrast to the existing results, the advantage of the scheme is that the number of the adjustable parameters is highly reduced. The effectiveness of the scheme is verified by a simulation example. PMID- 21659018 TI - EMG prediction from motor cortical recordings via a nonnegative point-process filter. AB - A constrained point-process filtering mechanism for prediction of electromyogram (EMG) signals from multichannel neural spike recordings is proposed here. Filters from the Kalman family are inherently suboptimal in dealing with non-Gaussian observations, or a state evolution that deviates from the Gaussianity assumption. To address these limitations, we modeled the non-Gaussian neural spike train observations by using a generalized linear model that encapsulates covariates of neural activity, including the neurons' own spiking history, concurrent ensemble activity, and extrinsic covariates (EMG signals). In order to predict the envelopes of EMGs, we reformulated the Kalman filter in an optimization framework and utilized a nonnegativity constraint. This structure characterizes the nonlinear correspondence between neural activity and EMG signals reasonably. The EMGs were recorded from 12 forearm and hand muscles of a behaving monkey during a grip-force task. In the case of limited training data, the constrained point process filter improved the prediction accuracy when compared to a conventional Wiener cascade filter (a linear causal filter followed by a static nonlinearity) for different bin sizes and delays between input spikes and EMG output. For longer training datasets, results of the proposed filter and that of the Wiener cascade filter were comparable. PMID- 21659020 TI - Iterative algorithm for joint zero diagonalization with application in blind source separation. AB - A new iterative algorithm for the nonunitary joint zero diagonalization of a set of matrices is proposed for blind source separation applications. On one hand, since the zero diagonalizer of the proposed algorithm is constructed iteratively by successive multiplications of an invertible matrix, the singular solutions that occur in the existing nonunitary iterative algorithms are naturally avoided. On the other hand, compared to the algebraic method for joint zero diagonalization, the proposed algorithm requires fewer matrices to be zero diagonalized to yield even better performance. The extension of the algorithm to the complex and nonsquare mixing cases is also addressed. Numerical simulations on both synthetic data and blind source separation using time-frequency distributions illustrate the performance of the algorithm and provide a comparison to the leading joint zero diagonalization schemes. PMID- 21659021 TI - Blur invariants constructed from arbitrary moments. AB - This paper deals with moment invariants with respect to image blurring. It is mainly a reaction to the works of Zhang and Chen , recently published in these Transactions. We present a general method on how to construct blur invariants from arbitrary moments and show that it is no longer necessary to separately derive the invariants for each polynomial basis. We show how to discard dependent terms in blur invariants definition and discuss a proper implementation of the invariants in orthogonal bases using recurrent relations. An example for Legendre moments is given. PMID- 21659022 TI - Fast O1 bilateral filtering using trigonometric range kernels. AB - It is well known that spatial averaging can be realized (in space or frequency domain) using algorithms whose complexity does not scale with the size or shape of the filter. These fast algorithms are generally referred to as constant-time or O(1) algorithms in the image-processing literature. Along with the spatial filter, the edge-preserving bilateral filter involves an additional range kernel. This is used to restrict the averaging to those neighborhood pixels whose intensity are similar or close to that of the pixel of interest. The range kernel operates by acting on the pixel intensities. This makes the averaging process nonlinear and computationally intensive, particularly when the spatial filter is large. In this paper, we show how the O(1) averaging algorithms can be leveraged for realizing the bilateral filter in constant time, by using trigonometric range kernels. This is done by generalizing the idea presented by Porikli, i.e., using polynomial kernels. The class of trigonometric kernels turns out to be sufficiently rich, allowing for the approximation of the standard Gaussian bilateral filter. The attractive feature of our approach is that, for a fixed number of terms, the quality of approximation achieved using trigonometric kernels is much superior to that obtained by Porikli using polynomials. PMID- 21659024 TI - A symmetric motion estimation method for motion-compensated frame interpolation. AB - This paper proposes a new motion-compensated frame interpolation (MCFI) method. The proposed method utilizes a symmetric motion estimation (SME) method, which is a new pixel-wise motion estimation method for intermediate frame interpolation. By using an adaptive search range for the motion estimation, the proposed method can obtain a more reliable motion vector for each pixel than previous MCFI methods that use a conventional block matching algorithm (BMA). In addition, we propose a combined method of the SME and BMA to reduce the computation time of the pixel-wise motion estimation method. The experimental results show that the proposed method outperforms other MCFI methods in terms of generating objectively and subjectively better interpolated frames. PMID- 21659023 TI - Image multidistortion estimation. AB - We present a method for estimating the amount of noise and blur in a distorted image. Our method is based on the multiscale structural similarity (MS-SSIM) framework that, although designed to measure image quality, is used to estimate the amount of blur and noise in a degraded image given a reference image. We show that there exists a bijective mapping between the 2-D noise/blur space and the 3 D MS-SSIM space, which allows to recover distortion parameters. That mapping allows to formulate the multidistortion-estimation problem as a classical optimization problem. Various search strategies such as Newton, simplex, NewUOA, and brute-force search are presented and compared. We also show that a bicubic patch can be used to approximate the bijective mapping between the noise/blur space and the 3-D MS-SSIM space. Interestingly, the use of such a patch reduces the processing time by a factor of 40 without significantly reducing precision. Based on quantitative results, we show that the amount of different types of blur and noise in a distorted image can be recovered with accuracy of roughly 2% and 8%, respectively. Our methods are compared with four state-of-the-art noise- and blur-estimation techniques. PMID- 21659025 TI - Cellular neural networks, the Navier-Stokes equation, and microarray image reconstruction. AB - Although the last decade has witnessed a great deal of improvements achieved for the microarray technology, many major developments in all the main stages of this technology, including image processing, are still needed. Some hardware implementations of microarray image processing have been proposed in the literature and proved to be promising alternatives to the currently available software systems. However, the main drawback of those proposed approaches is the unsuitable addressing of the quantification of the gene spot in a realistic way without any assumption about the image surface. Our aim in this paper is to present a new image-reconstruction algorithm using the cellular neural network that solves the Navier-Stokes equation. This algorithm offers a robust method for estimating the background signal within the gene-spot region. The MATCNN toolbox for Matlab is used to test the proposed method. Quantitative comparisons are carried out, i.e., in terms of objective criteria, between our approach and some other available methods. It is shown that the proposed algorithm gives highly accurate and realistic measurements in a fully automated manner within a remarkably efficient time. PMID- 21659026 TI - On regularized reconstruction of vector fields. AB - In this paper, we give a general characterization of regularization functionals for vector field reconstruction, based on the requirement that the said functionals satisfy certain geometric invariance properties with respect to transformations of the coordinate system. In preparation for our general result, we also address some commonalities of invariant regularization in scalar and vector settings, and give a complete account of invariant regularization for scalar fields, before focusing on their main points of difference, which lead to a distinct class of regularization operators in the vector case. Finally, as an illustration of potential, we formulate and compare quadratic (L(2)) and total variation-type (L(1)) regularized denoising of vector fields in the proposed framework. PMID- 21659027 TI - An edge-sensing generic demosaicing algorithm with application to image resampling. AB - In this paper, we introduce a new demosaicing algorithm that can be used for various sensor images captured by digital cameras equipped with various red-green blue color filter arrays. Our algorithm enhances the universal demosaicing algorithm of Lukac et al by defining a new spectral interpolation model that exploits not only the information on the color of pixels but also the relative distance between neighboring pixels within an image. Moreover, we include an edge detection model that makes our algorithm adaptive and reduces the presence of color shifts and artifacts. A series of tests has been made on images of the Kodak database, and our algorithm performs better than the universal demosaicing algorithm with regard to both subjective and objective evaluation. The versatility of our demosaicing algorithm is also highlighted through an application to the issue of color image resampling, and we obtain conclusive experimental results. PMID- 21659028 TI - Segmentation and tracking multiple objects under occlusion from multiview video. AB - In this paper, we present a multiview approach to segment the foreground objects consisting of a group of people into individual human objects and track them across the video sequence. Depth and occlusion information recovered from multiple views of the scene is integrated into the object detection, segmentation, and tracking processes. Adaptive background penalty with occlusion reasoning is proposed to separate the foreground regions from the background in the initial frame. Multiple cues are employed to segment individual human objects from the group. To propagate the segmentation through video, each object region is independently tracked by motion compensation and uncertainty refinement, and the motion occlusion is tackled as layer transition. The experimental results implemented on both our sequences and other's sequence have demonstrated the algorithm's efficiency in terms of subjective performance. Objective comparison with a state-of-the-art algorithm validates the superior performance of our method quantitatively. PMID- 21659029 TI - Improving Web image search by bag-based reranking. AB - Given a textual query in traditional text-based image retrieval (TBIR), relevant images are to be reranked using visual features after the initial text-based search. In this paper, we propose a new bag-based reranking framework for large scale TBIR. Specifically, we first cluster relevant images using both textual and visual features. By treating each cluster as a "bag" and the images in the bag as "instances," we formulate this problem as a multi-instance (MI) learning problem. MI learning methods such as mi-SVM can be readily incorporated into our bag-based reranking framework. Observing that at least a certain portion of a positive bag is of positive instances while a negative bag might also contain positive instances, we further use a more suitable generalized MI (GMI) setting for this application. To address the ambiguities on the instance labels in the positive and negative bags under this GMI setting, we develop a new method referred to as GMI-SVM to enhance retrieval performance by propagating the labels from the bag level to the instance level. To acquire bag annotations for (G)MI learning, we propose a bag ranking method to rank all the bags according to the defined bag ranking score. The top ranked bags are used as pseudopositive training bags, while pseudonegative training bags can be obtained by randomly sampling a few irrelevant images that are not associated with the textual query. Comprehensive experiments on the challenging real-world data set NUS-WIDE demonstrate our framework with automatic bag annotation can achieve the best performances compared with existing image reranking methods. Our experiments also demonstrate that GMI-SVM can achieve better performances when using the manually labeled training bags obtained from relevance feedback. PMID- 21659030 TI - A 124 Mpixels/s VLSI design for histogram-based joint bilateral filtering. AB - This paper presents an efficient and scalable design for histogram-based bilateral filtering (BF) and joint BF (JBF) by memory reduction methods and architecture design techniques to solve the problems of high memory cost, high computational complexity, high bandwidth, and large range table. The presented memory reduction methods exploit the progressive computing characteristics to reduce the memory cost to 0.003%-0.020%, as compared with the original approach. Furthermore, the architecture design techniques adopt range domain parallelism and take advantage of the computing order and the numerical properties to solve the complexity, bandwidth, and range-table problems. The example design with a 90 nm complementary metal-oxide-semiconductor process can deliver the throughput to 124 Mpixels/s with 356-K gate counts and 23-KB on-chip memory. PMID- 21659031 TI - Filtering Data Based on Human-Inspired Forgetting. AB - Robots are frequently presented with vast arrays of diverse data. Unfortunately, perfect memory and recall provides a mixed blessing. While flawless recollection of episodic data allows increased reasoning, photographic memory can hinder a robot's ability to operate in real-time dynamic environments. Human-inspired forgetting methods may enable robotic systems to rid themselves of out-dated, irrelevant, and erroneous data. This paper presents the use of human-inspired forgetting to act as a filter, removing unnecessary, erroneous, and out-of-date information. The novel ActSimple forgetting algorithm has been developed specifically to provide effective forgetting capabilities to robotic systems. This paper presents the ActSimple algorithm and how it was optimized and tested in a WiFi signal strength estimation task. The results generated by real-world testing suggest that human-inspired forgetting is an effective means of improving the ability of mobile robots to move and operate within complex and dynamic environments. PMID- 21659032 TI - Enhanced Sign Language Recognition Using Weighted Intrinsic-Mode Entropy and Signer's Level of Deafness. AB - Sign language (SL) forms an important communication canal for the deaf. In this paper, enhanced SL recognition, by relating the individual way of signing with the signer's level of deafness (LoD) through a novel hybrid adaptive weighting (HAW) process applied to surface electromyogram and 3-D accelerometer data, is proposed. Using a LoD-driven genetic algorithm, HAW optimally weights the intrinsic modes of the acquired signals, preparing them for sample entropy (SampEn) estimation that follows. The resulting feature set, namely, weighted intrinsic-mode entropy (IMEn) (wIMEn), aims at increasing the SL-sign classification accuracy alone or boosted by signer identification and/or signer's LoD-based group identification. The wIMEn was compared with three other feature sets, i.e., time frequency, SampEn, and IMEn, regarding their discrimination ability (both among signers and SL signs). Data from the dominant hand of nine subjects with various LoD were analyzed for the classification of 61 Greek SL (GSL) signs. Experimental results have shown that the introduced wIMEn feature set exhibited higher performance compared to others, both in signer identification and signer's LoD-based group identification and in GSL sign classification. The findings suggest that LoD could be considered in the construction of a signer-independent SL-classification system toward the enhancement of its performance. PMID- 21659033 TI - Delay-Dependent Stability Analysis for Switched Neural Networks With Time-Varying Delay. AB - In this paper, the problem of stability analysis is investigated for switched neural networks with time-varying delay using linear matrix inequality (LMI) approach. By taking advantage of the average dwell time method, two sufficient conditions are developed to ensure the global exponential stability of the considered neural networks, which are delay-dependent and formulated by LMIs. The state decay estimate is explicitly given. Numerical examples are provided to demonstrate the effectiveness and feasibility of the proposed techniques. PMID- 21659034 TI - A method for integrating expert knowledge when learning Bayesian networks from data. AB - Automatic learning of Bayesian networks from data is a challenging task, particularly when the data are scarce and the problem domain contains a high number of random variables. The introduction of expert knowledge is recognized as an excellent solution for reducing the inherent uncertainty of the models retrieved by automatic learning methods. Previous approaches to this problem based on Bayesian statistics introduce the expert knowledge by the elicitation of informative prior probability distributions of the graph structures. In this paper, we present a new methodology for integrating expert knowledge, based on Monte Carlo simulations and which avoids the costly elicitation of these prior distributions and only requests from the expert information about those direct probabilistic relationships between variables which cannot be reliably discerned with the help of the data. PMID- 21659035 TI - Ubiquitous human upper-limb motion estimation using wearable sensors. AB - Human motion capture technologies have been widely used in a wide spectrum of applications, including interactive game and learning, animation, film special effects, health care, navigation, and so on. The existing human motion capture techniques, which use structured multiple high-resolution cameras in a dedicated studio, are complicated and expensive. With the rapid development of microsensors on-chip, human motion capture using wearable microsensors has become an active research topic. Because of the agility in movement, upper-limb motion estimation has been regarded as the most difficult problem in human motion capture. In this paper, we take the upper limb as our research subject and propose a novel ubiquitous upper-limb motion estimation algorithm, which concentrates on modeling the relationship between upper-arm movement and forearm movement. A link structure with 5 degrees of freedom (DOF) is proposed to model the human upper limb skeleton structure. Parameters are defined according to Denavit-Hartenberg convention, forward kinematics equations are derived, and an unscented Kalman filter is deployed to estimate the defined parameters. The experimental results have shown that the proposed upper-limb motion capture and analysis algorithm outperforms other fusion methods and provides accurate results in comparison to the BTS optical motion tracker. PMID- 21659036 TI - Geometric calibration of a micro-CT system and performance for insect imaging. AB - Micro-CT with a high spatial resolution in combination with computer-based reconstruction techniques is considered a powerful tool for morphological study of insects. The quality of CT images crucially depends on the precise knowledge of the scan geometry of the micro-CT system. In this paper, we have proposed a method to calculate the deviation of rotating axis for compensating deficiency of existing methods. A practical application of this geometric calibration method of the micro-CT system for insect imaging is presented. We have performed the computer-simulation study and experimental study with our prototype micro-CT system. The results demonstrate that the proposed technique is accurate and robust. In addition, we have evaluated the imaging characteristics of the detector in terms of modulation-transfer function (MTF). Finally, insect imaging performance and image reconstruction from data acquired with different energies are presented. PMID- 21659038 TI - Climate extremes and the length of gestation. AB - BACKGROUND: Although future climate is predicted to have more extreme heat conditions, the available evidence on the impact of these conditions on pregnancy length is very scarce and inconclusive. OBJECTIVES: We investigated the impact of maternal short-term exposure to extreme ambient heat on the length of pregnancy. METHODS: This study was based on a cohort of births that occurred in a major university hospital in Barcelona during 2001-2005. Three indicators of extreme heat conditions based on 1-day exposure to an unusually high heat-humidity index were applied. Each mother was assigned the measures made by the meteorological station closest to maternal residential postcodes. A two-stage analysis was developed to quantify the change in pregnancy length after maternal exposure to extreme heat conditions adjusted for a range of covariates. The second step was repeated for lags 0 (delivery date) to 6 days. RESULTS: We included data from 7,585 pregnant women in our analysis. We estimated a 5-day reduction in average gestational age at delivery after an unusually high heat-humidity index on the day before delivery. CONCLUSION: Extreme heat was associated with a reduction in the average gestational age of children delivered the next day, suggesting an immediate effect of this exposure on pregnant women. Further studies are required to confirm our findings in different settings. PMID- 21659037 TI - Interfacing with the computational brain. AB - Neuroscience is just beginning to understand the neural computations that underlie our remarkable capacity to learn new motor tasks. Studies of natural movements have emphasized the importance of concepts such as dimensionality reduction within hierarchical levels of redundancy, optimization of behavior in the presence of sensorimotor noise and internal models for predictive control. These concepts also provide a framework for understanding the improvements in performance seen in myoelectric-controlled interface and brain-machine interface paradigms. Recent experiments reveal how volitional activity in the motor system combines with sensory feedback to shape neural representations and drives adaptation of behavior. By elucidating these mechanisms, a new generation of intelligent interfaces can be designed to exploit neural plasticity and restore function after neurological injury. PMID- 21659039 TI - Three measures of forest fire smoke exposure and their associations with respiratory and cardiovascular health outcomes in a population-based cohort. AB - BACKGROUND: During the summer of 2003 numerous fires burned in British Columbia, Canada. OBJECTIVES: We examined the associations between respiratory and cardiovascular physician visits and hospital admissions, and three measures of smoke exposure over a 92-day study period (1 July to 30 September 2003). METHODS: A population-based cohort of 281,711 residents was identified from administrative data. Spatially specific daily exposure estimates were assigned to each subject based on total measurements of particulate matter (PM) <= 10 MUm in aerodynamic diameter (PM10) from six regulatory tapered element oscillating microbalance (TEOM) air quality monitors, smoke-related PM10 from a CALPUFF dispersion model run for the study, and a SMOKE exposure metric for plumes visible in satellite images. Logistic regression with repeated measures was used to estimate associations with each outcome. RESULTS: The mean (+/- SD) exposure based on TEOM measured PM10 was 29 +/- 31 MUg/m3, with an interquartile range of 14-31 MUg/m3. Correlations between the TEOM, smoke, and CALPUFF metrics were moderate (0.37 0.76). Odds ratios (ORs) for a 30-MUg/m3 increase in TEOM-based PM10 were 1.05 [95% confidence interval (CI), 1.03-1.06] for all respiratory physician visits, 1.16 (95% CI, 1.09-1.23) for asthma-specific visits, and 1.15 (95% CI, 1.00-1.29) for respiratory hospital admissions. Associations with cardiovascular outcomes were largely null. CONCLUSIONS: Overall we found that increases in TEOM-measured PM10 were associated with increased odds of respiratory physician visits and hospital admissions, but not with cardiovascular health outcomes. Results indicating effects of fire smoke on respiratory outcomes are consistent with previous studies, as are the null results for cardiovascular outcomes. Some agreement between TEOM and the other metrics suggests that exposure assessment tools that are independent of air quality monitoring may be useful with further refinement. PMID- 21659040 TI - The Environmental Polymorphism Registry: a unique resource that facilitates translational research of environmental disease. AB - BACKGROUND: Dissecting complex disease has become more feasible because of the availability of large-scale DNA resources and advances in high-throughput genomic technology. Although these tools help scientists identify potential susceptibility loci, subjects with relevant genotypes are needed for clinical phenotyping and toxicity studies. OBJECTIVE: We have developed a resource of subjects and their DNA to use for translational research of environmental disease. METHODS: More than 15,000 individuals of diverse sex, age, race, and ethnicity were recruited from North Carolina. DNA was isolated from their blood and coded with personal identification numbers linked to their identities. This linked resource of subjects and their DNA-the Environmental Polymorphism Registry (EPR)-allows scientists to screen for individuals with genotypes of interest and invite them to participate in follow-up studies. DISCUSSION: The EPR is a phenotype-by-genotype resource designed to facilitate translational studies of environmental disease. Based on their genotypes, subjects are invited to participate at all levels of research, from basic laboratory ex vivo cell phenotyping experiments that require viable tissue to in vivo observational studies and clinical trials. Here we report on progress of the EPR since 2008. We also describe a major effort at the National Institute of Environmental Health Sciences (NIEHS) to investigate susceptibility loci in 87 environmental response genes and gene * environment interactions using EPR resources. CONCLUSION: The EPR is a unique and novel resource and is ideal for genotype-driven translational research of environmental disease. We expect that it will serve as a model for future resources. Such tools help scientists attain their ultimate goals: to identify at-risk populations and develop strategies for preventing and treating human disease. PMID- 21659041 TI - [Combining biochemical and ultrasonographic markers in predicting preeclampsia: a systematic review]. AB - Using a series of keywords, we reviewed electronic databases (Medline, Embase, all records to May 2009) reporting the performance of biological and ultrasonographic markers to predict preeclampsia, both single markers and combinations of markers. We analyzed the data according to gestational age and risk levels of the studied populations. We evaluated the methodological quality of included publications using QUADAS (quality assessment of diagnostic accuracy studies). We identified 37 relevant studies that assessed 71 different combinations of biochemical and ultrasonographic markers. Most studies were performed during the second trimester on small-scale high-risk populations with few cases of preeclampsia. Combinations of markers generally led to an increase in sensitivity and/or specificity compared with single markers. In low-risk populations, combinations including placental protein 13 (PP13), pregnancy associated plasma protein A (PAPP-A), a disintegrin and metalloprotease-12 (ADAM12), activin A, or inhibin Ameasured in first or early second trimester and uterine artery Doppler in second trimester appear promising (sensitivity 60%-80%, specificity > 80%). In high-risk populations, the combination of PP13 and pulsatility index in first trimester showed 90% sensitivity and 90% specificity in a single study limited to severe preeclampsia. Combinations of biochemical and ultrasonographic markers improved the performance of early prediction of preeclampsia. From a perspective of integrative medicine, large population-based studies evaluating algorithms combining multiple markers are needed, if screening approaches are to be eventually implemented. PMID- 21659042 TI - [Measurement of inulin: development]. AB - Inulin clearance is still considered as the gold standard method to measure glomerular filtration rate. This method has been proposed in thirties by Smith and Shannon but the inulin measurement method still remains complex. Interferences, notably with the glucose, must also be considered. Two main methods have been proposed to measure inulin both in urine and plasma: "acid" or enzymatic methods. "Acid" methods are colorimetric. Fructose is actually measured after inulin hydrolysis in acid milieu. Different methods have been described to measure fructose. Among these methods, the measurement using anthrone is the most popular. Several enzymatic methods have also been published. These have more precision and the interference with glucose is probably less even if relatively few studies are available. HPLC methods for inulin measurement have also been described. This method is specific and accurate. While inulin is an unquestioned reference method for glomerular filtration rate, its measurement in urine and plasma remains tricky and at risk of interferences. Additional trials seem necessary to analytically validate and compare all the methods available on the market. PMID- 21659043 TI - [Interest of microalbuminuria in preventing kidney damage during systemic lupus erythematosus (SLE) under corticoid therapy]. AB - This study aimed to evaluate the benefits of microalbuminuria in preventing kidney damage in systemic lupus erythemathosus. This was a prospective study of 6 months has focused on 25 patients of both sexes aged over 14 with SLE whose diagnosis was based on the criteria of the American College of Rheumatology, having a negative proteinuria at the dipstick (Ketodiastix((r))) and a balance sheet normal renal (creatinine and uraemia normal). Each month, samples of venous blood were achieved at the elbow in patients fasted for the night (12pm). The serum obtained was used for measurement of creatinine and urea, according to conventional methods, by a Hitachi 902((r)) automated random type. The determination of urinary albumin by immuno-nephelometric method (Hitachi 902((r))), in search of microalbuminuria has involved the collection of urine over 24 hours in a sterile jar containing crystals of thymol as an antiseptic. In the presence of microalbuminuria, the dose of prednisone was progressively increased by 5 mg until no microalbuminuria. We found: 1) that creatinine and blood urea remained normal during the 6 months of study, 2) the disappearance of microalbuminuria first two months after increasing the daily dose of corticosteroid with a significant decrease of albuminuria from day 0 to day 180 (p = 0.001, day 180 vs day 0), 3) a female predominance with a sex ratio of 0.13. In conclusion, the regular dosage and systematic albuminuria to microalbuminuria appears to be a reliable means for diagnosis of lupus glomerulonephritis in the subclinical stage to prevent renal complications that occur during the Supported Lupus erythematosus. PMID- 21659044 TI - Pulsed Field Gel Electrophoresis types of Candida albicans isolates from an intensive care unit in a Tunisian hospital. AB - Candida albicans is the most important cause of fungal infections in intensive care units. The aim of this work was to compare the profiles of C. albicans in order to specify their genetic polymorphism and to determine the origin of these infections. Thirty-five C. albicans strains were collected from different clinical samples of 12 patients and three health-workers in an intensive care unit (ICU) in Rabta hospital of Tunisia, between August 2007 and April 2008. After digestion with BssHII, the isolates were typed by pulsed field gel electrophoresis (PFGE). The PFGE profiles were analyzed using a visual method, which showed three PFGE types (A, B and C) and the dendrogram generated three clusters (clusters I to III). An average similarity coefficient of 0.83, suggests that isolates are related. PMID- 21659045 TI - Polymorphism of human leukocyte antigen-A, -B, and -DRB1 in a Moroccan population from Casablanca: study of the allelic and the haplotypic frequencies. AB - We have studied the distribution of HLA-A, -B and DRB1 alleles and haplotypes by sequence specific oligonucleotide amplification in a sample of 125 unrelated healthy Moroccan individuals from Casablanca in Morocco. The city of Casablanca is known of its big ethnic diversity, especially Arabs and Berbers. The most frequent alleles found were: HLA-A*02 (18.4%), -A*01 (11.2%), -A*03 (10.8%), B*51 (8.06%),-B*44 (7.66%), -B*08 (6.85%), -DRB1*04 (15.98%), DRB1*03 and DRB1*07 (13.92%) and -DRB1*01 (10%). High frequency for five two-locus haplotypes was observed for A*03-B*51 (5%), A*02-DRB1*03 (5.5%), A*02-DRB1*04 and A*01-DRB1*04 (5%) and B*35-DRB1*04 (4%). No predominant haplotype was observed for HLA A-B DRB1. Our results confirm and extend the current knowledge about genetic pattern of the Moroccan of Casablanca. This study will serve as a reference for further anthropological studies, as well as studies of HLA and disease associations in the Moroccan population. PMID- 21659046 TI - [Investigation on HPV DNA detection and genotyping practices used in French laboratories in 2009]. AB - The French National reference Laboratory for Human papillomavirus (HPV) performed in 2009 a national study in order to review the methods used to detect and identify HR HPV genotypes in microbiology laboratories. Results from this study show a great diversity in volumes of samples treated in laboratories. Among clinical indications, the most frequent is a result of ASC-US at a Pap smear. This indication in the only one covered by the National Public Insurance System and is mostly performed in laboratories from private sector. Other indications mainly correspond to research programs and are performed in public Hospitals. This study allowed also to review the adequacy between the liquid based cytology samples and the assays used for direct detection of HR HPV or identification of the genotypes present in the sample. The right tests were not carried in the right solution storage according to the recommendations from different HPV testing assays. National recommendations should be elaborated in order to improve the performance of the test used. PMID- 21659047 TI - [Evaluation of the analyzer Glycomat 3000 (Biocode Hycel) for HbA1c]. AB - HbA(1c) represents a key parameter in the monitoring of glycemic balance in diabetic patients. It may be assayed by various methods, among which high pressure liquid chromatography (HPLC). We have evaluated a new HPLC analyzer, Glycomat 3000 (Biocode Hycel). HbA(1c) values are well correlated (r(2) = 0.994) with those obtained by the HPLC analyzer used routinely in our laboratory (Variant II, Bio-Rad). However, the precision of assays can be at the limit of acceptability (CV of repeatability between 0.7 and 1.4% and CV of reproducibility between 3.3 and 4.1%) if strict conditions of calibration and quality control are not implemented. The assay is sensitive to the interference of modified fractions of hemoglobin (labile HbA(1c) and carbamylated Hb) in the clinical range, and to the presence of HbF. Besides, Glycomat 3000 is a friendly and easy to use analyzer. PMID- 21659048 TI - [Hodgkin lymphoma in the elderly]. AB - We report a case of Hodgkin's lymphoma in a patient aged 75, presenting with acute cardiopulmonary insufficiency, hospitalized in a geriatrics ward. The deterioration of his general condition and the discovery of several lymph nodes led us to perform an aspiration of a lymph node and a bone marrow biopsy. Reed Sternberg cells, pathognomonic of Hodgkin's disease were identified on the smears and biopsy sections. Due to the poor condition of the patient, it was decided not to treat with chemotherapy. The diagnostic approach and treatment strategy of Hodgkin's disease are summarized in this paper, especially the particular features of the disease in the elderly. PMID- 21659049 TI - [Biclonal or biphenotypic chronic lymphotic leukemia? An answer brought by the treatment]. AB - A 51-years-old patient with polyadenopathies presents a non monotypic chronic lymphocytic leukemia (CLL): lymphocytes B CD5+, CD23+, CD22-,CD79b dim, FMC7- express kappa (71%) and lambda (21%) light chains without coexpression. The caryotype shows two clones with one in evolution. Lymphoid clonality analysis by PCR (polymerase chain reaction) of the heavy and light chains genes of immunoglobulins shows two monoclonal rearrangements for each kind of chains. Lack of lymphoid cells sorting in function of the light chain doesn't allow us to conclude between a biclonal CLL and a biallelic monoclonal CLL. New adenopathies appearance in this patient, one year and a half after the end of his chemotherapy, leads to realisation of a new immunophenotyping: CLL is now monotypic with kappa light chains expressed at 95%. In the new caryotype, only one clone is still present: it is the clone in evolution in the first caryotype and which presents additional abnormalities. This evolution allows us to assert the biclonality of the primitive CLL, the two clones evolving differently under treatment. In conclusion, the patient presented a biclonal CLL with one clone responding to treatment and the other one resistant. PMID- 21659050 TI - [Pancytopenia and folate deficiency: a case report]. AB - Anemia is the most common pathology encountered in hematology. Etiologies are numerous, so it is important to adopt a rigorous approach. Complementary examinations must be specific to the clinical situation in order to determine the mechanisms on the one hand and decide the therapeutic management on the other. We report the observation of a case of sudden onset of profound pancytopenia. Investigation led to the diagnosis of major folic acid deficiency with favorable evolution. Through this case, we describe the diagnostic approach towards anemia and the mechanisms involved in the formation of folate deficiency. PMID- 21659051 TI - [Factor V deficiency and pregnancy: a case report]. AB - The factor V deficiency is a very rare hereditary disease of the coagulation, which is accompanied by a high hemorrhagic risk in the event of delivery and in the post-partum. We report the case of a woman having a factor V deficiency which had a pregnancy, and which gave birth by Cesarean, as replacement therapy we proposed the transfusion of 20 mL/kg of fresh frozen plasma before surgery and of 5 mL/kg by 12 h during 7 days in post-partum, this attitude allowed to avoid the hemorrhagic complications. PMID- 21659052 TI - [Sacrum B cell-non-Hodgkin's lymphoma complicating a chronic viral hepatitis C related to a blood exposure: a case report]. AB - Frequency of the association between non-Hodgkin's lymphoma (NHL) and the hepatitis C virus (HCV) infection is variable according to previous studies. Besides, direct and/or indirect implication of the HCV infection in the development of NHL is probable but, its pathophysiological mechanisms remain unclear. In this report, we described the case of a 49-year-old patient with a B cell NHL of the sacrum complicating a chronic HCV related to a blood exposure, and we report the recent data of this association. PMID- 21659053 TI - [Acute myeloid leukemia with bone marrow erythroblastosis: about one case illustrating the new WHO classification (2008)]. AB - We reported here a case of acute myeloid leukaemia (AML) in a 28-year-old male patient, which diagnosis is discussed according to the different classifications. This case focused on some new criteria and changes in the new WHO classification (2008) of AML, especially when erythroid precursors represent over 50% of bone marrow nucleated cells. It also pointed on some gene mutations (NPM1, CEPBA, FLT3, WT1...) and their prognostic features in AML with a normal karyotype, leading to individualize two new provisional entities in the WHO classification of tumours of hematopoietic and lymphoid tissues 2008. PMID- 21659054 TI - [Tuberculosis -HIV, a common and sensitive care in connection with a case of pleural tuberculosis revealing AIDS]. AB - Tuberculosis is the most common disease inaugural of AIDS in France and HIV serology should be offered routinely when a tuberculosis case is diagnosed. Similarly, tuberculosis should also be sought before starting antiretroviral treatment. The case of pleural tuberculosis revealing AIDS presented here illustrates the difficulties of management of this co-infection due to polychemotherapy used to treat each of these pathologies causing drug interactions requiring dose adjustments and changes in treatment protocol and an increase in side effects. This is especially true when combining rifampicin and protease inhibitors and non-nucleoside reverse transcriptase inhibitors. On the other hand, resistance of Mycobacterium tuberculosis is possible in these patients coinfected by HIV particularly among migrants and in the case history of tuberculosis treatment. PMID- 21659055 TI - Molecular characterization of a discrete hemoglobinopathy upon investigation for a lung hydatic cyst in an old Tunisian patient. AB - We report the case of an old Tunisian patient hospitalized for a complicated hydatic cyst of the right lung. Primary laboratory investigation showed a microcytic hypochromic anemia with an abnormal hemoglobin pattern. Hemoglobin analysis and DNA sequencing of the beta-globin gene revealed a compound heterozygote, HbO-Arab/cd 39 beta degrees -thalassemia. This hemoglobinopathy was never diagnosed earlier. It spent undiagnosed until the patient presented with hydatic cyst. Coexistence of the two pathologies complicated the general state of the patient and led to a severe anemia. The patient has undergone a surgical therapy for the hydatic cyst and was advised to start a follow up for her hemoglobinopathy. PMID- 21659056 TI - [Evaluation of the AFSSAPS clinical practice guidelines on prevention and treatment of thrombo-embolic disease in medicine (2009), in comparison with those of the American College of Chest Physicians (ACCP 2008) with the help of the AGREE tool]. AB - We have evaluated the methodological quality of the AFSSAPS French clinical practice guidelines on prevention and treatment of thrombo-embolic disease in medicine, published in 2009. We have evaluated in parallel the similar recommendations from north-America on the subject (ACCP 2008). Our evaluation tool was the AGREE instrument which is consensual at an international level, in particular at the WHO (World Health Organisation) and at the European Union. The methodological quality of the AFSSAPS guidelines is sub-optimal, significantly lower than that of the ACCP guidelines. Compared with the ACCP guidelines, the weakest points of the AFSSAPS guidelines are about rigor of development (AGREE domain 3), applicability (AGREE domain 5) and editorial independence (AGREE domain 6). The main common shortcoming in quality of both guidelines is about lack of stakeholder involvement (AGREE domain 2). A more important implication of methodologists might explain why the ACCP guidelines reach a higher level of quality than those of the AFSSAPS guidelines. We do not make judgments about the content of the recommendations of the AFSSAPS or of the ACCP. PMID- 21659057 TI - [Non-conformities management in laboratory of medical biology: application to non conformities of biological samples during 2009]. AB - The non-conformity management is required for the ISO 15189 standard. The laboratory of medical biology has to carry out suitable acts and procedures to exploit different indicators through the framework of continuous improvement. We particularly study the indicator of biological samples nonconformities and we report 2009 results to the nurses' team managers to find solutions for quality of care to the patient. PMID- 21659058 TI - Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial. AB - Studies in animals and in patients have suggested that magnesium (Mg), a physiological blocker of N-methyl-D-aspartate receptor, could have an antinociceptive effect in painful situations. This randomised, double-blind, controlled trial in two parallel groups aims at studying oral Mg effects in patients with neuropathic pain. It explores the impact of Mg (6x419 mg Mg chloride/capsule per day for a month), versus placebo (lactose) on pain [Neuropathic Pain Symptom Inventory (NPSI) and numerical scale (NS)], and on quality of life indicators after 4 weeks treatment, in 45 patients suffering from neuropathic pain. After 4 weeks, NPSI, NS and quality of life are not different in the Mg and placebo groups, while the frequency of pain paroxysms diminishes and the emotional component improves in the Mg group compared to baseline. This clinical trial displays a large placebo response and could not demonstrate any significant difference in pain alleviation after a month of oral treatment between Mg and placebo in patients suffering from neuropathic pain. Frequency of pain paroxysms and emotional impact will be explored in future studies as they constitute major aspects of pain alleviation in chronic pain conditions. PMID- 21659059 TI - The demand for dermatology and the spectrum of skin disease in the immigrant population of Southeast Spain. Differences depending on the geographical origin. AB - The aim of this study was to describe the dermatoses seen in the immigrant population and to perform a comparative study according to the different geographical areas. A prospective study performed from February 2005 to February 2006. All the visits of economic immigrants seen in the Dermatology Section were prospectively recorded. We examined 1,085 immigrant patients. Latin American patients were more frequently seen (n=706) and they consulted dermatologists more (8.9 visits per 100 people). Benign tumoral pathology was more frequent in Latin American patients (21.9 vs 15.7%; p=0.009). The percentage of infectious dermatoses was greater in the North African population (23.3 vs 17.9%; p=0.009). There was a lower percentage of pigmentary alterations in the Eastern European population (0.7% vs 6.6%; p=0.009). Pruritus was more common in Sub-Saharan immigrants (8.1% vs 1.4%; p=0.001), In the field of dermatology it is not possible to consider the immigrant population as a homogenous group since the dermatoses vary depending on the patients' geographical origin. PMID- 21659060 TI - Professional practice and accessibility to equipment in thoracic oncology. Results of a survey in Rhones-Alpes region (France). AB - This survey, conducted in region Rhone-Alpes (France), aims to assess some data in thoracic oncology practice including availability of specialized equipments. This study is based on a questionnaire mailed to oncologists and pulmonologists in the region. Of 401 questionnaires, the response rate was 56%. Responses of 71 (20%) physicians practicing thoracic oncology are presented in this article. Eighty percent of physicians routinely screen occupational exposure in case of lung cancer. The oncologists are less likely than pulmonologists to screen it (50% vs. 12%, p = 0.0015). Sixty-one percent of practitioners do not routinely propose smoking cessation in stage IV. Sixty-nine percent of practitioners' reports obtain an appointment for PET-scanner within 15 days and 72% indicate that this equipment is located within 50 km of their place of practice. Sixty-two percent reports using a surgical team specialized in chest disease, which is located in their city in 77% of cases. Sixty-one percent say that the period between the decision of an emergency radiotherapy and the start of it is less than one week. In 73% radiotherapy department is located in their city of practice. Forty-one percent of practitioners say they have a centralized and specialized preparation unit for cancer drugs. It seems that specialized equipment in Rhone-Alpes is adapted to practice with the exception of units dedicated to the preparation of cytotoxic drugs. PMID- 21659061 TI - Phacomatosis melanorosea with heterochromia of scalp hair. PMID- 21659062 TI - Reappraisal of the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of ovarian cancer: a single institutional experience. AB - The peritoneal carcinomatosis of ovarian cancer led to the development of optimal cytoreduction surgery completed by hyperthermic intraperitoneal chemotherapy (HIPEC). The main goal of this study is to evaluate the feasibility, tolerance and efficacy of this technique in patients with ovarian cancer. A retrospective monocentric study has evaluated 43 patients with HIPEC procedures from 1995 to 2009. After a complete cytoreduction surgery, a HIPEC procedure with cisplatin is performed. Data on complications and survival parameters were collected. Prognostic factors were also analyzed. Post-surgery complications included one death due to a septic shock (2.3%) and six patients have presented major complications (13.9%). The median of overall survival and progression free survival were 53.6 and 39 months, respectively. Patients with a primary complete surgical cytoreduction of the peritoneal carcinomatosis presented overall survival length of 131 months versus 84 months without initial complete resection (P < 0.0001). Surgical cytoreduction combined with HIPEC is a feasible procedure with acceptable morbid-mortality rates. The initial complete resection of the peritoneal carcinomatosis significantly increases survival and represents a strong prognostic factor. PMID- 21659063 TI - Generalized lichenoid dermatosis as a tumor-associated dermadrome in a patient with inoperable esophageal cancer. PMID- 21659064 TI - Metastatic renal cancer: evolution of five complete response cases after the antiangiogenic discontinuation. AB - Antiangiogenic therapies have led to substantial progress in the management of kidney cancer, highly vascular tumor, and chemoresistant. These molecules have improved the prognosis of metastatic renal cancer. However, only a few isolated cases of complete response have been described and the evolution of these patients after treatment discontinuation remains unclear. From a series of patients treated for kidney cancer with antiangiogenic in first line, the purpose of this study was to identify patients in complete response in whom treatment had been interrupted. Complete response was defined according to RECIST criteria and data were collected retrospectively at the Centre Francois Baclesse - Caen. Five patients were identified in complete response with a treatment discontinuation among sixty-seven patients. These five patients of good or intermediate prognosis received an initial nephrectomy followed by a first-line treatment by Sunitinib (ten cycles on average). After one year of stopping treatment, two patients are still in complete response and three patients relapsed at three, 12 and 15 months. The treatment of relapsing disease was surgical followed by monitoring or resumption of sunitinib resulting in new complete response for the all three patients. The interruption of antiangiogenic treatment seems acceptable after a complete response. PMID- 21659065 TI - Effect of methotrexate on serum levels of IL-22 in patients with psoriasis. AB - Interleukin-22 (IL-22) is the effector molecule of T-helper subset 22 (Th-22) lineage that promotes keratinocyte proliferation and dermal inflammation in psoriasis. Methotrexate is widely used as a first-line treatment in moderate to severe psoriasis. Methotrexate inhibits inflammatory and cytokinetic processes via various mechanisms, but the relevance of these to psoriasis is limited and whether methotrexate is specifically able to down-regulate Th22 cytokines is unknown. To determine if methotrexate reduces IL-22 in cases of psoriasis. Nineteen patients with moderate to severe psoriasis were given methotrexate 15 mg per week for up to 12 weeks. Serum levels of IL-22 were determined by enzyme linked immunosorbent assay (ELISA) before and after treatment. Eleven of 19 patients (57.8%) achieved a 75% PASI score reduction. IL-22 levels were significantly higher in untreated psoriasis patients (56.63 +/- 60.73 pg/mL) than in controls (12.58 +/- 12.59 pg/mL). Methotrexate significantly reduced serum levels of IL-22 in psoriasis patients to 5.91 +/- 7.97 pg/mL (p<0.001). Moreover, there was a significant positive correlation between IL-22 levels and PASI (r=0.63, p=0.004). Methotrexate significantly reduces serum IL-22 levels in cases of psoriasis. This is a novel mechanism by which methotrexate acts in the treatment of this disease. PMID- 21659066 TI - Erythropoietic protoporphyria: a family study and report of a novel mutation in the FECH gene. AB - Erythropoietic protoporphyria (EPP) is a rare inherited disorder of heme biosynthesis mostly caused by a deficient activity of the enzyme ferrochelatase (FECH), and consequent accumulation of protoporphyrin (PP) in various tissues. Clinical manifestations include a childhood onset, cutaneous photosensitivity and, sometimes, hepatobiliary disease. We report a 16-year-old male with EPP characterized by acute episodes of painful photosensitivity since early infancy, permanent changes in the photoexposed skin, microcytic anemia, thrombocytopenia, and mild hepatic dysfunction. His 18-year-old sister presented less acute symptoms with no chronic changes. Lesional biopsy disclosed perivascular deposition of PAS positive hyaline material. Rimington-Cripps test was positive and PP erythrocyte levels were >9,000 MUg/L (N<1,600), but normal in their parents and younger brother. Genetic studies in both patients and their mother revealed heterozygosity for a novel mutation (c.1052delA) in FECH gene of both children, and heterozygosity for the hypomorphic allele IVS3-48T>C in all of them. This confirms the "pseudodominant" inheritance pattern usually observed, explained by the combined presence of a disabling FECH mutation and a common intronic polymorphism affecting the counterpart allele (IVS3-48T>C). Phenotypic heterogeneity for this genotype explains the divergent clinical presentation. This is the first description of a Portuguese family with EPP characterized at the molecular level. PMID- 21659067 TI - Digital desmoplastic fibroma in a juvenile. PMID- 21659068 TI - Juvenile-onset keratosis lichenoides chronica treated successfully with topical tacrolimus: a safe and favourable outcome. PMID- 21659069 TI - Could cytomegalovirus infection play a causative role in epidermolysis bullosa acquisita? PMID- 21659071 TI - Videodermoscopy scalp psoriasis severity index (VSCAPSI): a useful tool for evaluation of scalp psoriasis. AB - The standard methods used to diagnose scalp psoriasis vary in sensitivity, reproducibility, and invasiveness. Videodermoscopy can be used to explore microcirculatory modifications in skin diseases. Psoriasis presents three pathognomonic vascular patterns: red dots, hairpin vessels and red globular rings. Our aim was to create a videodermoscopy scalp psoriasis severity index (VSCAPSI) for evaluation of scalp psoriasis, especially mild and moderate forms that often are not clinically appreciable. VSCAPSI takes into account the area of the scalp affected by psoriasis, the presence and morphology of vascular patterns, the erythema and desquamation. Videodermoscopy images obtained between November 2009 to June 2010 from 900 participants with various scalp and hair disorders were reviewed for distinguishing features. During the 2010 Italian congress on psoriasis, in order to assess the reproducibility and efficacy of the VSCAPSI, 146 dermatologists were asked to evaluate 16 videodermoscopy images of scalp psoriasis using the VSCAPSI. Of the 900 patients, 85 new cases of scalp psoriasis were diagnosed. The other 815 patients were found to be suffering from different scalp and hair diseases. Of 146 dermatologists, 28 did not recognize erythema, 15 desquamation and 7 the vascular patterns. The VSCAPSI provides important evidence for early diagnosis, differential diagnosis, for follow-up and screening. PMID- 21659070 TI - Leukonychia totalis associated with multiple pilar cysts: report of a five generation family: FLOTCH syndrome? AB - The association of familial totalis leukonychia with multiple pilar cysts is a rare condition that could represent a separate syndromic entity. Since Bauer described a family with totalis leukonychia and sebaceous cysts in 1920, only four new affected families have been reported. We report a five-generation family with a total leukonychia and multiple pilar cysts on the scalp. The hypothesis of a deficiency of a gene regulating the structure of keratin has been postulated but the exact genetic mechanism has not been yet determined. In our family, no other keratinizing structures were involved. PMID- 21659072 TI - Generalized lichen nitidus associated with postpartum thyroiditis. PMID- 21659074 TI - Eucommia (Eucommiaceae), a potential biothermometer for the reconstruction of paleoenvironments. AB - The living trees of Eucommia ulmoides, an endemic species in China, grow from 200 to 1700 m above sea level, within the geographic range from 102 degrees E to 118 degrees E and from 25 degrees N to 35 degrees N. Spring temperatures in these regions vary from 12.3 degrees C to 20.1 degrees C. A physiological study (using germination tests) of E. ulmoides has been undertaken to test the role of spring temperature as a factor controlling the distribution of Eucommia. Results show that the spring temperature is a limiting factor for Eucommia seed germination and hence for the distribution pattern of the genus. The suitable range of temperature for seed germination, established experimentally, is from 13 degrees C to 22 degrees C, with an optimum of 18 degrees C. Specimens of fossil Eucommia cf. ulmoides, preserved as a branch segment and leaves, showing the distinctive latex, were found in Middle Miocene sediments of Shanwang Formation, Shandong Province, East China. If the climatic tolerances documented here for E. ulmoides are extrapolated to Shanwang, they are in fact consistent with other predictions of the paleoclimate at this site, indicative of the potential value of Eucommia as a biothermometer. These Miocene fossils, and one previously described Eocene fruit specimen, prove the former existence of Eucommia in China in addition to North America and Europe. This confirms that the genus is not a recent arrival in China and extends our understanding of the past biogeography of the genus. PMID- 21659073 TI - Clinical and pathological features of 31 cases of lipedematous scalp and lipedematous alopecia. AB - Little is known about lipedematous scalp (LS) and lipedematous alopecia (LA). We investigated the clinical and histopathological features of LS and LA with a 7 year retrospective re-evaluation of 31 patients. 23 cases were LS and 8 LA, with 25 females and 6 males. The overweight and obese groups contained 15 patients with 16 within the normal weight range. Scalp thickness varied between 9-18 mm in our patients by magnetic resonance imaging. Thickening of the subcutaneous adipose tissue layer was present in all cases. Dermal edema was seen in 22 patients, lymphatic dilatation in 17 and elastic fiber fragmentation in 21. When the relationship between dermal edema and elastic fibers was investigated, elastic fiber fragmentation was found in 86.4% of cases with dermal edema. Collagen fragmentation and coarsening were seen in two cases, and collagen was normal in 24 cases. The number of follicles was decreased in 9 cases and normal in 17. The clinical and histopathological findings were not statistically different between LS and LA groups (p>0.05). The majority of the patients in our study were females, suggesting an underlying hormonal pathology. The association with obesity suggested that anatomical differences can be present in lipid distribution. Dermal edema and lymphatic dilatation suggested the primary pathology is lymphatic system. PMID- 21659075 TI - Cone and ovule development in Cunninghamia and Taiwania (Cupressaceae sensu lato) and its significance for conifer evolution. AB - We examined the early developmental stages of the seed cones and seeds of two conifer genera, Cunninghamia and Taiwania, using scanning electron microscope (SEM) images of freshly collected material. In recent similar studies, these two taxa were not described. The present paper aims to fill that gap. Both genera appear to have features crucial to the understanding of the evolution of the cupressaceous cone, characteristic of the families Cupressaceae and Taxodiaceae, and provide further evidence for the need to merge these families. These features are: the ovuliferous scale in Cunninghamia develops as a small lobe with each of three ovules; in Taiwania these lobes are absent, but a small ridge could be a vestige of them. In neither of these two genera does an ovuliferous scale develop to maturity and only limited intercalary growth transforms the bracts, of which only their width and final shape distinguishes them from sterile leaves. Thus, the bracts, not the ovuliferous scales, form the mature cone in these two genera. This trend is continued in more derived genera of Cupressaceae. Another key extant taxon that has helped to elucidate the evolution of this type of conifer cone is Sciadopitys; similar studies have already been done on this genus, and we compared our findings to them. We also considered certain fossil Mesozoic conifer cones, which shed further light on the evolution of the cupressaceous cone. The evidence from these various genera strongly indicates that recently reconstructed phylogenies of gymnosperms based on molecular evidence from extant taxa do not reflect the evolution that actually happened. Such studies need to take into account nonmolecular evidence, as detailed here. PMID- 21659076 TI - Intragenomic and interspecific 5S rDNA sequence variation in five Asian pines. AB - Patterns of intragenomic and interspecific variation of 5S rDNA in Pinus (Pinaceae) were studied by cloning and sequencing multiple 5S rDNA repeats from individual trees. Five pines, from both subgenera, Pinus and Strobus, were selected. The 5S rDNA repeat in pines has a conserved 120-base pair (bp) transcribed region and an intergenic spacer region of variable length (382-608 bp). The evolutionary rate in the spacer region is three- to sevenfold higher than in the genic region. We found substantial sequence divergence between the two subgenera. Intragenomic sequence heterogeneity was high for all species, and more than 86% of the clones within each individual were unique. The 5S gene tree revealed that different 5S repeats within individuals are polyphyletic, indicating that their ancestral divergence preceded the speciation events. The degrees of interspecific and intragenomic divergence among diploxylon pines are similar. The observed sequence patterns suggest that concerted evolution has been acting after the diversification of the two subgenera but very weak after the speciation of the four diploxylon pines. Sequence patterns in P. densata are consistent with hybrid origin. It had higher intragenomic diversity and maintained polymorphic copies of the parental types in addition to new and recombinant types unique to the hybrid. PMID- 21659077 TI - Spatial pattern of allozyme variation in a contact zone of Pinus Ponderosa and P. arizonica (Pinaceae). AB - The spatial distribution of genotypes for nine polymorphic allozyme loci was examined in a contact zone between Pinus ponderosa var. scopulorum and another tree regarded as either a separate species, Pinus arizonica, or variety, Pinus ponderosa var. arizonica, in southern Arizona. Previous work had identified a steep elevational cline for a key taxonomic trait, number of leaf-needles per fascicle, on the south slope of Mt. Lemmon. The present results indicate that the taxa are not fully interbreeding in this contact zone, because allozyme genotypes are considerably more spatially structured than expected for the dispersal characteristics of pines. The amount of spatial differentiation is also much less than that observed for needle number. It appears that this is due to the lack of differentiation for allozyme gene frequencies for the two types of trees, which is further evidenced by analysis of samples from two other populations away from the contact zone. It is likely that if the two taxa were isolated in the past, it was not for long enough nor complete enough to allow mutation-drift to create substantial differentiation between them. Another possible explanation is that introgression after recontact is so advanced that any differences have been erased throughout the Santa Catalina mountain range. PMID- 21659078 TI - The major veins of mesomorphic leaves revisited: tests for conductive overload in Acer saccharum (Aceraceae) and Quercus rubra (Fagaceae). AB - Many leaves survive the severing of their major veins in apparently excellent health. According to the classical explanation, the leaf minor veins provide "conductive overload," an excess of parallel conductive paths, rendering the major veins hydraulically dispensable. Whether such an excess of conductive paths exists has important implications for vascular design and for leaf response to vascular damage. We subjected leaves of Acer saccharum and Quercus rubra to cutting treatments that disrupted the major vein system and determined leaf survival, stomatal conductance (g), quantum yield of photosystem II (Phi(PSII)), and leaf hydraulic conductance (K(leaf)). For A. saccharum, the cuts led to the death of distal lamina. For Q. rubra, however, the treated leaves typically remained apparently healthy. Despite their appearance, the treated Q. rubra leaves had a strongly reduced K(leaf), relative to control leaves, and g and Phi(PSII) were reduced distal to the cuts, respectively, by 75-97% and 48-76%. Gas exchange proximal to the cuts was unaffected, indicating the independence of lamina regions and their local stomata. Analogous results were obtained with excised Q. rubra leaves. These studies demonstrate an indispensable, vital role of the major veins in conducting water throughout the lamina. PMID- 21659079 TI - Heat shock response of warm-incubated barley aleurone layers. AB - Heat shock suppresses secretory protein synthesis in GA(3)-stimulated barley (Hordeum vulgare cv. Himalaya) aleurone layers by selectively destabilizing their mRNAs and dissociating the stacked rough endoplasmic reticulum (ER) lamellae upon which they are translated. Heat shock also increases phosphatidylcholine (PC) synthesis, and these PC molecules have increased levels of fatty acid saturation. This appears to be adaptive, for aleurone layers maintained at heat shock temperatures for 18 h resynthesize secretory protein mRNAs, rebuild stacked ER lamellae, and resume secretory protein synthesis. In the present study aleurone layers were incubated at warmer than normal pre-heat shock temperatures to determine whether this would favor the formation of heat-resistant ER lamellae that could continue secretory protein synthesis during heat shock. Western blot and SDS-PAGE analyses showed that such treatment did not induce heat shock protein (HSP) synthesis, but it preserved significant secretory protein synthesis during heat shock. Northern hybridizations revealed that levels of mRNAs encoding secretory proteins were several-fold elevated as compared to 25 degrees C preincubated controls, and transmission electron microscopic observations revealed stacked ER lamellae. Thin layer and gas chromatography showed that PC molecules in warm-incubated barley aleurone layers had more fatty acid saturation than did controls. These observations indicate that previous incubation temperature influences both the induction of HSP synthesis and the suppression of normal protein synthesis in the heat shock response. However, we found that it does not affect the temperature at which heat shock becomes lethal. PMID- 21659080 TI - Ontogenetic origins of floral bilateral symmetry in Moringaceae (Brassicales). AB - Floral morphology of the 13 species of Moringa ranges from actinomorphic flowers with little hypanthium to highly zygomorphic flowers with well-developed hypanthia. Scanning electron and light microscopy were used to identify ontogenetic differences among two actinomorphic and eight zygomorphic species. All species show traces of zygomorphy between petal organogenesis and anther differentiation. At late organogenesis, zygomorphy is manifest by one petal being larger than the others, slight unidirectional maturation of the anthers, and in many species, some staminodes may be missing. At organ differentiation and beyond, the actinomorphic species show a trend toward increasing actinomorphy, whereas the zygomorphic features of early ontogeny are progressively accentuated throughout the ontogeny of the zygomorphic species. Because of the early traces of zygomorphy throughout the family, ontogeny in Moringa does not resemble that known from the sister taxon Caricaceae, which has flowers that are actinomorphic throughout ontogeny. Great intraspecific variation was found in floral plan in the actinomorphic-flowered species in contrast to the zygomorphic species. Each of the main clades in the family is distinguished by at least one feature of floral ontogeny. In general, ontogenetic differences that are congruent with deeper phylogenetic splits tend to occur earlier in ontogeny than those congruent with more recent divergences. PMID- 21659081 TI - Leaf biomechanics, morphology, and anatomy of the deciduous mesophyte Prunus serrulata (Rosaceae) and the evergreen sclerophyllous shrub Heteromeles arbutifolia (Rosaceae). AB - Leaf tensile properties were compared between the mesic deciduous tree Prunus serrulata (var. "Kwanzan") and the xeric and sclerophyllous chaparral evergreen shrub Heteromeles arbutifolia (M. Roem). All values for biomechanical parameters for H. arbutifolia were significantly greater than those of P. serrulata. The fracture planes also differed between the two species with P. serrulata fracturing along the secondary veins, while H. arbutifolia most often fractured across the leaf irrespective of the vein or mesophyll position, thus yielding qualitative differences in the stress-strain curves of the two species. Anatomically, P. serrulata exhibits features typical for a deciduous mesophytic leaf such as a thin cuticle, a single layer of palisade mesophyll, isodiametric spongy mesophyll, and extensive reticulation of the laminar veins. Heteromeles arbutifolia leaves, however, are typically two- to three-fold thicker with a 35% higher dry mass/fresh mass ratio. The vascular tissue is restricted to the interface of the palisade and spongy mesophyll near the center of the leaf. Both epidermal layers have a thick cuticle. The palisade mesophyll is tightly packed and two to three layers thick. The spongy mesophyll cells are ameboid in shape and tightly interlinked both to other spongy cells as well as to the overlying palisade layer. We conclude that the qualitative and quantitative biomechanical differences between the leaves of these two species are likely due to a complex interaction of internal architectural arrangement and the physical/chemical differences in the properties of their respective cell walls. These studies illustrate the importance that morphological and anatomical correlates play with mechanical behavior in plant material and ultimately reflect adaptations present in the leaves of chaparral shrubs that are conducive to surviving in arid environments. PMID- 21659082 TI - Asynchronous development of stigmatic receptivity in the pear (Pyrus communis; Rosaceae) flower. AB - While stigma anatomy is well documented for a good number of species, little information is available on the acquisition and cessation of stigmatic receptivity. The aim of this work is to characterize the development of stigma receptivity, from anthesis to stigma degeneration, in the pentacarpellar pear (Pyrus communis) flower. Stigma development and stigmatic receptivity were monitored over two consecutive years, as the capacity of the stigmas to offer support for pollen germination and pollen tube growth. In an experiment where hand pollinations were delayed for specified times after anthesis, three different stigmatic developmental stages could be observed: (1) immature stigmas, which allow pollen adhesion but not hydration; (2) receptive stigmas, which allow proper pollen hydration and germination; and (3) degenerated stigmas, in which pollen hydrates and germinates properly, but pollen tube growth is impaired soon after germination. This developmental characterization showed that stigmas in different developmental stages coexist within a flower and that the acquisition and cessation of stigmatic receptivity by each carpel occur in a sequential manner. In this way, while the duration of stigmatic receptivity for each carpel is rather short, the flower has an expanded receptive period. This asynchronous period of receptivity for the different stigmas of a single flower is discussed as a strategy that could serve to maximize pollination resources under unreliable pollination conditions. PMID- 21659083 TI - Genetic structure of an endangered plant, Antirrhinum microphyllum (Scrophulariaceae): allozyme and RAPD analysis. AB - Thirteen allozyme loci and 68 random amplified polymorphic DNA (RAPD) markers were analyzed to assess the genetic diversity and population structure of threatened Antirrhinum microphyllum (Scrophulariaceae), a narrow endemic of central Spain known from only four populations. According to allozyme data, species genetic diversity (p = 46.15%, A = 2.61, and H(e) = 0.218), as well as within-population genetic diversity (p = 44.23%, A = 2.10, and H(e) = 0.204), were high when compared to average estimates for other narrowly distributed plant species. Ninety-four percent of species genetic diversity corresponded to within population genetic diversity. Nevertheless, significant differences were found among populations in allele frequencies of four of the six polymorphic loci, and three private alleles were detected. Inbreeding coefficients (F(IS)) suggest that populations are structured in genetic neighborhoods. The RAPDs also showed high levels of genetic diversity (p = 89.71% and H(e) = 0.188 at the species level, and p = 67.65% and H(e) = 0.171 at the population level). Nei's genetic distances estimated both from allozymes and RAPDs indicated low differentiation among populations. In spite of this, the low frequencies of certain alleles and the presence of private alleles indicate that efforts should be made to conserve all four remaining populations. PMID- 21659084 TI - Phylogenetic relationships among Poaceae and related families as inferred from morphology, inversions in the plastid genome, and sequence data from the mitochondrial and plastid genomes. AB - A phylogenetic analysis of the Poales was conducted to assess relationships among Poaceae and allied families. The analysis included 40 taxa, representing all families of the Poales as circumscribed by the Angiosperm Phylogeny Group (APG), plus five of the six unplaced Commelinid families in the APG system. The data matrix included 98 informative characters representing variation in morphology and chloroplast genome structure (including three inversions in the chloroplast genome), and 563 informative characters derived from rbcL and atpA nucleotide sequences. Ecdeiocolea has the 6-kilobase (kb) chloroplast genome inversion previously reported in Joinvillea and Poaceae, and like Joinvillea it lacks the trnT inversion that occurs in grasses. Analysis of the morphological data places Poaceae in an unresolved relationship relative to several other taxa, including Joinvillea and Ecdeiocolea, while analysis of the molecular and combined data resolves Ecdeiocolea as sister of Poaceae, with Joinvillea the sister of this group. Although the 6-kb and trnT inversions are non-homoplasious in the phylogenies obtained in this study, the 28-kb inversion is optimized as having originated twice (once in Restionaceae and another time in the most recent common ancestor of Ecdeiocolea, Joinvillea, and the grasses); an alternative interpretation is that it arose once and was later lost in Anarthria. Ecdeiocolea shares with Poaceae the presence of operculate, annulate pollen that lacks scrobiculi, and a dry, indehiscent fruit. PMID- 21659085 TI - Family-level relationships of Onagraceae based on chloroplast rbcL and ndhF data. AB - Despite intensive morphological and molecular studies of Onagraceae, relationships within the family are not fully understood. One drawback of previous analyses is limited sampling within the large tribe Onagreae. In addition, the monophyly of two species-rich genera in Onagreae, Camissonia and Oenothera, has never been adequately tested. To understand relationships within Onagraceae, test the monophyly of these two genera, and ascertain the affinities of the newly discovered genus Megacorax, we conducted parsimony and maximum likelihood analyses with rbcL and ndhF sequence data for 24 taxa representing all 17 Onagraceae genera and two outgroup Lythraceae. Results strongly support a monophyletic Onagraceae, with Ludwigia as the basal lineage and a sister-taxon relationship between Megacorax and Lopezia. Gongylocarpus is supported as sister to Epilobieae plus the rest of Onagreae, although relationships within the latter clade have limited resolution. Thus, we advocate placement of Gongylocarpus in a monogeneric tribe, Gongylocarpeae. Most relationships within Onagreae are weakly resolved, suggesting a rapid diversification of this group in western North America. Neither Camissonia nor Oenothera appears to be monophyletic; however, increased taxon sampling is needed to clarify those relationships. Morphological characters generally agree with the molecular data, providing further support for relationships. PMID- 21659086 TI - The origin and evolution of Eragrostis tef (Poaceae) and related polyploids: evidence from nuclear waxy and plastid rps16. AB - Tef (Eragrostis tef; Poaceae) is an allotetraploid (2n = 4x = 40) cereal crop whose origin within the large genus Eragrostis is unknown. Previous studies have suggested a total of 14 wild Eragrostis species as potential progenitors. Phylogenetic analysis of sequence data from the nuclear gene waxy and the plastid locus rps16 strongly supports the widely held hypothesis of a close relationship between tef and E. pilosa, a wild allotetraploid. Eragrostis heteromera, another previously proposed progenitor, is shown by the waxy data to be a close relative of one of the tef genomes. Other putative progenitors included in the taxon sample are not supported as closely related to tef. Plastid sequences from five varieties of tef and four E. pilosa accessions are identical and therefore are uninformative with respect to the question of multiple origins of these polyploids. The waxy phylogeny also resolves the relationships among other allopolyploids, supporting a close relationship between the morphologically similar allotetraploids E. macilenta, E. minor, and E. mexicana. Eragrostis cilianensis, another morphologically similar allopolyploid, appears to have shared one diploid progenitor with these species but derived its other genome from an unrelated diploid. PMID- 21659087 TI - Phylogeny of the sundews, Drosera (Droseraceae), based on chloroplast rbcL and nuclear 18S ribosomal DNA Sequences. AB - The sundew genus Drosera consists of carnivorous plants with active flypaper traps and includes nearly 150 species distributed mainly in Australia, Africa, and South America, with some Northern Hemisphere species. In addition to confused intrageneric classification of Drosera, the intergeneric relationships among the Drosera and two other genera in the Droseraceae with snap traps, Dionaea and Aldrovanda, are problematic. We conducted phylogenetic analyses of DNA sequences of the chloroplast rbcL gene for 59 species of Drosera, covering all sections except one. These analyses revealed that five of 11 sections, including three monotypic sections, are polyphyletic. Combined rbcL and 18S rDNA sequence data were used to infer phylogenetic relationships among Drosera, Dionaea, and Aldrovanda. This analysis revealed that all Drosera species form a clade sister to a clade including Dionaea and Aldrovanda, suggesting that the snap traps of Aldrovanda and Dionaea are homologous despite their morphological differences. MacClade reconstructions indicated that multiple episodes of aneuploidy occurred in a clade that includes mainly Australian species, while the chromosome numbers in the other clades are not as variable. Drosera regia, which is native to South Africa, and most species native to Australia, were clustered basally, suggesting that Drosera originated in Africa or Australia. The rbcL tree indicates that Australian species expanded their distribution to South America and then to Africa. Expansion of distribution to the Northern Hemisphere from the Southern Hemispere occurred in a few different lineages. PMID- 21659088 TI - Light, salinity, and temperature effects on the seed germination of perennial grasses. AB - The germination requirements of four perennial halophytic grasses, Aeluropus lagopoides, Halopyrum mucronatum, Sporobolus ioclados, and Urochondra setulosa, were studied under control conditions in the laboratory. Treatments included two light levels (12 : 12 h light : dark period and 24-h dark environment), six salinity concentrations (0, 100, 200, 300, 400, and 500 mmol/L NaCl), and four temperature regimes (fluctuating day : night temperature regimes of 10 degrees : 20 degrees , 15 degrees : 25 degrees , 20 degrees : 30 degrees and 25 degrees : 35 degrees C), using a completely randomized block design. Best seed germination of all grasses was obtained in a distilled water control. Increase in salinity progressively inhibited germination of all species. For example, few seeds of H. mucronatum germinated above 300 mmol/L NaCl, while seeds of the other grasses germinated in up to 500 mmol/L NaCl. Optimal temperature regime for germination for all species was 20 degrees : 30 degrees C both for light- and dark-germinated seeds. At higher temperatures differences between light and dark treatments were not significant. Absence of light had no effect on the seed germination of U. setulosa and H. mucronatum; however, germination was lower in all salinity treatments. In the case of A. lagopoides, absence of light substantially inhibited the germination both in control and saline conditions. The light effect was marked in the case of S. ioclados, which showed very low germination in the absence of light both under saline and nonsaline conditions. PMID- 21659089 TI - A phylogenetic view of low-level CAM in Pelargonium (Geraniaceae). AB - Crassulacean acid metabolism (CAM) is common in several plant families and is often associated with succulence. Few studies have examined the occurrence of CAM from a phylogenetic perspective. The genus Pelargonium is promising for such a study because members are characterized by dramatic variation in growth form (including geophytes, shrubs, and stem succulents) and because growth form diversity is expressed to the greatest extent in a monophyletic group comprising 80% of Pelargonium species. This clade, predominantly from the winter rainfall region of southern Africa, likely proliferated in response to Miocene or Pliocene aridification. We present a survey for CAM across Pelargonium, emphasizing the winter rainfall clade. Dawn/dusk fluctuations in titratable acidity were examined in 41 species, with detailed measurements of carbon uptake and stomatal conductance under progressive water stress in four species. No species exhibited obligate CAM. When well-watered, most species exhibited stomatal conductances and acid fluctuations characteristic of C(3) photosynthesis, though some exhibited more pronounced increases in nocturnal acidity, suggesting CAM cycling. In four species examined during dry-down, water stress led to increased nighttime acid levels and decreased daytime stomatal conductance. Ultimately, stomata closed and external carbon uptake ceased, consistent with CAM idling. These results are discussed from the perspective of the evolution of CAM flexibility. PMID- 21659091 TI - Bee pollination and fruit set of Coffea arabica and C. canephora (Rubiaceae). AB - Self-sterile Coffea canephora and self-fertile C. arabica are important cash crops in many tropical countries. We examined the relative importance of insect, wind, and spontaneous self-pollination and the degree of self-fertility of these two coffee species in 24 agroforestry coffee fields in Indonesia. In both species, open pollination and cross pollination by hand led to the highest fruit set. Wind pollination (including self-pollination) led to 16% lower fruit set than open pollination in C. canephora and to 12.3% lower fruit set in C. arabica. Self-pollinated flowers and unmanipulated controls achieved an extremely low fruit set of 10% or less in the self-sterile species, and of 60% and 48%, respectively in the self-fertile species. These results constitute experimental evidence that cross pollination by bees causes a significant increase in fruit set of not only the self-sterile, but also the self-fertile coffee species. The practical implication is that coffee yield may be improved by managing fields for increased flower visitation by bees. PMID- 21659090 TI - A critical test of the two prevailing theories of plant response to nutrient availability. AB - Whereas the "law of the minimum" (LM) states that plant growth is limited by a single resource at any one time, the "multiple limitation hypothesis" (MLH) proposes that optimum plant behavior results from balancing resource costs and benefits so that all resources limit plant growth simultaneously. We tested the hypothesis that neither the LM nor the MLH account for plant responses to all mineral nutrients. Fronds of the aquatic plant Lemna minor were grown in nutrient solutions with increasing levels of four nutrients: nitrogen, phosphorus, potassium, and magnesium. Neither LM or MLH adequately predicted plant responses to all of these nutrients: 23 of the 60 responses analyzed were classified as belonging to the LM; 20 cases were classified as undefined; and 17 cases as MLH. The type of response strongly depended on the specific pair of nutrients considered. The validity of the MLH model would depend on the accompanying resource limiting plant growth and on the severity of the stress. We propose that a "nutrient-specific" analysis, considering the biology of each mineral nutrient rather than grouping plant resources as a whole, is more appropriate than general models in understanding plant responses to nutrient availability. PMID- 21659092 TI - Auxin regulation of axial growth in bryophyte sporophytes: its potential significance for the evolution of early land plants. AB - To identify developmental mechanisms that might have been involved in the evolution of axial sporophytes in early land plants, we examined the effects of auxin-regulatory compounds in the sporophytes of the hornwort Phaeoceros personii, the liverwort Pellia epiphylla, and the moss Polytrichum ohioense, members of the three divisions of extant bryophytes. The altered growth of isolated young sporophytes exposed to applied auxin (indole-3-acetic acid) or an auxin antagonist (p-chlorophenoxyisobutyric acid) suggests that endogenous auxin acts to regulate the rates of axial growth in all bryophyte divisions. Auxin in young hornwort sporophytes moved at very low fluxes, was insensitive to an auxin transport inhibitor (N-[1-naphthyl]phthalamic acid), and exhibited a polarity ratio close to 1.0, implying that auxin moves by simple diffusion in these structures. Emerging liverwort sporophytes had somewhat higher auxin fluxes, which were sensitive to transport inhibitors but lacked any measurable polarity. Thus, auxin movement in liverwort sporophytes appears to result from a unique type of apolar facilitated diffusion. In young Polytrichum sporophytes, auxin movement was predominantly basipetal and occurred at high fluxes exceeding those measured in maize coleoptiles. In older Polytrichum sporophytes, acropetal auxin flux had increased beyond the level measured for basipetal flux. Insofar as acropetal and basipetal fluxes had different inhibitor sensitivities, these results suggested that moss sporophytes carry out bidirectional polar transport in different cellular pathways, which resembles the transport in certain angiosperm structures. Therefore, the three lineages of extant bryophytes appear to have evolved independent innovations for auxin regulation of axial growth, with similar mechanisms operating in moss sporophytes and vascular plants. PMID- 21659093 TI - Effects of salinity on growth and cation accumulation of Sporobolus virginicus (Poaceae). AB - Optimal growth of euhalophytes requires moderate concentrations of salt and, in dicotyledons, is associated with succulence and accumulation of Na(+) in plant tissues. However, reports of salt-stimulated growth in monocotyledons are rare. Relative growth rate (RGR), biomass accumulation, and water content were studied in Sporobolus virginicus (Poaceae), a C(4) chloridoid grass, grown hydroponically with different concentrations of NaCl. Cation concentrations were determined by atomic absorption spectrophotometry. Optimal growth occurred at 100-150 mmol/L NaCl and was not dependent on nitrogen levels or accompanied by accumulation of Na(+) in leaves. Biomass accumulation and RGR in plants grown at 450 mmol/L NaCl were greater than in plants grown at 5 mmol/L. The Na : K ratios were lower in leaves than in roots, indicating discrimination in Na(+) and K(+) transport. Secretion of Na(+) increased from 166.5 to 336.7 mmol . g(-1) dry biomass . d(-1) as the NaCl concentration of the nutrient solution increased from 125 mmol/L to 450 mmol/L. Water concentrations of leaves and shoots were significantly greater in plants grown at optimal levels of salinity than in plants grown at lower or higher salinities. These results demonstrate salt-stimulated growth in a monocotyledon. PMID- 21659094 TI - Dose-response relationships between pollination and fruiting refine pollinator comparisons for cranberry (Vaccinium macrocarpon [Ericaceae]). AB - Comparisons of pollinator efficacy using pollen received on stigmas can be refined by incorporating experimental dose-response relationships for pollen deposition and fruiting responses. A range of discrete pollen doses applied to cranberry stigmas resulted in decelerating curvilinear responses for fruiting, berry size, and seed set. Minimum thresholds and maximum asymptotes bounded reproductive responses to incremental stigmatic pollen loads. Four bee species were compared for their pollination efficacies on commercial cranberries, using counts of pollen received by stigmas during single bee visits to previously virgin flowers. Differences between these bee species were found to be exaggerated when raw pollen counts were used for comparison because foragers of some species often delivered pollen in excess of that needed to maximize fruit and seed production. Sixfold differences between species in mean pollen deposition translated into 1.5-2-fold differences in predicted cranberry fruit set and size. Implications for pollen tube competition and agricultural production are discussed. PMID- 21659095 TI - A phylogenetic hypothesis for the Aizoaceae (Caryophyllales) based on four plastid DNA regions. AB - The Aizoaceae is the largest family of leaf succulent plants, and most of its species are endemic to southern Africa. To evaluate subfamilial, generic, and tribal relationships, we produced two plastid DNA data sets for 91 species of Aizoaceae and four outgroups: rps16 intron and the trnL-F gene region (both the trnL intron and the trnL-F intergenic spacer). In addition, we generated two further plastid data sets for 56 taxa restricted to members of the Ruschioideae using the atpB-rbcL and the psbA-trnH intergenic spacers. In the combined tree of the rps16 intron and trnL-F gene region, three of the currently recognized subfamilies (Sesuvioideae, Mesembryanthemoideae, and Ruschioideae) are each strongly supported monophyletic groups. The subfamily Tetragonioideae is polyphyletic, with Tribulocarpus as sister to the Sesuvioideae and Tetragonia embedded in the Aizooideae. Our study showed that the group consisting of the Sesuvioideae, Aizooideae, and Tetragonioideae does not form a monophyletic entity. Therefore, it cannot be recognized as a separate family in order to accommodate the frequently used concept of the Mesembryanthemaceae or "Mesembryanthema," in which the subfamilies Mesembryanthemoideae and Ruschioideae are included. We also found that several genera within the Mesembryanthemoideae (Mesembryanthemum, Phyllobolus) are not monophyletic. Within the Ruschioideae, our study retrieved four major clades. However, even in the combined analysis of all four plastid gene regions, relationships within the largest of these four clades remain unresolved. The few nucleotide substitutions that exist among taxa of this clade point to a rapid and recent diversification within the arid winter rainfall area of southern Africa. We propose a revised classification for the Aizoaceae. PMID- 21659096 TI - Repeat intercontinental dispersal and Pleistocene speciation in disjunct Mediterranean and desert Senecio (Asteraceae). AB - To explore the biogeographic history of Mediterranean/arid plant disjunctions, Old and New World Senecio sect. Senecio were analyzed phylogenetically using nuclear ribosomal DNA sequences (ITS). A clade corresponding to sect. Senecio was strongly supported. Area optimization indicated this clade to be of southern African origin. The Mediterranean and southern African floras were not distinguishable as sources of the main New World lineage, estimated to have become established during the middle Pliocene. Another previously suspected recent dispersal to the New World from the Mediterranean was confirmed for the recently recognized disjunction in S. mohavensis. The loss of suitable land connections by the Miocene means that both New World lineages must represent long distance dispersal, providing the first evidence of repeat intercontinental dispersal in a Mediterranean group. In contrast, migration within Africa may have utilized an East African arid corridor. Recent dispersal to northern Africa is supported for S. flavus, which formed part of a distinct southern African lineage. Novel pappus modifications in both disjunct species may have enabled dispersal by birds. An estimated early Pliocene origin of sect. Senecio coincides with the appearance of summer-dry climate. However, diversification from 1.6 BP highlights the importance of Pleistocene climate fluctuations for speciation. PMID- 21659097 TI - Phylogenetic relationships within Colchicaceae. AB - Three plastid regions-the rps16 intron, the atpB-rbcL intergenic spacer, and the trnL-F region-in 73 taxa representing all the genera of Colchicaceae except Kuntheria were sequenced to investigate the intrafamilial relationships of the family. In total, the three gene regions, comprising 3830 characters, were analyzed both separately and in a combined matrix. The results did not support the division of the family into two subfamilies, but they did support a core clade of mainly African genera and a grade of Australian, North American, and Asian taxa. One of the four tribes, Iphigenieae, was grossly paraphyletic, and, unexpectedly, Colchicum was nested within Androcymbium. Further, taxa of Gloriosa and Littonia were intermixed. PMID- 21659098 TI - Phylogenetic relationships of the Aurantioideae inferred from chloroplast DNA sequence data. AB - The tribes and subtribes of Aurantioideae, an economically important subfamily of the Rutaceae, have a controversial taxonomic history because of the lack of a phylogenetic framework. The rps16 and trnL-trnF sequences of the chloroplast were analyzed phylogenetically to construct an evolutionary history and evaluate the most recent classification system of Swingle and Reece (The Citrus Industry, volume 1 [1967]). Taxa representing tribes Citreae and Clauseneae and five of the six subtribes were sampled. Conflicts in the positions of some taxa between the rps16 and trnL-trnF trees are poorly supported. In all analyses, the Aurantioideae are monophyletic. The strict consensus tree of the combined analysis indicates that the two tribes along with the subtribes sampled are not monophyletic. The combined topology is not congruent with the widely used classification of Aurantioideae by Swingle and Reece. The tribes and subtribes are in need of revision. PMID- 21659099 TI - Implications of ITS sequences and RAPD markers for the taxonomy and biogeography of the Oxytropis campestris and O. arctica (Fabaceae) complexes in Alaska. AB - Taxonomic consensus is lacking on the Oxytropis arctica and O. campestris species complexes, two polyploid complexes found in the interior and arctic areas of Alaska. One classification has emphasized flower size, whereas flower color is considered a key diagnostic character in another classification. Our analyses of internal transcribed spacer (ITS) sequences and random amplified polymorphic DNA (RAPD) markers provided no support for either classification system. The trees generated from ITS sequences and the phenogram derived from RAPD markers suggest that most recognized taxa in the two complexes are probably polyphyletic, including O. arctica var. barnebyana, which is listed as threatened in Alaska. The only consistent pattern detected by both types of molecular markers was a geographic split dividing the northeastern arctic populations from most other populations (48.60-55.03% in AMOVA analyses). This genetic subdivision probably reflects a Pleistocene barrier formed by the northern coastal ice shield. Our molecular data, in conjunction with the previously reported variation of ploidy levels in these groups, suggest a scenario of recent and multiple origins of polyploidy. It is possible that most Alaskan populations of these two complexes are best referred to as a single taxonomic species despite morphological differentiation within the complexes. PMID- 21659100 TI - Population- and family-level variation of brittlebush (Encelia farinosa, Asteraceae) pubescence: its relation to drought and implications for selection in variable environments. AB - Because leaf pubescence of the desert shrub Encelia farinosa increases in response to drought and influences photosynthesis and transpiration, we hypothesized that differences in water availability across the range of this species may result in genetic differentiation for pubescence and associated productivity traits. We examined maternal family variation of pubescence moderated light absorption (absorptance) in three populations of E. farinosa. Absorptance was always greatest for plants from the high-rainfall environment and lowest for those from the driest site, but the rate of absorptance change in response to drought was similar among all populations. Similar patterns were found when we compared families within populations-all genotypes had similar initial leaf absorptances, differentiated very early in seasonal growth, then had concordant changes in absorptance thereafter. However, family-level variance was greatest for plants from the driest site, a region with highly heterogeneous precipitation patterns, whereas low variance was found for plants from the wettest, least heterogeneous site. The concordance of leaf absorptance changes, within and among populations, may be due to integration with other drought related traits; however, the differences in absorptance values within and among populations suggest that variation of leaf pubescence results from selection associated with geographical and local patterns of water availability. PMID- 21659101 TI - Vegetative regeneration in invasive Reynoutria (Polygonaceae) taxa: the determinant of invasibility at the genotype level. AB - Vegetative regeneration of individual genotypes of Asian Reynoutria taxa, which are invasive in the Czech Republic, was studied in R. sachalinensis (five genotypes), R. japonica (a single genotype present in the country), and their hybrid R. *bohemica (nine genotypes). Identity of genotypes was confirmed by isozyme analysis. Ten rhizome segments of each genotype were planted in a randomized block design. After 30 d, the regeneration rate of each genotype was measured as the proportion of rhizomes that produced shoots. Emergence time and final mass of each shoot were recorded. The regeneration rate and final shoot mass were significantly affected by genotype in R. *bohemica but not in R. sachalinensis. In R. *bohemica, easily regenerating genotypes grew faster. Regeneration characteristics that crucially contribute to the fitness of these vegetatively spreading plants are closely related to each other. In genotypes with a low regeneration rate, early-emerging shoots produced more biomass, while in those with a high regeneration rate, shoot mass was independent of emergence time. Mean clone size recorded in the field was marginally significantly related to emergence time during regeneration; regeneration characteristics might thus affect the extent of R. *bohemica invasion at a regional scale. Hybrids genetically intermediate between the parents regenerated better than those closely related to parents. Novel hybrid invasive genotypes may be produced by rare sexual reproduction, fixed by clonal growth, and present a previously unknown threat to native vegetation. PMID- 21659102 TI - C3 shrub expansion in a C4 grassland: positive post-fire responses in resources and shoot growth. AB - Changes in land management and reductions in fire frequency have enabled woody species to increase in grasslands worldwide. Nevertheless, fire is rarely eliminated from grasslands, and for shrubs to survive, they must be able cope with fire and replace aboveground structures. Because new shoots may have more available solar radiation, greater root : shoot ratios, and thus more resources available belowground after fire compared to undisturbed shrub communities, we hypothesized that carbon, nutrient, and water relations may be enhanced in stems compared to those in an undisturbed grassland. However, this same post-fire resource pulse stimulates the grasses and may intensify competitive interactions between shrubs and grasses. To test these predictions, we measured seasonal patterns in net photosynthesis (A), predawn xylem pressure potentials (XPP), leaf nitrogen (N) content, and productivity of Cornus drummondii shoots from shrub patches (islands) of different sizes in mesic grasslands burned annually, burned infrequently, and protected from fire. Seasonal average A was 20% higher (P = 0.016) in burned than in unburned shrubs, regardless of island size. Shrubs in burned sites also produced shoots with higher leaf N than unburned shrubs, and N content was higher in leaves from small islands compared to large islands (P < 0.0001). Burning caused a decrease in late summer predawn XPP in small islands ( 3.1 MPa), whereas burned large islands did not differ from unburned shrubs. Post fire productivity of new shoots was significantly greater compared to shoots in unburned sites. These results indicate that a transient period of high resource availability after fire allows for increased growth and rapid recovery of grassland shrubs. Thus, although fire has a negative effect on aboveground biomass of shrubs, the post-fire increases in resource availability, which enhance growth in the dominant grasses, are also important for recovery of woody species. PMID- 21659103 TI - Hydraulic architecture and the evolution of shoot allometry in contrasting climates. AB - We used pairs of congeneric shrub species from contrasting habitats to test for repeated evolutionary divergence in leaf-stem allometry and shoot hydraulic architecture in response to water availability. Allometric relationships and mean ratios between leaf size (individual and total area and mass per shoot) and stem cross-sectional area were compared between habitats using six species pairs representing three genera (Arctostaphylos, Baccharis, Ceanothus). We measured correlations among evolutionary changes in allometric, morphological, and physiological traits using phylogenetic independent contrasts. Allometric analysis revealed habitat differences: slopes were homogeneous among species (=1.46), but the more mesic-adapted species generally supported more leaf area at a common stem cross-sectional area. Reducing bivariate allometry to a ratio obscured this pattern because ratios varied with stem size, which was unrelated to habitat. Mean individual leaf size also was not correlated with either water availability or leaf-stem allometry. Stem hydraulic conductivity was generally lower in the xeric-adapted species of each pair, and its evolution mirrored changes in shoot allometry. This study provides evidence for repeated evolutionary divergence in shoot allometry and hydraulic architecture associated with water availability and demonstrates the importance of shoot allometry to water relations, independent of leaf size. PMID- 21659104 TI - Characterization and adaptive evolution of {alpha}-tubulin genes in the Miscanthus sinensis complex (Poaceae). AB - To investigate the organization of and mode of selection in the alpha-tubulin genes, full-length alpha-tubulin genes were cloned from four intraspecific taxa of Miscanthus sinensis and its close relatives M. floridulus and M. condensatus using standard polymerase chain reaction (PCR) and rapid amplification of genomic ends (RAGE)-PCR strategies. Genealogical analysis of angiosperms recovered a monophyletic group of Miscanthus alpha-tubulin genes, which is homologous to the tua5 locus of maize. Two clusters of nearly equal frequency revealed paraphyly within each Miscanthus taxon. Between-cluster recombination was frequent. Additional evidence for co-occurrence of two haplotypes within individuals and a large-scale crossover all suggested a likely allelic relationship between the Miscanthus clusters. Given a long between-species divergence time in Miscanthus, wide occurrence of the trans-species polymorphisms in alpha-tubulin genes and the approximately equal frequency of each allelic type make it extremely unlikely that alpha-tubulin diversity has been maintained under neutrality. Balancing selection may have contributed to such an apportioning of genetic variability as well as to high levels of genetic variation in alpha-tubulin and higher substitution rates at synonymous sites of exons than at intron bases of M. sinensis. In addition, certain effects of demographic oscillation may have distorted the scenario of a functional locus operating under balancing selection. PMID- 21659105 TI - Herbarium studies on the distribution of anther-smut fungus (Microbotryum violaceum) and Silene species (Caryophyllaceae) in the eastern United States. AB - We used herbarium specimens of Silene virginica, S. caroliniana, S. rotundifolia, and S. latifolia to survey the incidence of anther-smut disease (caused by Microbotryum violaceum sensu lato) in the eastern USA. We found no evidence of a collector bias against diseased specimens. Diseased specimens were frequently found in collections of S. virginica and S. caroliniana, but not in those of S. rotundifolia or S. latifolia. Disease incidence in S. virginica and S. caroliniana increased significantly over the past century and was higher in marginal populations. The absence of disease in specimens of S. rotundifolia is consistent with field observations, but its presence in natural populations of S. latifolia (especially in Virginia) suggests that the disease is recently introduced. Changes in the host distributions were also evident. The relative abundance of S. caroliniana declined over time (especially further north), while the relative abundance of S. virginica increased. Silene latifolia was absent or rare south of Pennsylvania before ca. 1920, indicating that S. latifolia and its anther smut are likely to be recent introductions in Virginia. Methods are also presented that quantify the completeness of coverage provided by herbarium specimens. PMID- 21659106 TI - A new species of Thuja (Cupressaceae) from the Late Cretaceous of Alaska: implications of being evergreen in a polar environment. AB - A branch bearing a number of seed cones of Thuja L. (Cupressaceae) has been recovered from a Late Cretaceous (Turonian) deposit from the North Slope of Alaska. This reproductive material is the oldest known for the genus and is indistinguishable from the seed cones of most of the extant species of Thuja, indicating that the seed cones of this Alaskan fossil Thuja had attained a modern morphological appearance early in the evolutionary history of the genus. From a physiological standpoint, the ability of modern species of Thuja to tolerate cold to freezing conditions and the ability of fossil representatives of the genus to survive periods of extended darkness during the polar winters supports the contention that the polar winters during the Late Mesozoic and early Cenozoic were cold. PMID- 21659107 TI - Species separation of Taxus baccata, T. canadensis, and T. cuspidata (Taxaceae) and origins of their reputed hybrids inferred from RAPD and cpDNA data. AB - Species delimitation in Taxus (Taxaceae) has been controversial due to high levels of phenotypic plasticity. Reputed hybrids between species have been questioned due to the original crosses' accidental nature and the uncertainty regarding the parent species' distinctness. In this study 19 samples from three species (T. baccata, T. canadensis, T. cuspidata) and 31 from putative hybrids (T. * hunnewelliana, T. * media) have been DNA-fingerprinted using RAPDs and characterized for their respective chloroplast genotype using restriction digestions of polymerase chain reaction- (PCR) amplified trnL-F fragments. All samples showed unique RAPD banding profiles. Twenty-one RAPD bands were species specific; the presence of these bands in the putative hybrids confirmed the hybrid origin and parentage suspected from morphological studies (T. cuspidata * T. canadensis = T. * hunnewelliana, T. baccata * T. cuspidata = T. * media). Principal coordinates analysis (PCO) and unweighted pair-group method algorithm (UPGMA) analyses of RAPD bands clearly separated the species, indicating that they belong to discrete genetic stocks and supporting their individual species status. The two hybrid groups also clustered discretely. Chloroplast typing confirmed the direction of crosses. The data further suggested that repeated reciprocal crossings occurred in the production of the hybrid cultivars. PMID- 21659108 TI - The development of enantiostyly. AB - Enantiostyly, the deflection of the style either to the left (left-styled) or right (right-styled) side of the floral axis, has evolved in at least ten angiosperm families. Two types of enantiostyly occur: monomorphic enantiostyly, in which individuals exhibit both stylar orientations, and dimorphic enantiostyly, in which the two stylar orientations occur on separate plants. To evaluate architectural or developmental constraints on the evolution of both forms of enantiostyly, we examined inflorescence structure and floral development among unrelated enantiostylous species. We investigated relations between the position of left- and right-styled flowers and inflorescence architecture in four monomorphic enantiostylous species, and we examined the development of enantiostyly in nine monomorphic and dimorphic enantiostylous species from five unrelated lineages. The location of left- and right-styled flowers within inflorescences ranged from highly predictable (in Solanum rostratum) to random (in Heteranthera mexicana). There were striking differences among taxa in the timing of stylar bending. In Wachendorfia paniculata, Dilatris corymbosa, and Philydrum lanuginosum, the style deflected in the bud, whereas in Heteranthera spp., Monochoria australasica, Cyanella lutea, and Solanum rostratum, stylar bending occurred at the beginning of anthesis. Comparisons of organ initiation and development indicated that asymmetries along the left-right axis were expressed very late in development, despite the early initiation of a dorsiventral asymmetry. We suggest that the evolution of dimorphic enantiostyly from monomorphic enantiostyly may be constrained by a lack of left-right positional information in the bud. PMID- 21659109 TI - Shoot morphogenesis associated with flowering in Populus deltoides (Salicaceae). AB - Temporal and spatial formation and differentiation of axillary buds in developing shoots of mature eastern cottonwood (Populus deltoides) were investigated. Shoots sequentially initiate early vegetative, floral, and late vegetative buds. Associated with these buds is the formation of three distinct leaf types. In May of the first growing season, the first type begins forming in terminal buds and overwinters as relatively developed foliar structures. These leaves bear early vegetative buds in their axils. The second type forms late in the first growing season in terminal buds. These leaves form floral buds in their axils the second growing season. The floral bud meristems initiate scale leaves in April and begin forming floral meristems in the axils of the bracts in May. The floral meristems subsequently form floral organs by the end of the second growing season. The floral buds overwinter with floral organs, and anthesis occurs in the third growing season. The third type of leaf forms and develops entirely outside the terminal buds in the second growing season. These leaves bear the late vegetative buds in their axils. On the basis of these and other supporting data, we hypothesize a 3-yr flowering cycle as opposed to the traditional 2-yr cycle in eastern cottonwood. PMID- 21659110 TI - Heterozygote advantage in the American chestnut, Castanea dentata (Fagaceae). AB - The American chestnut (Castanea dentata; Fagaceae) was a dominant canopy tree in the Appalachian Mountains of North America. Since the introduction of the chestnut blight fungus (Cryphonectria parasitica; Valsaceae) in America, the American chestnut has been reduced to a predominantly clonal, understory species. Our objective was to determine whether the ecological changes and absence of new recruits have influenced the population genetics of American chestnut. Leaf samples were collected from four populations in southwestern Virginia. Electrophoretic data from five polymorphic loci were used to determine the genetic diversity and population structure of the populations and subpopulations. Growth data and infection status were recorded for one of the populations to determine their relationship with heterozygosity. F statistics revealed a significant amount of differentiation among subpopulations and an excess of heterozygotes within subpopulations. Heterozygous individuals also had higher rates of vegetative growth. The superior performance and excess of heterozygotes suggests that selection favors heterozygous individuals. The prolonged absence of sexual reproduction in C. dentata has allowed subtle fitness differences to accumulate to the extent that they have had significant effects on the genetics of chestnut populations. PMID- 21659111 TI - Variation in pollinator effectiveness in swamp milkweed, Asclepias incarnata (Apocynaceae). AB - The contribution of a pollinator toward plant fitness (i.e., its "effectiveness") can determine its importance for the plant's evolutionary ecology. We compared pollinators in a population of Asclepias incarnata (Apocynaceae) for several components of pollinator effectiveness over two flowering seasons to evaluate their importance to plant reproduction. Insects of the order Hymenoptera predominate in A. incarnata pollination, but there appears to be no specialization for pollination within this order. Pollinators varied significantly in nearly every component of effectiveness that we measured, including pollen load, removal and deposition of pollen, pollination efficiency (deposition/removal), flower-handling time, and potential for geitonogamy (fractional pollen deposition). The visitation rate of pollinators also varied significantly between years and through time within years. Pollination success and percentage fruit-set of unmanipulated plants in the population also varied significantly between years, and pollination success varied among sample times within years. Most components of effectiveness were weakly correlated, suggesting that the contributions of visitor species toward pollination varied among effectiveness components. Mean flower-handling time, however, was strongly correlated with several components, including pollen removal and deposition, pollination efficiency, and fractional pollen deposition. These findings highlight the significance of pollination variability for plant reproduction and suggest that time-dependent foraging behaviors may play an important role in determining pollinator effectiveness. PMID- 21659112 TI - Female frequency and relative fitness of females and hermaphrodites in gynodioecious Geranium sylvaticum (Geraniaceae). AB - We determined female frequency of 23 populations of the gynodioecious Geranium sylvaticum (Geraniaceae) in Finland. We compared our results to previous results on this species from the 1960s in order to reveal putative changes in female frequencies. Because females may be maintained in gynodioecious populations if their seed production or offspring quality is higher than that of hermaphrodites, we explored reproductive success of females and hermaphrodites in detail in 11 populations for two consecutive years. Female frequencies varied from 0.4 to 27.2%; this variation is similar to that observed in the 1960s. Contrary to previous results that indicated lower seed production in females, females produced 1.2 and 1.7 times more seeds per flower than hermaphrodites in 2000 and 2001, respectively. Females also had higher fruit set than hermaphrodites. Thus, higher seed production of females partly explains the maintenance of gynodioecy in this species. Furthermore, female frequency correlated negatively with relative seed fitness of hermaphrodites suggesting that relative seed fitness is related to population sex ratio. Female frequency and the distance of the population from the most southern population also tended to correlate positively, suggesting that harsher environmental conditions in the north may benefit female plants. Given the observed yearly variation, our results also highlight the importance of temporal variation for the relative seed fitness of females and hermaphrodites. PMID- 21659113 TI - The cost of inbreeding in Platanthera leucophaea (Orchidaceae). AB - Fragmentation and isolation are expected to have a considerable impact on viability and recruitment in populations of rare species. Platanthera leucophaea (Orchidaceae), a rare orchid, currently exists in a fragmented landscape of its natural habitat. Floral morphology suggests this species is predominantly outcrossing, but surveys of allozyme diversity suggest high, variable levels of inbreeding in populations (F(IS) = -0.078 to 1.0). This study examines the potential cost of inbreeding and the extent to which inbreeding depression can vary temporally and in populations of different size and genetic structure. Flowers were pollinated by hand in one large population and one small population over three seasons. Seed set, seed mass, and seed viability were compared among self-, outcross-, and open-pollinated fruits. Seed set was greater than 50% in both populations for all years of study. High levels of inbreeding depression were detected in seed viability but not in seed mass in both populations. However, the magnitude of inbreeding depression differed over years and between populations, a pattern that reflects differing environmental conditions and variable evolutionary and demographic histories. Consequently, conservation of this species will be most successful if outcrossing is promoted in populations by maximizing population size and genetic variability. PMID- 21659114 TI - Effects of simulated herbivory and resources on Chinese tallow tree (Sapium sebiferum, Euphorbiaceae) invasion of native coastal prairie. AB - Trade-offs associated with maintaining herbivory resistance and herbivory tolerance are frequently inferred in plant life histories. Invasive success for many non-native plants is often attributed to novel resistance that repels native herbivores. Chinese tallow tree (Sapium sebiferum, Euphorbiaceae) is a non-native invader that threatens ecosystems throughout the southeastern United States, including imperiled coastal prairie regions. Low herbivore loads due to costly resistance are generally assumed to give Sapium a competitive advantage over native plants. We predicted that if Sapium experienced higher damage levels it would show significant decreases in growth and reduced ability to compete with native prairie vegetation. We conducted full-factorial, paired greenhouse and field experiments designed to assess the effects of simulated leaf herbivory on Sapium growth in the presence of prairie vegetation at different levels of light and nitrogen. Contrary to our expectations, neither low-intensity, chronic defoliation nor high-intensity, acute defoliation negatively affected Sapium seedlings in any resource combination in either experiment. These studies reveal that Sapium possesses considerable phenotypic plasticity, and herbivory tolerance is a newly appreciated trait that likely contributes to its invasive potential. PMID- 21659115 TI - Reexamination of a canonical model for plant organ biomass partitioning. AB - A previously proposed "canonical" model for the scaling relations among leaf, stem, and root biomass (M(L), M(S), and M(R), respectively) asserts that the proportional relations M(L) ? M(S)(3/4) ? M(R)(3/4) and M(S) ? M(R) hold across seed plant species. This model is scrutinized by determining whether the scaling relations between M(L), M(S), and M(R) vs. basal stem diameter D(S) and between M(L), M(S), and M(R) vs. plant height h are logically consistent with previously predicted scaling exponents. For example, if M(L) is observed to scale as the 2 power of D(S) and the model asserts that M(L) ? M(S)(3/4), then M(S) must scale as the 8/3-power of D(S) if the model is valid. Using a large data base for species with self-supporting stems, statistical support was found for most such comparisons between predicted and observed scaling relationships. However, this judgement is predicated on (1) the assertion that the scaling exponents for M(R) with respect to D(S) (or h) are numerically "deflated" due to a systematic underestimate of fine and small root biomass and (2) the stringent protocol used to calculate the 95% confidence intervals of scaling exponents, which favors rejection of the model. In light of these features, the "canonical" model is logically consistent with the new scaling relations reported here. Therefore, the model is judged valid within the context of this evaluation. PMID- 21659116 TI - Effects of tree crown structure on biomass of the epiphytic fern Polypodium scouleri (Polypodiaceae) in redwood forests. AB - Redwood forests contain some of the largest and most structurally complex trees on Earth. The most abundant vascular epiphyte in these forests is the fern Polypodium scouleri (Polypodiaceae). We measured dimensions of all 765 P. scouleri mats on 32 trees (27 Sequoia sempervirens, 5 Picea sitchensis). Eighteen P. scouleri mats from 11 trees were randomly selected for removal and dissection in the laboratory. The total fern mat mass consisted of live fronds (3.3%), dead fronds (2.4%), live rhizomes (4.2%), dead rhizomes (8.9%), roots (34.4%), humus (28.0%), and debris (18.8%). We used multiple regression analysis to develop equations for estimation of fern masses, and we applied these equations to undisturbed fern mats on the 32 trees. Individual trees supported up to 742 kg dry mass of P. scouleri mats. These are the highest whole-tree epiphyte masses ever reported. We also quantified crown structure and counted the number of vascular plant species occurring as epiphytes on each tree. Very large, complex trees had more fern mat mass and higher vascular epiphyte species richness than smaller, simpler trees. Desiccation-sensitive organisms dependent on water stored in fern mats may be unable to survive in managed redwood forests lacking large, complex trees with abundant P. scouleri. PMID- 21659117 TI - Hummingbirds as vectors of fungal spores in Moussonia deppeana (Gesneriaceae): taking advantage of a mutualism? AB - Hummingbirds act as vectors of Fusarium moniliforme spores on protandrous flowers of Moussonia deppeana. The resulting interactions between the pathogen and plant pollinator interactions were investigated in a 4-yr study to determine the pathogen's impact on host flowering phenology, flower longevity, nectar production, and fruit and seed production. We also evaluated hummingbird behavior on healthy and diseased plants and its effectiveness on spore transmission. Individual plants expressed the disease from year to year, and new infected individuals were detected every year. A fraction of the flowers in a plant expressed the disease, and this varied among and within years. Diseased plants produced more inflorescences, buds, and open healthy flowers than did healthy plants. Further, diseased plants bore proportionally fewer pistillate flowers than did healthy plants when considering only healthy flowers. Neither nectar nor fruit production differed between healthy and diseased plants, but healthy plants produced more seeds. Infected flowers were retained longer than uninfected ones, producing an additional 2 mg . MUL(-1) . flower(-1) of nectar sugar. Hummingbirds visited more flowers on diseased plants than they did on healthy plants, regardless of number and sexual phase. Most pollen and spores were deposited within plants. These behavioral outcomes may promote geitonogamy and limit fungal spore mixing. PMID- 21659118 TI - Prevalence and predictability of handling effects in field studies: results from field experiments and a meta-analysis. AB - Various effects on plant growth associated with handling or touching plants are well documented from greenhouse and laboratory studies, but are generally unknown or ignored under field conditions. We examined the prevalence of the effects of handling, at levels typical of many ecological experiments, on aboveground biomass and damage by invertebrate herbivores for a total of 16 common species from three plant communities in western Canada. Significant effects of handling were observed in the alpine meadow and grassland, but not in the boreal forest. Handling reduced aboveground biomass and increased the mean intensity of invertebrate leaf damage for most species. A meta-analysis of the relationship between plant traits and response to handling indicated that woody plants and species without strong chemical or conspicuous morphological defenses were most strongly affected. Overall, our results indicate that potentially confounding effects of routinely sampling plants in the field are widespread and merit further investigation. PMID- 21659119 TI - A mixed strategy in the annual endemic Aster laurentianus (Asteraceae)--a stress tolerant, yet opportunistic species. AB - Several environmental factors influence the distribution of plants in coastal salt marshes. Substrate salinity is among the major factors preventing several species from establishing near the water line. However, interspecific competition for light and nutrients is often significant in determining the upper limit of plants along the salt marsh gradient. In this study, we tested the effects of substrate salinity and light and nutrient availability on the performance of the annual Aster laurentianus (Asteraceae), an endangered species of eastern Canadian salt marshes. This species is typically found in a narrow band along the shores of shallow lagoons, cornered between the high water line and the dense, herbaceous community of the upper marsh. Low light availability was the most significant factor limiting plant performance. Salinity had little effect on A. laurentianus as, unexpectedly, did nutrient availability. Yet plants were able to absorb nutrients when these were made more available. Luxury consumption, the uptake of excess nutrients, may make sense for this annual plant because the habitat in which it grows is subject to frequent disturbances (e.g., sand accretion and salinity pulses) that may kill canopy species and release suppressed A. laurentianus individuals. These results suggest that interspecific competition for light may play a significant role in restraining A. laurentianus from the upper part of salt marshes. Luxury consumption may help the species to opportunistically take advantage of release from taller species, particularly towards the upper edge of the salt marsh gradient. PMID- 21659120 TI - Reassessment of phylogenetic relationships in Clarkia sect. Sympherica. AB - Clarkia (Onagraceae) is a genus of 42 annual species, mostly native to California, that has served as a model for many studies of plant evolutionary biology, particularly morphological, cytological, and genetic divergence; reproductive isolation; and speciation. Section Sympherica is the largest section with eight diploid and one allotetraploid species. Species in the section have provided important evidence about the evolution of reproductive isolation (C. lingulata derived from C. biloba) and large morphological change (C. dudleyana thought to be sister to the morphologically distinct C. heterandra, recently transferred into Clarkia from the monotypic Heterogaura). Clarkia epilobioides, another diploid species in the section, was previously shown to be one parent of the allotetraploid C. delicata, the other parent being C. unguiculata from sect. Phaeostoma. Lewis and Lewis (1955) interpreted the parentage of C. delicata and other evidence of intersectional hybridization to mean that the diploid sections of the genus, though highly diverse, were closely related and should be maintained in the single genus Clarkia. Here we assess phylogenetic relationships among the species of sect. Sympherica and related species by analyzing the nucleotide sequences of PgiC1 and PgiC2, a pair of paralogous genes that encode the cytosolic isozyme of phosphoglucose isomerase (EC 5.3.1.9). The major results were the following: (1) C. unguiculata and both genomes of C. delicata are within a well-defined "Sympherica" clade; thus, C. delicata should not be considered an intersectional hybrid; (2) C. heterandra belongs in the clade and is closely related to C. unguiculata; and (3) on the evidence of PgiC1, C. dudleyana is not in the clade and is not closely related to C. heterandra. PMID- 21659121 TI - Molecular phylogeny and floral evolution of Penaeaceae, Oliniaceae, Rhynchocalycaceae, and Alzateaceae (Myrtales). AB - We derive detailed relationships among and within the African Penaeaceae, Oliniaceae, Rhynchocalycaceae, and Central and South American Alzateaceae based on six chloroplast data sets that include sequences of all genera and most species. This is the first study addressing intrafamilial relationships of Penaeaceae and Oliniaceae based on molecular data. All analyses conducted on the six separate and combined data sets produce similar tree topologies without any major conflicts. The resulting phylogenies suggest that the monospecific New World Alzateaceae is sister to the three African taxa and that the monospecific Rhynchocalycaceae is sister to Oliniaceae/Penaeaceae. Within Penaeaceae, our results partially contradict traditional generic circumscriptions, suggesting, for example, that Brachysiphon and Stylapterus are paraphyletic. Within the monogeneric Oliniaceae the analyses reveal two well-supported clades. We also performed comparative studies of floral development and morphology of Penaeaceae, Oliniaceae, and Rhynchocalycaceae. We analyze the results of these comparativel studies in the context of the molecular phylogeny to test competing hypotheses of perianth organ homology in Penaeaceae and Oliniaceae. Our analyses show that flowers of both families are most parsimoniously interpreted as having an obhaplostemonous organization. The respective homology of calyx and corolla among the three families is further supported by congruent patterns of floral development and structural similarities including anatomical and histological features. PMID- 21659122 TI - Phylogenetic relationships in Gleditsia (Leguminosae) based on ITS sequences. AB - We used nucleotide sequences from the internal transcribed spacers and 5.8S gene of nuclear ribosomal DNA to test competing phylogenetic and biogeographic hypotheses in Gleditsia. Eleven of 13 Gleditsia species were sampled, along with two species of its sister genus, Gymnocladus. Analyses of ITS data and of a combined data set that included sequences of ITS and two chloroplast genes supported several conclusions that were interpreted in light of fossil data and current legume phylogeny. Gleditsia and Gymnocladus appear to have originated in eastern Asia during the Eocene. Eastern North American species of both genera most likely evolved from ancestors that migrated across the Bering land bridge, but the eastern Asian/eastern North American disjunction appears to be much older in Gymnocladus than in Gleditsia. Gleditsia amorphoides, from temperate South America, is sister to the rest of the genus, suggesting early long-distance dispersal from Asia. The remainder of Gleditsia is divided into three unresolved clades, possibly indicating a split early in the evolution of the genus. Two of those clades contain only Asian species, and one contains Asian and North American species. The North American species, Gleditsia triacanthos and Gleditsia aquatica, are polymorphic and paraphyletic with respect to their ITS and cpDNA sequences, which suggests recent diversification. PMID- 21659123 TI - Phylogenetic position and generic differentiation of Epithemateae (Gesneriaceae) inferred from plastid DNA sequence data. AB - The systematic position and generic differentiation of the morphologically and geographically outstanding tribe Epithemateae (Gesneriaceae) was analyzed using the rbcL/atpB-spacer and trnL-F intron-spacer regions of chloroplast DNA. In our analysis Epithemateae forms a strongly supported monophyletic clade (bootstrap [BS] = 100%; jackknife [JK] = 100%; decay index [DI] = 12) and appears as sister to the rest of the paleotropical Gesneriaceae (= subfamily Cyrtandroideae). The paleotropical Gesneriaceae form a monophyletic group (BS = 88%; JK = 85%; DI = 3) that is sister to the neotropical Gesneriaceae (subfamily Gesnerioideae) plus Austral Gesneriaceae (subfamily Coronantheroideae) (BS = 99%; JK = 98%; DI = 10). Within Epithemateae Rhynchoglossum is sister to the remaining Epithemateae (BS = 97%; JK = 96%; DI = 12), in which Epithema is sister to a clade of two genera: Loxonia/Stauranthera (BS = 68%; JK = 64%; DI = 1), which form, together with Epithema, a sister clade (BS = 85%; JK = 83%; DI = 2) to Whytockia and Monophyllaea. While the support for Loxonia and Stauranthera is moderate, the relationship of Whytockia and Monophyllaea is very strongly supported (BS = 100%; JK = 100%; DI = 13). Apart from the somewhat surprising (but well-substantiated) isolated position of Rhynchoglossum, the results are in perfect accordance with the relationships worked out earlier on grounds of architectural and floral characters. Especially remarkable is the predicted coherence between the morphologically and geographically different genera Whytockia and Monophyllaea. PMID- 21659124 TI - A generic geometric transformation that unifies a wide range of natural and abstract shapes. AB - To study forms in plants and other living organisms, several mathematical tools are available, most of which are general tools that do not take into account valuable biological information. In this report I present a new geometrical approach for modeling and understanding various abstract, natural, and man-made shapes. Starting from the concept of the circle, I show that a large variety of shapes can be described by a single and simple geometrical equation, the Superformula. Modification of the parameters permits the generation of various natural polygons. For example, applying the equation to logarithmic or trigonometric functions modifies the metrics of these functions and all associated graphs. As a unifying framework, all these shapes are proven to be circles in their internal metrics, and the Superformula provides the precise mathematical relation between Euclidean measurements and the internal non Euclidean metrics of shapes. Looking beyond Euclidean circles and Pythagorean measures reveals a novel and powerful way to study natural forms and phenomena. PMID- 21659125 TI - Intraspecific cpDNA variations of diploid and tetraploid perennial buckwheat, Fagopyrum cymosum (Polygonaceae). AB - We investigated the phylogenetic and biogeographic relationships of natural populations of diploid and tetraploid Fagopyrum cymosum (Polygonaceae). Intraspecific variation of chloroplast DNA sequences was detected in three regions approximately 5 kb long in total: the 3' end of rbcL, accD and associated intergenic spacer region, the trnC (GCA)-rpoB spacer region, the trnK (UUU) intron, and the matK region. The accessions of F. cymosum were divided into two major groups, a Tibet-Himalayan clade and a Yunnan-Sichuan clade, with a high bootstrap probability. It was estimated that these two clades diverged about 0.7 million years ago. The geographical and climatic interruption by the Hengduanshan mountains might have caused the genetic divergence in F. cymosum. Autotetraploid populations of F. cymosum have arisen allopatrically from a diploid progenitor at least twice, once in the Tibet-Himalayan area and once in the Yunnan-Sichuan area. This conclusion reinforces a previous study based on allozyme variation. We also found that F. tataricum, a close relative of F. cymosum, was completely included within the Tibet-Himalayan clade in the phylogenetic tree. This suggests that F. tataricum speciated from F. cymosum in the Tibet-Himalayan area. PMID- 21659126 TI - Sexes show contrasting patterns of leaf and crown carbon gain in a dioecious rainforest shrub. AB - The sexes of dioecious species may differ in a range of vegetative and reproductive traits as well as in physiological traits. In Siparuna grandiflora, a Neotropical dioecious shrub, we examined differences in leaf-level photosynthesis of different classes of leaf age and, using simulation models, explored whether differences in leaf-level carbon gain led to sex differences in whole-plant daily carbon gain. Male plants had higher photosynthetic capacity at the leaf level. As leaves of both sexes aged their photosynthetic capacity and specific leaf area declined as expected. Simulations of daily carbon gain using the architecturally explicit model Y-Plant and a non-architectural model incorporating a wide range of realistic light environments revealed that the difference in leaf-level photosynthetic capacity did not translate into greater crown-level carbon gain for males. Rather, differences in patterns of allocation to leaf area allow females to achieve higher crown-level carbon gain. The results demonstrate that sex differences at the leaf level do not necessarily predict patterns at the whole-plant level. PMID- 21659127 TI - On the economy and safety of hollow non-septate peduncles. AB - We examined the allometry and mechanical properties of the peduncles of Hieracium pilosella and other species in the Asteraceae (H. aurantiacum, Taraxicum officinale, Tragopogon pratensi) to evaluate the hypothesis that tapered, tubular, and non-septate peduncles optimize the trade-offs among stem biomass allocation, elevating flowers and thus their wind-dispersed fruits, and the requirement for a factor of safety against mechanical failure. This hypothesis was evaluated by comparing peduncle morphometry (e.g., biomass M(s), floral biomass M(f), and length L) and mechanical properties (e.g., bending rigidity EI) for populations growing in windy and wind-sheltered sites as well as transplants between sites. Regardless of ambient wind speeds, M(s) ? L(4/3) and EI ? L(11/4) ? M(s)(5/3), whereas M(f) /M(s) ? L(-1.15), i.e., peduncles disproportionately increase in their biomass as they increase in length, but mechanically support a disproportionately smaller floral biomass relative to their biomass. Calculations show that the tall peduncles from wind-sheltered sites have a larger fruit dispersal range and a lower factor of safety than the shorter peduncles produced in open sites. These and other observations are interpreted to indicate that tubular peduncles enhance relative fitness in terms of propagule dispersal (but not propagule number per stem) while maintaining a sufficient factor of safety against mechanical failure. PMID- 21659128 TI - Random amplified polymorphic DNA assessment of diversity in western Mediterranean populations of the seagrass Posidonia oceanica. AB - Posidonia oceanica is an endemic Mediterranean seagrass species that has often been assumed to contain low levels of genetic diversity. Random amplified polymorfic DNA (RAPD) markers were used to assess genetic diversity among five populations from three geographical regions (north, central, and south) of the western Mediterranean Sea. Stranded germinating seeds from one of the central populations were also included in the analysis. Forty-one putative genets were identified among 76 ramets based on 28 RAPD markers. Genotypic diversity strongly depended on the spatial structure, age, and maturity of the meadows. The lowest clonal diversity was found in the less structured and youngest prairies. Conversely, a high genotypic diversity was found in the highly structured meadows. The genotypic diversity in these meadows was at the same level as in P. australis and higher than previously reported data for P. oceanica populations in the Tyrrhenian Sea near the coast of Italy. PMID- 21659129 TI - Floral scents affect reproductive success in fly-pollinated Alocasia odora (Araceae). AB - We evaluated the role of floral scents in the reproductive success of Alocasia odora C. Koch (Araceae). Alocasia odora is pollinated by its specific pollinators, Colocasiomyia alocasiae (Okada) and C. xenalocasiae (Okada) (Diptera: Drosophilidae). These flies use the spadix of A. odora as breeding sites. The appendix, which is at an upper part of the spadix and is the most attractive region, attracted these pollinators by emitting volatiles, although the male zone of the inflorescence was also attractive. The number of flies attracted was positively correlated with appendix size. During the pistillate phase of the protogynous spadix, attracted flies aggregated in the lower part (female zone) to mate, lay eggs, and perhaps obtain nutrients. The flies moved to the upper part (male zone) of the spadix by the tightening of the constriction separating the upper and lower parts, and then the staminate phase started. This movement of the flies on the spadix promotes outcrossing of A. odora. Removal of the appendix or the whole upper part of the spadix resulted in much reduced fruit set, suggesting that the absence of the scent-producing region leads to insufficient pollination because of reduced pollinator attraction. PMID- 21659130 TI - Geographic patterns in the reproductive ecology of Agave lechuguilla (Agavaceae) in the Chihuahuan desert. I. Floral characteristics, visitors, and fecundity. AB - Floral characteristics such as morphology and flower color have been interpreted as adaptive traits that evolved through selective pressures generated by pollinators. Differences among populations in the expression of floral characters could result from natural selection for their adaptive value to local conditions. We describe the patterns of variation of flower morphology, color, and fecundity of Agave lechuguilla in 11 populations along a latitudinal gradient encompassing the whole range of the species in the Chihuahuan desert. We found a latitudinal pattern in flower shape and color. Flowers tended to be shorter, more open, and colorful toward the northern part of the gradient. We also recorded flower visitation, discriminating between pollinators and floral robbers. The main pollinators seems to be nocturnal hawk moths (Hyles lineata) and diurnal large bees (Bombus pennsylvanicus and Xylocopa californica). In all populations large bees were the most abundant potential pollinators. However, the abundance of the potential pollinators varied along the gradient. We observed no bat visits along the gradient. The number of visits by all potential pollinators decreased significantly with latitude as did fruit set. PMID- 21659131 TI - Erratum. PMID- 21659132 TI - Cecropia as a food resource for bats in French Guiana and the significance of fruit structure in seed dispersal and longevity. AB - Cecropia (Cecropiaceae) is a Neotropical genus of pioneer plants. A review of bat/plant dispersal interactions revealed that 15 species of Cecropia are consumed by 32 species of bats. In French Guiana, bats were captured in primary and secondary forests, yielding 936 fecal samples with diaspores, among which 162 contained fruits of C. obtusa, C. palmata, and C. sciadophylla. A comparative morphological and anatomical study of fruits and seeds taken directly from herbarium specimens, bat feces, and an experimental soil seed bank was made. Contrary to previous reports, the dispersal unit of Cecropia is the fruit not the seed. Bats consume the infructescence, digest pulp derived from the enlarged, fleshy perianth, and defecate the fruits. The mucilaginous pericarp of Cecropia is described. The external mucilage production of Cecropia may facilitate endozoochory. The exocarp and part of the mesocarp may be lost after passage through the digestive tract of bats, but fruits buried for a year in the soil seed bank remain structurally unchanged. Fruit characters were found to be useful for identifying species of bat-dispersed Cecropia. Bat dispersal is not necessary for seed germination but it increases seed survival and subsequent germination. Fruit structure plays a significant role in seed longevity. PMID- 21659133 TI - Allometry and development in herbaceous plants: functional responses of meristem allocation to light and nutrient availability. AB - We examined the relationship between meristem allocation and plant size for four annual plant species: Arabidopsis thaliana, Arenaria serphyllifolia, Brassica rapa, and Chaenorrhinum minus. Gradients of light and nutrient availability were used to obtain a range of plant sizes for each of these species. Relative allocation to reproductive, inactive, and growth meristems were used to measure reproductive effort, apical dominance, and branching intensity, respectively. We measured allocation to each of these three meristem fates at weekly intervals throughout development and at final developmental stage. At all developmental stages reproductive effort and branching intensity tended to increase with increasing plant size (i.e., due to increasing resource availability) and apical dominance tended to decrease with increasing plant size. We interpret these responses as a strategy for plants to maximize fitness across a range of environments. In addition, significant differences in meristem response among species may be important in defining the range of habitats in which a species can exist and may help explain patterns of species competition and coexistence in habitats with variable resource availability. PMID- 21659134 TI - Seedling competition between native Populus deltoides (Salicaceae) and exotic Tamarix ramosissima (Tamaricaceae) across water regimes and substrate types. AB - Populus deltoides subsp. wislizinii (Salicaceae), a cottonwood native to the Middle Rio Grande of New Mexico, must potentially compete against exotic Tamarix ramosissima (Tamaricaceae) during establishment after flooding. We investigated competitive interactions between seedlings of Tamarix and Populus in two substrates representing field textures and declining (i.e., draw-down) or stagnant water tables. The experiment was performed using a full-additive series design and interpreted with response surface models for each species. As reflected in both aboveground mass and height, Populus suppressed aboveground growth of Tamarix across all treatments, whereas competitive effects of Tamarix against Populus could only be seen at low Populus densities. Clay substrates with draw-down stimulated the greatest growth and created the most intense competitive environment for both species. Tamarix was competitively suppressed in every substrate tested, with the weakest response in sand with no draw-down, where growth of Populus was poorest. These results suggest that stream flow management that promotes Populus establishment could also aid in controlling Tamarix invasion across a range of substrates. PMID- 21659135 TI - Long-term patterns of shrub expansion in a C4-dominated grassland: fire frequency and the dynamics of shrub cover and abundance. AB - Worldwide, grassland ecosystems have experienced a major shift in growth-form dominance as woody plant species have expanded and replaced native grasses. In the C(4)-dominated grasslands of central North America, a reduction in fire frequency is the most cited cause of this shift in growth forms as fire both enhances grass productivity and constrains the establishment and expansion of native woody vegetation. Using an 18-yr plant species composition data set, we quantified patterns of change in shrub cover, frequency, and species richness associated with three distinct fire regimes. During the study period (1983-2000), shrub cover increased most dramatically in sites in which the frequency of fire was once every 4 yr (intermediate frequency; 28.6%) followed by sites in which fire occurred only once during the 18-yr period (low frequency; 23.7%). Annual fire effectively prevented the recruitment of new woody species, but even with this high fire frequency, shrub cover increased slightly (3.7%). Comparatively, shrub species richness increased by three and six, respectively, in the intermediate- and low-frequency fire sites. These data indicate that within this grassland, periods without fire are necessary for recruitment of both new individuals and additional shrub species; however, once established, shrub cover will increase regardless of fire frequency and even annual fire will not reduce shrub abundance. PMID- 21659136 TI - Molecular systematics and biogeography of the amphibious genus Littorella (Plantaginaceae). AB - Littorella (Plantaginaceae) is a disjunct, amphibious genus represented by three closely related species. Littorella uniflora occurs in Europe including Iceland and the Azores, L. americana is found in temperate North America, and L. australis grows in temperate South America. Littorella has been recognized in numerous floristic treatments, but its status as a genus has recently been questioned. Rahn (Botanical Journal of the Linnean Society 120: 145-198, 1996) proposed a new phylogeny for Plantaginaceae based on morphological, embryological, and chemical data in which he reduced Littorella to a subgenus of Plantago. This article compares the phylogeny proposed by Rahn to one based on DNA sequence data from the internal transcribed spacer (ITS) region. In our analysis, Littorella forms a strongly supported monophyletic clade sister to Plantago and its recognition at the generic rank appears warranted. Littorella australis is sister to L. americana, and this clade is sister to the European L. uniflora. This more distant relationship between L. uniflora and L. americana provides support for maintaining both taxa at the specific rank and suggests a European origin for Littorella. Our studies also indicate that the monotypic genus Bougueria is deeply nested within Plantago and that its inclusion within Plantago as proposed by Rahn appears justified. PMID- 21659137 TI - Reexamination of relationships, habital evolution, and phylogeography of checker mallows (Sidalcea; Malvaceae) based on molecular phylogenetic data. AB - Phylogenetic analysis of nuclear ribosomal DNA external and internal transcribed spacer region (ETS and ITS) sequences for Sidalcea (Malvaceae) resolved five major, well-supported lineages, three of which represent species groups that have each been noted for complex patterns of morphological variation: the oregana, malviflora, and glaucescens clades. Very low variation within each of the three groups in the sequenced regions is consistent with recent radiation of each clade. We reject the previously suggested hypothesis of monophyly for the annual species of Sidalcea. Based on our findings, the annual habit in Sidalcea arose at least four times, probably as an adaptation to seasonally dry habitats. The hypothesis that the perennial species S. hickmanii and S. malachroides represent basally divergent groups within Sidalcea is supported, but the more recently discovered S. stipularis represents an additional basally divergent lineage. The previous suggestion that the genus spread northward from Mexico along two major routes (through the Rocky Mountains and the Sierra Nevada foothills), with the Rocky Mountain species S. candida and S. neomexicana representing basally divergent lineages, is not supported. Sidalcea neomexicana is nested within the malviflora clade and is likely a lineage of relatively recent descent that originated in California and subsequently spread to the Rocky Mountains. PMID- 21659138 TI - Systematics and evolution of tribe Sinningieae (Gesneriaceae): evidence from phylogenetic analyses of six plastid DNA regions and nuclear ncpGS. AB - For nearly all species in the three genera of tribe Sinningieae (Gesneriaceae), Sinningia, Paliavana, and Vanhouttea (mostly in southeastern Brazil) plus 10 outgroups, we have sequenced six non-coding DNA regions (i.e., plastid intergenic spacers trnT-trnL, trnL-trnF, trnS-trnG, atpB-rbcL, and introns in the trnL and rpl16 genes) and four introns in nuclear plastid-expressed glutamine synthetase gene (ncpGS). Separate and combined analyses of these data sets using maximum parsimony supported the monophyly of Sinningieae, but the genera Paliavana and Vanhouttea were found embedded within Sinningia; therefore a new infrageneric classification is here proposed. Mapping of pollination syndromes on the DNA based trees supported multiple origins of hummingbird and bee syndromes and derivation of moth and bat syndromes from hummingbird flowers. Perennial tubers were derived from perennial stems in non-tuberous plants. PMID- 21659139 TI - Gunnerales are sister to other core eudicots: implications for the evolution of pentamery. AB - Phylogenetic relationships among many lineages of angiosperms have been clarified via the analysis of large molecular data sets. However, with a data set of three genes (18S rDNA, rbcL, and atpB), relationships among lineages of core eudicots (Berberidopsidales, Caryophyllales, Gunnerales, Santalales, Saxifragales, asterids, rosids) remain essentially unresolved. We added 26S rDNA sequences to a three-gene matrix for 201 eudicots (8430 base pair aligned nucleotides per taxon). Parsimony analyses provided moderate (84%) jackknife support for Gunnerales, which comprise the two enigmatic families Gunneraceae and Myrothamnaceae, as sister to all other core eudicots. This position of Gunnerales has important implications for floral evolution. A dimerous or trimerous perianth is frequently encountered in early-diverging eudicots (e.g., Buxaceae, Proteales, Ranunculales, Trochodendraceae), whereas in core eudicots, pentamery predominates. Significantly, dimery is found in Gunneraceae and perhaps Myrothamnaceae (the merosity of the latter has also been interpreted as labile). Parsimony reconstructions of perianth merosity demonstrate lability among early diverging eudicots and further indicate that a dimerous perianth could be the immediate precursor to the pentamerous condition characteristic of core eudicots. Thus, the developmental canalization that yielded the pentamerous condition of core eudicots occurred after the node leading to Gunnerales. PMID- 21659140 TI - Molecular phylogenetics of Meliaceae (Sapindales) based on nuclear and plastid DNA sequences. AB - Phylogenetic analyses of Meliaceae, including representatives of all four currently recognized subfamilies and all but two tribes (32 genera and 35 species, respectively), were carried out using DNA sequence data from three regions: plastid genes rbcL, matK (partial), and nuclear 26S rDNA (partial). Individual and combined phylogenetic analyses were performed for the rbcL, matK, and 26S rDNA data sets. Although the percentage of informative characters is highest in the segment of matK sequenced, rbcL provides the greatest number of informative characters of the three regions, resulting in the best resolved trees. Results of parsimony analyses support the recognition of only two subfamilies (Melioideae and Swietenioideae), which are sister groups. Melieae are the only tribe recognized previously that are strongly supported as monophyletic. The members of the two small monogeneric subfamilies, Quivisianthe and Capuronianthus, fall within Melioideae and Swietenioideae, respectively, supporting their taxonomic inclusion in these groups. Furthermore, the data indicate a close relationship between Aglaieae and Guareeae and a possible monophyletic origin of Cedreleae of Swietenioideae. For Trichilieae (Melioideae) and Swietenieae (Swietenioideae) lack of monophyly is indicated. PMID- 21659141 TI - Phylogenetic analysis of Asplenium subgenus Ceterach (Pteridophyta: Aspleniaceae) based on plastid and nuclear ribosomal ITS DNA sequences. AB - Phylogenetic relationships among 20 taxa of the fern genus Asplenium subgenus Ceterach (Filicopsida, represented by 73 accessions) were investigated using DNA sequence data from the nuclear ribosomal internal transcribed spacers (ITS nDNA) and plastid trnL-F intergenic spacer. In addition, a single sample per taxon was used in an analysis of the plastid rbcL gene. Chromosome counts were determined for all the samples, and these demonstrated a range from diploid to octoploid. Analyses of the DNA sequence data indicated that Asplenium subgenus Ceterach is polyphyletic, implicating homoplasy in the characters previously used to circumscribe this taxon. Plastid trnL-F and rbcL analyses resulted in identical tree topologies. The trees produced from the separate plastid and nuclear matrices agree in (1) the recognition of identical groups of accessions corresponding to A. dalhousiae, A. ceterach, A. aureum, A. cordatum, A. phillipsianum, and A. haughtonii; (2) the division of A. subg. Ceterach into two subclades, a Eurasian-Macaronesian and a strictly African alliance; (3) the position of A. dalhousiae as a member of the former subclade; (4) the lack of genetic variation in A. cordatum despite its morphological variability; and (5) the clustering of each autopolyploid with their diploid ancestor. However, the plastid and nuclear trees differ in their placement of A. haughtonii and A. dalhousiae, which might be due to different evolutionary histories of nuclear and plastid genomes, and is possibly an indication of ancient hybridization. The analyses confirm the existence of several strictly African taxa. Asplenium phillipsianum and A. cordatum each form species complexes of diploid and autopolyploid taxa, from which a third, morphologically intermediate, allotetraploid species has originated. Asplenium haughtonii is a distinct endemic species from Saint Helena. The maternally inherited plastid sequences support the hypothesis that A. aureum is an ancestor of A. lolegnamense and of A. octoploideum. Because gene conversion did not eliminate divergent ITS alleles in the allopolyploids, their reticulate ancestry could be demonstrated. Biparentally inherited nrITS sequences support the allopolyploid status of A. aureum, A. lolegnamense, and A. punjabense, indicating they share the ancestral A. javorkeanum genome. PMID- 21659142 TI - Phylogenetic relationships among species of Hypochaeris (Asteraceae, Cichorieae) based on ITS, plastid trnL intron, trnL-F spacer, and matK sequences. AB - Nuclear internal transcribed spacer (ITS) regions and chloroplast trnL intron and trnL/trnF spacer and matK sequences were used from 86 accessions to assess relationships among 31 European and South American species of Hypochaeris plus 18 representatives of related genera of tribe Cichorieae. The ITS tree shows high resolution compared to that of the maternally inherited trnL intron, trnL/F spacer, and matK sequences. The ITS and the combined tree reveal clades that agree well with sections of the genus established previously on morphological and cytological grounds, except for H. robertia, which groups with Leontodon helveticus and L. autumnalis. Monophyly of species of Hypochaeris from South America is strongly supported by both ITS and the joint matrix of ITS, trnL, and matK data. European species lie basal to South American taxa, which suggests that species in South America evolved from a single introduction from European progenitors and not from H. robertia as suggested previously. Low levels of sequence divergence among South American taxa suggest a pattern of rapid speciation, in contrast to much greater divergence among European representatives. Different species of Leontodon form two different clades that are also supported by chromosome numbers and morphology. Both nuclear and chloroplast markers suggest that Helminthotheca, Leontodon, and Picris are closely related to each other as well as to Hypochaeris. PMID- 21659143 TI - Major evolutionary events in the origin and diversification of the fern genus Polystichum (Dryopteridaceae). AB - Recent advances in molecular systematics of the ferns make it possible to address long-standing questions about classification of the major fern genera, such as the worldwide genus Polystichum (Dryopteridaceae), comprising at least 200 species. In this study we examined rbcL sequences and morphological characters from 55 fern taxa: 34 were from Polystichum and 21 were from other genera in the Dryopteridaceae. We found that Phanerophlebia, possibly including Polystichopsis, is the sister group to Polystichum sensu lato (s.l.), including Cyrtomium. Polystichum as commonly recognized is paraphyletic. Our results lead us to suggest recognizing the clade of earliest diverging Polystichum species as a distinct genus (Cyrtomidictyum) and to continue to recognize Cyrtomium as a separate genus, leaving a monophyletic Polystichum sensu stricto (s.s.). We resolved a tropical American clade and an African clade within Polystichum s.s. However, the resemblance between the once-pinnate, bulb-bearing calciphilic species found in Asia and the West Indies appears to be the result of convergent evolution. Optimizing our morphological character transformations onto the combined phylogeny suggests that the common ancestor of Polystichum s.l. and Phanerophlebia had evolved the common features of the alliance, including ciliate petiole-base scales, once-pinnate fronds, ultimate segments with scarious tips, peltate indusia, and microscales. PMID- 21659144 TI - The Bio-Logic and machinery of plant morphogenesis. AB - Morphogenesis (the development of organic form) requires signal-trafficking and cross-talking across all levels of organization to coordinate the operation of metabolic and genomic networked systems. Many biologists are currently converging on the pictorial conventions of computer scientists to render biological signaling as logic circuits supervising the operation of one or more signal activated metabolic or gene networks. This approach can redact and simplify complex morphogenetic phenomena and allows for their aggregation into diagrams of larger, more "global" networked systems. This conceptualization is discussed in terms of how logic circuits and signal-activated subsystems work, and it is illustrated for examples of increasingly more complex morphogenetic phenomena, e.g., auxin-mediated cell expansion, entry into the mitotic cell cycle phases, and polar/lateral intercellular auxin transport. For each of these phenomena, a posited circuit/subsystem diagram draws rapid attention to missing components, either in the logic circuit or in the subsystem it supervises. These components must be identified experimentally if each of these basic phenomena is to be fully understood. Importantly, the power of the circuit/subsystem approach to modeling developmental phenomena resides not in its pictorial appeal but in the mathematical tools that are sufficiently strong to reveal and quantify the synergistics of networked systems and thus foster a better understanding of morphogenesis. PMID- 21659145 TI - The ribosomal small-subunit protein S28 gene from Helianthus annuus (Asteraceae) is down-regulated in response to drought, high salinity, and abscisic acid. AB - A partial cDNA for the ribosomal S28 gene from sunflower was initially cloned and identified to be down-regulated by high salinity, using differential display reverse transcriptase-polymerase chain reaction (PCR). Using this sequence, a 502 base pair (bp) full-length cDNA was cloned by rapid amplification of cDNA ends. This cDNA (designated Ha-RPS28) encodes a protein component of the small subunit of cytoplasmic ribosomes. The predicted 65 amino acid residue sequence of Ha RPS28, with an estimated molecular mass of 7.5 kD, has 92, 89, and 86% identity with the S28 ribosomal proteins from peach, maize, and Arabidopsis, respectively. Ha-RPS28 was expressed in all organs examined, and the highest level was detected in fully expanded leaves. Furthermore, expression of Ha-RPS28 was down-regulated in both seedling roots and shoots in response to drought, high salinity, or abscisic acid. PMID- 21659146 TI - Lack of latitudinal trends in wood anatomy of Dodonaea viscosa (Sapindaceae), a species with a worldwide distribution. AB - Latitudinal or altitudinal variation in several anatomical characters of wood is common for woody dicotyledonous genera with a wide distribution, but whether such variation exists at the species level is disputed. Latitudinal and altitudinal trends in wood anatomy of Dodonaea viscosa were studied, using 102 samples collected between 41.2 degrees S and 33.3 degrees N latitude and 7-2750 m altitude. We studied variation in four quantitative features: vessel element length, fiber length, vessel frequency, and tangential vessel diameter. Ontogenetic trends were minimal with a slight decrease or increase in the innermost stem and were negligible among the studied specimens. Throughout the distributional range of the species, no latitudinal trends were detected in either the Northern or Southern Hemispheres. Altitudinal trends were also nonexistent, except for two features in specimens from China and Japan. Absence of latitudinal or altitudinal trends in this widely distributed species suggests that in some species the species-level variation in wood anatomy is not controlled by ecological gradients. PMID- 21659147 TI - Intercontinental Mediterranean disjunct mosses: morphological and molecular patterns. AB - This study focused on three species that occur disjunctly between western North America and the Mediterranean region of southern Europe, northern Africa, and western Asia, forming the so-called Madrean-Tethyan distribution pattern. Quantitative morphological characters were measured in New and Old World plants to find any subtle phenotypic differentiation between the disjunct populations. Sequences from the nuclear ribosomal internal transcribed spacer region were obtained from the same populations to assess differentiation at the molecular level and to compare molecular diversity with patterns of morphological similarity among plants. Little or no morphological differentiation existed between New and Old World plants in any of the species, but internal transcribed spacer (ITS) sequences revealed some phylogeographic structure. Patterns of morphological similarity in all three species were incongruent with phylogeographic structure revealed by sequence data. New World populations were more variable than Old World populations at the molecular level in the three species. Despite some evidence for differentiation between disjunct plants, no plausible mutation rate would date the divergence at >=20 million years ago (MYA), as implied by the Madrean-Tethyan hypothesis. Recent long-distance dispersal is a more likely explanation for intercontinental disjunctions in these species. PMID- 21659148 TI - The wandering carpel mutation of Zea mays (Gramineae) causes misorientation and loss of zygomorphy in flowers and two-seeded kernels. AB - We have isolated a new mutation, wandering carpel (wcr), which affects polarity of the maize flower, altering its orientation or converting it from zygomorphy to radial symmetry. These changes result in the development of embryos on locations other than the normal, acropetal side of the kernel. More than two carpels can develop into silks. More rarely, two ovules develop in a single ovary, giving rise to kernels with two seeds. The wcr mutation is a maternal-sporophyte-effect, semidominant mutation whose expression is background dependent. As spikelets with abnormal flowers are almost always paired with a normal spikelet, we hypothesize that WCR+ is required for establishing polarity in spikelet meristems during inflorescence development. PMID- 21659149 TI - Contrasting selection modes at the Adh1 locus in outcrossing Miscanthus sinensis vs. inbreeding Miscanthus condensatus (Poaceae). AB - We estimated DNA sequence variation of the Adh1 locus in the outcrossing Miscanthus sinensis (Poaceae) and its close selfing relative, M. condensatus. Tajima's test of selection is significantly negative for both overall exons and replacement sites in M. sinensis. Among its entire sample, nucleotide diversity of nonsynonymous sites is higher than that of synonymous sites. A McDonald and Kreitman test of neutrality indicates an excess of intraspecific replacement polymorphisms, suggesting possible directional selection toward advantageous mutants. However, frequent intragenic recombination suggests both purifying and positive selection is unlikely. Recent demographic expansions coupled with relaxation of purifying selection may have resulted in elevated genetic diversity at the Adh1 locus as well as the trnL-trnF intergenic spacer of cpDNA in this outcrossing species. In contrast, low levels of genetic diversity were detected at both the Adh1 locus and the cpDNA spacer in M. condensatus, consistent with bottlenecks associated with selfing in all populations. While Tajima's D and Fu and Li's F statistics did not reveal deviation from neutrality at the Adh1 locus in M. condensatus, 12 replacements vs. 10 synonymous changes were detected. Based on pairwise comparisons of the d(N)/d(S) ratio, lineages of closely related populations of the species distributed along saline habitats appeared to be under directional selection. PMID- 21659150 TI - Frequency-dependent fitness of hybrids between oilseed rape (Brassica napus) and weedy B. rapa (Brassicaceae). AB - Fitness of interspecific hybrids is sometimes high relative to their parents, despite the conventional belief that they are mostly unfit. F(1) hybrids between oilseed rape (Brassica napus) and weedy B. rapa can be significantly more fit than their weedy parents under some conditions; however, under other conditions they are less fit. To understand the reasons, we measured the seed production of B. napus, B. rapa, and different generations of hybrid plants at three different densities and in mixtures of different frequencies (including pure stands). Brassica napus, B. rapa, and backcross plants (F(1) ? * B. rapa) produced many more seeds per plant in pure plots than in mixtures and more seeds in plots when each was present at high frequency. The opposite was true for F(1) plants that produced many more seeds than B. rapa in mixtures, but fewer in pure stands. Both vegetative and reproductive interactions may be responsible for these effects. Our results show that the fitness of both parents and hybrids is strongly frequency-dependent and that the likelihood of introgression of genes between the species thus may depend on the numbers and densities of parents and their various hybrid offspring in the population. PMID- 21659151 TI - Erratum. PMID- 21659152 TI - Outcrossing rates in the gynomonoecious-gynodioecious species Dianthus sylvestris (Caryophyllaceae). AB - Some species described as gynodioecious are truly gynomonoecious-gynodioecious. Three distinct phenotypes may be found in their natural populations-female and hermaphrodite pure-sexed plants bearing either only pistillate or perfect flowers, respectively, and mixed plants bearing both types of flowers. In one such species, Dianthus sylvestris, we investigated mating system parameters using allozyme data. Outcrossing rates and correlations of outcrossed paternity were calculated for the three types of plants and separately for pistillate and perfect flowers on mixed plants. The mean outcrossing rate for the population was t(m) +/- SD = 0.885 +/- 0.032. Females were more outcrossed than hermaphrodites (0.987 +/- 0.112 and 0.790 +/- 0.076, respectively), whereas mixed plants were not significantly more or less outcrossed than hermaphrodites (0.840 +/- 0.060). Within mixed plants, perfect flowers showed an intermediate outcrossing rate (0.898 +/- 0.057), whereas pistillate flowers were as selfed as perfect flowers on hermaphrodite plants (0.782 +/- 0.111). Family estimates of outcrossing rates were highly variable. Globally, no biparental inbreeding was detected in this species, and there was a mean of 61.5 +/- 19.9% of full-sibs within families. Floral dimorphism between small pistillate and large perfect flowers together with pollinator preference for larger flowers could explain the observed patterns for both mating parameters. The advantages of gynomonoecy-gynodioecy are discussed. We conclude that mixed plants do not reduce selfing for all flowers on a plant, but perfect flowers on these plants seem to have an outcrossing advantage. PMID- 21659153 TI - Sexual reproduction in the invasive species Fallopia japonica (Polygonaceae). AB - Fallopia japonica (Polygonaceae) is an invasive perennial plant, well known in North America for its ability to spread aggressively via vegetative reproduction. The contribution of sexual reproduction to the distribution of this species is not well documented, and as a result, F. japonica is treated solely as a clonal species. To investigate the role of sexual reproduction in this species, germination experiments were conducted using seed collected from 29 parents from field sites in Massachusetts and from four greenhouse-grown cultivars. Results showed that wild F. japonica produce large quantities of seed that typically have high germinability. This seed is viable whether sown immediately after collection or subjected to various conditions during the winter season and germinated the following spring. Cultivars of F. japonica also produce viable seed and can thus contribute to the invasiveness of this species. In addition, wild F. japonica seedlings were observed at several field sites, with several of these seedlings surviving the winter and resprouting the following spring. That sexual reproduction and seedling survival occur in the wild has strong implications for the development of management strategies for this species. PMID- 21659154 TI - Evolution of Polaskia chichipe (Cactaceae) under domestication in the Tehuacan Valley, central Mexico: reproductive biology. AB - Polaskia chichipe, a columnar cactus, is cultivated for its edible fruits in central Mexico. This study analyzed whether artificial selection has modified its reproduction patterns and caused barriers to pollen exchange between wild, managed in situ, and cultivated populations. Anthesis was diurnal (~16 h in winter, ~10 h in spring) as well as partly nocturnal (~12 h in winter, ~3 h in spring), and flowers were pollinated by bees, hummingbirds, and hawk moths. Manual cross-pollination was ~37-49% effective in all populations. Self pollination was ~12% successful in the wild, but twice as successful (~22-27%) in managed and cultivated populations. Diurnal pollination was ~35-55% effective in winter and 100% in spring. Nocturnal pollination was successful only in winter (15%). Crosses among individuals were more effective within populations than among populations, including populations under a similar management regimen. The least successful crosses were between wild and cultivated populations. Flowers were produced in all populations from January to March, but flowering peaks differed by 1 mo among wild, managed, and cultivated populations and by 2 mo between wild and cultivated populations. The latter interrupted pollen exchange in May. Seeds from managed and cultivated populations germinated faster than those from wild individuals. Domestication has seemingly favored self-compatible P. chichipe plants with higher fruit yield, a longer period of fruit production, and faster seed germination, attributes that have resulted in partial reproductive barriers between wild and manipulated populations. PMID- 21659155 TI - Female sterility in Ulmus minor (Ulmaceae): a hypothesis invoking the cost of sex in a clonal plant. AB - A high incidence of individuals with low seed set was found in two populations of the field elm Ulmus minor, a European tree that reproduces sexually and via vegetative propagation through root sprouting. One population was a seminatural stand, while the other was established by artificial propagation of genotypes sampled widely across Spain. The low seed set in both populations was due to both pre- and post-zygotic factors, the importance of which vary between genotypes. These factors included gynoecial malformations that produced a non-ovulated pistil, early gynoecial necrosis (i.e., necrosis before any opportunities for pollination), and seed abortion. Female sterility gave rise to two classes of individuals: trees that were largely female-sterile but dispersed normal quantities of viable pollen, and trees that dispersed both normal pollen and substantial numbers of seeds. Reduced production of protein-rich seeds may increase the resource availability for clonal propagation, helping to maintain female-sterile individuals with hermaphrodites. PMID- 21659156 TI - Stomatal frequency adjustment of four conifer species to historical changes in atmospheric CO2. AB - The species-specific inverse relation between atmospheric CO(2) concentration and stomatal frequency for many woody angiosperm species is being used increasingly with fossil leaves to reconstruct past atmospheric CO(2) levels. To extend our limited knowledge of the responsiveness of conifer needles to CO(2) fluctuations, the stomatal frequency response of four native North American conifer species (Tsuga heterophylla, Picea glauca, Picea mariana, and Larix laricina) to a range of historical CO(2) mixing ratios (290 to 370 ppmV) was analyzed. Because of the specific mode of leaf development and the subsequent stomatal patterning in conifer needles, the stomatal index of these species was not affected by CO(2). In contrast, a new measure of stomatal frequency, based on the number of stomata per millimeter of needle length, decreased significantly with increasing CO(2). For Tsuga heterophylla, the stomatal frequency response to CO(2) changes in the last century is validated through assessment of the influence of other biological and environmental variables. Because of their sensitive response to CO(2), combined with a high preservation capacity, fossil needles of Tsuga heterophylla, Picea glauca, P. mariana, and Larix laricina have great potential for detecting and quantifying past atmospheric CO(2) fluctuations. PMID- 21659157 TI - Ethylene as a possible cue for seed germination of Schoenoplectus hallii (Cyperaceae), a rare summer annual of occasionally flooded sites. AB - The purpose of our research was to determine why seeds of Schoenoplectus hallii germinate only in some wet years. Seeds mature in autumn, at which time they are dormant. Seeds come out of dormancy during winter, if buried in nonflooded, moist soil, but they remain dormant if buried in flooded soil. Nondormant seeds require flooding, light, and exposure to ethylene to germinate. One piece of apple in water (1/12 of an apple in 125 mL of water in a glass jar for a depth of 5 cm) or a 1-MUmol/L solution of ethephon elicited very similar (high) germination percentages and vigor of seedlings. Apple, which was shown to produce ethylene in the air space of the jar, was used in a series of experiments to better understand germination. Seeds germinated to 72% if apple was removed from the water after 1 d of incubation, and they germinated to 97% if seeds were washed and placed in fresh water after 3 d of exposure to apple. No seeds germinated in control with no apple. Seeds incubated in apple leachate for 5 d and then transferred to filter paper moistened with distilled water germinated to 90%. Minimum depth of flooding in apple leachate (no soil in jars) for optimum germination was >=3 cm. Buried seeds of S. hallii exhibited an annual conditional dormancy/nondormancy cycle. Regardless of the month in which seeds were exhumed, they germinated to 59-100% in light in water with apple at daily alternating temperature regimes of 25 degrees /15 degrees , 30 degrees /15 degrees , and 35 degrees /20 degrees C, but germination at 20 degrees /10 degrees C (and to some extent at 15 degrees /6 degrees C) tended to peak in autumn to spring. Thus, seeds can germinate throughout the summer if flooded (ethylene production) and exposed to light. An ethylene cue for germination serves as a "flood-detecting" mechanism and may serve as an indirect signal that water is available for completion of the life cycle and competing species are absent. PMID- 21659158 TI - Occurrence of matK in a trnK group II intron in charophyte green algae and phylogeny of the Characeae. AB - A group II intron containing the matK gene, which encodes a splicing-associated maturase, was found in the trnK (lysine tRNA) exon in the chloroplast genome of the six extant genera of green algae in the family Characeae, which among green algae are the sister group to embryophytes (land plants). The characean trnK intron (~2.5 kilobases [kb]) and matK ORF (~1.5 kb) are comparable in size to the intron and ORF of land plants, in which they are similarly found inserted in the trnK exon. Domain X, a sequence of conserved amino acid residues within matK, occurs in the Characeae. Phylogenetic analysis using maximum likelihood (GTR + I + gamma likelihood model) and parsimony (branch and bound search) yielded one tree with high bootstrap support for all branches. The matK tree was congruent with the rbcL tree for the same taxa. The number and proportion of informative sites was higher in matK (501, 31% of matK sequence) compared to rbcL (122, 10%). Characeae branch lengths were on average more than five times longer for matK compared to rbcL and provided better resolution within the Characeae. These findings along with recent genomic analyses demonstrate that the intron and matK invaded the chloroplast genome of green algae prior to the evolution of land plants. PMID- 21659159 TI - Phylogenetic evaluation of Xylothamia, Gundlachia, and related genera (Asteraceae, Astereae) based on ETS and ITS nrDNA sequence data. AB - Previous molecular investigations of the phylogenetic relationship for Xylothamia employed exemplar taxa and indicated its affiliation is either with the Gutierrezia or the Ericameria alliances. The present 3' ETS and ITS nrDNA gene phylogenies yielded the unexpected result that Xylothamia is polyphyletic. Species within its circumscription are placed into two well-supported evolutionary lineages with other genera of Astereae. Of nine species of Xylothamia, four species plus Gundlachia constitute one clade. The other five species are placed in a sister clade with several other genera including Amphiachyris, Bigelowia, Euthamia, Gutierrezia, and others. Except for X. johnstonii and X. palmeri, these five species of Xylothamia have little affinity for one another or for other genera in the same clade. Morphological similarities in foliar features between certain species in both lineages are possibly from a convergence resulting in adaptation to arid habitats. Such similarities were also the basis, in part, for their taxonomic treatment within Xylothamia or their earlier affiliation with Ericameria, which has similar features. The uncharacteristic leaf form in Xylothamia purpursii has a pattern of adaptation considerably different from its allies. Whether the Xylothamia-containing clades are related to Solidaginineae or represent an independently derived lineage remains equivocal because this outcome rested with the choice of data and optimality criteria. PMID- 21659160 TI - Pollination systems of trees in Kakachi, a mid-elevation wet evergreen forest in Western Ghats, India. AB - A long-term survey (1990-2000) of pollination modes of 86 tree species was carried out at Kakachi, a mid-elevation wet forest site in southern Western Ghats, India. Observations were made on 86 tree species. This comprises 80% of the total arborescent species present in the site. Approximately 75% of these species were specialized to a single pollinator group such as bee, beetle, or moth. Pollinators from diverse groups pollinate the remaining 25% of the tree species. Global comparison with other wet forest sites showed that diversity and specialized pollination modes observed in Kakachi bore closer resemblance to other lowland than montane forest sites described so far. However, the number of pollinators involved in pollination was comparable with montane sites. We examine the consequences that might have led to selection of the observed pollination modes in Kakachi. We discuss the conservation implications of these results. PMID- 21659161 TI - On the mechanical properties of the rare endemic cactus Stenocereus eruca and the related species S. gummosus. AB - We examined the hypothesis that the procumbent growth habit of the rare, columnar cactus Stenocereus eruca is in part the result of a diminution of the mechanical properties of stem tissues by comparing the properties of S. eruca plants with those of the putatively closely related semi-erect shrub S. gummosus. Intact stems and surgically removed anatomically comparable regions of the stems of both species were tested in bending and tension to determine their Young's modulus and breaking stress. A computer program was used to evaluate the contribution of each region to the capacity of entire stems to resist bending forces. Our analyses indicate that the principal stiffening agent in the stems of both species is a peripheral tissue complex (= epidermis and collenchyma in the primary plant body) that has a significantly higher tensile breaking stress and greater extensibility for S. gummosus than that of S. eruca. Computer simulations indicate that the wood of either species contributes little to bending stiffness, except in very old portions of S. gummosus stems, because of its small volume and central location in the stem. These and other observations are interpreted to support the hypothesis that S. eruca evolved a procumbent growth habit as the result of manifold developmental alterations some of which reduced the capacity of tissues to support the weight of stems. PMID- 21659162 TI - Characterization and localization of short-specific polygalacturonase in distylous Turnera subulata (Turneraceae). AB - We describe for distylous Turnera subulata a polygalacturonase specific to short styled plants that is localized to the style transmitting tissue (the tissue through which pollen tubes grow). The polygalacturonase gene is linked to and may be upregulated by the S allele of the distyly locus. Because of its tissue specific location, the polygalacturonase may be involved in the self incompatibility response, acting in a complementary or antagonistic manner, or possibly in signalling downstream events. A pollen-specific polygalacturonase was also identified and may be a member of a small multigene family of pollen polygalacturonases. The role, if any, played by the pollen polygalacturonase in distyly, is presently unknown. PMID- 21659163 TI - The Effect of NaCl on growth, N2 fixation (acetylene reduction), and percentage total nitrogen in Leucaena leucocephala (Leguminosae) var. K-8. AB - Leucaena leucocephala var. K-8 is a fast-growing, tropical leguminous tree that has multiple economic uses. This study was conducted to evaluate the effect(s) of varying NaCl concentrations on growth, N(2) fixation, and percentage of total tissue nitrogen in different organs in L. leucocephala. Seeds were germinated and grown for 10 wk with a nitrogen-free fertilizer applied every 2 wk. At 10 wk, plants were treated for either 0, 7, 14, 21, or 28 wk with either deionized water (control), 0.00625 mol/L, 0.0125 mol/L, 0.025 mol/L, 0.05 mol/L, or 0.1 mol/L NaCl in addition to the fertilizer every 2 wk. Growth was measured as plant height, nodule number and mass, and dry tissue mass. N(2) fixation was measured by the acetylene reduction assay. Percentage of tissue nitrogen was determined using Kjeldahl analysis. In younger plants (7-wk treatment), major fluctuations in NaCl tolerance were observed in the different plant organs. As plants matured (14- and 21-wk treatment) NaCl concentrations of 0.025 mol/L and higher caused the greatest reduction in growth and tissue nitrogen. We conclude that NaCl concentrations of 0.025 mol/L and greater caused a major decrease in growth, N(2) fixation, and percentage of tissue nitrogen in L. leucocephala plants that were less than 1 yr old. PMID- 21659164 TI - Hydraulic, biomechanical, and anatomical interactions of xylem from five species of Acer (Aceraceae). AB - Possible trade-offs between hydraulic conductivity and mechanical properties of woody stems from five species were assessed. Acer negundo is a ruderal tree, A. saccharinum, and A. rubrum are fast-growing and shade-intolerant soft maples, whereas A. nigrum and A. saccharum are slow-growing and shade-tolerant hard maples. It was hypothesized that the ruderal and soft maples would have lower modulus of elasticity (MOE) and modulus of rupture (MOR), but higher maximum specific conductivity (K(s max)) than hard maples. Many anatomical and general morphological characteristics were measured in an attempt to correlate them to water transport and/or mechanical strength differences between species. No difference was found between species in vessel diameter, fiber wall thickness, initial hydraulic conductivity (K(h initial)), specific conductivity (K(s max)), native percent embolism, or Huber value. Similarly, no trade-off was found between K(s max) and MOE or MOR across the genus. However, fiber lumen diameter was inversely correlated to MOE and MOR. Surprisingly, percentage of ray parenchyma was positively related to MOE. The results suggest transport/mechanical trade-offs do not occur in Acer and differences in mechanical properties may be due to fiber lumen differences that do not influence the efficient transport of water. PMID- 21659165 TI - Geographic patterns in the reproductive ecology of Agave lechuguilla (Agavaceae) in the Chihuahuan desert. II. Genetic variation, differentiation, and inbreeding estimates. AB - Plants with natural variation in their floral traits and reproductive ecology are ideal subjects for analyzing the effects of natural selection and other evolutionary forces on genetic structure of natural populations. Agave lechuguilla shows latitudinal changes in floral morphology, color, and nectar production along its distribution through north-central Mexico. Both the type and abundance of its pollinators also change with latitude. Using starch electrophoresis, we examined the levels and patterns of variation of 13 polymorphic allozyme loci in 11 populations of A. lechuguilla. The overall level of genetic variability was high (H(e) = 0.394), but the levels of genetic variation had no geographic pattern. However, the southern populations exhibited an excess of heterozygotes in relation to expectations for Hardy-Weinberg equilibrium, whereas the northern populations had an excess of homozygotes. Total differentiation among populations was low (theta = 0.083), although gene flow estimates (Nm) varied among groups of populations: southern populations had the lowest levels of genetic differentiation, suggesting high levels of gene flow; northern populations had greater levels of genetic differentiation (theta = 0.115), suggesting low gene flow among them. The patterns and inferences of the genetic structure of the population at the molecular level is consistent with variation in floral traits and pollinator visitation rates across the range of the species. PMID- 21659166 TI - Diversification of andromonoecy in Solanum section Lasiocarpa (Solanaceae): the roles of phenotypic plasticity and architecture. AB - Quantitative analyses of sexual expression show extensive interspecific variation in the strength of andromonoecy (proportions of hermaphroditic and staminate flowers) among Solanum species in the monophyletic section Lasiocarpa. The roles of phenotypic plasticity and inter- and intra-inflorescence architecture in the diversification of andromonoecy within this small clade were analyzed. Four species that represent a range of expression of andromonoecy were examined. Staminate flowers produced within inflorescences ranged from 3% (S. candidum) to 7% (S. ferox) in weakly andromonoecious species and from 39% (S. pseudolulo) to 60% (S. quitoense) in more strongly andromonoecious species. Manipulation of fruit set on clonal replicates of multiple genotypes demonstrated variation among species for phenotypic plasticity. The strongly andromonoecious species, S. pseudolulo and S. quitoense, were not plastic and produced a large proportion of staminate flowers regardless of fruiting treatment, whereas S. candidum and S. ferox were phenotypically plastic and produced significantly more staminate flowers in the presence of developing fruit. Staminate flower production of all four species varied both within and among inflorescences. A greater proportion of staminate flowers were produced in distal (later produced) inflorescences. Within inflorescences, hermaphroditic flowers occurred in basal positions, whereas staminate flowers, when produced, occurred more distally. This pattern of staminate flower production is qualitatively the same in all species investigated; however, quantitative variation in the transition from hermaphroditic to staminate flower production within and among inflorescences is associated with variation in the strength of andromonoecy. At least three factors have contributed to the diversification of andromonoecy in section Lasiocarpa including the presence or absence of phenotypic plasticity in response to fruit set, quantitative variation in intra- and inter-inflorescence architectural effects, and total flower production. PMID- 21659167 TI - Low selfing in a mass-flowering, endangered perennial, Eryngium alpinum L. (Apiaceae). AB - We investigated the reproductive ecology of an endangered alpine species, Eryngium alpinum L., to determine its selfing rate and to propose possible mechanisms that may shape its breeding system. Whereas pollinators' foraging behavior suggested a high potential for geitonogamy (70% of the flights occur within plants), microsatellite analyses of seed progenies demonstrated that plants are primarily outcrossing (outcrossing rate [tm] = 0.65, 0.96, and 1 in three populations). Given the relatively long pollen viability (at least 4-5 d) and the high number of simultaneously opened flowers on each plant, protandry is not sufficient to eliminate selfing. Second, controlled crosses demonstrated not only auto-fertility, but also partial self-incompatibility. Partial self incompatibility is probably due to the competitive advantage of cross vs. self pollen, and, together with protandry, could lead the species to selfing as a reproductive assurance. These results are encouraging for the maintenance of large populations. However, higher selfing was observed in a small population that could suffer inbreeding depression, as observed on experimentally selfed seeds. Thus, these populations should be carefully monitored. Finally, this study shows how molecular markers and field experiments may complement each other in our reaching a global understanding of mating patterns. PMID- 21659168 TI - Sunny-side up: flower heliotropism as a source of parental environmental effects on pollen quality and performance in the snow buttercup, Ranunculus adoneus (Ranunculaceae). AB - Floral traits affect mating success via their influence on the microenvironment in which sexual reproduction occurs as well as their impact on pollinator attraction. Here we investigate the importance of flower heliotropism as a source of parental environmental effects on pollen quality and performance. Flowers of the snow buttercup, Ranunculus adoneus, closely track the sun's rays. We experimentally restrained flowers to test for effects of heliotropism on pollen quality and performance after pollination. When equivalent amounts of pollen were transferred to recipient pistils, pollen from solar-tracking donor flowers exhibited a 32% advantage in germination compared to pollen from stationary (tethered) donor flowers. By the end of anthesis, pistils of tracking flowers contained 40% more germinating pollen grains and 44% more pollen tubes midway down the style than pistils of stationary ones. Solar tracking had no direct effect on pollen tube growth. The greater amount of germinating pollen in tracking flowers accounted for the treatment effect on pollen tube density. A survey of pollen receipt and pollen germination in naturally tracking flowers indicated that solar tracking primarily affects pollen tube density by promoting pollen germination rather than pollen deposition. We conclude that flower heliotropism, by enhancing the paternal environment for pollen development and the maternal environment for pollen germination, represents a source of positive parental environmental effects on pollen performance in snow buttercups. PMID- 21659169 TI - Post-dispersal seed fates of four prairie species. AB - After dispersal, seeds can germinate and establish as seedlings, persist as seeds, or die. Knowledge of these three seed fates is crucial for understanding the abundance and distribution of plant populations and ultimately, community composition and diversity. Few studies, however, have simultaneously measured these fates, while also examining the factors causing mortality. The goal of this research was to simultaneously quantify the three seed fates and factors causing death (predation and fungal disease) for four species found in prairies in western Oregon, USA. The most common seed fate for the four study species was death (44-80%). Fungal disease, which has seldom been quantified in natural ecosystems, generally caused less than 10% mortality for each of the four species. Vertebrate predation substantially reduced seed numbers only for Bromus carinatus (21%). Of the unmeasured mortality factors, indirect evidence showed invertebrate predation was a cause of death for seeds of only one species, Prunella vulgaris. In addition, competitive pressures caused seedling death for only the two grass species, Bromus carinatus and Cynosurus echinatus. Survival as established seedlings was generally much more common than survival as persistent seed, with the exception of Daucus carota, in which 14% of the sown seeds persisted the first year. PMID- 21659170 TI - Interactive effects of redox intensity and phosphate availability on growth and nutrient relations of Cladium jamaicense (Cyperaceae). AB - Expansion of Typha domingensis into areas previously dominated by Cladium jamaicense in the Florida Everglades has been linked to anthropogenic phosphorus (P) enrichment and increased hydroperiod. The principal stress factor for plants in flooded soils is biochemical reduction, the intensity of which is measured as redox potential (Eh). The objective of this study was to assess the growth response of C. jamaicense to Eh (-150, +150, and +600 mV) and P availability (10, 80, and 500 MUg P/L). Plants were grown hydroponically in a factorial experiment using titanium (Ti(3+)) citrate as an Eh buffer. Treatment effects on growth, biomass partitioning, and tissue nutrients were recorded. Growth approximately doubled in response to a 50-fold increase in P availability. Low redox significantly reduced growth and tissue P concentration. While plant P concentrations increased 20-fold between the 10 and 500 MUg P/L treatments, P concentrations were 50-100% higher at +600 mV than at -150 mV within each phosphate level. At high Eh, C. jamaicense appears well adapted to low nutrient environments because of its low P requirement and high retention of acquired P. However, at low Eh the ability to acquire or conserve acquired P decreases and as a consequence, higher phosphate levels are required to sustain growth. Findings of this study indicate that young C. jamaicense exhibits low tolerance to strongly reducing conditions when phosphate is scarce. PMID- 21659171 TI - Phenotypic trade-offs in the sexual reproduction of Salicaceae from flood plains. AB - We studied the relationship of seed mass to seed longevity (controlled conditions) and to seed number in six species of Salicaceae (Populus nigra, Salix alba, S. daphnoides, S. elaeagnos, S. purpurea, and S. triandra) that frequently co-occur on European flood plains. These species regenerate sexually in the same habitat but differ in seed mass. Half-viability periods, i.e., the time after which 50% of the initially viable seeds no longer germinate, were short (between 6.5 +/- 0.1 and 23.3 +/- 0.3 d), and large numbers of seeds were produced (between 10 000 and 1 * 10(6) per plant). Mean seed mass ranged from 0.02 +/- 0.001 mg in S. triandra to 0.80 +/- 0.05 mg in P. nigra. Whereas seed mass was, against expectation, positively related to half-viability periods, seed number generally decreased with increasing seed mass. Thus, a phenotypic trade-off between seed mass and seed number appears to be accentuated by an increase in seed longevity with increasing seed mass. PMID- 21659172 TI - Cyathea cranhamii sp. nov. (Cyatheaceae), anatomically preserved tree fern sori from the Lower Cretaceous of Vancouver Island, British Columbia. AB - Permineralized cyatheaceous sori occur among remains of conifers, fungi, and other plants in newly discovered calcareous concretions from Early Cretaceous (Barremian) marine sediments of Vancouver Island, British Columbia, Canada. Sori are superficially attached in two rows to narrow pinnules and display a globose sphaeropteroid indusium. Annulate sporangia with multicellular stalks diverge from a basal, vascularized receptacle. The nearly vertical uniseriate annulus is not interrupted by the stalk. The sporangia bear 64 trilete spores with perispore sculpturing that ranges from irregular granulate/echinate to prominent rodlets. These specimens, described as Cyathea cranhamii sp. nov., are the first anatomically preserved tree fern sori from the fossil record. They represent the most ancient evidence for fertile structures of the Cyatheaceae and demonstrate that essentially modern species of cyatheaceous tree ferns had evolved by the Early Cretaceous. PMID- 21659173 TI - A Middle-Late Eocene inflorescence of Caryophyllaceae from Tasmania, Australia. AB - A new genus and species (Caryophylloflora paleogenica genus and species nova G. J. Jord. & Macphail) are proposed for a fossil inflorescence found in Middle-Late Eocene sediments at Locharbour, northeastern Tasmania, Australia. A parsimony analysis of 75 extant species of the order Caryophyllales and five outgroups placed the fossil within Caryophyllaceae, either subfamily Alsinoideae or Caryophylloideae. The analysis used molecular (rbcL and/or matK), morphological, and anatomical data for the extant species and morphological data for the fossil. Tests on extant species imply that the placement of the fossil should be convincing. The fossil appears to be of a lineage distinct from any extant Australian Caryophyllaceae. In situ pollen are consistent with the form species, Periporopollenites polyoratus. This relatively simple pollen type first appears in Australia and New Zealand in the Late Cretaceous, the oldest known record of the Caryophyllaceae. The last appearance of P. polyoratus in Australia is in the Oligocene, and extant Australian members of the Caryophyllaceae are best interpreted as having evolved from species that dispersed from elsewhere during the Neogene or Quaternary. PMID- 21659174 TI - Differentiation and hybridization between Quercus crispula and Q. dentata (Fagaceae): insights from morphological traits, amplified fragment length polymorphism markers, and leafminer composition. AB - Quercus crispula and Q. dentata (Fagaceae) are dominant members of cool-temperate forests of Japan and are assumed to hybridize in nature. To characterize and discriminate these two species and their hybrids, we carried out multivariate analysis using several morphological traits and principal coordinate analysis using molecular (amplified fragment length polymorphism [AFLP]) data. Further, we examined the composition of Phyllonorycter species (leafmining insects) on individuals from a mixed forest. Morphological traits and Phyllonorycter composition differ enough in these two oak species to be useful for identification of species and hybrids. AFLP data, however, are less informative because the degree of molecular differentiation between the two species is low. Nine out of 105 individuals from a mixed stand had intermediate morphologies according to the multivariate analysis, and eight out of the nine individuals had intermediate Phyllonorycter composition in either one or both of the two study years. These eight individuals were tentatively assigned as hybrids or backcross individuals, and the remaining individual with intermediate morphologies was assigned as Q. dentata according to its Phyllonorycter composition and the AFLP analysis. PMID- 21659175 TI - Phylogenetics of Cranichideae with emphasis on Spiranthinae (Orchidaceae, Orchidoideae): evidence from plastid and nuclear DNA sequences. AB - DNA sequences from plastid rbcL and matK genes and the trnL-F region, as well as the nuclear ribosomal ITS region, were used to evaluate monophyly and subtribal delimitation of Cranichideae and generic relationships in Spiranthinae. Cranichideae are moderately supported as monophyletic, with Chloraeinae and Pterostylis-Megastylis indicated as their collective sisters. Within Cranichideae, Pachyplectroninae and Goodyerinae form a well-supported monophyletic group sister to a "core spiranthid" clade that includes, according to their branching order, Galeottiellinae, Manniellinae, and a Prescottiinae Cranichidinae-Spiranthinae subclade. Inclusion of Galeottiella in Spiranthinae, as in previous classifications, renders the latter paraphyletic to all other spiranthid subtribes. Cranichidinae and Spiranthinae (minus Galeottiella) are monophyletic and strongly supported, but Prescottiinae form a grade that includes a strongly supported prescottioid Andean clade and a weakly supported Prescottia Cranichidinae clade sister to Spiranthinae. Well-supported major clades in Spiranthinae identified in this study do not correspond to previous alliances or the narrowly defined subtribes in which they have been divided recently. Morphological characters, especially those that have been used for taxonomic delimitation in Cranichideae, are discussed against the framework of the molecular trees, emphasizing putative synapomorphies and problems derived from lack of information or inadequate interpretation of the characters. PMID- 21659176 TI - A molecular phylogeny of Panicum (Poaceae: Paniceae): tests of monophyly and phylogenetic placement within the Panicoideae. AB - Panicum L. is a cosmopolitan genus with approximately 450 species. Although the genus has been considerably reduced in species number with the segregation of many taxa to independent genera in the last two centuries, Panicum remains a heterogeneous assemblage, as has been demonstrated in recent years. The genus is remarkably uniform in its floral characters but exhibits considerable variation in anatomical, physiological, and cytological features. As a result, several classifications, and criteria of what the genus should really include, have been postulated in modern literature. The purpose of this research, based on molecular data of the chloroplast ndhF gene, is to test the monophyly of Panicum, to evaluate infrageneric classifications, and to propose a robust phylogenetic hypothesis. Based on the present results, previous morphological and molecular phylogenetic studies, and inferred diagnostic morphological characters, we restrict Panicum sensu stricto (s.s.) to the former subgenus Panicum and support recognition of Dichanthelium, Phanopyrum, and Steinchisma as distinct genera. We have transfered other species of Panicum to other genera of the Paniceae. Most of the necessary combinations have been made previously, so few nomenclatural changes have been required. The remaining species of Panicum sensu lato (s.l.) are included within Panicum incertae sedis representing isolated species or species grouped within monophyletic clades. Additionally, we explore the performance of the three codon position characters in producing the supported phylogeny. PMID- 21659177 TI - Water deficit accelerates determinate developmental program of the primary root and does not affect lateral root initiation in a Sonoran Desert cactus (Pachycereus pringlei, Cactaceae). AB - Determinate root growth is an important adaptation feature for seedling establishment in some Cactaceae. We show that seedlings of Pachycereus pringlei have primary roots with a stable determinate developmental program. How water stress affects determinate root growth and lateral root development has not been studied. Here we address this question. Root growth was analyzed in plants growing in vitro under well-watered and water-deficient (created by polyethylene glycol) growth conditions. Under severe water stress roots terminated their growth earlier and the rate of growth was significantly decreased as a result of inhibition of both cell elongation and cell production. Under severe water stress the number of lateral roots and primordia per millimeter of primary root was 1.5 1.7 times greater than under well-watered conditions; however, the total number of lateral roots and primordia was the same under all conditions. Lateral roots resembled root spurs found in some Opuntioideae. Analysis of the dynamics of meristem exhaustion indicated that initial-cell activities are required for the maintenance of proliferation before meristem exhaustion. We conclude that lateral root formation is a stable developmental process resistant to severe water stress and that water stress accelerates the determinate developmental program of the primary root. Both of these features appear to be important for successful seedling establishment in a desert. PMID- 21659178 TI - Comparative development of aseptate and septate anthers of Annonaceae. AB - We compared anther development in 13 genera and 15 species of Annonaceae to document the nature and development of anther septa. In aseptate anthers, all sporogenous initials proceed to sporogenesis and meiosis. In septate anthers, a small number of sporogenous initials, in a discontinuous distribution pattern, differentiate into sporogenous cells; the remaining initials become sterile and form cellular septa that partition each anther lobe into multiple sporangial chambers. In species where the septum is 1-2 cell layers thick, the entire septum becomes tapetal (T-type septa) and breaks down before anther dehiscence. In species in which the septum is three or more cell layers thick, only the layer in direct contact with the sporogenous cells becomes tapetal, and the remaining cells become parenchymatous (P-type septa). These thicker P-type septa are sometimes visible in dehisced anthers. Both types are homologous in ontogeny and are highly associated with the production of compound pollen. We propose that the evolution of anther septation in Annonaceae was mainly driven by the requirement for highly efficient nutrient and physical support to the development of large, compound pollen units. PMID- 21659179 TI - Characterization of the asymmetric growth of gravistimulated snapdragon spikes by stem and cell dimension analyses. AB - Growth patterns of detached spikes of gravistimulated snapdragon (Antirrhinum majus L.) were analyzed in detail. The length increment of 5-mm marked subsections in the upper and lower flanks of the stem-bending zone was measured during gravistimulation using time-lapse photographs. At the onset of bending, a negative relative growth rate of the upper flank was detected, followed by increased relative growth rate in both lower and upper flanks. Consequently, a differential stem growth pattern was obtained during gravistimulation, which was significantly and specifically abolished by calcium antagonists reported previously to inhibit stem curvature of snapdragon. The differential growth patterns resulted from dynamic modifications of the cell dimensions in the epidermal and cortical stem layers. Bending started with both shrinking and widening of the epidermal cells and a parallel decrease in length and height of cortical cells at the upper stem flank. These changes were accompanied with a concomitant increase in length and height of the cortical cells on the lower stem flank, followed by a growth increase of epidermal cells. Our results suggest that both the epidermal and cortical cells play an important role in gravitropic shoot bending of snapdragon. PMID- 21659180 TI - Susceptibility of clover species to fungal infection: the interaction of leaf surface traits and environment. AB - Many foliar pathogens require free water to germinate; therefore, disease pressure should favor plants that are able to repel water. For a suite of 18 sympatric clover species (Trifolium and Medicago, Fabaceae), we evaluated leaf traits affecting leaf wetness and susceptibility to infection by the fungal pathogen Stemphylium sp., causal agent of Stemphylium leaf spot. Spore germination increased with time in free water, and the relative susceptibility of host plants to infection was proportional to the duration of water retention on leaves. Larger leaves captured more water and retained it longer. Unexpectedly, trichomes and leaf wettability did not affect water capture. For clovers planted within natural clover populations at two sites, infection was threefold greater at the wetter site. At the drier site, water retention on the leaf surface was an important predictor of infection rates across host species, but persistent fog and dew at the wetter site reduced the importance of rapid leaf drying. Our results suggest that plant adaptations that reduce water retention on leaves may also reduce disease incidence, but the selective advantage of these traits will vary among habitats. PMID- 21659181 TI - Effects of successional status, habit, sexual systems, and pollinators on flowering patterns in tropical rain forest trees. AB - Based on data from observations of 302 tree species at La Selva, Costa Rica, we tested a range of hypotheses about the relationship between flowering parameters such as time, frequency, and duration and ecological features such as successional status, habit, sexual systems, and pollen vectors with and without considering the effect of family membership. We predicted that early successional species would flower any time of the year, but species pollinated by different vectors as well as dioecious species would flower nonrandomly across seasons. However, there was little evidence that flowering time varied with successional status, pollen vectors, and sexual systems. As we predicted, supra-annual flowering was proportionately less common in early successional species as compared to late ones, in understory species as compared to canopy species, and in dioecious species as compared to those with hermaphroditic flowers. When considering phylogeny, however, supra-annual flowering in the understory was not as rare as predicted. Our prediction of longer flowering in the early successional species as compared to late successional species was also supported. Predictions about longer flowering of dioecious species as compared to hermaphroditic species and of species pollinated by generalist vectors as compared to the specialists were not supported, though there was a trend in the expected direction. PMID- 21659182 TI - Relationships among time, frequency, and duration of flowering in tropical rain forest trees. AB - Flowering patterns are defined by the timing, duration, and frequency of flowering. Plants, particularly in the tropics, vary enormously with respect to these main variables of flowering. We used data from 302 tree species in a wet tropical forest to test a series of predictions regarding timing, duration, and frequency of flowering and examined the effect of each variable on the other two. Because timing, duration, and frequency of flowering can be constrained by phylogeny, we analyzed the data before and after considering phylogenetic effects at the level of family. Flowering activity peaked in the first wet season from May to July, refuting our prediction of peak flowering during the dry season. Our prediction that most species should flower several times a year was supported when species flowering more or less continually throughout the year were included in this category. Our prediction that supra-annually flowering species should be the least frequent was also supported with some qualifications. As we predicted, species flowering several times a year bloomed relatively briefly per flowering episode. Our prediction of shorter flowering duration for species flowering in the dry season and for those with a temporal separation between flowering and vegetative growth was also supported. Furthermore, supra-annually flowering species flowered for a shorter duration than annually flowering species and had a higher probability of flowering in the dry season compared to episodically or annually flowering species. Phylogeny significantly constrained variation in flowering frequency, but not in flowering time or duration, among confamilial species. PMID- 21659183 TI - Reproductive assurance varies with flower size in Collinsia parviflora (Scrophulariaceae). AB - A central question in plant evolutionary ecology is how mixed mating systems are maintained in the face of selection against self-pollination. Recently, attention has focused on the potential reproductive assurance (RA) benefit of selfing: the ability to produce seeds via autonomous selfing when the potential for outcrossing is reduced or absent. To date, there is little experimental support for this benefit under natural pollination conditions. In addition, the RA hypothesis has not been tested experimentally in a species displaying morphological variation for traits expected to influence the mating system, such as flower size, which affects both attractiveness to pollinators and ability to self autonomously. Here, we document significant among-population variation in flower size in Collinsia parviflora and show that pollinators preferred large flowers over small flowers in experimental arrays. The pollinator community varied among three study sites, and two small-flowered populations had lower pollinator visitation rates than one large-flowered population. We compared seed production between intact flowers (can self) and experimentally emasculated flowers (require a pollinator) on large- and small-flowered plants. As predicted by the RA hypothesis, small-flowered plants show a greater RA benefit of selfing than large-flowered plants; emasculated, small flowers produced very few seeds, relative to intact, small flowers or either emasculated or intact, large flowers. We also show that the RA benefit is pollination-context dependent, differing between small- and large-flowered test sites, likely due to a combination of pollinator discrimination against small flowers and differences between test sites in the pollinator community. This paper is the first experimental evidence showing a trait-dependent RA benefit of selfing under natural pollination conditions. PMID- 21659184 TI - Population genetic structure of wild Phaseolus lunatus (Fabaceae), with special reference to population sizes. AB - To set up an in situ conservation strategy for Phaseolus lunatus, we analyzed the genetic structure of 29 populations in the Central Valley of Costa Rica. Using 22 enzyme loci, we quantified the proportion of polymorphic loci (P(p)), the mean number of alleles per locus (A), and the mean effective number of alleles per locus (A(e)), which equaled to 10.32%, 1.10, and 1.05, respectively. The total heterozygosity (H(T)), the intrapopulation genetic diversity (H(S)), and the interpopulation genetic diversity (D(ST)) were 0.193, 0.082, and 0.111, respectively. The genotypic composition of the analyzed populations showed a deviation from the Hardy-Weinberg proportions (F(IT) = 0.932). This disequilibrium was due to either genetic differentiation between populations (F(ST) = 0.497) or nonrandom mating within populations (F(IS) = 0.866). From the level of genetic differentiation between populations and the private alleles frequencies estimates, gene flow was calculated: Nm(W) = 0.398 and Nm(S) = 0.023, respectively. The results suggested that wild Lima bean maintains most of its isozyme variation among populations. Significant positive correlation was observed between population size and P(p), A, and H(o) (observed heterozygosity), whereas no correlation was observed with the average fixation index of population (F). The loss of genetic variability in populations was attributed to inbreeding and the bottleneck effects that characterized the target populations. In situ conservation and management procedures for wild Lima bean are discussed. PMID- 21659185 TI - Environmental influences on the phenology and abundance of flowering by Androsace septentrionalis (Primulaceae). AB - We studied the timing and abundance of flowering by Androsace septentrionalis L. (Primulaceae), an indeterminate winter annual or short-lived perennial, in 2 * 2 m plots at the Rocky Mountain Biological Laboratory in Colorado, USA, from 1982 to 2000. Flowers were counted every other day for most or all of the growing season in seven plots in a rocky meadow habitat and nine plots in a wet meadow habitat. The phenology and abundance of flowering were both highly variable, with mean dates of first flowering ranging from 16 May to 12 July and maximum daily counts of flowers ranging from 1 to 1187. Snowmelt date was the primary determinant of timing of flowering. For rocky meadow plots, the previous year's summer precipitation and the current year's average minimum temperature in May had significant effects on maximum number of flowers produced, but no environmental variable we considered was significantly correlated with flower abundance in the wet meadow plots. Length of flowering in individual plots ranged from 2 to 85 d, and many plot-years had both primary (about 1 mo) and secondary (about 10-12 d) flowering periods. The predicted increase in variability of precipitation accompanying climate change will affect negatively the long-term abundance and persistence of this species at our study site. PMID- 21659186 TI - Saguaro (Carnegiea gigantea, Cactaceae) age-height relationships and growth: the development of a general growth curve. AB - Because the growth rate of saguaros varies across different environments, past studies on saguaro population structure required extensive data collection (often over many decades) followed by site-specific analysis to estimate age at the sampled locale. However, when height-growth data from different populations are compared, the overall shape of the growth curves is similar. In this study, a formula was developed to establish saguaro age-height relationships (using stepwise regression) that can be applied to any saguaro population and only requires a site-specific factor to adjust the curve to the local growth rate. This adjustment factor can be established more efficiently and requires less data than the full analyses required for previous studies. Saguaro National Park East (SNP-E) was used as the baseline factor, set to 1.0. Results yielded a factor of 0.743 for SNP West. When the formula was applied to 10-yr interval data from Organ Pipe Cactus National Monument (OPCNM) in Arizona, USA, this location had a factor of 0.617 (relative to SNP-E). With this formula and relatively little field sampling, the age of any individual saguaro (whether the individual was sampled or not) in any population can be estimated. PMID- 21659187 TI - Phylogenetics of the genus Scaevola (Goodeniaceae): implication for dispersal patterns across the Pacific Basin and colonization of the Hawaiian Islands. AB - Scaevola, the only genus of Goodeniaceae that has extensively radiated outside of Australia, has dispersed throughout the Pacific Basin, with a few species reaching the tropical coastal areas of the Atlantic and Indian Oceans. Five Australian and most of the non-Australian species are placed in Scaevola section Scaevola based on their fleshy fruits, indeterminate inflorescences, and more arborescent habits. Analyses of ITS sequence data demonstrate that Scaevola is a monophyletic group if S. collaris is excluded and Diaspasis filifolia is included. The genus is Australian in origin, but there have been at least six separate dispersal events from Australia. Four of these dispersals each resulted in single extra-Australian species. The remaining two were followed by radiations that gave rise to large groups, each including one of the widespread strand species, S. taccada and S. plumieri. Remarkably, three of the six dispersals established species on the remote Hawaiian Archipelago, representing at present the largest number of colonizations by any flowering plant genus to these islands. PMID- 21659188 TI - Annulus-pore relationship in Gramineae (Poaceae) pollen: the pore margin of Pariana. AB - Pariana, a primitive bamboo, is the only genus in the Gramineae (Poaceae) to have pollen grains without an annulus as part of its single aperture (porate) system. In contrast, the markedly thickened exine layer underlying the pore margin is similar to counterparts in all grass genera. Components of the future annulus in Gramineae pollen develop toward the cytoplasm (proximally) and begin to be pressed outward by an increase in the cytoplasm during the microspore vacuolate stage, culminating in an annulus by maturity. However, in some species of Pariana these components are either not sufficiently developed or the cytoplasmic expansion is not sufficient to press the components into an annular ring around the pore. The structural relationship of exine layering in this type of pollen grain in Gramineae and other families with similar apertures has not hitherto been extensively studied. A critical examination of the apertures in bambusoid grasses may clarify their systematic position within the Gramineae. PMID- 21659189 TI - Phylogeography of the Arctic-Alpine Saxifraga oppositifolia (Saxifragaceae) and some related taxa based on cpDNA and ITS sequence variation. AB - Saxifraga oppositifolia (Saxifragaceae) is an important model system for the evolution of Arctic-Alpine plant species. Sequences of the psbA-trnH intergenic spacer of chloroplast DNA and of the internal transcribed spacer region, ITS1 5.8S-ITS2, of the nuclear ribosomal DNA were used to investigate the intraspecific evolution and phylogeography of this species. Samples from nearly the species' entire circumpolar distribution were included in the analysis as well as samples from the closely related taxa S. smalliana from Alaska and S. blepharophylla and S. biflora from the Alps (S. aizoides served as outgroup). These latter taxa showed a low number of parsimony informative characters, in both cpDNA and ITS sequences, which separated them from S. oppositifolia. Two main cpDNA haplotypes were detected within S. oppositifolia, one with a Eurasian distribution and one with an East Asian-North American distribution. This confirmed the existence of two cpDNA lineages with different geographical distributions in this species, which had previously been reported based on a RFLP analysis. The ITS phylogeny was not useful with respect to the intraspecific evolution and phylogeography of S. oppositifolia, because it showed a largely unresolved topology with low statistical support. The cpDNA sequence analysis, however, also suggested a putative long-distance dispersal event. All investigated taxa had cpDNA haplotypes that were congruent with their geographical origin rather than their phylogeny. This could point to putative lineage sorting in S. oppositifolia and related taxa. PMID- 21659190 TI - Development of ovule, embryo sac, and endosperm in Triteleia (Themidaceae) relative to taxonomy. AB - Six of 14 species of Triteleia were studied. All possess septal nectaries, raphides in the ovary wall, an anatropous and crassinucellate ovule with a micropyle formed by the inner integument only, and parietal cells. A short and thick nucellus, which is not penetrated by the embryo sac, has a one-layered apical epidermis and thickens from its subepidermal layer. The permanently two layered inner integument is made up of normal, i.e., not greatly enlarged, cells. The embryo sac is of the Polygonum type, and the endosperm is of the helobial type. Embryo development is of the Asterad type in Triteleia laxa and T. ixioides. From an embryological point of view, Triteleia is closely related to Muilla maritima because the two taxa are alike in all characteristics, except for the number of layers in the apical nucellar epidermis. Triteleia is only distantly related to Dipterostemon, Dichelostemma, and Brodiaea, judging from the numerous differences in embryology. Both Triteleia and Muilla maritima are embryologically more primitive than the Dipterostemon-Dichelostemma-Brodiaea group. Embryologically, the Themidaceae are more similar to the Hyacinthaceae than to Allium. However, all embryological similarities with Hyacinthaceae are in plesiomorphic characters. PMID- 21659191 TI - Males outcompete hermaphrodites for seed siring success in controlled crosses in the polygamous Fraxinus excelsior (Oleaceae). AB - Polygamy (including trioecy and subdioecy), the co-occurrence of males, hermaphrodites, and females in natural populations, is a rare and poorly studied breeding system expressed in Fraxinus excelsior L. (Oleaceae), a wind-pollinated tree. Here we investigate siring ability of pollen from male vs. hermaphrodite individuals to better understand this sex polymorphism. We conducted single-donor and two-donor pollination experiments and compared both fruit set and seed siring success, assessed with polymorphic microsatellite markers, of male and hermaphrodite individuals. Single pollen donor crosses allowed us to verify the male function of hermaphrodites. However, pollen from hermaphrodites was much less proficient than male pollen, with males siring 10 times as many fruits in single donor pollination treatments. This result was strengthened by the surprisingly low reproductive success of hermaphrodites in pollen competition conditions: of the 110 seedlings analyzed three were selfed and only one was sired by the hermaphrodite donor. The remaining 106 were sired by the male pollen donor. These results raise the question of the maintenance of male fertility in hermaphrodites in Fraxinus excelsior. Male function of hermaphrodites in this species now needs to be assessed under field conditions. PMID- 21659192 TI - Molecular data from 27 proteins do not support a Precambrian origin of land plants. AB - Heckman et al. (Science 293: 1129-1133) used sequences obtained from GenBank to infer divergence times in fungi and green plants. They estimated that the crown group of land plants originated in the Precambrian, at 703 +/- 45 mya, a date much older than dates implied by the fossils, which are no older than about 450 mya. This paper presents an analysis of an entirely different set of sequence data from 27 plastid protein-coding genes in 10 land plants and a green algal outgroup. It uses a calibration point closer to the origin of land plants and inference methods that do not assume a molecular clock. This leads to estimates ranging from 425 to 490 mya, which brackets the age suggested by the fossil record. Possible explanations for the differing conclusions in the two studies include differences in calibration points and use of single-copy plastid genes rather than nuclear gene families. PMID- 21659193 TI - First fossil record of transfer cells in angiosperms. AB - Transfer cells are specialized plant cells that optimize short-distance transport by an extension of the interior surface of the cell walls. Using scanning electron microscopy (SEM), we found transfer cells in the fossil seed coat of Ehretia clausentia (Ehretiaceae, Boraginales) from the London Clay flora (Lower Eocene). This is the first fossil record of transfer cells in angiosperms. PMID- 21659194 TI - Development of gelatinous (reaction) fibers in stems of Gnetum gnemon (Gnetales). AB - In extraxylary tissues of the stem Gnetum gnemon produces gelatinous fibers that can also function as reaction or tension fibers. These gelatinous fibers occur in all axes in the outer cortex and in displaced axes progressively in the middle and inner cortex and finally in the secondary phloem. Early cell differentiation in the cortex produces initials of laticifers that are unique in gymnosperms. Subsequently narrow fibers differentiate from cells that undergo both extensive passive elongation, as a result of internodal elongation, together with their active apical intrusive growth. Outer fibers always complete secondary wall development and become an important mechanical component of stems. Differentiation of fiber initials continues in the middle and inner cortex, but secondary wall formation can only be determined by a gravimorphic stimulus that produces eccentric development of fibers. Further eccentric development of fibers then continues in the outer secondary phloem from dedifferentiated phloem parenchyma cells that initially undergo extensive intrusive growth. All such cells have characteristic features of tension fibers of angiosperms. They exhibit a pronounced purely cellulosic innermost layer of the secondary wall (Sg layer). In addition, fiber initials are coenocytic, including up to eight nuclei that become distributed uniformly throughout the length of the cell. Mature macerated fibers are markedly brittle, making accurate length measurements difficult. Although cytologically uniform, these fibers thus originate from two kinds of initial (primary and secondary). They also differ in their response to a gravimorphic stimulus determined by their times of inception and their eccentric location. These cells show a suite of positional and gravimorphic responses that illustrate the complexity of plant cell differentiation. PMID- 21659195 TI - Comparative anatomy and morphology of Vitis vinifera (Vitaceae) somatic embryos from solid- and liquid-culture-derived proembryogenic masses. AB - Ontogeny of somatic embryos of grapevine (Vitis vinifera) produced from solid- and liquid-culture-derived proembryogenic masses (PEM) was compared using light and scanning electron microscopy. Somatic embryos produced from solid-medium derived PEM (SPEM) had large cotyledons, little or no visible suspensor structure, and a relatively undeveloped concave shoot apical meristem, whereas those from liquid-medium-derived PEM (LPEM) had smaller cotyledons, a distinct suspensor, and a flat-to-convex shoot apical meristem. The convex shoot apical meristem in LPEM-derived somatic embryos formed as early as the heart stage of development; it was 4-6 cell layers deep and rich in protein. Suspensors persisted in fully developed and mature LPEM-derived somatic embryos. The SPEM derived somatic embryos exhibited dormancy, as do mature zygotic embryos, which also have a rudimentary suspensor, whereas LPEM-derived embryos were not dormant. We hypothesize that the presence of a persistent suspensor in LPEM-derived somatic embryos modulates development, ultimately resulting in rapid germination and a high plant-regeneration rate. PMID- 21659196 TI - Karyotype analysis and chromosome evolution in South American species of Lathyrus (Leguminosae). AB - The karyotypes of 10 species and one variety of South American Lathyrus were determined and compared with those obtained of five entities from the Northern Hemisphere. Although all the species have a chromosome number of 2n = 14, they could be differentiated by their karyotype formula and quantitative parameters of the karyotypes. Phenetic distance and principal component analysis showed that in spite of the differences observed among entities, they can be grouped in clusters that coincide with the taxonomic sections established by F. K. Kupicha and with the life cycle of the species. South American species form a homogeneous group and can be distinguished by the presence of a subtelocentric pair, which has a macrosatellite in the long arm, and the lack of a short metacentric pair characteristic of most species of the Northern Hemisphere. From an evolutionary point of view, variation in total chromosome length without major changes in the karyotype formula suggests that changes in the amounts of genomic DNA are proportional to the relative length of each chromosome arm and that species of Notolathyrus evolved in a concerted fashion. Variation in genome size, however, is congruent with morphological variation of some reproductive organs as well as with the life cycle and minimum generation time, as predicted by the nucleotype hypothesis. PMID- 21659197 TI - Rapid evolution of parental rDNA in a synthetic tobacco allotetraploid line. AB - Unidirectional gene conversion of rDNA units has occurred in the evolution of natural tobacco (Nicotiana tabacum). In this paper we report the use of the synthetic tobacco line Th37, 4n (N. sylvestris * N. tomentosiformis), to study early rDNA evolution associated with allopolyploidy. At least three classes of newly amplified rDNA unit variants were identified (17/20 plants). Their presence was often accompanied by near-complete elimination of N. tomentosiformis-donated rDNA units (15/20 plants). Novel rDNA units were of N. tomentosiformis-type and contained rearranged subrepeats in the intergenic spacer. The maternal N. sylvestris-derived units were unchanged, except for some alteration in the ratio of individual gene family members. A cytogenetic analysis revealed rDNA sites on N. sylvestris-derived chromosomes S10, S11, and S12 and N. tomentosiformis derived chromosomes T3 and in some cases T4. An rDNA locus does not occur on N. tomentosiformis chromosome 4. The locus on chromosome T4 of some hybrids correlates with the occurrence of the novel units that probably amplified at the locus. Combined with an analysis of tobacco cultivars, the data indicate that an initial burst of rDNA evolution associated with allopolyploidy was followed by a slower process that led towards reduced complexity and a decreased number of rDNA variants. PMID- 21659198 TI - Evolutionary patterns and genetic structure in localized and widespread species in the Stylidium caricifolium complex (Stylidiaceae). AB - The Stylidium caricifolium (Stylidiaceae) complex consists of seven currently recognized species and a taxon of putative hybrid origin endemic to southwest Western Australia. These taxa vary in geographical distribution from widespread, extending over a range of 500 km, to extremely localized, covering a range of only 0.5 km. Patterns of allozyme variation were investigated in 61 populations covering all taxa and two closely related species. Measures of genetic diversity were consistently lower and in some cases significantly lower in four rare and geographically restricted taxa compared with their widespread relatives. In contrast, genetic diversity in two other localized taxa was comparable or higher than in the widespread taxa. The level of divergence among populations was moderate to high, with a significant trend of higher F(ST) values for the widespread species to lower values for the geographically restricted and rare taxa. Phylogenetic relationships and levels of divergence indicate that most taxa are probably relictual rather than recently evolved. Geographical localization and rarity in this complex can be attributed to a range of factors associated with habitat specificity, historical and ecological processes that characterize the southwest region, and mode of origin. PMID- 21659199 TI - Facilitated selfing offers reproductive assurance: a mutualism between a hemipteran and carnivorous plant. AB - Reproductive assurance is frequently used to explain the evolution of selfing but has become controversial from lack of evidence. We studied the pollination system of the near carnivorous plant genus Roridula and showed that reproductive assurance is important in this system. Hemipterans have a digestive mutualism with Roridula and have been implicated in pollination but flowers show adaptations to hymenopteran pollination. We deduce that hemipterans are the primary pollinators of Roridula because seed set is significantly reduced when hemipterans are excluded from the flowers. Using allozyme electrophoresis, we show that hemipterans are responsible for mostly selfed progeny. Although bees still pollinate Roridula on very rare occasions, their exclusion does not affect seed set. The complicated floral structures that occur in Roridula most likely evolved as adaptations for bee pollination. Resident hemipterans facilitate selfing by Roridula, and this acts as a reproductive assurance mechanism because it increases seed production and ensures that plants still reproduce in the absence of more motile, outcrossing pollinators. PMID- 21659200 TI - The pollination biology of two paniculate agaves (Agavaceae) from northwestern Mexico: contrasting roles of bats as pollinators. AB - Paniculate agaves from tropical deserts depend on nectar-feeding bats for their reproduction, while species from extratropical areas near the northern limit of Leptonycteris curasoae are pollinated by diurnal and nocturnal insects and birds. Agave angustifolia is a paniculate agave with a broad distribution in Mexico whose range coincides with the distribution of L. curasoae, while A. subsimplex has a narrow distribution in Sonora within the range of nectar-feeding bats. We studied the pollination biology of A. angustifolia and A. subsimplex in northwestern Mexico to evaluate the relative importance of bat pollination in a region where L. curasoae is seasonal. Flower visitors included a wide variety of animals, with bats having greater visitation rates in A. angustifolia. A pollinator-exclusion experiment revealed that bats were responsible for most of the control fruit set in A. angustifolia, whereas for A. subsimplex, diurnal and nocturnal visitors were equally effective. Overall, our data indicate that in central Sonora, A. angustifolia depends on nectar-feeding bats for its sexual reproductive success, while A. subsimplex relies on both diurnal and nocturnal pollinators. Given the contrasting distribution ranges of paniculate agaves, our results seem to support the trend from specialization to generalization along the continuum of tropical to extratropical deserts. PMID- 21659201 TI - Temporal and spatial patterns of mass flowerings on the Malay Peninsula. AB - We propose a hypothesis to explain the temporal and spatial patterns of mass flowerings in dipterocarp tree species on the Malay Peninsula. The literature on these mass flowerings reveals that during 1980-2002 at least 11 flowerings occurred at irregular intervals of 1-6 yr in a lowland rain forest. Five of them were typical mass flowerings-a high density of flowering trees and the characteristic sequential flowering of Shorea species. The 11 flowerings were classified into two flowering times: spring and autumn. There is evidence that low temperature and drought triggered the flowerings. Therefore, the seasonality of mass flowerings is characterized by the annual patterns of rainfall and low temperature. In addition, changes in El Nino-Southern Oscillation (ENSO) may play important roles in determining the supra-annual occurrence of mass flowerings. Flowering surveys on the Malay Peninsula implied that regions with spring or autumn mass flowerings corresponded geographically to those regions that had one cool season (December-February) or two (December-February and June-August), respectively. This finding anticipates the seasonal pattern and geographical distribution of mass flowerings on the Malay Peninsula. PMID- 21659202 TI - Fitness of Cuscuta salina (Convolvulaceae) parasitizing Beta vulgaris (Chenopodiaceae) grown under different salinity regimes. AB - The distribution of saltmarsh dodder (Cuscuta salina) worldwide is restricted to areas of high salinity, where it parasitizes a variety of salt-tolerant plants. Because dodders do not maintain root connections to the soil, this pattern of parasitization may be related to the effects of salt stress on the host that increase the ability of attached dodders to more easily transfer host contents. This study explored whether a saline host environment is required for successful infection and whether stem contents of potential hosts become more concentrated in response to salinity. Fecundity of dodder was highest when hosts (Beta vulgaris) were grown either without salt or at high (250 mmol/L) salinity; it produced significantly fewer flowers and fruit at intermediate salinities. Stem constituents of two unparasitized host species had high conductivity and elevated levels of dissolved sugars at increasing salinities. Nitrate content of stems was also increased by salinity, but declined at the extreme salinity (400 mmol/L). Salinity effects on host suitability may partially explain differences in growth and vigor of C. salina in certain areas of salt marsh, but information on nonrandom dispersal of C. salina seeds may be needed to fully explain this parasite's distribution. PMID- 21659203 TI - The response of Ammophila breviligulata and Spartina patens (Poaceae) to grazing by feral horses on a dynamic mid-Atlantic barrier island. AB - Ammophila breviligulata, American beachgrass, and Spartina patens, salt meadow hay, have been grazed by feral horses on the dunes of Assateague Island for hundreds of years; however, because of a significant increase in the horse population since the 1960s, overgrazing and dune erosion have become problems. Grazing was assessed on foredunes of four different morphologies along a 21-km stretch of the Maryland portion of the island using 17 exclosure plot pairs. In addition to decreased cover and biomass of the two species, plant structure was significantly affected by grazing. Leaf length and width, stem diameter, and stem density of A. breviligulata and stem diameter of S. patens were reduced in the grazed plots. Especially sensitive to grazing were reproductive characteristics. Percentage of plants in flower, height of flowering stems, and inflorescence length were all significantly reduced by grazing (nongrazed individuals measured). Species composition was not affected by horse accessibility. PMID- 21659204 TI - Are Mojave Desert annual species equal? Resource acquisition and allocation for the invasive grass Bromus madritensis subsp. rubens (Poaceae) and two native species. AB - Abundance of invasive plants is often attributed to their ability ot outcompete native species. We compared resource acquisition and allocation of the invasive annual grass Bromus madritensis subsp. rubens with that of two native Mojave Desert annuals, Vulpia octoflora and Descurainia pinnata, in a glasshouse experiment. Each species was grown in monoculture at two densities and two levels of N availability to compare how these annuals capture resources and to understand their relative sensitivities to environmental change. During >4 mo of growth, Bromus used water more rapidly and had greater biomass and N content than the natives, partly because of its greater root-surface area and its exploitation of deep soils. Bromus also had greater N uptake, net assimilation and transpiration rates, and canopy area than Vulpia. Resource use by Bromus was less sensitive to changes in N availability or density than were the natives. The two native species in this study produced numerous small seeds that tended to remain dormant, thus ensuring escape of offspring from unfavorable germination conditions; Bromus produced fewer but larger seeds that readily germinated. Collectively, these traits give Bromus the potential to rapidly establish in diverse habitats of the Mojave Desert, thereby gaining an advantage over coexisting native species. PMID- 21659205 TI - Factors affecting phenological patterns of bombacaceous trees in seasonal forests in Costa Rica and Mexico. AB - We compared phenological patterns of tree species of the family Bombacaceae in three seasonal forests in Mexico and Costa Rica whose dry seasons vary in duration and intensity. The objectives were to (1) determine intraspecific variation in phenology between sites in different geographic locations with different precipitation regimes, (2) compare interspecific phenological patterns within sites during one year, and (3) document seasonal pollinator use of floral resources at one site in relation to the flowering phenology of these species. To determine the sequence of phenological events in trees of the family Bombacaceae across three study sites, phenology of marked individuals was recorded every 2 wk from September 2000 through August 2001 for six species. To estimate the importance of bombacaceous species in the diet of nectarivorous bats, pollen samples were collected from the bodies or feces of bats once every 2 wk during flowering. Our study suggests that phenological patterns of the Bombacaceae family in Neotropical dry forests are mainly constrained by phylogenetic membership and adaptive selective pressures associated with competition for pollinators. Abiotic factors related to precipitation and soil water content appear to be regulating leaf flushing and abscission, but the principal causes of flowering are related to ultimate factors associated with competition for pollinators. This study is the first that evaluates the phenological pattern of species and genera of the same family at different latitudes in a similar life zone. PMID- 21659206 TI - Drought constraints on leaf gas exchange by Miconia ciliata (Melastomataceae) in the understory of an eastern Amazonian regrowth forest stand. AB - Analyses of the effects of drought stress on Amazonian regrowth stands are lacking. We measured leaf gas exchange and leaf water potential of Miconia ciliata (Melastomataceae) in a dry-season irrigation experiment in 14-yr-old regrowth. In the dry season, irrigated plants maintained significantly higher leaf water potentials, photosynthetic capacity at light saturation (A(max)), stomatal conductance (g(s)), internal CO(2) concentration (C(i)), and lower A(max)/g(s) than control plants. The degree of dry-season down-regulation of control plant A(max), along with its fast recovery following rain, reveals the importance of occasional dry-season rains to the carbon budget of M. ciliata. During the wet season, we observed higher A(max) for control plants than for plants that had been irrigated during the dry season. We hypothesize that reduced drought constraints on photosynthesis of irrigated plants advanced the flowering and fruiting phenology of irrigated plants into the dry season. Flowers and fruits of control plants developed later, during the wet season, potentially stimulating a compensatory reproductive photosynthesis response in nearby leaves. The relative drought intolerance of M. ciliata may be a deciding factor in its ability to survive through the dynamic successional development of the regrowth stand studied. PMID- 21659207 TI - Phylogenetic relationships in Cyperaceae subfamily Mapanioideae inferred from pollen and plastid DNA sequence data. AB - Cyperaceae are the third largest monocotyledon family, with considerable economic and conservation importance. In subfamily Mapanioideae there is particular specialization of the inflorescence into units termed spicoids. The structural homology of the spicoid is difficult to interpret, making determination of intrafamilial relationships problematic. To address this, pollen from eight species in Mapanioideae was investigated using light microscopy and scanning and transmission electron microscopy. Pollen development was also examined to identify the type of pollen present in these species. We also analyzed DNA sequence data using the trnL-F and rps16 regions from 25 genera and 35 species of Cyperaceae, Juncaceae, and Thurniaceae. Two types of pollen, Mapania-type and pseudomonad, were identifed. Analysis of combined DNA and pollen data resolved a clade sister to the rest of Cyperaceae, corresponding to Mapanioideae. Within this, two further clades were resolved. One comprised taxa assigned to tribe Hypolytreae, which had Mapania-type pollen. The other comprised taxa mainly assigned to tribe Chrysitricheae, but included two taxa from Hypolytreae, Capitularina and Exocarya. All taxa in this clade had pseudomonad pollen. Thus new groupings within the subfamily have been discovered based on the specialization of some taxa in terms of their pollination biology. PMID- 21659208 TI - Phylogeographic relationships within Packera sanguisorboides (Asteraceae), a narrow endemic species that straddles a major biogeographic boundary. AB - Packera sanguisorboides is endemic to the Sangre de Cristo and Sacramento Mountains of New Mexico, USA. As such, its distribution spans the boundary between two major floristic regions: the southern Rocky Mountain region and the Madrean region. Chloroplast DNA haplotype polymorphism patterns in populations from both regions show that most of the molecular variance exists among populations rather than between mountain ranges and that hybridization with at least one other Packera species containing distinct cpDNA haplotypes has contributed to the cpDNA diversity within P. sanguisorboides. Based on morphological and cpDNA data, the closest relatives to P. sanguisorboides are thought to be mesic species similar to P. glabella and P. sanguisorbae. PMID- 21659209 TI - Phylogenetic study of Fulgensia and allied Caloplaca and Xanthoria species (Teloschistaceae, lichen-forming ascomycota). AB - Fulgensia Massal. & De Not. is a widespread genus with considerable morphological and ecological heterogeneity across species. For this reason, the taxonomic delimitation of this genus has been controversial. Relationships among species of Fulgensia, Caloplaca Th. Fr., and Xanthoria (Fr.) Th. Fr. (Lecanorales) were investigated based on a comprehensive phylogenetic analysis of 62 DNA sequences from the nuclear ribosomal internal transcribed spacer (ITS) region using maximum parsimony (MP) and likelihood (ML). Ambiguously aligned (INAASE coded characters) and unambiguous regions were analyzed separately and combined when using MP as the optimization criterion. All our analyses confirm the polyphyly of this genus as three distinct lineages: Fulgensia sensu stricto, F. australis, and F. schistidii. We report here that Caloplaca, Fulgensia, and Xanthoria together form two main sister lineages. One lineage includes Fulgensia schistidii (part of the C. saxicola group), Xanthoria, and most of the lobed Caloplaca species belonging to the Gasparrinia group. A second main lineage comprises the remaining Caloplaca species, Fulgensia sensu stricto, and F. australis. Therefore, the traditional generic level classification schemes for the family Teloschistaceae appear to be highly artificial. All three genera were found to be nonmonophyletic. We demonstrate here that the ITS is appropriate to resolve relationships across the Teloschistaceae. However, a combination of an MP analysis, in which ambiguously aligned regions are accommodated using INAASE, with an ML analysis, in which phylogenetic confidence is estimated using a Bayesian approach, is needed. PMID- 21659210 TI - The effect of nutrient stress on developmental instability in leaves of Acer platanoides (Aceraceae) and Betula pendula (Betulaceae). AB - Studies of developmental stability can provide insights into the amount of genetic or environmental stress experienced by individuals or populations. In the present study, we used young plants of Acer platanoides (Norway maple) and Betula pendula (silver birch), two distantly related tree species with widely different leaf morphologies, to compare the expression of developmental instability in two contrasting environments: one with free access to nutrients and the other with a severely limited supply of nutrients. Using the difference in size between the right and left side of each leaf as a measure of developmental instability, we found no effect of nutrient deficiency on leaf asymmetry, despite large sample sizes (370-380 plants per species and treatment) and evidence for stress-related changes in overall leaf size and plant biomass. Moreover, there was no consistent relationship between individual leaf asymmetry and plant biomass within each nutrient treatment. In view of these observations, leaf asymmetry appears to be a poor indicator of nutrient stress in young plants of Acer platanoides and Betula pendula. PMID- 21659211 TI - Nuclear and cytoplasmic variation within and between Eurasian Larix (Pinaceae) species. AB - The genetic variation in nuclear and cytoplasmic markers was investigated in 28 populations belonging to Eurasian Larix species (L. decidua, L. sibirica, L. gmelinii, L. olgensis, and L. kaempferi). Nuclear genetic variation was assessed at 214 AFLP loci, and both PCR-RFLP and four microsatellite loci were used to estimate variation of the chloroplast DNA. Variation of the mitochondrial genome was measured using RFLPs. Although population differentiation at both nuclear and chloroplast markers was much weaker than at mitochondrial DNA, it nonetheless corroborated the grouping observed with mitochondrial DNA. The AFLPs led to the same population grouping as mtDNA. Notably, the presence of two ancient western and eastern groups within L. sibirica was confirmed and possible postglacial routes inferred. The genetic composition of the northernmost L. sibirica population in our sample established that it is located at the confluence of the eastern and western recolonization routes. The joint use of the three markers also indicated that populations around Lake Baikal are hybrids between L. gmelinii and L. sibirica, with L. gmelinii primarily acting as the pollinator. Finally, AFLP-based estimates of nucleotide variation were an order of magnitude larger than the strikingly low estimates of nucleotide variation recently reported in Pinus sylvestris. PMID- 21659212 TI - Floral development and phyllotactic variation in Ceratophyllum demersum (Ceratophyllaceae). AB - The floral development of staminate and pistillate flowers of Ceratophyllum demersum was observed, with particular focus on the phyllotactic variation in staminate flowers, using scanning electronic microscopy (SEM). We discerned patterns of development of some important new morphological features, e.g., the difference and discontinuity between the organ initiation in stamens and that in bracts (or tepals) and the initial presence of a mucilaginous appendage on each pistil. Female flowers are considered to be very specialized through reduction. In male flowers stamen initiation changes between early and late floral development. The four or five stamens in the outermost whorl initiate first on the abaxial and lateral sides of the floral apex and only later on the adaxial side (unidirectional). Later the inner stamens initiate spirally, and this is the main pattern in the stamen initiation. Members of each whorl differ among themselves in time of initiation and in ultimate size. The phyllotactic variation in staminate flowers of Ceratophyllum, suggested by previous studies, is derived from the variation in stamen number and the difference of stamen initiation between the early and later stages. The development in Ceratophyllum has some similarities to those of ANITA plants except for Nymphaeales. PMID- 21659213 TI - Geometrical relationships specifying the phyllotactic pattern of aquatic plants. AB - The complete range of various phyllotaxes exemplified in aquatic plants provide an opportunity to characterize the fundamental geometrical relationships operating in leaf patterning. A new polar-coordinate model was used to characterize the correlation between the shapes of shoot meristems and the arrangements of young leaf primordia arising on those meristems. In aquatic plants, the primary geometrical relationship specifying spiral vs. whorled phyllotaxis is primordial position: primordia arising on the apical dome (as defined by displacement angles theta <= 90 degrees during maximal phase) are often positioned in spiral patterns, whereas primordia arising on the subtending axis (as defined by displacement angles of theta >= 90 degrees during maximal phase) are arranged in whorled patterns. A secondary geometrical relationship derived from the literature shows an inverse correlation between the primordial size : available space ratio and the magnitude of the Fibonacci numbers in spiral phyllotaxis or the number of leaves per whorl in whorled phyllotaxis. The data available for terrestrial plants suggest that their phyllotactic patterning may also be specified by these same geometrical relationships. Major exceptions to these correlations are attributable to persistent embryonic patterning, leaflike structures arising from stipules, congenital splitting of young primordia, and/or non-uniform elongating of internodes. The geometrical analysis described in this paper provides the morphological context for interpreting the phenotypes of phyllotaxis mutants and for constructing realistic models of the underlying mechanisms responsible for generating phyllotactic patterns. PMID- 21659214 TI - The reproductive biology of the invasive ferns Lygodium microphyllum and L. japonicum (Schizaeaceae): implications for invasive potential. AB - The effect of culture system and population source on sexual expression and sporophyte production was examined for two invasive fern species in Florida, USA, Lygodium microphyllum and L. japonicum (Schizaeaceae). Both species are currently spreading through Florida. Long-distance dispersal of ferns is thought to rely on successful intragametophytic selfing. Given the rate of spread observed in both Lygodium species, we hypothesized that both species are capable of intragametophytic selfing. To test this hypothesis, gametophytes of both species were grown in vitro as isolates, pairs, and groups. Both species were capable of intragametophytic selfing; 78% of L. microphyllum isolates produced sporophytes and over 90% of the L. japonicum isolates produced sporophytes. Lygodium microphyllum also displayed the ability to reproduce via intergametophytic crossing, facilitated by an antheridiogen pheromone. Sporophyte production was rapid across mating systems for both species, an advantage in Florida's wet and dry seasonal cycles. The high intragametophytic selfing rate achieved by both species has likely facilitated their ability to colonize and spread through Florida. The mixed mating system observed in L. microphyllum appears to give this species the ability to invade distant habitats and then adapt to local conditions. PMID- 21659215 TI - Consequences of differences in flowering date on seed production in Heloniopsis orientalis (Liliaceae). AB - We examined the consequences of differences in flowering date on seed production in the self-compatible herb Heloniopsis orientalis. The number of selfed seeds per fruit, as determined by microsatellite markers, did not depend on when the plant flowered, whereas the number of outcrossed seeds per fruit increased with later flowering dates. Consequently, the selfing rate decreased with later flowering dates. The number of seeds (including both selfed and outcrossed ones) per fruit and the seed : ovule ratio increased with later flowering dates. We also examined the effects of pollinators and plant size on seed production. The visitation rate of Diptera did not depend on the flowering season, whereas that of Hymenoptera markedly increased as the flowering season progressed. Diptera stayed longer than Hymenoptera on each plant and flower. Seed production per fruit did not depend on plant size. Thus, the change in selfing rate associated with later flowering dates resulted from the seasonal change in pollinators rather than plant size. PMID- 21659216 TI - Dispersal biology of Liatris scariosa var. novae-angliae (Asteraceae), a rare New England grassland perennial. AB - Propagule dispersal biology is a crucial avenue of research for rare plant species, especially those adapted to disturbance, such as northern blazing star (Liatris scariosa var. novae-angliae), a rare, early-successional New England grassland perennial. We examined the dispersal ability of northern blazing star propagules collected from 14 populations covering the entire latitudinal range of the taxon. Multiple regression demonstrated that dispersal ability, as measured by drop time in still air and flight distance in a low-speed wind tunnel, decreased significantly with propagule size and achene length, and increased with achene width and (for flight distance) pappus length. We used this multiple regression model to test for differences in predicted dispersal capability among maternal families, populations, and inland, coastal, and island habitats. Dispersal capability differed significantly among families and populations but not regions, and allometric relationships between morphological measurements were consistent across populations. Overall, dispersal capability was negatively correlated with germination success in a common greenhouse environment. However, germination success for a given dispersal ability, as well as achene shape, differed among populations. These results suggest specific populations to be targeted for management efforts promoting dispersal and establishment. PMID- 21659217 TI - Divergence in mycorrhizal specialization within Hexalectris spicata (Orchidaceae), a nonphotosynthetic desert orchid. AB - Evidence is accumulating for specialized yet evolutionarily dynamic associations between orchids and their mycorrhizal fungi. However, the frequency of tight mycorrhizal specificity and the phylogenetic scale of changes in specificity within the Orchidaceae are presently unknown. We used microscopic observations and PCR-based methods to address these questions in three taxa of nonphotosynthetic orchids within the Hexalectris spicata complex. Fungal ITS RFLP analysis and sequences of the ITS and nuclear LSU ribosomal gene fragments allowed us to identify the fungi colonizing 25 individuals and 50 roots. Thanatephorus ochraceus (Ceratobasidiaceae) was an occasional colonizer of mycorrhizal roots and nonmycorrhizal rhizomes. Members of the Sebacinaceae were the primary mycorrhizal fungi in every Hexalectris root and were phylogenetically intermixed with ectomycorrhizal taxa. These associates fell into six ITS RFLP types labeled B through G. Types B, C, D, and G were found in samples of H. spicata var. spicata, while only type E was found in H. spicata var. arizonica and only type F was found in H. revoluta. These results provide preliminary evidence for divergence in mycorrhizal specificity between these two closely related orchid taxa. We hypothesize that mycorrhizal interactions have contributed to the evolutionary diversification of the Orchidaceae. PMID- 21659218 TI - Breeding system and pollination of a narrowly endemic herb of the Lower Florida Keys: impacts of the urban-wildland interface. AB - We examined the breeding system and pollination of Chamaecrista keyensis Pennell (Fabaceae: Caesalpinioideae) and the effects of urban edge and mosquito control on reproduction of this rare endemic herb of the Lower Florida Keys. Controlled hand-pollination treatments were applied to plants in the field. Although C. keyensis flowers are self-compatible, they are not capable of automatic selfing. Inbreeding depression was observed in both seed set and percentage seed germination. Bees of seven genera were observed visiting C. keyensis flowers during the peak flowering season (June to July). Only Xylocopa micans and Melissodes spp. may be effective pollinators for C. keyensis, as they were the only bees that "buzz pollinate" this species, which has poricidal anther dehiscence. Chamaecrista keyensis received substantially more visits by X. micans, but fewer visits from Melissodes spp. in urban-edge vs. forest sites. Aerial mosquito spraying may exacerbate the existing pollinator limitation suffered by C. keyensis by reducing the number of visits by the buzz-pollinating bees. Individuals of C. keyensis at urban edges produced fewer seeds per fruit than did individuals in a pristine forest mainly because of greater insect seed predation. PMID- 21659219 TI - Salt spray differentially affects water status, necrosis, and growth in coastal sandplain heathland species. AB - Sandplain heathlands are disturbance-dependent plant communities that occur infrequently in coastal areas of the northeastern United States. We hypothesize that salt spray plays a role in maintaining the composition of the heathland community by excluding salt-intolerant species close to the ocean. We examined the distributions of Solidago nemoralis, Myrica pensylvanica, Pinus rigida, and Quercus spp. in heathlands and conducted greenhouse studies to determine whether different levels of salt spray tolerance explain patterns found in the field. We found that common heathland forb and shrub species grow closer to the ocean than successional woody species. In greenhouse experiments, these species differ in their water status, necrosis, and growth responses to salt spray. The tree species P. rigida and Q. rubra are more susceptible to salt spray than the common heathland species M. pensylvanica. Our results suggest that salt spray may prevent tree species in heathlands from growing close to the ocean and therefore might be an important factor in maintaining the characteristic community composition of these dwarf shrublands in coastal habitats. PMID- 21659220 TI - Seedling demography in an alpine ecosystem. AB - Seedling establishment has long been believed to be rare on alpine tundra because of predicted life history trade-offs, the clonality of alpine species, and the harshness of the alpine climate. Contrary to the idea that seedlings are rare on alpine tundra, a 4-yr demographic study of seedlings at Niwot Ridge, Colorado, USA, found seedlings at high densities, particularly in wetter plant communities. Higher germination densities were associated with higher soil moistures both across communities and across time. Mortality of seedlings was highest in the first year and decreased in subsequent years. Species' abundances differed between seedling and adult populations. Many forbs that lacked vegetative reproduction were significantly more abundant among seedling populations, and many monocots and clonal forbs were more abundant among adult populations. In a comparison with published demographic rates, seedling recruitment and mortality rates of Niwot Ridge species fell above or within rates for a wide range of perennial species. Therefore, germination and seedling establishment stages are no more limiting to sexual reproduction in alpine plants than in other perennial plants. PMID- 21659221 TI - Effects of herbivory and its timing across populations of Trillium grandiflorum (Liliaceae). AB - The goal of this study was to identify the degree to which the frequency and timing of herbivory by white-tailed deer (Odocoileus virginianus) and subsequent plant response varied across 12 populations of the perennial herb Trillium grandiflorum. Effects of natural and experimental herbivory on the stage and size of reproductive plants were measured. Both the frequency and timing of herbivory varied across T. grandiflorum populations. Reproductive plants were more likely to regress to nonreproductive stages in the next growing season when (1) reproductive plants were consumed by deer (vs. intact reproductive plants); (2) reproductive plants were consumed early in the growing season (vs. reproductive plants consumed late in the growing season); (3) reproductive plants were smaller in size. Clipped plants that remained reproductive were smaller in the following season than unclipped controls. Plant size was positively correlated with the number of ovules, suggesting that reductions in the growth rate of reproductive plants diminish their future reproductive success. Populations with high levels of natural herbivory had a greater proportion of reproductive plants that regressed to nonreproductive stages, probably because reproductive plants in these populations were smaller in size. However, the plant response to herbivory was similar across populations. PMID- 21659222 TI - The major clades of Loasaceae: phylogenetic analysis using the plastid matK and trnL-trnF regions. AB - Phylogenetic analyses of Loasaceae that apply DNA sequence data from the plastid trnL-trnF region and matK gene in both maximum-parsimony and maximum-likelihood searches are presented. The results place subfamily Loasoideae as the sister of a subfamily Gronovioideae-Mentzelia clade. Schismocarpus is the sister of the Loasoideae-Gronovioideae-Mentzelia clade. The Schismocarpus-Loasoideae Gronovioideae-Mentzelia clade is the sister of Eucnide. Several clades in Loasoideae receive strong support, providing insights on generic circumscription problems. Within Mentzelia, several major clades receive strong support, which clarifies relationships among previously circumscribed sections. Prior taxonomic and phylogenetic hypotheses are modeled using topology constraints in parsimony and likelihood analyses; tree lengths and likelihoods, respectively, are compared from constrained and unconstrained analyses to evaluate the relative support for various hypotheses. We use the Shimodaira-Hasegawa (SH) test to establish the significance of the differences between constrained and unconstrained topologies. The SH test rejects topologies based on hypotheses for (1) the placement of gronovioids as the sister of the rest of Loasaceae, (2) the monophyly of subfamily Mentzelioideae as well as Gronovioideae and Loasoideae, (3) the monophyly of Loasa sensu lato as circumscribed by Urban and Gilg, and (4) the monophyly of Mentzelia torreyi and Mentzelia sect. Bartonia. PMID- 21659223 TI - A first molecular phylogenetic analysis of Passiflora (Passifloraceae). AB - Passiflora, a genus with more than 400 species, exhibits a high diversity of floral and vegetative structures and a complex taxonomy, which includes 23 subgenera and many sections and series. To better understand Passiflora's variability and interspecific relationships, the phylogeny of 61 species, classified in 11 of 23 suggested subgenera, was investigated. Three molecular markers were used, the nuclear ribosomal internal transcribed spacers (nrITS), the plastid trnL-trnF spacer regions (~1000 bp), and the rps4 plastid gene (~570 bp). Three major clades were highly supported, independent of the marker and phylogenetic method used; one included the subgenera Distephana, Dysosmia, Dysosmioides, Passiflora, and Tacsonioides, a second, the subgenera Adopogyne, Decaloba, Murucuja, and Pseudomurucuja, and a third, the subgenus Astrophea. We call these the Passiflora, Decaloba, and Astrophea clades, respectively. The position of subgenus Deidamioides is undefined. The monophyly of Passiflora could not be statistically corroborated, and the relationships among the major clades and of these clades with the related genera remain unresolved. Our results indicate that a reevaluation of the monophyly of Passiflora and its infrageneric classification is necessary. PMID- 21659224 TI - On Paleozoic plants from marine strata: Trivena arkansana (Lyginopteridaceae) gen. et sp. nov., a lyginopterid from the Fayetteville Formation (middle Chesterian/Upper Mississippian) of Arkansas, USA. AB - Five permineralized seed fern stems from the Fayetteville Formation (middle Chesterian/Upper Mississippian) of Arkansas conform to the concept of lyginopterid seed ferns. However, these specimens are unlike all previously reported lyginopterids, and the name Trivena arkansana (Lyginopteridaceae) gen. et sp. nov. is proposed. The stems are up to 30 by 19 mm in diameter and have pentagonal pith and eustele of five cryptic sympodia. Secondary tissues include abundant xylem with numerous wide rays and phloem surrounded by a periderm. The cortex is parenchymatous with abundant sclerotic clusters: some clusters are randomly dispersed and some are in discontinuous rows. Sclerenchyma bands form the "Dictyoxylon"-type outer cortex. Leaf traces diverge in a 2/5 phyllotaxy. Traces, accompanied by concentric secondary xylem, increase in size as they extend through the secondary xylem of the stem. The trace assumes a squat C shape at the outer margin of the secondary xylem and in the cortex divides into three discrete bundles, each surrounded by secondary xylem. Galleries within the phloem contain arthropod coprolites and exhibit wound response, suggesting plant arthropod coevolution. The discovery of this new lyginopterid stem adds to the growing list of unique taxa described from the Fayetteville Formation and further solidifies its reputation as one of the most important Upper Mississippian plant fossil sites in North America. PMID- 21659225 TI - Field measurements of wind speed and reconfiguration in Arundo donax (Poaceae) with estimates of drag forces. AB - The giant reed (Arundo donax) is well known as a species that can withstand high wind loads without mechanical damage. To examine wind impact, profiles of vertical wind speeds in the plant's natural habitat (southern France) were measured at the edge and within a stand in the main wind direction. Wind speed was recorded simultaneously at five heights. For 75 measurements of within-canopy wind speed profiles, the attenuation coefficient was 4.4 +/- 0.5, a value typical for plant stands with very dense canopies. Video recordings proved that A. donax becomes streamlined with increasing wind speed, reducing the projected surface area of leaves and stem. The total projected surface area is a function of wind speed and can be characterized by a second-order polynomial regression curve. For small wind velocities up to 1 m/s, the calculated drag force is proportional to the square of the wind speed. However, when A. donax plants are subjected to higher wind speeds (1.5-10 m/s), the drag force becomes directly proportional to the wind speed. Streamlining is a potentially important adaptation for withstanding high wind loads, especially for individual plants and plants at the edge of stands, whereas in dense stands streamlining probably plays a minor role. PMID- 21659226 TI - Incongruence between cladistic and taxonomic systems. AB - Cladistic and taxonomic treatments of the same plant group usually exhibit a mixture of congruences and incongruences. The question arises in the case of the incongruences as to which version is right and which is wrong. Many cladists believe that cladistics is a superior approach and gives the best results. There are several conceptual and methodological differences between cladistics and taxonomy that cause incongruence. One important conceptual difference is the use of different criteria for grouping: order of branching vs. similarity and difference (clades vs. taxa). Another is the policy regarding paraphyletic groups: to ban them in cladistics but ignore the ban in taxonomy. These two differences automatically lead to some incongruences. One approach is not right and the other wrong; each is operating by its own standards. However, when cladists apply the paraphyly rule to a taxonomic system and conclude that it needs revision to eliminate paraphyly, as cladists often do, they are judging the taxonomic system by a wrong standard. Several differences between the two schools in the use and handling of characters can also cause incongruence. First consider phenetic characters. Taxonomy uses a very wide range of these, whereas phenetic cladistics sets restrictions on the selection of characters, which deprive it of potentially useful evidence. Taxonomic systems generally rest on a broader empirical foundation than phenetic cladistic systems. Next, consider molecular cladistics, which is the leader in the use of DNA evidence. Two sources of incongruence between molecular cladistics and taxonomic systems can come into play here. First, the molecular evidence used in cladistics comes mainly from cytoplasmic organelles, whereas taxonomic systems are based on characters that are determined mainly by the chromosomal genome. More generally, the database in a molecular cladogram is, in itself, too narrow to serve as a foundation for an organismic classification. In cases of incongruence, the molecular evidence can be a reliable indicator of taxonomic relationships sometimes, misleading other times, and may afford no clear basis for a systematic decision. In this situation, it is helpful, indeed necessary, to integrate the molecular evidence with the phenetic evidence and bring more characters to bear on the question. PMID- 21659227 TI - Floral ontogeny in Swartzia (Leguminosae: Papilionoideae: Swartzieae): distribution and role of the ring meristem. AB - The anomalous systematic position of Swartzieae at the base of Papilionoideae is correlated with unusual developmental features: one petal or none; a ring meristem; polystemony; heterostemony; little or no alignment of stamens as antesepalous or antepetalous; multicarpely; and absence of unidirectional order of organs except in the calyx. Symmetry is zygomorphic throughout development. Floral ontogeny of four species of Swartzia reveals five sepals are initiated successively, beginning abaxially, but intercalary growth below the separate sepals forms a tubular calyx that splits irregularly, a feature typifying the genus. A single petal is initiated adaxially or may be missing altogether (in S. sericea). The apex enlarges and forms a ring meristem concurrently with carpel initiation. Several large-stamen primordia (2-15, according to the species) initiate first on the ring, followed by 40-150 small-stamen primordia. The latter initiate in centrifugal order in S. aureosericea and S. laurifolia or in acropetal order in S. sericea and S. madagascariensis. While ring meristems are considered to be homologous among Neotropical species studied as well as in the African S. madagascariensis, they vary in extent, duration, order of initiation, and productivity. Swartzieae is unlikely to be ancestral to the rest of Papilionoideae, based on radically differing floral ontogeny in the two groups. PMID- 21659228 TI - Androecium diversity and evolution in Myristicaceae (Magnoliales), with a description of a new Malagasy genus, Doyleanthus gen. nov. AB - Myristicaceae (Magnoliales) consist of 20 genera and nearly 500 species of lowland rainforest trees with a pantropical distribution. They are distinctive in having small, unisexual flowers with stamens fused into a synandrium, which consists of a single whorl of sessile anthers borne around a sterile central column. With its short filaments and more complex anther phyllotaxy, the Malagasy genus Mauloutchia represents a notable exception to this pattern. New scanning electron microscope (SEM) examinaitons of Brochoneura, Cephalosphaera, Knema, Mauloutchia, and Staudtia are incorporated into a broader review of androecium diversity across the family. These new results are discussed in the context of a phylogenetic study of the family, based on combined molecular and morphological data. The unusual synandrium of Mauloutchia, nested among genera with strictly sessile anthers fused to the column, appears to be secondarily derived. Furthermore, the diversity of patterns observed within the genus may be interpreted as the result of a stepwise transformation involving reappearance and elongation of filaments, increase of anther number, and modification of anther phyllotaxy. However, the question of the origin of stamen fusion in Myristicaceae remains unanswered and requires more developmental studies. Finally, a new Malagasy genus of Myristicaceae (Doyleanthus) is described, which is similar to Mauloutchia in most characters but fundamentally different in androecial traits. PMID- 21659229 TI - Genetic and historical relationships among geothermally adapted Agrostis (bentgrass) of North America and Kamchatka: evidence for a previously unrecognized, thermally adapted taxon. AB - Agrostis species have been known to evolve ecotypes rapidly in response to unusual edaphic conditions. The geographic distribution of Agrostis taxa in Lassen Volcanic National Park (California) and Yellowstone National Park (Wyoming) in the United States and the Valley of the Geysers (Kamchatka Peninsula) in Russia suggests that Agrostis scabra might have independently evolved morphologically similar ecotypes several times. We used RAPDs to show that, contrary to expectation, the thermal populations are not independently evolved, but instead constitute a single taxon that currently has four names. A UPGMA including the four thermal and nine nonthermal Agrostis taxa showed that the thermal cluster divides into geographically distinct subclusters, but that two morphologically distinct thermal taxa do not cluster independently. Even though currently confused with the thermal populations, nonthermal A. scabra is not closely related. An analysis of molecular variance (AMOVA) showed significant differentiation between the thermal populations and the nonthermal species sampled in this study. Splitting a hypothesized thermal operational taxonomic unit (OTU) into its components (geographically separated populations) does not greatly affect the partitioning of variation among OTUs. All thermal populations therefore should be assigned to the same taxon, but its taxonomic rank cannot be determined at this time. PMID- 21659230 TI - The pattern of carbon allocation supporting growth of preformed shoot primordia in Acomastylis rossii (Rosaceae). AB - Extreme preformation, the initiation of leaves or inflorescences more than 1 yr before maturation and function, is common in arctic and alpine habitats. This extended pattern of development provides a potential means to alleviate an apparent asynchrony between carbon supplied by photosynthesis in the summer and carbon demanded by growth in the spring. Allocation of resources to preforming organs has not been studied in herbs with multi-year patterns of preformation. Acomastylis rossii (Rosaceae) in the southern Rockies initiates leaves and inflorescences 2 yr prior to their maturation and function. Allocation to preforming organs in A. rossii was studied by means of a labeled carbon pulse chase experiment. During the summer, carbon is allocated directly to preforming organs and rhizomes from the mature leaves. Additional allocation of carbohydrate into preforming organs occurs in autumn after photosynthesis by mature leaves has ceased. Organ primordia initiated in the second year do not receive a substantial quantity of the labeled carbon from reserves stored in the rhizome the previous year. We conclude that concurrent photosynthesis is the primary source of carbon for preformation development. PMID- 21659231 TI - Variations in bumble bee preference and pollen limitation among neighboring populations: comparisons between Phyllodoce caerulea and Phyllodoce aleutica (Ericaceae) along snowmelt gradients. AB - Two alpine-snowbed shrubs, Phyllodoce caerulea and P. aleutica (Ericaceae), co occur in locales in northern Japan with early to late snowmelt, but they have different mating systems. Phyllodoce caerulea is an obligate outcrosser in any population, whereas the selfing ability of P. aleutica is highly variable among neighboring populations along snowmelt gradients: it shows high self compatibility in early to middle snowmelt populations but low self-compatibility in late snowmelt populations. We investigated the relationships between pollinator availability and mating systems of these species along three snowmelt gradients. Relative abundance of flowers and nectar standing crop of P. caerulea decreased from early to late snowmelt plots. Bumble bees preferred P. caerulea to P. aleutica in early and middle snowmelt plots, while their preference shifted to P. aleutica in late snowmelt plots. Pollen limitation was severe in P. aleutica in early to middle snowmelt plots but it was severe in P. caerulea in late snowmelt plots. Seed-set success under natural conditions of P. aleutica was higher than that of P. caerulea in all plots. Thus, we infer that the selfing ability of P. aleutica under pollinator limitation acts as a reproductive assurance. We conclude that the interaction through pollination between the sympatric species is strong enough to cause a phenotypic change in mating system even within a local area. PMID- 21659232 TI - Floral longevity and reproductive assurance: seasonal patterns and an experimental test with Kalmia latifolia (Ericaceae). AB - Floral longevity is assumed to reflect a balance between the benefit of increased pollination success and the cost of flower maintenance. Flowers of Kalmia latifolia (Ericaceae), mountain laurel, have a long duration and can remain viable up to 21 d if unpollinated. I experimentally tested whether this long duration increases pollination success by clipping stigmas to reduce functional floral longevity to 3-4 d. Clipping stigmas decreased fruit set from 65% to only 10%. Flowers with natural life spans were not pollination-limited, demonstrating that long floral duration ensured female reproductive success. The long floral duration of K. latifolia was unique in this site (the Great Swamp, Rhode Island, USA). Coflowering shrubs in summer had a mean floral life span of 3.4 d. Spring flowering species had significantly longer mean floral durations (7.2 d). These duration differences may reflect seasonal variation in pollinator availability. However, K. latifolia flowers in summer, when its bumble bee pollinators are abundant but it is a poor competitor for bees because its flowers produce little nectar. The long floral duration allows K. latifolia to outlast coflowering competitors and attract sufficient pollinators. I hypothesize that the long floral duration of K. latifolia functions as a mechanism for competitive avoidance and reproductive assurance. PMID- 21659233 TI - Natural selection on floral traits of Lobelia (Lobeliaceae): spatial and temporal variation. AB - The strength and direction of natural selection on floral traits can vary spatially and temporally because of variation in the biotic and abiotic environment. High spatial variation in selection should lead to differentiation of floral traits among populations. In contrast, high temporal variation in selection should retard the evolution of population-specific floral phenotypes. To determine the relative importance of spatial vs. temporal variation in natural selection, we measured phenotypic selection on seven floral traits of the wildflowers Lobelia cardinalis and L. siphilitica in 1999 and 2000. Lobelia cardinalis experienced significant temporal variation in selection, whereas L. siphilitica experienced spatial variation in selection on the same traits. This variation in selection on floral traits was associated with spatial and temporal differences in the soil microenvironment. Although few studies of natural selection include spatial or temporal replicates, our results suggest that such replication is critical for understanding the distribution of phenotypes in nature. PMID- 21659234 TI - Patterns of prey capture and prey availability among populations of the carnivorous plant Pinguicula moranensis (Lentibulariaceae) along an environmental gradient. AB - In this study we explored the effect of the physical environment and the availability of prey (biomass and taxonomic composition) on the patterns of prey capture and reproduction on five populations of Pinguicula moranensis (Lentibulariaceae) in areas ranging from pine-oak forests to desert scrublands. Environmental variation was summarized using principal factor analysis. Prey availability and prey capture increased toward the shadiest, most humid, and fertile population. The probability of reproduction and average bud production per population did not follow the same tendency because both fitness components peaked at the middle of the environmental gradient. These results suggest that the benefits derived from carnivory are maximized at sites fulfilling a trade-off between light, moisture, and prey availability. We also found that the taxonomic composition of both the available prey and that of the prey captured by plants varied among populations. The results also indicated that the prey captured by plants are not a random sample of prey available within populations. Overall, the results from this study revealed a marked amount of heterogeneity in the physical and biotic environment among the populations of P. moranensis, which has the potential to affect the outcome of the interaction between this carnivorous species and its prey. PMID- 21659235 TI - Biomechanics of buttressed trees: bending strains and stresses. AB - The different hypotheses about buttress function and formation mainly involve mechanical theory. Forces were applied to two trees of Sloanea spp., a tropical genus that develops typical thin buttresses, and the three-dimensional strains were measured at different parts of the trunk base. Risks of failure were greater on the buttress sides, where shear and tangential stresses are greater, not on the ridges, in spite of high longitudinal (parallel to the grain) stresses. A simple beam model, computed from the second moment of area of digitized cross sections, is consistent with longitudinal strain variations but cannot predict accurately variations with height. Patterns of longitudinal strain variation along ridges are very different in the two individuals, owing to a pronounced lateral curvature in one specimen. The constant stress hypothesis is discussed based on these results. Without chronological data during the development of the tree, it cannot be proved that buttress formation is activated by stress or strain. PMID- 21659236 TI - Phylogenetic analyses of Cornales based on 26S rRNA and combined 26S rDNA-MATK RBCL sequence data. AB - Nuclear 26S rDNA sequences were used to corroborate and test previously published matK-rbcL-based hypotheses of phylogenetic relationships in Cornales. Sequences were generated for 53 taxa including Alangium, Camptotheca, Cornus, Curtisia, Davidia, Diplopanax, Mastixia, Nyssa, and four families: Grubbiaceae, Hydrangeaceae, Hydrostachyaceae, and Loasaceae. Fifteen taxa from asterids were used as outgroups. The 26S rDNA sequences were initially analyzed separately and then combined with matK-rbcL sequences, using both parsimony and maximum likelihood methods. Eight strongly supported major clades were identified within Cornales by all analyses: Cornus, Alangium, nyssoids (Nyssa, Davidia, and Camptotheca), mastixioids (Mastixia and Diplopanax), Hydrangeaceae, Loasaceae, Grubbia-Curtisia, and Hydrostachys. However, relationships among the major lineages are not strongly supported in either 26S rDNA or combined 26S rDNA-matK rbcL topologies, except for the sister relationships between Cornus and Alangium and between nyssoids and mastixioids in the tree from combined data. Discrepancies in relationships among major lineages, especially the placement of the long-branched Hydrostachys, were found between parsimony and maximum likelihood trees in all analyses. Incongruence between the 26S rDNA and matK-rbcL data sets was suggested, where Hydrangeaceae was found to be largely responsible for the incongruence. The long branch of Hydrostachys revealed in previous analyses was reduced significantly with more sampling. Maximum likelihood analysis of combined 26S rDNA-matK-rbcL sequences suggested that Hydrostachys might be sister to the remainder of Cornales, that Cornus-Alangium are sisters, that nyssoids-mastixioids are sisters, and that Hydrangeaceae-Loasaceae are sisters, consistent with previous analyses of matK-rbcL sequence data. PMID- 21659237 TI - Divisestylus gen. nov. (aff. Iteaceae), a fossil saxifrage from the Late Cretaceous of New Jersey, USA. AB - Fossilized flowers and fruits from the Upper Cretaceous (Turonian, ca. 90 million years [my] before present) Raritan Formation of New Jersey are described as the new genus Divisestylus with two species, D. brevistamineus and D. longistamineus. The fossils are fusainized and three-dimensionally preserved. Morphological characteristics suggest affinities with extant Saxifragaceae and Iteaceae, two closely related families in Saxifragales. Similarities include a pentamerous perianth, calyx fused below into a hypanthium with free sepal lobes above, haplostemonous androecium with stamens situated opposite the calyx lobes, inferior ovary, bicarpellate gynoecium, numerous ovules on axile placentas, conspicuous intrastaminal nectary ring, and capsulate fruit opening apically. The unique fusion of the gynoecium, with carpels and stigmas fused but styles free, indicates closer affinities with extant Iteaceae, whereas other characters, such as basifixed anthers in D. brevistamineus, tricolpate and striate pollen grains, and anomocytic stomata, indicate closer affinities to Saxifragaceae. Cladistic analyses utilizing molecular data from a previously published analysis and morphological data as well as morphological data alone demonstrate the fossils share a more recent common ancestor with Iteaceae than Saxifragaceae, thereby making Divisestylus the oldest fossils known with clear affinities to Iteaceae. PMID- 21659238 TI - An extinct genus of Salicaceae based on twigs with attached flowers, fruits, and foliage from the Eocene Green River Formation of Utah and Colorado, USA. AB - A newly recovered twig with attached leaves and flowers from the Eocene Green River Formation of Utah provides the basis for recognizing a new, extinct genus of Salicaceae sensu lato (s.l.). Pseudosalix handleyi gen. et sp. nov. has alternate lanceolate leaves with pinnate, semicraspedodromous venation and a serrate margin with glandular teeth. The inflorescence is terminal on the twig and is unisexual, composed of flowers organized in a paniculoid cyme, with lateral paraclades of pedicellate flowers. The attached pistillate flowers have four prominent sepals that are valvate in bud, spreading but basally fused at anthesis; the single pistil of each flower is ovoid with three or four longitudinal sutures, indicating development to a capsular fruit. Three or four recurved styles radiate from the apex of the pistil, each with a distal globose stigma. The infructescence, verified by attachment to twigs with the same kind of leaves, bore capsular fruits of three and four valves. Associated but unattached, staminate flowers also have four well-developed, basally connate sepals. They are pedicellate and bear several stamens, each with a short filament and globose anther. The available morphological characters place the fossil species within the Salicaceae s.l. as an immediate sister to the clade containing Populus and Salix. Although the likely outgroup genera (including Itoa, Poliothyrsis, Carrierea, and Idesia) to tribe Saliceae all occur in Asia today and not North America, the occurrence of both Pseudosalix and Populus in the Eocene of Utah raises the possibility of a North American origin for the Saliceae. PMID- 21659239 TI - Transgenic overproduction of glutathione reductase does not protect cotton, Gossypium hirsutum (Malvaceae), from photoinhibition during growth under chilling conditions. AB - In some studies, tissues from plants that have been genetically transformed to overproduce antioxidant enzymes sustain less damage when abruptly exposed to short-term chilling in the laboratory. However, few studies have examined the performance of transgenic plants during longer-term growth under chilling conditions. We compared growth of transgenic cotton that overproduces glutathione reductase (GR+; ~40-fold overproduction) to growth of the wild type in a controlled environment chamber as leaf temperature was lowered from 28 degrees to 14 degrees C over 9 d and for a subsequent 9-d period at 14 degrees C. In wild type and GR+ cotton, chilling temperatures resulted in decreased dark-adapted F(v)/F(m) (the ratio of variable to maximal fluorescence; a measure of maximum photosystem II quantum yield) and mid-light period photosystem II quantum yield, coupled with increased 1 - q(P) (a nonlinear estimate of the reduction state of the primary quinone acceptor of photosystem II). The capacity for photosynthetic oxygen evolution decreased during the first portion of the chilling exposure, but recovered slightly during the second half. At no point during the chilling exposure did the performance of GR+ plants differ significantly from that of wild type plants in any of the above parameters. The absence of an effect of GR overproduction under longer-term chilling may be explained, in part, by the fact that wild-type cotton acclimated to chilling by upregulating native GR activity. PMID- 21659240 TI - Transcranial Magnetic Stimulation (TMS): An Entirely Novel Form of Treatment in Psychiatry and a Groundbreaking Opportunity for Psychiatric Mental Health Nursing. PMID- 21659242 TI - A review of studies comparing methods for determining transcranial magnetic stimulation motor threshold: observation of movement or electromyography assisted. AB - BACKGROUND: Early in the development of transcranial magnetic stimulation (TMS) as a research tool, scientists developed the concept of motor threshold (MT) as a method of quantifying dose and establishing safety. Neurophysiologists determined the MT with the aid of peripheral electromyography (EMG). More recently, clinicians started substituting the EMG with observed movements (OM) of the hand or digits. It is unclear whether the two approaches (EMG and OM) reach similar conclusions about an individual's cortical excitability and when best to use each approach. OBJECTIVE: To review TMS studies directly comparing the EMG and OM MT methods. DESIGN: A systematic search of the literature on Medline from January 1995 through April 2008. RESULTS: Four articles directly compared the two approaches, reaching different and opposing findings. CONCLUSION S: The evidence supporting the substitution of EMG with OM is sparse and conflicting. Clinicians stimulating at or near safety guidelines should use the EMG method. PMID- 21659243 TI - Effective utilization and future directions for repetitive transcranial magnetic stimulation: a guide for psychiatric nurses. AB - Repetitive transcranial magnetic stimulation (rTMS) and magnetic seizure therapy (MST) represent new and promising avenues for treating mild and severe treatment resistant depression, respectively. A further understanding of these modalities and the contribution of psychiatric nurses in the emerging field of brain stimulation would be of great use to the nursing community. This article serves as a primer for those who are interested in participating in or referring patients for research or treatment with rTMS or MST. Of particular emphasis is the role of certified psychiatric nurses as clinical rater, patient liaison, and evidence-based practitioner: PMID- 21659244 TI - A Psychiatric Nurse's Perspective: Helping Patients Undergo Repetitive Transcranial Magnetic Stimulation (rTMS) for Depression. AB - With the October 2008 Food and Drug Administration approval of repetitive transcranial magnetic stimulation (rTMS) for depression treatment, the establishment and administration of rTMS clinical treatment programs are critically important and emerging areas for psychiatric nursing leadership. There is growing recognition that many patients are unable to tolerate antidepressant medications and require alternative antidepressant treatment approaches. The enormous growth in the field of brain stimulation creates exciting new therapeutic options for patients with treatment-resistant depression. As with any clinical breakthrough, new treatments offer exciting possibilities but also require growth in psychiatric nursing knowledge, different practice competencies, and new ways of organizing care. This article discusses current practice guidelines, psychiatric nursing qualifications, and essential details about developing an rTMS clinical service. This is the first article to describe the role of a psychiatric nurse establishing a clinical rTMS service, administering rTMS, and helping patients undergo the treatment. The authors share the progress made and the lessons learned. PMID- 21659245 TI - The Structure of the Lived Experience for Persons Having Undergone rTMS for Depression Treatment. AB - OBJECTIVE: This phenomenological research study reports preliminary findings about experiences of persons undergoing repeated transcranial magnetic stimulation (rTMS) for depression treatment. METHODS: Giorgi's phenomenology was the method used to describe the structure of the lived experience for persons having undergone rTMS treatment for depression. Participants were recruited from the OPT-TMS pivotal depression study that resulted in the October 2008 FDA approval of rTMS. Thus far, nine persons comprise the purposive sample. Each participant was asked to describe the experience of undergoing rTMS for depression treatment and encouraged to provide as much details as possible. RESULTS: Four preliminary themes emerged to describe participants' experiences of rTMS for depression treatment: (a) a narrative of frustration and helplessness with medication treatment resistance, (b) the sensory experience of rTMS, (c) mindfulness- an enhanced awareness of the content of consciousness, and (d) the importance of connection with clinicians. CONCLUSIONS: Preliminary results of this phenomenological study make the struggle of persons with treatment-resistant depression more visible and should assist clinicians to understand how rTMS is experienced by depressed persons undergoing treatment. Moreover, results shed new light on the changes participants observe and describe with rTMS and the high value they place on a therapeutic relationship with clinicians administering treatment. PMID- 21659246 TI - A Milestone in JAPNA's Development: The Dialogue and Discourse Has Begun! PMID- 21659247 TI - Letters to the editor. PMID- 21659248 TI - Letters to the editor. PMID- 21659249 TI - Letters to the editor. PMID- 21659250 TI - The cost of stress: a dilemma with healthy mutation carriers. AB - Literature poses the question of whether people bear a prior physiological tendency to react to stress that makes them more susceptible to onset of diseases or whether traumatic events are powerful enough to trigger a physiological reaction that ultimately induces a disease. Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder with a sudden and rapid onset and progression. Thus far, no therapeutic or prophylactic treatment has been available. Recently, it was found that apparently healthy mutation carriers of CJD demonstrate higher anxiety levels than noncarriers from the same families. Furthermore, there seems to be a connection between stressful life events and the onset of CJD. Over the past few years, people whose relatives died due to CJD are becoming increasingly interested in genetic consultation based on a fear that they too are carrying the mutation. The dilemma of "cost-benefit" of making available such information in this unique stressed population is discussed. PMID- 21659251 TI - The inextricable nature of mental and physical health: implications for integrative care. AB - There is growing evidence that physical health problems are caused and exacerbated by psychological factors. Research indicates that psychological distress leads to physical disease through impairment of the neuroendocrine system and its interface with the body's immune response. However, the current health care delivery system splinters care into "psychiatric" and "physical" health silos. New approaches are needed to assure adequate professional knowledge of behavioral health at basic licensure, to increase the use of advanced practice psychiatric-mental health nurses in primary care settings, to identify and teach behavioral competencies for primary care providers, and to fund the design and evaluation of integrative models of care. PMID- 21659253 TI - The impact of opening a smoking room on psychiatric inpatient behavior following implementation of a hospital-wide smoking ban. AB - BACKGROUND: Psychiatric patients are significantly more likely to smoke than mentally healthy persons, presenting a challenge for inpatient psychiatric care when smoking bans are instituted. OBJECTIVE: To assess the impact of opening a smoking room within a psychiatric unit following a hospital smoking ban. STUDY DESIGN: A staff survey and a chart review of 180 inpatient admissions before and after the opening of a smoking room. RESULTS: Patient records revealed no significant differences between recorded indices of disruptive patient behavior before or after the smoking room opening. The staff survey identified a perceived beneficial impact on unit atmosphere, where less time was spent discussing smoking privileges and off-unit privileges were granted more appropriately. CONCLUSIONS: Implementation of a smoking room failed to reduce indices of disruptive patient behavior. Despite the absence of objective evidence, the attitude among staff was in support of allowing patients to smoke on the unit. PMID- 21659252 TI - National survey of psychiatric mental health advanced practice nursing: the adequacy of educational preparation: voices of our graduates. AB - BACKGROUND: Little is known about the fit between practice and graduate education from the perspective of psychiatric mental health advanced practice registered nurses (PMH APRNs). OBJECTIVE: With the purpose of addressing this gap in our knowledge, an e-mail survey that was sent to certified PMH APRNs included a query "Did your program prepare you for your role?" and an open-ended follow-up question: "Please explain how your graduate program did not prepare you adequately for your role?" DESIGN: Descriptive survey. RESULTS: Although 70% of respondents reported satisfaction with their educational programs, content analysis of the comments indicated that the most pressing concerns related to instructional content about psychopharmacology, the practice of prescribing and psychiatric diagnosing, and that there was a perception of a disconnect between the role they were prepared for and their role in the present-day world of work. CONCLUSIONS: The findings reinforce the need for the PMH nursing specialty to further define the optimal methods for preparing APRNs for the full scope of psychiatric services they are licensed to provide as the size of the PMH APRN workforce increases. PMID- 21659254 TI - A clinical translation of the research article titled, "the impact of opening a smoking room on psychiatric inpatient behavior following implementation of a hospital-wide smoking ban". PMID- 21659255 TI - Authors' response to commentary. PMID- 21659256 TI - Report From the APNA Tobacco Dependence Council. PMID- 21659257 TI - Schizophrenia: what do we know and how do we know it? PMID- 21659259 TI - Schizophrenia: women bear a disproportionate toll of antipsychotic side effects. AB - BACKGROUND: Men and women with schizophrenia suffer not only from their illness but also from the side effects of their medications. OBJECTIVE: To review the toll of antipsychotic side effects specifically on women. STUDY DESIGN: A review of the literature in the PubMed database since 1990 using search terms: sex difference, antipsychotics, schizophrenia, pharmacokinetics, pharmacodynamics, and pharmacogenomics and retrieving additional publications from the reference lists of the original articles. RESULTS: Findings suggest that, because of differing pharmacokinetics, women are more vulnerable than men to weight gain secondary to antipsychotics and to the consequences (metabolic, cardiovascular, reproductive) of weight gain. They are also more vulnerable to hyperprolactinemia and QTc prolongation. CONCLUSIONS: Dosing guidelines need to be critically appraised. The greater toll of side effects in women may undermine adherence to prescribed treatments, add to the stigma that attaches to mental illness, and diminish the quality of women's lives. Side effects increase the cost of mental illness and heighten the burden experienced by caregivers. They exacerbate morbidity and raise mortality rates. They affect the children of women treated with antipsychotic medication. PMID- 21659260 TI - Successful change in tobacco use in schizophrenia. AB - The high rates of tobacco use among individuals with schizophrenia are well documented, but there has been less attention paid to identifying what are the special needs for this population. In fact, there have even been suggestions from early work that standard interventions and approaches might be adequate. In contrast, based on more than a decade of experience supporting change smoking behavior among people with schizophrenia, three key factors were identified as unique considerations that are associated with success. The first factor involves readiness to change; smokers with schizophrenia are rarely given opportunities to even try to quit unlike their counterparts in the general population and therefore have not benefited from the self-efficacy aspects of attempt experiences. The second factor is medication and symptom monitoring; there are special needs for nurses and medical staff to monitor symptoms (including schizophrenia symptoms and mood symptoms), medication dosage and side-effects, during the period when individuals with schizophrenia are changing (reducing) their tobacco use, particularly when nicotine replacement therapy is being implemented. Finally, the third factor is peer and caregiver support; the use of peer assistants in group-based programs and the teaching of nurses and other professional casegivers as well as family members about their role as supports can make an important difference in tipping the balance toward successful change and toward maintenance of change over time. PMID- 21659261 TI - Recovery and wellness amidst schizophrenia: definitions, evidence, and the implications for clinical practice. AB - Emerging evidence from longitudinal studies has suggested that many with schizophrenia can meaningfully recover over time. Recovery, though, is not a uniform process but varies from person to person and can involve a range of different experiences including the attainment of psychosocial milestones, the remission of symptoms, and changes in self-experience or personal narrative. To address the issue of recovery from schizophrenia, this article reviews currently evolving definitions of recovery and possible ways to understand recovery as involving both an objective and two subjective dimensions. Emerging operational definitions are explored and then empirical research is reviewed regarding actual rates and forms of recovery. It is concluded that although many with schizophrenia experience significant challenges linked with illness over time, more people than not experience meaningful periods of relative wellness. Implications for how daily practice can reinforce and promote recovery are discussed. PMID- 21659262 TI - Coming back normal: the process of self-recovery in those with schizophrenia. AB - BACKGROUND: Researchers have identified the reestablishment of self-identity as a key part of recovery in individuals with schizophrenia. Previous studies have increased scholars' understanding about how and when identity changes occur in those with schizophrenia; less is understood about the process by which individuals with schizophrenia reconstruct their self-identity. OBJECTIVE: The objective of this study is to describe the process of self-identity reconstruction in people with schizophrenia. STUDY DESIGN: A grounded theory study was conducted with 10 purposively selected participants and 4 significant others; 19 semistructured interviews were completed. RESULTS: Constant comparative analysis led to a theory of a six-stage process of self-recovery in those with schizophrenia. For some participants, the successful struggle to care for a new self led to the refinement and eventual recovery of self-identity. CONCLUSIONS: Individuals with schizophrenia experience a process of distinct changes in self-identity occurring between engulfment by a severe mental illness and emergence of a new self. PMID- 21659263 TI - Clinical translation of the article titled "coming back normal: the process of self-recovery in those with schizophrenia". PMID- 21659264 TI - Exploring the impact of race on mental health service utilization among african americans and whites with severe mental illness. AB - BACKGROUND: Disparities among African Americans and Whites with severe mental illness have been identified in numerous studies. Yet it remains unknown if disparities are associated with race or other vulnerabilities common to this population. OBJECTIVES: This study used the Behavioral Model for Vulnerable Populations to examine mental health service utilization among 155 African Americans and Whites with severe mental illness for 12 months after discharge from a residential crisis program. DESIGN: This cross-sectional study was a secondary analysis of data from a randomized trial. RESULTS: Race did not emerge as a significant predictor of mental health service utilization. Factors associated with frequency of service use were diagnosis, age, drug use, gender, health benefit status, and enrollment in an outpatient mental health program. CONCLUSION: It is possible that the geographic location of the study, equal access to services, and equal rates of substance use between racial groups explain the lack of racial differences found in this sample. PMID- 21659265 TI - A clinical translation of the research article titled, "exploring the impact of race on mental health service utilization among african americans and whites with severe mental illness". PMID- 21659266 TI - Rapid response team for behavioral emergencies. AB - Behaviors of patients with psychiatric illness who are hospitalized on nonbehavioral health units can be difficult to address by staff members. Instituting a rapid response team to proactively de-escalate potential volatile situations on nonpsychiatric units in a hospital allows earlier treatment of behavioral issues with these patients. The behavioral emergency response team (BERT) consists of staff members (registered nurses, social workers) from behavioral health services who have experience in caring for patients with acute psychiatric disorders as well as competence in management of assaultive behavior. BERT services were trialed on a medical pulmonary unit; gradual housewide implementation occurred over 2 years. Tools developed for BERT include an activation algorithm, educational cue cards for staff, and a staff survey. Results of a performance improvement survey reveal that staff nurses have had positive experiences with BERT but that many nurses are still not comfortable caring for psychiatric patients on their units. PMID- 21659267 TI - Role of hyperparathyroidism in the management of depression and anxiety. AB - A thorough workup of patients who present with depression and anxiety is imperative to treat underlying conditions in order to potentially decrease psychiatric symptoms. This case describes the hospital course of a patient previously diagnosed with depression and anxiety who experienced an exacerbation of symptoms that may have been related to hyperparathyroidism. PMID- 21659268 TI - Effect of a motivational group intervention on exercise self-efficacy and outcome expectations for exercise in schizophrenia spectrum disorders. AB - BACKGROUND: Persons with schizophrenia spectrum disorders (SSDs) contend with multiple barriers to exercise. Interventions are needed to enhance attitudes theoretically linked to exercise behavior. OBJECTIVE: To examine the effect of Walk, Address Sensations, Learn About Exercise, Cue Exercise for SSDs (WALC-S) intervention on exercise self-efficacy (SEE) and outcome expectations (OEES) in 97 outpatients with SSDs. DESIGN: Experimental, pre- and posttest. Randomization to experimental (WALC-S) or time-and-attention control (TAC) after baseline SEE and OEES measures. Measures repeated after WALC-S or TAC. RESULTS: N = 97, 46% female, 43% African American, average age 46.9 years (SD = 2.0). Mean SEE scores were significantly higher in WALC-S participants after intervention, F(1, 95) = 5.92, p = .0168, however, mean OEES scores were significantly higher in control participants after intervention, F(1, 95) = 5.76, p = .0183. CONCLUSION: This is the first study to examine SEE and OEES in SSDs. Interventions to enhance exercise attitudes are a critical first step toward the ultimate goal of increasing exercise participation. PMID- 21659269 TI - Teaching in a technology-enhanced and web-connected world. PMID- 21659270 TI - A clinical translation of the research article titled "antisocial behavioral syndromes and additional psychiatric comorbidity in posttraumatic stress disorder among u.s. Adults: results from wave 2 of the national epidemiologic survey on alcohol and related conditions". PMID- 21659271 TI - An exploratory study of postpartum depression and vitamin d. AB - BACKGROUND: Low levels of serum 25-hydroxyvitamin D (25[OH]D), a reliable measurement of vitamin D, have been implicated in several mood disorders. To date, studies exploring the relationship between vitamin D and postpartum depression are absent from the literature. OBJECTIVES: To determine whether a relationship exists between symptoms associated with postpartum depression and vitamin D levels and to determine if serum 25(OH) D levels can predict the incidence of symptoms associated with postpartum depression. STUDY DESIGN: An exploratory, descriptive study using a convenience sample of 97 postpartum women attending seven monthly visits. Women provided serum 25(OH)D samples and completed the Edinburgh Postpartum Depression Scale (EPDS) at each visit. RESULTS: A significant relationship over time was found between low 25(OH)D levels and high EPDS scores, indicative of postpartum depression. CONCLUSIONS: Future rigorous studies investigating vitamin D and postpartum depression are warranted with larger sample sizes using confirmatory methods to diagnose postpartum depression. PMID- 21659272 TI - Clothes encounter: patient perception of nursing attire in a behavioral health unit. AB - BACKGROUND: In an acute behavioral health unit, patients' perceptions of nurses can be influenced by the type of clothing they wear. OBJECTIVES: The purposes of this study were to determine if mental health patients had preferences related to nursing attire, to determine if patient preference varied with age, and to determine if nursing attire affected patients' thoughts on approachability, competence, and professionalism. STUDY DESIGN: A six-question survey was distributed to patients who met specific criteria between August and December 2008. RESULTS: Overall, patients did not have a preference for the type of attire worn by staff. Identification of nurses was a concern for many. More than half of the respondents indicated approachability was not affected by attire; however, 29% said that street clothes made the nurse less approachable. Attire did not affect patient perception of competence or professionalism. CONCLUSION: As behavioral health care changes, staff attire may need to be reconsidered. PMID- 21659273 TI - Letter to the editor. PMID- 21659275 TI - A clinical translation of the research article titled, "alcohol and violence related injuries among emergency room patients in an international perspective". PMID- 21659276 TI - Early drinking and its association with adolescents' participation in risky behaviors. AB - BACKGROUND: Adolescent alcohol use is a significant public health problem. Drinking before 13 years of age is correlated to the use of illicit drugs and other risky behaviors, such as cigarette smoking. OBJECTIVE: The purpose of this research was to examine the relationship between adolescents' early alcohol use and participation in risky behaviors such as smoking marijuana and cigarettes, as well as risky sexual behaviors. STUDY DESIGN: Respondents for this cross sectional secondary analysis came from a sample of 809 racially diverse adolescents in a community-based study examining familial influences on offspring outcomes. RESULTS: Early-onset drinking, compared with nondrinking, was significantly related to participating in many of the risky behaviors. Many of the relationships persisted in the multivariable models that adjusted for demographic characteristics. CONCLUSIONS: Early drinking was associated with participation in various risky behaviors (e.g., multiple sexual partners, unprotected intercourse), which may negatively alter an adolescent's future. Screening should focus on the co-occurrence of such behaviors. PMID- 21659277 TI - Nursing knowledge about alcohol use and alcohol problems in women: a review of the literature. AB - In this article, the authors review the nursing empirical literature on alcohol and women's health published over the past 5 years (2005-2010). A total of 36 data-based articles authored by nurse investigators met eligibility criteria and were included in this review. Most were single studies by individual nurse investigators; few studies reflected ongoing programs of research related to alcohol and women's health. Studies were categorized into four main groups, including (a) determinants of alcohol use and alcohol problems; (b) patterns of use, assessment of alcohol use, and comorbidity; (c) consequences of alcohol use; and (d) the effects of treatment or specific interventions and the contributions of nursing research to the knowledge base of each group are summarized. The authors then propose a research agenda for nursing that addresses the most pressing issues related to alcohol use and alcohol problems in women. PMID- 21659278 TI - Descriptive study of shared decision making about lifestyle modifications with individuals who have psychiatric disabilities. AB - BACKGROUND: Shared decision making (SDM) is a process of active participation by clients with practitioners in weighing the risks and benefits of treatments. It has not been extended to decisions about making lifestyle modifications. OBJECTIVE: Describe how frequently health lifestyle behaviors are addressed in 15 to 20-minute medicine clinic visits with individuals who have psychiatric disabilities and how often SDM is used in reaching decisions. DESIGN: Content analysis of 98 audiotaped transcripts from practitioner and client medicine clinic visits. RESULTS: The most frequently discussed lifestyle behaviors discussed were sleep (89%) and diet (61%). SDM, defined as sharing information and options about behavior by either or both practitioner and client and affirmation of a decision by both, occurred 48 times (44%) when a problem existed. CONCLUSION: Discussion of lifestyle behaviors along with use of SDM in negotiating changes in behavior is feasible in a 15- to 20-minute visit. PMID- 21659279 TI - Barriers and motivating factors in reporting incidents of assault in mental health care. AB - BACKGROUND: There is a high incidence of assault against nursing staff in mental health care. Efforts to reduce the incidence of assault are hindered by the complexity and nature of the problem and by the fact that incidents of assault are underreported. OBJECTIVE: To identify factors influencing nurses to report staff assault by patients in an inpatient mental health care facility. DESIGN: The study used a modified nominal group technique in which nurses worked together to identify themes in decisions about reporting incidents of assault. The participants were nurses at two sites of a mental health care organization. RESULTS: Nurses used a complex decision-making process to decide whether an incident of assault was worth reporting. Safety culture, the design of the incident reporting system, and the effect on patients were important components of the decision-making process. CONCLUSION: Strategies that consider all levels of the organization's system should be used to improve reporting of assault incidents. PMID- 21659280 TI - The effects of gender discrimination on refugee torture survivors: a cross cultural traumatology perspective. AB - Trauma developmental theory identifies gender discrimination (GD) as a type of persistent, ongoing trauma that has the potential for serious, negative effects on mental health. This study was conducted to examine the potential role of GD in the development of cumulative trauma disorders (CTD) and symptoms of posttraumatic stress disorder (PTSD) as well as the role of GD in mediating the effects of other traumas on these disorders. The sample included 160 female torture survivors from more than 30 countries. Measures of PTSD, CTD, and types of trauma exposure were acquired as part of a larger study on refugee torture survivors. Structural equation modeling was used to test several plausible models for the direct and indirect effects of GD on PTSD and CTD, within the context of other trauma exposure. Results suggest that GD mediates the effects of identity traumas on CTD and PTSD. GD also had direct effects on CTD, including relationships with dissociation, suicidality, and deficits in executive function. GD did not appear to directly influence the development of PTSD. The implications of these results for assessment and treatment of women's trauma-related disorders as well as strategies for their prevention are discussed. PMID- 21659281 TI - Evidence-based practice problems: form and focus. AB - Health care reform poses major challenges for psychiatric mental health care. Foremost among the challenges is a mandate for reimbursement based on performance based outcomes. Clinicians can increase the efficiency of evidence-based practice searches by using the correct form of PICOT (population, intervention, comparator, outcome, time frame) question to focus the search, based on (a) diagnosis, (b) treatment, (c) prognosis, (d) etiology, (e) prevention, and (f) meaning. The correct form of a PICOT question focuses the literature search by requiring a minimum of sorting to find relevant studies. Quickly and effectively locating the critical evidence will help meet the performance standard mandates required by new health care reform legislation. PMID- 21659282 TI - Sim-y{schwa}-'la-sh{schwa}n. PMID- 21659283 TI - Facilitating knowledge translation in the "real world" of community psychiatry. AB - BACKGROUND: Tobacco use disproportionately affects the well-being of individuals with mental illness. In community psychiatric settings, there are culturally embedded attitudes and behaviors regarding smoking that enable practitioners to remain ambivalent about their clients' tobacco use. OBJECTIVES: Given these cultural norms, the authors aimed to introduce evidence-informed smoking cessation interventions to a variety of interdisciplinary mental health care providers by using an innovative approach to knowledge translation. DESIGN: The authors used a case study design in which six community psychiatric settings were targeted. The organizational culture related to smoking was examined at each site before tailored tobacco reduction interventions were delivered. The study design was guided by the knowledge-to-action (KTA) process and two supplementary approaches to change: motivational interviewing (MI) and appreciative inquiry (AI). RESULTS/CONCLUSIONS: The principles of the KTA process, MI, and AI helped the authors to meaningfully engage with practice groups and change the organizational culture surrounding tobacco use in several community psychiatric settings. PMID- 21659284 TI - How persons with chronic hepatitis C in residential substance abuse treatment programs think about depression and interferon therapy. AB - OBJECTIVE: This secondary analysis of existing qualitative descriptive data is the first to specifically report on how persons undergoing residential treatment for substance abuse think about depression and the risks of neuropsychiatric side effects associated with interferon (IFN) treatment for hepatitis C virus (HCV) infection. METHOD: Krippendorff 's method for qualitative content analysis was used to describe patient perspectives about psychiatric symptoms and potential side effects of IFN treatment. Transcripts from face-to-face, semistructured interviews with 20 patients in 3 residential substance abuse treatment programs were analyzed. RESULTS: Themes included patients' powerlessness and their evaluation of risk and confidence. Participants commented that residential substance abuse treatment programs offered a unique opportunity to undergo antiviral treatment because they capitalized on a patient's heightened readiness for change. Barriers to treatment included perceived obstacles, such as compulsory waiting periods before treatment initiation, fear that neuropsychiatric treatment side effects would sabotage addiction recovery, and concern that psychiatric providers lacked sufficient HCV knowledge. However, when patients perceived clinicians as knowledgeable and genuinely caring, they were amenable to considering antiviral treatment. CONCLUSION: Increasing HCV-specific psychiatric education and staff training, exploring combined psychiatric and antiviral treatment combinations, and therapeutically supporting patient decision making are needed to better use substance abuse residential treatment programs as sites for treating HCV infection. Novel antidepressant treatment approaches are required in this population. Advanced practice psychiatric nurses are well positioned to develop new integrative models of care addressing the medical, psychiatric, and substance abuse comorbidities in this highly vulnerable group. PMID- 21659285 TI - A clinical translation of the research article titled "how persons with chronic hepatitis C in residential substance abuse treatment programs think about depression and interferon therapy". PMID- 21659286 TI - Mind to care and a future of hope. PMID- 21659287 TI - 24th Annual Conference of the American Psychiatric Nurses Association, Louisville, KY, October 13-16, 2010. PMID- 21659289 TI - The TMACT: a new tool for measuring fidelity to assertive community treatment. AB - BACKGROUND: Fidelity assessment is important for implementation of evidence-based practices (EBPs), including assertive community treatment (ACT). OBJECTIVES: The TMACT, an enhanced fidelity tool, was developed and pilot-tested to better assess critical ACT structures and processes. DESIGN: Ten ACT teams were administered the TMACT and the long-standing ACT fidelity measure, the Dartmouth Assertive Community Treatment Scale (DACTS), at baseline, 6, 12, and 18 months. RESULTS: Overall, fidelity scores for all 10 teams were relatively high. Six teams showed improvement, concluding with high TMACT scores at 18 months. Four teams with significantly lower total scores had experienced turnover and organizational barriers. TMACT ratings were higher in core ACT practices than in recovery practices and EBPs. TMACT scores rose steadily but were significantly lower than DACTS scores, which remained unchanged. CONCLUSIONS: The TMACT sets higher performance standards through enhanced assessment of recovery-orientation, EBPs, and teamwork and is more sensitive to change than the DACTS. PMID- 21659290 TI - The TMACT: a new tool for measuring fidelity to assertive community treatment: a clinical translation. PMID- 21659291 TI - The TMACT: evidence based or eminence based? PMID- 21659293 TI - A review of consumer-provided services on assertive community treatment and intensive case management teams: implications for future research and practice. AB - BACKGROUND: Assertive community treatment (ACT) is an evidence-based practice that provides intensive, in vivo services for adults with severe mental illness. Some ACT and intensive case management teams have integrated consumers as team members with varying results. METHODS: The authors reviewed the literature examining the outcomes of having consumer providers on case management teams, with attention devoted to randomized controlled trials (RCTs). RESULTS: Sixteen published studies were identified, including eight RCTs. Findings were mixed, with evidence supporting consumer-provided services for improving engagement and limited support for reduced hospitalizations. However, evidence was lacking for other outcomes areas such as symptom reduction or improved quality of life. CONCLUSION: Including a consumer provider on an ACT team could enhance the outreach mechanisms of ACT, using a more recovery-focused approach to bring consumers into services and help engage them over time. More rigorous research is needed to further evaluate integrating consumer providers on teams. PMID- 21659294 TI - Does assertive community treatment increase medication adherence for people with co-occurring psychotic and substance use disorders? AB - OBJECTIVE: This study analyzed data from a randomized trial to examine the impact on medication adherence of integrated treatment delivered via assertive community treatment (ACT) versus standard clinical case management (SCCM). METHOD: Data from the original study included 198 study participants with co-occurring psychotic and substance use disorders who were randomly assigned to receive integrated treatment via ACT or SCCM and were followed for 3 years. We applied mixed-effects logistic regression to estimate group (ACT vs. SCCM) by time effects on a self-report measure of medication adherence. Adherence was dichotomized as 20% or more missed medication days ("poor adherence") versus less than 20% missed medication days ("adequate adherence"). RESULTS: Participants who were assigned to ACT reported significant improvement in medication adherence compared with those assigned to SCCM. CONCLUSIONS: Integrated treatment delivered via ACT may benefit persons with co-occurring psychotic and substance use disorders who are poorly adherent to medications. PMID- 21659295 TI - Assertive community treatment and the physical health needs of persons with severe mental illness: issues around integration of mental health and physical health. AB - BACKGROUND: Assertive community treatment (ACT) is characterized as a service delivery platform and represents an ideal setting in which mental health and physical health care can be integrated. OBJECTIVE: Little is known about the extent to which ACT integrates physical health care with mental health care or the challenges ACT teams experience. To address this gap, focus groups were conducted with five ACT teams in a Midwestern US state to explore how ACT teams address the physical health care needs of persons with severe mental illness. DESIGN: A qualitative study design was used. RESULTS: Three major themes emerged: ACT teams recognize serious and chronic physical health problems, ACT teams take on a variety of roles to address physical health problems, and there are challenges to integrating primary and mental health care within an ACT setting. CONCLUSIONS: ACT needs to be adapted to incorporate promising practices designed to better integrate physical health care and mental health care. PMID- 21659297 TI - Barriers to vocational effectiveness in ACT: staff perspectives. AB - Assertive community treatment (ACT), for persons with serious mental illness, includes a vocational focus as an important aspect of community integration. Nevertheless, research suggests that ACT does not assist significant numbers of consumers in achieving employment goals. A two-step survey of New Jersey ACT team members was designed to identify the key issues that hinder ACT staff members in assisting consumers with obtaining employment. Survey items were categorized into three sections: (a) staff attitudes, (b) consumer barriers, and (c) staff barriers to working on employment. The initial survey asked staff members to rate items in each of these categories. Highly rated items were used in a subsequent paired comparison survey to determine the relative importance of each. This method highlighted the following issues: four staff attitude items-(a) returning to work is positive, (b) employment is key to recovery, (c) abstinence from substance abuse is needed to work, and (d) consumers are too ill to work; four consumer barrier items-(a) fear of loss of Social Security Administration benefits, (b) symptoms related to the illness, (c) lack of motivation, and (d) poor social skills; and three barriers to working on employment issues items-(a) clinical issues take priority, (b) other case management issues takes priority, and (c) too many emergencies. The implications for staff training are discussed. PMID- 21659296 TI - Transforming assertive community treatment into an integrated care system: the role of nursing and primary care partnerships. AB - Despite the high rate of co-occurring medical conditions experienced by individuals receiving assertive community treatment (ACT), this comprehensive service model continues to be considered primarily a mental health intervention. Without compromising fidelity to the model, ACT can serve as an ideal platform from which to provide both primary and behavioral health care to those with complex service needs. Using a case example, this article considers the transformation of the ACT mental health care model into an integrated health care delivery system through establishing nursing and primary care partnerships. Specifically, by expanding and explicitly redefining the role of the ACT nurse, well-developed care models, such as Guided Care, can provide additional guidelines and training to ACT nurses who are uniquely trained and oriented to serve as the leader and coordinator of health integration efforts. PMID- 21659298 TI - Practitioner attributes as predictors of restrictive practices in assertive community treatment. AB - BACKGROUND: Practitioners variably use restrictive practices with assertive community treatment (ACT) consumers. Little is known about practitioner attributes, such as pessimistic attitudes and lack of advanced education, which may predict greater use of restrictive practices. OBJECTIVES: To describe the frequency of restrictive practices in ACT and examine the relationship between practitioner attributes, particularly pessimistic attitudes and education, and the frequency with which restrictive practices are reportedly used in daily treatment of adults with severe mental illness. DESIGN: A cross-sectional study of 122 ACT practitioners in one state. RESULTS: More restrictive practices were rarely reported by practitioners. Pessimistic attitudes and lack of graduate level training were associated with self-reported higher use of restrictive practices, even when controlling for select consumer caseload variables and ACT program fidelity. CONCLUSIONS: This study indicates the need to identify practitioner-related factors that may contribute to the high use of restrictive practices, and develop and implement relevant staff training. PMID- 21659299 TI - Program planning and staff competencies for forensic assertive community treatment: ACT-eligible versus FACT-eligible consumers. AB - PURPOSE: Forensic assertive community treatment (FACT) is a recent adaptation of the assertive community treatment (ACT) model; however, more information is needed about how FACT and ACT consumers differ and how FACT should be modified to accommodate these differences. METHOD: Linked, multisystem administrative data from King County, Washington, were used to compare the demographic, clinical, and criminal justice characteristics of ACT- and FACT-eligible consumers. RESULTS: FACT consumers were more likely to be male, persons of color, and had more complex clinical profiles. Also, some FACT consumers were incarcerated for sex offenses, and more than half had violent offenses. CONCLUSIONS: Traditionally, ACT teams avoid serving consumers with personality disorders, violent consumers, and sex offenders; however, given increased use of mandated outpatient treatment and mental health courts, FACT teams may have less discretion to choose whom they serve. The addition of clinical interventions and other modifications may be particularly important for FACT teams. PMID- 21659302 TI - A clinical translation of the research article titled "adolescents' experiences with uxoricide". PMID- 21659301 TI - Adolescents' experiences with uxoricide. AB - The purpose of this study was to describe the experiences of individuals who survived the loss of one or both parents through parental homicide or homicide/suicide as adolescents. Participants (N = 34) were aged between 12 and 19 years at the time of the death and were aged between 29 and 64 years at the time of the interview. Participants were interviewed twice and asked to tell the story of their lives. Data were analyzed in the hermeneutic phenomenological tradition using a stepwise process of developing categories and then a single complex theme. Common categories of participants' childhoods included abuse both before and after the uxoricide and vivid memories of the homicide. As adults, most participants reported difficulties with intimate relationships, legal problems, and substance use. Integrity was an overarching theme for these participants. Among those who had integrated the story of the homicide into their adult lives, some believed that they were doing well whereas others did not. Some participants had isolated the event and considered that they were doing well as a result. These findings are limited by the convenience sample but offer a rich portrait of the lives of individuals who experienced uxoricide as adolescents. Clinicians might be advised to tread carefully if individuals report that they have isolated rather than integrated the uxoricide into their adult lives. No evidence exists in support that either stance is preferable. PMID- 21659303 TI - Implementing and maintaining nurse-led healthy living programs in forensic inpatient settings: an illustrative case study. AB - BACKGROUND: Healthy living programs (HLPs) within the context of mental health units are an applied response to the concerns of metabolic syndrome and the associated physical illnesses to which people with serious mental illness are susceptible. OBJECTIVE: To illustrate how nurses, with other health professionals and service users, have established and maintained HLPs in two locked forensic mental health units in New Zealand. DESIGN: This illustrative case study adopts a multimodal approach to data collection and analysis. Across two programs, interviews were undertaken with service users (n = 15) and staff (n = 17), minutes of meetings were analyzed for major decision points, and clinical notes were reviewed to identify which service-user health status measures (body mass index, glucose tolerance test results, blood pressure, and medication use) were recorded. RESULTS: Similarities were identified in the way the HLPs were implemented and maintained by champions who advocated for change, challenged staff attitudes, secured funding, and established new systems and protocols. Successful implementation depended on involvement of the multidisciplinary team. Each program operated within a different physical environment and adopted its own philosophical approach that shaped the style of the program. The HLPs had an impact on nurses, other staff, and on the culture of the institutions. The programs raised dilemmas about restrictions and risk versus autonomy and self management. CONCLUSION: Understanding the effects of the clinical and philosophical contexts in which HLPs are established and the way challenges and benefits are affected by context has practical significance for the future development of health programs in forensic settings, prisons, and general mental health units. PMID- 21659304 TI - "It's not just a job. This is where we live. This is our backyard": the experiences of expert legal and advocate providers with sexually assaulted women in rural areas. AB - Sexual assault research has focused almost exclusively on urban areas, and research examining the experiences of expert service providers is nearly nonexistent. The purpose of this study was to add to the understanding of providers' experiences in working with sexually assaulted women in rural communities. Secondary victimization theory suggests that the nature of postassault expert interventions may have an adverse impact on victims. The focus of this hermeneutic phenomenological study was to explore the lived experiences of providers regarding their interactions with sexual assault survivors living in rural communities. Data were gathered from prosecutors, law enforcement, crisis center advocates, social workers, and victim-witness associates. Data analysis led to the identification of five significant themes: (a) rural-specific confidentiality issues, (b) resource needs in a rural setting, (c) the connection between victim blaming and low levels of reporting, (d) negative provider views of the community, and (e) smaller communities provided better victim care. Psychiatric nurses and mental health care systems have many opportunities to intervene with abused women in inpatient, outpatient, and other community settings. In primary and acute care setting, nurses should assess patients for a history of violence using multiple screening questions and should also educate victims and their families about available resources. PMID- 21659305 TI - A process evaluation of START NOW Skills Training for inmates with impulsive and aggressive behaviors. AB - AIM: To conduct a formative evaluation of a treatment program designed for inmates with impulsive and aggressive behavior disorders in high-security facilities in Connecticut correctional facilities. METHOD: Pencil-and-paper surveys and in-person inmate interviews were used to answer four evaluation questions. Descriptive statistics and content analyses were used to assess context, input, process, and products. FINDINGS: A convenience sample of 26 adult male (18) and female (8) inmates participated in the study. Inmates were satisfied with the program (4-point scale, M = 3.38, SD = 0.75). Inmate hospital stays were reduced by 13.6%, and psychotropic medication use increased slightly (0.40%). Improved outcomes were noted for those inmates who attended more sessions. CONCLUSIONS: The findings of the formative evaluation were useful for moving the START NOW Skills Training treatment to the implementation phase. Recommendations for implementation modifications included development of an implementation team, reinforcement of training, and attention applied to uniform collection of outcome data to demonstrate its evidence base. PMID- 21659306 TI - Understanding the health needs of incarcerated men living with HIV/AIDS: a primary health care approach. AB - Nearly 20% of American men with HIV/AIDS pass through a correctional facility each year. As these men pass through the criminal justice system, discontinuation of health care access and nonadherence to prescribed treatments often occur. Men who are not engaged in health care during and after incarceration are at risk for treatment interruption and disease progression. Correctional facilities are therefore important sites for secondary prevention of HIV/AIDS. Unprecedented scientific attention and resources are currently directed at detecting and treating HIV in the criminal justice system. To support these efforts to increase health care access, we must have a better understanding of the cultural and situational factors that structure opportunities for secondary prevention during incarceration and during the transition from correctional facilities back into the community. This article presents a timely review of the literature on the health needs of incarcerated men living with HIV/AIDS. The author uses the primary health care framework to describe the movement of HIV-positive men through the criminal justice system as a series of strategic opportunities to initiate and establish a process of care. The author concludes that although we understand many of the challenges of providing care to men who become incarcerated, and have evidence of effective health-promoting services, we are only beginning to understand how to make health care services accessible and acceptable to HIV-positive male inmates, and we have not yet used some proven HIV prevention tools. PMID- 21659308 TI - Letter to the Editor: Ursula A. Kelly, PhD, ANP-BC, PMHNP-BC, Guest Editor. PMID- 21659307 TI - Advanced practice psychiatric nurses legislative update: State of the States, 2010. AB - This article provides an update regarding individual state legislation for advanced practice psychiatric nursing, building on previous briefings. Specific attention is given to independent versus collaborative practice regulations, titling, and prescriptive authority. There is review of contemporary issues and focus on scope and standards of practice, workforce data, certification, and advanced practice regulatory models. PMID- 21659309 TI - Multiplex ligation-dependent probe amplification analysis of uveal melanoma with extraocular extension demonstrates heterogeneity of gross chromosomal abnormalities. AB - PURPOSE: To determine whether biopsy of extraocular extension of uveal melanoma (UM) is representative of the intraocular tumor with respect to copy number of chromosomes 1p, 3, 6, and 8. METHODS: Multiplex ligation-dependent probe amplification (MLPA) using the P027 assay was performed on formalin-fixed, paraffin-embedded sections from 10 UMs. The intraocular and extraocular parts of the tumor were microdissected and analyzed separately. RESULTS: Of the 10 UMs analyzed, seven showed heterogeneity for at least one chromosome arm; the most frequently heterogeneous chromosome arm was 6p. No heterogeneity of 8p was observed between the intraocular and extraocular areas of the tumor. One tumor showed monosomy 3 in the intraocular area of the tumor but loss of the 3q arm only for the extraocular area. CONCLUSIONS: Biopsy of an extraocular tumor extension may not be representative of the underlying UM with respect to chromosome 1p, 3, 6, and 8q abnormalities detectable by MLPA. These results suggest that for UM with extraocular extension, both the intraocular and the extraocular parts of the tumor should be sampled for accurate genetic prognostic testing. PMID- 21659310 TI - Association of TCF4 gene polymorphisms with Fuchs' corneal dystrophy in the Chinese. AB - PURPOSE: To test the association between TCF4, a gene recently found to confer susceptibility to Fuchs' corneal dystrophy (FCD) in Caucasian populations, and Chinese patients with FCD. METHODS: Fifty-seven Chinese subjects with clinically diagnosed FCD and 121 normal control subjects were recruited. Genomic DNA was extracted and the 18 single nucleotide polymorphisms (SNPs) within TCF4 were genotyped (Sequenom MassArray primer extension system; Sequenom, Inc., San Diego, CA). Statistical association between individual SNPs and FCD was evaluated using 1 df additive genetic models, and verified with 2 df unguided genotype tests of association. P < 0.002 was considered statistically significant after accounting for the 18 SNPs. RESULTS: The affected individuals ranged in age from 48 to 87 years, with an average age of 67 years. There was no statistical difference in the demographic information between the FCD and the control group (mean age of 65.1 years; range, 39-85, P = 0.12). Two SNPs within TCF4 (rs17089887 and rs17089925) were significant experiment-wide (P = 7.34 * 10(-5) and P = 0.00045 respectively) with an increase in disease risk of >2.3-fold per copy of the risk allele compared with individuals who were wild type. However, the most significantly associated SNP from the original report (rs613872) was not found to be present in Chinese FCD subjects. CONCLUSIONS: Polymorphisms within TCF4, a gene which has been implicated in FCD susceptibility among Europeans, was also found to be strongly associated with FCD in Chinese. PMID- 21659311 TI - An experimental study of retinal endovascular surgery with a microfabricated needle. AB - PURPOSE: To study the feasibility of performing retinal endovascular surgery with a microfabricated needle-based cannulation system at the level of the retinal microvasculature. METHODS: A total of 40 retinal vein vessels, and 40 porcine eyes were used, and the eyecups were prepared under an operating microscope. Twenty retinal veins each were pierced with a microfabricated needle having an outer diameter of 50 MUm and with a micropipette having an outer diameter of 50 MUm, respectively, and each vessel that was successfully pierced was injected with a solution. The piercing success rates and injection success rates were calculated, and a histologic examination of the site was performed in each eye. RESULTS: Piercing and injection with the microneedle were successful in all 20 eyes (100%). Histologic examination showed that the retinal vasculature was well preserved in all eyes in which piercing had been performed with the microneedle. Piercing with the micropipette, on the other hand, was successful in only 8 eyes (40%), and injection with the micropipette was successful in only 5 eyes (25%). The tip of the micropipette broke in 12 vessels during piercing and in 3 vessels during injection. CONCLUSIONS; The feasibility of performing microvascular piercing and intravascular injection of retinal veins with a microneedle was demonstrated in porcine eyes. It may be possible to administer solutions into retinal vessels more effectively with a microfabricated needle, and that may contribute to improving retinal endovascular surgery in human eyes. PMID- 21659312 TI - Energy distribution between distance and near images in apodized diffractive multifocal intraocular lenses. AB - PURPOSE: To determine the energy distribution between the distance and near images formed in a model eye by spherical and aspheric apodized diffractive multifocal intraocular lenses (IOLs). METHODS: The IOL was inserted in a model eye with an artificial cornea with positive spherical aberration (SA) similar to that of the human cornea. The energy of the distance and near images, as a function of the pupil size, was experimentally obtained by image analysis. The level of SA on the IOL, which is pupil-size-dependent, was determined from simulations. The influence of the SA was deduced from results obtained in monofocal IOLs and by comparison of the experimentally obtained energy efficiency to theoretical results based solely on the diffractive profile of the IOL. RESULTS: In contrast with theoretical predictions, the energy efficiency of the distance image strongly decreased for large pupils, because of the high level of SA in the IOL. The decrease was smaller in the apodized diffractive multifocal lens with aspheric design. As for the near image, since the diffractive zone responsible for the formation of this image was the same in the spherical and aspheric lenses and the apertures involved were small (and so the level of SA), the results turned out to be similar for both designs. CONCLUSIONS: For large pupils, the energy efficiency of the distance image is strongly affected by the level of SA, although aspheric IOLs perform slightly better than their counterparts with a spherical design. For small pupils, there are no differences between the spherical and aspheric IOLs. PMID- 21659314 TI - Final ART success rates: a 10 years survey. AB - BACKGROUND: Cumulative pregnancy rates (CPRs) and live birth rates (CLBRs) are much better indicators of success in IVF programmes than cross-sectional figures per cycle or embryo transfer. They allow a better estimation of patient's chances of having a child and enable comparisons between centres and treatment strategies. METHODS: A 10 year cohort study of patients undergoing their first assisted reproductive technique cycle was conducted. Patients were followed until live birth or discontinuation of treatment. All IVF and ICSI cycles and cryo cycles with embryos derived from frozen pronuclear stage oocytes were included. The CPR and CLBR were estimated using the Kaplan-Meier method for both the number of treatment cycles and transferred embryos. The analysis assumed that couples who did not return for subsequent treatment cycles would have had the same chance of success as those who had continued treatment. RESULTS: A total of 3011 women treated between 1998 and 2007 were included, and 2068 children were born; women already with a live birth re-entered the analysis as a 'new patient'. For 3394 'patients under observation' with 8048 cycles, the CLBR was 52% after 3 cycles (the median number of cycles per patient), 72% after 6 cycles and 85% after 12 cycles. A CLBR of ~ 50% was achieved for patients aged under 40 years, after the cumulative transfer of six embryos. The mean live birth rate from one fresh cycle and its subsequent cryo-cycle(s) was 33%. Our analysis also shows that ART can reach natural fertility rates but not exceed them. CONCLUSIONS: Most couples with infertility problems can be treated successfully if they continue treatment. Thereby ART can reach natural fertility rates. Even with the restrictions in place as a result of the German Embryo Protection Law, CLBR reach internationally comparable levels. PMID- 21659313 TI - Variation in distress among women with infertility: evidence from a population based sample. AB - BACKGROUND: We examine variation in fertility-specific distress (FSD) and general distress according to different experiences of infertility among 1027 US women who have experienced infertility within the previous 10 years. METHODS: General distress was measured by a short form of the Center for Epidemiological Studies Depression. Multiple regression analysis was conducted on self-report data (based on a telephone interview) from a probability-based sample of US women aged 25-45 years. We compare women with infertility who have had a prior pregnancy (secondary infertility, n = 628) to women with infertility with no prior pregnancies (primary infertility, n = 399). We further distinguish between women with infertility who were actually 'trying' to become pregnant (the infertile with intent) with those who met the medical definition of infertile but did not describe themselves as trying to become pregnant (infertile without intent). RESULTS: Both types of infertility (primary versus secondary) (beta = 0.31*) and intentionality (infertile with and without intent) (beta = 0.08*) are associated with FSD. These associations persist when we control for resource and demographic variables, life course variables, social support and social pressure variables. General distress does not vary by infertility type or intentionality. CONCLUSIONS: Results reveal variation in women's recalled experiences of infertility and that FSD is more sensitive to effects of different experiences than general distress. Women with primary infertility who were explicitly trying to become pregnant at the time of the infertility episode stand out as a particularly distressed group. Caregivers should be aware that the emotional needs of women with primary infertility may differ from those with secondary infertility. PMID- 21659315 TI - The effect of modified quarter laser-assisted zona thinning on the implantation rate per embryo in frozen/vitrified-thawed/warmed embryo transfer cycles: a prospective randomized controlled trial. AB - BACKGROUND: Freezing/vitrifying and thawing/warming of embryos may impair the successful hatching process of the embryo out of its zona pellucida (ZP) and its following implantation into the uterus. Theoretically, assisted hatching (AH) may facilitate the hatching process and subsequently increase implantation rates (IRs). METHODS: In this prospective randomized controlled trial (RCT), the hypothesis was tested that the IR per embryo transferred is higher after transfer (ET) of frozen/vitrified-thawed/warmed embryos with thinned ZP after AH by modified quarter laser-assisted zona thinning (mQLAZT) when compared with ET of frozen/vitrified-thawed/warmed embryos without mQLAZT. Patients with frozen/vitrified embryos were randomized at the time of thawing/warming to a study group (with mQLAZT) or a control group (without mQLAZT). After thawing/warming, embryos were kept in culture for 24h, and mQLAZT was performed prior to ET. RESULTS: A total of 647 thawing cycles were randomized to either the mQLAZT group (n = 324) or the control group (n = 323). Reproductive outcome data were available for 302 cycles in the mQLAZT group and 317 cycles in the control group. Transfer could be performed in 73.5% and in 71.9% of the thawing/warming cycles in the mQLAZT group and the control group (P = 0.78), respectively. No significant differences were observed between the mQLAZT group and the control group for the IR [13.3%; 15.6%; rate ratio 0.85; 95% confidence interval (CI), 0.596-1.224], the ongoing IR (10.5 and 13.5%, P = 0.25) and the live birth rate [10.5%;13.3%; rate ratio 0.79; (95% CI), 0.530-1.189] per embryo transferred. CONCLUSIONS: In this RCT, mQLAZT did not improve the IR per embryo transferred in frozen/vitrified-thawed/warmed embryo transfer cycles. ClinicalTrials.govID NCT00593775. PMID- 21659317 TI - Can health insurance improve access to quality care for the Indian poor? AB - PURPOSE: Recently, the Indian government launched health insurance schemes for the poor both to protect them from high health spending and to improve access to high-quality health services. This article aims to review the potentials of health insurance interventions in order to improve access to quality care in India based on experiences of community health insurance schemes. DATA SOURCES: PubMed, Ovid MEDLINE (R), All EBM Reviews, CSA Sociological Abstracts, CSA Social Service Abstracts, EconLit, Science Direct, the ISI Web of Knowledge, Social Science Research Network and databases of research centers were searched up to September 2010. An Internet search was executed. STUDY SELECTION: One thousand hundred and thirty-three papers were assessed for inclusion and exclusion criteria. Twenty-five papers were selected providing information on eight schemes. DATA EXTRACTION: A realist review was performed using Hirschman's exit voice theory: mechanisms to improve exit strategies (financial assets and infrastructure) and strengthen patient's long voice route (quality management) and short voice route (patient pressure). RESULTS OF DATA SYNTHESIS: All schemes use a mix of measures to improve exit strategies and the long voice route. Most mechanisms are not effective in reality. Schemes that focus on the patients' bargaining position at the patient-provider interface seem to improve access to quality care. CONCLUSION: Top-down health insurance interventions with focus on exit strategies will not work out fully in the Indian context. Government must actively facilitate the potential of CHI schemes to emancipate the target group so that they may transform from mere passive beneficiaries into active participants in their health. PMID- 21659316 TI - Endometriosis expresses a molecular pattern consistent with decreased retinoid uptake, metabolism and action. AB - BACKGROUND: Retinoic acid (RA) regulates key biological processes, including differentiation, apoptosis and cell survival. RA mediates induction of 17 beta hydroxysteroid dehydrogenase type 2 mRNA, catalyzing the conversion of estradiol to estrone, in endometrium but not endometriosis because of a defect in endometriotic stromal cells. This defect may involve both the uptake and metabolism of RA. In this study, we analyze the expression of genes involved in RA signaling in normal endometrium and endometriosis. METHODS: Tissue and stromal cells from ovarian endometriomas and eutopic endometrium from disease-free women were collected. Real-time reverse transcription-polymerase chain reaction was used to measure mRNA levels. Western blotting was used to evaluate protein expression. RESULTS: We found that endometriotic tissue and stromal cells demonstrated significantly decreased mRNA expression of the major genes involved in RA signaling, including STRA6, CRBP1, ALDH1A2, CRABP2 and FABP5. We found increased levels of CYP26B1, responsible for RA metabolism. Nuclear extracts showed that RARalpha, RXRalpha and PPARbeta/delta were underexpressed in both tissues and stromal cells from endometriotic tissue. Differences in protein levels were confirmed by western blotting. CONCLUSIONS: Endometriosis is characterized by a gene expression pattern suggesting a decrease in uptake and metabolism of RA. Because RA is integral in regulating key biological processes involved in cell survival, this alteration could partially explain the resistance to apoptosis found in endometriosis. PMID- 21659318 TI - A randomized controlled trial of a novel self-help technique for impulse control disorders: a study on nail-biting. AB - Nail-biting is currently classified as an impulse control disorder not otherwise specified. Although seldom targeted as a primary symptom, nail-biting is often associated with somatic complications and decreased quality of life. The present study assessed the effectiveness of an innovative self-help technique, titled decoupling (DC). DC aims at attenuating pathological nail-biting by performing motor sequences that decouple and rearrange the behavioral elements involved in the habit. A total of 72 participants with excessive nail-biting were recruited via specialized self-help forums and were randomized to either DC or progressive muscle relaxation (PMR) groups after baseline assessment. Four weeks later, participants underwent a similar assessment as before and were asked to rate the effectiveness of the intervention. The primary outcome parameter was the Massachusetts General Hospital Scale (MGH) adapted. Relative to the PMR group, the DC group showed significant progress in withstanding the urge to bite their nails. Furthermore, they appraised the appearance of their nails as considerably less compromised at the end of the treatment relative to participants undergoing PMR. At statistical trend level, the DC group showed a significantly greater decline on the adapted MGH relative to PMR. Despite methodological limitations, the present study asserts that the effectiveness of DC, previously shown for trichotillomania, extends to nail-biting. PMID- 21659319 TI - mapDamage: testing for damage patterns in ancient DNA sequences. AB - SUMMARY: Ancient DNA extracts consist of a mixture of contaminant DNA molecules, most often originating from environmental microbes, and endogenous fragments exhibiting substantial levels of DNA damage. The latter introduce specific nucleotide misincorporations and DNA fragmentation signatures in sequencing reads that could be advantageously used to argue for sequence validity. mapDamage is a Perl script that computes nucleotide misincorporation and fragmentation patterns using next-generation sequencing reads mapped against a reference genome. The Perl script outputs are further automatically processed in embedded R script in order to detect typical patterns of genuine ancient DNA sequences. AVAILABILITY AND IMPLEMENTATION: The Perl script mapDamage is freely available with documentation and example files at http://geogenetics.ku.dk/all_literature/mapdamage/. The script requires prior installation of the SAMtools suite and R environment and has been validated on both GNU/Linux and MacOSX operating systems. PMID- 21659320 TI - The LabelHash server and tools for substructure-based functional annotation. AB - SUMMARY: The LabelHash server and tools are designed for large-scale substructure comparison. The main use is to predict the function of unknown proteins. Given a set of (putative) functional residues, LabelHash finds all occurrences of matching substructures in the entire Protein Data Bank, along with a statistical significance estimate and known functional annotations for each match. The results can be downloaded for further analysis in any molecular viewer. For Chimera, there is a plugin to facilitate this process. AVAILABILITY: The web site is free and open to all users with no login requirements at http://labelhash.kavrakilab.org PMID- 21659321 TI - RNASAlign: RNA structural alignment system. AB - MOTIVATION: Structural alignment of RNA is found to be a useful computational technique for idenitfying non-coding RNAs (ncRNAs). However, existing tools do not handle structures with pseudoknots. Although algorithms exist that can handle structural alignment for different types of pseudoknots, no software tools are available and users have to determine the type of pseudoknots to select the appropriate algoirthm to use which limits the usage of structural alignment in identifying novel ncRNAs. RESULTS: We implemented the first web server, RNASAlign, which can automatically identify the pseudoknot type of a secondary structure and perform structural alignment of a folded RNA with every region of a target DNA/RNA sequence. Regions with high similarity scores and low e-values, together with the detailed alignments will be reported to the user. Experiments on more than 350 ncRNA families show that RNASAlign is effective. AVAILABILITY: http://www.bio8.cs.hku.hk/RNASAlign. PMID- 21659322 TI - The standardize uptake value: light and shade of positron emission tomography. PMID- 21659323 TI - Preoperative embolization for giant thoracic masses. PMID- 21659324 TI - RETRACTED: Successful correction of congenital giant right coronary artery aneurysm with fistula to left ventricle: [Interact CardioVasc Thorac Surg 2011;12(4):639-641]. PMID- 21659325 TI - Organization of ribonucleoside diphosphate reductase during multifork chromosome replication in Escherichia coli. AB - Ribonucleoside diphosphate reductase (RNR) is located in discrete foci in a number that increases with the overlapping of replication cycles in Escherichia coli. Comparison of the numbers of RNR, DnaX and SeqA protein foci with the number of replication forks at different growth rates reveals that fork : focus ratios augment with increasing growth rates, suggesting a higher cohesion of the three protein foci with increasing number of forks per cell. Quantification of NrdB and SeqA proteins per cell showed: (i) a higher amount of RNR per focus at faster growth rates, which sustains the higher cohesion of RNR foci with higher numbers of forks per cell; and (ii) an equivalent amount of RNR per replication fork, independent of the number of the latter. PMID- 21659326 TI - Superoxide dismutase C is required for intracellular survival and virulence of Burkholderia pseudomallei. AB - Burkholderia pseudomallei is an intracellular pathogen and the causative agent of melioidosis, a life-threatening disease of humans. Within host cells, superoxide is an important mediator of pathogen killing. In this study, we have identified the B. pseudomallei K96243 sodC gene, shown that it has superoxide dismutase activity, and constructed an allelic deletion mutant of this gene. Compared with the wild-type, the mutant was more sensitive to killing by extracellular superoxide, but not to superoxide generated intracellularly. The sodC mutant showed a markedly decreased survival in J774A.1 mouse macrophages, and reduced numbers of bacteria were recovered from human polymorphonuclear neutrophils (PMNs) when compared with the wild-type. The numbers of wild-type or mutant bacteria recovered from human diabetic neutrophils were significantly lower than from normal human neutrophils. The sodC mutant was attenuated in BALB/c mice. Our results indicate that SodC plays a key role in the virulence of B. pseudomallei, but that diabetics are not more susceptible to infection because of a reduced ability of PMNs to kill by superoxide. PMID- 21659327 TI - Alterations in the mitochondrial alternative NAD(P)H Dehydrogenase NDB4 lead to changes in mitochondrial electron transport chain composition, plant growth and response to oxidative stress. AB - The branched respiratory electron transport chain of plants contains a non phosphorylating alternative pathway consisting of type II NAD(P)H dehydrogenases on both sides of the inner membrane linked through the ubiquinone pool to an alternative oxidase (AOX). T-DNA and RNA interference (RNAi) were used to reduce gene expression to characterize the external NAD(P)H dehydrogenase NDB4 in Arabidopsis. The ndb4 lines showed different levels of suppression of NDB4 protein, leading to increases in NBD2 and AOX1a mRNA and protein levels in all lines. These changes were associated with lower reactive oxygen species formation and an altered phenotype, including changes in growth rate, root : shoot ratios and leaf area. The general growth pattern for the ndb4 mutants was decreased leaf area early in development (6-15 d) followed by a prompt subsequent increase in leaf area that exceeded the leaf area of the wild type by maturity (the 10-12 rosette stage). This pattern was most evident for the RNAi lines that had increased mitochondrial electron transport capacity. The RNAi lines also exhibited better tolerance to salinity stress, with better growth rates and lower shoot Na+ content compared with controls when grown under saline conditions. We hypothesize that these differences reflect the enhanced expression of NDB2 and AOX in the ndb4 mutant plants. PMID- 21659328 TI - Plasma membrane domains participate in pH banding of Chara internodal cells. AB - We investigated the identity and distribution of cortical domains, stained by the endocytic marker FM 1-43, in branchlet internodal cells of the characean green algae Chara corallina and Chara braunii. Co-labeling with NBD C(6)-sphingomyelin, a plasma membrane dye, which is not internalized, confirmed their location in the plasma membrane, and co-labelling with the fluorescent pH indicator Lysotracker red indicated an acidic environment. The plasma membrane domains co-localized with the distribution of an antibody against a proton-translocating ATPase, and electron microscopic data confirmed their identity with elaborate plasma membrane invaginations known as charasomes. The average size and the distribution pattern of charasomes correlated with the pH banding pattern of the cell. Charasomes were larger and more frequent at the acidic regions than at the alkaline bands, indicating that they are involved in outward-directed proton transport. Inhibition of photosynthesis by DCMU prevented charasome formation, and incubation in pH buffers resulted in smaller, homogenously distributed charasomes irrespective of whether the pH was clamped at 5.5 or 8.5. These data indicate that the differential size and distribution of charasomes is not due to differences in external pH but reflects active, photosynthesis-dependent pH banding. The fact that pH banding recovered within several minutes in unbuffered medium, however, confirms that pH banding is also possible in cells with evenly distributed charasomes or without charasomes. Cortical mitochondria were also larger and more abundant at the acid bands, and their intimate association with charasomes and chloroplasts suggests an involvement in carbon uptake and photorespiration. PMID- 21659329 TI - Endoplasmic reticulum-located PDAT1-2 from castor bean enhances hydroxy fatty acid accumulation in transgenic plants. AB - Ricinoleic acid (12-hydroxy-octadeca-9-enoic acid) is a major unusual fatty acid in castor oil. This hydroxy fatty acid is useful in industrial materials. This unusual fatty acid accumulates in triacylglycerol (TAG) in the seeds of the castor bean (Ricinus communis L.), even though it is synthesized in phospholipids, which indicates that the castor plant has an editing enzyme, which functions as a phospholipid:diacylglycerol acyltransferase (PDAT) that is specific to ricinoleic acid. Transgenic plants containing fatty acid Delta12 hydroxylase encoded by the castor bean FAH12 gene produce a limited amount of hydroxy fatty acid, a maximum of around 17% of TAGs present in Arabidopsis seeds, and this unusual fatty acid remains in phospholipids of cell membranes in seeds. Identification of ricinoleate-specific PDAT from castor bean and manipulation of the phospholipid editing system in transgenic plants will enhance accumulation of the hydroxy fatty acid in transgenic seeds. The castor plant has three PDAT genes; PDAT1-1 and PDAT2 are homologs of PDAT, which are commonly found in plants; however, PDAT1-2 is newly grouped as a castor bean-specific gene. PDAT1-2 is expressed in developing seeds and localized in the endoplasmic reticulum, similar to FAH12, indicating its involvement in conversion of ricinoleic acid into TAG. PDAT1-2 significantly enhances accumulation of total hydroxy fatty acid up to 25%, with a significant increase in castor-like oil, 2-OH TAG, in seeds of transgenic Arabidopsis, which is an identification of the key gene for oilseed engineering in production of unusual fatty acids. PMID- 21659330 TI - Comparative risks of venous thromboembolism among users of oral contraceptives containing drospirenone and levonorgestrel. PMID- 21659331 TI - Interspousal communication on family planning and its effect on contraceptive adoption in Bangladesh. AB - This article explores the hypothesis that interspousal communication on family planning significantly influences the use of contraceptive method in Bangladesh using the nationally representative 2007 Bangladesh Demographic and Health Survey data. Both bivariate and multivariate statistical analyses were employed in the study. The findings are consistent with the hypothesis. Both cross-sectional and fixed-effect binary logistic regression models yielded quantitatively important and statistically reliable estimates of the positive effect of husband-wife discussion on family planning on the current use of contraceptive method. Son preference, current residence, region, and visitations by family planning workers are also important determinants of contraceptive use. Programs should be undertaken on behalf of the government to involve men in family planning to increase the contraceptive prevalence rate at the point that needs to achieve the replacement level of fertility in Bangladesh. PMID- 21659332 TI - Process of care and prescribing practices for hypertension in public and private primary care clinics in Malaysia. AB - This study aimed to compare the process of care and the choice of antihypertensive medications used in both public and private primary care clinics in Malaysia. A cross-sectional survey was completed in 2008 on randomly selected 100 public health clinics and 114 private primary care clinics in Malaysia. A total of 4076 patient records, 3753 (92.1%) from public clinics and 323 (7.9%) from private clinics were analyzed. Less than 80% of the records documented the recommended clinical and laboratory assessments. The rates of documentation for smoking status, family history of premature death, retinal assessment, and urine albumin tests were lower in public clinics. Overall, 21% of the prescription practices were less than optimal. The process of care and the use of antihypertensive medications were not satisfactory in both settings. PMID- 21659333 TI - Minocycline inhibits cell death and decreases mutant Huntingtin aggregation by targeting Apaf-1. AB - Minocycline (7-dimethylamino-6-dimethyl-6-deoxytetracycline) is a second generation tetracycline that can cross the blood-brain barrier and has anti inflammatory and neuroprotective effects. The potential of minocycline as a drug for treating Huntington's disease has been studied; however, the molecular mechanism underlying the neuroprotective properties of minocycline remains elusive. In this study, we tested the hypothesis that a principal cellular target of minocycline is Apaf-1, a key protein in the formation of the apoptosome, a multiprotein complex involved in caspase activation. Minocycline binds to Apaf-1, as shown by nuclear magnetic resonance spectroscopy, and inhibits apoptosome activity in vitro and in ex vivo models. As a consequence, minocycline-treated cells as well as Apaf-1 knock-out cells are resistant to the development of mutant huntingtin-dependent protein aggregation. PMID- 21659334 TI - Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C. AB - Hematologic abnormalities during current therapy with pegylated interferon and ribavirin (PEG-IFN/RBV) for chronic hepatitis C (CHC) often necessitate dose reduction and premature withdrawal from therapy. The aim of this study was to identify host factors associated with IFN-induced thrombocytopenia by genome-wide association study (GWAS). In the GWAS stage using 900K single-nucleotide polymorphism (SNP) microarrays, 303 Japanese CHC patients treated with PEG IFN/RBV therapy were genotyped. One SNP (rs11697186) located on DDRGK1 gene on chromosome 20 showed strong associations in the minor-allele-dominant model with the decrease of platelet counts in response to PEG-IFN/RBV therapy [P = 8.17 * 10(-9); odds ratio (OR) = 4.6]. These associations were replicated in another sample set (n = 391) and the combined P-values reached 5.29 * 10(-17) (OR = 4.5). Fine mapping with 22 SNPs around DDRGK1 and ITPA genes showed that rs11697186 at the GWAS stage had a strong linkage disequilibrium with rs1127354, known as a functional variant in the ITPA gene. The ITPA-AA/CA genotype was independently associated with a higher degree of reduction in platelet counts at week 4 (P < 0.0001), as well as protection against the reduction in hemoglobin, whereas the CC genotype had significantly less reduction in the mean platelet counts compared with the AA/CA genotype (P < 0.0001 for weeks 2, 4, 8, 12), due to a reactive increase of the platelet count through weeks 1-4. Our present results may provide a valuable pharmacogenetic diagnostic tool for tailoring PEG-IFN/RBV dosing to minimize drug-induced adverse events. PMID- 21659335 TI - Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle. AB - A therapeutic approach for Duchenne muscular dystrophy (DMD) is to up-regulate utrophin in skeletal muscle in an effort to compensate for the lack of dystrophin. We previously hypothesized that promotion of the slow, oxidative myogenic program, which triggers utrophin up-regulation, can attenuate the dystrophic pathology in mdx animals. Since treatment of healthy mice with the AMP activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-beta-D ribofuranoside (AICAR) enhances oxidative capacity and elicits a fast-to-slow fiber-type transition, we evaluated the effects of chronic AMPK stimulation on skeletal muscle phenotype and utrophin expression in mdx mice. Daily AICAR administration (500 mg/kg/day, 30 days) of 5-7-week-old mdx animals induced an elevation in mitochondrial cytochrome c oxidase enzyme activity, an increase in myosin heavy-chain type IIa-positive fibers and slower twitch contraction kinetics in the fast, glycolytic extensor digitorum longus muscle. Utrophin expression was significantly enhanced in response to AICAR, which occurred coincident with an elevated beta-dystroglycan expression along the sarcolemma. These adaptations were associated with an increase in sarcolemmal structural integrity under basal conditions, as well as during damaging eccentric contractions ex vivo. Notably, peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) and silent information regulator two ortholog 1 protein contents were significantly higher in muscle from mdx mice compared with wild-type littermates and AICAR further increased PGC-1alpha expression. Our data show that AICAR-evoked muscle plasticity results in beneficial phenotypic adaptations in mdx mice and suggest that the contextually novel application of this compound for muscular dystrophy warrants further study. PMID- 21659336 TI - An absence of both lamin B1 and lamin B2 in keratinocytes has no effect on cell proliferation or the development of skin and hair. AB - Nuclear lamins are usually classified as A-type (lamins A and C) or B-type (lamins B1 and B2). A-type lamins have been implicated in multiple genetic diseases but are not required for cell growth or development. In contrast, B-type lamins have been considered essential in eukaryotic cells, with crucial roles in DNA replication and in the formation of the mitotic spindle. Knocking down the genes for B-type lamins (LMNB1, LMNB2) in HeLa cells has been reported to cause apoptosis. In the current study, we created conditional knockout alleles for mouse Lmnb1 and Lmnb2, with the goal of testing the hypothesis that B-type lamins are crucial for the growth and viability of mammalian cells in vivo. Using the keratin 14-Cre transgene, we bred mice lacking the expression of both Lmnb1 and Lmnb2 in skin keratinocytes (Lmnb1(Delta/Delta)Lmnb2(Delta/Delta)). Lmnb1 and Lmnb2 transcripts were absent in keratinocytes of Lmnb1(Delta/Delta)Lmnb2(Delta/Delta) mice, and lamin B1 and lamin B2 proteins were undetectable. But despite an absence of B-type lamins in keratinocytes, the skin and hair of Lmnb1(Delta/Delta)Lmnb2(Delta/Delta) mice developed normally and were free of histological abnormalities, even in 2-year-old mice. After an intraperitoneal injection of bromodeoxyuridine (BrdU), similar numbers of BrdU positive keratinocytes were observed in the skin of wild-type and Lmnb1(Delta/Delta)Lmnb2(Delta/Delta) mice. Lmnb1(Delta/Delta)Lmnb2(Delta/Delta) keratinocytes did not exhibit aneuploidy, and their growth rate was normal in culture. These studies challenge the concept that B-type lamins are essential for proliferation and vitality of eukaryotic cells. PMID- 21659337 TI - A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center. AB - The human chromosomal 15q11-15q13 region is subject to both maternal and paternal genomic imprinting. Absence of paternal gene expression from this region results in Prader-Willi syndrome (PWS), while absence of maternal gene expression leads to Angelman syndrome. Transcription of paternally expressed genes in the region depends upon an imprinting center termed the PWS-IC. Imprinting defects in PWS can be caused by microdeletions and the smallest commonly deleted region indicates that the PWS-IC lies within a region of 4.3 kb. The function and location of the PWS-IC is evolutionarily conserved, but delineation of the PWS-IC in mouse has proven difficult. The first targeted mutation of the PWS-IC, a deletion of 35 kb spanning Snrpn exon 1, exhibited a complete PWS-IC deletion phenotype. Pups inheriting this mutation paternally showed a complete loss of paternal gene expression and died neonatally. A reported deletion of 4.8 kb showed only a reduction in paternal gene expression and incomplete penetrance of neonatal lethality, suggesting that some PWS-IC function had been retained. Here, we report that a 6 kb deletion spanning Snrpn exon 1 exhibits a complete PWS-IC deletion phenotype. Pups inheriting this mutation paternally lack detectable expression of all PWS genes and paternal silencing of Ube3a, exhibit maternal DNA methylation imprints at Ndn and Mkrn3 and suffer failure to thrive leading to a fully penetrant neonatal lethality. PMID- 21659338 TI - Male and female child murderers: an empirical analysis of U.S. arrest data. AB - Recent U.S. cases of murders by children below age 11 have captured national headlines. A review of the literature reveals that little is known about this population of juvenile homicide offenders (JHOs). Most studies on juvenile murderers have used small clinical samples, focused on adolescents, and concentrated on male offenders. Studies that have used Supplementary Homicide Report (SHR) data have found significant gender differences among juveniles below 18 years arrested for murder. This study investigated gender differences among 226 juvenile murderers ages 6 through 10 involved in single-victim incidents using bivariate and multivariate statistical techniques. Consistent with previous research, bivariate analyses revealed gender differences with respect to the type of weapon used, age of the victim, relationship to the victim, and circumstances of the crime. Logistic regression analysis identified female JHOs as more likely to use a knife, kill a family member, and kill a victim below age 5, when compared with male JHOs. From these findings, profiles of young male and female JHOs can be drawn. The article concludes with a discussion of the study's implications for prevention and treatment. The authors recommend that future research in gender differences among young children focus on examining psychological, neurological, and sociological variables not included in the SHR data set. PMID- 21659339 TI - Longitudinal changes in adiponectin and inflammatory markers and relation to survival in the oldest old: the Cardiovascular Health Study All Stars study. AB - BACKGROUND: Adiponectin has anti-inflammatory properties, and its production is suppressed by inflammatory factors. Although elevated levels of adiponectin and inflammatory markers each predict mortality in older adults, the implications of their interdependent actions have not been examined. METHODS: We investigated the joint associations of levels and interval changes in adiponectin, C-reactive protein (CRP), and interleukin 6 (IL-6) with risk of death in 840 older adults participating in a population-based study. Adiponectin, CRP, and IL-6 were measured in samples collected 8.9 (8.2-9.8) years apart, and all-cause mortality was subsequently ascertained (n = 176). RESULTS: Interval changes and end levels of adiponectin, CRP, and IL-6 showed mostly positive, independent associations with mortality, without evidence of multiplicative interaction. Joint models, however, showed an U-shaped relationship between end level of adiponectin and outcome (hazard ratio [HR] [95% CI] = 0.72 [0.52-0.99] per standard deviation [SD] for levels <20.0 mg/L; HR = 1.91 [1.61-3.44] per SD for levels >=20.0 mg/L). Participants with the greatest longitudinal increases (upper quartile) in both adiponectin and inflammatory markers had a higher risk of death (HR = 2.85 [1.78 4.58]) than those with large increases in adiponectin alone (HR = 1.87 [1.20 2.92]) (p = .043), but not inflammatory markers alone (HR = 2.48 [1.67-3.67]) (p = .55), as compared with smaller changes for both. CONCLUSION: Higher levels or interval change in adiponectin and inflammatory markers predict increased mortality in older persons independent of each other, although for adiponectin, the association appears inverse below 20 mg/L. These findings suggest that inflammatory and noninflammatory mechanisms governing aging-related decline operate in parallel and provide a potential explanation for paradoxical adiponectin-outcome associations reported previously. PMID- 21659341 TI - Unexplained anemia predominates despite an intensive evaluation in a racially diverse cohort of older adults from a referral anemia clinic. AB - BACKGROUND: To accurately determine the causes of anemia and proportion of unexplained anemia in a racially diverse cohort of older adults after a comprehensive and standardized evaluation. METHODS: We evaluated results from a single-institutional university anemia clinic. Patients with anemia, defined as a hemoglobin less than 13.0 g/dL for men and less than 12.0 g/dL for women, underwent a prospective standardized history, physical examination, and laboratory measures, with additional studies including bone marrow examination as indicated. Empiric treatment trials were given for identified deficiencies. RESULTS: One hundred and seventy-four primarily community-dwelling adults aged 65 years and older were evaluable. African Americans accounted for 69% of patients and whites were 27%. Anemia etiologies included iron deficiency anemia at 25.3%, anemia of chronic inflammation at 9.8%, and hematologic malignancy in 7.5%. Unexplained anemia in the elderly accounted for 43.7% and predominated in both African Americans and whites. The prevalence of iron deficiency anemia and hematologic malignancies did not differ by race. Unexplained anemia in the elderly showed a consistent phenotype composed of a hypoproliferative mild-to moderate anemia with suppressed serum erythropoietin. Specifically, erythropoietin levels showed no correlation with hemoglobin concentration in unexplained anemia in the elderly (r = -.15, p = .19) as opposed to iron deficiency anemia (r = -.63, p < .0001). CONCLUSIONS: In summary, an intensive hematologic evaluation reveals a wide number of anemia etiologies among older adults, including 7.5% with hematologic malignancies; nevertheless, unexplained anemia in the elderly prevails as the most common category in whites and African Americans. PMID- 21659342 TI - Older adults at high risk of falling need more time for anticipatory postural adjustment in the precrossing phase of obstacle negotiation. AB - BACKGROUND: Obstacles are a common cause of falls among older adults. Anticipatory motor planning for obstacle negotiation must be completed during the precrossing phase in order to step over the obstacle safely. This cognitive load may affect anticipatory postural adjustments (APAs) in older adults at high risk of falling. This study explored the effect of obstacle negotiation on APA during gait initiation in older adults at high risk of falling. METHODS: Seventy-six elderly volunteers (mean age: 80.5 [7.6 years]) from the community participated in this study. Participants performed gait initiation tasks from a starting position on a force platform under the following two conditions: (1) unobstructed (smooth walkway) and (2) obstructed (walkway with an obstacle placed at 1 m from the initial position). The reaction and APA phases were measured from the data of center of pressure. Each participant was categorized as a high-risk or a low-risk individual according to the presence or absence of a fall experience within the past year. RESULTS: High-risk participants had significantly longer APA phases than low-risk participants under the obstructed condition even though there was no significant difference between groups under the unobstructed condition. Reaction phase was not significantly different between groups in either the unobstructed or the obstructed condition. CONCLUSION: Motor performance deterioration occurred in high-risk participants in the beginning of the precrossing phase of obstacle negotiation. A slow and inefficient APA at the precrossing phase of obstacle negotiation might be one of the causes of accidental falls. PMID- 21659340 TI - Myosin heavy chain plasticity in aging skeletal muscle with aerobic exercise training. AB - To assess myosin heavy chain (MHC) plasticity in aging skeletal muscle with aerobic exercise training, MHC composition was measured at the messenger RNA (mRNA) level and protein level in mixed-muscle homogenates and single myofibers. Muscle samples were obtained from eight nonexercising women (70 +/- 2 years) before and after 12 weeks of training (20-45 minutes of cycle exercise per session at 60%-80% heart rate reserve, three to four sessions per week). Training elevated MHC I mRNA (p < .10) and protein (p < .05) in mixed-muscle (54% +/- 4% to 61% +/- 2%) and single myofibers (42% +/- 4% to 52% +/- 3%). The increase in MHC I protein was positively correlated (p < .05) with improvements in whole muscle power. Training resulted in a general downregulation of MHC IIa and IIx at the mRNA and protein levels. The training-induced increase in MHC I protein and mRNA demonstrates the maintenance of skeletal muscle plasticity with aging. Furthermore, these data suggest that a shift toward an oxidative MHC phenotype may be beneficial for metabolic and functional health in older individuals. PMID- 21659343 TI - Transplacental genotoxicity evaluation of cypermethrin using alkaline comet assay. AB - Transplacental genotoxic effect of cypermethrin technical was investigated. Three doses (25, 50 and 75 mg/kg body weight) were administered to groups of pregnant Wistar rats during 6-15 days of gestation. Animals were killed on gestation day 20. Fetal blood and liver samples were evaluated for DNA damage using alkaline comet assay. A marginal increase in the mean percentage of DNA damage was recorded in both blood and liver samples of fetuses from cypermethrin-treated dams, but the values were not statistically significant. No skeletal or visceral fetal abnormalities were recorded in treated groups. Nevertheless, the results lead to an understanding that transplacental exposure to cypermethrin can induce low levels of DNA damage in fetuses. This observation could be an explanation for the teratogenic effect exhibited by this chemical in many other studies. The results indicate that cypermethrin may be transplacentally genotoxic. The authors propose more detailed investigations for validating the current findings. PMID- 21659344 TI - Study on the effect of different oxygen therapies on rats with acute carbon dioxide poisoning. AB - OBJECTIVE: To study the effect of different oxygen therapies on the rats with carbon dioxide poisoning for screening out the best on-the-spot oxygen-therapy technology for treating acute carbon dioxide poisoning. METHODS: The 60 healthy male Sprague Dawley rats were randomly divided into normal control group (A group), carbon dioxide poisoning group (B group), low-concentration oxygen inhalation treatment group (C group), high-concentration oxygen inhalation treatment group (D group) and hyperbaric oxygen-therapy group (E group). Various kinds of oxygen therapies were given after the contamination. The pH, partial pressure of oxygen (PO(2)) and partial pressure of carbon dioxide (PCO(2)) of arterial blood, serum troponin I (CTNI), creatine kinase (CK), glutamic oxaloacetic transaminase (AST), gamma-glutamyl transpeptidase (GGT), blood urea nitrogen (BUN), potassium (K), sodium (Na) and chlorine (Cl) for the rats of each group were inspected. The lung and the brain tissues were taken for observing the pathological changes. RESULTS: There is no significant difference in pH, PO(2) and PCO(2) among all oxygen-therapy groups (p > 0.05). The levels of CTNI, CK and AST in E group are obviously lower than that in B, C and D groups (p < 0.05). The level of serum K in E group is obviously lower than that in B, C and D groups (p < 0.05). The levels of serum Na and Cl in E group are obviously higher than that in B, C and D groups (p < 0.05). The pathological change of lungs in E group is significantly better than that in C and D groups. CONCLUSIONS: We recommend that the medical units with related conditions can give the hyperbaric oxygen therapy to patients as soon as possible. PMID- 21659345 TI - Effects of electromagnetic radiation produced by 3G mobile phones on rat brains: magnetic resonance spectroscopy, biochemical, and histopathological evaluation. AB - OBJECTIVE: The effects of electromagnetic radiation (EMR) produced by a third generation (3G) mobile phone (MP) on rat brain tissues were investigated in terms of magnetic resonance spectroscopy (MRS), biochemistry, and histopathological evaluations. METHODS: The rats were randomly assigned to two groups: Group 1 is composed of 3G-EMR-exposed rats (n = 9) and Group 2 is the control group (n = 9). The first group was subjected to EMR for 20 days. The control group was not exposed to EMR. Choline (Cho), creatinin (Cr), and N-acetylaspartate (NAA) levels were evaluated by MRS. Catalase (CAT) and glutathione peroxidase (GSH-Px) enzyme activities were measured by spectrophotometric method. Histopathological analyses were carried out to evaluate apoptosis in the brain tissues of both groups. RESULTS: In MRS, NAA/Cr, Cho/Cr, and NAA/Cho ratios were not significantly different between Groups 1 and 2. Neither the oxidative stress parameters, CAT and GSH-Px, nor the number of apoptotic cells were significantly different between Groups 1 and 2. CONCLUSIONS: Usage of short-term 3G MP does not seem to have a harmful effect on rat brain tissue. PMID- 21659346 TI - Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations. AB - INTRODUCTION: Inherited bone marrow failure syndromes (IBMFSs) often have substantial phenotypic overlap, thus genotyping is often critical for establishing a diagnosis. OBJECTIVES AND METHODS: To determine the genetic characteristics and mutation profiles of IBMFSs, a comprehensive population-based study that prospectively enrols all typical and atypical cases without bias is required. The Canadian Inherited Marrow Failure Study is such a study, and was used to extract clinical and genetic information for patients enrolled up to May 2010. RESULTS: Among the 259 primary patients with IBMFS enrolled in the study, the most prevalent categories were Diamond-Blackfan anaemia (44 patients), Fanconi anaemia (39) and Shwachman-Diamond syndrome (35). The estimated incidence of the primary IBMFSs was 64.5 per 10(6) births, with Fanconi anaemia having the highest incidence (11.4 cases per 10(6) births). A large number of patients (70) had haematological and non-haematological features that did not fulfil the diagnostic criteria of any specific IBMFS category. Disease-causing mutations were identified in 53.5% of the 142 patients tested, and in 16 different genes. Ten novel mutations in SBDS, RPL5, FANCA, FANCG, MPL and G6PT were identified. The most common mutations were nonsense (31 alleles) and splice site (28). Genetic heterogeneity of most IBMFSs was evident; however, the most commonly mutated gene was SBDS, followed by FANCA and RPS19. CONCLUSION: From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools. PMID- 21659347 TI - Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley Ruvalcaba syndrome clinical features. AB - BACKGROUND: Cowden syndrome (CS) is associated with benign hamartomatous lesions and risks for thyroid, breast and endometrial cancers. Bannayan-Riley-Ruvalcaba syndrome is an allelic disorder characterised by macrocephaly, intestinal polyps, lipomas, and pigmented penile macules. Diagnostic criteria for CS are based on the presence of a range of clinical features. However, prior data on the component clinical features have been based primarily on compilations of cases reported before development of consensus diagnostic criteria. OBJECTIVE: This study sought to determine the clinical features most predictive of a mutation in the largest single cohort of patients with clinical testing for PTEN mutations reported to date. METHODS: Molecular and clinical data were reviewed on 802 patients referred for PTEN analysis by a single laboratory. RESULTS: Deleterious mutations were found in 172 (21.4%) subjects. Among mutation carriers significant differences from previous reports were found for the frequencies of several clinical features, including macrocephaly, uterine fibroids, benign breast disease, and endometrial cancer. Logistic regression analyses indicated that female mutation carriers were best identified by the presence of macrocephaly, endometrial cancer, trichilemmomas, papillomatous papules, breast cancer, benign thyroid disease, and benign gastrointestinal (GI) lesions. For males, the most discriminating features were macrocephaly, lipomas, papillomatous papules, penile freckling, benign GI lesions, and benign thyroid disease. Age related differences were also identified. CONCLUSION: The mutation frequency in patients meeting CS diagnostic criteria (34%) was significantly lower than previously reported, suggesting a need for reevaluation of these criteria. A mutation prediction model has been developed which can help identify patients appropriate for PTEN testing in clinical practice. PMID- 21659348 TI - NLRP7 in the spectrum of reproductive wastage: rare non-synonymous variants confer genetic susceptibility to recurrent reproductive wastage. AB - BACKGROUND: NLRP7 mutations are responsible for recurrent molar pregnancies and associated reproductive wastage. To investigate the role of NLRP7 in sporadic moles and other forms of reproductive wastage, the authors sequenced this gene in a cohort of 135 patients with at least one hydatidiform mole or three spontaneous abortions; 115 of these were new patients. METHODS/RESULTS: All mutations were reviewed and their number, nature and locations correlated with the reproductive outcomes of the patients and histopathology of their products of conception. The presence of NLRP7 mutations was demonstrated in two patients with recurrent spontaneous abortions, and some rare non-synonymous variants (NSVs), present in the general population, were found to be associated with recurrent reproductive wastage. These rare NSVs were shown to be associated with lower secretion of interleukin 1beta and tumour necrosis factor and therefore to have functional consequences similar to those seen in cells from patients with NLRP7 mutations. The authors also attempted to elucidate the cause of stillbirths observed in 13% of the patients with NLRP7 mutations by examining available placentas of the stillborn babies and live births from patients with mutations or rare NSVs. A number of severe to mild placental abnormalities were found, all of which are known risk factors for perinatal morbidity. CONCLUSIONS: The authors recommend close follow-up of patients with NLRP7 mutations and rare NSVs to prevent the death of the rare or reduced number of babies that reach term. PMID- 21659349 TI - Propensity score-based sensitivity analysis method for uncontrolled confounding. AB - The authors developed a sensitivity analysis method to address the issue of uncontrolled confounding in observational studies. In this method, the authors use a 1-dimensional function of the propensity score, which they refer to as the sensitivity function (SF), to quantify the hidden bias due to unmeasured confounders. The propensity score is defined as the conditional probability of being treated given the measured covariates. Then the authors construct SF corrected inverse-probability-weighted estimators to draw inference on the causal treatment effect. This approach allows analysts to conduct a comprehensive sensitivity analysis in a straightforward manner by varying sensitivity assumptions on both the functional form and the coefficients in the 1-dimensional SF. Furthermore, 1-dimensional continuous functions can be well approximated by low-order polynomial structures (e.g., linear, quadratic). Therefore, even if the imposed SF is practically certain to be incorrect, one can still hope to obtain valuable information on treatment effects by conducting a comprehensive sensitivity analysis using polynomial SFs with varying orders and coefficients. The authors demonstrate the new method by implementing it in an asthma study which evaluates the effect of clinician prescription patterns regarding inhaled corticosteroids for children with persistent asthma on selected clinical outcomes. PMID- 21659350 TI - Indoor air pollution from coal combustion and the risk of neural tube defects in a rural population in Shanxi Province, China. AB - The authors evaluated indoor air pollution from coal combustion (IAPCC) as a potential risk factor for neural tube defects (NTDs) in a rural population in Shanxi Province, China. The studied rural population has both high IAPCC exposure and a high prevalence of NTDs. A population-based case-control study was used to identify 610 NTD cases and 837 normal controls between November 2002 and December 2007. Information was collected within 1 week following delivery or pregnancy termination due to prenatal NTD diagnosis. The authors derived an exposure index by integrating a series of IAPCC-related characteristics concerning dwelling and lifestyle. Compared with women with no IAPCC exposure, women with any exposure at all had a 60% increased risk of having a child with an NTD (adjusted odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.1, 2.1). An increased NTD risk was linked to both residential heating (adjusted OR = 1.7, 95% CI: 1.1, 2.4) and cooking (adjusted OR = 1.5, 95% CI: 1.1, 2.1). The risk increased with increases in the exposure index, showing a dose-response trend (P < 0.001). This is the first known study to link IAPCC to NTDs. Additional studies are needed to confirm the link between IAPCC and NTDs. PMID- 21659351 TI - Ultraviolet sunlight exposure during adolescence and adulthood and breast cancer risk: a population-based case-control study among Ontario women. AB - Recent studies suggest that vitamin D may be associated with reduced breast cancer risk, but most studies have evaluated only dietary vitamin D intake. The associations among ultraviolet radiation from sunlight, factors related to cutaneous vitamin D production, and breast cancer risk were evaluated in a population-based case-control study conducted in Ontario, Canada, between 2003 and 2004 (n = 3,101 cases and n = 3,471 controls). Time spent outdoors was associated with reduced breast cancer risk during 4 periods of life (>21 vs. <=6 hours/week age-adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI): 0.60, 0.85 in the teenage years; OR = 0.64, 95% CI: 0.53, 0.76 in the 20s-30s; OR = 0.74, 95% CI: 0.61, 0.88 in the 40s-50s; and OR = 0.50, 95% CI: 0.37, 0.66 in the 60s-74 years). Sun protection practices and ultraviolet radiation were not associated with breast cancer risk. A combined solar vitamin D score, including all the variables related to vitamin D production, was significantly associated with reduced breast cancer risk. These associations were not confounded or modified by menopausal status, dietary vitamin D intake, or physical activity. This study suggests that factors suggestive of increased cutaneous production of vitamin D are associated with reduced breast cancer risk. PMID- 21659352 TI - Perceptions of testicular cancer and testicular self-examination among college men: a report on intention, vulnerability, and promotional material preferences. AB - Testicular self-exam (TSE) is an important tool to prevent late-stage diagnosis of testicular cancer (TC). However, most young men remain unaware of their risk for TC despite a growing number of interventions promoting knowledge and awareness of the disease. Of those interventions, very few discuss perceived vulnerability, perceived value of health promotion, and/or preference for informational materials as viable predictors of behavioral change. In this study, 300 university males were surveyed on their perceptions of vulnerability, perceived value of health promotion methods, TC/TSE knowledge, and preference for health promotional information. The results indicated that men were generally unaware of TC and were unsure of their risk of developing the disease. Participants reported very positive responses to questions about the value of health promotion methods, particularly TSE, and indicated a high intention to perform health promotion behaviors. Most important, participants noted that they preferred personalized, tailored information to learn about TC and TSE. Significant predictors of intention to perform TSE include knowledge and awareness of TC/TSE, perceived value of health promotion, and attitudes. Significant predictors of promotional tool preferences differed among generalized pamphlets, personalized messages, and group training sessions. The authors recommend that researchers tailor promotional messages in TC/TSE awareness campaigns with an individual's preference for promotional tool. PMID- 21659353 TI - Beyond ballistics: expanding our conceptualization of men's health-related help seeking. AB - Although the literature on men's help seeking offers important insights into health service engagement patterns within this population, there remain gaps in our understanding. In addition to insufficient attention to a range of male experiences and a restricted focus on sex-specific or associated diseases, much of the extant work is limited by insufficient attention to how men navigate needs and supports across illness and a narrow conceptualization of the core concept of help seeking. Specifically, as research focuses on masculinity as a determinant of the decision to seek medical help (emphasis on prediction), less is known about how men, as gendered beings, are experiencing help seeking over the course of illness (emphasis on understanding). In this article, it is argued that research on men's help seeking can benefit from the integration of a dynamic conceptualization of help seeking that is considerate of shifting needs and a diversity of supports and which emphasizes the subjective, interactive, and ongoing patterns in how men are perceiving, interpreting, and responding to the challenges of illness. PMID- 21659354 TI - Using the internet in pursuit of public sexual encounters: is frequency of use associated with risk behavior among MSM? AB - The current study investigated a subgroup of 112 men who have sex with men who use the Internet in search of partners for sex venue encounters to understand what types of venues they frequent and whether their behaviors are associated with an increased risk of HIV/STI transmission. An initial cluster analysis revealed two patterns of Internet use-low and high frequency-among these men. Although frequency of Internet use to find partners for venue encounters did not cluster with venue attendance, there was a trend among high-frequency Internet users to attend gyms, public bathrooms, and sex clubs more than low-frequency users. Furthermore, high-frequency users attended more venues, preferred venues where multiple partners can be found, and were marginally more likely to engage in unprotected anal sex across venues compared with low-frequency users. Knowing that some venue users initiate venue encounters on the Internet may be useful in targeting appropriate HIV/STI interventions. PMID- 21659355 TI - The association between giant hydrocele and depression in a rural clinic in Nigeria. AB - One of the dreaded disfiguring disease conditions among the Andoni tribesmen in the Nigerian Niger delta region is hydrocele, especially when its size is large (giant hydrocele) and it cannot be concealed. This case-control study was designed to evaluate the prevalence of depression among patients with giant hydrocele presenting to Bethesda Clinic Ngo, Andoni, Nigeria. A total of 52 patients were recruited into this study: 26 in the giant hydrocele group and 26 in the control group. Their age range was 23 to 78 years, with a mean age of 53.4 +/- 15.5 years for the giant hydrocele group and 53.6 +/- 14.2 years for the control group. The difference between the prevalence of depression among patients that presented with giant hydrocele (61.54%) and the controls (15.38%) was statistically significant (p = .0015). The authors conclude that depression is common among patients with giant hydrocele when compared with patients with other disease conditions. PMID- 21659356 TI - Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial. AB - BACKGROUND: An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome. DESIGN AND METHODS: A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3*14 g/m(2) treosulfan and 5*30 mg/m(2) fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival. RESULTS: All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III-IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II-IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively. CONCLUSIONS: Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: NCT01062490. PMID- 21659357 TI - Clinical outcome and gene- and microRNA-expression profiling according to the Wilms tumor 1 (WT1) single nucleotide polymorphism rs16754 in adult de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. AB - BACKGROUND: The alleles of the Wilms tumor 1 (WT1) polymorphism rs16754 harbor adenine (A) or guanine (G). Recently, rs16754 has been reported to affect the outcome of patients with cytogenetically normal acute myeloid leukemia. To validate this finding, we investigated pretreatment features and outcome associated with rs16754 in a large cohort of patients with cytogenetically normal acute myeloid leukemia. DESIGN AND METHODS: Four-hundred and thirty-three intensively treated and molecularly characterized cytogenetically normal patients with de novo acute myeloid leukemia (18-83 years old) were analyzed for rs16754. To gain biological insights, we studied the gene- and microRNA-expression profiles for associations with rs16754. RESULTS: Three-hundred and nine (71%) patients were homozygous for A (WT1(AA)), 112 (26%) were heterozygous (WT1(AG)) and 12 (3%) were homozygous for G (WT1(GG)). For comparison with previous studies, we grouped WT1(AG) and WT1(GG) patients and compared them with WT1(AA) patients divided into younger (<60 years) and older (>=60 years) adults. We found no independent prognostic impact of WT1(AA). However, WT1(GG) patients, who were less often Caucasian than WT1(AG) (P=0.001) or WT1(AA) (P=0.008) patients, and had TET2 mutations more often than WT1(AG) (P=0.02) patients, had, among patients with FLT3-internal tandem duplication and/or NPM1 wild-type, better disease-free (P=0.02) and overall survival (P=0.04) than WT1(AA) and WT1(AG) patients combined. Unsupervised and supervised analyses of the gene- and microRNA expression profiles suggested that there were no distinct expression patterns associated with any rs16754 genotype. CONCLUSIONS: We did not observe the previously reported adverse impact of WT1(AA) but found favorable outcomes associated with the homozygous WT1(GG). Considering its low frequency, confirmatory studies are necessary. The biological significance of rs16754 remains questionable as no distinct expression profiles were associated with the genotypes. PMID- 21659358 TI - The Wiskott-Aldrich syndrome protein permits assembly of a focused immunological synapse enabling sustained T-cell receptor signaling. AB - BACKGROUND: T-cell activation relies on the assembly of the immunological synapse, a structure tightly regulated by the actin cytoskeleton. The precise role of the Wiskott-Aldrich syndrome protein, an actin cytoskeleton regulator, in linking immunological synapse structure to downstream signaling remains to be clarified. DESIGN AND METHODS: To address this point, CD4(+) T cells from patients with Wiskott-Aldrich syndrome were stimulated with antigen-presenting cells. The structure and dynamics of the immunological synapse were studied by confocal and video-microscopy. RESULTS: Upon stimulation by antigen-presenting cells, Wiskott-Aldrich syndrome protein-deficient T cells displayed reduced cytokine production and proliferation. Although Wiskott-Aldrich syndrome T cells formed conjugates with antigen-presenting cells at normal frequency and exhibited normal T-cell receptor down-regulation, they emitted actin-rich protrusions away from the immunological synapse area and their microtubule organizing center failed to polarize fully towards the center of the immunological synapse. In parallel, abnormally dispersed phosphotyrosine staining revealed unfocused synaptic signaling in Wiskott-Aldrich syndrome T cells. Time-lapse microscopy confirmed the anomalous morphology of Wiskott-Aldrich syndrome T-cell immunological synapses and showed erratic calcium mobilization at the single-cell level. CONCLUSIONS: Taken together, our data show that the Wiskott-Aldrich syndrome protein is required for the assembly of focused immunological synapse structures allowing optimal signal integration and sustained calcium signaling. PMID- 21659359 TI - Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS). AB - BACKGROUND: Anemia is an established negative prognostic factor in myelodysplastic syndromes but the relationship between its degree and clinical outcome is poorly defined. We, therefore, studied the relationship between severity of anemia and outcome in myelodysplastic syndrome patients. DESIGN AND METHODS: We studied 840 consecutive patients diagnosed with myelodysplastic syndromes at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, and 504 patients seen at the Heinrich-Heine-University Hospital, Dusseldorf, Germany. Hemoglobin levels were monitored longitudinally and analyzed by means of time dependent Cox's proportional hazards regression models. RESULTS: Hemoglobin levels lower than 9 g/dL in males (HR 5.56, P=0.018) and 8 g/dL in females (HR=5.35, P=0.026) were independently related to reduced overall survival, higher risk of non-leukemic death and cardiac death (P<0.001). Severe anemia, defined as hemoglobin below these thresholds, was found to be as effective as transfusion dependency in the prognostic assessment. After integrating this definition of severe anemia into the WHO classification-based Prognostic Scoring System, time dependent regression and landmark analyses showed that the refined model was able to identify risk groups with different survivals at any time during follow up. CONCLUSIONS: Accounting for severity of anemia through the WHO classification based Prognostic Scoring System provides an objective criterion for prognostic assessment and implementation of risk-adapted treatment strategies in myelodysplastic syndrome patients. PMID- 21659360 TI - Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial. AB - BACKGROUND: There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients' outcome and response to treatment may provide important insights into the biology of the disease. DESIGN AND METHODS: We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients' outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology. RESULTS: The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72*10(-7)) and rs11158493 (PPP2R5E; P=8.50*10(-7)). In addition, the 52 single nucleotide polymorphisms associated at P<10(-4) included rs438034 (CENPF; P=4.86*10(-6)), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10*10(-5)) and rs2064501 (IL22RA2; P=4.81*10(-5)) which map to B-cell genes. CONCLUSIONS: Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses. PMID- 21659361 TI - Efficacy of prolonged therapy with combined arsenic trioxide and ATRA for relapse of acute promyelocytic leukemia. PMID- 21659362 TI - Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. AB - BACKGROUND: According to the current World Health Organization Classification of Lymphoid Tumours, follicular lymphoma is subclassified into three grades according to the number of centroblasts. Follicular lymphoma grade 3 can be further divided into types A and B. Almost all available genetic data on grade 3B follicular lymphomas have been generated from tumors with an additional diffuse large B-cell lymphoma component. The purely follicular type of follicular lymphoma grade 3B is a rare neoplasm. DESIGN AND METHODS: We performed a detailed immunohistochemical (CD10, IRF4/MUM1, BCL2, Ig light chains) and genetic (translocations of BCL2, BCL6, MYC, IRF4) characterization of the largest series of purely follicular cases of grade 3B follicular lymphoma available to date, comprising 23 tumor samples. We also included 25 typical grade 1 or 2 follicular lymphomas, 9 follicular lymphomas with large centrocytes and/or high proliferation indices (FL/LCC), 12 cases of follicular lymphoma grade 3A, 16 cases of diffuse large B-cell lymphoma/follicular lymphoma grade 3B and 15 follicular lymphomas in which a straightforward distinction between grades 3A and 3B was not possible. RESULTS: Translocations affecting BCL2 and BCL6 genes are rare in grade 3B follicular lymphomas (2/23, 9% and 4/23, 17%) when compared with grade 1 or 2 follicular lymphomas (22/25, 88%, P<0.001 and 0/25, P<0.05), FL/LCC (7/9, 78%, P<0.001 and 2/9, 22%), grade 3A follicular lymphomas (7/12, 58%, P<0.01 and 2/12, 17%), unclassified grade 3 follicular lymphomas (6/15, 40% and 2/15, 13%) and diffuse large B-cell lymphoma/follicular lymphoma grade 3B (2/16, 13% and 8/16, 50%, P<0.05). MYC translocations were detected occasionally in FL/LCC, follicular lymphoma grade 3B, and diffuse large B-cell lymphoma/follicular lymphoma grade 3B (13%-22%), but not in grade 1, 2 or 3A follicular lymphomas (P<0.05 when compared with follicular lymphoma grade 3B). Both follicular lymphoma grade 3B and diffuse large B-cell lymphoma/follicular lymphoma grade 3B were enriched in samples with a CD10(-)IRF4/MUM1(+) immunophenotype (8/19, 42% and 7/16, 44%), with the vast majority of them lacking BCL2 translocations. In contrast, 42/46 grade 1 or 2 follicular lymphomas, FL/LCC and grade 3A follicular lymphomas were CD10(+) (91%) while 0/46 expressed IRF4/MUM1. None of the tumor samples tested with increased IRF4/MUM1-expression harbored a translocation of the IRF4 gene locus. CONCLUSIONS: Our results show that grade 3B follicular lymphomas form a distinct category of follicular lymphomas with infrequent BCL2 and BCL6 translocations, while grades 1, 2 and 3A follicular lymphomas and FL/LCC display homogeneous features with frequent BCL2 translocations and a CD10(+)IRF4/MUM1(-) immunophenotype. PMID- 21659364 TI - A newborn with hypotonia and abnormal facies. PMID- 21659363 TI - A prospective multicenter observational study of decitabine treatment in Korean patients with myelodysplastic syndrome. AB - BACKGROUND: Decitabine was evaluated for its efficacy and safety in Korean patients with myelodysplastic syndrome with IPSS score of 0.5 or over. DESIGN AND METHODS: Decitabine 20 mg/m(2)/day was given intravenously over one hour for five consecutive days every four weeks. The primary end point was overall response rate. RESULTS: A total of 101 patients were analyzed. The International Prognostic Scoring System risk category was Intermediate-2/High in 47.5%. A median of 5 courses (range 1-18) were delivered. The overall response rate was 55.4% (13 complete responses, one partial response, 23 marrow complete responses, and 19 hematologic improvements). Forty-eight patients (47.5%) showed some hematologic improvement. With a median follow-up duration of 478 days (range 69 595), median overall survival was 17.7 months. Patients who showed hematologic improvement had significantly longer overall survival than those who did not (19.2 vs. 15.9 months, P=0.006 by landmark analysis at six months). The difference in overall survival was evident in the Intermediate-2/High risk group but not in the Intermediate-1 risk group. The progression-free survival and acute myeloid leukemia-free survival were 61.9% and 77.9% at one year, respectively. Among 489 assessable treatment courses, there were 97 fever episodes requiring intravenous antimicrobials. CONCLUSIONS: Decitabine treatment was feasible and effective in Korean patients with myelodysplastic syndrome, and the overall survival was significantly longer in patients showing hematologic improvement. PMID- 21659365 TI - An unusual cause of fever of unknown origin. PMID- 21659366 TI - Evidence against the proposition that "UK cancer survival statistics are misleading": simulation study with National Cancer Registry data. AB - OBJECTIVES: To simulate each of two hypothesised errors in the National Cancer Registry (recording of the date of recurrence of cancer, instead of the date of diagnosis, for registrations initiated from a death certificate; long term survivors who are never notified to the registry), to estimate their possible effect on relative survival, and to establish whether lower survival in the UK might be due to one or both of these errors. DESIGN: Simulation study. SETTING: National Cancer Registry of England and Wales. Population Patients diagnosed as having breast (women), lung, or colorectal cancer during 1995-2007 in England and Wales, with follow-up to 31 December 2007. MAIN OUTCOME MEASURE: Mean absolute percentage change in one year and five year relative survival associated with each simulated error. RESULTS: To explain the differences in one year survival after breast cancer between England and Sweden, under the first hypothesis, date of diagnosis would have to have been incorrectly recorded by an average of more than a year for more than 70% of women known to be dead. Alternatively, under the second hypothesis, failure to register even 40% of long term survivors would explain less than half the difference in one year survival. Results were similar for lung and colorectal cancers. CONCLUSIONS: Even implausibly extreme levels of the hypothesised errors in the cancer registry data could not explain the international differences in survival observed between the UK and other European countries. PMID- 21659367 TI - Pressure to work through periods of short term sickness. PMID- 21659368 TI - Diagnosis, classification, and treatment of diabetes. PMID- 21659369 TI - Peer review must stay as guarantee of quality, research leaders tell MPs. PMID- 21659370 TI - Serious human rights breaches occurred in more than 50 countries in past year, says UN. PMID- 21659371 TI - NHS Confederation calls for action to halt loss of clinical trials from UK. PMID- 21659372 TI - Cameron proposes radical changes to England's NHS reforms. PMID- 21659373 TI - Edible house raises funds for children's hospital. PMID- 21659375 TI - Cancer care in England lags behind other countries, confirms review. PMID- 21659374 TI - Living with obstetric fistula. PMID- 21659376 TI - Four out of five respondents back GMC plans to reduce public hearings. PMID- 21659377 TI - More than half of GPs say NHS reforms are a factor for them retiring, shows BMA survey. PMID- 21659378 TI - Public health advice won't be as respected if it comes from health department rather than arm's length bodies, experts warn. PMID- 21659379 TI - UK government sues Servier for 220m pound over alleged blocking of generic substitute. PMID- 21659380 TI - Proteomic profiling of hepatitis B virus-related hepatocellular carcinoma with magnetic bead-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Proteomic techniques are promising strategies in the surveillance of hepatocellular carcinoma (HCC). This study aimed to investigate the serum profiling with magnetic bead (MB) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and to further identify the biomarkers for HCC. Serum samples from 80 chronic hepatitis B (CHB) patients, 94 HCC concomitant with HBV patients and 24 healthy subjects were examined by MALDI TOF MS after peptide enrichment on MBs. Based on the genetic algorithm, diagnostic models for HCC were established between 30 HCC patients and 24 healthy subjects/30 CHB patients. Validations were done with the remaining cases. Markers in the models were identified through liquid chromatography (LC)/MS-MS. The three groups were well separated from each other and two discrimination models were established for HCC. The overall recognition capability of these two models was 96.25% and 93.33%, respectively. Validations showed the misdiagnosis ratio for HCC was 1.6% and 23.4%, respectively. The identified biomarkers for HCC included prothrombin precursor (fragment), calcium-dependent secretion activator 1, Baculoviral inhibitor of apoptosis repeat-containing protein 6, etc. MB-based MALDI-TOF MS is applicable in identifying the serum biomarkers and can be used in the surveillance of HCC among HBV-infected patients. PMID- 21659381 TI - Differential gene expression during atrial structural remodeling in human left and right atrial appendages in atrial fibrillation. AB - Extracellular matrix (ECM) remodeling increases the vulnerability to atrial fibrillation (AF). Some gene expressions are crucial for the metabolism of ECM. The left atrium plays an important role in maintaining AF. However, most studies investigated only the right atrial tissue. We therefore chose human tissue samples from both the left and right atrial to detect the different gene expressions during structural remodeling in AF. The atrial appendages tissue samples from 24 patients with chronic AF and 12 patients with sinus rhythm were obtained when they were undergoing mitral/aortic valve replacement operation. The mRNA levels of matrix metalloproteinases-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), disintegrin, metalloproteases-15, and integrins beta1 were determined by reverse transcription-polymerase chain reaction (RT PCR). In AF group, the level of MMP-9 in left atrial appendage (LAA) was increased (P< 0.001), while integrin beta1 level was decreased (P< 0.05) compared with those expressed in right atrial appendage (RAA) tissue. The levels of disintegrin, metalloproteinases-15, and TIMP-1 genes in the LAA and RAA had no significant differences. The results demonstrated that the gene expressions in the LAA and RAA are different during AF, which implied that the mechanism of atrial structural remodeling in AF is due to multiple sources and is complicated. PMID- 21659382 TI - Purification, cDNA cloning, and recombinant expression of chymotrypsin C from porcine pancreas. AB - Chymotrypsin C is a bifunctional secretory-type serine protease in pancreas; besides proteolytical activity, it also exhibits a calcium-decreasing activity in serum. In this study, we purified activated chymotrypsin C from porcine pancreas, and identified its three active forms. Active chymotrypsin C was found to be different in the length of its 13-residue activation peptide due to carboxydipeptidase (present in the pancreas) degradation or autolysis of the activated chymotrypsin C itself, resulting in the removal of several C-terminus residues from the activation peptide. After limited chymotrypsin C cleavage with endopeptidase Lys C, several purified peptides were partially sequenced, and the entire cDNA sequence for porcine chymotrypsin C was cloned. Recombinant chymotrypsinogen C was successfully expressed in Escherichia coli cells as inclusion bodies. After refolding and activation with trypsin, the comparison of the recombinant chymotrypsin C with the natural form showed that their proteolytic and calcium-decreasing activities were at the same level. The successful expression of chymotrypsin C gene paves the way to further mutagenic structure-function studies. PMID- 21659384 TI - Compositional or charge density modification of the endothelial glycocalyx accelerates flow-dependent concentration polarization of low-density lipoproteins. AB - We hypothesized that diminished endothelial glycocalyx (GCX) at atherosclerotic lesion-prone sites accelerates flow-dependent concentration polarization of low density lipoproteins (LDLs) at the luminal surface, and in turn contributes to vulnerability of these sites to atherosclerosis. A parallel plate flow chamber was applied to expose cultured endothelial monolayers to three different levels of shear stress (3, 12, 20 dyn/cm(2)). Heparinase III (Hep.III) was employed to degrade heparan sulfate proteoglycans selectively and 3-(N-morpholino) propanesulfonic acid-buffered physiological salt solutions (MOPS-PSS) were used at either normal ionic strength (Normal-MOPS), low ionic strength (LO-MOPS) or high ionic strength (HI-MOPS) to modify the effective charge density of the endothelial GCX. Water filtration velocity (V(w)) across the endothelial monolayer, the luminal concentration of LDLs (C(w)) and the uptake of LDLs by endothelial cells were measured and compared among the following five groups of cells: (1) Control; (2) Hep.III treatment; (3) LO-MOPS; (4) Normal-MOPS; and (5) HI-MOPS. The results obtained substantiated the aforementioned hypothesis and demonstrated that compositional or charge density modification of the endothelial GCX facilitated water filtration across the endothelium, enhanced the accumulation of LDLs on the luminal surface and increased the uptake of LDLs by endothelial cells, therefore contributing to atherogenesis. PMID- 21659383 TI - Baicalein potently suppresses angiogenesis induced by vascular endothelial growth factor through the p53/Rb signaling pathway leading to G1/S cell cycle arrest. AB - Vascular endothelial growth factor (VEGF) is a key modulator of angiogenesis. Recent studies have shown that VEGF stimulates endothelial cell growth and modulates the cell cycle by reactivation of G0 cells and by reducing the duration of the G1 phase. This study examined the effect of baicalein, a well-known flavonoid, on VEGF-induced angiogenesis and further investigated the role of cell cycle regulators on the antiangiogenic effects of baicalein. Classic in vivo and in vitro models, including a rat aortic ring model, a wound healing model and a tube formation model were used to evaluate angiogenesis in vivo and in vitro. Baicalein exerted marked inhibition of angiogenesis, significantly inhibited migration of human umbilical vein endothelial cells (HUVECs), suppressed tube formation and reduced new blood vessel growth inducted by VEGF. Baicalein reduced phosphorylation of VEGF receptor 2 and extracellular signal-regulated protein kinase, two major signaling elements modulating endothelial cell proliferation. Baicalein also inhibited colony formation by HUVECs, further confirming the suppression of proliferation. Cell cycle analysis demonstrated that baicalein treated HUVECs were arrested in the G1/S phase. Baicalein also induced a decline in the expression of G1-related proteins that normally promote transition from the G1 phase to the S phase, including cyclin D, cyclin E, cdk-4, cdk-6 and p-Rb. In contrast, several proteins upstream of cdks and cyclins, including p16, p21, p27 and p53, were up-regulated by baicalein, indicating that baicalein may inhibit angiogenesis, at least in part, by effects on the p53/Rb signaling pathway. Baicalein could exert antitumor effects by inhibiting VEGF-induced angiogenesis and endothelial cell proliferation. PMID- 21659385 TI - StHsp14.0, a small heat shock protein of Sulfolobus tokodaii strain 7, protects denatured proteins from aggregation in the partially dissociated conformation. AB - The small heat shock protein (sHsp), categorized into a class of molecular chaperones, binds and stabilizes denatured proteins for the purpose of preventing aggregation. The sHsps undergo transition between different oligomeric states to control their nature. We have been studying the function of sHsp of Sulfolobus tokodaii, StHsp14.0. StHsp14.0 exists as 24meric oligomer, and exhibits oligomer dissociation and molecular chaperone activity over 80 degrees C. We constructed and characterized StHsp14.0 mutants with replacement of the C-terminal IKI to WKW, IKF, FKI and FKF. All mutant complexes dissociated into dimers at 50 degrees C. Among them, StHsp14.0FKF is almost completely dissociated, probably to dimers. All mutants protected citrate synthase (CS) from thermal aggregation at 50 degrees C. But, the activity of StHsp14.0FKF was the lowest. Then, we examined the complexes of StHsp14.0 mutants with denatured CS by SAXS. StHsp14.0WKW protects denatured CS by forming the globular complexes of 24 subunits and a substrate. StHsp14.0FKF also formed similar complex but the number of subunits in the complex is a little smaller. These results suggest that the dimer itself exhibits low chaperone activity, and a partially dissociated oligomer of StHsp14.0 protects a denatured protein from interacting with other molecules by surrounding it. PMID- 21659386 TI - A simple intervention. PMID- 21659387 TI - Successful deinstitutionalization of mental health care: increased life expectancy among people with mental disorders in Finland. AB - To assess impact of deinstitutionalization of mental health care, we studied life expectancy for 341 630 people with hospitalization or early retirement pension for mental disorders in 1981-2003 in Finland. Life expectancy at the age of 15 years was significantly shorter for men/women with serious mental disorder (59.0/70.8 years) than in the general population (75.3/82.1 years) in 2001-03. Life expectancy increased for people with schizophrenia and other psychoses, mood disorders and neurotic disorders, but decreased for people with substance use disorders. Deinstitutionalization and decentralization of mental health services did not affect life expectancy negatively. Policy measures to control adverse effects of alcohol and substance abuse have failed. PMID- 21659389 TI - Right of access to health care for undocumented migrants in EU: a comparative study of national policies. AB - BACKGROUND: The aim of this article is to characterize policies regarding the right of access to health care for undocumented migrants in the 27 Member States of the European Union and to identify the extent to which these entitlements are congruent with human rights standards. METHODS: The study is based on a questionnaire sent to experts, non-governmental organizations and authorities in the Member States between April and December 2009, as well as on available reports and official websites. Primary sources were also consulted as regards legislation. RESULTS: Right of access to health care differs considerably between Member States. States can be grouped into 3 clusters: in 5 countries undocumented migrants have the right to access care that is more extensive than emergency care; in 12 countries they can only access emergency care and in 10 countries not even emergency care can be accessed. These variations are independent of the system of financing or the numbers of undocumented migrants present. Rather, they seem to relate to the intersection between practices of control of migration, the main types of undocumented migrants present and the basic norms of the welfare state-the 'moral economy' of the work society. CONCLUSION: International obligations articulated in human rights standards are not fully met in the majority of Member States. A more complete understanding of the differing policies might be obtained by considering the relationship between the formal and informal economy, as well as the role of human rights standards within the current 'moral economy'. PMID- 21659390 TI - What role does socio-economic position play in the link between functional limitations and self-rated health: France vs. USA? AB - BACKGROUND: Our objective was to analyse the influence of education on the link between functional limitation (FL) and self-rated health (SRH) in two countries, France and the USA. METHODS: The data of the North American NHANES study (n = 9254) and the French National Health Survey (n = 25 559) were used. FL was measured by the ADL and IADL scales. We constructed a logistic regression model with SRH as the outcome and included variables for education, FL and the interaction between education and FL. All results were adjusted for age. RESULTS: Poor SRH was more frequently reported in France than in the USA (24.1% vs. 18.4% for men, 29.0% vs. 19.7% for women). The most highly educated persons in the USA had similar FL (25.4% for men, 32.9% for women) to the least educated French persons (22.8% for men, 31.8% for women). In the USA, FL was associated more strongly with poor SRH in the most educated men than in the least educated. In France, the same interaction was observed although the link was weaker than in the USA. FL was more strongly associated with poor SRH in the most educated women than in the least educated in both countries. CONCLUSION: Functional limitation had a greater impact on the most highly educated persons in both France and the USA. Using SRH as a measure of health for evaluating social inequalities could lead to underestimation of the true magnitude of functional health inequalities existing within and between countries. PMID- 21659391 TI - Hatching behavior in turtles. AB - Incubation temperature plays a prominent role in shaping the phenotypes and fitness of embryos, including affecting developmental rates. In many taxa, including turtles, eggs are deposited in layers such that thermal gradients alter developmental rates within a nest. Despite this thermal effect, a nascent body of experimental work on environmentally cued hatching in turtles has revealed unexpected synchronicity in hatching behavior. This review discusses environmental cues for hatching, physiological mechanisms behind synchronous hatching, proximate and ultimate causes for this behavior, and future directions for research. Four freshwater turtle species have been investigated experimentally, with hatching in each species elicited by different environmental cues and responding via various physiological mechanisms. Hatching of groups of eggs in turtles apparently involves some level of embryo-embryo communication and thus is not a purely passive activity. Although turtles are not icons of complex social behavior, life-history theory predicts that the group environment of the nest can drive the evolution of environmentally cued hatching. PMID- 21659392 TI - BigDog-inspired studies in the locomotion of goats and dogs. AB - Collision-based expenditure of mechanical energy and the compliance and geometry of the leg are fundamental, interrelated considerations in the mechanical design of legged runners. This article provides a basic context and rationale for experiments designed to inform each of these key areas in Boston Dynamic's BigDog robot. Although these principles have been investigated throughout the past few decades within different academic disciplines, BigDog required that they be considered together and in concert with an impressive set of control algorithms that are not discussed here. Although collision reduction is an important strategy for reducing mechanical cost of transport in the slowest and fastest quadrupedal gaits, walking and galloping, BigDog employed an intermediate-speed trotting gait without collision reduction. Trotting, instead, uses a spring loaded inverted pendulum mechanism with potential for storage and return of elastic strain energy in appropriately compliant structures. Rather than tuning BigDog's built-in leg springs according to a spring-mass model-based virtual leg spring constant , a much stiffer distal leg spring together with actuation of the adjacent joint provided good trotting dynamics and avoided functional limitations that might have been imposed by too much compliance in real-world terrain. Adjusting the directional compliance of the legs by adopting a knee-forward, elbow-back geometry led to more robust trotting dynamics by reducing perturbations about the pitch axis of the robot's center of mass (CoM). BigDog is the most successful large-scale, all-terrain trotting machine built to date and it continues to stimulate our understanding of legged locomotion in comparative biomechanics as well as in robotics. PMID- 21659393 TI - Environmentally cued hatching in reptiles. AB - Evidence is accumulating for the widespread occurrence of environmentally cued hatching (ECH) in animals, but its diversity and distribution across taxa are unknown. Herein I review three types of ECH in reptiles: early hatching, delayed hatching, and synchronous hatching. ECH is currently known from 43 species, including turtles, crocodilians, lizards, snakes, tuatara, and possibly worm lizards. Early hatching caused by physical disturbance (e.g., vibrations) is the most commonly reported ECH across all groups; although it apparently serves an antipredator function in some species, its adaptive value is unknown in most. Delayed hatching, characterized by metabolic depression or embryonic aestivation, and sometimes followed by a hypoxic cue (flooding), occurs in some turtles and possibly in monitor lizards and crocodilians; in some of these species delayed hatching serves to defer hatching from the dry season until the more favorable conditions of the wet season. Synchronous hatching, whereby sibling eggs hatch synchronously despite vertical thermal gradients in the nest, occurs in some turtles and crocodilians. Although vibrations and vocalizations in hatching competent embryos can stimulate synchronous hatching, cues promoting developmentally less advanced embryos to catch up with more advanced embryos have not been confirmed. Synchronous hatching may serve to dilute predation risk by promoting synchronous emergence or reduce the period in which smells associated with hatching can attract predators to unhatched eggs. Within species, advancing our understanding of ECH requires three types of studies: (1) experiments identifying hatching cues and the plastic hatching period, (2) experiments disentangling hypotheses about multiple hatching cues, and (3) investigations into the environmental context in which ECH might evolve in different species (major predators or abiotic influences on the egg, embryo, and hatchling). Among species and groups, surveys for ECH are required to understand its evolutionary history in reptiles. The probability of ECH occurring is likely influenced by a species's life history, ecology, behavior, and interrelationships with other species (e.g., sizes of predator and prey). More broadly, the discovery of embryo embryo communication as a mechanism for synchronous hatching in crocodilians and turtles indicates that the social behavior of (nonavian) reptiles has been underestimated. PMID- 21659394 TI - Grand opportunities: strategies for addressing grand challenges in organismal animal biology. PMID- 21659395 TI - Cut jargon, save the NHS. PMID- 21659396 TI - An information revolution: time for the NHS to step up to the challenge. PMID- 21659397 TI - Reconciling managers, doctors, and patients: the role of clear communication. PMID- 21659398 TI - John Bostock's first description of hayfever. PMID- 21659399 TI - Chronic diseases influence major life changing decisions: a new domain in quality of life research. AB - The purpose of this review is to identify knowledge about the influence of chronic disease on major life changing decisions (MLCDs). This review was carried out in three stages: identification of key search terms; selection of databases and searching parameters; and evaluation of references. Only two articles matched the main search term 'major life changing decisions'. No article reviewed or measured the influence of chronic disease on major life changing decisions. However, 76 articles and various sections of seven books were identified that provided insight into this area and these are reviewed in detail. This literature review has brought together previously scattered information on chronic disease impact on important patient life decisions. These include decisions related to having children, marriage and divorce, job and career choice, social life, holidays, travelling and education. Lifestyle decisions viewed by patients as major decisions are also documented. The influence of cancer on life decisions is discussed, as are affected life decisions of other family members. Very little information is available about the long-term impact of chronic disease on patients' lives and methodology to assess long-term impact is incomplete. This review points to a novel dimension to health-related outcome research, the impact of chronic disease on major life changing decisions, and its possible implication for patients' future health. PMID- 21659401 TI - Park's story and Winters' tale: alternate allocation clinical trials in turn of the century America. PMID- 21659400 TI - How has healthcare research performance been assessed?: a systematic review. AB - Objectives Healthcare research performance is increasingly assessed through research indicators. We performed a systematic review to identify the indicators that have been used to measure healthcare research performance. We evaluated their feasibility, validity, reliability and acceptability; and finally assessed the utility of these indicators in terms of measuring performance in individuals, specialties, institutions and countries. Design A systematic review was performed by searching EMBASE, PsycINFO, Ovid MEDLINE and Cochrane Library databases between 1950 and September 2010. Setting Studies of healthcare research were appraised. Healthcare was defined as the prevention, treatment and management of illness and the preservation of mental and physical wellbeing through the services offered by the medical and allied health professions. Participants All original studies that evaluated research performance indicators in healthcare were included. Main outcome measures Healthcare research indicators, data sources, study characteristics, results and limitations for each study were studied. Results The most common research performance indicators identified in 50 studies were: number of publications (n = 38), number of citations (n = 27), Impact Factor (n = 15), research funding (n = 10), degree of co-authorship (n = 9), and h index (n = 5). There was limited investigation of feasibility, validity, reliability and acceptability, although the utility of these indicators was adequately described. Conclusion Currently, there is only limited evidence to assess the value of healthcare research performance indicators. Further studies are required to define the application of these indicators through a balanced approach for quality and innovation. The ultimate aim of utilizing healthcare research indicators is to create a culture of measuring research performance to support the translation of research into greater societal and economic impact. PMID- 21659402 TI - Latest developments in the treatment of melanoma: 'a penicillin moment for cancer'? PMID- 21659404 TI - Computerized model for preoperative risk assessment. AB - BACKGROUND: In order to improve the consistency of anaesthetic risk scoring, we have developed an automated method for the calculation of ASA (cASA) scores using decision logic programming. We investigated whether ASA scoring by anaesthetic caregivers could be matched or closely approximated by a cASA. METHODS: We used a web-based preoperative assessment system to present a structured questionnaire comprising 22 questions. These were designed to score and identify conditions that are known, from the literature and expert opinion, to be risk factors. The answers from 14,349 cases were processed using decision logic to provide a variety of risk scores including a computed overall anaesthetic risk (cASA), which was then compared with the ASA score estimated by anaesthesia caregivers (eASA). RESULTS: We found a close agreement between the two measures in almost all cases. In 159 cases (1.1%), there was an underestimation of cASA, in comparison with the eASA, which appeared to be a result predominantly of incorrect or incomplete answers, or an overestimation of the ASA score by the human classifier (43%). CONCLUSION: We showed that ASA scores estimated by a heterogeneous group of anaesthesia caregivers (anaesthetists, anaesthesia trainees, and physician assistants) could be mimicked by the cASA computed by our preoperative assessment system. PMID- 21659405 TI - Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis. AB - BACKGROUND: Development of organ dysfunction associated with sepsis is due in part to oxidative damage to mitochondria. Melatonin regulates the sleep-wake cycle and also has potent antioxidant activity. The aim of this study was to determine the effects of melatonin and other structurally related compounds on mitochondrial function, endogenous glutathione (GSH), and control of cytokine expression under conditions mimicking sepsis. METHODS: Human endothelial cells were treated with lipopolysaccharide (LPS) plus peptidoglycan G (PepG) to simulate sepsis, in the presence of melatonin, 6-hydroxymelatonin, tryptamine, or indole-3-carboxylic acid. Nuclear factor kappaB (NFkappaB) activation, interleukin (IL)-6 and IL-8, total glutathione, mitochondrial membrane potential, and metabolic activity were measured. RESULTS: LPS and PepG treatment resulted in elevated IL-6 and IL-8 levels preceded by activation of NFkappaB (all P<0.0001). Treatment with all four compounds resulted in lower IL-6 and IL-8 levels, and lower NFkappaB activation (P<0.0001). Loss of mitochondrial membrane potential and endogenous glutathione was seen when cells were exposed to LPS/PepG, but these were maintained in cells co-treated with melatonin, tryptamine, or 6 hydroxymelatonin (P<0.05), but not indole-3-carboxylic acid. Metabolic activity decreased after exposure to LPS/PepG and was maintained by melatonin and 6 hydroxymelatonin at the highest concentrations only. CONCLUSIONS: We have shown that in addition to melatonin, other structurally related indoleamine compounds have effects on NFkappaB activation and cytokine expression, GSH, mitochondrial membrane potential, and metabolic activity in endothelial cells cultured under conditions mimicking sepsis. Further work is needed to determine whether these compounds represent therapeutic approaches for disrupting the oxidative stress inflammatory response signalling pathway in sepsis. PMID- 21659406 TI - Complex procedural skills are retained for a minimum of 1 yr after a single high fidelity simulation training session. AB - BACKGROUND: Simulation has been shown to be effective in teaching complex emergency procedural skills. However, the retention of these skills for a period of up to 1 yr has not been studied. We aimed to investigate the 6 month and 1 yr retention of the complex procedural skill of cricothyroidotomy in attending anaesthetists using a high-fidelity-simulated cannot intubate, cannot ventilate (CICV) scenario. METHODS: Thirty-eight attending anaesthetists participated individually in a high-fidelity-simulated CICV scenario (pretest) that required a cricothyroidotomy for definitive airway management. Immediately after a debriefing and structured teaching session on cricothyroidotomy insertion, subjects managed a second identical CICV scenario (post-test). Each anaesthetist was randomized to either a '6 month retention' or a '12 month retention' group. No further teaching occurred. At their respective retention times, each anaesthetist managed a third identical CICV scenario (retention post-test). Two blinded experts independently rated videos of all performances in a random order, using a specific checklist (CL) score, a global-rating scale (GRS) score, and procedural time (PT). RESULTS: Subjects from both groups improved on their cricothyroidotomy skill performances from pretest to immediate post-test and from pretest to retention post-test, irrespective of the retention interval; CL mean (sd) 8.00 (2.39) vs 8.88 (1.53), P=0.49; GRS 28.00 (7.80) vs 31.25 (5.31), P=0.25; PT 102.83 (63.81) s vs 106.88 (36.68) s, P=0.73. CONCLUSIONS: After a single simulation training session, improvements in cricothyroidotomy skills are retained for at least 1 yr. These findings suggest that high-fidelity simulation training, along with practice and feedback, can be used to maintain complex procedural skills for at least 1 yr. PMID- 21659407 TI - Feasibility study of real-time three-/four-dimensional ultrasound for epidural catheter insertion. AB - BACKGROUND: Real-time two-dimensional (2D) ultrasound can be used to facilitate neuraxial anaesthesia. Four-dimensional (4D) ultrasound allows the use of multiple imaging planes and three-dimensional reconstruction of ultrasound data. We assessed how 4D ultrasound could be used to perform epidural catheter insertion in a cadaver model. We then also compared 4D ultrasound and a previously described 2D technique in real-time epidural catheterization. METHODS: Epidural catheter insertion was attempted on four embalmed cadavers using a variety of 4D techniques. A feasible, 4D ultrasound-guided in-plane needle insertion technique was then compared qualitatively with the 2D technique in a further six cadavers. RESULTS: A feasible technique of real-time 4D ultrasound guided epidural insertion used two perpendicular imaging planes to improve the orientation of the operator. It resulted in changes in the needle direction in half of the approaches. Using 4D ultrasound, the Tuohy needle could only be seen reliably in the primary imaging plane. In-plane needle visibility using 4D imaging was inferior to 2D imaging. Successful epidural catheterization was also aided by an acoustic window being present, which allowed visualization of the vertebral body. CONCLUSIONS: The study demonstrates that 4D ultrasound can be used for real-time epidural catheter insertion and has both advantages and limitations compared with the 2D technique. Four-dimensional ultrasound has the potential to improve operator orientation on the vertebral column. However, this comes at the price of decreased resolution, frame rate, and needle visibility. Prospective evaluation of the importance of an acoustic window in neuraxial anaesthesia is required. PMID- 21659408 TI - Maternal B vitamin supplementation from preconception through weaning suppresses intestinal tumorigenesis in Apc1638N mouse offspring. AB - OBJECTIVE: Variations in the intake of folate are capable of modulating colorectal tumorigenesis; however, the outcome appears to be dependent on timing. This study sought to determine the effect of altering folate (and related B vitamin) availability during in-utero development and the suckling period on intestinal tumorigenesis. DESIGN: Female wildtype mice were fed diets either mildly deficient, replete or supplemented with vitamins B(2), B(6), B(12) and folate for 4 weeks before mating to Apc(1638N) males. Females remained on their diet throughout pregnancy and until weaning. After weaning, all Apc(1638N) offspring were maintained on replete diets for 29 weeks. RESULTS: At 8 months of age tumour incidence was markedly lower among offspring of supplemented mothers (21%) compared with those of replete (59%) and deficient (55%) mothers (p=0.03). Furthermore, tumours in pups born to deficient dams were most likely to be invasive (p=0.03). The expression of Apc, Sfrp1, Wif1 and Wnt5a--all of which are negative regulatory elements of the Wnt signalling cascade--in the normal small intestinal mucosa of pups decreased with decreasing maternal B vitamin intake, and for Sfrp1 this was inversely related to promoter methylation. beta-Catenin protein was elevated in offspring of deficient dams. CONCLUSIONS: These changes indicate a de-repression of the Wnt pathway in pups of deficient dams and form a plausible mechanism by which maternal B vitamin intake modulates tumorigenesis in offspring. These data indicate that maternal B vitamin supplementation suppresses, while deficiency promotes, intestinal tumorigenesis in Apc(1638N) offspring. PMID- 21659410 TI - Exposure to thoracic dust, airway symptoms and lung function in cement production workers. AB - Cement dust exposure has previously been associated with airway symptoms and ventilatory impairment. The aim of the present study was to examine lung function and airway symptoms among employees in different jobs and at different levels of exposure to thoracic dust in the cement production industry. At the start of a 4 yr prospective cohort study in 2007, exposure to cement dust, symptoms and lung function were recorded cross-sectionally in 4,265 employees in 24 European cement plants. Bronchial exposure was assessed by 2,670 full-shift dust samples with cyclones collecting the thoracic aerosol fraction. A job exposure matrix was constructed by grouping dust concentrations according to job type and plant. Elevated odds ratios for symptoms and airflow limitation (range 1.2-2.6 in the highest quartile), but not for chronic bronchitis, were found in the higher quartiles of exposure compared with the lowest quartile. Forced expiratory volume in 1 s (FEV(1)) showed an exposure-response relationship with a 270-mL deficit of FEV(1) (95% CI 190-300 mL) in the highest compared with the lowest exposure level. The results support the hypothesis that exposure to dust in cement production may lead to respiratory symptoms and airway obstruction. PMID- 21659411 TI - Farming in childhood, diet in adulthood and asthma history. AB - The decrease in the number of children living on traditional farms in France during early childhood and changes in diet could both play a role in the increase in asthma prevalence over the last decades. This study aimed to assess 1) the association of farming lifestyle in childhood and asthma, and 2) whether diet in adulthood modifies the association between farming lifestyle in childhood and adult-onset asthma. In the French Etude Epidemiologique des Femmes de la Mutuelle Generale de l'Education Nationale (E3N) study (54,018 females; age 43-68 yrs), three indicators of farming lifestyle were defined: one using individual data (having farmer parents) and two using ecological data (born in a rural area and exposure to cattle). All farming lifestyle indicators were related to childhood- (<16 yrs) and adult-onset asthma (OR (95% CI) values for farmer parents were 0.54 (0.42-0.70) and 0.72 (0.62-0.84), respectively), and to diet in adulthood, in particular to high fruit and low wine intakes. The association between farmer parents and adult-onset asthma was not modified by diet in adulthood. Results extend previous observations in younger cohorts on the protective role of contact with livestock and farming lifestyle on asthma, in particular during childhood. PMID- 21659412 TI - High-resolution computed tomography and pulmonary function in children with common variable immunodeficiency. AB - High-resolution computed tomography (HRCT) may be useful to monitor lung disease in children with common variable immunodeficiency disorder (CVID). We evaluated interobserver agreement and correlation with pulmonary function tests (PFTs) for automated quantification and visual scoring of air trapping and airway wall thickening on HRCT in paediatric CVID patients. In a cohort of 51 children with CVID, HRCT was analysed visually and automated for presence of air trapping and airway wall thickening. PFTs were expressed as % predicted. Disease duration, physician-diagnosed pneumonias and antibiotic prophylaxis were recorded. Interobserver agreement for automated airway wall thickening was good with an intra-class correlation coefficient of 0.88, compared with 0.51 for visual scoring. Presence of air trapping on HRCT correlated significantly with PFTs and disease duration, but was not associated with previous pneumonias. Airway wall thickening did not correlate significantly with PFTs or disease duration and was not associated with previous pneumonias or prophylactic antibiotic use. In children with CVID disorders, HRCT air trapping measurements are significantly correlated with PFTs and disease duration. Quantitative air trapping is a feasible and promising technique for small airway disease quantification that may be applied to monitor (silent) disease progression in CVID. PMID- 21659409 TI - Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3. AB - Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-type EGFR or unknown status received docetaxel), compared with initiation with no patient selection (strategy reference). A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed. The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to ?5,020 and ?5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results. The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds. PMID- 21659413 TI - Comparative cost and performance of light-emitting diode microscopy in HIV tuberculosis-co-infected patients. AB - Light-emitting diode (LED) microscopy has recently been endorsed by the World Health Organization (WHO). However, it is unclear whether LED is as accurate and cost-effective as Ziehl-Neelsen (ZN) microscopy or mercury vapour fluorescence microscopy (MVFM) in tuberculosis (TB)-HIV-co-infected subjects. Direct and concentrated sputum smears from TB suspects were evaluated using combinations of LED microscopy, ZN microscopy and MVFM. Median reading time per slide was recorded and a cost analysis performed. Mycobacterial culture served as the reference standard. 647 sputum samples were obtained from 354 patients (88 (29.8%) were HIV-infected and 161 (26%) were culture-positive for Mycobacterium tuberculosis). Although overall sensitivity of LED compared with ZN microscopy or MVFM was similar, sensitivity of all three modalities was lower in HIV-infected patients. In the HIV-infected group, the sensitivity of LED microscopy was higher than ZN microscopy using samples that were not concentrated (46 versus 39%; p = 0.25), and better than MVFM using concentrated samples (56 versus 44; p = 0.5). A similar trend was seen in the CD4 count <200 cells . mL(-1) subgroup. Median (interquartile range) reading time was quicker with LED compared with ZN microscopy (1.8 (1.7-1.9) versus 2.5 (2.2-2.7) min; p <= 0.001). Average cost per slide read was less for LED microscopy (US$1.63) compared with ZN microscopy (US$2.10). Among HIV-TB-co-infected patients, LED microscopy was cheaper and performed as well as ZN microscopy or MVFM independent of the staining (ZN or auramine O) or processing methods used. PMID- 21659414 TI - Renin is an angiotensin-independent profibrotic mediator: role in pulmonary fibrosis. AB - The pathogenesis of idiopathic pulmonary fibrosis (IPF) is probably the result of interplay between cytokines/chemokines and growth factors. The renin-angiotensin (Ang) system is involved, although its profibrotic effect is attributed to Ang II. However, recent studies suggest that renin, through a specific receptor, is implicated in fibrogenesis. In this study, the expression of renin and renin receptor was examined in normal and IPF lungs and fibroblasts. Normal human lung fibroblasts were stimulated with renin or transfected with renin small interfering RNA (siRNA), and the expression of transforming growth factor (TGF) beta1 and alpha-1-type I collagen was analysed. Normal lungs and lung fibroblasts expressed renin, which was strongly upregulated in IPF lungs and fibroblasts (~10 fold increase; p<0.05). Immunocytochemistry showed intense renin staining in IPF fibroblasts. Renin-stimulated lung fibroblasts displayed an increase in the expression of TGF-beta1 (mean +/- sd 1.8 * 10(3) +/- 0.2 * 10(3) versus 1.2 * 10(3)+/- 0.3 * 10(3) mRNA copies per 18S ribosomal RNA; p<0.01) and collagen (5.93 * 10(2)+/- 0.66 * 10(2) versus 3.28 * 10(2) +/- 0.5 * 10(2); p<0.01), while knocking down renin expression using siRNA provoked a strong decrease of both molecules. These effects were independent of Ang II, since neither losartan nor captopril decreased these effects. Renin also decreased matrix metalloprotease-1 expression and induced TGF-beta1 activation (163 +/- 34 versus 110 +/- 15 pg active TGF-beta1 per mg total protein). These findings highlight the possible role of renin as an Ang II-independent profibrotic factor in lung fibrosis. PMID- 21659415 TI - Matrix metalloproteinases in tuberculosis. AB - Tuberculosis (TB) remains a global health pandemic. Infection is spread by the aerosol route and Mycobacterium tuberculosis must drive lung destruction to be transmitted to new hosts. Such inflammatory tissue damage is responsible for morbidity and mortality in patients. The underlying mechanisms of matrix destruction in TB remain poorly understood but consideration of the lung extracellular matrix predicts that matrix metalloproteinases (MMPs) will play a central role, owing to their unique ability to degrade fibrillar collagens and other matrix components. Since we proposed the concept of a matrix degrading phenotype in TB a decade ago, diverse data implicating MMPs as key mediators in TB pathology have accumulated. We review the lines of investigation that have indicated a critical role for MMPs in TB pathogenesis, consider regulatory pathways driving MMPs and propose that inhibition of MMP activity is a realistic goal as adjunctive therapy to limit immunopathology in TB. PMID- 21659416 TI - A therapeutic role for matrix metalloproteinase inhibitors in lung diseases? AB - Disruption of the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors is considered a key event in the development of pulmonary diseases such as chronic obstructive pulmonary disease, asthma, interstitial lung diseases and lung cancer. This imbalance often results in elevated net MMP activity, making MMP inhibition an attractive therapeutic strategy. Although promising results have been obtained, the lack of selective MMP inhibitors, together with limited knowledge regarding the exact functions of a particular MMP, hampers clinical application. This review discusses the involvement of different MMPs in lung disorders and future opportunities and limitations of therapeutic MMP inhibition. PMID- 21659417 TI - Alcohol drinking and risk of subsequent hospitalisation with pneumonia. AB - The dose-response relationship between alcohol consumption and pneumonia risk in healthy individuals is poorly understood. We examined 22,485 males and 24,682 females from Denmark who were aged 50-64 yrs. Subjects were without major chronic diseases at baseline and had a median follow-up of 12 yrs for first-time hospitalisation with pneumonia. 1,091 (males) and 944 (females) had pneumonia related hospitalisation. Among males, the risk of pneumonia was increased for alcohol abstainers and those who drank large weekly amounts. The adjusted hazard ratios (HRs) for 0, 7-20, 21-34, 35-50 and >50 drinks.week(-1) were 1.49 (95% CI 1.00-2.21), 0.88 (95% CI 0.76-1.03), 0.87 (95% CI 0.72-1.05), 1.15 (95% CI 0.93 1.44) and 1.81 (95% CI 1.40-2.33), respectively, compared with 1-6 drinks.week( 1). The association between high alcohol intake and pneumonia persisted after controlling for subsequent chronic diseases. Among females, HRs for 0, 7-20, 21 35 and >35 drinks.week(-1) were 1.26 (95% CI 0.89-1.79), 1.01 (95% CI 0.88-1.17), 1.10 (95% CI 0.88-1.37) and 0.54 (95% CI 0.29-1.01), respectively. For the same moderate to high weekly alcohol amount, infrequent intake yielded higher pneumonia HRs than more regular intake in both sexes. Regular moderate alcohol intake is not associated with increased risk of hospitalisation for pneumonia. High weekly alcohol consumption in males and infrequent heavy drinking in both sexes may increase pneumonia risk. PMID- 21659418 TI - The impact of weekends on outcome for acute exacerbations of COPD. AB - Differences in hospital staffing may influence outcomes for patients with acute conditions, including acute exacerbations of chronic obstructive pulmonary disease (COPD), depending on which day of the week the patients are admitted. This study was conducted to determine whether weekend admission increases the risk of dying in hospital. We analysed the clinical data of 289,077 adults with acute exacerbations of COPD admitted to the hospital at any public centre in Spain, during 2006 and 2007. We analysed the following factors for their association with death rate: day of admission, demographics, medical history and comorbidity. During the study period, there were 35,544 (12.4%) deaths during admission in COPD patients. Weekend admissions were associated with a significantly higher in-hospital mortality (12.9%) than weekday admissions (12.1%) among COPD patients (OR 1.07 (95% CI 1.04-1.10)). The differences in mortality persisted after adjustment for age, sex and coexisting disorders (OR 1.05 (95% CI 1.02-1.08)). Analyses of deaths within 2 days after admission showed larger relative differences in mortality between the weekend and weekday admissions (OR 1.17 (95% CI 1.11-1.23)). We conclude that patients with acute exacerbations of COPD are more likely to die in the hospital if they are admitted on a weekend compared with a weekday. PMID- 21659419 TI - Patient navigation: an update on the state of the science. AB - Although patient navigation was introduced 2 decades ago, there remains a lack of consensus regarding its definition, the necessary qualifications of patient navigators, and its impact on the continuum of cancer care. This review provides an update to the 2008 review by Wells et al on patient navigation. Since then, there has been a significant increase in the number of published studies dealing with cancer patient navigation. The authors of the current review conducted a search by using the keywords "navigation" or "navigator" and "cancer." Thirty three articles published from November 2007 through July 2010 met the search criteria. Consistent with the prior review, there is building evidence of some degree of efficacy of patient navigation in terms of increasing cancer screening rates. However, there is less recent evidence concerning the benefit of patient navigation with regard to diagnostic follow-up and in the treatment setting, and a paucity of research focusing on patient navigation in cancer survivorship remains. Methodological limitations were noted in many studies, including small sample sizes and a lack of control groups. As patient navigation programs continue to develop across North America and beyond, further research will be required to determine the efficacy of cancer patient navigation across all aspects of the cancer care continuum. PMID- 21659420 TI - Usefulness of pleural effusion antinuclear antibodies in the diagnosis of lupus pleuritis. AB - We performed this study to determine sensitivity and specificity of pleural effusion antinuclear antibodies (ANA) at a titer of >=1 : 160, and the ratio of pleural effusion to serum ANA of >=1, to distinguish between pleural fluid from lupus pleuritis and other causes. A prospective study of 54 patients with pleural effusion (12 lupus pleuritis, seven parapneumonic effusion, 26 malignancy associated pleural effusions, nine transudative effusions) was performed. ANA at a titer of >=1 : 160 were found in 11 of 12 lupus pleuritis samples, and in four of 42 pleural effusions from non-systemic lupus erythematosus (SLE) patients. The pleural effusion ANA at a titer of >=1 : 160 gave a sensitivity of 91.67% for lupus pleuritis, with a specificity of 83.33% when compared with all other pleural effusions, 90.91% when compared with exudative effusion (parapneumonic effusion and malignancy-associated effusion) and 55.56% when compared with the transudative pleural effusion group. Using the ratio of pleural effusion to serum ANA of >=1, the sensitivity and the specificity decreased to 75.00% and 78.57%, respectively. This study provides further evidence that the pleural effusion ANA at a titer of >=1 : 160 is a sensitive and specific diagnostic biomarker for lupus pleuritis in patients with lupus. However, pleural effusion ANA can occasionally be found in other conditions. PMID- 21659421 TI - Epidemiology and clinical outcomes of bloodstream infections among lupus patients. AB - Infection is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). This study was aimed at characterizing bloodstream infections in these patients and analysing factors associated with long term outcome. For this purpose, episodes of significant bacteraemia diagnosed from January 1991 to December 2006 among patients with SLE at a single centre were identified through a central database and clinical and analytical variables were recorded regarding short- and long-term follow-up. Univariate and multivariable analysis were performed to identify factors associated with long term outcome. Thirty-eight SLE patients had 48 episodes of significant bacteraemia, with a 30-day mortality rate of 6.25%. Escherichia coli and Staphylococcus aureus were the leading Gram-negative and Gram-positive pathogens, respectively. After a median follow-up of 25 months, eight of these 38 patients (21.1%) had a further episode of bacteraemia and 13 of them (34.21%) died. Community-acquired bacteraemia and C reactive protein levels lower than 8 mg/dl during episodes were factors associated with lower long-term mortality. These results reinforce previous findings suggesting that lupus patients with bacteraemia episodes have poor long-term outcomes. PMID- 21659422 TI - Relationship of leukocyte CR1 transcript and protein with the pathophysiology and prognosis of systemic lupus erythematosus: a follow-up study. AB - Complement Receptor 1 (CR1) is a key complement regulatory protein (CRP) involved in the clearance of immune complexes. Earlier, we reported a marked decline of leukocyte CR1 (L-CR1) transcript and protein in patients with active systemic lupus erythematosus (SLE) and suggested L-CR1 transcript as a putative non invasive disease marker for SLE. This follow-up study involving 18 patients with active SLE was conducted for further confirmation of the relationship between L CR1 and SLE. Blood samples from the patients were collected on day 1 of the diagnosis (0 month) and at different time intervals (3 and 6 months) for analysis of L-CR1 transcript and L-CR1 protein by semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and western blotting respectively. Within 6 months, 15 patients entered remission. On day 1, the mean values of L-CR1 transcript (8.42 +/- 3.53) and L-CR1 protein (4683 +/- 1094) in the SLE patients were 6 times and 12 times lower than the normal controls (n = 103). At the end of month 6, these values increased by 4.5 and 6.5 times respectively for CR1 transcript (37.86 +/- 8.52) and protein (30,265 +/- 8614). Simultaneously, the SLE Disease Activity Index (SLEDAI) scores decreased by 4.8 times (4.47 +/- 3.32) as compared with the scores obtained on day 1 (21.45 +/- 5.67). Moreover, CR1 values correlated negatively with the SLEDAI scores. Levels of L-CR1 protein and transcript remained low in the three patients who did not enter remission. All of the above results suggested that an increase in the levels of L-CR1 related to good prognosis. Since the levels of L-CR1 protein is influenced by variables like proteolytic cleavage and secretion from leukocytes, the values of L-CR1 transcript on day 1 and subsequent follow-up points may bring a better insight into the state of the disease activity. An extended follow-up study is needed to confirm the significance of L-CR1 as a prognostic marker for SLE. PMID- 21659423 TI - Glucocorticoid-induced diabetes mellitus in patients with systemic lupus erythematosus treated with high-dose glucocorticoid therapy. AB - The aim of this study was to investigate the prevalence and associated factors of glucocorticoid-induced diabetes mellitus (GDM) in patients with systemic lupus erythematosus (SLE) receiving high-dose glucocorticoid therapy. Patients with SLE who had received high-dose glucocorticoid therapy (prednisolone >=1 mg/kg/day) at Yonsei University Medical Center, Seoul, Korea, were recruited between January 1999 and June 2009. In total 127 patients with SLE were evaluated. Sixteen (12.6%) of them developed GDM after high-dose glucocorticoid therapy (95% confidence interval, 6.8-18.4%). Univariate analysis showed that old age, family history of diabetes mellitus (DM), hypertension, higher body mass index, higher mean dose of prednisolone before high-dose glucocorticoid therapy, and concurrent use of mycophenolate mofetil (MMF) were factors that would increase the likelihood of GDM. Multivariate analysis determined that age, family history of DM, mean dose of prednisolone before high-dose glucocorticoid therapy and concurrent use of MMF were independent associated factors for GDM. In summary, GDM was developed among 12.6% of patients with SLE after high-dose glucocorticoid therapy. Old age, family history of DM, higher mean dose of prednisolone before high-dose glucocorticoid therapy and concurrent use of MMF were determined to be factors responsible for increasing the risk of developing GDM. PMID- 21659424 TI - Genome-scale analysis of aberrant DNA methylation in colorectal cancer. AB - Colorectal cancer (CRC) is a heterogeneous disease in which unique subtypes are characterized by distinct genetic and epigenetic alterations. Here we performed comprehensive genome-scale DNA methylation profiling of 125 colorectal tumors and 29 adjacent normal tissues. We identified four DNA methylation-based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups. A CIMP-high (CIMP-H) subgroup, which exhibits an exceptionally high frequency of cancer-specific DNA hypermethylation, is strongly associated with MLH1 DNA hypermethylation and the BRAF(V600E) mutation. A CIMP-low (CIMP-L) subgroup is enriched for KRAS mutations and characterized by DNA hypermethylation of a subset of CIMP-H-associated markers rather than a unique group of CpG islands. Non-CIMP tumors are separated into two distinct clusters. One non-CIMP subgroup is distinguished by a significantly higher frequency of TP53 mutations and frequent occurrence in the distal colon, while the tumors that belong to the fourth group exhibit a low frequency of both cancer-specific DNA hypermethylation and gene mutations and are significantly enriched for rectal tumors. Furthermore, we identified 112 genes that were down-regulated more than twofold in CIMP-H tumors together with promoter DNA hypermethylation. These represent ~7% of genes that acquired promoter DNA methylation in CIMP-H tumors. Intriguingly, 48/112 genes were also transcriptionally down-regulated in non-CIMP subgroups, but this was not attributable to promoter DNA hypermethylation. Together, we identified four distinct DNA methylation subgroups of CRC and provided novel insight regarding the role of CIMP-specific DNA hypermethylation in gene silencing. PMID- 21659425 TI - Quantitative evaluation of all hexamers as exonic splicing elements. AB - We describe a comprehensive quantitative measure of the splicing impact of a complete set of RNA 6-mer sequences by deep sequencing successfully spliced transcripts. All 4096 6-mers were substituted at five positions within two different internal exons in a 3-exon minigene, and millions of successfully spliced transcripts were sequenced after transfection of human cells. The results allowed the assignment of a relative splicing strength score to each mutant molecule. The effect of 6-mers on splicing often depended on their location; much of this context effect could be ascribed to the creation of different overlapping sequences at each site. Taking these overlaps into account, the splicing effect of each 6-mer could be quantified, and 6-mers could be designated as enhancers (ESEseqs) and silencers (ESSseqs), with an ESRseq score indicating their strength. Some 6-mers exhibited positional bias relative to the two splice sites. The distribution and conservation of these ESRseqs in and around human exons supported their classification. Predicted RNA secondary structure effects were also seen: Effective enhancers, silencers and 3' splice sites tend to be single stranded, and effective 5' splice sites tend to be double stranded. 6-mers that may form positive or negative synergy with another were also identified. Chromatin structure may also influence the splicing enhancement observed, as a good correspondence was found between splicing performance and the predicted nucleosome occupancy scores of 6-mers. This approach may prove of general use in defining nucleic acid regulatory motifs, substitute for functional SELEX in most cases, and provide insights about splicing mechanisms. PMID- 21659426 TI - Transcription factor AP2 regulates human inhibin alpha subunit gene expression during in vitro trophoblast differentiation. AB - During human trophoblast differentiation, inhibin alpha subunit mRNA expression and protein secretion are increased. To understand how inhibin alpha subunit gene was regulated during syncytialization, we firstly cloned the inhibin alpha promoter and found a region with transcriptional activity related to the differentiation state. In this paper, we identified this protein and defined its DNA-binding site. Protein purification and identification were done by DNA affinity chromatography followed by mass spectrometry and western blotting. In order to confirm the identity of the protein, characterize its DNA-binding properties and to measure its expression during in vitro trophoblast differentiation, gel retardation assays and real-time polymerase chain reaction were done. We found that the cytotrophoblastic protein interacting with the inhibin alpha promoter was the transcription factor activating protein 2 (AP2). Western blotting using specific antibodies against AP2alpha and AP2gamma confirmed that AP2alpha was the main subtype present in trophoblast cells, while AP2gamma was barely detectable. Supershift experiments indicated that these two factors were able to bind to the sequence 5'-GCCtcaAGC-3'. We also observed an increase in AP2alpha mRNA and protein during in vitro trophoblast differentiation correlated with an increase in inhibin alpha subunit gene expression. Furthermore, AP2alpha and AP2gamma overexpression in these cells was responsible for an increase in inhibin alpha subunit mRNA expression. We conclude that AP2 regulates the inhibin alpha subunit gene expression during trophoblast differentiation and may be a key regulator of syncytialization. PMID- 21659427 TI - Color naming reveals our ability to distinguish between a colored background and colored light. AB - Objects appear to have much the same color under quite diverse illumination. This phenomenon, which is known as color constancy, can only be achieved by considering the color of surrounding surfaces. However, considering surrounding surfaces will yield errors if the chromaticity in such surfaces arises from the surface reflectance rather than from the illumination. Does the visual system treat chromaticity in the direct surrounding differently when it is evident that such chromaticity arises from the illumination than when it is evident that it arises from the surrounding surface reflectance? To investigate this, we briefly presented target patches on a simulation of a colorful ball rotating slowly under a lamp. Target patches were shown on differently colored surfaces, both under the lamp and in the shade. When naming the target patches' colors, surrounding colors had a larger influence on the named color when the simulated illumination was different than when the simulated reflectance of the surrounding surface of the ball was different. When matching the color rather than naming it, this distinction was only evident if the matching stimulus encouraged people to match the appropriate contrast. We propose that matching can reveal the sensed color, whereas naming reveals the interpretation in terms of surface reflectance. PMID- 21659428 TI - On the filter approach to perceptual transparency. AB - In F. Faul and V. Ekroll (2002), we proposed a filter model of perceptual transparency that describes typical color changes caused by optical filters and accurately predicts perceived transparency. Here, we provide a more elaborate analysis of this model: (A) We address the question of how the model parameters can be estimated in a robust way. (B) We show that the parameters of the original model, which are closely related to physical properties, can be transformed into the alternative parameters hue H, saturation S, transmittance V, and clarity C that better reflect perceptual dimensions of perceived transparency. (C) We investigate the relation of H, S, V, and C to the physical parameters of optical filters and show that C is closely related to the refractive index of the filter, whereas V and S are closely related to its thickness. We also demonstrate that the latter relationship can be used to estimate relative filter thickness from S and V. (D) We investigate restrictions on S that result from properties of color space and determine its distribution under realistic choices of physical parameters. (E) We experimentally determine iso-saturation curves that yield nominal saturation values for filters of different hue such that they appear equally saturated. PMID- 21659429 TI - A prerotational, simulation-based workshop improves the safety of central venous catheter insertion: results of a successful internal medicine house staff training program. AB - BACKGROUND: The purpose of this study was to evaluate the effectiveness of a simulation-based workshop with ultrasonography instruction in reducing mechanical complications associated with central venous catheter (CVC) insertion. METHODS: A single-center prospective cohort study was conducted in the medical ICU and respiratory step-down unit of an urban teaching hospital. Fifty-six medical house staff members were trained prior to their rotations over a 6-month period. The data on mechanical complication rates after the implementation of the workshop were compared with previous experience when no structured educational program existed. RESULTS: There were 334 procedures in the preeducation period compared to 402 procedures in the posteducation period. The overall complication rate, including placement failure, in the preeducation and posteducation period was 32.9% and 22.9%, respectively (P < .01). Placement failure rate decreased from 22.8% to 16.2% (P = .02), and arterial punctures decreased from 4.2% to 1.5% (P = .03). Ultrasonography usage increased from 3.0% to 61.4% (P < .01). Multivariate analysis demonstrated that interns were more likely to cause overall mechanical complications compared with fellows and attending physicians in the preeducation period (P = .02); however, this trend was not observed in the posteducation period. Catheter site and ultrasonography usage significantly affected the overall complication rate in both periods, and ultrasound-guided femoral CVC was the safest procedure in the posteducation period. CONCLUSIONS: Implementation of a prerotational workshop significantly improved the safety of CVC insertion, especially for CVCs placed by inexperienced operators. We suggest that simulation based training with ultrasonography instruction should be conducted if house staff members are responsible for CVC placement. PMID- 21659430 TI - How should we measure arm exercise capacity in patients with COPD? A systematic review. AB - BACKGROUND: There are no recommendations on how to measure arm exercise capacity in individuals with COPD. The objectives of this study were (1) to synthesize the literature on measures of arm exercise capacity in individuals with COPD, (2) to describe the psychometric properties and the target construct of each measure, and (3) to make recommendations for clinical practice and research. METHODS: Studies conducted in patients with COPD that included a measure of arm exercise capacity were identified after searches of five electronic databases (PubMed, CINAHL, EMBASE, PEDro, and Cochrane Library) and reference lists of pertinent articles. One reviewer performed data extraction, and two assessed the quality of the studies that described measurement properties, using the Consensus-based Standards for the Selection of Health Status Measurement Instruments (COSMIN) checklist. RESULTS: Of 654 reports, 41 met the study criteria. Five types of arm exercise tests were identified: arm ergometry, ring shifts, dowel lifts, proprioceptive neuromuscular facilitation, and activities of daily living. Four studies assessed the measurement properties of the unsupported upper-limb exercise test (UULEX), the 6-min pegboard and ring test (6PBRT), a test involving weight shifts, and the grocery-shelving task (GST). Validity studies were of fair to good quality, whereas reliability studies were of poor quality. CONCLUSIONS: Arm ergometry may be the best method for measuring peak supported arm exercise capacity and endurance. The UULEX, 6PBRT, and GST may better reflect activities of daily living and should be the tests of choice to measure peak unsupported arm exercise capacity (UULEX) and arm function (6PBRT and GST). PMID- 21659431 TI - Pain is a common problem affecting clinical outcomes in adults with cystic fibrosis. AB - BACKGROUND: As the cystic fibrosis (CF) population has aged, many chronic health problems have emerged, including diabetes mellitus and osteoporosis. Previous studies have suggested that pain is common in patients with CF; however, little is known about the factors associated with it or its impact on clinical outcomes. We hypothesized that pain is common, is associated with psychologic distress, and adversely affects clinical outcomes. METHODS: From February 1, 2008, to April 3, 2008, adults with CF from Johns Hopkins Hospital were surveyed about their pain. Outcomes were assessed for 12 months following survey completion. Bivariate analyses were performed using Wilcoxon log rank, Kruskal-Wallis tests, and Spearman correlations. Logistic regression models and Cox proportional hazard models were used to analyze clinical outcomes. RESULTS: Eighty-three patients (61%) completed the survey. Eighty-two percent of patients reported pain within the past month, the most common sites being the head, sinuses, back, and chest. Pain frequently interfered with general activities (41.9%), mood (56.8%), and work (47.3%). Symptoms of depression and anxiety, as well as lower quality-of life (QOL) scores, were associated with the presence of pain (P < .05 for each). The risk of pulmonary exacerbations was increased in patients with higher levels of pain, even after adjusting for FEV(1) and age (OR = 1.65; P = .038; 95% CI, 1.03-2.64). Additionally, the risk of death was higher in patients with higher average pain scores (HR = 2.28; P = .008; 95% CI = 1.2-4.2). CONCLUSIONS: Pain is common in adults with CF, interferes with activities, and is associated with lower QOL and an increased risk of both exacerbations and death. PMID- 21659432 TI - Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration: results of the AQuIRE Bronchoscopy Registry. AB - BACKGROUND: New transbronchial needle aspiration (TBNA) technologies have been developed, but their clinical effectiveness and determinants of diagnostic yield have not been quantified. Prospective data are needed to determine risk-adjusted diagnostic yield. METHODS: We prospectively enrolled patients undergoing TBNA of mediastinal lymph nodes in the American College of Chest Physicians Quality Improvement Registry, Evaluation, and Education (AQuIRE) multicenter database and recorded clinical, procedural, and provider information. All clinical decisions, including type of TBNA used (conventional vs endobronchial ultrasound-guided), were made by the attending bronchoscopist. The primary outcome was obtaining a specific diagnosis. RESULTS: We enrolled 891 patients at six hospitals. Most procedures (95%) were performed with ultrasound guidance. A specific diagnosis was made in 447 cases. Unadjusted diagnostic yields were 37% to 54% for different hospitals, with significant between-hospital heterogeneity (P = .0001). Diagnostic yield was associated with annual hospital TBNA volume (OR, 1.003; 95% CI, 1.000-1.006; P = .037), smoking (OR, 1.55; 95% CI, 1.02-2.34; P = .042), biopsy of more than two sites (OR, 0.57; 95% CI, 0.38-0.85; P = .015), lymph node size (reference > 1-2 cm, <= 1 cm: OR, 0.51; 95% CI, 0.34-0.77; P = .003; > 2-3 cm: OR, 2.49; 95% CI, 1.61-3.85; P < .001; and > 3 cm: OR, 3.61; 95% CI, 2.17 6.00; P < .001), and positive PET scan (OR, 3.12; 95% CI, 1.39-7.01; P = .018). Biopsy was performed on more and smaller nodes at high-volume hospitals (P < .0001). CONCLUSIONS: To our knowledge, this is the first bronchoscopy study of risk-adjusted diagnostic yields on a hospital-level basis. High-volume hospitals were associated with high diagnostic yields. This study also demonstrates the value of procedural registries as a quality improvement tool. A larger number and variety of participating hospitals is needed to verify these results and to further investigate other determinants of diagnostic yield. PMID- 21659433 TI - Patterns of retention of particulate matter in lung tissues of patients with COPD: potential role in disease progression. AB - BACKGROUND: Particulate matter (PM) is present in lung tissues of smokers and urban dwellers. This study was designed to quantify the burden of PM in different lung tissues of subjects with COPD and determine its relationship to disease severity. METHODS: Surgical lung tissue samples from nonsmokers (control subjects) were compared with those from smokers with normal spirometry and subjects in the four other categories of the GOLD (Global Initiative for Obstructive Lung Disease) classification of COPD severity using quantitative histologic techniques. RESULTS: PM was present in the lung parenchyma, blood vessel walls, airways, lymphoid follicles, and alveolar macrophages. The total burden of PM (volume fraction [Vv]) in all tissues of the lung was higher in smokers than nonsmokers (P < .001) and also in smokers with airflow obstruction compared with the smokers with normal spirometry (P < .01). There was an incremental increase in total PM burden with increased COPD severity that peaked in GOLD II and then trended downward in GOLD III and IV COPD. This same pattern of PM retention was also observed in alveolar walls. The total burden of PM in lung tissues correlated with a decline in FEV(1)/FVC as well as pack-years smoking. mRNA expression of fibrinogen (gamma chain) correlated with total lung burden of PM and burden of PM in lung parenchyma (r(2) = 0.22, P < .001). CONCLUSIONS: We conclude that retained PM is widely distributed in lung tissues of subjects with COPD and that cigarette smoke exposure and airflow obstruction are associated with retention of PM in lung tissues. We attribute the downward trend in PM burden in severe COPD to either less deposition and retention or selective removal of PM containing tissues by emphysematous destruction. PMID- 21659434 TI - Interpreting lung function data using 80% predicted and fixed thresholds identifies patients at increased risk of mortality. AB - BACKGROUND: The GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages for COPD use a fixed ratio of the postbronchodilator FEV(1)/FVC ratio of 0.70 as a threshold to define obstruction. Others advocate using the lower limit of normal (LLN) for the FEV(1)/FVC ratio, FEV(1), and FVC to define abnormality. This study investigated mortality in a representative sample of the US adult population with COPD by comparing abnormality determined using GOLD criteria to that determined using LLN criteria. METHODS: We used baseline data from the Third National Health and Nutrition Examination Survey and follow-up mortality data. We classified subjects as obstructed, restricted, or normal based on GOLD vs LLN criteria and used Cox proportional hazards models to determine the relation between lung function impairment and mortality, adjusting for covariates. RESULTS: The study sample included 13,847 subjects, of whom 3,774 died during the follow-up period. Of subjects classified as obstructed and restricted using GOLD criteria, 20.9% and 18.0%, respectively, were classified as normal using LLN criteria. Compared with people with normal lung function, mortality was increased in the obstructed (hazard ratio, 1.46; 95% CI, 1.21-1.86) and restricted (hazard ratio, 1.94; 95% CI, 1.58-2.39) subjects classified as normal using the LLN. CONCLUSIONS: In the nationally representative Third National Health and Nutrition Examination Survey data, subjects classified as normal using LLN criteria but obstructed or restricted using GOLD criteria have a higher risk of mortality. PMID- 21659435 TI - Patients with obstructive sleep apnea syndrome benefit from acetazolamide during an altitude sojourn: a randomized, placebo-controlled, double-blind trial. AB - BACKGROUND: Many patients with obstructive sleep apnea syndrome (OSA) are unable or unwilling to use continuous positive airway pressure (CPAP) therapy when traveling to the mountains for work or recreation even though they risk pronounced hypoxemia and exacerbation of sleep apnea. Because the treatment of OSA at altitude has not been established, we tested the hypothesis that acetazolamide improves hypoxemia, sleep, and breathing disturbances in otherwise untreated patients with OSA at altitude. METHODS: Forty-five patients with OSA on long-term CPAP, median age 64 years, living at < 600 m underwent a placebo controlled, double-blind, crossover trial randomized for the sequence of drug and altitude exposure (490 m, 1,860 m, and 2,590 m). Patients spent two 3-day periods at altitude and a 2-week wash-out period at < 600 m. At altitude, patients discontinued CPAP and received acetazolamide 2 * 250 mg daily or placebo. Polysomnography, vigilance, and symptoms were evaluated. RESULTS: At 490 m, off CPAP, median nocturnal oxygen saturation was 93%, and the apnea/hypopnea index was 51.2/h. On placebo at 1,860 m and 2,590 m, the corresponding values were 89% and 85% and 63.6/h and 86.2/h, respectively (P < .01 vs 490 m, both instances). On acetazolamide at 1,860 m and 2,590 m, oxygen saturation was higher (91% and 88%) and apnea/hypopnea indices were lower (48.0/h and 61.4/h) than on placebo (P < .01 all instances). Acetazolamide reduced nocturnal transcutaneous Pco(2), improved sleep efficiency and subjective insomnia, and prevented excessive BP elevations at altitude. CONCLUSIONS: In patients with OSA discontinuing CPAP during an altitude sojourn, acetazolamide improves oxygenation, breathing disturbances, and sleep quality by stimulating ventilation. Therefore, patients with OSA may benefit from acetazolamide at altitude if CPAP therapy is not feasible. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00714740; URL: www.clinicaltrials.gov. PMID- 21659436 TI - Effect of antibiotic diversity on ventilator-associated pneumonia caused by ESKAPE Organisms. AB - BACKGROUND: The aim of this study was to test in the clinic whether antimicrobial diversity affects resistance of Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogens in ventilator-associated pneumonia (VAP). METHODS: Three different strategies of empirical antimicrobial prescription for VAP were consecutively implemented in an ICU: patient specific (10 months); scheduling, including sequential quarterly prioritization (12 months) and restriction (12 months) of antimicrobials; and mixing (10 months). Periods were compared, measuring the antimicrobial heterogeneity index (AHI). Incidence and resistance patterns of VAP caused by ESKAPE were compared. RESULTS: Overall, 127 microbiologic VAP episodes were documented. ESKAPE VAP increased significantly during scheduling (AHI, 0.65) compared with patient-specific (AHI, 0.88) and mixing (AHI, 0.87) periods (relative risk, 2.67 and 3.84, respectively). This finding was associated with a significant (P < .05) increase of carbapenem resistant A baumannii during the scheduling period (15.0%) compared with the patient-specific (2.4%) and mixing (0%) periods. ICU mortality of resistant patients with ESKAPE VAP was doubled that of patients without ESKAPE VAP (relative risk, 2.25; 95% CI, 1.67-9.48). Thirty-day mechanical ventilation-free days was significantly increased (5 days) in patients with resistant ESKAPE VAP. CONCLUSIONS: Antibiotic strategies promoting diversity may prevent the emergence of resistance of ESKAPE organisms, improving use of health-care resources. PMID- 21659437 TI - The effect of diluent pH on bloodstream infection rates in patients receiving IV treprostinil for pulmonary arterial hypertension. AB - BACKGROUND: Recent studies have reported an increase in catheter-related bloodstream infections (BSIs) and gram-negative BSIs among patients with pulmonary arterial hypertension treated with IV treprostinil. One possible explanation is the neutral pH of the treprostinil diluent compared with the basic pH of epoprostenol. We hypothesized that administering IV treprostinil with epoprostenol diluent will lower the rate of gram-negative BSI. METHODS: We prospectively enrolled patients treated with IV treprostinil and changed the diluent from native diluent to epoprostenol diluent. We compared the incidence of BSI and gram-negative BSI between those receiving IV treprostinil with epoprostenol diluent (n = 25) and those actively receiving IV epoprostenol (n = 61), as well as with a cohort of patients who received IV treprostinil in native diluent (n = 34). Incidence rates of BSI were expressed as a fraction of 1,000 medicine treatment days. RESULTS: There were similar rates of BSI in those treated with treprostinil with epoprostenol diluent and those treated with epoprostenol (0.32 of 1,000 vs 0.40 of 1,000; P = .79). Also, there were similar rates of gram-negative BSI in these two cohorts (0.08 of 1,000 vs 0.20 of 1,000; P = .46). BSI rates were not statistically different between those treated with treprostinil with epoprostenol diluent and those treated with treprostinil (0.32 of 1,000 vs 0.90 of 1,000; P = .06). However, gram-negative BSIs were significantly lower in patients treated with treprostinil with epoprostenol diluent than in those treated with treprostinil (0.08 of 1,000 vs 0.71 of 1,000, respectively; P = .01). CONCLUSIONS: Patients treated with treprostinil with epoprostenol diluent have a lower incidence of gram-negative BSI than do those treated with treprostinil and a similar rate to those treated with epoprostenol. Changing the diluent of treprostinil to epoprostenol diluent, in combination with the use of water-tight seals throughout the delivery system, appears to be an effective safety measure. PMID- 21659438 TI - Intrinsic cardiac origin of human cardiosphere-derived cells. AB - AIMS: Cardiosphere-derived cells (CDCs) are in clinical development as a regenerative cell product which can be expanded ex vivo from patient cardiac biopsies. Cardiosphere-derived cells are clonogenic, exhibit multilineage differentiation, and exert functional benefits in preclinical models of heart failure. The origin of CDCs remains unclear: are these cells endogenous to the heart, or do they arise from cells that populate the heart via blood-borne seeding? METHODS AND RESULTS: Right ventricular endomyocardial biopsies were obtained from cardiac transplant recipients (n = 10, age 57 +/- 15 years), and CDCs expanded from each biopsy. Donor-recipient mismatches were used to probe the origin of CDCs in three complementary ways. First, DNA analysis of short-tandem nucleotide repeats (STRs) was performed on genomic DNA from donor and recipient, then compared with the STR pattern of CDCs. Second, in two cases where the donor was male and the recipient female, CDCs were examined for the presence of X and Y chromosomes by fluorescence in situ hybridization. Finally, in two cases, quantitative PCR (qPCR) was performed for individual-specific polymorphisms of a major histocompatability locus to quantify the contribution of recipient cells to CDCs. In no case was recipient DNA detectable in the CDCs by STR analysis. In the two cases in which a female patient had received a male heart, all CDCs examined had an X and Y chromosome, similarly indicating exclusively donor origin. Likewise, qPCR on CDCs did not detect any recipient DNA. CONCLUSION: Cardiosphere derived cells are of endogenous cardiac origin, with no detectable contribution from extra-cardiac seeding. PMID- 21659440 TI - Role of cardiac resynchronization therapy and atrioventricular junction ablation in patients with permanent atrial fibrillation. PMID- 21659439 TI - Tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial. AB - AIMS: To compare the tissue coverage of a hydrophilic polymer-coated zotarolimus eluting stent (ZES) vs. a fluoropolymer-coated everolimus-eluting stent (EES) at 13 months, using optical coherence tomography (OCT) in an 'all-comers' population of patients, in order to clarify the mechanism of eventual differences in the biocompatibility and thrombogenicity of the devices. METHODS AND RESULTS: Patients randomized to angiographic follow-up in the RESOLUTE All Comers trial (NCT00617084) at pre-specified OCT sites underwent OCT follow-up at 13 months. Tissue coverage and apposition were assessed strut by strut, and the results in both treatment groups were compared using multilevel logistic or linear regression, as appropriate, with clustering at three different levels: patient, lesion, and stent. Fifty-eight patients (30 ZES and 28 EES), 72 lesions, 107 stents, and 23 197 struts were analysed. Eight hundred and eighty-seven and 654 uncovered struts (7.4 and 5.8%, P= 0.378), and 216 and 161 malapposed struts (1.8 and 1.4%, P= 0.569) were found in the ZES and EES groups, respectively. The mean thickness of coverage was 116 +/- 99 um in ZES and 142 +/- 113 um in EES (P= 0.466). No differences in per cent neointimal volume obstruction (12.5 +/- 7.9 vs. 15.0 +/- 10.7%) or other areas-volumetric parameters were found between ZES and EES, respectively. CONCLUSION: No significant differences in tissue coverage, malapposition, or lumen/stent areas and volumes were detected by OCT between the hydrophilic polymer-coated ZES and the fluoropolymer-coated EES at 13-month follow-up. PMID- 21659441 TI - 'It was a freak accident': an analysis of the labelling of injury events in the US press. AB - OBJECTIVES: Given that the news media shape our understanding of health issues, a study was undertaken to examine the use by the US media of the expression 'freak accident' in relation to injury events. This analysis is intended to contribute to the ongoing consideration of lay conceptualisation of injuries as 'accidents'. METHODS: LexisNexis Academic was used to search three purposively selected US news sources (Associated Press, New York Times and Philadelphia Inquirer) for the expression 'freak accident' over 5 years (2005-9). Textual analysis included both structured and open coding. Coding included measures for who used the expression within the story, the nature of the injury event and the injured person(s) being reported upon, incorporation of prevention information within the story and finally a phenomenological consideration of the uses and meanings of the expression within the story context. Results The search yielded a dataset of 250 human injury stories incorporating the term 'freak accident'. Injuries sustained by professional athletes dominated coverage (61%). Fewer than 10% of stories provided a clear and explicit injury prevention message. Stories in which journalists employed the expression 'freak accident' were less likely to include prevention information than stories in which the expression was used by people quoted in the story. CONCLUSIONS: Journalists who frame injury events as freak accidents may be an appropriate focus for advocacy efforts. Effective prevention messages should be developed and disseminated to accompany injury reporting in order to educate and protect the public. PMID- 21659442 TI - The right not to know: the case of psychiatric disorders. AB - This paper will consider the right not to know in the context of psychiatric disorders. It will outline the arguments for and against acquiring knowledge about the results of genetic testing for conditions such as breast cancer and Huntington's disease, and examine whether similar considerations apply to disclosing to clients the results of genetic testing for psychiatric disorders such as depression and Alzheimer's disease. The right not to know will also be examined in the context of the diagnosis of psychiatric disorders that are associated with stigma or for which there is no effective treatment. PMID- 21659443 TI - Understanding the mobile internet to develop the next generation of online medical teaching tools. AB - Healthcare providers (HCPs) use online medical information for self-directed learning and patient care. Recently, the mobile internet has emerged as a new platform for accessing medical information as it allows mobile devices to access online information in a manner compatible with their restricted storage. We investigated mobile internet usage parameters to direct the future development of mobile internet teaching websites. Nephrology On-Demand Mobile (NOD(M)) (http://www.nephrologyondemand.org) was made accessible to all mobile devices. From February 1 to December 31, 2010, HCP use of NOD(M) was tracked using code inserted into the root files. Nephrology On-Demand received 15,258 visits, of which approximately 10% were made to NOD(M), with the majority coming from the USA. Most access to NOD(M) was through the Apple iOS family of devices and cellular connections were the most frequently used. These findings provide a basis for the future development of mobile nephrology and medical teaching tools. PMID- 21659444 TI - Phased implementation of electronic health records through an office of clinical transformation. AB - Evidence suggests that when carefully implemented, health information technologies (HIT) have a positive impact on behavior, as well as operational, process, and clinical outcomes. Recent economic stimulus initiatives have prompted unprecedented federal investment in HIT. Despite strong interest from the healthcare delivery community to achieve 'meaningful use' of HIT within a relatively short time frame, few best-practice implementation methodologies have been described. Herein we outline HIT implementation strategies at an academic health center with an office of clinical transformation. Seven percent of the medical center's information technology budget was dedicated to the Office of Clinical Transformation, and successful conversion of 1491 physicians to electronic-based documentation was accomplished. This paper outlines the process re-design, end-user adoption, and practice transformation strategies that resulted in a 99.7% adoption rate within 6 months of the introduction of digital documentation. PMID- 21659445 TI - The impact of the electronic medical record on structure, process, and outcomes within primary care: a systematic review of the evidence. AB - BACKGROUND: The electronic medical record (EMR)/electronic health record (EHR) is becoming an integral component of many primary-care outpatient practices. Before implementing an EMR/EHR system, primary-care practices should have an understanding of the potential benefits and limitations. OBJECTIVE: The objective of this study was to systematically review the recent literature around the impact of the EMR/EHR within primary-care outpatient practices. MATERIALS AND METHODS: Searches of Medline, EMBASE, CINAHL, ABI Inform, and Cochrane Library were conducted to identify articles published between January 1998 and January 2010. The gray literature and reference lists of included articles were also searched. 30 studies met inclusion criteria. RESULTS AND DISCUSSION: The EMR/EHR appears to have structural and process benefits, but the impact on clinical outcomes is less clear. Using Donabedian's framework, five articles focused on the impact on healthcare structure, 21 explored healthcare process issues, and four focused on health-related outcomes. PMID- 21659446 TI - The marginal value of pre-visit paper reminders when added to a multifaceted electronic health record based quality improvement system. AB - OBJECTIVE: We have reported that implementation of an electronic health record (EHR) based quality improvement system that included point-of-care electronic reminders accelerated improvement in performance for multiple measures of chronic disease care and preventive care during a 1-year period. This study examined whether providing pre-visit paper quality reminders could further improve performance, especially for physicians whose performance had not improved much during the first year. DESIGN: Time-series analysis at a large internal medicine practice using a commercial EHR. All patients eligible for each measure were included (range approximately 100-7500). MEASUREMENTS: The proportion of eligible patients in the practice who satisfied each of 15 quality measures after removing those with exceptions from the denominator. To analyze changes in performance for individual physicians, two composite measures were used: prescribing seven essential medications and completion of five preventive services. RESULTS: During the year after implementing pre-encounter reminders, performance continued to improve for eight measures, remained stable for four, and declined for three. Physicians with the worst performance at the start of the pre-encounter reminders showed little absolute improvement over the next year, and most remained below the median performance for physicians in the practice. CONCLUSIONS: Paper pre encounter reminders did not appear to improve performance beyond electronic point of-care reminders in the EHR alone. Lagging performance is likely not due to providers' EHR workflow alone, and trying to step backwards and use paper reminders in addition to point-of-care reminders in the EHR may not be an effective strategy for engaging slow adopters. PMID- 21659447 TI - Smoking cessation improves mortality in Japanese men: the Hisayama study. AB - BACKGROUND: Although the smoking rate among Japanese men has been the highest in developed countries, the epidemiological evidence about whether smoking cessation can extend their lifespan is not well established. METHODS: A total of 1083 Japanese men aged >=40 years were classified by their smoking status and followed up prospectively for 18 years (1988-2006). RESULTS: Current smoking was a significant risk factor for all-cause death: the multivariate-adjusted HRs of all cause death for current smokers of 1-19, 20-39 and >=40 cigarettes per day were 1.61 (95% CI 1.16 to 2.22), 1.56 (95% CI 1.08 to 2.23) and 3.15 (95% CI 1.59 to 6.24), respectively. Former smokers did not have an increased risk of all-cause death compared with never smokers. The excess risk of all-cause death for current smokers tended to decrease within 5 years after smoking cessation, eventually reaching a level almost equivalent to that of never smokers. The risk of cancer death decreased by 53% in subjects who had quit smoking for >=10 years, while the risk of cardiovascular death decreased by 56% in subjects with the cessation period of <10 years. CONCLUSIONS: Our findings suggest that even a modest smoking habit significantly increases the risk of death among Japanese men, and the risk of death diminishes soon after cessation of smoking. These results imply the importance of smoking cessation to extend life in Japanese men. PMID- 21659448 TI - Tobacco industry attempts to influence and use the German government to undermine the WHO Framework Convention on Tobacco Control. AB - BACKGROUND: Germany has been identified as one of a few high-income countries that opposed a strong Framework Convention on Tobacco Control (FCTC), the WHO's first global public health treaty. This paper examines whether the tobacco industry had influenced the German position on the FCTC. METHODS: Analysis of previously confidential tobacco industry documents. RESULTS: The tobacco industry has identified Germany as a key target within its global strategy against the FCTC. Building on an already supportive base, the industry appears to have successfully lobbied the German government, influencing Germany's position and argumentation on key aspects of the FCTC. It then used Germany in its efforts to weaken the FCTC. The evidence suggests that the industry enjoyed success in undermining the Federal Health Ministry's position and using Germany to limit the European Union negotiating mandate. The tactics used by the tobacco industry included the creation of controversy between the financial, trade and other ministries on one side and the health ministry on the other side, the use of business associations and other front groups to lobby on the industry's behalf and securing industry access to the FCTC negotiations via the International Standardization Organization. CONCLUSION: The evidence suggests that Germany played a major role in the tobacco industry's efforts to undermine the FCTC. Germany's position consistently served to protect industry interests and was used to influence and constrain other countries. Germany thus contributed significantly to attempts to weaken an international treaty and, in doing so, failed in its responsibility to advance global health. PMID- 21659449 TI - Two-year impact of the Spanish smoking law on exposure to secondhand smoke: evidence of the failure of the 'Spanish model'. AB - OBJECTIVE: Studies evaluating the long-term impact of smoking laws on secondhand smoke (SHS) exposure using airborne markers are scarce. This study aimed to assess the long-term impact of the Spanish smoking law on SHS levels, using a specific and objective marker. METHODS: Follow-up study, measuring vapour-phase nicotine levels before the implementation of the law and 6, 12 and 24 months after the initial assessment. A total of 443 samples were taken at baseline in eight different regions in offices in the public administration, private sector, universities and hospitality venues. RESULTS: Two years after the law was implemented, the nicotine concentration decreased by a minimum of 60% in public administration, university and private sector offices, as well as in venues where smoking was totally banned. However, nicotine levels significantly increased by 40% in hospitality venues allowing smoking. No significant differences were found in hospitality venues with areas for smokers and non-smokers or in pubs and discotheques. CONCLUSIONS: Two years after the smoking law came into force, levels of SHS exposure in the workplace were significantly lower than before the law was implemented. Importantly, however, SHS levels were even higher than before the law was implemented in venues still allowing smoking. The data obtained in this study clearly show that the 'Spanish model' is not protecting the health of hospitality workers and that a complete ban is required. Furthermore, this study highlights the importance of long-term monitoring of compliance with smoking laws over time. PMID- 21659451 TI - Anaemia in rheumatoid arthritis: can we afford to ignore it? AB - INTRODUCTION Anaemia is common in rheumatoid arthritis (RA). Clinicians may focus on rheumatological issues and assume anaemia of chronic disease (ACD). This study challenged this assumption and investigated the causes of anaemia in a large cohort of RA patients to assess its implications. METHODS The hospital where the study was conducted monitors regular full blood count and erythrocyte sedimentation rate (ESR) monthly in all RA patients on disease modifying drugs to assess efficacy and safety. A computerised system identifies and records abnormal results. The database for 2009 was interrogated to find all patients with two consecutive haemoglobin values <11 g/dl. Using a proforma, patients were defined as having iron deficiency anaemia (IDA), ACD, macrocytic anaemia (MCA) or another cause. All results of further tests investigating the anaemia were recorded. RESULTS Among 2000 RA patients on the system, 199 (10%) were identified as having anaemia over a year. Of these, 90 had IDA, 78 had ACD, 25 had MCA, and 6 had postoperative anaemia. Among 90 patients with IDA, investigations were performed in 53, with 23 normal. An explanation for IDA was found in 30: gastrointestinal bleeding in 25, gynaecological blood loss in 3, and urinary bleeding in 2. Among 78 patients with ACD, response to intensification of RA treatment occurred in 45, but erythropoietin therapy was required in 9. Within the 25 patients with MCA, 12 had unrecognised vitamin B(12) deficiency, 4 drug induced changes, 3 myeloid malignancy, 2 hypothyroidism, and 2 alcoholism. CONCLUSIONS Anaemia in RA is common, multifactorial, and potentially both serious and correctable. Established malignancy was present in 10 patients and premalignancy in a further 10 (10% of total). Treatable causes were commonly identified. Clinicians need to investigate the nature and cause of persistent anaemia, and must not assume it to be simply ACD without evidence. PMID- 21659450 TI - Electronic nicotine delivery systems in the hands of Hollywood. PMID- 21659452 TI - Intracranial hypotension and venous sinus thrombosis: two postpartum headaches. PMID- 21659453 TI - Successful pregnancies with uterine leiomyomas and myomectomy at the time of caesarean section. AB - OBJECTIVE To ascertain the impact of uterine leiomyomas on pregnancy outcome, and to determine the effectiveness of myomectomy at the time of caesarean delivery. METHODS A retrospective study was conducted on pregnant women with uterine leiomyomas. Clinical information including the course of the pregnancy, mode of delivery, pathology findings, and postpartum course were extracted from medical records and analysed for statistical significance. RESULTS There were 50 pregnancies associated with uterine leiomyomas. During pregnancy, the leiomyomas grew >2 cm in 46% of cases. Only 6% were affected by symptoms of red degeneration. There were 2% mid trimester inductions of labour, 6% vaginal deliveries, and 92% caesarean sections. Of the 46 caesarean sections, 47% were due to obstetrical factors and 89% of patients underwent myomectomy at the time of caesarean delivery. The mean blood loss from myomectomy at the time of caesarean section was 260 ml (200-700 ml), and 5% of patients who underwent myomectomy were transfused. CONCLUSIONS It is possible to carry a pregnancy successfully to term when the pregnancy is complicated by uterine leiomyomas. When caesarean delivery is needed, myomectomy can be performed at the time of caesarean section routinely without significant complications. PMID- 21659454 TI - A hands-on guide on obtaining research ethics approval. AB - It is an uncontested truth that many medical students and practising clinicians dread having to get their research proposal through a research ethics committee. In this paper, the author, a long-standing member of a research ethics committee, offers a practical guide on applying for research ethics approval, detailing common mistakes and flaws in applications, and giving specific guidance on getting through what can seem a daunting process. PMID- 21659455 TI - Serum calcium level is associated with metabolic syndrome in the general population: FIN-D2D study. AB - BACKGROUND: The aim of this cross-sectional study was to examine the association between serum calcium and the components of metabolic syndrome (MetS). METHODS: As a part of the national prevention program of diabetes in Finland (FIN-D2D), a randomly selected study population of 4500 middle-aged men and women were recruited from three central hospital district areas. Anthropometric measurements were performed by a trained nurse. An oral glucose tolerance test was performed and serum calcium and lipids were measured. We assessed current medications, physical activity, smoking, alcohol consumption, calcium intake, and vitamin D intake. The MetS was defined according to the criteria of the updated National Education Program. The study population consisted of 2896 individuals: 1396 men (62% of invited individuals) and 1500 women (66.7% of invited individuals). RESULTS: The mean age was 60.3+/-8.3 years in men and 59.8+/-8.5 years in women. The prevalence of MetS was 50.7% in women and 55.8% in men. The prevalence of MetS and its components, except high-density lipoprotein (HDL)-cholesterol, increased linearly with increasing serum calcium (P<0.001), even after adjustment for age, physical activity, alcohol, vitamin D intake, calcium intake, and smoking. The threshold value for serum calcium for MetS was 2.50 mmol/l in this population. The association of MetS with total serum calcium was similar even after exclusion of patients treated with hypertensive drugs. The drug treatments for hypertension, dyslipidemia, and diabetes increased in a similar pattern. CONCLUSIONS: Serum calcium level is associated with MetS and its components, except HDL-cholesterol. PMID- 21659456 TI - A new Epichloe species with interspecific hybrid origins from Poa pratensis ssp. pratensis in Liyang, China. AB - We describe a new Epichloe species found in symbiosis with Poa pratensis ssp. pratensis in Liyang, China. Stromata characteristic of Epichloe spp. were present on some of the reproductive tillers of individual host grasses. Only three of the 98 stromata observed on field plants became orange and produced perithecia. Phylogenetic analyses based on sequences of tubB and tefA indicated that this Epichloe sp. was an interspecific hybrid related to both E. yangzii and members in the E. typhina complex clade (ETC). Allele-1 of tefA and tubB grouped in the E. bromicola/E. yangzii clade; allele-2 of these two genes clustered in a distinct subclade in the ETC. This is the first report of an Epichloe species that has interspecific hybrid origins. We propose the name Epichloe liyangensis Z. Wang, Y. Kang et H. Miao, sp. nov. for this species. PMID- 21659457 TI - Biodiversity of Asterina species on Neotropical host plants: new species and records from Panama. AB - Two new species of the genus Asterina are described from living leaves collected in provinces Chiriqui and Bocas del Toro in western Panama. Asterina alloplecti on Alloplectus ichtyoderma (Gesneriaceae) differs from other Asterina on Gesneriaceae by its stalked appressoria and host relationship. Asterina compsoneurae on Compsoneura sprucei (Myristicaceae) can be distinguished from other members of Asterina on Myristicaceae by its larger ascomata, larger, prominently spinose ascospores and host relationship. New records for Panama are Asterina corallopoda from a new host plant species (Solanum trizygum, Solanaceae), A. diplopoda, A. ekmanii from a new host plant species (Gonzalagunia rudis, Rubiaceae), A. siphocampyli from a new host plant genus and species (Burmeistera vulgaris, Campanulaceae) and A. styracina from a new host-plant species (Styrax argenteus, Styracaceae). This study increases the number of species of Asterina known for Panama from 12 to 19 and the number of Asterinaceae from 14 to 21. Asterina corallopoda, A. diplopoda, A. ekmanii, A. siphocampyli and A. styracina are illustrated for the first time. A phylogeny inferred from the analysis of LSU rDNA sequences of species of Asterina is presented. The diversity and host-plant patterns of known Neotropical species of Asterina are discussed. PMID- 21659458 TI - DNA barcoding in the rust genus Chrysomyxa and its implications for the phylogeny of the genus. AB - Chrysomyxa rusts are fungal pathogens widely present in the boreal forest. Taxonomic delimitation and precise species identification are difficult within this genus because several species display similar morphological features. We applied a DNA barcode system based on the ribosomal internal transcribed spacer region (ITS), large subunit (28S) ribosomal RNA gene, mitochondrial cytochrome oxidase 1 (CO1) and mitochondrial NADH dehydrogenase subunit 6 (NAD6) in 86 strains from 16 different Chrysomyxa species, including members of the Chrysomyxa ledi species complex. The nuclear ITS and 28S loci revealed higher resolving power than the mitochondrial genes. Amplification of the full CO1 barcode region failed due to the presence of introns limiting the dataset obtained with this barcode. In most cases the ITS barcodes were in agreement with taxonomic species based on phenotypic characters. Nevertheless we observed genetically distinct (different DNA barcodes) lineages within Chrysomyxa pyrolae and Chrysomyxa rhododendri, providing some evidence for allopatric speciation within these morphologically defined species. This finding, together with the observed pattern of host specificities of the studied rust fungi, suggest that species diversification within the C. ledi species complex might be governed by a set of factors such as specialisation to certain Ericaceae species as telial hosts and to a lesser extent specialization to different spruce species as aecial hosts. Moreover allopatric speciation by geographic disruption of species also seems to take place. When our data were integrated into a broader phylogenetic framework the Chrysomyxa genus unexpectedly was not resolved as a monophyletic group. Indeed the spruce cone rusts C. pyrolae and C. monesis coalesced with the pine needle rusts belonging to the genus Coleosporium, whereas the microcyclic species Chrysomyxa weirii was embedded within a clade comprising the genus Melampsora. PMID- 21659459 TI - Reciprocal interactions between the bark beetle-associated yeast Ogataea pini and host plant phytochemistry. AB - Here we report the first experiments testing reciprocal effects between the bark beetle-associated yeast, Ogataea pini, and phytochemicals present in tree tissues (Pinus ponderosa). We tested two hypotheses: (i) tree phytochemicals mediate O. pini growth and (ii) O. pini affects chemical composition of plant tissues. We tested six monoterpenes on O. pini biomass growth in vitro and found that most monoterpenes inhibited O. pini growth; however mean O. pini biomass increased 21.5% when treated with myrcene and 75.5% when treated with terpinolene, relative to control. Ogataea pini was grown on phloem tissue ex vivo to determine whether O. pini affected phloem chemistry. Monoterpene concentrations declined in phloem over time, but phloem colonized by O. pini had significantly different concentrations of monoterpenes at two periods than phloem with no yeast. After 7 d, when O. pini was present, concentrations of the monoterpene Delta-3-carene was 42.9% lower than uncolonized phloem and concentrations of the monoterpene terpinolene was 345.0% higher than uncolonized phloem. After 15 d phloem colonized by O. pini had 505.4% higher concentrations of alpha-pinene than uncolonized phloem. These experiments suggest that O. pini responds to phytochemicals present in host tissues and the presence of O. pini might alter the chemical environment of phloem tissues during the early stages of beetle development. The interactions between O. pini and phytochemicals in pine vascular tissues might have consequences for the bark beetle that vectors O. pini, Dendroctonus brevicomis. PMID- 21659460 TI - PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. AB - Tumor relapses remain a serious problem after allogeneic stem cell transplantation (alloSCT), despite the long-term persistence of minor histocompatibility antigen (MiHA)-specific memory CD8(+) T cells specific for the tumor. We hypothesized that these memory T cells may lose their function over time in transplanted patients. Here, we offer functional and mechanistic support for this hypothesis, based on immune inhibition by programmed death-1 (PD-1) expressed on MiHA-specific CD8(+) T cells and the associated role of the PD-1 ligand PD-L1 on myeloid leukemia cells, especially under inflammatory conditions. PD-L1 was highly upregulated on immature human leukemic progenitor cells, whereas costimulatory molecules such as CD80 and CD86 were not expressed. Thus, immature leukemic progenitor cells seemed to evade the immune system by inhibiting T-cell function via the PD-1/PD-L1 pathway. Blocking PD-1 signaling using human antibodies led to elevated proliferation and IFN-gamma production of MiHA specific T cells cocultured with PD-L1-expressing leukemia cells. Moreover, patients with relapsed leukemia after initial MiHA-specific T-cell responses displayed high PD-L1 expression on CD34(+) leukemia cells and increased PD-1 levels on MiHA-specific CD8(+) T cells. Importantly, blocking PD-1/PD-L1 interactions augment proliferation of MiHA-specific CD8(+) memory T cells from relapsed patients. Taken together, our findings indicate that the PD-1/PD-L pathway can be hijacked as an immune escape mechanism in hematological malignancies. Furthermore, they suggest that blocking the PD-1 immune checkpoint offers an appealing immunotherapeutic strategy following alloSCT in patients with recurrent or relapsed disease. PMID- 21659461 TI - Prognostic immune markers in non-small cell lung cancer. AB - Tumor-associated immune responses have polarized effects in regulating tumor growth. Although a clear association has been shown between the tumor immune response and clinical outcome in colorectal and ovarian cancers, the role of immune markers for stratifying prognosis in non-small cell lung cancer (NSCLC) is less defined. Herein, we review the prognostic significance of published immune markers in the tumor microenvironment and peripheral blood of NSCLC patients. To identify prognostic immune genes, we reviewed all published gene-profiling studies in NSCLC and delineated the significance of immune genes by doing subanalysis on the microarray database of the NIH Director's Challenge study. This first comprehensive review of prognostic immune markers provides a foundation for further investigating immune responses in NSCLC. PMID- 21659462 TI - Melanoma prognosis: a REMARK-based systematic review and bioinformatic analysis of immunohistochemical and gene microarray studies. AB - Despite intensive research efforts, within-stage survival rates for melanoma vary widely. Pursuit of molecular biomarkers with improved prognostic significance over clinicohistological measures has produced extensive literature. Reviews have synthesized these data, but none have systematically partitioned high-quality studies from the remainder across different molecular methods nor examined system properties of that output. Databases were searched for studies analyzing protein expression by immunohistochemistry (n = 617, extending the only systematic review to date by 102 studies) or for gene expression microarray studies (n = 45) in melanoma in relation to outcome. REMARK-derived criteria were applied to identify high-quality studies. Biomarkers and pathways were functionally assessed by using gene ontology software. Most manuscripts did not meet REMARK-based criteria, an ongoing trend that can impede translational research. Across REMARK-compliant literature, 41 proteins were significantly associated with outcome. Multimarker tests consistently emerged among the most promising potential biomarkers, indicating a need to continue assessing candidates in that composite setting. Twenty-one canonical pathways were populated by outcome-related proteins but not by those that failed to show such an association; we propose that this set of pathways warrants closer investigation to understand drivers of poor outcome in melanoma. Two-gene expression microarray studies met REMARK-based criteria reflecting a genuine paucity of literature in the area. The 254 outcome-related genes were examined for correspondences with the systematically identified protein signature. This analysis highlighted proliferating cell nuclear antigen and survivin as priorities for further examination as biomarkers in melanoma prognosis, and illustrated ongoing need to integrate alternative approaches to biomarker discovery in melanoma translational research. PMID- 21659463 TI - Enhanced efficacy of IGF1R inhibition in pediatric glioblastoma by combinatorial targeting of PDGFRalpha/beta. AB - Pediatric glioblastoma (pGBM), although rare, is one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. We have identified IGF1R to be a potential therapeutic target in pGBM due to gene amplification and high levels of IGF2 expression in some tumor samples, as well as constitutive receptor activation in pGBM cell lines. To evaluate the therapeutic potential of strategies targeting the receptor, we have carried out in vitro and in vivo preclinical studies using the specific IGF1R inhibitor NVP-AEW541. A modest inhibitory effect was seen in vitro, with GI(50) values of 5 to 6 MUmol/L, and concurrent inhibition of receptor phosphorylation. Specific targeting of IGF1R with short interfering RNA decreased cell viability, diminished downstream signaling through phosphoinositide 3-kinase (PI3K), and induced G(1) arrest, effects mimicked by NVP-AEW541, both in the absence and presence of IGF2. Hallmarks of PI3K inhibition were observed after treatment with NVP-AEW541 by expression profiling and Western blot analysis. Phospho-receptor tyrosine kinase (RTK) arrays showed phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha/beta in pGBM cells, suggesting coactivation of an alternative RTK pathway. Treatment of KNS42 with the PDGFR inhibitor imatinib showed additional effects targeting the mitogen-activated protein kinase pathway, and cotreatment of the PDGFR inhibitor imatinib with NVP-AEW541 resulted in a highly synergistic interaction in vitro and increased efficacy after 14 days therapy in vivo compared with either agent alone. These data provide evidence that inhibition of IGF1R, in combination with other targeted agents, may be a useful and novel therapeutic strategy in pGBM. PMID- 21659465 TI - Electromyographic activity of the cervical flexor muscles in patients with temporomandibular disorders while performing the craniocervical flexion test: a cross-sectional study. AB - BACKGROUND: Most patients with temporomandibular disorders (TMD) have been shown to have cervical spine dysfunction. However, this cervical dysfunction has been evaluated only qualitatively through a general clinical examination of the cervical spine. PURPOSE: The purpose of this study was to determine whether patients with TMD had increased activity of the superficial cervical muscles when performing the craniocervical flexion test (CCFT) compared with a control group of individuals who were healthy. DESIGN: A cross-sectional study was conducted. METHODS: One hundred fifty individuals participated in this study: 47 were healthy, 54 had myogenous TMD, and 49 had mixed TMD. All participants performed the CCFT. Data for electromyographic activity of the sternocleidomastoid (SCM) and anterior scalene (AS) muscles were collected during the CCFT for all participants. A 3-way mixed-design analysis of variance for repeated measures was used to evaluate the differences in EMG activity for selected muscles while performing the CCFT under 5 incremental levels. Effect size values were calculated to evaluate the clinical relevance of the results. RESULTS: Although there were no statistically significant differences in electromyographic activity in the SCM or AS muscles during the CCFT in patients with mixed and myogenous TMD compared with the control group, those with TMD tended to have increased activity of the superficial cervical muscles. LIMITATIONS: The results obtained in this research are applicable for the group of individuals who participated in this study under the protocols used. They could potentially be applied to people with TMD having characteristics similar to those of the participants of this study. CONCLUSION: This information may give clinicians insight into the importance of evaluation and possible treatment of the deep neck flexors in patients with TMD. However, future research should test the effectiveness of this type of program through a randomized controlled trial in people with TMD in order to determine the real value of treating this type of impairment in this population. PMID- 21659466 TI - Content validity of the Extended ICF Core Set for stroke: an international Delphi survey of physical therapists. AB - BACKGROUND: The "Extended ICF Core Set for stroke" is an application of the International Classification of Functioning, Disability and Health (ICF) and represents the typical spectrum of problems in functioning of people with stroke. OBJECTIVE: The objective of this study was to validate this ICF Core Set from the perspective of physical therapists. DESIGN AND METHODS: Physical therapists experienced in stroke intervention were asked about their patients' problems and resources and about aspects of the environment that physical therapists treat in people with stroke in a 3-round electronic-mail survey using the Delphi technique. The responses were linked to the ICF. The degree of agreement was calculated using the kappa statistic. RESULTS: One hundred twenty-five physical therapists from 24 countries named 4,793 problems treated by physical therapists in people with stroke. They identified 10 second-level ICF categories that currently are not represented in the Extended ICF Core Set for stroke. Twelve responses of the participants were linked to the ICF component personal factors, and 15 responses were not covered by the current version of the classification. The kappa coefficient for the linking agreement was 0.39 (95% bootstrapped confidence interval=0.34-0.41). LIMITATIONS: Two World Health Organization regions were not represented in the sample of physical therapists. CONCLUSIONS: According to the physical therapists, the current version of the Extended ICF Core Set for stroke largely covers the types of problems that their interventions address. However, some aspects of functioning emerged that are not yet covered and may need further investigation. PMID- 21659467 TI - Vitalizing practice through research and research through practice: the outcomes of a conference to enhance the delivery of care. PMID- 21659468 TI - Estimation of RF energy absorbed in the brain from mobile phones in the Interphone Study. AB - OBJECTIVES: The objective of this study was to develop an estimate of a radio frequency (RF) dose as the amount of mobile phone RF energy absorbed at the location of a brain tumour, for use in the Interphone Epidemiological Study. METHODS: We systematically evaluated and quantified all the main parameters thought to influence the amount of specific RF energy absorbed in the brain from mobile telephone use. For this, we identified the likely important determinants of RF specific energy absorption rate during protocol and questionnaire design, we collected information from study subjects, network operators and laboratories involved in specific energy absorption rate measurements and we studied potential modifiers of phone output through the use of software-modified phones. Data collected were analysed to assess the relative importance of the different factors, leading to the development of an algorithm to evaluate the total cumulative specific RF energy (in joules per kilogram), or dose, absorbed at a particular location in the brain. This algorithm was applied to Interphone Study subjects in five countries. RESULTS: The main determinants of total cumulative specific RF energy from mobile phones were communication system and frequency band, location in the brain and amount and duration of mobile phone use. Though there was substantial agreement between categorisation of subjects by cumulative specific RF energy and cumulative call time, misclassification was non negligible, particularly at higher frequency bands. Factors such as adaptive power control (except in Code Division Multiple Access networks), discontinuous transmission and conditions of phone use were found to have a relatively minor influence on total cumulative specific RF energy. CONCLUSIONS: While amount and duration of use are important determinants of RF dose in the brain, their impact can be substantially modified by communication system, frequency band and location in the brain. It is important to take these into account in analyses of risk of brain tumours from RF exposure from mobile phones. PMID- 21659469 TI - Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries. AB - OBJECTIVES: The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones. METHODS: Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the 'tumour location' of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants. RESULTS: ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0. CONCLUSIONS: There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made. PMID- 21659470 TI - Polymorphic variants of cytochrome P450 2B6 (CYP2B6.4-CYP2B6.9) exhibit altered rates of metabolism for bupropion and efavirenz: a charge-reversal mutation in the K139E variant (CYP2B6.8) impairs formation of a functional cytochrome p450 reductase complex. AB - In this study, metabolism of bupropion, efavirenz, and 7-ethoxy-4 trifluoromethylcoumarin (7-EFC) by CYP2B6 wild type (CYP2B6.1) and six polymorphic variants (CYP2B6.4 to CYP2B6.9) was investigated in a reconstituted system to gain a better understanding of the effects of the mutations on the catalytic properties of these naturally occurring variants. All six variants were successfully overexpressed in Escherichia coli, including CYP2B6.8 (the K139E variant), which previously could not be overexpressed in mammalian COS-1 cells (J Pharmacol Exp Ther 311:34-43, 2004). The steady-state turnover rates for the hydroxylation of bupropion and efavirenz and the O-deethylation of 7-EFC showed that these mutations significantly alter the catalytic activities of CYP2B6. It was found that CYP2B6.6 exhibits 4- and 27-fold increases in the K(m) values for the hydroxylation of bupropion and efavirenz, respectively, and CYP2B6.8 completely loses its ability to metabolize any of the substrates under normal turnover conditions. However, compared with CYP2B6.1, CYP2B6.8 retains 77% of its 7-EFC O-deethylase activity in the presence of tert-butyl hydroperoxide as an alternative oxidant, indicating that the heme and the active site are catalytically competent. Presteady-state measurements of the rate of electron transfer from NADPH-dependent cytochrome P450 reductase (CPR) to CYP2B6.8 using stopped-flow spectrophotometry revealed that CYP2B6.8 is incapable of accepting electrons from CPR. These observations provide conclusive evidence suggesting that the charge-reversal mutation in the K139E variant prevents CYP2B6.8 from forming a functional complex with CPR. Results from this work provide further insights to better understand the genotype-phenotype correlation regarding CYP2B6 polymorphisms and drug metabolism. PMID- 21659471 TI - Inhibition of monoacylglycerol lipase attenuates nonsteroidal anti-inflammatory drug-induced gastric hemorrhages in mice. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including cannabinoid receptor type 1 (CB(1)), cannabinoid receptor type 2 (CB(2)), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl 4 (dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184), a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage. Food-deprived mice administered the nonselective cyclooxygenase inhibitor diclofenac sodium displayed gastric hemorrhages and increases in proinflammatory cytokines. JZL184, the proton pump inhibitor omeprazole (positive control), or the primary constituent of marijuana, Delta(9)-tetrahydrocannabinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, arachidonic acid, or the prostaglandins E(2) and D(2). MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor, as well as IL 10. Pharmacological inhibition or genetic deletion of CB(1) or CB(2) revealed that the gastroprotective effects of JZL184 and THC were mediated via CB(1). The antihemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance. These data indicate that increasing 2-AG protects against gastric damage induced by NSAIDs, and its primary catabolic enzyme MAGL offers a promising target for the development of analgesic therapeutics possessing gastroprotective properties. PMID- 21659472 TI - Tetrahydroberberine, an isoquinoline alkaloid isolated from corydalis tuber, enhances gastrointestinal motor function. AB - Because delayed gastric emptying and impaired gastric accommodation are regarded as pathophysiological mechanisms underlying functional dyspepsia (FD), prokinetics and fundic relaxants have been suggested as a new treatment for FD. We isolated tetrahydroberberine (THB), an isoquinoline alkaloid (5,8,13,13a tetrahydro-9,10-dimethoxy-6H-benzo[g]-1,3-benzodioxolo[5,6-a]quinolizine) from Corydalis tuber, and found that it has micromolar affinity for dopamine D(2) (pK(i) = 6.08) and 5-HT(1A) (pK(i) = 5.38) receptors but moderate to no affinity for other relevant serotonin receptors (i.e., 5-HT(1B), 5-HT(1D), 5-HT(3), and 5 HT(4); pK(i) < 5.00). Oral administration of THB not only resulted in significantly accelerated gastric emptying of normal rats in a bell-shaped relationship, with a maximal efficacy at a dose of 30 MUg/kg, but also restored the delayed gastric emptying caused by apomorphine, which might be mediated by an antidopaminergic effect. Data from electromyography indicated enhanced motor function of the upper gastrointestinal tract by THB, which occurred through strengthening contractility and shortening the contraction interval. Furthermore, in rats stressed by repeated restraint, a significantly higher shift in the pressure-volume curve by THB (10 MUg/kg, p < 0.05), which was inhibited by [O methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2 pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635), a 5-HT(1A) antagonist, and N(omega)-nitro-l-arginine methyl ester, a nitric-oxide synthase inhibitor but not a vasoactive intestinal peptide antagonist, was observed. Oral administration of THB resulted in a drastic increase of gastric accommodation in Beagle dogs. Area under the volume versus time curve was increased significantly by THB (30 MUg/kg, p < 0.01) and comparable with that of sumatriptan (3 mg/kg), a potent fundic relaxant. Taken together, our data suggested that THB, with D(2) receptor antagonist and 5-HT(1A) receptor agonist properties, has significant potential as a therapeutic for treatment of FD. PMID- 21659473 TI - Decorin is a novel VEGFR-2-binding antagonist for the human extravillous trophoblast. AB - Extravillous trophoblasts (EVT) of the human placenta invade the uterine decidua and its arteries to ensure successful placentation. We previously identified two decidua-derived molecules, TGF-beta and a TGF-beta-binding proteoglycan decorin (DCN), as negative regulators of EVT proliferation, migration, and invasiveness and reported that DCN acts via multiple tyrosine kinase receptors [epidermal growth factor-receptor (EGF-R), IGF receptor-1 (IGFR1), and vascular endothelial growth factor 2 receptor (VEGFR-2)]. Because binding of DCN to VEGFR-2 has never been reported earlier, present study explored this binding, the approximate location of VEGFR-2-binding site in DCN, and its functional role in our human first trimester EVT cell line HTR-8/SVneo. Based on far-Western blotting and coimmunoprecipitation studies, we report that DCN binds both native (EVT expressed) and recombinant VEGFR-2 and that this binding is abrogated with a VEGFR-2 blocking antibody, indicating an overlap between the ligand-binding and the DCN-binding domains of VEGFR-2. We determined that (125)I-labeled VEGF-E (a VEGFR-2 specific ligand) binds EVT with a dissociation constant (K(d)) of 566 pM, and DCN displaced this binding with an inhibition constant (K(i)) of 3.93-5.78 nM, indicating a 7- to 10-fold lower affinity of DCN for VEGFR-2. DCN peptide fragments derived from the leucine rich repeat 5 domain that blocked DCN-VEGFR-2 interactions or VEGF-E binding in EVT cells also blocked VEGF-A- and VEGF-E induced EVT cell proliferation and migration, indicative of functional VEGFR-2 binding sites of DCN. Finally, DCN inhibited VEGF-E-induced EVT migration by interfering with ERK1/2 activation. Our findings reveal a novel role of DCN as an antagonistic ligand for VEGFR-2, having implications for pathophysiology of preeclampsia, a trophoblast hypoinvasive disorder in pregnancy, and explain its antiangiogenic function. PMID- 21659474 TI - Glucocorticoid activity during lung maturation is essential in mesenchymal and less in alveolar epithelial cells. AB - Corticosteroid treatment is an established therapy for preterm infants, and germline inactivation of the glucocorticoid receptor (GR) gene in the mouse leads to respiratory failure and postnatal lethality. Although glucocorticoids have been thought to critically act in epithelial cells inducing the functional maturation of the lung, inactivation of the GR gene exclusively in the epithelium of the developing murine lung did not impair survival. In contrast, mice lacking GR specifically in mesenchyme-derived cells displayed a phenotype strongly reminiscent of GR knockout animals and died immediately after birth. Detailed analysis of gene expression allows the conclusion that GR acts in cells of the fibroblast lineage controlling their proliferation rate and the composition of the extracellular matrix. PMID- 21659475 TI - Vitamin D receptor (VDR) regulation of voltage-gated chloride channels by ligands preferring a VDR-alternative pocket (VDR-AP). AB - We have postulated that the vitamin D receptor (VDR) contains two overlapping ligand binding sites, a genomic pocket and an alternative pocket (AP), that mediate regulation of gene transcription and rapid responses, respectively. Flexible VDR + ligand docking calculations predict that the major blood metabolite, 25(OH)-vitamin D(3) (25D3), and curcumin (CM) bind more selectively to the VDR-AP when compared with the seco-steroid hormone 1alpha,25(OH)(2) vitamin D(3) (1,25D3). In VDR wild-type-transfected COS-1 cells and TM4 Sertoli cells, 1,25D3, 25D3, and CM each trigger voltage-gated, outwardly rectifying chloride channel (ORCC) currents that can be blocked by the VDR antagonist 1beta,25(OH)(2)-vitamin D(3) and the chloride channel antagonist (4,4' diisothiocyanatostilbene-2,2'-disulfonic acid). VDR mutational analysis in transfected COS-1 cells demonstrate the DNA-binding domain is not, but the ligand binding and hinge domains of the VDR are, required for 1,25D3 and 25D3 to activate the ORCC. Dose-response studies demonstrate that 25D3 and 1,25D3 are approximately equipotent in stimulating ORCC rapid responses, whereas 1 nm 1,25D3 was 1000-fold more potent than 25D3 and CM in stimulating gene expression. The VDR-AP agonist effects of 1,25D3, 25D3, and low-dose CM are lost after pretreatment of TM4 cells with VDR small interfering RNA. Collectively, these results are consistent with an essential role for the VDR-AP in initiating the signaling required for rapid opening of ORCC. The fact that 25D3 is equipotent to 1,25D3 in opening ORCC suggests that reconsideration of the ability of 25D3 to generate biological responses in vivo may be in order. PMID- 21659476 TI - Orphan receptor TR3 enhances p53 transactivation and represses DNA double-strand break repair in hepatoma cells under ionizing radiation. AB - In response to ionizing radiation (IR)-induced DNA double-strand breaks (DSB), cells elicit an evolutionarily conserved checkpoint response that induces cell cycle arrest and either DNA repair or apoptosis, thereby maintaining genomic stability. DNA-dependent protein kinase (DNA-PK) is a central enzyme involved in DSB repair for mammalian cells that comprises a DNA-PK catalytic subunit and the Ku protein, which act as regulatory elements. DNA-PK also functions as a signaling molecule to selectively regulate p53-dependent apoptosis in response to IR. Herein, we demonstrate that the orphan nuclear receptor TR3 suppresses DSB repair by blocking Ku80 DNA-end binding activity and promoting DNA-PK-induced p53 activity in hepatoma cells. We find that TR3 interacts with Ku80 and inhibits its binding to DNA ends, which then suppresses DSB repair. Furthermore, TR3 is a phosphorylation substrate for DNA-PK and interacts with DNA-PK catalytic subunit in a Ku80-independent manner. Phosphorylated TR3, in turn, enhances DNA-PK induced phosphorylation and p53 transcription activity, thereby enhancing IR induced apoptosis in hepatoma cells. Together, our findings reveal novel functions for TR3, not only in DSB repair regulation but also in IR-induced hepatoma cell apoptosis, and they suggest that TR3 is a potential target for cancer radiotherapy. PMID- 21659479 TI - Carcinoid tumor metastases to the extraocular muscles: MR imaging and CT findings and review of the literature. AB - Although a relatively rare neoplasm, primary carcinoid tumor has an unusual propensity to metastasize to the orbits. Within the orbit, metastatic EOM lesions have been described in scattered reports in the ophthalmology literature but have received little to no attention in the radiology literature. After a retrospective review, we identified CT and MR imaging studies of 7 patients with carcinoid tumor metastatic to the EOM. Our findings suggest that in patients with known carcinoid tumor, well-defined, round, or fusiform masses of the EOM should strongly suggest metastatic involvement. Our series suggests that bilateral lesions may occur and that any EOM can be involved. Knowledge of this pattern of metastatic disease may spare biopsies in some patients, and with current orbit sparing therapy for patients with localized orbital disease, early and accurate diagnosis can significantly improve patient outcomes. PMID- 21659478 TI - Esterase 1 is a novel transcriptional repressor of growth hormone receptor gene expression: a unique noncatalytic role for a carboxyesterase protein. AB - The pleiotropic actions of GH result from its engagement with the GH receptor (GHR). GHR expression is regulated by free fatty acids (FFA). A cDNA phage expression library was screened to identify a phage clone expressing esterase 1 (ES1) binding to the FFA-response element (FARE), L2-D1, in the murine GHR promoter. Ectopically expressed ES1 inhibited GHR promoter activity via effects at two FARE, L2-D1 and L2-A2. Chromatin immunoprecipitation experiments demonstrated specific association of ES1 with the FARE. Catalytically inactive ES1 retained inhibitory activity on the GHR promoter and excluded the possibility that the effect on the GHR promoter was an indirect effect secondary to ES1's actions on the intracellular metabolism of FFA. Ectopically expressed ES1 inhibited the endogenous GHR mRNA and protein expression in 3T3-F442A preadipocytes. Subcellular fractionation and confocal microscopy established that ES1 localizes both to the cytoplasm and the nucleus. Experiments demonstrated chromosome region maintenance 1-dependent nuclear export and the presence of a functional nuclear export signal in ES1. The domain of ES1 responsible for the effect on the GHR promoter was localized to the C-terminal portion of the protein. The in vivo significance of ES1's effect on GHR expression was suggested by decreased liver GHR mRNA expression in mice on a high-fat diet correlating with increased steady-state abundance of liver ES1 mRNA. Our results identify and characterize ES1 as a novel transcriptional regulator of GHR gene expression, thereby establishing a unique nonenzymatic role for a carboxyesterase and expanding the potential biological roles of this protein superfamily. PMID- 21659480 TI - Intraosseous CSF fistula in a patient with Gorham disease resulting in intracranial hypotension. AB - A 7-year-old girl with a history of headaches and Gorham disease was surgically treated in infancy for Chiari I malformation. Subsequent investigation revealed that her cerebellar tonsillar ectopia was due to a long-standing spinal CSF lymphatic fistula causing intracranial hypotension. Percutaneous fistula closure was performed several times, resulting in transient symptomatic improvement. PMID- 21659477 TI - Gonadotropin-releasing hormone pulse sensitivity of follicle-stimulating hormone beta gene is mediated by differential expression of positive regulatory activator protein 1 factors and corepressors SKIL and TGIF1. AB - Gonadotropin synthesis and release is dependent on pulsatile stimulation by the hypothalamic neuropeptide GnRH. Generally, slow GnRH pulses promote FSH production, whereas rapid pulses favor LH, but the molecular mechanism underlying this pulse sensitivity is poorly understood. In this study, we developed and tested a model for FSHbeta regulation in mouse LbetaT2 gonadotropes. By mining a previous microarray data set, we found that mRNA for positive regulators of Fshb expression, such as Fos and Jun, were up-regulated at slower pulse frequencies than a number of potential negative regulators, such as the corepressors Skil, Crem, and Tgif1. These latter corepressors reduced Fshb promoter activity whether driven by transfection of individual transcription factors or by treatment with GnRH and activin. Overexpression of binding or phosphorylation-defective ski oncogene-like protein (SKIL) and TG interacting factor (TGIF1) mutants, however, failed to repress Fshb promoter activity. Knockdown of the endogenous repressors SKIL and TGIF1, but not cAMP response element-modulator, increased Fshb promoter activity driven by constant GnRH or activin. Chromatin immunoprecipitation analysis showed that FOS, SKIL, and TGIF1 occupy the FSHbeta promoter in a cyclical manner after GnRH stimulation. Overexpression of corepressors SKIL or TGIF1 repressed induction of the Fshb promoter at the slow GnRH pulse frequency but had little effect at the fast pulse frequency. In contrast, knockdown of endogenous SKIL or TGIF1 selectively increased Fshb mRNA at the fast GnRH pulse frequency. Therefore, we propose a potential mechanism by which production of gonadotropin Fshb is modulated by positive transcription factors and negative corepressors with different pulse sensitivities. PMID- 21659481 TI - Mumps virus encephalitis with symmetric claustrum lesions. PMID- 21659482 TI - Forensic application of postmortem diffusion-weighted and diffusion tensor MR imaging of the human brain in situ. AB - BACKGROUND AND PURPOSE: DWI and DTI of the brain have proved to be useful in many neurologic disorders and in traumatic brain injury. This prospective study aimed at the evaluation of the influence of the PMI and the cause of death on the ADC and FA for the application of DWI and DTI in forensic radiology. MATERIALS AND METHODS: DWI and DTI of the brain were performed in situ in 20 deceased subjects with mapping of the ADC and FA. Evaluation was performed in different ROIs, and the influence of PMI and cause of death was assessed. RESULTS: Postmortem ADC values of the brain were decreased by 49%-72% compared with healthy living controls. With increasing PMI, ADCs were significantly reduced when considering all ROIs together and, particularly, GM regions (all regions, P < .05; GM, P < .01), whereas there was no significant effect in WM. Concerning the cause of death, ADCs were significantly lower in mechanical and hypoxic brain injury than in brains from subjects having died from heart failure (traumatic brain injury, P < .005; hypoxia, P < .001). Postmortem FA was not significantly different from FA in living persons and showed no significant influence of PMI or cause of death. CONCLUSIONS: Performing postmortem DWI and DTI of the brain in situ can provide valuable information for application in forensic medicine. ADC could be used as an indicator of PMI and could help in the assessment of the cause of death. PMID- 21659483 TI - The relation of carotid calcium volume with carotid artery stenosis in symptomatic patients. AB - BACKGROUND AND PURPOSE: Recent research showed a strong correlation of calcium volume scores with degree of stenosis, suggesting that calcium volume could be used in the diagnosis of carotid artery stenosis. We investigated the accuracy of the use of calcium volume scores to diagnose carotid artery stenosis in our target population of recently symptomatic patients. MATERIALS AND METHODS: Ninety symptomatic patients suspected of having carotid artery stenosis underwent CTA, resulting in images of 159 evaluable arteries. The correlation between calcium volume and degree of stenosis was calculated by using the Pearson correlation coefficient. With thresholds of 0.03 and 0.09 mL, we assessed the diagnostic performance of a calcium volume-based evaluation of stenosis for a previously reported stenosis cutoff of 40% and for the clinically important cutoffs of 50% and 70%. RESULTS: In our patients series, the calcium volume score was not related to the stenosis degree on the symptomatic side (R = 0.04, P = .7) and was weakly related on the asymptomatic side (R = 0.29, P = .005). The diagnostic accuracy of the calcium volume score to estimate 40% stenosis was relatively low: a sensitivity of 47% or 64% and a specificity of 52% or 82%, for the 0.09 and 0.03 mL thresholds, respectively. The diagnostic accuracy decreased with increasing degree of stenosis. CONCLUSIONS: We could not confirm the previously reported strong correlation of calcium volume with stenosis degree in our population of patients with recent neurologic symptoms. We conclude that in this particular domain, calcium volume cannot be used to estimate the degree of stenosis. PMID- 21659485 TI - Twenty-five years of preconditioning: are we ready for ischaemia? From coronary occlusion to systems biology and back. AB - It was 25 years ago that the phenomenon of ischaemic preconditioning was first described. The protection afforded by preconditioning was found to be exceptionally robust and aroused immediate interest amongst the scientific community. During the last quarter century, a large research effort has been made to elucidate its molecular mechanisms with the final aim of using this knowledge to develop new cardioprotective treatments. The scientific impact of the discovery of ischaemic preconditioning has been huge-it has allowed a change of paradigm in the understanding of ischaemia-reperfusion injury, from being a mere consequence of energy deprivation to being a complex, active process taking place to a large extent during the reperfusion phase. However, the clinical impact has been small, and some have anticipated a loss of interest in preconditioning unless this changes in the near future. We propose that the failure to develop clinical applications from ischaemic preconditioning is due in part to the incomplete understanding of its mechanisms and that a new integrative scientific approach should be used to resolve the complex networks of preconditioning protection signalling. PMID- 21659484 TI - High-resolution diffusion-weighted imaging of neck lymph nodes using 2D-single shot interleaved multiple inner volume imaging diffusion-weighted echo-planar imaging at 3T. AB - BACKGROUND AND PURPOSE: 2D-ss-IMIV-DWEPI is an ss-DWEPI with greatly reduced geometric distortion. The purposes of this paper are to 1) evaluate of the utility of 2D-ss-IMIV-DWEPI for high-resolution neck LN imaging; 2) determine whether 2D-ss-IMIV-DWEPI can depict normal LN hilum; and 3) evaluate whether the inclusion of LN hilum within ROIs affects the measured LN ADC. MATERIALS AND METHODS: HR-DWI was acquired with 1-mm2 in-plane resolution and 2-mm section thickness by using 2D-ss-IMIV-DWEPI. In total, 58 LNs from 18 subjects were evaluated. The ADC map was calculated by using DWI with b = 10 and 300 s/mm2. In those LNs where the LN hilum could be recognized, the LN ADC was measured with and without inclusion of the hilum, and the mean difference of the resulting ADC values was determined. RESULTS: The hilar structure was identified by DWI in 15 LNs. The ADC of the hilum was 1.981 +/- 0.331 * 10-3 mm2/s. In these 15 LNs, the ADC value excluding hilar structure was significantly lower than the ADC value including hilar structure (0.983 +/- 0.169 versus 1.206 +/- 0.244 * 10-3 mm2/s; P < .0001). The mean ADC in a total of 58 LNs excluding the hilar structure was significantly lower than the value obtained including the hilar structure (1.034 +/- 0.183 versus 1.095 +/- 0.213 * 10-3 mm2/s; P = .0002). CONCLUSIONS: HR-DWI of neck LNs obtained by using 2D-ss-IMIV-DWEPI could identify the hilar structure. The ADC of normal neck LNs seemed significantly different when the hilum was included. The results suggest that HR-DWI may be helpful to aid selection of proper ROIs within LNs for accurate and reliable ADC measurements. PMID- 21659486 TI - Draft genome sequencing and comparative analysis of Aspergillus sojae NBRC4239. AB - We conducted genome sequencing of the filamentous fungus Aspergillus sojae NBRC4239 isolated from the koji used to prepare Japanese soy sauce. We used the 454 pyrosequencing technology and investigated the genome with respect to enzymes and secondary metabolites in comparison with other Aspergilli sequenced. Assembly of 454 reads generated a non-redundant sequence of 39.5-Mb possessing 13 033 putative genes and 65 scaffolds composed of 557 contigs. Of the 2847 open reading frames with Pfam domain scores of >150 found in A. sojae NBRC4239, 81.7% had a high degree of similarity with the genes of A. oryzae. Comparative analysis identified serine carboxypeptidase and aspartic protease genes unique to A. sojae NBRC4239. While A. oryzae possessed three copies of alpha-amyalse gene, A. sojae NBRC4239 possessed only a single copy. Comparison of 56 gene clusters for secondary metabolites between A. sojae NBRC4239 and A. oryzae revealed that 24 clusters were conserved, whereas 32 clusters differed between them that included a deletion of 18 508 bp containing mfs1, mao1, dmaT, and pks-nrps for the cyclopiazonic acid (CPA) biosynthesis, explaining the no productivity of CPA in A. sojae. The A. sojae NBRC4239 genome data will be useful to characterize functional features of the koji moulds used in Japanese industries. PMID- 21659487 TI - Silencing of NHE-1 blunts the slow force response to myocardial stretch. AB - Myocardial stretch induces a biphasic force response: a first abrupt increase followed by a slow force response (SFR), believed to be the in vitro manifestation of the Anrep effect. The SFR is due to an increase in Ca2+ transient of unclear mechanism. We proposed that Na+/H+ exchanger (NHE-1) activation is a key factor in determining the contractile response, but recent reports challenged our findings. We aimed to specifically test the role of the NHE-1 in the SFR. To this purpose small hairpin interference RNA capable of mediating specific NHE-1 knockdown was incorporated into a lentiviral vector (l shNHE1) and injected into the left ventricular wall of Wistar rats. Injection of a lentiviral vector expressing a nonsilencing sequence (scramble) served as control. Myocardial NHE-1 protein expression and function (the latter evaluated by the recovery of pH(i) after an acidic load and the SFR) were evaluated. Animals transduced with l-shNHE1 showed reduced NHE-1 expression (45 +/- 8% of controls; P < 0.05), and the presence of the lentivirus in the left ventricular myocardium, far from the site of injection, was evidenced by confocal microscopy. These findings correlated with depressed basal pH(i) recovery after acidosis [(max)dpH(i)/dt 0.055 +/- 0.008 (scramble) vs. 0.009 +/- 0.004 (l-shNHE1) pH units/min, P < 0.05], leftward shift of the relationship between J(H+) (H+ efflux corrected by the intrinsic buffer capacity), and abolishment of SFR (124 +/- 2 vs. 101 +/- 2% of rapid phase; P < 0.05) despite preserved ERK1/2 phosphorylation [247 +/- 12 (stretch) and 263 +/- 23 (stretch l-shNHE1) % of control; P < 0.05 vs. nonstretched control], well-known NHE-1 activators. Our results provide strong evidence to propose NHE-1 activation as key factor in determining the SFR to stretch. PMID- 21659488 TI - Is sprint exercise a leptin signaling mimetic in human skeletal muscle? AB - This study was designed to determine whether sprint exercise activates signaling cascades linked to leptin actions in human skeletal muscle and how this pattern of activation may be interfered by glucose ingestion. Muscle biopsies were obtained in 15 young healthy men in response to a 30-s sprint exercise (Wingate test) randomly distributed into two groups: the fasting (n = 7, C) and the glucose group (n = 8, G), who ingested 75 g of glucose 1 h before the Wingate test. Exercise elicited different patterns of JAK2, STAT3, STAT5, ERK1/2, p38 MAPK phosphorylation, and SOCS3 protein expression during the recovery period after glucose ingestion. Thirty minutes after the control sprint, STAT3 and ERK1/2 phosphorylation levels were augmented (both, P < 0.05). SOCS3 protein expression was increased 120 min after the control sprint but PTP1B protein expression was unaffected. Thirty and 120 min after the control sprint, STAT5 phosphorylation was augmented (P < 0.05). Glucose abolished the 30 min STAT3 and ERK1/2 phosphorylation and the 120 min SOCS3 protein expression increase while retarding the STAT5 phosphorylation response to sprint. Activation of these signaling cascades occurred despite a reduction of circulating leptin concentration after the sprint. Basal JAK2 and p38 MAPK phosphorylation levels were reduced and increased (both P < 0.05), respectively, by glucose ingestion prior to exercise. During recovery, JAK2 phosphorylation was unchanged and p38 MAPK phosphorylation was transiently reduced when the exercise was preceded by glucose ingestion. In conclusion, sprint exercise performed under fasting conditions is a leptin signaling mimetic in human skeletal muscle. PMID- 21659489 TI - Sweating responses and the muscle metaboreflex under mildly hyperthermic conditions in sprinters and distance runners. AB - To investigate the effects of different training methods on nonthermal sweating during activation of the muscle metaboreflex, we compared sweating responses during postexercise muscle occlusion in endurance runners, sprinters, and untrained men under mild hyperthermia (ambient temperature, 35 degrees C; relative humidity, 50%). Ten endurance runners, nine sprinters, and ten untrained men (maximal oxygen uptakes: 57.5 +/- 1.5, 49.3 +/- 1.5, and 36.6 +/- 1.6 ml.kg( 1).min(-1), respectively; P < 0.05) performed an isometric handgrip exercise at 40% maximal voluntary contraction for 2 min, and then a pressure of 280 mmHg was applied to the forearm to occlude blood circulation for 2 min. The Delta change in mean arterial blood pressure between the resting level and the occlusion was significantly higher in sprinters than in untrained men (32.2 +/- 4.4 vs. 17.3 +/ 2.6 mmHg, respectively; P < 0.05); however, no difference was observed between distance runners and untrained men. The Delta mean sweating rate (averaged value of the forehead, chest, forearm, and thigh) during the occlusion was significantly higher in distance runners than in sprinters and untrained men (0.38 +/- 0.07, 0.19 +/- 0.03, and 0.11 +/- 0.04 mg.cm(-2).min(-1), respectively; P < 0.05) and did not differ between sprinters and untrained men. Our results suggest that the specificity of training modalities influences the sweating response during activation of the muscle metaboreflex. In addition, these results imply that a greater activation of the muscle metaboreflex does not cause a greater sweating response in sprinters. PMID- 21659491 TI - "What trains together, gains together": strength training strengthens not only muscles but also neural networks. PMID- 21659490 TI - Myosin filament polymerization and depolymerization in a model of partial length adaptation in airway smooth muscle. AB - Length adaptation in airway smooth muscle (ASM) is attributed to reorganization of the cytoskeleton, and in particular the contractile elements. However, a constantly changing lung volume with tidal breathing (hence changing ASM length) is likely to restrict full adaptation of ASM for force generation. There is likely to be continuous length adaptation of ASM between states of incomplete or partial length adaption. We propose a new model that assimilates findings on myosin filament polymerization/depolymerization, partial length adaptation, isometric force, and shortening velocity to describe this continuous length adaptation process. In this model, the ASM adapts to an optimal force-generating capacity in a repeating cycle of events. Initially the myosin filament, shortened by prior length changes, associates with two longer actin filaments. The actin filaments are located adjacent to the myosin filaments, such that all myosin heads overlap with actin to permit maximal cross-bridge cycling. Since in this model the actin filaments are usually longer than myosin filaments, the excess length of the actin filament is located randomly with respect to the myosin filament. Once activated, the myosin filament elongates by polymerization along the actin filaments, with the growth limited by the overlap of the actin filaments. During relaxation, the myosin filaments dissociate from the actin filaments, and then the cycle repeats. This process causes a gradual adaptation of force and instantaneous adaptation of shortening velocity. Good agreement is found between model simulations and the experimental data depicting the relationship between force development, myosin filament density, or shortening velocity and length. PMID- 21659492 TI - CPAP as a novel treatment for bronchial asthma? PMID- 21659493 TI - Tympanic membrane rupture in the survivors of the July 7, 2005, London bombings. AB - OBJECTIVE: The goal of this study was to analyze the prevalence of tympanic membrane rupture in the survivors of the London bombings of July 2005 and to assess whether tympanic membrane rupture provides a useful biomarker for underlying primary blast injuries. STUDY DESIGN: Cross-sectional study. SUBJECTS AND METHODS: Survivors of the 4 blasts of London bombings on July 7, 2005. Data were gathered from medical records and the London's Metropolitan Police evidence documenting the injuries sustained by 143 survivors of the blasts. All patients with tympanic membrane rupture or primary blast injury were identified. Analysis was made of distance against prevalence of tympanic membrane rupture. Correlation between tympanic membrane rupture and other forms of primary blast injury was then assessed. RESULTS: Results from the 143 survivors showed a 48% prevalence of tympanic membrane rupture across all 4 sites. Fifty-one patients had isolated tympanic membrane rupture with no other primary blast injuries. Eleven patients had tympanic membrane rupture and other primary blast injuries, but only one of these was an initially concealed injury (blast lung). CONCLUSIONS: Tympanic membrane rupture in survivors of the London bombings on July 7, 2005, had a high prevalence affecting half of patients across a range of distances from the blasts. Tympanic membrane did not act as an effective biomarker of underlying blast lung. In a mass casualty event, patients with isolated tympanic membrane rupture with normal observations and chest radiography can be monitored for a short period and safely discharged with arrangement for ear, nose, and throat follow-up. PMID- 21659494 TI - Septal perforation repairing with combination of mucosal flaps and auricular interpositional grafts in revision patients. AB - OBJECTIVES: To examine the closure of nasal septal perforations with bilateral nasal floor flaps combined with auricular cartilage grafts and a normally functioning nose in revision patients. STUDY DESIGN: Case series with chart review. SETTING: A tertiary referral hospital in Turkey. SUBJECTS AND METHODS: Seventeen patients (11 men, 6 women) with nasal septal reperforation were treated surgically using combined bilateral nasal floor mucosal flaps with bilateral auricular cartilage interpositional grafts. RESULTS: The mean follow-up was 15.2 (range, 9-28) months. The average anteroposterior diameter of perforation was 28 +/- 3 (range, 20-38) mm, and the average vertical diameter was 23 +/- 8 (range, 20-27) mm at the widest site. The nasal septal perforations were closed completely in 16 cases; in 1 case, the perforation was not repaired completely. CONCLUSIONS: A successful multilayer closure technique with good exposure was applied in patients with reperforation. PMID- 21659495 TI - False-negative sentinel lymph node biopsy in head and neck melanoma. AB - OBJECTIVE: The results of sentinel lymph node biopsy (SLNB) can be useful for staging and deciding on adjuvant treatment for patients with head and neck melanoma. False-negative SLNB can result in treatment delay. This study aimed to evaluate the characteristics and outcome of patients with false-negative SLNB in cutaneous melanoma of the head and neck. STUDY DESIGN: Longitudinal cohort study using a prospective institutional tumor registry. SETTING: Academic health center. SUBJECTS AND METHODS: Data from 153 patients who underwent SLNB for melanoma of the head and neck were analyzed. False-negative biopsy was defined as recurrence of tumor in a previously identified negative nodal basin. Statistical analysis was performed on registry data. RESULTS: Positive sentinel lymph nodes were identified in 19 (12.4%) patients. False-negative SLNB was noted in 9 (5.9%) patients, with a false-negative SLNB rate of 32.1%. Using multivariate regression analysis, only examination of a single sentinel lymph node was a significant predictor of false-negative SLNB (P = .01). The mean treatment delay for the false-negative SLNB group was 470 days compared with 23 days in the positive SLNB group (P < .001). The 2-year overall survival of patients with false-negative SLNB was 75% compared with 84% and 98% in positive and negative SLNB groups, respectively (P = .02). CONCLUSIONS: False-negative SLNB is more likely to occur when a single sentinel lymph node is harvested. There is significant treatment delay in patients with false-negative SLNB. False-negative SLNB is associated with poor outcome in patients with melanoma of the head and neck. PMID- 21659496 TI - Association between cerebrospinal fluid leak and meningitis after skull base surgery. AB - BACKGROUND: Meningitis and cerebrospinal fluid (CSF) leak are serious complications of skull base surgery, but whether postoperative CSF leak increases the risk of meningitis is unknown. OBJECTIVE: To evaluate any association between meningitis and CSF leak after open or endoscopic skull base resection. STUDY DESIGN AND SETTING: A retrospective case series with chart review in a tertiary care university-affiliated medical center. METHODS: A total of 156 patients underwent intradural tumor resection in our institution between 1994 and 2009, 135 (86%) via the subcranial approach and 21 (14%) through the expanded endonasal approach. All occurrences of meningitis, brain abscess, and CSF leak had been recorded and were available for analysis. RESULTS: Nine patients (5.7%) had postoperative meningitis, and 3 patients had postoperative CSF leak (1.9%). The risk of meningitis in patients without CSF leak was 4.5% (7/153) compared to 66% (2/3) in those with CSF leak. A statistical analysis revealed a significant association between CSF leak and meningitis, with a relative risk of 14.6 (95% confidence interval, 4.95-42; P = .008). CONCLUSION: Postoperative CSF leak significantly increases the risk of meningitis. Most cases of meningitis after skull base operation are probably associated with lumbar drainage infection or from an obscure leak. PMID- 21659497 TI - Progressive erosion of beta-cell function precedes the onset of hyperglycemia in the NOD mouse model of type 1 diabetes. AB - OBJECTIVE: A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice-the prototypic model for human type 1 diabetes. RESEARCH DESIGN AND METHODS: Morning blood glucose was measured every other day in a cohort of NOD females. Glucose tolerance and insulin secretion were measured longitudinally by intraperitoneal glucose tolerance tests in NOD/ShiLtJ and BALB/cJ mice 6 to 14 weeks of age. Arginine-stimulated insulin secretion and insulin sensitivity were assessed during intraperitoneal arginine or intraperitoneal insulin tolerance tests. RESULTS: During prediabetes, NOD females displayed a progressive increase in glucose levels followed by an acute onset of hyperglycemia. First-phase insulin responses (FPIRs) during the intraperitoneal glucose tolerance test (IPGTT) declined before loss of glucose tolerance in NOD. The failure of FPIR could be detected, with a decline in peak insulin secretion during IPGTT. Arginine-stimulated insulin secretion remained unchanged during the study period. The decline in insulin secretion in NOD mice could not be explained by changes in insulin sensitivity. CONCLUSIONS: There was an impressive decline in FPIR before changes in glucose tolerance, suggesting that impairment of FPIR is an early in vivo marker of progressive beta-cell failure in NOD mice and human type 1 diabetes. We portend that these phenotypes in NOD mice follow a similar pattern to those seen in humans with type 1 diabetes and validate, in a novel way, the importance of this animal model for studies of this disease. PMID- 21659498 TI - The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic Charcot neuroarthropathy. AB - OBJECTIVE: The receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling pathway (RANKL/RANK/OPG signaling) is implicated in the osteolysis associated with diabetic Charcot neuroarthropathy (CN); however, the links with medial arterial calcification (MAC) seen in people with CN are unclear. This study aimed to investigate the role of RANKL/OPG in MAC in patients with CN. RESEARCH DESIGN AND METHODS: Enzyme-linked immunosorbent assay and Bio-plex multiarray technology were used to quantify a range of cytokines, including RANKL and OPG in sera from 10 patients with diabetes, 12 patients with CN, and 5 healthy volunteers. Human tibial artery segments were immunohistochemically stained with Alizarin red and human RANKL antibody. Human vascular smooth muscle cells (VSMCs) were also explanted from arterial segments for in vitro studies. RESULTS: We demonstrate colocalization and upregulation of RANKL expression in areas displaying MAC. Systemic levels of RANKL, OPG, and inflammatory cytokines (interleukin-8, granulocyte colony-stimulating factor) were elevated in those with CN compared with diabetic patients and healthy control subjects. Human VSMCs cultured in CN serum showed accelerated osteoblastic differentiation (alkaline phosphatase activity) and mineralization (alizarin red staining) compared with cells treated with diabetic or control serum (P < 0.05). Coincubation with OPG, the decoy receptor for RANKL, attenuated osteogenic differentiation of VSMCs and was independent of a high calcium phosphate milieu. The accelerated mineralization induced by RANKL and CN serum correlated with nuclear translocation of nuclear factor-kappaB, a process abrogated by OPG. CONCLUSIONS: Our data provide direct evidence that RANKL/RANK/OPG signaling is modulated in patients with CN and plays a role in vascular calcification. This study highlights this pathway as a potential target for intervention. PMID- 21659499 TI - Heterozygous inactivation of the Na/Ca exchanger increases glucose-induced insulin release, beta-cell proliferation, and mass. AB - OBJECTIVE: We have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca(2+) extrusion from cells, increases beta cell programmed cell death (apoptosis) and reduces beta-cell proliferation. To further characterize the role of NCX1 in beta-cells under in vivo conditions, we developed and characterized mice deficient for NCX1. RESEARCH DESIGN AND METHODS: Biologic and morphologic methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release, and point counting morphometry) were used to assess beta-cell function in vitro. Blood glucose and insulin levels were measured to assess glucose metabolism and insulin sensitivity in vivo. Islets were transplanted under the kidney capsule to assess their performance to revert diabetes in alloxan-diabetic mice. RESULTS: Heterozygous inactivation of Ncx1 in mice induced an increase in glucose-induced insulin release, with a major enhancement of its first and second phase. This was paralleled by an increase in beta-cell proliferation and mass. The mutation also increased beta-cell insulin content, proinsulin immunostaining, glucose-induced Ca(2+) uptake, and beta-cell resistance to hypoxia. In addition, Ncx1(+/-) islets showed a two- to four-times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted into diabetic animals. CONCLUSIONS: Downregulation of the Na/Ca exchanger leads to an increase in beta-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in beta-cell function that are opposite to the major abnormalities seen in type 2 diabetes. This provides a unique model for the prevention and treatment of beta-cell dysfunction in type 2 diabetes and after islet transplantation. PMID- 21659500 TI - Storage of circulating free fatty acid in adipose tissue of postabsorptive humans: quantitative measures and implications for body fat distribution. AB - OBJECTIVE: Preferential upper-body fat gain, a typical male pattern, is associated with a greater cardiometabolic risk. Regional differences in lipolysis and meal fat storage cannot explain sex differences in body fat distribution. We examined the potential role of the novel free fatty acid (FFA) storage pathway in determining body fat distribution in postabsorptive humans and whether adipocyte lipogenic proteins (CD36, acyl-CoA synthetases, and diacylglycerol acyltransferase) predict differences in FFA storage. RESEARCH DESIGN AND METHODS: Rates of postabsorptive FFA (palmitate) storage into upper-body subcutaneous (UBSQ) and lower-body subcutaneous (LBSQ) fat were measured in 28 men and 53 premenopausal women. Stable and radiolabeled palmitate tracers were intravenously infused followed by subcutaneous fat biopsies. Body composition was assessed with a combination of dual-energy X-ray absorptiometry and computed tomography. RESULTS: Women had greater FFA (palmitate) storage than men in both UBSQ (0.37 +/ 0.15 vs. 0.27 +/- 0.18 MUmol . kg(-1) . min(-1), P = 0.0001) and LBSQ (0.42 +/- 0.19 vs. 0.22 +/- 0.11 MUmol . kg(-1) . min(-1), P < 0.0001) fat. Palmitate storage rates were significantly greater in LBSQ than UBSQ fat in women, whereas the opposite was true in men. Plasma palmitate concentration positively predicted palmitate storage in both depots and sexes. Adipocyte CD36 content predicted UBSQ palmitate storage and sex-predicted storage in LBSQ fat. Palmitate storage rates per kilogram fat did not decrease as a function of fat mass, whereas lipolysis did. CONCLUSIONS: The FFA storage pathway, which had remained undetected in postabsorptive humans until recently, can have considerable, long-term, and sex specific effects on body fat distribution. It can also offer a way of protecting the body from excessive circulating FFA in obesity. PMID- 21659502 TI - The new health legacy: when pertussis becomes a heritage transmitted from mothers to infants. AB - Despite high vaccination coverage rates, there has been a gradual increase in reported pertussis cases. Although whooping cough affects all ages, young infants continue to suffer the greatest pertussis disease burden. Adolescents and adults are the primary source of infection for young babies. In this paper, we report two cases involving the likely transmission of pertussis from mothers to infants in Tunisia. PMID- 21659501 TI - Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated beta-cell death. AB - OBJECTIVE: CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to beta-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for beta-cells. RESEARCH DESIGN AND METHODS: Peripheral blood CD4 T-cell responses to beta-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat beta-cells, and the rat insulinoma cell line INS-1E were examined. RESULTS: A total of 27 patients (54%) showed IL 17 reactivity to one or more beta-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL 1beta/interferon (IFN)-gamma-induced and tumor necrosis factor (TNF)-alpha/IFN gamma-induced apoptosis in human islets, rat beta-cells, and INS-1E cells, in association with significant upregulation of beta-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-kappaB. CONCLUSIONS: Circulating IL-17(+) beta-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to beta-cell death involving IL-17 and STAT1 and NF-kappaB, rendering this cytokine a novel disease biomarker and potential therapeutic target. PMID- 21659503 TI - Isoniazid-resistant intracranial tuberculoma treated with a combination of moxifloxacin and first-line anti-tuberculosis medication. AB - We report a case of a previously healthy 23-year-old Somalian care assistant. She presented with a 4 month history of persistent occipital headaches associated with intermittent nausea and vomiting. Computed tomography and magnetic resonance imaging of the brain showed a large enhancing lesion in the right cerebellar hemisphere with surrounding ring lesions, suggestive of an intracranial neoplasm with metastases. However, tuberculoma of the brain was confirmed based on histology of the excision biopsy and cerebrospinal fluid (CSF) culture results: Mycobacterium tuberculosis resistant to isoniazid (INH) with sensitivity to other standard drugs, including fluoroquinolones, was cultured from CSF. No primary focus to suggest spread from elsewhere was found. The patient was treated successfully with moxifloxacin, rifampicin, pyrazinamide and ethambutol. Isolated INH-resistant intracranial tuberculoma is rare in adults. It can mimic other intracranial masses and should be kept in mind, especially in populations with a high risk of tuberculosis. Clinical use of moxifloxacin in INH-resistant tuberculomas is limited in humans and this case demonstrates that moxifloxacin may be an effective alternative treatment. PMID- 21659504 TI - Genetic characteristics and changing antimicrobial resistance among Shigella spp. isolated from hospitalized diarrhoeal patients in Kolkata, India. AB - To study the prevalence pattern and trends in the phenotypic and genetic characteristics of shigellae, we tested 212 isolates isolated from diarrhoeal patients admitted to the Infectious Diseases Hospital, Kolkata, India, from November 2007 to October 2010. Prevalence of Shigella spp. was higher in the >5 years age group (69 %) than in children in the <5 years age group (31 %). Serotypes 2a, 3a and untypable isolates of Shigella flexneri were frequently detected. An increase in the isolation of Shigella sonnei (15 %) is a novel trend in this region. Fluoroquinolone resistance among S. flexneri serotypes 2a, 3a and other serogroups of shigellae is another evolving trend. The set gene was exclusively present in S. flexneri 2a, and the sen gene was detected in all serogroups. PFGE revealed the grouping of S. flexneri isolates according to their serotypes with approximately 80-100 % similarity, whilst Shigella dysenteriae type 2 and S. sonnei were clonal in nature. There was no demarcation in the prevalence of serotypes, antimicrobial resistance or clonality between the two age groups. PMID- 21659505 TI - Growth Arrest Specific 8 (Gas8) and G protein-coupled receptor kinase 2 (GRK2) cooperate in the control of Smoothened signaling. AB - The G protein-coupled receptor (GPCR)-like molecule Smoothened (Smo) undergoes dynamic intracellular trafficking modulated by the microtubule associated kinase GRK2 and recruitment of beta-arrestin. Of this trafficking, especially the translocation of Smo into primary cilia and back to the cytoplasm is essential for the activation of Hedgehog (Hh) signaling in vertebrates. The complete mechanism of this bidirectional transport, however, is not completely understood. Here we demonstrate that Growth Arrest Specific 8 (Gas8), a microtubule associated subunit of the Dynein Regulatory Complex (DRC), interacts with Smo to modulate this process. Gas8 knockdown in ciliated cells reduces Smo signaling activity and ciliary localization whereas overexpression stimulates Smo activity in a GRK2-dependent manner. The C terminus of Gas8 is important for both Gas8 interaction with Smo and facilitating Smo signaling. In zebrafish, knocking down Gas8 results in attenuated Hh transcriptional responses and impaired early muscle development. These effects can be reversed by the co-injection of Gas8 mRNA or by constitutive activation of the downstream Gli transcription factors. Furthermore, Gas8 and GRK2 display a synergistic effect on zebrafish early muscle development and some effects of GRK2 knockdown can be rescued by Gas8 mRNA. Interestingly, Gas8 does not interfere with cilia assembly, as the primary cilia architecture is unchanged upon Gas8 knock down or heterologous expression. This is in contrast to cells stably expressing both GRK2 and Smo, in which cilia are significantly elongated. These results identify Gas8 as a positive regulator of Hh signaling that cooperates with GRK2 to control Smo signaling. PMID- 21659506 TI - NC4 Domain of cartilage-specific collagen IX inhibits complement directly due to attenuation of membrane attack formation and indirectly through binding and enhancing activity of complement inhibitors C4B-binding protein and factor H. AB - Collagen IX containing the N-terminal noncollagenous domain 4 (NC4) is unique to cartilage and a member of the family of fibril-associated collagens with both collagenous and noncollagenous domains. Collagen IX is located at the surface of fibrils formed by collagen II and a minor proportion of collagen XI, playing roles in tissue stability and integrity. The NC4 domain projects out from the fibril surface and provides sites for interaction with other matrix components such as cartilage oligomeric matrix protein, matrilins, fibromodulin, and osteoadherin. Fragmentation of collagen IX and loss of the NC4 domain are early events in cartilage degradation in joint diseases that precedes major damage of collagen II fibrils. Our results demonstrate that NC4 can function as a novel inhibitor of the complement system able to bind C4, C3, and C9 and to directly inhibit C9 polymerization and assembly of the lytic membrane attack complex. NC4 also binds the complement inhibitors C4b-binding protein and factor H and enhances their cofactor activity in degradation of activated complement components C4b and C3b. NC4 interactions with fibromodulin and osteoadherin inhibited binding to C1q and complement activation by these proteins. Taken together, our results suggest that collagen IX and its interactions with matrix components are important parts of a machinery that protects the cartilage from complement activation and chronic inflammation seen in diseases like rheumatoid arthritis. PMID- 21659507 TI - Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I). AB - Complex I (NADH-ubiquinone oxidoreductase) can form superoxide during forward electron flow (NADH-oxidizing) or, at sufficiently high protonmotive force, during reverse electron transport from the ubiquinone (Q) pool (NAD(+)-reducing). We designed an assay system to allow titration of the redox state of the superoxide-generating site during reverse electron transport in rat skeletal muscle mitochondria: a protonmotive force generated by ATP hydrolysis, succinate:malonate to alter electron supply and modulate the redox state of the Q pool, and inhibition of complex III to prevent QH(2) oxidation via the Q cycle. Stepwise oxidation of the QH(2)/Q pool by increasing malonate concentration slowed the rates of both reverse electron transport and rotenone-sensitive superoxide production by complex I. However, the superoxide production rate was not uniquely related to the resultant potential of the NADH/NAD(+) redox couple. Thus, there is a superoxide producer during reverse electron transport at complex I that responds to Q pool redox state and is not in equilibrium with the NAD reduction state. In contrast, superoxide production during forward electron transport in the presence of rotenone was uniquely related to NAD redox state. These results support a two-site model of complex I superoxide production; one site in equilibrium with the NAD pool, presumably the flavin of the FMN moiety (site I(F)) and the other dependent not only on NAD redox state, but also on protonmotive force and the reduction state of the Q pool, presumably a semiquinone in the Q-binding site (site I(Q)). PMID- 21659508 TI - Eicosapentaenoic acid demethylates a single CpG that mediates expression of tumor suppressor CCAAT/enhancer-binding protein delta in U937 leukemia cells. AB - Polyunsaturated fatty acids (PUFAs) inhibit proliferation and induce differentiation in leukemia cells. To investigate the molecular mechanisms whereby fatty acids affect these processes, U937 leukemia cells were conditioned with stearic, oleic, linolenic, alpha-linolenic, arachidonic, eicosapentaenoic, and docosahexaenoic acids. PUFAs affected proliferation; eicosapentaenoic acid (EPA) was the most potent on cell cycle progression. EPA enhanced the expression of the myeloid lineage-specific transcription factors CCAAT/enhancer-binding proteins (C/EBPbeta and C/EBPdelta), PU.1, and c-Jun, resulting in increased expression of the monocyte lineage-specific target gene, the macrophage colony stimulating factor receptor. Indeed, it is known that PU.1 and C/EBPs interact with their consensus sequences on a small DNA fragment of macrophage colony stimulating factor receptor promoter, which is a determinant for expression. We demonstrated that C/EBPbeta and C/EBPdelta bind the same response element as a heterodimer. We focused on the enhanced expression of C/EBPdelta, which has been reported to be a tumor suppressor gene silenced by promoter hypermethylation in U937 cells. After U937 conditioning with EPA and bisulfite sequencing of the 370/-20 CpG island on the C/EBPdelta promoter region, we found a site-specific CpG demethylation that was a determinant for the binding activity of Sp1, an essential factor for C/EBPdelta gene basal expression. Our results provide evidence for a new role of PUFAs in the regulation of gene expression. Moreover, we demonstrated for the first time that re-expression of the tumor suppressor C/EBPdelta is controlled by the methylation state of a site-specific CpG dinucleotide. PMID- 21659510 TI - Clostridium difficile has two parallel and essential Sec secretion systems. AB - Protein translocation across the cytoplasmic membrane is an essential process in all bacteria. The Sec system, comprising at its core an ATPase, SecA, and a membrane channel, SecYEG, is responsible for the majority of this protein transport. Recently, a second parallel Sec system has been described in a number of gram-positive species. This accessory Sec system is characterized by the presence of a second copy of the energizing ATPase, SecA2; where it has been studied, SecA2 is responsible for the translocation of a subset of Sec substrates. In common with many pathogenic gram-positive species, Clostridium difficile possesses two copies of SecA. Here, we describe the first characterization of the C. difficile accessory Sec system and the identification of its major substrates. Using inducible antisense RNA expression and dominant negative alleles of secA1 and secA2, we demonstrate that export of the S-layer proteins (SLPs) and an additional cell wall protein (CwpV) is dependent on SecA2. Accumulation of the cytoplasmic precursor of the SLPs SlpA and other cell wall proteins was observed in cells expressing dominant-negative secA1 or secA2 alleles, concomitant with a decrease in the levels of mature SLPs in the cell wall. Furthermore, expression of either dominant-negative allele or antisense RNA knockdown of SecA1 or SecA2 dramatically impaired growth, indicating that both Sec systems are essential in C. difficile. PMID- 21659509 TI - External Cu2+ inhibits human epithelial Na+ channels by binding at a subunit interface of extracellular domains. AB - Epithelial Na(+) channels (ENaCs) play an essential role in the regulation of body fluid homeostasis. Certain transition metals activate or inhibit the activity of ENaCs. In this study, we examined the effect of extracellular Cu(2+) on human ENaC expressed in Xenopus oocytes and investigated the structural basis for its effects. External Cu(2+) inhibited human alphabetagamma ENaC with an estimated IC(50) of 0.3 MUM. The slow time course and a lack of change in the current-voltage relationship were consistent with an allosteric (non pore plugging) inhibition of human ENaC by Cu(2+). Experiments with mixed human and mouse ENaC subunits suggested that both the alpha and beta subunits were primarily responsible for the inhibitory effect of Cu(2+) on human ENaC. Lowering bath solution pH diminished the inhibition by Cu(2+). Mutations of two alpha, two beta, and two gamma His residues within extracellular domains significantly reduced the inhibition of human ENaC by Cu(2+). We identified a pair of residues as potential Cu(2+)-binding sites at the subunit interface between thumb subdomain of alphahENaC and palm subdomain of betahENaC, suggesting a counterclockwise arrangement of alpha, beta, and gamma ENaC subunits in a trimeric channel complex when viewed from above. We conclude that extracellular Cu(2+) is a potent inhibitor of human ENaC and binds to multiple sites within the extracellular domains including a subunit interface. PMID- 21659511 TI - Distribution and biochemical properties of an M1-family aminopeptidase in Plasmodium falciparum indicate a role in vacuolar hemoglobin catabolism. AB - Aminopeptidases catalyze N-terminal peptide bond hydrolysis and occupy many diverse roles across all domains of life. Here we present evidence that an M1 family aminopeptidase, PfA-M1, has been recruited to specialized roles in the human malaria parasite Plasmodium falciparum. PfA-M1 is abundant in two subcellular compartments in asexual intraerythrocytic parasites; that is, the food vacuole, where the catabolism of host hemoglobin takes place, and the nucleus. A unique N-terminal extension contributes to the observed dual targeting by providing a signal peptide and putative alternate translation initiation sites. PfA-M1 exists as two major isoforms, a nuclear 120-kDa species and a processed species consisting of a complex of 68- and 35-kDa fragments. PfA-M1 is both stable and active at the acidic pH of the food vacuole lumen. Determination of steady-state kinetic parameters for both aminoacyl-beta-naphthylamide and unmodified dipeptide substrates over the pH range 5.0-8.5 reveals that k(cat) is relatively insensitive to pH, whereas K(m) increases at pH values below 6.5. At the pH of the food vacuole lumen (5.0-5.5), the catalytic efficiency of PfA-M1 remains high. Consistent with the kinetic data, the affinity of peptidic competitive inhibitors is diminished at acidic pH. Together, these results support a catalytic role for PfA-M1 in the food vacuole and indicate the importance of evaluating the potency of peptidic inhibitors at physiologically relevant pH values. They also suggest a second, distinct function for this enzyme in the parasite nucleus. PMID- 21659512 TI - USP13 enzyme regulates Siah2 ligase stability and activity via noncatalytic ubiquitin-binding domains. AB - The RING finger E3 ubiquitin ligase Siah2 is implicated in control of diverse cellular biological events, including MAPK signaling and hypoxia. Here we demonstrate that Siah2 is subject to regulation by the deubiquitinating enzyme USP13. Overexpression of USP13 increases Siah2 stability by attenuating its autodegradation. Consequently, the ability of Siah2 to target its substrates prolyl hydroxylase 3 and Spry2 (Sprouty2) for ubiquitin-mediated proteasomal degradation is attenuated. Conversely, inhibition of USP13 expression with corresponding shRNA decreases the stability of both Siah2 and its substrate Spry2. Thus, USP13 limits Siah2 autodegradation and its ubiquitin ligase activity against its target substrates. Strikingly, the effect of USP13 on Siah2 is not mediated by its isopeptidase activity: mutations in its ubiquitin-binding sequences positioned within the ubiquitin-specific processing protease and ubiquitin-binding domains, but not within putative catalytic sites, abolish USP13 binding to and effect on Siah2 autodegradation and targeted ubiquitination. Notably, USP13 expression is attenuated in melanoma cells maintained under hypoxia, thereby relieving Siah2 inhibition and increasing its activity under low oxygen levels. Significantly, on melanoma tissue microarray, high nuclear expression of USP13 coincided with high nuclear expression of Siah2. Overall, this study identifies a new layer of Siah2 regulation mediated by USP13 binding to ubiquitinated Siah2 protein with a concomitant inhibitory effect on its activity under normoxia. PMID- 21659513 TI - Low resolution structure of a bacterial SLC26 transporter reveals dimeric stoichiometry and mobile intracellular domains. AB - The SLC26/SulP (solute carrier/sulfate transporter) proteins are a superfamily of anion transporters conserved from bacteria to man, of which four have been identified in human diseases. Proteins within the SLC26/SulP family exhibit a wide variety of functions, transporting anions from halides to carboxylic acids. The proteins comprise a transmembrane domain containing between 10-12 transmembrane helices followed a by C-terminal cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domain. These proteins are expected to undergo conformational changes during the transport cycle; however, structural information for this family remains sparse, particularly for the full-length proteins. To address this issue, we conducted an expression and detergent screen on bacterial Slc26 proteins. The screen identified a Yersinia enterocolitica Slc26A protein as the ideal candidate for further structural studies as it can be purified to homogeneity. Partial proteolysis, co-purification, and analytical size exclusion chromatography demonstrate that the protein purifies as stable oligomers. Using small angle neutron scattering combined with contrast variation, we have determined the first low resolution structure of a bacterial Slc26 protein without spectral contribution from the detergent. The structure confirms that the protein forms a dimer stabilized via its transmembrane core; the cytoplasmic STAS domain projects away from the transmembrane domain and is not involved in dimerization. Supported by additional biochemical data, the structure suggests that large movements of the STAS domain underlie the conformational changes that occur during transport. PMID- 21659514 TI - p53-Inducible DHRS3 is an endoplasmic reticulum protein associated with lipid droplet accumulation. AB - The transcription factor p53 plays a critical role in maintaining homeostasis as it relates to cellular growth, proliferation, and metabolism. In an effort to identify novel p53 target genes, a microarray approach was utilized to identify DHRS3 (also known as retSDR1) as a robust candidate gene. DHRS3 is a highly conserved member of the short chain alcohol dehydrogenase/reductase superfamily with a reported role in lipid and retinoid metabolism. Here, we demonstrate that DHRS3 is an endoplasmic reticulum (ER) protein that is shuttled to the ER via an N-terminal endoplasmic reticulum targeting signal. One important function of the ER is synthesis of neutral lipids that are packaged into lipid droplets whose biogenesis occurs from ER-derived membranes. DHRS3 is enriched at focal points of lipid droplet budding where it also localizes to the phospholipid monolayer of ER derived lipid droplets. p53 promotes lipid droplet accumulation in a manner consistent with DHRS3 enrichment in the ER. As a p53 target gene, the observations of Dhrs3 location and potential function provide novel insight into an unexpected role for p53 in lipid droplet dynamics with implications in cancer cell metabolism and obesity. PMID- 21659515 TI - Transcription factor BORIS (Brother of the Regulator of Imprinted Sites) directly induces expression of a cancer-testis antigen, TSP50, through regulated binding of BORIS to the promoter. AB - Cancer-testis antigens (CTAs) are normally expressed in testis but are aberrantly expressed in a variety of cancers with varying frequency. More than 100 proteins have been identified as CTA including testes-specific protease 50 (TSP50) and the testis-specific paralogue of CCCTC-binding factor, BORIS (brother of the regulator of imprinted sites). Because many CTAs are considered as excellent targets for tumor immunotherapy, understanding the regulatory mechanisms governing their expression is important. In this study we demonstrate that BORIS is directly responsible for the transcriptional activation of TSP50. We found two BORIS binding sites in the TSP50 promoter that are highly conserved between mouse and human. Mutations of the binding sites resulted in loss of BORIS binding and the ability of BORIS to activate the promoter. However, although expression of BORIS was essential, it was not sufficient for high expression of TSP50 in cancer cells. Further studies showed that binding of BORIS to the target sites was methylation-independent but was diminished by nucleosomal occupancy consistent with the findings that high expression of TSP50 was associated with increased DNase I sensitivity and high BORIS occupancy of the promoter. These findings indicate that BORIS-induced expression of TSP50 is governed by accessibility and binding of BORIS to the promoter. To our knowledge this is the first report of regulated expression of one CTA by another to be validated in a physiological context. PMID- 21659516 TI - Pathways regulating the trafficking and turnover of pannexin1 protein and the role of the C-terminal domain. AB - Pannexin1 (Panx1) is an integral membrane protein comprised of three species as follows: an unglycosylated core-Gly0, a high mannose-Gly1, and a complex glycosylated Gly2 species. Although Panx1 channels mediate several cellular responses, the domain regulating its oligomerization and cell surface trafficking and the mechanisms governing its internalization and degradation have not been identified. This study characterizes the role of the Panx1 C-tail domain by truncating the polypeptide at residue 307 and expressing the mutant in BICR M1R(k) and HEK-293T cells. Enzymatic digestion and immunolabeling assays revealed that the Panx1(T307)-RFP was glycosylated primarily to the high mannose species consistent with its retention in the endoplasmic reticulum. Co-expression of Panx1(T307)-RFP with Panx1 followed by co-immunoprecipitation assays revealed that the mutant and Panx1 could interact, whereas biotinylation assays showed that this interaction inhibited Panx1 from maturing into the Gly2 species and reaching the cell surface. Additional inhibitor studies indicated that the degradation of the mutant was via proteasomes, whereas Panx1 was degraded by lysosomes. Analysis of the pathways important in Panx1 internalization revealed partial co-distribution of Panx1 with many molecular constituents of the endocytic machinery that include clathrin, AP2, dynamin II, caveolin-1, and caveolin-2. However, co-immunoprecipitation assays together with the disruption of lipid rafts by methyl-beta-cyclodextrin suggest that Panx1 does not engage this endocytic machinery. Furthermore, dominant-negative and pharmacological studies revealed that Panx1 internalization was dynamin II-independent. Collectively, these results indicate that the oligomerization and trafficking of Panx1 are regulated by the C-terminal domain, whereas internalization of long lived Panx1 channels occurs in a manner that is distinct from classical endocytic pathways. PMID- 21659518 TI - Ligand-modulated parallel mechanical unfolding pathways of maltose-binding proteins. AB - Protein folding and unfolding are complex phenomena, and it is accepted that multidomain proteins generally follow multiple pathways. Maltose-binding protein (MBP) is a large (a two-domain, 370-amino acid residue) bacterial periplasmic protein involved in maltose uptake. Despite the large size, it has been shown to exhibit an apparent two-state equilibrium unfolding in bulk experiments. Single molecule studies can uncover rare events that are masked by averaging in bulk studies. Here, we use single-molecule force spectroscopy to study the mechanical unfolding pathways of MBP and its precursor protein (preMBP) in the presence and absence of ligands. Our results show that MBP exhibits kinetic partitioning on mechanical stretching and unfolds via two parallel pathways: one of them involves a mechanically stable intermediate (path I) whereas the other is devoid of it (path II). The apoMBP unfolds via path I in 62% of the mechanical unfolding events, and the remaining 38% follow path II. In the case of maltose-bound MBP, the protein unfolds via the intermediate in 79% of the cases, the remaining 21% via path II. Similarly, on binding to maltotriose, a ligand whose binding strength with the polyprotein is similar to that of maltose, the occurrence of the intermediate is comparable (82% via path I) with that of maltose. The precursor protein preMBP also shows a similar behavior upon mechanical unfolding. The percentages of molecules unfolding via path I are 53% in the apo form and 68% and 72% upon binding to maltose and maltotriose, respectively, for preMBP. These observations demonstrate that ligand binding can modulate the mechanical unfolding pathways of proteins by a kinetic partitioning mechanism. This could be a general mechanism in the unfolding of other large two-domain ligand-binding proteins of the bacterial periplasmic space. PMID- 21659517 TI - Drug transporter-independent liver cancer cell killing by a marine steroid methyl spongoate via apoptosis induction. AB - Hepatocellular carcinoma (HCC) is inherently resistant to the majority of clinical anticancer drugs. To obtain drugs that can circumvent or evade such inherent drug resistance of HCC, we investigated the effect of the marinely derived steroid methyl spongoate (MESP) on HCC cells. MESP displayed potent cell killing against a panel of six HCC cell lines, independent of their expression of drug transporters. MESP did not change the function of the drug transporters, and its cell killing was not impaired in multidrug-resistant cancer cells overexpressing the transporters. The cell killing of MESP was irrelevant to estrogen or androgen signaling and was not associated with cell cycle progression, inhibition of microtubules, and topoisomerases. In contrast, MESP potently induced apoptosis via activation of a proapoptotic caspase cascade and relief of the suppression of antiapoptotic signal transducers and activators of transcription 3 (STAT3) signaling. MESP inhibited the phosphorylation of STAT3, a critical survival signaling factor that reduced the expression of the antiapoptotic protein x-linked inhibitor of apoptosis protein but enhanced the expression of the proapoptotic protein Bax, thus promoting caspase-dependent apoptosis. These data reveal that MESP may well serve as an important candidate drug lead for HCC therapy. PMID- 21659519 TI - Role of putative second transmembrane region of Nox2 protein in the structural stability and electron transfer of the phagocytic NADPH oxidase. AB - Flavocytochrome b(558) (cytb) of phagocytes is a heterodimeric integral membrane protein composed of two subunits, p22(phox) and gp91(phox). The latter subunit, also known as Nox2, has a cytosolic C-terminal "dehydrogenase domain" containing FAD/NADPH-binding sites. The N-terminal half of Nox2 contains six predicted transmembrane alpha-helices coordinating two hemes. We studied the role of the second transmembrane alpha-helix, which contains a "hot spot" for mutations found in rare X(+) and X(-) chronic granulomatous disease. By site-directed mutagenesis and transfection in X-CGD PLB-985 cells, we examined the functional and structural impact of seven missense mutations affecting five residues. P56L and C59F mutations drastically influence the level of Nox2 expression indicating that these residues are important for the structural stability of Nox2. A53D, R54G, R54M, and R54S mutations do not affect spectral properties of oxidized/reduced cytb, oxidase complex assembly, FAD binding, nor iodonitrotetrazolium (INT) reductase (diaphorase) activity but inhibit superoxide production. This suggests that Ala-53 and Arg-54 are essential in control of electron transfer from FAD. Surprisingly, the A57E mutation partially inhibits FAD binding, diaphorase activity, and oxidase assembly and affects the affinity of immunopurified A57E cytochrome b(558) for p67(phox). By competition experiments, we demonstrated that the second transmembrane helix impacts on the function of the first intracytosolic B-loop in the control of diaphorase activity of Nox2. Finally, by comparing INT reductase activity of immunopurified mutated and wild type cytb under aerobiosis versus anaerobiosis, we showed that INT reduction reflects the electron transfer from NADPH to FAD only in the absence of superoxide production. PMID- 21659520 TI - Phosphorylation directly regulates the intrinsic DNA cytidine deaminase activity of activation-induced deaminase and APOBEC3G protein. AB - The beneficial effects of DNA cytidine deamination by activation-induced deaminase (AID; antibody gene diversification) and APOBEC3G (retrovirus restriction) are tempered by probable contributions to carcinogenesis. Multiple regulatory mechanisms serve to minimize this detrimental outcome. Here, we show that phosphorylation of a conserved threonine attenuates the intrinsic activity of activation-induced deaminase (Thr-27) and APOBEC3G (Thr-218). Phospho-null alanine mutants maintain intrinsic DNA deaminase activity, whereas phospho mimetic glutamate mutants are inactive. The phospho-mimetic variants fail to mediate isotype switching in activated mouse splenic B lymphocytes or suppress HIV-1 replication in human T cells. Our data combine to suggest a model in which this critical threonine acts as a phospho-switch that fine-tunes the adaptive and innate immune responses and helps protect mammalian genomic DNA from procarcinogenic lesions. PMID- 21659521 TI - Molecular mechanism of signal perception and integration by the innate immune sensor retinoic acid-inducible gene-I (RIG-I). AB - RIG-I is a major innate immune sensor for viral infection, triggering an interferon (IFN)-mediated antiviral response upon cytosolic detection of viral RNA. Double-strandedness and 5'-terminal triphosphates were identified as motifs required to elicit optimal immunological signaling. However, very little is known about the response dynamics of the RIG-I pathway, which is crucial for the ability of the cell to react to diverse classes of viral RNA while maintaining self-tolerance. In the present study, we addressed the molecular mechanism of RIG I signal detection and its translation into pathway activation. By employing highly quantitative methods, we could establish the length of the double-stranded RNA (dsRNA) to be the most critical determinant of response strength. Size exclusion chromatography and direct visualization in scanning force microscopy suggested that this was due to cooperative oligomerization of RIG-I along dsRNA. The initiation efficiency of this oligomerization process critically depended on the presence of high affinity motifs, like a 5'-triphosphate. It is noteworthy that for dsRNA longer than 200 bp, internal initiation could effectively compensate for a lack of terminal triphosphates. In summary, our data demonstrate a very flexible response behavior of the RIG-I pathway, in which sensing and integration of at least two distinct signals, initiation efficiency and double strand length, allow the host cell to mount an antiviral response that is tightly adjusted to the type of the detected signal, such as viral genomes, replication intermediates, or small by-products. PMID- 21659522 TI - Specificity protein-1 as a critical regulator of human cystathionine gamma-lyase in smooth muscle cells. AB - Cystathionine gamma-lyase (CSE) is the major enzyme in vascular smooth muscle cells (SMCs) that catalyzes the endogenous production of H(2)S. Phenotypic switching of SMCs is affected by endogenous H(2)S level and alterations of this switching may result in vascular disorders. To date, the mechanisms underlying the alteration of CSE expression and H(2)S production in vascular proliferative diseases have been unclear. In the present study, we found that serum deprivation induced SMC differentiation marker gene expressions and increased CSE expression and H(2)S production in cultured human aorta SMCs (HASMCs). Carotid artery ligation in mice resulted in enhanced neointima formation and down-regulation of CSE expression, suggesting an important role of CSE in SMC differentiation. Transient transfection of HASMCs with human CSE (hCSE) promoter/luciferase reporter revealed that the region between -226 to +140 base pair contains the core promoter for the hCSE gene. Deletion and mutation analysis demonstrated that two specificity protein-1 (Sp1) consensus binding sites were present in the core promoter region of the hCSE gene. Incubation of HASMCs with Sp1 binding inhibitor mithramycin inhibited CSE mRNA expression in a dose-dependent manner. Overexpression of Sp1 alone was sufficient to increase the activity of the hCSE core promoter and CSE protein expression. Chromatin immunoprecipitation assay showed that the binding of Sp1 to the hCSE promoter was increased in differentiated HASMCs compared with that in proliferated HASMCs. Exogenously applied H(2)S at 100 MUM stimulated SMC differentiation, which was reversed by p38 MAPK inhibitor SB203580. These results suggest that transcript factor Sp1 is a critical regulator of the hCSE expression during SMC differentiation, and CSE/H(2)S system is essential for maintenance of SMC phenotype. PMID- 21659523 TI - Highly potent chimeric inhibitors targeting two steps of HIV cell entry. AB - Blocking HIV-1 cell entry has long been a major goal of anti-HIV drug development. Here, we report a successful design of two highly potent chimeric HIV entry inhibitors composed of one CCR5-targeting RANTES (regulated on activation normal T cell expressed and secreted) variant (5P12-RANTES or 5P14 RANTES (Gaertner, H., Cerini, F., Escola, J. M., Kuenzi, G., Melotti, A., Offord, R., Rossitto-Borlat, I., Nedellec, R., Salkowitz, J., Gorochov, G., Mosier, D., and Hartley, O. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 17706-17711)) linked to a gp41 fusion inhibitor, C37. Chimeric inhibitors 5P12-linker-C37 and 5P14-linker C37 showed extremely high antiviral potency in single cycle and replication competent viral assays against R5-tropic viruses, with IC(50) values as low as 0.004 nm. This inhibition was somewhat strain-dependent and was up to 100-fold better than the RANTES variant alone or in combination with unlinked C37. The chimeric inhibitors also fully retained the antiviral activity of C37 against X4 tropic viruses, and this inhibition can be further enhanced significantly if the target cell co-expresses CCR5 receptor. On human peripheral blood mononuclear cells, the inhibitors showed very strong inhibition against R5-tropic Ba-L strain and X4-tropic IIIB strain, with IC(50) values as low as 0.015 and 0.44 nm, which are 45- and 16-fold better than the parent inhibitors, respectively. A clear delivery mechanism requiring a covalent linkage between the two segments of the chimera was observed and characterized. Furthermore, the two chimeric inhibitors are fully recombinant and are easily produced at low cost. These attributes make them excellent candidates for anti-HIV microbicides. The results of this study also suggest a potent approach for optimizing existing HIV entry inhibitors or designing new inhibitors. PMID- 21659524 TI - High glucose-treated macrophages augment E-selectin expression in endothelial cells. AB - E-selectin expression by endothelial cells (ECs) is crucial for leukocyte recruitment during the inflammatory response. Macrophage accumulation and serum E selectin elevation are features of type 2 diabetes mellitus. However, the interactions between macrophages and ECs in regulating vascular endothelial function are not clearly understood. We investigated the mechanisms underlying the modulation of EC E-selectin expression by high glucose (HG)-treated macrophages. Macrophage-conditioned media (MCM) were prepared from HG-treated macrophages. EC stimulation with HG-MCM induced increases the expression and secretion of E-selectin. By using specific inhibitors and small interfering RNAs, we demonstrate that the activation of the JNK and p38 MAPK pathways are critical for HG-MCM-induced E-selectin expression. Transcription factor ELISA and chromatin immunoprecipitation assays further showed that HG-MCM increases the NF kappaB- and AP-1 DNA-binding activities in ECs. The inhibition of NF-kappaB and AP-1 activation by specific siRNAs blocks the HG-MCM-induced E-selectin promoter activity and expression. Protein arrays and blocking assays using neutralizing antibodies demonstrated that macrophage inflammatory protein 1alpha and 1beta in HG-MCM are major mediators for the induction of EC E-selectin expression. These data support the hypothesis that E-selectin up-regulation stimulated by macrophages may play an active role in atherogenesis in the HG condition and suggest a new mechanism by which arterial disease is accelerated in diabetes. PMID- 21659525 TI - Tau protein assembles into isoform- and disulfide-dependent polymorphic fibrils with distinct structural properties. AB - Tauopathies are neurodegenerative diseases in which insoluble fibrillar aggregates of a microtubule-binding protein, Tau, are abnormally accumulated. Pathological Tau fibrils often exhibit structural polymorphisms that differ among phenotypically distinct tauopathies; however, a molecular mechanism to generate polymorphic Tau fibrils remains obscure. Here, we note the formation of a disulfide bond in isoforms of full-length Tau and show that the thiol-disulfide status as well as the isoform composition determines structural and morphological properties of Tau fibrils in vitro. Mainly two regions in a Tau primary sequence are found to act as structural blocks for building a protease-resistant core of Tau fibrils. Interactions among those two blocks for building a core structure depend upon the thiol-disulfide status in each isoform of Tau, which results in the formation of polymorphic fibrils with distinct structural properties. Furthermore, we have found that more diverse structures of Tau fibrils emerge through a cross-seeded fibrillation between heterologous pairs of Tau isoforms. We thus propose that isoform- and disulfide-dependent combinatorial interactions among multiple regions in a Tau sequence endow Tau fibrils with various structures, i.e. polymorphism. PMID- 21659526 TI - Thermal properties of rhodopsin: insight into the molecular mechanism of dim light vision. AB - Rhodopsin has developed mechanisms to optimize its sensitivity to light by suppressing dark noise and enhancing quantum yield. We propose that an intramolecular hydrogen-bonding network formed by ~20 water molecules, the hydrophilic residues, and peptide backbones in the transmembrane region is essential to restrain thermal isomerization, the source of dark noise. We studied the thermal stability of rhodopsin at 55 degrees C with single point mutations (E181Q and S186A) that perturb the hydrogen-bonding network at the active site. We found that the rate of thermal isomerization increased by 1-2 orders of magnitude in the mutants. Our results illustrate the importance of the intact hydrogen-bonding network for dim-light detection, revealing the functional roles of water molecules in rhodopsin. We also show that thermal isomerization of 11 cis-retinal in solution can be catalyzed by wild-type opsin and that this catalytic property is not affected by the mutations. We characterize the catalytic effect and propose that it is due to steric interactions in the retinal binding site and increases quantum yield by predetermining the trajectory of photoisomerization. Thus, our studies reveal a balancing act between dark noise and quantum yield, which have opposite effects on the thermal isomerization rate. The acquisition of the hydrogen-bonding network and the tuning of the steric interactions at the retinal-binding site are two important factors in the development of dim-light vision. PMID- 21659527 TI - Disruption of Bcr-Abl coiled coil oligomerization by design. AB - Oligomerization is an important regulatory mechanism for many proteins, including oncoproteins and other pathogenic proteins. The oncoprotein Bcr-Abl relies on oligomerization via its coiled coil domain for its kinase activity, suggesting that a designed coiled coil domain with enhanced binding to Bcr-Abl and reduced self-oligomerization would be therapeutically useful. Key mutations in the coiled coil domain of Bcr-Abl were identified that reduce homo-oligomerization through intermolecular charge-charge repulsion yet increase interaction with the Bcr-Abl coiled coil through additional salt bridges, resulting in an enhanced ability to disrupt the oligomeric state of Bcr-Abl. The mutations were modeled computationally to optimize the design. Assays performed in vitro confirmed the validity and functionality of the optimal mutations, which were found to exhibit reduced homo-oligomerization and increased binding to the Bcr-Abl coiled coil domain. Introduction of the mutant coiled coil into K562 cells resulted in decreased phosphorylation of Bcr-Abl, reduced cell proliferation, and increased caspase-3/7 activity and DNA segmentation. Importantly, the mutant coiled coil domain was more efficacious than the wild type in all experiments performed. The improved inhibition of Bcr-Abl through oligomeric disruption resulting from this modified coiled coil domain represents a viable alternative to small molecule inhibitors for therapeutic intervention. PMID- 21659528 TI - Common molecular determinants of tarantula huwentoxin-IV inhibition of Na+ channel voltage sensors in domains II and IV. AB - The voltage sensors of domains II and IV of sodium channels are important determinants of activation and inactivation, respectively. Animal toxins that alter electrophysiological excitability of muscles and neurons often modify sodium channel activation by selectively interacting with domain II and inactivation by selectively interacting with domain IV. This suggests that there may be substantial differences between the toxin-binding sites in these two important domains. Here we explore the ability of the tarantula huwentoxin-IV (HWTX-IV) to inhibit the activity of the domain II and IV voltage sensors. HWTX IV is specific for domain II, and we identify five residues in the S1-S2 (Glu 753) and S3-S4 (Glu-811, Leu-814, Asp-816, and Glu-818) regions of domain II that are crucial for inhibition of activation by HWTX-IV. These data indicate that a single residue in the S3-S4 linker (Glu-818 in hNav1.7) is crucial for allowing HWTX-IV to interact with the other key residues and trap the voltage sensor in the closed configuration. Mutagenesis analysis indicates that the five corresponding residues in domain IV are all critical for endowing HWTX-IV with the ability to inhibit fast inactivation. Our data suggest that the toxin-binding motif in domain II is conserved in domain IV. Increasing our understanding of the molecular determinants of toxin interactions with voltage-gated sodium channels may permit development of enhanced isoform-specific voltage-gating modifiers. PMID- 21659529 TI - Transmembrane region of N-methyl-D-aspartate receptor (NMDAR) subunit is required for receptor subunit assembly. AB - N-Methyl-D-aspartate receptors (NMDARs), one of three main classes of ionotropic glutamate receptors, play major roles in synaptic plasticity, synaptogenesis, and excitotoxicity. Unlike non-NMDA receptors, NMDARs are thought to comprise obligatory heterotetrameric complexes mainly composed of GluN1 and GluN2 subunits. When expressed alone in heterogenous cells, such as HEK293 cells, most of the NMDAR subunits can neither leave the endoplasmic reticulum (ER) nor be expressed in the cell membrane because of the ER retention signals. Only when NMDARs are heteromerically assembled can the ER retention signals be masked and NMDARs be expressed in the surface membrane. However, the mechanisms underlying NMDAR assembly remain poorly understood. To identify regions in subunits that mediate this assembly, we made a series of truncated or chimeric cDNA constructs. Using FRET measurement in living cells combined with immunostaining and coimmunoprecipitation analysis, we examined the assembly-determining domains of NMDAR subunits. Our results indicate that the transmembrane region of subunits is necessary for the assembly of NMDAR subunits, both for the homodimer and the heteromer. PMID- 21659530 TI - Highly conserved structural properties of the C-terminal tail of HIV-1 gp41 protein despite substantial sequence variation among diverse clades: implications for functions in viral replication. AB - Although the HIV-1 Env gp120 and gp41 ectodomain have been extensively characterized in terms of structure and function, similar characterizations of the C-terminal tail (CTT) of HIV gp41 remain relatively limited and contradictory. The current study was designed to examine in detail CTT sequence conservation relative to gp120 and the gp41 ectodomain and to examine the conservation of predicted physicochemical and structural properties across a number of divergent HIV clades and groups. Results demonstrate that CTT sequences display intermediate levels of sequence evolution and diversity in comparison to the more diverse gp120 and the more conserved gp41 ectodomain. Despite the relatively high level of CTT sequence variation, the physicochemical properties of the lentivirus lytic peptide domains (LLPs) within the CTT are evidently highly conserved across clades/groups. Additionally, predictions using PEP-FOLD indicate a high level of structural similarity in the LLP regions that was confirmed by circular dichroism measurements of secondary structure of LLP peptides from clades B, C, and group O. Results demonstrate that LLP peptides adopt helical structure in the presence of SDS or trifluoroethanol but are predominantly unstructured in aqueous buffer. Thus, these data for the first time demonstrate strong conservations of characteristic CTT physicochemical and structural properties despite substantial sequence diversity, apparently indicating a delicate balance between evolutionary pressures and the conservation of CTT structure and associated functional roles in virus replication. PMID- 21659532 TI - Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. AB - 5-Aminolevulinic acid synthase (ALAS-1) is the first rate controlling enzyme that controls cellular heme biosynthesis. Negative feedback regulation of ALAS-1 by the end product heme is well documented and provides the foundation for heme treatment of acute porphyrias, a group of diseases caused by genetic defects in the heme biosynthesis pathway and exacerbated by controlled up-regulation of ALAS 1. Heme is known to affect ALAS-1 activity by repressing gene transcription, accelerating mRNA degradation, and impeding pre-ALAS-1 mitochondrial translocation. In the current study, we examined the effect of heme on the rate of mature ALAS-1 protein turnover in human cells and tissues and explored the mediator involved in this new regulatory mechanism. We found that heme and other metalloporphyrins such as CoPP and CrPP decreased mitochondrial ALAS-1 protein through proteolysis. This degradative effect cannot be emulated by iron or free protoporphyrin, two major chemical components of the heme ring, and is independent of oxidative stress. Down-regulating the activity of mitochondrial LONP1, an ATP-dependent protease that controls the selective turnover of mitochondrial matrix proteins, with potent inhibitors and specific siRNA diminished the negative effect of heme on mitochondrial ALAS-1. Therefore, our data support the existence of a conserved heme feedback regulatory mechanism that functions on the mature form of ALAS-1 protein through the activity of a mitochondrial proteolytic system. PMID- 21659531 TI - Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability. AB - The H3K27 histone methyltransferase, Ezh2 (enhancer of zeste 2), is a Polycomb group protein that plays important roles in many biological processes including cellular differentiation, stem cell biology, and cancer development. Up regulation of Ezh2 is observed in various human cancers consistent with its role in cell proliferation. Thus, understanding the regulation of Ezh2 may reveal how it contributes to the cellular proliferation process. Here, we demonstrate that Ezh2 can be regulated by the cyclin-dependent kinase, CDK1, which phosphorylates Ezh2 at threonines 345 and 487. Consistent with the cell cycle phase during which CDK1 exhibits peak activity, Ezh2 phosphorylation is enriched in cells arrested in mitosis when compared with S-phase. Phosphorylation of Thr-345 and Thr-487 promotes Ezh2 ubiquitination and subsequent degradation by the proteasome. Furthermore, expression of T345A/T487A confers a proliferative disadvantage when compared with cells expressing wild-type Ezh2, which suggests that phosphorylation of Ezh2 is important for cell proliferation. Collectively, these results establish a novel function for CDK1-mediated Ezh2 phosphorylation and provide a mechanism by which Ezh2 protein levels can be regulated in cells. PMID- 21659533 TI - Stimulation of yeast telomerase activity by the ever shorter telomere 3 (Est3) subunit is dependent on direct interaction with the catalytic protein Est2. AB - Telomerase is a multisubunit enzyme that maintains genome stability through its role in telomere replication. Although the Est3 protein is long recognized as an essential telomerase component, how it associates with and functions in the telomerase complex has remained enigmatic. Here we provide the first evidence of a direct interaction between Saccharomyces cerevisiae Est3p and the catalytic protein subunit (Est2p) by demonstrating that recombinant Est3p binds the purified telomerase essential N-terminal (TEN) domain of Est2p in vitro. Mutations in a small cluster of amino acids predicted to lie on the surface of Est3p disrupt this interaction with Est2p, reduce assembly of Est3p with telomerase in vivo, and cause telomere shortening and senescence. We also show that recombinant Est3p stimulates telomerase activity above basal levels in vitro in a manner dependent on the Est2p TEN domain interaction. Together, these results define a direct binding interaction between Est3p and Est2p and reconcile the effect of S. cerevisiae Est3p with previous experiments showing that Est3p homologs in related yeast species influence telomerase activity. Additionally, it contributes functional support to the idea that Est3p is structurally related to the mammalian shelterin protein, TPP1, which also influences telomerase activity through interaction with the Est2p homolog, TERT. PMID- 21659534 TI - Superoxide flashes: early mitochondrial signals for oxidative stress-induced apoptosis. AB - Irreversible mitochondrial permeability transition and the resultant cytochrome c release signify the commitment of a cell to apoptotic death. However, the role of transient MPT (tMPT) because of flickering opening of the mitochondrial permeability transition pore remains elusive. Here we show that tMPT and the associated superoxide flashes (i.e. tMPT/superoxide flashes) constitute early mitochondrial signals during oxidative stress-induced apoptosis. Selenite (a ROS dependent insult) but not staurosporine (a ROS-independent insult) stimulated an early and persistent increase in tMPT/superoxide flash activity prior to mitochondrial fragmentation and a global ROS rise, independently of Bax translocation and cytochrome c release. Selectively targeting tMPT/superoxide flash activity by manipulating cyclophilin D expression or scavenging mitochondrial ROS markedly impacted the progression of selenite-induced apoptosis while exerting little effect on the global ROS response. Furthermore, the tMPT/superoxide flash served as a convergence point for pro- and anti-apoptotic regulation mediated by cyclophilin D and Bcl-2 proteins. These results indicate that tMPT/superoxide flashes act as early mitochondrial signals mediating the apoptotic response during oxidative stress, and provide the first demonstration of highly efficacious local mitochondrial ROS signaling in deciding cell fate. PMID- 21659535 TI - Protein kinase R as mediator of the effects of interferon (IFN) gamma and tumor necrosis factor (TNF) alpha on normal and dysplastic hematopoiesis. AB - IFNgamma and TNFalpha are potent inhibitors of hematopoiesis and have been implicated in the pathophysiology of bone marrow failure and myelodysplastic syndromes (MDS). We examined the role of protein kinase R (PKR) in the generation of the inhibitory effects of these myelosuppressive cytokines on hematopoiesis. Our data demonstrate that PKR is rapidly phosphorylated/activated in response to engagement of IFNgamma or TNFalpha receptors in normal human hematopoietic progenitors. Such engagement of PKR is important for the suppressive effects of these cytokines on normal hematopoiesis. Pharmacological targeting of PKR using a specific inhibitor or siRNA-mediated PKR knockdown results in partial reversal of the suppressive effects of IFNgamma and TNFalpha on normal human CD34+-derived myeloid (colony-forming unit-granulocyte-monocytic) and erythroid (burst-forming unit-erythroid) progenitors. Importantly, inhibition of PKR activity or expression increases hematopoietic colony formation from human MDS progenitors, suggesting that drugs that target PKR may provide a novel approach for the treatment of MDS and marrow failure syndromes. Altogether, our data establish that beyond its key role in the induction of IFN-antiviral responses, PKR plays important roles in signaling for IFNgamma and other myelosuppressive cytokine receptors as a common mediator of signals for hematopoietic suppression. PMID- 21659536 TI - Distinct roles for Nod2 protein and autocrine interleukin-1beta in muramyl dipeptide-induced mitogen-activated protein kinase activation and cytokine secretion in human macrophages. AB - Elucidating factors regulating Crohn's disease-associated nucleotide-binding oligomerization domain 2 (Nod2) responses is critical to understanding the mechanisms of intestinal immune homeostasis. Stimulation of primary monocyte derived macrophages by muramyl dipeptide (MDP), a component of bacterial peptidoglycan and specific Nod2 ligand, produces cytokines, including IL-1beta. We found that IL-1beta blockade profoundly inhibits MDP-induced cytokine production in human monocyte-derived macrophages, demonstrating a key role for IL 1beta autocrine secretion in Nod2-mediated responses. Importantly, although MAPK activation has previously been attributed directly to Nod2 signaling, we determined that the IL-1beta autocrine loop is responsible for the majority of MDP-induced MAPK activation. Because the critical effects of IL-1beta autocrine secretion on MAPK activation are observed as early as 10 min after Nod2 stimulation, we hypothesized that secretion of IL-1beta from preexisting intracellular pro-IL-1beta stores is necessary for optimal MDP-mediated cytokine induction. Consistently, we detected IL-1beta secretion within 10 min of MDP treatment. Moreover, caspase-1 inhibition significantly attenuates MDP-mediated early MAPK activation. Importantly, selective JNK/p38 activation is sufficient to rescue the decreased cytokine secretion during Nod2 stimulation in the absence of autocrine IL-1beta. Finally, we found that the IL-1beta autocrine loop significantly enhances responses by a broad range of pattern recognition receptors. Taken together, MDP stimulation activates Nod2 to process and release preexisting pro-IL-1beta stores in a caspase-1-dependent fashion; this secreted IL-1beta, in turn, contributes to the majority of MDP-initiated MAPK activation and leads to subsequent cytokine secretion. Our findings clarify mechanisms of IL 1beta contributions to Nod2 responses and elucidate the dominant role of IL-1beta in MDP-initiated MAPK and cytokine secretion. PMID- 21659538 TI - Kinetics of doubletime kinase-dependent degradation of the Drosophila period protein. AB - Robust circadian oscillations of the proteins PERIOD (PER) and TIMELESS (TIM) are hallmarks of a functional clock in the fruit fly Drosophila melanogaster. Early morning phosphorylation of PER by the kinase Doubletime (DBT) and subsequent PER turnover is an essential step in the functioning of the Drosophila circadian clock. Here using time-lapse fluorescence microscopy we study PER stability in the presence of DBT and its short, long, arrhythmic, and inactive mutants in S2 cells. We observe robust PER degradation in a DBT allele-specific manner. With the exception of doubletime-short (DBT(S)), all mutants produce differential PER degradation profiles that show direct correspondence with their respective Drosophila behavioral phenotypes. The kinetics of PER degradation with DBT(S) in cell culture resembles that with wild-type DBT and posits that, in flies DBT(S) likely does not modulate the clock by simply affecting PER degradation kinetics. For all the other tested DBT alleles, the study provides a simple model in which the changes in Drosophila behavioral rhythms can be explained solely by changes in the rate of PER degradation. PMID- 21659537 TI - Pharmacological and genetic evaluation of proposed roles of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), extracellular signal-regulated kinase (ERK), and p90(RSK) in the control of mTORC1 protein signaling by phorbol esters. AB - The mammalian target of rapamycin complex 1 (mTORC1) links the control of mRNA translation, cell growth, and metabolism to diverse stimuli. Inappropriate activation of mTORC1 can lead to cancer. Phorbol esters are naturally occurring products that act as potent tumor promoters. They activate isoforms of protein kinase C (PKCs) and stimulate the oncogenic MEK/ERK signaling cascade. They also activate mTORC1 signaling. Previous work indicated that mTORC1 activation by the phorbol ester PMA (phorbol 12-myristate 13-acetate) depends upon PKCs and may involve MEK. However, the precise mechanism(s) through which they activate mTORC1 remains unclear. Recent studies have implicated both the ERKs and the ERK activated 90-kDa ribosomal S6 kinases (p90(RSK)) in activating mTORC1 signaling via phosphorylation of TSC2 (a regulator of mTORC1) and/or the mTORC1 component raptor. However, the relative importance of each of these kinases and phosphorylation events for the activation of mTORC1 signaling is unknown. The recent availability of MEK (PD184352) and p90(RSK) (BI-D1870) inhibitors of improved specificity allowed us to address the roles of these protein kinases in controlling mTORC1 in a variety of human and rodent cell types. In parallel, we used specific shRNAs against p90(RSK1) and p90(RSK2) to further test their roles in regulating mTORC1 signaling. Our data indicate that p90(RSKs) are dispensable for the activation of mTORC1 signaling by phorbol esters in all cell types tested. Our data also reveal striking diversity in the requirements for MEK/ERK in the control of mTORC1 between different cell types, pointing to additional signaling connections between phorbol esters and mTORC1, which do not involve MEK/ERK. This study provides important information for the design of efficient strategies to combat the hyperactivation of mTORC1 signaling by oncogenic pathways. PMID- 21659539 TI - CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics. AB - Continuous migration of B cells at the follicle contrasts with their stable arrest after encounter with antigen. Two main ligand/receptor pairs are involved in these cell behaviors: the chemokine CXCL13/chemokine receptor CXCR5 and antigen/BCR. Little is known regarding the interplay between CXCR5 and BCR signaling in the modulation of B-cell dynamics and its effect on B-cell activation. We used a 2-dimensional model to study B-cell migration and antigen recognition in real time, and found that BCR signaling strength alters CXCL13 mediated migration, leading to a heterogeneous B-cell behavior pattern. In addition, we demonstrate that CXCL13/CXCR5 signaling does not impair BCR triggered immune synapse formation and that CXCR5 is excluded from the central antigen cluster. CXCL13/CXCR5 signaling enhances BCR-mediated B-cell activation in at least 2 ways: (1) it assists antigen gathering at the synapse by promoting membrane ruffling and lymphocyte function-associated antigen 1 (LFA-1)-supported adhesion, and (2) it allows BCR signaling integration in motile B cells through establishment of LFA-1-supported migratory junctions. Both processes require functional actin cytoskeleton and non-muscle myosin II motor protein. Therefore, the CXCL13/CXCR5 signaling effect on shaping B-cell dynamics is an effective mechanism that enhances antigen encounter and BCR-triggered B-cell activation. PMID- 21659541 TI - Association of natural anti-platelet factor 4/heparin antibodies with periodontal disease. AB - Platelet factor 4 (PF4) and heparin (H) form PF4/H complexes, the target of the immune reaction in heparin-induced thrombocytopenia (HIT). HIT seems to be a secondary immune response as anti-PF4/H-IgG antibodies occur as early as day 4 of heparin treatment. This study investigated whether prevalent infections such as periodontitis may induce the PF4/H immune response as: (1) natural anti-PF4/H Abs are present in the normal population; (2) PF4 bound to bacteria exposes the same antigen(s) as PF4/H complexes; and (3) sepsis induces PF4/H Abs in mice. We found PF4 bound to periodontal pathogens (Aggregatibacter actinomycetemcomitans; Porphyromonas gingivalis) enabling subsequent binding of human anti-PF4/H Abs. The association of natural PF4/H Abs and periodontitis was assessed in a case control study, enrolling individuals with natural anti-PF4/H Abs (n = 40 matched pairs), and in the cross-sectional population-based Study of Health in Pomerania (SHIP; n = 3500). Both studies showed a robust association between periodontitis and presence of anti-PF4/H Abs independent of inflammation markers (case-control study: lowest vs highest tertile, odds ratio, 7.12 [95% confidence interval, 1.73 46.13; P = .005]; SHIP study, p(trend) <= 0.001). Thus, preimmunization to PF4/bacteria complexes by prevalent infections, for example, periodontitis, likely explains the presence of natural anti-PF4/heparin Abs and the early occurrence of anti-PF4/H-IgG in HIT. PMID- 21659540 TI - Delivery of progenitors to the thymus limits T-lineage reconstitution after bone marrow transplantation. AB - T-cell production depends on the recruitment of hematopoietic progenitors into the thymus. T cells are among the last of the hematopoietic lineages to recover after bone marrow transplantation (BMT), but the reasons for this delay are not well understood. Under normal physiologic conditions, thymic settling is selective and either CCR7 or CCR9 is required for progenitor access into the thymus. The mechanisms of early thymic reconstitution after BMT, however, are unknown. Here we report that thymic settling is briefly CCR7/CCR9-independent after BMT but continues to rely on the selectin ligand PSGL-1. The CCR7/CCR9 independence is transient, and by 3 weeks after BMT these receptors are again strictly required. Despite the normalization of thymic settling signals, the rare bone marrow progenitors that can efficiently repopulate the thymus are poorly reconstituted for at least 4 weeks after BMT. Consistent with reduced progenitor input to the thymus, intrathymic progenitor niches remain unsaturated for at least 10 weeks after BMT. Finally, we show that thymic recovery is limited by the number of progenitors entering the thymus after BMT. Hence, T-lineage reconstitution after BMT is limited by progenitor supply to the thymus. PMID- 21659542 TI - Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. AB - Current guidelines discourage combined oral contraceptive (COC) use in women with hereditary thrombophilic defects. However, qualifying all hereditary thrombophilic defects as similarly strong risk factors might be questioned. Recent studies indicate the risk of venous thromboembolism (VTE) of a factor V Leiden mutation as considerably lower than a deficiency of protein C, protein S, or antithrombin. In a retrospective family cohort, the VTE risk during COC use and pregnancy (including postpartum) was assessed in 798 female relatives with or without a heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin G20210A mutation. Overall, absolute VTE risk in women with no, single, or combined defects was 0.13 (95% confidence interval 0.08-0.21), 0.35 (0.22-0.53), and 0.94 (0.47-1.67) per 100 person-years, while these were 0.19 (0.07-0.41), 0.49 (0.18-1.07), and 0.86 (0.10-3.11) during COC use, and 0.73 (0.30-1.51), 1.97 (0.94-3.63), and 7.65 (3.08-15.76) during pregnancy. COC use and pregnancy were independent risk factors for VTE, with highest risk during pregnancy postpartum, as demonstrated by adjusted hazard ratios of 16.0 (8.0 32.2) versus 2.2 (1.1-4.0) during COC use. Rather than strictly contraindicating COC use, we advocate that detailed counseling on all contraceptive options, including COCs, addressing the associated risks of both VTE and unintended pregnancy, enabling these women to make an informed choice. PMID- 21659543 TI - Comparative promoter analysis in vivo: identification of a dendritic cell specific promoter module. AB - Dendritic cells (DCs) are important immune cells. This study focused on transcriptional networks active in murine DCs, but DCs are difficult to study using conventional molecular techniques. Therefore, comparative promoter analysis was used to identify evolutionarily conserved features between the murine CD11c and DC-STAMP promoters. A promoter framework consisting of 4 transcription factor binding sites was identified that included signal transducer and activator of transcription, homeodomain transcription factors, and 2 members of the Brn POU domain factors family. This promoter module was functionally verified by in vivo promoter analysis and site-directed mutagenesis. Hematopoietic stem cells were engineered by lentiviral vectors and expression of green fluorescent protein reporter was monitored in primary hematopoietic cell types that develop without further manipulation in irradiated recipient mice. The verified promoter module was then modeled and used in a bioinformatics-based search for other potential coregulated genes in murine DCs. A promoter database search identified 2 additional genes, Ppef2 and Pftk1, which have a similar promoter organization and are preferentially expressed in murine DCs. The results define a regulatory network linked to development of murine DCs. PMID- 21659544 TI - Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL/Bcl-2 in Mcl-1-expressing myeloma cells. AB - Dependence on Bcl-2 proteins is a common feature of cancer cells and provides a therapeutic opportunity. ABT-737 is an antagonist of antiapoptotic Bcl-2 proteins and therefore is a good predictor of Bcl-x(L)/Bcl-2 dependence. Surprisingly, analysis of Mcl-1-dependent multiple myeloma cell lines revealed codependence on Bcl-2/Bcl-x(L) in half the cells tested. Codependence is not predicted by the expression level of antiapoptotic proteins, rather through interactions with Bim. Consistent with these findings, acquired resistance to ABT-737 results in loss of codependence through redistribution of Bim to Mcl-1. Overall, these results suggest that complex interactions, and not simply expression patterns of Bcl-2 proteins, need to be investigated to understand Bcl-2 dependence and how to better use agents, such as ABT-737. PMID- 21659545 TI - Btk is a positive regulator in the TREM-1/DAP12 signaling pathway. AB - The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knockdown, phosphorylation of Erk1/2 and PLCgamma1 and Ca2+ mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-alpha and IL-8, and up regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk(-/-) mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1-mediated signaling. Finally, after TREM-1 engagement, TNF-alpha production by PBMCs was reduced in the majority of patients suffering from X linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes. PMID- 21659546 TI - Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus mediated B-cell proliferation. AB - EBV, an oncogenic human herpesvirus, can transform primary B lymphocytes into immortalized lymphoblastoid cell lines (LCLs) through multiple regulatory mechanisms. However, the involvement of protein tyrosine kinases in the infinite proliferation of B cells is not clear. In this study, we performed kinase display assays to investigate this subject and identified a specific cellular target, Recepteur d'Origine Nantais (RON) tyrosine kinase, expressed in LCLs but not in primary B cells. Furthermore, we found that latent membrane protein 1 (LMP1), an important EBV oncogenic protein, enhanced RON expression through its C-terminal activation region-1 (CTAR1) by promoting NF-kappaB binding to the RON promoter. RON knockdown decreased the proliferation of LCLs, and transfection with RON compensated for the growth inhibition caused by knockdown of LMP1. Immunohistochemical analysis revealed a correlation between LMP1 and RON expression in biopsies from posttransplantation lymphoproliferative disorder (PTLD), suggesting that LMP1-induced RON expression not only is essential for the growth of LCLs but also may contribute to the pathogenesis of EBV-associated PTLD. Our study is the first to reveal the impact of RON on the proliferation of transformed B cells and to suggest that RON may be a novel therapeutic target for EBV-associated lymphoproliferative diseases. PMID- 21659547 TI - Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980 2009: an international collaborative study. AB - In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications. PMID- 21659548 TI - Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells. AB - Although well recognized that expression of E-selectin on marrow microvessels mediates osteotropism of hematopoietic stem/progenitor cells (HSPCs), our knowledge regarding the cognate E-selectin ligand(s) on HSPCs is incomplete. Flow cytometry using E-selectin-Ig chimera (E-Ig) shows that human marrow cells enriched for HSPCs (CD34(+) cells) display greater E-selectin binding than those obtained from mouse (lin(-)/Sca-1(+)/c-kit(+) [LSK] cells). To define the relevant glycoprotein E-selectin ligands, lysates from human CD34(+) and KG1a cells and from mouse LSK cells were immunoprecipitated using E-Ig and resolved by Western blot using E-Ig. In both human and mouse cells, E-selectin ligand reactivity was observed at ~ 120- to 130-kDa region, which contained two E selectin ligands, the P-selectin glycoprotein ligand-1 glycoform "CLA," and CD43. Human, but not mouse, cells displayed a prominent ~ 100-kDa band, exclusively comprising the CD44 glycoform "HCELL." E-Ig reactivity was most prominent on CLA in mouse cells and on HCELL in human cells. To further assess HCELL's contribution to E-selectin adherence, complementary studies were performed to silence (via CD44 siRNA) or enforce its expression (via exoglycosylation). Under physiologic shear conditions, CD44/HCELL-silenced human cells showed striking decreases (> 50%) in E-selectin binding. Conversely, enforced HCELL expression of LSK cells profoundly increased E-selectin adherence, yielding > 3-fold more marrow homing in vivo. These data define the key glycoprotein E-selectin ligands of human and mouse HSPCs, unveiling critical species-intrinsic differences in both the identity and activity of these structures. PMID- 21659549 TI - A switch toward angiostatic gene expression impairs the angiogenic properties of endothelial progenitor cells in low birth weight preterm infants. AB - Low birth weight (LBW) is associated with increased risk of cardiovascular diseases at adulthood. Nevertheless, the impact of LBW on the endothelium is not clearly established. We investigate whether LBW alters the angiogenic properties of cord blood endothelial colony forming cells (LBW-ECFCs) in 25 preterm neonates compared with 25 term neonates (CT-ECFCs). We observed that LBW decreased the number of colonies formed by ECFCs and delayed the time of appearance of their clonal progeny. LBW dramatically reduced LBW-ECFC capacity to form sprouts and tubes, to migrate and to proliferate in vitro. The angiogenic defect of LBW-ECFCs was confirmed in vivo by their inability to form robust capillary networks in Matrigel plugs injected in nu/nu mice. Gene profile analysis of LBW-ECFCs demonstrated an increased expression of antiangiogenic genes. Among them, thrombospondin 1 (THBS1) was highly expressed at RNA and protein levels in LBW ECFCs. Silencing THBS1 restored the angiogenic properties of LBW-ECFCs by increasing AKT phosphorylation. The imbalance toward an angiostatic state provide a mechanistic link between LBW and the impaired angiogenic properties of ECFCs and allows the identification of THBS1 as a novel player in LBW-ECFC defect, opening new perspectives for novel deprogramming agents. PMID- 21659551 TI - A knockout for knockin. PMID- 21659550 TI - Autografting CLL: the game is over! PMID- 21659552 TI - FVIII, CD4, and liaisons dangereuses. PMID- 21659553 TI - T-cell depletion in GVHD: less is more? PMID- 21659554 TI - APOE epsilon4 is associated with higher vitamin D levels in targeted replacement mice and humans. AB - The allele epsilon4 of apolipoprotein E (APOE), which is a key regulator of lipid metabolism, represents a risk factor for cardiovascular diseases and Alzheimer's disease. Despite its adverse effects, the allele is common and shows a nonrandom global distribution that is thought to be the result of evolutionary adaptation. One hypothesis proposes that the APOE epsilon4 allele protects against vitamin D deficiency. Here we present, for the first time, experimental and epidemiological evidence that the APOE epsilon4 allele is indeed associated with higher serum vitamin D [25(OH)D] levels. In APOE4 targeted replacement mice, significantly higher 25(OH)D levels were found compared with those in APOE2 and APOE3 mice (70.9 vs. 41.8 and 27.8 nM, P<0.05). Furthermore, multivariate adjusted models show a positive association of the APOE epsilon4 allele with 25(OH)D levels in a small collective of human subjects (n=93; P=0.072) and a general population sample (n=699; P=0.003). The novel link suggests epsilon4 as a modulator of vitamin D status. Although this result agrees well with evolutionary aspects, it appears contradictory with regard to chronic diseases, especially cardiovascular disease. Large prospective cohort studies are now needed to investigate the potential implications of this finding for chronic disease risks. PMID- 21659556 TI - Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase-9 in the absence of Apaf-1. AB - The protein kinase inhibitor staurosporine is one of the most potent and frequently used proapoptotic stimuli, although its mechanism of action is poorly understood. Here, we show that staurosporine as well as its analog 7 hydroxystaurosporine (UCN-01) not only trigger the classical mitochondrial apoptosis pathway but, moreover, activate an additional novel intrinsic apoptosis pathway. Unlike conventional anticancer drugs, staurosporine and UCN-01 induced apoptosis in a variety of tumor cells overexpressing the apoptosis inhibitors Bcl 2 and Bcl-x(L). Furthermore, activation of this novel intrinsic apoptosis pathway by staurosporine did not rely on Apaf-1 and apoptosome formation, an essential requirement for the mitochondrial pathway. Nevertheless, as demonstrated in caspase-9-deficient murine embryonic fibroblasts, human lymphoma cells, and chicken DT40 cells, staurosporine-induced apoptosis was essentially mediated by caspase-9. Our results therefore suggest that, in addition to the classical cytochrome c/Apaf-1-dependent pathway of caspase-9 activation, staurosporine can induce caspase-9 activation and apoptosis independently of the apoptosome. Since staurosporine derivatives have proven efficacy in clinical trials, activation of this novel pathway might represent a powerful target to induce apoptosis in multidrug-resistant tumor cells. PMID- 21659555 TI - Defective photoreceptor phagocytosis in a mouse model of enhanced S-cone syndrome causes progressive retinal degeneration. AB - Enhanced S-cone syndrome (ESCS), featuring an excess number of S cones, manifests as a progressive retinal degeneration that leads to blindness. Here, through optical imaging, we identified an abnormal interface between photoreceptors and the retinal pigment epithelium (RPE) in 9 patients with ESCS. The neural retina leucine zipper transcription factor-knockout (Nrl(-/-)) mouse model demonstrates many phenotypic features of human ESCS, including unstable S-cone-positive photoreceptors. Using massively parallel RNA sequencing, we identified 6203 differentially expressed transcripts between wild-type (Wt) and Nrl(-/-) mouse retinas, with 6 highly significant differentially expressed genes of the Pax, Notch, and Wnt canonical pathways. Changes were also obvious in expression of 30 genes involved in the visual cycle and 3 key genes in photoreceptor phagocytosis. Novel high-resolution (100 nm) imaging and reconstruction of Nrl(-/-) retinas revealed an abnormal packing of photoreceptors that contributed to buildup of photoreceptor deposits. Furthermore, lack of phagosomes in the RPE layer of Nrl( /-) retina revealed impairment in phagocytosis. Cultured RPE cells from Wt and Nrl(-/-) mice illustrated that the phagocytotic defect was attributable to the aberrant interface between ESCS photoreceptors and the RPE. Overcoming the retinal phagocytosis defect could arrest the progressive degenerative component of this disease. PMID- 21659557 TI - Delayed preconditioning by sevoflurane elicits changes in the mitochondrial proteome in ischemia-reperfused rat hearts. AB - BACKGROUND: Delayed myocardial preconditioning by volatile anesthetics involves changes in DNA transcription and translation. Mitochondria play a central role in myocardial ischemia/reperfusion (I/R) injury and in ischemic or pharmacologic preconditioning. In this study, we investigated whether there are alterations in myocardial mitochondrial protein expression after volatile anesthetic preconditioning (APC) to examine the underlying mechanisms of delayed cardioprotection. METHODS: Thirty-six Sprague-Dawley rats were randomly assigned to 1 of 3 groups (n = 12 for each group). Rats in the delayed APC group were exposed to sevoflurane (2.5% for 60 minutes) 24 hours before myocardial ischemia was induced. Myocardial ischemia in the I/R and APC groups was induced by left coronary artery occlusion for 30 minutes, followed by 120 minutes of reperfusion. The control group received no treatment. The mitochondria fractions were prepared by differential centrifugation with density gradient isolation for proteomic analysis. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization with time-of-flight mass spectrometry was used to identify differences in the protein expression from mitochondria of the rat hearts. RESULTS: Fifteen differentially expressed mitochondrial proteins between the APC group and I/R group were identified and the expression patterns of 2 of the proteins were confirmed by Western blot analysis. These proteins were associated with mitochondrial substrate metabolism, respiration, and adenosine triphosphate (ATP)/adenosine diphosphate transport. The modifications of the mitochondrial proteome suggest an enhanced capacity of mitochondria to maintain myocardial ATP levels after I/R injury. CONCLUSION: Delayed sevoflurane myocardial preconditioning induces mitochondrial proteome remodeling, which mainly involves proteins that are related to ATP generation and transport. Therefore, proteomic changes related to bioenergetic balance may be the mechanistic basis of delayed anesthetic myocardial preconditioning. PMID- 21659559 TI - Using research findings in nursing practice. PMID- 21659560 TI - What is a systematic review? PMID- 21659562 TI - Self-management of hypertension in Hispanic adults. AB - Almost one third of the U.S. population has hypertension. Compared to non Hispanic Whites, Hispanic individuals have significantly lower levels of hypertension awareness, treatment, and control. This article provides an integrative review of factors that may influence self-management of hypertension among Hispanic adults. A detailed literature search of articles published between 1985 and 2010 was performed. Twelve articles based on quantitative studies (n = 9) and qualitative studies (n = 3) were reviewed. Barriers and facilitators to self-management of hypertension were identified. The findings in this review may help health care professionals in recognizing factors that need to be considered in the development of self-management interventions for Hispanic patients with hypertension. Future research is needed to further explore facilitators to self management, and to implement and evaluate intervention studies aimed at blood pressure management in Hispanics with hypertension. PMID- 21659564 TI - Stereotypes as justifications of prejudice. AB - Three experiments investigate how stereotypes form as justifications for prejudice. The authors created novel content-free prejudices toward unfamiliar social groups using either subliminal (Experiment 1, N = 79) or supraliminal (Experiment 2, N = 105; Experiment 3, N = 130) affective conditioning and measured the consequent endorsement of stereotypes about the groups. Following the stereotype content model, analyses focused on the extent to which stereotypes connoted warmth or competence. Results from all three experiments revealed effects on the warmth dimension but not on the competence dimension: Groups associated with negative affect were stereotyped as comparatively cold (but not comparatively incompetent). These results provide the first evidence that-in the absence of information, interaction, or history of behavioral discrimination stereotypes develop to justify prejudice. PMID- 21659563 TI - Self-rated health status and cardiorespiratory fitness as predictors of mortality in men. AB - Self-rated health (SRH) and cardiorespiratory fitness (fitness) are independent risk factors for all-cause mortality. The purpose of this report is to examine the single and joint effects of these exposures on mortality risk. The study included 18 488 men who completed a health survey, clinical examination and a maximal exercise treadmill test during 1987-2003. Cox regression analysis was used to quantify the associations of SRH and fitness with all-cause mortality. There were 262 deaths during 17 years of follow-up. There was a significant inverse trend (p(trend) <0.05) for mortality across SRH categories after adjustment for age, examination year, body mass index, physical activity, smoking, alcohol consumption, abnormal ECG, hypertension, hypercholesterolaemia, cardiovascular disease, diabetes and cancer. Adjustment for fitness attenuated the association (p value =0.09). The authors also observed an inverse association between fitness and mortality after controlling for the same covariates and SRH (p(trend) = 0.006). The combined analysis of SRH and fitness showed that fit men with good or excellent SRH had a 58% lower risk of mortality than their counterparts. SRH and fitness were both associated with all-cause mortality in men. Fit men with good or excellent SRH live longer than unfit men with poor or fair SRH. PMID- 21659565 TI - School-based early childhood education and age-28 well-being: effects by timing, dosage, and subgroups. AB - Advances in understanding the effects of early education have benefited public policy and developmental science. Although preschool has demonstrated positive effects on life-course outcomes, limitations in knowledge on program scale, subgroup differences, and dosage levels have hindered understanding. We report the effects of the Child-Parent Center Education Program on indicators of well being up to 25 years later for more than 1400 participants. This established, publicly funded intervention begins in preschool and provides up to 6 years of service in inner-city Chicago schools. Relative to the comparison group receiving the usual services, program participation was independently linked to higher educational attainment, income, socioeconomic status (SES), and health insurance coverage, as well as lower rates of justice-system involvement and substance abuse. Evidence of enduring effects was strongest for preschool, especially for males and children of high school dropouts. The positive influence of four or more years of service was limited primarily to education and SES. Dosage within program components was mostly unrelated to outcomes. Findings demonstrate support for the enduring effects of sustained school-based early education to the end of the third decade of life. PMID- 21659566 TI - Climate-forced variability of ocean hypoxia. AB - Oxygen (O(2)) is a critical constraint on marine ecosystems. As oceanic O(2) falls to hypoxic concentrations, habitability for aerobic organisms decreases rapidly. We show that the spatial extent of hypoxia is highly sensitive to small changes in the ocean's O(2) content, with maximum responses at suboxic concentrations where anaerobic metabolisms predominate. In model-based reconstructions of historical oxygen changes, the world's largest suboxic zone, in the Pacific Ocean, varies in size by a factor of 2. This is attributable to climate-driven changes in the depth of the tropical and subtropical thermocline that have multiplicative effects on respiration rates in low-O(2) water. The same mechanism yields even larger fluctuations in the rate of nitrogen removal by denitrification, creating a link between decadal climate oscillations and the nutrient limitation of marine photosynthesis. PMID- 21659567 TI - Palladium-catalyzed aerobic dehydrogenation of substituted cyclohexanones to phenols. AB - Aromatic molecules are key constituents of many pharmaceuticals, electronic materials, and commodity plastics. The utility of these molecules directly reflects the identity and pattern of substituents on the aromatic ring. Here, we report a palladium(II) catalyst system, incorporating an unconventional ortho dimethylaminopyridine ligand, for the conversion of substituted cyclohexanones to the corresponding phenols. The reaction proceeds via successive dehydrogenation of two saturated carbon-carbon bonds of the six-membered ring and uses molecular oxygen as the hydrogen acceptor. This reactivity demonstrates a versatile and efficient strategy for the synthesis of substituted aromatic molecules with fundamentally different selectivity constraints from the numerous known synthetic methods that rely on substitution of a preexisting aromatic ring. PMID- 21659568 TI - Long unfolded linkers facilitate membrane protein import through the nuclear pore complex. AB - Active nuclear import of soluble cargo involves transport factors that shuttle cargo through the nuclear pore complex (NPC) by binding to phenylalanine-glycine (FG) domains. How nuclear membrane proteins cross through the NPC to reach the inner membrane is presently unclear. We found that at least a 120-residue-long intrinsically disordered linker was required for the import of membrane proteins carrying a nuclear localization signal for the transport factor karyopherin alpha. We propose an import mechanism for membrane proteins in which an unfolded linker slices through the NPC scaffold to enable binding between the transport factor and the FG domains in the center of the NPC. PMID- 21659569 TI - The unusual nature of recent snowpack declines in the North American cordillera. AB - In western North America, snowpack has declined in recent decades, and further losses are projected through the 21st century. Here, we evaluate the uniqueness of recent declines using snowpack reconstructions from 66 tree-ring chronologies in key runoff-generating areas of the Colorado, Columbia, and Missouri River drainages. Over the past millennium, late 20th century snowpack reductions are almost unprecedented in magnitude across the northern Rocky Mountains and in their north-south synchrony across the cordillera. Both the snowpack declines and their synchrony result from unparalleled springtime warming that is due to positive reinforcement of the anthropogenic warming by decadal variability. The increasing role of warming on large-scale snowpack variability and trends foreshadows fundamental impacts on streamflow and water supplies across the western United States. PMID- 21659571 TI - Rekindling Japan's spirit. PMID- 21659570 TI - Evolution of the TIR domain-containing adaptors in humans: swinging between constraint and adaptation. AB - Natural selection is expected to act strongly on immune system genes as hosts adapt to novel, diverse, and coevolving pathogens. Population genetic studies of host defense genes with parallel functions in model organisms have revealed distinct evolutionary histories among the different components-receptors, adaptors, and effectors-of the innate immune system. In humans, however, detailed evolutionary studies have been mainly confined to the receptors and in particular to Toll-like receptors (TLRs). By virtue of a toll/interleukin-1 receptor (TIR) domain, TLRs activate distinct signaling pathways, which are mediated by the five TIR-containing adaptors: myeloid differentiation factor-88 (MyD88), myeloid differentiation factor-88 adaptor-like protein (MAL), toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon (IFN)beta (TRIF), toll/interleukin-1 receptor domain-containing adaptor protein inducing IFNbeta related adaptor molecule (TRAM), and sterile alpha- and armadillo motif containing protein (SARM). Here, we have examined the extent to which natural selection has affected immune adaptors in humans, using as a paradigm the TIR containing adaptors. To do so, we characterized their levels of naturally occurring genetic variation in various human populations. We found that MyD88 and TRIF have mainly evolved under purifying selection, suggesting that their role in the early stages of signal transduction is essential and nonredundant for host survival. In addition, the adaptors have been targeted by multiple episodes of positive selection, differing in timing and spatial location. MyD88 and SARM display signatures of a selective sweep that has occurred in all humans, whereas for the other three adaptors, we detected signatures of adaptive evolution that are restricted to specific populations. Our study provides evidence that the contemporary diversity of the five TIR-containing adaptors results from the intermingling of different selective events, swinging between constraint and adaptation. PMID- 21659576 TI - Germany. Scientists rush to study genome of lethal E. coli. PMID- 21659577 TI - Newsmaker interview: John Mashey. Computer scientist goes on offensive to defend climate scientists. PMID- 21659578 TI - Endocrinology. Mice prompt look at cholesterol's role in female fertility. PMID- 21659579 TI - China. Stigma of HIV imperils hard-won strides in saving lives. PMID- 21659580 TI - Planetary science. Planetary two-step reshaped solar system, saved Earth? PMID- 21659581 TI - A Bengali recipe for disaster. PMID- 21659582 TI - Planetary science. Enceladus now looks wet, so it may be ALIVE! PMID- 21659583 TI - Archaeology. South African cave slowly shares secrets of human culture. PMID- 21659585 TI - Experimental philosophy: surveys alone won't fly. PMID- 21659586 TI - Taking experimental philosophy to the people. PMID- 21659589 TI - Dealing with data: governments records. PMID- 21659590 TI - Education. Preparing future math teachers. PMID- 21659591 TI - Immunology. No need to coax monocytes. PMID- 21659592 TI - Chemistry. Taking the high road and getting there before you. PMID- 21659593 TI - Cell signaling. New mTOR targets Grb attention. PMID- 21659594 TI - Economics. Why finance matters. PMID- 21659595 TI - Terrestrial ecosystem responses to species gains and losses. AB - Ecosystems worldwide are losing some species and gaining others, resulting in an interchange of species that is having profound impacts on how these ecosystems function. However, research on the effects of species gains and losses has developed largely independently of one another. Recent conceptual advances regarding effects of species gain have arisen from studies that have unraveled the mechanistic basis of how invading species with novel traits alter biotic interactions and ecosystem processes. In contrast, studies on traits associated with species loss are fewer, and much remains unknown about how traits that predispose species to extinction affect ecological processes. Species gains and losses are both consequences and drivers of global change; thus, explicit integration of research on how both processes simultaneously affect ecosystem functioning is key to determining the response of the Earth system to current and future human activities. PMID- 21659596 TI - Microcredit in theory and practice: using randomized credit scoring for impact evaluation. AB - Microcredit institutions spend billions of dollars fighting poverty by making small loans primarily to female entrepreneurs. Proponents argue that microcredit mitigates market failures, spurs micro-enterprise growth, and boosts borrowers' well-being. We tested these hypotheses with the use of an innovative, replicable experimental design that randomly assigned individual liability microloans (of $225 on average) to 1601 individuals in the Philippines through credit scoring. After 11 to 22 months, we found evidence consistent with unmet demand at the current price (a roughly 60% annualized interest rate): Net borrowing increased in the treatment group relative to controls. However, the number of business activities and employees in the treatment group decreased relative to controls, and subjective well-being declined slightly. We also found little evidence that treatment effects were more pronounced for women. However, we did find that microloans increase ability to cope with risk, strengthen community ties, and increase access to informal credit. Thus, microcredit here may work, but through channels different from those often hypothesized by its proponents. PMID- 21659597 TI - Real-time dynamics of quantized vortices in a unitary Fermi superfluid. AB - We introduce a comprehensive theoretical framework for the fermionic superfluid dynamics, grounded on a local extension of the time-dependent density functional theory. With this approach, we describe the generation and the real-time evolution and interaction of quantized vortices, the large-amplitude collective modes, as well as the loss of superfluidity at high flow velocities. We demonstrate the formation of vortex rings and provide a microscopic description of the crossing and reconnection of quantized vortex lines in a fermion superfluid, which provide the mechanism for the emergence of quantum turbulence at very low temperatures. We observe that superfluidity often survives when these systems are stirred with velocities far exceeding the speed of sound. PMID- 21659598 TI - Transformation optics using graphene. AB - Metamaterials and transformation optics play substantial roles in various branches of optical science and engineering by providing schemes to tailor electromagnetic fields into desired spatial patterns. We report a theoretical study showing that by designing and manipulating spatially inhomogeneous, nonuniform conductivity patterns across a flake of graphene, one can have this material as a one-atom-thick platform for infrared metamaterials and transformation optical devices. Varying the graphene chemical potential by using static electric field yields a way to tune the graphene conductivity in the terahertz and infrared frequencies. Such degree of freedom provides the prospect of having different "patches" with different conductivities on a single flake of graphene. Numerous photonic functions and metamaterial concepts can be expected to follow from such a platform. PMID- 21659599 TI - Wafer-scale graphene integrated circuit. AB - A wafer-scale graphene circuit was demonstrated in which all circuit components, including graphene field-effect transistor and inductors, were monolithically integrated on a single silicon carbide wafer. The integrated circuit operates as a broadband radio-frequency mixer at frequencies up to 10 gigahertz. These graphene circuits exhibit outstanding thermal stability with little reduction in performance (less than 1 decibel) between 300 and 400 kelvin. These results open up possibilities of achieving practical graphene technology with more complex functionality and performance. PMID- 21659600 TI - Methylhydroxycarbene: tunneling control of a chemical reaction. AB - Chemical reactivity is conventionally understood in broad terms of kinetic versus thermodynamic control, wherein the decisive factor is the lowest activation barrier among the various reaction paths or the lowest free energy of the final products, respectively. We demonstrate that quantum-mechanical tunneling can supersede traditional kinetic control and direct a reaction exclusively to a product whose reaction path has a higher barrier. Specifically, we prepared methylhydroxycarbene (H(3)C-C-OH) via vacuum pyrolysis of pyruvic acid at about 1200 kelvin (K), followed by argon matrix trapping at 11 K. The previously elusive carbene, characterized by ultraviolet and infrared spectroscopy as well as exacting quantum-mechanical computations, undergoes a facile [1,2]hydrogen shift to acetaldehyde via tunneling under a barrier of 28.0 kilocalories per mole (kcal mol(-1)), with a half-life of around 1 hour. The analogous isomerization to vinyl alcohol has a substantially lower barrier of 22.6 kcal mol(-1) but is precluded at low temperature by the greater width of the potential energy profile for tunneling. PMID- 21659601 TI - Origin and evolution of prebiotic organic matter as inferred from the Tagish Lake meteorite. AB - The complex suite of organic materials in carbonaceous chondrite meteorites probably originally formed in the interstellar medium and/or the solar protoplanetary disk, but was subsequently modified in the meteorites' asteroidal parent bodies. The mechanisms of formation and modification are still very poorly understood. We carried out a systematic study of variations in the mineralogy, petrology, and soluble and insoluble organic matter in distinct fragments of the Tagish Lake meteorite. The variations correlate with indicators of parent body aqueous alteration. At least some molecules of prebiotic importance formed during the alteration. PMID- 21659602 TI - Activation of visual pigments by light and heat. AB - Vision begins with photoisomerization of visual pigments. Thermal energy can complement photon energy to drive photoisomerization, but it also triggers spontaneous pigment activation as noise that interferes with light detection. For half a century, the mechanism underlying this dark noise has remained controversial. We report here a quantitative relation between a pigment's photoactivation energy and its peak-absorption wavelength, lambda(max). Using this relation and assuming that pigment activations by light and heat go through the same ground-state isomerization energy barrier, we can predict the relative noise of diverse pigments with multi-vibrational-mode thermal statistics. The agreement between predictions and our measurements strongly suggests that pigment noise arises from canonical isomerization. The predicted high noise for pigments with lambda(max) in the infrared presumably explains why they apparently do not exist in nature. PMID- 21659603 TI - A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. AB - The DNA damage response (DDR) is brought about by a protein kinase cascade that orchestrates DNA repair through transcriptional and posttranslational mechanisms. Cell cycle arrest is a hallmark of the DDR. We screened for cells that lacked damage-induced cell cycle arrest and uncovered a critical role for Fanconi anemia and homologous recombination proteins in ATR (ataxia telangiectasia and Rad3 related) signaling. Three DDR candidates, the RNA processing protein INTS7, the circadian transcription factor CLOCK, and a previously uncharacterized protein RHINO, were recruited to sites of DNA damage. RHINO independently bound the Rad9 Rad1-Hus1 complex (9-1-1) and the ATR activator TopBP1. RHINO was recruited to sites of DNA damage by the 9-1-1 complex to promote Chk1 activation. We suggest that RHINO functions together with the 9-1-1 complex and TopBP1 to fully activate ATR. PMID- 21659604 TI - The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. AB - The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology. PMID- 21659606 TI - Adaptation and evolutionary rescue in metapopulations experiencing environmental deterioration. AB - It is not known whether evolution will usually be rapid enough to allow a species to adapt and persist in a deteriorating environment. We tracked the eco evolutionary dynamics of metapopulations with a laboratory model system of yeast exposed to salt stress. Metapopulations experienced environmental deterioration at three different rates and their component populations were either unconnected or connected by local dispersal or by global dispersal. We found that adaptation was favored by gradual deterioration and local dispersal. After further abrupt deterioration, the frequency of evolutionary rescue depended on both the prior rate of deterioration and the rate of dispersal. Adaptation was surprisingly frequent and rapid in small peripheral populations. Thus, evolutionary dynamics affect both the persistence and the range of a species after environmental deterioration. PMID- 21659605 TI - Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. AB - The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1. PMID- 21659607 TI - Nicotine decreases food intake through activation of POMC neurons. AB - Smoking decreases appetite, and smokers often report that they smoke to control their weight. Understanding the neurobiological mechanisms underlying the anorexic effects of smoking would facilitate the development of novel treatments to help with smoking cessation and to prevent or treat obesity. By using a combination of pharmacological, molecular genetic, electrophysiological, and feeding studies, we found that activation of hypothalamic alpha3beta4 nicotinic acetylcholine receptors leads to activation of pro-opiomelanocortin (POMC) neurons. POMC neurons and subsequent activation of melanocortin 4 receptors were critical for nicotinic-induced decreases in food intake in mice. This study demonstrates that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identifies critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite. PMID- 21659608 TI - Part 3: Pharmacogenetic variability in phase II anticancer drug metabolism. AB - Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects. We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug-metabolizing enzymes (glutathione S transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are proposed. PMID- 21659609 TI - Outcome analysis of invasive aspergillosis in hematologic malignancy and hematopoietic stem cell transplant patients: the role of novel antimold azoles. AB - BACKGROUND: Invasive aspergillosis (IA) continues to be a leading cause of morbidity and mortality in hematologic malignancy (HM) patients. We evaluated the prognostic factors for IA in HM patients. METHODS: In this retrospective study, we included all HM patients diagnosed with proven or probable IA between June 1993 and June 2008. RESULTS: A total of 449 HM patients were analyzed, the majority of which (75%) had underlying leukemia. Multivariate logistic regression analysis showed that neutropenia for more than two weeks during IA, steroid use, and intensive care admission were independently associated with failure to respond to antifungal therapy, as well as increased IA-attributable mortality (all p-values < .01). Antifungal therapy with an antimold azole-containing regimen (voriconazole or posaconazole) was also independently associated with improved response to treatment, as well as decreased IA-attributable mortality (all p-values < .0001). Survival analysis showed that primary or salvage therapy with a regimen that contained antimold azoles was significantly associated with improved survival (p < .001). CONCLUSIONS: In HM patients, persistent neutropenia and the need for intensive care are associated with failure to respond to antifungal therapy. Use of novel antimold azoles, either as primary or salvage therapy, improves the overall outcome and IA-attributable death of HM patients with IA. PMID- 21659610 TI - Analysis of morbidity and clinical implications of laparoscopic para-aortic lymphadenectomy in a continuous series of 98 patients with advanced-stage cervical cancer and negative PET-CT imaging in the para-aortic area. AB - BACKGROUND: Laparoscopic para-aortic lymphadenectomy (PAL) is being used increasingly to stage patients with locally advanced cervical cancer (LACC) and to define radiation field limits before chemoradiation therapy (CRT). This study aimed to define clinical implications, review complications, and determine whether surgical complications delayed the start of CRT. METHODS: We retrospectively reviewed a continuous series of patients with LACC, with no positive para-aortic (PA) nodes on positron emission tomography-computed tomography (PET-CT) and who had undergone a primary laparoscopic PAL. RESULTS: From November 2007 to June 2010, 98 patients with LACC underwent pretherapeutic PAL. Two patients did not undergo PAL: extensive carcinomatosis was discovered in one case and a technical problem arose in the other. No perioperative complications occurred. Seven patients had a lymphocyst requiring an imaging guided (or laparoscopic) puncture. Eight patients (8.4%, which corresponds to the false-negative PET-CT rate) had metastatic disease within PA lymph nodes. In cases of suspicious pelvic nodes on PET-CT, the risk for PA nodal disease was greater (24.0% versus 2.9%). When patients with and without surgical morbidity were compared, the median delay to the start of treatment was not significantly different (15 days; range, 3-49 days versus 18 days; range, 3-42 days). CONCLUSIONS: The morbidity of laparoscopic PAL was limited and the completion of treatment was not delayed when complications occurred. Nevertheless, if PET-CT of the pelvic area is negative, the interest in staging PAL could be discussed because the risk for PA nodal disease is very low. PMID- 21659611 TI - Dendritic cells and malignant plasma cells: an alliance in multiple myeloma tumor progression? AB - The crosstalk of myeloma cells with accessory cells drives the expansion of malignant plasma cell clones and the hyperactivation of osteoclastogenesis that occurs in multiple myeloma (MM). These reciprocal interactions promote defective dendritic cell (DC) function in terms of antigen processing, clearance of tumor cells, and efficacy of the immune response. Thus, myeloma cells exert immune suppression that explains, at least in part, the failure of therapeutic approaches, including DC vaccination. Impairment of DCs depends on high bone marrow levels of cytokines and adhesion molecules that affect both maturation and expression of costimulatory molecules by DCs. Moreover, DCs share with osteoclasts (OCs) a common ontogenetic derivation from the monocyte lineage, and thus may undergo OC-like transdifferentiation both in vitro and in vivo. Immature DCs (iDCs) induce clonogenic growth of malignant plasma cells while displaying OC like features, including the ability to resorb bone tissue once cultured with myeloma cells. This OC-like transdifferentiation of iDCs is dependent on the activation of both the receptor activator of nuclear factor kappaB (RANK)-RANK ligand (RANK-L) and CD47-thrombospondin (TSP)-I axes, although interleukin 17 producing T helper-17 clones within the bone microenvironment may also take part in this function. Therefore, iDCs allied with malignant plasma cells contribute to MM osteoclastogenesis, although other molecules released by tumor cells may independently contribute to the bone-resorbing machinery. PMID- 21659612 TI - Part 4: pharmacogenetic variability in anticancer pharmacodynamic drug effects. AB - Response to treatment with anticancer drugs is subject to wide interindividual variability. This variability is expressed not only as differences in severity and type of toxicity, but also as differences in effectiveness. Variability in the constitution of genes involved in the pharmacokinetic and pharmacodynamic pathways of anticancer drugs has been shown to possibly translate into differences in treatment outcome. The overall knowledge in the field of pharmacogenetics has tremendously increased over the last couple of years, and has thereby provided opportunities for patient-tailored anticancer therapy. In previous parts of this series, we described pharmacogenetic variability in anticancer phase I and phase II drug metabolism and drug transport. This fourth part of a four-part series of reviews is focused on pharmacodynamic variability and encompasses genetic variation in drug target genes such as those encoding thymidylate synthase, methylene tetrahydrofolate reductase, and ribonucleotide reductase. Furthermore, genetic variability in other pharmacodynamic candidate genes involved in response to anticancer drugs is discussed, including genes involved in DNA repair such as those encoding excision repair crosscomplementing group 1 and group 2, x-ray crosscomplementing group 1 and group 3, and breast cancer genes 1 and 2. Finally, somatic mutations in KRAS and the gene encoding epidermal growth factor receptor (EGFR) and implications for EGFR-targeted drugs are discussed. Potential implications and opportunities for patient and drug selection for genotype-driven anticancer therapy are outlined. PMID- 21659613 TI - Short-course chemotherapy with TMC207 and rifapentine in a murine model of latent tuberculosis infection. AB - RATIONALE: Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients. OBJECTIVES: The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI. METHODS: Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guerin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + isoniazid and daily rifapentine +/- isoniazid. MEASUREMENTS: Outcomes included monthly lung colony-forming unit counts and relapse rates. MAIN RESULTS: Lung colony-forming unit counts were stable at about 3.75 log(10) for up to 7.5 months postinfection in untreated mice. Rifamycin containing regimens were superior to isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + isoniazid, but daily rifapentine +/- isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model. CONCLUSIONS: TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months. PMID- 21659614 TI - Praziquantel reverses pulmonary hypertension and vascular remodeling in murine schistosomiasis. AB - RATIONALE: Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice. OBJECTIVES: We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni. METHODS: Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection. MEASUREMENTS AND MAIN RESULTS: Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels. CONCLUSIONS: The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines. PMID- 21659616 TI - Methyleugenol genotoxicity in the Fischer 344 rat using the comet assay and pathway-focused gene expression profiling. AB - Methyleugenol (MEG), a constituent of human food, induces malignant tumors in multiple tissues of rats and mice. Although MEG forms DNA adducts and induces unscheduled DNA synthesis in rat liver, it is negative in many in vitro genetic toxicity assays. In the present study, we evaluated MEG-induced DNA damage in the rat using (1) the alkaline Comet assay, (2) the oxidative Comet assay, and (3) expression profiling of genes associated with DNA damage pathways. Male F344 rats received single oral doses of 400 or 1000 mg/kg body weight (bw) MEG and DNA damage was assessed by the Comet assay in liver, bladder, bone marrow, kidney, and lung 3 h and 24 h later. MEG failed to produce any increase in DNA damage. In addition, rats were given a single oral dose of 2000 mg/kg bw MEG, and Comet assays were performed with liver, bone marrow, and bladder 1, 3, 6, and 8 h later. With one exception (bone marrow at 8 h), no DNA damage was detected. Enzyme-modified Comet assays were conducted in parallel with standard Comet assays in liver. Whereas no MEG-induced DNA damage was detected following formamidopyrimidine DNA glycosylase digestion, digestion with endonuclease III resulted in increases in DNA damage at the 6- and 8-h sampling times. Gene expression analysis on the livers from MEG-exposed rats showed significant reduction in genes associated with DNA repair. The results indicate that MEG induces DNA damage in rat liver and that oxidative DNA damages may be partly responsible for the genotoxicity of MEG in rodents. PMID- 21659617 TI - Manganese interferes with calcium, perturbs ERK signaling, and produces embryos with no skeleton. AB - Manganese (Mn) has been associated with embryo toxicity as it impairs differentiation of neural and skeletogenic cells in vertebrates. Nevertheless, information on the mechanisms operating at the cellular level remains scant. We took advantage of an amenable embryonic model to investigate the effects of Mn in biomineral formation. Sea urchin (Paracentrotus lividus) embryos were exposed to Mn from fertilization, harvested at different developmental stages, and analyzed for their content in calcium (Ca), expression of skeletogenic genes, localization of germ layer markers, and activation of the extracellular signal-regulated kinase (ERK). By optical and immunofluorescence microscopy, we found that Mn exposure produced embryos with no skeleton, by preventing the deposition of the triradiate calcitic spicules usually produced only by specialized mesoderm cells. On the contrary, ectoderm and endoderm differentiation was not impaired. Endogenous Ca content in whole embryos and its localization in Golgi regions of skeletogenic cells was strongly reduced, as measured by atomic absorption spectrometry and in vivo calcein labeling. Spicule-lacking embryos showed persistent ERK activation by immunocytochemistry and immunoblotting, contrary to the physiological oscillations observed in normal embryos. The expression of the skeletogenic genes, Pl-msp130 and Pl-sm30, was also differentially affected if compared with controls. Here, we showed for the first time the ability of Mn to interfere with Ca uptake and internalization into skeletogenic cells and demonstrate that Ca content regulates ERK activation/inactivation during sea urchin embryo morphogenesis. The use of Mn-exposed sea urchin embryos as a new model to study signaling pathways occurring during skeletogenesis will provide new insights into the mechanisms involved in Mn embryo toxicity and underlie the role of calcium in the biomineralization process in vertebrates. PMID- 21659618 TI - Aspirin-triggered lipoxin enhances macrophage phagocytosis of bacteria while inhibiting inflammatory cytokine production. AB - The macrophage plays a major role in the induction and resolution phases of inflammation; however, how lipid mediator-derived signals may modulate macrophage function in the resolution of inflammation driven by microbes (e.g., in inflammatory bowel disease) is not well understood. We examined the effects of aspirin-triggered lipoxin (ATL), a stable analog of lipoxin A(4), on the antimicrobial responses of human peripheral blood mononuclear cell-derived macrophages and the monocytic THP-1 cell line. Additionally, we assessed the expression and localization of the lipoxin receptor, formyl peptide receptor 2 (FPR2), in colonic mucosal biopsies from patients with Crohn's disease to determine whether the capacity for lipoxin signaling is altered in inflammatory bowel disease. We found that THP-1 cells treated with ATL (100 nM) displayed increased phagocytosis of inert fluorescent beads and Escherichia coli in a scavenger receptor- and PI3K-dependent, opsonization-independent manner. This ATL induced increase in phagocytosis was also observed in primary human macrophages, where it was associated with an inhibition of E. coli-induced IL-1beta and IL-8 production. Finally, we found that FPR2 gene expression was increased approximately sixfold in the colon of patients with Crohn's disease, a finding reproduced in vitro by the treatment of THP-1 cells with interferon-gamma or lipopolysaccharide. These results suggest that lipoxin signaling is upregulated in inflammatory environments, and, in addition to their known role in tissue resolution following injury, lipoxins can enhance macrophage clearance of invading microbes. PMID- 21659620 TI - Role of integrins in fibrosing liver diseases. AB - Integrins and other cell adhesion molecules regulate numerous physiological and pathological mechanisms by mediating the interaction between cells and their extracellular environment. Although the significance of integrins in the evolution and progression of certain cancers is well recognized, their involvement in nonmalignant processes, such as organ fibrosis or inflammation, is only beginning to emerge. However, accumulating evidence points to an instrumental role of integrin-mediated signaling in a variety of chronic and acute noncancerous diseases, particularly of the liver. PMID- 21659619 TI - Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium. AB - Maldigestion due to exocrine pancreatic insufficiency leads to intestinal malabsorption and consequent malnutrition, a mechanism proposed to cause growth retardation associated with cystic fibrosis (CF). However, although enzyme replacement therapy combined with increased caloric intake improves weight gain, the effect on stature is not significant, suggesting that growth retardation has a more complex etiology. Mouse models of CF support this, since these animals do not experience exocrine pancreatic insufficiency yet are growth impaired. Cftr absence from the intestinal epithelium has been suggested as a primary source of growth retardation in CF mice, a concept we directly tested by generating mouse models with Cftr selectively inactivated or restored in intestinal epithelium. The relationship between growth and functional characteristics of the intestines, including transepithelial electrophysiology, incidence of intestinal obstruction, and histopathology, were assessed. Absence of Cftr exclusively from intestinal epithelium resulted in loss of cAMP-stimulated short-circuit current, goblet cell hyperplasia, and occurrence of intestinal obstructions but only slight and transient impaired growth. In contrast, specifically restoring Cftr to the intestinal epithelium resulted in restoration of ion transport and completely protected against obstruction and histopathological anomalies, but growth was indistinguishable from CF mice. These results indicate that absence of Cftr in the intestinal epithelium is an important contributor to the intestinal obstruction phenotype in CF but does not correlate with the observed growth reduction in CF. PMID- 21659621 TI - The role of dystroglycan in PDGF-BB-dependent migration of activated hepatic stellate cells/myofibroblasts. AB - Hepatic stellate cells are embedded in the loose connective tissue matrix within the space of Disse. This extracellular matrix contains several basement membrane components including laminin, but its composition changes during liver injury because of the production of extracellular matrix components found in scar tissue. These changes in extracellular matrix composition and in cell extracellular matrix interactions may play a key role in hepatic stellate cell transdifferentiation. In this communication we used early passages of mouse hepatic stellate cells (activated HSC/myofibroblasts) to study the platelet derived growth factor BB (PDGF-BB)-dependent expression and regulation of beta dystroglycan and its role in activated HSC/myofibroblast migration. We used Northern and Western analysis to study dystroglycan expression and confocal microscopy to investigate changes in subcellular distribution of the protein. Activated HSC migration was investigated using an in vitro wound-healing assay. PDGF-BB induced significant changes in dystroglycan regulation and subcellular distribution of the protein. Whereas steady-state levels of dystroglycan mRNA remained constant, PDGF-BB increased dystroglycan transcription but shortened the t(1/2) by 50%. Moreover, PDGF-BB changed dystroglycan and alpha5-integrin cellular distribution. Cell migration experiments revealed that PDGF-BB-dependent migration of activated HSC/myofibroblasts was completely blocked by neutralizing antibodies to fibronectin, alpha5-integrin, laminin, and beta-dystroglycan. Overall, these findings suggest that both laminin and fibronectin and their receptors play a key role in PDGF-BB-induced activated HSC migration. PMID- 21659622 TI - Prognostic value of EEG in very premature newborns. AB - OBJECTIVE: To evaluate the prognostic value of EEG regarding the psychomotor outcomes of very premature newborns. METHODS: 76 premature infants <30 weeks gestation were enrolled between January 2001 and August 2004. They were examined at 4 and 9 months corrected ages, and at 18 months, 3-4 years and 5-6 years. EEGs performed in the neonatal period were analysed by two neurologists blind to the child's outcome. RESULTS: The mean follow-up was 5.6 years. 25 infants had normal neurological development and all EEGs were normal for 22 of these. 36 others had developmental disabilities (7 motor sequelae and 29 delayed psychomotor development). Of 187 EEGs, 43 were dysmature, 13 disorganised, 2 displayed electrical seizures without clinical manifestations and 15 showed other abnormal features. Dysmaturity was the predominant EEG pattern in newborns with severe or moderate sequelae and was persistent on several EEGs in 12 of these. In contrast, only three infants with normal development had a dysmature pattern on one EEG. All infants with a disorganised pattern had cognitive sequelae, and two had cerebral palsy. The sensitivity of EEG regarding psychomotor outcome was 83.3%, the specificity was 88% and the positive predictive value was 90.9%. CONCLUSIONS: Very preterm neonates remain at high risk of neurological sequelae and EEG is a sensitive method for assessing neuromotor and cognitive prognosis. A dysmature pattern was the predominant EEG characteristic in infants who developed severe or moderate impairment. Early postnatal tracing is useful but additional recordings are generally necessary to detect high-risk newborns. PMID- 21659624 TI - Population pharmacokinetics of vernakalant hydrochloride injection (RSD1235) in patients with atrial fibrillation or atrial flutter. AB - Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant. PMID- 21659625 TI - An improved model for disease progression in patients from the Alzheimer's disease neuroimaging initiative. AB - The objective of this analysis was to develop a semi-mechanistic nonlinear disease progression model using an expanded set of covariates that captures the longitudinal change of Alzheimer's Disease Assessment Scale (ADAS-cog) scores from the Alzheimer's Disease Neuroimaging Initiative study that consisted of 191 Alzheimer disease patients who were followed for 2 years. The model describes the rate of progression and baseline disease severity as a function of influential covariates. The covariates that were tested fell into 4 categories: (1) imaging volumetric measures, (2) serum biomarkers, (3) demographic and genetic factors, and (4) baseline cognitive tests. Covariates found to affect baseline disease status were years since disease onset, hippocampal volume, and ventricular volume. Disease progression rate in the model was influenced by age, total cholesterol, APOE epsilon4 genotype, Trail Making Test (part B) score, and current levels of impairment as measured by ADAS-cog. Rate of progression was slower for mild and severe Alzheimer patients compared with moderate Alzheimer patients who exhibited faster rates of deterioration. In conclusion, this model describes disease progression in Alzheimer patients using novel covariates that are important for understanding the worsening of ADAS-cog scores over time and may be useful in the future for optimizing study designs through clinical trial simulations. PMID- 21659626 TI - Pharmacokinetics and pharmacodynamics of aliskiren/hydrochlorothiazide single pill combination tablets and free combination of aliskiren and hydrochlorothiazide. AB - Single-pill combinations (SPCs) of complementary antihypertensive agents provide patients with a simple and effective treatment regimen. To ensure that the efficacy and safety of an SPC is the same as that for the individual drugs administered together (free combination), SPC and free-combination formulations must be shown to be bioequivalent. Three open-label, randomized studies compared the pharmacokinetics of SPC tablets of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT), at doses of 150/25, 300/12.5, and 300/25 mg, with the corresponding free combinations in healthy volunteers. Data from 2 randomized, double-blinded studies of patients with hypertension were used to assess inhibition of plasma renin activity (PRA) by the aliskiren/HCT 300/25 mg SPC and the free combination. At all dose combinations, aliskiren and HCT systemic drug exposure was similar when administered as an SPC or free combination, indicating bioequivalence. Aliskiren/HCT 300/25 mg SPC inhibited PRA to the same extent as the free combination. HCT alone increased PRA through activation of the renin angiotensin system; aliskiren prevented this diuretic-induced increase to the same extent when administered as the free combination or as the SPC. In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination. PMID- 21659628 TI - Characterization of the human QT interval: novel distribution-based assessment of the repolarization effects of moxifloxacin. AB - The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer. Distribution-based analysis was applied to the placebo and moxifloxacin (400 mg) arms to characterize the nature of the QT interval and to assess the efficacy of distribution-based analysis for QTc determination. Novel statistics using continuous means and bootstrapped 95% confidence intervals were developed to facilitate QT analysis. Machine-read QT values were compared with core laboratory semiautomated values for verification. RR intervals demonstrated repetitive protocol-dependent variations (50-250 milliseconds); QT intervals were normally distributed, spanning 60 to 100 milliseconds for each RR interval. Distribution-based analysis detected a moxifloxacin response identical to semiautomated analysis, but with reduced variability and improved statistical power, where n = 12 satisfied the ICH E14 criteria for a positive control. Distribution-based analysis has the potential to provide a universal method for clinical QT heart rate correction, enabling accurate detection of QT changes when limited numbers of volunteers are exposed to drug. PMID- 21659627 TI - Lack of effect of brivanib on the pharmacokinetics of midazolam, a CYP3A4 substrate, administered intravenously and orally in healthy participants. AB - Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to 48 hours after brivanib alaninate. Twenty-four participants were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on the overall exposure to midazolam following IV or oral administration was observed. Orally administered brivanib alaninate was generally well tolerated in the presence of IV or oral midazolam. The lack of a pharmacokinetic interaction between brivanib and midazolam indicates that brivanib alaninate does not influence either intestinal or hepatic CYP3A4 and confirms that brivanib alaninate may be safely coadministered with midazolam and other CYP3A4 substrates. PMID- 21659629 TI - Novel p38alpha mitogen-activated protein kinase inhibitor shows analgesic efficacy in acute postsurgical dental pain. AB - SCIO-469 is a selective p38alpha mitogen-activated protein kinase (MAPK) inhibitor for preclinical models of acute pain. This prospective, double-blind, randomized clinical study compared efficacy and safety of oral SCIO-469, ibuprofen, and placebo in postsurgical dental pain. Subjects (n = 263) undergoing extraction of 1 or more impacted mandibular third molars received preoperative treatment with SCIO-469 (150, 210, or 300 mg), ibuprofen (400 mg), or placebo; the 210-mg group received 90 mg postoperatively. A 4-point categorical scale and a 100-mm visual analogue scale were used to measure pain intensity. The primary end point was median time from first incision to first rescue medication using the Kaplan-Meier product limit estimator. All SCIO-469 groups had significantly longer times to rescue medication compared with placebo; preoperative and postoperative treatment with 210 + 90 mg SCIO-469 resulted in 8.1 hours versus 4.1 hours to rescue for placebo (P = .003). Ibuprofen also increased time to rescue medication (6.6 hours) versus placebo (P = .04). Dizziness, headache, and nausea were the most frequently reported adverse events. This is the first clinical demonstration of antinociceptive effects in acute pain with preoperative administration of a p38alpha MAPK inhibitor. PMID- 21659630 TI - Enhancement of biomixing by swimming algal cells in two-dimensional films. AB - Fluid mixing in active suspensions of microorganisms is important to ecological phenomena and presents a fascinating stochastic process. We investigate the mixing produced by swimming unicellular algal cells (Chlamydomonas) in quasi-two dimensional liquid films by simultaneously tracking the motion of the cells and that of microscopic passive tracer particles advected by the fluid. The reduced spatial dimension of the system leads to long-range flows and a surprisingly strong dependence of tracer transport on the concentration of swimmers, which is explored over a wide range. The mean square displacements are well described by a stochastic Langevin model, which is used to parameterize the mixing. The effective diffusion coefficient D grows rapidly with the swimmer concentration Phi as D ~ Phi(3/2), as a result of the increasing frequency of tracer-swimmer interactions and the long-range hydrodynamic disturbances created by the swimmers. Conditional sampling of the tracer data based on the instantaneous swimmer position shows that the rapid growth of the diffusivity enhancement with concentration must be due to particle interactions with multiple swimmers simultaneously. Finally, the anomalous probability distributions of tracer displacements become Gaussian at high concentration, but manifest strong power law tails at low concentration, while the tracer displacements always grow diffusively in time. PMID- 21659631 TI - Risk of collective failure provides an escape from the tragedy of the commons. AB - From group hunting to global warming, how to deal with collective action may be formulated in terms of a public goods game of cooperation. In most cases, contributions depend on the risk of future losses. Here, we introduce an evolutionary dynamics approach to a broad class of cooperation problems in which attempting to minimize future losses turns the risk of failure into a central issue in individual decisions. We find that decisions within small groups under high risk and stringent requirements to success significantly raise the chances of coordinating actions and escaping the tragedy of the commons. We also offer insights on the scale at which public goods problems of cooperation are best solved. Instead of large-scale endeavors involving most of the population, which as we argue, may be counterproductive to achieve cooperation, the joint combination of local agreements within groups that are small compared with the population at risk is prone to significantly raise the probability of success. In addition, our model predicts that, if one takes into consideration that groups of different sizes are interwoven in complex networks of contacts, the chances for global coordination in an overall cooperating state are further enhanced. PMID- 21659633 TI - Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation. AB - BACKGROUND: Autonomic denervation may suppress atrial fibrillation (AF) vulnerability. This study was designed to assess the short- to mid-term effects of botulinum toxin, a cholinergic neurotransmission blocker, on AF inducibility. METHODS AND RESULTS: A total of 23 mongrel dogs were studied. The sinus node and atrioventricular node epicardial fat pads were exposed through a right lateral thoracotomy. Botulinum toxin (Botox, 50 U per fat pad) or 0.9% normal saline (control) was injected into the center of each of the 2 fat pads. The electrophysiological effects were evaluated at 1, 2, and 3 weeks (7 to 8 animals at each time point) with and without cervical vagal stimulation. The vagal stimulation effects on the sinus and atrioventricular nodes were inhibited, and dispersion of atrial effective refractory period was lower at 1 week in the Botox group. Significant suppression of AF inducibility was observed at 1 week but disappeared at 2 and 3 weeks. These changes were not observed in the control group. CONCLUSIONS: Temporary suppression of vagally mediated AF, for at least 1 week, was achieved with botulinum toxin injection in this canine model. This effect might be associated with reduced dispersion of effective refractory period. A temporary autonomic block using botulinum toxin might be a novel therapeutic option for several clinical conditions such as post-cardiac surgery AF. PMID- 21659632 TI - Adaptation-induced synchronization in laminar cortical circuits. AB - A fundamental feature of information processing in neocortex is the ability of individual neurons to adapt to changes in incoming stimuli. It is increasingly being understood that cortical adaptation is a phenomenon that requires network interactions. The fact that the structure of local networks depends critically on cortical layer raises the possibility that adaptation could induce specific effects in different layers. Here we show that brief exposure (300 ms) to a stimulus of fixed orientation modulates the strength of synchronization between individual neurons and local population activity in the gamma-band frequency (30 80 Hz) in macaque primary visual cortex (V1) and influences the ability of individual neurons to encode stimulus orientation. Using laminar probes, we found that although stimulus presentation elicits a large increase in the gamma synchronization of rhythmic neuronal activity in the input (granular) layers of V1, adaptation caused a pronounced increase in synchronization in the cortical output (supragranular) layers. The increase in gamma synchronization after adaptation was significantly correlated with an improvement in neuronal orientation discrimination performance only in the supragranular layers. Thus, synchronization between the spiking activity of individual neurons and their local population may enhance sensory coding to optimize network processing across laminar circuits. PMID- 21659635 TI - Telling things apart: the distance between response keys influences categorization times. AB - People use spatial distance to talk and think about differences between concepts, and it has been argued that using space to think about different categories provides a scaffold for the categorization process. In the current study, we investigated the possibility that the distance between response keys can influence categorization times in binary classification tasks. In line with the hypothesis that distance between response keys can facilitate response selection in a key-press version of the Stroop task, our results showed that responses on incongruent Stroop trials were significantly facilitated when participants performed the Stroop task with response keys located far apart, compared with when they performed the task with response keys located close together. These results support the idea that the spatial structuring of response options facilitates categorizations that require cognitive effort, and that people can incorporate environmental structures such as spatial distance in their thought processes. Keeping your hands apart might actually help to keep things apart in your mind. PMID- 21659634 TI - Sex differences in the electrophysiological characteristics of pulmonary veins and left atrium and their clinical implication in atrial fibrillation. AB - BACKGROUND: Sex and the autonomic nervous system play critical roles in the pathophysiology of atrial fibrillation (AF). Sex differences in electrophysiological characteristics of the pulmonary veins (PVs, AF initiator) and left atrium (LA, AF substrate) are not clear. METHODS AND RESULTS: Conventional microelectrodes were used to record the action potential in isolated PV and LA tissue preparations from male and female (age, 8~10 months) rabbits before and after drug administration (adenosine, acetylcholine, and isoproterenol). Male PVs (n = 7) had a higher spontaneous beating rate (1.7 +/- 0.2 versus 1.2 +/- 0.1 Hz, P = 0.021) and incidence of burst firing (72% versus 11%, P = 0.038) than female PVs (n = 9). Male PVs without spontaneous activity (n = 10) and the LA (n = 11) had longer action potential durations than female PVs (n = 9) and LA (n = 9). Additionally, male PVs had a more-positive resting membrane potential (79 +/- 3 versus 84+/-2 mV, P=0.022). Isoproterenol (3 MUmol/L) increased the delayed afterdepolarizations to a greater extent in male than in female PVs. In PVs without spontaneous activity or LA, isoproterenol (0.1 and 3 MUmol/L) consistently shortened the action potential durations in females but not in males. Acetylcholine (5.5 MUmol/L) decreased the spontaneous activity of PVs and shortened the action potential durations in both groups. Adenosine (10 MUmol/L) also similarly decreased the spontaneous activity of PVs and delayed afterdepolarizations in both groups. CONCLUSIONS: There are significant sex differences in PV and LA action potential characteristics in rabbits. The higher amplitude of delayed afterdepolarizations after isoproterenol superfusion in male PVs may contribute to sex-related arrhythmogenesis. PMID- 21659637 TI - What is the current status of invasive treatment of extracranial carotid artery disease? AB - Year 2011 sees the publication of U.S. guidelines that recommend expanding indications for carotid artery stenting into "average-risk" patients, whereas guidelines from Australia/New Zealand largely do not. This article reviews the status of invasive treatment of carotid disease and highlights 2 controversial issues that were not really addressed in these guidelines: (1) a lack of emphasis on the importance of intervening rapidly after transient ischemic attack/minor stroke; and (2) why continue to recommend that only "highly selected" asymptomatic patients should undergo intervention when virtually no-one pays any attention? PMID- 21659639 TI - Subtherapeutic international normalized ratio in warfarin-treated patients increases the risk for symptomatic intracerebral hemorrhage after intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: There is uncertainty whether warfarin-treated patients (despite international normalized ratio < 1.7) have increased risks of symptomatic intracerebral hemorrhage after intravenous thrombolysis. METHODS: Vascular risk factors, stroke subtype, and outcome measures were compared between warfarin- and nonwarfarin-treated patients undergoing acute thrombolysis within 3 hours of symptom onset. RESULTS: From 212 patients (mean age, 74 +/- 14 years; 50% men) studied, 14 (6.5%) had prior warfarin use. After adjusting for age, baseline National Institutes of Health Stroke Scale, and stroke subtype, warfarin treated patients had significantly increased risks of developing symptomatic intracerebral hemorrhage (adjusted OR, 14.7; 95% CI, 1.3 to 54.3). A trend for poorer stroke recovery and increased mortality was observed in warfarin-treated patients on univariate, but not on multivariable, analyses. CONCLUSIONS: Warfarin treated patients with stroke have increased risks of symptomatic intracerebral hemorrhage after thrombolytic treatment. These data raise safety concerns of thrombolytic treatment in warfarin-treated patients with subtherapeutic international normalized ratio. PMID- 21659638 TI - Prehospital notification by emergency medical services reduces delays in stroke evaluation: findings from the North Carolina stroke care collaborative. AB - BACKGROUND AND PURPOSE: Individuals with stroke-like symptoms are recommended to receive rapid diagnostic evaluation. Emergency medical services (EMS) transport, compared with private modes, and hospital notification before arrival may reduce delays in evaluation. This study estimated associations between hospital arrival modes (EMS or private and with or without EMS prenotification) and times for completion and interpretation of initial brain imaging in patients with presumed stroke. METHODS: Among patients with suspected stroke identified and enrolled by the North Carolina Stroke Care Collaborative registry in 2008 to 2009, we analyzed data on arrival modes, meeting recommended targets for brain imaging completion and interpretation times (<25 minutes and <45 minutes since hospital arrival, respectively) and patient- and hospital-level characteristics. We used modified Poisson regression to estimate adjusted risk ratios and 95% CIs. RESULTS: Of 13 894 eligible patients, 21% had their brain imaging completed and 23% had their brain imaging interpreted by a physician within target times. Arrival by EMS (versus private transport) was associated with both brain imaging completed within 25 minutes of arrival (EMS with prenotification: risk ratio, 3.0; 95% CI, 2.1 to 4.1; EMS without prenotification: risk ratio, 1.9; 95% CI, 1.6 to 2.3) and brain imaging interpreted within 45 minutes (EMS with prenotification: risk ratio, 2.7; 95% CI, 2.3 to 3.3; EMS without prenotification: risk ratio, 1.7; 95% CI, 1.4 to 2.1). CONCLUSIONS: Patients with presumed stroke arriving to the hospital by EMS were more likely to receive brain imaging and have it interpreted by a physician in a timely manner than those arriving by private transport. Moreover, EMS arrivals with hospital prenotification experienced the most rapid evaluation. PMID- 21659640 TI - Right-left propensity and lesion patterns between cardiogenic and aortogenic cerebral embolisms. AB - BACKGROUND AND PURPOSE: Based on thrombus location and nature and anatomic features of aorta and cerebral arteries, we hypothesized that cardiogenic embolisms (CE) and aortogenic embolisms (AE) might have different right-left propensity and lesion patterns. METHODS: We retrospectively reviewed patients with acute ischemic stroke with high-risk CE sources or moderate-or-severe aortic atherosclerotic plaques on transesophageal echocardiography. Lesion side and patterns on diffusion-weighted imaging were compared between CE and AE. RESULTS: CE was identified in 123 and AE in 63. In multivariate analysis, right-sided lesions and corticosubcortical infarcts were independently associated with CE, and left-sided lesions and pial infarcts were independently associated with AE. CONCLUSIONS: CE and AE have different radiological characteristics, as shown by the right-left propensity and lesions patterns of cerebral infarcts. PMID- 21659641 TI - Youth and parent knowledge and communication about major complications of type 1 diabetes: associations with diabetes outcomes. AB - OBJECTIVE: Previously, we studied clinicians' and parents' perspectives about what, when, and how youth with type 1 diabetes (T1D) and parents should be taught about major complications (MC) of T1D. Results showed that this topic creates considerable anxiety among youth and parents, that there is a perceived need to tailor these experiences to each patient's circumstances, and that there is considerable variability in opinions about appropriate MC education. Prior studies did not measure youths' or parents' actual knowledge of complications, how they cope with that knowledge, or how these variables relate to T1D outcomes. The current study addresses these gaps. RESEARCH DESIGN AND METHODS: This article reports a cross-sectional study of 151 8- to 18-year-old youths with T1D and their parents in which their knowledge of MC (nephropathy, retinopathy, neuropathy, and cardiovascular disease) was ascertained by structured interview. Family communication about MC was assessed using a questionnaire validated in this study. Regression analyses explored youth age, parent and youth MC knowledge, and positive family communication about MC as predictors of T1D outcomes (hemoglobin A(1c), treatment adherence, quality of life, and family conflict about T1D). RESULTS: Parental MC knowledge was not associated with any T1D outcome; greater youth MC knowledge predicted better treatment adherence. More frequent optimistic family communication about MC was associated with more favorable status on all outcomes. CONCLUSIONS: Optimistic family communication about MC, more so than MC knowledge, predicted favorable T1D outcomes. Longitudinal studies are needed to confirm these associations and to evaluate pertinent psychoeducational interventions. PMID- 21659642 TI - Chromobox protein homolog 3 is essential for stem cell differentiation to smooth muscles in vitro and in embryonic arteriogenesis. AB - OBJECTIVE: Smooth muscle cell (SMC) differentiation is a critical process during cardiovascular formation and development, but the underlying molecular mechanism remains unclear. METHODS AND RESULTS: Here we demonstrated that chromobox protein homolog 3 (Cbx3) is crucial for SMC differentiation from stem cells and that the chromodomain and chromoshadow domain of Cbx3 are responsible for Cbx3-induced SMC differentiation. Moreover, we identified that 4 amino acids (165 to 168) within the chromoshadow domain of Cbx3 are key elements for Cbx3 interaction with Dia-1- and Cbx3-induced SMC differentiation. Mechanistically, we found that Cbx3 mediates SMC differentiation through modulating serum response factor (SRF) recruitment to the promoters of SMC genes, in which the interaction between Cbx3 and Dia-1/SRF plays a crucial role in this process. Moreover, our in vivo study demonstrated that the misexpression of Cbx3 within neural crest cells of chick embryos resulted in the death of chick embryos at early stages because of the maldevelopment of branchial arch arteries. CONCLUSIONS: Our findings suggest that the interaction between Cbx3 and Dia-1/SRF is essential for SMC differentiation from stem cells and for the development of functional cardiovascular system. PMID- 21659644 TI - Moderate caveolin-1 downregulation prevents NADPH oxidase-dependent endothelial nitric oxide synthase uncoupling by angiotensin II in endothelial cells. AB - OBJECTIVE: We analyzed the role of caveolin-1 (Cav-1) in the cross-talk between NADPH oxidase and endothelial nitric oxide synthase (eNOS) signaling in endothelial caveolae. METHODS AND RESULTS: In intact endothelial cells, angiotensin II (AII) concurrently increased NO and O(2)(-.) production (to 158+/ 12% and 209+/-5% of control). NO production was sensitive to inhibition of NADPH oxidase and small interfering RNA downregulation of nonreceptor tyrosine kinase cAbl. Reciprocally, N-nitro-l-arginine methyl ester, a NOS inhibitor, partly inhibited O(2)(-.) stimulated by AII (by 47+/-11%), indicating eNOS uncoupling, as confirmed by increased eNOS monomer/dimer ratio (by 35%). In endothelial cell fractions separated by isopycnic ultracentrifugation, AII promoted colocalization of cAbl and the NADPH oxidase subunit p47phox with eNOS to Cav-1-enriched fractions, as confirmed by proximity ligation assay. Downregulation of Cav-1 by small interfering RNA (to 50%), although it preserved eNOS confinement, inhibited AII-stimulated p47phox translocation and NADPH oxidase activity in Cav-1-enriched fractions and reversed eNOS uncoupling. AII infusion produced hypertension and decreased blood hemoglobin-NO in Cav-1(+/+) mice but not in heterozygote Cav-1(+/ ) mice with similar Cav-1 reduction. CONCLUSIONS: Cav-1 critically regulates reactive oxygen species-dependent eNOS activation but also eNOS uncoupling in response to AII, underlining the possibility to treat endothelial dysfunction by modulating Cav-1 abundance. PMID- 21659643 TI - Cdc42 controls vascular network assembly through protein kinase Ciota during embryonic vasculogenesis. AB - OBJECTIVE: The goal of this study was to determine the role of Cdc42 in embryonic vasculogenesis and the underlying mechanisms. METHODS AND RESULTS: By using genetically modified mouse embryonic stem (ES) cells, we demonstrate that ablation of the Rho GTPase Cdc42 blocks vascular network assembly during embryoid body (EB) vasculogenesis without affecting endothelial lineage differentiation. Reexpression of Cdc42 in mutant EBs rescues the mutant phenotype, establishing an essential role for Cdc42 in vasculogenesis. Chimeric analysis revealed that the vascular phenotype is caused by inactivation of Cdc42 in endothelial cells rather than surrounding cells. Endothelial cells isolated from Cdc42-null EBs are defective in directional migration and network assembly. In addition, activation of atypical protein kinase Ciota (PKCiota) is abolished in Cdc42-null endothelial cells, and PKCiota ablation phenocopies the vascular abnormalities of the Cdc42 null EBs. Moreover, the inhibitory phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) at Ser9 depends on Cdc42 and PKCiota, and expression of kinase dead GSK-3beta in Cdc42-null EBs promotes the formation of linear endothelial segments without branches. These results suggest that PKCiota and GSK-3beta are downstream effectors of Cdc42 during vascular morphogenesis. CONCLUSIONS: Cdc42 controls vascular network assembly but not endothelial lineage differentiation by activating PKCiota during embryonic vasculogenesis. PMID- 21659646 TI - An activation-specific platelet inhibitor that can be turned on/off by medically used hypothermia. AB - OBJECTIVE: Therapeutic hypothermia is successfully used, for example, in cardiac surgery to protect organs from ischemia. Cardiosurgical procedures, especially in combination with extracorporeal circulation, and hypothermia itself are potentially prothrombotic. Despite the obvious need, the long half-life of antiplatelet drugs and thus the risk of postoperative bleedings have restricted their use in cardiac surgery. We describe here the design and testing of a unique recombinant hypothermia-controlled antiplatelet fusion protein with the aim of providing increased safety of hypothermia, as well as cardiac surgery. METHODS AND RESULTS: An elastin-mimetic polypeptide was fused to an activation-specific glycoprotein (GP) IIb/IIIa-blocking single-chain antibody. In silico modeling illustrated the sterical hindrance of a beta-spiral conformation of elastin mimetic polypeptide preventing the single-chain antibody from inhibiting GPIIb/IIIa at 37 degrees C. Circular dichroism spectra demonstrated reverse temperature transition, and flow cytometry showed binding to and blocking of GPIIb/IIIa at hypothermic body temperature (<=32 degrees C) but not at normal body temperature. In vivo thrombosis in mice was selectively inhibited at hypothermia but not at 37 degrees C. CONCLUSIONS: This is the first description of a broadly applicable pharmacological strategy by which the activity of a potential drug can be controlled by temperature. In particular, this drug steerability may provide substantial benefits for antiplatelet therapy. PMID- 21659645 TI - Retinal arteriolar tortuosity and cardiovascular risk factors in a multi-ethnic population study of 10-year-old children; the Child Heart and Health Study in England (CHASE). AB - OBJECTIVE: To examine the association between cardiovascular risk factors and retinal arteriolar tortuosity in a multi-ethnic child population. METHODS AND RESULTS: Cross sectional study of 986 UK primary school children of South Asian, black African Caribbean, and white European origin aged 10 to 11 years. Anthropometric measurements and retinal imaging were carried out and a fasting blood sample collected. Digital images of retinal arterioles were analyzed using a validated semiautomated measure of tortuosity. Associations between tortuosity and cardiometabolic risk factors were analyzed using multi-level linear regression, adjusted for gender, age, ethnicity, arteriole branch status, month, and school. Levels of arteriolar tortuosity were similar in boys and girls and in different ethnic groups. Retinal arteriolar tortuosity was positively associated with levels of triglyceride, total and LDL cholesterol, and systolic and diastolic blood pressure. One standard deviation increases in these risk factors were associated with 3.7% (95% CI: 1.2%, 6.4%), 3.3% (0.9%, 5.8%), 3.1% (0.6%, 5.6%), 2.0% (-0.3%, 4.2%), and 2.3% (0.1%, 4.6%) increases in tortuosity, respectively. Adiposity, insulin resistance, and blood glucose showed no associations with tortuosity. CONCLUSIONS: Established cardiovascular risk factors, strongly linked to coronary heart disease in adulthood, may influence retinal arteriolar tortuosity at the end of the first decade of life. PMID- 21659647 TI - Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle. AB - RATIONALE: The proper function of cardiac muscle requires the precise assembly and interactions of numerous cytoskeletal and regulatory proteins into specialized structures that orchestrate contraction and force transmission. Evidence suggests that posttranscriptional regulation is critical for muscle function, but the mechanisms involved remain understudied. OBJECTIVE: To investigate the molecular mechanisms and targets of the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1), an RNA binding protein whose loss leads to perinatal lethality in mice and cardiomyopathy in zebrafish. METHODS AND RESULTS: Using RNA immunoprecipitation approaches we found that desmoplakin and talin2 mRNAs associate with FXR1 in a complex. In vitro assays indicate that FXR1 binds these mRNA targets directly and represses their translation. Fxr1 KO hearts exhibit an up-regulation of desmoplakin and talin2 proteins, which is accompanied by severe disruption of desmosome as well as costamere architecture and composition in the heart, as determined by electron microscopy and deconvolution immunofluorescence analysis. CONCLUSIONS: Our findings reveal the first direct mRNA targets of FXR1 in striated muscle and support translational repression as a novel mechanism for regulating heart muscle development and function, in particular the assembly of specialized cytoskeletal structures. PMID- 21659648 TI - Autophagy and p62 in cardiac proteinopathy. AB - RATIONALE: Recent studies suggest an important role of autophagy in protection against alphaB-crystallin-based (CryAB(R120G)) desmin-related cardiomyopathies (DRC), but this has not been demonstrated in a different model of cardiac proteinopathy. Mechanisms underlying the response of cardiomyocytes to proteotoxic stress remain incompletely understood. OBJECTIVE: Our first objective was to determine whether and how the autophagic activity is changed in a mouse model of desminopathy. We also investigated the role of p62 in the protein quality control of cardiomyocytes. METHODS AND RESULTS: Using an autophagosome reporter and determining changes in LC3-II protein levels in response to lysosomal inhibition, we found significantly increased autophagic flux in mouse hearts with transgenic overexpression of a DRC-linked mutant desmin. Similarly, autophagic flux was increased in cultured neonatal rat ventricular myocytes (NRVMs) expressing a mutant desmin. Suppression of autophagy by 3-methyladenine increased, whereas enhancement of autophagy by rapamycin reduced the ability of a comparable level of mutant desmin overexpression to accumulate ubiquitinated proteins in NRVMs. Furthermore, p62 mRNA and protein expression was significantly up-regulated in cardiomyocytes by transgenic overexpression of the mutant desmin or CryAB(R120G) both in intact mice and in vitro. The p62 depletion impaired aggresome and autophagosome formation, exacerbated cell injury, and decreased cell viability in cultured NRVMs expressing the misfolded proteins. CONCLUSIONS: Autophagic flux is increased in desminopathic hearts, and as previously suggested in CryAB(R120G)-based DRC, this increased autophagic flux serves as an adaptive response to overexpression of misfolded proteins. The p62 is up-regulated in mouse proteinopathic hearts. The p62 promotes aggresome formation and autophagy activation and protects cardiomyocytes against proteotoxic stress. PMID- 21659650 TI - Saying yes to exercise and NO to cardiac injury. PMID- 21659651 TI - Mutations in KCNJ5 gene cause hyperaldosteronism. PMID- 21659649 TI - A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium. AB - RATIONALE: Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during beta-adrenergic stimulation. OBJECTIVE: This study sought to determine the effects of a novel RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca(2+)). METHODS AND RESULTS: Functional characterizations of recombinant human RyR2-G230C channels were performed under conditions mimicking stress. Human RyR2 mutant channels were generated by site-directed mutagenesis and heterologously expressed in HEK293 cells together with calstabin2. RyR2 channels were measured to examine the regulation of the channels by cytosolic versus luminal sarcoplasmic reticulum Ca(2+). A 50-year-old white man with repeated syncopal episodes after exercise had a cardiac arrest and harbored the mutation RyR2-G230C. cAMP-dependent protein kinase-phosphorylated RyR2-G230C channels exhibited a significantly higher open probability at diastolic Ca(2+) concentrations, associated with a depletion of calstabin2. The luminal Ca(2+) sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like. CONCLUSIONS: The RyR2-G230C mutant exhibits similar biophysical defects compared with previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca(2+) dependence for activation under conditions that simulate exercise, consistent with a "leaky" channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca(2+) activation. Thus, diastolic sarcoplasmic reticulum Ca(2+) leak caused by reduced calstabin2 binding and a leftward shift in the Ca(2+) dependence for activation by diastolic levels of cytosolic Ca(2+) is a common mechanism underlying CPVT. PMID- 21659653 TI - Fetuin-A regulation of calcified matrix metabolism. AB - The final step of biomineralization is a chemical precipitation reaction that occurs spontaneously in supersaturated or metastable salt solutions. Genetic programs direct precursor cells into a mineralization-competent state in physiological bone formation (osteogenesis) and in pathological mineralization (ectopic mineralization or calcification). Therefore, all tissues not meant to mineralize must be actively protected against chance precipitation of mineral. Fetuin-A is a liver-derived blood protein that acts as a potent inhibitor of ectopic mineralization. Monomeric fetuin-A protein binds small clusters of calcium and phosphate. This interaction results in the formation of prenucleation cluster-laden fetuin-A monomers, calciprotein monomers, and considerably larger aggregates of protein and mineral calciprotein particles. Both monomeric and aggregate forms of fetuin-A mineral accrue acidic plasma protein including albumin, thus stabilizing supersaturated and metastable mineral ion solutions as colloids. Hence, fetuin-A is a mineral carrier protein and a systemic inhibitor of pathological mineralization complementing local inhibitors that act in a cell restricted or tissue-restricted fashion. Fetuin-A deficiency is associated with soft tissue calcification in mice and humans. PMID- 21659652 TI - The roles of lipid oxidation products and receptor activator of nuclear factor kappaB signaling in atherosclerotic calcification. AB - This review focuses on the roles of oxylipids and receptor activator of nuclear factor-kappaB ligand signaling in calcific cardiovascular disease. Both intimal and valvular calcifications are closely associated with atherosclerosis, leading investigators to study the role of atherogenic oxidatively modified lipids (oxylipids). Results have identified the molecular signaling through which oxylipids induce osteogenic differentiation and calcification in vascular cells. A surprising concomitant finding was that, in bona fide osteoblasts from skeletal bone, oxylipids have the opposite effect, ie, inhibiting osteoblastic maturation. This is the basis for the lipid hypothesis of osteoporosis. Oxylipids also induce resorptive osteoclastic cells within the bone environment, raising the question of whether resorptive osteoclasts can be harnessed in the vascular context for cell-based therapy to remove artery wall mineral deposits. The challenge is that vascular cells produce antiosteoclastogenic factors, including the soluble decoy receptor for receptor activator of nuclear factor-kappaB ligand, possibly accounting for the paucity of resorptive cells and the dominance of mineral in atherosclerotic plaque. These factors may have therapeutic use in osteoclastogenic removal of mineral deposits from arteries. PMID- 21659654 TI - Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. AB - The hallmarks of calcific aortic valve disease (CAVD) are the significant changes that occur in the organization, composition, and mechanical properties of the extracellular matrix (ECM), ultimately resulting in stiffened stenotic leaflets that obstruct flow and compromise cardiac function. Increasing evidence suggests that ECM maladaptations are not simply a result of valve cell dysfunction; they also contribute to CAVD progression by altering cellular and molecular signaling. In this review, we summarize the ECM changes that occur in CAVD. We also discuss examples of how the ECM influences cellular processes by signaling through adhesion receptors (matricellular signaling), by regulating the presentation and availability of growth factors and cytokines to cells (matricrine signaling), and by transducing externally applied forces and resisting cell-generated tractional forces (mechanical signaling) to regulate a wide range of pathological processes, including differentiation, fibrosis, calcification, and angiogenesis. Finally, we suggest areas for future research that should lead to new insights into bidirectional cell-ECM interactions in the aortic valve, their contributions to homeostasis and pathobiology, and possible targets to slow or prevent the progression of CAVD. PMID- 21659655 TI - Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. AB - Oxidant stress, resulting from an excess of reactive electrophiles produced in the lung by both resident (epithelial and endothelial) and infiltrated leukocytes, is thought to play an obligatory role in tissue injury and abnormal repair. Previously, using a conventional (whole-body) knockout model, we showed that antioxidative gene induction regulated by the transcription factor Nrf2 is critical for mitigating oxidant-induced (hyperoxic) stress, as well as for preventing and resolving tissue injury and inflammation in vivo. However, the contribution to pathogenic acute lung injury (ALI) of the cellular stress produced by resident versus infiltrated leukocytes remains largely undefined in vivo. To address this critical gap in our knowledge, we generated mice with a conditional deletion of Nrf2 specifically in Clara cells, subjected these mice to hyperoxic insult, and allowed them to recover. We report that a deficiency of Nrf2 in airway epithelia alone is sufficient to contribute to the development and progression of ALI. When exposed to hyperoxia, mice lacking Nrf2 in Clara cells showed exacerbated lung injury, accompanied by greater levels of cell death and epithelial sloughing than in their wild-type littermates. In addition, we found that an Nrf2 deficiency in Clara cells is associated with a persistent inflammatory response and epithelial sloughing in the lungs during recovery from sublethal hyperoxic insult. Our results demonstrate (for the first time, to the best of our knowledge) that Nrf2 signaling in Clara cells is critical for conferring protection from hyperoxic lung injury and for resolving inflammation during the repair process. PMID- 21659658 TI - Cur l 3, a major allergen of Curvularia lunata-derived short synthetic peptides, shows promise for successful immunotherapy. AB - Allergens with reduced IgE binding and intact T cell reactivity are required for safety and efficacy of immunotherapy (IT). Curvularia lunata is an important fungus for respiratory allergic disorders having cross-reactive and specific allergens. Previously, we have identified major allergens-namely, Cur l 1 (31 kD, serine protease), Cur l 2 (48 kD, enolase), and Cur l 3 (12 kD, cytochrome c) from this fungus. Furthermore, Cur l 3 epitope-peptide, P6, showed immunogenicity and higher IgE binding, where cysteine and histidine were observed to be vital for IgE binding. Thus, this peptide and three derivatives with reduced IgE binding were selected for analysis in mice. In the present study, the effect of IT was assessed with Cur l 3, P6, its derivatives (P6.1-6.3), and P10 in a mouse model of allergy. IT with P6.2 and P10 reduced IgE and IgG1 levels significantly (P < 0.05), with increase in IgG2a levels as compared to other antigens. There was a significant reduction of IL-4 level associated with increased IFN-gamma after IT. Airway inflammation was reduced significantly in terms of eosinophil counts in lung tissue and bronchoalveolar lavage fluid. IT with P6 and P6.2 induced significantly higher IL-10 secretion than baseline after 40 days of treatment. Generally, the effect of IT was more pronounced after 40 days than after 10 days of treatment. In summary, the modified peptide, P6.2, with reduced IgE binding, but intact immunogenicity, showed promise for successful IT. PMID- 21659656 TI - Ezrin, radixin, and moesin are phosphorylated in response to 2-methoxyestradiol and modulate endothelial hyperpermeability. AB - We showed previously that microtubule disruptor 2-methoxyestradiol (2ME) induces hyperpermeability of the endothelial monolayer via mechanisms that include the activation of p38 and Rho kinase (ROCK) and rearrangement of the actin cytoskeleton. Using the protein kinase C (PKC) inhibitors Ro-31-7549 and Ro-32 0432, we show in vitro and in vivo that 2ME-induced barrier dysfunction is also PKC-dependent. The known PKC substrates ezrin, radixin, and moesin (ERM) were recently implicated in the regulation of endothelial permeability. This study tested the hypotheses that ERM proteins are phosphorylated in response to 2ME, and that this phosphorylation is involved in 2ME-induced barrier dysfunction. We show that the application of 2ME leads to a dramatic increase in the level of ERM phosphorylation. This increase is attenuated in cells pretreated with the microtubule stabilizer taxol. In human pulmonary artery endothelial cells (HPAECs), the phosphorylation of ERM occurs in a p38-dependent and PKC-dependent manner. The activation of p38 appears to occur upstream from the activation of PKC, in response to 2ME. Phosphorylated ERM are localized at the cell periphery during the early phase of response to 2ME (15 minutes), and colocalize with F actin branching points during the later phase of response (60 minutes). Using the short interfering RNA approach, we also showed that individual ERM depletion significantly attenuates 2ME-induced hyperpermeability. HPAEC monolayers, depleted of ERM proteins and monolayers, overexpressing phosphorylation-deficient ERM mutants, exhibit less attenuation of 2ME-induced barrier disruption in response to the PKC inhibitor Ro-31-7549. These results suggest a critical role of PKC activation in response to microtubule-disrupting agents, and implicate the phosphorylation of ERM in the barrier dysfunction induced by 2ME. PMID- 21659659 TI - Connective tissue growth factor antibody therapy attenuates hyperoxia-induced lung injury in neonatal rats. AB - Despite recent advances in neonatal intensive care and surfactant therapy, bronchopulmonary dysplasia (BPD) continues to be one of the most common long-term pulmonary complications associated with preterm birth. Clinical efforts to prevent and treat BPD have been largely unsuccessful due to its multifactorial nature and poorly understood disease process. Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling. Previous studies have demonstrated that hyperoxia exposure up-regulates CTGF expression in neonatal rat lungs. Whether CTGF overexpression plays a role in the pathogenesis of BPD, and whether CTGF antagonism has a therapeutic potential for BPD, are unknown. In the present study, we examined CTGF expression in lung autopsy specimens from patients with BPD and control subjects with no BPD. We assessed the effect of a CTGF neutralizing monoclonal antibody (CTGF Ab) on preventing hyperoxia-induced lung injury in neonatal rats. Our study demonstrates that CTGF expression is increased in BPD lungs. In newborn rats, exposure to 90% oxygen for 14 days resulted in activation of beta-catenin signaling, decreased alveolarization and vascular development, and physiological and histological evidence of pulmonary hypertension (PH). However, treatment with CTGF Ab prevented beta-catenin signaling activation, improved alveolarization and vascular development, and attenuated PH during hyperoxia. These data indicate that CTGF-beta-catenin signaling plays a critical role in the pathogenesis of experimental BPD. CTGF antagonism may offer a novel therapeutic strategy to alleviate BPD and PH in neonates. PMID- 21659660 TI - Modulators of sphingolipid metabolism reduce lung inflammation. AB - The investigation of novel targets for the treatment of cystic fibrosis (CF) lung inflammation is a major priority, considering that no effective therapy is available for this purpose. Consistent with the evidence that the sphingolipid (SL) ceramide regulates airway inflammation and infection in mice and patients with CF, SLs were identified as targets for treating pulmonary disorders, including CF. Because miglustat, an inhibitor of the synthesis of glycosphingolipids, reduces the Pseudomonas aeruginosa-dependent transcription of the IL-8 gene in bronchial cells, we examined the effects of miglustat and amitriptyline, another drug affecting ceramide metabolism, on the expression of 92 genes implicated in host immune defense. Infection with the P. aeruginosa strain PAO1 up-modulated the expression of 14 (27%) genes in IB3-1 cells and 15 (29%) genes in CF primary respiratory epithelia grown at an air-liquid interface, including chemokines (IL-8, growth-regulated Gro-alpha/beta/gamma proteins, and granulocyte chemotactic peptide-2 [GCP-2]), proinflammatory cytokines (IL 1alpha/beta, IL-6, and TNF-alpha), and the intercellular adhesion molecule-1, nuclear factor kB1, toll like receptor 2, and human defensin B4 genes, confirming that bronchial epithelium is an important source of inflammatory mediators. Both miglustat and amitriptyline reduced the immune response, an effect that paralleled a decrease in the P. aeruginosa-induced accumulation of ceramide. Miglustat (100 mg/kg), given to C57BL/6 mice once daily for a period of 3 consecutive days before lipopolysaccharide (LPS) challenge, strongly reduced the number of neutrophils recruited in the airways and the expression of the keratinocyte-derived chemokine in lung extracts. Collectively, these results indicate that targeting the metabolism of SLs can down-modulate the recruitment of neutrophils into the lung. PMID- 21659657 TI - The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility. AB - Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate. PMID- 21659661 TI - Opposing effects of bone morphogenetic protein-2 and endothelin-1 on lung fibroblast chloride currents. AB - Alteration in the control of bone morphogenetic protein (BMP)-regulated genes and increased expression of endothelin (ET)-1 are both believed to play important roles in the still incompletely understood pathobiology of pulmonary vascular remodeling and fibrosis. Recent studies have drawn attention to the contribution of adventitial fibroblast activation in these phenomena. Because chloride channels are involved in the control of physiological function of fibroblasts, we hypothesized that these channels are differentially regulated by BMPs and ET. We measured chloride ion currents by whole-cell path-clamping in cultured primary human pulmonary fibroblasts. The application of BMP2 prevented activation of these currents by hypotonic challenge in a time- and dose-dependent manner, partially via protein kinase C signaling. Maximal inhibition was observed after 45-minute incubation of cells in the presence of 10 ng/ml of BMP2. ET-1 did not activate chloride channels acutely; however, prolonged treatment of cells with ET 1 (100 nM, 2 h) induced the appearance of lysophosphatidic acid-activated chloride currents (a marker of differentiated myofibroblasts), and this induction could be effectively blocked by BMP2 pretreatment (10 ng/ml). BMP2 also prevented stimulation of alpha-smooth muscle actin gene expression and cell migration of fibroblasts induced by ET-1. We conclude that ET-1 and BMP2 have opposing effects on chloride channel activity in human fibroblasts. This is a potentially relevant mechanism involved in pulmonary vascular remodeling and fibrosis. PMID- 21659663 TI - Allelochemical stress inhibits growth, leaf water relations, PSII photochemistry, non-photochemical fluorescence quenching, and heat energy dissipation in three C3 perennial species. AB - In this study, the effect of two allelochemicals, benzoxazolin-2(3H)-one (BOA) and cinnamic acid (CA), on different physiological and morphological characteristics of 1-month-old C(3) plant species (Dactylis glomerata, Lolium perenne, and Rumex acetosa) was analysed. BOA inhibited the shoot length of D. glomerata, L. perenne, and R. acetosa by 49%, 19%, and 19% of the control. The root length of D. glomerata, L. perenne, and R. acetosa growing in the presence of 1.5 mM BOA and CA was decreased compared with the control. Both allelochemicals (BOA, CA) inhibited leaf osmotic potential (LOP) in L. perenne and D. glomerata. In L. perenne, F(v)/F(m) decreased after treatment with BOA (1.5 mM) while CA (1.5 mM) also significantly reduced F(v)/F(m) in L. perenne. Both allelochemicals decreased PhiPSII in D. glomerata and L. perenne within 24 h of treatment, while in R. acetosa, PhiPSII levels decreased by 72 h following treatment with BOA and CA. There was a decrease in qP and NPQ on the first, fourth, fifth, and sixth days after treatment with BOA in D. glomerata, while both allelochemicals reduced the qP level in R. acetosa. There was a gradual decrease in the fraction of light absorbed by PSII allocated to PSII photochemistry (P) in R. acetosa treated with BOA and CA. The P values in D. glomerata were reduced by both allelochemicals and the portion of absorbed photon energy that was thermally dissipated (D) in D. glomerata and L. perenne was decreased by BOA and CA. Photon energy absorbed by PSII antennae and trapped by 'closed' PSII reaction centres (E) was decreased after CA exposure in D. glomerata. BOA and CA (1.5 mM concentration) decreased the leaf protein contents in all three perennial species. This study provides new understanding of the physiological and biochemical mechanisms of action of BOA and CA in one perennial dicotyledon and two perennial grasses. The acquisition of such knowledge may ultimately provide a rational and scientific basis for the design of safe and effective herbicides. PMID- 21659664 TI - Induced epidermal permeability modulates resistance and susceptibility of wheat seedlings to herbivory by Hessian fly larvae. AB - Salivary secretions of neonate Hessian fly larvae initiate a two-way exchange of molecules with their wheat host. Changes in properties of the leaf surface allow larval effectors to enter the plant where they trigger plant processes leading to resistance and delivery of defence molecules, or susceptibility and delivery of nutrients. To increase understanding of the host plant's response, the timing and characteristics of the induced epidermal permeability were investigated. Resistant plant permeability was transient and limited in area, persisting just long enough to deliver defence molecules before gene expression and permeability reverted to pre-infestation levels. The abundance of transcripts for GDSL-motif lipase/hydrolase, thought to contribute to cuticle reorganization and increased permeability, followed the same temporal profile as permeability in resistant plants. In contrast, susceptible plants continued to increase in permeability over time until the entire crown of the plant became a nutrient sink. Permeability increased with higher infestation levels in susceptible but not in resistant plants. The ramifications of induced plant permeability on Hessian fly populations are discussed. PMID- 21659665 TI - Effect of mechanical stress on Zea root apex. I. Mechanical stress leads to the switch from closed to open meristem organization. AB - The effect of mechanical stress on the root apical meristem (RAM) organization of Zea mays was investigated. In the experiment performed, root apices were grown through a narrowing of either circular (variant I) or elliptical (variant II) shape. This caused a mechanical impedance distributed circumferentially or from the opposite sides in variant I and II, respectively. The maximal force exerted by the growing root in response to the impedance reached the value of 0.15 N for variant I and 0.08 N for variant II. Significant morphological and anatomical changes were observed. The changes in morphology depended on the variant and concerned diminishing and/or deformation of the cross-section of the root apex, and buckling and swelling of the root. Anatomical changes, similar in both variants, concerned transformation of the meristem from closed to open, an increase in the number of the cell layers at the pole of the root proper, and atypical oblique divisions of the root cap cells. After leaving the narrowing, a return to both typical cellular organization and morphology of the apex was observed. The results are discussed in terms of three aspects: the morphological response, the RAM reorganization, and mechanical factors. Assuming that the orientation of division walls is affected by directional cues of a tensor nature, the changes mentioned may indicate that a pattern of such cues is modified when the root apex passes through the narrowing, but its primary mode is finally restored. PMID- 21659666 TI - Costs of early adjuvant radiation therapy after radical prostatectomy: a decision analysis. AB - BACKGROUND: This analysis was carried out to evaluate the cost-effectiveness of adjuvant radiation therapy (ART) versus observation, using a decision analysis model based primarily upon the published results of the Southwest Oncology Group prospective trial (SWOG 8794). PATIENTS AND METHODS: A decision analysis model was designed to compare ART versus observation over a 10-year time horizon. Probabilities of treatment success, utilization of salvage treatments, and rates of adverse events were taken from published results of SWOG 8794. Cost inputs were based on 2010 Medicare reimbursement rates. Primary outcome measure was incremental cost per prostate-specific antigen (PSA) success (i.e. serum PSA level <0.4 ng/ml). RESULTS: ART results in a higher PSA success rate than observation with probability of 0.43 versus 0.22. The mean incremental cost per patient for ART versus observation was $6023. The mean incremental cost effectiveness ratio was $26,983 over the 10-year period. CONCLUSIONS: ART appears cost effective compared with observation based upon this decision analysis model. Future research should consider more costly radiation therapy (RT) approaches, such as intensity-modulated RT, and should evaluate the cost-effectiveness of ART versus early salvage RT. PMID- 21659662 TI - Evidence for mycobacteria in sarcoidosis. AB - Despite its recognition as a distinct granulomatous disease for over a century, the etiology of sarcoidosis remains to be defined. Since the early 1900s, infectious agents have been suspected in causing sarcoidosis. For much of this time, mycobacteria were considered a likely culprit, yet until recently, the supporting evidence has been tenuous at best. In this review, we evaluate the reported association between mycobacteria and sarcoidosis. Historically, mycobacterial infection has been investigated using histologic stains, cultures of lesional tissue or blood, and identification of bacterial nucleic acids or bacterial antigens. More recently, advances in biochemical, molecular, and immunological methods have produced a more rigorous analysis of the antigenic drivers of sarcoidosis. The result of these efforts indicates that mycobacterial products likely play a role in at least a subset of sarcoidosis cases. This information, coupled with a better understanding of genetic susceptibility to this complex disease, has therapeutic implications. PMID- 21659667 TI - Automaticity of exercise self-regulatory efficacy beliefs in adults with high and low experience in exercise self-regulation. AB - Guided by social cognitive theory (SCT), we investigated whether exercise self regulatory efficacy beliefs can be activated nonconsciously in individuals experienced and inexperienced in exercise self-regulation, and whether these beliefs are automatically associated with exercise self-regulation processes. The study used a 2 (Exercise Self-Regulation Experience Group) * 3 (Prime Condition) between-subjects design in which individuals experienced and inexperienced in exercise self-regulation were randomly assigned to receive subliminal, supraliminal, or no priming of exercise self-regulatory efficacy beliefs. Participants completed hypothetical diary entries, which were assessed for exercise self-regulatory efficacy and self-regulation expressions using content analyses with a SCT coding system and the Linguistic Inquiry and Word Count (LIWC) text analysis program. For both exercise self-regulation experience groups, self-efficacy priming led to more expressions of low exercise self regulatory efficacy and dysfunctional exercise self-regulation strategies compared with the control prime. For participants experienced in exercise self regulation, supraliminal priming (vs. control priming) led to more expressions of high exercise self-regulatory efficacy and functional exercise self-regulation strategies. For the experienced groups, priming led to automaticity of exercise expressions compared with the control condition. For inexperienced participants in the subliminal prime condition, priming led to automaticity of self-regulatory efficacy beliefs and work-related goals compared with the control condition. Automatic activation of exercise self-regulatory efficacy and exercise self regulation processes suggests that self-regulation of exercise behavior can occur nonconsciously. PMID- 21659668 TI - Perception and action in golf putting: skill differences reflect calibration. AB - We assessed how golfers cope with the commonly observed systematic overshoot errors in the perception of the direction between the ball and the hole. Experiments 1 and 2, in which participants were required to rotate a pointer such that it pointed to the center of the hole, showed that errors in perceived direction (in degrees of deviation from the perfect aiming line) are destroyed when the head is constrained to move within a plane perpendicular to the green. Experiment 3 compared the errors in perceived direction and putting errors of novice and skilled players. Unlike the perceived direction, putting accuracy (in degrees of deviation from the perfect aiming line) was not affected by head position. Novices did show a rightward putting error, while skilled players did not. We argue that the skill-related differences in putting accuracy reflect a process of recalibration. Implications for aiming in golf are discussed. PMID- 21659669 TI - The relationship between developmental experiences and mental toughness in adolescent cricketers. AB - The present study investigated the contribution of positive and negative youth sport experiences (i.e., processes or experiences that occur in a particular activity or setting) to self-reported mental toughness among youth-aged cricketers. A sample of 308 male cricketers aged between 13 and 18 years self reported mental toughness using the Cricket Mental Toughness Inventory (CMTI; Gucciardi & Gordon, 2009), with 187 of these cricketers also documenting their exposure to a variety of positive and negative developmental experiences. Confirmatory factor and internal reliability analyses supported the hypothesized mental toughness measurement model. Structural equation modeling analyses indicated that a variety of developmental experiences were related to various mental toughness components, with initiative experiences evidencing the strongest overall relationship with mental toughness followed by negative peer influences. The number of years playing experience and hours per week training evidenced largely insignificant relationships with the exception of desire to achieve and attentional control components of mental toughness, as well as its global factor. Collectively, these findings lend support for the validity of the CMTI as a valid measure among adolescent cricketers, and highlight the importance of initiative and interpersonal experiences for mental toughness in cricket. PMID- 21659670 TI - Tripartite efficacy profiles: a cluster analytic investigation of athletes' perceptions of their relationship with their coach. AB - Recent studies of coach-athlete interaction have explored the bivariate relationships between each of the tripartite efficacy constructs (self-efficacy; other-efficacy; relation-inferred self-efficacy, or RISE) and various indicators of relationship quality. This investigation adopted an alternative approach by using cluster analyses to identify tripartite efficacy profiles within a sample of 377 individual sport athletes (Mage = 20.25, SD = 2.12), and examined how individuals in each cluster group differed in their perceptions about their relationship with their coach (i.e., commitment, satisfaction, conflict). Four clusters emerged: High (n = 128), Moderate (n = 95), and Low (n = 78) profiles, in which athletes reported relatively high, moderate, or low scores across all tripartite perceptions, respectively, as well as an Unfulfilled profile (n = 76) in which athletes held relatively high self-efficacy, but perceived lower levels of other-efficacy and RISE. Multivariate analyses revealed differences between the clusters on all relationship variables that were in line with theory. These results underscore the utility of considering synergistic issues in the examination of the tripartite efficacy framework. PMID- 21659671 TI - Measuring athlete imagery ability: the sport imagery ability questionnaire. AB - This research aimed to develop and provide initial validation of the Sport Imagery Ability Questionnaire (SIAQ). The SIAQ assesses athletes' ease of imaging different types of imagery content. Following an extensive pilot study, 375 athletes completed a 20-item SIAQ in Study 1. Exploratory factor analysis revealed a 4-factor model assessing skill, strategy, goal, and affect imagery ability. Confirmatory factor analysis (CFA) established this 4-factor structure in Study 2 (N = 363 athletes). In Study 3 (N = 438 athletes), additional items were added to create a fifth mastery imagery subscale that was confirmed through CFA. Study 4 (N = 220 athletes) compared the SIAQ to the Movement Imagery Questionnaire-3. Significant bivariate correlations (p < .05) confirmed the SIAQ's concurrent validity but demonstrated differences in imagery ability of different content. Overall, the SIAQ demonstrates good factorial validity, internal and temporal reliability, invariance across gender, and an ability to distinguish among athletes of different competitive levels. Findings highlight the importance of separately assessing imagery ability of different content. PMID- 21659672 TI - Self-presentation origins of choking: evidence from separate pressure manipulations. AB - Whether self-presentation is involved in the choking process remains unknown. The purpose of the current study was to determine the role of self-presentation concerns on the frequency of choking within the context of a recently proposed self-presentation model. Experienced field hockey players (N = 45) were randomly assigned to one of five groups (i.e., performance-contingent monetary incentive, video camera placebo, video camera self-presentation, audience, or combined pressure), before taking penalty strokes in low- and high-pressure phases. Results indicated that groups exposed to self-presentation manipulations experienced choking, whereas those receiving motivational pressure treatments decreased anxiety and increased performance under pressure. Furthermore, cognitive state anxiety mediated the relationship between the self-presentation group and performance. These findings provide quantitative support for the proposed self-presentation model of choking, while also holding implications for anxiety manipulations in future sport psychology research. PMID- 21659673 TI - Perception of coaching behaviors, coping, and achievement in a sport competition. AB - This study examined the relationship between perceived coaching behaviors, coping strategies during a sport competition, and sport achievement. A prospective design was used in which 80 athletes from individual sports completed measures of perceived coaching behaviors two days before a competition (Time 1) and measures of coping and sport achievement within three hours after a sport competition (Time 2). As expected, results of multiple regressions indicated that supportive coaching was a positive predictor of task-oriented coping and sport achievement whereas unsupportive coaching was a positive predictor of disengagement-oriented coping. Both types of coping were significantly associated with sport achievement. Task-oriented coping was a significant partial mediator in the relation between supportive coaching and sport achievement. This study, which contributes to both the coaching and coping literatures, highlights the role of supportive coaching behaviors in the initiation of effective stress management during sport competitions. PMID- 21659674 TI - [Harvest as we sow]. PMID- 21659676 TI - [Spontaneous subarachnoid haemorrhage--review]. AB - Spontaneous subarachnoid hemorrhage is a bleeding in to the subarachnoid space without trauma. Aneurysms are the underlying cause in 80% of the cases. Among other causes are: arteriovenous malformations, anticoagulation, vasculitis or brain tumor. Spontaneous subarachnoid hemorrhage is a serious disease, where up to half of the patients die. Of those who survive, only half return to work and many have a reduced quality of life. To prevent rebleeding the aneurysm is closed either with endovascular coiling or neurosurgical clipping. PMID- 21659675 TI - [Phenylketonuria (PKU) in Iceland]. AB - INTRODUCTION: PKU is a metabolic disorder caused by a mutation in the phenylalanine hydroxylase (PAH) gene. Icelandic neonatal screening for PKU started in 1972. The mutation causes a variable [corrected] dysfunction in PAH, that metabolizes phenylalanine (Phe) to tyrosine (Tyr) with the cofactor tetrahydrobiopterin (BH4). Accumulation of Phe causes mental retardation and seizures. Current therapy focuses on Phe-restrictive diet and newer methods like BH4 in large doses. The primary aim was to collect data about PKU in Iceland and evaluate therapy and screening. Additional focus was on BH4 therapy. MATERIALS AND METHODS: Information was gathered from Landspitali medical charts retrospectively. Serum-Phe (S-Phe) measurements, age at initiation of therapy, PAH mutation types and information on current therapy was collected. RESULTS from BH4 loading tests were collected. RESULTS: 27 patients have been diagnosed with PKU in Iceland since 1947. Incidence 1972-2008 is 1/8400 living births. Classic PKU is the most common presentation in Iceland. Patients diagnosed after screening started have normal intelligence. Age at initiation of therapy and S Phe average values lower with time. 12 PAH mutation types have been found in Iceland. A novel Icelandic mutation, Y377fsdelT, did not respond to BH4 loading test. Two patients responded to a BH4 loading test and four other patients are likely to respond to BH4 loading test. CONCLUSION: PKU incidence in Iceland is slightly higher than in neighboring countries. Therapy compliance is adequate and international consensuses regarding therapy are met. PKU patients in Iceland are generally in good health. Screening is efficient and save. BH4 therapy is a an optional alternative therapy in Iceland. PMID- 21659677 TI - Fusing multiview and photometric stereo for 3D reconstruction under uncalibrated illumination. AB - We propose a method to obtain a complete and accurate 3D model from multiview images captured under a variety of unknown illuminations. Based on recent results showing that for Lambertian objects, general illumination can be approximated well using low-order spherical harmonics, we develop a robust alternating approach to recover surface normals. Surface normals are initialized using a multi-illumination multiview stereo algorithm, then refined using a robust alternating optimization method based on the l(1) metric. Erroneous normal estimates are detected using a shape prior. Finally, the computed normals are used to improve the preliminary 3D model. The reconstruction system achieves watertight and robust 3D reconstruction while neither requiring manual interactions nor imposing any constraints on the illumination. Experimental results on both real world and synthetic data show that the technique can acquire accurate 3D models for Lambertian surfaces, and even tolerates small violations of the Lambertian assumption. PMID- 21659678 TI - Representativity for robust and adaptive multiple importance sampling. AB - We present a general method enhancing the robustness of estimators based on multiple importance sampling (MIS) in a numerical integration context. MIS minimizes variance of estimators for a given sampling configuration, but when this configuration is less adapted to the integrand, the resulting estimator suffers from extra variance. We address this issue by introducing the notion of "representativity" of a sampling strategy, and demonstrate how it can be used to increase robustness of estimators, by adapting them to the integrand. We first show how to compute representativities using common rendering informations such as BSDF, photon maps, or caches in order to choose the best sampling strategy for MIS. We then give hints to generalize our method to any integration problem and demonstrate that it can be used successfully to enhance robustness in different common rendering algorithms. PMID- 21659679 TI - Fast exact nearest patch matching for patch-based image editing and processing. AB - This paper presents an efficient exact nearest patch matching algorithm which can accurately find the most similar patch-pairs between source and target image. Traditional match matching algorithms treat each pixel/patch as an independent sample and build a hierarchical data structure, such as kd-tree, to accelerate nearest patch finding. However, most of these approaches can only find approximate nearest patch and do not explore the sequential overlap between patches. Hence, they are neither accurate in quality nor optimal in speed. By eliminating redundant similarity computation of sequential overlap between patches, our method finds the exact nearest patch in brute-force style but reduces its running time complexity to be linear on the patch size. Furthermore, relying on recent multicore graphics hardware, our method can be further accelerated by at least an order of magnitude (>=10*). This greatly improves performance and ensures that our method can be efficiently applied in an interactive editing framework for moderate-sized image even video. To our knowledge, this approach is the fastest exact nearest patch matching method for high-dimensional patch and also its extra memory requirement is minimal. Comparisons with the popular nearest patch matching methods in the experimental results demonstrate the merits of our algorithm. PMID- 21659680 TI - Hierarchical line integration. AB - This paper presents an acceleration scheme for the numerical computation of sets of trajectories in vector fields or iterated solutions in maps, possibly with simultaneous evaluation of quantities along the curves such as integrals or extrema. It addresses cases with a dense evaluation on the domain, where straightforward approaches are subject to redundant calculations. These are avoided by first calculating short solutions for the whole domain. From these, longer solutions are then constructed in a hierarchical manner until the designated length is achieved. While the computational complexity of the straightforward approach depends linearly on the length of the solutions, the computational cost with the proposed scheme grows only logarithmically with increasing length. Due to independence of subtasks and memory locality, our algorithm is suitable for parallel execution on many-core architectures like GPUs. The trade-offs of the method--lower accuracy and increased memory consumption--are analyzed, including error order as well as numerical error for discrete computation grids. The usefulness and flexibility of the scheme are demonstrated with two example applications: line integral convolution and the computation of the finite-time Lyapunov exponent. Finally, results and performance measurements of our GPU implementation are presented for both synthetic and simulated vector fields from computational fluid dynamics. PMID- 21659684 TI - Magnetic properties of nanomagnetic and biomagnetic systems analyzed using cantilever magnetometry. AB - Magnetic properties of nanomagnetic and biomagnetic systems are investigated using cantilever magnetometry. In the presence of a magnetic field, magnetic films or particles deposited at the free end of a cantilever give rise to a torque on the mechanical sensor, which leads to frequency shifts depending on the applied magnetic field. From the frequency response, the magnetic properties of a magnetic sample are obtained. The magnetic field dependences of paramagnetic and ferromagnetic thin films and particles are measured in a temperature range of 5 320 K at a pressure below 10(-6) mbar. We present magnetic properties of the ferromagnetic materials Fe, Co and Ni at room temperature and also for the rare earth elements Gd, Dy and Tb at various temperatures. In addition, the magnetic moments of magnetotactic bacteria are measured under vacuum conditions at room temperature. Cantilever magnetometry is a highly sensitive tool for characterizing systems with small magnetic moments. By reducing the cantilever dimensions the sensitivity can be increased by an order of magnitude. PMID- 21659685 TI - Biexciton emission and crystalline quality of ZnO nano-objects. AB - The design of cost-effective standards for the quality of nano-objects is currently a key issue toward their massive use for optoelectronic applications. The observation by photoluminescence of narrow excitonic and biexcitonic emission lines in semiconductor nanowires is usually accepted as evidence for high structural quality. Here, we perform time-resolved cathodoluminescence experiments on isolated ZnO nanobelts grown by chemical vapor deposition. We observe narrow emission lines at low temperature, together with a clear biexciton line. Still, drastic alterations in both the CL intensity and lifetime are observed locally along the nano-object. We attribute these to non-radiative recombinations at edge dislocations, closing basal plane stacking faults, inhomogeneously distributed along the NB length. This leads us to the conclusion that the observation of narrow excitonic and biexcitonic emission lines is far from sufficient to grade the quality of a nano-object. PMID- 21659686 TI - The effect of the concentration and oxidation state of Sn on the structural and electrical properties of indium tin oxide nanowires. AB - High quality single-crystalline indium tin oxide (ITO) nanowires with controlled Sn contents of up to 32.5 at.% were successfully synthesized via a thermal metal co-evaporation method, based on a vapor-liquid-solid growth mode, at a substrate temperature of as low as 540 degrees C. The high solubility of Sn in the nanowires was explained with the existence of Sn(2+) ions along with Sn(4+) ions: the coexistence of Sn(2+) and Sn(4+) ions facilitated their high substitutional incorporation into the In(2)O(3) lattice by relaxing structural and electrical disturbances due to the differences in ionic radii and electrical charges between Sn and In(3+) ions. It was revealed that, while the lattice parameter of the ITO nanowires had a minimum value at a Sn content of 6.3 at.%, the electrical resistivity had a minimum value of about 10(-3) Omega cm at a Sn content of 14 at.%. These structural and electrical behaviors were explained by variation in the relative and total amounts of the two species, Sn(2+) and Sn(4+). PMID- 21659687 TI - Temperature effect on electrospinning of nanobelts: the case of hafnium oxide. AB - Electrospinning is a convenient and versatile method for fabricating different kinds of one-dimensional nanostructures such as nanofibres, nanotubes and nanobelts. Environmental parameters have a great influence on the electrospinning nanostructure. Here we report a new method to fabricate hafnium oxide (HfO(2)) nanobelts. HfO(2) nanobelts were prepared by electrospinning a sol-gel solution with the implementation of heating and subsequent calcination treatment. We investigate the temperature dependence of the products by scanning electron microscopy (SEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and energy-dispersive x-ray (EDX) spectroscopy. The heating temperature of spinning ambient is found to be crucial to the formation of HfO(2) nanobelts. By tuning the temperature, the morphological transformation of HfO(2) from nanowires to nanobelts was achieved. It was found that the rapid evaporation of solvent played an important role in the formation process of HfO(2) nanobelts. It is shown that nanobelts can only be obtained with the temperature higher than 50 degrees C and they are in the high quality monoclinic phase. A possible growth mechanism of the nanobelts based on phase separation is proposed. The enhanced photoluminescence (PL) of HfO(2):Eu(3+) nanobelts is also illustrated. PMID- 21659688 TI - Direct observation of enhanced cathodoluminescence emissions from ZnO nanocones compared with ZnO nanowire arrays. AB - We report, for the first time, direct observation of enhanced cathodoluminescence (CL) emissions from ZnO nanocones (NCs) compared with ZnO nanowires (NWs). For direct and unambiguous comparison of CL emissions from NWs and nanocones, periodic arrays of ZnO NW were converted to nanocone arrays by our unique HCl [aq] etching technique, enabling us to compare the CL emissions from original NWs and final nanocones at the same location. CL measurements on NW and nanocone arrays reveal that emission intensity of the nanocone at ~ 387 nm is over two times larger than that of NW arrays. The enhancement of CL emission from nanocones has been confirmed by finite-difference time-domain simulation of enhanced light extraction from ZnO nanocones compared to ZnO NWs. The enhanced CL from nanocones is attributed to its sharp morphology, resulting in more chances of photons to be extracted at the interface between ZnO and air. PMID- 21659689 TI - Synthesis of WS2 nanostructures from the reaction of WO3 with CS2 and mechanical characterization of WS2 nanotube composites. AB - Tungsten disulfide (WS(2)) nanometer sheets, spheres, fibers and tubes were generated by a synthetic pathway that avoids the use of H(2)S as the source of sulfur and employs instead CS(2) vapor, carried by an Ar or N(2)/H(2) stream in a heated tubular furnace, for the reaction with WO(3) precursor powders. The experiments were conducted at temperatures between 700 and 1000 degrees C, while the reaction times expanded between 30 min and 24 h. Characterization methods used to analyze the products of the synthesis include TEM, SEM, XRD and EDX. We found a strong correlation between precursor and product microstructure, although the temperature and reaction times play a critical role in the products' microstructural features as well. WS(2) inorganic fullerene (IF) nanospheres are generated in a wide window of conditions, while nanotubes and nanofibers are only produced at high temperatures or long reaction times. A proposed growth mechanism based on the CS(2) synthetic approach is presented. Nanoindentation and nano impulse techniques were used to characterize the mechanical properties of polymer matrix-WS(2) nanotube composites, finding them superior to equivalent SWCNT composites. The improvements in toughness of nanocomposites based on WS(2) can be attributed to geometrical and morphological effects that assisted several toughening mechanisms such as crack pinning and the formation of an immobilized polymeric interphase around the nanotubes. PMID- 21659690 TI - The effect of Fe3O4 nanoparticles on the thermal conductivities of various base fluids. AB - Conventional heat transfer fluids have intrinsically poor heat transfer properties compared to solids. Enhancing the efficiency of heat transfer is of great interest for various industrial applications. Suspending solid particles in a fluid increases the thermal conductivity of the resulting suspension and enhances the heat transfer properties. In this work, changes in thermal conductivities of fluids upon the addition of magnetic nanoparticles have been investigated. Fe(3)O(4) nanoparticles are synthesized using different synthesis methods and are suspended in various oils. The effect of the base fluid and the type of magnetic particle on the thermal conductivity is investigated in detail. Up to 28% increase in the thermal conductivity is obtained with 2.5 wt% magnetic particles in hexane. The thermal conductivity enhancement is found to depend on the particle concentration, method of preparation and base fluid. The enhancements obtained are higher than those estimated using any theoretical model present in the literature. PMID- 21659691 TI - A quadruple-scanning-probe force microscope for electrical property measurements of microscopic materials. AB - Four-terminal electrical measurement is realized on a microscopic structure in air, without a lithographic process, using a home-built quadruple-scanning-probe force microscope (QSPFM). The QSPFM has four probes whose positions are individually controlled by obtaining images of a sample in the manner of atomic force microscopy (AFM), and uses the probes as contacting electrodes for electrical measurements. A specially arranged tuning fork probe (TFP) is used as a self-detection force sensor to operate each probe in a frequency modulation AFM mode, resulting in simultaneous imaging of the same microscopic feature on an insulator using the four TFPs. Four-terminal electrical measurement is then demonstrated in air by placing each probe electrode in contact with a graphene flake exfoliated on a silicon dioxide film, and the sheet resistance of the flake is measured by the van der Pauw method. The present work shows that the QSPFM has the potential to measure the intrinsic electrical properties of a wide range of microscopic materials in situ without electrode fabrication. PMID- 21659692 TI - Rapid and precise scanning helium ion microscope milling of solid-state nanopores for biomolecule detection. AB - We report the formation of solid-state nanopores using a scanning helium ion microscope. The fabrication process offers the advantage of high sample throughput along with fine control over nanopore dimensions, producing single pores with diameters below 4 nm. Electronic noise associated with ion transport through the resultant pores is found to be comparable with levels measured on devices made with the established technique of transmission electron microscope milling. We demonstrate the utility of our nanopores for biomolecular analysis by measuring the passage of double-strand DNA. PMID- 21659693 TI - Local structural investigation of SmFeAsO1-xF(x) high temperature superconductors. AB - A strong revitalization of the field of high temperature superconductivity (HTSC) has been induced recently by the discovery of T(C) around 26 K in F-doped LaFeAsO iron pnictides. Starting from this discovery, a huge amount of experimental data have been accumulated. This important corpus of results will allow the development of suitable theoretical models aimed at describing the basic electronic structure properties and nature of superconducting states in these fascinating new systems. A close correlation between structural features and physical properties of the normal and superconducting states has already been demonstrated in the current literature. Advanced theoretical models are also based on the close correlation with structural properties and in particular with the Fe-As tetrahedral array. As for other complex materials, a deeper understanding of their structure-properties correlation requires a full knowledge of the atomic arrangement within the structure. Here we report an investigation of the local structure in the SmFeAsO1- xF(x) system carried out by means of x ray total scattering measurements and pair distribution function analysis. The results presented indicate that the local structure of these HTSC significantly differs from the average structure determined by means of traditional diffraction techniques, in particular the distribution of Fe-As bond lengths. In addition, a model for describing the observed discrepancies is presented. PMID- 21659694 TI - Silica through the eyes of colloidal models--when glass is a gel. AB - We perform molecular dynamics simulations of 'floating bond' (FB) models of network-forming liquids and compare the structure and dynamics against the BKS model of silica (van Beest et al 1990 Phys. Rev. Lett. 64 1955), with the aim of gaining a better understanding of glassy silica in terms of the variety of non ergodic states seen in colloids. At low densities, all the models form tetrahedral networks. At higher densities, tailoring the FB model to allow a higher number of bonds does not capture the structure seen in BKS. Upon rescaling the time and length in order to compare mean squared displacements between models, we find that there are significant differences in the temperature dependence of the diffusion coefficient at high density. Additionally, the FB models show a greater range in variability in the behavior of the non-ergodicity parameter and caging length, quantities used to distinguish colloidal gels and glasses. Hence, we find that the glassy behavior of BKS silica can be interpreted as a 'gel' at low densities, with only a marginal gel-to-glass crossover at higher densities. PMID- 21659695 TI - Iterative N-way partial least squares for a binary self-paced brain-computer interface in freely moving animals. AB - In this paper a tensor-based approach is developed for calibration of binary self paced brain-computer interface (BCI) systems. In order to form the feature tensor, electrocorticograms, recorded during behavioral experiments in freely moving animals (rats), were mapped to the spatial-temporal-frequency space using the continuous wavelet transformation. An N-way partial least squares (NPLS) method is applied for tensor factorization and the prediction of a movement intention depending on neuronal activity. To cope with the huge feature tensor dimension, an iterative NPLS (INPLS) algorithm is proposed. Computational experiments demonstrated the good accuracy and robustness of INPLS. The algorithm does not depend on any prior neurophysiological knowledge and allows fully automatic system calibration and extraction of the BCI-related features. Based on the analysis of time intervals preceding the BCI events, the calibration procedure constructs a predictive model of control. The BCI system was validated by experiments in freely moving animals under conditions close to those in a natural environment. PMID- 21659696 TI - Optimized multi-electrode stimulation increases focality and intensity at target. AB - Transcranial direct current stimulation (tDCS) provides a non-invasive tool to elicit neuromodulation by delivering current through electrodes placed on the scalp. The present clinical paradigm uses two relatively large electrodes to inject current through the head resulting in electric fields that are broadly distributed over large regions of the brain. In this paper, we present a method that uses multiple small electrodes (i.e. 1.2 cm diameter) and systematically optimize the applied currents to achieve effective and targeted stimulation while ensuring safety of stimulation. We found a fundamental trade-off between achievable intensity (at the target) and focality, and algorithms to optimize both measures are presented. When compared with large pad-electrodes (approximated here by a set of small electrodes covering 25 cm(2)), the proposed approach achieves electric fields which exhibit simultaneously greater focality (80% improvement) and higher target intensity (98% improvement) at cortical targets using the same total current applied. These improvements illustrate the previously unrecognized and non-trivial dependence of the optimal electrode configuration on the desired electric field orientation and the maximum total current (due to safety). Similarly, by exploiting idiosyncratic details of brain anatomy, the optimization approach significantly improves upon prior un-optimized approaches using small electrodes. The analysis also reveals the optimal use of conventional bipolar montages: maximally intense tangential fields are attained with the two electrodes placed at a considerable distance from the target along the direction of the desired field; when radial fields are desired, the maximum intensity configuration consists of an electrode placed directly over the target with a distant return electrode. To summarize, if a target location and stimulation orientation can be defined by the clinician, then the proposed technique is superior in terms of both focality and intensity as compared to previous solutions and is thus expected to translate into improved patient safety and increased clinical efficacy. PMID- 21659697 TI - The effect of fluoride surface modification of ceramic TiO2 on the surface properties and biological response of osteoblastic cells in vitro. AB - This study investigates the effect of fluoride surface modification on the surface properties of polycrystalline ceramic TiO(2) and the biological response of murine osteoblast cells to fluoride-modified TiO(2) in vitro. Fluoride concentrations up to 9 at.% were detected and the fluoride was found to bind to the surface in a ligand exchange reaction between surface hydroxyl groups and the fluoride anions from the HF. No significant changes in the surface topography were detected. In vitro experiments were performed in order to evaluate the biological response of the MC3T3-E1 cells to the fluoride-modified ceramic TiO(2) surfaces. No difference in the lactate dehydrogenase (LDH) activity was seen in comparison to unmodified samples, apart from the highest fluoride concentration (~9 at.%) which was found to be more toxic to the cells. Real-time PCR analysis showed no conclusive evidence for the fluoride-induced promotion of osteoblast differentiation as no significant increase in the collagen-1, osteocalcin, or BMP 2 mRNA levels was detected on the fluoride-modified ceramic TiO(2) surfaces apart from one group, which showed an elevated osteocalcin level and higher number of cells. Since the observed grain boundary corrosion is also anticipated to reduce the mechanical properties of ceramic TiO(2), this surface modification method may not be an ideal method for improving the osteogenic response of ceramic TiO(2) scaffolds. PMID- 21659698 TI - Synthetical bone-like and biological hydroxyapatites: a comparative study of crystal structure and morphology. AB - Phase composition, crystal structure and morphology of biological hydroxyapatite (BHAp) extracted from human mandible bone, and carbonated hydroxyapatite (CHAp), synthesized by the chemical precipitation method, were studied by x-ray powder diffraction (XRD), Fourier transform infrared (FTIR) and Raman (R) spectroscopy techniques, combined with transmission electron microscopy (TEM). Structural and microstructural parameters were determined through Rietveld refinement of recorded XRD data, performed using the FullProf computing program, and TEM. Microstructural analysis shows anisotropic extension along the [00l] crystallographic direction (i.e. elongated crystallites shape) of both investigated samples. The average crystallite sizes of 10 and 8 nm were estimated for BHAp and CHAp, respectively. The FTIR and R spectroscopy studies show that carbonate ions substitute both phosphate and hydroxyl ions in the crystal structure of BHAp as well as in CHAp, indicating that both of them are mixed AB type of CHAp. The thermal behaviour and carbonate content were analysed using thermogravimetric and differential thermal analysis. The carbonate content of about 1 wt.% and phase transition, at near 790 degrees C, from HAp to beta tricalcium phosphate were determined in both samples. The quality of synthesized CHAp powder, particularly, the particle size distribution and uniformity of morphology, was analysed by a particle size analyser based on laser diffraction and field emission scanning electron microscopy, respectively. These data were used to discuss similarity between natural and synthetic CHAp. Good correlation between the unit cell parameters, average crystallite size, morphology, carbonate content and crystallographic positions of carbonate ions in natural and synthetic HAp samples was found. PMID- 21659717 TI - Concomitant carcinoma in situ in cystectomy specimens is not associated with clinical outcomes after surgery. AB - OBJECTIVE: The aim of this study was to externally validate the prognostic value of concomitant urothelial carcinoma in situ (CIS) in radical cystectomy (RC) specimens using a large international cohort of bladder cancer patients. METHODS: The records of 3,973 patients treated with RC and bilateral lymphadenectomy for urothelial carcinoma of the bladder (UCB) at nine centers worldwide were reviewed. Surgical specimens were evaluated by a genitourinary pathologist at each center. Uni- and multivariable Cox regression models addressed time to recurrence and cancer-specific mortality after RC. RESULTS: 1,741 (43.8%) patients had concomitant CIS in their RC specimens. Concomitant CIS was more common in organ-confined UCB and was associated with lymphovascular invasion (p < 0.001). Concomitant CIS was not associated with either disease recurrence or cancer-specific death regardless of pathologic stage. The presence of concomitant CIS did not improve the predictive accuracy of standard predictors for either disease recurrence or cancer-specific death in any of the subgroups. CONCLUSIONS: We could not confirm the prognostic value of concomitant CIS in RC specimens. This, together with the discrepancy between pathologists in determining the presence of concomitant CIS at the morphologic level, limits the clinical utility of concomitant CIS in RC specimens for clinical decision-making. PMID- 21659716 TI - Cytomegalovirus: pathogen, paradigm, and puzzle. AB - Human cytomegalovirus (CMV), one of the eight herpesviruses that commonly infect humans, is best known for its propensity to cause disease in immunocompromised patients, especially transplant recipients, patients with advanced AIDS, and congenitally infected newborns. Advances in molecular virology coupled with improvements in diagnostic methods and treatment options have vastly improved our understanding of and ability to manage CMV, but many uncertainties remain, including the mechanisms of persistence and pathogenesis and its hypothesized roles in a variety of human illnesses. Here we review recent advances that are reshaping our view and approach to this fascinating virus. PMID- 21659718 TI - Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: comparison between JI-8 and 7-nitroindazole. AB - Cerebral palsy and death are serious consequences of perinatal hypoxia-ischemia (HI). Important concepts can now be tested using an animal model of cerebral palsy. We have previously shown that reactive oxygen and nitrogen species are produced in antenatal HI. A novel class of neuronal nitric oxide synthase (nNOS) inhibitors have been designed, and they ameliorate postnatal motor deficits when administered prior to the hypoxic-ischemic insult. This study asks how the new class of inhibitors, using JI-8 (K(i) for nNOS: 0.014 MUM) as a representative, compare with the frequently used nNOS inhibitor 7-nitroindazole (7-NI; K(i): 0.09 +/- 0.024 MUM). A theoretical dose equivalent to 75 K(i) of JI-8 or equimolar 7 NI was administered to pregnant rabbit dams 30 min prior to and immediately after 40 min of uterine ischemia at 22 days gestation (70% term). JI-8 treatment resulted in a significant decrease in NOS activity (39%) in fetal brain homogenates acutely after HI, without affecting maternal blood pressure and heart rate. JI-8 treatment resulted in 33 normal kits, 2 moderately and 13 severely affected kits and 5 stillbirths, compared with 8 normal, 3 moderately affected and 5 severely affected kits and 10 stillbirths in the 7-NI group. In terms of neurobehavioral outcome, 7-NI was not different from saline treatment, while JI-8 was superior to saline and 7-NI in its protective effect (p < 0.05). In the surviving kits, JI-8 significantly improved the locomotion score over both saline and 7-NI scores. JI-8 was also significantly superior to saline in preserving smell, muscle tone and righting reflex function, but 7-NI did not show significant improvement. Furthermore, a 100-fold increase in the dose (15.75 MUmol/kg) of 7-NI significantly decreased systolic blood pressure in the dam, while JI-8 did not. The new class of inhibitors such as JI-8 shows promise in the prevention of cerebral palsy and is superior to the previously more commonly used nNOS inhibitor. PMID- 21659719 TI - Deleterious effect of hyperoxia at birth on white matter damage in the newborn rat. AB - White matter damage (WMD) remains the leading cause of cerebral palsy in children born prematurely. The release of an excessive amount of reactive oxygen species is recognized as a risk factor for WMD. We hypothesize that free radical injury during reoxygenation at birth may be harmful to the immature white matter and may underlie, at least in part, the pathogenesis of WMD. We tested this hypothesis in rat pups delivered from normoxic pregnant rats, and by investigating an animal model based on protracted antenatal hypoxia in the pregnant rat and mimicking the main features of human WMD in rat pups. From embryonic day (E)5 to E21, the pregnant rats were placed in a chamber supplied with a gas mixture that either induced hypoxia (FiO(2) = 10%) or maintained normoxia (FiO(2) = 21%). On E21, the dams were removed from the chamber and housed under either normoxia (FiO(2) = 21%), hyperoxia (FiO(2) = 60%) or slowly reoxygenated (FiO(2) from 15% at E21 to 21% at postnatal day 7). Postnatal hyperoxia was associated with a significantly increased density of activated microglial cells (+105%) and TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling)-positive cells (+85%) within the developing white matter. Myelin content (-31%) and mature oligodendrocyte density (-37%) in the normal developing white matter were significantly decreased by postnatal hyperoxia. Postnatal hyperoxia significantly potentiated the myelination delay and oligodendroglial dysmaturation induced by antenatal hypoxia. In contrast, progressive reoxygenation at birth did not induce any change in white matter inflammation, myelination and cell death as compared with normoxic controls, and prevented most of the WMD observed following antenatal hypoxia. This study demonstrates a deleterious effect of hyperoxia at birth on the developing white matter in normal rat pups. Postnatal hyperoxia worsened the WMD induced by antenatal hypoxia. Hyperoxia at birth should be avoided in preterm infants at risk of WMD. PMID- 21659721 TI - Serum insulin, cortisol, leptin, neuropeptide Y, galanin and ghrelin levels in epileptic children receiving valproate. AB - AIMS: The objective of this study was to investigate the cause of valproate (VPA) associated weight gain in children. METHODS: Eighteen children (10.94 +/- 3.78 years) with epilepsy were assigned to VPA therapy. Serum levels of glucose, insulin, cortisol, leptin, neuropeptide Y (NPY), galanin and ghrelin were assessed before (month 0) and after 18 months of therapy. Eighteen age- and gender-matched patients (10.78 +/- 3.95 years) were enrolled as the control group. RESULTS: Excess per capita weight of 2.3 kg was determined in the children receiving VPA over 18 months compared to the control group. In these patients, a statistically significant increase in standardized weight score, Homeostasis Model Assessment index, serum leptin, NPY and galanin values was determined at the 18th month compared to those before VPA treatment and in the control group, and there was also a significant decrease in ghrelin values. CONCLUSION: Increased serum levels of leptin, NPY and galanin play an important role in VPA associated weight gain in children. While ghrelin is not directly associated with weight gain, its serum levels decline as a response to weight gain. PMID- 21659722 TI - Effect of nilotinib on bleomycin-induced acute lung injury and pulmonary fibrosis in mice. AB - BACKGROUND: The tyrosine kinase inhibitor imatinib mesylate was developed as an inhibitor of the kinase activity of BCR-ABL. However, imatinib also has potent inhibitory activity against the platelet-derived growth factor receptor (PDGFR). Nilotinib is approved for treating patients with chronic myeloid leukemia showing resistance or intolerance to imatinib. Like imatinib, nilotinib selectively inhibits the tyrosine kinase activity of PDGFR. OBJECTIVES: We examined the effect of imatinib and nilotinib on acute lung injury and pulmonary fibrosis in a mouse model. METHODS: Mice were treated by intratracheal instillation of bleomycin. Imatinib or nilotinib were administered by oral gavage. To study the early inflammatory and late fibrotic phases of lung injury, mice were sacrificed on days 3, 7, 14 and 21 after bleomycin instillation. RESULTS: Histopathology showed that imatinib and nilotinib attenuated the extent of lung injury and fibrosis. The numbers of inflammatory cells and levels of IL-6, IL-1beta and tumor necrosis factor-alpha were decreased in the imatinib and nilotinib groups on days 3 and 7. Imatinib and nilotinib therapy significantly reduced the levels of hydroxyproline on days 14 and 21, which was accompanied by decreased expression levels of transforming growth factor (TGF)-beta1 and PDGFR-beta. Imatinib and nilotinib also significantly reduced the expression levels of the genes for TGF-beta1 and platelet-derived growth factor (PDGF). Imatinib and nilotinib treatment also significantly inhibited the PDGF-induced proliferation of lung fibroblasts in vitro. When imatinib or nilotinib was given 7 days after the instillation of bleomycin, only nilotinib attenuated pulmonary fibrosis. CONCLUSIONS: Imatinib and nilotinib attenuated bleomycin-induced acute lung injury and pulmonary fibrosis in mice. In a therapeutic model, nilotinib showed more potent antifibrotic effects than imatinib. PMID- 21659720 TI - Perinatal asphyxia in a nonhuman primate model. AB - Perinatal asphyxia is a leading cause of brain injury in neonates, occurring in 2 4 per 1,000 live births, and there are limited treatment options. Because of their similarity to humans, nonhuman primates are ideal for performing preclinical tests of safety and efficacy for neurotherapeutic interventions. We previously developed a primate model of acute perinatal asphyxia using 12-15 min of umbilical cord occlusion. Continuing this research, we have increased cord occlusion time from 15 to 18 min and extended neurodevelopmental follow-up to 9 months. The purpose of this report is to evaluate the increase in morbidity associated with 18 min of asphyxia by comparing indices obtained from colony controls, nonasphyxiated controls and asphyxiated animals. Pigtail macaques were delivered by hysterotomy after 0, 15 or 18 min of cord occlusion, then resuscitated. Over the ensuing 9 months, for each biochemical and physiologic parameters, behavioral and developmental evaluations, and structural and spectroscopic MRI were recorded. At birth, all asphyxiated animals required resuscitation with positive pressure ventilation and exhibited biochemical and clinical characteristics diagnostic of hypoxic-ischemic encephalopathy, including metabolic acidosis and attenuated brain activity. Compared with controls, asphyxiated animals developed long-term physical and cognitive deficits. This preliminary report characterizes the acute and chronic consequences of perinatal asphyxia in a nonhuman primate model, and describes diagnostic imaging tools for quantifying correlates of neonatal brain injury as well as neurodevelopmental tests for evaluating early motor and cognitive outcomes. PMID- 21659723 TI - Transcranial sonography reveals cerebellar, nigral, and forebrain abnormalities in Friedreich's ataxia. AB - BACKGROUND: Friedreich's ataxia (FA) is essentially characterized by degeneration of the dorsal root ganglia, the dorsal nuclei of Clarke, and the long spinal fiber tracts, yet there is accumulating evidence that neurodegeneration extends beyond these predilection sites. Transcranial sonography (TCS) has evolved as a valuable complementary neuroimaging tool in the assessment of neurodegenerative diseases due to its capacity to well depict structural changes and the accumulation of heavy metals. Its use for assessing cerebellar neurodegeneration, however, has not yet been investigated.Here we investigated whether TCS allows to assess particular features of cerebellar as well as midbrain and forebrain abnormalities in FA. METHODS: Comprehensive TCS imaging of 34 FA patients and 34 age-matched healthy controls. RESULTS: Hyperechogenicity of the dentate nucleus was very frequent in FA patients (85%) and could even be observed in patients with short disease duration, suggesting that dentate alterations are a common and probably early feature of FA. Substantia nigra was significantly hypoechogenic, possibly indicating regional changes in subcellular brain iron regulation. FA patients showed significantly enlarged 4th, 3rd, and lateral ventricles, thus corroborating earlier MRI and postmortem findings of substantial cerebellar and forebrain atrophy in FA. CONCLUSIONS: TCS provides a quick-to-apply and inexpensive in vivo assessment of both cerebellar and noncerebellar abnormalities in FA, in particular highlighting dentate hyperechogenicity as a core feature. It might serve as a promising tool for imaging aspects of cerebellar neurodegeneration also in other neurodegenerative disorders. PMID- 21659724 TI - Corpus callosum atrophy in patients with mild Alzheimer's disease. AB - BACKGROUND/OBJECTIVES: Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain, such as age-related white matter changes (ARWMC) and progression of the disease. METHODS: Twenty-eight patients in the early stages of AD and 50 non-demented elderly subjects with varying degrees of ARWMC were investigated using MRI. The CC was assessed semi-automatically, and ARWMC were rated according to the Fazekas scale. RESULTS: A significant difference in posterior CC size could be detected between non-demented elderly subjects and early stage AD patients. The sizes of the total CC, rostral body and splenium at baseline were correlated with change from baseline MMSE score after a 1-year follow-up in AD patients. There was no association between CC size and ARWMC. CONCLUSIONS: The present findings indicate that posterior CC atrophy is present in mild AD independently of ARWMC. Furthermore, CC atrophy may be associated with cognitive deterioration. PMID- 21659727 TI - Iron chelation with deferasirox in two patients with HFE hemochromatosis and chronic anemia. AB - We present 2 patients with hyperferritinemia, increased liver iron and hemochromatosis-associated HFE genotypes. At diagnosis, both patients had chronic anemia that prevented initiation of phlebotomy. Iron chelation with deferasirox proved to be a safe and effective means of substantially lowering ferritin levels. PMID- 21659726 TI - Genetic variation in KIFAP3 is associated with an upper motor neuron-predominant phenotype in amyotrophic lateral sclerosis. AB - BACKGROUND: Some authors have recently reported that the CC genotype of single nucleotide polymorphism (SNP) rs1541160 mapping within the kinesin-associated protein 3 (KIFAP3) gene is associated with increased survival in sporadic amyotrophic lateral sclerosis (sALS). OBJECTIVE AND METHODS: The relationship between the rs1541160 genotype and several clinical features of 228 ALS patients was evaluated with the intent of assessing any association between the ALS phenotype and KIFAP3. The SNP rs1541160 within the KIFAP3 expression profile was investigated using real-time PCR in a group of 6 patients harboring the CC genotype and in 12 patients harboring the TT genotype. RESULTS: Analysis of our patients' clinical features showed that almost half of those with the CC genotype were classified as having upper motor neuron-predominant ALS (UMN-ALS). Conversely, there was an approximately 10% frequency of UMN-ALS in both the TT and the TC patient groups as well as in the entire cohort considered as a whole (p < 0.005). The SNP rs1541160 genotype did not appear to have any effect on patient survival or on KIFAP3 expression. CONCLUSIONS: The incidence of the UMN ALS phenotype in the CC patients of this cohort supports the hypothesis that the SNP rs1541160 within the KIFAP3 gene is a potential modifier of the ALS phenotype. PMID- 21659728 TI - Using stereologic techniques for podocyte counting in the mouse: shifting the paradigm. AB - BACKGROUND: The podocyte serves the important function of maintaining the glomerular filtration barrier, and many studies report a decrease in podocyte number relative to the development of proteinuric states. However, there is significant inconsistency in the number of podocytes counted, possibly due to different counting methods. We previously counted the three glomerular cell types in the mouse kidney and showed that the fractionator/disector method is a close approximation of the exhaustive count or the gold standard method. In this study, we compared the commonly used model-based approach with the design-based approach to count podocytes in the db/m and db/db mouse and illustrate that the design based approach, which uses the fractionator/disector method, provides an accurate determination of podocyte number. METHODS: In the design-based approach, toluidine blue-stained 1-MUm-thick sections from glutaraldehyde perfusion-fixed kidneys were used (n = 15) with the fractionator/disector method. In the model based approach, WT-1-immunolabeled podocyte nuclei in 3- to 4-MUm-thick formalin fixed paraffin-embedded sections of the same kidneys were counted with the Weibel Gomez method. Glomerular volume was determined for each method. RESULTS: We discovered that the fractionator/disector method counted 89 +/- 10 podocytes compared to the Weibel-Gomez method, which counted 137 +/- 38 podocytes and overestimated podocyte number by 54% (p < 0.05). In addition, glomerular volume (231 +/- 52 * 10(3) vs. 192 +/- 64 * 10(3) MUm(3)) was significantly underestimated by 17% (p < 0.0002). Moreover, the model-based approach was more time consuming. CONCLUSION: We conclude that the fractionator/disector method offers an unbiased and efficient determination of podocyte counts. PMID- 21659725 TI - Suicidal behavior in prodromal Huntington disease. AB - BACKGROUND: Several studies have suggested a greater risk of suicide in Huntington disease (HD); however, unique risk factors for suicide in HD are not established. OBJECTIVE: We sought to determine risk factors for suicidal behavior, defined as suicide or attempted suicide, in prodromal HD. METHODS: From the prospective PREDICT-HD cohort, we identified 735 cases with HD gene expansion but no manifest symptoms of HD and 194 non-gene-expanded controls. In survival analysis, a number of potential risk factors for suicidal behavior were assessed, including symptoms of depression, hopelessness, substance abuse, marital status, gender, and psychiatric history. RESULTS: During a mean of 3.7 years of prospective follow-up, 12 cases (1.6%) attempted suicide and 1 completed suicide (0.1%). No suicides were observed among controls. In univariate Cox proportional hazards regression models, a history of suicide attempts (HR 8.5, 95% CI 2.8 26.1, p < 0.0002) and a Beck Depression Inventory II score >13 (HR 7.2, 95% CI 2.3-22.0, p < 0.0006) were associated with suicidal behavior. These risk factors had independent effects in multivariate models. A history of incarceration in the past 2 years was also associated (HR 12.5, 95% CI 2.7-56.6, p < 0.002), though uncommon. No further risk factors were identified. CONCLUSION: A history of suicide attempts and the presence of depression are strongly predictive of suicidal behavior in prodromal HD. As these risk factors are among the most robust risk factors for suicide, established suicide risk factors appear applicable to those with prodromal HD. PMID- 21659729 TI - TEM stereometric analyses of glomeruli in aging OVE26 transgenic diabetic mice. AB - BACKGROUND/AIMS: Glomerular lesions in diabetic nephropathy (DN) have been studied in numerous murine diabetic models, but the critical feature of aging is often absent. Since histopathology indicates that in mice, DN glomerular lesions may just begin to develop at about 5 months of age, we utilized the long-lived OVE26 transgenic diabetic model for stereometric analyses of DN glomerulopathic aging. METHODS: Albuminuria was determined by ELISA, and transmission electron microscopy stereometry was utilized exclusively to demonstrate changes in glomerular cell density and number, and alterations in the glomerular filtration barrier in OVE26 mice at 60, 150, and 450 days of age. RESULTS: Compared to age matched controls, albuminuria in diabetic mice is significant at 60 days. At 150 days, glomerular volume and mesangial, endothelial and total cell numbers, and podocyte effacement are significantly increased, while podocyte, endothelial, and total cell density are significantly decreased. Endothelial fenestrations are decreased, and glomerular basement membrane thickness is increased. At 450 days, stereometric alterations are exacerbated. CONCLUSION: Our data indicate that in OVE26 mice, albuminuria precedes morphological glomerular lesions and could be due to early-onset hyperglycemia. Moreover, in this model, most DN glomerulopathic lesions occur relatively late in life, and it is possible that they may result from prolonged hyperglycemia-induced oxidative stress. PMID- 21659730 TI - Distribution of volumes of individual glomeruli in kidneys at autopsy: association with physical and clinical characteristics and with ethnic group. AB - We have demonstrated considerable variability in the volumes of different glomeruli in given individuals (individual glomerular volume: IGV) in a stereologic study of kidneys at forensic autopsy performed to investigate sudden or unexpected death in people without manifest kidney disease. We review some important associations of IGV by subject characteristics and by ethnic groups. IGVs were measured by the Cavalieri method in 30 glomeruli in each of 111 adult males who belonged to 4 ethnic groups, i.e. US Whites, African-Americans, Africans from Senegal, and Australian Aborigines. Correlations of pooled IGV values with certain subject characteristics were evaluated in the US Whites. Pooled IGV data were compared in subjects across the 4 ethnic groups. In US Whites, mean IGV and its variance were greater with higher age, lower nephron number, lower birth weight, and with gross obesity, hypertension and cardiovascular death. In comparisons by ethnic group, mean IGV and IGV ranges were higher in African-Americans and Australian Aborigines than in US Whites and African Senegalese subjects. We conclude that glomerular enlargement with volume heterogeneity marks more advanced age, relative nephron deficiency, lower birth weight, obesity, hypertension, and advanced cardiovascular disease. The findings in African-Americans and Australian Aborigines suggest that larger IGVs and volume heterogeneity might mark populations with accentuated susceptibility to hypertension and kidney disease, but the data need to be further examined in the context of the determining characteristics defined in the US Whites. PMID- 21659731 TI - Podocyte detachment in type 2 diabetic nephropathy. AB - BACKGROUND: Glomerular podocyte number declines and urinary excretion of podocytes increases as kidney disease progresses in persons with type 2 diabetes mellitus (T2DM). METHODS: Using high-power electron microscopy, we quantified podocyte detachment in T2DM. RESULTS: We evaluated 106 glomeruli (range 1-6 per subject) from 40 Pima Indian subjects with T2DM enrolled in a clinical trial. On high-power electron micrographs, 35% of the subjects had no evidence of podocyte detachment. Among the remaining subjects, the median percentage of basement membrane with podocyte detachment was 0.62% (interquartile range = 0.32-1.52%). CONCLUSION: Podocyte detachment from the glomerular basement membrane has been described and measured in type 1 diabetes mellitus using a different method. We now document podocyte detachment microscopically and quantify it morphometrically in humans with T2DM. The findings offer quantitative histologic support to a potential mechanism for the functional impairment, and possibly the sclerosis of glomeruli, in diabetic glomerular injury. PMID- 21659732 TI - Stereological assessment of renal development in a baboon model of preterm birth. AB - At the time when most preterm babies are delivered, nephrogenesis is still ongoing, with the majority of nephrons normally formed during the third trimester of pregnancy. The extrauterine environment, however, is suboptimal for organogenesis, and therefore renal development is likely to be adversely affected by preterm birth. In the long-term, there is emerging evidence of high blood pressure and renal dysfunction amongst young adults born preterm. There is little knowledge to date, however, regarding the effects of preterm birth on renal structural development, perhaps due to the lack of an appropriate animal model. We have demonstrated that the baboon (Papio sp.) has a similar time course of nephrogenesis as the human kidney, and the baboon neonate can also be cared for in the same manner as a human neonate following preterm birth. Through a series of studies assessing renal development in the baboon model of preterm birth, involving the use of gold-standard stereological techniques, we have demonstrated that nephron endowment in the preterm baboon kidney is not reduced. Furthermore, antenatal glucocorticoid exposure prior to preterm delivery was associated with an increase in mature nephrons. There was, however, evidence of morphological abnormalities in a variable percentage of the glomeruli formed ex utero. Further research is therefore essential in order to establish what factors are involved in contributing to the glomerular abnormalities, and to identify ways in which 'normal' renal development can be conserved and optimised in the extrauterine setting. PMID- 21659733 TI - Quantitating glomerular endothelial fenestration: an unbiased stereological approach. AB - BACKGROUND/AIMS: Glomerular endothelial cells are fenestrated, allowing for especially high transcellular hydraulic conductivity. Current knowledge about endothelial fenestration structural changes in disease conditions is limited, partly due to the absence of robust methodologies to quantitate these structures. Herein, we propose a novel method for estimating the percentage of endothelial fenestration. METHODS: An unbiased stereological method based on contiguity of two phases and surface area density estimation using isotropic uniform random line probes was developed. A line grid for intercept counting and classifying endothelial coverage of fenestrated versus non-fenestrated areas was designed. The method was applied to renal biopsies from 15 patients with Fabry disease and 9 normal living kidney donor controls. RESULTS: The percentage of glomerular capillary endothelial coverage which was fenestrated was lower in Fabry patients (43 +/- 12%) versus controls (53 +/- 9%; p = 0.047). The fraction of endothelial surface which was fenestrated was greater on the peripheral versus mesangial zones of the capillary walls in both Fabry patients (p = 0.00002) and controls (p = 0.0005). CONCLUSION: The proposed method provides an unbiased tool to quantitate endothelial fenestration changes in glomeruli. The practical example introduced showed reduced glomerular endothelial fenestration in Fabry nephropathy. PMID- 21659734 TI - Advantages and controversies in the era of intrarenal volumetry. AB - BACKGROUND/AIMS: Ultrasound is the preferred imaging modality in nephrology. In many kidney diseases, however, more accurate methods are needed to distinguish between relevant intrarenal structures. MRI could be a solution, although the use of MRI contrast has caused severe complications in some cases, and invasive kidney biopsies may follow, even though such small specimens traditionally provide inaccurate quantitative data. We evaluated the usefulness of MRI volumetry and quantitative kidney biopsies to assess glomerular number and volume as well as cortical volume. METHODS: We specifically highlight an experimental study in which different MRI scans were performed in healthy pigs as well as pigs with unilateral ureteral obstruction to assess intrarenal volume. Single-kidney glomerular filtration rate (GFR) was measured using ureteral cannulation and (51)Cr-EDTA. Kidney biopsies were taken and evaluated employing stereological techniques to measure number and volume of glomeruli. Pigs were sacrificed and kidneys were removed for stereological analysis. Non-contrast-based MRI intrarenal volumes were - without significant difference to intrarenal volumes - obtained using contrast-enhanced MRI and ex vivo techniques. RESULTS: Kidney biopsies gave valid estimates regarding quantitative parameters, such as mean number and volume of glomeruli in the cortex. Different structural parameters correlated with kidney GFR with high, although varying, correlation coefficients. CONCLUSION: Non-contrast MRI is suitable for estimating intrarenal volumes in healthy and diseased kidneys. We advocate further research in diagnostic modalities combining MRI and biopsies. Major challenges are the cortical architecture and heterogeneous distribution of glomeruli within the kidney. PMID- 21659735 TI - Protein expression profile of human renal mesangial cells under high glucose. AB - BACKGROUND: To understand the spectrum of proteins affected by diabetic nephropathy and to characterize the molecular functions and biological processes they control, the protein expression profile of human renal mesangial cells (HMCs) under high glucose was analyzed. METHODS: HMCs were divided into a high glucose-cultured group (30 mmol/l) and a normal glucose-cultured group (5 mmol/l). The total proteins of the two groups were separated and analyzed by two dimensional difference gel electrophoresis (DIGE). Spots that were differentially expressed were picked and digested with trypsin and subjected to MALDI-TOF MS for protein identification. RESULTS: 147 protein spots whose expression levels were significantly increased or decreased more than 1.5-fold in HMCs under high glucose culture were identified. 32 proteins were identified by peptide mass fingerprinting. The protein spots of phosphatidylethanolamine-binding protein 1, granulysin, ATP synthase, H(+) transporter, mitochondrial F0 complex and subunit F2 were observed only in the high glucose group. The expression of 24 proteins was upregulated by high glucose, including eosinophil cationic protein and others. The expression of 5 proteins was downregulated by high glucose, including proteasome beta6 subunit precursor, among others. CONCLUSION: 32 protein expressions of human glomerular mesangial cells were regulated by high glucose. In-depth analysis of these differentially expressed proteins' function and crosstalk is expected to provide an experimental basis for clarifying the pathogenesis of diabetic nephropathy. PMID- 21659736 TI - Smoking is a risk factor for graft failure and mortality after renal transplantation. AB - BACKGROUND: Smoking in renal transplant recipients (RTR) is an acknowledged cardiovascular risk factor. It is, however, unclear whether smoking also increases the risk of graft failure (GF). METHOD: In this study, we prospectively assessed the association of current smoking versus past and never smoking with GF and mortality in 604 RTR (age 51.5 +/- 12.1 years, 55% male). RESULTS: At inclusion, 133 (22%) were current smokers, 255 (42%) were past smokers and 216 (36%) never smoked. During follow-up of 5.3 (4.7-5.7) years, 41 (7%) RTR experienced GF and 95 RTR (16%) died. Current smoking RTR had higher risk for GF compared to never smoking RTR (hazard ratio, HR = 3.3, 95% CI 1.5-7.1, p = 0.002). Past smoking RTR had similar risk of GF as never smoking RTR (HR = 1.1, 95% CI 0.5-2.6, p = 0.7). Current smoking RTR and past smoking RTR were at higher risk for death than never smoking RTR (HR = 2.1, 95% CI 1.1-3.8, p = 0.016, and HR = 2.4, 95% CI 1.4-4.0, p = 0.001, respectively). CONCLUSION: Smoking after renal transplantation is associated with risk for GF and mortality. Since past smoking is a risk factor for mortality but not for GF, smoking cessation may be beneficial to RTR in delaying GF in long term. PMID- 21659737 TI - Relationship between glycosylated hemoglobin and blood glucose during progression of chronic kidney disease. AB - BACKGROUND: The value of measurement of glycosylated hemoglobin (HgbA(1C)) in determining the degree of glycemic control in patients with chronic kidney disease (CKD) is unclear. METHODS: A single-center, prospective cohort study was conducted in 128 veterans with diabetes mellitus and CKD. HgbA(1C) was measured as clinically indicated and its relationship with random blood glucose (RBG) measurement evaluated prospectively over up to 10 years in three groups (end stage renal disease (ESRD), CKD and controls who had diabetes but no CKD). RESULTS: Between 1995 and 2011, in the control group, glycemic control as assessed by HgbA(1C) was stable but improved when assessed by RBG. However, both the CKD and ESRD groups experienced declines in RBG and HgbA(1C). Declining HgbA(1C) and RBG were noted prior to onset of dialysis. A fall in HgbA(1C) remained after adjustment for RBG. A strong inverse relationship was seen between CKD stage and HgbA(1C) even after adjusting for RBG such that the relationship between RBG levels and HgbA(1C) was modified by CKD. CONCLUSIONS: In diabetic patients with late-stage CKD, glycemic control shows an improvement. However, HgbA(1C) <7% may overestimate the degree of glycemic control. Therefore, reliance on HgbA(1C) without home blood glucose monitoring may result in poor diabetes control. PMID- 21659738 TI - Malignancies confined to disused arteriovenous fistulae in renal transplant patients: an important differential diagnosis. AB - BACKGROUND: Swelling in an arteriovenous fistula (AVF) is commonly caused by thrombosis, aneurysm and infection. However, due to the increased risk of malignancy after transplantation, this should also be considered. PATIENTS: We discuss 4 patients with malignancy confined to an AVF after renal transplantation presenting in a 2-year period. Angiosarcoma was diagnosed in 3 patients and the other had post-transplant lymphoproliferative disorder (PTLD). Angiosarcoma behaves aggressively and 2 of our patients died within 6 months of diagnosis. There are 6 previous cases and 5 died within 16 months of diagnosis. PTLD at AVFs has not been documented previously. CONCLUSION: Malignancy at an AVF is a rare but important differential that can impact significantly on patient morbidity and mortality. Predilection for malignancy at an AVF is not understood. We review the literature and discuss possible aetiologies. PMID- 21659740 TI - Activation of intrarenal renin-angiotensin system during metabolic acidosis. AB - BACKGROUND: Chronic metabolic acidosis is a common metabolic disturbance and its clinical impact can be severe and extensive. The role and the change of the intrarenal renin-angiotensin system (RAS) during metabolic acidosis are uncertain, and whether acidosis can evoke inflammation remains unclear. METHODS: Male Sprague-Dawley rats were fed with water containing 0.14 M NH(4)Cl to induce metabolic acidosis for 1 and 8 weeks, respectively. They were compared with animals fed with deionized water (control) and equimolar sodium chloride water (NaCl). Gene expression analysis of RAS components included renin, renin/prorenin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II type 1 and 2 receptors (AT1R and AT2R). Histological examination was also performed to detect morphological change. RESULTS: Acidosis was found in 1-week NH(4)Cl-treated rats but not in the 8-week group. More than twofold proteinuria and a significant decline of glomerular filtration rate (GFR) were observed in acid-loaded rats. Compared to the control and NaCl groups, angiotensinogen, ACE, AT1R and AT2R were significantly increased in the 1-week acidosis group (all p < 0.05). Sustained increase of AT1R expression was found as NH(4)Cl was continued for 8 weeks. There was no significant change in transforming growth factor-beta and nuclear factor-kappaB. The architecture of tubular epithelial cells was affected during our experiment. CONCLUSION: Metabolic acidosis induced proteinuria and decline of GFR in association with activation of intrarenal RAS. PMID- 21659739 TI - Relationship between uric acid and subtle cognitive dysfunction in chronic kidney disease. AB - BACKGROUND: Elevated serum uric acid has been associated with cognitive dysfunction and vascular cognitive impairment in the elderly. Serum uric acid is also commonly elevated in chronic kidney disease (CKD), but its relationship with cognitive function in these patients has not been addressed. METHODS: Subjects with CKD (defined as eGFR <60/ml/min/1.73 m(2)) were evaluated for cognitive dysfunction using the validated Standardized Mini-Mental State Examination (SMMSE). Individuals with dementia, depression or other psychiatric disorders were excluded, as were subjects on uric acid-lowering therapy or with serious illnesses such as severe anemia or active or ongoing cardiovascular or cerebrovascular disease. RESULTS: 247 subjects were enrolled. SMMSE scores showed stepwise deterioration with increasing quartile of serum uric acid (26.4; 26.1; 25.5; 25.3, score range 20-30, p = 0.019). Post-hoc analysis demonstrated that there was no linear trend and only groups 1 and 4 were different with respect to SMMSE scores (p = 0.025). Stepwise multivariate linear regression revealed that age, educational status, presence of cerebrovascular disease, and serum uric acid were independently related to SMMSE scores. CONCLUSION: Serum uric acid levels are independently and inversely associated with mild cognitive dysfunction in subjects with CKD. PMID- 21659741 TI - Hepatitis C virus adversely affects quality of life. AB - BACKGROUND: Chronic liver disease secondary to hepatitis C virus (HCV) infection is a common clinical problem. HCV is likely to adversely affect the quality of life (QoL) of the patient. This effect is said to be disproportionate to the severity of the disease. The aim of our study was to evaluate QoL in HCV-positive patients focusing both on health status and subjective satisfaction. METHODS: Twenty-four patients with combined HCV and alcoholic liver disease (ETOH-HCV) were enrolled in the study. We adopted two generic tools: SF-36 (a health status questionnaire) and SAT-P (a satisfaction profile) for psychological assessment of the patients. SF-36 and SAT-P scores of ETOH-HCV patients were compared with scores of 23 patients with alcoholic liver disease (ETOH). The scores obtained from the study groups were also compared with the reference scores of the healthy Italian population. RESULTS: Both the groups were comparable with respect to age, histological and clinical severity of liver disease (as assessed by MELD and Child Pugh scores). Patients with ETOH-HCV scored less in the vitality and role emotional status domains of the SF-36 scores and the psychological function, social function and free time domains of the satisfaction profile. CONCLUSIONS: These results show a significant impact of HCV infection on health status and subjective satisfaction. PMID- 21659742 TI - A heparin-coated dialysis filter (AN69 ST) does not reduce clotting during hemodialysis when compared to a conventional polysulfone filter (F*8). AB - BACKGROUND: We investigated whether the heparin-coated AN69 ST hemodialysis (HD) filter induced less hypercoagulability during HD than a conventional polysulfone filter (F*8). METHODS: In a crossover design, 11 patients were treated alternately with AN69 ST and F*8 filters (45 sessions). All filters were primed with unfractionated heparin (UFH) and unadsorbed UFH was removed by saline flushing. Half the conventional dalteparin dose was given as a bolus dose at the start of HD. Clotting was evaluated hourly in the venous air trap. Prothrombin fragments 1 and 2 (PF1 + 2), antithrombin (AT), beta-TG and anti-FXa activity were repeatedly measured. RESULTS: One patient treated with enalapril had two repeated adverse reactions to the AN69 ST filter and was excluded from the study. Use of the AN69 ST filter did not decrease the mean clot score or PF1 + 2, but decreased beta-TG compared to the F*8 filter. CONCLUSION: The heparin-coated AN69 ST filter did not induce less coagulation when compared to the F*8 filter. PMID- 21659743 TI - Association of interleukin-1beta gene polymorphism and peritonitis in uremic patients undergoing peritoneal dialysis. AB - OBJECTIVE: Interleukin-1 (IL-1) is involved in the disease process of peritonitis. We hypothesize that IL-1 gene polymorphism may have an impact on the occurrence of peritonitis in uremic patients undergoing peritoneal dialysis (PD). METHODS: Uremic patients were recruited for the study of IL-1beta (-511) C/T gene polymorphism in 2002. These patients were then prospectively followed up to monitor their peritoneal membrane characteristics, biochemical parameters, occurrence of peritonitis and patient as well as PD technique survival. RESULTS: A total of 74 patients were enrolled in the study. During follow-up, at least one episode of peritonitis occurred in 36 patients. Compared with patients without peritonitis, the carriage of C allele in IL-1beta gene polymorphism (C/C and C/T genotypes) was significantly associated with the occurrence of peritonitis (p = 0.013). This was further confirmed in the multivariate logistic regression analysis (odds ratio 8.18, p = 0.017). CONCLUSION: Carriers of C allele were associated with an increased risk of peritonitis. PMID- 21659744 TI - Roger C. Bone, MD and the evolving paradigms of sepsis. AB - Severe sepsis and septic shock are frequent causes of ICU admission, commonly encountered complications during the course of hospitalization, and among the most common causes of death in the noncoronary ICU. Dr. Roger C. Bone was a pioneer in our struggles to improve the early recognition and management of severe sepsis and septic shock. Through his leadership and guidance, great strides were made to develop a uniform definition and to ensure the comparability of clinical research trials to evaluate new therapeutic strategies and antimediator agents. Dr. Bone also helped shape our understanding of the various stages or physiologic alterations that occur in the septic patient which also drove forward the development of new therapeutic strategies. This chapter briefly reviews the impact Roger Bone has had on our current understanding and approach to the septic patient. PMID- 21659745 TI - Clinical aspects of sepsis. AB - Sepsis is still a serious threat, especially to patients hospitalized in intensive care units (ICUs). Despite advances in modern technology that lead to an improved outcome in individuals suffering from sepsis, clinicians must be cautious when the septic condition is suspected. Changes in the epidemiology, etiology and foci of sepsis, together with a rise of antimicrobial resistance in the causative agents responsible for sepsis, create a qualitatively new situation. Because the septic patient must be treated without delay, the diagnosis of sepsis is usually based on the clinical findings, the knowledge of epidemiological history and predisposing conditions. Traditional methods used in the diagnosis of sepsis must be employed and used in combination with novel approaches of diagnosis, such as the detection of DNA from pathogenic microorganisms in the sterile body fluids and routine measurements of procalcitonin levels in the serum. Since many septic patients are hospitalized in ICUs, complications associated with the development of multiple organ dysfunction/failure are important. Respiratory, circulatory and renal failures are the most frequent types of organ dysfunction in the ICU. Furthermore, secondary nosocomial infections develop in about 20-50% of ICU patients. Thus, facing sepsis is a significant challenge, even for an experienced clinician. PMID- 21659746 TI - Virulence factors of gram-negative bacteria in sepsis with a focus on Neisseria meningitidis. AB - Gram-negative bacterial pathogens of humans have evolved a range of virulence factors to promote motility, attach to epithelial or endothelial cell surfaces, avoid host immune responses, activate or inactivate host cellular pathways and ultimately cause clinical disease. Gram-negative sepsis is a life-threatening complication of these events. This review discusses the virulence factors of common Gram-negative bacteria causing human sepsis with a focus on Neisseria meningitidis. Adherence, motility, colonization and cell entry involve bacterial pili, flagella and outer membrane proteins. Endotoxin (lipopoly-or lipo oligosaccharide), other membrane components or exotoxins can be potent inducers of the host inflammatory cascade via innate receptor pathways. Capsular polysaccharides and outer membrane proteins can help the bacterium evade immune defenses. The role in pathogenesis of iron acquisition, bacterial secretion systems, quorum sensing, and biofilm formation is also reviewed. Through multiple genetic mechanisms leading to phase variation, Gram-negative bacteria can adapt to changing host and environmental conditions and selective pressures. Further, the antimicrobial resistance of Gram-negative bacteria driven by antibiotic use will continue to influence the clinical outcomes of Gram-negative sepsis in the coming years. PMID- 21659747 TI - Molecular mechanisms of sepsis. AB - In cancer, therapies are targeted at 6 important pathways. In sepsis, there is ongoing controversy regarding the number and relative roles of pathways that are activated or repressed and which are important in the progression from health to death. Adding to complexity, there is interaction of pathways, there are differences in temporal pattern of up and down-regulation of pathways and there are different responses of pathways to therapies of sepsis. In this review, we define four key pathways of sepsis: (1) inflammation and immunity, (2) coagulation and fibrinolysis, (3) apoptosis, and (4) endocrine. Each of these pathways can impair endothelial function, a unifying aspect of the pathophysiology of sepsis. There are few studies of interactions of pathways except for the interacttion of inflammation/immunity with coagulation/fibrinolysis. Successful treatment of cancer requires that cancer therapies interrupt several key pathways of cancer. Accordingly, we suggest that successful treatment of sepsis will require therapies that interrupt several key pathways of sepsis. Perhaps the paucity of approved therapies for sepsis is related in part to the underevaluation of novel pathways, to lack of understanding of interactions of pathways and to lack of interruption of key pathways of sepsis. PMID- 21659748 TI - Pro-inflammatory mechanisms in sepsis. AB - Sepsis is characterised by a hyper-inflammatory response due to microbial infection. We here review our current understanding of host mechanisms employed to mediate this hyper-inflammatory response, drawing together current knowledge pertaining to pathogen recognition and host pro-inflammatory response. Recognition of microbial derived ligands by pattern recognition receptors (PRRs) is a key step in initiating pro-inflammatory signalling pathways. Examples of PRRs linked to the aetiology of sepsis include Toll-like, C-type lectin, RIG-1 like and also Nod-like receptors, which are involved in the formation of the inflammasome, crucial for the maturation of some pro-inflammatory cytokines. Bacterial superantigens have evolved to exploit host MHC class II and T cell receptors (normally considered part of the adaptive immune response) as innate PRRs to propagate a so-called 'cytokine storm', while synergy between different microbial ligands and host-derived alarmins can augment the inflammatory response still further through as yet poorly understood interactions. The host pro inflammatory response results in the characteristic features of inflammation: rubor, calor, dolor, and tumor. We will review herein the key mediators of inflammation in sepsis, identifying their overlapping and intersecting roles in vascular changes in tone, endothelial permeability, coagulation and contact activation, leukocyte mobilisation and activation. PMID- 21659749 TI - Anti-inflammatory mechanisms of sepsis. AB - Over the past two decades, it has become well accepted that sepsis exhibits two, oftentimes concomitant, inflammatory stages; a pro-inflammatory phase, referred to as the systemic inflammatory response syndrome (SIRS), and an anti inflammatory phase, called the compensatory anti-inflammatory response syndrome (CARS). Considering that therapeutic interventions designed to attenuate the pro inflammatory septic response have generally failed, much recent research has gone into understanding how and why septic patients display immunosuppressive characteristics, what the significance of septic immunosuppression may be and if there exists any therapeutic targets within the CARS. Herein, we describe the potential mechanisms of the immunosuppressive/CARS phase of sepsis by discussing what anti-inflammatory agents, receptors and cell populations are currently believed to contribute to CARS. PMID- 21659750 TI - Regulation of pro-and anti-inflammatory host responses. AB - Sepsis is a very heterogeneous clinical syndrome broadly defined as the systemic host response to an infection. Until recently, the concept that mortality is the consequence of an uncontrolled hyperinflammatory response of the host was widely accepted. However, although some patients may die rapidly from septic shock accompanied by an overwhelming systemic inflammatory response syndrome triggered by a highly virulent pathogen, most patients survive the initial phase of sepsis, showing multiple organ failure days or weeks later. These patients often demonstrate signs of immune suppression rather than enhanced inflammation. As such, sepsis is now considered a misbalance between proinflammatory reactions (designed to kill invading pathogens but at the same time responsible for tissue damage) and anti-inflammatory responses (designed to limit excessive inflammation, but at the same time making the host more vulnerable for secondary infections). This chapter discusses key components of the pro- and anti inflammatory response to sepsis and the regulation thereof. PMID- 21659751 TI - Future perspectives on regulating pro-and anti-inflammatory responses in sepsis. AB - Therapy for severe sepsis and septic shock remains a major unmet medical need and novel treatments to regulate the disordered inflammatory response in sepsis are needed if improved outcomes in sepsis are to be realized in the future. Current therapy is primarily supportive and includes timely administration of antibiotics, source control of infection, aggressive fluid resuscitation, organ support and use of activated protein C where clinically indicated. Bacterial mediators including endotoxin and superantigens as well endogenous proinflammatory cytokines are critical to the pathogenesis of sepsis-induced organ failure and are being targeted with numerous molecules and removal devices. Additional therapeutic strategies are focused at restoring the natural anticoagulant levels, blocking deleterious effects of the complement cascade, preserving mitochondrial function, and inhibiting excessive lymphocyte apoptosis. Molecules with pluripotent activity such as inter-alpha inhibitor proteins, sirtuin activators and estrogen-receptor ligands are also being investigated. Efforts are underway to re-establish microbial clearance mechanisms and permit immune reconstitution following sepsis-induced immune suppression. A review of the most current agents being investigated and their current status are presented in this chapter. The organization of this chapter includes sections addressing therapies targeting microbial mediators, including endotoxin, as well as therapies targeting inflammation and coagulation. There is also a section on agents targeting novel mediators and pathways. PMID- 21659752 TI - Epidemiology of diabetic nephropathy. AB - Diabetic nephropathy affects approximately one third of people with type 1 or type 2 diabetes mellitus. Risk factors affecting progression of kidney disease include baseline albumin excretion, age, glycemic control, blood pressure, serum cholesterol and use of renin-angiotensin system blockers. As the total number of people with diabetes is projected to increase substantially to 2050, the prevalence of diabetic nephropathy will rise dramatically, with concomitant increase in associated cardiovascular mortality and endstage renal disease. This will produce significant social and economic ramifications, particularly in the developing world. PMID- 21659753 TI - Genetics of diabetic nephropathy in diverse ethnic groups. AB - Genetic susceptibility is considered an important factor for the development and progression to diabetic nephropathy (DN), and for more than 20 years researchers have tried tounravel the genetic determinants of the disease. It is now clear that the pathogenesis of DN is most likely multifactorial and attributed to several genetic and environmental risk factors. Several candidate genes have been shown to be associated with the disease, but the results have not been consistent and most of the genes conferring risk to DN remain to be identified. In addition, studies have suggested that there might be differences in susceptibility loci and/or alleles between diverse populations. Recent developments in genotyping technology and increased information on the human genome have facilitated genome wide association scans (GWAS) for investigating novel disease susceptibility across the entire human genome. The few GWAS performed for DN so far in combination with improved understanding of the human genome have identified novel risk loci and emphasized the importance of performing detailed genetic studies across diverse ethnic populations to fully unravel the genetic susceptibility to DN. PMID- 21659754 TI - Clinical manifestation and natural history of diabetic nephropathy. AB - The prevalence of diabetes, predominantly of type 2, and the incidence of diabetic nephropathy have dramatically increased worldwide. Diabetic patients constitute the largest proportion of patients with end-stage renal disease (ESRD) requiring dialysis or transplantation; in developed countries, this accounts for up to 50% of ESRD patients, but this proportion has stabilized and possibly somewhat decreased in recent years. Chronic kidney disease in diabetic patients is more heterogeneous than previously thought. The largest proportion suffers from proteinuric diabetic nephropathy with Kimmelstiel-Wilson lesions as the underlying pathology, but reduced glomerular filtration rate in the absence of albuminuria/proteinuria is recognized in an increasing proportion of type 2 diabetic patients. Of particular interest is the recent recognition of vascular lesions in the brain and retina as predictors of nonproteinuric nephropathy with reduced GFR; although currently unproven, such lesions may also be of potential relevance for target blood pressure. Because of the high prevalence of type 2 diabetes in the population, coexisting primary kidney disease and diabetic nephropathy occur in a sizable proportion of type 2 diabetic patients with ESRD. The optimal point to start treatment differs according to target organs. There is no doubt that in proteinuric diabetic patients the earlier the treatment (blood pressure lowering, renin-angiotensin system blockade) is started, the greater is the benefit--at least in patients with proteinuric disease and no major cardiovascular damage. In our opinion, there is no one target blood pressure that fits all patients. Survival of patients with diabetic nephropathy is to a large extent determined by cardiovascular comorbidity. It is currently a matter of debate whether the current definition of type 2 diabetes is appropriate. Some recent findings suggest that minor renal hemodynamic and morphological changes are seen even in (prediabetic) patients who fail to meet the current definition of type 2 diabetes. PMID- 21659755 TI - Obesity, metabolic syndrome and diabetic nephropathy. AB - Diabetic nephropathy is becoming an increasingly important cause of morbidity and mortality worldwide owing to the increasing prevalence of type 2 diabetes, largely driven by increasing obesity. There is considerable evidence that obesity, hypertension and other elements of the metabolic syndrome also contribute to the progression of renal disease independent of diabetes. How they interact and contribute to diabetic nephropathy, however, is not completely understood. Clinical diabetic nephropathy is preceded by an increase in glomerular filtration rate, microalbuminuria and glomerular hypertrophy. Poor glycemic control and elevated systolic blood pressure exacerbate proteinuria and renal injury that may culminate in end-stage renal disease. A similar sequence of events may lead to obesity-related renal disease even in the absence of diabetes. This chapter compares and contrasts factors involved in the development of glomerular hemodynamic and kidney pathological processes associated with diabetes and obesity. PMID- 21659756 TI - Pathology of human diabetic nephropathy. AB - Diabetic nephropathy (DN) develops in a subset of diabetic patients, on average about 15 years after onset of metabolic abnormalities. The earliest lesions consist of thickened glomerular basement membranes (GBM), mild mesangial expansion, and arteriolar accumulation of hyaline. Mesangiolysis and exuberant mesangial repair then develop, ultimately resulting in marked increase in mesangial matrix. Established nephropathy is characterized by mesangial expansion which may be nodular, so-called Kimmelstiel-Wilson nodules, hyaline in both afferent and efferent arterioles, and markedly thickened GBM by electron microscopy. Podocyte loss may be a crucial contributor to this progressive sclerosis. There is a distinct predilection of segmental sclerosis to occur at the glomerulotubular junction in type 1 diabetic patients, which can lead to disruption of outflow from the glomerulus, resulting in so-called a tubular glomeruli. A recent classification of DN may be useful for categorizing stages of development of the diabetic lesions. Diabetic injury also affects the tubulointerstitium. Tubular basement membranes thicken in parallel to GBM. Early interstitial inflammation with predominantly mononuclear cells is followed by later increased interstitial fibrosis and tubular atrophy. Lesions in type 1 and type 2 diabetic patients share many similarities, with more severe vascular disease and heterogeneous lesions, perhaps reflecting older age and comorbid conditions such as hypertension, in the latter. Diabetic patients typically undergo diagnostic renal biopsies only when the clinical course is not typical for DN, and not surprisingly, a range of other lesions may then be present in addition to DN. DN also recurs or occurs de novo in the transplant, developing more quickly than in the native kidney. Efforts to develop rodent animal models that more completely capture these key features of human DN will allow advances to be made in understanding pathogenesis and targeting novel treatment. PMID- 21659757 TI - Pathogenesis and progression of proteinuria. AB - Progressive albuminuria is the sine qua non of diabetic nephropathy. It is not only a marker of renal damage but also significantly contributes to its development and progression. However, the precise mechanisms by which escalating amounts of albumin leave the blood stream, cross the endothelial glycocalyx, the glomerular basement membrane and the slit pores between the foot processes of the podocytes, transit through Bowman's space, bypass the resorptive mechanisms of the nephron and ultimately pass into the urineremain hotly debated. Certainly, diabetes is associated with significant dysfunction at each of these levels, and will be discussed in detail in this review. Moreover, dilation of the afferent and constriction of the efferent arterioles triggered by defective autoregulation and subsequently by loss of peritubular capillaries also act to increase the glomerular transcapillary hydrostatic pressure and facilitate a far greater transit of albumin into the urine. Importantly, none of these mechanisms exists in isolation. Indeed, the most likely reason for progression of albuminuria is the fact that dysfunction initiated by compromise of one component will inevitably modify other parts, and ultimately affect the whole nephron function. From this 'holonephric' view of albuminuria, the best treatment will be a combination that can promote regression and restore the integrity of the entire pathway, as while fixing one part may slow the process, because of the integrated nature of renal function, it will not completely prevent nephropathy. PMID- 21659758 TI - Epigenetic mechanisms. AB - The incidence of diabetes and related complications like nephropathy is growing rapidly and has become a major health care issue. Changes in the environment and nutritional habits have been implicated as major players. Furthermore, it is becoming increasingly clear that epigenetic factors may modulate the connections between genes and the environment. While diabetes in itself is treatable to a large extent, it is still associated with significantly increased risk for complications including chronic kidney and cardiovascular diseases. Current treatments have added preventative approaches so as to avoid future diabetic complications. Unfortunately, diabetic patients are often plagued with the continued development of various complications even after achieving glucose control. This has been suggested to be attributable to a mysterious phenomenon termed 'metabolic memory' of the prior glycemic state. Recent studies have suggested that epigenetic changes to chromatin can affect gene expression in response to various stimuli, and changes in key biochemical pathways and epigenetic histone and DNA methylation patterns in chromatin have been observed in a diabetic milieu. These accumulating data suggest that metabolic or hyperglycemic memory may be due to epigenetic changes in specific target tissues altering gene expression without changing the genetic code itself. While the genetics of diabetes has long been the focus of scientific research, much less is known about the role of epigenetics and the related molecular pathways that might affect the development of diabetes and the associated complications. Further studies of epigenetic mechanisms are therefore timely and could provide valuable new insights into the pathology of diabetic complications and also uncover much needed new therapeutic targets. PMID- 21659759 TI - Advanced glycation end products. AB - Prolonged hyperglycemia, dyslipidemia and oxidative stress in diabetes result in the increased production and accumulation of advanced glycation end products (AGEs) in the kidney. Covalent AGE modifications significantly influence the structure and function of key protein targets. In addition, activation of AGE receptors, alone or in combination with other ligands, is able to promote renal damage, fibrosis and inflammation associated with diabetic nephropathy. The actions of AGEs synergize and potentiate the activity of other pathogenic mediators in the diabetic kidney, including oxidative stress, protein kinase C and renin-angiotensin system activation, which subsequently promote the development and progression of kidney disease in a vicious and progressive cycle. Their importance as downstream mediators of hyperglycemia in diabetes has been amply demonstrated in studies using mechanistically different inhibitors of advanced glycation to retard the development of kidney disease without directly influencing plasma glucose levels. Furthermore, direct exposure to AGEs is able to generate lesions similar to those seen in diabetic nephropathy. The human body has a number of natural defenses against AGE accumulation, which are reduced in diabetic individuals, and in particular those with nephropathy, while the receptor for AGEs and its ligands are significantly increased. Given such data, a number of different pharmacological agents have been developed to reduce AGEs and with it prevent diabetic kidney disease. Although many have proved effective in experimental models of diabetes, their clinical utility remains unproven. PMID- 21659760 TI - Transforming growth factor-beta and Smads. AB - Diabetic nephropathy (DN) is a major diabetic complication. Transforming growth factor-beta(TGF-beta) is a key mediator in the development of diabetic complications. It is well known that TGF-beta exerts its biological effects by activating downstream mediators, called Smad2and Smad3, which is negatively regulated by an inhibitory Smad7. Recent studies also demonstrated that under disease conditions Smads act as signal integrators and interact with other signaling pathways such as the MAPK and NF-kappaB pathways. In addition, Smad2and Smad3 can reciprocally regulate target genes of TGF-beta signaling. Novel research into microRNA has revealed the complexity of TGF-beta signaling during DN. It has been found that TGF-beta and elevated glucose concentration can positively regulate miR-192 and miR-377, but negatively regulate miR-29a in a diabetic milieu. These microRNAs are found to contribute to DN. Although targeting TGF-beta may exert adverse effects on immune system, therapeutic approach against TGF-beta signaling during DN still draws much attention. Blocking TGF-beta signaling by neutralizing antibody, anti-sense oligonucleotides, and soluble receptors have been tested, but effects are limited. Gene transfer of Smad7 into diseased kidneys demonstrates a prominent inhibition on renal fibrosis and amelioration of renal impairment. Alteration of TGF-beta-regulated microRNA expression in diseased kidneys may provide an alternative therapeutic approach against DN. In conclusion, TGF-beta/Smad signaling plays a critical role in DN. A better understanding of the role of TGF beta/Smad signaling in the development of DN should provide an effective therapeutic strategy to combat DN. PMID- 21659761 TI - Angiogenic factors. AB - Diabetic nephropathy (DN) is in essence a microvascular disease that develops as a result of a confluence of hemodynamic and metabolic perturbations. Angiogenic factors are prime candidates to explain the vascular and pathologic findings of DN; however, analysis of their pathophysiology shows that they have a constellation of effects on the glomerulus that go beyond angiogenesis. Vascular endothelial growth factor (VEGF) is an exemplary candidate for fulfilling the criteria for Koch's postulate as an etiologic agent of the glomerulopathy in diabetes. Its expression and signaling in the kidney are amplified early on in the diabetic state. Moreover, counteracting its effects reverses the albuminuria and other hemodynamic and structural features of experimental DN. Finally, experimental overexpression of VEGF in adult mice replicates several aspects of diabetic kidney disease. Under the influence of a variety of diabetic mediators, the podocyte becomes the main source of increased expression of VEGF in the kidney. The cytokine then exerts its multitude of effects in an autocrine fashion on the podocyte itself, on the endothelial cell in a paracrine manner, and finally contributes to macrophage recruitment acting as a chemokine. The angiopoietins consist primarily of two main factors acting in contrast to each other: Ang1--an antiangiogenic ligand, and Ang2--its competitive inhibitor. Both, however, seem to have important roles in the maintenance of glomerular homeostasis. Diabetes disrupts the tight balance that controls angiopoietin expression and functions and decreases theAng1/Ang2 ratio. The end physiologic result seems to be dependent on the concomitant VEGF changes in the kidney. Because of the intricacy of their control, angiogenic factors are difficult to manipulate therapeutically. However, they remain valid target points for the treatment of DN. PMID- 21659762 TI - Endothelial nitric oxide synthase. AB - Diabetic nephropathy remains a leading cause for end-stage renal disease indicating a failure of current therapeutic strategies. One factor that impairs our ability to make advances has been the inadequacy of most animal models in manifesting advanced diabetic renal disease. Since these animal models develop marked hyperglycemia, one could assume that hyperglycemia is not enough for the development of advanced nephropathy and thereby additional factors are likely involved. Recently, our research group and others have discovered a new mouse model in which diabetes is induced in mice lacking endothelial nitric oxide synthase (eNOS). Diabetic eNOS knockout mice develop severe renal injuries resembling advanced human diabetic nephropathy. This model thereby suggests a key role for reduced nitric oxide levels in the pathogenesis of diabetic nephropathy. In this article, we summarize recent clinical and experimental evidence for the role of eNOS in diabetic nephropathy. PMID- 21659763 TI - Reactive oxygen species and oxidative stress. AB - Oxidative stress defined as an excessive production of reactive oxygen species (ROS) surpassing existing antioxidative defense mechanisms plays a critical role in the development and progression of diabetic vascular complications including nephropathy. Over production of ROS in diabetic milieu is both a direct consequence of hyperglycemia and an indirect consequence through advanced glycation end products (AGEs) or mediators of glucotoxicity such as cytokines and growth factors. Among many pathways, nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase and mitochondrial dysfunction have been recognized as two major sources of ROS generation in diabetic kidneys, and NADPH oxidase derived ROS has been shown to facilitate renal mitochondrial superoxide production in hyperglycemia. Low antioxidant bioavailability promotes cellular oxidative stress leading to additional cellular damage. Although large-scale clinical trials using classical antioxidants have failed to show a significant effect on the development of vascular complications in diabetes, new strategies targeting NF-E2-related factor 2, the primary transcription factor that controls the antioxidant response, mitochondrial dysfunction, or NADPH oxidase might provide a potential approach for the prevention and treatment of diabetic nephropathy. PMID- 21659764 TI - Inflammatory pathways. AB - Diabetes mellitus and its complications have become one of the most important health problems in the world. Nowadays, diabetic nephropathy is the main cause of end-stage renal failure and need for renal substitutive therapy. The exact mechanisms leading to the development and progression of renal damage in diabetes are not yet completely known. Growing evidence indicates that activation of innate immunity with the development of a chronic low-grade inflammatory response is a recognized factor in the pathogenesis of this disease. Inflammatory molecules and pathways, including metabolic routes, oxidative stress, growth factors, chemokines, adhesion molecules and inflammatory cytokines, interact in manifold ways leading to renal injury responsible for the development and progression of this complication. The increasing knowledge and understanding of the role of these inflammatory mechanisms, with an integrative comprehension of this network, will facilitate the identification of new therapeutic targets and the development of new strategies that can be translated successfully into clinical applications. PMID- 21659765 TI - Diabetic tubulopathy: an emerging entity. AB - In chronic glomerulopathic disease, renal function correlates more with the degree oftubulointerstitial injury than that of the glomerular lesions. Proteinuria may be one of the pathologic links between these two intrarenal compartments. It is apparent that the proximal tubular epithelial cell (PTEC) assumes a proinflammatory and profibrotic role during proteinuria in which the PTEC expresses a variety of chemokines and injury signals that culminate in progressive interstitial inflammation and fibrosis. During diabetes, other substrates including advanced glycation end products (AGEs), AGE intermediates, and high glucose (HG) may provoke the PTEC even further. Glycated albumin, but not the equivalent dose of bovine serum albumin (BSA), stimulates tubular IL-8 and ICAM-1 expression via NF-kappaB-, MAPK- and STAT-1-dependent pathways. Human biopsies of diabetic nephropathy (DN) reveal colocalization of AGE and ICAM-1 in proximal tubules. The biologically active carbonyl intermediates methylglyoxal BSA-AGE and AGE-BSA upregulate tubular expression of CTGF, TGF-beta, and VEGF, whereas carboxymethyllysine-BSA stimulates tubular expression of IL-6, CCL-2, CTGF, TGF-beta, and VEGF via RAGE activation and NF-kappaB signal transduction. Hyperglycemia (30 mM), but not the equivalent dose of mannitol, promotes proinflammatory (IL-6 and CCL-2), profibrotic (TGF-beta) and angiogenic (VEGF) responses in tubular cells via MAPK and PKC signaling and induces epithelial mesenchymal transition, which is TGF-beta1 mediated. It has recently been shown that toll-like receptor (TLR) is implicated in the diabetic kidney. In human DN biopsies and PTEC, TLR4is upregulated and plays a permissive role in HG-induced IL-6 and CCL-2 overexpression and monocyte transmigration. In streptozotocin induced rat DN and PTEC, TLR2 appears to be upregulated. Other novel mediators that become activated in PTEC exposed to HG include macrophage inflammatory protein-3-alpha, Kruppel-like factor 6 and thioredoxin-interacting protein, which may be attenuated by peroxisome proliferator-activate dreceptor-gamma activation. Collectively, these phenomena suggest that the renal tubules are heavily involved in the pathogenesis of DN. These pathophysiologic responses may be collectively described as diabetic tubulopathy. PMID- 21659766 TI - The renin-angiotensin system. AB - Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in developed countries where type 2 diabetes mellitus has reached epidemic proportions. Although the exact pathogenesis of DN is not fully understood and is likely diverse in nature, there are convincing data that the renin-angiotensin system (RAS) is a major mediator of renal injury. Angiotensin II (Ang II), traditionally playing a central role as a mediator of glomerular hemodynamic adaptation and injury, is now recognized to exert proinflammatory action leading to upregulation of chemokines, adhesion molecules, and other fibrogenic growth factors that culminate in a decline of renal function. Hyperglycemia and mechanical stress deriving from glomerular hypertension are the key factors underlying pathogenesis of DN. The common signaling pathways stimulated by high glucose and mechanical insult may act synergistically, thereby accelerating the cell damage. Podocytes are subjected not only to the load of filtered glucose but also to diverse mechanical forces. Both high glucose and mechanical stress may impair the protein systems anchoring the podocyte foot processes in the glomerular basement membrane, therefore blunting resistance of these cells to mechanical forces in addition to the inflammatory insults. Loss of the podocytes is irreversible due to their inability to proliferate and to replenish damaged cells. Podocytes are injured early in the course of DN, which, most likely, underlies further glomerular and renal damage in diabetes. Under normal physiological conditions, podocytes play a specific role in the maintenance of intraglomerular RAS balance with enzymatic activities that predominantly lead to ANG1-7 and ANG1-9 formation, as well as Ang II degradation. ANG1-7 counteracts the proinflammatory actions of Ang II. These enzymatic activities are altered in a nonphysiological environment such as hyperglycemia that mimics diabetic kidney disease. An understanding of the local intraglomerular RAS will provide a novel approach for early stages of DN. PMID- 21659767 TI - The kallikrein-kinin system. AB - Emerging evidence suggests a role of the kallikrein-kinin system (KKS) in the pathogenesis of diabetic nephropathy (DN). Tissue kallikrein 1 is a member of the tissue kallikrein family that is mainly responsible for the generation of kinins, and bradykinin (BK) is the principal kinin responsible for the biologic actions of the KKS that acts through the ubiquitous BK 2receptor (B2R) and the inducible B1R. In the kidney, all KKS components are expressed. In particular, kallikrein 1 that is traditionally thought to be solely confined to the distal nephron has recently been identified in the proximal tubule of the human diabetic kidney. Current evidence suggests conflicting roles of the KKS in DN. For a renoprotective role of the KKS, BK reduces mesangial cell proliferation under the diabetic milieu; Akita B2R-/- or STZ-induced KLK-/- mice (T1DM) have more severe albuminuria and glomerulosclerosis, while antagonizing the B2R with icatibant attenuates the antiproteinuric effect of ramiprilin db/db mice (T2DM). For a detrimental role of the KKS, BK upregulates tubular cell IL-6, CCL-2, and TGF beta expression via ERK1/2 activation; the B2R-/- status protects against the development of DN lesions in STZ-injected mice, while blocking B2R with icatibant alleviates biochemical and histologic injuries in uninephrectomized db/db mice. These opposite findings may arise from multiple factors and call for further evaluation to clarify the role of the KKS in DN and diabetic tubulopathy. PMID- 21659768 TI - Translating experimental diabetic nephropathy studies from mice to men. AB - The laboratory mouse is among the best characterized and flexible experimental platforms available for the study of diabetic nephropathy (DN). However, studies of progressive kidney disease in mice have underscored several important technical considerations for accurate phenotyping of renal function. Most mouse models of DN fail to exhibit progressive kidney disease. However, a few models have proved particularly useful. Despite the utility of these models, whether they can accurately predict clinical benefit of therapeutics in human DN remains to be established. PMID- 21659769 TI - Role of triglyceride-rich lipoproteins in renal injury. AB - Dyslipidemia is implicated as a risk factor for the development of atherosclerosis. Specifically triglyceride-rich lipoproteins and their lipolysis products are shown to be proinflammatory and proapoptosis in both in vivo and in vitro studies with endothelium. However, the role of triglyceride-rich lipoproteins in the progression of kidney diseases is not clear. Epidemiology studies demonstrated a correlation between renal disease and blood lipids. Recent evidence suggests that the mechanism may involve cellular uptake of lipid and de novo lipogenesis. Further studies are needed to establish the relevance of these mechanistic studies in human pathophysiology. PMID- 21659770 TI - Study of diabetic nephropathy in the proteomic era. AB - Diabetic nephropathy (DN) remains a major complication of diabetes leading to end stage renal disease (ESRD). The number of diabetic patients with ESRD who require renal replacement therapy has been increasing, implicating unsuccessful prevention of diabetic renal complication. This unfavorable outcome reflects insufficient knowledge on pathogenic mechanisms of DN and its detection at late stage. Currently, microalbuminuria is used for diagnosis of DN. However, some patients with microalbuminuria have advanced renal pathological changes indicating that microalbuminuria is not the perfect marker for early detection of DN and a better biomarker is urgently needed. Recently, particularly after the completion of the Human Genome Project, proteomics (systematic analysis of proteins for their identity, quantity and function) has been recognized as an emerging subdiscipline of modern sciences. During the past decade, proteomics has been widely applied to several areas of biomedical research, including the investigation of DN. This chapter summarizes recent progress of proteomics applied to DN with ultimate goals to better understand its pathogenic mechanisms and to search for novel bio-markers for earlier diagnosis. PMID- 21659771 TI - Treatment and landmark clinical trials for renoprotection. AB - During the last two decades, many large-scale randomized clinical trials have confirmed the importance of lowering blood pressure and inhibiting the renin angiotensin-aldosterone system (RAAS) to preserve renal function in patients with chronic kidney disease due to different causes. With growing epidemic of type 2 diabetes, the burden of diabetic nephropathy (DN) will continue to grow. Based on a large body of epidemiological, experimental and interventional studies, strict glycemic control, blood pressure lowering and RAAS blockade are now the recommended strategies in the prevention and control of DN. Both angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) have been shown unequivocally to reduce proteinuria and preserve renal function in affected patients. Importantly, therapeutic responses are dose dependent, and these drugs should be given in maximal dosages as tolerated. Combined use of ACEI and ARB reduced proteinuria and rate of decline of renal function, although it did not appear to confer extra renoprotection over the use of either agent alone. Spironolactone and aliskiren are alternative drugs that block the RAAS and have been demonstrated to further reduce proteinuria when added to ACEI or ARB. In the absence of long-term data about their safety and efficacy on renal function, combined use of these agents must be administered with caution after careful consideration of risk-benefit ratio with close monitoring for adverse effects, notably hyperkalemia. Pending further evidence, the use of a team approach to attain multiple treatment goals will improve renal outcomes in these high risk subjects. PMID- 21659772 TI - Intensive glycemic control and renal outcome. AB - Diabetes is the leading cause of chronic kidney disease (CKD) in many countries around the world, accounting for up to 50% of people who develop end-stage renal disease. The risk of morbidity and mortality is particularly high in people with both conditions, highlighting the importance of preventing the development and progression of earlier stage CKD in people with diabetes. Inadequate glycemic control has been associated with poor outcomes in diabetes, with early observational studies suggesting that tighter glycemic control may improve microvascular and macrovascular outcomes in patients with diabetes. Since then, large trials assessing the effect of intensive glycemic control in the general diabetic population have provided strong evidence that intensive therapy reduces the incidence and progression of microvascular outcomes including microalbuminuria, a key early marker of diabetic nephropathy (DN). These results have been consistent across both type 1 and type 2 diabetic populations demonstrating that intensive glycemic therapy provides clear benefits, delays the onset or progression of DN, particularly in its early stages. Whilst the benefits of intensive glycemic therapy for people with diabetes and early stage CKD have been well established, controversy remains as to whether intensive therapy slows the progression of established DN, particularly among individuals who have a reduced glomerular filtration rate. In addition, severe hypoglycemia has been associated with intensive glycemic therapy, raising safety concerns that may be of particular relevance for patients with decreased kidney function (CKD stages 3 5). Until further data are available, an individualized approach to glucose management is recommended in people with reduced glomerular filtration rate. PMID- 21659773 TI - Nuclear hormone receptors as therapeutic targets. AB - In spite of excellent glucose and blood pressure control, including administration of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy (DN) still develops and progresses. The development of additional protective therapeutic interventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, inflammation and development of fibrosis. The increasing prevalence of DN has led to intense investigation of the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. Several nuclear receptor-activating ligands (agonists) have been shown to have a renal protective effect in the context of DN. This review will discuss the evidence regarding the beneficial effects of the activation of the vitamin D receptor (VDR) and the farnesoid X receptor (FXR) in preventing the progression of DN, and will describe how the discovery and development of compounds that modulate the activity of VDR and FXR may provide potential additional therapeutic approaches in the management of DN. PMID- 21659775 TI - Kidney regeneration: any prospects? AB - Chronic kidney disease is a leading cause of mortality and morbidity in western countries which affects about 11% of the adult population. With the increasing rate of chronic kidney disease and limited alternatives for its treatment, potential regenerative approaches for kidney damage are urgently needed, but are limited by the complexity of this organ. Bone marrow-derived stem cells as well as mesenchymal stem cells were envisioned for the development of this type of treatment. However, most studies suggested that these cells cannot differentiate into renal epithelial cells, and concluded that their beneficial effects are probably related to secretion of growth factors. In addition, a long-term partial maldifferentiation of injected mesenchymal stem cells into adipocytes accompanied by glomerular sclerosis was reported. The incapacity of bone marrow-derived stem cells to differentiate into renal cells suggested that turnover of resident renal epithelial cells may be related to the existence of potential stem/progenitor cells within the adult human kidney. Consistently, renal progenitors with the potential to differentiate into podocytes as well as tubular cells were recently identified at the urinary pole of the Bowman's capsule in adult kidneys. The discovery of renal progenitors that encourage regeneration and promote functional repair of glomerular injury demonstrates that prevention and treatment of glomerulosclerosis may be possible. In addition, converging evidence suggests that the outcome of glomerular disorders depends on a balance between injury and regeneration provided by renal progenitors. In summary, understanding how self renewal and fate decision of renal progenitors may be perturbed or modulated will be of crucial importance to obtain novel pharmacological tools for prevention and treatment of diabetic nephropathy, as well as other causes of glomerulosclerosis. PMID- 21659774 TI - Antifibrotic treatment and other new strategies for improving renal outcomes. AB - Diabetic nephropathy (DN) is clinically characterized by proteinuria and hypertension. Investigations suggest that matrix accumulation and inflammatory processes contribute to the pathological features of this progressive disease. This chapter reviews novel targeted approaches to the treatment of DN, with the goal of slowing the progression and improving renal function. Many studies support the use of agents that block the renin-angiotensin-aldosterone system in DN. Novel, oral agents that are promising in early clinical studies are agents such as pirfenidone and bardoxolone as they are associated with early improvement in renal function in patients with advanced diabetic kidney disease. Additionally, strategies that inhibit inflammatory cytokines, chemokines, adhesion molecules and mediators of the innate immune response may provide novel targets for the treatment of DN. Larger clinical studies are eagerly awaited to determine if new agents that specifically block kidney fibrosis and inflammation will delay, arrest and possibly reverse progressive renal failure. PMID- 21659777 TI - New-onset diabetes and nephropathy after renal transplantation. AB - New-onset diabetes mellitus after transplantation (NODAT) is an important complication after kidney transplantation, responsible for increased mortality mainly related to cardiovascular events and infections. It has been also identified as an independent risk factor associated with graft loss. The varying definitions of diabetes used in the literature, and the prevalence and incidence of NODAT, are difficult to establish: it varies from 2 to 50% in the kidney transplant population. However, using the World Health Organization and the American Diabetes Association criteria, it occurs in ~15% of transplant recipients at 1 year in the USA, and ~5-10% in Europe. The main recipient-related risk factors include old age, high body weight and high body mass index (BMI) before transplantation, Afro-American or Hispanic ethnicity, hepatitis C virus (HCV) infection, and impaired fasting glucose level before transplantation. The other significant risk factors include male donor, acute rejection episodes, cytomegalovirus (CMV) infection and the immunosuppressive regimen, especially the use of tacrolimus (FK506), steroids, or mammalian target for rapamycin inhibitors. While some risk factors cannot be modified, others, such as recipient body weight, BMI, HCV or CMV infection, and immunosuppressive regimen can be controlled with an appropriate diet or treatment. Screening for impaired fasting glucose should be done before transplantation in dialysis or end-stage renal disease patients to identify patients at risk for NODAT. In patients with increased BMI, weight loss before transplantation reduces the risk of NODAT. HCV infection should be treated before transplantation. Prolonged anti-CMV prophylaxis may be used. Cyclosporine A is preferred to tacrolimus in patients at high risk of NODAT. A steroid-free regimen or early steroid withdrawal is encouraged to reduce the risk of NODAT. PMID- 21659778 TI - Into the future: prevention of diabetes. AB - With the increasing prevalence of obesity and an aging population, type 2 diabetes mellitus (T2DM) is rapidly becoming the most common chronic disease in the US. In the US alone, over 1.5 million new cases by the Center for Disease Control are diagnosed per year. Concomitant with the rising epidemic in diabetes are the resulting severe complications such as renal and cardiac dysfunction, amputations, impairment in vision and increased mortality. Since T2DM has such an enormous cost in terms of quality of life and mortality as well as economic cost, prevention of T2DM is an important and appropriate target. Interventions for T2DM range from lifestyle modifications such as weight loss and diet to pharmacological agents and surgical intervention such as bariatric surgery. Of the various lifestyle modifications studied, weight loss has consistently been shown to be an effective mechanism of T2DM prevention. Regarding dietary interventions, only the increased consumption of green, leafy vegetables reduces the risk of T2DM in contrast to the popular belief that a diet high in fruits and vegetables reduces this risk. Pharmacological agents investigated in preventing diabetes primarily target the same pathological pathways found in T2DM. Metformin has consistently been shown to reduce the incidence of T2DM and improve impaired glucose tolerance. alpha2-Glucosidase inhibitors are also effective in prevention of T2DM, but are limited by their gastrointestinal side effects. Interestingly, although ramipril showed no effect on development of diabetes, valsartan did reduce the incidence of diabetes in patients with impaired glucose tolerance and cardiovascular disease. Although single intervention studies are important in delineating whether an intervention or agent is effective, a multi-faceted approach has been shown to be more effective. Importantly, such an approach is pragmatic and urgently needed to stem the tide of T2DM and its significant human and financial cost. PMID- 21659779 TI - Takotsubo cardiomyopathy followed by neurogenic stunned myocardium in the same patient: gradations of the same disease? AB - Takotsubo cardiomyopathy is a phenomenon of transient acute left ventricular dysfunction without obstructive coronary disease seen predominantly in postmenopausal women in the setting of acute emotional or physical stress. Neurocardiogenic injury from acute neurologic events such as intracranial bleeding can precipitate transient left ventricular dysfunction (termed 'neurogenic stunned myocardium') that may be indistinguishable from takotsubo cardiomyopathy. There is controversy about the diagnosis of takotsubo cardiomyopathy in the setting of acute neurologic disorders. We describe a case of a 67-year-old female who initially presented with takotsubo cardiomyopathy due to an acute gastrointestinal illness and 4 years later developed a recurrence in the setting of an ischemic cerebrovascular accident that was associated with more prominent EKG changes and much higher cardiac biomarker release but similar degree of left ventricular dysfunction. This case suggests that susceptibility to this disorder is likely due to patient-specific factors rather than etiology, and acute neurologic disorders should be included as precipitants of takotsubo cardiomyopathy. We also theorize that there may be patients with milder forms of stress-related cardiac injury who do not develop left ventricular dysfunction, being similar to the wide range of cardiac manifestations in patients with acute neurologic disorders. We review published literature on neurologic precipitants of takotsubo cardiomyopathy. PMID- 21659776 TI - Effects of pancreas transplantation on the prevention and reversal of diabetic nephropathy. AB - Pancreas transplantation (PTx) is the only available treatment which is able to restore normoglycemia without exposing patients to the risks of severe hypoglycemia, thus allowing testing the effects of very long-term euglycemia in preventing, halting and reversing diabetic nephropathy (DN). Pancreas and islet transplantation in animal models have been shown to prevent, ameliorate or reverse the development of DN lesions. PTx, performed simultaneously or shortly after kidney transplantation in patients with type 1 diabetes prevents the recurrence of diabetic glomerulopathy lesions in the renal allograft. To test whether DN lesions are reversible in humans, we studied renal structure before and 5 and 10 years after PTx in nonuremic patients with long-term type 1 diabetes, with mild to advanced DN lesions at baseline. Diabetic glomerular lesions were not significantly changed at 5 years after PTx, but were markedly improved after 10 years. Indeed, in most patients glomerular structure had returned to normal at 10-year follow-up. These pancreas transplant studies also showed that remodeling of the tubulointerstitium and decrease in interstitial collagen was possible. Thus, the lesions of DN are reversible by long-term normoglycemia, and that it is possible in humans associated with substantial architectural remodeling and healing of glomerular, tubular, and interstitial structures. PMID- 21659780 TI - The 'centre effect' in nephrology: what do differences between nephrology centres tell us about clinical performance in patient management? AB - Improving the quality of care provided by nephrology centres to patients with kidney disease requires a clear understanding of how to compare performance after adjustment for case mix, combined with a detailed understanding of the structure and processes that are associated with the achievement of good clinical results. In this review, we discuss how to measure quality of care (using process or outcome measures), how to take case mix into account, how best to display comparisons between nephrology centres, and how to study the causes of real variations in quality between centres. This is a narrative review; we include examples from other fields in which the centre effect has been studied, including education. PMID- 21659781 TI - IgA-dominant postinfectious glomerulonephritis: a new twist on an old disease. AB - IgA-dominant acute postinfectious glomerulonephritis (APIGN) is an increasingly recognized morphologic variant of APIGN, particularly in the elderly. In contrast to classic APIGN, in which there is typically glomerular deposition of IgG and C3 or C3 only, IgA is the sole or dominant immunoglobulin in IgA-dominant APIGN. Because the vast majority of reported cases occur in association with staphylococcal infections, the alternative designation 'IgA-dominant acute poststaphylococcal glomerulonephritis' has been applied. Diabetes is a major risk factor, likely reflecting the high prevalence of staphylococcal infection in diabetics, particularly involving skin. Patients typically present with severe renal failure, proteinuria and hematuria. Prognosis is guarded with less than a fifth of patients fully recovering renal function. This variant of APIGN must be distinguished from IgA nephropathy. Features that favor IgA-dominant APIGN over IgA nephropathy include initial presentation in older age or in a diabetic patient, acute renal failure, intercurrent culture-documented staphylococcal infection, hypocomplementemia, diffuse glomerular endocapillary hypercellularity with prominent neutrophil infiltration on light microscopy, stronger immunofluorescence staining for C3 than IgA, and the presence of subepithelial humps on electron microscopy. The pathogenetic mechanism of selective IgA deposition in patients with poststaphylococcal glomerulonephritis likely involves specific host responses to the inciting pathogen. PMID- 21659782 TI - Uninephrectomy of diabetic OVE26 mice greatly accelerates albuminuria, fibrosis, inflammatory cell infiltration and changes in gene expression. AB - BACKGROUND/AIMS: OVE26 (OVE) mice provide a valuable model of advanced diabetic nephropathy (DN), but they take 8 months to develop moderate interstitial fibrosis and reduced glomerular filtration rate (GFR). The aim of this project was to produce a more rapid and advanced model of DN. METHODS: Uninephrectomy was applied to OVE and FVB mice at 2 months of age. Albuminuria, GFR, glomerulosclerosis, interstitial fibrosis, gene expression and monocyte infiltration were evaluated as a function of diabetes and uninephrectomy. RESULTS: Albuminuria, monocyte infiltration, mesangial matrix expansion and renal fibrosis were greatly accelerated in uninephrectomized mice. DN was more advanced 10 weeks after uninephrectomy than in untreated OVE mice at 8 months of age. Uninephrectomy had almost no effect on these characteristics in non-diabetic mice. Microarray studies indicated that the accelerated fibrosis and cell infiltration in nephrectomized OVE mice were accompanied by corresponding gene expression changes in canonical pathways for fibrosis and inflammation. CONCLUSION: Uninephrectomy greatly accelerates all features of diabetic renal damage. This procedure provides a 10-week period after surgery to examine very large changes in the pathology of DN. The model may be particularly useful for testing new therapies and for analysis of the progression of albuminuria and fibrosis in DN. PMID- 21659783 TI - Proteomic approaches in understanding a detected relationship between chemotherapy-induced nephrotoxicity and cell respiration in HK-2 cells. AB - BACKGROUND/AIMS: Nephrotoxicity is a prominent component of the profile of chemotherapeutic agents and to date proteomics has represented the main technique to identify protein profiles in response to xenobiotic exposure. METHODS: We made use of two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight analysis to evaluate chemotoxicity effects of cisplatin (CPT) and carboplatin (CB) on proteins from human renal proximal tubule epithelial cells (HK-2). RESULTS: Tandem mass spectrometry analysis showed that ATP synthase subunit alpha and serine hydroxymethyltransferase were only expressed in HK-2 cells exposed to CPT. Since CPT causes damage in cellular respiration, we suggest that this might be a protective adaptation to CPT-induced nephrotoxicity. Thioredoxin-dependent peroxide reductase disappeared in the CPT group and was upregulated in the CB group, suggesting that CB exposure stimulates preventive apoptotic mechanisms. We suggest a relationship between chemotherapeutic agent-induced nephrotoxicity and cell respiration. The identification of proteins differentially expressed in HK-2 cells, when exposed to CPT and CB, not only supplies important information to understand the molecular action mechanisms, which are triggered by metal-based drugs in cell nephrotoxicity, but also can lead to the design of more effective anticancer drugs. CONCLUSION: These results provide important insights into the investigation of possible biomarker(s) of toxicity that could eventually reduce the side effects of chemotherapeutic agents. PMID- 21659784 TI - Long-term outcome of combined interferon-alpha and 5-fluorouracil treatment for advanced hepatocellular carcinoma with major portal vein thrombosis. AB - BACKGROUND/AIM: We previously reported the beneficial effects of a combination therapy of interferon (IFN)-alpha/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumor thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than twice the number of patients relative to the previous report; it also evaluates the clinical predictor on the response to the combination therapy and long-term survival. METHODS: The study subjects were 102 patients with advanced HCC and tumor thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least 2 courses of IFN-alpha/5-FU. RESULTS: No major treatment-related complications were noted. In the 102 patients, 40 (39.2%) showed objective response [11 (10.8%) showed complete response, 29 (28.4%) partial response], 8 (7.9%) showed no response and 54 (52.9%) showed progressive disease. CONCLUSION: IFN-alpha/5-FU combination therapy is a promising modality for advanced HCC with tumor thrombi in the major portal branches. PMID- 21659785 TI - Phase II study of combined treatment with irinotecan and S-1 (IRIS) in patients with inoperable or recurrent advanced colorectal cancer (HGCSG0302). AB - OBJECTIVES: This phase II study was designed to evaluate the efficacy and safety of oral fluoropyrimidine S-1 plus irinotecan (IRIS regimen) in patients with previously untreated metastatic colorectal cancer. METHODS: The response rate was the primary endpoint. Safety, progression-free survival time, and median survival time were secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer. Irinotecan was administered at a dose of 100 mg/m2 (on days 1 and 15). S-1 (40 mg/m2) was administered for 2 weeks (on days 1 to 14) and followed by a 2-week rest. RESULTS: Forty patients were enrolled. Four patients had grade 4 neutropenia, and six patients had grade 3 diarrhea. No other serious hematologic or nonhematologic adverse reactions occurred, and all patients received IRIS safely on an outpatient basis. The response rate was 52.5% (95% confidence interval [CI], 36.1-68.5%). Median progression-free survival was 8.6 months (95% CI, 5.3-11.9), and median survival time was 23.4 months (95% CI, 15.9-30.8). CONCLUSIONS: IRIS produced a high response rate and could be given safely. IRIS may become a first-line treatment for inoperable or recurrent advanced colorectal cancer. PMID- 21659788 TI - Are stalkers disordered or criminal? Thoughts on the psychopathology of stalking. AB - Although stalking is a widespread phenomenon that can be caused by different motives, consideration of the psychopathological underpinnings of stalking behaviour is scarce. In rare cases, stalking can be an expression of mental disorder. Psychotic stalking, for example, can occur as a symptom of schizophrenia or erotomania. Psychotic stalkers are criminally not responsible for their acts and have to be treated in a psychiatric hospital. The majority of stalkers, however, do not suffer from a disorder in need of treatment, and therefore their criminal responsibility is not diminished. Although legislative approaches to protecting victims of stalking differ widely in the European Union, mentally not severely disturbed stalkers can be prosecuted and punished according to criminal law in most countries. In some cases, the differentiation between mentally sane and mentally disturbed stalkers is difficult. This paper focuses on the psychopathology of such 'borderline cases', using the example of a court decision in Germany. PMID- 21659786 TI - A phase II multi-center study of triple therapy with paclitaxel, S-1 and cisplatin in patients with advanced gastric cancer. AB - OBJECTIVES: To carry out a phase II multi-center study on the efficacy and safety of triple combination therapy with paclitaxel, S-1, and cisplatin in patients with unresectable/metastatic gastric cancer. METHODS: A total of 63 patients from 8 institutions were included in this study. Paclitaxel (160 mg/m2) was administered by infusion for 3 h on the first day. S-1 (70 mg/m2/day) was administered orally for 14 consecutive days from the first day. Cisplatin (60 mg/m2) was administered intravenously over 24 h on day 14 of every 28-day cycle. RESULTS: All 63 patients were assessed for clinical efficacy and safety. A total of 259 cycles of treatment were administered (median 4, range 1-10). Grade 3-4 toxicities included neutropenia in 30.2%, thrombocytopenia in 12.7%, and anemia in 11.1%. There was no grade 3-4 non-hematological toxicity or treatment-related death. Complete response was observed in 6 patients and partial response in 34 patients. The overall response rate was 63.5%. The median progression-free survival and response duration were 8.0 and 8.8 months, respectively, and median survival time was 15 months. CONCLUSIONS: Triple combination therapy with paclitaxel, S-1, and cisplatin showed promising safety and efficacy profiles with the potential to become a standard regimen for unresectable/metastatic gastric cancer. PMID- 21659787 TI - Evoked stapedius reflex and compound action potential thresholds versus most comfortable loudness level: assessment of their relation for charge-based fitting strategies in implant users. AB - AIM: The main goal of the present study was to assess the feasibility of using evoked stapedius reflex (eSR) and evoked compound action potential (eCAP) thresholds to create speech processor programs for children using Med-El Maestro software. The secondary goals were (1) to compare the eSR and eCAP thresholds recorded using charge units in experienced adults fitted with Med-El Pulsar CI100 cochlear implants with most comfortable loudness levels (MCLs) obtained for the apical, medial and basal electrodes, and (2) to compare eSR and eCAP thresholds for the apical, medial and basal electrodes between adults and children. METHODS: Fourteen children and 16 adults participated in the study. eSR and eCAP thresholds were measured in both groups using the auditory nerve response telemetry algorithm, with MCL being behaviourally measured only in the adult group. RESULTS: In the adult population, the correlation between eSR threshold and MCL was better for apical, medial and basal electrodes than that between eCAP threshold and MCL. There was no significant difference in the means obtained for eCAP and eSR thresholds in children and adults for any of the electrodes tested. This finding suggests that in children, the correlations between eCAP thresholds and MCL values, and those between eSR thresholds and MCL values are not lower than those generally found in adults. CONCLUSIONS: Although the eSR threshold is a better predictor of MCL values, both eSR and eCAP thresholds can be useful tools for assisting with map creation for children. PMID- 21659789 TI - Magical thinking in somatoform disorders: an exploratory study among patients with suspected allergies. AB - BACKGROUND: In order to reconceptualize somatoform disorders (SFDs), the psychological characteristics of SFD patients are increasingly investigated. The cognitive style of magical thinking (MT) has not been studied so far in patients with SFDs. SAMPLING AND METHODS: In a cross-sectional study, 201 allergy workup patients were interviewed using the Structured Clinical Interview for DSM-IV; they answered a set of self-report questionnaires including the Schizotypal Personality Questionnaire subscale for MT and the Patient Health Questionnaire (PHQ). The expression of MT was explored in 61 patients with SFDs compared to 140 patients without SFDs. RESULTS: Patients with SFDs reached higher scores of MT, also when controlled for gender, depression, and anxiety. In particular, they stated more frequently that they were believers in telepathy (64 vs. 44%) and clairvoyance (43 vs. 16%). MT correlated only weakly with somatization/somatic symptom severity, depression, and anxiety. CONCLUSIONS: Among allergy workup patients with SFDs we found considerable MT. This indicates that SFD patients may tend to mistake correlation for causality in a more general way, and not just in an illness-related context. The relation to indicators of illness severity (somatic symptom severity/somatization, depression, and anxiety) was relatively weak. Possible implications for research, diagnostics, and therapy are discussed. PMID- 21659790 TI - Anxiety and depression in cardiac patients: age differences and comparisons with the general population. AB - BACKGROUND: Anxiety and depression are often found in cardiac patients, but also in the general population. Therefore, evaluation of these symptoms in patients requires a comparison with norm values. The purpose of this study was to explore differences between cardiac patients and the general population in age dependency of anxiety and depression, and to discuss possible reasons for these differences. METHODS: A sample of German cardiac patients (n = 2,696) and a sample of the German general population (n = 2,037) were tested using the Hospital Anxiety and Depression Scale (HADS). RESULTS: While we confirmed a linear age trend of anxiety and depression in the general population, we observed an inverted U shaped age dependency in the patient sample. Young patients are especially affected by anxiety and depression. Five items of the HADS that mainly contributed to the age differences were identified. Formal characteristics of these 5 items could not explain the age differences. Concerning the meaning of the items, however, most of the items refer to worrying about the future. CONCLUSIONS: The relatively low rates of anxiety and depression in older patients (compared with the general population) indicate that adaptation processes took place, which should be taken into account in studies concerning the psychological status of patients. Young patients need special attention when dealing with mental distress. PMID- 21659791 TI - Bipolar mood disorder, creativity and schizotypy: an experimental study. AB - AIMS: Our purpose was to make an experimental assessment of the elements of creativity and the features of schizotypy in patients with bipolar disorder, compared with healthy control subjects and to investigate the effect of an acute affective episode (depressed or manic) and the features of schizotypy on the measurements of creativity. METHODS: Forty patients with bipolar disorder, and 48 age- and gender-matched control subjects were studied. For the assessment of creativity the Revised Art Scale and the 'inventiveness' part of the Berlin Intelligence Structure Test (BIS) were used. The Oxford-Liverpool Inventory of Feelings and Experiences was applied for estimation of schizotypy. RESULTS: The bipolar patients did not differ on the RAS scale from the control subjects but obtained significantly higher scores on the BIS-total as well as on the verbal part of the test. Their scores on the BIS scale during depression were significantly lower than in remission. The bipolar patients obtained significantly higher scores on all dimensions of schizotypy compared with the controls. CONCLUSIONS: These results confirm previous data showing higher scores on some creativity scales in bipolar patients compared with healthy subjects. They also corroborate a relationship between the features of schizotypy and creativity scores in bipolar patients. PMID- 21659792 TI - Combining self-defeating and depressive personality symptoms into one construct. AB - In the history of the DSM, two disorders have been proposed for consideration that shared much in common - self-defeating personality disorder (SDPD) and depressive personality disorder (DPD). In a previous paper, it was reported that SDPD (n = 34) and DPD (n = 240) shared a diagnostic overlap of 70%. It was concluded that SDPD could not be empirically supported as a diagnostic category. In this paper, the overlap of the two disorders was explored further in this same sample (n = 1,200) of psychiatric outpatients. We found that symptoms of the two disorders were positively correlated. Confirmatory factor analysis (CFA) provided strong support for a model with two distinct, but very highly correlated constructs. Based on the hypothesis that SDPD and DPD are separate but related, a second-order CFA factor was fit to the data to further examine the strong association between the two disorders. Taken collectively, it is concluded that DPD and SDPD are components of the same construct, and that the current DPD and SDPD diagnoses as proposed in the DSM are actually subtypes of a common personality pathology (i.e. a second-order factor). PMID- 21659793 TI - Art therapy may reduce psychopathology in schizophrenia by strengthening the patients' sense of self: a qualitative extended case report. AB - BACKGROUND: Many forms of artistic expression and art therapy are widely used in psychiatric treatment, but we lack an understanding of how artistic expression may interfere with psychopathology. METHOD: Art therapy inspired by the Expressive Arts was offered for 1 year to two groups of outpatients. One group consisted of patients with severe schizophrenia and the other group of 5 nonpsychotic psychiatric patients with depression and/or personality disorders. The course of therapy was described systematically, and the experience of each patient was examined using interviews and written evaluations before and after therapy and at a 1-year follow-up. A qualitative analysis was done to determine how art therapy affects the psychopathology of the patients. RESULTS: The patients used the art therapy in many different ways. The most important benefit of the art therapy was a strengthening of the patients' sense of self. This was accomplished by engagement in the artistic process and by aesthetic reflections on the painted images. The stronger sense of self diminished the tension arising from interpersonal contact, boosting their self-esteem and thereby improving their social competences. CONCLUSION: All patients reported a very good outcome, and the qualitative analysis showed that the positive effect of art therapy is mainly due to a strengthening of the patients' minimal sense of self. PMID- 21659795 TI - The heterologous systems in the study of cardosin B trafficking pathways. AB - Cardosins are abundant in cardoon pistils and were found to accumulate in different cell compartments: cardosin A was detected in the vacuoles of stigmatic papillae and cardosin B accumulates in the extracellular matrix of the transmitting tissue. Due to the fact that cardoon system imposes some limitations to the study of processing and trafficking events, heterologous species have been employed to study cardosins trafficking pathways. Cardosin B was successfully expressed both in Arabidopsis and Tobacco plants, where it accumulated mainly in the vacuole but it was also detected in the cell wall. The glycosylation pattern of cardosin B was replicated in these systems - high-mannose type glycans. In tobacco leaves, cardosin B is transported through the Golgi in a RAB-D2a dependent route, and is delivered to the vacuole via the prevacuolar compartment in a RAB-F2b-dependent pathway. PMID- 21659794 TI - Thyroid-stimulating hormone levels in the first days of life and perinatal factors associated with sub-optimal neuromotor outcome in pre-term infants. AB - AIM: To identify perinatal factors associated with sub-optimal neuromotor outcome in infants without evident central nervous system lesions (intraventricular hemorrhage/ periventricular leukomalacia), with gestational age <=30 (group I) and of 31-32 weeks (group II). PATIENTS AND METHODS: A total of 102 premature infants admitted to the Neonatal Intensive Care Unit of Pisa, at 26-32 weeks of gestation, were studied. Data about perinatal factors and TSH values at 3-4 days of life were collected. The assessment of neuromotor development was performed at 18 months of corrected age, using the locomotor subscale of the Griffiths Scales of Mental Development. RESULTS: Risk factors supposed to be predictive of sub optimal neuromotor outcome (odds ratio >1) were at <=30 weeks: male sex, small for gestational age, patent duct arterious, respiratory distress syndrome, and at 31-32 weeks: Apgar at 5 min <7, respiratory distress syndrome, patent duct arterious and birth weight <1500 g. A strong correlation was also found between TSH screening values >4,3 mU/l and suboptimal neuromotor outcome in both groups. CONCLUSIONS: Several perinatal factors, acting on an immature and more vulnerable nervous system, such as the pre-term one, different for different gestational ages, are associated with a sub-optimal neuromotor outcome. Higher, but within the normal range, TSH values at screening seem to be a strong risk factor for neuromotor outcome in preterm infants without intraventricular hemorrhage or periventricular leukomalacia. PMID- 21659797 TI - Cushing's syndrome and adrenal axis suppression in a patient treated with ritonavir and corticosteroid eye drops. PMID- 21659796 TI - A complex crosstalk between polymorphic microRNA target sites and AD prognosis. AB - Genetic variation associated with different diseases interferes with microRNA mediated regulation by creating, destroying, or modifying microRNA (miRNA) binding sites. Alzheimer's disease (AD) is a common neurodegenerative disorder that affects cognitive function in the elderly and has associated genetic variation within the diseased genome. We investigated the extent to which these SNPs interfere with miRNA gene regulation and affect AD susceptibility. We designed a sophisticated computational pipeline to predict the potential miRNA target SNP interactions followed by a rigorous bioinformatic analysis to establish the effect of "gain-of-function" or "loss-of-function" of the miRNA mediated regulatory network on the etiology of the disease. The significant interactions include target SNPs present in seven genes-related to AD prognosis with the miRNAs- miR-214, -23a & -23b, -486-3p, -30e*, -143, -128, -27a &-27b, 324-5p and -422a. Further our study provides novel insight on the contribution of synonymous mutations towards AD pathogenesis. The putative miRNA::target SNP interactions suggest that the dysregulated miRNA network contributes to the aberrant gene expression in AD. Our results show that miRNA-target variability is a ubiquitous phenomenon in the adult human brain, which may influence gene expression in physiological and pathological conditions. The experimental assay of these miRNA::target SNP predictions will be the next step towards determining the functional effects of these SNPs on miRNA targets and their association with disease susceptibility. Overall, this work may serve as the cornerstones for understanding the variables of the molecular pathways relevant to the development of the disease and designing therapeutic miRNA regimens to modify diseased gene expression profiles in AD patients. PMID- 21659798 TI - Effect of continuous venovenous hemodiafiltration on darunavir and raltegravir exposure after administration via a gastroduodenal tube. PMID- 21659799 TI - The contribution of HIV-discordant relationships to new HIV infections: a rebuttal. PMID- 21659803 TI - Bibliography. Genes and cell metabolism. Current world literature. PMID- 21659804 TI - Adherence to guidelines for improved quality of data reporting: where are we today? PMID- 21659802 TI - Sleep and obesity. AB - PURPOSE OF REVIEW: This review summarizes the most recent evidence linking decreased sleep duration and poor sleep quality to obesity, focusing upon studies in adults. RECENT FINDINGS: Published and unpublished health examination surveys and epidemiological studies suggest that the worldwide prevalence of obesity has doubled since 1980. In 2008, 1 in 10 adults was obese, with women more likely to be obese than men. This obesity epidemic has been paralleled by a trend of reduced sleep duration. Poor sleep quality, which leads to overall sleep loss has also become a frequent complaint. Growing evidence from both laboratory and epidemiological studies points to short sleep duration and poor sleep quality as new risk factors for the development of obesity. SUMMARY: Sleep is an important modulator of neuroendocrine function and glucose metabolism and sleep loss has been shown to result in metabolic and endocrine alterations, including decreased glucose tolerance, decreased insulin sensitivity, increased evening concentrations of cortisol, increased levels of ghrelin, decreased levels of leptin, and increased hunger and appetite. Recent epidemiological and laboratory evidence confirm previous findings of an association between sleep loss and increased risk of obesity. PMID- 21659806 TI - Writing the abstract: completeness and accuracy matter. PMID- 21659807 TI - Global cardiovascular disease prevention: a call to action for nursing: the global burden of cardiovascular disease. PMID- 21659805 TI - Is propofol an analgesic? PMID- 21659809 TI - A life course approach to cardiovascular disease prevention. AB - During the past 2 decades, life-course social-ecological frameworks have emerged across health, developmental, social, behavioral, and public health disciplines as useful models for explaining how health trajectories develop over an individual's lifetime and how this knowledge can guide and inform new approaches to clinical and public health practice, multilevel policies, and research. Viewed from this perspective, and with emphasis on global cardiovascular health promotion and prevention of cardiovascular disease (CVD), this article summarizes evidence on the early origins and progression of CVD processes across the life course of individuals and diverse populations. Current evidence-based guidelines for CVD prevention are summarized, and recommendations for future research are suggested. PMID- 21659808 TI - Global cardiovascular disease prevention: a call to action for nursing: multilevel policies. AB - This section, multilevel policies, reviews the impact that has been and can be made by health policy changes at multiple levels, strategies and resources for increasing adherence to population prevention recommendations, and how changes at the microlevel and macrolevel of the environment can provide opportunities and rewards for healthy behaviors and disincentives for unhealthy behaviors. Policies that support primary prevention of cardiovascular disease require the participation of numerous stakeholders at multiple levels, such as governmental and regulatory agencies. Such policy changes support a healthy lifestyle, as in designated smoke-free areas; laws that mandate that food purveyors reduce sodium and fat content or, eliminate trans-fats; and availability of safe parks and bike and walking trails; and also provide a supportive environment that in turn reinforces adherence to primary prevention. Health-related policies have a major impact at the societal level in both developed and developing countries; thus, it is important to understand the role that policy plays in promoting a healthier lifestyle and the prevention of cardiovascular disease. This section discusses how health policies can impact primary prevention and adherence to healthful recommendations, with examples focused on physical activity and diet. PMID- 21659810 TI - Statements from participating organizations. PMID- 21659811 TI - Global cardiovascular disease prevention: a call to action for nursing: community based and public health prevention initiatives. AB - Policy changes are necessary to promote cardiovascular disease prevention. These will involve community-based and public health initiatives for primary and secondary prevention of cardiovascular disease. In this article, we discuss such interventions, community-based participatory research that has been conducted in this area, and implications for capacity building in genetics research. Finally, areas for future research in this area will be identified. PMID- 21659812 TI - Global cardiovascular disease prevention: a call to action for nursing. PMID- 21659813 TI - Nurse-based models for cardiovascular disease prevention: from research to clinical practice. AB - The worldwide personal and societal costs related to diseases of the vascular system are enormous. International research efforts have focused on discovering ways to implement prevention strategies shown to be both effective and cost efficient. Teams comprising health care professionals with expertise in nursing, dietetics, physical activity, and behavioral skills have shown high levels of success in preventive efforts, particularly in high-risk and vulnerable populations. Used appropriately, team-based, nurse-directed case management has the potential to effect positive change in both primary and secondary prevention of cardiac and other vascular diseases. PMID- 21659814 TI - The global burden of cardiovascular disease. AB - Cardiovascular disease (CVD) today is responsible for approximately one-third of deaths worldwide, and that figure will surely increase in both developing and developed countries as risk factors for the disease-primarily dyslipidemia, hypertension, obesity, diabetes, physical inactivity, poor diet, and smoking continue to increase. Although these risk factors are modifiable, to date there is a relative paucity of measures to prevent or control them, particularly in developing countries. A population strategy combined with a high-risk strategy for CVD prevention could greatly reduce the burden of disease in the coming decades. Many initiatives are working, but many more are needed. This chapter provides background on the global burden of CVD and provides the context for the subsequent chapters addressing nurses' roles in reversing the bleak predictions for the ravages of CVD if risk factors are left unchecked in the coming decades. PMID- 21659817 TI - Current and projected prevalence of arterial hypertension in sub-Saharan Africa by sex, age and habitat: an estimate from population studies. PMID- 21659815 TI - Preparing nurses for leadership roles in cardiovascular disease prevention. AB - Cardiovascular disease (CVD) is a critical global health issue, and cardiovascular nurses play a vital role in decreasing the global burden and contributing to improving outcomes in individuals and communities. Cardiovascular nurses require the knowledge, skills, and resources that will enable them to function as leaders in CVD. This article addresses the education, training, and strategies that are needed to prepare nurses for leadership roles in preventing and managing CVD. Building on the World Health Organization core competencies for 21st-century health care workers, the specific competencies of cardiovascular nurses working in prevention are outlined. These can be further strengthened by investing in the development of cultural, system change and leadership competencies. Mentorship is proposed as a powerful strategy for promoting the cardiovascular nursing role and equipping individual nurses to contribute meaningfully to health system reform and community engagement in CVD risk reduction. PMID- 21659818 TI - Blood pressure management in diabetes: a path forward? PMID- 21659819 TI - Present trends and future directions in the analysis of cardiovascular variability. PMID- 21659820 TI - The renaissance of the retinal microvascular network assessment in hypertension: new challenges. PMID- 21659821 TI - The proximal tubular renin-angiotensin system during albuminuria. PMID- 21659822 TI - Obesity can break your heart and more so when you are a woman. PMID- 21659823 TI - Lowering blood pressure with beta-blockers in peripheral artery disease: the importance of comorbidity. PMID- 21659824 TI - Isolated systolic hypertension of young-to-middle-age individuals implies a relatively low risk of developing hypertension needing treatment when central blood pressure is low. AB - OBJECTIVES: The clinical significance of isolated systolic hypertension (ISH) in the young is still controversial. Aim of the present study was to investigate whether prognosis of ISH in young-to-middle-age individuals differs according to central blood pressure (BP). DESIGN: We studied 354 participants screened for stage 1 hypertension and 34 normotensive controls to determine which individuals developed hypertension needing drug therapy. Among the hypertensive patients, 67 had ISH and were divided according to whether their central SBP, measured with applanation tonometry, was above (ISH-high) or below (ISH-low) the median (120.5 mmHg). Large artery (C1) and small artery (C2) compliance were also measured. RESULTS: Compared to normotensive individuals, ISH-high had decreased C1 (P = 0.02) and C2 (P = 0.01), and higher peripheral resistance (P = 0.01). In contrast, in ISH-low, all these variables were similar to those in normotensive individuals. During 9.5 years of follow-up, incident hypertension was more common among participants with systolic-diastolic hypertension (SDH) and ISH-high than the other two groups [odds ratio (OR) = 6.2, 95% confidence interval (CI) = 1.8 21.1, P = 0.003 for SDH; OR = 6.0, 95% CI = 1.5-24.0, P = 0.01 for ISH-high, versus normotensive individuals]. Among ISH-low, incidence of hypertension was only slightly higher than that in normotensive individuals (OR = 1.1, 95% CI 0.2 5.3, P = 0.90) and lower than that in ISH-high (P = 0.03). These associations remained significant when ambulatory BP was included in the models or when the 125 mmHg cut-off for central BP was used to identify ISH subgroups. CONCLUSION: These data show that young-to-middle-age ISH individuals with low central BP have a lower risk of hypertension needing treatment than those with high central BP. These results are applicable mainly to male individuals. PMID- 21659827 TI - Methodological remarks about plasma renin assays. PMID- 21659825 TI - Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension. AB - BACKGROUND: Glucocorticoid-mediated hypertension is incompletely understood. Recent studies have suggested the primary mechanism of this form of hypertension may be through the effects of glucocorticoids on vascular tissues and not to excess sodium and water re-absorption as traditionally believed. OBJECTIVE: The goal of this study was to better understand the role of the vasculature in the generation and maintenance of glucocorticoid-mediated hypertension. METHODS: We created a mouse model with a tissue-specific knockout of the glucocorticoid receptor in the vascular endothelium. RESULTS: We show that these mice are relatively resistant to dexamethasone-induced hypertension. After 1 week of dexamethasone treatment, control animals have a mean blood pressure (BP) increase of 13.1 mmHg, whereas knockout animals have only a 2.7 mmHg increase (P < 0.001). Interestingly, the knockout mice have slightly elevated baseline BP compared with the controls (112.2 +/- 2.5 vs. 104.6 +/- 1.2 mmHg, P = 0.04), a finding which is not entirely explained by our data. Furthermore, we demonstrate that the knockout resistance arterioles have a decreased contractile response to dexamethasone with only 6.6% contraction in knockout vessels compared with 13.4% contraction in control vessels (P = 0.034). Finally, we show that in contrast to control animals, the knockout animals are able to recover a significant portion of their normal circadian BP rhythm, suggesting that the vascular endothelial glucocorticoid receptor may function as a peripheral circadian clock. CONCLUSION: Our study highlights the importance of the vascular endothelial glucocorticoid receptor in several fundamental physiologic processes, namely BP homeostasis and circadian rhythm. PMID- 21659828 TI - Screening for aortic coarctation by comparing blood pressure in the arms and legs is more convenient and reliable than examination of the femoral pulses. PMID- 21659829 TI - Can exercise prevent preeclampsia? PMID- 21659830 TI - Clinical outcomes and dosimetric considerations using stereotactic body radiotherapy for abdominopelvic tumors. AB - PURPOSE/OBJECTIVES: To present clinical outcomes, early toxicity, and dosimetric constraints for patients undergoing stereotactic body radiation therapy (SBRT) for abdominal or pelvic tumors. MATERIALS AND METHODS: From May 2008 to February 2010, 47 patients with 50 lesions in proximity to hollow viscous organs at risk, including stomach, duodenum, small bowel, and colon, underwent SBRT at Mayo Clinic. Treated sites included liver (21), lymph node (14), adrenal gland (6), intramuscular (4), pancreas (3), and spleen (2). Treatment planning was performed with full body immobilization and 4-dimensional computed tomography (CT)-based planning with daily cone-beam CT or stereoscopic kV imaging for pretreatment image guidance. SBRT was delivered in 1 to 5 consecutive daily fractions in a single week. The most commonly prescribed dose was 50 Gy in 5 fractions (median 45 Gy, range: 20 to 60 Gy). Toxicities were scored by CTCAE v.3. Local failure was defined as per the Response Evaluation Criteria in Solid Tumors. RESULTS: Median follow-up was 12 months (range: 2 to 28 mo). Tumor responses of the 48 target lesions evaluable by Response Evaluation Criteria in Solid Tumor were complete response in 18 lesions (36%), partial response in 12 lesions (24%), stable disease in 12 lesions (24%), and progressive disease in 6 lesions (12%). Kaplan-Meier estimates of local control, overall survival, and freedom from metastasis at 6 and 12 months were 98%, 90%, and 63%, and 87%, 62%, 37%, respectively. Treatment was well-tolerated acutely without reported grade >=3 toxicity. Five grade 3 late toxicities were reported, and 1 patient died of complications from duodenal perforation 11 months after SBRT. No dose correlation with toxicity could be established. CONCLUSIONS: SBRT is a practical treatment option for patients with abdominopelvic tumors. Relapse typically occurs outside treatment fields, and most patients achieve a favorable response. The dose constraints used in this cohort of patients was associated with acceptable early treatment-related toxicity. PMID- 21659831 TI - Fractionated radiotherapy in the management of benign vascular tumors. AB - PURPOSE: To better characterize the long-term therapeutic ratio of fractionated radiotherapy for benign vascular and lymphatic tumors. METHODS: We retrospectively reviewed 19 medical records with 13 hemangiomas, 3 hemangioblastomas, and 3 benign lymphatic tumors treated with radiotherapy at the University of Florida from 1984 to 2007 to assess clinical presentation, treatment, and outcomes. The 10 men and 9 women had a median age of 43 years (range, 2 to 74 y). Six patients underwent radiotherapy alone; 13 patients underwent radiotherapy after surgery. Median radiotherapy dose was 40 Gy (range, 15 to 63.6 Gy). Median observed follow-up was 6.2 years (range, 1.6 to 25.0 y). Disease-free survival was defined by the absence of tumor progression or death from disease. Event-free survival was defined by the absence of tumor progression, death from disease, or severe complication. RESULTS: The 5-year overall survival, disease-free survival, and event-free survival rates were 87%, 84%, and 74%, respectively. Immediately after treatment, there was 1 patient with tumor progression, 10 with stable disease, 7 with partial tumor regression, and 1 complete tumor regression. Ultimately, 3 patients experienced local tumor progression and 16 patients had long-term tumor control. Twelve patients had symptom improvement. Thirteen patients were alive with no evidence of progressive disease. Two patients were alive with symptomatic tumors. Four patients died: 2 from disease and 2 from unrelated causes. Two grade 3 and 2 grade 4 complications were noted. CONCLUSIONS: When symptomatic benign vascular and lymphatic tumors are unresectable and not amenable to radiosurgery or embolization, fractionated radiotherapy represents a viable alternative with an acceptable long-term therapeutic ratio. PMID- 21659832 TI - Role of adjuvant chemoradiotherapy for duodenal cancer: a single center experience. AB - OBJECTIVES: To compare the treatment outcome of surgery alone with that of surgery followed by adjuvant chemoradiotherapy (CRT) for duodenal cancer. METHODS: Between January 1991 and December 2002, 24 patients with duodenal cancer underwent pancreaticoduodenectomy. There were 14 males and 10 females, and median age was 61 years (range, 33-75). Nine patients received adjuvant CRT, and 15 did not. Postoperative radiotherapy was delivered up to 40 Gy at 2 Gy/fraction with a 2-week planned rest. Intravenous 5-fluorouracil (500 mg/m/d) was given on days 1 to 3 of each split course. Median follow-up period was 32 months (range, 5-170). RESULTS: Nodal stage and stage group were more advanced in CRT (+) group (P=0.0894 and 0.0361, respectively). However, other patient and tumor characteristics were similar in each group. Five-year overall survival rates of CRT (-) and CRT (+) group were 47% and 30%, respectively (P=0.3799). Five-year locoregional relapse-free survival rates of CRT (-) and CRT (+) group were 64% and 80%, respectively (P=0.4188). On multivariate analysis, patients treated with adjuvant CRT had better locoregional relapse-free survival with borderline significance (P=0.0750). No patient suffered grade 3 or higher toxicity during CRT. CONCLUSIONS: Adjuvant CRT is feasible and may enhance locoregional control in advanced-staged duodenal cancer after curative resection. PMID- 21659833 TI - Clinical course of neuroendocrine tumors with different origins (the pancreas, gastrointestinal tract, and lung). AB - OBJECTIVES: Neuroendocrine tumor originates from several sites. This study was conducted to reveal the differences in clinical course of neuroendocrine tumors by the origin. METHODS: We reviewed data of patients diagnosed with neuroendocrine tumor between January 1996 and July 2007. RESULTS: A total of 371 patients were enrolled [pancreas 60, gastrointestinal (GI) tract 210, lung 35, other sites 46, unknown primary sites 20]. The primary tumor site correlated with the stage (P=0.000) and grade (P=0.000). At diagnosis, metastasis was observed in 28.3%, 6.7%, and 2.9% of the cases in pancreatic, GI, and pulmonary neuroendocrine tumors, respectively. Grade 3 neuroendocrine tumor was observed in 7.7%, 0.5%, and 0.0% in pancreatic, GI, and pulmonary neuroendocrine tumors. Overall survival was 116.0 months (95% confidence interval, 86.9-145.1). Overall survival was 116.0 months in pancreatic neuroendocrine tumor, not reached in GI neuroendocrine tumor and 120.0 months in pulmonary neuroendocrine tumor (P=0.024). The recurrence rate was 18.0%. It was 20.9%, 11.9%, and 2.9% in pancreatic, GI, and pulmonary neuroendocrine tumors (P=0.062). In multivariate analysis, stage, grade, and age were prognostic for overall survival (OS). Stage, grade, and sex were prognostic for disease-free survival. CONCLUSIONS: Neuroendocrine tumors from the pancreas, GI tract, and lung showed different clinical characteristics. PMID- 21659834 TI - Dual primary gastric and colorectal cancer: is the prognosis better for synchronous or metachronous? AB - OBJECTIVES: The purpose of this study was to investigate the prognosis and clinicopathologic features of synchronous and metachronous dual primary gastric and colorectal cancer (DPGCC). METHODS: We reviewed clinical data of 96 patients with DPGCC, comprising 63 men and 33 women, from among 4523 patients with gastric or colorectal cancer who underwent surgical treatment or chemotherapy, but no endoscopic resection, for colorectal cancer between 1990 and 2009. The selected patients were classified into 2 groups according to the time of gastric or colorectal cancer detection as follows: synchronous group (n= 42) and metachronous group (n = 54). RESULTS: Among 4523 patients treated for gastric and colorectal cancer, DPGCC was diagnosed in 96 (2.1%). In terms of clinicopathologic features, the proportion of early-stage gastric and colorectal cancer was higher in the metachronous DPGCC group, with P values of 0.02 and 0.01, respectively. Overall survival in the metachronous DPGCC group was significantly longer than in the synchronous DPGCC group (P = 0.02). Metachronous DPGCC was identified as an independent predictor of survival by both univariate and multivariate analyses, with a P value of 0.02 and 0.006, respectively. CONCLUSION: Metachronous DPGCC had a better prognosis than synchronous DPGCC due to the tendency for metachronous DPGCC to occur in patients with early-stage cancer. PMID- 21659835 TI - Massive ovarian cyst and sudden death. AB - Massive enlargement of an ovarian cyst is an uncommon cause of morbidity and a rare cause of mortality due in large to part to noninvasive imaging techniques that usually permit early detection. When an ovarian cyst reaches giant proportions, it produces abdominal enlargement often with a fluid wave resulting in a condition that mimics ascites, called pseudoascites. Despite their impressive appearances, such cysts often are operable for cure. We describe a case of a middle-aged woman who presented 3 years before her death with symptoms from an undiagnosed giant cyst and given a diagnosis of ascites of undetermined etiology. She subsequently died at home unexpectedly, and at autopsy, she was found to have a massively enlarged but otherwise benign mucinous cystadenoma. PMID- 21659836 TI - Fatal epiglottic abscess after radiotherapy for laryngeal carcinoma. AB - Acute epiglottitis is a rare condition, especially in adults, largely owing to the widespread vaccination against Haemophilus influenzae. Traumatic epiglottitis as a result of thermal or caustic insults is documented. Epiglottic abscess formation is described as a sequela of epiglottitis in some cases. The development of epiglottic abscess from epiglottitis secondary to radiotherapy has previously been described in the literature; however, there are no reports of fatalities due to epiglottic abscess after radiotherapy. We present an unusual case of an adult sudden death due to epiglottic abscess formation subsequent to radiotherapy for laryngeal squamous cell carcinoma. PMID- 21659838 TI - Pontomedullary lacerations in unhelmeted motorcyclists and bicyclists: a retrospective autopsy study. AB - Pontomedullary lacerations (PMLs) have often been reported in car occupants and pedestrians, are less frequently described in motorcyclists, and are very rarely described in bicyclists. The aim of this study was to determine the frequency of brainstem PMLs among fatally injured motorcyclists and bicyclists as well as the frequency of concomitant cranial, facial, and cervical spine injuries in such cases. A possible underlying mechanism of PML in fatally injured motorcyclists and bicyclists might thus be established. Of 443 cases of fatally injured motorcyclists and bicyclists, a sample of 381 cases of fatally injured motorcyclists and bicyclists with head injury of Abbreviated Injury Scale score of 3 or greater was formed and further analyzed. This group was composed of 345 men and 36 women. The average age was 48.8 +/- 20.8 years (range, 15-99 years). In the analyzed sample group, there were 158 motorcyclists and 223 bicyclists. Partial PMLs were present in 44 cases (12%) within the sample of 381 head injuries, which breaks down to 40 men and 4 women. In our study, the impact area on the head and the specific skull base fracture type were good predictors of either PML occurrence or absence (B = -2.036, Wald = 161.312, P < 0.01, for the whole model). Impact to the chin, with or without a skull base fracture, most often led to this fatal injury due to impact force transmission, either through jawbone or vertebral column. Also, lateral head impact, the most frequent in bicyclists, with subsequent hinge fracture, PML, and frontoposterior hyperextension of the head that is associated with upper spine fracture, could be possible mechanisms of brainstem injury in fatally injured motorcyclists or bicyclists. Our study showed that the jawbone, as well as other facial bones, could act as shock absorbers, and their fracture could diminish energy transfer toward the skull and protect the brain and brainstem from injury. PMID- 21659837 TI - DNA collection from used toothbrushes as a means to decedent identification. AB - Comparison of DNA profiles is often used in verifying the identification of deceased human beings when other easier, quicker, and less expensive means to identification are not possible. Fifty-five adult subjects divided into 3 groups provided a used toothbrush along with a small bloodstain control for DNA analysis and comparison. Results indicate that there is no significant difference in the quantity and quality of DNA recovered from a toothbrush that has been used for 1 month versus 3 months versus random periods. The results of this study confirm earlier conclusions that a used toothbrush is a reliable source of antemortem DNA from a putative decedent. The use of aviation snips to remove a small portion of the toothbrush head provides an easy, inexpensive method of obtaining a sample for DNA extraction. The authors recommend this method as a standardized technique for use in forensic DNA laboratories. PMID- 21659839 TI - Dieulafoy lesion of the esophagus causing massive upper gastrointestinal bleeding and death: a case report. AB - Dieulafoy lesion is a rare cause of upper gastrointestinal bleeding. We present a case report of sudden and unexpected death in a previously healthy male where autopsy revealed a classic Dieulafoy lesion with a submucosal artery protruding through a small mucosal defect in the esophagus, thereby exposing it to stress and consequent rupture. Advances in endoscopic techniques have drastically reduced mortality from Dieulafoy lesion. Nevertheless, it is an important diagnosis to be kept in mind when autopsy reveals an upper gastrointestinal bleeding. PMID- 21659840 TI - Foreign body penetration of the fontanelle: mechanisms and manner of death. AB - Penetrating injuries of the anterior fontanelle are exceedingly uncommon and are most often associated with inflicted injury. This report of an 11-month-old boy, who fell backward onto a lamp-shade strut that penetrated his anterior fontanelle and left frontal lobe, demonstrates that accidental injuries may also rarely occur. Death was due to hypoxic-ischemic encephalopathy complicating raised intracranial pressure after a penetrating injury of the brain. Careful evaluation of the death scene with reconstruction incorporating the autopsy findings was required to establish the veracity of the history and the credibility of the proposed sequence of events. Mechanisms of death after penetrating injuries of the fontanelle include immediate effects from direct damage to cerebral vital structures or blood vessels with hemorrhage or delayed effects from either cerebral edema with hypoxic-ischemic encephalopathy or sepsis. PMID- 21659841 TI - An uncommon delayed sequela after pressure on the neck: an autopsy case report. AB - Delayed sequelae after pressure on the neck are rare. Awareness of such sequelae as well as a high degree of suspicion is essential for early detection and proper clinical management. Injuries to the common carotid artery and pseudo aneurysm formation leading to fatal hemorrhage are still rare occurrences after attempts of manual strangulation. When such cases are presented to the forensic pathologist, he has to establish the link between the cause and effect, excluding other possible causes for such complications. In addition, he may have to give opinions in possible medical negligence charges. PMID- 21659842 TI - Analysis of complications and patient satisfaction in pedicled transverse rectus abdominis myocutaneous and deep inferior epigastric perforator flap breast reconstruction. AB - The purpose of this study was to evaluate complications and patient satisfaction after pedicled transverse rectus abdominis myocutaneous (TRAM) and deep inferior epigastric perforator (DIEP) flap reconstruction at a single institution. There were 346 patients identified from 1999 to 2006 who underwent 197 pedicled TRAM and 217 DIEP flap reconstructions. Flap complication rates were similar between groups, whereas pedicled TRAM reconstructions had higher rates of abdominal bulge (9.5% vs. 2.3%, P = 0.0071) and hernias (3.9% vs. 0%, P = 0.0052). DIEP flap patients had significantly higher general satisfaction (81.7% vs. 70.2%, P = 0.0395), whereas aesthetic satisfaction was similar between groups. Furthermore, DIEP flap patients, particularly those undergoing bilateral reconstructions, were more likely to choose the same type of reconstruction compared with pedicled TRAM patients (92.5% vs. 80.7%, P = 0.0113). Understanding the differences in complications and satisfaction will help physicians and patients make informed decisions about abdominal-based autologous breast reconstruction. PMID- 21659843 TI - Breast implants and minimally invasive cardiac surgery: a case series. AB - INTRODUCTION: The number of women affected by valvular heart disease and the number of women with breast implants are both on the rise. Minimally invasive heart surgery using a limited thoracotomy offers many potential benefits including reduction in blood loss, shorter hospital stay, faster recovery time, decreased pain, and improved cosmesis. Minimally invasive heart surgery often requires access to the second, third, or fourth intercostal space of the anterior chest wall. The presence of a breast implant may interfere with the surgeon's ability to gain adequate exposure for entry to the appropriate intercostal space. We present a case series of 5 women with breast implants who successfully underwent minimally invasive cardiac valve surgery. METHODS: A retrospective review was conducted of all patients with breast implants who underwent minimally invasive cardiac valve surgery at the University of Southern California University Hospital. In each patient, an inframammary incision was performed, facilitating removal of the implant, performance of the cardiac operation, and reimplantation of the implant. RESULTS: Five women with breast implants who underwent minimally invasive cardiac valve surgery were identified; of these, 4 (80%) patients underwent repair of the mitral valve for mitral regurgitation, whereas 1 (20%) underwent an aortic valve replacement for aortic stenosis. Two patients underwent a concomitant maze procedure for atrial fibrillation during the same operation. The median follow-up time was 7.4 months, and the follow-up period ranged from 2 to 12 months. There were no significant postoperative complications such as infection, hematoma, or need for reoperation. CONCLUSIONS: Our series of 5 patients demonstrates that minimally invasive heart surgery performed through an inframammary incision can be safely performed in those with breast implants. PMID- 21659844 TI - Recurrent inverted nipple: a reliable technique for the most difficult cases. AB - The inverted nipple is a frequent pathologic condition, involving up to 10% of women. This deformity results in a negative self-image for the affected patient. Recurrence after corrective surgery is possible and may represent extreme frustration for the patient and the surgeon. The aim of our study is to propose a useful and reliable technique to employ in case of recurrence or severe inverted nipple. During 2000 and 2010, the study was conducted on 19 patients treated with this procedure: 10 patients (20 nipples) having severe inverted nipple (grade III according to Han and Hong classification) and 9 patients (15 nipples) presenting with relapses. One nipple could not be corrected. One patient developed a temporary loss of sensibility. No major complications (necrosis, infection, hematoma, and permanent numbness), no recurrences, and no noticeable scars have been reported at follow-up. In our series, the shape and the projection after the procedure were evaluated as satisfactory by the patients, remained consistent over time, and no protective devices were required. In conclusion, although our technique is not the best in terms of invasiveness, it is one of the few truly effective ones in treating relapses. For patients who have already undergone surgery, the priority is certainly to solve this clinical anomaly and the psychological sequelae; a "microincision" or a scar-free technique is the secondary aspect to be taken into account. PMID- 21659845 TI - The use of intra-abdominal tissue expansion for the management of giant omphaloceles: review of literature and a case report. AB - Giant omphaloceles present a reconstructive challenge in planning, management, and eventual closure of the abdominal wall defect. The goal of reconstruction is to recreate a functional abdominal wall domain and return the extra-anatomically placed viscera into the peritoneal cavity in a safe manner. Traditionally, placement of tissue expanders has been in the subcutaneous and intramuscular planes. Recently, however, there have been reports of intra-abdominal placement of expanders. We present a detailed review of the literature regarding the use of tissue expanders in the management of giant omphaloceles with specific emphasis on the intra-abdominal technique of placement. We also present a case report with the longest follow-up till date in which the patient underwent staged reduction using the intra-abdominal approach. Initial reports of this modality are promising both as a primary strategy and in patients in whom conventional techniques have failed. Results from our review of literature and case report suggest that this technique appears to be durable and effective with successful functional and cosmetic outcomes. PMID- 21659846 TI - The use of Mitek bone anchors for synthetic mesh fixation to repair recalcitrant abdominal hernias. AB - INTRODUCTION: Repair of recurrent abdominal hernias is a surgical challenge. These patients usually present to the plastic surgeon as a last resort for treatment. Such recalcitrant hernias cause enormous morbidity and constitute a financial burden to any health service. It is important to explore novel and potentially effective repair methods. We report on a technique using overlay prolene mesh fixed to bone by Mitek anchors. METHODS: All patients who had Mitek bone anchor fixation of synthetic mesh, to repair recurrent iatrogenic abdominal hernias between 2003 and 2010 by one surgeon (C.M.M.), were retrospectively reviewed. The indications, operative details, and clinical outcomes were documented. RESULTS: A total of 7 patients (6 females, 1 male) aged 35 to 60 (average 53) years were included in the study. The causes of herniation were previous surgical incisions (3) and abdominal flap harvests (4). They had had a median of 3 hernia repairs before referral to plastic surgery. The operations lasted for a mean of 6 hours (range, 3-101/2 hr). There were no major intra- and postoperative problems although 1 patient requested removal of 2 of his 8 Mitek anchors because of persistent localized pain and tenderness. After a mean follow up of 24 months (range, 4-34), only 1 patient developed a recurrent lower abdominal bulge. CONCLUSION: Our single operator series demonstrated that Mitek bone anchor fixation of prosthetic mesh reinforcement of abdominal wall hernia repair is an effective treatment technique associated with a low morbidity. This method of recalcitrant hernia repair may be a useful addition to the armamentarium of the plastic surgeon. PMID- 21659847 TI - A modified free muscle transfer technique to effectively treat chronic and persistent calcaneal osteomyelitis. AB - Successful management of chronic calcaneal osteomyelitis presents a major challenge for the plastic and reconstructive surgeon, especially in cases involving soft-tissue defects. This article describes a modified free muscle transfer technique to effectively eradicate chronic and persistent calcaneal osteomyelitis. METHODS: Between February 2009 and September 2009, 3 male patients with persistent calcaneal osteomyelitis were treated in our clinic. All 3 had purulent drainage for a minimum of 6 months and a maximum of 23 years. Multiple surgical debridements and vacuum-assisted closure had been used in the past, but the infection remained. We used a therapeutic protocol of repeated and radical surgical debridement with removal of nearly all cancellous bone and preservation of the cortical shell of the calcaneus. After the final debridement, the bone cavity was plugged by a free gracilis muscle flap from the contralateral side. A meshed split thickness skin graft was applied. Culture-specific antibiotics were administered for 2 weeks. RESULTS: All flaps healed uneventfully except for a minor hematoma that was treated conservatively. All 3 patients were able to return to ambulatory status with regular foot apparel. At last follow-up evaluation, they had no clinical, laboratory, or radiologic signs of osteomyelitis. CONCLUSION: This modified free muscle transfer technique seems to be successful in managing chronic and persistent calcaneal osteomyelitis. Infected and healthy cancellous bone of the calcaneus is removed to eradicate all possible foci that maintain inflammation. The resulting bony defect after the aggressive surgical debridement is sufficiently filled with a well-vascularized muscle that ensures a good wound healing. We consider this method to be a promising treatment option, which needs to be supported by further cases. PMID- 21659848 TI - A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients. AB - BACKGROUND: Pathologic skin scarring reversion remains a big challenge for surgeons, as disfiguring scars have a dramatic influence on patient's quality of life. METHODS: A controlled clinical trial was conducted to evaluate 8% pirfenidone (PFD) gel administered topically 3 times a day during 6 months to 33 pediatric patients with hypertrophic scars caused by burns. A total of 30 patients with hypertrophic scars with identical Vancouver Scar Scale values were treated with pressure therapy and included as controls. Improvements were evaluated by Vancouver Scar Scale and a Visual Analog Scale. Safety parameters were determined by the presence of adverse events and monitoring laboratory and hematology parameters. RESULTS: Patients treated with PFD during 6 months presented a continuous monthly statistically significant scar regression in comparison with the initial Vancouver measurement (P = <0.001). PFD group showed a higher improvement of all scar features as compared with control group treated with pressure therapy (P = <0.001). In the PFD group, 9 of 33 patients (27%) had their scores decreased in Vancouver classification by more than 55%, 22 patients (67%) had a 30% to 45% decrease, whereas 2 patients (6%) had a 30% decrease or less. Control group treated with pressure therapy showed a slight improvement in 16% of cases on an average. Patients did not show serious adverse effects or laboratory alterations throughout the study. CONCLUSIONS: Topical administration of 8% PFD gel 3 times a day is more effective and safe in the treatment of hypertrophic scars caused by burns in children, as compared with standard pressure therapy. PMID- 21659849 TI - Scalp defect repair: a comparative analysis of different surgical techniques. AB - Scalp defects often arise in multimorbid patients. This study aimed at establishing an algorithm of defect repair with particular focus on new regenerative options.All patients, who consulted to the Department of Oral and Maxillofacial Surgery/Plastic Surgery, University Jena between April 2005 and March 2010 were reviewed. Different reconstructive options were compared with regard to duration of hospital stay as well as rate of reoperations needed to achieve full closure.Sixty-eight patients were identified. Local flaps were more effective than skin grafts (P = 0.038) and microvascular free flaps (P = 0.037) in case of skin-galea-periosteal-defects. However, no differences were found between skin grafting in combination with wound bed preconditioning using a dermal regeneration template and microvascular free flap transfer. Scalp defects should be repaired based on careful evaluation of defect anatomy as well as patient's general health. Application of dermal regeneration templates allows for an increase of the indication spectrum of free skin grafts. PMID- 21659850 TI - A new technique for closure of infraorbital defects. AB - BACKGROUND: The infraorbital region is a unique facial subunit surrounded with several important structures, such as the lower eyelids, oral commissure, ala nasi, and the sideburns. The potential for distortion of these neighboring anatomic landmarks and the absence of natural creases where incisional scars can be camouflaged make reconstruction of large infraorbital defects a challenge. PURPOSE: A new local flap procedure for reconstruction of large infraorbital skin defects, named Mutaf triangular closure technique, is described. MATERIAL AND METHOD: In this procedure, the defect is surgically converted to a triangle in shape. Then, the triangular defect is closed by transposition of 2 skin flaps designed in an unequal Z-plasty manner. Over 4 years, this technique has been used for closure of the infraorbital defects in 12 patients (7 men and 5 women), aged 28 to 83 years. The defect size ranged between 1.7 and 8 cm in diameter. RESULTS: A tension-free defect closure was obtained in all patients. All flaps healed with no complications. No patient had "dog-ear" formation, ectropion, scleral show, or distortion of the surrounding anatomic structures. A mean follow up of 18 months (5 months-3.5 years) revealed an aesthetically acceptable scar formation in all patients. CONCLUSIONS: The Mutaf triangular closure technique seems to be a useful procedure for the closure of considerably large infraorbital defects with alike local tissue. It provides a tension-free closure without displacement and/or distortion of the neighboring mobile anatomic structures. PMID- 21659851 TI - Surgical treatment of the synkinetic eyelid closure in Marin-Amat syndrome. AB - Marin-Amat syndrome is a synkinesis which develops following facial nerve palsy and manifests as an involuntary eyelid closure when the jaw is opened. We presented 2 patients with Marin-Amat syndrome. One patient developed this syndrome after Bell palsy and the other after cross-facial nerve graft and free functional muscle transfer. Surgery was planned with an attempt to resect the target muscle innervated by the aberrant nerve to eliminate the paradoxical synkinesis. We developed a new surgical technique by resection of the upper or lower preseptal orbicularis oculi muscle (OOM) to treat the synkinetic eyelid closure effectively in both cases. Since the pretarsal and orbital OOM remain intake, patients can close their eyes smoothly. No recurrence or any sequela was noted after long-term follow-up. Careful preoperative electromyography study and detailed dynamic facial image analysis of both upper and lower lid OOM are very important to locate the synkinetic muscle. To the best of our knowledge, this is the first report to treat Marin-Amat syndrome successfully with surgical resection of preseptal OOM. PMID- 21659852 TI - Forty-year experience with flow-diversion surgery for patients with congenital choledochal cysts with pancreaticobiliary maljunction at a single institution. AB - BACKGROUND: Congenital choledochal cyst with pancreaticobiliary maljunction (PBM) is known as a high-risk factor for various complications such as cholangitis, pancreatitis, and carcinogenesis of the biliary system by mutual refluxes of bile and pancreatic juice. Furthermore, it is not rare to suffer from postoperative complications if the wrong operative procedure is chosen. Therefore, we sought to review the relationship between operative procedure for types I and IV-A (Todani's classification) congenital choledochal cyst with PBM, and long-term treatment outcome. SUBJECTS AND METHODS: A retrospective review was carried out of 144 patients who underwent flow diversion surgery in our institution during the 40-year period from 1968 to 2008 and who did not have a coexisting malignant tumor at the time of surgery. RESULTS: Of these 144 patients, 137 underwent complete cyst excision and 7 underwent pancreas head resection as flow diversion surgery. The follow-up periods ranged from 1 to 345 months and from 1 to 271 months (average, 100.2 and 94.1) in patients with type I and type IV-A cysts, respectively. Regarding surgical treatment outcome, postoperative progress was good in 130 (90.3%) of the 144 patients. Fourteen patients required hospitalization for long-term postoperative complications such as cholangitis, pancreatitis, intrahepatic calculi, pancreatic calculus, and carcinogenesis during postoperative follow-up. Of these, 2 patients who underwent surgery for type IV-A cysts died because of secondary biliary cirrhosis with liver failure and advanced intrahepatic cholangiocarcinoma, respectively. CONCLUSIONS: The present study shows that flow diversion surgery for congenital choledochal cysts with PBM significantly reduces the risk of subsequent development of malignancy in the biliary tract, and it is vital to choose the appropriate operative procedure to prevent occurrence of these postoperative complications. PMID- 21659853 TI - Establishment of a rabbit model for keratoconjunctivitis sicca. AB - PURPOSE: To establish a rabbit model for keratoconjunctivitis sicca (KCS) to study autologous submandibular gland transfer for treating severe KCS. METHODS: In 2 groups of 10 rabbits, left eyes were operated and right eyes were controls. In the trichloroacetic acid-treated group, the lacrimal and harderian glands and nictitating membrane were removed surgically; the palpebral and bulbar conjunctiva were swabbed with 50% trichloroacetic acid. In the non trichloroacetic acid-treated group, the lacrimal and harderian glands and nictitating membrane were surgically removed. The Schirmer test was performed preoperatively and 1, 2, 3, and 4 months postoperatively. Corneal densities of rose bengal and fluorescein staining were scored every month postoperatively. At 4 months, the cornea and bulbar conjunctiva were removed from operated and control eyes for histopathology. The upper bulbar conjunctiva was used to determine goblet cell density. RESULTS: Compared with preoperative conditions, tear secretion of operated eyes significantly decreased in both groups postoperatively, then gradually increased. Scores for corneal rose bengal and fluorescein staining were higher and conjunctival goblet cell density was lower in the operated eyes than in control right eyes in both groups, but no significant difference was found between the operated eyes of the two groups. Inflammatory histopathologic changes of the cornea and conjunctiva were not found in either of the eyes in the two groups. CONCLUSIONS: A new rabbit model for KCS could be created by either of these methods. Experimental KCS with reduction of tear production was possible with surgical ablation of the lacrimal and harderian glands and nictitating membrane. It is unnecessary to apply trichloroacetic acid to burn the conjunctiva. Our modified incision better exposed the surgical field. PMID- 21659854 TI - Biologic modulators in allergic and autoinflammatory diseases. AB - PURPOSE OF REVIEW: The advent of molecular techniques has resulted in the ability to tailor medications to specific protein targets. This review will emphasize several biological therapies, specifically directed toward cytokine receptors and inhibitors, and their role in the treatment of atopic and autoinflammatory diseases. RECENT FINDINGS: Translational research and the identification of the molecular pathophysiology of diseases have led to more targeted treatment approaches. The biologic modulators encompassing monoclonal antibodies as cytokine inhibitors, receptor blocking antibodies, and new fusion receptors are now being applied to diseases beyond their original application. SUMMARY: The expanded use of biological therapies has experienced success in the treatment of numerous disorders, especially in subsets of patients with disease that has been refractory to conventional therapies. PMID- 21659855 TI - Controversies regarding long-acting beta2-agonists. AB - PURPOSE OF REVIEW: This review examines the literature regarding the efficacy and safety of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids. RECENT FINDINGS: The Global Initiative for Asthma (GINA) 2009 guidelines and the National Heart, Lung, and Blood Institute (NHLBI) 2007 asthma guidelines recommend adding long-acting beta2-agonists to patients inadequately controlled on inhaled corticosteroids. These recommendations must be balanced against published data which demonstrate a signal of increased morbidity and mortality with use of long-acting beta2-agonists. These conflicting data raise the question of whether or not there may be genotypic or phenotypic discriminators leading to disparate responses to long-acting beta2-agonists. SUMMARY: The combination of long-acting beta2-agonists and inhaled corticosteroids demonstrates improvement in asthma control and exacerbation rates; however, long-acting beta2-agonists are not recommended for use as monotherapy or without optimization of inhaled corticosteroid dose. Although the majority of asthmatic patients appear to benefit from the addition of long-acting beta2-agonists, there are concerns that a small proportion of patients, including steroid-naive patients and African Americans, may not obtain such benefits. Thus far, studies have not clearly demonstrated genotypic or phenotypic differences explaining the variability in response. PMID- 21659856 TI - Drug provocation tests in hypersensitivity drug reactions. AB - PURPOSE OF REVIEW: Drug provocation test (DPT) is necessary to diagnose most drug hypersensitivity reactions (HSRs) due to decreased sensitivity of skin testing even when combined with in-vitro tests in immunonologic drug HSR and limited availability of these tests in nonimmunologic reaction. We review the principles and controversial issues of DPT, and recent studies using DPT as a diagnostic tool. RECENT FINDINGS: DPT is recommended in the diagnosis of HSR to beta lactams, as well as other drug classes [such as acetylsalicylic acid-NSAIDs (ASA NSAIDs), non-beta-lactams antibiotics, heparin, glucocorticoids, and local anesthetic agents]. In view of the decreased sensitivity of skin testing, limited accessibility to new benzylpenicillin polylysine (PPL)/mixture of minor determinant (MDM) test reagents and limited availability of validated sensitive in-vitro tests, individuals who require DPT to beta-lactams are increasing. The negative predictive value of allergologic work-up is very high, ranging from 94 to 98% for beta-lactams and those reactions after negative tests are mostly nonimmediate and mild. Finally, DPT is recommended to ascertain tolerability of alternative compound when evaluating cross-reactivity among different classes of beta-lactams, NSAIDs and glucocorticoids, and possibly iodinated contrast media. SUMMARY: DPT is often needed when evaluating patients with suspected drug HSR. More studies regarding standardization of the various protocols are needed in order to increase its acceptance and adoption as a standard practice in the diagnostic algorithm for drug HSR. PMID- 21659857 TI - Symmetrical drug-related intertriginous and flexural exanthema. AB - PURPOSE OF REVIEW: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), previously termed drug-related baboon syndrome, is a benign and self limiting type IV hypersensitivity reaction characterized by symmetrical erythema involving the gluteal and intertriginous areas in the absence of systemic involvement. It may also occur in the absence of previous drug exposure. RECENT FINDINGS: Antibiotics, in particular beta-lactams, comprise the majority of causes of SDRIFE. Other drugs which have been implicated include antihypertensives, radiocontrast media, chemotherapeutic agents, and biologics. Histology of lesional skin is variable with predominance of superficial perivascular inflammatory cell infiltrates. Outcomes of allergy tests are variable with positive delayed intradermal tests reported for penicillin V, allopurinol; positive patch tests for erythromycin, mitomycin, nystatin, pseudoephdrine; positive lymphocyte transformation tests for erythromycin; and positive drug provocation tests for clindamycin, cimetidine, corticosteroids, terbinafine, and valacyclovir. SUMMARY: Diagnosis of SDRIFE is dependent upon recognition of the clinical morphology and distribution of the rash, and its temporal relationship to the use of the suspected drug. Outcomes of in-vivo and in-vitro tests have been inconsistent, and thus may not be useful in the identification of the putative drug. PMID- 21659858 TI - The innate immune system in delayed cutaneous allergic reactions to medications. AB - PURPOSE OF REVIEW: Innate immune responses are attracting increasing interest from researchers in the field of drug allergy. This review discusses recent advances in the understanding of several innate immune components in delayed cutaneous hypersensitivity reactions to medications, with special attention on severe reactions. RECENT FINDINGS: The mechanism of activation of dendritic cells in response to drugs is being unravelled. Activated monocytes and macrophages have been found in affected skin of bullous diseases. Increased gene expression of monomyeloid cell products including several 'alarmins' or endogenous damage associated molecular patterns has been described in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Natural killer (NK) cells from patients respond to drugs in vitro. In-vivo, NK cells may contribute to severe diseases through the secretion of effector molecules such as granulysin. The innate receptor CD94/NKG2C is expressed by NK cells and cytotoxic T lymphocytes in SJS/TEN and triggers degranulation in response to human leukocyte antigen-E expressing keratinocytes. T cells with innate activities have been detected in patients during severe acute reactions. SUMMARY: Humoral and cellular components of the innate immune response have been identified in association with delayed drug hypersensitivity reactions. Their participation in certain diseases may explain the variability of phenotypes in hypersensitivity reactions to medications. PMID- 21659859 TI - Towards the Grade of Recommendations, Assessment, Development and Evaluation system: methods and results of budesonide/formoterol maintenance and reliever therapy research. AB - PURPOSE OF REVIEW: Guidelines for clinical practice are expected to gather evidence-based recommendations to support optimal medical behaviours. The aim of the current review is to explore how currently available research regarding the strategy of using budesonide/formoterol (BUD/FORM) as maintenance and reliever therapy (Symbicort SMART) covers the items considered by the Grade of Recommendations, Assessment, Development and Evaluation (GRADE) system, through a comparative analysis of methodological approaches, clinical outcomes, patient reported outcomes and costs, in order to highlight uncovered areas. RECENT FINDINGS: Thirteen trials providing data on 21 095 analysed patients were available. No serious limits in methodological study features were found. Evaluation of the clinical outcome was consistent with the efficacy of BUD/FORM maintenance and reliever therapy. As the time to first exacerbation was the primary outcome in most of the studies, conclusive indications cannot be drawn regarding other clinical outcomes or patient-reported outcomes, which were investigated as secondary outcomes. A comprehensive systematic review exploring all critical and important outcomes is desirable, but further research concerning the safety issues of Long Acting beta2 Agonists (LABA) and patients' reported outcomes about the SMART in respect to alternative strategies is likely to affect a clear recommendation in the near future. SUMMARY: The efficacy of BUD/FORM maintenance and reliever therapy in extending the time to first exacerbation appears consistent between studies. Further studies exploring all patients' important outcomes are needed. Clinical and economic assessments are worthy of being investigated to verify the directness of the evidence in respect to real life patients and different geographical realities. PMID- 21659860 TI - Hypersensitivity reactions to quinolones. AB - PURPOSE OF REVIEW: The purpose of this review is to examine in detail the new advances in the pathomechanisms and diagnosis of immediate and nonimmediate hypersensitivity reactions to quinolones, as well as analyze cross-reactivity among different quinolones. RECENT FINDINGS: Hypersensitivity reactions to quinolones, especially anaphylactic reactions, have become more common in the past decade. This phenomenon could be related to their increased consumption. Although attempts have been made to standardize skin testing, the diagnosis of immediate hypersensitivity reactions to quinolones is mainly based on drug provocation. Some in-vitro, radioimmunoassay and basophil activation tests have also been used for diagnostic purposes, with results indicating that they could be complementary to in-vivo tests. Cross-reactivity seems to exist between first and second-generation quinolones, with lower levels with the third and fourth generations. However, no general rules exist for predicting cross-reactivity and it needs to be analyzed patient by patient. Nonimmediate hypersensitivity reactions also exist, especially maculopapular exanthema and fixed drug eruptions, and a T-cell mechanism has been demonstrated. SUMMARY: Over the past decade the number of hypersensitivity reactions to quinolones has increased. These reactions can be severe and diagnosis difficult to confirm. Although new in vitro tests hold promise, drug provocation testing remains the most frequently used and reliable diagnostic method. PMID- 21659861 TI - Role of dendritic cells in drug allergy. AB - PURPOSE OF REVIEW: Immune reactions to drugs can cause a variety of diseases involving organs such as the skin, liver, kidney, and lung. Although the role of T cells in hypersensitivity reactions to drugs (HDRs) have been demonstrated by several studies, little is known about the role of the innate immune system, served mainly by dendritic cells, in the hypersensitivity response. RECENT FINDINGS: Our knowledge about the mechanisms of HDRs is very superficial, and the hypotheses for the involvement of reactive metabolites in many cases are circumstantial and with no evidence. It is not clear which group of HDRs is due to reactive metabolites, nor is it clear the mechanisms by which reactive metabolites can cause allergic reactions. Several studies support the hypothesis that drugs interact differently with dendritic cells from drug-allergic and nonallergic patients, modifying their maturation level. Dendritic cells are also able to metabolize drugs and to present their metabolites to T lymphocytes eliciting a hypersensitivity response. All these findings show that the innate immune system and mainly dendritic cells might play a critical role in drug allergy. SUMMARY: The interaction of drugs with dendritic cells is an emerging area of research which can bring new insights in order to have a better understanding about the physiopathology of HDRs. PMID- 21659862 TI - Proteomics in immunological reactions to drugs. AB - PURPOSE OF REVIEW: To discuss the avenues that proteomic techniques are opening for the study of the chemical basis and cellular mechanisms of immunological reactions to drugs. RECENT FINDINGS: Technical developments in recent years are allowing a detailed characterization of drug-protein interactions. In addition, novel metabolic pathways for drug biotransformation are being uncovered and potential targets for protein haptenation are being proposed that may help in the understanding of these complex processes. SUMMARY: Immunological reactions to drugs pose important clinical problems. Since early works exploring drug-protein interactions, there has been steady progress in this field. However, the mechanisms involved remain incompletely understood. The availability of proteomic techniques with high resolution and sensitivity presents a unique opportunity to tackle this subject from a broad perspective, integrating work in model systems and in patients. Chemical and metabolic characterization of immunological reactions to drugs may also help in the prevention, diagnosis and/or treatment of these processes. PMID- 21659863 TI - Anaphylaxis to radiographic contrast media. AB - PURPOSE OF REVIEW: Radiographic contrast media (RCM) are increasingly used in modern diagnostic medicine. Hypersensitivity reactions to nonionic RCM still occur in a significant number of exposed patients, because of the increased use of contrasted radiological investigations. Hypersensitivity reactions may be divided into immediate (<1 h of administration) and nonimmediate responses (>1 h). Immediate reactions present with anaphylaxis. RECENT FINDINGS: Although described less commonly, anaphylaxis to gadolinium contrast media have been increasingly reported in recent literature. In most patients, immunoglobulin (IgE)-mediated allergy cannot be demonstrated and the underlying mechanism remains unknown. In some patients, positive skin tests, specific IgE antibodies or specific cellular tests have been demonstrated. It may be speculated that more allergic reactions could be described, if more adequate methods were developed. Skin prick tests and intradermal tests with 1 : 10 diluted RCM are specific and confirm the diagnosis of RCM hypersensitivity. SUMMARY: There are not enough data yet about the value of skin tests for the selection of a 'well tolerated' RCM. Premedication of previous reactors is common among radiologists. However, breakthrough reactions are a concern and physicians should not rely on the efficacy of pharmacological premedication. Instead, radiologists should be prepared to treat severe RCM-induced allergic reactions in their practice. PMID- 21659865 TI - Pathophysiology of anaphylaxis. AB - PURPOSE OF REVIEW: This review aims to provide an overview of the evolving understanding of the pathophysiology of anaphylaxis. RECENT FINDINGS: Immunopathologic mechanisms of anaphylaxis have traditionally focused on the IgE dependent and IgE-independent release of mediators from mast cells and basophils. There are accumulating data supporting the significance of alternative pathways of anaphylaxis. Increasing attention has also focused on the internal compensatory mechanisms activated in response to anaphylaxis. SUMMARY: Recent advances will enhance understanding of the pathophysiology of anaphylaxis and might have future implications for diagnosis and management. PMID- 21659864 TI - Insect anaphylaxis: addressing clinical challenges. AB - PURPOSE OF REVIEW: Few allergic reactions are as potentially life-threatening, or frightening to the patient, as anaphylaxis. Food, medications, and insect stings are the three most common triggers of anaphylaxis, but insect allergy provides the best opportunity to understand the biology of anaphylaxis. If the physician can establish a diagnosis of insect allergy, treatment with nearly 98% effectiveness can be initiated. However, sometimes patients have a compelling history of insect sting anaphylaxis, but negative skin and blood tests. This situation presents us with a fascinating opportunity to understand the biology of insect anaphylaxis. RECENT FINDINGS: Recent and ongoing work shows that occult mast cell disease may be critical in insect anaphylaxis. Mastocytosis, serum tryptase and basophil biology are key elements; genetic markers may potentially help us diagnose at-risk individuals and determine proper treatment. Understanding basophil activation may play an additional role both in diagnosis and knowing when therapy might be terminated. SUMMARY: Mast cell disease, serum tryptase and basophil biology are providing an opportunity to better understand and manage insect allergy. This evolving understanding should improve long-term management of insect anaphylaxis and help us to better understand the clinical dilemma of appropriate management of the history-positive patient in which testing is unable to detect venom-specific IgE. Furthermore, omalizumab's immunomodulatory effects may play a role in difficult-to-treat insect allergy and mastocytosis. Finally, unrelated to these, but still important as an ongoing risk factor, is the continued underutilization of epinephrine for both acute and long term management of insect anaphylaxis. PMID- 21659866 TI - Intraoperative management of pulmonary arterial hypertension in infants and children--corrected and republished article. AB - PURPOSE OF REVIEW: Pediatric pulmonary arterial hypertension (PAH) continues to be a considerable problem to the pediatric anesthesiologist even if its management has seen remarkable advances in recent years. It is important that anesthesiologists caring for children with PAH be aware of the increased risk, understand the pathophysiology of PAH, form an appropriate anesthetic management plan. A review of some of the latest medical advances will provide the reader with a better understanding of the most current anesthetic management options. RECENT FINDINGS: The literature reviewed demonstrate sustained clinical and hemodynamic improvement in children with various types of PAH as well as increased survival in patients with idiopathic PAH using current treatment strategies. This article will provide an overview of the current treatment and anesthetic strategies about idiopathic PAH in children over the last years. SUMMARY: The first important aspect of anesthetic management is to provide adequate intraoperative anesthesia and analgesia while minimizing increases in pulmonary vascular resistance and myocardial. Depending on the procedure, these goals can be met with the administration of either sedation/analgesia or general anesthesia together with new drugs for PAH treatment in association with a high potential for adverse events. PMID- 21659867 TI - Linking inflammation and coagulation: novel drug targets to treat organ ischemia. AB - PURPOSE OF REVIEW: Activation of the coagulation system during ischemia/reperfusion injury is an unavoidable event and even further augmented during cardiovascular surgery. Clotting not only leads to disturbance of blood rheology but also enhances the inflammatory response. We aim to highlight the inflammatory properties of the coagulation system and novel potential therapeutic approaches targeting both features. RECENT FINDINGS: Heparin, a thrombin inhibitor, is still the drug of choice for preventing coagulation following, for example, cardiovascular surgery. On the contrary, much effort is done to evaluate the utilization of direct thrombin inhibitors to prevent ischemia/reperfusion injury. Furthermore, targeting the inflammatory potential of the coagulation system seems to be very promising. Fibrin(ogen) and its degradation products modulate the inflammatory response, especially by inducing leukocyte migration. Inhibiting these pro-inflammatory effects, for example, by administration of Bbeta15-42 was recently shown to be beneficial under various inflammatory conditions. SUMMARY: Ischemia and reperfusion are common activators of coagulation that is also accompanied by inflammation. Therefore, targeting this well orchestrated system might be of therapeutic benefit, as its mode of action is dual: clotting inhibition and anti-inflammation. This novel therapeutic approach might at least be of benefit in the treatment of systemic inflammatory syndromes following, that is, cardiovascular surgery. PMID- 21659869 TI - Pharmacology of peripheral opioid receptors. AB - PURPOSE OF REVIEW: Since the detection of morphine by the pharmacologist Friedrich Serturner in 1806, opioids have been used as potent centrally acting analgesics. In addition to the central site of action, peripheral endogenous opioid analgesic systems have been extensively studied, especially in the past two decades. This review is not only mentioned to give a brief summary in this well investigated field of peripheral opioid receptors, but also to highlight the role of peripheral opioid receptors in other physiological and pathophysiological conditions. RECENT FINDINGS: A number of studies, which initially focused on nociception, also revealed an important role of the peripheral opioid receptor system in opioid-induced bowel dysfunction and pruritus, as well as in wound healing, cardioprotection, and the analgesic effects of celecoxib. SUMMARY: Efforts continue to develop opioid analgesics unable to cross the blood-brain barrier, which act only peripherally in low doses, thus providing adequate analgesia without central and systemic side-effects.The awareness of the influence of peripheral opioid receptors beyond nociception may also have therapeutic ramifications on the other fields mentioned above. For example, the treatment of opioid-induced bowel dysfunction by methylnaltrexone is one of the major findings in the previous years. PMID- 21659868 TI - The hypoxia-inflammation link and potential drug targets. AB - PURPOSE OF REVIEW: Hypoxia represents one of the strongest transcriptional stimuli known to us. In most cases, hypoxia-induced changes in gene expression are directed towards adapting tissues to conditions of limited oxygen availability. RECENT FINDINGS: As a well known example, physical exercise at high altitude results in the transcriptional induction of erythropoietin that functions to increase oxygen carrying capacity and red cell volume. Studies of the transcriptional pathway responsible for the induction of erythropoietin during conditions of hypoxia led to the discovery of the transcription factor hypoxia-inducible factor (HIF) that is known today as the key transcription factor for hypoxia adaptation. Surgical patients are frequently at risk for experiencing detrimental effects of hypoxia or ischemia, for example, in the context of acute kidney injury, myocardial, intestinal or hepatic ischemia, acute lung injury, or during organ transplantation. SUMMARY: In the present review, we discuss the mechanisms of transcriptional adaptation to hypoxia and provide evidence supporting the hypothesis that targeting hypoxia-induced inflammation can represent novel pharmacologic strategies to improve perioperative outcomes. Currently, such strategies are being explored at an experimental level, but we hope that some of these targets can be translated into perioperative patient care within the next decade. PMID- 21659870 TI - Effects of anaesthesia on the inflammatory response to injury. AB - PURPOSE OF REVIEW: The systemic inflammatory response to injury is essential for wound healing and recovery in concert with other endocrinological, metabolic and immunological changes. However, recent studies suggest that a hyperinflammatory state is associated with adverse perioperative outcomes. Therefore interventions that modulate the inflammatory response, surgical, anaesthetic and pharmacological, may enhance recovery with fewer complications. RECENT FINDINGS: Basic research on wound biology has shown the importance of genetic variability in determining the initial inflammatory response. Clinically, studies of cardiac surgery predominate in which genetic polymorphisms have been shown to result in a hyperinflammatory state. SUMMARY: The use of an interleukin-1 receptor antagonist to control wound pain and limit local inflammation is under consideration. The role of glucocorticoids in obtunding the inflammatory response to injury with improved outcome requires confirmation with better-quality trials. Systemic lidocaine is anti-inflammatory but is effective only in abdominal surgery. NSAIDs are neglected, despite their widespread clinical use and merit detailed investigation. PMID- 21659871 TI - Anesthesia and the developing brain: are we getting closer to understanding the truth? AB - PURPOSE OF REVIEW: Due to increased frequency of surgical interventions, infants and young children are exposed to anesthesia, often repeatedly, during an extremely delicate period of brain development. We review new evidence that continues to challenge the safety of this practice. RECENT FINDINGS: In animal models, anesthesia impairs normal synapse development and sculpting, which are crucial elements of developmental synaptogenesis. This age-dependent phenomenon is caused in part by actin cytoskeleton disorganization and impaired dendritic branching. Recent evidence also suggests that developing glia are sensitive to anesthesia-induced toxicity, which is manifested as stunted growth, delayed maturation, and disturbed process formation. Newly published findings in nonhuman primates, which report long-lasting cognitive impairment, stress the potential seriousness of anesthesia-induced developmental neurotoxicity. SUMMARY: Although clinical importance remains to be substantiated, results to date do indicate that exposure of animals to general anesthesia during active synaptogenesis is most detrimental. Accordingly, it is essential to determine when synaptogenesis begins and ends in developing humans. It is also imperative that effective preventive techniques be developed so that existing anesthetics can be used with minimum risk of neurotoxic side-effects of anesthesia. PMID- 21659874 TI - Telemedicine in anesthesia: an update. AB - PURPOSE OF REVIEW: Advances in health information technology and broadband Internet connections provide novel opportunities for anesthesiologists to extend perioperative consultation services to remote geographic areas. Increasing economic pressures on healthcare delivery systems make initiatives such as telemedicine, which reduce costs while achieving excellent outcomes, an attractive option. RECENT FINDINGS: Initiatives in remote access to anesthesiology services are emerging throughout the world in the areas of preoperative evaluation, intraoperative consultation, postoperative management and critical care as well as simulation and education. Physicians caring for patients in remote areas can benefit from the expertise found in subspecialty centers. In the US a number of states provide reimbursement for telemedicine services offered in several specialties, including anesthesiology. SUMMARY: Anesthesiologists have the opportunity to develop telemedicine programs that can improve the delivery of care to patients. Current programs offer services ranging from remote preoperative evaluation to international collaboration for intraoperative management and consultation. Simulation using telemedicine services can provide educational opportunities and test the effectiveness of institutions' communications systems. PMID- 21659875 TI - Current approaches to septal saddle nose reconstruction using autografts. AB - PURPOSE OF REVIEW: To describe the contemporary techniques used for septal saddle nose and, based on these, present our approaches for correction of a spectrum of deformity severities. RECENT FINDINGS: A review of different techniques currently in practice. These reflect greater emphasis on nasal structural framework repair rather than disguise and the use of autografts rather than allografts. SUMMARY: We present our classification of septal saddle deformity, demonstrating that this condition requires a flexible surgical approach with different techniques required depending on the extent of the defect. PMID- 21659873 TI - Anesthetic modulation of neuroinflammation in Alzheimer's disease. AB - PURPOSE OF REVIEW: To summarize key studies and recent thought on the role of neuroinflammation in chronic neurodegeneration, and whether it can be modulated by anesthesia and surgery. RECENT FINDINGS: A large and growing body of evidence shows that neuroinflammation participates in the development of neurodegeneration associated with Alzheimer's disease. Modulation may be possible early in the pathogenesis, and less so when cognitive symptoms appear. A dysfunctional hypoinflammatory response may permit accelerated damage due to other mechanisms in late disease. The peripheral inflammatory response elicited by surgery itself appears to provoke a muted neuroinflammatory response, which enhances ongoing neurodegeneration in some models. Anesthetics have both anti-inflammatory and proinflammatory effects depending on the drug and concentration, but in general, appear to play a small role in neuroinflammation. Human studies at the intersection of chronic neurodegeneration, neuroinflammation, and surgery/anesthesia are rare. SUMMARY: The perioperative period has the potential to modulate the progression of chronic neurodegenerative diseases. The growing number of elderly having surgery, combined with the expanding life expectancy, indicates the potential for this interaction to have considerable public health implications, and call for further research, especially in humans. PMID- 21659872 TI - A brief comparison of the pathophysiology of inflammatory versus neuropathic pain. AB - PURPOSE OF REVIEW: The causes of inflammatory pain and neuropathic pain are fundamentally different. There are, however, common mechanisms underlying the generation of each pain state. We will discuss some specific elements observed in both tissue and nerve injury pain states and consider the hypothesis that these two states actually demonstrate a convergence over time. RECENT FINDINGS: The increased pain sensation following tissue and nerve injury results from several mechanisms, including altered ion channel expression in dorsal root ganglion neurons, enhanced dorsal horn glutamate release from primary afferents, enhanced glutamate receptor function in second-order neurons, disinhibition in the dorsal horn and glia cell activation. The role of specific subtypes of receptors, ion channels and glutamate transporters is revealed at peripheral and central sites. Importantly over time, a number of changes, in the dorsal root ganglion and in dorsal horn observed after tissue injury resemble changes observed after nerve injury. SUMMARY: Recognition of mechanisms common to both inflammatory pain and neuropathic pain might shed light on the understanding of the transition from acute pain to persistent pain. PMID- 21659876 TI - Laser treatment of facial scars. AB - PURPOSE OF REVIEW: Facial scars can develop as a result of trauma, surgery, burns, acne, or other conditions. These scars are often quite distressing to patients. Lasers were first used to treat these scars in the 1990s. Recently, new laser technology has been used to prevent and treat scars. This literature review and the report of the senior author's recent experience summarize the recent advances in laser treatment of scars. RECENT FINDINGS: With the development of new laser technology, the treatment options for hypotrophic scars and developing scars have increased. Furthermore, there are expanded options for treatment of established hypertrophic scars. Recent studies have shown that nonablative and fractionated lasers can be effective for treating hypotrophic and developing scars. Scar improvements may be due to direct effects of the laser and/or histochemical effects, including production of heat shock proteins and tumor growth factors. Nonablative and fractionated lasers have a shorter recovery period than CO2 resurfacing lasers. This can vary from a few hours to up to 7 days. SUMMARY: Recent new laser technology has increased the options for treatment of scars. These have been shown to be beneficial for hypotrophic, incipient, and established scars. The benefits of laser therapy may be due to direct and/or histochemical effects. PMID- 21659877 TI - Lipotransfer in the upper third of the face. AB - PURPOSE OF REVIEW: The purpose of this article is to review the latest developments and techniques in lipotransfer to the upper third of the face. RECENT FINDINGS: Volume loss is becoming increasingly recognized as a significant contributor to upper facial aging. Lipotransfer has been used more extensively because fat exhibits many qualities of an ideal filler, able to restore volume to deflated tissues. Whereas certain nuances and differences in techniques exist, all authors agree that transfer of conservative volumes of fat in key regions of the upper face restores a natural youthful look. SUMMARY: Volume loss in the upper third of the face contributes significantly to aging. The use of lipotransfer in this area is an important adjunct to traditional surgical techniques. It can also be used as a primary rejuvenation procedure in select patients. More studies are needed to elucidate the optimal method of fat harvest, processing, and injection as well as longevity of transplanted grafts. PMID- 21659878 TI - Skeletal surgery in sleep apnea. AB - PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is a common condition, increasing in incidence along with obesity in Americans. This review looks at skeletal surgery to treat sleep apnea and recent advancements. RECENT FINDINGS: Skeletal surgery for OSA has improved with recent advancements in surgical genioplasty now able to advance the genioglossus as well as inferior mandible muscles without changing aesthetics. Some investigators have called for maxillomandibular advancement to be considered as a first-line therapy over continuous positive airway pressure. SUMMARY: Maxillomandibular advancement appears safe and effective for consideration as a first-line therapy for select patients with OSA. PMID- 21659879 TI - Advances in nasal reconstruction. AB - PURPOSE OF REVIEW: Recent advances in nasal reconstruction are provided within the framework of traditional reconstructive principles. RECENT FINDINGS: Recent advances build upon and challenge the established tenets and principles of nasal reconstruction. Advances focus on achieving perfection in restoration of form and function with the absolute minimum of donor site morbidity. Specifically, advances in tissue engineering show promise in recreating cartilaginous framework. SUMMARY: This article summarizes the most recent developments in nasal reconstruction. The focus of recent advances in nasal reconstruction centers on minimizing morbidity while achieving an inconspicuous result. PMID- 21659880 TI - Advances in surgical approaches to the upper facial skeleton. AB - PURPOSE OF REVIEW: Surgical approaches to the upper facial skeleton comprise the coronal, lower eyelid and midface degloving approaches. These are routinely employed in both ablative and reconstructive craniofacial procedures. The ability to perform them in a well tolerated and predictable manner is predicated on knowledge of the indications and the exposure afforded by each approach, detailed appreciation of the anatomy and awareness of potential complications. This article reviews the literature for recent advancements and surgical refinements for each approach. RECENT FINDINGS: Multiple studies over the past 20 years have offered insight into many technical refinements in these surgical approaches. The choice of dissection plane in the lateral extension of the coronal approach affects the integrity of the frontal branch of the facial nerve and the temporal fat pad. A transcaruncular extension of the transconjunctival approach provides unprecedented access to the medial orbital wall and the midface degloving approach renders complex reconstructive procedures feasible. SUMMARY: These techniques continue to evolve and become more precise so that better results can be achieved and devastating complications can be avoided. This study reviews the literature and summarizes preferred options for craniofacial exposure, recent technical refinements, and our current preferred surgical approaches. PMID- 21659881 TI - Folic acid intake and spina bifida in the era of dietary folic acid fortification. AB - BACKGROUND: The US Food and Drug Administration mandated that enriched grain products be fortified with folic acid by 1998. We evaluated whether intake of folic acid from supplements and diet was associated with a reduction in spina bifida in the setting of folic acid fortification. METHODS: Data were collected as part of the Slone Birth Defects Study from 1998 to 2008. Mothers of infants with and without birth defects were interviewed within 6 months of delivery about pregnancy exposures, including details of diet and vitamin intake. Dietary natural folate and synthetic folic acid from fortification were combined into a single, weighted measure--dietary folate equivalent. Periconceptional folic acid supplementation and dietary folate consumption were compared between 205 mothers of spina bifida cases and 6357 mothers of nonmalformed controls. Relative risks of a spina bifida-affected birth were estimated with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Spina bifida was not associated with regular folic acid supplementation (>=4 days per week) either around the time of conception (adjusted OR = 1.1 [95% CI = 0.74-1.7]) or initiated in early pregnancy (0.79 [0.54-1.2]). After adjustment for confounders, a 13% reduced odds of spina bifida was estimated for each 100-MUg increase in daily dietary folate equivalent consumed. CONCLUSIONS: In the setting of folic acid fortification of grains, our data suggest that folic acid supplementation does not appear to offer further benefit for reducing risk of spina bifida. Rather, the folate-associated benefit on spina bifida risk was found with increasing amounts of dietary folic acid consumed, regardless of folic acid supplementation level. PMID- 21659882 TI - Invasive bacterial infections in a paediatric emergency department in the era of the heptavalent pneumococcal conjugate vaccine. AB - OBJECTIVE: To describe the characteristics of patients diagnosed with invasive bacterial infections (IBIs) in a Paediatric Emergency Department (PED) following the introduction of the heptavalent pneumococcal conjugated vaccine (PCV7). METHODS: Descriptive retrospective study of children under 14 years of age diagnosed with IBIs in a PED of a tertiary hospital between January 2008 and December 2009. RESULTS: In this period we registered 123 396 episodes and 59 patients who were diagnosed with IBIs (22 patients under 1 year of age, 37.2%). Of these, 11 (18.6%) had some severe underlying condition and 38 (64.4%) were stable on arrival. The most common diagnoses were sepsis with/without meningitis (23, 38.9%) and bacteraemia (14, 23.7%), while the pathogens most frequently isolated were Streptococcus pneumoniae (23, 38.9%) and Neisseria meningitidis (18, 30.5%). Pathogens were isolated from blood in 57 patients and from the cerebrospinal fluid in eight (in these, the same bacterial species was isolated in the blood, except for two cases with S. pneumoniae). Of the pneumococci isolated, 80% corresponded to serotypes included in the 13-valent PCV13. In seven cases, pathogens were detected using only PCR analysis (N. meningitidis, four; S. pneumoniae, three). Twenty-five patients were admitted to the Paediatric Intensive Care Unit. No patient died but two had sequelae. CONCLUSION: In the era of PCV7, pneumococcus is the leading cause of IBI in PED. The introduction of PCV13 may lead to a very significant decrease in the IBI rate and meningococcus may become the leading cause of IBI. PMID- 21659883 TI - Web survey and embedded intervention on emergency department personnel perceptions of role in patient experience. AB - Investigators examined emergency department (ED) personnel's perceived job responsibilities and insights into determinants of patient experience. Surveys queried subjects on their perceptions of select clinical care-related actions (CCAs) to assess discipline-specific and service-specific CCA ownership and valuation. Investigators surveyed 153 of 634 ED personnel. A total of 3047 responses to 3802 queries indicated that a specified CCA was 'always' (58.2%) or 'sometimes' (21.9%) the subject's responsibility. A total of 3645 of 3797 responses indicated the CCA specified was 'always' (84.2%) or 'sometimes' (11.8%) important to the patient experience. Twelve percent of subjects reported not being responsible for monitoring or correcting medical errors. After exposure to survey queries, subjects indicated changing or re-considering how they communicate with patients (28.1%), deliver clinical care (20.2%), and arrange disposition/follow-up (20.3%). ED personnel's perceptions of CCA ownership and importance to patient experience were assessed. Subjects reported detectable levels of anticipated job-related behavioral changes traceable to survey-embedded intervention. PMID- 21659884 TI - Data collection in a live mass casualty incident simulation: automated RFID technology versus manually recorded system. AB - OBJECTIVES: To demonstrate the applicability and the reliability of a radio frequency identification (RFID) system to collect data during a live exercise. METHODS: A rooftop collapse of a crowded building was simulated. Fifty-three volunteers were trained to perform as smart victims, simulating clinical conditions, using dynamic data cards, and capturing delay times and triage codes. Every victim was also equipped with a RFID tag. RFID antenna was placed at the entrance of the advanced medical post (AMP) and emergency department (ED) and recorded casualties entering the hospital. RESULTS: A total of 12 victims entered AMP and 31 victims were directly transferred to the ED. 100% (12 of 12 and 31 of 31) of the time cards reported a manually written hospital admission time. No failures occurred in tag reading or data transfers. A correlation analysis was performed between the two methods plotting the paired RFID and manual times and resulted in a r=0.977 for the AMP and r=0.986 for the ED with a P value of less than 0.001. CONCLUSION: We confirmed the applicability of RFID system to the collection of time delays. Its use should be investigated in every aspect of data collection (triage, treatments) during a disaster exercise. PMID- 21659885 TI - Intervertebral disc degeneration-induced expression of pain-related molecules: glial cell-derived neurotropic factor as a key factor. AB - BACKGROUND: Discogenic low back pain has been shown to develop into chronic intractable pain due to an unknown pathogenesis. To study the mechanism of discogenic pain, we analyzed the serial expression of pain-related molecules in the dorsal root ganglia (DRG) and thalamus using a newly developed rat model of disc degeneration. METHODS: Ten microliters of complete Freund's adjuvant was injected into the L5-6 disc of male Sprague-Dawley rats for 10 minutes using a 26 gauge needle. Using a behavioral test, rats with significant pain were selected and subsequently serial gene expression of pain-related molecules in the DRG and the thalamus was analyzed by reverse transcriptase polymerase chain reaction. RESULTS: The expression of tumor necrosis factor-alpha and interleukin-1beta significantly increased at 4 and 8 weeks in the DRG of rats with pain. Furthermore, interleukin-6 was significantly increased at 4 weeks in the DRG; however, these cytokines did not show a significant change in the thalamus. Calcitonin gene-related peptide and substance P were significantly increased in DRG at 4 and 8 weeks and in the thalamus at 2 and 4 weeks. The level of nerve growth factor-beta did not significantly increase in the DRG or thalamus, whereas glial cell line-derived neurotropic factor (GDNF) was significantly increased at 2 weeks and was sustained through 8 weeks in both the DRG and thalamus. CONCLUSIONS: The disc degeneration rat model described herein led to significant pain of a chronic nature. The gradual and persistent increase of GDNF in both the thalamus and DRG suggests that GDNF might be a key factor in the development of intractable, chronic discogenic pain. PMID- 21659886 TI - Effect of training with and without a load on military fitness tests and marksmanship. AB - The purpose of this study was to determine whether military-style training performed while carrying a weighted vest and backpack (Load condition) resulted in superior training adaptations (specifically, changes in military fitness and marksmanship) than did more conventional training (No-Load condition). A total of 33 college-aged men and women (16 Load, 17 No-Load) completed all testing and 9 weeks of training (1 h.d, 4 d.wk). No-Load training consisted of military calisthenics, sprints, agility drills, and running. Load training was similar except that running was replaced with stair climbing, and Load increased across the 9 weeks to 20 kg for women and 30 kg for men. Pretraining and posttraining, all subjects performed an uphill treadmill test with full load to determine peak oxygen consumption (VO(2)peak), the marine physical fitness test (PFT) and combat fitness test (CFT) without load, other fitness tests, and an indoor marksmanship test using a laser-fitted carbine. The marksmanship test was performed with full load and done before and immediately after a 200-m shuttle run performed in 60 seconds. Both groups significantly improved their VO(2)peak, PFT, and CFT scores by similar amounts. Pretraining, shooting score decreased significantly after the 200-m run and then rapidly recovered, with no difference between groups. A similar, but nonsignificant, pattern in shooting scores was seen in both groups posttraining. In conclusion, loaded training did not produce measurable advantages compared with unloaded training in this population. A strenuous anaerobic challenge caused a temporary reduction in marksmanship. PMID- 21659887 TI - The effect of pomegranate juice supplementation on strength and soreness after eccentric exercise. AB - The purpose of this study was to determine if pomegranate juice supplementation improved the recovery of skeletal muscle strength after eccentric exercise in subjects who routinely performed resistance training. Resistance trained men (n = 17) were randomized into a crossover design with either pomegranate juice or placebo. To produce delayed onset muscle soreness, the subjects performed 3 sets of 20 unilateral eccentric elbow flexion and 6 sets of 10 unilateral eccentric knee extension exercises. Maximal isometric elbow flexion and knee extension strength and muscle soreness measurements were made at baseline and 2, 24, 48, 72, 96, and 168 hours postexercise. Elbow flexion strength was significantly higher during the 2- to 168-hour period postexercise with pomegranate juice compared with that of placebo (main treatment effect; p = 0.031). Elbow flexor muscle soreness was also significantly reduced with pomegranate juice compared with that of placebo (main treatment effect; p = 0.006) and at 48 and 72 hours postexercise (p = 0.003 and p = 0.038, respectively). Isometric strength and muscle soreness in the knee extensors were not significantly different with pomegranate juice compared with those using placebo. Supplementation with pomegranate juice attenuates weakness and reduces soreness of the elbow flexor but not of knee extensor muscles. These results indicate a mild, acute ergogenic effect of pomegranate juice in the elbow flexor muscles of resistance trained individuals after eccentric exercise. PMID- 21659888 TI - The effects of diverting activities on recovery from fatiguing concentric isokinetic muscle actions. AB - The purpose of this study was to examine the effects of diverting activities on recovery from fatiguing concentric isokinetic muscle actions. On 3 separate occasions, 11 men (mean +/- SD age = 22.2 +/- 1.5 years) and 8 women (mean +/- SD age = 22.2 +/- 2.1 years) performed 2 bouts of 50 consecutive maximal concentric isokinetic muscle actions of the dominant leg extensors. Between these bouts, the subjects either performed math problems (mental diverting activity), contralateral dynamic constant external resistance (DCER) leg extensions (physical diverting activity), or rested quietly (control). For each trial, the peak torque data from the first and second bouts of 50 muscle actions served as the pretest (Pre) and posttest (Post) data, respectively. The results indicated that when the subjects rested quietly or performed contralateral DCER leg extensions between the fatiguing bouts, the initial peak torque values observed for Post were significantly less than those for Pre. When the subjects performed math problems, however, no decline in the initial peak torque values was observed, thus indicating better recovery. In addition, a decline in the average torque values was observed from Pre to Post for the control trial but not for the math problem or contralateral exercise trials. No differences were observed among the trials for final peak torque, percent decline, or the linear slope of the decline in peak torque. These findings demonstrated that performing either mental or physical diverting activities after fatiguing isokinetic muscle actions enhanced recovery. PMID- 21659889 TI - Similarity in adaptations to high-resistance circuit vs. traditional strength training in resistance-trained men. AB - To compare the effects of 8 weeks of high-resistance circuit (HRC) training (3-6 sets of 6 exercises, 6 repetition maximum [RM], ~35-second interset recovery) and traditional strength (TS) training (3-6 sets of 6 exercises, 6RM, 3-minute interset recovery) on physical performance parameters and body composition, 33 healthy men were randomly assigned to HRC, TS, or a control group. Training consisted of weight lifting 3 times a week for 8 weeks. Before and after the training, 1RM strength on bench press and half squat exercises, bench press peak power output, and body composition (dual x-ray absorptiometry ) were determined. Shuttle run and 30-second Wingate tests were also completed. Upper limb (UL) and lower limb 1RM increased equally after both TS and HRC training. The UL peak power at various loads was significantly higher at posttraining for both groups (p <= 0.01). Shuttle-run performance was significantly better after both HRC and TS training, however peak cycling power increased only in TS training (p <= 0.05). Significant decreases were found in % body fat in the HRC group only; HRC and TS training both resulted in an increased lean but not bone mass. The HRC training was as effective as TS for improving weight lifting 1RM and peak power, shuttle-run performance and lean mass. Thus, HRC training promoted a similar strength-mass adaptation as traditional training while using a shorter training session duration. PMID- 21659890 TI - A training program to improve neuromuscular indices in female high school volleyball players. AB - The purpose of this study was to determine if a sports-specific training program could improve neuromuscular indices in female high school volleyball players. We combined components from a previously published knee ligament injury prevention intervention program for jump and strength training with additional exercises and drills to improve speed, agility, overall strength, and aerobic conditioning. We hypothesized that this sports-specific training program would lead to significant improvements in neuromuscular indices in high school female volleyball players. Thirty-four athletes (age 14.5 years +/- 1.0) participated in the supervised 6 week program, 3 d.wk(-1) for approximately 90-120 minutes per session. The program was conducted on the school's volleyball court and weight room facilities. The athletes underwent a video drop-jump test, multistage fitness test, vertical jump test, and sit-up test before and after training. A significant increase was found in the mean VO2max score (p < 0.001), where 73% of the athletes improved this score. A significant improvement was found in the sit up test (p = 0.03) and in the vertical jump test (p = 0.05), where 68% of the athletes increased their scores. In the drop-jump video test, significant increases were found in both the mean absolute knee separation distance (p = 0.002) and in the mean normalized knee separation distance (p = 0.04), indicating improved lower limb alignment on landing. No athlete sustained an injury or developed an overuse syndrome during training. This program significantly improved lower limb alignment on a drop-jump test, abdominal strength, estimated maximal aerobic power, and vertical jump height and may be implemented in high school female volleyball programs. PMID- 21659891 TI - Resistance training improves depressive symptoms in individuals at high risk for type 2 diabetes. AB - Depression is more prevalent in obese individuals and those with diabetes, compared to the general population. This study examined the effect of resistance training on depressed mood in individuals with high (HiMF, n >= 2) and low (LoMF, n <= 1) numbers of risk factors for metabolic syndrome and type 2 diabetes. The primary hypothesis was that resistance training would significantly reduce depressed mood, as measured by the Cardiac Depression Scale (CDS), in individuals with HiMF. Fifty-five middle-aged volunteers (50.8 +/- 0.9 years, mean +/- SEM) from the general community participated in the study. After initial allocation to HiMF or LoMF, participants were randomly allocated to 4 groups, HiMF training (HiMFT), HiMF control (HiMFC), LoMF training (LoMFT), and LoMF control (LoMFC). Participants underwent resistance training involving major muscle groups on 3 d.wk(-1) for 10 weeks. Before and after interventions (training or control), participants completed the CDS to assess change in the level of depressed mood. Following resistance training, the CDS score of the HiMFT group was reduced by 14.8 +/- 4.9 points on the CDS, a significant improvement in comparison to both baseline (p = 0.01) and HiMFC (p = 0.049) values. No significant change was observed for LoMFT. In the HiMF group only, the percent change in relative muscle strength was correlated with the Delta change in CDS; r = -0.46, p = 0.008. Resistance exercise training programs that consist 7 exercises for the major muscle groups at both low-moderate and moderate-high intensities appear to alleviate depressed mood in individuals with clusters of metabolic risk factors. PMID- 21659892 TI - A comparison of three training programs with the same workload on overhead throwing velocity with different weighted balls. AB - The purpose of this study was to determine if different throwing programs based upon velocity (throwing with a regular sized soccer ball), resistance (throwing with heavy medicine ball), or a combination of both with the same workload would enhance 2-handed overhead throwing velocity with different ball weights. Sixty eight high-school students (16.5 +/- 1.8 years, 57.8 +/- 12 kg, 164 +/- 9 cm), divided into 3 groups, participated in the study. The training programs were matched on total workload, which resulted in the velocity-training group performing 6 series of 14 reps per session with soccer balls, whereas the resistance-training group performed 3 series of 6 throws with a 3-kg medicine ball, and the combination-training group threw 9 times with a 3-kg medicine ball and 3 series of 14 reps with a soccer ball per session. Throwing velocity with a soccer ball, a 1- and 3-kg medicine ball was tested before and after a training period of 6 weeks with 2 sessions per week. A significant (p <= 0.05) increase in throwing velocity was found after the 6-week training period with the soccer ball (6.9%) and the 1-kg medicine ball (2.8%), but not with the 3-kg medicine ball ( 2.5%). In contrast, no group interaction was found with the different balls indicating that velocity, resistance, or a combination as a form of training increased the throwing velocity. Different types of training with the same total workload can increase the throwing velocity in a similar way, which shows that workload is of importance in designing training programs and comparing training with each other. Therefore, those that train high-school soccer players could implement any one of these 3 6-week programs to increase 2-handed overhead soccer throw-in velocity. This could allow the throw-in to be harder or potentially thrown farther if the right trajectory is used. PMID- 21659893 TI - Effects of beta-alanine supplementation on performance and body composition in collegiate wrestlers and football players. AB - The purpose of this study was to examine the effectiveness of beta-alanine as an ergogenic aid in tests of anaerobic power output after 8 weeks of high-intensity interval, repeated sprint, and resistance training in previously trained collegiate wrestlers (WR) and football (FB) players. Twenty-two college WRs (19.9 +/- 1.9 years, age +/- SD) and 15 college FB players (18.6 +/- 1.5 years) participated in this double-blind, placebo-controlled study. Each subject ingested either 4 g.d beta-alanine or placebo in powdered capsule form. Subjects were tested pre and posttreatment in timed 300-yd shuttle, 90 degrees flexed-arm hang (FAH), body composition, and blood lactate after 300-yd shuttle. Although not statistically significant (p > 0.05) subjects taking beta-alanine achieved more desirable results on all tests compared to those on placebo. Performance improvements were greatest in the FB supplement group, decreasing 300 shuttle time by 1.1 seconds (vs. 0.4-second placebo) and increasing FAH (3.0 vs. 0.39 seconds). The wrestlers, both placebo and supplement, lost weight (as was the goal, i.e., weight bracket allowance); however, the supplement group increased lean mass by 1.1 lb, whereas the placebo group lost lean mass (-0.98 lb). Both FB groups gained weight; however, the supplement group gained an average 2.1-lb lean mass compared to 1.1 lb for placebo. beta-Alanine appears to have the ability to augment performance and stimulate lean mass accrual in a short amount of time (8 weeks) in previously trained athletes. Training regimen may have an effect on the degree of benefit from beta-alanine supplementation. PMID- 21659894 TI - A biomechanical analysis of straight and hexagonal barbell deadlifts using submaximal loads. AB - The purpose of the investigation was to compare the kinematics and kinetics of the deadlift performed with 2 distinct barbells across a range of submaximal loads. Nineteen male powerlifters performed the deadlift with a conventional straight barbell and a hexagonal barbell that allowed the lifter to stand within its frame. Subjects performed trials at maximum speed with loads of 10, 20, 30, 40, 50, 60, 70, and 80% of their predetermined 1-repetition maximum (1RM). Inverse dynamics and spatial tracking of the external resistance were used to quantify kinematic and kinetic variables. Subjects were able to lift a heavier 1RM load in the hexagonal barbell deadlift (HBD) than the straight barbell deadlift (SBD) (265 +/- 41 kg vs. 245 +/- 39 kg, p < 0.05). The design of the hexagonal barbell significantly altered the resistance moment at the joints analyzed (p < 0.05), resulting in lower peak moments at the lumbar spine, hip, and ankle (p < 0.05) and an increased peak moment at the knee (p < 0.05). Maximum peak power values of 4,388 +/- 713 and 4,872 +/- 636 W were obtained for the SBD and HBD, respectively (p < 0.05). Across the submaximal loads, significantly greater peak force, peak velocity and peak power values were produced during the HBD compared to during the SBD (p < 0.05). The results demonstrate that the choice of barbell used to perform the deadlift has a significant effect on a range of kinematic and kinetic variables. The enhanced mechanical stimulus obtained with the hexagonal barbell suggests that in general the HBD is a more effective exercise than the SBD. PMID- 21659895 TI - A case of idiopathic azygos vein aneurysm and review of the literature. AB - Azygos vein aneurysm is extremely rare. Herein we report a 41-year-old woman whose chest radiograph showed right paratracheal opacity. During 6-month follow up, she underwent computed tomography scanning 3 times and magnetic resonance imaging. The mass enlarged gradually and changed its position from the posterior to the anterior upper right mediastinum. Venography and surgery were finally performed, which confirmed an aneurysm of the azygos vein. Pathologic findings indicated a congenital etiology. To the best of our knowledge, such an azygos vein aneurysm with changeable position during follow-up has not been reported previously. PMID- 21659896 TI - Achilles tendinopathy has an aberrant strain response to eccentric exercise. AB - PURPOSE: Eccentric exercise has become the treatment of choice for Achilles tendinopathy. However, little is known about the acute response of tendons to eccentric exercise or the mechanisms underlying its clinical benefit. This research evaluated the sonographic characteristics and acute anteroposterior (AP) strain response of control (healthy), asymptomatic, and symptomatic Achilles tendons to eccentric exercise. METHODS: Eleven male adults with unilateral midportion Achilles tendinopathy and nine control male adults without tendinopathy participated in the research. Sagittal sonograms of the Achilles tendon were acquired immediately before and after completion of a common eccentric rehabilitation exercise protocol and again 24 h later. Tendon thickness, echogenicity, and AP strain were determined 40 mm proximal to the calcaneal insertion. RESULTS: Compared with the control tendon, both the asymptomatic and symptomatic tendons were thicker (P < 0.05) and hypoechoic (P < 0.05) at baseline. All tendons decreased in thickness immediately after eccentric exercise (P < 0.05). The symptomatic tendon was characterized by a significantly lower AP strain response to eccentric exercise compared with both the asymptomatic and control tendons (P < 0.05). AP strains did not differ in the control and asymptomatic tendons. For all tendons, preexercise thickness was restored 24 h after exercise completion. CONCLUSIONS: These observations support the concept that Achilles tendinopathy is a bilateral or systemic process and structural changes associated with symptomatic tendinopathy alter fluid movement within the tendon matrix. Altered fluid movement may disrupt remodeling and homeostatic processes and represents a plausible mechanism underlying the progression of tendinopathy. PMID- 21659897 TI - Physical activity and body mass: changes in younger versus older postmenopausal women. AB - PURPOSE: The study's purpose was to investigate the relationship of sedentary (<= 100 MET . min . wk(-1)), low (>100-500 MET . min . wk(-1)), moderate (>500-1200 MET . min . wk(-1)), and high (>1200 MET . min . wk(-1)) habitual physical activity with body weight, body mass index, and measures of fat distribution (waist-to-hip ratio) in postmenopausal women by age decades. METHODS: A prospective cohort study of 58,610 postmenopausal women age 50-79 yr weighed annually during 8 yr at one of 40 US clinical centers was analyzed to determine the relationship of high versus low habitual physical activity with changes in body weight and fat distribution by age group. RESULTS: Among women age 50-59 yr, there was significant weight loss in those expending >500-1200 MET . min . wk(-1) (coefficient = -0.30, 95% confidence interval = -0.53 to -0.07) compared with the group expending <= 100 MET . min . wk(-1). Among women age 70-79 yr, higher physical activity was associated with less weight loss (coefficient = 0.34, 95% confidence interval = 0.04-0.63). Age at baseline significantly modified the association between physical activity and total weight change, whereas baseline body mass index did not. CONCLUSIONS: High habitual physical activity is associated with less weight gain in younger postmenopausal women and less weight loss in older postmenopausal women. These findings suggest that promoting physical activity among postmenopausal women may be important for managing body weight changes that accompany aging. PMID- 21659899 TI - Lumbopelvic landing kinematics and EMG in women with contrasting hip strength. AB - PURPOSE: Hip muscle weakness has been associated with altered lower extremity mechanics and the increased likelihood of receiving treatment for low back problems, although biomechanical injury mechanisms focused on the trunk have not been investigated. The purpose of this study was to compare lumbopelvic kinematic variables and muscle activation of the trunk and gluteal muscles in females with strong and weak hip muscle strength during a demanding single-leg task. METHODS: Twenty-two asymptomatic females were categorized into a strong or weak group (11 per group) as determined by isometric hip extension and abduction dynamometry profiles. Participants performed a single-leg landing task during which three dimensional lumbopelvic kinematics and trunk (lumbar erector spinae, external obliques, and rectus abdominis) and gluteal (gluteus maximus and gluteus medius) muscle activities were recorded. Peak lumbopelvic angular displacement, total angular excursion, and mean and peak angular velocity during the first 0.5 s of landing were reported. Mean normalized EMG and muscle cocontraction index (between the lumbar erector spinae and the external obliques) were also reported. RESULTS: Significant between-group differences existed for each of the following: peak displacement, excursion, velocity, and muscle activity. Differences in peak angular displacement occurred in the frontal plane, whereas excursion differences were observed in all planes. Differences in peak velocity were noted in the sagittal and frontal planes. Weaker subjects showed increased muscle activation (across all muscles except the rectus abdominis) and cocontraction index. CONCLUSIONS: Individuals with diminished hip muscle strength exhibit greater lumbopelvic angular displacement, velocity, and muscle activity during the single leg landing task. Future studies targeting hip strengthening may provide more insight to rehabilitation protocols as well as the relation between hip strength, low back motion, and muscle activity. PMID- 21659898 TI - Oxidative stress effects on endothelial cells treated with different athletes' sera. AB - PURPOSE: Exercise training is a nonpharmacological intervention that improves cardiovascular function and enhances endothelial homeostasis in patients with cardiovascular diseases. However, the amount of benefit achieved varies widely depending on the type and duration of exercise. Moreover, data about the long term effects of physical activity are scarce. METHODS: In this study, endothelial cells, exposed or not to oxidative stress, were conditioned with sera from athletes regularly participating in sports classified as "aerobic" (triathlon), "mixed aerobic-anaerobic" (soccer), and "anaerobic" (sprint running). RESULTS: Functional and hemodynamic variables did not differ between groups of athletes, whereas there were dramatic changes in serum markers for oxidative stress. Lipid peroxidation assessed by the thiobarbituric acid reactive substances assay and catalase activity were the lowest and nitric oxide availability was the highest in sera of triathletes. Endothelial cells cultured in serum from triathletes (T endothelial cells) had the highest survival, evaluated by viability assay, BrdU incorporation, and senescence-associated beta galactosidase assays, and preserved the endothelial appearance before and after stress in contrast to the cells grown in sera from the other athletes. T-endothelial cells also had the highest catalase messenger RNA expression and, after stress, the highest catalase activity of all the endothelial cells. Moreover, poststress activity of Sirt1, a NAD(+)-dependent deacetylase involved in cellular stress resistance and a key regulator of longevity, was significantly increased in T-endothelial cells. CONCLUSIONS: Different types of exercise training induced different molecular effects in terms of survival, morphology, and antioxidant system efficiency. The in vitro technique used herein may help to shed light on the molecular basis of effects of long-term physical activity in humans. PMID- 21659900 TI - Effects of resistance training on adiposity and metabolism after spinal cord injury. AB - PURPOSE: This pilot work was conducted to evaluate the effects of neuromuscular electrical stimulation resistance training (RT) of the paralyzed knee extensor muscle groups on skeletal muscle and intramuscular fat (IMF) cross-sectional areas, trunk visceral adipose tissue (VAT), carbohydrate, and lipid profiles in men with spinal cord injury. METHODS: Nine individuals with motor complete spinal cord injury were randomly assigned to an RT + diet group (n = 5) or a diet group (n = 4). The RT + diet underwent 12 wk of progressive RT, twice weekly, to the knee extensor muscle groups using neuromuscular electrical stimulation and ankle weights. Weekly feedback was provided to both groups to maintain a standard diet. Magnetic resonance imaging and a whole-body dual-energy x-ray absorptiometric images were obtained before and 1 wk after interventions. Participants underwent a metabolic study after a 12-h overnight fast to measure fasting and postchallenge plasma glucose, insulin, and lipid profiles. RESULTS: Skeletal muscle hypertrophy was detected in the whole thigh, knee extensors, and flexors in the RT + diet group compared with the diet group. VAT cross-sectional area, VAT/subcutaneous adipose tissue ratio at L5-S3, and percent IMF decreased significantly in the RT + diet group. Plasma insulin area under the curve decreased in the RT + diet group but not in the diet group. Fasting triglycerides and cholesterol/HDL decreased in the RT + diet group. CONCLUSIONS: Twice-weekly evoked RT to the paralyzed lower extremities resulted in significant skeletal muscle hypertrophy that was associated with reduction in VAT, VAT/subcutaneous adipose tissue ratio, and percent IMF. Significant improvements in insulin profile and lipid metabolism were noted in the RT + diet when compared with diet alone. PMID- 21659901 TI - Effect of acute static stretch on maximal muscle performance: a systematic review. AB - INTRODUCTION: The benefits of preexercise muscle stretching have been recently questioned after reports of significant poststretch reductions in force and power production. However, methodological issues and equivocal findings have prevented a clear consensus being reached. As no detailed systematic review exists, the literature describing responses to acute static muscle stretch was comprehensively examined. METHODS: MEDLINE, ScienceDirect, SPORTDiscus, and Zetoc were searched with recursive reference checking. Selection criteria included randomized or quasi-randomized controlled trials and intervention-based trials published in peer-reviewed scientific journals examining the effect of an acute static stretch intervention on maximal muscular performance. RESULTS: Searches revealed 4559 possible articles; 106 met the inclusion criteria. Study design was often poor because 30% of studies failed to provide appropriate reliability statistics. Clear evidence exists indicating that short-duration acute static stretch (<30 s) has no detrimental effect (pooled estimate = -1.1%), with overwhelming evidence that stretch durations of 30-45 s also imparted no significant effect (pooled estimate = -1.9%). A sigmoidal dose-response effect was evident between stretch duration and both the likelihood and magnitude of significant decrements, with a significant reduction likely to occur with stretches >= 60 s. This strong evidence for a dose-response effect was independent of performance task, contraction mode, or muscle group. Studies have only examined changes in eccentric strength when the stretch durations were >60 s, with limited evidence for an effect on eccentric strength. CONCLUSIONS: The detrimental effects of static stretch are mainly limited to longer durations (>= 60 s), which may not be typically used during preexercise routines in clinical, healthy, or athletic populations. Shorter durations of stretch (<60 s) can be performed in a preexercise routine without compromising maximal muscle performance. PMID- 21659902 TI - Physical activity and cardiovascular mortality risk: possible protective mechanisms? AB - INTRODUCTION: The biological mechanisms through which increased physical activity or structured exercise training lowers the risk of recurrent cardiac events are incompletely understood. We examined the extent to which modification of primary risk markers explains the association between physical activity and cardiovascular death in participants with diagnosed cardiovascular disease (CVD). METHODS AND RESULTS: In a prospective study of 1429 participants with physician diagnosed CVD living in England and Scotland (age = 66.5 +/- 11.1 yr (mean +/- SD), 54.2% men), we measured physical activity and several risk markers (body mass index, total-to-HDL cholesterol ratio, diagnosed diabetes, systolic blood pressure, resting heart rate, C-reactive protein) at baseline. The main outcome was CVD death. There were a total of 446 all-cause deaths during an average of 7.0 +/- 3.1 yr of follow-up, of which 213 were attributed to cardiovascular causes. Participation in moderate to vigorous physical activity at least three sessions per week was associated with lower risk of CVD death (hazard ratio = 0.61, 95% confidence interval = 0.38-0.98). Physically active participants demonstrated significantly lower levels of body mass index, diabetes, and inflammatory risk (C-reactive protein). Metabolic (body mass index, total-to-HDL cholesterol ratio, and physician-diagnosed diabetes) and inflammatory risk factors explained an estimated 12.8% and 15.4%, respectively, of the association between physical activity and CVD death. CONCLUSIONS: Physical activity may reduce the risk of secondary CVD events, in part, by improving metabolic and inflammatory risk markers. PMID- 21659903 TI - Validity of the occupational sitting and physical activity questionnaire. AB - PURPOSE: Sitting at work is an emerging occupational health risk. Few instruments designed for use in population-based research measure occupational sitting and standing as distinct behaviors. This study aimed to develop and validate brief measure of occupational sitting and physical activity. METHODS: A convenience sample (n = 99, 61% female) was recruited from two medium-sized workplaces and by word-of-mouth in Sydney, Australia. Participants completed the newly developed Occupational Sitting and Physical Activity Questionnaire (OSPAQ) and a modified version of the MONICA Optional Study on Physical Activity Questionnaire (modified MOSPA-Q) twice, 1 wk apart. Participants also wore an ActiGraph accelerometer for the 7 d in between the test and retest. Analyses determined test-retest reliability with intraclass correlation coefficients and assessed criterion validity against accelerometers using the Spearman rho. RESULTS: The test-retest intraclass correlation coefficients for occupational sitting, standing, and walking for OSPAQ ranged from 0.73 to 0.90, while that for the modified MOSPA-Q ranged from 0.54 to 0.89. Comparison of sitting measures with accelerometers showed higher Spearman correlations for the OSPAQ (r = 0.65) than for the modified MOSPA-Q (r = 0.52). Criterion validity correlations for occupational standing and walking measures were comparable for both instruments with accelerometers (standing: r = 0.49; walking: r = 0.27-0.29). CONCLUSIONS: The OSPAQ has excellent test-retest reliability and moderate validity for estimating time spent sitting and standing at work and is comparable to existing occupational physical activity measures for assessing time spent walking at work. The OSPAQ brief instrument measures sitting and standing at work as distinct behaviors and would be especially suitable in national health surveys, prospective cohort studies, and other studies that are limited by space constraints for questionnaire items. PMID- 21659904 TI - Nonalcoholic beer reduces inflammation and incidence of respiratory tract illness. AB - PURPOSE: Strenuous exercise significantly increases the incidence of upper respiratory tract illness (URTI) caused by transient immune dysfunction. Naturally occurring polyphenolic compounds present in food such as nonalcoholic beer (NAB) have strong antioxidant, antipathogenic, and anti-inflammatory properties.The objective of this study was to determine whether ingestion of NAB polyphenols for 3 wk before and 2 wk after a marathon would attenuate postrace inflammation and decrease URTI incidence. METHODS: Healthy male runners (N = 277, age = 42 +/- 9 yr) were randomly assigned to 1-1.5 L . d(-1) of NAB or placebo (PL) beverage (double-blind design) for 3 wk before and 2 wk after the Munich Marathon. Blood samples were collected 4 and 1 wk before the race and immediately and 24 and 72 h after the race and analyzed for inflammation measures (interleukin-6 and total blood leukocyte counts). URTI rates, assessed by the Wisconsin Upper Respiratory Symptom Survey, were compared between groups during the 2-wk period after the race. RESULTS: Change in interleukin-6 was significantly reduced in NAB compared with PL immediately after the race (median (interquartile range) = 23.9 (15.9-38.7) vs 31.6 (18.5-53.3) ng . L(-1), P = 0.03). Total blood leukocyte counts were also reduced in NAB versus PL by approximately 20% immediately and 24 h after the race (P = 0.02). Incidence of URTI was 3.25-fold lower (95% confidence interval = 1.38-7.66) (P = 0.007) in NAB compared with PL during the 2-wk postmarathon period. CONCLUSIONS: Consumption of 1-1.5 L . d(-1) of NAB for 3 wk before and 2 wk after marathon competition reduces postrace inflammation and URTI incidence. PMID- 21659905 TI - Attenuated inheritance of body weight by running in monozygotic twins. AB - PURPOSE: Genetic factors account for 40%-70% of the population variation in body mass index (BMI), suggesting that genetic predisposition is a major risk factor for excess weight. The purpose of this study was to test whether exercise attenuates the inherited risk for excess body weight. METHODS: Survey questionnaires of exercise (usual running distance) and BMI were obtained from a national sample of 582 female and 344 male self-identified monozygotic (MZ) twins. Regression analyses were used to test whether running disparity diminished the inheritance of BMI when adjusted for age, education, cigarette use, and selected dietary variables. RESULTS: The active twins ran between 0 and 10.7 km . d(-1) more than their less active twins if female (mean +/- SD = 1.61 +/- 1.50 km . d(-1)) and between 0 and 13.7 km . d(-1) more if male (1.88 +/- 1.78 km . d( 1)). Average BMIs of the less active twins were 22.38 +/- 3.56 and 24.59 +/- 3.08 kg . m(-2) in females and males, respectively. Within-twin correlations were significant (P < 0.0001) for usual distance run (females: r = 0.64; males: r = 0.61) and BMI (females: r = 0.67; males: r = 0.71). Greater running differences (Deltakm . d(-1)) attenuated the effect of the less active twins' BMIs on their active MZ twins' BMI (females: -14.3% per Deltakm . d(-1), P < 10(-7); males: 7.4% per Deltakm . d(-1), P = 0.004), such that by 4 Deltakm . d(-1), the inherited risk was reduced by 58.8% in females and 29.6% in males. CONCLUSIONS: These results are consistent with the attenuation of the inherited risk of excess body weight by running, which is remarkable because BMI regulation is assumed to be multifactorial, its genetic inheritance is polygenic, and no single genetic polymorphism currently explains >1% of the BMI variance. PMID- 21659906 TI - Reproductive risk factors for cardiovascular disease mortality among postmenopausal women in Korea: the Kangwha Cohort Study, 1985-2005. AB - OBJECTIVE: The relationship between reproductive factors and the risk of mortality from cardiovascular disease in postmenopausal women is unclear. In this study, we aimed to investigate this relationship in Korean postmenopausal women. METHODS: Subcohort analysis was carried out using the data of 3,257 postmenopausal women (age, >=55 y at study entry) from the Kangwha Cohort Study who were followed up from 1985 until 2005. Cox proportional hazards models were used to evaluate the associations between reproductive factors and cardiovascular disease mortality. RESULTS: The risk of cardiovascular mortality in women who were 20 to 22 years old at first childbirth was 26% lower (95% CI, 0.60-0.92) than that in women younger than 20 years at first childbirth, after adjustment for age at entry, body mass index, hypertension, drinking, smoking, education, and occupation. Early first childbirth was associated with increased cardiovascular disease mortality (P trend = 0.036). The risk of coronary heart disease mortality was 51% lower in women who were 17 to 18 years old at menarche (95% CI, 0.25-0.95) than that in women who were younger than 17 years at menarche. CONCLUSIONS: An inverse relationship between age at first childbirth and the risk of cardiovascular disease mortality exists. In addition, early menarche may be a reproductive risk factor for coronary heart disease mortality. PMID- 21659907 TI - Genistein, a phytoestrogen, improves total cholesterol, and Synergy, a prebiotic, improves calcium utilization, but there were no synergistic effects. AB - OBJECTIVE: Prebiotics and phytoestrogens have sparked great interest because evidence indicates that the consumption of these dietary constituents leads to lower cholesterol levels and inhibition of postmenopausal bone loss. The aim of this study was to determine the effect of both a prebiotic (Synergy) and a phytoestrogen (genistein) on bone and blood lipid levels in an animal model of postmenopausal women. METHODS: A 4-week feeding study was conducted in 5-month old ovariectomized (OVX) Sprague-Dawley rats to examine the effect of genistein, Synergy (a prebiotic), and genistein and Synergy combined on bone density and strength, calcium metabolism, and lipid biomarkers. There were six treatment groups: sham control, OVX control, OVX rats receiving daily estradiol injections, and OVX rats receiving an AIN-93M diet supplement with 200 ppm genistein, with 5% Synergy or with 200 ppm genistein and 5% Synergy combined. RESULTS: The rats receiving genistein had significantly lower total serum cholesterol concentrations than OVX rats in the control group (17%), OVX rats receiving daily estradiol injections (14%), and OVX rats fed the 5% Synergy diet (19%). Consumption of Synergy improved calcium absorption efficiency (41%) compared with nonconsumption (OVX control). Sham control rats had a significantly higher femoral bone density, as determined by underwater weighing, than did the rats in all of the OVX groups. Genistein consumption restored total and trabecular bone mineral density at the distal femur similar to the levels of sham rats. CONCLUSIONS: Genistein supplementation imparts modest heart health benefits and improves bone geometry at the distal femur, and prebiotic consumption (Synergy) results in improved calcium utilization strength in ovariectomized rats, but the combination produced no synergistic effects. PMID- 21659908 TI - A higher sense of purpose in life is associated with sexual enjoyment in midlife women. AB - OBJECTIVE: The aim of this study was to understand the association between sense of purpose in life and sexual well-being in a cohort of midlife women. METHODS: Participation in partnered sexual activities and indicators of sexual well-being (the engagement in and enjoyment of sexually intimate activities) were measured in a longitudinal cohort of 677 eligible women aged 40 to 65 years. At a single time point, women completed the Life Engagement Test, a measure of life purpose. Univariable and multivariable mixed models were used to assess the association between the Life Engagement Test and longitudinal sexual well-being. RESULTS: A higher sense of purpose in life was associated with higher levels of enjoyment (coefficient = 2.89, P < 0.001) but not with participation in partnered sexual activity (coefficient = 0.49, P = 0.63) or engagement in partnered sexually intimate activities (coefficient = 1.0, P = 0.30). Participation was associated with younger age, lower body mass index, being married, reporting any vaginal dryness, and better emotional well-being. Hormone therapy use approached, but did not reach significance in association with participation, with P = 0.05. Engagement in sexually intimate activities was associated with younger age, more social support, and better emotional well-being. Higher levels of enjoyment were associated with more social support, better emotional well-being, and less vaginal dryness. Menopause status was not associated with engagement or enjoyment, and only being 5 years or more postmenopausal was related to decreased participation. CONCLUSIONS: Higher sense of purpose in life is associated with more enjoyment of sexually intimate activities, adjusting for other known factors that influence sexual well-being and independent of demographic factors and menopause or hormone therapy status. PMID- 21659909 TI - Role of 99mTc-ubiquicidin 29-41 scintigraphy to monitor antibiotic therapy in patients with orthopedic infection: a preliminary study. AB - INTRODUCTION: Ubiquicidin (UBI) 29-41 is a cationic synthetic antimicrobial peptide fragment that binds preferentially with anionic microbial cell membranes at the site of infection. This study evaluated the potential ability of Tc-UBI 29 41 to assess response to antibiotic therapy in orthopedic infection. METHODS: A total of 12 patients, 10 men and two women (mean age, 41.6 years; range, 23-75 years), with suspected orthopedic infection (bone, soft tissue, or prosthesis) and positive Tc-UBI scan for infection were included in the study. One day after the Tc-UBI scan, a bone scan was performed as well. After this evaluation, eight of the nine treated cases responded to the treatment. Then, one nonresponder patient and two nontreated patients of three cases underwent antibiotic therapy and were evaluated again 10-14 days later. After this, one of the two patients not treated the first time responded to therapy and two patients did not. Moreover, one patient refused to undergo therapy both the first and second time. Thus, 11 treated cases were analyzed in this study and divided in two groups: (a) nine treated responders and (b) two treated nonresponders. In all patients, erythrocyte sedimentation rate and C-reactive protein were measured and also wound cultures were assessed. RESULTS: Quantitative analysis of erythrocyte sedimentation rate, C-reactive protein, and bone scan before and after the 10-14 day interval showed no significant change in either group, but a quantitative Tc UBI scan at 30, 60, and 120 min after tracer injection indicated significant reduction in radiotracer uptake after the 10-14-day interval compared with the Tc UBI scan before this interval in the responder group, and no significant change in the nonresponder group. CONCLUSION: The Tc-UBI scan can determine response to antibiotic therapy in orthopedic infection in humans. PMID- 21659910 TI - Evaluation of relative renal function for patients who had undergone simultaneous liver-kidney transplants using Tc-99m-MAG3 scintigraphy with attenuation correction from anatomical images and SPECT/CT. AB - OBJECTIVE: Assessing the relative function of each of the three kidneys using nuclear scintigraphy with standard planar imaging in patients having undergone kidney transplant is problematic because of the different photon-attenuation factors associated with native versus transplanted kidneys. To address this, we applied a correction for the attenuation of 140-keV photons based on measurements taken on cross-sectional anatomical images. We performed a validation of the method using single-photon emission computed tomography/computed tomography (SPECT/CT). METHODS: Abdominal CT scans of 13 patients who had undergone simultaneous liver-kidney transplants were examined for kidney depth. Ten of those patients had undergone Tc-99m-mercaptoacetyltriglycine (MAG3) renal scans, using a Philips Precedence SPECT/CT scanner by which abdominal CT and renal SPECT acquisition followed the planar scintigraphic renogram. Kidney depth at the level of the renal hilum was measured on the concurrently acquired CT images, and it was used to derive an attenuation correction factor (ACF) that was applied to the background-subtracted activity in the planar scintigraphic renogram. RESULTS: ACFs calculated from kidney depths ranged from 1.31 to 4.33. The ratio of ACFs for transplant to native kidneys ranged from 0.63 to 1.51, with an average of 0.90. Applying attenuation correction when calculating relative function increased the value of native kidney function by as much as 40%. CONCLUSION: Attenuation correction through measurements taken on anatomical images, preferably obtained concurrently using a hybrid SPECT/CT scanner, should improve the accuracy of functional measurements in renal scintigraphy. This improved accuracy is clinically important in assessing the relative function of native and transplant kidneys in recipients of simultaneous liver-kidney transplants. PMID- 21659911 TI - Automatic classification of 123I-FP-CIT (DaTSCAN) SPECT images. AB - INTRODUCTION: We present a method of automatic classification of I-fluoropropyl carbomethoxy-3beta-4-iodophenyltropane (FP-CIT) images. This technique uses singular value decomposition (SVD) to reduce a training set of patient image data into vectors in feature space (D space). The automatic classification techniques use the distribution of the training data in D space to define classification boundaries. Subsequent patients can be mapped into D space, and their classification can be automatically given. METHODS: The technique has been tested using 116 patients for whom the diagnosis of either Parkinsonian syndrome or non Parkinsonian syndrome has been confirmed from post I-FP-CIT imaging follow-up. The first three components were used to define D space. Two automatic classification tools were used, naive Bayes (NB) and group prototype. A leave-one out cross-validation was performed to repeatedly train and test the automatic classification system. Four commercially available systems for the classification were tested using the same clinical database. RESULTS: The proposed technique combining SVD and NB correctly classified 110 of 116 patients (94.8%), with a sensitivity of 93.7% and specificity of 97.3%. The combination of SVD and an automatic classifier performed as well or better than the commercially available systems. CONCLUSION: The combination of data reduction by SVD with automatic classifiers such as NB can provide good diagnostic accuracy and may be a useful adjunct to clinical reporting. PMID- 21659912 TI - Dacryocystorhinostomy precipitating keratoconjunctivitis sicca in aplasia of lacrimal and major salivary glands (ALSG). AB - We report a 16-month-old girl referred for bilateral epiphora and sticky eyes since birth. Examination revealed a refluxible left lacrimal sac mucocele, agenesis of the left lower punctum, and agenesis of both puncta on the right side. Complete bony obstruction was noted on probing of the left nasolacrimal duct. At 4 years of age, she underwent left external dacryocystorhinostomy (DCR) with silicone intubation because of chronic dacryocystitis. Her epiphora and stickiness improved significantly in the first postoperative year, but she subsequently developed dryness of the left eye, dry mouth, and dental caries. CT and MRI scans revealed the absence of the lacrimal and salivary glands. The clinical signs and symptoms improved with plugging the left upper punctum and topical lubricants. Aplasia of the lacrimal and salivary glands may present with symptoms of congenital lacrimal obstruction, and failure to make an early diagnosis will result in inappropriate lacrimal surgery and dry eye. PMID- 21659913 TI - Lateral canthal resuspension sine canthotomy. AB - PURPOSE: The purpose of this study is to describe a novel canthopexy technique the lateral canthal resuspension sine canthotomy (LCR-SC)-performed via an upper eyelid incision and to compare it with the lateral tarsal strip procedure (LTS). METHODS: This is a retrospective study in which the pre- and postoperative photographs of 20 patients per group who had LCR-SC, LCR-SC + midface lift (LCR SC+ML), or LTS were analyzed by using the Image-J 1.40 software. Parameters measured were as follows: the horizontal palpebral aperture margin-reflex distance 2 (MRD-2) and the height of lateral canthus. LCR-SC was performed through an upper-eyelid incision, by using a 4.0 Prolene suture. For the LCR SC+ML, a large myocutaneous flap was created first and anchored to the orbital rim periosteum. The surgical technique is described. Two-way ANOVA was used for analysis. RESULTS: The horizontal palpebral aperture was significantly increased by LCR-SC and LCR-SC+ML when compared with LTS (1.61 +/- 0.22 mm and 1.56 +/- 0.14 vs. 0.04 +/- 0.12 mm; p < 0.01). LCR-SC and LCR-SC+ML decreased the MRD-2 more than the LTS (1.06 +/- 0.26 and 1.50 +/- 0.23 mm vs. 0.86 +/- 0.1 mm; p < 0.01). All 3 procedures increased the lateral canthal height by less than 0.5 mm. CONCLUSIONS: LCR-SC is a safe and effective procedure for tightening the lower eyelids. It tightens both the upper and the lower cruri of the lateral canthal tendon, avoiding imbrication of the eyelids. LCR-SC obviates the need for a lateral canthal incision and widens the horizontal palpebral aperture. LCR-SC is more effective than LTS at decreasing the MRD-2. Concomitant midface elevation (LCR-SC+ML) further decreases MRD-2. PMID- 21659914 TI - Intralesional interferon for extensive squamous papilloma of the eyelid margin. AB - Eyelid margin papillomas are challenging because complete excision may be cosmetically unacceptable. Interferon has been previously reported as an effective treatment for conjunctival papillomas. We report successful treatment of a large upper eyelid margin papilloma with intralesional interferon. PMID- 21659915 TI - Computed tomography dimensions of the lacrimal gland in normal Caucasian orbits. AB - INTRODUCTION: CT is frequently used to assess the lacrimal gland, yet no published reports exist of normal dimensions using this modality. We retrospectively evaluated CT data from normal orbits and measured the lacrimal gland dimensions. METHODS: Two-hundred ninety-three consecutive orbital CT scans (586 orbits) of 282 patients were identified. Caucasian patients aged 18 years and older without known orbital disease were included. Traumatized orbits were excluded. All repeated scans were excluded. Length and width of the lacrimal gland were measured in axial and coronal sections with GE Centricity Software. The primary outcome was a descriptive analysis of the distribution of dimensions in normal orbits. A random subset of patient scans was measured independently by observers at different levels of training, and intraclass correlation coefficients (ICCs) were established. RESULTS: Three hundred orbits (150 right orbits and 150 left orbits) of 282 patients were included. Normal distributions occurred with axial and coronal length measurements. Mean (10th and 90th percentiles) lacrimal gland axial length in right orbits was 14.7 mm (10.9 mm and 18.3 mm) and 14.5 mm in left orbits (10.3 mm and 18.3 mm). Coronal length averaged 17.7 mm in right eyes (13.9 mm and 21.8 mm) and 16.9 mm in left eyes (12.8 mm and 20.8 mm). Axial and coronal width showed non-normal distributions. No statistically significant difference in dimensions was found between genders, and a significant inverse linear relation occurred between gland size and age. Agreement was significant among the observers (ICC >0.7). CONCLUSION: This study presents a normal range of Caucasian lacrimal gland dimensions seen on CT. Lacrimal gland size decreases with age, and no gender difference exists. This range can aid in differentiating diseased and nondiseased lacrimal glands, especially when correlated with physical examination. This may be useful in clinical trials that involve lacrimal gland size. PMID- 21659916 TI - Delayed Eikenella corrodens orbital infection after fracture repair. AB - Orbital cellulitis and abscess after fracture repair are rare. Ophthalmic infection with Eikenella species is even more unusual, but can be severe. We report a case of Eikenella corrodens infection in a 28-year-old man who underwent zygomaticomaxillary and orbital floor blowout fracture surgery 4 years before presentation. Eikenella species are often resistant to frequently used empiric antibiotics, and because of specific growth conditions, easily missed on standard cultures. Appropriate efforts should be made to identify and treat E. corrodens in atypical orbital and periocular infections. PMID- 21659917 TI - Periocular changes following long-term administration of latanoprost 0.005%. AB - This is a case series of 3 patients who presented with periocular changes in the treated eye following chronic administration of unilateral latanoprost 0.005%. The clinical changes included worsening of dermatochalasis, deepening of superior sulcus and hollowness of the lid. This similar observation was previously described in usage of bimatoprost 0.03% and travoprost 0.004%. However this has not been reported in latanoprost instillation. Therefore, patients should be made aware of these potential side effects. PMID- 21659918 TI - Prevalence of lacrimal gland prolapse in the functional blepharoplasty population. AB - Traditional functional blepharoplasty has focused on the excision of variable amounts of skin, muscle, and fat, with little attention given to the finding of the lacrimal gland prolapse (LGP). The reported incidence of LGP found on clinical examination, on patients of all ages presenting for blepharoplasty, is 15%. The author's experience with the procedure in the older age group (older than 60), is that this percentage is much lower than that found at surgery. To verify whether this is correct, the author evaluated lacrimal gland position intraoperatively in a group of patients undergoing functional upper blepharoplasty. In those patients who had LGP, the author routinely repositioned the gland and evaluated surgical outcomes. METHODS: The author evaluated the presence of an intraoperatively displaced lacrimal gland in his functional blepharoplasty population over a 2.5-year period (2008-2010). Patients with a history of previous eyelid surgery, trauma, or who had concurrent ptosis or other eyelid malpositions were excluded from the study. When present, the degree of prolapse was graded as mild (0-2 mm), moderate (3-5 mm), or severe (6 mm or more). The author arbitrarily suture-repositioned the gland in all patients with 4 mm or more of prolapse. In cases with less prolapse, light cautery to the tip of the gland capsule and surrounding soft tissue allowed adequate repositioning without suture fixation. Pertinent patient demographics and postoperative complications were documented. Patients were seen consistently to 6 months after surgery with an average follow up of 12 months. RESULTS: Fifty-seven patients were included in the study. Thirty-four patients (60%) had some degree of LGP. Of these, 8 patients (24%) had mild prolapse, 23 patients (67%) had moderate prolapse, and 3 patients (9%) had severe prolapse. Nineteen patients (56%) with LGP had the gland suture-repositioned, and 15 patients (44%) received cautery to retro-place the gland. In one patient (3%), transient dry-eye symptoms developed after surgery. Otherwise, there were few benign and self-limiting postoperative complications, consisting of prolonged upper eyelid swelling and transient mild pain. CONCLUSION: Lacrimal gland prolapse is a common finding during functional upper blepharoplasty surgery and appears to be a normal involutional periorbital aging change. Most cases are moderate in degree (as defined in the article), and not associated with specific preoperative symptoms or complaints, except lateral hooding with concomitant visual field deficit. Repositioning the gland intraoperatively is generally complication free and typically not associated with increased morbidity or healing time. The clinical significance of LGP in the elderly undergoing blepharoplasty surgery is unknown and requires further study. PMID- 21659919 TI - Primary, unilateral ocular adnexal lymphoma: disease progression and long-term survival. AB - PURPOSE: This investigation aimed to improve our understanding of the disease characteristics and clinical course for primary unilateral ocular adnexal lymphoma (OAL). METHODS: In this retrospective case series, all consecutive biopsy confirmed cases of lymphoma confined to a single ocular adnexa (unilateral stage 1E) during a 30-year period were included. All histologic classification conformed to the current World Health Organization classification. Descriptive statistics and standard survival analyses were performed. RESULTS: 122 patients were included in this study. The most common primary unilateral OAL were indolent B-cell lymphomas (mucosa-associated lymphoid tissue (MALT)-type marginal zone, follicular and small lymphocytic lymphoma) representing 80% of cases. Typically aggressive lymphomas were found in only 7% of patients (diffuse large B-cell lymphoma, immunoblastic lymphoma, diffuse large cell lymphoma, and mantle cell lymphoma). Overall, 24.4% of patients experienced progression of their disease after initial therapy, the majority occurring within 5 years. For the 80% of OAL of indolent B-cell type, progression free and disease specific survivals were 71 and 98% at 5 years and 61 and 90% at 10 years, respectively. Diffuse large B-cell lymphoma was more likely to progress overall (p < 0.01) and progress earlier (log rank, p < 0.01). Additionally, these patients were also more likely to succumb to disease (p < 0.01) in a shorter interval (log rank, p < 0.01). CONCLUSION: Most primary unilateral OALs are indolent lymphomas with good prognosis for survival and freedom from progression. However, a minority present with more aggressive lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, immunoblastic lymphoma, and diffuse large cell lymphoma), carrying a more guarded prognosis. PMID- 21659920 TI - Standardized clinical photography: the role of flash. AB - Medical photographic documentation is important for professional, research, and ethical concerns. This study analyzed the possible interference that the flash could cause on evaluation of lower eyelid cosmetic results. Standardized photographs with and without flash were taken of 10 patients with dermatochalasis. The photographs were evaluated by 3 independent observers, as before (without flash) and after (with flash) an alternative esthetic treatment of the lower eyelid. The observers rated the overall cosmetic improvement of the lower eyelid photographs on a visual analog scale. The 3 surgeons believed that there was improvement in cosmetic outcome from the first (without flash) to the second (with flash) picture. The results indicate that a simple flash addition in one of 2 consecutive photographs, taken seconds apart, could influence the impression of experienced surgeons on the final outcome of oculoplastic surgeries and may constitute a bias in observer-dependent studies. PMID- 21659921 TI - Nodular fasciitis presenting in an adult woman. AB - The authors report a 30-year-old Caucasian woman with nodular fasciitis presenting as a nontender lesion to right temporal area. The lesion was removed by en bloc excision and the base was cauterized. Six months later, the patient returned to the clinic for possible recurrence of lesion or for residual lesion; the patient was then injected with a total of 1 cc of kenalog at 20 mg/kg. Two weeks later, the lesion had greatly subsided and the patient was satisfied with the esthetic appearance. Nodular fasciitis is a rare reactive growth with even fewer cases of recurrence. In young patients, steroid injection is an alternative to repeat resection. PMID- 21659923 TI - Histopathologic categorization of presbycusis. PMID- 21659922 TI - Implications of minimizing trauma during conventional cochlear implantation. AB - OBJECTIVE: To describe the relationship between implantation-associated trauma and postoperative speech perception scores among adult and pediatric patients undergoing cochlear implantation using conventional length electrodes and minimally traumatic surgical techniques. STUDY DESIGN: Retrospective chart review (2002-2010). SETTING: Tertiary academic referral center. PATIENTS: All subjects with significant preoperative low-frequency hearing (<=70 dB HL at 250 Hz) who underwent cochlear implantation with a newer generation implant electrode (Nucleus Contour Advance, Advanced Bionics HR90K [1J and Helix], and Med El Sonata standard H array) were reviewed. INTERVENTION(S): Preimplant and postimplant audiometric thresholds and speech recognition scores were recorded using the electronic medical record. MAIN OUTCOME MEASURE(S): Postimplantation pure tone threshold shifts were used as a surrogate measure for extent of intracochlear injury and correlated with postoperative speech perception scores. RESULTS: : Between 2002 and 2010, 703 cochlear implant (CI) operations were performed. Data from 126 implants were included in the analysis. The mean preoperative low-frequency pure-tone average was 55.4 dB HL. Hearing preservation was observed in 55% of patients. Patients with hearing preservation were found to have significantly higher postoperative speech perception performance in the CI only condition than those who lost all residual hearing. CONCLUSION: Conservation of acoustic hearing after conventional length cochlear implantation is unpredictable but remains a realistic goal. The combination of improved technology and refined surgical technique may allow for conservation of some residual hearing in more than 50% of patients. Germane to the conventional length CI recipient with substantial hearing loss, minimizing trauma allows for improved speech perception in the electric condition. These findings support the use of minimally traumatic techniques in all CI recipients, even those destined for electric-only stimulation. PMID- 21659925 TI - Cochlear implantation in children with cochlear nerve absence or deficiency. AB - OBJECTIVE: To evaluate speech perception after cochlear implantation in children with cochlear nerve absence or deficiency. METHODS: A retrospective case review was performed to identify children who underwent cochlear implantation with cochlear nerve absence or deficiency. The cochlear nerve was evaluated by high resolution three-dimensional T2-weighted fast spin echo MR in the oblique sagittal and axial planes. A deficient cochlear nerve was defined as a cochlear nerve that is smaller in diameter when compared with the adjacent facial nerve in the midportion of the internal auditory canal. The cochlear nerve was considered absent if there was no imaging evidence of a cochlear nerve. Speech awareness threshold and the speech perception category score were used to measure speech perception after cochlear implantation. RESULTS: Seven children who underwent cochlear implantation in an ear without imaging evidence of a cochlear nerve were identified. One child developed early closed-set speech recognition. The other 6 children developed only speech detection or pattern perception. Two children underwent cochlear implantation with a deficient cochlear nerve. One developed consistent closed-set word recognition and the other developed early closed-set word recognition. The mean follow-up time for all patients was 3.8 years (range, 1.1-7.1 yr). CONCLUSION: Cochlear nerve deficiency is not an uncommon cause for profound sensorineural hearing loss and presents a challenge in the decision making process regarding whether to proceed with a cochlear implant. Children with a deficient but visible cochlear nerve on magnetic resonance image can expect to show some speech understanding after cochlear implantation; however, these children do not develop speech understanding to the level of implanted children with normal cochlear nerves. Children with an absent cochlear nerve determined by magnetic resonance imaging can be expected to have limited postimplantation sound and speech awareness. PMID- 21659926 TI - Reversible posterior leukoencephalopathy syndrome after lateral skull base surgery. AB - OBJECTIVE: To describe the clinical course, diagnostic features and management of a case of reversible posterior leukoencephalopathy syndrome after a lateral cranial base removal. PATIENT: A 58-year-old male patient with an inconspicuous clinical history presented with a lethargic state without localized neurologic deficit in the postoperative period of a subtotal petrosectomy for an adenoid cystic carcinoma of the temporal bone. INTERVENTIONS: Cranial T2-weighted magnetic resonance imaging showed increased signal intensity in the occipital and cerebellar regions, centered at the cortical and subcortical white matter. Antihypertensive drugs, anticonvulsants, and antibiotics were administered. A complete resolution of the symptoms and radiologic findings were achieved within 1 to 2 weeks. RESULTS: The clinical presentation, radiologic findings, and resolution of the clinical setting are consistent with a diagnosis of reversible posterior leukoencephalopathy syndrome. CONCLUSION: To our knowledge, this is the first report of reversible posterior leukoencephalopathy syndrome after a lateral cranial base surgery. PMID- 21659924 TI - ErbB expression, activation, and inhibition with lapatinib and tyrphostin (AG825) in human vestibular schwannomas. AB - BACKGROUND: Pharmacologic agents targeted against the ErbB family, or the intracellular pathways that mediate their effects, could slow clinical progression of vestibular schwannoma (VS) in patients where other modalities carry a high risk-to-benefit ratio. OBJECTIVE: Determine the identity of the predominant ErbB dimer partners in VS tumors and assess the effects of targeted inhibition of the ErbB molecules on VS growth and proliferation, as well as apoptosis. SETTING: Academic tertiary referral center. METHODS: Coimmunoprecipitation and Western blotting of VS tissue, in vitro BrdU assays of proliferation in the presence of lapatinib and tyrphostin (AG825) using primary VS cultures, and annexin V cell death assays and cell cycle assays using propidium iodide staining were performed on HEI193 cell line derived from an neurofibromatosis type 2-associated VS. RESULTS: Activated ErbB family receptor heterodimers in VS contain predominantly epidermal growth factor receptor (EGFR) and ErbB2. A robust, dose-dependent inhibition of VS growth and proliferation with the dual EGFR/ErbB2 inhibitor, lapatinib, was demonstrated. Lapatinib also inhibited EGF-induced VS proliferation. The selective ErbB2 inhibitor, AG825, inhibited growth to a lesser extent. HEI193 demonstrated apoptosis after lapatinib treatment. CONCLUSION: Dual EGFR and ErbB2 inhibition with lapatinib or combination therapy may provide therapeutic benefit in VS treatment, but further studies are necessary. PMID- 21659927 TI - Cochlear nerve and hearing loss. PMID- 21659929 TI - Stereotactic radiosurgery for vestibular schwannomas: a survey of current practice patterns of neurotologists. AB - OBJECTIVE: To evaluate the use of radiation by neurotologists practicing in the United States as a treatment modality for vestibular schwannomas (VSs). STUDY DESIGN: Cross-sectional survey. METHODS: We surveyed 302 members of the American Neurotology Society to assess the number of VS seen, the frequency with which radiation is used as a treatment modality, radiation training and experience, the impact of tumor size and patient age on treatment decisions, and radiation dose ultimately used by neurotologists. RESULTS: Responses were received from 43% (132/302) of surveyed neurotologists; of the respondents, 42% (54/132) perform stereotactic radiation. Approximately 58% (30/54) of those use gamma knife, and 44% (24/54) use Cyberknife; 36.7% of VS patients seen by neurotologists received radiation. On average, 6 additional neurotologists per year begin treating VS with stereotactic radiation. Academic and private neurotologists showed significant differences (p < 0.05) between new VS patients per year, years in practice, and maximum tumor size recommended for radiation. The most common barrier to using radiation was prevention by a neurosurgical or radiation oncology service. Neurotologists use radiation to treat other cranial base tumors as well, most commonly glomus tumors or meningiomas, and 64% of respondents irradiate neurofibromatosis Type 2. Total radiation dose and fractionation were variable. CONCLUSION: Neurotologists are increasingly choosing to treat VS with stereotactic radiation. There seem to be significant differences between academic and private neurotologists' practice characteristics. Not all neurotologists strictly adhere to the consensus statement by the International RadioSurgery Association with regard to radiation dosing and tumor size limits. PMID- 21659930 TI - Predicting the long-term outcome after idiopathic facial nerve paralysis. AB - OBJECTIVE: To investigate long-term recovery after Bell's palsy and evaluate specific parameters for predicting the long-term outcome of facial weakness. STUDY DESIGN: Retrospective clinical study combined with long-term follow-up. SETTING: Tertiary care university hospital (Department of Otorhinolaryngology, Head and Neck Surgery, University of Thessaloniki, Greece). PATIENTS: Forty-four patients who were followed up 2 to 6 years (mean, 4.01 yr) after the onset of facial weakness. MAIN OUTCOME MEASURES: The failure rate of complete recovery was studied for age, initial nerve excitability test, electroneurography, initial severity of paralysis, and number of days from onset of facial weakness to the start of medical treatment. RESULTS: Thirty-two (73%) of 44 patients had a satisfactory outcome, and 12 (27%) had a nonsatisfactory recovery. Initial House Brackmann grades V/VI and electroneurographically detected degeneration of 90% or more were shown to affect the long-term outcome of facial weakness significantly (p = 0.024 and p = 0.000, respectively). CONCLUSION: The initial severity of facial weakness and the electroneurographically detected facial nerve degeneration were found to be important factors in predicting the long-term prognosis of Bell's palsy. PMID- 21659931 TI - Perception threshold for tilt. AB - The aim of this study was to determine the thresholds for perception of tilt and translation using 3 motion/tilt profile paradigms. Healthy subjects were submitted to the following: 1) unilateral and bilateral eccentric rotations (centrifugation), 2) whole body translatory decelerations opposite to the movement direction while seated on a linear sled, and 3) discrete slow velocity platform tilts. Subjects were instructed to verbally indicate the perceived direction of tilt or translation. Fifteen healthy subjects (12 male and 3 female subjects, 18-31 yr) without any history or evidence of any ophthalmologic or neuro-otologic disorder participated in this study. Our results from unilateral centrifugation indicate a threshold for body tilt perception of approximately 2 degrees with a substantial interindividual range (1.9-5.6 degrees, 52% interindividual and 34% intraindividual variability), which, to our interpretation, mainly depends on otolithic function. Tilt perception during whole body decelerations and discrete platform tilts mainly depends on somatosensory information, showing the dominant role of the somatosensory system for the perception of body orientation. Thus, tilt sensations during eccentric rotations seems to be a promising tool for the evaluation of utricular dysfunction. PMID- 21659932 TI - Improving the evaluation of sensorineural hearing loss in children. PMID- 21659933 TI - Spontaneous regression of petrous apex cholesterol granuloma. PMID- 21659934 TI - Mucoepidermoid carcinoma of the external auditory canal. PMID- 21659935 TI - Schwannoma of the external auditory canal. PMID- 21659936 TI - Management of patulous eustachian tube with habitual sniffing. AB - OBJECTIVES: Evaluation of the effect of conservative and surgical treatment in patients with patulous Eustachian tube (PET) associated with habitual sniffing. STUDY DESIGN: Retrospective case review. SETTING: University hospital otolaryngology department. PATIENTS: Ninety-seven (23.4%) of 414 PET patients were found to have habitual sniffing to alleviate uncomfortable aural symptoms. Of these, 38 PET patients with sniffing habit were selected. INTERVENTIONS: Conservative intervention included instructions to stop sniffing and nasal instillation of saline. Surgical interventions used ventilation tube (VT) insertion to the eardrum and/or transmyringeal insertion of the PET plug (PEP). MAIN OUTCOME MEASURES: Relief of uncomfortable symptoms and stopping sniffing. RESULTS: In 52 (53.6%) of the 97 sniff-positive cases, retraction-type eardrum abnormalities or operated ear due to cholesteatoma were identified, whereas normal bilateral eardrums were observed in 34 (87.2%) of 39 sniff (-) cases. Abnormal findings in the eardrum were significantly more common in the sniff positive group than in the sniff-negative group (p < 0.0001). Twenty-three patients (65.7%) stopped sniffing with conservative treatment. VT insertion was performed in 8 ears. Subsequent PEP was necessary in 2 of the 8 ears because of PET symptoms. PEP was successful in the other 11 ears, including one ear which needed additional VT insertion because of middle ear effusion. CONCLUSION: The management of habitual sniffing is difficult, but blocking the Eustachian tube by nasal instillation of saline and/or PEP could help PET patients to stop sniffing. PMID- 21659937 TI - A white mass behind the tympanic membrane: adenoma of the middle ear with neuroendocrine differentiation. PMID- 21659938 TI - Transmastoid middle fossa craniotomy repair of superior semicircular canal dehiscence using a soft tissue graft. AB - OBJECTIVE: To describe the successful surgical treatment of 5 cases of superior semicircular canal dehiscence via a transmastoid middle fossa craniotomy using a soft tissue graft. DESIGN: Case report. SETTING: Private practice otologic referral center. RESULTS: All patients have experienced reduction in auditory and vestibular symptoms. Pulsatile tinnitus and autophony are now absent in the operated ears. Chronic disequilibrium is subjectively improved. Patients with sound evoked eye movements no longer have sound sensitivity on the operated side. Head thrust testing indicates no obstruction of the operated superior canal in all patients with normal head thrust preoperatively. Audiometry is unchanged from preoperation, and cervical vestibular-evoked myogenic potential thresholds have increased on the operated side in 4 of 4 patients. Three patients had dehiscence at the superior petrosal sinus inaccessible to standard middle fossa repair. All patients were discharged to home the morning after surgery. CONCLUSION: Transmastoid craniotomy repair of the superior semicircular canal dehiscence using a soft tissue graft offers numerous advantages over traditional surgical approaches and can be performed safely in the outpatient setting. The strategy is particularly useful in patients with dehiscence at the superior petrosal sinus. This article will review our strategy and discuss the advantages and disadvantages of the different surgical treatments used for patients with severe symptoms from superior canal dehiscence. PMID- 21659939 TI - Probing residual vestibular function with galvanic stimulation in vestibular loss patients. AB - INTRODUCTION: Galvanic vestibular stimulation (GVS) was used to probe the residual vestibular function in unilateral vestibular loss. METHODS: 39 control subjects, 60 patients areflexic to caloric tests, 21 patients with pre-operative acoustic neurinoma, and 26 patients with surgical deafferentation were tested with 4mA trapezoidal GVS. Horizontal slow phase velocity and vertical slow phase velocity components of the slow phase of induced nystagmus were recorded with videonystagmography. RESULTS: All patients had lower horizontal slow phase velocity compared with intact subject. In caloric areflexic patients, the intact ear responded similarly to controls. The lesioned ear was less excitable but could be inhibited as in controls. In patients with acoustic neurinoma, the intact ear was normally excitable but less sensitive to inhibition. The lesioned ear, although not excitable, could be inhibited. In patients with surgical deafferentation, the intact ear could be barely excited and not inhibited. The lesioned ear could not be excited but slightly inhibited. These results fit well with previous data in animal models after unilateral vestibular loss. CONCLUSION: Unilateral vestibular patients exhibit a progressive deterioration of the horizontal canal function, corresponding to 4 different patterns of GVS response. This study confirms that GVS is useful to probe evolution of the residual vestibular function in patients. PMID- 21659940 TI - Commotio retinae with spectral-domain optical coherence tomography. AB - PURPOSE: To characterize retinal changes in areas of commotio retinae using spectral-domain optical coherence tomography. METHODS: In this retrospective observational case series, we included 14 eyes of 14 patients who had experienced blunt ocular trauma and underwent spectral-domain optical coherence tomography and fundus photography evaluation on the same day. The retinal thickness and volume of eyes with commotio retinae were compared with those of eyes without it. Normal untraumatized fellow eyes served as control. Fundus images obtained by spectral-domain optical coherence tomography were compared with fundus photographs. The retinal tissue reflectivities indicated by the images were compared across each lesion. RESULTS: There were 7 eyes with commotio retinae involving the macula and 7 eyes without it. Macular thickness and volume were not different between eyes with and without commotio retinae involving the macula. Photoreceptor outer segment reflectivity corresponding to the area of retinal opacity was increased with characteristic features and recovered with the disappearance of retinal opacity over time. CONCLUSION: Lesions exhibiting retinal opacity characteristic of commotio retinae corresponded to hyperreflective outer segment lesions without the increase in retinal thickness on spectral-domain optical coherence tomography. PMID- 21659942 TI - Diagnostic and therapeutic challenges. PMID- 21659941 TI - Prophylactic antibiotic use after intravitreal injection: effect on endophthalmitis rate. AB - PURPOSE: Endophthalmitis after intravitreal injection is a serious complication. There are limited data to support the use of postinjection antibiotics to prevent endophthalmitis. Current endophthalmitis rates after intravitreal injection in the literature are based on studies where patients routinely received postinjection antibiotics. This study retrospectively compares the rate of endophthalmitis in a cohort of patients receiving postinjection antibiotics with that in a group that does not. METHODS: A retrospective chart review was performed comparing a 12-month period where patients received postinjection topical antibiotics for several days after intravitreal injection with the next 12-month period where no postinjection topical antibiotics were used. Cases of suspected endophthalmitis after intravitreal injection during this period were identified and reviewed. RESULTS: The rate of clinically suspected endophthalmitis in the cohort of patients receiving postinjection antibiotics after intravitreal injection and that in the cohort that did not was 0.22% and 0.20%, respectively. One culture-positive case was found overall. The difference between the 2 groups is not statistically significant (P = 0.75). CONCLUSION: The rate of endophthalmitis after intravitreal injections administered in a clinical practice setting when aseptic technique is used is similar with or without the use of postinjection antibiotics. PMID- 21659943 TI - Intravitreal bevacizumab for macular edema secondary to branch retinal vein occlusion. AB - PURPOSE: To evaluate the effect of intravitreal bevacizumab on the visual and anatomical outcome in eyes with macular edema secondary to branch retinal vein occlusion. METHODS: A retrospective, consecutive case series identified 53 consecutive patients with a branch retinal vein occlusion treated with intravitreal bevacizumab. Clinical variables were analyzed, including best corrected visual acuity, angiographic characteristics, central foveal thickness, and complications. RESULTS: Fifty-three eyes were identified with a mean initial best-corrected visual acuity of 20/137 and final best-corrected visual acuity of 20/96 (P = 0.05). The mean final line change was +1.6 lines (95% confidence interval, +0.7 to +2.3; +8 letters [95% confidence interval, +3.5 to 11.5]). At final follow-up, 28% gained >= 3 lines, whereas a loss of >3 lines was seen in 6% of eyes. The mean initial central foveal thickness of 425 MUm decreased to 289 MUm (P < 0.001). Mean number of injections was 2.5, and mean follow-up was 9 months. Eyes treated for <= 6 months after the onset of branch retinal vein occlusion showed improved functional outcomes (e.g., final best-corrected visual acuity, mean line change) as compared with those treated with >6 months of symptoms (P < 0.01). CONCLUSION: Intravitreal bevacizumab appears to be an effective treatment for macular edema secondary to branch retinal vein occlusion in many subjects. Eyes treated with intravitreal bevacizumab showed a significant reduction in central foveal thickness and improvement in visual acuity. Early treatment with intravitreal bevacizumab resulted in a greater improvement in visual acuity compared with delayed treatment. PMID- 21659944 TI - Characterization of the fluidic properties of a syringe-based portable vitrectomy device. AB - PURPOSE: To compare the fluidic properties of the Intrector syringe-based vitrectomy device with other commercially available systems to evaluate its safety in the treatment of vitreoretinal diseases. METHODS: Mean operator comfortable sustainable syringe plunger pull force was determined using a spring loaded digital scale. Vacuum levels for syringes of different volumes (3, 5, and 10 mL) and pulling forces were quantified with a pressure transducer. Flow rates of water and egg white were measured both with the cutter at 600 cuts per minute and in the off position with the port open. Infusion flow of water was evaluated using a 1-mL syringe. RESULTS: The mean plunger pull force among operators (n = 8) was 0.80 kg (SD, 0.20 kg). Using the 3-mL syringe with 0.91 kg pull force, mean vacuum level was 135.9 mmHg (SD, 4.8 mmHg) and mean cutter-on flow rates of water and egg white were 1.9 mL/min (SD, 0.1 mL/min) and 0.5 mL/min (SD, 0.1 mL/min), respectively. Larger-bore syringes generated lower vacuum levels and liquid flow rates. CONCLUSION: The fluidic parameters of the Intrector vitrectomy device measured in this study suggest that at comfortable sustainable syringe pull forces, vacuum levels and liquid aspiration rates are similar to some other commercially available systems and are likely safe. PMID- 21659946 TI - Long-term follow-up of liver transplantation for Budd-Chiari syndrome with antithrombotic therapy based on the etiology. AB - BACKGROUND: Because myeloproliferative disorders (MPDs) are a frequent cause of Budd-Chiari syndrome (BCS), treatment directed toward altering platelet production and function may be more rational and effective than anticoagulation after liver transplantation. METHODS: We reviewed data on 25 patients who received liver transplantation for BCS at our institution from 1987 to 2007. Posttransplant antithrombotic treatment was based on the cause of BCS: 17 patients with MPDs received hydroxyurea/aspirin; 5 received warfarin; and 3 (2 whose hypercoagulable disorder was corrected and 1 with sarcoidosis) received no therapy. RESULTS: Both graft survival (88% at 5 years) and patient survival (92% at 5 years) were superior in the BCS group compared with the 2609 patients who received liver transplants for other indications. Vascular complications included three instances of hepatic artery stenosis (NS compared with non-BCS liver recipients), one of portal vein thrombosis (nonsignificant [NS]), and one of portal vein stenosis (NS). All 25 patients underwent multiple liver biopsies with no bleeding complications. CONCLUSIONS: Using hydroxyurea and aspirin to treat patients with BCS caused by an MPD seems to be safe and effective and avoids the risks of anticoagulation with warfarin. PMID- 21659945 TI - Consideration of donor age and human leukocyte antigen matching in the setting of multiple potential living kidney donors. AB - BACKGROUND: Defining living donor (LD)-related risk factors affecting kidney transplant outcome will allow better donor selection and more educated informed consent when there is more than one potential donor. We studied risk factors in a large cohort at a single institution. METHODS: We reviewed 1632 recipients who underwent LD kidney transplantation at the University of Minnesota between January 1, 1990, and October 1, 2009. Using Cox regression, we studied the effect of donor and recipient risk factors on patient and graft survival. We specifically examined the effect of donor age and human leukocyte antigen (HLA) matching because these are variables that may help clinical decision making when multiple potential donors exist. RESULTS: Mean donor age was 40.6 years for all transplants; 180 (11%) donors were 55 years or older, and 24 (1.5%) donors were older than 65 years. Mean number of HLA mismatches (per transplant) was 2.9 (29.2% of recipients had one to two HLA mismatches, 39.8% had three to four HLA mismatches, and 25% had five to six HLA mismatches). Donor age more than 65 years, five to six HLA mismatches, delayed graft function, and acute rejection were independent predictors of decreased patient and graft survival. When controlling for recipient age, donor age more than 65 years remained a risk factor for worse outcome. CONCLUSIONS: Our data suggest that advanced donor age (>65 years) and degree of HLA mismatch (>=5) are independent donor-related risk factors associated with worse outcome. When multiple potential LDs exist, it may be ideal to attempt to use a donor younger than 65 years and with less than five HLA mismatches. PMID- 21659947 TI - Cytomegalovirus neutralization by hyperimmune and standard intravenous immunoglobulin preparations. AB - BACKGROUND: Cytomegalovirus (CMV) remains one of the most important pathogens after transplantation, potentially leading to CMV disease, allograft dysfunction, acute, and chronic rejection and opportunistic infections. Immunoglobulin G (IgG) preparations with high antibody titers against CMV are a valuable adjunctive prevention and treatment option for clinicians and apart from standard intravenous immunoglobulin (IVIG), CMV hyperimmune preparations are available. The CMV antibody titer of these preparations is typically determined by Enzyme linked immunosorbent assay (ELISA), also used for the selection of high titer plasma donors for the production of the CMV Hyperimmune product. However, CMV ELISA titers do not necessarily correlate with CMV antibody function which is determined by virus neutralization tests. METHODS: CMV antibody titers were determined by both ELISA and virus neutralization assay and the IgG subclass distribution was compared between a CMV hyperimmune licensed in Europe and standard IVIG preparations. RESULTS: Although the expected high CMV IgG ELISA antibody titers were confirmed for three lots of a CMV hyperimmune preparation, the functionally more relevant CMV neutralizing antibody titers were significantly higher for 31 lots of standard IVIG preparations. Moreover, considerably lower IgG3 levels were found for the CMV hyperimmune preparation compared with standard IVIG preparations. CONCLUSIONS: The higher functional CMV neutralization titers of standard IVIG preparations and the better availability of these preparations, suggest that these products could be a valuable alternative to the CMV hyperimmune preparation. PMID- 21659948 TI - Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study. AB - BACKGROUND: The influence of immunosuppression on the response to antiviral treatment in recurrent hepatitis C is still under debate. The purpose of this study was to identify those factors that might predict sustained viral response and relapse. METHODS: The ReViS-TC, a multicenter cohort study conducted in 14 Spanish liver centers, included data from liver transplant recipients from January 2000 to December 2006 who had recurrent hepatitis C virus and who had undergone antiviral treatment with pegylated interferon plus ribavirin. Sustained virological response (SVR) and viral relapse were evaluated. A multivariate logistic regression model was used to investigate host, donor, and therapeutic factors associated with SVR and relapse. RESULTS: The analysis included 410 patients, 30% treated with cyclosporine A (CsA) and 70% with tacrolimus. SVR was achieved in 48% of patients with CsA and in 37% with tacrolimus (P=0.037), with a relapse rate of 18% and 36%, respectively (P=0.008). In the multivariate model, the administration of CsA (odds ratio [OR] 0.37, P=0.021) in conjunction with a longer antiviral treatment duration (OR 0.86, P=0.024) correlated with lower relapse rate, whereas the older age of the donor (OR 1.03, P=0.006) and the presence of genotype 1 (OR 3.45, P=0.032) were associated with a higher probability of relapse. CONCLUSIONS: Our results suggest that the use of CsA based immunosuppression regimens and longer treatment duration may protect patients against viral relapse after a positive response to pegylated interferon plus ribavirin therapy. These data need to be further confirmed in clinical trials. PMID- 21659949 TI - Correlations between pretransplant dialysis duration, bladder capacity, and prevalence of vesicoureteral reflux to the graft. AB - BACKGROUND: Urinary bladder capacity is reduced in patients undergoing long-term dialysis, which may increase the risk of vesicoureteral reflux (VUR) to a transplanted kidney. This study investigated the correlations between dialysis duration, pretransplant and posttransplant bladder capacity, and prevalence of VUR to the graft. METHODS: Voiding cystography was performed in 101 adult renal transplant recipients without neurogenic disorders immediately before and 1 year after transplantation to evaluate bladder capacity and VUR. Nonstented extravesical antireflux ureteroneocystostomy was performed in all patients. RESULTS: The median dialysis duration and pretransplant bladder capacity were 32 months (range 1-426 months) and 120 mL (range 15-450 mL), and 21 patients (20.8%) underwent dialysis for more than 120 months, and 30 patients (29.7%) had a pretransplant bladder capacity of less than 80 mL. Dialysis duration was correlated with pretransplant bladder capacity (R=0.466, P<0.001). Bladder capacity expanded more than 6-fold from pretransplantation to posttransplantation, and all recipients had a bladder capacity greater than 150 mL at 1 year posttransplantation. Thirty patients had VUR to the graft. Dialysis duration longer than 60 months (P=0.021) and pretransplant bladder capacity of less than 130 mL (P=0.024) were associated with VUR. VUR was associated with lower graft function. CONCLUSIONS: Although bladder capacity decreased because of long-term dialysis, it exceeded 150 mL at 1 year posttransplantation. A small bladder can be used in renal transplantation, but it may increase the risk of VUR. PMID- 21659950 TI - Sequential therapeutic penetrating keratoplasty with cryopreserved and fresh corneal tissue for severe infectious keratitis: a case-control study. AB - PURPOSE: Sequential therapeutic penetrating keratoplasty (TPK) using a cryopreserved cornea followed soon after by a fresh optical grade cornea for severe infectious keratitis may improve the survival of the optical graft. The aim of this study was to compare the therapeutic efficacy, visual outcomes, and graft survival for sequential TPK against TPK using a fresh optical grade cornea alone. METHODS: This was a retrospective case-control study. Case records were reviewed for clinical and surgical outcomes. RESULTS: Thirty-two eyes of 32 patients were included. Ten eyes underwent sequential TPK (TPK cases), and there were 22 age- and sex-matched controls, which underwent TPK with optical grade tissue alone. The mean interval between the TPK with the frozen cornea and the subsequent optical keratoplasty in the TPK cases was 16.8 +/- 12.9 days. Therapeutic success, defined as the eradication of the primary infection, was achieved in all the TPK cases but only in 13 controls (59.1%) (P = 0.06). Graft survival at 1 year was better in the TPK cases than the controls (72.9% vs 53.8%). An improvement in Snellen acuity by at least 2 lines was more likely in the TPK cases than the controls (80% vs 14%; P = 0.001). CONCLUSIONS: Sequential TPK is an effective surgical therapy for active severe infectious keratitis and also helps to conserve valuable optical grade corneal tissue. PMID- 21659951 TI - Severe acute pancreatitis: advances and insights in assessment of severity and management. AB - The patients with acute pancreatitis are at risk to develop different complications from ongoing pancreatic inflammation. Often, there is no correlation between the degree of structural damage to pancreas and clinical manifestation of the disease. The effectiveness of any treatment is related to the ability to predict severity accurately, but there is no ideal predictive system or biochemical marker. Severity assessment is indispensable to the selection of proper initial treatment in the management of acute pancreatitis. The use of multiparametric criteria and the evaluation of severity index permit us to select high-risk patients. Furthermore, contrast-enhanced computed tomographic scanning and contrast-enhanced MRI play an important role in severity assessment. The adoption of multiparametric criteria proposed together with morphological evaluation consents the formulation of a discreetly reliable prognosis on the evolution of the disease a few days from onset. PMID- 21659952 TI - "That's a good question": university researchers' views on ownership and retention of human genetic specimens. AB - PURPOSE: To explore the views of university-based investigators conducting genetic research with human specimens regarding ownership and retention of specimens, and knowledge of related institutional review board and university policies. METHODS: Data were collected in three phases: a qualitative pilot study of 14 investigators; a web-based survey taken by 80 investigators; and follow-up, in-depth interviews with 12 survey respondents. RESULTS: Investigators named a variety of single or multiple owners of human specimens and often expressed confusion regarding specimen ownership. Most associated ownership with rights to control, and responsibilities to maintain, specimens. Investigators viewed specimens as "precious" resources whose value could be increased through long term or infinite retention, particularly in light of anticipated technological advances in genome science. Their views on ownership and retention were shaped by perceptions of institutional review board policies as immortalized in subject informed consent documents, rather than knowledge of actual policies. CONCLUSION: Long-term retention of human specimens makes confusion about ownership particularly problematic. Given findings that investigators' views on ownership and retention are largely guided by their perception of university policies, the need for clear, consistent policies at the institution level is urgent. PMID- 21659954 TI - Computed tomographic evaluation of thoracic pedicle screw placement in idiopathic scoliosis. AB - This retrospective observational study aimed to determine the accuracy of the placement of transpedicular thoracic screws used in idiopathic scoliosis and to evaluate the position and safety of the implants using postoperative computed tomography. Twenty-nine patients who underwent surgery for scoliosis between May 2003 and November 2005 were included in this study. The mean spinal curvature was 67 degrees , and all of the patients had thoracic screws or hooks implanted. The positioning of 78 pedicle screws was evaluated using computed tomography after the free-handed technique was performed. The mean spinal curvature after surgery was 29 degrees . Seventy-six percent of the screws were fully contained within the pedicle. Twenty-one screws breached the pedicle by between 2 and 4 mm (three medially and 18 laterally). Two screws were broken. A neurological deficit was identified in one case after surgery, but the deficit was reversed after the removal of the screws. This screw had a medial breach of greater than 4 mm. Most screws were inserted between the cortical vertebrae. Misplaced screws were most commonly inserted with a lateral cortical perforation. PMID- 21659955 TI - Soft tissue release of the spastic hip by psoas-rectus transfer and adductor tenotomy for long-term functional improvement and prevention of hip dislocation. AB - The purpose of this study was to assess the long-term development of children with cerebral palsy treated with soft tissue releases of the hip and, if necessary, also of the hamstrings and the Achilles tendon. The follow-up had to consider the functional status and the hip centration. Seventy-one patients (46 with tetrapareses, 24 with dipareses, and one with triparesis) who underwent soft tissue releases of the hip by the so-called psoas-rectus transfer at an average age of 7 years were assessed preoperatively, after 1 year and at an average age of 19 years. Functional status and the radiological lapse were assigned. The functional status of the patients significantly improved (P<0.001) after surgery. The number of patients who were able to walk increased from 49.3 to 80.3%. The migration percentage decreased from 26.6 to 17.3%. For medium-to-severe functional deficits, a clear gain of function and a safe prevention of spastic hip luxation were achieved. PMID- 21659953 TI - Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia. AB - PURPOSE: Autosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene. The full spectrum of SPAST mutations causing SPG4 and their mechanisms of formation remain to be determined. METHODS: We used multiplex ligation-dependent probe amplification, locus-specific array comparative genomic hybridization, and breakpoint DNA sequencing to identify and describe genomic rearrangements in three patients with a clinical presentation of hereditary spastic paraplegia. RESULTS: We describe three SPG4 patients with intragenic rearrangements in SPAST; all specifically delete the final exon, exon 17. Breakpoint sequence analyses provide evidence for Alu-specific microhomology mediated deletion as the mechanism of exon loss; one complex rearrangement apparently occurred by multiple Alu-facilitated template switches. CONCLUSION: We hypothesize that the high concentration of Alu family members in the introns and flanking sequence of SPAST may predispose to intragenic rearrangements. Thus, Alu specific microhomology-mediated intragenic rearrangements in SPAST may be a common cause of SPG4. Furthermore, we propose that genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer disease, potentially explaining recent reports of dementia in selected SPG4 patients. PMID- 21659956 TI - Subchondral fracture after ischemic osteonecrosis of the immature femoral head in piglet model. AB - This experimental investigation was performed to study the development of a subchondral fracture after ischemic osteonecrosis of the immature femoral head using a piglet model. Forty-eight male piglets were studied after placing a ligature tightly around the femoral neck to disrupt the blood supply to the femoral head. Animals were euthanized 2-8 weeks after the induction of ischemia. Radiographic, histologic, and histomorphometric assessments were made. A subchondral fracture was seen in 12 out of 32 infarcted femoral heads (38%) that were in the initial radiographic stage of ischemic osteonecrosis. The fracture was seen mainly in those femoral heads that had a prolonged period of the initial stage where the initiation of revascularization and repair was delayed. Histomorphometric assessment showed decreased trabecular thickness and volume in the subchondral region of the infarcted femoral heads compared with the contralateral normal heads. After ischemic osteonecrosis, the trabecular bone in the subchondral region is thinner and less bone volume is present because of a lack of new bone formation. The results of this study support the hypothesis that a subchondral fracture in the immature femoral head develops as a result of mechanic failure of the trabecular bone in the subchondral region. PMID- 21659958 TI - Lipopolysaccharide-induced preconditioning against ischemic injury is associated with changes in toll-like receptor 4 expression in the rat developing brain. AB - Lipopolysaccharide (LPS) preconditioning reduces ischemic injury in adult brain by activating Toll-like receptor 4 (TLR-4). We sought to investigate the effect of brain maturity on the efficacy of LPS preconditioning against hypoxic-ischemic (HI) injury in the developing rat brain. Rat pups at the specified age were randomly assigned to LPS-treated (0.1 mg/kg) or saline-treated groups. HI injury was induced 48 h later by occluding the right common carotid artery followed by transient hypoxia. Brains were removed 1 wk after HI injury, and infarct volumes were compared between the two groups. TLR-4 expression was also compared among different ages. We found that LPS treated P7, P9, and P14 rat pups had significantly smaller infarct volume compared with saline-treated pups (p = 0.006, 0.03, and 0.01, respectively). This significant reduction in infarct volume was not observed in P3 and P5 rats. TLR-4 expression was significantly higher in older rats compared with P3 and P5 rats (p < 0.01). These findings indicate that LPS-induced preconditioning is a robust neuroprotective phenomenon in the ischemic developing brain that is age dependent. Pattern of TLR-4 expression is also affected by brain maturity and likely to be responsible for differences in the efficacy of LPS preconditioning. PMID- 21659957 TI - Baby STEPS: a giant leap for cell therapy in neonatal brain injury. AB - We advance Baby STEPS or Stem cell Therapeutics as an Emerging Paradigm in Stroke as a guide in facilitating the critical evaluation in the laboratory of the safety and efficacy of cell therapy for neonatal encephalopathy. The need to carefully consider the clinical relevance of the animal models in mimicking human neonatal brain injury, selection of the optimal stem cell donor, and the application of functional outcome assays in small and large animal models serve as the foundation for preclinical work and beginning to understand the mechanism of this cellular therapy. The preclinical studies will aid our formulation of a rigorous human clinical trial that encompasses not only efficacy testing but also monitoring of safety indices and demonstration of mechanisms of action. This schema forms the basis of Baby STEPS. Our goal is to resonate the urgent call to enhance the successful translation of cell therapy from the laboratory to the clinic. PMID- 21659959 TI - Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice. AB - Using a combination of N-ethyl-N-nitrosourea-mediated mutagenesis and metabolomics-guided screening, we identified mice with elevated blood levels of short-chain C4-acylcarnitine and increased urine isobutyryl-glycine. Genome-wide homozygosity screening, followed by fine mapping, located the disease gene to 15 25 Mb of mouse chromosome 9 where a candidate gene, Acad8, encoding mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a single-nucleotide mutation at -17 of the first intron of Acad8 in affected mice. cDNA sequencing revealed an intronic 28-bp insertion at the site of the mutation, which caused a frame shift with a premature stop codon. In vitro splicing assay confirmed that the mutation was sufficient to activate an upstream, aberrant 3' splice site. There was a reduction in the expression of Acad8 at both the mRNA and protein levels. The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. Homozygous mutant mice hepatocytes had abnormal mitochondria with crystalline inclusions, suggestive of mitochondriopathy. This mouse model of isobutyryl-CoA dehydrogenase deficiency could provide us a better understanding of the possible role of IBD deficiency in mitochondriopathy and fatty liver. PMID- 21659961 TI - An initial sustained inflation improves the respiratory and cardiovascular transition at birth in preterm lambs. AB - A sustained inflation (SI) facilitates lung aeration after birth but may impair the neonatal cardiovascular transition. We aimed to determine the effect of an initial SI on pulmonary arterial and carotid blood flow (PBF and CBF) after preterm birth. Fetal sheep were instrumented at ~ 122 d of gestation (d). Lambs were delivered at ~ 127 d and received either an initial SI (40 cm H2O for 1 min or until a volume of 20 mL/kg was administered) followed by ventilation for 30 min (SI; n = 7) or ventilation for 30 min (non-SI; n = 6). At 10 min after ventilation onset, inspired O2 content increased from 21 to 100% for 10 min. PBF, CBF, pulmonary arterial and carotid pressures, tidal volume, and inspiratory pressures were recorded. PBF was greater during the SI (p < 0.05) but thereafter was similar between groups. Non-SI lambs were hypoxemic and had higher CBF than SI lambs (p < 0.05). Cerebral oxygen delivery was constant in SI lambs but increased ~ 4-fold in non-SI lambs during ventilation with 100% O2 (p < 0.05). Lung compliance and respiratory status were better in SI than non-SI lambs (p < 0.05). A SI improved lung function without adverse circulatory effects, seemed to stabilize neonatal cerebral O2 delivery, and may protect against cerebral hyperoxia. PMID- 21659960 TI - Fibroblasts expressing PDGF-receptor-alpha diminish during alveolar septal thinning in mice. AB - In mice, secondary alveolar septal formation primarily occurs during a brief postnatal period and is accompanied by transient expansion of the interstitial lung fibroblast (LF) population. PDGF-A, which solely signals through PDGF receptor-alpha (PDGF-Ralpha), is required for expansion, but the receptor's relevant downstream targets remain incompletely defined. We have evaluated the proliferation, apoptosis, and differential response to the selective protein tyrosine kinase inhibitor, imatinib, by pdgfralpha-expressing LF (pdgfralpha-LF) and compared them with their nonexpressing LF counterparts. Our objective was to determine whether diminished signaling through PDGF-Ralpha-mediated pathways regulates the decline in myofibroblasts, which accompanies septal thinning and ensures more efficient alveolar gas exchange. Using quantitative stereology and flow cytometry at postnatal d 12 and 14, we observed that imatinib caused a selective suppression of proliferation and an increase in apoptosis. The number of the alpha smooth muscle actin (alphaSMA) producing pdgfralpha-LF was also reduced. Using cultures of neonatal mouse LF, we showed that imatinib did not suppress PDGF-Ralpha gene expression but reduced PDGF-A-mediated Akt phosphorylation, potentially explaining the increase in apoptosis. Our findings are relevant to bronchopulmonary dysplasia in which positive pressure ventilation interferes with myofibroblast depletion, septal thinning, and capillary maturation. PMID- 21659963 TI - Gene polymorphisms impact the risk of rejection with hemodynamic compromise: a multicenter study. AB - BACKGROUND: Rejection with hemodynamic compromise (RHC) is associated with high mortality in heart recipients. This study investigates the association between genetic polymorphisms and RHC in pediatric heart recipients. METHODS: Data from 532 pediatric heart recipients from six centers in the Pediatric Heart Transplant Study were analyzed for time to RHC by recipient race, age at transplantation, and genotype at 13 genetic polymorphisms (TNF-alpha A-308G, IL-6 G-174C, INF gamma T+874A, IL-10 G-1082A, C-819T, and C-592A; FAS A-670G, FASL C-843T, and ACE I/D; and VEGF A-2578C, C-1451T, C+405G, and -2549 I/D). RESULTS: RHC occurred in 126 (23.7%) patients during the study period. Adjusting for age and race, IL-10 G 1082A, FAS A-670G, and ACE I/D genotypes were associated with RHC. IL-10 G-1082A GG genotype was associated with decreased risk of RHC with an adjusted hazard ratio (HR) of 0.49 (95% confidence interval [CI], 0.27-0.90; P=0.020). FAS A-670G AA genotype was associated with increased risk of RHC with an adjusted HR of 1.84 (95% CI, 1.25-2.69; P=0.002). ACE II genotype was associated with decreased risk of RHC with an adjusted HR of 0.58 (95% CI, 0.36-0.95; P=0.031). CONCLUSIONS: Recipients with a high anti-inflammatory and immune-regulatory genetic profile (high interleukin-10) were protected from RHC. Conversely, recipients with a pro apoptotic genetic profile (high Fas) or high angiotensin-1-converting enzyme producing genotype were at increased risk of RHC. This represents progress toward understanding the genetic risk factors of posttransplantation outcomes in pediatric heart recipients. PMID- 21659962 TI - Replication of genetic associations in the inflammation, complement, and coagulation pathways with intraventricular hemorrhage in LBW preterm neonates. AB - Intraventricular hemorrhage (IVH) is a significant morbidity seen in very LBW infants. Genes related to the inflammation, infection, complement, or coagulation pathways have been implicated as risk factors for IVH. We examined 10 candidate genes for associations with IVH in 271 preterm infants (64 with IVH grades I-IV and 207 without IVH) weighing <1500 g. The heterozygous genotype OR = 8.1, CI = 2.5-26.0, p = 4 * 10(-4)) and the A allele (OR = 7.3, CI = 2.4-22.5, p = 1 * 10( 4)) of the coagulation factor V (FV) Leiden mutation (rs6025) were associated with an increased risk of developing IVH grade I or II but not grade III or IV after correction for multiple testing with Bonferroni. Lack of association in the severe grades of IVH may be a result of lack of power to detect an effect given the small sample size (n = 8). However, this result is consistent with previous research that demonstrates that the heterozygous genotype of the FV mutation is associated with increased risk for the development of IVH but a decreased risk for the progression or extension to more severe grades of IVH. PMID- 21659964 TI - Associations of renal function at 1-year after kidney transplantation with subsequent return to dialysis, mortality, and healthcare costs. AB - BACKGROUND: Improved early kidney transplant outcomes limit the contemporary utility of standard clinical endpoints. Quantifying the relationship of renal function at 1 year after transplant with subsequent clinical outcomes and healthcare costs may facilitate cost-benefit evaluations among transplant recipients. METHODS: Data for Medicare-insured kidney-only transplant recipients (1995-2003) were drawn from the United States Renal Data System. Associations of estimated glomerular filtration rate (eGFR) level at the first transplant anniversary with subsequent death-censored graft failure and patient death in posttransplant years 1 to 3 and 4 to 7 were examined by parametric survival analysis. Associations of eGFR with total health care costs defined by Medicare payments were assessed with multivariate linear regression. RESULTS: Among 38,015 participants, first anniversary eGFR level demonstrated graded associations with subsequent outcomes. Compared with patients with 12-month eGFR more than or equal to 60 mL/min/1.73 m, the adjusted relative risk of death-censored graft failure in years 1 to 3 was 31% greater for eGFR 45 to 59 mL/min/1.73 m (P<0.0001) and 622% greater for eGFR 15 to 30 mL/min/1.73 m (P<0.0001). Associations of first anniversary eGFR level with graft failure and mortality remained significant in years 4 to 7. The proportions of recipients expected to return to dialysis or die attributable to eGFR less than 60 mL/min/1.73 m over 10 years were 23.1% and 9.4%, respectively, and were significantly higher than proportions attributable to delayed graft function or acute rejection. Reduced eGFR was associated with graded and significant increases in health care spending during years 2 and 3 after transplant (P<0.0001). CONCLUSION: eGFR is strongly associated with clinical and economic outcomes after kidney transplantation. PMID- 21659965 TI - Synthesis and in vitro antiproliferative activity of novel androst-5-ene triazolyl and tetrazolyl derivatives. AB - A straightforward and reliable method for the regioselective synthesis of steroidal 1,4-disubstituted triazoles and 1,5-disubstituted tetrazoles via copper(I)-catalyzed cycloadditions is reported. Heterocycle moieties were efficiently introduced onto the starting azide compound 3beta-acetoxy-16beta azidomethylandrost-5-en-17beta-ol through use of the "click" chemistry approach. The antiproliferative activities of the newly-synthesized triazoles were determined in vitro on three human gynecological cell lines (HeLa, MCF7 and A2780) using the microculture tetrazolium assay. PMID- 21659966 TI - Lichtheimia blakesleeana as a new potencial producer of phytase and xylanase. AB - Brazil is known for its great potential for production of renewable resources such as agro-industrial residues. These residues can be used as alternative sources of new products. Meanwhile, solid-state fermentation, with its advantages of energy conservation and pollution reduction, has been identified as a process of great potential for the production of bioactive compounds, especially enzymes. In the present work, a 2(3) factorial design was used to evaluate the effects of pH, temperature and moisture on the production of phytase and xylanase by Lichtheimia blakesleeana URM 5604 through the fermentation of citrus pulp. Statistical analyses of the results showed that the only the pH influenced the production of these enzymes, with the best phytase production (264.68 U/g) ocurring at pH 6.0, 34 degrees C, initial moisture 50%, after 48 hours of culture. The best conditions for xylanase production (397.82 U/g) were fermentation for 120 hours at pH 4.0, 26 degrees C and initial moisture of 70%. The best parameters for the simultaneous production of phytase (226.92 U/g) and xylanase (215.59 U/g) were determined to be initial moisture of 50%, pH 6.0, 26 degrees C, and 48 hours of fermentation. PMID- 21659967 TI - Effects of fractionation and combinatorial evaluation of Tamarindus indica fractions for antibacterial activity. AB - Six fractions, named TiA - TiF, were obtained by fractionating the crude ethanol extract of the stem bark of Tamarindus indica using column chromatographic techniques. On TLC, fraction TiB showed five bands, TiC three bands, while TiD and TiE showed two bands each. TiC, TiD and TiE were re-eluted with different solvent systems to yield two fractions each, while TiB yielded four. These subfractions were designated B1-B4; C1-C2; D1-D2 and E1-E2, respectively. Tannins, flavonoids and alkaloids, among other components, were detected, albeit in different proportions with respect to fractions and subfractions and were compartmentalized with respect to the solvent systems used. The in vitro antibacterial activity of fractions and subfractions was tested separately and in combinations using the agar well diffusion technique. The susceptibly of test strains (expressed as %) were: 83.3% (TiA and TiB), 75.0% (crude extract and TiC), 66.7% (TiD), 50.0% (TiE) and 16.7% (TiF) when used singly, whereas in combination, the corresponding susceptibilities were 100% (CE), 83.3% (DE), 66.7% (AB, AF, BC, BD, DE and EF), 50% (AC and CD), 33.3% (BE and BF) and 16.7% (AD) against Gram negative bacteria strains and 100% (EF), 80% (DE), 60% (AB, BC and CE), 40% (AC, BD, BF, CF and DF) and 20% (AE, AF, BE and CD) against Gram positive strains. Percentage susceptibility with combinatorial use of re fractions ranged from 85.7-57.1% and 60-40% against Gram negative and positive strains (TiB subfractions), respectively, 100-85.7% and 40-0% against Gram negative and positive strains (TiC, TiD and TiE sub-fractions). PMID- 21659968 TI - Belimumab (Benlysta) for systemic lupus eruthematosus. PMID- 21659969 TI - Dextromethorphan/quinidine (Nuedexta) for pseudobulbar affect. PMID- 21659970 TI - Aromatase inhibitors for adjuvant treatment of postmenopausal breast cancer. PMID- 21659971 TI - In brief: An aromatase inhibitor is reported to prevent postmenopausal breast cancer. PMID- 21659972 TI - Evaluation of weekly risedronate treatment in postmenopausal women with osteoprotegerin. AB - AIM: The aim of this study was to evaluate the effect of risedronate treatment on OPG, C-terminal cross-linking telopeptide of type 1 collagen (CTX), osteocalcin (OC), deoxypyridinoline (DPD), and to establish the correlation of OPG levels with other bone turnover markers. METHODS: Eighty postmenopausal osteoporotic patients were randomized into two groups. In the first group, 37 patients received 35 mg of risedronate once a week, and 600 mg of elementary calcium with 400 IU of vitamin D per day. In the second group, 34 patients received only 600 mg of elementary calcium with 400 IU of vitamin D per day. OPG, OC, CTX and DPD levels were measured at baseline, then at 1, 3 and 6 months of treatment. RESULTS: OPG levels were significantly reduced at 1 and 6 months of treatment in both the risedronate and control group (p<0.05, p<0.01, respectively), but no statistically significant difference was detected between the two groups (p>0.05). In the group treated with risedronate, a difference in CTX level was observed at 3 months of treatment, while a difference in DPD and OC levels were observed 6 months of treatment. The baseline OPG levels correlated with age, menopause duration and CTX levels. There was no correlation between OPG levels and the levels of the other markers. CONCLUSION: Our results showed that using risedronate to treat postmenopausal osteoporosis causes no specific changes in OPG levels; thus, measurement of OPG levels as a marker may not be useful in the monitoring of bisphosphonate treatment. PMID- 21659973 TI - In vivo evaluation of labial microcirculation in diabetics: a comparison with healthy subjects. AB - AIM: Diabetes mellitus, a systemic chronic disease considered an epidemic by the World Health Organization (WHO) due to the rate of increase in the prevalence of diabetes, is a cause of microvascular and macrovascular complications leading to a significant burden for the individual and society. The aim of this study was to evaluate in vivo the effects of type II diabetes mellitus on the microcirculation of oral mucosa. METHODS: Forty-six subjects, 23 patients with type II diabetes mellitus (10 men, 13 women) and 23 healthy patients (9 men, 14 women) were examined in our laboratory. Oral microcirculation was evaluated on labial mucosa using oral video-capillaroscopy: a diagnostic method that permits the in vivo analysis of oral microcirculation. RESULTS: Capillary density, total loop length and total diameter resulted significantly altered in diabetics. The density of loops, observed on labial mucosa, is on average lower in diabetics than in healthy patients. The length and total diameter of loops are increased in diabetics. CONCLUSION: This study shows the capillary alterations that occur in the oral mucosa of diabetics. The loop density decrease is probably a symptom of peripheral microangiopathy. Ultimately, this study demonstrates that there is peripheral damage to microcirculation at the level of the labial mucosa in diabetic subjects and that these alterations are instrumentally "objectivable" and "quantifiable" through the videocapillaroscope technique. PMID- 21659974 TI - Non-invasive ventilation in severe asthma attack, its possibilities and problems. AB - Asthma attack is characterized by episodic attacks of cough, dyspnea and wheeze occurring due to bronchoconstriction, airway hyperresponsiveness and mucous hypersecretion. Although nationwide clinical guidelines have been published to establish the standard care of asthma, choices in the treatment of fatal asthma attacks remain of clinical significance. Especially, in a severe asthma attack, despite the application of conventional medical treatment, respiratory management is critical. Even though non-invasive ventilation (NIV) has been shown to be effective in a wide variety of clinical settings, reports of NIV in asthmatic patients are scarce. According to a few prospective clinical trials reporting promising results in favour of the use of NIV in a severe asthma attack, a trial of NIV prior to invasive mechanical ventilation seems acceptable and may benefit patients by decreasing the need for intubation and by supporting pharmaceutical treatments. Although selecting the appropriate patients for NIV use is a key factor in successful NIV application, how to distinguish such patients is quite controversial. Larger high quality clinical trails are urgently required to confirm the benefits of NIV to patients with severe asthma attack. In this article, we focus on the body of evidence supporting the use of NIV in asthma attacks and discuss its advantages as well its problems. PMID- 21659975 TI - Allergic rhinitis in asthma. AB - Allergic rhinitis and asthma are different pathologies deeply connected. Despite anatomical related differences existing between these two clinical conditions, they share a pathogenetic mechanism represented by an inflammatory pattern in which many upper airways cells and mediators are the same involved in lower airway disease. In other words, they seem to be a different phenothypical expression of a common immunological process. Allergic rhinitis is a very common pathology, it often precedes the onset of clinical asthma, and is associated to a worsening in both asthma control and patient quality of life. Available knowledge suggests that a well performed treatment of rhinitis can lead to a better asthma control, as well as its treatment with specific immunotherapy can prevent or delay asthma onset. Since inhaled corticosteroids represent the most effective treatment in both cases, a long term combined therapeutic plan is needed in order to ameliorate overall patients health status and to improve their health related quality of life avoiding the risk of dose related drugs side effects. PMID- 21659976 TI - Growing up with a congenital heart disease: neuro-cognitive, psychopathological and quality of life outcomes. AB - About 1% of newborn presents some form of congenital heart disease (CHD). Eighty five percent of these children, thanks to medical and surgical improvement, reaches adulthood. This open up new challenges in patients management, such as the evaluation and optimization of psychosocial functioning and quality of life of CHD subjects. The present review collects research literature regarding neurocognitive and psychopathological adjustment, and personality and quality of life of these patients, analyzing variables that may influence their development. Literature data lean towards a multifactorial process implied into an insufficient outcome of neurocognitive development in many patients. Psychopathological development seems "problematic" with the expression of behavioural disorders both externalising and internalising. But current researches don't consent univocal and definitive conclusions. The need for interventions to improve existential outcome for CHD subjects emerges: research on genetic factors and early recognition of at risk subjects must go with the necessity for research aiming to determine protective and risk factors related to personality, environment and relational aspects entailed in the development of CHD subjects. Finally, some evidences noticed in CHD subjects psychopathological and quality of life outcomes which are even better than normal ones. These results depend on the elaboration of their disease that CHD subjects have carried on. Factors regarding mainly personality development are essential in determining these outcomes. PMID- 21659977 TI - Animal-assisted interventions in internal and rehabilitation medicine: a review of the recent literature. AB - While conventional wisdom has always affirmed the value of animals in promoting human well-being, only recently has their therapeutic role in medicine become the focus of dedicated research. Therapeutic modalities that use animals as a tool for improving the physical, emotional, cognitive and/or social functioning of humans are called animal-assisted interventions (AAI), and are classified into: animal-assisted activities (AAA); animal-assisted therapy (AAT); and service animal programs (SAP). The aim of this review is to analyze the papers published between 2001 and 2010 in the most influential medical journals dealing with AAI, and discuss their findings in the light of what may be of interest for internal medicine and rehabilitation. A total of 35 articles met the strict inclusion criteria for this review: 18 papers dealing with AAA, 8 with AAT, and 9 with SAP. The therapeutic outcomes associated with AAA are: enhancement of socialization; reduction of stress, anxiety and loneliness; improvement in mood and general well being; and development of leisure/recreation skills. Regarding AAT, horses are often used as a complementary strategy to facilitate the normalization of muscle tone and improve motor skills in children with cerebral palsy and persons with lower limb spasticity. Finally, most SAP utilize dogs, that assist people with various disabilities in performing everyday activities, thus reducing their dependence on other persons. Further studies are needed to better define the fields and programs for the therapeutic use of animals and to increase their utilization in medicine, as a promising, complementary and natural means to improve both functional autonomy and quality of life. PMID- 21659978 TI - On the efficacy of penicillins for Helicobacter pylori eradication. PMID- 21659979 TI - Ranitidine bismuth citrate in the first-line of Helicobacter pylori treatment. PMID- 21659980 TI - Nonfatal bathroom injuries among persons aged >=15 years--United States, 2008. AB - In 2008, approximately 21.8 million persons aged >=15 years sustained nonfatal, unintentional injuries, resulting in approximately $67.3 billion in lifetime medical costs. Information about where injuries occur is limited, but bathrooms commonly are believed to be a particularly hazardous location. To investigate this assumption, CDC analyzed data from a nationally representative sample of emergency departments (EDs) to describe the incidence and circumstances of nonfatal injuries in bathrooms (in any setting) among persons aged >=15 years in the United States. This report describes the results of that investigation, which found that, based on 3,339 cases documented in the 2008 National Electronic Surveillance System All Injury Program (NEISS-AIP) database, an estimated 234,094 nonfatal bathroom injuries were treated in U.S. EDs. Injury rates increased with age, and most injuries (81.1%) were caused by falls. All persons, but especially older adults, should be aware of bathroom activities that are associated with a high risk for injury and of environmental modifications that might reduce that risk. PMID- 21659981 TI - Ocular toxocariasis--United States, 2009-2010. AB - Ocular toxocariasis (OT) is caused by the zoonotic parasites Toxocara canis and Toxocara cati, roundworms of dogs and cats. Persons become infected with Toxocara when they unintentionally ingest embryonated eggs that have been shed in the feces of infected animals. Although OT is uncommon, it most often affects young children and can cause debilitating ophthalmologic disease, including blindness. Previous studies of OT in the United States have been conducted in single institutions. This report describes the results of a web-based survey distributed to uveitis, retinal, and pediatric ophthalmology specialists nationwide to collect epidemiologic, demographic, and clinical information on patients with OT. A total of 68 patients were newly diagnosed with OT from September 2009 through September 2010. Among the 44 patients for whom demographic information was available, the median patient age was 8.5 years (range: 1-60 years), and 25 patients (57%) lived in the South at the time of diagnosis. Among 30 patients with reported clinical data, the most common symptom was vision loss, reported by 25 (83%) patients; of these, 17 (68%) suffered permanent vision loss. The results of this first national level survey demonstrate that OT transmission continues to occur in the United States, frequently affecting children and causing permanent vision loss in the majority of reported patients. Good hygiene practices, timely disposal of pet feces, and routine deworming of pets are strategies necessary to reduce OT in humans. PMID- 21659982 TI - Interim results: state-specific influenza vaccination coverage--United States, August 2010-February 2011. AB - The 2010--11 influenza season was unusual because it followed the 2009 influenza A pandemic (H1N1) season and it was the first season the Advisory Committee on Immunization Practices (ACIP) recommended influenza vaccination of all persons aged >=6 months. The season also was notable because a record number of seasonal influenza vaccine doses (approximately 163 million) were distributed in the United States. To provide preliminary state-specific influenza vaccination coverage estimates, CDC analyzed Behavioral Risk Factor Surveillance System (BRFSS) data for adults aged >=18 years and National Immunization Survey (NIS) data for children aged 6 months-17 years collected September 2010 through March 2011. By February 28, the preliminary national vaccination coverage estimate was 49.0% for children aged 6 months-17 years; among 43 states and the District of Columbia (DC), coverage ranged from 30.2% for adults aged 18-49 years to 68.6% for adults aged >=65 years. The record high seasonal vaccination coverage achieved during 2009-10 (41.3%) among persons aged >=6 months in 43 states and DC was sustained during the 2010--11 season (42.8%). Coverage for Hispanic and non Hispanic black children increased by 11-12 percentage points from 2009-10 levels. Opportunity exists to improve coverage in all age groups, particularly among adults. To accomplish that, health departments and other nonoffice-based vaccination providers can increase access to vaccination at work and school locations, pharmacies and stores, and other nonmedical sites. In addition, physicians and clinics should implement proven strategies for improving vaccination coverage (e.g., office-based protocols, including reminder/recall notification and standing orders). PMID- 21659983 TI - Renewed transmission of dracunculiasis--Chad, 2010. AB - Transmission of dracunculiasis (Guinea worm disease), a waterborne, parasitic disease targeted for eradication, was thought to have been interrupted in Chad since 2000, when the last case was reported. However, in 2010, 10 cases were confirmed by the Chad Ministry of Public Health (Ministere de la Sante Publique [MSP]) and the World Health Organization (WHO) during field investigations in which rumored cases were investigated and nearby villages were actively searched for additional cases. Because patients were not prevented from contaminating water sources, new cases were expected in 2011. During January-February 2011, MSP, WHO, and CDC conducted an investigation to gather additional information to guide prevention and response activities before the 2011 transmission season. Seven districts where cases had been confirmed or suspected in 2010 or where dracunculiasis was endemic during 1994-2000 were surveyed. The results of those surveys indicated that residents of 116 (55%) of 210 villages and 13 (87%) of 15 nomad camps consumed water from unsafe sources; 157 (75%) of 209 village key informants (KIs) and five (33%) of 15 nomad camp KIs knew about dracunculiasis. Thirty-one villages had confirmed or suspected cases during 2009-2011 and were classified as at-risk, requiring weekly active surveillance and urgent pre positioning of materials for the 2011 transmission season. Nomadic populations are at risk for dracunculiasis because of unsafe water consumption and minimal knowledge of the disease. These populations also require targeted surveillance and prevention efforts (e.g., filter distribution, education, and case containment) to interrupt dracunculiasis transmission . PMID- 21659984 TI - Vital signs: incidence and trends of infection with pathogens transmitted commonly through food--foodborne diseases active surveillance network, 10 U.S. sites, 1996-2010. AB - BACKGROUND: In the United States, contaminated food causes approximately 1,000 reported disease outbreaks and an estimated 48 million illnesses, 128,000 METHODS: The Foodborne Diseases Active Surveillance Network (FoodNet) conducts surveillance among 15% of the U.S. population for laboratory-confirmed infections with nine pathogens transmitted commonly through food. Overall and pathogen specific changes in incidence were estimated from 1996-1998 to 2010 and from 2006 2008 to 2010.hospitalizations, and 3,000 deaths annually. This report summarizes 2010 surveillance data and describes trends since 1996. RESULTS: A total of 19,089 infections, 4,247 hospitalizations, and 68 deaths were reported from FoodNet sites in 2010. Salmonella infection was the most common infection reported (17.6 illnesses per 100,000 persons) and was associated with the largest number of hospitalizations (2,290) and deaths (29); no significant change in incidence of Salmonella infection has occurred since the start of surveillance during 1996-1998. Shiga toxin-producing Escherichia coli (STEC) O157 infection caused 0.9 illnesses per 100,000. Compared with 1996-1998, overall incidence of infection with six key pathogens in 2010 was 23% lower, and pathogen-specific incidence was lower for Campylobacter, Listeria, STEC O157, Shigella, and Yersinia infection but higher for Vibrio infection. Compared with a more recent period, 2006--2008, incidence in 2010 was lower for STEC O157 and Shigella infection but higher for Vibrio infection. CONCLUSIONS: The incidence of STEC O157 infection has declined to reach the 2010 national health objective target of >=1 case per 100,000. This success, as well as marked declines since 1996-1998 in overall incidence of six key foodborne infections, demonstrates the feasibility of preventing foodborne illnesses. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Salmonella infection should be targeted because it has not declined significantly in more than a decade, and other data indicate that it is one of the most common foodborne infections, resulting in an estimated $365 million in direct medical costs annually. The prevention measures that reduced STEC O157 infection need to be applied more broadly to reduce Salmonella and other infections. Effective measures from farm to table include preventing contamination of meat during slaughter and of all foods, including produce, during processing and preparation; cooking meat thoroughly; vigorously detecting and investigating outbreaks; and recalling contaminated food. PMID- 21659985 TI - Sexual identity, sex of sexual contacts, and health-risk behaviors among students in grades 9-12--youth risk behavior surveillance, selected sites, United States, 2001-2009. AB - PROBLEM: Sexual minority youths are youths who identify themselves as gay or lesbian, bisexual, or unsure of their sexual identity or youths who have only had sexual contact with persons of the same sex or with both sexes. Population-based data on the health-risk behaviors practiced by sexual minority youths are needed at the state and local levels to most effectively monitor and ensure the effectiveness of public health interventions designed to address the needs of this population. REPORTING PERIOD COVERED: January 2001-June 2009. DESCRIPTION OF SYSTEM: The Youth Risk Behavior Surveillance System (YRBSS) monitors priority health-risk behaviors (behaviors that contribute to unintentional injuries, behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, sexual behaviors, dietary behaviors, physical activity and sedentary behaviors, and weight management) and the prevalence of obesity and asthma among youths and young adults. YRBSS includes state and local school-based Youth Risk Behavior Surveys (YRBSs) conducted by state and local education and health agencies. This report summarizes results from YRBSs conducted during 2001-2009 in seven states and six large urban school districts that included questions on sexual identity (i.e., heterosexual, gay or lesbian, bisexual, or unsure), sex of sexual contacts (i.e., same sex only, opposite sex only, or both sexes), or both of these variables. The surveys were conducted among large population-based samples of public school students in grades 9-12. RESULTS: Across the nine sites that assessed sexual identity, the prevalence among gay or lesbian students was higher than the prevalence among heterosexual students for a median of 63.8% of all the risk behaviors measured, and the prevalence among bisexual students was higher than the prevalence among heterosexual students for a median of 76.0% of all the risk behaviors measured. In addition, the prevalence among gay or lesbian students was more likely to be higher than (rather than equal to or lower than) the prevalence among heterosexual students for behaviors in seven of the 10 risk behavior categories (behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, sexual behaviors, and weight management). Similarly, the prevalence among bisexual students was more likely to be higher than (rather than equal to or lower than) the prevalence among heterosexual students for behaviors in eight of the 10 risk behavior categories (behaviors that contribute to unintentional injuries, behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, sexual behaviors, and weight management). Across the 12 sites that assessed sex of sexual contacts, the prevalence among students who had sexual contact with both sexes was higher than the prevalence among students who only had sexual contact with the opposite sex for a median of 71.1% of all the risk behaviors measured, and the prevalence among students who only had sexual contact with the same sex was higher than the prevalence among students who only had sexual contact with the opposite sex for a median of 29.7% of all the risk behaviors measured. Furthermore, the prevalence among students who had sexual contact with both sexes was more likely to be higher than (rather than equal to or lower than) the prevalence among students who only had sexual contact with the opposite sex for behaviors in six of the 10 risk behavior categories (behaviors that contribute to violence, behaviors related to attempted suicide, tobacco use, alcohol use, other drug use, and weight management). The prevalence among students who only had sexual contact with the same sex was more likely to be higher than (rather than equal to or lower than) the prevalence among students who only had sexual contact with the opposite sex for behaviors in two risk behavior categories (behaviors related to attempted suicide and weight management). INTERPRETATIONS: Sexual minority students, particularly gay, lesbian, and bisexual students and students who had sexual contact with both sexes, are more likely to engage in health-risk behaviors than other students. PUBLIC HEALTH ACTION: Effective state and local public health and school health policies and practices should be developed to help reduce the prevalence of health-risk behaviors and improve health outcomes among sexual minority youths. In addition, more state and local surveys designed to monitor health-risk behaviors and selected health outcomes among population-based samples of students in grades 9-12 should include questions on sexual identity and sex of sexual contacts. PMID- 21659986 TI - A qualitative investigation of the views of primary care dentists on participating in prospective studies in the North-West of England. AB - BACKGROUND: There is a poor understanding of to how to recruit and involve primary care dentists in clinical trials. AIM: To use a qualitative paradigm to explore the views of primary care dentists towards participating in clinical trials and develop an understanding of the factors that facilitate and prevent their involvement. DESIGN, SETTING, SUBJECTS AND METHODS: An iterative approach was undertaken using a focus group (n = 6) followed by phased semi-structured interviews (n = 18). Data were analysed using thematic analysis and constant comparative analysis. FINDINGS: The semi-structured interviews generated nine codes which were organised into three themes: technical issues for trials in primary dental care, practical issues for research in primary dental care and primary care dentists as research consumers. Overall, primary care dentists had a poor understanding of research methodology and clinical research. Barriers to participation included loss of clinical freedom and control, practice disruption, patient welfare, staff workload, financial loss and time. CONCLUSIONS: Barriers to primary dental care research need to be overcome through appropriate protocols, funding, training and support. Joint working of primary dental care teams and academic researchers is essential, along with a constructive and open dialogue, if clinical trials are to be successfully undertaken in a practice environment. PMID- 21659988 TI - Faith, hope and objectives. PMID- 21659987 TI - The survival of Class V restorations in general dental practice. Part 2, early failure. AB - OBJECTIVE: To evaluate Class V restorations placed by UK general practitioners comparing those failing or surviving after two years, and to identify factors associated with early failure. DESIGN: Prospective longitudinal cohort multi centre study. Setting UK general dental practices. MATERIALS & METHODS: Ten dentists each placed 100 Class V restorations and recorded selected clinical information at placement and recall visits. Univariate associations were assessed between recorded clinical factors and whether restorations had failed or not at two years. Multi-variable binary logistic regression was also undertaken to identify which combination of factors had a significant effect on the probability of early failure. RESULTS: At two years, 156 of 989 restorations had failed (15.8%), with 40 (4%) lost to follow-up. Univariate analysis showed a significant association between restoration failure and increasing patient age, payment method, the treating practitioner, non-carious cavities, cavities involving enamel and dentine, cavity preparation and restoration material. Multi-variable analysis indicated a higher probability of early failure associated with the practitioner, older patients, glass ionomer and flowable composite, bur preparation and moisture contamination. CONCLUSIONS: Among these practitioners, both analytic methods identified significant associations between early failure of Class V restorations and the practitioner, cavity preparation method, restoration material and patient's age. PMID- 21659989 TI - Cultural awareness. PMID- 21659990 TI - AED value. PMID- 21659991 TI - Remains of the day. PMID- 21659992 TI - Refreshingly realistic. PMID- 21659993 TI - Refreshing discussion. PMID- 21659994 TI - Splints as placebos. PMID- 21659995 TI - Council appointments. PMID- 21659996 TI - Daylight robbery. PMID- 21659997 TI - QIPP, or just Q? PMID- 21659998 TI - OSA and MAD. PMID- 21659999 TI - Alarm bells. PMID- 21660000 TI - CQC sea change. PMID- 21660012 TI - Dental volunteering - a time for reflection and a time for change. AB - Dental volunteers and their NGOs may have the potential to make a significant and long-lasting contribution to global oral health. However, their traditional approach to volunteering in developing countries can be questioned as to its appropriateness and sustainability combined with potential harmful effects that it might bring to the local health system. This article reviews the positive and negative aspects of this approach to dental volunteering and examines possible changes that could be made to the prevailing volunteer paradigm. PMID- 21660013 TI - The political culture of healthcare: why substantial dental care in Canada is covered by government insurance only in Quebec - lessons for the United States? AB - This opinion paper explains the unique and favourable terms of dental health insurance coverage available to residents (both permanent and temporary) of the Province of Quebec, Canada. In comparison, the United States and British Canada are the poor stepchildren of government-mediated provision of dental health coverage. The differences in dental healthcare provision between these regions are a question of culture - more specifically, of differing socio-political cultures and different perspectives on the importance of dental care. Lawmakers in the United States can learn from this policy of government-administered dental insurance that appears to work well in Quebec. PMID- 21660014 TI - Zinc-containing denture adhesive: a potential source of excess zinc resulting in copper deficiency myelopathy. AB - Copper deficiency in humans can result in both anaemia and neurological symptoms affecting walking and balance. Recently zinc excess due to overuse of zinc containing denture adhesive has been recognised as a potential cause of copper deficiency. Recovery from neurological symptoms with replacement therapy appears to be limited and so emphasis falls on education and early detection. Dentists are well placed to educate patients on use of denture adhesives and to detect early signs of copper deficiency in patients who may be using zinc-containing denture adhesive to excess. A case of a 58-year-old man diagnosed with copper deficiency myelopathy possibly due to zinc-containing denture cream overuse is presented. PMID- 21660020 TI - Summary of: a qualitative investigation of the views of primary care dentists on participating in prospective studies in the North-West of England. PMID- 21660021 TI - Summary of: the survival of Class V restorations in general dental practice. Part 2, early failure. PMID- 21660022 TI - Evidence summary: which dental liners under amalgam restorations are more effective in reducing postoperative sensitivity? AB - Since August 2009, members of the Primary Care Dentistry Research Forum (www.dentistryresearch.org) have taken part in an online vote to identify questions in day-to-day practice that they felt most needed to be answered with conclusive research. The question that receives the most votes each month forms the subject of a critical appraisal of the relevant literature. Each month a new round of voting takes place to decide which further questions will be reviewed. Dental practitioners and dental care professionals are encouraged to take part in the voting and submit their own questions to be included in the vote by joining the website. The paper below details a summary of the findings of the ninth critical appraisal. In order to address the question raised by dentistry research forum, first a search was conducted for systematic reviews on the topic. There was one systematic review retrieved comparing bonded amalgam restorations versus non-bonded amalgam restorations. However, there was no other systematic review identified assessing the effectiveness of dental liners under amalgam restorations in general. Therefore, a search was conducted for any randomised controlled trial (RCT) comparing use of a lining under amalgam restorations versus no lining or RCTs comparing differing lining materials under amalgam against each other. There were eight relevant RCTs identified. Due to the low quality, small sample sizes or lack of adequate reporting of the outcome data, the evidence is inadequate to claim or refute a difference in postoperative sensitivity between different dental liners. Further well-conducted RCTs are needed to answer this question. These RCTs would be preferably included and synthesised in a systematic review. PMID- 21660042 TI - Low expression of PP2A regulatory subunit B55alpha is associated with T308 phosphorylation of AKT and shorter complete remission duration in acute myeloid leukemia patients. AB - The regulation of protein kinase B (AKT) is a dynamic process that depends on the balance between phosphorylation by upstream kinases for activation and inactivation by dephosphorylation by protein phosphatases. Phosphorylated AKT is commonly found in acute myeloid leukemia (AML) and confers an unfavorable prognosis. Understanding the relative importance of upstream kinases and AKT phosphatase in the activation of AKT is relevant for the therapeutic targeting of this signaling axis in AML. The B55alpha subunit of protein phosphatase 2A (PP2A) has been implicated in AKT dephosphorylation, but its role in regulating AKT in AML is unknown. We examined B55alpha protein expression in blast cells derived from 511 AML patients using reverse phase protein analysis. B55alpha protein expression was lower in AML cells compared with normal CD34+ cells. B55alpha protein levels negatively correlated with threonine 308 phosphorylation levels. Low levels of B55alpha were associated with shorter complete remission duration, demonstrating that decreased expression is an adverse prognostic factor in AML. These findings suggest that decreased B55alpha expression in AML is at least partially responsible for increased AKT signaling in AML and suggests that therapeutic targeting of PP2A could counteract this. PMID- 21660043 TI - Cooperative roles for emmprin and LYVE-1 in the regulation of chemoresistance for primary effusion lymphoma. AB - The Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), for which cytotoxic chemotherapy represents the standard of care. The high mortality associated with PEL may be explained in part by resistance of these tumors to chemotherapy. The membrane-bound glycoprotein emmprin (CD147) enhances chemoresistance in tumors through effects on transporter expression, trafficking and interactions. Interactions between hyaluronan and hyaluronan receptors on the cell surface also facilitate emmprin-mediated chemoresistance. Whether emmprin or hyaluronan-receptor interactions regulate chemotherapeutic resistance for virus-associated malignancies is unknown. Using human PEL tumor cells, we found that PEL sensitivity to chemotherapy is directly proportional to expression of emmprin, the lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and a drug transporter known as the breast cancer resistance protein/ABCG2 (BCRP), and that emmprin, LYVE-1 and BCRP interact with each other and colocalize on the PEL cell surface. In addition, we found that emmprin induces chemoresistance in PEL cells through upregulation of BCRP expression, and RNA interference targeting of emmprin, LYVE-1 or BCRP enhances PEL cell apoptosis induced by chemotherapy. Finally, disruption of hyaluronan receptor interactions using small hyaluronan oligosaccharides reduces expression of emmprin and BCRP while sensitizing PEL cells to chemotherapy. Collectively, these data support interdependent roles for emmprin, LYVE-1 and BCRP in chemotherapeutic resistance for PEL. PMID- 21660044 TI - The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis. AB - Hedgehog (Hh) is a developmental signaling pathway in which Hh ligands bind Patched (Ptch), which relieves its inhibition of Smoothened (Smo), allowing the Gli family of transcription factors to translocate to the nucleus and activate Hh target genes. The role of Hh signaling in hematopoiesis is controversial and ill defined. Although some groups observed self-renewal defects with decreased replating and reduced efficiency of secondary murine transplants, other groups reported no hematopoietic phenotypes, which may be related to the timing of Hh abrogation. In malignant hematopoiesis, most attention has been focused on the role of Hh signaling in chronic myeloid leukemia (CML), considered by many to be a stem cell disorder that bears the constitutively active BCR-ABL tyrosine kinase. Despite the elimination of most leukemia cells through BCR-ABL inhibition, most patients remain PCR positive, suggesting that the putative CML stem cell may be resistant to kinase antagonism. Groups are now exploring the Hh pathway as an alternate pathway supporting CML stem cell survival. Knockdown or inhibition of Smo abrogates or delays the appearance of CML in several in vitro and in vivo models. These data have lead to clinical trials using BCR-ABL kinase and novel Smo inhibitors in combination. PMID- 21660045 TI - Identification of novel myeloma-specific XBP1 peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma. AB - The purpose of these studies was to identify human leukocyte antigen (HLA)-A2(+) immunogenic peptides derived from XBP1 antigens to induce a multiple myeloma (MM) specific immune response. Six native peptides from non-spliced XBP1 antigen and three native peptides from spliced XBP1 antigen were selected and evaluated for their HLA-A2 specificity. Among them, XBP1(184-192), XBP1 SP(196-204) and XBP1 SP(367-375) peptides showed the highest level of binding affinity, but not stability to HLA-A2 molecules. Novel heteroclitic XBP1 peptides, YISPWILAV or YLFPQLISV, demonstrated a significant improvement in HLA-A2 stability from their native XBP1(184-192) or XBP1 SP(367-375) peptide, respectively. Cytotoxic T lymphocytes generated by repeated stimulation of CD3(+) T cells with each HLA-A2 specific heteroclitic peptide showed an increased percentage of CD8(+) (cytotoxic) and CD69(+)/CD45RO(+) (activated memory) T cells and a lower percentage of CD4(+) (helper) and CD45RA(+)/CCR7(+) (naive) T cells, which were distinct from the control T cells. Functionally, the cytotoxic T lymphocytes (CTL) demonstrated MM-specific and HLA-A2-restricted proliferation, interferon gamma secretion and cytotoxic activity in response to MM cell lines and importantly, cytotoxicity against primary MM cells. These data demonstrate the distinct immunogenic characteristics of unique heteroclitic XBP1 peptides, which induce MM-specific CTLs and highlights their potential application for immunotherapy to treat the patients with MM or its pre-malignant condition. PMID- 21660046 TI - Molecular analysis of neutrophil spontaneous apoptosis reveals a strong role for the pro-apoptotic BH3-only protein Noxa. AB - Neutrophils enter the peripheral blood from the bone marrow and die after a short time. Molecular analysis of spontaneous neutrophil apoptosis is difficult as these cells die rapidly and cannot be easily manipulated. We use conditional Hoxb8 expression to generate mouse neutrophils and test the regulation of apoptosis by extensive manipulation of B-cell lymphoma protein 2 (Bcl-2)-family proteins. Spontaneous apoptosis was preceded by downregulation of anti-apoptotic Bcl-2 proteins. Loss of the pro-apoptotic Bcl-2 homology domain (BH3)-only protein Bcl-2-interacting mediator of cell death (Bim) gave some protection, but only neutrophils deficient in both BH3-only proteins, Bim and Noxa, were strongly protected against apoptosis. Function of Noxa was at least in part neutralization of induced myeloid leukemia cell differentiation protein (Mcl-1) in neutrophils and progenitors. Loss of Bim and Noxa preserved neutrophil function in culture, and apoptosis-resistant cells remained in circulation in mice. Apoptosis regulated by Bim- and Noxa-driven loss of Mcl-1 is thus the final step in neutrophil differentiation, required for the termination of neutrophil function and neutrophil-dependent inflammation. PMID- 21660047 TI - Nucleolar NF-kappaB/RelA mediates apoptosis by causing cytoplasmic relocalization of nucleophosmin. AB - In a number of contexts, and particularly in response to cellular stress, stimulation of the NF-kappaB (NF-kappaB) pathway promotes apoptosis. One mechanism underlying this pro-apoptotic activity is nucleolar sequestration of RelA, which is reported to cause cell death by repressing NF-kappaB-driven transcription. Here, we identify a novel and distinct nucleolar activity of RelA that induces apoptosis. We demonstrate, using a viral nucleolar localization signal (NoLS)-RelA fusion protein, that direct targeting of RelA to the nucleolus mediates apoptosis, independent of NF-kappaB transcriptional activity. We demonstrate a requirement for nucleophosmin (NPM, B23.1) in this apoptotic effect, and the apoptotic effect of stress-induced nucleolar RelA. We show by multiple approaches that nucleolar translocation of RelA is causally involved in the relocalization of NPM from the nucleolus to the cytoplasm and that RelA induced cytoplasmic NPM mediates apoptosis by facilitating the mitochondrial accumulation of BAX. These data uncover a novel stress-response pathway and mechanism by which RelA promotes apoptosis, independent of its effects on NF kappaB transcriptional activity. These findings are relevant to the design of novel anticancer agents that target RelA to this compartment. PMID- 21660048 TI - Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery. AB - Autophagy is implicated in regulating cell death in activated T cells, but the underlying mechanism is unclear. Here, we show that inhibition of autophagy via Beclin 1 gene deletion in T cells leads to rampant apoptosis in these cells upon TCR stimulation. Beclin 1-deficient mice fail to mount autoreactive T-cell responses and are resistant to experimental autoimmune encephalomyelitis. Compared with Th17 cells, Th1 cells are much more susceptible to cell death upon Beclin 1 deletion. Cell death proteins are highly increased in Beclin 1-deficient T cells and inhibition of caspases and genetic deletion of Bim reverse apoptosis. In addition, p62/sequestosome 1 binds to caspase-8 but does not control levels of procaspase-8 or other cell death-related proteins. These results establish a direct role of autophagy in inhibiting the programmed cell death through degradation of apoptosis proteins in activated T cells. PMID- 21660050 TI - Ablation of Dido3 compromises lineage commitment of stem cells in vitro and during early embryonic development. AB - The death inducer obliterator (Dido) locus encodes three protein isoforms, of which Dido3 is the largest and most broadly expressed. Dido3 is a nuclear protein that forms part of the spindle assembly checkpoint (SAC) and is necessary for correct chromosome segregation in somatic and germ cells. Here we report that specific ablation of Dido3 function in mice causes lethal developmental defects at the onset of gastrulation. Although these defects are associated with centrosome amplification, spindle malformation and a DNA damage response, we provide evidence that embryonic lethality of the Dido3 mutation cannot be explained by its impact on chromosome segregation alone. We show that loss of Dido3 expression compromises differentiation of embryonic stem cells in vitro and of epiblast cells in vivo, resulting in early embryonic death at around day 8.5 of gestation. Close analysis of Dido3 mutant embryoid bodies indicates that ablation of Dido3, rather than producing a generalized differentiation blockade, delays the onset of lineage commitment at the primitive endoderm specification stage. The dual role of Dido3 in chromosome segregation and stem cell differentiation supports the implication of SAC components in stem cell fate decisions. PMID- 21660049 TI - A critical step for JNK activation: isomerization by the prolyl isomerase Pin1. AB - c-Jun N-terminal kinase (JNK) is activated by dual phosphorylation of both threonine and tyrosine residues in the phosphorylation loop of the protein in response to several stress factors. However, the precise molecular mechanisms for activation after phosphorylation remain elusive. Here we show that Pin1, a peptidyl-prolyl isomerase, has a key role in the JNK1 activation process by modulating a phospho-Thr-Pro motif in the phosphorylation loop. Pin1 overexpression in human breast cancer cell lines correlates with increased JNK activity. In addition, small interfering RNA (siRNA) analyses showed that knockdown of Pin1 in a human breast cancer cell line decreased JNK1 activity. Pin1 associates with JNK1, and then catalyzes prolyl isomerization of the phospho Thr-Pro motif in JNK1 from trans- to cis-conformation. Furthermore, Pin1 enhances the association of JNK1 with its substrates. As a result, Pin1(-/-) cells are defective in JNK activation and resistant to oxidative stress. These results provide novel insights that, following stress-induced phosphorylation of Thr in the Thr-Pro motif of JNK1, JNK1 associates with Pin1 and undergoes conformational changes to promote the binding of JNK1 to its substrates, resulting in cellular responses from extracellular signals. PMID- 21660051 TI - Intracellular zinc release-activated ERK-dependent GSK-3beta-p53 and Noxa-Mcl-1 signaling are both involved in cardiac ischemic-reperfusion injury. AB - Oxidative stress and nitrosative stress are both suggested to be involved in cardiac ischemia-reperfusion (I/R) injury. Using time-lapse confocal microscopy of cardiomyocytes and high-affinity O(2)(-*) and Zn(2+) probes, this study is the first to show that I/R, reactive oxygen species (ROS), and reactive nitrogen species (RNS) all cause a marked increase in the [O(2)(-*)](i), resulting in cytosolic and mitochondrial Zn(2+) release. Exposure to a cell-penetrating, high affinity Zn(2+)(i) chelator, TPEN, largely abolished the Zn(2+)(i) release and markedly protected myocytes from I/R-, ROS-, RNS-, or Zn(2+)/K(+) (Zn(2+)(i) supplementation)-induced myocyte apoptosis for at least 24 h after TPEN removal. Flavonoids and U0126 (a MEK1/2 inhibitor) largely inhibited the myocyte apoptosis and the TPEN-sensitive I/R- or Zn(2+)(i) supplement-induced persistent extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, dephosphorylation of p-Ser9 on glycogen synthase kinase 3beta (GSK-3beta), and the translocation into and accumulation of p-Tyr216 GSK-3beta and p53 in, the nucleus. Silencing of GSK-3beta or p53 expression was cardioprotective, indicating that activation of the ERK-GSK-3beta-p53 signaling pathway is involved in Zn(2+)-sensitive myocyte death. Moreover, the ERK-dependent Noxa-myeloid cell leukemia-1 (Mcl-1) pathway is also involved, as silencing of Noxa expression was cardioprotective and U0126 abolished both the increase in Noxa expression and in Mcl-1 degradation. Thus, acute upstream Zn(2+)(i) chelation at the start of reperfusion and the use of natural products, that is, flavonoids, may be beneficial in the treatment of cardiac I/R injury. PMID- 21660054 TI - Natural killer cells: NK cells get their VA-VAVoom. PMID- 21660052 TI - Epigenetics of haematopoietic cell development. AB - Cells of the immune system are generated through a developmental cascade that begins in haematopoietic stem cells. During this process, gene expression patterns are programmed in a series of stages that bring about the restriction of cell potential, ultimately leading to the formation of specialized innate immune cells and mature lymphocytes that express antigen receptors. These events involve the regulation of both gene expression and DNA recombination, mainly through the control of chromatin accessibility. In this Review, we describe the epigenetic changes that mediate this complex differentiation process and try to understand the logic of the programming mechanism. PMID- 21660055 TI - T cell activation: silent movies. PMID- 21660053 TI - Expanding TRAF function: TRAF3 as a tri-faced immune regulator. AB - Tumour necrosis factor receptor (TNFR)-associated factor (TRAF) proteins are essential components of signalling pathways activated by TNFR or Toll-like receptor (TLR) family members. Acting alone or in combination, the seven known TRAFs control many biological processes, including cytokine production and cell survival. The function of one TRAF in particular, TRAF3, remained elusive for many years. Recent work has revealed that TRAF3 is a highly versatile regulator that positively controls type I interferon production, but negatively regulates mitogen-activated protein kinase activation and alternative nuclear factor-kappaB signalling. In this Review, we discuss our current understanding of the role of TRAF3 in TNFR and TLR signalling pathways, and its role in disease. PMID- 21660056 TI - The roads and bridges of science. Research infrastructures are key components of Europe's future research, but their funding is not guaranteed. PMID- 21660057 TI - Research infrastructures for Europe's scientists. PMID- 21660059 TI - Crystal structure of the N-terminal region of human Ash2L shows a winged-helix motif involved in DNA binding. AB - Ash2L is a core component of the MLL family histone methyltransferases and has an important role in regulating the methylation of histone H3 on lysine 4. Here, we report the crystal structure of the N-terminal domain of Ash2L and reveal a new function of Ash2L. The structure shows that Ash2L contains an atypical PHD finger that does not have histone tail-binding activity. Unexpectedly, the structure shows a previously unrecognized winged-helix motif that directly binds to DNA. The DNA-binding-deficient mutants of Ash2L reduced Ash2L localization to the HOX locus. Strikingly, a single mutation in Ash2L(WH) (K131A) breaks the chromatin domain boundary, suggesting that Ash2L also has a role in chromosome demarcation. PMID- 21660058 TI - Regulation of mammalian DNA methyltransferases: a route to new mechanisms. AB - DNA methyltransferases (DNMTs) establish and maintain DNA methylation patterns at specific regions of the genome, thereby contributing to gene regulation. It is becoming evident that an intricate web of pathways target DNMTs to these genomic regions. Here, we review the understanding of these regulatory mechanisms and provide an overview of the new findings, emphasizing the emerging scenario in which several levels of regulation are coordinated to control DNMTs. The mechanisms involved include the dynamic interplay between interdependent post translational modifications that regulate DNMTs, post-transcriptional regulation by miRNAs and the emerging role of non-coding RNA in targeting mammalian DNMTs. The analysis of these mechanisms is imperative to the understanding of the role of DNA methylation in regulating gene expression during development and in disease. PMID- 21660060 TI - Enhanced tumor suppression by an ING4/IL-24 bicistronic adenovirus-mediated gene cotransfer in human non-small cell lung cancer cells. AB - ING4 as a member of inhibitor of growth (ING) tumor suppressor family has potent inhibitory effects on a variety of tumors. Interleukin-24 (IL-24), a cytokine tumor suppressor, also shows broad-spectrum and tumor-specific antitumor activities. In this report, we constructed an ING4/IL-24 bicistronic adenovirus (Ad-ING4-IL-24) and assessed its combined effect on in vitro and in vivo A549 human non-small cell lung cancer cells. We demonstrated that ING4 and IL-24 combination treatment by adenovirus-mediated ING4 and IL-24 coexpression induced additive growth suppression and apoptosis as well as an overlapping effect on upregulation of P21, P27, Fas, Bax and cleaved Caspases-8, 9, 3 and downregulation of Bcl-2 in in vitro A549 lung carcinoma cells. Moreover, Ad-ING4 IL-24 treatment additively inhibited in vivo A549 lung carcinoma subcutaneous (s.c.) xenografted tumor growth and reduced CD34 and microvessel density in A549 xenografted tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-ING4-IL-24 was closely associated with the coordinate activation of extrinsic and intrinsic apoptotic pathways and additive inhibition of tumor angiogenesis. Thus, our results indicate that cancer gene therapy combining two or more tumor suppressors such as ING4 and IL-24 may constitute a novel and effective therapeutic strategy for lung carcinoma and other cancers. PMID- 21660061 TI - Competitive electroporation formulation for cell therapy. AB - Established cell transfection via nucleofection relies on nucleofection buffers with unknown and proprietary makeup due to trade secrecy, inhibiting the possibility of using this otherwise effective method for developing cell therapy. We devised a three-step method for discovering an optimal formulation for the nucleofection of any cell line. These steps include the selection of the best nucleofection program and known buffer type, selection of the best polymer for boosting the transfection efficiency of the best buffer and the comparison with the optimal buffer from an established commercial vendor (Amaxa). Using this three-step selection system, competitive nucleofection formulations were discovered for multiple cell lines, which are equal to or surpass the efficiency of the Amaxa nucleofector solution in a variety of cells and cell lines, including primary adipose stem cells, muscle cells, tumor cells and immune cells. Through the use of scanning electron microscopy, we have revealed morphological changes, which predispose for the ability of these buffers to assist in transferring plasmid DNA into the nuclear space. Our formulation may greatly reduce the cost of electroporation study in laboratory and boosts the potential of application of electroporation-based cell therapies in clinical trials. PMID- 21660062 TI - Replication-competent retrovirus vector-mediated prodrug activator gene therapy in experimental models of human malignant mesothelioma. AB - Replication-competent retrovirus (RCR) vectors have been shown to achieve significantly enhanced tumor transduction efficiency and therapeutic efficacy in various cancer models. In the present study, we investigated RCR vector-mediated prodrug activator gene therapy for the treatment of malignant mesothelioma, a highly aggressive tumor with poor prognosis. RCR-GFP vector expressing the green fluorescent protein marker gene successfully infected and efficiently replicated in human malignant mesothelioma cell lines, as compared with non-malignant mesothelial cells in vitro. In mice with pre-established subcutaneous tumor xenografts, RCR-GFP vector showed robust spread throughout entire tumor masses after intratumoral administration. Next, RCR-cytosine deaminase (RCR-CD), expressing the yeast CD prodrug activator gene, showed efficient transmission of the prodrug activator gene associated with replicative spread of the virus, resulting in efficient killing of malignant mesothelioma cells in a prodrug 5 fluorocytosine (5FC)-dose dependent manner in vitro. After a single intratumoral injection of RCR-CD followed by intraperitoneal administration of 5FC, RCR vector mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous tumor growth, and significantly prolonged survival in the disseminated peritoneal model of malignant mesothelioma. These data indicate the potential utility of RCR vector-mediated prodrug activator gene therapy in the treatment of malignant mesothelioma. PMID- 21660063 TI - DNA triplex-mediated inhibition of MET leads to cell death and tumor regression in hepatoma. AB - Mesenchymal epithelial transition factor (MET) is one of the critical cell signaling molecules whose aberrant expression is reported in several human cancers. The aim of the study is to investigate the antigene and antiproliferative effect of short triplex forming oligonucleotides, TFO-1 (part of the positive regulatory element) and TFO-2 (away from the transcription start site) on MET expression. HepG2 cells transfected only with TFO-1 (but not with TFO-2 and non-specific TFO) significantly decreased MET levels, which is accompanied by decrease in antiapoptotic proteins and increase in pro-apoptotic proteins. Phosphoproteome-array analysis of 46 intracellular kinases revealed hypophosphorylation of about 15 kinases including ERK, AKT, Src and MEK, suggesting the growth inhibitory effect of TFO-1. Further, the efficacy of TFO-1 was tested on diethylnitrosamine-induced liver tumors in wistar rats. T2-weighted magnetic resonance imaging showed decrease in liver tumor volume up to 90% after treatment with TFO-1. Decreased MET expression and elevated apoptotic activity further indicate that TFO-1 targeted to c-met leads to cell death and tumor regression in hepatoma. Formation of stable DNA triplex between TFO-1 and targeted gene sequence was confirmed by circular dichroic spectroscopy and gel retardation assay. Therefore, it can be concluded that DNA triplex-based therapeutic approaches hold promise in the treatment of malignancies associated with MET overexpression. PMID- 21660064 TI - Enhanced specificity of HPV16 E6E7 siRNA by RNA-DNA chimera modification. AB - Although efforts have been made to develop new drugs for infectious and neoplastic diseases utilizing synthetic small interfering RNA(siRNAs), those intrinsically have undesirable effects, including silencing of unintended genes (off-target effect) and nonspecific cytotoxicity. Off-target effects can be avoided by DNA substitution in the guide strand (GS) seed region of nucleotide positions 1-8 and its complementary part of the passenger strand plus the 3' overhang, which is designated as a double-strand RNA-DNA chimera (dsRDC). In this study, we found that the specificity of potent siRNAs targeting human papillomavirus 16 (HPV16) E6 and E7 oncogenes, which we previously reported, could be enhanced by short dsRDC modification (first six nucleotides from the 5' end of the GS and its complementary nucleotides of the passenger strand). Such dsRDC modification reduced nonspecific cytotoxicity in two of three siRNAs (497 and 752), although not in the other (573), which correlated with their off-target effects. In addition, silencing activity was marginally impaired in two dsRDCs (497 and 573) and moderately in one (752). Finally, dsRDC-497 induced E6E7 specific growth suppression of cervical cancer cells as well as E6E7-immortalized human keratinocytes. Our results show that dsRDC modification enhances the specificity of E6E7 siRNA, which is required for use in in vivo settings. PMID- 21660065 TI - Macular findings on optical coherence tomography in cat-scratch disease neuroretinitis. AB - PURPOSE: To describe the macular findings on optical coherence tomography (OCT) in patients with cat-scratch disease (CSD) neuroretinitis. METHODS: Medical records of all patients diagnosed with CSD neuroretinitis at the Tel Aviv Medical Center between April 2006 and May 2010 were retrospectively reviewed. All patients underwent Stratus OCT macular examination. RESULTS: Eight eyes of seven patients with confirmed CSD neuroretinitis, (mean age 33 +/- 9.9 years, range 6 48 years) were included in the study. All patients presented clinically with optic nerve swelling and macular edema or macular exudates. OCT demonstrated flattening of the foveal contour, thickening of the neurosensory retina, and accumulation of subretinal fluid (SRF) in all studied eyes. Retinal exudates appeared as multiple hyper-reflective foci in the outer plexiform layer. The average central macular thickness was 460 MUm (range 170-906 MUm) and the average maximal retinal thickness was 613 MUm (range 387-1103 MUm), at presentation. The macula appeared normal on repeated exams during follow-up. CONCLUSION: Similar OCT findings were demonstrated in patients with CSD neuroretinitis. SRF was found in all eyes, although was not visible on clinical examination or fluorescein angiography. OCT may be used as an adjunct imaging tool in the diagnosis and follow-up of patients with CSD neuroretinitis. PMID- 21660066 TI - Psychophysical impact and optical and morphological characteristics of symptomatic non-advanced cataract. AB - PURPOSE: To investigate whether psychophysical, morphological, and/or optical characteristics of symptomatic non-advanced cataract are complementary to, or more appropriate than, visual acuity (VA) for the purposes of recording visual data that reflect subjective visual difficulty in patients with cataract that exhibit relative sparing of high contrast acuity (0.4 logarithm of minimal angle of resolution (logMAR) scale or better). METHODS: Eighty-two patients with symptomatic non-advanced cataract and no other ocular pathology were asked to complete a validated questionnaire, and to perform a series of visual function assessments including: corrected distance VA (CDVA); photopic and mesopic contrast sensitivity; photopic and mesopic glare disability (GD); reading acuity and reading speed; stereoacuity; and retinal sensitivity. Optical and morphological characteristics of the cataract were evaluated by lens optical density and by the Lens Opacities Classification System III, respectively. Correlations between questionnaire score and each of these measures were calculated. RESULTS: Statistically significant negative correlations were observed between the Rasch-scaled questionnaire score and mesopic GD (at 3 and 6 cycles per degree (cpd); r=-0.396 (P<0.01) and -0.451 (P<0.05), respectively) and between the Rasch-scaled questionnaire score and photopic GD (at 3 and 6 cpd; r= 0.328 (P<0.01) and -0.440 (P<0.01), respectively). CONCLUSION: Symptomatic non advanced cataract, in the presence of good CDVA, is associated with measurable subjective visual difficulty, best reflected in a decrease in mesopic and photopic GD (at medium spatial frequencies). CDVA does not reflect the patient's visual dissatisfaction in such cases. PMID- 21660067 TI - In vivo confocal microscopy of the corneal endothelium: comparison of three morphometry methods after corneal transplantation. AB - PURPOSE: The purpose of this study was to assess the endothelium of corneal grafts by in vivo confocal microscopy (IVCM), and to evaluate an automated endothelial software system in comparison with a manual cell count and planimetry. PATIENTS AND METHODS: Overall, 40 corneal grafts (20 deep anterior lamellar keratoplasties (DALKs) and 20 penetrating keratoplasties (PKs)) were assessed by scanning-slit IVCM. The endothelial cell density (ECD) was estimated with the automated and the manual cell count method of the instrument's Nidek Advanced Vision Information System (NAVIS) software. The results were compared with planimetry as the reference method, and the agreement was assessed. RESULTS: The mean (+/-SD) automated ECD was 2278+/-524 cells/mm(2) (range 1167-3192 cells/mm(2)), whereas the manual cell count method gave significantly lower ECDs with a mean of 1213+/-677 cells/mm(2) (range 218-2440 cells/mm(2); P<0.001). The manual cell counts were also significantly lower than those by planimetry, with a mean ECD of 1617+/-813 cells/mm(2) (range 336-2941, P<0.001). Bland-Altman analyses indicated that the limits of agreement (LoA) between the automated and the planimetry method were -671 and +1992 cells/mm(2), whereas they were -1000 and +202 cells/mm(2) when comparing the manual cell counts with planimetry. CONCLUSION: Following keratoplasty, the NAVIS automated method is likely to overestimate endothelial cell counts due to oversegmenting of the cell domains. Automated ECDs are substantially higher than those by the manual counting method or planimetry. The differences are considerably larger post-keratoplasty than for normal corneas, and the methods should not be used interchangeably. PMID- 21660068 TI - Prostate cancer: molecular insights into bone metastasis. PMID- 21660070 TI - Infection: Lactobacillus probiotic could prevent recurrent UTI. PMID- 21660072 TI - Surgery: managing urethral strictures after hypospadias repair. PMID- 21660073 TI - Imaging: transperineal ultrasound for post-prostatectomy incontinence. PMID- 21660074 TI - Prostate cancer: biopsy samples from noncancerous stromal tissue can be used to diagnose nearby cancer. PMID- 21660075 TI - Metabolic syndrome and incident coronary heart disease in Australian indigenous populations. AB - This report aims to compare the prediction of the metabolic syndrome (MetS) and its components for morbidity and mortality of coronary heart disease (CHD) in a cohort of Australian Aboriginal and Torres Strait Islander adults (TSIs). A total of 2,100 adults (1,283 Aborigines and 817 TSIs) was followed up for 6 years from 2000. Outcome measures were all CHD events (deaths and hospitalizations). Baseline anthropometric measurements, blood pressure (BP), fasting blood lipids and glucose were collected. Smoking and alcohol intake was self-reported. We found MetS was more prevalent in TSI (50.3%) compared to Aborigines (33.0%). Baseline MetS doubled the risk of a CHD event in Aborigines. Increased fasting triglycerides was stronger in predicting CHD (hazard ratio (HR): 2.8) compared with MetS after adjusted for age, sex, tobacco and alcohol consumption, and baseline diabetes and albuminuria for Aborigines but not among TSIs. MetS was not more powerful than its components in predicting CHD event. In Australian Aborigines, the "triglyceridemic waist" phenotype strongly predicts CHD event, whereas among TSI, baseline diabetes mediated the prediction of increased fasting glucose for CHD event. PMID- 21660077 TI - Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. AB - We examined the effects of combined pioglitazone (peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist) and exenatide (GLP-1 receptor agonist) therapy on hepatic fat content and plasma adiponectin levels in patients with type 2 diabetes (T2DM). Twenty-one T2DM patients (age = 52 +/- 3 years, BMI = 32.0 +/- 1.5, hemoglobin A(1c) (HbA(1c)) = 8.2 +/- 0.4%) on diet and/or metformin received additional treatment with either pioglitazone 45 mg/day for 12 months (n = 10) or combined therapy with pioglitazone (45 mg/day) and exenatide (10 ug subcutaneously twice daily) for 12 months (n = 11). At baseline, hepatic fat content and plasma adiponectin levels were similar between the two treatment groups. Pioglitazone reduced fasting plasma glucose (FPG) (P < 0.05), fasting free fatty acid (FFA) (P < 0.05), and HbA(1c) (Delta = 1.0%, P < 0.01), while increasing plasma adiponectin concentration by 86% (P < 0.05). Hepatic fat (magnetic resonance spectroscopy (MRS)) was significantly reduced following pioglitazone treatment (11.0 +/- 3.1 to 6.5 +/- 1.9%, P < 0.05). Plasma triglyceride concentration decreased by 14% (P < 0.05) and body weight increased significantly (Delta = 3.7 kg). Combined pioglitazone and exenatide therapy was associated with a significantly greater increase in plasma adiponectin (Delta = 193%) and a significantly greater decrease in hepatic fat (12.1 +/- 1.7 to 4.7 +/ 1.3%) and plasma triglyceride (38%) vs. pioglitazone therapy despite the lack of a significant change in body weight (Delta = 0.2 kg). Hepatic injury biomarkers aspartate aminotransferase and alanine aminotransferase (ALT) were significantly decreased by both treatments; however, the reduction in ALT was significantly greater following combined pioglitazone and exenatide therapy. We conclude that combined in patients with T2DM, pioglitazone and exenatide therapy is associated with a greater reduction in hepatic fat content as compared to the addition of pioglitazone therapy (Delta = 61% vs. 41%, P < 0.05). PMID- 21660078 TI - The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat. AB - Individual compartments of abdominal adiposity and lipid content within the liver and muscle are differentially associated with metabolic risk factors, obesity and insulin resistance. Subjects with greater intra-abdominal adipose tissue (IAAT) and hepatic fat than predicted by clinical indices of obesity may be at increased risk of metabolic diseases despite their "normal" size. There is a need for accurate quantification of these potentially hazardous depots and identification of novel subphenotypes that recognize individuals at potentially increased metabolic risk. We aimed to calculate a reference range for total and regional adipose tissue (AT) as well as ectopic fat in liver and muscle in healthy subjects. We studied the relationship between age, body-mass, BMI, waist circumference (WC), and the distribution of AT, using whole-body magnetic resonance imaging (MRI), in 477 white volunteers (243 male, 234 female). Furthermore, we used proton magnetic resonance spectroscopy (MRS) to determine intrahepatocellular (IHCL) and intramyocellular (IMCL) lipid content. The anthropometric variable which provided the strongest individual correlation for adiposity and ectopic fat stores was WC in men and BMI in women. In addition, we reveal a large variation in IAAT, abdominal subcutaneous AT (ASAT), and IHCL depots not fully predicted by clinically obtained measurements of obesity and the emergence of a previously unidentified subphenotype. Here, we demonstrate gender- and age-specific patterns of regional adiposity in a large UK-based cohort and identify anthropometric variables that best predict individual adiposity and ectopic fat stores. From these data we propose the thin-on-the-outside fat-on-the inside (TOFI) as a subphenotype for individuals at increased metabolic risk. PMID- 21660076 TI - The Women's Health Initiative: The food environment, neighborhood socioeconomic status, BMI, and blood pressure. AB - Using data (n = 60,775 women) from the Women's Health Initiative Clinical Trial (WHI CT)-a national study of postmenopausal women aged 50-79 years-we analyzed cross-sectional associations between the availability of different types of food outlets in the 1.5 miles surrounding a woman's residence, census tract neighborhood socioeconomic status (NSES), BMI, and blood pressure (BP). We simultaneously modeled NSES and food outlets using linear and logistic regression models, adjusting for multiple sociodemographic factors, population density and random effects at the tract and metropolitan statistical area (MSA) level. We found significant associations between NSES, availability of food outlets and individual-level measurements of BMI and BP. As grocery store/supermarket availability increased from the 10th to the 90th percentile of its distribution, controlling for confounders, BMI was lower by 0.30 kg/m(2). Conversely, as fast food outlet availability increased from the 10th to the 90th percentile, BMI was higher by 0.28 kg/m(2). When NSES increased from the 10th to the 90th percentile of its distribution, BMI was lower by 1.26 kg/m(2). As NSES increased from the 10th to the 90th percentile, systolic and diastolic BP were lower by 1.11 mm Hg and 0.40 mm Hg, respectively. As grocery store/supermarket outlet availability increased from the 10th and 90th percentiles, diastolic BP was lower by 0.31 mm Hg. In this national sample of postmenopausal women, we found important independent associations between the food and socioeconomic environments and BMI and BP. These findings suggest that changes in the neighborhood environment may contribute to efforts to control obesity and hypertension. PMID- 21660079 TI - Colon electrical stimulation: potential use for treatment of obesity. AB - Obesity is one of the most prevalent health problems in the United States. Current therapeutic strategies for the treatment of obesity are unsatisfactory. We hypothesized the use of colon electrical stimulation (CES) to treat obesity by inhibiting upper gastrointestinal motility. In this preliminary study, we aimed at studying the effects of CES on gastric emptying of solid, intestinal motility, and food intake in dogs. Six dogs, equipped with serosal colon electrodes and a jejunal cannula, were randomly assigned to receive sham-CES or CES during the assessment of: (i) gastric emptying of solids, (ii) postprandial intestinal motility, (iii) autonomic functions, and (iv) food intake. We found that (i) CES delayed gastric emptying of solids by 77%. Guanethidine partially blocked the inhibitory effect of CES on solid gastric emptying; (ii) CES significantly reduced intestinal contractility and the effect lasted throughout the recovery period; (iii) CES decreased vagal activity in both fasting and fed states, increased the sympathovagal balance and marginally increased sympathetic activity in the fasting state; (iv) CES resulted in a reduction of 61% in food intake. CES reduces food intake in healthy dogs and the anorexigenic effect may be attributed to its inhibitory effects on gastric emptying and intestinal motility, mediated via the autonomic mechanisms. Further studies are warranted to investigate the therapeutic potential of CES for obesity. PMID- 21660080 TI - Identification of overweight in children in the United States: a simplified approach. AB - The objective of this study was to develop a screening instrument for easy identification of overweight in children and adolescents in the United States. Data derived from the 2000 Growth Charts published by the Centers for Disease Control and Prevention (CDC) were utilized to compute gender-specific screening values for identification of overweight in children and adolescents. Computations were based on age- and gender-specific 85th percentile BMI calculated for the various height percentiles at 6-month age intervals. The simplified approach for identification of overweight in children and adolescents consisted of two tables, one each for males and females. Each table described the screening values for overweight at 6-month age intervals for all the nine height percentiles described in the CDC Stature for Age Tables. Two screening tables for identification of obesity were also developed in a similar manner using age- and gender-specific 95th percentile BMI. The simplified approach described for identification of overweight uses only the child's height and weight measurements and obviates the need to compute BMI or assess BMI percentile scores. PMID- 21660081 TI - Genetic polymorphisms in adipokine genes and the risk of obesity: a systematic review and meta-analysis. AB - Polymorphisms in adipokine genes, such as leptin (LEP), leptin receptor (LEPR), resistin (RETN), adiponectin (ADIPOQ), interleukin-1beta (IL-1beta), IL-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) may be involved in the development of obesity. We conducted a systematic review of published evidence on the association between different adipokine genes and the risk of obesity. Librarian designed searches of PubMed and HuGeNet, review of reference lists from published reviews and content expert advice identified potentially eligible studies. The genotyping information and polymorphisms of different adipokine genes, numbers of genotyped cases and controls and frequencies of genotypes were extracted from 48 eligible studies included in this review. Twenty-one polymorphisms each associated with obesity in at least one study were identified. Polymorphisms in the adipokine genes, LEP, LEPR, and RETN were not associated with obesity susceptibility, whereas ADIPOQ G276T (T vs. G: odds ratio (OR), 1.59; 95% confidence interval (CI), 1.39-1.81), IL-1beta C3953T (CC vs. CT+TT: OR, 1.61; 95% CI, 1.18-2.20), and TNF-alpha G308A (GG vs. GA+AA: OR, 1.19; 95% CI, 1.02 1.39) polymorphisms were associated with an increased risk of obesity. The IL-6 G174C polymorphism was also associated obesity when using allelic comparisons, the recessive genetic model and the dominant genetic model with OR (95% CI) of 1.95 (1.37-2.77), 1.44 (1.15-1.80), and 1.36 (1.16-1.59), respectively. No significant evidence of publication bias was present. However, these "null" results were underpowered due to a small pooled sample size, and analysis of additional case-control studies with larger sample sizes should provide further clarifications. PMID- 21660082 TI - MRI measured epicardial adipose tissue thickness at the right AV groove differentiates inflammatory status in obese men with metabolic syndrome. AB - Epicardial adipose tissue (EAT) is a metabolically active visceral fat, which secretes inflammatory cytokines and adipokines. In this study, our aim was to examine which measurements of EAT thickness by magnetic resonance imaging (MRI) could best help differentiate inflammatory status, classified by levels of high sensitivity C-reactive protein (hs-CRP), in obese men with metabolic syndrome (MetS). We prospectively enrolled 32 men with central obesity (waist circumference >=90 cm) and at least two other MetS criteria. MRI examinations for measurements of EAT, subcutaneous fat, and abdominal visceral fat as well as recordings of anthropometric parameters and tests for serum inflammatory cytokines and adipokines were conducted. Subjects with MetS (N = 32) were divided into three subgroups: (i) low inflammatory status (hs-CRP < 0.1 mg/dl, N = 8), [corrected] (ii) intermediate inflammatory status (hs-CRP 0.1-0.3 mg/dl, N = 15), and (iii) high inflammatory status (hs-CRP >0.3 mg/dl, N = 9). EAT thickness at the right atrioventricular (AV) groove showed a significant linear trend among the three subgroups of MetS (P for trend = 0.004). High inflammatory status MetS subgroup had a significantly thicker right AV groove EAT than did the low inflammatory status MetS subgroup (19.3 +/- 3.1 vs. 14.4 +/- 3.3 mm, P = 0.015). In binary logistic regression analysis, right AV groove EAT thickness was an independent predictor for differentiating inflammatory status in MetS while abdominal visceral fat area and insulin-resistance index were not. In conclusion, MRI measured EAT thickness at the right AV groove could be a useful marker for differentiating the inflammatory status in obese men with MetS. PMID- 21660083 TI - Evolution of obesity in a low birth weight cohort. AB - OBJECTIVE: The objective of this study was to determine the evolution of obesity status (OS) in a longitudinal cohort of low birth weight preterm (LBWPT) infants to an age of 8 years, and to determine whether rapid weight gain in the first year of life independently predicts 8-year OS. STUDY DESIGN: In total, 985 infants (birth weight <=2500 g, gestation age <=37 weeks) were recruited from the nursery in an eight-site intervention research program and were evaluated at an age of 3, 5, 6.5 and 8 years. Weight and height were measured by standard protocol at each visit and body mass index was calculated. Obesity status is >=95% for age and sex. Multiple logistic analyses were performed on 8-year OS with predictor variables including infant race, gender, small for gestational age status, birth weight category, neonatal health index, treatment group and first year weight gain; maternal education and weight status before conception; and HOME Inventory. RESULT: Overall, 2.3% were OS at an age of 3 years, 6.1% at an age of 5 years, 7.7% at age 6.5 years and 8.7% at an age 8 years. OS varied by birth weight category at each visit. The infants born <=1500 g had the lowest prevalence of OS at each age. In the logistic regression, maternal race (Hispanic) (adjusted odds ratio=2.8, confidence interval=1.2 to 6.8), maternal obese status (adjusted odds ratio 3.4, confidence interval=1.5 to 7.8) and first year weight gain (adjusted odds ratio=2.7, confidence interval=1.9 to 3.9), significantly predicted 8-year OS. CONCLUSION: OS is common in LBWPT infants during childhood, and prevalence varies by birth weight category. High weight gain in the first year of life is an important predictor of the development of OS in LBWPT children. PMID- 21660084 TI - The contribution of heart disease to pregnancy-related mortality according to the pregnancy mortality surveillance system. AB - OBJECTIVE: The objective of this study was to demonstrate the increasing importance of heart disease as a cause of pregnancy-related mortality in Hawaii and the rest of the United States. STUDY DESIGN: Hawaii's Department of Public Health identified all pregnancy-associated death certificates from 1991 to 2007. Hospital records and autopsy reports were reviewed to determine whether deaths were pregnancy-related. RESULT: From 1991 to 2007, Hawaii registered 156 deaths occurring within 1 year of pregnancy, which represented 4.2% of the total number of women who died in the same 17 to 46 years age group and 9.0% of the total number of women who died in the same 17 to 34 years age group. The pregnancy related mortality ratio was 22.4 and the pregnancy-associated mortality ratio was 50. The leading cause of pregnancy-associated mortality was heart disease (20.5%) followed by cancer (18.6%) and suicide/homicide (12.2%). Pregnancy-related deaths (n=70) were attributed to heart disease (45.7%) followed by sepsis (14.2%) and hemorrhage (12.9%). The new Hawaii death certificate beginning in 2006 increased the detection of both pregnancy-related and -associated deaths. CONCLUSION: Heart disease is the most common cause of pregnancy-related mortality in Hawaii, and with improved ascertainment, may be determined to be the most common cause of pregnancy-related mortality in the rest of the United States. PMID- 21660085 TI - The Effect of a Brief Mindfulness Intervention on Memory for Positively and Negatively Valenced Stimuli. AB - A core component of mindfulness is non-judgmental observation of internal and external stimuli. The present study investigated the effect of mindfulness on memory for emotional stimuli. Participants were exposed to a brief mindfulness intervention and subsequently performed a verbal learning test consisting of positive, neutral, and negative words. Control participants received no intervention and directly performed the verbal learning test. After 20 min, participants recalled as many words as possible. Participants in the mindfulness condition remembered a significantly lower proportion of negative words compared to control participants. No differences between both groups were observed for the proportion of remembered positive words. These findings suggest that memory processes may be a potential mechanism underlying the link between mindfulness and subjective well-being. PMID- 21660086 TI - Development of an SPR imaging biosensor for determination of cathepsin G in saliva and white blood cells. AB - Cathepsin G (CatG) is an endopeptidase that is associated with the early immune response. The synthetic compound cathepsin G inhibitor I (CGI-I) was tested for its ability to inhibit the activity of CatG via a new surface plasmon resonance imaging assay. CGI-I was immobilized on the gold surface of an SPR sensor that was first modified with 1-octadecanethiol. A concentration of CGI-I equal to 4.0 MUg.mL-1 and a pH of 8.0 were found to give the best results. The dynamic response of the sensor ranges from 0.25 to 1.5 ng.mL-1, and the detection limit is 0.12 ng.mL-1. The sensor was applied to detect CatG in human saliva and white blood cells.FigureThe synthetic compound cathepsin G inhibitor I (CGI-I) was tested for its ability to inhibit the activity of cathepsin G via a newly developed surface plasmon resonance imaging assay. The sensor was applied to detect cathepsin G in human saliva and white blood cells. PMID- 21660087 TI - Aleurites moluccana (L.) Willd. Leaves: Mechanical Antinociceptive Properties of a Standardized Dried Extract and Its Chemical Markers. AB - Seeking to develop a new analgesic phytomedicine, a spray-dried extract (SDE) of Aleurites moluccana (L.) Willd. leaves was developed in scale up (5 kg). The SDE was standardized at 3% w/w in relation to the flavonoid 2''-O-rhamnosylswertisin. The SDE batches were evaluated in relation to their physical, physiochemical, and pharmacological characteristics. The results demonstrated the reproducibility of the scale up SDE process which, when dosed orally, reduced carrageenan-induced mechanical hypernociception, with an ID(50)% of 443 mg/kg. Similar results were obtained with animals injected with complete Freund's adjuvant (CFA), in which SDE caused inhibition of 48 +/- 4%. SDE was effective in preventing prostaglandin E2 (PGE2)-induced mechanical hypernociception (inhibition of 26 +/- 10% and 33 +/ 3%, at 250 and 500 mg/kg, respectively). Swertisin and 2''-O-rhamnosylswertisin isolated from the own extract were effective in inhibiting the hypernociceptive response induced by carrageenan (70 +/- 2% and 50 +/- 5%, resp.). Furthermore, 2''-O-rhamnosylswertisin was capable of significantly inhibiting the mechanical sensitization induced by CFA or PGE2, with inhibitions of 25 +/- 3% and 94 +/- 6%, respectively. These results suggest that the effects of SDE are related, at least in part, to the presence of these flavonoids. PMID- 21660088 TI - Technology Innovation Enabling Falls Risk Assessment in a Community Setting. AB - Approximately one in three people over the age of 65 will fall each year, resulting in significant financial, physical, and emotional cost on the individual, their family, and society. Currently, falls are managed using on-body sensors and alarm pendants to notify others when a falls event occurs. However these technologies do not prevent a fall from occurring. There is now a growing focus on falls risk assessment and preventative interventions. Falls risk is currently assessed in a clinical setting by expert physiotherapists, geriatricians, or occupational therapists following the occurrence of an injurious fall. As the population ages, this reactive model of care will become increasingly unsatisfactory, and a proactive community-based prevention strategy will be required. Recent advances in technology can support this new model of care by enabling community-based practitioners to perform tests that previously required expensive technology or expert interpretation. Gait and balance impairment is one of the most common risk factors for falls. This paper reviews the current technical and non-technical gait and balance assessments, discusses how low-cost technology can be applied to objectively administer and interpret these tests in the community, and reports on recent research where body-worn sensors have been utilized. It also discusses the barriers to adoption in the community and proposes ethnographic research as a method to investigate solutions to these barriers. PMID- 21660089 TI - Happiness as alchemy: Positive mood leads to self-serving responses to social comparisons. AB - People in a positive mood process information in ways that reinforce and maintain this positive mood. The current studies examine how positive mood influences responses to social comparisons and demonstrates that people in a positive mood interpret ambiguous information about comparison others in self-benefitting ways. Specifically, four experiments demonstrate that compared to negative mood or neutral mood participants, participants in a positive mood engage in effortful re interpretations of ambiguously similar comparison targets so that they may assimilate to upward comparison targets and contrast from downward comparison targets. PMID- 21660090 TI - Sexuality of Young Adults with Cerebral Palsy: Experienced Limitations and Needs. AB - Objective of this study is to describe the problems young adults with Cerebral Palsy (CP) experience in the various stages of the sexual response cycle, and the physical and emotional obstacles they experience with sexuality. In this prospective cohort study 74 young adults (46 men; 28 women) with CP and average intelligence participated, aged 20-24 years. Twenty percent of these young adults with CP experienced anorgasmia, 80% reported physical problems with sex related to CP and 45% emotional inhibition to initiate sexual contact. In 90% of the participants, sexuality had not been discussed during the rehabilitation treatment. Many adolescents reported wanting information about the impact of CP on sexuality and reproduction (35%), about interventions (26%), tools and medicines (16%) and about problems with their partner (14%). Young adults with CP can experience various problems or challenges with sexuality. For preventing sexual difficulties and treating sexual problems, health care professionals need to proactively take the initiative to inform young people with CP about sexuality. PMID- 21660091 TI - The impact of group drumming on social-emotional behavior in low-income children. AB - Low-income youth experience social-emotional problems linked to chronic stress that are exacerbated by lack of access to care. Drumming is a non-verbal, universal activity that builds upon a collectivistic aspect of diverse cultures and does not bear the stigma of therapy. A pretest-post-test non-equivalent control group design was used to assess the effects of 12 weeks of school counselor-led drumming on social-emotional behavior in two fifth-grade intervention classrooms versus two standard education control classrooms. The weekly intervention integrated rhythmic and group counseling activities to build skills, such as emotion management, focus and listening. The Teacher's Report Form was used to assess each of 101 participants (n = 54 experimental, n = 47 control, 90% Latino, 53.5% female, mean age 10.5 years, range 10-12 years). There was 100% retention. ANOVA testing showed that intervention classrooms improved significantly compared to the control group in broad-band scales (total problems (P < .01), internalizing problems (P < .02)), narrow-band syndrome scales (withdrawn/depression (P < .02), attention problems (P < .01), inattention subscale (P < .001)), Diagnostic and Statistical Manual of Mental Disorders oriented scales (anxiety problems (P < .01), attention deficit/hyperactivity problems (P < .01), inattention subscale (P < .001), oppositional defiant problems (P < .03)), and other scales (post-traumatic stress problems (P < .01), sluggish cognitive tempo (P < .001)). Participation in group drumming led to significant improvements in multiple domains of social-emotional behavior. This sustainable intervention can foster positive youth development and increase student-counselor interaction. These findings underscore the potential value of the arts as a therapeutic tool. PMID- 21660092 TI - A Hypothesis: Supplementation with Mushroom-Derived Active Compound Modulates Immunity and Increases Survival in Response to Influenza Virus (H1N1) Infection. AB - We hypothesize that the mushroom-derived active compound may be a potential strategy for increasing survival in response to influenza virus (H1N1) infection through the stimulation of host innate immune response. The validity of the hypothesis can be tested by immune response to influenza infection as seen through survival percentage, virus clearance, weight loss, natural killer cell cytotoxicity, Tumor Necrosis Factor-alpha (TNF-alpha) and Interferon-gamma (IFN gamma) levels, lytic efficiency in the spleens of mice and inducible nitric oxide synthase mRNA expressions in RAW 264.7 murine macrophage cells. The hypothesis may improve people's quality of life, reduce the medical cost of our healthcare system and eliminate people's fears of influenza outbreak. PMID- 21660094 TI - Thoracopagus conjoined twins: a case report. AB - Objective. Conjoined twin is a rarely seen congenital anomaly together with severe mortality and morbidity. The more common types of conjoined twins include the thoracopagus type, where the fusion is anterior, at the chest, and involves the heart. We are reporting one case of conjoined thoracopagus twins diagnosed by ultrasonography at 11 weeks. Case Report. In a multigravid pregnant woman who has been admitted to our clinic with a diagnosis of conjoined twins, thoracopagus, by ultrasonography at an 11-week gestation, termination of the pregnancy was performed. Conclusion. Making an early diagnosis with ultrasonographic examination gives the parents a chance to elect pregnancy termination. PMID- 21660093 TI - The inhibition of lipase and glucosidase activities by acacia polyphenol. AB - Acacia polyphenol (AP) extracted from the bark of the black wattle tree (Acacia mearnsii) is rich in unique catechin-like flavan-3-ols, such as robinetinidol and fisetinidol. In an in vitro study, we measured the inhibitory activity of AP on lipase and glucosidase. In addition, we evaluated the effects of AP on absorption of orally administered olive oil, glucose, maltose, sucrose and starch solution in mice. We found that AP concentration-dependently inhibited the activity of lipase, maltase and sucrase with an IC(50) of 0.95, 0.22 and 0.60 mg ml(-1), respectively. In ICR mice, olive oil was administered orally immediately after oral administration of AP solution, and plasma triglyceride concentration was measured. We found that AP significantly inhibited the rise in plasma triglyceride concentration after olive oil loading. AP also significantly inhibited the rise in plasma glucose concentration after maltose and sucrose loading, and this effect was more potent against maltose. AP also inhibited the rise in plasma glucose concentration after glucose loading and slightly inhibited it after starch loading. Our results suggest that AP inhibits lipase and glucosidase activities, which leads to a reduction in the intestinal absorption of lipids and carbohydrates. PMID- 21660095 TI - In utero diagnosis of agenesis of the ductus arteriosus in a twin pregnancy: an unusual case presentation. AB - Agenesis of the ductus arteriosus is a rare congenital cardiac anomaly which should be considered within the differntial prenatal diagnosis of hydrops fetalis. PMID- 21660096 TI - The "lasso sign": an early sonographic sign of posterior meningocele. AB - Posterior meningocele is an uncommon form of spina bifida. We present a case of unique posterior meningocele diagnosed at the early second trimester anatomical scan using 2D and 3D ultrasound. The sonographic appearance resembled "lasso". The prenatal follow-up was uneventful, with no demonstration of tethered cord. Clinical, neurological and radiological examinations following delivery and at the age of four months were unremarkable. PMID- 21660097 TI - Different Effects of Mg and Zn on the Two Sites for Alkylammonium Compounds in Pseudomonas aeruginosa Phosphorylcholine Phosphatase. AB - Pseudomonas aeruginosa phosphorylcholine phosphatase (PchP) catalyzes the hydrolysis of phosphorylcholine (Pcho), is activated by Mg(2+) or Zn(2+), and is inhibited by high concentrations of substrate. This study has shown that PchP contains two sites for alkylammonium compounds (AACs): one in the catalytic site near the metal ion-phosphoester pocket, and the other in an inhibitory site responsible for the binding of the alkylammonium moiety. The catalytic mechanism for the entry of Pcho in both sites and Zn(2+) or Mg(2+) follows a random sequential mechanism. However, Zn(2+) is more effective than Mg(2+) at alleviating the inhibition produced by the entry of Pcho or different AACs in the inhibitory site. We postulate that Zn(2+) induces a conformational change in the active center that is communicated to the inhibitory site, producing a compact or closed structure. In contrast, Mg(2+) produces a relaxed or open conformation. PMID- 21660098 TI - Pharmacological and non-pharmacological recanalization strategies in acute ischemic stroke. AB - According to the guidelines of the European Stroke Organization (ESO) and the American Stroke Association (ASA), acute stroke patients should be managed at stroke units that include well organized pre- and in-hospital care. In ischemic stroke the restoration of blood flow has to occur within a limited time window that is accomplished by fibrinolytic therapy. Newer generation thrombolytic agents (alteplase, pro-urokinase, reteplase, tenecteplase, desmoteplase) have shorter half-life and are more fibrin-specific. Only alteplase has Food and Drug Administration (FDA) approval for the treatment of acute stroke (1996). The National Institute of Neurological Disorders and Stroke (NINDS) trial proved that alteplase was effective in all subtypes of ischemic strokes within the first 3 h. In the European cooperative acute stroke study III trial, intravenous (IV) alteplase therapy was found to be safe and effective (with some restrictions) if applied within the first 3-4.5 h. In middle cerebral artery (MCA) occlusion additional transcranial Doppler insonication may improve the breakdown of the blood clot. According to the ESO and ASA guidelines, intra-arterial (IA) thrombolysis is an option for recanalization within 6 h of MCA occlusion. Further trials on the IA therapy are needed, as previous studies have involved relatively small number of patients (compared to IV trials) and the optimal IA dose of alteplase has not been determined (20-30 mg is used most commonly in 2 h). Patients undergoing combined (IV + IA) thrombolysis had significantly better outcome than the placebo group or the IV therapy alone in the NINDS trial (Interventional Management of Stroke trials). If thrombolysis fails or it is contraindicated, mechanical devices [e.g., mechanical embolus removal in cerebral ischemia (MERCI)- approved in 2004] might be used to remove the occluding clot. Stenting can also be an option in case of acute internal carotid artery occlusion in the future. An intra-aortic balloon was used to increase the collateral blood flow in the Safety and Efficacy of NeuroFlo(TM) Technology in Ischemic Stroke trial (results are under evaluation). Currently, there is no approved effective neuroprotective drug. PMID- 21660099 TI - Shifting responsibly: the importance of striatal modularity to reinforcement learning in uncertain environments. AB - We propose here that the modular organization of the striatum reflects a context sensitive modular learning architecture in which clustered striosome-matrisome domains participate in modular reinforcement learning (RL). Based on anatomical and physiological evidence, it has been suggested that the modular organization of the striatum could represent a learning architecture. There is not, however, a coherent view of how such a learning architecture could relate to the organization of striatal outputs into the direct and indirect pathways of the basal ganglia, nor a clear formulation of how such a modular architecture relates to the RL functions attributed to the striatum. Here, we hypothesize that striosome-matrisome modules not only learn to bias behavior toward specific actions, as in standard RL, but also learn to assess their own relevance to the environmental context and modulate their own learning and activity on this basis. We further hypothesize that the contextual relevance or "responsibility" of modules is determined by errors in predictions of environmental features and that such responsibility is assigned by striosomes and conveyed to matrisomes via local circuit interneurons. To examine these hypotheses and to identify the general requirements for realizing this architecture in the nervous system, we developed a simple modular RL model. We then constructed a network model of basal ganglia circuitry that includes these modules and the direct and indirect pathways. Based on simple assumptions, this model suggests that while the direct pathway may promote actions based on striatal action values, the indirect pathway may act as a gating network that facilitates or suppresses behavioral modules on the basis of striatal responsibility signals. Our modeling functionally unites the modular compartmental organization of the striatum with the direct-indirect pathway divisions of the basal ganglia, a step that we suggest will have important clinical implications. PMID- 21660100 TI - A novel learning rule for long-term plasticity of short-term synaptic plasticity enhances temporal processing. AB - It is well established that short-term synaptic plasticity (STP) of neocortical synapses is itself plastic - e.g., the induction of LTP and LTD tend to shift STP towards short-term depression and facilitation, respectively. What has not been addressed theoretically or experimentally is whether STP is "learned"; that is, is STP regulated by specific learning rules that are in place to optimize the computations performed at synapses, or, are changes in STP essentially an epiphenomenon of long-term plasticity? Here we propose that STP is governed by specific learning rules that operate independently and in parallel of the associative learning rules governing baseline synaptic strength. We describe a learning rule for STP and, using simulations, demonstrate that it significantly enhances the discrimination of spatiotemporal stimuli. Additionally we generate a set of experimental predictions aimed at testing our hypothesis. PMID- 21660102 TI - What Can Tracking Fluctuations in Dozens of Sensory Neurons Tell about Selective Attention? PMID- 21660101 TI - The selfish brain: stress and eating behavior. AB - The brain occupies a special hierarchical position in human energy metabolism. If cerebral homeostasis is threatened, the brain behaves in a "selfish" manner by competing for energy resources with the body. Here we present a logistic approach, which is based on the principles of supply and demand known from economics. In this "cerebral supply chain" model, the brain constitutes the final consumer. In order to illustrate the operating mode of the cerebral supply chain, we take experimental data which allow assessing the supply, demand and need of the brain under conditions of psychosocial stress. The experimental results show that the brain under conditions of psychosocial stress actively demands energy from the body, in order to cover its increased energy needs. The data demonstrate that the stressed brain uses a mechanism referred to as "cerebral insulin suppression" to limit glucose fluxes into peripheral tissue (muscle, fat) and to enhance cerebral glucose supply. Furthermore psychosocial stress elicits a marked increase in eating behavior in the post-stress phase. Subjects ingested more carbohydrates without any preference for sweet ingredients. These experimentally observed changes of cerebral demand, supply and need are integrated into a logistic framework describing the supply chain of the selfish brain. PMID- 21660103 TI - Treatment discontinuation and clinical outcomes in the 1-year naturalistic treatment of patients with schizophrenia at risk of treatment nonadherence. AB - BACKGROUND: This study aimed to improve physicians' understanding of the treatment circumstances and needs of outpatients with schizophrenia at risk of nonadherence, by naturalistically assessing antipsychotic treatment patterns, clinical outcomes, and health care service use in this little-studied patient population. METHODS: In this one-year, prospective, multicenter, noninterventional, observational study, patients considered at risk of nonadherence by their physicians were switched from their primary oral antipsychotic to another oral or a depot antipsychotic at study entry. All cause treatment discontinuation (antipsychotic switch, augmentation, or discontinuation) during the study was assessed using Kaplan-Meier survival analyses and descriptive statistics. Patients' illness severity, quality of life, attitude towards medication, patient-reported adherence, and health care resource utilization were assessed during the study. RESULTS: Of the 406 enrolled patients, 43 (10.6%) were switched to depot and 363 (89.4%) were switched to oral antipsychotics at study entry. During the study, 99 (24.4%) patients switched, augmented, or discontinued their antipsychotic (all cause treatment discontinuation). Of the 99 patients who switched, augmented, or discontinued their antipsychotic, 8 (18.6%) were taking depot and 91 (25.0%) were taking oral antipsychotics. These patients were switched to either depot (n = 15) or oral (n = 78) antipsychotics, or discontinued their antipsychotic medication (n = 6). Inadequate response was the most frequently reported reason for medication discontinuation. During the study, patients' clinical and functional status improved significantly and service use was low. Most patients considered themselves to be adherent at study entry, and this favorable self-perception increased during the study (from 68.5% to 88.1%). CONCLUSION: Although identified as at risk of nonadherence, few patients in this naturalistic study discontinued their prescribed antipsychotic medication during the study. The discrepancy between the physicians' perception of their patient's medication adherence and the patients' self-perceived adherence highlights the need to better understand the underlying reasons for this phenomenon. PMID- 21660104 TI - Cost of surgical intervention for reconstructive therapy of HIV-associated facial lipoatrophy. AB - This study aims to assess direct cost of reconstructive interventions with facial fillers for treatment of HIV (human immunodeficiency virus)-associated facial lipoatrophy (FLA). Evaluation was performed on data from patients enrolled in one arm of a comparative study of immediate versus delayed reconstructive treatment of facial lipoatrophy. Median costs were standardized for efficacy, estimated using data reported by physicians and patient reported outcomes. The variations of the results were evaluated with a sensitivity analysis. Evaluation was performed on 66 patients characterized by significant differences in terms of severity of FLA. Total cost resulted of ?140,416.15, with a median cost per patient of ?2126.04 (interquartile range [IQR]: 1599-2822). Taking into consideration severity of disease, median costs were ?1641.67 (IQR: 1326.67 2126.04) and 2557.12 (IQR: 1939.34-2872.04) (P = 0.0) respectively for patients with low and high severity scores at baseline. Significant differences in term of cost-effectiveness ratios were also found between patients with different severity of FLA, and sensitivity analysis showed that these ratios increase with higher severity scores at baseline and vary widely depending on the costs of filler. Although these results cannot be considered representative because of important limitations, the present study suggests the severity of disease as an important determinant of costs. PMID- 21660105 TI - Patient preferences in the treatment of diabetic retinopathy. AB - OBJECTIVE: Accounting for patient preferences may be especially important in diabetes mellitus, given the challenge in identifying factors associated with treatment adherence. Although preference studies have been performed in diabetes, none have examined treatments used in diabetic retinopathy (DR). The objective of this study was to elicit patient preferences for attributes associated with antivascular endothelial growth factor, focal and panretinal laser, and steroid therapy used in DR management. METHODS: A cross-sectional conjoint survey was administered to DR patients at three Canadian eye centers. The survey involved making tradeoffs among 11 DR treatment attributes, including the chance of improving vision and risks of adverse events over a 1-year treatment period. Attribute utilities were summed for each product profile to determine the most preferred treatment. RESULTS: Based on the results from 161 patients, attributes affecting visual functioning, including improving visual acuity and reducing adverse events (eg, chance of cataracts), were more important than those not directly affecting vision (eg, administration). Overall, 52%, 20%, 17%, and 11% preferred the product profiles matching to the antivascular endothelial growth factor, steroid, focal laser, and panretinal laser therapies. Preferences did not vary substantially by previous treatment experience, age, or type of DR (macular edema, proliferative DR, both or neither), with the exception that more macular edema only patients preferred focal laser over steroid treatment (19% versus 14%, respectively). CONCLUSIONS: When considering the potential effects of treatment over a 1-year period, treatment preferences in DR are most influenced by those that may positively or negatively affect visual functioning. PMID- 21660106 TI - Development of a questionnaire to assess patient satisfaction with allergen specific immunotherapy in adults: item generation, item reduction, and preliminary validation. AB - BACKGROUND: Allergen-specific immunotherapy (SIT) is a treatment capable of modifying the natural course of allergy, so ensuring good adherence to SIT is fundamental. Up until now there has not existed an instrument specifically developed to measure patient satisfaction with SIT, although its assessment could help us to comprehend better and improve treatment adherence and effectiveness. The aim of this study was to develop an instrument to measure adult patient satisfaction with SIT. METHODS: Items were generated from a literature review, focus groups with allergic adult patients undergoing SIT, and a meeting with experts. Potential items were administered to allergic patients undergoing SIT in an observational, cross-sectional, multicenter study. Item reduction was based on quantitative and qualitative criteria. A preliminary assessment of feasibility, reliability, and validity of the retained items was performed. RESULTS: An initial pool of 70 items was administered to 257 patients undergoing SIT. Fifty four items were eliminated resulting in a provisional instrument with 16 items. Factor analysis yielded four factors that were identified as perceived efficacy, activities and environment, cost-benefit balance, and overall satisfaction, explaining 74.8% of variance. Ceiling and floor effects were negligible for overall score. Overall score was associated with the type and intensity of symptoms. CONCLUSION: This is the first attempt to develop a satisfaction with SIT measure from the perspective of the allergic patient, and evidence has been found in favor of its reliability and validity. PMID- 21660107 TI - Bone Induction: Regeneration through Chaos. PMID- 21660108 TI - A linear structural equation model for covert verb generation based on independent component analysis of FMRI data from children and adolescents. AB - Human language is a complex and protean cognitive ability. Young children, following well defined developmental patterns learn language rapidly and effortlessly producing full sentences by the age of 3 years. However, the language circuitry continues to undergo significant neuroplastic changes extending well into teenage years. Evidence suggests that the developing brain adheres to two rudimentary principles of functional organization: functional integration and functional specialization. At a neurobiological level, this distinction can be identified with progressive specialization or focalization reflecting consolidation and synaptic reinforcement of a network (Lenneberg, 1967; Muller et al., 1998; Berl et al., 2006). In this paper, we used group independent component analysis and linear structural equation modeling (McIntosh and Gonzalez-Lima, 1994; Karunanayaka et al., 2007) to tease out the developmental trajectories of the language circuitry based on fMRI data from 336 children ages 5-18 years performing a blocked, covert verb generation task. The results are analyzed and presented in the framework of theoretical models for neurocognitive brain development. This study highlights the advantages of combining both modular and connectionist approaches to cognitive functions; from a methodological perspective, it demonstrates the feasibility of combining data driven and hypothesis driven techniques to investigate the developmental shifts in the semantic network. PMID- 21660109 TI - Putative cholinergic interneurons in the ventral and dorsal regions of the striatum have distinct roles in a two choice alternative association task. AB - The striatum consists of GABAergic projection neurons and various types of interneurons. Despite their relative scarcity, these interneurons play a key role in information processing in the striatum. One such class of interneurons is the cholinergic tonically active neurons (TANs). In the dorsal striatum, TANs are traditionally considered to be responsive to events of motivational significance. However, in recent years, studies have suggested that TANs are not exclusively related to reward and reward-predicting stimuli, but may contribute to other processes, including responses to aversive stimuli, detecting the spatial location of stimuli and generating movement. Currently there is little data concerning TAN activity in the ventral striatum (VS) of behaving animals. Here, we simultaneously recorded neurons in the ventral and the dorsolateral (DLS) regions of the striatum while animals performed a two choice alternative association task. Our data show that a large percentage of the putative TANs in both regions responded around movement initiation and execution. The majority of these neurons exhibited directional selectivity which was stronger in DLS relative to VS. In addition, the preferred directions in VS were mostly contralateral to the recording site whereas the observed preferred directions in DLS were equally distributed contralaterally and ipsilaterally to the recording site. The most interesting difference between DLS and VS was that DLS TANs maintained activity alterations throughout the movement whereas TANs in VS exhibited short-lasting phasic activity alterations that were maintained throughout the movement by different neurons. Our findings suggest that coding of movement by TANs in both regions overlaps to some degree, yet the differences in response patterns support the notion that the TANs in DLS participate in the motor loop whereas TANs in VS convey event-related information such as movement initiation, movement direction, and end of movement. PMID- 21660110 TI - Correlation of transcranial color Doppler to n20 somatosensory evoked potential detects ischemic penumbra in subarachnoid hemorrhage. AB - BACKGROUND: Normal subjects present interhemispheric symmetry of middle cerebral artery (MCA) mean flow velocity and N20 cortical somatosensory evoked potential (SSEP). Subarachnoid haemorrhage (SAH) can modify this pattern, since high regional brain vascular resistances increase blood flow velocity, and impaired regional brain perfusion reduces N20 amplitude. The aim of the study is to investigate the variability of MCA resistances and N20 amplitude between hemispheres in SAH. METHODS: Measurements of MCA blood flow velocity (vMCA) by transcranial color-Doppler and median nerve SSEP were bilaterally performed in sixteen patients. MCA vascular changes on the compromised hemisphere were calculated as a ratio of the reciprocal of mean flow velocity (1/vMCA) to contralateral value and correlated to the simultaneous variations of interhemispheric ratio of N20 amplitude, within each subject. Data were analysed with respect to neuroimaging of MCA supplied areas. RESULTS: Both interhemispheric ratios of 1/vMCA and N20 amplitude were detected >0.65 (p <0,01) in patients without neuroimages of injury. Both ratios became <0.65 (p <0.01) when patients showed unilateral images of ischemic penumbra and returned >0.65 if penumbra disappeared. The two ratios no longer correlated after structural lesion developed, as N20 detected in the damaged side remained pathological (ratio <0.65), whereas 1/vMCA reverted to symmetric interhemispheric state (ratio >0.65), suggesting a luxury perfusion. CONCLUSION: Variations of interhemispheric ratios of MCA resistance and cortical N20 amplitude correlate closely in SAH and allow identification of the reversible ischemic penumbra threshold, when both ratios become <0.65. The correlation is lost when structural damage develops. PMID- 21660111 TI - Cerebral epiphyseal proteins and melatonin modulate the hepatic and renal antioxidant defense of rats. AB - The cerebral epiphysis (pineal gland) secrets melatonin and number of other proteins and peptides. It was thus hypothesized that antioxidant properties of epiphyseal proteins and melatonin could potentially benefit from exogenous therapies. In view of the therapeutic potential of these proteins, the present experiment was conducted to investigate the effect of buffalo epiphyseal proteins (BEP, at 100 MUg/kg BW, i.p.) and melatonin (MEL, at 10 mg/kg BW, i.p) on changes in hepatic and renal antioxidant enzymes of adult female Wistar rats. Buffalo epiphyseal proteins significantly (P < .05) increased hepatic lipid peroxidation (LPO), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), reduced glutathione (GSH), and renal LPO, catalase (CAT), GR, GSH, GPx levels as compared to control animals. Similarly, MEL treatment significantly (P < .05) up-regulated hepatic SOD and GPx activity, whereas CAT, GR, GPx, and GSH levels in renal tissues were increased while SOD and LPO remained unaffected. Buffalo epiphyseal protein treatment produced greater effects on hepatic GPx and renal CAT and GSH levels than did MEL. These findings support the conclusion that buffalo epiphyseal proteins and melatonin activate a number of antioxidant mechanisms in hepatic and renal tissues. PMID- 21660112 TI - Genomic analysis reveals versatile organisms for quorum quenching enzymes: acyl homoserine lactone-acylase and -lactonase. AB - Microbial virulence and their resistance to multiple drugs have obliged researchers to look for novel drug targets. Virulence of pathogenic microbes is regulated by signal molecules such as acylated homoserine lactone (AHL) produced during a cell density dependent phenomenon of quorum sensing (QS). In contrast, certain microbes produce AHL-lactonases and -acylases to degrade QS signals, also termed as quorum quenching. Mining sequenced genome databases has revealed organisms possessing conserved domains for AHL-lactonases and -acylases: i) Streptomyces (Actinobacteria), ii) Deinococcus (Deinococcus-Thermus), iii) Hyphomonas (alpha-Proteobacteria), iv) Ralstonia (beta-Proteobacteria), v) Photorhabdus (gamma-Proteobacteria), and certain marine gamma proteobacterium. Presence of genes for both the enzymes within an organism was observed in the following: i) Deinococcus radiodurans R1, ii) Hyphomonas neptunium ATCC 15444 and iii) Photorhabdus luminescens subsp. laumondii TTO1. These observations are supported by the presence motifs for lactonase and acylase in these strains. Phylogenetic analysis and multiple sequence alignment of the gene sequences for AHL-lactonases and -acylases have revealed consensus sequences which can be used to design primers for amplifying these genes even among mixed cultures and metagenomes. Quorum quenching can be exploited to prevent food spoilage, bacterial infections and bioremediation. PMID- 21660114 TI - Facile Routes to Manganese(II) Triflate Complexes. AB - Manganese(II) chloride reacts with trimethylsilyl triflate (TMS(OTf) where OTf = (-)OSO(2)CF(3)) in a 1:1 mixture of acetonitrile and tetrahydrofuran, and after recrystallization affords the linear coordination polymer [Mn(II)(CH(3)CN)(2)(OTf)(2)](n). Each distorted octahedral manganese(II) center in the polymeric chain has trans-acetonitriles and the remaining equatorial coordination positions are occupied by the bridging triflate anions. Dissolving [Mn(II)(CH(3)CN)(2)(OTf)(2)](n) in equal volumes of acetonitrile and pyridine followed by recrystallization with diethyl ether yields trans [Mn(II)(C(5)H(5)N)(4)(OTf)(2)]. The distorted octahedral geometry of the manganese center features monodentate trans-triflate anions and four equatorial pyridines. Exposure of either [Mn(II)(CH(3)CN)(2)(OTf)(2)](n) or [Mn(II)(C(5)H(5)N)(4)(OTf)(2)] to water readily gives [Mn(II)(H(2)O)(6)](OTf)(2). XRD reveals hydrogen-bonding interactions between the [Mn(II)(H(2)O)(6)](2+) cation and the triflate anion. All three of these species are easily crystallized and provide convenient sources of manganese(II) for further synthetic elaboration. PMID- 21660115 TI - Genotype-environment interactions and their translational implications. AB - Organisms frequently encounter different environmental conditions. The physiological and behavioral responses to these conditions depend on the genetic make up of individuals. Genotype generally remains constant from one environment to another, although occasional spontaneous mutations may occur which cause it to change. However, when the same genotype is subjected to different environments, it can produce a wide range of phenotypes. These phenotypic variations are attributable to the effect of the environment on the expression and function of genes influencing the trait. Changes in the relative performance of genotypes across different environments are referred to as genotype-environment interactions (GEI). A general argument for research on the impact of GEI in common diseases is that it provides insights into disease processes at the population, individual and molecular levels. In humans, GEI is complicated by multiple factors including phenocopies, genocopies, epigenetics and imprinting. A better understanding of GEI is essential if patients are to make informed health choices guided by their genomic information. In this article, we clarify the role of the environment on phenotype, we describe how human population structure can obscure the resolution of GEI and we discuss how emerging biobanks across the globe can be coordinated to further our understanding of genotype-phenotype associations within the context of varying environment. PMID- 21660113 TI - Improving prognosis estimation in patients with heart failure and the cardiorenal syndrome. AB - The coexistence of heart failure and renal dysfunction constitutes the "cardiorenal syndrome" which is increasingly recognized as a marker of poor prognosis. Patients with cardiorenal dysfunction constitute a large and heterogeneous group where individuals can have markedly different outcomes and disease courses. Thus, the determination of prognosis in this high risk group of patients may pose challenges for clinicians and for researchers alike. In this paper, we discuss the cardiorenal syndrome as it pertains to the patient with heart failure and considerations for further refining prognosis and outcomes in patients with heart failure and renal dysfunction. Conventional assessments of left ventricular function, renal clearance, and functional status can be complemented with identification of coexistent comorbidities, medication needs, microalbuminuria, anemia, biomarker levels, and pulmonary pressures to derive additional prognostic data that can aid management and provide future research directions for this challenging patient group. PMID- 21660117 TI - Simultaneous Stripping Detection of Pb(II), Cd(II) and Zn(II) Using a Bimetallic Hg-Bi/Single-Walled Carbon Nanotubes Composite Electrode. AB - A new, sensitive platform for the simultaneous electrochemical assay of Zn(II), Cd(II) and Pb(II) in aqueous solution has been developed. The platform is based on a new bimetallic Hg-Bi/single-walled carbon nanotubes (SWNTs) composite modified glassy carbon electrode (GCE), demonstrating remarkably improved performance for the anodic stripping assay of Zn(II), Cd(II) and Pb(II). The synergistic effect of Hg and Bi as well as the enlarged, activated surface and good electrical conductivity of SWNTs on GCE contribute to the enhanced activity of the proposed electrode. The analytical curves for Zn(II), Cd(II) an Pb(II) cover two linear ranges varying from 0.5 to 11 MUg L(-1) and 10 to 130 MUg L(-1) with correlation coefficients higher than 0.992. The limits of detection for Zn(II), Cd(II) are lower than 2 MUg L(-1) (S/N = 3). For Pb(II), moreover, there is another lower, linear range from 5 to 1100 ng L(-1) with a coefficient of 0.987 and a detection limit of 0.12 ng L(-1). By using the standard addition method, Zn(II), Cd(II) and Pb(II) ions in river samples were successfully determined. These results suggest that the proposed method can be applied as a simple, efficient alternative for the simultaneous monitoring of heavy metals in water samples. In addition, this method demonstrates the powerful application of carbon nanotubes in electrochemical analysis of heavy metals. PMID- 21660116 TI - Development of an Automated High Throughput LCP-FRAP Assay to Guide Membrane Protein Crystallization in Lipid Mesophases. AB - Crystallization in lipidic mesophases (in meso) has been successfully used to obtain a number of high-resolution membrane protein structures including challenging members of the human G protein-coupled receptor (GPCR) family. Crystallogenesis in arguably the most successful mesophase, lipidic cubic phase (LCP), critically depends on the ability of protein to diffuse in the LCP matrix and to form specific protein-protein contacts to support crystal nucleation and growth. The ability of an integral membrane protein to diffuse in LCP is strongly affected by the protein aggregation state, the structural parameters of LCP, and the chemical environment. In order to satisfy both requirements of diffusion and specific interactions, one must balance multiple parameters, such as identity of LCP host lipid, composition of precipitant solution, identity of ligand, and protein modifications. Screening within such multi-dimensional crystallization space presents a significant bottleneck in obtaining initial crystal leads. To reduce this combinatorial challenge, we developed a pre-crystallization screening assay to measure the diffusion characteristics of a protein target in LCP. Utilizing the Fluorescence Recovery After Photobleaching (FRAP) technique in an automated and high throughput manner, we were able to map conditions that support adequate diffusion in LCP using a minimal amount of protein. Data collection and processing protocols were validated using two model GPCR targets: the beta(2) adrenergic receptor and the A(2A) adenosine receptor. PMID- 21660118 TI - Synthesis and Evaluation of the alpha-D-/alpha-L-Rhamnosyl and Amicetosyl Digitoxigenin Oligomers as Anti-tumor Agents. AB - A highly regio- and stereo-selective asymmetric synthesis of rhamnosyl- and amicetosyl-digitoxigenin analogues has been established via palladium-catalyzed glycosylation followed by bis-/tris-dihydroxylation or bis-/tris-diimide reduction. The alpha-l-rhamnose and alpha-l-amicetose digitoxin monosaccharide analogues displayed stronger apoptosis inducing activity and cytotoxicity against non-small cell human lung cancer cells (NCI-H460) than its d-diastereomeric isomers in a sugar-chain length dependent manner. PMID- 21660119 TI - SCORE Study Report 8: Closed Tests for All Pair-Wise Comparisons of Means. AB - We compare five closed tests for strong control of family-wide type I error (FWE) while making all pair-wise comparisons of means in clinical trials with multiple arms such as the SCORE Study. We simulated outcomes of the SCORE Study under its design hypotheses, and used p-values from chi-squared tests to compare performance of a "pairwise" closed test described below to Bonferroni and Hochberg adjusted p-values. "Pairwise" closed testing was more powerful than Hochberg's method by several definitions of multiple-test power. Simulations over a wider parameter space, and considering other closed methods, confirmed this superiority for p-values based on normal, logistic, and Poisson distributions. The power benefit of "pair-wise" closed testing begins to disappear with 5 or more arms, and with unbalanced designs. For trials with 4 or fewer arms and balanced designs, investigators should consider using "pair-wise" closed testing in preference to Shaffer's, Hommel's, and Hochberg's approaches when making all pairwise comparisons of means. If not all p-values from the closed family are available, Shaffer's method is a good choice. PMID- 21660120 TI - Heterogeneous path ensembles for conformational transitions in semi-atomistic models of adenylate kinase. AB - We performed "weighted ensemble" path-sampling simulations of adenylate kinase, using several semi-atomistic protein models. The models have an all-atom backbone with various levels of residue interactions. The primary result is that full statistically rigorous path sampling required only a few weeks of single processor computing time with these models, indicating the addition of further chemical detail should be readily feasible. Our semi-atomistic path ensembles are consistent with previous biophysical findings: the presence of two distinct pathways, identification of intermediates, and symmetry of forward and reverse pathways. PMID- 21660121 TI - The Influence of Linguistic Acculturation and Gender on the Initiation of Substance Use Among Mexican Heritage Preadolescents in the Borderlands. AB - This article examined the impact of linguistic acculturation and gender on the substance use initiation of a sample of 1,473 Mexican heritage preadolescents attending 30 public schools in Phoenix, Arizona. It was hypothesized that linguistic acculturation operates differently as a risk or protective factor for young children than for older youth. The study used discrete-time event history methods to model the rate at which nonusing children initiate substance use. Alcohol, cigarettes, marijuana, and inhalants were studied separately while inhalant use was examined more closely. Results suggested that while linguistic acculturation is a risk factor for Mexican heritage preadolescents, this association depended on gender, the linguistic acculturation context (family, friends, or media), and the type of substance. For inhalants, higher linguistic acculturation with friends was inversely associated with drug initiation both for boys and girls. Implications for preventive science and future intervention research are discussed. PMID- 21660122 TI - In vivo photoacoustic mapping of lymphatic systems with plasmon-resonant nanostars. AB - Plasmon-resonant nanostars (NSTs) provide excellent contrast enhancement for photoacoustic tomography. The high photoacoustic sensitivity of NSTs at near infrared wavelengths enable their in vivo detection in rat sentinel lymph nodes and vessels, with direct application toward lymphangiography. PMID- 21660123 TI - AN EFFICIENT HIGHER-ORDER FAST MULTIPOLE BOUNDARY ELEMENT SOLUTION FOR POISSON BOLTZMANN BASED MOLECULAR ELECTROSTATICS. AB - In order to compute polarization energy of biomolecules, we describe a boundary element approach to solving the linearized Poisson-Boltzmann equation. Our approach combines several important features including the derivative boundary formulation of the problem and a smooth approximation of the molecular surface based on the algebraic spline molecular surface. State of the art software for numerical linear algebra and the kernel independent fast multipole method is used for both simplicity and efficiency of our implementation. We perform a variety of computational experiments, testing our method on a number of actual proteins involved in molecular docking and demonstrating the effectiveness of our solver for computing molecular polarization energy. PMID- 21660124 TI - Development of an ultra fast online-solid phase extraction (SPE) liquid chromatography electrospray tandem mass spectrometry (LC-ESI-MS/MS) based approach for the determination of drugs in pharmacokinetic studies. AB - High-throughput analyses of a large number of samples for pharmacokinetic (PK) studies are essential in drug development. Analysis of drug candidates from blood using LC-ESI-MS generally requires separation of the plasma fraction followed by various offline sample preparation procedures. This step is a bottleneck that impedes throughput. In order to overcome this difficulty and accelerate analysis in PK and other studies, we developed an approach allowing the direct analysis of low volumes of whole blood (10 MUL) after dilution and centrifugation. Samples were injected in an online-SPE-LC-ESI-MS/MS setup allowing a total run time of only 126 s for a full gradient separation. Analytes were extracted from the matrix within 30 s by turbulent flow chromatography. Subsequently, a full gradient separation was carried out within 1.5 minutes on a 50 * 2.1 mm (1.7 MUm) RP-18 column and the analytes were sensitively detected by ESI-MS/MS in SRM mode. The performance of this new ultra fast online SPE-LC-ESI-MS/MS approach was demonstrated by the analysis of diclofenac (DCF), a widely used anti-inflammatory drug. DCF eluted at stable retention times (+/-0.33%) with narrow peak width (FWHM 3.3 +/- 0.15 s). The method displays excellent analytical performance, with a limit of detection of 6 fmol on column, a linear range of over four orders of magnitude and a negligible carry over of 0.12 +/- 0.03% for DCF. The PK profile of DCF administered by topical and intraperitoneal routes in rats and by oral route in one human volunteer is investigated using this method. Finally, general applicability of the approach for drugs is demonstrated by analysis of rofecoxib and several inhibitors of the soluble epoxide hydrolase. This new method requires only readily available, off the shelf standard LC instrumentation, and is compliant with the requirements of green analytical chemistry. PMID- 21660125 TI - A Stochastic Kinematic Model of Class Averaging in Single-Particle Electron Microscopy. AB - Single-particle electron microscopy is an experimental technique that is used to determine the 3D structure of biological macromolecules and the complexes that they form. In general, image processing techniques and reconstruction algorithms are applied to micrographs, which are two-dimensional (2D) images taken by electron microscopes. Each of these planar images can be thought of as a projection of the macromolecular structure of interest from an a priori unknown direction. A class is defined as a collection of projection images with a high degree of similarity, presumably resulting from taking projections along similar directions. In practice, micrographs are very noisy and those in each class are aligned and averaged in order to reduce the background noise. Errors in the alignment process are inevitable due to noise in the electron micrographs. This error results in blurry averaged images. In this paper, we investigate how blurring parameters are related to the properties of the background noise in the case when the alignment is achieved by matching the mass centers and the principal axes of the experimental images. We observe that the background noise in micrographs can be treated as Gaussian. Using the mean and variance of the background Gaussian noise, we derive equations for the mean and variance of translational and rotational misalignments in the class averaging process. This defines a Gaussian probability density on the Euclidean motion group of the plane. Our formulation is validated by convolving the derived blurring function representing the stochasticity of the image alignments with the underlying noiseless projection and comparing with the original blurry image. PMID- 21660126 TI - Efficient Classification-Based Relabeling in Mixture Models. AB - Effective component relabeling in Bayesian analyses of mixture models is critical to the routine use of mixtures in classification with analysis based on Markov chain Monte Carlo methods. The classification-based relabeling approach here is computationally attractive and statistically effective, and scales well with sample size and number of mixture components concordant with enabling routine analyses of increasingly large data sets. Building on the best of existing methods, practical relabeling aims to match data:component classification indicators in MCMC iterates with those of a defined reference mixture distribution. The method performs as well as or better than existing methods in small dimensional problems, while being practically superior in problems with larger data sets as the approach is scalable. We describe examples and computational benchmarks, and provide supporting code with efficient computational implementation of the algorithm that will be of use to others in practical applications of mixture models. PMID- 21660128 TI - Acculturation Status and Substance Use Prevention with Mexican and Mexican American Youth. AB - This study examined whether language preference, as an indicator of acculturation, moderated the effects of a culturally grounded substance use prevention intervention for Mexican and Mexican American middle school students (N = 2,146) in Phoenix, Arizona. The main hypothesis was that levels of program effectiveness would vary based on the language preference of the students and the specific culturally grounded version of the intervention they were assigned. Findings show that matching language preference to particular versions of the intervention did not influence substance use related program outcomes, but that overall program effects (intervention versus control) did vary by language preference. English-language dominant participants, the most at risk sub-group, responded more positively to the intervention, while Spanish dominant, who had low substance use rates at baseline, and bilingual participants did not demonstrate significant differences between the intervention and control groups. Implications for school social work prevention interventions and prevention science in general, are discussed. PMID- 21660129 TI - Systematic implicit solvent coarse-graining of bilayer membranes: lipid and phase transferability of the force field. AB - We study the lipid and phase transferability of our recently developed systematically coarse-grained solvent-free membrane model. The force field was explicitly parameterized to describe a fluid 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) bilayer at 310 K with correct structure and area per lipid, while gaining at least three orders of magnitude in computational efficiency (see Wang and Deserno 2010 J. Phys. Chem. B 114 11207-20). Here, we show that exchanging CG tails, without any subsequent re-parameterization, creates reliable models of 1,2-dioleoylphosphatidylcholine (DOPC) and 1,2 dipalmitoylphosphatidylcholine (DPPC) lipids in terms of structure and area per lipid. Furthermore, all CG lipids undergo a liquid-gel transition upon cooling, with characteristics like those observed in experiments and all-atom simulations during phase transformation. These studies suggest a promising transferability of our force field parameters to different lipid species and thermodynamic state points, properties that are a prerequisite for even more complex systems, such as mixtures. PMID- 21660130 TI - TOWARD A MENTALISTIC ACCOUNT OF EARLY PSYCHOLOGICAL REASONING. AB - Recent investigations of early psychological understanding have revealed three key findings. First, young infants attribute goals and dispositions to any entity they perceive as an agent, whether human or non-human. Second, when interpreting an agent's actions in a scene, young infants take into account the agent's representation of the scene, even if this representation is less complete than their own. Third, at least by the second year of life, infants recognize that agents can hold false beliefs about a scene. Together, these findings support a system-based, mentalistic account of early psychological reasoning. PMID- 21660131 TI - Robust Feature Selection in Resting-State fMRI Connectivity Based on Population Studies. AB - We propose an alternative to univariate statistics for identifying population differences in functional connectivity. Our feature selection method is based on a procedure that searches across subsets of the data to isolate a set of robust, predictive functional connections. The metric, known as the Gini Importance, also summarizes multivariate patterns of interaction, which cannot be captured by univariate techniques. We compare the Gini Importance with univariate statistical tests to evaluate functional connectivity changes induced by schizophrenia. Our empirical results indicate that univariate features vary dramatically across subsets of the data and have little classification power. In contrast, relevant features based on Gini Importance are considerably more stable and allow us to accurately predict the diagnosis of a test subject. PMID- 21660127 TI - Arousal-Biased Competition in Perception and Memory. AB - Our everyday surroundings besiege us with information. The battle is for a share of our limited attention and memory, with the brain selecting the winners and discarding the losers. Previous research shows that both bottom-up and top-down factors bias competition in favor of high priority stimuli. We propose that arousal during an event increases this bias both in perception and in long-term memory of the event. Arousal-biased competition theory provides specific predictions about when arousal will enhance memory for events and when it will impair it, which accounts for some puzzling contradictions in the emotional memory literature. PMID- 21660132 TI - Molecular imaging, pharmacokinetics, and dosimetry of In-AMBA in human prostate tumor-bearing mice. AB - Molecular imaging with promise of personalized medicine can provide patient specific information noninvasively, thus enabling treatment to be tailored to the specific biological attributes of both the disease and the patient. This study was to investigate the characterization of DO3A-CH(2)CO-G-4-aminobenzoyl-Q-W-A-V G-H-L-M-NH(2) (AMBA) in vitro, MicroSPECT/CT imaging, and biological activities of (111)In-AMBA in PC-3 prostate tumor-bearing SCID mice. The uptake of (111)In AMBA reached highest with 3.87 +/- 0.65% ID/g at 8 h. MicroSPECT/CT imaging studies suggested that the uptake of (111)In-AMBA was clearly visualized between 8 and 48 h postinjection. The distribution half-life (t(1/2alpha)) and the elimination half-life (t(1/2beta)) of (111)In-AMBA in mice were 1.53 h and 30.7 h, respectively. The C(max) and AUC of (111)In-AMBA were 7.57% ID/g and 66.39 h % ID/g, respectively. The effective dose appeared to be 0.11 mSv/MBq(-1). We demonstrated a good uptake of (111)In-AMBA in the GRPR-overexpressed PC-3 tumor bearing SCID mice. (111)In-AMBA is a safe, potential molecular image-guided diagnostic agent for human GRPR-positive tumors, ranging from simple and straightforward biodistribution studies to improve the efficacy of combined modality anticancer therapy. PMID- 21660133 TI - Effect of one year of cryopreservation on the activity of lysosomal hydrolases from EBV-transformed lymphocytes. AB - BACKGROUND: The Epstein-Barr virus (EBV) was used as an agent of B lymphocyte proliferation for subsequent diagnosis of lysosomal storage disease. Due to the constant handling of long-preserved samples in our cell bank, we decided to observe the behavior and then compare cultured and frozen samples for at least one year's cryopreservation. METHODS: Twenty-five samples from healthy individuals were used to assess the possible changes in activity of enzymes beta galactosidase, beta-glucosidase, alpha-iduronidase, alpha-galactosidase, and alpha-glucosidase. Transmission electron microscopy was used to confirm cell transformation of B lymphocytes into EBV-infected cells, generating lymphoblastoid cell lines. RESULTS: Transmission electron microscopy findings confirmed previous reports in the literature that is, significant and evident morphological changes in the nucleus occur after day 12 and the consequent cell transformation into EBV-infected cells. After thawing and subsequent treatment with the five enzymes utilized, we observed no significant changes in samples cryopreserved for more than one year, as compared to samples cultured for 12 days. PMID- 21660134 TI - Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. AB - Natural killer (NK) cells are powerful effector cells that can be directed to eliminate tumor cells through tumor-targeted monoclonal antibodies (mAbs). Some tumor-targeted mAbs have been successfully applied in the clinic and are included in the standard of care for certain malignancies. Strategies to augment the antitumor response by NK cells have led to an increased understanding of how to improve their effector responses. Next-generation reagents, such as molecularly modified mAbs and mAb-cytokine fusion proteins (immunocytokines, ICs) designed to augment NK-mediated killing, are showing promise in preclinical and some clinical settings. Continued research into the antitumor effects induced by NK cells and tumor-targeted mAbs suggests that additional intrinsic and extrinsic factors may influence the antitumor response. Therefore more research is needed that focuses on evaluating which NK cell and tumor criteria are best predictive of a clinical response and which combination immunotherapy regimens to pursue for distinct clinical settings. PMID- 21660135 TI - Dysfunction of lacrimal and salivary glands in Sjogren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model. AB - Sjogren's syndrome (SjS) is a chronic autoimmune disorder characterized by dry eyes and dry mouth due to dacryoadenitis and sialoadenitis with SS-A/Ro and/or SS B/La autoantibodies in genetically predisposed individuals. Destruction of lacrimal and salivary glands by autoimmune reactions may lead to clinical manifestation. However, the mechanisms behind the decreased volume of secretions in tears and saliva are complex and are not fully understood. Exocrine gland dysfunction may precede autoimmunity (acquired immunity) or represent a process independent from inflammation in the pathogenesis of SjS. The preceded functional and morphologic changes of those tissues by nonimmunologic injury before the development of inflammation at the sites of target organs have been implicated. This paper focuses on the several factors and components relating to glandular dysfunction and morphologic changes by nonimmunologic injury during the preinflammatory phase in mouse model, including the factors which link between innate immunity and adaptive immunity. PMID- 21660136 TI - Role of natural killer and dendritic cell crosstalk in immunomodulation by commensal bacteria probiotics. AB - A cooperative dialogue between natural killer (NK) cells and dendritic cells (DCs) has been elucidated in the last years. They help each other to acquire their complete functions, both in the periphery and in the secondary lymphoid organs. Thus, NK cells' activation by dendritic cells allows the killing of transformed or infected cells in the periphery but may also be important for the generation of adaptive immunity. Indeed, it has been shown that NK cells may play a key role in polarizing a Th1 response upon interaction with DCs exposed to microbial products. This regulatory role of DC/NK cross-talk is of particular importance at mucosal surfaces such as the intestine, where the immune system exists in intimate association with commensal bacteria such as lactic acid bacteria (LAB). We here review NK/DC interactions in the presence of gut-derived commensal bacteria and their role in bacterial strain-dependent immunomodulatory effects. We particularly aim to highlight the ability of distinct species of commensal bacterial probiotics to differently affect the outcome of DC/NK cross talk and consequently to differently influence the polarization of the adaptive immune response. PMID- 21660137 TI - Orange juice and its component, hesperidin, decrease the expression of multidrug resistance-associated protein 2 in rat small intestine and liver. AB - We investigated the effects of orange juice (OJ) or hesperidin, a component of OJ, on the pharmacokinetics of pravastatin (PRV) and the expression of both protein and mRNA of multidrug resistance-associated protein 2 (Mrp2) in the rat small intestine and liver. Eight-week-old male Sprague-Dawley rats were used in this study. OJ or a 0.079% hesperidin suspension was administered orally for 2 days. Tap water was given as a control. A single dose of PRV at 100 mg/kg p.o. was administered after 2 days of OJ, hesperidin, or tap water ingestion. The AUC, C(max), and t(1/2) values of PRV were significantly increased in OJ group. Mrp2 protein and mRNA levels in the small intestine and liver, respectively, were significantly decreased after the ingestion of OJ. The same results were obtained with hesperidin. These results suggest that the changes in PRV pharmacokinetic parameters and the decrease in Mrp2 expression caused by OJ are due to hesperidin in the juice. PMID- 21660139 TI - Manipulation of pH shift to enhance the growth and antibiotic activity of Xenorhabdus nematophila. AB - To evaluate the effects of pH control strategy on cell growth and the production of antibiotic (cyclo(2-Me-BABA-Gly)) by Xenorhabdus nematophila and enhance the antibiotic activity. The effects of uncontrolled- (different initial pH) and controlled-pH (different constant pH and pH-shift) operations on cell growth and antibiotic activity of X. nematophila YL00I were examined. Experiments showed that the optimal initial pH for cell growth and antibiotic production of X. nematophila YL001 occurred at 7.0. Under different constant pH, a pH level of 7.5 was found to be optimal for biomass and antibiotic activity at 23.71 g/L and 100.0 U/mL, respectively. Based on the kinetic information relating to the different constant pH effects on the fermentation of X. nematophila YL001, a two stage pH control strategy in which pH 6.5 was maintained for the first 24 h, and then switched to 7.5 after 24 h, was established to improve biomass production and antibiotic activity. By applying this pH-shift strategy, the maximal antibiotic activity and productivity were significantly improved and reaching 185.0 U/mL and 4.41 U/mL/h, respectively, compared to values obtained from constant pH operation (100.0 U/mL and 1.39 U/mL/h). PMID- 21660138 TI - The impact of Ly49-NK cell-dependent recognition of MCMV infection on innate and adaptive immune responses. AB - Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV). Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV infected cell and the ensuing NK cell regulatory responses. PMID- 21660140 TI - Antioxidant and antinociceptive effects of Citrus limon essential oil in mice. AB - The antioxidant and antinociceptive activities of Citrus limon essential oil (EO) were assessed in mice or in vitro tests. EO possesses a strong antioxidant potential according to the scavenging assays. Moreover, it presented scavenger activity against all in vitro tests. Orally, EO (50, 100, and 150 mg/kg) significantly reduced the number of writhes, and, at highest doses, it reduced the number of paw licks. Whereas naloxone antagonized the antinociceptive action of EO (highest doses), this suggested, at least, the participation of the opioid system. Further studies currently in progress will enable us to understand the action mechanisms of EO. PMID- 21660141 TI - Inducible nitric oxide synthase genetic polymorphism and risk of asbestosis. AB - Asbestos, a known occupational pollutant, may upregulate the activity of inducible nitric oxide synthase (iNOS) and thus the production of nitric oxide (NO). This study investigated whether iNOS (CCTTT)(n) polymorphism is associated with an increased asbestosis risk in exposed workers. The study cohort consisted of 262 cases with asbestosis and 265 controls with no asbestos-related disease. For each subject the cumulative asbestos exposure data were available. The number of CCTTT repeats was determined following PCR amplification of the iNOS promoter region. Logistic regression was performed to estimate asbestosis risk. The OR of asbestosis was 1.20 (95% CI = 0.85-1.69) for the LL genotype compared to the combined SL and SS genotypes and 1.26 (95% CI = 0.86-1.85) for the LL genotype compared to the SL genotype. The results of this study are borderline significant and suggest a possible role of iNOS (CCTTT)(n) polymorphism in the risk of asbestosis; however, further studies are needed. PMID- 21660142 TI - The over-expression of the beta2 catalytic subunit of the proteasome decreases homologous recombination and impairs DNA double-strand break repair in human cells. AB - By a human cDNA library screening, we have previously identified two sequences coding two different catalytic subunits of the proteasome which increase homologous recombination (HR) when overexpressed in the yeast Saccharomyces cerevisiae. Here, we investigated the effect of proteasome on spontaneous HR and DNA repair in human cells. To determine if the proteasome has a role in the occurrence of spontaneous HR in human cells, we overexpressed the beta2 subunit of the proteasome in HeLa cells and determined the effect on intrachromosomal HR. Results showed that the overexpression of beta2 subunit decreased HR in human cells without altering the cell proteasome activity and the Rad51p level. Moreover, exposure to MG132 that inhibits the proteasome activity reduced HR in human cells. We also found that the expression of the beta2 subunit increases the sensitivity to the camptothecin that induces DNA double-strand break (DSB). This suggests that the beta2 subunit has an active role in HR and DSB repair but does not alter the intracellular level of the Rad51p. PMID- 21660143 TI - Induction and flow cytometry identification of tetraploids from seed-derived explants through colchicine treatments in Catharanthus roseus (L.) G. Don. AB - The tetraploid plants of Catharanthus roseus (L.) G. Don was obtained by colchicine induction from seeds explants, and the ploidy of the plants was identified by flow cytometry. The optimal treatment is 0.2% colchicine solution treated for 24 hours, and the induction rate reaches up to 30%. Comparing with morphological characteristics and growth habits between tetraploids and the control, we found that tetraploids of C. roseus had larger stoma and more branches and leaves. HPLC analysis showed tetraploidization could increase the contents of terpenoid indole alkaloids in C. roseus. Thus, tetraploidization could be used to produce higher alkaloids lines for commercial use. QRT-PCR results showed that the expression of enzymes involved in terpenoid indole alkaloids biosynthesis pathway had increased in the tetraploid plants. To our knowledge, this was the first paper to explore the secondary metabolism in autotetraploid C. roseus induced by colchicine. PMID- 21660144 TI - Gefitinib in non small cell lung cancer. AB - Gefitinib is an oral, reversible, tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) that plays a key role in the biology of non small cell lung cancer (NSCLC). Phase I studies indicated that the recommended dose of gefitinib was 250 mg/day. Rash, diarrhea, and nausea were the most common adverse events. The positive results obtained in early phase 2 clinical trials with gefitinib were not confirmed in large phase 3 trials in unselected patients with advanced NSCLC. The subsequent discovery that the presence of somatic mutations in the kinase domain of EGFR strongly correlates with increased responsiveness to EGFR tyrosine kinase inhibitors prompted phase 2 and 3 trials with gefitinib in the first line-treatment of EGFR-mutated NSCLC. The results of these trials have demonstrated the efficacy of gefitinib that can be now considered as the standard first-line treatment of patients with advanced NSCLC harbouring activating EGFR mutations. PMID- 21660145 TI - Black Cohosh Hepatic Safety: Follow-Up of 107 Patients Consuming a Special Cimicifuga racemosa rhizome Herbal Extract and Review of Literature. AB - European Medicines Agency (EMEA) and the Committee on Herbal Medicinal Products (HMPC) on July 2006 have released an alert to get European sanitary authorities aware of 42 cases of suspected hepatotoxic reactions in patients consuming Cimicifuga racemosa rhizome. In the public statement EMEA itself considered reliable as hepatotoxic reactions only four cases, on the base of RUCAM score: two were considered possible and two probable. Lacking in almost all of them a precise description of cases, especially a botanical-chemical analysis of the suspected substance, we think there is no real proof of supposed C. racemosa rhizome hepatotoxicity. In our department we administer from about 10 years C. racemosa as special herbal dry extract as single substance or mixed with other medicinal plants at the dose of 500-1000 mg daily, for treatment of menopause related disorders without any reported adverse effect. After EMEA's official signal we have contacted all our patients using a C. racemosa rhizome herbal extract continuously from more than 12 months to verify possible hepatotoxic effects. We followed-up 107 women, and asked them by telephone (33/107) and/or after anamnesis and clinical examination (74/107) to undergo a blood sample examination. In all the patients there was no sign of hepatic disease, or worsening of already altered but stable parameters. We think on the base of these data and current literature C. racemosa rhizome extract should not be considered a potential hepatotoxic substance. PMID- 21660148 TI - Fucoidan enhances the survival and sustains the number of splenic dendritic cells in mouse endotoxemia. AB - Fucoidan is a sulfated polysaccharide derived from brown algae that has been reported to perform multiple biological activities, including immunostimulation. In this study, we investigated whether fucoidan has beneficial effects on endotoxemia induced by LPS, a septic model in mice. The focus of this study was on survival rates and spleen function of the mice upon treatment. We found that fucoidan had prophylactic effects on the survival rate of mice with endotoxemia. Flow cytometric analysis using antibodies for subset-specific markers revealed that fucoidan profoundly reversed the depleted population of dendritic cells in mice with endotoxemia. According to Western blot analysis, the spleen cells of LPS/fucoidan-treated mice showed a higher expression of anti-apoptotic molecules compared to those of LPS-treated mice. Also, fucoidan-treated spleen cells were more responsive to mitogens. Taken together, these results demonstrate that fucoidan pre-treatment has beneficial effects on the survival rate and function of the spleen in mice with endotoxemia. This study may broaden the use of fucoidan in clinical fields, especially endotoxemia. PMID- 21660147 TI - HO-1 Induced by Cilostazol Protects Against TNF-alpha-associated Cytotoxicity via a PPAR-gamma-dependent Pathway in Human Endothelial Cells. AB - A large body of evidence has indicated that induction of endogenous antioxidative proteins seems to be a reasonable strategy for delaying the progression of cell injury. In our previous study, cilostazol was found to increase the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in synovial cells. Thus, the present study was undertaken to examine whether cilostazol is able to counteract tumor necrosis factor-alpha (TNF-alpha)-induced cell death in endothelial cells via the induction of HO-1 expression. We exposed human umbilical vein endothelial cells (HUVECs) to TNF-alpha (50 ng/ml), with or without cilostazol (10 uM). Pretreatment with cilostazol markedly reduced TNF-alpha-induced viability loss in the HUVECs, which was reversed by zinc protoporphyrine IX (ZnPP), an inhibitor of HO-1. Moreover, cilostazol increased HO-1 protein and mRNA expression. Cilostazol induced HO-1 induction was markedly attenuated not only by ZnPP but also by copper-protoporphyrin IX (CuPP). In an assay measuring peroxisome proliferator activated receptor-gamma (PPAR-gamma) transcription activity, cilostazol directly increased PPAR-gamma transcriptional activity which was completely abolished by HO-1 inhibitor. Furthermore, increased PPAR-gamma activity by cilostazol and rosiglitazone was completely abolished in cells transfected with HO-1 siRNA. Taken together, these results indicate that cilostazol up-regulates HO-1 and protects cells against TNF-alpha-induced endothelial cytotoxicity via a PPAR gamma-dependent pathway. PMID- 21660149 TI - Regulation of DREAM Expression by Group I mGluR. AB - DREAM (downstream regulatory element antagonistic modulator) is a calcium-binding protein that regulates dynorphin expression, promotes potassium channel surface expression, and enhances presenilin processing in an expression level-dependent manner. However, no molecular mechanism has yet explained how protein levels of DREAM are regulated. Here we identified group I mGluR (mGluR1/5) as a positive regulator of DREAM protein expression. Overexpression of mGluR1/5 increased the cellular level of DREAM. Up-regulation of DREAM resulted in increased DREAM protein in both the nucleus and cytoplasm, where the protein acts as a transcriptional repressor and a modulator of its interacting proteins, respectively. DHPG (3,5-dihydroxyphenylglycine), a group I mGluR agonist, also up regulated DREAM expression in cortical neurons. These results suggest that group I mGluR is the first identified receptor that may regulate DREAM activity in neurons. PMID- 21660150 TI - Characterization and immunopotentiating effects of the glycoprotein isolated from dioscorea batatas. AB - We demonstrate that glycoprotein isolated from Dioscorea batatas (GDB) has immunostimulatory effects including macrophage activation. Analysis of infiltration of inflammatory cells into peritoneal cavity showed GDB treatment significantly increased the recruitment of macrophages, lymphocytes, neutrophils, and monocytes into the peritoneal cavity. Treatment of spleen cells isolated from C57BL/6 mice with GDB significantly increased the proliferation of B cells and T cells induced by LPS and ConA, respectively. Treatment with GDB significantly increased the cytolytic capacity of NK cells and macrophages against YAC-1 and B16 cells, respectively. In order to further confirm and investigate the mechanism of GDB on macrophage activation, we analyzed the effects of GDB on the cytokine expression including iNOS, IL-1beta, and TNF-alpha in mouse macrophage cell line, RAW 264.7 cells. RT-PCR and ELISA showed that GDB increased the expression of IL-1beta, and TNF-alpha, whereas iNOS was not induced by GDB. Collectively, this series of experiments indicates that GDB stimulates immune system including macrophage activation. PMID- 21660146 TI - Modern methods for analysis of antiepileptic drugs in the biological fluids for pharmacokinetics, bioequivalence and therapeutic drug monitoring. AB - Epilepsy is a chronic disease occurring in approximately 1.0% of the world's population. About 30% of the epileptic patients treated with availably antiepileptic drugs (AEDs) continue to have seizures and are considered therapy resistant or refractory patients. The ultimate goal for the use of AEDs is complete cessation of seizures without side effects. Because of a narrow therapeutic index of AEDs, a complete understanding of its clinical pharmacokinetics is essential for understanding of the pharmacodynamics of these drugs. These drug concentrations in biological fluids serve as surrogate markers and can be used to guide or target drug dosing. Because early studies demonstrated clinical and/or electroencephalographic correlations with serum concentrations of several AEDs, It has been almost 50 years since clinicians started using plasma concentrations of AEDs to optimize pharmacotherapy in patients with epilepsy. Therefore, validated analytical method for concentrations of AEDs in biological fluids is a necessity in order to explore pharmacokinetics, bioequivalence and TDM in various clinical situations. There are hundreds of published articles on the analysis of specific AEDs by a wide variety of analytical methods in biological samples have appears over the past decade. This review intends to provide an updated, concise overview on the modern method development for monitoring AEDs for pharmacokinetic studies, bioequivalence and therapeutic drug monitoring. PMID- 21660151 TI - Suppression of autophagy and activation of glycogen synthase kinase 3beta facilitate the aggregate formation of tau. AB - Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3beta has been reported to play a major role in the NFT formation of tau. Dysfunction of autophagy might facilitate the aggregate formation of tau. The present study examined the role of GSK3beta-mediated phosphorylation of tau species on their autophagic degradation. We transfected wild type tau (T4), caspase-3-cleaved tau at Asp421 (T4C3), or pseudophosphorylated tau at Ser396/Ser404 (T4-2EC) in the presence of active or enzyme-inactive GSK3beta. Trehalose and 3-methyladenine (3-MA) were used to enhance or inhibit autophagic activity, respectively. All tau species showed increased accumulation with 3-MA treatment whereas reduced with trehalose, indicating that tau undergoes autophagic degradation. However, T4C3 and T4-2EC showed abundant formation of oligomers than T4. Active GSK3beta in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3beta-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation. PMID- 21660153 TI - The james a vohs award for quality-the seventh annual permanente journal special issue. PMID- 21660154 TI - Tobacco dependence program: a multifaceted systems approach to reducing tobacco use among kaiser permanente members in northern california. PMID- 21660152 TI - Matrix metalloproteinase inhibitors attenuate neuroinflammation following focal cerebral ischemia in mice. AB - The aim of this study was to investigate whether matrix metalloproteinase (MMP) inhibitors attenuate neuroinflammation in an ischemic brain following photothrombotic cortical ischemia in mice. Male C57BL/6 mice were anesthetized, and Rose Bengal was systemically administered. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold white light. MMP inhibitors, such as doxycycline, minocycline, and batimastat, significantly reduced the cerebral infarct size, and the expressions of monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF alpha), and indoleamine 2,3-dioxygenase (IDO). However, they had no effect on the expressions of heme oxygenase-1 and neuroglobin in the ischemic cortex. These results suggest that MMP inhibitors attenuate ischemic brain injury by decreasing the expression levels of MCP-1, TNF-alpha, and IDO, thereby providing a therapeutic benefit against cerebral ischemia. PMID- 21660155 TI - The kaiser permanente northwest cardiovascular risk factor management program: a model for all. AB - Proof of the effectiveness of preventive measures that reduce established risk traits for atherothrombotic disorders has spurred attempts to systematically apply these interventions among susceptible populations. One such attempt is the Cardiovascular Risk Factor Management (CVRFM) Program, launched in 2003 to optimize clinical management and outcomes for 75,000 Kaiser Permanente Northwest Region (KPNW) members with atherosclerotic cardiovascular disease (CVD) or hypertension. The CVRFM Program is a centralized, multidisciplinary, proactive telephone-based clinical management intervention consisting of an "outreach" call, an interview, a mailed individualized care plan and information packet, regular follow-up (including protocolized medication management) and-when "goal status" is achieved-transfer of the patient to a maintenance plan.Quarterly evaluation of effectiveness entailed measurement of a range of clinical, utilization, and member satisfaction outcomes. Results by the fourth quarter were outstanding: For example, >98% of participants with coronary disease or diabetes had LDL cholesterol testing, >90% of coronary patients received aspirin or statin treatment, 99% were "extremely" or "very" satisfied with the program, and reductions were observed in the number of hospitalizations and visits to the emergency department and clinic. Mathematical models predict a decrease in myocardial infarctions and cardiovascular mortality within two years after implementing the program, the underlying principles of which should yield similar improvement in other Kaiser Permanente (KP) Regions and in other health care organizations. PMID- 21660156 TI - The Second David M Lawrence, MD, Chairman's Patient Safety Award. PMID- 21660157 TI - Perinatal patient safety project. AB - The Perinatal Patient Safety Project (PPSP) was created as a systemic strategy for creating high-reliability perinatal units by preventing identified causes of perinatal events in the clinical setting. With developmental funding from a Garfield grant, implementation of the PPSP has been completed at four pilot sites in the Kaiser Permanente Northern California (KPNC) Region. Its success has resulted in implementation at all perinatal units in the KPNC Region as well as being promoted by National Risk Management for nationwide implementation. PPSP emphasizes structured communication, multidisciplinary rounds, a definition of fetal well-being, and practicing for emergencies. Steps taken to create high reliability perinatal care include improved communication, patient safety focus, and satisfaction among perinatal patients, providers, and staff. PMID- 21660158 TI - KP Northwest Preoperative Briefing Project. AB - In June 2001, members of the KP Northwest Region (KPNW) Patient Safety Team attending a Human Factors training program considered the patient safety challenges faced in the operating suite and identified pre-operative briefing as a necessary component of safe practice. After receiving the Human Factors training, the KPNW Patient Safety Team obtained sponsorship for a pilot project to develop preoperative briefing as a way to transform the patient safety culture in the KP Northwest Region's operating suites and to reduce the number of errors (especially burns). The project led to the KP Sunnyside Medical Center's current policy requiring preoperative briefing before each surgical intervention so that information regarding the patient's care is verified and shared.Since initiation of the preoperative briefings-which are increasingly being conducted on a routine basis-a trend of decreasing accidental injuries has been observed in the operating suite. In addition, recent questionnaire responses show an improved team culture of safety and an improved overall work climate (including such factors as teamwork, safety, perceptions of management, and working conditions). Measures reported by surgical teams in Orange County (California) and KPNW indicate the project can be transferred successfully. Staff are also expanding the briefings project to the ambulatory setting. PMID- 21660160 TI - The electronic health record "toolbox". PMID- 21660159 TI - Pain Management Doesn't have to be a Pain: Working and Communicating Effectively with Patients who have Chronic Pain. PMID- 21660161 TI - The permanente journal cosponsorship of the evidence-based medicine symposium, december 3 & 4, 2004. PMID- 21660162 TI - Permanente medicine in a changing world: challenges and opportunities. PMID- 21660164 TI - Acquiring evidence-tips for effective literature searching. PMID- 21660163 TI - The care management institute: making the right thing easier to do. PMID- 21660165 TI - Balance sheets: tools to inform changes in practice. PMID- 21660166 TI - From evidence to outcomes: implementing clinically effective and cost-efficient population-based interventions. PMID- 21660167 TI - Evidence-based medicine and population-based care: caring for patients with heart failure. PMID- 21660169 TI - Integrating Evidence Into KP HealthConnect: Making the Right Thing Easier to Do. PMID- 21660168 TI - Sharing clinical decisions by discussing evidence with patients. PMID- 21660170 TI - Diffusing innovation in your practice. PMID- 21660171 TI - KP Evidence-Based Medicine in the Community. PMID- 21660172 TI - Evidence-based guidelines. AB - The Advanced/Policy Track of the 2004 Kaiser Permanente Evidence-Based Medicine Symposium was an interactive session that focused on developing evidence-based clinical practice guidelines. The hypothetical scenario involved the imaginary drug "Memoryboost," a treatment for dementia. The participants were given materials describing the national Kaiser Permanente (KP) methodology for developing evidence-based guidelines and a summary of the highest-quality articles about the efficacy of this drug. The participants then formed small groups and used this information to develop a recommendation about its use for the treatment of dementia. In spite of having the same evidence, the groups developed three different recommendations. The entire group then explored some of the reasons for this variability. This article also addresses the reasons KP develops its own national guidelines, as well as who oversees the national guideline initiative and who develops guidelines. PMID- 21660173 TI - Care, Whether it's Called Population-or Disease-Management, Sidney Garfield, MD, Would Like the Idea. PMID- 21660175 TI - Enclave services: an office with a purpose. PMID- 21660174 TI - Managing high-risk, high-cost patients: the southern california kaiser permanente experience in the medicare ESRD demonstration project. PMID- 21660176 TI - The current role of sublingual immunotherapy in the treatment of allergic rhinitis in adults and children. AB - Allergic rhinitis is a very common disease affecting about 20% of people. It may be treated by allergen avoidance when possible, by antiallergic drugs such as antihistamines and topical corticosteroids, and by allergen-specific immunotherapy. The latter is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy and is able to maintain its efficacy even after stopping, provided an adequate duration of treatment of 3-5 years is ensured. Sublingual immunotherapy (SLIT) was introduced in the 1990s as a possible solution to the problem of adverse systemic reactions to subcutaneous immunotherapy and has been demonstrated by more than 50 trials and globally evaluated thus far by five meta-analyses as an effective and safe treatment for allergic rhinitis. Life-threatening reactions are extremely rare. However, it is important to note that clinical efficacy occurs only if SLIT meets its needs, ie, sufficiently high doses are regularly administered for at least 3 consecutive years. This is often overlooked in the current practice and may prevent the same success reported by trials from being achieved. PMID- 21660177 TI - Anti-inflammatory effects of pre-seasonal Th1-adjuvant vaccine to Parietaria judaica in asthmatics. AB - BACKGROUND: The ultra-short course pre-seasonal allergy vaccine, containing appropriate allergoids with the adjuvant monophosphoryl lipid A (MPL), may be effective in treating allergic symptoms. OBJECTIVE: To explore the timing of the immunological responses to the pre-seasonal allergy vaccine. METHODS: Four subcutaneous injections of the active product (Pollinex Quattro) were administered to 20 Parietaria-sensitive intermittent asthmatics (M/F: 12/8; age: 48 +/- 10 years; FEV(1)% predicted: 108% +/- 12%) during the 6 weeks prior to the start of the pollen season. Exhaled breath condensate (EBC) was collected immediately before the first and immediately after the last injections (t(1) and t(2)), during the pollen season (t(3)) and after (t(4)) the pollen season. EBC was analyzed to determine the levels of pH and 8-isoprostane. Ten Parietaria sensitive asthmatics served as the untreated control group at t(1) and t(2). RESULTS: Measured pH levels were 7.64 +/- 0.33 at t(1), 7.67 +/- 0.23 at t(2), 7.72 +/- 0.34 at t(3), and 7.82 +/- 0.34 at t(4) (P = 0.049 vs baseline). 8 isoprostane levels were significantly lower than baseline at each visit (mean difference from baseline, for t(2): -0.77 pg, P = 0.031; for t(3): -0.92 pg, P = 0.010; for t(4): -0.70 pg, P = 0.048). In the control group, pH levels were 7.73 +/- 0.26 at baseline and did not change after 6 weeks (7.79 +/- 0.25, P = 0.33). Similarly, the concentrations of 8-isoprostane in the control group were not different from those of the study group at baseline (P = 0.86), and the levels remained unchanged after 6 weeks (P = 0.58). CONCLUSION: These findings show that the ultra-short course of vaccine adjuvated with MPL acutely reduces the degree of airway inflammation, as expressed by markers of oxidative stress, and suggest that this reduction is maintained during and after the pollen season. PMID- 21660178 TI - The meaning of awaiting bariatric surgery due to morbid obesity. AB - BACKGROUND: The understanding of the association between the objective conditions of health and the subjective perceptions of morbidly obese patients appears to be poor. The use of objective indicators alone produces results totally unrelated to the feelings and experiences of the bariatric patients studied. No study has approached the bariatric patient from both an inside and a preoperative perspective. PURPOSE: The aim of this study was to investigate the meaning of awaiting bariatric surgery due to morbid obesity. METHOD: Twenty-three patients admitted to a Swedish University Hospital for bariatric surgery were included. Data were collected by interviews and the analysis was performed using the phenomenological hermeneutics method developed by Lindseth and Norberg. MAIN FINDINGS: Two structural thematic analyses revealed six main themes: experiencing food as a complex element in life, feeling hopeless regarding weight loss, living in fear of future sickness and death, living a restricted life, being ignored by health care professionals and hoping for control and opportunities. The informants experienced addiction to food and dependence on others for managing their daily life, which constituted an infringement of their freedom. Loss of control meant giving in to the desire for food, but also being subjected to stigmatizing remarks from persons in their environment or uncaring approaches from health care professionals. CONCLUSION: Being scheduled for bariatric surgery meant developing an awareness of how completely dependent they were on surgery for their survival and prospective health. The scheduled bariatric surgery constituted tangible confirmation that weight loss and restored health were possible. PMID- 21660179 TI - The attending nurse: an evolving model for integrating nursing education and practice. AB - The discipline of nursing continues to evolve in keeping with the dramatic expansion of scientific knowledge, technology, and a concomitant increase in complexity of patient care in all practice settings. Changing patient demographics require complex planning for co-morbidities associated with chronic diseases and life-saving advances that have altered mortality in ways never before imagined. These changes in practice, coupled with findings from sophisticated nursing research and the continuous development of new nursing knowledge, call for realignments of the relationships among academic faculty in schools of nursing, advanced practice nurse administrators, and staff nurses at the forefront of practice. This article offers a model designed to bridge the gaps among academic settings, administrative offices and the euphemistic "bedsides" where staff nurses practice. Here we describe the nurse attending model in place at the New York University Langone Medical Center (NYULMC) and provide qualitative data that support progress in our work. PMID- 21660180 TI - Longitudinal evaluation of the impact of placement development teams on student support in clinical practice. AB - AIMS: To investigate the impact of a new structure for supporting healthcare students and mentors in practice placements (Placement Development Teams). INTRODUCTION: The English Model National Partnership Agreement for healthcare education required Strategic Health Authorities, Higher Education Institutions and National Health Service Trusts to redesign strategies for student support. Placement Development Teams are one English University's response to this. MATERIALS AND METHODOLOGY: This study was phase 2 of a longitudinal qualitative evaluation of Placement Development Teams. Data were collected after establishment of Placement Development Teams, and compared and contrasted with those collected prior to their implementation. Telephone interviews were conducted with key educational stakeholders in Trusts and Strategic Health Authorities. Focus groups were conducted with third year non-medical healthcare students and first year paramedics working in 16 NHS Trusts in the south west peninsula of England. RESULTS: Pre-Placement Development Teams, themes from the students' data were: Supportive and unsupportive behaviour of staff; Mentor allocation; Placement allocation; Benefits of students to the placement area and Perceived control over the learning experience. Post-Placement Development Teams, the themes were Communication; Supportive and unsupportive behaviour of staff; The effect of peers on the placement experience; Knowledge and perceptions of the work of the PDTs. Form the staff data, pre-Placement Development Teams the themes were: Vision for improving student support. Post-Placement Development Teams themes from the staff data were how they provided a central point of contact for student and mentor support; and how they supported students and mentors. CONCLUSION: Support of students and mentors is particularly important following the introduction of The English Model National Partnership Agreement for healthcare education. Placement Development Teams can facilitate partnership working between higher education institutions and placement providers for student support. PMID- 21660182 TI - A nurse-led telephone session and quality of life after radiotherapy among women with breast cancer: a randomized trial. AB - The purpose of this study was to investigate whether a nurse-led telephone session with patients suffering from breast cancer approximately ten days after final radiotherapy treatment affected their quality of life two to four weeks after radiotherapy. The study was conducted at the Radiotherapy ward at Vejle Hospital, Denmark between January and May 2010. The study population consisted of 100 patients, who were randomized with a 1:1 ratio to have either ordinary supportive conversations (control group), or ordinary supportive conversations and a supplementary nurse-led telephone session (intervention group). The quality of life was assessed using the questionnaires EORTC QLQ-C30 and EORTC QLQ-BR23. For statistical comparison of quality of life and for adjustment for covariates, multiple linear regression analysis was conducted. The mean [95 % CI] quality of life was 72.0 [66.4-77.6] in the control group and 69.9 [64.3-75.2] in the intervention group. Adjustment for covariates did not change the estimates. No statistically significant differences were found in the groups in either of the analyses. The nurse-led telephone session had no positive effect on the quality of life of patients with breast cancer two to four weeks after their final radiotherapy. PMID- 21660181 TI - Barriers and benefits associated with nurses information seeking related to patient education needs on clinical nursing units. AB - The purpose of this study was to answer the following two questions: What are clinical nurses' rationales for their approaches to finding patient educational materials on the web? What are perceived barriers and benefits associated with the use of web-based information resources for patient education in the context of nursing clinical practice?Over 179 individual data units were analyzed to understand clinical nurses' rationales for their approaches to find patient educational materials on the web. Rationales were defined as those underlying catalysts or activators leading to an information need. Analyses found that the primary reasons why clinical nurses conducted web-based information searches included direct patient requests ( 9 requests), colleague requests (6 requests), building patient materials collections (4), patients' family requests (3), routine teaching (1), personal development (1), or staff development (1). From these data, four broad themes emerged: professional reasons, personal reasons, technology reasons, and organization reasons for selecting information resources. Content analysis identified 306 individual data units representing either 'benefits' (178 units) or 'barriers' (128) to the nurses' use of web resources for on-unit patient care. Inter-rater reliability was assessed and found to be excellent (r = 0.943 to 0.961). The primary themes that emerged as barriers to the used of web-based resources included: 1) time requirements to perform a search, 2) nurses' experience and knowledge about the resources or required technology, 3) specific characteristics of individuals electronic information resources, and 4) organizational procedures and policies. Three primary themes that represented the benefits of using web-based resources were also identified: 1) past experiences and knowledge of a specific resource or the required technologies, 2) availability and accessibility on the unit, and 3) specific characteristics of individual information tool. In many cases, nurses commented on specific characteristics or features of favorite information resources. Favorite sites included a variety or reputable health care organizations that displayed context in text, audio, and/or video. In addition such sites were described as easy-to read and provided content related to patient-focused information or specific content such as toll free telephone contact numbers.Information searching is the interaction between and among information users and computer-based information systems. Information seeking is becoming an important part of the knowledge work of nurses. Information seeking and searching intersects with the field of human computer interaction (HCI), which focuses on all aspects of human, and computer interactions. Users of an information system are understood as "actors" in situations, with a set of skills and shared practices based on work experiences with others. Designing better tools and developing information searching strategies that support, extend, and transform practices, begins by asking: Who are the users? What are the tasks? What is the interplay between the technology and the organization of the task? This study contributes fundamental data and information about the rationales nurses use in information seeking tasks. In addition it provides empirical evidences regarding barriers and benefits of information seeking in the context of patient education needs in inpatient clinical settings. PMID- 21660183 TI - Implementing and evaluating the first german young-carers project: intentions, pitfalls and the need for piloting complex interventions. AB - The aim of the study was to develop, implement and evaluate a concept for the first support program for young carers and their families in Germany. This paper intends to critically review the implementation of that study and describe the problems experienced by the research team, including: the complexity of the intervention itself, the difficulty of finding host organizations, the lack of infrastructure, different values and beliefs about the project aims held between the host organization and the research team, shortage of time, identifying and recruiting families among the hidden population of young carers. These initial problems led to the re-constructuring of the original research design. In order to evaluate factors that influenced these difficulties, the original research intentions, emerging problems and their consequences will be presented. PMID- 21660184 TI - The Role of Microtubule Association in Plasmodesmal Targeting of Potato mop-top virus Movement Protein TGBp1. AB - Cell-to-cell movement of Potato mop-top virus (PMTV) is mediated by three virus encoded 'triple gene block' (TGB) proteins termed TGBp1, TGBp2 and TGBp3. TGBp1 binds virus RNAs to form viral ribonucleoprotein complexes (vRNPs), the transport form of viral genome. TGBp2 and TGBp3 are necessary for intracellular delivery of TGBp1-containing vRNPs to plasmodesmata. To analyze subcellular localization and transport of TGBp1 we used a single binary vector for agrobacterium-mediated co expression of PMTV TGBp1 fused to green fluorescent protein and TGBp2/TGBp3. At two days post infiltration (dpi) TGBp1 was found in the nucleus and in association with microtubules (MTs). Similar localization pattern was revealed in cells expressing GFP-TGBp1 alone after particle bombardment. At 3 dpi, in addition to the nucleus and MTs, TGBp1 was detected in numerous granular bodies located both along the MTs and at the cell wall. The latter structures co localized with plasmodesmata-associated callose depositions. At 4 dpi, GFP-TGBp1 was detected in cell wall-associated bodies and also in residual MTs, the nucleoplasm and large perinuclear inclusions resembling aggresomes. Therefore GFP TGBp1 association with MTs preceded to its localization to plasmodesmata. Disassembly of cell MTs by colchicine prevented GFP-TGBp1 targeting to plasmodesmata and the MT-dependent aggresome formation. Deletion analysis also revealed a correlation between TGBp1 microtubule association and plasmodesmata targeting. We propose that TGBp1 interaction with MTs may be important for the formation of vRNP bodies destined for the transport to plasmodesmata as well as degradation of the excessive TGBp1. PMID- 21660185 TI - In Vivo Interaction of the Hepatitis Delta Virus Small Antigen with the ELAV-Like Protein HuR. AB - The small and large delta antigens (S-HDAg and L-HDAg, respectively) represent two forms of the only protein encoded by the hepatitis delta virus (HDV) RNA genome. Consequently, HDV relies, at a large extent, on the host cell machinery for replication and transcription. Until now, only a limited number of cellular proteins were identified as S-HDAg or L-HDAg partners being involved in the modulation of the virus life cycle. In an attempt to identify cellular S-HDAg binding proteins we made use of a yeast two-hybrid approach to screen a human liver cDNA library. We were able to identify HuR, a ubiquitously expressed protein involved in RNA stabilization, as an S-HDAg partner both in vitro and in vivo. HuR was found to be overexpressed and colocalize with HDAg in human hepatoma cells. siRNA knockdown of HuR mRNA resulted in inhibition of S-HDAg and L-HDAg expression. PMID- 21660186 TI - Phylogenesis and Clinical Aspects of Pandemic 2009 Influenza A (H1N1) Virus Infection. AB - During the spring of 2009, a new influenza A (H1N1) virus of swine origin emerged and spread worldwide causing a pandemic influenza. Here, 329 naso-pharyngeal swabs collected from patients with flu-like symptoms were analyzed by real-time PCR for the presence of H1N1 2009 pandemic virus. Twenty-five samples collected from immunocompetent and immunodepressed patients contained the H1N1 pandemic virus. Phylogenetic analysis of the hemagglutinin and neuraminidase genes showed no obvious differences in terms of similarity and/or homology between the sequences identified in immunocompetent individuals and those obtained from immunocompromised patients. Pre-existing clinical conditions may influence the outcome of H1N1 disease. PMID- 21660187 TI - Modulation of HIV Binding to Epithelial Cells and HIV Transfer from Immature Dendritic Cells to CD4 T Lymphocytes by Human Lactoferrin and its Major Exposed LF-33 Peptide. AB - Lactoferrin (LF), a multifunctional molecule present in human secretions, has potent inhibitory activities against human immunodeficiency virus (HIV). The aim of the study was to evaluate whether human LF (hLF) and its exposed domain LF-33 represented by the peptide (LF-33-GRRRRSVQWCAVSQPEATKCFQWQRNMRKVRGP) involved in LF-HIV gag binding and endotoxines neutralization, may inhibit early steps of HIV mucosal transmission. Human LF and the peptide LF-33 inhibited the attachment of primary X4-tropic HIV-1(NDK) and R5-tropic HIV-1(JR-CSF) strains to human endometrial (HEC-1) and colorectal (HT-29) CD4-negative epithelial cells, the purified hLF being more potent (up to 80%) than the LF-33 peptide. In addition, the hLF, but not the LF-33 peptide, inhibited up to 40% the transfer in trans of HIV-1(JR-CSF) and HIV-1(NDK,) from immature dendritic cells to CD4 T lymphocytes, likely in a DC-SIGN-dependent manner. Altogether, these findings demonstrate that hLF can interfere with HIV-1 mucosal transmission by blocking virus attachment to epithelial cells and by inhibiting virus transfer from dendritic cells to CD4 T cells, two crucial steps of HIV dissemination from mucosae to lymphoid tissue. PMID- 21660189 TI - Inhibition of HIV-1 Env-Mediated Cell-Cell Fusion by Lectins, Peptide T-20, and Neutralizing Antibodies. AB - BACKGROUND: Broadly cross-reactive, neutralizing human monoclonal antibodies, including 2F5, 2G12, 4E10 and IgG1 b12, can inhibit HIV-1 infection in vitro at very low concentrations. We examined the ability of these antibodies to inhibit cell-cell fusion between Clone69TRevEnv cells induced to express the viral envelope proteins, gp120/gp41 (Env), and highly CD4-positive SupT1 cells. The cells were loaded with green and red-orange cytoplasmic fluorophores, and fusion was monitored by fluorescence microscopy. RESULTS: Cell-cell fusion was inhibited completely by the carbohydrate binding proteins (CBPs), Hippeastrum hybrid (Amaryllis) agglutinin (HHA), and Galanthus nivalis (Snowdrop) agglutinin (GNA), and by the peptide, T-20, at relatively low concentrations. Anti-gp120 and anti gp41 antibodies, at concentrations much higher than those required for neutralization, were not particularly effective in inhibiting fusion. Monoclonal antibodies b12, m14 IgG and 2G12 had moderate inhibitory activity; the IC(50) of 2G12 was about 80 ug/ml. Antibodies 4E10 and 2F5 had no inhibitory activity at the concentrations tested. CONCLUSIONS: These observations raise concerns about the ability of neutralizing antibodies to inhibit the spread of viral genetic material from infected cells to uninfected cells via cell-cell fusion. The interaction of gp120/gp41 with cell membrane CD4 may be different in cell-cell and virus-cell membrane fusion reactions, and may explain the differential effects of antibodies in these two systems. The fluorescence assay described here may be useful in high throughput screening of potential HIV fusion inhibitors. PMID- 21660188 TI - Genetic and Immunological Factors Involved in Natural Resistance to HIV-1 Infection. AB - Infection with Human immunodeficiency virus type-1 (HIV-1) induces severe alterations of the immune system leading to an increased susceptibility to opportunistic infections and malignancies. However, exposure to the virus does not always results in infection. Indeed, there exist individuals who have been repeatedly exposed to HIV-1 but do not exhibit clinical or serological evidence of infection, known as exposed seronegative individuals. Many studies have focused on the different mechanisms involved in natural resistance to HIV-1 infection, and have reported several factors associated with this phenomenon, including the presence of genetic polymorphisms in the viral coreceptors, innate and adaptive immune cells with particular phenotypic and functional features, and molecules such as antibodies and soluble factors that play an important role in defense against infection by HIV-1. The study of these factors could be the key for controlling this viral infection. This review summarizes the main mechanisms involved in resistance to HIV-1 infection. PMID- 21660190 TI - Detection and identification of common food-borne viruses with a tiling microarray. AB - Microarray hybridization based identification of viral genotypes is increasingly assuming importance due to outbreaks of multiple pathogenic viruses affecting humans causing wide-spread morbidity and mortality. Surprisingly, microarray based identification of food-borne viruses, one of the largest groups of pathogenic viruses, causing more than 1.5 billion infections world-wide every year, has lagged behind. Cell-culture techniques are either unavailable or time consuming for routine application. Consequently, current detection methods for these pathogens largely depend on polymerase chain reaction (PCR) based techniques, generally requiring an investigator to preselect the target virus of interest. Here we describe the first attempt to use the microarray as an identification tool for these viruses. We have developed methodology to synthesize targets for virus identification without using PCR, making the process genuinely sequence independent. We show here that a tiling microarray can simultaneously detect and identify the genotype and strain of common food-borne viruses in a single experiment. PMID- 21660191 TI - Sprengel's deformity of the shoulder: Current perspectives in management. AB - Sprengel's deformity or congenital elevation of scapula is a complex deformity of the pectoral girdle, and results in symptomatic cosmetic and functional disability. Several studies have attempted to analyze the three-dimensional aspects of this deformity; optimal methodologies of quantification and surgical correction techniques have been debated since the condition was first described. This article presents a concise review of the exact pathoanatomy, clinical presentation, imaging techniques, and surgical procedures described in the management of this condition. PMID- 21660193 TI - Use of a partial humeral head resurfacing system for management of an osseous mechanical block to glenohumeral joint range of movement secondary to proximal humeral fracture malunion. AB - Malunion of proximal humeral fractures can lead to a severely impaired shoulder function. Loss of motion is often the main issue in patients and can be secondary to osseous, soft-tissue as well as neurological damage to the shoulder. Malunion of the articular surface of the humeral head can lead to pain, chronic degenerative changes secondary to joint incongruity and mechanical block to the range of movement. A 46-year-old otherwise healthy male chef presented with malunion and collapse of his previous plate fixation for a four-part proximal humerus fracture. We describe the first documented case of the use of a focal resurfacing system for dealing with such an osseous mechanical block in the presence of an otherwise preserved articular surface in a high-demand patient. HemiCAP can be successfully used in proximal humeral fracture malunion where there is a localized cartilage defect, allowing restoration of joint congruity while preserving the bone stock. PMID- 21660192 TI - Systematic review of the surgical treatment for symptomatic os acromiale. AB - The optimal surgical treatment for symptomatic os acromiale that has failed nonoperative management is unclear in the literature. We conducted a systematic review of multiple medical databases for level I-IV evidence. Both radiographic and clinical outcomes were analyzed. Nine studies met the inclusion criteria (118 subjects, 125 shoulders). One hundred and fifteen subjects were treated surgically (122 shoulders). The mean age of the subjects was 49+/-11 years. The mean preoperative duration of symptoms was 12+/-8.6 months. Mesoacromiale was the most common type treated (94%). Internal fixation was the most common surgical technique used (60%), followed by excision (27%) and acromioplasty (13%). Rotator cuff repair was the most common concurrent surgical technique (performed in 59% of the surgically treated shoulders), followed by distal clavicle excision (25%). All surgical techniques resulted in improvement in clinical outcomes. Surgical management of symptomatic os acromiale that has failed nonoperative measures may predictably lead to improved outcomes. PMID- 21660194 TI - The anterolateral approach to the proximal humerus for nonunions and delayed unions. AB - Nonunions of proximal humerus fractures can be disabling as a result of pain, deformity and instability, and are often found in geriatric patients with poor bone quality. There are relatively few studies examining the treatment of nonunions of the proximal third of the humerus and the ideal treatment and surgical approach remains unclear. This case series reports the successful use of the anterolateral acromial approach for treatment of the symptomatic proximal third humerus nonunions in a geriatric group of patients with clear challenges as a result of patient comorbidities and bone quality. PMID- 21660195 TI - Bilateral hypoplasia of the long head of the biceps brachii muscle. PMID- 21660197 TI - Editorial: secondary dyslipidemias. PMID- 21660196 TI - Rectus sheath hematoma: a simplified emergency surgical approach. AB - Rectus sheath hematoma (RSH) is an uncommon clinical event usually associated with trauma or coagulation disorders. It can also occur spontaneously. RSH usually runs a benign course but it can present with hypovolemic shock. When conservative management fails, surgical exploration becomes mandatory. We propose a technique of emergency ligation of the inferior epigastric artery. This is a simple approach as this artery originates at the posterior rectus sheath above the inguinal ligament. This safe technique provides immediate hemodynamic stabilization. PMID- 21660198 TI - Aza-Nazarov cyclization cascades. AB - Benzamides with tethered acetal groups undergo reactions in CF(3)SO(3)H to give ring-fused isoindolinones by a cyclization cascade. The reaction initially forms an N-acyliminium ion which then gives the isoindolinone by the aza-Nazarov reaction. An unusual variant also cyclizes at the allylic position. PMID- 21660199 TI - Rheumatoid arthritis-associated interstitial lung disease: diagnostic dilemma. AB - Interstitial lung disease (ILD) is an increasingly recognized complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Diagnosis can be challenging since patients are unlikely to report dyspnea due to an overall decrease in physical activity with advanced arthritic symptoms. Additionally, infections, drug toxicity, and environmental toxins can mimic ILD, creating significant diagnostic dilemmas for the clinician. In this paper we will explore an effective clinical algorithm for the diagnosis of RA ILD. We will also discuss features of drug-related toxicities, infections, and environmental toxins that comprise the main entities in the differential diagnosis of RA-ILD. Finally, we will explore the known and experimental treatment options that may have some benefit in the treatment of RA-ILD. PMID- 21660200 TI - Memory Awareness Influences Everyday Decision Making Capacity about Medication Management in Alzheimer's Disease. AB - Memory awareness in early Alzheimer's disease (AD) influences capacity to provide informed consent for a memory treatment. This study investigated the extent to which aspects of memory awareness influence everyday decision-making capacity about medication management in AD. 42 participants with mild AD and 50 healthy elders underwent clinical ratings of memory awareness, metamemory testing, and an interview of everyday decision-making capacity regarding medication management. 45% of AD subjects were classified as aware (AAD) and 55% as unaware (UAD) based on clinical ratings and supported by metamemory testing (P = .015). Capacity was impaired in each of the AD groups as compared to the healthy elders F(2, 67) = 17.63, UAD, P < .01; AAD, P = .01). Within the AD group, capacity correlated selectively with awareness as measured with clinical ratings (r = -.41, P = .007) but not objective metamemory testing (r = -.10, P = .60 ). Appreciation scores were lower in UAD as compared with AAD F(1,35) = 8.36, P = .007. Unawareness of memory loss should heighten clinicians' concern about everyday decision-making capacity in AD. PMID- 21660201 TI - Adherence with preventive medication in childhood asthma. AB - Suboptimal adherence with preventive medication is common and often unrecognised as a cause of poor asthma control. A number of risk factors for nonadherence have emerged from well-conducted studies. Unfortunately, patient report a physician's estimation of adherence and knowledge of these risk factors may not assist in determining whether non-adherence is a significant factor. Electronic monitoring devices are likely to be more frequently used to remind patients to take medication, as a strategy to motivate patients to maintain adherence, and a tool to evaluate adherence in subjects with poor disease control. The aim of this paper is to review non-adherence with preventive medication in childhood asthma, its impact on asthma control, methods of evaluating non-adherence, risk factors for suboptimal adherence, and strategies to enhance adherence. PMID- 21660203 TI - The Development and Evaluation of Procedures to Assess Child Self-report Item Validity. AB - Cognitive pretesting (CP) is an interview methodology for pretesting the validity of items during the development of self-report instruments. The present research evaluates a systematic approach to the analysis of CP data. Materials and procedures were developed to rate self-report item performance with CP interview text data. Five raters were trained in the application of that system. Estimates of inter-rater reliability found acceptable to substantial levels of inter-rater agreement. Results from the present study suggest that excellent inter-rater reliability can be achieved in the evaluation of CP data. Guidelines for systematically rating the qualitative data collected using CP methods are provided. Future research should focus on empirical demonstrations of how such rating procedures can lead to improvements in self-report instruments. PMID- 21660204 TI - Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus. AB - The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is still challenging. Alzheimer's disease (AD), along with vascular dementia, the most important differential diagnosis for iNPH, has several potential cerebrospinal fluid (CSF) biomarkers which might help in the selection of patients for shunt treatment. The aim of this study was to compare a battery of CSF biomarkers including well-known AD-related proteins with CSF from patients with suspected iNPH collected from the external lumbar drainage test (ELD). A total of 35 patients with suspected iNPH patients were evaluated with ELD. CSF was collected in the beginning of the test, and the concentrations of total tau, ptau(181), Abeta(42), NFL, TNF-alpha, TGFbeta1, and VEGF were analysed by ELISA. Twenty-six patients had a positive ELD result-that is, their gait symptoms improved; 9 patients had negative ELD. The levels of all analyzed CSF biomarkers were similar between the groups and none of them predicted the ELD result in these patients. Contrary to expectations lumbar CSF TNF-alpha concentration was low in iNPH patients. PMID- 21660205 TI - Biomarkers of the dementia. AB - Recent advances in biomarker studies on dementia are summarized here. CSF Abeta40, Abeta42, total tau, and phosphorylated tau are the most sensitive biomarkers for diagnosis of Alzheimer's disease (AD) and prediction of onset of AD from mild cognitive impairment (MCI). Based on this progress, new diagnostic criteria for AD, MCI, and preclinical AD were proposed by National Institute of Aging (NIA) and Alzheimer's Association in August 2010. In these new criteria, progress in biomarker identification and amyloid imaging studies in the past 10 years have added critical information. Huge contributions of basic and clinical studies have established clinical evidence supporting these markers. Based on this progress, essential therapy for cure of AD is urgently expected. PMID- 21660206 TI - Genetics and genomics of late-onset Alzheimer's disease and its endophenotypes. PMID- 21660202 TI - Dyslipidaemia in rheumatological autoimmune diseases. AB - Autoimmunity forms the basis of many rheumatological diseases, and may contribute not only to the classical clinical manifestations but also to the complications. Many of the autoimmune rheumatological diseases, including rheumatoid arthritis and systemic lupus erythematosus are associated with an excess cardiovascular morbidity and mortality. Much of this excess cardiovascular risk can be attributed to atherosclerotic disease. Atherosclerosis is a complex pathological process, with dyslipidaemia and inflammation fundamental to all stages of plaque evolution. The heightened inflammatory state seen in conjunction with many rheumatological diseases may accelerate plaque formation, both through direct effects on the arterial wall and indirectly through inflammation-mediated alterations in the lipid profile. Alongside these factors, antibodies produced as part of the autoimmune nature of these conditions may lead to alterations in the lipid profile and promote atherosclerosis. In this review, we discuss the association between several of the rheumatological autoimmune diseases and dyslipidaemia, and the potential cardiovascular impact this may confer. PMID- 21660207 TI - LSPR Biosensor Signal Enhancement Using Nanoparticle-Antibody Conjugates. AB - A method to amplify the wavelength shift observed from localized surface plasmon resonance (LSPR) bioassays is developed using gold nanoparticle-labeled antibodies. The technique, which involves detecting surface-bound analytes using gold nanoparticle conjugated antibodies, provides a way to enhance LSPR shifts for more sensitive detection of low-concentration analytes. Using the biotin and antibiotin binding pair as a model, we demonstrate up to a 400% amplification of the shift upon antibody binding to analyte. In addition, the antibody nanoparticle conjugate improves the observed binding constant by 2 orders of magnitude, and the limit of detection by nearly 3 orders of magnitude. This amplification strategy provides a way to improve the sensitivity of plasmon-based bioassays, paving the way for single molecule-based detection and clinically relevant diagnostics. PMID- 21660208 TI - Molecular Dynamics Simulations on High-Performance Reconfigurable Computing Systems. AB - The acceleration of molecular dynamics (MD) simulations using high-performance reconfigurable computing (HPRC) has been much studied. Given the intense competition from multicore and GPUs, there is now a question whether MD on HPRC can be competitive. We concentrate here on the MD kernel computation: determining the short-range force between particle pairs. In one part of the study, we systematically explore the design space of the force pipeline with respect to arithmetic algorithm, arithmetic mode, precision, and various other optimizations. We examine simplifications and find that some have little effect on simulation quality. In the other part, we present the first FPGA study of the filtering of particle pairs with nearly zero mutual force, a standard optimization in MD codes. There are several innovations, including a novel partitioning of the particle space, and new methods for filtering and mapping work onto the pipelines. As a consequence, highly efficient filtering can be implemented with only a small fraction of the FPGA's resources. Overall, we find that, for an Altera Stratix-III EP3ES260, 8 force pipelines running at nearly 200 MHz can fit on the FPGA, and that they can perform at 95% efficiency. This results in an 80-fold per core speed-up for the short-range force, which is likely to make FPGAs highly competitive for MD. PMID- 21660210 TI - Pulmonary Arteriovenous Malformation (AVM) Causing Tension Hemothorax in a Pregnant Woman Requiring Emergent Cesarean Delivery. AB - Pulmonary arteriovenous malformations (PAVMs), although most commonly congenital, are usually detected later in life. We present a case of a 25-year-old woman with no previous history of AVM or telangiectasia, who presented with life-threatening hypoxia, hypotension, and pleuritic chest pain in 36th week of gestation. Chest tube placement revealed 4 liters of blood. Patient was subsequently found to have bleeding pulmonary AVM as the source of hemothorax. Successful embolisation of the bleeding vessel followed by thoracoscopic evacuation of the organized clot relieved the hypoxia. Further screening for AVM revealed large splenic AVM for which patient underwent splenectomy in the coming months. PMID- 21660209 TI - Family and parenting characteristics associated with marijuana use by Chilean adolescents. AB - OBJECTIVE: Family involvement and several characteristics of parenting have been suggested to be protective factors for adolescent substance use. Some parenting behaviors may have stronger relationships with adolescent behavior while others may have associations with undesirable behavior among youth. Although it is generally acknowledged that families play an important role in the lives of Chilean adolescents, scant research exists on how different family and parenting factors may be associated with marijuana use and related problems in this population which has one of the highest rates of drug use in Latin America. METHODS: Using logistic regression and negative binomial regression, we examined whether a large number of family and parenting variables were associated with the possibility of Chilean adolescents ever using marijuana, and with marijuana related problems. Analyses controlled for a number of demographic and peer related variables. RESULTS: Controlling for other parenting and family variables, adolescent reports of parental marijuana use showed a significant and positive association with adolescent marijuana use. The multivariate models also revealed that harsh parenting by fathers was the only family variable associated with the number of marijuana-related problems youth experienced. CONCLUSION: Of all the family and parenting variables studied, perceptions of parental use of marijuana and harsh parenting by fathers were predictors for marijuana use, and the experience of marijuana-related problems. Prevention interventions need to continue emphasizing the critical socializing role that parental behavior plays in their children's development and potential use of marijuana. PMID- 21660211 TI - Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease. AB - Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of beta-amyloid (Abeta) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na(+)-K(+) ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Abeta, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis. PMID- 21660212 TI - Beta-Amyloid Downregulates MDR1-P-Glycoprotein (Abcb1) Expression at the Blood Brain Barrier in Mice. AB - Neurovascular dysfunction is an important component of Alzheimer's disease, leading to reduced clearance across the blood-brain barrier and accumulation of neurotoxic beta-amyloid (Abeta) peptides in the brain. It has been shown that the ABC transport protein P-glycoprotein (P-gp, ABCB1) is involved in the export of Abeta from the brain into the blood. To determine whether Abeta influences the expression of key Abeta transporters, we studied the effects of 1-day subcutaneous Abeta1-40 and Abeta1-42 administration via Alzet mini-osmotic pumps on P-gp, BCRP, LRP1, and RAGE expression in the brain of 90-day-old male FVB mice. Our results demonstrate significantly reduced P-gp, LRP1, and RAGE mRNA expression in mice treated with Abeta1-42 compared to controls, while BCRP expression was not affected. The expression of the four proteins was unchanged in mice treated with Abeta1-40 or reverse-sequence peptides. These findings indicate that, in addition to the age-related decrease of P-gp expression, Abeta1-42 itself downregulates the expression of P-gp and other Abeta-transporters, which could exacerbate the intracerebral accumulation of Abeta and thereby accelerate neurodegeneration in Alzheimer's disease and cerebral beta-amyloid angiopathy. PMID- 21660213 TI - Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease. AB - Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Abeta), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology. PMID- 21660214 TI - Genomic Copy Number Analysis in Alzheimer's Disease and Mild Cognitive Impairment: An ADNI Study. AB - Copy number variants (CNVs) are DNA sequence alterations, resulting in gains (duplications) and losses (deletions) of genomic segments. They often overlap genes and may play important roles in disease. Only one published study has examined CNVs in late-onset Alzheimer's disease (AD), and none have examined mild cognitive impairment (MCI). CNV calls were generated in 288 AD, 183 MCI, and 184 healthy control (HC) non-Hispanic Caucasian Alzheimer's Disease Neuroimaging Initiative participants. After quality control, 222 AD, 136 MCI, and 143 HC participants were entered into case/control association analyses, including candidate gene and whole genome approaches. Although no excess CNV burden was observed in cases (AD and/or MCI) relative to controls (HC), gene-based analyses revealed CNVs overlapping the candidate gene CHRFAM7A, as well as CSMD1, SLC35F2, HNRNPCL1, NRXN1, and ERBB4 regions, only in cases. Replication in larger samples is important, after which regions detected here may be promising targets for resequencing. PMID- 21660215 TI - Feasibility of Predicting MCI/AD Using Neuropsychological Tests and Serum beta Amyloid. AB - We examined the usefulness of brief neuropsychological tests and serum Abeta as a predictive test for detecting MCI/AD in older adults. Serum Abeta levels were measured from 208 subjects who were cognitively normal at enrollment and blood draw. Twenty-eight of the subjects subsequently developed MCI (n = 18) or AD (n = 10) over the follow-up period. Baseline measures of global cognition, memory, language fluency, and serum Abeta(1-42) and the ratio of serum Abeta(1 42)/Abeta(1-40) were significant predictors for future MCI/AD using Cox regression with demographic variables, APOE epsilon4, vascular risk factors, and specific medication as covariates. An optimal sensitivity of 85.2% and specificity of 86.5% for predicting MCI/AD was achieved using ROC analyses. Brief neuropsychological tests and measurements of Abeta(1-42) obtained via blood warrants further study as a practical and cost effective method for wide-scale screening for identifying older adults who may be at-risk for pathological cognitive decline. PMID- 21660216 TI - Safety Nets and Scaffolds: Parental Support in the Transition to Adulthood. AB - Using longitudinal data from the Youth Development Study (analytic sample N = 712), we investigate how age, adult role acquisition and attainments, family resources, parent-child relationship quality, school attendance, and life events influence support received from parents in young adulthood. Parental assistance was found to be less forthcoming for those who had made greater progress on the road to adulthood, signified by socioeconomic attainment and union formation. The quality of mother-child and father-child relationships affected parental support in different ways, positively for mothers, negatively for fathers. School enrollment, negative life events, and employment problems were associated with a greater likelihood of receiving support. The findings suggest that parents act as "scaffolding" and "safety nets" to aid their children's successful transition to adulthood. PMID- 21660217 TI - Nondestructive Assessment of Early Tooth Demineralization Using Cross Polarization Optical Coherence Tomography. AB - New methods are needed for the nondestructive measurement of tooth demineralization and remineralization to monitor the progression of incipient caries lesions (tooth decay) for effective nonsurgical intervention and to evaluate the performance of anticaries treatments such as chemical treatments or laser irradiation. Studies have shown that optical coherence tomography (OCT) has great potential to fulfill this role since it can be used to measure the depth and severity of early lesions with an axial resolution exceeding 10 um, it is easy to apply in vivo and it can be used to image the convoluted topography of tooth occlusal surfaces. In this paper, a review of the use of polarization sensitive-OCT for the measurement of tooth demineralization is provided along with some recent results regarding improved methods for the detection of caries lesions in the earliest stages of development. Automated methods of analysis were used to measure the depth and severity of demineralized bovine enamel produced using simulated caries models that emulate demineralization in the mouth. Significant differences in the depth and integrated reflectivity from the lesions were detected after only a few hours of demineralization. These results demonstrate that cross-polarization-OCT is ideally suited for the nondestructive assessment of early demineralization. PMID- 21660218 TI - Inhibitory effect of dietary atorvastatin and celecoxib together with voluntary running wheel exercise on the progression of androgen-dependent LNCaP prostate tumors to androgen independence. AB - We determined the inhibitory effect of dietary atorvastatin, dietary celecoxib and voluntary running wheel exercise (RW) alone or in combination on the formation and growth of androgen-independent LNCaP tumors in castrated SCID mice. Male SCID mice were injected subcutaneously with androgen-dependent prostate cancer LNCaP cells. When the tumors reached a moderate size, the mice were surgically castrated and treated with atorvastatin (0.02% in the diet), celecoxib (0.05% in the diet) or RW alone or in combination for 42 days. RW or celecoxib alone had a moderate inhibitory effect on the androgen-independent growth of LNCaP tumors, but atorvastatin alone had little or no effect on tumor growth. Combinations of atorvastatin and celecoxib had a stronger inhibitory effect on the formation and growth of androgen-independent LNCaP tumors than either drug alone. A combination of RW together with atorvastatin and celecoxib had the most potent inhibitory effect on the progression of LNCaP tumors to androgen independent growth. The serum concentration of atorvastatin after two weeks of oral administration of atorvastatin was 6.1 ng/ml. The serum concentration of celecoxib after treatment with dietary celecoxib for two weeks was 1090 ng/ml. The serum concentration of atorvastatin but not that of celecoxib was substantially reduced when the two drugs were given in combination. The drug concentrations observed in our animal studies are comparable or less than those commonly found in humans treated with atorvastatin or celecoxib. Our results indicate that administration of atorvastatin and celecoxib together with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence. PMID- 21660219 TI - Personal Dietary Assessment Using Mobile Devices. AB - Dietary intake provides valuable insights for mounting intervention programs for prevention of disease. With growing concern for adolescent obesity, the need to accurately measure diet becomes imperative. Assessment among adolescents is problematic as this group has irregular eating patterns and have less enthusiasm for recording food intake. Preliminary studies among adolescents suggest that innovative use of technology may improve the accuracy of diet information from young people. In this paper we describe further development of a novel dietary assessment system using mobile devices. This system will generate an accurate account of daily food and nutrient intake among adolescents. The mobile computing device provides a unique vehicle for collecting dietary information that reduces burden on records that are obtained using more classical approaches. Images before and after foods are eaten can be used to estimate the amount of food consumed. PMID- 21660220 TI - Targeting Interventions: Moderators of the Effects of Expressive Writing and Assertiveness Training on the Adjustment of International University Students. AB - Acculturative stress is a common experience for international students and is associated with psychological and physical problems. In a previous study, the authors reported that two stress reduction interventions-expressive writing (EW) and assertiveness training (AT)-had limited overall benefits among international students at an American University. The current analyses of data from that study investigated whether individual differences moderated the effects of EW and AT. Results indicate that greater acculturative stress at baseline predicted greater improvement from both interventions, compared with control. Women benefited more from AT than EW, except that EW improved women's physical symptoms. Men benefited more from EW than AT. Students with limited emotional awareness and expression tended to benefit from both interventions, relative to control. Finally, nation of origin cultural differences generally did not predict outcomes. It is concluded that the benefits of EW and AT and can be enhanced by targeting these interventions to specific subgroups of international students. PMID- 21660221 TI - Games Parents and Adolescents Play: Risky Behaviors, Parental Reputation, and Strategic Transfers. AB - This paper examines parental reputation formation in intra-familial interactions. In a repeated two-stage game, children decide whether to drop out of high school or daughters decide whether to have births as teens and parents then decide whether to provide support to their children beyond age 18. Drawing on Milgrom and Roberts (1982) and Kreps and Wilson (1982), we show that, under certain conditions, parents have the incentive to penalize older children for their adolescent risk-taking behaviours in order to dissuade their younger children from such behaviours when reaching adolescence. We find evidence in favour of this parental reputation model. PMID- 21660222 TI - Fungal Biofilms: Relevance in the Setting of Human Disease. AB - The use of indwelling medical devices is rapidly growing and is often complicated by infections with biofilm-forming microbes that are resistant to antimicrobial agents and host defense mechanisms. Fungal biofilms have emerged as a clinical problem associated with these medical device infections, causing significant morbidity and mortality. This review discusses the recent advances in the understanding of fungal biofilms, including the role of fungal surface components in adherence, gene expression, and quorum sensing in biofilm formation. We propose novel strategies for the prevention or eradication of microbial colonization of medical prosthetic devices. PMID- 21660224 TI - The Conformation of the Estrogen Receptor Directs Estrogen-Induced Apoptosis in Breast Cancer: A Hypothesis. AB - BACKGROUND: Estrogens are classified as type I (planar) and type II (angular) based on their structures. In this study we have used triphenylethylenes (TPEs) compounds related to 4OHT to address the hypothesis that the conformation of the liganded estrogen receptor (ERalpha) may dictate the E2-induced apoptosis of the ER+ breast cancer cells. MATERIALS AND METHODS: ERalpha positive MCF7:5C cells were used to study the apoptosis induced by E2, 4OHT and TPEs. Growth and apoptosis assay were used to evaluate apoptosis and the ability to reverse the E2 induced apoptosis. ERalpha protein were measured by western blotting to investigate the destruction of ERalpha by TPEs in MCF7 cells. ChIP assay were performed to study the in-vivo recruitment of ERalpha and SRC3 at classical E2 responsive promoter TFF1 (PS2) by TPEs. Molecular modeling was used to predict the binding mode of the TPE to the ERalpha. RESULTS: TPEs were not only unable to induce efficient apoptosis in MCF7:5C cells but also reversed the E2-induced apoptosis similar to 4OHT. Furthermore, the TPEs and 4OHT did not reduce the ERalpha protein levels unlike E2. ChIP assay confirmed very weak recruitment of SRC3 despite modest recruitment of ERalpha in the presence of TPEs. Molecular modeling suggested the TPE would bind in antagonistic mode with the ERalpha. CONCLUSION: Our results advances the hypothesis that the TPE liganded ERalpha complex structurally resembles the 4OHT bound ERalpha and cannot efficiently recruit co-activator SRC3. As a result, the TPE complex cannot induce apoptosis of ER+ breast cancer cells although it may cause growth of the breast cancer cells. The conformation of the estrogen-ER complex differentially controls growth and apoptosis. PMID- 21660223 TI - Malignancy-associated dyslipidemia. AB - Cholesterol and triglycerides, important lipid constituents of cell, are essential to carry out several vital physiological functions. Lipids might be associated with cancers because they play a key role in the maintenance of cell integrity. The pathway for cholesterol synthesis may also produce various tumorigenic compounds and cholesterol serves as a precursor for the synthesis of many sex hormones linked to increased risk of various cancers. In some malignant diseases, blood cholesterol undergoes early and significant changes. The mechanism for the link between cancer and cholesterol remains controversial. The dates from studies are confusing because both hypolipidemia and hypercholesterolemia might be connected with malignancy. Not only cancers but also antineoplastic therapies have an influence on lipid profile. There are also dates suggesting that antihyperlipemic drugs might nfluenced malignancy. PMID- 21660225 TI - Statistical Fusion of Continuous Labels: Identification of Cardiac Landmarks. AB - Image labeling is an essential task for evaluating and analyzing morphometric features in medical imaging data. Labels can be obtained by either human interaction or automated segmentation algorithms. However, both approaches for labeling suffer from inevitable error due to noise and artifact in the acquired data. The Simultaneous Truth And Performance Level Estimation (STAPLE) algorithm was developed to combine multiple rater decisions and simultaneously estimate unobserved true labels as well as each rater's level of performance (i.e., reliability). A generalization of STAPLE for the case of continuous-valued labels has also been proposed. In this paper, we first show that with the proposed Gaussian distribution assumption, this continuous STAPLE formulation yields equivalent likelihoods for the bias parameter, meaning that the bias parameter one of the key performance indices-is actually indeterminate. We resolve this ambiguity by augmenting the STAPLE expectation maximization formulation to include a priori probabilities on the performance level parameters, which enables simultaneous, meaningful estimation of both the rater bias and variance performance measures. We evaluate and demonstrate the efficacy of this approach in simulations and also through a human rater experiment involving the identification the intersection points of the right ventricle to the left ventricle in CINE cardiac data. PMID- 21660226 TI - Ganciclovir antiviral therapy in advanced idiopathic pulmonary fibrosis: an open pilot study. AB - Hypothesis. Repeated epithelial cell injury secondary to viruses such as Epstein Barr and subsequent dysfunctional repair may be central to the pathogenesis of IPF. In this observational study, we evaluated whether a combination of standard and anti-viral therapy might have an impact on disease progression. Methods. Advanced IPF patients who failed standard therapy and had serological evidence of previous EBV, received ganciclovir (iv) at 5 mg/kg twice daily. Forced vital capacity (FVC), shuttle walk test, DTPA scan and prednisolone dose were measured before and 8 weeks post-treatment. Results. Fourteen patients were included. After ganciclovir, eight patients showed improvement in FVC and six deteriorated. The median reduction of prednisolone dose was 7.5 mg (44%). Nine patients were classified "responders" of whom four showed an improvement in all four criteria, while three of the five "non-responders" showed no response in any of the criteria. Responders showed reduction in prednisolone dosage (P = .02) and improved DTPA clearance (P = .001). Conclusion. This audit outcome suggests that 2-week course of ganciclovir (iv) may attenuate disease progression in a subgroup of advanced IPF patients. These observations do not suggest that anti-viral treatment is a substitute for the standard care, however, suggests the need to explore the efficacy of ganciclovir as adjunctive therapy in IPF. PMID- 21660227 TI - Morphological analysis of CDC2 and glycogen synthase kinase 3beta phosphorylation as markers of g2 -> m transition in glioma. AB - G2 -> M transition is a strategic target for glioma chemotherapy. Key players in G2 -> M transition include CDC2 and glycogen synthase kinase 3beta (GSK3beta), which are highly regulated by posttranslational phosphorylation. This report is a morphological analysis of CDC2 and GSK3beta phosphorylation using immunohistochemistry in gliomas with different biological properties. GBM showed a 2.8-fold and 5.6-fold increase in number of cells positive for pThr161CDC2 and a 4.2- and 6.9-fold increase in number of cells positive for pTyr15CDC2 relative to oligodendroglioma and ependymoma, respectively. Elevated labeling for inhibited phospho-CDC2 (pTyr15CDC) correlates with elevated levels of phosphorylated glycogen synthase kinase 3beta (GSK3beta). 71% of the GBM cases showed intermediate to high intensity staining for pSer9SGK3beta 53% of oligodendroglioma, and 73% of ependymoma showed low intensity staining. CDC2 gene amplification correlates with increased survival in glioblastoma multiforme (GBM) and astrocytoma WHO grades II-III, but not in oligodendroglioma WHO grades II III. PMID- 21660228 TI - Update on pharmaceutical and minimally invasive management strategies for chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a debilitating pulmonary disorder with systemic effects, and it is the fourth leading cause of death in the United States. COPD patients not only develop respiratory limitations, but can also demonstrate systemic wasting, features of depression, and can succumb to social isolation. Smoking cessation is crucial, and pharmacotherapy with bronchodilators is helpful in symptom management. Inhaled corticosteroids may be beneficial in some patients. In addition, pulmonary rehabilitation and palliative care are important components under the right clinical circumstance. This review highlights current guidelines and management strategies for COPD and emphasizes novel pharmacotherapy and minimally invasive (nonsurgical) lung-volume reduction interventions that may prove to be of significant benefit in the future. PMID- 21660230 TI - Immersion pulmonary edema in female triathletes. AB - Pulmonary edema has been reported in SCUBA divers, apnea divers, and long distance swimmers however, no instances of pulmonary edema in triathletes exist in the scientific literature. Pulmonary edema may cause seizures and loss of consciousness which in a water environment may become life threatening. This paper describes pulmonary edema in three female triathletes. Signs and symptoms including cough, fatigue, dyspnea, haemoptysis, and rales may occur within minutes of immersion. Contributing factors include hemodynamic changes due to water immersion, cold exposure, and exertion which elevate cardiac output, causing pulmonary capillary stress failure, resulting in extravasation of fluid into the airspace of the lung. Previous history is a major risk factor. Treatment involves immediate removal from immersion and in more serious cases, hospitalization, and oxygen administration. Immersion pulmonary edema is a critical environmental illness of which triathletes, race organizers, and medical staff, should be made aware. PMID- 21660229 TI - Human papillomavirus types 52 and 58 are prevalent in uterine cervical squamous lesions from Japanese women. AB - Objective. To estimate the prevalence and genotypes of high-risk human papillomavirus (HPV) focusing HPV 16, 18, 52, and 58 in Japan. Methods. Liquid base cytology specimens were collected from Japanese women (n = 11022), aged 14 98. After classifying cytodiagnosis, specimens were analyzed for HPV DNA by the multiplex polymerase chain reaction method, where 1195 specimens were positive for cervical smear, except adenomatous lesions. Result. HPV genotypes were detected in 9.5% of NILM and 72.2% of ASC-US or more cervical lesions. In positive cervical smears, HPV genotypes were HPV 52 at 26.6%, HPV 16 at 25.2%, HPV 58 at 21.8%, and HPV 18 at 7.1%. Most patients infected with HPV 16 were between 20-29 years old, decreasing with age thereafter. As for HPV 52 and 58, although the detection rate was high in 30- to 39-year-olds, it also was significant in the 50s and 60s age groups. Conclusion. In Japan, as a cause of abnormal cervical cytology, HPV52 and 58 are detected frequently in addition to HPV 16. In older age groups, HPV 52 and 58 detection rates were higher than that observed for HPV 16. After widespread current HPV vaccination, we still must be aware of HPV 52 and 58 infections. PMID- 21660231 TI - Base-rate error in the interpretation of immunohistochemistry. AB - Failure to appreciate the importance of the frequency of a disorder in the appropriate population (the base rate) may lead to the misinterpretation of the diagnostic significance of unexpected test results (unexpected test result defined in this context as a test result that is positive in a higher proportion of cases of an alternative diagnosis than in the diagnosis considered most likely before the test). This study aimed to determine whether pathologists are vulnerable to this error. Pathologists were asked to estimate the probability of tumour B in a scenario in which, prior to the immunostaining result, an experienced pathologist considers there to be a 99% chance that the patient has tumour A and a 1% chance that they have tumour B. Antibody X is positive in 80% of cases of tumour B and negative in 90% of cases of tumour A and is positive in the case described in the scenario. The estimates made by consultant pathologists ranged from 0 to 100% (mean 29.7%). The Bayesian answer would be 7.5%. These findings suggest that base-rate error may lead some pathologists to overestimate the implications for the likelihood of a diagnosis in the light of an unexpected immunohistochemical result. PMID- 21660232 TI - The curious question of exercise-induced pulmonary edema. AB - The question of whether pulmonary edema develops during exercise on land is controversial. Yet, the development of pulmonary edema during swimming and diving is well established. This paper addresses the current controversies that exist in the field of exercise-induced pulmonary edema on land and with water immersion. It also discusses the mechanisms by which pulmonary edema can develop during land exercise, swimming, and diving and the current gaps in knowledge that exist. Finally, this paper discusses how these fields can continue to advance and the areas where clinical knowledge is lacking. PMID- 21660233 TI - A Method to Assess Linkage Disequilibrium between CNVs and SNPs Inside Copy Number Variable Regions. AB - Since the discovery of the ubiquitous contribution of copy number variation to genetic variability, researchers have commonly used metrics such as r (2) to quantify linkage disequilibrium (LD) between copy number variants (CNVs) and single nucleotide polymorphisms (SNPs). However, these reports have been restricted to SNPs outside copy number variable regions (CNVR) as current methods have not been adapted to account for SNPs displaying variable copy number. We show that traditional LD metrics inappropriately quantify SNP/CNV covariance when SNPs lie within CNVR. We derive a new method for measuring LD that solves this issue, and defaults to traditional metrics otherwise. Finally, we present a procedure to estimate CNV-SNP allele frequencies from unphased CNV-SNP genotypes. Our method allows researchers to include all SNPs in SNP/CNV LD measurements, regardless of copy number. PMID- 21660234 TI - Pulmonary hypertension related to left-sided cardiac pathology. AB - Pulmonary hypertension (PH) is the end result of a variety of diverse pathologic processes. The chronic elevation in pulmonary artery pressure often leads to right ventricular pressure overload and subsequent right ventricular failure. In patients with left-sided cardiac disease, PH is quite common and associated with increased morbidity and mortality. This article will review the literature as it pertains to the epidemiology, pathogenesis, and diagnosis of PH related to aortic valve disease, mitral valve disease, left ventricular systolic and diastolic dysfunction, and pulmonary veno-occlusive disease. Moreover, therapeutic strategies, which focus on treating the underlying cardiac pathology will be discussed. PMID- 21660235 TI - Effects of ischemic acute kidney injury on lung water balance: nephrogenic pulmonary edema? AB - Pulmonary edema worsens the morbidity and increases the mortality of critically ill patients. Mechanistically, edema formation in the lung is a result of net flow across the alveolar capillary membrane, dependent on the relationship of hydrostatic and oncotic pressures. Traditionally, the contribution of acute kidney injury (AKI) to the formation of pulmonary edema has been attributed to bulk fluid accumulation, increasing capillary hydrostatic pressure and the gradient favoring net flow into the alveolar spaces. Recent research has revealed more subtle, and distant, effects of AKI. In this review we discuss the concept of nephrogenic pulmonary edema. Pro-inflammatory gene upregulation, chemokine over-expression, altered biochemical channel function, and apoptotic dysregulation manifest in the lung are now understood as "extra-renal" and pulmonary effects of AKI. AKI should be counted as a disease process that alters the endothelial integrity of the alveolar capillary barrier and has the potential to overpower the ability of the lung to regulate fluid balance. Nephrogenic pulmonary edema, therefore, is the net effect of fluid accumulation in the lung as a result of both the macroscopic and microscopic effects of AKI. PMID- 21660236 TI - Factors influencing oxidative imbalance in pulmonary fibrosis: an immunohistochemical study. AB - Background. Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease of unknown etiology characterized by interstitial fibrosis determining irreversible distortion of pulmonary architecture. Reactive oxygen species (ROS) and markers of oxidative stress play a pivotal role in human IPF pathology, possibly through induction of epithelial-mesenchymal transition (EMT). Methods. We investigated by immunohistochemistry, in UIP and COP tissue samples, the expression of most relevant markers of the molecular interplay involving RAGE, oxidant/antioxidant balance regulation, tissue nitrosylation, and mediators of EMT. Results. In both UIP and COP, the degree of RAGE expression was similarly high, while SODs and i NOS, diffusely present in COP endoalveolar plugs, were almost absent in UIP fibroblast foci. A lower degree of tissue nitrosilation was observed in UIP than in COP. Conclusions. Fibroblast lesions of UIP and of COP share a similar degree of activation of RAGE, while antioxidant enzyme expression markedly reduced in UIP. PMID- 21660237 TI - Cell-specific dual role of caveolin-1 in pulmonary hypertension. AB - A wide variety of cardiopulmonary and systemic diseases are known to lead to pulmonary hypertension (PH). A number of signaling pathways have been implicated in PH; however, the precise mechanism/s leading to PH is not yet clearly understood. Caveolin-1, a membrane scaffolding protein found in a number of cells including endothelial and smooth muscle cells, has been implicated in PH. Loss of endothelial caveolin-1 is reported in clinical and experimental forms of PH. Caveolin-1, also known as a tumor-suppressor factor, interacts with a number of transducing molecules that reside in or are recruited to caveolae, and it inhibits cell proliferative pathways. Not surprisingly, the rescue of endothelial caveolin-1 has been found not only to inhibit the activation of proliferative pathways but also to attenuate PH. Recently, it has emerged that during the progression of PH, enhanced expression of caveolin-1 occurs in smooth muscle cells, where it facilitates cell proliferation, thus contributing to worsening of the disease. This paper summarizes the cell-specific dual role of caveolin-1 in PH. PMID- 21660238 TI - Differential contribution of specific working memory components to mathematics achievement in 2nd and 3rd graders. AB - The contribution of the three core components of working memory (WM) to the development of mathematical skills in young children is poorly understood. The relation between specific WM components and Numerical Operations, which emphasize computation and fact retrieval, and Mathematical Reasoning, which emphasizes verbal problem solving abilities in 48 2nd and 50 3rd graders was assessed using standardized WM and mathematical achievement measures. For 2nd graders, the central executive and phonological components predicted Mathematical Reasoning skills; whereas the visuo-spatial component predicted both Mathematical Reasoning and Numerical Operations skills in 3rd graders. This pattern suggests that the central executive and phonological loop facilitate performance during early stages of mathematical learning whereas visuo-spatial representations play an increasingly important role during later stages. We propose that these changes reflect a shift from prefrontal to parietal cortical functions during mathematical skill acquisition. Implications for learning and individual differences are discussed. PMID- 21660239 TI - Rapamycin Regulates Bleomycin-Induced Lung Damage in SP-C-Deficient Mice. AB - Injury to the distal respiratory epithelium has been implicated as an underlying cause of idiopathic lung diseases. Mutations that result in SP-C deficiencies are linked to a small subset of spontaneous and familial cases of interstitial lung disease (ILD) and interstitial pulmonary fibrosis (IPF). Gene-targeted mice that lack SP-C (Sftpc(-/-)) develop an irregular ILD-like disease with age and are a model of the human SP-C related disease. In the current study, we investigated whether rapamycin could ameliorate bleomycin-induced fibrosis in the lungs of Sftpc(-/-) mice. Sftpc(+/+) and -/- mice were exposed to bleomycin with either preventative administration of rapamycin or therapeutic administration beginning eight days after the bleomycin injury. Rapamycin-treatment increased weight loss and decreased survival of bleomycin-treated Sftpc(+/+) and Sftpc(-/-) mice. Rapamycin did not reduce the fibrotic disease in the prophylactic or rescue experiments of either genotype of mice. Further, rapamycin treatment augmented airway resistance and reduced lung compliance of bleomycin-treated Sftpc(-/-) mice. Rapamycin treatment was associated with an increased expression of profibrotic Th2 cytokines and reduced expression of INF-gamma. These findings indicate that novel therapeutics will be required to treat individuals with SP-C deficient ILD/IPF. PMID- 21660240 TI - Silver-Polymer Composite Stars: Synthesis and Applications. AB - Colloidal "silver stars" were synthesized upon poly(lactic-co-glycolic) acid nanosphere templates via a facile two-step silver reduction method. Myriad dendrimer-like Ag star morphologies were synthesized by varying the amount of poly(vinyl alcohol) and trisodium citrate used during silver reduction. Scanning electron microscopy studies revealed that star-shaped silver-polymer composites possessing nanoscopic, fractal morphologies with diameters ranging from 500 nm to 7 MUm were produced. These composites have broad applications from antibacterial agents to catalysis; two such applications were tested here. Surface-enhanced Raman spectroscopy (SERS) studies showed multiple hot spots of SERS activity within a single star. Electrochemical catalysis experiments demonstrated the feasibility of using the silver stars instead of platinum for the oxygen reduction reaction in alkaline fuel cells. PMID- 21660242 TI - Improving the specificity of EEG for diagnosing Alzheimer's disease. AB - Objective. EEG has great potential as a cost-effective screening tool for Alzheimer's disease (AD). However, the specificity of EEG is not yet sufficient to be used in clinical practice. In an earlier study, we presented preliminary results suggesting improved specificity of EEG to early stages of Alzheimer's disease. The key to this improvement is a new method for extracting sparse oscillatory events from EEG signals in the time-frequency domain. Here we provide a more detailed analysis, demonstrating improved EEG specificity for clinical screening of MCI (mild cognitive impairment) patients. Methods. EEG data was recorded of MCI patients and age-matched control subjects, in rest condition with eyes closed. EEG frequency bands of interest were theta (3.5-7.5 Hz), alpha(1) (7.5-9.5 Hz), alpha(2) (9.5-12.5 Hz), and beta (12.5-25 Hz). The EEG signals were transformed in the time-frequency domain using complex Morlet wavelets; the resulting time-frequency maps are represented by sparse bump models. Results. Enhanced EEG power in the theta range is more easily detected through sparse bump modeling; this phenomenon explains the improved EEG specificity obtained in our previous studies. Conclusions. Sparse bump modeling yields informative features in EEG signal. These features increase the specificity of EEG for diagnosing AD. PMID- 21660241 TI - GSK3 Function in the Brain during Development, Neuronal Plasticity, and Neurodegeneration. AB - GSK3 has diverse functions, including an important role in brain pathology. In this paper, we address the primary functions of GSK3 in development and neuroplasticity, which appear to be interrelated and to mediate age-associated neurological diseases. Specifically, GSK3 plays a pivotal role in controlling neuronal progenitor proliferation and establishment of neuronal polarity during development, and the upstream and downstream signals modulating neuronal GSK3 function affect cytoskeletal reorganization and neuroplasticity throughout the lifespan. Modulation of GSK3 in brain areas subserving cognitive function has become a major focus for treating neuropsychiatric and neurodegenerative diseases. As a crucial node that mediates a variety of neuronal processes, GSK3 is proposed to be a therapeutic target for restoration of synaptic functioning and cognition, particularly in Alzheimer's disease. PMID- 21660243 TI - Chronic Proliferative Dermatitis in Mice: NFkappaB Activation Autoinflammatory Disease. AB - Autoinflammatory diseases are a heterogeneous group of congenital diseases characterized by the presence of recurrent inflammation, in the absence of infectious agents, detectable autoantibodies or antigen-specific autoreactive T cells. SHARPIN deficient mice presents multiorgan chronic inflammation without known autoantibodies or autoreactive T-cells, designated Sharpin(cpdm). Histological studies demonstrated epidermal hyperproliferation, Th-2 inflammation, and keratinocyte apoptosis in this mutant. The mutant mice have decreased behavioral mobility, slower growth, and loss of body weight. Epidermal thickness and mitotic epidermal cells increase along with disease development. K5/K14 expression is distributed through all layers of epidermis, along with K6 expression in interfollicular epidermis, suggesting epidermal hyperproliferation. K1/K10 is only detectable in outer layers of spinosum epidermis, reflecting accelerated keratinocyte migration. Alpha smooth muscle actin is overexpressed in skin blood vessels, which may release the elevated white blood cells to dermis. CD3(+)CD45(+) cells and granulocytes, especially eosinophils and mast cells, aggregate in the mutant skin. TUNEL assay, together with Annexin-V/propidium iodide FACS analysis, confirmed the increase of apoptotic keratinocytes in skin. These data validate and provide new lines of evidence of the proliferation inflammation-apoptosis triad in Sharpin(cpdm) mice, an NFkappaB activation autoinflammatory disease. PMID- 21660245 TI - The Link between Cognitive Measures and ADLs and IADL Functioning in Mild Alzheimer's: What Has Gender Got to Do with It? AB - Objectives. To investigate the link between neurocognitive measures and various aspects of daily living (ADL and IADL) in women and men with mild Alzheimer's disease (AD). Methods. Participants were 202 AD patients (91 male, 111 female) with CDR global scores of <=1. ADLs and IADLs ratings were obtained from caregivers. Cognitive domains were assessed with neuropsychological testing. Results. Memory and executive functioning were related to IADL scores. Executive functioning was linked to total ADL. Comparisons stratified on gender found attention predicted total ADL score in both men and women. Attention predicted bathing and eating ability in women only. Language predicted IADL functions in men (food preparation) and women (driving). Conclusions. Associations between ADLs/IADLs and memory, learning, executive functioning, and language suggest that even in patients with mild AD, basic ADLs require complex cognitive processes. Gender differences in the domains of learning and memory area were found. PMID- 21660246 TI - Quantification and evaluation of the role of antielastin autoantibodies in the emphysematous lung. AB - Chronic obstructive pulmonary disease (COPD) may be an autoimmune disease. Smoking causes an imbalance of proteases and antiproteases in the lung resulting in the generation of elastin peptides that can potentially act as autoantigens. Similar to COPD, Z alpha-1 antitrypsin deficiency (Z-A1ATD) and cystic fibrosis (CF) are associated with impaired pulmonary antiprotease defences leading to unopposed protease activity. Here, we show that there is a trend towards higher bronchoalveolar lavage fluid (BALF) antielastin antibody levels in COPD and Z A1ATD and significantly lower levels in CF compared to control BALF; the lower levels in CF are due to the degradation of these antibodies by neutrophil elastase. We also provide evidence that these autoantibodies have the potential to induce T cell proliferation in the emphysematous lung. This study highlights that antielastin antibodies are tissue specific, can be detected at elevated levels in COPD and Z-A1ATD BALF despite their being no differences in their levels in plasma compared to controls, and suggests a therapeutic role for agents targeting these autoantibodies in the lungs. PMID- 21660244 TI - Effects of thyroid dysfunction on lipid profile. AB - Thyroid dysfunction has a great impact on lipids as well as a number of other cardiovascular risk factors. Hypothyroidism is relatively common and is associated with an unfavorable effect on lipids. Substitution therapy is beneficial for patients with overt hypothyroidism, improving lipid profile. However, whether subclinical hypothyroidism should be treated or not is a matter of debate. On the other hand, hyperthyroidism can be associated with acquired hypocholesterolemia or unexplained improvement of lipid profile. Overall, thyroid dysfunction should be taken into account when evaluating and treating dyslipidemic patients. PMID- 21660247 TI - Efficacy of aliskiren/hydrochlorothiazide combination for the treatment of hypertension: a meta-analytical approach. AB - BACKGROUND: Single-pill combinations of aliskiren/hydrochlorothiazide have recently been approved by the European Medicines Agency for the treatment of hypertension. OBJECTIVE: This study aimed to assess the antihypertensive efficacy of aliskiren/hydrochlorothiazide combination in reducing systolic and diastolic blood pressure in hypertensive patients. METHODS: A search in International Pharmaceutical Abstracts, MEDLINE, The Cochrane Library and ISI Web of Knowledge was performed from 2000 to November 2009, to identify randomized, double-blind, clinical trials using aliskiren/hydrochlorothiazide for the treatment of hypertension. Studies were included if they evaluated the antihypertensive efficacy of aliskiren/hydrochlorothiazide in patients with mild or moderate essential hypertension and age >= 18 years. The meta-analytical approach calculated the weighted average reductions of systolic and diastolic blood pressure for each daily dosage combination. RESULTS: We included 5 clinical trials testing several combinations of aliskiren/hydrochlorothiazide and containing data on 5448 patients. In all studies blood pressure was assessed at inclusion (baseline) and after 8 weeks of therapy. Blood pressure reductions and control rates were significantly (p < 0.05) higher with the aliskiren/hydrochlorothiazide combinations than with placebo and the same doses of aliskiren or hydrochlorothiazide alone. The weighted mean reductions (mm Hg) from baseline of systolic and diastolic blood pressure for each aliskiren/hydrochlorothiazide combination were: -15.8/-10.3 (150/25 mg); -15.9/ 11.8 (300/12.5 mg); -16.9/-11.6 (300/25 mg). Blood pressure control rates (%) for the above combinations were, at least, respectively: 43.8, 50.1 and 51.9. CONCLUSIONS: Aliskiren/hydrochlorothiazide provided clinically significant additional blood pressure reductions and improved blood pressure control rates over aliskiren or hydrochlorothiazide monotherapy. PMID- 21660249 TI - An Approach to Constructing Nested Space-Filling Designs for Multi-Fidelity Computer Experiments. AB - Multi-fidelity computer experiments are widely used in many engineering and scientific fields. Nested space-filling designs (NSFDs) are suitable for conducting such experiments. Two classes of NSFDs are currently available. One class is based on special orthogonal arrays of strength two and the other consists of nested Latin hypercube designs. Both of them assume all factors are continuous. We propose an approach to constructing new NSFDs based on powerful (t, s)-sequences. The method is simple, easy to implement, and quite general. For continuous factors, this approach produces NSFDs with better space-filling properties than existing ones. Unlike the previous methods, this method can also construct NSFDs for categorical and mixed factors. Some illustrative examples are given. Other applications of the constructed designs are briefly discussed. PMID- 21660250 TI - Patient characteristics in persistent pulmonary hypertension of the newborn. AB - Objective. To assess the impact of PPHN on mortality, morbidity, and behavioural skills. Methods. A retrospective observational study of 143 newborns with PPHN, over an 11-year period, using objective health-status data from medical records and family doctors, and subjective health status data from a standardized Child Behaviour Checklist. Results. The majority of patients were males, treated with inhaled nitric oxide had maladaptation/maldevelopment as pathophysiological mechanism and a gestational age >37 weeks. In term newborns, types of pathophysiological mechanism (P < .001) and Oxygen Index (P = .02) were independent predicting risk factors for PPHN-related mortality. Analysis of preexisting disease and outcome categories in term newborns showed only a significant correlation between the use of iNO and respiratory complaints (P = .03), not confirmed by multivariate analysis and regression analysis. Conclusions. PPHN is a serious, often fatal condition. The incidence of PPHN in preterm newborns is high. In term survivors, PPHN had no additional role in morbidity/outcome. PMID- 21660251 TI - Cannabinoid Receptor 2 Deficiency in Haematopoietic cells Aggravates Early Atherosclerosis in LDL Receptor Deficient Mice. AB - OBJECTIVE: The cannabinoid receptor 2 (CB2) has been implicated to play a role in various inflammatory processes. Since atherosclerosis is currently considered a chronic inflammatory disease, we studied the effect of haematopoietic CB2 deficiency on atherosclerosis development. METHODS AND RESULTS: To investigate the effect of CB2 deficiency in immune cells on atherogenesis in vivo, a bone marrow transplantation was performed in irradiated LDL receptor deficient mice (LDLr(-/-)), using CB2 deficient (CB2(-/-)) or wildtype (WT) donor mice. After 12 weeks on a high fat-high cholesterol diet, en face analysis showed that atherosclerosis in the aortic arch was significantly increased in CB2(-/-) transplanted animals (6.40 +/- 3.21%) as compared to WT transplanted mice (3.85 +/- 1.61%). Although the total lesion area in the aortic root was not significantly different between WT and CB2(-/-) transplanted mice (0.45 +/- 0.13 mm(2) and 0.51 +/- 0.17 mm(2), respectively), CB2(-/-) transplanted mice showed a significantly larger plaque area (0.13 +/- 0.07 mm(2)) than WT transplanted mice (0.08 +/- 0.05 mm(2)) in the aortic valve in which atherogenesis is in an earlier stage than in the other aortic valves. CONCLUSIONS: Lack of endocannabinoid signaling via the CB2 receptor aggravates early atherosclerosis development in LDLr(-/-) mice, suggesting that CB2 specific activation may prevent the development of atherosclerosis. PMID- 21660248 TI - Dyslipidaemia of obesity, metabolic syndrome and type 2 diabetes mellitus: the case for residual risk reduction after statin treatment. AB - Dyslipidaemia is frequently present in obesity, metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). The predominant features of dyslipidaemia in these disorders include increased flux of free fatty acids (FFA), raised triglyceride (TG) and low high density lipoprotein cholesterol (HDL-C) levels, a predominance of small, dense (atherogenic) low density lipoprotein cholesterol (LDL) particles and raised apolipoprotein (apo) B values Posprandial hyperlipidaemia may also be present. Insulin resistance (IR) appears to play an important role in the pathogenesis of dyslipidaemia in obesity, MetS and T2DM. The cornerstone of treatment of this IR-related dyslipidaemia is lifestyle changes and in diabetic patients, tight glycaemic control. In addition to these measures, recent clinical trials showed benefit with statin treatment. Nevertheless, a substantial percentage of patients treated with statins still experience vascular events. This residual vascular risk needs to be addressed. This review summarizes the effects of hypolipidaemic drug combinations (including statins with cholesterol ester protein inhibitors, niacin, fibrates or fish oil, as well as fibrate-ezetimibe combination) on the residual vascular risk in patients with obesity, MetS or T2DM. PMID- 21660252 TI - Cardiac arrest caused by torsades de pointes tachycardia after successful atrial flutter radiofrequency catheter ablation. AB - A 66-year-old woman underwent successful radiofrequency catheter ablation for long-lasting, drug refractory fast atrial flutter. Two days later she had a cardiac arrest due to torsades de pointes (TdP) tachycardia attributed to relative sinus bradycardia and QT interval prolongation. After successful resuscitation further episodes of TdP occurred, which were treated with temporary pacing. Because of concomitant systolic dysfunction due to ischemic and valvular heart disease she was finally treated with an implantable defibrillator. In conclusion we strongly advise prolonged monitoring for 2 or more days for patients with structural heart disease following successful catheter ablation for long lasting tachyarrhythmias. PMID- 21660253 TI - A novel study and meta-analysis of the genetic variation of the serotonin transporter promoter in the italian population do not support a large effect on Alzheimer's disease risk. AB - Alzheimer's disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped the SLC6A4 promoter functional variant rs25531 (A -> G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between 5-HTTLPR and AD (odds ratio for the L-allele versus the S allele: 0.74, associated P value = .03), while no difference was found for the rs25531. A meta-analysis of studies in Italy assessing 5-HTTLPR and AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associated P value = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk. PMID- 21660254 TI - Development and Validation of a Multidimensional Measure of Family Supportive Supervisor Behaviors (FSSB). AB - Due to growing work-family demands, supervisors need to effectively exhibit family supportive supervisor behaviors (FSSB). Drawing on social support theory and using data from two samples of lower wage workers, the authors develop and validate a measure of FSSB, defined as behaviors exhibited by supervisors that are supportive of families. FSSB is conceptualized as a multidimensional superordinate construct with four subordinate dimensions: emotional support, instrumental support, role modeling behaviors, and creative work-family management. Results from multilevel confirmatory factor analyses and multilevel regression analyses provide evidence of construct, criterion-related, and incremental validity. The authors found FSSB to be significantly related to work family conflict, work-family positive spillover, job satisfaction, and turnover intentions over and above measures of general supervisor support. PMID- 21660255 TI - ? AB - Argentina ha sido un campo fertil para los intentos de reforma del sector salud, en la busqueda por mejorar la calidad de sus servicios y, consecuentemente, la accesibilidad y la equidad del mismo. Los resultados obtenidos no han sido proporcionales a los esfuerzos desarrollados. Aunque la bioetica deberia, como forma de reflexion interdisciplinaria, participar en la fundamentacion de nuevas politicas sanitarias y sus efectos sobre los usuarios, parece haber permanecido ajena, en general, a los graves problemas derivados de la corrupcion, prefiriendo enfocarse en cuestiones vinculadas a planteos abstractos de justicia y solidaridad, atribuyendo los fracasos a la imposicion de modelos economicos foraneos. PMID- 21660256 TI - A complex renal cyst: it is time to call the oncologist? AB - Introduction. Hydatid disease is a cyclozoonotic parasitic infestation caused by the cestode Echinococcus granulosus. The cysts mainly arise in the liver (50 to 70%) or lung (20 to 30%), but any other organ can be involved, in abdominal and pelvic locations, as well as in other less common sites, which may make both diagnosis and treatment more complex. Isolated renal involvement is extremely rare. Case Presentation. We report a rare case of isolated renal hydatid disease in a 71-year-old man with a history of vague abdominal pain, anemia, fever, and microhematuria. Ultrasonographic examination revealed a complex cyst in the right kidney, including multiple smaller cysts with internal echoes. A magnetic resonance scan of the abdomen confirmed the findings, and hydatid cyst disease was diagnosed. Right nephrectomy was performed, and microscopic examination confirmed the diagnosis of hydatid cyst. Albendazole, 10 mg/kg per day, was given for 4 weeks (2 weeks preoperatively and 2 weeks postoperatively). Conclusion. Isolated primary hydatidosis of the kidney should always be considered in the differential diagnosis of any cystic renal mass, even in the absence of accompanying involvement of liver or other visceral organs. PMID- 21660257 TI - Cardiorenal syndrome: an unsolved clinical problem. AB - The clinical relevance of the bidirectional cross-talk between heart and kidney is increasingly recognized. However, the optimal approach to the management of kidney dysfunction in heart failure remains unclear. The purpose of this article is to outline the most plausible pathophysiologic theories that attempt to explain the renal impairment in acute and chronic heart failure, and to review the current treatment strategies for these situations. PMID- 21660258 TI - Action of Coriandrum sativum L. Essential Oil upon Oral Candida albicans Biofilm Formation. AB - The efficacy of extracts and essential oils from Allium tuberosum, Coriandrum sativum, Cymbopogon martini, Cymbopogon winterianus, and Santolina chamaecyparissus was evaluated against Candida spp. isolates from the oral cavity of patients with periodontal disease. The most active oil was fractionated and tested against C. albicans biofilm formation. The oils were obtained by water distillation and the extracts were prepared with macerated dried plant material. The Minimal Inhibitory Concentration-MIC was determined by the microdilution method. Chemical characterization of oil constituents was performed using Gas Chromatography and Mass Spectrometry (GC-MS). C. sativum activity oil upon cell and biofilm morphology was evaluated by Scanning Electron Microscopy (SEM). The best activities against planktonic Candida spp. were observed for the essential oil and the grouped F(8-10) fractions from C. sativum. The crude oil also affected the biofilm formation in C. albicans causing a decrease in the biofilm growth. Chemical analysis of the F(8-10) fractions detected as major active compounds, 2-hexen-1-ol, 3-hexen-1-ol and cyclodecane. Standards of these compounds tested grouped provided a stronger activity than the oil suggesting a synergistic action from the major oil constituents. The activity of C. sativum oil demonstrates its potential for a new natural antifungal formulation. PMID- 21660259 TI - Association of Serum Phosphate and Related Factors in ESRD-Related Vascular Calcification. AB - Vascular calcification is common in ESRD patients and is important in increasing mortality from cardiovascular complications in these patients. Hyperphosphatemia related to chronic kidney disease is increasingly known as major stimulus for vascular calcification. Hyperphosphatemia and vascular calcification become popular discussion among nephrologist environment more than five decades, and many researches have been evolved. Risk factors for calcification are nowadays focused for the therapeutic prevention of vascular calcification with the hope of reducing cardiovascular complications. PMID- 21660260 TI - Optimal hemodialysis prescription: do children need more than a urea dialysis dose? AB - When prescribing hemodialysis in children, the clinician should first establish an adequate regimen, before seeking to optimize the treatment (Fischbach et al. 2005). A complete dialysis dose should consist of a urea dialysis dose and a determined convective volume. Intensified and more frequent dialysis regimens should not be considered exclusively as rescue therapy. Interestingly, a recent single-center study demonstrated that frequent on-line HDF provides an optimal dialysis prescription, both in terms of blood pressure control (and therefore avoidance of left ventricular hypertrophy), and catch-up growth, that is, no malnutrition or cachexia and less resistance to growth hormone. Nevertheless, this one-center experience would benefit from a prospective randomized study. PMID- 21660261 TI - Phosphate Metabolism in CKD Stages 3-5: Dietary and Pharmacological Control. AB - When compared to the available information for patients on dialysis (CKD stage 5D), data on the epidemiology and appropriate treatment of calcium and phosphate metabolism in the predialysis stages of chronic kidney disease (CKD) are quite limited. Perceptible derangements of calcium and phosphate levels start to become apparent when GFR falls below 30 mL/min in some, but not all, patients. However, hyperphosphatemia may be a significant morbidity and mortality risk predictor in predialysis CKD stages. The RIND study, evaluating progression of coronary artery calcification in incident hemodialysis patients, indirectly demonstrated that vascular calcification processes start to manifest in CKD patients prior to the dialysis stage, which may be closely linked to early and invisible derangements in calcium and phosphate homeostasis. Novel insights into the pathophysiology of calcium and phosphate handling such as the discovery of FGF23 and other phosphatonins suggest that a more complex assessment of phosphate balance is warranted, possibly including measurements of fractional phosphate excretion and phosphatonin levels in order to appropriately evaluate disordered metabolism in earlier stages of kidney disease. As a consequence, early and preventive treatment approaches may have to be developed for patients in CKD stages 3-5 to halt progression of CKD-MBD. PMID- 21660262 TI - Synchronous Presence of Nasopharyngeal Carcinoma and Marginal Zone (MALT-Type) B Cell Lymphoma in the Pharynx. AB - Synchronous malignancy of squamous cell carcinoma and malignant lymphoma in the head and neck region is extremely rare. Nasopharyngeal carcinoma is a nonlymphomatous, squamous cell carcinoma that occurs in the nasopharyngeal epithelium. Reported herein is a unique case of nasopharyngeal carcinoma occurring simultaneously with MALT-type lymphoma in an 83-year-old woman, who complained of deglutition dysfunction. Endoscopic examination of respective organs revealed a submucosal tumour on the posterior wall of pharynx. Biopsy of the hypopharynx was taken and sent for histological examination, which revealed two different neoplasms. Immunohistochemical and molecular analysis confirmed the diagnosis of nasopharyngeal carcinoma coexisting with a MALT-type lymphoma. PMID- 21660263 TI - Osteoimmunopathology in HIV/AIDS: A Translational Evidence-Based Perspective. AB - Infection with the human immunodeficiency virus-1 (HIV) and the resulting acquired immune deficiency syndrome (AIDS) alter not only cellular immune regulation but also the bone metabolism. Since cellular immunity and bone metabolism are intimately intertwined in the osteoimmune network, it is to be expected that bone metabolism is also affected in patients with HIV/AIDS. The concerted evidence points convincingly toward impaired activity of osteoblasts and increased activity of osteoclasts in patients with HIV/AIDS, leading to a significant increase in the prevalence of osteoporosis. Research attributes these outcomes in part at least to the ART, PI, and HAART therapies endured by these patients. We review and discuss these lines of evidence from the perspective of translational clinically relevant complex systematic reviews for comparative effectiveness analysis and evidence-based intervention on a global scale. PMID- 21660264 TI - Genetic Polymorphism of Cancer Susceptibility Genes and HPV Infection in Cervical Carcinogenesis. AB - It is widely accepted that specific human papillomavirus (HPV) types are the central etiologic agent of cervical carcinogenesis. However, a number of infected women do not develop invasive lesions, suggesting that other environmental and host factors may play decisive roles in the persistence of HPV infection and further malignant conversion of cervical epithelium. Although many previous reports have focused on HPV and environmental factors, the role of host susceptibility to cervical carcinogenesis is largely unknown. Here, we review the findings of genetic association studies in cervical carcinogenesis with special reference to polymorphisms of glutathione-S-transferase (GST) isoforms, p53 codon 72, murine double-minute 2 homolog (MDM2) gene promoter 309, and FAS gene promoter -670 together with HPV types including our recent research results. PMID- 21660265 TI - Screening for tuberculosis and its histological pattern in patients with enlarged lymph node. AB - Settings. Tuberculosis is a major health problem in the Republic of Yemen. Tuberculous lymphadenitis is one of the most common forms of extrapulmonary tuberculosis. Therefore, this retrospective descriptive study was conducted in Yemen to investigate the morphological pattern of tuberculous lymphadenitis, as well as to assess the reliability measures of (ZN) Ziehl-Neelsen and fluorescent methods in identification of Mycobacterium tuberculosis. Methodology. One hundred lymph nodes tissue biopsies that were previously diagnosed by conventional histopathology as having tuberculous lymphadenitis were reinvestigated. Five micron in thickness sections were obtained from formalin-fixed paraffin wax processed tissues. The sections were stained using Haematoxylin and eosin (H & E), ZN, and fluorescent methods. Results. All of the 100 specimens were proved as having histopathological pattern of tuberculosis lymphadenitis. The most major histological features were giant cell (88%), caseation (84%), epithelioid cells (80%), granuloma and caseation (68%), lymphocytes (31%), and histiocytes (4%). After staining the specimens with ZN and fluorescent, of the 100 specimens only 3 (3%) and 9 (9%) specimens were found positive, by ZN and fluorescent methods, respectively. Conclusion. Conventional ZN and fluorescent methods have limitations in diagnosis of tuberculous lymphadenitis due to their lower sensitivity. Histopathology remains the most suitable method for the diagnosis of tuberculous lymphadenitis. In cases of suspected tuberculous lymphadenitis, it is advisable to confirm with more sensitive and specific method, such as polymerase chain reaction PCR or immunohistochemistry before reporting the negative results. PMID- 21660266 TI - Oral carcinogenesis and oral cancer chemoprevention: a review. AB - Oral cancer is one of the major global threats to public health. The development of oral cancer is a tobacco-related multistep and multifocal process involving field cancerization and carcinogenesis. The rationale for molecular-targeted prevention of oral cancer is promising. Biomarkers of genomic instability, including aneuploidy and allelic imbalance, are possible to measure the cancer risk of oral premalignancies. Understanding of the biology of oral carcinogenesis will yield important advances for detecting high-risk patients, monitoring preventive interventions, and assessing cancer risk and pharmacogenomics. In addition, novel chemopreventive agents based on molecular mechanisms and targets against oral cancers will be derived from studies using appropriate animal carcinogenesis models. New approaches, such as molecular-targeted agents and agent combinations in high-risk oral individuals, are undoubtedly needed to reduce the devastating worldwide consequences of oral malignancy. PMID- 21660267 TI - Comparison of standard and nonstandard helmets and variants influencing the choice of helmets: A preliminary report of cross-sectional prospective analysis of 100 cases. AB - BACKGROUND: The literature does not offer the rate of protection provided by different types of helmets used, especially as it applies to developing countries. We hypothesize that standard versus nonstandard types of helmets might differ in the rate of complications of head and neck trauma occurring in victims of motorcycle accidents. Here we report the rate of occurrence, the type of injuries and differences thereof in standard and nonstandard helmet bearers, and its relevance to protection from serious injury. METHODS: The data were gathered from a data set of motorcycle accident victims admitted to the emergency department of Sina Hospital (Teheran/Iran). A cross-sectional study was designed for a 6-month period of time, June to December 2007. Variants analyzed included: demographics, types of helmets used, level of education of the victims (as in: being trained for using helmets and status of holding a valid driving license). The latter variants were evaluated for possibly influencing the outcome of the injured motorcyclists using either kind of helmets. RESULTS: Among a total of 576 injured motorcyclists who had head, face, or neck injuries, 432 (75%) were using some kind of helmet. A total of 144 (25%) of the injured patients were admitted to the neurosurgical emergency service. There were 100 patients whose data sheets contained all variables which could be included in the pilot analysis of this cohort. DISCUSSION: All 100 subjects were male patients with the age range of 32 +/- 11 years. Twenty-five percent were using standard helmets at the time of accident, 43% had no cranio-facio-cervical injury except very mild skin abrasions, and 23% had facial injury, including skin lacerations needing sutures, two nasal bone fractures, and no maxillofacial damage. Among the patients using standard helmets, 44% had head injuries which needed to be taken care of (mostly nonoperatively), while 61% using nonstandard helmets had head trauma (P > 0.05). The other variables did not reach a significant value affecting the use of either standard or nonstandard helmets in prevention of craniofacial damages. CONCLUSION: This pilot analysis (comprising the data from 100 cases of motorcycle accidents) could not demonstrate statistically significant differences in injury patterns of different types of helmets and variants influencing their respective use. However, it can lead the way for further analysis of larger and more comprehensive head trauma databases regarding factors contributing to the issue of head injury. PMID- 21660268 TI - Recurrent paraganglioma of Meckel's cave: Case report and a review of anatomic origin of paragangliomas. AB - BACKGROUND: Paragangliomas are rare, usually benign tumors of neural crest origin. They account for only 0.6% of all head and neck tumors. In the craniocervical area, they are more common in the carotid body and tympanico jugular regions. To the authors' knowledge, a case of paraganglioma in Meckel's cave has not yet been reported in the medical literature. The pathogenesis and natural history of paragangliomas are still not well understood. We present a case of recurrent paraganglioma in Meckel's cave. CASE DESCRIPTION: A 53-year-old woman was diagnosed with trigeminal neuralgia, dysesthesia and hypoesthesia on the left side of the face, hearing disturbance and a history of chronic, persistent temporal headaches. Magnetic resonance imaging (MRI) showed a lesion located in Meckel's cave on the left side, extending to the posterior cranial fossa and compressing the left cerebral peduncle. The lesion was first thought to be a recurrence of an atypical meningioma, as the pathologist described it in the tissue specimen resected 3 years earlier, and a decision for re-operation was made. A lateral suboccipital approach to the lesion was used under neuronavigational guidance. The tumor was removed, and histological examination proved the lesion to be a paraganglioma. Five months later, the follow-up MRI showed local regrowth, which required subsequent surgical intervention. CONCLUSIONS: A paraganglioma in Meckel's cave is an uncommon tumor in this location. Although ectopic paragangliomas have been described in the literature, a paraganglioma atypically located in Meckel's cave makes a topographic correlation difficult, mainly because paraganglionic cells are usually not found in Meckel's cave. Another peculiarity of the case is the local recurrence of the tumor in a relatively short time despite an attempted, almost gross total resection. PMID- 21660269 TI - Cerebral artery restenosis following transluminal balloon angioplasty for vasospasm after subarachnoid hemorrhage. AB - BACKGROUND: Although percutaneous transluminal angioplasty (PTA) is a widely used less invasive method to treat coronary artery stenosis, 10% of treated patients experience restenosis. Restenosis also occurs in approximately 5% of patients subjected to carotid artery stenting. Animal and human data suggested that restenosis is a response to injury incurred during PTA. As PTA has come into wide use to manage symptomatic cerebral vasospasm after subarachnoid hemorrhage (SAH) we studied the incidence of restenosis after PTA for cerebral vasospasm. METHODS: Our study population consisted of 32 patients who had undergone PTA. They were followed by cerebral or 3DCT angiography or MRA for 6 126 months post-PTA (mean 48.65 months) to diagnose restenosis of the cerebral artery. We compared the size of the cerebral artery on the PTA and the contralateral side. RESULTS: All 32 patients underwent successful PTA of 38 vascular territories and all manifested angiographic improvement of vasospasm. None suffered restenosis during the follow up period. CONCLUSION: PTA resulted in a significant improvement in the vessel diameter in patients with vasospasm after SAH and they did not suffer restenosis in the course of prolonged follow-up. PMID- 21660270 TI - Wrong-level surgery: A unique problem in spine surgery. AB - BACKGROUND: Even though a lot of effort has gone into preventing operating at the wrong site and wrong patient, wrong-level surgery is a unique problem in spine surgery. METHODS: The current method to prevent wrong level spine surgery performed is mainly relied on intra-operative X-ray. Unfortunately, because of the unique features and anatomy of the spinal column, wrong level spine surgery still happens. There are situations that even with intraoperative X-ray, correct level still cannot be reliably identified. RESULTS: Examples of patient whose surgery can easily be performed on the wrong level are illustrated. A protocol to prevent wrong-level spine surgery preformed is developed. CONCLUSION: The consequence of wrong-level spine surgery not only generates another surgery of the intended level; it is usually also associated with lawsuit. Strictly following this protocol can prevent wrong-level spine surgery. PMID- 21660272 TI - Endovascular stenting of an extracranial-intracranial saphenous vein high-flow bypass graft: Technical case report. AB - BACKGROUND: The authors describe a case of endovascular stenting of an extracranial-intracranial saphenous vein high-flow bypass graft in the management of a complex bilateral carotid aneurysm case. CASE DESCRIPTION: A 43-year-old woman was admitted with progressive visual field restriction and headache. Imaging studies revealed bilateral supraclinoid carotid aneurysms. The right carotid aneurysm was clipped and the left one was treated by an endovascular procedure, after performing an internal carotid artery-middle cerebral artery (ICA-MCA) saphenous vein bypass graft. A few months following the bypass procedure, a 70-80% stenosis of the graft was discovered and treated endovascularly with a stenting procedure. Follow-up at 36 months after the first operation showed the patency of the venous graft and no neurological deficits. CONCLUSIONS: Endovascular stenting of the extracranial-intracranial saphenous vein high-flow bypass graft is technically feasible when postoperative graft occlusion is discovered. PMID- 21660271 TI - Spontaneous acute subdural hematoma due to fondaparinux: Report of two cases. AB - BACKGROUND: Spontaneous acute subdural hematomas (SDHs) are rare. Risk factors for development of these hematomas include conditions such as hypertension, vascular abnormalities such as aneurysm or arteriovenous malformation, or consumption of anticoagulants. CASE DESCRIPTION: Here, the authors report two patients who suffered from spontaneous acute SDH while taking fondaparinux for venous thromboembolism prophylaxis. One patient suffered from a remote episode of traumatic brain injury and underwent a decompressive craniectomy 3 weeks prior to presentation, whereas the other patient had been self-medicating with aspirin. CONCLUSION: To our knowledge, these two patients illustrate the first cases of spontaneous acute SDH formation most likely attributed to consumption of fondaparinux. PMID- 21660273 TI - A Review of Carcinomas Arising in the Head and Neck Region in HIV-Positive Patients. AB - The majority of malignancies arising in the head and neck among patients with AIDS are Kaposi sarcoma and non-Hodgkin lymphoma. Patients with HIV/AIDS are also at increased risk of developing several carcinomas of the head and neck. This paper focuses on these less common, albeit important, carcinomas. An English language literature search identified numerous population-based studies evaluating carcinomas in the head and neck of HIV-positive patients. Published results indicate that patients with HIV/AIDS are at an increased risk of developing mucosal squamous cell carcinoma, nasopharyngeal carcinoma, lymphoepithelial carcinoma of the salivary gland, and Merkel cell carcinoma in this anatomic region. Data also suggest that HIV-positive patients with these cancers present at a younger age, with more aggressive disease and worse prognosis compared to HIV-negative patients. Treatment involves surgical resection with or without radiation therapy and chemotherapy for locally advanced and metastatic disease. AIDS patients, however, are more likely to suffer radiation treatment complications. Highly active antiretroviral therapy (HAART) has not altered the incidence of these malignancies. PMID- 21660274 TI - Bilateral giant juvenile fibroadenomas of breasts:a case report. AB - Juvenile fibroadenoma constitutes only 4% of the total fibroadenomas. The incidence of giant juvenile fibroadenomas is found to be only 0.5% of all the fibroadenomas. Bilateral giant juvenile fibroadenomas are extremely rare, and only four cases have been reported in the literature. To the best of our knowledge, we are presenting the fifth case of bilateral giant juvenile fibroadenomas in a 12-year-old prepubertal girl. The diagnosis was made on fine needle aspiration cytology which was confirmed on histopathology. In this paper, we present this rare case to illustrate the diagnosis and management of this tumour and to emphasize that these tumours are almost always benign and should be treated with breast-conserving surgery to provide a healthy physical and social life to the patient. PMID- 21660275 TI - Fine needle aspiration cytology of the breast: the nonmalignant categories. AB - Currently, accurate diagnosis of breast lesions depends on a triple assessment approach comprising clinical, imaging and pathologic examinations. Fine needle aspiration cytology (FNAC) is widely adopted for the pathologic assessment because of its accurracy and ease of use. While much has been written about the atypical and maliganant categories of FNAC diagnosis, little covers the non malignanat category which represents a sheer number in all FNAC cases. Moreover, any false-negative diagnosis of the non-malignant cases may lead to missed diagnosis of cancer. This paper aims to discuss the issues of smear adequacy, the cytologic features of benign breast lesions and the dilemma of a false-negative aspirate. Much has been suggested about the smear adequacy criterion, including quantifying epithelial clusters, whereas others advocate basing adequacy on qualitative quantum of using noncellular features of FNAC. Various benign lesions could be easily diagnosed at FNAC; however, they have cytologic features overlapped with malignant lesions. False negativity of FNAC does occur; this could be caused by either "true" false-negative cases attributed to suboptimal sampling technique, poor localization of the mass or nonpalpable lesions or "false" false-negative cases due to interpretational errors. Though false positive cases are less commonly found, they will also be discussed briefly. PMID- 21660276 TI - The spectrum of clinical and pathological manifestations of AIDS in a consecutive series of 236 autopsied cases in mumbai, India. AB - The HIV epidemic in the Asian subcontinent has a significant impact on India. The AIDS associated pathology has not been well evaluated in a representative study hence very little is known about the spectrum of HIV/AIDS associated diseases in Indian subcontinent. To determine the important postmortem findings in HIV infected individuals in Mumbai, autopsy study was carried out. The patient population included patients with AIDS who died at the tertiary care hospital over a 20 year period from 1988 to 2007. A total of 236 (182; 77% males and 54; 23%) females) patients with AIDS were autopsied. The main risk factor for HIV transmission was heterosexual contact (226 patients; 96%) and 223/236 (94%) patients died of HIV-related diseases. Tuberculosis was the prime cause of death in 149 (63%) patients, followed by bacterial pneumonia 33 (14%), cryptococcosis 18 (8%), toxoplasmosis of brain 15 (6%), pneumocystis jiroveci (PCJ) 1 (0.5%) and Non-Hodgkin's lymphoma 7 (3%) cases. The major underlying pathologies are either preventable or treatable conditions. There is an urgent need for attention towards the diagnosis, issue of therapy, and care of HIV disease in developing countries. Reducing mortality in patients with AIDS from infections must be highest public health policy in India. PMID- 21660277 TI - Imaging of the Head and Neck following Radiation Treatment. AB - Squamous cell carcinoma of the head and neck occurs in approximately 40,000 patients annually in the United States and is often treated with radiation therapy. Radiological studies are obtained following treatment for head and neck malignancies to assess for recurrent tumor, posttreatment changes, and associated complications. Radiation treatment creates a difficult clinical picture for oncologists, head and neck surgeons, neuroradiologists, and neuropathologists. As post-treatment imaging studies are often discussed at radiology/pathology working conferences, knowledge of the imaging appearance of radiation-associated changes in the head and neck and the terminology used by neuroradiologists may not only aid in interpretation of the pathologic specimen, but also assist in communications with neuroradiologists and referring clinicians. PMID- 21660278 TI - The impact of neural stem cell biology on CNS carcinogenesis and tumor types. AB - The incidence of gliomas is on the increase, according to epidemiological data. This increase is a conundrum because the brain is in a privileged protected site behind the blood-brain barrier, and therefore partially buffered from environmental factors. In addition the brain also has a very low proliferative potential compared with other parts of the body. Recent advances in neural stem cell biology have impacted on our understanding of CNS carcinogenesis and tumor types. This article considers the cancer stem cell theory with regard to CNS cancers, whether CNS tumors arise from human neural stem cells and whether glioma stem cells can be reprogrammed. PMID- 21660279 TI - Nanotherapeutics Using an HIV-1 Poly A and Transactivator of the HIV-1 LTR-(TAR-) Specific siRNA. AB - HIV-1 replication can be efficiently inhibited by intracellular expression of an siRNA targeting the viral RNA. We used a well-validated siRNA (si510) which targets the poly A/TAR (transactivator of the HIV-1 LTR) site and suppresses viral replication. Nanotechnology holds much potential for impact in the field of HIV-1 therapeutics, and nanoparticles such as quantum rods (QRs) can be easily functionalized to incorporate siRNA forming stable nanoplexes that can be used for gene silencing. We evaluated the efficacy of the QR-si510 HIV-1 siRNA nanoplex in suppressing viral replication in the HIV-1-infected monocytic cell line THP-1 by measuring p24 antigen levels and gene expression levels of HIV-1 LTR. Our results suggest that the QR-si510 HIV-1 siRNA nanoplex is not only effective in delivering siRNA, but also in suppressing HIV-1 viral replication for a longer time period. HIV-1 nanotherapeutics can thus enhance systemic bioavailability and offer multifunctionality. PMID- 21660280 TI - Comparison of fine needle aspiration cytology and thyroid scan in solitary thyroid nodule. AB - Objective. This was a comparative study between FNAC and thyroid scan used to diagnose the solitary thyroid nodule and histopathology was used as gold standard to compare the results of both modalities. We hypothesized that Fine needle aspiration cytology and thyroid scan diagnose solitary thyroid nodule (STN) as accurately as histopathology. Materials and Methods. This study comprised of 50 patients with solitary thyroid nodules (STN) presented to OPD. After clinical examination these patients were referred to Centre for Nuclear Medicine, Mayo Hospital Lahore for thyroid function tests and thyroid scan (TS). These patients underwent FNAC in the department of Pathology and surgery in Mayo Hospital. The cases were operated and evaluated for histopathological changes. Results. On thyroid scan, 40 patients (80%) having cold nodule were labeled as suspicious 10 patients (20%) had hot nodule. On FNAC 23 patients (46%) had benign lesion, 22 patients (44%) had indeterminate lesion and 5 patients (10%) had malignant lesions. On histopathology, 45 patients (90%) were confirmed to have benign lesions and 5 patients (10%), malignant lesions. After comparison of results of thyroid scan and FNAC with histopathology, the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of thyroid scan were 80%, 20%, 10%, 90% and 26%, respectively whereas those of FNAC were 80%, 97.7%, 80%, 97.7% and 96%, respectively. Conclusion. Fine needle aspiration was a significantly better predictor of malignancy than thyroid scan and resulted in a smaller proportion of excisions for benign nodules. PMID- 21660281 TI - Breast Cancer in the Setting of HIV. AB - Oncogenesis in immunocompromised patients occurs due to a number of factors including reduced immune surveillance or other viral pathogens. Breast cancer, unlike other non-AIDS-defining cancers, does not appear associated and has rarely been reported. We describe a case with evidence of immune reactivity around the tumor, but not in the tumor itself. PMID- 21660282 TI - Potential role of the inflammasome-derived inflammatory cytokines in pulmonary fibrosis. AB - Pulmonary fibrosis is a progressive, disabling disease with mortality rates that appear to be increasing in the western population, including the USA. There are over 140 known causes of pulmonary fibrosis as well as many unknown causes. Treatment options for this disease are limited due to poor understanding of the molecular mechanisms of the disease progression. However, recent progress in inflammasome research has greatly contributed to our understanding of its role in inflammation and fibrosis development. The inflammasome is a multiprotein complex that is an important component of both the innate and adaptive immune systems. Activation of proinflammatory cytokines following inflammasome assembly, such as IL-1beta and IL-18, has been associated with development of PF. In addition, components of the inflammasome complex itself, such as the adaptor protein ASC have been associated with PF development. Recent evidence suggesting that the fibrotic process can be reversed via blockade of pathways associated with inflammasome activity may provide hope for future drug strategies. In this paper we will give an introduction to pulmonary fibrosis and its known causes. In addition, we will discuss the importance of the inflammasome in the development of pulmonary fibrosis as well as discuss potential future treatment options. PMID- 21660284 TI - Standardization of methods for early diagnosis and on-site treatment of high altitude pulmonary edema. AB - High-altitude pulmonary edema (HAPE) is a life-threatening disease of high altitude that often affects nonacclimatized apparently healthy individuals who rapidly ascend to high altitude. Early detection, early diagnosis, and early treatment are essential to maintain the safety of people who ascend to high altitude, such as construction workers and tourists. In this paper, I discuss various methods and criteria that can be used for the early diagnosis and prediction of HAPE. I also discuss the preventive strategies and options for on site treatment. My objective is to improve the understanding of HAPE and to highlight the need for prevention, early diagnosis, and early treatment of HAPE to improve the safety of individuals ascending to high altitude. PMID- 21660283 TI - Serrated polyposis: an enigmatic model of colorectal cancer predisposition. AB - Serrated polyposis has only recently been accepted as a condition which carries an increased personal and familial risk of colorectal cancer. Described over four decades ago, it remains one of the most underrecognized and poorly understood of all the intestinal polyposes. With a variety of phenotypic presentations, it is likely that serrated polyposis represents a group of diseases rather than a single entity. Further, neoplastic progression in serrated polyposis may be associated with premature aging in the normal mucosa, typified by widespread gene promoter hypermethylation. From this epigenetically altered field, arise diverse polyps and cancers which show a range of molecular features. Despite a high serrated polyp count, only one-third of colorectal cancers demonstrate a BRAF V600E mutation, the molecular hallmark of the canonical serrated pathway, suggesting that though multiple serrated polyps act as a marker of an abnormal mucosa, the majority of CRC in these patients arise within lesions other than BRAF-mutated serrated polyps. PMID- 21660285 TI - Fine needle aspiration cytology in diagnosis of pure neuritic leprosy. AB - Leprosy is a chronic infection affecting mainly the skin and peripheral nerve. Pure neuritic form of this disease manifests by involvement of the nerve in the absence of skin lesions. Therefore, it can sometimes create a diagnostic problem. It often requires a nerve biopsy for diagnosis, which is an invasive procedure and may lead to neural deficit. Fine needle aspiration cytology (FNAC) of an affected nerve can be a valuable and less invasive procedure for the diagnosis of such cases. We report five suspected cases of pure neuritic Hansen's disease involving the common and superficial peroneal, ulnar, and median nerve, who underwent FNAC. Smears revealed nerve fibers infiltrated by chronic inflammatory cells in all cases, presence of epithelioid cells granulomas, and Langhans giant cells in three cases, and acid fast bacilli in two cases. In conclusion, FNAC is a safe, less invasive, and time saving procedure for the diagnosis of pure neuritic leprosy. PMID- 21660286 TI - Relationship between Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphism and Susceptibility of Minimal Change Nephrotic Syndrome: A Meta Analysis. AB - Aim. This meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and MCNS susceptibility. Method. A predefined literature search and selection of eligible relevant studies were performed to collect the data from electronic databases. Results. Six articles were identified for the analysis of association between ACE I/D gene polymorphism and MCNS risk, including 4 for Asians, one in Caucasian population and one for Africans. There was a markedly positive association between D allele or DD genotype and MCNS susceptibility in Asians (D: P = .01, DD: P = .02), but not for Caucasians and Africans (Caucasians: D: P = .16, DD: P = .98; Africans: D: P = .81, DD: P = .49). Furthermore, the II genotype seemed not to play a protective role against MCNS risk for Asians, Caucasians and Africans (P = .12, P = .09, P = .76, resp.). Interestingly, there was also significant association between ACE I/D gene polymorphism and MCNS susceptibility in overall populations (D: P = .007, DD: P = .04, II: P = .03). Conclusion. D allele or DD genotype might be a significant genetic molecular marker for MCNS susceptibility in Asians and overall populations, but not for Caucasians and Africans. More larger and rigorous genetic epidemiological investigations are required to further explore this association. PMID- 21660287 TI - Tracheal occlusion conditioning in conscious rats modulates gene expression profile of medial thalamus. AB - The thalamus may be the critical brain area involved in sensory gating and the relay of respiratory mechanical information to the cerebral cortex for the conscious awareness of breathing. We hypothesized that respiratory mechanical stimuli in the form of tracheal occlusions would modulate the gene expression profile of the thalamus. Specifically, it was reasoned that conditioning to the respiratory loading would induce a state change in the medial thalamus consistent with a change in sensory gating and the activation of molecular pathways associated with learning and memory. In addition, respiratory loading is stressful and thus should elicit changes in gene expressions related to stress, anxiety, and depression. Rats were instrumented with inflatable tracheal cuffs. Following surgical recovery, they underwent 10 days (5 days/week) of transient tracheal occlusion conditioning. On day 10, the animals were sacrificed and the brains removed. The medial thalamus was dissected and microarray analysis of gene expression performed. Tracheal obstruction conditioning modulated a total of 661 genes (p < 0.05, log(2) fold change >=0.58), 250 genes were down-regulated and 411 up-regulated. There was a significant down-regulation of GAD1, GAD2 and HTR1A, HTR2A genes. CCK, PRKCG, mGluR4, and KCJN9 genes were significantly up regulated. Some of these genes have been associated with anxiety and depression, while others have been shown to play a role in switching between tonic and burst firing modes in the thalamus and thus may be involved in gating of the respiratory stimuli. Furthermore, gene ontology and pathway analysis showed a significant modulation of learning and memory pathways. These results support the hypothesis that the medial thalamus is involved in the respiratory sensory neural pathway due to the state change of its gene expression profile following repeated tracheal occlusions. PMID- 21660288 TI - Emulation as an integrating principle for cognition. AB - Emulations, defined as ongoing internal representations of potential actions and the futures those actions are expected to produce, play a critical role in directing human bodily activities. Studies of gross motor behavior, perception, allocation of attention, response to errors, interoception, and homeostatic activities, and higher cognitive reasoning suggest that the proper execution of all these functions relies on emulations. Further evidence supports the notion that reinforcement learning in humans is aimed at updating emulations, and that action selection occurs via the advancement of preferred emulations toward realization of their action and environmental prediction. Emulations are hypothesized to exist as distributed active networks of neurons in cortical and sub-cortical structures. This manuscript ties together previously unrelated theories of the role of prediction in different aspects of human information processing to create an integrated framework for cognition. PMID- 21660289 TI - Voltage-gated channel mechanosensitivity: fact or friction? AB - The heart is a continually active pulsatile fluid pump. It generates appropriate forces by precisely timed and spaced engagement of its contractile machinery. Largely, it makes its own control signals, the most crucial of which are precisely timed and spaced fluxes of ions across the sarcolemma, achieved by the timely opening and closing of diverse voltage-gated channels (VGC). VGCs have four voltage sensors around a central ion-selective pore that opens and closes under the influence of membrane voltage. Operation of any VGC is secondarily tuned by the mechanical state (i.e., structure) of the bilayer in which it is embedded. Rates of opening and closing, in other words, vary with bilayer structure. Thus, in the intensely mechanical environment of the myocardium and its vasculature, VGCs kinetics might be routinely modulated by reversible and irreversible nano-scale changes in bilayer structure. If subtle bilayer deformations are routine in the pumping heart, VGCs could be subtly transducing bilayer mechanical signals, thereby tuning cardiac rhythmicity, collectively contributing to mechano-electric feedback. Reversible bilayer deformations would be expected with changing shear flows and tissue distension, while irreversible bilayer restructuring occurs with ischemia, inflammation, membrane remodeling, etc. I suggest that tools now available could be deployed to help probe whether/how the inherent mechanosensitivity of VGCs - an attribute substantially reflecting the dependence of voltage sensor stability on bilayer structure - contributes to cardiac rhythmicity. Chief among these tools are voltage sensor toxins (whose inhibitory efficacy varies with the mechanical state of bilayer) and arrhythmia-inducing VGC mutants with distinctive mechano-phenotypes. PMID- 21660290 TI - Distinct Inter-Joint Coordination during Fast Alternate Keystrokes in Pianists with Superior Skill. AB - Musical performance requires motor skills to coordinate the movements of multiple joints in the hand and arm over a wide range of tempi. However, it is unclear whether the coordination of movement across joints would differ for musicians with different skill levels and how inter-joint coordination would vary in relation to music tempo. The present study addresses these issues by examining the kinematics and muscular activity of the hand and arm movements of professional and amateur pianists who strike two keys alternately with the thumb and little finger at various tempi. The professionals produced a smaller flexion velocity at the thumb and little finger and greater elbow pronation and supination velocity than did the amateurs. The experts also showed smaller extension angles at the metacarpo-phalangeal joint of the index and middle fingers, which were not being used to strike the keys. Furthermore, muscular activity in the extrinsic finger muscles was smaller for the experts than for the amateurs. These findings indicate that pianists with superior skill reduce the finger muscle load during keystrokes by taking advantage of differences in proximal joint motion and hand postural configuration. With an increase in tempo, the experts showed larger and smaller increases in elbow velocity and finger muscle co-activation, respectively, compared to the amateurs, highlighting skill level-dependent differences in movement strategies for tempo adjustment. Finally, when striking as fast as possible, individual differences in the striking tempo among players were explained by their elbow velocities but not by their digit velocities. These findings suggest that pianists who are capable of faster keystrokes benefit more from proximal joint motion than do pianists who are not capable of faster keystrokes. The distinct movement strategy for tempo adjustment in pianists with superior skill would therefore ensure a wider range of musical expression. PMID- 21660291 TI - Multiple birthdating analyses in adult neurogenesis: a line-up of the usual suspects. AB - Analyzing the variation in different subpopulations of newborn neurons is central to the study of adult hippocampal neurogenesis. The acclaimed working hypothesis that different subpopulations of newborn, differentiating neurons could be playing different roles arouses great interest. Therefore, the physiological and quantitative analysis of neuronal subpopulations at different ages is critical to studies of neurogenesis. Such approaches allow cells of different ages to be identified by labeling them according to their probable date of birth. Until very recently, only neurons born at one specific time point could be identified in each experimental animal. However the introduction of different immunohistochemically compatible markers now enables multiple subpopulations of newborn neurons to be analyzed in the same animal as in a line-up, revealing the relationships between these subpopulations in response to specific influences or conditions. This review summarizes the current research carried out using these techniques and outlines some of the key applications. PMID- 21660292 TI - Strategy to combat obesity and to promote physical activity in Arab countries. AB - Obesity has become a major public health problem in the Arab countries, creating a health and economic burden on these countries' government services. There is an urgent need to develop a strategy for prevention and control of obesity. The third Arab Conference on Obesity and Physical Activity was held in Bahrain in January 2010, and proposed the Strategy to Combat Obesity and Promote Physical Activity in Arab Countries. This strategy provides useful guidelines for each Arab country to prepare its own strategy or plan of action to prevent and control obesity. The strategy focused on expected outcomes, objectives, indicators to measure the objectives, and action needs for 9 target areas: child-care centers for preschool children, schools, primary health care, secondary care, food companies, food preparation institutes, media, public benefit organizations, and the workplace. Follow-up and future developments of this strategy were also included. PMID- 21660294 TI - Awareness of Abdominal Adiposity as a Cardiometabolic Risk Factor (The 5A Study): Mexico. AB - BACKGROUND: The Awareness of Abdominal Adiposity as a Cardiometabolic Risk Factor Study assesses the prevalence of cardiometabolic risk factors in adults with abdominal obesity (waist circumference >=90 cm in men and >=80 cm in women) and evaluates how physicians manage these patients. METHODS: This is an observational cross-sectional study. Internists, cardiologists, and endocrinologists contributed patients to the study. A standardized questionnaire was completed and registered demographics, anthropometric measurements, lab results from the medical files, and any treatment utilized to manage dyslipidemia, arterial hypertension, diabetes, and cardiovascular disease. RESULTS: A total of 1312 patients was included. The mean age was 49.3 +/- 14.6 years and 834 (63.6%) were female. The primary reason for the physician consultation was treatment of obesity (47.5%), followed by management of arterial hypertension (27.7%), diabetes (18.3%), dyslipidemia (14.2%), and cardiovascular disease (7.1%). The majority of patients identified excess body weight as a health problem (81.4%). However, patients had lost a mean of 4.3 +/- 3.5 kg. Only 63.4% of patients with arterial hypertension were on drug therapy. Few of them had reached target values for diastolic (24.1%) and systolic/diastolic (13.3%) pressure. Less than half of the patients with dyslipidemia were receiving lipid-lowering medication. Only 32.2% were at their target low-density lipoprotein cholesterol levels. In patients with type 2 diabetes, mean fasting plasma glucose level (8.9 +/- 3.4 mmol/L) was above the threshold recommended by current guidelines. CONCLUSIONS: The study describes the medical care given to individuals with abdominal obesity during daily clinical practice by general practitioners, cardiologists, and endocrinologists in urban Mexico. Our data confirm that a large proportion of patients are undertreated. Only a small percentage of patients with obesity related comorbidities reach treatment targets. Interventions proven to be effective in the prevention of chronic complications have in general not been implemented. PMID- 21660293 TI - Morbid obesity and metabolic syndrome in Ossabaw miniature swine are associated with increased platelet reactivity. AB - BACKGROUND: Metabolic syndrome (MetS) and type 2 diabetes mellitus in humans are associated with increased platelet activation and hyperreactivity of platelets to various agonists. Ossabaw swine develop all the hallmarks of MetS including obesity, insulin resistance, hypertension, dyslipidemia, endothelial dysfunction, and coronary artery disease when being fed excess calorie atherogenic diet. We hypothesized that Ossabaw swine with MetS would exhibit increased platelet reactivity compared with lean pigs without MetS. MATERIALS AND METHODS: Ossabaw swine were fed high caloric, atherogenic diet for 44 weeks to induce MetS (n = 10) and were compared with lean controls without MetS that had been fed normal calorie standard diet (n = 10). Light transmittance aggregometry was performed using adenosine diphosphate (ADP), collagen, thrombin, and arachidonic acid (AA) at different concentrations. Dose response curves and EC50 were calculated. Glucose tolerance testing and intravascular ultrasound study of coronary arteries were performed. RESULTS: MetS pigs compared with lean controls were morbidly obese, showed evidence of arterial hypertension, elevated cholesterol, low density lipoprotein/high-density lipoprotein, and triglycerides, and insulin resistance. Platelets from MetS pigs were more sensitive to ADP-induced platelet aggregation than leans (EC50: 1.83 +/- 1.3 MUM vs 3.64 +/- 2.2 MUM; P = 0.02). MetS pigs demonstrated higher platelet aggregation in response to collagen than lean pigs (area under the curve: 286 +/- 74 vs 198 +/- 123; P = 0.037) and a trend for heightened response to AA (AUC: 260 +/- 151 vs 178 +/- 145; P = 0.13). No significant difference was found for platelet aggregation in response to thrombin. CONCLUSIONS: MetS in Ossabaw swine is associated with increased reactivity of platelets to ADP and collagen. The Ossabaw swine may be a practical, large animal model for the study of certain aspects of platelet pathophysiology and examine vascular devices in a metabolic environment comparable to humans with MetS. PMID- 21660295 TI - Relationship between sleep duration and clustering of metabolic syndrome diagnostic components. AB - OBJECTIVE: To examine the relation between sleep duration and metabolic syndrome (MetS). METHODS: We examined the baseline data from 4356 healthy workers (3556 men and 800 women) aged 19-69 years. The physical activity of each participant was classified according to the International Physical Activity Questionnaire (IPAQ). We defined four components of MetS diagnostic components in this study as follows: 1) high blood pressure (BP) systolic BP [SBP] >= 130 mmHg, or diastolic BP [DBP] >= 85 mmHg, or on medication; 2) dyslipidemia (high-density lipoprotein cholesterol concentration <40 mg/dL, or triglycerides concentration >=150 mg/dL, or on medication; 3) impaired glucose tolerance (fasting blood sugar concentration >= 110 mg/dL, or if less than 8 hours after meals >= 140 mg/dL), or on medication; and 4) overweight (body mass index [BMI] >= 25 kg/m(2)), or obesity (BMI >= 30 kg/m(2)). There were 680 participants in the group, with sleep duration <6 hours (15.6%). RESULTS: Those who had 0-4 MetS diagnostic components, including overweight, accounted for 2159, 1222, 674, 255, and 46 participants, respectively, in the Poisson distribution. Poisson regression analysis revealed that independent factors that contributed to the number of MetS diagnostic components were being male (regression coefficient b = 0.752, P < 0.001), age (b = 0.026, P < 0.001), IPAQ classification (b = -0.238, P = 0.034), and alcohol intake (mL/day) (b = 0.018, P < 0.001). Short sleep duration (<6 hours) was also related to the number of MetS (b = 0.162, P < 0.001). The results of analyses with obesity component showed a similar association. CONCLUSION: Short sleep duration was positively associated with the number of MetS diagnostic components independent of other lifestyle habits. PMID- 21660296 TI - Lung injury after cigarette smoking is particle related. AB - The specific component responsible and the mechanistic pathway for increased human morbidity and mortality after cigarette smoking are yet to be delineated. We propose that 1) injury and disease following cigarette smoking are associated with exposure to and retention of particles produced during smoking and 2) the biological effects of particles associated with cigarette smoking share a single mechanism of injury with all particles. Smoking one cigarette exposes the human respiratory tract to between 15,000 and 40,000 MUg particulate matter; this is a carbonaceous product of an incomplete combustion. There are numerous human exposures to other particles, and these vary widely in composition, absolute magnitude, and size of the particle. Individuals exposed to all these particles share a common clinical presentation with a loss of pulmonary function, increased bronchial hyperresponsiveness, pathologic changes of emphysema and fibrosis, and comorbidities, including cardiovascular disease, cerebrovascular disease, peripheral vascular disease, and cancers. Mechanistically, all particle exposures produce an oxidative stress, which is associated with a series of reactions, including an activation of kinase cascades and transcription factors, release of inflammatory mediators, and apoptosis. If disease associated with cigarette smoking is recognized to be particle related, then certain aspects of the clinical presentation can be predicted; this would include worsening of pulmonary function and progression of pathological changes and comorbidity (eg, emphysema and carcinogenesis) after smoking cessation since the particle is retained in the lung and the exposure continues. PMID- 21660298 TI - Oxidative DNA damage in lung tissue from patients with COPD is clustered in functionally significant sequences. AB - Lung tissue from COPD patients displays oxidative DNA damage. The present study determined whether oxidative DNA damage was randomly distributed or whether it was localized in specific sequences in either the nuclear or mitochondrial genomes. The DNA damage-specific histone, gamma-H2AX, was detected immunohistochemically in alveolar wall cells in lung tissue from COPD patients but not control subjects. A PCR-based method was used to search for oxidized purine base products in selected 200 bp sequences in promoters and coding regions of the VEGF, TGF-beta1, HO-1, Egr1, and beta-actin genes while quantitative Southern blot analysis was used to detect oxidative damage to the mitochondrial genome in lung tissue from control subjects and COPD patients. Among the nuclear genes examined, oxidative damage was detected in only 1 sequence in lung tissue from COPD patients: the hypoxic response element (HRE) of the VEGF promoter. The content of VEGF mRNA also was reduced in COPD lung tissue. Mitochondrial DNA content was unaltered in COPD lung tissue, but there was a substantial increase in mitochondrial DNA strand breaks and/or abasic sites. These findings show that oxidative DNA damage in COPD lungs is prominent in the HRE of the VEGF promoter and in the mitochondrial genome and raise the intriguing possibility that genome and sequence-specific oxidative DNA damage could contribute to transcriptional dysregulation and cell fate decisions in COPD. PMID- 21660297 TI - Hypoxemia in patients with COPD: cause, effects, and disease progression. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain. PMID- 21660300 TI - Bronchodilation improves endurance but not muscular efficiency in chronic obstructive pulmonary disease. AB - We hypothesized that bronchodilator treatment not only improves hyperinflation and endurance capacity but also muscular efficiency in stable chronic obstructive pulmonary disease (COPD). We aimed to demonstrate that tiotropium and salmeterol improve muscular efficiency compared with placebo. Twenty-five COPD patients were studied, including 20 males of mean (standard deviation) age 62 years (7 years) with baseline forced expiratory volume in 1 second of 41% (10%) predicted, and maximal workload of 101 Watt (36 Watt). Subjects were randomized for 6-week treatment with tiotropium 18 MUg once daily, salmeterol 50 MUg twice daily, or placebo using a double-blind, crossover design. Muscular efficiency and endurance time were measured during cycling at 50% of maximal work load. Resting energy expenditure was measured using a ventilated hood. Muscular efficiency after tiotropium, salmeterol, and placebo treatment was 14.6%, 14.4%, and 14.4%, respectively (P > 0.05), and resting energy expenditure was 1485 kcal/24 hours, 1709 kcal/24 hours, and 1472 kcal/24 hours (P > 0.05), respectively. Endurance time after tiotropium treatment was significantly higher than that after placebo (27.0 minutes versus 19.3 minutes [P = 0.02]), whereas endurance time after salmeterol treatment was not higher than that after placebo (23.3 minutes [P = 0.22]). In this small study, we were not able to demonstrate that bronchodilator therapy improved muscular efficiency. Apparently, reduced costs of breathing relative to total energy expenditure were too small to be detected. PMID- 21660299 TI - Comparison of efficacy of long-acting bronchodilators in emphysema dominant and emphysema nondominant chronic obstructive pulmonary disease. AB - BACKGROUND: The purpose of this study was to clarify the association between morphological phenotypes according to the predominance of emphysema and efficacy of long-acting muscarinic antagonist and beta(2) agonist bronchodilators in patients with chronic obstructive pulmonary disease (COPD). METHODS: Seventy-two patients with stable COPD treated with tiotropium (n = 41) or salmeterol (n = 31) were evaluated for pulmonary function, dynamic hyperinflation following metronome paced incremental hyperventilation, six-minute walking distance, and St George's Respiratory Questionnaire (SGRQ) before and 2-3 months following treatment with tiotropium or salmeterol. They were then visually divided into an emphysema dominant phenotype (n = 25 in the tiotropium-treated group and n = 22 in the salmeterol-treated group) and an emphysema nondominant phenotype on high resolution computed tomography, and the efficacy of the two drugs in each phenotype was retrospectively analyzed. RESULTS: Tiotropium significantly improved airflow limitation, oxygenation, and respiratory impedance in both the emphysema dominant and emphysema nondominant phenotypes, and improved dynamic hyperinflation, exercise capacity, and SGRQ in the emphysema dominant phenotype but not in the emphysema nondominant phenotype. Salmeterol significantly improved total score for SGRQ in the emphysema phenotype, but no significant effects on other parameters were found for either of the phenotypes. CONCLUSION: These findings suggest that tiotropium is more effective than salmeterol for airflow limitation regardless of emphysema dominance, and also can improve dynamic hyperinflation in the emphysema dominant phenotype, which results in further improvement of exercise capacity and health-related quality of life. PMID- 21660301 TI - Racial and Ethnic Variation in Lipoprotein (a) Levels among Asian Indian and Chinese Patients. AB - Background. Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease (CVD) in Non-Hispanic Whites (NHW). There are known racial/ethnic differences in Lp(a) levels, and the association of Lp(a) with CVD outcomes has not been examined in Asian Americans in the USA. Objective. We hypothesized that Lp(a) levels would differ in Asian Indians and Chinese Americans when compared to NHW and that the relationship between Lp(a) and CVD outcomes would be different in these Asian racial/ethnic subgroups when compared to NHW. Methods. We studied the outpatient electronic health records of 2022 NHW, 295 Asian Indians, and 151 Chinese adults age >=18 y in Northern California in whom Lp(a) levels were assessed during routine clinical care from 2001 to 2008, excluding those who had received prescriptions for niacin (14.6%). Nonparametric methods were used to compare median Lp(a) levels. Significance was assessed at the P < .0001 level to account for multiple comparisons. CVD outcomes were defined as ischemic heart disease (IHD) (265 events), stroke (122), or peripheral vascular disease (PVD) (87). We used logistic regression to determine the relationship between Lp(a) and CVD outcomes. Results. Both Asian Indians (36 nmol/L) and NHW (29 nmol/L) had higher median Lp(a) levels than Chinese (22 nmol/L, P <= .0001 and P = .0032). When stratified by sex, the differences in median Lp(a) between these groups persisted in the 1761 men (AI v CH: P = .001, NHW v CH: P = .0018) but were not statistically significant in the 1130 women (AI v CH: P = .0402, NHW v CH: P = .0761). Asian Indians (OR = 2.0) and Chinese (OR = 4.8) exhibited a trend towards greater risk of IHD with high Lp(a) levels than NHW (OR = 1.4), but no relationship was statistically significant. Conclusion. Asian Indian and NHW men have higher Lp(a) values than Chinese men, with a trend toward, similar associations in women. High Lp(a) may be more strongly associated with IHD in Asian Indians and Chinese, although we did not have a sufficient number of outcomes to confirm this. Further studies should strive to elucidate the relationship between Lp(a) levels, CVD, and race/ethnicity among Asian subgroups in the USA. PMID- 21660302 TI - Comparison of sustained hemodiafiltration with acetate-free dialysate and continuous venovenous hemodiafiltration for the treatment of critically ill patients with acute kidney injury. AB - We conducted a prospective, randomized study to compare conventional continuous venovenous hemodiafiltration (CVVHDF) with sustained hemodiafiltration (SHDF) using an acetate-free dialysate. Fifty critically ill patients with acute kidney injury (AKI) who required renal replacement therapy were treated with either CVVHDF or SHDF. CVVDHF was performed using a conventional dialysate with an effluent rate of 25 mL.kg(-1) . (h-1), and SHDF was performed using an acetate free dialysate with a flow rate of 300-500 mL/min. The primary study outcome, 30 d survival rate was 76.0% in the CVVHDF arm and 88.0% in the SHDF arm (NS). Both the number of patients who showed renal recovery (40.0% and 68.0%, CVVHDF and SHDF, resp.; P < .05), and the hospital stay length (42.3 days and 33.7 days, CVVHDF and SHDF, resp.; P < .05), significantly differed between the two treatments. Although the total convective volumes did not significantly differ, the dialysate flow rate was higher and mean duration of daily treatment was shorter in the SHDF treatment arm. Our results suggest that compared with conventional CVVHDF, more intensive renal support in the form of post-dilution SHDF with acetate-free dialysate may accelerate renal recovery in critically ill patients with AKI. PMID- 21660303 TI - The Dynamics of Oxidized LDL during Atherogenesis. AB - Accumulating evidence indicates that oxidized low-density lipoprotein (OxLDL) is a useful marker for cardiovascular disease. The uptake of OxLDL by scavenger receptors leads to the accumulation of cholesterol within the foam cells of atherosclerotic lesions. OxLDL has many stimulatory effects on vascular cells, and the presence of OxLDL in circulating blood has been established. According to the classical hypothesis, OxLDL accumulates in the atherosclerotic lesions over a long duration, leading to advanced lesions. However, recent studies on time course changes of OxLDL in vivo raised a possibility that OxLDL can be transferred between the lesions and the circulation. In this paper, the in vivo dynamics of OxLDL are discussed. PMID- 21660304 TI - Dilemma of HCV infection in renal transplant recipients. AB - Hepatitis C virus, which usually starts during dialysis therapy, is currently the main cause of chronic liver disease in such population. The majority of patients acquired the disease through intravenous drug use or blood transfusion, with some risk factors identified. In this review we are dealing with the effect of renal transplantation on HCV infection and HCV-related complications after renal transplantation. Moreover, we are discussing the therapeutic options of HCV infection before and after renal transplantation, the best immunosuppressive protocol and lastly graft and patient survival in patients who underwent pretransplant management vs. those who were transplanted without treatment. PMID- 21660305 TI - Emodin Induces Apoptotic Death in Murine Myelomonocytic Leukemia WEHI-3 Cells In Vitro and Enhances Phagocytosis in Leukemia Mice In Vivo. AB - Emodin is one of major compounds in rhubarb (Rheum palmatum L.), a plant used as herbal medicine in Chinese population. Although many reports have shown that emodin exhibits anticancer activity in many tumor cell types, there is no available information addressing emodin-affected apoptotic responses in the murine leukemia cell line (WEHI-3) and modulation of the immune response in leukemia mice. We investigated that emodin induced cytotoxic effects in vitro and affected WEHI-3 cells in vivo. This study showed that emodin decreased viability and induced DNA fragmentation in WEHI-3 cells. Cells after exposure to emodin for 24 h have shown chromatin condensation and DNA damage. Emodin stimulated the productions of ROS and Ca(2+) and reduced the level of DeltaPsi(m) by flow cytometry. Our results from Western blotting suggest that emodin triggered apoptosis of WEHI-3 cells through the endoplasmic reticulum (ER) stress, caspase cascade-dependent and -independent mitochondrial pathways. In in vivo study, emodin enhanced the levels of B cells and monocytes, and it also reduced the weights of liver and spleen compared with leukemia mice. Emodin promoted phagocytic activity by monocytes and macrophages in comparison to the leukemia mice group. In conclusions, emodin induced apoptotic death in murine leukemia WEHI-3 cells and enhanced phagocytosis in the leukemia animal model. PMID- 21660306 TI - Membrane fusion induced by small molecules and ions. AB - Membrane fusion is a key event in many biological processes. These processes are controlled by various fusogenic agents of which proteins and peptides from the principal group. The fusion process is characterized by three major steps, namely, inter membrane contact, lipid mixing forming the intermediate step, pore opening and finally mixing of inner contents of the cells/vesicles. These steps are governed by energy barriers, which need to be overcome to complete fusion. Structural reorganization of big molecules like proteins/peptides, supplies the required driving force to overcome the energy barrier of the different intermediate steps. Small molecules/ions do not share this advantage. Hence fusion induced by small molecules/ions is expected to be different from that induced by proteins/peptides. Although several reviews exist on membrane fusion, no recent review is devoted solely to small moleculs/ions induced membrane fusion. Here we intend to present, how a variety of small molecules/ions act as independent fusogens. The detailed mechanism of some are well understood but for many it is still an unanswered question. Clearer understanding of how a particular small molecule can control fusion will open up a vista to use these moleucles instead of proteins/peptides to induce fusion both in vivo and in vitro fusion processes. PMID- 21660307 TI - Nephronophthisis: a genetically diverse ciliopathy. AB - Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease and a leading genetic cause of established renal failure (ERF) in children and young adults. Early presenting symptoms in children with NPHP include polyuria, nocturia, or secondary enuresis, pointing to a urinary concentrating defect. Renal ultrasound typically shows normal kidney size with increased echogenicity and corticomedullary cysts. Importantly, NPHP is associated with extra renal manifestations in 10-15% of patients. The most frequent extrarenal association is retinal degeneration, leading to blindness. Increasingly, molecular genetic testing is being utilised to diagnose NPHP and avoid the need for a renal biopsy. In this paper, we discuss the latest understanding in the molecular and cellular pathogenesis of NPHP. We suggest an appropriate clinical management plan and screening programme for individuals with NPHP and their families. PMID- 21660309 TI - Indices of kidney damage and cardiovascular disease risk factors in a semiurban community of iloye, South-west Nigeria. AB - Health screening exercises are important, as they enable early detection of diseases in individual subjects and also enable data collection, useful in estimating disease burden in the community. This paper describes the findings of a health screening exercise conducted in a semiurban population of Iloye, by the Rotary Club of Ota, Ogun State, Western Nigeria, as a part of its community oriented services and projects. Three hundred and twenty six community members were screened during the exercise. There were 189 (57.97%) females and 137 (42.03%) males, with a mean age of 43.5 +/- 14.88 yrs. Urinary abnormality and/or creatinine clearance less than 90 mls/min was detected in 147 (45.09%) participants. 99 (30.37%) participants had proteinuria, 16 (4.91%) had haematuria, and 5 (1.53%) participants had both haematuria and proteinuria. Eight (2.45%) participants had GFR less than 60 mls/min. Elevated blood pressure was found in 152 (46.63%), while 3 (0.9%) participants had diabetes, 71 (21.8%) were obese, 16 (4.9%) had hypercholesterolaemia, and 3 (0.9%) had hypertriglyceridaemia. Prevalence of both smoking and alcohol consumption was 6 (1.84%). It was concluded that the prevalence of indices of kidney damage and cardiovascular risk factors is high in Iloye community. PMID- 21660308 TI - Traditional Japanese formula kigikenchuto accelerates healing of pressure-loading skin ulcer in rats. AB - We evaluated the effect of kigikenchuto (KKT), a traditional Japanese formula, in a modified rat pressure-loading skin ulcer model. Rats were divided into three groups, KKT extract orally administered (250 or 500 mg/kg/day for 35 days) and control. KKT shortened the duration until healing. Immunohistochemically, KKT increased CD-31-positive vessels in early phase and increased alpha-smooth muscle actin-(alpha-SMA-) positive fibroblastic cells in early phase and decreased them in late phase of wound healing. By Western blotting, KKT showed the potential to decrease inflammatory cytokines (MCP-1, IL-1beta, and TNF-alpha) in early phase, decrease vascular endothelial growth factor in early phase and increase it in late phase, and modulate the expression of extracellular protein matrix (alpha SMA, TGF-beta1, bFGF, collagen III, and collagen I). These results suggested the possibility that KKT accelerates pressure ulcer healing through decreases of inflammatory cytokines, increase of angiogenesis, and induction of extracellular matrix remodeling. PMID- 21660310 TI - Suan zao ren tang as an original treatment for sleep difficulty in climacteric women: a prospective clinical observation. AB - Little scientific evidence supports the efficacy of herbal medicines in the treatment of women with sleep difficulty during the climacteric period. The purpose of this study is to evaluate the efficacy and safety of Suan Zao Ren Tang (SZRT) in reducing the impact of sleep disturbance on climacteric women, as measured by Pittsburg sleep quality index (PSQI) and the World Health Organization quality of life (WHOQOL). Sixty-seven climacteric women with sleep difficulty intending to treat received SZRT at a rate of 4.0 g, thrice daily for four weeks (MRS < 16, n = 34; MRS >= 16, n = 33). After taking into account potential confounding factors, the mean PSQI total scores had fallen from 13.0 (+/-2.9) to 9.0 (+/-3.2) (95% confidence interval -4.93, -3.10). Further analyses showed that SZRT produced superior benefit of daytime dysfunction in women with severe menopausal symptoms (MRS >= 16). There were three of the withdrawals involved treatment-related adverse events (stomachache, diarrhea, and dizziness). Excluding women with a past history of stomachache, diarrhea, or dizziness, four weeks of therapy with SZRT appears to be a relatively safe and effective short term therapeutic option in improving daytime function of climacteric women with poor sleep quality. PMID- 21660311 TI - Pharmacological management of cardiorenal syndromes. AB - Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pharmacological management of Cardiorenal syndromes may be complicated by unanticipated or unintended effects of agents targeting one organ on the other. Hence, a thorough understanding of the pathophysiology of these disorders is paramount. The treatment of cardiovascular diseases and risk factors may affect renal function and modify the progression of renal injury. Likewise, management of renal disease and associated complications can influence heart function or influence cardiovascular risk. In this paper, an overview of pharmacological management of acute and chronic Cardiorenal Syndromes is presented, and the need for high-quality future studies in this field is highlighted. PMID- 21660312 TI - Vascular calcification in an adolescent treated with long-term peritoneal dialysis. AB - The reason of high mortality in patients with chronic kidney disease (CKD) is cardiovascular disease and arterial calcification has been accepted as an additive factor on this status. In this report we described vascular and cardiac valvular calcifications in an adolescent on CAPD. PMID- 21660313 TI - Arterial stiffness in chronic kidney disease: the usefulness of a marker of vascular damage. AB - Increased arterial stiffness is a marker of vasculopathy in chronic kidney disease (CKD) patients, suggesting a significant cardiovascular damage. Detection of arterial stiffness provides physicians with useful prognostic information independent of traditional cardiovascular (CV) risk factors. In addition, this knowledge may help guide appropriate therapeutic choices and monitor the effectiveness of antihypertensive therapies. We review the relationship between arterial stiffness and CKD, as well as the prognostic implications of increased arterial stiffness and the potential therapeutic strategies to ameliorate arterial compliance and outcome in CKD. PMID- 21660316 TI - Fluorescence correlation spectroscopy evidence for structural heterogeneity in ionic liquids. AB - In this work, we provide new experimental evidence for chain length-dependent self-aggregation in room temperature ionic liquids (RTILs) using fluorescence correlation spectroscopy (FCS). In studying a homologous series of N-alkyl-N methylpyrrolidinium bis(trifluoromethylsulfonyl) imide, [C(n)MPy][Tf(2)N] RTILs of varying alkyl chain length (n = 3, 4, 6, 8, and 10), biphasic rhodamine 6G solute diffusion dynamics were observed; both the fast and slow diffusion coefficients decreased with increasing alkyl chain length, with the relative contribution from slower diffusion increasing for longer-chain [C(n)MPy][Tf(2)N]. We propose that the biphasic diffusion dynamics originate from self-aggregation of the nonpolar alkyl chains in the cationic [C(n)MPy](+). PMID- 21660315 TI - The comparative protective effects of ganoderma spores lipid and fish oil on N methyl-N-nitrosourea-induced photoreceptor cell lesion in rats. AB - Purpose. To compare Ganoderma spores lipid (GSL) and fish oil (FO) in inhibiting retinal photoreceptor cell lesions induced by N-methyl-N-nitrosourea (MNU) in rats. Methods. 120 rats were untreated (normal control, NC group) or treated with a single intraperitoneal injection of 40 mg/kg MNU (MNU group) then treated with GSL (GSL group) or FO (FO group). Eyes were obtained at 1, 3, 5, 7, and 10 days. Results. Light microscopy assay demonstrated that GSL and FO alleviated rat retinal photoreceptor cell damage (GSL and FO versus MNU group P < .001) similarly (GSL versus FO group P = .980). Electron microscopy confirmed that GSL and FO reversed damage to photoreceptor segments and photoreceptor cell nuclei. GSL-treated rats showed significantly elevated a-wave and b-wave amplitudes over MNU group (P < .05) but less than NC group (P < .05) and not significantly different from FO group (P > .05). Conclusion. GSL, like FO, alleviates rat retinal photoreceptor cell damage induced by MNU. PMID- 21660314 TI - Acute kidney injury: controversies revisited. AB - This paper addresses the epidemiology of AKI specifically in relation to recent changes in AKI classification and revisits the controversies regarding the timing of initiation of dialysis and the use of peritoneal dialysis as a renal replacement therapy for AKI. In summary, the new RIFLE/AKIN classifications of AKI have facilitated more uniform diagnosis of AKI and clinically significant risk stratification. Regardless, the issue of timing of dialysis initiation still remains unanswered and warrants further examination. Furthermore, peritoneal dialysis as a treatment modality for AKI remains underutilised in spite of potential beneficial effects. Future research should be directed at identifying early reliable biomarkers of AKI, which in conjunction with RIFLE/AKIN classifications of AKI could facilitate well-designed large randomised controlled trials of early versus late initiation of dialysis in AKI. In addition, further studies of peritoneal dialysis in AKI addressing dialysis dose and associated complications are required for this therapy to be accepted more widely by clinicians. PMID- 21660317 TI - Salting out in organic solvents: a new route to carbon nanotube bundle engineering. AB - In this study we investigate salt effects on bundle formation of carbon nanotubes (CNTs) dispersed in an organic solvent, N-methyl-2-pyrrolidone (NMP). Addition of NaI salt leads to self-assembly of CNTs into well-recognizable bundles. It is possible to control the size of the CNT bundles by varying the salt concentration. PMID- 21660318 TI - Anomalous decline of water transport in covalently modified carbon nanotube membranes. AB - Carbon nanotube membranes have been shown to rapidly transport liquids; but progressive hydrophilic modification--contrary to expectations--induces a drastic reduction of water flow. Enhanced electrostatic interaction and the disruption of the mechanically smooth graphitic walls is the determinant of this behavior. These results have critical implications in the design of nanofluidic devices. PMID- 21660319 TI - Facile fabrication of noble metal nanoparticles encapsulated in hollow silica with radially oriented mesopores: multiple roles of the N-lauroylsarcosine sodium surfactant. AB - A facile one-pot method was reported to fabricate noble metal nanoparticles encapsulated in silica hollow nanospheres with radially oriented mesopores, and the anionic amino acid surfactant, N-lauroylsarcosine sodium, played multiple roles: reducing agent, stabilizer, emulsion droplets and mesopore template. PMID- 21660320 TI - Hybrid density functional theory/molecular mechanics calculations of two-photon absorption of dimethylamino nitro stilbene in solution. AB - The dimethylamino nitro stilbene (DANS) molecule is studied for exploring solvent effects on two-photon absorption using the quantum mechanical/molecular mechanical (QM/MM) response theory approach, where the quantum part is represented by density functional theory. We have explored the role of geometrical change of the chromophore in solution, the importance of taking a dynamical average over the sampled structures and the role of a granular representation of the polarization and electrostatic interactions with the classically described medium. The line shape function was simulated by the QM/MM technique thereby allowing for non-empirical prediction of the absolute two photon cross section. We report a maximum in the TPA cross section for a medium of intermediate solvent polarity (i.e. in chloroform) and provide the grounds for an explanation of this effect which recently has been experimentally observed for a series of charge transfer species in solvents of different polarity. The calculations of absorption energies reproduce well the positive solvatochromic behavior of DANS and are in good agreement with experimental spectra available for the chloroform and DMSO solvents. In line with recent development of the QM/MM response technique for color modeling, we find this methodology to offer a versatile tool to predict and analyze two-photon absorption phenomena taking place within a medium. PMID- 21660322 TI - Photoselective excited state dynamics in ZnO-Au nanocomposites and their implications in photocatalysis and dye-sensitized solar cells. AB - Improving the performance of photoactive solid-state devices begins with systematic studies of the metal-semiconductor nanocomposites (NCs) upon which such devices are based. Here, we report the photo-dependent excitonic mechanism and the charge migration kinetics in a colloidal ZnO-Au NC system. By using a picosecond-resolved Forster resonance energy transfer (FRET) technique, we have demonstrated that excited ZnO nanoparticles (NPs) resonantly transfer visible optical radiation to the Au NPs, and the quenching of defect-mediated visible emission depends solely on the excitation level of the semiconductor. The role of the gold layer in promoting photolytic charge transfer, the activity of which is dependent upon the degree of excitation, was probed using methylene blue (MB) reduction at the semiconductor interface. Incident photon-to-current efficiency measurements show improved charge injection from a sensitizing dye to a semiconductor electrode in the presence of gold in the visible region. Furthermore, the short-circuit current density and the energy conversion efficiency of the ZnO-Au NP based dye-sensitized solar cell (DSSC) are much higher than those of a DSSC comprised of only ZnO NP. Our results represent a new paradigm for understanding the mechanism of defect-state passivation and photolytic activity of the metal component in metal-semiconductor nanocomposite systems. PMID- 21660321 TI - Thiazole orange (TO) as a light-switch probe: a combined quantum-mechanical and spectroscopic study. AB - A Density Functional Theory (DFT) study of the absorbance and fluorescence emission characteristics of the cyanine thiazole orange (TO) in solution and when intercalated in DNA was carried out in combination with spectrophotometric and spectrofluorometric experiments under different conditions (temperature, concentration, solvent viscosity). T-jump relaxation kinetics of the TO monomer dimer conversion enabled the thermodynamic parameters of this process to be evaluated. The overall data collected provided information on the features of the "light-switch" by the fluorescent TO and the comparison between experimental and calculated photo-physical properties allowed us to explain and rationalize both shifts and quenching/enhancing effects on fluorescence due to solvation, dimerisation and intercalation in the DNA. PMID- 21660323 TI - How do electron localization functions describe pi-electron delocalization? AB - Scalar fields provide an intuitive picture of chemical bonding. In particular, the electron localization function (ELF) has proven to be highly valuable in interpreting a broad range of bonding patterns. The discrimination between enhanced or reduced electron (de)localization within cyclic pi-conjugated systems remains, however, challenging for ELF. In order to clearly distinguish between the local properties of ten highly and weakly pi-(de)localized prototype systems, we compare the ELFs of both the canonical wave functions and electron-localized states (diabatic) with those of two closely related scalar fields: the electron localizability indicator (ELI-D) and the localized orbital locator (LOL). The simplest LOL function distinguishes enhanced from weak pi-(de)localization in an insightful and reliable manner. LOL offers the finest contrast between annulenes with 4n/4n + 2 pi electrons and their inorganic analogues as well as between hyperconjugated cyclopentadiene derivatives. LOL(pi) also gives an appealing and intuitive picture of the pi-bond. In contrast, the most popular ELF fails to capture subtle contrasting local electronic properties and suffers from the arbitrariness of the sigma/pi dissection. The orbital separation of the most recent ELI-D is clear-cut but the interpretations sometime less straightforward in the present context. PMID- 21660324 TI - Complementary and partially complementary DNA duplexes tethered to a functionalized substrate: a molecular dynamics approach to biosensing. AB - Molecular dynamics simulations (90 ns) of different DNA complexes attached to a functionalized substrate in solution were performed in order to clarify the behavior of mismatched DNA sequences captured by a tethered DNA probe (biochip). Examination of the trajectories revealed that the substrate influence and a series of cooperative events, including recognition, reorientation and reorganization of the bases, could induce the formation of stable duplexes having non-canonical arrangements. Major adjustment of the structures was observed when the mutated base was located in the end region of the chain close to the surface. PMID- 21660325 TI - Site-selective labeling at Cys302 of aldehyde dehydrogenase unveils a selective mitochondrial stain. AB - A mitochondria-trackable fluorophore, CDy2, selectively labels Cys302 in the active site of mitochondrial aldehyde dehydrogenase (ALDH2). PMID- 21660326 TI - Efficient palladium-catalyzed N-arylation of a sulfoximine with aryl chlorides. AB - The efficient N-arylation of a sulfoximine with aryl chlorides was developed by using Pd(2)(dba)(3) as a catalyst and various ligands. The reactions using RuPhos as a ligand afforded the coupled products in fair to excellent yields. PMID- 21660327 TI - In situ infrared monitoring of the solid/liquid catalyst interface during the three-phase hydrogenation of nitrobenzene over nanosized Au on TiO2. AB - The three-phase hydrogenation of nitrobenzene catalysed by nanosized gold over titania was investigated in a slurry. Simultaneous in situ ATR-FTIR monitoring of the liquid phase and at the solid/liquid catalyst interface identified the species adsorbed on the catalyst and those in the liquid phase during the reaction. Nitrosobenzene was not detected analytically while the spectroscopic measurements strongly indicated phenylhydroxylamine as an intermediate reacting before desorbing from the catalyst surface. Under the same reaction conditions, azobenzene and hydrazobenzene were identified as intermediates during the hydrogenation of azoxybenzene to aniline. When nitrosobenzene or phenylhydroxylamine was alternately fed as reactant, azoxybenzene was produced via a disproportionation route. With the former, azoxybenzene was not further reduced by hydrogen because nitrosobenzene deactivated the catalyst. Combined with H(2) uptake, the spectroscopic measurements provided new insights into the reaction mechanism of the gold catalysed hydrogenation of nitrobenzene and an update of the corresponding kinetics. PMID- 21660328 TI - Plasma electrochemistry in ionic liquids: an alternative route to generate nanoparticles. AB - In this perspective, the application of stable glow discharge plasmas as free electrodes for the generation of nanoparticles in ionic liquids is reported. The basic concepts of plasma electrochemistry as well as a few other concepts in this field will be presented. One focus is the interaction of the plasma with the ionic liquids itself and possible influences on the production process of the particles. Several examples of the plasma generation and characterisation of nanoparticles in ionic liquids will be presented. The starting point is thereby the generation of noble metals and at the end the efforts to synthesize semiconductor nanoparticles will be discussed. In all examples the benefits, the difficulties and the challenges of this method and the outcome for the future will be addressed. PMID- 21660329 TI - N-donor ligands based on bipyridine and ionic liquids: an efficient partnership to stabilize rhodium colloids. Focus on oxygen-containing compounds hydrogenation. AB - Polynitrogen ligands and/in ionic liquids (ILs) are described as a pertinent tandem to efficiently stabilize rhodium nanoparticles (NPs) in the size range of 2.0 nm for catalytic applications. Several N-donor ligands based on bipyridine skeleton were used as extra protective agents in [BMI][PF(6)] and compared in the hydrogenation of functionalized aromatic compounds at 80 degrees C and under 40 bar H(2). The nature of the bipyridine derivative and its influence on the coordination mode on the particle surface were proposed to explain the observed different kinetic properties. The hydrogenation of various oxygen-containing arenes was investigated and original results were described in the reduction of anisole and cresols as model lignin compounds, providing a significant ratio of ketone derivatives. A first explanation based on possible reaction routes is proposed to justify the formed products. PMID- 21660330 TI - Enhanced role of Al or Ga-doped graphene on the adsorption and dissociation of N2O under electric field. AB - To find an effective strategy for the capture and decomposition of nitrous oxide (N(2)O) is very important in order to protect the ozone layer and control the effects of global warming. Based on first-principles calculations, such a strategy is proposed by the systemic study of N(2)O interaction with pristine and Al (or Ga)-doped graphene, and N(2)O dissociation on the surface of Al (or Ga) doped graphene in an applied electric field. The calculated adsorption energy value shows the N(2)O molecule more firmly adsorbs on the surface of Al (or Ga) doped graphene than that of pristine graphene, deriving from a stronger covalent bond between the N(2)O molecule and the Al (or Ga) atom. Furthermore, our study suggests that N(2)O molecules can be easily decomposed to N(2) and O(2) with the appropriate electric field, which reveals that Al-doped graphene may be a new candidate for control of N(2)O. PMID- 21660331 TI - Pronounced sponge-like nanostructure in propylammonium nitrate. AB - The bulk structure of the ionic liquid propylammonium nitrate (PAN) has been determined using neutron diffraction. Empirical potential structure refinement (EPSR) fits to the data show that PAN self-assembles into a quasi-periodic bicontinuous nanostructure reminiscent of an amphiphile L(3)-sponge phase. Atomic detail on the ion arrangements around the propylammonium cation and nitrate anion yields evidence of hydrogen bonding between ammonium and nitrate groups and of strong alkyl chain aggregation and interdigitation. The resultant amphiphilic PAN nanostructure is more pronounced than that previously determined for ethylammonium nitrate (EAN) or ethanolammonium nitrate (EtAN). PMID- 21660332 TI - Differences of crystal structure and dynamics between a soft porous nanocrystal and a bulk crystal. AB - We have demonstrated downsizing effects of the soft porous crystal, [Zn(isophthalate)(4,4'-bipyridyl)](n) (CID-1), on the adsorption behavior between CID-1 and CID-1 nanocrystal (NCID-1). The difference results from the packing crystal structures and the dynamics of the frameworks. PMID- 21660333 TI - Postsynthetic modification at orthogonal reactive sites on mixed, bifunctional metal-organic frameworks. AB - A series of mixed, bifunctional metal-organic frameworks were synthesized and subsequent postsynthetic modification was demonstrated on the two, orthogonal functional sites. The use of differentially 'tagged' ligands combined with postsynthetic modification provides a facile route to a large number of functionally diverse materials. PMID- 21660334 TI - Template induced structural isomerism and enhancement of porosity in manganese(II) based metal-organic frameworks (Mn-MOFs). AB - Three new metal-organic framework isomers have been synthesized by using the organic linker 5-triazole isophthalic acid and Mn(NO(3))(2).xH(2)O. Structural conversions from non-porous to porous MOFs due to the template effect have been observed. The cross-sectional pore apertures of the resulting Mn-MOFs are comparable to the molecular dimensions of the template (pyrazine and 4,4' bipyridine). The periodic increased porosity in Mn-MOFs depending on the size of the template used has been further confirmed by the CO(2) adsorption isotherms. PMID- 21660336 TI - Solvent-dependent supramolecular assemblies of pi-conjugated anion-responsive acyclic oligopyrroles. AB - Amide-attached pyrrole-based pi-conjugated anion receptors showed solvent dependent assembled modes such as H-aggregates that were soluble in octane and highly organized structures that provided supramolecular gels in CH(2)Cl(2) and 1,4-dioxane in the absence of pi-pi stacking. PMID- 21660335 TI - Carbon nanospheres for highly sensitive electrochemical detection of sequence specific protein-DNA interactions. AB - A carbon nanosphere-based electrochemical detection method is developed for the highly sensitive detection of Sp1-DNA interactions. PMID- 21660337 TI - Synthesis of arylketones by ruthenium-catalyzed cross-coupling of aldehydes with arylboronic acids. AB - The first ruthenium-catalyzed cross-coupling of aldehydes with arylboronic acids is reported. Various aliphatic and aromatic aldehydes are transformed to the corresponding arylketones. A total of 31 examples with moderate to excellent yields are presented, together with the results of an initial mechanistic investigation. PMID- 21660338 TI - Organoplatinum(II) complexes containing chelating or bridging bis(N-heterocyclic carbene) ligands: formation of a platinum(II) carbonate complex by aerial CO2 fixation. AB - The preparation of two new bis(N-heterocyclic carbene) platinum(II) complexes, in which NHC rings are joined by a CH(2) linker group, is described. While, the chelate complex [PtMe(2)(bis-NHC1)], 1, was formed with large tert-butyl wingtips, the iso-propyl N-substituent analogue favors formation of the cluster complex [Pt(2)Me(4)(MU-SMe(2))(MU-bis-NHC2)](2)(MU-Ag(2)Br(2)), 2, in which two binuclear platinum(II) complexes are linked together by an Ag(2)Br(2) unit. The chelating platinum complex 1 undergoes aerial CO(2) fixation and forms platinum(II) carbonate complex [Pt(CO(3))(bis-NHC1)], 3. PMID- 21660339 TI - On the mechanism of the reaction of white phosphorus with silylenes. AB - Four different mechanisms and the effect of bulky groups were studied in the reaction of ({HC[CMeN(R)]2}Si, R = 2,6-diisopropylphenyl) with white phosphorus. The carefully tested B3LYP-D, omegaB97X-D, and SOS-MP2 methods, by the CCSD(T) method, with cc-pVTZ basis set provided consonant results which support the reliability of our results and the applicability of these methods. The dispersion energy contribution to the total energy is estimated to about ~70 kJ mol(-1) which proves the essential role of dispersion corrected methods. Based on the computed results we suggest a new mechanism which is fully supported by the experimental conditions. The investigation of the bulky groups clearly demonstrates an internal catalytic feature which has an essential role in the reaction mechanism. Usually bulky substituents prevent or reduce the reactivity, in this case however, substituents promote the reaction. PMID- 21660340 TI - Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins. AB - Thioglycosides offer the advantage over O-glycosides to be resistant to hydrolysis. Based on initial evidence of this recognition ability for glycosyldisulfides by screening dynamic combinatorial libraries, we have now systematically studied dithiodigalactoside on a plant toxin (Viscum album agglutinin) and five human lectins (adhesion/growth-regulatory galectins with medical relevance e.g. in tumor progression and spread). Inhibition assays with surface-presented neoglycoprotein and in solution monitored by saturation transfer difference NMR spectroscopy, flanked by epitope mapping, as well as isothermal titration calorimetry revealed binding properties to VAA (K(a): 1560 +/- 20 M(-1)). They were reflected by the structural model and the affinity on the level of toxin-exposed cells. In comparison, galectins were considerably less reactive, with intrafamily grading down to very minor reactivity for tandem repeat-type galectins, as quantitated by radioassays for both domains of galectin 4. Model building indicated contact formation to be restricted to only one galactose moiety, in contrast to thiodigalactoside. The tested glycosyldisulfide exhibits selectivity between the plant toxin and the tested human lectins, and also between these proteins. Therefore, glycosyldisulfides have potential as chemical platform for inhibitor design. PMID- 21660341 TI - Synthesis, structures, and magnetic properties of transition metal compounds with 2,2'-dinitrobiphenyl-4,4'-dicarboxylate and N,N'-chelating ligands. AB - Solvothermal reactions of Co(II), Ni(II), Zn(II) salts with 2,2'-dinitrobiphenyl 4,4'-dicarboxylate (dnpdc) and 2,2'-bipyridyl-like chelating ligands yielded five compounds formulated as [Co(dnpdc)(bipy)](n).nH(2)O (1), [M(dnpdc)(phen)](n) (2, M = Co; 3, M = Ni; 4, M = Zn) and [Co(dnpdc)(biql)](n).2nH(2)O (5) (bipy = 2,2' bipyridine, phen = 1,10-phenanthroline and biql = 2,2'-biquinoline). With bipy or phen as coligands, compounds 1-4 exhibit isomorphous 3D M(dnpdc) metal-organic frameworks in which double carboxylate bridged chains are interlinked by the backbones of the dicarboxylate ligands. The bipy or phen ligands are involved in interchain hydrogen bonding or pi-pi interactions to form 1D zipper-like arrays in the rhombic channels of the frameworks, playing a templating role and determining the channel dimensions. The biql coligand is too bulky for the 1D double carboxylate bridged chain and the rhombic channel. Instead, in compound 5, the dnpdc ligands link metal ions into 1D zigzag metal-organic chains and the biql ligands are arranged into 2D (6,3) arrays through extensive pi-pi stacking interactions. In compounds 1-3, the double carboxylate bridges in the nonplanar syn-skew conformation mediate ferromagnetic interactions along the chains, while the chelating ligands provide supramolecular pathways for interchain antiferromagnetic interactions. The pi-pi interactions in 5 also evoke weak antiferromagnetic interactions. PMID- 21660342 TI - A naphthalimide fluorophore with efficient intramolecular PET and ICT processes: application in molecular logic. AB - A novel 4-amino-1,8-naphthalimide (NDI) with two different metal cation receptors connected at 4-amino or imide nitrogen positions respectively was designed and prepared. Significant internal charge transfer (ICT) as well as photoinduced electron transfer (PET) from the receptors to NDI is revealed by the shifted UV vis absorption spectra and significant fluorescence quenching. Both Zn(2+) and Cu(2+) can coordinate selectively with the two cation receptors in this molecule with different affinities. The coordination of Zn(2+) with the receptor at imide nitrogen hindered the PET process and accordingly restored the quenched fluorescence of NDI. But the coordination of Zn(2+) at 4-amino position blocked the ICT process and caused significant blue-shift on the absorption peak with the fluorescence intensity unaffected. Similarly, coordination of Cu(2+) with the receptor at imide nitrogen can block the PET process, but can not restore the quenched fluorescence of compound 3 due to the paramagnetic properties of Cu(2+), which quench the fluorescence significantly instead. With Cu(2+) and Zn(2+) as two chemical inputs and absorption or fluorescence as output, several logic gate operations, such as OR, NOR and INHIBIT, can be achieved. PMID- 21660343 TI - ECHO probes: a concept of fluorescence control for practical nucleic acid sensing. AB - An excitonic interaction caused by the H-aggregation of fluorescent dyes is a new type of useful photophysical process for fluorescence-controlled nucleic acid sensing. This critical review points out the recent advances in exciton controlled hybridization-sensitive fluorescent oligonucleotide (ECHO) probes, which have a fluorescence-labeled nucleotide in which two molecules of thiazole orange or its derivatives are linked covalently. ECHO probes show absorption shift and emission switching depending on hybridization with the target nucleic acid. The hybridization-sensitive fluorescence emission of ECHO probes and the further modification of probes have made possible a variety of practical applications, such as multicolor RNA imaging in living cells and facile detection of gene polymorphism (144 references). PMID- 21660344 TI - The N-heterocyclic carbene chemistry of transition-metal carbonyl clusters. AB - In the last decade, chemists have dedicated many efforts to investigate the coordination chemistry of N-heterocyclic carbenes (NHCs). Although most of that research activity has been devoted to mononuclear complexes, transition-metal carbonyl clusters have not escaped from these investigations. This critical review, which is focussed on the reactivity of NHCs (or their precursors) with transition-metal carbonyl clusters (mostly are of ruthenium and osmium) and on the transformations underwent by the NHC-containing species initially formed in those reactions, shows that the polynuclear character of these metallic compounds or, more precisely, the close proximity of one or more metal atoms to that which is or can be attached to the NHC ligand, is responsible for reactivity patterns that have no parallel in the NHC chemistry of mononuclear complexes (74 references). PMID- 21660345 TI - Solution and mechanochemical syntheses, and spectroscopic and structural studies in the silver(I) (bi-)carbonate: triphenylphosphine system. AB - Syntheses of a number of adducts of silver(I) (bi-)carbonate with triphenylphosphine, both mechanochemically, and from solution, are described, together with their infra-red spectra, (31)P CP MAS NMR and crystal structures. Ag(HCO(3)):PPh(3) (1:4) has been isolated in the ionic form [Ag(PPh(3))(4)](HCO(3)).2EtOH.3H(2)O. Ag(2)CO(3):PPh(3) (1:4) forms a binuclear neutral molecule [(Ph(3)P)(2)Ag(O,MU-O'.CO)Ag(PPh(3))(2)](.2H(2)O), while Ag(HCO(3)):PPh(3) (1:2) has been isolated in both mononuclear and binuclear forms: [(Ph(3)P)(2)Ag(O(2)COH)] and [(Ph(3)P)(2)Ag(MU-O.CO.OH)(2)Ag(PPh(3))(2)] (both unsolvated). A more convenient method for the preparation of the previously reported copper(I) complex [(Ph(3)P)(2)Cu(HCO(3))] is also reported. PMID- 21660346 TI - Synthesis and characterization of fluorophenylpalladium pincer complexes: electronic properties of some pincer ligands evaluated by multinuclear NMR spectroscopy and electrochemical studies. AB - Palladium fluorophenyl complexes with different pincer ligands Pd(Ar)[2,6 (tBu(2)PCH(2))(2)C(6)H(3)] (13), Pd(Ar)[2,6-(tBu(2)PO)(2)C(6)H(3)] (14), Pd(Ar)[{2,5-(tBu(2)PCH(2))(2)C(5)H(2)}Fe(C(5)H(5))] (15), and Pd(Ar)[{2,5 (tBu(2)PCH(2))(2)C(5)H(2)}Ru(C(5)H(5))] (16) were synthesized by the reaction of LiAr (Ar = C(6)H(4)F-4) with the respective trifluoroacetate palladium pincer complexes 9-12. The molecular structures of 14 and 16 were determined by an X-ray crystallographic method. Complexes 13-16 and {Pd(Ar)[{2,5 (tBu(2)PCH(2))(2)C(5)H(2)}Fe(C(5)H(5))]}PF(6) (17) were studied by multinuclear NMR spectroscopy and cyclic voltammetry. On the basis of (19)F NMR chemical shifts and (1)J((13)C-(19)F) coupling constants, as well as Pd(II)/Pd(IV) oxidation potentials, electronic characteristics of the corresponding pincer ligands were elucidated. PMID- 21660347 TI - Mechanoluminescent light source for a fluorescent probe molecule. AB - We have demonstrated an innovative ability of mechanoluminescent (ML) material as a light source for the first time. By appropriate smart size control and nondestructive mechanical stimulation, the ML particle can be considered a promising candidate of in situ light source for bio-imaging and photo-therapy even in a human body. PMID- 21660348 TI - Multiscale quantum mechanics/electromagnetics simulation for electronic devices. AB - The continuous downsizing of modern electronic devices implies the increasing importance of quantum phenomena. As the feature sizes of transistors inch towards 10 nanometer, simulations including quantum effects and atomistic details are inevitable. Here we report a novel hybrid quantum mechanics and electromagnetics (QM/EM) method to model individual electronic components at the nanoscale. QM and EM models are solved in different regions of the system in a self-consistent manner. As a demonstration, we study a carbon nanotube based electronic device embedded in a silicon block. Good agreement is obtained between simulation by QM/EM method and full QM treatment of the entire system. PMID- 21660349 TI - An embedded microchannel in a MEMS plate resonator for ultrasensitive mass sensing in liquid. AB - A mass sensor innovative concept is presented here, based on a hollow plate Micro Electro Mechanical System (MEMS) resonator. This approach consists in running a solution through an embedded microchannel, while the plate resonator is actuated according to a Lame-mode by electrostatic coupling in dry environment. The experimental results have shown a clear relationship between the measured shift of the resonance frequency and the sample solution density. Additionally, depending on the channel design and the solution properties, the quality factor (Q-factor) was noticed maintaining its level and even substantial improvement in particular cases. Resonators demonstrate resonance frequencies close to 78 MHz and Q-factor of a few thousands for liquid phase detection operating at ambient temperature and atmospheric pressure. Frequency fluctuations study revealed a 13 Hz instability level, equivalent to 1.5 fg in mass. Using a fully electronic readout configuration, a mass responsivity of ca. 850 fg kHz(-1) was monitored. PMID- 21660350 TI - Graphene nanoplate-MnO2 composites for supercapacitors: a controllable oxidation approach. AB - Graphene nanoplate-MnO(2) composites have been synthesized by oxidising part of the carbon atoms in the framework of graphene nanoplates at ambient temperature. The composites were characterized by means of X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and cyclic voltammetry (CV). It was found that the oxidation extent of the carbon atoms in the graphene framework in these composites was dependent on the reaction time, which also influenced their microstructure, morphology and electrochemical properties. Compared with MnO(2) nanolamellas, the nanocomposite prepared with a reaction time of 3 h reveals better electrochemical properties as a supercapacitor electrode material. PMID- 21660351 TI - Tunable fluorescence in chromophore-functionalized nanodiamond induced by energy transfer. AB - Hybrid materials comprising diamond nanoparticles (ND) and oligo(phenylenevinylenes) (OPVs) have been synthesized by the covalent linking of acid-functionalized ND and OPV-amine. Chromophore-functionalized ND particles with long alkyl and pi-conjugated groups are readily dispersed in various organic solvents without any precipitation after several hours. A careful study of the properties of the hybrid materials revealed an aggregation-induced energy transfer from the blue fluorescent nanodiamonds to green emitting OPVs. At very low concentrations the hybrid emits in the blue region, but as the concentration is increased a gradual transition from blue to green emission occurs. Competitive processes such as aggregation-induced enhanced emission and self-absorption have been ruled out and a molecular picture of the phenomenon is proposed. This strategy can open a plethora of new avenues for fluorescent nanodiamonds in optoelectronics and light harvesting apart from bio-imaging. PMID- 21660352 TI - Isomerically pure electron-deficient anthradithiophenes and their acceptor performance in polymer solar cells. AB - Amide functionalized anthradithiophenes (ADTs) play active acceptor roles in polymer bulk-heterojunction solar cells. The first separation of ADT isomers is reported, and the regiochemistry of the ADT has significant impact on crystal packing and solar cell performance. Cell efficiency up to 0.80%, due in large part to high open-circuit voltage (V(OC) > 1.0 V), is achieved in bulk heterojunction solar cells comprising syn-ADT and poly(3-hexylthiophene). PMID- 21660353 TI - Ratiometric analysis of zidovudine (ZDV) incorporation by reverse transcriptases or polymerases via bio-orthogonal click chemistry. AB - A new fluorescence-based detection method was developed to visualize zidovudine incorporated DNA using click chemistry. This bio-orthogonal detection method was used to quantify the relative susceptibility of various DNA-synthesizing enzymes toward ZDV incorporation on the basis of ratiometric analysis of band shifts in the gel and the visual observation of cellular DNA. PMID- 21660354 TI - Multiplexed near-infrared in vivo imaging complementarily using quantum dots and upconverting NaYF4:Yb3+,Tm3+ nanoparticles. AB - A new multiplexed NIR in vivo imaging is showcased by using quantum dots and NaYF(4):Yb(3+),Tm(3+) nanoparticles. The 'temporal' multiplexing is demonstrated by alternating the excitation wavelengths and unmixing the emissions of different probes. Multiplexed cellular imaging and the cellular trafficking in animal models are shown. PMID- 21660355 TI - Feedback models for polarized auxin transport: an emerging trend. AB - The phytohormone auxin is vital to plant growth and development. A unique property of auxin among all other plant hormones is its cell-to-cell polar transport that requires activity of polarly localized PIN-FORMED (PIN) auxin efflux transporters. Despite the substantial molecular insight into the cellular PIN polarization, the mechanistic understanding for developmentally and environmentally regulated PIN polarization is scarce. The long-standing belief that auxin modulates its own transport by means of a positive feedback mechanism has inspired both experimentalists and theoreticians for more than two decades. Recently, theoretical models for auxin-dependent patterning in plants include the feedback between auxin transport and the PIN protein localization. These computer models aid to assess the complexity of plant development by testing and predicting plausible scenarios for various developmental processes that occur in planta. Although the majority of these models rely on purely heuristic principles, the most recent mechanistic models tentatively integrate biologically testable components into known cellular processes that underlie the PIN polarity regulation. The existing and emerging computational approaches to describe PIN polarization are presented and discussed in the light of recent experimental data on the PIN polar targeting. PMID- 21660356 TI - Nano-optical information storage induced by the nonlinear saturable absorption effect. AB - Nano-optical information storage is very important in meeting information technology requirements. However, obtaining nanometric optical information recording marks by the traditional optical method is difficult due to diffraction limit restrictions. In the current work, the nonlinear saturable absorption effect is used to generate a subwavelength optical spot and to induce nano optical information recording and readout. Experimental results indicate that information marks below 100 nm are successfully recorded and read out by a high density digital versatile disk dynamic testing system with a laser wavelength of 405 nm and a numerical aperture of 0.65. The minimum marks of 60 nm are realized, which is only about 1/12 of the diffraction-limited theoretical focusing spot. This physical scheme is very useful in promoting the development of optical information storage in the nanoscale field. PMID- 21660357 TI - Bioelectrocatalytic generation of directly readable code: harnessing cathodic current for long-term information relay. AB - Here we present an exceptionally stable bioelectrocatalytic architecture for electrocatalytic oxygen reduction using a carbon nanotube electrode as the electron donor and a fungal enzyme as electrocatalyst. Controlling oxygen content in the electrolyte enables generation of a directly readable barcode from monitoring the enzyme response. PMID- 21660358 TI - Photochromism of a water-soluble vesicular [2.2]paracyclophane-bridged imidazole dimer. AB - Here we report the first photochromism of a newly designed [2.2]paracyclophane bridged imidazole dimer in water. The photochromic dye with a hydrophilic and a hydrophobic substituent forms vesicles in water and shows instantaneous colouration upon UV light irradiation and successive rapid fading in the dark. PMID- 21660359 TI - Cucurbit[7]uril: an amorphous molecular material for highly selective carbon dioxide uptake. AB - Cucurbit[7]uril (CB[7]), in its amorphous solid state, shows one of the highest CO(2) sorption capacities among known organic porous materials at 298 K and 0.1 and 1 bar. In addition to the highest CO(2) capacity, CB[7] also shows remarkable selectivity of CO(2) over N(2) and CH(4). These properties, along with the existence of readily available precursors, indicate amorphous CB[7] might find applications in recycling CO(2) particularly considering the easy synthesis and potentially low manufacturing costs. PMID- 21660360 TI - Spontaneous pattern of linear molecules in strongly confined spaces. AB - In this work, we study the tight packing of short linear molecules in confined space by performing molecular dynamic simulations. The short chain-like molecules spontaneously arrange within single-walled carbon nanotubes (SWNTs) and exhibit a variety of chiral and achiral structures, depending on the pore size and molecule length. Simulation results show that the packing structures for these confined short linear molecules are controlled by the competition between positional order and orientational order. For linear molecules with short molecular length, such as the two-site Lennard-Jones molecules, the orientational order gradually decreases as temperature increases, and then the positional order begins to disappear. While for longer molecules, such as four-site Lennard-Jones molecules, the positional order decreases more rapidly than the orientational order as temperature increases. We also investigated the effect of molecular rigidity. For linear molecules with higher rigidity, part of packing structures may slowly rotate as a whole, and the rotation of packing arrangements is found to be induced by the preexisting defects. PMID- 21660361 TI - A novel water-soluble NHC-Pd polymer: an efficient and recyclable catalyst for the Suzuki coupling of aryl chlorides in water at room temperature. AB - A novel water-soluble NHC-Pd polymer with triethylene glycol legs was developed as a water soluble and highly recyclable catalyst that shows high catalytic activity in the Suzuki-Miyaura coupling of aryl chlorides in high yields in water at room temperature. PMID- 21660362 TI - Tetrahedron-structured DNA and functional oligonucleotide for construction of an electrochemical DNA-based biosensor. AB - Tetrahedron-structured DNA (ts-DNA) in combination with a functionalized oligonucleotide was used to develop a "turn-on" biosensor for Hg(2+) ions. The ts DNA provided an improved sensitivity and was used to block the active sites. PMID- 21660363 TI - Photoinduced ligand release in a ruthenium(II)-cobalt(III) heterodinuclear system. AB - Two Ru(II)-Co(III) heterodinuclear complexes have been synthesised as model complexes for photoactivated cytotoxins. Photoinduced ligand release has been demonstrated and the rate shown to depend on dioxygen concentration. Emission lifetimes and quantum yields are reported. These results validate the concept and justify further work to synthesise systems containing cytotoxic ligands. PMID- 21660364 TI - Anticancer activity of tetracationic arene ruthenium metalla-cycles. AB - A series of cationic metalla-cycles of the general formulae [(eta(6)-p cym)(4)Ru(4)(OO?OO)(2)(N?N)(2)](4+) and [(eta(6)-p cym)(4)Ru(4)(NO?NO)(2)(N?N)(2)](4+) has been prepared from the dinuclear arene ruthenium precursors [(eta(6)-p-cym)(2)Ru(2)(OO?OO)(2)Cl(2)] (OO?OO = oxalato, 1,4-benzoquinonato-2,5-diolato, 1,4-naphtoquinonato-5,8-diolato, 9,10 anthraquinonato-1,4-diolato, 5,12-tetraquinonato-6,11-diolato) and [(eta(6)-p cym)(2)Ru(2)(NO?NO)(2)Cl(2)] (NO?NO = oxamido, oxonico) by reaction with two different bidentate linkers (N?N = 1,2-bis(4-pyridyl)ethylene, 1,2-bis(4 pyridyl)ethane) in the presence of silver triflate. All complexes were isolated as triflate salts and characterised by NMR, infrared, UV-visible, mass spectrometry and by elemental analysis. The cytotoxicities of the tetranuclear ruthenium complexes have been established using ovarian A2780 and A2780cisR cancer cell lines. All complexes exhibit moderate to excellent activity on both the cisplatin resistant and cisplatin sensitive cells, thus suggesting a mode of action different from cisplatin. PMID- 21660365 TI - CuBr catalyzed C-N cross coupling reaction of purines and diaryliodonium salts to 9-arylpurines. AB - CuBr was found to be an efficient catalyst for the C-N cross coupling reaction of purine and diaryliodonium salts. 9-Arylpurines were synthesized in excellent yields with short reaction times (2.5 h). The method represents an alternative to the synthesis of 9-arylpurines via Cu(II) catalyzed C-N coupling reaction with arylboronic acids as arylating agents. PMID- 21660366 TI - Protein assisted fluorescence enhancement of a dansyl containing fluorescent reagent: detection of Hg+ ion in aqueous medium. AB - Intramolecular charge transfer (ICT) based fluorescent reagents containing a dansyl fluorophore have been synthesized and characterized. The reagent 1 and its complex, 1+Hg(2+) in sodium acetate buffer (pH 6.7) revealed considerable fluorescence enhancement (switched-on) in the presence of bovine serum albumin (BSA) with 10 ppb detection sensitivity. (1)H NMR spectral analysis suggests complexation between 1 and Hg(2+) ion involving the N,N-dimethylamino and carboxylic functions. PMID- 21660368 TI - Cross-sectional association between healthy and unhealthy food habits and leisure physical activity in adolescents. AB - OBJECTIVE: To analyze associations between two physical activity domains during leisure time and different food habits in adolescents. METHODS: The sample comprised 1,630 adolescents (46% male and 54% female). Physical activity level, television (TV) viewing, and eating behaviors were assessed through an interview. According to the results of the assessment, adolescents were classified as physically active or engaged in high amounts of TV viewing and unhealthy/healthy diets. RESULTS: Male adolescents were more active than females (21.7 and 9.4%, respectively; p = 0.001), while TV viewing was more frequent in females (44.0 and 29.2%; p = 0.001). Physical activity level was related to higher consumption of fruits (OR = 1.90; 95%CI 1.39-2.60) and vegetables (OR = 1.48; 95%CI 1.09-2.01), while higher consumption of fried foods (OR = 2.13; 95%CI 1.64-2.77) and snacks (OR = 1.91; 95%CI 1.49-2.45) was associated with TV viewing. CONCLUSION: This study presented epidemiological information indicating that active and inactive behaviors were differently and independently associated with healthy and unhealthy diets. PMID- 21660367 TI - Tetrahydrobiopterin responsiveness of patients with phenylalanine hydroxylase deficiency. AB - OBJECTIVE: To identify patients responsive to tetrahydrobiopterin (BH4) in a sample of Brazilians with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency (HPA-PAH). METHODS: Interventional study, convenience sampling. The inclusion criteria were: diagnosis of HPA-PAH; age >= 7 years; phenylalanine restricted diet and phenylalanine (Phe) levels >= 6 mg/dL in all blood tests 1 year before inclusion. Blood samples were obtained the day before (day 1) and at 0, 4, 8 (day 2) and 24 h (day 3) after BH4 intake. Phe levels were measured using tandem mass spectrometry. The criteria used to define responsiveness to BH4 were: criterion 1- Phe reduction >= 30% 8 h after BH4 administration; criterion 2 - Phe reduction >= 30% 24 h after BH4 administration. RESULTS: Eighteen patients were enrolled (median age, 14 years; 12 boys). Five patients were responsive to BH4, 3 according to both criteria (one classical PKU, two mild PKU); and two according to criterion 2 (one classical PKU; one indefinite PKU type). There were no differences between Phe serum levels on day 1 and at the other time points (p = 0.523). However, Phe levels on days 1 and 2 were significantly different (p = 0.006). The analysis of the phenotype-genotype association confirmed its multifactorial character. CONCLUSION: A relevant number of Brazilian patients with HPA-PAH are responsive to BH4, in agreement with other studies in the literature. PMID- 21660369 TI - Normalization of height and excess body fat in children with salt-wasting 21 hydroxylase deficiency. AB - OBJECTIVE: To evaluate growth and body composition of patients with the salt wasting form of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and to compare them with healthy children. METHODS: Twenty-one prepubertal patients (eight boys and 13 girls) between 2.1 and 10.2 years and 67 prepubertal healthy controls (36 boys and 31 girls) between 1.2 and 11.7 years were included. Weight, height, upper-arm circumference, skinfolds, body composition determined by bioimpedance, and bone age were measured. The following data were obtained from the medical records: parents' height, serum levels of 17 hydroxyprogesterone and Delta4-androstenedione, prescribed hydrocortisone doses, weight and length at birth, in the beginning of the treatment, and at 2 years. RESULTS: Patients had lower weight and length z scores at the first appointment compared with the same data at birth, showing recovery after the beginning of the treatment without advanced bone age. Mean height z score was higher in controls (0.28 +/- 0.86) than in patients (-0.61 +/- 0.99, p < 0.001); this difference disappeared when the patients' height was adjusted to their bone age (0.33 +/- 1.68, p = 0.912). Patients had higher body mass index (p < 0.001), fat mass (p < 0.001), and fat mass index (p < 0.001) than controls. There was no difference in the skinfolds between the two groups (p = 0.157). CONCLUSIONS: Patients had growth recovery with mean height similar to the general population; however, they had higher body fat, which seems to be visceral, since there was no difference between the skinfolds of both groups. PMID- 21660370 TI - Persistent diarrhea: still an important challenge for the pediatrician. AB - OBJECTIVE: To provide recent guidelines to reduce the incidence of diarrheal diseases. We discuss the definition, clinical aspects, pathophysiology, diagnosis, management, and prevention of persistent diarrhea. SOURCES: Electronic search of the MEDLINE database, Google search. SUMMARY OF THE FINDINGS: Acute diarrhea may be caused by a variety of agents, including bacterial, viral, and protozoan pathogens. The top priority in treatment of diarrhea is replacement of fluid and electrolytes losses, particularly at the acute stage, and, under certain circumstances, eradication of the enteropathogenic agent. On the other hand, treatment of persistent diarrhea should focus on prevention and management of food intolerance and malnutrition. CONCLUSIONS: Promotion of breastfeeding, adequate interventions in the treatment of acute diarrheal episodes, introduction of safe dietary strategies for prevention of malnutrition, and improvements in sanitation and hygiene conditions, including sewage and clean water, are essential measures for the reduction of diarrheal morbidity and mortality rates in children under 5 years of age. PMID- 21660371 TI - Music therapy intervention in the neonatal intensive care unit environment. PMID- 21660372 TI - Faecal elastase-1 (EL-1) in pediatric patients with cystic fibrosis. PMID- 21660374 TI - Hepatitis A virus infection: progress made, more work to be done. PMID- 21660375 TI - [One hundred years of the Sociedad Argentina de Pediatria. Interview with Dr. Miguel de Asua]. PMID- 21660376 TI - [Lumbar spinal cord injury without radiological abnormality in a child: an exceptional form of presentation]. AB - SCIWORA is an uncommon syndrome affecting mainly children and is defined as the occurrence of acute spinal cord injury despite normal plain radiography and normal computed tomography (CT). Lumbar SCIWORA is very rare in children, and to our knowledge, there is only one report of lumbar SCIWORA in the literature. We present the case of a 5 year-old boy who suffered acute bilateral lower limbs paralysis, associated to urinary and bowel incontinence following a 1.5 meter fall. Lumbar cord contusion could be demonstrated on MRI without other radiologic abnormalities, which confirmed SCIWORA diagnosis. Our case report illustrates the potential seriousness of this disease and the importance of a thorough and accurate clinical history for diagnosis. PMID- 21660377 TI - [Bowel obstruction due to an impacted bariolith. A case report]. AB - "Barolith" is an infrecuent complication of bowel contrast studies that occurs after barium oral administration. There are not many cases published in the literature regarding bariolith in pediatrics. It can be suspected after realization of an abdomen X Ray in a patient with a previous oral contrast study. We report a case of bariolith in a 2-month-old baby. We emphasize the need of a proper anamnesis in order to explore the history of contrasted examination, and the opportune diagnosis and treatment to prevent complications. PMID- 21660378 TI - [First two Mexican cases of monosomy 1p36: possible diagnosis in patients with mental retardation and dysmorphism]. AB - It is calculated that distal deletion of the short arm of chromosome 1 occurs in one out of every 5000 live births and causes approximately 1.2% of cases of mental retardation of unknown origin. This alteration usually cannot be detected in the standard karyotype, requiring molecular cytogenetic techniques for the diagnosis. In addition to the neurological manifestations, it may cause internal organs malformations, such as congenital heart disease, and a characteristic facial phenotype. This report describes the clinical and cytogenetic findings from the first two cases diagnosed in Mexico, confirmed by fluorescence in situ hybridization test, and compares them to those described in the literature. The probable subdiagnosis of this entity, the importance of improves its recognition and the useful data for the clinical suspicion are also discussed. PMID- 21660379 TI - [Neonatal cholestasis and hypoglycemia like form of congenital hypopituitarism presentation]. AB - Congenital hypopituitarism is a rare disease, of variable clinic. The neonatal hypoglycemia is one of the habitual forms of presentation; the cholestasis is a rare symptom of this disease. This is the case of a 2-months-old infant hospitalized for cholestatic jaundice. He added repeated episodes of severe hypoglycemia. We investigated metabolic and endocrine causes. The etiology was clarified by obtaining a critical sample that demonstrated the counterregulatory hormone deficiency. The diagnosis of congenital hypopituitarism was completed with confirmation of thyroid hormone and growth hormone deficiencies. It was confirmed the neuro-anatomical defect of "syndrome of pituitary stalk section" determined by pituitary stalk agenesis, pituitary hipoplasia, and ectopic neurohypophysis. Hormone replacement therapy was started with good response and outcome. PMID- 21660380 TI - [Bloch-Sulzberger's syndrome (Incontinentia pigmenti). Contribution with a case report]. AB - Incontinentia pigmenti (IP) is a rare genodermatosis. Skin lesions, that are present in all patients affected, evolve in stages. The first is the erythematous blistering stage, wich differential diagnosis includes a wide variety of diseases. We present a case of a female neonate with blisters present at birth, where the skin biopsy confirmed the diagnosis of IP. PMID- 21660381 TI - [The remarkable and significant increase in multiple pregnancies and their adverse consequences]. PMID- 21660382 TI - [General management for infections prevention and antimicrobial prophylaxis in primary immunodeficiencies]. PMID- 21660383 TI - [Guidelines for the prevention, diagnosis and treatment of obesity]. PMID- 21660384 TI - [Study of respiratory influenza A H1N1 Virus (pH1N1) in hospitalized children in the pandemic year. Experience in 34 centers in Argentina]. AB - INTRODUCTION: In Argentina, pandemic influenza pH1N1 caused nearly 10,000 confirmed cases with high impact in pediatrics. OBJECTIVES: To describe clinical and epidemiological characteristics and analyse the risk factor of lethality in children hospitalized with infection pH1N1 confirmed by PCR. POPULATION AND METHODS: We identifed all suspected cases (according to Ministry of health) in 34 centers and we included all the confirmed cases of 0-18 years from 1/4/09 to 31/8/09 in a retrospective cohort study. The viral diagnosis was confirmed by RT PCR method. Data are expressed in percentages, average, median, standard deviation, and range (IQR) as appropriate; and as a measure of association, relative risk (RR), with 95% confidence interval (95%CI). Multiple logistic regression was conducted to determine the independent risk predictors. RESULTS: Total number of suspected cases were: 2367; PCR was performed to 47.8% (n: 1131) being positive for pH1N1 65.5% (n: 741/1131); 57.2% males; 61.5% <24 months, median age: 14 months (IQR 6-46 months); 45.1% with underlying disease; more frequent clinical pictures were: pneumonia (39,7%) and bronchiolitis 25.8%; Case fatality rate: 5.9% (44/741). Mortality risk factors were [RR (95%CI)]: neurological disease [5.00 (2.84-8.81)], genetic disease [3.67 (1.58-8.52)], malnutrition [3,07 (1.46-6.48)] and prematurity [2.28 (1.14-4.56)]. Independent mortality predictor: neurological disease [3.84 (1.81-8.14)]. No significant association between age, chronic respiratory disease, immunosuppression and viral co-infection with lethality was observed. CONCLUSIONS: Almost half of children with pH1N1 infection had underlying disease; the neurological condition was a separate CFR predictor. PMID- 21660385 TI - [Prevalence of serotypes of Streptococcus pneumoniae and other agents that cause acute otitis media in children in Latin America. A systematic review of the literature]. AB - Acute otitis media (AOM) is a common diagnosis in children. Streptococcus pneumoniae remains the most prevalent agent worldwide, followed by Haemophilus influenzae. However, the introduction of pneumococcal vaccines has changed the microbiology of AOM. OBJECTIVE: To establish the prevalence of pneumococcal serotypes and other common germs in Latin American children with AOM. SOURCE OF DATA: We carried out a systematic search for original articles in seven databases, limited to publications between 1999 and 2010, children under 18, and English and Spanish languages. Search was completed with "snowball" strategy. REVIEW METHODS: Eligibility criteria included original prevalence cross-sectional articles, conducted in pediatric populations in Latin America, with homogeneous inclusion and exclusion criteria. Relevant information was extracted from the selected articles. RESULTS: Eleven articles met the eligibility criteria. In Latin America, specifically Costa Rica, Chile, Brazil and Argentina, Streptococcus pneumoniae (43.5%) was the most frequent germ, (serotype 19F is the most frequent, except in Argentina where it is 14) followed by Haemophilus influenzae (30%) and Moraxella catarrhalis (6.4%). CONCLUSIONS: The more prevalent germ in Latin American children AOM is Streptococcus pneumoniae, a finding consistent with those from Europe and the U.S. Further studies are required in the other countries of the region and its pediatric pneumococcal vaccinated population, in order to establish an updated epidemiological and microbiological profile in Latin America. PMID- 21660386 TI - [Resources use and direct medical costs in a pediatric population with chronic diseases]. AB - OBJECTIVES: To evaluate the distribution and analyze the use of resources and direct medical costs in children and adolescents diagnosed with a chronic disease and compare them with healthy children of the same age from a health insurer perspective. METHODS: We analyzed the resources used and direct medical costs generated during 2008 in 21-year-old patients or younger affiliated to a health plan of community hospital in Buenos Aires, Argentina. We compared the outcomes of patients with at least one chronic disease as defined by Stein with healthy patients from a health insurer perspective with a one year time horizon. The costs were expressed in U.S. dollars for 2008. RESULTS: We identified 1885 children and adolescents with chronic illness, accounting for 6.7% of the total pediatric population studied. This group had a greater number and length of hospitalization, greater use of medications, practices and medical consultations than the healthy pediatric population. The mean total annual costs were US$ 501 (95% CI: 419-583) and US$ 212 (95% CI: 188-236), respectively (p < 0.001). Overweight, obesity and asthma, even with relatively low or moderate costs per patient, generated almost 39% of the total costs of chronic diseases due to its high prevalence. CONCLUSION: The pediatric population with diagnosis of at least one chronic disease had significantly greater utilization of medical services and increased costs in all areas studied. It is also important to recognize that diseases of low or moderate cost per patient, but highly prevalent, generate the largest share of expenditure of chronic diseases in the population. PMID- 21660387 TI - [Delayed vaccine schedule and missed opportunities for vaccination in children up to 24 months. A multicenter study]. AB - INTRODUCTION: Delayed vaccine schedule (DVS) and missed opportunities of vaccination (MOV) are some of the main causes of low coverage in children <=24 month in Argentina. OBJECTIVES: To determine the prevalence of DVS and the rate of MOV during the frst 24 months of life and risk factors for their occurrence. POPULATION AND METHODS: We conducted a survey among children <=24 month's caregivers at five hospitals in different departments, between August December/2008. RESULTS: Total enrolled: 1591 children; 54.2% male, median of age 8 months (0-24 months). Eighty percent concurred with vaccine-card, 75.9% consulted by pathology. Overall DVS rate: 39.7%. Most common DVS reason: the current mild disease: 38.5%. Overall MOV rate: 19.8%. Most common MOV reason: no detection of the need to vaccinate 47.8%. DTPHib and OPV vaccines had a higher risk of DVS and MOV. DVS independent predictors: age >=6 months, administration for additionally recommended vaccines and prolonged waiting in the last vaccination. MOV independent predictors were: age >=6 months, no compliance with prior care, and not asking for vaccines. CONCLUSION: We found a high proportion of MOV and mainly of DVS; they were associated mostly to false contraindications, lack of questioning on vaccines and difficulties in the quality of care provided to parents. PMID- 21660388 TI - [Misoprostol teratogenicity: a prospective study in Argentina]. AB - INTRODUCTION: Misoprostol is commonly used in Argentina to attempt abortion, although a certain proportion of pregnancies is not interrupted. On the other hand, various reports showed an association between misoprostol and congenital anomalies. OBJECTIVES: To estimate the risk of major congenital anomalies in children prenatally exposed to misoprostol, and to know their way of consumption during pregnancy. METHOD: A cohort study compared the frequency of abortion and major congenital abnormalities in offspring of pregnant women exposed to misoprostol (94) and an unexposed group of pregnant women (401), both groups consulting to a teratology information service. RESULTS: Among women exposed to misoprostol only the 8.2% purchased it on prescription, 81.5% heard about its abortifacient effect by friends, neighbors or relatives, the average dose was 1.439 MUg which was used both orally and vaginally by the 77.2%; the mean gestational age was 48.5 days and 35.2% used an additional abortive agent. Women exposed to misoprostol had a significantly higher frequency of abortions (exposed: 17/94= 18.1%, unexposed, 29/401= 7.2%, RR= 2.27, 95%: 1,30-3,98), and offspring with major congenital abnormalities (exposed: 5/77= 6.49%, unexposed: 8/372= 2.15%, RR= 3.02, 95%:1,02-8.98). The five malformed children prenatally exposed to misoprostol showed: 1) encephalocele and transverse limb defects; 2) porencephaly, 3) pulmonary adenomatous cystic malformation, 4) occipital encephalocele and, 5) intestinal malrotation. CONCLUSIONS: The study found a significant association between prenatal exposure to misoprostol and the occurrence of major congenital anomalies. PMID- 21660389 TI - [Gene therapy: nucleic acids as drugs. Action mechanisms and delivery into the cell]. AB - Gene therapy involves the transference of new genetic material to the cell in order to obtain a therapeutic benefit, offering a new option for the treatment of various diseases. In this article, some of these nucleic acid-based drugs, such as plasmids, aptamers, oligonucleotides, ribozymes and small interfering ribonucleic acid, are presented. Their mechanism and level of action is commented and several delivery systems, such as liposomes, cationic polymers, direct nucleic acid transfer and viral vectors, are also discussed. PMID- 21660390 TI - [Perinatal dengue infection]. AB - Dengue is a mosquito-borne viral disease, with worldwide distribution in tropical and subtropical areas. Argentina was certified free of Aedes aegypti in the sixties, however the vector reappered in 1984. In the nineties, small dengue outbreaks occurred with autocthonus diseases at first limited to the northern provinces. In the summer of 2008-2009, autocthonus cases were reported in other parts of the country. Vertical dengue virus transmission has been infrequently described, and the effect on pregnant women and newborn has not been well documented. We review this condition and present a case of perinatal dengue infection in a newborn infant from Salta, Argentina. PMID- 21660391 TI - [Hepatitis C virus infection in children]. AB - The modes of transmission of hepatitis C virus are parenteral, sexual and maternal-fetal. It affects 3% of the population worldwide. Currently, vertical infection is the main way of virus spreading. Most children are clinically asymptomatic, but progression of liver disease has been described. The positivity of antibodies against hepatitis C virus does not discriminate between active and resolved infection, so determination of serum HCV-RNA is necessary. The combination of peginterferon and ribavirin appears to be the most effective treatment. Future challenges are the development of new drugs and a vaccine. PMID- 21660392 TI - [Dermatomyositis]. PMID- 21660394 TI - Understanding patients with asthma and COPD: insights from a European study. AB - AIMS: To understand the needs of people with asthma and COPD, and to identify opportunities for improved care. METHODS: Quantitative questionnaire-based survey performed in five European countries on patients with asthma and COPD. Questionnaires were administered to patients using Computer Assisted Web Interview methodology. RESULTS: 1022 patients with asthma (UK [n=190]; Germany [n=214]; France [n=200]; Italy [n=222]; Spain [n=196]) and 719 patients with COPD (UK [n=153]; Germany [n=147]; France [n=145]; Italy [n=140]; Spain [n=134]) were enrolled in the study. 32% of those with asthma and 67% of those with COPD considered that their condition had a significant effect on their quality of life, and stigma and emotional distress was common. Many expressed concern regarding potential medication side effects or that medicines might lose their effect with time. Major discrepancies between expectations and patient satisfaction with the doctor-patient relationship were observed, including a need to be consulted in the choice of inhalers. Consultations were infrequent, and 75% of respondents sought additional information beyond that received during consultations - commonly from the internet. CONCLUSIONS: Patient satisfaction was high but information needs were not addressed and the emotional burden of disease is underappreciated. PMID- 21660395 TI - Combined lumbar plexus and sciatic nerve block for hip fracture surgery in a patient with severe aortic stenosis. PMID- 21660397 TI - A randomized controlled trial of oral zinc in acute pneumonia in children aged between 2 months to 5 years. AB - OBJECTIVE: To evaluate the effectiveness and safety of zinc supplementation as adjuvant in treatment of pneumonia. METHODS: Ninety-eight children with acute bacterial pneumonia, aged between 2 months to 5 years, were studied in a randomized controlled single blind design. They received either zinc supplementation, as zinc acetate syrup, or placebo, as vitamin B-complex syrup, for 14 days, concomitantly with antimicrobial treatment (49 per group). Chest radiograph and blood tests were done for confirmation of diagnosis and severity of pneumonia was assessed by breathing rate, chest in-drawing and body temperature. Potentially immunosuppressed children or those with serious comorbidity were excluded. Follow-up was done daily while subjects were admitted (generally 7 days) and the final assessment made on the 14th day on out-patient basis. RESULTS: Children enrolled in zinc and placebo groups were of comparable age [17 +/- 10 and 10 +/- 30 months (median +/- interquartile range) respectively] and sex distribution [34 (69.4%) vs 31 (63.3%) males respectively]. Duration of illness at diagnosis was also comparable. Patients supplemented with zinc showed no difference in clinical cure rate at 14 days when compared with placebo. Fast breathing was present after 1 wk of treatment in 49% subjects in zinc supplemented vs 43% on placebo (p = 0.685). There was also no difference in breathing rate at study end. Regarding fever, the mean temperature was <99 degrees F in both groups at study end. Hemoglobin, total leukocyte count, standard liver function tests and creatinine showed no difference between groups either at baseline or at study end. There were no treatment emergent adverse events attributable to zinc. CONCLUSIONS: Though well tolerated; the addition of zinc does not improve symptom duration or cure rate in acute bacterial pneumonia in under-five children. PMID- 21660398 TI - Prevalence of respiratory syncytial virus infection among hospitalized children presenting with acute lower respiratory tract infections. AB - OBJECTIVE: To evaluate the prevalence of RSV among hospitalized young children presenting with ALRI in Bangalore, India. METHODS: Respiratory syncytial virus (RSV) antigen detection was performed by direct fluorescent antibody (DFA) staining on 77 nasopharyngeal wash samples collected from hospitalized children below 2 years of age with a diagnosis of acute lower respiratory tract infection (ALRI). RESULTS: Out of 77 samples tested for RSV with DFA, 17 (22.1%) were found RSV-positive with a mean age of 8.24 +/- 7.21 months (M:F = 1.8:1). Three children had congenital cardiac disease and one child had a history of prematurity. One child had re-infection within one month of primary infection. RSV-infected children were more likely to have a diagnosis of bronchiolitis than RSV-negative children (p < 0.001). CONCLUSIONS: RSV infection is a significant cause of morbidity among children presenting with ALRI in southern India. In resource-limited settings, DFA can be used as an important tool for rapid detection of RSV and can potentially eliminate prolonged hospitalization and unnecessary use of antibiotics. PMID- 21660399 TI - Health consequences of childhood obesity. AB - OBJECTIVES: To evaluate the cardiovascular and endocrine effects of childhood obesity as well as prevalence of metabolic syndrome associated with it. METHODS: 49 obese and overweight children aged between 6 and 11 years as study group and 45 healthy non-obese controls of same age were selected for the study. Both the groups were evaluated for height, weight, BMI, waist circumference, blood pressure, fasting serum lipid fractions, insulin level, fasting and post-prandial blood glucose and C-reactive protein. Screening for metabolic syndrome was performed following most acceptable criteria. RESULTS: The study group children had significantly higher blood pressure, altered lipid fractions and high C reactive Protein. Criteria-wise insulin resistance, hypertriglyceridemia and low high density lipoprotein also were found at significantly higher rate among obese children. The metabolic syndrome existed at a high prevalence of 14.1% in the study group. CONCLUSIONS: Obesity in childhood causes cardiovascular and endocrine dysregulation with onset of insulin resistance and metabolic syndrome even in absence of significant evidence of hypertension and type 2 diabetes mellitus in this age group. PMID- 21660400 TI - Approach to a child with sore throat. AB - Sore throat is one of the common reasons for outpatient and emergency visits among children. It could be because of several etiologies; of these bacterial pharyngitis is the most important. Major challenge for the clinician is to diagnose group A beta hemolytic streptococcus (GABHS) pharyngitis and diphtheria, which are associated with serious complications. Throat swab smear with culture and rapid antigen tests are useful for making the diagnosis but the later may not be available in resource poor settings. Many clinical scores have been devised to diagnose GABHS with variable success but usually clinical features, epidemiological criteria and expert clinical judgment with or without supportive investigations indicate need for antibiotics. A child with sore throat and toxic look may have diphtheria or parapharyngeal/retropharyngeal abscess, and therefore should be hospitalized. PMID- 21660401 TI - Impact of inborn errors of metabolism on admission in a neonatal intensive care unit--a prospective cohort study. AB - OBJECTIVE: To estimate the incidence of Inborn errors of metobolism (IEM) in Neonatal intensive care unit (NICU) using tandem mass spectrometry and to determine the impact that these disorders have on NICU resources. METHODS: During the period of study, 724 (81% eligible cases) dried blood filter-paper samples were collected from a NICU. The samples were analysed using tandem mass spectrometry. The diagnosis was further confirmed through clinical symptoms and by gas chromatography-mass spectrometry. The results were also confirmed by clinical follow-up of all positive patients in an overall interval of 1 year. The mean observation period was 11 months per neonate. RESULTS: In total, 22 cases were screen positive and 8 cases of inborn errors of metabolism were detected. The incidence of IEM in the population of patients admitted to the authors' NICU was 1.1%. The most common inborn error found was methylmalonic acidemia (3 cases, 37.5%), and all of the cases needed aggressive treatment and invasive mechanical ventilation. There were two cases of Tyrosinemia type 1, one case each of Maple Syrup Urine Disease, Propionic Acidemia, and Multiple Acyl-CoA dehydrogenase deficiency (MADD). Five of the eight patients required invasive mechanical ventilation. The median length of NICU stay was 3 days (1~7 days) and early therapeutic intervention was effective for four of them and other four patients (50%) died. CONCLUSIONS: The incidence of IEM in NICU was 1.1%, indicating an underestimation of the incidence of metabolic disorders prior to implementing screening. Most patients with IEM in the NICU required invasive mechanical ventilation and the mortality was increased due to underlying IEM. PMID- 21660402 TI - The efficacy of zinc supplementation on outcome of children with severe pneumonia. A randomized double-blind placebo-controlled clinical trial. AB - OBJECTIVE: To compare the clinical outcome of children having severe pneumonia, with and without zinc supplementation by a randomized double-blind placebo controlled trial. METHODS: In this study, 128 children (3-60 months old) admitted to the hospital with severe pneumonia were randomly divided into 2 groups (64 in each) that received either zinc sulfate (2 mg/kg/d, maximum 20 mg in 2 divided doses, for 5 days) or a placebo, along with the standard antimicrobial therapy. Primary outcome measurements included the time taken for clinical symptoms of severe pneumonia such as fever and respiratory distress symptoms to resolve, and the secondary outcome included the duration of hospital stay. RESULTS: The time taken for all the symptoms to resolve in the zinc-supplemented group was significantly lesser then that in the placebo group (42.26 [6.66] vs. 47.52 [7.15] h respectively, p < 0.001). The zinc-treated group had a significantly shorter duration of fever (23.29 [6.67] vs. 26.6 [6.26] h, p = 0.024), respiratory distress (32.87 [7.85] vs. 37.37 [4.43] h, p = 0.001), required a shorter hospital stay (126.74 [12.8] vs. 137.74 [11.52] h, p < 0.001) than did the controls. The zinc supplement was well tolerated by the children. CONCLUSIONS: The results suggest that adjuvant treatment with zinc accelerates recovery from severe pneumonia in young children and significantly reduces the duration of hospital stay. Further studies are required to develop appropriate recommendations for the use of zinc in the treatment of severe pneumonia in other populations. PMID- 21660403 TI - Billateral polycystic kidneys in a girl with WAGR syndrome. AB - The WAGR contiguous gene deletion syndrome is a combination of Wilms tumor, aniridia, genito-urinary abnormalities, and mental retardation. An 8.5-year-old girl was initially investigated at the age of 18 months for congenital bilateral aniridia, cataracts, glaucoma and epicantus. The ultrasound (US) scan showed polycystic kidney disease. FISH study revealed deletion of the WT1 and PAX6 gene in the 11p13 WAGR region. Forty days after the first kidney US, the second US revealed a 3 cm tumor in the right kidney: a Wilms tumour, treated successfully with the Wilm's tumor protocol. The authors conclude that the identification of the deletions in the WAGR region in patients with aniridia should definitely be done. In addition, Wilms tumor can have a very rapid growth, which, per se requires frequent and careful ultrasound kidney controls. Polycystic kidneys can be part of the WAGR presentation. PMID- 21660404 TI - Cystic bone tuberculosis. PMID- 21660405 TI - A panchayat level primary-care approach for adolescent services. AB - OBJECTIVE: To develop a model for providing community adolescent care services in the primary care setting METHODS: Need assessment was done among adolescents and perceived problems of adolescents were studied using qualitative and quantitative methods. Based on the results of these studies, a Family Life Education (FLE) module was prepared. Awareness programs were organized for all stakeholders in the community on adolescent issues. All anganwadi workers in the panchayat were trained to take interactive sessions for all the adolescents in the panchayat using the FLE module. Ward based Teen Clubs were formed in all the 13 wards of the Panchayat separately for boys and girls and FLE classes were given to them through anganwadi workers. An Adolescent Clinic was set up to provide necessary medical and counseling facilities. Adolescent Health Card was distributed to all Teen Club members and those who attended the adolescent clinics. RESULTS: The present approach stresses the need and feasibility of adolescent-centered, community-based interventions. The authors' experience showed that before starting any adolescent program, community awareness generation about the need and content of the program is very important for its success. The experience of this model has made it possible to up-scale the program to seven districts of southern Kerala as a service model. CONCLUSIONS: The experiences of the program gave a realistic picture of the needs and problems of adolescents and a simple feasible model for providing services to adolescents in the primary care setting that can be easily replicated in other parts of India. PMID- 21660406 TI - Tuberous sclerosis complex: imaging findings. PMID- 21660407 TI - Cardamom ingestion as a possible cause of hematuria. PMID- 21660408 TI - High prenatal and postnatal lead exposure associated lead encephalopathy in an infant. AB - An 11-month-old child presented with persistent seizures requiring ventilator support. The child had global developmental delay, was staying in the premises of battery manufacturing unit, had microcytic and hypochromic anemia with basophilic stripling on peripheral smear, lead line on radiograph of the long bones and BLL of 244 MUg/dl. The CT scan of the brain revealed cerebral atrophy. The mother also had high BLL and lead line in the radiograph of the long bones. The child was managed with chelation therapy. Given the continuing lead exposure among occupational and general populations in India, this case study highlights the need for prompt environmental preventive actions as well as nutritional and preventive counseling for occupational populations. PMID- 21660409 TI - Priority mental health disorders of children and adolescents in primary-care pediatric setting in India 1: developing a child and adolescent mental health policy, program, and service model. AB - India has a huge child and adolescent population. Psychiatric disorders are widely prevalent and the mental health needs of these children are well recognized. Nonetheless, there are no country-centric and child specific mental health policies, plans or programs. There is also a significant lack of human resources for child and adolescent mental health in India. This combination of factors makes the primary care a critical setting for the early identification, treatment, consultation and referral of children and adolescents with mental health and developmental needs. Even though the importance of primary care as a system for addressing the mental health care has been recognized for decades, its potential requires further development in India as the Child and Adolescent Mental Health Services (CAMHS) emerge and evolve. A country and child specific mental health policy, plan and program needs to be formulated as well an integrated, multi-tier CAMHS with a focus on the primary-care physicians as care providers for this population has to be developed. PMID- 21660410 TI - A man with Klinefelter's syndrome and new abdominal distension: a discussion of evaluation and management. PMID- 21660411 TI - Glycan structures of the structural subunit (HtH1) of Haliotis tuberculata hemocyanin. AB - The oligosaccharide structures of the structural subunit HtH1 of Haliotis tuberculata hemocyanin (HtH) were studied by mass spectral sequence analysis of the glycans. The proposed structures are based on MALDI-TOF-MS data before and after treatment with the specific exoglycosidases beta1-3,4,6-galactosidase and alpha1-6(>2,3,4) fucosidase followed by sequence analysis via electrospray ionization MS/MS-spectra. In total, 15 glycans were identified as a highly heterogeneous group of structures. As in most molluscan hemocyanins, the glycans of HtH1 contain a terminal MeHex, but more interestingly, a novel structural motif was observed: MeHex[Fuc(alpha1-3)-]GlcNAc, including thus MeHex and (alpha1 3)-Fuc residues being linked to an internal GlcNAc residue. While the functional unit (FU) c (HtH1-c) is completely lacking any potential glycosylation site, FU-h possesses a second exposed sugar attachment site between beta-strands 8 and 9 within the beta sandwich domain compared to the other FUs. The glycosylation pattern/sites show a high degree of conservation. In FU-h two prominent potential glycosylation sites can be detected. The finding that HtH1 is not able to form multidecameric structures in vivo could be explained by the presence of the exposed glycan on the surface of FU-h. PMID- 21660413 TI - Development of a combined SEM and ICP-MS approach for the qualitative and quantitative analyses of metal nano and microparticles in food products [corrected]. AB - An integrated approach based on the use of inductively coupled plasma mass spectrometry (ICP-MS) and scanning electron microscopy (SEM) for the qualitative and quantitative analyses of metal particles in foods was devised and validated. Different raw materials and food products, like wheat, durum wheat, wheat flour, semolina, cookies, and pasta were considered. Attention was paid to the development of sample treatment protocols for each type of sample to avoid potential artifacts such as aggregation or agglomeration. The analytical protocols developed followed by ICP-MS and SEM investigations allowed us the quantitative determination and the morphological and dimensional characterization of metal nano- and microparticles isolated from the raw materials and finished food products considered. The ICP-MS method was validated in terms of linearity (0.8-80 MUg/g and 0.09-9 MUg/g for Fe and Ti, respectively), quantification limits (0.73 MUg/g for Fe and 0.09 MUg/g for Ti), repeatability (relative standard deviation (RSD) % equal to 10% for Fe and 20% in a wheat matrix as an example), and extraction recoveries (93 +/- 2-101 +/- 2%). Validation of the scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS) measurements was performed working in a dimensional range from 1 to 100 MUm with an estimated error in the size determination equal to 0.5 MUm. ICP-MS data as well as SEM measurements showed a decrease in the concentration of metal particles from wheat to flour and from durum wheat to semolina samples, thus indicating an external contamination of grains by metal particles. These findings were confirmed by environmental SEM analysis, which allowed investigation of particles of lower dimensions. Generally, the largest number of particles was found in the case of iron and titanium, whereas particles of copper and zinc were only occasionally found without any possibility of quantifying their number. PMID- 21660412 TI - Efficient generation of useful monoclonal antibodies reactive with globotriaosylceramide using knockout mice lacking Gb3/CD77 synthase. AB - Efficient generation of useful monoclonal antibodies (mAbs) with high performance in cancer therapeutics has been expected. Generation of mAbs reactive with globotriaosylceramide (Gb3/CD77) was compared between A/J mice and Gb3/CD77 synthase-deficient (A4GalT-knockout) mice by immunizing Gb3-liposome. Specificity and functions of established antibodies were examined by ELISA, TLC- immunostaining, cytotoxicity of cancer cells and immunoblotting. Compared with results with conventional mice, better generation of mAbs with higher functions has been achieved with A4GalT-knockout mice, i.e. acquisition of IgG class antibodies, activities in antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and aggregation activity toward a Burkitt's lymphoma line Ramos. Binding of mAb k52 induced tyrosine phosphorylation of several proteins in Ramos cells. One of the strongest phosphorylation bands turned out to be c-Cbl. Pretreatment of B cell lines with mAbs resulted in the attenuation of BCR-mimicking signaling. All these results suggested that A4GalT knockout mice are very useful to generate mAbs against globo-series glycolipids, and that suppressive signaling pathway driven by endogenous Gb3-ligand molecules might be present in B cells. PMID- 21660414 TI - Residue analysis of four diacylhydrazine insecticides in fruits and vegetables by Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) method using ultra performance liquid chromatography coupled to tandem mass spectrometry. AB - The new analytical method using Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) procedure for simultaneous determination of diacylhydrazine insecticide residues in fruits and vegetables was developed using ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC MS/MS). The four insecticides (tebufenozide, methoxfenozide, chromafenozide, and halofenozide) were extracted from six fruit and vegetable matrices using acetonitrile and subsequently cleaned up using primary secondary amine (PSA) or octadecylsilane (C18) as sorbent prior to UPLC-MS/MS analysis. The determination of the target compounds was achieved in less than 3.0 min using an electrospray ionization source in positive mode (ESI+) for tebufenozide, methoxfenozide, and halofenozide and in negative mode (ESI-) for chromafenozide. The limits of detection were below 0.6 MUg kg(-1), while the limit of quantification did not exceed 2 MUg kg(-1) in different matrices. The QuEChERS procedure by using two sorbents (PSA and C18) and the matrix-matched standards gave satisfactory recoveries and relative standard deviation (RSD) values in different matrices at four spiked levels (0.01, 0.05, 0.1, and 1 mg kg(-1)). The overall average recoveries for this method in apple, grape, cucumber, tomato, cabbage, and spinach at four levels ranged from 74.2% to 112.5% with RSDs in the range of 1.4 13.8% (n = 5) for all analytes. This study provides a theoretical basis for China to draw up maximum residue limits and analytical method for diacylhydrazine insecticide in vegetables and fruits. PMID- 21660415 TI - Chemometrics in comprehensive multidimensional separations. AB - Chemometric methods have critical importance for the discovery of the information/knowledge buried or concealed in high-dimensional datasets acquired from comprehensive multidimensional separations (CMDS), and for interpretation of experiments or chemical processes. In this work, employment of new developments in chemometrics making full use of the data to maximize the potential of CMDS to resolve mathematically a variety of practical problems is reviewed whilst providing the authors' point of view. During the past several years, chemometrics has been successfully applied to many areas of concern to CMDS investigation, including experimental parameter optimization, data quality improvement, identification and quantification of target chemical components, pattern recognition technique for clustering and classification, multivariate model establishment to correlate chromatographic properties and molecular descriptors. On the basis of the high-dimensionality characteristics of CMDS, some special aspects such as evaluation of orthogonality and image processing have also been included in this review. It is expected that an overview of the diverse ways in which chemometrics can aid CMDS investigations will prove valuable to interested users in this area through a comprehensive survey of previous research contributions. Chemometrics lends itself well to the powerful separation capability of CMDS. PMID- 21660416 TI - A biospectroscopic interrogation of fine needle aspirates points towards segregation between graded categories: an initial study towards diagnostic screening. AB - Fine needle aspirates (FNAs) of suspicious breast lesions are often used to aid the diagnosis of female breast cancer. Biospectroscopy tools facilitate the acquisition of a biochemical cell fingerprint representative of chemical bonds present in a biological sample. The mid-infrared (IR; 4,000-400 cm(-1)) is absorbed by the chemical bonds present, allowing one to derive an absorbance spectrum. Complementary to IR spectroscopy, Raman spectroscopy measures the scattering by chemical bonds following excitation by a laser to generate an intensity spectrum. Our objective was to apply these methods to determine whether a biospectroscopy approach could objectively segregate different categories of FNAs. FNAs of breast tissue were collected (n = 48) in a preservative solution and graded into categories by a cytologist as C1 (non-diagnostic), C2 (benign), C3 (suspicious, probably benign) or C5 (malignant) [or C4 (suspicious, probably malignant); no samples falling within this category were identified during the collection period of the study]. Following washing, the cellular material was transferred onto BaF(2) (IR-transparent) slides for interrogation by Raman or Fourier-transform IR (FTIR) microspectroscopy. In some cases where sufficient material was obtained, this was transferred to low-E (IR-reflective) glass slides for attenuated total reflection-FTIR spectroscopy. The spectral datasets produced from these techniques required multivariate analysis for data handling. Principal component analysis followed by linear discriminant analysis was performed independently on each of the spectral datasets for only C2, C3 and C5. The resulting scores plots revealed a marked overlap of C2 with C3 and C5, although the latter pair were both significantly segregated (P < 0.001) in the Raman spectra. Good separation was observed between C3 and C5 in all three spectral datasets. Analysis performed on the average spectra showed the presence of three distinct cytological groups. Our findings suggest that biospectroscopy tools coupled with multivariate analysis may support the current FNA tests whilst increasing the sensitivity and associated reliability for improved diagnostics. PMID- 21660417 TI - Perineal hernia after laparoscopic abdominoperineal resection--reconstruction of the pelvic floor with a biological mesh (PermacolTM). PMID- 21660418 TI - Focused preoperative patient stoma education, prior to ileostomy formation after anterior resection, contributes to a reduction in delayed discharge within the enhanced recovery programme. AB - PURPOSE: Stoma formation is a well-known cause for delayed discharge following colorectal surgery. This has been addressed by the enhanced recovery programme (ERP) preoperatively through stoma counselling sessions. These aim to promote independent stoma management post-operatively, thus expediting hospital discharge. We compared the numbers of patients with prolonged hospital stay secondary to delayed independent stoma management prior to and following the introduction of an enhanced recovery programme with preoperative stoma education. METHODS: Data collection on patients undergoing anterior resection with the formation of a loop ileostomy was carried out retrospectively prior to ERP (January 2006 to August 2008) and prospectively following the introduction of ERP (September 2008 to October 2010). Comparisons were made in patients with prolonged hospital stay (defined as hospital stay of more than 5 days) secondary to stoma management. RESULTS: Two hundred forty patients underwent elective anterior resection with the formation of a loop ileostomy, 120 prior ERP and 120 post-ERP. Average length of hospital stay was 14 days before ERP introduction, with a range of 7-25 days. The mean length of stay amongst the ERP patients was 8 days (p = 0.17), ranging from 3 to 17 days. Twenty-one patients in the pre-ERP group (17.5%) experienced postponed hospital discharge due to a delay in independent stoma management, compared to one patient experiencing such a delay after the introduction of ERP (0.8%, p < 0.0001). CONCLUSIONS: Delayed discharge secondary to independent stoma management can be significantly reduced with preoperative stoma management teaching as part of an enhanced recovery programme. PMID- 21660419 TI - Recurrence of autoimmunity following pancreas transplantation. AB - Pancreas transplantation is a therapeutic option for patients with type 1 diabetes. Advances in immunosuppression have reduced immunologic failures, and these are usually categorized as chronic rejection. Yet studies in our cohort of pancreas transplant recipients identified several patients in whom chronic islet autoimmunity led to recurrent diabetes, despite immunosuppression that prevented rejection. Recurrent diabetes in our cohort is as frequent as chronic rejection, and thus is a significant cause of immunologic graft failure. Our studies demonstrated islet autoimmunity by the presence of autoantibodies and autoreactive T cells, which mediated beta-cell destruction in a transplantation model. Biopsy of the transplanted pancreas revealed variable degrees of beta-cell loss, with or without insulitis, in the absence of pancreas and kidney transplant rejection. Additional research is needed to better understand recurrent disease and to identify new treatment regimens that can suppress autoimmunity, as in our experience this is not effectively inhibited by conventional immunosuppression. PMID- 21660421 TI - Motor-evoked potentials (MEP) during brainstem surgery to preserve corticospinal function. AB - BACKGROUND: Brainstem surgery bears a risk of damage to the corticospinal tract (CST). Motor-evoked potentials (MEPs) are used intraoperatively to monitor CST function in order to detect CST damage at a reversible stage and thus impede permanent neurological deficits. While the method of MEP is generally accepted, warning criteria in the context of brainstem surgery still have to be agreed on. METHOD: We analyzed 104 consecutive patients who underwent microsurgical resection of lesions affecting the brainstem. Motor grade was documented prior to surgery, early postoperatively and at discharge. A baseline MEP stimulation intensity threshold was defined and intraoperative testing aimed to keep MEP response amplitude constant. MEPs were considered deteriorated and the surgical team was notified whenever the threshold was elevated by >=20 mA or MEP response fell under 50%. FINDINGS: On the first postoperative day, 18 patients experienced new paresis that resolved by discharge in 11. MEPs deteriorated in 39 patients, and 16 of these showed new postoperative paresis, indicating a 41% risk of new paresis. In the remaining 2/18 patients, intraoperative MEPs were stable, although new paresis appeared postoperatively. In one of these patients, intraoperative hemorrhage caused postoperative swelling, and the new motor deficit persisted until discharge. Of all 104 patients, 7 deteriorated in motor grade at discharge, 92 remained unchanged, and 5 patients have improved. CONCLUSIONS: Adjustment of surgical strategy contributed to good motor outcome in 33/39 patients. MEP monitoring may help significantly to prevent motor deficits during demanding neurosurgical procedures on the brainstem. PMID- 21660420 TI - Tissue engineering and cell-based therapy toward integrated strategy with artificial organs. AB - Research in order that artificial organs can supplement or completely replace the functions of impaired or damaged tissues and internal organs has been underway for many years. The recent clinical development of implantable left ventricular assist devices has revolutionized the treatment of patients with heart failure. The emerging field of regenerative medicine, which uses human cells and tissues to regenerate internal organs, is now advancing from basic and clinical research to clinical application. In this review, we focus on the novel biomaterials, i.e., fusion protein, and approaches such as three-dimensional and whole-organ tissue engineering. We also compare induced pluripotent stem cells, directly reprogrammed cardiomyocytes, and somatic stem cells for cell source of future cell-based therapy. Integrated strategy of artificial organ and tissue engineering/regenerative medicine should give rise to a new era of medical treatment to organ failure. PMID- 21660422 TI - Pituitary tumours and pregnancy. PMID- 21660423 TI - Neurosurgery and pregnancy. AB - BACKGROUND: Pregnant women with pathological conditions requiring a neurosurgical intervention pose a unique therapeutic challenge. Changes in normal physiology add to the complexity of patient management. We describe our experience in treating various neurosurgical diseases in parturient women. METHODS: Thirty-four pregnant and early postpartum women were treated at our center between 2003 and 2010. The general guideline used in these patients (now deserving re-evaluation based on the presented data) was to postpone surgery until the patient reached term (weeks 34-38 of gestation) unless there was evidence of a life- or function threatening condition, in which case surgery was promptly performed. RESULTS: Sixteen patients underwent neurosurgical intervention during pregnancy between 11 to 34 weeks of gestation (7 tumor, 3 vascular, 2 VP shunt, 2 spinal, 2 trauma). Thirteen women underwent a neurosurgical procedure after delivery (12 tumor, 1 spine), and 5 women were treated conservatively (2 vascular lesions, 3 trauma). Three patients underwent abortions (one spontaneous and two elective). The other 31 women delivered at 30-42 weeks' gestation. Of 12 patients whose definitive neurosurgical procedure was initially delayed, 5 were not able to complete their pregnancy naturally. Of 21 patients that underwent a cesarean section (CS), 3 were performed urgently. Although two pairs of twins and two singletons had an initial low Apgar score (<7), the outcome for all the neonates was good. Neurosurgical outcome was satisfactory. CONCLUSIONS: Our experience demonstrates the safety of neurosurgical intervention and anesthesia during pregnancy. Delaying intervention often resulted in maternal deterioration and urgent intervention. Thus, pregnancy by itself should not be considered a major contraindication for performing a neurosurgical procedure, which should be considered early rather than late in most patients. PMID- 21660424 TI - Metabolic syndrome in chronic kidney disease and renal transplant patients in North India. AB - AIM: The cluster of biochemical and clinical abnormalities known as metabolic syndrome (MS) has become a public health problem even in developing countries. Previous studies have shown a graded relationship between MS components and worsening renal function in the general population. The prevalence of MS in non dialysis-dependent CKD (NDD-CKD) and kidney transplant recipients in the North Indian population is unknown. METHODS: We studied all patients with stable CKD and with renal transplantation attending the nephrology clinic in a large centre in North India over an eight-week period. All transplant patients had stable graft function for 3 months prior to recruitment. MS was defined according to the International Diabetes Federation (IDF) 2007 guidelines. A total of 252 (155 NDD CKD and 97 renal transplant recipients) patients were studied. RESULTS: MS was present in 86 (34%) patients. The prevalence of MS was similar in NDD-CKD and transplant patients [60 (39%) vs. 26 (27%), P = 0.052]. Patients with MS were older than those without MS (48 +/- 12 years-old vs. 40 +/- 14 years-old, P < 0.001) and MS was more common in women than in men (59% vs. 26%, P < 0.001). Female gender was an independent risk factor for MS in this population [adjusted OR 5.25 (95% CI: 2.74-10.06)]. With advancing CKD, the prevalence of MS decreased in the NDD-CKD patients. Impaired glucose tolerance and hypertriglyceridemia were independent predictors of MS. Hypertension was not a predictor of MS in NDD-CKD. In transplant recipients, hypertriglyceridemia, hypertension and low HDL cholesterol predicted the risk for MS. CONCLUSION: MS is common in CKD and renal transplant patients in North India. The risk of MS decreases with declining eGFR in CKD patients. Female gender and hypertriglyceridemia independently predict the risk of MS in both NDD-CKD and transplant recipients. PMID- 21660425 TI - Antitumor effect of meclofenamic acid on human androgen-independent prostate cancer: a preclinical evaluation. AB - PURPOSE: Prostate cancer is a worldwide public health problem and its treatment continues to be a therapeutic challenge especially in patients with metastatic androgen-independent cancer. Inflammation is a process that has been involved in the origin of this cancer and its inhibition has been postulated as a prophylactic and therapeutic strategy. The present study evaluated two non steroidal anti-inflammatory drugs (meclofenamic acid and mefenamic acid) that have been studied very little in regard to cancer treatment. METHODS: In vitro, the cytotoxic effects of meclofenamic acid and mefenamic acid were determined in human prostate cancer cell lines (LNCaP: androgen-dependent; and PC3: androgen independent). In vivo trials were divided into two phases; meclofenamic acid toxicity was initially determined at different doses (0, 5, 10 and 20 mg/kg/day/25 days) in BALB/c mice, after which a trial using non-toxic doses was carried out to evaluate the antitumor efficacy of the drug in a PC3/nude-mouse model of human androgen-independent prostate cancer. RESULTS: In vitro trials showed that only meclofenamic acid is highly cytotoxic in neoplastic prostate cells. The 5 and 10 mg/kg/day/25 day doses did not cause relevant toxicity in the BALB/c mouse trial, and so both doses were used in the nude-mouse model of cancer trial. This latter trial showed that meclofenamic acid significantly reduces tumor growth, prolongs survival, and is even capable of generating total tumor regression in up to 25% of mice treated at high dose. CONCLUSIONS: Meclofenamic acid was shown to be a potential antineoplastic agent for both androgen-dependent and androgen-independent prostate cancer. PMID- 21660426 TI - Urodynamically diagnosed detrusor hypocontractility: should transurethral resection of the prostate be contraindicated? AB - BACKGROUND: Patients with benign prostatic hyperplasia (BPH) suffering from hypocontractile detrusor were generally regarded unsuitable for surgery. This prospective study is to evaluate the efficacy of transurethral resection of the prostate (TURP) on BPH patients diagnosed detrusor hypocontractility on urodynamic study (UDs). METHODS: Twenty patients were included in the study with mean age of 74.20 +/- 7.93 years (range: 57-88). Outcomes were determined by patients' self-assessment questionnaires, International Prostate Symptom Score (IPSS) and Quality of Life (QoL), and UDs parameters including maximum uroflow rate (Qmax), postvoid urine volume (PVR), bladder compliance, maximal cystometric capacity (MCC), and maximum detrusor pressure (Pdetmax). RESULTS: Median follow up duration was 12 months (range: 10-16). After TURP, IPSS/QoL, Qmax, PVR, and Pdetmax were significantly improved and there were no significant differences with regard to bladder compliance and MCC. CONCLUSION: UDs may play a very limited role in detecting bladder outlet obstruction (BOO) in BPH patients with hypocontractile detrusor. TURP may obtain a promising effect on such patients with unidentified BOO. These patients should not be arbitrarily excluded from surgical indications simply based on UDs findings. PMID- 21660428 TI - Effects of cognitive-behavioral therapy on anxiety in children with autism spectrum disorders: a randomized controlled trial. AB - We compared the effects of a 16-week Cognitive-Behavioral Therapy (CBT) program and a Social Recreational (SR) program on anxiety in children with Autism Spectrum Disorders (ASD). Seventy children (9-16 years old) were randomly assigned to either of the programs (n (CBT) = 36; n (SR) = 34). Measures on child's anxiety using the Spence Child Anxiety Scale--Child (SCAS-C) and the Clinical Global Impression-Severity scale (CGI--S) were administered at pre-, post-treatment, and follow-ups (3- and 6-month). Children in both programs showed significantly lower levels of generalized anxiety and total anxiety symptoms at 6 month follow-up on SCAS-C. Clinician ratings on the CGI-S demonstrated an increase in the percentage of participants rated as "Normal" and "Borderline" for both programs. Findings from the present study suggest factors such as regular sessions in a structured setting, consistent therapists, social exposure and the use of autism-friendly strategies are important components of an effective framework in the management of anxiety in children and adolescents with ASD. PMID- 21660429 TI - Migraine and restless legs syndrome: is there an association? AB - Occasional clinical reports have suggested a link between migraine and restless legs syndrome. We undertook a systematic review of the evidence, which supports this association, and consider possible shared pathogenic mechanisms and the implications for current clinical practice. PMID- 21660427 TI - Variations on a theme: plant autophagy in comparison to yeast and mammals. AB - Autophagy is an evolutionary conserved process of bulk degradation and nutrient sequestration that occurs in all eukaryotic cells. Yet, in recent years, autophagy has also been shown to play a role in the specific degradation of individual proteins or protein aggregates as well as of damaged organelles. The process was initially discovered in yeast and has also been very well studied in mammals and, to a lesser extent, in plants. In this review, we summarize what is known regarding the various functions of autopahgy in plants but also attempt to address some specific issues concerning plant autophagy, such as the insufficient knowledge regarding autophagy in various plant species other than Arabidopsis, the fact that some genes belonging to the core autophagy machinery in various organisms are still missing in plants, the existence of autophagy multigene families in plants and the possible operation of selective autophagy in plants, a study that is still in its infancy. In addition, we point to plant-specific autophagy processes, such as the participation of autophagy during development and germination of the seed, a unique plant organ. Throughout this review, we demonstrate that the use of innovative bioinformatic resources, together with recent biological discoveries (such as the ATG8-interacting motif), should pave the way to a more comprehensive understanding of the multiple functions of plant autophagy. PMID- 21660430 TI - The Eurolight project: the impact of primary headache disorders in Europe. Description of methods. AB - The Eurolight project is the first at European Union level to assess the impact of headache disorders, and also the first of its scale performed by collaboration between professional and lay organizations and individuals. Here are reported the methods developed for it. The project took the form of surveys, by structured questionnaire, conducted in ten countries of Europe which together represented 60% of the adult population of the European Union. In Lithuania, the survey was population-based. Elsewhere, truly population-based studies were impractical for reasons of cost, and various compromises were developed. Closest to being population-based were the surveys in Germany, Luxembourg, the Netherlands, Italy and Spain. In Austria, France and UK, samples were taken from health-care settings. In addition in the Netherlands, Spain and Ireland, samples were drawn from members of national headache patient organizations and their relatives. Independent double data-entry was performed prior to analysis. Returned questionnaires from 9,269 respondents showed a moderate female bias (58%); of respondents from patients' organizations (n = 992), 61% were female. Mean age of all respondents was 44 years; samples from patients' organizations were slightly older (mean 47 years). The different sampling methods worked with differing degrees of effectiveness, as evidenced by the responder-rates, which varied from 10.8 to 90.7%. In the more population-based surveys, responder-rates varied from 11.3 to 58.8%. We conclude that the methodology, although with differences born of necessity in the ten countries, was sound overall, and will provide robust data on the public ill-health that results from headache in Europe. PMID- 21660431 TI - Iatrogenic damage to the mandibular nerves as assessed by the masseter inhibitory reflex. AB - Iatrogenic injury of the inferior alveolar or lingual nerves frequently leads to legal actions for damage and compensation for personal suffering. The masseter inhibitory reflex (MIR) is the most used neurophysiological tool for the functional assessment of the trigeminal mandibular division. Aiming at measuring the MIR sensitivity and specificity, we recorded this reflex after mental and tongue stimulations in a controlled, blinded study in 160 consecutive patients with sensory disturbances following dental procedures. The MIR latency was longer on the affected than the contralateral side (P < 0.0001). The overall specificity and sensitivity were 99 and 51%. Our findings indicate that MIR testing, showing an almost absolute specificity, reliably demonstrates nerve damage beyond doubt, whereas the relatively low sensitivity makes the finding of a normal MIR by no means sufficient to exclude nerve damage. Probably, the dysfunction of a small number of nerve fibres, insufficient to produce a MIR abnormality, may still engender important sensory disturbances. We propose that MIR testing, when used for legal purposes, be considered reliable in one direction only, i.e. abnormality does prove nerve damage, normality does not disprove it. PMID- 21660433 TI - Effect of exclusive breastfeeding on the development of children's cognitive function in the Krakow prospective birth cohort study. AB - The main goal of the study was to assess the effect of exclusive breastfeeding on the neurodevelopment of children over a 7-year follow-up period and to test the hypothesis that the observed cognitive gain in breastfed children in the first years of life is a strong predictor of their cognitive development trajectory, which may be continued in later life. The analysis is based on data from the 7 year follow-up of 468 term babies (>36 weeks of gestation) born to non-smoking mothers participating in an ongoing prospective cohort study. The cognitive function of children was assessed by psychometric tests performed five times at regular intervals from infancy through the preschool age. The study included valid neurodevelopmental assessment of the children-443 participants were evaluated least twice; 425, three times; and 307, five times in the follow-up period. The association between the cognitive achievements of preschool age children and exclusive breastfeeding of various durations was performed using the generalized estimating equation longitudinal model, adjusted for major confounders such as maternal education, gender, parity, and weight gain in pregnancy. Children breastfed exclusively for up to 3 months had intelligence quotients (IQs) that were on average 2.1 points higher compared to the others (95% confidence interval (CI), 0.24-3.9); children breastfed for 4-6 months scored higher by 2.6 points (95% CI, 0.87-4.27); and the benefit for children breastfed even longer (>6 months) increased by 3.8 points (95% CI, 2.11-5.45). Other predictors were maternal education, gender of the child, having an older sibling, and weight gain during pregnancy. The results of the study support the WHO expert recommendations on exclusive breastfeeding for 6 months; moreover, they provide evidence that even a shorter duration of exclusive breastfeeding in early infancy produces beneficial effects on the cognitive development of children. The breastfeeding-related IQ gain observed already at the age of 1 was sustained through preschool age, and the difference in terms of IQ score between breastfed children and the reference group (mixed breastfeeding) held constant over the whole preschool period. PMID- 21660434 TI - Resection of a primary oral malignant melanoma and rehabilitative management using nasolabial flap: a case report. AB - BACKGROUND: The primary malignant melanoma is a rare neoplasm of melanocytic origin in the oral cavity. Only about 1% of all melanomas arise in the oral mucosa and these account for 0.5% of all oral malignancies CASE REPORT: This report describes an oral malignant melanoma occurring in the right maxilla of a 73-year-old patient. The interdisciplinary management using a nasolabial flap and prosthetic oral rehabilitation procedure is described. DISCUSSION: The nasolabial flap technique offers the possibility of an immediate reconstruction of the maxillary defect and obviated problems with speech, swallowing, and permitted oral intake. As a supplementary benefit, the resection area can support the prosthetic rehabilitation. PMID- 21660435 TI - Multinodular neck recurrence of parotid gland pleomorphic adenoma: a case report. AB - BACKGROUND: Pleomorphic adenoma is the most common neoplasm of the parotid gland. It is a benign tumor composed of epithelial and myoepithelial cells arranged in various morphological patterns. The most common reasons contributing to a recurrent disease are obvious or underestimated tumor spillage, incomplete excision, and violation of the pseudocapsule of the tumor. CASE REPORT: This article presents a case of gross multinodular recurrence of a parotid gland pleomorphic adenoma in a 38-year-old female patient. Upon clinical examination of the homolateral neck, multiple, painless, well-defined, palpable, nontender masses and subcutaneous nodules of the right parotid and homolateral neck region were revealed. The patient was treated with surgery and subsequent radiation therapy. Histologic examination of the resected specimen was suggestive of a recurrent pleomorphic adenoma disease. There were no signs of malignant transformation in the specimen. The diagnostic procedure followed, and management of the patient is outlined in the paper. DISCUSSION: Pleomorphic adenoma is the most common tumor of the parotid gland. In spite of being a benign neoplasm, inadequate management of the lesion may lead to problems such as local recurrence or malignant transformation. Management of recurrent tumors is challenging because the probability of subsequent recurrence increases with each recurrent episode, thus making local control increasingly difficult and damage to the facial nerve more likely. PMID- 21660436 TI - Maxillofacial injuries in western Iran: a prospective study. AB - INTRODUCTION: Although the epidemiology of facial injuries has been studied in many populations, there is a paucity of information in the literature in this relation in the Middle East including Iran. The aim of this study was to assess the epidemiology and mode of treatment of facial injuries in western Iran. MATERIAL AND METHODS: We examined all patients with a maxillofacial injury who presented to the outpatient department or who were hospitalized in the Besat Hospital of Hamedan City, Iran, between 20 December 2007 and 20 December 2009. RESULTS: Of 2,450 patients (77% male, 23% female) with a facial injury, 90% sustained soft tissue injuries and 37% had bone fractures. Motor vehicle accidents (MVAs) were the most common cause of injuries (35%). The most frequent bone fracture occurred in the nasal bone (63.4%). The incidence of associated injuries was 8.3% (mostly orthopedic). Rigid internal fixation was the main treatment of facial fractures. Malpositioned zygomas and functional and aesthetic problems after reconstruction of nasal-orbital-ethmoid injuries were the most common postoperative complications. DISCUSSION: Although in many countries the rate of facial injuries due to traffic accidents is decreasing, MVA is still the major cause of facial trauma in Iran. This may be due to the lack of enforcement of traffic laws by police and insufficient compliance of the population in obeying traffic rules. Rigid internal fixation was the most common mode of treatment of facial fractures, and in spite of the severity of facial injuries, the rate of postoperative complications was relatively low. PMID- 21660437 TI - Single-nucleotide polymorphisms of MAMDC1 are associated with rash and photosensitivity, but not disease risk, of systemic lupus erythematosus in Chinese mainland population. AB - Systemic lupus erythematosus (SLE) is a complex immune disease affected by both genetic dispositions and environmental factors. Recently, the polymorphisms in MAMDC1 gene have been reported to associate with disease risk of SLE in European population. However, whether this association is replicated in Chinese population is unknown yet. A total of 491 SLE patients and 533 controls were recruited. Unlabeled probe-based high-resolution melting analysis (HRMA) was used in genotyping. HRMA with unlabeled probe successfully distinguished all genotypes. SNP rs961616 was associated with rash [P = 0.015, odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.57-0.94] and photosensitivity (P = 0.001, OR = 0.63, 95%CI = 0.48-0.84), but not the disease risk (P = 0.133, OR = 0.88, 95%CI = 0.74 1.04), of SLE in Chinese population. Polymorphisms of rs961616 in MAMDC1 gene were associated with rash and photosensitivity, but not disease risk, of systemic lupus erythematosus in Chinese population. PMID- 21660438 TI - Foot health needs in people with systemic sclerosis: an audit of foot health care provision. AB - The vascular and cutaneous alterations evident in systemic sclerosis/scleroderma (SSc) place the foot at risk of ulceration. The UK Podiatry Rheumatic Care Association (PRCA)/Arthritis and Musculoskeletal Alliance standards of care recommend that all people with SSc should receive at least basic information about their foot health, and that those with foot problems should have access to self-management advice and care where needed. The aim of this study was to evaluate foot health services offered in Leeds (UK) for people with SSc, against nationally agreed standards of care. Ninety-one consecutive patients with SSc were selected from either the connective tissue disease outpatient clinic (n = 70) or the specialist rheumatology foot health clinic (n = 21) at Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust. All the patients completed a disease-specific audit tool developed by the UK PRCA that evaluates provision of foot health care for patients with SSc. Sixty-one patients (67%) reported having had foot problems at some point in time and 54 (59%) had current foot problems. Of these 54 patients, 17 (32%) had not received any foot care. Only 36 (39%) of the 91 patients had received any foot health information. This audit demonstrates that patients with SSc have a relatively high prevalence of self-reported foot problems. Foot health care and information are inadequate for people with SSc and foot problems, and preventative information is almost non-existent. Improved foot health information will better empower patients to self-manage low risk problems, and help identify high risk problems which require specialist care. PMID- 21660439 TI - Mislocalization or low expression of mutated Shwachman-Bodian-Diamond syndrome protein. AB - Shwachman-Diamond syndrome (SDS) is an autosomal-recessive disorder characterized by exocrine pancreatic insufficiency and bone marrow failure. Mutations in the SBDS gene are identified in most patients with SDS. Recent studies have shown that SBDS is involved in ribosome biogenesis and is localized to the nucleolus. The significance of cellular localization in SBDS is unknown, particularly as SBDS does not exhibit canonical nuclear localization signals. In this study, we have constructed wild-type deletion mutants of the critical domains and disease associated mutants of the SBDS gene. These constructs were expressed in HeLa cells to explore the subcellular distribution of normal and mutant proteins. Wild type SBDS was detected in the nucleus. However, constructs lacking N-terminal Domain I and two disease-associated mutants (C31W and N34I) failed to localize SBDS to the nucleus. Moreover, the amount of mutated SBDS protein was decreased. When N-terminal Domain I was overexpressed in HeLa cells, the localization of endogenous SBDS protein was changed from nuclei to cytosolic fraction. These data indicate that the N-terminal Domain I is responsible for nuclear localization. Furthermore, low expression of SBDS, as exhibited in some of the disease associated mutants, may be associated with the pathogenesis of SDS. PMID- 21660440 TI - Dengue hemorrhagic fever as a rare cause of bleeding following percutaneous nephrolithotomy. AB - Post percutaneous nephrolithotomy (PNL) bleeding is an uncommon yet serious complication and is almost always related to a surgical cause. Nevertheless, medical cause of bleeding is rarely encountered as a cause of this dangerous complication. Dengue has been rarely reported as a cause of post operative bleeding. Bleeding diathesis in dengue occurs not only due to thrombocytopenia but also due to dysfunctional surviving platelets and increased fibrinolysis. We report a patient who developed bleeding after an uneventful PNL due to dengue hemorrhagic fever. Medical causes of bleeding such as locally endemic viral hemorrhagic fevers should also be kept in mind and evaluated especially when a surgical cause of the bleed is not found or suspected in bleeding after any surgery. PMID- 21660441 TI - Metabolic diagnosis in stone formers in relation to body mass index. AB - It is known that several metabolic abnormalities that favor stone formation have a strong dependence on environmental and nutritional factors. The incidence and prevalence of kidney stone is increasing while there has been a parallel growth in the overweight/obesity rate, and epidemiologic studies have shown a significant association between overweight/obesity and increased nephrolithiasis risk. The aim of this study was to assess if metabolic abnormalities observed in stone patients differ in relation to their BMI. We evaluated 817 renal stone formers (459 men and 358 woman) in an outpatient setting. They were all studied with a standard protocol (two 24 h urine collections and serum parameters) and classified according to their BMI in normal, overweight and obese and according to age in <50 or >50 year old. In the whole population we found that 58.7% were either overweight or obese: 39.4% (n = 322) were OW and 19.3% (n = 158) were OB. The proportion of overweight was significantly higher among men than women. In women of all ages regardless of BMI, hypercalciuria was the most prevalent diagnosis. Hyperuricosuria increased its prevalence significantly only in overweight and obese women <50 years of age (p < 0.01). Hypercalciuria was the predominant diagnosis in normal weight men of both age groups. Hyperuricosuria was the most frequent abnormality in overweight and obese men followed by gouty diathesis and both increased their prevalence significantly from normal weight to obesity and in both age groups (p < 0.05 and <0.01). We conclude that the only abnormalities that increased their prevalence significantly with increasing BMI were hyperuricosuria and gouty diathesis, the first one in men of all ages and women under 50 years of age, while the second one only in men. PMID- 21660442 TI - Changes in the sex hormone profile of male patients with moderate-to-severe plaque-type psoriasis under systemic therapy: results of a prospective longitudinal pilot study. AB - Patients with moderate-to-severe plaque-type psoriasis exhibit increased cardiovascular mortality. Recent publications point towards psoriasis-induced insulin resistance as an important pathomechanism driving cardiovascular comorbidity in these patients. As the hormonal status in general and sex hormone binding globulin (SHBG) in particular serve as sensitive indicators for insulin resistance, we analysed these parameters in the context of a set of multiple additional clinical and laboratory measurements in a cohort of male patients. Of 33 consecutively enrolled male patients receiving continuous systemic therapy for their moderate-to-severe plaque-type psoriasis, 23 male patients for whom all parameters could be collected over a 24-week treatment period were included in this analysis. At baseline, testosterone levels varied between 212 and 660 ng/ml (median: 377.0), and SHBG between 11.9 and 46.0 nmol/l (median: 29.2), thus documenting lack of hypogonadism among these patients. Clinically, 19/23 patients experienced at least a 50% reduction in their PASI under therapy. Using a multivariate regression model to further analyse the sub-group of patients responding to treatment, hs-CRP, PASI, leptin and resistin all improved under effective systemic anti-inflammatory therapy, thus losing their significant influence on SHBG. SHBG performed well as a sensitive biomarker for insulin resistance and systemic inflammation in these patients. Its improvement, as well as the reduction of resistin serum levels, most likely reflects a state of reduced cardiovascular risk in patients undergoing effective continuous systemic therapy. Long-term safety data, generated e.g. from psoriasis registries, are needed to assess whether this effect translates into reduced cardiovascular mortality. PMID- 21660443 TI - Aromatic-turmerone inhibits alpha-MSH and IBMX-induced melanogenesis by inactivating CREB and MITF signaling pathways. AB - This study investigated the anti-melanogenic effect of aromatic (ar)-turmerone on alpha-melanocyte stimulating hormone (alpha-MSH) and 3-isobuty-1-methxlzanthine (IBMX)-induced tyrosinase (Tyr), tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2) expression in B16F10 melanoma cells. We demonstrated that ar-turmerone inhibits alpha-MSH and IBMX-induced melanin synthesis and tyrosinase activity. Data also showed that ar-turmerone inhibits the expression of tyrosinase, TRP-1, and TRP-2 in alpha-MSH- and IBMX-stimulated B16F10 cells. In addition, ar-turmerone exhibits stronger anti-melanogenic effects than curcumin. Furthermore, ar-turmerone strongly inhibited alpha-MSH- and IBMX-induced microphthalmia-associated transcription factor by suppressing the activity of cyclic adenosine monophosphate (cAMP)-responsive element binding protein in alpha-MSH-stimulated B16F10 cells. Our data revealed that ar-turmerone is a novel, effective, anti-melanogenic agent that functions by downregulating tyrosinase, Trp-1, and Trp-2 gene expression. Therefore, ar-turmerone may be a useful therapeutic agent for treating hyperpigmentation disorders, such as freckles and melasma, and as a beneficial additive in whitening cosmetics. PMID- 21660444 TI - Clomipramine, but not haloperidol or aripiprazole, inhibits quinpirole-induced water contrafreeloading, a putative animal model of compulsive behavior. AB - RATIONALE: Repeated administrations of the D2/D3 agonist quinpirole (QNP) to rats elicit an antieconomical pattern of drinking called "contrafreeloading" (CFL), a putative model of compulsive-like behavior. OBJECTIVES: We tested the sensitivity of QNP-induced CFL to haloperidol (HAL), aripiprazole (ARI), and clomipramine (CIM), the latter proven effective in the treatment of obsessive-compulsive disorder (OCD). METHODS: Rats were trained under a schedule of reinforcement (FR3) for water. On days 1-6, water was only available through lever pressing. On days 7-15, a choice between operant and free access was provided. QNP 0.5 mg/kg was administered alone or in combination with HAL (0.1 or 0.2 mg/kg), ARI (0.3 or 1 mg/kg), or CIM (5 or 10 mg/kg). RESULTS: Acutely QNP suppressed operant behavior and, therefore, water intake; upon repeated administrations, tolerance developed to this suppressant effect on responding but only to a lesser extent to the antidipsic effect. In choice conditions, QNP induced a progressive preference for the operant access (CFL). HAL per se, but not CIM and ARI, significantly reduced both responding and drinking (operant phase). In the choice phase, HAL and CIM inhibited CFL, but only the latter reinstated total water intake. ARI, in combination with QNP, increased responding. CONCLUSIONS: CIM reinstates control patterns of drinking, while HAL and ARI where partially or not effective at all, respectively. As far as CIM is considered a first line treatment in OCD, these results further strengthen the notion that QNP-induced CFL belongs to the realm of dopaminergic drug-induced compulsive behaviors. PMID- 21660445 TI - Serotonin-2A receptor regulation of panic-like behavior in the rat dorsal periaqueductal gray matter: the role of GABA. AB - RATIONALE: Electrical stimulation of the dorsal periaqueductal gray (dPAG) evokes escape, a defensive response associated with panic attacks. Stimulation of 5-HT1A or 5-HT2A receptors in this midbrain area equally inhibits escape performance, even though at the molecular level these receptors cause opposite effects, i.e., activation of the former hyperpolarizes the cell membrane, while the latter excites it. A proposal has been made that 5-HT2A receptor agonists exert their inhibitory effect on escape by activating GABAergic interneurons located in the dPAG. OBJECTIVES: In the present study, we evaluated this hypothesis by investigating whether previous intra-dPAG administration of the GABAA receptor antagonist bicuculline blocks the anti-escape effect caused by the local injection of different 5-HT2A/2C receptor agonists. RESULTS: Intra-dPAG administration of 5-HT, the preferential 5-HT2A receptor agonist DOI, the nonselective 5-HT2C receptor agonist mCPP or the 5-HT2C receptor agonist RO 60 0175 significantly inhibited the escape reaction induced by electrical stimulation of the same brain area. In all cases, this panicolytic-like effect was blocked by previous microinjection of bicuculline. This GABAA antagonist, however, failed to antagonize the anti-escape effect caused by the 5-HT1A receptor agonist 8-OH-DPAT. The inhibitory effect caused by DOI, RO 60-0175, and mCPP was also blocked by previous intra-dPAG injection of the preferential 5-HT2A receptor antagonist ketanserin. Pre-administration of the 5-HT2C receptor antagonist SB-242084 in the dPAG did not block the anti-escape effect of RO 60 0175. CONCLUSIONS: Stimulation of 5-HT2A but not 5-HT2C receptors in the dPAG causes a panicolytic-like effect that is mediated by facilitation of GABAergic neurotransmission. PMID- 21660446 TI - Forequarter amputation as a life-saving procedure. AB - Forequarter amputation is performed for high-grade malignant tumours in the proximal part of the upper extremity with palliative or curative intentions. Two cases are included in this report of patients who presented in need of urgent surgical intervention. Both patients had an actively bleeding, ulcerated or fungating mass and were haemodynamically unstable. The purpose of this report is to highlight the importance of emergency surgical intervention for such selected patients. PMID- 21660448 TI - 5, 7-Dimethoxyflavone sensitizes TRAIL-induced apoptosis through DR5 upregulation in hepatocellular carcinoma cells. AB - PURPOSE: 5, 7-dimethoxyflavone (DMF) has been reported to induce apoptosis in various cancer cells. The aim of this study was to examine whether DMF sensitizes human hepatocellular carcinoma (HCC) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and its mechanism. METHODS: Human hepatocellular carcinoma cell lines Hep3B, Huh-7, and Hep G2 and human embryo liver L-02 cells were cultured in vitro. The cytotoxic activities were determined using MTT assay. The apoptotic cell death was examined using Flow cytometry using PI staining and DNA agarose gel electrophoresis. The activities of caspase-3, caspase-8, and caspase-9 were measured using ELISA. Intracellular ROS was measured by FCM using the fluorescent probe DCHF-DA, and the expression of DR4, DR5, CHOP, GPR78, and ATF4 proteins was analyzed using Western blot. RESULTS: Our results demonstrated subtoxic concentrations of DMF sensitize HCC cells to TRAIL-induced apoptosis and induce the death receptor 5 (DR5) expression level, accompanying the generation of reactive oxygen species (ROS) and the upregulation of CHOP, GPR78, and ATF4 protein expression. Pretreatment with N acetylcysteine (NAC) inhibited DMF-induced upregulation of DR5, CHOP, GPR78, and ATF4 protein expression and blocked the cotreatment-induced apoptosis. Furthermore, DMF-mediated sensitization of HCC cells to TRAIL was reduced by administration of a blocking antibody or small interfering RNAs for DR5, salubrinal, an inhibitor of ER stress, and the small interfering RNAs for CHOP. However, DMF could not induce the upregulation of DR5 expression, generation of ROS, and sensitization of TRAIL-induced apoptotic cell death in human embryo liver L-02 cells or normal human peripheral blood mononuclear cells (PBMCs). CONCLUSION: The present study demonstrates that DMF selectively enhances TRAIL induced apoptosis by ROS-stimulated ER-stress triggering CHOP-mediated DR5 upregulation in HCC. PMID- 21660447 TI - The inhibition of Endostar on the angiogenesis and growth of gastrointestinal stromal tumor xenograft. AB - To investigate whether Endostar can inhibit the angiogenesis and growth of gastrointestinal stromal tumor (GIST) xenografts in nude mice and the feasibility of antiangiogenesis as a treatment modality for GIST. Twenty Balb/c-nu/nu mice burdened with GIST were randomly divided into two groups. Endostar (2 mg/kg) was injected around the tumor once per day for 10 days in the experimental group and with normal saline (NS) (0.1 ml) in the control group. The tumor bulk was measured every 5 days until 5 days after the end of the injections. The inhibition tumor rate (ITR) was calculated. Tumor bulk, microvascular density (MVD), rate of bcl-2-positive expression, and AI were assessed in the two groups. Tumor volumes were compared before and after treatment in the experimental group. The difference in tumor bulk between the two groups was not statistically significant before treatment (P = 0.628), but at the end of test, the difference was significant (P < 0.0001), and in the test group, the tumor bulk was also decreased significantly after treatment (P < 0.0001). The ITR was 86.5%. All xenografts showed CD117-positive staining. MVD and bcl-2-positive rate were lower in the experimental group than in the control group (P = 0.020 and P = 0.023, respectively). AI increased significantly in the experimental group compared with the control group (P = 0.020). Endostar can reduce angiogenesis,promote cell apoptosis, and inhibit the growth of a GIST xenograft. It is possible that Endostar will be used as an effective drug for GIST in the future. PMID- 21660449 TI - Predictors of prolonged drainage of chylothorax after cardiac surgery: single centre study. AB - INTRODUCTION AND AIM OF THE WORK: Chylothorax is a clinical challenge. This study aims at determination of the predictors of prolonged drainage of chylothorax after cardiac surgery in a single tertiary centre in Jeddah, Saudi Arabia. PATIENTS AND METHODS: A retrospective analysis of 52 patients of chylothorax with a mean age of 30 months (range 1 month to 60 years) who developed chylothorax after heart surgery (January 2007-September 2010). Data were collected regarding patients demographics, procedures, chylous drainage and its management, complications and follow-up. RESULTS: There was one hospital mortality. All patients were managed by fat-free diet or Monogen. Lone fat-free diet with steroids were used a in eight patients (15.4%). Somatostatin analogue (Octreotide) was used adjunctively in 7 (13.5%) patients and in two patients (3.8%), steroids and octreotide were used adjunctively. The median duration of chest tube drainage was 10.5 days (range 4-34 days). The median amount of chest tube drainage/kg/day was 18 mL (range 6.6-72 mL). All patients responded to medical treatment except one case who required thoracic duct ligation and a patient who died. The use of octreotide and steroids therapy significantly reduced the amount chest tube drainage. At median follow-up of 12 months (range 1 40 months) after hospital discharge, no recurrence of chylothorax was observed. CONCLUSIONS: Chylothorax is much more common post-pediatric cardiac than post adult cardiac surgery. Conservative therapy of chylothorax after cardiac surgery remains the standard approach. Steroids and or octreotide can be used with an acceptable success. The most significant predictor of prolonged chest tube drainage in chylothorax is triglyceride/cholesterol ratio more than 2. PMID- 21660450 TI - Th17 and Th17-stimulated CD8+ T cells play a distinct role in Th17-induced preventive and therapeutic antitumor immunity. AB - CD4(+) Th17 cells induce antitumor immunity leading to the eradication of established tumors. However, the mechanism of antitumour immunity and CTL activation by Th17 cells and the distinct role of Th17 and Th17-activated CTLs in antitumor immunity are still elusive. In this study, we generated ovalbumin (OVA) specific Th17 cells by cultivating OVA-pulsed dendritic cells with CD4(+) T cells derived from transgenic OTII mice in the presence of IL-6, IL-23, TGF-beta, and anti-IFN-gamma antibody. We demonstrated that Th17 cells acquired major histocompatibility complex/peptide (pMHC)-I and expressed RORgammat, IL-17, and IL-2. Th17 cells did not have any direct in vitro tumor cell-killing activity. However, Th17 cells were able to stimulate CD8(+) CTL responses via IL-2 and pMHC I, but not IL-17 signaling, which play a major role in Th17-induced preventive immunity against OVA-expressing B16 melanoma. Th17 cells stimulated the expression of CCL2 and CCL20 in lung tumor microenvironments promoting the recruitment of various inflammatory leukocytes (DCs, CD4(+), and CD8(+) T cells) stimulating more pronounced therapeutic immunity for early-stage (5-day lung metastases or 3 mm, s.c.) tumor than for well-established (6 mm, s.c.) tumor. The therapeutic effect of Th17 cells is associated with IL-17 and is mediated by Th17 stimulated CD8(+) CTLs and other inflammatory leukocytes recruited into B16 melanoma via Th17-stimulated CCL20 chemoattraction. Taken together, our data elucidate a distinct role of Th17 and Th17-stimulated CD8(+) CTLs in the induction of preventive and therapeutic antitumor immunity, which may greatly impact the development of Th17-based cancer immunotherapy. PMID- 21660451 TI - Serum levels of cytoplasmic melanoma-associated antigen at diagnosis may predict clinical relapse in neuroblastoma patients. AB - The high molecular weight melanoma-associated antigen (HMW-MAA) and the cytoplasmic melanoma-associated antigen (cyt-MAA/LGALS3BP) are expressed in melanoma. Their serum levels are increased in melanoma patients and correlate with clinical outcome. We investigated whether these molecules can serve as prognostic markers for neuroblastoma (NB) patients. Expression of cyt-MAA and HMW MAA was evaluated by flow cytometry in NB cell lines, patients' neuroblasts ((FI) NB), and short-term cultures of these latter cells (cNB). LGALS3BP gene expression was evaluated by RT-qPCR on (FI)-NB, cNB, and primary tumor specimens. Soluble HMW-MAA and cyt-MAA were tested by ELISA. Cyt-MAA and HMW-MAA were expressed in NB cell lines, cNB, and (FI)-NB samples. LGALS3BP gene expression was higher in primary tumors and cNB than in (FI)-NB samples. Soluble cyt-MAA, but not HMW-MAA, was detected in NB cell lines and cNBs supernatants. NB patients' serum levels of both antigens were higher than those of the healthy children. High cyt-MAA serum levels at diagnosis associated with higher incidence of relapse, independently from other known risk factors. In conclusion, both HMW MAA and cyt-MAA antigens, and LGALS3BP gene, were expressed by NB cell lines and patients' neuroblasts, and both antigens' serum levels were increased in NB patients. Elevated serum levels of cyt-MAA at diagnosis correlated with relapse, supporting that cyt-MAA may serve as early serological biomarker to individuate patients at higher risk of relapse that may require a more careful follow-up, after being validated in a larger cohort of patients at different time-points during follow-up. Given its immunogenicity, cyt-MAA may also be a potential target for NB immunotherapy. PMID- 21660452 TI - The Pott's puffy tumor: a dangerous sign for intracranial complications. AB - The Pott's puffy tumor is a subperiosteal abscess of the frontal bone associated with osteomyelitis. The purpose of this article is to alert the physician to the severe complications of this entity. The records of six patients were reviewed retrospectively. There were four adults and two adolescents. Nasal endoscopy showed edematous, polypoid mucosa in middle meatus in three and nasal polyps in the rest. At initial admission, two had orbital subperiosteal abscess, but normal cranial CT findings. During hospitalization, three experienced frontal lobe abscess and one frontal cerebritis. Endoscopic sinus surgery was performed in all with external drainage of Pott's puffy tumor in addition to antibiotherapy. Three patients underwent craniotomy/craniectomy for removal of frontal lobe abscesses. One patient with frontal lobe abscess died. Pott's puffy tumor may result in potentially dangerous intracranial complications. Early diagnosis and treatment are essential to reduce morbidity and mortality. PMID- 21660453 TI - The coping flexibility questionnaire: development and initial validation in patients with chronic rheumatic diseases. AB - Coping flexibility may be beneficial for the adjustment in the context of a progressive and unpredictable course of chronic rheumatic diseases. The aim of this study was to develop and initially validate a self-report measure that assesses coping flexibility. Study participants were 147 outpatients with chronic rheumatic diseases (73% women, mean age 59 (range 20-79) years). Principal axis factoring analysis with oblique rotation was applied and internal consistency was determined. To investigate the initial validity of the coping flexibility questionnaire (COFLEX), hypothesised correlations with psychological and physical adjustment outcomes, pain, and coping strategies were examined. Factor analysis yielded a two-factor model of coping flexibility with acceptable internal consistency: versatility, the capability of switching between assimilative and accommodative coping strategies according to personal goals and situational demands (alpha = .88) and reflective coping, the capability of generating and considering coping options, and appraising the suitability of a coping strategy in a given situation (alpha = .70). Versatility was correlated with adaptive ways of coping and psychological adjustment, but not with physical adjustment and pain. Reflective coping was correlated with both adaptive and maladaptive ways of coping, but it was not correlated with adjustment outcomes. In conclusion, the current study suggests acceptable internal consistency of the COFLEX. Preliminary evidence of the validity of the versatility dimension is indicated, while the validity of reflective coping could not be firmly established. The associations of versatility with favourable adjustment to the disease warrant future confirmatory and validity research in larger samples of patients with chronic rheumatic diseases. PMID- 21660455 TI - Characterization of alpha/beta- and gamma-gliadins in commercial varieties and breeding lines of durum wheat using MALDI-TOF and A-PAGE gels. AB - In this work, gliadin composition has been analyzed in 33 accessions of durum wheat using MALDI-TOF MS and compared with A-PAGE results. The MALDI-TOF MS spectra were 29,900-42,500 Da, which corresponds to the alpha/beta- and gamma gliadin regions in A-PAGE. The average of gliadin peaks per line was 23 for MALDI TOF MS and only 14.8 bands for A-PAGE. MALDI-TOF MS identified 33 gliadin peaks in the durum wheat collection, 20 of which were unique peaks present in 7 lines. A-PAGE analysis identified 30 bands, of which only 4 were unique. Thus, the MALDI TOF MS method was more sensitive than A-PAGE for identifying alpha/beta- and gamma-gliadins in the 33 durum wheat lines studied. Phylogenetic analyses performed using MALDI-TOF MS data assigned the durum wheat lines to two groups. The utility of MALDI-TOF MS to determine relationships among genotypes and for identification of durum wheat accessions is discussed. PMID- 21660454 TI - Association of secondhand smoke exposures with DNA methylation in bladder carcinomas. AB - BACKGROUND: The association between secondhand smoke (SHS) exposure and bladder cancer is inconclusive. Epigenetic alterations in bladder tumors have been linked to primary cigarette smoking and could add to the biological plausibility of an association between SHS exposure and bladder cancer. HYPOTHESIS: SHS exposure is associated with DNA methylation in bladder tumors. METHODS: Using an array-based approach, we profiled DNA methylation from never smoking cases of incident bladder cancer. Analyses examined associations between individual loci's methylation with SHS variables (exposure in adulthood, childhood, occupationally, and total exposure). A canonical pathway analysis was used to find pathways significantly associated with each SHS exposure type. RESULTS: There is a trend toward increased methylation of numerous CpG loci with increasing exposure to adulthood, occupational, and total SHS. Discrete associations between methylation extent of several CpG loci and SHS exposures demonstrated significantly increased methylation of these loci across all types of SHS exposure. CpGs with SHS-related methylation alterations were associated with genes in pathways involved in carcinogenesis, immune modulation, and immune signaling. INTERPRETATION: Exposures to SHS in adulthood, childhood, occupationally, and in total are each significantly associated with changes in DNA methylation of several CpG loci in bladder tumors, adding biological plausibility to SHS as a risk factor for bladder cancer. PMID- 21660456 TI - Histological characterization of gonadotropin-releasing hormone (GnRH) in the hypothalamus of the South American plains vizcacha (Lagostomus maximus). AB - In contrast to most mammalian species, females of the South American plains vizcacha, Lagostomus maximus, show an extensive suppression of apoptosis dependent follicular atresia, continuous folliculogenesis, and massive polyovulation. These unusual reproductive features pinpoint to an eventual peculiar modulation of the hypothalamo-hypophyseal-gonadal axis through its main regulator, the gonadotropin-releasing hormone (GnRH). We explored the hypothalamic histological landscape and cellular and subcellular localization of GnRH in adult non-pregnant L. maximus females. Comparison to brain atlases from mouse, rat, guinea pig and chinchilla enabled us to histologically define and locate the preoptic area (POA), the ventromedial nucleus, the median eminence (ME), and the arcuate nucleus (Arc) of the hypothalamus in vizcacha's brain. Specific immunolocalization of GnRH was detected in soma of neurons at medial POA (MPA), ventrolateral preoptic nucleus, septohypothalamic nucleus (SHy) and Arc, and in beaded fibers of MPA, SHy, ventromedial hypothalamic nucleus, anterior hypothalamic area and ME. Electron microscopy examination revealed GnRH associated to cytoplasmic vesicles of the ME and POA neurons, organized both in core and non-core vesicles within varicosities, and in neurosecretory vesicles within the myelinated axons of the MPA. Besides the peculiar and unusual features of folliculogenesis and ovulation in the vizcacha, these results show that hypothalamus histology and GnRH immune-detection and localization are comparable to those found in other mammals. This fact leads to the possibility that specific regulatory mechanisms should be in action to maintain continuous folliculogenesis and massive polyovulation. PMID- 21660457 TI - In vitro cultured primary cells from a human utricle explant possesses hair cell like characteristics. AB - The utricle is the enlarged portion of the membranous labyrinth of the inner ear and is essential for balance. It comprises of fine hair cells (mechanoreceptors), supporting cells and calcareous otoliths. Utricle cells are considered to be post mitotic and possess a limited capacity for regeneration. Unlike birds and reptiles, mammalian mechanosensory hair cells do not regenerate. The in vitro culture of primary cells from the utricle and other inner ear structures of mammals have proven difficult. Presented here for the first time is the culture of primary cells derived from an explant of an adult human utricle, without any intervention or manipulation. Cells were proliferative until cellular quiescence occurred during passage six. Cell morphology was atypical of epithelial cells, appearing as a homogenous, slightly elongated population. Analysis of cultured utricle cells by immunofluorescent staining (IF) and reverse transcriptase polymerase chain reaction (RT-PCR) have shown these cells to possess epithelial (Epithelium-specific ets-1 (ESE-1)), supporting hair cell (p27(Kip1)), and hair cell specific (Atoh1 and Myosin VI) markers. Additionally, RT-PCR revealed positive gene expression for the proliferation control marker fibroblast growth factor receptor 1 (FGFR1) and negative gene expression for E-cadherin (CDH1), a vestibular cell differentiation marker. PMID- 21660458 TI - Influence of preoperative leg pain and radiculopathy on outcomes in mono segmental lumbar total disc replacement: results from a nationwide registry. AB - PURPOSE: Currently, many pre-conditions are regarded as relative or absolute contraindications for lumbar total disc replacement (TDR). Radiculopathy is one among them. In Switzerland it is left to the surgeon's discretion when to operate if he adheres to a list of pre-defined indications. Contraindications, however, are less clearly specified. We hypothesized that, the extent of pre-operative radiculopathy results in different benefits for patients treated with mono segmental lumbar TDR. We used patient perceived leg pain and its correlation with physician recorded radiculopathy for creating the patient groups to be compared. METHODS: The present study is based on the dataset of SWISSspine, a government mandated health technology assessment registry. Between March 2005 and April 2009, 577 patients underwent either mono- or bi-segmental lumbar TDR, which was documented in a prospective observational multicenter mode. A total of 416 cases with a mono-segmental procedure were included in the study. The data collection consisted of pre-operative and follow-up data (physician based) and clinical outcomes (NASS form, EQ-5D). A receiver operating characteristic (ROC) analysis was conducted with patients' self-indicated leg pain and the surgeon-based diagnosis "radiculopathy", as marked on the case report forms. As a result, patients were divided into two groups according to the severity of leg pain. The two groups were compared with regard to the pre-operative patient characteristics and pre- and post-operative pain on Visual Analogue Scale (VAS) and quality of life using general linear modeling. RESULTS: The optimal ROC model revealed a leg pain threshold of 40 <= VAS > 40 for the absence or the presence of "radiculopathy". Demographics in the resulting two groups were well comparable. Applying this threshold, the mean pre-operative leg pain level was 16.5 points in group 1 and 68.1 points in group 2 (p < 0.001). Back pain levels differed less with 63.6 points in group 1 and 72.6 in group 2 (p < 0.001). Pre-operative quality of life showed considerable differences with an 0.44 EQ-5D score in group 1 and 0.29 in group 2 (p < 0.001, possible score range -0.6 to 1). At a mean follow-up time of 8 months, group 1 showed a mean leg pain improvement of 3.6 points and group 2 of 41.1 points (p < 0.001). Back pain relief was 35.6 and 39.1 points, respectively (p = 0.27). EQ-5D score improvement was 0.27 in group 1 and 0.41 in group 2 (p = 0.11). CONCLUSIONS: Patients labeled as having radiculopathy (group 2) do mostly have pre-operative leg pain levels >= 40. Applying this threshold, the patients with pre-operative leg pain do also have more severe back pain and a considerably lower quality of life. Their net benefit from the lumbar TDR is higher and they do have similar post-operative back and leg pain levels as well as the quality of life as patients without pre-operative leg pain. Although randomized controlled trials are required to confirm these findings, they put leg pain and radiculopathy into perspective as absolute contraindications for TDR. PMID- 21660460 TI - Acute effects of firefighting on cardiac performance. AB - This study examined standard echocardiographic measures of cardiac size and performance in response to a 3-h firefighting training exercise. Forty experienced male personnel completed a standardized 3 h live firefighting exercise. Before and after the firefighting activities, participants were weighed, height, heart rate, blood pressure and blood samples were obtained, and echocardiographic measurements were made. Firefighting produced significant decreases in left ventricular diastolic dimension, stroke volume, fractional shortening, and mitral E velocity, tachycardia, a rise in core temperature, and a reduction in calculated plasma volume. On tissue Doppler imaging, there were no changes in systolic contractile function, but a decreased lateral wall diastolic velocity was observed. These findings show that 3 h of live firefighting produced cardiac changes consistent with cardiac fatigue, coupled with a decrease in systemic arterial compliance. These data show that live firefighting produces significant cardiovascular changes and future work is needed to evaluate if these changes are related to the increase in cardiovascular risk during live firefighting. PMID- 21660461 TI - Microstructural changes following inadvertent multi-spot laser photocoagulation of the fovea. PMID- 21660459 TI - Improving the diagnosis of tuberculosis: From QuantiFERON to new techniques to diagnose tuberculosis infections. AB - The diagnosis of latent and active tuberculosis in the HIV-positive population is challenged by diminished sensitivity of conventional tests, atypical presentations, and the lack of culture methods in the developing world, where the burden of co-infection is greatest. In response to these challenges, a variety of new diagnostics have emerged. These include interferon-gamma release assays for the diagnosis of latent tuberculosis (TB) infection and novel culture methods and molecular assays for the diagnosis of active tuberculosis. Although some tests (such as interferon-gamma release assays) are not clearly superior to existing diagnostics, other novel diagnostics, such as real-time polymerase chain reaction and the microscopic observed direct susceptibility assay hold much promise for prompt and accurate TB diagnosis in this population. Line-probe, nitrate reductase, and mycobacteriophage assays have also provided rapid alternatives to conventional time-consuming drug susceptibility testing and are critical to curtailing the spread of multidrug-resistant TB. PMID- 21660462 TI - Angiotensin II downregulates catalase expression and activity in vascular adventitial fibroblasts through an AT1R/ERK1/2-dependent pathway. AB - Angiotensin II (Ang II) plays a profound regulatory effect on NADPH oxidase and the functional features of vascular adventitial fibroblasts, but its role in antioxidant enzyme defense remains unclear. This study investigated the effect of Ang II on expressions and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in adventitial fibroblasts and the possible mechanism involved. Ang II decreased the expression and activity of CAT in a dose- and time-dependent manner, but not that of SOD and GPx. The effects were abolished by the angiotensin II type 1 receptor (AT1R) blocker losartan and AT1R small-interfering RNA (siRNA). Incubation with polyethylene glycol-CAT prevented the Ang II-induced effects on reactive oxygen species (ROS) generation and myofibroblast differentiation. Moreover, Ang II rapidly induced phosphorylation of ERK1/2, which was reversed by losartan and AT1R siRNA. Pharmacological blockade of ERK1/2 improved Ang II-induced decrease in CAT protein expression. These in vitro results indicate that Ang II induces ERK1/2 activation, contributing to the downregulation of CAT as well as promoting oxidative stress and adventitial fibroblast phenotypic differentiation in an AT1R mediated manner. PMID- 21660463 TI - ARF triggers cell G1 arrest by a P53 independent ERK pathway. AB - In this study, in order to investigate the p53-independent function of p14ARF, we established p14ARF-inducible clones in the p53-deficient HCT cell line using the doxycycline-inducible expression system. A strong cell growth inhibition and G1/S arrest were observed after doxycycline induction in p53-/-HCT cells, and the cells also exhibited an obvious decrease of DNA synthesis. We further examined if the MEK/ERK pathway is involved in the G1 arrest induced by p14ARF in p53-/-HCT cells. The results indicate that ERK1/2 and p21 were activated upon p14ARF induction. Totally, the functional roles of ERK and p21 for ARF in p53 independent tumor suppression were demonstrated. PMID- 21660464 TI - Direct evidence of abca1-mediated efflux of cholesterol at the mouse blood-brain barrier. AB - We investigated the expression and function of Abca1 in wild-type C57BL/6, abca1(+/+), and abca1(-/-) mice brain capillaries forming the blood-brain barrier (BBB). We first demonstrated by quantitative RT-PCR and Western immunoblot that Abca1 was expressed and enriched in the wild-type mouse brain capillaries. In abca1(-/-) mice, we reported that the lack of Abca1 resulted in an 1.6-fold increase of the Abcg4 expression level compared to abca1(+/+) mice. Next, using the in situ brain perfusion technique, we showed that the [(3)H]cholesterol brain uptake clearance (Cl(up), MUl/s/g brain), was significantly increased (107%) in abca1(-/-) mice compared to abca1(+/+) mice, meaning that the deficiency of Abca1 conducted to a significant decrease of the cholesterol efflux at the BBB level. In addition, the co-perfusion of probucol (Abca1 inhibitor) with [(3)H]cholesterol resulted in an increase of [(3)H]cholesterol Cl(up) (115%) in abca1(+/+) but not in abca1(-/-) mice, meaning that probucol inhibited selectively the efflux function of Abca1. In conclusion, our results demonstrated that Abca1 was expressed in the mouse brain capillaries and that Abca1 functions as an efflux transporter through the mouse BBB. PMID- 21660465 TI - Spatial priming in visual search: memory for body-centred information. AB - Spatial priming allows memory for target locations to be evaluated, whereby when a target appears in the same location across trials, participants become more efficient at locating it and consequently their search times decrease. Previously, we reported priming effects when the location of a target was repeated with respect to the participant's body but not when it was repeated relative to their eye position; therefore, suggesting that body-centred information is available after a delay of at least a few seconds (Ball et al. in Exp Brain Res 204:585-594, 2010). However, we were unable to rule out the possibility that stable allocentric cues within the room may have contributed to the priming effects that we observed. In this current study, we introduced a condition where despite participants moving to a new location between trials, their position relative to the target was maintained. This movement disrupted any potential room-based cues about the target location. While we replicated our previous finding of priming when the location of the target was repeated relative to the viewer when no movement was required, we also found robust priming effects when participants moved to a new location in between trials. Thus, we provide clear evidence that in our spatial priming task, the location of the target was being coded in a body-centred reference frame and that this information is available after a delay. PMID- 21660466 TI - The time course of online trajectory corrections in memory-guided saccades. AB - Recent investigations have revealed the kinematics of horizontal saccades are less variable near the end of the trajectory than during the course of execution. Converging evidence indicates that oculomotor networks use online sensorimotor feedback to correct for initial trajectory errors. It is also known that oculomotor networks express saccadic corrections with decreased efficiency when responses are made toward memorized locations. The present research investigated whether repetitive motor timekeeping influences online feedback-based corrections in predictive saccades. Predictive saccades are a subclass of memory-guided saccades and are observed when one makes series of timed saccades. We hypothesized that cueing predictive saccades in a sequence would facilitate the expression of trajectory corrections. Seven participants produced a number of single unpaced, visually guided saccades, and also sequences of timed predictive saccades. Kinematic and trajectory variability were used to measure the expression of online saccadic corrections at a number of time indices in saccade trajectories. In particular, we estimated the minimum time required to implement feedback-based corrections, which was consistently 37 ms. Our observations demonstrate that motor commands in predictive memory-guided saccades can be parameterized by spatial working memory and retain the accuracy of online trajectory corrections typically associated with visually guided behavior. In contrast, untimed memory-guided saccades exhibited diminished kinematic evidence for online corrections. We conclude that motor timekeeping and sequencing contributed to efficient saccadic corrections. These results contribute to an evolving view of the interactions between motor planning and spatial working memory, as they relate to oculomotor control. PMID- 21660467 TI - The effect of visual spatial attention on audiovisual speech perception in adults with Asperger syndrome. AB - Individuals with Asperger syndrome (AS) have problems in following conversation, especially in the situations where several people are talking. This might result from impairments in audiovisual speech perception, especially from difficulties in focusing attention to speech-relevant visual information and ignoring distracting information. We studied the effect of visual spatial attention on the audiovisual speech perception of adult individuals with AS and matched control participants. Two faces were presented side by side, one uttering /aka/ and the other /ata/, while an auditory stimulus of /apa/ was played. The participants fixated on a central cross and directed their attention to the face that an arrow pointed to, reporting which consonant they heard. We hypothesized that the adults with AS would be more distracted by a competing talking face than the controls. Instead, they were able to covertly attend to the talking face, and they were as distracted by a competing face as the controls. Independently of the attentional effect, there was a qualitative difference in audiovisual speech perception: when the visual articulation was /aka/, the control participants heard /aka/ almost exclusively, while the participants with AS heard frequently /ata/. This finding may relate to difficulties in face-to-face communication in AS. PMID- 21660468 TI - Epilepsy and menopause. AB - INTRODUCTION: Epilepsy and menopause have complicated interactions. Treatment of epilepsy may cause exacerbation of osteoporosis and alter the effects of hormone replacement therapy (HRT) whereas HRT may influence the frequency of seizures. MATERIALS AND METHODS: An extensive search was performed in the Cochrane Central Trials Registry, the Web of Science, and PubMed for publications using the keywords "(epilepsy OR Seizure) AND (menopause OR osteoporosis)"; "Anti-epileptic drugs AND (menopause OR osteoporosis); HRT AND epilepsy" between 1970 and 2010 and English language. All eligible trials were included. CONCLUSION: The frequency of catamenial type of epileptic seizures may increase during perimenopause due to hyperestrogenism and subside after menopause. Sexual dysfunction can be severe depending upon the effect of lack of estrogen in menopause and epilepsy itself. Osteoporosis and fractures may increase due to hypoestrogenism in menopause and cytochrome P450 inducing anti-epileptic drugs. According to the current data, conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate may increase the frequency of epileptic seizures. Women with epilepsy may need to take HRT, at least for symptomatic relief and to allow adequate sleep when "hot flushes" are disruptive. A combination of a single estrogenic compound such as 17-beta-estradiol along with natural progesterone could be considered in these patients. PMID- 21660469 TI - Are performance-based measures predictive of work participation in patients with musculoskeletal disorders? A systematic review. AB - OBJECTIVE: Assessments of whether patients with musculoskeletal disorders (MSDs) can participate in work mainly consist of case history, physical examinations, and self-reports. Performance-based measures might add value in these assessments. This study answers the question: how well do performance-based measures predict work participation in patients with MSDs? METHODS: A systematic literature search was performed to obtain longitudinal studies that used reliable performance-based measures to predict work participation in patients with MSDs. The following five sources of information were used to retrieve relevant studies: PubMed, Embase, AMA Guide to the Evaluation of Functional Ability, references of the included papers, and the expertise and personal file of the authors. A quality assessment specific for prognostic studies and an evidence synthesis were performed. RESULTS: Of the 1,230 retrieved studies, eighteen fulfilled the inclusion criteria. The studies included 4,113 patients, and the median follow-up period was 12 months. Twelve studies took possible confounders into account. Five studies were of good quality and thirteen of moderate quality. Two good-quality and all thirteen moderate-quality studies (83%) reported that performance-based measures were predictive of work participation. Two good-quality studies (11%) reported both an association and no association between performance-based measures and work participation. One good-quality study (6%) found no effect. A performance-based lifting test was used in fourteen studies and appeared to be predictive of work participation in thirteen studies. CONCLUSIONS: Strong evidence exists that a number of performance-based measures are predictive of work participation in patients with MSDs, especially lifting tests. Overall, the explained variance was modest. PMID- 21660470 TI - Imprinting analysis of porcine DIO3 gene in two fetal stages and association analysis with carcass and meat quality traits. AB - Imprinted genes play important roles in mammalian growth, development and behavior. In this study, we obtained 1568 bp mRNA sequence of porcine DIO3 (deiodinase, iodothyronine, type III), and also identified its imprinting status during porcine fetal development. The complete open reading frame (ORF) encoding 278 amino acids. The porcine DIO3 mRNA was expressed predominantly in backfat, mildly in liver, uterus, kidney, heart, small intestine, muscle and stomach, and almost absent in spleen and lung. A single nucleotide polymorphism in exon (A/C (687)) was used to investigate the allele frequencies in different pig breeds and the imprinting status in porcine embryonic tissues. The results indicate that DIO3 was imprinted in all the tested tissues. Statistical analysis showed the DIO3 gene polymorphism was significantly associated with almost all the fat deposition and carcass traits, including lean meat percentage (LMP), fat meat percentage (FMP), ratio of lean to fat (RLF), shoulder fat thickness (SFT), sixth seventh rib fat thickness (RFT), buttock fat thickness (BFT), loin eye area (LEA), and intramuscular fat (IMF). PMID- 21660471 TI - Molecular and physiological strategies to increase aluminum resistance in plants. AB - Aluminum (Al) toxicity is a primary limitation to plant growth on acid soils. Root meristems are the first site for toxic Al accumulation, and therefore inhibition of root elongation is the most evident physiological manifestation of Al toxicity. Plants may resist Al toxicity by avoidance (Al exclusion) and/or tolerance mechanisms (detoxification of Al inside the cells). The Al exclusion involves the exudation of organic acid anions from the root apices, whereas tolerance mechanisms comprise internal Al detoxification by organic acid anions and enhanced scavenging of free oxygen radicals. One of the most important advances in understanding the molecular events associated with the Al exclusion mechanism was the identification of the ALMT1 gene (Al-activated malate transporter) in Triticum aestivum root cells, which codes for a plasma membrane anion channel that allows efflux of organic acid anions, such as malate, citrate or oxalate. On the other hand, the scavenging of free radicals is dependent on the expression of genes involved in antioxidant defenses, such as peroxidases (e.g. in Arabidopsis thaliana and Nicotiana tabacum), catalases (e.g. in Capsicum annuum), and the gene WMnSOD1 from T. aestivum. However, other recent findings show that reactive oxygen species (ROS) induced stress may be due to acidic (low pH) conditions rather than to Al stress. In this review, we summarize recent findings regarding molecular and physiological mechanisms of Al toxicity and resistance in higher plants. Advances have been made in understanding some of the underlying strategies that plants use to cope with Al toxicity. Furthermore, we discuss the physiological and molecular responses to Al toxicity, including genes involved in Al resistance that have been identified and characterized in several plant species. The better understanding of these strategies and mechanisms is essential for improving plant performance in acidic, Al-toxic soils. PMID- 21660472 TI - Molecular cloning and expression analysis of CmMlo1 in melon. AB - Mlo gene encodes an important transmembrane protein that is involved in biotic/abiotic stresses. Using the method of homologous, we cloned a Mlo gene from melon, named CmMlo1. The gene is 1551 bp in length, encoding 516 amino acids; it has seven-transmembrane domain topology and is a typical transmembrane protein. Localization analysis in onion epidermal cells showed that CmMlo1-GFP is localized to the plasma membrane. RT-PCR results indicated that CmMlo1 is mainly expressed in melon cotyledon and flower, with a tissue-specific distribution manner. CmMlo1 expression is not obvious under powdery mildew stress, but under cadmium stress, its expression was significantly up-regulated, indicating that CmMlo1 is possibly involved in abiotic stress. PMID- 21660473 TI - Effects of different starch sources on Bacillus spp. in intestinal tract and expression of intestinal development related genes of weanling piglets. AB - The study was conducted to evaluate the effects of different starch sources on Bacillus spp. in intestinal tract and expression of intestinal development related genes of weanling piglets. Twenty-eight PIC male piglets were divided into four homogeneous groups according to initial body weight (similar birth and parity, weaned at 21 +/- 1.5 days). Diets for the four treatments consisted of corn starch, wheat starch, tapioca starch and pea starch with the determined ratio for amylose to amylopectin of 0.21, 0.24, 0.12 and 0.52 respectively. Real time quantitative polymerase chain reaction was applied to: (1) detect genomic DNA of Bacillus and to quantify the number of Bacillus in the intestinal tract chyme of piglets with the primers and probe which designed based on the 16S rRNA sequences of maximum species of Bacillus on GenBank; (2) measure the mRNA level of glucagon-like peptide 2 (GLP-2), insulin-like growth factors 1 (IGF-1) and epidermal growth factor (EGF) in duodenum, jejunum and ileum. Results showed that the number of Baciilus and the percentage based on all bacteria in the whole intestinal content of piglets fed pea starch was highest in all groups (P < 0.05). There was no significant differance on copy numbers for all bacteria and Bacillus in the whole intestinal tract of piglets between the corn starch group and wheat starch group (P > 0.05). In addition, the expression level of GLP-2, IGF-1 mRNA in jejunum and ileum of pea starch treatment (the high amylose/amylopectin ratio) were increased while the tapioca starch decreased their mRNA level significantly compared to other three treatments (P < 0.05). There was no significant difference for the mRNA level of EGF in each group. The present study revealed that high amylose/amylopectin ratio of starches significantly enhanced the numbers of Bacillus in all segments of intestine and the mRNA level of intestinal development related genes. PMID- 21660474 TI - Cloning and characterization of boron transporters in Brassica napus. AB - Six full-length cDNA encoding boron transporters (BOR) were isolated from Brassica napus (AACC) by rapid amplification of cDNA ends (RACE). The phylogenic analysis revealed that the six BORs were the orthologues of AtBOR1, which formed companying with the triplication and allotetra-ploidization process of B. napus, and were divided into three groups in B. napus. Each group was comprised of two members, one of which was originated from Brassica rapa (AA) and the other from Brassica oleracea (CC). Based on the phylogenetic relationships, the six genes were named as BnBOR1;1a, BnBOR1;1c, BnBOR1;2a, BnBOR1;2c, BnBOR1;3a and BnBOR1;3c, respectively. The deduced BnBOR1 s had extensive similarity with other plant BORs, with the identity of 74-96.8% in amino acid sequence. The BnBOR1;3a and BnBOR1;3c resembled AtBOR1 in number and positions of the 11 introns, but the others only have 9 introns. After the gene duplication, there was evidence of purifying selection under a divergent selective pressure. The expression patterns of the six BnBOR1 s were detected by semi-quantitative RT-PCR. The BnBOR1;3a and BnBOR1;3c showed a ubiquitous expression in all of the investigated tissues, whereas the other four genes showed similar tissue-specific expression profile. Unlike the non-transcriptional regulation of AtBOR1, the expression of BnBOR1;1c and BnBOR1;2a were obviously induced by boron deficiency. This study suggested that the BOR1 s had undergone a divergent expression pattern in the genome of B. napus after that the B. napus diverged from Arabidopsis thaliana. PMID- 21660475 TI - Identification and characterization of the pumilio-2 expressed in zebrafish embryos and adult tissues. AB - Pumilio proteins regulate the translation of specific proteins required for germ cell development and morphogenesis. In the present study, we have identified the pumilio-2 in zebrafish and analyze its expression in adult tissues and early embryos. Pumilio-2 codes for the full-length Pumilio-2 protein and contains a PUF domain. When compared to the mammalian and avian Pumilio-2 proteins, zebrafish Pumilio-2 protein was found to contain an additional sequence of 24 amino acid residues within the PUF-domain. Zebrafish pumilio-2 mRNA is expressed in the ovary, testis, liver, kidney and brain but is absent in the heart and muscle as detected by RT-PCR. The results of in situ hybridization indicate that transcripts of pumilio-2 are distributed in all blastomeres from the 1-cell stage to the sphere stage and accumulate in the head and tail during the 60%-epiboly and 3-somite stages. Transcripts were also detected in the brain and neural tube of the 24 h post-fertilization (hpf) embryos. Western blot analyses indicate that the Pumilio-2 protein is strongly expressed in the ovary, testis and brain but not in other tissues. These data suggest that pumilio-2 plays an important role in the development of the zebrafish germ cells and nervous system. PMID- 21660476 TI - [Pathological work-up of rectal cancer following partial/total mesorectal excision]. AB - Total mesorectal excision (TME) refers to the anatomically accurate surgical resection of the rectum from its surrounding fascias and has become the gold standard for treating rectal cancer. The pathologist plays a key role in the assessment of these specimens and good pathological reporting of rectal cancer is essential to achieving the optimum possible results for patients with rectal cancer. In experienced hands, these techniques result in a dramatic improvement in cancer-related cure rates from 45% to 75% and a reduction in pelvic recurrences from 40% to 5%-10%. Moreover, preservation of sexual and urinary functions is possible in the majority of cases. This article reviews the pathological assessment of the TME specimen in detail with regards to current international guidelines and describes its anatomical background. In addition, particular issues relating to margins, lymph node dissection and effects of neoadjuvant therapy are discussed. PMID- 21660477 TI - [Polypoid dysplasia in inflammatory bowel disease: differential diagnosis and further diagnostic and therapeutic approaches]. AB - Polypoid dysplasia in inflammatory bowel disease (IBD) is categorized as DALM (dysplasia associated lesion or mass) or ALM (adenoma-like mass). DALMs are etiologically related to the underlying inflammatory disease, have a high risk of cancer and remain an indication for colectomy. Sporadic adenomas occur coincidentally according to the adenoma-carcinoma sequence. They are adequately treated by polypectomy. More recently, a special group of lesions has been termed as "adenoma-like DALM" which shows a morphological overlap with sporadic adenomas in spite of arising against the background of chronic IBD. Adenoma-like DALMs may possess a lower risk of malignancy in contrast to non-adenoma-like DALMs. They may be treated adequately by polypectomy and continued monitoring if the lesion has been excised completely and there is no evidence of flat dysplasia elsewhere in the colon. PMID- 21660478 TI - [Microscopic colitis: histopathological review with a clinicopathological correlation]. AB - Microscopic colitis is a clinicopathological entity which, in addition to typical symptoms such as watery diarrhea, is characterized by its specific histopathology. Since colonoscopy yields normal findings, microscopic colitis belongs in a histological domain. The term encompasses two forms: lymphocytic and collagenous colitis. Histologically, lymphocytic colitis shows an increase in intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colonocytes, while collagenous colitis is characterized by a thickened subepithelial collagen layer of more than 10 um. Specific stains help in the quantification of both. Since microscopic colitis does not always affect the entire colon and the number of intraepithelial lymphocytes varies physiologically, obtaining stepwise biopsies of the colon (with information on location where possible) is recommended. A thickened collagen layer is relatively specific for collagenous colitis, whereas intraepithelial lymphocytosis is also found in other diseases. Therefore, to make a correct diagnosis, it is important to correlate histological findings with clinical symptoms, including the main symptom of watery diarrhea. PMID- 21660479 TI - Thromboembolism prophylaxis with dabigatran leads to lower perioperative blood loss than with dalteparin in primary knee arthroplasty. AB - INTRODUCTION: Low-molecular-weight heparins (LMWH) are commonly used in thrombosis prophylaxis after total knee arthroplasty. In contrast to LMWH, dabigatran etexilate is an oral and direct acting anticoagulant. The hypothesis of the present study was that blood loss occurring in total knee arthroplasty (TKA) is not greater after dabigatran etexilate than after dalteparin. METHOD: All patients suffering from primary arthrosis of knee joint that had received a total knee arthroplasty were included in this retrospective case-control study. Two groups were formed (dalteparin versus dabigatran etexilate) and the perioperative blood loss was compared using the formula of Nadler (V = EBV * ln (Hct(0)/Hct(1)) [V = blood loss (l); EBV = blood volume (l); Hct(0) = preoperative haematocrit; Hct(1) = haematocrit on the first postoperative day]. PATIENTS: A total of 155 patients, 61 men and 94 women, were included. The calculated blood loss differed significantly between the two groups. The blood loss was on average 1.5 +/- 0.58 l [0.32-2.9 l] in the dalteparin group, compared with 1.3 +/- 0.63 l [0.29-4.31 l] in the dabigatran etexilate group (p < 0.01). None of the patients of both observed groups showed clinical signs of thrombosis or pulmonary artery embolism. RESULTS: Dabigatran etexilate showed a lower perioperative blood loss than dalteparin by comparable safety of both drugs. CONCLUSION: Whether the timing of administration or pharmacological factors were responsible for this cannot be explained by our study. PMID- 21660480 TI - Septic arthritis of the hip in patients with femoral head osteonecrosis. AB - Septic hip is rare in patients with femoral head osteonecrosis (FHON) and has been known to occur in those who are immune compromised. Thus, surgeons do not concern about the superimposed septic hip in immunocompetent patients. We report five patients who had FHON and concomitant septic arthritis of the hip. No patients were immune compromised. All patients had an elevation of ESR and CRP. Two patients had an otherwise unexplained fever preoperatively. Two patients had had a remote septic focus. When a patient with FHON has an unexplained elevation of ESR and CRP, concomitant septic arthritis of the hip should be suspected even though the patient is not immune compromised. PMID- 21660481 TI - A sweetpotato SRD1 promoter confers strong root-, taproot-, and tuber-specific expression in Arabidopsis, carrot, and potato. AB - Harvestable, starch-storing organs of plants, such as fleshy taproots and tubers, are important agronomic products that are also suitable target organs for use in the molecular farming of recombinant proteins due to their strong sink strength. To exploit a promoter directing strong expression restricted to these storage organs, we isolated the promoter region (3.0 kb) of SRD1 from sweetpotato (Ipomoea batatas cv. 'White Star') and characterized its activity in transgenic Arabidopsis, carrot, and potato using the beta-glucuronidase (GUS) gene (uidA) as a reporter gene. The SRD1 promoter conferred root-specific expression in transgenic Arabidopsis, with SRD1 promoter activity increasing in response to exogenous IAA. A time-course study of the effect of IAA (50 MUM) revealed a maximum increase in SRD1 promoter activity at 24 h post-treatment initiation. A serial 5' deletion analysis of the SRD1 promoter identified regions related to IAA-inducible expression as well as regions containing positive and negative elements, respectively, controlling the expression level. In transgenic carrot, the SRD1 promoter mediated strong taproot-specific expression, as evidenced by GUS staining being strong in almost the entire taproot, including secondary phloem, secondary xylem and vascular cambium. The activity of the SRD1 promoter gradually increased with increasing diameter of the taproot in the transgenic carrot and was 10.71-fold higher than that of the CaMV35S promoter. The SRD1 promoter also directed strong tuber-specific expression in transgenic potato. Taken together, these results demonstrate that the SRD1 promoter directs strong expression restricted to the underground storage organs, such as fleshy taproots and tubers, as well as fibrous root tissues. PMID- 21660482 TI - Learning and transfer of category knowledge in an indirect categorization task. AB - Knowledge representations acquired during category learning experiments are 'tuned' to the task goal. A useful paradigm to study category representations is indirect category learning. In the present article, we propose a new indirect categorization task called the "same"-"different" categorization task. The same different categorization task is a regular same-different task, but the question asked to the participants is about the stimulus category membership instead of stimulus identity. Experiment 1 explores the possibility of indirectly learning rule-based and information-integration category structures using the new paradigm. The results suggest that there is little learning about the category structures resulting from an indirect categorization task unless the categories can be separated by a one-dimensional rule. Experiment 2 explores whether a category representation learned indirectly can be used in a direct classification task (and vice versa). The results suggest that previous categorical knowledge acquired during a direct classification task can be expressed in the same different categorization task only when the categories can be separated by a rule that is easily verbalized. Implications of these results for categorization research are discussed. PMID- 21660483 TI - The homophone effect during visual word recognition in children: an fMRI study. AB - Functional magnetic resonance imaging was used to investigate the role of phonology in visual word recognition (VWR). A group of children between the ages of 7 and 13 participated in a lexical decision task in which lexical frequency and homophony were manipulated. A significant homophone effect was observed for the high-frequency condition, indicating that phonology does indeed play a significant role in VWR. The brain activation patterns also support this idea in that regions that have been linked to phonological processing, the inferior frontal gyrus and the inferior parietal lobe, also revealed a homophone effect. Additionally, the posterior superior temporal cortex showed a homophone effect; however, this activation is argued to be related to lexical competition generated by the high-frequency homophone via the activation of multiple semantic representations. PMID- 21660484 TI - Immunolocalization of WNK4 in mouse kidney. AB - Initial reports claim that WNK4 localization is mainly at intercellular junctions of distal convoluted tubules (DCT) and cortical collecting ducts (CCD) in the kidney. However, we recently clarified the major targets of WNK4 kinase to be the OSR1/SPAK kinases and the Na-Cl co-transporter (NCC), an apical membrane protein in the DCT, thus raising the question of whether the cellular localization of WNK4 is at intercellular junctions. In this study, we re-evaluate the intrarenal and intracellular immunolocalization of WNK4 in the mouse kidney using a newly generated anti-WNK4 antibody. By performing double immunofluorescence of WNK4 with several nephron-segment-specific markers, we have found that WNK4 is present in podocytes in glomeruli, the cortical thick ascending limb of Henle's loop including macula densa, and the medullary collecting ducts (MCD), in addition to the previously identified nephron segments, i.e., DCT and CCD. These results are consistent with the finding that WNK4 constitutes a kinase cascade with OSR1/SPAK and NCC in the DCT, and highlights a novel role for WNK4 in nephron segments newly identified as being WNK4-positive in this study. PMID- 21660485 TI - New insight into the antidepressants action: modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio. AB - Altered function of kynurenine pathway has emerged recently as one of the factors contributing to the pathogenesis of depression. Neuroprotective kynurenic acid (KYNA) and neurotoxic 3-hydroxykynurenine (3-HK) are two immediate metabolites of L: -kynurenine. Here, we aimed to assess the hypothesis that antidepressant drugs that may change brain KYNA/3-HK ratio. In primary astroglial cultures, fluoxetine, citalopram, amitriptyline and imipramine (1-10 MUM) increased de novo production of KYNA and diminished 3-HK synthesis (24 and 48, but not 2 h). RT-PCR studies revealed that Kat1, Kat2 and kynurenine-3-monooxygenase (Kmo) gene expressions were not altered after 2 h. At 24 h, the expression of Kat1 and Kat2 genes was enhanced by all studied drugs, whereas Kmo expression was diminished by citalopram, fluoxetine and amitriptyline, but not imipramine. After 48 h, the expression of Kat1 and Kat2 was further up-regulated, and Kmo expression was down regulated by all antidepressants. The ratio KYNA/3-HK was increased by fluoxetine, citalopram, amitriptyline and imipramine in a time-dependent manner the effect was not observed after 2 h, modest after 24 h and robust after 48 h incubation time. Our findings indicate that the action of antidepressants may involve re-establishing of the beneficial ratio between KYNA and 3-HK. Shift in the kynurenine pathway, observed after prolonged exposure to antidepressant drugs, may partly explain their delayed therapeutic effectiveness. PMID- 21660486 TI - Prevalence of autoimmune liver disease related autoantibodies in Chinese patients with primary biliary cirrhosis. AB - BACKGROUND: The prevalence of autoimmune liver disease (AiLD)-related autoantibodies has not been defined in Chinese patients with primary biliary cirrhosis (PBC) and therefore needs to be characterized. AIMS: The purpose of this study was to explore the prevalence of AiLD-related autoantibodies in Chinese patients with PBC. METHODS: Indirect immunofluorescence was used to detect anti-mitochondrial antibodies (AMA) in the sera from 198 PBC, 44 autoimmune hepatitis (AIH) and 41 non-autoimmune liver disease controls (LDC). ELISA assays were used to test the presence of anti-M2, anti-gp210, anti-sp100, anti-SLA, anti-LC1 and anti-LKM-1 antibodies. RESULTS: AMA was present in 92.4, 15.9 and 7.3%, respectively, of patients with PBC, AIH and LDC. Anti-M2 was present in 87.4% of the PBC patients, but only in 4.5 and 4.9%, respectively, of AIH and LDC patients. Anti-gp210 and anti-sp100 were detected in 34.3 and 25.8% of PBC, 6.8 and 15.9% of AIH and in 4.9 and 17.1% of LDC patients. Anti-LC1, anti SLA and anti-LKM-1 were, respectively, present in 1.5, 0.0 and 0.5% of PBC, and 9.1, 11.4 and 2.3% of AIH, and none of LDC. PBC patients that were AMA-positive presented with higher IgM levels but lower CRP levels than negative ones. ALT, TBIL, DBIL, GGT, ALP, and AST were detected at higher levels and ALB at lower levels in PBC positive for anti-gp210 (P < 0.05). CONCLUSIONS: The prevalence of AiLD-related autoantibodies we provided might help define PBC in China. Anti sp100 is not a better prognostic marker for Chinese PBC patients compared to anti gp210. The identification of effective diagnostic biomarkers for AMA-negative PBC patients is still needed. PMID- 21660487 TI - Is subdivision of pT2 tumors superior to lymph node metastasis for predicting survival of patients with gastric cancer? Review of 224 patients from four centers. AB - BACKGROUND: The prognostic significance of the subclassification of pT2 tumors and the association of these categories with other clinicopathological factors in gastric cancer patients were investigated. METHODS: A total of 224 patients with pT2 gastric cancer who had undergone curative gastrectomy and lymph node dissection were retrospectively analyzed. The prognostic role of the subclassification of pT2 tumors was evaluated by univariate and multivariate analysis. RESULTS: Of 224 patients, 75 (33.5%) were classified as having pT2a tumors and 149 (66.5%) as having pT2b tumors. The prevalence of large-sized tumors (P < 0.003), lymph node involvement (P < 0.018), and lymphatic (P = 0.016), blood vessel (P = 0.001), and perineural invasion (P = 0.001) was significantly higher for pT2b tumors than for pT2a tumors. The rate of recurrence for pT2a cancers was significantly lower than that for pT2b cancers (P = 0.001).Median overall survival (OS) times and three-year OS of patients with a pT2b tumor were significantly worse than for patients with a pT2a tumor (P < 0.001).When patients were analyzed according to lymph node involvement, the prognosis of patients with pT2aN(1) cancers was significantly better than that of patients with pT2bN(1) (P < 0.001). Multivariate analysis indicated that the pT2 subdivision was an independent prognostic factor for OS (P = 0.006), as were pN stage, clinical stage, and recurrence. CONCLUSION: Our results showed that subclassification of pT2 tumors into pT2a or pT2b was an important prognostic indicator for patients with pT2 gastric cancers who underwent curative gastrectomy. In the TNM staging system, subdivision of pT2 tumors should be undertaken routinely to detect gastric cancer patients who have a poor prognosis and to define patients more accurately in terms of their mortality after curative resection in accordance with the new 2010 AJCC TNM staging classification. This may also help as a guide to more appropriate therapy for tumors with subserosal invasion (old pT2b or new pT3). PMID- 21660488 TI - Predicting the potency of hERG K+ channel inhibition by combining 3D-QSAR pharmacophore and 2D-QSAR models. AB - Blockade of the hERG K(+) channel has been identified as the most important mechanism of QT interval prolongation and thus inducing cardiac risk. In this work, an ensemble of 3D-QSAR pharmacophore models was constructed to provide insight into the determinants of the interactions between the hERG K(+) channel and channel inhibitors. To predict hERG inhibitory activities, the predicted values from the ensemble of models were averaged, and the results thus obtained showed that the predictive ability of the combined 3D-QSAR pharmacophore model was greater that those of the individual models. Also, using the same training and test sets, a 2D-QSAR model based on a heuristic machine-learning method was developed in order to analyze the physicochemical characters of hERG inhibitors. The models indicated that the inhibitors have certain key inhibitory features in common, including hydrophobicity, aromaticity, and flexibility. A final model was developed by combining the combined 3D-QSAR pharmacophore with the 2D-QSAR model, and this final model outperformed any other individual model, showing the highest predictive ability and the lowest deviation. This model can not only predict hERG inhibitory potency accurately, thus allowing fast cardiac safety evaluation, but it provides an effective tool for avoiding hERG inhibitory liability and thus enhanced cardiac risk in the design and optimization of new chemical entities. PMID- 21660489 TI - The insertion reactions of the p-complex silylenoid H2SiLiF with Si-X (X=F, Cl, Br, O, N) bonds. AB - The insertion reactions of the silylenoid H(2)SiLiF with SiH(3)XH(n-1) (X = F, Cl, Br, O, N; n = 1, 1, 1, 2, 3) have been studied by DFT calculations. The results indicate that the insertions proceed in a concerted manner, forming H(3)SiSiH(2)XH(n-1) and LiF. The essence of H(2)SiLiF insertion into Si-X bonds reactions are the donations of the electrons of X into the p orbital on the Si atom in H(2)SiLiF and the sigma electrons on the Si atom in H(2)SiLiF to the positive SiH(3) group. The order of reactivity by H(2)SiLiF insertion in vacuum indicates the reaction barriers decrease for the same-row element X from right to left and the same-family element X from up down in the periodic table. The insertion reactions in ether are similar to those in vacuum. The energy barriers in vacuum are higher than those in ether. The silylenoid insertions are thermodynamically exothermic both in vacuum and in ether. PMID- 21660490 TI - The F279Y polymorphism of the GHR gene and its relation to milk production and somatic cell score in German Holstein dairy cattle. AB - The bovine growth hormone receptor (GHR) gene has been identified as a strong positional and functional candidate gene influencing milk production. A non synonymous single nucleotide polymorphism (SNP) in exon 8 leads to a phenylalanine to tyrosine amino acid substitution (F279Y) in the receptor. The aim of the study was to estimate the effects of the F279Y mutation on milk yield, fat, protein, casein, and lactose yield and content, as well as somatic cell score (SCS), in a German Holstein dairy cattle population. The analysis of 1,370 dairy cows confirmed a strong association of the F279Y polymorphism with milk yield, as well as with fat, protein, and casein contents. Furthermore, increasing effects on lactose yield and content for the 279Y allele were found. Even though the tyrosine variant occurred as the minor allele (16.5%), its substitution effects were 320 kg (305 d), 0.02 kg per day, and 0.07 kg per day for milk, casein, and lactose yields, respectively. The same allele had negative effects on fat, protein, and casein contents. Finally, the high-milk-yield tyrosine allele was also associated with lower SCS (p < 0.05). The data support the high potential of the F279Y polymorphism as a marker for the improvement of milk traits in selection programs. PMID- 21660491 TI - PET scan in a patient with pneumococcal sepsis. PMID- 21660492 TI - Prevalence of risk factors for venous thromboembolism in the Italian population: results of a cross-sectional study from the Master Registry. AB - The prevalence of major risk factors for VTE may differ according to age, gender and clinical presentation. We tested this hypothesis in a large Italian VTE population. MASTER is a multicenter registry aimed to prospectively collect information on a large cohort of patients with acute VTE. The presence of major risk factors was captured by an electronic data network in consecutive patients with objectively confirmed acute VTE. We enrolled 2,119 patients (49.8% men) of whom 424 (20%) <40 years, 529 (25%) between 41 and 60 years, 943 (44.5%) between 61 and 80 years, and 223 (10.5%) >80 years. The prevalence of known risk factors in the four age groups is 63.9, 52.6, 54.6, and 58.3%, respectively (p = 0.002). Immobilization and severe medical disorders are more commonly associated with VTE in patients >80 years, trauma is significantly more common in patients <40 years than in older patient groups. The prevalence of unprovoked events is the highest in patients 41-60 years, and lowest in patients less than 40 years. After logistic regression analysis, patients with pulmonary embolism are more likely to have known risk factors for VTE than patients with deep vein thrombosis at presentation (p = 0.0021), and women are less likely than men to have an unprovoked VTE (p < 0.0001). In conclusion, a substantial proportion of VTE events remain classified as unprovoked. Unprovoked events are more common in middle aged patients, in men, and in patients presenting with deep vein thrombosis. PMID- 21660493 TI - Effect of acute exacerbations on circulating endothelial, clotting and fibrinolytic markers in COPD patients. AB - Patients with chronic obstructive pulmonary disease (COPD) are prone to clinical exacerbations that are associated with increased airway inflammation, a potent pro-thrombotic stimulus. Limited information is available on the mechanisms underlying the putative alterations of the endothelial-coagulative system during acute exacerbations. The aim was to investigate whether the activation of the endothelial-coagulative system occurs in association with the acute inflammatory response of COPD exacerbation. We monitored the blood levels of surrogate markers of inflammation: interleukin-6 (IL-6); endothelium damage: von Willebrand's factor (vWF); clotting activation: D-dimer (D-D), and prothrombin fragment 1+2 (F1+2); fibrinolytic response: plasminogen activator inhibitor 1 (PAI-1), in COPD subjects, during hospital admission and after clinical resolution. In 30 COPD subjects, IL-6, vWF, D-D and F1+2 levels were elevated during exacerbation and decreased significantly at clinical stability (IL-6, p = 0.005; vWF, p < 0.001; D D, p < 0.001; F1+2, p < 0.001). PAI-1 levels did not change at exacerbation compared to clinically stable situations. Positive correlations were observed between several of the markers measured. Elevation of IL-6, vWF, D-D and F1+2 levels during COPD exacerbations implies a strict association between acute inflammation, endothelial activation and clotting initiation. This was not associated with a change in PAI-1, implying an increase in the fibrinolytic response to inflammation. The pro-thrombotic nature of COPD exacerbations sustained by enhanced clotting activation appears to be mitigated by excessive fibrinolysis. PMID- 21660494 TI - Polycythemia vera: gender-related phenotypic differences. AB - In polycythemia vera, gender has recently been shown to influence the JAK2(V617F) allele burden, but its effect on the disease phenotype is unknown. This issue was investigated using the database of the European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study. The ECLAP Study recruited 1,638 polycythemic subjects and followed for 2.7 +/- 1.3 years. At study entry, men, compared to women, had a higher prevalence of myocardial infarction (11.3 vs. 5.8%; P < 0.0001) and peripheral arterial disease (6.1 vs. 2.9%; P < 0.05) while a history of venous thrombosis was more common in women (11.4 vs. 7.9%, P = 0.016). Among 234 venous thrombosis, there were 39 splanchnic vein thromboses (33 extra-hepatic portal vein thromboses and 6 Budd-Chiari syndromes). Most of these events occurred as an early disease presentation in young female subjects. Women, compared to men, had higher platelet counts (average value 430 +/- 213 vs. 375 +/ 201 * 10(9)/L; P < 0.0001) and lower hematocrits (0.46 +/- 0.06 vs. 0.48 +/- 0.06 l/l; P < 0.0001). Cholesterol plasma level, available in 995 subjects (61%), was lower in male patients (180.8 +/- 43.1 vs. 196 +/- 46.6 mg/dl; P < 0.0001). During follow-up there were 205 major thromboses confirming an high incidence of myocardial infarction in men although not statistically significant (1.2 vs. 0.6 cases per 100 person-years; P > 0.05). These data show several gender-related differences both in the thrombotic diathesis and in the prevalence of vascular risk factors of PV patients. PMID- 21660496 TI - Endoscopic vs robotic thyroidectomy: which is better? PMID- 21660495 TI - High detection rate of Trichomonas vaginalis in benign hyperplastic prostatic tissue. AB - While Trichomonas vaginalis, a protozoan parasite, is a well-investigated pathogen in the female population, there is little awareness of its significance in the male uro-genital tract. The presence of T. vaginalis in the prostate gland has only been scarcely investigated and has never been attested in conditions other than clinical prostatitis. Still, by some authors, this organ is regarded as ecologic niche for T. vaginalis. Since normal prostate tissue of sufficient quality is hard to come by, we investigated samples from 86 patients (mean age 68.7 +/- 7.6 years) suffering from benign prostatic hyperplasia (BPH), a medical condition currently ranked as noninfectious, but characterized by chronic inflammatory tissue infiltrates of unknown etiology. Applying two different PCR protocols and sequence analysis of the respective amplicons, we detected T. vaginalis DNA in 29/86 (34%) BPH tissue samples, whereas in only 2/86 (2.3%) cases T. vaginalis grew in culture. Detection of T. vaginalis DNA correlated significantly (P < 0.01) with elevated peripheral blood monocytic cell counts, appearing along with protozoan infections. Given the unexpected high prevalence of T. vaginalis in BPH tissue of a nonselected, elderly study population from Austria, further epidemiological studies have to confirm this finding. Potential interactions of T. vaginalis in its prostatic habitat may be investigated with respect to their possible contribution to the inflammatory pathogenesis of BPH, since inflammatory cytokines have been shown to sustain prostatic hyperplastic growth. PMID- 21660497 TI - Significance of perineural invasion, lymphovascular invasion, and high-grade prostatic intraepithelial neoplasia in robot-assisted laparoscopic radical prostatectomy. AB - BACKGROUND: Recently, more detailed histopathological variables such as perineural invasion (PNI), lymphovascular invasion (LVI), and high-grade prostatic intraepithelial neoplasia (HGPIN) have been investigated as prognostic factors for adverse pathologic findings on the radical prostatectomy specimen. We aim to determine whether these pathological factors are associated with adverse pathologic features after robot-assisted laparoscopic radical prostatectomy (RALP). METHODS: All 407 patients who underwent RALP with pelvic lymphadenectomy between July 2005 and December 2009 were analyzed, retrospectively. We investigated the association of these three pathological parameters with adverse pathological findings in RALP specimen and biochemical recurrence using Kaplan Meier analysis with log-rank test and a multivariate Cox proportional hazard model. RESULTS: The PNI and LVI were significantly associated with a higher pathological stage, a higher pathological Gleason score, a higher tumor volume in RALP specimen, a higher frequency of positive surgical margins, and a higher frequency of seminal vesicle invasion. In addition, PNI correlated with preoperative PSA, clinical stage, and Gleason score on needle biopsy. However, the HGPIN was not significantly associated with the clinicopathological characteristics studied. Using log-rank test, presence of PNI (P < 0.001) increases the probability of biochemical recurrence. On multivariate analysis, all three pathological parameters were not significantly correlated with biochemical recurrence. CONCLUSION: Although presence of PNI and LVI in RALP specimen correlated with multiple adverse clinicopathological factors, it did not predict biochemical recurrence, thus limiting its clinical usefulness. HGPIN was not significantly associated with the clinicopathological characteristics studied. PMID- 21660498 TI - A close eye on the eagle-eyed visual acuity hypothesis of autism. AB - Autism spectrum disorders (ASD) have been associated with sensory hypersensitivity. A recent study reported visual acuity (VA) in ASD in the region reported for birds of prey. The validity of the results was subsequently doubted. This study examined VA in 34 individuals with ASD, 16 with schizophrenia (SCH), and 26 typically developing (TYP). Participants with ASD did not show higher VA than those with SCH and TYP. There were no substantial correlations of VA with clinical severity in ASD or SCH. This study could not confirm the eagle-eyed acuity hypothesis of ASD, or find evidence for a connection of VA and clinical phenotypes. Research needs to further address the origins and circumstances associated with altered sensory or perceptual processing in ASD. PMID- 21660500 TI - Clinical predictive values of extended-spectrum beta-lactamase carriage in patients admitted to medical wards. AB - We aimed to reassess, through clinical items, populations at risk for extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) carriage at admission to hospital and to assess the risk of further positive clinical culture of ESBL-E among carriers. We performed a 5-month cohort study in a medicine ward of a 500-bed university teaching hospital in the Parisian area of France. All admitted patients were prospectively enrolled for rectal swabbing and clinical data collection, including bacterial infection at admission and during stay. Variables associated with ESBL-E carriage were identified by univariate and multivariate analysis. Five hundred patients were included. The prevalence of ESBL-E was 6.6% (33/500) upon admission. Only previous carriage of multidrug resistant bacteria (MDRB) was associated with carriage (odds ratio [OR]: 17.7, 95% confidence interval (CI) 5.8-54.2, p < 0.001), yet, the positive predictive value (PPV) was not higher than 50%. When prior MDRB carriage was not considered in the multivariate analysis, only prior antibiotic consumption was found to be associated with carriage at admission (OR: 2.2 [1.1-4.5], p = 0.02). Two patients had ESBL-E infection at admission, yet, no patient became infected with ESBL-E during their stay. The clinical prediction of ESBL carriage at admission in our wards was found to be poorly efficient for assessing the at-risk population. PMID- 21660499 TI - Differentiation of high-functioning autism and Asperger's disorder based on neuromotor behaviour. AB - Autism and Asperger's disorder (AD) are characterised by impairments in social interaction, stereotypic behaviours or restricted interests. Although currently listed as distinct clinical disorders, the validity of their distinction remains controversial. This study examined gait in children with autism and AD. Eleven children with high-functioning autism and eleven children with AD completed a series of walking tasks. Results indicated distinct movement disturbance; these findings are discussed in light of seminal papers in this field by Vilensky et al. (Arch Neurol 38:646-649, 1981) and Hallett et al. (Arch Neurol 50:1304-1308, 1993) who interpret the gait of individuals with autism using parkinsonian and cerebellar-ataxia patient models, respectively. Distinctions in gait patterns implicating perhaps unique motor circuit disturbances support the hypothesis that autism and AD may have unique neurodevelopmental trajectories. PMID- 21660501 TI - Enterococcus faecalis from patients with chronic periodontitis: virulence and antimicrobial resistance traits and determinants. AB - This study investigated the presence of virulence and resistance traits, as well as their genetic determinants in subgingival Enterococcus faecalis from patients with chronic periodontitis. Twenty-four E. faecalis strains from a previously multi-locus sequence typing (MLST)-characterized strain collection were examined for virulence-associated phenotypes, antimicrobial susceptibility, and virulence- and antimicrobial-resistant determinants. Gelatinase, hemolysin, and biofilm production were detected in 50, 17, and 100% of the strains, respectively. Genes encoding adherence factors such as ace, efaA, and bopD were detected in all isolates. Other putative virulence determinants, i.e., EF3314, gelE, asa, esp, cylA, ef1841/fsrC, and asa373, were found in a portion of the strains. Different levels of resistance were observed in these strains, with two strains expressing high-level resistance to erythromycin and gentamicin. The integrase gene and accessory gene(s) of the Tn916/Tn1545 family were detected in ten strains. A direct link was shown between the presence of Tn916/Tn1545-like elements and resistance to doxycycline and/or erythromycin. The results demonstrated that virulence and antibiotic resistance determinants were prevalent in oral E. faecalis strains. It implicates that oral E. faecalis might play a role in the pathogenesis of chronic periodontitis and be a potential reservoir for the transferable elements of virulence and antimicrobial resistance. PMID- 21660502 TI - Model organisms reveal insight into human neurodegenerative disease: ataxin-2 intermediate-length polyglutamine expansions are a risk factor for ALS. AB - Model organisms include yeast Saccromyces cerevisae and fly Drosophila melanogaster. These systems have powerful genetic approaches, as well as highly conserved pathways, both for normal function and disease. Here, we review and highlight how we applied these systems to provide mechanistic insight into the toxicity of TDP-43. TDP-43 accumulates in pathological aggregates in ALS and about half of FTD. Yeast and fly studies revealed an interaction with the counterparts of human Ataxin-2, a gene whose polyglutamine repeat expansion is associated with spinocerebellar ataxia type 2. This finding raised the hypothesis that repeat expansions in ataxin-2 may associate with diseases characterized by TDP-43 pathology such as ALS. DNA analysis of patients revealed that intermediate length polyglutamine expansions in ataxin-2 are a risk factor for ALS, such that repeat lengths are greater than normal, but lower than that associated with spinocerebellar ataxia type 2 (SCA2), and are more frequent in ALS patients than in matched controls. Moreover, repeat expansions associated with ALS are interrupted CAA-CAG sequences as opposed to the pure CAG repeat expansions typically associated with SCA2. These studies provide an example of how model systems, when extended to human cells and human patient tissue, can reveal new mechanistic insight into disease. PMID- 21660504 TI - Population Fisher information matrix and optimal design of discrete data responses in population pharmacodynamic experiments. AB - In the recent years, interest in the application of experimental design theory to population pharmacokinetic (PK) and pharmacodynamic (PD) experiments has increased. The aim is to improve the efficiency and the precision with which parameters are estimated during data analysis and sometimes to increase the power and reduce the sample size required for hypothesis testing. The population Fisher information matrix (PFIM) has been described for uniresponse and multiresponse population PK experiments for design evaluation and optimisation. Despite these developments and availability of tools for optimal design of population PK and PD experiments much of the effort has been focused on repeated continuous variable measurements with less work being done on repeated discrete type measurements. Discrete data arise mainly in PDs e.g. ordinal, nominal, dichotomous or count measurements. This paper implements expressions for the PFIM for repeated ordinal, dichotomous and count measurements based on analysis by a mixed-effects modelling technique. Three simulation studies were used to investigate the performance of the expressions. Example 1 is based on repeated dichotomous measurements, Example 2 is based on repeated count measurements and Example 3 is based on repeated ordinal measurements. Data simulated in MATLAB were analysed using NONMEM (Laplace method) and the glmmML package in R (Laplace and adaptive Gauss-Hermite quadrature methods). The results obtained for Examples 1 and 2 showed good agreement between the relative standard errors obtained using the PFIM and simulations. The results obtained for Example 3 showed the importance of sampling at the most informative time points. Implementation of these expressions will provide the opportunity for efficient design of population PD experiments that involve discrete type data through design evaluation and optimisation. PMID- 21660505 TI - Radiotherapy for mucosa-associated lymphoid tissue (MALT) lymphoma of the esophagus: a case report with a diagnostic and therapeutic discussion. AB - Mucosa-associated lymphoid tissue (MALT) lymphoma is increasing common in various sites; however, MALT lymphoma in the esophagus is still rare, so its diagnostic features have not yet been well recognized and optimal treatment has not been properly discussed. Though radiotherapy is widely preferred for gastric and orbital MALT lymphoma, surgery has been the most frequently reported treatment for esophageal MALT lymphoma. This raises the question: why not radiotherapy for esophageal MALT lymphoma instead of surgery? The only reported case of definitive radiotherapy for esophageal MALT lymphoma lacks follow-up data. Three years ago (2007), we treated a 59-year-old male patient with a large esophageal submucosal tumor, diagnosed as MALT lymphoma, with 36 Gy of solo external beam radiotherapy. The tumor was 15 cm in craniocaudal length, homogeneously weakly contrast enhanced on X-ray computed tomography (CT), homogeneously hypoechoic and clearly demarcated from the surrounding adventitia, and had a concave pattern between the folds. During and after radiotherapy, no treatment-related complications occurred except for transient Grade 2 leukocytopenia. The tumor showed remarkable reduction and histological negativity in the next month. Over the follow-up period, no recurrence was observed in semiannual PET/CT/MRI studies. Taking the current observation with the well known effectiveness of radiotherapy for MALT lymphoma in various other sites, we recommend considering radiotherapy as a reasonable less-invasive treatment for this rare entity. PMID- 21660503 TI - Specifying the neuropsychology of affective disorders: clinical, demographic and neurobiological factors. AB - Neuropsychological research in patients with affective disorders shows heterogeneous results with regard to the severity and profile of cognitive impairments. In this paper we hypothesize that the investigation of clinical (subtypes, comorbidity, traumatization, personality, severity, diurnal swings, course, duration, age of onset, biased processing, rumination, motivation, experience of failure, sleep, suicidal tendencies, computer attitudes), demographic (age, education, gender) and neurobiological factors (structural and functional brain changes, glucocorticoids, medication, ECT) that are related to cognitive performance has specified the understanding of severity and profile of neuropsychological impairments. We reviewed the literature pertaining to clinical, demographic and neurobiological factors following Pubmed and PsychInfo databases using different combinations of general key-terms including "Affective Disorder," "Depression," "Mania," "Neuropsychological," "Neurobiological," "Moderator," and "Review" as well as more specific demographic, clinical and neurobiological search terms. Findings from the literature show that the consideration of these factors has improved knowledge about the severity of neuropsychological impairments in patients with affective disorders whereas the neuropsychological profile is still poorly understood. Despite limited understanding, however, the existent results provide promising suggestions for the development of treatment programs. PMID- 21660506 TI - Children and biobanks: a review of the ethical and legal discussion. AB - The use of tissue samples from children is vital to genetic research. Collections of such tissue, in so-called biobanks, can take the form of large-scale prospective cohort studies or disease-specific studies using tissue of children with that specific disease. Collections of samples gathered in a diagnostics context, such as blood spot cards, can also be used for genetic research. Research on stored tissue samples from children poses ethical questions that are different from those posed by the use of samples from adults. Also, the ethical questions raised by the participation of children in biobanks are not analogous to those raised by the participation of children in clinical trials. In this review we first give an overview of the international ethical guidelines and legal regulations concerning biobanking and minors. Next, we review the different themes that occur in the ethical literature on this subject. Specifically we focus on questions of risk and benefit, consent and assent and the return of individual results. We also discuss the concept of solidarity, which is a relatively new concept in the context of children and biomedical research. To conclude, we discuss the gaps and questions raised by the review. PMID- 21660507 TI - A scaffold for X chromosome inactivation. AB - X chromosome inactivation (XCI), the silencing of one of the two X chromosomes in XX female cells, equalises the dosage of X-linked genes relative to XY males. The process is mediated by the non-coding RNA X inactive specific transcript (Xist) that binds in cis and propagates along the inactive X chromosome elect, triggering chromosome-wide silencing. The mechanisms by which Xist RNA binds and spreads along the chromosome, and initiates Xist-mediated chromosome silencing remain poorly understood. Accumulating evidence suggests that chromosome and nuclear organisation are important in both processes. Notably, recent studies have identified specific factors, previously shown to be components of the nuclear matrix or scaffold, to play a role both in Xist RNA-binding and in Xist mediated silencing. In this review we provide a perspective on these studies in the context of previous work on chromosome/nuclear architecture in XCI. PMID- 21660508 TI - A signature of balancing selection in the region upstream to the human UGT2B4 gene and implications for breast cancer risk. AB - UDP-glucuronosyltransferase 2 family, polypeptide B4 (UGT2B4) is an important metabolizing enzyme involved in the clearance of many xenobiotics and endogenous substrates, especially steroid hormones and bile acids. The HapMap data show that numerous SNPs upstream of UGT2B4 are in near-perfect linkage disequilibrium with each other and occur at intermediate frequency, indicating that this region might contain a target of natural selection. To investigate this possibility, we chose three regions (4.8 kb in total) for resequencing and observed a striking excess of intermediate-frequency alleles that define two major haplotypes separated by many mutation events and with little differentiation across populations, thus suggesting that the variation pattern upstream UGT2B4 is highly unusual and may be the result of balancing selection. We propose that this pattern is due to the maintenance of a regulatory polymorphism involved in the fine tuning of UGT2B4 expression so that heterozygous genotypes result in optimal enzyme levels. Considering the important role of steroid hormones in breast cancer susceptibility, we hypothesized that variation in this region could predispose to breast cancer. To test this hypothesis, we genotyped tag SNP rs13129471 in 1,261 patients and 825 normal women of African ancestry from three populations. The frequency comparison indicated that rs13129471 was significantly associated with breast cancer after adjusting for ethnicity [P = 0.003; heterozygous odds ratio (OR) 1.02, 95% confidence interval (CI) 0.81-1.28; homozygous OR 1.50, 95% CI 1.15-1.95]. Our results provide new insights into UGT2B4 sequence variation and indicate that a signal of natural selection may lead to the identification of disease susceptibility variants. PMID- 21660510 TI - [Operative technique for the rupture of the deep flexor tendon close to the insertion]. PMID- 21660509 TI - Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. AB - A missense mutation of Gipc3 was previously reported to cause age-related hearing loss in mice. Point mutations of human GIPC3 were found in two small families, but association with hearing loss was not statistically significant. Here, we describe one frameshift and six missense mutations in GIPC3 cosegregating with DFNB72 hearing loss in six large families that support statistically significant evidence for genetic linkage. However, GIPC3 is not the only nonsyndromic hearing impairment gene in this region; no GIPC3 mutations were found in a family cosegregating hearing loss with markers of chromosome 19p. Haplotype analysis excluded GIPC3 from the obligate linkage interval in this family and defined a novel locus spanning 4.08 Mb and 104 genes. This closely linked but distinct nonsyndromic hearing loss locus was designated DFNB81. PMID- 21660511 TI - [Primary treatment of complicated flexor tendon injuries of the hand]. AB - Complicated flexor tendon injuries are classified into lacerations, avulsions, ruptures, and defects. They are often a challenge for hand surgeons and frequently they present unsatisfactory functional results postoperatively. Lacerations and avulsions are usually treated by pull-out sutures and suture anchors. In ruptures, the causality should be sought. Tendon-linking, transposition and tenodesis/arthrodesis are the domain of rheumatoid arthritis. The primary transplantation of tendons is rarely indicated, ideally in non contaminated flexor tendon defects in zones III-V with an uninjured surrounding soft tissue situation. Postoperative rehabilitation programs are very the same as in normal flexor tendon injuries. PMID- 21660512 TI - [Complications after pertrochanteric fractures]. AB - Fractures at the coxal end of the femur have an incidence of almost 100.000 p.a. in Germany. Pertrochanteric femur fractures make up almost half of this collective. The highest incidence of 1.32% is seen in patients over the age of 85. Osteosynthesis is the treatment of choice. The options include extramedullary nail/screw systems or intramedullary nail systems. Study findings to date do not show a clear advantage of one procedure over another. The published complication rates remain high. The main complication is secondary reduction loss with cutout of the hip screw. Other complications include femoral neck shortening and lateralization of the hip screw with local irritation at the iliotibial tract. Functional outcomes after osteosynthesis are still less than satisfactory. Surgery only frees one third of patients from pain. In addition, a majority of patients also suffer loss of independence and social contacts. An alternative approach to treatment is total joint replacement. This is indicated in extreme cases of osteoporosis in combination with osteoarthritis. However, initial high stability must be weighed against an increased risk of dislocation and a higher rate of 1-year mortality. PMID- 21660513 TI - Novel botanical drug for the treatment of diabetic neuropathy. AB - Diabetic neuropathy has multiple aspects of pathophysiology including metabolic derangements and alterations of microvessel with hyperglycemia. Currently, there is no effective long-term treatment based on the pathologic mechanisms. Nerve regeneration with nerve growth factor (NGF) has been on clinical trials as a treatment option. This article reviews an action of a herbal medicine, DA 9801, whose mechanism of action is related to NGF in treating diabetic neuropathy. PMID- 21660514 TI - Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase. AB - DNA methyltransferase 1 (DNMT1) is an emerging epigenetic target for the treatment of cancer and other diseases. To date, several inhibitors from different structural classes have been published. In this work, we report a comprehensive molecular modeling study of 14 established DNTM1 inhibitors with a herein developed homology model of the catalytic domain of human DNTM1. The geometry of the homology model was in agreement with the proposed mechanism of DNA methylation. Docking results revealed that all inhibitors studied in this work have hydrogen bond interactions with a glutamic acid and arginine residues that play a central role in the mechanism of cytosine DNA methylation. The binding models of compounds such as curcumin and parthenolide suggest that these natural products are covalent blockers of the catalytic site. A pharmacophore model was also developed for all DNMT1 inhibitors considered in this work using the most favorable binding conformations and energetic terms of the docked poses. To the best of our knowledge, this is the first pharmacophore model proposed for compounds with inhibitory activity of DNMT1. The results presented in this work represent a conceptual advance for understanding the protein-ligand interactions and mechanism of action of DNMT1 inhibitors. The insights obtained in this work can be used for the structure-based design and virtual screening for novel inhibitors targeting DNMT1. PMID- 21660515 TI - Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information. AB - The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu. PMID- 21660516 TI - Biosensor-based small molecule fragment screening with biolayer interferometry. AB - Biosensor-based fragment screening is a valuable tool in the drug discovery process. This method is advantageous over many biochemical methods because primary hits can be distinguished from non-specific or non-ideal interactions by examining binding profiles and responses, resulting in reduced false-positive rates. Biolayer interferometry (BLI), a technique that measures changes in an interference pattern generated from visible light reflected from an optical layer and a biolayer containing proteins of interest, is a relatively new method for monitoring small molecule interactions. The BLI format is based on a disposable sensor that is immersed in 96-well or 384-well plates. BLI has been validated for small molecule detection and fragment screening with model systems and well characterized targets where affinity constants and binding profiles are generally similar to those obtained with surface plasmon resonsance (SPR). Screens with challenging targets involved in protein-protein interactions including BCL-2, JNK1, and eIF4E were performed with a fragment library of 6,500 compounds, and hit rates were compared for these targets. For eIF4E, a protein containing a PPI site and a nucleotide binding site, results from a BLI fragment screen were compared to results obtained in biochemical HTS screens. Overlapping hits were observed for the PPI site, and hits unique to the BLI screen were identified. Hit assessments with SPR and BLI are described. PMID- 21660517 TI - Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. AB - BACKGROUND: X-linked cerebral creatine deficiency is caused by the deficiency of the creatine transporter (CTP) encoded by the SLC6A8 gene. PATIENTS AND METHODS: We report here a series of six patients with severe CTP deficiency, four males and two females; clinical presentations include mild to severe mental retardation (6/6), associated with psychiatric symptoms (5/6: autistic behaviour, chronic hallucinatory psychosis), seizures (2/6) and muscular symptoms (2/4 males). Diagnosis was suspected upon elevated urinary creatine/creatinine (except in one of the female patients) and on a markedly decreased creatine peak on magnetic resonance spectroscopy (MRS). Diagnosis was confirmed by molecular analysis that identified four novel mutations not reported so far, including a mutation found twice in two male patients. All patients were treated successively and according to the same protocol by creatine alone then combined to its precursors, L-glycine and L-arginine for 42 months. RESULTS AND CONCLUSION: In our patients, creatine supplementation alone or with its precursors L-glycine and L-arginine showed benefit only in the muscular symptoms of the disease and no improvement in the cognitive and psychiatric manifestations and did not modify brain creatine content on MRS of male and female CTP deficient patients. New treatment strategies are required including creatine derivatives transported independently from CTP or using alternative pathways and transporters. PMID- 21660518 TI - Doubling in the use of thyroid hormone replacement therapy in Denmark: association to iodization of salt? AB - Iodization of salt is an effective strategy to prevent iodine deficiency disorders. Recent studies, however, indicate that increasing the iodine intake in a population may give rise to an increased incidence of hypothyroidism, but the association has not been fully clarified. In Denmark, iodization of salt was initiated in 1998 because of mild-to-moderate iodine deficiency. The aim of this study was to evaluate the effect of the raised iodine intake on the nationwide incident use of thyroid hormone replacement therapy (levothyroxine) to treat hypothyroidism. Data on all use of levothyroxine was extracted from the Register of Medicinal Product Statistics during the period 1995-2009 and linked to other nationwide registers by use of the Danish identification number. Persons with previous thyroid surgery were excluded. In the studied period 71,565 incident users were identified. The incidence rate increased 75% in the moderately iodine deficient region (72.2 incident users/100,000 person-years in 1997 to 126.6 in 2008) and 87% in the mildly deficient region (86.9-162.9). When stratified by sex and age-group (00-39, 40-64, 65+) the largest relative increase was seen among women in the youngest age-group, where more than a doubling was seen. The mechanisms behind the increase may be a result of iodine-induced hypothyroidism, although a higher diagnostic activity with regard to thyroid dysfunction and intensified treatment of subclinical hypothyroidism may also play a role. Our findings stress the need for caution when initiating iodine fortification programs to keep the intake within the optimal range, and the need for continuous monitoring. PMID- 21660520 TI - Be careful... She has a pituitary gland in her nose. AB - In this case report we describe a 38 year-old-female with galactorrhea several months after the birth of an anencephalic child. She had hyperpolactemia and imaging of the pituitary gland revealed a midline defect and a nasopharyngeal mass compatible with a meningo-(hypophyso-) encephalocele and possibly an ectopic teratoma or desmoid. She was treated with dopamine agonists for 10 years and after cessation of therapy her prolactin levels remain normal. The nasopharyngeal mass remained unchanged over time and there were no signs of hypopituitarism. The hyperprolactinemia at presentation was probably caused by earlier pregnancy and stalk dysfunction due to traction by the mass. With decline of pituitary size, after starting dopamine agonists, the traction probably reduced resulting in a normal prolactin level. Our patient was warned against manipulation in de nose, because this could damage the meningo-encephalocele. An MRI will be preformed every 2 years to monitor changes in de mass. PMID- 21660519 TI - Dairy products and its association with incidence of cardiovascular disease: the Malmo diet and cancer cohort. AB - It is unclear whether specific dairy products are associated with risk of cardiovascular disease (CVD). The aim of this project was therefore to examine the association between intake of milk, cheese, cream and butter, and incidence of CVD in the Swedish Malmo Diet and Cancer cohort. Milk was separated into fermented (yoghurt and cultured sour milk) versus non-fermented milk, and low-fat versus high-fat milk. Among 26,445 individuals without a history of myocardial infarction, stroke and diabetes (44-74 years; 62% females), 2,520 CVD cases (coronary and stroke events) were identified during a mean follow-up time of 12 years. Dietary data was collected using a modified diet history method. Overall consumption of dairy products was inversely associated with risk of CVD (P (trend) = 0.05). Among the specific dairy products, a statistically significant inverse relationship was observed only for fermented milk. The highest versus lowest intake category of fermented milk was associated with 15% (95% CI: 5-24%; P (trend) = 0.003) decreased incidence of CVD. We observed a statistically significant interaction between sex and cheese intake (P = 0.046). Cheese intake was significantly associated with decreased CVD risk in women (P (trend) = 0.03), but not in men (P (trend) = 0.98). The main finding was that a high intake of fermented milk may reduce the risk of CVD. This study suggests that it is important to examine dairy products separately when investigating their health effects. PMID- 21660521 TI - Afferent arteriolopathy and glomerular collapse but not segmental sclerosis induce tubular atrophy in old spontaneously hypertensive rats. AB - In chronic renal disease, the temporal and spatial relationship between vascular, glomerular and tubular changes is still unclear. Hypertension, an important cause of chronic renal failure, leads to afferent arteriolopathy, segmental glomerulosclerosis and tubular atrophy in the juxtamedullary cortex. We investigated the pathological changes of hypertensive renal disease in aged spontaneously hypertensive rats using a large number of serial sections, where we traced and analyzed afferent arteriole, glomerulus and proximal tubule of single nephrons. Our major finding was that both afferent arteriolopathy and glomerular capillary collapse were linked to tubular atrophy. Only nephrons with glomerular collapse (n = 13) showed tubules with reduced diameter indicating atrophy [21.66 +/- 2.56 MUm vs. tubules in normotensive Wistar Kyoto rats (WKY) 38.56 +/- 0.56 MUm, p < 0.05], as well as afferent arteriolar wall hypertrophy (diameter 32.74 +/- 4.72 MUm vs. afferent arterioles in WKY 19.24 +/- 0.98 MUm, p < 0.05). Nephrons with segmental sclerosis (n = 10) did not show tubular atrophy and tubular diameters were unchanged (35.60 +/- 1.43 MUm). Afferent arteriolar diameter negatively correlated with glomerular capillary volume fraction (r = 0.36) and proximal tubular diameter (r = -0.46) implying reduced glomerular and tubular flow. In line with this, chronically damaged tubules showed reduced staining for the ciliary protein inversin indicating changed ciliary signalling due to reduced urinary flow. This is the first morphological study on hypertensive renal disease making correlations between vascular, glomerular and tubular components of individual nephron units. Our data suggest that afferent arteriolopathy leads to glomerular collapse and reduced urinary flow with subsequent tubular atrophy. PMID- 21660522 TI - Musculoskeletal: what is different in children? Jumping around and falls on floor: will not move right arm. PMID- 21660523 TI - Local and systemic application of tranexamic acid in heart valve surgery: a prospective, randomized, double blind LOST study. AB - The study was performed to examine a possible augmentation of systemic administration of tranexamic acid by the additional topical application during heart valve surgery in the post-aprotinin era. One-hundred patients were enrolled in the study and all the patients were given tranexamic acid intravenously. The participants were randomized into two groups (A, n = 49; B, n = 51), and before commencing the sternal suturing, the study solution (group A: 250 ml of normal saline + tranexamic acid 2.5 g, placebo group B: 250 ml of normal saline) was poured into the pericardial cavity. The cumulative blood loss (geometric means [95% confidence intervals]) 4 h after the surgery was 86.1 [56.1, 132.2] ml in group A, and 135.4 [94.3, 194.4] in group B, test for equality of geometric means P = 0.107, test for equality of variances P = 0.059. Eight hours after the surgery, the blood loss was 199.4 [153.4, 259.2] ml in group A, 261.7 [205.1, 334.0] ml in group B, P = 0.130 and P = 0.050, respectively. Twenty-four hours postoperatively the blood loss was 504.2 [436.0, 583.0] ml in group A, 569.7 [476.0, 681.7] ml in group B, P = 0.293 and P = 0.014, respectively. The proportion of patients transfused postoperatively by fresh frozen plasma differed significantly between the two study groups (group A: n = 21, group B: n = 36, P = 0.008). Our hypothesis is supported by a significant difference in the inter group variance of blood loss and the proportion of patients requiring fresh frozen plasma; however evident differences in mean postoperative blood loss were not statistically significant. PMID- 21660524 TI - Spontaneous remission in localized diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is an aggressive neoplastic disease of the lymphatic system, the activated B-cell type of this disease is likely to have a substantially worse prognosis. In this study, we report the favorable outcome of the activated B-cell type of DLBCL, though untreated, 7 years after diagnosis. In 2003, DLBCL localized to the root of tongue was found in the patient complaining of dysphonia and a pharyngeal globus perception but the patient did not agree to get any active hematological treatment. During the following years, the patient did not have any complaints. At the otorhinolaryngological control examination, in 2010, she was complaint-free, had normal laboratory parameters. Moreover a PET CT scan did not reveal metabolic activity relating to malignancy. The extraordinary disease process can be explained by the spontaneous regression of the activated B-cell type DLBCL. Spontaneous regression of oral lymphoma has been published only exceptionally. To our knowledge, no report of spontaneous regression of activated B-cell type DLBLC has been reported. PMID- 21660525 TI - [Procalcitonin-based algorithm. Management of antibiotic therapy in critically ill patients]. AB - Sepsis is one of the most cost-intensive conditions of critically ill patients in intensive care medicine. Furthermore, sepsis is known to be the leading cause of morbidity and of mortality in intensive care patients. Early initiation of antibiotic therapy can significantly reduce mortality. The development of resistance of bacterial species against antibiotics is a compelling issue to reconsider indications and administration of antibiotic treatment. Adequate indications and duration of therapy are particularly important for the use of highly potent substances in the intensive care setting. Until recently no laboratory marker has been available to distinguish bacterial infections from viral or non-infectious inflammatory responses. However, procalcitonin (PCT) appears to be the first among a large array of inflammatory markers that offers this possibility. Regular procalcitonin measurements can significantly shorten the length of antibiotic therapy, show positive influence on antibiotic costs and have no adverse affects on patient outcome. PMID- 21660526 TI - Tandem carrying, a new foraging strategy in ants: description, function, and adaptive significance relative to other described foraging strategies. AB - An important aspect of social insect biology lies in the expression of collective foraging strategies developed to exploit food. In ants, four main types of foraging strategies are typically recognized based on the intensity of recruitment and the importance of chemical communication. Here, we describe a new type of foraging strategy, "tandem carrying", which is also one of the most simple recruitment strategies, observed in the Ponerinae species Pachycondyla chinensis. Within this strategy, workers are directly carried individually and then released on the food resource by a successful scout. We demonstrate that this recruitment is context dependent and based on the type of food discovered and can be quickly adjusted as food quality changes. We did not detect trail marking by tandem-carrying workers. We conclude by discussing the importance of tandem carrying in an evolutionary context relative to other modes of recruitment in foraging and nest emigration. PMID- 21660527 TI - Is advanced treated water truly high quality?: the answer from a viewpoint of cancer risk induced by trihalomethane class. AB - Before and after switching to the advanced treatment, a total of 48 trihalomethanes measurements was made at household taps in the specific distribution area in Osaka City, Japan. An average of total trihalomethanes concentrations in advanced treated water was three-fifths of that in conventionally treated water. The average lifetime cancer risks for total trihalomethanes were 48.5 * 10(-6) in conventionally treated water and 44.8 * 10( 6) in advanced treated water, which were higher than 10(-6), the negligible risk level. Surprisingly, the average lifetime cancer risk of conventionally treated water was not significantly different from that of advanced treated water. The highest value of hazard index found was an order of magnitude lower than unity. PMID- 21660528 TI - Toxicity of cadmium, lead, mercury and methyl parathion on Euchlanis dilatata Ehrenberg 1832 (Rotifera: Monogononta). AB - Acute toxicity tests with Cd, Pb, Hg, and methyl parathion were developed to compare the sensitivity of the rotifer Euchlanis dilatata with other model organisms used in aquatic ecotoxicology. Cd was the most toxic chemical (LC50 = 14.8 MUg L(-1)), while methyl parathion was the least toxic (LC50 = 864.2 MUg L( 1)). E. dilatata was more sensitive that other rotifer species, particularly of the genera Brachionus and Lecane. However, E. dilatata was less sensitive to mercury and methyl parathion than the crustacean, Daphnia magna. The high sensitivity of E. dilatata suggests that it may be an adequate benthic model to use in toxicity assessments of metal-contaminated sediments. PMID- 21660530 TI - Frameless stereotactic procedures in pediatric patients: safety and diagnostic efficacy. AB - PURPOSE: The aim of our retrospective study was to evaluate the feasibility, safety, and diagnostic yield of a frameless method for stereotactic neurosurgical procedures in pediatric patients. METHODS: Twenty-two frameless stereotactic neurosurgical procedures (18 biopsies, 4 catheter placements), using a modified frameless stereotactic navigational system, were performed in 21 pediatric patients in our institution from 2004 to 2009. All procedures were performed by the senior authors (AAK, SC). RESULTS: We completed 18 biopsy procedures in 18 patients, yielding usable diagnostic specimens in 100% of the procedures. Of this biopsy group, two patients experienced an asymptomatic hemorrhage per CT, and one patient experienced a transient hemiparesis, recovering to baseline within 1 week after surgery. Four catheter placement procedures were completed in three patients, including one patient who had to have the procedure repeated. We had no peri-operative mortality or technical difficulties related to the catheter placements. CONCLUSIONS: Frameless stereotactic neurosurgical procedures in the pediatric population are feasible and can be completed safely for histological tumor diagnosis as well as for accurate placement of intracranial catheters. This method has low rates of morbidity comparable to frame-based procedures, with the advantage of greater operative convenience. PMID- 21660531 TI - QTL identification of flowering time at three different latitudes reveals homeologous genomic regions that control flowering in soybean. AB - Since the genetic control of flowering time is very important in photoperiod sensitive soybean (Glycine max (L.) Merr.), genes affecting flowering under different environment conditions have been identified and described. The objectives were to identify quantitative trait loci (QTLs) for flowering time in different latitudinal and climatic regions, and to understand how chromosomal rearrangement and genome organization contribute to flowering time in soybean. Recombinant inbred lines from a cross between late-flowering 'Jinpumkong 2' and early-flowering 'SS2-2' were used to evaluate the phenotypic data for days to flowering (DF) collected from Kamphaeng Saen, Thailand (14 degrees 01'N), Suwon, Korea (37 degrees 15'N), and Longjing, China (42 degrees 46'N). A weakly positive phenotypic correlation (r = 0.36) was found between DF in Korea and Thailand; however, a strong correlation (r = 0.74) was shown between Korea and China. After 178 simple sequence repeat (SSR) markers were placed on a genetic map spanning 2,551.7 cM, four independent DF QTLs were identified on different chromosomes (Chrs). Among them, three QTLs on Chrs 9, 13 and 16 were either Thailand- or Korea-specific. The DF QTL on Chr 6 was identified in both Korea and China, suggesting it is less environment-sensitive. Comparative analysis of four DF QTL regions revealed a syntenic relationship between two QTLs on Chrs 6 and 13. All five duplicated gene pairs clustered in the homeologous genomic regions were found to be involved in the flowering. Identification and comparative analysis of multiple DF QTLs from different environments will facilitate the significant improvement in soybean breeding programs with respect to control of flowering time. PMID- 21660533 TI - Trace elements and heavy metals in hair of stage III breast cancer patients. AB - This prospective study was designed to compare the hair levels of 36 elements in 52 patients with stage III breast cancer to those of an equal number of healthy individuals. Principal component and cluster analysis were used for source of identification and apportionment of heavy metals and trace elements in these two groups. A higher average level of iron was found in samples from patients while controls had higher levels of calcium. Both patients and controls had elevated levels of tin, magnesium, zinc, and sodium. Almost all element values in cancer patients showed higher dispersion and asymmetry than in healthy controls. Between the two groups, there were statistically significant differences in the concentrations of silver, arsenic, gold, boron, barium, beryllium, calcium, cadmium, cerium, cobalt, cesium, gadolinium, manganese, nickel, lead, antimony, scandium, selenium, and zinc (p < 0.05). Strong positive correlations were found between lead and gold (r = 0.785) in the cancer group and between palladium and cobalt (r = 0.945) in the healthy individuals. Our results show that there are distinct patterns of heavy metals and trace elements in the hair of breast cancer patients in comparison to healthy controls. These results could be of significance in the diagnosis of breast cancer. PMID- 21660532 TI - Effects of manganese deficiency and added cerium on nitrogen metabolism of maize. AB - Manganese is one of the essential microelements for plant growth, and cerium is a beneficial element for plant growth. However, whether manganese deficiency affects nitrogen metabolism of plants and cerium improves the nitrogen metabolism of plants by exposure to manganese-deficient media are still unclear. The main aim of the study was to determine the effects of manganese deficiency in nitrogen metabolism and the roles of cerium in the improvement of manganese-deficient effects in maize seedlings. Maize seedlings were cultivated in manganese present Meider's nutrient solution. They were subjected to manganese deficiency and to cerium chloride administered in the manganese-present and manganese-deficient media. Maize seedlings grown in the various media were measured for key enzyme activities involved in nitrogen metabolism, such as nitrate reductase, glutamate dehydrogenase, glutamine synthetase, and glutamic-oxaloace transaminase. We found that manganese deficiency restricted uptake and transport of NO(3)(-), inhibited activities of nitrogen-metabolism-related enzymes, such as nitrate reductase, glutamine synthetase, and glutamic-oxaloace transaminase, thus decreasing the synthesis of chlorophyll and soluble protein, and inhibited the growth of maize seedlings. Manganese deficiency promoted the activity of glutamate dehydrogenase and reduced the toxicity of excess ammonia to the plant, while added cerium relieved the damage to nitrogen metabolism caused by manganese deficiency in maize seedlings. However, cerium addition exerted positively to relieve the damage of nitrogen metabolism process in maize seedlings caused by exposure to manganese-deficient media. PMID- 21660534 TI - End-of-life attitudes of intensive care physicians in Poland: results of a national survey. AB - PURPOSE: This study was designed to assess the ethical attitudes and practices of intensive care physicians regarding life-sustaining treatment in intensive care units (ICUs) in Poland. METHODS: A questionnaire was distributed to intensive care physicians taking part in a national medical congress. Participation in the study was voluntary and anonymous. RESULTS: A total of 400 questionnaires were distributed, of which 217 (54%) were returned completed. Almost all respondents (93%) reported having withheld therapy, and 75% of respondents reported withdrawing therapy. Physicians aged 40 years and over who had no religious affiliation more frequently reported withholding treatment. Only 5% of physicians reported deliberately administering drugs until death ensued. Respondents from large hospitals (more than 400 beds) more easily accepted foregoing life sustaining therapy in ICU patients. In clinical scenario in which the family demanded the maximum available treatment, physicians reported that they were considerably influenced to modify decisions concerning life-sustaining therapy. CONCLUSIONS: The ethical attitudes of intensive care physicians regarding end-of life decisions are similar to the opinion presented in other European survey studies. The practice of withholding and withdrawing therapy in ICU patients is common in Poland. Actively shortening life is considered unacceptable. The request of the family even without legal consultation can influence physicians' decisions. PMID- 21660536 TI - Transfer of take-home messages in graduate ICU education. AB - PURPOSE: Teaching by lecture (lecture format) is widely used at congresses and in medical educational programmes. The process involves the transfer of take-home messages. The aim of this study was to assess the number of take-home messages identified by postgraduate critical care junior doctors (juniors) during lectures. METHODS: This was a prospective observational study of 13 lectures. Lecturers were not informed in advance of the study. At the end of the lecture (30 or 50 min), the lecturer (senior doctor) and juniors listed the three main take-home messages on a form. Subjective elements of the juniors' appraisal (quality of the presentation, explanation of the topic's relevance, enthusiasm of the lecturer, background, case-based, delivery and personality, comprehensibility, practical applicability of information given, prioritization, presence of raw data, references, overall satisfaction) and objective elements (length of lecture, number of take-home messages written on the slides) of the lectures were recorded. Successful knowledge transfer was assessed by matching lecturers' and juniors' take-home messages. RESULTS: In total, 367 forms completed by 367 juniors were analysed. A match equal to 3 (highest match), 2, 1 or 0 was observed in 3.8, 26.7, 48.2 and 21.2% of the forms, respectively. No single subjective or objective element of the lecture was associated with the number of identified take-home messages. CONCLUSIONS: Two-thirds of critical care junior doctors identified at best only one of the three main take-home messages of a lecture, suggesting that knowledge transfer is poor during passive format learning. These results suggest that there is a need to develop strategies to improve the performance of lecture-based learning. PMID- 21660535 TI - Severity assessment tools to guide ICU admission in community-acquired pneumonia: systematic review and meta-analysis. AB - BACKGROUND: The aim of this meta-analysis was to determine if severity assessment tools can be used to guide decisions regarding intensive care unit (ICU) admission of patients with community-acquired pneumonia. METHODS: A search of PUBMED and EMBASE (1980-2009) was conducted to identify studies reporting pneumonia severity scores and prediction of ICU admission. Two reviewers independently collected data and assessed study quality. Performance characteristics were pooled using a random-effects model. RESULTS: Sufficient data were collected to perform a meta-analysis on five current scoring systems: the Pneumonia Severity Index (PSI), the CURB65 score, the CRB65 score, the American Thoracic Society (ATS) 2001 criteria and the Infectious Disease Society of America/ATS (IDSA/ATS) 2007 criteria. The analysis was limited due to large variations in the ICU admission criteria, ICU admission rates and patient characteristics between different studies and different healthcare systems. In the pooled analysis, PSI, CURB65 and CRB65 performed similarly in terms of sensitivity and specificity across a range of cut-offs. Patients in CURB65 group 0 were at lowest risk of ICU admission (negative likelihood ratio 0.14; 95% confidence interval 0.06-0.34) while the ATS 2001 criteria had the highest positive likelihood ratio (7.05; 95% confidence interval 4.39-11.3). CONCLUSION: Large variations exist in the use of ICU resources between different studies and different healthcare systems. Scoring systems designed to predict 30-day mortality perform less well when ICU admission is taken into account. Further studies of dedicated ICU admission scores are required. PMID- 21660537 TI - Do anatomic variants of the acromion shape in the frontal plane influence pain and function in calcifying tendinitis of the shoulder? AB - PURPOSE: To evaluate the relationship of a large acromion index and calcifying tendinitis of the supraspinatus tendon at the shoulder. MATERIALS AND METHODS: Between 2002 and 2008, 109 consecutive patients with isolated calcifying tendinitis of the supraspinatus tendon were prospectively analysed by clinical investigation and standardized radiographs. Deposit size and appearance were measured and classified according to Bosworth and Gartner. The acromion index (AI) was calculated based on measurements on true anteroposterior radiographs. Pain record on VAS scale, active and passive range of motion and the constant score (CS) were recorded. RESULTS: The mean age of the patients was 48.2 +/- 8.0 (n = 46 male 48.6 +/- 7.3; n = 63 female 47.9 +/- 8.6; P > 0.05). Pain and function were not significantly correlated with deposit size or classification. The acromion index (mean 0.64 +/- 0.08) was not significantly correlated with the affected or dominant side, gender, deposit size or classification or any functional parameter like pain and the CS or its subgroups. CONCLUSION: The theoretical concept of a high acromion index resulting in an increased resulting upward force against the subacromial space, which influences pain and function in calcifying tendinitis of the shoulder, was not supported. PMID- 21660538 TI - The effect of L-arginine on bladder dysfunction following ovariectomy in a rabbit model. AB - INTRODUCTION AND HYPOTHESIS: The present study was designed to investigate the effect of nitric oxide precursor, L: -arginine, on bladder function following ovariectomy. METHODS: Twenty-eight New Zealand white female rabbits were separated into seven groups. Groups 1 to 6 underwent ovariectomy surgery. Among them, groups 1 and 2 received ovariectomy without treating with L-arginine. Groups 3, 4, 5, and 6 were given high L-arginine diet and were sacrificed 1, 3, 7, and 14 days after ovariectomy, respectively. Group 7 served as the control group. The effects of L: -arginine on the contractility of bladder tissues were determined in response to various stimulations. In addition, L-arginine effects on the expression of Rho kinase (ROK), protein kinase C potentiated inhibitor (CPI-17), caldesmon (CaD), and calponin (CaP) were studied by immunoblotting. RESULTS: Ovariectomy significantly decreases contractile response to all forms of stimulation. Feeding rabbits L: -arginine significantly increases contractile response at 1 day following ovariectomy, but the response decreases to the control level by 14 days. Ovariectomy increases the expressions of both isoforms of CaD, CaP, and CPI-17; L-arginine treatment induces ROK underexpression, while CaP is overexpressed in the early few days of ovariectomy but returns to the control level at 2 weeks after ovariectomy. CONCLUSIONS: Ovariectomy appreciably reduced bladder contractility. Treatment with L-arginine reversed the ovariectomy induced bladder dysfunction. Decreased bladder contractile response was observed in the early days following ovariectomy. PMID- 21660539 TI - Oral budesonide treatment for protein-losing enteropathy in Fontan-palliated patients. AB - Protein-losing enteropathy (PLE) is a rare complication of Fontan palliation associated with significant morbidity and mortality. It is characterized by the loss of serum proteins into the intestinal lumen, and its pathophysiology likely involves enteral inflammation. Budesonide, an oral steroid, is an attractive treatment option because of its potent enteral activity and minimal systemic side effects. A single-center, retrospective review of Fontan-palliated PLE patients treated with oral budesonide for 6 months or longer was performed. The patient characteristics reviewed were demographics, anatomic diagnosis, budesonide treatment (dose and duration), other medications and therapeutic interventions, hospitalizations, serum albumin levels, medical complications, and patient status at the time of follow-up assessment. The study enrolled 10 patients representing 228 patient-months of on-therapy follow-up evaluation. Serum albumin levels increased after initiation of budesonide for 90% of the patients, and clinical evidence of fluid overload improved for 60% of them. Symptomatic improvement was reported in 80% of the cases. During the treatment period, 50% of the patients met the primary end point of death or cardiac transplantation. In this series of PLE patients, oral budesonide therapy was associated with significant symptomatic improvement and sustained increases in serum albumin. However, budesonide therapy may not alter the long-term outcome for patients with advanced PLE. PMID- 21660540 TI - Surgical resection of brain metastases: the prognostic value of the graded prognostic assessment score. AB - There is a need for better predictors for short survival in patients with brain metastases undergoing open surgery. The graded prognostic assessment (GPA) has recently been developed to predict survival in patients with brain metastases. We explored the prognostic capabilities of GPA in a consecutive neurosurgical population of brain metastases. Secondarily, we evaluated if GPA scores can provide information on safety of the operation and postoperative functional outcome. We retrospectively included all adult (>= 18 years) patients undergoing open surgery for brain metastases from 2004 through 2009 (n = 141). The population was grouped into GPA 0-1 (n = 22, 16%), GPA 1.5-2.5 (n = 90, 64%), GPA 3 (n = 19, 14%), and GPA 3.5-4 (n = 10, 7%) according to the prognostic indices. Median survival times were 6.3 months (range 0.8-23.7) in GPA 0-1, 7.8 months in GPA 1.5-2.5 (range 0.2-75.0), 14.0 months in GPA 3 (range 0.0-77.4), and 18.4 months in GPA 3.5-4 (range 0.1-63.7). This represents a significant difference between groups (P = 0.010). There were no associations between GPA and 30-day mortality (P = 0.871), 3-month mortality (P = 0.750), complications (P = 0.330) or change in Karnofsky Performance status postoperatively (P = 0.558). GPA scores hold prognostic properties in patients operated for brain metastases. However, GPA did not predict short-term mortality, limiting the clinical usefulness in a neurosurgical population. The prognostic indices cannot be used alone to decide if surgery is warranted on an individual basis, or to evaluate risks and benefits of surgery. PMID- 21660541 TI - Myoinhibitory peptide (MIP) immunoreactivity in the visual system of the blowfly Calliphora vomitoria in relation to putative clock neurons and serotonergic neurons. AB - A few types of peptidergic clock neurons have been identified in the fruitfly Drosophila, whereas in blowflies, only pigment-dispersing factor (PDF) immunoreactive lateral ventral clock neurons (LN(v)s) have been described. In blowflies, but not Drosophila, a subset of these PDF-expressing neurons supplies axon branches to a region outside the synaptic layer of the lamina, the most peripheral optic lobe neuropil. In Drosophila, similar lamina processes are instead supplied by non-clock neurons (LMIo) that express myoinhibitory peptide (MIP). We have investigated the distribution of MIP-immunoreactive neurons in the visual system of the blowfly Calliphora vomitoria and found neurons resembling the three LMIos, but without processes to the lamina. In Calliphora, PDF immunoreactive processes of LN(v)s in the lamina closely impinge on branching serotonin-immunoreactive axon terminations in the same region. We have also identified, in the blowfly, two types of putative clock neurons that label with an antiserum to ion-transport peptide (ITP). The presence of serotonin immunoreactive neurons supplying processes to the lamina seems to be a conserved feature in dipteran flies. The morphology of the two types of ITP-immunoreactive clock neurons might also be conserved. However, peptidergic neurons with branches converging on the serotonin-immunoreactive neurons in the lamina are of different morphological types and express PDF in blowflies and MIP in Drosophila. The central circuitry of these PDF- and MIP-expressing neurons probably differs; consequently, whether their convergence on serotonergic neurons subserves similar functions in the two species is unclear. PMID- 21660542 TI - Effects of entrapment on nucleic acid content, cell morphology, cell surface property, and stress of pure cultures commonly found in biological wastewater treatment. AB - The effects of cell entrapment on nucleic acid content, cell morphology, cell surface property, and stress of major groups of bacteria (betaproteobacteria and gammaproteobacteria) in biological municipal wastewater treatment were investigated. Three different entrapment media (alginate, carrageenan, and polyvinyl alcohol) were examined. Results indicated that the entrapment and type of entrapment media affected nucleic acid content, cell morphology, cell surface property, and stress of the three representative species (Alcaligenes faecalis, Comamonas testosteroni, and Pseudomonas putida) studied. The highest deoxyribonucleic acid and ribonucleic acid increases were observed with the alginate and polyvinyl alcohol (PVA) entrapment, respectively. A cell morphological change from bacilli to coccoidal was observed in the case of alginate entrapment while the PVA-entrapped cells had a slim morphology when compared to non-entrapped cells and formed putative nanowires. The entrapment increased or decreased the surface roughness of cells depending on the type of entrapment media. Expression of a nitrosative stress gene, which is linked to oxygen deprivation, was observed more in the alginate-entrapped cells. These research findings advance the fundamental understanding of the entrapped cell physiology which can lead to more efficient entrapped cell-based wastewater treatment. PMID- 21660543 TI - Biodegradation of Enteromorpha prolifera by mangrove degrading micro-community with physical-chemical pretreatment. AB - The bacteria involved in the biodegradation of Enteromorpha prolifera (EP) are largely unknown, especially in offshore mangrove environments. In order to obtain the bacterial EP-degrading communities, sediments from a typical mangrove forest were sampled on the roots of mangrove in Dongzhai Port (Haikou, China). The sediments were enriched with crude EP powders as the sole carbon source. The bacterial composition of the resulting mangrove-degrading micro-community (MDMC), named D2-1, was analysed. With methods of plate cultivation and polymerase chain reaction-denaturing gradient gel electrophoresis and 16S rRNA library analysis, 18 bacteria belonging to nine genera were detected from this community. Among these detected bacteria, five major bands closely related to Bacillus, Marinobacter, Paenibacillus, Photobacterium, and Zhouia were determined. A novel two-step pretreatment for EP was proposed to lower the severity requirement of biodegraded pretreatment time. It consisted of a mild physical or chemical step (ultrasonic or H(2)O(2)) and a subsequent biological treatment with community D2 1. The combined treatment led to significant increases in the EP degradation. After combined treatment, the net yields of total soluble sugars and reducing sugars increased. The combined pretreatment of H(2)O(2) (2%, 48 h) and MDMC (7 days) was more effective than the treatment of MDMC only for 15 days. It could remarkably shorten the residence time and reduce the losses of carbohydrates. PMID- 21660544 TI - Are alkane hydroxylase genes (alkB) relevant to assess petroleum bioremediation processes in chronically polluted coastal sediments? AB - The diversity of alkB-related alkane hydroxylase sequences and the relationship between alkB gene expression and the hydrocarbon contamination level have been investigated in the chronically polluted Etang-de-Berre sediments. For this purpose, these sediments were maintained in microcosms and submitted to a controlled oil input miming an oil spill. New degenerated PCR primers targeting alkB-related alkane hydroxylase sequences were designed to explore the diversity and the expression of these genes using terminal restriction fragment length polymorphism fingerprinting and gene library analyses. Induction of alkB genes was detected immediately after oil addition and their expression detected only during 2 days, although the n-alkane degradation was observed throughout the 14 days of incubation. The alkB gene expression within triplicate microcosms was heterogeneous probably due to the low level of alkB transcripts. Moreover, the alkB gene expression of dominant OTUs has been observed in unoiled microcosms indicating that the expression of this gene cannot be directly related to the oil contamination. Although the dominant alkB genes and transcripts detected were closely related to the alkB of Marinobacter aquaeolei isolated from an oil producing well, and to alkB genes related to the obligate alkanotroph Alcanivorax borkumensis, no clear relationship between the oil contamination and the expression of the alkB genes could be established. This finding suggests that in such coastal environments, alkB gene expression is not a function relevant enough to monitor bacterial response to oil contamination. PMID- 21660545 TI - Diversity and phylogeny of bacteria on Zimbabwe tobacco leaves estimated by 16S rRNA sequence analysis. AB - Microorganisms play important roles in the tobacco aging process. However, microbial communities on flue-cured tobacco leaves (FCTL) remain largely unknown. In this study, the total microbial genomic DNA of unaged and aging FCTL from Zimbabwe were isolated using a culture-independent method, and the bacterial communities were investigated through analyzing two 16S rRNA gene libraries. Eighty-four and 65 operational taxonomic units were obtained from the libraries of the unaged and aging FCTL, respectively. The following genera were represented more than 4% in both libraries (aging and unaged library): Sphingomonas (4.84%, 4.18%), Stenotrophomonas (4.84%, 5.23%), Erwinia (5.81%, 4.88%), Pantoea (19.35%, 18.47%), and Pseudomonas (21.29%, 24.04%). The dominant species varied between the two libraries. Specifically, several dominant species in unaged FCTL including Pseudomonas fulva, Pseudomonas sp. (AM909658), Klebsiella sp. (HM584796), and Pantoea sp. (AY501386) were not identified in aging FCTL, while several dominant species in aging FCTL such as Pantoea sp. (GU566350), Pseudomonas sp. (EF157292), and Buttiauxella izardii were not found in unaged FCTL. The phylogenetic analysis showed that bacteria from unaged and aging FCTL were divided into two clades, and two unique subclades were identified in aging FCTL. Our results revealed for the first time the bacterial diversities on Zimbabwe tobacco, and provided a basis for clarifying the roles of bacteria in aging process of FCTL. PMID- 21660546 TI - Zinc homeostasis and signaling in health and diseases: Zinc signaling. AB - The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn's dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis. PMID- 21660548 TI - The expression of floral organ identity genes in contrasting water lily cultivars. AB - The floral organs of typical eudicots such as Arabidopsis thaliana are arranged in four characteristic whorls, namely the sepal, petal, stamen and carpel, and the "ABC" floral organ identity model has been based on this arrangement. However, the floral organs in most basal angiosperms are spirally arranged with a gradual transition from the inside to outside, and an alternative model referred to as "fading borders" was developed to take account of this. The flower morphology of the water lily was tested against the "fading borders" model by determining the expression profile of the six primary floral organ identity genes AP2, AGL6, AP3, PI, AG and SEP1 in two cultivars showing contrasting floral morphology. In addition, to get accurate floatation of the genes expression level from outer to inner, we divided the floral organs into eight whorls according to morphological features. All these genes were expressed throughout all whorls of the flower, but their expression level changed gradually from the outside of the flower to its inside. This pattern was consistent with the "fading borders" model. PMID- 21660547 TI - Cell biology of molybdenum in plants. AB - The transition element molybdenum (Mo) is of essential importance for (nearly) all biological systems as it is required by enzymes catalyzing important reactions within the cell. The metal itself is biologically inactive unless it is complexed by a special cofactor. With the exception of bacterial nitrogenase, where Mo is a constituent of the FeMo-cofactor, Mo is bound to a pterin, thus forming the molybdenum cofactor (Moco) which is the active compound at the catalytic site of all other Mo-enzymes. In plants, the most prominent Mo-enzymes are nitrate reductase, sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase, and the mitochondrial amidoxime reductase. The biosynthesis of Moco involves the complex interaction of six proteins and is a process of four steps, which also includes iron as well as copper in an indispensable way. After its synthesis, Moco is distributed to the apoproteins of Mo-enzymes by Moco-carrier/binding proteins that also participate in Moco-insertion into the cognate apoproteins. Xanthine dehydrogenase and aldehyde oxidase, but not the other Mo-enzymes, require a final step of posttranslational activation of their catalytic Mo-center for becoming active. PMID- 21660549 TI - Asymmetric somatic hybridization between Bupleurum scorzonerifolium Willd. and Taxus chinensis var. mairei. AB - In an attempt to transfer the genetic components needed for taxol synthesis into a more tractable plant, protoplasts of Taxus chinensis var. mairei were UV irradiated for various times prior to their fusion with protoplasts of Bupleurum scorzonerifolium. Of the 60 presumptive hybrid calli obtained, selections of the 9 most rapidly growing were recognized as hybrid clones based on a combination of their callus morphology, esterase profile, chromosome number, and RAPD genotype. The RAPD data showed that 82.4-96.8% of the hybrid genome was inherited from the recipient (B. scorzonerifolium) and 4.6-13.9% from the donor (T. chinensis), with 1.6-6.9% of the RAPD fragments being not present in either parent. None of the hybrid clones expressed a detectable quantity of taxol, but four produced more of the triterpenoid oleanolic acid than did calli of the recipient. With the use of semi-quantitative reverse transcriptase PCR, it was possible to show variation in the expression of several triterpenoid biosynthetic pathway related genes between B. scorzonerifolium and the hybrids. Increasing the concentration of oleanolic acid requires that the expression levels of the genes encoding IPP isomerase, squalene synthase, squalene epoxidase and beta-amyrin synthase are increased, while at the same time, those of the genes encoding the branching enzymes cycloartenol synthase and lupeol synthase need to be reduced. PMID- 21660550 TI - Geospatial strategy for sustainable management of municipal solid waste for growing urban environment. AB - This paper presents the implementation of a Geospatial approach for improving the Municipal Solid Waste (MSW) disposal suitability site assessment in growing urban environment. The increasing trend of population growth and the absolute amounts of waste disposed of worldwide have increased substantially reflecting changes in consumption patterns, consequently worldwide. MSW is now a bigger problem than ever. Despite an increase in alternative techniques for disposing of waste, land filling remains the primary means. In this context, the pressures and requirements placed on decision makers dealing with land-filling by government and society have increased, as they now have to make decisions taking into considerations environmental safety and economic practicality. The waste disposed by the municipal corporation in the Bhagalpur City (India) is thought to be different from the landfill waste where clearly scientific criterion for locating suitable disposal sites does not seem to exist. The location of disposal sites of Bhagalpur City represents the unconsciousness about the environmental and public health hazards arising from disposing of waste in improper location. Concerning about urban environment and health aspects of people, a good method of waste management and appropriate technologies needed for urban area of Bhagalpur city to improve this trend using Multi Criteria Geographical Information System and Remote Sensing for selection of suitable disposal sites. The purpose of GIS was to perform process to part restricted to highly suitable land followed by using chosen criteria. GIS modeling with overlay operation has been used to find the suitability site for MSW. PMID- 21660551 TI - Development and use of a Floristic Quality Index for coastal Louisiana marshes. AB - The Floristic Quality Index (FQI) has been used as a tool for assessing the integrity of plant communities and for assessing restoration projects in many regions of the USA. Here, we develop a modified FQI (FQI(mod)) for coastal Louisiana wetlands and verify it using 12 years of monitoring data from a coastal restoration project. Plant species that occur in coastal Louisiana were assigned a coefficient of conservatism (CC) score by a local group with expertise in Louisiana coastal vegetation. Species percent cover and both native and non native species were included in the FQI(mod) which was scaled from 0-100. The FQI(mod) scores from the long-term monitoring project demonstrated the utility of this index for assessing wetland condition over time, including its sensitivity to a hurricane. Ultimately, the FQI developed for coastal Louisiana will be used in conjunction with other wetland indices (e.g., hydrology and soils) to assess wetland condition coastwide and these indices will aid managers in coastal restoration and management decisions. PMID- 21660552 TI - Concentrations of some heavy metals in commercially important finfish and shellfish of the River Ganga. AB - Heavy metals are dangerous to aquatic organisms and it can be bioaccumulated in the food chain leading to diseases in human. Cumulative effects of metals or chronic poisoning may occur as a result of long-term exposure even to low concentrations. The accumulation of heavy metals varies depending upon the species, environmental conditions, and inhibitory processes. Concentrations of zinc, copper, lead, and cadmium were determined in finfish and shellfish species in the Gangetic delta using a PerkinElmer Sciex ELAN 5000 ICP mass spectrometer and expressed as milligrams per kilogram of dry weight. In finfish and shellfish species the concentrations of Zn, Cu, Pb, and Cd were comparatively higher at stations 1 and 2 than the permissible level of WHO. The concentration of metals exhibited significant spatial variation and followed the order station 1 > station 2 > station 3 > station 4, which may be related to different degree of contamination in different location. The metal accumulation exhibited species specificity. PMID- 21660553 TI - Environmental genotoxicity and cytotoxicity studies in mussels before and after an oil spill at the marine oil terminal in the Baltic Sea. AB - Environmental genotoxicity and cytotoxicity effects in the gills of mussels Mytilus edulis, from the Baltic Sea areas close to the Butinge oil terminal (Lithuania) before and after accidental oil spill in 31 January 2008 were studied. Mussels from the oil spillage zones were collected in 12 days, in 3 and 6 months after the spill to determine the effects of the spill. Mussels sampled in 2006-2007 were used for the assessment of the background levels of genotoxicity and cytotoxicity in the Butinge oil terminal area. Comparison of the responses in M. edulis before and after the oil spill revealed significant elevation of frequencies of micronuclei (MN), nuclear buds (NB) and fragmented apoptotic (FA) cells. Environmental genotoxicity and cytotoxicity levels in mussels from the Palanga site before the accident (in June 2007) served as a reference. Six months after the accident, in July 2008, 5.6-fold increase of MN, 2.9-fold elevation of NB, and 8.8-fold elevation of FA cells were observed in mussels from the same site. PMID- 21660555 TI - Similar maternal and paternal relationships with offspring bone mass do not exclude an intrauterine mechanism: evidence from Southampton Women's Survey. PMID- 21660556 TI - Non-elite gymnastics participation is associated with greater bone strength, muscle size, and function in pre- and early pubertal girls. AB - Recent reports indicate an increase in forearm fractures in children. Bone geometric properties are an important determinant of bone strength and therefore fracture risk. Participation in non-elite gymnastics appears to contribute to improving young girls' musculoskeletal health, more specifically in the upper body. INTRODUCTION: The primary aim of this study was to determine the association between non-elite gymnastics participation and upper limb bone mass, geometry, and strength in addition to muscle size and function in young girls. METHODS: Eighty-eight pre- and early pubertal girls (30 high-training gymnasts [HGYM, 6-16 hr/ wk], 29 low-training gymnasts [LGYM, 1-5 h r/wk] and 29 non gymnasts [NONGYM]), aged 6-11 years were recruited. Upper limb lean mass, BMD and BMC were derived from a whole body DXA scan. Forearm volumetric BMD, bone geometry, estimated strength, and muscle CSA were determined using peripheral QCT. Upper body muscle function was investigated with muscle strength, explosive power, and muscle endurance tasks. RESULTS: HGYM showed greater forearm bone strength compared with NGYM, as well as greater arm lean mass, BMC, and muscle function (+5% to +103%, p < 0.05). LGYM displayed greater arm lean mass, BMC, muscle power, and endurance than NGYM (+4% to +46%, p < 0.05); however, the difference in bone strength did not reach significance. Estimated fracture risk at the distal radius, which accounted for body weight, was lower in both groups of gymnasts. Compared with NONGYM, HGYM tended to show larger skeletal differences than LGYM; yet, the two groups of gymnasts only differed for arm lean mass and muscle CSA. CONCLUSION: Non-elite gymnastics participation was associated with musculoskeletal benefits in upper limb bone geometry, strength and muscle function. Differences between the two gymnastic groups emerged for arm lean mass and muscle CSA, but not for bone strength. PMID- 21660557 TI - Calcitonin for treating acute and chronic pain of recent and remote osteoporotic vertebral compression fractures: a systematic review and meta-analysis. AB - Vertebral collapse is a common fracture associated with osteoporosis. Subsequent pain may be severe and often requires medications and bed rest. Several studies have suggested the use of calcitonin for the treatment of fracture pain. We sought to determine the analgesic efficacy of calcitonin for acute and chronic pain of osteoporotic vertebral compression fractures (OVCF). We searched for randomized, placebo, and controlled trials that evaluated the analgesic efficacy of calcitonin for pain attributable to OVCFs. We performed meta-analyses to calculate standardized mean differences (SMDs) using a fixed or random effects model. The combined results from 13 trials (n = 589) determined that calcitonin significantly reduced the severity of acute pain in recent OVCFs. Pain at rest was reduced by week 1 [mean difference (MD) = -3.39, 95% confidence interval (CI) = -4.02 to -2.76), with continued improvement through 4 weeks. At week 4, the difference in pain scores with mobility was even greater (SMD = -5.99, 95% CI = 6.78 to -5.19). For patients with chronic pain, there was no statistical difference between groups while at rest; there was a small, statistically significant difference between groups while mobile at 6 months (SMD = 0.49, 95% CI = -0.85 to -0.13, p = 0.008). Side effects were mild, with enteric disturbances and flushing reported most frequently. Although calcitonin has proven efficacy in the management of acute back pain associated with a recent OVCF, there is no convincing evidence to support the use of calcitonin for chronic pain associated with older fractures of the same origin. PMID- 21660558 TI - Long-term treatment with raloxifene, but not bisphosphonates, reduces circulating sclerostin levels in postmenopausal women. AB - We determined whether suppression of sclerostin levels by estrogen treatment was mediated by anti-resorptive effect. Raloxifene, but not bisphosphonates, suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti resorptive effects. INTRODUCTION: Circulating sclerostin concentrations are higher in postmenopausal than in premenopausal women, and estrogen treatment suppresses sclerostin levels in both men and women. We determined whether anti resorptives may suppress the circulating sclerostin levels. METHODS: We conducted a retrospective observational study. Eighty postmenopausal women were treated with raloxifene for 19.4 +/- 7.7 months (n = 16), bisphosphonates for 19.2 +/- 6.7 months (n = 32), or were untreated (n = 32) for 17.1 +/- 4.6 months. Plasma sclerostin concentrations were measured before and after treatment. RESULTS: Plasma sclerostin levels after treatment were significantly lower in the raloxifene than in the control group (55.8 +/- 23.4 pmol/l vs. 92.1 +/- 50.4 pmol/l, p = 0.046), but were similar between the bisphosphonate and control groups. Relative to baseline, raloxifene treatment markedly reduced plasma sclerostin concentration (-40.7 +/- 22.8%, p < 0.001), with respect to both control (-7.5 +/- 29.1%) and bisphosphonate (-3.1 +/- 35.2%) groups. Changes in bone-specific alkaline phosphatase and osteocalcin levels showed reverse associations with sclerostin concentration changes in the raloxifene (gamma = 0.505, p = 0.017) and control (gamma = -0.410, p = 0.020) groups. CONCLUSIONS: Raloxifene, but not bisphosphonates, significantly suppressed circulating sclerostin concentration, suggesting that sclerostin may mediate the action of estrogen on bone metabolism, independently of their anti-resorptive effects. PMID- 21660559 TI - LDH-A influences hypoxia-inducible factor 1alpha (HIF1 alpha) and is critical for growth of HT29 colon carcinoma cells in vivo. AB - Serum lactate dehydrogenase (LDH) is a well-known clinical surrogate parameter. A high activity of LDH is associated with a poor prognosis in different tumor types. Here we demonstrate by a gene silencing approach that LDH-A is critical for in vivo but not in vitro growth of HT29 colon carcinoma cells. We provide evidence that the suppression of the LDH-A gene leads to an increased level of hypoxia inducible factor 1alpha (HIF1alpha) but in consequence not to an increase of HIF1 regulated proteins such as carbonic anhydrase IX (CAIX), vascular endothelial growth factor (VEGF), prolyl-hydroxylase 2 (PHD2), and factor inhibiting HIF (FIH) in cell cultures and tumor lysates. This effect is independent of LDH activity in vivo. We conclude that LDH-A has an influence on the activity of HIF1alpha and thus on the adaptation of cells to a hypoxic tumor microenvironment in HT29 colon cells. We suggest the use of LDH-M as a potential therapeutic target for anticancer treatment. PMID- 21660560 TI - Time optimal control of spiking neurons. AB - By injecting an electrical current control stimulus into a neuron, one can change its inter-spike intervals. In this paper, we investigate the time optimal control problem for periodically firing neurons, represented by different one-dimensional phase models, and find analytical expressions for the minimum and maximum values of inter-spike intervals achievable with small bounded control stimuli. We consider two cases: with a charge-balance constraint on the input, and without it. The analytical calculations are supported with numerical results for examples of qualitatively different neuron models. PMID- 21660562 TI - Economic evaluation of pay-for-performance in health care: a systematic review. AB - BACKGROUND: Pay-for-performance (P4P) intents to stimulate both more effective and more efficient health care delivery. To date, evidence on whether P4P itself is an efficient method has not been systematically analyzed. OBJECTIVE: To identify and analyze the existing literature regarding economic evaluation of P4P. DATA SOURCES: English, German, Spanish, and Turkish language literature were searched in the following databases: Business Source Complete, the Cochrane Library, Econlit, ISI web of knowledge, Medline (via PubMed), and PsycInfo (January 2000-April 2010). STUDY SELECTION: Articles published in peer-reviewed journals and describing economic evaluations of P4P initiatives. Full economic evaluations, considering costs and consequences of the P4P intervention simultaneously, were the prime focus. Additionally, comparative partial evaluations were included if costs were described and the study allows for an assessment of consequences. Both experimental and observational studies were considered. RESULTS: In total, nine studies could be identified. Three studies could be regarded as full economic evaluations, and six studies were classified as partial economic evaluations. Based on the full economic evaluations, P4P efficiency could not be demonstrated. Partial economic evaluations showed mixed results, but several flaws limit their significance. Ranges of costs and consequences were typically narrow, and programs differed considerably in design. Methodological quality assessment showed scores between 32% and 65%. CONCLUSION: The results show that evidence on the efficiency of P4P is scarce and inconclusive. P4P efficiency could not be demonstrated. The small number and variability of included studies limit the strength of our conclusions. More research addressing P4P efficiency is needed. PMID- 21660561 TI - Energy failure in multiple sclerosis and its investigation using MR techniques. AB - Energy failure is an emerging concept in multiple sclerosis research. Pathological studies have indicated that axonal modifications in response to demyelination may increase neuronal energy demand. At the same time, soluble mediators of inflammation may impair mitochondrial function, and brain perfusion may also be decreased. Insufficient energy production for demand can lead to intracellular sodium accumulation, calcium influx and cell death. Magnetic resonance (MR) is a promising technique to investigate these pathology driven hypotheses in vivo. MR spectroscopy can inform on mitochondrial function with measures of N acetyl aspartate (NAA), and requirement for extra-mitochondrial glycolysis via measurement of lactate. MR measurement of phosphorous ((31)P) and sodium ((23)Na) allows direct assessment of energy availability and axonal sodium handling. MR techniques for imaging perfusion can quantify oxygen delivery and nascent MR techniques that exploit the paramagnetism of deoxyhaemaglobin may be able to quantify oxygen utilization. This report reviews the physical principles underlying these techniques, their implementation for human in vivo imaging, and their application in neurological conditions with an emphasis on multiple sclerosis. Combination of these techniques to obtain a comprehensive picture of oxygen delivery, energy production and utilization may provide new insights into the pathophysiology of multiple sclerosis and may provide outcome measures for trials of novel treatments. PMID- 21660563 TI - Cancer patients' willingness to pay for blood transfusions at home: results from a contingent valuation study in a French cancer network. AB - Home blood transfusion may be an interesting alternative to hospital transfusion, especially when given with curative or palliative intent or for terminal care in advanced-stage cancer patients. However, there is limited information about patients' attitude toward this type of care. The purpose of this study was to measure French cancer patients' willingness to pay (WTP) for home blood transfusion and to analyze determinants of their choice. A contingent valuation survey was administered to 139 patients receiving transfusions in the framework of a regional home care network or in the hospital outpatient department. Participation was high (90%). Most patients (65%) had received home care, including 43% blood transfusions. Just under half of the patients gave a zero WTP, among which we identified 8 protest bidders. The median WTP for home blood transfusion was 26.5 per patient. In multivariate analysis, long home hospital distance, poor quality of life, and previous experience of home care were identified as important factors in determining how much more patients would be willing to pay for transfusion at home. These results demonstrate the benefits of developing domiciliary services to improve patient well-being, notably for the weakest among them. The significant impact of previous home care experience on WTP is probably related to the strong involvement of physicians from the blood center and to their active contribution to a high-level homecare network. Some of our findings could be useful for policy decision-making regarding home care. PMID- 21660564 TI - Health care usage among immigrants and native-born elderly populations in eleven European countries: results from SHARE. AB - Differences in health care utilization of immigrants 50 years of age and older relative to the native-born populations in eleven European countries are investigated. Negative binomial and zero-inflated Poisson regression are used to examine differences between immigrants and native-borns in number of doctor visits, visits to general practitioners, and hospital stays using the 2004 Survey of Health, Ageing, and Retirement in Europe database. In the pooled European sample and in some individual countries, older immigrants use from 13 to 20% more health services than native-borns after demographic characteristics are controlled. After controlling for the need for health care, differences between immigrants and native-borns in the use of physicians, but not hospitals, are reduced by about half. These are not changed much with the incorporation of indicators of socioeconomic status and extra insurance coverage. Higher country level relative expenditures on health, paying physicians a fee-for-service, and physician density are associated with higher usage of physician services among immigrants. PMID- 21660565 TI - The use of cost per life year gained as a measurement of cost-effectiveness in Spain: a systematic review of recent publications. AB - OBJECTIVES: The objective of this study was to evaluate the methodological characteristics of cost-effectiveness evaluations carried out in Spain, since 1990, which include LYG as an outcome to measure the incremental cost effectiveness ratio. METHODS: A systematic review of published studies was conducted describing their characteristics and methodological quality. We analyse the cost per LYG results in relation with a commonly accepted Spanish cost effectiveness threshold and the possible relation with the cost per quality adjusted life year (QALY) gained when they both were calculated for the same economic evaluation. RESULTS: A total of 62 economic evaluations fulfilled the selection criteria, 24 of them including the cost per QALY gained result as well. The methodological quality of the studies was good (55%) or very good (26%). A total of 124 cost per LYG results were obtained with a mean ratio of 49,529 and a median of 11,490 (standard deviation of 183,080). Since 2003, a commonly accepted Spanish threshold has been referenced by 66% of studies. A significant correlation was found between the cost per LYG and cost per QALY gained results (0.89 Spearman-Rho, 0.91 Pearson). CONCLUSIONS: There is an increasing interest for economic health care evaluations in Spain, and the quality of the studies is also improving. Although a commonly accepted threshold exists, further information is needed for decision-making as well as to identify the relationship between the costs per LYG and per QALY gained. PMID- 21660566 TI - A combination of 2-deoxy-D-glucose and 6-aminonicotinamide induces oxidative stress mediated selective radiosensitization of malignant cells via mitochondrial dysfunction. AB - Oxidative stress-mediated mitochondrial dysfunction is known to induce intrinsic pathway of apoptosis. Previously, we have shown that a combination of metabolic modifiers 2-deoxy-D-glucose (2-DG) and 6-aminonicotinamide (6-AN) results in oxidative stress-mediated radiosensitization of malignant cells via noncoordinated expression of antioxidant defense. We now show that the combination (2-DG + 6-AN + 2Gy) induces significant alterations in mitochondrial membrane potential and oxidative damage to lipid and proteins selectively in malignant cells resulting in the release of cytochrome c from mitochondria and increase in Bax/Bcl-2 ratio stimulating intrinsic pathway of apoptosis, besides enhancing the mitotic death linked to cytogenetic damage. These results highlight the role of mitochondrial dysfunction in selective radiosensitization by 2-DG + 6 AN, besides inhibition of energy-linked DNA repair processes and generation of oxidative stress reported earlier. PMID- 21660567 TI - Expression of PIK3CA and FOXP1 in gastric and intestinal non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue type. AB - Non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue (MALT) type arises from a wide variety of extranodal sites, most frequently from the gastrointestinal tract. Recently, it has been demonstrated that karyotypic alterations involving the PIK3CA and FOXP1 genes of chromosome 3 occur in MALT lymphoma. However, their associated protein expression has not been extensively studied. Tumor tissues from 27 gastric and 23 intestinal MALT lymphomas were analyzed for PIK3CA and FOXP1 protein expression using immunohistochemistry and correlated with histological features and treatment outcomes. Expression of PIK3CA, a novel indicator, was found in 40% of gastrointestinal cases and indicated an inferior progression-free survival in both gastric and intestinal MALT lymphomas (P = 0.001 and P = 0.015). Tumor staining of nuclear FOXP1 (46.0%) was more common in gastric than intestinal MALT lymphomas (P = 0.042) and was significantly associated with polymorphic histology (P = 0.007). FOXP1 expression was identified as an adverse prognostic factor for overall survival in gastric MALT lymphomas (P = 0.035). We further combined these two markers and observed that patients that are positive for both PIK3CA and FOXP1 had a worse overall and progression-free survival. Considering the small sample size of this study, these results should be confirmed in a large prospective study. PMID- 21660568 TI - Role of alkaline phosphatase in insecticidal action of Cry1Ac against Helicoverpa armigera larvae. AB - Cry1Ac delta-endotoxin produced by Bacillus thuringiensis (Bt) is used as a bio pesticide for the control of Helicoverpa armigera. Aminopeptidases N (APN) and alkaline phosphatase (ALP) play critical roles in its action against H. armigera larvae. The binding of Cry1Ac with brush border membrane vesicle (BBMV) proteins was increased with the larval development although the sensitivity of larvae to delta-endotoxins decreased. There was higher expression of ALP than APN in early instar larvae with a ~10-fold higher affinity of Cry1Ac towards ALP than to APN. Binding to a specific receptor is therefore more important for the insecticidal activity rather than overall binding to the BBMV proteins. ALP might play a major role in toxicity as compared to APN. PMID- 21660569 TI - The significance of peroxisomes in secondary metabolite biosynthesis in filamentous fungi. AB - Peroxisomes are ubiquitous organelles characterized by a protein-rich matrix surrounded by a single membrane. In filamentous fungi, peroxisomes are crucial for the primary metabolism of several unusual carbon sources used for growth (e.g. fatty acids), but increasing evidence is presented that emphasize the crucial role of these organelles in the formation of a variety of secondary metabolites. In filamentous fungi, peroxisomes also play a role in development and differentiation whereas specialized peroxisomes, the Woronin bodies, play a structural role in plugging septal pores. The biogenesis of peroxisomes in filamentous fungi involves the function of conserved PEX genes, as well as genes that are unique for these organisms. Peroxisomes are also subject to autophagic degradation, a process that involves ATG genes. The interplay between organelle biogenesis and degradation may serve a quality control function, thereby allowing a continuous rejuvenation of the organelle population in the cells. PMID- 21660570 TI - Lipase-catalyzed syntheses of sugar esters in non-aqueous media. AB - The lipase-catalyzed reaction is useful to obtain sugar esters with chemically defined structures and will contribute to the synthesis of sugar-based compounds by a chemo-enzymatic pathway. The synthesis of sugar esters in nonaqueous media has been attempted for a quarter century. To facilitate the reactions, they have been performed either in an organic solvent with/without a polar adjuvant or in an ionic liquid, or by using a hydrophobic sugar derivative. In this review, the following points are discussed: (1) various synthetic methods of sugar esters; (2) role of the solvents or adjuvants; and (3) improvement in the productivity. PMID- 21660571 TI - Biotechnological perspectives of microbes in agro-ecosystems. AB - In subsistence agricultural systems, crop yields are directly dependent on the inherent soil fertility and on microbial processes that govern the mineralization and mobilization of nutrients required for plant growth. An impact of different crop species that are used in various combinations is likely to be an important factor in determining the structure of plant beneficial microbial communities that function in nutrient cycling, the production of plant growth hormones, and suppression of root diseases. In addition, studies are needed to elucidate the signal transduction pathways that result from treatment of plants with plant growth-promoting rhizobacteria under stress conditions. In the present review an emphasis has been given on plant-microbe interactions and their mitigation under abiotic and biotic stresses. PMID- 21660572 TI - Isotopic labeling of the heme cofactor in cytochrome P450 and other heme proteins. AB - A recombinant bacterial expression system that generates (13)C-labeled heme or (15)N-labeled heme in functional cytochrome P450 enzymes and other heme containing systems is reported here using a mutant strain of Escherichia coli (HU227) in which the HemA gene is inactive. By synthesizing several isotopomers of aminolevulinic acid with (13)C or (15)N at different locations, isotopes have been incorporated with high abundance into the heme cofactor of five different cytochrome P450 isoforms, along with one peroxidase. Confirmed both (13)C- and (15)N-incorporation; spectral and catalytic assays show the labeled enzymes produced in this system are functional. PMID- 21660573 TI - A rapid column technique for trapping and collecting of volatile fungal hydrocarbons and hydrocarbon derivatives. AB - A custom-made stainless steel column was designed to contain various materials that would trap the hydrocarbons and hydrocarbon derivatives during the processes of fungal fermentation ultimately yielding preparative amounts of volatile organic substances (VOCs). Trapping materials tested in the column were Carbotrap materials A and B (Supelco) as well as bentonite-shale from the oil bearing areas of Eastern Montana, the former allowed for the effective and efficient trapping of VOCs from purged cultures of Hypoxylon sp. Trapping efficiencies of various materials were measured by both gravimetric as well as proton transfer reaction mass spectroscopy with the Carbotraps A and B being 99% efficient when tested with known amounts of 1,8-cineole. Trapped fungal VOCs could effectively be removed and recovered via controlled heating of the stainless steel column followed by passage of the gases through a liquid nitrogen trap at a recovery rate of ca 65-70%. This method provides for the recovery of mg quantities of compounds normally present in the gas phase that may be needed for spectroscopy, bioassays and further separation and analysis and may have wide applicability for many other biological systems involving VOCs. Other available Carbotraps could be used for other applications. PMID- 21660574 TI - Overexpression of a novel chrysanthemum NAC transcription factor gene enhances salt tolerance in tobacco. AB - The plant-specific NAC (for NAM, ATAF1, 2 and CUC2) transcription factors (TFs) have been implicated in different cellular processes involved in stress responses such as cold, high salinity or drought as well as abscisic acid (ABA) signalling. However, the roles of the chrysanthemum NAC TF genes in plant stress responses are still unclear. A full-length cDNA designated DgNAC1, containing a highly conserved N-terminal DNA-binding NAC domain, has been isolated from chrysanthemum by RACE (rapid amplification of cDNA ends). It encodes a protein of 284 amino acids residues (=~32.9 kDa) and theoretical pI of 7.13. The transcript of DgNAC1 was enriched in roots and flowers than in stems and leaves of the adult chrysanthemum plants. The gene expression was strongly induced by ABA, NaCl, drought and cold treatment in the seedlings. Subcellular localization revealed that DgNAC1:GFP fusion protein was preferentially distributed to nucleus. To assess whether DgNAC1 is a practically useful target gene for improving the stress tolerance of chrysanthemum, we ectopically over-expressed the full-length DgNAC1 cDNA in tobacco and found that the 35S:DgNAC1 transgenic tobacco exhibited a markedly increased tolerance to salt. Despite this increased salt stress tolerance, the transgenic tobacco showed no detectable phenotype defects under normal growth conditions. These results proposed that DgNAC1 is appropriate for application in genetic engineering strategies aimed at improving salt stress tolerance in chrysanthemum. PMID- 21660575 TI - Homology modeling, molecular docking and spectra assay studies of sterol 14alpha demethylase from Penicillium digitatum. AB - Sterol 14alpha-demethylase from Penicillium digitatum (PdCYP51) is a prime target of antifungal drugs for citrus disease in plants. To design novel antifungal compounds, a homology model of PdCYP51 was constructed using the recently reported crystal structure of human CYP51 as the template. Molecular docking was performed to investigate the interaction of four commercial fungicides with the modeled enzyme. The side chain of these compounds interplayed with PdCYP51 mainly through hydrophobic and van der Waals interactions. Biochemical spectra analysis of inhibitors combined with PdCYP51 are also compatible with the docking results. This is the first molecular modeling for PdCYP51 based on the eukaryotic crystal structure of CYP51. The structural information and binding site mapping of PdCYP51 for different inhibitors obtained from this study could aid in screening and designing new antifungal compounds targeting this enzyme. PMID- 21660576 TI - An efficient and rapid method for cDNA cloning from difficult templates using codon optimization and SOE-PCR: with human RANK and TIMP2 gene as examples. AB - As gene cloning from difficult templates with regionalized high GC content is a long recognized problem, we have developed a novel and reliable method to clone such genes. Firstly, the high GC content region of the target cDNA was synthesized directly after codon optimization and the remaining cDNA fragment without high GC content was generated by routine RT-PCR. Then the entire redesigned coding sequence of the target gene was obtained by fusing the above available two cDNA fragments with SOE-PCR (splicing by overlapping extension PCR). We have cloned the human RANK gene (ten exons; CDS 1851 bp) using this strategy. The redesigned cDNA was transfected into an eukaryotic expression system (A459 cells) to verify its expression. RT-PCR and western blotting confirmed this. To validate our method, we also successfully cloned human TIMP2 gene (five exons; CDS 660 bp) also having a regionalized high GC content. Our strategy for combining codon optimization and SOE-PCR to clone difficult genes is thus feasible and potentially universally applicable. PMID- 21660577 TI - Biocatalysed halogenation of nucleobase analogues. AB - The synthesis of halogenated nucleosides and nucleobases is of interest due to their chemical and pharmacological applications. Herein, the enzymatic halogenation of nucleobases and analogues catalysed by microorganisms and by chloroperoxidase from Caldariomyces fumago has been studied. This latter enzyme catalysed the chlorination and bromination of indoline and uracil. Pseudomonas, Citrobacter, Aeromonas, Streptomyces, Xanthomonas, and Bacillus genera catalysed the chlorination and/or bromination of indole and indoline. Different products were obtained depending on the substrate, the biocatalyst and the halide used. In particular, 85% conversion from indole to 5-bromoindole was achieved using Streptomyces cetonii. PMID- 21660578 TI - Osteogenic and angiogenic effects of mesenchymal stromal cells with co transfected human Ang-1 gene and BMP2 gene. AB - To increase the osteogenic and angiogenic effects of marrow-derived mesenchymal stromal cells (MSCs), we co-transfected (by means of lentivirus) the human angiopoietin-1 gene (hAng-1) and human bone morphogenetic protein 2 gene (hBMP2) into MSCs. Real-time PCR and ELISA showed that both genes were successfully co expressed in the MSCs with expression sustained until the eighth week. The alkaline phosphatase activity of the MSCs was more significantly augmented by the co-transfection with both genes than by any single gene transfection. These results demonstrate that the combined gene therapy with hAng-1 and hBMP2 using lentivirally co-transfected MSCs is feasible. PMID- 21660579 TI - Analysis of collagen expression during chondrogenic induction of human bone marrow mesenchymal stem cells. AB - Adult mesenchymal stem cells (MSCs) are currently being investigated as an alternative to chondrocytes for repairing cartilage defects. As several collagen types participate in the formation of cartilage-specific extracellular matrix, we have investigated their gene expression levels during MSC chondrogenic induction. Bone marrow MSCs were cultured in pellet in the presence of BMP-2 and TGF-beta3 for 24 days. After addition of FGF-2, at the fourth passage during MSC expansion, there was an enhancing effect on specific cartilage gene expression when compared to that without FGF-2 at day 12 in pellet culture. A switch in expression from the pre-chondrogenic type IIA form to the cartilage-specific type IIB form of the collagen type II gene was observed at day 24. A short-term addition of FGF-2 followed by a treatment with BMP-2/TGF-beta3 appears sufficient to accelerate chondrogenesis with a particular effect on the main cartilage collagens. PMID- 21660580 TI - Retrieval of rat aortic smooth muscle cells as intact cell sheet for regenerative medicine: a cost effective approach using photo polymerization. AB - Cell-based therapeutics are promising routes for the regeneration of damaged cells and organs. The recovery of cells cultured in vitro for such applications requires the use of proteolytic enzymes which deteriorate its property by disruption of cell-cell and cell-matrix interactions. Intact cell sheets can be retrieved with the use of thermo responsive polymer grafted on to the culture plates. Our study presents the use of photo-polymerization as a simple and inexpensive way to create thermo-responsive culture surfaces for the detachment of intact cell sheet. Poly (N-isopropyl acrylamide) (PNIPAAm) was synthesized by photo-polymerization and characterized by NMR spectroscopy, differential scanning calorimetry and gel permeation chromatography. Thermo-responsive culture dishes were prepared by the coating method and characterized for its thermo-responsive efficacy using FTIR spectroscopy and water contact angle measurements. Atomic force microscopy depicted the thin coating achieved with this method is similar to the conventional grafting method. Suitability for cell culture and cell sheet retrieval was assessed by culturing rat aortic smooth muscle cells in the PNIPAAm coated tissue culture plates. The cells remained viable as evident from the live dead assay and the cell sheet was detached by low temperature treatment. The results demonstrate a versatile method for creating thermo responsive culture surfaces while eliminating the use of expensive radiation sources for the conventional grafting method. PMID- 21660581 TI - Secondary metabolites and nutrients of woody plants in relation to browsing intensity in African savannas. AB - Carbon-based secondary metabolites (CBSMs) are assumed to function as defences that contribute to herbivore-avoidance strategies of woody plants. Severe browsing has been reported to reduce concentrations of CBSMs and increase N concentrations in individual plants, causing heavily browsed plants to be characterised by N-rich/C-poor tissues. We hypothesised that concentrations of condensed tannins (CT) and total polyphenols (TP) should decrease, or N increase, in relation to increasing intensity of browsing, rendering severely browsed plants potentially more palatable (increased N:CT) and less N-limited (increased N:P) than lightly browsed ones. We sampled naturally browsed trees (taller than 2 m) of four abundant species in southern Kruger National Park, South Africa. Species-specific relationships between N:CT, CT, TP and P concentrations and increasing browsing intensity were detected, but N and N:P were consistently invariable. We developed a conceptual post-hoc model to explain diverse species specific CBSM responses on the basis of relative allocation of C to total C-based defence traits (e.g. spines/thorns, tough/evergreen leaves, phenolic compounds). The model suggests that species with low allocation of C to C-based defence traits become C-limited (potentially more palatable) at higher browsing intensity than species with high allocation of C to C-based defences. The model also suggests that when N availability is high, plants become C-limited at higher browsing intensity than when N availability is low. PMID- 21660582 TI - Bromeliad growth and stoichiometry: responses to atmospheric nutrient supply in fog-dependent ecosystems of the hyper-arid Atacama Desert, Chile. AB - Carbon, nitrogen, and phosphorus (C, N, P) stoichiometry influences the growth of plants and nutrient cycling within ecosystems. Indeed, elemental ratios are used as an index for functional differences between plants and their responses to natural or anthropogenic variations in nutrient supply. We investigated the variation in growth and elemental content of the rootless terrestrial bromeliad Tillandsia landbeckii, which obtains its moisture, and likely its nutrients, from coastal fogs in the Atacama Desert. We assessed (1) how fog nutrient supply influences plant growth and stoichiometry and (2) the response of plant growth and stoichiometry to variations in nutrient supply by using reciprocal transplants. We hypothesized that T. landbeckii should exhibit physiological and biochemical plastic responses commensurate with nutrient supply from atmospheric deposition. In the case of the Atacama Desert, nutrient supply from fog is variable over space and time, which suggests a relatively high variation in the growth and elemental content of atmospheric bromeliads. We found that the nutrient content of T. landbeckii showed high spatio-temporal variability, driven partially by fog nutrient deposition but also by plant growth rates. Reciprocal transplant experiments showed that transplanted individuals converged to similar nutrient content, growth rates, and leaf production of resident plants at each site, reflecting local nutrient availability. Although plant nutrient content did not exactly match the relative supply of N and P, our results suggest that atmospheric nutrient supply is a dominant driver of plant growth and stoichiometry. In fact, our results indicate that N uptake by T. landbeckii plants depends more on N supplied by fog, whereas P uptake is mainly regulated by within-plant nutrient demand for growth. Overall, these findings indicate that variation in fog nutrient supply exerts a strong control over growth and nutrient dynamics of atmospheric plants, which are ubiquitous across fog-dominated ecosystems. PMID- 21660583 TI - Genetic influences on pulmonary function: a large sample twin study. AB - Heritability of forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), and peak expiratory flow (PEF) has not been previously addressed in large twin studies. We evaluated the genetic contribution to individual differences observed in FEV(1), FVC, and PEF using data from the largest population-based twin study on spirometry. Specially trained lay interviewers with previous experience in spirometric measurements tested 4,314 Danish twins (individuals), 46-68 years of age, in their homes using a hand-held spirometer, and their flow-volume curves were evaluated. Modern variance component sex limitation models were applied to evaluate possible genetic differences between the sexes for FEV(1), FVC, and PEF. Estimates were adjusted for age, height, and smoking. For FEV(1), additive genetic effects of 61% (95% CI 56-65) were observed. For FVC, the additive genetic contribution was 26% (3-49%) and the dominant genetic contribution was 29% (4-54%). For PEF, our models showed an additive genetic contribution of 43% (31-52%) for men, but genetic influences were not significant in women. We found no significant differences between dizygotic same-sex twins and dizygotic opposite-sex twins for FEV(1), FVC, and PEF, suggesting absence of qualitative genetic differences between the sexes. Sex difference heritability for PEF suggested possible quantitative genetic differences between the sexes for this index. Genetic effects contributed significantly to individual differences observed in FEV(1), FVC, and PEF. Qualitative sex differences were absent for all spirometric measures, while quantitative sex differences were observed only for PEF, with heritability being substantial in men but negligible in women. PMID- 21660585 TI - Surface modification of Ti-6Al-4 V alloy for biomineralization and specific biological response: part II, alkaline phosphatase grafting. AB - Titanium and its alloys are the most widespread materials for the realization of orthopaedic and dental implants due to their good mechanical properties and biocompatibility. Surface functionalization of biomaterials aimed to improve and quicken implant integration and tissue regeneration is an active research field. The opportunity to confer biological activity (ability to directly stimulate cells with proper biological signals) to the Ti6Al4 V alloy, previously modified to be bioactive from the inorganic point of view (apatite precipitation), was explored in this research work. The alkaline phosphatase (ALP) enzyme was grafted to metal surface via tresyl chloride activation, maintaining its activity. A synergistic effect between biological functionalization and inorganic bioactivity was observed. PMID- 21660584 TI - Prevalence of pulmonary hypertension in patients with idiopathic pulmonary fibrosis: correlation with physiological parameters. AB - The aim of this study was to prospectively evaluate the prevalence of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF). One hundred thirty-nine patients (101 male, mean age = 68.6 +/- 9 years), with confirmed IPF and who were admitted to eight Pulmonary Departments in Greece between November 2005 and December 2006 were included in the study. Pulmonary artery systolic pressure (PASP) was estimated by echocardiography, and PH was defined as PASP > 36 mmHg. We compared demographics, pulmonary function tests, NYHA functional status, 6-min walk distance (6MWD), B-type natriuretic peptide (BNP), PaO(2), and P(A-a)O(2) at rest data between patients with PH and without PH (PASP <= 36 mmHg). Increased estimated right ventricular systolic pressure was present in 55% of patients (mean PASP = 47.1 +/- 11.2 mmHg vs. 30.3 +/- 3.8 mmHg, respectively). Patients with PH had a lower but not statistically significant DL(CO) (47.1 +/- 18.8 vs. 52.5 +/- 20.1), lower PaO(2) at rest (64.6 +/- 12.2 vs. 71.1 +/- 11.3, P = 0.004), and lower mean 6MWD (282 +/- 118 vs. 338 +/- 91, P = 0.007). Significant differences were also observed in the NYHA functional status between the two groups (P = 0.02). Statistically significant correlations were observed between PASP and PaO(2) at rest (r = -0.331, P = 0.00), P(A-a)O(2) at rest (r = 0.494, P = 0.00)(,) 6MWD (r = -0.264, P = 0.01), SpO(2) at rest (r = 0.293, P = 0.00), SpO(2) at the end of exercise (r = -0.364, P = 0.00), and also BNP values (r = 0.319, P = 0.01). Moreover, PaO(2) (P = 0.02), P(A-a)O(2) (P = 0.005), and SpO(2) at the end of exercise (P = 0.023) were independent predictors of the presence of estimated PH. Using Doppler echocardiography as a screening tool for the estimation of PH, we found that PH is common in patients with IPF. Gas exchange parameters at rest and exercise desaturation might indicate underlying PH in IPF. PMID- 21660586 TI - Electrochemical and mechanical behavior of laser processed Ti-6Al-4V surface in Ringer's physiological solution. AB - Laser surface modification of Ti-6Al-4V with an existing calcium phosphate coating has been conducted to enhance the surface properties. The electrochemical and mechanical behaviors of calcium phosphate deposited on a Ti-6Al-4V surface and remelted using a Nd:YAG laser at varying laser power densities (25-50 W/mm(2)) have been studied and the results are presented. The electrochemical properties of the modified surfaces in Ringer's physiological solution were evaluated by employing both potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) methods. The potentiodynamic polarizations showed an increase in the passive current density of Ti-6Al-4V after laser modification at power densities up to 35 W/mm(2), after which it exhibited a decrease. A reduction in the passive current density (by more than an order) was observed with an increase in the laser power density from 25 to 50 W/mm(2). EIS studies at the open circuit potential (OCP) and in the passive region at 1.19 V showed that the polarization resistance increased from 8.274 * 10(3) to 4.38 * 10(5) Omega cm(2) with increasing laser power densities. However, the magnitudes remain lower than that of the untreated Ti-6Al-4V at OCP. The average hardness and modulus of the laser treated Ti-6Al-4V, evaluated by the nanoindentation method, were determined to be 5.4-6.5 GPa (with scatter <+/-0.976 GPa) and 124-155 GPa (with scatter <+/-13 GPa) respectively. The corresponding hardness and modulus of untreated Ti-6Al-4V were ~4.1 (+/-0.62) and ~148 (+/-7) GPa respectively. Laser processing at power densities >35 W/mm(2) enhanced the surface properties (as passive current density is reduced) so that the materials may be suitable for the biomedical applications. PMID- 21660587 TI - Energy restriction negates NMDA receptor antagonist efficacy in ischemic stroke. AB - Preclinical evaluation of drugs for neurological disorders is usually performed on overfed rodents, without consideration of how metabolic state might affect drug efficacy. Using a widely employed mouse model of focal ischemic stroke, we found that that the NMDA receptor antagonist dizocilpine (MK-801) reduces brain damage and improves functional outcome in mice on the usual ad libitum diet, but exhibits little or no therapeutic efficacy in mice maintained on an energy restricted diet. Thus, NMDA receptor activation plays a central role in the mechanism by which a high dietary energy intake exacerbates ischemic brain injury. These findings suggest that inclusion of subjects with a wide range of energy intakes in clinical trials for stroke may mask a drug benefit in the overfed/obese subpopulation of subjects. PMID- 21660588 TI - Avoidant coping moderates the association between anxiety and patient-rated physical functioning in heart failure patients. AB - Previous research has indicated that anxiety may be associated with adverse health outcomes in heart failure patients. Little research, however, has explored whether anxiety interacts with patients' coping strategies in their associations with physical functioning. The present study examined whether coping strategies moderated the association between anxiety and self-rated physical functioning in 273 heart failure patients. Hierarchical multiple regression analysis, adjusting for demographic and medical covariates, indicated that both anxiety (b=1.15, beta=0.46, P<0.001) and avoidant coping (b=0.43, beta=0.16, P<0.01) were significantly associated with poorer physical functioning in separate models. Results also demonstrated a significant interaction between avoidant coping and anxiety (b=0.56, beta=0.14, P<0.01), such that the association between anxiety and poorer physical functioning was stronger for patients who frequently used avoidant coping strategies than for those who avoided less frequently. Approach coping, however, was not directly associated with physical functioning, nor did it moderate the association between anxiety and physical functioning. The findings suggest that anxious heart failure patients who engage in avoidant coping may be at particular risk for physical dysfunction. PMID- 21660589 TI - Determination of oxidative glucose metabolism in vivo in the young rat brain using localized direct-detected 13C NMR spectroscopy. AB - Determination of oxidative metabolism in the brain using in vivo 13C NMR spectroscopy (13C MRS) typically requires repeated blood sampling throughout the study to measure blood glucose concentration and fractional enrichment (input function). However, drawing blood from small animals, such as young rats, placed deep inside the magnet is technically difficult due to their small total blood volume. In the present study, a custom-built animal holder enabled temporary removal of the animal from the magnet for blood collection, followed by accurate repositioning in the exact presampling position without degradation of B0 shimming. 13C label incorporation into glutamate C4 and C3 positions during a 120 min [1,6-13C2] glucose infusion was determined in 28-day-old rats (n = 4) under alpha-chloralose sedation using localized, direct-detected in vivo 13C MRS at 9.4T. The tricarboxylic acid cycle activity rate (V(TCA)) determined using a one compartment metabolic modeling was 0.67 +/- 0.13 MUmol/g/min, a value comparable to previous ex vivo studies. This methodology opens the avenue for in vivo measurements of brain metabolic rates using 13C MRS in small animals. PMID- 21660590 TI - Risperidone in ultra low dose protects against stress in the rodent cold restraint model by modulating stress pathways. AB - The present investigation evaluates the anti-stress activity of risperidone (RIS) in the cold restraint stress (CRS) model and related stress pathways. Rats were pretreated with RIS (0.1 and 1.0 mg/kg) for 21 days before subjecting to CRS. Ultra low dose of RIS (ULD; 0.1 mg/kg) in contrast to higher dose (1.0 mg/kg) significantly reduced stress in terms of ulcer index. ULD also reversed stress induced increase in plasma corticosterone and norepinephrine levels used as markers for the function of hypothalamo-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) respectively. ULD caused dose and brain region (hippocampus, prefrontal cortex and striatum) specific changes to stress-induced perturbations of serotonin, dopamine and its metabolites indicating modulation of brain monoaminergic system (BMS). ULD did not show any extrapyramidal side effects. Thus, the anti-stress effect ULD is probably mediated through the HPA axis, SNS and BMS. The study indicates a potential use of ULD in stress disorders. PMID- 21660591 TI - Characterization of the MHC class II alpha-chain gene in ducks. AB - In humans, classical MHC class II molecules include DQ, DR, and DP, which are similar in structure but consist of distinct alpha- and beta-chains. The genes encoding these molecules are all located in the MHC class II gene region. In non mammalian vertebrates such as chickens, only a single class II alpha-chain gene corresponding to the human DRA has been identified. Here, we report a characterization of the duck MHC class II alpha-chain (Anpl-DRA) encoding gene, which contains four exons encoding a typical signal peptide, a peptide-binding alpha1 domain, an immunoglobulin-like alpha2 domain, and Tm/Cyt, respectively. This gene is present in the duck genome as a single copy and is highly expressed in the spleen. Sequencing of cDNA and genomic DNA of the Anpl-DRA of different duck individuals/strains revealed low levels of genetic polymorphism, especially in the same strain, although most duck individuals have two different alleles. Otherwise, we found that the duck gene is located next to class II beta genes, which is the same as in humans but different from the situation in chickens. PMID- 21660593 TI - Parents and teachers make different contributions to a shared perspective on hyperactive-impulsive and inattentive symptoms: a multivariate analysis of parent and teacher ratings on the symptom domains of ADHD. AB - Attention deficit hyperactivity disorder (ADHD) is characterised by developmentally inappropriate and impairing levels of inattentive and hyperactive impulsive behaviours. We aimed to investigate the differential effects of parent and teacher ratings on inattention and hyperactivity-impulsivity and the extent of genetic overlap between the two behavioural dimensions. Multivariate structural equation modelling was performed on DSM-IV based ADHD ratings by parents and teachers collected on a general population sample of 672 twin pairs, at ages 7-10 years. This study is the first to simultaneously use parent and teacher ratings in twin modelling to examine the effects of different raters on the two behavioural dimensions of ADHD. The findings indicated that hyperactivity impulsivity and inattention load on to separate latent factors that represent a common behavioural view for both parents and teachers, although there are additional aspects to the observations of these behaviours that are unique to each type of rater. The findings further indicate some shared aetiology for hyperactivity-impulsivity and inattention as measured by both parent and teacher ratings, in agreement with previous findings on the aetiology of the two symptom dimensions of ADHD. PMID- 21660594 TI - The classic: Articular replacement for the humeral head. 1955. PMID- 21660592 TI - Absence of N addition facilitates B cell development, but impairs immune responses. AB - The programmed, stepwise acquisition of immunocompetence that marks the development of the fetal immune response proceeds during a period when both T cell receptor and immunoglobulin (Ig) repertoires exhibit reduced junctional diversity due to physiologic terminal deoxynucleotidyl transferase (TdT) insufficiency. To test the effect of N addition on humoral responses, we transplanted bone marrow from TdT-deficient (TdT(-/-)) and wild-type (TdT(+/+)) BALB/c mice into recombination activation gene 1-deficient BALB/c hosts. Mice transplanted with TdT(-/-) cells exhibited diminished humoral responses to the T independent antigens alpha-1-dextran and (2,4,6-trinitrophenyl) hapten conjugated to AminoEthylCarboxymethyl-FICOLL, to the T-dependent antigens NP(19)CGG and hen egg lysozyme, and to Enterobacter cloacae, a commensal bacteria that can become an opportunistic pathogen in immature and immunocompromised hosts. An exception to this pattern of reduction was the T-independent anti-phosphorylcholine response to Streptococcus pneumoniae, which is normally dominated by the N deficient T15 idiotype. Most of the humoral immune responses in the recipients of TdT(-/-) bone marrow were impaired, yet population of the blood with B and T cells occurred more rapidly. To further test the effect of N-deficiency on B cell and T cell population growth, transplanted TdT-sufficient and -deficient BALB/c IgM(a) and congenic TdT-sufficient CB17 IgM(b) bone marrow were placed in competition. TdT(-/-) cells demonstrated an advantage in populating the bone marrow, the spleen, and the peritoneal cavity. TdT deficiency, which characterizes fetal lymphocytes, thus appears to facilitate filling both central and peripheral lymphoid compartments, but at the cost of altered responses to a broad set of antigens. PMID- 21660595 TI - Surgical technique: medial collateral ligament reconstruction using Achilles allograft for combined knee ligament injury. AB - BACKGROUND: Previous approaches for medial collateral ligament (MCL) reconstruction have been associated with extensive exposure, risk of donor site morbidity with autografts, loss of motion, nonanatomic graft placement, and technical complexity with double-bundle constructs. Therefore, we implemented a technique that uses Achilles allograft, small incisions, and anatomic insertions to reconstruct the MCL. DESCRIPTION OF TECHNIQUE: The MCL femoral insertion was identified, and a socket reamed over a guide pin. The Achilles bone plug was fixed in the socket and the tendon passed distally under the skin and fixed on the tibia, creating isometric reconstruction. PATIENTS AND METHODS: We evaluated 14 patients who had this MCL reconstruction. We determined range of knee motion, knee ligament laxity, functional outcome scores (International Knee Documentation Committee [IKDC]-subjective, Lysholm, Knee injury and Osteoarthritis Outcome Score [KOOS]), and activity level scores (Tegner, Marx). Followup range was 24 to 61 months. RESULTS: Knee motion was maintained in 12 cases. Grade 0-1 + valgus stability was obtained in all 14 cases. In cases of MCL with primary ACL reconstruction, IKDC-subjective, Lysholm, and KOOS-sports scores were 91 +/- 6, 92 +/- 6, and 93 +/- 12, respectively, and return to preinjury activity levels was achieved. In cases of MCL with revision ACL reconstruction, function was inferior, and patients did not return to their preinjury activity levels. CONCLUSIONS: This technique uses allograft that provides bone-to-bone healing on the femur, requires small incisions, and creates isometric reconstruction. When performed with a cruciate reconstruction, knee stability can be restored at 2 to 5 years followup. In patients with MCL with primary ACL reconstruction, return to preinjury activity level in recreational athletes can be achieved. PMID- 21660596 TI - Diffusion-weighted MRI reveals epiphyseal and metaphyseal abnormalities in Legg Calve-Perthes disease: a pilot study. AB - BACKGROUND: Legg-Calve-Perthes disease (LCP) is thought to be associated with ischemic events in the femoral head. However, the types and patterns of reperfusion after these ischemic events are unclear. PURPOSES: We therefore determined whether (1) there would be any age-related diffusion changes; (2) diffusion-weighted MR imaging would reveal ischemic damage; and (3) diffusion changes are correlated with prognostic MR findings in patients with LCP. METHODS: We prospectively performed conventional, perfusion, and diffusion-weighted MR imaging studies in 17 children with unilateral LCP. We then measured the apparent diffusion coefficient (ADC) values in the epiphysis and the metaphysis, and compared them with those of the contralateral normal side. Based on perfusion MR imaging, we assessed reperfusion to the epiphysis as either periphyseal or transphyseal. We studied T2-signal intensity changes in the metaphysis and the presence of focal physeal irregularity. We correlated diffusion changes with reperfusion to the epiphysis, T2-signal intensity change, and focal physeal irregularity. RESULTS: Normal diffusion decreased with age. In LCP hips, epiphyseal diffusion increased early and remained elevated through the healing stage. Six of the 17 patients who had a metaphyseal ADC greater than 50% over the normal side had 13 times greater odds of having an association with transphyseal reperfusion to the epiphysis. The increase of metaphyseal ADC also was associated with an increased T2-signal intensity in the metaphysis and presence of focal physeal irregularity. CONCLUSIONS: Diffusion-weighted MR imaging can be used as a complimentary modality to evaluate ischemic tissue damage with a potential prognostic value in patients with LCP. PMID- 21660597 TI - Bony increased-offset reversed shoulder arthroplasty: minimizing scapular impingement while maximizing glenoid fixation. PMID- 21660598 TI - Trainee safety in global health. PMID- 21660600 TI - Regional and interspecific variation in Sr, Ca, and Sr/Ca ratios in avian eggshells from the USA. AB - To examine regional variation in strontium (Sr), which at high concentrations may reduce eggshell quality, increase egg breakage and reproductive failure, we analyzed Sr, and calcium (Ca) concentrations and Sr/Ca ratios in eggshells from 20 avian species from California, Texas, Idaho, Kansas, and Michigan. In addition, we included data previously reported from Arizona to expand the regional comparisons and to better establish patterns of Sr, and Sr/Ca ratios in bird species across the United States. We found Sr concentrations varied significantly among regions, among species, and among foraging guilds; this variability is strongly influenced by the Sr/Ca ratios in surface water from locations close to the region where the eggshells were collected. Sr concentrations and Sr/Ca ratios were significantly higher in bird eggshells from the Volta wildlife region in the San Joaquin Valley, California and in various locales from Arizona. Sr concentrations and Sr/Ca ratios in bird eggshells from other locations in the USA were lower than those detected in these two regions. Among foraging guilds, invertivores had the highest Sr concentrations and Sr/Ca ratios and carnivores had the lowest. In general, the Sr/Ca ratio increased strongly with increasing Sr concentrations (R(2) = 0.99, P < 0.0001). There was a significant correlation (R(2) = 0.58, P < 0.0001) between Sr/Ca ratios in water and the average Sr/Ca ratios in eggshells suggesting that these values could be determined from Sr/Ca ratios in water. Eggshell thickness was poorly correlated with Sr (R(2) = 0.03) but had a significant and positive correlation with Ca and was more properly correlated by a quadratic equation (R(2) = 0.50, Thickness = 2.13 - 0.02Ca - 3.07 * 10(-5)Ca(2)). Our study provides further evidence that Sr accumulates significantly in the avian eggshell, in some regions at concentrations which could be of concern for potential negative effects on reproduction. We suggest that when assessing the effects of metals on avian reproduction in regions with high Sr deposits in rock and soil, Sr concentrations in the eggshell also should be measured to evaluate additional effects on thickness and reproduction. PMID- 21660599 TI - Transcriptomic analyses in a benthic fish exposed to contaminated estuarine sediments through laboratory and in situ bioassays. AB - The transcription of contaminant response-related genes was investigated in juvenile Senegalese soles exposed to sediments from three distinct sites (a reference plus two contaminated) of a Portuguese estuary (the Sado, W Portugal) through simultaneous 28-day laboratory and in situ bioassays. Transcription of cytochrome P450 1A (CYP1A), metallothionein 1 (MT1), glutathione peroxidase (GPx), catalase (CAT), caspase 3 (CASP3) and 90 kDa heat-shock protein alpha (HSP90AA) was surveyed in the liver by real-time PCR. CASP3 transcription analysis was complemented by surveying apoptosis through the TUNEL reaction. After 14 days of exposure, relative transcription was either reduced or decreased in fish exposed to the contaminated sediments, revealing a disturbance stress phase during which animals failed to respond to insult. After 28 days of exposure all genes' transcription responded to contamination but laboratory and in situ assays depicted distinct patterns of regulation. Although sediments revealed a combination of organic and inorganic toxicants, transcription of the CYP1A gene was consistently correlated to organic contaminants. Metallothionein regulation was found correlated to metallic and organic xenobiotic contamination in the laboratory and in situ, respectively. The transcription of oxidative stress related genes can be a good indicator of general stress but caution is mandatory when interpreting the results since regulation may be influenced by multiple factors. As for MT1, HSP90 up-regulation has potential to be a good indicator for total contamination, as well as the CASP3 gene, even though hepatocyte apoptosis depicted values inconsistent with sediment contamination, showing that programmed cell death did not directly depend on caspase transcription alone. PMID- 21660601 TI - Neurotoxic effects of the HCV core protein are mediated by sustained activation of ERK via TLR2 signaling. AB - Hepatitis C virus (HCV) infection is a serious problem among those co-infected with human immunodeficiency virus; however, its impact in the central nervous system (CNS) remains unclear. This study aimed to investigate the mechanisms underlying HCV core protein-mediated neurodegeneration. Analysis of human HCV seropositive cases demonstrated widespread damage to neuronal dendritic processes and sustained activation of extracellular signal-related kinase (ERK); analogous pathologies were observed in wild type injected with HCV core protein into the hippocampus. In vitro analysis in neuronal cells exposed to HCV core demonstrated retraction of the neuronal processes in an ERK/Signal Transducer and Activator of Transcription 3 (STAT3)-dependent manner dependent on toll-like receptor 2 (TLR2) signaling activation. These results indicate that HCV core protein neurotoxicity may be mediated by the sustained activation of ERK/STAT3 via TLR2-IRAK1 signaling pathway. These pathways provide novel targets for development of neuroprotective treatments for HCV involvement of the CNS. PMID- 21660602 TI - Effects of Lipofectamine 2000/siRNA complexes on autophagy in hepatoma cells. AB - Lipofectamine 2000 is commonly used for siRNA transfections. However, few studies have examined cellular responses to this delivery system. The purpose of this study is to evaluate the effect of siRNA transfection using Lipofectamine 2000 on cellular autophagy. Huh7.5 cells, stably transfected to express GFP-LC3, were treated with Lipofectamine 2000/negative control siRNA (NC siRNA) complexes. At different time points after treatment, cells were lysed and analyzed by immunoblotting and fluorescence spectroscopy. Cells were also observed using confocal microscopy. An increase of endogenous LC3 lipidation, GFP-LC3 fluorescence, and autophagosomal puncta was observed in cells treated with Lipofectamine 2000/NC siRNA complexes. The kinetics of the increase of GFP-LC3 fluorescence correlated with the concentration of NC siRNA transfected, where 50, 100, and 200 nM NC siRNA caused a significant increase at 72, 48, and 24 h, respectively, after transfection. A similar effect on the GFP-LC3 signal was also observed for cells treated with Lipofectamine 2000 complexed with two other NC siRNAs. The effects were also confirmed in another hepatoma cell line, H4IIE, by immunoblotting. Lipofectamine 2000-mediated transport of NC siRNAs led to an increase of autophagosomes in a dose- and time-dependent manner. Thus, this effect on cells should be taken into consideration when using this approach for intracellular delivery of siRNA. PMID- 21660603 TI - Elective delivery before 39 weeks: the risk of infant admission to the neonatal intensive care unit. AB - Despite American College of Obstetricians and Gynecologists guidelines suggesting that non-urgent planned deliveries be scheduled at/after 39 weeks; elective delivery before 39 weeks occurs often in the United States. The objective of this study is to estimate the elective delivery rate between 36(0/7) and 38(6/7) weeks gestation and compare NICU admission rates between elective and non-elective deliveries. We conducted a retrospective cohort (n = 1,577) study. Charts were reviewed for all singleton deliveries (2006-2007) between 36(0/7) and 38(6/7) weeks gestation taking place at one hospital in NYS to determine delivery status. We computed adjusted relative risks (RR) with 95% confidence intervals (CI) for elective delivery in relation to NICU admission using robust Poisson regression. 32.8% of all births were elective: 20.7% of vaginal and 55.7% of cesarean births. Elective delivery increased with increasing gestational age. After controlling for potential confounders, infants born via a vaginal elective delivery (RR = 1.40, CI: 1.00, 1.94), an elective cesarean (RR = 2.05, CI: 1.53, 2.76), or a non elective cesarean (RR = 2.00, CI: 1.50, 2.66) are at significantly increased risk of NICU admission compared to infants born via a non-elective vaginal delivery. Elective delivery before 39 weeks is common and increases the risk of infant NICU admission. PMID- 21660604 TI - A qualitative analysis of vaccine safety perceptions and concerns among caretakers in Uganda. AB - Parents and caretakers of young children often have concerns about vaccine safety and adverse events following immunization (AEFI). Little is known about vaccine safety perceptions in Uganda and their influence on parental decision-making about infant immunization. The study objectives were: to identify community sources of information on immunization, vaccine safety and AEFI; determine caretakers' knowledge of immunization; identify community concerns/fears about immunization and AEFI and their influence on caretakers' decisions to vaccinate; and obtain an understanding of knowledge, perceptions, and experience of health care workers (HCWs) and policy administrators on vaccine safety and AEFI. Twelve focus group discussions with 136 caretakers who were very or somewhat concerned about vaccine safety and 25 key informant interviews were conducted in two districts (1 urban and 1 rural) with district authorities and health facility staff as well as national level decision-makers between December and April 2006. Content analysis was used to analyze the results. The main themes identified related to general lack of information among caretakers about immunization, perceived immunization benefits, immunization concerns, and misconceptions. Specific caretaker concerns related to vaccine administration, immunization services and vaccine safety. Experiences with AEFI and concerns about vaccine safety negatively affected caretakers' decisions to vaccinate their children, notably in rural areas. HCWs demonstrated knowledge about AEFI and their management although incidences reported to facilities were rare. Inadequate communication between HCWs and caretakers was noted. Concerns and misconceptions about vaccination still exist among caretakers in Uganda and influence decisions to vaccinate. Effective inter personal communication initiated by HCWs towards caretakers is needed. PMID- 21660608 TI - Black esophagus: the only clue. PMID- 21660609 TI - Response of native soil microbial functions to the controlled mycorrhization of an exotic tree legume, Acacia holosericea in a Sahelian ecosystem. AB - Fifty years of overexploitation have disturbed most forests within Sahelian areas. Exotic fast growing trees (i.e., Australian Acacia species) have subsequently been introduced for soil improvement and fuelwood production purposes. Additionally, rhizobial or mycorrhizal symbioses have sometimes been favored by means of controlled inoculations to increase the performance of these exotic trees in such arid and semiarid zones. Large-scale anthropogenic introduction of exotic plants could also threaten the native biodiversity and ecosystem resilience. We carried out an experimental reforestation in Burkina Faso in order to study the effects of Acacia holosericea mycorrhizal inoculation on the soil nutrient content, microbial soil functionalities and mycorrhizal soil potential. Treatments consisted of uninoculated A. holosericea, preplanting fertilizer application and arbuscular mycorrhizal inoculation with Glomus intraradices. Our results showed that (i) arbuscular mycorrhizal (AM) inoculation and prefertilizer application significantly improved A. holosericea growth after 4 years of plantation and (ii) the introduction of A. holosericea trees significantly modified soil microbial functions. The results clearly showed that the use of exotic tree legume species should be directly responsible for important changes in soil microbiota with great disturbances in essential functions driven by microbial communities (e.g., catabolic diversity and C cycling, phosphatase activity and P availability). They also highlighted the importance of AM symbiosis in the functioning of soils and forest plantation performances. The AM effect on soil functions was significantly correlated with the enhanced mycorrhizal soil potential recorded in the AM inoculation treatment. PMID- 21660610 TI - [Static posturography in selected Parkinson syndromes: quantitative analysis of postural control]. AB - OBJECTIVES: Idiopathic Parkinson's disease (IPD) is associated with postural disturbances and falls. The assessment of postural instability by the pull test may lead to inconclusive results. Static posturography measurements may give more reliable information regarding the differential diagnosis of Parkinson syndromes. PATIENTS AND METHODS: We compared results of the pull test and static posturography (sway area in eyes-open/eyes-closed conditions) in healthy controls (C) and patients with akinetic-rigid IPD (n=18), atypical Parkinson syndromes (APS; n=18) and secondary Parkinson syndromes (SPS; n=17). RESULTS: Static posturography and the pull test results did not differ significantly between controls and patients with akinetic-rigid IPD. APS patients had significantly greater postural sway areas when tested with eyes open compared to controls (APS: 16.89 vs C: 6.89 mm, p<=0.001) and IPD patients (APS: 16.89 vs IPD: 9.55 mm, p=0.005). The correlation in the APS group between the pull test and sway area in the eyes-open condition was significant (r=0.526, p=0.025). With eyes closed, postural instability in APS patients was not significantly increased (+2%, p=.847). SPS patients were more unstable under the eyes-closed condition compared to controls (sway area SPS: 26.29 vs C: 8.79 mm, p<=0.001), IPD patients (sway area SPS: 26.29 vs IPD: 11.06 mm, p<=0.001) and APS patients (sway area SPS: 26.29 vs APS: 17.28 mm, p=0.027), without a significant correlation to the pull test. The sway area in the SPS patients increased significantly by 67% (p=0.001) under the eyes-closed condition. CONCLUSION: Static posturography may be a helpful tool for the differentiation of Parkinson syndromes. PMID- 21660611 TI - [Neuromuscular diseases]. PMID- 21660614 TI - Affective and behavioral changes following exposure to traumatic events: the moderating effect of religiosity on avoidance behavior among students studying under a high level of terror event exposure. AB - The goals of this study were to examine the development of affective and behavioral changes following exposure to traumatic events among Israeli students studying under a high level of terror event exposure and to assess the effects of religiosity on those changes development. A questionnaire was administered to 770 students in the Ariel University Center in Judea and Samaria. Higher levels of terror exposure were associated with higher levels of avoidance behavior, subjective feelings of insecurity, and emotional distress. Higher religiosity moderated avoidance behavior, even when controlling for the level of objective exposure to terror events exposure, but had no influence on subjective sense of insecurity, or the level of emotional distress. These findings suggest that religiosity moderates behavioral changes development after traumatic event exposure mainly by reducing avoidance behavior. PMID- 21660616 TI - Delayed presentation of splenic injury following diagnostic colonoscopy. AB - Splenic injury (SI) is a rare complication after colonoscopy, but should be considered in the differential diagnosis of acute abdominal pain following this procedure. We report a case of delayed rupture and review pertinent literature. A 70-year-old patient on oral warfarin intake underwent colonoscopy that diagnosed obstructive rectal cancer and elongated colon conditioning the endoscope's passage. After 48 h, patient experienced sharp abdominal pain with mild peritoneal signs. Contrast-enhanced CT scan evidenced large amount of abdominal free blood collection from grade II SI. Hypovolemic shock occurred following brief clinical observation. Urgent laparotomic splenectomy and contextual Hartmann's procedure were then carried out. Postoperative course was uneventful and definitive histology confirmed splenic subcapsular haematoma and locally advanced adenocarcinoma. Perforation and bleeding more likely occurred after colonoscopy, while few cases of SI are reported in literature since 1974. Traction on the splenocolic ligament and direct trauma has been advocated as possible causes. Peritoneal adhesions and splenic diseases usually are predisposing factors although not confirmed in our patient. Anticoagulant therapy favoured delayed filling up of subcapsular haematoma while bowel obstruction added further surgical challenge. Rapid onset of hemorrhagic shock required urgent splenectomy that remains the procedure of choice among the literature reviewed. PMID- 21660615 TI - Splenic localization of the peritoneal mesothelioma: case report and literature revue. AB - Peritoneal mesothelioma is a rare form of malignant mesothelioma, making up <30% of diagnosed mesothelioma cases. Because of a lack of specific symptoms (abdominal pain, abdominal swelling), normally it is diagnosed in advanced stages, sometimes in a surgical emergency (intestinal obstruction, severe ascites) and occasionally during image procedures or laparoscopy which can show a mass developing from peritoneal mesothelium surfaces, or an accumulation of small irregularities that may be tumors or plaques. The reported case refers to a particular localization of a peritoneal mesothelioma, the spleen, discovered only after a splenectomy, due to the clinical and radiological suspect of a rupture. PMID- 21660617 TI - Outcome of surgical treatment of colorectal cancer in the elderly. AB - The aim of this study is to compare the clinical features and the perioperative and long-term outcomes after primary surgery for colorectal cancer (CRC) in the elderly population with those observed in younger patients. All the patients over the age of 55 who underwent primary surgery for CRC in our clinic from 1988 to 2008 were included in this study and divided into two age groups: 55-75 and >75 years considering the age of diagnosis. 914 consecutive patients were enrolled in the study (352 > 75 years). In the elderly group, tumors were predominantly right sided, and the overall number of comorbidities was statistical more frequent. Elderly patients underwent emergency surgery more than the control group (p = 0.0008). There were no significant differences between the two groups in terms of curative and palliative resections. The overall operative mortality rate was 5.9% in the study group compared with 2.1% in the control study (p = 0.0033). The overall 3-year, 5-year and 10-year survival rates were, respectively, 37, 16.2 and 5.1% in the study group, when compared with 52.3, 35.1 and 24.7% in the control group (p = 0.022, p = 0.0001 and p = 0.0001, respectively). More patients were lost during the follow-up in the elderly group (p = 0.0003) and more deaths unrelated to cancer were found in the study group compared with the control group (p = 0.0005). The cancer specific mortality was similar between the two groups. In conclusion, elderly patients that underwent major colorectal resection have an acceptable perioperative morbidity, mortality and survival rate when compared with younger patients. Age alone should not be considered a reason to deny surgery to these patients. PMID- 21660619 TI - Clinical implications of mismatched repair gene promoter methylation in pancreatic cancer. AB - To investigate the relationship between the hypermethylation statuses of the mismatch repair genes (hMLH1 and hMSH2) promoters and explore the correlation between it and the development of pancreatic cancer and the biological behavior of pancreatic cancer. We selected 90 patients who were diagnosed with pancreatic cancer and underwent radical operations in the First Affiliated Hospital of the Dalian Medical University between January 2002 and June 2008. The methylation status of the hMLH1 and hMSH2 promoters was detected by methylation-specific polymerase chain reaction (MSP). Meanwhile, the expression of hMLH1 and hMSH2 protein was detected by Western blot and immunohistochemistry, and its correlation with biological behavior of pancreatic cancer was explored. Of the 90 cases, hMLH1 promoter methylation was detected in 54 (60.0%) patients, while none of the paracancerous tissues indicated methylation. In the study, the hMLH1 methylated tumors lost hMLH1 protein expression, but the non-hMLH1-methylated tumors were not seen to have a loss of hMLH1 protein expression (P < 0.001). On the other hand, there were four cases of hMSH2 promoter methylation. However, no significant difference was found between hMSH2 promoter methylation and non-hMSH2 promoter methylation cases (P > 0.05). After universal analysis, hMLH1 expression was significantly related to tumor differentiation, lymph node metastasis, and tumor location (P < 0.05) while not related to the age, sex, and tumor size (P > 0.05). Our study suggests that the mismatch repair genes play an important role in pancreatic cancer carcinogenesis and progression through epigenetic modification, and it may be regarded as a potential target for the management of pancreatic cancer. PMID- 21660618 TI - Phase I and pharmacokinetic study of trabectedin 3-hour infusion every three weeks in patients with advanced cancer and alteration of hepatic function. AB - Maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics (PK) were evaluated for trabectedin 3-h every-3-weeks schedule in 33 cancer patients stratified according to liver dysfunction degree as per baseline alkaline phosphatase (AP). Stratification was as follows: stratum I [upper limit of normal (ULN) < AP <= 1.5 * ULN; n = 16], stratum II [1.5 * ULN < AP <= 2.5 * ULN; n = 12], and stratum III [AP >2.5 * ULN; n = 5] (bilirubin <2.5 * ULN for all 3 strata). In each stratum, patients were treated in sequential cohorts at escalating doses. Dose-limiting toxicities (DLTs) were grade 3 transaminase increases not recovering baseline values on day 21, febrile neutropenia/grade 4 neutropenia lasting >5 days and AP increase more than twice over baseline. The MTD and RD for stratum I (mild baseline AP) was 1.3 mg/m(2). Recruitment was stopped early in strata II/III (moderate/severe baseline AP) without reaching the MTD due to slow accrual and difficulty in finding patients. Biochemical parameters other than AP (bilirubin, AST or ALT) were similar between strata. No relevant PK differences were found between strata. In conclusion, the MTD and RD (1.3 mg/m(2)) were confirmed only for stratum I. Stratification criteria based on baseline AP apparently did not segregate the patients according to their liver dysfunction degree. Antitumor activity was found in patients with pretreated ovarian cancer. PMID- 21660620 TI - Word knowledge influences character perception. AB - In two experiments, we examined whether context information can affect the activity of the nodes at the character level. Chinese readers viewed two Chinese characters; one was intact, but the other (the target) was embedded in a rectangle of visual noise and increased in visibility over time. The two characters constituted a word in one condition but did not in the other condition. The task was to press a button to indicate whether the character in the noise was at the top or bottom of the rectangle. (They did not have to identify the character.) Response times were faster in the word condition than in the nonword condition. Because the "wordness" of the stimulus was logically irrelevant to judging the location of the target character, the data indicate that processing at the word level can feed back to fairly low-level judgments, such as where a character is. PMID- 21660621 TI - [Non-invasive thermoablation of symptomatic uterine fibroids with magnetic resonance-guided high-energy ultrasound]. AB - Uterine fibroids are the most common benign tumors in postmenopausal women which can cause severe symptoms and considerably reduce the quality of life. Patients are requesting minimally invasive, organ-saving therapies increasingly more often and magnetic resonance-guided focused ultrasound is a promising new technology which even surpasses these requirements as it is a totally non-invasive approach. The possibility of real-time temperature mapping allows a safe and precise thermal ablation of uterine fibroids. The rate of adverse events is low and safety and efficiency have been proven in several clinical studies. Further studies will have to be carried out to demonstrate long-term success and comparability to the established therapies and clarify if focused ultrasound is a safe treatment for women with the desire for future pregnancy. The MR-guided focused ultrasound technique is an effective and gentle treatment for uterine fibroids and holds a great potential for further indications. PMID- 21660622 TI - An unusual case of relay pentobarbital toxicosis in a dog. AB - Sodium pentobarbital and phenytoin are common constituents of veterinary euthanasia solutions in the United States. Relay, or secondary, barbiturate toxicosis has been reported in carnivorous animals that have fed from the carcasses of euthanized livestock. This case report presents barbiturate toxicosis in a dog. A 2-year-old female spayed Australian shepherd presented comatose 2 h after ingesting an unknown substance on the beach. The material was retrieved from the stomach by gastric lavage and visually identified as fish or other animal tissue. The dog recovered with symptomatic and supportive therapy and was released on the third day of hospitalization. Tissue found on the beach near where the dog walked and a urine sample from the dog were analyzed by gas chromatography/mass spectrometry. Both samples were positive for pentobarbital and phenytoin. The tissue was consistent with mammalian blubber based on gross and histological examination. Three weeks previously, a juvenile humpback whale had stranded on the beach where the dog had ingested the unknown substance. The whale had been euthanized with a barbiturate solution, necropsied, and removed from the beach. It was not definitively determined that the pentobarbital containing blubber ingested by the dog was from the euthanized whale, but that was the most likely source. Although attempts were made to remove the whale's remains from the beach, practical considerations made complete removal challenging, if not impossible. PMID- 21660623 TI - Withdrawal of life-sustaining treatment in a mixed intensive care unit: most common in patients with catastropic brain injury. AB - OBJECTIVE: To determine the incidence of withdrawal of life-sustaining treatment in various groups of patients in a mixed intensive care unit (ICU). DESIGN: Observational retrospective. SETTING: University hospital mixed medical, neurological, neurosurgical and surgical ICU. PATIENTS: All patients admitted to the ICU between 1 November 2006, and 31 October 2007. RESULTS: 1,353 Patients were admitted to our ICU between 1 November 2006, and 31 October 2007. During this period, 218 (16.1%) patients died in the ICU, 10 of which were excluded for further analysis. In 174 (83.7%) of the remaining 208 patients, life-sustaining treatment was withdrawn. Severe CNS injury was in 86 patients (49.4%) being the reason for withdrawal of treatment, followed by MODS in 67 patients (38.5%). Notably, treatment was withdrawn in almost all patients (95%) who died of CNS failure. Patients who died in the ICU were significantly older, more often admitted for medical than surgical reasons, and had higher SOFA and APACHE II scores compared with those who survived their ICU stay. Also, SOFA scores before discharge/death were significantly different from admission scores. Of the 1,135 patients who survived their ICU stay, only 51 patients (4.5%) died within 28 days after ICU discharge. CONCLUSIONS: In 83, 7% of patients who die in the mixed ICU life-sustaining treatment is withdrawn. Severe cerebral damage was the leading reason to withdraw life-sustaining treatment. PMID- 21660624 TI - 99mTc-HYNIC-spermine for imaging polyamine transport system-positive tumours: preclinical evaluation. AB - PURPOSE: F14512 exploiting the polyamine transport system (PTS) for tumour cell delivery has been described as a potent antitumour agent. The optimal use of this compound will require a probe to identify tumour cells expressing a highly active PTS that might be more sensitive to the treatment. The aim of this study was to design and characterize a scintigraphic probe to evaluate its uptake in cancer cells expressing the PTS. METHODS: Three polyamines coupled to a hydrazinonicotinamide (HYNIC) moiety were synthesized and labelled with 99mTc. Their radiochemical purity was determined by HPLC. The plasma stability of the 99mTc-HYNIC-spermine probe and its capacity to accumulate into PTS-active cells were also evaluated. In vitro internalization was tested using murine melanoma B16/F10 cells and human lung carcinoma A549 cells. Biodistribution was determined in healthy mice and tumour uptake was studied in B16/F10 tumour-bearing mice. A HL-60-Luc human leukaemia model was used to confront single photon emission computed tomography (SPECT) images obtained with the 99mTc-labelled probe with those obtained by bioluminescence. RESULTS: The 99mTc-HYNIC-spermine probe was selected for its capacity to accumulate into PTS-active cells and its stability in plasma. In vitro studies demonstrated that the probe was internalized in the cells via the PTS. In vivo measurements indicated a tumour to muscle scintigraphic ratio of 7.9+/-2.8. The combined bioluminescence and scintigraphic analyses with the leukaemia model demonstrated that the spermine conjugate accumulates into the tumour cells. CONCLUSION: The 99mTc-HYNIC-spermine scintigraphic probe is potentially useful to characterize the PTS activity of tumours. Additional work is needed to determine if this novel conjugate may be useful to analyse the PTS status of patients with solid tumours. PMID- 21660625 TI - Population-based time determinant for termination of resuscitation: reply. PMID- 21660626 TI - Learning curve of transumbilical single incision laparoscopic cholecystectomy (SILS): a preliminary study of 80 selected patients with benign gallbladder diseases. AB - BACKGROUND: Transumbilical single incision laparoscopic surgery (SILS) is a new laparoscopic procedure in which only one transumbilical incision is made, demonstrated as a scarless procedure. Here we report a single-center preliminary experience of transumbilical single incision laparoscopic cholecystectomy (SILC) in the treatment of benign gallbladder diseases, defining a single surgeon's learning curve. METHODS: A total of 80 patients underwent SILC successfully by a single experienced laparoscopic surgeon. The operation was performed following the routine LC procedure. Then the perioperative demographics were recorded and the operative time was used to define the learning curve. RESULTS: The study group included 27 male and 53 female patients with gallstones (56 cases), cholesterol polyps (16 cases), an adenomatous polyp (3 cases), adenomyomatosis (1 case), or complex diseases (4 cases), and all consented to undergo SILC. No patient was converted to normal LC or open surgery. There were no perioperative port-related or surgical complications. The average operative time was 46.9 +/- 14.6 min. The average postoperative hospital stay was 1.8 +/- 1.3 days. The learning curve of the SILC procedures for this series of selected patients confirmed that SILC is a feasible, safe, and effective approach to the treatment of benign gallbladder diseases. CONCLUSIONS: For experienced laparoscopic surgeons, SILC is an easy and safe procedure. Patients benefit from milder pain, a lower incidence of port-related complications, better cosmesis, and fast recovery. The SILC procedure may become another option for the treatment of benign gallbladder diseases for selected patients. PMID- 21660627 TI - In search of the malarial parasite: biographical sketches of the blood stain contributors. AB - Methylene blue was synthesized by Caro in 1876 at BASF, a chemical company. Six years later, Koch employed methylene blue when he discovered the tubercle bacillus. In 1880, Ehrlich described what he termed "neutral" dyes: mixtures of acidic and basic dyes for the differentiation of cells in peripheral blood smears. Bernthsen prepared in 1886 a relatively pure dye, obtained by decomposition of methylene blue, and called it methylene azure. In 1891, Malachowski developed a method which used mixtures of eosin and "ripened" methylene blue that not only differentiated blood cells, but also demonstrated the nuclei of malarial parasites. Romanowsky later performed the same feat with an unrepeatable method. A number of "ripening" (polychroming) techniques were investigated by different groups (Nocht 1899) but the aqueous dye solutions produced were unstable and precipitated rapidly. Subsequently, methanol was introduced as a solvent for the dye precipitate (Jenner 1899) and techniques were developed that utilized the fixative properties of the methanolic solution prior to aqueous dilution for staining (Wright 1902). Giemsa (1902) further improved these techniques by developing more precise methods of methylene blue demethylation and adding glycerol as a stabilizing agent to the methanol solvent. Today, the Malachowski-Wright-Giemsa stain continues to be regarded as the world's standard diagnostic technique for malaria. PMID- 21660628 TI - Life shocks and crime: a test of the "turning point" hypothesis. AB - Other researchers have posited that important events in men's lives-such as employment, marriage, and parenthood-strengthen their social ties and lead them to refrain from crime. A challenge in empirically testing this hypothesis has been the issue of self-selection into life transitions. This study contributes to this literature by estimating the effects of an exogenous life shock on crime. We use data from the Fragile Families and Child Wellbeing Study, augmented with information from hospital medical records, to estimate the effects of the birth of a child with a severe health problem on the likelihood that the infant's father engages in illegal activities. We conduct a number of auxiliary analyses to examine exogeneity assumptions. We find that having an infant born with a severe health condition increases the likelihood that the father is convicted of a crime in the three-year period following the birth of the child, and at least part of the effect appears to operate through work and changes in parental relationships. These results provide evidence that life events can cause crime and, as such, support the "turning point" hypothesis. PMID- 21660629 TI - Video: laparoscopy distinctive technique for suprapancreatic lymph node dissection: medial approach for laparoscopic gastric cancer surgery. AB - BACKGROUND: Suprapancreatic lymph node (LN) dissection is critical for gastric cancer surgery. Until currently, a number of laparoscopic gastrectomy procedures have been performed in the same manner as open surgery procedures [3, 4, 6]. Using the characteristic of laparoscopic surgery, the authors developed a new technique of suprapancreatic LN dissection. METHODS: After division of the duodenum, No. 8a LN is raised, and the surrounding tissue is dissected to identify the outmost layer of the nerves around the common hepatic artery. This layer can be dissected as the next step is headed for the root of the left gastric artery. Thin layers can be identified on the left and right sides of the artery. After this step, the LN dissection is performed toward both lateral sites, keeping the outmost layer of the nerves. At this stage, the surgeon should envision the "U" shape on the right side and the "V" shape on the left side for a superior performance. This technique was performed by the same surgeon for 20 consecutive patients with advanced gastric cancer. RESULTS: All the patients successfully underwent laparoscopic distal gastrectomy with D2 LN dissection. The mean number of regional LNs retrieved was 45.1 +/- 13.5. The mean number of only LNs around the celiac artery (No. 7, 8a, 9, 11p, and 12a) was 17.8 +/- 5.5. This was not less than reported previously [1, 2, 5]. The mean blood loss was 91.1 ml, and the mean operative time was 296.0 min. At this writing, all the patients are disease free after a mean follow-up period of 15.4 months. CONCLUSIONS: The nerves are thick and sturdy around the root of the left gastric artery. Additionally, the magnified and horizontal laparoscope view provides a straightforward approach and visibility to the layer. The authors believe that the "medial approach" is a straightforward method of suprapancreatic LN dissection in laparoscopic gastric cancer surgery. PMID- 21660630 TI - Transmural inflammation is not pathognomonic for Crohn's disease of the pouch. AB - BACKGROUND: Transmural inflammation shown by imaging and histology has been considered a hallmark of Crohn's disease (CD). However, the diagnostic and prognostic value of this feature in CD of the pouch has not been evaluated. This study aimed to evaluate the clinical utility of transmural inflammation in patients with ileal pouch-anal anastomosis (IPAA) using in vivo optical coherence tomography (OCT) and histopathology. METHODS: All the patients were recruited from the subspecialty Pouchitis Clinic. The study consisted of two parts: (1) a prospective study with in vivo through-the-scope OCT for the evaluation of transmural disease in patients with normal or diseased pouches and (2) a retrospective pathology re-review for transmural inflammation in excised pouch specimens of CD and chronic pouchitis. RESULTS: This prospective OCT study enrolled 53 patients: 11 (20.8%) with normal pouches or irritable pouch syndrome, 10 (18.9%) with acute pouchitis, 11 (20.8%) with chronic antibiotic-refractory pouchitis (CARP), and 21 (39.6%) with CD of the pouch. Transmural inflammation, characterized by the loss of layered structure on OCT, was detected in 16 patients (30.2%): 4 with chronic pouchitis and 12 with CD of the pouch. None of the patients with normal pouches, irritable pouch syndrome, or acute pouchitis had transmural disease shown on OCT. Of the 26 patients with pouch failure who had pouch excision, the surgical specimens showed transmural disease in 30% of the CARP patients (3/10) and 12.5% (2/16) of those with CD of the pouch. CONCLUSIONS: Transmural disease in the setting of IPAA is not pathognomonic of CD. Transmural inflammation shown by imaging or histopathology was seen in both CD and CARP. Transmural inflammation of the pouch appeared to be associated with poor pouch outcome. PMID- 21660631 TI - Postbariatric buttock contouring with dermolipectomy and gluteal implants. AB - The authors present their experience with the use of silicone implants in the buttocks after massive weight loss. The procedure is used in combination with gluteal dermolipectomy with or without dermal fat flaps. This report highlights the simplified method of identifying the gluteal muscles, recommends using the superior margin of the gluteus maximus muscle to access the space for implant placement, and prescribes placement of the implants in either the submuscular or the intramuscular space. The described procedure has been performed for two patients to date, with encouraging and long-lasting results. PMID- 21660632 TI - [Intensive care and inflammatory bowel diseases (IBD). The severe and fulminant flare]. AB - Inflammatory bowel disease (IBD) is a non-curable disease. Although we seem to have a definitive surgical solution for ulcerative colitis, patients are at risk of suffering from acute and chronic pouchitis as well as peri- and postoperative complications. In Crohn's disease medical treatment is able to prolong surgery free survival, but no definitive healing strategy is as yet at hand. Moreover, effective medication exposes patients to potentially life-threatening complications. The severely compromised patient in particular needs careful surveillance and requires a balanced treatment strategy endorsed by gastroenterologists and surgeons. Treatment is still aimed at suppressing immune mechanisms and is far from being causal. Nevertheless, this approach has resulted in a reduction in surgical procedures and hospitalizations. The following overview covers special issues related to strategies for severe and fulminant flares of inflammatory bowel disease. PMID- 21660634 TI - Pseudobulbar affect: an under-recognized and under-treated neurological disorder. AB - INTRODUCTION: Pseudobulbar affect (PBA) is a neurologic syndrome of emotional affect disinhibition, characterized by uncontrollable, exaggerated, and often inappropriate emotional outbursts, which may cause severe distress, embarrassment, and social dysfunction. However, the US prevalence of PBA remains unknown. METHODS: An online survey was conducted primarily to estimate the US prevalence of PBA in patients with the six most commonly associated conditions: Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, stroke, and traumatic brain injury. Invitations to participate were randomly sent online to adults (aged >= 18 years) registered in the Harris Poll Online Panel who were patients or belonged to a household with a patient diagnosed with one of the six conditions (identified through previous screening by Harris Interactive). Participants were screened for PBA using the Pathological Laughing and Crying Scale (PLACS) and the Center for Neurologic Study-Lability Scale (CNS-LS). PBA estimates were made using a cut-off score of >= 13 on the PLACS and two different cut-off thresholds on the CNS-LS, a lower one of >= 13 and a more rigorous one of >= 21. Existing US prevalence data for the six underlying conditions were used to estimate US prevalence of PBA. RESULTS: Of 38,000 individuals invited to participate, 8876 responded (23%) and 2318 (26%) completed the questionnaire. Mean prevalence of PBA across all six conditions was 10.1%, 9.4%, and 37.5% with the PLACS >= 13, CNS-LS >= 21, and CNS LS >= 13 thresholds, respectively. Using disease population estimates from government agencies and professional organizations, the estimated US population with PBA ranged from 1.8 to 7.1 million. Among patients who discussed their laughing and/or crying episodes with a physician, 41% were diagnosed, and about half received a medication for their episodes. CONCLUSIONS: The overall prevalence of PBA was estimated to be about 10% across these commonly associated underlying neurological conditions and appears to be under-recognized. PMID- 21660635 TI - Risk scores for predicting type 2 diabetes: using the optimal tool. PMID- 21660637 TI - Natural attenuation is enhanced in previously contaminated and coniferous forest soils. AB - PURPOSE: Prevalence of organic pollutants or their natural analogs in soil is often assumed to lead to adaptation in the bacterial community, which results in enhanced bioremediation if the soil is later contaminated. In this study, the effects of soil type and contamination history on diesel oil degradation and bacterial adaptation were studied. METHODS: Mesocosms of mineral and organic forest soil (humus) were artificially treated with diesel oil, and oil hydrocarbon concentrations (GC-FID), bacterial community composition (denaturing gradient gel electrophoresis, DGGE), and oil hydrocarbon degraders (DGGE + sequencing of 16S rRNA genes) were monitored for 20 weeks at 16 degrees C. RESULTS: Degradation was advanced in previously contaminated soils as compared with pristine soils and in coniferous organic forest soil as compared with mineral soil. Contamination affected bacterial community composition especially in the pristine mineral soil, where diesel addition increased the number of strong bands in the DGGE gel. Sequencing of cloned 16S rRNA gene fragments and DGGE bands showed that potential oil-degrading bacteria were found in mineral and organic soils and in both pristine and previously contaminated mesocosms. Fast oil degradation was not associated with the presence of any particular bacterial strain in soil. CONCLUSIONS: We demonstrate at the mesocosm scale that previously contaminated and coniferous organic soils are superior environments for fast oil degradation as compared with pristine and mineral soil environments. These results may be utilized in preventing soil pollution and planning soil remediation. PMID- 21660636 TI - Leptin administered in physiological or pharmacological doses does not regulate circulating angiogenesis factors in humans. AB - AIM/HYPOTHESIS: Leptin has been shown to regulate angiogenesis in animal and in vitro studies by upregulating the production of several pro-angiogenic factors, but its role in regulating angiogenesis has never been studied in humans. METHODS: The potential angiogenic effect of two doses of metreleptin (50 and 100 ng/ml) was evaluated in vitro, using a novel three-dimensional angiogenesis assay. Fifteen healthy, normoleptinaemic volunteers were administered both a physiological (0.1 mg/kg) and a pharmacological (0.3 mg/kg) single dose of metreleptin, in vivo, on two different inpatient admissions separated by 1-12 weeks. Serum was collected at 0, 6, 12 and 24 h after metreleptin administration. Twenty lean women, with leptin levels <5 ng/ml, were randomised in a 1:1 fashion to receive either physiological replacement doses of metreleptin (0.04-0.12 mg/kg q.d.) or placebo for 32 weeks. Serum was collected at 0, 8, 20 and 32 weeks after randomisation. Proteomic angiogenesis array analysis was performed to screen for angiogenic factors. Circulating concentrations of angiogenin, angiopoietin-1, platelet derived endothelial factor (PDGF)-AA, matrix metalloproteinase (MMP) 8 and 9, endothelial growth factor (EGF) and vascular EGF (VEGF) were also measured. RESULTS: Both metreleptin doses failed to induce angiogenesis in the in vitro model. Although leptin levels increased significantly in response to both short-term and long-term metreleptin administration, circulating concentrations of angiogenesis markers did not change significantly in vivo. CONCLUSIONS/INTERPRETATIONS: This is the first study that examines the effect of metreleptin administration in angiogenesis in humans. Metreleptin administration does not regulate circulating angiogenesis related factors in humans. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00140205 and NCT00130117. FUNDING: This study was supported by National Institutes of Health-National Center for Research Resources grant M01-RR-01032 (Harvard Clinical and Translational Science Center) and grant number UL1 RR025758. Funding was also received from the National Institute of Diabetes and Digestive and Kidney Diseases grants 58785, 79929 and 81913, and AG032030. PMID- 21660638 TI - Mediastinal involvement in lymphangiomatosis: a previously unreported MRI sign. AB - BACKGROUND: Multifocal lymphangiomatosis is a rare systemic disorder affecting children. Due to its rarity and wide spectrum of clinical, histological and imaging features, establishing the diagnosis of multifocal lymphangiomatosis can be challenging. OBJECTIVES: The purpose of this study was to describe a new imaging sign in this disorder: paraspinal soft tissue and signal abnormality at MRI. MATERIALS AND METHODS: We retrospectively reviewed the imaging, clinical and histopathological findings in a cohort of eight children with thoracic involvement from this condition. RESULTS: Evidence of paraspinal chest disease was identified at MRI and CT in all eight of these children. The changes comprise heterogeneous intermediate-to-high signal parallel to the thoracic vertebrae on T2-weighted sequences at MRI, with abnormal paraspinal soft tissue at CT and plain radiography. CONCLUSION: Multifocal lymphangiomatosis is a rare disorder with a broad range of clinicopathological and imaging features. MRI allows complete evaluation of disease extent without the use of ionising radiation and has allowed us to describe a previously unreported imaging sign in this disorder, namely, heterogeneous hyperintense signal in abnormal paraspinal tissue on T2 weighted images. PMID- 21660639 TI - Does adiponectin upregulation attenuate the severity of acute pancreatitis in obesity? AB - INTRODUCTION: Obesity is an independent risk factor for severe acute pancreatitis, though the mechanisms underlying this association are unknown. The powerful anti-inflammatory adipokine adiponectin is decreased in obesity. We recently showed that the severity of pancreatitis in obese mice is inversely related to circulating adiponectin levels, and therefore hypothesized that adiponectin upregulation would attenuate the severity of pancreatitis in obese mice. METHODS: Forty congenitally obese mice were studied. Seven days prior to study, 20 mice received a single tail vein injection of adenovirus expressing recombinant murine adiponectin (APN; 2 * 108 plaque forming unit (pfu)), and the remainder received a control adenoviral vector expressing beta-galactosidase (beta-gal; 2 * 108 pfu). Half of the mice in each group had pancreatitis induced by cerulein injection (50 mcg/kg IP hourly for 6 h). The other half received saline on the same schedule. Serum APN concentration and pancreatic tissue concentrations of interleukin (IL)-6, IL-1beta, and MCP-1 were measured by ELISA. Histologic pancreatitis score was calculated based on the degree of inflammation (0-4), edema (0-4), and vacuolization (0-4). Data were analyzed by ANOVA and Tukey's tests; p < 0.05 was considered significant. RESULTS: No difference in body weight was observed between groups. Serum APN was significantly upregulated in the APN group compared with the beta-gal group. Pancreatic tissue concentration of IL-6 was significantly decreased in the APN group compared with the beta-gal group. No change either in pancreatic tissue concentration of IL 1beta and MCP-1 or in the severity of histologic pancreatitis were observed. CONCLUSION: Adiponectin upregulation modulates the pancreatic cytokine milieu but does not attenuate pancreatitis in this model of mild acute pancreatitis. PMID- 21660640 TI - Endoscopic fundoplication: real or fantasy? PMID- 21660641 TI - Pouch size after gastric bypass does not correlate with weight loss outcome. AB - A large gastric pouch is a classic explanation for weight loss problems after gastric bypass. However, several reports have emphasized the role of others, essentially behavorial, factors. We reviewed the outcomes of 151 patients who were operated on over a period of nearly 2 years. 132 patients who had not been reoperated on were assessed between June and September 2009. A barium swallow was available to assess the gastric pouch volume which was determined by the radiologist. %EWL was compared to the pouch volume using ANOVA test. Pouch volumes were compared using t test. The gastric pouch was dilated when >50 ml and failure to lose enough weight was defined by a %EWL<50%. 107 patients (81%) had a complete follow up of 35.7 +/- 5.8 months. Mean pouch volume was 68 +/- 4.5 ml with a %EWL of 68 +/- 26.1%. 59 patients had a large pouch with a weight loss similar to those with a normally sized pouch (68 +/- 3.6 vs 66 +/- 3.6%EWL). 25 patients (23.3%) had weight loss failure with a similar pouch volume. No correlation was found between the %EWL and the pouch volume. Pouch size probably plays a role in the weight loss process of RYGB. However, 3 years later, pouch volume does not appear to be the most important factor. Behavorial factors such as recurrent eating disorders and failure to adapt to the changes induced by the surgery may explain at least in part weight loss failure. PMID- 21660642 TI - Bariatric surgery pharmacy consultation service. AB - Bariatric surgical patients often need changes in formulation and dosages of their medications. The literature contains minimal information regarding pharmaceutical care and consultation services for the bariatric surgery patient. Complex medication regimens and safety concerns initiated a collaborative effort between surgeons and pharmacists to manage more effectively bariatric patients perioperatively. The consultation service included patient identification, pharmacy referral, pharmacist consultation with the patient, communication of recommendations with surgeons, follow-up, and documentation. There were 124 consultations performed from February 2, 2009 to December 1, 2010 with an average of 7.7 medications optimized per patient. Every patient required a minimum of one adjustment to their regimen. The surgeons approved 98% of these recommendations. Of recommendations provided, the majority focused on changing the formulation of the medication in some manner. The collaborative effort between surgeons and pharmacists effected changes in medication transitioning perioperatively and resulted in improved pharmaceutical care for this patient population. PMID- 21660643 TI - Preoperative transabdominal ultrasonography (US) prior to laparoscopic Roux-en-Y gastric bypass (LRYGBP) and laparoscopic sleeve gastrectomy (LSG) in the first 100 operations. Was it beneficial and reliable during the learning curve? AB - BACKGROUND: Preoperative ultrasonography (US) prior to laparoscopic Roux-en-Y gastric bypass (LRYGBP) aimed to find possible gallstones. The aim of this study was to evaluate the reliability of the US in evaluating the size and consistency of the left lobe of the liver. METHODS: One hundred LRYGBP and LSG were performed in our new bariatric surgery unit by two surgeons. All patients underwent preoperative US to evaluate the size and consistency of the left lobe of the liver. A consultant radiologist reviewed the US findings, which were then compared to the intraoperative findings. RESULTS: The mean preoperative body mass index was 49. All patients had co-morbidities. The intraoperative evaluation showed an enlarged left lobe of the liver in 23 patients, whereas the US found enlargement only in eight patients, but revealed eight false positives. In the intraoperative evaluation, fatty liver was observed in five patients, only four of whom were shown in the US, but US revealed 77 false positives. In evaluating the size of the left lobe, US had 35% sensitivity, 90% specificity, 65% false negative rate (FNR) and 10% false positive rate (FPR). In evaluating the consistency, US had 80% sensitivity, 18% specificity, 20% FNR and 82% FPR. CONCLUSION: Preoperative US is unreliable in evaluating the size and consistency of the left lobe of the liver prior to LRYGBP and LSG and has limited prognostic value for surgical complications and complexity of surgery. PMID- 21660644 TI - I used to cry every day: a model of the family process of managing displacement. AB - Community displacing events, natural or human made, are increasing in frequency. By the end of 2009, over 36 million people were known to be displaced worldwide. Displacement is a traumatic experience with significant short- and long-term health consequences. The losses and costs associated with displacement-social connections, employment, property, and economic capital-are felt not only by the displaced individuals but also the communities they have left behind, and the communities that receive displaced individuals. Many researchers have explored the link between health and reduced social, cultural, and economic capital. Most of the displacement literature focuses on the effect of displacement on the displaced individual; however, many families move as a group. In this study, we examined the family process of managing displacement and its associated capital losses by conducting interviews with 20 families. We found that families undergo a four-phase process of displacement: antecedent, uprooting, transition, and resettlement. The losses families experience impact the health and well-being of individuals, families, and communities. The degree to which the displacement process ends successfully, or ends at all, can be affected by efforts to both create connections within the new communities and rebuild economic and social capital. PMID- 21660645 TI - Body fat composition and occurrence of kidney stones in hypercalciuric children. AB - In the last 10 years, the incidence of kidney stones has increased in the pediatric population, and this rise has been paralleled by a significant increase in pediatric obesity rates in the USA. The purpose of this study was to evaluate percentage body fat (%BF) measured by dual energy X-ray absorptiometry (DXA) in hypercalciuric children with and without kidney stones. A retrospective chart review was performed on children with idiopathic hypercalciuria based on a 24-h urine calcium excretion of >4 mg/kg/day or >200 mg/day who had undergone DXA scanning. Patients were then classified by sex and by %BF (3 categories; normal: <27% girls, <21% boys; at risk for obesity: 27-36% girls, 21-30% boys; obese: >36% girls, >30% boys). The 2003-2004 NHANES data were used as a control. Fifty patients (24 males) were analyzed, of whom 26% were assessed as having a normal %BF, 44% as being at risk for obesity, and 30% as being obese. Children with an increased %BF had a significantly higher occurrence of kidney stones (p = 0.03) than those with a normal %BF. No significant differences were noted in 24-h urine chemistries between the groups. In conclusion, an increased %BF was associated with an increased occurrence of kidney stones in children with idiopathic hypercalciuria. PMID- 21660646 TI - Predicting the functionally distinct residues in the heme, cation, and substrate binding sites of peroxidase from stress-tolerant mangrove specie, Avicennia marina. AB - Recent work was conducted to predict the structure of functionally distinct regions of Avicennia marina peroxidase (AP) by using the structural coordinates of barley grains peroxidase as the template. This enzyme is utilized by all living organisms in many biosynthetic or degradable processes and in defense against oxidative stress. The homology model showed some distinct structural changes in the heme, calcium, and substrate-binding regions. Val53 was found to be an important coordinating residue between distal calcium ion and the distal heme site while Ser176 is coordinated to the proximal histidine through Ala174 and Leu172. Different ionic and hydrogen-bonded interactions were also observed in AP. Analyses of various substrate-enzyme interactions revealed that the substrate-binding pocket is provided by the residues, His41, Phe70, Gly71, Asp138, His139, and Lys176; the later three residues are not conserved in the peroxidase family. We have also performed structural comparison of the A. marina peroxidase with that of two class III salt-sensitive species, peanut and soybean. Four loop regions were found to have largest structural deviation. The overall protein sequence was also analyzed for the presence of probable post translational modification sites and the functional significance of these sites were outlined. PMID- 21660647 TI - Infection of cattle in Kenya with Brucella abortus biovar 3 and Brucella melitensis biovar 1 genotypes. AB - Brucella melitensis biovar 1 was isolated from bovine milk samples from a herd in central Kenya, and Brucella abortus biovar 3 was isolated from aborted fetus materials and vaginal discharge fluids from cattle in central and eastern provinces of Kenya. All infections including those with B. melitensis were in cattle with reproductive problems kept in mixed herds indicating that cross infection occurs from small ruminants. Multiple-locus variable-number tandem repeat analysis genotyping revealed a close molecular homology of the B. melitensis isolates with an isolate from Israel and a close homology of the B. abortus isolates with an isolate from Uganda indicating that these genotypes have a wide geographic distribution. Infection of cattle with B. melitensis may complicate the control of brucellosis in this country. PMID- 21660648 TI - Risk factors associated with prevalence and major bacterial causes of mastitis in dromedary camels (Camelus dromedarius) under different production systems. AB - A cross-sectional study was conducted in desert environment of Jhang (Pakistan) from November 2008 to October 2009 on she-camels kept under pastoralist conditions to determine the prevalence of mastitis, impact of risk factors, and isolate the dominant mastitis-causing bacteria on total of 150 lactating she camels by using clinical examination and surf field mastitis test. From the 150 she-camels examined, 69 (46%) were positive for mastitis at animal level, 12 (8%) clinical, and 57 (38%) subclinical. Age, parity number, stage of lactation, breed, production system, hygiene of milking process, and presence of lesion on udder/teat were found significantly associated (p<0.05) with the prevalence of mastitis in she-camels. There was the lowest prevalence (33.33%; 15 of 45) of mastitis in she-camels of 5-7 years of age, while the highest (80%; 12 of 15) in the animals aged between 14 to 16 years. Stage of lactation significantly affected (p<0.05) and was found to be associated with the prevalence of mastitis being the highest (54.55%; 18 of 33) during the initial stage of lactation (0 to 1 month) followed by last 2 months (10-12 months) as 54.17% and mid-stages (1-3 and 3-10 months) of lactation as 28.57% (6 of 21) and 37.50% (9 of 24), respectively. According to breed of camels, it was noted that the prevalence of mastitis affected significantly (p<0.05) being the highest in crossbred (Desi * Mareecha) as 51.39% (37 of 72) followed in order by Mareecha and Desi as 43.14% and 37.04%, respectively. Staphylococcus (42.19%) and Streptococcus (15.63%) genera were the dominant isolates identified. Good hygiene in milking process, milking clinically infected she-camels at last, culling chronic mastitis carriers, treating clinically infected she-camels, and dry period therapy could reduce the prevalence of contagious mastitis in the study area. PMID- 21660649 TI - Serological evidence of caprine arthritis-encephalitis virus (CAEV) infection in indigenous goats in the Sultanate of Oman. AB - Caprine arthritis encephalitis (CAE) is a chronic debilitating disease of goats caused by a lentivirus responsible for economic losses as a result of a drop in milk production and weight loss. The objective of the study was to determine if indigenous goats from five different regions in the Sultanate of Oman exhibit serological evidence of exposure to CAEV using a competitive-inhibition ELISA technique. Blood samples were collected from slaughtered goats (N=1,110) and from the National Serum Bank (n=528). In total, 83 (5.1%) of screened samples were classed as seropositive. The results provide the first serological evidence for the presence of CAEV in Oman. PMID- 21660650 TI - Health-related quality of life in breast cancer survivors of different sexual orientations. AB - PURPOSE: Sexual minority women, e.g., lesbians and bisexuals, are an underserved population but not much is known about their quality of life (QOL) after a breast cancer diagnosis. For this reason, this study examines the physical and mental QOL and its association with sexual orientation in a cohort of long-term nonrecurring breast cancer survivors. METHODS: Survivors were recruited from a cancer registry and additional sexual minority survivors through convenience methods. Data were collected via telephone survey from all 438 survivors, who were disease free and diagnosed with nonmetastatic breast cancer an average of 5 years earlier. Sexual orientation was the primary independent factor, and QOL, measured with the SF-12, was the outcome. Demographic and clinical factors were considered as correlates. RESULTS: Sexual orientation was not significantly associated with survivors' physical or mental QOL. The majority of survivors reported good physical and mental QOL. The demographic and clinical factors explained about one-third of the variation in survivors' physical QOL, but did not account for most of survivors' mental QOL. CONCLUSIONS: The lack of an association between sexual orientation and QOL suggests that if there is a link, it does not relate directly to clinical and demographic factors. Future studies need to identify areas of similarity and difference between sexual minority and heterosexual survivors and mechanisms to explain the similarity in QOL. PMID- 21660651 TI - Lack of awareness of risk factors for primary toxoplasmosis in pregnancy. AB - BACKGROUND: The overall seroprevalence of toxoplasma antibodies in women of childbearing age in Ireland is 25% [1]. Hence, 75% of women remain susceptible to primary toxoplasma infection during pregnancy, which if transmitted to the foetus can cause ocular, neurological and other sequelae. Toxoplasma exposure during pregnancy can be avoided if there is an awareness of the potential sources of infection, mainly contaminated food, water, soil and cat faeces. AIMS: To determine risk factor exposure in a cohort of women with congenitally infected infants and to assess maternal risk awareness prior to diagnosis of infection. METHODS: Data, prospectively gathered during 2 years of pilot newborn screening for congenital toxoplasmosis in Ireland, was retrospectively analysed. Known risk factors for acquisition of infection were identified. Women were questioned regarding risk awareness and implementation of avoidance measures, if any, during pregnancy. RESULTS: Fifteen congenitally infected infants were identified by newborn screening. Seventy-three percent of their mothers (11/15) reported lack of knowledge concerning risk factors for toxoplasma infection or its potential threat to the foetus. Ingestion of raw or undercooked meat during pregnancy was the predominant source of toxoplasma cyst exposure identified. Contact with cats was reported in just one case. CONCLUSIONS: Most women were uneducated about the risks posed by Toxoplasma gondii exposure during pregnancy. There is a clear need for better educational programmes regarding primary prevention of congenital toxoplasmosis if neonatal infection is to be avoided. PMID- 21660652 TI - Intra subject variation and correlation of motor potentials evoked by transcranial magnetic stimulation. AB - BACKGROUND: Characterising intra and inter-subject variability of motor-evoked potential (MEP) measurements from transcranial magnetic stimulation (TMS) is key to its development as a diagnostic tool. METHODS: We performed three experiments to elucidate MEP variability within subjects: (i) repeated measurements at different levels of stimulation and muscle activation, (ii) simultaneous measurements at pairs of ipsilateral and contralateral muscles, (iii) simultaneous measurements of contralateral muscles when one is activated. RESULTS: Cube root transformation of MEP data produces approximately constant coefficient of variation with Gaussian distribution and no significant autocorrelation between repeat measurements. After adjustment of intersubject variability, correlation between simultaneous muscle pairs was insignificant (p = 0.36). Highly significant effects were observed due to increase in intensity of stimulation: (0.07, 0.23) mV, p < 0.0001, muscle type: (p < 0.009) and activation of ipsilateral muscle: (0.10, 0.49) mV, p < 0.0001. CONCLUSION: Corticospinal effect is dominated by intersubject variability in simultaneous measurements on normal population. PMID- 21660653 TI - The sleep/wake state scoring from mandible movement signal. AB - PURPOSE: Estimating the total sleep time in home recording devices is necessary to avoid underestimation of the indices reflecting sleep apnea and hypopnea syndrome severity, e.g., the apnea-hypopnea index (AHI). A new method to distinguish sleep from wake using jaw movement signal processing is assessed. METHODS: In this prospective study, jaw movement signal was recorded using the Somnolter (SMN) portable monitoring device synchronously with polysomnography (PSG) in consecutive patients complaining about a lack of recovery sleep. The automated sleep/wake scoring method is based on frequency and complexity analysis of the jaw movement signal. This computed scoring was compared with the PSG hypnogram, the two total sleep times (TST(PSG) and TST(SMN)) as well. RESULTS: The mean and standard deviation (in minutes) of TST(PSG) on the whole dataset (n = 124) were 407 +/- 95.6, while these statistics were 394.2 +/- 99.3 for TST(SMN). The Bland and Altman analysis of the difference between the two TST was 12.8 +/- 57.3 min. The sensitivity and specificity (in percent) were 85.3 and 65.5 globally. The efficiency decreased slightly when AHI lies between 15 and 30, but remained similar for lower or greater AHI. In the 24 patients with insomnia/depression diagnosis, a mean difference in TST of -3.3 min, a standard deviation of 58.2 min, a sensitivity of 86.3%, and a specificity of 66.2% were found. CONCLUSIONS: Mandible movement recording and its dedicated signal processing for sleep/wake recognition improve sleep disorder index accuracy by assessing the total sleep time. Such a feature is welcome in home screening methods. PMID- 21660654 TI - Role of tyrosine kinase inhibitors in the management of Philadelphia chromosome positive acute lymphoblastic leukemia. AB - The Philadelphia chromosome is the most common cytogenetic abnormality found in adult patients diagnosed with acute lymphoblastic leukemia. The result of this abnormality is the BCR-ABL protein, a constitutively active kinase involved in cell signaling and survival. When managed with multiagent chemotherapy regimens alone, patients have traditionally had an inferior outcome in terms of remission duration and overall survival when compared with patients who are Philadelphia chromosome-negative. Small-molecule tyrosine kinase inhibitors, such as imatinib and dasatinib, directly inhibit the BCR-ABL kinase, offering a targeted approach as a therapeutic option. As a result of several clinical trials with adequate follow-up, imatinib combined with chemotherapy represents the current standard of care for patients with newly diagnosed disease. Allogeneic stem cell transplantation has previously been the only modality to offer the potential for a cure, and it still should be considered for all patients deemed able to tolerate such an intervention. Second-generation tyrosine kinase inhibitors, such as dasatinib, may further improve the outcome in these patients. The role of molecular monitoring and the use of tyrosine kinase inhibitors after stem cell transplantation are areas of active investigation, and the results of ongoing trials will help to clarify the optimal management of these patients. PMID- 21660655 TI - Papain-like proteases of Staphylococcus aureus. AB - Staphylococcus aureus remains one of the major humanpathogens, causing a number of diverse infections. the growing antibiotic resistance, including vancomycin and methicilin-resistant strains raises the special interest in virulence mechanism of this pathogen. among a number of extracellular virulence factors, S. aureus secretes several proteases of three catalytic classes-metallo, serine and papain-like cysteine proteases. the expression of proteolytic enzymes is strictly controlled by global regulators of virulence factors expression agr and sar and proteases take a role in a phenotype change in postlogarithmic phase of growth. the staphylococcal proteases are secreted as proenzymes and undergo activation in a cascade manner. Staphopains, two cysteine, papain-like proteases of S. aureus are both approximately 20 kDa proteins that have almost identical three dimensional structures, despite sharing limited primary sequence identity. although staphopain a displays activity similar to cathepsins, recognising hydrophobic residues at P2 position and large charged residues at P1, staphopain B differs significantly, showing significant preference towards beta-branched residues at P2 and accepting only small, neutral residues at the P1 position. there is limited data available on the virulence potential of staphopains in in vivo models. However, in vitro experiments have demonstrated a very broad activity of these enzymes, including destruction of connective tissue, disturbance of clotting and kinin systems and direct interaction with host immune cells. Staphopain genes in various staphylococci species are regularly followed by a gene encoding an extremely specific inhibitor of the respective staphopain. This pattern is conserved across species and it is believed that inhibitors (staphostatins) protect the cytoplasm of the cell from premature activation of staphopains during protein folding. Notably, production and activity of staphopains is controlled on each level, from gene expression, through presence of specific inhibitors in cytoplasm, to the cascade-like activation in extracellular environment. Since these systems are highly conserved, this points to the importance of these proteases in the survival and/or pathogenicity of S. aureus. PMID- 21660656 TI - The lysine-specific gingipain of Porphyromonas gingivalis : importance to pathogenicity and potential strategies for inhibition. AB - Periodontitis is a disease affecting the supporting structures of the teeth. The most severe forms of the disease result in tooth loss and have recently been strongly associated with systemic diseases, including cardiovascular and lung diseases and cancer. The disease is caused by biofilms of predominantly anaerobic bacteria. A major pathogen associated with severe, adult forms of the disease is Porphyromonas gingivalis. This organism produces potent cysteine proteases known as gingipains, which have specificity for cleavage after arginine or lysine residues. The lysine-specific gingipain, Kgp, appears to be the major virulence factor of this organism and here we describe its structure and function. We also discuss the inhibitors of the enzyme produced to date and the potential pathways to newer versions of such molecules that will be required to combat periodontitis. PMID- 21660657 TI - Falcipains and other cysteine proteases of malaria parasites. AB - A number of cysteine proteases of malaria parasites have been described and many more are suggested by analysis of the Plasmodium falciparum genome sequence. The best characterized of these proteases are the falcipains, a family of four papain family enzymes. Falcipain-2 and falcipain-3 act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. Disruption of the falcipain-2 gene led to a transient block in hemoglobin hydrolysis and parasites with increased sensitivity to protease inhibitors. Disruption of the falcipain-3 gene was not possible, strongly suggesting that this protease is essential for erythrocytic parasites. Disruption of the falcipain-1 gene did not alter development in erythrocytes, but led to decreased production of oocysts in mosquitoes. other papain-family proteases predicted by the genome sequence include dipeptidyl peptidases, a calpain homolog and serine-repeat antigens (SERAs). Dipeptidyl aminopeptidase 1 appears to be essential and localized to the food vacuole, suggesting a role in hemoglobin hydrolysis. Dipeptidyl aminopeptidase 3 appears to play a role in the rupture of erythrocytes by mature parasites. the P. falciparum calpain homolog gene could not be disrupted, suggesting that the protein is essential and a role in the parasite cell cycle has been suggested. Nine P. falciparum SERAs have cysteine protease motifs, but in some the active site cys is replaced by a Ser. Gene disruption studies suggested that SERA-5 and SERA-6 are essential. activation of SERA-5 by a serine protease seems to be required for merozoite egress from the erythrocyte. New drugs for malaria are greatly needed and cysteine proteases represent potential drug targets. cysteine protease inhibitors have demonstrated potent antimalarial effects and the optimization and testing of falcipain inhibitor antimalarials is underway. PMID- 21660658 TI - Cathepsin proteases in Toxoplasma gondii. AB - Cysteine proteases are important for the growth and survival of apicomplexan parasites that infect humans. The apicomplexan Toxoplasma gondii expresses five members of the C1 family of cysteine proteases, including one cathepsin L-like (TgCPL), one cathepsin B-like (TgCPB) and three cathepsin C-like (TgCPC1, 2 and 3) proteases. Recent genetic, biochemical and structural studies reveal that cathepsins function in microneme and rhoptry protein maturation, host cell invasion, replication and nutrient acquisition. here, we review the key features and roles of T. gondii cathepsins and discuss the therapeutic potential for specific inhibitor development. PMID- 21660659 TI - Entamoeba histolytica cathepsin-like enzymes : interactions with the host gut. AB - Cysteine proteases of the protozoan parasite Entamoeba histolytica are key virulence factors involved in overcoming host defences. These proteases are cathepsin-like enzymes with a cathepsin-L like structure, but cathepsin-B substrate specificity. In the host intestine, amoeba cysteine proteases cleave colonic mucins and degrade secretory immunoglobulin (Ig) A and IgG rendering them ineffective. They also act on epithelial tight junctions and degrade the extracellular matrix to promote Cell death. They are involved in the destruction of red blood cells and the evasion of neutrophils and macrophages and they activate pro-inflammatory cytokines IL- 1beta and IL-18. In short, amoeba cysteine proteases manipulate and destroy host defences to facilitate nutrient acquisition, parasite colonization and/or invasion. Strategies to inhibit the activity of amoeba cysteine proteases could contribute significantly to host protection against E. histolytica. PMID- 21660660 TI - Cysteine peptidases of kinetoplastid parasites. AB - We review Clan CA Family C1 peptidases of kinetoplastid parasites (Trypanosoma and Leishmania) with respect to biochemical and genetic diversity, genomic organization and stage-specificity and control of expression. We discuss their contributions to parasite metabolism, virulence and pathogenesis and modulation of the host's immune response. Their applications as vaccine candidates and diagnostic markers as well as their chemical and genetic validation as drug targets are also summarized. PMID- 21660661 TI - Cruzain : the path from target validation to the clinic. AB - Cruzain is the major papain-like cysteine protease of Trypanosoma cruzi, the etiological agent causing Chagas' disease in humans in South America. Cruzain is indispensable for the survival and propagation of this protozoan parasite and therefore, it has attracted considerable interest as a potential drug target. This chapter charts the path from the initial identification of this proteases activity and its validation as a bone fide drug target to the arduous task of the discovery of an inhibitor targeting this protease and finally the path towards the clinic. PMID- 21660662 TI - The phylogeny, structure and function of trematode cysteine proteases, with particular emphasis on the Fasciola hepatica cathepsin L family. AB - Helminth parasites (nematodes, flatworms and cestodes) infect over 1 billion of the world's population causing high morbidity and mortality. The large tissue dwelling worms express papain-like cysteine peptidases, termed cathepsins that play important roles in virulence including host entry, tissue migration and the suppression of host immune responses. Much of our knowledge of helminth cathepsins comes from studies using flatworms or trematode (fluke) parasites. The developmentally-regulated expression of these proteases correlates with the passage of parasites through host tissues and their encounters with different host macromolecules. Recent phylogenetic, biochemical and structural studies indicate that trematode cathepsins exhibit overlapping but distinct substrate specificities due to divergence within the protease active site. Here we provide an overview of the evolution, biochemistry and structure of these important enzymes and highlight how recent advances in proteomics and gene silencing techniques are allowing researchers to probe their biological functions. We focus mainly on members of the cathepsin L gene family of the animal and human pathogen, Fasciola hepatica, because of our deep understanding of their function, biochemistry and structure. PMID- 21660663 TI - Cathepsins B1 and B2 of Trichobilharzia SPP., bird schistosomes causing cercarial dermatitis. AB - Trichobilharzia regenti and T. szidati are schistosomes that infect birds. although T. regenti/T. szidati can only complete their life cycle in specific bird hosts (waterfowl), their larvae-cercariae are able to penetrate, transform and then migrate as schistosomula in nonspecific hosts (e.g., mouse, man). Peptidases are among the key molecules produced by these schistosomes that enable parasite invasion and survival within the host and include cysteine peptidases such as cathepsins B1 and B2. These enzymes are indispensable bio-catalysts in a number of basal biological processes and host-parasite interactions, e.g., tissue invasion/migration, nutrition and immune evasion. Similar biochemical and functional characteristics were observed for cathepsins B1 and B2 in bird schistosomes (T. regenti, T. szidati) and also for their homologs in human schistosomes (Schistosoma mansoni, S. japonicum). Therefore, data obtained in the research of bird schistosomes can also be exploited for the control of human schistosomes such as the search for targets of novel chemotherapeutic drugs and vaccines. PMID- 21660664 TI - Proteases in blood-feeding nematodes and their potential as vaccine candidates. AB - Parasitic nematodes express and secrete a variety of proteases which they use for many purposes including the penetration of host tissues, digestion of host protein for nutrients, evasion of host immune responses and for internal processes such as tissue catabolism and apoptosis. For these broad reasons they have been examined as possible parasite control targets. Blood-feeding nematodes such as the barber-pole worm Haemonchus contortus that infect sheep and goats and the hookworms, Ancylostoma spp. and Necator americanus, affecting man, use an array of endo- and exopeptidases to digest the blood meal. Haemoglobin digestion occurs by an ordered and partly conserved proteolytic cascade. These proteases are accessible to host immune responses which can block enzyme function and lead to parasite expulsion and/or death. Thus they are receiving attention as components of vaccines against several parasitic nematodes of social and economic importance. PMID- 21660666 TI - How pathogen-derived cysteine proteases modulate host immune responses. AB - In mammals, cysteine proteases are essential for the induction and development of both innate and adaptive immune responses. These proteases play a role in antigen and pathogen-recognition and elimination, signal processing and cell homeostasis. Many pathogens also secrete cysteine proteases that often act on the same target proteins as the mammalian proteases and thereby can modulate host immunity from initial recognition to effector mechanisms. Pathogen-derived proteases range from nonspecific proteases that degrade multiple proteins involved in the immune response to enzymes that are very specific in their mode of action. Here, we overview current knowledge of pathogen-derived cysteine proteases that modulate immune responses by altering the normal function of key receptors or pathways in the mammalian immune system. PMID- 21660665 TI - Cysteine proteases from bloodfeeding arthropod ectoparasites. AB - Cysteine proteases have been discovered in various bloodfeeding ectoparasites. Here, we assemble the available information about the function of these peptidases and reveal their role in hematophagy and parasite development. While most of the data shed light on key proteolytic events that play a role in arthropod physiology, we also report on the association of cysteine proteases with arthropod vectorial capacity. With emphasis on ticks, specifically Ixodes ricinus, we finally propose a model about the contribution of cysteine peptidases to blood digestion and how their concerted action with other tick midgut proteases leads to the absorbance of nutrients by the midgut epithelial cells. PMID- 21660667 TI - Cystatins of parasitic organisms. AB - The cystatin superfamily comprises several groups of protease inhibitors. In this chapter we will focus on I25 family members, which consist predominantly of the type 2 cystatins. Recently, a wealth of information on these molecules and their activities has been described. Parasite cystatins are shown to have dual functions via interaction with both parasite and host proteases. Thereby, parasite cystatins are not only essentially involved in the regulation of physiological processes during parasite development, but also represent important pathogenicity factors. Interestingly, some studies indicate that parasite cystatins evolved exceptional immuno-modulatory properties. these capacities could be exploited to interfere with unwanted immune responses in unrelated human inflammatory diseases. We highlight the different biological roles of parasite cystatins and the anticipated future developments. PMID- 21660668 TI - Fertility and cancer--a qualitative study of Australian cancer survivors. AB - PURPOSE: This study aims to assess the fertility concerns among cancer survivors aged 50 and under as part of a larger study investigating the survivors' concerns regarding fertility, sexuality and parenting. METHODS: Cancer survivors who were at least 1 month post-treatment were invited to a recorded interview. The patients were identified from an oncology database and invited to participate via letter or during clinic consultation. The participants were recruited until saturation of themes was achieved. Transcripts were coded thematically, with greater emphasis given to frequently raised themes. RESULTS: Twenty-five survivors (19 women) were interviewed. The median age was 37 (range 24-50). Median time since completion of treatment was 7 months. Twenty were married or in a relationship; 18 had children at the time of diagnosis. Two became pregnant after treatment. Four themes were identified: (1) Fertility represents more than child-bearing capacity: potential fertility loss was a concern for participants, irrespective of their desire for future children; (2) Assumed infertility: There was a tendency for participants to assume that they were infertile; (3) Lack of information regarding decision-making and fertility: The respondents reported a perceived lack of consideration of fertility at diagnosis by medical professionals, and this impacted upon the decision-making process; and (4) Participant recommendations: The respondents wanted more information and for support services to be offered. CONCLUSIONS: Fertility is an important concern for young cancer survivors. There is a need for strategies regarding information provision and support for cancer patients with regard to these concerns. PMID- 21660671 TI - ECG changes after electroconvulsive therapy, cause or consequence? PMID- 21660670 TI - A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in cancer therapy-induced oral mucositis. AB - PURPOSE: The purpose of this study is to review the effects of low-level laser therapy (LLLT) in the prevention and treatment of cancer therapy-induced oral mucositis (OM). METHODS: A systematic review and meta-analysis of randomised placebo-controlled trials of LLLT performed during chemotherapy or radiation therapy in head and neck cancer patients. RESULTS: We found 11 randomised placebo controlled trials with a total of 415 patients; methodological quality was acceptable at 4.10 (SD +/- 0.74) on the 5-point Jadad scale. The relative risk (RR) for developing OM was significantly (p = 0.02) reduced after LLLT compared with placebo LLLT (RR = 2.03 (95% CI, 1.11 to 3.69)). This preventive effect of LLLT improved to RR = 2.72 (95% CI, 1.98 to 3.74) when only trials with adequate doses above 1 J were included. For treatment of OM ulcers, the number of days with OM grade 2 or worse was significantly reduced after LLLT to 4.38 (95% CI, 3.35 to 5.40) days less than placebo LLLT. Oral mucositis severity was also reduced after LLLT with a standardised mean difference of 1.33 (95% CI, 0.68 to 1.98) over placebo LLLT. All studies registered possible side-effects, but they were not significantly different from placebo LLLT. CONCLUSIONS: There is consistent evidence from small high-quality studies that red and infrared LLLT can partly prevent development of cancer therapy-induced OM. LLLT also significantly reduced pain, severity and duration of symptoms in patients with cancer therapy-induced OM. PMID- 21660669 TI - Light treatment prevents fatigue in women undergoing chemotherapy for breast cancer. AB - PURPOSE: Fatigue is one of the most disturbing complaints of cancer patients and is often the reason for discontinuing treatment. This randomized controlled study tested the hypothesis that increased morning bright light, compared to dim light, would result in less fatigue in women with breast cancer undergoing chemotherapy. METHODS: Thirty-nine women newly diagnosed with stage I-III breast cancer were randomized to either bright white light (BWL) or dim red light (DRL) treatment and were instructed to use the light box for 30 min every morning throughout the first four cycles of chemotherapy. The Multidimensional Fatigue Symptom Inventory was administered prior to the start of chemotherapy (baseline), during the chemotherapy treatment week of cycle 1 (C1TW), the last week (recovery week) of cycle 1 (C1RW), the chemotherapy treatment week of cycle 4 (C4TW), and the last week (recovery week) of cycle 4 (C4RW). RESULTS: The DRL group reported increased fatigue at C1TW (p = 0.003) and C4TW (p < 0.001) compared to baseline, while there was no significant change from baseline in the BWL group. A secondary analysis showed that the increases in fatigue levels in the DRL group were not mediated through nor associated with changes in sleep or in circadian rhythms as measured with wrist actigraphy. CONCLUSIONS: The results of this study suggest that morning bright light treatment may prevent overall fatigue from worsening during chemotherapy. Although our hypothesis that overall fatigue would improve with bright light treatment was not supported, the lack of deterioration in total fatigue scores suggests that bright morning light may be a useful intervention during chemotherapy for breast cancer. PMID- 21660673 TI - Review on efficacy and health services research studies of complementary and alternative medicine in inflammatory bowel disease. AB - OBJECTIVE: To assess the evidence of the use and efficacy for complementary and alternative medicine (CAM) in inflammatory bowel disease (IBD). METHODS: A systematic literature search in MEDLINE was performed for randomized controlled trials (RCTs) in Crohn's disease and ulcerative colitis. Moreover, a selective literature search for health services research studies on the use of CAM in patients with IBD was performed. RESULTS: Health services research studies showed a high use of CAM in adult and pediatric patients with IBD worldwide. In contrast to the high use among IBD patients, there was a lack of high-quality data for many of the used CAM methods. Although most of the studies showed positive results, the methodological quality of most studies was rather low; therefore, the results had to be interpreted with caution. While there were many studies for probiotics and fish oil, RCTs for the highly used method homeopathy, for most herbal products, and for traditional Chinese medicine methods apart from acupuncture RCTs were completely lacking. CONCLUSIONS: The lack of high-quality studies might be the consequence of the problems: associated with the funding of clinical trials involving CAM. However, having the high user rates in mind, high quality studies assessing efficacy and safety of those methods are urgently needed. Furthermore, there is a quality need for better representation of CAM in undergraduate and postgraduate medical education. PMID- 21660674 TI - Irritable bowel syndrome: common integrative medicine perspectives. AB - Previous reviews have highlighted complementary and alternative medicine therapies that are used to treat irritable bowel syndrome (IBS) based on published clinical trial data. Here the author describes and comments on a number of potentially relevant factors that have been commonly emphasized by practitioners who treat IBS and patients who have the disease. They include gluten and other food allergies, the candida syndrome and biofilm, interference fields and post-infectious IBS, as well as mind-body factors. PMID- 21660676 TI - A model and treatment for autism at the convergence of Chinese medicine and Western science: first 130 cases. AB - OBJECTIVE: To present a model for autism showing that impairment of sensory and self-regulation is the core deficit that underlies delays in social/language skills and abnormal behavior in autism; and to demonstrate the efficacy of a treatment for autism based on Chinese medicine. METHODS: Children with autism under 6 years of age were assigned to treatment or wait-list conditions. A total of 130 children were treated and the results compared with 45 wait-list controls. Treatment is a tuina methodology directed at sensory impairment--Kai Qiao Tuina. The treatment was a five-month protocol that was implemented daily by trained parents via trained support staff. The effects of treatment on the main symptoms, autistic behavior, social/language delay, sensory and self-regulatory impairment, as well as on parenting stress, were observed and compared. RESULTS: The treatment had a large effect size (P<0.0001) on measures of sensory and self regulation. The evaluations done by pre-school teachers demonstrated improvement in the measures of autism (P<0.003), and were confirmed by evaluations done by parents (P<0.0001). There was a large decrease (P<0.0001) in parenting stress. CONCLUSIONS: Sensory and self-regulatory impairment is a main factor in the development and severity of autism. Treatment of young children with autism with Kai Qiao Tuina resulted in a decrease in sensory and self-regulatory impairment and a reduction in severity of measures of autism. PMID- 21660675 TI - Effect of Chinese herbal medicine for calming Gan (?) and suppressing hyperactive yang on arterial elasticity function and circadian rhythm of blood pressure in patients with essential hypertension. AB - OBJECTIVE: To observe the effect of Chinese herbal medicine for calming Gan (?) and suppressing hyperactive yang (????, CGSHY) on arterial elasticity function and the circadian rhythm of blood pressure in patients with essential hypertension (EH). METHODS: Adopting a parallel, randomized design, sixty-four patients with EH of stages I and II were randomly divided into two groups according to a random number table, with 32 in each group. The patients in the treatment group were treated with CGSHY and those in the control group were treated with Enalapril. All patients were given 24-h ambulatory blood pressure monitoring (ABPM) before and after a 12-week treatment. Trough/peak (T/P) ratios of systolic and diastolic blood pressure (SBP & DBP) of each group were calculated. The circadian rhythm of their blood pressure was observed at the same time. The changes in elasticity of the carotid artery in the patients, including stiffness parameter (beta), pressure-strain elastic modulus (Ep), arterial compliance (AC), augmentation index (AI), and pulse wave velocity (PVWbeta) were determined by the echo-tracking technique before and after a 12-week treatment. In the meantime, their levels of nitric oxide (NO) and endothelin-1 (ET-1) were measured respectively. RESULTS: After treatment, all parameters in the 24-h ABPM and the elasticity of the carotid artery (beta, Ep, AC and PVWbeta) were markedly improved, the level of NO was increased, and ET-1 was decreased in both groups as compared with values before treatment (P<0.05 or P<0.01). Further, the improvements in the ratio of T/P of SBP & DBP and in the level of NO and ET-1 in the treatment group were more significant than those in the control group (P<0.05). There were no significant differences in all parameters in the ABPM monitoring and the elasticity of the carotid artery, the recovery of blood pressure circadian rhythm, and the therapeutic effect of antihypertension in EH patients between the two groups (P>0.05). CONCLUSIONS: Chinese herbal medicine for CGSHY may lower the blood pressure smoothly and recover the circadian rhythm of blood pressure in EH patients. They may also improve the carotid elasticity of EH patients similar to that of Enalapril. The mechanism of action of Chinese herbs on EH might be related to the regulation of vascular endothelium function. PMID- 21660677 TI - Effect of early intervention with extract of Huannao Yicong Decoction (?????) on the pathologic picture of hippocampus and neurocyte apoptosis in APP transgenic mice model of dementia. AB - OBJECTIVE: To observe the effect of early intervention using extract of Huannao Yicong Decoction (, HYD) on the pathological picture of hippocampus, neurocyte apoptosis, and associated regulatory genes in beta-amyloid precursor protein (APP) transgenic mice model of dementia. METHODS: Sixty APP695(V7171) transgenic mice were randomly divided into four groups of 15. The model group was treated with distilled water, the positive control group was treated with donepezil (0.65 mg/kg), and the two HYD groups were treated with high dose (2.8 g/kg) and low dose (1.4 g/kg) HYD, respectively. All testing drugs were administered through gastrogavage by dissolving in equal volume of distilled water, once a day for six successive months. In addition, a normal control group with 15 healthy C57BL/6J mice of the same age and genetic background was set up with distilled water treatment. The pathologic picture of brain tissue was observed by microscopy with HE stain; the amount of apoptosis cells in the hippocampal CA1 area was detected by TUNEL; and expressions of associated genes, Bcl-2, and Bax were determined by immunohistochemical method. RESULTS: Pathologic pictures of hippocampus showed that in the model group, cells messily arranged, neurons markedly decreased, and the surrounding tissue of some cells was loosened with edema, necrosis, and widened gap with glia cells proliferation. Compared with those in the normal group, the amount of apoptosis cells in the CA1 area was increased, Bcl-2 expression decreased, and Bax expression increased significantly, with markedly reduced Bcl-2/Bax ratio in the model group. Compared to the model group, the pathological changes were significantly milder in the HYD-treated groups, showing rather regularly arranged cells, significantly increased neurons, only few denatured necrotic cells with milder edema, less proliferation of glia cells, and obviously reduced cell apoptosis in CA1 area (P<0.05 or P<0.01). Besides, Bcl-2 expression was up-regulated and Bax expression down-regulated, and Bcl-2/Bax ratio significantly increased in the two HYD groups (P<0.05 or P<0.01). CONCLUSION: Early intervention with HYD could improve the abnormal pathologic picture of hippocampus and regulate the expressions of associated genes to suppress cell apoptosis, which might be its mechanism of action in alleviating cognitive functional disorder. PMID- 21660678 TI - Experimental study on the suppression of sodium nitroprussiate-induced chondrocyte apoptosis by Tougu Xiaotong Capsule (??????)-containing serum. AB - OBJECTIVE: To study the mechanism of action of Tougu Xiaotong Capsule (??????, TGXTC) ex vivo in suppressing chondrocyte (CD) apoptosis induced by sodium nitroprussiate (SNP). METHODS: Thirty New Zealand rabbits, 2 months old, were randomized by lottery into five groups, six in each: the blank group treated with saline, the positive control group treated with Zhuanggu Guanjie Pill (?????, 70 mg/kg), and the three experimental groups, EGA, EGB, and EGC, treated with low dose (35 mg/kg), moderate dose (70 mg/kg), and high dose (140 mg/kg) of TGXTC, respectively. All treatments were administered via gastrogavage twice a day for 3 days. Arterial blood was collected from the abdominal aorta and drug or drug metabolites-containing serum was prepared. CDs obtained from knee joints of 16 four-week-old New Zealand rabbits were cultured to the third passage and confirmed by toluidine blue staining. SNP of various final concentrations (0, 0.5, 1.0, and 2.0 mmol/L) was used to induce CD apoptosis, and the dosage-effect relationship of SNP in inducing CD apoptosis was determined. Serum samples from the blank, control, and three dosages of TGXTC-treated rabbits were tested in the CD culture in the presence of SNP. Cell apoptosis was determined by Hoechst 33342 staining, viability of CDs was quantified by MTT, CD apoptosis rate was determined by annexin V-FITC/PI staining, levels of p53 and Bcl-2 mRNA expression in CDs were determined with RT-PCR, and contents of caspase-3 and caspase-9 proteins were determined by colorimetry. RESULTS: CD apoptosis was induced by SNP at all concentrations tested and in a dose-dependent manner. The SNP concentration of 1 mmol/L and treatment duration of 24 h appeared to be optimal and were selected for the study. Serum samples from the positive control rabbits and from the two higher doses of TGXTC-treated rabbits showed reduction of SNP induced CD apoptosis, decrease in p53 mRNA expression, inhibition of catalytic activities of caspase-3 and caspase-9, and increase in Bcl-2 mRNA expression when compared with the serum from the blank group (P<0.05). CONCLUSION: TGXTC containing sera antagonized SNP-induced CD apoptosis and the molecular basis for the action was associated with up-regulation of Bcl-2, down-regulation of p53 expression, and inhibition of caspase-3 and caspase-9 catalytic activities. PMID- 21660679 TI - In vivo and in vitro antiviral effects of berberine on influenza virus. AB - OBJECTIVE: To explore the potential effects of berberine on influenza virus infection both in vitro and in vivo. METHODS: In vitro anti-influenza virus assays were performed by cytopathogenic effect and neuraminidase assays in Madin Darby canine kidney cells. In vivo anti-influenza virus assays were performed on the viral pneumonia model of mice. The numbers of mice that died within day 2 to day 14 postinfection were recorded to calculate the mortality. On days 2, 4, and 6, the viral titers in the lungs were determined by hemagglutination assay; hematoxylin/eosin staining was used to assess the pathogenic changes of lung tissues; the concentrations of tumor necrosis factor-alpha (TNF-alpha) and monocyte specific chemoattractant molecule (MCP-1) were measured by radio immunoassay or enzyme-linked immunosorbent assay; the concentrations of nitric oxide (NO) and inducible nitric oxide synthetase (iNOS) were detected by colorimetric method; reverse transcription polymerase chain reaction was used to detect the mRNA level of TNF-alpha and MCP-1. RESULTS: Berberine showed inhibitory effects on cytopathogenic effects and neuraminidase activity of virus, with the therapeutic index 9.69. In vivo, berberine decreased mice mortality from 90% to 55%, reduced virus titers in the lungs on day 2 postinfection (P<0.05). The lung histology scores were 1.50 +/- 0.67, 4.50 +/- 1.00, and 5.50 +/- 1.00 in the berberine group on days 2, 4, and 6, respectively, which were significantly reduced compared to 2.17 +/- 0.22, 6.83 +/- 0.44, and 8.50 +/- 0.33 in the infected group (P<0.05). The productions of NO and iNOS were repressed by berberine compared with those in the infected group (P<0.01). The transcription and expression of TNF-alpha were inhibited by berberine on day 4 (P<0.01) and day 6 (P<0.05), and those of MCP-1 were inhibited on day 6 (P<0.01) compared with the infected group. CONCLUSIONS: Berberine exhibited antiviral effects on the influenza virus both in vitro and in vivo. The possible therapeutic mechanism of berberine on influenza-induced viral pneumonia might be inhibiting the virus infection, as well as improving the pathogenic changes by repressing inflammatory substances release. PMID- 21660680 TI - Anticancer activity of total flavonoids isolated from Xianhe Yanling Recipe (?????). AB - OBJECTIVE: To investigate the anticancer activity of the total flavonoids isolated from a herbal formula, Xianhe Yanling Recipe (?????), a recipe commonly used in cancer patients in China. METHODS: The in vitro anticancer activity of the total flavonoids was determined using the 3-(4,5-dimethylthiazole-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay on three cancer cell lines: MCF-7 (a human breast adenocarcinoma cell line), HepG-2 (a human hepatocellular carcinoma cell line) and ES-2 (a human ovarian cancer cell line). The in vivo anticancer effect of the total flavonoids was assessed in a mouse tumor model bearing H22 induced hepatocellular carcinoma, and cisplatin was used as a positive control. RESULTS: The total flavonoids exerted a powerful inhibitory effect on the three cell lines, with 50% inhibiting concentrations (IC(50)) of 24.948, 31.569 and 6.923 MUg/mL, respectively. In vivo studies showed that the total flavonoids had dose-dependent inhibitory effects on hepatocellular carcinoma in mice. CONCLUSION: The total flavonoids from Xianhe Yanling Recipe have potential anticancer activity, and further researches and development are warranted. PMID- 21660681 TI - Effect of acupoint Sanyinjiao (SP6) moxibustion on the first stage of labor and uterine contractive pain in primiparae. AB - OBJECTIVE: To observe the effect of acupoint Sanyinjiao (SP6) moxibustion (S-Mox) on the duration of the first labor stage and uterine contractive pain in primiparae. METHODS: Sixty primipara women in labor were equally assigned according to their choice to three groups: women in the S-Mox group received bilateral S-Mox for 30 min, women in the non-acupoint group received moxibustion (Mox) applied on non-acupoints for 30 min, and those in the control group did not receive Mox intervention. The duration of the first labor stage was recorded and the degree of labor pain was estimated by a visual analogue scale (VAS) before and after Mox. RESULTS: The duration of the first stage active phase in the S-Mox group was significantly shorter than that in the other two groups (P<0.05, P<0.01); the VAS score after Mox was lower in the S-Mox group, showing a statistical difference in comparison with the control group (P<0.05). CONCLUSIONS: Applying S-Mox could markedly shorten the active phase of the first stage of labor and lower the VAS score of uterine contractive pain, which means alleviating the pain caused by vaginal delivery. Its mechanism is worthy of further study. PMID- 21660682 TI - The earliest acupuncture and moxibustion manuscript was found in Dunhuang. PMID- 21660683 TI - Progress in the research of Radix Astragali in treating chronic heart failure: effective ingredients, dose-effect relationship and adverse reaction. AB - Radix Astragali, a Chinese herbal medicine possessing important cardiovascular pharmacologic effects, is widely applied for the treatment of chronic heart failure (CHF) in clinical practice. This paper summarizes briefly the researches in the last 10 years on its chemical compositions, effective ingredients for improving cardiac function, dose-effect relationship in treating CHF, and adverse reactions that occurred in clinical practice. PMID- 21660684 TI - Development and current status of National Cancer Center for Chinese medicine. PMID- 21660685 TI - Methods to study mitotic homologous recombination and genome stability. AB - Spontaneous mitotic recombination occurs in response to DNA damage incurred during DNA replication or from lesions that do not block replication but leave recombinogenic substrates such as single-stranded DNA gaps. Other types of damages result in general genome instability such as chromosome loss, chromosome fragmentation, and chromosome rearrangements. The genome is kept intact through recombination, repair, replication, checkpoints, and chromosome organization functions. Therefore when these pathways malfunction, genomic instabilities occur. Here we outline some general strategies to monitor a subset of the genomic instabilities: spontaneous mitotic recombination and chromosome loss, in both haploid and diploid cells. The assays, while not inclusive of all genome instability assays, give a broad assessment of general genome damage or inability to repair damage in various genetic backgrounds. PMID- 21660686 TI - Characterizing resection at random and unique chromosome double-strand breaks and telomere ends. AB - Resection of DNA double-strand break (DSB) ends, which results in 3(') single stranded tails, is an early event of DSB repair and can be a critical determinant in choice of repair pathways and eventual genome stability. Current techniques for examining resection are restricted to model in vivo systems with defined substrates (i.e., HO-endonuclease targets). We present here a robust assay that can analyze not only the resection of site-specific DSBs which typically have "clean" double-strand ends but also random "dirty-ended" DSBs such as those generated by ionizing radiation and chemotherapeutic agents. The assay is based on our finding that yeast chromosomes with single-stranded DNA tails caused by resection are less mobile during pulsed-field gel electrophoresis (PFGE) than those without a tail. In combination with the use of a circular chromosome and enzymatic trimming of single-stranded DNA, resection of random DSBs can be easily detected and analyzed. This mobility-shift assay provides a unique opportunity to examine the mechanisms of resection, early events in DSB repair, as well as factors involved in pathway regulation. PMID- 21660687 TI - Characterization of meiotic recombination initiation sites using pulsed-field gel electrophoresis. AB - High levels of homologous recombination are induced during meiosis. This meiotic recombination is initiated by programmed formation of DNA double-strand breaks (DSBs) by a conserved meiosis-specific protein, Spo11. Meiotic DSBs are not formed at random along chromosomes but are formed in clusters known as recombination hot spots. To understand the regulation of this initiation step of meiotic recombination, determining the timing and location of meiotic DSBs is essential. In this chapter, we describe a method to detect genome-wide meiotic DSBs by using a combination of pulsed-field gel electrophoresis and Southern blotting. PMID- 21660688 TI - Genome-wide detection of meiotic DNA double-strand break hotspots using single stranded DNA. AB - The controlled fragmentation of chromosomes by DNA double-strand breaks (DSBs) initiates meiotic recombination, which is essential for meiotic chromosome segregation in most eukaryotes. This chapter describes a straightforward microarray-based approach to measure the genome-wide distribution of meiotic DSBs by detecting the single-stranded DNA (ssDNA) that transiently accumulates at DSB sites during recombination. The protocol outlined here has been optimized to detect meiotic DSBs in Saccharomyces cerevisiae. However, because ssDNA is a universal intermediate of homologous recombination, this method can ostensibly be adapted to discover and analyze programmed or damage-induced DSB hotspots in other organisms whose genome sequence is available. PMID- 21660689 TI - Detection of covalent DNA-bound Spo11 and topoisomerase complexes. AB - Topoisomerases can release topological stress and resolve DNA catenanes by a DNA strand breakage and re-ligation mechanism. During the lifetime of the DNA break, the topoisomerase remains covalently linked to the DNA and removes itself when the break is re-ligated. While the lifetime of a covalent topoisomerase-DNA complex is usually short, several clinically important cancer drugs kill cancer cells by inhibiting the removal of covalently linked topoisomerases. The topoisomerase-like protein Spo11 is responsible for meiotic double strand break formation. Spo11 is not able to remove itself and is removed by nucleolytic cleavage. This chapter describes a method which allows the reproducible and quantitative detection of proteins covalently bound to the DNA. PMID- 21660690 TI - Molecular assays to investigate chromatin changes during DNA double-strand break repair in yeast. AB - Multiple types of DNA damage, including bulky adducts, DNA single-strand breaks, and DNA double-strand breaks (DSBs), have deleterious effects on the genomes of eukaryotes. DSBs form normally during a variety of biological processes, such as V-D-J recombination and yeast mating type switching, but unprogrammed DSBs are among the most dangerous types of lesion because if left unrepaired they can lead to loss of genetic material or chromosomal rearrangements. The presence of DSBs leads to a DNA damage response involving activation of cell cycle checkpoints, recruitment of repair proteins, and chromatin remodeling. Because many of the proteins that mediate these processes are evolutionarily conserved, the budding yeast, Saccharomyces cerevisiae, has been used as a model organism to investigate the factors involved in the response to DSBs. Recent research on DSB repair has focused on the barrier that chromatin represents to the repair process. In this article, we describe molecular techniques available to analyze chromatin architecture near a defined DSB in budding yeast. These techniques may be of value to experimentalists who are investigating the role of a novel protein in DSB repair specifically in the context of chromatin. PMID- 21660691 TI - Analysis of meiotic recombination intermediates by two-dimensional gel electrophoresis. AB - During meiosis, programmed double strand breaks give rise to crossover and non crossover recombination products. Meiotic recombination products are formed via several branched intermediates, including single end invasions and double Holliday junctions. Two-dimensional gel electrophoresis provides a sensitive and specific approach for detecting branched recombination intermediates, determining their genetic requirements, and enriching intermediates for further analysis. Here, we describe analysis of branched recombination intermediates in the yeast Saccharomyces cerevisiae by two-dimensional gel electrophoresis. We also provide an introduction to meiotic time-course procedures, stabilization of branched DNA molecules by interstrand crosslinking, extraction of genomic DNA from meiotic cultures, and quantitative analysis of two-dimensional gel blots. PMID- 21660692 TI - Mapping of crossover sites using DNA microarrays. AB - Crossovers (COs) play an essential role in promoting successful chromosome segregation during meiosis. Crossing over generates chiasmata, which are physical bridges between homologs that provide the appropriate tension to properly align chromosomes on the meiosis I spindle. Homolog pairs that fail to cross over can result in meiosis I nondisjunction, leading to aneuploid gametes. Therefore, the number and distribution of crossovers are tightly regulated to ensure that each chromosome pair receives at least one CO. Here, we describe a DNA microarray based method to map CO distribution genome-wide, on a cell-by-cell basis, allowing for rapid and accurate analysis of multiple aspects of CO control. PMID- 21660693 TI - Using the semi-synthetic epitope system to identify direct substrates of the meiosis-specific budding yeast kinase, Mek1. AB - Recent studies have shown that the meiosis-specific kinase, Mek1, plays a key role in promoting recombination between homologous chromosomes during meiosis in budding yeast by suppressing recombination between sister chromatids, as well as playing a role in the meiotic recombination checkpoint. Understanding how Mek1 regulates recombination requires the identification of direct substrates of the kinase. We have applied the semi-synthetic epitope method developed by Shokat and colleagues to Mek1. This method uses an analog-sensitive version of Mek1, GST Mek1-as, in conjunction with an ATPgammaS analog, for kinase assays that detect only those proteins that are directly phosphorylated by Mek1. This method may be applicable to any kinase for which an analog-sensitive version is available. In addition, it provides a non-radioactive alternative for kinase assays with wild type kinases. PMID- 21660694 TI - Genetic and molecular analysis of mitotic recombination in Saccharomyces cerevisiae. AB - Many systems have been developed for the study of mitotic homologous recombination (HR) in the yeast Saccharomyces cerevisiae at both genetic and molecular levels. Such systems are of great use for the analysis of different features of HR as well as of the effect of mutations, transcription, etc., on HR. Here we describe a selection of plasmid- and chromosome-borne DNA repeat assays, as well as plasmid-chromosome recombination systems, which are useful for the analysis of spontaneous and DSB-induced recombination. They can easily be used in diploid and, most importantly, in haploid yeast cells, which is a great advantage to analyze the effect of recessive mutations on HR. Such systems were designed for the analysis of a number of different HR features, which include the frequency and length of the gene conversion events, the frequency of reciprocal exchanges, the proportion of gene conversion versus reciprocal exchange, or the molecular analysis of sister chromatid exchange. PMID- 21660695 TI - In vivo site-specific mutagenesis and gene collage using the delitto perfetto system in yeast Saccharomyces cerevisiae. AB - Delitto perfetto is a site-specific in vivo mutagenesis system that has been developed to generate changes at will in the genome of the yeast Saccharomyces cerevisiae. Using this technique, it is possible to rapidly and efficiently engineer yeast strains without requiring several intermediate steps as it functions in only two steps, both of which rely on homologous recombination to drive the changes to the target DNA region. The first step involves the insertion of a cassette containing two markers at or near the locus to be altered. The second step involves complete removal of this cassette with oligonucleotides and/or other genetic material and transfer of the expected genetic modification(s) to the chosen DNA locus. Here we provide a detailed protocol of the delitto perfetto approach and present examples of the most common and useful applications for in vivo mutagenesis to generate base substitutions, deletions, insertions, as well as for precise in vivo assembly and integration of multiple genetic elements, or gene collage. PMID- 21660696 TI - Detection of RNA-templated double-strand break repair in yeast. AB - The discovery of RNA-templated DNA repair has revealed a novel case where genetic information can flow directly from RNA to genomic DNA without passing through a reverse transcript intermediate. As initially demonstrated in the yeast Saccharomyces cerevisiae via transformation by RNA-containing oligonucleotides (oligos), RNA sequences can serve as templates for chromosomal double-strand break (DSB) repair. Synthetic oligos containing embedded RNA tracts of various sizes, or even RNA-only molecules, although with lower efficiency, can guide DNA repair synthesis at sites of broken DNA. Mechanisms and circumstances in which cells can use RNA to repair DNA damage such as a DSB are yet to be identified. Here we show the approach we utilize to detect repair of a chromosomal DSB by RNA containing oligos in yeast cells. PMID- 21660697 TI - SNP-based mapping of crossover recombination in Caenorhabditis elegans. AB - Caenorhabditis elegans is an important experimental organism for the study of recombination during meiosis. Here, we provide methods for the use of single nucleotide polymorphisms (SNPs) for the study of crossing over in C. elegans. PMID- 21660698 TI - Characterization of meiotic crossovers in pollen from Arabidopsis thaliana. AB - Homologous recombination processes, which occur during the prophase of the first meiotic division, while generating new allelic combinations, are mechanistically important for the regular segregation of homologous chromosomes. They generate either crossovers, which are reciprocal exchanges between chromosome segments, or gene conversions. Both kinds of events occur in narrow regions (less than 10 kb) called hotspots, which are distributed along chromosomes. Classical genetic methods for CO characterization, which rely on the building of large populations and require appropriately located markers, are not well suited to the study of meiotic recombination hotspots. Here, we present a method based on allele specific PCR amplification of single molecules from pollen genomic DNA. It allows detection, quantification and characterization of CO events arising at low frequencies in recombination hotspots. PMID- 21660700 TI - Homologous recombination assay for interstrand cross-link repair. AB - DNA interstrand cross-links (ICLs) covalently link both strands of the DNA duplex, impeding cellular processes like DNA replication. Homologous recombination (HR) is considered to be a major pathway for the repair of ICLs in mammalian cells as mutants for HR components are highly sensitive to DNA-damaging agents that cause ICLs. This chapter describes GFP assays to measure HR following site-specific ICL formation with psoralen through DNA triplex technology. This approach can be used to determine the genetic requirements for ICL-induced HR in relation to those involved in HR repair of other DNA lesions such as double strand breaks. PMID- 21660699 TI - Isolation of meiotic recombinants from mouse sperm. AB - Homologous recombination during meiosis is critical for the formation of gametes. Recombination is initiated by programmed DNA double-strand breaks which preferentially occur at hotspots dispersed throughout the genome. These double strand breaks are repaired from the homolog, resulting in either a crossover or noncrossover product. Multiple noncrossover events are required for homolog pairing, and at least one crossover is critical for proper chromosome segregation at the first meiotic division. Consequently, homologous recombination in meiosis occurs at high frequencies. This chapter describes how to characterize crossovers and noncrossovers at a hotspot in mice using allele-specific PCR. Amplification of recombinant products directly from sperm DNA is a powerful approach to determine recombination frequencies and map recombination breakpoints, providing insight into homologous recombination mechanisms. PMID- 21660701 TI - Evaluation of homologous recombinational repair in chicken B lymphoma cell line, DT40. AB - Homologous recombination (HR) is a mode of double-strand break (DSB) repair required for cell viability in vertebrate cells. Targeted integration of homologous DNA fragment by HR is usually a very rare event in vertebrate cells; however, in chicken B lymphoma cell line DT40, the ratio of targeted to random integration is extremely high. Although the underlying mechanism of this phenotype is not fully understood, DT40 has been utilized as a model cell line for a number of genetic analyses. Here we describe three assays for evaluating homologous recombinational repair (HRR) using DT40 as a model system, measuring gene-targeting frequency, analyzing HRR process of single DSB induced by yeast homing endonuclease I-SceI, and measuring sister chromatid exchange frequency. Combined with generation of gene-disrupted DT40 mutant cell line, these assays have been highly useful to investigate the mechanisms in HRR. Using these techniques, a role of HRR of not only Rad52 epistasis group genes but also genes whose mutation cause hereditary cancer syndrome, such as Fanconi anemia, has been established. PMID- 21660702 TI - Understanding the immunoglobulin locus specificity of hypermutation. AB - The immunoglobulin (Ig) genes of B cells are diversified at high rate by point mutations whereas the non-Ig genes of B cells accumulate no or significantly fewer mutations. Ig hypermutations are critical for the affinity maturation of antibodies for most of jawed vertebrates and also contribute to the primary Ig diversity repertoire formation in some species. How the hypermutation activity is specifically targeted to the Ig loci is a long-standing debate. Here we describe a new experimental approach to investigate the locus specificity of Ig hypermutation using the chicken B-cell line DT40. One feature is the use of a green fluorescent protein (GFP) gene as a mutation reporter. Some nucleotide changes produced by somatic hypermutation can cripple the GFP gene which leads to a decrease or loss of the green fluorescence. Therefore such changes can be easily quantified by fluorescence-activated cell sorting (FACS). Another advantage of this approach is the targeted integration of the mutation reporter into a defined chromosomal position. This system allowed us to identify a 10 kb sequence within the Ig light chain (IgL) locus, which is both necessary and sufficient to activate hypermutation in the neighboring reporter gene. We have called this sequence Diversification Activator (DIVAC) and postulated that similar cis-acting sequences exist in the heavy and light chain Ig loci of all jawed vertebrate species. Our experimental system promises further insight into the molecular mechanism of Ig hypermutation. For example, it may be possible to identify smaller functional motifs within DIVAC and address the role of putative transacting binding factors by gene knock-outs. PMID- 21660703 TI - Quality control of purified proteins involved in homologous recombination. AB - Biochemical reconstitution using purified proteins and defined DNA substrates is a key approach to develop a mechanistic understanding of homologous recombination. The introduction of sophisticated purification tags has greatly simplified the difficult task of purifying individual proteins or protein complexes, generating a wealth of mechanistic information. Using purified proteins in reconstituted recombination assays necessitates strict quality control to eliminate the possibility that relevant protein or nucleic acid contaminations lead to misinterpretation of experimental data. Here we provide simple protocols that describe how to detect in purified protein preparations contaminating nucleic acids and relevant enzymatic activities that may interfere with in vitro recombination assays. These activities include ATPases, indicating the potential presence of helicases or translocases, endo- and exonucleases, phosphatases, and type I or type II topoisomerases. PMID- 21660704 TI - Assays for structure-selective DNA endonucleases. AB - Structure-selective nucleases perform DNA strand incisions crucial to the repair/resolution of branched DNA molecules arising during DNA replication, recombination, and repair. From a combination of genetics and in vitro nuclease assay studies, we are just beginning to understand how these enzymes recognize their substrates and to identify their in vivo DNA structure targets. By performing nuclease assays on a variety of substrates meant to mimic cellular intermediates, structural features of branched DNA molecules that are important for robust catalysis can be defined. However, since these enzymes often are capable of cleaving a range of DNA structures, caution must be taken not to overemphasize the significance of incision of a certain structure before a careful and detailed kinetic analysis of a variety of DNA substrates with different polarities and structural features has been completed. Here, we provide protocols for the production of a variety of oligo-based DNA joint molecules and their use in endonuclease assays, which can be used to derive the kinetic parameters KM and kcat. Determination of these values for a variety of substrates provides meaningful comparisons that allow inferences to be made regarding in vivo DNA structure target(s). PMID- 21660705 TI - In vitro assays for DNA pairing and recombination-associated DNA synthesis. AB - Homologous recombination (HR) is a high-fidelity DNA repair pathway that maintains genome integrity, by repairing double strand breaks (DSBs) and single stranded DNA (ssDNA) gaps and by supporting stalled/collapsed replication forks. The RecA/Rad51 family of proteins are the key enzymes in this homology-directed repair pathway, as they perform DNA strand invasion and exchange, in concert with a host of ancillary factors. In vitro, the RecA/Rad51 family of proteins share similar enzymatic activities including catalyzing ssDNA-stimulated ATP hydrolysis, formation of displacement loops (D-loops), and DNA strand exchange. After successful DNA strand invasion, DNA synthesis restores the lost genetic information using an undamaged DNA template. In this chapter, we describe two well-established biochemical assays to investigate the signature DNA strand transfer activity of RecA/Rad51 family of proteins: the D-loop assay and the DNA strand exchange reaction. Moreover, we describe a D-loop extension assay coupling D-loop formation with DNA synthesis, which can be used to define the roles of DNA polymerases in HR. Additionally, we present a protocol to investigate protein mediated DNA annealing, a critical step in the synthesis-dependent strand annealing (SDSA) and double-Holliday junction (dHJ) pathways as well as the single-strand annealing (SSA) pathway. The quality of supercoiled plasmid DNA is critical in reconstituted HR reactions, and a protocol describing the preparation of this DNA substrate is included. PMID- 21660706 TI - An in vitro assay for monitoring the formation and branch migration of holliday junctions mediated by a eukaryotic recombinase. AB - DNA strand exchange is a core reaction of homologous recombination directly catalyzed by Rad51/Dmc1 RecA family recombinases in eukaryotes. This reaction proceeds through the formation of several DNA intermediates. The X-shaped four way DNA structure known as a Holliday junction (HJ) is a central intermediate in homologous recombination. Genetic and biochemical studies indicate that the HJ is important for the production of crossover-type recombinants, which are reciprocal exchange products. According to a recombination model for the repair of DNA double-strand breaks, the formation of HJs requires a reciprocal duplex-duplex DNA exchange known as the DNA four-strand exchange reaction. In vitro analyses using purified recombination proteins and model DNA substrates provide a mechanistic insight into the DNA strand exchange reaction, including the steps leading to the formation and branch migration of Holliday junctions. PMID- 21660707 TI - Reconstituting the key steps of the DNA double-strand break repair in vitro. AB - Double-stranded DNA breaks (DSB), the most harmful type of DNA lesions, cause cell death and genome instability. Homologous recombination repairs DSB using homologous DNA sequences as templates. Here we describe a set of reactions that lead to reconstitution of the double-stranded DNA break repair process in vitro employing purified human homologous recombination proteins and DNA polymerase eta. Reconstitution of critical steps of DSB repair in vitro may help to better understand the mechanisms of recombinational DNA repair and the role of various human homologous recombination proteins in this process. PMID- 21660708 TI - Biochemical studies on human Rad51-mediated homologous recombination. AB - Rad51-mediated pairing between homologous DNA sequences during homologous recombination (HR) plays pivotal roles in DNA double-strand break repair. The multi-step process occurs through cooperation of Rad51 and a number of accessory protein factors. The development of various biochemical analyses with the requisite purified factors provides an opportunity to understand the molecular mechanisms of HR. In this chapter, we describe detailed procedures of in vitro assays using human Rad51, a polypeptide derived from the BRCA2 protein, and the Hop2-Mnd1 complex, to examine (1) homologous DNA pairing, (2) Rad51 targeting to single-stranded DNA, (3) stabilization of the Rad51 nucleoprotein filament, and (4) duplex capture by the Rad51 nucleoprotein filament. These methods are invaluable for delineating the functional interplay of HR factors. PMID- 21660709 TI - Studying DNA replication fork stability in Xenopus egg extract. AB - A crucial process to ensure cell survival and genome stability is the correct replication of the genome. DNA replication relies on complex machinery whose mechanisms are being elucidated using different model systems. A major aspect of this process, which is an intense subject of investigation, is what happens when replication forks encounter obstacles impairing their progression such as modified bases, pausing sites, and single strand breaks. The detailed biochemical analysis of DNA replication in the presence of DNA damage has been impeded by the lack of a cell-free system recapitulating DNA replication. Here we describe assays based on the vertebrate Xenopus laevis egg extract to study the biochemical aspects of replication fork stability. PMID- 21660710 TI - Supported lipid bilayers and DNA curtains for high-throughput single-molecule studies. AB - Single-molecule studies of protein-DNA interactions continue to yield new information on numerous DNA processing pathways. For example, optical microscopy based techniques permit the real-time observation of proteins that interact with DNA substrates, which in turn allows direct insight into reaction mechanisms. However, these experiments remain technically challenging and are limited by the paucity of stable chromophores and the difficulty of acquiring statistically significant observations. In this protocol, we describe a novel, high-throughput, nanofabricated experimental platform enabling real-time imaging of hundreds of individual protein-DNA complexes over hour timescales. PMID- 21660711 TI - FRET-based assays to monitor DNA binding and annealing by Rad52 recombination mediator protein. AB - During homologous recombination and homology-directed repair of broken chromosomes, proteins that mediate and oppose recombination form dynamic complexes on damaged DNA. Quantitative analysis of these nucleoprotein assemblies requires a robust signal, which reports on the association of a recombination mediator with its substrate and on the state of substrate DNA within the complex. Eukaryotic Rad52 protein mediates recombination, repair, and restart of collapsed replication forks by facilitating replacement of ssDNA binding protein replication protein A (RPA) with Rad51 recombinase and by mediating annealing of two complementary DNA strands protected by RPA. The characteristic binding mode whereby ssDNA is wrapped around the Rad52 ring allowed us to develop robust and sensitive FRET-based assays for monitoring Rad52 interactions with protein-free DNA and ssDNA-RPA complexes. By reporting on the configuration of ssDNA dually labeled with Cy3 and Cy5 fluorescent dyes, solution-based FRET is used to analyze Rad52-RPA-DNA interactions under equilibrium binding conditions. Finally, FRET between Cy3 and Cy5 dyes incorporated into two homologous ssDNA molecules can be used to analyze interplay between Rad52-mediated DNA strand annealing and duplex DNA destabilization by RPA. PMID- 21660712 TI - Visualization of human Dmc1 presynaptic filaments. AB - Meiosis is initiated by the programmed formation of DNA double-strand breaks (DSBs). These DSBs are repaired by homologous recombination to promote crossover formation that ensures proper chromosomal segregation in meiosis. hRad51 and hDmc1 are two human recombinases present during meiosis that are homologous to the RecA recombinase from Escherichia coli. The hRad51 and hDmc1 recombinases bind the nucleolytically processed ends of the DSB forming a presynaptic filament. Formation of the presynaptic filament is necessary for the search for homology and the progression of recombination. In this chapter, we provide a method to purify hDmc1 and prepare samples for visualizing hDmc1 nucleoprotein presynaptic filaments via transmission electron microscopy. PMID- 21660713 TI - Tracking of single and multiple genomic loci in living yeast cells. AB - Nuclear organization is involved in numerous aspects of cellular function. In yeast, analysis of the nuclear position and dynamics of the silent and active mating-type loci has allowed to gain insight into the mechanisms involved in directing mating-type switching. The fluorescent repressor operator systems (FROS) have proven to be a powerful technique to tag DNA sequences to investigate chromosome position and dynamics in living cells. FROS rely on the transgenic expression of a bacterial repressor fused to a fluorescent protein which can bind to its respective operator DNA sequence integrated as multicopy tandem arrays at a specific genomic site. Different FROS exist which facilitate the tagging of up to three different loci simultaneously. This chapter describes detailed protocols for FROS usage and analysis in the yeast Saccharomyces cerevisiae. PMID- 21660714 TI - Cell biology of homologous recombination in yeast. AB - Homologous recombination is an important pathway for error-free repair of DNA lesions, such as single- and double-strand breaks, and for rescue of collapsed replication forks. Here, we describe protocols for live cell imaging of single lesion recombination events in the yeast Saccharomyces cerevisiae using fluorescence microscopy. PMID- 21660715 TI - Live cell imaging of meiotic chromosome dynamics in yeast. AB - Recombination in first meiotic prophase is initiated by endogenous breaks in double-stranded DNA (DSBs) which occurs during a time when chromosomes are remodeled and proteinaceous cores (axes) are assembled along their length. DSBs are instrumental in homologue recognition and underlie the crossovers that form between parental chromosomes to ensure genome haploidization during the following two successive meiotic divisions. Advances in fluorescence microscopy and genetic engineering of GFP-tagged fusion proteins have made it possible to observe the behavior of entire chromosomes and specific subregions in live cells of the yeast Saccharomyces cerevisiae. In meiosis we observed that telomeres are dynamic and move about the entire nuclear periphery, only interrupted by their fleeting clustering at the spindle pole body (the centrosome equivalent), known as bouquet formation. This mobility translates to whole chromosomes and nuclei during the entire prophase I. Here we describe a simple setup for live cell microscopy that we used to observe chromosome movements during a time when DSBs are formed and transform into crossover and non-crossover products. PMID- 21660716 TI - Chromosome structure and homologous chromosome association during meiotic prophase in Caenorhabditis elegans. AB - Successful meiotic recombination is driven by a series of programmed chromosome dynamics that include changes in the protein composition of meiotic chromosomes and the juxtaposition of homologous chromosomes. The simultaneous visualization of both chromosome-bound proteins and the status of homologous association is an important experimental approach to analyze the mechanisms supporting proper meiotic chromosome association. One of a number of model organisms used for meiosis research, the nematode Caenorhabditis elegans offers an excellent environment to study meiotic chromosome dynamics. Here I will describe how to visualize both chromosome structure and specific chromosomal loci simultaneously, in a whole-mount C. elegans germ line. It combines immunofluorescent (IF) staining for a meiotic chromosome structural component with fluorescent in situ hybridization (FISH). PMID- 21660717 TI - How the atomic force microscope works? AB - This chapter aims at giving a quick but precise introduction of the atomic force microscope from the working principle point of view. It is intended to provide a useful starting point to those who first approach the instrument giving a general sketch of the working principles and technical implementations as well as last improvements. Subheading 1 is introductory: it gives an overview of what the instrument does and why it has been developed. Subheading 2 is focused on measurement ranges and on the comparison with scanning electron microscope (SEM) and transmission electron microscope (TEM) which have similar ranges and resolutions but different sample interactions and applications. Subheading 3 gives an overview of the working principles and the most diffused technical implementations on which most of the commercial microscopes rely, as we think it gives the useful base knowledge to understand possible applications, instrument capabilities, and results. In particular, technical improvements taking place over the past few years are highlighted. Despite of the simple and not very technical approach, it has a key importance in understanding concepts at the base of Chapter 3, which is, on the other side, useful for beginners and experienced users as well. Subheading 4 compares different instrument architectures and can, therefore, be useful for those who are going to choose an instrument having clear final applications. Latest solutions are once more highlighted. Subheading 5 gives an overview and some suggestions to start working, both in air and in liquid. Following the general philosophy of the book, it follows more an "how to do" concept than a general theoretical approach. Subheading 6 contains the future developments of the techniques. PMID- 21660719 TI - Recognizing and avoiding artifacts in atomic force microscopy imaging. AB - Atomic force microscopy (AFM) measurements could be affected by different kinds of artifacts; some of them derive from the improper use of the instrument and can be avoided by setting the correct experimental parameters and conditions. In other cases, distortions of the images acquired by AFM are intrinsically related to the operating principle of the instrument itself and to the kind of interactions taken into account for the reconstruction of the sample topography. A perfect knowledge of all the artifacts that can perturb AFM measurements is fundamental to avoid misleading interpretations of the results. In this chapter, all the most common sources of artifact are presented, and strategies to avoid them are proposed.Subheading 1 is a brief introduction to the chapter. In Subheading 2, the artifacts due to the interactions between the sample and the AFM tip are presented. Subheading 3 is focused on the deformations due to the AFM scanner nonlinear movements. The interaction with the environment surrounding the instrument can affect the quality of the AFM results and the environmental instability are discussed in Subheading 4. Subheading 5 shows the effects of an incorrect setting of the feedback gains or other parameters. Subheading 6 aims on the artifacts that can be produced by the improper use of the image processing software. Subheading 7 is a short guide on the test that can be done to easily recognize some of the artifacts previously described. PMID- 21660718 TI - Measurement methods in atomic force microscopy. AB - This chapter is introductory to the measurements: it explains different measurement techniques both for imaging and for force spectroscopy, on which most of the AFM experiments rely. It gives a general overview of the different techniques and of the output expected from the instrument; therefore it is, at a basic level, a good tool to properly start a new experiment. Concepts introduced in this chapter give the base for understanding the applications shown in the following chapters. Subheading 1 introduces the distinction between spectroscopy and imaging experiments and, within the last ones, between DC and AC mode. Subheading 2 is focused on DC mode (contact), explaining the topography and the lateral force channel. Subheading 3 introduces AC mode, both in noncontact and intermittent contact case. Phase imaging and force modulation are also discussed. Subheading 4 explains how the AFM can be used to measure local mechanical and adhesive properties of specimens by means of force spectroscopy technique. An overview on the state of the art and future trends in this field is also given. PMID- 21660720 TI - Imaging the spatial orientation of subunits within membrane receptors by atomic force microscopy. AB - Our experimental approach is based on the atomic force microscope (AFM) imaging of epitope-tagged subunits within membrane protein complexes purified in small amounts and decorated by anti-tag antibodies. Furthermore, we can produce simultaneous decoration of protein complexes using Fab fragments and IgG antibodies, which, combined with chemical modification of the substrate, allows us to determine the protein orientation across the cell membrane. Here, we describe a detailed protocol for membrane protein purification, AFM data collection, analysis, and interpretation of results. The protocol also covers basic AFM instrument settings and best practices for both observation of membrane protein complexes by AFM and automatic detection of the structures by an in-house algorithm. Once a sufficient number of membrane protein complexes have been visualized by AFM, data acquisition and processing can be completed in approximately 10 min using a scanning surface of 1 MUm(2). PMID- 21660722 TI - Atomic force microscopy of ex vivo amyloid fibrils. AB - Here, we report a study of ex vivo amyloid fibrils formed, respectively, by the Leu174Ser Apolipoprotein A-I (ApoA-I-LS) variant and by beta2-microglobulin (beta2-m) (Relini et al., J. Biol. Chem. 281:16521-16529, 2006; Relini et al., Biochim. Biophys. Acta 1690:33-41, 2004). In the work on ApoA-I-LS, the AFM has been used to characterize and compare the morphologies of amyloid fibrils isolated from two different patients, while in the study on beta2-m our investigation provided important information about the factors that can promote the aggregation in vivo. PMID- 21660721 TI - High resolution imaging of immunoglobulin G antibodies and other biomolecules using amplitude modulation atomic force microscopy in air. AB - The atomic force microscope (AFM) is a very versatile tool for studying biological samples at -nanometre-scale resolution. The resolution one achieves depends on many factors, including the sample properties, the imaging environment, the AFM tip and cantilever probe characteristics, and the signal detection and feedback control mechanism, to name a few. This chapter describes how to routinely achieve the highest possible spatial resolution on isolated protein molecules on mica surfaces. This is illustrated with Immunoglobulin G antibodies but the methods apply equally well to any other globular multi-subunit protein, as well as other biomolecules. Double-stranded DNA is used as a model sample to illustrate the effects of the force regime in amplitude modulation atomic force microscopy (AM AFM) on the image resolution and contrast. AM control is a widely used technique in biological AFM for reasons which are discussed. PMID- 21660724 TI - Atomic force microscopy imaging of human metaphase chromosomes in liquid. AB - Methods for atomic force microscopy (AFM) imaging of human metaphase chromosomes were -introduced in the present study. Chromosomes from the lymphocytes were fixed and prepared onto glass slides as the chromosome spread, and observed in phosphate-buffered saline by dynamic mode AFM. On the contrary, chromosomes from the human cell line BALL-1 were isolated using the hexylene glycol method, absorbed onto a silane-coated glass slide, and observed in a hexylene glycol buffer solution by dynamic mode AFM. AFM provides three-dimensional topographic images of both fixed and unfixed human chromosomes with height information. The ultrastructural image of a pair of chromatids was also obtained by AFM in a liquid condition. The combined use of the AFM and light microscopy of cytochemically and/or immunocytochemically stained chromosomes is also expected to be useful for studies on the localization of chemical components in relation to the higher-order structure of the chromosomes. PMID- 21660723 TI - Studying collagen self-assembly by time-lapse high-resolution atomic force microscopy. AB - Fibrillar collagens constitute a main component of many tissues, where they form a scaffold for cell attachment and provide mechanical strength. Gaining insight into molecular mechanisms of collagen self-assembly from in vitro experiments is important for better understanding the complex hierarchical processes involved in collagen fibril formation in vivo. In addition, such insight can be used to assemble collagen into desirable structures for the biofunctionalization of surfaces in different biotechnological and medical applications. Here, we describe a method to direct the assembly of type I collagen into well-defined nanoscopic matrices of different patterns. Within these matrices, the self assembly of collagen molecules into fibrils can be directly observed by time lapse atomic force microscopy (AFM). High-resolution AFM topographs reveal substructural details of the collagen fibril architecture and provide information about mechanisms and dynamics of fibril formation. PMID- 21660725 TI - Atomic force microscopy of proteasome assemblies. AB - The proteasome is the essential prime protease in all eukaryotes. The large, multisubunit, modular, and multifunctional enzyme is responsible for the majority of regulated intracellular protein degradation. It constitutes a part of the multienzyme ubiquitin-proteasome pathway, which is broadly implicated in recognition, tagging, and cleavage of proteins. The name "proteasome" refers to several types of protein assemblies sharing a common catalytic core particle. Additional protein modules attach to the core, regulate its activities, and broaden its functional capabilities. The structure of proteasomes has been studied extensively with multiple methods. The crystal structure of the core particle was solved for several species. However, only a single structure of the core particle decorated with PA26 activator has been determined. NMR spectroscopy was successfully applied to probe a much -simpler, archaebacterial type of the core particle. In turn, electron microscopy was very effective in exploring the spatial arrangement of many classes of assemblies. Still, the makeup of higher order -complexes is not well established. Besides, the crystal structure provided very limited information on proteasome molecular dynamics. Atomic force microscopy (AFM) is an ideal technique to address questions that are unanswered by other approaches. For example, AFM is perfectly suited to study allosteric regulation of proteasome, the role of protein dynamics in enzymatic catalysis, and the spatial organization of modules and subunits in assemblies. Here, we present a method that probes the conformational diversity and dynamics of yeast core particle using the oscillating mode AFM in liquid. We are taking advantage of the observation that the tube-shaped core particle is equipped with a swinging gate leading to the catalytic chamber. We demonstrate how to identify distinct gate conformations in AFM images and how to characterize the gate dynamics controlled with ligands and disturbed by mutations. PMID- 21660726 TI - Atomic force microscopy of isolated mitochondria. AB - This chapter describes methods for isolating and imaging metabolically and toxicologically challenged mitochondria with atomic force microscopy. Mitochondria were isolated from rat dorsal root ganglia or brain and exposed to glucose or dinitrobenzene (DNB) to simulate the cellular environment of a diabetic animal that has been exposed to excess glucose or to DNB. It is one of only a few articles to present images of membrane structures, such as voltage dependent, anion-selective channel pores, on intact organelles. The purpose of the chapter is not to report on the metabolic or toxic effects, but to communicate in more detail than a typical journal paper allows the methods used to image isolated organelles. We also provide a series images revealing the outer membrane and outer membrane pores. An image of an isolated nucleus as well as a set of notes written to avoid common pitfalls in isolation, labeling, and imaging is also included. PMID- 21660727 TI - Imaging and interrogating native membrane proteins using the atomic force microscope. AB - Membrane proteins exist in a lipid bilayer and provide for cell-cell communication, transport solutes, and convert energies. Detergents are used to extract membrane proteins and keep them in solution for purification and subsequent analyses. The atomic force microscope (AFM) is a powerful tool for imaging and manipulating membrane proteins in their native state without the necessity to solubilize them. It allows membranes that are adsorbed to flat solid supports to be raster-scanned in physiological solutions with an atomically sharp tip. Therefore, AFM is capable of observing biological molecular machines at work. Superb images of native membranes have been recorded, and a quantitative interpretation of the data acquired using the AFM tip has become possible. In addition, multifunctional probes to simultaneously acquire information on the topography and electrical properties of membrane proteins have been produced. This progress is discussed here and fosters expectations for future developments and applications of AFM and single-molecule force spectroscopy. PMID- 21660728 TI - Atomic force microscopy investigation of viruses. AB - Atomic force microscopy (AFM) has proven to be a valuable approach to delineate the architectures and detailed structural features of a wide variety of viruses. These have ranged from small plant satellite viruses of only 17 nm to the giant mimivirus of 750 nm diameter, and they have included diverse morphologies such as those represented by HIV, icosahedral particles, vaccinia, and bacteriophages. Because it is a surface technique, it provides images and information that are distinct from those obtained by electron microscopy, and in some cases, at even higher resolution. By enzymatic and chemical dissection of virions, internal structures can be revealed, as well as DNA and RNA. The method is relatively rapid and can be carried out on both fixed and unfixed samples in either air or fluids, including culture media. It is nondestructive and even non-perturbing. It can be applied to individual isolated virus, as well as to infected cells. AFM is still in its early development and holds great promise for further investigation of biological systems at the nanometer scale. PMID- 21660729 TI - Determination of the kinetic on- and off-rate of single virus-cell interactions. AB - Human rhinoviruses are the causative agents of the common cold. The serotypes belonging to the minor receptor group attach to members of the low-density lipoprotein receptor family and enter the host cell via receptor-mediated endocytosis. Receptor binding, the very first step in infection, was characterized by force spectroscopy measurements at the single molecule level. We demonstrate how kinetic on- and off-rate constants can be derived from such experiments carried out with the atomic force microscope. PMID- 21660730 TI - Atomic force microscopy as a tool for the study of the ultrastructure of trypanosomatid parasites. AB - Here, we describe the methodology currently used to analyze the structural organization of protozoa of the Trypanosomatidae family by atomic force microscopy. The results are compared with those obtained using light, scanning, and transmission electron microscopy. PMID- 21660731 TI - Normal and pathological erythrocytes studied by atomic force microscopy. AB - Erythrocytes (red blood cells, RBCs) are the most common type of blood cells in vertebrates. Many diseases and dysfunctions directly affect their structure and function. Employing the atomic force microscope (AFM) physical, chemical, and biological/physiological properties of RBCs can be studied even under near physiological conditions. In this chapter, we present the application of different AFM techniques to investigate and compare normal and pathological RBCs. We give a detailed description for nondestructive immobilization of whole intact RBCs and explain preparation techniques for isolated native RBC membranes. High resolution imaging of morphological details and pathological differences are demonstrated with healthy and systemic lupus erythematosus (SLE) erythrocytes revealing substructural changes due to SLE. We also present the technique of simultaneous topography and recognition imaging, which was used to map the distribution of cystic fibrosis transmembrane conductance regulator sites on erythrocyte membranes in healthy and cystic fibrosis-positive RBCs. PMID- 21660732 TI - The growth cones of living neurons probed by the atomic force microscope. AB - A detailed report of experimental findings concerning the use of atomic force microscopy to probe growth cones of chick embryo spinal cord neurons under vital conditions is given.The role played by indentation in the making of images and force-versus-distance curves is critically discussed. As a result, the thickness of growth cone regions is quantitatively estimated. By comparing the obtained images with descriptions given in the literature on the basis of other microscopy techniques, a central (C) region and a peripheral (P) region are identified, characterized by a different thickness and a different structural organization. Moreover, clusters of adhesion molecules are tentatively identified in regions where neuron arborizations were challenged by the atomic force microscope (AFM) tip. PMID- 21660733 TI - Highlights on ultrastructural pathology of human sperm. AB - Applications of atomic force microscopy to ultrastructural investigation of human spermatozoa are -discussed, with particular emphasis to their most common pathological alterations, which are recognized to be associated with male infertility. Morphological alterations can be located in the head, neck piece, and/or in the flagellum. The consequences of these defects on infertility-related topics are examined in the light of aberrations caused in varicocele and in other spermatozoa morphological alterations like globozoospermia, oligoasthenospermia, and in semen from patients with HIV syndrome. Special attention is given to the temperature effects on sperm abnormalities. The application of the present approach to pharmacology, namely, the development of male contraceptive methods, is also referred. PMID- 21660734 TI - High-speed atomic force microscopy and biomolecular processes. AB - Atomic force microscope (AFM) is unique in its capability to capture high resolution images of biological samples in liquids. This capability will become more versatile to biological sciences if AFM additionally acquires an ability of high-speed imaging, because "direct and real-time visualization" is a straightforward and powerful means to understand biomolecular processes. However, the imaging speed of conventional AFM is too slow to capture moving protein molecules at high resolution. In order to fill this large gap, various efforts have been carried out in the past decade. In this chapter, the past efforts for increasing the scan rate and reduction of tip-sample interaction force of AFM and demonstration of direct visualization of biomolecular processes are described. PMID- 21660735 TI - Atomic force microscopy in mechanobiology: measuring microelastic heterogeneity of living cells. AB - Recent findings clearly demonstrate that cells feel mechanical forces, and respond by altering their -phenotype and modulating their mechanical environment. Atomic force microscope (AFM) indentation can be used to mechanically stimulate cells and quantitatively characterize their elastic properties, providing critical information for understanding their mechanobiological behavior. This review focuses on the experimental and computational aspects of AFM indentation in relation to cell biomechanics and pathophysiology. Key aspects of the indentation protocol (including preparation of substrates, selection of indentation parameters, methods for contact point detection, and further post processing of data) are covered. Historical perspectives on AFM as a mechanical testing tool as well as studies of cell mechanics and physiology are also highlighted. PMID- 21660736 TI - Force-clamp measurements of receptor-ligand interactions. AB - Protein-protein interactions are the basis of both biochemical and biophysical signaling of living cells. In many cases, the receptor is present on the cell surface while the ligand is in solution or linked to another support (extracellular matrix or another cell). In the case of cellular adhesion, forces are continuously applied to receptor-ligand complexes and, as a consequence, the dissociation kinetics of the bonds may change. It is, thus, relevant to study the kinetics of protein-protein interactions in response to applied forces, as this is the most physiologically relevant situation. The atomic force microscope (AFM) was one of the first nanotools to be applied to this end. However, new approaches need to be developed to better understand the complex energy landscape of molecular interactions under applied stress. In this chapter, we described the use of the AFM to carry out force-clamp measurements on receptor-ligand bonds. Force-clamp measurements on bonds consist of applying a constant and controlled force to a receptor-ligand bond and measure the resulting dissociation lifetime. The described methods include the required materials, functionalization of tips and substrates, force-clamping measurements, and processing and interpretation of the results. An illustrative example is given with the well-studied streptavidin biotin complex. PMID- 21660737 TI - Measuring cell adhesion forces: theory and principles. AB - Cell adhesion is an essential prerequisite for survival, communication, and navigation of cells in organisms. It is maintained by the organized binding of molecules from the cell membrane to the extracellular space. This chapter focuses on direct measurements of cellular binding strength at the level of single adhesion molecules. Using atomic force microscopy-based force measurements, adhesion strength can be monitored as a function of adhesion time and environmental conditions. In this way, cellular adhesion strategies like changes in affinity and avidity of adhesion molecules (e.g., integrins) are characterized as well as the molecular arrangement of adhesion molecules in the cell membrane (e.g., molecular clusters, focal adhesion spots, and linkage to the cytoskeleton or tether). Some prominent values for the data evaluation are presented as well as constraints and preparative techniques for successful cell adhesion force experiments. PMID- 21660738 TI - Nanoscale investigation on E. coli adhesion to modified silicone surfaces. AB - Bacterial infection is a major challenge in biomaterials development. The adhesion of microorganisms to the material surface is the first step in infectious conditions and this quickly leads to the formation of biofilms on a material surface. A unique attribute of atomic force microscopy (AFM) is that it reveals not only the morphology of cells and the surface roughness of the substrate, but it can also quantify the adhesion force between bacteria and surfaces. We have shown that fluoroalkylsilane (FAS) and octadecyltrichlorosilane (OTS)-coated silicone samples exhibit greater potential for reducing E. coli JM 109 adhesion than heparin- and hyaluronan-modified samples. The force curves obtained from AFM can be used as a primary indicator in predicting bacterial adhesion. PMID- 21660739 TI - Imaging bacterial shape, surface, and appendages before and after treatment with antibiotics. AB - Antibiotics are particular type of drugs that are able to interfere in different ways to the metabolic -pathways of bacteria. This causes also morphostructural alterations of cell wall and surface appendages (flagella, fimbriae or pili, and filaments).Atomic force microscopy (AFM) is extremely useful for analyzing the three-dimensional structure of the surface of biological specimens, particularly bacteria. A step-by-step AFM methodology to be applied to different type of bacteria is reported and visual examples of the action of antibiotics are shown. Although scanning electron microscopy is still frequently used, the introduction of the AFM technique offers substantial benefits in real quantitative data acquisition in three dimensions, minimal sample preparation times, flexibility in ambient operating conditions (i.e., no vacuum is necessary), and effective three dimensional magnification at submicron level. PMID- 21660740 TI - Thymol-induced alterations in Candida albicans imaged by atomic force microscopy. AB - Thymol, a constituent of thyme essential oil that has been credited with interesting antimicrobial and antifungal effects, acts by interfering with the envelope of Candida albicans and this activity has been investigated by means of atomic force microscopy (AFM). Candida culture samples incubated with 1, 1/2, and 1/4 MIC of thymol or vehicle were taken at time 0 and after 1, 2, and 4 h, the envelopes of 100 cells in each of five randomly chosen fields were analysed by means of AFM. Our AFM findings show that thymol affects the envelope of C. albicans cells. The cells showed major morphostructural deformities with envelope damage becoming greater at increasing thymol concentrations and longer times of incubation, including the number of flattened cells with surface folds, cells with holes, and collapsed cells and ghosts. Thymol is an amphipathic monoterpene, which suggests that it affects cell membrane structure by generating asymmetries and membrane tensions. This is confirmed by the fact that terpenes alter cell permeability by entering between the fatty acyl chains making up the membrane lipid bilayers, disrupting lipid packing, and changing membrane fluidity. All of these phenomena lead to major surface alterations and deformities that also reduce the ability of fungi to adhere to mucosal cells, and decrease their virulence and infectiousness. PMID- 21660741 TI - Atomic force microscope-enabled studies of integrin-extracellular matrix interactions in vascular smooth muscle and endothelial cells. AB - The interactions between cell surface integrins and extracellular matrix (ECM) play important roles in the function of vascular smooth muscle and endothelial cells. Atomic force microscopy (AFM) has emerged as a powerful tool to mechanically engage cell surface integrins through functionalized probes, and to apply mechanical forces directly to cells or to specific protein-protein receptor ligand interactions, such as integrin-ECM interactions. In the example of integrins, this approach allows more accurate evaluation of the regulation of integrin adhesive activities, and provides a unique approach to access and investigate integrin-mediated cellular mechanical responses. In addition, the AFM is also useful for the measurement of the cell topographic features and cell and cytoskeletal mechanical properties, such as stiffness/elasticity. PMID- 21660743 TI - Combined atomic force microscopy and fluorescence microscopy. AB - The atomic force microscope (AFM) is a high-resolution scanning-probe instrument which has become an important tool for cellular and molecular biophysics in recent years, but lacks the time resolution and functional specificities offered by fluorescence microscopic techniques. The advantages of both methods may be exploited by combining and synchronizing them. In this paper, the biological applications of AFM, fluorescence, and their combinations are briefly reviewed, and the assembly and utilization of a spatially and temporally synchronized AFM and total internal reflection fluorescence microscope are described. The application of the method is demonstrated on a fluorescently labeled cell culture. PMID- 21660742 TI - Atomic force microscopy studies on circular DNA structural changes by vincristine and aspirin. AB - In this chapter, we have presented materials and methods to study the interaction between DNA and small molecule drugs by AFM. The detailed AFM imaging of the circular DNA after incubation with -various concentrations of vincristine and aspirin have been demonstrated. The immobilization of DNA fragments on mica surface as well as the force between tip and sample plays an important role for successful imaging of DNA-drug complexes. How to quantitatively describe the conformations and structures of circular DNA molecules and their changes is also introduced. Our work indicates that the AFM is a powerful tool in studying the interaction between DNA and small molecules. PMID- 21660744 TI - Chemical modifications of atomic force microscopy tips. AB - Atomic force microscopy (AFM) works by scanning a very tiny tip over a surface with great precision. The microscope tips can be chemically functionalized to improve the images obtained. Well-defined chemical functionalization of AFM tips is especially important for experiments, such as chemical force microscopy and single molecule recognition force microscopy, to examine specific interactions at the single molecular level. In this chapter, we present an overview of chemical modifications of tips that have been reported to date with regards to the proper fixation of probe molecules, focusing particularly on chemical procedures developed to anchor biological molecules on AFM tips. PMID- 21660745 TI - Atomic force microscopy as nanorobot. AB - Atomic force microscopy (AFM) is a powerful and widely used imaging technique that can visualize single molecules under physiological condition at the nanometer scale. In this chapter, an AFM-based nanorobot for biological studies is introduced. Using the AFM tip as an end effector, the AFM can be modified into a nanorobot that can manipulate biological objects at the single-molecule level. By functionalizing the AFM tip with specific antibodies, the nanorobot is able to identify specific types of receptors on the cell membrane. It is similar to the fluorescent optical microscopy but with higher resolution. By locally updating the AFM image based on interaction force information and objects' model during nanomanipulation, real-time visual feedback is obtained through the augmented reality interface. The development of the AFM-based nanorobotic system enables us to conduct in situ imaging, sensing, and manipulation simultaneously at the nanometer scale (e.g., protein and DNA levels). The AFM-based nanorobotic system offers several advantages and capabilities for studying structure-function relationships of biological specimens. As a result, many biomedical applications can be achieved by the AFM-based nanorobotic system. PMID- 21660746 TI - Preventing HIV in women: a top priority in China's efforts in fighting AIDS. PMID- 21660747 TI - Review of HIV and other sexually transmitted infections among female sex workers in China. AB - Female sex workers (FSW) are at greater risk for HIV and STIs. A systematic literature review of HIV and STI prevalence and incidence data for FSW in China was conducted to assess current trends. Studies between 1996 and 2010 detailing seroprevalence or incidence data, other laboratory-based tests, and clinical diagnoses of infections among FSW were reviewed. Select articles from Chinese literature around street-based and drug-abusing FSW were also reviewed. Results revealed high median prevalence for a variety of STIs among FSW: active syphilis range 0.8-12.5% (median = 6.9%), herpes range 29.7-70.8% (median = 56.2%), chlamydia range 3.9-58.6% (median = 25.7%), gonorrhea range 2.0-85.4% (median = 16.4%), and trichomoniasis range 7.1-43.2% (median = 12.5%). HIV prevalence has remained relatively low and stable with a range of 0-10.3% (median = 0.6%), with the exception of higher prevalence in several areas of Yunnan and some areas of Guangxi. The FSW who are injecting drug users may be at even greater risk for HIV infection with 12-49% found to be HIV positive and 7-25% self-reporting positive status. A number of gaps in the literature remain, especially in the number of studies that detail prevalence confirmed by laboratory testing or that collect incidence data. Assessment of incidence and prevalence according to sampling methodology appropriate for the population, behavioral risks such as injecting drug use, and diverse venues especially those at the lower end are needed. Theory based interventions to reduce the incidence and prevalence of HIV/STIs need to be piloted with successful models scaled-up. PMID- 21660748 TI - Commercial sex venues, syphilis and methamphetamine use among female sex workers. AB - The objective of this study was to assess the factors associated with methamphetamine (MA) use, syphilis, and unprotected sex among female sex workers from different type of venues in Qingdao City, Shandong Province of China. Three consecutive cross-sectional surveys provided information on demographics, sexual and drug use behaviors, and HIV-related services. Of 1187 participants, 3.0% were infected with syphilis; 30.2% ever used MA; 58.3% ever had unprotected commercial sex in the past month. The prevalence rates of syphilis and MA use were 2.5% and 33.0% for participants recruited from saunas, night clubs, bars or hotels; 2.7% and 28.3% for hair/beauty salon-based participants; and 4.5% and 15.8% for street based participants. Street-based MA users were more likely to be single, non Shandong residents, have first lifetime sex act at younger age, and recruited in 2008 (vs. 2006). Saunas, night clubs, bars, or hotels-based MA users were more likely to be younger, sex debut at younger age, have longer duration of sex work, have unprotected commercial sex, and be syphilis-infected. Hair/beauty salon based MA users were more likely to be non-Shandong residents, younger, and to have unprotected commercial sex. Syphilis among the sauna-, night club-, bar-, or hotel-based participants was associated with MA use and ever receipt of HIV testing. Syphilis among the hair/beauty salon-based participants was associated with longer duration of sex work. MA users who frequent commercial sex venues are engaging in high-risk behaviors and are at risk for syphilis/other sexually transmitted diseases. Better-targeted intervention efforts to curtail the epidemics of MA use and HIV/syphilis should therefore take cognizance of the role of commercial sex venues as focal points of MA use and syphilis/sexually transmitted disease transmission. PMID- 21660749 TI - Herpes simplex virus type 2 infection among female sex workers in Shanghai, China. AB - A study with two cross-sectional surveys in two consecutive years was conducted in Shanghai, China to examine the seroprevalence of herpes simplex virus type 2 (HSV-2), syphilis and HIV among female sex workers (FSW). A total of 793 FSW participated in the survey, 382 in 2008 only, 382 in 2009 only, and 29 in both 2008 and 2009. The majority of them were less than 30 years and two-thirds were married. All were migrants and a half was from rural areas. Some of them have stayed in Shanghai and engaged in commercial sex for more than two years. Their knowledge of HIV/AIDS was limited. Condom use was not common for both marital sex and non-commercial extramarital sex but fairly frequent for commercial sex. Two percent were using drugs in the past year. Nearly one quarter reported having syndromes of sexually transmitted diseases (STD) in the past year, with a substantial proportion of them untreated or treated inappropriately. No one was HIV-infected. The overall HSV-2 seroprevalence was 47.3% (375/793), 45.5% (187/411) in 2008 and 50.1% (206/411) in 2009. The overall prevalence of syphilis was 4.5% (36/793), 7.0% (29/411) in 2008 and 2.4% (10/411) in 2009. Multiple logistic regression analyses indicated that HSV-2 infection was statistically associated with age, type of working venue, origin, and period of staying in Shanghai; whereas syphilis infection was statistically associated with year of participation and smoking status. In conclusion, HSV-2 is highly prevalent among FSW in Shanghai, with a relatively low prevalence of syphilis. The currently low HIV epidemic in this population provides a window of opportunity to implement tailored HIV/STD prevention and control efforts targeting them, with particular attentions to large numbers of HSV-2-infected FSW and their clients. PMID- 21660750 TI - "Bridge population": sex workers or their clients?--STI prevalence and risk behaviors of clients of female sex workers in China. AB - As the HIV/AIDS epidemic and the spread of sexually transmitted infections (STIs) in China has come to the forefront of public health attention, female sex workers (FSWs) and their clients (CFSWs) are becoming increasingly important to HIV/STI prevention efforts. This secondary analysis uses data abstracted from the Chinese Health and Family Life Survey 1999-2000 to report prevalence rates of two STIs as well as sexual risk behaviors for CFSWs - men who paid for sex with FSWs in the past 12 months - in comparison with men who had not patronized FSWs. Among 1879 Chinese CFSWs who completed anonymous interviews and urine testing, 152 (6.3%, weighted) said they had paid for sex in the past 12 months and 18.8% of CFSWs (weighted) tested positive for gonorrhea. CFSWs were 10 times more likely to have an STI (either self-reported or tested) than non-client Chinese men, and they were equally likely to use condoms inconsistently with their spouses. This study highlights the importance of studying CFSWs who use condoms inconsistently and do not practice safe sex with their spouse as a potential bridge population. Prevention and intervention efforts should target this bridge population and include education on HIV/AIDS and STI transmission, condom promotion, marriage counseling, destigmatization of HIV and STIs, and promotion of STI diagnosis and treatment. PMID- 21660751 TI - HIV/STI prevention interventions targeting FSWs in China: a systematic literature review. AB - A rapid increase in heterosexual transmission of HIV and a high prevalence of sexually transmitted infections (STIs) in China signals potential outbreaks of generalized epidemics. A large proportion of heterosexual transmission has been through commercial sex; thus, millions of female sex workers (FSWs) and their clients play a critical role in the country's HIV/STI epidemics. A number of prevention interventions targeting FSWs have been implemented in response to changes in policy toward HIV as well as growing epidemics. This study reviews existing HIV/STI prevention interventions studies targeting FSWs in China. A total of 25 studies (28 articles) were identified from English and Chinese journal databases. Most studies recruited FSWs from entertainment establishments and had small sample sizes of less than 400. A majority employed a simple pre post design with an open cohort, none applied a randomized controlled trial, and only two studies had a quasi-experimental design. Venue-based knowledge education and condom promotion represented the typical intervention approach. Some adapted internationally validated programs such as Voluntary Counseling and Testing and 100% Condom Use Programs (CUP), but no scale-up data were reported. Significant intervention effects were reported in most studies, especially increases in HIV/STI-related knowledge and condom use rates. Of the nine studies reporting STI rates, the results were mixed; some even reported increased STIs despite higher condom use. We call for more HIV/STI interventions targeting FSWs in China, particularly, interventions with rigorous design and externally validated measures, and more diversity in intervention programs including biomedical and structural interventions as well as innovative intervention delivery. We also advocate that effective intervention programs be translated into sustainable policies and programs that could have an impact on China's HIV and STI epidemics. PMID- 21660752 TI - Female condom use in the rural sex industry in China: analysis of users and non users at post-intervention surveys. AB - Changes in sexual attitudes and behaviors and resurgence of the sex industry in China have increased concerns about HIV/AIDS and sexually transmitted infections (STI) epidemics. Little attention has been paid to the significant and growing sex industry in rural China. Promotion of barrier protection in this context is most effective to prevent STIs and pregnancy. The female condom (FC) is a barrier method that gives women more autonomy in its application, and has other advantages, but has been little promoted and tested in high risk contexts in China. The China/US Women's Health Project was designed to promote FC use in addition to male condoms (MC) through outreach intervention conducted in sex work establishments in rural and small urban towns in southern China, using the original prototype FC1. The study used quantitative and qualitative methods to document the pre-intervention context, intervention delivery process, and post intervention outcomes of FC use. In this paper we compare post-intervention FC users and non-users in the first study sites, two rural towns in a single county in Hainan Province. Examination of cross-sectional six-month and 12-month surveys indicated that, despite relatively high MC use, about one-third of the women in sex work establishments in these rural towns had adopted FC at each post intervention survey. Compared with non-users, FC users were more likely to be freelance women in boarding houses, more sexually experienced, married with children, more sexually active in the prior month, and more exposed to the intervention. The rural context hampered intervention implementation, particularly the significant limits in health and human resources available to manage prevention of HIV/STIs among women in the sex industry. These challenges highlight the need to better understand the context of the rural sex industry and capacity of local resources for better prevention efforts and the benefits that new prevention technologies like FC can offer. PMID- 21660753 TI - Prevalence and correlates of HIV unsafe sex and STIs among women working in China's entertainment industry. AB - Female entertainment workers in China are at risk of sexually acquiring HIV, but risk factors of their unsafe sex remain understudied. Using information from a venue-based sample of 724 female entertainment workers in Shanghai, this paper examines the prevalence and risk factors of unsafe sex and STIs. While both measures of unsafe sex and history of common STIs suggest that participants in this study appear to have lower rates of unsafe sex and STIs than reported in the literature, venue-based female entertainment workers are at risk of sexually acquiring HIV. Risk factors of unsafe sex include both individual cognitive (information, motivation, and behavioral skills) and social factors. However, HIV related information and most social factors are not directly and independently associated with unsafe sex. Behavioral intervention is needed for female entertainment workers in China. However, individual-based cognitive approach alone may be limited in effectiveness in reducing unsafe sex among female entertainment workers. Effective intervention needs to take a multi-level approach that addresses both individual cognitive and social risk factors and can particularly benefit from attention to empowering women in sexual relationships and creating a supportive social and working environment. PMID- 21660754 TI - Organizational policy recommendations for control of STI/HIV among female sex workers in China: regular examination of workers in social hygiene clinics. AB - This article aims to address female sex workers at high risk for contracting HIV in China by recommending evidence-based socio-structural interventions and policies at the national level that have yielded effective outcomes in other countries. National governments such as the Philippines and Hong Kong have utilized the Social Hygiene Clinic (SHC) model. A similar national policy can be highly effective in China. Evidence-based research study results indicate significant reductions in STI and consistent condom use among female sex workers in both China and the Philippines. Consistent condom use in both countries continues to be significantly associated with interpersonal- and venue-level factors. Individuals who had higher appointment-keeping ratios in the Philippines had higher rates of consistent condom use (OR = 2.7, 95% CI = 1.6-3.7) and significantly lower rates of STI (OR = 0.43, 95% CI = 0.26-0.57). By beginning with provinces, which already have a good relationship between establishment venues and the local Health Department, China can develop city ordinances and establishment regulations that begin to require regular examinations of female sex workers and entertainers in the local STI clinic. PMID- 21660755 TI - Changes and correlates in multiple sexual partnerships among Chinese adult women- population-based surveys in 2000 and 2006. AB - The sexual transmission of HIV and STI is becoming a major public health concern in China. However, studies on sexuality in China remain scant, particularly those that analyze female sexuality. This study is to investigate the prevalence of multiple sexual partnerships (MSP) among adult women, and to examine trends and correlates for having more than one lifetime sexual partner. MSP, coded as having one or none vs. two or more lifetime sexual partners, was the key binary outcome measure. The data were from two national probability surveys on sexual behaviors in China carried out in 2000 and 2006. The sample size of adult women was 1899 in 2000 (total sample n=3812), and 2626 in 2006 (n=5404). Overall prevalence of MSP increased from 8.1% in 2000 to 29.6% in 2006 (chi-square test, significance = 0.000). The most rapid changes took place among women with less education, those who worked in blue-collar jobs and lower social-status positions, and those living in rural areas or small towns. Women who were better educated, lived in big cities, and held management-level occupations exhibited less change but had a higher baselines prevalence of MSP, suggesting that changes in MSP behavior may occur initially among women of higher socioeconomic status. Based on the 2006 data-set, significant positive correlates of MSP included more years of education, being in a long-term relationship, being middle aged, having a lower status job, going out dancing at entertainments venues, and being a state of overall health in the past 12 months. The significant recent increase in MSP among women reinforces the need to examine China's sexual revolution in the context of a rapidly transitioning society. Findings regarding female sexuality also raise new questions to be explored in further sexuality studies, in order to better understand population sexual behaviors and to inform future HIV-prevention efforts. PMID- 21660756 TI - Sexual revolution in China: implications for Chinese women and society. AB - China is undergoing rapid changes in sexual mores due to several reasons such as decreasing control of the state over private lives of individuals, globalization of its economy, and some policies initiated by the state. There is increased acceptance of premarital sex and extramarital sex in China, especially among youth. In historically conservative China, influenced by Confucian ideals of patriarchal dominance for centuries, the sexual freedom currently enjoyed by many is unprecedented. This has impacted women's status and sexual lives in several positive ways such as increasing freedom of sexual expression, control over their bodies, sexual choices, and increasing equality with men in all spheres of life. However several negative consequences such as a rise in STD/HIV prevalence, commercial sex, and divorce rates have also been attributed to the ongoing sexual revolution in China. Recommendations combating these and suggestions for directions in future research are discussed. PMID- 21660757 TI - Childhood sexual abuse and sexual risks among young rural-to-urban migrant women in Beijing, China. AB - BACKGROUND: Child sexual abuse (CSA) has substantial impact on women. The current study aims to explore the patterns of CSA in migrant women in China. Moreover, a relationship between experience of CSA and increased sexual risks was also examined among this vulnerable population. METHODS: A final sample of 478 rural to-urban migrant women was recruited from different work places in two urban districts of Beijing, China. RESULTS: About 17% (n=80) of migrant women reported ever experienced any kind of CSA before 16 years of age. Participants who had multiple sexual partners, drank before sex and had early age of sexual debut reported higher rate of overall CSA (45.7% vs. 23%, p<0.01; 41.2% vs. 24%, p<0.05; and 47.8% vs. 24.4%, p<0.05) and contact CSA (37.1% vs. 15.6%, p<0.01; 32.4% vs. 16.8%, p<0.05; and 39.1% vs. 17%, p<0.05) compared to their counterparts. The multivariate analysis confirmed the results of bivariate analysis that a history of CSA was associated with increased sexual risks in adulthood. CONCLUSION: The current study suggests that health-related prevention intervention programs (i.e., HIV-related sexual risks prevention intervention) targeting the migrant women population needs to take in consideration the possible experience of CSA. Moreover, effective school-based or community-based CSA prevention intervention should be conducted to reduce CSA rate and improve attention to CSA issues in rural communities in China. PMID- 21660758 TI - In sickness and in health: a qualitative study of how Chinese women with HIV navigate stigma and negotiate disclosure within their marriages/partnerships. AB - In China, there are currently an estimated 180,000 women between 16 and 45 years of age living with HIV. However, we know very little about their lived experiences. Given the spread of the AIDS epidemic in China and the burden it exerts on quality of life, there is an urgent need to understand how HIV affects Chinese women, particularly in the context of their marriages. How do they negotiate the extreme stigma of their illness in making decisions about disclosure and social support, especially in the context of their family life? We recruited 26 Chinese women with HIV in Beijing and Shanghai for in-depth interviews employing a phenomenological approach. We examined the process and outcomes of disclosure within the course of the women's search for social support. Women in HIV-discordant relationships often experienced a termination of their marriage after disclosure, yet others exhibited remarkable resilience, finding new strength through the challenge of their illness. Findings underscore the need for accessible and culturally acceptable interventions for Chinese women with HIV who face considerable stigma in their search for support. PMID- 21660759 TI - Intersubtest discrepancies on the RBANS: results from the OKLAHOMA study. AB - The present study provides supplemental data for the Repeatable Battery for the Assessment of Neuropsychological Status (Randolph, 1998) by reporting base rate data on discrepancies between subtests of this measure. These discrepancies are organized by general level of ability and include both age and education corrections. The data come from the Oklahoma Longitudinal Assessment of Health Outcomes in Mature Adults study and include cognitive performances of 718 community-dwelling older adults. These findings offer the possibility of increased sensitivity at detecting clinically significant differences that might not be identified when relying on base rate data from a greater age range. Similarly, these data highlight the mediating effects of the global level of cognitive functioning on discrepancy scores. PMID- 21660760 TI - High specificity of the Word Memory Test and Medical Symptom Validity Test in groups with severe verbal memory impairment. AB - By definition, false positives occur when an otherwise very easy symptom validity test (SVT) or effort test is failed because of cognitive impairment and not because of poor effort. Therefore, the highest rate of false positives will be found in those groups with the most severe cognitive impairment. For that reason, it is important to study people with severe impairment when evaluating the specificity of SVTs. Some people with various types of dementia, notably those with Alzheimer's disease, suffer from severe impairment of memory and other cognitive abilities. In this study, patients with possible or probable dementia were tested with the Word Memory Test (WMT; Green, 2003; Green & Astner, 1995) and the Medical Symptom Validity Test (MSVT; Green, 2004). While some dementia patients failed the easy subtests of these instruments and had severe verbal memory impairment, they showed distinctive profiles of scores that have been reported to be characteristic of people with severe impairment. Using profile analysis, the WMT and MSVT achieved a specificity of 98.4% or higher in the patients of the current study. This suggests that there will be extremely low false positive rates using the same methods in people with relatively minor impairment of the type found in, for example, mild traumatic brain injury or depression. PMID- 21660762 TI - Sustained attention and behavioral characteristics associated with ADHD in adults. AB - The goal of the current study was to investigate whether two cognitive functions (i.e., sustained attention and response inhibition) were related to a general model of personality traits and behavioral characteristics associated with attention-deficit hyperactivity disorder (ADHD). To examine these relations, the Conjunctive Continuous Performance Test was used to measure the two cognitive functions, the Mini-Marker was used to measure the Big Five domains of personality, and the Wender Utah Rating Scale (WURS) was used to index ADHD symptoms. Correlations and multiple regression analyses showed that difficulties in sustained attention were associated with the WURS behavioral symptoms of inattention, oppositional/defiant behavior, impulsivity, and Big Five low conscientiousness, but were not associated with emotional problems such as neuroticism or low agreeableness (Big Five). Difficulties in response inhibition were marginally correlated with behavioral symptoms of inattention and low conscientiousness. Surprisingly, response inhibition was also highly correlated with sustained attention. In addition, neuroticism independently was highly associated with the WURS emotional and oppositional/defiant behavior symptoms. The findings suggest that deficient sustained attention relates specifically to the main ADHD behaviors but not to the emotional problems typically associated with the disorder. PMID- 21660763 TI - Differences in participation according to specific cognitive deficits following a stroke. AB - This study compared participation following a stroke according to the presence of specific cognitive deficits. Participation is defined as the involvement of a person in daily activities and social roles. Three weeks after being discharged home, 197 older adults (aged 65 years and older) who had a stroke were evaluated using the Assessment of Life Habits, which includes 12 domains of daily activities and social roles. The presence of a cognitive deficit was determined by the scores obtained on tests assessing memory, visual perception, language, unilateral attention, and the inhibition component of executive functions. After adjusting for depressive symptoms, time since stroke, and comorbidities, five of the domains of participation are significantly more restricted by some cognitive deficits. Memory deficits affect the communication (p = .006) and leisure (p = .032) domains. In the presence of visual perception deficits, the nutrition (p = .019), communication (p = .004), and responsibilities (p < .0005) domains are more limited. Language deficits have an impact on several domains of participation, namely communication (p < .0005), responsibilities (p < .0005), community life (p = .001), and leisure (p = .021). Unilateral neglect and deficits in the inhibition component of executive functions are not found to restrict participation. Overall, participation after stroke is related to cognitive function. Looking carefully at individual domains of activities and roles provides essential information in guiding rehabilitation interventions aimed at enhancing participation after discharge. PMID- 21660761 TI - Designing rehabilitation programs for neglect: could 2 be more than 1+1? AB - Unilateral neglect is a multimodal neuropsychological disorder that has puzzled scientists for a long time. Many interventions have been developed, but only a handful has proven to be effective. This review examines whether applying different therapeutic techniques in combination will increase therapeutic benefits. Studies were reviewed where therapies are applied sequentially or in combination with other techniques. The results indicate that combining different interventions leads to increased general improvement compared with other noncombined designs, even when the number of treatment sessions is not constant. Practical and theoretical aspects of different treatments are discussed. The combined approach to treatment may have direct relevance to disorders other than neglect. This report introduces a new classification scheme for different interventions with the aim of facilitating more focused therapy. Finally, suggestions are made as to what the focus of future studies of neglect therapy should be and how therapeutic benefits might be maximized. PMID- 21660764 TI - Cognitive complaints and neuropsychological functioning in adults with and without attention-deficit hyperactivity disorder referred for multidisciplinary assessment. AB - The present study aims to gain insight into the clinical presentation (viz., self reported complaints and neuropsychological functioning) of adults referred for an attention-deficit hyperactivity disorder (ADHD) diagnosis. The investigation evaluated group differences between an ADHD and a non-ADHD sample (n = 30 and n = 42, respectively), all of which had been clinically referred for multidisciplinary assessment of ADHD. Forty-two percent of all referred patients were diagnosed with adult ADHD. Adults with ADHD made significantly more errors on a verbal learning task than the non-ADHD control group, which could indicate an impairment of the self-monitoring function in adult ADHD. The ADHD group reported more problems than the control group in the domains of executive functioning but not in the domains of attention and hyperactivity. More attention should be paid to executive complaints and functioning (present and past) when referring adults suspected of ADHD for multidisciplinary assessment. Also, characteristics that are thought to be striking symptoms of adult ADHD, such as problems with concentration and hyperactive behavior, are in fact not distinctive symptoms of ADHD at all. PMID- 21660765 TI - The Flynn effect in neuropsychological assessment. AB - The Flynn effect refers to the rise in IQ throughout the 20th century. This study examined whether the Flynn effect has also elevated performance on neuropsychological tests. A search of published norms revealed five tests with appropriate normative data available for comparison. These tests were the Trail Making Test (TMT), Symbol Digit Modalities Test (SDMT), Boston Naming Test, Finger Tapping, and Grooved Pegboard. Results indicated a strong Flynn effect for Parts A and B of the TMT and a probable Flynn effect for the oral SDMT. No Flynn effect was evident for the other tests. Implications for clinical assessment are discussed. PMID- 21660766 TI - A case of malingering by proxy in a Social Security disability psychological consultative examination. AB - The term "malingered neurocognitive dysfunction by proxy" was discussed by Slick, Sherman, and Iverson (1999) as part of the differential for defining malingering when a patient is responding to directions or pressure from others. In Chafetz (2008), rates of symptom validity failure in children whose parents are seeking Social Security Disability (SSD) on their behalf were presented and showed 20% to 26% symptom validity test failure rates at chance or below-chance levels. The objective of the current case study was to determine whether the requirements of malingering were met in a 9-year-old whose parent was seeking SSD on his behalf. A retrospective approach was employed using an archived case from one of the author's records. This case shows a practical application of a symptom validity scale for low-functioning individuals (Chafetz, Abrahams, & Kohlmaier, 2007), which was designed initially for use with adult and child SSD claimants. The egregious nature of symptom validity failure, coupled with SSD seeking for the whole family, along with conduct disorder symptoms provided a strong suggestion of malingering by proxy. The present results are discussed with respect to low functioning claimants. PMID- 21660770 TI - Modern health worries, health care utilization, and symptom reporting: a cross cultural comparison. AB - Perception of risk to personal health from features of modern life and technology is increasing across the globe. We investigated whether these concerns exist in the Turkish setting in the same degree and whether symptom reports mediate the relationship between modern health worries (MHWs) and health care utilization in the UK and Turkish settings. A total of 506 University of St Andrews students and a total of 424 Turkish university students in Istanbul Bilgi University participated in the study. The factor structure of the MHW scale was similar in both samples and previous literature with the addition of a new factor, "ingested toxins." Turkish sample had higher scores on all items compared to the UK sample. We also tested a moderated mediational hypothesis in both samples which showed that subjective health complaints mediated the relationship between MHWs and health care utilization in both samples. PMID- 21660771 TI - Antidepressant-like effect of altered Korean red ginseng in mice. AB - Altered Korean red ginseng has been used as a treatment for patients suffering from anxiety. We assessed whether red ginseng hydrolyzed by malted barley (HRG) and acetate-fermented red ginseng (ARG) would improve brain activity, by using forced swimming test (FST) in mice. The effect of the fluoxetine (a classical antidepressant), ginsenoside Rg3 (Rg3), red ginseng (RG), HRG, and the ARG groups for two weeks on the immobility time was significantly decreased in comparison with the control group (p<0.05). The immobility time of HRG and ARG in FST was lower than that of RG. The plasma level of glucose and total protein was significantly increased in the HRG and ARG group compared with the control group (p<0.05), whereas albumin, lactate dehydrogenase, creatine kinase, and blood urea nitrogen levels were not changed. In conclusion, altered Korean red ginsengs, HRG, and ARG therapy appeared to be effective in improving depression. PMID- 21660772 TI - Testing a brief self-directed behavioral weight control program. AB - Clinical obesity treatments are of limited reach. Self-directed weight control attempts are common, but little attention has been given to providing guidance for such efforts in the population. The present research tests a brief intervention approach to weight control. Pilot data were collected from 66 University of Minnesota employees (72.7% women, 81.8% white) randomized to an assessment-only control condition or a single intervention session to teach empirically valid self-directed weight-control methods. Mean baseline weight was 87.1 kilograms (range 64.0-120.3 kilograms). Though statistically nonsignificant, intervention participants averaged greater weight loss by 6 months than controls (-.80 kilograms vs. -.19 kilograms), F(1, 44)=.47, p=.50, Cohen's d=.21. There was a significant group*time interaction for self-weighing frequency, F(2, 41)=10.84, p<.001. With some enhancement and more attention to dissemination, a brief self-directed program has potential as a useful approach to population weight-gain prevention. PMID- 21660773 TI - Does race or sex moderate the perceived built environment/physical activity relationship in college students? AB - The purpose of this research was to explore the relationship between the perceived built environment and physical activity (PA) among college students, and to determine whether race and/or sex moderate this relationship. Participants were 785 college students (435 students in Study 1 and 350 in Study 2). Students completed questionnaires assessing characteristics of their neighborhood, and were followed up 1 (Study 1) or 2 (Study 2) weeks later to measure PA levels. Seeing others in one's neighbourhood being active was found to be significantly related (p<.01) to higher levels of PA for students in both studies. In Study 2, race was found to moderate the relationship between having many places within walking distance and PA, affecting African Americans more strongly than Caucasians. Sex was not found to moderate the perceived built environment/PA relationship. It appears that certain aspects of the perceived built environment may have an effect on the level of PA in college students, with race moderating this relationship. PMID- 21660774 TI - Effects of a print-mediated intervention on physical activity during transition to the first year of university. AB - Transition to the first year of university is linked to steep declines in moderate-vigorous physical activity (MVPA). The purpose of this study was to investigate the effects of a targeted, theory-driven, print-based intervention on MVPA during transition to university. Volunteer participants from five Canadian universities (n=255) completed measures of MVPA at the start of their first semester at university and were randomly assigned to conditions receiving a first year-student physical activity and action-planning brochure, Canada's Physical Activity Guide (CPAG), or a no-intervention control group. Six weeks later, a follow-up measure of MVPA was obtained as well as retrospective accounts of physical activity action-planning strategies and self-efficacy for scheduling physical activity. At the follow-up, students who received the targeted first year student physical activity brochure reported significantly higher levels of MVPA compared to controls (p<.05) and a trend towards higher MVPA compared to the CPAG group (p=.06). However, there were no differences between groups on action planning or self-efficacy. A theory-driven and targeted print media intervention can offer low-cost and broad-reaching effects that may help students stay more active or curb declining levels of MVPA that occur during transition to university. PMID- 21660775 TI - Interfacial morphology and nanomechanics of cement of the barnacle, Amphibalanus reticulatus on metallic and non-metallic substrata. AB - The barnacle exhibits a high degree of control over its attachment onto different types of solid surface. The structure and composition of barnacle cement have been reported previously, but mostly for barnacles growing on low surface energy materials. This article focuses on the strategies used by barnacles when they attach to engineering materials such as polymethylmethacrylate (PMMA), titanium (Ti) and stainless steel 316L (SS316L). Adhesion to these substrata is compared in terms of morphological structure, thickness and functional groups of the primary cement, the molting cycle and the nanomechanical properties of the cement. Structural characterization studies using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) in conjunction with nanomechanical characterization and infrared spectroscopy (FTIR) are used to understand the differences in the adhesion of primary barnacle cement to the different substrata. The results provide new insights into understanding the mechanisms at work across the barnacle-substratum interface. PMID- 21660776 TI - Ecological role of a seaweed secondary metabolite for a colonizing bacterial community. AB - Bacteria associated with seaweeds can both harm and benefit their hosts. Many seaweed species are known to produce compounds that inhibit growth of bacterial isolates, but the ecological role of seaweed metabolites for the associated bacterial community structure is not well understood. In this study the response of a colonizing bacterial community to the secondary metabolite (1,1,3,3 tetrabromo-2-heptanone) from the red alga Bonnemaisonia hamifera was investigated by using field panels coated with the metabolite at a range of concentrations covering those measured at the algal surface. The seaweed metabolite has previously been shown to have antibacterial effects. The metabolite significantly affected the natural fouling community by (i) altering the composition, (ii) altering the diversity by increasing the evenness and (iii) decreasing the density, as measured by terminal restriction fragment length polymorphism in conjunction with clone libraries of the 16S rRNA genes and by bacterial enumeration. No single major bacterial taxon (phylum, class) was particularly affected by the metabolite. Instead changes in community composition were observed at a more detailed phylogenetic level. This indicates a broad specificity of the seaweed metabolite against bacterial colonization, which is supported by the observation that the bacterial density was significantly affected at a lower concentration (0.02 MUg cm-2) than the composition (1-2.5 MUg cm-2) and the evenness (5 MUg cm-2) of the bacterial communities. Altogether, the results emphasize the role of secondary metabolites for control of the density and structure of seaweed-associated bacterial communities. PMID- 21660777 TI - Exploring the relationship between facets of mindfulness and eating pathology in women. AB - Although researchers have examined the efficacy of acceptance- and mindfulness based interventions in the treatment of eating disorders, few studies have explored the association between trait mindfulness and eating pathology. Therefore, the purpose of the current investigation was to examine the unique associations between multiple facets of mindfulness (acting with awareness, nonreactivity, nonjudgment, describing, and observing) and eating pathology. Undergraduate women (N = 276) completed the Eating Attitudes Test-26, the Five Facet Mindfulness Questionnaire, and the 21-item version of the Depression Anxiety Stress Scales. A hierarchical regression analysis revealed that four mindfulness facets (awareness, nonreactivity, nonjudgment, and describing) were uniquely associated with eating pathology above and beyond anxiety and depression symptoms. Results are discussed with regard to the potential role of various facets of trait mindfulness in eating pathology as well as the possible utility of mindfulness-based treatments for eating disorders. PMID- 21660778 TI - All at once or one at a time? A randomized controlled trial comparing two ways to deliver bibliotherapy for panic disorder. AB - Bibliotherapy is potentially effective in the treatment of panic disorder (PD). A still unanswered question is whether pacing is important. This study was designed to test whether there is a difference between being assigned a full book as therapy and receiving one individual chapter every week (i.e. pacing). A total of 28 participants were randomized to either 10 paced chapters or one book with 10 chapters. To maximize compliance, short weekly telephone calls were added in both conditions (M = 17.8 min, SD = 4.2). Both treatments showed promising results, with effects maintained up to 2 years and with within-group effect sizes (Cohen's d) between 0.95 and 1.11. Pretreatment ratings of credibility were positively correlated with the change scores at both posttest and 2-year follow-up for three panic measures. Pacing of text material in bibliotherapy for PD is not needed, and all material can be provided at once when the treatment is guided by a therapist. PMID- 21660779 TI - Estimation of trunk mechanical properties using system identification: effects of experimental setup and modelling assumptions. AB - The use of system identification to quantify trunk mechanical properties is growing in biomechanics research. The effects of several experimental and modelling factors involved in the system identification of trunk mechanical properties were investigated. Trunk kinematics and kinetics were measured in six individuals when exposed to sudden trunk perturbations. Effects of motion sensor positioning and properties of elements between the perturbing device and the trunk were investigated by adopting different models for system identification. Results showed that by measuring trunk kinematics at a location other than the trunk surface, the deformation of soft tissues is erroneously included into trunk kinematics and results in the trunk being predicted as a more damped structure. Results also showed that including elements between the trunk and the perturbing device in the system identification model did not substantially alter model predictions. Other important parameters that were found to substantially affect predictions were the cut-off frequency used when low-pass filtering raw data and the data window length used to estimate trunk properties. PMID- 21660780 TI - Finite element and photoelastic modelling of an abdominal aortic aneurysm: a comparative study. AB - Rupture prediction of abdominal aortic aneurysms (AAAs) remains a clinical challenge. Finite element analysis (FEA) may allow for improved identification for intervention timing, but the method needs further substantiation. In this study, experimental photoelastic method and finite element techniques were compared using an idealised AAA geometry. There was good agreement between the numerical and experimental results. At the proximal and distal end of the AAA model, the maximum differences in principle strain for an internal pressure of 120 mmHg had differences ranging from 0.03 to 10.01%. The maximum difference in principle strain for the photoelastic and the finite element model at a pressure of 120 mmHg was 0.167 and 0.158, respectively. The current research strengthens the case for using FEA as an adjunct to the current clinical practice of utilising diameter measurement for intervention timing. PMID- 21660781 TI - Multiaxial mechanical behaviour of the passive ureteral wall: experimental study and mathematical characterisation. AB - There is a scarcity of data regarding the mechanical properties of the ureter, although this would facilitate our understanding of its physiology and pathophysiology, and the development of suitable biomaterials for replacement. There is hence an urgent need for multiaxial experimental data and methodical constitutive formulations, which we aim at presenting through this report. The zero-stress state of wall tissue, serving as the starting geometry for biomechanical analyses, was accordingly determined and the 3D passive behaviour of ureteral specimens, isolated from healthy rabbits, was studied under a physiologic range of finite inflation and longitudinal extension. Two most commonly employed descriptors of soft tissue behaviour were chosen to fit the material response: the Fung-type strain-energy function (SEF) and its combination with a quadratic function. Both SEFs were tested in the thick-walled setting, with incompressibility enforced explicitly or via a Lagrange multiplier. The deformational response of the ureter exhibited an exponential and not the sigmoidal dependency on pressure that requests implementation of two-term SEFs. Indeed, the four-parameter Fung-type SEF resulted in reasonable fit of both the external radius and longitudinal force vs. lumen pressure data, and fitting accuracy was not improved when attempting the seven-parameter Fung-type or biphasic SEFs. There were also serious over-parameterisation problems with those models, favouring the implementation of the SEF with the smallest number of parameters. The material parameters optimised revealed significant mechanical anisotropy, with longitudinal properties being stiffer than circumferential ones under equibiaxial stress states. We conclude that ureter displays a nonlinear anisotropic mechanical response that is well-characterised by the four-parameter Fung-type SEF. PMID- 21660782 TI - Towards an efficient and robust foot classification from pedobarographic images. AB - This paper presents a new computational framework for automatic foot classification from digital plantar pressure images. It classifies the foot as left or right and simultaneously calculates two well-known footprint indices: the Cavanagh's arch index (AI) and the modified AI. The accuracy of the framework was evaluated using a set of plantar pressure images from two common pedobarographic devices. The results were outstanding, as all feet under analysis were correctly classified as left or right and no significant differences were observed between the footprint indices calculated using the computational solution and the traditional manual method. The robustness of the proposed framework to arbitrary foot orientations and to the acquisition device was also tested and confirmed. PMID- 21660784 TI - Naming and framing-the making of sexual (in)equality. Abstracts of the IASSCS Conference. July 6-9, 2011. Madrid, Spain. PMID- 21660783 TI - An expanding sexual economy along National Route 3 in Luang Namtha Province, Lao PDR. AB - With some of the lowest development indicators in Southeast Asia, remote upland areas of the Lao People's Democratic Republic are among the poorest in the region. The advent of improved transport and communication links, along with opportunities for wage employment, have accelerated the growth of a cash economy in traditionally isolated farming communities of Luang Namtha Province. Interviews and focus group discussions with young people, women in the sexual service business and health workers indicate that the lure of the new economy is wooing villagers away from their agrarian roots. Motorbikes and mobile phones have expanded the sexual territory of indigenous youth at a time when international commerce and a cash economy along improved highways are bringing new people into the region. Among the concerns for their health and safety are at risk behaviours involving alcohol and sexual practices, especially HIV and sexually transmitted infections. Of particular concern is the sexual trade in the province with a predominance of young, poorly educated Khmou women providing sexual services in a growing number of entertainment places. PMID- 21660785 TI - 'We are (not) the master of our body': elderly Jewish women's attitudes towards euthanasia and assisted suicide. AB - OBJECTIVES: In Belgium, dominant ideological traditions--Christianity and non religious humanism--have the floor in debates on euthanasia and hardly any attention is paid to the practices and attitudes of ethnic and religious minorities, for instance, Jews. This article aims to meet this lacuna. DESIGN: Qualitative empirical research was performed in the Orthodox Jewish community of Antwerp (Belgium) with a purposive sample of elderly Jewish (non-)Hasidic and secularised Orthodox women. In-depth interviews were conducted to elicit their attitudes towards (non-)voluntary euthanasia and assisted suicide. RESULTS: The research reveals diverse views among women in the community on intentionally terminating a patient's life. Absolute rejection of every act which deliberately terminates life is found among the overwhelming majority of (religiously observant) Orthodox (Hasidic and non-Hasidic) women, as they have an unconditional faith and trust in God's sovereign power over the domain of life and death. On the other hand, the views of secularised Orthodox women--mostly irreligious women, who do not consider themselves Orthodox, thus not following Jewish law, yet say they belong to the Orthodox Jewish community--show an acceptance of voluntary euthanasia and assisted suicide but non-voluntary euthanasia is approached more negatively. As they perceive illness and death as merely profane facts, they stress a patient's absolute right towards self determination, in particular with regard to one's end of life. Among non-Hasidic Orthodox respondents, more openness is found for cultivating a personal opinion which deviates from Jewish law and for the right of self-determination with regard to questions concerning life and death. In this study, these participants occupy an intermediate position. CONCLUSION: Our study reveals an interplay between ethical attitudes on euthanasia and religious convictions. The image one has of a transcendental reality, or of God, has a stronger effect on one's (dis)approval of euthanasia than being (ir)religious. PMID- 21660786 TI - Perceptions of risk factors for diabetes among Norwegian-Pakistani women participating in a culturally adapted intervention. AB - OBJECTIVE: To explore perceptions of diabetes risk factors among Pakistani immigrant women, as part of their explanatory model of the disease, and the changes in these perceptions after a culturally adapted intervention. DESIGN: Intervention study, carried out in Oslo, Norway, comprising 198 women. RESULTS: At baseline, about 75% of the women perceived sugar to be a risk factor for diabetes, about 30% mentioned physical inactivity and stress and close to 20% mentioned overweight. Twelve per cent could not identify any risk factors. When asked about foods to include in a diet to prevent diabetes, vegetables were mentioned by 45%, while 33% did not know any foods to include. Among those attending >=60% of the educational sessions, the proportions mentioning little physical activity (p<0.001), overweight (p=0.001) and family history (p=0.007) as risk factors increased. Furthermore, the proportions mentioning legumes (p=0.001), fish (p<0.001), fibre (p=0.035) or vegetables (p=0.015) as important in a diet to prevent diabetes increased, and the proportion not knowing any food to include was reduced to 10% (p=0.004). Except for little physical activity, similar changes in responses were not registered in the control group. CONCLUSIONS: There is a need for improved knowledge about diabetes prevention among Pakistani immigrant women, and a culturally adapted intervention may contribute to this. PMID- 21660787 TI - 'If your husband doesn't humiliate you, other people won't': gendered attitudes towards sexual violence in eastern Democratic Republic of Congo. AB - More than a decade of fighting in the Democratic Republic of the Congo (DRC) has resulted in extensive human rights abuses, of which sexual and gender-based violence (SGBV) is one of the most salient and disturbing features. This paper uses qualitative data, based on 10 focus groups with 86 women and men to better understand gendered community perspectives on SGBV and its consequences in South Kivu. We conclude that for many survivors, rape has consequences far beyond the physiological and psychological trauma associated with the attack. Respondents say sexual violence has become a societal phenomenon, in which the community isolation and shame experienced as a result of the attack become as important as concerns about the attack itself. Male focus group participants explain their own feelings of shame and anger associated with knowing their female relatives were raped. These findings highlight the complexity of community reintegration for survivors and identify a number of programmatic and policy implications, such as the need for counselling for survivors of sexual violence with their families as well as individually; the importance of income-generating training; and the need for improved justice mechanisms to bring perpetrators to justice. PMID- 21660788 TI - Cohesive subgroups and drug user networks in Dhaka City, Bangladesh. AB - The purpose of this paper was to explore group drug taking behaviour in a slum area of Dhaka, Bangladesh. We set out to examine the relationships between those who met, at least weekly, to take illegal drugs together, and how these relationships might shape their drug behaviour. Sociometric and behavioural data were collected using questionnaires via semi-structured interviews. We found that the likelihood of injecting drugs and sharing needles increased with age, duration of group membership and length of drug use. Drug users were classified into two clusters: one was more cohesive and comprised longer-term users, who were more likely to inject drugs and had poorer physical and mental health. The other cluster comprised younger, better educated members who were more transient, less cohesive, less likely to inject drugs and had better health. Qualitative data suggested that members of the first cluster were less accepting of outsiders and confirmed more to group norms. We conclude that emotionally bonded cohesive subgroups acquire norms, which reinforce problematic drug-using behaviour. Thus, health initiatives need to consider group relationships and norms and those initiatives which work with networks may be more effective and more appropriate for low-income countries. PMID- 21660789 TI - Older adults' perspectives on HIV/AIDS prevention strategies for rural Kenya. AB - HIV/AIDS is devastating sub-Saharan Africa with great impact in the rural communities. Though prevention is the mainstay of various responses to the epidemic, communication strategies used to influence risk perception and motivate behavior change are culturally inappropriate, hence the lack of success. The bulk of prevention efforts target the 15-49 age group, resulting in limited knowledge and understanding of HIV/AIDS in adults over age 50 who are considered at a lower or no risk of infection. This paper addresses older adults as a key segment of the population in HIV/AIDS prevention given the increasing number that is living with the disease or newly infected. Many older adults are also caregivers of those infected and affected by the disease. As cultural, social, political, and opinion leaders in rural Kenya, older adults are in a position to influence attitudes and behaviors of their community members, but they have not been involved in the current intervention strategies. Through application of a participatory and culture-centered approach, the study sought views of older adults on the factors contributing to the epidemic in rural Kenya and their opinions on effective prevention strategies that are culturally appropriate. Several recommendations are made for a culture-specific HIV/AIDS prevention intervention for rural Kenya. PMID- 21660790 TI - Internet-based survey on medical manga in Japan. AB - The more manga (Japanese graphic novels) communicate medical information, the more people are likely to be influenced by manga. We investigated through an Internet search using Google the characteristics of medical manga published in Japan, defined as those in which the main character is a medical professional and that occur in a medical setting. As of December 2008, 173 medical manga had been published. For a period of time after the first medical manga by Osamu Tezuka in 1970, the number of publications maintained a steady level, but increased rapidly in the mid 1980s. The professions of the protagonist were 134 doctors, 19 nurses, 3 dentists, 3 medical students, and 1 nursing student. Although the main character was mostly a doctor, manga featuring paramedical professionals have increased since 1990s. Medical manga may be a powerful tool for increasing the awareness of the public regarding medicine. PMID- 21660791 TI - Public information officers' perceived control in building local public health agendas and the impact of community size. AB - Using data collected from 280 local public health information officers (PIOs) serving community sizes from rural to urban across the United States, this study examines issues of local autonomy or lack thereof in establishing local health agendas. It specifically addresses how size of community as well as state and federal agencies' agendas affect public health promotion at the local level. Findings reveal low levels of perceived local departmental control in building public health agendas among rural PIOs. Alternatively, urban PIOs report low levels of both perceived state and federal departmental control yet higher levels of local departmental control compared to counterparts in other sized locales. Implications and importance of findings are discussed. PMID- 21660792 TI - Intentions and beliefs about getting tested for STDs: implications for communication interventions. AB - Although sexually transmitted diseases (STDs) are common among college students, there have been few studies that examine the psychological determinants of STD testing. To help address this gap in the literature, we drew on the reasoned action framework to gain insight into the cognitive processes underlying STD testing intentions for two samples of college students (n = 181 and n = 160). More generally, we demonstrate how behavioral theory can be applied in formative research to generate recommendations for developing communication interventions. Our findings suggest that attitudes toward getting tested for STDs were the strongest determinant of intentions for the college students in our samples. Further, results of a belief analysis indicate that students who did not intend to get tested for STDs might change their mind if they could be persuaded that getting tested would show that they respect their sexual partner or that getting tested would prevent them from spreading an STD to someone else. PMID- 21660793 TI - Communication in genetic counseling: cognitive and emotional processing. AB - The profession of genetic counseling has received limited guidance from theoretical models in how to communicate complex health information so that clients can actively use the information. In this study of a national sample of 145 genetic counselors conducting sessions with simulated clients, we apply two different approaches for analyzing and describing verbal health communication. The Roter interaction analysis system (RIAS) and linguistic inquiry word count (LIWC) were used to identify evidence of communication behaviors consistent with tenets of the social cognitive processing model (SCPM). These tools revealed descriptive evidence of counselor facilitation of client emotional processing and, to a lesser extent, facilitation of client cognitive processing and understanding. Conversely, descriptive analysis of client communication revealed evidence of cognitive processing, but less affective processing. Second, we assessed whether genetic counselor facilitative communication predicted simulated client responses consistent with the cognitive and emotional processing inherent in SCPM. These analyses revealed that counselor attempts to promote emotional expression and client insight were positively associated with client word usage indicative of expression of negative affect and cognitive processing. This study is the first to our knowledge to apply RIAS and LIWC in tandem and gives us a description of current practices within genetic counseling within a theoretical framework. Additionally, it provides suggestions for education and communication goals to improve providers' responses to patient emotions as well as skills to engender patient understanding and personal meaning-making of complex medical information. PMID- 21660794 TI - Lead, cadmium, manganese, cobalt, zinc and copper levels in whole blood of urban teenagers with non-toxic diffuse goiter. AB - The amount of lead (Pb), cadmium (Cd), manganese (Mn), cobalt (Co), zinc (Zn), and copper (Cu) present in whole blood of 118 teenagers were determined by atomic absorption spectrometry. The blood samples of 23 healthy teenagers were compared with the blood samples of 95 adolescents who were diagnosed with non-toxic diffuse goiter (NTDG). The study was aimed at examining whether in addition to mild iodine deficiency other trace elements could contribute to the development of non-toxic diffuse goiter. The results indicated that the levels of Pb, Cd and Mn in the blood samples of teenagers diagnosed with NTDG were higher than that in healthy children. Also, the results indicated that higher levels of metals were present in the blood samples with NTDG in adolescent patients who lived in areas with a higher amount of pollution. PMID- 21660795 TI - Pattern of childhood falls in a low-income setting: a cross-sectional study in Dar es Salaam. AB - The objective was to determine patterns and circumstances of childhood falls in a low-income setting in Dar es Salaam, Tanzania. This cross sectional study is based on a household survey conducted in July 2009. A total of 3927 children up to age 18 from 1928 households in 15 sampled wards were surveyed through a structured questionnaire. The current study includes information regarding fall occurrence, socio-demographic and economic factors. Data were analysed using chi square, t-test and logistic regression. Male children had 42% higher odds of falls compared to females, and rural residents had more than two times higher odds compared to urban residents. Falls occurred three times more among age group 1-4 and two times more among age group 5-9 compared to those between 15 and 18 years. Most falls occurred outdoors (62%) while playing (51%) with boys being over-represented. Females and children aged 1-4 years fell more from stairs whereas most infants fell from furniture. Male gender, younger age groups and rural residence were significant factors for fall injuries. The circumstances in which these falls occur also differ significantly. Intervention efforts should emphasise these patterns. PMID- 21660796 TI - Drivers' behaviour at roundabouts in Riyadh. AB - As is the case in many cities, roundabouts are used extensively in Riyadh. However, instead of improving safety, driving through roundabouts in Riyadh can be a dangerous experience as many drivers do not follow regulations. Unfortunately, no official statistics exist on accidents or violations at roundabouts and no studies have been done to assess this problem. A field study to collect data on drivers' behaviour at five roundabouts in Riyadh was done and a questionnaire was randomly distributed to drivers to explore this issue. Results showed that the percentage of drivers breaching at least one traffic regulation is approximately 90% of all drivers driving through these roundabouts, with leaving without flashing and entering the roundabout without giving way being the most frequent violation types. Questionnaire results from 384 respondents showed that there is a lack of information among most drivers on roundabout driving regulations and that driver training and licensing process does not include enough information related to this matter. Finally, practical suggestions as how to tackle this issue in terms of education, training and policing are given. PMID- 21660797 TI - National burden of road traffic injuries in Argentina. AB - More than 1.2 million people die and as many as 50 million people are injured or disabled due to road traffic injuries (RTIs) every year worldwide. The lack of reliable data hinders efforts to describe the characteristics of the issue and prioritise prevention activities. The objective was to provide a snapshot of fatal and non-fatal RTI in Argentina. We used the methodology proposed by the Global Burden of Disease Injury Expert group. External causes of deaths with unknown codes were proportionately redistributed over the known categories. In 2007 in Argentina, we estimated 5915 RTI deaths, compared with 3983 RTI deaths reported previously by the Ministry of Health, accounting for 1931 additional cases. The highest number of deaths occurred in young men (15-29 years old), although the highest RTI death rates were in the age group of 55 years and older. Four-wheeled vehicle occupants were the most common road user type killed (59.1%); vulnerable road users represented one third (29.5%) of deaths and 64% of non-fatal RTI. The national and regional estimates of RTI in Argentina should help policy makers and public-health researchers to understand the importance of RTI prevention and design specific interventions to further reduce these preventable deaths and injuries. PMID- 21660798 TI - The special historical section of the journal of american college health. PMID- 21660799 TI - Student bodies, past and present. AB - This article examines how the field of college health has evolved over time to address the needs of an increasingly diverse student population. The central argument is that college and university health programs developed in conjunction with shifting standards of medical care and public health practices in the United States. The author reviews the role of college health programs as public health agencies for campus communities, and describes contemporary public health challenges facing college campuses. She shows how the history of college health is intertwined with the history of diversity in higher education. In particular, the author outlines how the growth of health services made higher education accessible to women, racial minorities, veterans, and persons with disabilities. PMID- 21660800 TI - The history of college health nursing. AB - Almost from the beginning of formal college health programs in the second half of the 19th century, college health nurses were there to care for students in college and university settings. By the end of the 20th century, the role of college health nurses had evolved with the nursing field in general, but with enough unique features for the American Nurses' Credentialing Center to recognize college health nursing as a professional subspecialty and administer the first College Health Nurse Certification examinations. In addition, new nurse practitioner programs provided practicing nurses with more independence, and their duties continued to expand beyond care of the sick to include health promotion, administrative, and teaching activities. As a result of these changes, college health nurses now play a larger role in the life of students and promoting a healthy campus community than ever before in the history of college health. PMID- 21660801 TI - One hundred years of college mental health. AB - Although the first student health service is credited to Amherst College in 1861, almost 50 years passed before Princeton University established the first mental health service in 1910. At that time, a psychiatrist was hired to help with student personality development. Although other schools subsequently established such services, the first 50 years of college mental health were marked by a series of national conferences. At the American Student Health Association's annual meeting in 1920, "mental hygiene" was identified as critical for college campuses to assist students to reach their highest potential. However, it took another 40 years before mental health and psychological counseling services became common on college and university campuses. The American College Health Association formed a Mental Health Section to serve mental health professionals in 1957, and most colleges and universities have now developed mental health and counseling programs commensurate with the size of their student bodies. PMID- 21660802 TI - History of the american college health association. AB - Following Dr Edward Hitchcock's lead at Amherst College in 1861, soon other institutions of higher education established physical education departments that evolved into independent college health programs. As the field of college health expanded, leaders from numerous campuses began meeting to share information and discuss formation of a national organization. As a result, the American Student Health Association was founded in 1920 to promote campus health care for students and advance the interests of college health. The name was changed to the American College Health Association in 1948. The past history of this organization has been well documented in the literature, so this review will focus more on ACHA's accomplishments over the past 20 years.(1)(,) (2)(,) (3)(,) (4). PMID- 21660803 TI - Missions and medicine at Amherst: family ties to Edward Hitchcock jr, the missionary movement, and the American University of Beirut. AB - The Haystack Movement began at Williams College in 1805, occasioning the spread of American missions throughout the world. A half century later, two graduates of nearby Amherst College, Edward Hitchcock Jr and Daniel Bliss, laid the foundations for college health services in this country and for mission work and education in the Middle East. The influences of these two 19th century Amherst alumni are still felt today in our college health services and at the American University of Beirut. PMID- 21660804 TI - Campus-based college health services before the Amherst program (1860): military academies lead the way. AB - Over the past 70 years a legend has evolved that the first college health program in the United States was established at Amherst College in 1861. Although the program at Amherst was innovative in its day and served as a model for the field of college health, several other institutions prior to 1860 appropriated funds, hired staff, and established on-campus programs to improve the health of their students. The military academies led the way, and the first of these early programs to become operational was located at the US Military Academy at West Point, New York, in 1830. PMID- 21660805 TI - Moderators of the relationship between physical activity and alcohol consumption in college students. AB - OBJECTIVE: Among college students, several studies have found a positive relationship between physical activity and alcohol use. The current study tested gender, Greek status, and ethnicity as potential moderators of the physical activity-alcohol use relationship. PARTICIPANTS: Participants were college freshmen (n = 310) endorsing alcohol/drug use. METHODS: Students completed questionnaires assessing a number of health behaviors. RESULTS: Results indicated that gender and Greek status were significant moderators of the relationship between physical activity and alcohol consumption. There was a positive relationship between physical activity and alcohol use for men and Greeks, but not for females and non-Greeks. CONCLUSIONS: These findings suggest that exercise does not serve as a protective factor for any of the subgroups of college students studied and is positively associated with drinking among college students who are men and/or involved with the Greek system. PMID- 21660806 TI - Declining physical activity levels as an unintended consequence of abolishing mandatory campus service fees. AB - OBJECTIVE: This study investigates the effect of the introduction of voluntary student unionism and subsequent increase in campus facility fees on engagement in physical activity on campus. PARTICIPANTS: Participants were 1,904 students from a large regional NSW (Australia) university across 3 time periods (926 in 2005, 504 in 2006, and 474 in 2007). METHODS: Students completed a survey across the 3 time periods, responding to questions about physical activity levels, use of on campus and off-campus facilities, and barriers to facility use. RESULTS: Participation in physical activity at university facilities was low overall, and declined substantially between 2005 and 2007, with the proportion of students identifying cost as a barrier more than doubling over this time period. CONCLUSIONS: There is a need for policy makers to consider the unintended health impacts of such policy changes, particularly in relation to the impact on already insufficient levels of physical activity. PMID- 21660807 TI - Peer 2 peer: efficacy of a course-based peer education intervention to increase physical activity among college students. AB - There are few physical activity (PA) interventions in higher education, and they have been only minimally effective. OBJECTIVE: To determine if a course-based, peer education intervention was associated with increases in PA and physical fitness. PARTICIPANTS: Participants were 178 students enrolled in a personal health class during the 2007-2008 academic year. METHODS: A quasi-experimental design was used to assess the effect of the intervention. Repeated measures analysis of covariance was employed to test the impact of the intervention on students' PA, body composition, waist-to-hip ratio, cardiovascular fitness, flexibility, and muscular strength. RESULTS: Women in the treatment group classified as "Inactive" at baseline increased PA, whereas "Inactive" control women had reductions in PA. Women in the treatment group who were "Active" at baseline reduced their waist-to-hip ratio and increased flexibility. There were no differences by treatment group among men. CONCLUSIONS: The intervention was effective in improving PA and physical fitness among college women. PMID- 21660808 TI - Psychosocial and environmental determinants of eating behaviors, physical activity, and weight change among college students: a qualitative analysis. AB - OBJECTIVE: The goal of this study was to identify factors that college students perceived as contributing to healthy and unhealthy eating patterns, physical activity (PA) levels, and weight change. PARTICIPANTS: Forty-nine 18- to 22-year old students at a midwestern university participated. METHODS: Six focus groups (3 with each gender) were conducted, and data were analyzed using qualitative software to code and categorize themes and then reduce these to clusters according to commonly practiced methods of qualitative analysis. RESULTS: Eating and PA behaviors appear to be determined by a complex interplay between motivations and self-regulatory skills as well as the unique social and physical environment comprising college life. Moreover, there appear to be gender differences in how these determinants impact behavior. CONCLUSIONS: Future research should examine these interactions in the college context in order to further our understanding of potential interventions or environmental modifications that support healthy eating and PA. PMID- 21660809 TI - Anthropometric and behavioral measures related to mindfulness in college students. AB - OBJECTIVE: To determine whether mindfulness is associated with physical and behavioral measures in first semester college students. PARTICIPANTS: Male and female first year college students (n = 75) from the University of Rhode Island. METHODS: Height, weight, waist circumference (WC), and blood pressure were assessed and online questionnaires were completed. Independent t tests and Pearson correlations were utilized for analysis. RESULTS: The less mindful group had a higher WC than the more mindful group. Correlations were seen between mindfulness and weight-related behaviors. CONCLUSIONS: Mindfulness can impact health status of first year college students, particularly with behavioral measures that have been found to effect weight status. However, additional research is needed focusing on mindfulness as a potential weight gain prevention technique for first year college students in order to decrease chronic disease prevalence. PMID- 21660810 TI - Protective effects of parent-college student communication during the first semester of college. AB - OBJECTIVE: Recent studies suggest that parents maintain influence as their adolescents transition into college. Advances in communication technology make frequent communication between parents and college students easy and affordable. This study examines the protective effect of parent-college student communication on student drinking behaviors, estimated peak blood alcohol concentration (eBAC), and serious negative consequences of drinking. PARTICIPANTS: Participants were 746 first-year, first-time, full-time students at a large university in the United States. METHODS: Participants completed a baseline and 14 daily Web-based surveys. RESULTS: The amount of time spent communicating with parents on weekend days predicted the number of drinks consumed, heavy drinking, and peak eBAC, consistent with a protective within-person effect. No association between communication and serious negative consequences was observed. CONCLUSIONS: Encouraging parents to communicate with their college students, particularly on weekend days, could be a relatively simple, easily implemented protective process to reduce dangerous drinking behaviors. PMID- 21660811 TI - Flourishing, substance use, and engagement in students entering college: a preliminary study. AB - OBJECTIVE: The present study explores the association between positive mental health or flourishing, depression, and engaged learning in undergraduates. PARTICIPANTS: Entering first year students (N = 428) at a liberal arts college. METHODS: Students completed measures of depression, flourishing, substance use, and student engagement. RESULTS: Based on Keyes' model of mental health,(1) 69.1% of students were flourishing, 29.0% were moderately mentally healthy, and 1.9% were languishing. In addition, 21.8% of students had elevated depression scores, and these scores were highly correlated with languishing. Alcohol consumption and binge drinking were not associated with measures of mental health. However, certain kinds of student engagement were associated with flourishing. CONCLUSIONS: Results suggest more flourishing in this sample entering college than in previous studies of high school students or adults. Future research should explore flourishing in undergraduates in more diverse samples across educational institutions, and employ prospective designs. PMID- 21660812 TI - A survey of 100 community colleges on student substance use, programming, and collaborations. AB - OBJECTIVE: The objective was to survey community college personnel about student substance use, and infrastructure (staff and funding), programs, and collaborations dedicated to substance use prevention. PARTICIPANTS: The sample included 100 administrators, faculty, and health services staff at 100 community colleges. METHODS: Participants completed a Web-based survey. RESULTS: Participants reported a number of alcohol and other drug (AOD) related concerns. Despite limited staff and funding dedicated to AOD, institutions are implementing a number of programs, although many are not implementing some of the programs popular at traditional 4-year colleges. They are also collaborating with a number of on- and off-campus groups. The availability of staff and funding dedicated to AOD, and the presence of residence halls, is associated with health programming and substance abuse collaborations. CONCLUSIONS: Results suggest that there is a need for increased research to understand the most effective AOD prevention strategies for community colleges. PMID- 21660813 TI - Sexual offending in adolescence: a comparison of sibling offenders and nonsibling offenders across domains of risk and treatment need. AB - Sibling sexual offending has received limited empirical attention, despite estimates that approximately half of all adolescent-perpetrated sexual offenses involve a sibling victim. The present study addresses this gap by examining male adolescent sibling (n = 100) and nonsibling offenders (n = 66) with regard to maltreatment histories and scores on two adolescent risk/need assessment instruments, the ERASOR and YLS/CMI. Adolescents who sexually abused a sibling, versus a nonsibling, were more likely to have histories of sexual abuse and been exposed to domestic violence and pornography. There were no group differences on ERASOR and YLS/CMI scales. This study adds to the limited discourse on sibling sexual offending and the larger literature on the heterogeneity of adolescents who have sexually offended. PMID- 21660814 TI - Child abuse, early maladaptive schemas, and risky sexual behavior in college women. AB - Previous research suggests that individuals abused as children are more likely to engage in risky sexual behavior during adulthood. The present study examined early maladaptive schemas as mediators of the child abuse-risky sexual behavior relationship among 653 college women. Self-report surveys assessed three forms of child abuse: Sexual, physical, and emotional, and assessed early maladaptive schemas within two domains: Disconnection/rejection and Other-Directedness. Disconnection/rejection schemas fully mediated the relation between child emotional abuse and number of sexual partners and partially mediated the relationship for sexual and physical abuse. However, when frequency of specific risky sexual acts (e.g., sex without contraception) was examined in the previous six months, only abandonment was a partial mediator. Implications for intervention and future research are discussed. PMID- 21660815 TI - Examining the relationship between childhood sexual abuse and borderline personality disorder: does social support matter? AB - The relationship between childhood sexual abuse and borderline personality disorder is a prominent issue in the etiological research on borderline personality disorder. This study further explored the relationship between childhood sexual abuse and the development of borderline personality features while evaluating the moderating role of a primary social support source in a sample of 290 female undergraduate students enrolled at a major southeastern university. Consistent with previous research, retrospective self-reports of childhood sexual abuse and low social support were both positively correlated with current borderline personality features. It was hypothesized that the presence of a supportive relationship at the time the childhood sexual abuse occurred would moderate the relationship between childhood sexual abuse and borderline personality features. This moderation hypothesis was not supported in the current study, but post-hoc analyses reveal the need to further examine how we define social support following childhood sexual abuse. This research is a stepping stone toward the prevention of borderline personality disorder following childhood sexual abuse. PMID- 21660816 TI - Early marriage, rape, child prostitution, and related factors determining the psychosocial effects severity of child sexual abuse in Ethiopia. AB - This study was aimed at identifying factors that determine the psychosocial effects severity of child sexual abuse. Data were collected from 318 female children in Ethiopia using the Children's Impact of Traumatic Events Scale Revised and the Rosenberg Self-Esteem Scale. The results revealed that respondents who survived rape and child prostitution were more symptomatic than those who were married early. Respondents for whom less time had elapsed since their first experience of abuse demonstrated a significantly higher level of post traumatic stress disorder symptoms, negative reactions by others, self-blame, and guilt than those for whom more time had elapsed since such an experience. The respondents in an intact marital relationship were found to be less symptomatic than their never married and divorced counterparts. Implications for intervention and further investigations are discussed. PMID- 21660817 TI - Disclosure of sexual abuse in sport organizations: a case study. AB - The disclosure of sexual abuse in the world of sports is a process that has not been widely documented. This article presents the results of a document analysis of sport organization policies and interviews conducted with 27 sport stakeholders. The interviews focus on these stakeholders' perceptions of how the disclosure process would unfold if a case of sexual abuse were to arise in their organization and their perceptions of the actual cases experienced in the sport organizations participating in this study. The results reveal several problems affecting the disclosure of sexual abuse in sport organizations. PMID- 21660818 TI - Psychological assessment through performance-based techniques and self-reports: a case study of a sexually abused girl at preschool age. AB - We investigated the implicit psychological and behavioral consequences of sexual abuse in an adolescent girl who suffered child sexual abuse at preschool age in this case report. We report the manifestations of this abuse on her personality and psychological functioning using a structured clinical interview and a comprehensive psychological battery including the Beck Anxiety Inventory, the Beck Depression Inventory, the Standard Progressive Matrices, Rorschach Ink Blots, and the Schema Mode Inventory. These investigations were useful in formulating both a diagnosis and a management plan. The girl fulfilled diagnostic criteria for a major depressive episode and borderline personality disorder. This combination of psychological testing may be useful in establishing an accurate multiaxial diagnosis and for understanding the behavioral and psychological sequelae of child sexual abuse in similar cases. The study further suggests that schema-focused therapy is a useful therapeutic tool for individuals who have suffered child sexual abuse at an early age and who have borderline personality disorder. PMID- 21660819 TI - Should atrazine and related chlorotriazines be considered carcinogenic for human health risk assessment? AB - Chloro-s-triazines have been a mainstay of preemergent pesticides for a number of decades and have generally been regarded as having low human toxicity. Atrazine, the major pesticide in this class, has been extensively studied. In a number of experimental studies, exposure to high doses of atrazine resulted in increased weight loss not attributable to decreased food intake. Chronic studies of atrazine and simazine and their common metabolites show an elevated incidence of mammary tumors only in female Sprague Dawley (SD) rats. On the basis of the clear tumor increase in female SD rats, atrazine was proposed to be classified as a likely human carcinogen by US Environmental Protection Agency (EPA) in 1999. With Fischer rats, all strains of mice, and dogs, there was no evidence of increased incidence of atrazine-associated tumors of any type. Evidence related to the pivotal role of hormonal control of the estrus cycle in SD rats appears to indicate that the mechanism for mammary tumor induction is specific to this strain of rats and thus is not relevant to humans. In humans the menstrual cycle is controlled by estrogen released by the ovary rather than depending on the LH surge, as estrus is in SD rats. However, the relevance of the tumors to humans continues to be debated based on endocrine effects of triazines. No strong evidence exists for atrazine mutagenicity, while there is evidence of clastogenicity at elevated concentrations. Atrazine does not appear to interact strongly with estrogen receptors alpha or beta but may interact with putative estrogen receptor GPR30 (G-protein-coupled receptor). A large number of epidemiologic studies conducted on manufacturing workers, pesticide applicators, and farming families do not indicate that triazines are carcinogenic in these populations. A rat-specific hormonal mechanism for mammary tumors has now been accepted by US EPA, International Agency for Research on Cancer, and the European Union. Chlorotriazines do influence endocrine responses, but their potential impact on humans appears to be primarily on reproduction and development and is not related to carcinogenesis. PMID- 21660820 TI - Oxidative stress and hepatotoxicity induced by synthetic pyrethroids organophosphate insecticides mixture in rat. AB - The effects of organophosphorus [fenitrothion (FNT)] and pyrethroid (lambda cyhalothrin (LC)] pesticides mixture on the antioxidant defense system and liver function enzymes in rat liver were assessed. Various concentrations of FNT+LC were incubated with liver homogenate at 37 degrees C for various incubation times. Results showed that FNT plus LC caused a significant concentration dependent and time-related inhibition of glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activities, and reduction of glutathione (GSH) content. The depletion of GSH might indicate that reactive oxygen species could be involved in the toxic effects of FNT plus LC. In addition, a significant inhibition in transaminases (AST, ALT) and phosphatases (AcP, AlP) activities was observed. On the other hand, FNT+LC increased the activity of lactate dehydrogenase (LDH) and thiobarbituric acid reactive substances (TBARS) levels. It can be concluded that such biomarkers may be used in assessing adverse/toxic effects of pesticides as environmental stressors. PMID- 21660821 TI - A survey of spontaneous occurrence of ochratoxin A residues in chicken tissues and concurrence with histopathological changes in liver and kidneys. AB - Toxicological and histopathological investigations of tissues of commercially slaughtered chickens were carried out to provide a preliminary evaluation of the incidence of occurrence of ochratoxin A (OTA) in chicken sold in Serbian retail market. In addition, the etiology of nephropathies of these chickens was elucidated. The majority of these tissue samples were not found to contain measurable amounts of OTA. Moreover, the OTA levels found in analyzed tissues were generally low and there was no positive correlation between the presence of OTA and the frequency of histopathological changes. Histopathological changes such as degenerative changes in the kidneys and liver differed from the classical description of the mycotoxic nephropathy, indicating that the chicken nephropathy observed in Serbia may have a multitoxic etiology with possible synergistic effect between microorganisms and natural toxins, usually present in low concentrations. The low OTA results also suggested that chicken meat available in the retail market in Serbia are unlikely to pose any significant adverse health risk to the consumers with respect to OTA toxicity. PMID- 21660822 TI - The (non)comparability of the correlation effect size across different measurement procedures: a challenge to meta-analysis as a tool for identifying "evidence based practices". AB - Meta-analysis is becoming a principal tool for research synthesis and for the identification and justification of evidence based practices. A fundamental assumption in meta-analysis is that effect sizes based upon different measures are comparable. Recent work has challenged this assumption in the case of the standardized mean difference. In this article it is shown that population universe (true) score level correlation effect sizes, for the relationship between two constructs A and B, based upon different measures will be comparable only if construct validity invariance holds across the measures used to make inferences to A and the measures used to make inferences to B. The results of a simulation study are also reported which show that the results of a meta-analysis may be significantly and adversely affected by violations of construct validity invariance. Finally, it is concluded that the theoretical results obtained in this article, and the results of the simulation study, combine to suggest that the role of meta-analysis in the synthesis of social work research, and in the identification of evidence based practices, be de-emphasized until important questions about the sensitivity of meta-analysis to violations of construct validity invariance are answered. PMID- 21660823 TI - Provider perceptions of the social work environment and the state of pediatric care in a downsized urban public academic medical center. AB - The author's purpose through this study was to document and analyze health provider perceptions of their social work environment and the state of pediatric care at Los Angeles County King/Drew Hospital and Medical Center in 2000, after the restructuring and downsizing of the hospital and its community clinics. The research results showed nurses and physicians reporting that both the quality of pediatric care and the provider social work environment were poor. Negative factors in the social work environment included: low employee morale, poorly staffed clinical teams, lack of professional autonomy, perceptions of low quality of care for pediatric patients, and interpersonal issues of poor communication and collaboration among providers. Providers also perceived a non-supportive work environment, sense of powerlessness, poor quality of work, lack of goal clarity from leadership, lack of fairness in leadership behavior, and an organizational leadership that is abandoning its core mission and values, thereby making it difficult for providers to carry out their professional functions. The author's findings in this study suggest a relationship between intra-role conflict, social employment environment and quality of care at King/Drew Medical Center in 2000. Lessons for practice are presented. PMID- 21660824 TI - A study of the learning styles of undergraduate social work students. AB - This study examines the learning styles of students in social work classes at Norfolk State University. Knowledge of learning styles can enhance the ability of faculty to build on student experiences and construct new learning opportunities. Kolb's Learning Style Inventory was administered to identify each student's dominate learning style. The theoretical underpinning is experiential learning, which supports the concept that learning styles are developed through experiences. The results indicated that diverging and accommodating learning styles occurred most often. Students with these styles learn best in classes where activities include lectures, role playing exercises, discussions, opportunities to practice skills, and reflection. PMID- 21660825 TI - A systematic review of evidence-based interventions for students with challenging behaviors in school settings. AB - The author's systematic review of 2,294 articles from 10 journals in the fields of education, special education, school social work, school psychology, and school counseling identified 42 articles meeting search criteria of addressing evidence-based interventions for students with challenging behaviors in school settings. Interventions were considered evidence-based if they were (a) manualized or structured to facilitate replication; (b) evaluated with an experimental design; and (c) demonstrated to be effective. Current practices available to address students who require evidence-based interventions for challenging behaviors are summarized. Suggestions for intervention development to address the needs of students with difficult behaviors are offered. PMID- 21660826 TI - The development of an evidence based assessment protocol for intimate partner violence in the U.S. Army. AB - The importance of conducting evidence based assessment has been widely acknowledged by many professions, including social work. In this study, the U.S. Army, in partnership with University researchers, developed an evidence based assessment protocol to assist the individual social worker in conducting his/her assessment of intimate partner violence. The protocol development process involved posing answerable research questions about intimate partner violence assessment content and method and then adhering to the steps of evidence based practice to answer those questions. Key to the protocol development process was the partnership created between researchers and practitioners as part of an expert panel. PMID- 21660827 TI - The Foreign Language Anxiety in a Medical Office Scale: developing and validating a measurement tool for Spanish-speaking individuals. AB - Communication research has been hindered by a lack of validated measures for Latino populations. To develop and validate a foreign language anxiety in a medical office scale (the Foreign Language Anxiety in a Medical Office Scale [FLAMOS]), the authors conducted a survey of low income, primarily Spanish speaking Latinos (N=100). The scale factored into a unidimensional construct and showed high reliability (alpha=.92). The Foreign Language Anxiety in a Medical Office Scale also demonstrated convergent and divergent validity compared with other communication anxiety scales (Personal Report of Communication Apprehension 24, Communication Anxiety Inventory, and Recipient Apprehension Test), and predictive validity for acculturation measures (the Short Acculturation Scale for Hispanics). The Foreign Language Anxiety in a Medical Office Scale provides a validated measure for researchers and may help to explain Latino health care communication barriers. PMID- 21660828 TI - Testing the effect of framing and sourcing in health news stories. AB - This study examines whether changing the way news stories report on health can induce shifts in readers' perceptions of problems of obesity, diabetes, immigrant health, and smoking. The authors manipulated two variables in a controlled experiment: the quality of sourcing-the number of sources and their expertise-and the framing-changing from an episodic, traditional frame to a thematic frame that incorporated information on context, risk factors, prevention strategies, and social attributions of responsibility. The authors found that a thematic frame made readers more supportive of public policy changes and encouraged them to improve their own health behaviors. However, it did not alter their attributions of responsibility for health problems from one of blaming individuals to seeing the larger social factors. Adding richer sourcing to the thematic frame did not increase these effects, nor did readers find the thematic stories to be more interesting, relevant, believable, important, and informative. In addition, there were differential results because of story topics that represent uncontrolled effects. The implications for improving health reporting to encourage positive change in society are discussed. PMID- 21660829 TI - Living kidney donor decision making and communication. AB - There is high demand for kidney donors in the United States, and it is widely accepted that living donation is optimal for individuals who need a kidney. Much research has focused on the potential recipient, but little has been studied about the communication and decision making of living kidney donors. Interviews assessed the communication and decision-making processes of 43 kidney donor volunteers. Almost all of the participants were not asked, but instead volunteered, to donate. The majority of donors reported having conversations with the recipient and speaking about their decisions with other individuals in their social networks besides the recipient. Some participants said that they stopped talking to others because of negative feedback. Future research should further examine the communication of donors with non-recipient others and potential methods of training recipients and donors to communicate effectively about the donation process. PMID- 21660831 TI - NIOSH Manual of Analytical Methods 5th Edition--new resources and direction. PMID- 21660830 TI - Development of solvent exposure index for construction painters. AB - This article describes methodological approaches for reconstructing long-term occupational exposure to organic solvents among construction painters. A detailed exposure questionnaire was administered to 125 painters to develop a job exposure matrix (JEM). The questionnaire inquired about painting activities with solvent based paints and use of protection equipment for the previous 25 years in 5-year intervals. Current and historical distributions of solvent air concentrations were assessed for the same time period based on the following information: industrial hygiene measurements, paint composition changes, and VOC emission rate changes from architectural and industrial maintenance coatings. Changes in protection factors of respirators were also assessed. A cumulative solvent exposure index was calculated for each painter through Monte Carlo simulations by combining appropriate input distributions of solvent air concentrations and protection factors of respirators with JEM. Sensitivity simulations revealed that the historical variations in solvent air concentrations had a higher impact on the cumulative solvent exposure index than changes in protection factors for respirators. Fifty-eight percent of painters were classified with a different exposure quartile when the solvent exposure index was used vs. an exposure based only on years using solvent-based paints, suggesting the need for more detailed exposure analysis than just years working when conducting epidemiologic studies for this worker population. PMID- 21660832 TI - Supplemental personal noise sampling data. PMID- 21660834 TI - Effects of liquid cooling garments on recovery and performance time in individuals performing strenuous work wearing a firefighter ensemble. AB - This study investigated the effects of body cooling using liquid cooling garments (LCG) on performance time (PT) and recovery in individuals wearing a fully equipped prototype firefighter ensemble (PFE) incorporating a self-contained breathing apparatus (SCBA). Six healthy male participants (three firefighters and three non-firefighters) completed six experimental sessions in an environmental chamber (35 degrees C, 50% relative humidity), consisting of three stages of 15 min exercise at 75% VO2max, and 10 min rest following each exercise stage. During each session, one of the following six conditions was administered in a randomized order: control (no cooling, CON); air ventilation of exhaust SCBA gases rerouted into the PFE (AV); top cooling garment (TCG); TCG combined with AV (TCG+AV); a shortened whole body cooling garment (SCG), and SCG combined with AV (SCG+AV). Results showed that total PT completed was longer under SCG and SCG+AV compared with CON, AV, TCG, and TCG+AV (p<0.01). Magnitude of core temperature (Tc) elevation was significantly decreased when SCG was utilized (p<0.01), and heart rate recovery rate (10 min) was enhanced under SCG, SCG+AV, TCG, and TCG+AV compared with CON (p<0.05). Estimated Esw rate (kg.h(-1)) was the greatest in CON, 1.62 (0.37), and the least in SCG+AV 0.98 (0.44): (descending order: CON>AV>TCG=TCG+AV>SCG>SCG+AV) without a statistical difference between the conditions (p<0.05). Results of the present study suggest that the application of LCG underneath the PFE significantly improves the recovery during a short period of rest and prolongs performance time in subsequent bouts of exercise. LCG also appears to be an effective method for body cooling that promotes heat dissipation during uncompensable heat stress. PMID- 21660833 TI - Exposure assessment in auto collision repair shops. AB - Workers in auto collision shops are exposed to a variety of chemical and physical hazards. Previous studies have focused on measuring levels of isocyanates, but little is known about exposures to dust, noise, and solvents. In preparation for an intervention effectiveness study in small collision repair businesses, sampling was conducted on 3 consecutive days in four representative businesses with three to seven employees. Full-shift and task-specific exposures were measured for dust and solvents (for operations other than painting and spray gun cleaning). Full-shift personal exposures and tool-specific noise levels were also evaluated. Samples of banded earplugs were distributed to employees and feedback was collected after 1 week of wear time. Dust and solvent exposures did not exceed the OSHA PELs. Noise exposure doses were below the OSHA PEL; however, 4 of the 18 measurements were in excess of the ACGIH(r) threshold limit value. The majority of tools generated noise levels above 85 dBA. Air guns, wrenches, cutoff wheels, and air drills generated noise levels with the 5th percentile above 90 dBA. Mean noise levels generated by hammers, grinders, and ratchets were also above 95 dBA. Three pairs of banded earplugs had the best reviews in terms of comfort of use. This study was conducted during a time when all shops reported relatively low production levels. Noise exposure results suggest that it is likely that technicians' 8-hr time-weighted average exposures may be in excess of 85 dBA during periods of higher production, but exposures to dust and solvents are unlikely to approach OSHA exposure limits. These pilot test results will be useful when developing recommendations and technical assistance materials for health and safety interventions in auto collision repair businesses. PMID- 21660835 TI - Correlates of male condom use skills among high-risk women in South Africa. AB - This exploratory study examined the performance of 295 South African women--who recently traded sex for goods or had unprotected sex--on a male condom use mastery index. Bivariate and multivariate logistic regression analyses were conducted to determine whether age, marital status, highest education obtained, male condom use at first penetrative sex, receiving prior demonstration of male condom use, recent sexually transmitted infection symptoms, and recently trading sex were significantly associated with index scores. Adjusted odds ratios indicated that age and sexually transmitted infection symptoms were negatively associated with condom skills; women who were older and had a higher number of recent sexually transmitted infection symptoms were more likely to have lower scores. Furthermore, participants executed, on average, approximately one third of condom use steps correctly. These findings suggest a need for increased behavioral skills training for women engaging in sexual risk behaviors because many lack the skills required to use a male condom properly. PMID- 21660836 TI - A content analysis of the prevalence and portrayal of sexual activity in adolescent literature. AB - Most research on sexual content in the media has focused on visual images such as those in TV, film, advertisements, and magazines. However, researchers have largely overlooked sexual content in novels. The popularity of novels and the potential for such literature to educate teens on sexual behaviors merits a closer examination into the sexual messages contained in popular adolescent literature. This study content analyzes the top 40 novels targeting adolescents. Results show that adolescent novels are replete with sex-related information, especially in novels targeted to girls. These sexual behaviors range from passionate kissing and romantic ideation to sexual intercourse. Over one third of the instances focus on references to sex, suggestive innuendos, or sexual descriptions; and an additional one third of sexual behavior involved sexual affection in the form of passionate kissing, intimate touching, and playful sexual behavior. Across the 40 books, there were 56 instances of sexual intercourse, most of which involved unmarried couples (94%); and many were in non committal relationships. Moreover, sexual material rarely dealt with issues of abstinence, safe sex practices, and the health risks associated with sex. PMID- 21660837 TI - Exploring the intention-behavior relationship in the prediction of sexual risk behaviors: can it be strengthened? AB - Many theoretical models examining health risk behaviors, such as sexual risk taking, assume intentions directly predict behavior, and intentions are sometimes measured as a proxy for behavior. Given that there is often a discrepancy between intentions and behaviors (e.g., Sheeran, 2002 ), this study addressed factors that predict intention-behavior congruence. Specifically, utilizing a prospective design, the goal of the study was to determine if characteristics of university students' last sexual encounter predicted whether those students who intended to use condoms, contraception, or dual methods did so in their last sexual encounter with both relationship and casual partners. The seven tested variables were condom planning and preparatory behaviors, mood, sexual arousal, substance use, perceived partner attractiveness, intention certainty, and intention stability. Data were collected from 520 American undergraduate students at a medium-sized university. The six discriminant function analyses examining the intention behavior relationship were able to correctly classify between 74% and 92% of the participants concerning whether intenders engaged in safe sex behaviors. The variables that best discriminated between behavior engagement over the six analyses were intention stability, intention certainty, and engagement in condom preparatory behaviors. The implications of these results for sexual risk prevention and intervention research are discussed. PMID- 21660838 TI - Carbohydrates for training and competition. AB - An athlete's carbohydrate intake can be judged by whether total daily intake and the timing of consumption in relation to exercise maintain adequate carbohydrate substrate for the muscle and central nervous system ("high carbohydrate availability") or whether carbohydrate fuel sources are limiting for the daily exercise programme ("low carbohydrate availability"). Carbohydrate availability is increased by consuming carbohydrate in the hours or days prior to the session, intake during exercise, and refuelling during recovery between sessions. This is important for the competition setting or for high-intensity training where optimal performance is desired. Carbohydrate intake during exercise should be scaled according to the characteristics of the event. During sustained high intensity sports lasting ~1 h, small amounts of carbohydrate, including even mouth-rinsing, enhance performance via central nervous system effects. While 30 60 g . h(-1) is an appropriate target for sports of longer duration, events >2.5 h may benefit from higher intakes of up to 90 g . h(-1). Products containing special blends of different carbohydrates may maximize absorption of carbohydrate at such high rates. In real life, athletes undertake training sessions with varying carbohydrate availability. Whether implementing additional "train-low" strategies to increase the training adaptation leads to enhanced performance in well-trained individuals is unclear. PMID- 21660839 TI - Nutrition guidelines for strength sports: sprinting, weightlifting, throwing events, and bodybuilding. AB - Strength and power athletes are primarily interested in enhancing power relative to body weight and thus almost all undertake some form of resistance training. While athletes may periodically attempt to promote skeletal muscle hypertrophy, key nutritional issues are broader than those pertinent to hypertrophy and include an appreciation of the sports supplement industry, the strategic timing of nutrient intake to maximize fuelling and recovery objectives, plus achievement of pre-competition body mass requirements. Total energy and macronutrient intakes of strength-power athletes are generally high but intakes tend to be unremarkable when expressed relative to body mass. Greater insight into optimization of dietary intake to achieve nutrition-related goals would be achieved from assessment of nutrient distribution over the day, especially intake before, during, and after exercise. This information is not readily available on strength power athletes and research is warranted. There is a general void of scientific investigation relating specifically to this unique group of athletes. Until this is resolved, sports nutrition recommendations for strength-power athletes should be directed at the individual athlete, focusing on their specific nutrition related goals, with an emphasis on the nutritional support of training. PMID- 21660840 TI - Effect of Andrographis paniculata leaf extract on wound healing in rats. AB - This work was carried out to study the effect of topical application of Andrographis paniculata on the rate of wound enclosure and its histological features. A wound was created in four groups of rat in posterior neck region. Blank placebo was applied topically to the wounds of Group 1. Groups 2 and 3 were dressed with placebo containing 5% and 10% extracts of A. paniculata, respectively. Intrasite gel was applied topically to the wounds of Group 4. Macroscopical examination revealed that the rate of wound healing was significantly accelerated in the wound dressed with A. paniculata extract compared to the blank placebo. The wounds dressed with 10% extract or Intrasite gel healed earlier compared to the wounds dressed with placebo containing 5% A. paniculata extract. Histologically, wounds dressed with A. paniculata extracts showed markedly less scar width and contained large amounts of fibroblast proliferation. More collagen and less angiogenesis with absence of inflammatory cells were seen for wounds dressed with 10% A. paniculata compared to the blank placebo. Conclusion, A. paniculata extracts significantly enhanced rate of wound healing in rats. PMID- 21660841 TI - The effects of Brazilian and Bulgarian propolis in vitro against Salmonella Typhi and their synergism with antibiotics acting on the ribosome. AB - Salmonella enterica serovar Typhi is the causative agent of typhoid fever in humans, and the use of antibiotics is essential for controlling this infection; however, the excessive use of antibiotics may select resistant strains. Propolis is a honeybee product and its antimicrobial activity has been intensively investigated. Thus, the objective of this study was to investigate a possible synergism between propolis (collected in Brazil and Bulgaria) and antibiotics acting on the ribosome (chloramphenicol, tetracycline and neomycin) against Salmonella Typhi in vitro. The synergism was investigated by using 1/2 and 1/4 of the minimum inhibitory concentration for propolis and these antimicrobial agents, evaluating the number of viable cells according to the incubation time. Brazilian propolis showed a bacteriostatic action against S. Typhi, while Bulgarian propolis showed a bactericidal activity and a synergistic effect with the three antibiotics. Variations in the biological assays might be due to the differences in their chemical compositions. Based on the results, one may conclude that Bulgarian propolis showed an important antibacterial action, as well as a synergistic effect with antibiotics acting on the ribosome, which points out a possible therapeutic strategy evaluating the use of propolis preparations for the treatment of Salmonella Typhi infection. PMID- 21660842 TI - Involvement of central noradrenaline, serotonin and dopamine system in the antidepressant activity of fruits of Solanum torvum (Solanaceae). AB - The methanolic extract (ME) of Solanum torvum seeds and its ethyl acetate fraction (EAF) were investigated for their antidepressant activity using behavioral (forced swim test, FST and tail suspension test, TST) and biochemical (monoamine oxidase, MAO reduced activity) tests. ME (10, 30 and 100 mg kg(-1)) and EAF (10 and 30 mg kg(-1)) dose dependently inhibited the immobility period, increased noradrenaline, serotonin and dopamine levels and inhibited the MAO enzymes in FST and TST using mice. Furthermore, we have observed antagonism between the threshold dose of ME (30 and 100 mg kg(-1)) and EAF (10 and 30 mg kg( 1)) with antagonists on behaviour mediated by neurotransmitters noradrenaline, serotonin and dopamine. MAO-A inhibition was more prominent as compared to MAO-B inhibition. The study provides evidence for antidepressant actions of S. torvum. PMID- 21660843 TI - Serological survey of Toxoplasma gondii and Campylobacter fetus fetus in sheep from New Zealand. AB - AIM: To determine the prevalence of antibody titres to Toxoplasma gondii and Campylobacter fetus fetus in sheep from New Zealand. METHODS: As part of a free screening service, unsolicited blood samples were supplied by veterinarians wishing to gauge the exposure of their clients' ewe flocks to T. gondii and C. fetus fetus. Blood samples were submitted from mixed-age ewes throughout New Zealand, from 2006 to 2009, that had not been vaccinated for T. gondii and C. fetus fetus. A total of 2,254 sera were serologically titrated for T. gondii and 3,429 for C. fetus fetus. A latex agglutination kit available commercially was used to quantify antibodies to T. gondii, and an agglutination test developed in house was used for C. fetus fetus. For T. gondii, titres of >=1:16 and >=1:64 were used to define a positive response, and for C. fetus fetus a titre of >=1:10 was defined as positive. A flock was defined as positive if >=1 ewe had a positive titre. RESULTS: Of the sera tested for T. gondii, 1,917/2,254 (85%) were positive, using a titre of >=1:16, and 1,384/2,254 (61%) with a titre of >=1:64. All 198 ewe flocks tested were seropositive to T. gondii, at a titre of >=1:16, and all but three were at a titre of >=1:64. A bimodal distribution was evident in the prevalence of titres to T. gondii suggesting that a percentage of titres <=1:64 may have been non-specific. Of the sera tested for C. fetus fetus, 1,644/3,429 (48%) were positive to at least one of the four test antigens at titre of >=1:10. Only 34/298 (11%) flocks tested for C. fetus fetus were completely seronegative. The percentage of seropositive ewes to both T. gondii and C. fetus fetus was significantly higher in the North Island than the South Island. CONCLUSIONS: The study demonstrated that exposure to these two important infectious abortifacients was both considerable and widespread. Minimum titres were postulated to establish a 'cut-off' for a positive result and to allow comparison with past and future studies. The bimodal distribution evident for T. gondii suggested a titre of 1:64 may be an appropriate cut-off. The widespread on farm exposure probably stimulates the immune response of vaccinated ewes. CLINICAL RELEVANCE: Further studies are required to confirm the clinical significance of flock-based antibody responses, and to validate their use in identifying recently aborted ewes, especially where there are no aborted fetuses for examination. PMID- 21660844 TI - A retrospective study of post-mortem examination findings in takahe (Porphyrio hochstetteri). AB - AIMS: To identify the major diseases or disease processes affecting both captive and wild populations of takahe (Porphyrio hochstetteri) in birds submitted for post-mortem examination between 1992 and 2007, and to survey archived wild dead takahe for the presence of Erysipelothrix rhusiopathiae. METHODS: Reports of 199 post-mortem examinations submitted between 1992 and 2007 were reviewed retrospectively. The reports comprised 56 eggs, 51 chicks up to 6 months of age, 13 sub-adults 6-18 months old, 74 adults and five birds where age was not recorded. Bone marrow flushed from the keel of 34 frozen adult takahe was assayed for the presence of E. rhusiopathiae, using PCR analysis. RESULTS: Of the eggs examined, 6/56 (11%) had no recorded diagnosis, 24/56 (43%) were infertile and 26/56 (46%) showed embryonic mortality at various stages. Excluding eggs, the cause of death could not be determined in 64/138 (46%) birds with a recorded age that were examined. Contributing factors for the low rate of diagnosis included advanced decomposition of many carcasses, the freezing of some birds prior to pathological investigation, long delays between recovery and submission for post mortem examination, and variation in the extent of post-mortem examination and ancillary diagnostic testing. Common post-mortem examination findings in chicks included those related to cardiac disease [11/51 (22%)], infectious or inflammatory disease [9/51 (18%)] and trauma [7/51 (14%)]. In adult birds, the most common post-mortem examination findings were due to infectious or inflammatory disease [15/74 (20%)] including septicaemia due to E. rhusiopathiae [3/74 (7%)], followed by degenerative conditions due to diet, age and husbandry [9/74 (12%)]. Bacteria implicated in the causes of death included Escherichia coli, E. rhusiopathiae, Salmonella enterica serovar Typhimurium, and Pseudomonas aeruginosa. Only 1/34 (3%) of the frozen carcass examined using PCR was positive for E. rhusiopathiae. CONCLUSIONS: This study highlights a need for improved recovery, storage and submission of dead takahe for pathological examination; consistency in post-mortem examination, ancillary testing and recording of findings; and finally, regular communication between wildlife pathologists, conservation workers and representatives of Ngai Tahu. PMID- 21660845 TI - The comparative efficacy of two long-acting dry-cow cephalonium products in curing and preventing intramammary infections. AB - AIMS: To test equivalence between two different cephalonium dry-cow therapy (DCT) products with regard to the incidence of bacteriological cure of existing infections of quarters, the incidence of new intramammary infections (IMI) from 2 5 days postpartum and the incidence of clinical mastitis from drying-off to 21 days postpartum. METHODS: All cows (n=1,570) on four commercial dairy farms in Southland were eligible for inclusion. Power analysis using a variance inflation factor indicated a required minimum of 2,101 quarters per treatment group. Cows were blocked by herd, parity, previous history of mastitis and most recent somatic cell count (SCC), and then randomly allocated to either of two cephalonium treatments at the cow level, viz the treatment group (new formulation cephalonium) or the positive control group (existing reference formulation cephalonium). All quarters within a cow were assigned the same treatment. Samples collected from all quarters with a SCC >=500,000 cells/mL at drying-off, and those with a positive culture postpartum were cultured, as well as samples from all quarters collected between 2-5 days postpartum. All cases of mastitis were recorded and sampled for culture. The risk of quarter-level incidence of bacteriological cure, IMI and clinical mastitis was modelled using a GLM and generalised estimating equation (GEE), including the effects of treatment group, age,farm, udder-health status at drying-off and length of dry period. RESULTS: For 829 infected quarters, the estimated incidence of bacteriological cure for all pathogens was 78.0 (95% CI=64.3-91.6)% for the treatment group and 75.7 (95% CI=61.6-89.8)% for the positive control group (p=0.71). Incidence of cure varied with the farm (p=0.001), type of pathogen pre-treatment (p=0.009) and log(10)SCC at drying-off (p<0.001). For 4,530 quarters, the estimated incidence of new IMI, with any pathogen, for treatment and positive control groups was 16.1 (95% CI=13.1-19.7)% and 16.0 (95% CI=13.0-19.5)% respectively (p=0.91). Incidence of IMI varied with farm (p<0.001), pathogen and SCC status before treatment (p<0.001), and length of the dry period (in days) (p<0.001). For 5,136 quarters, the estimated incidence of clinical mastitis was 1.0 (95% CI=0.5-1.7)% in the treatment group and 1.1 (95% CI=0.6-2.0)% in the positive control group (p=0.64). CONCLUSIONS: Use of the two different cephalonium products at drying-off in four dairy herds in Southland resulted in equivalence with respect to incidence of bacteriological cure of existing infections, incidence of new IMI postpartum, and incidence of clinical mastitis in early lactation. PMID- 21660846 TI - Prevalence of Salmonella spp., and serovars isolated from captive exotic reptiles in New Zealand. AB - AIM: To investigate the prevalence of Salmonella spp. in captive exotic reptile species in New Zealand, and identify the serovars isolated from this population. METHODS: Cloacal swabs were obtained from 378 captive exotic reptiles, representing 24 species, residing in 25 collections throughout New Zealand between 2008 and 2009. Samples were cultured for Salmonella spp., and suspected colonies were serotyped by the Institute of Environmental Science and Research (ESR). RESULTS: Forty-three of the 378 (11.4%) reptiles sampled tested positive for Salmonella spp., with 95% CI for the estimated true prevalence being 12-25% in exotic reptiles in this study population. Lizards tested positive for Salmonella spp. more often than chelonians. Agamid lizards tested positive more often than any other family group, with 95% CI for the estimated true prevalence being 56-100%.. Six Salmonella serovars from subspecies I and two from subspecies II were isolated. The serovar most commonly isolated was S. Onderstepoort (30.2%), followed by S. Thompson (20.9%), S. Potsdam (14%), S. Wangata (14%), S. Infantis (11.6%) and S. Eastbourne (2.3%). All of the subspecies I serovars have been previously reported in both reptiles and humans in New Zealand, and include serovars previously associated with disease in humans. CONCLUSIONS AND CLINICAL RELEVANCE: This study showed that Salmonella spp. were commonly carried by exotic reptiles in the study population in New Zealand. Several serovars of Salmonella spp. with known pathogenicity to humans were isolated, including S. Infantis, which is one of the most common serovars isolated from both humans and non-human sources in New Zealand. The limitations of this study included the bias engendered by the need for voluntary involvement in the study, and the non-random sampling design. Based on the serovars identified in this and previous studies, it is recommended native and exotic reptiles be segregated within collections, especially when native reptiles may be used for biodiversity restoration. Veterinarians and reptile keepers are advised to follow hygiene protocols developed to minimise reptile-associated salmonellosis. PMID- 21660847 TI - Haemodynamics of lambs grazing perennial ryegrass (Lolium perenne L.) either infected with AR6 novel, wild-type endophyte, or endophyte-free. AB - AIM: To compare vasoconstriction of the auricular artery and characteristics of blood flow in the carotid arteries between lambs grazing perennial ryegrass that was either infected with the AR6 novel endophyte (AR6), wild-type endophyte or endophyte-free. METHODS: Sixteen Coopworth lambs, mean 23.7 (SD 1.8) kg, were randomly assigned to graze three, 0.10-ha pastures of perennial ryegrass (cultivar Extreme) located in Lincoln, New Zealand, that were infected with either the AR6 novel endophyte (n=5) or wild-type endophyte (n=6) or were endophyte-free (n=5), for 18 days until 16 March 2009. Lambs on AR6 pasture were then switched to endophyte-free pasture, and those on endophyte-free were switched to AR6 pasture, for 18 days. Lambs continued grazing the wild-type ryegrass during both phases of the study. Colour Doppler ultrasonography was used to monitor cross-sectional area of lumina in the auricular and carotid arteries as measurements of vasoconstriction, and to measure pulsatility indices, heart rate, systolic and diastolic velocities, and mean velocity in the carotid artery. Urine was sampled once during each phase, to measure the concentration of urinary alkaloids. A heat challenge (32 degrees C) was imposed on the last day of the experiment, to determine treatment effects on rectal temperature and respiration rate. RESULTS: Vasoconstriction was detected in the auricular arteries of lambs grazing AR6 and wild-type pastures. Areas of lumina declined linearly over 9 days in lambs that were switched from endophyte-free to AR6 pastures (p<0.05), and areas increased linearly in lambs that were switched from AR6 to endophyte-free pasture (p<0.001). Resistance to blood flow in the carotid arteries decreased linearly in the 9 days after lambs were switched from AR6 to endophyte-free pasture(p<0.05), and tended to increase after lambs on endophyte-free pasture were switched to AR6 (p<0.10). The concentrations of urinary alkaloids decreased after switching lambs from AR6 to endophyte-free pasture, and increased after switching from endophyte-free to AR6 pasture (p<0.05). The concentrations of urinary alkaloids of lambs on wild-type pasture were similar between the conditioning and experimental phases. There were no treatment effects on rectal temperature and respiration rate during the heat challenge. CONCLUSIONS: These results indicated that management approaches are needed to overcome potential vulnerabilities to heat stress for sheep grazing AR6 perennial ryegrass. Furthermore, following grazing such pasture, lambs will need to graze endophyte free ryegrass for >18 days, to completely clear ergot alkaloids from their vasculature, assuming that complete clearance can be achieved. PMID- 21660848 TI - Inflammatory responses to Mycoplasma hyopneumoniae in murine alveolar macrophage cell lines. AB - AIM: To investigate the mechanism by which Mycoplasma hyopneumoniae induces inflammatory responses in murine alveolar macrophage (MH-S) cells. METHODS: A pathogenic strain of M. hyopneumoniae cultured in modified Friis medium was used to investigate the inflammatory response in MH-S cell lines. The effect of stimulation by M. hyopneumoniae on the production of nitric oxide (NO) and cytokines in MH-S cells and inhibition of their production, using specific inhibitors of signalling pathways, was investigated using the Griess reaction and ELISA respectively. A Western blot assay was used to confirm activation of the nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways. Nuclear translocation of NF-kappaB was further confirmed using transient transfection and luciferase gene reporter assay. RESULTS: The results revealed dose-dependent production of NO in MH-S cells stimulated by M. hyopneumoniae. Increased concentrations of the cytokines tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta and IL-6 were also observed (p<0.05). Using immunoblot analysis, involvement of three MAPK pathways, extracellular signal-regulated kinase I/II (ERK1/2), p38 and Jun N-terminal kinases/stress activated protein kinases (JNK/SAPK) was confirmed. Specific inhibitors of signal pathways also demonstrated their effect on the NO and cytokine responses of MH-S cells. Degradation and phosphorylation of inhibitory kappa B (IkappaB)-alpha was observed, while the luciferase gene reporter assays revealed activation of NF kappaB after stimulation by M. hyopneumoniae. Inhibition of NF-kappaB by pyrrolidine dithiocarbamate decreased M. hyopneumoniae-induced production of NO and IL-1beta (p<0.05), whereas no inhibitory effect was observed on concentrations of TNF-alpha, and IL-6. CONCLUSION: These findings indicate that M. hyopneumoniae induces NO and pro-inflammatory cytokines, and NF-kappaB and the three MAPK pathways are involved in the process. PMID- 21660849 TI - Vaccination for leptospirosis improved the weaning percentage of 2-year-old farmed red deer hinds in New Zealand. AB - AIM: To investigate the effect of leptospiral vaccination against serovars Hardjo bovis and Pomona on fetal loss and weaning percentage in rising 2-year-old farmed red deer hinds. METHODS: In mid-February 2007, 252 rising 2-year-old hinds on four farms received a single dose of streptomycin (25 mg/kg), to minimise leptospiral infection. They were randomly allocated to vaccinated and control groups. Vaccinated hinds (n=125) received a 2-ml S/C injection of a bivalent whole-cell killed leptospiral vaccine (Leptavoid-2) followed by a booster 4-6 weeks later, and were grazed with control hinds (n=127). These animals were isolated from other hinds on each property, until after mating (June 2007), when all vaccinated and control hinds were combined with hinds not treated with streptomycin, for maximum exposure to natural leptospiral challenge. Evidence of natural challenge by Leptospira spp. was assessed in blood samples from control hinds by serology against L. borgpetersenii serovar Hardjo-bovis and L. interrogans serovar Pomona, using the microscopic agglutination test (MAT), and in hinds not treated with streptomycin by detection of shedding of organisms in urine, using bacterial culture and real-time PCR. Pregnancy diagnosis was carried out in May/June 2007, using transrectal ultrasonography, to determine conception. In late October, prior to calving, the pregnant vaccinated and control hinds were examined by palpation of the abdomen and udder, to determine the percentage of hinds pregnant at term and assess fetal loss. In March 2008, at weaning, vaccinated and control hinds were examined for lactation status, using observation and palpation of the udder. The differences between the groups were evaluated using matched logistic regression analysis. RESULTS: After mating, pregnancy was diagnosed in 97/125 (77.6%) vaccinated and 106/127 (83.5%) control hinds. All four farms had serological evidence of Hardjo-bovis infection, and a single hind was serologically positive for Pomona between October and March. Real time PCR confirmed urinary shedding on two farms. The mean percentage of hinds pregnant at term, for those animals confirmed pregnant after mating, in the vaccinated and control groups was 95/97 (98%) (range 95-100%) and 103/106 (97%) (range 94-100%), respectively (p>0.05). The mean weaning percentage for vaccinated and control groups was 86/97 (89%) (range 78-95%) and 88/106 (83%) (range 76-88%), respectively (p=0.015). CONCLUSION: Vaccination for leptospirosis resulted in no difference in the percentage of hinds pregnant at term, but a higher weaning percentage compared with unvaccinated controls suggesting that vaccination reduced perinatal and/or pre-weaning mortality. PMID- 21660851 TI - Idiopathic canine juvenile cranial hyperostosis in a Pit Bull Terrier. AB - CASE HISTORY: An 8-month-old male Pit Bull Terrier was presented with bilateral firm swellings of the cranium in the region of the frontal sinuses. The dog was aggressive when approached and had also been anorexic during the 3.5 days prior to presentation. CLINICAL FINDINGS: Using computed tomography (CT) and radiology, periosteal new bone formation and hyperostosis were detected on the frontal, parietal and mandibular bones bilaterally. Histopathology of the calvarial and mandibular bones was similar, comprised of thick trabeculae of immature woven and mature lamellar bone separated by cementing lines. Sites of prominent osteoblastic and osteoclastic activity were also present. DIAGNOSIS: Craniomandibular osteopathy with clinical similarities to calvarial hyperostosis. CLINICAL RELEVANCE: Pit Bull Terriers are not predisposed to either craniomandibular osteopathy or calvarial hyperostosis. This observation, in addition to the clinical and pathological similarities between the two diseases, suggests that craniomandibular osteopathy and calvarial hyperostosis may represent a single disorder, with predilection sites that vary between breeds of dog. We propose a new term, idiopathic canine juvenile cranial hyperostosis, for this disorder, to include both craniomandibular osteopathy and calvarial hyperostosis. PMID- 21660850 TI - Possible subclinical hepatopathy after copper supplementation in farmed red deer. AB - AIM: To determine the effect of parenteral supplementation with Cu on the activities of hepatic enzymes in deer with adequate concentration(s) of Cu in liver and serum. METHODS: Male red deer aged 12 months were given either 0.8 or 1.6 mg of Cu/kg of a S/C injectable Cu formulation or no Cu (n=10/group) on 03 December 2007 (Day 0). Concentration of Cu in liver was measured in biopsies taken on Days -13 and 17, and that in serum on Days 0, 1, 3 and 17. Liver enzymes, gamma-glutamyl transferase (GGT) and glutamate dehydrogenase (GDH), were measured in serum on Days 3 and 7. Deer were weighed on Days 0 and 17. RESULTS: The mean concentration of Cu in liver was 203 (range 50-460) MUmol/kg fresh weight (FW) on Day -13 and that in serum was 14.8 (range 7.8-25.0) MUmol/mL on Day 0. Concentrations of Cu in liver were adequate (>100 MUmol/kg FW) in 25/30 deer. Injection with 0.8 mg of Cu/kg resulted in elevated mean concentrations of Cu in serum to 20.3 (range 14-26) and 17.4 (range 12-26) MUmol/mL on Days 1 and 3 respectively, whereas 1.6 mg/kg resulted in mean concentrations of Cu in serum of 26.7 (range 20-42) and 19.3 (range 16-25) MUmol/mL on Days 1 and 3 respectively (p<0.05). The mean concentration of Cu in liver on Day 17 was 1,460 (range 1,000 2,300) after injection with 0.8 mg/kg, 1,666 (range 1,100-2,200) after 1.6 mg/kg, and 280 (range 75-420) MUmol/kg FW in controls. Injection with 1.6 mg Cu/kg, but not 0.8 mg/kg, resulted in an increase in the activity of GGT (p=0.05), and in 4/10 deer a marked change in the activity of GDH, between Day 3 and Day 7, indicating that injection of copper induced a moderate degree of subclinical hepatopathy. Mean liveweight gain (g/day) to Day 17 was 105.9 (range -176 to 411) in control animals and 64.7 (range -59 to 176) 64.7 and -61.7 (range -294 to 117) in deer given 0.8 and 1.6 mg/Cu/kg respectively (p=0.003). CONCLUSIONS: S/C administration of 1.6 mg of Cu/kg in deer which had adequate Cu status pre treatment resulted in elevated activities of GGT and GDH in serum, indicating hepatopathy, and both this dose rate and 0.8 mg/kg resulted in reduced liveweight gain post-treatment compared with untreated controls. CLINICAL SIGNIFICANCE: Cu supplementation should not be administered when the Cu status of deer is adequate or unknown. PMID- 21660856 TI - Induction of apoptosis by gamma-tocotrienol in human cancer cell lines and leukemic blasts from patients: dependency on Bid, cytochrome c, and caspase pathway. AB - Tocotrienols (Toc3) have been suggested to possess anticancer effects besides antioxidant and antiinflammatory effects. Previous studies have demonstrated that Toc3 induce apoptosis in epithelial carcinoma. However, the effects of Toc3 on malignant hematopoietic cells have not yet been thoroughly investigated. We investigated Toc3-induced apoptosis in human hematological cancer cell lines. alpha-, delta-, and gamma-Toc3 induced concentration-dependent apoptosis, and gamma-Toc3 demonstrated more effective induction than the other Toc3 derivatives in HL-60 cells. gamma-Toc3 may have induced apoptosis by activation of the caspase cascade, cytochrome c (Cyt.c) release, Bid cleavage, and mitochondorial membrane depolarization in HL-60, NB-4, Raji, and SY-5Y cells. Furthermore, 10-30 MUM gamma-Toc3 showed cytotoxicity for leukemic cells from various patients regardless of lymphoblastic, myeloblastic, or relapsed leukemia, but the cytotoxic effect was weak in normal mononuclear cells, interestingly. gamma-Toc3 may have a role in cancer prevention and potential for treating hematological malignancies. PMID- 21660857 TI - GST polymorphisms and potential chemopreventive strategies in individuals at risk for lung cancer. PMID- 21660858 TI - Food, beverage, and macronutrient intakes in postmenopausal Caucasian and Chinese Canadian women. AB - International differences in breast cancer rates and diet, and studies in migrants, suggest that diet may be a modifiable risk factor for breast cancer. The goal of this cross-sectional study was to examine the dietary intakes of women from populations considered to be at different risks for breast cancer. We collected four 24-h food recalls in 3 groups of postmenopausal Canadian women: Caucasians (n = 392), Chinese women born in the West or who migrated to the West before age 21 (n = 156), and recent Chinese migrants (n = 383). Compared to Caucasians, recent Chinese migrants had lower energy and fat intakes and higher protein and carbohydrate intakes. Recent Chinese migrants consumed higher amounts of grains, vegetables, fish, and soy and lower amounts of alcohol, meat, dairy products, and sweets than Caucasians. Western-born Chinese and early Chinese migrants had intakes intermediate between the other 2 groups. The differences in intake between the ethnic groups suggest foods and nutrients that may contribute to the differences in risk of breast cancer between women in Canada and China. Future work will examine whether these dietary differences are associated with biological markers of breast cancer risk. PMID- 21660859 TI - Dietary patterns and risk of adenocarcinoma of the lung in males: a factor analysis in Uruguay. AB - In the period 1996-2004, a hospital-based case-control study on diet and adenocarcinoma of the lung in men was conducted in Montevideo, Uruguay. The study included 200 cases and 800 controls, frequency matched on age, residence, and interviewers. Factor analysis (principal components) was used to identify the major food patterns associated with adenocarcinoma. The analysis of food groups led to the identification of 4 patterns, arbitrarily labeled as Western, starchy vegetables, prudent, and milk/coffee. Whereas the Western pattern (OR 1.94, 95% CI 1.08-3.45) and the milk/coffee pattern (OR 2.30, 95% CI 1.35-3.90) were positively associated with risk of adenocarcinoma of the lung, the starchy vegetables (OR 0.49, 95% 0.28-0.86) and prudent patterns (OR 0.54, 95% CI 0.32 0.92) were significantly protective against this malignancy. The results suggests that adenocarcinoma of the lung could be considered a different nosologic entity, compared with the other histologies of lung cancer. PMID- 21660861 TI - The effects of social capital and social pressure on the intention to have a second or third child in France, Germany, and Bulgaria, 2004-05. AB - This study investigates the importance of the effect of an individual's web of informal relationships with family and peers on the intention to have a second or third child. Drawing on sociological theories of social capital (help with childcare, emotional support) and social pressure, the study extends existing research by evaluating cross-national differences (between France, Germany, and Bulgaria) in the impact of personal network and institutional circumstances. It tests a non-linear relationship between social capital and fertility intentions. Social pressure and social capital are highly institutionally filtered, with the impact of personal network stronger where institutions are less family supportive. PMID- 21660862 TI - Statistical optimization of single-cell production from Taxus cuspidata plant cell aggregates. AB - Flow-cytometric characterization of plant cell culture growth and metabolism at the single-cell level is a method superior to traditional culture average measurements for collecting population information. Investigation of culture heterogeneity and production variability by obtaining information about different culture subpopulations is crucial for optimizing bio-processes for enhanced productivity. Obtaining high yields of intact and viable single cells from aggregated plant cell cultures is an enabling criterion for their analysis and isolation using high-throughput flow cytometric methods. The critical parameters affecting the enzymatic isolation of single cells from aggregated Taxus cuspidata plant cell suspensions were optimized using response-surface methodology and factorial central composite design. Using a design of experiments approach, the output response single-cell yield (SCY, percentage of cell clusters containing only a single cell) was optimized. Optimal conditions were defined for the independent parameters cellulase concentration, pectolyase Y-23 concentration, and centrifugation speed to be 0.045% (w/v), 0.7% (w/v), and 1200 * g, respectively. At these optimal conditions, the model predicted a maximum SCY of 48%. The experimental data exhibited a 72% increase over previously attained values and additionally validated the model predictions. More than 99% of the isolated cells were viable and suitable for rapid analysis through flow cytometry, thus enabling the collection of population information from cells that accurately represent aggregated suspensions. These isolated cells can be further studied to gain insight into both growth and secondary metabolite production, which can be used for bio-process optimization. PMID- 21660860 TI - Oral resveratrol therapy inhibits cancer-induced skeletal muscle and cardiac atrophy in vivo. AB - The mechanism by which cancer mediates muscle atrophy has been delineated in the past 3 decades and includes a prominent role of tumor-derived cytokines, such as IL-6, TNFalpha, and IL-1. These cytokines interact with their cognate receptors on muscle to activate the downstream transcription factor NF-kappaB and induce sarcomere proteolysis. Experimentally, inhibiting NF-kappaB signaling largely prevents cancer-induced muscle wasting, indicating its prominent role in muscle atrophy. Resveratrol, a natural phytoalexin found in the skin of grapes, has recently been shown to inhibit NF-kappaB in cancer cells, which led us to hypothesize that it might have a protective role in cancer cachexia. Therefore, we investigated whether daily oral resveratrol could protect against skeletal muscle loss and cardiac atrophy in an established mouse model. We demonstrate resveratrol inhibits skeletal muscle and cardiac atrophy induced by C26 adenocarcinoma tumors through its inhibition of NF-kappaB (p65) activity in skeletal muscle and heart. These studies demonstrate for the first time the utility of oral resveratrol therapy to provide clinical benefit in cancer-induced atrophy through the inhibition of NF-kappaB in muscle. These findings may have application in the treatment of diseases with parallel pathophysiologies such as muscular dystrophy and heart failure. PMID- 21660863 TI - Trace element analysis of proteins directly from 2d-page: an efficient strategy for metalloproteomics. AB - Inductively coupled plasma-mass spectrometry (ICP-MS) is a sensitive analytical method to detect the total concentrations of elements in biological samples, but it is unable to identify molecules that can bind to metals, and for this reason it is vital to combine this method's use with other biochemical techniques. Therefore, in order to identify elements complexed to specific proteins, a very relevant combination of bidimensional electrophoresis followed by ICP-MS was used. Protein spots from gels were excised and submitted directly to element detection, a method not reported before. This report focused on the use of plasma from people with laryngeal carcinoma. Most elements were below detection level, with only Cr and Pb being observed in all samples. Although the relationship between metals and laryngeal cancer was not conclusive, it is possible to affirm that the methodology utilized here is successful and has the advantage of determining to which proteins the elements bind. PMID- 21660864 TI - Different multiwalled carbon nanotubes-enzyme system and enzymatic activity. AB - The interactions between enzyme and nanoparticles (NPs) are governed by the key properties of NPs, such as structure, size, surface chemistry, charge, and surface shape. In this report, we compared the effect of oxidized multiwalled carbon nanotubes (OXWNT) and irradiated multiwalled carbon nanotubes (IRWNT) on the enzymatic activity of PchPipA. Both OXWNT and IRWNT decreased the biocatalytic activity of PchPipA to some extent when they were added in the reaction system, while OXWNT exhibited higher inhibition of the activity of PchPipA than IRWNT. These results suggested that the water solubility may be another property that can affect the interaction of bio-macromolecular products and nanoparticles. PMID- 21660865 TI - Purification and characterization of pullulanase from Lactococcus lactis. AB - This paper describes a simple and efficient method of isolation of a plullulanase type I from amylolytic lactic acid bacteria (ALAB). Extracellular pullulanase type I was purified from a cell-free culture supernatant of Lactococcus lactis IBB 500 by using ammonium sulfate fractionation and dialysis (instead of ultrafiltration), and ion-exchange chromatography with CM Sepharose FF followed by gel filtration chromatography with Sephadex G-150 as the final step. A final purification factor of 14.36 was achieved. The molecular mass of the enzyme was estimated as 73.9 kD. The optimum temperature for the enzyme activity was 45 degrees C and the optimum pH was 4.5. Pullulanase activity was increased by addition Co(2+) and completely inhibited by Hg(2+). The enzyme activity was specifically directed toward alpha-1,6 glycosidic linkages of pullulan giving maltotriose units. Enzymatic hydrolysis of starch and amylose produced a mixture of maltose and maltotriose. PMID- 21660866 TI - Purification and characterization of phosphodiesterase i from Walterinnesia aegyptia venom. AB - A phosphodiesterase I (EC 3.1.4.1; PDE-I) was purified from Walterinnesia aegyptia venom by preparative native polyacrylamide gel electrophoresis (PAGE). A single protein band was observed in analytical native PAGE and sodium dodecyl sulfate (SDS)-PAGE. PDE-I was a single-chain glycoprotein with an estimated molecular mass of 158 kD (SDS-PAGE). The enzyme was free of 5'-nucleotidase and alkaline phosphatase activities. The optimum pH and temperature were 9.0 and 60 degrees C, respectively. The energy of activation (Ea) was 96.4, the V(max) and K(m) were 1.14 uM/min/mg and 1.9 * 10(-3) M, respectively, and the K(cat) and K(sp) were 7 s(-1) and 60 M(-1) min(-1) respectively. Cysteine was a noncompetitive inhibitor, with K(i) = 6.2 * 10(-3) M and an IC(50) of 2.6 mM, whereas adenosine diphosphate was a competitive inhibitor, with K(i) = 0.8 * 10( 3) M and an IC(50) of 8.3 mM. Glutathione, o-phenanthroline, zinc, and ethylenediamine tetraacetic acid (EDTA) inhibited PDE-I activity whereas Mg(2+) slightly potentiated the activity. PDE-I hydrolyzed thymidine-5'-monophosphate p nitrophenyl ester most readily, whereas cyclic 3'-5'-AMP was least susceptible to hydrolysis. PDE-I was not lethal to mice at a dose of 4.0 mg/kg, ip, but had an anticoagulant effect on human plasma. These findings indicate that W. aegyptia PDE-I shares various characteristics with this enzyme from other snake venoms. PMID- 21660867 TI - Screening of iron- and zinc-enriched yeast strain and optimization of cultivation conditions. AB - Saccharomyces cerevisiae LN-17 was selected from 26 kinds of primary yeast strains that belong to different genera and species. The iron- and zinc-enriched capability of strain LN-17 was higher than the others. The highest iron and zinc contents of the strain were obtained when the strain grew up under the following conditions: The strain was incubated (5%, v/v) in 50 mL wort medium (pH 6.0) with 100 mg/L Fe ion and 120 mg/L Zn ion. The medium was loaded into a 250-mL Erlenmeyer flask and shaken in a rotary shaker (200 rpm) at 30 degrees C for 60 h. Ferrous sulfate and zinc sulfate were chosen as the source of Fe and Zn. The Fe and Zn contents of the dry cells were determined by atomic absorption spectrum analysis. Under the optimized cultivation conditions, the Fe and Zn contents reached 7.854 mg/g dry cells and 4.976 mg/g dry cells. PMID- 21660868 TI - Magnetic dye-affinity beads for human serum albumin purification. AB - Cibacron Blue F3GA was covalently attached onto magnetic poly(vinyl alcohol) (mPVAL) beads (100-150 MUm in diameter) for human serum albumin (HSA) adsorption from human plasma. Despite low nonspecific adsorption of HSA on mPVAL beads, Cibacron Blue F3GA attachment significantly increased the HSA adsorption. The maximum HSA adsorption was observed at pH 5.0. Higher HSA adsorption was observed from human plasma. Desorption of HSA from mPVAL beads was achieved by medium containing 1.0 M KSCN at pH 8.0. To test the efficiency of albumin adsorption from human serum, before and after albumin adsorption was demonstrated with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analyses. HSA molecules could be reversibly adsorbed and desorbed 10 times with the magnetic beads without noticeable loss in their HSA adsorption capacity. PMID- 21660869 TI - Radical scavenging potential of phenolics from Bryophyllum pinnatum (LAM.) OKEN. AB - Optimization of the extraction process of phenolics from Bryophyllum pinnatum was carried out using response-surface methodology (RSM). The effect of different variables such as ratio of solvents, plant material/solvent ratio, extraction time, and temperature were investigated. An optimal phenolics yield of 7.952 mg/g gallic acid equivalence (GAE) was achieved at reduced levels of methanol/water ratio (1:1, v/v). During optimization, the product yield was enhanced by ~2-fold at reduced extraction solvent (methanol/water) up to 37%. Validation of the RSM model for extraction of total phenolic content (TPC) was confirmed by high performance liquid chromatography (HPLC) analysis. The obtained experimental values were in good agreement with the predicted values, thereby indicating the appropriateness of the model generated. Phenolic extracts from B. pinnatum were further examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) methods for determining the radical scavenging activities. EC(50) values of B. pinnatum extracts (BPEs) obtained by these methods were in accordance with the amount of phenolics present in the extract. Significant correlation was found between total phenolic content and antioxidant activities (p < 0.05). PMID- 21660871 TI - Alcohol medical scholars program--a mentorship program for improving medical education regarding substance use disorders. AB - The Alcohol Medical Scholars Program (AMSP) is designed to improve medical education related to substance use disorders (SUDs) through mentorship of junior, full-time academic faculty from medical schools across the United States. Scholarship focuses on literature review and synthesis, lecture development and delivery, increasing SUD education in their medical schools, professional development, and networking. Results are reported from an anonymous survey of self-reported changes in educational involvement by 28 of 33 AMSP graduates. Participation was associated with a 4-fold increase in yearly SUD lecture time and topics, increased numbers of medical disciplines taught and trained in clinical rotations, design of new SUD-related electives and journal clubs, and membership on medical education committees. Sixty percent of scholars reported promotion since involvement in AMSP, with the majority endorsing the organization's contribution to professional development. AMSP is a useful mentorship model for junior faculty and is associated with increasing SUD-related medical education. PMID- 21660870 TI - Modelling decisions to undergo genetic testing for susceptibility to common health conditions: an ancillary study of the Multiplex Initiative. AB - New genetic tests reveal risks for multiple conditions simultaneously, although little is understood about the psychological factors that affect testing uptake. We assessed a conceptual model called the multiplex genetic testing model (MGTM) using structural equation modelling. The MGTM delineates worry, perceived severity, perceived risk, response efficacy and attitudes towards testing as predictors of intentions and behaviour. Participants were 270 healthy insured adults aged 25-40 from the Multiplex Initiative conducted within a health care system in Detroit, MI, USA. Participants were offered a genetic test that assessed risk for eight common health conditions. Confirmatory factor analysis revealed that worry, perceived risk and severity clustered into two disease domains: cancer or metabolic conditions. Only perceived severity of metabolic conditions was correlated with general response efficacy (beta = 0.13, p<0.05), which predicted general attitudes towards testing (beta = 0.24, p<0.01). Consistent with our hypothesised model, attitudes towards testing were the strongest predictors of intentions to undergo testing (beta = 0.49, p<0.01), which in turn predicted testing uptake (OR 17.7, beta = 0.97, p<0.01). The MGTM explained a striking 48% of the variance in intentions and 94% of the variation in uptake. These findings support use of the MGTM to explain psychological predictors of testing for multiple health conditions. PMID- 21660872 TI - Substance use prevalence and screening instrument comparisons in urban primary care. AB - Substance use screening in a primary care setting compared the Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST version 3.0), Two-Item Conjoint Screen (TICS), National Institute on Alcohol Abuse and Alcoholism (NIAAA) daily limit single item, and electronic medical record (EMR). Among 236 consecutive adults, ASSIST moderate- to high-risk substance use prevalence was tobacco, 15.3%; alcohol, 8.5%; cannabis, 5.1%; cocaine, 2.5%; and opioids, 2.5%. Compared to ASSIST, a positive TICS was 45% (95% confidence interval [CI], 27-64%) sensitive, 99% (95-100%) specific; the NIAAA single-item screen was 80% (56-94%) sensitive, 87% (82-91%) specific. The NIAAA single item correlated closely with alcohol ASSIST. TICS and EMR were less sensitive for any nontobacco substance use. PMID- 21660873 TI - Prevention of alcohol dependence: strategies for selective, indicated, and universal prevention. AB - Study of the chronology of criteria of dependence in alcohol dependence syndrome (ADS) can enable us to design strategies for the prevention for ADS, which takes into account primary prevention (indicated, selective, and universal prevention) approaches and aims at reducing the occurrence of ADS. The objective of this work is to study the age-wise and order-wise chronologies of International Classification of Diseases Tenth Revision Diagnostic Criteria for Research (ICD 10 DCR) dependence criteria in individuals with ADS. Consecutively admitted and consenting inpatients with ICD-10 DCR diagnosis of ADS were evaluated in a structured interview after detoxification using Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA)-II. The total sample size was 81. The mean ages at the first onset of alcohol use, development of the first criterion, and ICD-10 dependence was 18.72 years (SD: 6.84), 24.33 years (SD: 9.21), and 27.51 years (SD: 9.28), respectively. In age-wise chronology, tolerance, loss of control, and craving were present in 97.53%, 80.24%, and 79%, respectively, of our study sample. In order-wise chronology, either craving (16%) or tolerance (71.6%) was present as the first criterion and the presence of craving (16%), tolerance (21%), or loss of control (18.5%) was observed as the first criterion in 55.5% of the subjects. Indicated prevention may be attempted by enquiring about craving, tolerance, and loss of control and use of anticraving medications or behavioral strategies. Selective prevention by using naltrexone for those genetically inclined and universal prevention by use of "clinical" labeling on alcoholic beverages can also be attempted. PMID- 21660874 TI - Six-month follow-up of computerized alcohol screening, brief intervention, and referral to treatment in the emergency department. AB - The goal of this observational study was to measure change in alcohol consumption at 6 months following emergency department computerized alcohol screening brief intervention (CASI) and referral to treatment (ED-SBIRT) with integrated brief negotiated interview (BNI) and computer-generated personal alcohol reduction plans. At-risk patients received a BNI by CASI, including personalized feedback, assessment of readiness to change, reasons for cutting down, goal setting, and a printed personal alcohol reduction plan. Alcohol use was assessed by telephone interview 6 months after CASI. Factors associated with lower alcohol consumption were examined. Of the 385 participants who completed the BNI, were consented, and enrolled, 221 subjects completed the 6-month follow-up interview. Forty-seven percent of the study sample of at-risk patients were no longer drinking over the National Institute on Alcohol Abuse and Alcoholism (NIAAA)-recommended limits. Reductions were greater for patients with Alcohol Use Disorders Identification Test (AUDIT) scores of 1 to 7. Readiness to change was a good predictor of drinking below the recommended limits. The use of computerized ED-SBIRT with integrated personalized messaging and BNI holds promise as a viable screening and intervention modality for a wide range of emergency department patients. PMID- 21660875 TI - Recovery from a Staphylococcus aureus--induced spinal epidural abscess despite late surgical decompression in a heroin addict. PMID- 21660876 TI - Heroin-dependent family: a biopsychosocial context. PMID- 21660877 TI - Prenatal toxicology screening for substance abuse in research: codes and consequences. PMID- 21660878 TI - Reflections on 10 years of training students and professionals in addiction treatment. PMID- 21660879 TI - Quetiapine dependence and withdrawal: a case report. AB - Quetiapine is a new-generation antipsychotic medication approved in the treatment of schizophrenia, bipolar disorder, and related disorders. There are reports about the abuse and possible dependence of quetiapine. We present the first case of definite quetiapine dependence. This is a 37-year-old male who applied to the addiction unit because he could not control quetiapine use. He had a history of alcohol and benzodiazepine dependence as well as cannabis abuse. He reported to have a rush on quetiapine and suffered from its withdrawal when he tried to wean off the medication. This case and similar other suggest that while quetiapine may be beneficial in the treatment of some patients with addictive disorders, we should be cautious when using quetiapine to treat patients with drug or alcohol dependence. PMID- 21660880 TI - Osteonecrosis following alcohol, cocaine, and steroid use. AB - Alcohol, steroids and cocaine have all been shown to be independent risk factors for osteonecrosis when taken in excess. Here we present a case of a young girl who developed debilitating osteonecrosis secondary to low doses of alcohol, steroids and cocaine. We feel it is important to highlight to those caring for such patients of the potential devastating complication of these three agents. PMID- 21660881 TI - A preliminary neuroimaging study of preschool children with ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that, by current definition, has onset prior to age 7 years. MRI studies have provided some insight into brain differences associated with ADHD, but thus far have almost exclusively focused on children ages 7 years and older. To better understand the neurobiological development of ADHD, cortical and subcortical brain development should be systematically examined in younger children presenting with symptoms of the disorder. High-resolution anatomical (MPRAGE) images, acquired on a 3.0T scanner, were analyzed in a total of 26 preschoolers, ages 4-5 years (13 with ADHD, 13 controls, matched on age and sex). The ADHD sample was diagnosed using DSM-IV criteria, and screened for language disorders. Cortical regions were delineated and measured using automated methods in Freesurfer; basal ganglia structures were manually delineated. Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this age range. After controlling for age and total cerebral volume, left caudate volume was a significant predictor of hyperactive/impulsive, but not inattentive symptom severity. Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD. PMID- 21660883 TI - Commentary: graduated licensing--moving forward or standing still? AB - The widespread application of graduated driver licensing (GDL), starting in the mid-1990s, has greatly reduced young driver crashes. Substantial further reductions are possible by raising the licensing age to 17. This can be done indirectly, through extension of GDL policies (minimum learner age of 16, one year holding period), or by legislation directly establishing 17 as the licensing age. Other approaches are likely to have limited impact. PMID- 21660884 TI - Patterns of recidivism related to case dispositions of alcohol-impaired driving offenses. AB - OBJECTIVES: The current study examined the relationship between court outcomes of a first alcohol-impaired driving charge and recidivism. METHODS: Data on arrests for alcohol-impaired driving offenses (driving under the influence [DUI] and the lesser offense of driving while impaired [DWI]) and associated court dispositions were obtained from the State of Maryland for 1994-2003. Drivers whose first DUI- or DWI-related disposition took place during 1999-2000 were included in analysis. Eighty-two percent of arrests resulted in conviction (29% without probation before judgment [PBJ] and 53% with PBJ); 10 percent of defendants were not prosecuted, 3 percent were acquitted, and all other adjudications combined (eg, abated by death, failure to appear) accounted for 5 percent. Recidivism was tracked by compiling instances of rearrest for an alcohol-related driving offense during the 3 years following disposition. RESULTS: Approximately 10 percent of all drivers arrested for DUI/DWI recidivated within 3 years after their first disposition, and the rate of recidivism varied by court outcome. The rate of recidivism was lowest (10%) for drivers who were convicted (with or without PBJ), followed by 13 percent for cases not prosecuted and 16 percent for acquittals. After controlling for other factors and relative to drivers who were acquitted, it was estimated that drivers who were not prosecuted were 23 percent less likely to recidivate, whereas drivers who were convicted with or without PBJ were 39 percent less likely to recidivate. CONCLUSIONS: Data limitations prevented comparison of recidivism rates for convictions with and without PBJ. Reasons for not prosecuting are unknown, but the findings indicate that the decision is resulting in higher recidivism rates than would occur with prosecution and conviction. PMID- 21660885 TI - Driving citations: relationships with criminal behavior. AB - OBJECTIVE: The purpose of the present study was to examine relationships, if any, between the number of lifetime driving citations and the number of lifetime criminal charges. METHODS: Using a cross-sectional, consecutive sample of internal medicine outpatients and a self-report survey methodology, we queried participants about the number of past driving citations as well as charges for any of 27 criminal behaviors as delineated by the crime cataloguing schema of the Federal Bureau of Investigation. RESULTS: Scores on the measure of driving citations were positively correlated with scores on the measure of different forms of illegal behavior (r = .39, p < .001). Additional analyses indicated that the relationship between driving citations and illegal behaviors did not vary by sex. CONCLUSIONS: Though the receipt of driving citations is fairly common, an increasing number of driving citations demonstrates a relationship with criminal behavior. This relationship may be mediated by a number of psychological variables, including various Axis I and II disorders. PMID- 21660886 TI - A preliminary analysis of traffic crashes by out-of-state drivers. AB - OBJECTIVE: This study was designed to investigate the relationship between the involvement of out-of-state drivers in fatal crashes and each US state's fatality rate per distance driven. METHOD: Two analyses were performed. In the first analysis, we examined the percentages of out-of-state drivers among those involved in fatal crashes using the data from the Fatal Analysis Reporting System (FARS). In the second analysis, we correlated these percentages with the states' fatality rates per distance driven. Both analyses used the data for 2008. RESULTS: There are two main findings of this study. First, there is wide variability across the 50 states in the percentage of all drivers involved in fatal crashes who were out-of-state drivers, with a minimum of 5.0 percent in California and a maximum of 41.2 percent in Wyoming. Second, there is a positive correlation between this percentage and the corresponding fatality rate per distance driven. CONCLUSIONS: There are two main findings. First, states vary greatly in terms of the involvement of out-of-state drivers in fatal crashes. Second, the states with higher fatality rates tend to have higher percentages of out-of-state drivers among the persons involved in fatal crashes. However, whether this relationship is causative (ie, the extent of the involvement of out of-state drivers among the persons involved in fatal crashes influences the states' overall fatality rates) or noncausative (eg, there is more out-of-state traffic in states with higher fatality rates) cannot be ascertained from the available data. The missing data concern the relative distance driven in each state by out-of-state drivers. PMID- 21660887 TI - Identifying traditional and nontraditional predictors of crash injury severity on major urban roadways. AB - OBJECTIVE: This study identifies and compares the factors that contribute to injury severity on urban freeways and arterials and recommends potential countermeasures to enhance the safety of both facilities. The study makes use of an extensive data set from the State of Florida in the United States. To obtain a more complete picture, this study explores both traditional and nontraditional severity predictors. Some traditional predictors include traffic volume, speed limit, and road surface condition. The nontraditional predictors are comprised of those rarely explored in previous severity studies, including crash distance to the nearest ramp location, detailed vehicle types, and lighting and weather conditions. METHODS: The analysis was conducted using the ordered and binary probit models, which are well suited for the inherently ordered property of injury severity. RESULTS: An important finding is the significance of the distance of crash to the nearest ramp junction/access point, for which the increase in the distance yielded a severity increase at both facilities. Other significant factors included traffic volume, speed limit, at-fault driver's age, road surface condition, alcohol and drug involvement, and left and right shoulder widths. In comparing both facilities, sport utility vehicles (SUVs) and pickup trucks showed a fatality/severity increase on freeways and a decrease on arterials. Furthermore, the detailed list of variables such as crash time provided pertinent severity trend information that showed that, compared to the other periods, the afternoon peak period had the highest reduction in fatality/severity. CONCLUSIONS: Both probit models succeeded in identifying significant severity predictors for each facility. The binary probit model outperformed the ordered probit model based on the higher elasticities (marginal effects) for the fatality/severity probability change, as well as the goodness of fit. As such, this study provides the guidelines for assessing the impact of important roadway and traffic characteristics on crash injury severity along freeways and arterials. PMID- 21660888 TI - Toward understanding on-road interactions of male and female drivers. AB - OBJECTIVE: This study examined gender effects in six geometric scenarios of 2 vehicle crashes in which an involved driver could potentially ascertain the gender of the other driver prior to the crash. METHOD: The actual frequencies of different combinations of the involved male and female drivers in these crash scenarios were compared with the expected frequencies if there were no gender interactions. The expected frequencies were based on annual distance driven for personal travel by male and female drivers. RESULTS: The results indicate that in certain crash scenarios, male-to-male crashes tend to be underrepresented and female-to-female crashes tend to be overrepresented. CONCLUSIONS: The obtained pattern of results could be due to either differential gender exposure to the different scenarios, differential gender capabilities to handle specific scenarios, or differential gender expectations of actions by other drivers based on their gender. The current lack of information on gender exposure in different scenarios, scenario-specific driver skills, and driver expectations based on other drivers' gender prevents ruling out any of these possible explanations. PMID- 21660889 TI - Prediction of helmet use among Iranian motorcycle drivers: an application of the health belief model and the theory of planned behavior. AB - OBJECTIVE: The aim of this study was to investigate the predictors of self reported motorcycle helmet use in a sample of motorcycle riders in Bandar Abbas, Iran. The theory of planed behavior and the health belief model served as the conceptual framework for the study. METHODS: In total, 221 male motorcycle drivers participated in this cross-sectional study. A self-administered questionnaire, including demographic characteristics and items related to both the theory of planned behavior and the health belief model constructs, was used to collect data. RESULTS: The mean age of the subjects was 26.8 years (SD = 7.2). Multiple regression analyses revealed that perceived behavioral control significantly predicted the intention to use a motorcycle helmet (R(2)= 0.47, F = 19.5, p < .001); also, perceived behavioral control and behavioral intention significantly predicted motorcycle helmet use (R(2)= 0.49, F = 51.7, p < .001). Moreover, perceived barriers, self-efficacy, and cues to action significantly predicted motorcycle helmet use (R(2)= 0.35, F = 19.5, p < .001). CONCLUSION: This study concluded that motorcycle drivers who perceived a high level of behavioral control, intention to use a motorcycle helmet, few barriers, high self efficacy, and a high number of cues to action were the most likely to use a motorcycle helmet. PMID- 21660890 TI - Cycling crashes in children, adolescents, and adults--a comparative analysis. AB - OBJECTIVE: To compare rates, circumstances, and outcomes of cyclist crashes between children (aged 0-9 years), adolescents (aged 10-19 years), and adults (aged 20 years and over) in Victoria, Australia. METHODS: A retrospective analysis of cyclist crashes in police records and the Victorian Admitted Episodes Dataset during the period 2004-2008. RESULTS: Adolescent cyclists had the highest rates, per 100 000 people, of police-reported (32.6, 95% confidence interval [CI]: 30.7-34.5) and hospitalized cyclist crashes (71.6, 95% CI: 68.7-74.4). Police-reported helmet use at the time of the crash was lowest among children (57.1%, 95% CI: 49.5-64.8) compared to 60.2 percent (95% CI: 57.3-63.1) in adolescents and 77.7 percent (95% CI: 76.5-78.8) in adults. This was reflected in the hospital data, which indicated that more than one third of cyclist hospitalizations among children (37.4%) resulted in head injuries compared to around 1 in 4 hospitalized cyclist crashes in adolescents (26.8%) and adults (23.7%). Cyclists emerging off a footpath into the path of a vehicle as well as cyclists struck by vehicles emerging form a driveway were the most frequent types of police-reported crashes involving children (73.9%) and adolescents (48.1%). In contrast, most adult cyclist crashes occurred on the roadway, mainly at intersections. CONCLUSIONS: Programs to improve the safety knowledge and behavior of children and adolescent cyclists, particularly focusing on helmet use, should be part of a comprehensive approach that encompasses legislative and environmental changes, including appropriate cyclist facilities and reduced speed limit in residential areas. PMID- 21660882 TI - Estimating premorbid IQ in the prodromal phase of a neurodegenerative disease. AB - Estimates of premorbid intellect are often used in neuropsychological assessment to make inferences about cognitive decline. To optimize the method of controlling for premorbid intellect in assessments of prodromal neurodegenerative disease, we examined performance on the American National Adult Reading Test (ANART; administered during Years 1 and 3) and the two-subtest version of the Wechsler Abbreviated Scale of Intelligence (WASI; administered in Years 2 and 4) in an ongoing prospective longitudinal study of 371 participants with prodromal Huntington disease and 51 participants with normal CAG repeats. Although both measures performed similarly, the ANART demonstrated slightly lower variability in performance over a 2-year period and had slightly higher test-retest reliability than the WASI. PMID- 21660891 TI - The burden of unhelmeted and uninsured ATV drivers and passengers. AB - OBJECTIVE: Injured all-terrain vehicle (ATV) riders contribute to the national trauma burden. The importance of helmet use on injury severity and outcomes in ATV drivers versus passengers that receive care is unknown along with the association of payor status and helmet use in this population. An investigation of whether helmet use protects ATV drivers and passengers resulting in less severe injuries, better outcomes, and a lower cost burden to society is to be conducted. METHODS: A retrospective review of injured ATV riders in the National Trauma Data Bank from the United States for 2000-2004. RESULTS: Helmet use status was recorded for 5897 drivers and 836 passengers; 83 percent of drivers were male; 41 percent of passengers were female. Helmets were not widely worn (35% of drivers, 19% of passengers, p < .0001) and were less common among female than male drivers who crashed and received care (26% versus 37%, p < .0001). Drivers were older than passengers (p < .0001) and had more thorax, spine, and upper extremity injuries (p < .05). Helmets protected drivers and passengers: decreased head injuries, face injuries, injury severity, and mortality with increased likelihood of being discharged home rather than elsewhere (p < .0001). Personal insurance was more frequent in helmeted riders: 66 percent versus 55 percent of helmeted versus nonhelmeted drivers (p < .0001) and 69 percent versus 55 percent of helmeted versus nonhelmeted passengers (p = .03). CONCLUSIONS: Helmets are frequently not worn by ATV riders. Helmets protect ATV drivers and passengers and decrease societal costs associated with ATV crashes. PMID- 21660892 TI - BioTab--a new method for analyzing and documenting injury causation in motor vehicle crashes. AB - OBJECTIVE: To describe a new method for analyzing and documenting the causes of injuries in motor vehicle crashes that has been implemented since 2005 in cases investigated by the Crash Injury Research Engineering Network (CIREN). METHODS: The new method, called BioTab, documents injury causation using evidence from in depth crash investigations. BioTab focuses on developing injury causation scenarios (ICSs) that document all factors considered essential for an injury to have occurred as well as factors that contributed to the likelihood and/or severity of an injury. The elements of an injury causation scenario are (1) the source of the energy that caused the injury, (2) involved physical components (IPCs) contacted by the occupant that are considered necessary for the injury to have occurred, (3) the body region or regions contacted by each IPC, (4) the internal paths between body regions contacted by IPCs and the injured body region, (5) critical intrusions of vehicle components, and (6) factors that contributed to the likelihood and/or the severity of injury. RESULTS: Advantages of the BioTab method are that it attempts to identify all factors that cause or contribute to clinically significant injuries, allows for coding of scenarios where one injury causes another injury, associates injuries with a source of energy and allows injuries to be associated with sources of energy other than the crash, such as air bag deployment energy, allows for documenting scenarios where an injury was caused by two different body regions contacting two different IPCs, identifies and documents the evidence that supports ICSs and IPCs, assigns confidence levels to ICSs and IPCs based on available evidence, and documents body region and organ/component-level "injury mechanisms" and distinguishes these mechanisms from ICSs. CONCLUSION: The BioTab method provides for methodical and thorough evidenced-based analysis and documentation of injury causation in motor vehicle crashes. PMID- 21660893 TI - Examining traffic flow and speed data: determining imitative behavior. AB - OBJECTIVES: This article will empirically examine the contagion theory using traffic count and speed data. This theory proposes that a driver's choice of speed will be influenced by the speed of other drivers on the road. Thus, if a person is driving at the speed limit but a certain number of the surrounding vehicles are driving faster, the person can be influenced to increase his speed. It is implied that there would be different types or groups of drivers, each with different propensities toward imitation. Imitative behavior will be considered as a possible mechanism behind contagion theory. METHODS: A standard traffic counter was used to collect for a period of 8 days. Using cluster analysis, the data will be differentiated and the group characteristics examined. Finally, these effects will be examined on an hourly basis to determine whether time of day has any effect upon the outcome. RESULTS: The analysis produced several groups of drivers similar to that predicted by contagion theory. Two groups of drivers, high-speed and lower speed drivers, remain relatively stable in numbers as expected. Two intermediate groups showed signs of imitative behavior. CONCLUSIONS: The results appear to support contagion theory as a social mechanism influencing individual drivers' choices of speed. Several alternative explanations are introduced as partial explanations. In light of the traffic accident problem in the United Arab Emirates and recent police programs aimed at reducing this problem, such studies aid in determining the extent of speeding behavior and the effectiveness of recent initiatives. PMID- 21660894 TI - Predictors of speeding behavior among a sample of Iranian commercial automobile drivers: an application of the theory of planned behavior. AB - OBJECTIVE: Speeding has been reported as one of the most important public health issues worldwide. Using the theory of planned behavior (TPB), this study examined the self-reported behavior of driving within posted speed limits for a sample of commercial automobile drivers. METHODS: In this cross-sectional study, all commercial automobile drivers who were literate and who transported people to and from Bandar Abbas and other cities in August 2010 were likely to be included in the study. A self-administered questionnaire including demographic characteristics and a questionnaire based on TPB constructs were used to collect data. Multiple regression analyses were used to predict factors of driving within speed limits at a level of p < .05. RESULTS: In all, 246 eligible drivers with a mean age of 32.2 years (SD = 6.7) were studied. The mean years of automobile driving was 8.7 (SD = 5.0). Multiple regression analysis revealed that subjective norms and perceived behavioral control could predict the intention to drive within speed limits (R(2)= 0.25, F = 27.2, p < .001). Furthermore, behavioral intention and perceived behavioral control predicted driving within speed limits (R(2)= 0.41, F = 85.1, p < .001). CONCLUSION: This study concluded that commercial automobile drivers in Bandar Abbas, Iran, are most in need of appropriate interventions based on improving their subjective norms and behavioral control. PMID- 21660895 TI - Comparison of highway crash reporting in pakistan with the world health organization injury surveillance guidelines. AB - OBJECTIVES: To compare the crash reporting system of National Highways & Motorways Police (NH&MP), Pakistan, with the World Health Organization (WHO) injury surveillance guidelines. METHODS: Based on information collected from field observations, key informant interviews, and review of official documents, this note firstly describes the reporting system according to the components of a surveillance system. Then the reporting is compared with WHO criteria for designing and building an injury surveillance system and attributes of such a system. RESULTS: After a crash, a patrol officer communicates the information to the higher police authorities by wireless, fax, and on paper in the first 24 hours. Microcomputer Accident Analysis Package (MAAP) Performa filed by the officers are collected at a central location in the following 4 days, and reports are published biannually. Notable deficiencies in the reporting were nonidentification of stakeholders for data utilization and limited prospects of data recording process modification and its monitoring. Moreover, crash and injury definitions do not conform to international standards practiced elsewhere. CONCLUSION: NH&MP crash reporting needs to be simplified and standardized, and steps should be taken to improve its utilization for prevention purposes. PMID- 21660896 TI - Investigation of the effectiveness of traffic sign training in terms of training methods and sign characteristics. AB - OBJECTIVE: This research investigated whether different training methods had any effect on the effectiveness of traffic sign training and whether there were any relationships between traffic sign characteristics and effectiveness of the training. METHODS: Thirty-six participants were randomly assigned into 4 equal sized groups (control, paired-associate learning, recall training, and recognition training) to study the learnability of Mainland China traffic signs. In paired-associate learning, participants studied each traffic sign along with a referent describing its meaning. In addition to being informed of the meaning of traffic signs, both recall training and recognition training provided participants with questions and feedback. For recall training, the questioning process was a recall task in which participants had to produce a meaning for a given traffic sign from memory. For recognition training, the questioning process was a recognition task that required participants to identify the most appropriate referent corresponding to a given sign. No traffic sign training was given to the control group. RESULTS: Each training method significantly improved comprehension of the meaning of traffic signs. Participants from recall training performed better in a posttraining test than those from paired-associate learning and recognition training, indicating that the recall training elicited a deeper level of learning. In addition, questioning and feedback had a positive influence on training effectiveness. Performance in the posttest was found to be better when the questioning process matched the test process. Regarding the traffic sign characteristics, semantic closeness had a long-lasting effect, in terms of the timescale of this experiment on traffic sign comprehension, and traffic signs were perceived as more meaningful after their intended meanings were studied. CONCLUSIONS: Recall training is more effective in enhancing comprehension of traffic signs than paired-associate learning and recognition training. The findings of this study provide a basis for useful recommendations for designing symbol-training programs to improve road safety for road users. PMID- 21660897 TI - [Emotional Childhood Parentification and Mental Disorders in Adulthood.] PMID- 21660898 TI - The rates of abnormal glucose challenge tests and gestational diabetes in women receiving 17alpha-hydroxyprogesterone caproate. AB - We compared the rates of abnormal 1-hour glucose challenge tests (GCT) and gestational diabetes (GDM) between women receiving 17alpha-hydroxyprogesterone caproate (17-P) and women who did not receive 17-P to determine if the effect varies based on the number of doses received or in a group of high-risk obese women. We performed a secondary analysis of a prospective cohort study where women with a history of a previous preterm delivery in the antecedent pregnancy followed at a high-risk clinic were offered 17-P. GCT was performed after the initiation of 17-P, and doses given prior to testing were recorded. Rates of abnormal GCT and GDM were compared between those receiving 17-P ( N = 67) and controls ( N = 140). Mean glucose values (112.4 versus 111.3, P = 0.8), rate of abnormal GCT (23.9% versus 20%, adjusted odds ratio 1.45, 95% confidence interval 0.7 to 3.0), and rate of GDM (6% versus 8.6%, adjusted odds ratio 1.21, 95% confidence interval 0.3 to 4.5) were similar between groups. In this prospective study, 17-P administration to women at risk of recurrent preterm delivery did not significantly affect glucose tolerance. PMID- 21660899 TI - Maternal goals for childbirth associated with planned vaginal and planned cesarean birth. AB - We describe maternal childbirth goals among women planning either cesarean or vaginal birth. Women in the third trimester planning cesarean or vaginal birth were asked to report up to five childbirth goals. Goal achievement was assessed postpartum. Based on free-text responses, discrete goal categories were identified. Goals and goal achievement were compared between the two groups. Satisfaction was rated on a visual analogue scale and was compared with goal achievement. The sample included 163 women planning vaginal birth and 69 women planning cesarean. Twelve goal categories were identified. Only women planning vaginal birth reported a desire to achieve fulfillment related to childbirth. Women planning cesarean were less likely to express a desire to maintain control over their own responses during childbirth and more likely to report a desire to avoid complications. The 72 women who achieved all stated goals reported significantly higher mean satisfaction scores than the 94 women reporting that at least one goal was not achieved (P = 0.001). Goal achievement was higher among women planning cesarean than among those planning vaginal birth (52.2% versus 23.1%, P < 0.001). This research furthers our understanding of women's attitudes regarding cesarean childbirth and definitions of a successful birth experience. PMID- 21660900 TI - Extreme morbid obesity and labor outcome in nulliparous women at term. AB - We examined the prevalence of cesarean delivery (CD) among women with morbid obesity and extreme morbid obesity. Using Kentucky birth certificate data, a cross-sectional analysis of nulliparous singleton gestations at term was performed. We examined the prevalence of CD by body mass index (BMI; in kg/m2) using the National Institutes of Health/World Health Organization schema and a modified schema that separates extreme morbid obesity (BMI >= 50) from morbid obesity (BMI >= 40 to < 50). Bivariate and multivariate analyses were performed. Multivariate modeling controlled for maternal age, estimated gestational age, birth weight, diabetes, and hypertensive disorders. Overall, 83,278 deliveries were analyzed. CD was most common among women with a prepregnancy BMI >= 50 (56.1%, 95% confidence interval 50.9 to 61.4%). Extreme morbid obesity was most strongly associated with CD (adjusted odds ratio 4.99, 95% confidence interval 4.00 to 6.22). Labor augmentation decreased the likelihood of CD among women with extreme morbid obesity, but this failed to reach statistical significance. We speculate a qualitative or quantitative deficiency in the hormonal regulation of labor exists in the morbidly obese parturient. More research is needed to better understand the influence of morbid obesity on labor. PMID- 21660901 TI - Placenta previa in the second trimester: sonographic and clinical factors associated with its resolution. AB - We identify characteristics that predict resolution of placenta previa and develop a clinical model for likelihood of resolution. We conducted a retrospective study of 366 singleton pregnancies complicated by placenta previa diagnosed with resolution of the previa as the primary outcome. Regression analyses were performed to determine variables associated with resolution and optimal timing for repeat sonographic evaluation. A likelihood of resolution model was created using a parametric survival model with Weibull hazard function. Of the 366 cases, 84% of complete placentae previae and 98% of marginal placentae previae resolved at a mean gestational age of 28.6 +/- 5.3 weeks. Only gestational age and distance from the internal cervical os at the time of diagnosis were significantly associated with resolution ( P < 0.01). Likelihood of resolution was not significantly associated with any other variables. Marginal previae diagnosed in the second trimester do not appear to warrant repeat ultrasound evaluation for resolution. PMID- 21660902 TI - The late preterm birth rate and its association with comorbidities in a population-based study. AB - We sought to identify rates, associated morbidities, and preventable causes of late preterm birth (LPB) in a defined population. We conducted a retrospective cross-sectional analysis using deidentified delivery data for all who delivered in San Antonio/Bexar County, Texas between 2000 and 2008 (N = 259,576). LPB was defined as a live birth from 34(0/7) to 36(6/7) weeks. Variables analyzed included age, race/ethnicity, weight gain, hypertensive disease, diabetes, and preterm labor including premature rupture of membranes. From 2000 to 2006, the LPB rate in San Antonio/Bexar County, Texas, was slightly higher than the national average, 9% versus 8.7% (P < 0.01). From 2000 to 2008, 23,312 LPBs occurred in San Antonio/Bexar County and 53% experienced at least one studied comorbidity. Using logistic regression comparing LPB to term, variables associated with an increased risk of LPB were black race, age < 17, age >= 35, gestational hypertension, eclampsia, chronic hypertension, and diabetes. LPB was higher than the national average in our population, and preventable causes of LPB (extremes of age, hypertensive disease, and diabetes) were commonly associated with LPB. We speculate that teenage pregnancy prevention, counseling regarding risks associated with advanced maternal age, and improved management and prevention of hypertensive disease and diabetes should prove beneficial in decreasing the LPB rate. PMID- 21660903 TI - Maternal obesity and nonstress testing. AB - We evaluated the impact of maternal obesity on the characteristics and results of nonstress tests (NST). This prospective 1-year cohort study included 2026 NSTs performed on 575 consecutively chosen women with singleton gestations >= 32 weeks and no known fetal anomalies. Body mass index (BMI) class was determined at the first prenatal visit. The primary outcome was the duration of fetal heart rate monitoring before a reactive result. Obese women were not more likely to have nonreactive NST results. The mean duration before obtaining a reactive result was unaffected by obesity after controlling for diabetes and gestational age. The overall number of NSTs per patient was higher in obese than in nonobese women (3.9 versus 3.1, P < 0.01). More tests per patient are performed among obese subjects, yet the ability to perform an NST and the duration before obtaining a final result were unaffected by obesity. PMID- 21660904 TI - A right-to-left or bidirectional ductal shunt in preterm neonates: grave implication? AB - We delineate the natural history of a right-to-left or bidirectional (RL/BD) patent ductus arteriosus (PDA) in preterm infants and compare outcomes of an RL/BD and a left-to-right (LR) ductal shunt. We performed a retrospective chart review of preterm infants (< 32 weeks), who, between 2 and 30 days of age, had an RL/BD PDA > 1.5 mm (study group; N = 74) or an LR PDA (N = 87) on echocardiogram (ECHO). In the study group, 27% of infants who were of significantly lower gestational age and birth weight had a "prolonged" RL/BD PDA on two or more ECHOs. Infants with RL/BD PDA required significantly greater surfactant (98.6% versus 94.2%) and less PDA therapy (27% versus 92%) and had higher mortality (48.6% versus 21.8%) compared with those with LR PDA. On regression analysis, lower gestation (odds ratio [OR] 1.45; 95% confidence interval [CI]: 1.15 to 1.83) and RL/BD PDA (OR 4.74; 95% CI: 2.18 to 10.3) were significantly associated with mortality. The independent association between an RL/BD PDA shunt and mortality warrants further investigation. Insights into the etiology of pulmonary hypertension may optimize outcomes in this population. PMID- 21660905 TI - [The objective evaluation of sibilants]. AB - BACKGROUND: The inaccurate production of 's-sounds', i. e. sibilants represents the most common speech disorder. An objective description of such inaccurate speech sound production is mandatory. Several tools have been proposed and might be of great value, amongst them spectral analysis. The latter can nowadays be performed easily without the need for expensive equipment. METHOD: Different sibilants were uttered either as isolated speech sounds or embedded in test words and sentences. These were then digitized and spectral analysis was performed. Since several protocols have been put forward on how to execute the spectral analysis of sibilants, we replicated those protocols and evaluated how they exert influence on the analysis results. The selection of time windows or frequency bands regarding the computation of spectral moments will be considered in particular. RESULTS: Sibilants are characterised by a band-pass noise. Usage of power spectral density functions for the extraction of features from temporal and spatial signals is a standard approach. Thus, we calculated spectral moments to describe noise signals derived from sibilant productions. We demonstrate differing results based on varying frequency and time analysis windows. CONCLUSION: Unfortunately to date there is no generally accepted "gold standard" for the spectro analysis of speech sounds. For clinical routine, we recommend using a time window of 40 ms around the temporal midpoint, extracted from utterances or words. It is important, however, that recording conditions and analysis parameters are identical pre- and post therapy. PMID- 21660908 TI - Bloody diarrhea caused by enterohemorrhagic Escherichia coli (EHEC). PMID- 21660907 TI - Comparison of transnasal small-caliber vs. peroral conventional esophagogastroduodenoscopy for evaluating varices in unsedated cirrhotic patients. AB - BACKGROUND AND STUDY AIMS: We aimed to evaluate the accuracy of transnasal small caliber esophagogastroduodenoscopy (TNSC-EGD) compared with peroral conventional EGD (POC-EGD) for evaluating varices in unsedated patients with liver cirrhosis. The success rate, safety, endoscopist satisfaction, and patient tolerability of TNSC-EGD were also addressed. PATIENTS AND METHODS: One hundred patients with liver cirrhosis participated in this randomized crossover trial, and 84 subjects completed both procedures. Of the 84 patients, 28 had marked bleeding diathesis (platelet count <= 50000/mm (3) and/or prothrombin time >= 1.7 INR). Endoscopists and patients answered questionnaires using a 100-mm visual analog scale about, respectively, their satisfaction and their tolerance of the procedure. RESULTS: The success rate of TNSC-EGD was comparable to that of POC-EGD (96% vs. 99%). Nasal mucosal hemorrhages induced by TNSC-EGD occurred in 5 patients (6%), but were easily controlled. Compared to the POC-EGD reference test, diagnostic accuracies of TNSC-EGD for detecting esophageal varices, gastric varices, and red color signs were 98%, 98%, and 96%, respectively. Concordance rates on grading esophageal varices and gastric varices were excellent at 93% (kappa = 0.85) and 96% (kappa = 0.87). Endoscopist satisfaction was not significantly different between TNSC-EGD and POC-EGD, whereas patient tolerance of TNSC-EGD was significantly greater than that of POC-EGD (79.0 +/- 14.4 vs. 69.5 +/- 16.1; P = 0.001). CONCLUSION: TNSC-EGD without sedation was found to be feasible, safe, and accurate for evaluating esophageal varices, gastric varices, and red color signs in patients with cirrhosis - even in those with marked bleeding diathesis. Furthermore, it was significantly better tolerated by patients, without altering endoscopist satisfaction. Our findings indicate that TNSC-EGD without sedation might be viewed as a potential alternative to POC-EGD for evaluation of varices. PMID- 21660909 TI - [Ecological management in hospitals]. PMID- 21660910 TI - Women with acute coronary syndromes have a worse prognosis - why? The need to reduce 'treatment-seeking delay'. PMID- 21660911 TI - Diastolic heart failure: predictors of mortality. AB - Diastolic heart failure (HF) as defined by the symptoms and signs of HF, preserved ejection fraction and abnormal diastolic function is estimated to occur in half of all patients presenting with HF. Patients with preserved ejection fraction are older and more often female. The underlying etiology of HF differs, with hypertension being more common in patients with preserved ejection fraction and ischemic heart disease predominant among those with reduced ejection fraction. Diastolic HF is associated with high mortality comparable with that of HF with depressed ejection fraction with a five year survival rate after a first episode of 43% and a higher excess mortality compared with the general population. Despite significant disease burden, clinical and biological prognostic factors in diastolic HF remain poorly understood. There is limited data from well designed studies regarding the effective treatment strategies for this group of patients. The purpose of this review is to summarize the mortality data and predictors of mortality in patients with diastolic HF for better understanding of the prognosis. In patients with diastolic HF older age, male gender, non-Caucasian ethnicity, history of coronary artery disease and atrial fibrillation are associated with poor prognosis. Anemia and B-type natriuretic peptide are significant laboratory variable that predict mortality. Two dimensional echocardiography and tissue Doppler imaging measurements including left ventricular ejection fraction, E/Ea ratio >= 15, restrictive transmiral filling (deceleration time L 140 ms) and Em < 3.5 cm/s are predictors of adverse outcomes in diastolic HF patients. PMID- 21660912 TI - Electrolyte disorders and arrhythmogenesis. AB - Electrolyte disorders can alter cardiac ionic currents kinetics and depending on the changes can promote proarrhythmic or antiarrhythmic effects. The present report reviews the mechanisms, electrophysiolgical (EP), electrocardiographic (ECG), and clinical consequences of electrolyte disorders. Potassium (K+) is the most abundent intracellular cation and hypokalemia is the most commont electrolyte abnormality encountered in clinical practice. The most significant ECG manifestation of hypokalemia is a prominent U wave. Several cardiac and non cardiac drugs are known to suppress the HERG K+ channel and hence the I(K), and especially in the presence of hypokalemia, can result in prolonged action potential duration and QT interval, QTU alternans, early afterdepolarizations, and torsade de pointes ventricular tachyarrythmia (TdP VT). Hyperkalemia affects up to 8% of hospitalized patients mainly in the setting of compromised renal function. The ECG manifestation of hyperkalemia depends on serum K+ level. At 5.5 7.0 mmol/L K+, tall peaked, narrow-based T waves are seen. At > 10.0 mmol/L K+, sinus arrest, marked intraventricular conduction delay, ventricular techycardia, and ventricular fibrillation can develop. Isolated abnormalities of extracellular calcium (Ca++) produce clinically significant EP effects only when they are extreme in either direction. Hypocalcemia, frequently seen in the setting of chronic renal insufficiency, results in prolonged ST segment and QT interval while hypercalcemia, usually seen with hyperparathyroidism, results in shortening of both intervals. Although magnesium is the second most abudent intracellular cation, the significance of magnesium disorders are controversial partly because of the frequent association of other electrolyte abnormalities. However, IV magnesium by blocking the L-type Ca(++) current can successfully terminate TdP VT without affecting the prolonged QT interval. Finally, despite the frequency of sodium abnormalities, particularly hyponatremia, its EP effects are rarely clinically significant. PMID- 21660913 TI - The multiplicative interactions of leukocyte counts with some other risk factors enhance the prognostic value for coronary artery disease. AB - BACKGROUND: The markers of inflammation and (apo)lipoproteins are associated with coronary artery disease (CAD). Simultaneous assessment of the risk factors has been proposed to improve the diagnosis of CAD. The aim of this study was to examine the potential interactions between leukocyte counts and other risk factors. METHODS: The markers of inflammation, (apo)(lipo)proteins, (non)electrolytes, hematological parameters and classical risk factors, were determined in 264 clinically stable angiographically documented subjects. The subjects were classified as CAD cases or controls according to the results of coronary angiography. RESULTS: The frequency and severity of CAD, Framingham CAD scores, relative and absolute risk for CAD and the prevalence of diabetes mellitus and smoking were significantly higher in the third relative to the first tertile of leukocyte counts. Subjects with leukocyte counts in the upper tertile had significant higher levels of serum glucose, triglyceride, hsC-reactive protein, potassium, phosphorus and measured osmolality, and lower levels of apoAI, total protein, albumin and the ratio of albumin/globulins. Analyses by bivariate correlation on differential leukocyte counts showed that these associations are carried mostly by neutrophil, except for diabetes, glucose and triglyceride which were due to lymphocyte counts. By constructing dummy combined variables, high leukocyte counts accompanied by smoking, hypertension, diabetes, and high levels of serum glucose, cholesterol, apoB and apoB/apoAI ratio, exhibited amplified high risk for CAD. CONCLUSIONS: The results show that leukocyte count does interact multiplicatively with smoking, hypertension, diabetes, glucose, cholesterol, apoB and apoB/AI ratio. The simultaneous assessment of leukocyte counts and interactive risk factors enhances the diagnosis of CAD. PMID- 21660914 TI - Gender-related benefit of transport to primary angioplasty: is it equal? AB - BACKGROUND: Infarct size is correlated with duration of coronary artery occlusion. Evidence suggests that transport for primary angioplasty improves outcomes, but there is no agreement regarding differences in prognosis between men and women. We compared outcomes in men and women with ST-segment elevation myocardial infarction (STEMI) transferred from another hospital against those who had been transported directly to an invasive treatment center. METHODS: Data was collected between June 2005 and May 2006 from a registry of 26,035 patients with STEMI and in whom primary angioplasty had been performed. RESULTS: A total of 10,708 patients underwent primary angioplasty. Of these, 3,359 men and 1,469 women were transported directly, while 4,135 men and 1,745 women were transferred from another site. In-hospital mortality and at one month, six months and 12 months after hospital discharge was significantly higher in women than in men. The prognosis of women transported directly was similar to that of women transferred from another site. However, there was a tendency, albeit insignificant, towards higher mortality at six and 12 months in women transported from another hospital. CONCLUSIONS: To reduce mortality in STEMI, an immediate reperfusion must not be delayed. This conclusion is valid particularly for women who are at greater risk of death. PMID- 21660915 TI - Assessment of ventricular and left atrial mechanical functions, atrial electromechanical delay and P wave dispersion in patients with scleroderma. AB - BACKGROUND: The aim of this study was to investigate ventricular functions and left atrial (LA) mechanical functions, atrial electromechanical coupling, and P wave dispersion in scleroderma patients. METHODS: Twenty-six patients with scleroderma and twenty-four controls were included. Left and right ventricular (LV and RV) functions were evaluated using conventional echocardiography and tissue Doppler imaging (TDI). LA volumes were measured using the biplane area- length method and LA mechanical function parameters were calculated. Inter intraatrial electromechanical delays were measured by TDI. P wave dispersion was calculated by 12-lead electrocardiograms. RESULTS: LV myocardial performance indices (MPI) and RV MPI were higher in patients with scleroderma (p = 0.000, p = 0.000, respectively) while LA passive emptying fraction was decreased and LA active emptying fraction was increased (p = 0.051, p = 0.000, respectively). P wave dispersion and inter-intraatrial electromechanical delay were significantly higher in patients with scleroderma (25 [10-60] vs 20 [0-30], p = 0.000, 16.50 [7.28-26.38] vs 9.44 [3.79-15.78] and 11.33 [4.88-16.06] vs 4.00 [0-12.90], p < 0.05, respectively). Interatrial electromechanical delay was negatively correlated with LV E wave, (p = 0.018). LV E wave was demonstrated to be a factor independent of the interatrial electromechanical delay (R2 = = 0.270, b = -0.52, p = 0.013). CONCLUSIONS: This study showed that in scleroderma patients, global functions of LV, RV and mechanical functions of LA were impaired, intra interatrial electromechanical delays were prolonged and P wave dispersion was higher. LV E wave was demonstrated to be a factor that is independent of the interatrial electromechanical delay. Reduced LV E wave may also give additional information on the process of risk stratification of atrial fibrillation. PMID- 21660916 TI - Skin microcirculation and echocardiographic and biochemical indices of left ventricular dysfunction in non-diabetic patients with heart failure. AB - BACKGROUND: We sought to noninvasively investigate skin microcirculation and to assess the relation between parameters of microcirculation and echocardiographic and biochemical parameters of left ventricular (LV) function in non-diabetic patients with heart failure (HF). METHODS AND RESULTS: We measured skin microcirculation with laser Doppler flowmetry (LDF) at basal conditions (MFb), after warming to 44 degrees Centigrade (MF44) and after occlusion (AUC, PF%). Blood was sampled for NT-proBNP. We obtained information on patients' medical history and medication status. The mean (SD) age of 100 patients (43 women) was 68.2 +/- 11.5 years. LV ejection fraction (LVEF) averaged 34.9 +/- 13.3%, LV end diastolic diameter (LVEDD) 6.0 +/- 0.9 cm, NT-proBNP 4,582.6 +/- 6,339.7 pg/mL. The parameters of microcirculation averaged: MFb 6.2 +/- 4.7 perfusion units (PU), PF% 716.0 +/- 437.8%, AUC 794 +/- 706.1 PU/s, and MF44 77.9 +/- 40.2 PU. NT proBNP correlated negatively with LVEF (p <= 0.0001) and positively with LVEDD (p = 0.003). MFb was positively correlated with LVEF (r = 0.24, p = 0.03), and MF44 was negatively correlated with LVEDD (r = 0.22, p = 0.02). The relations remained significant after adjustments for sex, age, and use of medication. We observed no relation between NT-proBNP and microcirculatory derangement. CONCLUSIONS: LDF derived parameters of skin microcirculation are related to echocardiographic, but not biochemical, indices of HF. PMID- 21660917 TI - Impact of moderate coronary atherosclerosis on long-term left ventricular remodeling after aortic valve replacemen. AB - BACKGROUND: The role of coronary atherosclerosis (CA+) in ventricular remodeling after aortic valve replacement (AVR) for isolated aortic stenosis (AS) is not well defined. We sought to evaluate the impact of not revascularized moderate coronary atherosclerosis in long-term left ventricular (LV) remodeling after AVR. METHODS: We assessed by coronariography the coronary artery disease in 66 patients referred for AVR and evaluated morphological and functional LV data by echocardiography both preoperatively and postoperatively (3 +/- 1.2 years). RESULTS: In patients without coronary atherosclerosis, hypertrophy regression was more intense and the absolute reverse remodeling was higher in LV mass index ( 55.8 +/- 36 g/m2 vs -28.4 +/- 34 g/m2, p = 0.004), reduction of LV dimensions (LV end-diastolic diameter [LVEDD]: -4.1 +/- 7.4 mm vs -2.2 +/- 8.3 mm, p = 0.04), and regression of wall thickness (interventricular septum [IVS]: -3.3 +/- 2.6 mm vs -1.6 +/- 2.2 mm, p = 0.01; and posterior wall thickness [PWT]: -2.1 +/- 2.1 mm vs 0.6 +/- 2.1 mm, p = 0.012). CONCLUSIONS: After AVR for AS, not revascularized moderate coronary atherosclerosis determines a long-term lesser degree of LV hypertrophy regression and a worse absolute reverse remodeling of LV mass index, LVEDD, IVS and PWT. PMID- 21660918 TI - Prevalence of orthostatic hypotension in a series of elderly Mexican institutionalized patients. AB - BACKGROUND: Orthostatic hypotension (OH) is a common problem among the elderly. It is associated with an increase in morbidity and mortality, but its prevalence in Mexico is unknown. METHODS: We conducted a cross-sectional prospective study of intern patients at several Mexican elderly assistance institutions. We carried out a history and took blood pressure readings in a seated position, immediately after standing up, and again after 3 min of standing up. RESULTS: We evaluated 132 patients, mean age 82.3 +/- 9.5 years, 74.1% of them female. Thirty-nine (29.3%) subjects had OH. They had a higher prevalence of hypothyroidism, Parkinson's disease, depression and alcoholism. Their Minimental result was 15.45 +/- 7.2 vs 16.12 +/- 7.9 (p = 0.6) among those without OH, and their quality of life (Minnesota scale) was 12.1 +/- 7.3 vs 9.15 +/- 7.05 (p = 0.03). They used more ACEI, digoxin and levothyroxin. Hypertension and alcoholism showed respectively a RR of 2.6 (95% CI 0.9-7.6, p = 0.06) and 3.18 (95% CI 0.96-10.48, p = 0.05) to develop OH. CONCLUSIONS: OH was present in 29.3% of the studied population. A third of them had hypertension. The use of different medications does not solely explain OH, so it is necessary to look for different associations. Among those, chronic alcoholism stands out. OH is associated with a poorer quality of life and cognitive performance. OH is asymptomatic in most cases. PMID- 21660919 TI - Interventional creation of an atrial septal defect and its impact on right ventricular function: an animal study with the pressure-volume conductance system. AB - BACKGROUND: The aim of our study was to assess the suitability of different interventional techniques to create an atrial septal defect (ASD) and to evaluate the short-term effects of right ventricular (RV) volume overload on RV contractility in the growing swine. METHODS: Thirteen ASD and six control animals were studied. An ASD was created by balloon dilatation (BD) of the fossa ovalis (n = 4) or by implantation of a multi-perforated Amplatzer Septal Occluder (n = 4) or a patch-less nitinol device (n = 5). After 4.8 (3.9-6.0) weeks, the amounts of left-to-right shunting (Qp/Qs) and RV contractility (end systolic elastance - Ees) were assessed. RESULTS: In the ASD group, a significant left-to-right shunt could be documented (Qp/Qs 1.5 +/- +/- 0.4). However, a shunt was absent in the BD subgroup (Qp/Qs 1.1 +/- 0.1). In animals with devices implanted, a significant relationship between the post-mortem ASD area and Qp/Qs was found (r = 0.68, p < 0.05). Compared to controls, RV contractility was not significantly impaired at rest and during dobutamine in ASD animals (Ees: 0.40 +/- 0.20 vs 0.54 +/- 0.12 and 0.75 +/- 0.29 vs 1.04 +/- 0.24 mm Hg/mL, p = NS for both). CONCLUSIONS: Device implantation is necessary to create a patent ASD resulting in significant left-to-right shunting. In an experimental ASD model, a five week period of chronic RV volume overload does not alter RV contractility significantly. PMID- 21660920 TI - Low admission triglyceride and mortality in acute coronary syndrome patients. AB - BACKGROUND: The relationship between admission triglyceride (TG) levels and long term outcomes has not been established in patients with acute coronary syndrome. We tested the hypothesis that patients who develop non-ST segment elevation myocardial infarction (NSTEMI) despite low TG have a worse cardiovascular outcome in the long term. METHODS: Patients admitted with NSTEMI between 1 January 1997 and 31 December 2000 and with fasting lipid profiles measured within 24 hours of admission were included for analysis. Baseline characteristics and three-year all cause mortality were compared between the patients with TG above and below the median. Multivariate analysis was used to determine the predictors of all-cause mortality and adjusted survival was analyzed using the Cox proportional hazard model. RESULTS: Of 517 patients, 395 had TG L 200 mg/dL and 124 had TG > 200 mg/dL. Patients with low TG were more often Caucasian, with no significant differences in gender or severity of coronary artery disease between the two groups. There was a trend for increased all-cause mortality at six months (9% vs 3%, p = 0.045) and three years (13.4% vs 5.6%, p = 0.016) in patients with low TG. In multivariate analysis, low TG level at admission was an independent predictor of increased mortality at three years (adjusted OR 2.5, 95% CI = 1.04 5.9, p = 0.04). CONCLUSIONS: In our cohort, lower TG at admission is associated with increased three-year mortality in patients with NSTEMI. Whether this is a result of current therapy, or a marker for worse baseline characteristics, needs to be studied further. PMID- 21660921 TI - Aortic atresia with normally developed left ventricle in a young adult. AB - Congenital aortic valve atresia is usually part of a developmental anomaly usually called 'hypoplastic left-heart syndrome'. To the best of our knowledge, most reported cases of aortic atresia have been associated with hypoplasia of the ascending aorta, of the left ventricle, and of the mitral valve. We report a patient presenting with aortic atresia with a ventricular septal defect and a normally sized left ventricle. PMID- 21660922 TI - Coronary artery-left ventricular microfistulae associated with apical hypertrophic cardiomyopathy. AB - A 58 year-old Caucasian man was admitted to the coronary care unit with angina pectoris. There were deep inverted T waves and ST segment depression at anterior precordial derivations. Coronary angiography revealed widespread coronary artery to left ventricular microfistulae arising from distal portions of both left and right coronary systems. Left ventriculography and transthoracic echocardiography revealed typical features of apical hypertrophic cardiomyopathy. Angina pectoris was alleviated by beta-blocker therapy. Both multiple coronary artery to left ventricular microfistulae and apical hypertrophic cardiomyopathy are rare conditions and little is known about pathophysiological and clinical aspects of this combination. Accumulating evidence will provide us this information so that the management of the patients will be enhanced. PMID- 21660923 TI - Ventricular and supraventricular arrhythmias and heart failure in a patient with left ventricular noncompaction and Brugada syndrome. AB - We report a 47 year-old male patient with coexistence of left ventricular noncompaction and Brugada syndrome. He presented malignant ventricular arrhythmias followed by cardioverter- -defibrillator implantation, atrial fibrillation and flutter and progressive heart failure. This case could be an example of the coexistence of two rare diseases of various genetic patterns that only partially showed overlapping symptomatology and complications, particularly ventricular arrhythmias. PMID- 21660924 TI - Paradoxical systolic and diastolic flow abnormalities in hypertrophic cardiomyopathy with mid-cavity systolic obstruction. AB - Systolic obstruction of the left ventricular outflow tract, either at rest or during provocation, is a frequent finding in patients with hypertrophic cardiomyopathy. Mid-cavity obstruction is uncommon, and intraventricular diastolic pressure gradients in association with either mid-cavity of apical hypertrophy are reported only rarely. We describe a patient with hypertrophic cardiomyopathy with evidence of systolic mid-cavity obstruction, and with complex diastolic paradoxical flow abnormalities within the left ventricular cavity detected by colour and pulsed-wave Doppler. Contrast echocardiography confirmed the presence of diastolic and systolic obstruction at the mid-ventricular level, with evidence of an apical cavity sequestered from the main body of the left ventricle during systolic mid-cavity obliteration. PMID- 21660925 TI - A rare type of 'coronary arterial - left ventricular fistula' via thebesian veins in a Fragile X syndrome carrier. PMID- 21660926 TI - A giant right atrial myxoma demonstrated by RT-3D transesophageal echocardiography and magnetic resonance imaging. PMID- 21660927 TI - Progressive conduction disturbance in myotonic dystrophy. AB - Myotonic dystrophy (DM), the commonest dystrophy in adults, is an autosomal dominant disease characterized by a variety of multisystemic features. Two main genetically distinct forms of DM have been identified: type 1 (DM1), the classic form first described by Steinert, and type 2 (DM2), identified by Ricker. DM1 is caused by trinucleotide expansion of cytosine- -thymine-guanine (CTG) in the myotonic dystrophy protein kinase gene, whereas in DM2 the expansion of tetranucleotide repeats (CCTG) in the zinc finger protein 9 gene was identified. Both mutations are dynamic and are located in non-coding parts of the genes. Phenotype variability of DM1 and DM2 is caused by a molecular mechanism due to mutated RNA toxicity. DM1 is characterized by myotonia and multi-organ damage with major cardiac involvement. The disease is usually slowly progressive and life expectancy is reduced by the increased mortality associated with cardiopulmonary complications. Sudden death can occur as a consequence of cardiac conduction abnormalities. We present the ECG of a 26 year-old male with DM1 and progressive conduction system disturbance characterized by syncopal episodes. PMID- 21660928 TI - Subcutaneous implantable cardioverter-defibrillator (S-ICD). AB - Current state-of-the art implantable cardioverter-defibrillator (ICD) systems have been proven to be safe and effective in treating ventricular arrhythmias leading to cardiac death. ICDs require placement of at least one lead in, or on, the heart. Surgical placement under fluoroscopy and the ongoing presence of the transvenous leads within the patient's heart are associated with a significant proportion of the complications related to this well-established and highly effective therapy. A new ICD has been developed that is implanted entirely subcutaneously (S-ICD), thus eliminating the need for lead placement in or on the heart and simplifying surgery by eliminating the need for imaging equipment. Recent clinical studies suggest that the S-ICD system provides a viable alternative to conventional transvenous devices that may reduce barriers to treatment and lead to the wider adoption of this life-saving therapy. PMID- 21660929 TI - Imaging of persistent left sided superior vena cava with echocardiography and multi-slice computed tomography: implications for daily practice. AB - Persistent left sided superior vena cava is a congenital abnormality encountered not uncommonly by the echocardiographer or cardiac radiologist. Recognition of its presence is important in the differential diagnosis of dilatation of the coronary sinus. We discuss the echocardiographic and computed tomography findings of this congenital abnormality, and the implications for clincal practice. PMID- 21660930 TI - Karel Frederick Wenckebach (1864-1940): a giant of medicine. PMID- 21660931 TI - Population history of the Red Sea--genetic exchanges between the Arabian Peninsula and East Africa signaled in the mitochondrial DNA HV1 haplogroup. AB - Archaeological studies have revealed cultural connections between the two sides of the Red Sea dating to prehistory. The issue has still not been properly addressed, however, by archaeogenetics. We focus our attention here on the mitochondrial haplogroup HV1 that is present in both the Arabian Peninsula and East Africa. The internal variation of 38 complete mitochondrial DNA sequences (20 of them presented here for the first time) affiliated into this haplogroup testify to its emergence during the late glacial maximum, most probably in the Near East, with subsequent dispersion via population expansions when climatic conditions improved. Detailed phylogeography of HV1 sequences shows that more recent demographic upheavals likely contributed to their spread from West Arabia to East Africa, a finding concordant with archaeological records suggesting intensive maritime trade in the Red Sea from the sixth millennium BC onwards. Closer genetic exchanges are apparent between the Horn of Africa and Yemen, while Egyptian HV1 haplotypes seem to be more similar to the Near Eastern ones. PMID- 21660932 TI - Climate-related variation of the human nasal cavity. AB - The nasal cavity is essential for humidifying and warming the air before it reaches the sensitive lungs. Because humans inhabit environments that can be seen as extreme from the perspective of respiratory function, nasal cavity shape is expected to show climatic adaptation. This study examines the relationship between modern human variation in the morphology of the nasal cavity and the climatic factors of temperature and vapor pressure, and tests the hypothesis that within increasingly demanding environments (colder and drier), nasal cavities will show features that enhance turbulence and air-wall contact to improve conditioning of the air. We use three-dimensional geometric morphometrics methods and multivariate statistics to model and analyze the shape of the bony nasal cavity of 10 modern human population samples from five climatic groups. We report significant correlations between nasal cavity shape and climatic variables of both temperature and humidity. Variation in nasal cavity shape is correlated with a cline from cold-dry climates to hot-humid climates, with a separate temperature and vapor pressure effect. The bony nasal cavity appears mostly associated with temperature, and the nasopharynx with humidity. The observed climate-related shape changes are functionally consistent with an increase in contact between air and mucosal tissue in cold-dry climates through greater turbulence during inspiration and a higher surface-to-volume ratio in the upper nasal cavity. PMID- 21660933 TI - Exacerbated egg-induced immunopathology in murine Schistosoma mansoni infection is primarily mediated by IL-17 and restrained by IFN-gamma. AB - In schistosomiasis, the severity of CD4(+) T-cell-mediated hepatic granulomatous inflammation against parasite eggs varies considerably in humans and among mouse strains. In C57BL/6 mice, pronounced exacerbation of immunopathology induced by immunization with schistosome egg Ag in CFA (SEA/CFA) substantially recapitulates the natural high pathology seen in CBA mice; both are associated with a significant elevation of Th17- and Th1-cell-derived proinflammatory cytokines. We now investigated the relative contribution of the effector cytokines IL-17 and IFN-gamma in pathology development of 7 wk-infected, SEA/CFA-immunized, IL-17(-/ ) , IFN-gamma(-/-) , and IL-17/IFN-gamma(-/-) mice. In IL-17(-/-) mice there was significant reduction of immunopathology despite increased levels of IFN-gamma, whereas in IFN-gamma(-/-) mice, markedly exacerbated immunopathology correlated with an increase in IL-17. In IL-17/IFN-gamma(-/-) mice, complete resistance to SEA/CFA-induced disease exacerbation was associated with a reduction in IL-23p19, IL-1beta, CXCL1 and iNOS, and with an increase in IL-5, IL-10 and Relmalpha. IL 17 and IFN-gamma were derived from distinct CD4(+) T cells in which production of each cytokine was suppressed by the other. Our results indicate that severe immunopathology in murine schistosomiasis is mainly driven by IL-17 and regulated by IFN-gamma; however, in the absence of IL-17, IFN-gamma is capable of exerting a limited, yet significant, pathogenic function. PMID- 21660934 TI - Specific depletion reveals a novel role for neutrophil-mediated protection in the liver during Listeria monocytogenes infection. AB - Previous studies have suggested that neutrophils are required for resistance during infection with multiple pathogenic microorganisms. However, the depleting antibody used in those studies binds to both Ly6G and Ly6C (anti-Gr-1; clone RB6 8C5). This antibody has been shown to deplete not only neutrophils but also monocytes and a subset of CD8(+) T cells. Recently, an antibody against Ly6G, which specifically depletes neutrophils, was characterized. In the present study, neutrophils are depleted using the antibody against Ly6G during infection with the intracellular bacterium Listeria monocytogenes (LM). Our data show that neutrophil-depleted mice are much less susceptible to infection than mice depleted with anti-Gr-1. Although neutrophils are required for clearance of LM, their importance is more pronounced in the liver and during a high-dose bacterial challenge. Furthermore, we demonstrate that the protection mediated by neutrophils is due to the production of TNF-alpha, but not IFN-gamma. Additionally, neutrophils are not required for the recruitment of monocytes or the generation of adaptive T-cell responses during LM infection. This study highlights the importance of neutrophils during LM infection, and indicate that depletion of neutrophils is less detrimental to the host than depletion of all Gr 1-expressing cell populations. PMID- 21660935 TI - Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model. AB - Lipopolysaccharide (LPS) triggers deleterious systemic inflammatory responses when released into the circulation. LPS-binding protein (LBP) in the serum plays an important role in modifying LPS toxicity by facilitating its interaction with LPS signaling receptors, which are expressed on the surface of LPS-responsive cells. We have previously demonstrated that high mobility group box 1 (HMGB1) can bind to and transfer LPS, consequently increasing LPS-induced TNF-alpha production in human peripheral blood mononuclear cells (PBMCs). We report here on the identification of two LPS-binding domains within HMGB1. Furthermore, using 12 synthetic HMGB1 peptides, we define the LPS-binding regions within each domain. Among them, synthetic peptides HPep1 and HPep6, which are located in the A and B box domains of HMGB1, bind to the polysaccharide and lipid A moieties of LPS respectively. Both HPep1 and HPep6 peptides inhibited binding of LPS to LBP and HMGB1, LBP-mediated LPS transfer to CD14, and cellular uptake of LPS in RAW264.7 cells. These peptides also inhibited LPS-induced TNF-alpha release in human PBMCs and induced lower levels of TNF-alpha in the serum in a subclinical endotoxemia mouse model. These results indicate that HMGB1 has two LPS-binding peptide regions that can be utilized to design anti-sepsis or LPS-neutralizing therapeutics. PMID- 21660936 TI - Regulation of antigen-expressing dendritic cells by double negative regulatory T cells. AB - TCRalphabeta(+) CD3(+) CD4(-) CD8(-) NK1.1(-) double negative (DN) Tregs comprise 1-3% of peripheral T lymphocytes in mice and humans. It has been demonstrated that DN Tregs can suppress allo-, xeno- and auto-immune responses in an Ag-specific fashion. However, the mechanisms by which DN Tregs regulate immune responses remain elusive. Whether DN Tregs can regulate DCs has not been investigated previously. In this study, we demonstrate that DN Tregs express a high level of CTLA4 and are able to down-regulate costimulatory molecules CD80 and CD86 expressed on Ag-expressing mature DCs (mDCs). DN Tregs from CTLA4 KO mice were not able to downregulate CD80 and CD86 expression, indicating that CTLA4 is critical for DN Treg-mediated downregulation of costimulatory molecule expression on Ag-expressing mature DCs. Furthermore, DN Tregs could kill both immature and mature allogeneic DCs, as well as Ag-loaded syngeneic DCs, in an Ag specific manner in vitro and in vivo, mainly through the Fas-FasL pathway. These data demonstrate, for the first time, that DN Tregs are potent regulators of DCs and may have the potential to be developed as a novel immune suppression treatment. PMID- 21660937 TI - The role of tetraspanin CD63 in antigen presentation via MHC class II. AB - Interactions between MHC class II (MHC II)-positive APCs and CD4(+) T cells are central to adaptive immune responses. Using an Epstein-Barr virus (EBV) transformed B lymphoblastoid cell line (LCL) as MHC II-positive APCs and CD4(+) T-cell clones specific for two endogenously expressed EBV antigens, we found that shRNA knockdown of the tetraspanin protein CD63 in LCL cells consistently led to increased CD4(+) T-cell recognition. This effect was not due to enhanced antigen processing nor to changes in MHC II expression since CD63 knockdown did not influence the amount or dimerization of MHC II in LCL cells. We therefore investigated the possible involvement of exosomes, small MHC II- and tetraspanin abundant vesicles which are secreted by LCL cells and which we found could themselves activate the CD4(+) T-cell clones in an MHC II-dependent manner. While equal loadings of exosomes purified from the control and CD63(low) LCLs stimulated T cells to a comparable degree, we found that exosome production significantly increased following CD63-knockdown, suggesting that this may underlie the greater T-cell stimulatory capacity of the CD63(low) LCLs. Taken together, our data reveal a new insight into the mechanisms by which tetraspanins are involved in the regulation of MHC II-dependent T-cell stimulation. PMID- 21660938 TI - GM-CSF increases cross-presentation and CD103 expression by mouse CD8+ spleen dendritic cells. AB - Resident CD8(+) DCs perform several functions, including cross-presenting antigen and rapidly engulfing the Gram-positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8(+) DCs are modulated. Here, we show that granulocyte-macrophage CSF (GM-CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross-presentation and rapid uptake of L. monocytogenes by resident CD8(+) DCs. This previously unrecognized functional enhancement of CD8(+) DCs by GM-CSF was independent of promoting DC survival in vitro. Enhancement of these functions by GM-CSF was also marked by CD103 expression on CD8(+) DCs that was strongly regulated by GM-CSF. Our findings not only identify GM-CSF as a key molecule regulating CD8(+) DC function, but also as a factor responsible for functional heterogeneity of CD8(+) DCs that is at least substantially demarcated by CD103 expression. PMID- 21660939 TI - Division of labor between subsets of lymph node dendritic cells determines the specificity of the CD8+ T-cell recall response to influenza infection. AB - Cytotoxic T lymphocytes (CTLs) are important targets for vaccines against a wide variety of infections that enter the body via mucosal tissues. To induce effective immunity these vaccines must include the most protective epitopes and elicit rapid recall responses at the site of infection. Although live attenuated viruses are sometimes used to induce cellular immunity against recurrent influenza infections, the mechanisms that determine the magnitude of the response to individual viral components are very poorly defined. Heterosubtypic infections in C57BL/6 mice illustrate an additional level of complexity, when the antigen specificity of the response shifts dramatically between primary and secondary challenge. This model provides a unique opportunity to identify the mechanisms that regulate memory CD8(+) T-cell reactivation in vivo and control the specificity of the recall response by pathogen-specific CTL. We show that multiple factors contribute to the changing pattern of immunodominance during secondary infection, including the location of the memory CD8(+) T cells at the time of reinfection and their ability to directly recognize migratory CD103(+) DCs as they arrive in the lung draining LN. PMID- 21660940 TI - Enhancing alloreactivity does not restore GVHD induction but augments skin graft rejection by CD4+ effector memory T cells. AB - Graft-versus-host disease (GVHD) caused by donor T cells attacking recipient tissues is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloSCT). Studies have shown that effector memory T (T(EM) ) cells do not cause GVHD but are capable of immune functions post-transplant, including graft-versus-leukemia (GVL) effects, but the reasons for this are unclear. In mice, the T(EM) pool may have a less diverse T cell receptor (TCR) repertoire than naive T (T(N) ) cells with fewer alloreactive clones. We therefore tested whether enhancing the alloreactivity of T(EM) cells would restore their ability to cause GVHD. In an MHC-matched system, alloreactive T(EM) cells were created by transferring GVHD effector cells into syngeneic recipients and allowing conversion to T(EM) cells. Upon retransfer to freshly transplanted recipients, these cells caused only mild GVHD. Similarly, in an MHC mismatched system, T(EM) cells with a proven increased precursor frequency of alloreactive clones only caused limited GVHD. Nonetheless, these same cells mounted strong in vitro alloresponses and caused rapid skin graft rejection. T(EM) cells created from CD4(+) T cells that had undergone lymphopenia-induced proliferation (LIP) also caused only mild GVHD. Our findings establish that conversion to T(EM) cells significantly reduces GVHD potency, even in cells with a substantially enhanced alloreactive repertoire. PMID- 21660943 TI - Reducing the risk of overdiagnosis in lung cancer: a support from molecular biology. AB - Early detection and swift treatment, when achievable, may significantly affect prognosis in lung cancer patients. Therefore, individuals with a high risk for lung cancer are invited to participate into international screening programs, such as the International Early Lung Cancer Action Program (I-ELCAP). An undesirable consequence of such massive enterprises is the detection of pulmonary nodules also in subjects who are unlikely to ultimately die from lung cancer. Nevertheless, the individuals with pulmonary nodule undergo stringent diagnostic procedures to assess the nature of the lesion. This implies a noticeable (physical and emotional) stress for our patients and the likelihood of overdiagnosis and, potentially, consequent overtreatment. Molecular markers, more specifically, microRNAs, might significantly add value to the workup process aiming at the distinction between benign and malignant lesions and, among the malignant ones, those concretely threatening for the patients' survival. We are confident that such a multidisciplinary approach would better suit our patients' diagnostic and/or therapeutic, actual needs. PMID- 21660945 TI - Growth factors controlling ovarian functions. AB - The present review demonstrates an important role of different growth factors (of insulin-like growth factors, epidermal growth factors, vascular endothelial growth factor, thrombopoietin, erytropoietin, hepatocyte growth factor, and growth factors of Hedgehog, Wnt and Notch families) in control of different ovarian functions--ovarian cell proliferation, apoptosis, folliculogenesis, luteogenesis, oogenesis, release of hormones, response to upstream hormonal regulators, fertility and, in some cases, in development of ovarian disorders. The possibility of practical application of these growth factors for characterization, prediction, and regulation the ovarian state is demonstrated. PMID- 21660946 TI - Adipogenic differentiation of human mesenchymal stromal cells is down-regulated by microRNA-369-5p and up-regulated by microRNA-371. AB - Long-term culture of human mesenchymal stromal cells (MSC) has implications on their proliferation and differentiation potential and we have demonstrated that this is associated with up-regulation of the five microRNAs miR-29c, miR-369-5p, miR-371, miR-499, and let-7f. In this study, we examined the role of these senescence-associated microRNAs for cellular aging and differentiation of MSC. Proliferation was reduced upon transfection with miR-369-5p, miR-371, and miR 499. Adipogenic differentiation was impaired by miR-369-5p whereas it was highly increased by miR-371. This was accompanied by respective gene expression changes of some adipogenic key molecules (adiponectin and fatty acid-binding protein 4 [FABP4]). Furthermore luciferase reporter assay indicated that FABP4 is a direct target of miR-369-5p. Microarray analysis upon adipogenic or osteogenic differentiation revealed down-regulation of several microRNAs albeit miR-369-5p and miR-371 were not affected. Expression of the de novo DNA methyltransferases DNMT3A and DNMT3B was up-regulated by transfection of miR-371 whereas expression of DNMT3A was down-regulated by miR-369-5p. In summary, we identified miR-369-5p and miR-371 as antagonistic up-stream regulators of adipogenic differentiation and this might be indirectly mediated by epigenetic modifications. PMID- 21660944 TI - The p53 tumor suppressor protein regulates hematopoietic stem cell fate. AB - The p53 tumor suppressor protein is a key transcription factor that regulates several signaling pathways involved in the cell's response to stress. Through stress-induced activation, p53 accumulates and triggers the expression of target genes that protect the genetic integrity of all cells including hematopoietic stem cells (HSCs). These protective mechanisms include cell-cycle arrest, DNA repair, induction of apoptosis, or initiation of senescence. In addition to its function under stress conditions, p53 has important functions during steady-state hematopoiesis, regulating HSC quiescence and self-renewal. In addition, it appears that p53 levels affect HSC competition for the hematopoietic niche, with the less p53 activated HSCs preferentially surviving. The specific genes and precise mechanisms underlying p53's effects on normal HSCs are slowly being clarified. p53 also plays an important role in leukemia stem cell (LSC) behavior, with p53 loss affecting drug resistance and disease progression. Pharmacologic activation of p53 function could overcome the adverse impact of p53 inactivation in LSCs. Thus, understanding the p53 regulatory mechanisms active in HSCs and LSCs may promote the development of new therapeutic strategies that could eliminate the population of largely quiescent LSCs. PMID- 21660947 TI - The effect of exercise training on transverse tubules in normal, remodeled, and reverse remodeled hearts. AB - The response of transverse (T)-tubules to exercise training in health and disease remains unclear. Therefore, we studied the effect of exercise training on the density and spacing of left ventricle cardiomyocyte T-tubules in normal and remodeled hearts that associate with detubulation, by confocal laser scanning microscopy. First, exercise training in normal rats increased cardiomyocyte volume by 16% (P < 0.01), with preserved T-tubule density. Thus, the T-tubules adapted to the physiologic hypertrophy. Next, we studied T-tubules in a rat model of metabolic syndrome with pressure overload-induced concentric left ventricle hypertrophy, evidenced by 15% (P < 0.01) increased cardiomyocyte size. These rats had only 85% (P < 0.01) of the T-tubule density of control rats. Exercise training further increased cardiomyocyte volume by 8% (P < 0.01); half to that in control rats, but the T-tubule density remained unchanged. Finally, post myocardial infarction heart failure induced severe cardiac pathology, with a 70% (P < 0.01) increased cardiomyocyte volume that included both eccentric and concentric hypertrophy and 55% (P < 0.01) reduced T-tubule density. Exercise training reversed 50% (P < 0.01) of the pathologic hypertrophy, whereas the T tubule density increased by 40% (P < 0.05) compared to sedentary heart failure, but remained at 60% of normal hearts (P < 0.01). Physiologic hypertrophy associated with conserved T-tubule spacing (~1.8-1.9 um), whereas in pathologic hypertrophy, T-tubules appeared disorganized without regular spacing. In conclusion, cardiomyocytes maintain the relative T-tubule density during physiologic hypertrophy and after mild concentric pathologic hypertrophy, whereas after severe pathologic remodeling with a substantial loss of T-tubules; exercise training reverses the remodeling and partly corrects the T-tubule density. PMID- 21660948 TI - Nitric oxide production by endothelin-1 enhances astrocytic migration via the tyrosine nitration of matrix metalloproteinase-9. AB - The deleterious effects of endothelin-1 (ET-1) in the central nervous system (CNS) include disturbance of water homeostasis and blood-brain barrier (BBB) integrity. In the CNS, ischemic injury elicits ET-1 release from astrocytes, behaving through G-protein coupled ET receptors. These considerations raise the question of whether ET-1 influences cellular functions of astrocytes, the major cell type that provides structural and functional support for neurons. Uncontrolled nitric oxide (NO) production has been implicated in sterile brain insults, neuroinflammation, and neurodegenerative diseases, which involve astrocyte activation and neuronal death. However, the detailed mechanisms of ET-1 action related to NO release on rat brain astrocytes (RBA-1) remain unknown. In this study, we demonstrate that exposure of astrocytes to ET-1 results in the inducible nitric oxide synthase (iNOS) up-regulation, NO production, and matrix metalloproteinase-9 (MMP-9) activation in astrocytes. The data obtained with Western blot, reverse transcription-PCR (RT-PCR), and immunofluorescent staining analyses showed that ET-1-induced iNOS expression and NO production were mediated through an ET(B)-dependent transcriptional activation. Engagement of G(i/o)--and G(q) -coupled ET(B) receptors by ET-1 led to activation of c-Src-dependent phosphoinositide 3-kinase (PI3K)/Akt and p42/p44 mitogen-activated protein kinase (MAPK) and then activated transcription factor nuclear factor-kappaB (NF-kappaB). The activated NF-kappaB was translocated into nucleus and thereby promoted iNOS gene transcription. Ultimately, NO production stimulated by ET-1 enhanced the migration of astrocytes through the tyrosine nitration of MMP-9. Taken together, these results suggested that in astrocytes, activation of NF-kappaB by ET(B) dependent c-Src, PI3K/Akt, and p42/p44 MAPK signalings is necessary for ET-1 induced iNOS gene up-regulation. PMID- 21660949 TI - Expression of members of the miRNA17-92 cluster during development and in carcinogenesis. AB - The six microRNAs (miRNA) encoded by the miR-17-92 cluster, also named oncomir-1, have been associated with carcinogenesis and typically exhibit-increased expression in tumors. Despite the well-established role for the miR-17-92 cluster in an oncogenic network, the physiological function of these miRNAs in normal tissues remains unresolved. In order to investigate whether there are similar patterns of miR-17-92 expression during embryogenesis and carcinogenesis, we have preformed a systematic study of the expression in cultured carcinoma cells, cultured primary human keratinocytes (KC), and during development of some murine tissues. Both levels of expression of the primary transcript (pri-miRNA) and levels of expression of the individual members of the cluster were monitored. Irrespectively of tissue examined we found that the level of expression decreased markedly during development. With cultured primary human KCs their levels of expression of some of these microRNAs decreased as the number of cell passages increased. Their levels of expression in cultured carcinoma cells, in contrasts, increased, or remained unchanged, with increasing number of cell passages. The results suggest these microRNAs are involved in the regulation of foetal development and that they may promote proliferation and inhibit differentiation during embryogenesis and carcinogenesis. Additionally, the six microRNAs exhibit variable tissue expression, suggesting selective processing of these microRNAs. PMID- 21660950 TI - EGF-induced ERK-activation downstream of FAK requires rac1-NADPH oxidase. AB - Reactive oxygen species (ROS) function as signaling molecules mainly by reversible oxidation of redox-sensitive target proteins. ROS can be produced in response to integrin ligation and growth factor stimulation through Rac1 and its effector protein NADPH oxidase. One of the central roles of Rac1-NADPH oxidase is actin cytoskeletal rearrangement, which is essential for cell spreading and migration. Another important regulator of cell spread is focal adhesion kinase (FAK), a coordinator of integrin and growth factor signaling. Here, we propose a novel role for NADPH oxidase as a modulator of the FAK autophosphorylation site. We found that Rac1-NADPH oxidase enhanced the phosphorylation of FAK at Y397. This site regulates FAK's ability to act as a scaffold for EGF-mediated signaling, including activation of ERK. Accordingly, we found that EGF-induced activation of FAK at Y925, the following activation of ERK, and phosphorylation of FAK at the ERK-regulated S910-site depended upon NADPH oxidase. Furthermore, the inhibition of NADPH oxidase caused excessive focal adhesions, which is in accordance with ERK and FAK being modulators of focal adhesion dissociation. Our data suggest that Rac1 through NADPH oxidase is part of the signaling pathway constituted by FAK, Rac1, and ERK that regulates focal adhesion disassembly during cell spreading. PMID- 21660951 TI - Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells. AB - The soluble member of the TNF-R superfamily osteoprotegerin (OPG) is abundantly released under basal conditions by both mesenchymal stem cells (MSC) and fibroblasts and by endothelial cells upon stimulation with inflammatory cytokines. Since MSC, fibroblasts and endothelial cells represent key elements of the normal and tumor microenvironment and express detectable levels of surface TRAIL receptors, we investigated the effect of TRAIL on OPG release. Unexpectedly, recombinant TRAIL decreased the spontaneous OPG release in all cell types examined. Moreover, TRAIL decreased OPG release also in stromal cells co cultured with lymphoma cells and counteracted the OPG induction by TN-alpha in HUVEC and MSC. Such down-regulation was not due to a masking effect in the ELISA quantification of the OPG released in the culture supernatants due to binding of OPG to its ligands (TRAIL and RANKL), as demonstrated by competition experiments with recombinant TRAIL and by the lack of RANKL release/induction. In addition, OPG down-regulation was not due to induction of cytotoxic effects by TRAIL, since the degree of apoptosis in response to TRAIL was negligible in all primary cell types. With regards to the possible molecular mechanism accounting for the down regulation of OPG release by TRAIL, we found that treatment of MSC with TRAIL significantly decreased the phosphorylation levels of p38/MAPK. There is a suggestion that this pathway is involved in the stabilization of OPG mRNA. In this respect, the ability of TRAIL to decrease the release of OPG, in the absence of cell cytotoxicity, was mimicked by the p38/MAPK inhibitor SB203580. PMID- 21660952 TI - R-Ras interacts with filamin a to maintain endothelial barrier function. AB - The molecular mechanisms regulating vascular barrier integrity remain incompletely elucidated. We have previously reported an association between the GTPase R-Ras and repeat 3 of Filamin A (FLNa). Loss of FLNa has been linked to increased vascular permeability. We sought to determine whether FLNa's association with R-Ras affects endothelial barrier function. We report that in endothelial cells endogenous R-Ras interacts with endogenous FLNa as determined by co-immunoprecipitations and pulldowns with the FLNa-GST fusion protein repeats 1-10. Deletion of FLNa repeat 3 (FLNaDelta3) abrogated this interaction. In these cells FLNa and R-Ras co-localize at the plasma membrane. Knockdown of R-Ras and/or FLNa by siRNA promotes vascular permeability, as determined by TransEndothelial Electrical Resistance and FITC-dextran transwell assays. Re expression of FLNa restored endothelial barrier function in cells lacking FLNa whereas re-expression of FLNaDelta3 did not. Immunostaining for VE-Cadherin in cells with knocked down R-Ras and FLNa demonstrated a disorganization of VE Cadherin at adherens junctions. Loss of R-Ras and FLNa or blocking R-Ras function via GGTI-2133, a selective R-Ras inhibitor, induced vascular permeability and increased phosphorylation of VE-Cadherin (Y731) and Src (Y416). Expression of dominant negative R-Ras promoted vascular permeability that was blocked by the Src inhibitor PP2. These findings demonstrate that maintaining endothelial barrier function is dependent upon active R-Ras and association between R-Ras and FLNa and that loss of this interaction promotes VE-Cadherin phosphorylation and changes in downstream effectors that lead to endothelial leakiness. PMID- 21660953 TI - Macrophage-conditioned medium inhibits the activation of cyclin-dependent kinase 2 by adipogenic inducers in 3T3-L1 preadipocytes. AB - Macrophage infiltration into adipose tissue, associated with obesity, is thought to contribute to abnormal adipose tissue remodeling, low-grade inflammation, and insulin resistance. Medium conditioned by macrophages (MacCM) inhibits 3T3-L1 and human adipocyte differentiation, as well as early adipogenic cell cycle events including MCE and retinoblastoma protein (Rb) phosphorylation. Our objective was to determine if the inhibition of Rb phosphorylation was linked to changes in cell cycle-related proteins. We treated 3T3-L1 preadipocytes with adipogenic inducers for 24 h in control medium versus J774A.1-MacCM. The differentiation induced mRNA and protein expression of cyclin A, an activator of cyclin-dependent kinase (cdk) 2 which phosphorylates Rb, was inhibited by 82% and 73%, respectively, by J774A.1-MacCM; adipogenic expression of Myc, a transcriptional regulator of cyclin A, was also suppressed significantly. Consistent with the reduction in cyclin A levels, the activation of cdk2 by adipogenic inducers was inhibited by 75% by J774A.1-MacCM. J774A.1-MacCM also lowered levels of cyclins D1 and D2. Inhibition studies demonstrated that platelet-derived growth factor, an anti-adipogenic factor found in J774A.1-MacCM, was not responsible for the inhibitory effect on differentiation. The anti-adipogenic effect of J774A.1-MacCM was resistant to proteinase K and heat treatment, and was present in a <3 kDa fraction. Our data indicate that J774A.1-MacCM interferes with the upregulation of cyclin A levels and cdk2 activity that are required for Rb phosphorylation and MCE in 3T3-L1 adipogenesis. PMID- 21660954 TI - Effects of insulin and high glucose on mobilization of slo1 BKCa channels in podocytes. AB - Podocytes are dynamic polarized cells that lie on the surface of glomerular capillaries and comprise an essential component of the glomerular filtration barrier. Podocytes are affected in the earliest stages of diabetic nephropathy and insulin signaling to podocytes is essential for normal glomerular function. Large-conductance Ca(2+)-activated K(+) channels (BK(Ca) channels) encoded by the Slo1 gene are expressed in podocytes in a complex with multiple glomerular slit diaphragm proteins including nephrin, TRPC6 channels, and several different actin binding proteins. Here we show that insulin increases cell surface expression of podocyte BK(Ca) channels, which is accompanied by a corresponding increase in the density of current flowing through these channels. Insulin stimulation of BK(Ca) channels was detectable in 15 min and required activation of both Erk and Akt signaling cascades. Exposure to high glucose (36.1 mM) for 24 h caused a marked reduction in the steady-state surface expression of BK(Ca) channels as well as of the slit diaphragm signaling molecule nephrin. High glucose treatment also abolished the stimulatory effects of insulin on BK(Ca) current density, although insulin continued to increase phosphorylation of Erk and Akt under those conditions. Therefore, in contrast to most other cell types, high glucose abrogates the effects of insulin in podocytes at relatively distal steps in its signaling pathway. Insulin stimulation of BK(Ca) channels in podocytes may prepare podocytes to adapt to changes in pressure gradients that occur during postprandial hyperfiltration. PMID- 21660956 TI - Sphingosine induces apoptosis in hippocampal neurons and astrocytes by activating caspase-3/-9 via a mitochondrial pathway linked to SDK/14-3-3 protein/Bax/cytochrome c. AB - The present study examined sphingosine-induced apoptosis in cultured rat hippocampal neurons and astrocytes. Sphingosine induced apoptosis in a concentration (1-100 uM)-dependent manner, that is inhibited by the PKC-delta inhibitor rottlerin, and a similar effect was obtained with the sphingosine kinase inhibitors, to raise intracellular sphingosine concentrations. Sphingosine increased presence of sphingosine-dependent protein kinase (SDK), and the effect was suppressed by rottlerin. Sphingosine increased phosphorylated 14-3-3 protein, thereby transforming the protein from a dimeric structure into a monomeric structure. Sphingosine accumulated Bax in the mitochondria and stimulated cytochrome c release into the cytosol, and those effects were inhibited by rottlerin. Sphingosine disrupted mitochondrial membrane potentials, that was abolished by silencing the PKC-delta-targeted gene. Moreover, sphingosine activated caspase-9 and the effector caspase-3 in a PKC-delta-dependent manner. Taken together, the results of the present study indicate that sphingosine activates SDK, produced through proteolytic processing of an active form of PKC delta, to phosphorylate 14-3-3 protein and transform into a monomeric structure, causing Bax dissociation from 14-3-3 protein and accumulation in the mitochondria, which perturbs mitochondrial membrane potentials allowing cytochrome c release into the cytosol, to activate caspase-9 and the effector caspase-3, responsible for apoptosis in hippocampal neurons and astrocytes. PMID- 21660957 TI - Honokiol inhibits LPS-induced maturation and inflammatory response of human monocyte-derived dendritic cells. AB - Honokiol (HNK) is a phenolic compound isolated from the bark of houpu (Magnolia officinalis), a plant widely used in traditional Chinese and Japanese medicine. While substantial evidence indicates that HNK possesses anti-inflammatory activity, its effect on dendritic cells (DCs) during the inflammatory reaction remains unclear. The present study investigates how HNK affects lipopolysaccharide (LPS)-stimulated human monocyte-derived DCs. Our experimental results show that HNK inhibits the inflammatory response of LPS-induced DCs by (1) suppressing the expression of CD11c, CD40, CD80, CD83, CD86, and MHC-II on LPS-activated DCs, (2) reducing the production of TNF-alpha, IL-1beta, IL-6, and IL-12p70 but increasing the production of IL-10 and TGF-beta1 by LPS-activated DCs, (3) inhibiting the LPS-induced DC-elicited allogeneic T-cell proliferation, and (4) shifting the LPS-induced DC-driven Th1 response toward a Th2 response. Further, our results show that HNK inhibits the phosphorylation levels of ERK1/2, p38, JNK1/2, IKKalpha, and IkappaBalpha in LPS-activated DCs. Collectively, the findings show that the anti-inflammatory actions of HNK on LPS-induced DCs are associated with the NF-kappaB and mitogen-activated protein kinase (MAPK) signaling pathways. PMID- 21660955 TI - Lipid raft localization of EGFR alters the response of cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. AB - Epidermal growth factor receptor (EGFR) is overexpressed in many cancer types including ~30% of breast cancers. Several small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR have shown clinical efficacy in lung and colon cancers, but no benefit has been noted in breast cancer. Thirteen EGFR expressing breast cancer cell lines were analyzed for response to EGFR TKIs. Seven were found to be EGFR TKI resistant; while shRNA knockdown of EGFR determined that four of these cell lines retained the requirement of EGFR protein expression for growth. Interestingly, EGFR localized to plasma membrane lipid rafts in all four of these EGFR TKI-resistant cell lines, as determined by biochemical raft isolation and immunofluorescence. When lipid rafts were depleted of cholesterol using lovastatin, all four cell lines were sensitized to EGFR TKIs. In fact, the effects of the cholesterol biosynthesis inhibitors and gefitinib were synergistic. While gefitinib effectively abrogated phosphorylation of Akt- and mitogen-activated protein kinase in an EGFR TKI-sensitive cell line, phosphorylation of Akt persisted in two EGFR TKI-resistant cell lines, however, this phosphorylation was abrogated by lovastatin treatment. Thus, we have shown that lipid raft localization of EGFR correlates with resistance to EGFR TKI induced growth inhibition and pharmacological depletion of cholesterol from lipid rafts decreases this resistance in breast cancer cell lines. Furthermore, we have presented evidence to suggest that when EGFR localizes to lipid rafts, these rafts provide a platform to facilitate activation of Akt signaling in the absence of EGFR kinase activity. PMID- 21660959 TI - RASSF1A suppresses melanoma development by modulating apoptosis and cell-cycle progression. AB - The tumor suppressor candidate gene Ras association domain family 1, isoform A (RASSF1A) encodes a microtubule-associated protein that is implicated in the regulation of cell proliferation, migration, and apoptosis. Several studies indicate that down-regulation of RASSF1A resulting from promoter hypermethylation is a frequent epigenetic abnormality in malignant melanoma. In this study, we report that compared with melanocytes in normal skins or benign skin lesions, RASSF1A is down-regulated in melanoma tissues as well as cell lines, and its expression negatively correlates with lymph node metastasis. Following ectopic expression in RASSF1A-deficient melanoma A375 cell line, RASSF1A reduces cell viability, suppresses cell-cycle progression but enhances apoptotic cell death. In vivo, RASSF1A expression inhibits the tumorigenic potential of A375 cells in nude mice, which also correlates with decreased cell proliferation and increased apoptosis. On the molecular level, ectopic RASSF1A expression leads to differential expression of 209 genes, including 26 down-regulated and 183 up regulated ones. Among different signaling pathways, activation of the apoptosis signal-regulating kinase 1 (ASK1)/p38 MAP kinase signaling is essential for RASSF1A-induced mitochondrial apoptosis, and the inhibition of the Akt/p70S6 kinase/eIF4E signaling is also important for RASSF1A-mediated apoptosis and cell cycle arrest. This is the first study exploring the biological functions and the underlying mechanisms of RASSF1A during melanoma development. It also identifies potential targets for further diagnosis and clinical therapy. PMID- 21660958 TI - Effects of membrane cholesterol depletion and GPI-anchored protein reduction on osteoblastic mechanotransduction. AB - We previously demonstrated that oscillatory fluid flow activates MC3T3-E1 osteoblastic cell calcium signaling pathways via a mechanism involving ATP releases and P2Y(2) puringeric receptors. However, the molecular mechanisms by which fluid flow initiates cellular responses are still unclear. Accumulating evidence suggests that lipid rafts, one of the important membrane structural components, may play an important role in transducing extracellular fluid shear stress to intracellular responses. Due to the limitations of current techniques, there is no direct approach to study the role of lipid rafts in transmitting fluid shear stress. In this study, we targeted two important membrane components associated with lipid rafts, cholesterol, and glycosylphosphatidylinositol anchored proteins (GPI-anchored proteins), to disrupt the integrity of cell membrane structures. We first demonstrated that membrane cholesterol depletion with the treatment of methyl-beta-cyclodextrin inhibits oscillatory fluid flow induced intracellular calcium mobilization and ERK1/2 phosphorylation in MC3T3-E1 osteoblastic cells. Secondly, we used a novel approach to decrease the levels of GPI-anchored proteins on cell membranes by overexpressing glycosylphosphatidylinositol-specific phospholipase D in MC3T3-E1 osteoblastic cells. This resulted in significant inhibition of intracellular calcium mobilization and ERK1/2 phosphorylation in response to oscillatory fluid flow. Finally, we demonstrated that cholesterol depletion inhibited oscillatory fluid flow induced ATP releases, which were responsible for the activation of calcium signaling pathways in MC3T3-E1 osteoblastic cells. Our findings suggest that cholesterol and GPI-anchored proteins, two membrane structural components related to lipid rafts, may play an important role in osteoblastic cell mechanotransduction. PMID- 21660960 TI - Essential roles of sphingosine 1-phosphate receptor types 1 and 3 in human hepatic stellate cells motility and activation. AB - The biological roles of sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) have been broadly investigated. However, at present pathophysiological roles of S1P/S1PRs axis in liver fibrosis are not well defined. Here, we investigated the functions of S1P/S1PRs axis in human hepatic stellate cells (HSC) line, LX-2 cells. We found that S1PR types 1, 2 and 3 (S1PR1-3) are clearly detected in LX-2 cells, as determined by RT-PCR, Western blot and immunocytochemistry analysis. S1P exerted a powerful migratory action on LX-2 cells, as determined in Boyden chambers, and stimulated fibrogenic activity of LX-2 cells, as demonstrated by increase of expression of smooth muscle alpha-actin, procollagen alpha1(I) and alpha1(III) and total hydroxyproline content. Moreover, the effects of S1P were mimicked by S1PR1 agonist SEW2871, and abrogated by W146 (S1PR1 antagonist) and/or silencing S1PR1, three expression with small interfering RNA, suggesting the main roles of S1PR1 and 3. However, studies with S1PR2 antagonist JTE-013 and silencing S1PR2 expression indicated that S1PR2 negatively regulated S1P-induced cell migration. Interestingly, exogenously added S1P induced significant up regulation of sphingosine kinase-1 and the synthesis of additional S1P, and expression of S1PR1,3, but not S1PR2. In conclusion, our data have identified an additional function regulated by S1P/S1PR1,3 axis involving migration and fibrogenic activation of HSCs. These results suggest that selective modulation of S1PR activity may represent a new antifibrotic strategy. PMID- 21660961 TI - HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. AB - Potentiation of epidermal growth factor receptor (EGFR) inhibitors is required in squamous cell carcinoma of head and neck (SCCHN) to improve their therapeutic index. We demonstrated that the histone deacetylase inhibitor vorinostat in combination with the EGFR tyrosine kinase inhibitor gefitinib induced synergistic inhibition of proliferation, migration, and invasion as well as induction of apoptosis in SCCHN cells, including cells resistant to gefitinib. We provided evidence suggesting that differential modulation of ErbB receptors together with reversion of epithelial-to-mesenchymal transition (EMT) by vorinostat represent mechanistic bases for the observed synergism. We demonstrated in epithelial CAL27 cells expressing EGFR, ErbB2, and ErbB3 that vorinostat downregulated the expression and signaling of all three receptors. In gefitinib-resistant KB and Hep-2 cells, both of which had undergone EMT and expressed very low levels of ErbB3, vorinostat reverted the mesenchymal phenotype by inducing both E-cadherin and ErbB3 and downregulating vimentin as well as EGFR and ErbB2. Both transcriptional and post-translational mechanisms were involved in the modulation of ErbB receptors by vorinostat. Attenuation of all ErbB transcripts in CAL27 cells as well as induction of ErbB3 transcript in Hep-2 and KB cells was seen upon vorinostat treatment. We showed that vorinostat induced ubiquitination of EGFR and ErbB2 and targeted them predominantly to lysosome-degradation in all cell lines, while the induction of ErbB3-ubiquitination in CAL27 cells led to proteasomes-degradation. Overall, this study suggests that the vorinostat/gefitinib combination represents a promising therapeutic strategy that warrants further clinical evaluation in SCCHN, including tumors intrinsically resistant to EGFR-inhibitors. PMID- 21660962 TI - Long-term regulation of Na+,K+-ATPase in opossum kidney cells by ouabain. AB - Na(+),K(+)-ATPase, a basolateral transporter responsible for tubular reabsorption of Na(+) and for providing the driving force for vectorial transport of various solutes and ions, can also act as a signal transducer in response to the interaction with steroid hormones. At nanomolar concentrations ouabain binding to Na(+),K(+)-ATPase activates a signaling cascade that ultimately regulates several membrane transporters including Na(+),K(+)-ATPase. The present study evaluated the long-term effect of ouabain on Na(+),K(+)-ATPase activity (Na(+) transepithelial flux) and expression in opossum kidney (OK) cells with low (40) and high (80) number of passages in culture, which are known to overexpress Na(+),K(+)-ATPase (Silva et al., 2006, J Membr Biol 212, 163-175). Activation of a signal cascade was evaluated by quantification of ERK1/2 phosphorylation by Western blot. Na(+),K(+)-ATPase activity was determined by electrophysiological techniques and expression by Western blot. Incubation of cells with ouabain induced activation of ERK1/2. Long-term incubation with ouabain induced an increase in Na(+) transepithelial flux and Na(+),K(+)-ATPase expression only in OK cells with 80 passages in culture. This increase was prevented by incubation with inhibitors of MEK1/2 and PI-3K. In conclusion, ouabain-activated signaling cascade mediated by both MEK1/2 and PI-3K is responsible for long-term regulation of Na(+) transepithelial flux in epithelial renal cells. OK cell line with high number of passages is suggested to constitute a particular useful model for the understanding of ouabain-mediated regulation of Na(+) transport. PMID- 21660963 TI - Pulmonary epithelial CCR3 promotes LPS-induced lung inflammation by mediating release of IL-8. AB - Interleukin (IL)-8 from pulmonary epithelial cells has been suggested to play an important role in the airway inflammation, although the mechanism remains unclear. We envisioned a possibility that pulmonary epithelial CCR3 could be involved in secretion and regulation of IL-8 and promote lipopolysaccharide (LPS) induced lung inflammation. Human bronchial epithelial cell line NCI-H292 and alveolar type II epithelial cell line A549 were used to test role of CCR3 in production of IL-8 at cellular level. In vivo studies were performed on C57/BL6 mice instilled intratracheally with LPS in a model of acute lung injury (ALI). The activity of a CCR3-specific inhibitor (SB-328437) was measured in both in vitro and in vivo systems. We found that expression of CCR3 in NCI-H292 and A549 cells were increased by 23% and 16%, respectively, 24 h after the challenge with LPS. LPS increased the expression of CCR3 in NCI-H292 and A549 cells in a time dependent manner, which was inhibited significantly by SB-328437. SB-328437 also diminished neutrophil recruitment in alveolar airspaces and improved LPS-induced ALI and production of IL-8 in bronchoalveolar lavage fluid. These results suggest that pulmonary epithelial CCR3 be involved in progression of LPS-induced lung inflammation by mediating release of IL-8. CCR3 in pulmonary epithelia may be an attractive target for development of therapies for ALI. PMID- 21660964 TI - t10c12-CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity. AB - Conjugated linoleic acid (CLA) has been shown to positively influence calcium and bone metabolism. Earlier, we showed that CLA (equal mixture of c9t11-CLA and t10c12-CLA) could protect age-associated bone loss by modulating inflammatory markers and osteoclastogenesis. Since, c9t11-CLA and t10c12-CLA isomers differentially regulate functional parameters and gene expression in different cell types, we examined the efficacy of individual CLA isomers against age associated bone loss using 12 months old C57BL/6 female mice fed for 6 months with 10% corn oil (CO), 9.5% CO + 0.5% c9t11-CLA, 9.5% CO + 0.5% t10c12-CLA or 9.5% CO + 0.25% c9t11-CLA + 0.25% t10c12-CLA. Mice fed a t10c12-CLA diet maintained a significantly higher bone mineral density (BMD) in femoral, tibial and lumbar regions than those fed CO and c9t11-CLA diets as measured by dual energy-X-ray absorptiometry (DXA). The increased BMD was accompanied by a decreased production of osteoclastogenic factors, that is, RANKL, TRAP5b, TNF alpha and IL-6 in serum. Moreover, a significant reduction of high fat diet induced bone marrow adiposity was observed in t10c12-CLA fed mice as compared to that of CO and c9t11-CLA fed mice, as measured by Oil-Red-O staining of bone marrow sections. In addition, a significant reduction of osteoclast differentiation and bone resorbing pit formation was observed in t10c12-CLA treated RAW 264.7 cell culture stimulated with RANKL as compared to that of c9t11 CLA and linoleic acid treated cultures. In conclusion, these findings suggest that t10c12-CLA is the most potent CLA isomer and it exerts its anti-osteoporotic effect by modulating osteoclastogenesis and bone marrow adiposity. PMID- 21660965 TI - Knockdown of CITED2 using short-hairpin RNA sensitizes cancer cells to cisplatin through stabilization of p53 and enhancement of p53-dependent apoptosis. AB - CITED2 is a transcriptional modulator which has been implicated in human oncogenesis. In the present study, we examined whether CITED2 is also involved in the resistance of cancer cells to the chemotherapeutic drug cisplatin. We first observed that knockdown of CITED2 using short-hairpin RNA sensitized non tumorigenic HEK293 cells to cisplatin. Sensitization to cisplatin following knockdown of CITED2 was also observed in cervical carcinoma HeLa cells and in cisplatin-resistant HeLa cells, thereby showing that acquired cisplatin resistance could be reversed by CITED2 knockdown. This sensitization response was dependent on the status of p53 since efficient sensitization was observed in p53 positive hepatocellular carcinoma (HCC) Sk-Hep-1 cells, whereas a negligible response was produced in the two p53-defective cell lines HCC Mahlavu and lung cancer H1299. In contrast, overexpression of CITED2 decreased sensitivity of HEK293 cells to cisplatin, while moderate resistance was produced in HeLa cells. Overexpression of CITED2 also decreased sensitivity to cisplatin in p53-defective H1299 cells when exogenous p53 expression was re-introduced. We observed that knockdown of CITED2-induced CBP/p300-mediated p53 acetylation (Lys373) in HEK293 cells, thereby leading to a decrease of p53 ubiquitination and subsequent accumulation of the p53 protein. Notably, the effects of CITED2 knockdown on p53 accumulation and the increase of p53's target Bax were more pronounced after treatment with cisplatin. Based on these results, we propose that a combination of cisplatin and CITED2 shRNA may represent an effective treatment against p53 sensitive cancer cells. PMID- 21660966 TI - Oxygen tension affects terminal differentiation of corneal limbal epithelial cells. AB - Oxygen concentration has been shown to be crucial in the proliferation and differentiation of various types of cells, while the impact of oxygen tension on the lineage commitment of epithelial cells remains elusive. In this study, we investigated the effect of hypoxia on the differentiation of corneal limbal epithelium using an ex vivo squamous metaplasia model. Under normoxic conditions when exposed to air, the hyperproliferation and abnormal epidermal-like differentiation of human corneal limbal epithelium was induced, whereas when exposed to air under hypoxic conditions, although we observed augmented proliferation, the abnormal differentiation was inhibited. The Notch signaling pathway was activated in hypoxic cultures, whereas the p38 MAPK signaling pathway was downregulated. The addition of Notch inhibitor under hypoxic conditions restored the activation of p38 MAPK and resulted in the recidivation of limbal epithelial cells to epidermal-like differentiation. Moreover, the epidermal-like differentiation of rabbit limbal epithelial cells was also blocked under hypoxic conditions in corneal epithelial cell sheets engineered ex vivo. We concluded that hypoxia can prevent abnormal differentiation while enhancing the proliferation of corneal limbal epithelial cells. Hypoxia coupled with air exposure can be used in the tissue engineering of corneal limbal epithelium. PMID- 21660967 TI - CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver. AB - The Gi protein-associated A(3) adenosine receptor (A(3) AR) is a member of the adenosine receptor family. Selective agonists at the A(3) AR, such as CF101 and CF102 were found to induce anti-inflammatory and anti-cancer effects. In this study, we examined the differential effect of CF102 in pathological conditions of the liver. The anti-inflammatory protective effect of CF101 was tested in a model of liver inflammation induced by Concanavalin A (Con. A) and the anti-cancer effect of CF102 was examined in vitro and in a xenograft animal model utilizing Hep-3B hepatocellular carcinoma (HCC) cells. The mechanism of action was explored by following the expression levels of key signaling proteins in the inflamed and tumor liver tissues, utilizing Western blot (WB) analysis. In the liver inflammation model, CF102 (100 ug/kg) markedly reduced the secretion of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase in comparison to the vehicle-treated group. Mechanistically, CF102 treatment decreased the expression level of phosphorylated glycogen synthase kinase-3beta, NF-kappaB, and TNF-alpha and prevented apoptosis in the liver. This was demonstrated by decreased expression levels of Fas receptor (FasR) and of the pro apoptotic proteins Bax and Bad in liver tissues. In addition, CF102-induced apoptosis of Hep-3B cells both in vitro and in vivo via de-regulation of the PI3K NF-kappaB signaling pathway, resulting in up-regulation of pro-apoptotic proteins. Taken together, CF102 acts as a protective agent in liver inflammation and inhibits HCC tumor growth. These results suggest that CF102 through its differential effect is a potential drug candidate to treat various pathological liver conditions. PMID- 21660968 TI - Epidermal growth factor increases clathrin-dependent endocytosis and degradation of claudin-2 protein in MDCK II cells. AB - Epidermal growth factor (EGF) decreases the mRNA and protein levels of claudin-2 (CLDN2) in Madin-Darby canine kidney (MDCK) II cells. Here we examined whether EGF affects the stability and intracellular distribution of CLDN2 protein. EGF decreased surface and total levels of CLDN2, which was inhibited by U0126, a MEK inhibitor. CLDN2 was co-localized at the tight junctions (TJs) with ZO-1, a scaffolding protein. The fluorescence signal for CLDN2 disappeared on treatment with EGF, which was inhibited by U0126. EGF accelerated the decrease in CLDN2 in the presence of cycloheximide, a translation inhibitor, indicating that EGF reduces the stability of the protein. Chloroquine, a lysosomal protease inhibitor, blocked the EGF-induced decrease in CLDN2 protein and caused the co localization of CLDN2 with Lamp-1, a marker of lysosome. Monodancylcadaverine, an inhibitor of endocytosis, and clathrin siRNA blocked the EGF-induced decrease in CLDN2 and the translocation of CLDN2 from the TJs to the lysosome. EGF increased the association of CLDN2 with clathrin and adaptin alpha which was inhibited by U0126. These results suggest that EGF accelerates clathrin-dependent endocytosis and lysosomal degradation of CLDN2 protein mediated by the activation of a MEK/ERK pathway. PMID- 21660970 TI - Effects of self-esteem on state and trait components of interpersonal dependency and depression in the workplace. AB - This longitudinal study was undertaken to clarify the relationships among self esteem, interpersonal dependency, and depression, focusing on a trait and state component of interpersonal dependency and depression. In a sample of 466 working people, self-esteem, interpersonal dependency, job stressor, and depression were assessed at 2 points of time. A structural equation model (SEM) was created to differentiate the trait component of interpersonal dependency, depression and the state component of interpersonal dependency, depression. The model revealed that self-esteem influenced trait interpersonal dependency and trait depression but not state interpersonal dependency or depression. Setting a latent variable as a trait component to differentiate trait and state in interpersonal dependency and depression in SEM was found to be effective both statistically and clinically. PMID- 21660969 TI - PKCepsilon promotes cardiac mitochondrial and metabolic adaptation to chronic hypobaric hypoxia by GSK3beta inhibition. AB - PKCepsilon is central to cardioprotection. Sub-proteome analysis demonstrated co localization of activated cardiac PKCepsilon (aPKCepsilon) with metabolic, mitochondrial, and cardioprotective modulators like hypoxia-inducible factor 1alpha (HIF-1alpha). aPKCepsilon relocates to the mitochondrion, inactivating glycogen synthase kinase 3beta (GSK3beta) to modulate glycogen metabolism, hypertrophy and HIF-1alpha. However, there is no established mechanistic link between PKCepsilon, p-GSK3beta and HIF1-alpha. Here we hypothesized that cardiac restricted aPKCepsilon improves mitochondrial response to hypobaric hypoxia by altered substrate fuel selection via a GSK3beta/HIF-1alpha-dependent mechanism. aPKCepsilon and wild-type (WT) mice were exposed to 14 days of hypobaric hypoxia (45 kPa, 11% O(2)) and cardiac metabolism, functional parameters, p-GSK3beta/HIF 1alpha expression, mitochondrial function and ultrastructure analyzed versus normoxic controls. Mitochondrial ADP-dependent respiration, ATP production and membrane potential were attenuated in hypoxic WT but maintained in hypoxic aPKCepsilon mitochondria (P < 0.005, n = 8). Electron microscopy revealed a hypoxia-associated increase in mitochondrial number with ultrastructural disarray in WT versus aPKCepsilon hearts. Concordantly, left ventricular work was diminished in hypoxic WT but not aPKCepsilon mice (glucose only perfusions). However, addition of palmitate abrogated this (P < 0.05 vs. WT). aPKCepsilon hearts displayed increased glucose utilization at baseline and with hypoxia. In parallel, p-GSK3beta and HIF1-alpha peptide levels were increased in hypoxic aPKCepsilon hearts versus WT. Our study demonstrates that modest, sustained PKCepsilon activation blunts cardiac pathophysiologic responses usually observed in response to chronic hypoxia. Moreover, we propose that preferential glucose utilization by PKCepsilon hearts is orchestrated by a p-GSK3beta/HIF-1alpha mediated mechanism, playing a crucial role to sustain contractile function in response to chronic hypobaric hypoxia. PMID- 21660971 TI - Manny's legacy: paying forward my personal therapy. AB - The lessons of childhood will often last a lifetime. Two lessons that I learned early in life were that loss can occur quickly, unexpectedly, and have monumental consequences such as when my father died when I was 9 years old. I also learned that losses can be assuaged or mitigated in many ways, not the least of which would be the replacement of my father with a father figure, who filled the needs of an adolescent and later an adult with a role model, keen insights, and emotional support. This article traces my experiences with personal therapy and addresses how lessons learned can be used and passed on to succeeding generations comprised of one's children and, in my case, my patients and students for the past 45 years. PMID- 21660973 TI - A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys. AB - The farnesoid X receptor (FXR) belongs to one of the human nuclear receptor superfamilies that regulate gene transcription. FXR is widely expressed in liver, gall bladder, intestine, kidney, and adrenal glands. It serves as a key controller of bile acid homeostasis through its regulation of bile acid synthesis, conjugation, secretion, and absorption. FXR is also known to play a role in lipid regulation, triglyceride synthesis, and lipoprotein metabolism and clearance. We used a commercially available FXR agonist, GW4064, as a model compound to assess preclinical efficacy in two species (hamster and cynomolgus monkey). The crystalline GW4064, however, was found to have limited solubility, which resulted in poor oral bioavailability. This made it difficult to assess in vivo efficacy at the exposure levels desired. The physiochemical properties of GW4064 were assessed and both salt and self-emulsifying drug delivery system (SEDDS) formulation were developed and tested. The SEDDS formulation was found to greatly improve the oral bioavailability of GW4064, and permitted the evaluation of FXR agonist target efficacy. PMID- 21660972 TI - Comprehensive analysis of CpG island methylator phenotype (CIMP)-high, -low, and negative colorectal cancers based on protein marker expression and molecular features. AB - CpG island methylator phenotype (CIMP) is being investigated for its role in the molecular and prognostic classification of colorectal cancer patients but is also emerging as a factor with the potential to influence clinical decision-making. We report a comprehensive analysis of clinico-pathological and molecular features (KRAS, BRAF and microsatellite instability, MSI) as well as of selected tumour- and host-related protein markers characterizing CIMP-high (CIMP-H), -low, and negative colorectal cancers. Immunohistochemical analysis for 48 protein markers and molecular analysis of CIMP (CIMP-H: >= 4/5 methylated genes), MSI (MSI-H: >= 2 instable genes), KRAS, and BRAF were performed on 337 colorectal cancers. Simple and multiple regression analysis and receiver operating characteristic (ROC) curve analysis were performed. CIMP-H was found in 24 cases (7.1%) and linked (p < 0.0001) to more proximal tumour location, BRAF mutation, MSI-H, MGMT methylation (p = 0.022), advanced pT classification (p = 0.03), mucinous histology (p = 0.069), and less frequent KRAS mutation (p = 0.067) compared to CIMP-low or -negative cases. Of the 48 protein markers, decreased levels of RKIP (p = 0.0056), EphB2 (p = 0.0045), CK20 (p = 0.002), and Cdx2 (p < 0.0001) and increased numbers of CD8+ intra-epithelial lymphocytes (p < 0.0001) were related to CIMP-H, independently of MSI status. In addition to the expected clinico pathological and molecular associations, CIMP-H colorectal cancers are characterized by a loss of protein markers associated with differentiation, and metastasis suppression, and have increased CD8+ T-lymphocytes regardless of MSI status. In particular, Cdx2 loss seems to strongly predict CIMP-H in both microsatellite-stable (MSS) and MSI-H colorectal cancers. Cdx2 is proposed as a surrogate marker for CIMP-H. PMID- 21660974 TI - Randomly methylated beta-cyclodextrin derivatives enhance taxol permeability through human intestinal epithelial Caco-2 cell monolayer. AB - Intestinal absorption and bioavailability of taxol are limited by its low solubility and P-glycoprotein (Pgp) activity. Methylated beta-cyclodextrins (CDs) effectively form complexes with paclitaxel but randomly methylated beta cyclodextrin (RAMEB) is cytotoxic in high concentrations. Second-generation derivatives containing monoamino (MaRAMEB) and succinylated (SuRAMEB) ionic substituents with similar inclusion capacity but less toxicity could be promising alternatives of RAMEB. Our aim was to examine and compare the efficacy of MaRAMEB and SuRAMEB with the parental RAMEB on taxol bidirectional permeability using the Caco-2 model. Taxol permeability was not changed by 30-min pretreatment with CDs. In co-treatment with beta-cyclodextrins, the apical to basolateral taxol flux was 4 to 6 times greater than in untreated monolayers and it was also higher than in cells treated with Pgp inhibitor cyclosporin A. No decrease in basolateral to apical taxol flux was observed in pretreatment or co-treatment with CDs, suggesting no Pgp inhibition. All three CDs showed similar effects on taxol permeability but RAMEB altered tight junction protein distribution and significantly decreased transepithelial electrical resistance. None of the CDs modified paracellular permeability to mannitol and polyethylene glycol 4000. In conclusion, second-generation derivatives of methyl-beta-cyclodextrin, especially MaRAMEB, enhanced taxol permeability across Caco-2 cells with less toxicity and similar effectiveness as RAMEB. PMID- 21660975 TI - Intraoperative tumor localization with surgeon-performed ultrasound-guided needle dye injection. AB - OBJECTIVES: To describe our technique and initial experience of intraoperative tumor localization with surgeon-performed ultrasound-guided needle dye injection. STUDY DESIGN: Prospective case series. Technique description. METHODS: Using surgeon-performed ultrasonography (SP-US), 20 tumors (lymph node metastases of papillary thyroid carcinoma [15], Hurthle cell carcinoma [2], medullary thyroid carcinoma [1], and lymphoma [1], and a parathyroid adenoma [1]) were localized in 13 patients. With ultrasound guidance, 0.1 mL of 1% methylene blue dye was injected into each targeted tumor. The blue color in contrast helped guide the dissection. Sixteen of 20 (80%) of dissections were revision cases through scar. RESULTS: Using SP-US and US-guided injection with blue dye, 20 of 20 (100%) of cases were successful in retrieving the target tumor with no inadvertent nerve injuries (nerves at risk in scar: recurrent laryngeal [12], phrenic [3], vagus [3], and sympathetic chain [3]). Dye injection adds 5 to 10 minutes of time prior to incision. Injections appeared to increase visual differentiation of tissue, save time during dissection, particularly during revision dissections, and help ensure successful target retrieval. Injection into a parathyroid adenoma resulted in an overabundance of blue dye in nontumor tissue. CONCLUSIONS: Surgeon performed ultrasound guided needle dye injection is particularly helpful in directing the surgeon to the appropriate area for tumor resection in fibrotic areas and thereby possibly reducing surgical time, sampling error, and morbidity. A lower concentration or a different dye may be more helpful for parathyroid adenomas. Further study on this technique is needed and is under way with a larger group of patients. EDUCATIONAL OBJECTIVE: At the conclusion of this manuscript, the participants should be able to understand the technique and advantages of intraoperative tumor localization with surgeon-performed ultrasound guided needle blue dye injection. PMID- 21660976 TI - Sensitivity and specificity of computed tomography and magnetic resonance imaging in the diagnosis of isolated sphenoid sinus diseases. AB - OBJECTIVES/HYPOTHESIS: The sphenoid sinus is uncommonly affected by inflammatory or neoplastic lesions. Initial onset of isolated sphenoid sinus diseases (ISSD) is generally asymptomatic. The objectives of this study were to estimate the sensitivity and specificity of computed tomography (CT) and magnetic resonance imaging (MRI) in diagnosing ISSD and establish guidelines to declare hidden ISSD through correlation of radiological diagnosis to final pathological diagnosis. STUDY DESIGN: A prospective cohort study. METHODS: There were 66 patients with isolated sphenoid sinus lesions presenting to Ain-Shams University Hospitals, Cairo, Egypt. Provisional diagnosis of ISSD was done by CT and MRI, followed by histopathologic and immunohistochemical staining, and if needed microbiological examination of resected specimens to establish the final diagnosis. RESULTS: Patients were classified into four groups according to the type of lesion: inflammatory, neoplastic, bony dysplastic disorders, and sphenoid sinus roof defect-related lesions. Radiological imaging provided the greatest diagnostic information and guided management. The sensitivity of CT and MRI in diagnosing inflammatory lesions was 95% versus 61%, whereas those of the neoplastic group were 72% and 100%, respectively. In the osseous group the sensitivity was 100% for both CT and MRI, whereas in sphenoid sinus roof defect the sensitivity was 50% and 100% for CT and MRI, respectively. CONCLUSIONS: Because of CT's superiority in defining the bony margins and MRI's superior soft tissue resolution, CT and MRI should be used in a complementary manner in the evaluation of isolated sphenoid sinus disease in addition to mapping the lesion better and identifying intracranial and intraorbital extension. The use of one modality only should be restricted to straightforward lesions. PMID- 21660977 TI - Quantitative analysis of endoscopic endonasal approaches to the infratemporal fossa. AB - OBJECTIVES/HYPOTHESIS: The operative management of infratemporal skull base lesions is challenging. Expanded endonasal approaches to this area can decrease surgical morbidity. Access lateral to the natural nasal corridor can be achieved via a middle meatal antrostomy, medial maxillectomy complemented by a septotomy, or anteromedial maxillotomy (i.e., Denker's approach). We sought to compare the access to the infratemporal fossa offered by these endoscopic endonasal approaches. STUDY DESIGN: Software-enabled CT scan measurements. METHODS: Axial CT scans obtained with submillimeter cuts through the skull base were examined. All calculations were performed on axial images obtained at the level of the sphenoid floor using Kodak Carestream Image Software (Rochester, NY) measuring tools. RESULTS: Fifty sides were examined. A medial maxillectomy increased the exposure on average by 18.5 degrees (SD = 4.28), when compared to maxillary antrostomy. When we augmented the access with an ipsilateral Denker's approach, an additional 33.5 degrees (SD = 4.81) of exposure were obtained (P < .0001). The addition of a 1-cm anteromedial maxillotomy accessed the entire posterior maxillary wall in 54% of cases. Equivalent access was obtained via a contralateral approach with a septotomy at 1.56 cm from the columella. To access the entire posterior maxillary wall the average anterior maxillotomy should be 1.1 cm (SD = 0.42). In contrast, to access the entire posterior maxillary wall using a contralateral approach the average septotomy position should be 1.52 cm (SD = 0.39) from the columella. CONCLUSIONS: This radioanatomic study provides objective support for the use of an ipsilateral Denker's approach to augment an endoscopic endonasal approach to the infratemporal fossa. PMID- 21660978 TI - Physiological modeling and assessments of regional drug bioavailability of danoprevir to determine whether a controlled release formulation is feasible. AB - Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half-life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal-vein-cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal-vein-cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4-28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open-label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an EnterionTM capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an EnterionTM capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible. PMID- 21660979 TI - Acellular nerve allografts in peripheral nerve regeneration: a comparative study. AB - INTRODUCTION: Processed nerve allografts offer a promising alternative to nerve autografts in the surgical management of peripheral nerve injuries where short deficits exist. METHODS: Three established models of acellular nerve allograft (cold-preserved, detergent-processed, and AxoGen-processed nerve allografts) were compared with nerve isografts and silicone nerve guidance conduits in a 14-mm rat sciatic nerve defect. RESULTS: All acellular nerve grafts were superior to silicone nerve conduits in support of nerve regeneration. Detergent-processed allografts were similar to isografts at 6 weeks postoperatively, whereas AxoGen processed and cold-preserved allografts supported significantly fewer regenerating nerve fibers. Measurement of muscle force confirmed that detergent processed allografts promoted isograft-equivalent levels of motor recovery 16 weeks postoperatively. All acellular allografts promoted greater amounts of motor recovery compared with silicone conduits. CONCLUSION: These findings provide evidence that differential processing for removal of cellular constituents in preparing acellular nerve allografts affects recovery in vivo. PMID- 21660980 TI - The effect of paired stimuli on blink reflex latencies in normal subjects. AB - INTRODUCTION: In this study we assessed the effect of paired stimuli on the latencies and amplitudes of the blink reflex. METHODS: Blink reflexes were performed with single and paired (5-ms interstimulus interval) stimuli in 47 patients. The changes in latencies between paired and single stimuli were calculated. RESULTS: Paired stimulation produced two types of R1 waveform morphologies: single- and double-peaked waveforms. Increases in R1 and contralateral R2 latencies with paired stimulation were significantly higher in those with single-peaked R1 responses compared to those with double-peaked R1 responses. CONCLUSIONS: Interpreting the blink reflex latencies using paired stimulation requires visualization of the R1 waveform morphology. A double-peaked R1 response requires no change in normal latency values, but the latency of a single-peaked R1 should be interpreted from the second shock artifact. The effect on the R2 latency is variable. PMID- 21660981 TI - Repeated ultrasound studies may help us understand what's going on inside the nerve. PMID- 21660982 TI - Unilateral calf atrophy secondary to a de novo mutation of the caveolin-3 gene. AB - A 23-year-old man was evaluated for atrophy of the left calf. He had a myopathic pattern on electromyography. Light microscopy showed dystrophic changes and reduced immunostaining for dysferlin and caveolin-3. The subsarcolemmal space was enlarged, and abnormal vesicles were visible with electron microscopy. A genetic study showed a heterozygous A45T mutation at exon 2 of the caveolin-3 gene. Such a mutation has been reported previously with limb-girdle muscular dystrophy type 1C and rippling muscle disease phenotypes. PMID- 21660983 TI - Ultrasound-guided steroid injection to treat mild ulnar neuropathy at the elbow. AB - There exists no "gold standard" in the treatment of ulnar neuropathy at the elbow (UNE). We treated 7 patients with mild UNE using a local steroid injection with ultrasonographic monitoring. At clinical follow-up after 6 weeks, 4 patients had improved, 2 were stable, and 1 reported an increase in symptoms. Ultrasound guided steroid injection in mild UNE is safe and could be effective. Further investigation is needed to prove its efficacy. PMID- 21660984 TI - Paraspinal myopathy with novel shard-like compact aggregates of thin filaments. PMID- 21660986 TI - Demyelinating symmetric motor polyneuropathy with high anti-GM1 antibody titer: do we need to split? PMID- 21660988 TI - A comment on novel mutation in the PMP22 gene causing an axonal neuropathy. PMID- 21660989 TI - The struggle to model muscular dystrophy. PMID- 21660990 TI - Sixty years of preventive cardiology: a Framingham perspective. PMID- 21660991 TI - Myocardial perfusion defect in patients with coronary artery disease demonstrated by 64-multidetector computed tomography at rest. AB - BACKGROUND: The first-pass imaging of 64-multidetector computed tomography (MDCT) using pharmacological stress has been used to assess myocardial perfusion. However, detection of myocardial ischemia at rest using MDCT has yet to be elucidated. We studied the incidence of myocardial perfusion defect (MPD) by 64 MDCT at rest and the effect of coronary revascularization therapy on MPD in patients with coronary artery disease. HYPOTHESIS: MPD by 64-MDCT at rest indicates myocardial ischemia. METHODS: We studied 76 patients with coronary artery disease who underwent 64-MDCT before and after revascularization therapy and 55 patients who did not undergo revascularization therapy. According to percent diameter stenosis, we defined group A, B, C, and D to have stenosis between 70% and 90%, 50% and 69%, 30% and 49%, and 10% and 29%, respectively. We evaluated regional myocardial contrast enhancement by long and short axis planes. MPD was defined as hypoenhancement area of some extent with CT value <50 HU during diastole. RESULTS: MPD was found in 60.0% and 32.4% of group A and B patients, respectively (P = 0.0176). The incidence was 4.8% and 0% in group C and D patients, respectively (P<0.0001 compared with group A and B). All patients in group A and B and 2 patients with MPD in group C underwent coronary revascularization therapy. MPD disappeared after revascularization therapy in all but 3 group A patients. No patients showed new MPD after revascularization therapy. CONCLUSIONS: Our results demonstrate that a significant percentage of patients with significant coronary artery stenosis show MPD by 64-MDCT at rest, and these MPDs may represent myocardial ischemia. PMID- 21660992 TI - Is door-to-balloon time the best metric to assess successful treatment of STEMI? PMID- 21660993 TI - Floc architecture of bioflocculation sediment by ESEM and CLSM. AB - Sediment flocculation is a critical component for the understanding of cohesive sediment dynamics. Traditionally, the referred study has largely been devoted to forming mechanism, influencing factors and physicochemical sediment conditions of all kinds of organic-flocculation and inorganic-flocculation. However, during the last decade, the bioflocculation of sediment by biological activity has been given increasing attention. But most studies have focused on the interrelations between biological and sedimentological variables. With the assistance of a newly developed field kit and correlative microscopy (which includes environmental scanning electron microscopy and confocal laser scanning microscopy), this article begins to bridge the resolution gap between sediment particles and biological activities as well as its metabolic products biofilm, in order to better understand the role of polymeric material biofilm in floc ultrastructure and outward floc behavior of bioflocculation sediment. Results have demonstrated that bioflocculation sediment was observed to be composed of complex networks of biofilm and appeared to be of complicated physical floc structures. The biofilm was found to embed particles and permeate the void space, representing the dominant physical bridging mechanism of the flocs and contributed to the extensive surface area, architecture characteristics, and mechanical properties of bioflocculation sediment. PMID- 21660994 TI - 3-dimensional microscope analysis of bone and tooth surface modifications: comparisons of fossil specimens and replicas. AB - Cut-marks on fossil bones and teeth are an important source of evidence in the reconstruction of ancient butchery practices. The analysis of butchery marks has allowed archaeologists to interpret aspects of past subsistence strategies and the behavior of early humans. Recent advances in optical scanning microscopy allow detailed measurements of cut-mark morphology to be undertaken. An example of this technology is the Alicona 3D InfiniteFocus imaging microscope, which has been applied recently to the study of surface modifications on bones and teeth. Three-dimensional models generated by the Alicona microscope have been used to identify cross-sectional features of experimental cut-marks that are characteristic for specific cutting actions (e.g., slicing, chopping, scraping) and different tool types (e.g., metal versus stone tools). More recently, this technology has been applied successfully to the analysis of ~500,000 year-old cut marked animal bones from Boxgrove (U.K.), as well as cannibalized 14,700 cal BP year-old human bones from Gough's Cave (U.K.). This article describes molding methods used to replicate fragile prehistoric bones and teeth, where image quality was adversely affected by specimen translucency and reflectivity. Alicona images generated from molds and casts are often of better quality than those of the original specimen. PMID- 21660995 TI - Nonideality in diffusion of ionic and neutral solutes and hydrogen bond dynamics in dimethyl sulfoxide-chloroform mixtures of varying composition. AB - Molecular dynamics simulations of charged and neutral solutes in dimethyl sulfoxide (DMSO)-chloroform mixtures reveal pronounced nonideality in the solute diffusion with changes of composition of the mixtures. The diffusion coefficient of the anionic solute first decreases, passes through a minimum at DMSO mole fraction of about 0.50, and then increases to reach its value for pure DMSO. The diffusion coefficients of the cationic and neutral solutes are found to decrease with increase in DMSO content of the solvent mixture. The extent of nonideality in the diffusion and orientational relaxation of solvent molecules is found to be somewhat stronger than that in diffusion of the anionic solute in these mixtures. We have also calculated the relaxation of hydrogen bonds formed between DMSO and chloroform molecules. The lifetimes of DMSO-chloroform hydrogen bonds are found to increase monotonically with increase in DMSO concentration. The average number of hydrogen bonds and their average energies are also computed. It is found that an increase in DMSO concentration causes a decrease in the number of DMSO chloroform hydrogen bonds per DMSO or chloroform molecules but increases the strength of these hydrogen bonds. PMID- 21660996 TI - Long-term outcome after intrauterine laser treatment for twin-twin transfusion syndrome. AB - Twin-twin transfusion syndrome (TTTS) is a severe complication occurring in about 10% of monochorionic twin pregnancies. The chronic unbalanced transfusion of blood across placental vascular communications from the donor to the recipient twin may lead to impairment of various organ systems in the affected twins. In Hamburg, Germany, since 1995 patients with TTTS were treated with fetoscopic laser coagulation as the first causal therapeutic strategy. All survivors after laser surgery were followed up in the University Children's Hospital in Bonn, Germany. In this article, we summarize long-term follow-up studies from our German study population and compare our results with data from the literature. PMID- 21660998 TI - Fetal therapy: practical ethical considerations. AB - Progress in prenatal diagnosis can lead to the diagnosis of severe fetal abnormalities for which natural history anticipates a fatal outcome or the development of severe disability despite optimal postnatal care. Intrauterine therapy can be offered in these selected cases. Prenatal diagnosis is the only field of medicine in which termination is an option in the management of severe diseases. Fetal therapy has therefore developed as an alternative to fatalist expectant prenatal management as well as to termination of pregnancy (TOP). There are few standards of fetal care that have gone beyond the stage of equipoise and even fewer have been established based on appropriate studies comparing pre- and postnatal care. Several ethical questions are being raised as fetal surgery develops, including basic Hippocratic principles of patients' autonomy and doctors' duty of competence moving the boundaries between experimental surgery, therapeutic innovation and standard care. In addition, the technical success of a fetal intervention can only rarely fully predict the postnatal outcome. Managing uncertainty regarding long-term morbidity and the possibility for fetal therapy to change the risk of perinatal death into that of severe handicap remains a critical factor affecting women's choice for TOP as an alternative to fetal therapy. PMID- 21660997 TI - Laser therapy for twin-to-twin transfusion syndrome (TTTS). AB - Monochorionic twins are subjected to specific complications which originate in either imbalance or abnormality of the single placenta serving two twins including twin-to-twin transfusion syndrome. The diagnosis is well established in overt clinical forms with the association of polyuric polyhydramnios and oliguric oligohydramnios. The best treatment of cases presenting before 26 weeks of gestion is fetoscopic laser ablation of the intertwin anastomoses on the chorionic plate. Although subjected to subtle variations, the core technique follows robust guidelines which could help understanding and acquiring the required skills and experience to perform this procedure. However appropriate and tailored hands-on training and appropriate perinatal set-up are critical not only for surgical management but also for the follow-up and management of related complications. PMID- 21660999 TI - Fetal therapy: progress made and lessons learnt. PMID- 21661000 TI - 5-HTTLPR moderates the relation between changes in depressive and bulimic symptoms in adolescent girls: a longitudinal study. AB - OBJECTIVE: Depression and bulimia both are associated with low serotonin levels. We examined whether the serotonin transporter gene (5-HTTLPR) moderates the relation between depressive and bulimic symptoms over time. METHOD: Fifty adolescent girls with no current or past Axis I disorder were genotyped for the 5 HTTLPR gene. Twice, 6 months apart, participants completed self-report measures of depressive symptoms and bulimic symptoms. RESULTS: The association between change in depressive symptoms and change in bulimic symptoms over time was significantly stronger in girls who are homozygous for the short 5-HTTLPR allele than for girls with at least one long allele. DISCUSSION: This finding is consistent with previous studies documenting a relation between depressive and bulimic symptoms in adolescents. Few studies, however, considered the possible role of serotonin linking both disorders. Gaining a better understanding of developmental effects of low serotonin could help to identify high-risk individuals and provide effective prevention and intervention. PMID- 21661001 TI - Brain tissue volume changes following weight gain in adults with anorexia nervosa. AB - OBJECTIVE: To measure brain volume deficits among underweight patients with anorexia nervosa (AN) compared to control participants and evaluate the reversibility of these deficits with short-term weight restoration. METHOD: Brain volume changes in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) were examined in 32 adult women with AN and compared to 21, age and body mass index-range matched control women. RESULTS: Patients with AN had a significant increase in GM (p = .006, eta(2) = 0.14) and WM volume (p = .001, eta(2) = 0.19) following weight restoration. Patients on average had lower levels of GM at low weight (647.63 +/- 62.07 ml) compared to controls (679.93 +/- 53.31 ml), which increased with weight restoration (662.64 +/- 69.71 ml), but did not fully normalize. DISCUSSION: This study suggests that underweight adult patients with AN have reduced GM and WM volumes that increase with short-term weight restoration. PMID- 21661002 TI - Gestational weight gain of women with eating disorders in the Norwegian pregnancy cohort. AB - OBJECTIVE: To examine the amount of weight women with eating disorders [anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED)] gained during pregnancy and to evaluate the adequacy of total weight gain. METHOD: Data from the Norwegian Mother and Child Cohort Study were used in a cross-sectional manner, n = 35,148. Descriptive statistics and Generalized Estimating Equations to calculate the relative risk estimates were employed. RESULTS: Mean gestational weight gain for the entire sample was 2.5 kg at 17.0-20.1 weeks gestation, 9.3 kg at 27.4-29.7 weeks gestation and 15.0 kg at delivery. Women with BN and BED gained significantly more weight on average than those with no eating disorders at each time point. Women with AN had a lower risk (AOR = 0.65 (0.24, 1.72) of gaining inadequately while women with BN and BED were more likely to gain excessively, AOR = 1.09 (1.01, 1.18) and 1.11 (1.08, 1.14), respectively. DISCUSSION: The pattern of weight gain identified for each eating disorder subtype may help explain the birth outcomes of women with eating disorders. PMID- 21661003 TI - Eating patterns in patients with spectrum binge-eating disorder. AB - OBJECTIVE: We sought to describe meal and snack frequencies of individuals with recurrent binge eating and examine the association between these eating patterns and clinical correlates. METHOD: Data from 106 women with a minimum diagnosis of recurrent binge eating were used. Meal and snack frequencies were correlated with measures of weight, eating disorder features, and depression. Participants who ate breakfast every day (n = 25) were compared with those who did not (n = 81) on the same measures. RESULTS: Breakfast was the least, and dinner the most, commonly consumed meal. Evening snacking was the most common snacking occasion. Meal patterns were not significantly associated with clinical correlates; however, evening snacking was associated with binge eating. DISCUSSION: Our findings largely replicated those reported in earlier research. More research is needed to determine the role of breakfast consumption in binge eating. PMID- 21661004 TI - Associations between body checking and disordered eating behaviors in nonclinical women. AB - OBJECTIVE: Recent research suggests that body checking cognitions and behaviors are differentially associated with pathological eating behaviors in clinical women. However, it is unknown whether similar associations exist in nonclinical populations. The aim of this study is to examine whether body checking (cognitions and behaviors) is associated with pathological eating behaviors in a nonclinical sample of women. METHOD: Validated measures of pathological eating behaviors, body checking cognitions, and body checking behaviors were completed by 342 nonclinical university women. RESULTS: Women engaging in binging (objective and subjective), purging, restraint, and excessive exercise reported consistently higher scores across all body checking cognitions and behaviors. All body checking cognitions and behaviors independently contributed to distinguishing those who reported each behavior as opposed to those who did not. The predicted classification was most accurate for the cardinal diagnostic symptoms for bulimia-objective binging and purging. DISCUSSION: Body checking cognitions are implicated in the development of pathological eating behaviors in nonclinical populations, requiring consideration for planning prevention programs. PMID- 21661005 TI - EIC lead editorial 30 #5. PMID- 21661006 TI - Frontiers in urology - the potential for animal models in the assessment of lower urinary tract disorders. PMID- 21661007 TI - Rodent models for urodynamic investigation. AB - Rodents, most commonly rats, mice, and guinea pigs are widely used to investigate urinary storage and voiding functions, both in normal animals and in models of disease. An often used methodology is cystometry. Micturitions in rodents and humans differ significantly and this must be considered when cystometry is used to interpret voiding in rodent models. Cystometry in humans requires active participation of the investigated patient (subject), and this can for obvious reasons not be achieved in the animals. Cystometric parameters in rodents are often poorly defined and do not correspond to those used in humans. This means that it is important that the terminology used for description of what is measured should be defined, and that the specific terminology used in human cystometry should be avoided. Available disease models in rodents have limited translational value, but despite many limitations, rodent cystometry may give important information on bladder physiology and pharmacology. The present review discusses the principles of urodynamics in rodents, techniques, and terminology, as well as some commonly used disease models, and their translational value. PMID- 21661008 TI - Afferent signaling from the bladder: species differences evident from extracellular recordings of pelvic and hypogastric nerves. AB - The afferent nervous system plays an important role in the regulation of lower urinary tract (LUT) function. Multiple methods to study the afferent nervous system in the LUT have been described. This overview focuses on extracellular afferent nerve recordings of the pelvic and hypogastric nerves in cat, rat, mouse, and guinea pig from in vivo and in vitro models and considers how such recordings may lend to the understanding of interspecies differences. PMID- 21661009 TI - Models for sensory neurons of dorsal root ganglia and stress urinary incontinence. AB - AIMS: To discuss (1) animal models for investigating bladder afferent pathways from the spinal cord to the brain and (2) animal models of stress urinary incontinence (SUI) with a special emphasis on functional and histopathological characteristics of each model. METHODS: Literature review of spinal mechanisms of bladder afferent pathways and animal models of SUI. RESULTS: Electrophysiological studies in the rat using pelvic nerve stimulation and recording of evoked potentials in the periaqueductal gray (PAG) prove to be a valuable tool to examine spinal mechanisms of bladder afferent pathways. Animal models of SUI in the rat include vaginal distention as simulated birth trauma, pudendal nerve crush or transection, urethral sphincter injury by electrocauterization, transabdominal urethrolysis, periurethral botulinum-A toxin injection, and pubo urethral ligament transection. Functional and histopathological changes in the continence mechanism after injury are different between models. CONCLUSIONS: Using animal models for sensory neurons, intrathecal and intravenous administration of certain drugs can be tested whether they affect the bladder afferent pathways from the spinal cord to the PAG. Animal models of SUI can serve as a tool to develop new pharmacologic therapies or periurethral injection therapies using stem cell implants. PMID- 21661010 TI - Sophisticated models and methods for studying neurogenic bladder dysfunction. AB - AIM: To describe how the use of new and established animal models and methods can generate vital and far reaching experimental data in the study of mechanism underlying neurogenic bladder overactivity. METHODS: Bladder and colonic irradiated mice and those with upper and lower motor neuron lesions were used to study neurogenic bladder overactivity. Methods included cystometry, tension measurements, afferent nerve recordings and optical mapping of action potentials and intracellular Ca(2+) transients. Recordings were made in a number of innovative preparations including in-line cultured cells, bladder-urethra sheets and cross-sections, spinal cord slices and the cerebral cortex. RESULTS: The animal models and methods used allow for the study of peripheral and central mechanisms of neurogenic overactivity. While colonic irradiation results in solely neurogenic dysfunction, spinal cord lesions also induce non-neural changes resulting in increased spontaneous detrusor contractions that can directly stimulate afferent nerves. Imaging of cultured bladder interstitial cells reveals spontaneous firing that could contribute to detrusor overactivity, while optical imaging of the spinal cord and brain could identify changes in central pathways that underlie lower urinary tract dysfunction. CONCLUSIONS: The animal models and methods described allow for the study of neurogenic overactivity at the peripheral, spinal and cortical levels. This may lead to greater understanding of sensory and motor mechanisms involved in incontinence, the contributions of interstitial cells and spontaneous detrusor contractions, and the involvement of the cortex. PMID- 21661013 TI - The 2nd International Consultation on Incontinence, Research Society (ICI-RS) meeting 2010. PMID- 21661011 TI - Cystitis, co-morbid disorders and associated epithelial dysfunction. PMID- 21661014 TI - Researching bladder afferents-determining the effects of beta(3) -adrenergic receptor agonists and botulinum toxin type-A. AB - A substantial portion of the current research on lower urinary tract dysfunction is focused on afferent mechanisms. The main goals are to define and modulate the signaling pathways by which afferent information is generated, enhanced and conveyed to the central nervous system. Alterations in bladder afferent mechanisms are a potential source of voiding dysfunction and an emerging source for drug targets. Established drug therapies such as muscarinic receptor antagonists, and two emerging therapies, beta(3) -adrenergic receptor agonists and botulinum toxin type-A, may act partly through afferent mechanisms. This review focuses on these two new principles and new and established methods for determining their sites of action. It also provides brief information on the innervation of the bladder, afferent receptors and transmitters and how these may communicate with the urothelium, interstitial cells and detrusor smooth muscle to regulate micturition. Peripheral and central mechanisms of afferent sensitization and myogenic mechanisms that lead to detrusor overactivity, overactive bladder symptoms and urgency sensations are also covered. This work is the result from 'Think Tank' presentations, and the lengthy discussions that followed, at the 2010 International Consultation on Incontinence Research Society meeting in Bristol, UK. PMID- 21661012 TI - Models of inflammation of the lower urinary tract. AB - Inflammation of the lower urinary tract occurs frequently in people. The causes remain obscure, with the exception of urinary tract infection. Animal models have proven useful for investigating and assessing mechanisms underlying symptoms associated with lower urinary tract inflammation and options for suppressing these symptoms. This review will discuss various animal models of lower urinary tract inflammation, including feline spontaneous (interstitial) cystitis, neurogenic cystitis, autoimmune cystitis, cystitis induced by intravesical instillation of chemicals or bacterial products (particularly lipopolysaccharide or LPS), and prostatic inflammation initiated by transurethral instillation of bacteria. Animal models will continue to be of significant value in identifying mechanisms resulting in bladder inflammation, but the relevance of some of these models to the causes underlying clinical disease is unclear. This is primarily because of the lack of understanding of causes of these disorders in people. Comparative and translational studies are required if the full potential of findings obtained with animal models to improve prevention and treatment of lower urinary tract inflammation in people is to be realized. PMID- 21661015 TI - Modeling the urinary tract-computational, physical, and biological methods. AB - Models of the lower urinary tract are used to understand better the physiological and pathological functions of the tract and to gain insight into the relative importance of different components. The key requirement of a model is described, namely: to involve a continuous iteration with experiment; whereby experiments provide parameters and validation for components of the model, which is then used to generate hypotheses, which are tested experimentally. Different types of models are described: computational models that describe mathematically the whole urinary tract or components; physical models useful especially in testing medical devices; and tissue-engineered models. The purpose of modeling is first described in terms of the ability of models to predict the properties of the system of interest, using components that have a physiological interpretation, and to gain insight into the relative importance of different components. Examples are used to illustrate the use of modeling the urinary tract with reference to the different categories listed above. PMID- 21661016 TI - Nocturia: new directions. AB - The Nocturia Think Tank (TT) met during the 2010 meeting of the International Consultation on Incontinence-Research Society to discuss present knowledge and future directions in care and research of this prominent component of the spectrum of lower urinary tract symptoms. Questions raised included whether nocturia should be re-defined as a function of its bother, effects on quality of life, and economic impact upon society. At issue is the need to delineate the determinants of successful nocturia management. The multifactorial nature of nocturia requires that progress in its treatment will be dependent upon the cooperative investigation on the part of urologists, urogynecologists, geriatricians, epidemiologists, medical economists and pharma. Areas for future avenues of research were outlined at the conclusion of the meeting. PMID- 21661017 TI - Mechanisms of continence and surgical cure in female and male SUI: surgical research initiatives. AB - AIMS: To report the conclusions of the Think Tank on mechanisms of incontinence and surgical cure in female and male SUI: surgical research initiatives during the ICI-RS meeting in 2010. METHODS: The sub-group considered five areas for future research in stress urinary incontinence (SUI); (i) epidemiology and public health efforts in SUI, (ii) the basic sciences examining the physiology and pathophysiology of the continence mechanism, (iii) diagnostic techniques and clinical assessment of SUI, (iv) the future of treatment and surgical cure, and (v) the separate issue of male SUI. RESULTS: Roadblocks to progress were identified for each of the five directions. CONCLUSIONS: Future research directions are suggested for each of these areas. PMID- 21661018 TI - Bladder outlet physiology in the context of lower urinary tract dysfunction. AB - Physiological function of the bladder outlet is complex and symptomatic consequences can result from outlet dysfunction. Within the outlet, smooth, and skeletal muscles constitute the contractile apparatus, but additional cell types include interstitial cells and neuroendocrine cells, and various transmitters are present in the innervation, raising the possibility of unrecognized functional subtleties. Key outlet functions are; maintained closure for urine storage, increased closure (guarding) during exertion, sustained opening for voiding, transient opening for territorial marking in animals and orthograde male ejaculation. These are co-ordinated by several spinal and higher CNS centers, with overlap of the somatic, sympathetic and parasympathetic nervous systems. During voiding, urethral afferents may be important in maintaining detrusor contraction until completion of bladder emptying. Some of the bladder outlet afferents may be shared with the anal sphincter. Dysfunction of the outlet leads to conditions such as retrograde ejaculation, Fowler's syndrome, and detrusor sphincter dyssynergia. Urethral relaxation during urine storage may lead to urinary urgency, which may be misleadingly labeled as overactive bladder. Research priorities are numerous, including; peripheral cellular integrative physiology, interactions with other pelvic organs, interconnectivity of the CNS centers at all levels of the neuraxis, and standardized animal models of outlet functions such as reflex-driven voiding. PMID- 21661019 TI - Bladder compliance what does it represent: can we measure it, and is it clinically relevant? AB - AIMS: To report the conclusion of the Think Thank 8 on Compliance Discussions during the second ICI-RS meeting in 2010. METHODS: During a 3-day meeting a group of specialists discussed bladder compliance, what it represents, how it can be measured and if it is clinically relevant. RESULTS: Bladder compliance is the result of a mathematical calculation of the volume required for a unit rise of pressure measured during a cystometric filling. It gives an indication on how the different mechanisms in the bladder wall react on stretching. There is a need of standardization of measurement and suggestions for this are given in the text. Pitfalls are described and how to avoid them. There is a wide range of compliance values in healthy volunteers and groups of patients. Poor compliance needs to be defined better as it can have significant clinical consequences. Prevention and treatment are discussed. CONCLUSION: If compliance is correctly measured and interpreted, it has importance in urodynamic testing and gives information relevant for clinical management. PMID- 21661020 TI - Detrusor underactivity: a plea for new approaches to a common bladder dysfunction. AB - AIMS: Detrusor underactivity (DU) is defined by the International Continence Society as a contraction of reduced strength and/or duration resulting in prolonged or incomplete emptying of the bladder but has yet received only little attention. The purpose of this report is to summarize the ICI-RS meeting in Bristol in 2010 exploring current knowledge on DU and outline directions for future research. METHODS: A think tank discussion was held and the summary of discussions was presented to all ICI-RS participants. This report is based on the final discussions. RESULTS: The understanding of the pathophysiology, epidemiology, assessment, and treatment of DU remains rudimentary. DU is defined by pressure-flow analysis but no consensus exists regarding which of the available formulae should be used for quantification of detrusor work. DU is likely to be multifactorial. Aging causes a decay in detrusor activity but other concomitant causes, either myogenic or neurogenic, may aggravate the problem resulting in decrease of detrusor contractility. No effective pharmacotherapy for the condition exists. Only a few surgical therapeutic strategies have been explored, such as neuromodulation and skeletal muscle myoplasties. Consequently, the management of affected individuals remains unsatisfactory. CONCLUSIONS: Future directions recommended by the ICI-RS panel include assessment of pathogenesis by developing novel animal models in addition to new non-invasive tests allowing longitudinal trials. Furthermore, optimizing the existing evaluation algorithms to support standard testing for DU and further epidemiological studies to quantify the size of the problem are required for the development of future treatment modalities. PMID- 21661021 TI - Ultrasound imaging of the pelvic floor: where are we going? AB - We produced a non systematic review of ultrasound imaging of the pelvic floor in women with urinary incontinence (UI) and/or pelvic organ prolapse (POP). We have searched the PubMed and Embase databases for the following PICO question: women; imaging; urinary incontinence, pelvic organ prolapse, pelvic floor, pelvic floor muscle, pelvic floor muscle training; physical examination, no imaging; diagnosis, prognosis, outcome. The production of a systematic review was deemed impossible based on the type and quality of the published evidence. Clinical research focused on the pathophysiology of the UI and POP looking relation between anatomic abnormalities, childbirth, the risk of UI or POP, the outcome of conservative treatment and reconstructive surgery. Published papers fall into the remits of diagnostic studies but often fail to comply with the recommendations of the STARD initiative. Most published evidence remains the product of a single institution effort and confirmatory studies are rarely found. Imaging studies in patients with UI did not provide evidence of any clinical benefit in the management of patients. In patients with POP, interesting correlations have been identified such as between childbirth, dimension of levator hiatus, avulsion of levator ani and risk of prolapse, but the non clinical benefit of pelvic floor imaging could still not be identified. Research on pelvic floor imaging requires a coordinated, international, multicentre effort to improve internal and external validity of imaging techniques, confirm observations published by single institutions and provide health technology assessment of imaging in the management of UI or POP patients. PMID- 21661022 TI - Constructing trials to show whether urodynamic studies are necessary in lower urinary tract dysfunction. AB - AIMS: This report reviews the evidence for the utility of urodynamic studies (UDS) in lower urinary tract dysfunction and tries to identify the necessity of constructing trials to show whether UDS are necessary. METHODS: An outline for a think tank discussion was prepared by the chairman of the session. Several experts selected relevant papers from a literature review of the Pubmed/Medline database (January 1966 to August 2010) and prepared a presentation of the evidence for the utility of UDS in the evaluation of several conditions, the prediction of treatment outcome, the prediction of complications and/or cost effectiveness. The following conditions were considered: urinary incontinence, symptoms suggestive of benign prostatic obstruction (LUTS/BPO), overactive bladder (OAB) and urogenital prolapse. Summary presentations were discussed by a large group of opinion leaders and experts and audio-recorded. The proceedings of this process are the basis for this manuscript. RESULTS: The structured sessions resulted in detailed statements about the existing evidence for the utility of UDS in men after radical prostatectomy, men with uncomplicated LUTS/BPO, patients with OAB, female stress urinary incontinence (SUI) and urogenital prolapse. CONCLUSIONS: UDS should be used for investigation of new treatment modalities and establishment of diagnoses whenever they are in doubt. UDS do not appear to be necessary before pelvic floor muscle training, medical treatment of LUTS/BPO or OAB, surgical treatment of primary female SUI or prolapse. RCT's with non inferiority design should be conducted to investigate UDS in patients before surgical treatment of the prostate, SUI or OAB. PMID- 21661023 TI - Defining cure. AB - This paper is a summary of the presentations made as Proposal 2-"Defining cure" to the 2nd Annual meeting of the ICI-Research Society, in Bristol, 16th June 2010. It reviews definitions of 'cure' and 'outcome', and considers the impact that varying definition may have on prevalence studies and cure rates. The difference between subjective and objective outcomes is considered, and the significance that these different outcomes may have for different stakeholders (e.g. clinicians, patients, carers, industry etc.) is discussed. The development of patient reported outcome measures and patient defined goals is reviewed, and consideration given to the use of composite end-points. A series of proposals are made by authors and discussants as to how currently validated outcomes should be applied, and where our future research activity in this area might be directed. PMID- 21661024 TI - Determining the optimal pelvic floor muscle training regimen for women with stress urinary incontinence. AB - Pelvic floor muscle (PFM) training has received Level-A evidence rating in the treatment of stress urinary incontinence (SUI) in women, based on meta-analysis of numerous randomized control trials (RCTs) and is recommended in many published guidelines. However, the actual regimen of PFM training used varies widely in these RCTs. Hence, to date, the optimal PFM training regimen for achieving continence remains unknown and the following questions persist: how often should women attend PFM training sessions and how many contractions should they perform for maximal effect? Is a regimen of strengthening exercises better than a motor control strategy or functional retraining? Is it better to administer a PFM training regimen to an individual or are group sessions equally effective, or better? Which is better, PFM training by itself or in combination with biofeedback, neuromuscular electrical stimulation, and/or vaginal cones? Should we use improvement or cure as the ultimate outcome to determine which regimen is the best? The questions are endless. As a starting point in our endeavour to identify optimal PFM training regimens, the aim of this study is (a) to review the present evidence in terms of the effectiveness of different PFM training regimens in women with SUI and (b) to discuss the current literature on PFM dysfunction in SUI women, including the up-to-date evidence on skeletal muscle training theory and other factors known to impact on women's participation in and adherence to PFM training. PMID- 21661025 TI - Estrogens and the lower urinary tract. AB - The urogenital tract is sensitive to the effect of oestrogen and progesterone throughout adult life. Epidemiological studies have implicated oestrogen deficiency in the aetiology of lower urinary tract symptoms occurring following the menopause. Although to date the role of oestrogen replacement therapy in the management of postmenopausal urinary incontinence remains controversial its use in the management of women complaining of urogenital atrophy is now well established. This aim of this paper is to review the recent evidence regarding the urogenital effects of hormone therapy with a particular emphasis on the management of postmenopausal urinary incontinence, overactive bladder, recurrent lower urinary tract infections and urogenital atrophy. In addition to a review of the available evidence suggestions are also made regarding priorities for further research in the field. PMID- 21661026 TI - SUI surgery at the time of vaginal POP repair: is a surgical algorithm possible or desirable? AB - AIMS: To review the question of whether SUI Surgery should be performed at the time of vaginal POP repair and whether a surgical algorithm is possible and report discussion on this topic from the ICI-RS meeting in 2010. METHODS: The literature on this topic was surveyed and discussion from ICI-RS is reported. RESULTS: There are multiple approaches to this question with literature supporting each of these approaches. Some perform an anti-incontinence procedure in all patients undergoing vaginal surgery, many are selective and only perform it in patients with symptoms or signs (including occult) of SUI and some perform it in no patients preferring to wait and see if they have symptoms of SUI post operatively. There are a number of algorithms in use reflecting these practices but none agreed on by all. Ongoing trials may provide more information that allows the construction of better algorithms. All agreed that preoperative counseling was critical. CONCLUSION: Surgical practice regarding SUI surgery at the time of vaginal POP repair varies widely and there is conflicting literature that supports different approaches and algorithms. Ongoing trials should provide more information to help construct better algorithms. Other approaches for designing prediction models for this problem may be useful. PMID- 21661027 TI - Neuromodulation for intractable OAB. AB - To review the current status of sacral neuromodulation (SNM) in the treatment of intractable overactive bladder symptoms, the PubMed English-language literature was used to address efficacy, technical issues, alternative techniques, the mechanism of action, adverse events, the cost-effectiveness, and current considerations on the use of SNM as second-line treatment in OAB. Several studies attest to the short- and long-term efficacy of SNM in reducing urgency incontinence and the remaining OAB symptoms. Few, medium-sized sample, randomized controlled trials exist. Little is known about long-term patient satisfaction from SNM and prognostic factors have not been identified. Technical advances have significantly improved patient selection and outcomes, as well as complication rates, but revision rates still remain high. The mechanism of action remains largely unknown, but appears to be associated with reorganization of spinal reflexes and regulation of cortical activity. Reports on cost-effectiveness are conflicting. Less invasive forms of SNM may offer a viable alternative to central SNM. In conclusion, current evidence supports the short- and long-term efficacy of SNM in treating intractable OAB, but further research is needed to improve patient selection, identify prognostic factors, clarify the mechanism of action and reduce complications and revision rates. PMID- 21661028 TI - Managing unsatisfactory outcome after mid-urethral tape insertion. AB - This article reviews the literature on the assessment and management of women whose previous mid-urethral tape surgery to manage stress urinary incontinence symptoms has failed to produce a satisfactory outcome. In many areas the literature is deficient and the article includes consensus statements drawn from the International Continence Society Research Society meeting in Bristol in June 2010. The need for a structured approach to assessment and management is highlighted, so that further research into areas of uncertainty can be prioritized. The article concludes with a number of research recommendations. PMID- 21661029 TI - Is tissue engineering and biomaterials the future for lower urinary tract dysfunction (LUTD)/pelvic organ prolapse (POP)? AB - The fields of tissue engineering and regenerative medicine have seen major advances over the span of the past two decades, with biomaterials playing a central role. Although the term "regenerative medicine" has been applied to encompass most fields of medicine, in fact urology has been one of the most progressive. Many urological applications have been investigated over the past decades, with the culmination of these technologies in the introduction of the first laboratory-produced organ to be placed in a human body.1 With the quality of life issues associated with urinary incontinence, there is a strong driver to identify and introduce new technologies and the potential exists for further major advancements from regenerative medicine approaches using biomaterials, cells or a combination of both. A central question is why use biomaterials? The answer rests on the need to make up for inadequate or lack of autologous tissue, to decrease morbidity and to improve long-term efficacy. Thus, the ideal biomaterial needs to meet the following criteria: (1) Provide mechanical and structural support, (2) Maintain compliance and be biocompatible with surrounding tissues, and (3) Be "fit for purpose" by meeting specific application needs ranging from static support to bioactive cell signaling. In essence, this represents a wide range of biomaterials with a spectrum of potential applications, from use as a supportive or bulking implant alone, to implanted biomaterials that promote integration and eventual replacement by infiltrating host cells, or scaffolds pre-seeded with cells prior to implant. In this review we shall discuss the structural versus the integrative uses of biomaterials by referring to two key areas in urology of (1) pelvic organ support for prolapse and stress urinary incontinence, and (2) bladder replacement/augmentation. PMID- 21661030 TI - Abstracts of the 35th Annual Congress of the Italian Urodynamics Society. June 9011, 2011. Turin, Italy. PMID- 21661031 TI - On the nature of bladder sensation: the concept of sensory modulation. AB - AIMS: Going to the toilet is an essential everyday event. Normally, we do not give much thought to the sensations and factors that trigger voiding behavior: we just go. For many people, this apparently simple task is complicated and dominates their life. They have strong sensations and sudden desires to void, often resulting in incontinence. It is therefore important that we understand the origins for this functional change and identify means to alleviate it. METHODS: Literature survey. RESULTS: A considerable body of work has focused on this problem and ideas and concepts on the nature of bladder sensations are embedded in the literature. In this paper we argue the necessity to return to first principles and a re-examination of the problem. We explore the use of focus groups to identify relevant bladder sensation and what triggers 'bladder' behavior. We argue that there are differences in what can be described as 'introspective bladder sensations' and the sensations reported immediately before a void, 'void sensations'. Finally, we propose an alternative model describing how peripheral information generating 'introspective sensations' and 'void sensations' might be different but interrelated sensations. By exploring such ideas and identifying such complexity it is our intention to stimulate debate and generate further research in the field in order to understand better the physiology of bladder sensation and the pathology of increased urge, frequency and incontinence. CONCLUSIONS: Review of the literature on bladder sensation and the established ideas suggests that we might be missing something and the problem of normal and increased sensation and of urgency may be much more complex. PMID- 21661032 TI - Beta3-adrenoceptors in the rat sacral spinal cord and their functional relevance in micturition under normal conditions and in a model of partial urethral obstruction. AB - AIMS: Beta3-adrenoceptor selective agonists are evaluated as a new treatment for patients with lower urinary tract symptoms . It is believed that beta3-AR selective agonists exert their effects via a peripheral site of action. However, beta3-ARs have been found in brain tissue. This study examined whether beta3-ARs are present in rat sacral spinal cord, and whether there are differences in beta3 AR expression between normal and partial urethral obstruction (PUO) animals, and furthermore assessed the functional relevance of spinal beta3-ARs for micturition. METHODS: Thirty-eight male Sprague-Dawley rats underwent either PUO or sham-operation. Two weeks after operation, half of the animals were used for histomorphological analysis. Remaining animals were used for functional experiments, where a beta3-AR selective agonist, BRL 37344, was given intrathecally. Bladder function was assessed by continuous cystometry in non anesthetized animals before and after drug administration. RESULTS: Beta3-ARs were found in sacral spinal cord segments with an accumulation in the ventral horn. There was a significant increase of beta3-AR expression in obstructed rats. In functional experiments obstructed rats showed increased bladder weight, micturition frequency, spontaneous activity, and bladder pressures (all P < 0.05) compared to controls. Intrathecally administered BRL 37344 showed no effect in non-obstructed rats. In obstructed rats intrathecal BRL 37344 significantly reduced bladder pressures, spontaneous activity, and micturition frequency (all P < 0.05). CONCLUSIONS: Beta3-ARs are present in rat sacral spinal cord, and are significantly up-regulated after PUO. Besides their well-established peripheral site of action in the treatment of voiding dysfunction, beta3-AR selective agonists might exert relevant effects at a central nervous site of action. PMID- 21661034 TI - Response to OAB, are we barking up the wrong tree? A lesson from my dog. PMID- 21661033 TI - Characterization of the urinary bladder dysfunction in renovascular hypertensive rats. AB - AIMS: Association between arterial hypertension and urinary bladder dysfunction has been reported in humans and spontaneously hypertensive rats. However, no study exists evaluating the bladder dysfunction in conditions of renovascular hypertension. The purpose of this study was to characterize the bladder dysfunction in two kidney-one clip (2K-1C) hypertensive rats. METHODS: A silver clip was placed around the renal artery of male Wistar rats. After 8 weeks, cystometric study, concentration-response curves to contractile and relaxant agents, frequency-dependent contractions, histomorphometry, muscarinic M(2) /M(3) mRNA expression and cyclic AMP measurements were performed. RESULTS: 2K-1C rats showed enhanced bladder volume, wall thickness and smooth muscle density. 2K-1C rats also exhibited increases in bladder capacity and non-void contractions, and decreases in the inter-contraction intervals. In isolated detrusor smooth muscle (DSM), contractions to carbachol and electrical-field stimulation (EFS) were significantly greater in 2K-1C rats. The Rho-kinase inhibitor Y27632 (10 uM) significantly reduced the carbachol-induced contractions in SHAM and 2K-1C rats, but DSM remained overactive in 2K-1C rats in presence of Y27632. Concentration dependent contractions to the P2X receptor agonist alpha,beta-methylene ATP, KCl and extracellular Ca(2+) did not change between SHAM and 2K-1C groups. In 2K-1C rats, isoproterenol, metaproterenol and BRL 37-344 (non-selective, beta(2) - and beta(3) -selective adrenoceptor agonists, respectively) produced significantly lower relaxations and decreased cAMP levels, whereas relaxant responses to sodium nitroprusside and BAY 41-2272 remained unchanged. Muscarinic M(3) mRNA expression receptors were higher in 2K-1C group. CONCLUSIONS: Renovascular hypertensive rats exhibit bladder dysfunction that involves tissue remodeling and enhanced muscarinic M(3) -mediated contractions associated with reduced beta-adrenoceptor mediated signal transduction. PMID- 21661036 TI - OAB. Are we barking up the wrong tree? A lesson from my dog. PMID- 21661037 TI - The natural history of the overactive bladder syndrome in females: a long-term analysis of a health screening project. AB - AIM: To analyze the natural history of the overactive bladder (OAB) syndrome in women over a period of 6.5 years. METHOD: Women participating in a health screening survey in the area of Vienna in 1998/1999 underwent a detailed health investigation and completed the Bristol Female Lower Urinary Tract Symptom (BFLUTS) Questionnaire. In 2005 all women who were still living in the area of Vienna, were contacted by mail to complete the BFLUTS questionnaire again. RESULTS: A total of 386 women with a mean age of 54 years (range: 21-81 years) entered this study and were all followed for a mean of 6.5 years. At baseline, the prevalence of OAB was 19.4% (n = 75/386) and increased to 27.2% (105/386) 6.5 years later resulting in an average annual progression rate of 1.2%. The incidence was 19.3% (n = 60/311; average annual rate: 2.9%), a remission was seen in 40% (n = 30/75; average annual rate: 6.2%), stable disease in 41.3% (n = 31/75; average annual rate: 6.4%), a progression was noticed in 6.7% (n = 5/75; average annual rate: 1.0%) and an improvement in 12% (n = 9/75; average annual rate: 1.8%). Women with a full remission were 49.9 years (+/- 13 years), those with stable disease 58.2 years (+/- 9.3 years), those with improvement 57.4 years (+/- 10.4 years), those with deterioration 61.8 years (+/- 12.8 years) and those with de novo OAB 57.3 years (+/- 12.3 years). CONCLUSION: OAB is a dynamic disease with long-lasting stable disease courses as well as remissions and progressions. PMID- 21661038 TI - Pilot study evaluating the safety of intradetrusor injections of botulinum toxin type A: investigation of generalized spread using single-fiber EMG. AB - AIMS: Intradetrusor botulinum toxin type-A injections are a novel therapy for treatment of neurogenic overactive bladder resistant to parasympatholytic treatment. In rare cases, however, it may be associated with generalized muscle weakness. Single-fiber electromyographic (SFEMG) analysis of neuromuscular jitter (NJ) was used to study OnabotulinumtoxinA (BOTOX(r)) migration to striated muscle. METHODS: This study comprised a prospective, single-center investigation of 21 spinal cord injured patients receiving intradetrusor OnabotulinumtoxinA. Clinical tolerance was assessed through muscle testing and para-clinical tolerance by systematic analysis of NJ in muscles distant from the bladder. RESULTS: Twenty-one patients (13 males, 8 females) received one intradetrusor injection of 300 U OnabotulinumtoxinA. Mean age was 42.1 +/- 14.4 and mean number of injections prior to study inclusion was 2.6 +/- 1.7. Clinical and para clinical assessments were performed on average 26 days +/- 8 days post OnabotulinumtoxinA injection. Seven patients had abnormal NJ results on SFEMG, but no patient had evidence of blocking. Four patients complained of tiredness (one with NJ abnormalities). CONCLUSIONS: Patients showed good tolerance to intradetrusor OnabotulinumtoxinA injections. Tiredness was not associated with generalized muscle weakness since testing remained unchanged and NMJ was normal in three of four patients. NJ analysis was abnormal in 7 of 21 patients, but this was not considered serious and there was no evidence of muscle fiber block. These results support the safety of bladder injections of OnabotulinumtoxinA and suggest that, although migration of OnabotulinumtoxinA to other muscle groups may impair NJ function in a minority of patients, this does not correlate with symptoms of tiredness or muscle weakness. PMID- 21661040 TI - Re: Cooper MA, fletter PC, Zaszczurynski, Damaser MS. Comparison of air-charged and water-filled urodynamic pressure measurement catheters. Neurourol Urodyn 2011;30:329-334. PMID- 21661041 TI - Coital incontinence: relation to detrusor overactivity and stress incontinence. A controversial topic. PMID- 21661042 TI - PSA levels in men with spinal cord injury and under intermittent catheterization. AB - AIM: To evaluate serum PSA levels of patients with spinal cord injury (SCI) submitted or not to CIC in comparison to those of the general population. METHODS: We retrospectively studied 140 men with SCI admitted in our department from January 2005 to May 2009. Thirty-four SCI patients had PSA levels available, comprising 21 under CIC and 13 without CIC. Patients under CIC performed it 4-6 times a day and mean time of catheterization was 72.4 months (range 30-192). The most common etiology of SCI was fall from height (33%), followed by car/motorcycle crashes (15%). Control group was composed by 670 healthy men that were referred to our service to evaluation of Kidney donation or cancer prostate screening. We used Student's t-test and variance analysis (ANOVA) for age and PSA comparison between the groups. RESULTS: Overall, patients with SCI and controls had similar mean age (54 vs. 57 years old, P = 0.11) and mean PSA level (1.81 vs. 1.95 ng/ml, P = 0.66). SCI patients were divided into with and without CIC. Patients without CIC had similar mean age (60 vs. 57 years old, P = 0.11) and similar PSA values when compared to controls (1.72 vs. 1.95 ng/ml, P = 0.89). Patients under CIC were compared to controls with similar age (50 vs. 47 years, P = 0.0332) and their PSA levels were greater (1.86 vs. 0.79 ng/ml, P = 0.026). CONCLUSION: Clean intermittent catheterization increased PSA levels approximately doubling its value. PMID- 21661043 TI - Tumor imaging using hyperpolarized 13C magnetic resonance spectroscopy. AB - Dynamic nuclear polarization is an emerging technique for increasing the sensitivity of magnetic resonance imaging and spectroscopy, particularly for low gamma nuclei. The technique has been applied recently to a number of 13C-labeled cell metabolites in biological systems: the increase in signal-to-noise allows the spatial distribution of an injected molecule to be imaged as well as its metabolic product or products. This review highlights the most significant molecules investigated to date in preclinical cancer models, either in terms of their demonstrated metabolism in vivo or the biological processes that they can probe. In particular, label exchange between hyperpolarized 13C-labeled pyruvate and lactate, catalyzed by lactate dehydrogenase, has been shown to have a number of potential applications. Finally, techniques to image these molecules are also discussed as well as methods that may extend the lifetime of the hyperpolarized signal. Hyperpolarized magnetic resonance imaging and magnetic resonance spectroscopic imaging have shown great promise for the imaging of cancer in preclinical work, both for diagnosis and for monitoring therapy response. If the challenges in translating this technique to human imaging can be overcome, then it has the potential to significantly alter the management of cancer patients. PMID- 21661044 TI - Dynamic contrast-enhanced-MRI of tumor hypoxia. AB - Patients with highly hypoxic primary tumors show increased frequency of locoregional treatment failure and poor survival rates and may benefit from particularly aggressive treatment. The potential of gadolinium diethylene triamine penta-acetic acid-based dynamic contrast-enhanced-MRI in assessing tumor hypoxia was investigated in this preclinical study. Xenografted tumors of eight human melanoma lines were subjected to dynamic contrast-enhanced-MRI and measurement of the fraction of radiobiologically hypoxic cells and the fraction of pimonidazole-positive hypoxic cells. Tumor images of K(trans) (the volume transfer constant of gadolinium diethylene-triamine penta-acetic acid) and v(e) (the fractional distribution volume of gadolinium diethylene-triamine penta acetic acid) were produced by pharmacokinetic analysis of the dynamic contrast enhanced-MRI data, and K(trans) and v(e) frequency distributions of the non necrotic tumor tissue were established and related to the extent of hypoxia. Tumors showing high K(trans) values and high v(e) values had low fractions of hypoxic cells, whereas tumors showing both low K(trans) values and low v(e) values had high hypoxic fractions. K(trans) differentiated better between tumors with low and high hypoxic fractions than did v(e). This study supports the current attempts to establish dynamic contrast-enhanced-MRI as a method for assessing the extent of hypoxia in human tumors, and it provides guidelines for the clinical development of valid assays. PMID- 21661045 TI - On the performance of T2* correction methods for quantification of hepatic fat content. AB - Nonalcoholic fatty liver disease is the most prevalent chronic liver disease in Western societies. MRI can quantify liver fat, the hallmark feature of nonalcoholic fatty liver disease, so long as multiple confounding factors including T(2)* decay are addressed. Recently developed MRI methods that correct for T(2)* to improve the accuracy of fat quantification either assume a common T(2)* (single-T(2)*) for better stability and noise performance or independently estimate the T(2)* for water and fat (dual-T(2)*) for reduced bias, but with noise performance penalty. In this study, the tradeoff between bias and variance for different T(2)* correction methods is analyzed using the Cramer-Rao bound analysis for biased estimators and is validated using Monte Carlo experiments. A noise performance metric for estimation of fat fraction is proposed. Cramer-Rao bound analysis for biased estimators was used to compute the metric at different echo combinations. Optimization was performed for six echoes and typical T(2)* values. This analysis showed that all methods have better noise performance with very short first echo times and echo spacing of ~pi/2 for single-T(2)* correction, and ~2pi/3 for dual-T(2)* correction. Interestingly, when an echo spacing and first echo shift of ~pi/2 are used, methods without T(2)* correction have less than 5% bias in the estimates of fat fraction. PMID- 21661046 TI - X-PROP: a fast and robust diffusion-weighted propeller technique. AB - Diffusion-weighted imaging (DWI) has shown great benefits in clinical MR exams. However, current DWI techniques have shortcomings of sensitivity to distortion or long scan times or combinations of the two. Diffusion-weighted echo-planar imaging (EPI) is fast but suffers from severe geometric distortion. Periodically rotated overlapping parallel lines with enhanced reconstruction diffusion weighted imaging (PROPELLER DWI) is free of geometric distortion, but the scan time is usually long and imposes high Specific Absorption Rate (SAR) especially at high fields. TurboPROP was proposed to accelerate the scan by combining signal from gradient echoes, but the off-resonance artifacts from gradient echoes can still degrade the image quality. In this study, a new method called X-PROP is presented. Similar to TurboPROP, it uses gradient echoes to reduce the scan time. By separating the gradient and spin echoes into individual blades and removing the off-resonance phase, the off-resonance artifacts in X-PROP are minimized. Special reconstruction processes are applied on these blades to correct for the motion artifacts. In vivo results show its advantages over EPI, PROPELLER DWI, and TurboPROP techniques. PMID- 21661047 TI - Genomewide linkage study of modifiers of LRRK2-related Parkinson's disease. AB - Mutations in the leucine-rich repeat kinase 2 gene, located at 12q12, are the most common known genetic causes of Parkinson's disease. Studies of leucine-rich repeat kinase 2 mutation carriers have shown incomplete and age-dependent penetrance, and previous studies have suggested that inherited susceptibility factors may modify the penetrance of leucine-rich repeat kinase 2 mutations. Genomewide linkage to age of onset of leucine-rich repeat kinase 2-related Parkinson's disease was evaluated in a sample of 113 leucine-rich repeat kinase 2 mutation carriers from 64 families using single-nucleotide polymorphism data from the Illumina HumanCNV370 genotyping array. Association between onset age and single-nucleotide polymorphisms under suggestive linkage peaks was also evaluated. The top logarithmic odds score for onset age (logarithmic odds score = 2.43) was in the chromosome 1q32.1 region. Moderate linkage to onset was also identified at 16q12.1 (logarithmic odds score = 1.58). Examination of single nucleotide polymorphism association to Parkinson's disease onset under the linkage peaks revealed no statistically significant single-nucleotide polymorphism associations. The 2 novel genomic regions identified may harbor modifiers of leucine-rich repeat kinase 2-related Parkinson's disease onset age or penetrance, and further study of these regions may provide important insight into leucine-rich repeat kinase 2-related Parkinson's disease. PMID- 21661048 TI - Long-term neuroprotection and neurorestoration by glial cell-derived neurotrophic factor microspheres for the treatment of Parkinson's disease. AB - BACKGROUND: Glial cell-derived neurotrophic factor is a survival factor for dopaminergic neurons and a promising candidate for the treatment of Parkinson's disease. However, the delivery issue of the protein to the brain still remains unsolved. Our aim was to investigate the effect of long-term delivery of encapsulated glial cell-derived neurotrophic factor within microspheres. METHODS: A single dose of microspheres containing 2.5 MUg of glial cell-derived neurotrophic factor was implanted intrastriatally in animals 2 weeks after a 6 hydroxydopamine lesion. RESULTS: The amphetamine test showed a complete behavioral recovery after 16 weeks of treatment, which was maintained until the end of the study (week 30). This effect was accompanied by an increase in dopaminergic striatal terminals and neuroprotection of dopaminergic neurons. CONCLUSIONS: The main achievement was the long-term neurorestoration in parkinsonian animals induced by encapsulated glial cell-derived neurotrophic factor, suggesting that microspheres may be considered as a means to deliver glial cell-derived neurotrophic factor for Parkinson's disease treatment. PMID- 21661049 TI - Altered eye-to-foot coordination in standing parkinsonian patients during large gaze and whole-body reorientations. AB - We investigated whether turning problems in Parkinson's disease may be the result of abnormal horizontal multisegmental angular coordination. Ten mildly affected patients and controls stood upright and voluntarily reoriented eyes and body to illuminated targets of eccentricities up to +/-180 degrees. The effects of target location, visibility, and predictability on movement parameters were evaluated. Patients' latencies were normal. Control subjects foveated large eccentricity targets with a single gaze shift in approximately 30% of predictable trials. Patients rarely did so (10% of predictable trials) because of reduced head-in space and trunk velocity. This resulted in massive foveation delays in patients an average of half a second for displacements of 180 degrees. The covariation of eye, head, and trunk rotations was quantified statistically by means of principal components analysis. In both groups, the combined movement was initially stereotyped and two principal components accounted for nearly all data variance the original three mechanical degrees of freedom (i.e., eye-head-trunk) are reduced to two kinematic degrees of freedom. However, in patients, the eye contributed more, and the head and trunk less, to the gaze shift than in control subjects. Although the eye-to-foot turning synergy is preserved in early-stage parkinsonism, quantitative differences are prominent, particularly a larger ocular (and smaller head-trunk) contribution in patients. Turning problems in Parkinson's disease do not result from inability to assemble multisegmental movements, as patients' ability to control numerous degrees of freedom is preserved. However, trunk bradykinesia reduces the frequency of single-step gaze shifts, thus prolonging target acquisition time. Preserved eye motion compensates for trunk slowness. PMID- 21661050 TI - Motor cortical plasticity is impaired in Unverricht-Lundborg disease. AB - Patients with Unverricht-Lundborg disease, also referred to as progressive myoclonus epilepsy type 1, exhibit widespread motor symptoms and signs in addition to epileptic seizures, which suggest abnormal excitability of the primary motor pathways. To explore the plasticity of the sensory-motor cortex, we employed a modern neurophysiological method, the paired associative stimulation protocol, which resembles the concept of long-term potentiation of experimental studies. Seven patients with genetically verified Unverricht-Lundborg disease and 13 healthy control subjects were enrolled in the study to characterize cortical sensory-motor plasticity. In the study protocol, peripheral electric median nerve stimulation preceded navigated transcranial magnetic stimulation targeted to the representation area of thenar musculature on the contralateral primary motor cortex. The protocol consisted of 132 transcranial magnetic stimulation trials at 0.2 Hz, preceded by peripheral sensory stimulation at 25 ms. Motor-evoked potential amplitudes were analyzed at baseline and after the paired associative stimulation protocol at an intensity of 130% of the individual motor threshold. The patients with Unverricht-Lundborg disease exhibited an average decrease of 15% in motor-evoked potential amplitudes 30 minutes after paired associative stimulation, whereas in the control subjects, a significant increase (101%) was observed (P < .05), as expected. The results indicate a lack of normal cortical plasticity in Unverricht-Lundborg disease, which stresses the role of abnormal motor cortical functions or sensorimotor integration as possible pathophysiological contributors to the motor symptoms. The impaired cortical plasticity may be associated with the previously reported structural and physiological abnormalities of the primary motor cortex. PMID- 21661052 TI - Anhedonia in Parkinson's disease: a systematic review of the literature. AB - Anhedonia, defined as lowered ability to experience physical or social pleasure, is a key symptom of several psychiatric illnesses. In this systematic review, we aimed to evaluate the role of anhedonia in Parkinson's Disease and its relationships with other clinical characteristics, dopamine dysfunction, and antiparkinsonian therapy. The database was selected using PubMed Services. Relevant journals were hand-searched, and the bibliographies of all the important articles were scrutinized to find additional publications. Fifteen studies assessed the topic of anhedonia in Parkinson's disease from 1984 to 2009 and mainly described it as a core symptom of depression in patients with Parkinson's disease. Some studies investigated the relationship between anhedonia and neuropsychological symptoms and found correlations with frontal lobe functions. Reports on the relationship between anhedonia and illness severity or motor symptoms are rather inconclusive. No definitive conclusions can be drawn because few studies have been published on this topic. Nevertheless, some evidence suggests that in Parkinson's disease anhedonia is a secondary phenomenon linked to depression, apathy severity, and frontal lobe dysregulation and that it could respond to antiparkinsonian treatment. Future studies of larger samples of patients are strongly required to definitively clarify the relationship between anhedonia and other clinical features, such as depression, anxiety, apathy, cognition, and motor status. Furthermore, more reliable tools and validated diagnostic criteria are necessary to assess anhedonia in patients with Parkinson's disease. PMID- 21661051 TI - The relation between cognition and motor dysfunction in drug-naive newly diagnosed patients with Parkinson's disease. AB - Recent studies have reported cognitive decline to be common in the early phase of Parkinson's disease. Imaging data connect working memory and executive functioning to the dopamine system. It has also been suggested that bradykinesia is the clinical manifestation most closely related to the nigrostriatal lesion. Exploring the relationship between motor dysfunction and cognition can help us find shared or overlapping systems serving different functions. This relationship has been sparsely investigated in population-based studies of untreated Parkinson's disease. The aim of the present study was to investigate the association between motor signs and cognitive performance in the early stages of Parkinson's disease before the intake of dopaminergic medication. Patients were identified in a population-based study of incident cases with idiopathic parkinsonism. Patients with the postural instability and gait disturbances phenotype were compared with patients with the tremor-dominant phenotype on demographics and cognitive measures. Associations between cognitive and motor scores were investigated, with age, education, and sex controlled for. Bradykinesia was associated with working memory and mental flexibility, whereas axial signs were associated with episodic memory and visuospatial functioning. No significant differences in the neuropsychological variables were found between the postural instability and gait disturbances phenotype and the tremor phenotype. Our results indicate a shared system for slow movement and inflexible thinking that may be controlled by a dopaminergic network different from dopaminergic networks involved in tremor and/or rigidity. The association between axial signs and memory and visuospatial function may point to overlapping systems or pathologies related to these abilities. PMID- 21661053 TI - Assessment of involuntary choreatic movements in Huntington's disease--toward objective and quantitative measures. AB - Objective measures of motor impairment may improve the sensitivity and reliability of motor end points in clinical trials. In Huntington's disease, involuntary choreatic movements are one of the hallmarks of motor dysfunction. Chorea is commonly assessed by subitems of the Unified-Huntington's Disease Rating Scale. However, clinical rating scales are limited by inter- and intrarater variability, subjective error, and categorical design. We hypothesized that assessment of position and orientation changes interfering with a static upper extremity holding task may provide objective and quantitative measures of involuntary movements in patients with Huntington's disease. Subjects with symptomatic Huntington's disease (n = 19), premanifest gene carriers (n = 15; Unified-Huntington's Disease Rating Scale total motor score <= 3), and matched controls (n = 19) were asked to grasp and lift a device (250 and 500 g) equipped with an electromagnetic sensor. While subjects were instructed to hold the device as stable as possible, changes in position (x, y, z) and orientation (roll, pitch, yaw) were recorded. These were used to calculate a position index and an orientation index, both depicting the amount of choreatic movement interfering with task performance. Both indices were increased in patients with symptomatic Huntington's disease compared with controls and premanifest gene carriers for both weights, whereas only the position index with 500 g was increased in premanifest gene carriers compared with controls. Correlations were observed with the Disease Burden Score based on CAG-repeat length and age and with the Unified Huntington's Disease Rating Scale. We conclude that quantitative assessment of chorea is feasible in Huntington's disease. The method is safe, noninvasive, and easily applicable and can be used repeatedly in outpatient settings. A use in clinical trials should be further explored in larger cohorts and follow-up studies. PMID- 21661054 TI - Pathological gambling in Parkinson's disease--a review of the literature. AB - The prevalence of pathological gambling is 3.4% to 6% in treated Parkinson's disease, which is higher than the background population rate. In this review we discuss current evidence to indicate that dopamine agonists are much more likely to trigger this behavior than either L-dopa or selective monoamine oxidase B inhibitor monotherapy. New insights from recent behavioral and functional imaging studies and possible treatment approaches are also covered. A PubMed literature search using the terms "gambling" and "Parkinson's disease," "impulse control disorder," "impulsive compulsive behaviour," "dopamine agonist," of individual dopamine agonists, and of ongoing drug trials, using http://www.clinicaltrials.gov, was carried out for the period up to January 2011. PMID- 21661056 TI - Do nonmotor symptoms in Parkinson's disease differ from normal aging? AB - BACKGROUND: Nonmotor symptoms in Parkinson's disease are frequent and affect health-related quality of life of patients. The severity and domains of nonmotor symptoms involved in Parkinson's disease and normal aging have not been compared before. METHODS: We performed a prospective case-control study to assess the frequency and severity of nonmotor symptoms in patients with Parkinson's disease (n = 174) and age-matched normal controls (n = 128) using the Non-Motor Symptoms Scale. RESULTS: Nonmotor symptoms in Parkinson's disease were ubiquitous, more frequent, and more severe than in normal aging, particularly in women. Cardiovascular, mood/cognition, and perceptual problems/hallucinations domains were rarely involved in age-matched controls. Age had no effect and sex some influence on nonmotor symptoms in Parkinson's disease. In contrast, in controls, nonmotor symptoms increased with age, and sex had no effect. CONCLUSIONS: Nonmotor symptoms in Parkinson's disease differ from those in aging in frequency, severity, sex predilection, and domain involvement. PMID- 21661057 TI - Mechanistic insight of photo-induced aggregation of chicken egg white lysozyme: the interplay between hydrophobic interactions and formation of intermolecular disulfide bonds. AB - Recently, it was reported that ultraviolet (UV) illumination could trigger the unfolding of proteins by disrupting the buried disulfide bonds. However, the consequence of such unfolding has not been adequately evaluated. Here, we report that unfolded chicken egg white lysozyme (CEWL) triggered by UV illumination can form uniform globular aggregates as confirmed by dynamic light scattering, atomic force microscopy, and transmission electron microscopy. The assembling process of such aggregates was also monitored by several other methods, such as circular dichroism, fluorescence spectroscopy, mass spectrometry based on chymotrypsin digestion, ANS-binding assay, Ellman essay, and SDS-PAGE. Our finding is that due to the dissociation of the native disulfide bonds by UV illumination, CEWL undergoes drastic conformational changes resulting in the exposure of some hydrophobic residues and free thiols. Subsequently, these partially unfolded molecules self-assemble into small granules driven by intermolecular hydrophobic interaction. With longer UV illumination or longer incubation time, these granules can further self-assemble into larger globular aggregates. The combined effects from both the hydrophobic interaction and the formation of intermolecular disulfide bonds dominate this process. Additionally, similar aggregation behavior can also be found in other three typical disulfide-bonded proteins, that is, alpha-lactalbumin, RNase A, and bovine serum albumin. Thus, we propose that such aggregation behavior might be a general mechanism for some disulfide-bonded proteins under UV irradiation. PMID- 21661055 TI - MDS Task Force on mild cognitive impairment in Parkinson's disease: critical review of PD-MCI. AB - There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson's disease. The Movement Disorder Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson's disease-mild cognitive impairment and its association with dementia. A comprehensive PubMed literature review was conducted using systematic inclusion and exclusion criteria. A mean of 26.7% (range, 18.9%-38.2%) of nondemented patients with Parkinson's disease have mild cognitive impairment. The frequency of Parkinson's disease-mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, nonamnestic is more common than amnestic impairment. A high proportion of patients with Parkinson's disease-mild cognitive impairment progress to dementia in a relatively short period of time. The primary conclusions of the Task Force are that: (1) Parkinson's disease-mild cognitive impairment is common, (2) there is significant heterogeneity within Parkinson's disease-mild cognitive impairment in the number and types of cognitive domain impairments, (3) Parkinson's disease-mild cognitive impairment appears to place patients at risk of progressing to dementia, and (4) formal diagnostic criteria for Parkinson's disease-mild cognitive impairment are needed. PMID- 21661058 TI - pKa predictions with a coupled finite difference Poisson-Boltzmann and Debye Huckel method. AB - Modeling charge interactions is important for understanding many aspects of biological structure and function, and continuum methods such as Finite Difference Poisson-Boltzmann (FDPB) are commonly employed. Calculations of pH dependence have identified separate populations; surface groups that can be modeled with a simple Debye-Huckel (DH) model, and buried groups, with stronger resultant interactions that are dependent on detailed conformation. This observation led to the development of a combined FDPB and DH method for pK(a) prediction (termed FD/DH). This study reports application of this method to ionizable groups, including engineered buried charges, in staphylococcal nuclease. The data had been made available to interested research groups before publication of mutant structures and/or pK(a) values. Overall, FD/DH calculations perform as intended with low DeltapK(a) values for surface groups (RMSD between predicted and experimental pK(a) values of 0.74), and much larger DeltapK(a) values for the engineered internal groups, with RMSD = 1.64, where mutant structures were known and RMSD = 1.80, where they were modeled. The weaker resultant interactions of the surface groups are determined mostly by charge charge interactions. For the buried groups, R(2) for correlation between predicted and measured DeltapK(a) values is 0.74, despite the high RMSDs. Charge charge interactions are much less important, with the R(2) value for buried group DeltapK(a) values increasing to 0.80 when the term describing charge desolvation alone is used. Engineered charge burial delivers a relatively uniform, nonspecific effect, in terms of pK(a) . How the protein environment adapts in atomic detail to deliver this resultant effect is still an open question. PMID- 21661059 TI - Application of the Gaussian dielectric boundary in Zap to the prediction of protein pKa values. AB - The results of two rounds of blind pK(a) predictions for ionizable residues in staphylococcal nuclease using OpenEye's legacy protein pK(a) prediction program based on the Zap Poisson-Boltzmann solver were submitted to the 2009 prediction challenge organized by the Protein pK(a) Cooperative and first round predictions were discussed at the corresponding June 2009 Telluride conference. To better understand these results, 21 additional sets of predictions were performed with the same program, varying the internal dielectric, reference pK(a), partial charge set, and dielectric boundary. The internal dielectric (epsilon(p)) and dielectric boundary were the two most important factors contributing to the quality of the predictions. Although the lowest overall errors were observed with a molecular dielectric boundary at epsilon(p) = 8, predictions using a smooth Gaussian dielectric boundary performed almost as well at lower epsilon(p) values because the Gaussian boundary implicitly accounts for a significant level of solvent penetration. Improved pK(a) predictions with the Gaussian boundary methodology will require better prediction and modeling of structural changes due to changes in ionization state, perhaps without resorting to the more exhaustive sampling of conformational states used by other recent continuum methods. PMID- 21661060 TI - Structure of the catalytic domain of glucuronoyl esterase Cip2 from Hypocrea jecorina. AB - The structure of the catalytic domain of glucuronoyl esterase Cip2 from the fungus H. jecorina was determined at a resolution of 1.9 A. This is the first structure of the newly established carbohydrate esterase family 15. The structure has revealed the residues Ser278-His411-Glu301 present in a triad arrangement as the active site. Ser278 is present in the novel consensus sequence GCSRXG reported earlier in the members of CE-15 family. The active site is exposed on the surface of the protein which has implications for the ability of the enzyme to hydrolyze ester bonds of large substrates. Efforts are underway to obtain crystals of Cip2_GE complexed with inhibitor and synthetic substrates. The activity of the glucuronoyl esterase could play a significant role in plant biomass degradation as its expected role is to separate the lignin from hemicelluloses by hydrolysis of the ester bond between 4-O-methyl-D-glucuronic acid moieties of glucuronoxylans and aromatic alcohols of lignin. PMID- 21661061 TI - An NMR study of the N-terminal domain of wild-type hERG and a T65P trafficking deficient hERG mutant. AB - The human Ether-a-go-go Related Gene (hERG) potassium channel plays an important role in the heart by controlling the rapid delayed rectifier current. The N terminal 135 residues (NTD) contain a Per-Arnt-Sim (PAS) domain and an N-terminal amphipathic helix. NMR relaxation analysis and H/D exchange experiments on the NTD demonstrated that the amphipathic helix is rigid and solvent accessible. An NTD containing a T65P mutation, which causes a hERG channel trafficking deficiency, was purified from E.coli. The mutant protein did not aggregate in gel filtration analysis and the amide cross peaks of its residues disappeared in an HSQC spectrum indicating the possibility of structural changes. A carbon chemical shift comparison of the residues with cross peaks in the HSQC spectrum showed no clear difference between the purified wild-type protein and the purified mutant. There were multiple conformations observed for the T65P mutant protein at high temperatures from HSQC experiments and a thermal stability assay showed that the T65P mutation reduced the thermal stability of NTD. This instability may affect protein folding or structural dynamics of other regions. PMID- 21661062 TI - Highly flexible, printed alkaline batteries based on mesh-embedded electrodes. PMID- 21661063 TI - Clay gels for the delivery of regenerative microenvironments. PMID- 21661065 TI - Photoinduced memory with hybrid integration of an organic fullerene derivative and an inorganic nanogap-embedded field-effect transistor for low-voltage operation. PMID- 21661064 TI - Solution-crystallized organic field-effect transistors with charge-acceptor layers: high-mobility and low-threshold-voltage operation in air. PMID- 21661066 TI - Nanoscale semiconductor "X" on substrate "Y"--processes, devices, and applications. AB - Recent advancements in the integration of nanoscale, single-crystalline semiconductor 'X' on substrate 'Y' (XoY) for use in transistor and sensor applications are presented. XoY is a generic materials framework for enabling the fabrication of various novel devices, without the constraints of the original growth substrates. Two specific XoY process schemes, along with their associated materials, device and applications are presented. In one example, the layer transfer of ultrathin III-V semiconductors with thicknesses of just a few nanometers on Si substrates is explored for use as energy-efficient electronics, with the fabricated devices exhibiting excellent electrical properties. In the second example, contact printing of nanowire-arrays on thin, bendable substrates for use as artificial electronic-skin is presented. Here, the devices are capable of conformably covering any surface, and providing a real-time, two-dimensional mapping of external stimuli for the realization of smart functional surfaces. This work is an example of the emerging field of "translational nanotechnology" as it bridges basic science of nanomaterials with practical applications. PMID- 21661067 TI - Co-evaporant induced crystalline donor: acceptor blends in organic solar cells. PMID- 21661068 TI - Hybrid nanoalloy: nanofibers fabricated by self-assembling dendrimers mediate in situ CdSe quantum dots and their metallization with discrete gold nanoparticles. PMID- 21661070 TI - A soluble high molecular weight copolymer of benzo[1,2-b:4,5-b']dithiophene and benzoxadiazole for efficient organic photovoltaics. AB - The synthesis and characterization of a soluble high molecular weight copolymer based on 4,8-bis(1-pentylhexyloxy)benzo[1,2-b:4,5-b']dithiophene and 2,1,3 benzoxadiazole is presented. High efficiency organic photovoltaic (OPV) devices comprised of this polymer and phenyl-C(71) -butyric acid methyl ester (PC(71) BM) were fabricated by additive processing with 1-chloronapthalene (CN). When the active layer is cast from pristine chlorobenzene (CB), power conversion efficiencies (PCEs) average 1.41%. Our best condition-using 2% chloronapthalene as a solvent additive in CB-results in an average PCE of 5.65%, with a champion efficiency of 6.05%. PMID- 21661069 TI - Cellulose hydrolysis by a new porous coordination polymer decorated with sulfonic acid functional groups. PMID- 21661071 TI - Spiropyran-based polymeric vesicles: preparation and photochromic properties. AB - A direct access to photochromic polymeric vesicles was demonstrated via polymerization-induced self-assembly and reorganization (PISR). The resulting vesicles displayed interesting photochromic behaviors different from that of their free polymer chains in DMF, and the vesicles exhibited stronger fluorescence and excellent photostability due to confinement of conformational flexibility of the polymer chains in aggregates. PMID- 21661072 TI - Cellulose-based sustainable polymers: state of the art and future trends. AB - Nowadays, nearly all polymeric materials are produced from crude oil-derived monomers. With the steadily increasing demand for oil-based products and their decreasing availability in the near future, one of the main challenges of mankind is the replacement of crude oil as raw material by renewable resources such as biomass. So far, only a few polymers are available derived directly from cellulose as a main component of biomass by regeneration. On the other hand, a significant potential lies in the production of polymers from cellulose-derived monomers. A huge variety of different monomers is already available by convenient catalytic processes. This feature article focuses on the current status of mono- and resulting polymers derived either directly from cellulose processing and regeneration or by catalytic conversion to a number of monomers for the production of novel polymers and co-polymers. PMID- 21661073 TI - Thermosensitivity of bile acid-based oligo(ethylene glycol) stars in aqueous solutions. AB - Amphiphilic star-shaped oligo(ethylene glycol)s with a hydrophobic bile acid core and varying number of hydrophilic arms have been made. Their thermal behavior in aqueous solutions depends on the number rather than the length of the arms. The two-armed lithocholate derivative showed the strongest tendency for association and exhibited the lowest cloud point (79 degrees C) of the oligomers made, as well as another phase separation at a lower temperature (31 degrees C). The "double thermosensitivity" arising both from the salt-dependent LCST of the oligo(ethylene glycol) segments and the temperature-responsive self-assembly of amphiphilic bile acid derivative provides an interesting path in the design of bile acid-based smart materials. PMID- 21661074 TI - Simultaneous detection and removal of mercury ions in aqueous solution with fluorescent conjugated polymer-based sensor ensemble. AB - A water-soluble, sulfur-containing fluorescent conjugated polymer exhibits a visible fluorescence color change for detection of mercury in the presence of thymine. A new concept provides the design of a sensor ensemble using a simple combination method. This strategy avoids the need for complicated design and synthesis of a recognition group, eliminating the tedious synthetic efforts for the preparation of a sensor material. PMID- 21661075 TI - Self-assembled single-crystal polyaniline microplates and their anisotropic electrical transport property. AB - Self-assembly of two-dimensional (2D) structures from functional molecules is of great scientific importance. Herein, using a typical linear conducting polymer, polyaniline as building blocks, 2D single crystalline microplates are successively produced. The structure of 2D microplates is clearly defined by selected area electron diffraction, X-ray diffraction, and Raman spectroscopy. Owing to the anisotropic arrangement of linear conjugated PANI molecules, the microplate shows a typical anisotropic electrical transport property. PMID- 21661076 TI - Reserve capacity of public and private hospitals in response to demand uncertainty. AB - A feature of hospitals is that they face uncertain demand for the services they offer. To cover fluctuations in demand, they need to maintain reserve service capacity in the form of beds, equipment, personnel, etc. to minimize the probability of excess queuing or turning away patients, creating a trade-off between reserve service capacity and economic costs. Using a simple theoretical framework, we show how the reserve capacity established depends on institutional characteristics that can affect the objective of the hospital. In particular, we show that private and public hospitals may provide different levels of reserve capacity. In an empirical application using a panel data set of Spanish hospitals over the period 1996-2006, we model reserve service capacity using a distance frontier approach. Our results show that private hospitals generally react to a lesser extent to demand uncertainty than public hospitals. PMID- 21661077 TI - Chemical synthesis of the third WW domain of TCERG 1 by native chemical ligation. AB - The human transcription elongation regulator 1 (TCERG1), with its modular architecture of 3 WW and 6 FF domains, inhibits RNA polymerase II elongation through these WW and FF domains, and interacts with pre-mRNA splicing factors such as SF1, U2 snRNP and U2AF. WW domains are known as the smallest naturally occurring, monomeric, triple stranded, anti-parallel beta-sheet structures, generally spanning only about 40 amino acids. The first and second WW domains of TCERG1 have been synthesized and successfully applied for screening cellular targets. In contrast, until now syntheses of the third WW domain yielded oligopeptides with an undefined fold, proving useless for screening cellular targets. This implied that sequence elongation to include the alpha-helical structure is crucial for proper folding. We describe here the chemical synthesis of such a 53 residue long TCERG1 WW-3 domain sequence that exhibits the typical WW domain fold, and could be useful for discovering cellular targets. PMID- 21661078 TI - Structural scaffold for eIF4E binding selectivity of 4E-BP isoforms: crystal structure of eIF4E binding region of 4E-BP2 and its comparison with that of 4E BP1. AB - To clarify the higher eukaryotic initiation factor 4E (eIF4E) binding selectivity of 4E-binding protein 2 (4E-BP2) than of 4E-BP1, as determined by Trp fluorescence analysis, the crystal structure of the eIF4E binding region of 4E BP2 in complex with m(7) GTP-bound human eIF4E has been determined by X-ray diffraction analysis and compared with that of 4E-BP1. The crystal structure revealed that the Pro47-Ser65 moiety of 4E-BP2 adopts a L-shaped conformation involving extended and alpha-helical structures and extends over the N-terminal loop and two different helix regions of eIF4E through hydrogen bonds, and electrostatic and hydrophobic interactions; these features were similarly observed for 4E-BP1. Although the pattern of the overall interaction of 4E-BP2 with eIF4E was similar to that of 4E-BP1, a notable difference was observed for the 60-63 sequence in relation to the conformation and binding selectivity of the 4E-BP isoform, i.e. Met-Glu-Cys-Arg for 4E-BP1 and Leu-Asp-Arg-Arg for 4E-BP2. In this paper, we report that the structural scaffold of the eIF4E binding preference for 4E-BP2 over 4E-BP1 is based on the stacking of the Arg63 planar side chain on the Trp73 indole ring of eIF4E and the construction of a compact hydrophobic space around the Trp73 indole ring by the Leu59-Leu60 sequence of 4E BP2. PMID- 21661079 TI - Functional association of the N-terminal residues with the central region in glucagon-related peptides. AB - GLP-1 is an incretin peptide involved in the regulation of glucose metabolism and the glucose-dependent stimulation of insulin secretion. Ex-4 is a paralog of GLP 1 that has comparable GLP-1R potency but extended physiological action. GLP-1 and Ex-4 are helical peptides that share ~50% sequence homology but differ at several residues, notably the second amino acid which controls susceptibility to DPP-IV cleavage. This single amino acid difference yields divergent receptor potency when studied in the context of the two hormone sequences. Ex-4 uniquely tolerates Gly2 through select amino acid differences in the middle region of the peptide that are absent in GLP-1. We report that substitution of Ex-4 amino acids Glu16, Leu21, and Glu24 to the GLP-1 sequence enabled Gly2 tolerance. The coordination of the N-terminus with these central residues shows an interaction of substantial importance not only to DPP-IV stability but also to receptor activation. Extension of this observation to glucagon-based co-agonist peptides showed different structural requirements for effective communication between the N terminus and the mid-section of these peptides in achieving high potency agonism at the GLP-1 and GCGRs. PMID- 21661080 TI - Highly selective decarbonylation of 5-(hydroxymethyl)furfural in the presence of compressed carbon dioxide. PMID- 21661081 TI - Is water necessary for contact electrification? PMID- 21661082 TI - Hydrogen bonding regulates the monomeric nonradiative decay of adenine in DNA strands. PMID- 21661083 TI - Catalytic hydrocarboxylation of alkenes and alkynes with CO2. PMID- 21661084 TI - Single gold nanoparticles as real-time optical probes for the detection of NADH dependent intracellular metabolic enzymatic pathways. PMID- 21661085 TI - Catalytic enantioselective addition of sodium bisulfite to chalcones. PMID- 21661086 TI - Fabrication of arbitrary three-dimensional polymer structures by rational control of the spacing between nanobrushes. PMID- 21661088 TI - Osteocalcin biomimic recognizes bone hydroxyapatite. PMID- 21661089 TI - Directed evolution: a powerful approach to optimising and understanding enzymes. PMID- 21661087 TI - Strain-promoted alkyne-azide cycloadditions (SPAAC) reveal new features of glycoconjugate biosynthesis. AB - We have shown that 4-dibenzocyclooctynol (DIBO), which can easily be obtained by a streamlined synthesis approach, reacts exceptionally fast in the absence of a Cu(I) catalyst with azido-containing compounds to give stable triazoles. Chemical modifications of DIBO, such as oxidation of the alcohol to a ketone, increased the rate of strain promoted azide-alkyne cycloadditions (SPAAC). Installment of a ketone or oxime in the cyclooctyne ring resulted in fluorescent active compounds whereas this property was absent in the corresponding cycloaddition adducts; this provides the first example of a metal-free alkyne-azide fluoro-switch click reaction. The alcohol or ketone functions of the cyclooctynes offer a chemical handle to install a variety of different tags, and thereby facilitate biological studies. It was found that DIBO modified with biotin combined with metabolic labeling with an azido-containing monosaccharide can determine relative quantities of sialic acid of living cells that have defects in glycosylation (Lec CHO cells). A combined use of metabolic labeling/SPAAC and lectin staining of cells that have defects in the conserved oligomeric Golgi (COG) complex revealed that such defects have a greater impact on O-glycan sialylation than galactosylation, whereas sialylation and galactosylation of N-glycans was similarly impacted. These results highlight the fact that the fidelity of Golgi trafficking is a critical parameter for the types of oligosaccharides being biosynthesized by a cell. Furthermore, by modulating the quantity of biosynthesized sugar nucleotide, cells might have a means to selectively alter specific glycan structures of glycoproteins. PMID- 21661090 TI - The excited-state decay of 1-methyl-2(1H)-pyrimidinone is an activated process. AB - The photophysics of 1-methyl-2(1H)-pyrimidinone (1MP) dissolved in water is investigated by steady-state and time-resolved fluorescence, UV/Vis absorption, and IR spectroscopy. In the experiments, excitation light is tuned to the lowest energy absorption band of 1MP peaking at 302 nm. At room temperature (291 K) its fluorescence lifetime amounts to 450 ps. With increasing temperature this lifetime decreases and equals 160 ps at 338 K. Internal conversion (IC) repopulating the ground state and intersystem crossing (ISC) to a triplet state are the dominant decay channels of the excited singlet state. At room temperature both channels contribute equally to the decay, that is, the quantum yields of IC and ISC are both approximately 0.5. The temperature dependence of UV/Vis transient absorption signals shows that the activation energy of the IC process (2140 cm(-1)) is higher than that of the ISC process (640 cm(-1)). PMID- 21661091 TI - Luminescence of polyethylene glycol coated CdSeTe/ZnS and InP/ZnS nanoparticles in the presence of copper cations. AB - The use of click chemistry for quantum dot (QD) functionalization could be very promising for the development of bioconjugates dedicated to in vivo applications. Alkyne-azide ligation usually requires copper(I) catalysis. The luminescence response of CdSeTe/ZnS nanoparticles coated with polyethylene glycol (PEG) is studied in the presence of copper cations, and compared to that of InP/ZnS QDs coated with mercaptoundecanoic acid (MUA). The quenching mechanisms appear different. Luminescence quenching occurs without any wavelength shift in the absorption and emission spectra for the CdSeTe/ZnS/PEG nanocrystals. In this case, the presence of copper in the ZnS shell is evidenced by energy-filtered transmission electron microscopy (EF-TEM). By contrast, in the case of InP/ZnS/MUA nanocrystals, a redshift of the excitation and emission spectra, accompanied by an increase in absorbance and a decrease in photoluminescence, is observed. For CdSeTe/ZnS/PEG nanocrystals, PL quenching is enhanced for QDs with 1) smaller inorganic-core diameter, 2) thinner PEG shell, and 3) hydroxyl terminal groups. Whereas copper-induced PL quenching can be interesting for the design of sensitive cation sensors, copper-free click reactions should be used for the efficient functionalization of nanocrystals dedicated to bioapplications, in order to achieve highly luminescent QD bioconjugates. PMID- 21661092 TI - Self-efficacy as an outcome measure and its association with physical disease related variables in persons with rheumatoid arthritis: a literature review. AB - BACKGROUND: Studies have demonstrated a positive impact of patient education on self-efficacy in persons with rheumatoid arthritis (RA). However, the relationship between self-efficacy, physical disease-related variables and educational interventions has not yet been reviewed. AIM: The aims of this study, in relation to persons with RA, were: 1) to provide an overview of the existing research into the association between self-efficacy and physical disease-related variables and, with this knowledge, 2) to provide an overview of the existing research on the effect of different types of educational interventions on self efficacy. METHOD: A systematic literature search was performed using eight databases, based on the terms 'rheumatoid arthritis' AND 'self-efficacy'. In total, 74 studies reporting associations between self-efficacy and physical disease-related variables and using self-efficacy as an outcome measure in educational interventions were included. RESULTS: The scores obtained by the most commonly used questionnaire, the Arthritis Self-Efficacy Scale (ASES), was highly associated with physical disability, pain, fatigue and disease duration. If educational activities had a positive impact on self-efficacy, disease-related variables usually improved as well. Evidence is scarce as to whether disease related variables affect patients' self-efficacy or vice versa and whether individual consultations can affect patients' self-efficacy. CONCLUSION: The scores attained by the ASES is highly associated with physical disease-related variables. This relationship requires further research using a specific study design to restrict bias when evaluating the impact of interventions on self efficacy in persons with RA. Research is needed on whether individual consultations can affect patients' self-efficacy. Disease-related variables do not affect the Rheumatoid Arthritis Self-Efficacy (RASE) questionnaire but this needs further exploration. PMID- 21661093 TI - Mesenchymal stem cell seeding promotes reendothelialization of the endovascular stent. AB - This study is designed to make a novel cell seeding stent and to evaluate reendothelialization and anti-restenosis after the stent implantation. In comparison with cell seeding stents utilized in previous studies, Mesenchymal stem cells (MSCs) have advantages on promoting of issue repair. Thus it was employed to improve the reendothelialization effects of endovascular stent in present work. MSCs were isolated by density gradient centrifugation and determined as CD29(+) CD44(+) CD34(-) cells by immunofluorescence and immunocytochemistry; gluten and polylysine coated stents were prepared by ultrasonic atomization spray, and MSCs seeded stents were made through rotation culture according to the optimized conditions that were determined in previous studies. The results from animal experiments, in which male New Zealand white rabbits were used, show that the reendothelialization of MSCs coated stents can be completed within one month; in comparison with 316L stainless steel stents (316L SS stents) and gluten and polylysine coated stents, the intimal hyperplasia and in-stent restenosis are significantly inhibited by MSCs coated stents. Endovascular stent seeded with MSCs promotes reendothelialization and inhibits the intimal hyperplasia and in-stent restenosis compared with the 316L SS stents and the gluten and polylysine coated stents. PMID- 21661094 TI - Epigallocatechin-3-gallate induced modulation of cell deadhesion and migration on thermosensitive poly(N-isopropylacrylamide). AB - Epigallocatechin-3-gallate (EGCG), which is the main polyphenolic constituent of green tea, has emerged as a promising candidate for potential applications in selected anticancer therapeutics. Generally, tumor metastasis is known to be correlated with the alterations in cell adhesion and migration of normal cells. Nevertheless, the effect of EGCG on the biophysical responses of tumor cell adhering on extracellular matrix remains obscure. In this study, a thermosenstive poly(N-isopropylacrylamide) (PIPAAm) system was developed to elucidate the potential anti-tumor effect of EGCG on the deadhesion and migration of HepG2 cells. First, both XPS and ELISA validated the coating of laminin (LA) on PIPAAm. Second, a change of nanotopology of LA layer on PIPAAm across the lower solution critical temperature (LCST) was detected with AFM. HepG2 cells seeded on LA coated PIPAAm surface was shown to go through deadhesion by lowering the temperature below the LCST. Interestingly, EGCG was shown to decelerate the thermally triggered deadhesion of HepG2 cell on LA coated PIPAAm. Moreover, the inhibition of cell deadhesion in EGCG treated cells was shown to be driven by actin remodeling. Interestingly, the modulation of cell deadhesion on LA coated PIPAAm by EGCG leads to the reduction of cell motility as shown by real-time cell migration assay. Overall, the use of PIPAAm system demonstrated the promise of EGCG as anticancer therapy through the suppression of cell deadhesion and migration. PMID- 21661095 TI - A novel dermal substitute based on biofunctionalized electrospun PCL nanofibrous matrix. AB - In this study, nanofibrous matrices of polycaprolactone (PCL) and PCL/collagen with immobilized epidermal growth factor (EGF) were successfully fabricated by electrospinning for the purpose of damaged skin regeneration. Nanofiber diameters were found to be 284 +/- 48 nm for PCL and 330 +/- 104 nm for PCL/collagen matrices. The porosities were calculated as 85% for PCL and 90% for PCL/collagen matrices. The covalent immobilization of EGF onto the nanofibrous matrices was verified by the increase of surface atomic nitrogen ratio from 1.0 to 2.4% for PCL and from 3.7 to 4.7% for PCL/collagen. Moreover, EGF immobilization efficiencies of PCL and PCL/collagen matrices were determined as 98.5 and 99.2%, respectively. Human dermal keratinocytes (HS2) were cultivated on both neat and EGF immobilized PCL and PCL/collagen matrices to investigate the effects of matrix chemical composition and presence of EGF on cell proliferation and differentiation. EGF immobilized PCL/collagen matrices exerted early cell spreading and rapid proliferation. Statistically high expression levels of loricrin in HS2 cells cultivated on EGF immobilized PCL/collagen matrices were (p < 0.001) regarding superior differentiation ability of these cells compared to HS2 cells cultured on neat PCL and PCL/collagen matrices. In conclusion, this novel EGF immobilized PCL/collagen nanofibrous matrix could potentially be considered as an alternative dermal substitutes and wound healing material for skin tissue engineering applications. PMID- 21661096 TI - Four nephrology myths debunked. AB - There are many controversial topics relating to renal disease in hospitalized patients. The aim of this review is to shed light on some important and often debated issues. Hypothyroidism, unlike myxedema, is not a cause of hyponatremia (although it can be sometimes seen in conjunction with the latter) and additional investigations should be done to determine its etiology. Sodium bicarbonate is effective for treatment of hyperkalemia primarily by enhancing renal potassium elimination rather than by translocating potassium into cells. Acetaminophen can be a cause of metabolic acidosis by causing 5-oxoprolinuria. Furosemide (and sulfa containing diuretics) can safely be used in patients with an allergy to sulfa-containing antibiotics (SCA). PMID- 21661097 TI - Understanding and meeting the hospitalist's challenge: caring for adults with sickle cell disease. PMID- 21661098 TI - Prediction of onset and course of high hospital utilization in sickle cell disease. AB - BACKGROUND: Although sickle cell disease (SCD) patients typically manage their pain at home, a small subgroup is frequently hospitalized and accounts for the majority of costs. OBJECTIVES: 1) To identify prospective diagnostic and demographic markers of new periods of high utilization; 2) To identify demographic and diagnostic markers of a persistent rather than moderating course of high utilization; 3) To replicate the finding that high utilization tends to moderate. DESIGN: The State Inpatient Databases for California, 2004-2007, were used. Patients with new onset periods of high utilization were compared with non high utilizers, and new high utilizers who moderated were compared with those who had a persistent course. SETTING: All hospitals in the state of California. PATIENTS: Patients age 13 years or older in 2004 with a recorded diagnosis of sickle cell disease and at least one hospitalization for crisis during the study period. MEASURES: METHODS: Groups from hospitals throughout California were compared on demographics and discharge diagnoses of SCD complications and comorbidities. Patients age 13 years or older in 2004 with a recorded diagnosis of sickle cell disease and at least 1 hospitalization for crisis during the study period were included. RESULTS: New periods of high utilization were associated with more prior hospitalizations and previous diagnoses of aseptic necrosis and renal disease. High utilization typically moderated. A persistent course was associated with slightly more hospitalizations during the initial year of high utilization, and, subsequently, by more mentions of septicemia and mood disorders. CONCLUSIONS: Overall, high utilization was difficult to predict, as was its course. The diagnoses most associated with high utilization indicated more severe sickle cell disease. Septicemia deserves further investigation as a preventable cause for high utilization, as do mood disorders. PMID- 21661099 TI - Factors predicting prolonged hospital stay for infants with bronchiolitis. AB - BACKGROUND: Prior prediction models for length of stay (LOS) in bronchiolitis have focused more on birth- and disease-related risk factors than on early hospital course factors, particularly common clinical markers including respiratory status and caloric intake. OBJECTIVES: 1) Study the associations of various clinical markers and LOS; and 2) develop a LOS prediction model. DESIGN: Retrospective cohort study. SETTING: Children's Hospital of Wisconsin. PATIENTS: Inclusion criteria were: age < 365 days old; admission between November 1, 2004 and April 15, 2005; final diagnosis of bronchiolitis; placement on the bronchiolitis treatment protocol; and lack of concurrent condition impacting LOS. RESULTS: During the study period, 272/347 infants admitted with bronchiolitis met inclusion criteria. On hospital day 2, infants in the prolonged LOS group (>= 108 hours) had a significantly greater number of hours on supplemental oxygen, maximum supplemental oxygen use, minimum supplemental oxygen use, maximum respiratory rate, mean respiratory score, and number of times suctioned. They had significantly lower minimum oxygen saturation and caloric intake. Recursive partitioning demonstrated five variables (hours of supplemental oxygen, maximum respiratory rate, minimum supplemental oxygen use, gestation, and caloric intake) to predict short or prolonged LOS with an area under the receiver-operator characteristic curve of 0.89/0.72 in the learning/test trees; sensitivity, 0.85; and specificity, 0.82. CONCLUSIONS: There are important differences between infants with bronchiolitis having short and prolonged hospital stays, including several clinical markers identifiable on hospital day 2. This model may be a useful prediction tool for targeting early interventions for high-risk infants. PMID- 21661100 TI - Treatment of inpatient hyperglycemia beginning in the emergency department: a randomized trial using insulins aspart and detemir compared with usual care. AB - OBJECTIVE: We examined the impact of an aspart insulin protocol for treatment of hyperglycemia in the emergency department (ED) coupled with rapid initiation of a detemir-aspart insulin protocol for patients admitted to the hospital. RESEARCH DESIGN AND METHODS: ED patients with type 2 diabetes mellitus and a blood glucose (BG) >= 200 mg/dL were randomized to intervention (INT) or usual care (UC). INT patients (n = 87) received aspart every 2 hours when BG > 200 mg/dL, and if admitted, began daily detemir in the ED. UC patients (n = 89) were treated per hospital physicians. RESULTS: The initial ED BG was 304 +/- 76 mg/dL. The final ED BG differed: 217 +/- 71 mg/dL for INT patients versus 257 +/- 89 mg/dL for UC patients (P < .01). No INT patients and 3 UC patients had a BG < 50 mg/dL (P = .5). ED length of stay (LOS) was similar: 5.4 +/- 1.8 hours for INT patients versus 4.9 +/- 1.9 hours for UC patients (P = .06). Sixty-nine percent from each group were admitted. Admission BG was 184 +/- 74 mg/dL for INT patients versus 224 +/- 93 mg/dL for UC patients (P < .01). Patient-day weighted mean glucose was 163 +/- 39 mg/dL for INT patients versus 202 +/- 39 mg/dL for UC patients (P < .01). One INT patient and 6 UC patients had a BG < 50 mg/dL (P = .11). Hospital LOS was similar: 2.7 +/- 2.0 versus 3.1 +/- 1.9 days, respectively (P = .58). CONCLUSIONS: An aspart insulin protocol safely lowers BG levels in the ED without prolonging LOS. During hospitalization, a detemir-aspart protocol achieves significantly better glycemic control compared with guideline-driven use of NPH aspart or glargine/detemir-aspart (usual care) without increasing hypoglycemia. Standardization of insulin protocols in the ED and hospital settings leads to improvement in overall glycemic control with greater safety and efficacy than usual care. PMID- 21661101 TI - Electrocardiogram score predicts severity of pulmonary embolism in hemodynamically stable patients. AB - BACKGROUND: Risk stratification of patients with pulmonary embolism (PE) is essential to guide therapy. The presence of right ventricle dysfunction (RVD) and the anatomic extent of PE have been suggested to predict clinical course. The aim of this study was to assess the ability of an electrocardiogram (ECG) scoring system to predict RVD or the clot load score in normotensive patients with PE. METHODS: Consecutive patients presenting to the emergency room with PE and hemodynamic stability were prospectively included. ECG, echocardiography and computed tomography pulmonary angiography (CTPA) were performed on all patients. RESULTS: A total of 103 patients were studied. ECG score correlated significantly with the clot load score (r = 0.41, 95% confidence interval [CI]: 0.22-0.57, P < 0.001), systolic pulmonary artery pressure (r= 0.31, 95% CI: 0.09-0.49, P = 0.006), pulmonary artery diameter (r = 0.28, 95% CI: 0.07-0.47, P = 0.011) and right ventricle to left ventricle ratio, both measured with echocardiography (r = 0.42, 95% CI: 0.22-0.57, P < 0.001) and with CTPA (r= 0.36, 95% CI: 0.13-0.56, P = 0.004). Area under the receiver operating characteristic curve for detecting RVD was 0.82 (95% CI: 0.72-0.89). Interobserver agreement regarding ECG score was substantial (kappa = 0.80). CONCLUSIONS: ECG score correlates with the severity of PE in hemodynamically stable patients. It is potentially useful for risk stratification strategies in this setting. PMID- 21661103 TI - Incidence and predictors of microbiology results returning postdischarge and requiring follow-up. AB - BACKGROUND: Failure to follow up microbiology results pending at discharge can delay appropriate treatment, increasing the risk of patient harm and litigation. Limited data describe the frequency of postdischarge microbiology results requiring a treatment change. OBJECTIVE: To determine the incidence and predictors of postdischarge microbiology results requiring follow-up. DESIGN: Cross-sectional. SETTING: Large academic hospital during 2007. MEASUREMENTS: We evaluated blood, urine, sputum, and cerebrospinal fluid (CSF) cultures ordered for hospitalized patients. We identified cultures that returned postdischarge and determined which were clinically important and not treated by an antibiotic to which they were susceptible. We reviewed a random subset to assess the potential need for antibiotic change. Using logistic regression, we identified significant predictors of results requiring follow-up. RESULTS: Of 77,349 inpatient culture results, 8668 (11%) returned postdischarge. Of these, 385 (4%) were clinically important and untreated at discharge. Among 94 manually reviewed cases, 53% potentially required a change in therapy. Urine cultures were more likely to potentially require therapy change than non-urine cultures (OR 2.8, 95% CI 1.1 7.2; P = 0.03). Also, 76% of 25 results from surgical services potentially required a therapy change, compared with 59% of 29 results from general medicine, 38% of 16 results from oncology, and 33% of 24 results from medical subspecialties. Overall, 2.4% of postdischarge cultures potentially necessitated an antibiotic change. CONCLUSIONS: Many microbiology results return postdischarge and some necessitate a change in treatment. These results arise from many specialties, suggesting the need for a hospital-wide system to ensure effective communication of these results. PMID- 21661104 TI - Frequently asked questions by hospitalists managing pain in adults with sickle cell disease. AB - Pain is the predominant medical presentation to hospitalists for patients with sickle cell disease (SCD). Dramatic treatment gains of SCD in childhood have resulted in more adults now requiring hospitalization than children. This has created new challenges to improve the quality of hospital care for SCD. The evidence base for pain management in SCD is lacking. We therefore offer some evidence and our informed opinion to answer frequently asked questions (FAQs) about pain management by hospitalists caring for adults with SCD. The most common questions center around defining a crisis; selecting and managing opioids; distinguishing between opioid tolerance, physical dependence, and addiction or misuse; determining appropriateness of discharge; and avoiding lengthy or recurrent hospitalizations. PMID- 21661105 TI - A lifetime in the making. PMID- 21661106 TI - Single-cell-level microplasma cancer therapy. AB - A flexible microplasma endoscope based on a 15 MUm hollow-core glass optical fiber is fabricated, and tumor cell apoptotic analysis supports its potential use in targeted cancer therapies. The optical-fiber microplasma jet reveals antitumor activity at a certain plasma dose in animal studies. PMID- 21661107 TI - Hybridization-induced "off-on" 19F-NMR signal probe release from DNA functionalized gold nanoparticles. PMID- 21661110 TI - Reversed-phase monoliths prepared by UV polymerization of divinylbenzene. AB - Many different techniques have been developed to prepare monolithic materials specifically for chromatographic techniques. The two most popular polymerization techniques being thermal or via ultra violet (UV) light. Whereas thermal polymerization is easily employed for a whole variety of monomer and porogen systems, UV polymerization has been limited to methacrylate-based systems, and styrenic systems have been avoided due to their strong absorbance at low wavelengths. By careful consideration of wavelength, initiator and other system components, it was proven that reversed-phase columns for the separation of proteins and peptides can be prepared using divinylbenzene through UV initiation of 2-methyl-4'-(methylthio)-2-morpholinopropiophenone at a wavelength of 350 nm. PMID- 21661109 TI - Capillary electrochromatographic testing of monolithic silica columns synthesized according to an experimental design approach. AB - Monolithic silica capillary columns synthesized following a three-level design were evaluated for the electrochromatographic separation of acidic and neutral compounds. The influences of four factors in the sol-gel synthesis, i.e. the concentrations of tetramethylorthosilicate (TMOS) and PEG in the starting mixture, the gelation temperature and the silanization modifying time, on the electrochromatographic performance of the resulting C18-silica capillary monoliths were studied. The considered responses were retention factor, resolution, symmetry factor, column efficiency, electrokinetic porosity and the equivalent length of the monolith. The four factors were varied to change the pore structure and the surface coverage with octadecyl moieties, resulting in nine stationary phases. The retentive properties of the columns were initially characterized with alkylbenzenes. Next, the separation for acetylsalicylic acid (ASA) and its related compounds was optimized and used to evaluate the performance of the nine stationary phases considering six responses. A compromise between the different responses was found around higher concentrations of tetramethylorthosilicate and PEG with a lower gelation temperature and a modifying time of 2 h. Column efficiencies up to 96,000 plates/m and resolutions above 1.9 were obtained for the acetylsalicylic acid separation, with a sufficient EOF to yield rapid analysis, which showed improvements over the center point stationary phase. PMID- 21661112 TI - Light-activated release of nitric oxide with fluorescence reporting in living cells. PMID- 21661111 TI - High-throughput analysis of drug dissociation from serum proteins using affinity silica monoliths. AB - A noncompetitive peak decay method was used with 1 mm*4.6 mm id silica monoliths to measure the dissociation rate constants (kd) for various drugs with human serum albumin (HSA) and alpha1-acid glycoprotein (AGP). Flow rates up to 9 mL/min were used in these experiments, resulting in analysis times of only 20-30 s. Using a silica monolith containing immobilized HSA, dissociation rate constants were measured for amitriptyline, carboplatin, cisplatin, chloramphenicol, nortriptyline, quinidine, and verapamil, giving values that ranged from 0.37 to 0.78 s(-1). Similar work with an immobilized AGP silica monolith gave kd values for amitriptyline, nortriptyline, and lidocaine of 0.39-0.73 s(-1). These kd values showed good agreement with values determined for drugs with similar structures and/or affinities for HSA or AGP. It was found that a kd of up to roughly 0.80 s(-1) could be measured by this approach. This information made it possible to obtain a better understanding of the advantages and possible limitations of the noncompetitive peak decay method and in the use of affinity silica monoliths for the high-throughput analysis of drug-protein dissociation. PMID- 21661113 TI - Benzisothiazolyliminothiazolidin-4-ones with chondroprotective properties: searching for potent and selective inhibitors of MMP-13. PMID- 21661114 TI - Diphosphine capsules for transition-metal encapsulation. AB - Self-assembly and characterization of novel heterodimeric diphosphine capsules formed by multiple ionic interactions and composed of one tetracationic diphosphine ligand and one complementary tetraanionic calix[4]arene are described. Encapsulation of a palladium atom within a diphosphine capsule is achieved successfully by using the metal complex of the tetracationic diphosphine ligand for the assembly process. In this templated approach to metal encapsulation, the transition-metal complex is an integrated part of the capsule with the transition metal located inside the capsule and is not involved in the assembly process. We present two approaches for capsule assembly by mixing solutions of the precharged building blocks in methanol and mixing solutions of the neutral building blocks in methanol. The scope of the diphosphine capsules and the metallodiphosphine capsules is easily extended by applying tetracationic diphosphine ligands with different backbones (ethylene, diphenyl ether, and xanthene) and cationic binding motifs (p-C(6)H(4)-CH(2)-ammonium, m-C(6)H(4) ammonium, and m-C(6)H(4)-guanidinium). These tetracationic building blocks with different flexibilities and shapes readily associate into capsules with the proper capsular structure, as is indicated by (1)H NMR spectroscopy, 1D NOESY, ESI-MS, and modeling studies. PMID- 21661115 TI - Precise design of artificial cofactors for enhancing peroxidase activity of myoglobin: myoglobin mutant H64D reconstituted with a "single-winged cofactor" is equivalent to native horseradish peroxidase in oxidation activity. AB - H64D myoglobin mutant was reconstituted with two different types of synthetic hemes that have aromatic rings and a carboxylate-based cluster attached to the terminus of one or both of the heme-propionate moieties, thereby forming a "single-winged cofactor" and "double-winged cofactor," respectively. The reconstituted mutant myoglobins have smaller K(m) values with respect to 2 methoxyphenol oxidation activity relative to the parent mutant with native heme. This suggests that the attached moiety functions as a substrate-binding domain. However, the k(cat) value of the mutant myoglobin with the double-winged cofactor is much lower than that of the mutant with the native heme. In contrast, the mutant reconstituted with the single-winged cofactor has a larger k(cat) value, thereby resulting in overall catalytic activity that is essentially equivalent to that of the native horseradish peroxidase. Enhanced peroxygenase activity was also observed for the mutant myoglobin with the single-winged cofactor, thus indicating that introduction of an artificial substrate-binding domain at only one of the heme propionates in the H64D mutant is the optimal engineering strategy for improving the peroxidase activity of myoglobin. PMID- 21661116 TI - Synthesis of 3,4-dimethylidene oxacycles through Prins-type cyclization of allenylmethylsilanes. AB - An efficient synthesis of 3,4-dimethylidene oxacycles including oxolanes and oxepanes through Prins-type cyclization of hydroxy(allenylmethyl)silanes is described. We have shown that 2-substituted tetrahydrofuran derivatives could be produced by using this strategy although the 5-endo-trig cyclization mode is stereoelectronically disfavored. We also applied our method to the stereoselective synthesis of 2,7-cis-3,4-dimethylidene oxepanes, which were used for constructing more complex ring systems, such as polyether bicycles or tricycles. PMID- 21661117 TI - Hydrothermal synthesis and properties of controlled alpha-Fe2O3 nanostructures in HEPES solution. AB - A facile, template-free, and environmentally friendly hydrothermal strategy was explored for the controllable synthesis of alpha-Fe(2)O(3) nanostructures in HEPES solution (HEPES=2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid). The effects of experimental parameters including HEPES/FeCl(3) molar ratio, pH value, reaction temperature, and reaction time on the formation of alpha Fe(2)O(3) nanostructures have been investigated systematically. Based on the observations of the products, the function of HEPES in the reaction is discussed. The different alpha-Fe(2)O(3) nanostructures possess different optical, magnetic properties, and photocatalytic activities, depending on the shape and size of the sample. In addition, a novel and facile approach was developed for the synthesis of Au/alpha-Fe(2)O(3) and Ag/alpha-Fe(2)O(3) nanocomposites in HEPES buffer solution; this verified the dual function of HEPES both as reductant and stabilizer. This work provides a new strategy for the controllable synthesis of transition metal oxide nanostructures and metal-supported nanocomposites, and gives a strong evidence of the relationship between the property and morphology/size of nanomaterials. PMID- 21661118 TI - Raman spectroscopic analysis of the carotenoid concentration in egg yolks depending on the feeding and housing conditions of the laying hens. AB - Resonance Raman spectroscopic measurements are suited to analyze the concentration of carotenoid antioxidants in biological samples. Previously, it has been shown that the carotenoid concentration of nutritional egg yolks has a direct influence on the carotenoid content of human skin in vivo. In the present study, resonance Raman spectroscopy was used to analyze the carotenoid concentration in the yolks of hen eggs, which were housed in battery cages or alternatively on free-range grassland. The egg yolks of hens, which had access to grassland, contained approximately double the amount of carotenoid concentration than the egg yolks of hens housed in battery cages (p < 0.001). The kinetics of the carotenoid concentration in the egg yolks, depending on fodder, housing and weather conditions, were investigated. PMID- 21661119 TI - Measuring the persistence length of MCF7 cell microtubules in vitro. AB - The dynamic and mechanical properties of mammalian neural microtubules have been widely studied; however, similar knowledge about these properties is limited for non-neural microtubules, which, unlike neural microtubules, consist of different beta-tubulin isotypes. In this study, we report, for the first time, an estimated value for the persistence length of a single non-neural microtubule polymerized from purified tubulin from human breast cancer cell lines (MCF7 tubulin). The method of measurement is based on an analysis of the local curvature of a microtubule as a result of thermal fluctuations. In parallel, we measured the persistence length of a single bovine brain microtubule under similar conditions. The results of our measurements indicate a higher value for the persistence length of MCF7 microtubules in vitro as compared to the persistence length of a neural microtubule. The difference can be associated with different beta-tubulin isotypes in the structure of MCF7 microtubules. PMID- 21661120 TI - Engineering antibiotic production and overcoming bacterial resistance. AB - Progress in DNA technology, analytical methods and computational tools is leading to new developments in synthetic biology and metabolic engineering, enabling new ways to produce molecules of industrial and therapeutic interest. Here, we review recent progress in both antibiotic production and strategies to counteract bacterial resistance to antibiotics. Advances in sequencing and cloning are increasingly enabling the characterization of antibiotic biosynthesis pathways, and new systematic methods for de novo biosynthetic pathway prediction are allowing the exploration of the metabolic chemical space beyond metabolic engineering. Moreover, we survey the computer-assisted design of modular assembly lines in polyketide synthases and non-ribosomal peptide synthases for the development of tailor-made antibiotics. Nowadays, production of novel antibiotic can be tranferred into any chosen chassis by optimizing a host factory through specific strain modifications. These advances in metabolic engineering and synthetic biology are leading to novel strategies for engineering antimicrobial agents with desired specificities. PMID- 21661128 TI - Pseudothrombocytopenia. PMID- 21661123 TI - Zic2 synergistically enhances Hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells. AB - Aberrant activation of Hedgehog (Hh) signalling has been implicated in the pathogenesis of human cancers. However, the cognate molecular mechanisms contributing to this disregulated pathway are incompletely understood. In this study, we showed that Zic2 was frequently over-expressed and associated with high grade cervical cancer (p = 0.032), high levels of Gli1 (p < 0.001) and CyclinD1 (p < 0.001) by immunohistochemical and quantitative RT-PCR analyses. Further biochemical studies using luciferase reporter, co-immunoprecipitation, subcellular fractionation and immunofluorescence analyses demonstrated that Zic2 can physically interact with Gli1 and retain it in the nucleus, which in turn increases Gli-mediated transcriptional activity. Gain- and loss-of-function analyses of Zic2 showed that Zic2 could increase Hh signalling activity, cell proliferation and anchorage-independent growth ability in cervical cancer cells. Conversely, deletion of the zinc finger domain at C-terminus of Zic2 significantly abrogated its interaction with Gli1, the retention of Gli1 in the nucleus, effects on Hh signalling activity and oncogenic properties in cervical cancer cells. Our findings suggest that Zic2 is a positive modulator increasing Gli1 transcriptional and oncogenic activity by retaining Gli1 in the nucleus of cervical cancer cells. PMID- 21661129 TI - Total anomalous pulmonary venous return with connection to the supradiaphragmatic inferior vena cava: assessment and diagnosis by multidetector computed tomography. PMID- 21661130 TI - Real-time three-dimensional transoesophageal echocardiography for guidance of transcatheter closure of a complex multifenestrated atrial septal defect. PMID- 21661131 TI - Abstracts of the 53rd Annual Scientific Meeting of the American Headache Society. June 2-5, 2011. Washington, D.C., USA. PMID- 21661133 TI - Abstracts of the 3rd North American Congress of Epidemiology. June 21-24, 2011. Montreal, Canada. PMID- 21661132 TI - Abstracts of the 20th World Congress of Sexual Health. June 12-16, 2011. Glasgow, Scotland, United Kingdom. PMID- 21661134 TI - Abstracts of the 2011 AWHONN (Association of Women's Health, Obstetric and Neonatal Nurses) Convention. June 2011. Denver, Colorado, USA. PMID- 21661136 TI - Update on emerging infections: news from the Centers for Disease Control and Prevention. PMID- 21661135 TI - Hirayama, passive smoking and lung cancer: 30 years on and the numbers still don't lie. PMID- 21661137 TI - End-of-life issues. PMID- 21661138 TI - Finding buried treasure. PMID- 21661139 TI - [Collaborative care for depression in general practice: overview of systematic reviews]. PMID- 21661141 TI - [Significance of international standardization of HbA1c measurement]. PMID- 21661140 TI - [New diagnostic criteria of diabetes mellitus in Japan, 2010]. PMID- 21661142 TI - [AGE-RAGE system in diabetic vascular complications]. PMID- 21661143 TI - [The polyol and hexosamine pathways]. PMID- 21661144 TI - [Microinflammation in diabetic microvascular complications]. PMID- 21661145 TI - [Genetic factors for diabetic microvascular complications]. PMID- 21661146 TI - [JDCP study]. PMID- 21661147 TI - [Steno2 study]. PMID- 21661149 TI - [Blood pressure control]. PMID- 21661148 TI - [UKPDS]. PMID- 21661150 TI - [Meaning and policy of treatment for dyslipidemia in diabetic microangiopathy]. PMID- 21661151 TI - [AGE inhibitors]. PMID- 21661152 TI - [The effect of PKC inhibitor on diabetic vascular complications]. PMID- 21661153 TI - [Renin inhibitor]. PMID- 21661154 TI - [Incretin-related medicine (GLP-1 receptor agonists, DPP-IV inhibitors)]. PMID- 21661155 TI - [Phosphodiesterase-3 inhibitor]. PMID- 21661156 TI - [Perspective on the role of Rho-kinase inhibitor in the treatment of diabetic vascular complications]. PMID- 21661157 TI - [Regenerative therapy in vascular medicine and diabetic microvasculopathy--lesson from the bedside]. PMID- 21661158 TI - [Gene therapy for diabetic microangiopathy]. PMID- 21661159 TI - [International clinical diabetic retinopathy disease severity scale]. PMID- 21661160 TI - [The latest trend of research of susceptibility gene in diabetic retinopathy]. PMID- 21661161 TI - [AGE and PKC]. PMID- 21661162 TI - [Fundus photography and fluorescein angiography]. PMID- 21661163 TI - [Diabetic retinopathy delineated by optical coherence tomography]. PMID- 21661164 TI - [Diabetic retinopathy candesartan trial]. PMID- 21661165 TI - [Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study]. PMID- 21661166 TI - [Guideline-based planning for the treatment of diabetic retinopathy]. PMID- 21661167 TI - [Risk factors of diabetic retinopathy and their treatment]. PMID- 21661168 TI - [VEGF blockers]. PMID- 21661169 TI - [Retinal photocoagulation]. PMID- 21661170 TI - [Surgical management of diabetic retinopathy]. PMID- 21661171 TI - [Clinical features and pathogenesis of diabetic maculopathy]. PMID- 21661172 TI - [Drug therapy for diabetic macular edema]. PMID- 21661173 TI - [Roles of guidance molecules in retinal angiogenesis]. PMID- 21661174 TI - [Concept and symptomatology in diabetic nephropathy]. PMID- 21661175 TI - [Epidemiology of diabetic nephropathy]. PMID- 21661176 TI - [Diagnostic criteria and the stage of a disease classification of the diabetic nephropathy]. PMID- 21661177 TI - [Recent advances in the genetic study for diabetic nephropathy]. PMID- 21661178 TI - [Alterations of mesangial cell and matrix]. PMID- 21661179 TI - [EGFR (estimated GFR)]. PMID- 21661180 TI - [Urinary angiotensinogen]. PMID- 21661181 TI - [Urinary podocytes]. PMID- 21661182 TI - [The Shiga Microalbuminuria Reduction Trial]. PMID- 21661183 TI - [Lowering blood pressure and glucose reduces renal events in type 2 diabetes; ADVANCE study]. PMID- 21661184 TI - [New therapeutic strategy for diabetic nephropathy--remission and regression]. PMID- 21661185 TI - [Erythrocyte stimulating agents]. PMID- 21661186 TI - [Thiazolidinediones]. PMID- 21661187 TI - [Tricks in salt restriction for treatment of diabetes mellitus]. PMID- 21661188 TI - [Peritoneal dialysis guideline 2009]. PMID- 21661189 TI - [Pancreas transplantation in Japan]. PMID- 21661190 TI - [Epidemiology of diabetic neuropathy]. PMID- 21661191 TI - [Pathology of diabetic neuropathy]. PMID- 21661192 TI - [Cell fusion]. PMID- 21661193 TI - [Evaluation of the cardiovascular nervous system]. PMID- 21661194 TI - [Diabetic neuropathy--treatment strategy based on clinical guideline of the Japan Diabetes Society]. PMID- 21661195 TI - [Diabetic footcare]. PMID- 21661196 TI - [Periodontal disease]. PMID- 21661197 TI - [Dementia (cognitive impairment)]. PMID- 21661198 TI - [Osteoporosis]. PMID- 21661199 TI - [Image of the month. Necrobiosis lipoidica]. PMID- 21661200 TI - [Clinical case of the month. Cerebral air embolism arising during a procedure of thermocoagulation of a bronchial epidermoid carcinoma in situ by fiberscopy]. AB - Patient aged 48 years followed for COPD evolutionary stage 3 according to the GOLD classification. In the waning of a unifocal lung, bronchial endoscopy performed to bacteriological referred highlights a squamous cell carcinoma in situ. During an endoscopic re-evaluation and treatment by local thermocoagulation, the patient experienced a massive cerebral embolism. Despite treatment with hyperbaric oxygen therapy and resuscitation care, he died in an array of postanoxic coma and acute renal failure in a tank. PMID- 21661201 TI - [Sexual dysfunction and antidepressants]. AB - Over the last two decades, several antidepressants (AD) were marketed. These drugs are not only used for the treatment of depression, but also for many other indications like anxiety disorders, eating disorders, premenstrual syndrome and neuropathic pain of diabetic origin... During several years, sexual side-effects of AD have been ignored. These side-effects have a great impact on the quality of life of patients and increase the risk of non-compliance to treatment. Presently, few reliable scientific data are available concerning the frequency and the nature of sexual disorders induced by AD. Overall, these effects are grossly underestimated because the problem is rarely addressed directly. In this review, the sexual side-effects of AD and the possible strategies to limit their consequences will be discussed. PMID- 21661202 TI - [Dementia in Parkinson's disease: risk factors, diagnosis and treatment]. AB - Aside from limb tremor, bradykinesia, rigidity and gait disturbances, Parkinson's disease (PD) is also characterized by non-motor symptoms. A cognitive decline can occur early in the disease course and undoubtedly impact of the patient's quality of life. Dementia affects 80% of patients 20 years after disease onset but a small subgroup of patients remain free of dementia even after decades with PD. Risk factors and diagnosis of dementia can be easily assessed using bed-side clinical instruments. Advances in genetics and imagery will allow improving the diagnosis and therapeutic strategy dementia in Parkinson's disease. PMID- 21661203 TI - [Neuropsychiatric side effects of antituberculosis agents]. AB - Accurency of neurological or psychiatric complications secondary to the administration of antituberculosis may be at the origin of diagnosis and therapeutic problems. This work aims at studying the frequency of these manifestations, their clinical presentations and their therapeutic approach. PATIENTS AND METHODS: This retrospective study was carried on from January 1990 to June 2008 at Ibn Nafis Pulmonary Department of Abderrahmen Mami Hospital in Ariana. It dealt with 18 in-patients with a neurologic or a psychiatric complication due to antituberculous drugs. Peripheral neuropathy was noted in 6 patients (33%). One of them had a history of chronic alcoolism, another one had a history of diabetes mellitus and 2 other patients were more than 72 years old. We had definitively stopped isoniazide in 2 cases and decreased the dosage in 4 other patients. However, all patients received B6 vitamin. Convulsions occured in 2 women without any history of epileptic status. Anticonvulsivant treatment was prescribed and isoniazid definitively stopped. Hallucinosis was noted in 4 patients, with one having a history of chronic alcoolism. Isoniazide was stopped in all cases. Agressivity, insomnia and memory problems were noted in 6 patients. Isoniazid was interrupted in only one woman who had history of depression. In 5 other patients, anxiolytics were prescribed. Isoniazide was incrimined in all cases and evolution was favorable for the 18 patients. A close monitoring of patients on antituberculous treatment is required to detect the onset of any neuropsychiatric complications incriminating usually isoniazid. Definitive interruption or decrease of the dose of isoniazid depending of the acetylation test were necessary. PMID- 21661204 TI - [Two post-traumatic "Gilliatt-Sumner hands" from decompensation of thoracic outlet syndrome]. AB - The clinical picture of hand atrophy related to a cervical rib has been well described in 1970 by Gilliatt and Sumner. These authors reported a series of nine patients whose motor status was stabilized following decompressive surgery of the brachial plexus. We report two young patients decompensating a predisposed thoracic outlet (rudimentary cervical rib), following a scapular or cervical trauma. After several years of neck and arm painful complaints, the two patients progressively developed hand atrophy. One patient had been operated both at cervical (double discectomy and disc prosthesis) and elbow (ulnar nerve neurolysis) levels, before the diagnosis of thoracic outlet syndrome (TOS) was attained. Decompression of the brachial plexus by anterior approach has improved the painful symptoms and stabilized the motor status of our two patients. The diagnosis of plexus disease was reached in our two patients at the "true" neurogenic TOS stage (hand atrophy), evolving several years after a "disputed" neurogenic TOS (subjective complaints). These cases remind us to keep in mind the diagnosis of TOS in front of a cervicobrachialgia not or insufficiently explained by a cervical pathology. PMID- 21661205 TI - [General practitioner--psychiatrist: friends or enemies?]. AB - The author's purpose is to highlight the role differences between a general practitioner and a psychiatrist. She bases her review on the literature as well as on her personal experience which consists of 25 years as a general practitioner followed by 10 years as a psychiatrist. The colleagues' respective opinion of one another was assessed by means of two questionnaires. One was administered to a hundred psychiatrists and the other to a hundred general practitioners on the occasion of two separate medical meetings. The results of these questionnaires, statements found in the medical literature as well as the author's personal experience confirm that, even if the collaboration between general practitioners and psychiatrists is considered important, it remains very difficult and conditioned by numerous preconceived ideas. By clarifying the roles and specificities of each practitioner, this article aims at improving this collaboration which is pivotal for the patient's mental health progression. PMID- 21661206 TI - [Unraveling the ichthyosis types]. AB - Ichthyoses are hereditary and sometimes acquired diseases of keratinisation. They are heterogeneous according to their clinical and histopathological presentations, as well as to the nature of their molecular and genetic alterations. We present the most frequent types of hereditary ichthyoses. PMID- 21661207 TI - [The student diagnostic vignette. Electrocardiographical criteria for the diagnosis of ventricular tachycardia]. AB - Recording of a regular wide QRS tachycardia is often source of panic and anxiety for the young clinician who has to make the differential diagnosis between ventricular tachycardia and supraventricular tachycardia with aberration associated with fundamentally different vital prognosis. Most of the time, a rigorous approach and a systematic analysis of the electrocardiogram associated with clinical examination allow to obtain the correct diagnosis. PMID- 21661208 TI - [Importance of early Anatolian medical books regarding Turkish medical terms and the language of medicine]. AB - Turkish language was under the dominance of Arabian and Persian languages during the Seljukian period in Anatolia. Turkish gained importance at the period of the small Turcomen states, founded after the great Seljukian State had fallen this period some books were written with the countenance of the statesmen, and about thirty of this books were on medicine. These books were written in plain Turkish, and they are important regarding the Turkish language, because of the Turkish medical terms, besides medical knowledge. The development of Turkish in these books and examples of medical terms are given in this study. PMID- 21661209 TI - [Old medical terms of otorhinolaryngology]. AB - The study of preparing a new medical terminology had been intensified with the efforts of converting medical lessons into Turkish, in the second half of 19th century. The new medical language was mainly based on Arabic and Persian words. In the first years of the republic period there has been a movement of leaving foreign words. There are not much Arabic or Persian words in medical language today. Current medical terminology and the terminology which had used from the second half of the 19th century until the first years of the Republic are different considerably. As a result it is rather difficult to understand old medical texts today. A limited glossary of three otorhinolaryngology books, which are written with the medical terminology used until 1930's, is being presented in this study. PMID- 21661210 TI - [The use of Aloe and Urtica species in Avicenna's canon of medicine]. AB - Ibn-i Sina (Avicenna) is a famous Turkish philosopher who lived between the years 980-1037. He described Aloe and Urtica species besides many other drugs drogues, in his great book El Kanun fi't-Tibb (Canon of Medicine). In this study, we compare the use of Aloe and Urtica in El Kanun fi't-Tibb and today's science. PMID- 21661211 TI - [The tradition of swaddling with soil and usage of ash in Erzin District]. AB - Erzin, a county of Hatay, has been a place of settlement for nomadic Turkoman tribes since 17th century. Utilization of soil for nursing babies is a widely accepted tradition among these tribes. Before placing the soil in the swaddling clothes it must be prepared properly. In spring the untouched soil, unearthed by moles is collected from the fields. It is sifted with a sieve called "sarat". Then it's "cooked" in big pans and stored in sacks knitted with cotton treads called "tirlik cuval". When swaddling a baby, a handful of this soil is placed between the clothes and the skin. Another tradition in this district is the ash usage, especially wood ash in different areas such as washing the clothes and dishes, protecting the kettles being sooted by the fire. PMID- 21661212 TI - [One of our pioneer women surgeons, Nermin Unalan Berkan]. AB - Nermin Unalan was born in 1922 in Izmir. Her family moved to Istanbul after her birth. Her father was a medical doctor. When she decided to study medicine, her father warned her about the difficulties of the profession. After her graduation from the medical school, she wanted to be a general surgeon, and her father warned her again. However, as she was so determined, he took her to the General Surgery Department of Istanbul Medical Faculty. With not to marry during residency--she was accepted. In 8 January, 1951 she became a general surgeon. She worked in Bilecik, than in Istanbul in different hospitals. She married in 1956, has a son. She retired in 1982. She lives in Istanbul. PMID- 21661213 TI - [Ismail Pasha and the treatise on cholera (Kolera Risalesi)]. AB - Since the beginning of 19th century, cholera, which was an endemic disease in India and Bengal, started epidemics in Europe and Middle East and affected the Ottoman Empire first in 1831. Ismail Pasha, who was one of the last Ottoman hekimbashis, wrote a treatise named "Kolera Risalesi" (The Treatise on Cholera), after the cholera epidemic that had broken out in Istanbul in October 1847. In this treatise, which aimed to inform people about cholera, description and causes of cholera is briefly described, and precautions which are necessary to prevent the disease and treatment methods be performed after the disease spread. PMID- 21661214 TI - [Dr. Mehmed Emin Fehmi's pioneering medical history work: the Hakayik-i Tababet]. AB - Mehmed Emin Fehmi, who graduated in 1866 with the rank of captain from the Ottoman Medical School (Mekteb-i Tibbiye), died in 1871, During his short life, Dr. Fehmi taught physics classes and translated two books, as well as writing two books and several articles himself. Mehmed Emin Fehmi's "Hakayik-1 Tababet [Facts of Medicine], "published for the first time in 1870, was the earliest printed Ottoman Turkish work on the history of medicine. In the Hakayik-1 Tababet, the medical history of the Greek and Roman eras, the duties of physicians and medical care, and the advancement of medicine are examined from a philosophical and critical perspective. In our research we aimed to clarify the importance and significance of the work in medical history by analyzing its physical characteristics and contents, since it is a pioneering work in Turkish medical history among Ottoman medical publications. PMID- 21661215 TI - ["Turkish Anthropology Journal (Turk Antropoloji Mecmuasi)", is it a medicine journal?]. AB - Turkish Journal of Anthropology had published between 1925-1939. In this article it is discussed whether this journal would be regarded as a medical journal or not. PMID- 21661217 TI - [An anonymous surgical manuscript of 15th century, the sections of surgical procedures, medical terminology and the names of herbs, drugs and substances]. PMID- 21661216 TI - [Kitabu'l-Fusual of Fenerizade and its place in Ottoman medical education]. AB - The Aphorisms are among the most effective fundamental works of Hippocrates. While all of the works of Hippocrates were translated into Arabic from the Greek origins in the period of Abbasi sons of Islamic civilisation, his Aphorisms were also translated into Arabic and then named "Fusul-i Ibbukrat" accordingly. This thesis titled "Kitabu' I-Fusul of Fenarizade and Its Place in the Ottoman Medical Education", was studied on the first Turkish translation of the medical recommendations of Hippocrates which are known as Aphorisms. There are two copies of the mentioned work at present. In this study, the copy which is kept in the Istanbul University Cerrahpasha Faculty of Medicine the History of Medicine Library was taken as basis. The work was then encrypted and simplified properly, and it was taken as basis. The work was then encrypted and simplified properly, and it was converted into the texts on which the researchers of the day could easily work on. No other information could be obtained about the identity of the translator other than the information which is given in the introductory chapter of the work. In the work of Hippocrates which is composed of seven main sections some detailed information is given on various subjects such as the definition of medicine, the relations of diseases with the climate, fiery illnesses, women diseases, the prognoses of diseases, the relationships of diseases with each other and chest diseases. In a period that efforts were being started to make medical education better and further comprehensible, this work was probably realised with the instruction of Abdulhak Molla who chaired the medical school Tiphane-i Amire in the year 1834, the Aphorisim of Hippoerates was aimed to be benefited as a text book in the education of students in the first classes of medical education, as it was translated as arasult of being valued greatly even at these years. However the translation of Aphorisms which was prepared with the instruction fo Abdulhak Molla could not be published. PMID- 21661218 TI - [The portrait of an elite, during the transformation from the Ottoman Empire to the Turkish Republic (1861-1940)]. AB - Having spent the first half of his lifetime during declining years of the Ottoman Empire and the other half, at the first reformative, energetic decades of the Turkish Republic, Besim Omer Akalin, M.D. exemplifies very well of a new urban elite at the turn of the 20th century, regarding his education, formation, professional and administrative roles in the society He is known of his remarkable contributions in obstetrics, in pediatrics; and also of his fundamental works for the education of midwifery and nursing in Turkey. He carried out several duties at the same time, such as professor at the Istanbul medical School (Mekteb-i Tibbiye-i Sahane - Darulfunun Tip Fakultesi), head of the first Obstetrical clinic (Viladethane) in Turkey, leader of several associations such as the Red Crescent Society (Hilal-i Ahmer Cemiyeti), the Society for the Protection of Children (Himaye-i Etfal Cemiyeti), Anti Tuberculosis Society (Verem Savas Dernegi), member of several commissions concerning the public sanitation and health affairs, rector of the Istanbul University, Turkish delegate of the international medical congresses and associations, member of Parliament. Among all those responsibilities, the accomplished to write numerous books, yearbooks and articles on the above mentioned topics. He was also famous for his initiative supporting women to educate at the university and also to come up at the public and socialarena. This study deals with his activities and works on the basis of his biography studied on archival and bibliographical sources. The list of his complete works is annexed to the text. PMID- 21661219 TI - [Personal experiences of health practitioners noted by themselves]. PMID- 21661220 TI - [The Institut de recherches scientifiques et industrielles Jacquemin (1894-1967), in Malzeville, near Nancy. An almost pharmaceutical industry]. AB - First devoted to research and its applications in chemistry and microbiology, the institute was created in 1894. Its founder, Georges Jacquemin was the son of the professor of chemistry of the school of pharmacy of Nancy. He was first a student in pharmacy but he did not finish the last examinations... Three years ago, he created or participated to the creation of the Institut La Claire, near Morteau in the Jura, with same activities. The Institut Jacquemin settled in special houses and laboratories where were studied and prepared numerous chemical and biological products, particularly selected yeasts used in wine-making, brewery, cider-making, also phytosanitary chemical products and, in 1902, Ferment Jacquemin which was a depurative and was considered as a drug. Georges Jacquemin died in 1925 but his institute remainded in activity with his coworkers until 1967 and closed totally only in 1976. PMID- 21661221 TI - [The French chemist M.-E. Chevreul (1786-1889) in several topics of public health]. AB - Famed owing to his research works about fats and colours, the chemist M.-E. Chevreul was also greatly interested in public health. He expressed himself on this matter especially as member then chairman of the Advisory Committee of Crafts et Factories: set of laws on insanitary factories to be reconsidered, choices of processes which do not affect workers' health. He has relations with old pupils of the Polytechnics School: so he was at the beginning of Charles Freycinet's brilliant career. He read papers to the French Agricultural Society and Sciences Academy and was a juror of the academic committees of insanitary crafts. PMID- 21661222 TI - [Ayurvedics drugs in France. Laboratories polytherapic, a test]. AB - In the beginning of the thirties, Dr Jean Saidman, who has already created a rotative solarium at Aix-les-Bains, built another one in Jamnagar (India). When he was there, he discovered ayurvedic therapy. After the Second World War, with his friends Dr Remus Krainik and the chemist Rene-Henri Monceaux, he set up a "neo-ayurvedic action committee", and then a pharmaceutical laboratory, "Polytherapic", to export to french colonies patents medicines inspired by indian medicine. The authors tale this experience suddenly stopped by the unexpected death of Jean Saidman, in 1949. PMID- 21661223 TI - [Pharmacopea of the Farmacia Esteva of Llivia in the 18th century and his use]. AB - A dispensary register from 1725 and contemporaneous container subscriptions allows an approach of 18th century pharmacopea different from the treatises' in a Catalonian farmacy. The drugs panel shows comparisons with regional scheme and the role of local flora. The prescription register--exceptional document- exhibits differences between pharmacopea and daily use through medical prescription, and influences of local conditions and Lights Century's scientific contribution. PMID- 21661224 TI - [Nicolas Lemery and his sons Louis and Jacques at the Academie Royale des Sciences (1s Part)]. AB - This first part of our study of the activities of Nicolas Lemery and his sons Louis and Jacques at the Academie Royale des Sciences begins with a description of the structure of the Academie as a result of its reformation in 1699, with an emphasis on the roles of its members as defined in its reglement. Then we concentrate on how Nicolas Lemery performed his duties at the Academie beginning from 1699 until his illness and death in 1715. Nicolas's most important contributions were his study on antimony, published as a treatise, and other memoirs on different subjects, mainly related to chemistry, which was the field in which he excelled and has remained famous. This first part is going to be followed by two parts where the activities of Nicolas's sons Louis and Jacques at the Academie are examined in a similar way. PMID- 21661225 TI - [The "Journal de Pharmacie et de Chimie" and the two world wars]. AB - The "Journal de Pharmacie et de Chimie" was the official publication of the Societe de Pharmacie de Paris which became later on the French Academy of pharmacy. It is consequently the organ that presented scientific publications and independent position papers from pharmacists being part of this assembly and coming from universities, drugstores or pharmaceutical industries. We have analyzed the content of this journal during the last two world wars in order to evaluate to what extent the members of the Societe de Pharmacie de Paris were part of the war efforts, and encouraged or criticized the on-going events. We can observe that, in both cases, pharmacists used their expert opinions to better react and manage consequences of the conflicts, but also to express their disagreement with enemy's opinions or actions, the Society doing everything possible to maintain its activities. One can observe also that both conflicts were an opportunity to reconsider the organization of pharmacy in France, especially during the Second World War where took place discussions on pharmacy reform (1941 law) and creation of the Pharmacists' Order which will ultimately occur after the war end. PMID- 21661226 TI - [The Le Camus apothecary-grocers in Paris from the XVth to the XVIIth century. Nicolas IV Le Camus owned the Pavillon des Singes in the Rue Saint-Honore, the residence of the Pocquelin family]. AB - Five members of the Le Camus family of Paris were apothecary-grocers, a situation passed down from father to son from the end of the reign of Charles VII up to the reign of Louis XIV, in other words for nearly two centuries. Four of them were called Nicolas and the fifth Jehan. Nicolas I practised his trade in the Rue Saint-Antoine; Nicolas II and Jehan lived in the district of Les Halles, on the corner of the Rue Saint-Denis and the Rue de la Chanvrerie. Nicolas IV was a tenant in a house at the crossroads of the Rue Saint-Honore and the Rue des Poulies, later absorbed by the opening of the Rue du Louvre. In 1638, Nicolas IV bought the house known as "Le Pavillon des Singes" on the corner of the Rue Saint Honore and the Rue des Vieilles Etuves (now the Rue Sauval), the home of the family of Jean Pocquelin, father of Jean-Baptiste, the future Moliere. When Nicolas IV died, his goods were divided between his son Francois, lawyer in Parliament, and his daughter Anne who inherited the "Pavillon des Singes". In 1680, she sold it to an administrator of the Hotel-Dieu. Nicolas IV Le Camus was the last Parisian apothecary of this dynasty and no other Le Camus practised pharmacy in Paris until the Royal Declaration of 25th April 1777 which created the College of Pharmacy and the Master of Pharmacy. PMID- 21661227 TI - [The end of the theriac in modern medicine in the sixteenth to nineteenth century]. AB - Theriaca, after the Greco-Roman antiquity, survived centuries with some continuity. The formula used during the 17th century, inherited from the tradition of Hippocrates and Galen is closed to what it was centuries earlier, despite the difficulties of supply of raw materials. It is considered a mainstay of therapy by the apothecaries of the 16th century as Houel or Bauderon and 17th as Charas or Lemery. In contrast, the 18th and the "Lumieres" with Baume, will contrive to challenge the validity of the preparation. In France, the last public preparation of the Theriaca was performed in 1798. Official pharmacopoeias of the 19th century (from 1818 to 1884) will all retain a formulation of Theriaca, where, according to tradition, dozens of ingredients are mixed in terms of unproven effectiveness that will lead to the withdrawal of the final preparation at the beginning of the 20th century, when the Theriaca passes controversial drug status to that of ancient and obsolete myth. PMID- 21661228 TI - [The three constituents of the idea of "medicine" in Hashida Kunihiko's thought]. AB - According to Hashida's theory, the medical professions encounter not "a disease", but "the person who is suffering from his/her disorders". However, the medical professions cannot apply "I-GAKU" directly to him/her who exists as an individual and specific empirical fact because "I-GAKU" is nothing more than a "medical science", a theory based on a collection of scientific facts which are abstract and notional. Therefore, "I-JUTSU" is required to convert scientific facts to empirical facts. Then, "I-DOU" moves the medical professions into "I-JUTSU", and also it demands observance from not only the medical profession, but also from the person who undergoes "I-JUTSU". Ultimately, "Medicine" is realized when these three constituents works mutually. PMID- 21661229 TI - [OKA Kenkai's medical achievements in Shimonoseki and a discussion of the various circumstances leading to his decision to live there: how did western medicine develop in a port located on the western tip of Honshu at the end of the Bunsei era?]. AB - Oka Kenkai began practicing medicine in Shimonoseki following the conclusion of his training in western medicine in Nagasaki. He lived there from early spring in the 12th year of the Bunsei Era until mid-March of the following year. During that time, he wrote the "Oka-jyoyoho" and completed a translation of the "Seiki ron". In addition, Kenkai established the school Seian-juku where he taught Western medicine to the approximately 20 students enrolled there. The school provided instruction not only in Westen medicine, but also other subjects such as the Dutch language and physiology. Notably, Kenkai enriched the field of basic medicine and regarded systematic understanding of academics as important. He came to Shimonoseki in part because of his distant relative SAKOU, who was an influential individual from a prominent Shimonoseki family and a devotee of Dutch culture. SAKOU hired Kenkai as the family physician so Kenkai could look after his personal residence and the honjin (the chief hotel of a post-town). Although Kenkai was only in Shimonoseki for a short year, he left behind exceptional achievements in medical education and literary works. PMID- 21661230 TI - [The old transcript "Kosha-hon" quoted by Chusai Shibue in his lecture manuscript for Spiritual Pivot (Lingshu) "Reisu Kogi"]. AB - The details about the old transcript "Kosha-hon" quoted by Chusai Shibue in his Reisu Kogi had remained unspecified. However, the author found that the Kosha-hon is probably now in the possession of the Peking University Library. In addition, through the investigation, the following facts emerged: 1) The date of writing of the transcript can be presumed to be between the Kanbun and Enpo eras in the Edo period. 2) The book, called "Kosha-hon", can be presumed to transcribe the lost version of the text in the group of the twelve volumes of XinKan Huangdi Neijing Lingshu. 3) Shibue left side notes, headed "Kosha-hon Hoki", and he used them for revision, but in fact these notes originated in the Ma Taixuan's Huangdi Neijing Lingshu Zhuzheng Fawei. PMID- 21661231 TI - [Primitive treatment of the Shanghan by Huatuo in the chapter "Shanghanmen" of Qianjinfang]. AB - This report considers the primitive treatment of the "Shanghan" in the chapter "Shanghanmen" of the Qianjinfang. In the primitive etiology of"Shanghan", there were three stages of the recognition of disease pathogenesis, which were first the existence in fear and awe, second the poison, and the last the cold and fever. The etiology seemed to develop into that of the Shanghanlun. Furthermore, from the standpoint of therapeutics, the target for the diseases changed from influences of the external world to the body, as well. Although "Huatuo" used pills and powder formulations which have the effects of a diaphoretic, an emetic and a laxative to reject the outside diseases, he adopted the decoctions for complicated symptoms of diseases. In conclusion, the etiology and therapeutics discussed in the chapter "Shanghanmen" of the Qianjinfang are related to the formation of the Shanghanlun. PMID- 21661233 TI - [Research on the Ikeda documents (38)]. PMID- 21661232 TI - [A study of Hashida Kunihiko's thought: the life history and thought of an "outcast thinker"]. AB - Hashida Kunihiko, described and known as "an Outcast Thinker", was born in Tottori, in 1882. From his young age, he was taught oriental thought by his father Fujita Kenzo, a practitioner of Kampo medicine. While Hashida taught physiology as a faculty member at the Imperial University of Tokyo, he studied Dogen's Zen philosophy and developed his original philosophy of science to answer the question: "What is Life/Living?". After taking the oath of office as the 56th education minister of Japan from 1940 to 1943, he committed suicide in 1945, taking the responsibility for his policy-making of nationalistic education at time of the Second World War. Some previous studies on Hashida have focused on various aspects such as his work as a physiologist, a scientist, a scholar of Zen philosophy, and an educrat. He may be well known in each of these different disciplines, whereas how these different aspects are integrated in Hashida's thought as a whole has not been clarified yet. Taking the propositions in those previous studies on him into account to totally understand Hashida as a thinker, this note will focus on the potential perspective for his undiscovered aspect: "Hashida as Medical Philosopher". Hashida has perused and loved two classical texts on oriental thought and oriental medicine, which are "Chuan Xi Lu" and "Shang Han Lun", during his lifetime and learned many things about "Medicine". He has tried to implement his philosophy of medicine to set up and maturate "Japanese medicine". Hence, to dissert "Hashida as Medical Philosopher" may become a ground for argument to understand his thought as a whole from the genetic perspective on the process of thought formation of Hashida. Therefore this note can be characterized as a preliminary survey to develop the further studies on Hashida's thought. PMID- 21661234 TI - [The history of drug reevaluation in Japan]. AB - The drug reevaluation system was established to review the quality, efficacy and safety of drugs approved in the past based on current medical and pharmaceutical scientific standards. There have been three reevaluations of ethical drugs in Japan implemented according to the approved dates. The first reevaluation started in 1971 and finished in 1995 for the drugs that were approved up until September 1967. The second reevaluation started in 1984 and finished in 1996 for the drugs that were approved between October 1967 and March 1980. The new reevaluation system for all drugs regardless of the approval date consists of periodic reevaluation and Ad Hoc reevaluation. This system started in 1988 and has continued up to the present. Periodic reevaluation is a system where the efficacy and safety of drugs of all therapeutic categories are reviewed every five years based on literature screening. However, this system is currently suspended. Ad Hoc reevaluation is used to supplement periodic reevaluation and is performed at the onset of an emergency or when an entire therapeutic category becomes roblematic. In the second reevaluation and new reevaluation system, it is harder to judge which products must be reevaluated than in the first reevaluation for all drugs. In addition, the quality reevaluation for oral solid formulations based on dissolution studies started in February in 1997 and is almost finished. PMID- 21661235 TI - [Historical research of cinchona cultivation in Japan (Part 2). Useful tropical plants introduced from Java and India in the early Meiji era]. AB - In the early Meiji era, Takeaki Enomoto made a proposal to the government that cinchona and coffee seedlings be introduced to Japan. In response, the Meiji government dispatched Masatsugu Takeda of the Ministry of Internal Affairs to Java and India from March to August 1878 for the purpose of investigating useful plants of tropical origin and introducing them to Japan. This paper clarifies the route to those destinations and the plants obtained locally. Using the seeds obtained from India during his travels, the cultivation of cinchona was attempted in 1882 for the first time in Japan. In Ogasawara, coffee cultivation was conducted, again for the first time in Japan, using coffee seeds brought back from Java. The cultivation of coffee was successful and served as the foundation of the Ogasawara coffee that exists to this day. Takeda also introduced a number of books and materials related to useful tropical plants available as a result of his travels, which contributed to the promotion of new industries and businesses in the Meiji era. PMID- 21661236 TI - [Herbological studies on combination of rhubarb and mirabilite]. AB - In traditional Chinese medicine, it has long been thought that the medicinal effect of a crude drug can be modified by combination with other crude drugs. One well-known example is the combination of mirabilite (a purgative) and rhubarb (an anti-inflammatory and essentially anti-blood stasis drug). One description in the medicinal literature states that mirabilite has to be added after rhubarb has been decocted. Another description states that rhubarb needs to be processed with liquor when both crude drugs are used together. However, the reason why rhubarb and mirabilite are used together, why mirabilite is added afterward, and why rhubarb needs to be processed with liquor have not been elucidated completely. Therefore, we performed a herbological study and found that rhubarb is expected to act as a purgative while mirabilite is expected to act as a stool softener when they are used together. We also found that they are used together to speed up the onset of a purgative effect in each other. Secondly, we decocted rhubarb (unprocessed or liquor-processed) and mirabilite together, and analyzed the content of principal compounds. We found that sennoside and anthraquinone contents of the rhubarb decoction were reduced by adding mirabilite. However, when mirabilite was added after rhubarb had been decocted, the decrease was smaller than when they were put in water at the same time. In addition, the decoction of liquor-processed rhubarb showed low sennoside content. Therefore we conclude that mirabilite is added after rhubarb has been decocted to prevent the decrease of active compounds, and we consider that unprocessed rhubarb is suitable for expecting a purgative effect. PMID- 21661237 TI - [Significance of the term "huku-yaku" (taking medicines)]. AB - The term "Huku or Fu" in "Huku-yaku or Fu-yao", which means taking medicines, does not mean " to wear" , but means "to obey certain rituals or duties." Therefore "Huku-yaku (Fu-yao)" means " to obey the nature of a drug." From the viewpoint of "ShenXian" thought, the term used when referring to taking medicine depends on whether the purpose is to cure diseases or strengthen pneuma. The term "Huku (Fu)" is adopted for the latter. When the purpose is to strengthen pneuma, the drug does not only effect the inner body, but also works on the external world. Hence the "ShenXian" thought aims to conform to the rules of nature and obtain youth and longevity through taking medicines. PMID- 21661238 TI - [Historical research of cinchona cultivation in Japan (Part 3)--A proposal to introduce cinchona by Takeaki Enomoto]. AB - We attempted to determine how one of the most valuable medicinal plants, cinchona, was brought to and cultivated in Japan. In the course of the study, we report that cinchona seedlings were brought to Japan for the first time in 1876, as per Takeaki Enomoto's proposal to the Meiji government. We also examine the details of his proposal in effort to clarify that the written proposal was submitted between February and March, 1874, and considered his motives leading to the submission. Cinchona is a very important medicinal plant that has saved human lives. However, there was no proof that Takeaki Enomoto's proposal made it introduction to Japan possible, nor was there any evidence that its cultivation was attempted. In addition, it was not clear that the details of the above has been found in document including the Nomutenmatsu (agricultural report published by the Meiji Government). It is significant that the details has been clarified by our series of studies not only from the standpoint of the history of pharmacy, but also from the accounts of the great predecessors involved, such as Takeaki Emonoto and Yasusade Tashiro. PMID- 21661239 TI - [Also interesting to a layman]. PMID- 21661240 TI - [An implant supported dental prosthesis on 2 dental implants is standard treatment for an edentulous jaw. Yes]. PMID- 21661241 TI - [An implant supported dental prosthesis on 2 dental implants is standard treatment for an edentulous jaw. No]. PMID- 21661242 TI - [Diagnosis and classification of headache and temporomandibular disorders, a new opportunity]. AB - Patients with orofacial pains are generally treated by physicians. A small number of patients are treated for pain in the temporomandibular joint, the masticatory and the neck muscles, by dentists and orofacial surgeons. Among half of the patients being treated in neurological headache clinics, the temporomandibular joint and the masticatory muscles are the source of the pain. In order to achieve better research and a classification, the International Headache Society, consisting largely of neurologists, developed a classification system. A comparable development occurred among oral health specialists. Employing these 2 methods with the same patients leads to different diagnoses and treatments. Both the International Classification of Headache Disorders II and the Research Diagnostic Criteria for Temporomandibular Disorders are being revised. This creates the opportunity to establish a single classification for these orofacial pains, preferably within the new International Classification of Headache Disorders. PMID- 21661243 TI - [Andreas Vesalius: father of modern anatomy]. PMID- 21661244 TI - [Eczema herpeticum]. PMID- 21661245 TI - [Saliva and wound healing]. AB - The oral mucosa is frequently exposed to mechanical forces, which may result in tissue damage. Saliva contributes to the repair of the oral mucosa in several ways. In the first place, it creates a humid environment to improve the function of inflammatory cells. During the last few years, it has been shown that saliva also contains a large number of proteins with a role in wound healing. Saliva contains growth factors, especially Epidermal Growth FACTOR, which promotes the proliferation of epithelial cells. Trefoil factor 3 and histatin promote the process of wound closure. The importance of Secretory Leucocyte Protease Inhibitor is demonstrated by the fact that in the absence of this salivary protein, oral wound healing is considerably delayed. Understanding these salivary proteins opens the way for the development of new wound healing medications. PMID- 21661246 TI - [Orthodontic-surgical treatment puts an end to temporomandibular dysfunction complaints]. AB - Late in the last decade of the previous century, an orthodontic-surgical treatment was elected for a 31-years-old woman, who had severe malocclusion and temporomandibular complaints. The skeletal pattern (high angled mandibula) and degenerating joints were considered risk factors for relapse and condylar lysis. Nevertheless, the severity of the malocclusion justified the treatment. The goal was a stable occlusion and the creation ofa smooth articulation to eliminate dysfunction and facilitate later temporomandibular joint treatment with splints if necessary. In the 1990s this was considered state of the art treatment. Eliminating the scissors bite of 27 seemed instrumental in the elimination of the symptoms. Surgery brought the face and the occlusion further in harmony. The final occlusion features only one lower incisor. PMID- 21661247 TI - [An enlarged lymph node in the neck; what to do?]. AB - A swelling in the neck is often caused by one or more enlarged lymph nodes, usually due to a harmless disorder. Particularly in adults, a swelling in the neck may represent a metastasis of a malignancy in the head and neck region, for instance a squamous cell carcinoma arising from the oral mucosa. Palpation of the neck can provide valuable information, although its reliability is restricted, even when executed by an experienced clinician. Therefore, additional examination is required,for instance by fine needle aspiration cytology, ultrasound examination with or without guided fine needle aspiration, computer tomography and magnetic resonance imaging. In case a malignant tumour has been diagnosed in the upper aerodigestive tract, a sentinel node procedure may be performed. The question arises whether general practicing dentists should examine routinely every patient's neck, or only the necks of patients older than 40 years of age. PMID- 21661248 TI - [Oral health related quality of life among Dutch forensic psychiatric patients]. AB - In order to determine the effects ofa new approach to preventive oral health treatment for forensic psychiatric patients, 3 studies were carried out using a Dutch version of the Oral Health Impact Profile-14 (OHIP-14-NL), among Dutch forensic psychiatric patients. In the first study, it was determined that the psychometric characteristics of the OHIP-14-NL were good and that attention to oral healthcare contributed positively to quality of life. The second study, which made use of an improved version of the OHIP-14-NL indicated that patients with a high level of anxiety for dental treatment and poor oral health reported a lesser quality of life. The third study showed that an effectively carried out programme of personal oral care can play an important role in the reduction of halitosis and in the improvement of quality of life. Moreover, it appeared that the retrospective version of the OHIP-14-NL was a useful method for determining the correlation between quality of life and oral health and for evaluating change therein within a relatively short period of time. PMID- 21661249 TI - [Dissertations 25 years after date 25. Dentures: a question of grinning and bearing it]. AB - 'Dentures: A question of grinning and bearing it' is not just the title of a 25 year-old thesis, but it also reflects the content well. Dissatisfaction with complete dentures is not only determined by the quality of the dentures and the oral conditions, but also and just as much by the patient's capacity to adapt to and accept the dentures. In order to treat an edentulous patient adequately, an oral healthcare provider should pay special attention to these aspects. After 25 years of further scientific study, this conclusion is still true. The current care standard for edentulous patients with atrophy of the residual mandibular alveolar ridge is an overdenture supported by 2 implants. For edentulous patients with a solid residual mandibular alveolar ridge, conventional complete dentures are the first choice of treatment. Only in cases of obvious remaining complaints, should an implant-supported overdenture be considered. PMID- 21661250 TI - [The Berlin morgue of 1886--the 125-year-old morgue of Berlin-Mitte]. AB - On 1 March 1886, a new morgue built along the lines of the Paris morgue, was opened in Berlin, Germany. Experts from many European countries were interested in the new building with its modern design and equipment. As the morgue, the Institute of Legal Medicine of the Berlin University accommodated in the same building also acquired international reputation. However, neither the scientific nor the economic achievements of this long-standing institution could prevent the closure of this historic site in Berlin-Mitte after almost 125 years. PMID- 21661251 TI - [Medical and legal aspects of genital mutilation and circumcision. Part II: Male circumcision]. AB - In the last few years, male circumcision has become the subject of controversial discussion. On the one hand, medical and hygienic arguments, ideology, freedom of religion, cultural identity and social adequacy are claimed by those supporting male circumcision. On the other hand, the justification of this practice also has to be critically scrutinized just as the question whether the parents have the right to consent to the operation. Today, opinions range from those who claim that religion and culture alone justify the practice to those who consider circumcision of minors unable to give their consent as bodily injury subject to punishment. In contrast to female genital mutilation, most positions do not postulate that circumcision violates morality. If the person concerned is able to give his consent, freedom of religion may also justify circumcision after weighing its pros and cons as well as its risks and potential side effects. PMID- 21661253 TI - [Detection of latent fingerprints by the use of silver nitrate]. AB - Silver nitrate has been an established agent for the detection of latent fingerprints for some 120 years, and it was one of the few reagents suitable for use on porous surfaces until ninhydrin was introduced in forensics. The method is based on the reaction of silver ions with chlorides in the fingerprints, which are visualized in brown, violet or black. The literature describes many variations of the procedure, but the information provided is often vague and imprecise. The purpose of this study was to show whether this method can also be used on modern types of paper and how it should be applied. The results of the tests showed that silver nitrate solutions do work also on modern papers, but that they cannot be recommended as a standard, because the appearance of the prints and the paper background can strongly change in the course of time. The findings also do not justify the use of methanol-containing silver nitrate solutions in contrast to the variations based on water. For reasons of occupational safety, methanol, which is classified as poisonous, should not be used. The silver nitrate method may be taken into consideration, however, e.g. after the application of ninhydin, if there are hints that the potential fingerprints are not too old, have not been affected by moisture and if there are clues that the perpetrator perspired strongly while causing the prints. PMID- 21661254 TI - [Spontaneous Clostridium infection--often a post-mortem diagnosis]. AB - Infections with Clostridium species occur very seldom but then often as a lethal disease. They are mainly associated with trauma, surgery and malignancies, but can also occur with dermal and intestinal infections, burns and septic abortion. The development of gas gangrene is insidious and progression is very rapid. So it may stay unrealized until death and is often diagnosed only at autopsy. PMID- 21661252 TI - [Carbon monoxide poisoning from indoor barbecues--incidents reported to the German-speaking Poison Information Centers and the German Federal Institute for Risk Assessment (BfR) in Berlin]. AB - From 2008 to the end of 2009 the Joint Poison Information Center (PIC) in Erfurt observed 7 incidents involving 17 persons (1 fatality) with signs of carbon monoxide poisoning from indoor barbecues (COFIB). To find out whether COFIB is a regional or a general phenomenon in Germany, Austria and Switzerland, all information about COFIBs recorded by the 11 German-speaking Poison Information Centers and the BfR Berlin were retrospectively analyzed for the period 2000 to 2009. In all, 60 COFIBs (accidental: 90.0 %, suicidal: 8.3%, reason unknown: 1.7%) involving 146 individuals were reported. The number of incidents increased from one case with 2 persons in 2000 to 18 cases involving 34 persons in 2009. The 146 victims (female 26.7%, male 27.4%, gender unknown 45.9%; adults 58.2%, children 24.7%, age unknown 17.1%) lived in 15 of the 16 federal states of Germany and in Switzerland. The highest number of victims was found in Bavaria (23), Brandenburg (18), and Baden-Wuerttemberg (18). The symptoms according to the Poisoning Severity Score were none to mild in 60.3%, moderate in 13.7%, severe in 11.6%, fatal in 6.9% and unratable in 7.5%. No clear correlation was found between the carboxyhemoglobin concentration and the severity of the symptoms. As a rising number of COFIBs often involving several individuals was observed from 2000 to 2009, the general public was informed about the risks of indoor barbecues. PMID- 21661255 TI - [Reform of public health in Central Europe during the 18th century]. AB - Author outlines the history of making and of development of public health during the period of enlightenment in Central Europe, with special regards on the Habsurg Empire, on Poland and on Russia. This development--including the foundation or reforms of medical education--was highly influenced by the ideas of the enlightened absolutism and by other international trends of the age as well. The detailed analysis of the factors shaping the history of public health in the three rather different countries shows an interesing parallelism regarding main issues. While re-organization of public health in all these countries was initiated and directed by the government and shaped according to western models, it was strongly influenced by local possibilities, culture and history. PMID- 21661256 TI - [Proposals for inspecting pharmacies in Transylvania before the General Health Regulation of 1770]. AB - After sketching the history of the regulation of pharmacies in Hungary and in Transylvania during the Middle Ages and the 16-17. centuries, author analyses the attempts of the regulation of Translyvanian pharmacies during the second part of the 18th century including official and civil proposals for inspection of pharmacies written in the 1750ies by eminent Transylvanian physicians and pharmacists. These proposals were based on very informative reports written by Mihaly Felfalusi and Jozsef Zoltan--whose biographies are also attached and analysed here. Although these proposals--regarding their contents--mostly followed the scheme of the former Hungarian (and western) regulations, they contained lots of special local issues. The article--rich in details published first time--is illustrated by a supplement containing the original Latin texts of the reports and proposals and their Hungarian translations as well. PMID- 21661257 TI - [Anatomy of the skull]. AB - The anatomy of the human body based on a special teleological system is one of the greatest miracles of the world. The skull's primary function is the defence of the brain, so every alteration or disease of the brain results in some alteration of the skull. This analogy is to be identified even in the human embryo. Proportions of the 22 bones constituting the skull and of sizes of sutures are not only the result of the phylogeny, but those of the ontogeny as well. E.g. the age of the skeletons in archaeological findings could be identified according to these facts. Present paper outlines the ontogeny and development of the tissues of the skull, of the structure of the bone-tissue, of the changes of the size of the skull and of its parts during the different periods of human life, reflecting to the aesthetics of the skull as well. "Only the human scull can give me an impression of beauty. In spite of all genetical colseness, a skull of a chimpanzee cannot impress me aesthetically"--author confesses. In the second part of the treatise those authors are listed, who contributed to the perfection of our knowledge regarding the skull. First of all the great founder of modern anatomy, Andreas Vesalius, then Pierre Paul Broca, Jacob Benignus Winslow are mentioned here. The most important Hungarian contributors were as follow: Samuel Racz, Pal Bugat or--the former assistant of Broca--Aurel Torok. A widely used tool for measurement of the size of the skull, the craniometer was invented by the latter. The members of the family Lenhossek have had also important results in this field of research, while descriptive anatomy of the skull was completed by microsopical anatomy thanks the activity of Geza Mihalkovits. PMID- 21661258 TI - ["A man of exemplary zeal for the public good" -- Sandor Cseresnyes]. AB - Sandor Cseresnyes born on 15th September 1786 was one of the physicians of the first half of 19th century who efficiently practised in several scopes of activity. Having finished his studies at the college of Sarospatak he undertook family tutorship. In the autumn of 1814 he enrolled in the Medical Faculty for University of Pest together with his friend Laszlo Ungvarnemeti-Toth, a poet writing his poems in Hungarian and Greek. Besides being engaged in his studies he worked as a principal assistant at the eye-hospital of Ladies' Charity Association of Pest. In the autumn of 1818 he went to Vienna in order to obtain the medical certificate, however, in 1819 he was invited to go to county Somogy where he followed dominial doctor's activity until 1827. Meanwhile he finished his studies at Pest University in 1826. Utilizing his therapeutic experiences he wrote his medical dissertation on arthritis. He was appointed to chief medical officer of town Mako in 1827. The most part of the book which was the first comprehensive work of the Hungarian otological literature was written by him there. In 1831 at time of cholera-epidemic he practised so successfully in Horgos that not one single patient of his was lost. In 1832 he was appointed to a deputy chief physician of county Veszprem with a seat in Papa. He established there a hospital for nursing of psychotic patients and people with suspected rabies. He was among the first physicians who performed surgical interventions under unaesthesia using ether. His written communications were published in the local professional journals, some of his less extensive books on 'healing of rabies and snake-bite' and on 'the bath of Ugod' were also published. Moreover, he compiled a book comprising historical, geographical and literary selections on 'Somlo hill' being famous for its wine. He died in 1854. The Hungarian Society for Oto Rhino-Laringology treasures his memory also by giving Cseresnyes-commemorative medal to its praiseworthy members. PMID- 21661259 TI - [Monsters of Phlegon--hermaphrodites, sex-changers and other strange beings in Phlegon's marvellous stories]. AB - The 1st-2nd century greek writer, Phlegon was a representative of the genre "paradoxography". In his book entitled Peri thaumasion (Book of wonders) he collected 35 extraordinary stories among which he described hermaphrodites, sex changers and strange births. Phlegon's stories are only a part of the more than 79 ancient writings from Greek and Roman literature that describe children born with congenital defects. The article discusses the aspects of hermaphroditism in ancient times as well as ancient teratology. These stories might have had a core of truth. Although it is extremely difficult to identify a single potential cause for it, already ancient writers tried to give an explanation. With the help of modern teratology sciences many teratogenous causes can be partly identified. A part of the most probable factors among these were the same as today: malnutrition, viruses, alcohol, vitamin deficiencies etc., but lead poisoning has also be taken into account as a principal cause. PMID- 21661260 TI - [Magical and religious healing in Byzantium]. AB - Religious and magical ways of healing have been known and practiced since the very beginning of human history. In the present article, the Byzantine philosophical, cultural, historical and "methodological" aspects of this way of healing are discussed. The article outlines the development of magic healing in Byzantium from the 4th to the 15th century. During this period magical therapy included the cult of patron saints--listed by the author--and pleading for divine intervention as well. The activity of "anargyroi" and the use of magical objects and amulets is also discussed in detail. Exorcism was also a part of religious therapy both against psychical and somatical diseases. In early Christianity, and especially in Byzantium the devil or other demons were also supposed to cause various somatical or psychical illnesses by "intrusion" or "internalisation," i.e. by possession or obsession of their victims. PMID- 21661261 TI - [Andras Josa, the physician]. AB - Andras Josa was the most important and renowned physician in county Szabolcs (Hungary) in the 19th-20th centuries. Author outlines his biography and analyses his medical activity. Present article is based on a memorial lecture given at the meeting of the Hungarian Society for the History of Medicine in Budapest 24th September 2009. PMID- 21661262 TI - [Contagious diseases in the Austro-Hungarian Army during the First World War]. AB - Before the WWI significantly more loss was caused to armies by various epidemies, than by weapons. Although as a result of development of medical sciences in the WWI this rate changed, the main epidemies namely cholera, malaria and trachoma still ravaged quite often. In spite of the fact, that alimentation of Austro Hungarian soldiers gradually deteriorated during the war, so they fell victims more easily to diseases, the sanitary service successfully prevented outbreaks of larger epidemies. PMID- 21661263 TI - [Once upon a time there was a medical faculty--a brief history of the Medical Faculty of the Erzsebet University in Pressburg (1914-1919)]. AB - Despite the fact that the idea of expanding the medical faculties of Budapest and Kolozsvar was formed in the 1870s, it only came true in the 1910s. The XXXVI. Law of 1912 ensured establishing new faculties in Pozsony and Debrecen. The medical faculty of Erzsebet University in Pozsony opened in 1914. The first three professors, i.e. Lajos Bakay, Ferenc Herzog and Dezso Velits, who formerly worked as head physicians for the State Hospital in Pozsony and the Institute for Midwives, were appointed then. The appointment of further professors and launching the 3rd, 4th and 5th forms were delayed by the outbreak of the war until 1918. After the collapse of the Austro-Hungarian Monarchy the newly formed Czechoslovakia dissolved the Hungarian university in 1919. The clinics and institutes of the medical faculty were passed to Czechoslovak ownership, the Hungarian lecturers were dismissed. It is worth mentioning though that Albert Szent-Gyorgyi and Carl Ferdinand Cori (both Nobel Prize winners) started their scientific career in Pozsony. PMID- 21661264 TI - [Tibor Peterfi, the founder of micromanipulation]. AB - Tibor Peterfi (1883-1953) was an eminent and internationally renowned biologist. He made great advances in the field of experimental physiology focusing his cytological research on microscopic examination of living cells. For this task, he created a tool named micromanipulator basing the development of microsurgery and that of cell surgery as well. His histological and cytological researches took their beginning first in Kolozsvar/Cluj (then Hungary, now Romania), where he worked as an assistant of professor Istvan Apathy then in Budapest where he spent fruitful years under the tutorship of professor Mihaly Lenhossek. His scientific career however was broken by the political persecution which followed the fall of the communist revolution in 1919. He emigrated and spent the following decades in Prague, in Jena, in Berlin and in Cambridge. The apogee however of his scientific career proved to be the period he spent in Istanbul as a guest professor of the local university. He returned home only after the war already mortally ill. His illness did not allow him to continue his activity any more. Present article evaluates Tibor Peterfi's scientific achievements based mostly on recent archival researches. PMID- 21661265 TI - A call to action to assure our future. PMID- 21661266 TI - Dose reduction and cone beam CT: perception is reality. PMID- 21661267 TI - NAPNAP position statement on the acute care pediatric nurse practitioner. PMID- 21661268 TI - NAPNAP position statement on supporting children and families in early care and education. PMID- 21661269 TI - Drug-induced thrombocytopenia: an updated systematic review, 2010. PMID- 21661270 TI - Outbreak news.Ebola, Uganda. PMID- 21661271 TI - Review of the 2010-2011 winter influenza season, northern hemisphere. PMID- 21661272 TI - Meeting of the WHO Human Papillomavirus Vaccine Advisory Committee, April 2010. PMID- 21661273 TI - Monthly report on dracunculiasis cases, January-March 2011. PMID- 21661274 TI - Targeting influenza in Africa: strategic actions for assessing the impact of the disease and for developing control measures. PMID- 21661275 TI - Surveillance of drug resistance in leprosy: 2010. PMID- 21661276 TI - Vaccines against tick-borne encephalitis: WHO position paper. PMID- 21661278 TI - Rose Mary's lessons continue in those she mentored. PMID- 21661277 TI - [2011: not just PRAXIS, also dopa turns 100 years old...]. PMID- 21661279 TI - Nursing informatics 101. Using technology to improve patient care. PMID- 21661280 TI - Why should nurses be involved in informatics? PMID- 21661281 TI - Survivors seeking cancer information online can experience disenchantment, empowerment. PMID- 21661282 TI - Learn more about informatics on these websites. PMID- 21661283 TI - The case of the uncontrolled nausea and vomiting. PMID- 21661284 TI - Cancer survivors find blogging improves quality of life. PMID- 21661285 TI - 31 million new patients are coming. Are you prepared? PMID- 21661286 TI - Online healthcare: a new wave in convenience. PMID- 21661288 TI - Diabetes Insipidus. Navigating troubled waters. PMID- 21661287 TI - CMS incentives for quality care: get started now. PMID- 21661289 TI - Glucosamine for osteoarthritis. Select carefully for best results. PMID- 21661290 TI - Lupus in adolescents. PMID- 21661291 TI - Smoking cessation pharmacotherapy: a concise overview. PMID- 21661292 TI - Checking lipids after statins. Is 90 days too long to wait? PMID- 21661293 TI - Your journey is just beginning: getting your ducks in a row. PMID- 21661294 TI - What not to wear. At an interview, clothes make the man or woman. PMID- 21661295 TI - Cover up. Are you adequately protected from a lawsuit? PMID- 21661296 TI - Top 10 things I've learned. A senior student shares insight about his clinical rotations. PMID- 21661297 TI - The affordable care act: background and analysis. PMID- 21661298 TI - Sexual risk factors for HIV and violence among Puerto Rican women in New York City. AB - The authors examined sexual factors for HIV risk in 1,003 women of Puerto Rican heritage who attended a community-based NewYork City hospital clinic. Participants' ages ranged from 18 to 73 years. Half were born in the continental United States, and half were born in the Commonwealth of Puerto Rico. All were sexually active within the past 90 days with a male partner.The authors compared sociodemographic characteristics, experience of intimate partner violence (IPV), and HIV sexual risk factors (number of partners, history of sexually transmitted infections [STIs],condom use, and so on).Multiple regression analyses considering sociodemographic characteristics were a predictor for IPV and sexual risk behaviors. The authors found differences in sexual risk behaviors by place of birth (continental United States versus Commonwealth of Puerto Rico) and language chosen for the interview (Spanish or English).Puerto Rican women reported fewer sexual partners and STIs. Mainland-born and English-preference women reported more IPV, risky partners, and condom use. Birth in the continental United States and preference for English appear to be indicators of greater risk for IPV, risky sexual practices, and risky partners. HIV prevention intervention strategies for Puerto Rican women must address differences in heterosexual risk according to language and place of birth. PMID- 21661299 TI - Health literacy: critical opportunities for social work leadership in health care and research. AB - One-third of U.S. adults do not have adequate health literacy to manage their health care needs; and low health literacy is a major concern due to its association with poor health outcomes, high health care costs, and health communication problems. Low health literacy is a potential driver of health disparities, and its alleviation is central to the values and concerns of the social work profession. Despite the extensive knowledge and skills that social workers can bring to bear to assist patients with low health literacy, the concept of health literacy is underused in social work scholarship.This gap reflects missed opportunities for social workers to contribute their expertise to the evolving field of health literacy and to strategically align their work with organizational and national priorities.To address this gap, this article provides an overview of health literacy, its relevance to social work, and its representation in disciplinary literature; and it outlines opportunities for health social workers to systematically incorporate health literacy concepts and tools into their practices with patients and families. Implications for a social work research and practice agenda in health literacy are discussed. PMID- 21661301 TI - Contextual influences on women's health concerns and attitudes toward menopause. AB - Social factors that affect women's attitudes toward menopause were examined in a sample of 1,037 baby boomer women who took part in two waves of the Midlife in the United States survey. Survey data were collected in 1996 and 2005 from a nationally representative sample of women born between 1946 and 1964 residing in the United States. Women's attitudes toward the effects of menopause on fertility, health, and attractiveness were examined. Analyses supported a two factor model ofwomen's adaptation to menopause: attitudes concerning the effects of menopause on fertility and the cessation of menstruation had different antecedents than attitudes concerning the impact of menopause on health and attractiveness. Women who had more positive attitudes regarding loss of fertility occupied more roles, were older, less educated, yet more secure financially. Women who had more positive views of the effects of menopause on health and attractiveness reported fewer symptoms of menopause. These analyses were replicated in waves 1 and 2 of the data set. Results may be helpful to social work practitioners and social work policy advocates. PMID- 21661300 TI - Multimorbidity and persistent depression among veterans with diabetes, heart disease, and hypertension. AB - This study investigated the association between multimorbidity and persistent depression among cohorts of veterans with diabetes, heart disease, or hypertension. The retrospective longitudinal analysis used national administrative data on around 1.38 millionVeteran Health Administration clinic users merged with Medicare claims data. Multimorbidity was defined as the concurrent presence of two or more chronic conditions (for example, diabetes, heart disease, or hypertension). Chi-square tests and multinomial logistic regressions analyzed the odds in tested relationships. Of all veterans, 5.6 percent were diagnosed with persistent depression. Persistent depression was significantly more likely among veterans with multimorbidity than among those with only hypertension.Veterans with multiple chronic conditions have intensive, long-term health care needs due to persistent depression and, thus, require extensive coordination across a broad spectrum of services. PMID- 21661302 TI - Cumulative adverse financial circumstances: associations with patient health status and behaviors. AB - This article examines associations between cumulative adverse financial circumstances and patient health in a sample of 1,506 urban emergency department (ED) patients. Study participants completed a previously validated Social Health Survey between May and October 2009. Five categories of economic deprivation were studied: food insecurity, housing concerns, employment concerns, cost-related medication nonadherence, and cost barriers to accessing physician care. Logistic regression that adjusted for the effects of demographics (age, gender, race, education) tested the association between the cumulative number of adverse financial circumstances (range: 0 to 5) and patients' health status (self-rated health, stress level, depressed mood) and health behaviors (smoking and substance abuse). Approximately 48 percent of respondents reported one or more financial concern, and 31 percent reported two or more financial concerns. A significant graded relationship was found between the number of adverse financial circumstances and patients' poor/fair self-rated health, depressed mood, high stress, smoking, and illicit drug use. Findings suggest that in today's acute health safety net, patients' concerns related to financial insecurity are very relevant to patient health.This underscores the imperative for hospital-based social workers to design models of routine social health risk screening and system interventions that address patient financial well-being in the ED. PMID- 21661303 TI - Poststroke depression: social workers' role in addressing an underrecognized psychological problem for couples who have experienced stroke. AB - Depression is the most common psychological challenge faced by many individuals and families following stroke. Fortunately, poststroke depression is treatable, and even preventable, if social work and other rehabilitation practitioners understand the most common risk factors and become familiar with measures for assessing for depression among patients with medical comorbidities such as stroke.The purpose of this article is to raise awareness among readers about the strong potential for depression following stroke and to provide an overview of common assessment measures. On the basis of increasing numbers of patients being cared for by informal caregivers following discharge from inpatient care facilities, growing evidence of the interconnectedness of couples' emotional well being and the significance of couples-level factors like relationship quality and coping in the well-being of couples experiencing stroke, and current needs for effective interventions for poststroke depression, a secondary purpose of this article is to describe the importance of assessing and treating survivors in the context of their committed relationships. PMID- 21661304 TI - HIV/AIDS interventions in an aging U.S. population. AB - According to the Centers for Disease Control and Prevention (CDC), 25 percent of people living with HIV in the United States in 2006 were age 50 and older. HIV prevention for people over 50 is an important health concern, especially as the U.S. population grows older. Scholarly research has identified the need for HIV/AIDS interventions in the population of people over age 50, but few interventions have been established. The ecological perspective, which integrates intrapersonal, interpersonal, organizational, community, and policy factors, was used to review the current interventions and propose possible new HIV/AIDS prevention efforts for older adults. Intrapersonal interventions are often based on the health belief model. The precaution adoption process model was explored as an alternative intrapersonal theory for modeling prevention efforts. Community interventions using diffusion of innovations theory are fully explored, and new interventions are proposed as an option for preventing HIV/AIDS in older adults. An agenda for future research and interventions is proposed. Social workers will be at the forefront of the effort to prevent HIV/AIDS in older adults. They must accept this responsibility, propose interventions, and evaluate their effectiveness. PMID- 21661305 TI - Advancing HIV/AIDS domestic agenda: social work and community health workers unite. PMID- 21661306 TI - Pheromone gland development and pheromone production in lutzomyia longipalpis (Diptera: Psychodidae: Phlebotominae). AB - The sand fly Lutzomyia longipalpis (Lutz & Neiva) (Diptera: Psychodidae: Phlebotominae) is the main vector of American visceral leishmaniasis. Adult males produce a terpenoid sex pheromone that in some cases also acts as male aggregation pheromone. We have analyzed the correlation between male pheromone production levels and pheromone gland cell morphogenesis after adult emergence from pupae. The abdominal tergites of L. longipalpis males were dissected and fixed in glutaraldehyde for transmission electron microscopy, or the pheromone was extracted in analytical grade hexane. Pheromone chemical analysis was carried out at 3- to 6-h intervals during the first 24 h after emergence and continued daily until the seventh day. All extracts were analyzed by gas chromatography. For the morphological analysis, we used insects collected at 0-6, 9-12, 12-14, and 96 h after emergence. Ultrastructural data from 0- to 6-h-old adult males revealed smaller pheromone gland cells with small microvilli at the end apparatus. Lipid droplets and peroxisomes were absent or very rare, but a large number of mitochondria could be seen. Lipid droplets started to appear in the gland cells cytoplasm approximately 9 h after adult emergence, and their number and size increased with age, together with the presence of several peroxisomes, suggesting a role for these organelles in pheromone biosynthesis. At 12-15 h after emergence, the lipid droplets were mainly distributed near the microvilli but were smaller than those in mature older males (4 d old). Pheromone biosynthesis started around 12 h after emergence and increased continuously during the first 3 d, stabilizing thereafter, coinciding with the period when males are more able to attract females. PMID- 21661307 TI - Ultrastructural localization of basic proteins and carbohydrates in male accessory glands of two Triatoma species (Hemiptera, Reduviidae, Triatominae). AB - The male accessory glands in Triatoma are tubular and produce substances with some functions related to production of the spermatophore. In the current study, the cytochemistry of male accessory glands was evaluated in starved Triatoma brasiliensis and adult Triatoma melanica. The storage of carbohydrates and proteins in T. melanica male accessory glands occurs earlier than in T. brasiliensis. In addition, the occurrence of eletron-lucent granules without carbohydrates and proteins suggests that other substances are released by these glands, which may be used for lubrication of the male genitalia. Male T. brasiliensis has more intense secretory activity in the fifth day of adult life, which may indicate a higher reproductive capacity. The analysis of lipid production in male accessory glands can contribute to the knowledge of spermatophore formation in these species. PMID- 21661308 TI - Tick infestation on wild snakes in northern part of western Ghats of India. AB - In total, 167 individuals of 30 species of snakes belonging to 22 genera and five families were examined for tick infestation from November 2008 to March 2010. Only two species of snakes, Ptyas mucosa (L., 1758) (Indian rat snake) and Naja naja (L., 1758) (spectacled cobra), were found infested by ticks. All ticks collected were identified to be Amblyomma gervaisi [previously Aponomma gervaisi (Lucas, 1847) 1. The average prevalence of these ticks on Indian rat snakes (n=48) was 29.16%, with abundance of 7.02 ticks per individual; on spectacled cobras (n=20), average prevalence was 30.00%, with abundance of 6.9 ticks per individual. The nymphs and males were predominant. All the ticks were found on the dorsal aspect of the body of the snake, and no ticks were recorded on the head, tail, or ventral body. The rate of tick infestation was highest in scrubland and was lowest in evergreen forests. Female Indian rat snakes showed higher tick infestation rates than male Indian rat snakes. Using Mann-Whitney U test, we found that longer snakes of both species had significantly higher rate of tick infestation in both the species of snakes. PMID- 21661309 TI - Sampling high-altitude and stratified mating flights of red imported fire ant. AB - With the exception of an airplane equipped with nets, no method has been developed that successfully samples red imported fire ant, Solenopsis invicta Buren, sexuals in mating/dispersal flights throughout their potential altitudinal trajectories. We developed and tested a method for sampling queens and males during mating flights at altitudinal intervals reaching as high as "140 m. Our trapping system uses an electric winch and a 1.2-m spindle bolted to a swiveling platform. The winch dispenses up to 183 m of Kevlar-core, nylon rope and the spindle stores 10 panels (0.9 by 4.6 m each) of nylon tulle impregnated with Tangle-Trap. The panels can be attached to the rope at various intervals and hoisted into the air by using a 3-m-diameter, helium-filled balloon. Raising or lowering all 10 panels takes approximately 15-20 min. This trap also should be useful for altitudinal sampling of other insects of medical importance. PMID- 21661311 TI - Behavioral evidence for the presence of a sex pheromone in male Phlebotomus papatasi scopoli (Diptera: Psychodidae). AB - Phlebotomus papatasi (Diptera: Psychodidae) is the Old World sand fly vector of zoonotic cutaneous leishmaniasis caused by Leishmania major (Trypanosomatidae: Kinetoplastida), a debilitating and disfiguring protist parasitic disease prevalent throughout southern Mediterranean countries, the Middle East, as well as southern and eastern European countries, where it is regarded as a serious public health problem. Little is known of the mating ecology of P. papatasi, and, in particular, the role (if any) of pheromones is not known. In this laboratory- and field-based study, we have shown that a male-produced sex pheromone exists in P. papatasi. Young female P. papatasi are attracted to the headspace volatiles of small groups of males, males and females together, but not females alone. Males were not attracted to males, females, or mixed groups of males and females in the laboratory. Larger groups of males or males and females together were repellent in the laboratory study. Field experiments showed that Centers for Disease Control (CDC) light traps baited with small groups of males and females together were attractive to females, but not males. CDC traps baited with large groups of males and females together caught significantly fewer females and males than the control traps; however, the proportion of females caught compared with males overall was much higher than with CDC traps baited with small numbers of males and females. These results suggest that females may be attracted in preference to males to the vicinity of the baited traps and are highly sensitive to the concentration of male pheromone. It also suggests that P. papatasi mating behavior is fundamentally different from that of Lutzomyia longipalpis, where large mating aggregations of males and females occur. PMID- 21661310 TI - Bloodmeal host congregation and landscape structure impact the estimation of female mosquito (Diptera: Culicidae) abundance using dry ice-baited traps. AB - Vegetation patterns and the presence of large numbers of nesting herons and egrets significantly altered the number of host-seeking Culex tarsalis Coquillett (Diptera: Culicidae) collected at dry ice-baited traps. The numbers of females collected per trap night at traps along the ecotone of Eucalyptus stands with and without a heron colony were always greater or equal to numbers collected at traps within or under canopy. No Cx. tarsalis were collected within or under Eucaplytus canopy during the peak heron nesting season, even though these birds frequently were infected with West Nile virus and large number of engorged females could be collected at resting boxes. These data indicate a diversion of host-seeking females from traps to nesting birds reducing sampling efficiency. PMID- 21661312 TI - Behavioral differences of invasive container-dwelling mosquitoes to a native predator. AB - Aquatic prey show behavioral modifications in the presence of predation-risk cues that alleviate their risk from predation. Aedes albopictus (Skuse), Aedes japonicus (Theobald), and Culex pipiens L. are invasive mosquitoes in North America, and their larvae are prey for the native mosquito predator, Toxorhynchites rutilus (Coquillett). Ae. albopictus and Ae. japonicus are recent invaders, whereas Cx. pipiens has been in the United States for >100 yr. In the presence of predation-risk cues from Tx. rutilus larvae, Cx. pipiens larvae increased the time spent resting at the surface (least risky behavior) more than the other prey species. Ae. japonicus larvae increased resting at the surface of the containers more than Ae. albopictus larvae in the presence of predation-risk cues. Cx. pipiens larvae spent more time motionless at the surface even in the absence of predation-risk cues when compared with the other species, indicating that Cx. pipiens larvae are the least vulnerable prey. As compared with the other prey species, Ae. albopictus larvae exhibited more high-risk behaviors both in the presence and absence of predation-risk cues, indicating that they are the most vulnerable prey. Ae. albopictus is the superior competitor; however, predation by Tx. rutilus larvae may prevent competitive exclusion by Ae. albopictus and promote coexistence among the three prey species. PMID- 21661313 TI - Changes in host-seeking behavior of Puerto Rican Aedes aegypti after colonization. AB - The effects of colonization on host-seeking behavior of mosquitoes was examined by comparing attraction responses of newly colonized Aedes aegypti (L.) from field-collected eggs in Puerto Rico to that of the Gainesville (Florida) strain, originally from Orlando (Florida) and in colony since 1952. Females from the Orlando and the F0 through F10 generations of the Puerto Rico strain were evaluated using attractant odors in a triple-cage dual-port olfactometer. Two attractant sources were used: odors from the hand of a volunteer and a standard blend of L-lactic acid, acetone, and dimethyl disulfide. Convergence of the percentage of attraction responses occurred around the F4-F6 generations of the Puerto Rico strain. Both the Orlando and Puerto Rico strains exhibited similar responses for tests with the remaining F7-F10 generations. A temporal effect on mosquito responses was observed for both strains regardless of the attractant blend used in tests. This study indicates that Ae. aegypti host-seeking behavior changes significantly over the first four to six generations after introduction into the laboratory, whereas the field-collected strain increases in attraction response until it stabilizes at a new level. PMID- 21661314 TI - Impact of phlebotomine sand flies on United States military operations at Tallil Air Base, Iraq: 5. Impact of weather on sand fly activity. AB - In this study, we examined the effect of weather and moon illumination on sand fly activity, as measured by light trap collections made between 2 May 2003 and 25 October 2004 at Tallil Air Base, Iraq. Wind speed, temperature, dew point, percentage of sky cover, and moon illumination were entered into principal components analysis. The resulting principal components were entered into stepwise regression to develop a model of the impact of the weather on sand fly collections. Wind speed, percentage of sky cover, and moon illumination each had a strong inverse relationship with the number of sand flies collected, whereas temperature displayed a direct relationship to sand fly collections. Our data indicate that sand fly light trap catches at Tallil Air Base are highest on warm, clear nights with low wind speed and minimal illumination from the moon. PMID- 21661315 TI - Identification and transcription profiling of trypsin in Aedes taeniorhynchus (Diptera: Culicidae): developmental regulation, blood feeding, and permethrin exposure. AB - The cDNA of a trypsin gene from Aedes (Ochlerotatus) taeniorhynchus (Weidemann) was cloned and sequenced. The full-length mRNA sequence (890 bp) for trypsin from Ae. taeniorhynchus (AetTryp1) was obtained, which encodes an open reading frame of 765 bp (i.e., 255 amino acids). To detect whether AetTryp is developmentally regulated, a quantitative real-time polymerase chain reaction was used to examine AetTrypl mRNA expression levels in different developmental stages of Ae. taeniorhynchus. AetTryp1 was expressed at low levels in egg, larval, and pupal stages, but was differentially expressed in adult Ae. taeniorhynchus, with highest levels found in 5-d-old female adults when compared with teneral adults. In addition, AetTryp1 mRNA expression differed between sexes, with expression levels much lower in males. However, in both males and females, there was a significant increase in AetTryp1 transcription levels as age increased and peaked in 5-d-old adults. AetTrypl expressed in 5-d-old female Ae. taeniorhynchus significantly increased after 30 min postblood feeding compared with the control. The AetTryp1 mRNA expression in 5-d-old female Ae. taeniorhynchus was affected by different concentrations of permethrin. PMID- 21661316 TI - The potential of cladocerans as controphic competitors of the mosquito Culex pipiens. AB - This study assesses the potential of cladocerans as competitors for controlling the oviposition and larval abundances of mosquitoes. Control of mosquito larvae involving the use of antagonists has focused mostly on predators. We hypothesized that cladoceran competitors have a strong potential to control larval populations of some species of mosquitoes that can be early colonizers of newly-filled waterbodies, and should be less efficient competitors. To test this hypothesis, the establishment and development of larval populations of wild Culex pipiens were investigated in outdoor microcosms varying in terms of Daphnia magna populations. When the population was well established (i.e., high densities of D. magna), oviposition was fully inhibited and there was consequently no mosquito larvae. When the population was more recently established (i.e., lower densities of D. magna), oviposition and larval development of Cx. pipiens occurred. In the absence of D. magna, oviposition, larval biomass, and abundance of Cx. pipiens reached high values. In this situation, conspecifics were inhibiting further oviposition of Cx. pipiens. Based on these results, we suggest that competing zooplankton species, such as D. magna, could be used for the control of mosquito species such as Cx. pipiens. This approach could be beneficial for the management of wetlands. PMID- 21661317 TI - Glutathione S transferase activity in Indian vectors of malaria: A defense mechanism against DDT. AB - Glutathione S transferases (GSTs) are multifunctional enzymes involved in detoxification of xenobiotic compounds in majority of the insect groups. Significance of insect GSTs is their elevated level of activity in association with insecticide resistance. This investigation was to explore the metabolic status of GSTs in two Indian DDT-resistant malaria vectors, Anopheles culicifacies and Anopheles annularis, and one DDT-susceptible vector, Anopheles fluviatilis. Malkangiri and Koraput districts of Orissa State, endemic for falciparum malaria and having a long insecticide spraying history, were the study areas. F1 progeny was raised from wild-caught females of the three vectors and used for biochemical assays to detect the GST-mediated DDT resistance mechanism. Results of the enzyme assay showed a significant 3-fold increase in GST activity in DDT-resistant An. annularis compared with its susceptible population. In DDT resistant An. culicifacies, the median GST activity (71.8 micromol/min/mg) was almost the same as estimated in the DDT-resistant An. annularis (74.6 micromol/ min/mg), suggesting that the GST activity estimated in An. culicifacies could be an elevated level for detoxification of DDT. Furthermore, the GST activity in DDT resistant An. culicifacies and An. annularis was significantly higher than that in the DDT-susceptible An. fluviatilis, which had a GST activity of 20.0 micromol/min/mg. Also, the GST-mediated DDT detoxification was confirmed by comparing GST activity in wild-caught females with that in their F1 progeny. PMID- 21661318 TI - Spinosad toxicity to Simulium spp. larvae and associated aquatic biota in a coffee-growing region of Veracruz State, Mexico. AB - Spinosad is a naturally derived insecticide that has shown potential as a mosquito larvicide. To determine the activity of spinosad against blackflies, late-instar larvae from a community comprising Simulium triittatum (63.6%) and seven other species, including three known vectors of onchocerciasis in Mexico (S. metallicum, S. ochraceum, and S. callidum), were subjected to concentration mortality laboratory bioassays following World Health Organization guidelines. Cephalic capsule measurements confirmed the relatively homogeneous distribution of experimental larvae. The 50% lethal concentration of spinosad was estimated at 1.48 ppm spinosad (95% confidence interval: 1.07-2.33) for a 10-min exposure period, whereas larvae treated with 0.05 ppm of the organophosphate temephos experienced 61% mortality. Immature aquatic insects were identified to genus and tested for their susceptibility to spinosad in the laboratory. After exposure to 12 ppm spinosad for 10 min, ephemeropterans, odonates, trichopterans, and hemipterans did not experience significantly increased mortality over that of untreated controls, whereas a significant increase in mortality was observed in spinosad-treated Plecoptera (P < 0.001). Tilapia and trout fry exposed to 12 ppm spinosad for 10 min did not experience increased mortality at 24-h postexposure over that of the controls. We conclude that spinosad is less toxic than temephos to these blackfly species, but is likely to have a low impact on nontarget members of the aquatic community. PMID- 21661319 TI - A new strategy for Aedes aegypti (Diptera: Culicidae) control with community participation using a new fumigant formulation. AB - Dengue and dengue hemorrhagic fever are mosquito-borne viral diseases that coincide with the distribution of Aedes aegypti (L.), the primary vector in the tropical and semitropical world. With no available vaccine, controlling the dengue vector is essential to avoid epidemics. This study evaluates the efficacy of a new smoke-generating formulation containing pyriproxyfen and permethrin in Puerto Libertad, Misiones, Argentina. A fumigant tablet (FT) was applied inside the houses by the community members and compared with a professional application. A treatment combining the application of fumigant tablets indoors and ultralow volume fumigation outdoors was also assessed. The community perceptions and practices about dengue disease and the acceptance of this new nonprofessional FT were evaluated through surveys. Results show >90% adult emergence inhibition and 100% adult mortality with these treatments. More than 80% of the residents applied the FT and preferred participating in a vector control program by using a nonprofessional mosquito control tool, instead of attending meetings and workshops promoting cultural changes. PMID- 21661320 TI - Impact of phlebotomine sand flies on United State military operations at Tallil Air Base, Iraq: 6. Evaluation of insecticides for the control of sand flies. AB - We conducted a series of field experiments in 2003 and 2004 to evaluate the efficacy of a variety of insecticides and insecticide application technologies for the control of phlebotomine sand flies at Tallil Airbase, Iraq. During the experiments, 53,263 sand flies were collected. The experiments evaluated the following: (1) routine sand fly control operations using a variety of residual and area-wide insecticides; (2) a combination of five different insecticide application methods in and around tents; (3) residual application of lambda cyhalothrin and ultra-low volume application of pyrethrins in houses; (4) carbaryl and lambda-cyhalothrin applied as barrier sprays; (5) a deltamethrin impregnated fence; (6) lambda-cyhalothrin applied as a residual spray in concrete manholes; (7) deltamethrin-treated flooring in tents; and 8) ultra-low volume applied malathion. Although some of the experiments resulted in limited reductions in the number of sand flies collected in light traps, in no instance did we completely eliminate sand flies or reduce populations for a sustained period. The implications of these findings are discussed. PMID- 21661322 TI - Persistence of low-pathogenic avian influenza H5N7 and H7N1 subtypes in house flies (Diptera: Muscidae). AB - Avian influenza caused by avian influenza virus (AIV) has a negative impact on poultry production. Low-pathogenic AIV (LPAIV) is naturally present in wild birds, and the introduction of the virus into domestic poultry is assumed to occur through contact with wild birds and by human activity, including the movement of live and dead poultry, and fomites such as clothing and vehicles. At present, the possible role of insects in the spread of AIV is dubious. The objective of the present work was to investigate the potential transmission of LPAIV by persistence of the virus in the alimentary tract of house flies, Musca domestica L. (Diptera: Muscidae). Flies were fed three virus concentrations of two AIV strains and then incubated at different temperatures for up to 24 h. The persistence of the two virus strains in the flies declined with increasing incubation temperatures and incubation periods. Similarly, increased virus uptake by the flies increased the persistence of virus. Persistence of infective AIV in flies differed significantly between the two virus strains. The laboratory experiments of the present study indicate that the house fly can be a potential carrier of AIV. PMID- 21661321 TI - Entomological study on transmission of avian malaria parasites in a zoological garden in Japan: bloodmeal identification and detection of avian malaria parasite DNA from blood-fed mosquitoes. AB - Several species of captive and wild birds have been found to be infected with various avian blood protozoa in Japan. We investigated the prevalence and transmission of avian malaria parasite and determined the bloodmeal hosts of mosquitoes collected in a zoological garden in Tokyo, Japan, by using the polymerase chain reaction. In total, 310 unfed and 140 blood-fed mosquitoes of seven species were collected by using sweep nets and CDC traps. Bloodmeal identification indicated that mosquitoes had fed on 17 avian and five mammalian species, including captive animals. The results of avian malaria parasite detection from mosquitoes with avian bloodmeals indicated that Culex pipiens pallens Coquillet is a main vector of avian Plasmodium in the current study site and that some captive and wild birds could be infected with avian malaria parasites. Furthermore, the distances between the collection site of blood-fed mosquitoes and the locations of their blood-source captive animals were estimated. Most females with fresh bloodmeals were found within 40 m of caged animals, whereas half-gravid and gravid females were found between 10 and 350 m from caged host animals. We demonstrated that blood-fed mosquitoes can provide useful information regarding the mosquito vector species of avian malaria parasites and allows for noninvasive detection of the presence of avian malaria parasites in bird populations. PMID- 21661323 TI - Microclimate and the zoonotic cycle of tick-borne encephalitis virus in Switzerland. AB - The focal distribution of tick-borne encephalitis virus (TBEV; Flaviviridae, Flavivirus) appears to depend mainly on cofeeding transmission between infected Ixodes ricinus L. nymphs and uninfected larvae. To better understand the role of cofeeding ticks in the transmission of TBEV, we investigated tick infestation of rodents and the influence of microclimate on the seasonality of questing I. ricinus ticks. A 3-yr study was carried out at four sites, including two confirmed TBEV foci. Free-living ticks and rodents were collected monthly, and microclimatic data were recorded. A decrease in questing nymph density was observed in 2007, associated with low relative humidity and high temperatures in spring. One site, Thun, did not show this decrease, probably because of microclimatic conditions in spring that favored the questing nymph population. During the same year, the proportion of rodents carrying cofeeding ticks was lower at sites where the questing nymph density decreased, although the proportion of infested hosts was similar among years. TBEV was detected in 0.1% of questing ticks, and in 8.6 and 50.0% of larval ticks feeding on two rodents. TBEV was detected at all but one site, where the proportion of hosts with cofeeding ticks was the lowest. The proportion of hosts with cofeeding ticks seemed to be one of the factors that distinguished a TBEV focus from a non-TBEV focus. The enzootic cycle of TBEV might be disrupted when dry and hot springs occur during consecutive years. PMID- 21661324 TI - Wicking assay for the rapid detection of Rift Valley fever viral antigens in mosquitoes (Diptera: Culicidae). AB - Rift Valley fever virus (RVFV) causes outbreaks of severe disease in domestic ungulates as well as humans in Africa. There is a logical concern that RVFV could be introduced into the Americas and cause significant health and economic damage based on the precedent of the introduction and spread of West Nile virus (WNV). Unfortunately, there are currently no licensed diagnostic assays available for RVFV in the Americas. In this work, we report on the ability of a novel dipstick assay, VectorTest RVFV antigen assay, modeled on the VecTest assay for WNV, to detect a RVFV-infected female within a pool of mosquitoes. The dipsticks provided results in <20 min, were easy to use, and did not require a laboratory with containment facilities. Although readily able to detect a mosquito with a disseminated RVFV infection, it only occasionally detected RVFV in a mosquito with a nondisseminated infection, and therefore may fail to detect some pools that actually contain one or more positive mosquitoes. The RVFV dipstick assay was highly specific and did not react with samples to which had been added yellow fever, West Nile, Venezuelan equine encephalitis, sandfly fever Naples, sandfly fever Sicilian, or sandfly fever Toscana viruses. The RVFV assay can provide a rapid, safe, easy-to-use assay to alert public health personnel to the presence of RVFV in mosquitoes. Results from this assay will allow a rapid threat assessment and the focusing of vector control measures in high-risk areas. PMID- 21661325 TI - Distribution of Culicoides sonorensis (Diptera: Ceratopogonidae) in Nebraska, South Dakota, and North Dakota: clarifying the epidemiology of bluetongue disease in the northern Great Plains region of the United States. AB - The presence or absence of the biting midge Culicoides sonorensis Wirth & Jones (Diptera: Ceratopogonidae), a primary vector of bluetongue viruses (genus Orbivirus, family Reoviridae, BTV) in North America, was assessed on ranches and farms across the Northern Great Plains region of the United States, specifically Nebraska, South Dakota, and North Dakota, as part of a 2-yr regional study of BTV exposure among cattle. Blacklight/suction trap samples totaling 280 2-night intervals were taken at 140 aquatic sites (potential larval habitat for C. sonorensis) on 82 livestock operations (ranches and farms) that span a south-to north gradient of expected decreasing risk for exposure to BTV. In Nebraska, C. sonorensis populations were common and widespread, present at 15 of 18 operations. Of 32 operations sampled in South Dakota, seven of which were sampled in successive years, 18 were positive for C. sonorensis; 13 of 14 operations located west of the Missouri River were positive, whereas 13 of 18 operations east of the river were negative. Of 32 operations sampled in North Dakota, seven of which were sampled both years, 12 were positive for C. sonorensis. Six of eight operations located west and south of the Missouri River in North Dakota were positive, whereas 18 of 24 operations east and north of the river were negative for C. sonorensis. These data illustrate a well-defined pattern of C. sonorensis spatial distribution, with populations consistently present across Nebraska, western South Dakota, and western North Dakota; western South Dakota, and North Dakota encompass the Northwestern Plains Ecoregion where soils are nonglaciated and evaporation exceeds precipitation. In contrast, C. sonorensis populations were largely absent east of the Missouri River in South Dakota and North Dakota; this area comprises the Northwestern Glaciated Plains Ecoregion and Northern Glaciated Plains Ecoregion where surface soils reflect Wisconsinan glaciation and precipitation exceeds evaporation. In defining a well-demarcated pattern of population presence or absence on a regional scale, the data suggest that biogeographic factors regulate the distribution of C. sonorensis and in turn BTV exposure. These factors, ostensibly climate and soil type as they affect the suitability of larval habitat, may explain the absence of C. sonorensis, hence limited risk for exposure to BTV, across the eastern Northern Plains, upper Midwest, and possibly Northeast, regions of the United States. PMID- 21661326 TI - Productive container types for Aedes aegypti immatures in Merida, Mexico. AB - During 2007-2010, we examined which container types in Merida, Mexico, are most productive for Aedes aegypti (L.) immatures. Surveys for mosquito immatures followed routine surveillance methodology and container type classifications used by Servicios de Salud de Yucatan. Our main findings were that (1) small and larger discarded containers that serve no particular purpose and therefore can be removed from the environment contribute strongly to larval and pupal production in Merida, and (2) the importance of different container types can vary among sets of residential premises as well as between dry and wet periods. These results may help to guide future implementation in Merida of control efforts that target the most productive container types for Ae. aegypti immatures. Furthermore, if the Patio Limpio cleanup campaign that currently is ongoing in Merida proves successful in removing discarded containers as important immature development sites, then we should see dramatic changes in the most productive container types in the future as the mosquito is forced to switch to other container types, which perhaps also will be easier to include in highly targeted mosquito control interventions. PMID- 21661327 TI - Diversity and coexistence of tick-borne pathogens in central Germany. AB - In total, 1000 Ixodes ricinus L. ticks were collected from a small recreational forest area in central Germany (Thuringia) and investigated for the presence of Borrelia spp., Babesia spp., Anaplasma spp., Rickettsia spp., Coxiella burnetii, and Francisella tularensis. Overall, 43.6% of the ticks were infected with at least one pathogen. In 8.4% of ticks double infections were detected, and 1.6% harbored more than two pathogens. In this study, we present data on the coexistence of established and emerging pathogens in questing nymphs and adult ticks in a recreational area in central Germany, indicating the need for further studies for a reliable risk assessment. PMID- 21661328 TI - Vector competence of the stable fly (Diptera: Muscidae) for West Nile virus. AB - In 2006-2007, stable flies, Stomoxys calcitrans (L.) (Diptera: Muscidae), were suspected of being enzootic vectors of West Nile virus (family Flaviviridae, genus Flavivirus, WNV) during a die-off of American white pelicans (Pelecanus erythrorhynchos Gmelin) (Pelecanidae) in Montana, USA. WNV-positive stable flies were observed feeding en masse on incapacitated, WNV-positive pelicans, arousing suspicions that the flies could have been involved in WNV transmission among pelicans, and perhaps to livestock and humans. We assessed biological transmission by infecting stable flies intrathoracically with WNV and testing them at 2-d intervals over 20 d. Infectious WNV was detected in fly bodies in decreasing amounts over time for only the first 6 d postinfection, an indication that WNV did not replicate within fly tissues and that stable flies cannot biologically transmit WNV. We assessed mechanical transmission using a novel technique. Specifically, we fed WNV-infected blood to individual flies by using a cotton swab (i.e., artificial donor), and at intervals of 1 min-24 h, we allowed flies to refeed on a different swab saturated with WNV-negative blood (i.e., artificial recipient). Flies mechanically transmitted viable WNV from donor to recipient swabs for up to 6 h postinfection, with the majority of the transmission events occurring within the first hour. Flies mechanically transmitted WNV RNA to recipient swabs for up to 24 h, mostly within the first 6 h. Given its predilection to feed multiple times when disturbed, these findings support the possibility that the stable fly could mechanically transmit WNV. PMID- 21661330 TI - Histopathology of experimental myiasis in mice as a result of infestation and experimental implantation of Dermatobia hominis larvae. AB - A laboratory model of myiasis as a result of Dermatobia hominis (L.) larvae was developed using mice as hosts. Mice in three groups were each infested with one newly hatched larva and skin biopsies processed for histopathology at 4, 12, and 20 d postinfestation (dpi). Mice in three other groups were each subjected to implantation of one larva collected from an infested (donor) mouse at 4, 12, and 20 dpi. Skin lesions of these receptor mice were then assessed at 10, 14, and 6 d postimplantation (dpimp), respectively. The inflammatory process in infested mice at 4 dpi was discrete, consisting of a thin necrotic layer around the larva, edema, many neutrophils, few eosinophils, mast cells, and proliferation of fibroblasts. At 12 dpi, there was a thicker necrotic layer, edema, many neutrophils and eosinophils, few mast cells, neoformation of capillaries, proliferation of the endothelium and fibroblasts, and early stages of fibrosis. These histopathological characteristics together with fibrosis were observed over a large area of the lesion at 20 dpi. Mice submitted to larval implantations demonstrated similar skin histopathology to that seen in the infested rodents, 10 dpimp corresponding to 12 dpi and 6 or 14 dpimp to 20 dpi. In all mice, the progressive acute inflammatory process followed a sequence linked to factors such as size of larvae and presence of secretory-excretory products. Both infested mice and those implanted experimentally with D. hominis larvae were shown to be suitable models for the study of the parasite-host relationship in this important zoonotic myiasis. PMID- 21661329 TI - Weather and land cover influences on mosquito populations in Sioux Falls, South Dakota. AB - This study compared the spatial and temporal patterns of Culex tarsalis Coquillett and Aedes vexans Meigen populations and examined their relationships with land cover types and climatic variability in Sioux Falls, SD. Between 24 and 30 CDC CO2-baited light traps were set annually in Sioux Falls from May to September 2005-2008. Land cover data were acquired from the 2001 National Land Cover Dataset and the percentages of selected land cover types were calculated within a 600-m buffer zone around each trap. Meteorological information was summarized from local weather stations. Cx. tarsalis exhibited stronger spatial autocorrelation than Ae. vexans. Land cover analysis indicated that Cx. tarsalis was positively correlated with grass/hay, and Ae. vexans was positively correlated with wetlands. No associations were identified between irrigation and the host-seeking population of each species. Higher temperature in the current week and 2 wk prior and higher precipitation 3-4 wk before collection of host seeking adult mosquitoes had positive influences on Cx. tarsalis abundance. Temperature in the current week and rainfall 2-3 wk before sampling had positive influences on Ae. vexans abundance. This study revealed the different influences of weather and land cover on important mosquito species in the Northern Great Plains region, which can be used to improve local vector control strategies and West Nile virus prevention efforts. PMID- 21661331 TI - Distribution of spotted fever group rickettsiae in select tissues of experimentally infected and field-collected Gulf Coast ticks. AB - Salivary glands, midgut, Malpighian tubules, and ovaries were dissected from infected, colony-derived Amblyomma maculatum (Gulf Coast ticks) injected as nymphs with either Rickettsia parkeri (a spotted fever group rickettsia [SFGR]; treatment) or phosphate-buffered saline (negative control). For comparison, similar tissues were dissected from hemolymph-positive, field-collected ticks. Tissues were analyzed by indirect fluorescent antibody (IFA) tests. All phosphate buffered saline-injected ticks were IFA negative, whereas SFGR were detected by IFA in 100% of the salivary glands and ovaries and 78 and 75% of midgut and Malpighian tubule samples, respectively, of R. parkeri-injected ticks. Nearly 22% (10/46) of the field-collected ticks were hemolymph positive. Of those, SFGR were detected by IFA in 80% of the salivary glands, 67% of the ovaries, and 60% in the midgut and Malpighian tubules. This is the first study to assess the distribution of SFGR in select tissues of A. maculatum ticks. PMID- 21661332 TI - Immunoglobulin G antibody profiles against Anopheles salivary proteins in domestic animals in Senegal. AB - Although domestic animals may not be permissive for Plasmodium, they could nevertheless play a role in the epidemiology of malaria by attracting Anopheles away from humans. To investigate interactions between domestic animals and mosquitoes, we assayed immunoglobulin G (IgG) antibodies directed against the salivary proteins of Anopheles gambiae in domestic animals living in Senegalese villages where malaria is endemic. By Western blotting, sera from bovines (n=6), ovines (n=36), and caprines (n=36) did not react with Anopheles whole saliva. In contrast, equine sera recognized proteins in both saliva and salivary gland extracts. Two of the major immunogens (32 and 72 kDa) were also reactive in extracts from other major mosquito genera (Aedes and Culex), but reactions toAnopheles-specific antigens were detected in 12 of 17 horses. These data suggest that horses strongly react to Anopheles bites, and further experiments on horses are warranted to investigate the impact of this domestic animal species on the transmission of human malaria. PMID- 21661333 TI - Energetic cost of insecticide resistance in Culex pipiens mosquitoes. AB - The extensive use of insecticides to control vector populations has lead to the widespread development of different mechanisms of insecticide resistance. Mutations that confer insecticide resistance are often associated to fitness costs that prevent them from spreading to fixation. In vectors, such fitness costs include reductions in preimaginal survival, adult size, longevity, and fecundity. The most commonly invoked explanation for the nature of such pleiotropic effects of insecticide resistance is the existence of resource-based trade-offs. According to this hypothesis, insecticide resistance would deplete the energetic stores of vectors, reducing the energy available for other biological functions and generating trade-offs between insecticide resistance and key life history traits. Here we test this hypothesis by quantifying the energetic resources (lipids, glycogen, and glucose) of larvae and adult females of the mosquito Culex pipiens L. resistant to insecticides through two different mechanisms: esterase overproduction and acetylcholinesterase modification. We find that, as expected from trade-off theory, insecticide resistant mosquitoes through the overproduction of esterases contain on average 30% less energetic reserves than their susceptible counterparts. Acetylcholinesterase-modified mosquitoes, however, also showed a significant reduction in energetic resources (20% less). We suggest that, in acetylcholinesterase-modified mosquitoes, resource depletion may not be the result of resource-based trade-offs but a consequence of the hyperactivation of the nervous system. We argue that these results not only provide a mechanistic explanation for the negative pleiotropic effects of insecticide resistance on mosquito life history traits but also can have a direct effect on the development of parasites that depend on the vector's energetic reserves to fulfil their own metabolic needs. PMID- 21661335 TI - Biological and genetic aspects of crosses between phylogenetically close species of Mexican triatomines (Hemiptera: Reduviidae). AB - Reproductive isolation between Triatoma mexicana (Herrich-Scaeffer) and the six species of the Phyllosoma complex, belonging to the genus Meccus, was examined by analyzing the fertility of experimental hybrids. The percentage of couples with offspring was highest in the set of crosses between Meccus phyllosomus (Burmeister) and T. mexicana, and lowest in those between Meccus pallidipennis (Stal) and Meccus bassolsae (Alejandre-Aguilar, Nogueda-Torres, Cortes-Jimenez, Jurberg, Galvao, and Carcavallo) with respect to T. mexicana. Crosses between Meccus mazzottii (Usinger), Meccus picturatus (Usinger), and Meccus longipennis (Usinger) and T. mexicana had scarce offspring, whereas offspring from crosses between M. phyllosomus and T. mexicana were abundant. However, all F1 nymphs died in different instars before reaching sexual maturity. The biological evidence in this study suggests that different degrees of reproductive isolation exist between T mexicana and the different species of Meccus. Our data also support the current status of T. mexicana as a separate species. PMID- 21661334 TI - Mosquito (Diptera: Culicidae) bloodmeal sources during a period of West Nile virus transmission in Puerto Rico. AB - Host bloodmeals of indigenous Caribbean mosquitoes have not been studied previously. We identified vertebrate DNA in 90 blood-engorged mosquitoes belonging to four genera (Aedes, Culex, Deinocerites, and Uranotaenia) and 12 species that were collected in Puerto Rico within a geographic and temporal focus of West Nile virus transmission in 2007. It was found that 62 (68.8%) bloodmeals were from reptiles, 18 (20.0%) from birds, and 10 (11.1%) from mammals. Only one bloodmeal of 18 derived from Culex (Culex) species was passerine, suggesting a preference for nonpasserine birds and other vertebrates (i.e., reptiles) among the candidate WNV vectors. We interpret the results with respect to vectorial capacity for West Nile virus, an emerging arbovirus throughout the Caribbean Basin. PMID- 21661336 TI - Efficacy of dry ice-baited traps for sampling Amblyomma americanum (Acari: Ixodidae) varies with life stage but not habitat. AB - The carbon dioxide-baited trap is the most common and effective method for sampling vector life-stage Amblyomma americanum (L.) (Acari: Ixodidae), although confounding environmental variables are rarely considered. A mark-recapture experiment was designed to compare recapture proportions of A. americanum nymphs and adults between two habitat types: old field and oak-hickory forest. Powdered fluorescent dye was used to mark A. americanum ticks released in 1-m increments from carbon dioxide-baited traps. Adults were recaptured in significantly higher proportion than nymphs, but habitat type had no significant effect on recapture proportions. Tick abundance is an important parameter in the estimation of human risk of exposure to tick-borne disease and the influence of life stage on capture rates should be considered when calculating entomological risk. PMID- 21661338 TI - Putting things into perspective. PMID- 21661337 TI - A model to predict evaporation rates in habitats used by container-dwelling mosquitoes. AB - Container-dwelling mosquitoes use a wide variety of container habitats. The bottle cap is often cited as the smallest container habitat used by container species. When containers are small, the habitat conditions can greatly affect evaporation rates that in turn can affect the species dynamics within the container. An evaporation rate model was adapted to predict evaporation rates in mosquito container habitats. In both the laboratory and field, our model was able to predict actual evaporation rates. Examples of how the model may be applied are provided by examining the likelihood of Aedes albopictus (Skuse), Aedes aegypti (L.), and Culex pipiens pipiens (L.) completing their development within small volume containers under typical environmental conditions and a range of temperatures. Our model suggests that under minimal direct sunlight exposure, both Ae. aegypti and Ae. albopictus could develop within a bottle cap before complete evaporation. Our model shows that under the environmental conditions when a plastic field container was sampled, neither Ae. albopictus or Cx. p. pipiens could complete development in that particular container before the water evaporated. Although rainfall could replenish the habitat, the effects of evaporation would increase larval density, which could in turn further decrease developmental rates. PMID- 21661339 TI - Breast cancer awareness and survivorship. PMID- 21661340 TI - Where were you for your preceptorship? PMID- 21661341 TI - An uncommon etiology for a common problem: hirsutism. AB - Hirsutism is a common problem affecting women that is usually the result of a benign etiology. However, sudden onset or rapidly progressive hirsutism, especially when accompanied by virilizing signs, is suspicious for androgen producing neoplasms of the ovaries or adrenals. A 28-year-old female presented with the rapid onset of hirsutism and virilizing signs, accompanied by a markedly elevated serum testosterone. Initial imaging studies demonstrated normal adrenal glands and ovaries. She was later discovered to have a rare steroid-secreting ovarian tumor. This case emphasizes the importance of a high level of suspicion for an androgen-producing neoplasm in the patient with sudden onset or rapid progression of virilizing signs and symptoms. PMID- 21661342 TI - Bone-modifying agents in the treatment of advanced cancer. PMID- 21661343 TI - Extenuating circumstances: does a stereotypical surgical personality exist? PMID- 21661344 TI - Quality focus: patient safety. PMID- 21661345 TI - DAKOTACARE update: National Stroke Awareness Month. PMID- 21661346 TI - Inflammatory malignant fibrous histiocytoma of the retroperitoneum. AB - The authors present a case of inflammatory malignant fibrous histiocytoma located in the left retroperitoneum. The tumor was resected enblock with kidney and suprarenal gland. During the resection the system of retractors called the pillars of Kocman was used which allowed wide exposure of the abdominal cavity. The tumor measured 23 x 17 x 10 cm with the left kidney and suprarenal incorporated. The tumor was centrally pseudocystic made of xanthomatous cells, foamy cells and rare giant cells with storiform formations and infiltrated with neutrophils. Imunohistochemically, the tumor cells were vimentin and CD 68 positive and CD 20, CD3, EMA, S-100, HMB 45, CD 34 and CD 1a negative. Neutrophils were CD 15 positive. PMID- 21661347 TI - The influence of the different morphological changes on gastric mucosa on somatostatin cell number in antrum mucosa and serum somatostatin. AB - The aim of our paper was to investigate the influence of the different morphological changes on gastric mucosa on somatostatin D-cell number in antral mucosa and serum Somatostatin. We analyzed according to Sydney classification to what extent the severity of gastritis affect the observed hormonal values. somatostatin D-cell number in antral mucosa and serum Somatostatin values were compared between three groups of patients; mild, moderate and severe chronic gastritis. The average number of somatostatin cell in biopsy sample of antrum mucosa was 30.41 +/- 35.38 (N = 17) in the case of middle form, 18.69 +/- 26.65 (N = 56) in moderate and in severe case of chronic gastritis 5.23 +/- 5.93 (N = 7) cells in mm2 of mucosa. The level of somatostatin in the serum of middle form gastritis were 26.43 +/- 28.76, moderate 19.95 +/- 35.93 and severe 17.88 +/- 17.66 pg/mL. In order to determine the number of somatostatin cells in antrum mucosa and serum somatostatin with present morphological changes of mucosa, it might helpful to exclude the patients with non-ulcer dyspepsia, but with the higher risk of premalignant and malignant changes. PMID- 21661348 TI - Prevalence and risk factors for herpes simplex virus type 2 infections in East Croatia. AB - The aim of the study was to establish the seroprevalence of herpes simplex virus type 2 (HSV-2) among sexually active adults from East Croatia and to evaluate its correlates with demographic and behavioural risk factors. This cross-sectional study was conducted from the 1st June until the 30th September 2005 at the Department of Transfusion Medicine, Osijek University Hospital Center. The study included 423 blood donors composed of 366 (86.5%) men and 57 (13.5%) women. Demographic data and data on the risky sexual behaviour during the lifetime were collected with usage of an anonymous questionnaire consisting of 15 questions. Western blot testing revealed that 3.3% (14/423) subjects were positive for the presence of IgG antibodies to herpes simplex virus 2, i.e. 10 (2.7%) men and 4 (7.0%) women. A higher HSV-2 seroprevalence was associated with female sex, older age, marital status (with single subjects been under the greater risk), irregular condom use on sexual intercourses with new partners and with higher number (five or more) of sexual partners during lifetime. Among determined risk factors in the study population, only the connection between the HSV-2 positivity and the older age was statistically significant. The study has showed that the demographic rather than the behavioural risk factors are associated with higher prevalence of HSV-2 antibodies in the observed population. PMID- 21661349 TI - Thorough clinical evaluation of skin, as well as oral, genital and anal mucosa is beneficial in lichen planus patients. AB - Lichen planus (LP) is a common mucocutaneous disease of unknown aetiology with various geographical prevalence, may be related to some serious disorders such as squamous cell carcinoma and often remains underdiagnosed. The aim of this retrospective study was to thoroughly determine localization and clinical characteristics of LP lesions in a cohort of 173 Slovenian patients in association to the presence of accompanying symptoms and history of potential stressful events. Isolated cutaneous lesions of LP were found in 56.6% and isolated oral LP in 3.5% of patients. Thirty-four percent presented orocutaneous LP, whereas genitocutaneous LP was noted in 1.2%, orogenito-cutaneous LP in 4% and orogenital LP in 0.5% of patients. Underlying stressful events were noted in 36 out of 137 (26.3%) patients. Despite obviously visible localization of the lesions various medical specialists should be familiar with LP and thoroughly examine the complete skin, as well as oral, genital and anal mucosa in each LP patient to avoid a delay in diagnosing this disease and possibly disclose a much serious underlying condition. Psychological support should be offered, if needed. PMID- 21661350 TI - Prevalence and significance of vaginal group B streptococcus colonization in pregnant women from Osijek, Croatia. AB - The aim of the study was to determine the prevalence of vaginal group B streptococcus (GBS) colonization in pregnant women from Osijek area, the possible effect of GBS colonization on pregnancy outcome and neonatal complications and the role of intrapartum prophylaxis in this context. This retrospective case control study took place at the Department of Gynecology and Obstetrics, Osijek University Hospital Center from December 2003 to June 2006. A total of 118 pregnant women was enrolled in study and divided into two groups: 59 women in 35th-37th week of gestation, free from risk factors for infection (control group); and 59 women in 25th-41st week of gestation with risk factors for infection. Low vaginal swab for GBS isolation and identification on selective and enriched medium was obtained from each woman. GBS colonization was recorded in 29 (24.6%) women: 12 (20.3%) control and 17 (28.8%) women at risk of infection, yielding a statistically non-significant difference (Chi2 = 1.480489; p < 0.48). Early neonatal infection was observed in six (20.7%) neonates born to 29 mothers with GBS colonization, pointing to a correlation between vaginal GBS colonization and early neonatal infection (r(s) = 0.99). Early perinatal infection was found in 22 (18.6%) neonates, including 17 (28.8%) pregnancies with risk factors, pointing to a significant correlation between vaginal GBS colonization, risk factors and early perinatal infection (Chi2 = 88.68; p < 0.001); however, gestational age and pregnancy outcome were not influenced by GBS colonization. In eight (36.4%) newborns, early neonatal infection developed in spite of intrapartum administration of antibiotics; three of these children were born to GBS positive mothers, and perinatal GBS infection was demonstrated in one (0.84%) child. Study results revealed a relatively high rate of GBS colonization in the population of pregnant women in Croatia, occasionally leading to early neonatal infection. Large studies are needed to develop national strategy for the prevention of GBS infection in Croatia. PMID- 21661351 TI - Impaired cerebral vasoreactivity in type 2 diabetes mellitus. AB - The aim of our study was to assess cerebral vasoreactivity (CVR) in type 2 diabetes mellitus (DM2) and factors which may influence on it. According to previous studies, evaluating CVR in DM2 on the similar way, the results were dubious. For the evaluation CVR we used breath holding index (BHI) and transcranial Doppler ultrasound (TCD) in 50 patients with DM2 and 50 sex- and age matched healthy controls. We observed epidemiologic and clinic data, other vascular risk factors and laboratory parameters. We found statistically significant difference in BHI between patients with DM2 (BHI = 0.69 +/- 0.31) and age- and sex-matched healthy controls (BHI = 1.33+/-0.28) (p < 0.05 ). Because of a significant correlation between BHI and age (p < 0.001) in healthy controls we made an adjustment of BHI for age before further analyses (BHIadj). In DM2 group we found a significant correlation between BHIadj and age (p = 0.0004), fasting glycemia (p = 0.04), and albuminuria (p = 0.04) (creatinine clearance in multivariate analysis (p = 0.007)). Our study has shown that CVR is impaired in DM2 patients and that it's severity was associated with age, fasting glycemia and renal function. Functional TCD is a very good screening method for detection and monitoring of cerebral microangiopathic changes in DM2 patients. PMID- 21661352 TI - The role of contrast enchanced axillary ultrasonography in early breast cancer patients. AB - The most important prognostic factor for the patients with breast cancer are metastases to axillary lymph nodes (ALNs). Preoperative ultrasound (US) combined with fine needle aspiration biopsy (US-FNAB) has been proved to be the most reliable method to detect nonpalpable axillary metastases in patients with breast cancer. Our study was aimed to examine the value of US contrast agent (CA) SonoVue in the US examination of the axilla for the detection of axillary lymph node (ALN) metastases in breast cancer patients. Therefore, two studies were performed. The first study included 27/70 patients with breast cancer who had an indeterminate result of the standard US examination of the axilla (L/T < 1.2 or MCT > 3 mm or predominantly non-hilar vessel signal) and underwent US examination with CA. In the second study, 26 breast cancer patients underwent standard axillary US examination performed independently by two skilled operators. The patients with indeterminate or malignant ALN underwent US- guided fine needle aspiration biopsy (US-FNAB). For macrometastases, the sensitivity, specificity, NPV and PPV of US-FNAB were 91%, 93%, 100% and 100%, respectively. The reproducibility of the standard US examination (the second study) was 85% (22/26 patients), and for the metastases larger than 5 mm, it was 100%. Moreover, our second study proved that the same results as with CA can be achieved by two skilled operators performing a standard US examination. The sensitivity of both operators was 92%. In the case of metastases larger than 5 mm, the reproducibility was 100%. Micrometastases remain a problem also in the hands of very experienced operators even if using CA. PMID- 21661353 TI - ICTP in bone metastases of lung cancer. AB - Bone metastases often appear in advanced stages of lung cancer. They are the result of modulation of bone metabolism by tumor cells that migrated into bone microenvironment and degraded bone organic matrix. Measurement of C-terminal telopeptide of type I collagen (ICTP) in the serum of subjects with lung cancer with and without bone metastases and healthy population is the way to explore bone resorption. In 343 subjects included in this research ICTP level was significantly higher in the bone metastasis than other two groups. The existence of pathologic fracture significantly increased ICTP level. ICTP showed sensitivity of 66.0% in bone metastases at 95.0% specificity in lung cancer stages IA and IB. ICTP is a good diagnostic marker in detection of bone metastasis of lung cancer. Its level can distinguish lung cancer with and without bone involvement and can be used as an addition to standard techniques used in diagnostics of bone metastasis. PMID- 21661354 TI - Influence of surgery onto the appearance of the hip joint periarticular calcification in patients with the acetabular fracture. AB - The intention of this study was to investigate the influence of surgery onto the appearance of the hip joint periarticular calcification in different groups of patients who suffered the acetabular fracture. A series of 103 patients with the acetabular fracture was analysed in a retrospective case-control study during a seven-year period. The patients were divided into two groups. The case group was comprised of 21 patients who were operated on due to the posterior acetabular wall fracture, while the control group was formed from 82 patients who underwent conservative treatment and who suffered complex acetabular fracture. To obtain the results, the rate and grade of the hip joint post-injury periarticular calcification formation were observed and analysed. They were considerably lower in patients from the case group who were operated on, compared to patients from the control group where the hip joint arthrosis was more common. In conclusion, considering the results of this paper, the rate and grade of the hip joint osteodegenerative changes may be highly decreased by surgery in patients who sustained the acetabular fracture. PMID- 21661355 TI - Antropological measurement of the calcaneus. AB - Transfer of the forces from the trunk to the lower extremities end on calcaneus which transports these forces to the pad, and that is why it is very important to research this bone. This study was done on 57 calcaneal bones of the osteological collection of the Department of Anatomy "Drago Perovic" Zagreb School of Medicine and Department of Anatomy Osijek School of Medicine. The intention was to notice the regularity of the relations between specific dimensions and bone mass and structure, which is of great importance for understanding interrelation between biomechanical parameters of calcaneus and development of involutive changes. In this study geometrical parameters of the calcaneus have been defined, so length of the whole bone and especially frontal and back part, width, height, weight of dry bone, volume, geometrical surface of lateral and longitudinal cross section have been measured on every anatomical specimen. --Mean value, standard deviation and standard error have been calculated for every measured parameter. Positive correlation between most of the parameters of the calcaneus and negative correlation between specific weight and surface of cross section have been found. Coefficient of variation is the highest for weight, and the smallest for width. PMID- 21661356 TI - Anatomical study of the facial nerve canal in comparison to the site of the lesion in Bell's palsy. AB - The term Bell's palsy is used for the peripheral paresis of the facial nerve and is of unknown origin. Many studies have been performed to find the cause of the disease, but none has given certain evidence of the etiology. However, the majority of investigators agree that the pathophysiology of the palsy starts with the edema of the facial nerve and consequent entrapment of the nerve in the narrow facial canal in the temporal bone. In this study the authors wanted to find why the majority of the paresis are suprastapedial, i.e. why the entrapment of the nerve mainly occurs in the proximal part of the canal. For this reason they carried out anatomical measurements of the facial canal diameter in 12 temporal bones. By use of a computer program which measures the cross-sectional area from the diameter, they proved that the width of the canal is smaller at its proximal part. Since the nerve is thicker at that point because it contains more nerve fibers, the authors conclude that the discrepancy between the nerve diameter and the surrounding bony walls in the suprastapedial part of the of the canal would, in cases of a swollen nerve after inflammation, cause the facial palsy. PMID- 21661357 TI - Evaluation of periodontal status in HIV infected persons in Croatia. AB - A number of periodontal changes have been associated with human immunodeficiency virus (HIV) infection, however our knowledge of the epidemiology, microbiology, host response and natural history of these conditions remains limited. Therefore, the aim of our study was the assessment of possible differences in periodontal status of HIV infected subjects when compared with healthy controls matched for age, gender and smoking habit in Croatian population. Assessment included measurement of plaque accumulation using approximal plaque index, measurement of gingival inflammation by use of sulcus bleeding index, pocket depth, gingival recession as well as the number of decayed, missing and filled teeth in 25 HIV infected subjects (age range 22-61, X = 40.8 years) in comparison with 25 healthy controls (age range 20-62, X = 40.9 years). Statistical analysis was performed by use of descriptive statistics and Mann-Whitney U test showed significantly increased level of inflammation of the marginal gingiva in HIV infected subjects when compared to the controls (p < 0.002). Significantly increased mean values of periodontal pockets (p < 0.002) and the deepest periodontal pocket (p < 0.003) were also observed when HIV infected subjects were compared to the healthy controls. In HIV infected subjects there was significant increase in the number of decayed, missing and decrease in the number of filled teeth (p < 0.002; p < 0.002; p < 0.009, respectively). The results of this study once again highlight the need for more prevalent periodontal check-ups and treatments in HIV infected subjects. PMID- 21661358 TI - Contact allergy caused by fragrance mix and Myroxylon pereirae (balsam of Peru)- a retrospective study. AB - Because of their widespread use, fragrances are among the most common causes of contact allergic dermatitis, second only to nickel. During a five-year period 3,065 patients with contact dermatitis were patch tested using a specific mix of fragrances. 509 (16.6%) patients were allergic to the fragrance mix, while 258 (8.4%) patients exhibited an allergic reaction to Myroxylon pereirae (balsam of Peru). Between those 509 patients, 157 were patch tested with eight individual substances contained in the fragrance mix: cinnamal, cinnamyl alcohol, eugenol, isoeugenol, geraniol, hydroxycitronellal, alpha-amyl cinnamal and Evernia prunastri (oak moss). The most frequent allergens were isoeugenol 57.9% (91/157), eugenol 55.4% (87/157), cinnamyl alcohol 34.4% (54/157) and Evernia prunastri (oak moss) 24.2% (38/157). There were 62 patients (39.5%) who exhibited an allergic reaction to both the fragrance mix and Myroxylon pereirae (balsam of Peru). The results prove the importance of avoiding allergens in daily life, especially in industrial and cosmetic products. In order to prevent ACD, better cooperation between industry and dermatologists is needed. PMID- 21661359 TI - Determination of total chromium in tanned leather samples used in car industry. AB - Despite the high competition of synthetic fibers leather is nowadays still widely used for many applications. In order to ensure a sufficient stability of the skin matrix against many factors, such as microbial degradation, heat and sweat, a tanning process is indispensable. Using chromium (III) for this purpose offers a multitude of advantages, thus this way of tanning is widely applied. During the use of chromium tanned leather as clothing material as well as for decoration/covering purposes, chromium is extracted from the leather and may then cause nocuous effects to human skin, e.g. allergic reactions. Thus the knowledge of the total chromium content of leather samples expected to come into prolonged touch with human skin is very important. In car industry leather is used as cover for seats, steering wheel and gearshift lever The chromium contents often chromium tanned leather samples used in car industry were determined. First all samples were dried at 65 degrees C overnight and then cut in small pieces using a ceramic knife, weighed and analyzed by inductively coupled plasma--optical emission spectrometry (ICP-OES) after acidic microwave assisted digestion. The total chromium amounts found were in the range from 19 mg/g up to 32 mg/g. The extraction yield of chromium from leather samples in sweat is approximately 2-7%. Thus especially during long journeys in summer chromium can be extracted in amounts which may cause nocuous effects for example on the palm of the hands or on the back. PMID- 21661360 TI - Physical activity and sudden cardiac death in elders--a Croatian study. AB - The paper deals with the sudden cardiac death in elders due to physical activity in Croatia and to compare it to other population groups who practice physical activity. The data are a part of a retrospective study dealing with 59 sudden death due to physical activity in men in Croatia: from January 1, 1988 to December 31, 2008. Fifteen aged 65 to 82 years were recreationally engaged in physical activity: six in swimming, four in tennis, one in driving a bicycle, one in jogging, two in bowling and one died during sexual act. Only one had symptoms of pectoral angina, two suffered from arterial hypertension, and two had congestive heart failure. Eleven were without symptoms before exercise. At forensic autopsy, fourteen had coronary heart disease, seven had critical coronary artery stenosis, three had occluded left descendens anterior coronary artery and four critical coronary stenosis, four had a recent myocardial infarctions, and eleven had myocardial scars due to previous myocardial infarctions. Twelve of them had left ventricular hypertrophy: 15-25 mm. In Croatia, about 7per cent of the entire male population undertake recreational physical activity, while 13 per cent of them are elders. A sudden cardiac death due to recreational physical activity in elders reached 1.71/100 000 yearly, in the entire male population engaged in recreational physical exercise: 0.75/100 000 (p = 0.05730), in the total male population aged 15-40 engaged in sports and recreational physical exercise: 0.57/100.0000 (p = 0.00387), in young athletes: 0.15/100 000 (p = 0.00000). Medical examination of all elderly persons has to be done before starting of recreational physical activity: by clinical examination, searching for risk factors for atherosclerosis, performing ECG at rest, stress ECG, and echocardiography and to repeat the medical examination at least once a year Physical activity should start with a warm-up period and with a gradually increasing load, and usually not to exceed 6-7 metabolic equivalents (METs). PMID- 21661361 TI - Drinking in adolescents--qualitative analysis. AB - The aim of this paper was to explore alcohol consumption and the development of this habit in the adolescent population based on qualitative data from 59 anonymous essays written by high school students. We found that the most of adolescents had their first experiences with alcohol in the seventh or eighth grades. They reported that they usually drank alcohol to be happy, to relax, to be courageous in approaching the opposite sex, to fit into society, and to be popular. Factors affecting drinking are influence of peers, family and social attitude towards drinking, laws and enforcement of legislation. In further prevention programs, we must be able to demonstrate that "having a good time" does not mean drinking alcohol. Programs for the prevention of alcohol-related problems must begin by adolescence, including both sexes equally and can be achieved through a coordinated and intense public health effort. PMID- 21661362 TI - Growth modulation of human cells in vitro by mild oxidative stress and 1,4 dihydropyridine derivative antioxidants. AB - Reactive oxygen species and lipid peroxidation products are not only cytotoxic but may also modulate signal transduction in cells. Accordingly, antioxidants may be considered as modifiers of cellular redox signaling. Therefore, the effects of two novel synthetic antioxidants, analogues of 1,4-dihydropyridine derivatives, cerebrocrast and Z41-74 were analysed in vitro on human osteosarcoma cell line HOS, the growth of which can be modulated by lipid peroxidation. The cells were pretreated with either cerebrocrast or Z41-74 and afterwards exposed to mild, copper induced lipid peroxidation or to 4-hydroxynonenal (HNE), the end product of lipid peroxidation. The results obtained have shown that both antioxidants exert growth modulating effects interfering with the lipid peroxidation. Namely, cells treated with antioxidants showed increased metabolic rate and cell growth, thereby attenuating the effects of lipid peroxidation. Such biomodulating effects of cerebrocrast and Z41-74 resembled growth modulating effects of HNE, suggesting that the antioxidants could eventually promote cellular adaptation to oxidative stress interacting with redox signaling and hydroxynonenal HNE-signal transduction pathways. This may be of particular relevance for better understanding the beneficial role of hydroxynonenal HNE in cell growth control. Therefore, cerebrocrast and Z41-74 could be convenient to study further oxidative homeostasis involving lipid peroxidation. PMID- 21661363 TI - Efficacy and safety of inferior turbinate coblation-channeling in the treatment of nasal obstructions. AB - The aim of this study was to evaluate the safety and effectiveness of coblation channeling in the treatment of inferior turbinate hypertrophy. The study was conducted in the Department of ENT Head and Neck Surgery, Split University Hospital Center, Split, Croatia. Fifty-two patients with inferior turbinate hypertrophy who were refractory to medical therapy were evaluated for coblation. The procedures were performed under local anesthesia using an ArthroCare ReFlexUltra 45 wand; three submucosal channels were made per turbinate. Clinical examinations, a questionnaire on individual nasal symptoms (hyposmia, nasal drainage and post-nasal drip), a 10-cm visual analog scale (VAS) grading general nasal obstructions, and rhinomanometry before and 8 weeks after the treatment were administered to assess treatment outcomes. No adverse effects were encountered. Nasal breathing was significantly improved in all patients, decreasing the VAS from a median of 7 (range 2-9) to 1 (range 0-3) (p < 0.001). Total nasal resistance decreased from 0.44 Pa +/- 0.50 to 0.24 Pa +/- 0.11 (p = 0.005). Improvement was statistically significant for all three symptoms (hyposmia [p = 0.005], nasal drainage [p = 0.003] and post-nasal drip [p < 0.001]). In this paper, we demonstrate that coblation-channeling of the hypertrophic inferior turbinate is an effective and safe way to reduce nasal obstruction symptoms. PMID- 21661364 TI - Perception of arterial hypertension and myocardial infarction in hypertensive and normotensive men and women. AB - The research aims were to test perception of arterial hypertension and myocardial infarction in hypertensive and normotensive men and women as well as to test perception of arterial hypertension and myocardial infarction as predictors of blood pressure control in hypertensives. In the research 470 subjects of 4 general practices from Rijeka, Croatia participated, hypertensive group from the list of hypertensive patients without cardiovascular complications and other major chronic conditions, normotensive group from the list of patients without chronic conditions. Each group had 235 subjects, 128 men and 107 women. Perception of hypertension and myocardial infarction was measured as the result on semantic differential questionnaire. Factor analysis extracted evaluation, potency and activity factor. Blood pressure control was interpreteted on the five degrees scale. Statistical significance was defined under 5% (p < 0.05). Hypertensive subjects perceived hypertension as less negative and more active, while myocardial infarction was perceived as more potent term than by normotensives. Women perceived myocardial infarction as less negative, and less potent term than men. Both groups perceived myocardial infarction as more negative, potent and active term than hypertension. Normotensive women evaluated hypertension as more negative, and perceived myocardial infarction as less potent than other subjects. Well-controlled hypertension was correlated with a lower potency of hypertension and lower activity of myocardial infarction. Both conditions are perceived as more "male" diseases. As perception of hypertension and myocardial infarction is correlated with blood pressure regulation in hypertensives, and hypertension is major risk factor for myocardial infarction, family doctors should put additional effort in changing perception of cardiovascular diseases in their patients, especially in women. PMID- 21661365 TI - Perforin expression after acute myocardial infarction--a pilot study. AB - Perforin is an important mediator of inflammatory reactions. It is a quick-action cytotoxic mediator accumulated in the cytoplasmic granules of effector immunity cells (T lymphocytes, NK and NKT cells) which provide death signal in infected or transformed cells. Perforin-positive cells were previously detected in myocardial tissue during Trypanosoma cruzi infection and viral myocarditis while its role in chronic and progressive cardiovascular inflammatory disease such as atherosclerosis is almost completely unexplored. The perforin activity is also untested during acute coronary events that represent unexpected atherosclerotic complications due to the inflammatory destabilisation and atherosclerotic plaque rupture. The aim of this study was to investigate the presence of perforin, an important immunological inflammatory molecule in peripheral blood lymphocytes during the early period after acute myocardial infarction. We analyzed three subject groups: women with ST-segment elevation acute myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI), conservatively treated women with acute myocardial infarction without ST-segment elevation (NSTEMI) and a control group of healthy volunteers. The STEMI and NSTEMI groups did not basically differ in medication neither in levels of routine laboratory tests, while troponin I were significantly higher in the STEMI group. In the study, we detected an early decrease of perforin-positive lymphocytes in STEMI patients that were in contrast with their persisting elevation among NSTEMI patients. Despite greater myocardial necrosis in the STEMI group, results of this pilot-study indicated the prolonged perforin-mediated inflammatory response in patients with NSTEMI. This perforin down-regulation that follows the coronary interventional reperfusion in STEMI emphasized the possible anti-inflammatory role of primary PCI among patients with acute myocardial infarction. Given that the issue of routine primary PCI in NSTEMI is nowadays highly topical, the results we expect in the wake of this pilot study could demonstrate a significant impact on clinical practice. Further research is needed to confirm these results, compare the perforin-mediated activity to other inflammatory mediators in acute coronary events and to examine their impact on the long-term outcome. PMID- 21661366 TI - Correlation of cardio-ankle vascular index, ten-year risk assessment and other atherosclerosis risk factors. AB - The aim of the study was to assess correlation of atherosclerosis severity as determined by two different methods of screening for atherosclerosis: (A) measurement of the cardio-ankle vascular index-CAVI by use of the VaseraVS-1500 vascular screening device, and (B) Framingham scale scoring. 52 subjects (28 male and 24 female) were enrolled in the study. Classification of study subjects into four quartiles based on theoretically calculated 10-year risk according to Framingham scale (medians: 1%, 3%, 4% and 15%) confirmed the risk increase to be associated with a statistically significant increase in CAVI, age and total cholesterol, and a statistically significant decrease in HDL-cholesterol (p < 0.001 all). Spearman correlation coefficients showed a statistically significant correlation of 10-year risk with CAVI (p = 0.0242; r = 0.4494). Study results suggested that simultaneous determination of CAVI and 10-year risk might prove justified. They are not contradictory, the more so, these two parameters showed a significant positive correlation. This test panel yields comprehensible, implying all the possible consequences and highly motivating information that may stimulate the person for lifestyle modification. PMID- 21661367 TI - Clinical and no-clinical setting specificities in first session short-term psychotherapy psychodrama group. AB - Modern history of short-term group psychotherapy dates back to the late 1950-ies. From then to present day, this psychotherapeutic method has been used in various forms, from dynamic-oriented to cognitive behavioural psychotherapies. Although it has always been considered rather controversial, due its cost-effectiveness, it has been capturing more and more popularity. This paper presents the specificities of first session short-term psychotherapy psychodrama group through session work with two examined groups: a group of 20 adult women who suffer from mild or moderate forms of unipolar depression and a group of 20 students of the School of Medicine in Zagreb without any psychiatric symptomatology. The results indicate the high importance of having structure in first psychodrama session, of relating it with the previously thoroughly conducted, initial, clinical, interviews, and of the clarity and focus in terms of determining the goals of therapy, especially in a clinical context. This study also confirmed assumptions regarding the need for different approaches of warming-up in psychodrama, both in the clinical and in non-clinical samples. A psychodrama psychotherapist should have good time managing skills and capability to convert the time available into an opportunity for directly boosting the group energy and work on therapeutic alliance. PMID- 21661368 TI - Spontaneous perforation of the small intestine, a novel manifestation of classical homocystinuria in an adult with new cystathionine beta-synthetase gene mutations. AB - The clinical picture of classical homocystinuria is diverse. This is the first report of an adult homocystinuric patient with non-traumatic spontaneous small bowel perforation. A 47-year old man presented with abdominal rebound tenderness, hypotension and tachycardia, anemia, and elevated markers of inflammation. Other routine laboratory tests were normal. Abdominal x-ray showed no free air. An emergency laparotomy revealed jejunal perforation in the left upper quadrant. Histologic specimen showed full-thickness nonspecific inflammation of the intestinal wall with granulocytic infiltration, hemorrhage and necrosis. Tuberculosis, actinomycosis and typhus were histologically and clinically excluded. After excluding all known possible causes of perforation, we presumed a causative relationship between homocystinuria and small bowel perforation. It could be hypothesized that connective tissue weakness in homocystinuria is a result of homocysteine interference with recombinant human fibrillin-1 fragments or cross-linking of collagen through permanent degradation of disulfide bridges and lysine amino acid residues in proteins. DNA analysis showed three detectable mutations in the cystathionine beta-synthetase gene, 1278T:c.833T>C, and two new mutations, V372G:c.1133T > G, and D520G:c.1558A > G in the aternatively spliced exon 15. PMID- 21661369 TI - History and future of visual anthropology. AB - Visual recording of communication processes between communities or individuals by means of filming of photographing is of significant importance in anthropology, as it documents on site the specific features of various social communities in their encounter with the researcher. In terms of film industry, it is a sort of ethno-documentary pursuing originality and objectivity in recording the given subject, thus fulfilling the research mission. However, the potential of visual anthropology significantly exceeds the mere audiovisual recording of ethnologic realities. Modern methods of analysing and evaluating the role of visual anthropology suggest that it is a technical research service aimed at documenting the status quo. If the direction of proactive approach were taken, then the term ,visual anthropology' could be changed to ,anthropology of the visual,. This apparently cosmetic change of name is actually significantly more accurate, suggesting the denoted proactive swift in perceiving visual anthropology, where visual methods are employed to ,provoke< the reaction of an individual or of the community. In this way the "anthropology of the visual, is promoted to a new scientific sub-anthropological discipline. PMID- 21661370 TI - Successful use of recombinant factor Viia in traumatic liver injury--a case report. AB - The paper describe the use of rFVIIa in the management of massive bleeding in a patient with polytrauma involving liver injury. An 18-year-old girl with severe polytrauma sustained during a bus-car collision. She had multiple musculoskeletal injuries, severe concussion of the liver with amputation of the left liver lobe, disruption of the left hepatic vein from the inferior vena cava, and impaired hemostasis. Acute bleeding (> 5 L) was not improved by conservative methods and a single dose of rFVlla 90 pg/kg was administered. Infusion of rFVlla resulted in an immediate clinical effect with rapid improvements in blood laboratory measurements and coagulation parameters. rFVIIa should be considered as an adjunctive treatment for the control of hemorrhage in severely injured patients with uncontrolled bleeding and impaired hemostasis. PMID- 21661371 TI - Henoch-Schonlein purpura complicated by appendicitis, intussusception and ureteritis. AB - Henoch-Schonlein purpura (HSP) is the most common childhood systemic small-vessel vasculitis with skin, joint, gastrointestinal (GI) and renal involvement. Uncommon GI complications are intussusception, bowel perforation and rarely reported appendicitis. HSP-associated stenosing ureteritis represents a rare and potentially serious complication. We present a 5-year-old boy with severe and prolonged course of HSP and three very rare complications that occurred sequentially: appendicitis, intussusception and ureteritis. Only three days after admission, he developed clinical signs of acute appendicitis indicating surgical intervention. Histological analysis of excised appendix showed inflammation but without signs typical for vasculitis. Two weeks later, with the reccurence of HSP he again developed clinical picture of acute abdomen. Ultrasound and radiologic evaluation demonstrated ileo-ileal intussusception and the second laparotomy was undertaken. Histological analysis of the resected bowel tissue showed typical signs of leucocytoclastic vasculitis. In the fourth week of his illness, serial urinalysis showed nephritic urinary sediment indicative of renal involvement. Unexpectedly, control abdominal ultrasound demonstrated mild hydronephrosis of the left kidney, not seen on previous ultrasound evaluations. Undertaken excretory urography and computed tomography (CT) scan showed stenosis of upper/ midureter with mild dilation of upper part of the left ureter suggesting unilateral HSP-associated stenosing ureteritis. Eventually, the patient was discharged and closely followed-up for the next two years. He had no further reccurence of HSP, the urinalysis normalized after six months, while mild unilateral hydronephrosis remained unchanged. Our search of the literature did not show reports of HSP complicated by appendicitis, intussusception and ureteritis, and to our knowledge this is the first case with three different illness events that occured sequentially. We emphasize the necessity of repeated ultrasound evaluations in the course of HSR especially in cases with severe GI and renal invovement. PMID- 21661372 TI - Major defect to the brachial artery following blunt trauma--a five year follow up. AB - A 29-year-old soldier was injured when a collapsible side of an army truck fell on his left upper arm creating lesion to the brachial artery with a defect in the artery of about 10 cm in length. Injury to one brachial vein, of the same length, was also sustained without bone or neural injury. Intraoperative Doppler ultrasonography was performed. A reverse autologous saphenous vein interposition graft with a circumference similar to that of the injured brachial artery was used to perform end-to-end anastomosis between artery and reversed vein graft. The patient returned to his military formation 16 days post operatively, with a return to full military calisthenics routine 2 months after injury. Surgical and Doppler ultrasonography control was kept regularly. Excellent late result revascularization of the injured brachial artery with reversed interposition vein graft can be seen in CT angiography five years after injury. PMID- 21661373 TI - Angiomyoma--angioleiomyoma of the cheek. AB - The authors present the case of an angiomyoma--angioleiomyoma of the cheek in a 58-year-old man. The tumour was palpable, although clinically not visible, and the only case of a tumour of smooth muscle treated in the Clinical Department of Oral Surgery over the last 40 years. The operation was performed in the Outpatient Department by intraoral procedure. The postoperative course passed without complications. Current literature on leiomyomas is cited in the Introduction, followed by presentation of the case and histological characteristics of the tumour The example is presented as a rarity and one of the differential diagnostic possibilities in the diagnostics of soft tissue tumours in the oral cavity. PMID- 21661374 TI - Spontaneous regression of intervertebral disc herniation--case reports. AB - Lumbar disc hernia (LDH) is a common cause of low back pain and radicular leg pain. It is well known that the majority of LDH patients recover spontaneously. Since the advent of MRI, a spontaneous regression of fragment size of disc hernia occurs, as well as mitigation of subjective difficulties and neurological disorders. Therefore, surgical treatment is not always method of choice in this disease. Two cases of conservatively treated large disc extrusion which result in significant reduction of difficulties, with simultaneous reduction in fragment size of hernia which is documented by MR. PMID- 21661375 TI - Immediate implantation in infected tooth sockets. AB - Although immediate implantation has not been previously recommended in infected sites, it is now becoming a procedure of choice in modern implant dentistry. We report a case of a 65-year-old male patient, who required multiple tooth extractions in the lower jaw and fabrication of a new overdenture in the lower jaw and a complete denture in the upper jaw. Immediate implantation in infected tooth sockets followed extraction. Two NobelReplace Tapered implants (Nobel BioCare, Zurich, Switzerland), one 13 mm long and 4.3 mm wide and the other 13 mm long and 5.0 mm wide, were placed in the position 33 and 43. The site was sutured and a temporary denture was fabricated by adjusting the old denture. After a period of three months the implant site was reopened and healing abutments were placed. Impressions were made using the Impregum Penta Soft (3M ESPE, St. Paul, Minn, USA) polyether material. Ball Abutment Titanium" was used as a patrix attachment and a matrix was inserted into the denture. Clinical examination and x ray analysis after six months showed no significant changes of the implants. Bone resorption was within standard values. Although it is still a controversial subject, immediate implantation in infected sites can be a safe and predictable procedure if surgical protocols are followed. However, further research is needed to draw firm conclusions. PMID- 21661376 TI - Salmonella ovarian abscess in young girl presented as acute abdomen--case report. AB - Ovarian abscess in young sexually non-active girls can represent a diagnostic challenge. 15-years old girl was admitted to the Clinic for Gynaecology and Obstetrics under the suspicion of torsion of an ovarian cyst. Her clinical status deteriorated after the admission with development of acute abdomen. Laparoscopic exploration was performed and unilateral ovarian abscess was found without involvement of other pelvic structures. The surgical procedure was minimal invasive for a young girl and Salmonella staleyville was isolated from pus. Solitary ovarian abscess can be of hematogenous origin and the causative pathogens are different from pathogens usually involved in pelvic inflammatory disease. To avoid later fertility problems it is of great importance to treat infections in pelvic region correctly according to the isolated microorganism and that surgery is the least invasive. PMID- 21661377 TI - Comparison of the results of surgical and non-surgical treatment of combat urogenital injuries in Bosnia war 1992-1995. AB - Goal was to compare the results of surgical and non-surgical treatments of combat injuries of genitourinary system and to compare our data with data collected in the recent studies. The study was designed as a retrospective review of data collected in prospective databases. The data extracted from inpatients' medical records included demographics, mechanisms and type of injury, distribution of the lesions, clinical presentation features, applied diagnostic studies, treatment modalities, types of complication and results of treatment. Among 4.125 patients treated in the Mostar War Hospital, 111 had injury of genitourinary tract: 62 underwent a surgical and 49 non-surgical treatment. Mortality among operated patients was 16 (26%). Complications were noted in 47 patients (42%); in 33 (70%) were manifested as early complications, and 14 (30) as delayed ones (p = 0.006). Among the surgically treated patients, 40 (36%) had some complication, in comparison to 8 (7.2%) patients with complications among non-surgically treated patients; which represent a statistically significant difference (p < 0.05). In this study, there was a surprisingly high number of non-surgically treated patients, and this sub-group of UGT trauma patients had in some ways the superior treatment results in comparison with surgically treated patients. Conservatively treated patients had lower rate of complications, no mortality, and no patients with permanent disability. PMID- 21661378 TI - Tumor markers in breast cancer--evaluation of their clinical usefulness. AB - Breast cancer is the most common neoplasm affecting women in the Western world. Many studies are still conducted with the purpose of finding markers that could be used for early diagnosis and/or serve as possible reliable prognostic or predictive parameters, but with conflicting results. At present, no markers are available for an early diagnosis of breast cancer For surveillance of patients with diagnosed breast cancer the most widely used serum markers are CA 15-3 and CEA which, in combination with other clinical parameters, could have clinical significance. The most useful and clinically important tissue-based markers in breast cancer are estrogen and progesterone receptors, used as a basis for hormonal therapy, and HER-2 receptors, essential in selecting patients for the treatment with Herceptin. New or potentially new markers for breast cancer include BRCA1 and BRCA2 genes for selecting patients at high risk of developing hereditary breast cancer, as well as urokinase plasminogen activator and inhibitor for assessing prognosis in lymph node-negative patients. Results of tumor and patient genetic analyses including their clinical evaluation will enable application of more individualized and personalized approach in diagnosis and therapy of breast cancer patients. PMID- 21661379 TI - Klatskin-mimicking lesions: still a diagnostical and therapeutical dilemma? AB - BACKGROUND/AIMS: The preoperative as well as the intraoperative differentiation between Klatskin-mimicking lesions and malignant bile duct tumors at hilar bifurcation is still challenging. Our intention was to review the preoperative diagnostics including preoperative CA19-9 and bilirubin serum levels to compare benign and malignant tumors. METHODOLOGY: We analyzed our prospectively established bile duct tumor database. From 1999 to 2008, 238 patients suspicious for hilar cholangiocarcinoma underwent surgery. In 24 patients the postoperative histological diagnosis showed a Klatskin-mimicking lesion. The histological report from 20 out of the 24 patients showed a chronic inflammatory transformation of the bile ducts. The histology of two patients showed a primary sclerosing cholangitis and the histological examination of the two remaining patients diagnosed a sarcoidosis of the extrahepatic bile duct. RESULTS: Reassessment of preoperative diagnostics did not deliver any change of interpretation of the tumors' dignity compared to how it had been assessed preoperatively. Also, preoperative CA19-9 serum levels do not show a statistically reliable differentiation between benign or malignant dignity. CONCLUSION: Current diagnostics cannot differentiate malignant from benign tumor masses in the hepatic hilum with the necessitated reliability. Therefore surgical resection of suspect hilar tumors is still the only appropriate therapy. PMID- 21661380 TI - Single-agent gemcitabine in elderly patients with unresectable biliary tract cancer. AB - BACKGROUND/AIMS: This study examined the effect of systemic chemotherapy with gemcitabine (GEM) on survival in elderly patients (aged > or = 70 years) with unresectable biliary tract cancer as compared with best supportive care (BSC). METHODOLOGY: We conducted a retrospective study of consecutive patients with unresectable biliary tract cancer administered GEM (800-1,000 mg/m2) on days 1, 8 and 15 every 4 weeks as a first-line treatment. Eligibility included age 70 years and over, and bile duct carcinoma or gallbladder cancer. RESULTS: Twenty-eight patients were enrolled: 13 (46.4%) received chemotherapy with GEM and 15 (53.6%) received BSC. No cases of complete or partial response were observed. Stable and progressive disease was observed in 9 (69.2%) and 2 patients (15.4%), respectively. Disease control rate was 69.2%. The median overall survival time of patients treated with GEM and BSC was 9.1 and 2.9 months, and the 1-year survival rates were 15.4% and 6.7%, respectively. Grade 3/4 neutropenia occurred in three (23.1%), leukopenia in two (15.4%) and anemia in one patient (7.7%). Grade 3 non hematologic toxicities were constipation (7.7%) and fatigue (7.7%). CONCLUSIONS: Chemotherapy with single-agent GEM is a safe and well tolerated regimen for elderly patients with unresectable biliary tract cancer. PMID- 21661381 TI - Endoscopic approach in diagnosis and treatment of biliary complications after laparoscopic cholecystectomy. AB - BACKGROUND/AIMS: The aim of this retrospective study is to follow the main parameters such as the success of performing diagnostic endoscopic retrograde cholangiopancreatography (ERCP) and to determine the effectiveness and morbidity of therapeutic ERCP. METHODOLOGY: The study of the group took 12 years (January 1997-December 2008). The paper assesses in retrospect 138 patients who underwent laparoscopic cholecystectomy (LCE). Signs leading to the suspicion of possible biliary complications (BC) after previous LCE appeared in these patients in the postoperative period, indicating the performance of ERCP. RESULTS: Diagnostic ERCP was successful in all 138 patients (i.e. in 100% of cases). There were normal ERCP results in 8 patients and pathological results in the sense of some of the BC in the remaining 130 patients. Endoscopic therapy was performed after diagnostic ERCP in 115 of 130 patients with proved BC. Therapeutic ERCP was absolutely successful in altogether 111 of 130 patients (85.38%) with BC after LCE. CONCLUSIONS: The success rate of therapeutic ERCP in our group was 85.38%. Morbidity in relation to therapeutic ERCP was 4.2%. ERCP appears to be highly effective diagnostic and primarily therapeutic method in solving BC after LCE. PMID- 21661382 TI - Surgical management of acute cholecystitis (experience of 249 cases). AB - BACKGROUND/AIMS: Although laparoscopic cholecystectomy is the most widely used technique in the surgical treatment of acute cholecystitis, some schools continue to perform the open approach in the treatment of that disease. Our objective is to make a comparative analysis of results obtained with laparoscopic cholecystectomy (LC) and gall bladder removal by open cholecystectomy (OC). METHODOLOGY: The study includes 249 acute cholecystitis cases operated on between January 2007 to December 2008. Mean age was 60.9 years (+/- 16.6) (21-94 years); 51.8% men and 48.2% women. The diagnosis was made considering clinical, laboratory and echographic findings. There were 217 acute calculous cholecystititis and 32 noncalculous. Surgery was performed as follows: 167 LCs, 64 by OC and 18 percutaneous cholecystostomies (PC). RESULTS: The comparative analysis of mortality and morbidity of LC with gall bladder removal by OC showed the following results: mortality (1.19% vs 4.6% p=n.s.), major morbidity (5.3% vs 31.25% p<0.001), lesions of the main bile duct (0.5% vs 3.1% p=n.s.) reoperation (3.6% vs 12.5% p<0.05) and hospital discharge up to 48 hours (69.5% vs 10.9% p<0.001). CONCLUSIONS: Laparoscopic cholecystectomy provides superior results to open cholecystectomy, and is therefore the first choice treatment in acute cholecystitis. PMID- 21661383 TI - Application of an endo-GIA for ligation of the cystic duct during difficult laparoscopic cholecystectomy. AB - BACKGROUND/AIMS: Laparoscopic cholecystectomy has become the gold standard modality for treating gallbladder disease. There are many techniques for the ligation of a dilated and inflamed cystic duct. The aim of this study is to assess the efficacy and applicability of an Endo-GIA for dilated cystic duct ligation. METHODOLOGY: From October 1992 to September 2009, 3413 patients underwent laparoscopic cholecystectomy for gallbladder disease at the Dong-A Medical Center, and 92 (2.7%) patients' cystic ducts were ligated by an Endo-GIA. We retrospectively analyzed these 92 cases. RESULTS: The cystic ducts were successfully ligated with an Endo-GIA in 88 patients. Four patients required conversion to open surgery. The mean operation time was 111.9 minutes. The mean length of the hospital stay was 4.1 days. Postoperative complication occurred in 16 patients (17%). The follow-up period ranged from 0.5 to 75 months. CONCLUSIONS: Endo-GIA is safe and feasible. Postoperative complication occurred in 16 patients after application of an Endo-GIA. However, those complications were successfully managed by conservative treatment. The rate of complications was comparable to the best results from most of the large series in the West. Therefore, using an Endo-GIA could be attempted in carefully selected patients with difficult cases of laparoscopic cholecystectomy. PMID- 21661384 TI - Chemoprevention of chemically-induced biliary carcinogenesis in hamsters by vitamin K2. AB - BACKGROUND/AIMS: Pancreaticobiliary maljunction (PBM) is a high risk factor of biliary tract cancer. The chemopreventive effects of Vitamin K2 (menaquinone-4: MK4) in a hamster PBM model were investigated. METHODOLOGY: The extrahepatic bile duct at the distal end of the common duct was ligated and cholecystoduodenostomy was performed (Group I). The same surgery was performed and from 4 weeks after surgery, 10 mg/kg of N-nitrosobis (2-oxopropyl) amine was subcutaneously injected once a week with a one-week interval (Group II). In addition of Group II, MK4 was orally administered once a day, five times with every week (Group III). The hamsters were sacrificed 20 weeks after surgery and histopathological findings of gallbladder were investigated. RESULTS: Group I showed predominantly proper epithelium without cancer. In Group II, atypical epithelium (AE) was observed in 75% of animals and early cancer was observed in 25%. Group III showed less AE and no cancer. The PCNA labeling index in Group III was statistically significantly lower than in Group II. In addition, no statistically significant differences were noted among the groups in terms of the apoptosis labeling index. CONCLUSIONS: MK4 suppressed biliary carcinogenesis by the induction of cell cycle arrest in a hamster biliary carcinogenetic model. PMID- 21661385 TI - Transumbilical laparoscopic cholecystectomy: towards a scarless abdominal surgery. AB - BACKGROUND/AIMS: The aim of the study is to evaluate transumbilical laparoscopic cholecystectomy as a minimally invasive technique for removal of the gallbladder. METHODOLOGY: Fifty patients were included in the study. All patients underwent transumbilical removal of the gallbladder through 3 incisions of 5mm size. An ultrasonically activated shear was used for sealing and dividing the cystic duct and artery. A 5mm camera with 30 degrees angle was used. Patient characteristics and outcomes were reviewed. RESULTS: All cases were accomplished successfully. The operative time ranged from 30-85 minutes. All patients were discharged on the following day. The postoperative wound was minimal and well tolerated by patients. Postoperative pain was minimal to moderate as shown on a pain scale. CONCLUSIONS: Transumbilical laparoscopic cholecystectomy has the potential advantages of reduced postoperative pain and reduced port-site complications. Careful attention to closure can lead to virtually "scarless" surgery without any further effect on the total cost of the procedure. PMID- 21661387 TI - Risk factors of Helicobacter pylori infection among adults in northern China. AB - BACKGROUND/AIMS: Helicobacter pylori (H. pylori) infection is one of the leading causes of gastritis, gastric ulcer, gastric cancer and other gastrointestinal diseases. In this study we aim to evaluate those factors that involved in the prevalence of H. pylori infection, such as socioeconomic living conditions, socioeconomic level, eating habits, and H. pylori gene subtype. METHODOLOGY: Included in this study are data on the daily habits and chronic disease history obtained from personal interviews of 798 healthy adults. The presence ofH. pylori infection is identified using an ELISA kit for detection of H. pylori IgG antibodies in serum. H. pylori gene subtype is determined by polymerase chain reaction (PCR) and specific probes. RESULTS: H. pylori prevalence is 54.5% in Northern China and diabetes, hyperlipidemia and atherosclerosis, age and waist circumference played important roles in H. pylori prevalence. VacA-positive strains are the most popular genotype. The most common strain of H. pylori is vacuolating cytotoxin gene A product (VacA), VacA-sla-m2 subtype. CONCLUSIONS: These data support that personal and environmental conditions affect H. pylori infection in adults, and H. pylori gene subtype may play important role in the prevalence of its infection. PMID- 21661386 TI - The clinical outcome of capsule endoscopy in patients with obscure gastrointestinal bleeding. AB - BACKGROUND/AIMS: Capsule endoscopy (CE) represents a significant advance in the investigation of small bowel diseases. Little is known about the clinical outcome of patients with obscure gastrointestinal bleeding (OGIB). METHODOLOGY: Seventy eight patients underwent CE for OGIB and were followed up for at least 6 months after CE. The diagnostic yield of CE and the rate of re-bleeding during the follow-up period were established. RESULTS: Out of our 78 OGIB patients, 35 (44.9%) had significant lesions. There was a significant difference in the rate of identification of significant lesions between the on-going overt bleeding cases and previous overt bleeding cases (68.8% vs. 37.8%, respectively, p=0.043). Of the 46 patients with significant or insignificant lesions, 12 (26.1%) had one or more re-bleeding episodes during the follow-up period. On the other hand, only one (4%) of the 26 patients with negative findings had a re-bleeding episode (p=0.025). CONCLUSION: In conclusion, our study confirmed the role of CE in the diagnosis of OGIB, especially in the on-going overt bleeding cases. The OGIB patients with negative CE findings showed a low re-bleeding rate in the follow-up period. Further long-term follow-up studies are needed in future to examine the negative CE cases. PMID- 21661388 TI - Detailed dissection of hepato-caval junction and suprarenal inferior vena cava. AB - BACKGROUND/AIMS: There are few anatomical studies on hepatic vein compared to hepatic artery and portal vein. The aim of this study is to clarify the branching patterns of hepatic veins, supra and infra-diaphragmatic course of suprarenal inferior vena cava and its relation with the liver. METHODOLOGY: Between March and May 2008, 103 consecutive autopsy examinations were included in the study. Hepatic vein anatomy was classified according to the Broelsch classification. The anatomic relations of supra-diaphragmatic and infra-diaphragmatic (suprarenal) inferior vena cava were revealed. RESULTS: Majority of subjects have Type a (42.7%) variation. The inferior right hepatic vein was presented alone in 26 and together with middle right hepatic vein in 15 subjects. Most of the phrenic veins were drained to the right-anterior sidewall of inferior vena cava (n=21/25 above the diaphragm and, n=144/306 below the diaphragm). Drainage of the right adrenal vein directly into the right side of the inferior vena cava was found in 82 subjects (80%). Most of subjects had 2 lumbar branches in the posterior sidewall of infradiaphragmatic inferior vena cava (n=92/103). CONCLUSIONS: The proposed classification of hepatic veins and obtained anatomical details from this study provides useful assistance for hepatic surgeons in phases of operative planning and vascular control maneuvers required in liver surgery. PMID- 21661389 TI - Application of irregular mesohepatectomy with alternating regional blood occlusion for central liver tumors. AB - BACKGROUND/AIMS: Mesohepatectomy is rarely used to treat central liver tumors because of its technical complexity. This retrospective study aimed to evaluate the application of irregular mesohepatectomy with alternating regional blood occlusion for central liver tumors. METHODOLOGY: From 2003 to 2008, 128 patients with central liver tumors were treated by irregular mesohepatectomy (Group I, n=85) and anatomic mesohepatectomy (Group II, n=43) respectively. The clinical profiles and follow-up data, including the operation time, bleeding volume, blood transfusion volume, postoperative recovery of liver function and postoperative complications, were compared among the two groups. Kaplan-Meier analysis was made for survival rates comparison. RESULTS: The average operative durations were 195.1 +/- 52.4 min and 264.3 +/- 57.3 min in Group I and Group II, respectively. There was significant difference between the two groups in incidence of postoperative biliary fistula (18.8% vs 9.3%, p<0.05), but not in bleeding volume, blood transfusion volume, post-operative LFT changes and 1, 3 and 5-year survival rates. Kaplan-Meier survival analysis showed no significant difference between the two groups on survival rate. CONCLUSION: Irregular mesohepatectomy with alternating regional blood occlusion can achieve an efficacy comparable to anatomic mesohepatectomy. PMID- 21661390 TI - Analysis of acute to chronic hepatitis E: 6-10 year follow-up. AB - Hepatitis E as a self-limiting disease and is generally not chronic, although in a small number of cases it appears to be so. Complete data were collected from 1104 cases of hepatitis E out of which 28 did not heal after liver treatment. These 28 cases were followed-up for 6-10 years. It was found that hepatitis can be chronic. Chronic hepatitis cases are more common in males, but a high degree of inflammatory activity and fibrosis were not evident. After 6-10 years of follow-up observation, cirrhosis or liver cancer did not appear. This is significantly different from the hepatitis B and hepatitis C viruses. Further, most cases of chronic hepatitis E occurred in older patients, in which the ability to remove the virus may decline, contributing to the more than six months duration, along with other important reasons. In addition, we also observed that several cases were unhealed or chronic because of a combination with other viruses. Chronic disease or the long-term use of immune agents may be one of the causes for chronic hepatitis E. PMID- 21661391 TI - Application of Cox model in coagulation function in patients with primary liver cancer. AB - BACKGROUND/AIMS: To analyze the distribution of coagulation parameters in patients with primary liver cancer; explore the relationship between clinical staging, survival, and coagulation parameters by using Coxproportional hazard model; and provide a parameter for clinical management and prognosis. METHODOLOGY: Coagulation parameters were evaluated in 228 patients with primary liver cancer, 52 patients with common liver disease, and 52 normal healthy controls. The relationship between primary livercancer staging and coagulation parameters wasanalyzed. Follow-up examinations were performed. The Cox proportional hazard model was used to analyze the relationship between coagulationparameters and survival. RESULTS: The changes in the coagulation parameters in patients with primary liver cancer were significantly different from those in normal controls. The effect of the disease on coagulation function became more obvious as the severity of liver cancer increased (p<0.05). The levels of D-dimer, fibrinogen degradation products (FDP), fibrinogen (FIB), and platelets (PLT) were negatively correlated with the long-term survival of patients with advanced liver cancer. CONCLUSIONS: The stages of primary liver cancer are associated with coagulation parameters. Coagulation parameters are related to survival and risk factors. Monitoring of coagulation parameters may help ensure better surveillance and treatment for liver cancer patients. PMID- 21661392 TI - Intensity-modulated radiotherapy in the treatment of subhepatic carcinomas. AB - BACKGROUND/AIMS: The aim of our study was to evaluate preliminary results of intensity modulated radiotherapy (IMRT) in patients with inoperable subhepatic tumors. METHODOLOGY: Thirteen patients with inoperable cholangiocarcinoma or gall bladder carcinoma were treated by biliary drainage and intensity modulated radiotherapy. In patients with tumors limited to the biliary duct only tumor stenosis was irradiated to the dose of 50-60 Gy. In patients with bulky extraductal tumors the dose was 50 Gy/25 fractions to the whole tumor and an integrated boost was used to raise the dose to the malignant stenosis to 60 Gy/25 fractions. RESULTS: Doses to organs at risk (duodenum, small intestine, liver) were in tolerable limits. In four patients transient fever occurred; one patient had duodenal bleeding that resolved after conservative treatment. Recurrent dilatation of the biliary tract was observed in 4 patients and was managed by exchange of the internal biliary drainage. Median survival was 10.4 months, 5 patients survived for more than one year following diagnosis. CONCLUSIONS: IMRT of inoperable extrahepatic biliary tract tumors allows application of high doses of radiation to the tumor with effective sparing of healthy tissues. The control of jaundice is good. In selected cases IMRT may prolong overall survival. PMID- 21661393 TI - Non-surgical management in 336 patients of hydatid disease: 23 years experience at Riyadh Military Hospital. AB - BACKGROUND/AIMS: Patients with hydatid cysts (336) were studied at Riyadh Military Hospital, Saudi Arabia, between February 1985-June 2008, out of which 254 patients underwent non-surgical management and 82 patients had surgery. METHODOLOGY: Drug therapy was administered to 194 of 254 patients: albendazole was administered in 65 patients; (albendazole+praziquantel) in 129 patients; 12 patients had endoscopic management; 48 patients had Percutaneous-Aspiration Injection-Reaspiration (PAIR) and 82 patients had surgery. RESULTS: Out of 65 patients, 34 had completed albendazole of which 12 (35%), had cyst disappearance, 8 patients had partial cyst reduction, 12 had no response and were referred for combined therapy or PAIR; 66 patients with cysts in different organs completed the study using albendazole+praziquantel, in 50% of these cysts had disappeared and 16 (24%) observed reduction of cysts; 48 patients underwent PAIR, of which in 36 cysts (66.66%) disappeared; 82 patients had surgery and 20% had post-surgical complications. CONCLUSION: A great advance recently has happened in the non surgical management of hydatid cysts including medical, PAIR and endoscopic management, which has led to a significant reduction in the need for surgical intervention. PMID- 21661394 TI - Radioimmunoscintigraphy of colorectal carcinomas with 99mTc-labelled antibodies. AB - BACKGROUND/AIMS: The aim of the study was the evaluation of the clinical validity of immunoscintigraphy with 99mTc labeled antibodies for the detection of metastases and recurrences of colorectal carcinomas. METHODOLOGY: We examined 17 patients with colorectal carcinomas. Scintigraphy was performed with anti-CEA MoAb 99mTc-BW 431/26. RESULTS: Recurrences of carcinomas were detected and confirmed by surgery in 6 patients, recurrences with liver metastasis in 5 patients, and only liver metastases in 3 patients. Planar immunoscintigraphy was positive in 5/8 patients with liver metastases and 8/11 patients with recurrences, whereas in 1/8 liver metastases and 3/11 recurrences were detected only by tomography. In two patients with metastases in the abdominal lymph nodes immunoscintigraphic findings both on planar scintigraphy and tomoscintigraphy were false negative. CONCLUSIONS: Immunoscintigraphy with 99mTc labeled antibodies can be useful in the diagnosis of recurrences and metastases of colorectal carcinoma, viability assessment after radiotherapy and in the choice of the adequate surgical treatment. PMID- 21661395 TI - Infiltration of CD14-positive macrophages at the invasive front indicates a favorable prognosis in colorectal cancer patients with lymph node metastasis. AB - BACKGROUND/AIMS: To clarify the distribution of CD14+ macrophages in colorectal cancer using flow cytometry and immunohistochemistry, and to elucidate the roles of CD14+ macrophages in colorectal cancer. METHODOLOGY: We studied the paired cancerous and corresponding normal tissues from 52 patients with colorectal cancer for the distribution of CD14+, CD1a+, CD83+ and CD68+ cells, and correlated the findings with the clinicopathological characteristics and with the expression of CD86 and CD80 in the CD14+ macrophages, which are co-stimulatory factors for T cell activation. RESULTS: 1) CD14+ macrophages were distributed predominantly at the invasive front of colorectal cancer tissues, rather than in the normal tissues, 2) a high percentage of the CD14+ macrophages expressed CD86 and CD80, and 3) in the colorectal cancer cases with lymph node metastasis, the 5 year overall survival rate of the high CD14 group, in which the number of CD14+ macrophages was higher than the median, was better than that of the low CD14 group. CONCLUSION: The infiltration of CD140 macrophages at the invasive front indicates a favorable prognosis in colorectal cancer patients with lymph node metastasis. In addition, the activation of CD14+ macrophages and T cells may facilitate the development of new immunotherapeutic strategies for colorectal cancer patients. PMID- 21661396 TI - Human epidermal growth factor receptor-2 and topoisomerase II alpha expressions in rectal cancer. AB - BACKGROUND/AIMS: The objectives of the present study were to investigate human epidermal growth factor receptor-2 (HER2) and topoisomerase II alpha (T2a) expressions in rectal cancer (RC) and to evaluate their correlation. METHODOLOGY: The status of HER2 and T2a in tumor specimens from 302 RC patients was retrospectively assessed using immunohistochemistry. Clinicopathological parameters were compared. RESULTS: HER2 overexpression (2+ or 3+) was found in only 31 patients (10.3%), whereas positive immunostaining for the T2a protein was detected in most patients (n=272, 90.1%). HER2 expression tended to positively correlate with T2a level (r=0.224; p<0.001). Relationships between HER2 expression and patients' age and gender, tumor size, differentiation, and TNM stage, lymph node metastasis, and lymphovascular invasion were not found (p>0.05). Logistic regression analysis identified TNM stage III and lymphovascular invasion as independent risk factors for T2a overexpression (p<0.05). CONCLUSIONS: As the contribution of HER2 appears minimal, it has low potential as a therapeutic target in RC. T2a may play an important role in cancer cell progression and invasion, and T2a inhibitors could be used in the treatment of RC. PMID- 21661397 TI - TEM and conventional rectal surgery for T1 rectal cancer: a meta-analysis. AB - BACKGROUND/AIMS: To compare transanal endoscopic microsurgery (TEM) with conventional radical surgery (CRS) for T1 rectal cancer focusing on safety, feasibility and efficacy of both procedures. METHODOLOGY: An online search of Ovid, Medline, Embase, Pubmed and Cochrane Controlled Trials Register was undertaken to identify studies comparing TEM with CRS published in English between 1984 and March 2010. Only studies comparing TEM with CRS for T1 rectal cancer treatment and with a minimum of 20 cases were included. The parameters compared were postoperative complications, hospital mortality, recurrence rate and 5-year survival. RESULTS: Five studies met screening criteria and 397 patients were enrolled in the meta-analysis; 216 were treated with TEM and the rest received CRS. Complications were observed in 16/196 in the TEM group and 77/163 in the CRS group. The difference was significant (p=0.01). The rate of mortality was 3.68% in CRS group, and 0 in TEM group (p=0.01). The 5-year survival was similar (p=0.84), the TEM group was 80.1% and the CRS group was 81.0%. However, there was more recurrence in the TEM group compared to CRS group (p=0.0004). TEM group was 12.0%, while CRS group was 0.5%. CONCLUSION: Compared with CRS, TEM had significant shorter hospital stay and fewer postoperative complications. TEM is a safe, feasible and effective option for T1 rectal cancer. Though TEM had a slightly higher rate of recurrence than CRS, no significant difference on 5-year survival was observed. PMID- 21661398 TI - Expression of COX-2, MMP-2 and VEGF in stage II and III colorectal cancer and the clinical significance. AB - OBJECTIVES: To investigate the expression of COX-2, MMP-2 and VEGF in colorectal cancer and the clinical/pathological significance. METHODS: Stage II and III colorectal cancer patients (149 cases) that received radical resection between May 2003 and November 2008 and who had complete clinical and pathological data, were recruited in this study. Expression of COX-2, MMP-2 and VEGF were detected by immunohistochemistry. RESULTS: The positive rate of COX-2, MMP-2, and VEGF expression was 60.4%, 50.3% and 69.1%, respectively. COX-2 correlated with stage, lymph node metastasis, postoperative recurrence and metastasis, and survival rate; MMP-2 correlated with intestinal wall invasion, stage, number of lymph node metastasis, postoperative recurrence and metastasis, and survival rate; VEGF correlated with preoperative serum levels of CEA and CA199, postoperative recurrence and metastasis, and survival rate; the positive rate of COX-2, MMP-2 and VEGF co-expression was 32.9%, which correlated with stage, number of lymph node metastasis, preoperative serum level of CEA, postoperative recurrence and metastasis, and survival rate. CONCLUSION: The expression of COX-2, MMP-2 and VEGF in colorectal cancer plays a synergistic promoting effect on the malignant biological behavior of tumors, which could be used as a marker to determine the malignant progression, invasion and metastasis, and prognosis of the tumor. PMID- 21661399 TI - Preoperative serum carbohydrate antigen 242 is a useful predictive and prognostic marker in colorectal cancer. AB - BACKGROUND/AIMS: Tumor markers (TM) play an important role in the management of colorectal cancer (CRC). This study evaluates the predictive and prognostic value of preoperative serum carbohydrate antigen 242 (CA242) in CRC. METHODOLOGY: Preoperative serum CA242 level was detected by C12 protein-chip diagnostic system in 185 CRC patients, and the predictive value of CA242 in stage, lymph node metastasis and tumor invasion depth was assessed. The prognostic value of CA242 for 5-year overall survival (OS) was analyzed. RESULTS: CA242 positive rate elevated with stage advancing, lymph node metastasis and tumor invasion depth, the differences between stage III+IV and stage I+II, between positive lymph node and negative lymph node, between T3+T4 and T1+T2, reached statistical significance (all p<0.05). Receiver operating characteristic analysis demonstrated that the area under the curve of CA242 in stage, lymph node metastasis and tumor invasion depth were 0.677, 0.631 and 0.744, respectively. Patients with higher CA242 had worse 5-year OS compared to those with normal CA242 (p=0.0002). Multivariate analysis showed stage (p=0.000) and preoperative serum CA242 (p=0.026) as independent prognostic factors for 5-year OS of CRC patients. CONCLUSIONS: The preoperative serum CA242 can predict stage, lymph node metastasis and tumor invasion depth, and can be used as an independent prognostic factor for OS of CRC. PMID- 21661400 TI - Serum LDL-C and LDL-C/HDL-C ratio are positively correlated to lymph node stages in males with colorectal cancer. AB - BACKGROUND/AIMS: Although changes in serum lipid profile have been reported in CRC, the specific association between serum lipid profile and lymph node stages remains uncertain. METHODOLOGY: Fasting serum lipid profile, including TC, TG, HDL-C and LDL-C was retrospectively evaluated in 968 patients undergoing curative resection for primary CRC. To determine the nutritional status, the serum albumin levels were measured and BMI was calculated. Statistical analyses were performed to investigate the association of serum lipid profile with lymph node stages. RESULTS: Serum lipid levels correlated well with rate of lymph node metastasis and high LDL-C and low HDL-C levels tended to present more advanced lymph node stages. The observed elevation of the LDL-C/HDL-C ratio for patients with N2 stage was statistically significant when compared with patients with N1 stage. When separated by gender, multivariate logistic regression analysis showed that both LDL-C levels and LDL-C/HDL-C ratio had independent association with advanced N2 stage in males, but not in females. In addition, LDL-C/HDL-C ratio might be a more effective biomarker for identifying N2 stage than LDL-C levels alone (OR value: 2.85 vs. 1.63). CONCLUSIONS: Elevated serum LDL-C levels and an increased LDC-C/HDL-C ratio might favour development of lymph node metastasis and LDCC/HDL C ratio might be a more effective biomarker for identifying advanced N2 stage than LDL-C levels alone, especially for male patients with CRC. PMID- 21661401 TI - Longitudinal surveillance of mid- and distal rectum cancer in a subset of patients with specific histology. AB - OBJECTIVE: A prospective study in 82 consecutive patients with mid- and distal rectal adenocarcinomas having specific histology and tumor stage was conducted to asses impact of curative surgery. METHODS: Patients with moderately differentiated adenocarcinoma (MDAC) with or without mucinous differentiation underwent curative resection. Forty patients were in Stage B1-B2 and 42 patients were in Stage C1-C2. Surgery options were: (1) Abdominoperineal resection (APR) for tumors located within 6cm of the anal verge and (2) Tumor specific mesorectal excision (TSME) and low anterior anastomosis (LAA) for those located between 6 to 12cm from the anal verge. The primary endpoints were overall (OS) and disease free survival (DFS). RESULTS: Patients in Stage B1-B2 had a local failure rate of 15% compared with 31% of patients in stage C1-C2 (p=0.18). Satellite tumor nodule formation (STN) was observed in one patient in B group and in 13/42 (31%) of Stage C tumors. LR did not vary with mucinous differentiation. Only lymph node involvement (N1-3) (p=0.028) had an impact on locoregional recurrence and both lymph node involvement and STN formation influenced disease-free survival (p=0.008). CONCLUSION: Preoperative precise detection of Stage C rectal adenocarcinomas is of utmost importance to facilitate the implementation of therapies for downstaging and for better local and distant control following surgery. PMID- 21661402 TI - Aneurismal type of colorectal cancer: imaging characteristics of gastrointestinal endoscopy, computed tomography and magnetic resonance imaging. AB - BACKGROUND/AIMS: Only a few studies have investigated aneurismal large-intestinal malignant diseases. The present study reported five cases of aneurismal colon cancer that were experienced over 20 years. The present study aims to define the pathological and diagnostic imaging characteristics of aneurismal colon cancer. METHODOLOGY: A case series from a retrospective review of large-intestinal malignant tumors at Saga Medical School, Japan. Barium enema was performed in 876 patients with large-intestinal advanced cancer, which included five with aneurismal-type cancer. RESULTS: The characteristics of the 5 cases were as follows: (i) pathological findings were poorly differentiated adenocarcinoma without desmoplastic change or mucinous adenocarcinoma; (ii) a typical aneurismal type revealed by barium enema had a low elevated tumor edge without stenosis upon endoscopic examination; (iii) computed tomography showed low attenuation without enhancement of contrast material; and (iv) magnetic resonance imaging indicated high intensity in the T2-weighted images of mucinous adenocarcinoma. CONCLUSION: We revealed 5 cases of aneurismal colon cancer, which had characteristic pathological findings and diagnostic imaging, and poor prognosis. PMID- 21661403 TI - Prognostic value of preoperative CEA and CA 19-9 levels in patients with colorectal cancer. AB - AIMS: This study evaluated the prognostic value of the preoperative CEA and CA 19 9 levels on the survival time and TNM staging in patients with colorectal cancer. METHODOLOGY: We retrospectively analyzed 172 patients who underwent potentially curative resection of colorectal cancer (TNM I-III) between 2002 and 2007. Clinical data were obtained from medical charts, including age, gender, tumor location, TNM stage, mortality, follow-up duration, and preoperative CEA and CA 19-9 levels. A CEA > or = 5ng/mL was defined as abnormal (CEA+), while the cutoff for the CA19-9 was set at 37U/mL (CA19-9+). Patients were categorized into Groups I-IV according to the preoperative serum CEA and CA 19-9 levels [CEA/ CA 19-9: ( /-), (+/-), (-/+), and (+/+)]. RESULTS: Follow-up was longest for Group I (p<0.001). Mortality rates were higher in Groups V (p<0.001) and II (p<0.008). On comparing patients according to CEA levels, survival was longer in the CEA negative group (p=0.0001). On comparison according to CA 19-9 levels, survival was greater in the CA 19-9-negative group (p=0.0001). While CEA (p<0.016) and CA 19-9 (p<0.001) were independent prognostic factors according to the logistic regression analysis, TNM (p=0.002), CEA (p<0.001), and CA 19-9 (p<0.001) were prognostic factors in the ROC curve analysis. CONCLUSIONS: Colorectal cancer patients with elevated levels of both CEA and CA 19-9 have a significantly poorer prognosis than those with normal levels of these tumor markers. PMID- 21661404 TI - Solo surgery in laparoscopic colectomy: a case-matched study comparing robotic and human scopist. AB - BACKGROUND/AIMS: Recent technical developments have enabled solo surgery in laparoscopic surgery. Our experience of solo surgery using the voice-guided robotic arm in laparoscopic colectomy for colorectal cancer was analyzed. METHODOLOGY: The colon-lifting method was used in this study. The laparoscope was handled by AESOP3000. The colon was retracted anteriorly by the thread that passed through the mesocolon. This method enables lymphadenectomy by stretching of feeding vessels and obviates the need for an assistant. The short-term outcomes and survival between robotic arm and human scopist in a series of laparoscopic colectomies were compared with a case-matched control study. RESULTS: The numbers of both group patients were 11 respectively. There was no conversion to open surgery in both groups. The operation time (Robotic vs. Human=269 min. vs. 265) and laparoscopic time (209 vs. 212) were not significant differences. There were also no significant differences in the bleeding, the morbidity rate and the numbers of dissected lymph nodes between the two groups. The five-year overall (81.8% vs. 72.7%) and disease-free (72.7% vs. 62.3%) survivals showed no significant differences. CONCLUSIONS: Laparoscopic solo surgery in colectomy is safe and feasible, without any deterioration of the curative potential of the procedure. PMID- 21661405 TI - Heterogeneity in primary colorectal cancer and its corresponding metastases: a potential reason of EGFR-targeted therapy failure? AB - Epidermal growth factor receptor (EGFR)-targeted therapy represents an important approach in metastatic colorectal cancer (CRC) therapy. However, a number of CRC patients show intrinsic or acquired resistance to EGFR-targeted therapy. EGFR antibody therapy is established in CRC patients with wild-type KRAS. However, up to half of these patients do not respond to this therapy. This phenomenon implied some potential mechanisms of resistance to EGFR inhibitors might exist. One of the potential reasons to explain this phenomenon is heterogeneity of CRC. The heterogeneity of CRC has been well described at the morphological, molecular and genomic levels. This review discussed the potential relationship of heterogeneity, including intratumor heterogeneity of CRC and heterogeneity in primary CRC and its corresponding metastases, to EGFR-targeted therapy failure. PMID- 21661406 TI - Risk factors for mortality in patients with Mallory-Weiss syndrome. AB - BACKGROUND/AIMS: Although the majority of patients with Mallory-Weiss syndrome (MWS) have a benign course, in some patients MWS results in a fatal outcome. Therefore, this study was carried out to analyze the risk factors for mortality in patients with MWS. METHODOLOGY: The medical records of patients with MWS seen between March 1994 and July 2007 were reviewed retrospectively. The demographic characteristics, clinical and laboratory parameters, and endoscopic findings of the patients were analyzed and the risk factors for mortality were evaluated. RESULTS: A total of ninety-three patients (13 female and 80 male patients; median age, 53 years) were treated. The mortality rate was 9.7% (9/93). The patients with a fatal outcome were of advanced age and had a higher frequency of shock on arrival, lower hemoglobin level, more prolonged prothrombin time, higher AST and ALT levels, higher frequency of detection of exposed vessels on endoscopy, higher frequency of rebleeding, longer hospital stay, and required a larger volume of blood transfusion than those who did not have a fatal outcome. According to the results of a multivariate analysis, the significant risk factors for mortality in the MWS patients were advanced age (OR 1.222, 95% CI 1.015-1.028), very low hemoglobin level (OR 2.137, 95% CI 1.063-4.295), elevated AST level (OR 1.007, 95% CI 1.001-1.013), and presence of the clinical symptom of tarry stool (OR 45.45, 95% CI 1.080-1000). CONCLUSIONS: Intensive care with close monitoring is required for patients of advanced age with a low hemoglobin level, an elevated AST level, and the clinical symptom of tarry stool, since these are of prognostic importance in terms of the mortality in MWS patients. PMID- 21661407 TI - Long-term survivors of esophageal carcinoma with distant lymph node metastasis. AB - BACKGROUND/AIMS: Clinical extra-regional lymph node metastasis, M1 lymph node metastasis (M1 LYM), has been recognized as a far advanced condition in esophageal cancer. However, some patients with M1 LYM survive long-term. The purpose of this study was to identify the clinicopathological features of those patients with M1 LYM achieving long-term survival. METHODOLOGY: Between 2002 and 2008, 31 patients with squamous cell carcinoma of the thoracic esophagus with M1 LYM were treated at our institution. Of the 31 patients, four survived for more than three years. These four patients were examined retrospectively. RESULTS: Cervical lymph node metastasis was the cause of M1 LYM and no regional nodal metastasis was detected in any of the four patients. Primary lesions were non-T4 and located at the middle or lower thoracic esophagus in these patients. Two patients underwent radical esophagectomy with three-field lymphadenectomy and complete resection was confirmed by pathological examination. The other two patients underwent definitive chemoradiotherapy and complete response was confirmed. Three patients are alive without recurrence but one, who underwent definitive CRT, died of local recurrence. CONCLUSION: Solitary metastasis localized at the cervical node might be targeted specifically in an effort to improve the prognosis of M1 LYM patients with esophageal cancer. PMID- 21661408 TI - Clinicopathological and prognostic significance of EGFR over-expression in esophageal squamous cell carcinoma: a meta-analysis. AB - BACKGROUND/AIMS: To elucidate the clinicopathological and prognostic significance of epidermal growth factor receptor (EGFR) over-expression in esophageal squamous cell carcinoma (ESCC). METHODOLOGY: A meta-analysis of previous studies was performed to assess the effects of EGFR over-expression on clinicopathological parameters and overall survival (OS) in patients with ESCC, using pooled odds ratio (OR) with its 95% confidence interval (CI) and pooled hazard ratio (HR) with its 95% CI, respectively. RESULTS: A total of nine studies including 802 patients were subjected to the final analysis. The overall results suggested that over-expression of EGFR was significantly correlated with, not only the lymph node status and tumour differentiation grade, with a pooled OR of 0.64 (95% CI: 0.46-0.89; Z=2.62; p=0.009) and 1.60 (95% CI: 1.09-2.37; Z=2.37; p=0.018), respectively, but also the poorer OS with a pooled HR of 1.60 (95% CI: 1.05-2.43; Z=2.19 p=0.028). CONCLUSIONS: This meta-analysis suggests that over-expression of EGFR might play an important role in the progression of ESCC, and it might be useful as a predictive biomarker in clinical practice, yet the predictive value of EGFR in ESCC still needs further confirmation by prospective trials. PMID- 21661409 TI - Haplotype analysis of CTLA4 gene and risk of esophageal squamous cell carcinoma in Anyang area of China. AB - BACKGROUND/AIMS: To study the effect of cytotoxic T-lymphocyte antigen 4 gene haplotypes to susceptibility of esophageal squamous cell carcinoma. METHODOLOGY: A gender- and age-matched case-control design was used in this study. PCR-RFLP method was used to detect the genotype of CTLA4 in 205 patients and 205 control individuals in the Anyang area. Furthermore, haplotypes were calculated by PHASE2.1 software. Finally, the conditional logistic regression analysis was carried out to analyze the relevance between the risk of ESCC and the genotypes or haplotypes of CTLA4 gene. RESULTS: The CTLA4 rs231775 and rs4553808 genotypes in patients with ESCC were significantly different from controls (p=0.004, p=0.023, respectively). The AG and AA genotypes of rs231775 were highly correlated with the risk of ESCC (Adjusted OR=2.280, 95%CI=1.433-3.629, p=0.001; Adjusted OR=2.192, 95%CI=1.229-3.911, p=0.008, respectively), and AG genotype of rs4553808 also increased the susceptibility of ESCC (Adjusted OR=1.848, 95%CI=1.220-2.800, p=0.004). Further study suggested that AAG haplotype may enhance the risk of ESCC (Adjusted OR=5.035, 95%CI=1.599-15.860, p=0.005), but GAA haplotype played a protective role (Adjusted OR=0.413, 95%CI=0.251-0.680, p=0.001). CONCLUSIONS: Our research confirmed that CTLA4 genetic variation was related to ESCC in the Anyang area and GAA haplotype was the protective factor of ESCC. PMID- 21661410 TI - A randomized-controlled trial of endoscopic treatment of acute esophageal variceal hemorrhage: N-butyl-2-cyanoacrylate injection vs. variceal ligation. AB - BACKGROUND/AIMS: This prospective randomized trial compares the efficacy of N butyl-2-cyanoacrylate injection and variceal ligation in emergency endoscopic treatment of acute esophageal variceal hemorrhage in patients with portal hypertension and chronic liver disease. METHODOLOGY: Between January 2004 to December 2008 43 patients with endoscopy-proven acute esophageal variceal hemorrhage were randomly assigned to one of the two treatment groups: endoscopic injection with N-butyl-2-cyanacrylate (n=22) and endoscopic variceal ligation (n=21). Vital signs, the amount of blood transfusion and infection status were recorded before and after endoscopic treatment. Within two weeks after initial endoscopic treatment, prophylactic variceal ligation was performed until the varices were eradicated. RESULTS: Success in arresting acute bleeding was no different in either group. The re-bleeding rate was higher in the cyanoacrylate group than the ligation group (13.6% us. 4.7%), with no statistical difference (p=0.60692). The mean amount of blood transfused was similar in both groups. Ten (45.5%) patients in the cyanoacrylate group and 7 (33%) in the ligation group died during an observational period of 14.1 +/- 13.9 months and 21.0 +/- 17.2 months, respectively (p=0.3272). CONCLUSIONS: The efficacy of endoscopic injection therapy with N-butyl-2-cyanoacrylate to control acute esophageal variceal hemorrhage showed no difference to endoscopic variceal ligation nor did the esophageal variceal re-bleeding rate and mortality rate. PMID- 21661411 TI - A 10-year experience of shunt surgery for esophago-gastric varices in a single center in Japan. AB - BACKGROUND/AIMS: We report 10 years' experience of shunt surgeries, and in particular Inokuchi shunt operation, at a single Japanese center. METHODOLOGY: Subjects were 50 patients who underwent shunt surgery, including Inokuchi shunt, distal splenorenal shunt, H-graft shunt, and inferior mesenteric venous-left renal vein shunt from November 1997 to November 2007. These patients were divided into two groups, a selective shunt group and a non-selective shunt group. RESULTS: Surgical duration was significantly longer in the selective group than in the non-selective group (p<0.0001). Blood loss was also significantly larger in the non-selective group (p=0.012). Pre-portal venous pressure did not change significantly after shunting in the selective shunt group. On the other hand, it decreased significantly from 378 +/- 39.7 mmH2O to 246 +/- 56.0 mmH2O (p<0.0001) in the non-selective group. The 2 and 5 year patency rates were 87% and 68%, respectively, in the selective shunt group, and 87% and 87% in the non-selective shunt group. CONCLUSIONS: Our data on survival rate and shunt patency for Inokchi shunt are similar to those originally reported by Inokuchi in 1984. The consecutive experiences of shunt operation in a single center were important for the improvement of surgical skills, both of the individual surgeon and the team. PMID- 21661412 TI - Are symptomatic changes in irritable bowel syndrome correlated with the capsule endoscopy transit time? A pilot study using the 5-HT4 receptor agonist mosapride. AB - BACKGROUNDS/AIMS: A prospective correlation study of symptomatic changes due to administration of prokinetic drugs and changes of transit time of capsule endoscopy (CE), for patients with constipation-predominant irritable bowel syndrome (IBS-C), and examination of usefulness of CE in the objective evaluation of IBS-C. METHODOLOGY: Mosapride citrate was administered to ten subjects and CE transit evaluated together with a symptom questionnaire before and after administration. Frequency and severity of abdominal pain, times of defecation and Bristol stool scales were listed and scored. Primary and secondary endpoints were the correlation between symptomatic changes due to the administration and changes of CE transit and the effect of mosapride citrate on IBS-C, CE findings, and gastric and small bowel transit time (GTT, SBTT). RESULTS: After administration for 4 weeks, the mean scores of evaluated symptoms all improved. GTT was not significantly changed, but SBTT showed significant shortening post-administration (p=0.02). In only one patient's CE, three small erosions were detected. The changes in the times of defecation before and after the administration were significantly correlated with those in the SBTT of CE (R=0.888, p=0.0006). However, other symptoms were not significantly correlated with SBTT. CONCLUSIONS: CE transit correlated with intestinal motility in symptomatic changes and could be a possible index for the objective assessment of motility in IBS-C. PMID- 21661413 TI - A pilot study of capsule endoscopy for the diagnosis of radiation enteritis. AB - BACKGROUND/AIMS: Capsule endoscopy may be a useful diagnostic tool for radiation enteritis in select situations. We conducted this pilot study to test feasibility of capsule endoscopy in the diagnosis of radiation enteritis. METHODOLOGY: Patients who received chemoradiotherapy to treat pancreatic cancer were enrolled. To increase the diagnostic yield of radiation enteritis, capsule endoscopy was performed in patients having anemia or chronic abdominal pain after chemoradiotherapy. RESULTS: Fifteen patients were enrolled between June 2007 and December 2008. The mean age was 63.4 +/- 8.0 years. The median radiation dose was 5040cGy with range of 4500-5994cGy. The mean total operating time of capsule was 10h 12 min +/- 2h 37 min, and the complete examination rate to the cecum was 93.3%. Nine patients (60%) were suspected to have radiation enteritis, and of these, five (33.3%) had abnormal findings that strongly suggested radiation enteritis. Congested mucosa and erythematous mucosa were the most frequent abnormal lesions. No capsule retention or other complications occurred. CONCLUSIONS: Capsule endoscopy may safely and effectively diagnose radiation enteritis in patients previously treated with chemoradiotherapy on the upper abdomen, although a larger trial is needed to confirm this. PMID- 21661414 TI - Effects of dexamethasone on ischemia reperfusion injury following pringle maneuver. AB - BACKGROUND/AIMS: Hepatic ischemia reperfusion injury induced by Pringle maneuver leads to bacterial translocation, endotoxemia and apoptosis. Our aim was to compare the effects of low and high dose dexamethasone pretreatment on antioxidant enzyme activities, bacterial translocation, endotoxemia and apoptosis, following Pringle maneuver. METHODOLOGY: Thirty-two rats were randomized into four groups; sham, control and two treatment groups; low dose dexamethasone (0.1 mg/kg) and high dose dexamethasone (1 mg/kg). In the treatment groups dexamethasone was administered intraperitoneally one hour before Pringle maneuver. Twenty-four hours after closing rats' abdomen, re-laparotomy was performed and tissue samples were taken from the mesenteric lymph nodes, liver, ileum and spleen and 1 mL of blood was drawn from the aorta. Bacterial translocation, endotoxemia, apoptosis and enzyme activities of G6PD, 6-PGD, GR, GST, GPx and CAT were evaluated. RESULTS: Low dose dexamethasone significantly decreased bacterial translocation to mesenteric lymph nodes, and reduced liver and enterocyte apoptosis, whereas high dose dexamethasone caused only a significant reduction in enterocyte apoptosis (p<0.05). Dexamethasone both in low and high doses significantly reduced the decrease in antioxidant enzyme levels (p<0.05). CONCLUSIONS: Low dose dexamethasone pretreatment caused constructive therapeutic effects after Pringle maneuver, whereas these effects were seen partially with a high dose. PMID- 21661415 TI - Malignant potential of Barrett's esophagus: special reference to HDAC-1 and MTA-1 expression. AB - BACKGROUND/AIMS: Barrett's esophagus is a major risk factor for esophageal adenocarcinoma. It is important to decide when and how to treat the patients with Barrett's esophagus (BE). It was reported that HDAC-1 (Histone Deacetylase-1) and MTA-1 (Metastasis-Associated Protein-1) were associated with initiation and progression of cancer. The aim of this study is to assess malignant potential of BE using the expression of HDAC-1 and MTA-1. METHODOLOGY: Seven BE cases with pathological specialized columnar epithelium and CK7/20 in an immunohistochemically positive state were selected from resected specimens of 23 patients with gastro-esophageal junction cancer. The expression of HDAC-1 and MTA 1 protein was evaluated using an immunohistochemical method. RESULTS: All seven cases with Barrett's esophagus were diagnosed as low grade dysplasia. Positive expression of HDAC-1 and MTA-1 was found in 0 out of 7 cases (0%) with normal esophageal epithelium, and 0 out of 7 cases (0%) with normal gastric epithelium. On the other hand, positive expression of both HDAC-1 and MTA-1 was found in 6 out of 7 (85.7%) cases with Barrett's epithelium and 7 out of 7 (100%) cases with gastro-esophageal-junction-cancer, respectively. CONCLUSION: Positive expression of HDAC-1 and MTA-1 was found even in low grade dysplasia. Therefore, BE with HDAC-1 and MTA-1 expression is considered to be a precancerous lesion re quiring curative treatment. PMID- 21661416 TI - Double-balloon enteroscopy in the diagnosis and management of small-bowel diseases. AB - BACKGROUND/AIMS: The aim of this study was to investigate the diagnostic yield of double-balloon enteroscopy (DBE) and its impact on subsequent management. METHODOLOGY: This study is a retrospective analysis of 300 consecutive patients for investigation of small bowel disease that had been suspected by both clinical symptoms and imaging tests. The final management was guided by the results of DBE. Demographic, clinical, procedural and outcome data were collected for analysis. RESULTS: Among the 300 patients, lesions were found in 213 (70.1%). These lesions were small-intestinal ulcers, Crohn's disease, chronic inflammation, Meckel's diverticulae, angiodysplasia, polyps, ulcerative lipoma and tumor. Ninety-nine of the 115 patients with suspected intestinal hemorrhage were confirmed, with a positive rate of 86.1%. Also confirmed were 60 of the 99 patients with abdominal pain (positive rate of 60.6%); sixteen of 22 patients with chronic diarrhea (positive rate of 72.7%); thirty-three of the 55 patients with abdominal distention or malnutrition (positive rate of 60.0%); and 7 of 9 patients with refractory hypoalbuminemia. Treatment was performed in 2.3% of patients (3 polyps and 2 angiodysplasia). CONCLUSIONS: This large pilot series shows that DBE is a safe and feasible diagnostic and therapeutic tool for suspected or documented small-bowel diseases. PMID- 21661417 TI - STAT3 and beta-catenin signaling pathway may affect GSK-3beta expression in hepatocellular carcinoma. AB - BACKGROUND/AIMS: To study the correlation and significance of beta-catenin, STAT3 and GSK-3beta signaling pathway in hepatocellular carcinoma (HCC). METHODOLOGY: The HCC cell line HepG2 was transfected with small interfering RNA (siRNA) directed against 8-catenin or STAT3. After 72 and 96h, protein was extracted and the protein expression of beta-catenin, STAT3, and GSK-3beta was detected by Western blot analysis. RESULTS: After siRNA directed against beta-catenin was transfected into HepG2 cells, beta-catenin protein expression was decreased at 72 and 96h, GSK-3beta and p-GSK-3beta protein expression increased gradually at 72 and 96h, and STAT3 protein expression showed no change following transfection. After siRNA directed against STAT3 was transfected into HepG2 cells, STAT3 protein expression was decreased at 72 and 96h and beta-catenin, GSK-3beta and p GSK-3beta protein expression all increased at 72h and decreased at 96 h after transfection. CONCLUSION: In HCC, the beta-catenin signaling pathway may regulate GSK-3beta protein expression and the STAT3 signaling pathway may regulate beta catenin and GSK-3beta protein expression, thereby playing key roles during HCC genesis and development. PMID- 21661418 TI - Laparoscopic and hand-assisted liver resection: preliminary results at a mid sized hospital. AB - BACKGROUND/AIMS: Laparoscopic liver resection is controversial, specially for tumors. The aim of our study is to report our initial experience. METHODOLOGY: From October 2004 to October 2008, 15 patients underwent laparoscopic liver resection at our institution. RESULTS: Fifteen laparoscopic surgeries were performed on 15 patients. Five patients with hepatocellular carcinoma (HCC), six patients presented liver metastasis and four patients were diagnosed of hydatid cyst. In the HCC group two laparoscopic left lateral segmentectomies and 3 laparoscopic atypical resections were performed. Mean operative time was 230 minutes (95%CI 171-289). In the liver metastasis group six laparoscopic resections were performed. Two patients were converted to open surgery. The laparoscopic procedures were: 2 hand-assisted right hepatectomies, 1 left lateral segmentectomy and 1 atypical resection. The mean surgical time was 257.5 minutes, (95%CI 198-317). In the hydatid cyst group 4 laparoscopic surgeries were performed: three pericystectomies and one partial cystectomy. The mean operative time was 133.75 minutes, (95%CI 68-200). No re-operations were needed and no post operative deaths occurred. In oncological resections surgical margins were free of tumor in all cases. CONCLUSION: When liver laparoscopic surgery is performed in selected patients, it may offer similar results to conventional surgery with all the benefits of the minimal invasive procedures. PMID- 21661419 TI - Does interleukin-18 play a role in the pathogenesis of hepatic encephalopathy? AB - BACKGROUND/AIMS: It has been suggested that the presence of inflammation may accentuate the neuropsychologic alterations in hepatic encephalopathy (HE). The aim of the study was to investigate any association between alterations in plasma levels of the pro-inflammatory cytokine IL-18 and HE. METHODOLOGY: The study population included 63 patients with cirrhosis and 20 healthy controls. Laboratory data included international normalized ratio, plasma albumin, bilirubin, urea, creatinine, hsCRP and IL-18 (pg/mL). HE was assessed using West Haven criteria and critical flicker frequency (CFF) measurement. RESULTS: Forty two of the 63 cirrhotic patients had HE (4, 16, 21 and 1 patients in grade 0, 1, 2, 3, respectively). hsCRP and IL-18 were significantly increased in patients with HE compared with the control group (1.6 +/- 4.8 vs 0.5 +/- 0.8, p<0.001 and 121.4 (13.6-2043.6) vs 56.3 (13.0-174.0), p=0.006, respectively). The levels of hsCRP and IL-18 were significantly higher in the all cirrhotic patients than in the control subjects (p=0.002 and p=0.008 respectively). hsCRP was significantly higher in patients with HE (2.2 +/- 6) than in patients without HE (0.7 +/- 1.2) (p=0.013). The levels of IL-18 were found higher in patients with HE than in patients without HE [121.4 (13.6-2043.6) vs 103.8 (13.0-828.0)] but the difference was not significant (p=0.215). IL-18 was higher in patients with elevated hsCRP [124.6 (13.6-2043.6)] compared with those who had normal hsCRP [75.6 (13.0-753.2)] (p=0.029). CONCLUSION: There is an inflammatory response in the presence of cirrhosis and HE; and IL-18 may play a role in the perpetuation of chronic inflammation. PMID- 21661420 TI - Successful adult ABO incompatible living donor liver transplantation: experience with double infusion through the hepatic artery and portal vein. AB - BACKGROUND/AIMS: Multiple immunosuppressants, plasma exchanges (PEs), splenectomy, and/] or local infusion therapy (either hepatic artery (HA) or portal vein (PV) infusion) are needed in patients undergoing ABO-incompatible living donor liver transplantation (LDLT). Local infusion therapy is commonly undertaken using the single route, and double-infusion therapy has scarcely been investigated. Herein, we describe our experience with five ABO-incompatible LDLT patients who received double-infusion therapy via both the HA and PV. METHODOLOGY: Five patients (age 43-67 years, with HBV, HBV+HCC, HCV+HCC, PBC, cryptogenic) underwent ABO-incompatible LDLT. Following multiple PEs, LDLT with splenectomy was performed. Triple-immunosuppressant and double-infusion therapy, namely, methylprednisolone and PGE1 via the HA and gabexate mesilate via the PV were employed. RESULTS: All five patients achieved accommodation (22-66 months). One patient experienced transient AMR, and recovered after PE and intraarterial steroid infusion. Four of the five patients experienced PV mural thrombi near the PV catheter and recovered with pharmacological treatment. CONCLUSION: Thus, double-infusion therapy could also be useful for ABO-incompatible LDLT under control against PV mural thrombi. PMID- 21661421 TI - Efficacy of minimal dosage of calcineurin inhibitor for living donor liver transplant recipients with preoperative renal dysfunction. AB - BACKGROUND/AIMS: There is no standard protocol for immunosuppression for patients with preoperative chronic renal dysfunction (PCRD) scheduled for living donor liver transplantation (LDLT). In this prospective study, we evaluated the efficacy oflow-dose calcineurin inhibitor (CNI) protocol for such patients. METHODOLOGY: We studied 17 consecutive LDLT recipients with PCRD (creatinine clearance <50 mL/min). Six patients (LD-B group) received combination of low-dose CNI (LD-CNI), mycophenolate mofetil, corticosteroids, and anti-CD25 monoclonal antibody (mAb). Their clinical data were compared with conventional CNI group (N group, n=8) and LD-CNI without CD25 mAb group (LD group, n=3). RESULTS: Preoperative characteristics and incidence of acute rejection were similar in the three groups. None of the LD-B group recipients developed renal failure, while one (9%) did in the N group. Patient survival was better in the LD-B group than control groups. CONCLUSION: Our renal sparing protocol is feasible and effective for LDLT recipients with PCRD. PMID- 21661422 TI - Transcatheter arterial chemoembolization with fine-powder cisplatin-lipiodol for HCC. AB - BACKGROUND/AIMS: Fine-powder cisplatin has recently been developed, allowing the easy manufacture of high-density cisplatin-lipiodol suspensions. The aim of this study is to evaluate the efficacy and toxicity of transcatheter arterial chemoembolization (TACE) with fine-powder cisplatin and lipiodol suspension against advanced hepatocellular carcinoma (HCC). METHODOLOGY: We prospectively analyzed 20 patients (16 men, 4 women) with inoperative advanced HCC without extrahepatic metastases who underwent TACE with fine-powder cisplatin and lipiodol suspension in our hospital between August 2006 and December 2008. All patients were administered a suspension of fine-powder cisplatin at 10 mg/1 cm of tumor diameter. RESULTS: Partial response was seen in 10 cases, with stable disease in 7 cases and progressive disease in 3 cases. Overall response rate was 50%. The 1-year survival rate was 90%. Adverse effects (> or = grade 3) occurred in 40%, with vomiting in 5%, thrombocytopenia in 15%, elevated serum bilirubin in 20%, decreased serum albumin in 5%, fever in 65%, general fatigue in 15% and anorexia in 30%. However, no other life-threatening, adverse events were observed. CONCLUSION: TACE with fine-powder cisplatin suspended in lipiodol provides better therapeutic efficacy, suggesting the potential usefulness of this agent in the treatment of advanced HCC. PMID- 21661423 TI - The effect of preoperative portal vein embolization on liver regeneration after extended hepatic resection. AB - BACKGROUND/AIMS: This study was designed to evaluate the effect of portal vein embolization on liver regeneration after major liver resection. METHODOLOGY: A retrospective analysis was performed on 24 patients who underwent extended hepatectomy for hilar cholangicellular carcinoma between 2001 and 2008. Eleven patients underwent portal vein embolization and 13 did not. Computed tomography volumetry was used to assess liver volume. RESULTS: Clinical and operative characteristics were comparable between portal vein embolization group and non portal vein embolization group, except for mean estimated blood loss (p=0.034). Future remnant liver volume (p=0.004) differed between groups. However, preoperative future remnant liver volume (p=0.331), postoperative mean volume of the left lateral segement (p>0.9), total volume increase (p>0.9), and daily volume increase (p>0.9) did not differ significantly between groups. Within the portal vein embolization group, mean volume of the left lateral segment and daily volume increase after hepatic resection were significantly greater than after portal vein embolization (p=0.002). CONCLUSION: Liver regeneration after portal vein embolization was insignificant in comparison with that after extended hepatectomy. Moreover, portal vein embolization performed before extended hepatectomy did not reinforce liver regeneration after major liver resection. PMID- 21661424 TI - The correlation of hepatitis B virus pre-S mutation with mitochondrial D-loop mutations and common deletions in hepatocellular carcinoma. AB - BACKGROUND/AIMS: We investigated the correlation of HBV pre-S mutation with the sites and frequencies of mtDNA mutations in HCC patients. METHODOLOGY: Twenty seven HBV-related HCC patients and 8 control patients were included. HBV DNA was extracted from sera and the HBV S coding region was analyzed. Direct sequencing of the mtDNA D-loop was performed in paired HCC and adjacent non-neoplastic liver tissues. The common 4977 bp deletion of miDNA was examined by PCR. RESULTS: Study subjects were categorized into three groups: the pre-S mutant HBV-infected HCC patients (group 1), wild-type HBV-infected HCC patients (group 2) and HBV non infected patients (group 3). The frequency of mtDNA D-loop mutations in non neoplastic tissue was higher in group 1/2 than in group 3; however, there was no significant difference between group 1 and 2. The frequency of mtDNA D-loop mutations showed no significant difference between HCC and nonneoplastic tissues. The prevalence of the common 4977 bp deletion was lower in HCC compared to non neoplastic tissues, however, there was no difference according to the pre-S mutation. CONCLUSION: The present study does not support a pathophysiological role for the HBV pre-S mutation, related to mtDNA D-loop mutation or alteration of the common 4977 bp deletion, in hepatocarcinogenesis. PMID- 21661425 TI - Percutaneous liver biopsy: technique and safety. AB - BACKGROUND/AIMS: Percutaneous liver biopsy is a commonly used procedure for management of patients with liver diseases. We studied 107 patients of liver diseases with percutaneous liver biopsy to assess the need and usefulness of post procedure abdominal binder, analgesics, antibiotics or blood transfusion, and safety of the procedure. METHODOLOGY: We selected 107 consecutive patients having clear indication for liver biopsy. Each and every patient underwent percutaneous liver biopsy under uniform technique. The study was performed at the Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh during the period from July 2006 to December 2007. RESULTS: Mean age of the patients was 27.35 years with +/- 7.62 (SD) years. Eighty five of them were male and 22 were female. No abdominal binder or antibiotic was used after the procedure. No analgesic or blood transfusion was required after the procedure. CONCLUSION: Routine post procedure use of abdominal binder and antibiotic are needless. Analgesics and blood transfusion are not always needed after the procedure. Percutaneous liver biopsy is a safe procedure in expert hands. PMID- 21661426 TI - The influence of immunosuppression switching in liver function in adult hepatic transplantation. AB - We evaluate the 5-year results of a single-centre prospective randomized trial that compared cyclosporine microemulsion (CyA-me) in triple therapy (plus steroids and azathioprine) and Tacrolimus (Tac) in double therapy (plus steroids) for primary immunosuppression. One hundred adult patients undergoing liver transplantation were randomized to receive Tac (n=51) or CyA-me (n=49). Ten patients in group A, and thirty-one patients in group B had their main immunosuppressive agent switched. The switch was much more frequent from CyA-me to Tac (n=31; 62.3%), mainly because of lack of efficacy (n=12; 38.7%). Six of 10 patients were shifted from Tac to CyA-me for side effects. The clinical course of the majority of patients converted from CyA-me to Tac improved clearly after conversion. Donor age and acute rejection (number, severity and rejection free days) had a significative association with lack of efficacy in group B. In these series, the conversion to Tac from CyA-me could be accomplished safely, with an excellent long-term outcome. PMID- 21661427 TI - Treatment of recurrent hepatitis C (genotype 1) with pegylated interferon alfa-2b and ribavirin combination and maintenance therapy. AB - BACKGROUND/AIMS: This study aims at evaluating the efficacy of treatment with pegylated interferon (PEG-IFN) alfa-2b and ribavirin in patients with recurrent hepatitis C (genotype 1) after orthotopic liver transplantation (OLT) and the impact of this therapy on hepatic fibrosis at the end of conventional therapy and at the end of a period of maintenance treatment in non-responder patients. METHODOLOGY: Thirty-two consecutive patients diagnosed with recurrent HCV were considered candidates for antiviral therapy. RESULTS: Ten patients (31.2%) interrupted therapy due to side effects; sustained virological response (SVR) was observed in 27.2%, sustained biochemical response (SBR) in 31.8% and NR in 40.9% of cases. Eighteen patients underwent a biopsy at the end of conventional treatment: improved fibrosis score in all patients with SVR, improved score in 1 patient with SBR and stable score in 6 patients with SBR, worse score in 1 NR patient and stable in 6 NR patients. Six NR patients with stable score submitted to a maintenance therapy: improved score in 1 patient and stable score in 5 patients. CONCLUSIONS: In recurrent hepatitis C, in spite of the type of response, treatment slows down hepatic fibrotic evolution. PMID- 21661428 TI - Changes in liver stiffness measurement during antiviral therapy in patients with chronic hepatitis B. AB - BACKGROUND/AIMS: The usefulness of liver stiffness measurement (LSM) for monitoring changes in fibrosis and inflammation in chronic hepatitis B (CHB) patients receiving antiviral therapy is unknown. The aim of this study was to evaluate changes in liver stiffness and correlate them with changes in serological markers and histology in CHB patients receiving entecavir. METHODOLOGY: The study included 38 patients with CHB and 24 cirrhotic patients with CHB. All patients received entecavir for over 12 months. Liver stiffness was measured by transient elastography at baseline and after 48wks of therapy. Liver biopsy was performed on 15 patients at baseline and during therapy. RESULTS: Among 62 treated patients, 51 (82.2%) achieved HBV DNA <50 copies/mL and 43 (69%) achieved alanine aminotransferase (ALT) normalization at 48wks. The median liver stiffness value at baseline was 15.1 kPa (5.6-75.0) and decreased significantly to 8.8kPa (3.0-33.8) after 48wks. A decrease in liver stiffness value during therapy correlated significantly with decreases in albumin (r=-0.357, p=0.004), bilirubin (r=0.342, p=0.007), ALT (r=0.319, p=0.012), and aspartate aminotransferase (AST) (r=0.353, p=0.005) concentrations. Decreases in liver stiffness values correlated significantly with improvement in necroinflammatory scores. CONCLUSION: We suggest that LSM can reflect the changes of necroinflammation in patients with chronic hepatitis B receiving antiviral therapy. PMID- 21661429 TI - Isolated resection of the caudate lobe harboring hepatocellular carcinoma in the paracaval portion of the cirrhotic liver without complete interruption of hepatic outflow--an alternative surgical approach. AB - BACKGROUND/AIMS: Isolated resection of the caudate lobe harboring hepatocellular carcinoma (HCC) in the paracaval portion is a challenge. To obtain a bloodless surgical field and to minimize the intraoperative blood loss, various vascular procedures of the outflow occlusion have been introduced. However, in those with liver cirrhosis and portal hypertension total outflow occlusion, may increase the hemodynamic instability and postoperative morbidity. METHODOLOGY: Of 21 patients receiving curative resection of HCC in caudate lobe, 3 had tumors in the paracaval portion (a largest diameter of 2.5cm, 9.5cm and 7.3cm, respectively). A Satinsky vascular clamp was applied obliquely on one side of inferior vena cava (IVC) to preserve the hepatic outflow. Pringle's maneuver was used for inflow control. RESULTS: Using such measures, curative resection was performed smoothly in these 3 patients. Repair of an IVC defect by simple continuous suture with prolene 4-0 was undertaken in the second one. All patients had an uneventful postoperative course. CONCLUSION: During resection of HCC in the paracaval portion of caudate lobe, using side clamp ing of IVC without complete interruption of hepatic outflow is safe and feasible. We suggest it as an alternative approach. It would reduce the hemodynamic instability and perioperative morbidity in a cirrhotic liver. PMID- 21661430 TI - Diabetes may not affect outcomes in hepatocellular carcinoma after radio frequency ablation. AB - BACKGROUND/AIMS: Diabetes mellitus (DM) is prevalent in patients with hepatocellular carcinoma (HCC) but its effects on post-radiofrequency ablation (RFA) have not been elucidated. This study aims to determine whether DM significantly impacts the outcomes in patients with HCC after RFA. METHODOLOGY: This retrospective study included 161 HCC patients successfully treated with RFA. Intra-hepatic HCC recurrence and survival were analysed. RESULTS: No significant difference was found for 1-, 2-, 3- year's intra-hepatic HCC recurrence rates (DM: 45%, 61%, 74% vs. non-DM: 42%, 62%, 75%;p=0.935) and survival rates (DM: 83%, 80%, 73% vs. non-DM: 92%, 84%, 79%; p=0.218) between diabetics (53 patients) and non-diabetics (108 patients). In subgroup analysis of viral etiology and HCC, no significant difference was noted for intra-hepatic HCC recurrence or survival in hepatitis B virus-related or hepatitis C virus-related HCC. Multivariate analysis showed only persistent hepatitis influenced intra-hepatic HCC recurrence (p=0.021) and survival (p=0.022). CONCLUSION: DM may not affect the intra-hepatic HCC recurrence and survival in patients with HCC after RFA. However, persistent hepatitis after RFA may affect intra-hepatic HCC recurrence and survival. PMID- 21661431 TI - Transcatheter arterial chemoembolization enhances expression of Nm23-H1 and TIMP 2 in the tumor tissue of patients with hepatocellular carcinoma. AB - BACKGROUND/AIMS: To investigate the effects of transcatheter arterial chemoembolization (TACE) on expression of nm23-H1 and TIMP-2 in the tumor tissue and prognosis of patients with hepatocellular carcinoma (HCC). METHODOLOGY: Seventy-two patients with resectable HCC were randomized into two equal groups with 36 patients in each: TACE before surgical resection of HCC (Group A) and direct surgical resection of HCC (Group B). All samples were subjected to pathological examination and immunohistochemical staining using nm23-H1 and TIMP 2 antibodies. Expression level and distribution of nm23-H1 and TIMP-2 in tumor and adjacent tissue were assessed. Extrahepatic metastasis and survival time of patients in both groups were evaluated through 36 months follow-up. RESULTS: Immunohistochemical analysis showed that the tumor tissues from patients in Group A had a higher positive expression of nm23-H1 than Group B (chi2=15.52, p<0.01). Group A also showed a higher positive expression of TIMP-2 than Group B (chi2=9.00, p<0.05). Patients in Group A had a longer mean survival time (36 vs. 28 months in Groups A and B, respectively) and higher survival rate (chi2=5.734, p=0.017). CONCLUSIONS: Preoperative TACE enhances the expression of metastasis suppressors nm23-H1 and TIMP-2, and may potentially inhibit metastasis of HCC and increase the survival time of patients with the resectable HCC. PMID- 21661432 TI - Transarterial embolization for ruptured hepatocellular carcinoma: survival predictors. AB - BACKGROUND/AIMS: Survival predictors in patients with ruptured hepatocellular carcinoma (HCC) treated by transarterial embolization (TAE), have not been fully investigated. METHODOLOGY: Predictors of short-term (< or = 30 days) and long term (>30 days) survival were evaluated by using the logistic regression model and the Cox proportional hazard model, respectively. RESULTS: Forty-eight patients treated by emergency TAE were enrolled. The median survival time was 231 days. Although hemostasis was attained by TAE in 44 patients (91.7%), 15 patients (31.3%) died within 30 days. In a multivariate analysis, low serum creatinine level (p=0.018) was the only significant predictor of increased short-term survival. Of the 33 patients who survived more than 30 days after TAE, he patic resection was performed in 8, transarterial chemoembolization or chemotherapy in 8, and conservative treatment in 17. In a multivariate analysis, among the 33 who survived, unilateral location of tumors (p=0.041) and low a-fetoprotein level (p=0.004) were significant predictors of increased long-term survival. CONCLUSIONS: Short-term survival of patients with ruptured HCC who were treated by TAE depended on serum creatinine level on arrival. Long-term survival of patients who survived more than 30 days after TAE, was influenced by tumor location and a-fetoprotein level. PMID- 21661433 TI - Study of the efficacy of combination therapy of SiRNAs in HepG2.2.15 cells. AB - BACKGROUND/AIMS: Hepatitis B virus (HBV) infection is a world-wide health problem. The major obstacles for current anti-HBV therapy are the low efficacy and the occurrence of drug resistant HBV mutations. Recent studies have demonstrated that combination therapy can enhance antiviral efficacy and overcome the shortcomings. Here, the inhibitory effect mediated by combination of small interfering RNAs (siRNAs) targeting different sites of HBV nuclear localization signal (NLS) was monitored in HepG2.2.15 cells. METHODOLOGY: Recombinant plasmid psil-HBV was constructed and transfected into HepG2.2.15 cells. At 48, 72 and 96h after transfection, culture media were collected and cells were harvested for HBV replication assay. HBsAg and HBeAg in the cell culture medium were detected by enzyme-linked immunoadsorbent assay. Intracellular viral DNA and covalently closed circular DNA (cccDNA) was quantified by real-time PCR. HBV viral mRNA was measured by reverse-transcript PCR. RESULTS: Our data demonstrated that the three used siRNAs showed marked anti-HBV effects. Combination of siRNAs, compared with individual use of each siRNA, exerted a stronger inhibition on antigen expression and viral replication, even though the final concentration of siRNA in the therapy was the same. More importantly, we showed that combination therapy significantly suppressed HBV cccDNA amplification. CONCLUSION: Our results revealed that combination of siRNAs mediated a stronger inhibition on viral replication and antigen expression in HepG2.2.15 cells, especially, the amplification of cccDNA. PMID- 21661434 TI - Null-margin mesohepatectomy for centrally located hepatocellular carcinoma in cirrhotic patients. AB - BACKGROUND/AIMS: Anatomic mesohepatectomy is often anatomically restricted by the hilar structure and, therefore, difficult to perform with an adequate resection margin. Especially, in the case of a tumor which is in contact without infiltration with the critical intrahepatic vessels, mesohepatectomy has to be performed without a surgical margin. METHODOLOGY: From January 2005 to December 2009, thirty-seven patients with centrally located HCC underwent anatomic mesohepatectomy without resection margin in our hospital. The surgical techniques, clinicopathological characteristics and outcomes were reviewed. RESULTS: Mean operative time was 210 minutes (range 130 to 310 minutes) and mean intraoperative blood loss was 950 mL (range 150 to 4,500 mL). Mean postoperative hospitalization was 12.6 days (range 10 to 32 days). Postoperative complications were encountered in 37.8% of patients. The 1-, 3-, and 5-year recurrence-free survival rate was 75.1%, 39.3%, 22.5%, respectively, and the 1-, 3- and 5-year overall survival rate was 91.9%, 60.4%, 28.5%, respectively. CONCLUSION: Null margin mesohepatectomy is an oncologically radical but parenchyma-sparing hepatic resection. In patients with impaired functional liver reserve and with centrally located tumors in contact without infiltration with major vessels, expected zero resection margins should not be considered as a contraindication for surgery, and null-margin mesohepatectomy should be recommended as a reasonable surgical option. PMID- 21661435 TI - Intraepithelial ductal spread in colorectal carcinoma liver metastasis. AB - BACKGROUND/AIMS: This study aimed to evaluate the usefulness of immunohistochemical combinations for discrimination between intraepithelial ductal spread of colorectal carcinoma liver metastasis (CRLM) and that of intrahepatic cholangiocarcinoma (ICC). METHODOLOGY: A retrospective analysis of resected specimens from 151 patients with CRLM and 28 patients with ICC was conducted. Intraepithelial ductal spread along the bile ducts was judged positive when tumor cells spreading along the intact basement membranes of intrahepatic bile ducts. We evaluated immunoreactivity of cytokeratin (CK) 7, CK20, CDX2, MUC2, MUC5AC and human gastric mucin (HGM). RESULTS: Of the 151 patients with CRLM, 21 had intrahepatic bile duct involvement verified histologically. Intraepithelial ductal spread was detected in 17 of 21 (81%) patients with CRLM with bile duct involvement, whereas it was detected in 22 of 28 (79%) patients with ICC. CK20-positive/ CK7-negative immunophenotype demonstrated a high accuracy of 95% for evaluation of intraepithelial ductal spread from CRLM. CK7 positive/ CK20-negative immunophenotype demonstrated the highest accuracy of 85% for evaluation of intraepithelial ductal spread from ICC. CONCLUSION: Intraepithelial ductal spread is a common feature of CRLM with bile duct involvement. Immunohistochemical combination of CK7 and CK20 is useful for discrimination between intraepithelial ductal spread of CRLM and that of ICC. PMID- 21661436 TI - Gastric outlet obstruction caused by Riedel's lobe of the liver: a diagnostic and therapeutic challenge for surgeons. AB - Gastric outlet obstruction is commonly caused by gastric ulcers, pyloric stenosis, foreign bodies, and compression of the duodenum by pancreatic cancer and other intra-abdominal masses. There is no report on Riedel's lobe of the liver as a cause of this condition. This is the first report to describe Riedel's lobe of the liver as a cause of gastric outlet obstruction. An 81-year-old woman who complained of severe nausea and abdominal discomfort was admitted to our clinic. The physical examination revealed a mass in the right upper quadrant of the abdomen. An exploratory laparotomy showed an approximately 10x6-cm tongue like mass arising from the left lobe of the liver, extending to the umbilicus and compressing the prepyloric area of the stomach. The nature and location of the mass were compatible with Riedel's lobe. A cholecystectomy was performed and the compressing mass was fixed to the abdominal wall with a simple suture. The patient did well postoperatively and was discharged from the hospital. We also reviewed the English-language literature to provide an update on this subject. PMID- 21661437 TI - Surgical therapy of exocrine pancreatic carcinoma--results at an academic teaching hospital and evaluation of prognostic factors. AB - BACKGROUND/AIMS: Pancreatic cancer is among the top five cancer related death causes in countries like the US and Germany. Many studies have shown favorable results of pancreatic carcinoma resection at high-volume hospitals. It was the aim of this study to compare the results of pancreatic resection of exocrine pancreatic carcinoma at an academic teaching hospital with those of international centers for pancreatic surgery and to identify prognostic factors for survival. METHODOLOGY: Ninety-eight patients with exocrine pancreatic carcinoma were treated at our hospital, 42 of those underwent a resection. The data was collected from the patient files and statistically analyzed. A complete follow-up was reached. RESULTS: The resection rate was 42.9%, of which 83.3% were R0 resections. Mortality was 2.4%, morbidity 31%. Median survival after R0-resection was 14 months and 57.1% of the patients received adjuvant chemotherapy with gemcitabine. The performed surgical procedure and adjuvant chemotherapy were identified as independent determinants of long-term survival. CONCLUSION: This study shows that morbidity, mortality and survival rates reported in studies from international centers for pancreatic surgery can be reached at an academic teaching hospital as well. Adjuvant chemotherapy prolongs survival. PMID- 21661438 TI - GEMOX plus tomotherapy for unresectable locally advanced pancreatic cancer. AB - BACKGROUND/AIMS: The aim of this prospective phase II study was to evaluate the effect of neoadjuvant GEMOX plus helical tomotherapy on the resectability of locally advanced pancreatic cancer. METHODOLOGY: Between November 2004 and July 2008, 33 enrolled patients received gemcitabine (GEM) 1000 mg/m2 on day 1, and oxaliplatin (OX) 100 mg/m2 on day 2, every two weeks for 3-4 cycles. This was followed by radiotherapy (25 Gy, 5 fractions), 15 days after completion of GEMOX. Patients then received a further 3-4 cycles of GEMOX, underwent restaging and were evaluated for surgery. Potentially resectable patients were submitted to surgery, while unresectable responders received further GEMOX and radiotherapy. RESULTS: Toxicity to GEMOX was similar to that reported elsewhere and radiotherapy was also well tolerated. After treatment, one patient achieved a complete response, 14 had a partial response, 11 showed a stable disease, 6 progressed, and one was not evaluable. Eight patients (24%) underwent surgical laparotomy (7 radical pancreatic resections and one explorative laparotomy). CONCLUSIONS: Our study shows the feasibility and potential efficacy of the GEMOX plus helical tomotherapy regimen in unresectable locally advanced pancreatic cancer. PMID- 21661439 TI - A fibrin adhesive sealing method for the prevention of pancreatic fistula following distal pancreatectomy. AB - BACKGROUND/AIMS: Pancreatic fistula is the most common complication following distal pancreatectomy. We have developed a fibrin adhesive sealing method which covers the cut surface and parenchyma of the pancreas, to prevent pancreatic fistula. METHODOLOGY: We performed 25 distal pancreatectomies. Fibrin adhesive (TachoComb) was applied to the staple line of the pancreas before stapling. Pancreatic fistula was defined and graded according to the International Study Group of Postoperative Pancreatic Fistula (ISGPF) definition. RESULTS: The overall incidence of pancreatic fistula was five cases (20%). Four cases (16%) were classified as Grade A. Only one case (4%) was classified as Grade B. In patients with or without pancreatic fistula, the mean length of postoperative hospital stay was not significant. CONCLUSIONS: The fibrin adhesive sealing method is a simple and effective method of preventing postoperative pancreatic fistula formation after distal pancreatectomy. PMID- 21661440 TI - Incidence of and risk factors for developing pancreatic cancer in patients with chronic pancreatitis. AB - BACKGROUND/AIMS: Pancreatic cancer sometimes occurs during the course of chronic pancreatitis. This study aimed to identify risk factors for developing pancreatic cancer associated with chronic pancreatitis. METHODOLOGY: The incidence of pancreatic cancer developing in 218 patients with chronic pancreatitis and clinical features of the chronic pancreatitis patients who developed pancreatic cancer were studied. RESULTS: Nine patients developed pancreatic cancer. Average period from the diagnosis of chronic pancreatitis to the diagnosis of pancreatic cancer was 9.6 years. All pancreatic cancers were diagnosed at an advanced stage. Only 2 patients had been followed-up periodically. There were no significant differences between chronic pancreatitis patients who developed pancreatic cancer and those who did not in male/female ratio (3.5 vs. 8), average age on diagnosis (65.0 vs. 56.5), alcoholic/non-alcoholic chronic pancreatitis (1.6 vs. 2.6), smoking habits (62.5% vs. 70.7%), diabetes mellitus (77.8% vs. 54.4%), and continued alcohol drinking (37.5% vs. 53.1%). CONCLUSIONS: Over the period examined, 4% of chronic pancreatitis patients developed pancreatic cancer. Sex ratio, onset age, etiology, smoking habits, diabetes mellitus, and continued alcohol drinking were not significant risk factors for developing pancreatic cancer in chronic pancreatitis patients. Periodic follow-up due to the possibility of pancreatic cancer is necessary in chronic pancreatitis patients. PMID- 21661441 TI - Middle segmental pancreatic resection--a single-centre experience. AB - BACKGROUND/AIMS: A single-centre experience gained by middle segmental pancreatic resection and a brief survey of technique and indications are reported. METHODOLOGY: During the past 7 years 7 middle segmental pancreatic resections were performed for benign and low-grade malignant pancreatic lesions and in 1 case for pancreatic trauma. The preferred method was anastomosing the distal remnant to a Roux-en-Y limb, closure of the proximal cut end with sutures and in the last 4 patients covering this suture line with the limb. RESULTS: There were 3 complications out of 8 cases (37%) and the surgical morbidity rate was 12%. It did not come to reoperation and lethal outcome. During the follow-up time both the endocrine and exocrine functions remained normal in all patients. CONCLUSIONS: Middle segmental pancreatic resection could be carried out with an acceptable morbidity rate. However the proper indication and surgical technique are important factors in achieving advantageous results. PMID- 21661442 TI - Optimizing management of pancreatic cysts--prospective re-assessment for 157 cases. AB - BACKGROUND/AIMS: Ongoing debate continues regarding the appropriate management of pancreatic cysts (PCs). Disagreement prevails regarding frequency of needed follow-up, if and when to perform any PC needle biopsy and indications for surgical resection. EUS is increasingly used to help determine management of PCs. METHODOLOGY: One hundred and fifty seven consecutive patients with PCs were identified out of 5000 patients who underwent EUS between 1995-2007. In 2008, these patients were then prospectively provided clinical follow-up, and CEA, CA19 9 and CRP. RESULTS: No symptoms could be definitively related to the PCs. Twenty four of 157 patients with suspected malignant cysts, mucinous cysts or IPMN had undergone surgical treatment. Whipple's operation was performed in 14 patients and distal pancreatectomy in 10 patients. Fifty PCs were located in the head of pancreas. In 89 patients prospective blood tests were performed; in 6 of them elevated levels of CA-19-9 were detected, 3 of these also had elevated serum CEA. Twelve patients had increased CRP values. No complication (requiring hospitalization) and no mortality related to EUS had occurred. CONCLUSIONS: Elements identified as important for assessment of PCs included: size, serum and fluid markers, imaging characteristics and clinical follow-up. These factors should be included in the recommended guidelines. PMID- 21661443 TI - Long term results of pancreatectomy with portal-superior mesenteric vein resection for pancreatic carcinoma: a systematic review. AB - BACKGROUND/AIMS: Clinical benefit from pancreatectomy combined with portal vein/superior mesenteric resection in the pancreatic carcinoma with local venous invasion still remains controversial. The aim of this study was to review the overall outcome of the pancreatectomy combined with portal vein/superior mesenteric resection for pancreatic carcinoma with local venous invasion. METHODOLOGY: A systematic literature search (Medline, Embase, Cochrane Library, Biosis, Science Citation Index, Ovid Journals) was performed to identify all eligible articles from January 2000 to December 2009. The methodological quality of included studies on portal vein/superior mesenteric resection during pancreatectomy for pancreatic carcinoma was evaluated independently by 2 authors and 47 non-duplicated studies providing relevant data was found. Quantitative data on operation, perioperative results (blood loss, operative time, and length of hospital stay), mortality, morbidity, histopathology of resected specimens, adjuvant therapies, and overall outcome were extracted from included studies for systematic analysis. RESULTS: The median operating time was 480 (140-1340) min, blood loss 1420 (50-14280) ml and the length of hospital stay 16 (4-123) days. Operative mortality and postoperative morbidity rates ranged from 0 to 14.3 % and 6 % to 67 % with a median of 3.5 % and 33 %, respectively. Median survival was 15 months and ranged from 1.6 to 250 months, and 1-, 2-, 3- and 5-year survival rates ranged from 28.5 to 92, 6.7 to 81.1, 0 to 60.3 and 0 to 24 % with a media of 56.6, 31.5, 17 and 12 %, respectively. Specimen histopathology confirmed venous invasion, perineural invasion and lymphnodal involvement in 66.6,53 and 73%, respectively. CONCLUSIONS: In properly selected patients, pancreatectomy combined with portal vein/superior mesenteric resection is a feasible surgical procedure with a survival benefit for pancreatic carcinoma, and the systemic chemotherapy is indispensable as the common events of perineural invasion and lymphnodal involvement of the pancreatic carcinoma with local venous invasion. PMID- 21661444 TI - Screening the gastric cancer related tumor markers from multi-tumor markers protein chip with kappa coefficient and cost-effectiveness analysis. AB - BACKGROUND/AIMS: To retrospectively evaluate the clinical values of C12 multi tumor markers protein chip system in gastric cancer (GC) and screen for GC related tumor markers so as to provide a theoretical base for the establishment of GC diagnostic biochips. METHODOLOGY: The sera of 156 GC patients were detected for 12 common tumor markers using the C12 tumor markers protein chip. GC related parameters were analyzed by Kappa test and cost-effectiveness analysis to find the most optimal tumor marker combination. RESULTS: Carbohydrate antigen (CA) 19 9 (20.5%), CA242 (19.9%), carcinoembryonic antigen (CEA, 17.3%), CA125 (7.1%) were major tumor markers increased among the 156 GC patients. Kappa test revealed 6 tumor marker combinations having strong consistency with the detection results of C12 tumor markers proteinchip, and CA19-9 plus CEA proved to be the best combination by cost-effectiveness analysis. CONCLUSIONS: C12 tumor markers protein chip system had limited value in the diagnosis of GC, and the design of chip was too complicated and costly for widespread screening among the high risk populations. Searching for new GC biomarkers and designing small diagnostic chip could significantly enhance the clinical value of tumor markers in terms of diagnostic rate and practical utility. PMID- 21661445 TI - Effects of domperidone on gastric emptying: a crossover study using a continuous real-time 13C breath test (BreathID system). AB - BACKGROUND/AIMS: To determine the correlation between domperidone and gastric emptying using the continuous real time 13C breath-test (BreathID system), a novel non-invasive technique for measuring gastric emptying. METHODOLOGY: Six healthy male volunteers participated in this randomized, two-way crossover study. Subjects fasted overnight and were randomly assigned to receive a test meal (400kcal per 400mL) 30 minutes after intake of domperidone (10mg) with 50 mL of water or intake of 50 mL of water alone. Gastric emptying was monitored for 4h after administration of the test meal by 13C-acetic acid breath test continually performed using the BreathID system. The time taken for emptying of 50% of the labeled meals (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (T lag), the gastric emptying coefficient (GEC), and the regression-estimated constants (beta and kappa) were calculated. Differences in the parameters measured at two time-points were analyzed using the Wilcoxon's signed-rank test. RESULTS: No significant differences in calculated parameters (T lag, T1/2, GEC, beta or kappa) were observed between the treated and non-treated groups. CONCLUSIONS: This study showed that domperidone had no effect on gastric emptying. The drug ameliorates nausea and vomiting via its antagonic activity against dopamine receptor. Therefore, domperidone probably ameliorates nausea through other mechanisms. PMID- 21661446 TI - Prognostic significance of a new system for categorization of the number of lymph node metastases in gastric cancer. AB - BACKGROUND/AIMS: We examined whether a new system for categorization of the number or level of lymph node metastases would improve survival prediction in patients with gastric cancer. METHODOLOGY: Node-positive gastric cancer patients (361) were retrospectively studied. Cox proportional-hazards model analysis of the numbers of metastatic lymph nodes (numbers 1 to 11) showed the first peak of the hazard ratio for death at a threshold value of 4 lymph node metastases. We calculated cumulative 5-year survival rates and examined prognostic factors by multivariate analysis according to the numbers and levels of lymph node metastases. The effects of other prognostic factors were also examined. RESULTS: We divided the number of lymph node metastases into two groups (1-3 vs. > or =4), and classified the level of lymph node metastasis as level I or level II as defined by the Japanese Classification of Gastric Carcinoma. The 5-year survival rate differed significantly according to the number of lymph node metastases (1-3 vs. > or = 4) (p<0.0001). On multivariate regression analysis, the level of lymph node metastasis (level I or level II) and the number of lymph node metastases (1 3 or > or = 4) were independent predictors of survival. CONCLUSIONS: Categorization of the number of metastatic lymph nodes (1-3 or > or = 4) was easy and provided an accurate predictor of survival in patients with gastric cancer. PMID- 21661447 TI - Prognostic significance of splenic hilar nodal involvement in proximal third gastric carcinoma. AB - BACKGROUND/AIMS: The utility of prophylactic splenectomy in patients with proximal third gastric carcinoma is controversial. In this study, we investigated the significance of nodal involvement in the splenic hilum and the impact of splenectomy. METHODOLOGY: A total of 129 patients who underwent D2 radical resection with splenectomy for gastric carcinoma involving the upper portion of the stomach were analyzed. RESULTS: Lymph node metastasis at the splenic hilum was found in 21 (16.3%) of 129 cases. Multivariate analysis revealed that the number of metastatic lymph nodes was an independent risk factor for lymph node metastasis at the splenic hilum. The 5-year survival rate for patients with lymph node metastasis at the splenic hilum was 17.9%. There were significant differences in survival among patients grouped according to the extent of extraperigastric nodal involvement. While nodal involvement in the splenic hilum was found to be an independent prognostic factor, the number of metastatic lymph nodes was not. CONCLUSIONS: The prognosis of patients with lymph node metastasis at the splenic hilum was significantly poorer compared to that for patients with metastases in the other extraperigastric nodes. Furthermore, prophylactic splenectomy appears not to improve survival of patients with proximal third gastric carcinoma. PMID- 21661448 TI - Low peritoneal and systemic inflammatory response after laparoscopy-assisted gastrectomy compared to open gastrectomy. AB - BACKGROUND/AIMS: Peritoneal immune response as well as systemic response was objectively evaluated in laparoscopy-assisted distal gastrectomy (LADG) compared to open distal gastrectomy (ODG). METHODOLOGY: A total of 42 patients with gastric cancer were enrolled, with 23 undergoing LADG and 19 ODG. We evaluated the levels of IL-6 in peritoneal drain fluid, serum C-reactive protein (CRP), white blood cells (WBC), and the postoperative presence of systemic inflammatory response syndrome (SIRS). RESULTS: The serum CRP level was significantly higher in the ODG group than in the LADG group (p=0.007) on postoperative day (POD) 1. WBC counts showed no statistically significant difference between the two groups (p=0.105). The rate of cases exhibiting SIRS was significantly higher in the ODG group than in the LADG group (p<0.001). The IL-6 level of drain fluid was significantly higher in the ODG group than the LADG group (p<0.01) on POD1. Although weak correlation between IL-6 on POD1 and blood loss (R=0.38, p=0.0154) was observed, no significant correlation between IL-6 and operation time was noted. CONCLUSIONS: LADG seems to be a lesser traumatic approach for the treatment of gastric cancer. PMID- 21661449 TI - Plaunotol induces a comparative increase of acidic mucin fraction in gastric juice. AB - BACKGROUND/AIMS: Gastric mucus protects the gastric mucosa. Plaunotol, a gastroprotective agent, has been shown to increase mucus production in animal models. However, it is unclear whether plaunotol benefits human gastric mucus secretion. METHODOLOGY: Twenty-five patients with atrophic gastritis were studied. All patients underwent gastroendoscopy and gastric juice was collected before and after plaunotol treatment for 3 months. Gastric juice mucin was examined by gel filtration as well as anion-exchange chromatography. The identification of each fraction was examined by enzyme-linked immunosorbent assay (ELISA) with the use of HGM75 and HIK1083, antibodies against mucin from surface mucus cells and from gastric glandular mucus cells, respectively. RESULTS: Plaunotol significantly increased the total gastric juice volume (7.8mL before vs. 10.7mL, after administration; p=0.03). By anion exchange chromatography, we detected three mucin fractions (Fr I-III). Fr I strongly reacted with HGM75 but did not react with HIK1083. The other fractions (Fr II, III) reacted with HIK1083 but weakly reacted with HGM75. After administration of plaunotol, a significant increase in Fr III (acidic mucin) was observed (p=0.02). CONCLUSIONS: Long-term administration of plaunotol changes the composition of gastric juice mucin, including a significant increase in the proportion of acidic mucin fraction. PMID- 21661450 TI - Study for the quality of life following total gastrectomy of gastric carcinoma. AB - BACKGROUND/AIMS: The incidence of gastric carcinoma located in the upper third of the stomach has risen in recent years. The surgical procedure most selected is total gastrectomy (TG). So the quality of life (QOL) of the patients following TG arouses people's attention. It is not supported that the treatment for carcinoma located in the upper third of the stomach should be limited to TG. The aim of this study was to evaluate the short-term QOL after TG. METHODOLOGY: Patients with radical gastrectomy were included. We studied patients' diet, local symptoms and QOL. The questionnaire was a gastric cancer-specific Quality of Life Questionnaire of Stomach 22 (OLQ-STO22) according to the characteristics of gastric cancer (GC). RESULTS: Compared with patients after proximal subtotal gastrectomy (PSG), patients after TG had a poor recovery within a short time after surgery, but there was no statistical difference after that. The restoration of TG and PSG groups was not as good as that of distal subtotal gastrectomy (DSG) group. CONCLUSIONS: The indication of TG for carcinoma located in the upper third of the stomach may be extended properly. Evidence-based medicine should be used to screen better reconstruction mode. PMID- 21661452 TI - PinX1 gene transfection enhances the sensitivity of gastric carcinoma cell line to 5-fluorouracil. AB - BACKGROUND/AIMS: Since telomeres and telomerase play crucial roles in maintaining cell immortalization and cancer progression, they may be targets for anticancer treatment. PinX1 is a potent telomerase inhibitor, and a putative tumor suppressor. The use of PinX1 to treat cancers has not been reported yet. METHODOLOGY: In order to use PinX1 in gene therapy for gastric carcinoma, we transfected PinX1 gene into the gastric carcinoma line MKN28 using the eukaryotic expression vector pIRES2-EGFP. PinX1-expressing, drug-resistant clones were screened with G418 and used in the study. RESULTS: MKN28 cells transfected with PinX1 gene grew more slowly than the cells not transfected or transfected with void vectors (p<0.05). The IC50 value decreased markedly in cells transfected with PinX1 gene. PinX1 gene transfection enhanced the sensitivity of MKN28 cells to 5-fluorouracil (p<0.05). CONCLUSIONS: PinX1 may be used in gene therapy for gastric carcinoma. PMID- 21661451 TI - Cell cycle dependent genes from the gastric cancer cell MKN45 can affect tumorigenesis. AB - BACKGROUND/AIMS: To investigate the cell cycle dependent genes involved in gastric tumorigenesis, possibly determining the relationship between the cell cycle and tumorigenesis. METHODOLOGY: MKN45 cells were collected every hour from Oh to 12h after release from G2/M and G1/S blocks. Nine samples (a-i), chosen at key times of the cell cycle, were prepared for RNA isolation and cDNA microarray analysis. RESULTS: In 2001 viable clones, 959 genes showed periodic variations during the cell cycle. Among 2001 genes that were clustered, a series of up regulated genes were assigned to different cell cycle phases. Many periodically dependent genes in the cell cycle were ubiquitously expressed and participated in various cell physiological functions, such as transcription, translation, ubiquitination and signal transduction. These cell cycle dependent genes could affect cancer cell proliferation, apoptosis, activation of oncogenes and inactivation of tumor suppressor genes. CONCLUSIONS: We provided a comprehensive understanding of the gene expression profile involved in gastric cancer cell cycles and laid a foundation for further research on mechanisms of gastric tumorigenesis. PMID- 21661453 TI - Vector borne diseases: a glimpse. PMID- 21661454 TI - Wilms' tumour. PMID- 21661455 TI - A study of micronutrient status in pregnancy. AB - The present study was performed, to analyse the inter-relationship among trace elements: Iron, copper and zinc in pregnancy. Eighty-four pregnant women were compared with 30 age matched nonpregnant healthy controls. Fasting blood samples were analysed for heamoglobin, iron, copper and zinc. On the basis of Hb concentration (<10g/dl) and iron levels(<50microg/dl), the pregnant women were sub-grouped as anaemic, non-anaemic, Iron deficient anaemic and non-iron deficient anaemic. The level of copper was found to be significantly higher in iron deficiency anaemia, when compared to non-iron deficiency anaemia (p<0.05), and in non-anaemic pregnant women, compared to non-anaemic non-pregnant women (controls).The level of zinc is also significantly lower in Iron deficiency anaemic pregnancy, when compared to the other groups. There is evidence of influence of pregnancy, on the level of trace elements in blood. This could be a result of competitive inhibition in the absorption of trace elements in the intestine, or an effect of hormonal changes (insulin, oestrogen), during pregnancy. A judicious supplementation of micronutrients, during pregnancy, especially in iron deficiency anaemia, is essential. PMID- 21661456 TI - Changing trends of ocular anaesthesia in phaco-emulsification surgery. AB - This study was undertaken prospectively to assess the safety and effectiveness of topical anaeshthesia over sub-tenon and peribulbar anaesthesia during routine phaco-emulsification surgery. One hundred and fifty eyes undergoing clear corneal phaco-emulsification were randomly divided into 3 groups. Pain was assessed subjectively by the patients during introduction of anaesthetic agent, also intra operatively and 2 hours postoperatively on a visual analogue scale of 0 to 4 by the visual descriptive method. Ocular akinesia at the beginning and during the surgery was recorded by the operating surgeon. Any intra-operative complication was also noted at the end of the surgery. This analysis showed that topical anaesthesia caused no pain at all in 98% and sub-tenon anaesthesia caused minimum or no pain in 92% during introduction of anaesthetic agent as opposed to peribulbar (42%) and two values were also statistically significant. Sub-tenon and peribulbar anaesthesia provided significantly more intra-operative akinesia as compared to topical, the rate of intra-operative complications was comparable in all the 3 groups. So the recent trend of topical anaesthesia in phacosurgery is a safe and efficient alternative to sub-tenon and peribulbar anaesthesia. PMID- 21661457 TI - Micro-albuminuria: a predictor of 7-day mortality in acute myocardial infarction. AB - A study was undertaken amog 80 non-diabetic patients of acute myocardial infarction (AMI) admitted within 24 hours of the onset of pain, to investigate the prevalence and significance of microalbuminuria (MA) as a predictor of in hospital mortality, and also to correlate it with other well-established prognostic markers. Spot urinary albumin-to-creatinine ratio (ACR) was measured in first morning sample on day 1 (D1), day 4 (D4) and/or day 7 (D7). Haemodynamic status was assessed clinically by Killip's class and the ejection fraction was measured by echocardiography on D1, D4, and/or D7. Total 7 days mortality was recorded. MA (>30 microg/mg) was found in 95% of patients on 1,. In the group with higher value of MA (>100 microg/mg) on D1, there was significantly more deaths (p <0.01). Also there was significantly more deaths with static or increasing MA value from D1 to D4/D7 (p <0.01). Increasing or static MA had a positive correlation with deteriorating Killip's class in non-survivors, and also there was a correlation between decrease in left ventricular ejection fraction from D1 to D4/D7 and an increasing trend in MA over that period. Thus, MA was found to be a reliable predictor of short-term in-hospital mortality in AMI. PMID- 21661458 TI - Pharmaco-epidcemiology of drugs utilised for cataract surgery in a government medical college and hospital. AB - Prescription audit is a powerful tool for rational prescription. To evaluate pharmaco-epidemiology of drugs utilised for cataract surgery, a retrospective study was conducted in the department of pharmacology, RG Kar Medical College, Kolkata. Data from bed head tickets of one year, available in medical record section, were collected in case report forms and analysed. Utilisation pattern of drugs like dosage form, dose, route and frequency of administration and duration of therapy were audited. Drug prescription versus therapeutic indication was also evaluated. Price of the prescribed drugs was evaluated for rationality towards cost-effective prescription. For 848 cases of cataract surgery, drugs were prescribed pre-, per- and post-operatively. Different fluoroquinolone antibiotics, anti-inflammatory and mydriatic-cycloplegic agents were prescribed. High or low cost drugs were prescribed both in generic (52%) and brand (48%) names. Few Latin abbreviations were used in directions. Different parameters and study results were discussed from various aspects to explore their social impacts. Though prescription pattern was almost rational, some parts need improvement. Healthcare provider should be aware of cost-effectiveness of the prescribed drugs for the benefit of patients to provide a rational prescription. PMID- 21661459 TI - Study of salivary gland lesions with fine needle aspiration cytology and histopothology along with immunohistochemistry. AB - Salivary gland swelling is a common and important problem. Acute and chronic sialadenitis, different benign and malignant neoplasms are the common causes which present with salivary gland swelling. Imaging technique is not so helpful in pre-operative diagnosis; microscopical examination is required for diagnosis. Pre-operative core needle biopsy is hazardous and may damage facial nerve, lead to fistula formation or associated with tumour seeding. Fine needle aspiration cytology (FNAC) is however virtually risk-free. The study was done to assess the utility of FNAC and its accuracy and pitfalls with respect to histopathology and advantages of immunohistochemistry. The study was done with 40 cases of salivary gland swelling. After clinical examination, FNAC and histopathological examination along with immunohistochemistry was done and the results were correlated. Out of 40 cases, 25 involved the parotid gland, most common age group affected was 20 - 40 years and male: female ratio was 5: 3. Out of 40 cases 37 cases were cytologically and histopathologically correlated and rest 3 cases were different. Among these 3 cases, 2 were adenoid cystic carcinoma which was cytologically diagnosed as benign neoplasm (monomorphic adenoma). One case of Warthin's tumour was cytologically diagnosed as pleomorphic adenoma. The sensitivity of this study was found to be 71.43%, specificity 100% and accuracy was 93.10%. This study corroborates well with other studies including immunohistochemical findings. p53 expression was found to be related with nature of the neoplasm. FNAC is an important tool for early diagnosis of salivary gland lesions. PMID- 21661460 TI - Corporate guidelines to combat malaria. PMID- 21661462 TI - Revised National Drug Policy (2010) for treatment of malaria. PMID- 21661461 TI - Epidemiological status of malaria and scaling up of interventions in india. PMID- 21661463 TI - A success story: sharing experiences of implementing the global fund supported intensified malaria control project (IMCP). PMID- 21661464 TI - Challenges and role of private sector in the control of malaria in India. PMID- 21661465 TI - Progress towards morbidity management under elimination of lymphotic filariasis programme in India. PMID- 21661466 TI - Aspergillus hypersensitivity and allergic bronchopulmonary aspergillosis among asthma patients in eastern India. AB - To find out the clinicoradiomycopathological profile of allergic bronchopulmonary Aspergillosis (ABPA) and incidences of aspergillus hypersensitivity (AH) among asthma patients, 215 consecutive extrinsic asthma patients were screened with aspergillus intradermal test and those found positive for AH were investigated further for ABPA. Out of 215 asthma patients (124 males and 91 females), 54 were hypersensitive to AH and 15 of them fulfilled criteria for ABPA. On repeated culture of sputum and/or broncho-alveolar lavage fluid, A flavuswas the most common isolate (40%), followed by A fumigatus (26.67%). No species was isolated in 4 cases (26.6%). AH/ABPA is not very uncommon in this part of the country. Diseases similar to ABPA caused by other fungus might be diagnosed if allergen tests for other fungal antigens are made widely available. A strong clinical suspicion and proper laboratory backup is essential for diagnosing ABPA and related diseases. PMID- 21661467 TI - Deep vein thrombosis. AB - Occlusive clot formation in the veins causes venous thrombosis, the site most common in the deep veins of leg, called deep vein thrombosis. The clot can block blood flow and when it breaks off, called an embolism which in turn can damage the vital organs. Venous thrombosis occurs via three mechanisms ie, Virchow's triad. The mechanisms are decreased flow rate of blood, damage to the blood vessel wall and an increased tendency of the blood to clot. There are several factors which can increase a person's risk for deep vein thrombosis. The symptoms of deep vein thrombosis in the legs are pain, swelling and redness of the part. One variety of venous thrombosis is phlegmasia alba dolens where the leg becomes pale and cool. Investigations include Doppler ultrasound examination of the limb, D-dimer blood test, plethysmography of the legs, x-rays to show vein in the affected area (venography). Hospitalisation is necessary in some cases with some risk factors. The mainstream of treatment is with anticoagulants, mostly low molecular weight heparin for 6 months. Deep venous thrombosis is a rising problem. Early diagnosis and treatment is associated with a good prognosis. PMID- 21661468 TI - Revised National Tuberculosis Control Programme (RNTCP). AB - The global annual inicidence is estimated to be 1.98 million cases in India. This situation is further threatened by emergence of multidrug-resistant tuberculosis. The Revised National Tuberculosis Control Programme is based on Directly Observed Treatment Short-course (DOTS) strategy. DOTS facilitates relapse-free cure for TB. Diagnostic algorithms for pulmonary tuberculosis have been narrated in this article. Treatment of tuberculosis stands on patients' categorisation in 3 groups and schedule is described. The side-effects and their remedies are also narrated. The IMA has a role to join hands with the government to work closely to bring down the disease burden. PMID- 21661469 TI - Sweat gland carcinoma - a case report. AB - A 54 years male presented with painless, indolent ulcers in the left axilla in an area approximately of 5 cm diameter. They were fixed to the underlying structures. Some lymph nodes eg, pectoral, apical and central groups were also enlarged. Incision biopsy for the margin of the ulcer was done. It showed adenocarcinoma of the sweat glands. Wide local incision with 2 cm margin of surrounding skin was performed. The patient was discharged after a course of adjuvant radiotherapy and is doing well. PMID- 21661470 TI - Pyodcerma gangrenosum on glans penis: an unusual site. AB - Pyoderma gangrenosum is a rare, destructive, inflammatory disorder, which presents with progressively enlarging ulcers, single or multiple, mostly involving the lower extremities. It may occur alone or in association with other system diseases like inflammatory bowel disease, polyarthritis, gammopathy, etc. A case of pyoderma gangrenosum in a young male presenting with a single ulcer on the glans penis, an unusual site, without any systemic association is being reported. The prolonged history, typical raised, tender, undetermined border along with histopathological confirmation helped in clinching the diagnosis. The unusual site made it imperative to differentiate it from the common sexually transmitted ulcerative disorders and also from lupus vulgaris and squamous cell carcinoma of the penis. The ulcer showed improvement with a combination of systemic steroid and dapsone. PMID- 21661471 TI - Gastric tuberculosis - a diagnostic dilemma. AB - Gastric tuberculosis is an extremely rare entity particularly when it is not associated with pulmonary tuberculosis or an immunodeficient state. Here one patient required surgery for gastric outlet obstruction and was subsequently put on antituberculous drugs. The patient responded well to treatment and is currently doing well in follow-up. This disease though rare should be considered in the differential diagnosis of gastric malignancy and severe peptic ulcer disease. PMID- 21661472 TI - The ongoing campaign for reform of Australia's aged care system. PMID- 21661473 TI - Happiness a vital issue. PMID- 21661474 TI - Aged care campaign gets a boost. PMID- 21661475 TI - Productivity Commission report falls short. PMID- 21661476 TI - Ethics, cancer, and truth telling. PMID- 21661477 TI - Recognition due for practice nurses. PMID- 21661478 TI - First trip of many for volunteer nurse. PMID- 21661479 TI - Reform agenda must put care first. PMID- 21661480 TI - The successful implementation of nurse practitioner model of care for threatened or inevitable miscarriage. AB - The NP project has been successful in a variety of ways. Feedback through a patient satisfaction survey was very positive and showed that patients appreciated and responded well to the NP model of care (Scully 2006). According to the hospital patient advocate, Ruth Reid (March 2006), this has led to not only a reduction in waiting and treatment times for this cohort of patients, but also to complete elimination in complaints when the NP service is running. Medical staff support the service and find it a sensible use of nursing and medical resources. This mirrors the overseas experience of NPs who offer primary health care in EDs. Finally, through successful collaboration between the nurse practitioner, supportive emergency physicians and the O&G team, this service is now a permanent part of Sunshine Hospital. PMID- 21661481 TI - Dying with dignity--the case for end of life choices. PMID- 21661482 TI - RCN action threat over pay freeze. PMID- 21661483 TI - Degrees will build in values to underpin and ensure good care. PMID- 21661484 TI - I'm too busy to fill out a survey telling the world how busy I am. PMID- 21661485 TI - Pressure ulcers will still be seen until basic care is right. PMID- 21661486 TI - Can telehealth help patients with COPD? AB - Chronic obstructive pulmonary disease (COPD) is a growing challenge for the NHS. New technologies, such as telehealth, offer opportunities for health and social care providers to look at innovative ways to manage the condition. Studies show telehealth services can reduce admissions and bed days, and boost patient satisfaction, but more research is needed to establish whether these technologies are safe, efficient and economical. PMID- 21661487 TI - COPD and anxiety: its impact on patients' lives. AB - BACKGROUND: Anxiety is a common comorbidity in people with chronic obstructive pulmonary disease (COPD) but its identification and management are often insufficient. AIM: To explore the experience of living with and managing comorbid anxiety and COPD from a patient's perspective. METHOD: The study followed a qualitative approach. In-depth interviews were carried out with 14 patients who had COPD. RESULTS: Participants believed anxiety had a significant impact on their quality of life. It made them feel isolated and caused them to avoid social occasions and daily activities. Identifying anxiety was a challenge because of the overlap in the symptoms of anxiety and those of COPD, and the side-effects of medication. CONCLUSION: Nurses can play a vital role in screening and managing anxiety, and educating people in strategies to prevent episodes of panic. PMID- 21661488 TI - Intravenous antibiotics in cystic fibrosis. PMID- 21661489 TI - I've been made to feel like a number, not like a person. PMID- 21661490 TI - Passport to freedom. PMID- 21661491 TI - Could you turn all your team into champions? PMID- 21661492 TI - Standing up to Goliath. A victory in gender discrimination battle. PMID- 21661493 TI - Does nursing research have a future? PMID- 21661494 TI - Act II: A new career direction. PMID- 21661495 TI - On double duty in Labrador city. PMID- 21661496 TI - Getting to know you. PMID- 21661497 TI - Fluoride ...it's not just for kids. PMID- 21661498 TI - A more intellectually, medically and physically disabled society: the case of the United States. AB - To bring attention to the fact that repeated emphasis on the worldwide increasing number of elderly, with only a passing reference to the magnitude and consequences of the hundreds of millions of elderly with disabilities, neglects to consider the associated burgeoning human and financial costs. PMID- 21661499 TI - In my view: CT scanning in the dental office, cone beam computed tomography. PMID- 21661500 TI - Peace of mind. PMID- 21661501 TI - Just imagine... PMID- 21661502 TI - Social networking-- when is being social potentially dangerous? PMID- 21661504 TI - Characteristics of bonds. PMID- 21661503 TI - Small business IT trends for 2011. PMID- 21661505 TI - Blood glucose monitoring. What's in it for type 2? PMID- 21661506 TI - Going green in the kitchen. No-cook recipes. PMID- 21661507 TI - Finding health information on the Internet. PMID- 21661508 TI - High-fructose corn syrup. What's all the fuss about? PMID- 21661509 TI - Planning for a successful health-care visit. PMID- 21661510 TI - Eating well while traveling. PMID- 21661511 TI - Supermarket smarts. Got calcium? PMID- 21661512 TI - Positive growth: new addition helps hospital improve patient care. PMID- 21661513 TI - Join the team. Integrating medical equipment planning into the construction process. PMID- 21661514 TI - Sustainable by design. PMID- 21661515 TI - Green facilities finish first. PMID- 21661516 TI - Clean scene. Infection control. Suppliers respond to the challenge of health care associated infections. PMID- 21661517 TI - Continuous compliance. Maintaining a constant state of regulatory readiness. PMID- 21661518 TI - Disposal duties. The proper handling of regulated medical waste. PMID- 21661519 TI - United front in Liverpool. PMID- 21661520 TI - Carter seeks clarification on pay increment freeze after congress. PMID- 21661521 TI - A beleaguered Lansley concedes that nurses may benefit NHS commissioning after all. PMID- 21661522 TI - Disappointment at DH response to nursing commission's report . PMID- 21661523 TI - Health minister admits to a lack of clarity on student tuition fees. PMID- 21661524 TI - As fitness to practise cases rise, nurses debate what can be done. PMID- 21661525 TI - Are today's nursing students really supernumerary? PMID- 21661526 TI - Resisting the ritual. AB - People with obsessive compulsive disorder are plagued with repetitive, intrusive thoughts. But with increasing access to cognitive behavioural therapy, treatment is more available. PMID- 21661527 TI - Treat with care. AB - Lymphoedema affects at least 100,000 people in the UK but health professionals do not always know how to help prevent complications. PMID- 21661528 TI - Distressing sensations. AB - Restless legs syndrome is not always recognised by health professionals, but the condition can adversely affect patients' lives. PMID- 21661529 TI - Applying skills and knowledge: Principle Of Nursing Practice F. AB - This is the seventh article in a nine-part series describing the Principles of Nursing Practice developed by the Royal College of Nursing (RCN) in collaboration with patient and service organisations, the Department of Health, the Nursing and Midwifery Council, nurses and other healthcare professionals. The article discusses Principle F, the application of skills and knowledge to person-centred nursing care. PMID- 21661530 TI - Diagnosis, prevention and treatment of fungal infections . AB - Most fungi live harmlessly in the environment, but some species can cause disease in the human host. Nurses working in primary care are likely to see patients with superficial fungal infections and are well placed to offer advice about treatment and measures to prevent the spread of infection in the home. Patients with weakened immune function admitted to hospital are at high risk of developing serious, invasive fungal infections. Systemic fungal infections are a major problem among critically ill patients in acute care settings and are responsible for an increasing proportion of healthcare-associated infections. PMID- 21661531 TI - Preventing infection. PMID- 21661532 TI - Psychosocial aspects of living with non-cancer-related lymphoedema. AB - Lymphoedema is a chronic condition that causes swelling, pain, altered appearance and reduced mobility. Little is known about the psychosocial effects. This review aims to identify psychosocial aspects of living with non-cancer-related lymphoedema, as such information is not readily available to healthcare professionals or patients. PMID- 21661533 TI - Post-thrombotic syndrome: a case study. AB - Post-thrombotic syndrome is a common complication following deep vein thrombosis. The severity and incidence of this condition can be considerably decreased with the use of compression hosiery. This article focuses on a case study of a patient who had post-thrombotic syndrome for ten years before receiving effective treatment. PMID- 21661534 TI - Life-changing course. PMID- 21661535 TI - A revolution in the workplace. PMID- 21661536 TI - Degree of excellence. PMID- 21661537 TI - Sad to say: is it time for Sorrow Management Theory? AB - Terror Management Theory (TMT) research often asks respondents to describe their personal death. This exposure enables the testing of hypotheses regarding defenses ("buffers") against the anxious awareness of death. Curiously, though, the respondents' narratives are not analyzed or reported. The present study offers a qualitative analysis of 209 college student narrative responses provided for this purpose by TMT researchers Jeff Greenberg and Nathan Heflick. The narratives are reviewed with attention to affect (adjectives), semantic structure, and theme. Many responses are marked by anxiety, but sorrow is also pervasive. Individual differences in response substance and structure invite further exploration. It is suggested that our understanding of the response to personal death threat could be enhanced by encompassing sorrow as well as anxiety within the same conceptual framework. Several specific hypotheses and suggestions are offered. PMID- 21661538 TI - Cross-cultural re-entry for missionaries: a new application for the Dual Process Model. AB - Nearly half a million foreign aid workers currently work worldwide, including over 140,000 missionaries. During re-entry these workers may experience significant psychological distress. This article positions previous research about psychological distress during re-entry, emphasizing loss and grief. At present there is no identifiable theoretical framework to provide a basis for assessment, management, and prevention of re-entry distress in the clinical setting. The development of theoretical concepts and frameworks surrounding loss and grief including the Dual Process Model (DPM) are discussed. All the parameters of the DPM have been shown to be appropriate for the proposed re-entry model, the Dual Process Model applied to Re-entry (DPMR). It is proposed that the DPMR is an appropriate framework to address the processes and strategies of managing re-entry loss and grief. Possible future clinical applications and limitations of the proposed model are discussed. The DPMR is offered for further validation and use in clinical practice. PMID- 21661539 TI - Losing contact with one's unborn baby--mothers' experiences prior to receiving news that their baby has died in utero. AB - BACKGROUND: A change in the pattern of movement of her unborn baby could be indicative that the baby might die. AIM: To study mothers' experiences during the time prior to receiving news that their baby has died. METHOD: Interviews with 26 mothers. RESULTS: Premonition that something had happened to their baby, a sense based on a lack of movements were experienced. Six categories describe the mother's insight that the baby's life was threatened: not feeling in touch with their baby; worry feeling something is wrong; not understanding the unbelievable; wanting information; and being certain that their baby had died. The overarching theme "There is something wrong" was formulated. CONCLUSION: The mother could not understand the unbelievable: that the baby had died in utero. IMPLICATIONS: Mother's should be cautioned to trust their insights and seek medical advice if they are concerned over the lack of movement from the unborn baby. PMID- 21661540 TI - A sociocultural analysis of death anxiety among older Japanese urbanites in a citizens' movement. AB - By examining the experiences of death anxiety and attitudes toward personal deaths among members of a citizens' movement, the Grave-Free Promotion Society (GFPS), this study considers the applicability of the view that culture and high self-esteem serve as defenses against death anxiety in Japan's changing society. The GFPS promotes the scattering of ashes over the conventional interment of cremated remains in a family grave. GFPS members often lack descendants to care for a family grave, the neglect of which is thought to endanger the deceased's peaceful rest. By returning the dead to nature through ash scattering, the GFPS provides an alternative strategy of managing its members' posthumous well-being. GFPS members often report that their choice of ash scattering has reduced their anxiety about their personal deaths and improved the quality of their lives. Based upon these findings, this study offers some suggestions for increasing cultural sensitivities of test instruments commonly used to examine death anxiety among older persons for use in a Japanese context. PMID- 21661541 TI - Quality insights of university students on dying, death, and death education--a preliminary study in Hong Kong. AB - Death is a subject seldom studied in school and often misunderstood and feared by many people. Children often learn about death from their family and mass media. From the literature review on dying, death, and death education, it may be concluded that people are generally ignorant about the issues of death and dying. There is a need to investigate what young people, such as university students, know about death and dying, and their attitudes toward them. Eight university students were recruited for this study. Most participants have had death experiences. They seldom talked about death and loss. Some of these experiences were quite pleasant but some of them were not. Most participants addressed the need to have "life and death" education in schools at their young age. Such a need is further supported by the incidents of two participants who attempted suicide unsuccessfully when they encountered a life problem which they could not solve. PMID- 21661542 TI - Microbes do not follow the elevational diversity patterns of plants and animals. AB - The elevational gradient in plant and animal diversity is one of the most widely documented patterns in ecology and, although no consensus explanation exists, many hypotheses have been proposed over the past century to explain these patterns. Historically, research on elevational diversity gradients has focused almost exclusively on plant and animal taxa. As a result, we do not know whether microbes exhibit elevational gradients in diversity that parallel those observed for macroscopic taxa. This represents a key knowledge gap in ecology, especially given the ubiquity, abundance, and functional importance of microbes. Here we show that, across a montane elevational gradient in eastern Peru, bacteria living in three distinct habitats (organic soil, mineral soil, and leaf surfaces) exhibit no significant elevational gradient in diversity (r2<0.17, P>0.1 in all cases), in direct contrast to the significant diversity changes observed for plant and animal taxa across the same montane gradient (r2>0.75, P<0.001 in all cases). This finding suggests that the biogeographical patterns exhibited by bacteria are fundamentally different from those of plants and animals, highlighting the need for the development of more inclusive concepts and theories in biogeography to explain these disparities. PMID- 21661543 TI - When is an invasive not an invasive? Macrofossil evidence of doubtful native plant species in the Galapagos Islands. AB - The Galapagos Islands are globally renowned for their ecological value and as a world symbol of scientific discovery; however the native biodiversity of this unique region is currently under threat. One of the primary concerns is the detrimental impact of approximately 750 nonnative plants introduced over the last 500 years of human presence in the archipelago. In addition to these known introduced species, there are an additional 62 vascular plants classified as "doubtful natives," where native status remains unclear. To help address the questions of provenance regarding these doubtfully native species and their impact on highland ecosystems over the past 500-1000 years, we analyzed plant macrofossils in sedimentary records. Appropriate species classification (native or introduced) was determined using baseline data of species presence on the islands. We confirmed that six plants (Ageratum conyzoides, Solanum americanum, Ranunculus flagelliformis, Brickellia diffusa, Galium canescens, and Anthephora hermaphrodita) once considered doubtful natives or introduced are actually native to the Galapagos flora. These results have relevance not just for the Galapagos but also many other oceanic islands in demonstrating the application of palaeobotanical data to conserving and restoring native biodiversity. PMID- 21661544 TI - Individual heterogeneity and senescence in silvereyes on Heron Island. AB - Individual heterogeneity and correlations between life history traits play a fundamental role in life history evolution and population dynamics. Unobserved individual heterogeneity in survival can be a nuisance for estimation of age effects at the individual level by causing bias due to mortality selection. We jointly analyze survival and breeding output from successful breeding attempts in an island population of Silvereyes (Zosterops lateralis chlorocephalus) by fitting models that incorporate age effects and individual heterogeneity via random effects. The number of offspring produced increased with age of parents in their first years of life but then eventually declined with age. A similar pattern was found for the probability of successful breeding. Annual survival declined with age even when individual heterogeneity was not accounted for. The rate of senescence in survival, however, depends on the variance of individual heterogeneity and vice versa; hence, both cannot be simultaneously estimated with precision. Model selection supported individual heterogeneity in breeding performance, but we found no correlation between individual heterogeneity in survival and breeding performance. We argue that individual random effects, unless unambiguously identified, should be treated as statistical nuisance or taken as a starting point in a search for mechanisms rather than given direct biological interpretation. PMID- 21661545 TI - Use of the superpopulation approach to estimate breeding population size: an example in asynchronously breeding birds. AB - Many populations of animals are fluid in both space and time, making estimation of numbers difficult. Much attention has been devoted to estimation of bias in detection of animals that are present at the time of survey. However, an equally important problem is estimation of population size when all animals are not present on all survey occasions. Here, we showcase use of the superpopulation approach to capture-recapture modeling for estimating populations where group membership is asynchronous, and where considerable overlap in group membership among sampling occasions may occur. We estimate total population size of long legged wading bird (Great Egret and White Ibis) breeding colonies from aerial observations of individually identifiable nests at various times in the nesting season. Initiation and termination of nests were analogous to entry and departure from a population. Estimates using the superpopulation approach were 47-382% larger than peak aerial counts of the same colonies. Our results indicate that the use of the superpopulation approach to model nesting asynchrony provides a considerably less biased and more efficient estimate of nesting activity than traditional methods. We suggest that this approach may also be used to derive population estimates in a variety of situations where group membership is fluid. PMID- 21661546 TI - Plant invasions, generalist herbivores, and novel defense weapons. AB - One commonly accepted mechanism for biological invasions is that species, after introduction to a new region, leave behind their natural enemies and therefore increase in distribution and abundance. However, which enemies are escaped remains unclear. Escape from specialist invertebrate herbivores has been examined in detail, but despite the profound effects of generalist herbivores in natural communities their potential to control invasive species is poorly understood. We carried out parallel laboratory feeding bioassays with generalist invertebrate herbivores from the native (Europe) and from the introduced (North America) range using native and nonnative tetraploid populations of the invasive spotted knapweed, Centaurea stoebe. We found that the growth of North American generalist herbivores was far lower when feeding on C. stoebe than the growth of European generalists. In contrast, North American and European generalists grew equally well on European and North American tetraploid C. stoebe plants, lending no support for an evolutionary change in resistance of North American tetraploid C. stoebe populations against generalist herbivores. These results suggest that biogeographical differences in the response of generalist herbivores to novel plant species have the potential to affect plant invasions. PMID- 21661547 TI - Predicting community responses to perturbations in the face of imperfect knowledge and network complexity. AB - How best to predict the effects of perturbations to ecological communities has been a long-standing goal for both applied and basic ecology. This quest has recently been revived by new empirical data, new analysis methods, and increased computing speed, with the promise that ecologically important insights may be obtainable from a limited knowledge of community interactions. We use empirically based and simulated networks of varying size and connectance to assess two limitations to predicting perturbation responses in multispecies communities: (1) the inaccuracy by which species interaction strengths are empirically quantified and (2) the indeterminacy of species responses due to indirect effects associated with network size and structure. We find that even modest levels of species richness and connectance (-25 pairwise interactions) impose high requirements for interaction strength estimates because system indeterminacy rapidly overwhelms predictive insights. Nevertheless, even poorly estimated interaction strengths provide greater average predictive certainty than an approach that uses only the sign of each interaction. Our simulations provide guidance in dealing with the trade-offs involved in maximizing the utility of network approaches for predicting dynamics in multispecies communities. PMID- 21661548 TI - Connectivity for conservation: a framework to classify network measures. AB - Graph theory, network theory, and circuit theory are increasingly being used to quantify multiple aspects of habitat connectivity and protected areas. There has been an explosive proliferation of network (connectivity) measures, resulting in over 60 measures for ecologists to now choose from. Conceptual clarification on the ecological meaning of these network measures and their interrelationships is overdue. We present a framework that categorizes network measures based on the connectivity property that they quantify (i.e., route-specific flux, route redundancy, route vulnerability, and connected habitat area) and the structural level of the habitat network to which they apply. The framework reveals a lack of network measures in the categories of "route-specific flux among neighboring habitat patches" and "route redundancy at the level of network components." We propose that network motif and path redundancy measures can be developed to fill the gaps in these categories. The value of this framework lies in its ability to inform the selection and application of network measures. Ultimately, it will allow a better comparison among graph, network, and circuit analyses, which will improve the design and management of connected landscapes. PMID- 21661549 TI - Interactive effects of disturbance and dispersal directionality on species richness and composition in metacommunities. AB - Dispersal among ecological communities is usually assumed to be random in direction, or to vary in distance or frequency among species. However, a variety of natural systems and types of organisms may experience dispersal that is biased by directional currents or by gravity on hillslopes. We developed a general model for competing species in metacommunities to evaluate the role of directionally biased dispersal on species diversity, abundance, and traits. In parallel, we tested the role of directionally biased dispersal on communities in a microcosm experiment with protists and rotifers. Both the model and experiment independently demonstrated that diversity in local communities was reduced by directionally biased dispersal, especially dispersal that was biased away from disturbed patches. Abundance of species (and composition) in local communities was a product of disturbance intensity but not dispersal directionality. High disturbance selected for species with high intrinsic growth rates and low competitive abilities. Overall, our conclusions about the key role of dispersal directionality in (meta)communities seem robust and general, since they were supported both by the model, which was set in a general framework and not parameterized to fit to a specific system, and by a specific experimental test with microcosms. PMID- 21661550 TI - Directional changes in the species composition of a tropical forest. AB - Long-term studies have revealed that the structure and dynamics of many tropical forests are changing, but the causes and consequences of these changes remain debated. To learn more about the forces driving changes within tropical forests, we investigated shifts in tree species composition over the past 25 years within the 50-ha Forest Dynamics Plot on Barro Colorado Island (BCI), Panama, and examined how observed patterns relate to predictions of (1) random population fluctuations, (2) carbon fertilization, (3) succession from past disturbance, (4) recovery from an extreme El Nino drought at the start of the study period, and (5) long-term climate change. We found that there have been consistent and directional changes in the tree species composition. These shifts have led to increased relative representations of drought-tolerant species as determined by the species' occurrence both across a gradient of soil moisture within BCI and across a wider precipitation gradient from a dry forest near the Pacific coast of Panama to a wet forest near its Caribbean coast. These nonrandom changes cannot be explained by stochastic fluctuations or carbon fertilization. They may be the legacy of the El Nino drought, or alternatively, potentially reflect increased aridity due to long-term climate change. By investigating compositional changes, we increased not only our understanding of the ecology of tropical forests and their responses to large-scale disturbances, but also our ability to predict how future global change will impact some of the critical services provided by these important ecosystems. PMID- 21661551 TI - Increasing plant use of organic nitrogen with elevation is reflected in nitrogen uptake rates and ecosystem delta15N. AB - It is hypothesized that decreasing mean annual temperature and rates of nitrogen (N) cycling causes plants to switch from inorganic to organic forms of N as the primary mode of N nutrition. To test this hypothesis, we conducted field experiments and collected natural-abundance delta15N signatures of foliage, soils, and ectomycorrhizal sporocarps along a steep elevation-climate gradient in the White Mountains, New Hampshire, USA. Here we show that with increasing elevation organic forms of N became the dominant source of N taken up by hardwood and coniferous tree species based on dual-labeled glycine uptake analysis, an important confirmation of an emerging theory for the biogeochemistry of the N cycle. Variation in natural abundance foliar delta15N with elevation was also consistent with increasing organic N uptake, though a simple, mass balance model demonstrated that the uptake of delta15N depleted inorganic N, rather than fractionation upon transfer of N from mycorrhizal fungi, best explains variations in foliar delta15N with elevation. PMID- 21661552 TI - Substrate supply, fine roots, and temperature control proteolytic enzyme activity in temperate forest soils. AB - Temperature and substrate availability constrain the activity of the extracellular enzymes that decompose and release nutrients from soil organic matter (SOM). Proteolytic enzymes are the primary class of enzymes involved in the depolymerization of nitrogen (N) from proteinaceous components of SOM, and their activity affects the rate of N cycling in forest soils. The objectives of this study were to determine whether and how temperature and substrate availability affect the activity of proteolytic enzymes in temperate forest soils, and whether the activity of proteolytic enzymes and other enzymes involved in the acquisition of N (i.e., chitinolytic and ligninolytic enzymes) differs between trees species that form associations with either ectomycorrhizal or arbuscular mycorrhizal fungi. Temperature limitation of proteolytic enzyme activity was observed only early in the growing season when soil temperatures in the field were near 4 degrees C. Substrate limitation to proteolytic activity persisted well into the growing season. Ligninolytic enzyme activity was higher in soils dominated by ectomycorrhizal associated tree species. In contrast, the activity of proteolytic and chitinolytic enzymes did not differ, but there were differences between mycorrhizal association in the control of roots on enzyme activity. Roots of ectomycorrhizal species but not those of arbuscular mycorrhizal species exerted significant control over proteolytic, chitinolytic, and ligninolytic enzyme activity; the absence of ectomycorrhizal fine roots reduced the activity of all three enzymes. These results suggest that climate warming in the absence of increases in substrate availability may have a modest effect on soil-N cycling, and that global changes that alter belowground carbon allocation by trees are likely to have a larger effect on nitrogen cycling in stands dominated by ectomycorrhizal fungi. PMID- 21661553 TI - Quantifying the importance of regional and local filters for community trait structure in tropical and temperate zones. AB - The influence of regional and local processes on community structure is a major focus of ecology. Classically, ecologists have used local-regional richness regressions to evaluate the role of local and regional processes in determining community structure, an approach that has numerous flaws. Here, we implemented a novel trait-based approach that treats local and regional influences as a continuum, rather than a dichotomy. Using hylid frogs (Hylidae), we compared trait dispersion among members of local species assemblages to the trait dispersion in the regional assemblage from which they were drawn. Similarly, we compared trait dispersion in the regional assemblages to dispersion in the continental species pool. We estimated the contributions of local and regional filters, and we compared their strength in temperate and tropical zones. We found that regional and local filters explained 80% of the total variation among local assemblages in community body size dispersion. Overall, regional filters reduced trait dispersion, and local filters increased it, a pattern driven by particularly strong antagonistic effects in temperate zones that reduced the realized total variation by more than 40%. In contrast, local and regional filters acted in concert in tropical regions. Patterns within the tropics did not differ from the random expectation based on a null model, but within the temperate zone, local community filtering was stronger than expected by chance. Furthermore, in temperate regions, antagonistic regional and local filtering masked from 76% to 90% of the total variation in trait dispersion. Together, these results suggest that there are fundamental differences in the scale and identity of the processes determining community structure in temperate and tropical regions. PMID- 21661554 TI - A direct comparison of the consequences of plant genotypic and species diversity on communities and ecosystem function. AB - Biodiversity loss is proceeding at an unprecedented rate, yet we lack a thorough understanding of the consequences of losing diversity at different scales. While species diversity is known to impact community and ecosystem processes, genotypic diversity is assumed to have relatively smaller effects. Nonetheless, a few recent studies suggest that genotypic diversity may have quantitatively similar ecological consequences compared to species diversity. Here we show that increasing either genotypic diversity of common evening primrose (Oenothera biennis) or species diversity of old-field plant species resulted in nearly equivalent increases (approximately 17%) in aboveground primary production. The predominant mechanism explaining this effect, niche complementarity, was similar for each type of diversity. Arthropod species richness also increased with both types of plant diversity, but the mechanisms leading to this effect differed: abundance-driven accumulation of arthropod species was important in plant genotypic polycultures, whereas resource specialization was important in plant species polycultures. Thus, similar increases in primary productivity differentially impacted higher trophic levels in response to each type of plant diversity. These results highlight important ecological similarities and differences between genotypic and species diversity and suggest that genotypic diversity may play a larger role in community and ecosystem processes than previously realized. PMID- 21661555 TI - Disentangling the drivers of reduced long-distance seed dispersal by birds in an experimentally fragmented landscape. AB - Seed dispersal is a crucial component of plant population dynamics. Human landscape modifications, such as habitat destruction and fragmentation, can alter the abundance of fruiting plants and animal dispersers, foraging rates, vector movement, and the composition of the disperser community, all of which can singly or in concert affect seed dispersal. Here, we quantify and tease apart the effects of landscape configuration, namely, fragmentation of primary forest and the composition of the surrounding forest matrix, on individual components of seed dispersal of Heliconia acuminata, an Amazonian understory herb. First we identified the effects of landscape configuration on the abundance of fruiting plants and six bird disperser species. Although highly variable in space and time, densities of fruiting plants were similar in continuous forest and fragments. However, the two largest-bodied avian dispersers were less common or absent in small fragments. Second, we determined whether fragmentation affected foraging rates. Fruit removal rates were similar and very high across the landscape, suggesting that Heliconia fruits are a key resource for small frugivores in this landscape. Third, we used radiotelemetry and statistical models to quantify how landscape configuration influences vector movement patterns. Bird dispersers flew farther and faster, and perched longer in primary relative to secondary forests. One species also altered its movement direction in response to habitat boundaries between primary and secondary forests. Finally, we parameterized a simulation model linking data on fruit density and disperser abundance and behavior with empirical estimates of seed retention times to generate seed dispersal patterns in two hypothetical landscapes. Despite clear changes in bird movement in response to landscape configuration, our simulations demonstrate that these differences had negligible effects on dispersal distances. However, small fragments had reduced densities of Turdus albicollis, the largest bodied disperser and the only one to both regurgitate and defecate seeds. This change in Turdus abundance acted together with lower numbers of fruiting plants in small fragments to decrease the probability of long-distance dispersal events from small patches. These findings emphasize the importance of foraging style for seed dispersal and highlight the primacy of habitat size relative to spatial configuration in preserving biotic interactions. PMID- 21661556 TI - Assessing hypotheses about nesting site occupancy dynamics. AB - Hypotheses about habitat selection developed in the evolutionary ecology framework assume that individuals, under some conditions, select breeding habitat based on expected fitness in different habitat. The relationship between habitat quality and fitness may be reflected by breeding success of individuals, which may in turn be used to assess habitat quality. Habitat quality may also be assessed via local density: if high-quality sites are preferentially used, high density may reflect high-quality habitat. Here we assessed whether site occupancy dynamics vary with site surrogates for habitat quality. We modeled nest site use probability in a seabird subcolony (the Black-legged Kittiwake, Rissa tridactyla) over a 20-year period. We estimated site persistence (an occupied site remains occupied from time t to t+1) and colonization through two subprocesses: first colonization (site creation at the timescale of the study) and recolonization (a site is colonized again after being deserted). Our model explicitly incorporated site-specific and neighboring breeding success and conspecific density in the neighborhood. Our results provided evidence that reproductively "successful" sites have a higher persistence probability than "unsuccessful" ones. Analyses of site fidelity in marked birds and of survival probability showed that high site persistence predominantly reflects site fidelity, not immediate colonization by new owners after emigration or death of previous owners. There is a negative quadratic relationship between local density and persistence probability. First colonization probability decreases with density, whereas recolonization probability is constant. This highlights the importance of distinguishing initial colonization and recolonization to understand site occupancy. All dynamics varied positively with neighboring breeding success. We found evidence of a positive interaction between site-specific and neighboring breeding success. We addressed local population dynamics using a site occupancy approach integrating hypotheses developed in behavioral ecology to account for individual decisions. This allows development of models of population and metapopulation dynamics that explicitly incorporate ecological and evolutionary processes. PMID- 21661557 TI - Consequences of immune system aging in nature: a study of immunosenescence costs in free-living Tree Swallows. AB - Immunosenescence, the aging of the immune system, is well documented in humans and laboratory models and is known to increase infection risk, morbidity, and mortality among the old. Immunosenescence patterns have recently been unveiled in various free-living populations, but their consequences in the wild have not been explored. We investigated the consequences of immunosenescence in free-living Tree Swallows Tachycineta bicolor through a field experiment simulating a bacterial infection (challenge with lipopolysaccharide, LPS) in females of different ages during the nestling rearing period. We assessed behavioral and physiological responses of females, as well as growth and quality of their offspring, to determine the costs associated with the simulated infection. Results of the experiment differed between the two years of study. In the first year, old females challenged with LPS lost more body mass and reduced their nest visitation rates more, and their offspring tended to grow slower compared to similarly challenged younger females. In contrast, in the second year, old females did not appear to suffer larger costs than younger ones. Interestingly, immunosenescence was only detected during the first year of the study, suggesting that it is the dysregulated immune function characteristic of immunosenescent individuals rather than age per se that can lead to higher costs of immune defense in old individuals. These results provide the first evidence of costs of immunosenescence in free-living animals and support the hypothesis that old, immunosenescent individuals pay higher costs than younger ones when faced with a challenge to their immune system. Our results also suggest that these costs are mediated by an exaggerated sickness behavior, as seen in laboratory models, and can be modulated by ecological factors such as weather conditions and food availability. PMID- 21661558 TI - Alternative stable states and phase shifts in coral reefs under anthropogenic stress. AB - Ecosystems with alternative stable states (ASS) may shift discontinuously from one stable state to another as environmental parameters cross a threshold. Reversal can then be difficult due to hysteresis effects. This contrasts with continuous state changes in response to changing environmental parameters, which are less difficult to reverse. Worldwide degradation of coral reefs, involving "phase shifts" from coral to algal dominance, highlights the pressing need to determine the likelihood of discontinuous phase shifts in coral reefs, in contrast to continuous shifts with no ASS. However, there is little evidence either for or against the existence of ASS for coral reefs. We use dynamic models to investigate the likelihood of continuous and discontinuous phase shifts in coral reefs subject to sustained environmental perturbation by fishing, nutrification, and sedimentation. Our modeling results suggest that coral reefs with or without anthropogenic stress can exhibit ASS, such that discontinuous phase shifts can occur. We also find evidence to support the view that high macroalgal growth rates and low grazing rates on macroalgae favor ASS in coral reefs. Further, our results suggest that the three stressors studied, either alone or in combination, can increase the likelihood of both continuous and discontinuous phase shifts by altering the competitive balance between corals and algae. However, in contrast to continuous phase shifts, we find that discontinuous shifts occur only in model coral reefs with parameter values near the extremes of their empirically determined ranges. This suggests that continuous shifts are more likely than discontinuous shifts in coral reefs. Our results also suggest that, for ecosystems in general, tackling multiple human stressors simultaneously maximizes resilience to phase shifts, ASS, and hysteresis, leading to improvements in ecosystem health and functioning. PMID- 21661559 TI - Stronger predation in the tropics shapes species richness patterns in marine communities. AB - Species interactions are widely assumed to be stronger at lower latitudes, but surprisingly few experimental studies test this hypothesis, and none ties these processes to observed patterns of species richness across latitude. We report here the first experimental field test that predation is both stronger and has a disproportionate effect on species richness in the tropics relative to the temperate zone. We conducted predator-exclusion experiments on communities of sessile marine invertebrates in four regions, which span 32 degrees latitude, in the western Atlantic Ocean and Caribbean Sea. Over a three-month timescale, predation had no effect on species richness in the temperate zone. In the tropics, however, communities were from two to over ten times more species-rich in the absence of predators than when predators were present. While micro-and macro-predators likely compete for the limited prey resource in the tropics, micropredators alone were able to exert as much pressure on the invertebrate communities as the full predator community. This result highlights the extent to which exposure to even a subset of the predator guild can significantly impact species richness in the tropics. Patterns were consistent in analyses that included relative and total species abundances. Higher species richness in the absence of predators in the tropics was also observed when species occurrences were pooled across two larger spatial scales, site and region, demonstrating a consistent scaling relationship. These experimental results show that predation can both limit local species abundances and shape patterns of regional coexistence in the tropics. When preestablished diverse tropical communities were then exposed to predation for different durations, ranging from one to several days, species richness was always reduced. These findings confirmed that impacts of predation in the tropics are strong and consistent, even in more established communities. Our results offer empirical support for the long-held prediction that predation pressure is stronger at lower latitudes. Furthermore, we demonstrate the magnitude to which variation in predation pressure can contribute to the maintenance of tropical species diversity. PMID- 21661560 TI - Differential responses of vertebrate and invertebrate herbivores to traits of New Zealand subalpine shrubs. AB - Plant traits are influenced by herbivore diet selection, but little is known about how traits are affected by different types of herbivores. We related eight traits of 27 subalpine shrub species in South Island, New Zealand, to damage of these shrubs by introduced red deer (Cervus elaphus) and native invertebrate herbivores using phylogenetically explicit modeling. Deer preferentially consumed species that grew quickly, were low in foliar tannins, or had high leaf area per unit mass. However, these traits did not trade off against each other; rather, they could be related to different multivariate defense strategies. Although the proportion of leaves damaged by leaf-chewing invertebrates also increased with stem growth, invertebrates did not damage the same fast growing species as those preferred by deer. Other traits may also be important in determining herbivore preferences, as suggested by the high proportion of variation in herbivory explained by phylogeny. Last, we found that the composition of invertebrate herbivore communities was more similar among closely related shrubs, and consequently, the range of invertebrate-plant associations may change if introduced deer shift plant composition toward slow-growing species. Overall, our results demonstrate the importance of herbivore type and coevolved interactions for the adaptive significance of plant traits. PMID- 21661561 TI - Species' traits predict phenological responses to climate change in butterflies. AB - How do species' traits help identify which species will respond most strongly to future climate change? We examine the relationship between species' traits and phenology in a well-established model system for climate change, the U.K. Butterfly Monitoring Scheme (UKBMS). Most resident U.K. butterfly species have significantly advanced their dates of first appearance during the past 30 years. We show that species with narrower larval diet breadth and more advanced overwintering stages have experienced relatively greater advances in their date of first appearance. In addition, species with smaller range sizes have experienced greater phenological advancement. Our results demonstrate that species' traits can be important predictors of responses to climate change, and they suggest that further investigation of the mechanisms by which these traits influence phenology may aid in understanding species' responses to current and future climate change. PMID- 21661562 TI - Density-dependent biodiversity effects on physical habitat modification by freshwater bivalves. AB - Several decades of research have shown that biodiversity affects ecosystem processes associated with resource capture and the production of biomass within trophic levels. Although there are good reasons to expect that biodiversity influences non-trophic ecosystem processes, such as the physical creation or modification of habitat, studies investigating the role of biodiversity on physical processes are scarce. Here we report the results of a study using artificial streams to test the influence of freshwater mussel biodiversity on gravel erosion during high flows while manipulating mussel abundance. Mussel species vary in traits that should influence their effects on erosion, such as size, shell morphology, and burrowing behavior. We found that mussel species richness was associated with an increase in erosion at both low and high densities. Planned contrasts showed that the erosion observed in species mixtures was purely additive at low density, indicating that erosion in a species polyculture could routinely be predicted by the performance of monocultures. However, at high density certain combinations of species showed nonadditive effects on erosion, suggesting that organism abundance can fundamentally alter biodiversity effects. Although this may have been a result of altered species interactions at high density, our study design cannot confirm this. PMID- 21661563 TI - Growth, fire history, and browsing recorded in wood rings of shrubs in a mild temperate climate. AB - Separate effects of abiotic and biotic factors on the structure and dynamics of ecological communities may be recorded in growth rings of woody plants. We used Ceanothus cuneatus rigidus and Arctostaphylos pumila to tease apart the roles of fire, rain, and herbivores on the histories and community structure of four areas in a coastal mediterranean-type climate in central California with mild winters and mild summers. Ring widths of both species were related to rainfall in two of the areas; heavy deer browsing on Ceanothus overwhelmed the climate signal in the others. Ceanothus germination was more closely related to heavy rainfall, especially during ENSO years, than to fire events. In a related greenhouse experiment that evaluated these observations, the same proportions of new Ceanothus seeds germinated after burning and after receiving regular water for several months, but germination of old seeds responded primarily to the fire treatment. In areas where heavy browsing by mammals reduces recruitment and growth of Ceanothus and increases mortality, the continuance of the Ceanothus population must rely heavily on germination from the persistent seed bank during unusually wet years or after occasional fires. Because Arctostaphylos can produce new stems from underground roots, individual plants may survive and produce seeds until another fire. PMID- 21661564 TI - Effects of soil biota from different ranges on Robinia invasion: acquiring mutualists and escaping pathogens. AB - The net effects of soil biota on exotic invaders can be variable, in part, because net effects are produced by many interacting mutualists and antagonists. Here we compared mutualistic and antagonistic biota in soils collected in the native, expanded, and invasive range of the black locust tree, Robinia pseudoacacia. Robinia formed nodules in all soils with a broad phylogenetic range of N-fixing bacteria, and leaf N did not differ among the different sources of soil. This suggests that the global expansion of Robinia was not limited by the lack of appropriate mutualistic N-fixers. Arbuscular mycorrhizal fungi (AMF) from the native range stimulated stronger positive feedbacks than AMF from the expanded or invasive ranges, a biogeographic difference not described previously for invasive plants. Pythium taxa collected from soil in the native range were not more pathogenic than those from other ranges; however, feedbacks produced by the total soil biota were more negative from soils from the native range than from the other ranges, overriding the effects of AMF. This suggests that escape from other pathogens in the soil or the net negative effects of the whole soil community may contribute to superior performance in invaded regions. Our results suggest that important regional evolutionary relationships may occur among plants and soil biota, and that net effects of soil biota may affect invasion, but in ways that are not easily explained by studying isolated components of the soil biota. PMID- 21661565 TI - Plants control the seasonal dynamics of microbial N cycling in a beech forest soil by belowground C allocation. AB - Soil microbes in temperate forest ecosystems are able to cycle several hundreds of kilograms of N per hectare per year and are therefore of paramount importance for N retention. Belowground C allocation by trees is an important driver of seasonal microbial dynamics and may thus directly affect N transformation processes over the course of the year. Our study aimed at unraveling plant controls on soil N cycling in a temperate beech forest at a high temporal resolution over a time period of two years, by investigating the effects of tree girdling on microbial N turnover. In both years of the experiment, we discovered (1) a summer N mineralization phase (between July and August) and (2) a winter N immobilization phase (November-February). The summer mineralization phase was characterized by a high N mineralization activity, low microbial N uptake, and a subsequent high N availability in the soil. During the autumn/winter N immobilization phase, gross N mineralization rates were low, and microbial N uptake exceeded microbial N mineralization, which led to high levels of N in the microbial biomass and low N availability in the soil. The observed immobilization phase during the winter may play a crucial role for ecosystem functioning, since it could protect dissolved N that is produced by autumn litter degradation from being lost from the ecosystem during the phase when plants are mostly inactive. The difference between microbial biomass N levels in winter and spring equals 38 kg N/ha and may thus account for almost one-third of the annual plant N demand. Tree girdling strongly affected annual N cycling: the winter N immobilization phase disappeared in girdled plots (microbial N uptake and microbial biomass N were significantly reduced, while the amount of available N in the soil solution was enhanced). This was correlated to a reduced fungal abundance in autumn in girdled plots. By releasing recently fixed photosynthates to the soil, plants may thus actively control the annual microbial N cycle. Tree belowground C allocation increases N accumulation in microorganisms during the winter which may ultimately feed back on plant N availability in the following growing season. PMID- 21661566 TI - A new conceptual model for the fate of lignin in decomposing plant litter. AB - Lignin is a main component of plant litter. Its degradation is thought to be critical for litter decomposition rates and the build-up of soil organic matter. We studied the relationships between lignin degradation and the production of dissolved organic carbon (DOC) and of CO2 during litter decomposition. Needle or leaf litter of five species (Norway spruce, Scots pine, mountain ash, European beech, sycamore maple) and of different decomposition stage (freshly fallen and up to 27 months of field exposure) was incubated in the laboratory for two years. Lignin degradation was followed with the CuO method. Strong lignin degradation occurred during the first 200 incubation days, as revealed by decreasing yields of lignin-derived phenols. Thereafter lignin degradation leveled off. This pattern was similar for fresh and decomposed litter, and it stands in contrast to the common view of limited lignin degradation in fresh litter. Dissolved organic carbon and CO2 also peaked in the first period of the incubation but were not interrelated. In the later phase of incubation, CO2 production was positively correlated with DOC amounts, suggesting that bioavailable, soluble compounds became a limiting factor for CO2 production. Lignin degradation occurred only when CO2 production was high, and not limited by bioavailable carbon. Thus carbon availability was the most important control on lignin degradation. In turn, lignin degradation could not explain differences in DOC and CO2 production over the study period. Our results challenge the traditional view regarding the fate and role of lignin during litter decomposition. Lignin degradation is controlled by the availability of easily decomposable carbon sources. Consequently, it occurs particularly in the initial phase of litter decomposition and is hampered at later stages if easily decomposable resources decline. PMID- 21661567 TI - Tree cover in sub-Saharan Africa: rainfall and fire constrain forest and savanna as alternative stable states. AB - Savannas are known as ecosystems with tree cover below climate-defined equilibrium values. However, a predictive framework for understanding constraints on tree cover is lacking. We present (a) a spatially extensive analysis of tree cover and fire distribution in sub-Saharan Africa, and (b) a model, based on empirical results, demonstrating that savanna and forest may be alternative stable states in parts of Africa, with implications for understanding savanna distributions. Tree cover does not increase continuously with rainfall, but rather is constrained to low (<50%, "savanna") or high tree cover (>75%, "forest"). Intermediate tree cover rarely occurs. Fire, which prevents trees from establishing, differentiates high and low tree cover, especially in areas with rainfall between 1000 mm and 2000 mm. Fire is less important at low rainfall (<1000 mm), where rainfall limits tree cover, and at high rainfall (>2000 mm), where fire is rare. This pattern suggests that complex interactions between climate and disturbance produce emergent alternative states in tree cover. The relationship between tree cover and fire was incorporated into a dynamic model including grass, savanna tree saplings, and savanna trees. Only recruitment from sapling to adult tree varied depending on the amount of grass in the system. Based on our empirical analysis and previous work, fires spread only at tree cover of 40% or less, producing a sigmoidal fire probability distribution as a function of grass cover and therefore a sigmoidal sapling to tree recruitment function. This model demonstrates that, given relatively conservative and empirically supported assumptions about the establishment of trees in savannas, alternative stable states for the same set of environmental conditions (i.e., model parameters) are possible via a fire feedback mechanism. Integrating alternative stable state dynamics into models of biome distributions could improve our ability to predict changes in biome distributions and in carbon storage under climate and global change scenarios. PMID- 21661568 TI - The high cost of mutualism: effects of four species of East African ant symbionts on their myrmecophyte host tree. AB - Three recent meta-analyses of protective plant-ant mutualisms report a surprisingly weak relationship between herbivore protection and measured demographic benefits to ant-plants, suggesting high tolerance for herbivory, substantial costs of ant-mediated defense, and/or benefits that are realized episodically rather than continuously. Experimental manipulations of protective ant-plant associations typically last for less than a year, yet virtually all specialized myrmecophytes are long-lived perennials for which the costs and benefits of maintaining ant symbionts could accrue at different rates over the host's lifetime. To complement long-term monitoring studies, we experimentally excluded each of four ant symbionts from their long-lived myrmecophyte host trees (Acacia drepanolobium) for 4.5 years. Ant species varied in their effectiveness against herbivores and in their effects on intermediate-term growth and reproduction, but the level of herbivore protection provided was a poor predictor of the net impact they had on host trees. Removal of the three Crematogaster species resulted in cumulative gains in host tree growth and/or reproduction over the course of the experiment, despite the fact that two of those species significantly reduce chronic herbivore damage. In contrast, although T. penzigi is a relatively poor defender, the low cost of maintaining this ant symbiont apparently eliminated negative impacts on overall tree growth and reproduction, resulting in enhanced allocation to new branch growth by the final census. Acacia drepanolobium is evidently highly tolerant of herbivory by insects and small browsers, and the costs of maintaining Crematogaster colonies exceeded the benefits received during the study. No experimental trees were killed by elephants, but elephant damage was uniquely associated with reduced tree growth, and at least one ant species (C. mimosae) strongly deterred elephant browsing. We hypothesize that rare but catastrophic damage by elephants may be more important than chronic herbivory in maintaining the costly myrmecophyte habit in this system. PMID- 21661569 TI - Herbivores, tidal elevation, and species richness simultaneously mediate nitrate uptake by seaweed assemblages. AB - In order for research into the consequences of biodiversity changes to be more applicable to real-world ecosystems, experiments must be conducted in the field, where a variety of factors other than diversity can affect the rates of key biogeochemical and physiological processes. Here, we experimentally evaluate the effects of two factors known to affect the diversity and composition of intertidal seaweed assemblages--tidal elevation and herbivory--on nitrate uptake by those assemblages. Based on surveys of community composition at the end of a 1.5-year press experiment, we found that both tide height and herbivores affected seaweed community structure. Not surprisingly, seaweed species richness was greater at lower tidal elevations. Herbivores did not affect richness, but they altered the types of species that were present; seaweed species characterized by higher rates of nitrate uptake were more abundant in herbivore-removal plots. Both tide height and herbivores affected nitrate uptake by seaweed assemblages. Individual seaweed species, as well as entire seaweed assemblages, living higher on the shore had greater rates of biomass-specific nitrate uptake, particularly at high ambient nitrate concentrations. Grazed seaweed assemblages exhibited reduced nitrate uptake, but only at low nitrate concentrations. We evaluated the effect of seaweed richness on nitrate uptake, both alone and after accounting for effects of tidal elevation and herbivores. When only richness was considered, we found no effect on uptake. However, when simultaneous effects of richness, tide height, and herbivores on uptake were evaluated, we found that all three had relatively large and comparable effects on nitrate uptake coefficients and that there was a negative relationship between seaweed richness and nitrate uptake. Particularly because effects of richness on uptake were not apparent unless the effects of tide height and herbivory were also considered, these results highlight the importance of considering the effects of environmental context when evaluating the consequences of biodiversity change in more realistic systems. PMID- 21661570 TI - Spatially stochastic settlement and the coexistence of benthic marine animals. AB - For sessile organisms, dispersal and recruitment are typically spatially stochastic, but there is little understanding of how this variability scales up to influence processes such as competitive coexistence. Here we argue that coexistence of benthic marine animals is enhanced by stochastic differences between species in the spatial distribution of larval settlement. Differentiation of settlement distributions among competitors results in intraspecifically aggregated settlement, which can reduce overall interspecific competition and increase overall intraspecific competition. We test for the components of this mechanism using a pair of subtidal invertebrates, and we find that the mean interspecific effect of the dominant competitor is substantially reduced by natural settlement variability. Using a simulation parameterized with experimental data, we find that variable settlement could play an important role in long-term coexistence between these species. This mechanism may apply broadly to benthic marine communities, which can be highly diverse and typically exhibit large settlement fluctuation over a range of scales. PMID- 21661571 TI - Differential effects of energy and mass influx on the landscape synchrony of lake ecosystems. AB - Interannual variation of 45 annually resolved time series of environmental, limnological, and biotic parameters was quantified (1994-2009) in six lakes within 52,000 km2 to test the hypothesis that influx of energy (E; as irradiance, heat, wind) varies synchronously among sites and induces temporal coherence in lakes and their food webs, whereas influx of mass (m; as water, solutes, particles) reduces synchrony because local catchments uniquely modify hydrologic inputs. Overall, 82% of parameters exhibited significant (P < 0.05) synchrony (S) estimated as mean pair-wise correlation of Z-transformed time series. Influx of E as atmospheric heat and irradiance was both more highly synchronous and less temporally variable (months-to-decades) than influx of m as summer precipitation, snow, or river discharge. Similarly, S of limnological parameters varied from 0.08 to 0.85, with variables known to be regulated by E influx (ice melt, gas solubility) up to twofold more coherent than those regulated by m inputs (organic solutes). Pairs of variables linked by simple direct mechanisms exhibited similar S values (air temperature and ice melt, nutrients and algae), whereas the coherence of other parameters (water temperature, mixing) was intermediate to that of multiple regulatory agents. Overall, aggregate measures of plankton density varied more coherently among lakes than did constituent taxa. These findings suggest that environmental variability is transmitted to most levels of aquatic ecosystems, but that the precise effects depend on whether E or m fluxes predominate, the coherence of each forcing mechanism, and the strength of linkages between exogenous forcing and lake response. PMID- 21661572 TI - Terrestrial, benthic, and pelagic resource use in lakes: results from a three isotope Bayesian mixing model. AB - Fluxes of organic matter across habitat boundaries are common in food webs. These fluxes may strongly influence community dynamics, depending on the extent to which they are used by consumers. Yet understanding of basal resource use by consumers is limited, because describing trophic pathways in complex food webs is difficult. We quantified resource use for zooplankton, zoobenthos, and fishes in four low-productivity lakes, using a Bayesian mixing model and measurements of hydrogen, carbon, and nitrogen stable isotope ratios. Multiple sources of uncertainty were explicitly incorporated into the model. As a result, posterior estimates of resource use were often broad distributions; nevertheless, clear patterns were evident. Zooplankton relied on terrestrial and pelagic primary production, while zoobenthos and fishes relied on terrestrial and benthic primary production. Across all consumer groups terrestrial reliance tended to be higher, and benthic reliance lower, in lakes where light penetration was low due to inputs of terrestrial dissolved organic carbon. These results support and refine an emerging consensus that terrestrial and benthic support of lake food webs can be substantial, and they imply that changes in the relative availability of basal resources drive the strength of cross-habitat trophic connections. PMID- 21661573 TI - Species loss, delayed numerical responses, and functional compensation in an antbird guild. AB - When a community loses species through fragmentation, its total food consumption may drop. Compensatory responses of remaining species, whereby survivors assume roles of extinct competitors, may reduce the impact of species loss through numerical or functional responses. We measured compensatory responses in two remaining antbird species on Barro Colorado Island, Panama, four decades after the loss of their dominant competitor, the Ocellated Antbird, Phaenostictus mcleannani. We compared current abundances and behavior of these two species on Barro Colorado to those reported before the island lost Ocellated Antbirds, and to those in a nearby mainland population where all three species still exist as a space-for-time substitution. The smaller, more subordinate Spotted Antbird, Hylophylax naevioides, responded far more strongly than the larger Bicolored Antbird, Gymnopithys leucaspis, which is functionally more like the Ocellated Antbird. Islandwide density of Spotted Antbirds has more than doubled since the loss of Ocellated Antbirds. Moreover, Spotted Antbirds now spend so much more of their time following ant swarms that their metabolic biomass at these swarms has more than tripled since Ocellated Antbirds disappeared. These responses in Spotted Antbirds were apparently delayed by >20 years. Bicolored Antbirds have not increased substantially in islandwide density or metabolic biomass at ant swarms. We hypothesize that behavioral flexibility, as shown by Spotted Antbirds on Barro Colorado Island, is a major factor governing the extent to which fragmented ecosystems can buffer the impacts of species loss. PMID- 21661574 TI - Microbial and environmental effects on avian egg viability: do tropical mechanisms act in a temperate environment? AB - The viability of freshly laid avian eggs declines after several days of exposure to ambient temperatures above physiological zero, and declines occur faster in tropical than temperate ecosystems. Microbial infection during preincubation exposure has recently been shown as a second cause of egg viability decline in the tropics, but whether microbial processes influence the viability of wild bird eggs in temperate ecosystems is unknown. We determined the microbial load on eggshells, the incidence of microbial penetration of egg contents, and changes in the viability of wild bird eggs (Sialia mexicana, Tachycineta bicolor, Tachycineta thalassina) experimentally exposed to temperate-zone ambient conditions in situ in a mediterranean climate in northern California. Initial microbial loads on eggshells were generally low, although they were significantly higher on eggs laid in old boxes than in new boxes. Eggshell microbial loads did not increase with exposure to ambient conditions, were not reduced by twice-daily disinfection with alcohol, and were unaffected by parental incubation. The rate of microbial penetration into egg contents was low and unaffected by the duration of exposure. Nevertheless, egg viability declined very gradually and significantly with exposure duration, and the rate of decline differed among species. In contrast to studies performed in the tropics, we found little evidence that temperature or microbial mechanisms of egg viability decline were important at our temperate-zone site; neither temperatures above physiological zero nor alcohol disinfection was significantly related to hatching success. Delaying the onset of incubation until the penultimate or last egg of a clutch at our study site may maintain hatching synchrony without a large trade-off in egg viability. These results provide insight into the environmental mechanisms that may be responsible for large-scale latitudinal patterns in avian clutch size and hatching asynchrony. PMID- 21661575 TI - Integral projection models for finite populations in a stochastic environment. AB - Continuous types of population structure occur when continuous variables such as body size or habitat quality affect the vital parameters of individuals. These structures can give rise to complex population dynamics and interact with environmental conditions. Here we present a model for continuously structured populations with finite size, including both demographic and environmental stochasticity in the dynamics. Using recent methods developed for discrete age structured models we derive the demographic and environmental variance of the population growth as functions of a continuous state variable. These two parameters, together with the expected population growth rate, are used to define a one-dimensional diffusion approximation of the population dynamics. Thus, a substantial reduction in complexity is achieved as the dynamics of the complex structured model can be described by only three population parameters. We provide methods for numerical calculation of the model parameters and demonstrate the accuracy of the diffusion approximation by computer simulation of specific examples. The general modeling framework makes it possible to analyze and predict future dynamics and extinction risk of populations with various types of structure, and to explore consequences of changes in demography caused by, e.g., climate change or different management decisions. Our results are especially relevant for small populations that are often of conservation concern. PMID- 21661576 TI - Niche and fitness differences relate the maintenance of diversity to ecosystem function. AB - The frequently observed positive correlation between species diversity and community biomass is thought to depend on both the degree of resource partitioning and on competitive dominance between consumers, two properties that are also central to theories of species coexistence. To make an explicit link between theory on the causes and consequences of biodiversity, we define in a precise way two kinds of differences among species: niche differences, which promote coexistence, and relative fitness differences, which promote competitive exclusion. In a classic model of exploitative competition, promoting coexistence by increasing niche differences typically, although not universally, increases the "relative yield total", a measure of diversity's effect on the biomass of competitors. In addition, however, we show that promoting coexistence by decreasing relative fitness differences also increases the relative yield total. Thus, two fundamentally different mechanisms of species coexistence both strengthen the influence of diversity on biomass yield. The model and our analysis also yield insight on the interpretation of experimental diversity manipulations. Specifically, the frequently reported "complementarity effect" appears to give a largely skewed estimate of resource partitioning. Likewise, the "selection effect" does not seem to isolate biomass changes attributable to species composition rather than species richness, as is commonly presumed. We conclude that past inferences about the cause of observed diversity-function relationships may be unreliable, and that new empirical estimates of niche and relative fitness differences are necessary to uncover the ecological mechanisms responsible for diversity-function relationships. PMID- 21661577 TI - Aquatic herbivores facilitate the emission of methane from wetlands. AB - Wetlands are significant sources of atmospheric methane. Methane produced by microbes enters roots and escapes to the atmosphere through the shoots of emergent wetland plants. Herbivorous birds graze on helophytes, but their effect on methane emission remains unknown. We hypothesized that grazing on shoots of wetland plants can modulate methane emission from wetlands. Diffusive methane emission was monitored inside and outside bird exclosures, using static flux chambers placed over whole vegetation and over single shoots. Both methods showed significantly higher methane release from grazed vegetation. Surface-based diffusive methane emission from grazed plots was up to five times higher compared to exclosures. The absence of an effect on methane-cycling microbial processes indicated that this modulating effect acts on the gas transport by the plants. Modulation of methane emission by animal-plant-microbe interactions deserves further attention considering the increasing bird populations and changes in wetland vegetation as a consequence of changing land use and climate change. PMID- 21661578 TI - Interaction rules affect species coexistence in intransitive networks. AB - Intransitive communities, those in which species' abilities cannot be ranked in a hierarchy, have been the focus of theoretical and empirical research, as intransitivity could help explain the maintenance of biodiversity. Here we show that models for intransitive competition embedding slightly different interaction rules can produce opposite patterns. In particular, we find that interactions in which an individual can be outcompeted by its neighbors, but cannot outcompete its neighbors, produce negative frequency dependence that, in turn, promotes coexistence. Whenever the interaction rule is modified toward symmetry (the individual and the neighbors can outcompete each other) the negative frequency dependence vanishes, producing different coexistence levels. Macroscopically, we find that asymmetric interactions yield highest biodiversity if species compete globally, while symmetric interactions favor highest biodiversity if competition takes place locally. PMID- 21661579 TI - Nonlinear relationships between vital rates and state variables in demographic models. AB - To accurately estimate population dynamics and viability, structured population models account for among-individual differences in demographic parameters that are related to individual state. In the widely used matrix models, such differences are incorporated in terms of discrete state categories, whereas integral projection models (IPMs) use continuous state variables to avoid artificial classes. In IPMs, and sometimes also in matrix models, parameterization is based on regressions that do not always model nonlinear relationships between demographic parameters and state variables. We stress the importance of testing for nonlinearity and propose using restricted cubic splines in order to allow for a wide variety of relationships in regressions and demographic models. For the plant Borderea pyrenaica, we found that vital rate relationships with size and age were nonlinear and that the parameterization method had large effects on predicted population growth rates, X (linear IPM, 0.95; nonlinear IPMs, 1.00; matrix model, 0.96). Our results suggest that restricted cubic spline models are more reliable than linear or polynomial models. Because even weak nonlinearity in relationships between vital rates and state variables can have large effects on model predictions, we suggest that restricted cubic regression splines should be considered for parameterizing models of population dynamics whenever linearity cannot be assumed. PMID- 21661580 TI - TMJ implant makers ordered to conduct post-market studies. PMID- 21661581 TI - A call to civility. PMID- 21661582 TI - Commentary on The price of freedom--a counterpoint by Dr Heir. PMID- 21661583 TI - Dr. Barry Cooper's comments in support of Dr. Miller's guest editorial in the January 2011 issue of Cranio. PMID- 21661584 TI - Condylar shape in relation to anterior disk displacement in juvenile females. AB - The purpose of the study was to test the hypothesis that condylar shape varies based upon the condition of anterior disk displacement in young adolescent patients with temporomandibular disorder (TMD). The study design consisted of 96 juvenile female patients (aged 9 to 20; 15.1 +/- 2.3 yrs.) with clinical signs and/or symptoms of TMD. Bilateral high-resolution magnetic resonance imaging scans were performed in frontal and horizontal views with the mandible in the closed position. Disk positions were evaluated to classify the patients into three diagnostic groups. The results of the study, using ANOVA and Bonferroni tests, demonstrated significant differences among the groups. The conclusion drawn from the study was that condylar shape and size vary based on anterior disk position in juvenile females with TMD. The study's results suggest that disk displacement results in a smaller condyle. PMID- 21661585 TI - A preliminary anatomical study on the association of condylar and occlusal asymmetry. AB - The aim of this study was to test the hypothesis that condylar and occlusion asymmetry are not associated. For each of 22 skulls, the asymmetry of condyles was graded by one examiner and the asymmetry of occlusion by another examiner, both blinded to each other's evaluation, as 0 = symmetrical, 1 = mild asymmetrical and 2 = severe asymmetrical. There were 18 condyles graded the same as to their occlusion, but in four, the grades differed by one degree. Nine were graded symmetrical, seven were mild, and six were graded severely asymmetrical condyles. The corresponding figures for occlusion were: 10 were graded symmetrical, seven were graded mildly asymmetrical, and five were graded severely asymmetrical occlusion. The relation between occlusion and condylar asymmetry was tested using Goodman-Kruskal's gamma and was found to be 0.970 (p < 0.001). The null hypothesis was not supported. The results indicate that asymmetry of occlusion and condyles are associated, which indicates the need for further studies on larger samples, and in vivo studies. PMID- 21661586 TI - Association between disk position and degenerative bone changes of the temporomandibular joints: an imaging study in subjects with TMD. AB - The aim of this study was to determine the frequency and relationship between disk position and degenerative bone changes in the temporomandibular joints (TMJ), in subjects with internal derangement (ID). MRI and CT scans of 180 subjects with temporomandibular disorders (TMD) were studied. Different image parameters or characteristics were observed, such as disk position, joint effusion, condyle movement, degenerative bone changes (flattened, cortical erosions and irregularities), osteophytes, subchondral cysts and idiopathic condyle resorption. The present study concluded that there is a significant association between disk displacement without reduction and degenerative bone changes in patients with TMD. The study also found a high probability of degenerative bone changes when disk displacement without reduction is present. No association was found between TMD and condyle range of motion, joint effusion and/or degenerative bone changes. The following were the most frequent morphological changes observed: flattening of the anterior surface of the condyle; followed by erosions and irregularities of the joint surfaces; flattening of the articular surface of the temporal eminence, subchondral cysts, osteophytes; and idiopathic condyle resorption, in decreasing order. PMID- 21661587 TI - Occlusion factors influencing the magnitude of sleep bruxism activity. AB - The biomechanical load during strong bruxism activity reportedly causes many dental/oral problems. However, it is unknown whether the magnitude of muscle activity during sleep is controllable. In this study, the relationship between the magnitude of muscle activity during sleep and types of tooth contacts was examined, including anterior and posterior guidance, in order to clarify how occlusion factors contribute to sleep bruxism (SB). An EMG-2-axis accelerometer system was used for monitoring patterns and activities of SB. Bruxchecker was used to evaluate tooth contacts during SB, and a condylograph was used to measure posterior guidance (sagittal condylar inclination). Results show that grinding rather than clenching or tapping was observed in the high SB group, and there was Incisor-Canine-Premolar-Molar (ICPM) tooth contact during SB grinding movement. The canine occlusal guidance (COG) was flatter in the low SB group than in the moderate SB group. Relative canine occlusal guidance (rCOG), which is the difference between the sagittal condylar inclination (SCI) and COG, was larger in the low SB group than that in the high SB group. These findings suggest that the grinding pattern must be controlled to prevent strong bruxism, and that the muscle activity during bruxism can be reduced by controlling the tooth contact pattern during SB grinding. PMID- 21661588 TI - Comparison of patients with orofacial pain of different diagnostic categories. AB - The authors compared the pain intensity and difficulty experienced in performing activities of daily living (ADL) among 237 patients with orofacial pain. The patients underwent comprehensive examinations and recorded their subjective symptoms on a form (five items for pain intensity and six for ADL-related difficulty). On the basis of the primary diagnosis, the patients were divided into the temporomandibular joint dysfunction (TMJ), myofascial pain (MP), neuropathic pain (NP), and fibromyalgia (FM) groups. The intensity of pain in the jaw/face, tightness in the jaw/face, pain in the neck, and toothache significantly differed among the groups (p < 0.01, Kruskal-Wallis test). Compared to other patients, the FM and NP groups reported greater pain intensity, whereas those in the TMJ group reported lesser pain intensity. The ADL-related difficulty was not significantly different among the groups. Thus, compared to pain due to joint-related disorders, myalgic and neuropathic pain seem to be of higher intensity. PMID- 21661589 TI - Factors that affect pain behavior. AB - Emotions can and do affect the way one perceives pain, both acute and chronic. Many factors unconsciously alter the intensity in which pain is perceived even though human beings all have the same anatomical structures to convey nociception to the central nervous system. Pain cannot be measured, only observed by one's behavior to pain. Those who diagnose and treat craniofacial pain quickly realize that many factors in addition to pathological conditions affect patients differently and oftentimes, unpredictably. We, as those who attempt to treat these patients, need to recognize these factors and how they can influence our treatment and a patient's recovery. In this short article, factors that affect pain behavior are described. PMID- 21661590 TI - Treatment of a case of skeletal class II malocclusion with temporomandibular joint disorder using miniscrew anchorage. AB - At the present time, there are no reports in the literature on the treatment of temporomandibular joint disorder (TMD) by intrusion of molars using mini-screws. This case report describes the treatment for a female patient, aged 19 years seven months, with a TMD and an excessive lower anterior facial height. Overjet and overbite were +5.0 mm and +0.5 mm, respectively. The patient had a history of orthodontic treatment in which her first premolars were all extracted. During the first orthodontic treatment, a clockwise mandibular rotation was observed as a result of the increase of posterior dentoalveolar height. She had temporomandibular joint (TMJ) pain during mouth opening and complained of difficulty in eating due to masticatory dysfunction. The pretreatment Schuller views of both TMJ showed a posterior condyle position. In order to correct the overjet, molar relationship and the mandibular condyle position, a miniscrew was inserted into the palatal region of the upper first molar to intrude the upper posterior teeth. As the upper molars were intruded, the overjet was decreased, and a class I molar relationship was achieved by a counterclockwise mandibular rotation. After one year of treatment, an acceptable occlusion was achieved, and the condyle moved into centric position in the glenoid fossa. The patient's teeth continued to be stable, and she had no pain in TMJ after a retention period of three years. The result of this treatment showed that molar intrusion using miniscrew anchorage is effective for treatment of a TMD patient with a posterior condyle position. PMID- 21661593 TI - When one door closes... PMID- 21661592 TI - 2010 House of Delegates inaugural address. PMID- 21661591 TI - Is a marketing plan necessary? PMID- 21661594 TI - Report by physician Senators addresses effects of nation's new health care law. PMID- 21661595 TI - New name, school still addressing physician shortages in Georgia. PMID- 21661596 TI - Ethical response to outbreaks of vaccine-preventable diseases. PMID- 21661597 TI - Case study: clear rhinorrhea. PMID- 21661598 TI - Physician websites. PMID- 21661599 TI - A call to action: changing definitions of "quality" in health care. PMID- 21661600 TI - Hidden consequences of taking call. PMID- 21661601 TI - Catching the pinch. PMID- 21661602 TI - New candidates for pertussis immunization. PMID- 21661603 TI - 30-Second Head-to-Toe tool in pediatric nursing: cultivating safety in handoff communication. AB - Efforts to improve handoff practices among providers during shift changes are needed to augment patient safety, particularly among pediatric patients. To this aim, nurse faculty developed and enhanced a tool to standardize a thinking process for students during their pediatric clinical experience. The 30-Second Head-to-Toe checklist allows for rapid assessment of a child's condition and environment. It offers both students and nurses a consistent system for reducing errors attributable to incomplete or inaccurate information during this critical transition. Students completed checklists for 352 pediatric patients over a period of two years. Identified discrepancies were analyzed. Findings confirmed the importance of a standardized system during shift changes to reduce errors and achieve accurate, consistent communication. Students also reported that using the tool and reviewing it with instructors helped them overcome initial feelings of anxiety and fostered confidence. PMID- 21661604 TI - High school students with asthma: attitudes about school health, absenteeism, and its impact on academic achievement. AB - Asthma is the most frequent reason for absence from school; it accounts for one third of all days of missed instruction, placing students at risk for academic failure and social isolation. This study compared high school students with asthma with those without asthma, and examined the relationship of their attitudes toward school health services, absenteeism, academic achievement, and the supposition that school nurse services play an essential part in the academic process. Surveys were completed by all students who participated in the study. Twenty-eight students with asthma reported levels of illness and school nurse support in an additional survey. Data revealed that students with asthma were absent more frequently, scored lower in mathematics, and participated less in school activities than their peers without asthma. Their level of illness did not predict the number of days absent, which was negatively correlated with achievement and positively correlated with students' permissive attitudes toward absenteeism. Findings indicate that school nurse interventions were sources of physical, social, emotional, and academic support. PMID- 21661605 TI - Baccalaureate nursing student experiences at a camp for children with diabetes: the impact of a service-learning model. AB - Camp nurses deliver health care in a non-traditional setting. Research indicates that camp has a positive impact on campers with diabetes mellitus, but the impact on student nurse knowledge of diabetes care and confidence in the role as a member of the health care team is unknown. This study examined the experiences of student nurses at a summer residential camp for children with diabetes using a service-learning framework. Camp positively increased knowledge of diabetes in the nursing students. Reflective journals identified themes of anxiety, fatigue, responsibility, and increased confidence in the nursing student, while developing empathy for the lifestyle of children with diabetes. Future research on camp nursing is indicated. PMID- 21661606 TI - Service-learning research. PMID- 21661607 TI - Parents and technology in the inpatient pediatric setting: a beginning model for study. AB - Medical technology has an increasing presence in the pediatric general care unit (GCU) and is an important tool in the provision of nursing care to children. As a result, both nurses and parents or other patient caregivers have had to integrate medical technology into their roles in the GCU setting. For nurses, this integration of technology into their workflow may be less stressful because new technologies are seen as additional resources to be used to provide proficient, safe patient care. Parents and other caregivers, however, may be more challenged by the sudden presence of technology in their caregiver role. Despite the increased presence of technology in the GCU, the impact of medical technology on nurse-parent-child relationships has not been explicitly researched. A descriptive review of the literature addresses some of the elements in these relationships and nursing care. A theoretical model of the influence of technology on the nurse-parent-child relationship is proposed, and suggestions for future research are made. PMID- 21661608 TI - Evaluating web sites: reliable child health resources for parents. AB - This article describes a framework for evaluating the quality of health care information on the Internet and identifies strategies for accessing reliable child health resources. A number of methods are reviewed, including how to evaluate Web sites for quality using the Health Information Technology Institute evaluation criteria, how to identify trustworthy Web sites accredited by Health On the Net Foundation Code of Conduct, and the use of portals to access prescreened Web sites by organizations, such as the Medical Library Association. Pediatric nurses can use one or all of these strategies to develop a list of reliable Web sites as a supplement to patient and family teaching. PMID- 21661609 TI - Making a difference: establishing guidelines for admission to a Level II pediatric unit. PMID- 21661610 TI - Harnessing the power of digital devices. PMID- 21661611 TI - Post-traumatic stress disorder (PTSD) in parents: is this a significant problem? PMID- 21661612 TI - Practice, research, and knowledge: contributions to the promotion of the population's health. PMID- 21661613 TI - Young women and cervical cancer screening: what barriers persist? AB - A reduction in participation rates for cervical cancer screening (CCS) by women aged 20 to 24 in the Canadian province of British Columbia led to this study evaluating young women's knowledge of CCS and identifying barriers to and facilitators of participation in CCS. A qualitative design was used and focus groups were held with a total of 80 women. Barriers to participation in CCS included difficulty finding health-care providers and the invasiveness of the Pap test. Facilitators included assistance with finding a health-care provider, availability of female providers, established relationship with a provider or clinic, and education about Pap tests. Education about the importance of CCS and assistance with finding health-care providers are key factors in increasing young women's participation in screening. PMID- 21661614 TI - A framework to assess nurse practitioner role integration in primary health care. AB - In the Canadian province of British Columbia, the nurse practitioner (NP) role was formally introduced in 2005. A participatory action research study was undertaken with NPs to examine how collaboration advances NP role integration in primary health care (PHC). The authors report on the study, in which the meaning of NP role integration was explored. The study uncovered 5 dimensions of NP role integration: autonomy, recognition, inclusion, contribution, and alliance. These dimensions, along with sample indicators, informed development of the NP Role Integration in PHC Framework. The significance of collaboration for advancing NP role integration is discussed; NP role integration is linked to the politics of PHC reform and the promise of holistic health promoting care for clients and communities. The framework has utility for policy leaders, decision-makers, and researchers in addressing barriers to role integration, supporting role evaluation, and securing and safeguarding the NP role. PMID- 21661615 TI - Autonomy of the volunteer sector in the evaluation of public health programs: an exploration from the perspective of an HIV/AIDS coalition. AB - As recommended in the Ottawa Charter, Canadian government agencies are counting on the involvement of grassroots organizations to implement federal public health programs at the local level. At issue is the forced acceptance by community organizations of the predefined role of suppliers of services. Because of the top down issues of health promotion practice, the problem is crucial for public health nursing.The author uses reflexive analysis, grounded in the internal colonization framework, to explore the case of a Canadian public health program and its relations with a provincial coalition of volunteer organizations working on AIDS issues. Implementing the Ottawa Charter highlights the challenges of the meanings and actions inherent in the notion of partnership between public agencies and community organizations of volunteers. Participation suggests more democratic and egalitarian social organizations, with hierarchical structures in a broader image of a modern society. PMID- 21661616 TI - "I can't imagine my life without it!" Curling and health promotion: a photovoice study. AB - The sport of curling is an important activity in rural Canada, with many female participants. The health of women in rural Canada is much compromised compared to that of their urban counterparts, yet little research has explored ways to promote the health of rural women. This study examined the influence of curling on the health of women in rural Canada. A sample of 15 women and girls aged 12 to 72 from 2 communities in southwestern Ontario took pictures, kept logbooks, and participated in 2 group sessions to discuss the influence of curling on their health. The findings reveal that curling facilitates social connections, enhances physical and mental health, and provides a valued and visible way to support rural life. Clearly, curling promotes the health and community life of rural women in significant ways. More support for curling in rural settings is needed, and additional research on the topic of curling and the health of rural women is indicated. PMID- 21661617 TI - Exploring sexual networks: a pilot study of swingers' sexual behaviour and health care-seeking practices. AB - Very little scientific research exists about swingers. For sexual health nurses, this dearth of information may be problematic, particularly as the rates of many STIs are increasing across Canada. A pilot study was undertaken to explore the subculture of men and women who visit swingers' clubs. Data were collected through a survey distributed at 1 swingers' club on 2 separate occasions and through direct observation of the clubs on the same 2 occasions. The researchers engaged in 8 hours of direct observation and 72 individuals (32 men and 40 women) completed the survey. The respondents reported engaging in unprotected sex, whether oral (80.3%), vaginal (15.5%), or anal (30.8%), and rarely accessing STI health services (< 40.8%). The authors conclude that further research is needed to investigate the possible design and implementation of STI health services for swingers. PMID- 21661618 TI - Nurse case-managed tobacco cessation interventions for general hospital patients: results of a randomized clinical trial. AB - This randomized clinical trial was designed to test the efficacy of intensive versus brief smoking cessation interventions for hospital patients. The interventions included advice and pamphlets for Brief and bedside counselling, take-home materials, and 7 post-discharge telephone counselling calls over 2 months for Intensive. Confirmed 1-year abstinence was 28% for Intensive (85/301) and 24% for Brief (76/315). Abstinence was significantly higher for patients who did not use pharmacotherapy (36%) versus those who did (16%) and for patients with CVD (40%) versus other diagnoses (20%). Because this was a replication trial, benchmarks for planning can be suggested: 12% to 15% recruitment of identified smokers, 90% plus completion for Intensive, 15% drop-out, and 75% abstinence corroboration. The results consolidate findings for general inpatients, including expected absolute abstinence and treatment outcomes, the effect of CVD patients on outcomes, the reproducibility of high abstinence in a universal health-care system, and the need for more research to inform practice. PMID- 21661619 TI - Developing a program of research for an applied public health chair in public health education and population intervention research. PMID- 21661620 TI - Nursing inputs and outcomes of hospital care: an empirical analysis of Ontario's acute-care hospitals. AB - The authors analyze the association between intensity of nursing care (as measured by nursing hours per patient day), hospital bed days, and patient outcomes in acute-care hospitals in the province of Ontario, Canada, to determine whether higher levels of nursing inputs are associated with shorter lengths of stay (LOS) and, if so, whether these shorter LOS are achieved at the expense of health outcomes. After controlling for supply of nurses, workload, community characteristics, and hospital type, the authors found that nursing hours per patient day had a significant negative effect on LOS but had no significant effect on patient satisfaction, hospital mortality, or readmission rates. Further, there was no evidence that shorter than expected LOS were associated with poorer patient health. Such information is relevant for efforts to deploy efficient mixes of health-care resources and to identify future human resource requirements to support the efficient provision of health human resources. PMID- 21661621 TI - Oncology nurses' perceptions of their relations with family members in an ambulatory cancer care setting: a mixed methods study. AB - Trends signal an increasing prevalence of people living through and beyond a cancer diagnosis with an enhanced reliance on ambulatory cancer care services and family caregiving. Despite this trend, there has been limited focus on nurses' experiences with providing support to families who care for patients in the community. For oncology nurses in ambulatory care settings, job satisfaction has decreased significantly as they are concerned with their ability to consistently provide safe and quality care to patients and their family. Although other studies indicated that the lack of time and limited resources are regrettably accepted aspects of nurses' work environments, our mixed methods small-scale study addressed how work environments still can meet the growing need for enhanced support and relations among nurses, patients, and families in ambulatory cancer care. PMID- 21661623 TI - An exploration of the experience of compassion fatigue in clinical oncology nurses. AB - Compassion fatigue (CF) is "debilitating weariness brought about by repetitive, empathic responses to the pain and suffering of others" (LaRowe, 2005, p. 21). The work performed by oncology nurses, and the experiences of the people they care for, place oncology nurses at high risk for CF (Pierce et al., 2007; Ferrell & Coyle, 2008). Thus oncology nurses were chosen as the study focus. This paper details a descriptive exploratory qualitative research study that investigated the experience of CF in Canadian clinical oncology registered nurses (RNs). A conceptual stress process model by Aneshensel, Pearlin, Mullan, Zarit, and Whitlatch (1995) that considers caregivers' stress in four domains provided the study framework (see Figure 1). Nineteen study participants were recruited through an advertisement in the Canadian Oncology Nursing Journal (CONJ). The advertisement directed potential participants to a university-based online website developed for this study. Participants completed a questionnaire and wrote a narrative describing an experience with CF and submitted these through the secure research website. Data were analyzed thematically. Five themes include: defining CF, causes of CF, factors that worsen CF, factors that lessen CF, and outcomes of CF. Participants had limited knowledge about CF, about lack of external support, and that insufficient time to provide high quality, care may precipitate CF. The gap between quality of care nurses wanted to provide and what they were able to do, compounded by coexisting physical and emotional stress, worsened CF. CF was lessened by colleague support, work-life balance, connecting with others, acknowledgement, and maturity and experience. Outcomes of CF included profound fatigue of mind and body, negative effects on personal relationships, and considering leaving the specialty. Recommendations that may enhance oncology nurse well-being are provided. PMID- 21661622 TI - Courage, collaboration, complexity and chemotherapy safety: the view from the sharp end. AB - The Canadian oncology community was devastated by the news in August 2006 that a patient had died from an overdose of fluorouracil. Where we once thought our checks and balances ensured patient safety, we now knew they were not enough. Practice immediately began to change around the country. However, the incident report highlighted that there was much we still didn't know about safety issues in intravenous ambulatory chemotherapy safety in Canada. In response, an interdisciplinary, pan-Canadian team launched an 18-month exploratory study, resulting in a report identifying several safety issues and associated recommendations. This paper summarizes the key insights we have gathered for Canadian oncology nurses in being part of this study: that we need courage to come forward and disclose safety concerns; we should collaborate to come up with safety improvements that work for everyone; and we should strive to simplify our work at the sharp end by reducing complexity upstream and throughout the system. PMID- 21661624 TI - Gaining a better understanding of the support function of oncology nurse navigators from their own perspective and that of people living with cancer: Part 2. AB - Individuals living with cancer have a wide range of needs throughout the disease trajectory. To better meet them, the PQLC [French acronym of the Quebec Cancer Control Program] implemented the oncology nurse navigator (ONN) role. A first article presented the nature of the needs of individuals living with cancer and of the support provided by ONNs. This second article aims at gaining a better understanding of the ONN support function from the ONNs' own perspective and to complete an exploratory description of their support interventions for individuals living with cancer and their loved ones throughout the care trajectory. The sample includes ten ONNs. They reported doing support interventions for all the various types of needs, especially in the informational (44%) and practical areas such as coordinating appointments for exams, practitioners and various services (35%). The results also suggest that a needs assessment is a prerequisite to intervention. Lastly, all participants underscored the importance of the helping relation and trusting relationship to clarify their support function. These results are consistent with the findings of several recent articles on the psychosocial role of oncology nurses. PMID- 21661625 TI - Better lymphedema management needed--the role of the specialized oncology nurse. PMID- 21661626 TI - Dying due to terminal illness. PMID- 21661627 TI - Time to stop insurers from setting fees for non-covered services. PMID- 21661628 TI - The stories of others. PMID- 21661629 TI - Are we having fun yet? PMID- 21661631 TI - The philanthropic dentist: in good hands. PMID- 21661630 TI - Do it right, not over. PMID- 21661632 TI - Case study: immediate dentures. PMID- 21661633 TI - Websites for dentists 101: the benefits of using the web to grow your dental practice. PMID- 21661634 TI - Why so many cavities? PMID- 21661635 TI - An audit comparing the discrepancies between a verbal enquiry, a written history and an electronic medical history questionnaire: a suggested medical history/social history form for clinical practice. PMID- 21661636 TI - Here to help. PMID- 21661638 TI - Metal-ceramic versus all-ceramic restorations: part 3. PMID- 21661637 TI - A survey to assess the provision of conscious sedation by general dental practitioners in the Republic of Ireland. AB - AIM: To quantify and qualify how conscious sedation was used in general dental practice before the introduction of formal sedation teaching in the Republic of Ireland. OBJECTIVES: 1. To determine the extent of use of oral, inhalational and intravenous sedation; 2. to determine the training and experience of general dental practitioners providing conscious sedation; 3. to determine the perceived barriers to the practice of conscious sedation; and, 4. to gauge the level of interest in a postgraduate course in conscious sedation. METHOD: Postal questionnaire sent to one general practitioner in seven, selected randomly from the General Dental Council register, in 2007. RESULTS: Seventy six percent of respondents agreed that the provision of conscious sedation in general dental practice is important. However, the current provision of inhalation and intravenous sedation by respondents is low in comparison to provision in the UK. The main barrier to the use of conscious sedation in general dental practice appears to be lack of availability of training. CONCLUSIONS: The data from this study indicated the need for postgraduate training in conscious sedation in Ireland and a need for increased awareness of the Dental Council Code of Practice on sedation. PMID- 21661640 TI - Majority of NHS trusts refuse to pay extra for royal wedding shift. PMID- 21661639 TI - Induction of staff and team training. AB - Good training is vital for the safe and effective integration of a new team member. This training will be made easier if a deliberate, structured approach is taken, which takes due account of the need to safeguard their health, safety and welfare, from the moment they start. PMID- 21661641 TI - Assisted dying commission is told of need for robust protocols. PMID- 21661642 TI - I am deeply sorry, former SHA chief tells mid staffs inquiry. PMID- 21661643 TI - Experience needs recognition as profession moves to degree entry. PMID- 21661644 TI - Which of the parties will prove to have the 'X' factor on May 5? PMID- 21661645 TI - Help in a crisis. AB - Her own experiences of postnatal depression have led Ruth Jackson to set up a charity to provide Bluebell Nurses who can help. PMID- 21661646 TI - Learning from mistakes. AB - The Department of Health's list of 'never events' has been expanded from eight to 25. Most apply to secondary healthcare settings. PMID- 21661647 TI - Personal protection. AB - A health board in Scotland has introduced a policy to protect staff who are subjected to stalking. PMID- 21661648 TI - Continuous care across teams: principle of nursing practice G. AB - This is the eighth article in a nine-part series describing the Principles of Nursing Practice developed by the Royal College of Nursing (RCN) in collaboration with patient and service organisations, the Department of Health, the Nursing and Midwifery Council, nurses and other healthcare professionals. This article discusses Principle G, the need for nurses to work collaboratively with other healthcare professionals to improve patient outcomes. PMID- 21661649 TI - Using the hospital anxiety and depression scale in surgical patients. AB - Patients admitted to hospital to undergo an elective surgical procedure often feel frightened and anxious. Healthcare professionals have a responsibility to ensure that patients are physically and psychologically prepared for surgery. The provision of psychological care may be inadequate as there are few protocols for healthcare professionals to follow in this area. Psychological care should be provided routinely for every surgical patient not only those with cancer, for which psychological care forms part of the overall care package. The use of tools such as the Hospital Anxiety and Depression Scale allow staff to identify and monitor anxiety and depression in patients in a busy pre-operative setting. PMID- 21661650 TI - Thyroidectomy: post-operative care and common complications. AB - Any surgical procedure involves risks. Thyroid surgery can cause potentially fatal complications during the early post-operative phase. It is essential that nurses have the knowledge and skills to detect early signs and symptoms of potential complications and take appropriate action. Early detection and rapid response are key to maintaining patient safety and minimising harm. PMID- 21661651 TI - Plaster casting. PMID- 21661652 TI - Take charge of learning. PMID- 21661653 TI - Top of the class. PMID- 21661654 TI - Quality skills training. PMID- 21661655 TI - Multi-step protocol to collect what you produce. PMID- 21661656 TI - Treatment in conjunction with bisphosphonate therapy. PMID- 21661657 TI - Transcrestal sinus floor elevation with osteotomes: simplified technique and management of various scenarios. AB - In order to place implants subantrally when there is a reduced amount of bone, some form of bone augmentation is required. A transcrestal sinus floor elevation using osteotomes can increase bone levels and is a highly successful procedure. However, malleting osteotomes can be disconcerting for a patient. Therefore, a simplified technique is presented that minimizes the use of a mallet when executing a sinus floor elevation in medium dense bone. In addition, issues related to performing a transcrestal sinus floor elevation are addressed. PMID- 21661659 TI - Team treatment planning for the replacement of esthetic zone teeth with dental implants. AB - Implant therapy requires comprehensive preoperative planning and precise surgical execution based on a restorative-driven approach. Implant surgical demands in the esthetic zone require that the surgeon treating has extensive surgical experience in a variety of areas. Using a "team" approach to treat such cases allows the patient to receive care similar to the "medical model," in which each member of the clinical team specializes in his or her respective area. This interdisciplinary approach to implant therapy is demonstrated in the case presented, which describes the restoration of an elderly patient's failing maxillary dentition. PMID- 21661658 TI - Clinical decision making regarding endodontics versus implants. AB - This article discusses the current considerations in treatment planning for retention of the natural tooth through endodontic therapy (including orthograde first-time treatment, retreatment, and endodontic surgery) versus extraction and placement of a dental implant. As a secondary goal, the article describes several specific cases in which the best option is either an implant or retention of the natural tooth. The issue of tooth retention versus implant therapy is also addressed with regard to the specific clinical diagnosis of resorption in all of its various forms. Emphasis has been placed on practical strategies for treatment of cases involving internal and external root resorption using a comprehensive evidence-based approach. PMID- 21661660 TI - Immediate temporization of immediate implants in the esthetic zone: evaluating survival and bone maintenance. AB - This study followed 30 consecutively placed implants in the esthetic zone, inserted at the time of tooth extraction, and immediately temporized and augmented with bone grafting and resorbable guided bone regeneration. Implant survival, adverse events, and esthetic outcomes were evaluated. In this study, the esthetic zone is defined as the dentition spanning maxillary or mandibular first bicuspids. All implants osseointegrated and were ready for definitive restorative therapy by 12 weeks. No adverse events, such as infection, persistent inflammation, or abutment screw loosening, occurred. Radiographic bone levels were documented. This study also emphasizes clinical technique and rationale. PMID- 21661661 TI - Delayed implant procedure using deproteinized bovine bone mineral: A report of 109 consecutive cases. AB - PURPOSE: The purpose of this consecutive case series was to analyze the success rate of endosseous implants placed into deproteinized bovine bone mineral (DBBM) maxillary and mandibular grafted extraction sites during a 48-month period. METHODS: During a 48-month period, 69 consecutive patients presented with 109 nonrestorable teeth. The teeth were extracted and the sites grafted with DBBM, and the extraction sockets were allowed to heal for an average of 6 months. Following healing, implants were placed in the grafted sites. Osseointegration was assessed based on a lack of mobility and a radiographic evaluation. RESULTS: Implants were placed in all of the 109 grafted sites with no graft failures. No implant was mobile at uncovering. All 109 implants are currently loaded and have been in function for 6 months to 65 months with an average of 2 years for a 100% cumulative success rate. Marginal soft-tissue levels remain stable. CONCLUSION: The delayed implant approach using DBBM is a predictable treatment modality, resulting in long-term implant stability and predictable esthetic results. PMID- 21661662 TI - CAD/CAM Dental technology. PMID- 21661663 TI - Use of a powered toothbrush for hygiene of edentulous implant-supported prostheses. AB - Effective professional maintenance and personal oral hygiene are important for the long-term success and comfortable functioning of implant-assisted dental restorations. Incorporating the most effective oral hygiene devices into each patient's oral hygiene regimen facilitates optimal results. The use of a powered toothbrush with interchangeable brush heads permits effective cleaning of the most access-challenging prosthesis contours. This article presents a useful personal oral hygiene regimen for the long-term maintenance of various implant supported dental restorations. PMID- 21661664 TI - Education that makes a difference. PMID- 21661665 TI - Salzmann's nodular degeneration (subepithelial fibrosis). AB - Salzmann's nodular degeneration (subepithelial fibrosis) may cause symptoms of irritation and decreased vision. Removing the subepithelial fibrosis may improve symptoms and vision. In this article, a simple surgical technique to remove the subepithelial fibrosis is described. PMID- 21661666 TI - Effect of timing and duration of tamsulosin exposure on complications in resident performed phacoemulsification. AB - BACKGROUND AND OBJECTIVES: Tamsulosin can cause intraoperative floppy iris syndrome and increase the risk of phacoemulsification complications. This study evaluated whether the risk of complications was associated with the timing or duration of preoperative tamsulosin exposure. PATIENTS AND METHODS: The current study was a retrospective review of electronic medical records of resident performed phacoemulsification surgeries from 1998 to 2008 at a Veterans Administration Hospital. There were 73 eyes with recent tamsulosin exposure (within 30 days preoperatively) and 28 eyes with remote exposure (> 30 days preoperatively but within 3 years of surgery). RESULTS: There was a trend toward more total complications in recent compared with remote tamsulosin exposure cases (31.5% vs 14.3%, P = .09). A longer duration of tamsulosin use was not statistically associated with an increased risk of total complications. CONCLUSION: The authors were unable to detect a statistically significant effect of duration of tamsulosin use on the risk of intraoperative complications in phacoemulsification surgery. PMID- 21661667 TI - Idiopathic dural optic nerve sheath calcification associated with choroidal osteoma. AB - A 28-year-old woman presented with a choroidal osteoma in the right eye and optic atrophy in the left eye, associated with bilateral optic nerve sheath calcification and calcifications in the pineal, choroid plexus, and dura (falx and tentorium). Visual acuity, tumor size, and intracranial calcifications did not change over 16 years. The combination of bilateral optic nerve sheath calcification with multiple intracranial calcifications suggests an unexplained and generalized dural calcification process. To the authors' knowledge, this is the first case of choroidal ossifying tumor associated with calcified lesions of the optic nerves. Although the pathogenesis of bone formation in choroidal osteoma remains uncertain, intraocular inflammation might be one cause. PMID- 21661668 TI - Diffuse retinal pigment epithelial disease in an adult with cystic fibrosis. AB - An adult with cystic fibrosis presented for decreased vision in the right eye of several months' duration. Biomicroscopy and fluorescein angiography demonstrated bilateral large subretinal drusenoid deposits concentrated temporal to the fovea, as well as a small subretinal hemorrhage associated with focal leakage of fluid within the macula in the right eye. Optical coherence tomography demonstrated subretinal fluid consistent with choroidal neovascular membrane in the right eye with the absence of fluid in the left eye. The retinal manifestations of bilateral diffuse drusen associated with choroidal neovascular membrane may be consistent with autosomal dominant drusen, age-related macular degeneration, and type II glomerulonephritis, or alternatively may be a unique finding associated with cystic fibrosis. To the authors' knowledge, these findings have not previously been described in association with cystic fibrosis. PMID- 21661669 TI - Radiologic case study. Blastomycosis of bone. PMID- 21661670 TI - Acute traumatic sternal fracture in a female college hockey player. PMID- 21661671 TI - Developing and fractured bones are invaded by osteoblast precursors, not mature osteoblasts. PMID- 21661672 TI - Periprosthetic femoral fractures associated with hip arthroplasty. PMID- 21661673 TI - Outcome measurement tools for ACL reconstruction: we must do better. PMID- 21661674 TI - Double-bundle and double-tunnel ACL reconstruction with looped proximal tibial fixation. AB - Double-bundle anterior cruciate ligament (ACL) reconstruction can be demanding and time consuming and requires twice as many implants, increasing both costs and possible complications. In this article, we present a new approach to double bundle ACL reconstruction: a biological fixation of the tibial side by means of a double tunnel and a U-shape passage of an anterior tibialis allograft, fixed into a double tunnel on the femoral condyle with 2 interference bioabsorbable screws. The technique is designed to combine 2 known procedures for the regular knee surgeon: the mono-tunnel technique and the medial-portal approach. PMID- 21661675 TI - Periprosthetic joint infection. PMID- 21661676 TI - Single percutaneous injection of stromal cell-derived factor-1 induces bone repair in mouse closed tibial fracture model. AB - Stromal cell-derived factor-1 is a dominant chemokine in bone marrow that is known to be involved in inflammatory diseases, including rheumatoid arthritis. Its role in bone repair has recently been demonstrated. The purpose of this study was to investigate the role of extraneous stromal cell-derived factor-1 in fracture healing. PMID- 21661677 TI - Use of intranasal medications in pediatric patients. AB - A growing body of evidence supports the intranasal administration of atomized medications for a wide variety of pediatric indications. This article describes their use applicable to orthopedic specialists in the areas of pediatric pain management, as well as pre- and intraoperative sedation. As a quick, painless alternative to more invasive routes of administration, intranasal drug delivery has shown similar time to clinical effect compared to the intravenous route, while minimizing anxiety in both patients and their parents. PMID- 21661678 TI - Physical examination findings in young athletes correlate with history of shoulder instability. AB - The goal of this study was to evaluate physical examination findings in a healthy cohort and determine potential correlations with a history of shoulder instability. A cross-sectional analysis was performed using the baseline data for an ongoing prospective cohort study to examine the risk factors for shoulder instability. A complete history of shoulder instability events was obtained, and a blinded physical examination was performed. The cohort comprised 711 patients (627 men, 84 women) with a mean age of 18.8 years. A total of 100 patients had a history of shoulder instability. Patients with a history of instability were more likely to have increased posterior translation (P=.010), positive apprehension sign (P=.003), positive relocation sign (P=.007), and sulcus sign (P=.017). PMID- 21661679 TI - Single-level posterolateral arthrodesis, with or without posterior decompression, for the treatment of isthmic spondylolisthesis. PMID- 21661680 TI - COX-2 inhibitors for the prevention of heterotopic ossification after THA. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent heterotopic ossification after total hip arthroplasty (THA). Cyclooxygenase 2 (COX-2) inhibitors may minimize side effects. The goal of this review was to compare the effectiveness and side effects of the perioperative use of selective COX-2 inhibitors with those of conventional NSAIDs in patients undergoing THA. We followed the systematic reviews' updated methods of the Cochrane Collaboration Back Review Group and searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials. We identified all randomized controlled trials until April 2009 enrolling THA patients and comparing COX-2 inhibitors to NSAIDs. We assessed their methodological quality and extracted data. Five randomized controlled trials were included. Prevention of heterotopic ossification and side effects with COX-2 inhibitors were significant in 2 studies. Discontinuation for side effects was not significant. COX-2 inhibitors do not prevent heterotopic ossification after THA significantly better than conventional NSAIDs, while they are advantageous regarding side effects. PMID- 21661704 TI - Screening questionnaire for work-related health problems. PMID- 21661705 TI - Overuse of computed tomography and associated risks. PMID- 21661707 TI - Magnesium sulfate and other anticonvulsants for women with preeclampsia. PMID- 21661708 TI - Pre-employment examinations for preventing occupational injury and disease. PMID- 21661709 TI - Beyond words. PMID- 21661710 TI - Treatment of knee osteoarthritis. AB - Knee osteoarthritis is a common disabling condition that affects more than one third of persons older than 65 years. Exercise, weight loss, physical therapy, intra-articular corticosteroid injections, and the use of nonsteroidal anti inflammatory drugs and braces or heel wedges decrease pain and improve function. Acetaminophen, glucosamine, ginger, S-adenosylmethionine (SAM-e), capsaicin cream, topical nonsteroidal anti-inflammatory drugs, acupuncture, and tai chi may offer some benefit. Tramadol has a poor trade-off between risks and benefits and is not routinely recommended. Opioids are being used more often in patients with moderate to severe pain or diminished quality of life, but patients receiving these drugs must be carefully selected and monitored because of the inherent adverse effects. Intra-articular corticosteroid injections are effective, but evidence for injection of hyaluronic acid is mixed. Arthroscopic surgery has been shown to have no benefit in knee osteoarthritis. Total joint arthroplasty of the knee should be considered when conservative symptomatic management is ineffective. PMID- 21661711 TI - Knee osteoarthritis. PMID- 21661712 TI - Diagnosis and management of community-acquired pneumonia in adults. AB - Community-acquired pneumonia is diagnosed by clinical features (e.g., cough, fever, pleuritic chest pain) and by lung imaging, usually an infiltrate seen on chest radiography. Initial evaluation should determine the need for hospitalization versus outpatient management using validated mortality or severity prediction scores. Selected diagnostic laboratory testing, such as sputum and blood cultures, is indicated for inpatients with severe illness but is rarely useful for outpatients. Initial outpatient therapy should include a macrolide or doxycycline. For outpatients with comorbidities or who have used antibiotics within the previous three months, a respiratory fluoroquinolone (levofloxacin, gemifloxacin, or moxifloxacin), or an oral beta-lactam antibiotic plus a macrolide should be used. Inpatients not admitted to an intensive care unit should receive a respiratory fluoroquinolone, or a beta-lactam antibiotic plus a macrolide. Patients with severe community-acquired pneumonia or who are admitted to the intensive care unit should be treated with a beta-lactam antibiotic, plus azithromycin or a respiratory fluoroquinolone. Those with risk factors for Pseudomonas should be treated with a beta-lactam antibiotic (piperacillin/tazobactam, imipenem/cilastatin, meropenem, doripenem, or cefepime), plus an aminoglycoside and azithromycin or an antipseudomonal fluoroquinolone (levofloxacin or ciprofloxacin). Those with risk factors for methicillin-resistant Staphylococcus aureus should be given vancomycin or linezolid. Hospitalized patients may be switched from intravenous to oral antibiotics after they have clinical improvement and are able to tolerate oral medications, typically in the first three days. Adherence to the Infectious Diseases Society of America/American Thoracic Society guidelines for the management of community-acquired pneumonia has been shown to improve patient outcomes. Physicians should promote pneumococcal and influenza vaccination as a means to prevent community-acquired pneumonia and pneumococcal bacteremia. PMID- 21661713 TI - Caregiver care. AB - In 2009, nearly 66 million Americans (three in 10 U.S. households) reported at least one person providing unpaid care as a family caregiver. More adults with chronic conditions and disabilities are living at home than ever before, and family caregivers have an even higher level of responsibility. Caring for loved ones is associated with several benefits, including personal fulfillment. However, caregiving is also associated with physical, psychological, and financial burdens. Primary care physicians can aid in the identification, support, and treatment of caregivers by offering caregiver assessments-interviews directed at identifying high levels of burden-as soon as caregivers are identified. Repeat assessments may be considered when there is a change in the status of caregiver or care recipient. Caregivers should be directed to appropriate resources for support, including national caregiving organizations, local area agencies on aging, Web sites, and respite care. Psychoeducational, skills-training, and therapeutic counseling interventions for caregivers of patients with chronic conditions such as dementia, cancer, stroke, and heart failure have shown small to moderate success in decreasing caregiver burden and increasing caregiver quality of life. Further research is needed to further identify strategies to offset caregiver stress, depression, and poor health outcomes. Additional support and anticipatory guidance for the care recipient and caregiver are particularly helpful during care transitions and at the care recipient's end of life. PMID- 21661714 TI - Help for caregivers. PMID- 21661715 TI - Heat-related illness. AB - Heat-related illness is a set of preventable conditions ranging from mild forms (e.g., heat exhaustion, heat cramps) to potentially fatal heat stroke. Hot and humid conditions challenge cardiovascular compensatory mechanisms. Once core temperature reaches 104 degrees F (40 degrees C), cellular damage occurs, initiating a cascade of events that may lead to organ failure and death. Early recognition of symptoms and accurate measurement of core temperature are crucial to rapid diagnosis. Milder forms of heat-related illness are manifested by symptoms such as headache, weakness, dizziness, and an inability to continue activity. These are managed by supportive measures including hydration and moving the patient to a cool place. Hyperthermia and central nervous system symptoms should prompt an evaluation for heat stroke. Initial treatments should focus on lowering core temperature through cold water immersion. Applying ice packs to the head, neck, axilla, and groin is an alternative. Additional measures include transporting the patient to a cool environment, removing excess clothing, and intravenous hydration. Delayed access to cooling is the leading cause of morbidity and mortality in persons with heat stroke. Identification of at-risk groups can help physicians and community health agencies provide preventive measures. PMID- 21661716 TI - FPIN's clinical inquiries: brain natriuretic peptide for ruling out heart failure. PMID- 21661717 TI - Chronic unilateral preauricular rash. PMID- 21661720 TI - Biophysical mapping of the adenosine A2A receptor. AB - A new approach to generating information on ligand receptor interactions within the binding pocket of G protein-coupled receptors has been developed, called Biophysical Mapping (BPM). Starting from a stabilized receptor (StaR), minimally engineered for thermostability, additional single mutations are then added at positions that could be involved in small molecule interactions. The StaR and a panel of binding site mutants are captured onto Biacore chips to enable characterization of the binding of small molecule ligands using surface plasmon resonance (SPR) measurement. A matrix of binding data for a set of ligands versus each active site mutation is then generated, providing specific affinity and kinetic information (K(D), k(on), and k(off)) of receptor-ligand interactions. This data set, in combination with molecular modeling and docking, is used to map the small molecule binding site for each class of compounds. Taken together, the many constraints provided by these data identify key protein-ligand interactions and allow the shape of the site to be refined to produce a high quality three dimensional picture of ligand binding, thereby facilitating structure based drug design. Results of biophysical mapping of the adenosine A(2A) receptor are presented. PMID- 21661721 TI - Discrete covalent organic-inorganic hybrids: terpyridine functionalized polyoxometalates obtained by a modular strategy and their metal complexation. AB - The rational design and synthesis of organic-inorganic hybrids as functional molecular materials relies on both the careful conception of building-blocks and the strategy for their assembly. Three families of trialkoxo polyoxometalates (Lindqvist 2, Anderson 3, Dawson 4) grafted with remote terpyridine coordination sites have been synthesized to extend the available building-blocks. These new units can be combined with metal complexes that play a role as (i) chromophores toward charge-separated systems in light-harvesting devices and (ii) coordination motifs for metal-directed self-assembly toward multifunctional molecular hybrid materials. The X-ray crystal structures of polyoxometalate-terpyridine hybrids indicate distances of 21 A and 19 A between the two terpyridyl coordination sites in 2 and 3, respectively, with angles between the coordination vectors of 180 degrees and 177.4 degrees , respectively. Lindqvist 2 displays a reduction at 0.52 V vs SCE while Anderson 3 exhibits one reversible oxidation attributed to Mn(III)/Mn(IV) (+0.75 V vs SCE) and a broad wave at -1.28 V vs SCE assigned to the Mn(III)/Mn(II) reduction. Dawson 4 displays several processes on a wide range of potentials (+0.5 to -2.0 V vs SCE) centered on V(V), W(VI) and the organic ligand in order of decreasing potentials. The grafted terpyridine ligands in Anderson 3 and Dawson 4 were successfully coordinated to {PdCl}(+) and {RuCl(3)} moieties, respectively. The polyoxometalates and transition metal complexes retain their intrinsic properties in the final assemblies. PMID- 21661722 TI - Kinetics study of the aromatic bicyclic peroxy radical + NO reaction: overall rate constant and nitrate product yield measurements. AB - The measurements of the overall bicyclic peroxy radical + NO rate constant for the 1,3,5-trimethylbenzene (1,3,5-TMB) system and of the nitrate product yields for the benzene, toluene, p-xylene, and 1,3,5-TMB systems were performed via the turbulent flow chemical ionization mass spectrometry technique. While the overall rate constant was found to be consistent with the value used in the most detailed aromatic oxidation kinetic model (Master Chemical Mechanism, MCM), the nitrate product yields were found to be generally lower than predicted by the MCM and to have a different aromatic species-specific dependence than the MCM predicts. PMID- 21661723 TI - Influence of substrate surface chemistry on the performance of top-gate organic thin-film transistors. AB - Organic thin-film transistor (OTFT) performance depends on the chemical characteristics of the interface between functional semiconductor/dielectric/conductor materials. Here we report for the first time that OTFT response in top-gate architectures strongly depends on the substrate chemical functionalization. Depending on the nature of the substrate surface, dramatic variations and opposite trends of the TFT threshold voltage (~+/-50 V) and OFF current (10(5)*!) are observed for both p- and n-channel semiconductors. However, the field-effect mobility varies only marginally (~2*). Our results demonstrate that the substrate is not a mere passive mechanical support. PMID- 21661724 TI - Membrane-dependent effects of a cytoplasmic helix on the structure and drug binding of the influenza virus M2 protein. AB - The influenza A M2 protein forms a proton channel for virus infection and also mediates virus assembly and budding. The minimum protein length that encodes both functions contains the transmembrane (TM) domain (roughly residues 22-46) for the amantadine-sensitive proton-channel activity and an amphipathic cytoplasmic helix (roughly residues 45-62) for curvature induction and virus budding. However, structural studies involving the TM domain with or without the amphipathic helix differed on the drug-binding site. Here we use solid-state NMR spectroscopy to determine the amantadine binding site in the cytoplasmic-helix-containing M2(21 61). (13)C-(2)H distance measurements of (13)C-labeled protein and (2)H-labeled amantadine showed that in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers, the first equivalent of drug bound S31 inside the M2(21-61) pore, similar to the behavior of M2 transmembrane peptide (M2TM) in DMPC bilayers. The nonspecific surface site of D44 observed in M2TM is disfavored in the longer peptide. Thus, the pharmacologically relevant drug-binding site in the fully functional M2(21-61) is S31 in the TM pore. Interestingly, when M2(21-61) was reconstituted into a virus-mimetic membrane containing 30% cholesterol, no chemical shift perturbation was observed for pore-lining residues, whereas M2TM in the same membrane exhibited drug-induced chemical shift changes. Reduction of the cholesterol level and the use of unsaturated phospholipids shifted the conformational equilibrium of M2TM fully to the bound state but did not rescue drug binding to M2(21-61). These results suggest that the amphipathic helix, together with cholesterol, modulates the ability of the TM helix to bind amantadine. Thus, the M2 protein interacts with the lipid membrane and small molecule inhibitors in a complex fashion, and a careful examination of the environmental dependence of the protein conformation is required to fully understand the structure-function relation of this protein. PMID- 21661725 TI - Interaction of multiple bonded and unsaturated heavier main group compounds with hydrogen, ammonia, olefins, and related molecules. AB - We showed in 2005 that a digermyne, a main group compound with a digermanium core and aromatic substituents, reacted directly with hydrogen at 25 degrees C and 1 atm to give well-defined hydrogen addition products. This was the first report of a reaction of main group molecules with hydrogen under ambient conditions. Our group and a number of others have since shown that several classes of main group molecules, either alone or in combination, react directly (in some cases reversibly) with hydrogen under mild conditions. Moreover, this reactivity was not limited to hydrogen but also included direct reactions with other important small molecules, including ammonia, boranes, and unactivated olefins such as ethylene. These reactions were largely unanticipated because main group species were generally considered to be too unreactive to effect such transformations. In this Account, we summarize recent developments in the reactions of the multiple bonded and other open shell derivatives of the heavier main group elements with hydrogen, ammonia, olefins, or related molecules. We focus on results generated primarily in our laboratory, which are placed in the context of parallel findings by other researchers. The close relationship between HOMO-LUMO separations, symmetry considerations, and reactivity of the open shell in main group compounds is emphasized, as is their similarity in reactivity to transition metal organometallic compounds. The unexpectedly potent reactivity of the heavier main group species arises from the large differences in bonding between the light and heavy elements. Specifically, the energy levels within the heavier element molecules are separated by much smaller gaps as a result of generally lower bond strengths. In addition, the ordering and symmetries of the energy levels are generally different for their light counterparts. Such differences lie at the heart of the new reactions. Moreover, the reactivity of the molecules can often be interpreted qualitatively in terms of simple molecular orbital considerations. More quantitative explanations are accessible from increasingly sophisticated density functional theory (DFT) calculations. We open with a short description of the background developments that led to this work. These advances involved the synthesis and characterization of numerous new main group molecules involving multiple bonds or unsaturated configurations; they were pursued over the latter part of the last century and the beginning of the new one. The results firmly established that the structures and bonding in the new compounds differed markedly from those of their lighter element congeners. The knowledge gained from this fundamental work provided the framework for an understanding of their structures and bonding, and hence an understanding of the reactivity of the compounds discussed here. PMID- 21661726 TI - Withanolides from the rhizomes of Dioscorea japonica and their cytotoxicity. AB - Edible yams are tropical crops that serve as important staple foods in many parts of the world. The rhizome of Dioscorea japonica , well-known as "Japanese yam", is a food and medicinal source known as "San Yak" in Korea. Bioassay-guided fractionation and chemical investigation of the extract of this yam resulted in the identification of two new withanolides, named dioscorolide A (1) and dioscorolide B (2). The structures of these new compounds were determined by spectroscopic methods, including 1D and 2D nuclear magnetic resonance (NMR) techniques, high-resolution mass spectrometry (HRMS), and chemical methods. The cytotoxic activities of the isolates (1 and 2) were evaluated by determining their inhibitory effects on four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15) and a human normal cell line (HUVEC) using a sulforhodamine B (SRB) bioassay. Compounds 1 and 2 showed cytotoxicity against tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT15) with IC(50) values ranging from 6.3 to 26.9 MUM and exhibited lower activity against the normal cell line (HUVEC) with IC(50) values ranging from 27.1 to 28.8 MUM, suggesting selective toxicity among tumor and normal cells. PMID- 21661728 TI - Gadolinium tagging for high-precision measurements of 6 nm distances in protein assemblies by EPR. AB - Double electron-electron resonance (DEER) distance measurements of a protein complex tagged with two Gd(3+) chelates developed for rigid positioning of the metal ion are shown to deliver outstandingly accurate distance measurements in the 6 nm range. The accuracy was assessed by comparison with modeled distance distributions based on the three-dimensional molecular structures of the protein and the tag and further comparison with paramagnetic NMR data. The close agreement between the predicted and experimentally measured distances opens new possibilities for investigating the structure of biomolecular assemblies. As an example, we show that the dimer interface of rat ERp29 in solution is the same as that determined previously for human ERp29 in the single crystal. PMID- 21661729 TI - Transient enzyme-substrate recognition monitored by real-time NMR. AB - Slow protein folding processes during which kinetic folding intermediates occur for an extended time can lead to aggregation and dysfunction in living cells. Therefore, protein folding helpers have evolved, which prevent proteins from aggregation and/or speed up folding processes. In this study, we present the structural characterization of a long-living transient folding intermediate of RNase T1 (S54G/P55N) by time-resolved NMR spectroscopy. NMR resonances of this kinetic folding intermediate could be assigned mainly by a real-time 3D BEST HNCA. These assignments were the basis to investigate the interaction sites between the protein folding helper enzyme SlyD(1-165) (SlyD*) from Escherichia coli (E. coli) and this kinetic intermediate at a residue resolution. Thus, we investigated the Michaelis-Menten complex of this enzyme reaction, because the NMR data acquisition was performed during the actual catalysis. The interaction surface of the transient folding intermediate is restricted to a region around the peptidyl-prolyl bond (Y38-P39), whose isomerization is catalyzed by SlyD*. The interaction surface regarding SlyD* extends from specific amino acids of the FKBP domain forming the peptidyl-prolyl cis/trans-isomerase active site to almost the entire IF domain. This illustrates an effective interplay between the two functional domains of SlyD* to facilitate protein folding catalysis. PMID- 21661727 TI - Dextran-coated iron oxide nanoparticles: a versatile platform for targeted molecular imaging, molecular diagnostics, and therapy. AB - Advances in our understanding of the genetic basis of disease susceptibility coupled with prominent successes for molecular targeted therapies have resulted in an emerging strategy of personalized medicine. This approach envisions risk stratification and therapeutic selection based on an individual's genetic makeup and physiologic state (the latter assessed through cellular or molecular phenotypes). Molecularly targeted nanoparticles can play a key role in this vision through noninvasive assessments of molecular processes and specific cell populations in vivo, sensitive molecular diagnostics, and targeted delivery of therapeutics. A superparamagnetic iron oxide nanoparticle with a cross-linked dextran coating, or CLIO, is a powerful and illustrative nanoparticle platform for these applications. These structures and their derivatives support diagnostic imaging by magnetic resonance (MRI), optical, and positron emission tomography (PET) modalities and constitute a versatile platform for conjugation to targeting ligands. A variety of conjugation methods exist to couple the dextran surface to different functional groups; in addition, a robust bioorthogonal [4 + 2] cycloaddition reaction between 1,2,4,5-tetrazene (Tz) and trans-cyclooctene (TCO) can conjugate nanoparticles to targeting ligands or label pretargeted cells. The ready availability of conjugation methods has given rise to the synthesis of libraries of small molecule modified nanoparticles, which can then be screened for nanoparticles with specificity for a specific cell type. Since most nanoparticles display their targeting ligands in a multivalent manner, a detailed understanding of the kinetics and affinity of a nanoparticle's interaction with its target (as determined by surface plasmon resonance) can yield functionally important insights into nanoparticle design. In this Account, we review applications of the CLIO platform in several areas relevant to the mission of personalized medicine. We demonstrate rapid and highly sensitive molecular profiling of cancer markers ex vivo, as part of detailed, individualized molecular phenotyping. The CLIO platform also facilitates targeted magnetic resonance and combined modality imaging (such as MR/PET/fluorescence/CT) to enable multiplexed measurement of molecular phenotypes in vivo for early diagnosis and disease classification. Finally, the targeted delivery of a photodynamic therapy agent as part of a theranostic nanoparticle successfully increased local cell toxicity and minimized systemic side effects. PMID- 21661730 TI - (rac)-1,1'-binaphthyl-based simple receptors designed for fluorometric discrimination of maleic and fumaric acids. AB - (rac)-1,1'-Binaphthyl-based simple receptors 1 and 2 have been designed, synthesized and studied theoretically. The receptors utilize naphthyridine as the binding motifs for complexation of dicarboxylic acids in CHCl(3). The emission of the BINOL moiety was monitored experimentally to ascertain the selectivity and sensitivity of the receptors. Receptor 1 distinguishes maleic acid from isomeric fumaric acid by exhibiting different fluorescence behavior and demonstrates stronger binding in the excited state. Modulation of the binding sites of 1 leads to a new receptor structure 2, which was found to be less efficient in distinguishing maleic from fumaric acid, fluorometrically. Both 1 and 2 also recognize other hydroxy di- and tricarboxylic acids. The binding interactions were monitored by (1)H NMR, fluorescence and UV-vis spectroscopic methods. Structures of apo-hosts, guests and host-guest complexes were determined using force-field based conformational searching. Low energy ensembles were grouped into geometrically similar families, and low energy structures from each family were verified using B3LYP/6-31G*/PB-SCRF(CHCl(3)) calculations. The atomistic calculations provide insight into the differential dicarboxylic acid binding behavior of receptors 1 and 2. PMID- 21661732 TI - Seco-eremophiladiolides and eremophilane glucosides from Pittocaulon velatum. AB - Two seco-eremophiladiolides, velatumolide and epi-velatumolide, the trihydroxyfuranoeremophilane velatumin, and three eremophilane glucosides were isolated from Pittocaulon velatum, together with several known compounds. The structures of these compounds were elucidated by spectroscopic analysis and chemical reactions. The anti-inflammatory activity of the isolated compounds was investigated using the TPA-induced ear edema model. PMID- 21661733 TI - Omnidirectional 3D nanoplasmonic optical antenna array via soft-matter transformation. AB - Inspired by the natural processes during morphogenesis, we demonstrate the transformation capability of active soft-matter to define nanoscale metal-on polymer architectures below the resolution limit of conventional lithography. Specifically, using active polymers, we fabricate and characterize ultradense nanoplasmonic antenna arrays with sub-10 nm tip-to-tip nanogaps. In addition, the macroscale morphology can be independently manipulated into arbitrary three dimensional geometries, demonstrated with the fabrication of an omnidirectional nanoplasmonic optical antenna array. PMID- 21661731 TI - Synergy-directed fractionation of botanical medicines: a case study with goldenseal (Hydrastis canadensis). AB - It is often argued that the efficacy of herbal medicines is a result of the combined action of multiple constituents that work synergistically or additively. Determining the bioactive constituents in these mixtures poses a significant challenge. We have developed an approach to address this challenge, synergy directed fractionation, which combines comprehensive mass spectrometry profiling with synergy assays and natural products isolation. The applicability of synergy directed fractionation was demonstrated using the botanical medicine goldenseal (Hydrastis canadensis) as a case study. Three synergists from goldenseal were identified, sideroxylin, 8-desmethyl-sideroxylin, and 6-desmethyl-sideroxylin. These flavonoids synergistically enhance the antimicrobial activity of the alkaloid berberine (also a constituent of H. canadensis) against Staphylococcus aureus by inhibition of the NorA multidrug resistance pump. The flavonoids possess no inherent antimicrobial activity against S. aureus; therefore, they could have been missed using traditional bioactivity-directed fractionation. The flavonoid synergists are present at higher concentration in extracts from H. canadensis leaves, while the antimicrobial alkaloid berberine is present at higher levels in H. canadensis roots. Thus, it may be possible to produce an extract with optimal activity against S. aureus using a combination of goldenseal roots and leaves. PMID- 21661734 TI - Improved current extraction from ZnO/PbS quantum dot heterojunction photovoltaics using a MoO3 interfacial layer. AB - The ability to engineer interfacial energy offsets in photovoltaic devices is one of the keys to their optimization. Here, we demonstrate that improvements in power conversion efficiency may be attained for ZnO/PbS heterojunction quantum dot photovoltaics through the incorporation of a MoO(3) interlayer between the PbS colloidal quantum dot film and the top-contact anode. Through a combination of current-voltage characterization, circuit modeling, Mott-Schottky analysis, and external quantum efficiency measurements performed with bottom- and top illumination, these enhancements are shown to stem from the elimination of a reverse-bias Schottky diode present at the PbS/anode interface. The incorporation of the high-work-function MoO(3) layer pins the Fermi level of the top contact, effectively decoupling the device performance from the work function of the anode and resulting in a high open-circuit voltage (0.59 +/- 0.01 V) for a range of different anode materials. Corresponding increases in short-circuit current and fill factor enable 1.5-fold, 2.3-fold, and 4.5-fold enhancements in photovoltaic device efficiency for gold, silver, and ITO anodes, respectively, and result in a power conversion efficiency of 3.5 +/- 0.4% for a device employing a gold anode. PMID- 21661735 TI - Dynamic metabolic transformation in tumor invasion and metastasis in mice with LM 8 osteosarcoma cell transplantation. AB - While extensive evidence indicates that tumor cells shift their global metabolic programs, the molecular details of the metabolic transformation in tumor invasion, progression, and metastasis remain largely unknown. Characterization of the time-dependent metabolic shift during the tumor invasion, development, and metastasis will describe an important aspect of tumor phenotypes and potentially allow us to design therapies that inhibit tumor cell movement. In this study, a metabonomic study was performed to characterize the global metabolic changes during the process of tumor invasion and metastasis to lung in a mouse model with subcutaneous transplantation of murine osteosarcoma cell line (LM8). The serum metabolic profiling revealed that many key metabolites in glycolysis and tricarboxylic acid (TCA) cycle, as well as most of the amino acids were elevated at rapidly growing stage of tumor, presumably resulting from a high energy demand and turnover of anabolic metabolism during the tumor cell proliferation. Serum levels of succinic acid and proline significantly increased (with fold change FC = 10.75 and 4.43, relative to controls) among all the metabolites in the third week. The serum metabolic profile of lung metastasis at week 4 was different from that at week 3, in that most of previously increased serum metabolites were found decreased, except for cholesterol and several free fatty acids, suggesting lowered carbohydrate and amino acids metabolism, but an elevated lipid metabolism associated with tumor metastasis. PMID- 21661736 TI - Characterization of polymer-silica nanocomposite particles with core-shell morphologies using Monte Carlo simulations and small angle X-ray scattering. AB - A two-population model based on standard small-angle X-ray scattering (SAXS) equations is verified for the analysis of core-shell structures comprising spherical colloidal particles with particulate shells. First, Monte Carlo simulations of core-shell structures are performed to demonstrate the applicability of the model. Three possible shell packings are considered: ordered silica shells due to either charge-dependent repulsive or size-dependent Lennard Jones interactions or randomly arranged silica particles. In most cases, the two population model produces an excellent fit to calculated SAXS patterns for the simulated core-shell structures, together with a good correlation between the fitting parameters and structural parameters used for the simulation. The limits of application are discussed, and then, this two-population model is applied to the analysis of well-defined core-shell vinyl polymer/silica nanocomposite particles, where the shell comprises a monolayer of spherical silica nanoparticles. Comprehensive SAXS analysis of a series of poly(styrene-co-n-butyl acrylate)/silica colloidal nanocomposite particles (prepared by the in situ emulsion copolymerization of styrene and n-butyl acrylate in the presence of a glycerol-functionalized silica sol) allows the overall core-shell particle diameter, the copolymer latex core diameter and polydispersity, the mean silica shell thickness, the mean silica diameter and polydispersity, the volume fractions of the two components, the silica packing density, and the silica shell structure to be obtained. These experimental SAXS results are consistent with electron microscopy, dynamic light scattering, thermogravimetry, helium pycnometry, and BET surface area studies. The high electron density contrast between the (co)polymer and the silica components, together with the relatively low polydispersity of these core-shell nanocomposite particles, makes SAXS ideally suited for the characterization of this system. Moreover, these results can be generalized for other types of core-shell colloidal particles. PMID- 21661737 TI - A bipolar electrochemical approach to constructive lithography: metal/monolayer patterns via consecutive site-defined oxidation and reduction. AB - Experimental evidence is presented, demonstrating the feasibility of a surface patterning strategy that allows stepwise electrochemical generation and subsequent in situ metallization of patterns of carboxylic acid functions on the outer surfaces of highly ordered OTS monolayers assembled on silicon or on a flexible polymeric substrate. The patterning process can be implemented serially with scanning probes, which is shown to allow nanoscale patterning, or in a parallel stamping configuration here demonstrated on micrometric length scales with granular metal film stamps sandwiched between two monolayer-coated substrates. The metal film, consisting of silver deposited by evaporation through a patterned contact mask on the surface of one of the organic monolayers, functions as both a cathode in the printing of the monolayer patterns and an anodic source of metal in their subsequent metallization. An ultrathin water layer adsorbed on the metal grains by capillary condensation from a humid atmosphere plays the double role of electrolyte and a source of oxidizing species in the pattern printing process. It is shown that control over both the direction of pattern printing and metal transfer to one of the two monolayer surfaces can be accomplished by simple switching of the polarity of the applied voltage bias. Thus, the patterned metal film functions as a consumable "floating" stamp capable of two-way (forward-backward) electrochemical transfer of both information and matter between the contacting monolayer surfaces involved in the process. This rather unusual electrochemical behavior, resembling the electrochemical switching in nanoionic devices based on the transport of ions in solid ionic-electronic conductors, is derived from the nanoscale thickness of the water layer acting as an electrolyte and the bipolar (cathodic-anodic) nature of the water-coated metal grains in the metal film. The floating stamp concept introduced in this report paves the way to a series of unprecedented capabilities in surface patterning, which are particularly relevant to nanofabrication by chemical means and the engineering of a new class of molecular nanoionic systems. PMID- 21661738 TI - Binding stoichiometry and affinity of the manganese-stabilizing protein affects redox reactions on the oxidizing side of photosystem II. AB - It has been reported previously that the two subunits of PsbO, the photosystem II (PSII) manganese stabilizing protein, have unique functions in relation to the Mn, Ca(2+), and Cl(-) cofactors in eukaryotic PSII [Popelkova; (2008) Biochemistry 47, 12593]. The experiments reported here utilize a set of N terminal truncation mutants of PsbO, which exhibit altered subunit binding to PSII, to further characterize its role in establishing efficient O(2) evolution activity. The effects of PsbO binding stoichiometry, affinity, and specificity on Q(A)(-) reoxidation kinetics after a single turnover flash, S-state transitions, and O(2) release time have been examined. The data presented here show that weak rebinding of a single PsbO subunit to PsbO-depleted PSII repairs many of the defects in PSII resulting from the removal of the protein, but many of these are not sustainable, as indicated by low steady-state activities of the reconstituted samples [Popelkova; (2003) Biochemistry 42 , 6193]. High affinity binding of PsbO to PSII is required to produce more stable and efficient cycling of the water oxidation reaction. Reconstitution of the second PsbO subunit is needed to further optimize redox reactions on the PSII oxidizing side. Native PsbO and recombinant wild-type PsbO from spinach facilitate PSII redox reactions in a very similar manner, and nonspecific binding of PsbO to PSII has no significance in these reactions. PMID- 21661739 TI - Photochemical reduction of CO2 using TiO2: effects of organic adsorbates on TiO2 and deposition of Pd onto TiO2. AB - Reduction of CO(2) using semiconductors as photocatalysts has recently attracted a great deal of attention again. The effects of organic adsorbates on semiconductors on the photocatalytic products are noteworthy. On untreated TiO(2) (P-25) particles a considerable number of organic molecules such as acetic acid were adsorbed. Although irradiation of an aqueous suspension of this TiO(2) resulted in the formation of a significant amount of CH(4) as a major product, it was strongly suggested that its formation mainly proceeded via the photo-Kolbe reaction of acetic acid. Using TiO(2) treated by calcination and washing procedures for removal of the organic adsorbates, CO was photocatalytically generated as a major product, along with a very small amount of CH(4), from an aqueous suspension under a CO(2) atmosphere. In contrast, by using Pd (>0.5 wt %) deposited on TiO(2) (Pd-TiO(2)) on which organic adsorbates were not detected, CH(4) was the main product, but CO formation was drastically reduced compared with that on the pretreated TiO(2). Experimental data, including isotope labeling, indicated that CO(2) and CO(3)(2-) are the main carbon sources of the CH(4) formation, which proceeds on the Pd site of Pd-TiO(2). Prolonged irradiation caused deactivation of the photocatalysis of Pd-TiO(2) because of the partial oxidation of the deposited Pd to PdO. PMID- 21661740 TI - Inducing electronic changes in graphene through silicon (100) substrate modification. AB - We have performed scanning tunneling microscopy and spectroscopy (STM/STS) measurements as well as ab initio calculations for graphene monolayers on clean and hydrogen(H)-passivated silicon (100) (Si(100)/H) surfaces. In order to experimentally study the same graphene piece on both substrates, we develop a method to depassivate hydrogen from under graphene monolayers on the Si(100)/H surface. Our work represents the first demonstration of successful and reproducible depassivation of hydrogen from beneath monolayer graphene flakes on Si(100)/H by electron-stimulated desorption. Ab initio simulations combined with STS taken before and after hydrogen desorption demonstrate that graphene interacts differently with the clean and H-passivated Si(100) surfaces. The Si(100)/H surface does not perturb the electronic properties of graphene, whereas the interaction between the clean Si(100) surface and graphene changes the electronic states of graphene significantly. This effect results from the covalent bonding between C and surface Si atoms, modifying the pi-orbital network of the graphene layer. The local density of states shows that the bonded C and Si surface states are highly disturbed near the Fermi energy. PMID- 21661741 TI - Chemical functionalization of polysilicon microparticles for single-cell studies. AB - In this work, two types of polycrystalline silicon (polysilicon) microparticles were modified with specific ligands in order to be selectively attached to chemical residues located at the plasma membrane and thus to be applied to study individual cells in culture. Two different functionalization approaches based on adsorption and covalent attachment were assayed. A comparative study of the efficiency of the ligand immobilization and stability of the modified particle in the culture medium was carried out using the selected ligands labeled with a fluorophore. Cylindrical microparticles (nonencoded microparticles) and shape encoded microparticles (bar codes) were used with the aim of demonstrating the nondependence of the particle size and shape on the efficiency of the immobilization protocol. Fluorescence imaging and statistical analysis of the recorded fluorescence intensity showed that the covalent attachment of the ligand to the surface of the microparticle, previously modified with an aldehyde terminated silane, gave the best results. As a proof of concept, Vero cells in culture were labeled with the covalently modified bar codes and successfully tracked for up to 1 week without observing any alteration in the viability of the cells. Bar code numbers could be easily read by eye using a bright-field optical microscope. It is anticipated that such modified microparticles could be feasible platforms for the introduction of other analytical functions of interest in single-cell monitoring and cell sorting in automatic analysis systems. PMID- 21661742 TI - Shorter and modular synthesis of hemicryptophane-tren derivatives. AB - Hemicryptophanes are host molecules with many applications as supramolecular catalysts or in ion selective recognition. A very convenient and efficient modular approach for the synthesis of hemicryptophane-tren (tren, tris(2 aminoethyl)-amine) derivatives has been developed. For instance, hemicryptophane 1 was synthesized at the gram scale in four steps from vanillyl alcohol compared to the previous seven-step procedure. The size, shape, and functionalities of the molecular cavity were also easily modified. PMID- 21661743 TI - Fluorescent nanoparticles of chitosan complex for real-time monitoring drug release. AB - New types of fluorescent nanoparticles (FNPs) were prepared through ionic self assembly of anthracene derivative and chitosan for applications as drug delivery carriers with real-time monitoring of the process of drug release. Because of the presence of the hydrophilic groups, these FNPs showed excellent dispersion and stability in aqueous solution. The structure and properties of the FNPs were investigated by using means of (1)H NMR, FTIR, SEM, dynamic light scattering (DLS), and so on. The potential practical applications as drug delivery carriers for real-time detection of the drug release process were demonstrated using Nicardipine as a model drug. Upon loading the drug, the strong blue fluorescence of FNPs was quenched due to electron transfer and fluorescence resonance energy transfer (FRET). With release of drug in vitro, the fluorescence was recovered again. The relationship between the accumulative drug release of FNPs and the recovered fluorescence intensity has been established. Such FNPs may open up new perspectives for designing a new class of detection system for monitoring drug release. PMID- 21661744 TI - Structural study of a series of layered rare-earth hydroxide sulfates. AB - We report structure analysis of a new family of rare-earth hydroxides Ln(2)(OH)(4)SO(4).2H(2)O (Ln = Pr, Nd, Sm, Eu, Gd, Tb) from synchrotron X-ray and electron diffraction data. Rietveld profile analysis revealed that all members were isostructural and crystallized in a face-centered monoclinic system A2/m (No. 12), in which the monoclinic angles were approximately equal to the right angle, varying from 90.387(1) degrees for Pr sample to 90.0718(3) degrees for Tb sample. The structure consisted of LnO(9) polyhedra connected by MU(3) hydroxyl groups and MU(2)-water molecules, forming a corrugated two-dimensional layer, which was pillared by bidentated sulfate ions. This series of compounds had a supercell a' = 2a, b' = 2b because of the local orientation ordering of SO(4)(2-). Structural features along the series, such as unit-cell parameters and average Ln-O distances, represented a progressive contraction associated with the shrinking radius of the lanthanide cations from Pr to Tb. PMID- 21661745 TI - Intracellular targeting of PLGA nanoparticles encapsulating antigenic peptide to the endoplasmic reticulum of dendritic cells and its effect on antigen cross presentation in vitro. AB - Intracellularly targeted delivery system based on PLGA nanoparticles decorated with endoplasmic reticulum (ER)-targeting or control peptides and encapsulating antigenic peptide and fluorescent marker, was developed and characterized. The cellular uptake by dendritic cells (murine DC2.4 cells), intracellular trafficking, and cross-presentation efficiency of this delivery system were studied in vitro. The prepared nanoparticles (an average diameter of ~350 nm) efficiently encapsulated antigenic peptide and fluorescent marker and gradually released them over several days. Yet, the nanoparticles' size was small enough to allow their efficient endocytosis by the antigen-presenting cells in vitro. Surface conjugation of the targeting or control peptides enhanced the endocytosis of the nanoparticles, affected their intracellular trafficking, and induced prolonged low-magnitude cross-presentation of the antigenic peptide. We demonstrated in vitro that the intracellular fate of nanoparticulate drug delivery systems can be altered by their surface decoration with peptidic targeting residues. More detailed investigation is required to determine the mechanisms and therapeutic potential of intracellular targeting of nanodelivery systems in vivo for the goal of an anticancer vaccine. PMID- 21661746 TI - The natural resistance-associated macrophage protein from the protozoan parasite Perkinsus marinus mediates iron uptake. AB - Microbial pathogens succeed in acquiring essential metals such as iron and manganese despite their limited availability because of the host's immune response. The eukaryotic natural resistance-associated macrophage proteins mediate uptake of divalent metals and, during infection, may compete directly for metal acquisition with the pathogens' transporters. In this study, we characterize the Nramp gene family of Perkinsus marinus, an intracellular parasite of the eastern oyster, and through yeast complementation, we demonstrate for the first time for a protozoan parasite that Nramp imports environmental Fe. Three PmNramp isogenes differ in their exon-intron structures and encode transcripts that display a trans splicing leader at the 5' end. The protein sequences share conserved properties predicted for the Nramp/Solute carrier 11 (Slc11) family, such as 12-transmembrane segment (TMS) topology (N- and C-termini cytoplasmic) and preferential conservation of four TMS predicted to form a pseudosymmetric proton/metal symport pathway. Yeast fet3fet4 mutant complementation assays showed iron transport activity for PmNramp1 and a fusion chimera of the PmNramp3 hydrophobic core and PmNramp1 N- and C-termini. PmNramp1 site-directed mutagenesis demonstrated that Slc11 invariant and predicted pseudosymmetric motifs (TMS1 Asp-Pro-Gly and TMS6 Met-Pro-His) are key for transport function. PmNramp1 TMS1 mutants D76E, G78A, and D76E/G78A prevented membrane protein expression, while TMS6 M250A, H252Y, and M250A/H252Y specifically abrogated Fe uptake; the TMS6 H252Y mutation also correlates with divergence from Nramp specificity for divalent metals. PMID- 21661748 TI - Shock tube study on the thermal decomposition of ethanol. AB - The thermal decomposition of C(2)H(5)OH highly diluted in Ar (1 and 3 ppm) has been studied by monitoring H atoms using the atomic resonance absorption spectrometry (ARAS) technique behind reflected shock waves over the temperature range 1450-1760 K at fixed pressure: 1, 1.45, and 2 atm. The rate constant and the product branching fractions have been determined by analyzing temporal profiles of H atoms; the effect of the secondary reactions on the results has been examined by using a detailed reaction mechanism composed of 103 elementary reactions. The apparent rate constant of ethanol decomposition can be expressed as k(1)/s(-1) = (5.28 +/- 0.14) * 10(10) exp[-(23,530 +/- 980)/T] (T = 1450-1670 K, P = 1-2 atm) without a detectable pressure dependence within the tested pressure range of this study. Branching fractions for producing CH(3) + CH(2)OH (1a) and H(2)O + C(2)H(4) (1b) have been examined by a quantitative measurement of H atoms produced in the successive decompositions of the products CH(2)OH (1a): the pressure dependence of the branching fraction for channel 1a is obtained by a linear least-squares analysis of the experimental data and can be expressed as phi(1a) = (0.71 +/- 0.07) - (826 +/- 116)/T, (0.92 +/- 0.04) - (1108 +/- 70)/T, and (1.02 +/- 0.10) - (1229 +/- 168)/T for T = 1450-1760 K, at P = 0.99, 1.45, and 2.0 atm, respectively. The rate constant obtained in this study is found to be consistent with previous theoretical and experimental results; however, the pressure dependence of the branching fraction obtained in this study is smaller than those of previous theoretical works. Modification of the parameters for the decomposition rate in the falloff region is suggested to be important to improve the practical modeling of the pyrolysis and combustion of ethanol. PMID- 21661747 TI - Glucose autoxidation induces functional damage to proteins via modification of critical arginine residues. AB - Nonenzymatic modification of proteins in hyperglycemia is a major mechanism causing diabetic complications. These modifications can have pathogenic consequences when they target active site residues, thus affecting protein function. In the present study, we examined the role of glucose autoxidation in functional protein damage using lysozyme and RGD-alpha3NC1 domain of collagen IV as model proteins in vitro. We demonstrated that glucose autoxidation induced inhibition of lysozyme activity as well as NC1 domain binding to alpha(V)beta(3) integrin receptor via modification of critical arginine residues by reactive carbonyl species (RCS) glyoxal (GO) and methylglyoxal while nonoxidative glucose adduction to the protein did not affect protein function. The role of RCS in protein damage was confirmed using pyridoxamine which blocked glucose autoxidation and RCS production, thus protecting protein function, even in the presence of high concentrations of glucose. Glucose autoxidation may cause protein damage in vivo since increased levels of GO-derived modifications of arginine residues were detected within the assembly interface of collagen IV NC1 domains isolated from renal ECM of diabetic rats. Since arginine residues are frequently present within protein active sites, glucose autoxidation may be a common mechanism contributing to ECM protein functional damage in hyperglycemia and oxidative environment. Our data also point out the pitfalls in functional studies, particularly in cell culture experiments, that involve glucose treatment but do not take into account toxic effects of RCS derived from glucose autoxidation. PMID- 21661750 TI - Formation of a mesoscopic skin barrier in mesoglobules of thermoresponsive polymers. AB - With the combination of molecular scale information from electron paramagnetic resonance (EPR) spectroscopy and meso-/macroscopic information from various other characterization techniques, the formation of mesoglobules of thermoresponsive dendronized polymers is explained. Apparent differences in the EPR spectra in dependence of the heating rate, the chemical nature of the dendritic substructure of the polymer, and the concentration are interpreted to be caused by the formation of a dense polymeric layer at the periphery of the mesoglobule. This skin barrier is formed in a narrow temperature range of ~4 K above T(C) and prohibits the release of molecules that are incorporated in the polymer aggregate. In large mesoglobules, formed at low heating rates and at high polymer concentrations, a considerable amount of water is entrapped that microphase separates from the collapsed polymer chains at high temperatures. This results in the aggregates possessing an aqueous core and a corona consisting of collapsed polymer chains. A fast heating rate, a low polymer concentration, and hydrophobic subunits in the dendritic polymer side chains make the entrapment of water less favorable and lead to a higher degree of vitrification. This may bear consequences for the design and use of thermoresponsive polymeric systems in the fast growing field of drug delivery. PMID- 21661749 TI - Electrochemical formation mechanism for the controlled synthesis of heterogeneous MnO2/Poly(3,4-ethylenedioxythiophene) nanowires. AB - The formation mechanism of a coaxial manganese oxide/poly(3,4 ethylenedioxythiophene) (MnO(2)/PEDOT) nanowire is elucidated herein by performing electrodeposition of MnO(2) and PEDOT on Au-sputtered nanoelectrodes with different shapes (ring and flat-top, respectively) within the 200 nm diameter pores of an anodized aluminum oxide (AAO) template. It is found that PEDOT prefers to grow on the sharp edge of the ring-shaped electrode, while MnO(2) is more likely to deposit on the flat-top electrode due to its smooth surface. The formation of coaxial nanowires is shown to be a result of simultaneous growth of core MnO(2) and shell PEDOT by an analysis of the current density resulting from electrochemical deposition. Furthermore, the structures of the MnO(2)/PEDOT coaxial nanowires were studied for their application as supercapacitors by modifying their coelectrodeposition potential. A potential of 0.70 V is found to be the most favorable condition for synthesis of MnO(2)/PEDOT coaxial nanowires, resulting in a high specific capacitance of 270 F/g. Additionally, other heterogeneous MnO(2)/PEDOT nanostructures are produced, such as nanowires consisting of MnO(2) nanodomes with PEDOT crowns as well as segmented MnO(2)/PEDOT nanowires. This is accomplished by simply adjusting the parameters of the electrochemical deposition. Finally, in smaller diameter (50 nm) AAO channels, MnO(2) and PEDOT are found to be partially assembled into coaxial nanowires due to the alternative depletion of Mn(II) ions and EDOT monomers in the smaller diameter pores. PMID- 21661751 TI - Asymmetric organocatalytic synthesis of complex cyclopenta[b]quinoline derivatives. AB - An efficient one-pot procedure that provides a direct access to polycyclic hexahydrocyclopenta[b]quinoline derivatives having five stereogenic centers has been developed. The system displays great tolerance toward different aldehydes, anilines, and nitroalkenes. The products are obtained in high yields and excellent enantio- and diastereoselectivities. PMID- 21661752 TI - Tandem reaction of propargyl alcohol and N-sulfonylhydrazone: synthesis of dihydropyrazole and its utility in the preparation of 3,3-diarylacrylonitrile. AB - An efficient and straightforward strategy for the synthesis of 4-methylene-1 (phenylsulfonyl)-4,5-dihydro-1H-pyrazole from propargyl alcohol and N sulfonylhydrazone is described. N-Sulfonyl allenamide is postulated to be the key intermediate for this tandem transformation. PMID- 21661753 TI - Peculiar thermodynamics of the second critical point in supercooled water. AB - On the basis of the principle of critical-point universality, we examine the peculiar thermodynamics of the liquid-liquid critical point in supercooled water. We show that the liquid-liquid criticality in water represents a special kind of critical behavior in fluids, intermediate between two limiting cases: the lattice gas, commonly used to model liquid-vapor transitions, and the lattice liquid, a weakly compressible liquid with an entropy-driven phase separation. While the ordering field in the lattice gas is associated with the chemical potential and the order parameter with the density, in the lattice liquid the ordering field is the temperature and the order parameter is the entropy. The behavior of supercooled water is much closer to lattice-liquid behavior than to lattice-gas behavior. Using new experimental data recently obtained by Mishima [J. Chem. Phys. 2010, 133, 144503], we have revised the parametric scaled equation of state, previously suggested by Fuentevilla and Anisimov [Phys. Rev. Lett. 2006, 97, 195702], and obtain a consistent description of the thermodynamic anomalies of supercooled water by adjusting linear backgrounds, one critical amplitude, and the critical pressure. We also show how the lattice-liquid description affects the finite-size scaling description of supercooled water in confined media. PMID- 21661754 TI - Monodisperse magnetic nanoparticles for theranostic applications. AB - Effective medical care requires the concurrent monitoring of medical treatment. The combination of imaging and therapeutics allows a large degree of control over the treatment efficacy and is now commonly referred to as "theranostics". Magnetic nanoparticles (NPs) provide a unique nanoplatform for theranostic applications because of their biocompatibility, their responses to the external magnetic field, and their sizes which are comparable to that of functional biomolecules. Recent studies of magnetic NPs for both imaging and therapeutic applications have led to greater control over size, surface functionalization, magnetic properties, and specific binding capabilities of the NPs. The combination of the deep tissue penetration of the magnetic field and the ability of magnetic NPs to enhance magnetic resonance imaging sensitivity and magnetic heating efficiency makes magnetic NPs promising candidates for successful future theranostics. In this Account, we review recent advances in the synthesis of magnetic NPs for biomedical applications such as magnetic resonance imaging (MRI) and magnetic fluid hyperthermia (MFH). Our focus is on iron oxide (Fe(3)O(4)) NPs, gold-iron oxide (Au-Fe(3)O(4)) NPs, metallic iron (Fe) NPs, and Fe-based alloy NPs, such as iron-cobalt (FeCo) and iron-platinum (FePt) NPs. Because of the ease of fabrication and their approved clinical usage, Fe(3)O(4) NPs with controlled sizes and surface chemistry have been studied extensively for MRI and MFH applications. Porous hollow Fe(3)O(4) NPs are expected to have similar magnetic, chemical, and biological properties as the solid Fe(3)O(4) NPs, and their structures offer the additional opportunity to store and release drugs at a target. The Au-Fe(3)O(4) NPs combine both magnetically active Fe(3)O(4) and optically active Au within one nanostructure and are a promising NP platform for multimodal imaging and therapeutics. Metallic Fe and FeCo NPs offer the opportunity for probes with even higher magnetizations. However, metallic NPs are normally very reactive and are subject to fast oxidation in biological solutions. Once they are coated with a layer of polycrystalline Fe(3)O(4) or a graphitic shell, these metallic NPs are more stable and provide better contrast for MRI and more effective heating for MFH. FePt NPs are chemically more stable than Fe and FeCo NPs and have shown great potential as contrast agents for both MRI and X-ray computed tomography (CT) and as robust probes for controlled heating in MFH. PMID- 21661755 TI - Novel quantum interference effects in transport through molecular radicals. AB - We investigate electronic transport through molecular radicals and predict a correlation-induced transmission node arising from destructive interference between transport contributions from different charge states of the molecule. This quantum interference effect has no single-particle analog and cannot be described by effective single-particle theories. Large errors in the thermoelectric properties and nonlinear current-voltage response of molecular radical junctions are introduced when the complementary wave and particle aspects of the electron are not properly treated. A method to accurately calculate the low-energy transport through a radical-based junction using an Anderson model is given. PMID- 21661756 TI - Synthesis and electrochemical properties of spin-capable carbon nanotube sheet/MnO(x) composites for high-performance energy storage devices. AB - Inspired by the high specific capacitances found using ultrathin films or nanoparticles of manganese oxides (MnO(x)), we have electrodeposited MnO(x) nanoparticles onto sheets of carbon nanotubes (CNT sheets). The resulting composites have high specific capacitances (C(sp) <= 1250 F/g), high charge/discharge rate capabilities, and excellent cyclic stability. Both the C(sp) and rate capabilities are controlled by the average size of the MnO(x) nanoparticles on the CNTs. They are independent of the number of layers of CNT sheets used to form an electrode. The high-performance composites result from a synergistic combination of large surface area and good electron-transport capabilities of the MnO(x) nanoparticles with the good conductivity of the CNT sheets. Such composites can be used as electrodes for lithium batteries and supercapacitors. PMID- 21661757 TI - Paramagnetic-diamagnetic phase transition accompanied by coordination bond formation-dissociation in the dithiolate complex Na[Ni(pdt)2].2H2O. AB - Bis(2,3-pyrazinedithiolate)nickel complex Na[Ni(pdt)(2)].2H(2)O formed one dimensional stacks of the Ni(pdt)(2) units and showed strong antiferromagnetic interactions along the stacking direction. A first-order phase transition between the paramagnetic and diamagnetic states, which was driven by dimerization of the Ni(pdt)(2) units, accompanied by coordination bond formation, was observed. PMID- 21661759 TI - Osteoid-mimicking dense collagen/chitosan hybrid gels. AB - Bone extracellular matrix (ECM) is a 3D network, composed of collagen type I and a number of other macromolecules, including glycosaminoglycans (GAGs), which stimulate signaling pathways that regulate osteoblast growth and differentiation. To model the ECM of bone for tissue regenerative approaches, dense collagen/chitosan (Coll/CTS) hybrid hydrogels were developed using different proportions of CTS to mimic GAG components of the ECM. MC3T3-E1 mouse calvaria preosteoblasts were seeded within plastically compressed Coll/CTS hydrogels with solid content approaching that of native bone osteoid. Dense, cellular Coll/CTS hybrids were maintained for up to 8 weeks under either basal or osteogenic conditions. Higher CTS content significantly increased gel resistance to collagenase degradation. The incorporation of CTS to collagen gels decreased the apparent tensile modulus from 1.82 to 0.33 MPa. In contrast, the compressive modulus of Coll/CTS hybrids increased in direct proportion to CTS content exhibiting an increase from 23.50 to 55.25 kPa. CTS incorporation also led to an increase in scaffold resistance to cell-induced contraction. MC3T3-E1 viability, proliferation, and matrix remodeling capability (via matrix metalloproteinase expression) were maintained. Alkaline phosphatase activity was increased up to two-fold, and quantification of phosphate mineral deposition was significantly increased with CTS incorporation. Thus, dense Coll/CTS scaffolds provide osteoid like models for the study of osteoblast differentiation and bone tissue engineering. PMID- 21661758 TI - Development of a liver-targeted stearoyl-CoA desaturase (SCD) inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and dyslipidemia. AB - The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window. PMID- 21661760 TI - Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT). AB - A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC(50) of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI(50)) values ranging from 0.3 to >100 MUM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor. PMID- 21661761 TI - Nano-LC-MS/MS of glycopeptides produced by nonspecific proteolysis enables rapid and extensive site-specific glycosylation determination. AB - Given the biological importance of glycosylation on proteins, the identification of protein glycosylation sites is integral to understanding broader biological structure and function. Unfortunately, the determination of the microheterogeneity at the site of glycosylation still remains a significant challenge. Nanoflow liquid chromatography with tandem mass spectrometry provides both separation of glycopeptides and the ability to determine glycan composition and site-specific glycosylation. However, because of the size of glycopeptides, they are not often amenable to tandem MS. In this work, proteins are digested with multiple proteases to produce glycopeptides that are of suitable size for tandem MS analysis. The conditions for collision-induced dissociation are optimized to obtain diagnostic ions that maximize glycan and peptide information. The method is applied to glycoproteins with contrasting glycans and multiple sites of glycosylation and identifies multiple glycan compositions at each individual glycosylation site. This method provides an important improvement in the routine determination of glycan microheterogeneity by mass spectrometry. PMID- 21661762 TI - Structural basis for the catalytic mechanism of aspartate ammonia lyase. AB - Aspartate ammonia lyases (or aspartases) catalyze the reversible deamination of L aspartate into fumarate and ammonia. The lack of crystal structures of complexes with substrate, product, or substrate analogues so far precluded determination of their precise mechanism of catalysis. Here, we report crystal structures of AspB, the aspartase from Bacillus sp. YM55-1, in an unliganded state and in complex with L-aspartate at 2.4 and 2.6 A resolution, respectively. AspB forces the bound substrate to adopt a high-energy, enediolate-like conformation that is stabilized, in part, by an extensive network of hydrogen bonds between residues Thr101, Ser140, Thr141, and Ser319 and the substrate's beta-carboxylate group. Furthermore, substrate binding induces a large conformational change in the SS loop (residues G(317)SSIMPGKVN(326)) from an open conformation to one that closes over the active site. In the closed conformation, the strictly conserved SS loop residue Ser318 is at a suitable position to act as a catalytic base, abstracting the Cbeta proton of the substrate in the first step of the reaction mechanism. The catalytic importance of Ser318 was confirmed by site-directed mutagenesis. Site-directed mutagenesis of SS loop residues, combined with structural and kinetic analysis of a stable proteolytic AspB fragment, further suggests an important role for the small C-terminal domain of AspB in controlling the conformation of the SS loop and, hence, in regulating catalytic activity. Our results provide evidence supporting the notion that members of the aspartase/fumarase superfamily use a common catalytic mechanism involving general base-catalyzed formation of a stabilized enediolate intermediate. PMID- 21661763 TI - Pattern dimensions and feature shapes of ternary blends of block copolymer and low molecular weight homopolymers directed to assemble on chemically nanopatterned surfaces. AB - Ternary blends of cylinder-forming polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) and low molecular weight PS and PMMA were directed to assemble on chemically patterned surfaces with hexagonal symmetry. The chemical patterns consisted of strongly PMMA preferential spots, patterned by electron-beam lithography, in a matrix of PS. The spot-to-spot spacing of the chemical patterns (L(s)) was varied between 0.9L(0) and 1.1L(0), where L(0) is the cylinder-to cylinder spacing of the pure block copolymer in bulk. The homopolymer volume fraction of the blends (phi(H)) was varied between 0 and 0.3. In addition, chemical patterns were formed with selected spots missing from the perfect hexagonal array, such that the interpolation of domains between patterned spots could be examined on patterns where the polymer/pattern feature density ranged from 1:1 to 4:1. The assemblies were analyzed with top-down SEM, from which orientational order parameter (OP(o)) values were determined. The SEM analysis was complemented by Monte Carlo simulations, which offered insights into the shapes of the assembled cylindrical domains. It was found that, in comparison to pure block copolymer, adding homopolymer increased the range of L(s) values over which assemblies with high OP(o) values could be achieved for 1:1 assemblies. However, the corresponding simulations showed that in the 1:1 assemblies the shape of the cylinders was more uniform for pure block copolymer than for blends. In the case of the 4:1 assemblies, the range of L(s) values over which assemblies with high OP(o) values could be achieved was the same for all values of phi(H) tested, but the domains of the pure block copolymer had a more uniform shape. Overall, the results provided insights into the blend composition to be used to meet technological requirements for directed assembly with density multiplication. PMID- 21661764 TI - Restructuring the crystalline cellulose hydrogen bond network enhances its depolymerization rate. AB - Conversion of lignocellulose to biofuels is partly inefficient due to the deleterious impact of cellulose crystallinity on enzymatic saccharification. We demonstrate how the synergistic activity of cellulases was enhanced by altering the hydrogen bond network within crystalline cellulose fibrils. We provide a molecular-scale explanation of these phenomena through molecular dynamics (MD) simulations and enzymatic assays. Ammonia transformed the naturally occurring crystalline allomorph I(beta) to III(I), which led to a decrease in the number of cellulose intrasheet hydrogen bonds and an increase in the number of intersheet hydrogen bonds. This rearrangement of the hydrogen bond network within cellulose III(I), which increased the number of solvent-exposed glucan chain hydrogen bonds with water by ~50%, was accompanied by enhanced saccharification rates by up to 5 fold (closest to amorphous cellulose) and 60-70% lower maximum surface-bound cellulase capacity. The enhancement in apparent cellulase activity was attributed to the "amorphous-like" nature of the cellulose III(I) fibril surface that facilitated easier glucan chain extraction. Unrestricted substrate accessibility to active-site clefts of certain endocellulase families further accelerated deconstruction of cellulose III(I). Structural and dynamical features of cellulose III(I), revealed by MD simulations, gave additional insights into the role of cellulose crystal structure on fibril surface hydration that influences interfacial enzyme binding. Subtle alterations within the cellulose hydrogen bond network provide an attractive way to enhance its deconstruction and offer unique insight into the nature of cellulose recalcitrance. This approach can lead to unconventional pathways for development of novel pretreatments and engineered cellulases for cost-effective biofuels production. PMID- 21661766 TI - Amphiphilic properties of dumbbell-shaped inorganic-organic-inorganic molecular hybrid materials in solution and at an interface. AB - Five novel dumbbell-shaped polyoxometalate (POM)-based inorganic-organic inorganic molecular hybrids are investigated both in polar solvents and at interfaces for potential amphiphilic properties, which are compared with those of conventional surfactants. These hybrids with the general formula {P(2)V(3)W(15)}(2)-bis(TRIS)-linker are formed by linking two Wells-Dawson-type clusters, [P(2)V(3)W(15)O(62)](9-), with different linear bis(TRIS) linker ligands between the two TRIS moieties. Laser light scattering (LLS) studies reveal the presence of self-assembled vesicular structures in water/acetone mixed solvents, and the vesicle size increases with increasing acetone content, suggesting a charge-regulated process. The elastic constants, which are used to calculate the bending energy during vesicle formation, reveal that the organic ligands play an important role in determining the self-assembly process and that the hybrids do demonstrate amphiphilic behavior at the water/air interface. Furthermore, it is shown that some of the hybrids form monolayers at the interface, with an average molecular area that can be correlated with their organic linkers, as determined from their pi-A isotherms. Finally, the hybrids not only display amphiphilic behavior akin to that of a surfactant but also exhibit an unusually high entropy contribution to vesicle formation as a result of their unique large, polar head groups, complex organic linkers, and their special molecular architectures as well as because of the involvement of the amphiphilic tetrabutylammonium (TBA) counterions. PMID- 21661765 TI - Dimensional architecture of ferrocenyl-based oligomer honeycomb-patterned films: from monolayer to multilayer. AB - We report a fabrication of highly ordered honeycomb-patterned films by the breath figure method from ferrocenyl-based oligomer with ferrocene units in the main chain and hydrophobic cholesteryl groups as side chains and investigate their dimensionality nature, i.e., the array of pores varying from monolayer to multilayer structure. A tentative model, including several key influencing parameters, is described to illustrate the varying layer numbers in the one film. The formation of the multilayer structure is ascribed to the Marangoni convection, thermocapillary effects, wet thickness, and evaporation speed. PMID- 21661768 TI - Other/miscellaneous. PMID- 21661770 TI - Other/miscellaneous. PMID- 21661771 TI - Globalization and other changes. PMID- 21661772 TI - Technology Solutions: Green building's clean air could help set indoor standards. PMID- 21661773 TI - Disastrous cyanide spill could spawn liability reforms. PMID- 21661774 TI - Natural attenuation's popularity outpaces scientific support, NRC finds. PMID- 21661775 TI - England tries to make polluters pay. PMID- 21661776 TI - MTBE phaseout: A boon for ethanol producers. PMID- 21661778 TI - Internet tool reaches beyond politics to address climate change. PMID- 21661777 TI - Quantifying the benefits of biodiversity could help prevent extinction. PMID- 21661781 TI - EPA Watch: Pressure to set controversial arsenic standard increases. PMID- 21661780 TI - EPA Watch: White House vows to remove MTBE from gasoline supplies. PMID- 21661779 TI - Toxics: Emissions data weaken public support for U.K. chemical industry. PMID- 21661782 TI - EPA Watch: Guidance aimed at updating tests for waterborne diseases. PMID- 21661783 TI - Peer Reviewed: MTBE-To What Extent Will Past Releases Contaminate Community Water Supply Wells? PMID- 21661785 TI - What fate for brominated fire retardants? AB - The widespread distribution and environmental effects of these persistent chemicals are driving preventive measures. PMID- 21661784 TI - Managing China's Water Resources. AB - As its economy strengthens, the nation must confront increasingly challenging water resource management issues. PMID- 21661802 TI - Research Watch: Toxicity of landfill leachate. PMID- 21661788 TI - Research Watch: PCBs and diet. PMID- 21661808 TI - Online/In print: online/in print. PMID- 21661814 TI - Other/miscellaneous. PMID- 21661812 TI - Other/miscellaneous. PMID- 21661815 TI - An expanded view of life. PMID- 21661816 TI - EPA struggles to implement pesticide law. PMID- 21661817 TI - Ship study to assess emission impacts. PMID- 21661819 TI - North Carolina considers controls to protect contaminated waters. PMID- 21661818 TI - Maine seeks to drop MTBE from its clean fuels program. PMID- 21661820 TI - IMO will ban the use of a popular biocide. PMID- 21661821 TI - World Bank inspection panel weakened. PMID- 21661822 TI - Study alludes to deformities from dioxin in Vietnam. PMID- 21661823 TI - Biodiversity inventory stirs debate over ownership of organisms. PMID- 21661824 TI - News Briefs: States have paid to remediate nearly 41,000 sites. PMID- 21661825 TI - News Briefs: Forty percent of deaths worldwide can be linked to environmental factors. PMID- 21661826 TI - News Briefs: By openly reporting their greenhouse gas emissions and committing to reduce them. PMID- 21661828 TI - News Briefs: North American forests and crops are absorbing about as much carbon dioxide as is emitted from the burning of fossil fuels. PMID- 21661827 TI - News Briefs: Renewable energies cannot be expected to help the United States meet its greenhouse gas reductions within the next decade. PMID- 21661829 TI - News Briefs: Microevolutionary changes may be just as important as ecological shifts when assessing species' reactions to global warming. PMID- 21661830 TI - News Briefs: Developing countries are taking surprisingly bold steps to reduce greenhouse gas emissions. PMID- 21661831 TI - EPA Watch: HPV chemical testing program launched. PMID- 21661832 TI - Discussion: UNEP Helmsman Topfer Addresses Environmental Challenges. AB - The Director General is improving organizational efficiency and marshaling resources to achieve program goals. PMID- 21661833 TI - Commentary: ...and French President Voices Support for UNEP. AB - Sovereignty disputes that limit achievement of environmental goals may be settled if the organization's powers are strengthened. PMID- 21661834 TI - Building smart-growth communities. AB - City planners are combining traditional and contemporary design principles to preserve open spaces and reduce environmental impacts. PMID- 21661836 TI - Technology Update: Novel freezer cuts energy demand. PMID- 21661839 TI - Research Watch: Radionuclide mobility. PMID- 21661852 TI - Research Watch: Hydrophobic pollutant partitioning. PMID- 21661848 TI - Research Watch: Effluent testing. PMID- 21661854 TI - Online/In print: online/in print. PMID- 21661856 TI - 1999 advisory board: 1999 advisory board. PMID- 21661857 TI - Other/miscellaneous. PMID- 21661860 TI - Other/miscellaneous. PMID- 21661862 TI - Other/miscellaneous. PMID- 21661863 TI - Genetically modified crops under fire in EU and U.S. PMID- 21661865 TI - NSF exploring ways to increase its role in environmental research and encourage multidisciplinary science. PMID- 21661864 TI - Researchers question statistical power of PCB cancer study. PMID- 21661866 TI - Arsenic standard for drinking water too high, NRC says. PMID- 21661867 TI - Can farming changes help shrink the dead zone in the Gulf? PMID- 21661868 TI - Guidelines would allow companies to substantiate green claims. PMID- 21661869 TI - Livability agenda may be unable to encourage smart growth. PMID- 21661870 TI - News Briefs: a review by the Physicians Committee for Responsible Medicine finds that sufficient data already exist for performing basic hazard assessments for most of the 2800 HPV substances. PMID- 21661871 TI - News Briefs: To maintain adequate supplies of fresh water. PMID- 21661872 TI - News Briefs: Genuine incentives for reducing greenhouse gas emissions. PMID- 21661873 TI - News Briefs: People in the news. PMID- 21661874 TI - News Briefs: Although the greenest 1999 car is electric. PMID- 21661875 TI - News Briefs: Another major oil spill lurks just around the corner in Alaska. PMID- 21661876 TI - News Briefs: Suburban sprawl in the Atlanta metropolitan area is widening the gap between the region's wealthy and poor. PMID- 21661877 TI - News Briefs: Abnormaltooth development may be an indicator for low-level dioxin exposure. PMID- 21661878 TI - EPA Watch: Petitioners request improved focus on "inerts". PMID- 21661879 TI - EPA Watch: Proposal relaxes dumping rules for lead paint debris. PMID- 21661880 TI - EPA Watch: Feds launch civil rights investigation in NYC. PMID- 21661881 TI - EPA Watch: Corps, EPA agree on sediment quality criteria. PMID- 21661882 TI - Interview: A Formula for Germany's Environmental Future. AB - Environment Minister Jurgen Trittin describes his forward-looking environmental policy agenda. PMID- 21661883 TI - Other/miscellaneous. PMID- 21661884 TI - Still searching for environmental justice. AB - Communities want improved environmental conditions, a goal that is bogged down by strong views on poverty, racism, and development. PMID- 21661886 TI - Peer reviewed: using enantiomers to trace pesticide emissions. AB - This novel approach provides clues to sources of pesticides found in the atmosphere. PMID- 21661887 TI - Airport pollution prevention takes off. AB - Airports and airlines are under increasing pressure to prevent chemical runoff from polluting local waters. PMID- 21661888 TI - Technology Update: Building a better fire boom by adding water. PMID- 21661898 TI - Research Watch: Historic lead deposits. PMID- 21661899 TI - Buyer's Guide: Buyer's Guide. PMID- 21661900 TI - Online/In print: online/in print. PMID- 21661903 TI - Other/miscellaneous. PMID- 21661905 TI - Other/miscellaneous. PMID- 21661906 TI - Constructing a solution to a mercurial problem. PMID- 21661908 TI - Accelerating perchlorate detection. PMID- 21661907 TI - Analyzing toxicants on a chip. PMID- 21661909 TI - Social scientist wins Stockholm Water Prize. PMID- 21661910 TI - U.S. report strengthens scientists' call for a critical load approach to controlling acid rain. PMID- 21661911 TI - No new industry requirements under U.K.'s endocrine disrupter plan. PMID- 21661913 TI - In India, the next 10-15 years offer an "unparalleled opportunity" to shift to cleaner and more resource-efficient technologies. PMID- 21661912 TI - Conservation is key to preventing water exports from the Great Lakes, IJC concludes. PMID- 21661914 TI - News Briefs: The 25 most environmentally threatened areas of the world are home to roughly 20% of the world's population. PMID- 21661916 TI - News briefs: bias. PMID- 21661915 TI - News Briefs: Up to 80% of the emissions of smog-causing nitrogen oxides. PMID- 21661917 TI - News Briefs: Reducing pollution from older automobiles is becoming a major challenge in developing nations. PMID- 21661918 TI - News Briefs: The $27 billion worldwide market for environmental consulting services will grow 8 percent over the next three years. PMID- 21661919 TI - News Briefs: Industrial hog farms reduce the health and quality of life of their neighbors. PMID- 21661920 TI - Technology Solutions: Science behind controversial particulate studies vindicated. PMID- 21661921 TI - EPA Watch: Rural water systems to monitor for Cryptosporidium. PMID- 21661922 TI - EPA Watch: Widespread cheating triggers Clean Air Act enforcement initiative. PMID- 21661923 TI - The expanding use of forensics in environmental science. AB - Advances in the scientific investigation of environmental crimes are defining the emerging discipline of environmental forensics. PMID- 21661924 TI - Feature: Large reductions in toxic wastes and emissions are achievable at many if not most company sites. PMID- 21661925 TI - What direction for u.s. Senate environmental policy? AB - The new chair of the Senate Environment and Public Works Committee is surprising even his supporters with his moderate moves. PMID- 21661927 TI - Scientists debate fertilizing soils with sewage sludge. PMID- 21661928 TI - Online/In print: online/in print. PMID- 21661942 TI - Pcdd. PMID- 21661950 TI - Research Watch: Mercury speciation. PMID- 21661951 TI - Buyer's Guide: Buyer's Guide. PMID- 21661955 TI - Other/miscellaneous. PMID- 21661957 TI - Other/miscellaneous. PMID- 21661959 TI - Our energy future. PMID- 21661960 TI - EU white paper pressures polluters. PMID- 21661961 TI - World's most stringent arsenic standard proposed. PMID- 21661962 TI - The wrong place to perch. PMID- 21661964 TI - News Briefs: The federal government should develop a strategy to combat the nitrogen and phosphorus pollution causing serious damage on all the nation's coasts. PMID- 21661965 TI - News Briefs: The National Water Quality Inventory does not accurately portray water quality conditions nationwide. PMID- 21661963 TI - Citizens outraged over methane mining damages. PMID- 21661966 TI - News Briefs: Cleaning up contamination from nuclear weapons production could cost as much as 44% more than a 1998 estimate. PMID- 21661967 TI - News Briefs: The benefits of recycling are being dwarfed by a rising rate of waste generation. PMID- 21661968 TI - News Briefs: Most of the world's ecosystems are in decline. PMID- 21661969 TI - News Briefs: Companies in six developing nations received awards for their environmental performance. PMID- 21661970 TI - News Briefs: Freshwater species are disappearing as fast as rainforest species. PMID- 21661971 TI - Technology Solutions: An array of possibilities for evaluating environmental health. PMID- 21661972 TI - Government Watch: Federal court finds some carcinogens safe at low doses. PMID- 21661973 TI - Government Watch: New model reveals 50% funding shortfall for state water quality programs. PMID- 21661974 TI - Government Watch: Farmers say EPA should play no role in land-use decisions. PMID- 21661975 TI - Trading in hazardous waste. AB - Whether a gain for the environment or an impediment to international trade, the Basel Convention attempts to legislate global environmental accountability. PMID- 21661976 TI - The wind at the end of the tunnel. AB - Although the world's growing appetite for wind energy is largely being fueled by European technology, a crucial wind tunnel test being conducted in the United States will benefit turbine developers everywhere. PMID- 21661983 TI - Research Watch: Chinese scientists evaluate mercury emissions. PMID- 21661977 TI - Online/In print: online/in print. PMID- 21661992 TI - Other/miscellaneous. PMID- 21661993 TI - The universal language. PMID- 21661994 TI - Phosphate: How low can it go? PMID- 21661995 TI - Government Watch: Combustion emissions. PMID- 21661996 TI - Government watch: science at u.s. EPA. PMID- 21661997 TI - Scotchgard ban highlights unknowns. PMID- 21661998 TI - LC/MS tool to help military characterize fluorinated surfactants. PMID- 21661999 TI - Government Watch: Recycling computers. PMID- 21662000 TI - NRC urges pesticide alternatives. PMID- 21662001 TI - Surprising human health-perchlorate link. PMID- 21662002 TI - Government Watch: Cleaner waters? PMID- 21662003 TI - Arsenic in old herbicides comes back to haunt Denver. PMID- 21662004 TI - Obituary: remembering alvin alm. PMID- 21662006 TI - Peer reviewed: managing the health impacts of waste incineration. AB - The current framework used to assess incinerator health effects considers local populations, but often excludes workers and regional populations. PMID- 21662005 TI - Technology Solutions: Integrated technology targets mercury emissions. PMID- 21662008 TI - Research Watch: Haze in southeast Asia. PMID- 21662007 TI - Promoting a greener European union. AB - Europe's largest environmental organization is hard at work ensuring that the European Union keeps a high profile on environmental issues. PMID- 21662009 TI - Research Watch: Multimicrobial sensor. PMID- 21662010 TI - Research Watch: Tropospheric ozone. PMID- 21662011 TI - Research Watch: Cleaner paper pulp production. PMID- 21662012 TI - Research Watch: Rice field emissions. PMID- 21662013 TI - Research watch: bacteria transport. PMID- 21662014 TI - Research Watch: Heat and moisture. PMID- 21662015 TI - Research Watch: Atmospheric oxygen. PMID- 21662016 TI - Research Watch: Germany's water. PMID- 21662017 TI - Research Watch: Methane air-sea exchange. PMID- 21662018 TI - Research Watch: Minimizing DBPs. PMID- 21662019 TI - Research Watch: Redfield ratio. PMID- 21662021 TI - Research Watch: Pesticide contamination. PMID- 21662020 TI - Research Watch: Nonylphenol in trout. PMID- 21662023 TI - Research Watch: Aircraft cabins. PMID- 21662022 TI - Research Watch: Swine emissions faulted. PMID- 21662024 TI - Research Watch: TCDD remediation. PMID- 21662025 TI - Research Watch: Predicting aerosol response. PMID- 21662026 TI - Research Watch: Uranium accident. PMID- 21662028 TI - Online/In print: online/in print. PMID- 21662027 TI - Research Watch: Electrokinetic remediation. PMID- 21662030 TI - Buyer's Guide: Buyer's Guide. PMID- 21662033 TI - Other/miscellaneous. PMID- 21662035 TI - Other/miscellaneous. PMID- 21662037 TI - Connecting the dots. PMID- 21662038 TI - PCBs may mar results of in utero mercury testing. PMID- 21662039 TI - Government Watch: POPs worldwide. PMID- 21662040 TI - Government Watch: A boost for developing nations. PMID- 21662041 TI - Furniture plant reduces emissions, showcases innovations. PMID- 21662042 TI - McDonough to redesign Ford's industrial complex. PMID- 21662044 TI - Government Watch: Industrial waste in fertilizers. PMID- 21662043 TI - Gasoline additive gets physical to attack pollution. PMID- 21662045 TI - Action on Gulf hypoxic zone moves ahead. PMID- 21662046 TI - A new route for endocrine disruptors. PMID- 21662048 TI - Government Watch: EU harmonizes emissions monitoring. PMID- 21662047 TI - Drought curbs this year's dead zone. PMID- 21662049 TI - Chemical Exposure: Chemicals linked to development defects. PMID- 21662050 TI - News Briefs: Pollution prevention plans and best management practices have cost effectively reduced storm water pollution. PMID- 21662051 TI - News Briefs: A series of new OECD biotechnology reports summarize national and international efforts to address growing public concerns over the environmental and public health impacts of genetically modified (GM) foods. PMID- 21662052 TI - News Briefs: Expanding temperate and boreal forests in 55 countries absorb about as much carbon every year as is released by tropical deforestation. PMID- 21662053 TI - News Briefs: By 2050, the human population is projected to grow from today's 6 billion to between 8 and 11 billion. PMID- 21662054 TI - News Briefs: A report synthesizing the state-of-the-art knowledge on the control of health hazards from arsenic in drinking water. PMID- 21662055 TI - News Briefs: The cost of bringing East European industrial facilities in line with environmental standards in the European Union (EU) will be much lower than anticipated. PMID- 21662057 TI - Research Watch: The death of Milankovitch? PMID- 21662056 TI - News Briefs: By 2010, the $29.9 billion market for environmental technologies and services that assist in reducing greenhouse gas emissions could more than double to between $52 and $65 billion. PMID- 21662058 TI - Research Watch: Will ocean storage of CO2 get a lift? PMID- 21662059 TI - Research Watch: Concept and principle of proposed symptom. PMID- 21662061 TI - Research Watch: Recycling's dark side. PMID- 21662060 TI - Research Watch: Fuel cell breakthrough. PMID- 21662062 TI - Research Watch: A better bug beater. PMID- 21662064 TI - Engineering maintainable development. AB - Should environmental scientists intentionally interfere in major biogeochemical cycles? Brad Allenby says "yes." PMID- 21662063 TI - Technology Solutions: Nuclear transmutation attracts opposition. PMID- 21662065 TI - Sewage sludge, pros & cons. AB - The United States and the European nations are far apart on their views of what constitutes safe management. PMID- 21662066 TI - Online/In print: online/in print. PMID- 21662070 TI - Other/miscellaneous. PMID- 21662072 TI - Other/miscellaneous. PMID- 21662074 TI - The price of energy. PMID- 21662076 TI - Government Watch: Climate change switch. PMID- 21662075 TI - A river of air pollution. PMID- 21662077 TI - Government Watch: Diesel takes a hit. PMID- 21662078 TI - Homing in on the missing sink. PMID- 21662079 TI - Government Watch: Regional climate change. PMID- 21662080 TI - A doubling of renewable electricity could brighten the European Union. PMID- 21662081 TI - Green Chemistry Awards: Engineered enzymes catalyze a new field. PMID- 21662083 TI - Deadly E. Coli outbreak focuses Canadian privatization debate. PMID- 21662082 TI - Government Watch: Neem partially redeemed. PMID- 21662084 TI - News Briefs: Texas is the U.S. state with the weakest environmental regulation of its large-scale livestock farming industry. PMID- 21662085 TI - News Briefs: Some people may be genetically susceptible to particulate air pollution. PMID- 21662086 TI - News Briefs: The U.S. EPA's actions to improve the environment are difficult to assess. PMID- 21662087 TI - News Briefs: Market-based approaches can achieve greater water quality improvements at a much lower cost than traditional regulatory approaches. PMID- 21662088 TI - News Briefs: More than 95% of freshwater bathing areas in Europe met minimum water quality requirements in 1999, up from33% in 1996. PMID- 21662089 TI - News Briefs: By 2030, a new U.S. federal washing machine standard could save 4 5.5 quadrillion BTUs of energy and about 6 trillion gallons of water. PMID- 21662090 TI - News Briefs: Results from the primary model used to support the U.S. government's regulatory decisions to control vehicle emissions are unrealistic. PMID- 21662091 TI - News Briefs: Pesticide production, use, and exports are on the rise in China. PMID- 21662093 TI - Correction: correction. PMID- 21662092 TI - Technology Solutions: Cleaning up with heat treatment. PMID- 21662094 TI - Global freshwater scarcity: is privatization a solution? AB - Declining world water supplies may hinge more on improper water management than too little water. PMID- 21662095 TI - Peer reviewed: evaluating natural attenuation for groundwater cleanup. AB - The National Research Council has issued the first comprehensive assessment of when natural attenuation works. PMID- 21662096 TI - Research Watch: Novel cleanup of explosives. PMID- 21662103 TI - Research Watch: ships that pollute. PMID- 21662120 TI - Buyer's Guide: Buyer's Guide. PMID- 21662107 TI - Online/In print: online/in print. PMID- 21662124 TI - Other/miscellaneous. PMID- 21662125 TI - Other/miscellaneous. PMID- 21662127 TI - New directions in technology. PMID- 21662128 TI - Letters: In defense of ecorisk assessment. PMID- 21662130 TI - Letters: Authors' response. PMID- 21662129 TI - Letters: In defense of ecorisk assessment. PMID- 21662131 TI - Correction: correction. PMID- 21662132 TI - Technology Updates: Bioreactor reduces landfill volume. PMID- 21662133 TI - Technology Update: Bacteria spore removes dissolved metals. PMID- 21662135 TI - EPA Watch: Agency-wide plan to reduce mercury releases. PMID- 21662134 TI - Technology Updates: Waste acid recycling demonstrated in Japan. PMID- 21662136 TI - EPA WATCH: Reassessment of automotive emmission standards due. PMID- 21662137 TI - EPA WATCH: Lawsuit stalls internet toxic release database. PMID- 21662138 TI - EPA WATCH: More Great Lakes toxics target for reduction. PMID- 21662139 TI - EPA WATCH: Stormwater permits proposed for smaller municipalities. PMID- 21662140 TI - EPA WATCH: Unpublished health effects data sought for IRIS. PMID- 21662143 TI - Environmental News: Coalition pushes environmental industry's needs. PMID- 21662142 TI - Environmental News: Environmental industry at a critical juncture , studies say. PMID- 21662144 TI - Environmental News: Kyoto Protocol carbon targets could be met with forest credits. PMID- 21662145 TI - Environmental News: Regulatory reform report concludes there is no silver bullet. PMID- 21662146 TI - Environmental News: SAB project pubshes integrated approach to risk-based decisions. PMID- 21662147 TI - Environmental News: Chemical industry evaluates toxicity screening costs. PMID- 21662148 TI - Environmental News: British regulatory agency calls for action to reduce use of edocrine-disrupting chemical. PMID- 21662149 TI - Environmental News: Federal court ruling puts protection of isolated wetlands at risk. PMID- 21662150 TI - Environmental news: news briefs. PMID- 21662151 TI - Feature: the challenge of predicting nonpoint source pollution. PMID- 21662152 TI - Feature: dermal exposure: the missing link. PMID- 21662154 TI - Environmental policy analysis: evaluating toxic impact assessment methods: what works best. AB - EDGAR G. HERTWICH Energy and Resources Group University of California Berkeley, CA 94720-3050 WILLIAM S. PEASE Environmental Defense Fund Oakland, CA 95616 THOMAS E. MCKONE Environmental Health Science University of California Berkeley, CA 94720-7360. PMID- 21662170 TI - Research Watch: Measuring trace metals in soils. PMID- 21662160 TI - Research Watch: Soil organic matter controls sorption. PMID- 21662172 TI - Online/in Print: Online/in Print. PMID- 21662174 TI - Buyer's Guide: Buyer's Guide. PMID- 21662179 TI - Other/miscellaneous. PMID- 21662180 TI - Other/miscellaneous. PMID- 21662182 TI - Too little data, too many models. PMID- 21662183 TI - Drinking water proposal eases some health goals. PMID- 21662184 TI - NRC advises long-term particulate matter research plan needed. PMID- 21662185 TI - Perchlorate-tainted wells spur government action. PMID- 21662186 TI - GIS software aids environmental justice, emergency planning. PMID- 21662187 TI - Air toxics report rejects utility mercury controls. PMID- 21662188 TI - Right-to-Know: UN "public access" treaty to be signed in June. PMID- 21662189 TI - Advisory panel completes work on TMDL watershed guidelines. PMID- 21662190 TI - News Briefs: To protect farmland and limit suburban sprawl development. PMID- 21662191 TI - News Briefs: Manufacturers sent more than 22.5 million pounds of chemical waste directly to 381 facilities that "appear to be farms". PMID- 21662192 TI - News Briefs: Environmental and social regulations cost taxpayers $240 billion in 1997. PMID- 21662193 TI - News Briefs: People in the news. PMID- 21662194 TI - News Briefs: Soil fumigants in groundwater. PMID- 21662195 TI - News Briefs: Half of the top 12 greenest vehicles are electric. PMID- 21662196 TI - News Briefs: Innovative environmental technologies face significantly higher barriers to acceptance by industry. PMID- 21662197 TI - News Briefs: Indoor radon exposure contributes to about 12% of lung cancer deaths. PMID- 21662198 TI - News Briefs: Estuaries, marshes, and other wetlands generate three-quarters of the nation's fish production. PMID- 21662200 TI - EPA Watch: Guidance should increase peer review of agency work. PMID- 21662201 TI - Technology Update: EPA technology verification program hits its stride. PMID- 21662202 TI - The emergence of treatment wetlands. AB - As constructed wetlands for wastewater treatment grow in popularity, regulators and researchers strive to better understand this treatment option. PMID- 21662220 TI - Research Watch: Anaerobic benzene oxidation. PMID- 21662209 TI - Research Watch: Bioavailability of heavy metals. PMID- 21662230 TI - Online/In print: online/in print. PMID- 21662232 TI - Buyer's Guide: Buyer's Guide. PMID- 21662235 TI - Addition of porphyrins to cigarette filters to reduce the levels of benzo[a]pyrene (B[a]P) and tobacco-specific N-nitrosamines (TSNAs) in mainstream cigarette smoke. AB - Tobacco-specific N-nitrosamines (TSNAs) and benzo[a]pyrene (B[a]P) in mainstream cigarette smoke (MSS) cause smoking-related diseases and environmental pollution. Porphyrins were added to cigarette filters to reduce B[a]P (porphyrins A-E) and TSNAs (porphyrin F) in MSS. The porphyrin-B[a]P and porphyrin F-TSNAs (N' nitrosoanabasine (NAB), N'-nitrosoanatabine (NAT), 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK), and N-nitrosonornicotine (NNN)) interactions were investigated by fluorescence quenching and UV-visible spectroscopy. The correlation coefficients were 0.987-0.997 (B[a]P) and 0.994-0.999 (TSNAs), and the binding constants were (1.67-5.02) * 10(5) (B[a]P) and 3.42 * 10(3)-1.40 * 10(4) (TSNAs). Up to 36.72% of B[a]P and 46.67% of the TSNAs were eliminated from MSS, with greater reductions when more porphyrin was included in the filter. With the same mass of porphyrin in the filter, the reduction trend for B[a]P by porphyrins A-E was A > B > C > D > E. The reduction trend for TSNAs by porphyrin F was NNN > NAB > NNK > NAT. The porphyrin mode of action is possibly through strong pi-pi interactions. PMID- 21662236 TI - Methodology for imaging nano-to-microscale water condensation dynamics on complex nanostructures. AB - A better understanding of the role that nanoscale surface chemical heterogeneities and topographical features play in water droplet formation is necessary to improve design and robustness of nanostructured superhydrophobic surfaces as to make them fit for industrial applications. Lack of an imaging method capable of capturing the water condensation process on complex nanostructures with required magnification has thus far hindered experimental progress in this area. In this work, we demonstrate that by transferring a small part of a macroscale sample to a novel thermally insulated sample platform we are able to mitigate flooding and electron heating problems typically associated with environmental scanning electron microscopy of water condensation. We image condensation dynamics on individual complex particles and a superhydrophobic network of nanostructures fabricated from low thermal conductivity materials with an unobstructed 90 degrees perspective of the surface-to-water interface with field of view as small as 1 MUm(2). We clearly observe the three-stage drop growth process and demonstrate that even during late stages of the droplet growth the nearly spherical drop remains in a partially wetting Wenzel state. PMID- 21662237 TI - Capillary extraction. AB - A nonwetting slug placed at the end of a capillary tube is unstable: a small displacement results in the complete extraction of the liquid from the tube. We study two limiting cases, corresponding to a slug viscosity larger or smaller than that of the surrounding liquid. By varying parameters such as the drop and tube length, we identify in each case the dominant dissipation and describe experimentally and theoretically the dynamics of extraction. PMID- 21662238 TI - A rapid sample screening method for authenticity control of whiskey using capillary electrophoresis with online preconcentration. AB - The present study aimed to develop a methodology using capillary electrophoresis for the determination of sinapaldehyde, syringaldehyde, coniferaldehyde, and vanillin in whiskey samples. The main objective was to obtain a screening method to differentiate authentic samples from seized samples suspected of being false using the phenolic aldehydes as chemical markers. The optimized background electrolyte was composed of 20 mmol L(-1) sodium tetraborate with 10% MeOH at pH 9.3. The study examined two kinds of sample stacking, using a long-end injection mode: normal sample stacking (NSM) and sample stacking with matrix removal (SWMR). In SWMR, the optimized injection time of the samples was 42 s (SWMR42); at this time, no matrix effects were observed. Values of r were >0.99 for the both methods. The LOD and LOQ were better than 100 and 330 mg mL(-1) for NSM and better than 22 and 73 mg L(-1) for SWMR. The CE-UV reliability in the aldehyde analysis in the real sample was compared statistically with LC-MS/MS methodology, and no significant differences were found, with a 95% confidence interval between the methodologies. PMID- 21662239 TI - Phenolic constituents and antioxidant capacity of four underutilized fruits from the Amazon region. AB - The Amazon region comprises a plethora of fruit-bearing species of which a large number are still agriculturally unimportant. Because fruit consumption has been attributed to an enhanced physical well-being, interest in the knowledge of the chemical composition of underexplored exotic fruits has increased during recent years. This paper provides a comprehensive identification of the polyphenolic constituents of four underutilized fruits from the Amazon region by HPLC/DAD-ESI MS(n). Araca ( Psidium guineense ), jambolao ( Syzygium cumini ), muruci ( Byrsonima crassifolia ), and cutite ( Pouteria macrophylla ) turned out to be primarily good sources of hydrolyzable tannins and/or flavonols. Additionally, different flavanonols and proanthocyanidins were identified in some fruits. The antioxidant capacity was determined by using the total oxidant scavenging capacity (TOSC) assay. Cutite showed the highest antioxidant capacity followed by jambolao, araca, and muruci. PMID- 21662241 TI - Characterization of geosmin as source of earthy odor in different aroma type Chinese liquors. AB - Earthy odor is one of the most frequent and serious causes for the aroma deterioration in Chinese liquor, which causes a dirty and dusty impression. The odor in Chinese liquor is similar to that of rice husk, one kind of auxiliary material widely used as a filler in the distillation process. So it is experientially hypothesized that such odor may derive from rice husk. In this paper, the gas chromatography-olfactometry (GC-O) technique and gas chromatography-mass spectrometry (GC-MS) were used to discover and identify the characteristic odoriferous zone of Chinese liquor marked by earthy odor. Geosmin was found to be responsible for this odor. The levels of the compound in ten bottled liquors and thirty liquors aging for different years belonging to four different aroma types were determined by the optimized headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) method. Quantitative analysis of bottled liquor revealed the presence of geosmin in all aroma type liquors with concentrations ranging from 1.10 MUg/L to 9.90 MUg/L, except for strong-aroma type liquor. Meanwhile in the aged liquors belonging to the same aroma type, geosmin was detected with significant concentrations and high odor activity values (OAVs) during different years of aging. However, geosmin was not detected in steamed rice husk nor in nonsteamed rice husk, which suggests that rice husk is not the origin of earthy odor in Chinese liquor, and there may be another origin of it during the brewing process. PMID- 21662242 TI - PocketAlign a novel algorithm for aligning binding sites in protein structures. AB - A fundamental task in bioinformatics involves a transfer of knowledge from one protein molecule onto another by way of recognizing similarities. Such similarities are obtained at different levels, that of sequence, whole fold, or important substructures. Comparison of binding sites is important to understand functional similarities among the proteins and also to understand drug cross reactivities. Current methods in literature have their own merits and demerits, warranting exploration of newer concepts and algorithms, especially for large scale comparisons and for obtaining accurate residue-wise mappings. Here, we report the development of a new algorithm, PocketAlign, for obtaining structural superpositions of binding sites. The software is available as a web-service at http://proline.physics.iisc.ernet.in/pocketalign/. The algorithm encodes shape descriptors in the form of geometric perspectives, supplemented by chemical group classification. The shape descriptor considers several perspectives with each residue as the focus and captures relative distribution of residues around it in a given site. Residue-wise pairings are computed by comparing the set of perspectives of the first site with that of the second, followed by a greedy approach that incrementally combines residue pairings into a mapping. The mappings in different frames are then evaluated by different metrics encoding the extent of alignment of individual geometric perspectives. Different initial seed alignments are computed, each subsequently extended by detecting consequential atomic alignments in a three-dimensional grid, and the best 500 stored in a database. Alignments are then ranked, and the top scoring alignments reported, which are then streamed into Pymol for visualization and analyses. The method is validated for accuracy and sensitivity and benchmarked against existing methods. An advantage of PocketAlign, as compared to some of the existing tools available for binding site comparison in literature, is that it explores different schemes for identifying an alignment thus has a better potential to capture similarities in ligand recognition abilities. PocketAlign, by finding a detailed alignment of a pair of sites, provides insights as to why two sites are similar and which set of residues and atoms contribute to the similarity. PMID- 21662240 TI - A ligation-triggered DNAzyme cascade for amplified fluorescence detection of biological small molecules with zero-background signal. AB - Many types of fluorescent sensing systems have been reported for biological small molecules. Particularly, several methods have been developed for the recognition of ATP or NAD(+), but they only show moderate sensitivity, and they cannot discriminate either ATP or NAD(+) from their respective analogues. We have addressed these limitations and report here a dual strategy which combines split DNAzyme-based background reduction with catalytic and molecular beacon (CAMB) based amplified detection to develop a ligation-triggered DNAzyme cascade, resulting in ultrahigh sensitivity. First, the 8-17 DNAzyme is split into two separate oligonucleotide fragments as the building blocks for the DNA ligation reaction, thereby providing a zero-background signal to improve overall sensitivity. Next, a CAMB strategy is further employed for amplified signal detection achieved through cycling and regenerating the DNAzyme to realize the true enzymatic multiple turnover (one enzyme catalyzes the cleavage of several substrates) of catalytic beacons. This combination of zero-background signal and signal amplification significantly improves the sensitivity of the sensing systems, resulting in detection limits of 100 and 50 pM for ATP and NAD(+), respectively, much lower than those of previously reported biosensors. Moreover, by taking advantage of the highly specific biomolecule-dependence of the DNA ligation reaction, the developed DNAzyme cascades show significantly high selectivity toward the target cofactor (ATP or NAD(+)), and the target biological small molecule can be distinguished from its analogues. Therefore, as a new and universal platform for the design of DNA ligation reaction-based sensing systems, this novel ligation-triggered DNAzyme cascade method may find a broad spectrum of applications in both environmental and biomedical fields. PMID- 21662244 TI - Role of block junctions in the interplay of phase transitions of two-component polymeric systems. AB - Block junctions are the topological constraints of connecting two homopolymers of different species to form diblock copolymers, which make the phase transition behaviors of diblock copolymers deviate from that of parallel polymer blends. We performed dynamic Monte Carlo simulations of these two parallel polymeric systems to compare their behaviors in the interplay of phase transitions. The results showed the lowered melting point of one component in symmetric diblock copolymers, as well as their enhanced critical segregation strength for demixing prior to crystallization. Furthermore, prior microphase separation in symmetric diblock copolymers produces a template for parallel stacking of lamellar crystals, which is of practical importance in the barrier properties of polymeric materials. Our observations may facilitate a better understanding to the phase transition behaviors of copolymer systems. PMID- 21662243 TI - Protein adsorption on poly(N-isopropylacrylamide) brushes: dependence on grafting density and chain collapse. AB - The protein resistance of poly(N-isopropylacrylamide) brushes grafted from silicon wafers was investigated as a function of the chain molecular weight, grafting density, and temperature. Above the lower critical solution temperature (LCST) of 32 degrees C, the collapse of the water-swollen chains, determined by ellipsometry, depends on the grafting density and molecular weight. Ellipsometry, radio assay, and fluorescence imaging demonstrated that, below the lower critical solution temperature, the brushes repel protein as effectively as oligoethylene oxide-terminated monolayers. Above 32 degrees C, very low levels of protein adsorb on densely grafted brushes, and the amounts of adsorbed protein increase with decreasing brush-grafting-densities. Brushes that do not exhibit a collapse transition also bind protein, even though the chains remain extended above the LCST. These findings suggest possible mechanisms underlying protein interactions with end-grafted poly(N-isopropyl acrylamide) brushes. PMID- 21662245 TI - A neutral, monomeric germanium(I) radical. AB - Stoichiometric reduction of the bulky beta-diketiminato germanium(II) chloride complex [((But)Nacnac)GeCl] ((But)Nacnac = [{N(Dip)C(Bu(t))}(2)CH](-), Dip = C(6)H(3)Pr(i)(2)-2,6) with either sodium naphthalenide or the magnesium(I) dimer [{((Mes)Nacnac)Mg}(2)] ((Mes)Nacnac = [(MesNCMe)(2)CH](-), Mes = mesityl) afforded the radical complex [((But)Nacnac)Ge:](*) in moderate yields. X-ray crystallographic, EPR/ENDOR spectroscopic, computational, and reactivity studies revealed this to be the first authenticated monomeric, neutral germanium(I) radical. PMID- 21662246 TI - Aromatic-aromatic interactions in proteins: beyond the dimer. AB - Aromatic residues are key widespread elements of protein structures and have been shown to be important for structure stability, folding, protein-protein recognition, and ligand binding. The interactions of pairs of aromatic residues (aromatic dimers) have been extensively studied in protein structures. Isolated aromatic molecules tend to form higher order clusters, like trimers, tetramers, and pentamers, that adopt particular well-defined structures. Taking this into account, we have surveyed protein structures deposited in the Protein Data Bank in order to find clusters of aromatic residues in proteins larger than dimers and characterized them. Our results show that larger clusters are found in one of every two unique proteins crystallized so far, that the clusters are built adopting the same trimer motifs found for benzene clusters in vacuum, and that they are clearly nonlocal brining primary structure distant sites together. We extensively analyze the trimers and tetramers conformations and found two main cluster types: a symmetric cluster and an extended ladder. Finally, using calmodulin as a test case, we show aromatic clsuters possible role in folding and protein-protein interactions. All together, our study highlights the relevance of aromatic clusters beyond the dimer in protein function, stability, and ligand recognition. PMID- 21662248 TI - Other/miscellaneous. PMID- 21662250 TI - Other/miscellaneous. PMID- 21662251 TI - Letters: Natural attenuation short-shrifted? PMID- 21662253 TI - Sustainability engineering and green chemistry. PMID- 21662252 TI - Letters: Green building technology. PMID- 21662254 TI - Zebrafish assay detects endocrine disruptors. PMID- 21662255 TI - Controversial EU phthalate ban here to stay? PMID- 21662256 TI - Government Watch: International vehicle standards. PMID- 21662257 TI - Human phthalate study changes exposure picture. PMID- 21662258 TI - Increasing levels of flame retardants found in North American environment. PMID- 21662259 TI - Government Watch: Cross-border pollution talks heat up. PMID- 21662260 TI - Forest fires pollute western air. PMID- 21662261 TI - Endangered species could threaten fire plan. PMID- 21662262 TI - Cropland net emitter of greenhouse gases. PMID- 21662263 TI - Government Watch: Full disclosure on bottled water? PMID- 21662264 TI - Disconnect between Kyoto Protocol and clean energy? PMID- 21662265 TI - Government Watch: China toughens air pollution laws. PMID- 21662267 TI - News Briefs: Further delay in the regulation of mercury emissions from power plants cannot be justified on the basis of concerns over technology availability. PMID- 21662266 TI - EU sustainable development rules. PMID- 21662268 TI - News Briefs: Companies that adopt strict global environment standards abroad are rewarded with better stock market performance. PMID- 21662269 TI - News Briefs: Erosion will consume one quarter of all homes within 500 feet of America's oceans and Great Lakes shorelines over the next 60 years. PMID- 21662270 TI - News Briefs: More than 80% of the mercury found in domestic wastewater may come from particles loosened from dental amalgam fillings. PMID- 21662271 TI - News Briefs: Respect for ecological diversity implies respect for human diversity. PMID- 21662273 TI - News Briefs: Improving the fuel economy of new vehicles would reduce the annual fuel consumption and greenhouse gas emissions of cars and light trucks between 6 and 37% over a 15- to 18-year period. PMID- 21662272 TI - News Briefs: More stringent standards are needed to protect Canada's children from the toxic chemicals in their air, water, and food. PMID- 21662275 TI - Research Watch: Unlocking the secrets of freeze-thaw cycles. PMID- 21662274 TI - News Briefs: The number of people living in countries facing severe water shortages will increase more than four-fold over the next 25 years. PMID- 21662277 TI - Research Watch: Mashing malaria mania. PMID- 21662278 TI - Research Watch: Bye-bye birdie? PMID- 21662276 TI - Research Watch: Modeling climate change effects. PMID- 21662279 TI - Technology Solutions: The genetics behind environmental stress. PMID- 21662280 TI - Peer reviewed: making watershed management work. AB - New York City's watershed management strategy is unprecedented in its scope, scale, and cost. PMID- 21662281 TI - GMO testing hurdles. AB - Detecting the presence of genetically modified food may be more challenging than legislators expect. PMID- 21662283 TI - Online/In print: online/in print. PMID- 21662284 TI - Buyer's Guide: Buyer's Guide. PMID- 21662291 TI - Other/miscellaneous. PMID- 21662289 TI - Other/miscellaneous. PMID- 21662293 TI - Environmental education. PMID- 21662294 TI - Letters: More concerns about incineration. PMID- 21662295 TI - Letters: Authors' response. PMID- 21662296 TI - Letters: About hazardous waste incineration. PMID- 21662298 TI - Government Watch: 16 air regs in one. PMID- 21662297 TI - Science panel confirms low-dose estrogenic effects. PMID- 21662299 TI - Energy-gobbling water heaters soon passe? PMID- 21662301 TI - Environmental concerns linked to railroad creosote. PMID- 21662300 TI - Government Watch: French carbon tax. PMID- 21662302 TI - States get tough with nonpoint pollution. PMID- 21662303 TI - Government Watch: Rethinking environmental indicators. PMID- 21662304 TI - Fill 'er up with sun power. PMID- 21662305 TI - Stamping out dioxin in food? PMID- 21662306 TI - Government Watch: A nod to the protestors. PMID- 21662307 TI - Green chemistry gets a hood and gown. PMID- 21662309 TI - News Briefs: Soil dust swept off the African deserts and deposited in the Caribbean may be the cause of coral reef death and decline. PMID- 21662308 TI - News Briefs: American and British researchers hope to use the untapped power of thousands of desktop computers worldwide to create a more accurate model of global climate change in the coming century. PMID- 21662310 TI - News Briefs: More than 15% of the projects funded by EPA's Science To Achieve Results (STAR) program covered research that was not expected to be used. PMID- 21662311 TI - News Briefs: Despite the absense of federal standards, EPA has taken no action to protect children from pesticide exposures in schools. PMID- 21662312 TI - News Briefs: Dramatic increases in logging in remote tropical regions of Africa have made it possible for local disease outbreaks to spread worldwide. PMID- 21662313 TI - News Briefs: Sustainable development has created 14 million jobs. PMID- 21662314 TI - News Briefs: For the second year in a row, the Honda Insight was ranked as the most fuel-efficient car. PMID- 21662315 TI - News Briefs: One in every four mammals and one in every eight birds are at risk of extinction. PMID- 21662316 TI - Technology Solutions: Hovering over the past. PMID- 21662317 TI - Peer reviewed: understanding microcontaminants in recycled water. AB - Increasing attention is being given to the detection, treatment, and removal of problematic effluent-derived contaminants. PMID- 21662319 TI - 2000 index: 2000 a-page index. PMID- 21662318 TI - Peer Reviewed: The Complicated Challenge of MTBE Cleanups. AB - The way in which an MTBE plume responds to altered pumping rates at municipal wells can cause further contamination problems, some unexpected. PMID- 21662322 TI - Other/miscellaneous. PMID- 21662323 TI - Other/miscellaneous. PMID- 21662325 TI - New year, new format, new faces. PMID- 21662326 TI - Mercury health standard eased by U.S. agency. PMID- 21662327 TI - Human estrogens linked to endocrine disruption. PMID- 21662328 TI - Toxic chemical use reporting debated on state and national levels. PMID- 21662329 TI - Researchers find large discrepancy between dioxin deposition and emissions. PMID- 21662330 TI - Remediation: Alm to leave DOE cleanup program. PMID- 21662331 TI - Government officials call for relaxation of methyl bromide ban. PMID- 21662332 TI - Ecological Studies: Ultraviolet radiation linked to frog deformities. PMID- 21662333 TI - Companies signing on to EPA's revamped Project XL program. PMID- 21662334 TI - European News: Environmental progress in Central and Eastern Europe will be a key issue. PMID- 21662335 TI - European News: Opening the European Union's eco-management and auditing scheme (EMAS) to a broader range of industries. PMID- 21662336 TI - European News: A revised set of tougher standards for tropospheric ozone has been crafted. PMID- 21662337 TI - European News: European companies lead the world in ISO 14001 certifications. PMID- 21662338 TI - European News: Environmental technology suppliers have agreed to set up a European trade association. PMID- 21662340 TI - News Briefs: The U.S. Clean Air Act of 1970 has been worth more than $6 trillion. PMID- 21662339 TI - News Briefs: Emissions trading could be the key to reducing climate-warming greenhouse gases. PMID- 21662341 TI - News Briefs: U.S. carbon emissions from energy use will be 45% above 1990 levels by 2020. PMID- 21662342 TI - News Briefs: Acid rain will continue to damage southeastern Canada ecosystems, without further SO2 emissions cuts. PMID- 21662343 TI - News Briefs: Most U.S. states have failed to implement watershed protection provisions of the Clean Water Act. PMID- 21662344 TI - News Briefs: The U.S. public received a failing grade in basic environmental knowledge. PMID- 21662345 TI - News Briefs: The Netherlands, Denmark, and Germany have the most successful greenhouse gas reduction policies. PMID- 21662346 TI - EPA Watch: Metal finishers sign emission reduction pact. PMID- 21662348 TI - EPA Watch: Alternative multimedia monitoring plan floated. PMID- 21662347 TI - EPA Watch: Radioactive waste dump receives green light. PMID- 21662349 TI - EPA Watch: Chemical accident team issues first report. PMID- 21662350 TI - EPA Watch: High-risk drinking water contaminants identified. PMID- 21662351 TI - EPA Watch: TRI interpretive booklets update 1990 guidance. PMID- 21662354 TI - Technology Update: Software tackles sediment remediation. PMID- 21662353 TI - The pros and cons of carbon dioxide dumping. AB - Global warming concerns have stimulated a search for carbon sequestration technologies. PMID- 21662355 TI - Technology Update: Novel reactor destroys nitro-wastes. PMID- 21662356 TI - Technology Update: Getting to the root phytoremediation. PMID- 21662358 TI - What is causing toxic algal blooms? AB - New research is providing clues about possible links between Pfiesteria-like organisms and pollution. PMID- 21662380 TI - Online/In print: online/in print. PMID- 21662381 TI - Buyer's Guide: Buyer's Guide. PMID- 21662383 TI - Advisory board: 1998 advisory board. PMID- 21662386 TI - Adsorption and desorption of phenanthrene on carbon nanotubes in simulated gastrointestinal fluids. AB - Adsorption of phenanthrene on carbon nanotubes (CNTs) and bioaccessibility of adsorbed phenanthrene were studied in simulated gastrointestinal fluids. Adsorption of phenanthrene on CNTs was suppressed in pepsin (800 mg/L) solution (gastric) and bile salt (500 and 5000 mg/L) fluids (intestinal). In addition to competitive sorption, pepsin and high-concentration bile salt (5000 mg/L, above critical micelle concentration) solubilized phenanthrene (3 and 30 times of the water solubility, respectively), thus substantially reduced phenanthrene adsorption on CNTs. Pepsin and bile salts also increased the rapidly desorbing phenanthrene fraction from CNTs. The rapidly desorbing phase lasted less than 1 h for all CNTs. Further, 43-69% of phenanthrene was released from CNTs after desorption in the simulated gastric and intestinal fluid at low bile salt concentration while 53-86% was released in the gastric and intestinal fluid at high bile salt concentration. These findings suggest that the release of residual hydrophobic organic compounds from CNTs could be enhanced by biomolecules such as pepsin and bile salts in the digestive tract, thus increasing the bioaccessibility of adsorbed phenanthrene and possibly the overall toxicity of phenanthrene associated CNTs. PMID- 21662387 TI - Temperature dependence of the reaction between the hydroxyl radical and organic matter. AB - The temperature-dependent bimolecular rate constants for the reaction of the hydroxyl radical (HO(*)) with organic matter (OM) (k(OM-HO(*))) have been measured for three natural organic matter (NOM) isolates and three bulk effluent organic matter (EfOM) samples using electron pulse radiolysis and thiocyanate competition kinetics. The range of values for the room temperature k(OM-HO(*)) was 1.21-9.37 * 10(8) M(C)(-1)s(-1), with NOM isolates generally reacting slower than EfOM samples. The NOM isolates had an average apparent activation energy of 19.8 kJ mol(-1), while the EfOM samples had an average value slightly lower (14.3 kJ mol(-1)), although one NOM isolate (Elliot Soil Humic Acid, 29.9 kJ mol(-1)) was a factor of 2 times greater than other samples studied. These apparent activation energies are the first determined for OM and HO(*), and the Arrhenius plots obtained for NOM isolates (lowest R(2) > 0.993) suggest that no significant structural changes are occurring over the temperature range 8-41 degrees C. In contrast, the greater scatter (lowest R(2) > 0.903) observed for the EfOM samples suggests that some structural changes may be occurring. These results provide a deeper fundamental understanding of the reaction between OM and HO(*) and will be useful in quantifying HO(*) reactions in natural and engineered systems. PMID- 21662389 TI - Other/miscellaneous. PMID- 21662391 TI - Other/miscellaneous. PMID- 21662392 TI - Lessons from the exxon valdez. PMID- 21662393 TI - Letters: Widen areas of coverage in ES&T. PMID- 21662394 TI - Correction: correction. PMID- 21662395 TI - Letters: PCB-Laden sediment cleanup. PMID- 21662397 TI - EPA Watch: Consent decree requires TMDLs for California. PMID- 21662396 TI - EPA Watch: Clinton requests 5.3% drop in FY 2000 budget. PMID- 21662398 TI - EPA Watch: Bond initiative targets urban sprawl. PMID- 21662399 TI - Slow recovery after Exxon Valdez oil spill. PMID- 21662400 TI - Technology gaps exacerbate vulnerability to heavy oil spills. PMID- 21662401 TI - Excess nitrogen may not solve CO2 sink mystery. PMID- 21662403 TI - Environmentalists, water agencies seek stricter controls on ballast water discharges. PMID- 21662402 TI - Global talks to regulate genetically modified plants stall over potential trade impacts. PMID- 21662404 TI - House bills could weaken standards, environmentalists charge. PMID- 21662405 TI - News Briefs: The U.S. government wastes over $51 billion on programs that harm the environment. PMID- 21662406 TI - News Briefs: Uncertainty is no excuse for stalling on climate policy. PMID- 21662408 TI - News Briefs: Two ES&T advisors were recently elected to the National Academy of Engineering:. PMID- 21662407 TI - News Briefs: Most state laws contain enforceable provisions for dealing with nonpoint source discharges. PMID- 21662409 TI - News Briefs: Most urban children in the developing world inhale the equivalent of two packs of cigarettes each day. PMID- 21662411 TI - News Briefs: 1999 may be the "last chance" for the European Union to pass meaningful ecological tax reform measures. PMID- 21662410 TI - News Briefs: The World Bank has spent 25 times more on climate-changing fossil fuel projects than on renewables since the 1992 Rio Earth Summit. PMID- 21662412 TI - Interview: benchmarking industry views of environmental issues? AB - Chamber President Tom Donohue contends that the cumulative impact of environmental initiatives will reduce the nation's ability to protect its environment. PMID- 21662414 TI - Learning from polar ice core research. AB - An understanding of long-term climate changes, with some surprises, is emerging from analysis of ice core samples. PMID- 21662416 TI - Technology Update: CO2 gets taken to the cleaners. PMID- 21662415 TI - Peer reviewed: testing water quality for pesticide pollution. AB - U.S. GeologicalSurvey investigations reveal widespread contamination of the nation's water resources. PMID- 21662426 TI - Research Watch: Halomethane remediation. PMID- 21662428 TI - Research Watch: Herbicide contamination. PMID- 21662438 TI - Online/In print: online/in print. PMID- 21662444 TI - Other/miscellaneous. PMID- 21662439 TI - Buyer's Guide: Buyer's Guide. PMID- 21662446 TI - Other/miscellaneous. PMID- 21662447 TI - Letters: GIS has its limitations. PMID- 21662448 TI - Letters: Sulfur hexafluoride emissions. PMID- 21662449 TI - A swan song. PMID- 21662450 TI - Year 2000 chemical process malfunctions feared. PMID- 21662451 TI - Ocean health could presage what lies ahead. PMID- 21662452 TI - DDT measured directly from Palos Verdes seawater. PMID- 21662453 TI - MTBE health assessment may loosen California's drinking water standard. PMID- 21662454 TI - EU countries discussing framework for future emissions inventory. PMID- 21662456 TI - News Briefs: U.S. farm income would decrease by 24% to 48%. PMID- 21662455 TI - EPA to strengthen persistent, bioaccumulative, and toxic pollutant controls Mercury first to be targeted. PMID- 21662457 TI - News Briefs: U.S. consumers would save more than $1 billion each year. PMID- 21662459 TI - News Briefs: The world's least developed nations could design more effective development strategies and trade policies. PMID- 21662458 TI - News Briefs: Without new policies, the prospects for stabilizing greenhouse gases at 1990 levels look gloomy. PMID- 21662460 TI - News Briefs: The state of many of the world's tropical forests is "bleak,". PMID- 21662461 TI - News Briefs: Contradicting a long-held Exxon Corp. claim. PMID- 21662462 TI - News Briefs: American consumers would pay $5.60 to $15.14 per gallon of gasoline. PMID- 21662463 TI - News Briefs: Eleven industrial ecology research projects received $1.1 million. PMID- 21662464 TI - News briefs: nominations for the 2000 national technology medal. PMID- 21662465 TI - EPA Watch: Enforcement now a top priority for TRI reports. PMID- 21662468 TI - A closer look at chemical exposures in children. AB - New research initiatives should help regulators more accurately assess risks and set exposure tolerances. PMID- 21662469 TI - Peer reviewed: options for characterizing organic particulate matter. AB - New research strategies could help elucidate the mechanisms and causes of aerosol health effects. PMID- 21662466 TI - Exploring Options for CO2 Capture and Management. AB - Technologies for limiting emissions can be integrated into business operations, but some first require further development. PMID- 21662470 TI - Environmental policy analysis: modeling atmospheric particulate matter. PMID- 21662472 TI - Technology update: regional green chemistry awards. PMID- 21662471 TI - Technology Update: First electric buses transporting passengers. PMID- 21662490 TI - Research Watch: Nitrate in rainwater. PMID- 21662481 TI - Research Watch: Soil remediation. PMID- 21662493 TI - Other/miscellaneous. PMID- 21662498 TI - Other/miscellaneous. PMID- 21662496 TI - Other/miscellaneous. PMID- 21662500 TI - Letters: TRI toxicity changes. PMID- 21662499 TI - More than just a dream. PMID- 21662501 TI - Letters: In memoriam Paul L. Busch: Engineer, educator, leader. PMID- 21662502 TI - Erratum: erratum. PMID- 21662503 TI - Asbestos dust stirs trouble in Sierra Nevada foothills. PMID- 21662504 TI - Researchers will tap potential of deep-ocean sediment life. PMID- 21662505 TI - As computer junk pile grows, little is recycled, study confirms. PMID- 21662506 TI - Canadian pollution prevention bill may threaten current protections. PMID- 21662507 TI - Nearly 100,000 Canadian lakes in danger despite acid rain cuts. PMID- 21662509 TI - Health: Environmental research budget needs $1-billion boost, NSF says. PMID- 21662510 TI - News Briefs: Smog from cars kills more than twice as many people as car accidents in Europe each year. PMID- 21662508 TI - Testing the waters for new beach technology. PMID- 21662511 TI - News Briefs: No dioxin or furan releases from iron and steel producers have been measured in the United States and Canada. PMID- 21662512 TI - News Briefs: Requiring developing countries to adhere to emission caps could undermine the Kyoto Protocol's greenhouse gas reduction agreements. PMID- 21662513 TI - News Briefs: Marine mammals' ability to hunt for food, detect predators, and find mates is being corrupted by underwater noise. PMID- 21662514 TI - News Briefs: Coal-fired utilities release 46 tons of mercury per year. PMID- 21662515 TI - News Briefs: The struggle to achieve an environmentally sustainable economy will be won or lost in the world's urban areas. PMID- 21662516 TI - News Briefs: The risk of leukemia and kidney, breast, and bone cancers was elevated for people living within 6.2 miles of Ohio's Fernald uranium processing site. PMID- 21662517 TI - News Briefs: If U.S. highway planners continue to expand roadway capacity at the current rate, an additional 40 million metric tons of carbon emissions will be released between 1996 and 2010. PMID- 21662518 TI - EPA Watch: Trinational pact aims to cut dioxin, furan, and HCB releases. PMID- 21662519 TI - EPA Watch: Public fate of worst-case risk data in question. PMID- 21662520 TI - EPA Watch: Nitrate standard for drinking water too stringent, researcher finds. PMID- 21662522 TI - EPA Watch: Citizens' right to sue under fire in courts. PMID- 21662521 TI - EPA Watch: Agency taken to task over animal testing. PMID- 21662523 TI - Technology Update: A technology that fabricates clean air from oxygen. PMID- 21662524 TI - Peer reviewed: the promise of membrane technology. AB - An expanded understanding of membrane technology is fostering new environmental applications. PMID- 21662528 TI - Peer reviewed: environmental management in the 21st century. AB - The solution of complex environmental problems will require comprehensive system considerations, as well as multidisciplinary and holistic approaches. PMID- 21662526 TI - Peer reviewed: monitoring endocrine-disrupting chemicals. AB - Novel strategies are providing a more comprehensive and refined basis for understanding the occurrence and effects of endocrine disrupters. PMID- 21662532 TI - Research Watch: Radionuclides in the environment. PMID- 21662543 TI - Research Watch: Polybrominated diphenyl esthers synthesized. PMID- 21662548 TI - Online/In print: online/in print. PMID- 21662552 TI - Other/miscellaneous. PMID- 21662554 TI - Other/miscellaneous. PMID- 21662556 TI - We're making a few changes... PMID- 21662557 TI - Technology Update: Bioengineered bacteria show promise in mercury removal. PMID- 21662558 TI - DNA chip technology could revolutionize water testing. PMID- 21662559 TI - Bt pollen study casts doubt on plant safety as EU halts approval of genetically modified corn. PMID- 21662560 TI - In memoriam. PMID- 21662561 TI - Awards honor the growing greening of chemistry. PMID- 21662562 TI - Precautionary principle challenges U.S. policy, workshop finds. PMID- 21662563 TI - Predicted summer water shortages attributed to climate change. PMID- 21662564 TI - Trade versus environment: Is trade winning out? PMID- 21662565 TI - Sweeping court decision could crush smog plans, rein in TRI and wetlands rules. PMID- 21662566 TI - NIOSH study of chemical workers bolsters data on dioxin as cancer agent. PMID- 21662567 TI - Climate change meeting skirts decisions on emissions trading. PMID- 21662568 TI - News Briefs: Iceland may become the world's first hydrogen economy. PMID- 21662569 TI - News Briefs: Solar photovoltaic (PV) technology is poised to play a major role in bringing telecommunications services to developing countries. PMID- 21662570 TI - News Briefs: Fuel oxygenates like methyl-tertbutyl ether (MTBE) and ethanol do less to reduce ozone pollution. PMID- 21662572 TI - News Briefs: There is no evidence that the federal government's brownfields programs are working. PMID- 21662571 TI - News Briefs: Since 1989, losses from catastrophic natural disasters in the United States have often averaged around $1 billion per week. PMID- 21662573 TI - News Briefs: A U.S. ban on organophosphate and carbamate pesticides would boost foreign food imports while hurting American farmers. PMID- 21662574 TI - News Briefs: The U.S. Department of Energy (DOE) is spending too much to clean up contaminated sites. PMID- 21662575 TI - News Briefs: Renewable energies gained a stronger foothold in the global power market from 1990 to 1998. PMID- 21662577 TI - EPA Watch: NRDC report backs long-delayed stormwater rules. PMID- 21662578 TI - EPA Watch: Effluent trading could spur abandoned mine cleanups. PMID- 21662579 TI - EPA Watch: Politics influence Superfund decisions, study finds. PMID- 21662580 TI - EPA Watch: Dioxins added to TMDL list for San Francisco Bay. PMID- 21662582 TI - Peer reviewed: cleaning up the nuclear weapons complex. AB - Progress on groundwater and soil restoration is limited, and new technologies are needed. PMID- 21662583 TI - Peer reviewed: will risk-based cleanup work at navy facilities? AB - Process requirements include attention to long-term risk, public involvement, enforcement, and use of uncertainty analysis. PMID- 21662589 TI - Research Watch: Modeling dioxin emissions. PMID- 21662584 TI - Ford opens door to plastics recycling. AB - With the passage of the European "take-back" laws all but inevitable, American automakers are stepping up efforts to recycle U.S. cars. PMID- 21662605 TI - Research Watch: Streambed sediment quality. PMID- 21662608 TI - Online/In print: online/in print. PMID- 21662610 TI - Buyer's Guide: Buyer's Guide. PMID- 21662613 TI - Other/miscellaneous. PMID- 21662615 TI - Other/miscellaneous. PMID- 21662617 TI - Other/miscellaneous. PMID- 21662618 TI - "Nonpointing" the way. PMID- 21662619 TI - Technology Solutions: Getting the sulfur out of diesel fuel. PMID- 21662621 TI - Flame retardant levels in Virginia fish are among the highest found. PMID- 21662620 TI - Illuminating the future for bioremediation. PMID- 21662622 TI - Hydrogen likely to be an explosive topic in DOE budget hearings. PMID- 21662623 TI - Genomics technology revolutionizes environmental monitoring. PMID- 21662624 TI - Sustainability: New sustainability benchmark takes aim at the GDP. PMID- 21662625 TI - Biosafety debate inadequately addresses developing country priorities. PMID- 21662626 TI - EU formalizes use of controversial precautionary principle. PMID- 21662627 TI - News Briefs: Common indoor substances-dust mites, mold, secondhand smoke, and fragrances in personal hygiene products-can trigger or worsen asthma in susceptible people. PMID- 21662628 TI - News Briefs: Many developing countries could "leapfrog" from polluting, unsustainable energy sources to renewable technologies. PMID- 21662630 TI - News Briefs: Although sulfur dioxide emissions have fallen sharply over the past 20 years, greenhouse gas emissions continue to rise. PMID- 21662629 TI - News Briefs: This year's ACS Environmental Chemistry Graduate Student Award winners. PMID- 21662631 TI - News Briefs: The state of Russia's environment is grim. PMID- 21662633 TI - EPA Watch: New approaches needed to curb service sector impacts. PMID- 21662632 TI - EPA Watch: Lawsuit challenges agency's nonpoint source authority. PMID- 21662634 TI - EPA Watch: Kids' chemical testing program under fire. PMID- 21662635 TI - EPA Watch: Very little known about pesticide usage in schools. PMID- 21662636 TI - Is extended producer responsibility effective? AB - Although its costs and benefits are hotly debated, use of this policy tool is spreading rapidly. PMID- 21662637 TI - Peer reviewed: what course for carbon trading? AB - Although still without a legislative mandate, a marketplace for carbon trading is beginning to develop. PMID- 21662640 TI - Research Watch: PCBs in soil. PMID- 21662639 TI - Peer reviewed: managing the global environment. AB - To enable future generations to drastically-and affordably-reduce carbon emissions if required, we must deal now with science and technology uncertainties. PMID- 21662641 TI - Research watch: el nino. PMID- 21662642 TI - Research Watch: Lake microorganisms. PMID- 21662644 TI - Research Watch: Mineral water. PMID- 21662643 TI - Research Watch: Silver speciation. PMID- 21662645 TI - Research Watch: Particle-bound pollutants. PMID- 21662646 TI - Research Watch: Lead uptake. PMID- 21662647 TI - Research Watch: Octanol-water coefficients. PMID- 21662648 TI - Research Watch: Mining contamination. PMID- 21662649 TI - Research Watch: Cryptosporidium parvum transport. PMID- 21662650 TI - Research Watch: Ozone reactions. PMID- 21662651 TI - Research Watch: Ocean temperatures. PMID- 21662653 TI - Research Watch: Phosphine levels. PMID- 21662652 TI - Research Watch: Candles pose risk. PMID- 21662655 TI - Research Watch: River nutrients. PMID- 21662654 TI - Research watch: pollutants in europe. PMID- 21662656 TI - Research Watch: Chlorinated hydrocarbon destruction. PMID- 21662657 TI - Research Watch: Life-cycle assessment. PMID- 21662658 TI - Research Watch: Herbicide safeners. PMID- 21662659 TI - Research Watch: Identifying bacteria. PMID- 21662660 TI - Online/In print: online/in print. PMID- 21662663 TI - Other/miscellaneous. PMID- 21662664 TI - Other/miscellaneous. PMID- 21662666 TI - Balanced environmental R&D. PMID- 21662667 TI - Risk-based cleanup methods undergoing major scientific review. PMID- 21662668 TI - Kyoto treaty sets precedent for emissions trading program. PMID- 21662669 TI - Transgenic mice validated as faster, less expensive cancer test. PMID- 21662671 TI - Environmental reforms likely to take a back seat in Congress this year. PMID- 21662670 TI - States pushing experiments with "performance-based" regulations. PMID- 21662672 TI - California to clamp down on light truck emissions. PMID- 21662674 TI - European News: Two new taxes on volatile organic compounds and sulfur emissions will be levied in Switzerland. PMID- 21662675 TI - European News: Twenty countries bordering the Mediterranean Sea have agreed to eliminate discharges of persistent, bioaccumulative, and toxic substances. PMID- 21662673 TI - Pulp and paper "cluster rule" called burdensome by industry. PMID- 21662676 TI - World's worst radioactive contamination documented in central Russia. PMID- 21662677 TI - European News: A new European Union directive on incineration of nonhazardous waste could be formally proposed early this year. PMID- 21662678 TI - News Briefs: A U.S. Drinking Water Optimization Institute will be created at the University of Cincinnati. PMID- 21662679 TI - News Briefs: Lead tops the list of the five worst environmental threats to children. PMID- 21662680 TI - News Briefs: Rocket launches do not have "a globally significant impact on stratospheric chemistry,". PMID- 21662681 TI - News Briefs: More than half of U.S. companies that treat or store hazardous wastes have not yet begun cleanups. PMID- 21662682 TI - News Briefs: Environmentally and socially responsible investing grew dramatically in the United States in the past two years. PMID- 21662683 TI - News Briefs: Not eating fruits and vegetables poses a greater cancer risk than do the trace amounts of pesticides found on those foods. PMID- 21662684 TI - News Briefs: Economic growth cannot be sustained without addressing related environmental and social issues. PMID- 21662686 TI - EPA Watch: Health advisory set for fuel oxygenate MTBE. PMID- 21662687 TI - Technology Update: All-weather water quality monitor. PMID- 21662688 TI - Calculating the cost of natural resource damage. AB - Critics label Superfund's natural resources damage assessments a costly "sleeping giant". PMID- 21662691 TI - Research Watch: Mobility of copper in soils. PMID- 21662697 TI - Research Watch: Solubility of lead in soil. PMID- 21662708 TI - Online/In print: online/in print. PMID- 21662709 TI - Buyer's Guide: Buyer's Guide. PMID- 21662712 TI - Determination of oxide in fluoride salts using an yttria-stabilized-zirconia oxygen pump. AB - An improved method over a previous technique has been developed to determine the ppm oxide concentration of fluoride salts. The oxide is released as oxygen gas by the reaction of the test salt with potassium bromotetrafluoride at 450 degrees C. The molecular oxygen released is then passed through a zirconia oxygen pump which selectively removes the oxygen. The current response is recorded as a chronoamperogram, from which the ppm oxide content of the salt can be obtained. Oxygen recovery from an yttrium oxide standard was better than 99%. The precision of analysis of FLINAK was better than 13% for samples containing 110-170 ppm oxide. The LOD was 12 MUg of oxygen, and the analytical range was 120 ppm to >20% for a 0.1-g sample. PMID- 21662713 TI - Microfabricated recessed microdisk electrodes: characterization in static and convective solutions. AB - Construction and characterization of microfabricated recessed microdisk electrodes (RMDs) of 14- and 55-MUm diameters and 4-MUm depth are reported. For evaluation of electrode function, both faradaic current in Ru(NH(3))(6)(3+)/KNO(3) solution and charging current in KNO(3) solution were measured with cyclic voltammetry. The experimental maximum current was measured and compared to calculated values, assuming radial and linear diffusion. A model for diffusion to a RMD best matches the behavior of the 14-MUm RMD, which has a larger depth-to-diameter ratio than the 55-MUm RMD. At fast scan rates (204 V s( )(1)), where linear diffusion should dominate, there are large deviations from the linear diffusion model. Uncompensated resistance and overcorrection for background current contribute to this deviation. The dependence of capacitance on scan rate of the RMDs was found to be similar to that of a macroelectrode, indicating good adhesion between the insulator and the electrode. Chronoamperometry of Ru(NH(3))(6)(3+) in KNO(3) in both static and stirred solutions was performed using the RMDs and the current is compared to those from a 10-MUm-diameter planar microdisk electrode (PMD). The signal-to-noise ratio of the 14-MUm RMDs compared to the PMD is on average 4 times greater for stirred solutions. The 55-MUm RMD exhibited no protection to convection of the stirred solution. PMID- 21662714 TI - Multivariate sensitivity for the interpretation of the effect of spectral pretreatment methods on near-infrared calibration model predictions. AB - Predictions obtained from a multivariate calibration model are sensitive to variations in the spectra such as baseline shifts, multiplicative effects, etc. Many spectral pretreatment methods have been developed to reduce these distortions, and the best method is usually the one that minimizes the prediction error for an independent test set. This paper shows how multivariate sensitivity can be used to interpret spectral pretreatment results. Understanding why a particular pretreatment method gives good or bad results is important for ruling out chance effects in the conventional process of "trial and error", thus obtaining more confidence in the finally selected model. The principles are exemplified using the transmission near-infrared spectroscopic prediction of oxygenates in ampules of the standard reference material gasoline. The pretreatment methods compared are the multiplicative signal correction, first derivative method, and second-derivative method. It is shown that for this application the first- and second-derivative methods are successful in removing the background. However, differentiating the spectra substantially reduces multivariate net analyte signal (in the worst case by a factor of 21). Consequently, a significantly smaller multivariate sensitivity is obtained which leads to increased spectral error propagation resulting in a larger uncertainty in the regression vector estimate and larger prediction errors. Differentiating spectra also increases the spectral noise (each time by a factor 2(1/2)) but this effect, which is well-known, is of minor importance for the current application. PMID- 21662715 TI - Thermophoretic collection and analysis of submicrometer ag particles emitted from a graphite tube-type electrothermal vaporizer. AB - Using thermophoretic collection with a cooled Cu probe, particles generated in an electrothermal vaporizer (ETV) from a AgNO(3) solution sample have been collected and analyzed using transmission electron microscopy and high-energy electron diffraction (HEED). Ag particles are spherical and, interestingly, have diameters falling into one of four size regimes, <5, 15, 25, and >40 nm. An extremely large number (estimated at >10(8)) of particles with diameters of <100 nm are collected. For an aqueous AgNO(3) solution deposited in the ETV, the HEED pattern of the collected aerosol particles exiting the pulse heated ETV matched body centered cubic Ag((s)), and the large number of diffraction spots suggests that particles are composed of microcrystalline domains. The features of the particles confirm earlier predictions of homonucleation as the primary particle formation mechanism. "Groupings" of apparently disconnected particles were a unique feature seen from the pulse-heated vaporization of the dried sample. This morphology is unique and does not appear like any other clustering or aggregation of particles reported elsewhere. It is not clear what causes this particle grouping, although the absence of these groupings when a 700 degrees C thermal pretreatment step was introduced suggests that the AgNO(3) decomposition plays a role in their formation. It is suggested that the particles formed from homonucleation are created very near the graphite surface and are cooled quite rapidly to form the solid silver particles. A mechanism is presented to explain the appearance of silver in the gas phase at temperatures below the vaporization temperature for silver metal. PMID- 21662716 TI - Quantitative assessment of surface-enhanced resonance Raman scattering for the analysis of dyes on colloidal silver. AB - Factors that affect quantitative analysis by surface-enhanced resonance Raman scattering (SERRS) have been investigated using azobenzotriazol and reactive dyes. Preaggregation of the silver colloid was the most effective method to obtain repeatable and reproducible scattering. Aggregation by poly(l-lysine) or spermine provided better precision than aggregation by sodium chloride or nitric acid. Repeatable quantitative analysis was achieved with the azobenzotriazol dyes. A linear calibration graph was obtained over different concentration ranges below 10(-)(8) M, depending on the nature of the colloid. Calculations estimate that 10(-)(8) M is the concentration at which monolayer coverage of the dye on the silver colloid is achieved. Above 10(-)(8) M, there was only a minor increase in the scattering intensity from the azobenzotriazol dyes. In contrast, the reactive dyes did not give a response proportional to concentration over the range studied. The different responses obtained for the two types of dye are believed to be caused by differences in the nature of the interaction of the molecules with the silver surface. The conclusion reached is that control of the colloid preparation, aggregation process, and surface chemistry are essential for successful quantitative analysis of dyes on colloidal silver by SERRS. PMID- 21662717 TI - Detection and identification of a methanol-water complex by factor analysis of infrared spectra. AB - Fourier transform infrared absorption spectra, between 1850 and 2700 cm(-)(1), were used to study the intermolecular interactions between methanol and water. Digitized spectra obtained from methanol-water mixtures, with methanol mole fraction varying from 0 to 1.00, were subjected to factor analysis. Principal factor analysis indicated that three chemical factors were responsible for the data. Window factor analysis, a model-free method, was used to extract the concentration profiles of three species, which were identified as water, methanol, and a methanol-water complex. The profiles were used to deduce the stoichiometry of the complex, which was found to consist of one molecule of methanol and two molecules of water. The dissociation constant of the complex was determined to be 306 +/- 33 M(2). These results differ from those reported by other investigators. PMID- 21662718 TI - Two-beam cross-correlation: a method to characterize transport phenomena in micrometer-sized structures. AB - To determine flow properties, namely, the velocity and angle of the flow in microstructured channels, an experimental realization based on fluorescence correlation spectroscopy is described. For this purpose, two micrometer-sized spatially separated volume elements have been created. The cross-correlation signal from these has been recorded and evaluated mathematically. In addition to previous results, two-beam cross-correlation allows for fast and easy determination of even small (down to 200 MUm/s) flow velocities, as well as simultaneous measurement of diffusion properties of single dye molecules within a rather short detection time of 5-100 s and an error rate of less than 20%. The spatial flow resolution is around 1-2 MUm, limited by the diameter of the volume element. Furthermore, vectorial flow data can be obtained and evaluated. A discussion of the theoretical background and an experimental verification of the theoretical results is performed. The feasibility of fast and easy data processing is shown if the flow time is the only desired information. Possible applications of this precise and simple method are the determination of transportation effects within artificial microstructures for CE and HPLC, fast chemical kinetics, and high-throughput screening. PMID- 21662719 TI - Effective Sample Size in Diffuse Reflectance Near-IR Spectrometry. AB - Two independent methods for determination of the effectively sampled mass per unit area are presented and compared. The first method combines directional hemispherical transmittance and reflectance measurements. A three-flux approximation of the equation of radiative transfer is used, to separately determine the specific absorption and scattering coefficients of the powder material, which subsequently are used to determine the effective sample size. The second method uses a number of diffuse reflectance measurements on layers of controlled powder thickness in an empirical approach. The two methods are shown to agree well and thus confirm each other. From the determination of the effective sample size at each measured wavelength in the visible-NIR region for two different model powder materials, large differences was found, both between the two analyzed powders and between different wavelengths. As an example, the effective sample size ranges between 15 and 70 mg/cm(2) for microcrystalline cellulose and between 70 and 300 mg/cm(2) for film-coated pellets. However, the contribution to the spectral information obtained from a certain layer decreases rapidly with increasing distance from the powder surface. With both methods, the extent of contribution from various depths of a powder sample to the visible-NIR diffuse reflection signal is characterized. This information is valuable for validation of analytical applications of diffuse reflectance visible-NIR spectrometry. PMID- 21662720 TI - Routine Part-per-Million Mass Accuracy for High- Mass Ions: Space-Charge Effects in MALDI FT-ICR. AB - The effect of ion space-charge on mass accuracy in Fourier transform ion cyclotron resonance mass spectrometry is examined. Matrix-assisted laser desorption/ionization is used to form a population of high-molecular-weight polymer ions with a wide mass distribution. The density of the ions in the analyzer cell is varied using ion remeasurement and suspended trapping techniques to allow the effect of ion space charge to be examined independently of other experimental influences. Observed cyclotron frequency exhibits a linear correlation with ion population. Mass errors of 100 ppm or more in externally calibrated mass spectra result when ion number is not taken into account. By matching the total ion intensities of calibrant and analyte mass spectra, the protonated ion of insulin B-chain, 3494.6513 Da, is measured with an accuracy of 0.07 ppm (average of 10 measurements, sigma = 2.3 ppm, average absolute error 1.6 ppm) using a polymer sample as an external calibrant. Alternatively, the correction for space charge can be made by using a calibration equation that accounts for the total ion intensity of the mass spectrum. A calibration procedure is proposed and is tested with the measurement of the mass of insulin B chain. A mass accuracy of 2.0 ppm (average of 20 measurements, sigma = 4.2 ppm, average absolute error 3.5 ppm) is achieved. Space-charge-induced mass errors are more significant for samples with many components, such as a polymer, than for single-component samples such as purified peptides or proteins. PMID- 21662721 TI - Mass and collision cross-section determination using a low-vacuum mass spectrometer. AB - A simple low-vacuum mass spectrometer (LVMS) operating in the milliTorr pressure range was developed. The instrument resolves masses by time-of-flight measurements and employs a high-gain, fast-response detector that can operate at these pressures. This instrument allows simultaneous determination of mass and collision cross sections of the ions with the bath gas. Here we demonstrate the LVMS's abilities to determine total collision cross sections for the collisions of organic ions with three background gases, He, N(2), and SF(6). As a demonstration of the system capabilities, the unimolecular interconversion of photochemically produced C(7)H(7)(+) to the tropylium ion structure is investigated. PMID- 21662722 TI - Extraction Selectivities of Crown Ethers for Alkali Metal Cations: Differences between Single-Species and Competitive Solvent Extractions. AB - Separation factor values for pairs of alkali metal cations determined in competitive solvent extractions of alkali metal picrates from aqueous solutions into chloroform by a variety of benzo- and cyclohexano-group-containing crown ethers vary significantly from extrapolations based upon the results of single species extraction experiments. For almost all of the crown ether-alkali metal cation combinations examined, the separation factor values are greater for competitive solvent extraction. In view of the unexpected results for sodium picrate extraction by dibenzo-24-crown-8, the solid-state structure of the isolated complex was determined. PMID- 21662723 TI - Prediction of electrophoretic mobilities. 3. Effect of ionic strength in capillary zone electrophoresis. AB - Plots of mobility versus the square root of ionic strength (I(1/2)) do not show the linear behavior predicted by Kohlrausch's law. Classical electrolyte theory states that such deviations are to be expected due to the finite size of the ions. This paper uses the Pitts equation to account for the effect of ionic size on the ionic strength dependence of mobilities in CZE. Experimental mobilities for carboxylates, phenols, and sulfonates of -1 to -6 charge in aqueous buffers ranging from 0.001 to 0.1 M ionic strength were described by MU(-) = MU(0) - Az (I(1/2)/(1 + 2.4I(1/2))), where the constant in the denominator is empirically determined. Infinite dilution mobilities (MU(0)) determined by extrapolation of mobility data to zero ionic strength based on this expression yielded excellent agreement (100.3 +/- 3.3%) with literature values for 14 compounds in a variety of buffers. The Pitts equation provides a reasonable estimate of the constant A for solutes up to a charge of -5. However, this constant also depends on temperature and the nature of the buffer counterion, presumably due to ion association. Thus it is most appropriate to determine the constant A empirically for a given buffer system. PMID- 21662724 TI - On-line detection of antioxidative activity in high-performance liquid chromatography eluates by chemiluminescence. AB - Luminol chemiluminescence (CL) was employed for the on-line detection of radical scavengers in HPLC eluates. Optimization of CL reagents and instrumental setup resulted in a steady postcolumn luminol photochemical reaction in the presence of microperoxidase and hydrogen peroxide at pH 10. Quenching of the CL signal was utilized to detect radical scavenging activity of both natural and synthetic antioxidants at the nanogram level. The detection system can be used with isocratic or gradient elution. Several antioxidative compounds were detected in thyme and sage acetone extracts. Quantitative results can be obtained when antioxidants are analyzed at certain concentrations. The method is suitable for rapid screening of antioxidants in crude extracts. PMID- 21662725 TI - Conductometric detection of anions of weak acids in chemically suppressed ion chromatography: critical point concentrations. AB - Previously we demonstrated that the conductometric determination of anions of weak acids in chemically suppressed ion chromatography could be enhanced, by conversion of the acid to a conjugate salt, if the anion was present above what we termed the critical point concentration (CPC). In this paper we have developed a simple theoretical model for the calculation of CPCs for weak acid/conjugate salt pairs. The CPC was found to be dependent on the acid ionization constant K(a) and the molar ionic conductivities (MICs) of the ions present. For monovalent anions with a MIC in the common range 25-75 S cm(2) mol(-)(1), with sodium or potassium as cations, the CPCs could be estimated from the expression pC ~ pK(a) - 1, where pC = -log CPC. For formate, benzoate, and acetate, excellent agreement was found between the calculated and experimental CPCs, with a mean deviation of 0.05 mM. For fluoride, the calculated and experimental CPCs were 7.4 and 9.2 mM, respectively. Experimental CPCs could not be determined for other anions as their calculated CPCs were below the detection limits of the IC system. The simple theoretical model could also be used to estimate the expected conductivity enhancement for the conversion of weak acid to a particular conjugate salt. The effects of detector linearity and dispersion in the IC system on the use of CPCs are also discussed. PMID- 21662726 TI - Computational Simulation of Redox Reactions within a Metal Electrospray Emitter. AB - A computational simulation of the oxidation of chemical species inside a metal emitter electrospray ion source, in the context of electrospray mass spectrometry (ES-MS), has been developed. The analysis code employs a boundary integral method for the solution of the Laplace equation for the electric potential and current and incorporates standard activation and concentration polarization functions for the redox-active species in the system to define the boundary conditions. This paper provides a demonstration of the capability of this simulation method. Due to the approximate nature of some of the input data, and certain simplifying assumptions, the present results must be considered semiquantitative. The specific system modeled consisted of a 100-MUm-i.d., inert metal capillary ES emitter and a spray solution composed of an analyte dissolved in CH(3)CN/H(2)O (90/10 v/v). Variable parameters included the concentration (i.e., 5.0, 10, 20, and 50 MUM) of the easily oxidized analyte ferrocene (Fc, dicyclopentadienyl iron) in the solution, and solution conductivities of 1.9, 3.8, and 7.6 * 10( )(7) Omega(-)(1)/cm, with an operational flow rate of 5.0 MUL/min and ES currents on the order of 0.05 MUA. Under these defined conditions, the two most prominent reactions at the emitter metal/solution interface were assumed to be H(2)O oxidation (2H(2)O = O(2) + 4H(+) + 4e(-)) and ferrocene oxidation (Fc = Fc(+) + e(-)). Using this model, it was possible to predict the interfacial potentials, as well as the current density for each of the reactions, as a function of axial position from the emitter spray tip back upstream, under the various operational conditions. The simulations show that the majority of the current from the redox reactions is generated within a 200-300-MUm region near the spray tip. The lower the value of E(0) for a specific reaction, the further upstream from the tip the reaction extends. PMID- 21662727 TI - Simultaneous determination of the (2)h/(1)h, (17)o/(16)o, and (18)o/(16)o isotope abundance ratios in water by means of laser spectrometry. AB - We demonstrate the first successful application of infrared laser spectrometry to the accurate, simultaneous determination of the relative (2)H/(1)H, (17)O/(16)O, and (18)O/(16)O isotope abundance ratios in water. The method uses a narrow line width color center laser to record the direct absorption spectrum of low-pressure gas-phase water samples (presently 10 MUL of liquid) in the 3-MUm spectral region. It thus avoids the laborious chemical preparations of the sample that are required in the case of the conventional isotope ratio mass spectrometer measurement. The precision of the spectroscopic technique is shown to be 0.70/00 for delta(2)H and 0.50/00 for delta(17)O and delta(18)O (delta represents the relative deviation of a sample's isotope abundance ratio with respect to that of a calibration material), while the calibrated accuracy amounts to about 3 and 10/00, respectively, for water with an isotopic composition in the range of the Standard Light Antarctic Precipitation and Vienna Standard Mean Ocean Water international standards. PMID- 21662728 TI - Emulsion-based fluorosensors for potassium featuring improved stability and signal change. AB - A novel kind of potassium optode is presented which is based on the use of lipophilic droplets containing valinomycin and entrapped in a structured hydrogel. A positively charged solvatochromic dye located near the surface of the droplets responds to the valinomycin-assisted extraction of potassium from the sample by dramatic decrease of fluorescence intensity. The dynamic range is from 5 to 100 mM potassium, with negligible cross sensitivity to ionic strength. Cross sensitivity to pH is negligible too in the pH range from 6.5 to 7.3. The effect of interfering lipophilic anions is discussed. Response times within the dynamic range are less than 3 min on going from low to high potassium ion concentrations but about 10 min in the reverse direction. Response is fully reversible with only small drifts in baseline. The measurement uncertainty of determining 5 mM potassium is better than 0.2 mM. PMID- 21662729 TI - Analysis of diffusion coefficient distributions in humic and fulvic acids by means of diffusion ordered NMR spectroscopy. AB - The use of the computer program CONTIN to analyze pulsed-field gradient NMR (PFG NMR) data for several standard humic and fulvic acids is described. An advantage of PFG-NMR analysis is that integration of different spectral regions provides a picture of how the diffusion coefficients vary with functional group composition for a given sample. Using prior knowledge of the sample and the principle of parsimony, CONTIN approximates a solution to the inverse Laplace transform applied to the decay of peak intensity with gradient area in the PFG-NMR experiment. Thus, a continuous distribution of diffusion coefficients is resolved for the polydisperse humic and fulvic acids. The results of the CONTIN analyses are in the form of a distribution function and a two-dimensional DOSY plot. The 2D DOSY spectrum displays chemical shifts along one axis and diffusion coefficients along the other, while a number-average diffusion coefficient, D(N), a weight-average diffusion coefficient, D(W), and a most probable diffusion coefficient, D(P), are realized from the diffusion coefficient distribution. For all spectral regions of each humic sample, D(W) was greater than D(N), which in turn was greater than or equal to the D(P), suggesting that the diffusion coefficient distribution is weighted toward smaller, more rapidly diffusing molecules. Polydispersities, estimated from the ratio D(W)/D(N), were less than the reported M(W)/M(N) values for similar humic substances. Thus, the D(W)/D(N) ratio obtained by CONTIN analysis of PFG-NMR data can be at least a qualitative, and at best a semiquantitative, indication of the polydispersity of the humic sample, but should not be used as a quantitative measure of polydispersity. PMID- 21662730 TI - Selective metals determination with a photoreversible spirobenzopyran. AB - The photoreversible metal-ion complexation behavior of nitroquinolinospiropyranindoline (NQSP) was studied in combination with the selective identification of six different transition-metal ions, Zn(2+), Co(2+), Hg(2+), Cu(2+), Cd(2+), and Ni(2+), in single- and binary-component mixtures via partial least squares discriminant (PLSD) analysis. The plasticizer, dicapryl phthalate, was chosen as the support medium for this study on the basis of (1) its enhancement of the photoreversibility and hypsochromic shifts seen in metal complexation and (2) its potential application to supported liquid membranes for eventual sensor applications. Complexation of divalent transition-metal ions by NQSP in dicapryl phthalate produced variable hypsochromic shifts in the absorption spectra (30-60 nm), requiring chemometric techniques in order to overcome the spectral overlaps. PLSD analysis was used to build classification analysis models to differentiate between the six divalent transition-metal ions. The feasibility of performing mixture analysis was studied using the concept of net analyte signal prior to experimental verification. Single- and binary component mixtures of metals were identified with 100 and 97.4% accuracy, respectively, which included no false positives in either the training or prediction sets. PMID- 21662731 TI - Depth profiling of thin films with pulsed glow discharge atomic emission spectrometry. AB - The application of microsecond pulsed Grimm glow discharge atomic emission spectrometry for depth profiling of thin films is examined. The effects of pulsed conditions including pulse voltage, pulse frequency, pulse width, and Ar pressure on depth profiling performance were characterized for Zn and Cu coatings on steel. Using optimized conditions, linear calibration curves of coating thickness for Zn (6.1-26.9 MUm) and Cu (50-500 nm) on steel were achieved. A precision of 2 5% relative standard deviation was determined. An ultrathin coating of Cu (10 nm) on steel was also measured by this technique. PMID- 21662732 TI - Analysis of cationic surfactants by microbore high-performance liquid chromatography-electrospray mass spectrometry. AB - In the work reported here, a state-of-the-art analytical method for the quantitative analysis of cationic surfactants in environmental matrixes is described. High-performance liquid chromatography on-line coupled via an electrospray interface to a mass spectrometer (HPLC-ESP-MS) is used for the determination of ditallowdimethylammonium chloride (DTDMAC) and two of its most important substitution products, diethylester dimethylammonium chloride (DEEDMAC) and Diesterquaternary (DEQ). Using the analytical method developed in our laboratory, it is possible to determine single homologues of these surfactants as well as the first hydrolysis products of DEQ and DEEDMAC. In combination with our extraction procedure, which is based on ion-pair extraction, cationic surfactants were determined in environmental samples (sewage influent, sewage effluent, river water); concentrations ranged from 0.4 to 140 MUg/L. The linear dynamic range of the HPLC-ESP-MS method, which is an injected amount between 0.4 and 30 ng, is well suitable for the analysis of these samples, as well as the performance of the quantification through external standards. PMID- 21662733 TI - A Fluorogenic Reagent, 7-Phenylsulfonyl-4-(2,1,3-benzoxadiazolyl) Isocyanate for Alcohols, with Development Based on the Empirical Method for Prediction. AB - During the course of our studies, we found the relationship between the fluorescence characteristics (the fluorescence intensity and the maximum excitation and emission wavelengths) of benzofurazan compounds and the sum and difference of Hammett substituent constants (sigmap) at the 4- and 7- positions. This prompted us to design a useful fluorogenic derivatization reagent having the benzofurazan skeleton for alcohols along this line of thought. Accordingly, the fluorogenic derivatization reagents, which have no fluorescence themselves, 7-N,N dimethylaminosulfonyl-4-(2,1,3-benzoxadiazolyl) isocyanate (DBD-NCO), 7 phenylsulfonyl-4-(2,1,3-benzoxadiazolyl) isocyanate (PSBD-NCO), and 7 methylsulfonyl-4-(2,1,3-benzoxadiazolyl) isocyanate (MSBD-NCO), were synthesized. Among the derivatives derived from the three reagents, that from PSBD-NCO was most strongly fluorescent. PSBD-NCO reacted with 1-octanol within 4 h in acetonitrile solution in the absence of a catalyst at 60 degrees C. The derivatives with four alcohols (1-octanol, 1-nonanol, 1-decanol, and 1-undecanol) were separated on a reversed-phase column and detected fluorimetrically at 490 nm with the excitation at 368 nm. The detection limits were at the 10-femtomole level. PSBD-NCO was superior to other fluorescent-labeling reagents with regard to the avoidance of the interfering peaks derived from the reagents themselves and degradation products in the chromatogram. The effectiveness of our approach is disccussed in terms of the development of new fluorogenic reagents. PMID- 21662734 TI - Retention Behavior of Triglycerides in Octadecyl Packed Subcritical Fluid Chromatography with CO(2)/Modifier Mobile Phases. AB - A study of the retention behavior of vegetable oil triglycerides was carried out in subcritical fluid chromatography (SubFC) with CO(2)/modifier mobile phases. Analyses of 15 oils have enabled us to set up a retention diagram which includes ~30 triglycerides. This diagram establishes a relation between triglyceride series retention and their unsaturation number. Furthermore, another relationship between retention and the triglyceride carbon number was studied. The retention properties were identical with those reported in nonaqueous reversed-phase liquid chromatography or in SubFC with neat CO(2): the linearity of these relationships and retention order that follows the partition number. Moreover, specific effects of modifier on these relationships or on retention variations were observed. Using octadecyl packed columns, these particular behaviors underline that the compound solubility is different between modified subcritical phases and nonaqueous liquid phases. Finally, these behaviors can be useful to increase the triglyceride separation and the previous relationships can be applied to improve the identification of unknown triglycerides. PMID- 21662735 TI - Speciation of methylcyclopentadienyl manganese tricarbonyl by high-performance liquid chromatography-diode laser atomic absorption spectrometry. AB - Methylcyclopentadienyl manganese tricarbonyl (MMT) is a fuel additive that has been marketed for use in unleaded gasoline since December 1995. The widespread use of this additive has been suggested to cause health risks, but limitations in data regarding its degradation products and their toxicity prevent an accurate evaluation. To monitor the organomanganese compounds, it is clearly advantageous to employ low-cost, high-sensitivity, manganese-specific instrumentation to perform speciation. In this work, instrumentation fitting these criteria was obtained by the combination of high-performance liquid chromatography (HPLC) with diode laser atomic absorption spectrometry (DLAAS) and was used to determine MMT, its nonmethylated derivative, cyclopentadienyl manganese tricarbonyl (CMT), and inorganic manganese. DLAAS was shown to be a versatile analytical technique for total Mn determination, with a detection limit of 1 ng/mL and a linear dynamic range (LDR) of almost 5 orders of magnitude. Analytical figures of merit for HPLC DLAAS included a detection limit of 2 ng(as Mn)/mL, a LDR of 3 orders of magnitude, and an analysis time of three minutes. The organometallic compounds are characterized by rapid photolysis in sunlight, and hence, experiments were performed to evaluate whether normal laboratory lighting is suitable for their determination. Our results showed that normal laboratory protocols may be employed except that the organomanganese compounds should be stored away from light except during sample introduction procedures. The ability of the instrumentation to selectively preconcentrate organomanganese compounds while removing inorganic manganese was demonstrated. Sufficient resolution was obtained to determine a 20-fold excess of CMT compared with MMT. The ability of the system to do practical analysis was demonstrated by the accurate determination of MMT in spiked samples of gasoline, human urine, and tap water. These results demonstrate the suitability of HPLC-DLAAS for the speciation of MMT and its derivatives in industrial, toxicological, and environmental samples. PMID- 21662736 TI - Computation of the range of feasible solutions in self-modeling curve resolution algorithms. AB - Self-modeling curve resolution (SMCR) describes a set of mathematical tools for estimating pure-component spectra and composition profiles from mixture spectra. The source of mixture spectra may be overlapped chromatography peaks, composition profiles from equilibrium studies, kinetic profiles from chemical reactions and batch industrial processes, depth profiles of treated surfaces, and many other types of materials and processes. Mathematical solutions are produced under the assumption that pure-component profiles and spectra should be nonnegative and composition profiles should be unimodal. In many cases, SMCR may be the only method available for resolving the composition profiles and pure-component spectra from these measurements. Under ideal circumstances, the SMCR results are accurate quantitative estimates of the true underlying profiles. Although SMCR tools are finding wider use, it is not widely known or appreciated that, in most circumstances, SMCR techniques produce a family of solutions that obey nonnegativity constraints. In this paper, we present a new method for computation of the range of feasible solutions and use it to study the effect of chromatographic resolution, peak height, spectral dissimilarity, and signal-to noise ratios on the magnitude of feasible solutions. An illustration of its use in resolving composition profiles from a batch reaction is also given. PMID- 21662737 TI - A computational reaction-diffusion model for the analysis of transport-limited kinetics. AB - Optical, evanescent wave biosensors have become popular tools for quantitatively characterizing the kinetic properties of biomolecular interactions. Analyzing data from biosensor experiments, however, is often complicated when mass-transfer influences the detection kinetics. We present a computational, transport-kinetic model that can be used to analyze transport-limited biosensor data. This model describes a typical biosensor experiment in which a soluble analyte diffuses through a flow chamber and binds to a receptor immobilized on the transducer surface. Analyte transport in the flow chamber is described by the diffusion equation while the kinetics of analyte-surface association and dissociation are captured by a reactive boundary condition at the sensor surface. Numerical integration of the model equations and nonlinear least-squares fitting are used to compare model kinetic data to experimental results and generate estimates for the rate constants that describe analyte detection. To demonstrate the feasibility of this model, we use it to analyze data collected for the binding of fluorescently labeled trinitrobenzene to immobilized monoclonal anti-TNT antibodies. A successful analysis of this antigen-antibody interaction is presented for data collected with a fluorescence-based fiber-optic immunoassay. The results of this analysis are compared with the results obtained with existing methods for analyzing diffusion-limited kinetic data. PMID- 21662738 TI - Evaluation of metal migration and determination of trace metals after microwave digestion for lithographic materials. AB - The radioactive tracer technique was applied to investigate the migration of cesium and zinc impurities from bottom antireflective coating (BARC) and photoresist (PR) into underlying substrate. The effects of normal baking temperatures and substrate types were studied. Our results indicated that BARC has higher migration ratios than PR, irrespective of the substrate types and normal baking temperatures. The substrate type did not appear to strongly affect the metal migration ratios. However, water and/or solvent evaporation due to temperature change was found to have a significant effect on metal migration. The diffusion profiles of BARC and PR were depicted based on diffusion equations and the migration ratios. Both the UV/visible spectrometric and the gravimetric methods were successfully implemented to evaluate the feasibility of closed vessel microwave digestion efficiency for BARC and PR samples. By following the established microwave digestion method and the inductively coupled plasma mass spectrometer (ICPMS) determination, the detection limits obtained for multielements were in the ppb and sub-ppb levels. Except for calcium, the spike recoveries of metals ranged from 91 to 132% and 87 to 125% for BARC and PR, respectively. The analytical results were found to be in reasonably good agreement with the literature values. PMID- 21662739 TI - Radionuclide sensors based on chemically selective scintillating microspheres: renewable column sensor for analysis of (99)tc in water. AB - A method for chemically selective radiometric sensing of non-gamma-emitting radionuclides in solution is described. Using scintillating microspheres with selective radionuclide uptake properties, radiochemical separation and radiometric detection steps are integrated within a sensor device. These microspheres are loaded into a renewable minicolumn that serves to capture, preconcentrate, and separate radionuclides. The preconcentrating minicolumn also localizes and retains radionuclides within a detector of well-defined geometry and emits a photometric signal. The sensor material in the column can either be regenerated with eluent chemistries or be renewed by fluidic replacement of the beads. The latter method allows the use of materials that bind analytes irreversibly or are unstable under regeneration conditions. Radionuclide selective scintillating microspheres were prepared by coimmobilization of scintillating fluors and selective organic extractants within the pores of an inert polymeric support. Preparation and characterization of microspheres, and their use for selective quantitative sensing of (99)Tc(VII), is described in detail. A sensor-based procedure for (99)Tc(VII) analysis was developed and successfully applied toward the determination of (99)Tc(VII) in groundwater samples from the Hanford site, using standard addition techniques for quantification. Using a 50-mL sample volume and signal accumulation time of 30 min, the detection limit for (99)Tc(VII) was 0.37 dpm/mL (9.8 pg/mL). PMID- 21662740 TI - Micromachined electrophoresis chips with thick-film electrochemical detectors. AB - A capillary electrophoresis (CE) microsystem, based on the combination of microphotolithographically fabricated separation chips and thick-film electrochemical detector strips, is described. The microsystem consists of a planar screen-printed carbon line electrode mounted perpendicular to the flow direction. Such coupling obviates the need for permanent attachment of the detector, to allow easy and fast replacement of the working electrode. Variables influencing the separation efficiency and amperometric response, including the channel-electrode spacing, separation voltage, or detection potential, are assessed and optimized. The versatility, simplicity, and low-cost advantages of the new design are coupled to an attractive performance, with submicromolar detection limits, and good precision. Applicability for assays of mixtures of nitroaromatic explosives or catecholamines is demonstrated. Such use of screen printed detectors should also benefit conventional CE systems, particularly in applications requiring a frequent replacement of the working electrode. PMID- 21662741 TI - Hadamard transform capillary electrophoresis. AB - This paper reports the first demonstration of a multiplex sample injection technique in capillary electrophoresis. The sample was injected into a capillary (effective length, 4 cm) as a pseudorandam Hadamard sequence by a photodegradation technique using a high-power gating laser, and the fluorescence signal, which was measured using a probe excitation beam, was decoded by an inverse Hadamard transformation. The signal-to-noise ratio was improved by a factor of 8, which was in good agreement with the theoretically predicted value of 8.02. This approach is potentially useful for the enhancement of the sensitivity by 3 orders of magnitude in high-resolution capillary electrophoresis, combined with fluorescence detection. PMID- 21662742 TI - Some Considerations on the Correlation between Signal and Background in Laser Induced Breakdown Spectroscopy Using Single-Shot Analysis. PMID- 21662743 TI - Shape separation of nanometer gold particles by size-exclusion chromatography. AB - The shape separations of suspended gold nanoparticles were investigated using size-exclusion chromatography. The separations in shapes were identified by examining the 3-D chromatograms obtained by employing a diode-array detection system and were further confirmed by analyzing TEM images of fractional collection of particles. This shape separation was achieved by adding a mixed surfactant system containing sodium dodecyl sulfate and poluoxyethylene (23) dodecanol (Brij-35) into the eluent, which apparently affects the adsorption behaviors of both rodlike and spherical Au nanoparticles onto the column packing materials. While the overall particle gross sizes of these two shapes were similar, the baseline resolution was unfortunately not obtainable. However, the absorption spectra from the diode-array detector could be utilized to interpret the shapes of Au nanoparticles. The potential capability for the size separation of Au nanoparticles by size-exclusion chromatography with diode-array detection was also demonstrated. PMID- 21662744 TI - Method for synthesis and screening of large groups of molecularly imprinted polymers. AB - A technique for the synthesis of molecularly imprinted polymers (MIPs) in small scale (~55 mg) coupled with direct in situ processing and batch rebinding evaluation is reported. The primary assessment is based on quantification by HPLC or UV absorbance measurement of the amount of template released from the polymer in a given solvent. This method allows a rapid screening of the parameters of importance to reach a desired level of binding affinity capacity and selectivity for a given target molecule. This was demonstrated for the triazine herbicide terbutylazine, where an initial screening was performed for the type of functional monomer used in the MIP preparation. Thus among the six functional monomers tested, methyl methacrylate, 4-vinylpyridine, and N-vinyl-alpha pyrrolidone led to rapid and quantitative extraction whereas methacrylic acid and (trifluoromethyl)acrylic acid led to polymers that retained the template the most. After having established useful functional monomers, a secondary screening for selectivity was performed. In this, nonimprinted blank polymers were prepared and a normal batch rebinding evaluation was performed. The polymer showing the highest selectivity was the one prepared using methacrylic acid as functional monomer. This polymer was shown to strongly retain chlorotriazines including atrazine when a normal-scale batch of the polymer was evaluated in chromatography. PMID- 21662745 TI - Efficient detection of single DNA fragments in flowing sample streams by two photon fluorescence excitation. AB - This paper reports the demonstration of efficient single molecule detection in flow cytometry by two-photon fluorescence excitation. We have used two-photon excitation (TPE) to detect single DNA fragments as small as 383 base pairs (bp) labeled with the intercalating dye, POPO-1, at a dye:nucleotide ratio of 1:5. TPE of the dye-DNA complexes was accomplished using a mode-locked, 120 fs pulse width Ti:sapphire laser operating at 810 nm. POPO-1 labeled DNA fragments of 1.1 kilobase pairs (kbp) and larger were sequentially detected in our flow cytometry system with a detection efficiency of nearly 100%. The detection efficiency for the 383 bp DNA fragments was approximately 75%. We also demonstrate the ability to distinguish between different sized DNA fragments in a mixture by their individual fluorescence burst sizes by TPE. These studies indicate that using TPE for single molecule flow cytometry experiments lowers the intensity of the background radiation by approximately an order of magnitude compared to one photon excitation, due to the large separation between the excitation and emission wavelengths in TPE. PMID- 21662746 TI - Analysis of the (Trimethylsilyl)propionic Acid-beta(12-28) Peptide Binding Equilibrium with NMR Spectroscopy. AB - The binding of a small molecule, (trimethylsilyl)propionic acid (TSP), to a 17 residue peptide, beta(12-28), is examined using (1)H NMR spectroscopy. beta(12 28) (VHHQKLVFFAEDVGSNK) is a central fragment of the 40-42-residue Alzheimer's associated Abeta peptide. This peptide has been previously shown to form soluble aggregates in low-pH aqueous solution. The TSP resonance is broadened appreciably in solutions containing relatively high concentrations (~2 mM) of the peptide. The changes in TSP line width measured by titration of a peptide solution with TSP indicate a 1:1 binding stoichiometry. If the concentrations of both the peptide and TSP are reduced by 1 order of magnitude, the resonances of both species are sharp, suggesting that TSP binds predominately to the aggregated peptide. Nuclear Overhauser effect experiments indicate that the TSP interacts predominately with the side chains of the aliphatic peptide residues Leu(17) and Val(18). Pulsed-field gradient NMR measurements of TSP and peptide diffusion coefficients provide a more quantitative picture of the TSP-peptide binding equilibrium. The measured diffusion coefficients were used to calculate the fractions of the free and bound TSP. These results substantiate the conclusion that the stoichiometry of the TSP-peptide binding equilibrium is essentially 1:1 and further indicate anticooperative behavior in solutions containing an excess of TSP resulting in a dissociation of the peptide aggregates. PMID- 21662747 TI - Temperature Programming for High-Speed GC. AB - Fast temperature programming (20-50 degrees C/min) is used with relatively short separation columns to achieve high-speed separations of mixtures covering a wide boiling point range. A cryofocusing inlet is used to obtain narrow injection plugs. High-speed temperature-programmed chromatograms are evaluated by considering local peak capacity as a function of carbon number and boiling point for the normal alkanes in the range C(8)-C(19). The peak capacity generation rate (peaks per second) as a function of carbon number and the total cumulative peak capacity as a function of time are also considered for various column lengths and carrier gas flow rates. Column lengths in the range 3.6-25.4 m and average carrier gas velocity values in the range 50-200 cm/s are considered. For a 6.8-m long, 0.25-mm-i.d. column operated at an average carrier gas velocity of about 100 cm/s and using a nominal programming rate of 50 degrees C/min, C(19) elutes in 178 s with a total peak capacity of 168 peaks. If the programming rate is reduced to 20 degrees C/min, the C(19) elution time more than doubles but the total peak capacity increases by only 20%. For a 25.4-m-long column using a nominal 50 degrees C/min programming rate, the C(19) retention time is 262 s with a peak capacity of 279 peaks. The use of average carrier gas flow rates greater than about 100 cm/s, which is common in isothermal high-speed GC, results in a considerable loss in total peak capacity with remarkably little reduction in analysis time. PMID- 21662748 TI - Shah convolution fourier transform detection. AB - A new convolution-detection method was developed which converts multiple-point (Shah function) detection, time-domain electropherograms into frequency-domain plots by means of a Fourier transformation, allowing the analytes' speeds to be viewed in terms of their "blinking" frequency; we have named this method Shah convolution Fourier transform detection, or SCOFT. This paper represents proof of principle of the detection concept. A micromachined glass stucture with a patterned layer of Cr on its top surface to form regularly spaced detection slits was used to perform capillary electrophoresis separations with 55-point, laser induced fluorescence detection over 3.78 cm of the 6.6 cm separation channel. While this method can be easily integrated into a miniaturized total analysis system (MU-TAS), the principle is equally applicable to detection in full-sized analytical instrumentation. Single-component samples (fluorescein) migrating through the separation channel yielded a single peak in the frequency domain, and two-component samples (fluorescein and fluorescein isothiocyanate) yielded two resolved peaks, each at the expected frequency; harmonics were also observed. Advantages were seen in terms of isolation of the analyte peaks from interference such as baseline drift and line noise. Resolution is somewhat inferior to that seen in single-point detection, but it is thought that improved chip design and mathematical and instrument optimization will lead to performance superior to that of single-point detection. PMID- 21662749 TI - Chiral separations performed by enhanced-fluidity liquid chromatography on a macrocyclic antibiotic chiral stationary phase. AB - The use of enhanced-fluidity liquid chromatography (EFLC) for chiral separations was demonstrated on a macrocyclic antibiotic column, Chirobiotic-V. This technique was compared to high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) for the separation of chiral compounds in normal-phase mode. The highest resolution was always observed for EFLC condition. Higher efficiency and shorter retention time were also observed for most separations with portions of CO(2) in the range of 0-50 mol %. Larger amounts of CO(2) caused efficiency to decrease and retention time to be prolonged. For some separations, the temperature was elevated to bring the mobile phase to the supercritical condition. Improved efficiency was obtained in SFC, whereas resolution and selectivity were worse. The use of EFLC in reversed-phase chiral separations was also tested. Enantiomer resolution improved under the EFLC condition. For the tested methanol/H(2)O mixture, fluoroform provided more significant improvements in chromatographic performance than CO(2) when used as a fluidity enhancing liquid. The use of EFLC instead of HPLC also caused a markedly lower pressure drop across the column for commonly used flow rates. The low pressure drop will allow the use of longer columns or multiple columns to increase the total efficiency of the separation. Since chiral columns are often inefficient, this attribute may be very important for chiral separations. PMID- 21662750 TI - Artificial receptor-facilitated solid-phase microextraction of barbiturates. AB - A receptor for barbiturates, N,N'-Bis-[6-(2-ethylhexanoylamino)-pyridin-2-yl] isophthalamide, was designed to dissolve in plasticizers of poly(vinyl chloride) (PVC). Microextractions using receptor-doped films of PVC were carried out as a function of receptor concentration. The effect of the concentration of the receptor on extraction yield is considerable for barbiturates that have significant binding to the receptor but negligible for very similar molecules that do not bind to the receptor strongly. Thus, it is the receptor's ability in molecular recognition, not its generic ability as an H-bonding cosolvent, that is important. On the other hand, NMR data show that the receptor self-associates. A simple, approximate analysis is given to extract the amount of active receptor from the data. Receptor-enhanced extractions of barbiturates from urine are compared to extractions using a phosphate ester as solvent. PMID- 21662751 TI - On-line solid-phase extraction of triazine herbicides using a molecularly imprinted polymer for selective sample enrichment. AB - A coupled-column system, consisting of a combination of a molecularly imprinted polymer (MIP) and a C(18)-silica column, was used for selective triazine detection in the HPLC mode. Complex aqueous samples, spiked with triazines, were selectively extracted by the MIP followed by subsequent identification by analytical reversed-phase chromatography. The MIP showed good performance for selectively discriminating triazines from humic acid, whereas urine and apple extract had some tendency to be retained by the MIP. Enrichment was observed in all cases, and triazine-enrichment factors of up to 100 could be recorded, with good extraction efficiency (74-77%). The results indicate that the high selectivity of MIPs can be favorably used for selective sample enrichment in conjunction with reversed-phase HPLC. PMID- 21662752 TI - Multiresidue herbicide analysis in soil: subcritical water extraction with an on line sorbent trap. AB - We evaluated the feasibility of extracting selectively and rapidly herbicide residues in soils by hot water and collecting analytes with a Carbograph 4 solid phase extraction (SPE) cartridge set on-line with the extraction cell. Phenoxy acid herbicides and those nonacidic and acidic herbicides which are often used in combination with phenoxy acids were selected for this study. Five different soil samples were fortified with target compounds at levels of 100 and 10 ng/g (30 ng/g of clopyralid and picloram) by following a procedure able to mimic weathered soils. Herbicides were extracted with water at 90 degrees C and collected on line by the SPE cartridge. After the cartridge was disconnected from the extraction apparatus, analytes were recovered by stepwise elution to separate nonacidic herbicides from acidic ones. The two final extracts were analyzed by liquid chromatography/mass spectrometry with an electrospray ion source. At the lowest spike level considered, analyte recoveries ranged between 81 and 93%, except those for 2,4-DB and MCPB, which were 63%. For 16 herbicides out of 18, the ANOVA test showed recoveries were not dependent on the type of soil. The method detection limit was in the 1.7-10 ng/g range. For the analytes considered, method comparison showed this extraction method was overall more efficient than Soxhlet and sonication extraction techniques. PMID- 21662753 TI - Methylene Selectivity and Eluotropic Strength Variations in Subcritical Fluid Chromatography with Packed Columns and CO(2)-Modifier Mobile Phases. AB - This work has consisted of better understanding the chro-matographic behavior in subcritical fluid chromatography with CO(2)-acetonitrile and CO(2)-methanol mobile phases. To that end, the changes of solute solubility in the mobile phase have been studied by determination of methylene selectivity of a homologous series. Moreover, eluotropic strengths have been calculated for mobile phases containing from 5 to 45% modifier. To carry out the studies in all ranges of the subcritical area, experimental designs have been used. The influences of analytical temperature (from 10 to 30 degrees C) and outlet pressure (from 10 to 20 MPa) have also been investigated both on solubility and on eluotropic strength. A more general comparison of elu-otropic strengths of subFC and HPLC has been achieved. PMID- 21662754 TI - Spherical clay conglomerates: a novel stationary phase for solid-phase extraction and "reversed-phase" liquid chromatography. AB - A new solid phase is presented to be used for the solid-phase extraction (SPE) of organic compounds from aqueous solutions and as a stationary phase for the separation of organic compounds in "reversed-phase" HPLC. The material consists of spherical clay conglomerates (SCCs) in the size ranges of 2-5, 5-10, and 10-20 MUm. SCCs are especially well suited for the extraction and separation of aromatic compounds with electron-withdrawing substituents, because of the formation of specific electron donor-acceptor (EDA) complexes of such compounds with natural clay minerals. A series of nitroaromatic compounds (NACs), e.g., nitrophenols, and nitrotoluenes, served as probe substances for the characterization of the SPE with SCCs online coupled to a C18-HPLC-DAD system. Breakthrough volumes were > 1 L and method detection limits (MDLs) < 100 ng/L for compounds with moderate to high affinity towards clay minerals. The performance of the material is hardly affected by matrix effects and because of its excellent physical properties, i.e., regenerability and pressure-resistance, it meets the requirements for fully automated routine trace analysis of several primary pollutants, such as 6-methyl-2,4-dinitrophenol (DNOC) or 2,4,6-trinitrotoluene (TNT), in various natural waters. Offline SPE with SCCs was superior or equivalent to commercial SPE products for analysis of such compounds. Finally, SCCs are shown to be well suited as a stationary phase in reversed-phase HPLC. This opens a wide range of applications, e.g., as an easy and fast separation technique that is orthogonal to C18 reversed-phase HPLC. PMID- 21662755 TI - GC-AED Studies of Nicotine Fate in a Burning Cigarette. AB - An atomic emission detector (AED) for a gas chromatograph (GC) can be used to selectively detect compounds labeled with stable isotopes, such as D, (13)C, and (15)N. This capability can be used to determine precursor-fate relationships within complex matrixes, using stable isotopes rather than radiolabeled isotopes. Employing stable isotopes removes the safety consideration associated with radiolabeling studies. Two previous reports have employed GC-AED in fate studies for (13)C-labeled precursors. The goal of this study was to evaluate the utility of GC-AED for precursor-fate determinations in tobacco science. In this work, GC AED was used to determine the fate of nicotine-d(4) in a burning cigarette. GC MSD was then employed to identify the compounds that the AED indicated contained D. Spectral confirmation of the presence of D was performed on each chromatographic peak of interest with both AED and MSD to ensure that the identification of the products was correct. Nicotine and nicotine-d(4) standards were used to evaluate the effect of coelution of unlabeled compounds with the labeled compounds on the AED response for D. It was shown that the AED response for D at lambda = 308 nm decreases with increased concentration of unlabeled compound. Detection at lambda = 656 nm, however, is unaffected by the presence of the unlabeled compound. Compound-independent calibration is also possible at this wavelength. GC-AED studies with nicotine-d(4) core injected into cigarettes demonstrated that most of the nicotine (79%) is distilled, unchanged, into the mainstream (MS) and sidestream (SS) smoke. The degradation products that do occur include 3-substituted pyridines and nicotine-oxidation products. These are found only in the SS smoke. PMID- 21662756 TI - In situ, High-Resolution Measurement of Dissolved Sulfide Using Diffusive Gradients in Thin Films with Computer-Imaging Densitometry. AB - The technique of diffusive gradients in thin films (DGT) has been developed for the measurement of dissolved sulfide. Sulfide species from the sampled waters diffuse through a polyacrylamide hydrogel and then react with pale yellow AgI((s)), incorporated at the surface of a second gel, to form black Ag(2)S((s)). The accumulated sulfide can be measured with a conventional purge-and-trap method followed by colorimetry (methylene blue). This enables the dissolved-sulfide concentration to be calculated under suitable conditions. Alternatively, the color change in the accumulating gel can be used to measure sulfide. A conventional flat-bed scanner, allied to imaging software, provided a densitometric measurement that was quantitatively related to the amount of sulfide accumulated. DGT measurements on synthetic solutions accurately determined the sulfide concentration (95% recovery), thereby confirming the unobstructed diffusion of HS(-) through the gel. The accumulated mass was inversely proportional to the diffusion-layer thickness as theoretically predicted. With the selected geometry, the limit of detection of the densitometric procedure for a 24-h deployment was 0.13 MUmol L(-)(1), and the maximum concentration measurable was 60 MUmol L(-)(1). When used in anoxic lacustrine waters, DGT provided sensible concentrations. It was also used to measure depth profiles at submillimeter resolution in estuarine surface sediments. PMID- 21662757 TI - Hydrodynamics and mass transfer of the coaxial jet mixer in flow injection analysis. AB - A coaxial jet mixer that was previously proposed for rapid and efficient mixing under laminar flow conditions has been studied both theoretically and experimentally. A mathematical model that consists of a set of Navie-Stokes equations that determine the flow velocities and three diffusion-convection reaction equations that determine the reactant and product concentrations has been developed. Equations are solved with the help of finite difference techniques for different flow conditions. The quality of sample and reagent mixing is characterized by the mean product concentration and the amount of product produced. Theoretical results are compared with experimental ones for the mixing of bromothymol blue (a pH indicator) in the outer capillary with NaOH in the inner capillary of the jet mixer. PMID- 21662758 TI - Modeling the Responses of Thickness-Shear Mode Resonators under Various Loading Conditions. AB - We develop a general model that describes the electrical responses of thickness shear mode resonators subject to a variety of surface conditions. The model incorporates a physically diverse set of single-component loadings, including rigid solids, viscoelastic media, and fluids (Newtonian or Maxwellian). The model allows any number of these components to be combined in any configuration. Such multiple loadings are representative of a variety of physical situations encountered in electrochemical and other liquid-phase applications, as well as gas-phase applications. In the general case, the response of the composite load is not a linear combination of the individual component responses. We discuss application of the model in a qualitative diagnostic fashion to gain insight into the nature of the interfacial structure, and in a quantitative fashion to extract appropriate physical parameters such as liquid viscosity and density and polymer shear moduli. PMID- 21662759 TI - Continuous-Flow and Flow Injection pH Gradients for Spectrophotometric Determinations of Mixtures of Nucleic Acid Components. AB - A procedure for the rapid determination of mixtures of nucleic acid components from the analysis of spectrophotometric multivariate data obtained with continuous-flow and flow injection pH-gradient systems is proposed. Three flow systems have been developed and assayed in which an on-line pH gradient is generated from the mixing and controlled dispersion of acidic and basic titrant solutions. Quantitative determinations of any particular analyte in the unknown samples in the presence of interferences is performed with a single pure standard for this analyte. They are carried out using an alternating least squares multivariate curve resolution procedure. The methods proposed have been validated using synthetic and real sample mixtures. The results obtained are concordant with the labeled values, and the relative prediction errors are around 5%. PMID- 21662760 TI - Molecular sensors and sensor arrays based on polyaniline microtubules. AB - This paper describes the fabrication of microtubular biosensors and sensor arrays based on polyaniline with superior transducing ability. These sensors have been tested for the estimation of glucose, urea, and triglycerides. As compared to that of a macro sensor, the response of the microtubular sensor for glucose is higher by a factor of more than 10(3). Isoporous polycarbonate membranes have been used to fabricate inexpensive devices by simple thermal evaporation of gold using appropriate machined masks. Polyaniline deposition and enzyme immobilization have been done electrochemically. Electrochemical potential control has been used to direct enzyme immobilization to the chosen membrane device and avoid cross talk with adjacent devices. This has enabled the immobilization of a set of three different enzymes on three closely spaced devices, resulting in a microtubule array that can analyze a sample containing a mixture of glucose, urea, and triglycerides in a single measurement. This, in essence, is an "electronic tongue". PMID- 21662761 TI - Atmosphere generation system for the preparation of ambient air volatile organic compound standard mixtures. AB - A dynamic generation system based on permeation for the preparation of volatile organic compounds at ambient air concentration levels is described herein. The performance of the equipment, sources of uncertainties, and overall uncertainty value are also evaluated. The system is capable of generating multicomponent mixtures at ppb levels and simulating different atmospheric conditions by changing the humidity, concentration level, temperature, and wind velocity. A minimized value for the overall uncertainty in the concentration generated by the system was determined to be +/-1.9% for higher weighing time intervals of 4 weeks. PMID- 21662762 TI - Amperometric thick-film strip electrodes for monitoring organophosphate nerve agents based on immobilized organophosphorus hydrolase. AB - An amperometric biosensor based on the immobilization of organophosphorus hydrolase (OPH) onto screen-printed carbon electrodes is shown useful for the rapid, sensitive, and low-cost detection of organophosphate (OP) nerve agents. The sensor relies upon the sensitive and rapid anodic detection of the enzymatically generated p-nitrophenol product at the OPH/Nafion layer immobilized onto the thick-film electrode in the presence of the OP substrate. The amperometric signals are linearly proportional to the concentration of the hydrolyzed paraoxon and methyl parathion substrates up to 40 and 5 MUM, showing detection limits of 9 * 10(-)(8) and 7 * 10(-)(8) M, respectively. Such detection limits are substantially lower compared to the (2-5) * 10(-)(6) M values reported for OPH-based potentiometric and fiber-optic devices. The high sensitivity is coupled to a faster and simplified operation, and the sensor manifests a selective response compared to analogous enzyme inhibition biosensors. The applicability to river water sampling is illustrated. The attractive performance and greatly simplified operation holds great promise for on-site monitoring of OP pesticides. PMID- 21662763 TI - Influence of Thermal Annealing on the Thermodynamic and Mass-Transfer Kinetic Properties of d- and l-Phenylalanine Anilide on Imprinted Polymeric Stationary Phases. AB - An investigation of the material, chromatographic, thermodynamic, and kinetic properties of thermally treated (i.e., annealed) polymeric stationary phases imprinted with l-phenylalanine anilide (l-PA) was carried out. The imprinting procedure of the solid phase used in this study was the same as for the untreated imprinted stationary phase studied previously. However, after polymerization, these new stationary phases were treated at elevated temperatures (50, 120, 140, and 160 degrees C) for 24 h. The treatment at 120 and 140 degrees C led to a larger decrease in the retention of l-PA than that of d-PA. The polymer treated at 160 degrees C could no longer resolve the d,l-PA racemate. The heat treatments were accompanied by a decrease in swelling and an increase in density causing an increase in the density of the remaining active sites. The polymer treated at 120 degrees C was chosen for classical frontal analysis. The adsorption isotherms and the mass-transfer rate coefficients of d- and l-PA were derived from the experimental breakthrough curves. This study was carried out in the same temperature and concentration ranges as the previous one. A comparative discussion of the properties of the two polymeric molecular imprinted stationary phases is presented. The thermal treatment increases the saturation capacity of the packing material by one-third to one-half, reduces markedly the separation factor of the two enantiomers, and slightly accelerates their mass-transfer kinetics. There seems to be no interactions on the annealed polymer between the selective l-PA imprinted sites and the d-PA molecules. PMID- 21662764 TI - Trace Element Microanalysis in Iron Meteorites by Laser Ablation ICPMS. AB - A laser ablation microanalysis system has been developed that can analyze trace elements with a sensitivity in the ppb range, using a CETAC LSX-200 laser ablation system with a Finnigan Element. This capability has been applied to a set of iron meteorites to demonstrate the laser microprobe's analytical capability for the determination of platinum group elements (PGEs) with a spatial resolution of ~20 MUm, comparable to that of dynamic secondary ion mass spectrometry (SIMS). The laser is shown to provide an accurate means of solid sampling for magnetic sector inductively coupled plasma mass spectrometry (ICPMS), allowing the determination of bulk metal composition, chemical zoning within the sample, and depth profiling. Recovery of the chemical zoning in taenite lamellae was achieved for Ru, Rh, and Pd, which was not previously possible using SIMS. The methods presented here show that magnetic sector ICPMS can be successfully coupled to a laser ablation system, providing the advantages of higher sensitivity of the sector instrument, low background count rates (<0.1 counts/s), and flat-topped spectral peaks, while minimizing tradeoff against the speed of data acquisition required to handle the transient signals from the laser ablation system. PMID- 21662765 TI - Error analysis of the rapid lifetime determination method for double-exponential decays and new windowing schemes. AB - The rapid lifetime determination method (RLD) is a mathematical technique for extremely rapid evaluations of lifetimes in exponential decays. It has been applied in luminescence microscopy and single-molecule lifetime evaluation. To date, the primary application has been in single-exponential evaluations. We present extensions of the method to double exponentials. Using Monte Carlo simulations, we assess the performance of both the double-exponential decay with known lifetimes and the double-exponential decay with unknown preexponential factors and lifetimes. Precision is evaluated as a function of the noise level (Poisson statistics), the ratios of the lifetimes, the ratios of their preexponential factors, and the fitting window. Optimum measurement conditions are determined. RLD is shown to work well over a wide range of practical experimental conditions. If the lifetimes are known, the preexponential factors can be determined with good precision even at low total counts (10(4)). With unknown preexponential factors and lifetimes, precisions decrease but are still acceptable. A new gating scheme (overlapped gating) is shown to offer improved precision for the case of a single-exponential decay. Theoretical predictions are tested against actual experimental data from a laser-based lifetime instrument. PMID- 21662766 TI - Simplex Optimization of PCA-Based Infrared Expert Systems. AB - This paper describes an improved principal component analysis-based infrared expert system. The simplex algorithm is used to optimize the feature weight spectrum, thereby increasing the separation of different classes of compounds. First, the classification of a two-class system is significantly improved. Analysis indicates that compounds having more than three classes can also be separated in a single step using the same approach. This can simplify the structural elucidation tree in an expert system. Also reported here are factors influencing optimization of the feature weight spectra, including the initial data matrix and the step size of the optimization. PMID- 21662767 TI - Electrospray ionization mass spectrometry of tetracycline, oxytetracycline, chlorotetracycline, minocycline, and methacycline. AB - The effects of mobile-phase additives and analyte concentration on electrospray ionization mass spectra of a series of tetracyclines were investigated in both positive and negative ion modes. Only [M + H](+) and [M - H](-) ions were observed. The greatest sensitivity as [M + H](+) ions was obtained with 1% acetic acid and the greatest sensitivity as [M - H](-) ions was obtained using 50 mM ammonium hydroxide. Sensitivities in the positive ion mode were greater than those in the negative ion mode. The sensitivity as [M + H](+) showed no systematic variation with pH; however, the sensitivity as [M - H](-) did increase with increasing pH. A larger linear range was observed for [M - H](-) than for [M + H](+) ions. Both [M + Na](+) and [M + H](+) ions were observed with 0.5 mM sodium acetate and sodium iodide, but no adduct ions were observed with ammonium acetate. Some M(2)H(+) ions were observed at higher concentrations. Cluster ions, Na(NaOAc)(n)(+) or Na(NaI)(n)(+), but no sample ions were observed using 5 mM salts. The data suggest that mechanisms in addition to solution ionization are involved in the formation of the ESI sample ions. The utility of mobile phases containing 1% HOAc or 50 mM NH(4)OH was demonstrated for chromatographic separations. PMID- 21662768 TI - Dilute Solution Behavior of Dendrimers and Polysaccharides: SEC, ESI-MS, and Computer Modeling. AB - Dendrimers, the most highly branched structures achievable, have found numerous uses in the chemical, biological, and pharmaceutical fields. We have employed size exclusion chromatography (SEC) with universal calibration to determine molecular weight averages, distributions, intrinsic viscosities, and structural parameters of Starburst dendrimers, dextrans, and the starch degradation polysaccharides known as maltodextrins. Comparisons have been made in the dilute solution behavior of dendrimers and polysaccharides with equivalent weight average molecular weights. Intrinsic viscosities decreased in the order [eta](dextran) > [eta](dextrin) > [eta](dendrimer). While the difference between dendrimer and polysaccharides may be attributed to the higher branching of the former, which leads to a higher chain density in solution, the difference between dextran and dextrin is likely a result of the variation in solution behavior of alpha-(1->6) vs alpha-(1->4) linked carbohydrates. The solution behavior of the maltodextrins studied indicates that debranching in their manufacture appears to have been more thorough than in that of beta-limiting dextrins studied by other groups. Comparison of molecular radii obtained from SEC data to radii from molecular dynamics studies show Starburst dendrimers behave as theta-stars with functionality between 1 and 4. Additionally, electrospray ionization mass spectrometry was employed to determine M(w), M(n), and PD of Astramol dendrimers. PMID- 21662769 TI - Large-volume sample stacking in acidic buffer for analysis of small organic and inorganic anions by capillary electrophoresis. AB - This paper describes a straightforward approach for stacking extremely large volumes of sample solutions containing small organic and inorganic anions in capillary electrophoresis. The methodology involves the stacking of large sample volumes and the separation of the stacked anions in an acidic buffer (pH <4) without intermediate polarity switching. More than 300-fold enrichment was readily attained in a few minutes in the stacking of two similar organic (maleic and fumaric acids) and two inorganic (bromide and nitrate) anions. The applicability of the technique was tested in the determination of trace amounts of nitrate anion (analyte-to-matrix ratio being 1:2 * 10(4) and 1:2.5 * 10(6)) in analytical-grade potassium bromide and boric acid. PMID- 21662770 TI - Time-Dependent Permeance of Gas Mixtures through Zeolite Membranes. AB - The time-dependent permeation behavior of binary gas mixtures through a ZSM-5 zeolite membrane was studied. Although steady-state permeation rates were indistinguishable for CO(2) and N(2) or for cis- and trans-2-butene in binary mixtures, differences in the rate of approach to steady state allowed component distinction. In "normal" systems, one component is initially enriched in the permeate following application of a pulse of analyte gas to the membrane, and then disappears more quickly upon termination of the pulse. Mixtures of cis- and trans-2-butene exhibit qualitatively different behavior; the permeate is enriched in cis-2-butene during both the leading and trailing edges of a sample pulse (though not at steady state). These differences in permeation behavior reflect different balances among multiple transport mechanisms through the zeolite membrane, thought to reflect a combination of selective component sorption and intracrystalline diffusion; in the case of cis- and trans-2-butene, these two factors oppose one another. It is known that this mechanistic complexity can engender synergistic effects, wherein the presence of one component can affect the permeation of another. These may limit applicability to true "unknowns", but resulting complications should be less problematic in well-defined process applications. PMID- 21662771 TI - Effect of Structural Variation within Lipophilic Lariat Ether Phosphonic Acid Monoesters on the Selectivity and Efficiency of Competitive Alkali Metal Cation Extraction into Chloroform. AB - Lipophilic lariat ether phosphonic acid monoethyl esters with systematic crown ether ring size variation from 12-crown-4 to 24-crown-8 are utilized for competitive alkali metal cation extractions from aqueous solutions into chloroform. Effective alkali metal cation extraction from weakly acidic, neutral, and basic aqueous solutions is achieved. With 4, 5, and 6 oxygens in the crown ether rings, selectivities for Li(+), Na(+), and K(+), respectively, are observed. An 18-crown-6 phosphonic acid monoester exhibits excellent extraction selectivity for K(+) with K(+)/Li(+) and K(+)/Na(+) > 100. The lipophilic group attachment site, as well as the crown ether ring size, is shown to influence the extraction selectivity for the lariat ether phosphonic monoesters. PMID- 21662772 TI - Hydrogen bond acidic polymers for surface acoustic wave vapor sensors and arrays. AB - Four hydrogen bond acidic polymers are examined as sorbent layers on acoustic wave devices for the detection of basic vapors. A polysiloxane polymer with pendant hexafluoro-2-propanol groups and polymers with hexafluorobisphenol groups linked by oligosiloxane spacers yield sensors that respond more rapidly and with greater sensitivity than fluoropolyol, a material used in previous SAW sensor studies. Sensors coated with the new materials all reach 90% of full response within 6 s of the first indication of a response. Unsupervised learning techniques applied to pattern-normalized sensor array data were used to examine the spread of vapor data in feature space when the array does or does not contain hydrogen bond acidic polymers. The radial distance in degrees between pattern normalized data points was utilized to obtain quantifiable distances that could be compared as the number and chemical diversity of the polymers in the array were varied. The hydrogen bond acidic polymers significantly increase the distances between basic vapors and nonpolar vapors when included in the array. PMID- 21662773 TI - General description of the simultaneous response of potentiometric ionophore based sensors to ions of different charge. AB - The response of ion-selective membrane electrodes is usually still described with the semiempirical Nicolskii-Eisenman equation although it cannot correctly reproduce experimental data if ions of different charges are involved. The recently published self-consistent model that was derived for two ions of any charges is now extended to any number of ions of any charge. One single explicit equation is here given for the first time for any number of monovalent, divalent, and trivalent ions. Deviations relative to the Nicolskii-Eisenman equation are shown to be especially high at low interferences and bias calibrations if done in a mixed solution of a target sample as well as multivariate calibrations with sensor arrays. PMID- 21662774 TI - An ion-selective electrode for acetate based on a urea-functionalized porphyrin as a hydrogen-bonding ionophore. AB - An ion-selective electrode for acetate based on (alpha,alpha,alpha,alpha) 5,10,15,20-tetrakis[2-(4-fluorophenylureylene)phenyl]porphyrin as an ionophore that has no metal center and forms hydrogen bonds to the analyte is described. At pH 7.0 (0.1 M HEPES-NaOH buffer), the electrode based on this ionophore and cationic sites (50 mol % relative to the ionophore) responds to acetate in a linear range from 1.58 * 10(-)(4) to 1.58 * 10(-)(2) M with a slope of -54.8 +/- 0.8 mV/decade and a detection limit of (3.06 +/- 1.15) * 10(-)(5) M. Selectivity coefficients determined with the separate solution method (SSM) indicate that interferences of hydrophobic inorganic anions are relatively small (log[Formula: see text] (SSM): NO(3)(-), +0.68; SCN(-), +0.60; NO(2)(-), +0.22; I(-), +0.20; ClO(4)(-), +0.12; Br(-), -0.13). Responses to anions that are good hydrogen bond acceptors, i.e., Cl(-), HSO(3)(-), and HCO(3)(-), were Nernstian and were weaker than the response to acetate (log[Formula: see text] (SSM): -0.54, -0.56, and 1.34, respectively). Negligibly small responses were observed for very hydrophilic anions, i.e., F(-), SO(4)(2)(-), and H(2)PO(4)(-)/HPO(4)(2)(-). While aliphatic carboxylates such as formate, propanoate, pyruvate, and lactate gave Nernstian responses similar to acetate, interferences of salicylate and benzoate were considerably decreased in comparison with electrodes based on cationic sites only. Concentrations of acetic acid in vinegar samples were determined by direct potentiometry and agreed with values determined by a standard enzymatic method. PMID- 21662775 TI - Polyeugenol-modified platinum electrode for selective detection of dopamine in the presence of ascorbic Acid. AB - A platinum electrode was modified with electropolymerized films of 4-allyl-2 methoxyphenol (eugenol) by its oxidative polymerization from an alkaline solution by cyclic voltammetry. The modified electrode was than used to determine dopamine (DA) in an excess of ascorbic acid (AA) by differential pulse voltammetry. The peak positions as well as relative sensitivity DA/AA were affected by the potential window applied for the polymerization. For polymerization between 0 and 2.2 V, the peak potentials recorded in a phosphate buffer solution (pH 7.4) were 61 and +152 mV vs Ag/AgCl for AA and DA, respectively. After a 5-min equilibration, relative sensitivity DA/AA was 164 and the current sensitivity for DA was 7.9 nA MUM(-)(1). The detection limit for S/N = 3 is 0.1 MUM. The high selectivity and sensitivity for DA was found to be due to charge discrimination/analyte accumulation and an effect of catalytic mediation of redox sites. Chronocoulometric data reveal that DA is accumulated on the electrode as a monolayer. The electrode is stable, reversible, and free of fouling problems. PMID- 21662776 TI - Effect of ionic strength on the behavior of amperometric enzyme electrodes mediated by redox hydrogels. AB - The electron-transfer behavior of electroactive hydrogels formed by cross-linking ferrocene poly(allylamine) (Fc-PAA) and glucose oxidase is investigated as a function of electrolyte ionic strength using several techniques. Cyclic voltammetry and electrochemical impedance spectroscopy show that the quantity cD(e)(1/2) increases with electrolyte concentration. Enhancement of enzyme catalysis for the oxidation of glucose mediated by Fc-PAA is also apparent at higher KNO(3) concentration. The electroactive redox center concentration, c, and the diffusion coefficient due to electron hopping in the gel, D(e), are independently measured by chronoamperometry at ultramicroelectrodes. Larger electrolyte ionic strength induces an increase in electroactive redox center concentration while D(e) slightly decreases. These results are rationalized in terms of the electrostatic interactions within the redox gel backbone due to water and ion exchange with the external electrolyte, producing swelling and shrinking of the hydrogel. PMID- 21662777 TI - Optimization of (15)n detection with an atomic emission detector. AB - Gas chromatography with atomic emission detection is a useful tool for the detection of stable isotope labels in complex samples. While papers involving the analysis of D and (13)C are numerous, little work has been done in the area of (15)N detection. For (15)N isotope detection, three reagent gases are used: H(2), O(2), and CH(4). In this work, the reagent gas flows were varied to optimize the sensitivity of (15)N detection without sacrificing isotope selectivity. The optimal gas flows determined in this work produce the following ratios of the spectral peak areas: O 725 area/He 728 area = 0.039 with only O(2) flowing; H 486 area/He 492 area = 12 with only H(2) flowing; C 496 area/He 502 area = 0.41 with O(2), H(2), and CH(4) flowing for C and no gases flowing for He. When using these gas settings, the (15)N sensitivity is increased by nearly 2 orders of magnitude relative to the manufacturer-recommended settings. It was also demonstrated that the presence of a compound in both the labeled and unlabeled forms in the same sample does not affect the response. The ratios of (15)N to (14)N in standards, calculated from calibration plots (which are linear for both isotopes), agree well with the actual values. A tobacco smoke sample containing various (15)N-labeled compounds was used to show the utility of the GC AED for indicating which compounds in a complex sample contain the label. This sample also demonstrates the necessity for optimal sensitivity when dealing with samples containing small amounts of compounds with low incorporation levels. PMID- 21662778 TI - Diffractive optical chemical sensor based on light absorption. AB - A new type of chemical sensor based on light absorption is proposed. An array of zones alternatively containing the pH indicator thymolphthalein is formed in a gelatin film. By changing the sample solution from acidic to alkaline, a blue stripe appears in the gelatin film. This acts as a transmission grating and diffracts the introduced laser beam. Theory predicts that this method, which is based on light absorption/beam diffraction, is as sensitive as or more sensitive than fluorometry. PMID- 21662779 TI - Trace determination of glycols by HPLC with UV and electrospray ionization mass spectrometric detections. AB - A high-performance liquid chromatography/mass spectrometry (HPLC/MS) method is developed for trace determination of glycols (ethylene glycol, 1,2- and 1,3 propylene glycols, and 2,3-butylene glycol) in water after derivatization with benzoyl chloride. Benzoyl esters of glycols are separated by microcolumn reversed phase HPLC. Sensitivity and linearity of UV detection at 237 nm is compared with electrospray ionization mass spectrometric (ESI-MS) detection using selected ion monitoring. Limits of detection (LOD) and quantitation (LOQ) for UV detection are 1 and 2 mg/L, respectively. For ESI-MS detection, LOD and LOQ are in the ranges 10-25 and 20-50 MUg/L, respectively. LOD obtained by ESI-MS for the determination of glycols is improved by 2-3 orders of magnitude in comparison to previously published methods. The effect of the structure of isomeric glycols on their electrospray mass spectra is discussed. The method has been applied for the determination of glycols in aqueous matrixes containing high concentrations of salts occurring in nuclear waste disposal treatment. PMID- 21662780 TI - Consistency of NMR and mass spectrometry determinations of natural-abundance site specific carbon isotope ratios. The case of glycerol. AB - Quantitative determinations of natural-abundance carbon isotope ratios by nuclear magnetic resonance (SNIF-NMR) have been optimized by appropriate selection of the experimental conditions and by signal analysis based on a dedicated algorithm. To check the consistency of the isotopic values obtained by NMR and mass spectrometry (IRMS) the same glycerol samples have been investigated by both techniques. To have access to site-specific isotope ratios by IRMS, the products have been degraded and transformed into two derivatives, one of which contains carbons 1 and 3 and the other carbon 2 of glycerol. The sensitivity of the isotopic parameters determined by IRMS to fractionation effects possibly occurring in the course of the chemical transformations has been investigated, and the repeatability and reproducibility of both analytical chains have been estimated. The good agreement observed between the two series of isotopic results supports the reliability of the two different approaches. SNIF-NMR is therefore a very attractive tool for routine determination, in a single nondestructive experiment, of the carbon isotope distribution in glycerol, and the method can be applied to other compounds. Using this method, the isotopic distributions have been compared for glycerol samples, obtained from plant or animal oils, extracted from fermented media, or prepared by chemical synthesis. Typical behaviors are characterized. PMID- 21662781 TI - Relative dissociation energies of protonated peptides by electrospray ionization/surface-induced dissociation. AB - Relative dissociation energies (RDEs) are obtained for the major fragment ions produced by electrospray ionization/surface-induced dissociation of singly protonated triglycine, tetraglycine, leucine enkephalin, and leucine enkephalin arginine. A previously described data analysis method (Lim, H.; et al. J. Phys. Chem. B 1998, 102, 4753) is employed to analyze the energy-resolved mass spectra by subtracting out the distribution of energy transferred to the surface, integrating over the distribution of the incident ion energy, and taking into account the precursor ion initial internal energy and kinetic energy distributions. These variables are optimized by anchoring the RDE for the lowest energy fragment of a given precursor ion to its literature values and then using these optimized parameters to obtain the other RDEs. The RDEs of the four major fragments of triglycine vary from 2.4 eV for the b(2) fragment ion to 6.0 eV for the a(2) ion. The RDEs of the four major fragments of tetraglycine vary from 3.2 eV for the y(2) ion to 5.7 eV for the a(2) ion. The leucine enkephalin RDEs range from 1.1 eV for the b(4) ion to 2.1 eV for the b(2) ion. The leucine enkephalin arginine RDEs all lay between 2.5 and 3.5 eV. The overall trend of fragmentation order for all peptides is (y(n), b(n)) < a(n) and is consistent with the results from other experiments. The peptide RDEs presented here are only as accurate as the literature values to which they are anchored. Determination of absolute dissociation energies from SID data will require further refinement of the data analysis method. PMID- 21662782 TI - Capillary supercritical fluid chromatography/mass spectrometry of phenolic mannich bases with dimethyl ether modified ethane as the mobile phase. AB - The analysis of phenolic Mannich bases [Formula: see text] which are used as hardeners and accelerators for epoxy resins [Formula: see text] by capillary supercritical fluid chromatography (SFC) with dimethyl ether modified ethane as the mobile phase is described. The elution properties of several different mobile phases with respect to amines are shown. SFC with UV detection is coupled via a custom-built interface to a mass spectrometer with atmospheric pressure chemical ionization. Two technically important Mannich bases prepared by different production processes are characterized and compared with respect to their byproducts. The role of dimethyl ether during the ionization process and the fragmentation of phenolic Mannich bases is discussed. PMID- 21662783 TI - Electrospray ionization high-field asymmetric waveform ion mobility spectrometry mass spectrometry. AB - High-field asymmetric waveform ion mobility spectrometry (FAIMS) is a new technique that separates gas-phase ions at atmospheric pressure (760 Torr) and room temperature. A FAIMS instrument acts as an ion filter and can be set to continuously transmit one type of ion. Despite the stringent requirement for a flow of clean, dry gas in the FAIMS analyzer region, a method of coupling electrospray to FAIMS has been developed. The identity of the electrospray ions separated by FAIMS was determined using mass spectrometry (FAIMS-MS). The theory of FAIMS is discussed, and electrospray FAIMS-MS spectra of several compounds in modes P1, P2, N1, and N2 are presented. Ions appearing in P1 and N1 modes tend to have mobilities that increase as a function of increasing electric field strength, whereas ions appearing in P2 and N2 modes tend to have mobilities that decrease. In general, low-mass ions are focused in P1 and N1 modes, whereas larger ions (e.g., proteins) are focused in P2 and N2 modes. Short-chain peptides, (Gly)(n) where n = 1-6, are shown to cross over from P1 mode into P2 mode as the chain length increases. The removal of the low-mass solvent cluster ions, combined with a reduction of the background noise in electrospray FAIMS-MS, results in an improved signal-to-noise ratio for mass spectra of larger ions (e.g., cyctochrome c) when compared with conventional electrospray-MS. Preliminary results also suggest that various charge states of cytochrome c can be distinguished by FAIMS, implying that the ion mobility of these species at high electric field strength is sensitive to the structure of the protein ion. The linearity of response of electrospray FAIMS-MS was investigated using leucine enkephalin and shows the calibration curve to be linear for ~3 orders of magnitude. PMID- 21662784 TI - High-efficiency DNA separation by capillary electrophoresis in a polymer solution with ultralow viscosity. AB - The viscosities of some polymer solutions for DNA separation in capillary electrophoresis are generally very high, which makes them hard to pump into the capillaries. We have developed a novel sieving buffer, based on low-molecular weight hydroxypropylmethylcellulose, to separate DNA fragments. The viscosity of this sieving matrix was at least 1 order of magnitude lower than that of traditional buffers with similar sieving effect. The influence of additives such as urea and mannitol was investigated. It was found that the double-stranded DNA (ds DNA) fragments began to denature in 3.5 M urea, and 7 M urea can denature the ds DNA completely. The presence of mannitol will decrease the overlap threshold of the polymer solution (the concentration at which the polymer molecules begin to entangle with each other), which makes it possible to separate DNA fragments in a polymer solution of relatively low concentration. The influence of the electrical field was also investigated, and it was found that the mobility of DNA fragments up to 2000 bp in length did not change greatly with different electric fields. This phenomenon implies that the DNA fragments at this range do not change their conformation with the increase of electric field as was previously believed. The possible mechanism for the separation of DNA fragments is also discussed. PMID- 21662785 TI - Evaluation of automated isocratic and gradient nano-liquid chromatography and capillary electrochromatography. AB - An automated liquid nano-separation system has been developed for nano-liquid chromatography (nano-LC) and capillary electrochromatography (CEC) using both isocratic and gradient elution. One fused-silica nanocolumn, typically 75 MUm i.d. * 39 cm (25 cm effective packed length), packed with Spherisorb ODS 1, 3 MUm particle size, can be used with either technique without having to remove the column upon switching from one mode to the other. The mobile phase is delivered by two reciprocating micro-LC pumps at a flow rate of 30 MUL/min to a postinjection splitter that houses the nanocolumn inlet. The splitter is directly connected to a micro-injection valve with a 0.5 MUL injection volume. In the CEC mode, pressure is not applied (no restriction on splitter) to the column inlet or outlet and the voltage is continuously applied during sample injection and mobile phase delivery. In the nano-LC mode, the restrictor is coupled to the splitter. Using the same nanocolumn under isocratic conditions, the repeatabilities of retention time and peak area for nano-LC were better than 0.2% and 4%, respectively, and those for CEC were better than 0.6% and 6%, respectively. On average, column efficiency was 57% higher in CEC compared to nano-LC. Gradient elution separations of parabens and polynuclear aromatic hydrocarbons (PAHs) were accomplished by CEC. PMID- 21662786 TI - Packed column supercritical fluid chromatography/mass spectrometry for high throughput analysis. AB - A supercritical fluid chromatograph was interfaced to a mass spectrometer, and the system was evaluated for applications requiring high sample throughput. Experiments presented demonstrate the high-speed separation capability of supercritical fluid chromatography (SFC) and the effectiveness of supercritical fluid chromatography/mass spectrometry (SFC/MS) for fast, accurate determinations of multicomponent mixtures. A high-throughput liquid chromatography/mass spectrometry (LC/MS) analysis cycle time is reduced 3-fold using our general SFC/MS high-throughput method, resulting in substantial time saving for large numbers of samples. Unknown mixture characterization is improved due to the increased selectivity of SFC/MS compared to LC/MS. This was demonstrated with sample mixtures from a 96-well combinatorial library plate. In this paper, we report a negative mode atmospheric pressure chemical ionization (APCI) method for SFC/MS suitable for most of the components in library production mixtures. Flow injection analysis (FIA) also benefits from this SFC/MS system. A broader range of solvents is amenable to the SFC mobile phase compared with standard LC/MS solvents, and solutes elute more rapidly from the SFC/MS system, reducing sample carryover and cycle time. Finally, our instrumental setup allows for facile conversion between LC/MS and SFC/MS modes of operation. PMID- 21662787 TI - A systematic approach to optimize solid-phase microextraction. Determination of pesticides in ethanol/water mixtures used as food simulants. AB - The optimization of solid-phase microextraction (SPME) of several organochlorine and organophosphorus pesticides is presented, and the influence of variables is discussed. The optimized method is applied to several selected ethanol/water mixtures used as food simulants, and the influence of the ethanol content on the SPME performance is also discussed. Detection limits ranging from 0.02 to 0.04 ng/g for water simulant and from 38.7 to 205.5 ng/g for 95% ethanol simulant were obtained. The relative standard deviation (% RSD) was <20% in all cases. The optimized method is compared with classical liquid-liquid extraction (LLE). PMID- 21662788 TI - Chemical imaging of patterned inorganic thin-film structures by lateral force microscopy. AB - Factors influencing the chemical image formation by lateral force microscopy (LFM, or friction force microscopy, FFM) under normal ambient conditions were studied by applying LFM to patterned specimens of inorganic thin films deposited predominantly by atomic layer epitaxy. The patterned steps on SnO(2)/Si, CaS/Si, CeO(2)/Si, and Pt/Al(2)O(3) samples were formed by chemical etching or lift-off processing. The results of semiquantitative AFM and LFM studies were compared to the static contact angle studies using capillary force evaluation. The chemical contrast in LFM images of the patterned specimens was the highest in cases where silicon was present. This is in accordance with contact angle data, which showed much higher hydrophilicity on Si than on the other materials studied. Further experiments with a patterned SnO(2)/Si specimen indicated that chemical contrast can be significantly affected (i) by whether the surface was pretreated with ethanol, (ii) by the loading force (2-50 nN or 1-10 MUN) applied, and (iii) by using SnO(2)-coated AFM probes instead of the conventional Si probes. PMID- 21662789 TI - Detection of oxidized low-density lipoproteins using surface plasmon resonance. AB - Management of atherosclerosis is a high priority target. If this is to be achieved, the early detection of risk and risk factors are paramount and integrated with this is a need for the detection of the oxidation state of a patient's low density lipoprotein (LDL). Presently no readily usable technique exists for their rapid determination and in order to develop such a technique a monitoring system must be devised which distinguishes a parameter which changes on oxidation and distinguishes critical and noncritical oxidation products. The strategy which is investigated here is based on the use of a heparin-modified Au surface plasmon resonance (SPR) device as a modulator of LDL binding, according to its oxidation state. Heparin is strongly negatively charged and seven binding sites for heparin have been identified on the LDL apoprotein consisting of arginine and lysine clusters; these are regarded as identical to the LDL receptor binding sites. The heparin-modified surface was calibrated for LDL and a calibration factor of 1.84 * 10(9) particles mm(-)(2) Delta(o)(-)(1) SPR and instrumental resolution of 9 * 10(6) particles mm(-)(2) obtained which gives sufficient scope to distinguish LDL dependent binding. LDL oxidation could involve the protein and/or lipoprotein, the latter being of interest for athersclerosis risk and the LDL binding to heparin was shown to decrease with degree of protein oxidation as determined by the free amino groups (fluorescamine assay), but was not influenced by lipid oxidation (determined by thiobarbituric acid reactive substances assay, TBARS). The SPR based assay was tested for LDL in plasma and the calibration found to follow that obtained in buffer, although the scatter was higher, probably due to interference from other plasma species. Nevertheless, in the context of the normal distribution of LDL in healthy patients, the assay would almost certainly be able to determine Ox-LDL in atherosclerotic patients. PMID- 21662790 TI - Cloud point extraction as a preconcentration step prior to capillary electrophoresis. AB - Cloud point extraction was applied as a preconcentration step prior to capillary electrophoresis. The behavior of a surfactant-rich micellar phase injected into a capillary electrophoresis system was studied using different separation modes: micellar electrokinetic capillary chromatography and capillary zone electrophoresis (CZE). A problem that appeared on introducing a surfactant-rich phase into a bare fused silica capillary was that the surfactant was adsorbed onto the wall of the capillary, leading to a marked loss of efficiency and reproducibility both in the migration times and in the areas of the electrophoretic peaks. The use of cetyltrimethylammonium bromide dynamically coated capillaries afforded reproducible results, although the half-life of the capillary was short. The most satisfactory results were obtained by using nonaqueous media in the CZE mode, thus avoiding surfactant adsorption. Other parameters related to the composition of the injection medium were also studied to optimize the electrophoretic behavior of the analytes and the sensitivity of the determination. The optimized procedure was applied to the determination of triazines in tap and river water samples. PMID- 21662791 TI - New concepts in sample controlled thermal analysis: resolution in the time and temperature domains. AB - This paper describes the concepts of resolution in the time and temperature domains and illustrates the principles using two new sample controlled thermal analysis (SCTA) techniques. The use of SCTA, where the sample temperature is determined by the rate of reaction, offers a number of advantages over conventional (linear heating) thermal analysis methods. The operation, advantages, and disadvantages of the two new techniques are discussed with examples. PMID- 21662792 TI - Role of mass accumulation and viscoelastic film properties for the response of acoustic-wave-based chemical sensors. AB - The sensitivity of acoustic-wave microsensors coated with a viscoelastic film to mass changes and film modulus (changes) is examined. The study analyzes the acoustic load at the interface between the acoustic device and the coating. The acoustic load carries information about surface mass and film modulus; its determination has no restrictions in film thickness. Two regimes of film behavior can be distinguished: the gravimetric regime, where the sensor response is mainly mass sensitive, and the nongravimetric regime, where viscoelasticity gains influence on the sensor response. We develop a method, which allows the assignment of the sensor signal to a gravimetric or a nongravimetric response. The critical value can be determined from oscillator measurements. The related limits for the coating thickness are not the same for the coating procedure and mass accumulation during chemical sensing. As an example, we present results from a 10 MHz quartz crystal resonator. PMID- 21662793 TI - Grazing exit electron probe microanalysis for surface and particle analysis. AB - We developed a new method of grazing exit electron probe microanalysis (GE-EPMA) and applied it to analyze both Si surfaces and Mg-salt particles. In conventional EPMA, X-rays are detected at an exit (takeoff) angle of approximately 45 degrees . Therefore, when particles collected on a sample carrier are analyzed by EPMA, the X-rays from both the particles and the carrier are detected, although we need only the X-rays emitted from the particle itself. In contrast to this, the X-rays are detected at grazing exit angles in GE-EPMA. The X-rays emitted from deep inside of the sample are not detected under grazing exit conditions, and only X rays emitted from the surface and the particle are measured. It was found that surface-sensitive analysis of a Si wafer was possible with low background at grazing exit angles. The intensity ratio of O Kalpha to Si Kalpha increased near zero degrees, indicating that the Si wafer is covered with a native Si oxide. Moreover, Mg Kalpha X-rays from a Mg-salt particle, which was deposited on the Si wafer, were detected with a small Si Kalpha intensity at grazing exit angles of less than 0.5 degrees . By decreasing the exit angle to less than zero, only the top of the particle was observed; therefore, GE-EPMA measurement would make it possible to investigate the surface layer of one particle. PMID- 21662794 TI - PVC-Based Mn(III) Porphyrin Membrane-Coated Graphite Electrode for Determination of Histidine. AB - The construction, performance characteristics, and application of a polymeric membrane coated on a graphite electrode with unique selectivity toward histidine are reported. The electrode was prepared by incorporating chloro(5,10,15,20 tetraphenylporphyrinato) manganese(III) [Mn(TPP)Cl] into a plasticized poly(vinyl chloride) membrane. The influences of membrane composition, pH, and foreign ions were investigated. Calibration plots with near Nernstian slopes for histidine were observed, -55.4 mV/decade, over a linear range of four decades of concentration (1 * 10(-)(5) to 1 * 10(-)(1) M). The electrode has a detection limit of 5 * 10(-)(6) M histidine and shows a fast response time of about 1 min. The electrode shows high selectivities toward histidine over several amino acids and common inorganic anions. PMID- 21662795 TI - Electrochemical Oxidation of NADH at Highly Boron-Doped Diamond Electrodes. AB - Conductive boron-doped chemical vapor-deposited diamond thin films, already known to have superior properties for general electroanalysis, including low background current and a wide potential window, are here shown to have additional advantages with respect to electrochemical oxidation of nicotinamide adenine dinucleotide (NADH), including high resistance to deactivation and insensitivity to dissolved oxygen. Cyclic voltammetry, amperometry, and the rotating disk electrode technique were used to study the reaction in neutral pH solution. Highly reproducible cyclic voltammograms for NADH oxidation were obtained at as deposited diamond electrodes. The response was stable over several months of storage in ambient air, in contrast to glassy carbon electrodes, which deactivated within 1 h. The diamond electrode exhibited very high sensitivity for NADH, with an amperometric detection limit of 10 nM (S/N = 7). The response remained stable, even in the very low concentration range, for several months. In addition, interference effects due to ascorbic acid were minimal when the concentrations of NADH and ascorbic acid were comparable. An NADH-mediated dehydrogenese-based ethanol biosensor incorporating an unmodified diamond electrode is demonstrated. The present results indicate that diamond is a useful electrode material for the analytical detection of NADH, making it attractive for use in sensors based on enzyme-catalyzed reactions involving NADH as a cofactor. PMID- 21662796 TI - High-Performance Gas Sensing of CO: Comparative Tests for Semiconducting (SnO(2) Based) and for Amperometric Gas Sensors. AB - A comparison of the stability and sensitivity for two different sensor types (semiconductor SnO(2) devices, amperometric electrochemical sensors) has been performed. Sensitivities and drifts in the signal and in the background for various concentrations of CO have been studied for thick-film SnO(2) sensors (Pt and Pd doped) for a period in excess of 8 months. Similar performance data have been recorded for commercial amperometric sensors for a period in excess of 4 years. The two different sensor types investigated here were also compared to the well-known commercial Figaro TGS 822 sensor at similar concentrations. An objective approach for comparing different types of sensors has been developed using the "analytical sensitivity". PMID- 21662797 TI - Application of zetametry to determine concentrations of acidic and basic impurities in analytical reagents. AB - The sign and magnitude of the zeta potential of mineral oxides in allegedly pure organic solvents (high-quality chemical reagents) depends on the concentration of acidic and basic impurities, chiefly organic acids and amines. "Zetametric titration" with HClO(4) makes it possible to estimate the concentration of basic impurities and offers an attractive alternative to other analytical methods. Titanium(IV) oxide has been chosen as the probe powder in view of its very low solubility and nearly neutral point of zero charge in aqueous systems. Some systems have a high buffer capacity and addition of acid and base has a minor effect on the zeta potential of titania. Specific adsorption of alkali metal cations on anatase can be also a significant problem. PMID- 21662798 TI - Quenching of electrogenerated chemiluminescence by phenols, hydroquinones, catechols, and benzoquinones. AB - Efficient quenching of Ru(bpy)(3)(2+) (bpy = 2,2'-bipyridine) electrogenerated chemiluminescence has been observed in the presence of phenols, catechols, hydroquinones, and benzoquinones. In most instances, quenching is observed with 100-fold excess of quencher over Ru(bpy)(3)(2+), with complete quenching observed between 1000- and 2000-fold excess. The mechanism of quenching is believed to involve energy transfer from the excited-state luminophore to benzoquinone. In the case of phenols, catechols, and hydroquinones, quenching is believed to occur via a benzoquinone derivative formed at the electrode surface. Photoluminescence and UV-visible experiments coupled with bulk electrolysis support the formation of benzoquinone products upon electrochemical oxidation. PMID- 21662799 TI - Quantification of the Interaction between Charged Guest Molecules and Chemisorbed Monothiolated beta-Cyclodextrins. AB - The quantification of small molecules in aqueous solution by surface bound supramolecular host molecules is an important goal in the research field of chemo and biosensor development. In this paper we present an attempt to quantify the interaction of different charged guest molecules with chemisorbed monothiolated beta-cyclodextrin monolayers by means of impedance spectroscopy in the presence of the redox couple [Fe(CN)(6)](3)(-)/[Fe(CN)(6)](4)(-). Self-assembled monolayers of mercaptopropane-N-mono-6-deoxy-beta-cyclodextrin amide (MPA-CD) on gold surfaces were formed with coverage of 99-100%. The inclusion of charged guest molecules was detected by monitoring the changes in the charge-transfer resistance, which is sensitive to the surface charge density in terms of repulsion or attraction of the redox active ions. Adsorption of positively charged 1-adamantanamino hydrochloride (1-ADHC) led to a considerable increase in the charge-transfer resistance, whereas the inclusion of both negatively charged 1-adamantanecarboxylic acid (1-ADC) and 2-(p-toluidinyl)naphthalene-6-sulfonate (2,6-TNS) caused a decrease. Applying the Frumkin correction to obtain the surface charge density and the Gouy-Chapman-Stern theory to account for the electrochemical double layer, we were able to quantify the binding of the charged guest molecules in terms of binding isotherms. The isotherms display a distinct two step adsorption process probably owing to the presence of two energetically different binding sites on the surface. Complete reversibility of the binding process of the guest molecules could be demonstrated by the addition of beta cyclodextrin in solution, which allowed the reuse of the functionalized surfaces. PMID- 21662800 TI - Determination of boron by flow injection analysis using a conductivity detector. AB - A flow injection method for the determination of boron using a conductivity detector has been described. Boric acid injected into the flow system reacts with mannitol (0.3 M) in the mobile phase and an equivalent amount of H(+) is liberated in the stream. The increase in the conductance of the mobile phase due to the liberated H(+) has been equated to the boron concentration in the sample. A linear calibration for light- and heavy-water samples containing 0-20 MUg/mL boron was obtained. Boron concentrations in the samples of light and heavy water and lithium pentaborate solution have been measured. The interferences due to various ions such as Na(+), Li(+), Cu(2+), Ni(2+), Co(2+), Fe(3+), Al(3+), SO(4)(2-), NO(3)(-), F(-), and Cl(-) could be eliminated by adopting a two-step sample pretreatment procedure. In the first step, all the anions were converted to Cl(-) by treating the sample solution with a strong anion-exchange resin. In the second step, the solution obtained from the first step was passed through a silver-guard cartridge to remove interfering cations and Cl(-). The relative standard deviation was +/-0.25% for the determination of 1 MUg of boron in light water, and the limit of detection was 0.01 MUg present in an injection volume of 100 MUL. The corresponding values for heavy water were +/-0.38% and 0.1 MUg, respectively. PMID- 21662801 TI - Concentration Measurement by Proton NMR Using the ERETIC Method. AB - The ERETIC method (Electronic REference To access In vivo Concentrations) provides a reference signal, synthesized by an electronic device, which can be used for the determination of absolute concentrations. The results presented here demonstrate the accuracy and precision of the method in the case of (1)H high resolution NMR. Five tubes were filled with D(2)O solutions of trimethylamine hydrochloride (TMA) 3.84 mM and sodium lactate at concentrations ranging from 5.25 to 54.11 mM. Results obtained with the ERETIC method were compared to those obtained by using TMA as an internal reference. The standard deviations were the same for the two methods and always lower than 1% of the mean. The accuracy (difference between true value and measured value) was slightly better for the ERETIC method than for the internal reference. No significant variation was observed when the experiments were performed over 56 h. Measurements were repeated once a month during three months. As the values obtained showed a standard deviation of only 3%, we can conclude that the ERETIC method has a good stability and only requires monthly calibration. Furthermore, it must be noted that nothing is added to the sample and that the reference signal frequency can be freely chosen to fall within a transparent region of the spectrum. PMID- 21662802 TI - Quantitative SERS Measurements on Dielectric-Overcoated Silver-Island Films by Solution-Deposition Control of Surface Concentrations. AB - A simple method to control the dosing of small adsorbate molecules onto solid surfaces from liquid solution is applied to quantitative surface-enhanced Raman scattering measurements on dielectric-overcoated silver-island films. The deposition method, based on substrate withdrawal from solution, is evaluated by measuring fluorescence (ex situ) and optical absorption (in situ) of dye molecules deposited onto glass surfaces. Control of adsorbate surface concentrations was accomplished by varying the withdrawal rate and the concentration of the dye in solution. The dosing method was used to study the dependence of the electromagnetic contribution to SERS enhancement on surface coverage of scatterer. The sensitivity enhancement was found to be constant for adsorbate coverages up to 60-80% of a monolayer. Beyond a full monolayer, SERS enhancement for additional molecules deposited onto the surface was found to drop significantly, by as much as 1 order of magnitude. PMID- 21662803 TI - High-Speed TOFMS Detection for Capillary Electrophoresis. AB - A new, high-speed data acquisition system was tested for high storage rate time of-flight mass spectrometry (TOFMS) detection in capillary electrophoresis (CE). For high spectral acquisition rates of 4 kHz, a spectral storage rate of 80 spectra s(-)(1) was achieved. The resulting detection limit was in the low amol range (10-25 amol) for continuous infusion investigations. PMID- 21662804 TI - Two-fiber spectroscopic probe with improved scattered light rejection. AB - Our angled two-fiber probe design for in situ spectroscopic measurements (e.g., fluorescence, phosphorescence, or Raman) through a sapphire window has been modified to provide improved rejection of scattered excitation light while maintaining good efficiency of collection of the desired signal. The improvement is achieved by changing the probe axis to an off-normal configuration to minimize back reflection from window surfaces while maximizing the overlap of the light cones of the excitation and collection fibers at the outer window surface where the sample is in contact with the window. The results of laser-induced fluorescence measurements on phenol solution and sand samples, demonstrating the improved performance of the new probe, are reported. Up to 90-fold improvement in the fluorescence/scattered light ratio has been observed with the new probe. PMID- 21662805 TI - Solid-phase extraction procedure of polar benzene- and naphthalenesulfonates in industrial effluents followed by unequivocal determination with ion-pair chromatography/electrospray-mass spectrometry. AB - Highly water soluble benzene- and naphthalenesulfonates are widely used in the chemical, pharmaceutical, tannery, paper, and textile industries. In this work, Isolute ENV+ polystyrene divinylbenzene sorbent was used for the enrichment of 14 benzene- and naphthalenesulfonates from industrial wastewaters. The elution step was performed by adding 1 mL of water containing ion-pair reagent (5 mM of triethylamine (TEA) and 5 mM of acetic acid at pH 6.5) and 9 mL of methanol at 1 mL/min. The most relevant contribution was the use of ion-pair liquid chromatography followed by an orthogonal electrospray interface coupled to mass spectrometry in the negative ionization mode with postcolumn addition at 0.2 mL/min of methanol in combination with a volatile substance (triethylamine) as an ion-pair reagent. [M-H](-) ion was the base peak using low fragmentor voltages of 80 V with the electrospray interface. Significant fragmentation of the quasimolecular [M-H](-) ion occurs at high fragmentor voltage, producing [M SO(2)H](-), [M-SO(3)H](-), and [SO(3)](*)(-) as diagnostic ions. Collision induced dissociation of the parent ions for the benzene- and naphthalenesulfonates studied gave the [SO(3)](*)(-) fragment ion common to sulfonated compounds. At high fragmentor voltages of 150 V, [M-SO(3)H](-) ion is more abundant and therefore has a larger peak than the [M-H](-) peaks for 1,5 naphthalenedisulfonate, 2,6-naphthalenedisulfonate, 1-hydroxy-3,6 naphthalenedisulfonate, 2-hydroxy-3,6-naphthalenedisulfonate, and 2-amino-1,5 naphthalenedisulfonate. Recoveries were higher than 70%, with relative standard deviations between 1.3 and 10.7% with the exception of two naphthalenesulfonate compounds that had recoveries between 26 and 41%. Limits of detection (signal-to noise ratio, 3) ranging from 0.6 pg to 0.13 ng (0.03-6.48 MUg/L) were achieved when 150 mL of groundwater was processed. The aromatic sulfonates 3 nitrobenzenesulfonate, 4-methylbenzenesulfonate, 4-chlorobenzenesulfonate, 1 hydroxy-4-naphthalenosulfonate, 1-amino-6-naphthalenosulfonate, 1-amino-7 naphthalenosulfonate, and 1-naphthalenesulfonate and the linear alkyl benzenesulfonates C(10)-LAS and C(11)-LAS were unequivocally identified and quantitatively determined in MUg/L, in wastewater samples from wastewater treatment plants and textile and tannery industries. 2-Naphthalenesulfonate was found as a major pollutant at mg/L concentration levels. PMID- 21662806 TI - Fragment-Free Mass Spectrometric Analysis with Jet Cooling/VUV Photoionization. AB - We show that it is possible to obtain fragment-free mass spectra of large molecules by a combination of laser desorption, jet cooling, and VUV single photon photoionization. The ability to obtain parent molecular masses is particularly important for the analysis of mixtures, such as combinations of fully saturated hydrocarbons. By varying the cooling conditions, we can also achieve partial fragmentation in order to obtain further structural information. The use of different wavelengths provides additional selectivity between aromatic and aliphatic compounds. PMID- 21662807 TI - A universal concept for stacking neutral analytes in micellar capillary electrophoresis. AB - Unlike recent studies that have depended on manipulation of separation buffer parameters to facilitate stacking of neutral analytes in micellar capillary electrophoresis (MCE) mode, we have developed a method of stacking based simply on manipulation of the sample matrix. Many solutions for sample stacking in MCE are based on strict control of pH, micelle type, electroosmotic flow (EOF) rate, and separation-mode polarity. However, a universal solution to sample stacking in MCE should allow for free manipulation of separation buffer parameters without substantially affecting separation of analytes. Analogous to sample stacking in capillary zone electrophoresis by invoking field amplification of charged analytes in a low-conductivity sample matrix, the proposed method utilizes a high conductivity sample matrix to transfer field amplification from the sample zone to the separation buffer. This causes the micellar carrier in the separation buffer to stack before it enters the sample zone. Neutral analytes moving out of the sample zone with EOF are efficiently concentrated at the micelle front. Micelle stacking is induced by simply adding salt to the sample matrix to increase the conductivity 2-3-fold higher than the separation buffer. This solution allows free optimization of separation buffer parameters such as micelle concentration, organic modifiers, and pH, providing a method that may complement virtually any existing MCE protocol without restricting the separation method. PMID- 21662808 TI - Screening of mixture combinatorial libraries for chiral selectors: a reciprocal chromatographic approach using enantiomeric libraries. AB - An approach to screen mixture combinatorial libraries for chiral selectors is described. Crucial elements to such an approach are the reciprocity of chromatographic separation and the use of enantiomeric libraries. The feasibility of this method is demonstrated with a model study of the chiral resolution of (1 naphthyl)leucine ester 1 with a small peptide library. PMID- 21662809 TI - Determination of oxidative stability of oils and fats. AB - In a new approach to evaluating the oxidative stability of oils and fats, the consumption of oxygen by a sample confined in a reactor of adjustable temperature is monitored with a gas-phase flow injection analysis (FIA) system. Temperature dependent data are collected in a low-oxygen-content atmosphere. For a variety of samples, log(oxygen consumption) is linearly related to the reciprocal of the absolute temperature (minimum linear r(2) > 0.99). This makes it possible to extrapolate the temperature-dependent data to predict the stability of the samples at other temperatures, e.g., typical ambient storage temperatures at which the direct determination of oxidative stability would be too slow for most samples. The proposed method is instrumentally simple and is easily automated. The sample throughput rate is an order of magnitude faster relative to current alternatives; temperature-dependent stability characterization for a sample (three temperatures, triplicate measurement at each temperature) requires <= 2 h. The reproducibility of the results is excellent. For a cottonseed-oil sample studied over 3 days, the slope and intercept of the log(O(2) consumption) vs 1/T linear plot (for all the 45 measurements made) exhibited uncertainties of 2.1% and 2.0% for the slope and the intercept, respectively, with a linear r(2) value of 0.9929. In a high-temperature (160 degrees C) oxidation experiment with various oils, the oxygen consumption was well-correlated (linear r(2) 0.9692) with the concomitant decrease in iodine absorption number (IAN). In contrast, it was poorly and negatively correlated with an increase in the peroxide value. PMID- 21662810 TI - Polypyrrole-modified tips for functional group recognition in scanning tunneling microscopy. AB - Tailored chemical modification of scanning tunneling microscopy (STM) tips is a promising method for the recognition of specific chemical species and functional groups in STM images. The present study shows for the first time that tips modified with polypyrrole can be used to measure STM images with molecular resolution. A high conductivity of the polypyrrole film was found to be important for the observation of STM images, while the thickness of the polymer film did not affect the images significantly. Furthermore, it was shown that recognition of functional groups in STM images is possible with tips coated with conductive polypyrroles. 1-Octadecanol and 1-octadecanoic acid monolayers with polypyrrole modified tips gave high-resolution STM images in which aligned OH and COOH residues were represented by easily recognizable elevated bands. These selective contrast enhancements resemble those observed by us previously with gold tips modified with self-assembled monolayers (SAMs) and seem to be due to hydrogen bond interactions between functional groups of the tip-modifying molecules and the sample. The reproducibility of contrast enhancements in this study was significantly higher than for SAM-modified tips, suggesting that polymer modification of STM tips is particularly promising for specific functional group recognition with chemically modified STM tips. PMID- 21662811 TI - Separation of hafnium and zirconium from ti- and fe-rich geological materials by extraction chromatography. AB - This paper presents a new chemical separation method for Hf and Zr from rocks using extraction chromatographic resins prepared from inert polymeric supports and the liquid anionic exchangers tri-n-octylamine or trioctylmethylammonium chloride (Aliquat 336). The method was developed using basaltic and trachyandesitic rocks with high contents of Al, Fe, and Ti. A 100-mg rock sample was decomposed with HF-HNO(3)-HClO(4) and fumed with HClO(4). The residue of this process was dissolved in 10 M HCl and then loaded on the column (6 mm i.d. * 75 mm). The major elements (Al, Ca, Mg, Ti, etc.) were eluted with 10 mL of 10 M HCl, and then Hf, Zr, and Fe were eluted sequentially using 20 mL of 8 M HCl, 20 mL of 2 M HCl, and 5 mL of 1 M HNO(3). The removal efficiency of major elements (Al, Fe, Ca, Mg) was greater than 99% and that of Ti was greater than 95%. The recoveries of Hf and Zr were better than 90% and the Zr/Hf ratio decreased from the natural ratio of 45 in the rock sample to 0.3 in the Hf fraction. This method provides an alternative to the less straightforward procedures based on several stages of ion-exchange separation and might be used for sample preparation prior to (176)Hf/(177)Hf determinations by magnetic sector multicollection ICPMS. PMID- 21662812 TI - Identification of Mineral Phases on Basalt Surfaces by Imaging SIMS. AB - A method for the identification of mineral phases on basalt surfaces utilizing secondary ion mass spectrometry (SIMS) with imaging capability is described. The goal of this work is to establish the use of imaging SIMS for characterization of the surface of basalt. The basalt surfaces were examined by interrogating the intact basalt (heterogeneous mix of mineral phases) as well as mineral phases that have been separated from the basalt samples. Mineral separates from the basalt were used to establish reference spectra for the specific mineral phases. Electron microprobe and X-ray photoelectron spectroscopy were used as supplemental techniques for providing additional characterization of the basalt. Mineral phases that make up the composition of the basalt were identified from single-ion images which were statistically grouped. The statistical grouping is performed by utilizing a program that employs a generalized learning vector quantization technique. Identification of the mineral phases on the basalt surface is achieved by comparing the mass spectra from the statistically grouped regions of the basalt to the mass spectral results from the mineral separates. The results of this work illustrate the potential for using imaging SIMS to study adsorption chemistry at the top surface of heterogeneous mineral samples. PMID- 21662813 TI - Source of the Difference between the Measurement of Water in Hydrocarbons As Determined by the Volumetric and Coulometric Karl Fischer Methods. AB - The disparity between the volumetric and coulometric Karl Fischer methods for the measurement of water in hydrocarbons and hydrocarbon mixtures (oils) has been resolved. The amount of water detected by the volumetric method when the titration vessel solution is homogeneous is higher than that measured coulometrically or volumetrically when the titration vessel solution is heterogeneous. Water in oil that is not measured by the coulometric method when the oil is incompletely dissolved has been shown to reside in the oil phase of the heterogeneous (multiphasic) coulometric vessel suspension. Water that is not measured volumetrically under relatively low chloroform concentrations after the point of transition to a heterogeneous titration vessel solution is reached also appears to reside in the nonaqueous phase of the titration vessel solution. It appears that this water is retained in the hydrocarbon phase in a manner such that it is completely inaccessible to the volumetric or coulometric Karl Fischer reagents. PMID- 21662814 TI - Quantitative estimation of the bitter taste intensity of oxyphenonium bromide reduced by cyclodextrins from electromotive force measurements. AB - The bitter taste of oxyphenonium bromide, an antiacetylcholine drug, is suppressed by cyclodextrins. The extent of the suppression can be predicted from the electromotive force measurements with an oxyphenonium bromide-selective electrode. The relationship between the bitter taste intensity and the electromotive force holds true, regardless of the kind and concentration of natural and modified cyclodextrins. This result is explicable on the basis of the observation that both the bitter taste and the electric potential are determined by the concentration of free oxyphenonium bromide. Some implications and limitations of the present approach are discussed. PMID- 21662815 TI - Micromachined severinghaus-type carbon dioxide electrode. AB - The Severinghaus-type pCO(2) electrode was miniaturized and batch-fabricated using semiconductor and micromachining techniques. Anodically grown iridium oxide film (AIROF) was employed as the pH sensing element to detect a local pH change caused by the infusion of CO(2). The AIROF showed a super-Nernstian response with a slope of approximately -80 mV/pH at 25 degrees C. A novel thin-film Ag/AgCl structure was also used. It features a hydrophobic membrane which covers the entire silver layer and the AgCl layer grown from the periphery of the silver pattern. The open-circuit potential of the Ag/AgCl element drifted to the negative side at -0.1 to -0.2 mV h(-1). A microcavity in which the electrolyte solution was filled was anisotropically etched in a silicon substrate, and a silicone rubber gas-permeable membrane was formed on the sensitive area. The miniature pCO(2) electrode showed a distinct response to the variation in concentration of dissolved CO(2). The inherent characteristics of the Severinghaus electrode were confirmed in terms of its response and calibration curve. The selectivity of the electrode was satisfactory in view of its application to clinical analysis. PMID- 21662816 TI - Oxidation Reaction between Periodate and Polyhydroxyl Compounds and Its Application to Chemiluminescence. AB - The oxidation reaction between periodate and polyhydroxyl compounds was studied. A strong chemiluminescent (CL) emission was observed when the reaction took place in a strong alkaline solution without any special CL reagent. However, in acidic or neutral solution, it was hard to record the CL with our instrument. It was interesting to find that in the presence of carbonate the CL signal was enhanced significantly. When O(2) gas and N(2) gas were blown into the reagent solutions, both background and CL signals of the sample were enhanced by O(2) and decreased by N(2). The spectral distribution of the CL emission showed two main bands (lambda = 436-446 and 471-478 nm). Based on the studies of the spectra of CL, fluorescence and UV-visible, a possible CL mechanism was proposed. In strongly alkaline solution, periodate reacts with the dissolved oxygen to produce superoxide radical ions. A microamount of singlet oxygen ((1)O(2)*) could be produced from the superoxide radicals. A part of the superoxide radicals acts on carbonates and/or bicarbonates leading to the generation of carbonate radicals. Recombination of carbonate radicals may generate excited triplet dimers of two CO(2) molecules ((CO(2))(2)*). Mixing of periodate with carbonate generated were very few (1)O(2)* and (CO(2))(2)*. These two emitters contribute to the CL background. The addition of polyhydroxyl compounds or H(2)O(2) caused enhancement of the CL signal. It may be due to the production of (1)O(2)* during the oxidized decomposition of the analytes in periodate solution. This reaction system has been established as a flow injection analysis for H(2)O(2), pyrogallol, and alpha thioglycerol and their detection limits were 5 * 10(-)(9), 5 * 10(-)(9), and 1 * 10(-)(8) M, respectively. Considering the effective reaction ions, IO(4)(-), CO(3)(2)(-), and OH(-) could be immobilized on a strongly basic anion-exchange resin. A highly sensitive flow CL sensor for H(2)O(2), pyrogallol, and alpha thioglycerol was also prepared. PMID- 21662817 TI - Gas-Assisted IR-ATR Probe for Detection of Volatile Compounds in Aqueous Solutions. AB - The application of the principle of solid-phase microextraction (SPME) to attenuated total reflectance (ATR) infrared (IR) probes can provide a convenient and sensitive way to detect volatile organic compounds (VOCs) in aqueous solutions. In this paper a new method to increase the performance of this type of sensing device is proposed. A stream of gas purges out VOCs from aqueous solution. These compounds are directed to an internal-reflection sensor. Several advantages are recognized by this new method as compared with a conventional liquid probe; these include a longer lifetime for the probe, higher selectivity in the detection of VOCs, less limitation in the sample volume, and easier regeneration of the sensing probe. PMID- 21662818 TI - Separation and Identification of Tocotrienol Isomers by HPLC-MS and HPLC-NMR Coupling. AB - A crude palm-oil extract rich in vitamin E homologues was investigated by HPLC-MS and HPLC-NMR coupling. For mass spectrometry a newly introduced ionization technique called Coordination Ion Spray (CIS) was used. Through the addition of silver ions to the HPLC eluent, the ionization process of nonpolar substances is facilitated. Chromatography and all coupling experiments were conducted on a C(30) column which exhibited an extraordinary shape selectivity and overwhelming sample-loading capability. Experiments were performed with pure methanol as an eluent which proved to be ideal for NMR spectroscopy as well as mass spectrometry. All necessary information for unambiguous structural assignment was collected within 45 min of the LC-NMR experiment and 15 min of the LC-MS experiment. Six compounds were identified, i.e., alpha-, beta-, gamma-, and delta tocotrienol, alpha-tocoenol, and alpha-tocopherol. PMID- 21662819 TI - Mass Spectrometry of Liquid Aniline Aerosol Particles by IR/UV Laser Irradiation. AB - The first results are reported from a new single-particle two-color laser time-of flight mass spectrometer, incorporating a combination of infrared (CO(2)) and UV (excimer) laser irradiation. This combination of lasers has the capability to effectively separate the desorption or evaporation step from the ionization step, thereby greatly improving the analytical capabilities of such an instrument. The results on liquid aerosols, such as aniline, show that prior evaporation of the aerosol particle with the IR laser increases the ion signal produced by the excimer laser by more than 2 orders of magnitude. In the case of nitrobenzene aerosols, the excimer laser alone produces no ions, while a very large signal is observed when the aerosol is first irradiated with the CO(2) laser. A simple model, based on the Coulomb explosion of the ionized aerosol, is used to estimate the number of ions generated by the excimer laser (~10(5) ions). Experimental evidence based on the observed time delay of protonated aniline parent ions indicates that the laser irradiation of the liquid aerosol results in a stable neutral plasma which separates into positive and negative charges only after a 100-500-ns delay. PMID- 21662820 TI - Polymer Analysis by Liquid Chromatography/Electrospray Ionization Time-of-Flight Mass Spectrometry. AB - Hyphenation of liquid chromatography (LC) techniques with electrospray ionization (ESI) orthogonal acceleration time-of-flight (oa-TOF) mass spectrometry (MS) provides both MS-based structural information and LC-based quantitative data in polymer analysis. In one experimental setup, three different LC modes are interfaced with MS: size-exclusion chromatography (SEC/MS), gradient polymer elution chromatography (GPEC/MS), and liquid chromatography at the critical point of adsorption (LCCC/MS). In SEC/MS, both absolute mass calibration of the SEC column based on the polymer itself and determination of monomers and end groups from the mass spectra are achieved. GPEC/MS shows detailed chemical heterogeneity of the polymer and the chemical composition distribution within oligomer groups. In LCCC/MS, the retention behavior is primarily governed by chemical heterogeneities, such as different end group functionalities, and quantitative end group calculations can be easily made. The potential of these methods and the benefit of time-of-flight analyzers in polymer analysis are discussed using SEC/MS of a polydisperse poly(methyl methacrylate) sample, GPEC/MS of dipropoxylated bisphenol A/adipic acid polyester resin, LCCC/MS of alkylated poly(ethylene glycol), and LCCC/MS of terephthalic acid/neopentyl glycol polyester resin. PMID- 21662821 TI - Behavior of cation-exchange materials in capillary electrochromatography. AB - The behavior of a strong, cation-exchange material (propanesulfonic acid, SCX) has been studied in capillary electrophoresis (CE) and capillary electrochromatography (CEC) by the use of coated and packed capillaries. In aqueous electrolytes, the SCX-coated capillary showed a far more consistent electroosmotic flow over the pH range 3.6-10.5, compared to untreated fused silica. However, in similar electrolytes containing 80% (v/v) acetonitrile, both coated and untreated capillaries performed similarly, casting doubts upon the stability of the SCX coating. The effect of voltage and mobile-phase parameters such as pH, ionic strength, and organic content was studied in CEC for both 3-MUm SCX and C(18) packing materials, and the results were compared in terms of linear velocities, currents, and conductivities. Only at pH 5 and below was a higher EOF velocity than expected observed for the SCX column. In accordance with theory, the EOF was seen to increase with decreasing ionic strength for the C(18) column. However, for the SCX column, this was not the case: the EOF showed a general reduction as the ionic strength was decreased. The greatest anomaly was observed on changing the acetonitrile composition: the EOF showed a consistent decline with increasing organic, whereas the EOF in both the open capillary and C(18) column decreased and then started to rise with acetonitrile contents above 70% (v/v). PMID- 21662822 TI - Theoretical Migration Model for Micellar Capillary Electrophoresis and Its Application to the Separation of Anionic Metal Complexes of HEDTC and CDTA. AB - A mathematical model relating the effective mobility of an analyte in micellar capillary electrophoresis (MCE) to the concentration of surfactant and organic modifier in the background electrolyte (BGE) was derived. Effective mobility is expressed in terms of the electrophoretic mobility of the analyte, the partition coefficient of the analyte into the micelle, and the influence of organic modifier on these two factors. The performance of the model was evaluated using Cd(II), Pb(II), Co(II), Ni(II), Bi(III), Cu(II), and Hg(II) complexes of bis(2 hydroxyethyl)dithiocarbamate, all of which carry a partial negative charge, and Cd(II), Pb(II), Co(II), Ni(II), Bi(III), Cu(II), Hg(II), Fe(III), Ag(I), Tl(I), and Mn(II) complexes of trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid, all of which are anionic having charges in the range -1 to -3. These analytes were separated in borate BGEs containing 10-50 mM sodium dodecyl sulfate and 0 20% (v/v) methanol. Nonlinear regression was used to derive parameters for the model from experimental data and these parameters were used to predict effective mobilities of the analytes. Predicted values of effective mobilties agreed with experimental values to within 3.1%. Values of parameters from the model equation are used to explain changes in separation selectivity observed at different BGE compositions and the model equation is shown to be applicable to computer assisted optimization of the BGE composition, in MCE using a limited number of experiments. PMID- 21662823 TI - Preparation of soluble polypyrrole composites and their uptake properties for anionic compounds. AB - Soluble composite particles consisting of polypyrrole-poly(vinylpyrrolidone) and polypyrrole-poly(vinyl alcohol) were prepared, and their stabilities and ion exchange properties were compared with those for polyaniline-poly(vinyl alcohol) composites. The dispersions of the polypyrrole-based composites were more stable in solution than those for the polyaniline-based ones but extracted organic molecules less rapidly and quantitatively. However, EPR investigation indicated that the polypyrrole composites had substantially greater numbers of cationic sites than the polyaniline composites at pH greater than 6. Enantioseparation of amino acids was attempted by using a polypyrrole-poly(vinyl alcohol) composite doped with N-carbobenzoxy-l-aspartic acid as a chiral selector. PMID- 21662824 TI - Separation and purification of methadone enantiomers by continuous- and interval flow electrophoresis. AB - Continuous- or free-flow electrophoresis is based upon a thin film of fluid flowing between two parallel plates. The electrolytes and the sample are continuously admitted at one end of the electrophoresis chamber and are fractionated by an array of outlet tubes at the other. Using the Octopus apparatus in a horizontal position, continuous preparative separation of methadone enantiomers in the presence of (2-hydroxypropyl)-beta-cyclodextrin as a chiral selector was investigated under conditions of continuous-flow zone electrophoresis and continuous-flow isotachophoresis. The enantiomeric composition of methadone in the collected fractions was assessed by chiral capillary electrophoresis and circular-dichroism spectroscopy. In both electrophoretic modes, partial separation of the two enantiomers with an enrichment of about 80% and a throughput of 10-20 mg of racemic methadone per hour was obtained. Operating the Octopus apparatus with interrupted buffer flow during electrophoresis, a process termed interval-flow electrophoresis, resulted in complete separation of milligram quantities of the two methadone enantiomers. Furthermore, commencing with racemic methadone, continuous multistage isotachophoretic processing is shown to be suitable to purify (R)-(-)-methadone, the enantiomer with higher pharmacological activity, on a mg/h scale and at a mM concentration in the collected product stream. PMID- 21662825 TI - Liquid Chromatography Analysis of Carbonyl (2,4-Dinitrophenyl)hydrazones with Detection by Diode Array Ultraviolet Spectroscopy and by Atmospheric Pressure Negative Chemical Ionization Mass Spectrometry. AB - The (2,4-dinitrophenyl)hydrazones of carbonyls are separated by liquid chromatography and detected by ultraviolet spectroscopy (diode array detector) and by atmospheric pressure negative chemical ionization mass spectrometry. Results are presented for 78 carbonyls including 18 1-alkanals (from formaldehyde to octadecanal), 16 other saturated aliphatic carbonyls (5 C(4)-C(7) aldehydes and 11 C(3)-C(9) ketones), 16 unsaturated aliphatic carbonyls (9 C(3)-C(11) aldehydes and 7 C(4)-C(9) ketones), 13 aromatic carbonyls (including hydroxy- and/or methoxy-substituted compounds), 10 C(2)-C(10) aliphatic dicarbonyls, 3 aliphatic carbonyl esters, and 2 other carbonyls. Isomers were observed for alpha,beta-unsaturated ketones and saturated carbonyls that bear other oxygen containing substituents, e.g. methoxyacetone, 2-furaldehyde, and the 3 carbonyl esters. For all but two of the carbonyls studied, the base peak in the negative APCI mass spectrum was the M - 1 ion (NO(2))(2)C(6)H(3)NN [Formula: see text] CR(1)R(2) (R(1) = H for aldehydes), where M is the molecular mass of the carbonyl (2,4-dinitrophenyl)hydrazone derivative. The dicarbonyls 2,4-pentanedione and succinic dialdehyde reacted with DNPH to yield predominantly other products. Concentrations measured by ultraviolet spectroscopy (peak area) and by mass spectrometry (abundance of M - 1 ion) were in good agreement. Applications described include the measurement of 34 C(1)-C(18) carbonyls at levels of 0.015 14 parts per billion (ppb) in urban air and the identification of carbonyls at ppb concentrations as reaction products in laboratory studies of the atmospheric oxidation of unsaturated organic compounds. PMID- 21662826 TI - Effect of Stationary-Phase Sorption of Organic Modifier from a Water-Rich Mobile Phase on Solute Retention by an ODS Bonded Phase. AB - Sorption isotherms for 1-butanol (BuOH) and eucalyptol (Eu) on Partisil 10 ODS-3 are plotted as concentration sorbed versus activity in aqueous solution. The former follows the Langmuir equation and the latter follows the equation for an "associative bilayer isotherm with limited solubility in the aqueous phase". Two series of simultaneous sorption experiments of BuOH and Eu were also performed. One series involved measuring the influence of BuOH, as an organic modifier solvent in water, on the sorption of Eu as solute. In the second series, the roles of BuOH and Eu were reversed. These studies show that when sorption is treated as partitioning between two bulk liquid phases, the stationary phase behaves as an ideal solution which is composed of C(18) chains, sorbed organic modifier, and sorbed solute. Combined with the Langmuir isotherm behavior of BuOH, this ideal solution behavior supports the view that BuOH is sorbed at the stationary-phase/mobile-phase interface, with its hydrocarbon tail in the stationary phase. PMID- 21662827 TI - Chain Unfolding in an ODS-Bonded Phase Caused by the Sorbed Tetra-n-butylammonium Ion. AB - The simultaneous sorption of the tetra-n-butylammonium ion (TBA(+)) and butanol on the bonded phase sorbent Partisil-10 ODS-3 from an aqueous mobile phase, at the two different ionic strengths 0.50 and 0.050 mol/L, is studied by the column equilibration technique. When the TBA(+) concentration in the mobile phase is kept constant while the butanol concentration is varied, the plots of moles of TBA(+) sorbed versus moles of butanol sorbed decrease linearly. This indicates that butanol simply competes with TBA(+) for sorption space. In contrast, when the butanol concentration in the mobile phase is kept constant while the TBA(+) concentration is varied, the plots of moles of butanol sorbed versus moles of TBA(+) sorbed decrease nonlinearly. This indicates that, in addition to competing with butanol for space, sorbed TBA(+) also causes an unfolding of the originally collapsed C(18) chains. At 0.050 mol/L ionic strength, chain unfolding causes an increase in the total space that is available for sorption of butanol, a decrease in overlap between sorbed TBA(+) and butanol, and a decrease in the sorbent strength of the ODS phase for butanol. The last effect is likely due to a reduction in contact area between a sorbed butanol molecule and the C(18) chains. At 0.50 mol/L ionic strength, chain unfolding decreases both the TBA(+)/butanol overlap and the sorbent strength but does not increase the total space available for butanol sorption. A physicochemical model is developed which fits well to the experimental data. PMID- 21662828 TI - Chromatographic determination of metallic impurities in reversed-phase HPLC columns. AB - A new test procedure is proposed for the characterization of packed RP columns with respect to their metal content. It is based on the peak asymmetry of 2,2' bipyridyl, which can be directly correlated to the metal content of the stationary phase. Since an unbuffered eluent (methanol/water, 49:51 w/w) is used, the influence of the simultaneously present silanol groups on peak asymmetry is assessed via 4,4'-bipyridyl, which exhibits no chelating activity. A metal factor, MF, is introduced, which is the ratio of the peak asymmetries of 2,2' bipyridyl and 4,4'-bipyridyl multiplied by 100. The superiority of this test compared to others is demonstrated via various commercially available columns. It is also demonstrated that columns continuously collect metal ions from the column components and the instrument hardware. Stainless steel nets and frits are the principal source of the metallic contamination. But even in totally metal-free LC systems, the stationary phase collects metal ions from the HPLC grade eluent components. PMID- 21662829 TI - N-Methyl-4-hydrazino-7-nitrobenzofurazan as a New Reagent for Air Monitoring of Aldehydes and Ketones. AB - The synthesis of N-methyl-4-hydrazino-7-nitrobenzofurazan (MNBDH) and its application as a new reagent for the determination of aldehydes and ketones are described. MNBDH reacts with carbonyl compounds in acidic media to the corresponding MNBD-hydrazones. In contrast to the established reagent 2,4 dinitrophenylhydrazine (DNPH), MNBDH is oxidized by both ozone and nitrogen dioxide quantitatively to only one product, N-methyl-4-amino-7-nitrobenzofurazan (MNBDA). This can easily be separated from the hydrazones of lower aldehydes by means of HPLC. Due to larger molar absorptivities and absorption maxima at wavelengths over 470 nm, selectivity is higher and limits of detection are lower for the new reagent compared to DNPH. MNBDH reacts slightly faster than DNPH with carbonyl compounds and significantly faster than other N-alkylated hydrazine reagents. PMID- 21662830 TI - Ultratrace measurements of nucleic acids by baseline-corrected adsorptive stripping square-wave voltammetry. AB - The direct and reliable electrochemical detection of DNA is of paramount importance to the development of modern DNA hybridization chips, for the detection of nucleic acids following their electrophoretic separations, or for the sensing of DNA damage and interactions. Such solid electrode voltammetric measurements of nucleic acids have been traditionally hampered by the large solvent decomposition background current that obscures the oxidation signals of the purine nucleobases. This paper reports on the use of adsorptive stripping square-wave voltammetry, in connection with the "moving average baseline correction" approach, for monitoring ultratrace levels of DNA and RNA. Compared to other baseline-fitted or background-subtraction protocols, the moving average baseline scheme is particularly effective in isolating the small purine nucleobase peaks, which appear as small shoulders on the steep background discharge contribution. The remarkably flat baseline thus obtained (up to extreme potentials) leads to a dramatic lowering of the detection limits to the femtomole level and to a performance that compares favorably with that of computerized chronopotentiometric measurements of nucleic acids. Combined with the speed of square-wave voltammetric measurements, such developments should expand the role of voltammetry in DNA diagnostics and nucleic acid research. PMID- 21662831 TI - Automated derivatization instrument: preparation of alditol acetates for analysis of bacterial carbohydrates using gas chromatography/mass spectrometry. AB - An automated derivatization instrument was developed for preparation of alditol acetates for GC/MS profiling of bacterial carbohydrates. The multistage alditol acetate method is now performed sequentially by a computer-controlled instrument. A series of electrically driven solenoid valves are in-line with a 21-sample manifold. A set of solvent valves controls the input of solvent and/or nitrogen gas to each sample chamber. A set of gas valves controls output to atmosphere or vacuum. Additionally, closure of all valves allows the sample to be sealed in a closed chamber. Temperature is also determined automatically. The availability of this instrument could help popularize the alditol acetate procedure and serve as a prototype for automation of other complex derivatization procedures. PMID- 21662832 TI - Gel permeation chromatography coupled to fourier transform mass spectrometry for polymer characterization. AB - We report an on-line coupling of gel permeation chromatography (GPC) to Fourier transform mass spectrometry (FTMS) using a modified commercial electrospray ionization (ESI) interface. Selected oligomer profiles for the sodiated (1+ through 5+ charge states) oligomer ions of a narrow-molecular-weight poly(methyl methacrylate) were generated and used for obtaining a calibration curve. Using the MS-generated calibration curve and the refractive index response for quantification, an accurate molecular weight distribution was calculated and showed an excellent agreement with the value specified by the supplier. GPC/ESI/FTMS also allowed for an unequivocal end-group determination and characterization of a secondary distribution due to the formation of cyclic reaction products. We analyzed a glycidyl methacrylate/butyl methacrylate copolymer with a broad molecular weight distribution, where fractionation and high resolving power were required for adequate characterization. Molecular weight distribution data showed the advantage of coupling high-resolution MS and GPC to overcome the difficulty of analyzing polydisperse polymers with MS alone. PMID- 21662833 TI - Shape selectivity for constrained solutes in reversed-phase liquid chromatography. AB - In reversed-phase liquid chromatography (RPLC), the separation of compound mixtures of similar polarity can present a significant challenge for the analyst. Examples of such compounds include geometric isomers present in environmental samples (e.g., polycyclic aromatic hydrocarbons, polycyclic aromatic sulfur heterocycles, and polychlorinated biphenyl congeners) and compounds of biological significance (e.g., carotenoids and steroids). In general, compounds with rigid, well-defined molecular shape are best separated using a column with enhanced shape selectivity characteristics. This perspective presents an overview of column properties that influence shape selectivity for constrained solutes. Approaches to the characterization of stationary-phase structure are described, and the findings are correlated with chromatographic performance. Finally, retention models of shape discrimination are presented that are consistent with observed retention behavior. An appreciation for shape recognition effects in RPLC will facilitate method development for certain classes of difficult to resolve compounds. PMID- 21662834 TI - Analysis of C(14)-C(17) Polychloro-n-alkanes in Environmental Matrixes by Accelerated Solvent Extraction-High-Resolution Gas Chromatography/Electron Capture Negative Ion High-Resolution Mass Spectrometry. AB - A method for quantifying medium-chain (C(14)-C(17)) polychloroalkanes (mPCAs) in environmental matrixes by accelerated solvent extraction high-resolution gas chromatography/electron capture negative ion high-resolution mass spectrometry in the selected ion monitoring mode is presented. The formula group abundance profiles of industrial mPCA mixtures, which are used as standards, and of samples are first determined by monitoring [M - Cl](-) ions of specific m/z values corresponding to the molecular formulas present and by correcting the integrated ion signals for the fractional abundance of the specific m/z value monitored and the number of chlorine atoms in the formula group. mPCA concentrations in environmental samples are then determined by comparing the response of a specific m/z peak in the sample to that in the standard. Extraction recoveries of mPCAs from spiked fish and sodium sulfate (in place of sediment) were >79%. Method detection limits were 13 ng/g for fish and 1.4 ng/MUL for sediment, while the analytical detection limit was ~200 pg, at a signal-to-noise ratio of 4:1. By this method, mPCAs were detected in biota and sediment from the mouth of the Detroit River (MI) and ranged from 70 to 900 ng/g. The simultaneous quantitation of C(10)-C(13) (sPCAs) and C(14)-C(17) PCAs, based on monitoring two specific m/z peaks, one characteristic of sPCAs and the other of mPCAs, is also demonstrated. PMID- 21662835 TI - Aqua-Impregnated Resins. 2. Separation of Polyvalent Metal Ions on Iminodiacetic and Polyacrylic Resins Using Bis(2-ethylhexyl) Phosphoric and Bis(2-ethylhexyl) Dithiophosphoric Acids as Organic Eluents. AB - This paper dedicated to the further development of the novel aqua-impregnated resin (AIR) technique reports the results obtained by studying the column separation of equimolar mixtures of Cu(2+), Al(3+), and Zn(2+) on iminodiacetic (IDA) and polyacrylic (PAR) resins by using 0.2 M heptane solutions of either bis(2-ethylhexyl) phosphoric acid (DEHPA) or bis(2-ethyhexyl) dithiophosphoric acid (DEHDTPA) as selective eluents for extractive desorption of metal ions from the resin phase. The quantitative separation of Cu(2+)-Al(3+) mixtures has been achieved by sequential elution of metals from PAR with DEHDTPA and H(2)SO(4) solutions. Purification of Cu(2+) from Al(3+) and/or Zn(2+) and Al(3+) from Cu(2+) and Zn(2+) is achieved by extractive elution of metal mixtures from IDAR or PAR with DEHPA or DEHDTPA solutions, respectively, followed by stripping of the purified metals with 1.1 M H(2)SO(4). The resulting purity of metals obtained with the yield of >96% exceed 95%. PMID- 21662836 TI - Effect of thiol chemisorption on the transport properties of gold nanotubule membranes. AB - An electroless gold deposition method was used to deposit Au nanotubules within the pores of a polycarbonate template membrane. Membranes containing Au nanotubules with inside diameters of 2 and 3 nm were prepared for these studies. Thiols were chemisorbed to the inside tubule walls in order to change the chemical environment within the tubules. The effect of the chemical environment within the tubules on the transport properties of the tubule-containing membrane was investigated. Membranes modified with HS-C(16)H(33) preferentially transported hydrophobic permeant molecules. When a homologous series of permeant molecules was used, the most hydrophobic permeant was preferentially partitioned into and transported by the HS-C(16)H(33) derivatized membrane. In addition, the effect of alkyl chain length (R), in a homologous series of thiols R-SH, was investigated. Hydrophobic permeant molecules were preferentially partitioned into and transported by membranes containing the largest alkyl group. In contrast, membranes modified with HS-C(2)H(4)OH preferentially transported the more hydrophilic permeant pyridine. Finally, we show here that the HS-C(16)H(33) derivatized membrane can be used to separate hydrophobic species from hydrophilic species. PMID- 21662837 TI - Influence of mixed diffusional, migrational, and convective mass transport on the response of a wall-tube microelectrode in a flow injection system. AB - The current response of a 10-MUm wall-tube microelectrode in a flow injection system under the conditions of low ionic strength has been examined experimentally for several redox systems such as ferrocene in methanol, undiluted methanol, and water in acetone. The examination involved the dependence of the current on the positioning of the microelectrode relative to a 760-MUm-i.d. capillary outlet, flow rate, potential pulse time, and ratio between the concentrations of the supporting electrolyte and electroactive species (C(el)/C(redox)). For C(el)/C(redox) ratios smaller than ~0.001 and a flow rate of 200 MUL/min, the dependencies of the current on the flow rate and the positioning of the microelectrode versus the capillary tip were reversed compared to the presence of excess supporting electrolyte. The current was thus found to decrease with increasing flow rate while a local current maximum could be seen when the microelectrode was center-aligned with the capillary tip. The changes in the current are the results of local differences in convective transport. These differences alter the rate of migrational accumulation of counterions at the electrode surface. It is shown that results similar to those obtained for the excess supporting electrolyte case can be obtained for a low value of C(el)/C(redox) and a given flow rate if the electrode potential and time scale of the experiments are chosen appropriately. PMID- 21662838 TI - Potential Stability of All-Solid-State Ion-Selective Electrodes Using Conducting Polymers as Ion-to-Electron Transducers. AB - Demanding analytical applications such as on-line process analysis and clinical analysis require robust, reliable, and maintenance-free ion sensors of high potential stability. In this work the stability of the electrode potential of all solid-state ion-selective electrodes using conducting polymers as ion-to-electron transducers is critically evaluated by using chronopotentiometry and electrochemical impedance spectroscopy. This study is focused on the relationship between the potential stability of the electrode and the capacitance of the solid contact where ion-to-electron transduction takes place. The influence of this capacitance on the potential stability of all-solid-state ion-selective electrodes is studied experimentally by using conducting polymer layers of different thickness as solid contacts in potassium ion-selective electrodes based on a solvent polymeric membrane. Because of its excellent environmental stability, the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) is used as a model compound for the solid contact material. Chronopotentiometry is found to be a convenient and fast experimental method to critically evaluate the potential stability of different types of ion-selective electrodes. PMID- 21662839 TI - Strontium-selective membrane electrodes based on some recently synthesized benzo substituted macrocyclic diamides. AB - Eight different recently synthesized macrocyclic diamides were studied to characterize their abilities as strontium ion carriers in PVC membrane electrodes. The electrode based on 1,13-diaza-2,3;11,12-dibenzo-4,7,10 trioxacyclopentadecane-14,15-dione exhibits a Nernstian response for Sr(2+) ions over a wide concentration range (1.0 * 10(-)(1)-3.2 * 10(-)(5) M) with a limit of detection of 8.0 * 10(-)(6) M (0.7 ppm). The response time of the sensor is ~10 s, and the membrane can be used for more than three months without observing any deviation. The electrode revealed comparatively good selectivities with respect to many alkali, alkaline earth, and transition metal ions. It was used as an indicator electrode in potentiometric titration of carbonate ions with a strontium ion solution. PMID- 21662840 TI - Imaging of nonuniform current density at microelectrodes by electrogenerated chemiluminescence. AB - The chemiluminescence arising from reaction of electrogenerated radical cations of 9,10-diphenylanthracene (DPA) and benzonitrile (solvent) radical anions has been used to image microelectrodes with dimensions in the micrometer range. Experimental conditions including supporting electrolyte, DPA concentration, and excitation frequency were optimized to affect high luminescent intensity. In solutions of high resistance, the light was found to be temporally delayed with respect to the applied potential due to the increased time required to charge the double layer. Spatially nonuniform light at disk- and band-shaped microelectrodes was observed under certain conditions, with the highest intensity occurring at the region of the electrode with highest curvature. The optimum condition for observation of the nonuniform light was with very high electrode currents. Under this condition, the current density approaches that of the primary current distribution, a circumstance where spatially nonuniform potentials occur. This phenomenon was also examined at a conical electrode as a method of reducing the emission area. A submicrometer-size light source was obtained at high frequencies with an electrode that had a significantly larger uninsulated area. PMID- 21662841 TI - An On-Line Technique for the Determination of the delta(18)O and delta(17)O of Gaseous and Dissolved Oxygen. AB - Few studies have used the stable isotopic composition of O(2) as a tracer of gas transport or biogeochemical processes in environmental research. Here we demonstrate field sampling techniques for gaseous and dissolved O(2) and describe an analytical method for measuring delta(18)O and delta(17)O values of O(2) in air, soil gas, and water samples using continuous-flow isotope-ratio mass spectrometry (CF-IRMS). A Micromass CF-IRMS was altered to accommodate a sample gas injection port prior to a CO(2) and H(2)O trap and GC column. The GC column was a 1-m, 5-A molecular sieve column held at 35 degrees C. The resolved sample O(2) was introduced to the IRMS via an open split. delta(18)O and delta(17)O values were determined by measurement of O(2) isotopes at m/z 34/32 and 33/32 and comparison to a reference pulse of O(2). Repeated injections of atmospheric oxygen yielded a repeatability (+/-SD) of +/-0.170/00 for delta(18)O and +/ 0.50/00 for delta(17)O. IRMS source linearity was excellent for O(2) over a sample size range of 60-400 MUL. The smallest sample for routine delta(18)O and delta(17)O determinations was ~80 MUL of O(2), with a sample analysis time of 180 s. Preliminary results from a riverine and soil gas study illustrate natural oxygen isotope fractionation processes. PMID- 21662842 TI - An absorption detection approach for multiplexed capillary electrophoresis using a linear photodiode array. AB - A novel absorption detection method for highly multiplexed capillary electrophoresis is presented for zone electrophoresis and for micellar electrokinetic chromatography. The approach involves the use of a linear photodiode array on which a capillary array is imaged by a camera lens. Either a tungsten lamp or a mercury lamp can be used as the light source such that all common wavelengths for absorption detection are accessible by simply interchanging narrow-band filters. Each capillary spans several diodes in the photodiode array for absorption measurements. Over 100 densely packed capillaries can be monitored by a single photodiode array element with 1024 diodes. The detection limit for rhodamine 6G for each capillary in the multiplexed array is ~1.8 * 10(-)(8) M injected (S/N = 2). The cross-talk between adjacent capillaries is less than 0.2%. Simultaneous analysis of 96 samples is demonstrated. PMID- 21662843 TI - A design for low-flow sheathless electrospray emitters. AB - An extremely simple design has been developed for producing durable sheathless electrospray emitters that give highly stable electrospray for unlimited lifetimes. The emitters can be fashioned from any style fused-silica capillary and are ideally suited for generating "all-in-one" microcolumn-emitter systems thus eliminating unwanted void volumes. The emitters give stable electrospray at low (30 nL/min) as well as high (1 mL/min) flow rates without the aid of nebulizing gas. Fabrication of these emitters (aka the "fairy dust" technique) does not involve the use of a metallized coating but rather the adherance of 2 MUm gold particles to the capillary tip resulting in a robust approach to the problem of making an electrical contact with the electrospray solvent. PMID- 21662844 TI - In-injection port thermal desorption for explosives trace evidence analysis. AB - A gas chromatographic method utilizing thermal desorption of a dry surface wipe for the analysis of explosives trace chemical evidence has been developed and validated using electron capture and negative ion chemical ionization mass spectrometric detection. Thermal desorption was performed within a split/splitless injection port with minimal instrument modification. Surface abraded Teflon tubing provided the solid support for sample collection and desorption. Performance was characterized by desorption efficiency, reproducibility, linearity of the calibration, and method detection and quantitation limits. Method validation was performed with a series of dinitrotoluenes, trinitrotoluene, two nitroester explosives, and one nitramine explosive. The method was applied to the sampling of a single piece of debris from an explosion containing trinitrotoluene. PMID- 21662845 TI - Determination of Rh, Pd, and Pt in Polar and Alpine Snow and Ice by Double Focusing ICPMS with Microconcentric Nebulization. AB - The performance of a double-focusing inductively coupled plasma mass spectrometer equipped with a microconcentric nebulizer was investigated for the direct simultaneous determination of Rh, Pd, and Pt in less than 1 mL of melted snow and ice samples originating from remote sites. Ultraclean procedures were adopted in the laboratories and during the pretreatment steps, to avoid possible contamination problems. Spectroscopic and nonspectroscopic interferences affecting the determination of Rh, Pd, and Pt were carefully considered. Detection limits of 0.02, 0.08, and 0.008 pg g(-)(1) for Rh, Pd, and Pt, respectively, were obtained using the following isotopes: (103)Rh, (106)Pd, and (195)Pt. Repeatability of measurements, as RSD, was 27, 28, and 29%, for Rh, Pd, and Pt, respectively. The new method was applied to the analysis of samples coming from Greenland, Antarctica, and the Alps in order to assess the past natural background concentrations and to determine the present level of these polluting substances. The extremely low detection limits allowed the direct analysis of all samples except for two Greenland ice core sections dating from 7260 and 7760 years ago for which a preconcentration step was necessary. Concentration ranges for all snow samples were (in pg g(-)(1)) as follows: Rh (0.0005-0.39), Pd (0.01-16.9), and Pt (0.008-2.7). The lowest concentrations were measured in the enriched Greenland ancient ice samples. PMID- 21662846 TI - In-line catalytic derivatization method for selective detection of chlorinated aromatics with a hyphenated gas chromatography/laser mass spectrometry technique: a concept for comprehensive detection of isomeric ensembles. AB - The combination of gas chromatography (GC) and laser-based resonance-enhanced multiphoton ionization-time-of-flight mass spectrometry (REMPI-TOFMS) represents a three-dimensional analytical method, using the gas chromatographic retention time, the wavelength of the ionization laser for REMPI, and the molecular mass as analytical parameters. In this work, a novel analytical scheme for detection of chlorinated aromatic compounds, including isomeric ensembles, by GC/REMPI-TOFMS is presented. The concept uses an in-line hydrodechlorination catalyst for post- or precolumn derivatization of chlorinated aromatic compounds. The chlorinated aromatics are quantitatively reduced, forming their respective aromatic skeletons. These aromatic skeletons are detected selectively by REMPI-TOFMS. The first results for substance class selective detection of chlorinated benzene isomers are given, and potential applications in the field of the analysis of compounds such as polychlorinated dibenzo-p-dioxins and -furans are discussed. PMID- 21662847 TI - Kinetically labile equilibrium shifts induced by the electrospray process. AB - The complexation reactions between the alkaline earth metal ions and EDTA were studied by electrospray mass spectrometry to measure the change in concentration of the metal ion-EDTA complex (MY(2)(-)) in the gas phase relative to the solution-phase equilibrium concentration. This work focused on the solution pH range from 4 to 7 where there exists free metal ions in solution at equilibrium. The equilibrium shift, measured through quantitation of the increased abundance of the MY(2)(-) species in the gas phase, was largest for barium and smallest for magnesium. The cause of the net equilibrium shift of the MY(2)(-) species is the combined effect of an electrolytic increase in pH within the capillary plus an additional shift within the evaporating droplets. In a thin diffusion-limited layer created by the products of electrolysis mixing with the bulk solution at the ES capillary tip, the labile species reequilibrate at a new, higher pH. In the evaporating droplets, the formation of new labile species due to increased solute concentrations is kinetically controlled because the ion residence time in the droplet prior to desorption is only ~5 MUs. These results are briefly discussed with respect to the potential for utilizing electrospray mass spectrometry for kinetically labile equilibrium studies. PMID- 21662848 TI - Microchip flow cytometry using electrokinetic focusing. AB - Flow cytometry of fluorescently labeled and unlabeled latex particles is demonstrated on a microfabricated device. The latex particles were detected and counted using laser light scattering and fluorescence coincidence measurements. Sample confinement was accomplished using electrokinetic focusing at a cross intersection, and detection occurred 50 MUm downstream from the intersection. Particles with diameters of 1 and 2 MUm were analyzed and distinguished from each other based on their light scattering intensity and fluorescence. A maximum sample throughput of 34 particles/s was achieved. Sample mixtures with varying proportions of fluorescently labeled and unlabeled particles were also analyzed and found to be within experimental error of the expected ratios. PMID- 21662849 TI - Screening of a parallel combinatorial library for selectors for chiral chromatography. AB - A method to screen parallel combinatorial libraries for chiral selectors is described. Crucial elements to such an approach are the efficient syntheses of potential chiral selectors on synthesis resins and the rapid screening of selectors attached to these resins with circular dichroism measurement. The method does not require any immobilization of the analyte and could complement the mixture combinatorial library method developed earlier in this laboratory. The feasibility of this parallel library screening procedure is demonstrated with a model study of the chiral HPLC resolution of (1-naphthyl)leucine ester (1) using a 16-member small library. PMID- 21662850 TI - Real-Time Imaging through Optical Fiber Array-Assisted Laser-Induced Fluorescence of Capillary Electrophoretic Enantiomer Separations. AB - An advanced detection system based on laser-induced fluorescence imaging for capillary electrophoresis (CE) is presented. An optical fiber array was constructed for collection and transportation of the emitted fluorescent light to the charge-coupled device (CCD) camera. The fiber array makes the setup compact compared with a setup where the capillary is imaged through a camera objective. The imaging detector captures the sample zones in motion during the migration through the capillary. This allows unique studies on dynamic events otherwise unrevealed. During the study, unexplained nonlinear migration behavior was revealed. Enantiomer separations of dansylated amino acids using cyclodextrins, imaged between 1.5 and 12 cm of a 28-cm-long 50-MUm i.d. capillary, were used for evaluation of the system. Comparing the optical fiber array with a camera lens system, the signal-to-noise-ratio (S/N) was 10 times higher. This is due to a combination of both higher signal and lower noise levels. To improve the S/N ratio further, a computer program for signal processing was designed. Using dichlorofluorescein, a concentration limit of detection (CLOD) of 350 pM was achieved and improved 10 times to 35 pM with computer postprocessing using 79 images. This is equal to 400 zeptomole for a 3-mm-long sample zone in a 50-MUm i.d. capillary. PMID- 21662851 TI - Optimization of the Simultaneous Determination of Cr(III) and Cr(VI) by Ion Chromatography with Chemiluminescence Detection. AB - An optimized method for the simultaneous determination of Cr(III) and Cr(VI) in aqueous solutions using ion chromatography with chemiluminescence detection is described. Excellent resolution of the two chromium species was obtained using a single mixed-bed ion-exchange column with continuous elution. After postcolumn reduction of Cr(VI) to Cr(III), the light emitted during the Cr(III)-catalyzed oxidation of luminol with hydrogen peroxide was measured. Parameters affecting the postcolumn reactions such as reductant concentration, reductant mixing, point of luminol introduction, and luminol flow rate were optimized. The calibration curves in the range tested (0.01-50 MUg L(-)(1)) were linear, and detection limits of 0.002 MUg L(-)(1) for both Cr(III) and Cr(VI) were obtained. The results of the analyses of the water reference materials LGC CRM6010 and NIST SRM1643d with certified chromium values of 49 +/- 4 and 18.53 +/- 0.20 MUg L( )(1) and found to contain only Cr(III) were 49.2 +/- 1.8 and 19.0 +/- 1.5 MUg L( )(1), respectively. Values of 10.6 +/- 0.5 and 10.1 +/- 0.5 MUg L(-)(1) were obtained when a simulated water sample containing 10 MUg L(-)(1) Cr(III) and Cr(VI) was analyzed. PMID- 21662852 TI - Packed column supercritical fluid chromatography/mass spectrometry for high throughput analysis. Part 2. AB - A supercritical fluid chromatograph was previously interfaced to a mass spectrometer (SFC/MS) and the system evaluated for applications requiring high sample throughput using negative-mode atmospheric-pressure chemical ionization (APCI) (Ventura et al. Anal. Chem. 1999, 71, 2410-2416). This report extends the previous work demonstrating the effectiveness of SFC/MS, using positive ion APCI for the analysis of compounds with a wide range of polarities. Substituting SFC/MS for LC/MS results in substantial time saving, increased chromatographic efficiency, and more precise quantitation of sample mixtures. Flow injection analysis (FIA) also benefits from our SFC/MS system. A broader range of solvents is compatible with the SFC mobile phase compared with LC/MS, and solutes elute more rapidly from the SFC/MS system, reducing sample carryover and cycle time. Our instrumental setup also allows for facile conversion between LC/MS and SFC/MS modes of operation. PMID- 21662853 TI - Determination of trace c(1)-c(4) aliphatic alcohols in aqueous samples by 9 fluorenylmethyl chloroformate derivatization and reversed-phase high-performance liquid chromatography. AB - A simple procedure for precolumn fluorescence derivatization of low-molecular weight aliphatic alcohols (C(1)-C(4)) with 9-fluorenylmethyl chloroformate is presented. The derivatization reaction proceeds in 1:1 (v/v) aqueous-acetonitrile solution at room temperature with a sodium phosphate buffer of pH 12.5 as a catalyst. Stable fluorescent derivatives of the alcohols are formed within 10 min. The four derivatives are separated by reversed-phase high-performance liquid chromatography and detected by a fluorescence detector at an excitation wavelength of 259 nm and an emission wavelength of 311 nm. The method detection limits are 4, 40, 70, and 30 pmol for methanol, ethanol, propanol, and butanol, respectively, per 5-MUL injection volume. The relative standard deviations are 3.7% for methanol at 75 pmol and 2.1, 1.5, and 2.2% for ethanol, propanol, and butanol, respectively, at 750 pmol. As a preliminary application, the method was used to determine methanol concentration in laboratory air and ethanol content in a commercial alcoholic beverage. PMID- 21662854 TI - Coupled vectors resolution method for chemometric calibration with three-way data. AB - A new second-order calibration procedure, the coupled vectors resolution (COVER) method, has been developed. The objective of the method is to seek a couple of vectors that minimize a least-squares criterion. With the knowledge indispensable for quantitation, the method yields direct solutions to various cases of second order calibration. Moreover, it allows a statistically plausible way to make use of multisample information. In the case of multiple calibration samples, the method uses the calibration samples to resolve the profiles of the analytes in each order, and then calculates the concentrations of the analytes. This offers the advantage that unknown mixtures newly collected can be predicted in a direct manner. In the case of one calibration sample, the method provides an effective way to utilize the information of spectral profiles of the analytes. Results of simulated experiments and a real analytical example show that the proposed method produces acceptable performance in profile resolution and concentration estimation. PMID- 21662855 TI - Improved probabilistic neural network algorithm for chemical sensor array pattern recognition. AB - An improved probabilistic neural network (IPNN) algorithm for use in chemical sensor array pattern recognition applications is described. The IPNN is based on a modified probabilistic neural network (PNN) with three innovations designed to reduce the computational and memory requirements, to speed training, and to decrease the false alarm rate. The utility of this new approach is illustrated with the use of four data sets extracted from simulated and laboratory-collected surface acoustic wave sensor array data. A competitive learning strategy, based on a learning vector quantization neural network, is shown to reduce the storage and computation requirements. The IPNN hidden layer requires only a fraction of the storage space of a conventional PNN. A simple distance-based calculation is reported to approximate the optimal kernel width of a PNN. This calculation is found to decrease the training time and requires no user input. A general procedure for selecting the optimal rejection threshold for a PNN-based algorithm using Monte Carlo simulations is also demonstrated. This outlier rejection strategy is implemented for an IPNN classifier and found to reject ambiguous patterns, thereby decreasing the potential for false alarms. PMID- 21662856 TI - Electrochemical polymerization of aniline investigated using on-line electrochemistry/electrospray mass spectrometry. AB - A thin-layer electrochemical flow cell coupled on-line with electrospray mass spectrometry (EC/ES-MS) was used to investigate the soluble products from the controlled-potential anodic polymerization of aniline in H(2)O and H(2)O/CH(3)OH (1/1 v/v) with ammonium acetate and acetic acid or ammonium hydroxide as electrolytes (pH 4, 6.5, or 9). At a working electrode (glassy carbon) potential of 1.0 V versus Ag/AgCl, singly protonated aniline oligomers containing as many as 10 aniline units (10-mer) were observed in the ES mass spectra when the polymerization in H(2)O/CH(3)OH at pH 4 was carried out. The abundance of the higher n-mers decreased at higher solution pH and in 100% H(2)O at pH 4. Most of the oligomers were observed in more than one redox state ranging from fully oxidized (all imine nitrogens) to fully reduced (all amine nitrogens). The number of different redox states observed for the n-mers increased with increasing n. The structures of the reduced (m/z 185) and oxidized (m/z 183) aniline dimer ions (head-to-tail, tail-to-tail, or head-to-head) produced from the polymerization of aniline at pH 4, 6.5, and 9 in H(2)O/CH(3)OH were revealed to vary as a function of pH by comparison of their tandem mass spectrometry product ion spectra with the product ion spectra of the dimer standards. EC/ES-MS potential scan experiments, in which the working electrode current and major n-mer ions for n = 2, 3, and 4 were monitored as a function of electrode potential, were used to probe the growth mechanism to higher aniline oligomers. Under the conditions used, the controlled-current electrolytic process inherent to the operation of the ES ion source did not significantly influence the formation or nature of the oligomers observed. Beyond the current application, the results presented here serve to demonstrate the utility of EC/ES-MS as a tool in identifying the initial products of electropolymerization and in studying the products of electrode reactions in general. PMID- 21662857 TI - Electrochemical detection in polymer microchannels. AB - A method, using UV laser photoablation, is presented for the fabrication and the integration of an electrochemical detector in a microchannel device, where carbon microband electrodes are placed either in the bottom or in the side walls of the rectangular microchannel. The different electrochemical cell geometries are tested with a model compound (ferrocenecarboxylic acid) in 40- and 100-MUm-wide capillaries fabricated in planar polymer substrates. The experimental results are compared to numerical simulations for stagnant stream conditions. Depending on the scan rate and on the microchannel depth, the system behaves as a microband electrode until a linear diffusion field develops within the channel. The limit of detection for a one electron redox species within the 120-pL detection volume is ~1 fmol with both cyclic voltammetry and chronoamperometric detection. PMID- 21662858 TI - Probing morphological and compositional variations of anodized carbon electrodes with tapping-mode scanning force microscopy. AB - This paper demonstrates the first application of tapping-mode scanning force microscopy (TM SFM) in the compositional mapping of modified glassy carbon (GC) electrodes. Using TM SFM, we have been able to track both compositional and topographical changes of polished GC induced by electrochemical pretreatment (ECP). Photoresist-based microfabrication techniques were employed to produce surfaces consisting of segregated modified and unmodified regions for direct comparison in the same image. Our results show that ECP of GC via anodization in basic solutions for short times (~10 s) initially removes the ubiquitous layer of polishing debris via an etching process. Longer anodization in basic electrolyte results in significant etching of the GC surface. ECP in acidic solutions yields little topographic change compared to basic electrolytes. Electrochemical results obtained for three redox systems studied on both modified and unmodified GC electrodes correlate with the TM SFM images collected. PMID- 21662859 TI - Microstructure of Ion-Selective Plasticized PVC Membranes Studied by Small-Angle Neutron Scattering. AB - The microstructure of plasticized PVC membranes in the dry state and during the process of soaking in heavy water has been studied by small-angle neutron scattering. In the dry membrane, inhomogeneities were found. The membrane structure is well described by a polydisperse hard-sphere model. The mean diameter of the dispersed spherical inhomogeneities is ~6 nm, which is smaller than the estimated dimension of a single statistically curled PVC polymer chain in the membrane. The values of the best-fit parameters and their change with membrane composition suggest that the particles consist of unplasticized PVC, probably in the crystalline state. The type of plasticizer, the plasticizer content, and the addition of a lipophilic salt were found to influence the water uptake significantly. Water uptake did not change the microstructure due to the original (i.e., dry state) inhomogeneities in the membranes. PMID- 21662860 TI - Study of the Intercalation Equilibrium between the Polynucleotide Poly(adenylic) Poly(uridylic) Acid and the Ethidium Bromide Dye by Means of Multivariate Curve Resolution and the Multivariate Extension of the Continuous Variation and Mole Ratio Methods. AB - The intercalation equilibrium between the polynucleotide poly(adenylic) poly(uridylic) acid and the dye ethidium bromide was studied using molecular absorption spectrophotometry, spectrofluorimetry, and circular dichroism. The presence of an intercalation complex, its pure spectrum, and its concentration profile were clearly deduced using Multivariate Curve Resolution and a multivariate extension of the classical continuous variation and mole-ratio methods. The value of the polynucleotide/dye ratio (r(poly/dye)) in the intercalation complex and of its apparent formation log constant were estimated to be 4 and 6.2, respectively. The proposed multivariate methodology allowed an accurate qualitative and quantitative description of the intercalation process. PMID- 21662861 TI - Single-Microparticle Measurements: Laser Trapping-Absorption Microspectroscopy under Solution-Flow Conditions. AB - A laser trapping-microspectroscopy system combined with a fluid manifold was developed to manipulate and analyze "single" microparticles. A sample solution containing microparticles was introduced to a flow cell set on a microscope stage, and a single particle was trapped by a 1064-nm laser beam. With the particle being trapped, the other particles were pumped out by flowing water to hold the unique microparticle in the flow cell. Under solution-flow conditions, a single microparticle was laser trapped in balance with the gradient (F(g)) and Stokes forces (F(s)) experienced by the particle, and thus, the trapped position was shifted to the downstream side of the 1064-nm laser beam focus. Flow rate and particle size dependencies of this particular positional displacement of the particle were discussed in terms of F(g) and F(s). On the basis of these studies, optical requirements to conduct absorption microspectroscopy of a laser-trapped particle were optimized, and the technique was applied to study a time course of dye adsorption processes in single microparticles. The adsorption rate of Rhodamine B was determined for individual microparticles for the first time. PMID- 21662862 TI - Automated electrochemical analysis with combinatorial electrode arrays. AB - Two combinatorial approaches for rapid automated screening of electrochemical activity of modified electrode surfaces are described. One approach enables simultaneous comparison of electrochemical current by fluorescence associated with pH changes that accompany consumption or production of protons at the electrode surface during a redox process. However, this method cannot distinguish small differences in current at differently modified electrodes. A second approach relies on computer-automated, serial measurement of electrochemical current at each electrode of a 64-electrode array immersed in a single electrochemical cell. Unlike the fluorescent screen, the second method is capable of distinguishing small differences in current at differently modified electrodes, as demonstrated here for gold electrode surfaces covered with organosulfur monolayers of different chain lengths. The improved precision of the computer-automated direct electrochemical method enables examination of active zones that have been first identified by less precise parallel fluorescent screening methods. The direct electrochemical measurement method can easily be extended to a variety of electrode materials, including fuel cell electrocatalysts and redox storage materials. A complete description of the methodology, hardware and computer program for automated measurement is provided. PMID- 21662863 TI - A charge coupled device array detector for single-wavelength and multiwavelength ultraviolet absorbance in capillary electrophoresis. AB - A fundamental limitation to the use of single-point absorbance detection for capillary electrophoresis is irradiance, since it is not possible to create an image at the detection point on capillary that is brighter than the light source. This limitation may be overcome by illuminating a length of the capillary using a fiber-optic bundle and using a charge coupled device (CCD) camera that can image the full length of the illuminated zone. The present paper describes design and development of a CCD detector for UV absorbance that can be used in both multiwavelength and single-wavelength modes. The CCD camera images analyte peaks in the capillary dimension, together with wavelength-resolved absorbance in the dimension perpendicular to the capillary. Successive snapshots of the peaks are added together, after appropriate correction for time-dependent peak displacement, without sacrificing spatial resolution. Measured baseline rms noise values at 200 nm are 34 MUAU using a holographic grating in multiwavelength mode and 8 MUAU with the addition of a band-pass filter. Both values are in excellent agreement with calculations of limiting shot noise. Performance in multiwavelength mode is constrained by the 470-ms readout time of the CCD used, which sets a maximum duty cycle of 2.3%. Noise contributions from source intensity fluctuations are reduced by using a portion of the CCD image to provide a baseline reference signal. With 4-hydroxybenzoate as test analyte, the linear dynamic range in multiwavelength mode is shown to be between 3 and 4 orders of magnitude. High-quality spectra of 2-, 3-, and 4-methylbenzoates are obtained on capillary and used in deconvolution of closely migrating peaks of the 2- and 3 isomers. PMID- 21662864 TI - Mapping of platinum group metals in automotive exhaust three-way catalysts using laser-induced breakdown spectrometry. AB - The use of laser-induced breakdown spectrometry for spatial distribution analysis of platinum, rhodium, and palladium in car catalytic converters is discussed. Fresh converters were extracted from the car exhaust system, cut in pieces of an appropriate size, and analyzed for mapping purposes. Spectral detection, pulse energy, and beam focal conditions were optimized according to the ablation behavior of the material. Difficulties in distribution analysis caused by the complex elemental composition of the sample were overcome by an extensive spectral analysis using appropriate internal standards. Data on the spatial distribution of the active metals in both the axial and radial directions of the catalytic structures are presented. PMID- 21662865 TI - Temperature-Dependent Refractive Index Determination from Critical Angle Measurements: Implications for Quantitative SPR Sensing. AB - Temperature-dependent measurements of surface coverage and interfacial kinetics remain relatively unexploited in thin-film sensing applications that rely on optical surface-sensitive techniques such as surface plasmon resonance spectroscopy (SPR). These techniques are inherently sensitive to the optical properties of the bulk solution in contact with the thin film; therefore, quantitative thin-film sensing requires accurate refractive index data for bulk solutions at the conditions of interest. The refractive index for bulk solutions depends strongly on temperature, solution composition, and optical excitation wavelength. In this paper, we demonstrate the use of critical angle measurements for accurate, independent determination of the refractive index of bulk solutions and present results for different experimental conditions of solution temperature, solution concentration, and excitation wavelength. We also examine the implications of incorrect accounting of the bulk solution for the case of two color SPR sensing of ultrathin organic films. This sensing technique, which depends inherently on the contrast in the dispersion of the refractive index of the film and the bulk solution, can be over 1 order of magnitude more sensitive than single-color SPR measurements. Critical angle measurements can be implemented in conjunction with SPR measurements and will be invaluable for thin film sensing application in which the bulk refractive index varies during the experiment, for example, in temperature-dependent SPR measurements, or for applications in which the solution refractive index is not known. PMID- 21662866 TI - Dendrimer-Mediated Adhesion between Vapor-Deposited Au and Glass or Si Wafers. AB - Here, we report the use of amine-terminated poly(amidoamine) (PAMAM) dendrimers as adhesion promoters between vapor-deposited Au films and Si-based substrates. This method is relatively simple, requiring only substrate cleaning, dipping, and rinsing. Proof of concept is illustrated by coating glass slides and single crystal Si wafers with monolayers of PAMAM dendrimers and then evaporating adherent, 150-nm-thick Au films atop the dendritic adhesion promoter. Scanning tunneling microscopy and cyclic voltammetry have been used to assess the surface roughness and electrochemical stability of the Au films. The effectiveness of the dendrimer adhesion layer is demonstrated using standard adhesive-tape peel tests. PMID- 21662867 TI - Enhancement of extraction efficiency and reduction of boundary layer effects in pulse introduction membrane extraction. AB - Membrane separation has emerged as an attractive alternative for interfacing an extraction step directly to a gas chromatograph or to a mass spectrometer. In pulse introduction (or flow injection type) membrane extraction, a sample pulse is introduced onto an eluent stream that transports it onto the membrane. Since a fixed sample volume is injected, the detector response is directly proportional to the extraction efficiency. This in turn depends on membrane module design, flow conditions, etc. Also, when water contacts a membrane, a static boundary layer is formed at the membrane surface that serves as an additional diffusional barrier to the permeation process. Consequently, permeation slows down, which lowers the speed of analysis. In this paper, methods of increasing the extraction efficiency and decreasing boundary layer effects are presented. The goal is to have higher sensitivity at a shorter analysis time. A stream of nitrogen is introduced into the membrane after sample elution to eliminate the aqueous boundary layer. This technique is found to be effective not only for faster analysis, but also for increasing extraction efficiency. PMID- 21662868 TI - Application of direct electrospray probe to analyze biological compounds and to couple to solid-phase microextraction to detect trace surfactants in aqueous solution. AB - This work presents two novel direct electrospray probes (DEP) to generate an electrospray without using a capillary and/or syringe pump. One of the DEPs is simply a copper coil connecting to a high-voltage power supply. The sample solution is deposited on the coil by a micropipet and the electrospray is subsequently generated at the tip of the copper coil after high voltage is applied to it. Another DEP is constructed by inserting two parallel optical fibers through the copper coil. The two fibers extend one end of the copper coil by 1 cm. Electrospray is generated at the tip of the fibers through the solution predeposited on the copper coil as the high voltage is applied on the copper coil. The ES mass spectra of myoglobin in liquid or solid phases can be obtained using this DEP-MS. Coupling the DEP to a solid-phase microextraction fiber is extremely easy, and a trace amount (in ppb range) of surfactants (Triton X-100) in the aqueous solution are selectively concentrated and detected. PMID- 21662869 TI - Kinetic Resolution of d,l-Amino Acids Based on Gas-Phase Dissociation of Copper(II) Complexes. AB - Chiral recognition of d- and l-amino acids is achieved in the gas phase on the basis of the kinetics of competitive fragmentations of trimeric Cu(II)-bound complexes. The singly charged copper(II)-amino acid trimeric cluster ions [A(2)BCu(II) - H](+) dissociate to form [A(2)Cu(II) - H](+) and [ABCu(II) - H](+) upon collision-induced dissociation (CID) in a quadrupole ion trap. The abundance ratios of these fragments depend strongly on the stereochemistry of the ligands in the [A(2)BCu(II) - H](+) complex ion. The kinetic method was used to calculate relative Cu ion affinities (DeltaCu(II)') for homo- and heterochiral copper(II) bound dimeric cluster ions as the indicator of chiral discrimination. Six amino acids of four different types showed chiral distinctions which ranged from 0 to 6.5 kJ/mol in terms of values of DeltaCu(II)' with abundance ratios, referenced to the other enantiomer, ranging from 1 to 9.2. Amino acids with aromatic substituents displayed the largest chiral distinction, which correlates well with reported chromatographic results. The methodology presented here provides a sensitive means to study enantiomers by mass spectrometry, and initial results show that it is applicable to measurement of enantiomeric excess. PMID- 21662870 TI - Subattomole-Sensitivity Microchip Nanoelectrospray Source with Time-of-Flight Mass Spectrometry Detection. AB - A microfabricated microfluidic device coupled with a nanospray tip for electrospray ionization of dilute solutions is described. The device has been interfaced with a time-of-flight mass spectrometer and evaluated for sensitive, high-speed detection of peptides and proteins. The electrospray voltage was applied through the microchip to the nanospray capillary that was attached at the end of a microfabricated channel. Fluid delivery rates were 20-30 nL min(-)(1) through the hybridized structure without any pressure assistance. On-line microchip electrophoresis has been demonstrated and the effect of the capillary chip junction on band broadening examined. Full mass spectra are acquired within 10-20 ms at 50-100 spectra s(-)(1) storage rates. Detection of subattomole levels of sample from a 100 nM solution is demonstrated for infusion experiments. PMID- 21662871 TI - Multichannel quartz crystal microbalance. AB - Arrays of quartz crystal resonators are fabricated on a single quartz wafer as a multichannel quartz crystal microbalance (MQCM). Three types of four-channel array of 10-MHz resonators are prepared and tested. Mechanical oscillation of each channel is entrapped within the channel almost completely, so that the interference between the channels via the quartz crystal plate is almost negligible. A mass change on each channel is quantitatively evaluated on the basis of Sauerbrey's law. Thus, each channel of a MQCM device can be used as an independent QCM. Influence from a longitudinal wave generated from another channel is also negligible compared to the influence from the wave from the monitored channel itself. The simultaneous oscillation of channels is also possible. The potential applicability of MQCM to the two-dimensional mapping of mass changes is demonstrated. PMID- 21662872 TI - Determination of end groups of synthetic polymers by matrix-assisted laser desorption/ionization: high-energy collision-induced dissociation. AB - Matrix-assisted laser desorption/ionization has been combined with high-energy collision-induced dissociation for the analysis of poly(ethylene glycols) with butanoyl, benzoyl and acetyl end groups, using novel technology comprising a magnetic-sector mass spectrometer and ion buncher with an in-line quadratic-field ion mirror. High-energy (>8 keV) collision-induced dissociation facilitated unambiguous end-group determination of these polymers, providing masses of end groups and structural information. The high-energy collision-induced dissociation also provided information regarding repeat units. PMID- 21662873 TI - Coupled Electron- and Proton-Transfer Processes in the Reduction of alpha [P(2)W(18)O(62)](6)(-) and alpha-[H(2)W(12)O(40)](6)(-) As Revealed by Simulation of Cyclic Voltammograms. AB - Quantitative analysis of the complex problem of coupled electron- and proton transfer steps during reduction of the polyoxo anions alpha-[P(2)W(18)O(62)](6)( ) and alpha-[H(2)W(12)O(40)](6)(-) in aqueous NaCl (0.5 M) has been achieved by simulation of cyclic voltammograms (Rudolph, M.; Reddy, D. P.; Feldberg, S. W. Anal. Chem. 1994, 66, 589A) over wide ranges of anion concentration, pH, and scan rate. Since there are too many unknown parameters to attempt a one-step global form of simulation, a systematic, stepwise approach has been adopted by progressively accessing regimes of increasing voltammetric complexity. This protocol allows experimental behavior in each system over 5 orders of magnitude in proton concentration to be simulated by estimation of three protonation constants combined with experimentally determined reversible half-wave potentials for the two one-electron processes involved. Fast electron transfer and protonation kinetics are assumed. The importance of the values chosen for the diffusion coefficients of the proton and polyoxo anion species is considered. The simulations account for the fact that pairs of one-electron processes coalesce to give an apparent two-electron process in the pH range 1-6 for reduction of both anions. PMID- 21662874 TI - A chronoamperometric method to estimate ionophore loss from ion-selective electrode membranes. AB - A novel chronoamperometric method was developed to estimate the concentration of a neutral ionophore in fixed-site, dioctyl sebacate plasticized, poly(vinyl chloride)-based, ion-selective electrode membranes. The membranes contained between 0.5 and 16 mmol/kg valinomycin. The chronoamperometric technique was used to estimate the valinomycin concentration in freshly prepared membranes and after extraction of some of the ionophore from the membranes using dioctyl sebacate. Replicate measurements indicated a relative standard deviation in the calculated valinomycin concentration of less than 10%, and these values accurately represented the true concentration of valinomycin within 10%. The method permitted an estimate of the valinomycin concentration after valinomycin was leached from a membrane. The results of preliminary experiments using heparinized dog blood suggest that blood protein adsorption does not interfere qualitatively or quantitatively with the analysis. PMID- 21662875 TI - Quantitative in Situ Measurement of Ion Transport in Polypyrrole/Poly(styrenesulfonate) Films Using Rotating Ring-Disk Voltammetry. AB - An approach based on rotating ring-disk electrode (RRDE) voltammetry is described for the quantitative, in situ measurement of ion transport between solution and conducting polymer films. The specific composite film studied in this report is polypyrrole/poly(styrenesulfonate) (pPy(+)/pSS(-)). Cation flux in and out of the polymer was obtained from the mass-transport-limited reduction current for the dopant cation(s) measured at the ring during redox cycling of the polymer. Crucial to this method is the use of a supporting electrolyte that is sterically inhibited from passing into the film and the use of dopant ions that adhere to specific electrochemical constraints. With this method it was possible to quantitatively account for all changes in charge compensation in the film by the specific cation(s) involved. Three different cations were explored alone and in paired combinations. Solutions containing mixtures of dopant cations were studied to determine whether the pPy(+)/pSS(-) films exhibit preferential doping. Kinetic factors, likely due to steric differences in the dopant cations, were found to lead to significant preferential doping of the polymer. PMID- 21662876 TI - Determination of trace levels of anionic surfactants in river water and wastewater by a flow injection analysis system with on-line preconcentration and potentiometric detection. AB - The authors present an automated flow injection analysis (FIA) system for the determination of low levels of anionic surfactants in river water and wastewater. The system uses especially constructed tubular flow-through ion-selective electrodes (ISEs) as potentiometric sensors and on-line preconcentration techniques. The anionic surfactant ISEs employed are of the all-solid-state type with a plasticized PVC membrane. They show a general response to anionic surfactants with a lower limit of linear response of ~10(-)(5) M, when used in direct determinations. However, their specificity is limited, which hampers their direct use with environmental samples. Therefore, the FIA system presented here includes a solid-phase extraction procedure for purification and preconcentration of analytes. Breakthrough curves were constructed to characterize different sorbents and different eluents were tested to optimize the preconcentration process. The FIA system was first applied to the determination of different types of anionic surfactant standards. Potentially interfering substances such as chloride, nitrate, and nonionic surfactants were checked to verify that they did not interfere on the response of the system. Concentrations of ~10(-)(7) M (0.03 ppm) of sodium dodecyl sulfate could be detected in the nonlinear response region when 3 mL of sample was preconcentrated and eluted with 50 MUL of a 75% acetonitrile/water (v/v) solution. Precision was 2% RSD (n = 31) for a 1 * 10( )(6) M sodium dodecyl sulfate standard solution and the sample throughput was 10 h(-)(1). The FIA system was then used for the determination of total anionic surfactants in river water and wastewater. PMID- 21662877 TI - The monolayer thickness dependence of quantized double-layer capacitances of monolayer-protected gold clusters. AB - This report describes how the electrochemical double-layer capacitances of nanometer-sized alkanethiolate monolayer-protected Au clusters (MPCs) dissolved in electrolyte solution depend on the alkanethiolate chain length (C4 to C16). The double-layer capacitances of individual MPCs (C(CLU)) are sufficiently small (sub-attoFarad, aF) that their metal core potentials change by >0.1 V increments for single electron transfers at the electrode/solution interface. Thus, the current peaks observed are termed "quantized double layer charging peaks", and their spacing on the potential axis varies with C(CLU). Differential pulse voltammetric measurements of C(CLU) in solutions of core-size-fractionated (i.e., monodisperse) MPCs are compared to a simple theoretical model, which considers the capacitance as governed by the thickness of a dielectric material (the monolayer, whose chain length is varied) between concentric spheres of conductors (the Au core and the electrolyte solution). The experimental results fit the simple model remarkably well. The prominent differential pulse voltammetric charging peaks additionally establish this method, along with high-resolution transmission electron microscopy and laser ionization-desorption mass spectrometry, as a tool for evaluating the degree of monodispersity of MPC preparations. We additionally report on a new tactic for the preparation of monodisperse MPCs with hexanethiolate monolayers. PMID- 21662878 TI - Computer simulation of charge-selective electrochemistry of catechols at high surface-area carbon fibers. AB - The shape and size of cyclic voltammetric (CV) waves at the ultrahigh surface area carbon fiber are dependent on the pH and the charge of the electroactive species. The high surface area resulted from the fiber being fractured by application of a high anodic potential or current. The CV waves have been computer simulated with a model that assumes the entry of positively charged and, in some cases, neutral ones, but rejection of negatively charged species from the interior of the fractured fibers. Best fit between the computer-calculated and experimental CV waves is obtained for a model containing three components as the source of the current: (a) background capacitive charge, (b) diffusion to the outer cylindrical-shaped fiber, and (c) interior thin-layer volume. Simulation results indicate that the values for the inner void volume are in the nanoliter range when electroactive species penetrate the interior. PMID- 21662879 TI - Atmospheric pressure laser ionization. An analytical technique for highly selective detection of ultralow concentrations in the gas phase. AB - In this contribution a new analytical technique is presented for the direct mass spectrometric (MS) detection of gas-phase trace species at atmospheric pressure. Employing resonance-enhanced multiphoton ionization (REMPI) close to the inlet nozzle orifice, i.e., at high molecule densities, the sensitivity of the instrument has been increased by up to 3 orders of magnitude as compared to conventional REMPI-MS with ionization in a differentially coupled ion source. Furthermore, adiabatic cooling, resonant ionization, and mass-selective detection establish a highly selective analytical technique. Several atmospherically relevant compounds were investigated. The current detection limit for NO is 0.9 pptv, for acetaldehyde 1.7 pptv, for CO 15 pptv, and for 2,5-dichlorotoluene 12 pptv. We discuss APLI with regard to applications in medical and environmental research. PMID- 21662880 TI - Analysis of nucleic acids by capillary ion-pair reversed-phase HPLC coupled to negative-ion electrospray ionization mass spectrometry. AB - Ion-pair reversed-phase high-performance liquid chromatography was successfully coupled to negative-ion electrospray ionization mass spectrometry by using 60 * 0.20 mm i.d. capillary columns packed with 2.3-MUm micropellicular, octadecylated poly(styrene/divinylbenzene) particles as stationary phase and gradients of acetonitrile in 50 mM aqueous triethylammonium bicarbonate as mobile phase. Systematic variation of the eluent composition, such as concentration of ion-pair reagent, anion in the ion-pair reagent, solution pH, and acetonitrile concentration led to the conclusion that most parameters have opposite effects on chromatographic and mass spectrometric performances. The use of acetonitrile as sheath liquid enabled the rapid and highly efficient separation and detection of phosphorylated and nonphosphorylated oligonucleotides ranging in size from 8 to 40 nucleotides. High-quality full-scan mass spectra showing little cation adduction were acquired from which the molecular masses of the separated oligonucleotides were calculated with an accuracy of 0.011%. With calibration curves being linear over at least 2 orders of magnitude, the lower limits of detection for a oligodeoxythymidine 16-mer were 104 fmol with full scan and 710 amol with selected-ion-monitoring data acquisition. The potential of ion-pair reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry was demonstrated for mixed-sequence oligomers by the characterization of a reaction mixture from solid-phase synthesis of a 40-mer oligonucleotide. PMID- 21662881 TI - Development of an infrared hollow waveguide as a sensing device for detection of organic compounds in aqueous solutions. AB - In this paper, a new detection method based on an infrared hollow waveguide is developed to detect semivolatile to nonvolatile organic compounds in aqueous solutions. The hollow waveguide is produced by chemical deposition of silver on the inner surface of a polyethylene tube. The surface of the silver layer is further coated with a hydrophobic film to attract organic compounds in aqueous solution. Samples were pumped through this hollow waveguide sampler and organic compounds were attracted onto the hydrophobic film. After removal of the residual water molecules in the hollow waveguide sampler, organic compounds can be sensed by conventional Fourier transform infrared (FT-IR) spectrometry. Theoretical aspects of this type of sampler are also presented. The derived analytical equations for this type of sampler were consistent with experimental data. Under the condition of constant hydrophobic film volume, high linearity (R(2) equal to 0.9993) between the concentration of analyte and the detected signal was obtained for concentrations in the range from 2.5 ppm to 50 ppb. By co-adding 100 scans with 4 cm(-)(1) resolution, the typical detection limit in this type of sensing method can be lower than 10 ppb. Several factors such as sampling flow rate, sampling time, and hydrophobic film volume were also investigated in this work. PMID- 21662882 TI - Effect of laser pulse width on ionization efficiency in supersonic beam multiphoton ionization-mass spectrometry. AB - The efficiency in multiphoton ionization is calculated for various molecules with different lifetimes, based on a kinetic model using rate equations. The results are strongly dependent on the types of resonance ionization, i.e., ionization through congested intermediate levels or ionization through a discrete intermediate level. In the former case, a laser pulse shorter than the lifetime is always preferred for efficient ionization. In the latter case, a 10-ps laser pulse provides the maximum ionization efficiency for a molecule with a lifetime in excess of 10 ps. For a molecule having a lifetime shorter than 10 ps, the use of a laser whose pulse width is adjusted to the same value as the lifetime is suggested. The results obtained by a computer simulation are in reasonably good agreement with the experimental data obtained for monohalogenated benzenes. PMID- 21662883 TI - Evaluation of electrospray mass spectrometry as a technique for quantitative analysis of kinetically labile solution species. AB - The extent that a kinetically labile equilibrium reaction was perturbed by passage through the electrospray ion source has been measured. The reaction studied was strontium ion chelation by EDTA (Sr(2+) + Y(4)(-) ? SrY(2)(-)) in 100% aqueous solutions. The forward reaction rate is very fast (10(9) M(-)(1) s( )(1)) and the reverse rate is very slow (10(0) s(-)(1)) relative to the time scale of the ES process (~10(-2) s). The SrY(2-) detected with the mass spectrometer were expected to be representative of thermodynamic equilibrium within the droplets, but the position of the equilibrium shifted to the right relative to the solution equilibrium position. Given the current status of understanding of the ion generation process in the electrospray ion source, the degree that the [Sr(2+)] changed due to passage through this ion source was smaller than expected, which is fortuitous with respect to the quantitation of such species. The pH of each calibration set determined the fraction of strontium that was uncomplexed in solution. The equilibrium shift induced by passage through the ion source was constant for solutions at constant pH but differed for solutions at different pH. Decreasing the solution pH generated smaller equilibrium shifts as measured by the change in the [Sr(2+)]. In solutions with free Sr(2+) and excess EDTA at equilibrium, the free [Sr(2+)] decreased by ~100 and ~10% in solutions at pH 5.85 and 4.98, respectively. Quantitation of kinetically labile species in complex, multicomponent systems will be straightforward with ES-MS, provided all species involved in the equilibria can be identified and monitored. PMID- 21662884 TI - Extension of External Voltage Control of Electroosmosis to High-pH Buffers. AB - Control of electroosmosis by an applied external voltage field in capillary electrophoresis has been limited to buffer pH approximately 5 or below. This poor control at higher pH is caused by a high density of surface charge induced by chemical equilibrium overwhelming the influence of the external voltage-induced charges within the electric double layer. A tert-butyldiphenylchlorosilane treatment was used on fused-silica capillaries to minimize chemically generated zeta-potential where this treatment allowed for control of electroosmosis over a large pH range (2-10). Blocking the surface with traditional polymer-based surface treatments does not work in this application since the polymers increase the viscosity within the electric double layer and impede electroosmosis. The surface created by this reaction is demonstrated in extremely narrow capillaries, down to 2-MUm internal diameter. The treated surface is sterically hindered against acid- and base-catalyzed degradation reactions typically associated with organosilanes. This results in a surface that was stable to experimental buffer pH extremes, from pH 3 to pH 10, and was stable for at least 8 weeks exposed to both solution and air. PMID- 21662885 TI - Retention behavior of phenols, anilines, and alkylbenzenes in liquid chromatographic separations using subcritical water as the mobile phase. AB - The unique characteristic of subcritical water is its widely tunable physical properties. For example, the polarity (measured by dielectric constant) of water is significantly decreased by raising water temperature. At temperatures of 200 250 degrees C (under moderate pressure to keep water in the liquid state), the polarity of pure water is similar to that of pure methanol or acetonitrile at ambient conditions. Therefore, pure subcritical water may be able to serve as the mobile phase for reversed-phase separations. To investigate the retention behavior in subcritical water separation, the retention factors of BTEX (benzene, toluene, ethylbenzene, and m-xylene), phenol, aniline, and their derivatives have been determined using subcritical water, methanol/water, and acetonitrile/water systems. Subcritical water separations were also performed using alumina, silica bonded C18, and poly(styrene-divinylbenzene) columns to study the influence of the stationary phase on analyte retention under subcritical water conditions. PMID- 21662886 TI - Analytical- and preparative-scale isoelectric focusing separation of enantiomers. AB - Isoelectric focusing has been used to achieve the analytical- and preparative scale separation of the enantiomers of amphoteric analytes. By considering the simultaneous multiple equilibria involved in the chiral recognition process, a model has been developed to describe the magnitude of the DeltapI value that develops between the enantiomers in the presence of a noncharged chiral resolving agent, such as a noncharged cyclodextrin. Theoretical analysis of the model indicates that three kinds of IEF enantiomer separations are possible: aniono selective and cationo-selective, when only the identically charged forms of the enantiomers bind selectively to the resolving agent, and duo-selective, when the differently charged forms of the enantiomers bind selectively to the resolving agent. The model predicts that the DeltapI vs cyclodextrin concentration curves approach limiting DeltapI values which can be as large as 0.1, even when the binding constants of the enantiomers differ only by 10%. The parameters of the model can be readily determined by free solution capillary electrophoretic or pressure-mediated capillary electrophoretic experiments. The validity of the proposed model has been tested with hydroxypropyl beta-cyclodextrin as resolving agent and dansyl phenylalanine as probe. Capillary IEF enantiomer separations have been achieved using both ampholytes and binary propionic acid-serine buffers (Bier's buffers). Preparative-scale IEF enantiomer separations with production rates as high as 1.3 mg/h have been achieved in an Octopus continuous free-flow electrophoretic system. PMID- 21662887 TI - Capillary electrophoresis and contactless conductivity detection of ions in narrow inner diameter capillaries. AB - Capillary electrophoresis and conductometry represent a combination of a high resolution separation method with a sensitive detection principle for the analysis of ionic species. In this paper, results are reported that are obtained with a contactless conductivity detector. This device works without a galvanic contact of the electrolyte and the electrodes. The conductivity sensor is based on two metal tubes that act as cylindrical capacitors. These electrodes are both placed around a fused-silica capillary with a detection gap of 1 mm left in between. When a high audio or low ultrasonic oscillation frequency between 40 and 100 kHz is applied to one of the electrodes, a signal is produced as soon as an analyte zone with a different conductivity compared to the background electrolyte passes the detection gap. An amplifier and rectifier is connected to the other electrode where the signal is further processed. Limits of detection for lithium and fluoride are 4 and 13 ppb, respectively, with a linear range over 4 orders of magnitude from 90 ppb up to more than 1000 ppm for both anions and cations. Furthermore, it is demonstrated that for species with lower equivalent conductivities, such as organic ions, indirect conductivity detection is a sensitive alternative to indirect optical detection methods. Limits of detection of 50 ppb and below are obtained for organic acids. PMID- 21662888 TI - A method to estimate the octanol-air partition coefficient of semivolatile organic compounds. AB - A multicolumn method for the estimation of the octanol-air partition coefficient (K(OA)) of semivolatile compounds is described. The method is based on the retention time of a compound on gas chromatographic columns of different selectivity and polarity. Log K(OA) values of polychlorinated biphenyls (PCB) were estimated with the novel multicolumn method. The results were in excellent agreement with previously published data using a generator column method. Therefore, we used our multicolumn method to estimate K(OA) for more than 100 PCB congeners. PMID- 21662889 TI - A photovoltaic detection system for flow injection and liquid chromatography. AB - A photoionization system has been developed for flow injection and liquid chromatographic applications that employs photovoltaic rather than traditional photoconductive detection. This detection system utilizes an excimer laser at 248 nm (5.0 eV) to achieve one-photon excitation in alcoholic, aqueous, and ionic solutions. The photovoltaic response is reported for a variety of solutes including aliphatic and aromatic amines, aldehydes, ketones, carboxylic acids, and halogenated compounds. The photovoltaic method is characterized with respect to solute concentration and flow rate. The detection limit is 5 * 10(-)(6) M (2.3 ng) for aniline in methanol with a linear dynamic range greater than 2 orders of magnitude, which compares favorably to UV-visible absorbance detection. Photovoltaic detection is demonstrated for a series of substituted anilines and aldehydes separated by reversed-phase liquid chromatography. PMID- 21662890 TI - The strength of acids in alcohols as determined by steady-state voltammetry. AB - Steady-state voltammograms for reduction of acids of various strengths in alcohols with excess supporting electrolyte and without any supporting electrolyte can be used to infer charge type and strength of the acid on the basis of the phenomenon of migration. For strong and moderately weak acids (K(a)/[Formula: see text] > 10(-)(3)) in alcohols, the ratio of steady-state transport-limited current to diffusion-limited current, corrected appropriately for ion-ion interactions, the presence of ionic impurities, and changes in viscosity, for hydrogen ion reduction without supporting electrolyte and with excess supporting electrolyte equals 2. For acetic acid, which is very weak (K(a)/[Formula: see text] < 10(-)(6)), the value of the steady-state transport limited current is, under the experimental conditions applied here, independent of supporting electrolyte concentration. In the case of a homogeneous acid-base equilibrium, a novel analytical procedure yields diffusion coefficients of both hydrogen ion and undissociated weak acid molecules from the diffusional and migrational currents. Limiting currents obtained in alcohols with excess supporting electrolyte and without supporting electrolyte are compared by means of an extended formula that incorporates the ionic strength dependence of diffusion coefficients. PMID- 21662891 TI - Integrated electrophoresis chips/amperometric detection with sputtered gold working electrodes. AB - An on-chip electrochemical detector for micromachined capillary electrophoresis (CE) systems, based on sputtering a gold working electrode directly onto the capillary outlet, is described. The new on-chip detector preparation requires no microfabrication or alignment procedures nor a decoupling mechanism. The attractive performance of the integrated electrophoresis chips/amperometric detection was demonstrated for the anodic detection of neurotransmitters. The response for dopamine was linear from 20 to 200 MUM, with a LOD of 1.0 MUM and a sensitivity of 52 pA/MUM. Such intimate coupling of capillary electrophoresis chips and electrochemical detection facilitates the realization of complete integrated microanalytical devices. PMID- 21662892 TI - Chronoamperometry of surface-confined redox couples for irreversible two-step and three-step consecutive reaction mechanisms. AB - Chronoamperometry has been widely employed to determine kinetic rate constants for electron-transfer reactions of surface-confined redox couples. When the mechanism for the transformation is more complicated than a one-electron transfer, deviations can be expected from an exponential decay of the current transient. Theory is presented in this paper for irreversible, two-step and three step consecutive reaction mechanisms in the form of analytical solutions of the corresponding differential equations. The theory should find application to surface electrode reactions with two-electron "n-values". PMID- 21662893 TI - Test analytes for studies of the molecular mechanism of chromatographic separations by quantitative structure-retention relationships. AB - Three model series of nonionized in water analytes are proposed for objective interlaboratory comparisons of effects on chromatographic separations of the stationary and the mobile phases by means of the analysis of quantitative structure-retention relationships (QSRR). Each series was designed specifically for a given general QSRR model by selecting the analytes whose properties were well reflected by the respective structural descriptors. Rules of a meaningful chemometric analysis were observed, and the structural information content was compromised with the length of analyte series. Three QSRR models were verified and are recommended for studies of molecular mechanism of chromatographic retention: the reduced linear solvation energy relationship-based model of Abraham, a model employing structural descriptors from molecular modeling, and a model correlating retention to the 1-octanol-water partition coefficient, log P. All the models were demonstrated to provide reliable QSRR equations for five sets of diverse retention data. These equations discriminate quantitatively individual chromatographic systems and are interpretable in straightforward chemical categories. In view of QSRR analysis, the retention processes clearly emerge as the net effects of fundamental intermolecular interactions involving the analyte and the components of chromatographic systems. PMID- 21662894 TI - High-performance membrane chromatography of small molecules. AB - High-performance membrane chromatography (HPMC) proved to be a very efficient method for fast protein separations. Recently, it was shown to be applicable also for the isocratic chromatography of plasmid DNA conformations. However, no study about the separation of small molecules has been performed until now. In this work, we investigated the possibility of gradient and isocratic HPMC of small molecules with Convective Interaction Media disks of different chemistries and tried to explain the mechanism that enables their separation. We demonstrated that it is possible to achieve efficient separations of oligonucleotides and peptides in the ion-exchange mode as well as the separation of small hydrophobic molecules in the reversed-phase mode. It was shown that similar peak resolution can be provided in both gradient and isocratic modes. PMID- 21662895 TI - Systematic Study of Chromatographic Behavior vs Alkyl Chain Length for HPLC Bonded Phases Containing an Embedded Carbamate Group. AB - A series of HPLC bonded phases containing an internal carbamate group were studied by changing the terminal N-alkyl group from C(8)H(17) to C(18)H(37) in increments of two methylene units, i.e., C(8), C(10), C(12), C(14), C(16), and C(18). Each material was prepared via bonding of silica with the respective 3 (chlorodimethylsilyl)propyl N-alkylcarbamate silane. The materials were compared under reversed-phase conditions using a test mixture of nonpolar, polar, and basic compounds in a 65:35 (v/v) methanol/20 mM KH(2)PO(4)/K(2)HPO(4), pH 7, mobile phase. Retention factors were found to generally increase from the C(8) length to the C(12)-C(16) lengths but decreased for the C(18) length. Retention factors were also measured as a function of three ligand surface concentrations for the C(12), C(14), and C(18) materials. In this study, retention generally decreased with increasing surface concentration, especially for the C(18) chain length. Changes in particle surface area and porosity caused by bonding did not fully account for the observed changes in retention factors. Peak shapes for the basic analytes propranolol and amitriptyline were also studied as a function of N alkylcarbamate chain length and surface concentration. Tailing factors were unaffected by chain length and only weakly dependent on surface concentration. By comparison, tailing factors decreased significantly as surface concentration increased for a set of conventional C(18) alkyl packings. PMID- 21662896 TI - High-performance liquid chromatography of lignin-derived phenols in environmental samples with diode array detection. AB - Lignin-derived and standard phenols were successfully analyzed with reversed phase high-performance liquid chromatography (HPLC) with diode array detection. The 11 major phenols produced by cupric oxide (CuO) oxidation were clearly and rapidly separated. Determination by diode array detection also allowed detection of interfering impurities within individual HPLC peaks. The lignin phenols were accordingly corrected and quantified. This method yields precise and reliable data for various environmental samples such as dissolved organic matter from aqueous samples and sediments and can also be applied to various particulate materials such as detritus and plant tissues. An interlaboratory method comparison with humic substance standards from the International Humic Substances Society revealed differences in lignin phenol concentrations, whereas lignin parameters better coincided. PMID- 21662897 TI - Thermospray methods for rapid, sensitive, and nonchromatographic speciation of chromium oxidation States. AB - A sensitive technique for speciation and quantification of Cr(III) and Cr(VI) has been developed using thermospray (TSP) sample introduction with inductively coupled plasma atomic emission spectrometry (ICPAES). For unacidified solutions, the sensitivity for Cr(III) was found to be lower than that for Cr(VI). The sensitivity for Cr(III) was further depressed to a negligible level by adjusting sample and thermospray operating parameters. The low sensitivity for Cr(III) was thought to result from the precipitation of that species to form Cr(OH)(3), which deposited within the vaporizer. For acidic solutions (1% v/v HNO(3)), the sensitivities for both species were essentially identical. On the basis of these results, methods for speciation of Cr(III) and Cr(VI) were developed. With samples buffered to pH 4.4, Cr(VI) could be selectively determined. With acidic sample aliquots (1% v/v HNO(3)), the total chromium concentration could also be determined, and the Cr(III) concentration could be calculated by difference. Parameters affecting Cr(III) sensitivity, such as control temperature, pH, and pump flow rate, were studied in addition to optimal TSP-ICPAES parameters. The limits of detection (LODs) for Cr(VI) and for total Cr were 0.47 and 0.61 MUg/L with standard deviations of 1.5% and 2.0%, respectively. Good accuracy and precision of the method were demonstrated for analysis of spiked tap water and lake water samples. Mobile phase ion-pairing chromatography with ICPAES detection provided comparable results for moderately high concentration samples. Accuracy of measurements for Cr(VI) was within 1% of the certified value for NIST standard reference material 2109. PMID- 21662898 TI - Sampling and analysis of particulate matter by glow discharge atomic emission and mass spectrometries. AB - The direct introduction of particulate matter into glow discharge atomic emission and mass spectrometry sources through a particle beam/momentum separator apparatus is described. Vacuum action through a narrow (0.0625 in. i.d.) stainless steel tube allows the introduction of discrete samples of NIST SRM 1648 urban particulate matter (UPM) and caffeine in powder form. Introduction of "ambient" airborne particulate matter is also possible. Particles passing through the aerodynamic momentum separator impinge on the heated (~200-250 degrees C) inner surface of the glow discharge plasma volume and are flash-vaporized. The resultant atoms/molecules are subjected to excitation/ionization collisions within the low-pressure (0.5-5 Torr of He or Ar) plasma, producing characteristic photon emission and/or signature ionic species. In this way, atomic emission and mass spectrometry identification of particle constituents is possible. Basic design aspects of the apparatus are presented, and demonstrations of atomic emission detection of the constituents in the NIST SRM illustrate the general characteristics of the approach. Transient atomic emission signals are captured for the introduction of preweighed, discrete samples, with the integrated areas used to construct analytical response curves. Limits of detection using this relatively simple atomic emission system are on the order of tens of nanograms for sample masses of ~50 MUg. Mass spectrometric monitoring of introduced caffeine particles and a mixture of polycyclic aromatic hydrocarbons (PAHs) illustrates the ability of the glow discharge plasma to produce high-quality, library (electron impact) searchable mass spectra of molecular species while also yielding isotopic identification of elemental components of the UPM. Limits of detection for Fe in the NIST SRM are on the order of 175 ng of material, equivalent to ~7 ng of analyte Fe. It is believed that the small size, low power consumption, ease of operation, and multimode sampling capabilities (AES/MS) of the particle beam-glow discharge (PB-GD) apparatus hold promise for applications in continuous monitoring and discrete particle sampling. PMID- 21662899 TI - Ultratrace and isotope analysis of long-lived radionuclides by inductively coupled plasma quadrupole mass spectrometry using a direct injection high efficiency nebulizer. AB - The direct injection high efficiency nebulizer (DIHEN) was explored for the ultrasensitive determination of long-lived radionuclides ((226)Ra, (230)Th, (237)Np, (238)U, (239)Pu, and (241)Am) and for precise isotope analysis by inductively coupled plasma mass spectrometry (ICPMS). The DIHEN was used at low solution uptake rates (1-100 MUL/min) without a spray chamber. Optimal sensitivity (e.g., (238)U, 230 MHz/ppm; (230)Th, 190 MHz/ppm; and (239)Pu, 184 MHz/ppm) was achieved at low nebulizer gas flow rates (0.16 L/min), high rf power (1450 W), and low solution uptake rates (100 MUL/min). The optimum parameters varied slightly for the two DIHENs tested. The detection limits of long-lived radionuclides in aqueous solutions varied from 0.012 to 0.11 ng/L. The sensitivity of the DIHEN was improved by a factor of 3 to 5 compared with that of a microconcentric nebulizer (MicroMist used with a minicyclonic spray chamber at a solution uptake rate of 85 MUL/min) and a factor of 1.5 to 4 compared with that of a conventional nebulizer (cross-flow used with a Scott type spray chamber at a solution uptake rate of 1 mL/min). The precision of the DIHEN ranged from 0.5 to 1.7% RSD (N = 3) for all measurements at the 10 ng/L concentration level (~3 pg sample size). The sensitivity decreased to 10 MHz/ppm at a solution uptake rate of 1 MUL/min. The precision was about 5% RSD at a sample size of 30 fg for each long-lived radionuclide by the DIHEN-ICPMS method. The oxide to atom ratios were less than 0.05 (except ThO(+)/Th(+) ) and decreased under the optimum conditions in the following sequence: ThO(+)/Th(+) > UO(+)/U(+) > NpO(+)/Np(+) > PuO(+)/Pu(+) > AmO(+)/Am(+) > RaO(+)/Ra(+). Atomic and oxide ions were used as analyte ions for ultratrace and isotope analyses of long-lived radionuclides in environmental and radioactive waste samples. The analytical methods developed were applied to the determination of long-lived radionuclides and isotope ratio measurements in different radioactive waste and environmental samples using the DIHEN in combination with quadrupole ICPMS. For instance, the (240)Pu/(239)Pu isotope ratio was measured in a radioactive waste sample at a plutonium concentration of 12 ng/L. This demonstrates a main advantage of DIHEN-ICPMS compared with alpha-spectrometry, which cannot be used to selectively determine (239)Pu and (240)Pu because of similar alpha energies (5.244 and 5.255 MeV, respectively). PMID- 21662900 TI - Detection of minute chemical species by principal-component analysis. AB - A novel analytical technique based on the detection of minute bands in a mixture spectrum with the use of principal-component analysis (PCA) is presented. This new aspect of PCA indicates that overlapped spectra of some components can be separated with no a priori knowledge of the components when the absorbances of the components vary greatly. This technique can be used for the detection of minute chemical species. The concept was confirmed by computer simulations. In the simulations, abstract spectra (loading vectors) were successfully obtained, and the changes of the component absorbances were also successfully followed semiquantitatively by calculating their scores. The method developed with PCA was applied to the analysis of infrared reflection-absorption (RA) spectra to study molecular interaction mechanism between alkyl-deuterated dipalmitoylphosphatidylcholine (DPPC-d(62)) monolayer and sucrose. The samples were Langmuir-Blodgett (LB) films of the DPPC-d(62) monolayer that was prepared on a sucrose solution. The LB films consisted of the following phases: air/DPPC d(62) + sucrose/sucrose/substrate (gold). The abstract spectra corresponding to "DPPC-d(62) + sucrose" and "sucrose" phases were successfully separated by PCA, and the absorbance change of sucrose in each phase was semiquantitatively calculated from the score. The absorbance change was experimentally confirmed with quartz-crystal microbalance (QCM) experiments. In addition, minute water molecules that remained in the LB films after drying were readily detected from an abstract spectrum, and their binding site was found to be the phospholipid moiety in the head group of DPPC-d(62). PMID- 21662901 TI - Multiscale cluster analysis. AB - This article describes how the concept of multiresolution is used with cluster analysis of spectral data. Multiresolution analysis progressively increases the resolution of a spectrum profile by adding levels of details contained in scales obtained from a discrete wavelet transform. At each resolution level a cluster analysis is performed on all the spectra profiles in the data set. This allows the relating of changes in the cluster pattern to various broad and narrow features in the spectral data profiles. The analysis also provides an approximate location of the important features in the original wavenumber domain. PMID- 21662902 TI - Imaging single fluorescent molecules at the interface of an optical fiber probe by evanescent wave excitation. AB - We have developed a new fluorescent method for single-molecule detection (SMD) and imaging using an optical fiber probe. The fluorophores were excited by the evanescent wave field produced on the core surface of the optical fiber. This was achieved by exposing a section of the core of the optical fiber probe to the fluorophore solution. Both cylindrical and square optical fiber probes were used for SMD. The fluorescent signals were detected by an intensified charge-coupled device. Single rhodamine 6G molecules have been detected. The number of rhodamine 6G molecules imaged by the optical fiber probe showed an excellent linear relationship with the concentrations of the fluorophores. The SMD scheme was also applied to the imaging of biomolecules, such as molecular beacon DNA molecules, labeled with tetramethylrhodamine. Our results have shown that using an optical fiber is an easy yet effective approach to SMD. It represents a simpler fluorescent method for the detection of single-molecules in solution and at an interface. PMID- 21662903 TI - A Calixarene-Based Fluorogenic Reagent for Selective Mercury(II) Recognition. AB - The first calixarene-based fluorogenic Hg(II)-selective extractant, 5,11,17,23 tetrakis(1,1-dimethylethyl)-25,27-bis(N-(5-dimethylaminonaphthalene-1 sulfonyl)carbamoylmethoxy)-26,28-dimethoxycalix[4]arene (2), is reported. In solvent extraction from aqueous acidic solutions (HNO(3)), 2 exhibits excellent selectivity for Hg(II) over a wide range of transition, alkali, and alkaline earth metal cations. Quenching of its fluorescence due to Hg(II) coordination is unaffected by the presence of 100-fold excesses of alkali metal cations, alkaline earth metal cations, Ag(I), Tl(I), Cd(II), Co(II), Cu(II), Ni(II), Pb(II), Pd(II), Zn(II), or Fe(III). PMID- 21662904 TI - Noncomplexing Tertiary Amines as "Better" Buffers Covering the Range of pH 3-11. Temperature Dependence of Their Acid Dissociation Constants. AB - Most of a broad series of buffers developed by Good (often called "Good's" or "Good" buffers) have been shown to cause metal ion interference as a result of complexation. A series of tertiary amines, devoid of hydroxy groups or other weak donors on the alpha, beta, or gamma carbons, have been developed as "Better" pH buffers which, as a result of steric hindrance, are incapable of forming even weak complexes with metal ions. As a result, they avert interferences of the type often encountered in metal ion studies which require buffer use. The compounds studied are alkyl and alkylsulfonate derivatives of morpholine (3), piperazine (3), ethylenediamine (3), and methylenediamine (1). With the exception of the morpholine derivatives, these compounds have two protonatable sites and, therefore, can be used to buffer two separate pH regions. A series of 10 buffer compounds span the entire range of pH 3-11. The acid dissociation constants for these compounds have now been determined in aqueous solution at 15, 25, 35 and 45 degrees C, MU = 0.10 M. From these data, apparent enthalpy and entropy values have been calculated to permit application at other temperatures as well. These buffers are recommended for use in all situations in which metal ions are present. All of the reported compounds are now commercially available. PMID- 21662905 TI - Development of a high-pressure asher focused microwave system for sample preparation. AB - The development of high-pressure Asher focused microwaves (HPA-FMs), a novel approach to microwave assisted digestion, is described. The system uses focused microwaves, at 2.45 GHz, to improve digestion capability with up to 650 W microwave power concentrated into six quartz pressure vessels containing samples and nitric acid. The device combines microwave heating with high-pressure vessel technology (reactions can be conducted at pressures and temperatures up to 130 bar and 320 degrees C, respectively). Methodology was developed using powdered biological reference material. The residual carbon content of digested bovine liver sample was determined by Coulometry after combustion in an oxygen stream to evaluate the effectiveness of the decomposition procedure. With this new decomposition device, organic material is totally oxidized with nitric acid in a single-step digestion. PMID- 21662906 TI - Ligand binding to nicotinic acetylcholine receptor investigated by surface plasmon resonance. AB - Ligand binding to the nicotinic acetylcholine receptor is studied by surface plasmon resonance. Biotinylated bungarotoxin, immobilized on a streptavidin coated gold film, binds nicotinic acetylcholine receptor both in detergent solubilized and in lipid vesicle-reconstituted form with high specificity. In the latter case, nonspecific binding to the sensor surface is significantly reduced by reconstituting the receptor into poly(ethylene glycol)-lipid-containing sterically stabilized vesicles. By preincubation of a bulk nicotinic acetylcholine receptor sample with the competing ligands carbamoylcholine and decamethonium bromide, the subsequent specific binding of the receptor to the surface-immobilized bungarotoxin is reduced, depending on the concentration of competing ligand. This competition assay allows the determination of the dissociation constants of the acetylcholine receptor-carbamoylcholine complex. A K(D) = 3.5 * 10(-)(6) M for the detergent-solubilized receptor and a K(D) = 1.4 * 10(-)(5) M for the lipid vesicle-reconstituted receptor are obtained. For decamethonium bromide, a K(D) = 4.5 * 10(-)(5) M is determined for the detergent solubilized receptor. This approach is of general importance for investigating ligand-receptor interactions in case of small ligand molecules by mass-sensitive techniques. PMID- 21662907 TI - Scanning Electrochemical Microscopy of Metal/Metal Oxide Electrodes. Analysis of Spatially Localized Electron-Transfer Reactions during Oxide Growth. AB - Scanning electrochemical microscopy (SECM) has been used to study the oxidation of iodide at Ta electrodes covered by a thin (~2.5 nm) film of Ta(2)O(5). SECM images of surface activity reveal that the voltammetric response of a macroscopic Ta electrode comprises the individual responses of a large number of microscopic sites, each with its own unique electrochemical behavior. Oxide film growth and metal dissolution occur simultaneously with iodide oxidation, resulting in a complex voltammetric response. The component of the voltammetric current due to iodide oxidation can be separated from the total current by SECM analysis. The growth of nanometer-thick oxide films can also be studied using SECM by monitoring the rate at which iodide is oxidized at the electrode surface. PMID- 21662908 TI - Stripping analyses of mercury using gold electrodes: irreversible adsorption of mercury. AB - The electrochemical deposition and stripping of mercury on gold surfaces was investigated to assess whether gold electrodes would return to mercury-free states after stripping analyses. X-ray photoelectron spectroscopy studies demonstrate the presence of mercury on gold foil electrodes that have undergone controlled-potential deposition procedures in Hg(2+) solutions (10 nM-0.1 mM) followed by stripping and cleaning in mercury-free electrolyte. Results show that mercury is not completely removed electrochemically from the gold electrodes, even when the oxidizing potential is +2.5 V vs Ag/AgCl. Bulk electrolyses deposition and stripping procedures coupled with cold vapor atomic absorption spectroscopic analyses of solutions after deposition and stripping are also reported. Results suggest that the nature of the gold electrode is fundamentally altered by irreversible adsorption of mercury; that is, mercury is adsorbed during deposition and some of the mercury is retained even after stripping and cleaning. The implications and strategies for using stripping analysis and gold electrodes for the measurement of mercury under the experimental conditions employed in this study are discussed. PMID- 21662909 TI - An electrochemically driven actuator based on a nanostructured carbon material. AB - A new type of electrochemically driven actuator is described. This actuator uses graphitic carbon as the electroactive material (as opposed to the polymeric films used in previous devices of this type), and it is the first example of an actuator based on a nanostructured material. The actuator consists of branched carbon nanotubules embedded within the pores of a microporous alumina template membrane. Electrochemical Li(+) intercalation causes this nanotubule-containing membrane to flex, and electrochemical deintercalation causes the membrane to relax to its original position. The characteristics of this new actuator are described here. PMID- 21662910 TI - Ion-exchange voltammetry as a solid-phase microextraction analytical method: factors influencing the mass transfer to perfluorosulfonated ionomer film-coated electrodes and some of their consequences on the current responses. AB - A simple theoretical model of mass transfer kinetics at an electrode coated with an ion-exchange film polymer is proposed. The model takes into account the analyte depletion in solution and gives the relationship between the ion-exchange voltammetric (IEV) peak current and the initial analyte concentration in the sample matrix. The verification of the model is investigated at disposable Nafion film-coated screen-printed electrodes, using the redox cationic (ferrocenylmethyl)trimethylammonium salt. It is shown that the theoretical model and the experimental data fit satisfactorily insofar as the variation of the extraction and apparent diffusion coefficients of the salt with the film thickness are taken into account. Indeed, the film thickness plays a crucial role for the optimization of the IEV sensitivity, because the physicochemical properties of the recast Nafion polymer are dependent on the amount per unit area of Nafion deposited on the electrode surface. PMID- 21662911 TI - Parallel-opposed dual-electrode detector with recycling amperometric enhancement for capillary electrophoresis. AB - The assembly and characterization of dual-electrode amperometric detection for capillary electrophoresis are described. The detector consists of a disk electrode and an integrated on-capillary electrode fabricated by depositing a gold film onto the end of the separation capillary. The two electrodes are brought together, aligned, and fixed in position using a pair of acrylic plates with a straight groove on one of the plates, the same design as that of a conventional end-column detector. A portion of the on-capillary electrode is parallel-opposed to the disk electrode in a thin-layer geometry. In this region, the redox cycling established between these two electrodes significantly enhances the amperometric signals of electrochemically reversible analytes. For measurements of dopamine in pH 6.9 phosphate electrolyte with a 12.5-MUm-i.d. capillary, such a configuration is 10-fold more sensitive than conventional end column detection. The linear range exceeds 4 orders of magnitude (1.2 mM-50 nM) and the detection limit is 12 nM (4.2 amol, S/N = 3). Various modes of potential settings for the dual-electrode detection are also discussed. PMID- 21662912 TI - Glow discharge source interfacing to mass analyzers: theoretical and practical considerations. AB - The fundamental requirements for the optimum mechanical interface between a glow discharge ion source and a mass spectrometer are described in this paper. Specifically, the properties of a typical glow discharge ion source are compared and contrasted to those of a typical inductively coupled plasma ion source. The critical parameters and theoretical considerations of glow discharge and inductively coupled plasma ion source interfaces are reviewed, and the results of experiments using both quadrupole and time-of-flight mass spectrometers with a glow discharge source are presented. The experimental results clarify several important problems in the glow discharge ion sampling process. Our findings indicate that a shock wave structure does not occur in the supersonic expansion of the glow discharge ion source. Ions of different masses have similar initial kinetic energies in the glow discharge; thus, the angle of the skimmer cone is not a critical parameter for efficient ion beam extraction. Another consquence is that space charge effects in glow discharge ion sources repel heavy ions farther off axis than light ions. Thus, there are distinct and fundamental differences between glow discharge and inductively coupled plasma ion sources which are relevant to both ion sampling and ion extraction processes. PMID- 21662913 TI - Precise determination of element/calcium ratios in calcareous samples using sector field inductively coupled plasma mass spectrometry. AB - A new method was developed for rapid and precise simultaneous determination of Mg/Ca, Sr/Ca, Mn/Ca, Cd/Ca, Ba/Ca and U/Ca ratios in foraminiferal shells using sector field inductively coupled plasma mass spectrometry (ICPMS). Element/calcium ratios were determined directly from intensity ratios using external, matrix-matched standard to correct for instrumental mass discrimination. Because of large differences in the abundance of chemical constituents of the foraminiferal shell, major elemental ratios were determined in analog mode (using (24)Mg, (43)Ca, (44)Ca, (55)Mn, and (88)Sr) whereas trace elemental ratios were determined in pulse-counting mode (using (111)Cd, (138)Ba, (238)U, and the low-abundance (46)Ca isotope). Matrix-induced variations in mass discrimination over a calcium concentration range of 2.0-24.5 mM were observed only for Mg/Ca and Cd/Ca ratios. However, these effects are negligible if the samples and standard calcium concentration are within a factor of 2-3. Multiratio method reproducibility was better than previously reported for other ICPMS methods yielding precision (1sigma) of Sr/Ca = 0.45%; Mg/Ca = 0.45%, Mn/Ca = 0.8%, Cd/Ca = 1.7%, Ba/Ca = 0.7%, and U/Ca = 1.4% for foraminifera samples as small as 25 MUg. Using this approach for a single-ratio analysis, Sr/Ca ratios were determined with precision of 0.06% (1sigma) on carbonate samples as small as a single foraminifera shell (<10 MUg). The new method is more sensitive, more precise, and simpler to use than previously available ICPMS techniques. It provides an efficient tool for simultaneous determination of several elemental ratios of paleoceanographic interest in a single foraminiferal sample, thereby reducing overall sample size requirement and analysis time. PMID- 21662914 TI - Low-Temperature Thermal Decomposition of Sulfates to SO(2) for On-Line (34)S/(32)S Analysis. AB - We describe a fast, inexpensive, and safe method of direct SO(2) extraction from BaSO(4) for sulfur isotopic analysis by mass spectrometry. Only two reagents are used: (1) pure NaPO(3), which is mixed with BaSO(4) sample, and (2) Cu foil, from which reaction boats are manufactured. The extraction precedes in the Cu boat placed into a quartz tube connected to a vacuum line. The boat is heated to 650-700 degrees C while pure SO(2) produced is collected in a "cold finger". Reaction is complete in 7-10 min. We have proven by means of (18)O-enriched BaSO(4) specimens that the oxygen isotopic composition of the SO(2) is totally controlled by (18)O content in NaPO(3), when the weight ratio of the reagent to sample exceeds 6:1. The method described can be used for "on-line" SO(2) preparation for isotopic analysis. PMID- 21662915 TI - Size determination of diesel soot particles using flow and sedimentation field flow fractionation. AB - The applicability of field-flow fractionation (FFF) was investigated for determination of size and size distribution of diesel soot particles. A sample preparation procedure was developed for FFF analysis where soot particles are recovered from filters in an ethanol bath sonicator, and then they are dispersed in water containing 0.05% Triton X-100 and 0.02% NaN(3). Mean diameters obtained from sedimentation FFF (SdFFF) and flow FFF (FlFFF) agree well with each other and are in good agreement with diameters obtained from photon correlation spectroscopy (PCS) and scanning electron microscopy. The relative error was less than 11%. Data show diesel soot particles have broad size distributions ranging from 0.05 up to ~0.5 MUm with the mean diameters between 0.1 and 0.2 MUm. The use of FlFFF is more convenient as FlFFF fractograms can be converted directly to size distributions, while the conversion of the SdFFF fractogram needs the particle density information. The density needed for SdFFF analysis was obtained by combining the SdFFF retention data with the PCS size data. For samples whose density is known, SdFFF may be more useful as SdFFF provides a wider dynamic range than FlFFF under constant field strength. PMID- 21662916 TI - Minimizing the number of voltage sources and fluid reservoirs for electrokinetic valving in microfluidic devices. AB - A microchip gated valve is demonstrated that uses a single voltage source and three fluid reservoirs. The fluidic valve is a cross intersection, and the channels are dimensioned to perform the appropriate voltage division, simplifying the voltage control hardware. A single voltage source is applied directly to the sample reservoir and through a high-voltage relay to the buffer reservoir, and the waste reservoir is grounded. The volume of sample dispensed is determined by the duration that the high-voltage relay is open. Volumetric reproducibility is demonstrated to be <0.5% relative standard deviation for volumes of >=20 pL. The valve is tested for the minimum applied voltage necessary for leakage-free operation, i.e., sample diffusing from the cross intersection into the analysis channel. Moreover, appropriate channel dimensions are used to minimize the number of fluid reservoirs allowing effluent from the analysis and waste channels to be combined into a single reservoir. PMID- 21662917 TI - Capillary electrochromatography with novel stationary phases. 3. Retention behavior of small and large nucleic acids on octadecyl-sulfonated-silica. AB - In this investigation, the potentials of porous and nonporous octadecyl sulfonated-silica (ODSS) microparticles were demonstrated in the capillary electrochromatography (CEC) of small (e.g., nucleotides and dinucleotides) and large (e.g., transfer ribonucleic acids (t-RNAs)) nucleic acids. The ODSS stationary phase comprised two layers: a hydrophilic sulfonated (permanently charged) sublayer and an octadecyl top layer. While the sublayer is to provide a relatively strong electroosmotic flow, the octadecyl top layer is to ensure the retentivity and selectivity required for the separation of the analytes. Mono-, di-, and triphosphate nucleotides were best separated when a small amount of tetrabutylammonium bromide was added to the mobile phase. The tetrabutylammonium bromide functioned as an ion-pairing agent and consequently allowed the rapid separation of 12 different nucleotides. It is believed that the dynamic complex exchange model explains the basis of retention in ion pair reversed-phase CEC. Eight different dinucleotides, which have similar mass-to-charge ratios, separated very well by CEC. These solutes exhibited similar migration times (i.e., little or no separation) in capillary zone electrophoresis (CZE). Similarly, t-RNAs that did not separate by CZE were well resolved in CEC with nonporous ODSS. This demonstrates that CEC is very suitable for the separation of solutes that have similar mass-to-charge ratios but differ in their hydrophobicity. PMID- 21662918 TI - Determination of the analytical performance of a headspace capillary gas chromatographic technique and karl Fischer coulometric titration by system calibration using oil samples containing known amounts of moisture. AB - Over the past few years, concerns have been raised in the literature about the accuracy of the Karl Fischer (KF) method for assessing moisture in transformer mineral oils. To better understand this issue, the performance of a static headspace capillary gas chromatographic (HS-CGC) technique was compared to that of KF coulometric titration by analyzing moisture in samples containing known amounts of water and various samples obtained from the National Institute of Standards and Technology (NIST). Two modes of adding samples into the KF vessel were used: direct injection and indirect injection via an azeotropic distillation of the moisture with toluene. Under the conditions used for direct injection, the oil matrix was totally dissolved in the anolyte, which allowed the moisture to be titrated in a single-phase solution rather than in a suspension. The results have shown that when HS-CGC and combined azeotropic distillation/KF titration are calibrated with moisture-in-oil standards, a linear relation is observed over 0-60 ppm H(2)O with a correlation coefficient better than 0.9994 (95% confidence), with the regression line crossing through zero. A similar relation can also be observed when calibration is achieved by direct KF addition of standards prepared with octanol-1, but in this case an intercept of 4-5 ppm is noted. The amount of moisture determined by curve interpolation in NIST reference materials by the three calibrated systems ranges from 13.0 to 14.8 ppm for RM 8506 and 42.5 to 46.4 ppm for RM 8507, and in any case, the results were as high as those reported in the literature with volumetric KF titration. However, titration of various dehydrated oil and solvent samples showed that direct KF titration is affected by a small bias when samples contain very little moisture. The source of error after correction for the large sample volume used for the determination (8 mL) is about 6 ppm for Voltesso naphthenic oil and 4 ppm for toluene, revealing a matrix effect on the measurement. Finally, the results revealed that HS-CGC is a good technique for measuring moisture in oil samples and that the use of azeotropic vapors for introducing moisture into the titrator almost completely eliminates the matrix effect observed with the oil components. Direct KF injection could also be used provided the system is calibrated with moisture-in-oil standards prepared in the same matrix which is to be used for the determination. PMID- 21662919 TI - Microfluidic devices connected to fused-silica capillaries with minimal dead volume. AB - Fused-silica capillaries have been connected to microfluidic devices for capillary electrophoresis by drilling into the edge of the device using 200-MUm tungsten carbide drills. The standard pointed drill bits create a hole with a conical-shaped bottom that leads to a geometric dead volume of 0.7 nL at the junction, and significant band broadening when used with 0.2-nL sample plugs. The plate numbers obtained on the fused-silica capillary connected to the chip were about 16-25% of the predicted numbers. The conical area was removed with a flat tipped drill bit and the band broadening was substantially eliminated (on average 98% of the predicted plate numbers were observed). All measurements were made while the device was operating with an electrospray from the end of the capillary. The effective dead volume of the flat-bottom connection is minimal and allows microfluidic devices to be connected to a wide variety of external detectors. PMID- 21662920 TI - Evaluation of the Isotope Ratio Performance of an Axial Time-of-Flight ICP Mass Spectrometer. AB - The isotope ratio performance of an axial time-of-flight ICP mass spectrometer (Renaissance TOF-ICPMS, LECO Corp.) was evaluated. The isotope ratio precision, expressed as the relative standard deviation (RSD) for 10 successive measurements, was evaluated using multielement standard solutions with analyte concentrations of 50-500 MUg/L. The influence of the acquisition time per replicate measurement was studied by varying it between 0.5 and 300 s. For an acquisition time of 30 s per replicate and an elemental concentration of 500 MUg/L, typical isotope ratio precisions of <=0.05% RSD were obtained. The fact that this isotope ratio precision can be obtained for many ratios simultaneously is an especially attractive feature of TOF-ICPMS. In contrast to what was expected, increasing the acquisition time per replicate to values of >30 s resulted in a slightly deteriorated isotope ratio precision. At short acquisition times (<10 s), isotope ratio precisions similar to, or better than, the best values ever reported for quadrupole-based instruments were obtained. The latter observation remained valid when working with transient signals of corresponding duration. Mass discrimination was observed to be analogous to that observed with other types of ICPMS instrumentation (~1% per mass unit at midmass). The accuracy attainable was evaluated by comparing Pb isotopic results for a "natural" Pb standard solution obtained by TOF-ICPMS with those obtained by thermal ionization mass spectrometry. PMID- 21662921 TI - Use of electrolytes containing multiple co-anions in the analysis of anions by capillary electrophoresis using indirect absorbance detection. AB - Background electrolytes (BGEs) containing more than one UV-absorbing probe co anion were investigated as possible means to control peak symmetries and improve the sensitivity of indirect detection in the separation of a mixture of inorganic and organic anions having a range of electrophoretic mobilities. In initial experiments, chloride and propanoate, which do not absorb at the detection wavelength, were added individually to a BGE containing phthalate as the UV absorbing probe co-anion. The response ratios (i.e., the detector response for an analyte obtained with the BGE containing the probe and added co-anion divided by the response of the BGE containing the probe alone) were found to be dependent on the relative mobilities of the analyte, probe, and co-anion. In general, it was found that the analyte mainly displaced the BGE component to which its mobility was closest and exclusively displaced any BGE component having the same mobility. This behavior was utilized to design BGEs containing multiple probes to improve peak shapes by matching the mobilities of the BGE components with those of the analytes. A BGE comprising chromate and phthalate as probes was used to demonstrate the improvement in peak shapes when such an approach was used. This was further extended to a BGE containing three probes, namely, chromate, phthalate, and benzoate. System peaks were observed for each multiple-component BGE and for n BGE co-anions; n - 1 system peaks were induced. A simple linear function relating the mobility of the system peak for a two-co-anion BGE to the mobilities and relative concentrations of each of the co-anions was derived empirically. Finally, a series of probes was investigated to determine the optimum multiple BGE composition giving the best peak shapes and sensitivity in the separation of a mixture of 15 analytes. The best combination was a two-probe BGE consisting of chromate and 4-hydroxybenzenesulfonic acid. PMID- 21662922 TI - Comparison of Gas-Sampled and SPME-Sampled Static Headspace for the Determination of Volatile Flavor Components. AB - Traditional static headspace and headspace solid-phase microextraction (SPME) techniques were compared for their effectiveness in the extraction of volatile flavor compounds from the headspace of various juice samples. Each method was used to evaluate the responses of certain analytes from real samples and calibration standards in order to provide sensitivity comparisons between the two techniques. Experimental results showed traditional static headspace lacked the sensitivity needed to evaluate certain flavor volatiles, such as alpha-terpinene and linalool, and that further concentration of the headspace was necessary. Dramatic improvements in the extraction abilities of the SPME fibers over the traditional static headspace method were noted. Different SPME fibers were investigated to determine the selectivities of the various fibers to the different flavor compounds present in the juice samples. Of the various fibers investigated, the PDMS/DVB fiber proved to be the most useful for these analyses. Aging studies of juice samples were also performed which verified that degradation could be observed and quantified. PMID- 21662923 TI - Determination of Iodide and Iodate by Ion Chromatography with Postcolumn Reaction and UV/Visible Detection. AB - Iodide and iodate can be determined by two new methods using anion-exchange chromatography with postcolumn reaction and UV/visible detection. Iodide is determined as IBr(2)(-) at 249 nm. Iodate is determined as I(3)(-) at 288 nm. The analyses can be run completely automatically and do not require any sample pretreatment. The detection limits for iodide and iodate are 0.1 MUg/L. The methods have been successfully applied to determine iodide and iodate in several mineral waters and in drinking water as well as for the determination of iodide in table salt. PMID- 21662924 TI - Optimizing Spectroscopic Signal-to-Noise Ratio in Analysis of Data Collected by a Chromatographic/Spectroscopic System. AB - To get an accurate spectrum across a chromatographic peak when analyzing data collected from a chromatography/spectroscopy experiment such as liquid chromatography/mass spectrometry, it is often necessary to sum or average the spectra collected across the chromatographic peak. A common practice is to sum the spectra collected across the entire duration of the chromatographic peak. However, this practice is not ideal in terms of optimizing the signal-to-noise ratio (S/N) of the sum spectrum. In most instances, the spectral signals may be so weak at the earlier and later ends of the chromatographic peak that summing these spectra into the sum spectrum may decrease its overall S/N. This report describes some simple guidelines and methods to analyze data collected by a chromatography/spectroscopy system to achieve the maximum S/N from the available data. More specifically, to achieve a better S/N when summing spectra within one chromatographic peak, only the spectra whose relative abundance is above 38% should be included. To achieve the maximum possible S/N, a matched filter should be applied to the data before the spectra are summed. PMID- 21662925 TI - On-Line Emission Analysis of Polycyclic Aromatic Hydrocarbons down to pptv Concentration Levels in the Flue Gas of an Incineration Pilot Plant with a Mobile Resonance-Enhanced Multiphoton Ionization Time-of-Flight Mass Spectrometer. AB - A newly developed, mobile laser mass spectrometer (resonance-enhanced multiphoton ionization - time-of-flight mass spectrometer, REMPI-TOFMS) was applied to on line measurements at a waste incineration pilot plant. REMPI-TOFMS combines the optical selectivity of resonance-enhanced multiphoton ionization with a time-of flight mass analysis to give a two-dimensional analytical method. Special care was taken to build up a sampling and inlet system suitable for on-line measurements of large, semivolatile polycyclic aromatic hydrocarbons (PAHs). An effusive molecular beam inlet in combination with a fixed frequency UV laser (Nd:YAG at 266 nm or KrF excimer at 248 nm) was used. Under these conditions, many different PAHs can be ionized selectively from the complex flue gas matrix. For example, the achieved detection limit for naphthalene is in the 10 parts-per trillion by volume (pptv) concentration range. Calibration was performed by using external concentration standards supplied in low ppbv concentrations. The instrumentation is sufficiently robust to be operated under industrial conditions at incineration plants, for instance. The REMPI mass spectra can be acquired at 5 50 Hz. Time profiles of the concentrations of different PAHs in the flue gas were monitored with a time resolution of 200 ms. Significant variations in the concentration profile of several PAHs up to mass 276 amu (e.g., benzo[ghi]perylene) and methylated PAHs have been observed while combustion parameters were changing. In summary, it was demonstrated that laser mass spectrometry (REMPI-TOFMS) enables a real-time on-line trace analysis of combustion flue gases or industrial process gases. PMID- 21662926 TI - Determination of polycyclic aromatic sulfur heterocycles in fossil fuel-related samples. AB - An analytical method is described for the separation, identification, and quantification of a number of polycyclic aromatic sulfur heterocycles (PASHs) in three fossil fuel-related samples including two Standard Reference Materials (SRMs), SRM 1597 (coal tar) and SRM 1582 (petroleum crude oil), and a decant oil. The compounds measured include the 3 possible naphtho[b]thiophenes; dibenzothiophene and selected methyl-, ethyl-, dimethyl-, and trimethyl substituted isomers; the 3 possible benzo[b]naphthothiophenes; and the 30 methylbenzo[b]naphthothiophenes isomers. Because of the occurrence of polycyclic aromatic hydrocarbons and PASHs together with their large number of possible alkyl-substituted isomers, the analytical method described requires a number of prerequisites: effective sample cleanup, selective stationary phases, and selective methods of detection. The sample cleanup involves solid-phase extraction using aminopropylsilane cartridges with different solvent mixtures followed by normal-phase liquid chromatographic isolation of the PASHs based on the number of aromatic carbons. These aromatic ring fractions are then separated by capillary gas chromatography using two stationary phases with different selectivities, 5% phenyl-substituted methylpolysiloxane stationary phase and 50% phenyl-substituted methylpolysiloxane stationary phase, and analyzed with mass selective detection and atomic emission detection. A liquid crystalline stationary phase was also used to separate the methylbenzo[b]naphthothiophene isomers in the crude oil sample. Advantages and limitations of each chromatographic and detection technique are discussed. PMID- 21662927 TI - Simultaneous separation of coplanar and chiral polychlorinated biphenyls by off line pyrenyl-silica liquid chromatography and gas chromatography. Enantiomeric ratios of chiral congeners. AB - A method for the unambiguous determination of 41 key polychlorinated biphenyls (PCBs) (including coplanar and chiral congeners) and the enantiomeric ratio of chiral congeners is described. The method includes a fractionation step using a 2 (1-pyrenyl) ethyldimethylsilylated silica column for separating the polychlorinated biphenyls according to the number of chlorine atoms in the ortho positions. High-resolution gas chromatography with an electron capture detector and an achiral column was used to determine the PCB congener content in each fraction. The enantiomeric ratio of chiral congeners was calculated by high resolution gas chromatography with a mass spectrometry detector using a chiral column. The method was found to be inexpensive, rapid, effective, and reliable under the operational conditions proposed. It eliminates the main coelution problems among the polychlorinated biphenyl congeners. It also makes it possible to determine the enantiomeric ratio of nine chiral congeners using monodimensional gas chromatography. The method was applied successfully to the analysis of the coplanar and atropisomeric polychlorinated biphenyl congeners in dolphin liver samples. The enantiomeric ratio of nine chiral congeners is also reported for the first time. PMID- 21662928 TI - Determination of Pentachlorophenol and Its Oil Solvent in Wood Pole Samples by SFE and GC with Postcolumn Flow Splitting for Simultaneous Detection of the Species. AB - An alternative approach is described for the measurement of pentachlorophenol (PCP) and its oil solvent in wood samples by supercritical fluid extraction (SFE) and gas chromatography (GC). The determination is achieved over a single chromatographic run using postcolumn flow splitting for simultaneous ECD/FID detection of the SFE extracted species. First, PCP and oil components are quantitatively extracted from a 0.3-g wood sample using 10% MeOH/CO(2) supercritical fluid at 0.65 g/mL and 120 degrees C. An aliquot of the SFE solution is then mixed with 10 mL of a buffered aqueous phase at pH 9.4. After PCP is acetylated by the addition of 500 MUL of acetic anhydride, it is followed by its extraction with 2.00 mL of hexane along with oil. Then, 0.5 MUL of supernatant organic phase is injected into the GC for a selective and simultaneous determination of the species. The method has a linear response over 3 orders of magnitude for both species with a linear regression correlation coefficient higher than 0.98 (95% confidence limit) and an absolute detection limit of 60 ng of PCP and 80 MUg of oil per 0.1-g wood sample. The precision (relative standard deviation) is 4% for PCP and 1% for oil as established for a typical average concentration sample. The accuracy of the SFE GC-ECD/FID combined technique for PCP and oil was assessed by analyzing wood samples collected from newly and in-service PCP/oil-impregnated red pine poles. PMID- 21662929 TI - Quantitative RP-HPLC Determination of Some Aldehydes and Hydroxyaldehydes as Their 2,4-Dinitrophenylhydrazone Derivatives. AB - A high-performance liquid chromatographic (HPLC) method is described for the quantitative determination of some aliphatic aldehydes and beta-hydroxyaldehydes as their 2,4-dinitrophenylhydrazone derivatives. A method is described for the preparation of derivatives for those beta-hydroxyaldehydes where no reference compounds of known purity are available. The detection limit of the method was 4.3-21.0 MUg/L, depending on the aldehyde. PMID- 21662930 TI - Nonequilbrium quantitation of volatiles in air streams by solid-phase microextraction. AB - Solid-phase microextraction (SPME) is a valuable technique for analyzing air borne organic compounds; one important application is measuring concentrations when these are constant over time. Quantitation normally relies on the SPME fiber being fully equilibrated with the sample medium. Unfortunately, relatively heavy compounds do not equilibrate within a reasonable amount of time, and this has limited the scope of SPME. The ability to quantitate during equilibration was needed and was the focus of this investigation. This entailed having an accurate description of SPME kinetics, and the kinetics of extraction by poly(dimethylsiloxane) fibers was studied for alkanes of 9-22 carbons, primary alcohols of 6-13 carbons, and methyl esters of 6-16-carbon acids. Sampling was from air streams in which analyte concentrations were effectively constant, and sampling times ranged from 30 min to 3 days. Other experimental variables included sampling temperature, fiber coating thickness, air flow rate, and tubing diameter in which the SPME sampling took place. Over 1900 data points were acquired. Previous theoretical kinetic models were not applicable to the present experimental conditions, but a simple kinetic equation was formulated that described the data very well; its key property is an explicit relationship between fiber sensitivity and equilibration time. Using nonlinear regression, the equation parameters were linked to known properties of the analyte (the functional group and GC retention index on a nonpolar column) and to certain sampling conditions (temperature, sampling duration, air flow rate, tubing diameter). The regression equation serves as a practical quantitation formula and allows the absolute concentration of the analyte in the air stream to be calculated directly from the amount extracted by the SPME fiber (which is easily measured by GC), regardless of whether equilibrium has been established or not, as long as the above analyte properties and sampling conditions are known. The residual variability for the model (RSD = 9.4%) was only slightly larger than the variability inherent in SPME alone (~5%). Considerations for SPME sampling from air are discussed, and new fiber calibration information is presented for the larger hydrocarbons, alcohols, and methyl esters. PMID- 21662931 TI - A dual-detection strategy in the chromatographic analysis of 2-aminoacridone derivatized oligosaccharides. AB - A protocol has been developed involving the derivatization of glycan mixtures with 2-aminoacridone and co-injection with a dextran ladder derivatized with methyl 4-aminobenzoate (M-4AB). These two derivatizing agents have very different ultraviolet absorbance and fluorescence characteristics. A chromatographic separation using a normal-phase column support followed by in-series UV and fluorescence detection allowed simultaneous analysis of the two mixtures of the separately derivatized carbohydrates without any interference. This new approach uses the M-4AB dextran ladder derivatives as internal standards spanning the whole chromatogram, allowing an accurate and detailed comparison of glycosylation profiles. It also saves much time by avoiding the necessity of "sandwiching" an unknown glycan mixture between two chromatographic runs of a dextran ladder. The use of this technique has been demonstrated in the case of glycans released from ribonuclease B and human IgG. PMID- 21662932 TI - Determination of peroxygen species present in pulp fiber matrixes. AB - A new chromatographic method for the determination of oxidants, such as peroxyborates and peroxides, present in a pulp matrix has been developed. The new method is characterized by its high reproducibility, its low limit of detection, and its high selectivity. Thioanisole (methylphenyl sulfide) is shown to selectively and quantitatively react with oxidants that are present within a pulp matrix. The experimental protocol proposed requires an HPLC system with a normal phase column. The method allows for the quantitative monitoring of the thioanisole starting material, as well as the products of oxidation, methylphenyl sulfoxide and methylphenyl sulfone. After a 2-day reaction period, the analysis time for a sample is less than 20 min. The detection limit is 2.7 * 10(-6) M for the sulfoxide and sulfone and less than 5.0 * 10(-7) M for the thioanisole. This novel approach for monitoring oxidants present on solid lignocellulosic matrixes may provide pulp and paper manufacturers with a new tool for the study of the long-term bleaching effectiveness of peroxy-containing chemical additives. PMID- 21662933 TI - Chemisorption and chemical reaction effects on the resistivity of ultrathin gold films at the liquid-solid interface. AB - Ultrathin gold films, with thicknesses between the onset of conductivity (d ~ 5 nm) and the electron mean free path (d ~ 80 nm), display surface-sensitive resistivities, which have been exploited to follow the adsorption and desorption of molecular monolayers at the metal-solution interface with high precision. For nominal Au film thicknesses (d ~ 40 nm), strongly chemisorbed thiolate monolayers increase the resistivity of the thin Au films by ~4%, but weakly adsorbed species, such as pyridine or phenolate at open circuit, induce no observable change in the Au film resistance. Resistivity measurements implemented with a high-stability current source and high-precision digital voltmeter sampling at 1 Hz resulted in 3sigma uncertainties in alkanethiolate coverage of 1.4 * 10(-)(4) monolayer. Surface plasmon resonance measurements, performed simultaneously with resistivity measurements, indicate that changes in resistivity vary monotonically with coverage with three distinct regions: a low-coverage region of heightened adsorbate mobility, an intermediate-coverage region with generally linear behavior, and a chain length-dependent saturation region at high coverages. Resistivity measurements were also capable of reproducibly following the chemical state of the Au surface through a complex set of redox manipulations, demonstrating the versatility of this simple measurement. PMID- 21662934 TI - Procedure for the quantitative determination of mixtures of nucleic Acid components based on multivariate spectrophotometric Acid-base titrations. AB - A new procedure for the quantitative determination of mixtures of nucleic acid components, based on continuous spectrophotometric acid-base titrations and multivariate curve resolution, is proposed. The procedure simultaneously takes into account the spectroscopic and acid-base properties of the compounds, which leads to a higher selectivity. Furthermore, quantitative determination of an analyte in a complex mixture is performed using a synthetic solution as standard containing only the analyte of interest. An intrinsic difficulty in the analysis of spectrometric titration data is the presence of rank deficiency due to closure for the mixtures of two or more compounds. An additional problem can be encountered in some mixtures if species spectra or species concentration profiles are practically identical (rank overlap). However, even in the presence of these rank difficulties, accurate quantitation with prediction errors lower than 5% was obtained. The presence of unknown and uncalibrated interferences in the samples does not affect the quantitative determination of the analyte of interest. The proposed procedure was successfully applied to the analysis of real samples (pharmaceuticals) using synthetic external standards. PMID- 21662935 TI - Separation of thorium and uranium from silicate rock samples using two commercial extraction chromatographic resins. AB - A new chemical separation technique to isolate Th and U from silicate rocks was established by using two kinds of commercial extraction chromatographic resins. In the first column procedure, with U/TEVA.spec resin, almost all elements except Th and U were eluted by 4 M HNO(3). Th was then separated by using 5 M HCl, and U was finally isolated by successive addition of 0.1 M HNO(3). A significant amount of Zr still remained in the Th fraction, which was then further purified in the second column stage using TEVA.spec resin. In the second procedure, Zr was eluted first by using 2 M HNO(3), and then Th was collected by 0.1 M HNO(3). Both the Th and U fractions obtained by these procedures were sufficiently pure for thermal ionization mass spectrometric (TIMS) analysis. Recovery yields of Th and U exceeded 90%, and total blanks were <19 pg for Th and <10 pg for U. Our method has advantages over previous methods in terms of matrix effects, tailing problems, and degree of isolation. Since Th and U are effectively separated without suffering any matrix interference from coexisting cations and anions, this technique can be used not only for the analysis of igneous rock samples but also for the analysis of soils, marine sediments, carbonates, phosphates and seawater, groundwater, and surface water. PMID- 21662936 TI - Calixarene monolayers as quartz crystal microbalance sensing elements in aqueous solution. AB - We have examined p-tert-butylcalix[4]arenetetrathiolate (BCAT) monolayers for their potential use as molecular recognition elements for in situ aqueous chemical sensors. Spectroscopic and wetting studies of BCAT monolayers on Au{111} reveal that the calixarene molecules exist in monolayers, preferentially oriented with their phenyl rings parallel to the surface normal axis. Using quartz crystal microbalance (QCM) sensors with gold-coated electrodes, the chemical specificity of monolayers and thin films to a variety of aromatic and aliphatic analytes in aqueous solution was examined. The response of BCAT sensors was compared to the responses of p-tert-butylcalix[4]arene (BCA)- and decanethiolate (DT)-coated QCM electrodes. BCAT is very selective for alkylbenzenes, much more so than either its spray-coated thin-film analogue, BCA, or the highly ordered DT monolayer. From these measurements, the factors behind molecular differentiation in each film are explored. Drawing upon these findings, the roles of cavitation and film order in molecular recognition for calixarene films are discussed. PMID- 21662937 TI - Calcium Phosphate Phase Identification Using XPS and Time-of-Flight Cluster SIMS. AB - Reproducible time-of-flight cluster static secondary ion mass spectra (ToF-SSIMS) were obtained for various standard calcium phosphate (CP) powders, which allowed for phase identification. X-ray diffraction was not able to detect signals from microscopic amounts of CP (~15 mmol m(-)(2)). The phases studied were alpha tricalcium phosphate [alpha-Ca(3)(PO(4))(2)], beta-tricalcium phosphate [beta Ca(3)(PO(4))(2)], amorphous calcium phosphate [Ca(3)(PO(4))(2).xH(2)O], octacalcium phosphate [Ca(8)H(2)(PO(4))(6).H(2)O], brushite (CaHPO(4).2H(2)O), and hydroxyapatite [Ca(10)(PO(4))(6)(OH)(2)]. The SIMS spectra were obtained via bombardment with (CsI)Cs(+) projectiles. X-ray photoelectron spectroscopy (XPS) core levels of the P 2p, Ca 2p, and O 1s orbitals and the relative O 1s loss intensity were examined. The PO(3)(-)/PO(2)(-) ratios from ToF-SSIMS spectra in conjunction with XPS of the CP powders showed much promise in differentiating between these phases at microscopic CP coverages on the metal oxide surface. PMID- 21662938 TI - An Autonomous Sensor and Telemetry System for Low-Level pCO(2) Measurements in Seawater. AB - The measurement of low-level dissolved CO(2) using a fiber-optic sensor is described. The sensor, based on the Severinghaus CO(2) electrode principle, consists of a CO(2)-sensitive bicarbonate buffer solution containing the pH sensitive fluorescent dye carboxy-SNAFL-1 immobilized at the end of an optical fiber using a gas-permeable membrane. The sensor is used in a ratiometric mode and has a reversible working dynamic range between 200 and 1000 ppm pCO(2) and a sensitivity +/-1 ppm. Results are presented for the sensor calibration, effects of temperature, and response time characteristics. An integrated measurement system with electrooptic and data acquisition modules coupled to a satellite transmission system was tested in Vineyard Sound, MA, and data are presented that demonstrate continuous monitoring of pCO(2) in surface seawater. PMID- 21662939 TI - Migration and diffusion coupled with a fast preceding reaction. Voltammetry at a microelectrode. AB - A mathematical model implemented by simulation is presented for voltammetry of a reversible couple that involves a fast preceding chemical reaction and mixed diffusional and migrational transport. The hydrogen couple, H(+)/H(2), fulfills the above criteria. For strong acids there is no preceding reaction, whereas for weak acids the preceding reaction is HA = H(+) + A(-). The computed voltammograms are compared with experimental voltammograms for the reduction of strong and weak acids at Pt microelectrodes with excess of and without supporting electrolyte. The key assumption in the calculations is that the flux of hydrogen ion is independent of the anion. This assumption is supported by the experimental fact that the wave heights in the absence of supporting electrolyte of several strong acids of equal concentration and with anions of various size are identical. PMID- 21662940 TI - Using the pulsed nature of staircase cyclic voltammetry to determine interfacial electron-transfer rates of adsorbed species. AB - Staircase cyclic voltammetry (SCV) is the digital counterpart of analog cyclic voltammetry (CV). However, when the redox-active species is adsorbed at the electrode surface, the voltammetric peak shapes (width, height, area, and to a lesser extent the reduction potentials) obtained with SCV can be very different from those of CV, even when small potential steps are used. Like analog CV, SCV provides a straightforward method to estimate and subtract the background and charging currents from the desired Faradaic current, while the pulsed nature of SCV provides the time-dependent decay of the Faradaic current, similar to chronoamperometry. Thus, electron-transfer rate constants can be directly measured as a function of applied potential, and no a priori model is required. An SCV equivalent of the square wave "quasi-reversible maximum" of observed peak height versus sampling moment and step size is predicted. The SCV response can only become independent of potential step size and similar to CV at high scan rates (nu > 10 k(0)E(step)), if the current is sampled at half the step interval. The applicability of SCV to studies of redox centers in proteins is illustrated for the two-electron oxidation/reduction of yeast cytochrome c peroxidase, adsorbed at a pyrolytic graphite edge-plane electrode. PMID- 21662941 TI - Concentrations of Electroactive Solutes, during Cyclic and Other Voltammetries, at Points Away from the Electrode Surface. 1. Fundamental Relationships and Their Validation. AB - There are circumstances in which it is useful to know the concentration, or its gradient, of an electroactive product or reactant at some distance from an electrode. Here it is demonstrated that this information is available, in principle, under conditions of semiinfinite planar diffusion, provided that the surface concentration and/or the current are known as functions of time. Several methods of calculation are explored, using the example of linear sweep voltammetry. Some of these methods rely on analytical formulations; others are purely numerical. Concordance of the results of the various methods provides validation of all. A method based on the convolution of the current is especially versatile. PMID- 21662942 TI - Constant chemical potential titration. Application to determination of nonionic surfactant concentrations. AB - Titration is most often associated with the idea of a stoichiometric reaction. Generally, it is not considered possible to titrate a compound against a reagent unless the titration reaction is near total and if the result is not a product of well-defined stoichiometry. In this work, we illustrate that accurate titration is possible with compounds and reagents that interact to form an association of undefined stoichiometry. Our model is the potentiometric titration of nonionic surfactant with cationic surfactant using a cationic surfactant-selective electrode. The result of this reaction is mixed micelles, the composition of which depends on the concentrations of the two surfactants in solution. PMID- 21662943 TI - Laser desorption/ionization mass spectrometry of peptides and proteins with particle suspension matrixes. AB - Systematic investigations of particle suspensions for the laser desorption/ionization of peptides and proteins are presented. The performance and suitability for time-of-flight mass spectrometry of different particle materials and sizes, suspended in a variety of different liquids, are described. Performance characteristics such as accessible mass range, achievable mass resolution, analytical sensitivity, and fragmentation are reported. For the desorption of peptides and small proteins, nanoparticle suspensions in glycerol were found to perform comparably to UV-MALDI-MS with common "chemical" matrixes. For proteins in the mass range of ~12-30 kDa, mass resolution and analytical sensitivity decrease sizeably; for proteins with masses in excess of ~30 kDa, no spectra could be recorded with any of the tested particle/liquid combinations. The results were found to be largely independent of the laser wavelength in the range from the near-UV to the near-IR because of the strong particle absorption throughout this wavelength range. Ions are shown to originate predominantly from analyte molecules adsorbed at the particle surface. Nanoparticles with a diameter of a few nanometers were found to be superior to microparticles of ~1 MUm diameter or above. Thermodynamic modeling suggests that this different behavior is caused by the different achieved peak temperatures of the two particle sizes. PMID- 21662944 TI - Determination of (40)ca(+) in the presence of (40)ar(+): an illustration of the utility of time-gated detection in pulsed glow discharge mass spectrometry. AB - The glow discharge ionization source operated in the pulsed, or modulated, power mode affords a number of distinct advantages over its steady-state counterpart. It is well-known that pulsed plasma operation permits the application of higher instantaneous powers by allowing time for the sample to cool. This minimizes sample overheating while effecting higher sputtering yields and lower limits of detection. The presence of discrete time regimes affords the added advantage of temporal selectivity. Such selectivity allows the observation of analyte ions during a time regime in which their signal is at a maximum while that of electron ionized background species is declining. Significantly, time regimes are found when no background argon ion signals are observable but analyte ion signals remain. This means that discrimination against isobaric interferences arising from the discharge gas is possible. A prime example of the utility of this advantage arises in the determination of calcium with an argon glow discharge. Both the major argon and calcium isotopes are found at a nominal m/z of 40. Time gated mass spectrometeric detection during the afterpeak time regime enables the ready determination of (40)Ca(+) in samples at the ppm level. A linear calibration curve is obtained that also demonstrates the elimination of the (40)Ar(+) signal from mass spectra obtained with either a dc or rf glow discharge ion source. PMID- 21662945 TI - Conditions of strict voltammetric reversibility of the h(+)/h(2) couple at platinum electrodes. AB - Cyclic voltammetric curves obtained at Pt electrodes for the hydrogen couple, H(+)/H(2), fit very well the Shuman theory, as corrected, for reversible electrode processes of other than 1:1 stoichiometry. Good agreement was obtained for acid concentrations in the millimolar range and for normal scan rates, which minimize the effect of the adsorption peaks. An error in Shuman's equation for potential is corrected. Voltammograms obtained at Pt microelectrodes fit well the theoretical simulated data. PMID- 21662946 TI - Preparation and characterization of dendrimer-gold colloid nanocomposites. AB - Au colloids in the 2-3-nm size regime were prepared by in situ reduction of HAuCl(4) in the presence of poly(amidoamine) dendrimers. The dendrimers encapsulate the colloids, imparting stability to the aqueous colloidal solutions. The nanocomposite materials can be isolated by precipitation. The dendrimer generation used in the synthesis controls the size of the resultant colloids: lower-generation dendrimers give rise to larger colloids. The materials were characterized by infrared and UV-vis spectroscopy and transmission electron microscopy. PMID- 21662947 TI - Molecular Design, Characterization, and Application of Multiinformation Dyes (MIDs) for Optical Chemical Sensings. 3. Application of MIDs for lambda(max) Tunable Ion-Selective Optodes. AB - By utilizing "multiinformation dyes (MIDs)", which have plural spectral change characteristics such as an absorption maximum wavelength (lambda(max)) shift based on a polarity change and an absorbance change due to protonation, novel lambda(max)-tunable ion-selective optodes were proposed and prepared by employing MIDs with membrane solvents having different polarities. For controlling the detecting lambda(max) of the optode, the novel polar membrane solvent [2-[[6-(2 nitrophenoxy)hexyl]oxy]methyl]isobutane-1,3-diol was designed and synthesized, which was used together with a typical membrane solvent nitrophenyl octyl ether. By mixing these two membrane solvents, the lambda(max) position of the optode detection wavelength can be shifted and controlled and was successfully applied to a lambda(max)-tunable Li(+)-selective optode based on a highly Li(+)-selective ionophore TTD14C4. The lambda(max) tuning technique is useful for preparing an optode system using a low-cost light source such as a light-emitting diode or a popular laser. PMID- 21662948 TI - Surface ionization ion mobility spectrometry. AB - A surface ionization (SI) source was designed and constructed for ion mobility spectrometry (IMS). Compared with a conventional (63)Ni source, the surface ionization source is as simple and reliable, has an extended dynamic response range, is more selective in response, and does not have regulatory problems associated with radioactive ionization sources. The performance of this SI-IMS was evaluated with several different classes of compounds. Triethylamine was employed for studying the behavior of the ionization source under different source conditions and gaseous environments. Amines, tobacco alkaloids, and triazine herbicides were also investigated. Picogram level detection limits were achieved for target compounds with a response dynamic range of 5 orders of magnitude. Selective monitoring by IMS was also demonstrated. While the surface ionization source does not have the universality of response that is obtained with a (63)Ni ionization source, it is an excellent nonradioactive alternative for the ionization and ion mobility detection of those compounds to which it responds. PMID- 21662949 TI - Enhanced Microdialysis Extraction Efficiency of Ibuprofen in Vitro by Facilitated Transport with beta-Cyclodextrin. AB - A novel approach to increase microdialysis recovery (extraction efficiency, E(d)) by facilitated transport through the microdialysis membrane is described. This new approach facilitates mass transport into the microdialysis probe by inclusion of a complexation agent in the microdialysis perfusion fluid. In these studies, beta-cyclodextrin (beta-CD) (0.25-2.0 w/v%) was included in the microdialysis perfusion fluid consisting of a Ringer's solution (155 mM NaCl, 4.0 mM KCl, 2.4 mM CaCl(2)). beta-CD forms known inclusion complexes with 2-(4 isobutylphenyl)propionic acid (ibuprofen). Ibuprofen E(d) was significantly enhanced (1.5-2.0 times) through different microdialysis membrane materials. The effect of microdialysis membrane material (polycarbonate/polyether, AN-69, cuprophan), pH, beta-CD concentration, and ibuprofen concentration on the E(d) was examined. Only the polycarbonate/polyether membrane was able to give an E(d) greater than 100%. In general, a maximum increase in E(d) was found when 0.5 w/v% beta-CD was included in the perfusion fluid. Variations in the ibuprofen concentration external to the microdialysis probe did not significantly change E(d) when 0.5 w/v% beta-CD was included in the perfusion fluid. In contrast to the ibuprofen data, beta-CD inclusion in the microdialysis perfusion fluid did not affect antipyrine E(d). Antipyrine does not form known inclusion complexes with beta-CD. The ability of beta-CD to increase microdialysis E(d) is explained by facilitated transport. PMID- 21662950 TI - Ultrahigh-voltage capillary zone electrophoresis. AB - An ultrahigh-voltage capillary electrophoresis system was built to demonstrate the possibility of extending the applied potential and thus the separation power of capillary electrophoresis. A commercial 30-kV power supply was extensively modified in order to provide electrical potentials up to 120 kV. A unique electrical shielding system was developed to prevent capillary breakdown and corona or spark discharges. Electrophoretic studies using a mixture of peptide standards, as well as a complex mixture of peptides obtained from a protein digest, showed that the numbers of theoretical plates achieved increase linearly with applied voltage. Theoretical plate counts ranging from 2.7 to 6.1 million plates were obtained for peptides in a separation done at 120 kV. Resolution also increased with the square root of applied voltage, as predicted by theory. PMID- 21662951 TI - Na(4)EDTA-Assisted Sub-/Supercritical Fluid Extraction Procedure for Quantitative Recovery of Polar Analytes in Soil. AB - Supercritical carbon dioxide (SC-CO(2)) is effective in extracting nonpolar and slightly polar chemicals from soils. However, pure SC-CO(2) is unsatisfactory for recovering polar chemicals in soils. A simple supercritical fluid extraction (SFE) procedure was developed to quantitatively recover polar and nonpolar chemicals from soils. The polar chemicals tested were aromatic acids and phenols. The nonpolar and slightly polar chemicals used as model compounds were common pesticides and environmental pollutants such as polycyclic aromatic hydrocarbons. The procedure required pretreatment of the samples with 15% water (g/g), 5% (ethylenedinitrilo)tetraacetic acid tetrasodium salt (Na(4)EDTA) (g/g), and 50% methanol (mL/g) prior to extractions using SC-CO(2) at 60 degrees C and 34.5 MPa. Recoveries ranged from 90 to 106% for the aromatic acids using the Na(4)EDTA assisted SFE compared with only 7-63% recoveries of the corresponding chemicals when no Na(4)EDTA was used. The method quantitatively extracted 2,4-D and its close analogues aged in the soil for 2-30 days. The Na(4)EDTA-assisted SFE was also adequate for extracting phenolic analytes including picric acid and pentachlorophenol with recoveries from 85 to 104%. Na(4)EDTA is a good enhancer for extraction of the 29 analytes representing a wide range of polarity from the soil using SC-CO(2). The method is valuable for the analysis of parent pollutants and transformed products, particularly oxygen-borne metabolites in the environment. PMID- 21662952 TI - Characterization of natural resin shellac by reactive pyrolysis-gas chromatography in the presence of organic alkali. AB - A method to determine chemical composition of natural resin shellac was developed on the basis of reactive pyrolysis-gas chromatography (Py-GC) in the presence of an organic alkali, tetramethylammonium hydroxide ((CH(3))(4)NOH, TMAH). Py-GC using 25% TMAH aqueous solution enabled the highly sensitive determination of terpenic acids, aleuritic acid, several minor fatty acids, and the wax components of shellac as their methyl derivatives on the resulting pyrograms with less than 2.0% relative standard deviations without using any cumbersome pretreatment. The observed average distributions of each resin acid component determined by reactive Py-GC for shellac samples from India and Thailand showed that the average ratios among terpenic acids, aleuritic acid, and the other fatty acids were about 53:34:14 for Indian shellac and 51:35:14 for Thailand shellac, respectively, suggesting a slightly significant difference. However, clearer discrimination of the shellac samples from the two different growing places was attainable by applying principal component analysis for the mole percent distributions of all the acidic components determined by reactive Py-GC. PMID- 21662953 TI - Geometrical model for the retention of fullerenes in high-performance liquid chromatography. AB - In high-performance liquid chromatography (HPLC) using a poly(octadecylsiloxane) as a stationary phase, methanol as a mobile phase, C(60) and C(70) fullerenes as solutes, and water as a mobile phase modifier, a study on the surface tension effect of water on fullerene retention was carried out by varying the water concentration [W] and the column temperature T. The thermodynamic parameters for fullerene transfer from the mobile to the stationary phase were determined from linear van't Hoff plots. An enthalpy-entropy compensation revealed that the types of interactions between fullerenes and the stationary phase were independent of the fullerene structure and the mobile phase composition. An analysis of the experimental variations of the retention factor and the selectivity values with [W] was performed using a novel geometrical model. It was shown that the increase in fullerene retention accompanying the water concentration was due to the increased effects of surface tension. This brought about an increase in the interactions between fullerene and the stationary phase, explaining the observed thermodynamic parameter trends over the water concentration range. The theoretical model provided an estimation of the radius of fullerene which was found for C(60) to be equal to 3.3 A and an activation energy during the transfer equal to 9.8 kJ/mol. PMID- 21662954 TI - Sol-gel-based, planar waveguide sensor for water vapor. AB - A water vapor sensor based on a combination of sol-gel processing and planar optical waveguide technologies has been developed. The indicator erythrosin B was entrapped in a thin sol-gel film (thickness ~100 nm) prepared from methyltriethoxysilane, dimethyldiethoxysilane, and tetraethoxysilane. This dye exhibits an increase in absorbance in the presence of liquid or gaseous water. The sol-gel layer containing the dye was deposited onto a sol-gel-derived, single mode planar waveguide. Outcoupled light intensity measurements (at 514.5 nm) over a range of water vapor concentrations (in a nitrogen gas stream) yielded a response over a wide range of relative humidity (<1-~70%) at room temperature. Response and reversal times were less than 1 min, which may make this sensor attractive for real-time monitoring applications. PMID- 21662955 TI - Detection of volatile compounds with mass-sensitive sensor arrays in the presence of variable ambient humidity. AB - Mass-sensitive sensor arrays were established for the detection of isomeric or highly analogue analyte mixtures, which show similar physical and morphological properties. Supramolecular host-guest chemistry and arrays of four mass-sensitive quartz crystal microbalances have been successfully combined with multivariate calibration techniques in the presence of variable air moisture. This system enabled even the separation of xylene isomers [Formula: see text] a task that might be crucial even by gas chromatography. The data of the sensor arrays were analyzed with partial least squares and artificial neural networks. The xylene isomers could be detected with an accuracy of ~1% in the range of 0-200 ppm, nearly eliminating the residual water cross-sensitivity of the sensor coatings, which allows effective work place or environmental monitoring of toxic compounds with fast response levels. PMID- 21662956 TI - Optode Membrane for Determination of Nicotine via Generation of Its Bromoethane Derivative. AB - A plasticized poly(vinyl chloride) optode membrane incorporated with a valinomycin ionophore, a H(+)-selective chromoionophore (ETH 5294), and a lipophilic potassium tetrakis(4-chlorophenyl)borate was used as a reversible sensing device for the indirect optical determination of nicotine. Nicotine was extracted from a tobacco product (1-5 g) and converted to its bromoethane derivative (NBD(+)Br(-)) by reacting with a solution of bromoethane in ethanol. NBD(+)Br(-) in a solution of 0.05 M boric acid-Borax buffer and 0.2 mM Triton X 100 was extracted into the bulk of the membrane and subsequently caused changes in optical absorption of the sensing layer. The response slope, dynamic working range, detection limit, sensitivity, selectivity, effects of buffer solution and neutral surfactant Triton X-100, and lifetime were discussed in detail. The response was pH dependent. At pH 8.5, the detection range was extended from 0.4 MUM to 1 mM. Typical response times (t(95)) of the samples were 2-4 min. The optode method was successfully used to detect nicotine in a tobacco sample from the market (average content 0.720%; RSD 0.044%; n = 11). The interference of K(+) on the optode method can be prevented by the pre-extraction procedure. Malic acid and citrate showed no interferences. The recovery of nicotine as NBD(+) was 84 119% in the range 0.035-5% nicotine. The result was satisfactory compared with an AOAC UV standard method. PMID- 21662957 TI - Triiodide PVC Membrane Electrode Based on a Charge-Transfer Complex of Iodine with 2,4,6,8- Tetraphenyl-2,4,6,8-tetraazabicyclo[3.3.0]octane. AB - A novel triiodide ion-selective electrode based on a charge-transfer complex of iodine with 2,4,6,8-tetraphenyl-2,4,6,8-tetraazabicyclo[3.3.0]octane as membrane carrier was prepared. The electrode has a linear dynamic range between 5.0 * 10( )(2) and 3.5 * 10(-)(6) M, with a near-Nernstian slope of 54.7 +/- 0.8 mV decade( )(1) and a detection limit of 2.0 * 10(-)(6) M. The potentiometric response is independent of the pH of the solution in the pH range 4.0-10.5. The electrode possesses the advantages of low resistance, short conditioning time, fast response, and, especially, very good selectivities over a wide variety of other anions. The electrode can be used for at least 10 months without any considerable divergence in potentials. It was used as an indicator electrode in potentiometric titration of triiodide ions. PMID- 21662958 TI - SERS Titration of 4-Mercaptopyridine Self-Assembled Monolayers at Aqueous Buffer/Gold Interfaces. AB - Determination of the surface pK(a) of self-assembled monolayers (SAMs) at aqueous buffer/gold interfaces using surface-enhanced Raman scattering (SERS) measurements, namely, SERS titration, is reported for the first time. From the analysis of pH-dependent SERS spectra of 4-mercaptopyridine monolayers on gold, the pK(1/2) (3.9 +/- 0.2) was determined. By further correlating the surface pH value with the bulk pH value in terms of the Gouy-Chapmann model, the surface pK(a) (5.3 +/- 0.3) was evaluated accordingly. Compared to the conventional contact angle titration, SERS titration has the advantage of giving further insight into the microscopic and dynamic information of the surface-confined functional groups. In addition, such a technique has high sensitivity, micrometer spatial resolution, and chemical selectivity. PMID- 21662959 TI - Superoxide Dismutase Activity Measurement Using Cytochrome c-Modified Electrode. AB - SOD activity was quantified by the use of a cytochrome c-modified gold electrode. The electrode responded rapidly to superoxide radicals in solution. Steady-state superoxide concentrations were established by control of the calibration conditions. On this basis very low SOD activities were detected (10-200 munits/mL). This method showed good correlation with the standard photometric test and was applied for the determination of SOD activity entrapped into liposomes. Interference by hydrogen peroxide and uric acid was characterized and minimized using long-chain thiols for the first electrode modification step. The complete modification proved to be stable for several days. PMID- 21662960 TI - Molecularly imprinted electrosynthesized polymers: new materials for biomimetic sensors. AB - The preparation and characterization of electrosynthesized poly(o phenylenediamine) (PPD) imprinted by glucose (iPPD) is reported as the first case of an electrosynthesized polymer molecularly imprinted by a neutral template. The material is employed as the recognition element of a QCM biomimetic sensor for glucose. Scatchard analysis of the relevant calibration curve offers information on the equilibrium and binding sites involved in glucose detection. XPS comparison of PPD and iPPD supports the occurrence of a templating effect. On this basis, molecular imprinting electropolymerization is proposed as a possible strategy for the preparation of new materials with molecular recognition properties to be applied in biomimetic sensors. PMID- 21662961 TI - Sensitized and quenched phosphorescence as a detection mode in capillary electrophoresis. AB - The potential of sensitized and quenched phosphorescence of biacetyl as an optical detection mode in capillary electrophoresis (CE), complementary to absorption and fluorescence detection, was explored. From 24 naphthalenesulfonates (NS) that were studied in batch experiments, 5 NS were used as test compounds in CE. The technique is based on the intense phosphorescence emission of biacetyl (present as a constituent of the CE buffer) at room temperature in deoxygenated liquid solutions. A simple device, based on purging with nitrogen gas, was developed to meet this deoxygenation requirement in CE. A standard liquid chromatography luminescence detector, provided with a pulsed xenon light source, was used for detection. In view of the phosphoresence lifetime of biacetyl (70 MUs under present solution conditions), the background caused by scattered excitation light could be readily suppressed by using a delay time for detection. Both phosphorescence modes can be applied at a 0.02 M biacetyl concentration, though in the quenched mode a biacetyl concentration of 0.05 M yields better results. From the five test analytes considered, three show sensitized phosphorescence and two dynamically quenched phosphorescence. Though various experimental parameters still have to be optimized further, the results are quite encouraging: under stacking conditions (pt = 768 mbar.s), detection limits ranged from 5 * 10(-)(8) to 4 * 10(-)(7) M. PMID- 21662962 TI - A photothermal interferometer for gas-phase ammonia detection. AB - Detection of gas-phase ammonia is particularly challenging because ambient ammonia concentrations may be less than 1 ppb (molecules of NH(3) per 10(9) molecules of air), ammonia sticks to many materials commonly used to sample air, and particles containing ammonium may interfere with gas-phase measurements. We have built a new and sensitive photothermal interferometer to detect gas-phase ammonia in situ, under typical atmospheric conditions. Ammonia molecules in sampled air absorb infrared radiation from a CO(2) laser at 9.22 MUm, with consequent collisional heating, expansion, and refractive index change. This change in refractive index is detected as a phase shift in one arm of a homodyne interferometer. Measurements of vibrational and electrical noise in the interferometer correlate to an instrumental lower limit of detection of 6.6 ppt ammonia in 1 s. The CO(2) laser output is modulated at 1.2 kHz, and the ac signal from the interferometer is measured with a lock-in amplifier. The detector is zeroed by sampling through a H(3)PO(4)-coated denuder tube and is calibrated by dynamic dilution of two permeation tube outputs and by standard addition. Signal gain is insensitive to CO(2) or H(2)O in the sample, and the signal is linear over 5 orders of magnitude. The instrument 2sigma precision is 31 ppt when the signal is integrated for 100 s and 250 ppt with a 1-s integration time. The windowless sample cell and inlet is fabricated entirely of glass to minimize sample loss and hysteresis. The instrument response time is demonstrated to be about 1 s. PMID- 21662963 TI - Luminescence detection with a liquid core waveguide. AB - A new fluoropolymer tube is proposed as the basis of a novel class of liquid core waveguide-based luminescence detectors. Both chemiluminescence and photoluminescence detectors are possible. In the latter case, illumination is transverse to the main axis of the tube. With such a geometry, it is even possible to operate without monochromators, although limits of detection do improve with the incorporation of monochromators. The nature of the design is such that it is particularly simple to fabricate detectors in a flow-through configuration and where the light from the cell is coupled to a photodetector by an optical fiber. No focusing optics are necessary. A number of applications are illustrated. Attainable limits (LODs, S/N = 3) of detection include 150 pM fluorescein with a 254-nm excitation source, 200 amol of fluorescein in a capillary electrophoresis setup with excitation by two blue light-emitting diodes, 35 nM NH(3) as the isoindole derivative in a flow injection analysis system using a photodiode detector, 50 nM methylene blue and 1 nM Rhodamine 560 using respectively red and green LED arrays and an avalanche photodiode and a PMT in a FIA configuration, 100 parts per trillion by volume gaseous formaldehyde as the Hantzsch reaction product with cyclohexanedione using a diffusion scrubber, 2.7 MUM and 17 nM hypochlorite based on its chemiluminescence reaction with luminol with photodiode and PMT detectors, respectively, and 1 ppm SO(4)(2)(-) based on nephelometric detection at 470 nm. The approach described herein leads to particularly simple and inexpensive luminescence detectors with excellent sensitivity. PMID- 21662964 TI - Electrospray deposition as a method to fabricate functionally active protein films. AB - Electrospray ionization is a routine method in MS analysis of proteins and other biopolymers. Deposition of the electrospray products onto a conductive electrode is suggested here as a means to manufacture functionally active protein films. Recovery of the specific hydrolytic activity of the electrosprayed alkaline phosphatase (AP) was used as a probe for preservation of protein intactness in the electrospray deposition (ESD). It was shown that protein inactivation upon ESD is highly dependent on voltage and current used. Humidity and the presence of protective substances in solution also affect the process. Complete preservation of the enzyme activity was observed when the ESD was performed at low current and humidity in the presence of disaccharides. PMID- 21662965 TI - Detection and Mapping of Chimassorb 944FD Antioxidant Additive in Polyethylene Using TOF-SIMS. AB - Time-of-flight secondary ion mass spectrometry (TOF-SIMS) with either gallium or indium primary beams, has been evaluated as a method to measure the homogeneity of distribution of an antioxidant, Chimassorb 944FD (C944), in linear low-density polyethylene. The parent ion for the oligomer at m/z 599 is sufficiently weak that it could not be used to map the distribution of the additive throughout its most commonly used concentration range (0.1-0.5% (w/w)) in polyethylene. Instead, a mass fragment at m/z 58 was found to be sufficiently clear of interferences that it could be used as a surrogate for the parent ion. As a result, imaging of the antioxidant distribution was possible to concentrations as low as 0.1%, and a linear concentration calibration curve was obtained. The use of an indium primary beam improved the correlation coefficient for the quantitative measurement of C944; moreover, indium reduced the contribution from the polyethylene background at m/z 58 in relation to the total counts acquired. PMID- 21662966 TI - Improvements in LC/Electrospray Ion Trap Mass Spectrometry Performance Using an Off-Axis Nebulizer. AB - Charged residues from the electrospray process have been hypothesized to limit the sensitivity and dynamic range of an ion trap mass spectrometry operation. Incorporation of an off-axis nebulizer (positioned 90-95 degrees from the sampling orifice) was found to drastically reduce the detrimental effects caused by the charged particles or droplets compared to typical on-axis nebulization configurations (spraying 10-20 degrees from sampling orifices). The off-axis nebulizer reduced total ion currents that enter the ion trap (through the reduction of charged residues) by a factor of 5-7 while resulting in an increase of analyte [M + H](+) signal by a factor of 6 compared to an on-axis sprayer at flow rates of 20 MUL/min. At higher flow rates (e.g., 800 MUL/min) these enhancements are more evident. At flows greater than 200 MUL/min, off-axis nebulization reduced total ion current that enters the ion trap by a factor of 30 and resulted in a factor of more than 20 increase in [M + H](+) signal relative to on-axis nebulization. Incorporation of the off-axis nebulizer improved the detection limit and precision for determination of dihydroxyvitamin D(3) in plasma compared to on-axis nebulization. The LC/MS/MS detection limits obtained for the off-axis nebulizer on the ion trap was within a factor of 2 from the detection limit determined by the triple quadrupole. The relative standard deviation of the dihydroxyvitamin D(3) determination was less than 8% for both off-axis ion trap and triple-quadrupole determinations. PMID- 21662967 TI - Automated Toxaphene Quantitation by GC/MS. AB - Toxaphene is a complex mixture of at least 600 hexa- to decachlorinated bornanes and bornenes, which was used as an insecticide from the late 1950s to the early 1980s. Like PCBs and other environmentally persistent organochlorine pesticides, toxaphene is ubiquitous in the environment. Toxaphene's complex composition makes its accurate quantitation difficult. We report here an automatic, gas chromatographic mass spectrometry method (using electron capture negative ionization) that is precise and fast. This method is implemented by a small QBasic program that compares peak area ratios to the predicted chlorine isotopic ion ratios. This method decreases the time required for analysis while maintaining precise quantitation. The method is verified with standard and unknown samples contaminated with various amounts of other organochlorine pesticide interferents. PMID- 21662968 TI - Infinite-dilution diffusion coefficients of complex ions from solution conductivity data. AB - A technique is presented for determining infinite-dilution diffusion coefficients of complex ions from solution conductivity data. The method involves measuring the conductivities of dilute solutions in which the distribution of complex ions is systematically varied and statistically regressing the data to an equation that effectively relates individual ion diffusion coefficients to solution conductivity. The procedure is simple and requires no specialized equipment to perform. Unlike methods that require a concentration gradient, the solution composition is homogeneous and at equilibrium during measurements, which is a significant advantage when labile complexes are being studied. In this paper, diffusion coefficients of cuprous cyanide complexes are determined. Statistical analysis yields the infinite-dilution diffusion coefficients of Cu(CN)(2)(-), Cu(CN)(3)(2-), and Cu(CN)(4)(3-) at 25 degrees C as 1.43 * 10(-5) +/- 9%, 1.08 * 10(-5) +/- 9%, and 6.21 * 10(-6) +/- 22% cm(2)/s, respectively. PMID- 21662969 TI - An air to water bridge: air sampling and analysis using tetraglyme. AB - A water-soluble organic liquid is shown to scrub a wide variety of volatile organic compounds from air and gas streams. Gas pulled through impingers containing chilled tetraglyme (an organic solvent utilized in USEPA methods 3050A and 8240) is found to efficiently trap volatile Priority Pollutant, Hazardous Substance List and other organic species. A portion of the tetraglyme is subsequently dispersed into water and analyzed using conventional water analysis methodology. Practical quantitation limits of 100 ppbv have been demonstrated, and a potential to achieve lower limits of detection is clear. The method offers advantages over canister, adsorption tube, or Tedlar bag air-sampling techniques. Attributes include broad applicability, preservation of sample integrity ("plating out" of analytes is eliminated), freedom from water vapor interference, ready inclusion into water analysis methodology, simplicity, and low cost. Environmental laboratories with ordinary water/volatile organic analysis equipment are enabled to perform air-monitoring analyses without specialized hardware or expertise. PMID- 21662970 TI - An Autonomous Sensor and Telemetry System for Low-Level pCO(2) Measurements in Seawater. PMID- 21662971 TI - Synthesis of 8-arylquinolines via one-pot Pd-catalyzed borylation of quinoline-8 yl halides and subsequent Suzuki-Miyaura coupling. AB - A one-pot process has been developed for the synthesis of 8-arylquinolines via Pd catalyzed borylation of quinoline-8-yl halides and subsequent Suzuki-Miyaura coupling with aryl halides using n-BuPAd(2) as ligand. Yields of up to 98% were obtained. PMID- 21662973 TI - Tailoring electronic transparency of twin-plane 1D superlattices. AB - The structural properties of twin-plane superlattices in InP nanowires are systematically analyzed. First, we employ molecular dynamics simulations to determine the strain fields in nanowires grown in the [111] direction. These fields are produced by the formation of twin-planes and by surface effects. By using the stress tensor obtained from molecular dynamics simulations, we are able to describe changes on the electronic structure of these nanowires. On the basis of the resulting electronic structure, we confirm that a one-dimensional superlattice is indeed formed. Furthermore, we describe the transport properties of both electrons and holes in the twin-plane superlattices. In contrast to the predicted transparency of Gamma-electrons in heterolayered III-V semiconductor superlattices, we verify that surface effects in 1D systems open up possibilities of electronic structure engineering and the modulation of their transport and optical responses. PMID- 21662972 TI - Carbonaceous nanofiber membrane functionalized by beta-cyclodextrins for molecular filtration. AB - In this paper, we report the fabrication of carbonaceous nanofiber (CNF) membranes functionalized by beta-cyclodextrins (CNF-beta-CD membrane) and their application for molecular filtration. The chemically synthesized carbonaceous nanofibers were first functionalized by beta-CD, and the free-standing CNF membrane can be prepared by a simple filtration process. The membrane shows a remarkable capability to function as an ideal molecular filter through complexation of phenolphthalein molecules with the cyclodextrin molecules grafted on the CNFs. As a typical dye pollutant, fuchsin acid can also be effectively removed from the solution through such a membrane. Engineering the surface of this carbonaceous nanofiber membrane may allow it to be used for other applications such as chiral separation and drug delivery. PMID- 21662974 TI - Rhodium- and palladium-catalyzed 1,5-substitution reactions of 2-en-4-yne acetates and carbonates with organoboronic acids. AB - Two methods involving the rhodium-catalyzed reaction of 2-en-4-yne acetates and the palladium-catalyzed reaction of 2-en-4-yne carbonates with organoboronic acids were investigated; both afforded exclusively the (E)-configured vinylallenes. The coordinative interaction of the rhodium with the acetate group promoted the delta-elimination of Rh(I)-OAc from the alkenylrhodium intermediate II in both syn and anti modes, with the syn-elimination being the major path. DFT calculations revealed that a conformer of this intermediate (II), which can lead to the (E)-configured vinylallene product via the syn-elimination mode, is energetically the most favorable conformer. The rhodium-catalyzed procedure is not applicable to reactions involving (E)-configured enyne acetates, because the geometry of the alkenylrhodium intermediate that is derived from the corresponding (E)-enyne acetate would not allow such coordinative interaction to occur. The palladium-catalyzed method, which proceeds through formation of the sigma-vinylallenylpalladium intermediate, B, is suitable for both the (E)- and (Z)-configured enyne carbonates and appears to have a wider scope for both organoboronic acids and enyne substrates. The palladium-catalyzed reaction of an enantiomerically enriched enyne carbonate proceeded with racemization. PMID- 21662975 TI - Binding site influence on the electronic structure and electron paramagnetic resonance properties of the phyllosemiquinone free radical of photosystem I. AB - Electronic structure calculations are performed on models of the phyllosemiquinone (PhSQ) free radical in the A(1A) and A(1B) sites of photo system I. Partial geometry optimization of each site is performed, and from the resultant geometry spin densities and hyperfine couplings are calculated. We exploit the ONIOM methodology to progressively build up a model of the A(1A) site and monitor the effect on the spin density distribution of the PhSQ and its hyperfine couplings. For the A(1A) site, we show that while the O1 atom of the PhSQ is not involved in direct hydrogen bonding, the (17)O anisotropic hyperfine coupling for this position is sensitive to interactions with neighboring groups, especially Trp A697 and Phe A689. The results obtained are in agreement with experimental determinations which indicate small differences in (17)O hyperfine couplings for both oxygen atoms. Good agreement between calculated and experimental (1)H and (13)C hyperfine couplings is also found. In addition, we find that a significant (14)N isotropic coupling of 1.4 MHz is calculated for the peptide NH group of Leu A722. The (14)N isotropic hyperfine coupling obtained for the indole nitrogen atom of Trp A697 is calculated to be zero in disagreement with a previous experimental assignment. The spin density distribution of the PhSQ in the A(1B) site is calculated to be very similar to that in the A(1A) site. The presence of just one relatively weak hydrogen bond to the photo system I quinone is proposed to contribute substantially to its relatively low redox potential when compared with the more strongly hydrogen bonded quinone acceptors present in type II reaction centers. PMID- 21662976 TI - Novel DOTA-neurotensin analogues for 111In scintigraphy and 68Ga PET imaging of neurotensin receptor-positive tumors. AB - Overexpression of the high affinity neurotensin receptor 1 (NTSR1), demonstrated in several human cancers, has been proposed as a new marker for human ductal pancreatic carcinoma and as an independent factor for poor prognosis for ductal breast cancer, head and neck squamous cell carcinoma, and non-small cell lung cancer. The aim of the present study was to develop new DOTA-neurotensin analogues for positron emission tomography (PET) imaging with (68)Ga and for targeted radiotherapy with (90)Y or (177)Lu. We synthesized a DOTA-neurotensin analogue series. Two of these peptides bear two sequence modifications for metabolic stability: DOTA-NT-20.3 shares the same peptide sequence as the previously described DTPA-NT-20.3. In the sequence of DOTA-NT-20.4, the Arg(8) Arg(9) bond was N-methylated instead of the Pro(7)-Arg(8) bond in DOTA-NT-20.3. An additional sequence modification was introduced in DOTA-LB119 to increase stability. A spacer was added between DOTA and the peptide sequence to increase affinity. Binding to HT29 cells, which express NTSR1, in vivo stability, and biodistribution of the various analogues were compared, and the best candidate was used to image tumors of various sizes with the microPET in mice. (111)In-DOTA NT-20.3, in spite of a relatively high uptake in kidneys, showed specific tumor uptake and elevated tumor to other organ uptake ratios. High contrast images were obtained at early time points after injection that allowed tumor detection at a time interval postinjection appropriate for imaging with the short-lived radionuclide (68)Ga. (111)In-DOTA-NT-20.4 displayed inferior binding to HT29 cells and reduced tumor uptake. (111)In-DOTA-LB119 displayed at early time points a significantly lower renal uptake but also a lower tumor uptake than (111)In DOTA-NT-20.3, although binding to HT29 cells was similar. (68)Ga-DOTA-NT-20.3 displayed higher tumor uptake than (68)Ga-DOTA-LB119 and allowed the detection of very small tumors by PET. In conclusion, DOTA-NT-20.3 is a promising candidate for (68)Ga-PET imaging of neurotensin receptor-positive tumors. DOTA-NT-20.3 may also be considered for therapy, as the yttrium-labeled peptide has higher affinity than that of the indium-labeled one. A prerequisite for therapeutic application of this neurotensin analogue would be to lower kidney uptake, for example, by infusion of basic amino acids, gelofusin, or albumin fragments, to prevent nephrotoxicity, as with radiolabeled somatostatin analogues. PMID- 21662977 TI - Phosphonate-titanium dioxide assemblies: platform for multimodal diagnostic therapeutic nanoprobes. AB - Multimodal imaging-therapeutic nanoprobe TiO(2)@RhdGd was prepared and successfully used for in vitro and in vivo cell tracking as well as for killing of cancer cells in vitro. TiO(2) nanoparticles were used as a core for phosphonic acid modified functionalities, responsible for contrast in MRI and optical imaging. The probe shows high (1)H relaxivity and relaxivity density values. Presence of fluorescent dye allows for visualization by means of fluorescence microscopy. The applicability of the probe was studied, using mesenchymal stem cells, cancer HeLa cells, and T-lymphocytes. The probe did not exhibit toxicity in any of these systems. Labeled cells were successfully visualized in vitro by means of fluorescence microscopy and MRI. Furthermore, it was shown that the probe TiO(2)@RhdGd can be changed into a cancer cell killer upon UV light irradiation. The above stated results represent a valuable proof of a principle showing applicability of the probe design for diagnosis and therapy. PMID- 21662978 TI - Flexible organic memory devices with multilayer graphene electrodes. AB - We fabricated 8 * 8 cross-bar array-type flexible organic resistive memory devices with transparent multilayer graphene (MLG) electrodes on a poly(ethylene terephthalate) substrate. The active layer of the memory devices is a composite of polyimide and 6-phenyl-C61 butyric acid methyl ester. The sheet resistance of the MLG film on memory device was found to be ~270 Omega/?, and the transmittance of separated MLG film from memory device was ~92%. The memory devices showed typical write-once-read-many (WORM) characteristics and an ON/OFF ratio of over ~10(6). The memory devices also exhibited outstanding cell-to-cell uniformity with flexibility. There was no substantial variation observed in the current levels of the WORM memory devices upon bending and bending cycling up to 10 000 times. A retention time of over 10(4) s was observed without fluctuation under bending. PMID- 21662979 TI - Unprecedented observation of days-long remnant orientation of phospholipid bicelles: a small-angle X-ray scattering and theoretical study. AB - Nanometric bilayer-based self-assembled micelles commonly named as bicelles, formed with a mixture of long and short chains phosphatidylcholine lipids (PC), are known to orient spontaneously in a magnetic field. This field-induced orientational order strongly depends on the molecular structure of the phospholipids. Using small-angle X-ray scattering (SAXS), we performed detailed structural studies of bicelles and investigated the orientation/relaxation kinetics in three different systems: saturated-chain lipid bicelles made of DMPC (dimyristoyl PC)/DCPC (1,2-dicaproyl PC) with and without the added paramagnetic lanthanide ions Eu(3+), as well as bicelles of TBBPC (1-tetradecanoyl-2-(4-(4 biphenyl)butanoyl)-sn-glycero-3-PC)/DCPC. The structural study confirmed the previous NMR studies, which showed that DMPC bicelles orient with the membrane normal perpendicular (defined here as "nematic" orientation) to the magnetic field, whereas they orient parallel (defined here as "smectic" orientation) to the magnetic field in the presence of Eu(3+). The TBBPC bicelles also show smectic orientation. Surprisingly, the orientational order induced in the magnetic field remains even after the magnetic field is removed, which allowed us to investigate the orientation and relaxation kinetics of different bicelle structures. We demonstrate that this kinetics is very different for all three types of bicelles at the same lipid concentration; DMPC bicelles (~40 nm diameter) with and without Eu(3+) orient faster than TBBPC bicelles (~80 nm diameter). However, for the relaxation, DMPC bicelles (nematic) lose their macroscopic orientation only after one hour, whereas both DMPC bicelles with Eu(3+) and TBBPC bicelles (smectic) remarkably stay oriented for up to several days! These results indicate that the orientation mechanism of these nanometric disks in the magnetic field is governed by their size, with smaller bicelles orienting faster than the larger bicelles. Their relaxation mechanism outside the magnetic field, however, is governed by the degree of ordering. Indeed, the angular distribution of oriented bicelles is much narrower for the bicelles with smectic orientation, and, consequently, they keep aligned for much longer time (days) than those with nematic ordering (hours) outside the magnetic field. The understanding of the orientation/relaxation kinetics, as well as the morphologies of these "molecular goniometers" at molecular and supramolecular levels, allows controlling such an unprecedented long-range and long-lived smectic ordering of nanodisks and opens a wide field of applications for structural biology or material sciences. PMID- 21662980 TI - Size-dependent valence and conduction band-edge energies of semiconductor nanocrystals. AB - Through the use of photoelectron spectroscopy in air (PESA), we investigate the size-dependent valence and conduction band-edge energies of CdSe, CdTe, PbS, and PbSe semiconductor quantum dots (QDs). The results are compared to those of previous studies, based on differing experimental methods, and to theoretical calculations based on k.p theory and state-of-the-art atomistic semiempirical pseudopotential modeling. To accurately map out the energy level landscapes of QDs as a function of size, the QDs must be passivated by comparable surface chemistries. This is highlighted by studying the effect of surface chemistry on the valence band-edge energy in an ensemble of 4.7 nm CdSe QDs. An energy level shift as large as 0.35 eV is observed for this system through modification of surface chemistry alone. This shift is significantly larger than the size dependent valence band-edge shift that is observed when comparable surface chemistries are used. PMID- 21662981 TI - Atomically thin surface cloak using graphene monolayers. AB - We discuss here the use of a graphene monolayer to realize the concept of "cloaking by a surface", proposing the thinnest possible mantle cloak with operation in the far-infrared and terahertz (THz) regime. We show that an atomically thin graphene monolayer may drastically suppress the scattering of planar and cylindrical objects and, at the same time, preserve moderately broad bandwidth of operation. In addition, we exploit the large tunability of the graphene conductivity to provide active, dynamically tunable invisibility cloaks and versatile THz switching devices. PMID- 21662982 TI - Controlling DNA translocation through gate modulation of nanopore wall surface charges. AB - One major challenge of nanopore-based DNA sequencing technology is to find an efficient way to reduce DNA translocation speed so that each nucleotide can reside long enough in the pore for interrogation. Here we report the electrical tuning of DNA translocation speed by gate modulation of nanopore wall surface charges. We find that native surface-charge-induced counterions in the electroosmotic layer substantially enhance advection flow of fluid, which exerts stronger dragging forces on the translocating DNA, and thereby lowering the DNA translocation speed. We propose a feedback device architecture to regulate DNA translocation by modulating the effective wall surface charge density sigmaw*via lateral gate voltages--at the beginning, a positive gate bias is applied to weaken sigmaw* in order to enhance the capture rate of DNA molecule; upon detection of ionic current variance indicating DNA has been driven into the nanopore, gate bias is turned to be negative so that sigmaw* is reinforced and DNA translocation is retarded. We show that a gate electric field can dramatically decrease the DNA translocation speed at a rate about 55 MUm/s per 1 mV/nm. PMID- 21662983 TI - Quantifying in-use PM measurements for heavy duty diesel vehicles. AB - Heavy duty emissions regulations have recently expanded from the laboratory to include in-use requirements. This paradigm shift to in-use testing has forced the development of portable emissions measurement systems (PEMS) for particulate matter (PM). These PM measurements are not trivial for laboratory work, and are even more complex for in-use testing. This study evaluates five PM PEMS in comparison to UCR's mobile reference laboratory under in-use conditions. Three on highway, heavy-duty trucks were selected to provide PM emissions levels from 0.1 to 0.0003 g/hp-h, with varying compositions of elemental carbon (EC), organic carbon (OC), and sulfate. The on-road driving courses included segments near sea level, at elevations up to 1500 m, and coastal and desert regions. The photoacoustic measurement PEMS performed best for the non-after treatment system (ATS)-equipped engine, where the PM was mostly EC, with a linear regression slope of 0.91 and an R(2) of 0.95. The PEMS did not perform as well for the 2007 modified ATS equipped engines. The best performing PEMS showed a slope of 0.16 for the ATS-equipped engine with predominantly sulfate emissions and 0.89 for the ATS-equipped engine with predominantly OC emissions, with the next best slope at 0.45 for the predominantly OC engine. PMID- 21662984 TI - Exposure to particles from laser printers operating within office workplaces. AB - While recent research has provided valuable information as to the composition of laser printer particles, their formation mechanisms, and explained why some printers are emitters while others are low emitters, questions relating to the potential exposure of office workers remained unanswered. In particular, (i) what impact does the operation of laser printers have on the background particle number concentration (PNC) of an office environment over the duration of a typical working day? (ii) What is the airborne particle exposure to office workers in the vicinity of laser printers? (iii) What influence does the office ventilation have upon the transport and concentration of particles? (iv) Is there a need to control the generation of, and/or transport of particles arising from the operation of laser printers within an office environment? (v) What instrumentation and methodology is relevant for characterizing such particles within an office location? We present experimental evidence on printer temporal and spatial PNC during the operation of 107 laser printers within open plan offices of five buildings. The 8 h time-weighted average printer particle exposure is significantly less than the 8 h time-weighted local background particle exposure, but that peak printer particle exposure can be greater than 2 orders of magnitude higher than local background particle exposure. The particle size range is predominantly ultrafine (<100 nm diameter). In addition we have established that office workers are constantly exposed to nonprinter derived particle concentrations, with up to an order of magnitude difference in such exposure among offices, and propose that such exposure be controlled along with exposure to printer derived particles. We also propose, for the first time, that peak particle reference values be calculated for each office area analogous to the criteria used in Australia and elsewhere for evaluating exposure excursion above occupational hazardous chemical exposure standards. A universal peak particle reference value of 2.0 * 10(4) particles cm(-3) has been proposed. PMID- 21662985 TI - Epoxide and thiirane toxicity in vitro with the ciliates Tetrahymena pyriformis: structural alerts indicating excess toxicity. AB - The 48 h toxicity of 18 organic narcotics, 13 epoxides, and 2 thiiranes toward the ciliates Tetrahymena pyriformis was determined in terms of 50% growth inhibition EC(50). Nominal EC(50) was corrected for volatilization and sorption to quantify the freely dissolved compound fraction in solution. The derived baseline narcosis model served to evaluate toxicity enhancements T(e) as ratios of narcosis-predicted over experimental EC(50) values. Among the nine heterocycles with aliphatic side chains that include two thiiranes, three compounds yielded T(e) > 10, suggesting their covalent binding at nucleophilic protein sites such as -OH, -NHR, and -SH through S(N)2-type ring-opening. As a general trend of this group, T(e) decreases with increasing alkyl group size. Moreover, four of the six nonaliphatic epoxides exerted substantial excess toxicities with T(e) > 10, which could be rationalized by ring-opening activation through negative inductive effect, benzylic stabilization, and phenyl ring H bonding. By contrast, 1,2 substituted epoxides showed narcosis-level toxicity, despite the opportunity of side-chain Schiff-base formation with protein amino groups. The resulting structural alerts enable an in silico screening of epoxides and thiiranes for their potential to exert excess toxicity. Note that observed differences in T(e) sensitivity between ciliates, bacteria and fish should be taken into account when designing in vitro alternatives to fish toxicity studies. PMID- 21662986 TI - Significance of RuO2 modified SCR catalyst for elemental mercury oxidation in coal-fired flue gas. AB - Catalytic conversion of elemental mercury (Hg(0)) to its oxidized form has been considered as an effective way to enhance mercury removal from coal-fired power plants. In order to make good use of the existing selective catalytic reduction of NO(x) (SCR) catalysts as a cobenefit of Hg(0) conversion at lower level HCl in flue gas, various catalysts supported on titanium dioxide (TiO(2)) and commercial SCR catalysts were investigated at various cases. Among the tested catalysts, ruthenium oxides (RuO(2)) not only showed rather high catalytic activity on Hg(0) oxidation by itself, but also appeared to be well cooperative with the commercial SCR catalyst for Hg(0) conversion. In addition, the modified SCR catalyst with RuO(2) displayed an excellent tolerance to SO(2) and ammonia without any distinct negative effects on NO(x) reduction and SO(2) conversion. The demanded HCl concentration for Hg(0) oxidation can be reduced dramatically, and Hg(0) oxidation efficiency over RuO(2) doped SCR catalyst was over 90% even at about 5 ppm HCl in the simulated gases. Ru modified SCR catalyst shows a promising prospect for the cobenefit of mercury emission control. PMID- 21662987 TI - Combinatorial life cycle assessment to inform process design of industrial production of algal biodiesel. AB - The use of algae as a feedstock for biodiesel production is a rapidly growing industry, in the United States and globally. A life cycle assessment (LCA) is presented that compares various methods, either proposed or under development, for algal biodiesel to inform the most promising pathways for sustainable full scale production. For this analysis, the system is divided into five distinct process steps: (1) microalgae cultivation, (2) harvesting and/or dewatering, (3) lipid extraction, (4) conversion (transesterification) into biodiesel, and (5) byproduct management. A number of technology options are considered for each process step and various technology combinations are assessed for their life cycle environmental impacts. The optimal option for each process step is selected yielding a best case scenario, comprised of a flat panel enclosed photobioreactor and direct transesterification of algal cells with supercritical methanol. For a functional unit of 10 GJ biodiesel, the best case production system yields a cumulative energy demand savings of more than 65 GJ, reduces water consumption by 585 m(3) and decreases greenhouse gas emissions by 86% compared to a base case scenario typical of early industrial practices, highlighting the importance of technological innovation in algae processing and providing guidance on promising production pathways. PMID- 21662988 TI - Carbon-nanofiber-based nanocomposite membrane as a highly stable solid-state junction for reference electrodes. AB - There is currently a need for a reliable solid-state reference electrode, especially in applications such as autonomous sensing or long-term environmental monitoring. We present here for the first time a novel solid-state nanofiber junction reference electrode (NFJRE) incorporating a junction consisting of poly(methyl methacrylate) and carbon graphene stacked nanofibers. The NFJRE operates by using the membrane polymer junction, which has a very high glass transition temperature (T(g)) and small diffusion coefficient, to control the diffusion of ions, and the carbon nanofibers lower the junction resistance and act as ion-to-electron transducers. The fabrication of the NFJRE is detailed, and its behavior is characterized in terms of its impedance, stability, and behavior in comparison with traditional reference electrodes. The NFJRE showed a response of <5-13 mV toward a variety of electrolyte solutions from 10(-5) to 10(-2) M, <10 mV over a pH range of 2-12, and excellent behavior when used with voltammetric methods. PMID- 21662989 TI - Efficient direct electron transfer of PQQ-glucose dehydrogenase on carbon cryogel electrodes at neutral pH. AB - We present a comprehensive study of the direct electron transfer reaction of soluble PQQ-GDH from Acinetobacter calcoaceticus. Wild-type PQQ-sGDH nonspecifically adsorbed on carbon cryogel electrodes retained its enzymatic activity for glucose and maltose oxidation at pH 7.2 and 37 degrees C. The cyclic voltammograms in the absence of enzymatic substrate showed 2 redox peaks that suggest a two-step, one-electron oxidation/reduction of PQQ. Calibration curves showed a linear amperometric response for a wide glucose concentration range, including the values normally found in blood. At saturation, the catalytic current reached 0.93 mA cm(-2). Altogether the experimental results suggest that the amperometric output of the electrodes and the shape of the calibration curves represent a combination of the intrinsic enzyme kinetics, the maximum rate of heterogeneous electron transfer and the substrate accessibility to the enzyme's active center caused by the confinement of the enzyme into the mesoporous structure. A new mutant enzyme, N428C, developed in our group that shows almost twice the maximum catalytic activity in homogeneous experiments in solution, also showed a DET signal on carbon cryogel electrodes for glucose electro-oxidation. The higher activity for the mutant enzyme was also verified on the electrode surface. PMID- 21662991 TI - Cyclic volatile methylsiloxane bioaccumulation in flounder and ragworm in the Humber Estuary. AB - Cyclic volatile methylsiloxanes are being subjected to regulatory scrutiny as possible PBT chemicals. The investigation of bioaccumulation has yielded apparently contradictory results, with high laboratory fish bioconcentration factors on the one hand and low field trophic magnification factors on the other. In this study, octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) were studied along with polychlorinated biphenyls (PCBs) in sediments, ragworm, and flounder from six sites in the Humber Estuary. Bioaccumulation was evaluated using multimedia bioaccumulation factors (mmBAFs) which quantified the fraction of the contaminant present in the aquatic environment that is transferred to the biota. PCB 180, a known strongly bioaccumulative chemical, was used as a benchmark. The mean mmBAF of D5 was about twice that of PCB 180 in both polycheates and flounder, while for D4 it was 6 and 14 times higher, respectively. The mmBAF of D6 was a factor 5-10 lower than that of PCB180. The comparatively strong multimedia bioaccumulation of D4 and D5, even in the absence of biomagnification, was explained by both compounds having a >100 times stronger tendency to partition into lipid rather than into organic carbon, while PCB 180 partitions to a similar extent into both matrices. PMID- 21662990 TI - A 50-year record of platinum, iridium, and rhodium in Antarctic snow: volcanic and anthropogenic sources. AB - Antarctic snow preserves an atmospheric archive that enables the study of global atmospheric changes and anthropogenic disturbances from the past. We report atmospheric deposition rates of platinum group elements (PGEs) in Antarctica during the last ~ 50 years based on determinations of Pt, Ir, and Rh in snow samples collected from Queen Maud Land, East Antarctica to evaluate changes in the global atmospheric budget of these noble metals. The 50-year average PGE concentrations in Antarctic snow were 17 fg g(-1) (4.7-76 fg g(-1)) for Pt, 0.12 fg g(-1) (<0.05-0.34 fg g(-1)) for Ir, and 0.71 fg g(-1) (0.12-8.8 fg g(-1)) for Rh. The concentration peaks for Pt, Ir, and Rh were observed at depths corresponding to volcanic eruption periods, indicating that PGEs can be used as a good tracer of volcanic activity in the past. A significant increase in concentrations and crustal enrichment factors for Pt and a slight enhancement in enrichment factors for Rh were observed after the 1980s. This suggests that there has been large-scale atmospheric pollution for Pt and probably for Rh since the 1980s, which may be attributed to the increasing emissions of these metals from anthropogenic sources such as automobile catalysts and metal production processes. PMID- 21662994 TI - Other/miscellaneous. PMID- 21662992 TI - Combining land use information and small stream sampling with PCR-based methods for better characterization of diffuse sources of human fecal pollution. AB - Diffuse sources of human fecal pollution allow for the direct discharge of waste into receiving waters with minimal or no treatment. Traditional culture-based methods are commonly used to characterize fecal pollution in ambient waters, however these methods do not discern between human and other animal sources of fecal pollution making it difficult to identify diffuse pollution sources. Human associated quantitative real-time PCR (qPCR) methods in combination with low order headwatershed sampling, precipitation information, and high-resolution geographic information system land use data can be useful for identifying diffuse source of human fecal pollution in receiving waters. To test this assertion, this study monitored nine headwatersheds over a two-year period potentially impacted by faulty septic systems and leaky sanitary sewer lines. Human fecal pollution was measured using three different human-associated qPCR methods and a positive significant correlation was seen between abundance of human-associated genetic markers and septic systems following wet weather events. In contrast, a negative correlation was observed with sanitary sewer line densities suggesting septic systems are the predominant diffuse source of human fecal pollution in the study area. These results demonstrate the advantages of combining water sampling, climate information, land-use computer-based modeling, and molecular biology disciplines to better characterize diffuse sources of human fecal pollution in environmental waters. PMID- 21662997 TI - Showdown at the kyoto corral. PMID- 21662995 TI - Other/miscellaneous. PMID- 21663016 TI - Technology Update: Biofiltration system tackles styrene. PMID- 21663017 TI - Technology Update: Biosurfactants remove metals from soil. PMID- 21663018 TI - Technology Update: Novel ignition unit cuts emissions. PMID- 21663019 TI - EPA Watch: New research strategy for fuel oxygenate exposure. PMID- 21663020 TI - EPA Watch: Two states join lawsuit on new PM, ozone rules. PMID- 21663022 TI - EPA Watch: Science Advisory Board announces new chair. PMID- 21663021 TI - EPA Watch: Acute exposure guidelines for toxics to be set soon. PMID- 21663023 TI - EPA Watch: Genetically engineered insecticide under fire. PMID- 21663025 TI - EPA Watch: Heavy-duty diesel engines face controls for PM, Nox. PMID- 21663024 TI - EPA Watch: First controls for medical waste incinerator emissions. PMID- 21663027 TI - Deformities in Minnesota frogs linked to water in new study. PMID- 21663029 TI - EPA moves to clamp down on nonpoint sources of water pollution. PMID- 21663030 TI - Midwestern states balk at Nox reductions in EPA's ozone plan. PMID- 21663031 TI - New EPA budget boosts particulate matter research, Superfund cleanups. PMID- 21663032 TI - New RBCA standard for chemical waste cleanups developed by ASTM. PMID- 21663033 TI - New risk-based hazardous waste regulations draw fire in California. PMID- 21663034 TI - European news. PMID- 21663035 TI - News briefs: news briefs. PMID- 21663037 TI - Peer reviewed: hard times for innovative cleanup technology. AB - What can be done to remove market barriers to new groundwater and soil remediation technologies? PMID- 21663038 TI - Peer reviewed: massachusetts tries to cut toxic chemicals use. AB - An evaluation of statewide effort reveals toxic chemical use and waste generation have declined. PMID- 21663042 TI - Online/In print: online/in print. PMID- 21663040 TI - Viewpoint, peer reviewed: energy technology r&d essential to curb global warming. PMID- 21663046 TI - Amino acids as natural inhibitors for hydrate formation in CO2 sequestration. AB - The motivation for this work was the potential of hydrophobic amino acids such as glycine, l-alanine, and l-valine to be applied as thermodynamic hydrate inhibitors (THIs). To confirm their capabilities in inhibiting the formation of gas hydrates, three-phase (liquid-hydrate-vapor) equilibrium conditions for carbon dioxide hydrate formation in the presence of 0.1-3.0 mol % amino acid solutions were determined in the range of 273.05-281.45 K and 14.1-35.2 bar. From quantitative analyses, the inhibiting effects of the amino acids (on a mole concentration basis) decreased in the following order: l-valine > l-alanine > glycine. The application of amino acids as THIs has several potential advantages over conventional methods. First, the environmentally friendly nature of amino acids as compared to conventional inhibitors means that damage to ecological systems and the environment could be minimized. Second, the loss of amino acids in recovery process would be considerably reduced because amino acids are nonvolatile. Third, amino acids have great potential as a model system in which to investigate the inhibition mechanism on the molecular level, since the structure and chemical properties of amino acids are well understood. PMID- 21663047 TI - Biogenic palladium enhances diatrizoate removal from hospital wastewater in a microbial electrolysis cell. AB - To decrease the load of pharmaceuticals to the environment, decentralized wastewater treatment has been proposed for important point-sources such as hospitals. In this study, a microbial electrolysis cell (MEC) was used for the dehalogenation of the iodinated X-ray contrast medium diatrizoate. The presence of biogenic palladium nanoparticles (bio-Pd) in the cathode significantly enhanced diatrizoate removal by direct electrochemical reduction and by reductive catalysis using the H(2) gas produced at the cathode of the MEC. Complete deiodination of 3.3 MUM (2 mg L(-1)) diatrizoate from a synthetic medium was achieved after 24 h of recirculation at an applied voltage of -0.4 V. An equimolar amount of the deiodinated metabolite 3,5-diacetamidobenzoate (DAB) was detected. Higher cell voltages increased the dehalogenation rates, resulting in a complete removal after 2 h at -0.8 V. At this cell voltage, the MEC was also able to remove 85% of diatrizoate from hospital effluent containing 0.5 MUM (292 MUg L(-1)), after 24 h of recirculation. Complete removal was obtained when the effluent was continuously fed at a volumetric loading rate of 204 mg diatrizoate m(-3) total cathodic compartment (TCC) day(-1) to the MEC with a hydraulic retention time of 8 h. At -0.8 V, the MEC system could also eliminate 54% of diatrizoate from spiked urine during a 24 h recirculation experiment. The final product DAB was demonstrated to be removable by nitrifying biomass, which suggests that the combination of a MEC and bio-Pd in its cathode offers potential to dehalogenate pharmaceuticals, and to significantly lower the environmental burden of hospital waste streams. PMID- 21663050 TI - Other/miscellaneous. PMID- 21663053 TI - Letters: Lead-acid battery emissions. PMID- 21663052 TI - Certifying environmental scientists. PMID- 21663048 TI - Graphene sheets grafted Ag@AgCl hybrid with enhanced plasmonic photocatalytic activity under visible light. AB - Interfacing photocatalyst with graphene sheet gives rise to an extraordinary modification to the properties of the resulting hybrids. Graphene sheet grafted Ag@AgCl composite is fabricated by photoreducing AgCl/graphene oxide (GO) hybrids prepared by deposition-precipitation method. The microscopic analysis and Raman scattering reveal the direct interface between Ag nanocrystal and graphene sheet, which manipulates the electronic structures of Ag@AgCl. UV-vis absorption spectra of Ag@AgCl/reduced GO (RGO) hybrids exhibit strong absorbance in the visible region due to the surface plasmon resonance (SPR) absorption of Ag nanocrystal. In situ assembled Ag@AgCl/RGO plasmonic photocatalyst exhibits remarkable photocatalytic activity. Compared with bare Ag@AgCl nanoparticle, a 4-fold enhancement in the photodegradation rate toward rhodamine B is observed over Ag@AgCl/RGO hybrids under visible light irradiation. The large enhancement of photocatalytic activity was attributed to the effective charge transfer from plasmon-excited Ag nanocrystal to RGO, which suppress the charge recombination during photocatalytic process. This work could provide new insights into the fabrication of high performance plasmonic photocatalyst and facilitate their practical application in environmental issues. PMID- 21663054 TI - Letters: Author's response. PMID- 21663077 TI - Technology Update: Drinking water treatment system zaps microbes. PMID- 21663076 TI - Technology Update: Activated carbon filters from pecan shells. PMID- 21663078 TI - Technology Update: Thermophilic bacteria tackle nitroaromatic "pink water". PMID- 21663079 TI - Technology Update: Fuel cells turn landfill gas into electric power. PMID- 21663081 TI - EPA Watch: Government snares at least 11 smugglers of banned CFCs. PMID- 21663083 TI - EPA Watch: Farmers slow to switch to biopesticides. PMID- 21663082 TI - EPA Watch: Wetlands protection plans face funding hurdles. PMID- 21663084 TI - EPA Watch: Electric utilities sue over nitrogen oxide rule. PMID- 21663085 TI - EPA Watch: Indiana first state to adopt Great Lakes standards. PMID- 21663086 TI - EPA Watch: Program to protect watersheds under fire. PMID- 21663088 TI - Regional ozone group ends study; States, EPA near plan to cut Nox. PMID- 21663089 TI - Transportation planners lack clean air tools, NRC says. PMID- 21663090 TI - Risk commission issues guide for managers, calls for new approach. PMID- 21663092 TI - Phytoremediation of organics moving rapidly into field trials. PMID- 21663091 TI - States, EPA push to share confidential industry-provided toxic chemical data. PMID- 21663093 TI - EPA audits its peer reviews, begins agency-wide training program. PMID- 21663095 TI - U.S., Russia release wealth of classified Arctic environmental data. PMID- 21663094 TI - Scientists challenge EPA methods for assessing dioxin cancer risk. PMID- 21663096 TI - European Union grapples with noncompliance. PMID- 21663098 TI - News briefs: news briefs. PMID- 21663097 TI - Air-monitoring, pollution control technologies chosen for EPA verification program. PMID- 21663099 TI - U.s. Nuclear cleanup shows signs of progress. AB - Department of Energy plans promise to speed cleanups, but concerns about reducing risks remain. PMID- 21663100 TI - U.s nuclear cleanup shoes signs of progress: rocky flats. PMID- 21663101 TI - Environmental r&d shifts to pollution prevention. AB - Industry research is seeking to eliminate wastes, but can the investment pay off? PMID- 21663104 TI - Buyer's Guide: Buyer's Guide. PMID- 21663103 TI - Online/In print: online/in print. PMID- 21663107 TI - Other/miscellaneous. PMID- 21663109 TI - Other/miscellaneous. PMID- 21663111 TI - Other/miscellaneous. PMID- 21663112 TI - Letters: Uninformative data. PMID- 21663113 TI - Celebrating werner stumm. PMID- 21663114 TI - Other/miscellaneous. PMID- 21663115 TI - Study results fuel disagreements over health standards. PMID- 21663116 TI - White House calls for mercury workshop. PMID- 21663117 TI - American wins Japanese award for green chemistry. PMID- 21663118 TI - States slowly move ahead with water pollutant trading programs. PMID- 21663119 TI - State commissioners band together to reduce greenhouse gases. PMID- 21663120 TI - Wastewater reuse: Water shortage solution or long-term nightmare? PMID- 21663121 TI - European marine protection agreement aims for zero discharges. PMID- 21663122 TI - "No exceptions" for cleanup in former eastern block. PMID- 21663123 TI - News Briefs: Air pollution may exert an important effect on regional climate. PMID- 21663124 TI - News Briefs: Acid rain continues to harm sensitive lakes. PMID- 21663126 TI - News Briefs: Biotechnology is likely to become increasingly important. PMID- 21663125 TI - News Briefs: Agriculture and landscaping are changing temperatures. PMID- 21663127 TI - News Briefs: To reduce mercury, PCBs, and other persistent toxic substances. PMID- 21663128 TI - News Briefs: Nearly 40% of U.S. rivers, lakes, and estuaries. PMID- 21663129 TI - News Briefs: Risk is being overestimated, and remediation options are being restricted. PMID- 21663130 TI - News Briefs: "Smart" electronics and communications technologies can substantially reduce greenhouse gas emissions. PMID- 21663132 TI - EPA Watch: A reality check proposed for auto emissions testing. PMID- 21663133 TI - EPA WATCH: Will new PCB rule reduce disposal costs? PMID- 21663134 TI - EPA WATCH: Ozone deadline extension may spare Eastern cities. PMID- 21663135 TI - EPA WATCH: POTWs encouraged to submit proposals under Project XL. PMID- 21663136 TI - EPA WATCH: Contractors urge caution on SF contract reform. PMID- 21663137 TI - EPA WATCH: New drinking water data for risk calculations. PMID- 21663139 TI - Technology Update: Rotating ion-exchange system removes perchlorate. PMID- 21663140 TI - Peer reviewed: scanning probe microscopy of environmental interfaces. AB - The method is producing atomic-scale views and data needed to strengthen models. PMID- 21663141 TI - Peer reviewed: aquatic risk assessment of chemicals: is it working? PMID- 21663142 TI - Is coastal eutrophication out of control? AB - Although research is shedding new light on the phenomenon, it is proving difficult to manage. PMID- 21663144 TI - Research Watch: Aquatic colloid interactions. PMID- 21663167 TI - Research Watch: Cadmium in phytoplankton. PMID- 21663168 TI - Online/In print: online/in print. PMID- 21663169 TI - Buyer's Guide: Buyer's Guide. PMID- 21663173 TI - Other/miscellaneous. PMID- 21663175 TI - Other/miscellaneous. PMID- 21663176 TI - Confirming chemical identifications. PMID- 21663177 TI - California moves ahead on diesel exhaust study. PMID- 21663178 TI - Chemical industry pressured to test high-production volume chemicals. PMID- 21663179 TI - White House endocrine disrupter panel calls for more wildlife research. PMID- 21663180 TI - Global ban on organotin ship paints proposed by UN maritime group. PMID- 21663181 TI - Lake Erie fish declines hooked to phosphorus? PMID- 21663182 TI - DOD criticized for failure to estimate future environmental liability. PMID- 21663183 TI - EPA to share risk of innovative remediation technologies. PMID- 21663184 TI - News Briefs: The 80% increase in fish consumption advisories in the U.S. from 1993 to 1996 has not resulted in increased government efforts to protect public health. PMID- 21663185 TI - News Briefs: The idea of creating a "National Institute for the Environment" received a thumbs down. PMID- 21663186 TI - News Briefs: People in the news. PMID- 21663187 TI - News Briefs: An alternative method of wheat farming can reduce excess amounts of nitrogen entering the environment. PMID- 21663188 TI - News Briefs: Pesticide concentrations in Indiana's White River Basin are among the highest found at U.S. Geological Survey monitoring stations nationwide. PMID- 21663189 TI - News Briefs: The climate of the 1990s has been the warmest since the middle ages. PMID- 21663190 TI - News Briefs: At least 16 million hectares of natural forest a year are razed worldwide. PMID- 21663191 TI - News Briefs: The Blasker Award for Environmental Science and Engineering will award $250,000. PMID- 21663193 TI - EPA WATCH: Dredging planned for PCB-contaminated river. PMID- 21663194 TI - EPA Watch: Coal remining promoted to cut mine drainage. PMID- 21663196 TI - EPA WATCH: Annual TRI report to include in-depth industry profiles. PMID- 21663195 TI - EPA WATCH: Permitting water releases without endangering species. PMID- 21663197 TI - EPA WATCH: Soil screening guidance for eco-risk assessments. PMID- 21663200 TI - Peer reviewed: environmental forensics unraveling site liability. AB - An interdisciplinary analytical approach can unravel environmental liability at contaminated sites. PMID- 21663198 TI - EPA WATCH: New ecological assessments of mid-Atlantic watersheds. PMID- 21663202 TI - New cleanup technologies battle credibility gap. AB - More rigorous testing could help reinvigorate the market for innovative technologies, says a new study. But not everyone agrees that it is practical. PMID- 21663204 TI - Putting the brakes on clean cars. AB - Researchers agree that conventional high-sulfur gasoline can poison a catalyst. But is the effect reversible? PMID- 21663223 TI - Research Watch: Sediment pore water sampling. PMID- 21663211 TI - Research Watch: Fungal biosorbents for heavy metals. PMID- 21663233 TI - Online/In print: online/in print. PMID- 21663234 TI - Buyer's Guide: Buyer's Guide. PMID- 21663237 TI - Concentration-dependent mobility, retardation, and speciation of iodine in surface sediment from the Savannah River Site. AB - Iodine occurs in multiple oxidation states in aquatic systems in the form of organic and inorganic species. This feature leads to complex biogeochemical cycling of stable iodine and its long-lived isotope, (129)I. In this study, we investigated the sorption, transport, and interconversion of iodine species by comparing their mobility in groundwaters at ambient concentrations of iodine species (10(-8) to 10(-7) M) to those at artificially elevated concentrations (78.7 MUM), which often are used in laboratory analyses. Results demonstrate that the mobility of iodine species greatly depends on, in addition to the type of species, the iodine concentration used, presumably limited by the number of surface organic carbon binding sites to form covalent bonds. At ambient concentrations, iodide and iodate were significantly retarded (K(d) values as high as 49 mL g(-1)), whereas at concentrations of 78.7 MUM, iodide traveled along with the water without retardation. Appreciable amounts of iodide during transport were retained in soils due to iodination of organic carbon, specifically retained by aromatic carbon. At high input concentration of iodate (78.7 MUM), iodate was found to be reduced to iodide and subsequently followed the transport behavior of iodide. These experiments underscore the importance of studying iodine geochemistry at ambient concentrations and demonstrate the dynamic nature of their speciation during transport conditions. PMID- 21663239 TI - Other/miscellaneous. PMID- 21663241 TI - A reemphasis on significance. PMID- 21663278 TI - EPA Watch: "Talking" pesticide product labels under development. PMID- 21663279 TI - EPA Watch: For the first time, EPA withdraws from state-run emissions trading program. PMID- 21663280 TI - EPA Watch: Delay expected for rule exempting hazardous wastes. PMID- 21663281 TI - EPA Watch: Air quality improvements measured in Western states. PMID- 21663282 TI - EPA Watch: Cement kiln permit risk analysis challenged. PMID- 21663283 TI - EPA Watch: Long Island Sound to gain from nitrogen flow cuts. PMID- 21663284 TI - EPA Watch: $10 million in STAR research grants available. PMID- 21663285 TI - PM controls yield benefits; ozone gains trail costs. PMID- 21663286 TI - Opposition to proposed ozone and particulate standards runs high. PMID- 21663287 TI - ORD staff, managers meet to discuss management, morale. PMID- 21663288 TI - EPA readies study of future costs, benefits of implementing 1990 Clean Air Act. PMID- 21663289 TI - Canada acts to eliminate persistent organic pollutants. PMID- 21663290 TI - N.J. hazardous waste cleanup funds now guaranteed by constitution. PMID- 21663291 TI - Children's book publisher goes "chlorine free". PMID- 21663292 TI - Dioxins' toxicity works through multiple pathways, study finds. PMID- 21663293 TI - News briefs: news briefs. PMID- 21663294 TI - Six research priorities for the 21st century. AB - In an era of diminishing resources, which environmental research areas are most vital to society? PMID- 21663296 TI - Other/miscellaneous. PMID- 21663297 TI - Pump-and-Treat Enters the Supercomputer Age. AB - Research into optimizing pump-and-treat designs may lead to more economical cleanups. PMID- 21663298 TI - Analyzing chemical toxicity in 3-d on the web. AB - Aquatic toxicologists will soon be accessing three-dimensional chemical structures on a new EPA Web site. PMID- 21663302 TI - Editorial policy. PMID- 21663301 TI - ES&T Advisory Board: 1997 Advisory Board. PMID- 21663303 TI - Author guidelines. PMID- 21663304 TI - Peer review. PMID- 21663305 TI - Current research authors. PMID- 21663306 TI - Manuscript preparation: text and figures. PMID- 21663309 TI - Other/miscellaneous. PMID- 21663310 TI - Water-energy nexus. PMID- 21663311 TI - Making decisions. PMID- 21663312 TI - Tracing waterbird exposure to total mercury and selenium: a case study at the solar saltworks of Thyna (sfax, Tunisia). AB - Saltworks have emerged as important alternative/complementary feeding habitats for avifauna. However, the consequences of such habitat shifts in terms of changes in exposure to contaminants are poorly understood. We evaluated the exposure of the waterbird community breeding at the saltworks of Thyna (Tunisia) to total Hg (THg) and Se according to their differential use of saltworks dietary resources, as revealed by delta13C and delta15N values in their eggs (included species [n] -sorted according to increasing reliance on saltworks resources: Yellow-legged Gull Larus michahellis [12], Common Tern Sterna hirundo [12], Slender-billed Gull Larus genei [15], Little Egret Egretta garzetta [20], and Pied Avocet Recurvirostra avosetta [22]). Concentrations of THg and Se were under the threshold points for deleterious effects. Egg THg concentrations significantly decreased as the dietary contribution of saltworks resources increased (mean: 3.23, 1.66, 0.76, 0.4, and 0.27 MUg/g dw, respectively). Conversely, egg Se concentrations did not vary according to foraging habitats (2.49, 2.96, 2.61, 3.27, and 1.5 MUg/g dw, respectively). Tracing waterbird exposure to THg and Se at saltworks was feasible through the use stable isotopic assays of eggs. Birds using saltworks are not exposed to higher concentrations of THg and Se than in adjacent marine habitats. PMID- 21663313 TI - Occurrence and toxicity of 331 organic pollutants in large rivers of north Germany over a decade (1994 to 2004). AB - We analyzed the detection frequencies and concentrations for 331 organic compounds measured between 1994 and 2004 in the four largest rivers of north Germany, the Elbe, Weser, Aller, and Ems Rivers, and we assessed the potential risk for aquatic fauna using experimental and predicted acute toxicity data for the green alga Pseudokirchneriella subcapitata, the crustacean Daphnia magna, and the fish Pimephales promelas. The detection frequency for most compounds decreased significantly from 1994 to 2004. Polycyclic aromatic hydrocarbons (PAHs) were most frequently detected, while pesticides were the most important chemical group concerning toxicity for the standard test organisms. The predicted toxicity for D. magna was significantly higher than for the other organisms and reached levels envisaging acute toxic effects on the invertebrate fauna, still in 2004. Most of the compounds responsible for potential acute effects on aquatic organisms are currently not considered as priority substances in the European Union, while only 2 of 25 priority substances that have been measured occurred at levels that may be relevant in terms of toxicity for the selected test organisms. We conclude that attenuation of pesticides and other organic toxicants should play an increased role in river basin management. PMID- 21663314 TI - Structure of the HIV-1 5' untranslated region dimer alone and in complex with gold nanocolloids: support of a TAR-TAR-containing 5' dimer linkage site (DLS) and a 3' DIS-DIS-containing DLS. AB - The formation of a genomic RNA dimer is critical for the HIV-1 replication cycle, and dimerization is known to initiate within the 5'UTR (5' untranslated region) of the viral RNA. However, the 5'UTR constitutes the 335 terminal nucleotides, and because of this considerable size, it has been difficult to study the global structure using conventional structural methods. Here, the atomic force microscope has been used to directly visualize the dimer formed from RNAs including HIV-1 nucleotides 1-744. Gold nanocolloids were deposited on the primer binding site regions in the dimer as an internal control. The dimer showed distinct ring morphology with up to two gold nanocolloids deposited within the ring and one or two strands extending from the ring. This morphology implies a dimer including a DIS-DIS (dimerization initiation site)-containing 3' dimer linkage site (DLS) and a TAR-TAR (trans-activation region)-containing 5'DLS. Furthermore, the dimer was formed under the influence of Mg(2+) and was imaged with an atomic force microscope under buffer conditions. The overall ring morphology containing a 5'DLS and a 3'DLS with one or two strands extending from it was conserved in these atomic force microscopy images. This indicates that the observed dimer morphology is physiologically significant. Moreover, evidence of multiple dimer interstrand contacts downstream of the major splice donor were observed, which indicates a component in the selection of full-length genomic RNA in dimer formation during virion packaging. PMID- 21663315 TI - MALDI-MS-imaging of whole human lens capsule. AB - The ocular lens capsule is a smooth, transparent basement membrane that encapsulates the lens and is composed of a rigid network of interacting structural proteins and glycosaminoglycans. During cataract surgery, the anterior lens capsule is routinely removed in the form of a circular disk. We considered that the excised capsule could be easily prepared for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI-MSI) analysis. MALDI-MSI is a powerful tool to elucidate the spatial distribution of small molecules, peptides, and proteins within tissues. Here, we apply this molecular imaging technique to analyze the freshly excised human lens capsule en face. We demonstrate that novel information about the distribution of proteins by MALDI-MSI can be obtained from this highly compact connective tissue, having no evident histo-morphological characteristics. Trypsin digestion carried out on tissue is shown to improve MALDI-MSI analysis of human lens capsules and affords high repeatability. Most importantly, MALDI-MSI analysis reveals a concentric distribution pattern of proteins such as apolipoprotein E (ApoE) and collagen IV alpha-1 on the anterior surface of surgically removed lens capsule, which may indicate direct or indirect effects of environmental and mechanical stresses on the human ocular lens. PMID- 21663317 TI - Pd-catalyzed asymmetric allylic etherizations with oximes by chiral alkene phosphine ligands. AB - Palladium-catalyzed asymmetric allylic etherizations with a variety of oximes as nucleophiles utilizing a chiral alkene-phosphine hybrid ligand have been successfully achieved for the first time to afford the optical active oxime ethers in high yields with good to excellent enantioselectivities. PMID- 21663316 TI - A short total synthesis of (+/-)-epimeloscine and (+/-)-meloscine enabled by a cascade radical annulation of a divinylcyclopropane. AB - The first stereoselective synthesis of epimeloscine has been accomplished in 13 total steps with a longest linear sequence of 10 steps. The core of the synthesis takes only five steps, the key ones being acylation, stereoselective tandem radical cyclization of a divinylcyclopropane to make two rings, and group selective ring-closing metathesis of the resulting divinylcyclopentane to make the last ring. PMID- 21663318 TI - Design of acid-activated cell penetrating peptide for delivery of active molecules into cancer cells. AB - TP10-5 (TK) was screened as the most promising candidate among the designed analogues of transportan 10 (TP10), a cell penetrating peptide (CPP) with remarkable capacity for membrane translocation. However, low levels of specificity and high toxicity limit its successful use for drug delivery applications. Here, we developed a new type of acid-activated CPP (TH) by replacement of all lysines of TK with histidines. As expected, histidine containing TH can be activated and subsequently enter cells at pH 6.0, whereas it is less active at pH 7.4. In contrast, the uptake of TK has no significant difference for both pH values. Importantly, the toxicity of TH is significantly lower than that of TK under physiological conditions. After attachment of camptothecin (CPT) to TH, this conjugate exhibited remarkable cytotoxicity to cancer cells in a pH-dependent manner compared with free CPT and TK-CPT. This study opens a new avenue to design CPPs that preferentially enter cells in acidic solid tumors, with minimal cellular uptake in normal tissues. PMID- 21663320 TI - Ti-doped indium tin oxide thin films for transparent field-effect transistors: control of charge-carrier density and crystalline structure. AB - Indium tin oxide (ITO) films are representative transparent conducting oxide media for organic light-emitting diodes, liquid crystal displays, and solar cell applications. Extending the utility of ITO films from passive electrodes to active channel layers in transparent field-effect transistors (FETs), however, has been largely limited because of the materials' high carrier density (>1 * 10(20) cm(-3)), wide band gap, and polycrystalline structure. Here, we demonstrate that control over the cation composition in ITO-based oxide films via solid doping of titanium (Ti) can optimize the carrier concentration and suppress film crystallization. On 120 nm thick SiO(2)/Mo (200 nm)/glass substrates, transparent n-type FETs prepared with 4 at % Ti-doped ITO films and fabricated via the cosputtering of ITO and TiO(2) exhibited high electron mobilities of 13.4 cm(2) V(-1) s(-1), a low subthreshold gate swing of 0.25 V decade(-1), and a high I(on/)I(off) ratio of >1 * 10(8). PMID- 21663319 TI - Convergent synthesis and biological evaluation of 2-amino-4-(3',4',5' trimethoxyphenyl)-5-aryl thiazoles as microtubule targeting agents. AB - Combretastatin A-4, a potent tubulin polymerization inhibitor, caused us to synthesize a novel series of 2-amino-4-(3',4',5'-trimethoxyphenyl)-5-aryl thiazoles with the goal of evaluating the effects of substituents on the phenyl at the 5-position of the thiazole skeleton on biological activities. An ethoxy group at the para-position produced the most active compound in the series, with IC(50) values of 0.03-0.9 nM against five of seven cancer cell lines. The most active compounds retained full activity in multidrug resistant cancer cells and acted through the colchicine site of tubulin. Treated cells were arrested in the G2/M phase of the cell cycle, with cell death proceeding through an apoptotic pathway that was only partially caspase-dependent. Preliminary results suggest that, in addition to cell death by apoptosis, cells were also killed via mitotic catastrophe as an alternative cell death mechanism. PMID- 21663321 TI - Calcium carbonate mineralization: X-ray microdiffraction probing of the interface of an evaporating drop on a superhydrophobic surface. AB - The liquid/air interface of calcium bicarbonate solution drops was probed by synchrotron radiation microbeam scattering. The drops were deposited on a nanopatterned superhydrophobic poly(methyl methacrylate) surface and raster scanned during evaporation by small-angle and wide-angle X-ray scattering. The appearance of about 200-nm-size calcite crystallites at the interface could be spatially resolved at the onset of crystallization. Diffuse scattering from the interface is attributed to a dense nanoscale amorphous calcium carbonate phase. Calcite was found to be the major phase in the solid residue with vaterite as minor phase. PMID- 21663322 TI - Nitric oxide: a guardian for vascular grafts? PMID- 21663323 TI - Contact angles of surface nanobubbles on mixed self-assembled monolayers with systematically varied macroscopic wettability by atomic force microscopy. AB - The dependence of the properties of so-called "surface nanobubbles" at the interface of binary self-assembled monolayers (SAMs) of octadecanethiol (ODT) and 16-mercaptohexadecanoic acid (MHDA) on ultraflat template-stripped gold and water on the surface composition was studied systematically by in situ atomic force microscopy (AFM). The macroscopic water contact angle (theta(macro)) of the SAMs spanned the range between 107 degrees +/- 1 degrees and 15 degrees +/- 3 degrees . Surface nanobubbles were observed on all SAMs by intermittent contact mode AFM; their size and contact angle were found to depend on the composition of the SAM. In particular, nanoscopic contact angles theta(nano) < 86 degrees were observed for the first time for hydrophilic surfaces. From fits of the top of the bubble profile to a spherical cap in three dimensions, quantitative estimates of nanobubble height, width, and radius of curvature were obtained. Values of theta(nano) calculated from these data were found to change from 167 degrees +/- 3 degrees to 33 degrees +/- 58 degrees , when theta(macro) decreased from 107 degrees +/- 1 degrees to 37 degrees +/- 3 degrees . While the values for theta(nano) significantly exceeded those of theta(macro) for hydrophobic SAMs, which is fully in line with previous reports, this discrepancy became less pronounced and finally vanished for more hydrophilic surfaces. PMID- 21663324 TI - Energy transfer kinetics of the np5(n + 1)p excited states of Ne and Kr. AB - Energy transfer rate constants for Ne(2p(5)3p) and Kr(4p(5)5p) atoms colliding with ground state rare gas atoms (Rg) have been measured. In part, this study is motivated by the possibility of using excited rare gas atoms as the active species in optically pumped laser systems. Rg(np(5)(n + 1)s) metastable states may be produced using low-power electrical discharges. The potential then exits for optical pumping and laser action on the np(5)(n + 1)p <-> np(5)(n + 1)s transitions. Knowledge of the rate constants for collisional energy transfer and deactivation of the np(5)(n + 1)p states is required to evaluate the laser potential for various Rg + buffer gas combinations. In the present study we have characterized energy transfer processes for Ne (2p(5)3p) + He for the six lowest energy states of the multiplet. Rate constants for state-to-state transfer have been determined. Deactivation of the lowest energy level of Kr (4p(5)5p) by He, Ne, and Kr has also been characterized. Initial results suggest that Kr (4p(5)5p) + Ne mixtures may be the best suited for optically pumped laser applications. PMID- 21663325 TI - Effects of storage atmosphere and heme state on the color and visible reflectance spectra of salmon ( Salmo salar ) fillets. AB - It has previously been observed that the color of mackerel muscle is dependent on the status of heme as myoglobin and hemoglobin and hence the storage atmosphere. This study gives strong indications of this being the case also in salmon. Three different storage conditions were used to promote the oxidized, reduced, and carbon monoxide (CO) bound forms of heme in salmon and mackerel fillets. Color determination (instrumental color analysis, imaging, and sensory evaluation) and spectroscopic measurements were performed to study how spectral changes corresponded to color variations. Storage in CO significantly increased the redness in mackerel. This was also seen in salmon to such a degree that it was visible over normal levels of salmon carotenoids. Air storage increased the yellowness and reduced the redness in mackerel, but this effect was partly concealed in salmon by the astaxanthin absorption. The spectral differences due to storage condition could be ascribed to the spectral features characterizing heme of different oxidation states and bound to different ligands. The status of heme should therefore always be considered when experiments related to salmon color are performed. The findings could help in the understanding, control, and prediction of color loss in salmon during processing, storage, and transport. PMID- 21663326 TI - Understanding thermodynamic properties at the molecular level: multiple temperature charge density study of ribitol and xylitol. AB - X-ray diffraction data of high quality measured to high resolution on crystals of the two pentitol epimers ribitol (centric) and xylitol (acentric) at 101, 141, and 181 K and data on the two compounds previously recorded at 122 K have formed the basis for multipole refinements with the VALRAY system. Our analysis showed that it is possible to obtain a reliable crystal electron density for an acentric compound (xylitol) from X-ray diffraction data and that the thermal motion can be deconvoluted from the static density in this temperature range. The Bader-type topological analysis of the static electron densities revealed virtually identical intramolecular interactions as well as very similar hydrogen bond interactions of ribitol and xylitol; the only minor differences are found in the weaker intermolecular interactions. The high-level periodic DFT calculations are in accordance with the thermodynamic measurements that show that the two pentitols have identical sublimation energies. A rigid body normal coordinate analysis was performed on the atomic displacement parameters obtained at the four different temperatures. The translational and librational mean square deviations derived through this analysis were used in a quantum statistical approach to derive frequencies of the corresponding harmonic oscillators. The analysis showed a consistent vibrational model for all temperatures. The frequencies were subsequently used to calculate crystal entropies assuming an Einstein-type behavior. These calculations show that the crystal entropy of ribitol is 8 J K( 1) mol(-1) higher than the crystal entropy of xylitol, confirming that it is a difference in the entropy of the two compounds that causes the difference in their free energy. Our results presented in this Article show the potential to use X-ray diffraction data to obtain physicochemical properties of crystals. PMID- 21663327 TI - Vitamin D and sterol composition of 10 types of mushrooms from retail suppliers in the United States. AB - Vitamin D(2) (ergocalciferol) and sterols were analyzed in mushrooms sampled nationwide in the United States to update the USDA Nutrient Database for Standard Reference. Vitamin D(2) was assayed using HPLC with [(3)H]-vitamin D(3) internal standard and sterols by GC-FID mass spectrometric (MS) confirmation. Vitamin D(2) was low (0.1-0.3 MUg/100 g) in Agaricus bisporus (white button, crimini, portabella) and enoki, moderate in shiitake and oyster (0.4-0.7 MUg/100 g), and high in morel, chanterelle, maitake (5.2-28.1 MUg/100 g) and UV-treated portabella (3.4-20.9 MUg/100 g), with significant variability among composites for some types. Ergosterol (mg/100 g) was highest in maitake and shiitake (79.2, 84.9) and lowest in morel and enoki (26.3, 35.5); the range was <10 mg/100 g among white button composites but 12-50 mg/100 g among samples of other types. All mushrooms contained ergosta-5,7-dienol (22,23-dihydroergosterol) (3.53-18.0 mg/100 g) and (except morel) ergosta-7-enol. Only morel contained brassicasterol (28.6 mg/100 g) and campesterol (1.23-4.54 mg/100 g) and no ergosta-7,22-dienol. MS was critical in distinguishing campesterol from ergosta-7,22-dienol. PMID- 21663328 TI - Protein phosphorylation is a key event of flagellar disassembly revealed by analysis of flagellar phosphoproteins during flagellar shortening in Chlamydomonas. AB - Cilia are disassembled prior to cell division, which is proposed to regulate proper cell cycle progression. The signaling pathways that regulate cilia disassembly are not well-understood. Recent biochemical and genetic data demonstrate that protein phosphorylation plays important roles in cilia disassembly. Here, we analyzed the phosphoproteins in the membrane/matrix fraction of flagella undergoing shortening as well as flagella from steady state cells of Chlamydomonas. The phosphopeptides were enriched by a combination of IMAC and titanium dioxide chromatography with a strategy of sequential elution from IMAC (SIMAC) and analyzed by tandem mass spectrometry. A total of 224 phosphoproteins derived from 1296 spectral counts of phosphopeptides were identified. Among the identified phosphoproteins are flagellar motility proteins such as outer dynein arm, intraflagellar transport proteins as well as signaling molecules including protein kinases, phosphatases, G proteins, and ion channels. Eighty-nine of these phosphoproteins were only detected in shortening flagella, whereas 29 were solely in flagella of steady growing cells, indicating dramatic changes of protein phosphorylation during flagellar shortening. Our data indicates that protein phosphorylation is a key event in flagellar disassembly, and paves the way for further study of flagellar assembly and disassembly controlled by protein phosphorylation. PMID- 21663329 TI - Cloning, expression, and characterization of a D-psicose 3-epimerase from Clostridium cellulolyticum H10. AB - The noncharacterized protein ACL75304 encoded by the gene Ccel_0941 from Clostridium cellulolyticum H10 (ATCC 35319), previously proposed as the xylose isomerase domain protein TIM barrel, was cloned and expressed in Escherichia coli . The expressed enzyme was purified by nickel-affinity chromatography with electrophoretic homogeneity and then characterized as d-psicose 3-epimerase. The enzyme was strictly metal-dependent and showed a maximal activity in the presence of Co(2+). The optimum pH and temperature for enzyme activity were 55 degrees C and pH 8.0. The half-lives for the enzyme at 60 degrees C were 6.8 h and 10 min when incubated with and without Co(2+), respectively, suggesting that this enzyme was extremely thermostable in the presence of Co(2+) but readily inactivated without metal ion. The Michaelis-Menten constant (K(m)), turnover number (k(cat)), and catalytic efficiency (k(cat)/K(m)) values of the enzyme for substrate d-psicose were estimated to be 17.4 mM, 3243.4 min(-1), and 186.4 mM min(-1), respectively. The enzyme carried out the epimerization of d-fructose to d-psicose with a conversion yield of 32% under optimal conditions, suggesting that the enzyme is a potential d-psicose producer. PMID- 21663330 TI - Association between leukotriene-modifying agents and suicide: what is the evidence? AB - The US FDA has issued safety alerts and required manufacturers of leukotriene modifying agents (LTMAs), including montelukast, zafirlukast and zileuton, to include suicide and neuropsychiatric events as a precaution in the drug label. This paper reviews the existing evidence on the potential association between the LTMAs and suicidal behaviour. We conducted a literature search of MEDLINE, EMBASE and International Pharmaceutical Abstracts from 1995 to 2010 (inclusive) to identify pertinent studies and reports. We also examined data obtained from the FDA adverse event reporting system. To date, there are no well conducted, comparative, observational studies of this association, and the safety alerts are based primarily on case reports. While the FDA safety alerts apply to all three LTMAs, montelukast (known by its trade name Singulair(r)) is by far the most widely used of these drugs and most of the reports to date regarding suicide pertain to montelukast. From 1998 to 2009 there were 838 suicide-related adverse events associated with leukotrienes reported to the FDA, of which all but five involved montelukast. Nearly all cases were reported in 2008 and 2009 (96.1%) after the FDA warnings. LTMAs are approved for use in asthma and allergic rhinitis, and are effective drugs. Both of these diseases are also associated with suicide, making confirmation of the association more difficult. Given the lack of good evidence, we recommend that a large observational cohort or case control study be conducted to quantify the association between LTMAs and suicide. Until then, when prescribing LTMAs, clinicians should consider the potential for suicide and monitor patients who may be at elevated risk carefully for suicidal ideation or psychiatric symptoms associated with suicidal behaviour. PMID- 21663331 TI - The risk of ischaemic colitis in irritable bowel syndrome patients treated with serotonergic therapies. AB - Ischaemic colitis (IC) is the most common form of ischaemic injury to the gastrointestinal (GI) tract. IC typically presents with the sudden onset of lower abdominal pain, cramping and rectal bleeding, and is usually self-limited with low morbidity, although it may cause gangrenous or fulminant colitis, especially when the right colon is involved. Multiple medical conditions, as well as several pharmacological agents, are associated with IC, including irritable bowel syndrome (IBS) and drugs used for its treatment that act on gut serotonin 5-HT receptors. These include the selective 5-HT(3) receptor antagonist alosetron, currently approved for the treatment of severe diarrhoea-predominant IBS in women who fail to respond to conventional treatment, and cilansetron, another 5-HT(3) receptor antagonist that is no longer in clinical development. In addition, the 5 HT(4) receptor partial agonist tegaserod, which was approved for the treatment of constipation-predominant IBS in women, was associated with IC in the postmarketing setting, as was renzapride, a 5-HT(4) agonist/5-HT(3) antagonist. Although several hypotheses have been proposed, the pathophysiological basis for development of IC with 5-HT(3) receptor antagonists or 5-HT(4) receptor agonists remains unknown. Of interest, several population-based studies demonstrated that a diagnosis of IBS (independent of serotonergic therapies) increases the risk of developing IC 2- to 4-fold. As a result, IBS patients with the acute onset of abdominal pain, tenderness, diarrhoea or lower intestinal bleeding, especially those with predisposing conditions or medications, should be evaluated promptly for IC. The management of IC remains supportive; most cases of non-gangrenous IC, as seen in the alosetron and tegaserod databases, have been transient and have resolved spontaneously without complications or death. Despite the small number of deaths associated with alosetron in patients with complications of constipation and because of the ongoing requirement to prescribe alosetron under a risk management plan, misconceptions persist regarding the definition, incidence, severity and outcome of IC in clinical trials and the postmarketing setting. In this article, the frequency and clinical characteristics of IC associated with the use of alosetron and other serotonergic agents are examined, evidence of an association between IC and IBS is reviewed, and a scoring system to aid in the diagnosis of IC in any clinical situation is proposed. PMID- 21663332 TI - Risk of hospitalization for hip fracture and pneumonia associated with antipsychotic prescribing in the elderly: a self-controlled case-series analysis in an Australian health care claims database. AB - BACKGROUND: Antipsychotics are commonly used in the elderly to treat the behavioural symptoms of dementia. Randomized controlled trial data on the safety of antipsychotics are limited and little is known about the long-term effects of these medicines. Observational studies have investigated the risk of hip fracture and pneumonia associated with the use of antipsychotics, but varying results may be due to lack of control for unmeasured confounding. OBJECTIVE: The aim of the study was to investigate the risk of hospitalization for hip fracture and pneumonia in elderly subjects exposed to antipsychotic medication using the self controlled case-series design to control for unmeasured confounding. METHODS: The source of data for this study was the Australian Government Department of Veterans' Affairs Health Care Claims Database. A self-controlled case-series design was used to measure the excess risk of hospitalization for hip fracture and pneumonia after antipsychotic exposure compared with no-exposure over the 4 year period from 2005 to 2008. RESULTS: There was a significantly increased risk of hip fracture 1 week after exposure to typical antipsychotics, and the risk remained significantly raised with >12 weeks of continuous exposure (incidence rate ratio [IRR] 2.19; 95% CI 1.62, 2.95). The risk of hip fracture was highest in the first week after initiation of atypical antipsychotics (IRR 2.17; 95% CI 1.54, 3.06). The risk then declined with longer-term treatment; however, it remained significantly raised with >12 weeks of continuous exposure (IRR 1.43; 95% CI 1.23, 1.66). The risk of hospitalization for pneumonia was raised in all post-exposure periods for both typical and atypical antipsychotics. CONCLUSIONS: Antipsychotic use in the elderly is associated with an increased risk of hospitalization for hip fracture and pneumonia. Given the increased risks of morbidity and mortality associated with these outcomes, practitioners should consider these additional risks when prescribing antipsychotics to treat behavioural symptoms of dementia in the elderly. PMID- 21663334 TI - Electronic drug interaction alerts in ambulatory care: the value and acceptance of high-value alerts in US medical practices as assessed by an expert clinical panel. AB - BACKGROUND: Computerized physician order entry systems are known to improve patient safety in acute-care hospitals. However, as clinicians frequently override drug interaction and allergy alerts, their value in ambulatory care remains uncertain. OBJECTIVE: The purpose of the study was to examine whether ambulatory care clinicians were more likely to accept drug-drug interaction alerts that an expert panel judged to be of high clinical value. STUDY DESIGN: We convened an expert panel to examine drug-drug interaction alerts generated by 2872 clinicians in Massachusetts, Pennsylvania and New Jersey who used a common electronic prescribing system between 1 January 2006 and 30 September 2006. We selected 120 representative drug interaction alerts from the most commonly encountered class-class interactions. MEASUREMENTS: The expert panel rated each alert based on the following categories: (i) strength of the scientific evidence; (ii) probability that the interaction would result in an adverse drug event (ADE); (iii) severity of typical and most serious ADEs; (iv) the likelihood that a clinician could act on the information; and (v) the overall value of the alert to the average primary care clinician. We then used multivariate regression techniques to examine the relationship between the alert acceptance rate and the expert panel's mean rating of each category. RESULTS: The decision of clinicians to accept drug interaction alerts increased (relative to a baseline alert acceptance rate of 8.8%) by 2.7% (95% CI 0.4, 5.1) for interactions that panelists judged would result in an ADE, by 2.3% (95% CI 0.9, 3.7) when primary care providers (PCPs) lacked prior knowledge about the information presented in the alert, and by 3.3% (95% CI 0.9, 5.8) when the PCP could readily act on the information provided in the alert. CONCLUSION: The value of electronic drug interaction alerts is influenced heavily by clinicians' judgements about the clinical value of the alert. Expert judgement should be taken into account when developing electronic decision support. PMID- 21663335 TI - Drug prescribing before and during pregnancy in south west France: a retrolective study. AB - BACKGROUND: Several drugs that are known to exhibit teratogenic or fetotoxic risks when used during pregnancy should not be prescribed to pregnant women. However, most women of childbearing age use medications, and drug use cannot always be avoided during pregnancy, especially for women with chronic diseases for whom the benefit of treatment outweighs the potential risk of the drug for the fetus. Nevertheless, it is often possible to replace a drug with another one that has been better evaluated. OBJECTIVE: The aim of the present study was to describe the prescribing of drugs to pregnant women before and during pregnancy in order to examine whether the occurrence of pregnancy modifies drug prescribing and dispensing to women. In particular, drugs that are contraindicated or must be avoided during pregnancy, such as retinoids, ACE inhibitors, angiotensin II receptor blockers, NSAIDs and valproic acid, will be analysed. METHODS: This retrolective study used data already prospectively recorded in the database of the French Health Insurance Service. It analysed pharmacy records of women who gave birth between 1 January 2007 and 31 December 2007 in Midi-Pyrenees. Pharmacy data were analysed from 9 months before pregnancy until delivery. Drugs were classified according to the Anatomical Therapeutic Chemical code. RESULTS: The study included 23 898 women. Approximately 77% and 96% of the women received at least one prescription before and during pregnancy, respectively. The number of women who were prescribed contraindicated drugs significantly decreased with pregnancy (p < 0.0001). Most of the drugs were stopped during the 3 months before pregnancy without alternative treatment, even for chronic diseases. However, for some women, potentially dangerous prescriptions were maintained during pregnancy, and for others these drugs were dispensed for the first time during critical periods of pregnancy. CONCLUSION: Despite recommendations, some teratogenic and/or fetotoxic drugs are still prescribed and dispensed to pregnant women in France. There is a need to repeat information to sensitize health professionals and women to the harmful potential of drugs. Moreover, discontinuation of a needed treatment must be avoided. Therefore, attention must be given to ensuring that younger females and women of childbearing potential who are likely to need continued treatment in adolescence and adulthood are aware of the potential risks that some drugs may pose during pregnancy. PMID- 21663333 TI - Sources of information on lymphoma associated with anti-tumour necrosis factor agents: comparison of published case reports and cases reported to the French pharmacovigilance system. AB - BACKGROUND: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems. OBJECTIVE: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents. METHODS: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma. RESULTS: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p < 0.0001) were more frequently reported. Lymphomas in patients treated with anti TNF agents for Crohn's disease were more prevalent in published cases than in pharmacovigilance reports (p < 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001). CONCLUSIONS: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required. PMID- 21663337 TI - Communication: determination of the bond dissociation energy (D0) of the water dimer, (H2O)2, by velocity map imaging. AB - The bond dissociation energy (D(0)) of the water dimer is determined by using state-to-state vibrational predissociation measurements following excitation of the bound OH stretch fundamental of the donor unit of the dimer. Velocity map imaging and resonance-enhanced multiphoton ionization (REMPI) are used to determine pair-correlated product velocity and translational energy distributions. H(2)O fragments are detected in the ground vibrational (000) and the first excited bending (010) states by 2 + 1 REMPI via the C (1)B(1) (000) <- X (1)A(1) (000 and 010) transitions. The fragments' velocity and center-of-mass translational energy distributions are determined from images of selected rovibrational levels of H(2)O. An accurate value for D(0) is obtained by fitting both the structure in the images and the maximum velocity of the fragments. This value, D(0) = 1105 +/- 10 cm(-1) (13.2 +/- 0.12 kJ/mol), is in excellent agreement with the recent theoretical value of D(0) = 1103 +/- 4 cm(-1) (13.2 +/- 0.05 kJ/mol) suggested as a benchmark by Shank et al. [J. Chem. Phys. 130, 144314 (2009)]. PMID- 21663336 TI - Adherence to biochemical monitoring recommendations in patients starting with renin angiotensin system inhibitors: a retrospective cohort study in the Netherlands. AB - BACKGROUND: Renin angiotensin system inhibitors (RASIs) are frequently involved in serious adverse events. These events principally occur in high-risk patients and often arise within the first days after treatment initiation; therefore, guidelines recommend biochemical monitoring within 3 weeks after the start of therapy with RASIs. OBJECTIVE: The purpose of this study was to examine the level of biochemical monitoring directly after treatment initiation with RASIs in patients with different risk profiles and to study the attitudes of the physicians involved towards biochemical monitoring. METHODS: We carried out a retrospective analysis of 202 patients who started RASI therapy in 2006 in Groesbeek, the Netherlands. We determined the rate of serum creatinine and potassium monitoring within 3 weeks after the start of therapy. In addition, we studied the intentions and attitudes towards biochemical monitoring during RASI therapy among 68 general practitioners and medical specialists by way of a brief questionnaire. RESULTS: Serum creatinine and potassium monitoring after treatment initiation was performed in 34% and 28% of patients, respectively. Of all the patients, 29% had two or more additional risk factors for renal function deterioration. In these high-risk patients, creatinine was significantly less often monitored compared with low-risk patients (22% vs 39%). In contrast to these findings, the prescribing physicians claimed to check serum creatinine within 2 weeks after treatment initiation in 85% of their patients. Most of the prescribing physicians (88%) rated this monitoring as (very) important. CONCLUSIONS: We demonstrated that, despite positive intentions of physicians, the biochemical monitoring recommendation in patients treated with RASIs is poorly met. In addition, serum creatinine monitoring was significantly less often performed in high-risk patients compared with low-risk patients. PMID- 21663338 TI - Magnetic exchange couplings evaluated with Rung 3.5 density functionals. AB - Rung 3.5 exchange-correlation functionals are assessed for the calculation of magnetic exchange coupling parameters and atomic spin populations for a variety of inorganic and organic magnetic systems. Density functional theory calculations of exchange couplings sensitively depend on nonlocal contributions to the exchange-correlation functional. Semilocal functionals, Rungs 1-3 on "Jacob's Ladder" of density functional approximations, yield excessively delocalized electrons and overestimated absolute exchange couplings. Fourth-rung hybrid functionals admixing nonlocal exchange improve the results. We show that new "Rung 3.5" functionals give magnetic properties intermediate between semilocal and hybrid functionals, providing additional evidence that these functionals incorporate some desirable aspects of nonlocal exchange. Results for ferromagnetic complexes indicate areas for future improvement. PMID- 21663339 TI - Two- and four-component relativistic generalized-active-space coupled cluster method: implementation and application to BiH. AB - A string-based coupled-cluster method of general excitation rank and with optimal scaling which accounts for special relativity within the four-component framework is presented. The method opens the way for the treatment of multi-reference problems through an active-space inspired single-reference based state-selective expansion of the model space. The evaluation of the coupled-cluster vector function is implemented by considering contractions of elementary second quantized operators without setting up the amplitude equations explicitly. The capabilities of the new method are demonstrated in application to the electronic ground state of the bismuth monohydride molecule. In these calculations simulated multi-reference expansions with both doubles and triples excitations into the external space as well as the regular coupled-cluster hierarchy up to full quadruples excitations are compared. The importance of atomic outer core correlation for obtaining accurate results is shown. Comparison to the non relativistic framework is performed throughout to illustrate the additional work of the transition to the four-component relativistic framework both in implementation and application. Furthermore, an evaluation of the highest order scaling for general-order expansions is presented. PMID- 21663341 TI - Damped response theory description of two-photon absorption. AB - Damped response theory is applied to the calculation of two-photon absorption (TPA) spectra, which are determined directly, at each frequency, from a modified damped cubic response function. The TPA spectrum may therefore be evaluated for selected frequency ranges, making the damped TPA approach attractive for calculations on large molecules with a high density of states, where the calculation of TPA using standard theory is more problematic. Damped response theory can also be applied to the case of intermediate state resonances, where the standard TPA expression is divergent. Both exact damped response theory and its application within density functional theory are discussed. The latter is implemented using an atomic-orbital based density matrix formulation, which makes the approach especially suitable for studies on large systems. A test preliminary study is presented for the TPA spectrum of R-(+)-1,1'-bi(2-naphtol). PMID- 21663340 TI - A smoothly decoupled particle interface: new methods for coupling explicit and implicit solvent. AB - A common theme of studies using molecular simulation is a necessary compromise between computational efficiency and resolution of the forcefield that is used. Significant efforts have been directed at combining multiple levels of granularity within a single simulation in order to maintain the efficiency of coarse-grained models, while using finer resolution in regions where such details are expected to play an important role. A specific example of this paradigm is the development of hybrid solvent models, which explicitly sample the solvent degrees of freedom within a specified domain while utilizing a continuum description elsewhere. Unfortunately, these models are complicated by the presence of structural artifacts at or near the explicit/implicit boundary. The presence of these artifacts significantly complicates the use of such models, both undermining the accuracy obtained and necessitating the parameterization of effective potentials to counteract the artificial interactions. In this work, we introduce a novel hybrid solvent model that employs a smoothly decoupled particle interface (SDPI), a switching region that gradually transitions from fully interacting particles to a continuum solvent. The resulting SDPI model allows for the use of an implicit solvent model based on a simple theory that needs to only reproduce the behavior of bulk solvent rather than the more complex features of local interactions. In this study, the SDPI model is tested on spherical hybrid domains using a coarse-grained representation of water that includes only Lennard Jones interactions. The results demonstrate that this model is capable of reproducing solvent configurations absent of boundary artifacts, as if they were taken from full explicit simulations. PMID- 21663342 TI - Approaching the theoretical limit in periodic local MP2 calculations with atomic orbital basis sets: the case of LiH. AB - The atomic orbital basis set limit is approached in periodic correlated calculations for solid LiH. The valence correlation energy is evaluated at the level of the local periodic second order Moller-Plesset perturbation theory (MP2), using basis sets of progressively increasing size, and also employing "bond"-centered basis functions in addition to the standard atom-centered ones. Extended basis sets, which contain linear dependencies, are processed only at the MP2 stage via a dual basis set scheme. The local approximation (domain) error has been consistently eliminated by expanding the orbital excitation domains. As a final result, it is demonstrated that the complete basis set limit can be reached for both HF and local MP2 periodic calculations, and a general scheme is outlined for the definition of high-quality atomic-orbital basis sets for solids. PMID- 21663343 TI - A fluctuating quantum model of the CO vibration in carboxyhemoglobin. AB - In this paper, we present a theoretical approach to construct a fluctuating quantum model of the CO vibration in heme-CO proteins and its interaction with external laser fields. The methodology consists of mixed quantum-classical calculations for a restricted number of snapshots, which are then used to construct a parametrized quantum model. As an example, we calculate the infrared absorption spectrum of carboxy-hemoglobin, based on a simplified protein model, and found the absorption linewidth in good agreement with the experimental results. PMID- 21663344 TI - Two-component natural spinors from two-step spin-orbit coupled wave functions. AB - We developed an algorithm to obtain the natural orbitals (natural spinors) from the two-step spin-orbit coupled wave functions. These natural spinors are generally complex-valued, mixing two spin components, and they can have similar symmetry properties as the j-j spinors from the one-step spin-orbit coupling calculations, if the reduced density equally averages all the components of a multi-dimensional irreducible representation. Therefore, the natural spinors can serve as an approximation to the j-j spinors and any wave function analysis based on the j-j spinors can also be performed based on them. The comparison between the natural spinors and the j-j spinors of three representative atoms, Tl, At, and Lu, shows their close similarity and demonstrates the ability of the natural spinors to approximate the j-j spinors. PMID- 21663345 TI - Correcting model energies by numerically integrating along an adiabatic connection and a link to density functional approximations. AB - Model Hamiltonians are considered for which electrons interact via long-range forces. It is assumed that their eigenvalues can be obtained with satisfying accuracy. Extrapolation techniques using asymptotic behavior considerations provide estimates for the energy of the physical system. Results for the uniform electron gas and some two-electron systems show that very few quadrature points can already produce good quality results. Connections to the density functional theory are discussed. PMID- 21663347 TI - Development of a new variational approach for thermal density matrices. AB - A McLachlan-type variational principle is derived for thermal density matrices. In this approach, the trace of the mean square of the differences between the derivatives of the exact and model density matrices is minimized with respect to the parameters in the model Hamiltonian. Applications to model anharmonic systems in the independent particle model show that the method can provide thermodynamic state functions accurately (within 5% of the converged basis set results) and at the same level of accuracy as the results using Feynman-Gibbs-Bogoliubov variational principle at this level of approximation. PMID- 21663346 TI - A novel interpretation of reduced density matrix and cumulant for electronic structure theories. AB - We propose a novel interpretation of the reduced density matrix (RDM) and its cumulant that combines linear and exponential parametrizations of the wavefunction. Any n-particle RDM can be written as a weighted average of "configuration interaction" amplitudes. The corresponding n-particle cumulant is represented in terms of two types of contributions: "connected" (statistical averages of substitution amplitudes) and "disconnected" (cross-correlations of substitution amplitudes). A diagonal element of n-RDM represents the average occupation number of the orbital n-tuple. The diagonal elements of 2- and 3 cumulants take particularly elegant forms in the natural spin-orbital basis: they represent the covariances (correlated fluctuations) of the occupation numbers of the orbital pair and triples, respectively. Thus, the diagonal elements of the cumulants quantify the correlation between the orbital occupation numbers. Our interpretation is used to examine the weak to strong correlation transition in the "two electrons in two orbitals" problem. PMID- 21663348 TI - Transferable model of water with variable molecular size. AB - By decreasing the steepness of the repulsive wing in the intermolecular potential, one can extend the applicability of a water model to the high pressure region. Exploiting this trivial possibility, we published a polarizable model of water which provided good estimations not only of gas clusters, ambient liquid, hexagonal ice, but ice VII at very high pressures as well [A. Baranyai and P. Kiss, J. Chem. Phys. 133, 144109 (2010)]. This straightforward method works well provided the closest O-O distance is reasonably shorter in the high pressure phase than in hexagonal ice. If these O-O distances are close to each other and we fit the interactions to obtain an accurate picture of hexagonal ice, we underestimate the density of the high-pressure phases. This can be overcome if models use contracted molecules under high external pressure.In this paper we present a method, which is capable to describe the contraction of water molecules under high pressure by using two simple repulsion-attraction functions. These functions represent the dispersion interaction under low pressure and high pressure. The switch function varies between 0 and 1 and portions the two repulsions among the individual particles. The argument of the switch function is a virial-type expression, which can be interpreted as a net force compressing the molecule. We calculated the properties of gas clusters, densities, and internal energies of ambient water, hexagonal ice, ice III, ice VI, and ice VII phases and obtained excellent match of experimental data. PMID- 21663349 TI - Entropy production in a mesoscopic chemical reaction system with oscillatory and excitable dynamics. AB - Stochastic thermodynamics of chemical reaction systems has recently gained much attention. In the present paper, we consider such an issue for a system with both oscillatory and excitable dynamics, using catalytic oxidation of carbon monoxide on the surface of platinum crystal as an example. Starting from the chemical Langevin equations, we are able to calculate the stochastic entropy production P along a random trajectory in the concentration state space. Particular attention is paid to the dependence of the time-averaged entropy production P on the system size N in a parameter region close to the deterministic Hopf bifurcation (HB). In the large system size (weak noise) limit, we find that P ~ N(beta) with beta = 0 or 1, when the system is below or above the HB, respectively. In the small system size (strong noise) limit, P always increases linearly with N regardless of the bifurcation parameter. More interestingly, P could even reach a maximum for some intermediate system size in a parameter region where the corresponding deterministic system shows steady state or small amplitude oscillation. The maximum value of P decreases as the system parameter approaches the so-called CANARD point where the maximum disappears. This phenomenon could be qualitatively understood by partitioning the total entropy production into the contributions of spikes and of small amplitude oscillations. PMID- 21663350 TI - Extended multi-configuration quasi-degenerate perturbation theory: the new approach to multi-state multi-reference perturbation theory. AB - The distinctive desirable features, both mathematically and physically meaningful, for all partially contracted multi-state multi-reference perturbation theories (MS-MR-PT) are explicitly formulated. The original approach to MS-MR-PT theory, called extended multi-configuration quasi-degenerate perturbation theory (XMCQDPT), having most, if not all, of the desirable properties is introduced. The new method is applied at the second order of perturbation theory (XMCQDPT2) to the 1(1)A(')-2(1)A(') conical intersection in allene molecule, the avoided crossing in LiF molecule, and the 1(1)A(1) to 2(1)A(1) electronic transition in cis-1,3-butadiene. The new theory has several advantages compared to those of well-established approaches, such as second order multi-configuration quasi degenerate perturbation theory and multi-state-second order complete active space perturbation theory. The analysis of the prevalent approaches to the MS-MR-PT theory performed within the framework of the XMCQDPT theory unveils the origin of their common inherent problems. We describe the efficient implementation strategy that makes XMCQDPT2 an especially useful general-purpose tool in the high-level modeling of small to large molecular systems. PMID- 21663352 TI - A graph-theoretical kinetic Monte Carlo framework for on-lattice chemical kinetics. AB - Existing kinetic Monte Carlo (KMC) frameworks for the simulation of adsorption, desorption, diffusion, and reaction on a lattice often assume that each participating species occupies a single site and represent elementary events involving a maximum of two sites. However, these assumptions may be inadequate, especially in the case of complex chemistries, involving multidentate species or complex coverage and neighboring patterns between several lattice sites. We have developed a novel approach that employs graph-theoretical ideas to overcome these challenges and treat easily complex chemistries. As a benchmark, the Ziff-Gulari Barshad system is simulated and comparisons of the computational times of the graph-theoretical KMC and a simpler KMC approach are made. Further, to demonstrate the capabilities of our framework, the water-gas shift chemistry on Pt(111) is simulated. PMID- 21663351 TI - Reduction of the virtual space for coupled-cluster excitation energies of large molecules and embedded systems. AB - We investigate how the reduction of the virtual space affects coupled-cluster excitation energies at the approximate singles and doubles coupled-cluster level (CC2). In this reduced-virtual-space (RVS) approach, all virtual orbitals above a certain energy threshold are omitted in the correlation calculation. The effects of the RVS approach are assessed by calculations on the two lowest excitation energies of 11 biochromophores using different sizes of the virtual space. Our set of biochromophores consists of common model systems for the chromophores of the photoactive yellow protein, the green fluorescent protein, and rhodopsin. The RVS calculations show that most of the high-lying virtual orbitals can be neglected without significantly affecting the accuracy of the obtained excitation energies. Omitting all virtual orbitals above 50 eV in the correlation calculation introduces errors in the excitation energies that are smaller than 0.1 eV. By using a RVS energy threshold of 50 eV, the CC2 calculations using triple-zeta basis sets (TZVP) on protonated Schiff base retinal are accelerated by a factor of 6. We demonstrate the applicability of the RVS approach by performing CC2/TZVP calculations on the lowest singlet excitation energy of a rhodopsin model consisting of 165 atoms using RVS thresholds between 20 eV and 120 eV. The calculations on the rhodopsin model show that the RVS errors determined in the gas-phase are a very good approximation to the RVS errors in the protein environment. The RVS approach thus renders purely quantum mechanical treatments of chromophores in protein environments feasible and offers an ab initio alternative to quantum mechanics/molecular mechanics separation schemes. PMID- 21663354 TI - Phonostat: thermostatting phonons in molecular dynamics simulations. AB - Thermostat algorithms in a molecular dynamics simulation maintain an average temperature of a system by regulating the atomic velocities rather than the internal degrees of freedom. Herein, we present a "phonostat" algorithm that can regulate the total energy in a given internal degree of freedom. In this algorithm, the modal energies are computed at each time step using a mode tracking scheme and then the system is driven by an external driving force of desired frequency and amplitude. The rate and amount of energy exchange between the phonostat and the system is controlled by two distinct damping parameters. Two different schemes for controlling the external driving force amplitude are also presented. In order to test our algorithm, the method is applied initially to a simple anharmonic oscillator for which the role of various phonostat parameters can be carefully tested. We then apply the phonostat to a more realistic (10,0) carbon nanotube system and show how such an approach can be used to regulate energy of highly anharmonic modes. PMID- 21663353 TI - A state-specific partially internally contracted multireference coupled cluster approach. AB - A state-specific partially internally contracted multireference coupled cluster approach is presented for general complete active spaces with arbitrary number of active electrons. The dominant dynamical correlation is included via an exponential parametrization of internally contracted cluster operators ( T) which excite electrons from a multideterminantal reference function. The remaining dynamical correlation and relaxation effects are included via a diagonalization of the transformed Hamiltonian H =e(- T)He( T) in the multireference configuration interaction singles space in an uncontracted fashion. A new set of residual equations for determining the internally contracted cluster amplitudes is proposed. The second quantized matrix elements of H , expressed using the extended normal ordering of Kutzelnigg and Mukherjee, are used as the residual equations without projection onto the excited configurations. These residual equations, referred to as the many-body residuals, do not have any near singularity and thus, should allow one to solve all the amplitudes without discarding any. There are some relatively minor remaining convergence issues that may arise from an attempt to solve all the amplitudes and an initial analysis is provided in this paper. Applications to the bond-stretching potential energy surfaces for N(2), CO, and the low-lying electronic states of C(2) indicate clear improvements of the results using the many-body residuals over the conventional projected residual equations. PMID- 21663356 TI - I(-).(CH3I)2 photoexcitation: the influence of dipole bound states on detachment and fragmentation. AB - We present the results of a photoelectron imaging study of the I(-).(CH(3)I)(2) cluster anion over excitation wavelengths 355-260 nm. The resulting spectra and photoelectron angular distributions (PADs) suggest extensive electron-molecule interaction following photoexcitation. Fragmentation channels are observed subsequent to excitation between 355 and 330 nm. The origin of these features, which begin 200 meV and peak 70 meV below the X band direct detachment threshold, is described in terms of a predissociative dipole bound state. The nature of the fragments detected and the energetics of the channel opening argue strongly in favor of an asymmetric, head to tail cluster anion geometry posited by Dessent et al. [Acc. Chem. Res. 31, 527 (1998)]. Above the direct detachment threshold, PADs display evidence of phenomena akin to electron-molecule scattering. The fragment anions disappear above the X band threshold but reappear some distance below the second (A) direct detachment band. At these energies there is also rapid variation of the X band PAD, an observation attributed to autodetachment via spin orbit relaxation of the iodine core of the cluster. PMID- 21663355 TI - Multi-reference state-universal coupled-cluster approaches to electronically excited states. AB - The multi-reference (MR), general model space (GMS), state-universal (SU), coupled-cluster (CC) method with singles and doubles (GMS-SU-CCSD), as well as its triple-corrected versions GMS-SU-CCSD(T), are employed to assess their ability to describe low-lying excited states of various molecules, with an emphasis on a simultaneous handling of several states of the same symmetry species. A special attention is given to the role of the so-called C-conditions that account for non-vanishing internal cluster amplitudes when relying on an incomplete GMS, as well as to the choice of suitable model spaces and a perturbative account of secondary triples. The ambiguities arising when using large basis sets are also pointed out. To achieve a general assessment of the potential of the GMS-type SU-CC approaches, the vertical excitation energies of several species, including the challenging BN diatomic as well as larger systems, namely formaldehyde, trans-butadiene, formamide, and benzene are considered. These results are compared with those provided by the equation-of-motion EOM-CCSD method and, whenever available, the density functional theory results and experimental data. These comparisons clearly demonstrate the usefulness of GMS type MR-CC approaches. PMID- 21663357 TI - Rotationally resolved infrared spectrum of the Na(+)-D2 complex: an experimental and theoretical study. AB - The infrared spectrum of mass-selected Na(+)-D(2) complexes is recorded in the D D stretch vibration region (2915-2972 cm(-1)) by detecting Na(+) photofragments resulting from photo-excitation of the complexes. Analysis of the rotationally resolved spectrum confirms a T-shaped equilibrium geometry for the complex and a vibrationally averaged intermolecular bond length of 2.461 A. The D-D stretch band centre occurs at 2944.04 cm(-1), representing a -49.6 cm(-1) shift from the Q(1)(0) transition of the free D(2) molecule. Variational rovibrational energy level calculations are performed for Na(+)-D(2) utilising an ab initio potential energy surface developed previously for investigating the Na(+)-H(2) complex [B. L. J. Poad et al., J. Chem. Phys. 129, 184306 (2008)]. The theoretical approach predicts a dissociation energy for Na(+)-D(2) of 923 cm(-1) with respect to the Na(+)+ D(2) limit, reproduces the experimental rotational constants to within 1 2%, and gives a simulated spectrum closely matching the experimental infrared spectrum. PMID- 21663358 TI - Quantum dynamics of rovibrational transitions in H2-H2 collisions: internal energy and rotational angular momentum conservation effects. AB - We present a full dimensional quantum mechanical treatment of collisions between two H(2) molecules over a wide range of energies. Elastic and state-to-state inelastic cross sections for ortho-H(2) + para-H(2) and ortho-H(2) + ortho-H(2) collisions have been computed for different initial rovibrational levels of the molecules. For rovibrationally excited molecules, it has been found that state-to state transitions are highly specific. Inelastic collisions that conserve the total rotational angular momentum of the diatoms and that involve small changes in the internal energy are found to be highly efficient. The effectiveness of these quasiresonant processes increases with decreasing collision energy and they become highly state-selective at ultracold temperatures. They are found to be more dominant for rotational energy exchange than for vibrational transitions. For non-reactive collisions between ortho- and para-H(2) molecules for which rotational energy exchange is forbidden, the quasiresonant mechanism involves a purely vibrational energy transfer albeit with less efficiency. When inelastic collisions are dominated by a quasiresonant transition calculations using a reduced basis set involving only the quasiresonant channels yield nearly identical results as the full basis set calculation leading to dramatic savings in computational cost. PMID- 21663359 TI - Ab initio characterization of the Ne-I2 van der Waals complex: intermolecular potentials and vibrational bound states. AB - A theoretical study of the potential energy surface and bound states is performed for the ground state of the NeI(2) van der Waals (vdW) complex. The three dimensional interaction energies are obtained from ab initio coupled-cluster, coupled-cluster single double (triple)/complete basis set, calculations using large basis sets, of quadruple- through quintuple-zeta quality, in conjunction with relativistic effective core potentials for the heavy iodine atoms. For the analytical representation of the surface two different schemes, based on fitting and interpolation surface generation techniques, are employed. The surface shows a double-minimum topology for linear and T-shaped configurations. Full variational quantum mechanical calculations are carried out using the model surfaces, and the vibrationally averaged structures and energetics for the NeI(2) isomers are determined. The accuracy of the potential energy surfaces is validated by a comparison between the present results and the corresponding experimental data available. In lieu of more experimental measurements, we also report our results/predictions on higher bound vibrational vdW levels, and the influence of the employed surface on them is discussed. PMID- 21663360 TI - Measuring polarizability anisotropies of rare gas diatomic molecules by laser induced molecular alignment technique. AB - The polarizability anisotropies of homonuclear rare gas diatomic molecules, Ar(2), Kr(2), and Xe(2), are investigated by utilizing the interaction of the induced electric dipole moment with a nonresonant, nanosecond laser pulse. The degree of alignment, which depends on the depth of the interaction potential created by the intense laser field, is measured, and is found to increase in order of Ar(2), Kr(2), and Xe(2) at the same peak intensity. Compared with a reference I(2) molecule, Ar(2), Kr(2), and Xe(2) are found to have the polarizability anisotropies of 0.45 +/- 0.13, 0.72 +/- 0.13, and 1.23 +/- 0.21 A(3), respectively, where the uncertainties (one standard deviation) in the polarizability anisotropies are carefully evaluated on the basis of the laser intensity dependence of the degree of alignment. The obtained values are compared with recent theoretical calculations and are found to agree well within the experimental uncertainties. PMID- 21663361 TI - Nanoconfinement effects on the reversibility of hydrogen storage in ammonia borane: a first-principles study. AB - We investigate atomistic mechanisms governing hydrogen release and uptake processes in ammonia borane (AB) within the framework of the density functional theory. In order to determine the most favorable pathways for the thermal inter conversion between AB and polyaminoborane plus H(2), we calculate potential energy surfaces for the corresponding reactions. We explore the possibility of enclosing AB in narrow carbon nanotubes to limit the formation of undesirable side-products such as the cyclic compound borazine, which hinder subsequent rehydrogenation of the system. We also explore the effects of nanoconfinement on the possible rehydrogenation pathways of AB and suggest the use of photoexcitation as a means to achieve dehydrogenation of AB at low temperatures. PMID- 21663362 TI - Acceleration of the effect of solute on the entropy-volume cross fluctuation density in aqueous 2-butoxyethanol, 1-propanol, and glycerol: the fourth derivative of Gibbs energy. AB - Using a differential pressure perturbation calorimetry developed by us recently [K. Yoshida, S. Baluja, A. Inaba, K. Tozaki, and Y. Koga, "Experimental determination of third derivative of G (III): Differential pressure perturbation calorimetry (II)," J. Solution Chem. (in press)], we experimentally determined the partial molar S-V cross fluctuation density of solute B, (SV)delta(B) , in binary aqueous solutions for B = 1-propanol (1P) and glycerol (Gly). This third derivative of G provides information about the effect of solute B on the S-V cross fluctuation density, (SV)delta, in aqueous solution as the concentration of B varies. Having determined (SV)delta(B) by better than 1% uncertainty, we evaluated for the first time the fourth derivative quantity (SV)delta(B-B) = N(?(SV)delta(B) /?n(B)) for B = 1P and Gly graphically without resorting to any fitting functions within several percent. This model-free quantity gives information about the acceleration of the effect of solute B on (SV)delta. By comparing fourth derivative quantities, (SV)delta(B-B) , among B = 1P, Gly, and 2 butoxyethanol obtained previously, the distinction of the effect of solute on H(2)O becomes clearer than before when only the third derivative quantities were available. PMID- 21663363 TI - The role of attractive forces in viscous liquids. AB - We present evidence from computer simulation that the slowdown of relaxation of a standard Lennard-Jones glass-forming liquid and that of its reduction to a model with truncated pair potentials without attractive tails are quantitatively and qualitatively different in the viscous regime. The pair structure of the two models is however very similar. This finding, which appears to contradict the common view that the physics of dense liquids is dominated by the steep repulsive forces between atoms, is characterized in detail, and its consequences are explored. Beyond the role of attractive forces themselves, a key aspect in explaining the differences in the dynamical behavior of the two models is the truncation of the interaction potentials beyond a cutoff at typical interatomic distance. This leads us to question the ability of the jamming scenario to describe the physics of glass-forming liquids and polymers. PMID- 21663364 TI - Vibrational relaxation of azide ions in liquid-to-supercritical water. AB - The dynamics of vibrational energy relaxation (VER) of the aqueous azide anion was studied over a wide temperature (300 K <= T <= 663 K) and density (0.6 g cm( 3) <= rho <= 1.0 g cm(-3)) range thereby covering the liquid and the supercritical phase of the water solvent. Femtosecond mid-infrared spectroscopy on the nu(3) band associated with the asymmetric stretching vibration of the azide anion was used to monitor the relaxation dynamics in a time-resolved fashion. The variation of the vibrational relaxation rate constant with temperature and density was found to be rather small. Surprisingly, the simple isolated binary collision model is able to fully reproduce the experimentally observed temperature and density dependence of the relaxation rate provided a local density correction around the vibrationally excited solute based on classical molecular dynamics simulations is used. The simulations further suggest that head-on collisions of the solvent with the terminal nitrogen atoms rather than side-on collisions with the central nitrogen atom of the azide govern the vibrational energy relaxation of this system. Finally, the importance of hydrogen bonding for the VER dynamics in this system is briefly discussed. PMID- 21663365 TI - Singlet state relaxation via intermolecular dipolar coupling. AB - The intermolecular contribution to the relaxation of singlet states has been derived on the basis of a translational-rotational diffusion model that describes molecules as impenetrable spheres which translate and rotate in an isotropic low viscosity medium. The equations for the relaxation rate constants obtained are discussed and the dependence on physical parameters is exploited. Theoretical predictions are compared with experiments when the intermolecular relaxation is due to both protons and deuterons present in the sample. An agreement between experiments and theory of +/-4% was obtained when the physical parameters are estimated from first-principles calculation. PMID- 21663366 TI - Enhanced small-angle scattering connected to the Widom line in simulations of supercooled water. AB - We present extensive simulations on the TIP4P/2005 water model showing significantly enhanced small-angle scattering (SAS) in the supercooled regime. The SAS is related to the presence of a Widom line (T(W)) characterized by maxima in thermodynamic response functions and Ornstein-Zernike correlation length. Recent experimental small-angle x-ray scattering data [Huang et al., J. Chem. Phys. 133, 134504 (2010)] are excellently reproduced, albeit with an increasing temperature offset at lower temperatures. Assuming the same origin of the SAS in experiment and model this suggests the existence of a Widom line also in real supercooled water. Simulations performed at 1000 bar show an increased abruptness of a crossover from dominating high-density (HDL) to dominating low-density (LDL) liquid and strongly enhanced SAS associated with crossing T(W), consistent with a recent determination of the critical pressure of TIP4P/2005 at 1350 bar. Furthermore, good agreement with experimental isothermal compressibilities at 1000, 1500, and 2000 bar shows that the high pressure supercooled thermodynamic behavior of water is well described by TIP4P/2005. Analysis of the tetrahedrality parameter Q reveals that the HDL-LDL structural transition is very sharp at 1000 bar, and that structural fluctuations become strongly coupled to density fluctuations upon approaching T(W). Furthermore, the tetrahedrality distribution becomes bimodal at ambient temperatures, an observation that possibly provides a link between HDL-LDL fluctuations and the structural bimodality in liquid water indicated by x-ray spectroscopic techniques. Computed x-ray absorption spectra are indeed found to show sensitivity to the tetrahedrality parameter. PMID- 21663367 TI - Novel geminate recombination channel after indirect photoionization of water. AB - We studied the photolysis of neat protonated and heavy water using pump-probe and pump-repump-probe spectroscopy. A novel recombination channel is reported leading to ultrafast quenching (0.7 +/- 0.1 ps) of almost one third of the initial number of photo-generated electrons. The efficiency and the recombination rate of this channel are lower in heavy water, 27 +/- 5% and (0.9 +/- 0.1 ps)(-1), respectively. Comparison with similar data measured after photodetachment of aqueous hydroxide provides evidence for the formation of short-lived OH:e(-) (OD:e(-)) pairs after indirect photoionization of water at 9.2 eV. PMID- 21663368 TI - Product energy deposition of CN + alkane H abstraction reactions in gas and solution phases. AB - In this work, we report the first theoretical studies of post-transition state dynamics for reaction of CN with polyatomic organic species. Using electronic structure theory, a newly developed analytic reactive PES, a recently implemented rare-event acceleration algorithm, and a normal mode projection scheme, we carried out and analyzed quasi-classical and classical non-equilibrium molecular dynamics simulations of the reactions CN + propane (R1) and CN + cyclohexane (R2). For (R2), we carried out simulations in both the gas phase and in a CH(2)Cl(2) solvent. Analysis of the results suggests that the solvent perturbations to the (R2) reactive free energy surface are small, leading to product energy partitioning in the solvent that is similar to the gas phase. The distribution of molecular geometries at the respective gas and solution phase variational association transition states is very similar, leading to nascent HCN which is vibrationally excited in both its CH stretching and HCN bending coordinates. This study highlights the fact that significant non-equilibrium energy distributions may follow in the wake of solution phase bimolecular reactions, and may persist for hundreds of picoseconds despite frictional damping. Consideration of non-thermal distributions is often neglected in descriptions of condensed-phase reactivity; the extent to which the present intriguing observations are widespread remains an interesting question. PMID- 21663369 TI - Adhesive transitions in Newton black films: a computer simulation study. AB - We report molecular dynamics simulations of Newton black films (NBFs), ultra thin films of aqueous solutions stabilized with two monolayers of ionic surfactants, sodium dodecyl sulfate. We show that at low water content conditions and areas per surfactant corresponding to experimental estimates in NBFs, homogeneous films undergo an adhesion "transition," which results in a very thin adhesive film coexisting with a thicker film. We identify the adhesive film with the equilibrium structure of the Newton black film. We provide here a direct microscopic view of the formation of these important structures, which have been observed in experimental studies of emulsions and foams. We also report a detailed investigation of the structural properties and interfacial fluctuation spectrum of the adhesive film. Our analysis relies on the definition of an "intrinsic surface," which is used to remove the averaging effect that the capillary waves have on the film properties. PMID- 21663370 TI - Phase behavior of binary symmetric mixtures in pillared slit-like pores: a density functional approach. AB - Density functional approach is applied to study the phase behavior of symmetric binary Lennard-Jones(12,6) mixtures in pillared slit-like pores. Our focus is in the evaluation of the first-order phase transitions in adsorbed phases and lines delimiting mixed and demixed adsorbed phases. The scenario of phase changes is sensitive to the pore width, to the energy of fluid-solid interaction, the amount, and the length of the pillars. Quantitative trends and qualitative changes of the phase diagrams topology are examined depending on the values of these parameters. The presence of pillars provides additional excluded volume effects, besides the confinement due to the pore walls. The effects of attraction between fluid species and pillars counteract this additional confinement. We have observed that both the increasing surface pillar density and the augmenting strength of fluid-solid interactions can qualitatively change the phase diagrams topology for the model with sufficiently strong trends for demixing. If the length of pillars is sufficiently large comparing to the pore width at low temperatures, we observe additional phase transitions of the first and second order due to the symmetry breaking of the distribution of chain segments and fluid species with respect to the slit-like pore center. Re-entrant symmetry changes and additional critical points then are observed. PMID- 21663371 TI - Electrostatic charging and charge transport by hydrated amorphous silica under a high voltage direct current electrical field. AB - This work was initially based on the casual observation of an electrostatic phenomenon, in which particles of amorphous silica were attracted by a dc electrical field. The first observations were recently shown in a communication in this journal. To explain the electrical charge transport process observed in this work, all forces acting on silica particles were estimated and the significant ones were used to formulate a model made up of three elementary steps. Analyzing the experimental observations using this model, it was possible to suggest that electrons can be introduced into and removed from electronic bands of water. PMID- 21663372 TI - Morphological and chemical influences on alumina-supported palladium catalysts active for the gas phase hydrogenation of crotonaldehyde. AB - A series of five alumina-supported palladium catalysts have previously been prepared and characterised by a combination of CO chemisorption and infrared spectroscopy. The reactive attributes of these catalysts are examined using the hydrogenation of crotonaldehyde as a test reaction, using a modified infrared gas cell as a batch reactor. Periodic scanning of the infrared spectrum of the gaseous phase present over the Pd/Al(2)O(3) catalysts was used to construct reaction profiles. Four of the catalysts were able to facilitate a 2-stage hydrogenation process (crotonaldehyde -> butanal -> butanol), whilst one catalyst was totally selective for the first stage hydrogenation process (crotonaldehyde > butanal). Rate coefficients for the first and second stage hydrogenation processes are normalised to the number of surface palladium atoms for the particular catalyst. Correlation of these kinetic parameters as a function of mean particle size indicates the first stage process to be structure insensitive, whilst the second stage hydrogenation is structure sensitive. Chlorine residues associated with the preparative process of one of the catalysts is seen to selectively poison the second stage hydrogenation process for that catalyst. Structure/activity relationships are considered to explain the observed trends. PMID- 21663373 TI - The phase behavior of two-dimensional symmetrical mixtures in a weak external field of square symmetry. AB - Using Monte Carlo simulation methods in the grand canonical and semigrand canonical ensembles, we study the phase behavior of two-dimensional symmetrical binary mixtures of Lennard-Jones particles subjected to a weakly corrugated external field of a square symmetry. It is shown that the both vapor-liquid condensation and demixing transition in the liquid phase are not appreciably affected by a weakly corrugated external field. On the other hand, even a weakly corrugated external field considerably influences the structure of solid phases and the liquid-solid transition. In particular, the solid phases are found to exhibit uniaxially ordered distorted hexagonal structure. The triple point temperature increases with the corrugation of the external field, while the triple point density becomes lower when the surface corrugation increases. The changes in the location of the triple point are shown to lead to the changes of the phase diagram topology. It is also demonstrated that the solid phase undergoes a demixing transition, which is also very slightly affected by the weakly corrugated external potential. The demixing transition in the solid phase is shown to belong to the universality class of the Ising model. PMID- 21663374 TI - Hard sphere fluids at a soft repulsive wall: a comparative study using Monte Carlo and density functional methods. AB - Hard-sphere fluids confined between parallel plates at a distance D apart are studied for a wide range of packing fractions including also the onset of crystallization, applying Monte Carlo simulation techniques and density functional theory. The walls repel the hard spheres (of diameter sigma) with a Weeks-Chandler-Andersen (WCA) potential V(WCA)(z) = 4epsilon[(sigma(w)/z)(12) - (sigma(w)/z)(6) + 1/4], with range sigma(w) = sigma/2. We vary the strength epsilon over a wide range and the case of simple hard walls is also treated for comparison. By the variation of epsilon one can change both the surface excess packing fraction and the wall-fluid (gamma(wf)) and wall-crystal (gamma(wc)) surface free energies. Several different methods to extract gamma(wf) and gamma(wc) from Monte Carlo (MC) simulations are implemented, and their accuracy and efficiency is comparatively discussed. The density functional theory (DFT) using fundamental measure functionals is found to be quantitatively accurate over a wide range of packing fractions; small deviations between DFT and MC near the fluid to crystal transition need to be studied further. Our results on density profiles near soft walls could be useful to interpret corresponding experiments with suitable colloidal dispersions. PMID- 21663375 TI - Intramolecular relaxation dynamics in semiflexible dendrimers. AB - The intramolecular relaxation dynamics of semiflexible dendrimers in dilute solutions are theoretically investigated in the framework of optimized Rouse-Zimm formalism. Semiflexibility is implemented by modeling topological restrictions on the bond directions and orientations of the respective bond-vectors. Based on our recently developed approach for semiflexible dendrimers [A. Kumar and P. Biswas, Macromolecules 43, 7378 (2010)], the mechanical and dielectric relaxation moduli are studied as functions of local flexibility parameters and branching topology. It is rather interesting to observe that semiflexibility affects the local modes of G''(omega) and Deltaepsilon''(omega), which have lower relaxation rate with increasing bond restrictions, while the collective modes with small relaxation rate remain almost constant. The relaxation dynamics of the flexible dendrimer is similar to that of the semiflexible dendrimer with unrestricted bond orientations (Phi = 0) and is flanked by the compressed (Phi = 30 degrees ) and expanded (Phi = 150 degrees ) conformations, respectively. The effect of semiflexibility is typically reflected in the intermediate frequency regime. The expanded conformations of semiflexible dendrimers display a power-law behavior in the intermediate frequency regime for both loss and storage modulus resembling fractal structures, while the compressed and unrestricted bond orientation conformations exhibit an approximately logarithmic dependence. The power-law exponent is found to be similar to the flexible dendrimers with excluded volume interactions. Thus, by tuning Phi, a spectrum of dynamic relaxation pattern is obtained spanning a broad range of conformations from a power-law fractal network to a non-fractal one. In certain limits, this highly generalized model captures the characteristics of flexible dendrimers and also resembles La Ferla's model semiflexible dendrimers. The influence of hydrodynamic interactions reduces the dynamical range and the width of the intermediate domain by decreasing the smaller relaxation rates and increasing the higher relaxation rates correspondingly. PMID- 21663376 TI - Mesophase formation in a system of top-shaped hard molecules: density functional theory and Monte Carlo simulation. AB - We present the phase diagram of a system of mesogenic top-shaped molecules based on the Parsons-Lee density functional theory and Monte Carlo simulation. The molecules are modeled as a hard spherocylinder with a hard sphere embedded in its center. The stability of five different phases is studied, namely, isotropic, nematic, smectic A, smectic C, and columnar phases. The positionally ordered phases are investigated only for the case of parallel alignment. It is found that the central spherical unit destabilizes the nematic with respect to the isotropic phase, while increasing the length of the cylinder has the opposite effect. Also, the central hard sphere has a strong destabilizing effect on the smectic A phase, due the inefficient packing of the molecules into layers. For large hard sphere units the smectic A phase is completely replaced by a smectic C structure. The columnar phase is first stabilized with increasing diameter of the central unit, but for very large hard sphere units it becomes less stable again. The density functional results are in good agreement with the simulations. PMID- 21663377 TI - Correlating anomalous diffusion with lipid bilayer membrane structure using single molecule tracking and atomic force microscopy. AB - Anomalous diffusion has been observed abundantly in the plasma membrane of biological cells, but the underlying mechanisms are still unclear. In general, it has not been possible to directly image the obstacles to diffusion in membranes, which are thought to be skeleton bound proteins, protein aggregates, and lipid domains, so the dynamics of diffusing particles is used to deduce the obstacle characteristics. We present a supported lipid bilayer system in which we characterized the anomalous diffusion of lipid molecules using single molecule tracking, while at the same time imaging the obstacles to diffusion with atomic force microscopy. To explain our experimental results, we performed lattice Monte Carlo simulations of tracer diffusion in the presence of the experimentally determined obstacle configurations. We correlate the observed anomalous diffusion with obstacle area fraction, fractal dimension, and correlation length. To accurately measure an anomalous diffusion exponent, we derived an expression to account for the time-averaging inherent to all single molecule tracking experiments. We show that the length of the single molecule trajectories is critical to the determination of the anomalous diffusion exponent. We further discuss our results in the context of confinement models and the generating stochastic process. PMID- 21663378 TI - The expression and phosphorylation of acid sensing ion channel 1a in the brain of a mouse model of phenylketonuria. AB - The acid-sensing ion channel 1a (ASIC1a) is a proton-gated cation channel enriched in the mammalian brain. Recent studies suggest its diverse roles in ischemic acidosis, neurodegenerative diseases, and cognitive processes. Phenylketonuria (PKU) is the most commonly inherited defect in amino acid metabolism. Many facts make ASIC1a appear to be highly related to PKU. In this study, we explored the effect of PKU on the expression and serine phosphorylation of ASIC1a in a mouse model of PKU, BTBR-Pah(enu2). Genotyping was performed by blood phenylalanine (Phe) determination and gene analysis. ASIC1a mRNA, ASIC1a protein, and serine phosphorylated ASIC1a (pSer-ASIC1a) in the cerebral cortex and hippocampus were detected by real-time polymerase chain reaction (PCR), Western blot, and immunoprecipitation, respectively. The expression of ASIC1a mRNA and protein in the two encephalic regions showed no difference between wild type (WT) and PKU mice. In the hippocampus of the 2-week-old (2W) PKU mice, pSer ASIC1a was increased compared to WT mice. These data suggest that PKU-related brain injury is independent of ASIC1a expression. Serine phosphorylation of ASIC1a, however, may be involved. PMID- 21663379 TI - High mobility group box 1 in cerebrospinal fluid from several neurological diseases at early time points. AB - The present study aimed to elucidate the possible role of High Mobility Group Box 1 (HMGB1), which is a candidate prognostic marker in diseases that combine inflammation and tissue injury, in acute encephalopathy. HMGB1 in cerebrospinal fluid (CSF) obtained on admission from eight children with acute encephalopathy, and 16 children with febrile seizure, eight children with bacterial/aseptic meningitis, and eight children with fever without neurological symptoms were analyzed using enzyme-linked immunosorbent assay (ELISA). We found no increase in HMGB1 in CSF from acute encephalopathy or in CSF from febrile seizure or fever without neurological complications at early time points, while marked elevation of HMGB1 was seen in CSF from bacterial and aseptic meningitis. In conclusion, HMGB1 is a poor disease marker for acute encephalopathy. PMID- 21663380 TI - Association between the MTHFR gene and Alzheimer's disease: a meta-analysis. AB - BACKGROUND: The association between methylenetetrahydrofolate reductase (MTHFR) gene (rs1801133) 677C/T polymorphism and Alzheimer's disease (AD) is controversial. The objective of the study was to investigate the possible association between MTHFR 677C/T polymorphism and AD. METHOD: We performed a meta analysis pooling data from all relevant studies including 3,299 cases and 4,363 controls. We applied a random-effects or fixed-effects model to combine odds ratio (OR) and 95% confidence intervals (95% CI). RESULTS: This meta-analysis demonstrated that the MTHFR T allele or dominant model for T allele (CT + TT) had an increased risk for AD in combined populations (OR, 95% CI: 1.13, 1.05-1.21; 1.18, 1.07-1.31, respectively), and a significant association was found in allele contrast, recessive, and dominant model in Asian populations, but not in Caucasian populations. CONCLUSION: The MTHFR C677T polymorphism is associated with AD in Asian populations, but not in Caucasians. PMID- 21663381 TI - Clinical vignettes in Parkinson's disease: a collection of unusual medication induced hallucinations, delusions, and compulsive behaviours. AB - Hallucinations, delusions, and compulsive behaviors are frequent iatrogenic complications of the treatment of motor dysfunction in Parkinson's disease (PD). Although these have been studied, and the phenomenology described, there are few detailed descriptions of the various psychiatric problems our treated PD patients live with that allow physicians who do not have a great deal of experience with PD patients to appreciate the extent of their altered lives. This report is a compilation of vignettes describing these behavioral problems that the treating neurologist or psychiatrist attributed to the medications used for treating PD. PMID- 21663382 TI - Screening for well-characterized paraneoplastic antineuronal antibodies in multiple sclerosis. AB - Some epidemiological surveys have shown an increased incidence of malignancies in patients with multiple Sclerosis (MS). Furthermore, in rare cases central demyelinating disorders like optic neuritis, encephalomyelitis, and myelitis could be of paraneoplastic origin. Antineuronal antibodies are frequently associated with paraneoplastic neurological syndromes (PNS) but are also described in cancer patients without neurological symptoms. In this study, we retrospectively analyzed sera from 247 patients with MS and clinically isolated syndrome (CIS) for the presence of anti-HuD, Yo, Ri, CV2/CRMP5, Ma2, and amphiphysin antibodies using ELISA employing recombinant onconeural antigens. None of the sera revealed high titers of antineuronal antibodies and only two sera from MS patients show weak reactivity, representing in all probability background activity. Furthermore, cancer incidence in our study is low (0.8%). Our analysis does not support an association between MS and well-characterized paraneoplastic antineuronal antibodies, suggestive of a secondary humoral autoimmune response, underlying latent malignancy, or paraneoplastic origin in our cohort. In reverse, negative screening results in samples of MS patients confirm the high specificity of these antibodies for PNS. PMID- 21663383 TI - Study of methylation levels of parkin gene promoter in Parkinson's disease patients. AB - Mutations in the parkin gene have been significantly linked to autosomal recessive juvenile parkinsonism (ARJP). In addition to its association with ARJP, loss of heterozygosity of parkin has been found in several types of malignant tumors, including ovarian, breast, and hepatocellular tumors. Abnormal methylation of parkin promoter was observed in patients with acute lymphoblastic leukemia and chronic myelogenous leukemia in lymphoid blast crisis. We hypothesized that hypermethylation of the parkin promoter might reduce the expression of parkin, which would contribute to the pathogenesis of parkinson's disease (PD) in idiopathic patients and parkin heterozygotes. In this study, we analyzed samples from 17 PD patients with heterozygous parkin mutations, 17 PD patients without parkin mutations, and 10 normal controls. We determined the levels of methylation of the parkin gene promoter in each group using bisulfite genomic sequencing of a region containing 33 CpG sites in the CpG island of the parkin promoter. The methylation levels indicated hypomethylation, and there were no significant differences in the incidence of CpG site methylation among three groups (P > 0.05). These results suggest that the methylation mechanism is unlikely to play a role in the pathogenesis and development of PD. PMID- 21663384 TI - Live imaging of axon stretch growth in embryonic and adult neurons. AB - Strategies for nervous system repair arise from knowledge of growth mechanisms via a growth cone. The distinctive process of axon stretch growth is a robust, long-term growth that may reveal new pathways to accelerate nerve repair. Here, a live imaging bioreactor was engineered to closely explore cellular events initiated by applied tension. The stretch growth potential between adult and embryonic dorsal root ganglion (DRG) neurons was investigated, an important difference in nerve repair. Embryonic axons were capable of unidirectional stretch growth rates of 4?mm/d and reliably reached 4?cm in length within 2 weeks. Adult axons could only reach 2?mm/d and took over 3 weeks to reach 4?cm. Utilizing time-lapse imaging, we observed growth cone motility in coordination with stretch growth. Upon initiation of stretching, growth cones retracted. However, within 10?h of continuous stretching, growth cones extended at a rate of 0.2?mm/d opposite the direction of applied tension, contributing to overall axon elongation. We analyzed fast mitochondrial transport under increasing levels of strain to determine the effect of stretch on axonal transport. Transport began to diminish at 24% strain, and was almost completely absent at 39% strain. Surprisingly, axons recovered and were capable of subsequent stretch growth. When tension was completely released (?5% strain), stretch grown axons retracted at rates up to 6.1??m/sec and slowed as resting tension was restored. This ability to assess the process of axon stretch growth in real time will allow detailed study of how tension can be used to drive axonal growth and retraction. PMID- 21663385 TI - Evaluation of quality of care in a large Saudi Hemodialysis Center (Prince Salman Center for Kidney Diseases, Riyadh, KSA). AB - INTRODUCTION: The quality of care provided to dialysis patients is under increasing scrutiny and systematic measurements of clinical performance, relying on indicators such as levels of Kt/V, hemoglobin, and serum albumin, have been implemented. METHODS: In this retrospective study we revised clinical and laboratory data of 146 chronic hemodialysis (HD) patients who met our inclusion criteria in the dialysis unit at Prince Salman Center for Kidney Diseases for a whole year - 2009. This study looked at the extent of adherence to the kidney diseases outcome quality initiative kidney diseases outcome quality initiative (K/DOQI), Centers for Disease Control and Prevention guidelines for prevention of transmission of infections among HD patients, and American Association of Medical Instrumentation standards for dialysis water quality. RESULTS: A total of 146 HD patients (54.8% males and 45.2% females) were included in this study with mean age 51.21 +/- 15.33 years. About 97.94% of cases had thrice-weekly sessions. An arteriovenous fistula was the vascular access in 78.1% of cases, and a permanent catheter was used in 21.9%. The mean predialysis blood pressure was <=140/90 in 91.8% of cases. The mean hemoglobin level was 11.44 +/- 1.46 g/dL in prevalent HD patients; 79.45% of cases had a hemoglobin level >=11 g/dL. The mean serum albumin level was 33.53 +/- 4.02 g/L; only 31.33% of cases had serum albumin >=35 g/L. The mean parathormone level was 34.35 +/- 28.70 pmol/L; 43.0% of patients had the target range (16.5-33 pmol/L), and the mean calcium level was 2.17 mmol/L; 89.73% of cases had the target range (2.12-2.52 mmol/L) while the mean serum phosphorus level was 1.46 mmol/L; 83.56% of patients had the target range (0.81-1.78 mmol/L). The Ca * Pi product was <=4.5 in 83.56% of cases. The mean Kt/V value was 1.45 +/- 0.18 in prevalent HD patients (98.63% and 60.96% of cases had Kt/V >=1.2 and >= 1.4, respectively). All patients were negative for HIV serology test while the prevalence of hepatitis C virus-positive and hepatitis B virus-positive patients was 24.7% and 4.1%, respectively. All patients (except hepatitis B virus positive) were vaccinated against hepatitis B virus. The annual mortality rate was 5.67%. CONCLUSION: Our study revealed an excellent quality of care for HD patients in the field of vascular access care, hemoglobin level, blood pressure control, and dialysis adequacy. On the other hand, this study showed the need for improving the nutritional status of patients through more dietary counseling, nutritional education, and early management for nutritional problems. PMID- 21663386 TI - Inorganic phosphorus homeostasis during the first hour of dialysis. AB - BACKGROUND/AIM: Hyperphosphatemia is a well-recognized complication of chronic kidney disease, and phosphorus kinetics during hemodialysis (HD) remains a vague area of investigation. We studied the inorganic phosphorus homeostasis during the first hour of an HD session. MATERIALS/METHODS: Twelve patients were studied twice, in two consecutive HD sessions. Total (TPR), extracellular (EPR), and intracellular (IPR) phosphorus mass removal was determined using the direct dialysate quantification (DDQ) method. Alterations of serum inorganic phosphorus (sP), erythrocyte intracellular phosphorus (P(ERY)), and 2,3-diphosphoglycerate (2,3-DPG) concentrations were measured before HD initiation and at 1, 2, 3, 4, 5, 10, 30, and 60 min. RESULTS: The contribution of IPR to TPR was negative in the first 10 min of both HD sessions (-27.2 +/- 6.5 and -26.4 +/- 58 mmol, respectively, p = ns) while the contribution of the IPR to TPR increased as the time elapsed. Intracellular phosphorus and 2,3-DPG remained almost unchanged during the 60 min of HD session. CONCLUSIONS: Unchanged P(ERY) concentration during the first hour of an HD session does not reject the hypothesis of a simultaneous efflux and influx of phosphorus from/to intracellular compartment. PMID- 21663387 TI - Prognostic factors and therapy assessment of IgA nephropathy: report from a single unit in iran. AB - BACKGROUND: Immunoglobulin A (IgA) nephropathy is the most common cause of primary glomerulonephritis with slow progression to end-stage renal disease (ESRD) in up to 40% of patients. METHODS: A retrospective cohort study of patients with biopsy-proven IgA nephropathy was performed in our center from 1998 to 2009. We tried to determine the clinical and pathological factors which affect patients progressing to ESRD. We also compared the impact of renin-angiotensin system (RAS) blockers therapy alone or in combination with prednisone on baseline proteinuria and glomerular filtration rate (GFR) after 6 months of treatment in patients with proteinuria>1 g/d and GFR>30 mL/min. RESULTS: There were 70 IgA nephropathy patients of whom 46 were men. The average age of patients at biopsy was 39 +/- 12.1 years. During the median 23.5 (6-130) months of follow-up, 10 patients progressed to ESRD and no patient died. Five-year renal survival following biopsy was 88%. By multivariate analysis, age more than 50 years (p = 0.003) and baseline serum creatinine level (p = 0.012) were independent predictors of progressing to ESRD and poor prognosis. Although there was no significant difference in proteinuria reduction after 6 months of treatment, kidney function was less preserved in RAS inhibitors therapy alone than in the combination treatment with prednisone. CONCLUSION: We showed that late diagnosis of patients with IgA nephropathy might be associated with poor outcome. Our results also suggest that addition of prednisone to RAS blockers may lead to better preservation of kidney function. PMID- 21663388 TI - The comparison of cardiac biomarkers positivities in hemodialysis patients without acute coronary syndrome. AB - AIM: We aimed to compare heart-type fatty acid-binding proteins (H-FAB) and other cardiac biomarkers to determine the most reliable cardiac marker in hemodialysis (HD) patients without acute coronary syndrome (ACS). MATERIALS AND METHODS: Sixty HD patients without ACS were included the study. Blood samples were taken before HD session for measurement of H-FAB, troponin I, troponin T, creatine kinase-MB (CK-MB) isoforms. RESULTS: Mean age of patients was 55 +/- 15 years. Males were 55%. Mean serum level of blood urea nitrogen was 75 +/- 15 mg/dL, mean serum level of creatinine was 8.3 +/- 2.5 mg/dL, mean serum level of hematocrit was 33 +/- 5%, mean ejection fraction was 54 +/- 9%, and mean left ventricular mass index (LVMI) was 136 +/- 54 g/m(2). H-FAB was positive in 32%, troponin T in 20%, troponin I in 12%, and CK-MB in 5% of all patients. Three or four of all parameters were not positive together in any patient. While 5% of patients had positive troponin T with H-FAB, 3% of patients had positive troponin T with troponin I and 2% of patients had positive troponin I with H-FAB. CONCLUSION: Our study found that CK-MB had the lowest positivity in the HD patients without ACS. H-FAB had the highest rate of positivity in all markers. If only one marker is assessed it should be CK-MB. But using two parameters in HD patients in ACS diagnosis increases the reliability of diagnosis. If we use two biomarkers it should be CK-MB and troponin I. PMID- 21663390 TI - Bilateral renal hypoplasia and cystic dysplasia: a new phenotype of Thomas syndrome or a new syndrome? AB - Thomas syndrome is a rare syndrome including Potter sequence, renal anomalies, heart defects, cleft palate with other oropharyngeal anomalies. Here, we report a newborn with Potter sequence, bilateral renal hypoplasia and cystic dysplasia, multiple cardiovascular malformations, long large ears, frontal bossing, small lips, partial simple toe syndactyly, and cleft palate. To our best knowledge, this patient may be considered as a new variant of Thomas syndrome or a new syndrome. PMID- 21663389 TI - Effect of 5/6 nephrectomized rat serum on epithelial-to-mesenchymal transition in vitro. AB - OBJECTIVE: To investigate whether the 5/6 nephrectomized (5/6Nx) rats' 12-week serum could lead to tubular epithelial-to-mesenchymal transition (EMT) and its molecular mechanism, so as to probe the potential stimulation from circulation in chronic progressive kidney disease. METHODS: A total of 24 Sprague Dawley (SD) rats were randomly divided into two groups: sham operation group (sham group) and 5/6Nx group. Rats were killed 12 weeks after surgery to obtain 5/6Nx rats' 12 week serum. Then we detected the expression of E-cadherin in renal tubular epithelial cells of the remaining kidney and we investigated whether the 12th week serum of 5/6Nx rats could cause HK-2 (human kidney proximal tubular cell line) cells to transdifferentiate into fibroblasts. RESULTS: Our data confirmed that E-cadherin expression decreased significantly in the remaining kidney at 12 weeks, and the 5/6Nx rats' 12-week serum could suppress E-cadherin protein and mRNA expression (p < 0.05). We also found that the 5/6Nx rats' 12-week serum could upregulate ZEB1, beta-catenin, and wnt3 protein expression (p < 0.05). CONCLUSIONS: Our results demonstrated that the 5/6Nx rats' 12-week serum could suppress the expression of E-cadherin in HK-2 cells. It was partially through modulating the increase of ZEB1. The loss of E-cadherin could lead beta-catenin to localize to the cytoplasm and nucleus, and feed into the Wnt signaling pathway. It means that the pathogenic serum in chronic kidney disease (CKD) plays an important role in the loss of renal function and turns to be a new avenue of research with potential clinical implications. PMID- 21663391 TI - Is there differences in cognitive and motor functioning between hemodialysis and peritoneal dialysis patients? AB - OBJECTIVE: Change in cognitive function is one of the well-known consequences of the end-stage renal disease (ESRD). The aim of this study was to determine the effect of hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) on cognitive and motor functions. METHODS: In this cross-sectional study, cognitive and motor functions were investigated in a selected population of 42 patients with ESRD (22 patients on chronic HD and 20 patients on CAPD, aged 50.31 +/- 11.07 years). Assessment of cognitive and motor functions was performed by Symbol Digit Modalities Test (SDMT) and Complex Reactiometer Drenovac (CRD series), a battery of computer-generated psychological tests to measure simple visual discrimination of signal location, short-term memory, simple convergent visual orientation, and convergent thinking. RESULTS: The statistically significant difference in cognitive-motor functions between HD and CAPD patients was not found in any of the time-related parameters in all CRD-series tests or SDMT score. Higher serum levels of albumin, creatinine, and calcium were correlated with better cognitive-motor performance among all patients regardless of dialysis modality. The significant correlation between ultrafiltration rate per HD and short-term memory actualization test score (CRD-324 MT) among HD patients was found (r = 0.434, p = 0.025). CONCLUSION: This study has demonstrated that well-nourished and medically stable HD and CAPD patients without clinical signs of dementia or cognitive impairment and without significant difference in age and level of education performed all tests of cognitive-motor abilities without statistically significant difference. PMID- 21663392 TI - Isoenzyme A and urinary N-acetyl-beta-D-glucosaminidase activity in normal pregnancy. AB - OBJECTIVES: Urinary N-acetyl-beta-d-glucosaminidase (NAG) activity has been found to increase during normal uncomplicated pregnancy and such behavior could limit the diagnostic value of this enzyme for detection of subclinical tubular injury. The aim of this study was to evaluate urinary NAG activity and isoenzyme A in normal pregnant women at 30th week of pregnancy and in healthy women, to discriminate between physiological and lesional enzymuria. DESIGN AND METHODS: Enzyme activities in first morning fasting urine samples from 20 nonpregnant control and 20 normal pregnant women at 30th gestational week were evaluated by fluorometric methods. RESULTS: Both total and isoenzyme A activity was significantly higher ( p < 0.01) in urines of normal pregnant women compared with control urines, whereas ratio between these two parameters was significantly lower ( p < 0.001). CONCLUSIONS: The increase of urinary NAG activity during normal uncomplicated pregnancy appears to be characterized by a prevalent increase in isoenzyme A form, a finding associated with functional (not lesional) enzymuria. The fluorometric assays may represent a simple and rapid method to evaluate whether increase in urinary NAG activity represents a renal physiological adaptation during pregnancy. PMID- 21663393 TI - Differential mechanisms of x-ray-induced cell death in human endothelial progenitor cells isolated from cord blood and adults. AB - Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells that circulate at low concentration in human umbilical cord and adult peripheral blood and are largely resident in blood vessels. ECFCs not only appear to be critical for normal vascular homeostasis and repair but may also contribute to tumor angiogenesis and response to therapy. To begin to characterize the potential role of ECFCs during the treatment of tumors in children and adults with radiation, we characterized the X-ray sensitivity of cord and adult blood-derived ECFCs. We found both cord blood and adult ECFCs to be highly radiation sensitive (3 Gy resulted in >90% killing without induction of apoptosis). The X-ray survival curves suggested reduced potential for repair capacity, but X-ray fractionation studies demonstrated that all the ECFCs exhibited repair when the radiation was fractionated. Finally, the mechanisms of X-ray-induced cell death for cord blood and adult ECFCs were different at low and high dose. At low dose, all ECFCs appear to die by mitotic death/catastrophe. However, at high radiation doses (>= 10 Gy) cord blood ECFCs underwent p53 stabilization and Bax-dependent apoptosis as well as p21-dependent G1 and G2/M cell cycle checkpoints. By contrast, after 10 Gy adult ECFCs undergo only large-scale radiation-induced senescence, which is a cellular phenotype linked to premature development of atherosclerosis and vasculopathies. These data demonstrate that the ECFC response to radiation is dose-dependent and developmentally regulated and may provide potential mechanistic insight into their role in tumor and normal tissue response after ionizing radiation treatment. PMID- 21663395 TI - L-arginine mitigates radiation-induced early changes in cardiac dysfunction: the role of inflammatory pathways. AB - Our earlier studies demonstrated the ability of L-arginine (L-Arg) to reverse radiation-induced immune dysfunction. The aim of the present study was to investigate cardiac dysfunction up to 24 h after 2 Gy of total-body irradiation (TBI) and its mitigation by L-Arg. The current studies also explore the association of radiation-induced inflammation and electrocardiographic (ECG) abnormalities. TBI-induced cardiac iNOS and kinin B1 R, changes in the ECG profile like bradycardia, increased RR interval, ST elevation and increased QRS duration at 4 h and 24 h after TBI. TBI with 2 Gy induced inflammatory responses in spleen and cardiac tissue. L-Arg administered 2 h after TBI (TBI+L-Arg) mitigated the entire inflammatory response and ECG profile toward normalcy. L-Arg administered just before TBI (L-Arg +TBI) could not reverse the above-mentioned changes. Radiation-induced inflammatory responses at +4 h and +24 h after TBI in spleen and cardiac tissue correlated with the changes in ECG profile at the corresponding time. The results suggest the ability of L-Arg administered at the correct therapeutic window to mitigate radiation-induced cardiac dysfunction at 4 and 24 h after TBI. PMID- 21663394 TI - A novel bioluminescence orthotopic mouse model for advanced lung cancer. AB - Lung cancer is the leading cause of cancer-related death in the United States despite recent advances in our understanding of this challenging disease. An animal model for high-throughput screening of therapeutic agents for advanced lung cancer could help promote the development of more successful treatment interventions. To develop our orthotopic lung cancer model, luciferase-expressing A549 cancer cells were injected into the mediastinum of athymic nude mice. To determine whether the model would allow easy monitoring of response to therapeutic interventions, tumors were treated with 30 mg/kg Paclitaxel or were irradiated with 5 fractions of 2 Gy, and tumor burden was monitored using bioluminescence imaging. Evidence of radiation-induced lung injury was assessed using immunohistochemical staining for phospho-Smad2/3 and cleaved caspase-3. We found that tumor implantation recapitulated advanced human lung cancer as evidenced by tumor establishment and proliferation within the mediastinum. The tumor responded to Paclitaxel or radiation as shown by decreased tumor bioluminescence and improved overall survival. Immunohistochemistry revealed increased phospho-Smad2/3 and cleaved caspase-3 in irradiated lungs, consistent with radiation-induced lung injury. This orthotopic lung cancer model may help provide a method to assess therapeutic interventions in a preclinical setting that recapitulates locally advanced lung cancer. PMID- 21663396 TI - The role of radiation quality in the stimulation of intercellular induction of apoptosis in transformed cells at very low doses. AB - An important stage in tumorigenesis is the ability of precancerous cells to escape natural anticancer signals. Apoptosis can be selectively induced in transformed cells by neighboring normal cells through cytokine and ROS/RNS signaling. The intercellular induction of apoptosis in transformed cells has previously been found to be enhanced after exposure of the normal cells to very low doses of both low- and high-LET ionizing radiation. Low-LET ultrasoft X rays with a range of irradiation masks were used to vary both the dose to the cells and the percentage of normal cells irradiated. The results obtained were compared with those after alpha-particle irradiation. The intercellular induction of apoptosis in nonirradiated src-transformed 208Fsrc3 cells observed after exposure of normal 208F cells to ultrasoft X rays was similar to that observed for gamma rays. Intercellular induction of apoptosis was stimulated by irradiation of greater than 1% of the nontransformed 208F cells and increased with the fraction of cells irradiated. A maximal response was observed when ~10-12% of the cells were irradiated, which gave a similar response to 100% irradiated cells. Between 1% and 10%, high-LET alpha particles were more effective than low-LET ultrasoft X rays in stimulating intercellular induction of apoptosis for a given fraction of cells irradiated. Scavenger experiments show that the increase in intercellular induction of apoptosis results from NO(*) and peroxidase signaling mediated by TGF-beta. In the absence of radiation, intercellular induction of apoptosis was also stimulated by TGF-beta treatment of the nontransformed 208F cells prior to coculture; however, no additional increase in intercellular induction of apoptosis was observed if these cells were also irradiated. These data suggest that the TGF-beta-mediated ROS/RNS production reaches a maximum at low doses or fluences of particles, leading to a plateau in radiation-stimulated intercellular induction of apoptosis at higher doses. PMID- 21663397 TI - A single dose of an inhibitor of cyclooxygenase 2, meloxicam, administered shortly after irradiation increases survival of lethally irradiated mice. AB - This study extends earlier findings of the authors demonstrating that meloxicam, a selective inhibitor of cyclooxygenase 2, supports hematopoietic recovery in sublethally irradiated mice and is radioprotective when given before irradiation. We report here that when meloxicam was administered in a single dose 1 h after a lethal 9-Gy whole-body dose, an increased 30-day survival was achieved. Additional studies showed that administration of meloxicam 24 h after lethal irradiation is ineffective and its repeated administration deleterious. Possible mechanisms of the therapeutic effects of meloxicam administered early after irradiation are discussed. PMID- 21663398 TI - Geldanamycin analog 17-DMAG limits apoptosis in human peripheral blood cells by inhibition of p53 activation and its interaction with heat-shock protein 90 kDa after exposure to ionizing radiation. AB - Exposure to ionizing radiation induces p53, and its inhibition improves mouse survival. We tested the effect of 17-dimethylamino-ethylamino-17 demethoxygeldanamycin (17-DMAG) on p53 expression and function after radiation exposure. 17-DMAG, a heat-shock protein 90 (Hsp90) inhibitor, protects human T cells from ionizing radiation-induced apoptosis by inhibiting inducible nitric oxide synthase (iNOS) and subsequent caspase-3 activation. Using ex vivo human peripheral blood mononuclear cells, we found that ionizing radiation increased p53 accumulation, acute p53 phosphorylation, Bax expression and caspase-3/7 activation in a radiation dose- and time postirradiation-dependent manner. 17 DMAG inhibited these increases in a concentration-dependent manner (IC(50) = 0.93 +/- 0.01 uM). Using in vitro models, we determined that inhibition of p53 by genetic knockout resulted in lower levels of caspase-3/7 activity 1 day after irradiation and enhanced survival at 10 days. Analysis of p53-Hsp90 interaction in ex vivo cell lysates indicated that the binding between the two molecules occurred after irradiation but 17-DMAG prevented the binding. Taken together, these results suggest the presence of p53 phosphorylation and Hsp90-dependent p53 stabilization after acute irradiation. Hsp90 inhibitors such as 17-DMAG may prove useful with radiation-based cancer therapy as well as for general radioprotection. PMID- 21663399 TI - Toward a convergence of regenerative medicine, rehabilitation, and neuroprosthetics. AB - No effective therapeutic interventions exist for severe neural pathologies, despite significant advances in regenerative medicine, rehabilitation, and neuroprosthetics. Our current hypothesis is that a specific combination of tissue engineering, pharmacology, cell replacement, drug delivery, and electrical stimulation, together with plasticity-promoting and locomotor training (neurorehabilitation) is necessary to interact synergistically in order to activate and enable all damaged circuits. We postulate that various convergent themes exist among the different therapeutic fields. Therefore, the objective of this review is to highlight the convergent themes, which we believe have a common goal of restoring function after neural damage. The convergent themes discussed in this review include modulation of inflammation and secondary damage, encouraging endogenous repair/regeneration (using scaffolds, cell transplantation, and drug delivery), application of electrical fields to modulate healing and/or activity, and finally modulation of plasticity. PMID- 21663400 TI - Alkaline phosphatase based amperometric biosensor immobilized by cysteamine glutaraldehyde modified self-assembled monolayer. AB - Alkaline phosphatase (ALP) was immobilized with cross-linking agents glutaraldehyde and cysteamine by forming a self-assembled monolayer on a screen printed gold electrode. ALP converts p-nitrophenyl phosphate to p-nitrophenol and phosphate. p-Nitrophenol loses H(+) ion and turns into the negatively charged compound p-nitrophenolate at medium pH. As a result, the unstable product formed is measured chronoamperometrically at an application potential of + 0.95 V. The biosensor response depends linearly on p-nitrophenyl phosphate concentration between 0.05 - 0.6 mM with a response time of 40 seconds. Detection limit of the biosensor is 0.033 mM. PMID- 21663401 TI - Using biogenic sulfur gases as remotely detectable biosignatures on anoxic planets. AB - We used one-dimensional photochemical and radiative transfer models to study the potential of organic sulfur compounds (CS(2), OCS, CH(3)SH, CH(3)SCH(3), and CH(3)S(2)CH(3)) to act as remotely detectable biosignatures in anoxic exoplanetary atmospheres. Concentrations of organic sulfur gases were predicted for various biogenic sulfur fluxes into anoxic atmospheres and were found to increase with decreasing UV fluxes. Dimethyl sulfide (CH(3)SCH(3), or DMS) and dimethyl disulfide (CH(3)S(2)CH(3), or DMDS) concentrations could increase to remotely detectable levels, but only in cases of extremely low UV fluxes, which may occur in the habitable zone of an inactive M dwarf. The most detectable feature of organic sulfur gases is an indirect one that results from an increase in ethane (C(2)H(6)) over that which would be predicted based on the planet's methane (CH(4)) concentration. Thus, a characterization mission could detect these organic sulfur gases-and therefore the life that produces them-if it could sufficiently quantify the ethane and methane in the exoplanet's atmosphere. PMID- 21663402 TI - Pathological effects and motor response threshold changes following radiofrequency application at various distances from the L-5 nerve root: an experimental study. AB - OBJECT: Radiofrequency (RF) ablation is a minimally invasive technique often used percutaneously in the treatment of many conditions such as spasticity, pain, and osteoid osteoma. The purpose of this study was to assess the value of motor response threshold (MRT) as an indirect indicator of the RF generator's electrode to nerve distance, and to evaluate the effects of RF at various distances from a nervous structure. METHODS: The L-5 nerve root was studied in 102 Sprague-Dawley rats (sham contralateral side). Motor response thresholds at 0, 2, 4, 5, and 6 mm from the nerve root were assessed before and after RF application for 2 minutes at 80 degrees C on Days 0 and 7. Radiofrequency was applied 0, 2, 4, 5, and 6 mm away from L-5 and with the addition of interposed cortical bone. The effects of RF application on MRT were studied, and subsequent nerve injury was evaluated using light microscopy pathological examination. RESULTS: There is a significant correlation between MRT and the distance between the electrode tip and L-5, with MRT less than 0.5 V when the electrode was in direct contact with the root. Electrical and pathological changes following RF application were more pronounced at 0 mm, with worsening seen on Day 7. Radiofrequency at 2 and 4 mm produced fewer electrical and histological deleterious effects on the nerve on Days 0 and 7, with an obvious improvement on Day 7. At 5 mm, electrical and histological abnormalities were minimal on Day 0 and were fully reversible on Day 7. At 6 mm and with interposed cortical bone, MRT and pathological findings were unchanged on Days 0 and 7. CONCLUSIONS: The MRT proved to be a useful and reliable tool in decreasing nerve morbidity following RF ablation in animals and may be used in humans for the same purpose. It serves as an indirect indicator of the proximity of the RF generator's electrode tip to any adjacent motor nervous structure. A minimum safe distance of 5 mm between the electrode tip and the nerve is required to avoid irreversible nerve injury, unless a bony wall is interposed between them, thus serving as a nerve shield. In medical conditions that require RF ablation of the nerve, such as spasticity and pain, the MRT must be lower than 0.5 V. When a nerve lesion is to be avoided such as in cases of osteoid osteoma, an MRT higher than 2.5 V is considered safe, reflecting a distance greater than 5 mm. PMID- 21663403 TI - Repair of the injured human spinal cord. PMID- 21663404 TI - A rare intraosseous arteriovenous malformation of the spine. AB - The authors report the case of a patient with an intraosseous spinal arteriovenous malformation (AVM) presenting as an epidural mass lesion that was causing spinal cord compression. The 59-year-old woman had bilateral numbness, weakness, and hyperreflexia of both legs. Magnetic resonance imaging revealed intermediate T1 signal and hyperintense T2 signal involving the right transverse process, bilateral pedicles, and T-5 spinous process; the lesion's epidural extension was causing severe canal compromise and cord displacement. Coil embolization was performed, and the patient underwent resection, after which preoperative symptoms improved. Histopathological analysis revealed a benign vascular proliferation consistent with an intraosseous spinal AVM. On review of the literature, the authors found this case to be the second intraosseous spinal AVM, and the first in a patient whose clinical presentation was consistent with that of a mass lesion of the bone. PMID- 21663407 TI - Blood supply and vascular reactivity of the spinal cord under normal and pathological conditions. AB - The authors present a review of spinal cord blood supply, discussing the anatomy of the vascular system and physiological aspects of blood flow regulation in normal and injured spinal cords. Unique anatomical functional properties of vessels and blood supply determine the susceptibility of the spinal cord to damage, especially ischemia. Spinal cord injury (SCI), for example, complicating thoracoabdominal aortic aneurysm repair is associated with ischemic trauma. The rate of this devastating complication has been decreased significantly by instituting physiological methods of protection. Traumatic SCI causes complex changes in spinal cord blood flow, which are closely related to the severity of injury. Manipulating physiological parameters such as mean arterial blood pressure and intrathecal pressure may be beneficial for patients with an SCI. Studying the physiopathological processes of the spinal cord under vascular compromise remains challenging because of its central role in almost all of the body's hemodynamic and neurofunctional processes. PMID- 21663406 TI - Acidic fibroblast growth factor for repair of human spinal cord injury: a clinical trial. AB - OBJECT: The study aimed to verify the safety and feasibility of applying acidic fibroblast growth factor (aFGF) with fibrin glue in combination with surgical neurolysis for nonacute spinal cord injury. METHODS: This open-label, prospective, uncontrolled human clinical trial recruited 60 patients with spinal cord injuries (30 cervical and 30 thoracolumbar). The mean patient age was 36.5 +/- 15.33 (mean +/- SD) years, and the male/female ratio was 3:1. The mean time from injury to treatment was 25.7 +/- 26.58 months, and the cause of injury included motor vehicle accident (26 patients [43.3%]), fall from a height (17 patients [28.3%]), sports (4 patients [6.7%]), and other (13 patients [21.7%]). Application of aFGF with fibrin glue and duraplasty was performed via laminectomy, and an adjuvant booster of combined aFGF and fibrin glue (2 ml) was given at 3 and 6 months postsurgery via lumbar puncture. Outcome measurements included the American Spinal Injury Association (ASIA) motor scores, sensory scores, impairment scales, and neurological levels. Examination of functional independence measures, visual analog scale, MR imaging, electrophysiological and urodynamic studies, hematology and biochemistry tests, tumor markers, and serum inflammatory cytokines were all conducted. All adverse events were monitored and reported. Exclusions were based on refusal, unrelated adverse events, or failure to participate in the planned rehabilitation. RESULTS: Forty-nine patients (26 with cervical and 23 with thoracolumbar injuries) completed the 24-month trial. Compared with preoperative conditions, the 24-month postoperative ASIA motor scores improved significantly in the cervical group (from 27.6 +/- 15.55 to 37.0 +/- 19.93, p < 0.001) and thoracolumbar group (from 56.8 +/- 9.21 to 60.7 +/- 10.10, p < 0.001). The ASIA sensory scores also demonstrated significant improvement in light touch and pinprick in both groups: from 55.8 +/- 24.89 to 59.8 +/- 26.47 (p = 0.049) and 56.3 +/- 23.36 to 62.3 +/- 24.87 (p = 0.003), respectively, in the cervical group and from 75.7 +/- 15.65 to 79.2 +/- 15.81 (p < 0.001) and 78.2 +/- 14.72 to 82.7 +/- 16.60 (p < 0.001), respectively, in the thoracolumbar group. At 24-month follow-up, the ASIA impairment scale improved significantly in both groups (30% cervical [p = 0.011] and 30% thoracolumbar [p = 0.003]). There was also significant improvement in neurological level in the cervical (from 5.17 +/- 1.60 to 6.27 +/- 3.27, p = 0.022) and thoracolumbar (from 18.03 +/- 4.19 to 18.67 +/- 3.96, p = 0.001) groups. The average sum of motor items in functional independence measure also had significant improvement in both groups (p < 0.05). The walking/wheelchair locomotion subscale showed increased percentages of patients who were ambulatory (from 3.4% to 13.8% and from 17.9% to 35.7% in the cervical and thoracolumbar groups, respectively). There were no related adverse events. CONCLUSIONS: The use of aFGF for spinal cord injury was safe and feasible in the present trial. There were significant improvements in ASIA motor and sensory scale scores, ASIA impairment scales, neurological levels, and functional independence measure at 24 months after treatment. Further large scale, randomized, and controlled investigations are warranted to evaluate the efficacy and long-term results. PMID- 21663408 TI - Evolution of IL4 and pathogen antagonism. AB - Interleukin-4 (IL4) is a pleiotropic cytokine involved in host protection from gastrointestinal nematodes. Here, we review the structure, function, and evolutionary history of IL4. Cumulative evidence indicates that over 100 million years of eutherian mammalian evolution, IL4 has experienced multiple episodes of positive selection. We argue that IL4 may have evolved in conflict with pathogen derived antagonists, and therefore diversified to escape antagonism while being constrained to maintain binding to its cellular receptors. Selective pressure driving IL4 diversification may have arisen from ancient episodes of conflict with parasitic worm-derived IL4 antagonists. Descendants of such antagonists may still equip the armamentarium of contemporary gastrointestinal nematodes. PMID- 21663409 TI - Tracking accuracy of T2- and diffusion-weighted magnetic resonance imaging for infusate distribution by convection-enhanced delivery. AB - OBJECT: Because convection-enhanced delivery relies on bulk flow of fluid in the interstitial spaces, MR imaging techniques that detect extracellular fluid and fluid movement may be useful for tracking convective drug distribution. To determine the tracking accuracy of T2-weighted and diffusion-weighted MR imaging sequences, the authors followed convective distribution of radiolabeled compounds using these imaging sequences in nonhuman primates. METHODS: Three nonhuman primates underwent thalamic convective infusions (5 infusions) with (14)C-sucrose (MW 342 D) or (14)C-dextran (MW 70,000 D) during serial MR imaging (T2- and diffusion-weighted imaging). Imaging, histological, and autoradiographic findings were analyzed. RESULTS: Real-time T2- and diffusion-weighted imaging clearly demonstrated the region of infusion, and serial images revealed progressive filling of the bilateral thalami during infusion. Imaging analysis for T2- and diffusion-weighted sequences revealed that the tissue volume of distribution (Vd) increased linearly with volume of infusion (Vi; R(2) = 0.94, R(2) = 0.91). Magnetic resonance imaging analysis demonstrated that the mean +/- SD Vd/Vi ratios for T2-weighted (3.6 +/- 0.5) and diffusion-weighted (3.3 +/- 0.4) imaging were similar (p = 0.5). While (14)C-sucrose and (14)C-dextran were homogeneously distributed over the infused region, autoradiographic analysis revealed that T2 weighted and diffusion-weighted imaging significantly underestimated the Vd of both (14)C-sucrose (mean differences 51.3% and 52.3%, respectively; p = 0.02) and (14)C-dextran (mean differences 49.3% and 59.6%; respectively, p = 0.001). CONCLUSIONS: Real-time T2- and diffusion-weighted MR imaging significantly underestimate tissue Vd during convection-enhanced delivery over a wide range of molecular sizes. Application of these imaging modalities may lead to inaccurate estimation of convective drug distribution. PMID- 21663410 TI - Recurrent idiopathic perimesencephalic subarachnoid hemorrhage. AB - Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSAH) is a benign variant of SAH defined by clinical symptoms of SAH, a characteristic pattern of extravasated blood on noncontrast CT, and negative findings on cerebral angiography. This syndrome carries a favorable prognosis with reportedly no risk of recurrent hemorrhage. The authors present the case of a 62-year-old man with no significant medical history who experienced recurrent, spontaneous episodes of PNSAH within the course of 5 months. No precipitating causes were identified, but the patient had been involved in exertional activities preceding both events. To the authors' knowledge, this is the first conclusive report of recurrent, idiopathic PNSAH. The findings suggest that while the risk of recurrent hemorrhage in the setting of PNSAH is far less than that for aneurysmal SAH, rebleeding can still occur. The authors speculate on the etiology of this rare phenomenon. PMID- 21663411 TI - Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology. AB - OBJECT: The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high grade glioblastoma from low-grade pilocytic astrocytoma. METHODS: Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-MUm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 * 0.237 mm(2)). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen. RESULTS: Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma. CONCLUSIONS: This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma. PMID- 21663413 TI - Convexity meningiomas: study of recurrence factors with special emphasis on the cleavage plane in a series of 100 consecutive patients. AB - OBJECT: Convexity meningiomas are expected to have a low recurrence rate given their classically "easy resectability." Nonetheless, recurrence can occur. Factors playing a role in their recurrence are analyzed here, including the extent of resection and tumor histological type, among others, with a special emphasis on the cleavage plane. METHODS: The authors reviewed 100 cases of convexity meningiomas surgically treated between 1987 and 2001 with a median follow-up of 86 months (range 2-16 years). Preoperative and postoperative functional status, Simpson resection grade, histological type, and intraoperative surgical plane with pial vessel invasion were studied and correlated with the recurrence rate. RESULTS: The average tumor size was 3.6 +/- 0.4 cm. The pre- and postoperative Karnofsky Performance Scale scores were 92.6 +/- 4.6 and 97.9 +/- 2.2, respectively. Ninety-five lesions were benign (WHO Grade I) and 5 were atypical (WHO Grade II). Ninety-one and 9 tumors were subjected to Simpson Grade 1 and 3 resections (three Grade 3a and six Grade 3b), respectively. Surgical deaths did not occur. After a mean follow-up of 7.2 years, 4 meningiomas recurred; 2 (2.2%) after Simpson Grade 1 resections and 2 after Simpson Grade 3 (3a and 3b) resections (22.2%; p = 0.0034). When just the subgroup of Simpson Grade 1/WHO Grade I was studied, the recurrence rate decreased to 1.2% (1 of 86 cases). The recurrence of WHO Grade I tumors was higher in the subpial group than in the extrapial group (p = 0.025). No difference in recurrence according to the cleavage plane was seen in the WHO Grade II subgroup (p = 0.361). As for the subpial group, no difference in recurrence was noted between the WHO Grade I and II subgroups (p = 0.608). Importantly, however, the extrapial subgroup of WHO Grade II lesions had a higher recurrence rate compared with its counterpart in the WHO Grade I subgroup (p = 0.005). CONCLUSIONS: Pial and vascular invasion affect the recurrence rate in convexity meningioma surgery. The recurrence rate of WHO Grade I tumors was higher among those with a subpial plane of dissection than among those with an extrapial one. Histological type did not determine the degree of pial invasion in WHO Grade I and II lesions. PMID- 21663412 TI - Minimally invasive evacuation of spontaneous intracerebral hemorrhage using sonothrombolysis. AB - OBJECT: Catheter-based evacuation is a novel surgical approach for the treatment of brain hemorrhage. The object of this study was to evaluate the safety and efficacy of ultrasound in combination with recombinant tissue plasminogen activator (rt-PA) delivered through a microcatheter directly into spontaneous intraventricular (IVH) or intracerebral (ICH) hemorrhage in humans. METHODS: Thirty-three patients presenting to the Swedish Medical Center in Seattle, Washington, with ICH and IVH were screened between November 21, 2008, and July 13, 2009, for entry into this study. Entry criteria included the spontaneous onset of intracranial hemorrhage >= 25 ml and/or IVH producing ventricular obstruction. Nine patients (6 males and 3 females, with an average age of 63 years [range 38-83 years]) who met the entry criteria consented to participate and were entered into the trial. A ventricular drainage catheter and an ultrasound microcatheter were stereotactically delivered together, directly into the IVH or ICH. Recombinant tissue plasminogen activator and 24 hours of continuous ultrasound were delivered to the clot. Gravity drainage was performed. In patients with IVHs, 3 mg of rt-PA was injected; in patients with intraparenchymal hemorrhages, 0.9 mg of rt-PA was injected. The rt-PA was delivered in 3 doses over 24 hours. RESULTS: All patients had significant volume reductions in the treated hemorrhage. The mean percentage volume reduction after 24 hours of therapy, as determined on CT and compared with pretreatment stability scans, was 59 +/- 5% (mean +/- SEM) for ICH and 45.1 +/- 13% for IVH (1 patient with ICH was excluded from analysis because of catheter breakage). There were no intracranial infections and no significant episodes of rebleeding according to clinical or CT assessment. One death occurred by 30 days after admission. Clinical improvements as determined by a decrease in the National Institutes of Health Stroke Scale score were demonstrated at 30 days after treatment in 7 of 9 patients. The rate of hemorrhage lysis was compared between 8 patients who completed treatment, and patient cohorts treated for IVH and ICH using identical doses of rt-PA and catheter drainage but without the ultrasound (courtesy of the MISTIE [Minimally Invasive Surgery plus T-PA for Intracerebral Hemorrhage Evacuation] and CLEAR II [Clot Lysis Evaluating Accelerated Resolution of Intraventricular Hemorrhage II] studies). Compared with the MISTIE and CLEAR data, the authors observed a faster rate of lysis during treatment for IVH and ICH in the patients treated with sonolysis plus rt-PA versus rt-PA alone. CONCLUSIONS: Lysis and drainage of spontaneous ICH and IVH with a reduction in mass effect can be accomplished rapidly and safely through sonothrombolysis using stereotactically delivered drainage and ultrasound catheters via a bur hole. A larger clinical trial with catheters specifically designed for brain blood clot removal is warranted. PMID- 21663414 TI - Notch receptor and effector expression in von Hippel-Lindau disease-associated central nervous system hemangioblastomas. AB - OBJECT: Central nervous system hemangioblastomas are the most common manifestation of von Hippel-Lindau (VHL) disease, an autosomal dominant tumor suppressor syndrome that results in loss of VHL protein function and continuous upregulation of hypoxia-inducible factors. These tumors are composed of neoplastic stromal cells and abundant vasculature. Stromal cells express markers consistent with multipotent embryonically arrested hemangioblasts, which are precursors for hematopoietic and vascular lineages. Notch receptors are transmembrane signaling molecules that regulate multiple developmental processes including hematopoiesis and vasculogenesis. To investigate the importance of notch signaling in the development of VHL disease-associated CNS hemangioblastomas, the authors examined the presence of the four notch receptors and downstream notch effectors in this setting. METHODS: The authors used surgical specimens obtained from confirmed VHL-associated hemangioblastomas. Immunohistochemical analysis for the four notch receptors and the downstream effectors was performed on formalin-fixed paraffin-embedded sections. Western blot analysis for HES1 was performed on frozen specimens. RESULTS: All four notch receptors are present in hemangioblastomas. NOTCH1 and NOTCH4 receptors were widely and prominently expressed in both the stromal and vascular cells, NOTCH2 receptor expression was limited to primarily stromal cells, and NOTCH3 receptor expression was limited to vascular cells. All 4 receptors displayed a nuclear presence. Immunohistochemical analysis also demonstrated that downstream notch effectors, HES1 and HES5, were uniformly expressed in tumor stromal and vascular cells, but HES3, HEY1, and HEY2 were not. Strong HES1 expression was confirmed by Western blot analysis. CONCLUSIONS: The presence of all four notch receptors and downstream effector molecules suggests that the notch signaling pathway plays a critical role in the maintenance of the undifferentiated pluripotent phenotype of these tumors and in the associated vascular response. Moreover, the prominent expression of notch receptors in VHL-associated CNS hemangioblastomas reveals a new and possibly potent therapeutic target. PMID- 21663415 TI - Risk factors for posttraumatic vasospasm. AB - OBJECT: Posttraumatic vasospasm (PTV) is an underrecognized cause of ischemic damage after severe traumatic brain injury (TBI) that independently predicts poor outcome. There are, however, no guidelines for PTV screening and management, partly due to limited understanding of its pathogenesis and risk factors. METHODS: A database review of 46 consecutive cases of severe TBI in pediatric and adult patients was conducted to identify risk factors for the development of PTV. Univariate analysis was performed to identify potential risk factors for PTV, which were subsequently analyzed using a multivariate logistic regression model to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Fever on admission was an independent risk factor for development of PTV (OR 22.2, 95% CI 1.9-256.8), and patients with hypothermia on admission did not develop clinically significant vasospasm during their hospital stay. The presence of small parenchymal contusions was also an independent risk factor for PTV (OR 7.8, 95% CI 0.9-69.5), whereas the presence of subarachnoid hemorrhage or other patterns of intracranial injury were not. Other variables, such as age, sex, ethnicity, degree of TBI severity, or admission laboratory values, were not independent predictors for the development of clinically significant PTV. CONCLUSIONS: Independent risk factors for PTV include parenchymal contusions and fever. These results suggest that diffuse mechanical injury and activation of inflammatory pathways may be underlying mechanisms for the development of PTV, and that a subset of patients with these risk factors may be an appropriate population for aggressive screening. Further studies are needed to determine if treatments targeting fever and inflammation may be effective in reducing the incidence of vasospasm following severe TBI. PMID- 21663417 TI - New American Thyroid Association and American Association of Clinical Endocrinologists guidelines for thyrotoxicosis and other forms of hyperthyroidism: significant progress for the clinician and a guide to future research. PMID- 21663416 TI - Recruitment and retention of diverse populations in antiretroviral clinical trials: practical applications from the gender, race and clinical experience study. AB - BACKGROUND: Women, particularly women of color, remain underrepresented in antiretroviral (ARV) clinical trials. To evaluate sex-based differences in darunavir/ritonavir-based therapy, the Gender, Race And Clinical Experience (GRACE) study was designed to enroll and retain a high proportion of women representative of the racial/ethnic demographics of women with HIV/AIDS in the United States. The recruitment and retention strategies used in GRACE are described in this article. METHODS: Recruitment and retention strategies targeting women included selecting study sites that focused on women, involving community consultants, site-specific enrollment plans, access to other ARV drugs, study branding, site and patient toolkits, targeted public relations, site grants for patient support, and subsidized child care and transportation. RESULTS: The recruitment strategies were successful; 287 (67%) women were enrolled, primarily women of color (black, n=191 [67%], Hispanic, n=60 [21%]). Despite the focus on retention, a greater proportion of women (32.8%) discontinued compared with men (23.2%). CONCLUSIONS: The successes of GRACE in enrolling a representative population of women were rooted in pretrial preparation, engagement of community advisors, enrollment quotas, choice of study sites and site support. Lessons learned from GRACE may be applied to future study design. Further focus on factors that influence discontinuation is warranted. PMID- 21663418 TI - The American Thyroid Association and American Association of Clinical Endocrinologists hyperthyroidism and other causes of thyrotoxicosis guidelines: viewpoints from Japan and Korea. PMID- 21663419 TI - Highlights of the guidelines on the management of hyperthyroidism and other causes of thyrotoxicosis. PMID- 21663420 TI - The American Thyroid Association/American Association of Clinical Endocrinologists guidelines for hyperthyroidism and other causes of thyrotoxicosis: a European perspective. PMID- 21663422 TI - Dosing strategies for lithium monotherapy in children and adolescents with bipolar I disorder. AB - OBJECTIVE: The primary goal of this exploratory study was to obtain data that could lead to evidence-based dosing strategies for lithium in children and adolescents suffering from bipolar I disorder. METHODS: Outpatients aged 7-17 years meeting Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic criteria for bipolar I disorder (manic or mixed) were eligible for 8 weeks of open label treatment with lithium in one of three dosing arms. In Arm I, participants began treatment at a dose of 300 mg of lithium twice daily. The starting dose of lithium in Arms II and III was 300 mg thrice daily. Patients in Arms I and II could have their dose increased by 300 mg/day, depending on clinical response, at weekly visits. Patients in Arm III also had mid-week telephone interviews after which they could also have their dose of lithium increased by 300 mg per day. Youths weighing <30 kg were automatically assigned to Arm I, whereas youths weighing >=30 kg were randomly assigned to Arm I, II, or III. Randomization was balanced by age (7-11 years, 12-17 years) and sex in approximately equal numbers. A priori response criteria were defined as a Clinical Global Impressions-Improvement scale score of <= 2 and a 50% decrease from baseline on the Young Mania Rating Scale. RESULTS: Of the 61 youths [32 males (52.5%)] who received open-label lithium, 60 youths completed at least 1 week of treatment and returned for a postbaseline assessment. Most patients had a >= 50% improvement in Young Mania Rating Scale score, and more than half of the patients (58%) achieved response. Overall, lithium was well tolerated. All three treatment arms had similar effectiveness, side effect profiles, and tolerability of lithium. CONCLUSIONS: On the basis of these results, a dosing strategy in which pediatric patients begin lithium at a dose of 300 mg thrice daily (with an additional 300 mg increase during the first week), followed by 300 mg weekly increases until a priori stopping criteria are met, will be used in an upcoming randomized, placebo-controlled trial. PMID- 21663423 TI - A placebo-controlled pilot study of adjunctive olanzapine for adolescents with anorexia nervosa. AB - OBJECTIVE: The objective of this study was to explore whether the addition of olanzapine versus placebo increases weight gain and improves psychological symptoms in adolescents with anorexia nervosa-restricting type who are participating in a comprehensive eating disorders treatment program. METHODS: Twenty underweight females participated in this 10-week, double-blind, placebo controlled pilot study of olanzapine. The primary efficacy measure was change in percentage of median body weight measured at baseline and weeks 5 and 10. Secondary efficacy measures included clinician-rated and self-reported measures of psychological functioning measured at 2-week intervals and eating disorder symptoms measured at baseline and weeks 5 and 10 as well as laboratory assessments (including indirect calorimetry), which were also performed at baseline and weeks 5 and 10. A mixed models approach to repeated measures analysis of variance was utilized to detect any treatment-by-time interaction. RESULTS: Fifteen of 20 enrolled females (median age, 17.1 years; range, 12.3-21.8 years; mean body mass index, 16.3) completed this 10-week pilot study. Change in % median body weight did not differ between the treatment groups at midpoint or end of study. Both groups gained weight at a similar rate and had similar improvements in eating attitudes and behaviors, psychological functioning, and resting energy expenditure. A trend of increasing fasting glucose and insulin levels was found only in the olanzapine group at week 10. CONCLUSIONS: These preliminary findings do not support a role for adjunctive olanzapine for underweight adolescent females with anorexia nervosa-restricting type who are receiving standard care in an eating disorder treatment program (clinical trials.gov; no. NCT00592930). PMID- 21663424 TI - No unexpected adverse events and biochemical side effects of olanzapine as adjunct treatment in adolescent girls with eating disorders. AB - OBJECTIVE: Olanzapine has been recently tried to relieve anxiety and hyperactivity in adolescents with eating disorders (EDs). Presently, the side effects of the drug have been evaluated. METHOD: Forty-seven adolescents with EDs were followed up by repeated blood sampling before, during, and at 3 months after medication with olanzapine. RESULTS: Olanzapine medication was discontinued in three patients because of galactorrhea, seizures, and raised liver enzyme activities, respectively. There was a normalization of glucose, insulin, and lipid profiles during treatment, which was related to weight gain and resumption of menstruations but not to medication. Increases in thyroid-stimulating hormone and prolactin were related to olanzapine medication and comedication with selective serotonine reuptake inhibitors. Three months after discontinuing medication, there were no persisting biochemical effects. CONCLUSION: The side effects observed were those previously described for olanzapine. Most biochemical changes were related to weight (change) and amenorrhea and not to medication. Placebo-controlled studies are needed to investigate the efficacy of olanzapine in adolescents with EDs. PMID- 21663426 TI - An open-label trial of risperidone in children and adolescents with severe mood dysregulation. AB - OBJECTIVE: The diagnosis and treatment of youth with severe nonepisodic irritability and hyperarousal, a syndrome defined as severe mood dysregulation (SMD), has been the focus of increasing concern and debate among clinicians and researchers. Our main objective was to assess the effectiveness of risperidone for youths with SMD. METHODS: An 8-week open label trial with risperidone was conducted. We extensively assessed 97 subjects with semistructured and clinical interviews and enrolled 21 patients in the study. Risperidone was titrated from 0.5 to 3 mg/day in the first 2 weeks. Evaluations were performed at baseline and weeks 2, 4, 6, and 8. Clinical outcome measures were (1) Aberrant Behavior Checklist-Irritability Subscale, (2) Clinical Global Impressions, and (3) severity of co-morbid conditions. RESULTS: We found a significant reduction of the Aberrant Behavior Checklist-Irritability scores during the trial after risperidone use (p < 0.001). The scores at week 2 (mean = 12.03; standard error [SE] = 2.94), week 4 (mean = 15.48; SE = 2.93), week 6 (mean = 12.29; SE = 2.86), and week 8 (mean = 11.28; SE = 3.06) were significantly reduced compared with the baseline mean score (mean = 25.89; SE = 2.76) (p < 0.001). We also found an improvement in attention-deficit/hyperactivity disorder, depression, and global functioning (p < 0.001). CONCLUSION: Risperidone was effective in reducing irritability in SMD youth. To the best of our knowledge, this is the first psychopharmacological trial in this group of patients with positive results. Further randomized, controlled studies are needed. PMID- 21663425 TI - Aripiprazole in the treatment of irritability in pediatric patients (aged 6-17 years) with autistic disorder: results from a 52-week, open-label study. AB - AIM: To report the long-term efficacy of aripiprazole in the treatment of irritability in children and adolescents (ages 6-17 years) with autistic disorder. METHODS: This was a 52-week, open-label, flexible-dose (2-15 mg/day) study of aripiprazole for the treatment of children and adolescents with irritability associated with autistic disorder. Eligible subjects were enrolled from two 8-week randomized trials or were enrolled as de novo subjects. "Prior aripiprazole" subjects had received treatment with aripiprazole for 8 weeks before entering this study. Evaluation of efficacy, a secondary objective after evaluation of safety and tolerability in this study, was conducted using the caregiver-rated Aberrant Behavior Checklist-Irritability subscale and the clinician-rated Clinical Global Impression-Improvement score. RESULTS: Three hundred thirty subjects received treatment (de novo, n = 86; prior aripiprazole, n = 174; prior placebo, n = 70) and 199 subjects (60.3%) completed 52 weeks of treatment. At their last study visit, 38.2% of subjects were receiving concomitant central nervous system medications (commonly antidepressants, 13.4%; psychostimulants, 11.5%; antiepileptics, 5.9%). At week 52 (observed cases data set), the mean change from baseline in Aberrant Behavior Checklist Irritability subscale scores was -8.0 in de novo subjects and -6.1 in prior placebo subjects; prior aripiprazole subjects maintained symptom improvement that was achieved with treatment in the prior study. At endpoint, the majority of subjects had a Clinical Global Impressions-Improvement score of 2 (much improved) or 1 (very much improved). CONCLUSION: Aripiprazole reduced symptoms of irritability associated with autistic disorder in pediatric subjects ages 6-17 years who were studied for up to 1 year. PMID- 21663427 TI - Effects of methylphenidate on intelligence and attention components in boys with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Methylphenidate (MPH) is an efficient treatment to reduce behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD); however, its impact on cognitive functioning has not been sufficiently demonstrated so far. This study investigates the hypothesis that MPH improves attention-related cognitive functions. METHODS: Sixty-seven medication-naive boys aged 6-13, with newly diagnosed ADHD, were tested before treatment with a neuropsychological assessment battery, including the Wechsler Intelligence Scales for Children (WISC-IV) and the Test of Attentional Performance for Children (KITAP). A follow-up assessment was performed after 8-12 weeks, with 37 participants receiving MPH treatment and 30 controls without medication. The effect of MPH on test performance was analyzed by repeated measures analyses of variance. RESULTS: Both groups improved significantly across a broad range of psychometric measures of cognitive performance. There were no significant interaction effects of group and time on attention-related cognitive functions. Exploratory analyses revealed an effect of MPH on verbal comprehension in the WISC-IV. CONCLUSION: The study results do not support that MPH improves attention-related cognitive functions of boys with ADHD. The potential effect of MPH on verbal abilities deserves further research. PMID- 21663428 TI - Pharmacokinetics and therapeutic effect of OROS methylphenidate under different breakfast conditions in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: To examine the pharmacokinetics (PKs) and pharmacodynamics (PDs) of OROS methylphenidate (OROS MPH) dosed once daily (QD) versus an early standard regimen (immediate-release [IR] MPH dosed three times daily [TID]) under various breakfast conditions. METHODS: This single-center, double-blind, double-dummy, randomized, crossover study of OROS MPH (NCT00269815) in children aged 6 to 12 years with attention-deficit/hyperactivity disorder evaluated the PKs and PDs of MPH given with different breakfast conditions: OROS MPH administered after a high fat breakfast, after a normal breakfast, or after fasting and IR MPH administered after a normal breakfast or after fasting in the morning and at two subsequent time points during the day. To maximize information, patients were divided into two groups, each receiving three of the five treatments for 1 day in a three period, randomized, crossover design. Patients were assigned to 1 of 3 dosage levels (OROS MPH 18, 36, and 54 mg QD, and an assumed equivalent regimen of IR MPH 5, 10, and 15 mg given TID) based on their prestudy established clinical dose of IR MPH. PD measurements included Combined-Attention and Deportment scores on a rating scale of school behavior (the Swanson, Kotkin, Agler, M-Flynn, and Pelham), global assessments of efficacy, and activity monitor levels during academic seatwork. Serial blood samples for PK analysis were taken predose, and then every 60 to 90 minutes until 11.5 hours postdose. Vital signs were assessed predose, and then every 1.5 to 2.5 hours until 11.5 hours postdose. RESULTS: Of the 32 patients enrolled, 31 completed the study. The PK profiles for MPH after OROS MPH administration were similar under all conditions (with normal, high-fat breakfast, or fasting). No bioequivalence tests of OROS MPH and IR MPH under various breakfast conditions were done because there were so few patients in each dose level of treatment. The two IR MPH conditions (after normal breakfast and fasting) were not compared. The drug-to-metabolite ratios (area under the curve) for all OROS MPH and IR MPH treatments were similar. OROS MPH and IR MPH provided a similar therapeutic effect, irrespective of breakfast conditions, as demonstrated by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Attention and Deportment measures and global assessments. No serious adverse events, no deaths, and no clinically significant changes in vital signs were reported, except for one patient who was discontinued early because of repeated systolic blood pressure elevations on study day 1. CONCLUSIONS: The results of this study demonstrate that in children with attention-deficit/hyperactivity disorder, administering OROS MPH with or without food produces similar PK and PD profiles. PMID- 21663429 TI - Differential effects of predictors on methylphenidate initiation and discontinuation among young people with newly diagnosed attention deficit/hyperactivity disorder. AB - OBJECTIVE: Previous population-based studies have identified factors accounting for differential utilization of psychotropic medications among young patients with attention-deficit/hyperactivity disorders (ADHDs); yet, few analyses have addressed changes in such factors that can occur in the help-seeking process. The aim of this study was to examine patient- and service provider-level predictors for methylphenidate (MPH) initiation and discontinuation. METHOD: This cohort study included 10,153 newly diagnosed ADHD patients under 18 years of age in 2000, identified from the National Health Insurance Research Database. The risk association was estimated by time-dependent survival analyses, as indexed by hazard ratio. RESULTS: Approximately 30% of young people received MPH treatment within the year of their ADHD diagnosis, and virtually none remained in treatment beyond 12 months. Regardless of co-morbidity status, the following were significantly associated with earlier initiation of MPH treatment: older age (e.g., adjusted hazard ratio [aHR] for age 12-17 = 4.5-7.6), lower socioeconomic status (aHR = 1.2-1.4), southern residence (aHR = 1.4-1.6), receiving the diagnosis while school was in session (aHR = 1.3-1.4), receiving the diagnosis from a physician specializing in pediatrics or psychiatry (aHR = 7.3-16.8), and receiving the diagnosis in a district hospital/clinic (aHR = 1.3-1.7). However, once treatment started, older ages appeared to increase the risk of early discontinuation by 15%, and the corresponding estimates for receiving initial MPH in a regional hospital or district hospital/clinic were 27% and 32%, respectively. Change in treatment location upon subsequent visit was associated with a 58% reduction in early discontinuation. CONCLUSIONS: This information about time-varying predictors for MPH utilization throughout treatment may provide insight into the delivery of pediatric mental health services and has important implications for the design of clinical treatment programs. PMID- 21663432 TI - Treatment of bipolar disorder in an adolescent with autistic disorder: a diagnostic and treatment dilemma. PMID- 21663430 TI - A brief motivational intervention for preventing medication-associated weight gain among youth with bipolar disorder: treatment development and case report. AB - Bipolar disorder (BP) in youth is an impairing psychiatric disorder associated with high rates of relapse and recurrence. High rates of psychiatric and medical co-morbidities account for additional illness burden in pediatric BP. The elevated risk of overweight and obesity in this population is of particular concern. One of the likely etiologies for weight gain in youth with BP is use of mood-stabilizing medications. Although these medications can be effective for mood stabilization, excessive weight gain is a common side effect. Obesity is associated with a host of medical problems and is also correlated with worse psychiatric outcomes in BP, rendering the prevention of weight gain in this population particularly clinically relevant. In this article, we describe the rationale and development of a brief motivational intervention for preventing weight gain among youth with BP initiating mood-stabilizing pharmacological treatment and then present a case example illustrating the principles of the intervention. PMID- 21663433 TI - Guanfacine extended release in two patients with pervasive developmental disorders. PMID- 21663434 TI - Liquid melatonin via gastrostomy as an alternative hypnotic in a child with pervasive developmental disorder. PMID- 21663435 TI - Idiosyncratic liver failure probably associated with atomoxetine: a case report. PMID- 21663436 TI - Detection of diseased plants by analysis of volatile organic compound emission. AB - This review focuses on the detection of diseased plants by analysis of volatile organic compound (VOC) emissions. It includes an overview of studies that report on the impact of infectious and noninfectious diseases on these emissions and discusses the specificity of disease-induced emissions. The review also provides an overview of processes that affect the gas balance of plant volatiles, including their loss processes. These processes are considered as important because they contribute to the time-dynamic concentration profiles of plant emitted volatiles. In addition, we describe the most popular techniques currently in use to measure volatiles emitted from plants, with emphasis on agricultural application. Dynamic sampling coupled with gas chromatography and followed by an appropriate detector is considered as the most appropriate method for application in agriculture. It is recommended to evaluate the state-of-the-art in the fields concerned with this method and to explore the development of a new instrument based on the specific needs for application in agricultural practice. However, to apply such an instrument in agriculture remains a challenge, mainly due to high costs. PMID- 21663437 TI - Understanding and exploiting late blight resistance in the age of effectors. AB - Potato (Solanum tuberosum) is the world's third-largest food crop. It severely suffers from late blight, a devastating disease caused by Phytophthora infestans. This oomycete pathogen secretes host-translocated RXLR effectors that include avirulence (AVR) proteins, which are targeted by resistance (R) proteins from wild Solanum species. Most Solanum R genes appear to have coevolved with P. infestans at its center of origin in central Mexico. Various R and Avr genes were recently cloned, and here we catalog characterized R-AVR pairs. We describe the mechanisms that P. infestans employs for evading R protein recognition and discuss partial resistance and partial virulence phenotypes in the context of our knowledge of effector diversity and activity. Genome-wide catalogs of P. infestans effectors are available, enabling effectoromics approaches that accelerate R gene cloning and specificity profiling. Engineering R genes with expanded pathogen recognition has also become possible. Importantly, monitoring effector allelic diversity in pathogen populations can assist in R gene deployment in agriculture. PMID- 21663438 TI - Hormone crosstalk in plant disease and defense: more than just jasmonate salicylate antagonism. AB - Until recently, most studies on the role of hormones in plant-pathogen interactions focused on salicylic acid (SA), jasmonic acid (JA), and ethylene (ET). It is now clear that pathogen-induced modulation of signaling via other hormones contributes to virulence. A picture is emerging of complex crosstalk and induced hormonal changes that modulate disease and resistance, with outcomes dependent on pathogen lifestyles and the genetic constitution of the host. Recent progress has revealed intriguing similarities between hormone signaling mechanisms, with gene induction responses often achieved by derepression. Here, we report on recent advances, updating current knowledge on classical defense hormones SA, JA, and ET, and the roles of auxin, abscisic acid (ABA), cytokinins (CKs), and brassinosteroids in molding plant-pathogen interactions. We highlight an emerging theme that positive and negative regulators of these disparate hormone signaling pathways are crucial regulatory targets of hormonal crosstalk in disease and defense. PMID- 21663439 TI - Bacterial osmoregulation: a paradigm for the study of cellular homeostasis. AB - To thrive, cells must control their own physical and chemical properties. This process is known as cellular homeostasis. The dilute solutions traditionally favored by experimenters do not simulate the cytoplasm, where macromolecular crowding and preferential interactions among constituents may dominate critical processes. Solutions that do simulate cytoplasmic conditions are now being characterized. Corresponding cytoplasmic properties can be varied systematically by imposing osmotic stress. This osmotic stress approach is revealing how cytoplasmic properties modulate protein folding and protein?nucleic acid interactions. Results suggest that cytoplasmic homeostasis may require adjustments to multiple, interwoven cytoplasmic properties. Osmosensory transporters with diverse structures and bioenergetic mechanisms activate in response to osmotic stress as other proteins inactivate. These transporters are serving as paradigms for the study of in vivo protein-solvent interactions. Experimenters have proposed three different osmosensory mechanisms. Distinct mechanisms may exist, or these proposals may reflect different perceptions of a single, unifying mechanism. PMID- 21663440 TI - Lipoprotein sorting in bacteria. AB - Bacterial lipoproteins are synthesized as precursors in the cytoplasm and processed into mature forms on the cytoplasmic membrane. A lipid moiety attached to the N terminus anchors these proteins to the membrane surface. Many bacteria are predicted to express more than 100 lipoproteins, which play diverse functions on the cell surface. The Lol system, composed of five proteins, catalyzes the localization of Escherichia coli lipoproteins to the outer membrane. Some lipoproteins play vital roles in the sorting of other lipoproteins, lipopolysaccharides, and beta-barrel proteins to the outer membrane. On the basis of results from biochemical, genetic, and structural studies, we discuss the biogenesis of lipoproteins in bacteria, their importance in cellular functions, and the molecular mechanisms underlying efficient sorting of hydrophobic lipoproteins to the outer membrane through the hydrophilic periplasm. PMID- 21663442 TI - Genetics of speech and language disorders. AB - Vocal communication mediated by speech and language is a uniquely human trait, and has served an important evolutionary role in the development of our species. Deficits in speech and language functions can be of numerous types, including aphasia, stuttering, articulation disorders, verbal dyspraxia, and specific language impairment; language deficits are also related to dyslexia. Most communication disorders are prominent in children, where they are common. A number of these disorders have been shown to cluster in families, suggesting that genetic factors are involved, but their etiology at the molecular level is not well understood. In the past decade, genetic methods have proven to be powerful for understanding these etiologies. Linkage studies and molecular genetic analyses in a large family containing multiple individuals affected with verbal dyspraxia led to the discovery of mutations in the FOXP2 gene. This gene encodes a forkhead domain transcription factor, a finding that has led researchers to a new avenue of investigation into the substrates and mechanisms that underlie human speech development. In studies of stuttering, linkage and candidate gene approaches in consanguineous families identified mutations in the lysosomal enzyme-targeting pathway genes GNPTAB, GNPTG, and NAGPA, revealing a role for inherited defects in cell metabolism in this disorder. In specific language impairment, linkage studies have identified several loci, and candidate gene association studies are making progress in identifying causal variants at these loci. Although only a small fraction of all cases of speech and language disorders can be explained by genetic findings to date, the significant progress made thus far suggests that genetic approaches will continue to provide important avenues for research on this group of disorders. PMID- 21663441 TI - Ligand-binding PAS domains in a genomic, cellular, and structural context. AB - Per-Arnt-Sim (PAS) domains occur in proteins from all kingdoms of life. In the bacterial kingdom, PAS domains are commonly positioned at the amino terminus of signaling proteins such as sensor histidine kinases, cyclic-di-GMP synthases/hydrolases, and methyl-accepting chemotaxis proteins. Although these domains are highly divergent at the primary sequence level, the structures of dozens of PAS domains across a broad section of sequence space have been solved, revealing a conserved three-dimensional architecture. An all-versus-all alignment of 63 PAS structures demonstrates that the PAS domain family forms structural clades on the basis of two principal variables: (a) topological location inside or outside the plasma membrane and (b) the class of small molecule that they bind. The binding of a chemically diverse range of small-molecule metabolites is a hallmark of the PAS domain family. PAS ligand binding either functions as a primary cue to initiate a cellular signaling response or provides the domain with the capacity to respond to secondary physical or chemical signals such as gas molecules, redox potential, or photons. This review synthesizes the current state of knowledge of the structural foundations and evolution of ligand recognition and binding by PAS domains. PMID- 21663443 TI - Cooperation between integrins and growth factor receptors in signaling and endocytosis. AB - All multicellular animals express receptors for growth factors (GFs) and extracellular matrix (ECM) molecules. Integrin-type ECM receptors anchor cells to their surroundings and concomitantly activate intracellular signal transduction pathways. The same signaling mechanisms are regulated by GF receptors (GFRs). Recently, intensive research efforts have revealed novel mechanisms describing how the two receptor systems collaborate at many different levels. Integrins can directly bind to GFs and promote their activation. Adhesion receptors also organize signaling platforms and assist GFRs or even activate them via ligand independent mechanisms. Furthermore, integrins can orchestrate endocytosis and recycling of GFRs. Here, we review the present knowledge about the interplay between integrins and GFRs and discuss recent ideas of how this collaboration may explain some previous controversies in integrin research. PMID- 21663444 TI - Regulation of integrin activation. AB - Regulation of cell-cell and cell-matrix interaction is essential for the normal physiology of metazoans and is important in many diseases. Integrin adhesion receptors can rapidly increase their affinity (integrin activation) in response to intracellular signaling events in a process termed inside-out signaling. The transmembrane domains of integrins and their interactions with the membrane are important in inside-out signaling. Moreover, integrin activation is tightly regulated by a complex network of signaling pathways. Here, we review recent progress in understanding how the membrane environment can, in cooperation with integrin-binding proteins, regulate integrin activation. PMID- 21663446 TI - Ocular safety of infliximab. PMID- 21663445 TI - Therapeutic effects of high-dose intravenous prednisolone in methanol-induced toxic optic neuropathy. AB - PURPOSE: We evaluated the effects of high-dose steroids for the treatment of methanol optic neuropathy. METHODS: In an interventional case series, 6 patients with a history of sudden visual loss after an ingestion of homemade alcoholic beverages were included in the study. The patients received 250 mg intravenous methyl prednisolone every 6 h for 4 days and continued with oral prednisolone at 1 mg/kg for 10 days. Best-corrected visual acuity (BCVA), optical coherent tomography, fundus photo, and a complete ophthalmologic exam of the patients were taken before the treatment and 3 months after treatment. RESULTS: All the patients were male. The mean age was 26.34+/-2.7 years. The mean BCVA before the treatment was 0.86+/-0.08 in the right eye and 0.93+/-0.1 in the left eye using the logMAR scale. Four patients showed nerve fiber layer edema as a white density in peripapillary area. After treatment, the mean BCVA was 0.33+/-0.18 in the right eye and 0.29+/-0.2 in the left eye using the logMAR scale. The differences between before treatment and after treatment were significant (P=0.008 and P=0.003, respectively). The mean macular thickness and cup.to.disc ratio were unchanged. CONCLUSION: Intravenous high-dose methyl prednisolone may have benefits in the treatment of methanol optic neuropathy. PMID- 21663447 TI - Technologies in the patient-centered medical home: examining the model from an enterprise perspective. AB - Fee-for-service reimbursement has fragmented the healthcare system. Providers are paid based on the number of services rendered instead of quality, leading to the cost of care rising at a faster rate than its value. One approach to counter this is the Patient-Centered Medical Home (PCMH), a primary care model that emphasizes team-based medicine, a partnership between patients and providers, and expanded access and communication. The transition to PCMH is facilitated by innovative technologies, such as telemedicine for additional services, electronic medical records to document patients' health needs, and online portals for electronic visits and communication between patients and providers. Implementing these technologies involves tremendous investment of funds and time from practices and healthcare organizations. Although PCMH does not require such technologies, they facilitate its success, as care coordination and population management necessitated by the model are difficult to do without. This article argues that there is a paradox in PCMH and technology is at its center. Although PCMH intends to be cost effective by reducing hospital admissions and ER visits through providing better preventative services, it is actually a financial risk due to the very real upfront costs of implementing and sustaining technologies needed to carry out the intent of the PCMH model, which may not be made up immediately, if ever. This article delves into the rationale behind why payers, providers, and patients have adopted PCMH regardless of this risk and in doing so, maps out the roles that innovative technologies play in the conversion to PCMH. PMID- 21663450 TI - Growth and body composition of zebrafish (Danio rerio) larvae fed a compound feed from first feeding onward: toward implications on nutrient requirements. AB - Although zebrafish is used as a major model species for understanding a number of biological functions and mechanisms involved, there is practically no information on the nutritional requirements of this cyprinid. The rearing practices, especially with regard to feeds and feeding, also vary considerably. To obtain base line information on the nutrient requirements and to develop a standard diet, we initiated the present work of feeding zebrafish larvae with a formulated feed right from first feeding onward. Growth of zebrafish fed the compound feed was very good, reaching a total length of 23 +/- 4 mm in 9 weeks with a survival rate of 89% +/- 4%. We present the first ever published data on whole-body composition in terms of essential amino acids (ideal protein profile), total, neutral and polar fatty acid profiles, minerals, and trace elements. Results obtained here show clearly that zebrafish can be reared with formulated feed right from mouth opening without resorting to any live prey. PMID- 21663448 TI - Dishevelled2 is a stable protein during early zebrafish development. AB - Wnt signaling is a major player during development and its misregulation often leads to disease, especially cancer. The negative feedback Wnt regulator homologs, Nkd1 and Nkd2, have been shown to inhibit Wnt signaling during development, and current evidence suggests that Nkds degrade Dvl proteins to antagonize Wnt signaling. Here, we demonstrate that during early zebrafish development Nkd1 does not alter either endogenous or exogenous levels of Dvl2. Furthermore, Dvl2 does not affect the levels of Nkd1. Cumulatively, these results demonstrate that Dvl2 is a ubiquitous and stable protein and that Nkds may not always function to degrade Dvl proteins as a method of inhibiting Wnt signaling. PMID- 21663452 TI - Statistics. PMID- 21663453 TI - Oral rehabilitation following removal of a rhabdomyosarcoma and subsequent microstomia: a case report. AB - Rhabdomyosarcoma is a malignant tumor that is most often seen in children younger than 15 years of age. This pathology is found mainly in the head and neck region. Treatment of rhabdomyosarcoma at early stages of life usually affects the dental and osseous development of children. Because of impaired development, microstomia can arise, making dental treatment more difficult. This article presents a patient with microstomia caused by resection of an embryonal rhabdomyosarcoma in the nasolabial region. The patient was treated with 5 dental implants and fixed hybrid prosthesis in the maxilla and 2 implants supporting an overdenture in the mandible. PMID- 21663454 TI - Characterization of the human artemis promoter by heterologous gene expression in vitro and in vivo. AB - Artemis is an endonucleolytic enzyme involved in nonhomologous double-strand break repair and V(D)J recombination. Deficiency of Artemis results in a B- T- radiosensitive severe combined immunodeficiency, which may potentially be treatable by Artemis gene transfer into hematopoietic stem cells. However, we recently found that overexpression of Artemis after lentiviral transduction resulted in global DNA damage and increased apoptosis. These results imply the necessity of effecting natural levels of Artemis expression, so we isolated a 1 kilobase DNA sequence upstream of the human Artemis gene to recover and characterize the Artemis promoter (APro). The sequence includes numerous potential transcription factor-binding sites, and several transcriptional start sites were mapped by 5' rapid amplification of cDNA ends. APro and deletion constructs conferred significant reporter gene expression in vitro that was markedly reduced in comparison to expression regulated by the human elongation factor 1-alpha promoter. Ex vivo lentiviral transduction of an APro-regulated green fluorescent protein (GFP) construct in mouse marrow supported GFP expression throughout hematopoeitic lineages in primary transplant recipients and was sustained in secondary recipients. The human Artemis promoter thus provides sustained and moderate levels of gene expression that will be of significant utility for therapeutic gene transfer into hematopoeitic stem cells. PMID- 21663455 TI - Efficiency of CCR5 coreceptor utilization by the HIV quasispecies increases over time, but is not associated with disease progression. AB - CCR5 is the primary coreceptor for HIV entry. Early after infection, the HIV viral population diversifies rapidly into a quasispecies. It is not known whether the initial efficiency of the viral quasispecies to utilize CCR5 is associated with HIV disease progression or if it changes in an infected individual over time. The CCR5 and CXCR4 utilization efficiencies (R5-UE and X4-UE) of the HIV quasispecies were examined using a pseudovirus, single-round infection assay for samples obtained from known seroconverters from Rakai district, Uganda (n=88). Initial and longitudinal R5-UE values were examined to assess the association of R5-UE with HIV disease progression using multivariate Cox proportional hazard models. Longitudinal samples were analyzed for 35 seroconverters who had samples available from multiple time points. There was no association between initial or longitudinal changes in R5-UE and the hazard of HIV disease progression (p=0.225 and p=0.942, respectively). In addition, R5-UE increased significantly over time after HIV seroconversion (p<0.001), regardless of HIV subtype or the emergence of CXCR4-tropic virus. These data demonstrate that the R5-UE of the viral quasispecies early in HIV infection is not associated with disease progression, and that R5-UE levels increase in HIV-infected individuals over time. PMID- 21663456 TI - Nondestructive method to evaluate the collagen content of fibrin-based tissue engineered structures via ultrasound. AB - In the field of tissue engineering, there is a growing need for quantitative methods to analyze in situ and in real time the tissue development in three dimensional scaffolds. To evaluate the performance of cell-gel constructs in terms of extracellular matrix synthesis, we are still restricted to time consuming histological and biochemical assays that are not able, as a destructive method, to monitor the tissue formation online. Ultrasound is a well-known noninvasive and nondestructive imaging method. Therefore, the potential of ultrasound for the quantitative in vitro evaluation of tissue development in fibrin-based tissue-engineered structures was evaluated in this study. As simplified parameter, the gray-scale values of ultrasound scans of cell-embedded fibrin gels were correlated with the hydroxyproline content and the histological and immunohistological images of the same gels at different culturing time points. The gray-scale value of the ultrasound demonstrated a good correlation with the hydroxyproline content (Pearson correlation coefficient of 0.98) as marker of collagen formation and with the histological findings. In conclusion, the described simple ultrasound method is a good tool to evaluate the collagen formation of fibrin-based tissue-engineered constructs and facilitates the broad use to monitor tissue development and remodeling in bioreactor systems. PMID- 21663457 TI - Development of a bioreactor for axially loaded intervertebral disc organ culture. AB - Whole disc organ culture is needed for preclinical testing of biological repair of the degenerate intervertebral disc. Such organ culture is hampered by two major limitations: first obtaining adequate nutrition though the calcified cartilage endplates adjacent to the vertebral bone, and second by loss of tissue integrity if the endplates are removed from the discs. In this work we utilize a recently described technique for whole disc isolation that overcomes these problems, by removal of vertebral bone and the adjacent calcified portion of the endplate, and the construction of a bioreactor that permits long-term viability of these discs in loaded organ culture. The bioreactor consists of a culture chamber in which the disc can be dynamically loaded in a uniform manner. The culture chamber is large enough to accommodate discs up to 60 mm in diameter, and so is amendable to study both bovine and human discs. The discs are loaded in the culture chamber by upper and lower platens, which conform to the shape of the remaining cartilaginous endplate and permit fluid flow across its surface. The bioreactor is able to load the disc under a variety of conditions ranging from static to dynamic and from physiological to pathological, and monitor induced changes in disc height. To date, bovine caudal discs have been maintained viable in the bioreactor for up to 4 weeks without any appreciable loss of disc height under physiological cyclic load and, in principle, could be maintained in such a manner for several months. Such long-term organ culture is essential for studying biological repair of the disc. PMID- 21663458 TI - Ductus venosus flow at 11-13 weeks in the prediction of birth weight discordance in monochorionic twins. AB - OBJECTIVE: To examine if assessment of ductus venosus (DV) flow, crown-rump length (CRL) and nuchal translucency (NT) thickness can predict the discordance in birth weight in monochorionic (MC) twin pregnancies resulting in two live births. METHODS: In this prospective study, we assessed CRL, NT and DV flow at 11(+0)-13(+6) weeks' gestation in 326 MC twin pregnancies. The study population included 237 pregnancies without major abnormalities or prenatal interventions resulting in two live births. We examined the value of DV flow and discordance in NT and CRL in the prediction of discordance in birth weight. RESULTS: In the 237 MC twin pregnancies the median discordance in birth weight was 8.0% (range 0 42.2%). There was no significant association between discordance in either CRL or NT and discordance in birth weight (P=0.116 and P=0.332). In pregnancies with abnormal DV flow in at least one of the fetuses the median discordance in birth weight was higher than in those with normal DV flow in both twins (13.2% vs. 7.8%, P=0.006). CONCLUSIONS: In uncomplicated MC twin pregnancies, abnormal DV flow in at least one of the fetuses is associated with a higher discordance in birth weight than in those with normal flow in both fetuses. PMID- 21663459 TI - Drug safety evaluation of zonisamide for the treatment of epilepsy. AB - INTRODUCTION: Zonisamide is a broad spectrum antiepileptic drug with multiple mechanisms of action which has been recently approved in the US and Europe as an adjunctive therapy for refractory partial seizures in adults. AREAS COVERED: The adverse effect profile of this drug from controlled, randomized studies and open and long-term studies and case reports is described herein. EXPERT OPINION: Zonisamide has several CNS dose-dependent, metabolic and idiosyncratic adverse effects. Knowledge of these effects is essential for the prevention or minimization of several of them. For example, treatment-emergent adverse events may be prevented by slow titration; incidence of kidney stones may be reduced through an increase in fluid intake and avoidance of concomitant treatment with topiramate and/or ketogenic diet; and oligohydrosis may be prevented by hydratation and avoidance of hot temperatures. An accurate selection of patients can be useful for the prevention of some adverse effects. Psychiatric disturbances are mainly observed in predisposed subjects and patients with a previous allergic episode to sulfonamide-containing drugs are at a higher risk for developing a skin rash. PMID- 21663460 TI - Customer satisfaction survey to improve the European cystic fibrosis external quality assessment scheme. AB - BACKGROUND: The Cystic Fibrosis European Network, coordinated from within the Katholieke Universiteit Leuven, is the provider of the European cystic fibrosis external quality assessment (EQA) scheme. The network aimed to seek feedback from laboratories that participated in the cystic fibrosis scheme in order to improve services offered. In this study we analysed responses to an on-line customer satisfaction survey conducted between September and November 2009. METHODS: The survey was sent to 213 laboratories that participated in the cystic fibrosis EQA scheme of 2008; 69 laboratories (32%) responded. Scores for importance and satisfaction were obtained from a five-point Likert scale for 24 attributes. A score of one corresponded to very dissatisfied/very unimportant and five corresponded to very satisfied/very important. Means were calculated and placed in a two-dimensional grid (importance-satisfaction analysis). Means were subtracted from each other to obtain gap values (gap-analysis). RESULTS: No attribute had a mean score below 3.63. The overall mean of satisfaction was 4.35. Opportunities for improvement enclosed clarity, usefulness and completeness of the general report and individual comments, and user-friendliness of the electronic datasheet. CONCLUSIONS: This type of customer satisfaction survey was a valuable instrument to identify opportunities to improve the cystic fibrosis EQA scheme. It should be conducted on a regular basis to reveal new opportunities in the future and to assess effectiveness of actions taken. Moreover, it could be a model for other EQA providers seeking feedback from participants. Overall, the customer satisfaction survey provided a powerful quality of care improvement tool. PMID- 21663461 TI - Analytical performance of a multiplexed, bead-based cytokine detection system in small volume samples. AB - BACKGROUND: Multiplexed cytokine measurement offers many advantages over the conventional enzyme-linked immunosorbent assay (ELISA) format when applied in large-scale epidemiological studies or clinical trials. In the present study we set out to define the reliability and consistency of a suspension multiplexed protein array, the cytometric bead array (CBA), in large-scale, longitudinal studies. METHODS: The cytokines interleukin (IL)-5, IL-10, tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were measured in pediatric samples from childhood asthma and allergy studies. Analytical performance of CBA was determined in sample supernatants and CBA was compared to conventional ELISA. RESULTS: Within-run and total imprecision were between 5.2%-10.8% and 5.6%-13.2%, respectively, at three different concentrations for all cytokines. Slopes of dilution linearity were between 1.01 and 1.31 for the four cytokines. The recovery rate at two different concentrations of the cytokines was between 97% and 113%. Lower limits of detection and quantification as well as functional sensitivity were determined. Comparison of the multiplex array and solid phase method showed good correlation with r between 0.82 and 0.93. The sample volume required for the multiplex format was 25% of the ELISA sample volume. CONCLUSIONS: CBA analytical evaluation and comparison to an ELISA format demonstrated high reproducibility, sensitivity and good applicability for small volume samples. PMID- 21663462 TI - Development of candidate reference reagent for HIV-1 RNA and comparison analysis for different HIV-1 RNA quantitative assay. AB - BACKGROUND: Human immunodeficiency virus type-1 (HIV-1) RNA viral load is a surrogate marker that is routinely used to determine indications for, and monitor the effectiveness of HIV-1 treatment. We developed three reagents for potential use in routine quality control of HIV-1 RNA quantitative assays. In this report, we compare the stability of these re-agents in storage and compare their performance in three different HIV-1 RNA quantitative assays. METHODS: The candidate reagents were derived from readily available pre-existing reagents and examined for stability at different storage temperatures. They were compared in three commercially available HIV-1 RNA quantitative assays: the Cobas TaqMan HIV 1 Test (Cobas TaqMan), the RealTime HIV-1 Assay (Abbott RealTime), and the NucliSens EasyQ HIV-1 Assay v1.1 (NucliSens EasyQ). RESULTS: The candidate reagent derived from an HIV culture supernatant (candidate CS) was the most stable of the three candidates and showed good reproducibility. Candidate CS yielded the highest HIV-1 titer of the three candidates in the Cobas TaqMan assay and the lowest HIV-1 titer and stability of the three candidates in the NucliSens EasyQ system. CONCLUSIONS: The candidate CS is the most appropriate of the three candidate reagents for quantitative testing of HIV-1 RNA. This working reagent should be useful for use in routine calibration for quality control in centers with limited financial resources. The Cobas TaqMan assay tended to yield higher viral load results than the other assays when used with our three candidate reagents. PMID- 21663463 TI - Pneumatic tube delivery systems for patient samples: evidence of quality and quality of evidence. PMID- 21663464 TI - N Latex FLC - new monoclonal high-performance assays for the determination of free light chain kappa and lambda. AB - BACKGROUND: High serum concentrations of monoclonal free light chain (FLC) kappa or lambda are markers of plasma cell dyscrasia. METHODS: We developed new, latex enhanced, specific nephelometric assays based on monoclonal antibodies for the determination of FLC kappa and lambda in serum, EDTA plasma and Li-heparin plasma for use on the Siemens BNTM systems. RESULTS: Reference ranges were determined from 369 samples: FLC kappa 6.7-22.4 mg/L, FLC lambda 8.3-27.0 mg/L and kappa/lambda ratio 0.31-1.56. Protection from falsely low results due to antigen excess is obtained with a built-in pre-reaction in the assay protocols. Lot-to lot consistency between three different lots of reagent, calibrators and supplementary reagent lots showed normalized differences <7.5%. The reproducibility of serum samples varied between 4% and 7%. The method comparison with FreeliteTM assays showed normalized differences of 19.7%, 32.7% and 21.7%, respectively, for FLC kappa, lambda and ratio, correlations of 0.94, 0.77 and 0.73, and concordance rates of 99.2%, 94.2% and 95%. CONCLUSIONS: N Latex FLC demonstrates high precision, good lot-to-lot consistency and freedom from a high dose hook effect. The method comparison between FreeliteTM and the N Latex FLC assays showed good clinical concordance. Further studies need to reveal the clinical value of the new FLC assays. PMID- 21663465 TI - Pre-acquisition system assessment of the Sysmex((r)) Coagulation System CS-2100i and comparison with end-user verification; a model for the regional introduction of new analysers and methods. AB - BACKGROUND: Pre-acquisition system assessment of clinical laboratory analysers and/or methods are generally repeated independently in each individual organisation planning their introduction. In the course of replacing our 10-year old Sysmex((r)) CA-1500 for Sysmex((r)) CS-2100i coagulometers, we designed and tested a model based on CLSI protocols in which one laboratory performs an extensive validation, allowing others to rely on concise verification. METHODS: Validation of the Sysmex((r)) CS-2100i was performed largely according to CLSI Guideline H57-A and included EP-5, 7, 9 and 10 in the evaluation of 10 assays encompassing all measurement principles available. EP-15 was used for end-user verification. Practicability and results of validation and verification were compared. RESULTS: Analytical performance of the CS-2100i was as claimed by the manufacturer and complied with our own criteria. System verification results were compatible with those of the validation. Verification was time- and cost effective. CONCLUSIONS: We have approved the Sysmex((r)) CS-2100i analyser for introduction in our laboratory. For colleague laboratories in our region introducing this analyser, a system verification is proposed to be sufficient when referring to our data. It is our intention to use the validation vs. end user verification model for future method introduction, and when harmonising between our different laboratory locations. PMID- 21663466 TI - N-terminal pro-B-type natriuretic peptide in early and advanced phases of obesity. AB - BACKGROUND: Increased plasma amino-terminal-cleavage-fragment of NP (NT-proBNP) is an established indicator for heart failure. Moreover, obese adults had low circulating NT-proBNP suggesting an obesity-related dysregulation (natriuretic handicap). Secretion and/or clearance of NT-proBNP were discussed to be impaired in obesity. As only older adults were investigated so far, it remains unclear when during the evolution of obesity the state of a natriuretic handicap develops, and whether NT-proBNP may still serve as a relevant cardiac marker in obese juveniles. METHODS: We analysed NT-proBNP in juvenile (n=274, 10-18 years) and middle-aged (n=277, 18-50 years) normal weight (n=213) and obese (n=338) probands together with complex anthropometry, carotis sonography, clinical, and laboratory parameters. RESULTS: NT-proBNP showed a significant gender and age interaction. Adult females had significant higher NT-proBNP than adult males, and higher levels than juvenile females. Adult males had lower levels than juvenile males. Only a weak age and weight interaction was seen with obese juveniles which showed higher NT-proBNP than obese adults. Moreover, normal weight probands had higher NT-proBNP than overweight and obese. In a multiple regression including all probands, gender, creatinine and uric acid were the best predictors for NT proBNP. In adults, female gender is the strongest driver for increased NT-proBNP. CONCLUSIONS: These results argue against an essential influence of obesity to B type cardiac natriuretic hormone system regulation in the absence of heart failure, and suggest NT-proBNP as a useful cardiac marker irrespective of age and obesity. PMID- 21663467 TI - Soluble ST2 is not independently associated with androgen and estrogen status in healthy males and females. AB - BACKGROUND: Soluble ST2 (sST2) plasma concentrations are significantly higher in healthy men than in healthy women. The reason for the sex-specific difference of sST2 plasma concentrations is not established. The aim of this study was to evaluate the association of sST2 with sex-hormones in healthy males and females separately. METHODS: We recruited 528 consecutive blood donors and measured plasma concentrations of sST2 and several sex-hormones (i.e., total testosterone, estradiol, sex hormone-binding globulin, follicle-stimulating hormone, and luteinizing hormone). Of the 528 blood donors, 338 were male and 190 were female. For data analysis, we further divided the group of females into the subgroups of pre- and postmenopausal women using the age of 50 years as a proxy for menopause. RESULTS: In non-parametric Spearman's correlation analyses, we found a weak association between sST2 and total testosterone (r(s)+0.126, p=0.021) and also between sST2 and estradiol (r(s)+0.117, p=0.032) in males. In females <50 years of age (n=158) and >=50 years of age (n=32), respectively, we did not detect any significant association between sST2 and sex-hormones. As a result of multiple linear regression analyses (calculated with log sST2 as dependent variable and log of age and all sex-hormones as explanatory variables), there was no independent association between sST2 and any of the sex-hormones neither in males nor in females. CONCLUSIONS: In the present study cohort we did not find an independent association of sST2 with sex-hormones in healthy males and females. Therefore, the reason for the sex-specific difference of sST2 plasma concentrations still remains unclear. PMID- 21663468 TI - Post-mortem biochemistry of vitreous humor and glucose metabolism: an update. AB - Post-mortem biochemistry, also called thanatochemistry, has proved useful in forensics for estimating the time since death and assessing the cause of death. Ketoacidosis is a frequent complication of diabetes mellitus which can be lethal, with possible medicolegal implications. However, interpretation of biochemical analyses is difficult because of post-mortem blood alterations involving glucose metabolic pathways. Vitreous humor is better preserved than blood after death, and therefore is preferentially used in thanatochemistry. However, both the lack of experience of most biochemists with this matrix in clinical practice, and the paucity of post-mortem studies make interpretation of post-mortem analyses difficult. This review examines the recent advances in the knowledge of glucose metabolism in vitreous humor, and the methods used for the post-mortem diagnosis of diabetic complications. PMID- 21663469 TI - Golgi protein 73(GP73), a useful serum marker in liver diseases. AB - BACKGROUND: This study was performed to quantify the expression of Golgi protein 73 (GP73) in healthy controls and in patients with liver disease, and to evaluate the correlations between GP73 and other serum markers in different liver diseases. METHODS: Serum GP73 was measured in 478 healthy controls and 296 patients with different types of liver disease. Quantitative hepatitis B virus (HBV) DNA was determined in two chronic hepatitis B (CHB) groups. Other serum liver fibrosis markers were measured in the liver fibrosis group and alpha fetoprotein (AFP) was measured in hepatocellular carcinoma (HCC) group. The correlations between GP73 and these markers were evaluated. RESULTS: The GP73 value in hepatitis B e antigen (HBeAg)-positive CHB group, HBeAg-negative CHB group, liver fibrosis group and HCC group was significantly higher (p<0.001) than that in healthy controls. GP73 showed significant correlation with other markers in the liver fibrosis group and with AFP in the HCC group. CONCLUSIONS: Compared with healthy controls, GP73 in patients with liver disease was significantly increased. With the progression of liver disease, GP73 showed a significantly increasing trend. These results suggest that GP73 might be used as a serum marker for the diagnosis of liver diseases and for monitoring disease progression. PMID- 21663471 TI - Effect of combination on the antioxidant and inhibitory properties of tropical pepper varieties against alpha-amylase and alpha-glucosidase activities in vitro. AB - Pepper used as a spice for food preparations is usually a single type or a combination of several different varieties. This choice is usually based on individual preferences, without consideration of health benefits. Therefore, the present study investigated the health benefits of a combination of 3 pepper varieties commonly consumed in Nigeria. Aqueous extracts (1:100 w/v) of Capsicum annuum var. grossum, C. annuum var. abbreviatum, and C. annuum var. accuminatum and a combination of the 3 varieties (1:1:1) were assayed for phenolic content (total phenol and flavonoid), antioxidant activities (reducing power and 1,1 diphenyl-2-picrylhydrazyl radical-scavenging abilities), inhibitory effect on Fe2+-induced lipid peroxidation in rat pancreas in vitro, and the ability of the extracts to inhibit key enzymes linked with type 2 diabetes (alpha-amylase and alpha-glucosidase). The combination of peppers showed additive effects in their phenolic content and displayed antioxidant properties. However, the inhibition of pancreatic alpha-amylase activity showed an additive effect, whereas alpha glucosidase inhibitory activity was antagonistic with the combination. C. annuum var. accuminatum contributed most to the activities of the combined peppers. Strong inhibitory activities of the peppers against key enzymes linked to type 2 diabetes and Fe2+-induced lipid peroxidation in rat pancreas in vitro, coupled with their antioxidant properties, suggest that pepper could be used in the prevention and management of type 2 diabetes. The pepper combination showed additive tendencies of these properties. PMID- 21663470 TI - BRAF mutations in hairy-cell leukemia. AB - BACKGROUND: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. METHODS: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. RESULTS: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.). PMID- 21663472 TI - Alchornea glandulosa ethyl acetate fraction exhibits antiangiogenic activity: preliminary findings from in vitro assays using human umbilical vein endothelial cells. AB - Alchornea glandulosa has traditionally been used in Brazilian folk medicine for the treatment of immune-inflammatory diseases and as an antiulcer agent to heal gastric ulcer and gastritis. Angiogenesis is a complex multistep process that consists of proliferation, migration, and anastomosis of endothelial cells and has a major role in the development of pathologic conditions, such as inflammatory diseases. To investigate a possible link between the anti inflammatory activities and antiangiogenic effects of A. glandulosa ethyl acetate fraction (AGF), this study examined which features of the angiogenic process could be disturbed by this fraction. The antiangiogenic activity of AGF was determined in vitro by using human umbilical vein endothelial cells (HUVEC), and cell viability, proliferation, apoptosis, invasion, and capillary-like structures formation were addressed. To elucidate the mechanism of action, nuclear factor kappaB (NFkappaB), a transcription factor implicated in these processes, was also evaluated in HUVEC incubated with AGF. A significant decrease in proliferation, a relevant increase in apoptosis, and a strong reduction in invasion capacity (as assessed by bromodeoxyuridine, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and double-chamber assays, respectively) were observed. AGF also led to a drastic reduction in the number of capillary-like structures formed when HUVEC were cultured on growth factor reduced Matrigel-coated plates. In addition, incubation of HUVEC with AGF resulted in reduced NFkappaB activity. These findings emphasize the antiangiogenic potential of AGF and support its therapeutic use for disorders that involve excessive angiogenesis, such as chronic inflammation and tumor growth. PMID- 21663473 TI - The effect of supplementation of grape seed proanthocyanidin extract on vascular dysfunction in experimental diabetes. AB - Increased oxidative stress and impaired endothelium-dependent relaxation could underlie many of the vascular complications associated with diabetes. We aimed to investigate the effect of supplementation with grape seed proanthocyanidin extract (GSPE), a natural antioxidant, on vascular responses and oxidative stress in streptozotocin-induced diabetic rats. Male Sprague-Dawley rats were divided into three groups: control rats, untreated diabetic rats, and GSPE (100 mg/kg, for 6 weeks)-supplemented diabetic rats. Thoracic aorta rings of the rats were mounted in organ baths, and relaxant responses to acetylcholine (ACh), A23187, and sodium nitroprusside (SNP) were assayed in tissues precontracted with 60 mM KCl. Plasma samples used for the measurement of malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. The endothelium-dependent relaxations in response to ACh and A23187 were impaired, but endothelium-independent relaxation in response to SNP did not change in diabetic rats. Supplementation with GSPE significantly improved the relaxant responses to ACh and A23187. The MDA level was significantly elevated and the plasma SOD activity was decreased in diabetic rats, but supplementation with GSPE attenuated the elevated MDA levels and increased plasma SOD activity. Thus supplementation of GSPE may attenuate oxidative stress through the inhibition of lipid peroxidation and may restore endothelial function and reduce the risk of vascular disease in diabetes. PMID- 21663474 TI - Rosmarinus officinalis L. essential oil inhibits in vivo and in vitro leukocyte migration. AB - Rosmarinus officinalis L. (Lamiaceae), popularly known as rosemary, is used for food flavoring and in folk medicine as an antispasmodic, analgesic, antirheumatic, diuretic, and antiepileptic agent. Few studies have shown the anti inflammatory effects of rosemary essential oil (REO). This study evaluated the effects of REO on leukocyte migration through in vivo leukocyte migration and in vitro chemotaxis assay. REO was analyzed by using gas chromatography-mass spectometry, and the main components identified were camphor (27.59%), 1,8 cineole (15.74%), alpha-pinene (16.58%), and beta-myrcene (10.02%). In rats, administration of REO reduced the number of leukocytes that rolled, adhered, and migrated to the scrotal chamber after carrageenan injection. All doses of REO tested significantly inhibited leukocyte chemotaxis induced by casein. The effects of REO on leukocyte migration highlight an important mechanism of the anti-inflammatory action of rosemary. PMID- 21663475 TI - Evaluation of cholinesterase inhibitory and antioxidant activities of wild and cultivated samples of sage (Salvia fruticosa) by activity-guided fractionation. AB - In European folk medicine, Salvia species have traditionally been used to enhance memory. In our previous study of 55 Salvia taxa, we explored significant anticholinesterase activity of cultivated S. fruticosa. In this study, we compared the inhibitory activity of dichloromethane, ethyl acetate, and ethanol extracts of 3 wild-grown samples and 1 cultivated sample of S. fruticosa against acetylcholinesterase and butyrylcholinesterase enzymes (which are associated with pathogenesis of Alzheimer's disease) by using the spectrophotometric Ellman method. Antioxidant activities were assessed by determining 2,2-diphenyl-1 picrylhydrazyl radical-scavenging activity, iron-chelating capacity, and ferric reducing antioxidant power. The dichloromethane extract of the cultivated sample was then subjected to fractionation by using open column chromatography and medium-pressure liquid chromatography to obtain the most active fraction by activity-guided fractionation. All fractions and subfractions were tested in the same manner, and inactive subfractions were discarded. The essential oil of the cultivated sample was analyzed by gas chromatography-mass spectrometry. PMID- 21663476 TI - A survey of the in vitro antifungal activity of heather (Erica sp.) organic honey. AB - Monofloral heather (Erica sp.) honey samples (n=89), harvested in Portugal according to European organic beekeeping rules, were analyzed to test their antifungal effect against Candida albicans, Candida krusei, and Cryptococcus neoformans. A synthetic honey solution was also tested to determine antifungal activity attributable to sugars. The specific growth rate (MU) values showed that growth of all the yeasts was reduced in the presence of honey. The honey concentration (% wt/vol) that inhibited 10% of the yeast growth (X(min)) was 13.5% for C. albicans, 20.5% for C. krusei, and 17.1% for C. neoformans. The respective concentrations of heather honey and synthetic honey in the C. krusei culture medium above 60% (wt/vol) that inhibited 90% of the yeast growth (X(max)) and X(min), respectively, were established, whereas C. albicans and C. neoformans were more resistant because X(max) values were not reached over the range tested (10-60%, wt/vol). Heather honey might be tapped as a natural resource to look for new medicines for the treatment of mycotic infections. Further studies are now required to demonstrate if this antifungal activity has any clinical application. PMID- 21663477 TI - Antioxidant, antinociceptive, and anti-inflammatory properties of the ethanolic extract of Combretum duarteanum in rodents. AB - The antioxidant, antinociceptive, and anti-inflammatory activities of the ethanolic extract from leaves of Combretum duarteanum (EEC) were assessed in rodents through in vitro tests. The antioxidant activity was investigated by using thiobarbituric acid reactive species (TBARS), hydroxyl radical-scavenging, and scavenging activity of nitric oxide assays. The antinociceptive activity was investigated by using acetic acid-induced writhing, formalin, and hot-plate tests in mice. The anti-inflammatory activity was assessed in rats by using the carrageenan-induced hind-paw edema test and arachidonic acid-induced paw edema test. EEC possesses a strong antioxidant potential according to the TBARS, nitric oxide, and hydroxyl radical-scavenging assays; it also presented scavenger activity in all in vitro tests. After intraperitoneal injection, EEC (100, 200, and 400 mg/kg) significantly reduced the number of writhes (38.1%, 90.6%, and 97.8%, respectively) in a writhing test and the number of paw licks during phase 1 (30.5% and 69.5%, higher doses) and phase 2 (38.1%, 90.6%, and 97.8%, all doses) of a formalin test when compared with the control group. Naloxone (1.5 mg/kg, intraperitoneally) antagonized the antinociceptive action of EEC (400 mg/kg), and this finding suggests participation of the opioid system. Administration of 200 and 400 mg/kg (intraperitoneally) of EEC exhibited an anti inflammatory activity in the carrageenin test, which was based on interference with prostaglandin synthesis. This finding was confirmed by the arachidonic acid test. Together, these results indicate that properties of EEC might be further explored in the search for newer tools to treat painful inflammatory conditions, including those related to pro-oxidant states. PMID- 21663478 TI - Accessibility of 3H-secoisolariciresinol diglycoside lignan metabolites in skeletal tissue of ovariectomized rats. AB - Flaxseed, rich in the phytoestrogen lignan secoisolariciresinol diglycoside (SDG), provides protection against bone loss at the lumbar vertebrae primarily when combined with low-dose estrogen therapy in the ovariectomized rat model of postmenopausal osteoporosis. Whether SDG metabolites are accessible to skeletal tissue, and thus have the potential to interact with low-dose estrogen therapy to exert direct local action on bone metabolism, is unknown. The objective of this study was to determine whether metabolites of SDG are accessible to the skeleton of ovariectomized rats and to compare the distribution of SDG metabolites in skeletal tissue with that in other tissues. Rats were fed a 10% flaxseed diet and gavaged daily with tritium-labeled SDG (7.4 kBq/g of body weight) in deionized water (500 MUL) (n=3) or deionized water alone (n=3) for 7 days, after which tissues were collected for liquid scintillation counting. Radioactivity was detected in similar concentrations in the lumbar vertebrae, femurs, and tibias. Compared with non-skeletal tissues, total radioactivity in the skeleton was significantly lower than in the liver, heart, kidney, thymus, and brain (P < .001). There were no significant differences in levels of radioactivity between skeletal tissue versus the spleen, lung, bladder, uterus, vagina, and mammary gland. In conclusion, SDG metabolites are accessible to skeletal tissue of ovariectomized rats. Thus, it is biologically plausible that SDG metabolites may play a direct role in the protective effects of flaxseed combined with low-dose estrogen therapy against the loss of bone mass and bone strength in the ovariectomized rat model of postmenopausal osteoporosis. PMID- 21663479 TI - The protective effect of royal jelly on chronic lambda-cyhalothrin toxicity: serum biochemical parameters, lipid peroxidation, and genotoxic and histopathological alterations in swiss albino mice. AB - The present study was undertaken to investigate the protective effect of royal jelly (RJ) against toxicity induced by a synthetic pyrethroid insecticide, lambda cyhalothrin (LCT), in Swiss albino mice. Animals were randomly divided into six groups of six animals each. The control group received distilled water alone, whereas mice in the treatment groups received RJ alone (100 or 250 mg/kg of body weight), LCT alone (668 ppm), or RJ+LCT for 21 days. All mice (100%) survived until the end of experiment and were sacrificed at the end of 24 hours. Blood, bone marrow, and liver and kidney tissues were analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and reduced glutathione (GSH) levels and micronucleus (MN) frequency, chromosomal aberrations (CAs), and pathological damages. Serum AST, ALT, BUN, and creatinine levels were elevated in mice treated with LCT alone compared with the other tested groups (P<.05). LCT-induced oxidative damage caused a significant decrease in GSH levels and a significant rise in MDA levels of liver and kidney tissues. LCT alone-treated mice presented higher frequencies (P<.05) of MNs, CAs, and abnormal metaphases compared with the controls; moreover, the mitotic index was lower than in controls (P<.05). Oral treatment with RJ significantly ameliorated the indices of hepatotoxicity, nephrotoxicity, lipid peroxidation, and genotoxicity induced by LCT. Both doses of RJ tested provided significant protection against LCT-induced toxicity, and its strongest effect was observed at the dose level of 250 mg/kg of body weight. In vivo results suggest that RJ is a potent antioxidant against LCT-induced toxicity, and its protective effect is dose dependent. PMID- 21663480 TI - The mediterranean diet in cancer prevention: a review. AB - The Mediterranean dietary pattern has a well-established beneficial role in health promotion. Epidemiologic studies reveal the protective role of adherence to this pattern on overall cancer incidence and mortality. This review examines results from prospective cohort, cross-sectional, and case-control studies assessing the role of the Mediterranean diet in cancer prevention. Original research studies that were published in English between 1985 and April 6, 2010, were selected through a computer-assisted literature search (i.e., PubMed and Scopus). From the initial search, 273 papers were selected. After the titles and the abstracts of these papers were read for relevance to this review, 17 studies were selected and are discussed here; 8 had a prospective design, 7 were case control, 1 was a randomized screening study, and 1 was an interventional study. Although there is a lack of definitive evidence for the association of Mediterranean diet with various types of cancer, a dietary pattern emphasizing the consumption of fruits and vegetables, whole grains, legumes, nuts, seeds, and low-fat dairy products could be highly recommended for all people, and especially those at risk for cancer. PMID- 21663481 TI - Preventing bone loss and weight gain with combinations of vitamin D and phytochemicals. AB - Vitamin D and certain natural compounds have been shown to regulate both lipid metabolism and bone formation. Treatments that prevent or reverse age-related increase in bone marrow adiposity could both increase new bone formation and inhibit bone destruction. We tested the hypothesis that dietary supplementation with combinations of vitamin D and phytochemicals inhibits bone loss and decreases adiposity to a greater extent than control or vitamin D-alone diets. Aged ovariectomized female rats (12 months old, n=50, initial body weight=240 g) were given control (AIN-93M diet), vitamin D (2,400 IU/kg), or vitamin D plus resveratrol (16, 80, or 400 mg/kg of diet [low, medium, and high dose, respectively]), quercetin (80, 400, or 2,000 mg/kg of diet), and genistein (64, 256, or 1,040 mg/kg of diet) for 8 weeks. The high-dose treatment (vitamin D+400 mg/kg resveratrol+2,000 mg/kg quercetin+1,040 mg/kg genistein) reduced body weight gain (P<.05) and the fat pad weights (P<.05). This treatment also increased the serum concentration of insulin-like growth factor-1 (P<.05) and the bone mineral content of the femur. Micro-computed tomography and histomorphometric analyses indicated that the high-dose treatment prevented loss of trabecular bone (P<.05) and reduced marrow adipocytes (P<.001) and osteoclasts (P<.05) compared with the control and vitamin D alone (P<.05). We conclude that aged ovariectomized female rats supplemented with vitamin D combined with genistein, quercetin, and resveratrol had improved bone mineral density and reduced body weight gain and a significant decrease in bone marrow adipocytes. The synergistic effects of a combination of phytochemicals with vitamin D may be effective in reducing bone loss and weight gain after menopause. PMID- 21663482 TI - Jacaranda cuspidifolia Mart. (Bignoniaceae) as an antibacterial agent. AB - This study evaluated, in vitro, the antimicrobial activity of the hexane extract (JCHE), methanol extract (JCME), and chloroform fraction (JCCF) of bark from Jacaranda cuspidifolia Mart. (Family Bignoniaceae), a Brazilian medicinal plant, traditionally used as anti-syphilis and anti-gonorrhea treatment. The antimicrobial activity was evaluated using the disc diffusion method followed by the determination of minimum inhibitory concentration (MIC) values. JCHE was not active against the bacteria evaluated. JCME presented antibacterial activity against Streptococcus pyogenes, Staphylococcus aureus, and Neisseria gonorrhoeae with MIC values of 16.3 mg/mL, 9.1 mg/mL, and 25.2 mg/mL, respectively. JCCF was active against Staphylococcus epidermidis, S. aureus, Proteus mirabilis, Serratia marcescens, S. pyogenes, Enterobacter aerogenes, and N. gonorrhoeae with MIC values of 18.3 mg/mL, 9.3 mg/mL, 6.3 mg/mL, 6.1 mg/mL, 9.2 mg/mL, 6.2 mg/mL, and 25.2 mg/mL, respectively. Phytochemical analysis of JCME and JCCF gave positive results for saponins, coumarins, flavonoids, tannins, quinones, alkaloids, triterpenes, and steroids. Verbascoside was isolated and identified as a major peak in JCME and JCCF high-performance liquid chromatography fingerprints and might contribute to the observed antimicrobial activity. PMID- 21663483 TI - Suppression of tumor necrosis factor-alpha-induced nuclear factor kappaB activation and aromatase activity by capsaicin and its analog capsazepine. AB - Target-specific drugs, including natural products, offer promise for the amelioration of cancer and other human ailments. Capsaicin, the pungent ingredient present in chilies (Capsicum annuum L.), and capsazepine, a synthetic analog of capsaicin (collectively referred to as vanilloids), are known to possess a variety of pharmacological and physiological properties. In our continuous effort to discover and characterize cancer chemopreventive agents from natural products, we investigated the effect of vanilloids on nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) activation using stably transfected 293/NFkappaB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor-alpha (TNFalpha) and on aromatase activity. Capsaicin and capsazepine blocked TNFalpha-induced NFkappaB activation in a dose dependent manner with 50% inhibitory concentration (IC(50)) values of 0.68 and 4.2 MUM, respectively. No significant cytotoxicity was observed at the highest concentrations tested (53.1 MUM for capsazepine and 65.5 MUM for capsaicin). In addition, these vanilloids inhibited aromatase activity with IC(50) values of 13.6 and 8.8 MUM, respectively. Computer-aided molecular docking studies showed docking scores indicative of good binding affinity of vanilloids with aromatase and NFkappaB. The highly conserved residues for capsaicin and capsazepine binding with NFkappaB p50 were Ser299 and Ile278 (H-bond 2.81A) and with NFkappaB p100 were Ser6, Arg82, Val86, Arg90 (H-bond 2.89A), Gly4, and Ser2 (H-bond 2.81A). The amino acids Trp224, Arg435, and Val373 (H-bond 2.80A) were found to be important for the binding of capsaicin and capsazepine with aromatase. Based on these findings, aromatase and NFkappaB are suggested as valid targets for these compounds; additional investigation of chemopreventive or chemotherapeutic potential is required. PMID- 21663484 TI - Inhibitory potential of tea polyphenolics and influence of extraction time against Helicobacter pylori and lack of inhibition of beneficial lactic acid bacteria. AB - Tea polyphenolics such as catechins are known to have the potential to inhibit many bacterial pathogens. Helicobacter pylori has been identified as an etiologic agent in the development of gastric ulcer, peptic ulcer, gastritis, and many other stomach-related diseases. In this study, we investigated the effect of 9 tea extracts--3 different brands representing 4 different processed types (white, green, oolong, and black)--on the inhibition of H. pylori. Extraction times of 2 and 5 minutes were compared. Most 5-minute extracts showed H. pylori inhibition, whereas 2-minute extracts only of Choice darjeeling black and Tazo white showed inhibition. No recovery was observed after the addition of 0.5 and 5 mM proline, indicating that tea polyphenols do not inhibit H. pylori by inhibition of proline oxidation via proline dehydrogenase. Extracts that showed inhibition were further evaluated for their effect on beneficial lactic acid bacteria. None of the samples showed inhibition, suggesting that tea might be able to inhibit H. pylori without affecting the beneficial lactic acid bacteria. High-performance liquid chromatography indicated the presence of gallic acid, quercetin, caffeine, and tea catechins (including catechin, epicatechin, and epigallocatechin) in all the tea samples. Our study indicates that tea can be potentially used as a low-cost dietary support to combat H. pylori-linked gastric diseases without affecting the beneficial intestinal bacteria. PMID- 21663485 TI - Influence of contextual and individual level risk factors on adiposity in a preschool child cohort in Ho Chi Minh City, Vietnam. AB - OBJECTIVE: To identify risk factors associated with changes in BMI and sum of skinfold thickness (SSF) in a cohort of preschool children in Ho Chi Minh City (HCMC), Vietnam. METHODS: This one year follow-up study, using multi-stage cluster sampling, was conducted from 2005-2006 with 526 children aged 4-5 years in preschools in urban HCMC. Information on neighborhood, preschool and home environments, socio-economic status, the child and parental characteristics were collected using interview-administered questionnaires. Dietary intake and physical activity were measured using modified, validated questionnaires. Weight, height, and triceps, subscapular and suprailiac skinfold thickness were measured. Generalized estimating equations (GEEs) were used to assess the longitudinal relationships between the risk factors and the development of adiposity. RESULTS: A variety of factors at different levels were associated with changes in BMI and SSFs. As safety of the neighborhood increased, BMI and SSFs decreased (coefficients for BMI: -0.59; 95% CI: -1.16 to -0.01 for girls and -0.80; 95% CI: -1.53, -0.08 for boys, and coefficients for SSFs: -2.71; 95% CI: -5.07, -0.35 for girls and -4.16, 95% CI: -8.28, -0.05). Having both parents overweight was strongly predictive of an increase in BMI (1.18, 0.21-2.16). Maternal pre pregnant BMI status, breast-feeding, and high birth weight were also related to change in adiposity. CONCLUSION: Contextual variables in the community and home environment, and parental characteristics appeared to be more important than individual factors for explaining on changes in adiposity in this child population. PMID- 21663486 TI - Dose-response effect of Bifidobacterium lactis HN019 on whole gut transit time and functional gastrointestinal symptoms in adults. AB - OBJECTIVE: To assess the impact of Bifidobacterium lactis HN019 supplementation on whole gut transit time (WGTT) and frequency of functional gastrointestinal (GI) symptoms in adults. MATERIAL AND METHODS: We randomized 100 subjects (mean age: 44 years; 64% female) with functional GI symptoms to consume a proprietary probiotic strain, B. lactis HN019 (Fonterra Research Centre, Palmerston North, New Zealand), at daily doses of 17.2 billion colony forming units (CFU) (high dose; n = 33), 1.8 billion CFU (low dose; n = 33), or placebo (n = 34) for 14 days. The primary endpoint of WGTT was assessed by X-ray on days 0 and 14 and was preceded by consumption of radiopaque markers once a day for 6 days. The secondary endpoint of functional GI symptom frequency was recorded with a subject reported numeric (1-100) scale before and after supplementation. RESULTS: Decreases in mean WGTT over the 14-day study period were statistically significant in the high dose group (49 +/- 30 to 21 +/- 32 h, p < 0.001) and the low dose group (60 +/- 33 to 41 +/- 39 h, p = 0.01), but not in the placebo group (43 +/- 31 to 44 +/- 33 h). Time to excretion of all ingested markers was significantly shorter in the treatment groups versus placebo. Of the nine functional GI symptoms investigated, eight significantly decreased in frequency in the high dose group and seven decreased with low dose, while two decreased in the placebo group. No adverse events were reported in any group. CONCLUSIONS: Daily B. lactis HN019 supplementation is well tolerated, decreases WGTT in a dose dependent manner, and reduces the frequency of functional GI symptoms in adults. PMID- 21663487 TI - Phenolic composition and antimicrobial and antioxidant activities of Leucoagaricus leucothites (Vittad.) Wasser. AB - Leucoagaricus leucothites (Vittad.) Wasser is an edible macrofungus found limitedly in Turkey. The ethanolic extract of L. leucothites has shown strong antimicrobial activity against some foodborne and spoilage bacteria. Therefore, the phenolic composition of L. leucothites ethanolic extract was analyzed by using high-performance liquid chromatography. Catechin (288 mg/L) was found to be the major component in the extract. Antioxidant activity of the extract was evaluated by studying the scavenging ability of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, and chelating ability of the extract was assessed in a ferrous ion assay. The scavenging effect on DPPH radicals was 71% at 10 mg/mL, whereas the chelating effect on ferrous ions was 82% at 15 mg/mL. The total contents of phenol (3.40 +/- 0.5 mg/g), ascorbic acid (2.10 +/- 0.3 mg/g), beta-carotene (0.02 +/- 0.0 mg/g), and lycopene (0.01 +/- 0.0 mg/g) in the macrofungi ethanolic extract were also determined. PMID- 21663488 TI - Methyl-3-O-methyl gallate and gallic acid from the leaves of Peltiphyllum peltatum: isolation and comparative antioxidant, prooxidant, and cytotoxic effects in neuronal cells. AB - Methyl-3-O-methyl gallate (M3MG) is a rare natural product with close structural similarity to gallic acid. In the present report, the isolation of M3MG from Peltiphyllum peltatum leaves and its comparative antioxidant, prooxidant, and cytotoxicity to neuronal SH-SY5Y cells are discussed. When tested in concentrations up to 1 mM, M3MG consistently showed antioxidant activity without prooxidant effect both in cell and cell-free assay models. In contrast to M3MG, gallic acid showed a copper-dependent prooxidant effect that resulted in DNA damage, increased the level of intracellular reactive oxygen species, and induced cytotoxicity in neuronal cells. The identification of M3MG in P. peltatum leaves is furtherz evidence of the great antioxidant potential and nutritional value of the plant. PMID- 21663489 TI - Oral administration of an enzymatic protein hydrolysate from the green microalga Chlorella vulgaris enhances the nutritional recovery of malnourished mice. AB - This study examined the effects of oral administration of an enzymatic protein hydrolysate from green microalga Chlorella vulgaris (Cv-PH) on the nutritional recovery of malnourished Balb/c mice after a 3-day fasting period. Mice were refed with commercial diet supplemented or not supplemented with Cv-PH (500 mg/kg) for 8 days. Regardless of the diet used during refeeding, animal body weights and serum protein concentrations did not differ between groups. Mice given Cv-PH had a significant increase in hemoglobin concentrations. Most serum amino acid levels were similar in the control and Cv-PH animals. Starved mice refed with Cv-PH showed normal liver functions, as judged by liver weight, protein concentration, and the enzymatic activities of cholinesterase and arginase. Cv-PH increased DNA, protein content, and gut-mucosal weight. In addition, brush-border oligosaccharidase activities were also higher in the Cv-PH group. These findings suggest that Chlorella protein hydrolysate can be used to develop specific formulations suitable for pharmacologic nutrition. PMID- 21663490 TI - Effects of Stevia rebaudiana (Bertoni) extract and N-nitro-L-arginine on renal function and ultrastructure of kidney cells in experimental type 2 Diabetes. AB - Diabetes is the leading cause of chronic renal failure. Our purpose was to determine the effects of N-nitro-l-arginine (l-NNA) and an extract of Stevia rebaudiana (Bertoni) (SrB) leaves on renal function in streptozotocin nicotinamide (STZ-NA)-induced diabetic rats. Rats were divided into seven groups. Three of these groups were controls. Diabetes was induced by STZ-NA in the other four. Diabetic rats were treated with SrB (200 mg/kg), L-NNA (100 mg/kg), or SrB + L-NNA for 15 days after 5-8 weeks of diabetes. At the end of the experiments, urine and blood samples were collected from the rats, and kidney tissue samples were collected with the animals under ether anesthesia. Renal filtration changes were determined by measuring urine pH, urine volume, and serum and urine creatinine. Nitric oxide synthase (NOS) activity was measured in kidney homogenates. Alterations in kidney ultrastructure were determined by electron microscopy, and histological changes were examined by hematoxylin and eosin staining. No statistical differences were observed in urine creatinine or creatinine clearance. Even so, we observed higher NOS activity in SrB-treated diabetic rats. SrB-treated diabetic rats had less mitochondrial swelling and vacuolization in thin kidney sections than other diabetic groups. The control groups showed normal histological structure, whereas in the diabetic groups, membrane thickening, tubular epithelial cells, and cellular degeneration were observed. Thus, SrB has beneficial effects on diabetes compared with l-NNA. Our results support the validity of SrB for the management of diabetes as well as diabetes-induced renal disorders. PMID- 21663491 TI - Fructo-oligosaccharide production from inulin through partial citric or phosphoric acid hydrolyses. AB - Purified inulin from Dahlia tubers was partially hydrolyzed to form fructo oligosaccharides by using citric or phosphoric acids (pH, 2.0-2.5) as mild acid catalysts. The ideal kinetic conditions to ensure a high yield of fructo oligosaccharides relative to free fructose were a temperature range of 85 degrees C-95 degrees C, a hydrolysis time of 15-25 minutes, and a catalyst pH of 2.5. At the higher temperature and the longest hydrolysis time, an inversion of the product ratio occurred. Under these conditions, co-generation of hydroxymethylfurfural occurred, and it was eliminated by activated charcoal. Unlike in classic hydrolysis with hydrochloric or sulfuric acid, deionization of the actual hydrolysates was not necessary because the catalyst neutralization with common bases results in the formation of co-nutrients with alternative uses as foods or fermentation substrates. These whole hydrolysates can be advantageously added as nutraceuticals to carbonated beverages and acidic foods, such as soft drinks and yogurts. PMID- 21663492 TI - Antimicrobial activity of Northwestern Mexican plants against Helicobacter pylori. AB - Helicobacter pylori is the major etiologic agent of such gastric disorders as chronic active gastritis and gastric carcinoma. Over the past few years, the appearance of antibiotic-resistant bacteria has led to the development of better treatments, such as the use of natural products. This study evaluated the anti-H. pylori activity of 17 Mexican plants used mainly in the northwestern part of Mexico (Sonora) for the empirical treatment of gastrointestinal disorders. The anti-H. pylori activity of methanolic extracts of the plants was determined by using the broth microdilution method. The 50% minimum inhibitory concentrations ranged from less than 200 to 400 MUg/mL for Castella tortuosa, Amphipterygium adstringens, Ibervillea sonorae, Pscalium decompositum, Krameria erecta, Selaginella lepidophylla, Pimpinella anisum, Marrubium vulgare, Ambrosia confertiflora, and Couterea latiflora and were greater than 800 MUg/mL for Byophyllum pinnatum, Tecoma stans linnaeus, Kohleria deppena, Jatropha cuneata, Chenopodium ambrosoides, and Taxodium macronatum. Only Equisetum gigantum showed no activity against H. pylori. This study suggests the important role that these plants may have in the treatment of gastrointestinal disorders caused by H. pylori. The findings set the groundwork for further characterization and elucidation of the active compounds responsible for such activity. PMID- 21663493 TI - Antioxidant effect of trans-resveratrol in cultured human retinal pigment epithelial cells. AB - PURPOSE: Oxidative damages to the retinal pigment epithelium (RPE) have been suggested to play a key role in the pathogenesis of age-related macular degeneration. trans-Resveratrol (3,4',5-trihydroxystilbene) is a nonflavonoid dietary polyphenol with various pharmacological effects, including antioxidant activity. The purpose of this study was to evaluate the potential protective effect of resveratrol against hydrogen peroxide induced oxidative stress in cultured human RPE cells. METHODS: Human retinal D407 RPE cells were pretreated with resveratrol at 3 different concentrations (25, 50, and 100 MUM) for 24 h and exposed for 1 h to 500 MUM hydrogen peroxide. Cell viability, cytotoxicity, and the level of intracellular reactive oxygen species (ROS) were determined in basal and oxidative stress conditions. The concentration of reduced glutathione and the activities of catalase, superoxide dismutase, and glutathione peroxidase were also examined under both experimental conditions. RESULTS: Resveratrol in culture media had no cytotoxic effect at a concentration of 25-100 MUM but showed a protective effect against hydrogen peroxide-induced cytoxicity. Pretreatment with resveratrol induced a significant, dose-dependent increase of superoxide dismutase, glutathione peroxidase, and catalase activities. Moreover, resveratrol significantly enhanced the level of reduced glutathione under both basal and oxidative stress conditions. The significant inhibition of the intracellular ROS generation supports the hypothesis that resveratrol can also contribute to the antioxidant defense by directly scavenging the ROS in RPE cells. CONCLUSIONS: Our results indicate that treatment of RPE cells with resveratrol at micromolar concentrations confers a marked protection against oxidative stress. These data suggest that dietary supplementation of resveratrol may contribute to the prevention of RPE degeneration induced by oxidative stress. PMID- 21663494 TI - Hepatoprotective effect of aged black garlic on chronic alcohol-induced liver injury in rats. AB - The hepatoprotective effect of aged black garlic (ABG) against ethanol-induced oxidative liver damage was investigated in adult male Sprague-Dawley rats for 4 weeks. Rats were divided into three groups: a saline (WT) group, an ethanol (ET) group (15 mL/kg of body weight 20% [wt/vol] ethanol), and an ethanol + ABG (ET+ABG) group (ethanol + 100 mg/kg of body weight ABG). ABG administration led to decreased epididymal and total fat pad (P<.05) and liver weights, ameliorated prominent fatty changes around the portal triad, and reduced fat accumulation in liver. ABG caused a significant decrease of the alcohol-induced increases in hepatic activities of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase. Cytochrome P450 2E1 activity was reduced by 55%, whereas the activities of glutathione S-transferase and quinine reductase were increased by 1.5-fold (P<.05) and fourfold (P<.05), respectively, in the ET+ABG group compared with the ET group. ABG treatment significantly decreased the thiobarbituric acid-reactive substances level in liver, heart, and plasma. Glutathione content and the activities of antioxidant enzymes such as glutathione peroxidase, glutathione reductase, and catalase in liver were significantly enhanced. Furthermore, the oxidative damage to blood lymphocyte DNA caused by chronic alcohol ingestion was significantly decreased in the ET+ABG group. In conclusion, ABG has strong antioxidative properties and may be a promising agent for protecting against chronic alcohol-induced liver damage. PMID- 21663495 TI - The biflavonoid amentoflavone induces apoptosis via suppressing E7 expression, cell cycle arrest at sub-G1 phase, and mitochondria-emanated intrinsic pathways in human cervical cancer cells. AB - Amentoflavone, a biflavonoid from Selaginella tamariscina, is known to possess several bioactivities such as antitumor, anti-inflammatory, and antifungal effects. However, the mechanism of the anticancer effects of amentoflavone on human cervical cancer cells has not been studied in detail. In this study, we demonstrated that amentoflavone induces apoptosis in SiHa and CaSki cervical cancer cells by suppressing human papillomavirus protein E7 expression. The cyclins and tumor suppressors were modulated by amentoflavone in SiHa and CaSki human cervical cancer cells: cyclin and hyperphosphorylated retinoblastoma (p pRb) were down-regulated, whereas cyclin-dependent kinase inhibitors and p53 were enhanced. Amentoflavone up-regulated peroxisome proliferator-activated receptor gamma (PPARgamma) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression levels while inhibiting E7-mediated cyclooxygenase-2 (COX 2)/interleukin-32 (IL-32) expressions were downregulated, and Akt phosphorlylation was decreased in an amentoflavone-induced apoptotic process, suggesting that amentoflavone may be a PPARgamma activator. Additionally, the expression of the anti-apoptotic factor Bcl-2 was decreased, whereas that of the well-known apoptotic factor Bax was increased, thereby releasing cytochrome c into cytosol in amentoflavone-treated cervical cancer cells. Furthermore, amentoflavone treatment led to the activation of caspase-3 and -9 and proteolytic cleavage of poly(ADP-ribose) polymerase. The expression level of the extrinsic death receptor Fas (CD95) was not altered by amentoflavone treatment. When these findings are taken together, the biflavonoid amentoflavone activates PPARgamma/PTEN expressions and induces apoptosis via suppressing E7 expression, cell cycle arrest at sub-G1 phase, and mitochondria-emanated intrinsic pathways in SiHa and CaSki human cervical cancer cells. These findings suggest that amentoflavone has potential for development as a therapeutic agent for human cervical cancer. PMID- 21663496 TI - GLP-1 receptor agonists and HBA1c target of <7% in type 2 diabetes: meta-analysis of randomized controlled trials. AB - OBJECTIVE: Glucagon-like peptide-1 (GLP-1) receptor agonists are available for the treatment of type 2 diabetes. We assessed the efficacy of exenatide and liraglutide to reach the HbA(1c) target of <7% in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted an electronic search for randomized controlled trials (RCTs) involving GLP-1 agonists through September 2010. RCTs were included if they lasted at least 12 weeks, included 30 patients or more, and reported the proportion of patients reaching the HbA(1c) target of <7%. RESULTS: A total of 25 RCTs reporting 28 comparisons met the selection criteria, which included 9771 study participants evaluated for the primary endpoint, 5083 treated with a GLP-1 agonist and 4688 treated with placebo or a comparator drug. GLP-1 agonists showed a statistically significant reduction in HbA(1c) compared to placebo and the proportion of participants achieving the HbA(1c) goal <7% was 46% for exenatide, 47% for liraglutide, and 63% for exenatide LAR (long-acting release). Moreover, the reduction of the HbA(1c) level and the rate of HbA(1c) goal attainment were higher for both exenatide LAR and liraglutide, as compared to comparator drugs. Higher rates of hypoglycemia with exenatide b.i.d. and liraglutide compared to placebo were associated with the concomitant use of a sulfonylurea. Exenatide b.i.d. and liraglutide were associated with weight loss compared to placebo or other antidiabetic drugs. Baseline HbA(1c) was the best predictor for achievement of A1c target (overall weighted R(2) value = 0.513, p < 0.001). CONCLUSIONS: A greater proportion of patients with type 2 diabetes can achieve the HbA(1c) goal <7% with GLP-1 agonists compared to placebo or other antidiabetic drugs; in absolute terms, exenatide LAR was best for the attainment of the HbA(1c) goal. PMID- 21663497 TI - Psychological impact of premature ejaculation and barriers to its recognition and treatment. AB - BACKGROUND: Premature ejaculation (PE) is the most common male sexual dysfunction, occurring in 20-30% of men. Unlike erectile dysfunction, which increases with age, rates of PE remain constant across the adult life span. OBJECTIVE: To review the prevalence of PE, its psychological sequelae and barriers to effective treatment, treatment options, and the effects of treatment on the psychological burden of PE. METHODS: PubMed and Embase databases were searched to identify primary papers related to PE published between 1980 and 2010. Key words included premature ejaculation, prevalence, quality of life, interpersonal relationships, psychotherapy, drug therapy, and treatment barriers. RESULTS: Men with PE often suffer from significant psychological distress including anxiety, depression, lack of sexual confidence, poor self-esteem, impaired quality of life, sexual dissatisfaction, and interpersonal difficulties. Due to various reasons, however, most men do not seek treatment for PE. Many physicians are unaware of the distressful nature of PE and might be reluctant to ask patients about their sexual function. Nevertheless, increasing clinical research on pharmacologic treatment of PE, and the use of on-demand orally administered short-acting selective serotonin reuptake inhibitors or topically applied local anesthetics, appears promising. Although few rigorous studies assessing psychotherapeutic treatments have been conducted, many clinicians report the success of psychological treatments for PE. SUMMARY AND CONCLUSIONS: Conclusions drawn from this review are limited due to inherent variations across studies, including criteria to define PE, study designs, outcome measures, populations, survey instruments, and study settings. While the psychological distress associated with PE suggests the appropriateness of at least minimal counseling for couples, limited data are available to support a combined psychotherapeutic and pharmacologic treatment approach. The paucity of well designed psychotherapy or combination studies represents an important unmet need in the treatment of PE. PMID- 21663498 TI - Role of gut microbiota in graft-versus-host disease. AB - Our understanding of graft-versus-host disease (GVHD) has mostly focused on the role of adaptive immunity in mediating host-recipient genetic disparity in the proinflammatory milieu. These experimental models rarely address the unique biology of GVHD whereby it targets mainly epithelial compartments of the intestine, skin, and liver. Recent discoveries of the role of the microbiota in health and disease have reinvigorated questions about how the innate immunity contributes to the pathogenesis of GVHD and perhaps explains its tissue tropism. In this review, we discuss findings indicating the potential role of pattern recognition receptors of the innate immune system in mediating GVHD and present evidence that shows how the microbiota interact with the host to shape health and disease. These findings support a reevaluation of our current clinical practice and encourage further studies of the potential critical role of the gut microbiota in hematopoietic stem cell transplant which may lead to novel preventive and therapeutic targets against GVHD. PMID- 21663499 TI - Radiation therapy improves treatment outcome in patients with diffuse large B cell lymphoma. AB - The effects of radiotherapy (RT) after chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear; several trials have yielded conflicting results. This study examined the effect of RT after cyclophosphamide, doxorubicin, vincristine, and prednisone + rituximab (R-CHOP) treatment on event free (EFS) and overall (OS) survival. Data from 216 patients with DLBCL who were enrolled in two clinical trials at Italian Lymphoma Study Group sites and were subjected to six R-CHOP cycles and involved-field radiotherapy (IFRT) were retrospectively analyzed. IFRT treatment yielded significant EFS benefit, with a 66% reduction in the risk of death and/or disease progression. Cox analysis, when adjusted for age, gender, stage, performance status (PS), lactate dehydrogenase (LDH), and disease bulk, confirmed the significant EFS benefit of IFRT. The role of RT in DLBCL in the rituximab era is unclear. Future studies must take into account new radiation techniques and the response to chemotherapy based on functional imaging. Prospective randomized trials incorporating response-adapted therapy and modern radiation techniques are needed. PMID- 21663500 TI - Use of 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography in patients with Hodgkin lymphoma in daily practice: a population-based study from Northern Italy. AB - We conducted a population-based study to assess how positron emission tomography (PET) is currently used in patients with Hodgkin lymphoma (HL). Four cancer registries from northern Italy were used to identify patients with HL diagnosed from 2006 to 2008. Computed tomography (CT) and PET scans were collected before treatment start (B), at the end (F), and during treatment (I). One hundred and thirty-six patients were identified as the study population. B-PET, I-PET, and F PET were performed in 82%, 65%, and 85% of patients, respectively. Overall, I-PET was coded as positive in 16% of cases. F-PET was positive in 13% of cases. The I PET result was a prognostic factor for failure-free survival (FFS) (hazard ratio [HR] 5.33); the F-PET result was the only prognostic factor for overall survival (OS) (HR 14.2). This population-based study confirms the prognostic role of I-PET for FFS also in daily practice; the results of F-PET can be used to predict OS. PMID- 21663501 TI - Stem cell transplant: an effective salvage therapy for multiple myeloma. PMID- 21663502 TI - The pandemic H1N1 influenza vaccine results in low rates of seroconversion for patients with hematological malignancies. AB - Patients with hematological malignancies are at increased risk of influenza and its complications, but evidence for the efficacy of influenza vaccination in this population is limited. We sought to determine whether patients being treated for hematological malignancies were able to mount protective antibodies to the H1N1 influenza vaccine. Pre- and post-vaccination plasma samples were collected from patients with hematological malignancies during the 2009-2010 influenza season. Seroconversion was defined as a four-fold increase in antibody titer, as measured by the hemagglutinin inhibition test. Sixty-two patients received the H1N1 vaccine and 41 patients were unvaccinated controls. The rate of seroconversion among vaccinated patients was 21%, which was significantly higher than that in unvaccinated patients (0%), but significantly lower than that previously reported for healthy adults. Physicians should be aware that influenza vaccination may not generate an immune response in patients with hematological malignancies. Larger studies are required to confirm these results. PMID- 21663503 TI - Richter syndrome presenting as a solitary cerebellar tumor during first-line treatment for chronic lymphocytic leukemia. PMID- 21663504 TI - High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphoma. AB - The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL). However, combined therapy is associated with increased neurotoxicity. In an effort to limit this toxicity, we treated a series of non immunocompromised patients with HDMVP, a HD-MTX based regimen, with deferral of WBRT until progression. Twenty-three patients were treated with the HDMVP regimen consisting of MTX, vincristine, and procarbazine. The mean age at diagnosis was 60.9 years (range 45-79 years). The overall response rate was 65% (14 complete responses and one partial response). For patients achieving an initial response with HDMVP the median response duration was 40.4 months (95% confidence interval [CI] 19.5-61.3). The median progression-free survival was 4.6 months (95% CI 0.0 20.4) and median overall survival was 41.4 months (95% CI 0.0-95.5). Fourteen patients received WBRT for relapsed or progressive disease. The conclusion of this trial is that HDVMP results in good initial response rates but only moderate disease control. Ultimately the majority of the patients in this series required WBRT for salvage treatment, potentially enabling a delay in treatment-associated neurotoxicity. PMID- 21663505 TI - Myelodysplastic syndromes: the role of the immune system in pathogenesis. AB - The myelodysplastic syndromes (MDS) represent a complex spectrum of clonal hematopoietic stem cell disorders manifested by cytopenias, risk of infection, and variable risk of progression to acute myelogenous leukemia. Several theories of MDS pathogenesis exist, with contributions of genetic, epigenetic, apoptotic, differentiation, and cytokine milieu abnormalities. Immune dysregulation has also been implicated in MDS pathogenesis. In some forms of MDS it is evident that immune dysregulation may be a primary pathophysiologic abnormality, while in others the abnormal immune function may represent only a small part of the pathologic puzzle. We review the current literature regarding natural killer (NK) cell, T cell, and myeloid derived suppressor cell abnormalities in the spectrum of MDS. PMID- 21663506 TI - Imatinib mesylate in T-cell large granular lymphocyte leukemia associated with chronic graft-versus-host disease. PMID- 21663507 TI - Nodular lymphocyte predominant Hodgkin lymphoma behaves as a distinct clinical entity with good outcome: evidence from 14-year follow-up in the West of Scotland Cancer Network. AB - Clinically and biologically, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) has much more in common with germinal-center derived B-cell non-Hodgkin lymphoma (NHL) than with classical Hodgkin lymphoma (cHL). Management of NLPHL remains controversial. In a 14-year multicenter series, 69 cases were analyzed, and the median follow-up was 53 months (range 11-165.) B-symptoms were present in only 4.3% of patients, and 81.1% of patients had stage I/II disease. Treatment was with radiotherapy (53.6%), chemotherapy (21.7%), combined modality (17.4%), and observation (7.2%). In all, 10.1% of patients relapsed and 2.9% of patients developed high-grade transformation to DLBCL. All relapses and transformations were salvageable. No patient died of their disease. The 5-year relapse-free survival was 92%, transformation-free survival 98.4%, and overall survival 100%. We conclude that NLPHL behaves as a distinct clinical entity, often presenting at an early stage without risk factors. It has an excellent outcome. It may be possible, in early-stage disease, to reduce the intensity of therapy in NLPHL, to single-modality radiotherapy, without affecting OS. PMID- 21663508 TI - Efficacy and safety of rituximab treatment in patients with progressive transformation of germinal centers after Hodgkin lymphoma in complete remission post-induction chemotherapy and radiotherapy. AB - Because the lymphatic tissue of progressive transformation of germinal centers (PTGC) expresses CD20, rituximab treatment may prevent transformation to lymphoma of this rather atypical entity. We prospectively evaluated the efficacy of immunotherapy with rituximab (375 mg/m2 i.v. weekly for 4 consecutive weeks, followed by a single i.v. infusion of 375 mg/m2 every 3 months for 2 consecutive years) in 48 patients with biopsy-proven PTGC after Hodgkin lymphoma in complete remission post-induction therapy (4-6 courses of anthracycline-containing chemotherapy with radiotherapy). The event-free survival (EFS) of this series was compared with that of a historical cohort of 48 patients with PTGC developing after Hodgkin lymphoma in complete remission post-induction therapy, who underwent observation. At a median follow-up of 40 months, histology showed a malignancy in 27% of patients in the observation group (Hodgkin lymphoma, 13 patients) and in 2% of patients in the rituximab-protected group (non-Hodgkin lymphoma, one patient) (p ~ 0.001). Rituximab was well tolerated in all treated patients. All relapses in the group not protected by immunotherapy involved the PTGC regions and non-contiguous nodal sites, which suggests that PTGC is a reservoir for malignant transformation and dissemination. The number needed to treat with rituximab to avoid one Hodgkin lymphoma relapse was four. Our study shows that prophylaxis with rituximab helps improve EFS in patients with PTGC and a history of Hodgkin lymphoma. PMID- 21663509 TI - Plerixafor to rescue failing chemotherapy-based stem cell mobilization: it's not too late. AB - Plerixafor can rescue the outcome of failing chemotherapy-based stem cell mobilization. However, the optimal time for plerixafor injection in this setting has not been determined. This was investigated by retrospective analysis of data from 48 mobilizations with plerixafor, chemotherapy, and granulocyte-colony stimulating factor (G-CSF). The required yield of 2.0 * 10(6) CD34+ cells/kg was collected from 71% of patients; the median total yield was 4.1 * 10(6) CD34+ cells/kg. Patients to whom plerixafor was administered late (>= 15 days) after chemotherapy, after a long duration (>= 13 days) of treatment with G-CSF, or when the white blood cell count was high (>= 20 * 10(9)/L) were mobilized as efficiently as other patients. Plerixafor was shown to rescue mobilizations at a comparable rate in patients with critically low levels of peripheral blood CD34+ cells (<3/uL) and those with higher concentrations. These data suggest that late administration of plerixafor in the course of chemotherapy-based mobilization does not contribute to the failure of this strategy. PMID- 21663511 TI - Chromosomal translocation t(9;22)(p24;q11) appears to be recurrently associated with myeloid malignancy with aggressive course. PMID- 21663510 TI - Clinical outcome of chronic myeloid leukemia imatinib-resistant patients: do BCR ABL kinase domain mutations affect patient survival? First multicenter Argentinean study. AB - In imatinib-treated patients with chronic myeloid leukemia (CML), BCR-ABL mutations are the most common mechanism of resistance. Here we report the first multicenter Argentinean study investigating mutations in those patients with CML who fail or lose response to imatinib, with or without previous interferon treatment. Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255K/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses. While overall survival did not differ between patients with or without mutations, the probability of progression was higher in patients with mutations. Cases with non-P-loop mutations showed a significantly better overall survival from diagnosis. Multivariate analysis showed that the most significant variables related to the development of mutations were accelerated phase, duration of imatinib treatment, and time delay to starting imatinib. Our results demonstrated that mutation frequency increased with the progression of disease, and suggest that imatinib treatment should be started early. PMID- 21663512 TI - The prognostic relevance of tumor associated macrophages in advanced stage classical Hodgkin lymphoma. AB - Although the treatment of Hodgkin lymphoma (HL) has been improved, distinguishing reliable prognostic biomarkers could better stratify patients for more effective treatment. We analyzed the prognostic relevance of CD68+ tumor-associated macrophages (TAMs) by immunohistochemical analysis at diagnosis and standard clinical parameters in 52 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) treated patients with advanced stage classical HL (cHL). Patients with >25% CD68+ TAMs compared to those with <=25% had worse 5-year overall survival (45% vs. 77%, log-rank p = 0.019) and showed a trend toward shorter 5-year event-free survival (51% vs. 71%, log-rank p = 0.19). Additionally, no significant correlation with selected clinical features was found. Significantly shorter 5-year overall survival was associated with International Prognostic Score (IPS) >2, bulky disease, elevated erythrocyte sedimentation rate (log-rank test, p = 0.003, p = 0.049, p = 0.007, respectively). In multivariate analysis, increased CD68+TAMs, IPS >2, and bulky disease were identified as independent prognostic factors for overall survival (Cox multivariate model, p = 0.006, p = 0.007, p = 0.013, respectively). Tumor-associated macrophages represent a potential prognostic biomarker which could contribute to better risk stratification of patients with cHL. PMID- 21663513 TI - A randomized trial with melphalan and prednisone versus melphalan and prednisone plus thalidomide in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplant. AB - Several trials comparing the efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in elderly patients with multiple myeloma (MM) have been reported, with inconsistent results. The primary goal of our study was to evaluate the efficacy and toxicity of MP versus MPT in newly diagnosed patients with MM who were transplant-ineligible or over age 65. A total of 135 patients were enrolled. Either minimal response or better or partial response or better were more frequent with MPT treatment (p = 0.001). After a median follow up of 30 months, median progression-free survival (PFS) and overall survival (OS) were 33 and 52 months for MPT versus 22 and 32 months for MP, respectively. The comparison showed a significant advantage for MPT versus MP in PFS (p = 0.02) and only a trend for OS (p = 0.07). Severe adverse events were observed more frequently with MPT. In conclusion, our results show an improved activity of MPT at a cost of increased toxicity. We believe that MPT can be considered one of the new standard of care for elderly or transplant-ineligible patients with MM. PMID- 21663514 TI - Alternative technique for intrafemoral injection and bone marrow sampling in mouse transplant models. PMID- 21663515 TI - Development of imatinib and dasatinib resistance: dynamics of expression of drug transporters ABCB1, ABCC1, ABCG2, MVP, and SLC22A1. AB - About 20% of patients with chronic myeloid leukemia (CML) do not respond to treatment with imatinib either initially or because of acquired resistance. To study the development of CML drug resistance, an in vitro experimental system comprising cell lines with different resistance levels was established by exposing K562 cells to increasing concentrations of imatinib and dasatinib anticancer agents. The mRNA levels of BCR- ABL1 and of genes involved in drug transport or redistribution (ABCB1, ABCC1, ABCC3, ABCG2, MVP, and SLC22A1) were measured and the ABL1 kinase domain sequenced. Results excluded BCR- ABL1 overexpression and mutations as relevant resistance mechanisms. Most studied transporters were overexpressed in the majority of resistant cell lines. Their expression pattern was dynamic: varying with resistance level and chronic drug exposure. Studied efflux transporters may have an important role at the initial stages of resistance, but after prolonged exposure and for higher doses of drugs other mechanisms might take place. PMID- 21663516 TI - Tryptophan supplements promote pregnancy success in mice challenged with pseudorabies virus (PRV) by regulating the expression of systemic cytokines, immunoglobulins, PRV-specific protein profiles, and toll-like receptors. AB - Tryptophan (Trp) plays an important role in regulating the maternal immune response, a key determinant of the success or failure of pregnancy, but whether Trp supplements can prevent a pseudorabies virus (PRV)-induced failure of pregnancy remains unknown. This study examined the effect of three dietary Trp levels (0.25%, 0.35%, and 0.5%) on the immunity and reproduction of PRV challenged pregnant mice. PRV challenge resulted in decreased live embryo numbers, live litter sizes, and serum progesterone and interleukin (IL)-10 concentrations, but increased the levels of serum immunoglobulins (Igs) (PRV specific antibody [IgG, IgA, and IgM]) and IL-1beta. Live embryo numbers, live litter sizes, serum progesterone concentration, and IgG and PRV-specific antibody levels on day 9 of pregnancy were all increased dose-dependently by Trp inclusion in the diet of PRV-challenged mice. Increased Trp levels in PRV-challenged mice promoted the up-regulation of uterine and embryonic indoleamine 2,3-dioxygenase expression, but attenuated the up-regulation of uterine and embryonic Toll-like receptor (TLR) 3 and TLR9 expression and increased serum interferon-gamma concentration. Collectively, Trp supplements might improve reproductive performance of PRV-challenged pregnant mice by down-regulating TLR expression and pro-inflammatory cytokine synthesis, by up-regulating PRV-specific antibody and immunoglobulin synthesis, and by elevating the concentrations of anti inflammatory cytokines and progesterone. PMID- 21663517 TI - Comparison of intraocular pressure-lowering effect of every night versus every other night dosing of bimatoprost 0.03%. AB - PURPOSE: To compare intraocular pressure (IOP) reduction profiles of bimatoprost 0.03% administered every other night (QOD-HS) compared with every night (QHS) in patients with primary open angle glaucoma and pseudoexfoliation glaucoma. METHODS: A retrospective chart review of 68 eyes of 45 consecutive patients who were switched from QHS to QOD-HS bimatoprost due to intolerable conjunctival hyperemia between May 2005 and May 2008. IOP in the morning (AM) and afternoon (PM) of the next day after administration (day 1) and the day after (day 2) on QOD-HS regimen was compared with IOP in the AM and PM when they were on QHS regimen, 4-6 weeks after switching to QOD-HS. RESULTS: Mean IOPs on QHS bimatoprost were 15.9+/-3.4 mm Hg in the AM and 15.5+/-2.7 mm Hg in the PM, whereas mean IOPs on QOD-HS were 14+/-2 mm Hg (AM) and 14.2+/-2.5 mm Hg (PM) on day 1, and 14.7+/-2.6 mm Hg (AM) and 14.4+/-2.4 mm Hg (PM) on day 2 after administration. Differences between IOP fluctuation on QHS and QOD-HS days 1 and 2, respectively, were not significant (P=0.87 and 0.94). CONCLUSION: Every other night dosing of bimatoprost was effective in controlling IOP in this select group of patients with primary open angle glaucoma and pseudoexfoliation glaucoma who had troublesome side effects on bimatoprost 0.03% QHS regimen, and may be considered as an alternative to every day treatment. PMID- 21663518 TI - Effects of Passiflora edulis on the metabolic profile of diabetic Wistar rat offspring. AB - Dry extract of the genus Passiflora has been shown to help control glycemia and lipid levels. The objective of this study was to evaluate the effects of passion fruit (P. edulis) on the biochemical profile of offspring from diabetic rats. Diabetes was induced by streptozotocin. The diabetes group consisted of 10 rats with glucose levels greater than 200 mg/dL; the nondiabetic (control) group consisted of 10 rats with glucose levels less than 120 mg/dL. After the diagnosis of diabetes, the mating phase was started. By day 21 of pregnancy, the offspring were born; the dams were kept in individual cages with their offspring until the weaning period. The offspring were then divided into 4 groups (n=15 each): G1 were offspring from control dams, G2 were offspring from treated nondiabetic dams, G3 were offspring from diabetic dams, and G4 were offspring from treated diabetic dams. For 30 consecutive days, G1 and G3 offspring were treated with vehicle (oral gavage) and G2 and G4 offspring were treated with passion fruit juice (oral gavage). After 30-day treatment, the animals were anesthetized and killed, and blood was drawn immediately for analysis of the biochemical profile (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and glucose). The G2 and G4 rats showed significantly reduced total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels and an increased high-density lipoprotein cholesterol level. The use of passion fruit juice improved lipid profiles, suggesting that this plant may have beneficial effects in the prevention and treatment of dyslipidemias and hyperglycemia. PMID- 21663519 TI - Evaluation of soybean methanol fraction on acute inflammation. AB - Soybeans have been of interest of researchers because of the presence of isoflavones, a subclass of flavonoids, which have demonstrated anti-inflammatory activity. The aim of this study was investigate the anti-inflammatory activity of the methanol fraction from soybean, which contains mainly isoflavone glucosides and malonylglucosides. The anti-inflammatory activity of the methanol fraction from soybean was studied using croton oil-induced mouse ear edema and carrageenan induced pleurisy models. The methanol fraction inhibited the ear edema in a dose dependent manner: 0.625 mg/kg by 44.23% (P<.05), 1.25 mg/kg by 60.68% (P<.01), and 2.5 mg/kg by 65.68% (P<.01). Myeloperoxidase enzyme activity was reduced at the dose of 2.5 mg/kg (64.79%, P<.05). No effects were seen on carrageenan induced pleurisy at different doses of the methanol fraction (100 or 400 mg/kg). These results demonstrated that the methanol fraction containing conjugated isoflavones showed topical anti-inflammatory activity. There was no acute toxicity in Swiss mice after oral administration of the fraction, at doses of 1,000, 2,000, 3,000, and 4,000 mg/kg. PMID- 21663520 TI - Association between single-nucleotide polymorphisms in pre-miRNAs and the risk of asthma in a Chinese population. AB - Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA (miRNA) expression levels or processing and contribute to susceptibility to a wide range of diseases. We investigated the correlation between four SNPs (rs11614913, rs3746444, rs2910164, and rs229283) in pre-miRNAs and the risk of asthma in 220 asthma patients and 540 controls using polymerase chain reaction-restriction fragment length polymorphism methodology and DNA-sequencing. There were significant differences in the genotype and allelic distribution of rs2910164G/C and rs2292832C/T polymorphisms among cases and controls. The CC genotype and C allele of rs2910164G/C were significantly associated with a decreased risk of asthma (CC vs. GG, odds ratio [OR] = 0.51, 95% confidence interval [CI]: 0.31 0.82; C vs. G, OR = 0.74, 95% CI: 0.59-0.93). Similarly, the TT genotype and T allele of rs2292832C/T were significantly associated with a decreased risk of asthma (TT vs. CC, OR = 0.56, 95% CI: 0.33-0.95; T vs. C, OR = 0.71, 95% CI: 0.53 0.95). However, no significant association between the other two polymorphisms (i.e., rs11614913C/T and rs3746444C/T) and the risk of asthma was observed. Our data indicate that rs2910164G/C and rs2292832C/T may play a role in the development of asthma. PMID- 21663521 TI - Two successful pregnancies in a woman affected by cystic fibrosis: case report and review of the literature. AB - BACKGROUND: Pregnancies in patients with cystic fibrosis (CF) are subject to an increased risk of complications. METHODS: We have made a systematic review of the literature concerning pregnancies in women with CF to evaluate prognostic factors of pregnancy outcome such as lung function and nutritional status, also including and describing the case of a woman suffering from CF who had two pregnancies in her late thirties, both with a good outcome. RESULTS: Thirteen case series and 22 case reports involving 523 pregnancies in 401 women were extracted. 83.1% of 516 pregnancies whose outcome was known resulted in the delivery of live births, with preterm birth rate of 24%. Miscarriage occurred in 6.3% and therapeutic abortion in 10% of pregnancies. Indirect mother's death occurred in seven cases. In our case report, the course of the second pregnancy proved to be much more difficult than the first, with preterm delivery probably related to a worsening of lung disease in the third trimester of pregnancy. CONCLUSIONS: Pre-pregnant lung function as well as lung function deterioration, CF-related diabetes mellitus and weight gain in pregnancy, are parameters to consider in the counseling about the outcome of pregnancy. PMID- 21663522 TI - Impact of early chronic kidney disease on maternal and fetal outcomes of pregnancy. AB - BACKGROUND: Elevated serum creatinine is associated with higher maternal and fetal risks; however, the influence of milder degree of renal impairment diagnosed on basis on estimated glomerular filtration rate (eGFR) is less well defined. This study assesses the impact of early chronic kidney disease (CKD) utilizing eGFR in predicting adverse outcomes in women with CKD. METHODS: We analyzed outcomes of 98 pregnant women with CKD. Women with CKD stage 1 were used as control. RESULTS: Women with eGFR of 60?89 ml/min were at an increased risk for deterioration of renal function, preeclampsia, and cesarean section. The odd ratios for composite maternal complication of worsening of renal function or preeclampsia were 6.75 (95% confidence interval (CI), 1.84-24.80) in women with eGFR of 60?89. Similarly, women with an eGFR of 60?89 had a significantly increased risk for intrauterine growth restriction (38.5%), preterm birth (31.2%), and intrauterine fetal death (15.8%). The odds for composite fetal adverse outcomes were 2.91 (95% CI, 1.19-7.09) in women with eGFR of 60?89. CONCLUSIONS: Early CKD increases the risk of adverse outcomes in pregnancy. Estimated GFR ranging between 60?89 ml/min/1.73 m(2) is associated with significant maternal and fetal complications. The risk of adverse outcomes in pregnant women with early CKD can be more accurately stratified by using estimated GFR than the serum creatinine alone. PMID- 21663523 TI - Difficulties in establishing routine amniocentesis for preterm labor evaluation. AB - After a recent practice change implementing amniocentesis into the evaluation of preterm labor (PTL) or preterm premature rupture of membranes (PPROM), actual performance of the procedure was tracked. Fifty-nine patients were admitted with these diagnoses. Twenty-three patients (39%) were offered amniocentesis and 36 patients (61%) were not offered amniocentesis as part of the clinical protocol. Seven (30%) patients of those offered an amniocentesis underwent the procedure. The predominant reasons for not performing an amniocentesis were patient refusal and provider discomfort. In conclusion, implementation of amniocentesis to evaluate for subclinical infection/inflammation in the setting of PTL or PPROM proved difficult, as only 7 of 59 (11.9%) patients admitted with these diagnoses actually received an amniocentesis. PMID- 21663524 TI - Ku80 is differentially expressed in human lung carcinomas and upregulated in response to irradiation in mice. AB - Based on the role of Ku80 in mediating radiation-induced DNA repair, we investigated Ku80 expression in human lung cancers of different pathological types and evaluated the effect of radiotherapy on Ku80 expression levels in a mouse model. We used immunohistochemistry and real-time PCR to determine Ku80 protein and mRNA levels, respectively. We inoculated nude mice with A549 cells and subjected the tumor-bearing mice to varying doses of irradiation. Lung carcinoma tissue exhibited higher Ku80 mRNA and protein levels when compared with normal tissue. Among the tumor subtypes, lung adenocarcinoma and lung squamous carcinoma showed higher levels of Ku80 protein and mRNA, compared with small-cell lung carcinoma. There was a dose-dependent and time-dependent increase in Ku80 mRNA levels in nude mice that were inoculated with A549 cells and exposed to varying doses of irradiation. Ku80 may play an important role in the DNA damage response pathway. Higher Ku80 levels in lung squamous carcinoma and adenocarcinoma may explain their lower radiosensitivity when compared with small cell lung carcinoma. Ku80 expression levels could be useful in predicting radiosensitivity of lung tumors and inhibition of Ku80 may be an interesting target to improve radiosensitivity in lung cancer patients. PMID- 21663525 TI - Clopidogrel hydrogen sulphate for atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation is a common cardiac rhythm abnormality with a considerable cardiovascular disease burden worldwide. It is an independent major risk factor for stroke. Stroke prevention with anticoagulation or antiplatelet agents has been an important area of clinical research. Warfarin is the most widely used antithrombotic therapy for stroke prophylaxis for last several years, and now dabigatran (150 mg b.i.d.) is more effective than warfarin in stroke prevention in individuals at increased of stroke. In addition, several studies have evaluated the efficacy of clopidogrel for stroke prophylaxis either alone or in combination with aspirin. AREAS COVERED: This review summarizes the key findings of the trials looking at the efficacy of clopidogrel in stroke prevention. A literature search was performed using PubMed and Google Scholar. The trials that evaluated the efficacy of clopidogrel in preventing atherothrombotic events or stroke were also included. EXPERT OPINION: Clopidogrel prevents more vascular events, including stroke, in patients with a recent myocardial infarction, stroke or peripheral vascular disease than aspirin. Combination of clopidogrel and aspirin provides a greater reduction of stroke than aspirin or clopidogrel monotherapy, but at an increased risk of bleeding. Dual antiplatelet therapy (clopidogrel and aspirin) is inferior to warfarin in primary stroke prevention for patient with atrial fibrillation and thus should be considered for stroke prophylaxis only in patients ineligible for warfarin. However, with the advent of newer agents, like direct thrombin inhibitors and Factor Xa inhibitors, the role of antiplatelet therapy for stroke prevention in atrial fibrillation remains unclear. PMID- 21663526 TI - Novel opioid antagonists for opioid-induced bowel dysfunction. AB - INTRODUCTION: Adverse effects frequently limit the therapeutic benefits of opioid analgesics. Gastrointestinal adverse effects are common, burdensome, and can compromise the quality of life. It is estimated that up to 81% of patients still report constipation despite regular use of laxatives. Thus, the development of opioid antagonists that selectively target receptors in the gut without affecting central analgesia has provided new perspectives on the treatment of opioid induced gastrointestinal adverse effects. AREAS COVERED: In this paper, we review the pathophysiology, prevalence, and burden of opioid-induced bowel dysfunction (OBD). In addition, this study aims to provide a better understanding of the mechanism of action and reviews the efficacy, safety and the latest research on novel opioid antagonists for OBD. EXPERT OPINION: Two strategies effectively relieve OBD without interfering with centrally mediated analgesia: the administration of opioid antagonists with limited systemic absorption and peripherally acting mu-opioid receptor antagonists (PAMORA) that selectively target mu-receptors in the gastrointestinal tract. Methylnaltrexone and alvimopan are two recently marketed PAMORA and provide a new mechanism-based approach for the treatment of opioid-induced gastrointestinal dysfunction. However, its use in clinical practice is limited by various reasons such as its relatively low response rates and higher costs. Nevertheless, at least four new oral PAMORA (NKTR-118, TD-1211, ADL-7445, and ADL-5945) are under clinical development, further expanding the possibilities for a new paradigm for OBD management. PMID- 21663527 TI - VDR FokI polymorphism and its potential role in the pathogenesis of gestational diabetes mellitus and its complications. AB - The aim of the study is evaluating the associations of FokI vitamin D receptor (VDR) gene polymorphisms with gestational diabetes mellitus (GDM), and its relations with postpartum metabolic syndrome. In a cohort study, 303 women referred to outpatient clinic of Shariati Hospital. The VDR FokI genotypes were determined. All subjects were followed 6?12 weeks after delivery. The frequencies of Ff, FF, and ff genotypes were 30.4% (49), 63.4% (102), and 6.2% (10), respectively, in healthy pregnancies and 34.5% (49), 54.9% (78), and 10.6% (15), respectively, in GDM patients. The ff genotype was more common in GDM patients. Healthy individuals had higher frequency of F allele, suggesting that F allele may have a role in decreased incidence of GDM. Concerning the GDM risk factors, f allele had significant association with prepregnancy obesity and family history of diabetes. In postpartum follow-up, women who developed metabolic syndrome were significantly older with higher prepregnancy body mass index, had more family history of diabetes, and also their ff genotype was two fold more frequent. Our results indicate a meaningful association between FokI VDR genotypes and an increase risk of GDM in Iranian population as well as its effects on postpartum metabolic syndrome. PMID- 21663528 TI - Factors connected with the female sex seem to play an important role in differentiated thyroid cancer. AB - AIM: The aim of the study was to analyze whether female sex hormones and other factors connected with the female sex could increase the risk of differentiated thyroid cancer (DTC). MATERIAL AND METHODS: Ninety-nine patients with a mean age+/-SD of 40.5+/-5.9 years with DTC and 51 healthy women with a mean age of 36.52+/-8.3 years were examined. Gynecological and obstetric histories were taken and serum estradiol and progesterone levels were analyzed in all women. RESULTS: Patients with DTC had more frequent menstrual cycle disturbances, used hormone containing medicines more frequently, were mulitiparous more frequently, had spontaneous miscarriages more frequently, and their duration of lactation was significantly shorter than in controls. The mean serum estradiol level+/-SD in women with DTC was significantly higher than in the controls, in the follicular phase 193.74+/-66.31 vs. 157.63+/-42.88 pmol/l and in the luteal phase 519+/ 176.9 vs. 369+/-71.49 pmol/l. The mean serum progesterone level+/-SD was higher in the controls than in patients with DTC, in the follicular phase: 2.11+/-0.70 vs. 1.38+/-0.56 nmol/l and in the luteal phase 20.95+/-17.46 vs. 17.31+/-12.28 nmol/l. CONCLUSIONS: The results of these studies imply that estrogens may at least modify the proliferation of thyroid cancer cells. The sex hormones probably intensify the actions of other carcinogens as well. PMID- 21663529 TI - New therapies for castrate-resistant prostate cancer. AB - INTRODUCTION: Prostate cancer is the second leading cause of cancer death in men in the USA, and most of these deaths will occur as a result of castrate-resistant prostate cancer (CRPC) that has progressed despite androgen deprivation therapy. There has been better understanding of castration resistance and molecular mechanisms of prostate cancer progression recently, leading to new treatment strategies. AREAS COVERED: This review focuses on emerging and new therapies for castrate-resistant prostate cancer, including hormonal therapy, immunotherapy and cytotoxic agents. EXPERT OPINION: New treatment strategies have been developed in recent years and, with improved understanding of advanced CRPC, additional targeted treatments are expected in the near future. Further cost effectiveness research of these treatments is warranted before dissemination of these promising agents. PMID- 21663530 TI - Monoclonal antibodies and antibody fragments: state of the art and future perspectives in the treatment of non-haematological tumors. AB - INTRODUCTION: The use of monoclonal antibodies is one of the strategies for targeting the specific key points of the main pathways of cancer growth and survival, but only a few antibodies have offered a clear clinical benefit in the treatment of non-haematological malignancies. AREAS COVERED: This review summarizes the general properties of monoclonal antibodies, including structure, nomenclature and production techniques. The antibodies approved for use in clinical practice for the treatment of non-haematological tumors and those antibodies still being developed in this setting are briefly described. The types of antibody fragments are also reported. EXPERT OPINION: Monoclonal antibodies were initially developed in order to avoid the cytotoxic effects of chemotherapy on healthy tissues. However antibodies have not yet replaced chemotherapy agents, since the combination of both kinds of drugs have usually appeared to achieve higher benefit compared with chemotherapy alone. The research for the development of new monoclonal antibodies aims to identify further targets and to provide innovative antibody constructs. PMID- 21663531 TI - Cell and nuclear enlargement of SW480 cells induced by a plant lignan, arctigenin: evaluation of cellular DNA content using fluorescence microscopy and flow cytometry. AB - Arctigenin is a natural plant lignan previously shown to induce G(2)/M arrest in SW480 human colon cancer cells as well as AGS human gastric cancer cells, suggesting its use as a possible cancer chemopreventive agent. Changes in cell and nuclear size often correlate with the functionality of cancer-treating agents. Here, we report that arctigenin induces cell and nuclear enlargement of SW480 cells. Arctigenin clearly induced the formation of giant nuclear shapes in SW480, as demonstrated by fluorescence microscopic observation and quantitative determination of nuclear size. Cell and nuclear size were further assessed by flow cytometric analysis of light scattering and fluorescence pulse width after propidium iodide staining. FSC-H and FL2-W values (parameters referring to cell and nuclear size, respectively) significantly increased after arctigenin treatment; the mean values of FSC-H and FL2-W in arctigenin-treated SW480 cells were 572.6 and 275.1, respectively, whereas those of control cells were 482.0 and 220.7, respectively. Our approach may provide insights into the mechanism behind phytochemical-induced cell and nuclear enlargement as well as functional studies on cancer-treating agents. PMID- 21663532 TI - Unresolved inflammation: 'immune tsunami' or erosion of integrity in immune privileged and immune-responsive tissues and acute and chronic inflammatory diseases or cancer. AB - INTRODUCTION: Unresolved inflammation is loss of balance between two biologically opposing arms of acute inflammation, 'Yin' (tumoricidal) and 'Yang' (tumorigenic) processes that cause disruption of protective mechanisms of immune system. AREAS COVERED: HYPOTHESIS: Unresolved inflammation-induced exaggerated expression of apoptotic and/or wound healing mediators lead to fundamental erosion ('immune tsunami' or 'immune meltdown') of integrity in tissues that are naturally immune responsive (immune surveillance); or immune-privileged (immune tolerance). 'Immune tsunami' refers to end results of acute or chronic immune dysfunction leading to inflammatory diseases or cancer. Acute inflammatory diseases including drug-induced cancer cachexia, would fit features of 'immune meltdown' that are otherwise described for end results of age-associated diseases. Pathogens induce rapid destruction of vascular integrity, gain access to tissues and cause excessive expression of apoptotic factors leading to multiple organ failure (MOF). Significant disruptions of immunological barriers and response shifts lead to chronic neurodegenerative and autoimmune diseases, tumor growth, malignancies and angiogenesis and loss of natural immune response balances. EXPERT OPINION: Strategies to promote (stabilize) inherent properties of innate immune cells ('tumoricidal' versus 'tumorigenesis') that would influence polarization of adaptive immune (T or B) cells are key in reducing or preventing incidence of inflammatory and vascular diseases or cancer during aging process. PMID- 21663533 TI - Trials of bevacizumab in breast cancer--a safety review. AB - INTRODUCTION: Despite the significant gains in the treatment of breast cancer over the last decade, further improvements in survival using traditional chemotherapeutic agents have begun to plateau. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, has provided promise for continued gains in therapy efficacy. AREAS COVERED: The authors review Phase III data concerning the safety of bevacizumab in breast cancer, summarize data on efficacy and discuss the risk:benefit ratio of the drug. The data for this review were obtained by searching in the PubMed database. This review enables the reader to overview current knowledge on the efficacy and safety of bevacizumab in breast cancer. EXPERT OPINION: Insight into complex risk-benefit calculations for bevacizumab is missing. In unselected patients with HER2-negative metastatic breast cancer, the risk of serious side effects of bevacizumab overshadows the benefit of the drug. However, increased response rates and progression-free survival in the majority of Phase III trials suggest that the drug is of benefit in a subgroup of patients. Although requiring close monitoring, most side effects are manageable. Reliable, validated predictive biomarkers are of utmost importance to improve the likelihood of clinical benefit. PMID- 21663534 TI - Antimicrobial susceptibility pattern of Brachyspira intermedia isolates from European layers. AB - A broth microdilution method was used to determine the antimicrobial susceptibility of 20 Brachyspira intermedia isolates obtained from different layer flocks in Belgium and The Netherlands between 2008 and 2010. The antimicrobial agents used were tylosin, tilmicosin, tiamulin, valnemulin, doxycycline, and lincomycin. The minimal inhibitory concentration (MIC) distribution patterns of tylosin, tilmicosin, lincomycin, and doxycycline were bimodal, demonstrating acquired resistance against doxycycline in three strains, against the macrolides in two strains, and against lincomycin in one strain. The MICs of tiamulin and valnemulin showed a monomodal distribution, but with tailing toward the higher MIC values, possibly suggesting low-level acquired resistance in six isolates. Sequencing revealed a G1058C mutation in the 16S rRNA gene in all doxycycline-resistant strains. The strain resistant to tylosin, tilmicosin, and lincomycin had an A2058T mutation in the 23S rRNA gene. PMID- 21663535 TI - Reviews on stress neuroendocrinology from the 7th International Congress of Neuroendocrinology. PMID- 21663536 TI - Sex differences in prenatal epigenetic programming of stress pathways. AB - Maternal stress experience is associated with neurodevelopmental disorders including schizophrenia and autism. Recent studies have examined mechanisms by which changes in the maternal milieu may be transmitted to the developing embryo and potentially translated into programming of the epigenome. Animal models of prenatal stress have identified important sex- and temporal-specific effects on offspring stress responsivity. As dysregulation of stress pathways is a common feature in most neuropsychiatric diseases, molecular and epigenetic analyses at the maternal-embryo interface, especially in the placenta, may provide unique insight into identifying much-needed predictive biomarkers. In addition, as most neurodevelopmental disorders present with a sex bias, examination of sex differences in the inheritance of phenotypic outcomes may pinpoint gene targets and specific windows of vulnerability in neurodevelopment, which have been disrupted. This review discusses the association and possible contributing mechanisms of prenatal stress in programming offspring stress pathway dysregulation and the importance of sex. PMID- 21663537 TI - Endocannabinoids and stress. AB - Endogenous cannabinoids play an important role in the physiology and behavioral expression of stress responses. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, including the release of glucocorticoids, is the fundamental hormonal response to stress. Endocannabinoid (eCB) signaling serves to maintain HPA-axis homeostasis, by buffering basal activity as well as by mediating glucocorticoid fast feedback mechanisms. Following chronic stressor exposure, eCBs are also involved in physiological and behavioral habituation processes. Behavioral consequences of stress include fear and stress-induced anxiety as well as memory formation in the context of stress, involving contextual fear conditioning and inhibitory avoidance learning. Chronic stress can also lead to depression-like symptoms. Prominent in these behavioral stress responses is the interaction between eCBs and the HPA-axis. Future directions may differentiate among eCB signaling within various brain structures/neuronal subpopulations as well as between the distinct roles of the endogenous cannabinoid ligands. Investigation into the role of the eCB system in allostatic states and recovery processes may give insight into possible therapeutic manipulations of the system in treating chronic stress-related conditions in humans. PMID- 21663539 TI - Stimuli-responsive liposome-nanoparticle assemblies. AB - INTRODUCTION: Nanoscale assemblies are needed that achieve multiple therapeutic objectives, including cellular targeting, imaging, diagnostics and drug delivery. These must exhibit high stability, bioavailability and biocompatibility, while maintaining or enhancing the inherent activity of the therapeutic cargo. Liposome nanoparticle assemblies (LNAs) combine the demonstrated potential of liposome based therapies, with functional nanoparticles. Specifically, LNAs can be used to concentrate and shield the nanoparticles and, in turn, stimuli-responsive nanoparticles that respond to external fields can be used to control liposomal release. The ability to design LNAs via nanoparticle encapsulation, decoration or bilayer-embedment offers a range of configurations with different structures and functions. AREAS COVERED: This paper reviews the current state of research and understanding of the design, characterization and performance of LNAs. A brief overview is provided on liposomes and nanoparticles for therapeutic applications, followed by a discussion of the opportunities and challenges associated with combining the two in a single assembly to achieve controlled release via light or radiofrequency stimuli. EXPERT OPINION: LNAs offer a unique opportunity to combine the therapeutic properties of liposomes and nanoparticles. Liposomes act to concentrate small nanoparticles and shield nanoparticles from the immune system, while the nanoparticle can be used to initiate and control drug release when exposed to external stimuli. These properties provide a platform to achieve nanoparticle-controlled liposomal release. LNA design and application are still in infancy. Research concentrating on the relationships among LNA structure, function and performance is essential for the future clinical use of LNAs. PMID- 21663538 TI - Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic pituitary-adrenal axis. AB - Stress activation of the hypothalamic-pituitary-adrenal (HPA) axis culminates in increased circulating corticosteroid concentrations. Stress-induced corticosteroids exert diverse actions in multiple target tissues over a broad range of timescales, ranging from rapid actions, which are induced within seconds to minutes and gene transcription independent, to slow actions, which are delayed, long lasting, and transcription dependent. Rapid corticosteroid actions in the brain include, among others, a fast negative feedback mechanism responsible for shutting down the activated HPA axis centrally. We provide a brief review of the cellular mechanisms responsible for rapid corticosteroid actions in different brain structures of the rat, including the hypothalamus, hippocampus, amygdala, and in the anterior pituitary. We propose a model for the direct feedback inhibition of the HPA axis by glucocorticoids in the hypothalamus. According to this model, glucocorticoids activate membrane glucocorticoid receptors to induce endocannabinoid synthesis in the hypothalamic paraventricular nucleus (PVN) and retrograde cannabinoid type I receptor-mediated suppression of the excitatory synaptic drive to PVN neuroendocrine cells. Rapid corticosteroid actions in the hippocampus, amygdala, and pituitary are mediated by diverse cellular mechanisms and may also contribute to the rapid negative feedback regulation of the HPA neuroendocrine axis as well as to the stress regulation of emotional and spatial memory formation. PMID- 21663540 TI - An exploration of community reentry needs and services for prisoners: a focus on care to limit return to high-risk behavior. AB - Prisoner reentry is a stressful process and many prisoners return to behaviors that led to incarceration upon community reentry. We assess how individual-level vulnerabilities interact with system-level barriers that impact the community reentry process. An additional area explored was the impact of reentry services on risk behavior (i.e., sexual risk and substance use). Fifty-one (22 men, 29 women) primarily minority adults returning from the county jail or state prison participated in 4 focus groups in Febuary 2010. Participants took part in tape recorded focus groups facilitated by research staff trained in qualitative research methodology. Participants reported that a lack of discharge planning led to poor community reentry (basic needs such as stable housing and employment were not met). As a result of a difficulty in accessing services to meet basic needs, many participants used drugs or engaged in sex for drugs, money, or transportation early in the community reentry process. Given the individual-level vulnerabilities of prisoners, they are more likely to reengage in risk behavior, which increases the risk of acquiring and transmitting HIV, reengaging in substance use, and recidivism. In summary, discharge planning should focus not only on sexual and substance use risk reduction, but also confirm that basic needs are met soon, if not immediately, upon release and subsequent community reentry. PMID- 21663541 TI - Adherence, sexual risk, and viral load in HIV-infected women prescribed antiretroviral therapy. AB - Abstract The purpose of this study was to determine if there was a connection between adherence to antiretroviral therapy (ART) and use of risk reduction behaviors (RRB) in HIV-infected women who were prescribed antiretroviral therapy. The sample consisted of 193 predominately African American women with an average age of 44 who had been on ARV for approximately 9 years and had low annual incomes. All women were participating in a behavioral clinical trial focused on these dual outcomes. Using a risk index developed for this study, we examined the relationship of a composite of risk behaviors to electronically measured and self reported adherence over the approximately 13-month study period. Women were categorized based on levels of adherence and risky behaviors, and we sought to determine if these classifications were associated with clinical outcomes of HIV viral load and CD4 counts. High levels of adherence were correlated with low risk behaviors (abstinence, consistent use of condoms, etc.). Those classified as high adherence and low-risk behavior (HALR) as well as those classified as high adherence and high-risk behavior (HAHR) had lower mean viral loads and higher CD4 counts than those in the other categories. Women in the low adherence and high risk category (LAHR) had detectable viral loads and the lowest CD4 counts and are at higher risk for transmitting HIV to partners and unborn children. Our findings underscore the importance of addressing adherence to both ART and RRB in HIV clinical settings to improve clinical outcomes and reduce HIV transmission. PMID- 21663544 TI - Longitudinal outcome of patients with disordered consciousness in the NIDRR TBI Model Systems Programs. AB - Few studies address the course of recovery from prolonged disorders of consciousness (DOC) after severe traumatic brain injury (TBI). This study examined acute and long-term outcomes of persons with DOC admitted to acute inpatient rehabilitation within the National Institute on Disability and Rehabilitation Research (NIDRR) TBI Model Systems Programs (TBIMS). Of 9028 persons enrolled from 1988 to 2009, 396 from 20 centers met study criteria. Participants were primarily male (73%), Caucasian (67%), injured in motor vehicle collision (66%), with a median age of 28, and emergency department Glasgow Coma Scale (GCS) score of 3. Participant status was evaluated at acute rehabilitation admission and discharge and at 1, 2, and 5 years post-injury. During inpatient rehabilitation, 268 of 396 (68%) regained consciousness and 91 (23%) emerged from post-traumatic amnesia (PTA). Participants demonstrated significant improvements on GCS (z=16.135, p<=0.001) and Functional Independence Measure (FIM) (z=15.584, p<=0.001) from rehabilitation admission (median GCS=9; FIM=18) to discharge (median GCS=14; FIM=43). Of 337 with at least one follow-up visit, 28 (8%) had died by 2.1 years (mean) after discharge. Among survivors, 66 (21%) improved to become capable of living without in-house supervision, and 63 demonstrated employment potential using the Disability Rating Scale (DRS). Participants with follow-up data at 1, 2, and 5 years post-injury (n=108) demonstrated significant improvement across all follow-up evaluations on the FIM Cognitive and Supervision Rating Scale (p<0.01). Significant improvements were observed on the DRS and FIM Motor at 1 and 2 years post-injury (p<0.01). Persons with DOC at the time of admission to inpatient rehabilitation showed functional improvement throughout early recovery and in years post-injury. PMID- 21663543 TI - The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. AB - Bone marrow-derived mesenchymal stem cells (MSCs) modulate immune response and can produce significant levels of transforming growth factor-beta (TGF-beta) and interleukin-6 (IL-6). These 2 cytokines represent the key factors that reciprocally regulate the development and polarization of naive T-cells into regulatory T-cell (Treg) population or proinflammatory T helper 17 (Th17) cells. In the present study we demonstrate that MSCs and their products effectively regulate expression of transcription factors Foxp3 and RORgammat and control the development of Tregs and Th17 cells in a population of alloantigen-activated mouse spleen cells or purified CD4(+)CD25(-) T-cells. The immunomodulatory effects of MSCs were more pronounced when these cells were stimulated to secrete TGF-beta alone or TGF-beta together with IL-6. Unstimulated MSCs produce TGF beta, but not IL-6, and the production of TGF-beta can be further enhanced by the anti-inflammatory cytokines IL-10 or TGF-beta. In the presence of proinflammatory cytokines, MSCs secrete significant levels of IL-6, in addition to a spontaneous production of TGF-beta. MSCs producing TGF-beta induced preferentially expression of Foxp3 and activation of Tregs, whereas MSC supernatants containing TGF-beta together with IL-6 supported RORgammat expression and development of Th17 cells. The effects of MSC supernatants were blocked by the inclusion of neutralization monoclonal antibody anti-TGF-beta or anti-IL-6 into the culture system. The results showed that MSCs represent important players that reciprocally regulate the development and differentiation of uncommitted naive T-cells into anti inflammatory Foxp3(+) Tregs or proinflammatory RORgammat(+) Th17 cell population and thereby can modulate autoimmune, immunopathological, and transplantation reactions. PMID- 21663545 TI - Nanoparticle-rich diesel exhaust affects hippocampal-dependent spatial learning and NMDA receptor subunit expression in female mice. AB - We investigated the effect of exposure to nanoparticle-rich diesel exhaust (NRDE) on hippocampal-dependent spatial learning and memory function-related gene expressions in female mice. Female BALB/c mice were exposed to clean air, middle dose NRDE (M-NRDE), high-dose NRDE (H-NRDE) or filtered diesel exhaust (F-DE) for three months. A Morris water maze apparatus was used to examine spatial learning. The expression levels of the N-methyl-D-aspartate (NMDA) receptor subunit, proinflammatory cytokines and neurotrophin mRNAs in the hippocampus were then investigated using real-time RT-PCR. Mice exposed to H-NRDE required a longer time to reach the hidden platform and showed higher mRNA expression levels of the NMDA receptor subunit NR2A, the proinflammatory cytokine CCL3, and brain-derived neurotrophic factor (BDNF) in the hippocampus, compared with the findings in the control group. These results indicate that three months of exposure to NRDE affected spatial learning and memory function-related gene expressions in the female mouse hippocampus. PMID- 21663556 TI - Potential of whole blood coagulation reconstitution by desmopressin and fibrinogen under conditions of hypothermia and acidosis--an in vitro study using rotation thrombelastometry. AB - BACKGROUND: Desmopressin (DDAVP) and fibrinogen improve platelet function and clot stability. We investigated the influence of DDAVP and fibrinogen on whole blood coagulation in an in vitro model of hypothermia and acidosis. METHODS: After IRB approval and written consent blood samples were taken from 10 healthy volunteers. Samples were prepared with hydrochloric acid to maintain--beside normal pH--reduced pH (~7.2) and severely reduced pH (~7.0), and were assigned to four treatment groups: addition of either isotonic saline for compensation of dilutional effects (ISO), desmopressin (DDAVP+), fibrinogen (FIB+), or both substances (DDAVP+FIB+). Baseline was ISO at 37 degrees C and normal pH. Remaining samples were incubated for 30 min and measured at 32 degrees . Rotation thrombelastometry (ROTEM) after extrinsically activation and fibrin polymerization was tested. Repeated measures ANOVA were performed (p < 0.05). RESULTS: Hypothermia and acidosis synergistically impaired whole blood coagulation. DDAVP+ normalized maximum clot firmness (MCF) at normal pH. Coagulation time (CT) was not affected. FIB+ normalized MCF at pH 7.35 and pH 7.2. CT was normalized independently of pH. DDAVP+FIB+ did not show additional effects to FIB+. Fibrin polymerization was increased by FIB+ and DDAVP+FIB+ independently of pH. DDAVP+ did not alter fibrin polymerization. CONCLUSION: DDAVP and fibrinogen increased whole blood coagulation under hypothermia. Acidosis diminished this effect. Thus, acidosis should be corrected first and then both substances could be used for bridging until normothermia can be achieved. In combination, the effects of fibrinogen were overwhelming DDAVP effects. Thus, combined administration did not show any benefit compared to fibrinogen administration alone. PMID- 21663557 TI - Development of novel nucleic acid-loaded Bubble liposomes using cholesterol conjugated siRNA. AB - Recently, we developed polyethyleneglycol (PEG)-modified liposomes (Bubble liposomes; BLs) entrapping ultrasound (US) gas and reported that the combination of BLs and US exposure was an effective tool for the delivery of siRNA directly into cells and US-exposed tissues within a short period; however, the results were obtained using a mixture of BLs and naked siRNA. With systemic injections, it is important to control the biodistribution of both BLs and siRNA. In addition, the delivery of siRNA is affected by nuclease degradation and rapid removal from the circulation after intravenous administration. In this study, we attempted to prepare novel siRNA-loaded BLs (chol-si-BLs) using cholesterol conjugated siRNA (chol-siRNA). We demonstrated that chol-siRNA could be loaded into BLs, leading to the stability of siRNA even in the presence of an RNase. The specific gene-silencing effect was also achieved by transfection with chol-si-BLs and US. Thus, the combination of chol-si-BLs with US exposure is expected to deliver siRNA into a specific tissue via systemic injection. PMID- 21663558 TI - Mediation of cholino-piperine like receptors by extracts of Piper nigrum induces melanin dispersion in Rana tigerina tadpole melanophores. AB - AIM: The present study was carried out to determine the effects of lyophilized dried fruit extracts of Piper nigrum and pure piperine on the tadpole melanophores of frog Rana tigerina which offer excellent in vitro opportunities for studying the effects of pharmacological and pharmaceutical agents. The nature of specific cellular receptors present on the neuro-melanophore junction and their involvement in pigmentary responses has been explored. MATERIAL: Effects of lyophilized extracts of P. nigrum and pure piperine were studied on the isolated tail melanophores of tadpoles of the frog R. tigerina as per the modified method. RESULTS: The extract of P. nigrum and its active ingredient piperine caused significant melanin dispersal responses leading to darkening of the tail melanophores, which were completely antagonized by atropine and hyoscine. These per se melanin dispersal effects were also found to be markedly potentiated by neostigmine an anticholinesterase agent. CONCLUSION: It appears that the melanin dispersal effects of the extracts of P. nigrum and pure piperine leading to skin darkening are mediated by cholinergic muscarinic or piperine-like receptors having similar properties. PMID- 21663559 TI - Synthetic zinc finger nuclease design and rapid assembly. AB - Engineered zinc finger nucleases (ZFNs) are a tool for genome manipulation that are of great interest to scientists in many fields. To meet the needs of researchers wishing to employ ZFNs, an inexpensive, rapid assembly procedure would be beneficial to laboratories that do not have access to the proprietary reagents often required for ZFN production. Using freely available sequence data derived from the Zinc Finger Targeter database, we developed a protocol for synthesis and directed insertion of user-defined ZFNs into a versatile plasmid expression system. This oligonucleotide-based isothermal DNA assembly protocol was used to determine whether we could generate functional nucleases capable of endogenous gene editing. We targeted the human alpha-l-iduronidase (IDUA) gene on chromosome 4, mutations of which result in the severe lysosomal storage disease mucopolysaccharidosis type I. In approximately 1 week we were able to design, assemble, and test six IDUA-specific ZFNs. In a single-stranded annealing assay five of the six candidates we tested performed at a level comparable to or surpassing previously reported ZFNs. One of the five subsequently showed nuclease activity at the endogenous genomic IDUA locus. To our knowledge, this is the first demonstration of in silico-designed, oligonucleotide-assembled, synthetic ZFNs, requiring no specialized templates or reagents that are capable of endogenous human gene target site activity. This method, termed CoDA-syn (context dependent assembly-synthetic), should facilitate a more widespread use of ZFNs in the research community. PMID- 21663560 TI - Comparative evaluation of capillary zone electrophoresis and HPLC in the determination of carbohydrate-deficient transferrin. AB - BACKGROUND: Transferrin (Tf) glycoform lacking one or two complete or incomplete glycan chains (i.e., asialo-monosialo- and disialo-Tf) typically appear in blood after chronic alcohol consumption, though recently it was reported that monosialo Tf is associated with trisialo-Tf but not with alcohol consumption. These glycoforms are collectively known as carbohydrate-deficient transferrin (CDT). Since samples from alcoholic patients are characterized by decreased sialic acid content in serum transferrin, the assessment of CDT is thereby widely used for laboratory evaluation of chronic alcohol abuse. METHODS: CDT analysis has been performed in 6011 consecutive subjects undergoing national mandatory testing after the confiscation of driving license for driving under the influence of alcohol. Out of the 6011 specimens, 539 (9%) displayed values exceeding the specific cut-off (>1.3%) on multicapillary electrophoresis (MCE) (Capillarys2 Sebia, France), and were further analyzed with a routine high-pressure liquid chromatography (HPLC) technique. RESULTS: The overall correlation between the methods in the total 539 samples was satisfactory, displaying a correlation coefficient (r) of 0.960. Nevertheless, the correlation was lower in the group with CDT values comprised between 1.3% and 1.9% (group 1; r=0.60) than in those with CDT values >2.0% (group 2; r=0.98). Moreover, the discordance between values exceeding the method-specific threshold in the former group of samples was also remarkably high (62% of samples in group 1 vs. 0.6% in group 2). Finally, a significant difference of CDT values was observed in group 1 (p<0.001), and in group 2 (p<0.0001) by Wilcoxon test. CONCLUSIONS: The MCE is characterized by a high throughput and it seems a suitable approach for laboratory monitoring of alcohol abuse when CDT is used as medical parameter in the diagnosis and follow up of heavy drinking. However, CDT measured by screening techniques must be confirmed by a confirmatory technique, in particular for forensic purpose. PMID- 21663561 TI - Method comparison: where do we draw the line? PMID- 21663562 TI - Urine immunofixation electrophoresis remains important and is complementary to serum free light chain. AB - Articles have debated whether or not urine analysis remains valuable for identifying monoclonal gammopathies. A general impression is that the newer serum free light chain (FLC) assay is more analytically sensitive, more quantitative and simpler to perform. Many laboratory directors may have seized on the idea of eliminating urine analysis because it is a tedious procedure and requires expert interpretation while most laboratories can perform automated serum FLC assay. Others have concluded that urine immunofixation electrophoresis (IFE) optimizes the diagnostic sensitivity and should be included when there is a clinical indication. Here, I show that papers faulting urine analysis often used inappropriate urine methodology and this helps explain why there was misinterpretation. Moreover, the literature, shows urine IFE is often more sensitive for identifying low-level monoclonal FLC than the serum assay because urine IFE is as sensitive when performed appropriately and generally more specific. Besides, the reference range for serum FLC assay is unclear which is a great problem in assessing response to treatment and in identifying diseases when there is low concentration monoclonal FLC. I conclude that urine IFE remains important and is complementary to serum FLC assay, although the best algorithms for use remains to be elucidated. PMID- 21663563 TI - Collagen peptides, interstitial remodelling and sudden cardiac death in hypertrophic cardiomyopathy. PMID- 21663564 TI - Closing the brain-to-brain loop in laboratory testing. AB - Abstract The delivery of laboratory services has been described 40 years ago and defined with the foremost concept of "brain-to-brain turnaround time loop". This concept consists of several processes, including the final step which is the action undertaken on the patient based on laboratory information. Unfortunately, the need for systematic feedback to improve the value of laboratory services has been poorly understood and, even more risky, poorly applied in daily laboratory practice. Currently, major problems arise from the unavailability of consensually accepted quality specifications for the extra-analytical phase of laboratory testing. This, in turn, does not allow clinical laboratories to calculate a budget for the "patient-related total error". The definition and use of the term "total error" refers only to the analytical phase, and should be better defined as "total analytical error" to avoid any confusion and misinterpretation. According to the hierarchical approach to classify strategies to set analytical quality specifications, the "assessment of the effect of analytical performance on specific clinical decision-making" is comprehensively at the top and therefore should be applied as much as possible to address analytical efforts towards effective goals. In addition, an increasing number of laboratories worldwide are adopting risk management strategies such as FMEA, FRACAS, LEAN and Six Sigma since these techniques allow the identification of the most critical steps in the total testing process, and to reduce the patient-related risk of error. As a matter of fact, an increasing number of laboratory professionals recognize the importance of understanding and monitoring any step in the total testing process, including the appropriateness of the test request as well as the appropriate interpretation and utilization of test results. PMID- 21663565 TI - Towards laboratory knowledge, not data, in 70% of clinical decision-making. What "knowledge management" can add to clinical practice? PMID- 21663566 TI - Determinants of blood levels of some thrombogenic biomarkers in healthy Arab adolescent subjects. AB - BACKGROUND: Acute coronary syndromes present clinically as a consequence of plaque rupture and thrombosis possibly related to altered homeostasis of thrombogenic factors. It is speculated that this vulnerability in adults should be predictable from blood levels of thrombogenic biomarkers in children and adolescents. This study aims to examine the determinants and blood levels of lipoprotein(a) [Lp(a)], fibrinogen (FBG) and plasminogen activator inhibitor-1 (PAI-1) in healthy adolescents stratified according to age group, gender and body mass. METHODS: A total of 774 (316 males 458 females) healthy adolescent Arab subjects aged 10-19 years and attending secondary schools in Kuwait were interviewed by a validated questionnaire for variables relating to socio demographic variables, diet and physical activity. They also had anthropometry, BP measurement and determination of fasting blood levels of Lp(a), low density lipoprotein (LDL)-cholesterol, apolipoprotein (apo) B, PAI-1 activity and FBG. RESULTS: The median (interquartile range, IQR) plasma levels of PAI-1 activity, FBG, Lp(a) and apoB were respectively 1.59 (0.58-3.78) U/mL, 296 (190-417) mg/dL, 10.0 (4.8-21.0) mg/dL and 0.72 (0.60-0.85) g/L. Boys had significantly higher PAI 1, FBG and apoB concentrations than the girls, although Lp(a) levels were greater in the latter. The overweight and obese subjects tended to have higher levels of LDL, apoB, FBG and PAI-1 but not Lp(a). Furthermore, the younger adolescent males and females (age <14 years) consistently had higher FBG levels than the older ones (age >14 years). Lp(a) and PAI-1 levels did not appear significantly influenced by this age stratification. Bivariate and multivariate analyses with adjustment for putative body mass index (BMI) confounders indicated that the independent determinants of these biomarkers were (i) Lp(a): apoB, gender; (ii) PAI-1: BMI, apoB, diet; (iii) FBG: BMI, gender, age, family income; and (iv) apoB: BMI, gender and PAI-1. CONCLUSIONS: The blood levels of the prothrombotic biomarkers ;ibLp(a), PAI-1, and FBG;ic in healthy Kuwaiti adolescent subjects are variably influenced by age, gender, body mass and socio-demographic factors. PMID- 21663567 TI - Alterations of the preoperative coagulation profile in patients with acute appendicitis. AB - BACKGROUND: Acute appendicitis (AA) is usually associated with a systemic inflammatory response that often leads to activation of coagulation. However, limited data about coagulation changes in AA are available. METHODS: Results of preoperative coagulation testing in 702 patients with confirmed AA and 697 patients undergoing minor elective surgery (control) during the same period were analyzed retrospectively. Coagulation activity of factors VII, IX (FVII:C, FIX:C) and the concentration of plasma endotoxin from 40 patients with AA and 15 control subjects were measured. RESULTS: Compared with control subjects, prothrombin time (PT), fibrinogen (Fib) and endotoxin increased (all p<0.01), FVII:C decreased (p<0.05), and thrombin time shortened (p<0.01) significantly in patients with AA, which showed trends with increasing severity of disease. Areas under the receiver operating characteristic curve of Fib for discriminating complicated appendicitis or acute perforated appendicitis from enrolled patients were larger than those for leukocyte parameters. The concentration of endotoxin correlated negatively with FVII:C (r=-0.860, p<0.001), positively with PT (0.713, <0.001), and FVII:C negatively with PT (-0.729, <0.001) in individuals that were evaluated. The change in activated partial thromboplastin time and difference in FIX:C among patients with various pathological types of appendicitis were not significant. CONCLUSIONS: Endotoxin-induced activation of the extrinsic coagulation pathway was present in patients with AA. Fib may be useful as a potential indicator for excluding complicated appendicitis. PMID- 21663568 TI - Performance of the Roche Total Mycophenolic Acid(r) assay on the Cobas Integra 400(r), Cobas 6000(r) and comparison to LC-MS/MS in liver transplant patients. AB - BACKGROUND: Mycophenolic acid (MPA) is an immunosuppressant for which therapeutic drug monitoring (TDM) is performed for optimal prophylaxis and avoidance of toxicity in transplant patients. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is ideally suited for TDM of MPA. There have been several method comparisons of the Roche Total MPA assay, but none have been performed with respect to liver transplant patients. METHODS: We validated the Roche Total MPA assay on the Cobas Integra 400 and Cobas 6000 and compared it to a validated LC MS/MS (API 2000TM) method. Fifty-five EDTA plasma samples from liver transplant patients were measured with the Roche assay on these platforms and compared to the LC-MS/MS results. RESULTS: Validation of the LC-MS/MS, Cobas Integra 400 and 6000 was performed with good results. The LC-MS/MS/Integra 400/Cobas 6000 were linear up to 30, 15 and 17 mg/L, respectively. Imprecision was <10% for LC-MS/MS and <7% for the Roche assay on both platforms. The samples showed good agreement with LC-MS/MS. Passing-Bablok regression analysis showed Cobas Integra (mg/L)=1.02 * LC-MS/MS (mg/L)-0.50 and Cobas 6000 (mg/L)=0.98 * LC-MS/MS-0.47. CONCLUSIONS: The Roche Total Mycophenolic Acid-assay is suitable for measuring total MPA in plasma from liver transplant patients and is a good alternative for LC-MS/MS. PMID- 21663569 TI - Direct chromogenic substrate immuno-capture activity assay for testing of factor VII-activating protease. AB - BACKGROUND: The Marburg I (MRI) single nucleotide polymorphism (SNP) of the factor VII-activating protease (FSAP) gene has been associated with thrombophilia and atherosclerotic disease. PCR is used to detect the SNP. Also, the specific FSAP activity to cleave single-chain urokinase-type plasminogen activator (scu PA) serves as a surrogate for PCR testing. Development of further assays is indicated in order to increase testing opportunities for future studies. METHODS: A direct chromogenic substrate immuno-capture activity assay for FSAP (FSAP dcs activity assay) was established. Performance characteristics of the FSAP dcs activity assay were compared to the FSAP scu-PA activity assay. RESULTS: The FSAP dcs activity assay detects FSAP activity from 25% to 150% of the norm. Total CVs ranged from 6% to 10% for FSAP wild type samples and 9%-18% for MRI samples. Correlation between the FSAP dcs and scu-PA activity assays was low (R=0.7). The FSAP dcs activity determined the presence of the MRI FSAP alloenzyme with a diagnostic sensitivity and specificity of 100% [95% confidence interval (CI): 89.6%-100%] and 96.2% (95% CI: 93.2%-97.4%), respectively, whereas the specific FSAP dcs activity increased specificity to 99.0% (95% CI: 97.2%-99.6%). CONCLUSIONS: The specific FSAP dcs activity represents a reliable method for the detection of the FSAP MRI alloenzyme. Due to the limited correlation between the FSAP dcs and scu-PA activity assays, these different measurands may exhibit different utility in research and clinical applications. Thus, the FSAP dcs activity assay can represent a valuable complement or alternative for FSAP testing in future studies. PMID- 21663570 TI - Cerebrospinal fluid findings in infants with pertussis or parapertussis(1)). AB - BACKGROUND: Pertussis has been increasing in frequency and can cause protean manifestation in infants, often resulting in extensive laboratory evaluation. METHODS: We examined the prevalence of cerebrospinal fluid (CSF) anomalies in infants with pertussis and parapertussis over a 5-year period. RESULTS: In total, 239 of 1489 children (16.1%) had a positive PCR for pertussis or parapertussis. Eighty-three percent were infants; the mean age of the 39 years who received a lumbar puncture (LP) was 43 days. Reasons for performing LP included apnea (62%), toxic appearance (38%), fever (26%), and altered mentation (10%); several had >1 indication for LP. Twenty-four (62%) children had elevated CSF protein. No child had hypoglycorrhachia, bacterial meningitis, bacteremia, or intracranial hemorrhage; one child had a urinary tract infection and five had pneumonia. Seven children had brain imaging performed; one had a subarachnoid hemorrhage and six had normal studies. Elevated age-normalized CSF protein was a common finding in infants with pertussis, potentially due to transfer across a damaged or immature blood-brain barrier. This finding was seen in the absence of concomitant bacterial infections or detectable intracranial anomalies. CONCLUSIONS: While the diagnostic evaluation and clinical management of a toxic-appearing infant should not be limited by a positive pertussis or parapertussis PCR, it is useful for physicians to be cognizant that elevated CSF protein can be seen in association with these infections. PMID- 21663571 TI - Prognostic value of serum angiotensin-converting enzyme activity for outcome of community-acquired pneumonia. AB - BACKGROUND: In a previous study, a relation between decreased serum angiotensin converting enzyme (ACE) activity and physiological parameters was observed in patients with community-acquired pneumonia. The present study aims to further assess the prognostic value of serum ACE activity for outcome of community acquired pneumonia. METHODS: This was a prospective observational study including two cohorts of patients with community-acquired pneumonia (2004-2006; n=157 and 2007-2010; n=138). Serum ACE activity was measured at time of hospital admission. Based on reference values in healthy persons, patients were divided into subgroups of serum ACE activity: normal, low and extremely low. Physiological parameters, clinical outcomes and etiology were compared between the subgroups. RESULTS: A total of 265 patients were enrolled in this study. Mean age was 60+/ 19 years. In patients with low serum ACE activity (<20 U/L, n=53), compared to patients with normal serum ACE activity (>=20 U/L, n=212), C-reactive protein (CRP) was significantly increased, systolic blood pressure was significantly lower and there was a trend for higher heart rate and leukocyte counts. Furthermore, Streptococcus pneumoniae was significantly more identified in patients with low serum ACE activity. Serum ACE activity <24 U/L was independently associated with bacteremia (adjusted OR 3.93 [95% CI 1.57-9.87]). Low serum ACE activity was not prognostic for length of hospital stay nor mortality. CONCLUSIONS: This study did not show prognostic value for serum ACE activity regarding clinical outcome in patients with community-acquired pneumonia. Serum ACE activity <24 U/L at time of hospitalization appeared an independent indicator for the presence of bacteremia. Further research should elucidate the role of ACE in systemic infection and sepsis during pneumonia. PMID- 21663572 TI - Evaluation of the analytical performance of the Beckman Coulter AU680 automated analytical system based on quality specifications for allowable performance derived from biological variation. PMID- 21663573 TI - Clinically needed sensitivity for very low levels of Factor XIII: not yet proven for a new functional assay. PMID- 21663574 TI - Nanostructured materials in drug and gene delivery: a review of the state of the art. AB - A wide variety of drug delivery systems have been developed, each with its own advantages and limitations, but the important goals of all of the systems are to enhance bioavailability, reduce drug toxicity, target to a particular organ, and increase the stability of the drug. The development of nanostructured drug carriers have grasped increased attention from scientific and commercial organizations due to their unique ability to deliver drugs and challenging molecules such as proteins and nucleic acids. These carriers present many technological advantages such as high carrier capacity, high chemical and biological stability, feasibility of incorporating both hydrophilic and hydrophobic substances, and their ability to be administered by a variety of routes (including oral, inhalational, and parenteral) to provide controlled/sustained drug release. Moreover, applications of nanoparticulate formulations in enhancing drug solubility, dissolution, bioavailability, safety, and stability have already been proven. In the view of their multifaceted applications, the present review aims to discuss and summarize some of the interesting findings and applications, methods of preparation, and characterization of various nanostructured carriers useful in drug delivery. Included in this discussion are polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, dendrimers, cyclodextrins, fullerenes, gold and silica nanoparticles, and quantum dots. Because there are likely to be new applications for nanoparticles in drug delivery, they are expected to solve many problems associated with the delivery of drugs and biomolecules through different delivery routes. PMID- 21663575 TI - Newer therapeutic vistas for antiglaucoma medicines. AB - Glaucoma is second to cataract as a leading cause of global blindness and is the leading cause of irreversible visual loss. By the year 2020, almost 80 million people are estimated to be affected with open-angle glaucoma and angle-closure glaucoma. Sufficiently high concentrations of a free drug should be achieved within the aqueous humor and at the iris/ciliary body for sufficiently illustrating an antiglaucoma effect. Most drug groups including cholinergic agents, prostaglandin analogs, and carbonic anhydrase inhibitors being used in glaucoma were initially developed for other effects or routes and later found their use in the control of glaucoma. Hence, these molecules are not tailor made for delivery into the eye. Discovery of new molecules requires at least 15-20 years; hence, it may be concluded that instead of abandoning the existing molecules. It may be worthwhile to apply a novel drug-delivery approach to enhance ocular bioavailability and reduce systemic side effects of currently used agents. This review will elaborate on the potential to pharmaceutically tailor existing antiglaucoma agents using approaches including liposomes, collagen shields, dendrimers, in situ forming gels, and micro- and nanoparticles for achieving improved ocular effectiveness. Further to this, a preliminary discussion on miscellaneous agents such as siRNA, peptides, antioxidants and nitric oxide-releasing agents that are recently being proposed for the relief of glaucoma is also covered. PMID- 21663576 TI - Water-structuring technology with the molecular chaperone proteins: indicated application of the alpha-crystallin domains and imidazole-containing peptidomimetics in cosmetic skin care systems or dermatological therapeutic drug carrier formulations. AB - Changes in structural proteins and hydration during aging are responsible for altered skin morphologic and mechanical properties manifested as wrinkling, sagging, loss of elasticity, and apparent dryness. Impairment in protein hydration may add to the ultrastructural, mechanical, and biochemical changes in structural proteins in the aged skin. At Innovative Vision Products, Inc., we have pioneered a molecular chaperone protein-activated therapeutic or cosmetic platform to enable simultaneous analysis of water-binding and structuring characteristics for biology-related or skin aging and skin disease-related pathways. This cutting-edge technology has changed the hydration of proteins in photoaged skin which so that they are more compact and interact with water to limited degree. The mechanisms of skin diseases, aging, and cellular and signaling pathways mediated by targeting with molecular chaperone protein(s) are considered. Skin lesions that are growing, spreading, or pigmented, and those that occur on exposed areas of skin are likely to be treated by these emerging pharmacological chaperones that could have cosmetic or dermatological benefits. Examples of such chaperones are anti-/trans-glycation-imidazole-containing peptidomimetic(s) (natural L-carnosine derivatives and mimetics) combined with the molecular chaperone protein alpha-crystallin derived from a natural source, brine shrimp (Artemia franciscana) cysts, or with recombinant human alphaA crystallin. This patented biotechnology represents an efficient tool with which to mitigate the consequences of free radical-induced skin damage. The article is organized to provide in one place all of the relevant technical information, such as high-performance nuclear magnetic resonance and electron spin resonance application tools, and to describe the entire process from sample preparation to data analysis, which is moving from biological studies to biotechnology batches of the product. The proposed biotechnology results in a superior therapeutic treatment using the studied skin-rejuvenating, water-structuring, visible smoothing, and revitalizing beauty-performance agents to meet current challenges in skin care. PMID- 21663577 TI - Carbohydrate molecules: an expanding horizon in drug delivery and biomedicine. AB - This review presents successful applications of carbohydrate molecules in drug delivery, vaccine development, cancer, HIV and various other diseases based on advances in glycobiology and glycochemistry. Carbohydrate-mediated delivery could be site specific/cell specific. Carbohydrate-based delivery system has been successfully utilized for the delivery of macromolecular drugs, antigen, and potential therapeutic drug candidates. Lectin, the high affinity carbohydrate binding nonimmune glycoproteins has specific and noncovalent binding sites for defined carbohydrates. Endogenous surface lectins of cancer cells participate in the regulation of tumor cell growth. The oligosaccharides constitute potential recognition sites for carbohydrate-mediated interactions between cells and drug carriers bearing suitable site directing molecules. The recognition of carbohydrate immunodeterminants has created great attention in the development of carbohydrate-based vaccines. Peptide mimotopes provide a strategy to augment human immunodeficiency virus 1 (HIV-1) specific carbohydrate reactive immune responses. Experimental cancer and HIV vaccines are being developed in attempts to overcome weak immunological responses to carbohydrate-rich surface antigens using carriers, adjuvants, and novel carbohydrate antigen constructs. Current carbohydrate-based vaccines are used for prostate cancer, typhus, pneumonia, and meningitis; vaccines for malaria, anthrax, and leishmaniasis are under development. This article discusses the current research involved in the role of carbohydrate molecules in targeted controlled drug delivery, immunology, and vaccine development. PMID- 21663578 TI - Evolution of the coronary artery stent. AB - "Necessity, who is the mother of invention." - Plato. There has been a steady rise in the incidence and prevalence of coronary artery disease. In most developed countries, it is the number one cause of morbidity and mortality. As this disease has become an ever increasing burden on society, it has spurred on the development of many radical and innovative procedures and implants. This paper will discuss, briefly, the history of coronary interventions ranging from coronary artery bypass grafts (CABG) to drug-eluting stents. It will then compare and contrast some of the several drug-eluting stents available on the market today; specifically focusing on the CypherTM, TaxusTM, EndeavourTM, and Xience VTM stents. The comparisons will include a basic overview of the specifications of each stent as well as the short- and long-term outcomes of these implants. Finally, the paper will provide an introduction to some of the latest stent technology awaiting FDA approval. PMID- 21663579 TI - Abdominal wall reconstruction with implantable meshes. AB - Abdominal wall defects present a difficult problem for the reconstructive surgeon. Over the years, numerous implantable materials have becomes available to aid the surgeon in recreating the abdominal wall. This spectrum of implants includes permanent synthetic meshes, absorbable meshes, composite meshes and biomaterials. This review includes the pros and cons for the commercially available abdominal wall implants as well as a review of the literature regarding outcomes for each material. This review will provide the surgeon with current evidence-based information on implantable abdominal materials to be able to make a more informed decision about which implant to use. PMID- 21663580 TI - When do total knee replacements fail? AB - BACKGROUND: A recent study has provided evidence-based guidelines for the follow up of cemented total hip arthroplasty. As yet, there are no such guidelines on the surveillance of total knee arthroplasty. We reviewed the outcomes of patients who underwent this procedure in 1998 and 1999 at our institution. METHODS: All patients were identified from operating theater log books. The follow-up data was then retrieved from the electronic patient record system used at our institution. We recorded the age, sex, side of procedure, evidence of radiological loosening, and date of revision surgery. The data with regards to radiological evidence of loosening and revision surgery were then analyzed using a R statistical software package. From this we were able to plot Kaplan-Meier survival and hazard plots. RESULTS: We identified 296 primary total knee arthroplasties. Using radiological evidence of loosening as the end point, we found that there was a gradual increase in failure with a peak at 8 years (Fig. 1). There was a 10-year survival rate of 85.8%. Using revision surgery, for any cause, as the end point, we found that again there was a constant rate increase up to a peak at 8 years (Figs. 2 and 3). There was a 10-year survival rate of 91.5%. CONCLUSIONS: Once the patient has made it through the first postoperative year, they do not need to be followed up again until 8 years, assuming they remain asymptomatic. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 21663581 TI - Heat generated by hip resurfacing prostheses: an in vivo pilot study. AB - In order to determine the magnitude of temperature increases in resurfaced hips, temperature sensors were placed percutaneously in both hip joints of 12 volunteer patients who had 1 or both joints resurfaced. Temperature recordings were made with patients at rest (baseline) and after patients walked for 20 and 60 minutes. The hip resurfacing procedures were performed 12 to 36 months prior to this study using 9 different acetabular bearing surface components. At baseline (resting), a ceramic femoral prosthesis articulating with a poly-ether-ether-ketone (PEEK) acetabular prosthesis generated a temperature increase of 4 degrees C compared to a normal contralateral hip. After 60 minutes of walking, a ceramic femoral prosthesis articulating with a polyurethane acetabular prosthesis generated a temperature increase of 5 degrees C, whereas a ceramic femoral prosthesis articulating with a metal acetabular prosthesis generated a temperature increase of 6 degrees C, a cobalt-chromium alloy femoral prosthesis on a polyethylene acetabular prosthesis generated a temperature increase of 7 degrees C, and a cobalt-chromium alloy metal-on-metal prosthesis generated a temperature increase of 8 degrees C. Resurfaced hips generate more heat than arthritic and normal hips, and arthritic hips generate more heat than normal hips. A resurfaced hip with a ceramic femoral and PEEK or polyurethane acetabulum generated less heat than a resurfaced hip of the same design using a cobalt-chromium femur and either cobalt-chromium, or polyethylene for the acetabulum. Frictional heat generated in a resurfaced hip is not immediately dissipated and may result in increased bearing surface wear. Extended periods of elevated temperature within joints may inhibit periarticular cell growth and perhaps contribute to bone resorption or component loosening over the long term. PMID- 21663582 TI - Fixation of femoral neck fractures using divergent versus parallel cannulated screws. AB - Controversy exists regarding the optimal method of internal fixation in femoral neck fractures. Biomechanical data suggest that calcar fixation is superior to central screws placement. We propose a divergent technique for placing 3 cannulated stainless steel screws engaging the calcar femorale. Fifty two patients admitted to our institution for a femoral neck fracture were treated with the divergent screw technique, over a 7-year period. Four patients were deceased and 4 were lost to follow-up. Of the remaining 44 patients there were 10 males and 34 females, aged from 33 to 78 years (mean, 58 years). All patients were operated on by the same surgeon and were followed-up for a minimum of 2 years (mean: 33.6 months, range: 2-6 years). Twenty four patients sustained a non displaced fracture (Garden I-II) and 20 sustained a displaced fracture (Garden III-IV) of the femoral neck. Mean Harris hip score (HHS) was 89.6 points. Avascular necrosis was evident in 4 patients (9%) with displaced fractures. Non unions or failed internal fixations were not encountered. There was a significant difference in the HHS, in favor of the divergent group (P = 0.006), while more complications were encountered in the parallel group including 6 cases with non union. In conclusion, parallel screw placement is not critical for an excellent clinical outcome. Our proposed fixation method using 3 screws that diverge and lie in different coronal planes (1 engaging the calcar femorale) with a free-hand technique may offer enhanced fixation. Biomechanical data along with larger clinical studies are needed to establish our proposed method. PMID- 21663583 TI - Effect of bioactive ceramic and recombinant human transforming growth factor-beta (rhTGF-beta) on regeneration of parietal bone defects in rat. AB - AIMS: The purpose of this study was to evaluate the regenerative response of parietal bone defects in rats to bioactive ceramic and TGF-beta 1. MATERIALS AND METHODS: Sixty mature adult rats with initial weights of 300 g to 324 g were used. The diameter of each defect was 3 mm. The animals were divided into four study groups consisting of 15 rats per group. Groups 1 and 3 (control groups) received 30 MUg bioceramic per surgical defect site. Groups 2 and 4 (experimental groups) received 30 MUg bioceramic combined with 10 MUL of reconstituted TGF-beta 1 (200 ng). Animals of Groups 1 and 3 were euthanized at 18 days; Group 2 and 4 animals were terminated at 49 days after surgery. Each of the outcomes was analyzed via two-way analysis of variance model (ANOVA). RESULTS: Histologic reactions to the implants were similar with no significant difference between bioceramic and bioceramic + TGF-beta 1 specimens. In the 18-day specimens, the percentage of ceramic was marginally higher than the 49-day specimens. No significant difference was noted in the percentage of bone in 18-day and 49-day specimens. CONCLUSIONS: Based on the findings of this study, it was concluded that TGF-beta 1 promoted no significant increase in new bone when compared to bioactive ceramic alone. PMID- 21663584 TI - Fractionation and characterization of particles simulating wear of total joint replacement (TJR) following ASTM standards. AB - Reactions of bone cells to orthopedic wear debris produced by the articulating motion of total joint replacements (TJRs) are largely responsible for the long term failure of such replacements. Metal and polyethylene (PE) wear particles isolated from fluids from total joint simulators, as well as particles that are fabricated by other methods, are widely used to study such in vitro cellular response. Prior investigations have revealed that cellular response to wear debris depends on the size, shape, and dose of the particles. Hence, to have a better understanding of the wear-mediated osteolytic process it is important that these particles are well characterized and clinically relevant, both qualitatively, and quantitatively. In this study we have fractionated both ultra high molecular weight polyethylene (UHMWPE) and Ti particles, into micron (1.0 10.0 MUm), submicron (0.2-1.0 MUm), and nanoparticle (0.01-0.2 MUm) fractions, and characterized them based on the following size-shape descriptors as put forth in ASTM F1877: i) equivalent circle diameter (ECD), ii) aspect ratio (AR), iii) elongation (E), iv) roundness (R), and v) form factor (FF). The mean (+/- SD) ECDs (in MUm) for micron, submicron, and nanoparticles of UHMWPE were 1.652 +/- 0.553, 0.270 +/- 0.180, and 0.061 +/- 0.035, respectively, and for Ti were 1.894 +/- 0.667, 0.278 +/- 0.180, and 0.055 +/- 0.029, respectively. The values for other descriptors were similar (no statistically significant difference). The nanofraction particles were found to be more sphere-like (higher R and FF values, and lower E and AR values) as compared to larger particles. Future experiments will involve use of these well characterized particles for in vitro studies. PMID- 21663585 TI - The phage display technique: advantages and recent patents. AB - Phage display technology has advanced considerably since its creation, and the number of research projects using this technique is constantly increasing, generating numerous antibody and antigen libraries. These libraries, besides expediting library screening, improving selection methods and allowing evaluation of novel applications, have great potential for the development of new vaccines, drugs and diagnosis tests. Consequently, patent registries for the protection of these sequences are essential. PMID- 21663586 TI - Val17Ile single nucleotide polymorphisms similarly as Ala15Thr could be related to the lower secretory dynamics of PAI-1 secretion: theoretical evidence. AB - Plasminogen activator inhibitor (PAI-1) is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). In that way PAI-1 regulates proteolytic activity of many physiological and pathological processes [1-3]. PAI 1 plays an important role in blood coagulation controlling clot lysis which is triggered by tPA activated plasminogen [4]. Only two types of mutations are reported to be associated with PAI-1; one is the frame-shift mutation in exon 4 of PAI-1 gene resulting in a truncated nonfunctional protein and in complete PAI 1 deficiency. The other SNP causes Ala15Thr mutation in the signal peptide. A literature search revealed five variants of polymorphisms during a study of over one thousand individuals. Two are associated with thrombophilia (765 4G/5G and 844 A>G, in the promoter), risk of myocardial infarction and postoperative deep venous thrombosis related to higher than normal levels of PAI-1. The other SNPs associated with PAI-1 deficiency are Ala15Thr, Val17Ile and they are located in the central hydrophobic core of the PAI-1 signal peptide of PAI-1 and Asn195Ile in the 'A' beta sheet of the PAI-1. We have analyzed two SNPs not reported to be associated with PAI-1 deficiency. Our analysis suggests that Val17Ile PAI-1 variant might cause slower PAI-1 secretion leading to the deficiency at time and place where it is needed in a similar way as for Ala15Thr SNP. The Asn195Ile mutant may be more stable only as latent form thus no PAI-1 deficiency is expected in this mutant. PMID- 21663587 TI - Docosahexaenoic acid (DHA) sensitizes brain tumor cells to etoposide-induced apoptosis. AB - In this study, we investigated whether DHA, a nutritionally important n-3 unsaturated fatty acid, modulated the sensitivity of brain tumor cells to the anticancer drug, etoposide (VP16). Medulloblastoma (MB) cell lines, Daoy and D283, and glioblastoma (GBM) cell lines, U138 and U87, were exposed to DHA or VP16 alone or in combination. The effects on cell proliferation and the induction of apoptosis were determined by using MTS and Hoechest 33342/PI double staining. U87 and U138 cells were found to be insensitive to the addition of DHA and VP16, whereas the two MB cell lines showed high sensitivity. DHA or VP16 alone showed little effect on cell proliferation or death in either the MB or GBM cell lines, but pretreatment with DHA enhanced the responsiveness to VP16 in the MB cell lines. To understand the mechanisms of combined DHA and VP16 on MB cells, pathway specific oligo array analyses were performed to dissect possible signaling pathways involved. The addition of DHA and VP16, in comparison to VP16 added alone, resulted in marked suppression in the expression of several genes involved in DNA damage repair, cell proliferation, survival, invasion, and angiogenesis, including PRKDC, Survivin, PIK3R1, MAPK14, NFkappaB1, NFkappaBIA, BCL2, CD44, and MAT1. These results suggest (1) that the effects of DHA and VP16 in brain tumor cells are mediated in part by the down regulation of events involved in DNA repair and the PI3K/MAPK signaling pathways and (2) that brain tumors genotypically mimicked by MB cells may benefit from therapies combining DHA with VP16. PMID- 21663588 TI - Adipocytes derived from human bone marrow mesenchymal stem cells exert inhibitory effects on osteoblastogenesis. AB - The infiltration of adipocytes in osteoporotic patients' bone marrow suggests an important regulatory function of bone marrow fat on the development of aged bone. Therefore, we have examined the effects of adipocytes derived from bone mesenchymal stem cell (MSC) on osteoblast differentiation using two different co culture modes (direct mode and indirect mode). Alkaline phosphatase (ALP) positive areas and mineralized areas of MSC-derived osteoblasts decrease similarly in the two co-culture modes as the amount of MSC-derived adipocytes increases, suggesting that the crosstalk between adipocytes and osteoblasts may be mainly through secretory factors in the medium. To further understand the molecular mechanisms, both mRNA and protein expressions in osteoblasts in the lower layer of the indirect mode were analyzed, leading to identification of 12 differential genes/proteins. Among them, S100A6 and calreticulin are possibly related to bone formation. S100A6 was down-regulated and calreticulin was up regulated as MSC-derived adipocytes increased. Similarly, differential expression of these proteins was also observed in bone tissue slides from young (1-month old) and old (6-month-old) mice. The expression level of beta-catenin in osteoblasts of bone tissues was lower in 6-month-old mice compared to 1-month-old mice. Total TGF-beta analyzed with antibody-based protein microarray and active TGF-beta analyzed with ELISA in the co-cultured cell medium increased consistently as the amount of adipocytes increased. Taken together, our results suggest that MSC-derived adipocytes may regulate osteoblast differentiation in the aged bone through TGF-beta-mediated canonical Wnt signaling. PMID- 21663589 TI - Microarray profiling analysis uncovers common molecular mechanisms of rubella virus, human cytomegalovirus, and herpes simplex virus type 2 infections in ECV304 cells. AB - To study the common molecular mechanisms of various viruses infections that might result in congential cardiovascular diseases in perinatal period, changes in mRNA expression levels of ECV304 cells infected by rubella virus (RUBV), human cytomegalovirus (HCMV), and herpes simplex virus type 2 (HSV-2) were analyzed using a microarray system representing 18,716 human genes. 99 genes were found to exhibit differential expression (80 up-regulated and 19 down-regulated). Biological process analysis showed that 33 signaling pathways including 22 genes were relevant significantly to RV, HCMV and HSV-II infections. Of these 33 biological processes, 28 belong to one-gene biological processes and 5 belong to multiple-gene biological processes. Gene annotation indicated that the 5 multiple gene biological processes including regulation of cell growth, collagen fibril organization, mRNA transport, cell adhesion and regulation of cell shape, and seven down- or up-regulated genes [CRIM1 (cysteine rich transmembrane BMP regulator 1), WISP2 (WNT1 inducible signaling pathway protein 2), COL12A1 (collagen, type XII, alpha 1), COL11A2 (collagen, type XI, alpha 2), CNTN5 (contactin 5), DDR1 (discoidin domain receptor tyrosine kinase 1), VEGF (vascular endothelial growth factor precursor)], are significantly correlated to RUBV, HCMV and HSV-2 infections in ECV304 cells. The results obtained in this study suggested the common molecular mechanisms of viruses infections that might result in congential cardiovascular diseases. PMID- 21663590 TI - p53 peptide prevents LITAF-induced TNF-alpha-mediated mouse lung lesions and endotoxic shock. AB - Abnormal and prolonged inflammatory reaction is seen in a wide variety of disorders, and high level of Tumor Necrosis Factor alpha (TNF-alpha) has been linked to these disorders. Therefore, modulation of TNF-alpha expression is important in the regulation of inflammatory disorders. In our previous study, we have shown that a transcription factor LPS-induced TNF factor (LITAF) significantly induces TNF-alpha production. Furthermore, we found that p53 and its synthetic peptide 162-motif specifically downregulate LITAF/TNF-alpha gene expression in human cells in vitro. Thus, in the present study, the role of p53 in regulating TNF-alpha-mediated inflammation was investigated. Our data showed that a synthetic peptide, named 162-motif, corresponding to this region functions independently from p53 to cause a significant suppression of TNF-alpha gene expression in mouse primary macrophages. The 162-motif, when delivered into cells and organs, reduces serum TNF-alpha level in mice and prevents TNF-alpha-induced lung lesions and endotoxic shock. Our findings highlight the regulation of LITAF/TNF-alpha by p53 and its short peptide 162-motif. These in vitro and in vivo observations serve to pave the way for pharmacotherapeutic approaches in the treatment of inflammatory diseases. PMID- 21663591 TI - The role of combined assessment of defense against oxidative stress and inflammation in the evaluation of peripheral arterial disease. AB - Atherosclerosis in symptomatic peripheral arterial disease affects wide portions of numerous arteries in lower extremities. The resulting active inflammation in a considerable amount of arterial tissue facilitates systemic detection via measurement of inflammation-related variables. We reasoned that the combined assessment of defense against oxidative stress, in the form of paraoxonase-1 (PON1), and monocyte migration measured as circulating (C-C motif) ligand 2 (CCL2), may play a role in the evaluation of these patients. Plasma CCL2 and serum PON1-related variables, assessed by their interaction with functional genetic variants, were measured in a cross-sectional study in patients with symptomatic PAD. We found that PON1 activity and concentration were significantly lower and CCL2 concentration higher in PAD patients compared to controls, that the combination of plasma CCL2 and PON1- related values, especially PON1 concentration differentiated, almost perfectly, controls from patients and that the expression of CCL2 and PON1 generally co-localized in the atherosclerotic lesion. Since no association with genetic variants was found, such a relationship is probably the result of the disease. Our data suggest a coordinated role between CCL2 and PON1 that may be detected in blood with simple measurements and may represent an indicator of the extent of atherosclerosis. PMID- 21663592 TI - GEFT, A Rho family guanine nucleotide exchange factor, regulates lens differentiation through a Rac1-mediated mechanism. AB - The Rho-family of small GTPase specific guanine nucleotide exchange factor, GEFT, is expressed at high levels in adult human excitable tissues including the brain, heart, and skeletal muscle. Previously, we demonstrated that GEFT is specifically expressed in the adult mouse hippocampus and cerebellum, and that overexpression of this protein can result in neurite and dendrite remodeling. This finding prompted us to explore the expression of GEFT in other tissues, which share common developmental ancestry to the nervous system, specifically the ocular system. Using immunohistochemical analysis specific for GEFT protein expression, we observed the highest ocular expression of GEFT occurring in the neuroblastic layer and differentiating lens fibers of the late-stage mouse embryo, and in the postnatal corneal epithelium, lens epithelium, and throughout the retina. Exogenous expression of GEFT in N/N1003A rabbit lens epithelial cells induced lens fiber differentiation as reflected by cell elongation and lentoid formation, as well as a strong increase in beta-crystallin and filensin expression. Moreover, transfection of lens epithelial cells with GEFT resulted in a Rac-1 mediated up-regulation of alphaA-, alphaB-, betaB-, gammaC-, or gammaF-crystallin promoter activities that is in part dependent on the nuclear localization of Rac1. Furthermore, pharmacological inhibition of Rac1 blocked GEFT-induced N/N1003A lens fiber differentiation and betaB-crystallin expression in ex vivo mouse lens explants. These results demonstrate for the first time a role for GEFT in lens cell differentiation and mouse eye development. Moreover, GEFT regulation of lens differentiation and eye development occurs through a Rac1-dependent mechanism. PMID- 21663594 TI - A role for heparan sulfate proteoglycans in Plasmodium falciparum sporozoite invasion of anopheline mosquito salivary glands. AB - HS (heparan sulfate) has been shown to be an important mediator of Plasmodium sporozoite homing and invasion of the liver, but the role of this glycosaminoglycan in mosquito vector host-sporozoite interactions is unknown. We have biochemically characterized the function of AgOXT1 (Anopheles gambiae peptide-O-xylosyltransferase 1) and confirmed that AgOXT1 can modify peptides representing model HS and chondroitin sulfate proteoglycans in vitro. Moreover, we also demonstrated that the mosquito salivary gland basal lamina proteoglycans are modified by HS. We used RNA interference-mediated knockdown of HS biosynthesis in A. gambiae salivary glands to determine whether Plasmodium falciparum sporozoites that are released from mosquito midgut oocysts use salivary gland HS as a receptor for tissue invasion. Our results suggest that salivary gland basal lamina HS glycosaminoglycans only partially mediate midgut sporozoite invasion of this tissue, and that in the absence of HS, the presence of other surface co-receptors is sufficient to facilitate parasite entry. PMID- 21663595 TI - The co-transduction of Nurr1 and Brn4 genes induces the differentiation of neural stem cells into dopaminergic neurons. AB - Fetal brain tissue can be used in cell replacement therapy for PD (Parkinson's disease), but there is a poor donor supply of this tissue. NSCs (neural stem cells) may overcome this problem as they can be isolated and expanded in vitro. However, the usage of NSCs is limited because the differentiation of NSCs into specific dopaminergic neurons has proven difficult. In the present study, we investigated the effect of Nurr1 (nuclear receptor related factor 1), a transcription factor specific for the development and maintenance of the midbrain dopaminergic neurons on inducing the differentiation of NSCs into TH (tyrosine hydroxylase) immunoreactive dopaminergic neurons. Nonetheless, these cells exhibited an immature neuronal morphology with small cell bodies and short neurite processes, and they seldom expressed DAT (dopamine transporter), a late marker of mature dopaminergic neurons. However, forced co-expression of Nurr1 with Brn4, a member of the POU domain family of transcription factors, caused immature Nurr1-induced dopaminergic neurons to differentiate into morphologically and phenotypically more mature neurons. Thus the enriched generation of mature dopaminergic neurons by forced expression of Nurr1 with Brn4 may be of future importance in NSC-based cell replacement therapy for PD. PMID- 21663596 TI - Nano-biolistics: a method of biolistic transfection of cells and tissues using a gene gun with novel nanometer-sized projectiles. AB - BACKGROUND: Biolistic transfection is proving an increasingly popular method of incorporating DNA or RNA into cells that are difficult to transfect using traditional methods. The technique routinely uses 'microparticles', which are ~1 MUm diameter projectiles, fired into tissues using pressurised gas. These microparticles are efficient at delivering DNA into cells, but cannot efficiently transfect small cells and may cause significant tissue damage, thus limiting their potential usefulness. Here we describe the use of 40 nm diameter projectiles--nanoparticles--in biolistic transfections to determine if they are a suitable alternative to microparticles. RESULTS: Examination of transfection efficiencies in HEK293 cells, using a range of conditions including different DNA concentrations and different preparation procedures, reveals similar behaviour of microparticles and nanoparticles. The use of nanoparticles, however, resulted in ~30% fewer damaged HEK293 cells following transfection. Biolistic transfection of mouse ear tissue revealed similar depth penetration for the two types of particles, and also showed that < 10% of nuclei were damaged in nanoparticle transfected samples, compared to > 20% in microparticle-transfected samples. Visualising details of small cellular structures was also considerably enhanced when using nanoparticles. CONCLUSIONS: We conclude that nanoparticles are as efficient for biolistic transfection as microparticles, and are more appropriate for use in small cells, when examining cellular structures and/or where tissue damage is a problem. PMID- 21663597 TI - Motivational interviewing as an intervention to increase adolescent self-efficacy and promote weight loss: methodology and design. AB - BACKGROUND: Childhood obesity is associated with serious physiological and psychological consequences including type 2 diabetes, higher rates of depression and low self-esteem. With the population of overweight and obese youth increasing, appropriate interventions are needed that speak to the issue of readiness to change and motivation to maintain adherence to healthy behavior changes. Motivational Interviewing (MI) is a method of therapy found to resolve ambivalence, enhance intrinsic motivation and promote confidence in a person's ability to make behavior changes. While MI has shown promise in the adult obesity literature as effecting positive lifestyle change, little is known about the effectiveness of MI with overweight and obese youth. This study aims to: 1) demonstrate that MI is an effective intervention for increasing a person's self efficacy; 2) demonstrate that exposure to MI will facilitate healthy behavior changes; 3) explore psychological changes related to participation in MI and 4) compare physiological and anthropometric outcomes before and after intervention. METHODS/DESIGN: The current investigation is a prospective study conducted with ongoing participants who regularly attend an outpatient pediatric care center for weight-loss. Overweight youth (BMI > 85th %ile) between the ages of 10 and 18 who meet eligibility criteria will be recruited. Participants will be randomly assigned to a control group (social skills training) or a treatment group (MI). Participants will meet with the therapist for approximately 30 minutes prior to seeing the dietician, over the course of 6 months. Participants will also undergo a full day assessment at the beginning and end of psychology intervention to evaluate body fat, and metabolic risk (screening for diabetes, high cholesterol, high blood pressure and fitness level). The paper and pencil portions of the assessments as well as the clinical testing will occur at baseline and at the conclusion of the intervention (6 months) with a repeat assessment 6 months following the completion of the intervention. DISCUSSION: Results from this study are expected to enhance our understanding of the efficacy of MI with children and adolescents who are overweight or obese. PMID- 21663598 TI - The function of 7D-cadherins: a mathematical model predicts physiological importance for water transport through simple epithelia. AB - BACKGROUND: 7D-cadherins like LI-cadherin are cell adhesion molecules and represent exceptional members of the cadherin superfamily. Although LI-cadherin was shown to act as a functional Ca2+-dependent adhesion molecule, linking neighboring cells together, and to be dysregulated in a variety of diseases, the physiological role is still enigmatic. Interestingly 7D-cadherins occur only in the lateral plasma membranes of cells from epithelia of water transporting tissues like the gut, the liver or the kidney. Furthermore LI-cadherin was shown to exhibit a highly cooperative Ca2+-dependency of the binding activity. Thus it is tempting to assume that LI-cadherin regulates the water transport through the epithelium in a passive fashion by changing its binding activity in dependence on the extracellular Ca2+. RESULTS: We developed a simple mathematical model describing the epithelial lining of a lumen with a content of variable osmolarity covering an interstitium of constant osmolarity. The width of the lateral intercellular cleft was found to influence the water transport significantly. In the case of hypertonic luminal content a narrow cleft is necessary to further increase concentration of the luminal content. If the cleft is too wide, the water flux will change direction and water is transported into the lumen. Electron microscopic images show that in fact areas of the gut can be found where the lateral intercellular cleft is narrow throughout the lateral cell border whereas in other areas the lateral intercellular cleft is widened. CONCLUSIONS: Our simple model clearly predicts that changes of the width of the lateral intercellular cleft can regulate the direction and efficiency of water transport through a simple epithelium. In a narrow cleft the cells can increase the concentration of osmotic active substances easily by active transport whereas if the cleft is wide, friction is reduced but the cells can hardly build up high osmotic gradients. It is now tempting to speculate that 7D-cadherins, owing to their location and their Ca2+-dependence, will adapt their binding activity and thereby the width of the lateral intercellular cleft automatically as the Ca2+ concentration is coupled to the overall electrolyte concentration in the lateral intercellular cleft. This could provide a way to regulate the water resorption in a passive manner adapting to different osmotic conditions. PMID- 21663599 TI - Liposome-based DNA carriers may induce cellular stress response and change gene expression pattern in transfected cells. AB - BACKGROUND: During functional studies on the rat stress-inducible Hspa1b (hsp70.1) gene we noticed that some liposome-based DNA carriers, which are used for transfection, induce its promoter activity. This observation concerned commercial liposome formulations (LA), Lipofectin and Lipofectamine 2000. This work was aimed to understand better the mechanism of this phenomenon and its potential biological and practical consequences. RESULTS: We found that a reporter gene driven by Hspa1b promoter is activated both in the case of transient transfections and in the stably transfected cells treated with LA. Using several deletion clones containing different fragments of Hspa1b promoter, we found that the regulatory elements responsible for most efficient LA-driven inducibility were located between nucleotides -269 and +85, relative to the transcription start site. Further studies showed that the induction mechanism was independent of the classical HSE-HSF interaction that is responsible for gene activation during heat stress. Using DNA microarrays we also detected significant activation of the endogenous Hspa1b gene in cells treated with Lipofectamine 2000. Several other stress genes were also induced, along with numerous genes involved in cellular metabolism, cell cycle control and pro-apoptotic pathways. CONCLUSIONS: Our observations suggest that i) some cationic liposomes may not be suitable for functional studies on hsp promoters, ii) lipofection may cause unintended changes in global gene expression in the transfected cells. PMID- 21663600 TI - Value of arterial blood gas analysis in patients with acute dyspnea: an observational study. AB - INTRODUCTION: The diagnostic and prognostic value of arterial blood gas analysis (ABGA) parameters in unselected patients presenting with acute dyspnea to the Emergency Department (ED) is largely unknown. METHODS: We performed a post-hoc analysis of two different prospective studies to investigate the diagnostic and prognostic value of ABGA parameters in patients presenting to the ED with acute dyspnea. RESULTS: We enrolled 530 patients (median age 74 years). ABGA parameters were neither useful to distinguish between patients with pulmonary disorders and other causes of dyspnea nor to identify specific disorders responsible for dyspnea. Only in patients with hyperventilation from anxiety disorder, the diagnostic accuracy of pH and hypoxemia rendered valuable with an area under the receiver operating characteristics curve (AUC) of 0.86. Patients in the lowest pH tertile more often required admission to intensive care unit (28% vs 12% in the first tertile, P < 0.001) and had higher in-hospital (14% vs 5%, P = 0.003) and 30-day mortality (17% vs 7%, P = 0.002). Cumulative mortality rate was higher in the first (37%), than in the second (28%), and the third tertile (23%, P = 0.005) during 12 months follow-up. pH at presentation was an independent predictor of 12 month mortality in multivariable Cox proportional hazard analysis both for patients with pulmonary (P = 0.043) and non-pulmonary disorders (P = 0.038). CONCLUSIONS: ABGA parameters provide limited diagnostic value in patients with acute dyspnea, but pH is an independent predictor of 12 months mortality. PMID- 21663601 TI - Tick-borne lymphadenopathy (TIBOLA) acquired in Southwestern Germany. AB - BACKGROUND: Tick-borne lymphadenopathy (TIBOLA) was first described in 1997 in a patient in France. The causative agent, Rickettsia slovaca, is transmitted by Dermacentor ticks. CASE PRESENTATION: In southwestern Germany we encountered a patient with a tick bite at the dorsal scalp that resulted in an eschar and nuchal lymphadenopathy. Additionally, fever, malaise as well as elevated inflammatory markers and transaminases occurred. The characteristic clinical picture along with positive antibody testing for rickettsiae of the tick-borne spotted fever group strongly suggest the diagnosis TIBOLA. CONCLUSION: Human rickettsioses are emerging infections. Clinicians should be aware of TIBOLA as a newly described rickettsial disease. As in our case, TIBOLA may be encountered in regions/countries where R. slovaca and Dermacentor ticks are prevalent but autochthonous acquisition was not described before. PMID- 21663602 TI - Distress related to myocardial infarction and cardiovascular outcome: a retrospective observational study. AB - BACKGROUND: During acute coronary syndromes patients perceive intense distress. We hypothesized that retrospective ratings of patients' MI-related fear of dying, helplessness, or pain, all assessed within the first year post-MI, are associated with poor cardiovascular outcome. METHODS: We studied 304 patients (61 +/- 11 years, 85% men) who after a median of 52 days (range 12-365 days) after index MI retrospectively rated the level of distress in the form of fear of dying, helplessness, or pain they had perceived at the time of MI on a numeric scale ranging from 0 ("no distress") to 10 ("extreme distress"). Non-fatal hospital readmissions due to cardiovascular disease (CVD) related events (i.e., recurrent MI, elective and non-elective stent implantation, bypass surgery, pacemaker implantation, cerebrovascular incidents) were assessed at follow-up. The relative CVD event risk was computed for a (clinically meaningful) 2-point increase of distress using Cox proportional hazard models. RESULTS: During a median follow-up of 32 months (range 16-45), 45 patients (14.8%) experienced a CVD-related event requiring hospital readmission. Greater fear of dying (HR 1.21, 95% CI 1.03 1.43), helplessness (HR 1.22, 95% CI 1.04-1.44), or pain (HR 1.27, 95% CI 1.02 1.58) were significantly associated with an increased CVD risk without adjustment for covariates. A similarly increased relative risk emerged in patients with an unscheduled CVD-related hospital readmission, i.e., when excluding patients with elective stenting (fear of dying: HR 1.26, 95% CI 1.05-1.51; helplessness: 1.26, 95% CI 1.05-1.52; pain: HR 1.30, 95% CI 1.01-1.66). In the fully-adjusted models controlling for age, the number of diseased coronary vessels, hypertension, and smoking, HRs were 1.24 (95% CI 1.04-1.46) for fear of dying, 1.26 (95% CI 1.06 1.50) for helplessness, and 1.26 (95% CI 1.01-1.57) for pain. CONCLUSIONS: Retrospectively perceived MI-related distress in the form of fear of dying, helplessness, or pain was associated with non-fatal cardiovascular outcome independent of other important prognostic factors. PMID- 21663603 TI - Coexistence of early microinvasive endometrioid adenocarcinoma and CIN3 in the uterine cervix in a 32-year-old Japanese woman. AB - Simultaneous occurrence of early microinvasive endometrioid adenocarcinoma (EMEA) and CIN 3 in the uterine cervix is very rare in Japan. A 32-year-old Japanese woman was pointed out to have atypical cells in the cervical cytology. Colposcopic examination revealed irregular lesions in the cervix, and a biopsy showed simultaneous EMEA and CIN3. The EMEA was grade I and CIN3 corresponded to severe dysplasia/carcinoma in situ. Hysterectomy and lymph nodes dissection were performed. Grossly, mucosal irregularity and erosion were seen in the cervix. No tumor formation was recognized. The cervix was examined by serial sections. Microscopically, there were a tiny adenocarcinoma (0.5 cm in diameter and 0.3 cm in depth) and broad areas of CIN3. The adenocarcinoma was EMEA without mucins. The EMEA was FIGO stage 1A1. Immunohistochemically, the EMEA was positive for pancytokeratins (AE1/2 +++, CAM5.2 ++), cytokeratin (CK) 34betaE12 +, CK5/6 +, CK7 +, CK18 +++, CK19 ++, CA19-9 +, CA125 +++, p53 +, ER +++, PgR +++, while it was negative for CK8, CK14, CK20, EMA, vimentin, CEA, desmin, smooth muscle actin, p63, chromogranin, synaptophysin, CD56, CD68, HER2/neu, MUC1, MUC2, MUC5AC, and MUC6. The CIN 3 was positive for pancytokeratins (AE1/2 +++, CAM5.2 +), cytokeratin (CK) 34betaE12 +++, CK5/6 +++, CK7 +, EMA, CA19-9 +, CA125 +, p53 +, p63 +++, ER +++, and MUC1 +, while it was negative for CK8, CK14, CK18, CK19, CK20, vimentin, CEA, desmin, smooth muscle actin, chromogranin, synaptophysin, CD56, CD68, PgR, HER2/neu, MUC2, MUC5AC and MUC6. The lymph nodes showed no metastatic lesions (0/34). In conclusion, the author reported a rare case of simultaneous EMEA and CIN 3 with extensive immunohistochemical findings. PMID- 21663604 TI - Impact of different pack sizes of paracetamol in the United Kingdom and Ireland on intentional overdoses: a comparative study. AB - BACKGROUND: In order to reduce fatal self-poisoning legislation was introduced in the UK in 1998 to restrict pack sizes of paracetamol sold in pharmacies (maximum 32 tablets) and non-pharmacy outlets (maximum 16 tablets), and in Ireland in 2001, but with smaller maximum pack sizes (24 and 12 tablets). Our aim was to determine whether this resulted in smaller overdoses of paracetamol in Ireland compared with the UK. METHODS: We used data on general hospital presentations for non-fatal self-harm for 2002-2007 from the Multicentre Study of Self-harm in England (six hospitals), and from the National Registry of Deliberate Self-harm in Ireland. We compared sizes of overdoses of paracetamol in the two settings. RESULTS: There were clear peaks in numbers of non-fatal overdoses, associated with maximum pack sizes of paracetamol in pharmacy and non-pharmacy outlets in both England and Ireland. Significantly more pack equivalents (based on maximum non-pharmacy pack sizes) were used in overdoses in Ireland (mean 2.63, 95% CI 2.57-2.69) compared with England (2.07, 95% CI 2.03-2.10). The overall size of overdoses did not differ significantly between England (median 22, interquartile range (IQR) 15-32) and Ireland (median 24, IQR 12-36). CONCLUSIONS: The difference in paracetamol pack size legislation between England and Ireland does not appear to have resulted in a major difference in sizes of overdoses. This is because more pack equivalents are taken in overdoses in Ireland, possibly reflecting differing enforcement of sales advice. Differences in access to clinical services may also be relevant. PMID- 21663606 TI - The spatial distribution of pet dogs and pet cats on the island of Ireland. AB - BACKGROUND: There is considerable international research regarding the link between human demographics and pet ownership. In several international studies, pet ownership was associated with household demographics including: the presence of children in the household, urban/rural location, level of education and age/family structure. What is lacking across all these studies, however, is an understanding of how these pets are spatially distributed throughout the regions under study. This paper describes the spatial distribution of pet dog and pet cat owning households on the island of Ireland. RESULTS: In 2006, there were an estimated 640,620 pet dog owning households and 215,542 pet cat owning households in Ireland. These estimates are derived from logistic regression modelling, based on household composition to determine pet dog ownership and the type of house to determine pet cat ownership. Results are presented using chloropleth maps. There is a higher density of pet dog owning households in the east of Ireland and in the cities than the west of Ireland and rural areas. However, in urban districts there are a lower proportion of households owning pet dogs than in rural districts. There are more households with cats in the urban areas, but the proportion of households with cats is greater in rural areas. CONCLUSIONS: The difference in spatial distribution of dog ownership is a reflection of a generally higher density of households in the east of Ireland and in major cities. The higher proportion of ownership in the west is understandable given the higher proportion of farmers and rural dwellings in this area. Spatial representation allows us to visualise the impact of human household distribution on the density of both pet dogs and pet cats on the island of Ireland. This information can be used when analysing risk of disease spread, for market research and for instigating veterinary care. PMID- 21663605 TI - Children's active play: self-reported motivators, barriers and facilitators. AB - BACKGROUND: Physical activity has important benefits for children's physical health and mental wellbeing, but many children do not meet recommended levels. Research suggests that active play has the potential to make a valuable contribution to children's overall physical activity, whilst providing additional cognitive, social and emotional benefits. However, relatively little is known about the determinants of UK children's active play. Understanding these factors provides the critical first step in developing interventions to increase children's active play, and therefore overall physical activity. METHODS: Eleven focus groups were conducted with 77, 10-11 year old children from four primary schools in Bristol, UK. Focus groups examined: (i) factors which motivate children to take part in active play; (ii) factors which limit children's active play and (iii) factors which facilitate children's active play. All focus groups were audio-taped and transcribed verbatim. Data were analysed using a thematic approach. RESULTS: Children were motivated to engage in active play because they perceived it to be enjoyable, to prevent boredom, to have physical and mental health benefits and to provide freedom from adult control, rules and structure. However, children's active play was constrained by a number of factors, including rainy weather and fear of groups of teenagers in their play spaces. Some features of the physical environment facilitated children's active play, including the presence of green spaces and cul-de-sacs in the neighbourhood. Additionally, children's use of mobile phones when playing away from home was reported to help to alleviate parents' safety fears, and therefore assist children's active play. CONCLUSIONS: Children express a range of motivational and environmental factors that constrain and facilitate their active play. Consideration of these factors should improve effectiveness of interventions designed to increase active play. PMID- 21663608 TI - Time spent in primary care for hip osteoarthritis patients once the diagnosis is set: a prospective observational study. AB - BACKGROUND: Previous research on time to referral to orthopaedic surgery has predominantly used hip complaints as starting point instead of the moment the diagnosis of osteoarthritis (OA) of the hip is established, therefore little is known about the length of time a patient diagnosed with hip OA stays under the care of a general practitioner (GP). No knowledge on factors of influence on this time period is available either. Aim of this study was thus to determine the time an incident hip OA patient stays in the care of a GP until referral to an orthopaedic department. Influencing factors were also analyzed. METHODS: A prospective observational study was conducted based on data over a 10-year period from a general practice-based registration network (17 GPs, > 30,000 patients registered yearly). Patients with the diagnosis of hip OA were included. A survival analysis was used to determine time until referral to an orthopaedic department, and to determine factors of influence on this time. RESULTS: Of 391 patients diagnosed with hip OA, 121 (31%) were referred; average survival time until referral was 82.0 months (95% CI 76.6-87.5). Less contact with the GP for hip complaints before the diagnosis of hip OA was established resulted in a decreased time to referral. CONCLUSIONS: The results of this study show that patients with hip OA were under the care of a general practitioner, and thus in primary care, for a considerable amount of time once the diagnosis of hip OA was established. PMID- 21663607 TI - Lack of effect of apolipoprotein C3 polymorphisms on indices of liver steatosis, lipid profile and insulin resistance in obese Southern Europeans. AB - BACKGROUND: Apolipoprotein C3 (APOC3) is a component of triglyceride-rich lipoproteins, and APOC3 rs2854116 and rs2854117 polymorphisms have been associated with non-alcoholic fatty liver disease, hypertriglyceridaemia, and insulin-resistance. OBJECTIVE: To determine if the APOC3 variants alter the susceptibility of obese subjects to develop liver damage, hypertrigliceridaemia, and insulin-resistance. METHODS: The study was carried out on 585 unrelated obese Italians (median body mass index BMI = 41 kg/m2) who were genotyped for the rs2854116 and rs2854117 variants. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose, insulin, lipid parameters. Indices of insulin-resistance (HOMA and ISI) were calculated. Alanine transaminase (ALT) and aspartate transaminase (AST) were used as markers of liver injury. RESULTS: The study subjects were divided into two groups: those homozygous for the wild-type alleles at both SNPs (-482C and -455T alleles) and those who were carriers of at least one variant allele or both (-482T, -455C or both). Also each SNP was analysed independently. No significant differences were found in ALT and AST levels and in the lipid profile between the two groups. Insulin concentrations, glucose tolerance and insulin sensitivity were similar in the two groups. CONCLUSION: We did not identify any significant association between APOC3 polymorphisms and fatty liver disease, lipids, and insulin resistance in obese subjects, thus not confirming the suggested role of these APOC3 gene sequence variants. PMID- 21663609 TI - Novel study designs to investigate the placebo response. AB - BACKGROUND: Investigating the size and mechanisms of the placebo response in clinical trials have relied on experimental procedures that simulate the double blind randomized placebo-controlled design. However, as the conventional design is thought to elucidate drug rather than placebo actions, different methodological procedures are needed for the placebo response. METHODS: We reviewed the respective literature for trials designs that may be used to elucidate the size of the placebo response and the mechanisms associated with it. RESULTS: In general, this can be done by either manipulation the information provided to the subjects, or by manipulation the timing of the drug applied. Two examples of each strategy are discussed: the "balanced placebo design" (BDP) and the "balanced cross-over design" (BCD) and their variants are based on false information, while the "hidden treatment" (HT) and the ""delayed response test" (DRT) are based on manipulating the time of drug action. Since most such approaches include deception or incomplete information of the subjects they are suitable for patient only with authorized deception. CONCLUSION: Both manipulating the information provided to subjects (BDP, DCD) or manipulating the timing of drug application (HT, DRT) allows overcoming some of the restrictions of conventional drug trials in the assessment of the placebo response, but they are feasible mostly in healthy subjects for ethical reasons. PMID- 21663610 TI - A process evaluation of a worksite vitality intervention among ageing hospital workers. AB - BACKGROUND: The process evaluation of the Vital@Work intervention was primary aimed at gaining insight into the context, dose delivered, fidelity, reach, dose received, and participants' attitude. Further, the differences between intervention locations were evaluated. METHODS: Eligible for this study were 730 workers, aged >= 45 years, from two academic hospitals. Workers randomised to the intervention group (n = 367) received a 6-months intervention consisting a Vitality Exercise Programme (VEP) combined with three visits to a Personal Vitality Coach (PVC), aimed at goal setting, feedback, and problem solving. The VEP consisted of a guided yoga session, a guided workout session, and aerobic exercising without direct face-to-face instruction, all once a week. Data were collected by means of a questionnaire after the intervention, attendance registration forms (i.e. attendance at guided VEP group sessions), and coaching registration forms (filled in by the PVCs). RESULTS: The dose delivered of the yoga and workout sessions were 72.3% and 96.3%. All PVC visits (100%) were offered. The reach for the yoga sessions, workout sessions and PVC visits was 70.6%, 63.8%, and 89.6%, respectively. When taken these three intervention components together, the reach was 52%. This differed between the two locations (59.2% versus 36.8%). The dose received was for the yoga 10.4 sessions/24 weeks and for the workout 11.1 sessions/24 weeks. The attendance rate, defined as the mean percentage of attended group sessions in relation to the total provided group sessions, for the yoga and workout sessions was 51.7% and 44.8%, respectively. For the yoga sessions this rate was different between the two locations (63.2% versus 46.5%). No differences were found between the locations regarding the workout sessions and PVC visits. Workers attended on average 2.7 PVC visits. Overall, workers were satisfied with the intervention components: 7.5 for yoga sessions, 7.8 for workout sessions, and 6.9 for PVC visits. CONCLUSIONS: The implementation of the intervention was accomplished as planned with respect to the dose delivered. Based on the reach, most workers were willing to attend the guided group sessions and the PVC visits, although there were differences between the locations and between intervention components. Overall, workers were positive about the intervention. TRIAL REGISTRATION: Trial registration NTR1240. PMID- 21663611 TI - Effective inhibition of foot-and-mouth disease virus (FMDV) replication in vitro by vector-delivered microRNAs targeting the 3D gene. AB - BACKGROUND: Foot-and-mouth disease virus (FMDV) causes an economically important and highly contagious disease of cloven-hoofed animals. RNAi triggered by small RNA molecules, including siRNAs and miRNAs, offers a new approach for controlling viral infections. There is no report available for FMDV inhibition by vector delivered miRNA, although miRNA is believed to have more potential than siRNA. In this study, the inhibitory effects of vector-delivered miRNAs targeting the 3D gene on FMDV replication were examined. RESULTS: Four pairs of oligonucleotides encoding 3D-specific miRNA of FMDV were designed and selected for construction of miRNA expression plasmids. In the reporter assays, two of four miRNA expression plasmids were able to significantly silence the expression of 3D-GFP fusion proteins from the reporter plasmid, p3D-GFP, which was cotransfected with each miRNA expression plasmid. After detecting the silencing effects of the reporter genes, the inhibitory effects of FMDV replication were determined in the miRNA expression plasmid-transfected and FMDV-infected cells. Virus titration and real time RT-PCR assays showed that the p3D715-miR and p3D983-miR plasmids were able to potently inhibit the replication of FMDV when BHK-21 cells were infected with FMDV. CONCLUSION: Our results indicated that vector-delivered miRNAs targeting the 3D gene efficiently inhibits FMDV replication in vitro. This finding provides evidence that miRNAs could be used as a potential tool against FMDV infection. PMID- 21663613 TI - Cerebral vein thrombosis: clinical manifestation and diagnosis. AB - BACKGROUND: Cerebral venous thrombosis (CVT) is a disease with a wide spectrum of symptoms and severity. In this study we analysed the predictive value of clinical signs and symptoms and the contribution of D-dimer measurements for diagnosis. METHODS: We evaluated consecutive patients admitted with suspected CVT receiving non-invasive imaging. Symptoms and symptom combination as well as D-dimer levels were evaluated regarding their diagnostic value. RESULTS: 239 patients were included in this study, 170 (71%) were females. In 39 patients (16%) a CVT was found. For identifying a CVT patients underwent either a venous CT-angiography or MR-angiography or both. No combination of symptoms either alone or together with the D-dimer measurements had a sensitivity and positive predictive value as well as negative predictive value and specificity high enough to serve as red flag. D dimer testing produced rates of 9% false positive and of 24% false negative results. For D-dimer values a Receiver Operating Characteristic curve (ROC) and the area under the curve (AUC = 0.921; CI: 0.864-0.977) were calculated. An increase of sensitivity above 0.9 results in a relevant decrease in specificity; a sensitivity of 0.9 matches a specificity value of 0.9. This corresponds to a D dimer cut-off level of 0.16 MUg/ml. CONCLUSION: Imaging as performed by venous CT angiography or MR-angiography has a 1 to 2 in 10 chance to detect CVT when typical symptoms are present. D-dimer measurements are of limited clinical value because of false positive and negative results. PMID- 21663612 TI - The two tryptophans of beta2-microglobulin have distinct roles in function and folding and might represent two independent responses to evolutionary pressure. AB - BACKGROUND: We have recently discovered that the two tryptophans of human beta2 microglobulin have distinctive roles within the structure and function of the protein. Deeply buried in the core, Trp95 is essential for folding stability, whereas Trp60, which is solvent-exposed, plays a crucial role in promoting the binding of beta2-microglobulin to the heavy chain of the class I major histocompatibility complex (MHCI). We have previously shown that the thermodynamic disadvantage of having Trp60 exposed on the surface is counter balanced by the perfect fit between it and a cavity within the MHCI heavy chain that contributes significantly to the functional stabilization of the MHCI. Therefore, based on the peculiar differences of the two tryptophans, we have analysed the evolution of beta2-microglobulin with respect to these residues. RESULTS: Having defined the beta2-microglobulin protein family, we performed multiple sequence alignments and analysed the residue conservation in homologous proteins to generate a phylogenetic tree. Our results indicate that Trp60 is highly conserved, whereas some species have a Leu in position 95; the replacement of Trp95 with Leu destabilizes beta2-microglobulin by 1 kcal/mol and accelerates the kinetics of unfolding. Both thermodynamic and kinetic data fit with the crystallographic structure of the Trp95Leu variant, which shows how the hydrophobic cavity of the wild-type protein is completely occupied by Trp95, but is only half filled by Leu95. CONCLUSIONS: We have established that the functional Trp60 has been present within the sequence of beta2-microglobulin since the evolutionary appearance of proteins responsible for acquired immunity, whereas the structural Trp95 was selected and stabilized, most likely, for its capacity to fully occupy an internal cavity of the protein thereby creating a better stabilization of its folded state. PMID- 21663614 TI - Close 3D proximity of evolutionary breakpoints argues for the notion of spatial synteny. AB - BACKGROUND: Folding and intermingling of chromosomes has the potential of bringing close to each other loci that are very distant genomically or even on different chromosomes. On the other hand, genomic rearrangements also play a major role in the reorganisation of loci proximities. Whether the same loci are involved in both mechanisms has been studied in the case of somatic rearrangements, but never from an evolutionary standpoint. RESULTS: In this paper, we analysed the correlation between two datasets: (i) whole-genome chromatin contact data obtained in human cells using the Hi-C protocol; and (ii) a set of breakpoint regions resulting from evolutionary rearrangements which occurred since the split of the human and mouse lineages. Surprisingly, we found that two loci distant in the human genome but adjacent in the mouse genome are significantly more often observed in close proximity in the human nucleus than expected. Importantly, we show that this result holds for loci located on the same chromosome regardless of the genomic distance separating them, and the signal is stronger in gene-rich and open-chromatin regions. CONCLUSIONS: These findings strongly suggest that part of the 3D organisation of chromosomes may be conserved across very large evolutionary distances. To characterise this phenomenon, we propose to use the notion of spatial synteny which generalises the notion of genomic synteny to the 3D case. PMID- 21663615 TI - Bioethical differences between drug addiction treatment professionals inside and outside the Russian Federation. AB - This article provides an overview of a sociological study of the views of 338 drug addiction treatment professionals. A comparison is drawn between the bioethical approaches of Russian and foreign experts from 18 countries. It is concluded that the bioethical priorities of Russian and foreign experts differ significantly. Differences involve attitudes toward confidentiality, informed consent, compulsory treatment, opioid agonist therapy, mandatory testing of students for psychoactive substances, the prevention of mental patients from having children, harm reduction programs (needle and syringe exchange), euthanasia, and abortion. It is proposed that the cardinal dissimilarity between models for providing drug treatment in the Russian Federation versus the majority of the countries of the world stems from differing bioethical attitudes among drug addiction treatment experts. PMID- 21663616 TI - Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study. AB - INTRODUCTION: In adults, small (< 50%) serum creatinine (SCr) increases predict mortality. It is unclear whether different baseline serum creatinine (bSCr) estimation methods affect findings of acute kidney injury (AKI)-outcome associations. We characterized pediatric AKI, evaluated the effect of bSCr estimation approaches on AKI-outcome associations and evaluated the use of small SCr increases to predict AKI development. METHODS: We conducted a retrospective cohort database study of children (excluding postoperative cardiac or renal transplant patients) admitted to two pediatric intensive care units (PICUs) for at least one night in Montreal, QC, Canada. The AKI definition was based on the Acute Kidney Injury Network staging system, excluding the requirement of SCr increase within 48 hours, which was impossible to evaluate on the basis of our data set. We estimated bSCr two ways: (1) the lowest SCr level in the three months before admission or the average age- and gender-based norms (the standard method) or (2) by using average norms in all patients. Outcomes were PICU mortality and length of stay as well as required mechanical ventilation. We used multiple logistic regression analysis to evaluate AKI risk factors and the association between AKI and mortality. We used multiple linear regression analysis to evaluate the effect of AKI on other outcomes. We calculated diagnostic characteristics for early SCr increase (< 50%) to predict AKI development. RESULTS: Of 2,106 admissions (mean age +/- SD = 5.0 +/- 5.5 years; 47% female), 377 patients (17.9%) developed AKI (using the standard bSCr method) during PICU admission. Higher Pediatric Risk of Mortality score, required mechanical ventilation, documented infection and having a bSCr measurement were independent predictors of AKI development. AKI was associated with increased mortality (adjusted odds ratio (OR) = 3.7, 95% confidence interval (95% CI) = 2.1 to 6.4, using the standard bSCr method; OR = 4.5, 95% CI = 2.6 to 7.9, using normative bSCr values in all patients). AKI was independently associated with longer PICU stay and required mechanical ventilation. In children with no admission AKI, the initial percentage SCr increase predicted AKI development (area under the curve = 0.67, 95% CI = 0.60 to 0.74). CONCLUSIONS: AKI is associated with increased mortality and morbidity in critically ill children, regardless of the bSCr used. Paying attention to small early SCr increases may contribute to early AKI diagnosis in conjunction with other new AKI biomarkers. PMID- 21663617 TI - Evaluation of wet-cupping therapy for persistent non-specific low back pain: a randomised, waiting-list controlled, open-label, parallel-group pilot trial. AB - BACKGROUND: Persistent non-specific low back pain (PNSLBP) is one of the most frequently experienced types of back pain around the world. Wet-cupping is a common intervention for various pain conditions, especially in Korea. In this context, we conducted a pilot study to determine the effectiveness and safety of wet-cupping treatment for PNSLBP. METHODS: We recruited 32 participants (21 in the wet-cupping group and 11 in the waiting-list group) who had been having PNSLBP for at least 3 months. The participants were recruited at the clinical research centre of the Korea Institute of Oriental Medicine, Korea. Eligible participants were randomly allocated to wet-cupping and waiting-list groups. Following the practice of traditional Korean medicine, the treatment group was provided with wet-cupping treatment at two acupuncture points among the BL23, BL24 and BL25 6 times within 2 weeks. Usual care, including providing brochures for exercise, general advice for PNSLBP and acetaminophen, was allowed in both groups. Separate assessors participated in the outcome assessment. We used the 0 to 100 numerical rating scale (NRS) for pain, the McGill Pain Questionnaire for pain intensity (PPI) and the Oswestry Disability Questionnaire (ODQ), and we assessed acetaminophen use and safety issues. RESULTS: The results showed that the NRS score for pain decreased (-16.0 [95% CI: -24.4 to -7.7] in the wet cupping group and -9.1 [-18.1 to -0.1] in the waiting-list group), but there was no statistical difference between the groups (p = 0.52). However, the PPI scores showed significant differences between the two groups (-1.2 [-1.6 to -0.8] for the wet-cupping group and -0.2 [-0.8 to 0.4] for the waiting-list group, p < 0.01). In addition, less acetaminophen was used in the wet-cupping group during 4 weeks (p = 0.09). The ODQ score did not show significant differences between the two groups (-5.60 [-8.90 to -2.30] in the wet-cupping group and -1.8 [-5.8 to 2.2] in the waiting-list group, p = 0.14). There was no report of adverse events due to wet-cupping. CONCLUSION: This pilot study may provide preliminary data on the effectiveness and safety of wet-cupping treatments for PNSLBP. Future full scale randomised controlled trials will be needed to provide firm evidence of the effectiveness of this intervention. PMID- 21663618 TI - Drug Checking: A prevention measure for a heterogeneous group with high consumption frequency and polydrug use - evaluation of zurich's drug checking services. AB - BACKGROUND: The increasing party culture in Zurich presents new challenges, especially regarding the consumption of alcohol and so-called party drugs. Streetwork, the youth advisory service of the city of Zurich, has provided onsite and stationary Drug Checking facilities since 2001 and 2006, respectively. Drug Checking always involves filling out an anonymous questionnaire, which allows the collection of important information about a largely unknown group of users and their consumption patterns. METHODS: The questionnaires assessed sociodemographic characteristics, consumption patterns, Drug Checking experiences, information behavior and social support. The collected data were statistically analyzed by the Research Institute for Public Health and Addiction (RIPHA). RESULTS: The majority of Drug Checking service patrons were male and between 20 and 35 years old. These patrons reported high lifetime prevalences and high consumption frequencies of legal and illegal substances, and they often reported polydrug use. Aside from tobacco and alcohol, the most consumed drugs during typical party nights were ecstasy, amphetamines, cannabis and cocaine. Party drug consumers using Drug Checking services form a heterogeneous group with respect to sociodemographic characteristics and consumption patterns. Users of the onsite Drug Checking facilities were significantly younger, were less experienced with drug testing, and reported more polydrug use than users of the stationary Drug Checking service. CONCLUSIONS: Drug Checking combined with a consultation appears to be an important harm reduction and prevention measure that reaches a group of consumers with high consumption frequency and polydrug use. Because of the heterogeneity of the target group, different prevention measures must be offered and embedded in an overall local concept. PMID- 21663619 TI - Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. AB - INTRODUCTION: Epithelial to mesenchymal transition (EMT) is considered an essential process in the metastatic cascade. EMT is characterised by upregulation of vimentin, Twist, Snail, Slug and Sip1 among others. Metastasis is also associated with the presence of circulating tumour cells (CTCs) and disseminated tumour cells in the blood and bone marrow, respectively, of breast cancer patients, but the expression of EMT markers in these cells has not been reported so far. METHODS: The expression of Twist and vimentin in CTCs of 25 metastatic and 25 early breast cancer patients was investigated by using double immunofluorescence experiments in isolated peripheral blood mononuclear cell cytospins using anti-cytokeratin (anti-CK) anti-mouse (A45-B/B3) and anti-Twist or anti-vimentin anti-rabbit antibodies. RESULTS: Among early breast cancer patients, vimentin-and Twist-expressing CK(+) CTCs were identified in 77% and 73% of the patients, respectively, and in 100% of the patients with metastatic breast cancer for both markers (P = 0.004 and P = 0.037, respectively). Among patients with early disease, 56% and 53% of the CK(+) CTCs were double-stained with vimentin and Twist, and the corresponding values for metastatic patients were 74% and 97%, respectively (P = 0.005 and P = 0.0001, respectively). The median expression of CK(+)vimentin(+) and CK(+)Twist(+) cells per patient in metastatic patients was 98% and 100%, and in an adjuvant chemotherapy setting the corresponding numbers were 56% and 40.6%, respectively. Triple-staining experiments revealed that all CK(+)Twist(+) or CK(+)vimentin(+) cells were also CD45(-), confirming their epithelial origin. Immunomagnetic separation of CTCs and triple-immunofluorescence with anti-CK/anti-Twist/anti-vimentin antibodies demonstrated that both mesenchymal markers could be coexpressed in the same CK(+) cell, since 64% of the total identified CTCs were triple-stained. There was a significant correlation (P = 0.005) between the number of CTCs expressing Twist and vimentin within the same setting. CONCLUSIONS: CTCs expressing Twist and vimentin, suggestive of EMT, are identified in patients with breast cancer. The high incidence of these cells in patients with metastatic disease compared to early stage breast cancer strongly supports the notion that EMT is involved in the metastatic potential of CTCs. PMID- 21663620 TI - Cost-effectiveness of rotavirus vaccination in the Netherlands; the results of a consensus model. AB - BACKGROUND: Each year rotavirus gastroenteritis results in thousands of paediatric hospitalisations and primary care visits in the Netherlands. While two vaccines against rotavirus are registered, routine immunisation of infants has not yet been implemented. Existing cost-effectiveness studies showed inconsistent results for these vaccines because of lack of consensus on the impact. We aimed to investigate which factors had a major impact on cost-effectiveness and were primarily responsible for the large differences in previously estimated cost effectiveness ratios. METHODS: Based on updated data on health outcomes and cost estimates, we re-assessed the cost-effectiveness of routine paediatric rotavirus vaccination within the National Immunization Program for the Netherlands. Two consensus meetings were organised with national and international experts in the field to achieve consensus and resolve potential controversies. RESULTS: It was estimated that rotavirus vaccination in the Netherlands could avert 34,214 cases of rotavirus gastroenteritis in children aged less than 5 years. Notably, 2,779 hospitalisations were averted of which 315 were extensions of existing hospital stays due to nosocomial rotavirus infection. With a threshold varying from 20K ? 50K ? per QALY and according to the base-case scenario, the full vaccination costs per child leading to cost-effectiveness was ? 57.76 -? 77.71. Results were sensitive to the inclusion of potential vaccine induced herd protection, QALY losses and number of deaths associated with rotavirus gastroenteritis. CONCLUSIONS: Our economic analysis indicates that inclusion of rotavirus vaccination in the Dutch National Immunization Program might be cost-effective depending on the cost of the vaccine and the impact of rotavirus gastroenteritis on children's quality of life. PMID- 21663621 TI - PIK3CA-mediated PI3-kinase signalling is essential for HPV-induced transformation in vitro. AB - BACKGROUND: High-risk human papillomavirus (hrHPV) infections are causally related to cervical cancer development. The additional (epi)genetic alterations driving malignant transformation of hrHPV-infected cells however, are not yet fully elucidated. In this study we experimentally assessed the role of the PI3 kinase pathway and its regulator PIK3CA, which is frequently altered in cervical cancer, in HPV-induced transformation. METHODS: Cervical carcinomas and ectocervical controls were assessed for PIK3CA mRNA and protein expression by quantitative RT-PCR and immunohistochemical staining, respectively. A longitudinal in vitro model system of hrHPV-transfected keratinocytes, representing the immortal and anchorage independent phenotype, was assayed for PI3-kinase activation and function using chemical pathway inhibition i.e. LY294002 treatment, and PIK3CA RNA interference. Phenotypes examined included cellular viability, migration, anchorage independent growth and differentiation. mRNA expression of hTERT and HPV16 E6E7 were studied using quantitative RT-PCR and Northern blotting. RESULTS: Cervical carcinomas showed significant overexpression of PIK3CA compared to controls. During HPV-induced transformation in vitro, expression of the catalytic subunit PIK3CA as well as activation of downstream effector PKB/AKT progressively increased in parallel. Inhibition of PI3-kinase signalling in HPV16-transfected keratinocytes by chemical interference or siRNA-mediated silencing of PIK3CA resulted in a decreased phosphorylation of PKB/AKT. Moreover, blockage of PI3-kinase resulted in reduced cellular viability, migration, and anchorage independent growth. These properties were accompanied with a downregulation of HPV16E7 and hTERT mRNA expression. In organotypic raft cultures of HPV16- and HPV18-immortalized cells, phosphorylated PKB/AKT was primarily seen in differentiated cells staining positive for cytokeratin 10 (CK10). Upon PI3-kinase signalling inhibition, there was a severe impairment in epithelial tissue development as well as a dramatic reduction in p-PKB/AKT and CK10. CONCLUSION: The present data indicate that activation of the PI3 kinase/PKB/AKT pathway through PIK3CA regulates various transformed phenotypes as well as growth and differentiation of HPV-immortalized cells and may therefore play a pivotal role in HPV-induced carcinogenesis. PMID- 21663623 TI - A rapid assessment and response approach to review and enhance advocacy, communication and social mobilisation for tuberculosis control in Odisha state, India. AB - BACKGROUND: Tuberculosis remains a major public health problem in India with the country accounting for 1 in 5 of all TB cases reported globally. An advocacy, communication and social mobilisation project for Tuberculosis control was implemented and evaluated in Odisha state of India. The purpose of the study was to identify the impact of project interventions including the use of 'Interface NGOs' and involvement of community groups such as women's self-help groups, local government bodies, village health sanitation committees, and general health staff in promoting TB control efforts. METHODS: The study utilized a rapid assessment and response (RAR) methodology. The approach combined both qualitative field work approaches, including semi-structured interviews and focus group discussions with empirical data collection and desk research. RESULTS: Results revealed that a combination of factors including the involvement of Interface NGOs, coupled with increased training and engagement of front line health workers and community groups, and dissemination of community based resources, contributed to improved awareness and knowledge about TB in the targeted districts. Project activities also contributed towards improving health worker and community effectiveness to raise the TB agenda, and improved TB literacy and treatment adherence. Engagement of successfully treated patients also assisted in reducing community stigma and discrimination. CONCLUSION: The expanded use of advocacy, communication and social mobilisation activities in TB control has resulted in a number of benefits. These include bridging pre-existing gaps between the health system and the community through support and coordination of general health services stakeholders, NGOs and the community. The strategic use of 'tailored messages' to address specific TB problems in low performing areas also led to more positive behavioural outcomes and improved efficiencies in service delivery. Implications for future studies are that a comprehensive and well planned range of ACSM activities can enhance TB knowledge, attitudes and behaviours while also mobilising specific community groups to build community efficacy to combat TB. The use of rapid assessments combined with other complementary evaluation approaches can be effective when reviewing the impact of TB advocacy, communication and social mobilisation activities. PMID- 21663622 TI - SCAMP: standardised, concentrated, additional macronutrients, parenteral nutrition in very preterm infants: a phase IV randomised, controlled exploratory study of macronutrient intake, growth and other aspects of neonatal care. AB - BACKGROUND: Infants born <29 weeks gestation are at high risk of neurocognitive disability. Early postnatal growth failure, particularly head growth, is an important and potentially reversible risk factor for impaired neurodevelopmental outcome. Inadequate nutrition is a major factor in this postnatal growth failure, optimal protein and calorie (macronutrient) intakes are rarely achieved, especially in the first week. Infants <29 weeks are dependent on parenteral nutrition for the bulk of their nutrient needs for the first 2-3 weeks of life to allow gut adaptation to milk digestion. The prescription, formulation and administration of neonatal parenteral nutrition is critical to achieving optimal protein and calorie intake but has received little scientific evaluation. Current neonatal parenteral nutrition regimens often rely on individualised prescription to manage the labile, unpredictable biochemical and metabolic control characteristic of the early neonatal period. Individualised prescription frequently fails to translate into optimal macronutrient delivery. We have previously shown that a standardised, concentrated neonatal parenteral nutrition regimen can optimise macronutrient intake. METHODS: We propose a single centre, randomised controlled exploratory trial of two standardised, concentrated neonatal parenteral nutrition regimens comparing a standard macronutrient content (maximum protein 2.8 g/kg/day; lipid 2.8 g/kg/day, dextrose 10%) with a higher macronutrient content (maximum protein 3.8 g/kg/day; lipid 3.8 g/kg/day, dextrose 12%) over the first 28 days of life. 150 infants 24-28 completed weeks gestation and birthweight <1200 g will be recruited. The primary outcome will be head growth velocity in the first 28 days of life. Secondary outcomes will include a) auxological data between birth and 36 weeks corrected gestational age b) actual macronutrient intake in first 28 days c) biomarkers of biochemical and metabolic tolerance d) infection biomarkers and other intravascular line complications e) incidence of major complications of prematurity including mortality f) neurodevelopmental outcome at 2 years corrected gestational age. TRIAL REGISTRATION: Current controlled trials: ISRCTN76597892; EudraCT Number: 2008 008899-14. PMID- 21663624 TI - Quality of life associated to chronic pelvic pain is independent of endometriosis diagnosis--a cross-sectional survey. AB - BACKGROUND: Pain is strongly related to poor quality of life. We performed a cross-sectional study in a university hospital to investigate quality of life in women suffering from chronic pelvic pain (CPP) due to endometriosis and others conditions. METHODS: Fifty-seven patients aged between 25 and 48 years-old submitted to laparoscopy because of CPP were evaluated for quality of life and depressive symptoms. Quality of life was accessed by a quality of life instrument [World Health Organization Quality of Life Assessment-Bref (WHOQOL-bref)]. Causes of pelvic pain were determined and severity of CPP was measured with a visual analogue scale. According to the intensity of pelvic pain score, patients were classified in two groups (group Low CPP < 25th percentile visual analogue scale and group High CPP > 25th percentile). Four dimensions on quality of life were measured (physical, psychological, social and environmental). We stratified the analysis of quality of life according CPP causes (presence or not of endometriosis in laparoscopy). RESULTS: Patients with higher pain scores presented lower quality of life status in psychological and environmental dimensions. We found a negative correlation between pain scores and psychological dimension of quality of life (r = -0.310, P = .02). Quality of life scores were similar between groups with and without endometriosis (physical 54.2 +/- 12.8 and 51.1 +/- 13.8, P = 0.504; psychological 56.2 +/- 14.4 and 62.8 +/- 12.4, P = 0.182; social 55.6 +/- 18.2 and 62.1 +/- 19.1, P = 0.325; environmental 59.2 +/- 11.7 61.2 +/- 10.8, P = 0.608; respectively) CONCLUSIONS: Higher pain scores are correlated to lower quality of life; however the fact of having endometriosis in addition to CPP does not have an additional impact upon the quality of life. PMID- 21663625 TI - A case of bowel entrapment after penetrating injury of the pelvis: don't forget the omentumplasty. AB - Bowel entrapment within a pelvic injury is rare and difficult to diagnose. Usually, it is diagnosed late because of concomitant abdominal injuries. It may present itself as an acute intestinal obstruction or, more commonly, as a prolonged or intermittent ileus. Therefore, one should be aware of this late complication and primarily take measures for avoiding bowel entrapment. This report describes an unusual case of bowel entrapment within a pelvic fracture after a penetrating injury, and discusses options for preventing such a complication. PMID- 21663626 TI - Schwann cell hamartoma: case report. AB - BACKGROUND: Colorectal polyps of mesenchymal origin represent a small percentage of gastrointestinal (GI) lesions. Nevertheless, they are encountered with increasing frequency since the widespread adoption of colonoscopy screening. CASE PRESENTATION: We report a case of a small colonic polyp that presented as intramucosal diffuse spindle cell proliferation with a benign cytological appearance, strong and diffuse immunoreactivity for S-100 protein, and pure Schwann cell phenotype. Careful morphological, immunohistochemical and clinical evaluation emphasize the differences from other stromal colonic lesions and distinguish it from schwannoma, a circumscribed benign nerve sheath tumor that rarely arises in the GI tract. CONCLUSION: As recently proposed, this lesion was finally described as mucosal Schwann cell hamartoma. PMID- 21663627 TI - High-sensitivity versus conventional troponin in the emergency department for the diagnosis of acute myocardial infarction. AB - INTRODUCTION: Recently, newer assays for cardiac troponin (cTn) have been developed which are able to detect changes in concentration of the biomarker at or below the 99th percentile for a normal population. The objective of this study was to compare the diagnostic performance of a new high-sensitivity troponin T (HsTnT) assay to that of conventional cTnI for the diagnosis of acute myocardial infarction (AMI) according to pretest probability (PTP). METHODS: In consecutive patients who presented to our emergency departments with chest pain suggestive of AMI, levels of HsTnT were measured at presentation, blinded to the emergency physicians, who were asked to estimate the empirical PTP of AMI. The discharge diagnosis was adjudicated by two independent experts on the basis of all available data. RESULTS: A total of 317 patients were included, comprising 149 (47%) who were considered to have low PTP, 109 (34%) who were considered to have moderate PTP and 59 (19%) who were considered to have high PTP. AMI was confirmed in 45 patients (14%), 22 (9%) of whom were considered to have low to moderate PTP and 23 (39%) of whom were considered to have high PTP (P < 0.001). In the low to moderate PTP group, HsTnT levels >= 0.014 MUg/L identified AMI with a higher sensitivity than cTnI (91%, 95% confidence interval (95% CI) 79 to 100, vs. 77% (95% CI 60 to 95); P = 0.001), but the negative predictive value was not different (99% (95% CI 98 to 100) vs. 98% (95% CI 96 to 100)). There was no difference in area under the receiver operating characteristic (ROC) curve between HsTnT and cTnI (0.93 (95% CI 0.90 to 0.98) vs. 0.94 (95% CI 0.88 to 0.97), respectively). CONCLUSIONS: In patients with low to moderate PTP of AMI, HsTnT is slightly more useful than cTnI. Our results confirm that the use of HsTnT has a higher sensitivity than conventional cTnI. PMID- 21663628 TI - Identification of SNP and SSR markers in eggplant using RAD tag sequencing. AB - BACKGROUND: The eggplant (Solanum melongena L.) genome is relatively unexplored, especially compared to those of the other major Solanaceae crops tomato and potato. In particular, no SNP markers are publicly available; on the other hand, over 1,000 SSR markers were developed and publicly available. We have combined the recently developed Restriction-site Associated DNA (RAD) approach with Illumina DNA sequencing for rapid and mass discovery of both SNP and SSR markers for eggplant. RESULTS: RAD tags were generated from the genomic DNA of a pair of eggplant mapping parents, and sequenced to produce ~17.5 Mb of sequences arrangeable into ~78,000 contigs. The resulting non-redundant genomic sequence dataset consisted of ~45,000 sequences, of which ~29% were putative coding sequences and ~70% were in common between the mapping parents. The shared sequences allowed the discovery of ~10,000 SNPs and nearly 1,000 indels, equivalent to a SNP frequency of 0.8 per Kb and an indel frequency of 0.07 per Kb. Over 2,000 of the SNPs are likely to be mappable via the Illumina GoldenGate assay. A subset of 384 SNPs was used to successfully fingerprint a panel of eggplant germplasm, producing a set of informative diversity data. The RAD sequences also included nearly 2,000 putative SSRs, and primer pairs were designed to amplify 1,155 loci. CONCLUSION: The high throughput sequencing of the RAD tags allowed the discovery of a large number of DNA markers, which will prove useful for extending our current knowledge of the genome organization of eggplant, for assisting in marker-aided selection and for carrying out comparative genomic analyses within the Solanaceae family. PMID- 21663629 TI - HCV genotype-specific correlation with serum markers: higher predictability for genotype 4a. AB - BACKGROUND: Several factors have been proposed to assess the clinical outcome of HCV infection. The correlation of HCV genotypes to possible serum markers in clinical prediction is still controversial. The main objective of this study was to determine the existence of any correlation between HCV genotypes to viral load and different clinical serum markers. METHODS: We performed a prospective cross sectional and observational study. About 3160 serum HCV RNA positive patients were chosen from 4020 randomly selected anti-HCV positive patients. Statistical analysis was performed using the SPSS 16 software package. ROC (receiver operating characteristics) curves were used to compare diagnostic values of serum markers to predict genotypes. RESULTS: The most prevalent genotype was 3a (73.9%) followed by 1a (10.7%), 4a (6.4%) and 3b (6.1%) in Pakistani population. No correlation was found between viral load and serum markers for genotype 3a in a large no. of sample (n = 2336). While significant correlation was observed between viral load and AST in genotype 3b, ALP with viral load and ALT for genotype 1a. Patients with genotype 4a showed a significant inverse correlation with viral load and Hb level and AST with ALP. For genotype 4a, AUC (area under the curve) of ALT, ALP, AST, bilirubin, Hb level and viral load was 0.790, 0.763, 0.454, 0.664, 0.458 and 0.872 respectively. CONCLUSIONS: In conclusion, there was a significant variable response of HCV genotypes with serum markers. Severity of disease is independent of serum marker level in genotype 3a, while the liver damage in genotype 4a may associate with viral cytopathic effect as well as the immune-mediated process. An index using six serum markers may correctly predict genotype 4a in patients with >= 75% accuracy. PMID- 21663631 TI - The opinion of clinical staff regarding painfulness of procedures in pediatric hematology-oncology: an Italian survey. AB - BACKGROUND: Beliefs of caregivers about patient's pain have been shown to influence assessment and treatment of children's pain, now considered an essential part of cancer treatment. Painful procedures in hematology-oncology are frequently referred by children as the most painful experiences during illness. Aim of this study was to evaluate professionals' beliefs about painfulness of invasive procedures repeatedly performed in Pediatric Hemato-Oncology Units. METHODS: Physicians, nurses, psychologists and directors working in Hemato Oncology Units of the Italian Association of Pediatric Hematology-Oncology (AIEOP) were involved in a wide-nation survey. The survey was based on an anonymous questionnaire investigating beliefs of operators about painfulness of invasive procedures (lumbar puncture, bone marrow aspirate and bone marrow biopsy) and level of pain management. RESULTS: Twenty-four directors, 120 physicians, 248 nurses and 22 psychologists responded to the questionnaire. The score assigned to the procedural pain on a 0-10 scale was higher than 5 in 77% of the operators for lumbar puncture, 97.5% for bone marrow aspiration, and 99.5% for bone marrow biopsy. The scores assigned by nurses differed statistically from those of the physicians and directors for the pain caused by lumbar puncture and bone marrow aspiration. Measures adopted for procedural pain control were generally considered good. CONCLUSIONS: Invasive diagnostic-therapeutic procedures performed in Italian Pediatric Hemato-Oncology Units are considered painful by all the caregivers involved. Pain management is generally considered good. Aprioristically opinions about pain depend on invasiveness of the procedure and on the professional role. PMID- 21663632 TI - High prevalence of HIV-1 drug resistance among patients on first-line antiretroviral treatment in Lome, Togo. AB - BACKGROUND: With widespread use of antiretroviral (ARV) drugs in Africa, one of the major potential challenges is the risk of emergence of ARV drug-resistant HIV strains. Our objective is to evaluate the virological failure and genotypic drug resistance mutations in patients receiving first-line highly active antiretroviral therapy (HAART) in routine clinics that use the World Health Organization public health approach to monitor antiretroviral treatment (ART) in Togo. METHODS: Patients on HAART for one year (10-14 months) were enrolled between April and October 2008 at three sites in Lome, the capital city of Togo. Plasma viral load was measured with the NucliSENS EasyQ HIV-1 assay (Biomerieux, Lyon, France) and/or a Generic viral load assay (Biocentric, Bandol, France). Genotypic drug-resistance testing was performed with an inhouse assay on plasma samples from patients with viral loads of more than 1000 copies/ml. CD4 cell counts and demographic data were also obtained from medical records. RESULTS: A total of 188 patients receiving first-line antiretroviral treatment were enrolled, and 58 (30.8%) of them experienced virologic failure. Drug-resistance mutations were present in 46 patients, corresponding to 24.5% of all patients enrolled in the study. All 46 patients were resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs): of these, 12 were resistant only to NNRTIs, 25 to NNRTIs and lamivudine/emtricitabine, and eight to all three drugs of their ARV regimes. Importantly, eight patients were already predicted to be resistant to etravirine, the new NNRTI, and three patients harboured the K65R mutation, inducing major resistance to tenofovir. CONCLUSIONS: In Togo, efforts to provide access to ARV therapy for infected persons have increased since 2003, and scaling up of ART started in 2007. The high number of resistant strains observed in Togo shows clearly that the emergence of HIV drug resistance is of increasing concern in countries where ART is now widely used, and can compromise the long-term success of first- and second-line ART. PMID- 21663630 TI - A conserved juxtacrine signal regulates synaptic partner recognition in Caenorhabditis elegans. AB - BACKGROUND: An essential stage of neural development involves the assembly of neural circuits via formation of inter-neuronal connections. Early steps in neural circuit formation, including cell migration, axon guidance, and the localization of synaptic components, are well described. However, upon reaching their target region, most neurites still contact many potential partners. In order to assemble functional circuits, it is critical that within this group of cells, neurons identify and form connections only with their appropriate partners, a process we call synaptic partner recognition (SPR). To understand how SPR is mediated, we previously developed a genetically encoded fluorescent trans synaptic marker called NLG-1 GRASP, which labels synaptic contacts between individual neurons of interest in dense cellular environments in the genetic model organism Caenorhabditis elegans. RESULTS: Here, we describe the first use of NLG-1 GRASP technology, to identify SPR genes that function in this critical process. The NLG-1 GRASP system allows us to assess synaptogenesis between PHB sensory neurons and AVA interneurons instantly in live animals, making genetic analysis feasible. Additionally, we employ a behavioral assay to specifically test PHB sensory circuit function. Utilizing this approach, we reveal a new role for the secreted UNC-6/Netrin ligand and its transmembrane receptor UNC 40/Deleted in colorectal cancer (DCC) in SPR. Synapses between PHB and AVA are severely reduced in unc-6 and unc-40 animals despite normal axon guidance and subcellular localization of synaptic components. Additionally, behavioral defects indicate a complete disruption of PHB circuit function in unc-40 mutants. Our data indicate that UNC-40 and UNC-6 function in PHB and AVA, respectively, to specify SPR. Strikingly, overexpression of UNC-6 in postsynaptic neurons is sufficient to promote increased PHB-AVA synaptogenesis and to potentiate the behavioral response beyond wild-type levels. Furthermore, an artificially membrane-tethered UNC-6 expressed in the postsynaptic neurons promotes SPR, consistent with a short-range signal between adjacent synaptic partners. CONCLUSIONS: These results indicate that the conserved UNC-6/Netrin-UNC-40/DCC ligand-receptor pair has a previously unknown function, acting in a juxtacrine manner to specify recognition of individual postsynaptic neurons. Furthermore, they illustrate the potential of this new approach, combining NLG-1 GRASP and behavioral analysis, in gene discovery and characterization. PMID- 21663633 TI - Novel rapid infusion device for patients in emergency situations. AB - Rapid fluid administration is often required for resuscitation when patients are admitted in emergency department with hypovolemic shock or excessive blood loss. Various methods have been described earlier to increase the fluid administration speed. Larger vein size, larger bore cannula, height of fluid, pressure over fluid bottle etc. are some of methods described in such situations.We here describe a novel method to administer intravenous fluid rapidly and this method can be utilized in emergency and trauma settings. PMID- 21663634 TI - Long-term outcome and patterns of failure in patients with advanced head and neck cancer. AB - PURPOSE: To access the long-time outcome and patterns of failure in patients with advanced head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Between 1992 and 2005 127 patients (median age 55 years, UICC stage III n=6, stage IV n=121) with primarily inoperable, advanced HNSCC were treated with definite platinum-based radiochemotherapy (median dose 66.4 Gy). Analysed end points were overall survival (OS), disease-free survival (DFS), loco-regional progression-free survival (LPFS), development of distant metastases (DM), prognostic factors and causes of death. RESULTS: The mean follow-up time was 34 months (range, 3-156 months), the 3-, 5- and 10-year OS rates were 39%, 28% and 14%, respectively. The median OS was 23 months. Forty-seven patients achieved a complete remission and 78 patients a partial remission. The median LPFS was 17 months, the 3-, 5- and 10-year LPFS rates were 41%, 33% and 30%, respectively. The LPFS was dependent on the nodal stage (p=0.029). The median DFS was 11 months (range, 2-156 months), the 3-, 5- and 10-year DFS rates were 30%, 24% and 22%, respectively. Prognostic factors in univariate analyses were alcohol abuse (n=102, p=0.015), complete remission (n=47, p<0.001), local recurrence (n=71, p<0.001), development of DM (n=45, p<0.001; median OS 16 months) and borderline significance in nodal stage N2 versus N3 (p=0.06). Median OS was 26 months with lung metastases (n=17). Nodal stage was a predictive factor for the development of DM (p=0.025). Cause of death was most commonly tumor progression. CONCLUSIONS: In stage IV HNSCC long-term survival is rare and DM is a significant predictor for mortality. If patients developed DM, lung metastases had the most favourable prognosis, so intensified palliative treatment might be justified in DM limited to the lungs. PMID- 21663635 TI - Disruption of the NF-kappaB/IkappaBalpha Autoinhibitory Loop Improves Cognitive Performance and Promotes Hyperexcitability of Hippocampal Neurons. AB - BACKGROUND: Though originally discovered in the immune system as an important mediator of inflammation, NF-kappaB has recently been shown to play key roles in the central nervous system, such as synaptogenesis, synaptic plasticity, and cognition. NF-kappaB activity is normally tightly regulated by its primary inhibitor, IkappaBalpha, through a unique autoinhibitory loop. In this study, we tested the hypothesis that the IkappaBalpha autoinhibitory loop ensures optimal levels of NF-kappaB activity to promote proper brain development and function. To do so, we utilized knock-in mice which possess mutations in the IkappaBalpha promoter to disrupt the autoinhibitory loop (IkappaBalphaM/M KI mice). RESULTS: Here, we show that these mutations delay IkappaBalpha resynthesis and enhance NF kappaB activation in neurons following acute activating stimuli. This leads to improved cognitive ability on tests of hippocampal-dependent learning and memory but no change in hippocampal synaptic plasticity. Instead, hippocampal neurons from IkappaBalphaM/M KI mice form more excitatory and less inhibitory synapses in dissociated cultures and are hyperexcitable. This leads to increased burst firing of action potentials and the development of abnormal hypersynchronous discharges in vivo. CONCLUSIONS: These results demonstrate that the IkappaBalpha autoinhibitory loop is critical for titrating appropriate levels of endogenous NF kappaB activity to maintain proper neuronal function. PMID- 21663636 TI - Mass casualty modelling: a spatial tool to support triage decision making. AB - BACKGROUND: During a mass casualty incident, evacuation of patients to the appropriate health care facility is critical to survival. Despite this, no existing system provides the evidence required to make informed evacuation decisions from the scene of the incident. To mitigate this absence and enable more informed decision making, a web based spatial decision support system (SDSS) was developed. This system supports decision making by providing data regarding hospital proximity, capacity, and treatment specializations to decision makers at the scene of the incident. METHODS: This web-based SDSS utilizes pre-calculated driving times to estimate the actual driving time to each hospital within the inclusive trauma system of the large metropolitan region within which it is situated. In calculating and displaying its results, the model incorporates both road network and hospital data (e.g. capacity, treatment specialties, etc.), and produces results in a matter of seconds, as is required in a MCI situation. In addition, its application interface allows the user to map the incident location and assists in the execution of triage decisions. RESULTS: Upon running the model, driving time from the MCI location to the surrounding hospitals is quickly displayed alongside information regarding hospital capacity and capability, thereby assisting the user in the decision-making process. CONCLUSIONS: The use of SDSS in the prioritization of MCI evacuation decision making is potentially valuable in cases of mass casualty. The key to this model is the utilization of pre-calculated driving times from each hospital in the region to each point on the road network. The incorporation of real-time traffic and hospital capacity data would further improve this model. PMID- 21663637 TI - Association between fasting plasma glucose and high-sensitivity C-reactive protein: gender differences in a Japanese community-dwelling population. AB - BACKGROUND: High sensitivity C-reactive protein (hsCRP) is an acute phase reactant and a sensitive marker of inflammation. Hyperglycemia can potentially promote the production of CRP. The aim of this study was to determine whether increased fasting plasma glucose (FPG) levels are associated with elevated hsCRP concentrations by gender. METHODS: We recruited 822 men (mean age, 61 +/- 14 years) and 1,097 women (63 +/- 12 years) during their annual health examination from a single community. We cross-sectionally examined whether FPG levels are associated with hsCRP concentrations, and whether this association is independent of gender, body mass index (BMI) and other components of the metabolic syndrome. RESULTS: In women only, hsCRP increased significantly and progressively with increasing FPG (r = 0.169, P < 0.001). The stepwise multiple linear regression analysis using hsCRP as an objective variable, adjusted for confounding factors as explanatory variables, showed that FPG as well as age, BMI, systolic blood pressure, high-density lipoprotein cholesterol (HDL-C), uric acid, and high molecular weight adiponectin were significantly associated with hsCRP in women, but not in men. There was significant gender interaction, and an increase in hsCRP levels that was greater in women with BMI >= 25 kg/m2 and higher FPG than in men. CONCLUSIONS: These results suggested that hsCRP levels increase continuously across the FPG spectrum starting from the lowest FPG in both men and women. However, increase in hsCRP levels was greater in women than men. PMID- 21663638 TI - Curcumin ameliorates macrophage infiltration by inhibiting NF-kappaB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy. AB - BACKGROUND: Chronic inflammation plays an important role in the progression of diabetic nephropathy (DN) and that the infiltration of macrophages in glomerulus has been implicated in the development of glomerular injury. We hypothesized that the plant polyphenolic compound curcumin, which is known to exert potent anti inflammatory effect, would ameliorate macrophage infiltration in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetes was induced with STZ (55 mg/kg) by intraperitoneal injection in rats. Three weeks after STZ injection, rats were divided into three groups, namely, control, diabetic, and diabetic treated with curcumin at 100 mg/kg/day, p.o., for 8 weeks. The rats were sacrificed 11 weeks after induction of diabetes. The excised kidney was used to assess macrophage infiltration and expression of various inflammatory markers. RESULTS: At 11 weeks after STZ injection, diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, blood urea nitrogen and proteinuria, along with marked reduction in the body weight. All of these abnormalities were significantly reversed by curcumin. Hyperglycemia induced the degradation of IkappaBalpha and NF-kappaB activation and as a result increased infiltration of macrophages (52%) as well as increased proinflammatory cytokines: TNF-alpha and IL-1beta. Curcumin treatment significantly reduced macrophage infiltration in the kidneys of diabetic rats, suppressed the expression of above proinflammatory cytokines and degradation of IkappaBalpha. In addition, curcumin treatment also markedly decreased ICAM-1, MCP-1 and TGF-beta1 protein expression. Moreover, at nuclear level curcumin inhibited the NF-kappaB activity. CONCLUSION: Our results suggested that curcumin treatment protect against the development of DN in rats by reducing macrophage infiltration through the inhibition of NF kappaB activation in STZ-induced diabetic rats. PMID- 21663639 TI - Multifocal gastric gastrointestinal stromal tumors (GISTs) with lymph node metastases in children and young adults: a comparative clinical and histomorphological study of three cases including a new case of Carney triad. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract usually occurring in the 6th to 7th decade of life, while their occurrence in children is rare (1-2%). Carney triad (CT), a non-hereditary association of gastric GIST with pulmonary chondroma and/or extraadrenal paraganglioma, is an even much rarer disease (to date ~120 cases reported worldwide) usually affecting young adult females. Pediatric GISTs differ from CT-associated GISTs solely by the absence of other components of the triad and are completely different from sporadic GISTs of the adult. Both, pediatric and CT-GISTs, metastasize frequently to regional lymph nodes (29%) and are usually wild type (WT) for common KIT-/PDGFRA mutations. CASE PRESENTATION AND RESULTS: We compare one new CT GIST with two pediatric/young adult multifocal gastric GISTs presenting with lymph node metastases. We put special focus on histomorphological growth pattern in the primary tumors and in the metastases. The two cases of pediatric/young adult GIST without the other components of CT showed all the features of the triad: female gender, young age, multifocal antral based gastric GIST with biphasic histological growth pattern, lymph node metastases, hypercellularity and WT status for common KIT-, PDGFRA- and B-RAF mutations. DISCUSSION AND CONCLUSION: Pediatric/CT-associated GISTs and sporadic GISTs of the adults differ significantly from each other with regard to patients' age, gender, tumor localisation, histomorphological growth pattern, mutational status and risk for metastasis. Our cases of pediatric/young adult GISTs show all characteristics of CT except for the absence of other components of the triad. Therefore these GISTs are probably not sporadic, but may represent either early manifestation or forme fruste of the CT. Thus, these patients need to be regularly examined for the development of extraadrenal paraganglioma or pulmonary chondroma. PMID- 21663640 TI - A novel fusogenic herpes simplex virus for oncolytic virotherapy of squamous cell carcinoma. AB - BACKGROUND: R849 is a neurovirulent gamma134.5 gene-deficient form of herpes simplex virus type 1 (HSV-1) and has LacZ genes at the deleted sites of the gamma134.5 gene. HF is a spontaneously occurring, fusogenic HSV-1 strain. The purpose of this work was to generate a virus that has the syncytial character of HF, while preserving the gamma134.5 gene inactivation profile of R849 virus. RESULTS: Vero cells were infected with R849 and HF simultaneously and two viruses, RH1 and RH2, expressing the LacZ gene and inducing extensive cell fusion were selected. A polymerase chain reaction (PCR)-based analysis suggested that one copy of the gamma134.5 gene is lost in RH1, whereas both copies are lost in RH2, and that the gamma134.5 gene is replaced by a R849-derived DNA fragment with the LacZ gene. These viruses produced larger plaques and more progeny than the parental viruses. Infection with RH2 decreased the viability of oral squamous cell carcinoma (SCC) cells most strongly. When RH2 was injected into xenografts of oral SCC in nude mice, multinucleated cells were produced and the growth of the tumors was suppressed significantly. CONCLUSION: These results indicate that novel oncolytic HSV-1 vectors can be produced with the genetic background of the oncolytic HSV-1 HF, and that RH2 is deficient in gamma134.5 genes and shows extensive cytopathic effects in oral SCC cells. RH2 may be useful in oncolytic virotherapy for oral SCC. PMID- 21663641 TI - Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review. AB - BACKGROUND: Linoleic acid, with a DRI of 12-17 g/d, is the most highly consumed polyunsaturated fatty acid in the Western diet and is found in virtually all commonly consumed foods. The concern with dietary linoleic acid, being the metabolic precursor of arachidonic acid, is its consumption may enrich tissues with arachidonic acid and contribute to chronic and overproduction of bioactive eicosanoids. However, no systematic review of human trials regarding linoleic acid consumption and subsequent changes in tissue levels of arachidonic acid has been undertaken. OBJECTIVE: In this study, we reviewed the human literature that reported changes in dietary linoleic acid and its subsequent impact on changing tissue arachidonic acid in erythrocytes and plasma/serum phospholipids. DESIGN: We identified, reviewed, and evaluated all peer-reviewed published literature presenting data outlining changes in dietary linoleic acid in adult human clinical trials that reported changes in phospholipid fatty acid composition (specifically arachidonic acid) in plasma/serum and erythrocytes within the parameters of our inclusion/exclusion criteria. RESULTS: Decreasing dietary linoleic acid by up to 90% was not significantly correlated with changes in arachidonic acid levels in the phospholipid pool of plasma/serum (p = 0.39). Similarly, when dietary linoleic acid levels were increased up to six fold, no significant correlations with arachidonic acid levels were observed (p = 0.72). However, there was a positive relationship between dietary gamma-linolenic acid and dietary arachidonic acid on changes in arachidonic levels in plasma/serum phospholipids. CONCLUSIONS: Our results do not support the concept that modifying current intakes of dietary linoleic acid has an effect on changing levels of arachidonic acid in plasma/serum or erythrocytes in adults consuming Western-type diets. PMID- 21663642 TI - Anaphylaxis related to avocado ingestion: a case and review. AB - Anaphylaxis to avocado, independent of latex sensitization, has been rarely reported in the literature. This case report describes a 15 year old male who experienced anaphylaxis within half an hour after eating avocado-containing food. Avocado consumption is common in both North America and South America. It is important to consider avocado as a cause of anaphylaxis, even in patients not sensitized to latex. PMID- 21663643 TI - Delayed cell death associated with mitotic catastrophe in gamma-irradiated stem like glioma cells. AB - BACKGROUND AND PURPOSE: Stem-like tumor cells are regarded as highly resistant to ionizing radiation (IR). Previous studies have focused on apoptosis early after irradiation, and the apoptosis resistance observed has been attributed to reduced DNA damage or enhanced DNA repair compared to non-stem tumor cells. Here, early and late radioresponse of patient-derived stem-like glioma cells (SLGCs) and differentiated cells directly derived from them were examined for cell death mode and the influence of stem cell-specific growth factors. MATERIALS AND METHODS: Primary SLGCs were propagated in serum-free medium with the stem-cell mitogens epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). Differentiation was induced by serum-containing medium without EGF and FGF. Radiation sensitivity was evaluated by assessing proliferation, clonogenic survival, apoptosis, and mitotic catastrophe. DNA damage-associated gammaH2AX as well as p53 and p21 expression were determined by Western blots. RESULTS: SLGCs failed to apoptose in the first 4 days after irradiation even at high single doses up to 10 Gy, but we observed substantial cell death later than 4 days postirradiation in 3 of 6 SLGC lines treated with 5 or 10 Gy. This delayed cell death was observed in 3 of the 4 SLGC lines with nonfunctional p53, was associated with mitotic catastrophe and occurred via apoptosis. The early apoptosis resistance of the SLGCs was associated with lower gammaH2AX compared to differentiated cells, but we found that the stem-cell culture cytokines EGF plus FGF-2 strongly reduce gammaH2AX levels. Nonetheless, in two p53-deficient SLGC lines examined gammaIR-induced apoptosis even correlated with EGF/FGF-induced proliferation and mitotic catastrophe. In a line containing CD133-positive and negative stem-like cells, the CD133-positive cells proliferated faster and underwent more gammaIR-induced mitotic catastrophe. CONCLUSIONS: Our results suggest the importance of delayed apoptosis, associated mitotic catastrophe, and cellular proliferation for gammaIR-induced death of p53-deficient SLGCs. This may have therapeutic implications. We further show that the stem-cell culture cytokines EGF plus FGF-2 activate DNA repair and thus confound in vitro comparisons of DNA damage repair between stem-like and more differentiated tumor cells. PMID- 21663644 TI - Buffy coat specimens remain viable as a DNA source for highly multiplexed genome wide genetic tests after long term storage. AB - BACKGROUND: Blood specimen collection at an early study visit is often included in observational studies or clinical trials for analysis of secondary outcome biomarkers. A common protocol is to store buffy coat specimens for future DNA isolation and these may remain in frozen storage for many years. It is uncertain if the DNA remains suitable for modern genome wide association (GWA) genotyping. METHODS: We isolated DNA from 120 Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial buffy coats sampling a range of storage times up to 9 years and other factors that could influence DNA yield. We performed TaqMan SNP and GWA genotyping to test whether the DNA retained integrity for high quality genetic analysis. RESULTS: We tested two QIAGEN automated protocols for DNA isolation, preferring the Compromised Blood Protocol despite similar yields. We isolated DNA from all 120 specimens (yield range 1.1-312 ug per 8.5 ml ACD tube of whole blood) with only 3/120 samples yielding < 10 ug DNA. Age of participant at blood draw was negatively associated with yield (mean change -2.1 ug/year). DNA quality was very good based on gel electrophoresis QC, TaqMan genotyping of 6 SNPs (genotyping no-call rate 1.1% in 702 genotypes), and excellent quality GWA genotyping data (maximum per sample genotype missing rate 0.64%). CONCLUSIONS: When collected as a long term clinical trial or biobank specimen for DNA, buffy coats can be stored for up to 9 years in a -80 degrees C frozen state and still produce high yields of DNA suitable for GWA analysis and other genetic testing. PMID- 21663645 TI - CD39+ regulatory T cells suppress generation and differentiation of Th17 cells in human malignant pleural effusion via a LAP-dependent mechanism. AB - BACKGROUND: Both regulatory T cells (Tregs) and T helper IL-17-producing cells (Th17 cells) have been found to be involved in human malignancies, however, the possible implication of Tregs in regulating generation and differentiation of Th17 cells in malignant pleural effusion remains to be elucidated. METHODS: The numbers of both CD39(+)Tregs and Th17 cells in malignant pleural effusion and peripheral blood from patients with lung cancer were determined by flow cytometry. The regulation and mechanism of Tregs on generation and differentiation of Th17 cells were explored. RESULTS: Both CD39(+)Tregs and Th17 cells were increased in malignant pleural effusion when compared with blood, and the numbers of CD39(+)Tregs were correlated negatively with those of Th17 cells. It was also noted that high levels of IL-1beta, IL-6, and TGF-beta1 could be observed in malignant pleural effusion when compared the corresponding serum, and that pleural CD39(+)Tregs could express latency-associated peptide on their surface. When naive CD4(+) T cells were cocultured with CD39(+)Tregs, Th17 cell numbers decreased as CD39(+)Treg numbers increased, addition of the anti-latency associated peptide mAb to the coculture reverted the inhibitory effect exerted by CD39(+)Tregs. CONCLUSIONS: Therefore, the above results indicate that CD39(+)Tregs inhibit generation and differentiation of Th17 cells via a latency associated peptide-dependent mechanism. PMID- 21663646 TI - Evaluation of endoscopic vein extraction on structural and functional viability of saphenous vein endothelium. AB - OBJECTIVES: Endothelial injury during harvest influences graft patency post CABG. We have previously shown that endoscopic harvest causes structural and functional damage to the saphenous vein (SV) endothelium. However, causes of such injury may depend on the extraction technique. In order to assess this supposition, we evaluated the effect of VirtuoSaph endoscopic SV harvesting technique (VsEVH) on structural and functional viability of SV endothelium using multiphoton imaging, biochemical and immunofluorescence assays. METHODS: Nineteen patients scheduled for CABG were prospectively identified. Each underwent VsEVH for one portion and "No-touch" open SV harvesting (OSVH) for another portion of the SV. A two cm segment from each portion was immersed in GALA conduit preservation solution and transported overnight to our lab for processing. The segments were labeled with fluorescent markers to quantify cell viability, calcium mobilization and generation of nitric oxide. Morphology, expression, localization and stability of endothelial caveolin, eNOS, von Willebrand factor and cadherin were evaluated using immunofluorescence, Western blot and multiphoton microscopy (MPM). RESULTS: Morphological, biochemical and immunofluorescence parameters of viability, structure and function were well preserved in VsEVH group as in OSVH group. However, tonic eNOS activity, agonist-dependent calcium mobilization and nitric oxide production were partially attenuated in the VsEVH group. CONCLUSIONS: This study indicates that VirtuoSaph endoscopic SV harvesting technique preserves the structural and functional viability of SV endothelium, but may differentially attenuate the vasomotor function of the saphenous vein graft. PMID- 21663647 TI - Clinical characteristics and evaluation of LDL-cholesterol treatment of the Spanish Familial Hypercholesterolemia Longitudinal Cohort Study (SAFEHEART). AB - AIM: Familial hypercholesterolemia (FH) patients are at high risk for premature coronary heart disease (CHD). Despite the use of statins, most patients do not achieve an optimal LDL-cholesterol goal. The aims of this study are to describe baseline characteristics and to evaluate Lipid Lowering Therapy (LLT) in FH patients recruited in SAFEHEART. METHODS AND RESULTS: A cross-sectional analysis of cases recruited in the Spanish FH cohort at inclusion was performed. Demographic, lifestyle, medical and therapeutic data were collected by specific surveys. Blood samples for lipid profile and DNA were obtained. Genetic test for FH was performed through DNA-microarray. Data from 1852 subjects (47.5% males) over 19 years old were analyzed: 1262 (68.1%, mean age 45.6 years) had genetic diagnosis of FH and 590 (31.9%, mean age 41.3 years) were non-FH. Cardiovascular disease was present in 14% of FH and in 3.2% of non-FH subjects (P < 0.001), and was significantly higher in patients carrying a null mutation compared with those carrying a defective mutation (14.87% vs. 10.6%, respectively, P < 0.05). Prevalence of current smokers was 28.4% in FH subjects. Most FH cases were receiving LLT (84%). Although 51.5% were receiving treatment expected to reduce LDL-c levels at least 50%, only 13.6% were on maximum statin dose combined with ezetimibe. Mean LDL-c level in treated FH cases was 186.5 mg/dl (SD: 65.6) and only 3.4% of patients reached and LDL-c under 100 mg/dl. The best predictor for LDL-c goal attainment was the use of combined therapy with statin and ezetimibe. CONCLUSION: Although most of this high risk population is receiving LLT, prevalence of cardiovascular disease and LDL-c levels are still high and far from the optimum LDL-c therapeutic goal. However, LDL-c levels could be reduced by using more intensive LLT such as combined therapy with maximum statin dose and ezetimibe. PMID- 21663648 TI - Effect of dairy fat on plasma phytanic acid in healthy volunteers - a randomized controlled study. AB - BACKGROUND: Phytanic acid produced in ruminants from chlorophyll may have preventive effects on the metabolic syndrome, partly due to its reported RXR and PPAR- alpha agonist activity. Milk from cows fed increased levels of green plant material, contains increased phytanic acid concentrations, but it is unknown to what extent minor increases in phytanic acid content in dairy fat leads to higher circulating levels of phytanic acid in plasma of the consumers. OBJECTIVE: To investigate if cow feeding regimes affects concentration of plasma phytanic acid and risk markers of the metabolic syndrome in human. DESIGN: In a double-blind, randomized, 4 wk, parallel intervention study 14 healthy young subjects were given 45 g milk fat/d from test butter and cheese with 0.24 wt% phytanic acid or a control diet with 0.13 wt% phytanic acid. Difference in phytanic acid was obtained by feeding roughage with low or high content of chlorophyll. RESULTS: There tended to be a difference in plasma phytanic acid (P = 0.0730) concentration after the dietary intervention. Plasma phytanic acid increased significantly within both groups with the highest increase in control group (24%) compared to phytanic acid group (15%). There were no significant effects of phytanic acid on risk markers for the metabolic syndrome. CONCLUSIONS: The results indicate that increased intake of dairy fat modify the plasma phytanic acid concentration, regardless of cows feeding regime and the minor difference in dietary phytanic acid. Whether the phytanic acid has potential to affects the risk markers of the metabolic syndrome in human still remain to be elucidated. PMID- 21663650 TI - A follow-up study on the quality of alcohol dependence-related information on the web. AB - In order to evaluate the one-year evolution of web-based information on alcohol dependence, we re-assessed alcohol-related sites in July 2007 with the same evaluating tool that had been used to assess these sites in June 2006. Websites were assessed with a standardized form designed to rate sites on the basis of accountability, presentation, interactivity, readability, and content quality. The DISCERN scale was also used, which aimed to assist persons without content expertise in assessing the quality of written health publications. Scores were highly stable for all components of the form one year later (r = .77 to .95, p < .01). Analysis of variance for repeated measures showed no time effect, no interaction between time and scale, no interaction between time and group (affiliation categories), and no interaction between time, group, and scale. The study highlights lack of change of alcohol-dependence-related web pages across one year. PMID- 21663649 TI - Epithelial cell senescence impairs repair process and exacerbates inflammation after airway injury. AB - BACKGROUND: Genotoxic stress, such as by exposure to bromodeoxyuridine (BrdU) and cigarette smoke, induces premature cell senescence. Recent evidence indicates that cellular senescence of various types of cells is accelerated in COPD patients. However, whether the senescence of airway epithelial cells contributes to the development of airway diseases is unknown. The present study was designed to test the hypothesis that premature senescence of airway epithelial cells (Clara cells) impairs repair processes and exacerbates inflammation after airway injury. METHODS: C57/BL6J mice were injected with the Clara-cell-specific toxicant naphthalene (NA) on days 0, 7, and 14, and each NA injection was followed by a daily dose of BrdU on each of the following 3 days, during which regenerating cells were allowed to incorporate BrdU into their DNA and to senesce. The p38 MAPK inhibitor SB202190 was injected 30 minutes before each BrdU dose. Mice were sacrificed at different times until day 28 and lungs of mice were obtained to investigate whether Clara cell senescence impairs airway epithelial regeneration and exacerbates airway inflammation. NCI-H441 cells were induced to senesce by exposure to BrdU or the telomerase inhibitor MST-312. Human lung tissue samples were obtained from COPD patients, asymptomatic smokers, and nonsmokers to investigate whether Clara cell senescence is accelerated in the airways of COPD patients, and if so, whether it is accompanied by p38 MAPK activation. RESULTS: BrdU did not alter the intensity of the airway epithelial injury or inflammation after a single NA exposure. However, after repeated NA exposure, BrdU induced epithelial cell (Clara cell) senescence, as demonstrated by a DNA damage response, p21 overexpression, increased senescence-associated beta-galactosidase activity, and growth arrest, which resulted in impaired epithelial regeneration. The epithelial senescence was accompanied by p38 MAPK dependent airway inflammation. Senescent NCI-H441 cells impaired epithelial wound repair and secreted increased amounts of pro-inflammatory cytokines in a p38 MAPK dependent manner. Clara cell senescence in COPD patients was accelerated and accompanied by p38 MAPK activation. CONCLUSIONS: Senescence of airway epithelial cells impairs repair processes and exacerbates p38 MAPK-dependent inflammation after airway injury, and it may contribute to the pathogenesis of COPD. PMID- 21663651 TI - Clinical observations on intensive immunosuppressive therapy combined with umbilical cord blood support for the treatment of severe aplastic anemia. AB - OBJECTIVE: To evaluate the efficacy of enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support for severe aplastic anemia (SAA). METHODS: A total of 25 patients with SAA received enhanced, intensive, immuno suppressive therapy and a cord blood transfusion. Therapy protocol: Anti thymocyte globulin (ATG) 2.5 mg/(kg*d) * 5d; Cyclophosphamide 50 mg/(kg*d) * 2d; cyclosporin A (CsA) maintenance therapy. RESULT: 25 patients were enrolled. 18 underwent a complete recovery, 4 made significant improvements, 1 did not respond, and 2 died. Therefore, the efficacy rate was 88%. The median follow-up time was 35 months (range 13-47 months), and the 3-year overall survival rate was 92%. Patients rapidly achieved reconstitution of hematopoiesis. The median time to neutrophil ANC > 0.5 * 109/L was 18 days (range 8-36), platelets >20 * 109/L was 34 days (range 12-123), and Hb > 100 g/L 95 days (range 35-173). CONCLUSION: Enhanced, intensive, immuno-suppressive therapy with umbilical cord blood support may be an effective option for SAA therapy. PMID- 21663652 TI - H.U.B city steps: methods and early findings from a community-based participatory research trial to reduce blood pressure among African Americans. AB - BACKGROUND: Community-based participatory research (CBPR) has been recognized as an important approach to develop and execute health interventions among marginalized populations, and a key strategy to translate research into practice to help reduce health disparities. Despite growing interest in the CBPR approach, CBPR initiatives rarely use experimental or other rigorous research designs to evaluate health outcomes. This behavioral study describes the conceptual frameworks, methods, and early findings related to the reach, adoption, implementation, and effectiveness on primary blood pressure outcomes. METHODS: The CBPR, social support, and motivational interviewing frameworks are applied to test treatment effects of a two-phased CBPR walking intervention, including a 6 month active intervention quasi experimental phase and 12-month maintenance randomized controlled trial phase to test dose effects of motivational interviewing. A community advisory board helped develop and execute the culturally-appropriate intervention components which included social support walking groups led by peer coaches, pedometer diary self-monitoring, monthly diet and physical activity education sessions, and individualized motivational interviewing sessions. Although the study is on-going, three month data is available and reported. Analyses include descriptive statistics and paired t tests. RESULTS: Of 269 enrolled participants, most were African American (94%) females (85%) with a mean age of 43.8 (SD = 12.1) years. Across the 3 months, 90% of all possible pedometer diaries were submitted. Attendance at the monthly education sessions was approximately 33%. At the 3-month follow-up 227 (84%) participants were retained. From baseline to 3-months, systolic BP [126.0 (SD = 19.1) to 120.3 (SD = 17.9) mmHg; p < 0.001] and diastolic BP [83. 2 (SD = 12.3) to 80.2 (SD = 11.6) mmHg; p < 0.001] were significantly reduced. CONCLUSIONS: This CBPR study highlights implementation factors and signifies the community's active participation in the development and execution of this study. Reach and representativeness of enrolled participants are discussed. Adherence to pedometer diary self-monitoring was better than education session participation. Significant decreases in the primary blood pressure outcomes demonstrate early effectiveness. Importantly, future analyses will evaluate long-term effectiveness of this CBPR behavioral intervention on health outcomes, and help inform the translational capabilities of CBPR efforts. PMID- 21663653 TI - Emotional climate, feeding practices, and feeding styles: an observational analysis of the dinner meal in Head Start families. AB - BACKGROUND: A number of studies conducted with ethnically diverse, low-income samples have found that parents with indulgent feeding styles had children with a higher weight status. Indulgent parents are those who are responsive to their child's emotional states but have problems setting appropriate boundaries with their child. Because the processes through which styles impact child weight are poorly understood, the aim of this study was to observe differences in the emotional climate created by parents (including affect, tone of voice, and gestures) and behavioral feeding practices among those reporting different feeding styles on the Caregiver's Feeding Styles Questionnaire. A secondary aim was to examine differences on child weight status across the feeding styles. METHODS: Participants were 177 Head Start families from Houston, Texas (45% African-American; 55% Hispanic). Using an observational approach, the relationship between the observed emotional climate of the meal, behavioral feeding practices, and self-reported parent feeding styles were examined. Mean age of the children was 4.4 years (SD = 0.7) equally distributed across gender. Families were observed on 3 separate dinner occasions. Heights and weight were measured on the parents and children. RESULTS: Parents with self-reported indulgent feeding styles made fewer demands on their children to eat during dinner and showed lower levels of negative affect and intrusiveness. Surprisingly, these parents also showed higher levels of emotional detachment with their children during dinner. Hispanic boys with indulgent parents had significantly higher BMI z scores compared to Hispanic boys in the other three feeding style groups. No other differences were found on child weight status. CONCLUSIONS: Results suggest that the emotional climate created by indulgent parents during dinner and their lack of demands on their children to eat may play an important role in how young children become overweight. Numerous observed emotional climate and behavioral differences were found between the other self reported feeding styles as well. Results suggest that parents' self-reported feeding styles may be a proxy for the emotional climate of the dinner meal, which may in turn influence the child's eating behaviors and weight status. PMID- 21663654 TI - Assessing the impact of road traffic on cycling for leisure and cycling to work. AB - BACKGROUND: To explore the relationship between leisure and commuter cycling with objectively measured levels of road traffic and whether any relationship was affected by traffic levels directly outside of home or in local neighbourhood. FINDINGS: We conducted a secondary analysis of data from the UK European Prospective Investigation of Cancer (EPIC) Norfolk cohort in 2009. We used a geographical information system (GIS) and gender specific multivariate models to relate 13 927 participants' reported levels of cycling with an index of road traffic volume (Road Traffic Volume Index Score--RTVIS). RTVIS were calculated around each participants home, using four distance based buffers, (0.5 km, 1 km, 2 km and 3.2 km). Models were adjusted for age, social status, education, car access and deprivation. Both genders had similar decreases in leisure cycling as traffic volumes increased at greater distances from home (OR 0.42, (95% CI 0.32 0.52, p < 0.001) for women and OR 0.41, (95% CI 0.33-0.50, p < 0.001) for men in the highest quartile at 3.2 km). There was no effect of traffic volumes at any distance on commuter cycling. CONCLUSIONS: Traffic volumes appear to have greater impact on leisure cycling than commuter cycling. Future research should investigate the importance of traffic on different types of cycling and include psychosocial correlates. PMID- 21663655 TI - Application of GRADE: making evidence-based recommendations about diagnostic tests in clinical practice guidelines. AB - BACKGROUND: Accurate diagnosis is a fundamental aspect of appropriate healthcare. However, clinicians need guidance when implementing diagnostic tests given the number of tests available and resource constraints in healthcare. Practitioners of health often feel compelled to implement recommendations in guidelines, including recommendations about the use of diagnostic tests. However, the understanding about diagnostic tests by guideline panels and the methodology for developing recommendations is far from completely explored. Therefore, we evaluated the factors that guideline developers and users need to consider for the development of implementable recommendations about diagnostic tests. METHODS: Using a critical analysis of the process, we present the results of a case study using the Grading of Recommendations Applicability, Development and Evaluation (GRADE) approach to develop a clinical practice guideline for the diagnosis of Cow Milk Allergy with the World Allergy Organization. RESULTS: To ensure that guideline panels can develop informed recommendations about diagnostic tests, it appears that more emphasis needs to be placed on group processes, including question formulation, defining patient-important outcomes for diagnostic tests, and summarizing evidence. Explicit consideration of concepts of diagnosis from evidence-based medicine, such as pre-test probability and treatment threshold, is required to facilitate the work of a guideline panel and to formulate implementable recommendations. DISCUSSION: This case study provides useful guidance for guideline developers and clinicians about what they ought to demand from clinical practice guidelines to facilitate implementation and strengthen confidence in recommendations about diagnostic tests. Applying a structured framework like the GRADE approach with its requirement for transparency in the description of the evidence and factors that influence recommendations facilitates laying out the process and decision factors that are required for the development, interpretation, and implementation of recommendations about diagnostic tests. PMID- 21663656 TI - To assess whether indoor residual spraying can provide additional protection against clinical malaria over current best practice of long-lasting insecticidal mosquito nets in The Gambia: study protocol for a two-armed cluster-randomised trial. AB - BACKGROUND: Recently, there has been mounting interest in scaling-up vector control against malaria in Africa. It needs to be determined if indoor residual spraying (IRS with DDT) will provide significant marginal protection against malaria over current best practice of long-lasting insecticidal nets (LLINs) and prompt treatment in a controlled trial, given that DDT is currently the most persistent insecticide for IRS. METHODS: A 2 armed cluster-randomised controlled trial will be conducted to assess whether DDT IRS and LLINs combined provide better protection against clinical malaria in children than LLINs alone in rural Gambia. Each cluster will be a village, or a group of small adjacent villages; all clusters will receive LLINs and half will receive IRS in addition. Study children, aged 6 months to 13 years, will be enrolled from all clusters and followed for clinical malaria using passive case detection to estimate malaria incidence for 2 malaria transmission seasons in 2010 and 2011. This will be the primary endpoint. Exposure to malaria parasites will be assessed using light and exit traps followed by detection of Anopheles gambiae species and sporozoite infection. Study children will be surveyed at the end of each transmission season to estimate the prevalence of Plasmodium falciparum infection and the prevalence of anaemia. DISCUSSION: Practical issues concerning intervention implementation, as well as the potential benefits and risks of the study, are discussed. TRIAL REGISTRATION: ISRCTN01738840 - Spraying And Nets Towards malaria Elimination (SANTE). PMID- 21663657 TI - A molecular epidemiological study of respiratory viruses detected in Japanese children with acute wheezing illness. AB - BACKGROUND: Recent studies strongly suggest that some respiratory viruses are associated with the induction of acute wheezing and/or exacerbation of bronchial asthma. However, molecular epidemiology of these viruses is not exactly known. METHODS: Using PCR technology, we attempted to detect various respiratory viruses from 115 Japanese children. Furthermore, the detected viruses were subjected to homology, pairwise distance, and phylogenetic analysis. RESULTS: Viruses were detected from 99 (86.1%) patients. Respiratory syncytial virus (RSV) alone and human rhinovirus (HRV) alone were detected in 47 (40.9%) and 36 (31.3%) patients, respectively. Both RSV and HRV were detected in 14 (12.2%) patients. Human metapneumovirus (HMPV) alone and human parainfluenza virus (HPIV) alone were detected in 1 (0.9%) patient each, respectively. Homology and phylogenetic analyses showed that the RSV and HRV strains were classified into genetically diverse species or subgroups. In addition, RSV was the dominant virus detected in patients with no history of wheezing, whereas HRV was dominant in patients with a history of wheezing. CONCLUSIONS: The results suggested that these genetically diverse respiratory viruses, especially RSV and HRV, might be associated with wheezing in Japanese children. PMID- 21663658 TI - PAPC and the Wnt5a/Ror2 pathway control the invagination of the otic placode in Xenopus. AB - BACKGROUND: Paraxial protocadherin (PAPC) plays a crucial role in morphogenetic movements during gastrulation and somitogenesis in mouse, zebrafish and Xenopus. PAPC influences cell-cell adhesion mediated by C-Cadherin. A putative direct adhesion activity of PAPC is discussed. PAPC also promotes cell elongation, tissue separation and coordinates cell mass movements. In these processes the signaling function of PAPC in activating RhoA/JNK and supporting Wnt-11/PCP by binding to frizzled 7 (fz7) is important. RESULTS: Here we demonstrate by loss of function experiments in Xenopus embryos that PAPC regulates another type of morphogenetic movement, the invagination of the ear placode. Knockdown of PAPC by antisense morpholinos results in deformation of the otic vesicle without altering otocyst marker expression. Depletion of PAPC could be rescued by full-length PAPC, constitutive active RhoA and by the closely related PCNS but not by classical cadherins. Also the cytoplasmic deletion mutant M-PAPC, which influences cell adhesion, does not rescue the PAPC knockdown. Interestingly, depletion of Wnt5a or Ror2 which are also expressed in the otocyst phenocopies the PAPC morphant phenotype. CONCLUSIONS: PAPC signaling via RhoA and Wnt5a/Ror2 activity are required to keep cells aligned in apical-basal orientation during invagination of the ear placode. Since neither the cytoplasmic deletion mutant M PAPC nor a classical cadherin is able to rescue loss of PAPC we suggest that the signaling function of the protocadherin rather than its role as modulator of cell cell adhesion is required during invagination of the ear placode. PMID- 21663659 TI - Gain of DNA methylation is enhanced in the absence of CTCF at the human retinoblastoma gene promoter. AB - BACKGROUND: Long-term gene silencing throughout cell division is generally achieved by DNA methylation and other epigenetic processes. Aberrant DNA methylation is now widely recognized to be associated with cancer and other human diseases. Here we addressed the contribution of the multifunctional nuclear factor CTCF to the epigenetic regulation of the human retinoblastoma (Rb) gene promoter in different tumoral cell lines. METHODS: To assess the DNA methylation status of the Rb promoter, genomic DNA from stably transfected human erythroleukemic K562 cells expressing a GFP reporter transgene was transformed with sodium bisulfite, and then PCR-amplified with modified primers and sequenced. Single- and multi-copy integrants with the CTCF binding site mutated were isolated and characterized by Southern blotting. Silenced transgenes were reactivated using 5-aza-2'-deoxycytidine and Trichostatin-A, and their expression was monitored by fluorescent cytometry. Rb gene expression and protein abundance were assessed by RT-PCR and Western blotting in three different glioma cell lines, and DNA methylation of the promoter region was determined by sodium bisulfite sequencing, together with CTCF dissociation and methyl-CpG-binding protein incorporation by chromatin immunoprecipitation assays. RESULTS: We found that the inability of CTCF to bind to the Rb promoter causes a dramatic loss of gene expression and a progressive gain of DNA methylation. CONCLUSIONS: This study indicates that CTCF plays an important role in maintaining the Rb promoter in an optimal chromatin configuration. The absence of CTCF induces a rapid epigenetic silencing through a progressive gain of DNA methylation. Consequently, CTCF can now be seen as one of the epigenetic components that allows the proper configuration of tumor suppressor gene promoters. Its aberrant dissociation can then predispose key genes in cancer cells to acquire DNA methylation and epigenetic silencing. PMID- 21663660 TI - Validation of oral fluid samples to monitor serological changes to Plasmodium falciparum: an observational study in southern Zambia. AB - BACKGROUND: In formerly endemic areas where malaria transmission has declined, levels of population immunity to Plasmodium falciparum provide information on continued malaria transmission and potentially susceptible populations. Traditional techniques for measuring serological responses to P. falciparum antigens use plasma or dried blood spots (DBS). These invasive procedures pose a biohazard and may be unacceptable to communities if performed frequently. The use of oral fluid (OF) samples to detect antibodies to P. falciparum antigens may be a more acceptable strategy to monitor changes in population immunity. METHODS: An enzyme immunoassay was optimized to detect antibodies to whole, asexual stage P. falciparum antigens. Optical density (OD) values from paired DBS and OF samples collected as part of a community-based survey of malaria parasitaemia were compared. RESULTS: Oral fluid and dried blood spot samples were collected from 53 participants in Southern Province, Zambia. Their ages ranged from 1 to 80 years and 45% were female. A statistically significant correlation (r=0.79; P<0.01) was observed between OD values from OF and DBS samples. The OF assay identified all DBS-confirmed positive and negative samples, resulting in 100% sensitivity and specificity. CONCLUSIONS: Oral fluid is a valid alternative specimen for monitoring changes in antibodies to P. falciparum antigens. As OF collection is often more acceptable to communities, poses less of a biohazard than blood samples and can be performed by community volunteers, serological surveys using OF samples provide a strategy for monitoring population immunity in regions of declining malaria transmission. PMID- 21663661 TI - Use of remote sensing to identify spatial risk factors for malaria in a region of declining transmission: a cross-sectional and longitudinal community survey. AB - BACKGROUND: The burden of malaria has decreased dramatically within the past several years in parts of sub-Saharan Africa. Further malaria control will require targeted control strategies based on evidence of risk. The objective of this study was to identify environmental risk factors for malaria transmission using remote sensing technologies to guide malaria control interventions in a region of declining burden of malaria. METHODS: Satellite images were used to construct a sampling frame for the random selection of households enrolled in prospective longitudinal and cross-sectional surveys of malaria parasitaemia in Southern Province, Zambia. A digital elevation model (DEM) was derived from the Shuttle Radar Topography Mission version 3 DEM and used for landscape characterization, including landforms, elevation, aspect, slope, topographic wetness, topographic position index and hydrological models of stream networks. RESULTS: A total of 768 individuals from 128 randomly selected households were enrolled over 21 months, from the end of the rainy season in April 2007 through December 2008. Of the 768 individuals tested, 117 (15.2%) were positive by malaria rapid diagnostic test (RDT). Individuals residing within 3.75 km of a third order stream were at increased risk of malaria. Households at elevations above the baseline elevation for the region were at decreasing risk of having RDT positive residents. Households where new infections occurred were overlaid on a risk map of RDT positive households and incident infections were more likely to be located in high-risk areas derived from prevalence data. Based on the spatial risk map, targeting households in the top 80th percentile of malaria risk would require malaria control interventions directed to only 24% of the households. CONCLUSIONS: Remote sensing technologies can be used to target malaria control interventions in a region of declining malaria transmission in southern Zambia, enabling a more efficient use of resources for malaria elimination. PMID- 21663663 TI - A tissue-specific landscape of sense/antisense transcription in the mouse intestine. AB - BACKGROUND: The intestinal mucosa is characterized by complex metabolic and immunological processes driven highly dynamic gene expression programs. With the advent of next generation sequencing and its utilization for the analysis of the RNA sequence space, the level of detail on the global architecture of the transcriptome reached a new order of magnitude compared to microarrays. RESULTS: We report the ultra-deep characterization of the polyadenylated transcriptome in two closely related, yet distinct regions of the mouse intestinal tract (small intestine and colon). We assessed tissue-specific transcriptomal architecture and the presence of novel transcriptionally active regions (nTARs). In the first step, signatures of 20,541 NCBI RefSeq transcripts could be identified in the intestine (74.1% of annotated genes), thereof 16,742 are common in both tissues. Although the majority of reads could be linked to annotated genes, 27,543 nTARs not consistent with current gene annotations in RefSeq or ENSEMBL were identified. By use of a second independent strand-specific RNA-Seq protocol, 20,966 of these nTARs were confirmed, most of them in vicinity of known genes. We further categorized our findings by their relative adjacency to described exonic elements and investigated regional differences of novel transcribed elements in small intestine and colon. CONCLUSIONS: The current study demonstrates the complexity of an archetypal mammalian intestinal mRNA transcriptome in high resolution and identifies novel transcriptionally active regions at strand specific, single base resolution. Our analysis for the first time shows a strand specific comparative picture of nTARs in two tissues and represents a resource for further investigating the transcriptional processes that contribute to tissue identity. PMID- 21663662 TI - Testis-specific glyceraldehyde-3-phosphate dehydrogenase: origin and evolution. AB - BACKGROUND: Glyceraldehyde-3-phosphate dehydrogenase (GAPD) catalyses one of the glycolytic reactions and is also involved in a number of non-glycolytic processes, such as endocytosis, DNA excision repair, and induction of apoptosis. Mammals are known to possess two homologous GAPD isoenzymes: GAPD-1, a well studied protein found in all somatic cells, and GAPD-2, which is expressed solely in testis. GAPD-2 supplies energy required for the movement of spermatozoa and is tightly bound to the sperm tail cytoskeleton by the additional N-terminal proline rich domain absent in GAPD-1. In this study we investigate the evolutionary history of GAPD and gain some insights into specialization of GAPD-2 as a testis specific protein. RESULTS: A dataset of GAPD sequences was assembled from public databases and used for phylogeny reconstruction by means of the Bayesian method. Since resolution in some clades of the obtained tree was too low, syntenic analysis was carried out to define the evolutionary history of GAPD more precisely. The performed selection tests showed that selective pressure varies across lineages and isoenzymes, as well as across different regions of the same sequences. CONCLUSIONS: The obtained results suggest that GAPD-1 and GAPD-2 emerged after duplication during the early evolution of chordates. GAPD-2 was subsequently lost by most lineages except lizards, mammals, as well as cartilaginous and bony fishes. In reptilians and mammals, GAPD-2 specialized to a testis-specific protein and acquired the novel N-terminal proline-rich domain anchoring the protein in the sperm tail cytoskeleton. This domain is likely to have originated by exonization of a microsatellite genomic region. Recognition of the proline-rich domain by cytoskeletal proteins seems to be unspecific. Besides testis, GAPD-2 of lizards was also found in some regenerating tissues, but it lacks the proline-rich domain due to tissue-specific alternative splicing. PMID- 21663665 TI - Risk factors for Entamoeba histolytica infection in an agricultural community in Hanam province, Vietnam. AB - BACKGROUND: Entamoeba histolytica is an important protozoan intestinal infection in resource-poor settings, including Vietnam. The study objective was to assess risk factors of E. histolytica infection in a community in Vietnam, where wastewater and human excreta are used in agriculture. A case-control study was conducted among residents of Hanam province, Northern Vietnam. Cases (n = 46) infected with E. histolytica and non-infected controls (n = 138) were identified in a cross-sectional survey among 794 randomly selected individuals and matched for age, sex and place of residence. Potential risk factors including exposure to human and animal excreta and household wastewater were assessed with a questionnaire. RESULTS: People from households with an average socio-economic status had a much higher risk of E. histolytica infection (odds ratio [OR]=4.3, 95% confidence interval [CI]: 1.3-14.0) compared with those from households with a good socioeconomic status. Those individuals who never or rarely used soap for hand washing had a 3.4 times higher risk for infection (OR=3.4, 95% CI: 1.1 10.0), compared to those who used always soap. In contrast, none of the factors related to use of human or animal excreta was statistically significant associated with E. histolytica infection. People having close contact with domestic animals presented a greater risk of E. histolytica infection (OR = 5.9, 95% CI: 1.8-19.0) than those without animal contact. E. histolytica infection was not associated with direct contact with Nhue river water, pond water and household's sanitary conditions, type of latrine or water source used. CONCLUSIONS: Our study suggests that in settings where human and animal excreta and Nhue River water are intensively used in agriculture, socio-economic and personal hygiene factors determine infection with E. histolytica, rather than exposure to human and animal excreta in agricultural activities. PMID- 21663664 TI - Identification of ejaculated proteins in the house mouse (Mus domesticus) via isotopic labeling. AB - BACKGROUND: Seminal fluid plays an important role in successful fertilization, but knowledge of the full suite of proteins transferred from males to females during copulation is incomplete. The list of ejaculated proteins remains particularly scant in one of the best-studied mammalian systems, the house mouse (Mus domesticus), where artificial ejaculation techniques have proven inadequate. Here we investigate an alternative method for identifying ejaculated proteins, by isotopically labeling females with 15N and then mating them to unlabeled, vasectomized males. Proteins were then isolated from mated females and identified using mass spectrometry. In addition to gaining insights into possible functions and fates of ejaculated proteins, our study serves as proof of concept that isotopic labeling is a powerful means to study reproductive proteins. RESULTS: We identified 69 male-derived proteins from the female reproductive tract following copulation. More than a third of all spectra detected mapped to just seven genes known to be structurally important in the formation of the copulatory plug, a hard coagulum that forms shortly after mating. Seminal fluid is significantly enriched for proteins that function in protection from oxidative stress and endopeptidase inhibition. Females, on the other hand, produce endopeptidases in response to mating. The 69 ejaculated proteins evolve significantly more rapidly than other proteins that we previously identified directly from dissection of the male reproductive tract. CONCLUSION: Our study attempts to comprehensively identify the proteins transferred from males to females during mating, expanding the application of isotopic labeling to mammalian reproductive genomics. This technique opens the way to the targeted monitoring of the fate of ejaculated proteins as they incubate in the female reproductive tract. PMID- 21663666 TI - Multiple vaccinations with UV- attenuated cercariae in pig enhance protective immunity against Schistosoma japonicum infection as compared to single vaccination. AB - BACKGROUND: Schistosomiasis japonica is a major public health problem in the endemic areas of China, the Philippines, and Indonesia. To date, a vaccine has not been developed against this disease but immunization with UV-attenuated cercariae can induce a high level of protective immunity in Landrace/Yorkshire/Duroc crossbred pigs. To compare the efficacy of a single vaccination and multiple vaccinations with UV-attenuated Schistosoma japonicum cercariae, two groups of pigs received either one or three exposures to 10,000 cercariae attenuated with 400 MUw UV. RESULTS: Pigs with a single immunization had a 59.33% reduction in adult worm burden, a 89.87% reduction in hepatic eggs and a 86.27% reduction in fecal eggs at eight weeks post-challenge (P < 0.01). After three immunizations, protection increased to 77.62%, 88.8% and 99.78% reduction in adult worms, hepatic eggs and fecal eggs, respectively (P < 0.01). Humoral and cellular immunological parameters measured indicated that schistosome specific IgG1 and IgG2 levels in the vaccinated groups were higher than in the infection-control group. Triple vaccinations resulted in higher levels of antibodies, especially IgG2, compared with a single vaccination and IFN-gamma levels increased with repeated immunization with UV-irradiated cercariae. CONCLUSION: The high levels of protection against S. japonicum infection can be achieved with a UV-attenuated vaccine in pigs, and that three vaccinations were possibly more effective than a single vaccination. Moreover, triple vaccinations evoked a more vigorous IFN-gamma response and a stronger antibody-mediated response, especially an increase in the levels of IgG2 antibodies. PMID- 21663668 TI - Cytokeratin-19 mRNA-positive circulating tumor cells during follow-up of patients with operable breast cancer: prognostic relevance for late relapse. AB - BACKGROUND: The detection of cytokeratin-19 (CK-19) mRNA-positive circulating tumor cells (CTC) before and/or after adjuvant chemotherapy in patients with operable breast cancer is associated with poor clinical outcome. Reliable prognostic markers for late disease relapse are not available. In this study we investigated the value of CTC detection during the first five years of follow-up in predicting late disease relapse. METHODS: Blood was analyzed from 312 women with operable breast cancer who had not experienced disease relapse during the first two years of follow-up. A real-time reverse transcriptase polymerase chain reaction (RT-PCR) for CK-19 mRNA was used to detect CTC three months after the completion of adjuvant chemotherapy and every six months thereafter for a follow up period of five years. RESULTS: Eighty patients (25.6% of the study population) remained CTC free throughout the five-year period. A change in CTC status was observed in 133 patients (42.6%); 64 patients (20.5%) with initially CK-19 mRNA positive CTC during the first 24 months turned CTC-negative afterwards while 69 (22.1%) who were initially CTC-negative became CTC-positive. Ninety-nine patients (31.7%) remained persistently CK-19 mRNA-positive. After a median follow-up period of 107 months (range: 38 to 161 months), the persistently CTC-positive patients with either hormonal receptor positive or negative tumors, had a higher risk of late-disease relapse compared to the persistently CTC-negative patients (36.4% versus 11.2%, P <0.001). Multivariate analysis revealed that persistently CTC-positive patients also had a shorter disease-free (P = 0.001) and overall survival (P = 0.001). CONCLUSIONS: Persistent detection of CK-19 mRNA-positive CTC during the first five years of follow-up is associated with an increased risk of late relapse and death in patients with operable breast cancer and indicates the presence of chemo-and hormonotherapy-resistant residual disease. This prognostic evaluation may be useful when deciding on subsequent adjuvant systemic therapy. PMID- 21663667 TI - Effect of combined siRNA of HCV E2 gene and HCV receptors against HCV. AB - BACKGROUND/AIM: Hepatitis C virus (HCV) is a major threat as almost 3% of the world's population (350 million individual) and 10% of the Pakistani population is chronically infected with this virus. RNA interference (RNAi), a sequence specific degradation process of RNA, has potential to be used as a powerful alternative molecular therapeutic approach in spite of the current therapy of interferon-alpha and ribavirin against HCV which has limited efficiency. HCV structural gene E2 is mainly involved in viral cell entry via attachment with the host cell surface receptors i.e., CD81 tetraspanin, low density lipoprotein receptor (LDLR), scavenger receptor class B type 1 (SR-B1), and Claudin1 (CLDN1). Considering the importance of HCV E2 gene and cellular receptors in virus infection and silencing effects of RNAi, the current study was designed to target the cellular and viral factors as new therapeutic options in limiting HCV infection. RESULTS: In this study the potential of siRNAs to inhibit HCV-3a replication in serum-infected Huh-7 cells was investigated by combined treatment of siRNAs against the HCV E2 gene and HCV cellular receptors (CD81 and LDLR), which resulted in a significant decrease in HCV viral copy number. CONCLUSION: From the current study it is concluded that the combined RNAi-mediated silencing of HCV E2 and HCV receptors is important for the development of effective siRNA based therapeutic option against HCV-3a. PMID- 21663669 TI - Effect of different UCOE-promoter combinations in creation of engineered cell lines for the production of Factor VIII. AB - BACKGROUND: The most common approach used in generating cell lines for the production of therapetic proteins relies on gene amplification induced by a drug resistance gene e. g., DHFR and glutamine synthetase. Practically, this results in screening large number of clones for the one that expresses high levels of the biologic in a stable manner. The inefficiency of mammalian vector systems to express proteins in a stable manner typically involves silencing of the exogenous gene resulting from modifications such as methylation of CpG DNA sequences, histone deacetylation and chromatin condensation. The use of un-methylated CpG island fragments from housekeeping genes referred to as UCOE (ubiquitous chromatin opening elements) in plasmid vectors is now well established for increased stability of transgene expression. However, few UCOE-promoter combinations have been studied to date and in this report we have tested 14 different combinations. FINDINGS: In this report we describe studies with two different UCOEs (the 1.5 Kb human RNP fragment and the 3.2 Kb mouse RPS3 fragment) in combination with various promoters to express a large protein (B domain deleted factor VIII; BDD-FVIII) in a production cell line, BHK21. We show here that there are differences in expression of BDD-FVIII by the different UCOE promoter combinations in both attached and serum free suspension adapted cells. In all cases, the 1.5 Kb human RNP UCOE performed better in expressing BDD-FVIII than their corresponding 3.2 Kb mouse RPS3 UCOE. Surprisingly, in certain scenarios described here, expression from a number of promoters was equivalent or higher than the commonly used and industry standard human CMV promoter. CONCLUSION: This study indicates that certain UCOE-promoter combinations are better than others in expressing the BDD-FVIII protein in a stable manner in BHK21 cells. An empirical study such as this is required to determine the best combination of UCOE-promoter in a vector for a particular production cell line. PMID- 21663670 TI - Highly efficient PCR assay to discriminate allelic DNA methylation status using whole genome amplification. AB - BACKGROUND: We previously developed a simple method termed HpaII-McrBC PCR (HM PCR) to discriminate allelic methylation status of the genomic sites of interest, and successfully applied it to a comprehensive analysis of CpG islands (CGIs) on human chromosome 21q. However, HM-PCR requires 200 ng of genomic DNA to examine one target site, thereby precluding its application to such samples that are limited in quantity. FINDINGS: We developed HpaII-McrBC whole-genome amplification PCR (HM-WGA-PCR) that uses whole-genome-amplified DNA as the template. HM-WGA-PCR uses only 1/100th the genomic template material required for HM-PCR. Indeed, we successfully analyzed 147 CGIs by HM-WGA-PCR using only ~300 ng of DNA, whereas previous HM-PCR study had required ~30 MUg. Furthermore, we confirmed that allelic methylation status revealed by HM-WGA-PCR is identical to that by HM-PCR in every case of the 147 CGIs tested, proving high consistency between the two methods. CONCLUSIONS: HM-WGA-PCR would serve as a reliable alternative to HM-PCR in the analysis of allelic methylation status when the quantity of DNA available is limited. PMID- 21663671 TI - Detection of antibodies directed at M. hyorhinis p37 in the serum of men with newly diagnosed prostate cancer. AB - BACKGROUND: Recent epidemiologic, genetic, and molecular studies suggest infection and inflammation initiate certain cancers, including cancers of the prostate. Over the past several years, our group has been studying how mycoplasmas could possibly initiate and propagate cancers of the prostate. Specifically, Mycoplasma hyorhinis encoded protein p37 was found to promote invasion of prostate cancer cells and cause changes in growth, morphology and gene expression of these cells to a more aggressive phenotype. Moreover, we found that chronic exposure of benign human prostate cells to M. hyorhinis resulted in significant phenotypic and karyotypic changes that ultimately resulted in the malignant transformation of the benign cells. In this study, we set out to investigate another potential link between mycoplasma and human prostate cancer. METHODS: We report the incidence of men with prostate cancer and benign prostatic hyperplasia (BPH) being seropositive for M. hyorhinis. Antibodies to M. hyorhinis were surveyed by a novel indirect enzyme-linked immunosorbent assay (ELISA) in serum samples collected from men presenting to an outpatient Urology clinic for BPH (N = 105) or prostate cancer (N = 114) from 2006-2009. RESULTS: A seropositive rate of 36% in men with BPH and 52% in men with prostate cancer was reported, thus leading us to speculate a possible connection between M. hyorhinis exposure with prostate cancer. CONCLUSIONS: These results further support a potential exacerbating role for mycoplasma in the development of prostate cancer. PMID- 21663672 TI - Comparing comorbidity measures for predicting mortality and hospitalization in three population-based cohorts. AB - BACKGROUND: Multiple comorbidity measures have been developed for risk-adjustment in studies using administrative data, but it is unclear which measure is optimal for specific outcomes and if the measures are equally valid in different populations. This research examined the predictive performance of five comorbidity measures in three population-based cohorts. METHODS: Administrative data from the province of Saskatchewan, Canada, were used to create the cohorts. The general population cohort included all Saskatchewan residents 20+ years, the diabetes cohort included individuals 20+ years with a diabetes diagnosis in hospital and/or physician data, and the osteoporosis cohort included individuals 50+ years with diagnosed or treated osteoporosis. Five comorbidity measures based on health services utilization, number of different diagnoses, and prescription drugs over one year were defined. Predictive performance was assessed for death and hospitalization outcomes using measures of discrimination (c-statistic) and calibration (Brier score) for multiple logistic regression models. RESULTS: The comorbidity measures with optimal performance were the same in the general population (n = 662,423), diabetes (n = 41,925), and osteoporosis (n = 28,068) cohorts. For mortality, the Elixhauser index resulted in the highest c-statistic and lowest Brier score, followed by the Charlson index. For hospitalization, the number of diagnoses had the best predictive performance. Consistent results were obtained when we restricted attention to the population 65+ years in each cohort. CONCLUSIONS: The optimal comorbidity measure depends on the health outcome and not on the disease characteristics of the study population. PMID- 21663673 TI - Oncoprotein DEK as a tissue and urinary biomarker for bladder cancer. AB - BACKGROUND: Bladder cancer is a significant healthcare problem in the United States of America with a high recurrence rate. Early detection of bladder cancer is essential for removing the tumor with preservation of the bladder, avoiding metastasis and hence improving prognosis and long-term survival. The objective of this study was to analyze the presence of DEK protein in voided urine of bladder cancer patients as a urine-based bladder cancer diagnostic test. METHODS: We examined the expression of DEK protein by western blot in 38 paired transitional cell carcinoma (TCC) bladder tumor tissues and adjacent normal tissue. The presence of DEK protein in voided urine was analyzed by western blot in 42 urine samples collected from patients with active TCC, other malignant urogenital disease and healthy individuals. RESULTS: The DEK protein is expressed in 33 of 38 bladder tumor tissues with no expression in adjacent normal tissue. Based on our sample size, DEK protein is expressed in 100% of tumors of low malignant potential, 92% of tumors of low grade and in 71% of tumors of high grade. Next, we analyzed 42 urine samples from patients with active TCC, other malignant urogenital disease, non-malignant urogenital disease and healthy individuals for DEK protein expression by western blot analysis. We are the first to show that the DEK protein is present in the urine of bladder cancer patients. Approximately 84% of TCC patient urine specimens were positive for urine DEK. CONCLUSION: Based on our pilot study of 38 bladder tumor tissue and 42 urine samples from patients with active TCC, other malignant urogenital disease, non-malignant urogenital disease and healthy individuals; DEK protein is expressed in bladder tumor tissue and voided urine of bladder cancer patients. The presence of DEK protein in voided urine is potentially a suitable biomarker for bladder cancer and that the screening for the presence of DEK protein in urine can be explored as a noninvasive diagnostic test for bladder cancer. PMID- 21663674 TI - Is proximity to a food retail store associated with diet and BMI in Glasgow, Scotland? AB - BACKGROUND: Access to healthy food is often seen as a potentially important contributor to diet. Policy documents in many countries suggest that variations in access contribute to inequalities in diet and in health. Some studies, mostly in the USA, have found that proximity to food stores is associated with dietary patterns, body weight and socio-economic differences in diet and obesity, whilst others have found no such relationships. We aim to investigate whether proximity to food retail stores is associated with dietary patterns or Body Mass Index in Glasgow, a large city in the UK. METHODS: We mapped data from a 'Health and Well Being Survey' (n = 991), and a list of food stores (n = 741) in Glasgow City, using ArcGIS, and undertook network analysis to find the distance from respondents' home addresses to the nearest fruit and vegetable store, small general store, and supermarket. RESULTS: We found few statistically significant associations between proximity to food retail outlets and diet or obesity, for unadjusted or adjusted models, or when stratifying by gender, car ownership or employment. CONCLUSIONS: The findings suggest that in urban settings in the UK the distribution of retail food stores may not be a major influence on diet and weight, possibly because most urban residents have reasonable access to food stores. PMID- 21663675 TI - Identification of novel soybean microRNAs involved in abiotic and biotic stresses. AB - BACKGROUND: Small RNAs (19-24 nt) are key regulators of gene expression that guide both transcriptional and post-transcriptional silencing mechanisms in eukaryotes. Current studies have demonstrated that microRNAs (miRNAs) act in several plant pathways associated with tissue proliferation, differentiation, and development and in response to abiotic and biotic stresses. In order to identify new miRNAs in soybean and to verify those that are possibly water deficit and rust-stress regulated, eight libraries of small RNAs were constructed and submitted to Solexa sequencing. RESULTS: The libraries were developed from drought-sensitive and tolerant seedlings and rust-susceptible and resistant soybeans with or without stressors. Sequencing the library and subsequent analyses detected 256 miRNAs. From this total, we identified 24 families of novel miRNAs that had not been reported before, six families of conserved miRNAs that exist in other plants species, and 22 families previously reported in soybean. We also observed the presence of several isomiRNAs during our analyses. To validate novel miRNAs, we performed RT-qPCR across the eight different libraries. Among the 11 miRNAs analyzed, all showed different expression profiles during biotic and abiotic stresses to soybean. The majority of miRNAs were up-regulated during water deficit stress in the sensitive plants. However, for the tolerant genotype, most of the miRNAs were down regulated. The pattern of miRNAs expression was also different for the distinct genotypes submitted to the pathogen stress. Most miRNAs were down regulated during the fungus infection in the susceptible genotype; however, in the resistant genotype, most miRNAs did not vary during rust attack. A prediction of the putative targets was carried out for conserved and novel miRNAs families. CONCLUSIONS: Validation of our results with quantitative RT-qPCR revealed that Solexa sequencing is a powerful tool for miRNA discovery. The identification of differentially expressed plant miRNAs provides molecular evidence for the possible involvement of miRNAs in the process of water deficit- and rust-stress responses. PMID- 21663676 TI - Distance matters: a population based study examining access to maternity services for rural women. AB - BACKGROUND: In the past fifteen years there has been a wave of closures of small maternity services in Canada and other developed nations which results in the need for rural parturient women to travel to access care. The purpose of our study is to systematically document newborn and maternal outcomes as they relate to distance to travel to access the nearest maternity services with Cesarean section capability. METHODS: Study population is all women carrying a singleton pregnancy beyond 20 weeks and delivering between April 1, 2000 and March 31, 2004 and residing outside of the core urban areas of British Columbia. Maternal and newborn data was linked to specific geographic catchments by the B.C. prenatal Health Program. Catchments were stratified by distance to nearest maternity service with Cesarean section capability if greater than 1 hour travel time or level of local service. Hierarchical logistic regression was used to test predictors of adverse newborn and maternal outcomes. RESULTS: 49,402 cases of women and newborns resident in rural catchments were included. Adjusted odds ratios for prenatal mortality for newborns from catchments greater than 4 hours from services was 3.17 (95% CI 1.45-6.95). Newborns from catchments 2 to 4 hours, and 1 to 2 hours from services generated rates of 179 and 100 NICU 3 days per thousand births respectively compared to 42 days for newborns from catchments served by specialists. CONCLUSIONS: Distance matters: rural parturient women who have to travel to access maternity services have increased rates of adverse prenatal outcomes. PMID- 21663678 TI - The luxS mutation causes loosely-bound biofilms in Shewanella oneidensis. AB - BACKGROUND: The luxS gene in Shewanella oneidensis was shown to encode an autoinducer-2 (AI-2)-like molecule, the postulated universal bacterial signal, but the impaired biofilm growth of a luxS deficient mutant could not be restored by AI-2, indicating it might not have a signalling role in this organism. FINDINGS: Here, we provide further evidence regarding the metabolic role of a luxS mutation in S. oneidensis. We constructed a luxS mutant and compared its phenotype to a wild type control with respect to its ability to remove AI-2 from the medium, expression of secreted proteins and biofilm formation. We show that S. oneidensis has a cell-dependent mechanism by which AI-2 is depleted from the medium by uptake or degradation at the end of the exponential growth phase. As AI 2 depletion is equally active in the luxS mutant and thus does not require AI-2 as an inducer, it appears to be an unspecific mechanism suggesting that AI-2 for S. oneidensis is a metabolite which is imported under nutrient limitation. Secreted proteins were studied by iTraq labelling and liquid chromatography mass spectrometry (LC-MS) detection. Differences between wild type and mutant were small. Proteins related to flagellar and twitching motility were slightly up regulated in the luxS mutant, in accordance with its loose biofilm structure. An enzyme related to cysteine metabolism was also up-regulated, probably compensating for the lack of the LuxS enzyme. The luxS mutant developed an undifferentiated, loosely-connected biofilm which covered the glass surface more homogenously than the wild type control, which formed compact aggregates with large voids in between. CONCLUSIONS: The data confirm the role of the LuxS enzyme for biofilm growth in S. oneidensis and make it unlikely that AI-2 has a signalling role in this organism. PMID- 21663677 TI - Bicarbonate and dichloroacetate: evaluating pH altering therapies in a mouse model for metastatic breast cancer. AB - BACKGROUND: The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations. METHODS: We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically. RESULTS: Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment. CONCLUSIONS: DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment. PMID- 21663679 TI - Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism. AB - BACKGROUND: Secondary therapy-related acute lymphoblastic leukemia might emerge following chemotherapy and/or radiotherapy for primary malignancies. Therefore, other alternatives should be pursued to treat leukemia. RESULTS: It is shown that vitamin K3- or vitamin C- induced apoptosis in leukemia cells by oxidative stress mechanism involving superoxide anion radical and hydrogen peroxide generation, activation of NF-kappaB, p53, c-Jun, protease caspase-3 activation and mitochondria depolarization leading to nuclei fragmentation. Cell death was more prominent when Jurkat and K562 cells are exposed to VC and VK3 in a ratio 1000:1 (10 mM: 10 MUM) or 100:1 (300 MUM: 3 MUM), respectively. CONCLUSION: We provide for the first time in vitro evidence supporting a causative role for oxidative stress in VK3- and VC-induced apoptosis in Jurkat and K562 cells in a domino-like mechanism. Altogether these data suggest that VK3 and VC should be useful in the treatment of leukemia. PMID- 21663680 TI - Effectiveness of oral nutritional supplementation for older women after a fracture: rationale, design and study of the feasibility of a randomized controlled study. AB - BACKGROUND: Malnutrition is a problem for many older people recovering from a hip and other major fractures. Oral supplementation with high calorie high protein nutrients is a simple intervention that may help older people with fractures to improve their recovery in terms of rehabilitation time, length of hospital stay and mortality. This paper reports a pilot study to test the feasibility of a trial initiated in a hospital setting with an oral supplement to older people with recent fractures. METHOD: A randomized controlled trial with 44 undernourished participants admitted to a hospital following a fracture. The intervention group (n = 23) received a high calorie high protein supplement for forty days in addition to their diet of choice. The control group (n = 21) received high protein milk during their hospital stay in addition to their diet of choice and their usual diet when discharged from hospital. RESULTS: All participants were women and their mean age was 85.3 (+/- 6.1) years. Twenty nine (65%) participants had a hip fracture. At baseline no differences were measured between the two groups regarding their nutritional status, their cognitive ability or their abilities in activities of daily living. There were no significant differences between the intervention and control group with reference to nutritional or functional parameters at 40 day and 4 month follow-ups. Median length of stay in hospital was 18.0 days, with 12 participants being readmitted for a median of 7.0 days. CONCLUSION: It is feasible to perform a randomised trial in a hospital and community setting to test the effect of an oral high energy high protein supplement for older people. Due to the limited number of participants and incomplete adherence with use of the supplements no conclusion can be drawn about the efficacy or effectiveness of this intervention. PMID- 21663681 TI - Molecular basis of virulence in clinical isolates of Escherichia coli and Salmonella species from a tertiary hospital in the Eastern Cape, South Africa. AB - BACKGROUND: Apart from localized gastrointestinal infections, Escherichia coli and Salmonella species are major causes of systemic disease in both humans and animals. Salmonella spp. cause invasive infections such as enteric fever, septicemia, osteomyelitis and meningitis while certain types of E. coli can cause systemic infections, includingpyelonephritis, meningitis and septicemia. These characteristic requires the involvement of a myriad of virulence factors. METHODS: This study investigated the virulence factors of Escherichia coli and Salmonella species in clinical specimens from patients with diarrhoea presenting to health care centres in Oliver R. Tambo District Municipality, Eastern Cape Province, Republic of South Africa. Microbiology analysis involved the use of cultural and molecular techniques. RESULTS: Out of a total of 315 samples screened, Salmonella isolates were obtained in 119 (37.8%) of cases and these comprised: S. choleraesuis (6%), S. enteritidis (4%), S. eppendorf (1%), S. hadar (1%), S. isangi (8%), S. panama (1%), S. typhi (52%), S. typhimurium (25%) and untyped Salmonella spp. (2%). Among the Salmonella species 87 (73.1%) were invasive. Using molecular diagnostic methods, diarrheagenic E. coli were detected in 90 cases (28.6%): the greater proportion of this were enteroaggregative E. coli (EAEC) 37 (41.1%), enteropathogenic E. coli (EPEC) 21 (23.3%) and enterohemorrhagic E. coli (EHEC) 21 (23.3%). The predominant virulence gene among the diarrheagenic E. coli was EAEC heat-stable enterotoxin astA genes while the virulence genes identified in the Salmonella strains were 15 (12.6%) flic and 105 (88.2%) inv genes. The amino acid identity of the representative genes showed 95 100% similarity to corresponding blast searched sequence. CONCLUSIONS: This study showed the diversity of virulence gene expression in two major enteric pathogens. S. typhi and enteroaggregative E. coli were the predominant enteropathogens in our study area with an indication that EAEC is endemic within our study population. It was observed among other things that some diarrheagenic E. coli isolated from apparently asymptomatic subjects expressed some virulence genes at frequency as high as seen in diarrheagenic cases. This study underlines the importance of understanding the virulence composition and diversity of pathogens for enhanced clinico-epidemiological monitoring and health care delivery. PMID- 21663682 TI - Quantitative assessment of mammary gland density in rodents using digital image analysis. AB - BACKGROUND: Rodent models have been used extensively to study mammary gland development and for studies of toxicology and carcinogenesis. Mammary gland gross morphology can visualized via the excision of intact mammary gland chains following fixation and staining with carmine using a tissue preparation referred to as a whole mount. Methods are described for the automated collection of digital images from an entire mammary gland whole mount and for the interrogation of digital data using a "masking" technique available with Image-Pro(r) plus image analysis software (Mediacybernetics. Silver Spring, MD). RESULTS: Parallel to mammographic analysis in humans, measurements of rodent mammary gland density were derived from area-based or volume-based algorithms and included: total circumscribed mammary fat pad mass, mammary epithelial mass, and epithelium-free fat pad mass. These values permitted estimation of absolute mass of mammary epithelium as well as breast density. The biological plausibility of these measurements was evaluated in mammary whole mounts from rats and mice. During mammary gland development, absolute epithelial mass increased linearly without significant changes in mammographic density. Treatment of rodents with tamoxifen, 9-cis-retinoic acid, or ovariectomy, and occurrence of diet induced obesity decreased both absolute epithelial mass and mammographic density. The area and volumetric methods gave similar results. CONCLUSIONS: Digital image analysis can be used for screening agents for potential impact on reproductive toxicity or carcinogenesis as well as for mechanistic studies, particularly for cumulative effects on mammary epithelial mass as well as translational studies of mechanisms that explain the relationship between epithelial mass and cancer risk. PMID- 21663683 TI - Association between low-dose pulsed intravenous cyclophosphamide therapy and amenorrhea in patients with systemic lupus erythematosus: a case-control study. AB - BACKGROUND: The risk for amenorrhea following treatment of systemic lupus erythematosus (SLE) patients with low-dose intravenous cyclophosphamide (IVCY) has not been fully explored. Our objective was to ascertain the incidence of amenorrhea following treatment with low-dose IVCY and the association between amenorrhea and the clinical parameters of SLE. METHODS: A case-control retrospective study of premenopausal women <= 45 years old who had been treated for SLE with low-dose IVCY (500 mg/body/pulse) plus high-dose glucocorticoids (0.8-1.0 mg/kg/day of prednisolone; IVCY group) or glucocorticoids alone (0.8-1.0 mg/kg/day of prednisolone; steroid group) in our hospital from 2000 through 2009 was conducted using a questionnaire survey and medical record review. RESULTS: Twenty-nine subjects in the IVCY group and 33 subjects in the steroid group returned the questionnaire. A multivariate analysis revealed that age at initiation of treatment >= 40 years old was significantly associated with amenorrhea [p = 0.009; odds ratio (OR) 10.2; 95% confidence interval (CI) 1.8 58.7]. IVCY treatment may display a trend for association with amenorrhea (p = 0.07; OR 2.9; 95% CI 0.9-9.4). Sustained amenorrhea developed in 4 subjects in the IVCY group and 1 subject in the steroid group; all of these patients were >= 40 years old. Menses resumed in all subjects < 40 years old, irrespective of treatment. CONCLUSIONS: Although low-dose IVCY may increase the risk for amenorrhea, our data suggest that patients < 40 years old have a minimum risk for sustained amenorrhea with low-dose IVCY treatment. A higher risk for sustained amenorrhea following treatment with IVCY is a consideration for patients >= 40 years old. PMID- 21663684 TI - Estimation of allele frequency and association mapping using next-generation sequencing data. AB - BACKGROUND: Estimation of allele frequency is of fundamental importance in population genetic analyses and in association mapping. In most studies using next-generation sequencing, a cost effective approach is to use medium or low coverage data (e.g., < 15X). However, SNP calling and allele frequency estimation in such studies is associated with substantial statistical uncertainty because of varying coverage and high error rates. RESULTS: We evaluate a new maximum likelihood method for estimating allele frequencies in low and medium coverage next-generation sequencing data. The method is based on integrating over uncertainty in the data for each individual rather than first calling genotypes. This method can be applied to directly test for associations in case/control studies. We use simulations to compare the likelihood method to methods based on genotype calling, and show that the likelihood method outperforms the genotype calling methods in terms of: (1) accuracy of allele frequency estimation, (2) accuracy of the estimation of the distribution of allele frequencies across neutrally evolving sites, and (3) statistical power in association mapping studies. Using real re-sequencing data from 200 individuals obtained from an exon capture experiment, we show that the patterns observed in the simulations are also found in real data. CONCLUSIONS: Overall, our results suggest that association mapping and estimation of allele frequencies should not be based on genotype calling in low to medium coverage data. Furthermore, if genotype calling methods are used, it is usually better not to filter genotypes based on the call confidence score. PMID- 21663685 TI - Prevalence of HCV among the high risk groups in Khyber Pakhtunkhwa. AB - Hepatitis C is an infectious disease, caused by blood borne pathogen; the Hepatitis C Virus. In this study we analyzed blood samples collected from various risk groups for the prevalence of anti-HCV and active HCV infection with the help of Immunochromtographic tests and nested PCR. The prevalence of active HCV infection among the high risk groups was 15.57% (26/167). The prevalence of HCV in individual risk groups was 15%, 28%, 8%, 14.28% and 14.28% in the case of thalassemics, dialysis, major surgery group, dental surgery group and injection drug users respectively. Our analysis reveals the fact that health care facilities in the Khyber Pakhtunkhwa province of Pakistan are contributing a great deal towards the spread of HCV infection. PMID- 21663686 TI - Selecting synaptic partners: GRASPing the role of UNC-6/netrin. AB - Forming synaptic connections of the appropriate strength between specific neurons is crucial for constructing neural circuits to control behavior. A recent paper in Neural Development describes the use of a synapse-specific label in Caenorhabditis elegans to implicate local UNC-6/netrin signaling in this developmental process. Thus, as well as their well known roles in cell migration and axon guidance, UNC-6/netrin signals distinguish an appropriate synaptic partner from other potential targets. PMID- 21663687 TI - Cervical Mullerian adenosarcoma with heterologous sarcomatous overgrowth: a fourth case and review of literature. AB - BACKGROUND: Uterine sarcomas are relatively rare tumors that account for approximately 1-3% of female genital tract malignancies and between 4-9% of uterine cancers. Less than 8% of all cases are Mullerian adenosarcoma, a distinctive uterine neoplasm characterized by a benign, but occasionally atypical, epithelial and a malignant, usually low-grade, stromal component, both of which should be integral and neoplastic constituents of the tumor. Mullerian adenosarcoma with sarcomatous overgrowth (MASO) is a very aggressive variant, associated with post-operative recurrence, metastases, even when diagnosed in early stage. CASE PRESENTATION: We present a fourth MASO case derived from uterine cervix in a 72-year-old woman with metrorrhagia and a polypoid mass protruding through the cervical ostium. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, systematic pelvic lymph node dissection, omental biopsy and appendectomy were performed. Surgery treatment was associated with adjuvant whole-pelvis radiation (45 Gy) and adjuvant chemotherapy (cisplatin/ifosfamide). After nine months of follow up, the patient was free of tumor. CONCLUSIONS: The rarity of MASO of the cervix involves a management difficult. Most authors recommend total abdominal hysterectomy, usually accompanied by bilateral salpingo oophorectomy. There is no common agreement on staging by lymphadenectomy during primary surgery and adjuvant chemo-radio therapy. PMID- 21663689 TI - FARO server: Meta-analysis of gene expression by matching gene expression signatures to a compendium of public gene expression data. AB - BACKGROUND: Although, systematic analysis of gene annotation is a powerful tool for interpreting gene expression data, it sometimes is blurred by incomplete gene annotation, missing expression response of key genes and secondary gene expression responses. These shortcomings may be partially circumvented by instead matching gene expression signatures to signatures of other experiments. FINDINGS: To facilitate this we present the Functional Association Response by Overlap (FARO) server, that match input signatures to a compendium of 242 gene expression signatures, extracted from more than 1700 Arabidopsis microarray experiments. CONCLUSIONS: Hereby we present a publicly available tool for robust characterization of Arabidopsis gene expression experiments which can point to similar experimental factors in other experiments. The server is available at http://www.cbs.dtu.dk/services/faro/. PMID- 21663688 TI - Intimal hyperplasia in balloon dilated coronary arteries is reduced by local delivery of the NO donor, SIN-1 via a cGMP-dependent pathway. AB - BACKGROUND: To elucidate the mechanism by which local delivery of 3-morpholino sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA). METHODS: Porcine coronary arteries were treated with PTCA and immediately afterwards locally treated for 5 minutes, with a selective cytosolic guanylate cyclase inhibitor, 1 H-(1,2,4)oxadiazole(4,3 alpha)quinoxaline-1-one (ODQ) + SIN-1 or only SIN-1 using a drug delivery balloon. Arteries were angiographically depicted, morphologically evaluated and analyzed after one and eight weeks for actin, myosin and intermediate filaments (IF) and nitric oxide synthase (NOS) contents. RESULTS: Luminal diameter after PCI in arteries treated with SIN-1 alone and corrected for age-growth was significantly larger as compared to ODQ + SIN-1 or to controls (p < 0.01). IF/actin ratio after one week in SIN-1 treated segments was not different compared to untreated segments, but was significantly reduced compared to ODQ + SIN-1 treated vessels (p < 0.05). Expression of endothelial NADPH diaphorase activity was significantly lower in untreated segments and in SIN-1 treated segments compared to controls and SIN-1 + ODQ treated arteries (p < 0.01). Restenosis index (p < 0.01) and intimal hyperplasia (p < 0.01) were significantly reduced while the residual lumen was increased (p < 0.01) in SIN-1 segments compared to controls and ODQ + SIN-1 treated vessels. CONCLUSIONS: After PTCA local delivery of high concentrations of the NO donor SIN-1 for 5 minutes inhibited injury induced neointimal hyperplasia. This favorable effect was abolished by inhibition of guanylyl cyclase indicating mediation of a cyclic guanosine 3',5'-monophosphate (cGMP)-dependent pathway. The momentary events at the time of injury play crucial role in the ensuring development of intimal hyperplasia. PMID- 21663690 TI - A guide through the computational analysis of isotope-labeled mass spectrometry based quantitative proteomics data: an application study. AB - BACKGROUND: Mass spectrometry-based proteomics has reached a stage where it is possible to comprehensively analyze the whole proteome of a cell in one experiment. Here, the employment of stable isotopes has become a standard technique to yield relative abundance values of proteins. In recent times, more and more experiments are conducted that depict not only a static image of the up- or down-regulated proteins at a distinct time point but instead compare developmental stages of an organism or varying experimental conditions. RESULTS: Although the scientific questions behind these experiments are of course manifold, there are, nevertheless, two questions that commonly arise: 1) which proteins are differentially regulated regarding the selected experimental conditions, and 2) are there groups of proteins that show similar abundance ratios, indicating that they have a similar turnover? We give advice on how these two questions can be answered and comprehensively compare a variety of commonly applied computational methods and their outcomes. CONCLUSIONS: This work provides guidance through the jungle of computational methods to analyze mass spectrometry based isotope-labeled datasets and recommends an effective and easy-to-use evaluation strategy. We demonstrate our approach with three recently published datasets on Bacillus subtilis 12 and Corynebacterium glutamicum 3. Special focus is placed on the application and validation of cluster analysis methods. All applied methods were implemented within the rich internet application QuPE 4. Results can be found at http://qupe.cebitec.uni-bielefeld.de. PMID- 21663691 TI - Human fascioliasis in Argentina: retrospective overview, critical analysis and baseline for future research. AB - In Argentina, human fascioliasis has never been adequately analysed, although having a physiography, climate, animal prevalences and lymnaeids similar to those of countries where the disease is endemic such as Bolivia, Peru and Chile. We performed a literature search identifying 58 reports accounting for 619 cases, involving 13 provinces, their majority (97.7%) from high altitudes, in central mountainous areas and Andean valleys, concentrated in Cordoba (430 cases), Catamarca (73), San Luis (29) and Mendoza (28), the remaining provinces being rarely affected. This distribution does not fit that of animal fascioliasis. Certain aspects (higher prevalence in females in a local survey, although a trend non-significant throughout Argentina) but not others (patient's age 3-95 years, mean 37.1 years) resemble human endemics in Andean countries, although the lack of intensity studies and surveys in rural areas does not allow for an adequate evaluation. Human infection occurs mainly in January-April, when higher precipitation and temperatures interact with field activities during summer holidays. A second June peak may be related to Easter holidays. The main risk factor appears to be wild watercress ingestion (214) during recreational, weekend outings or holiday activities, explaining numerous family outbreaks involving 63 people and infection far away from their homes. Diagnosis mainly relied on egg finding (288), followed by serology (82), intradermal reaction (63), surgery (43), and erratic fluke observation (6). The number of fascioliasis-hydatidosis co-infected patients (14) is outstanding. Emetine appears as the drug most used (186), replaced by triclabendazole in recent years (21). Surgery reports are numerous (27.0%). A long delay in diagnosis (average almost 3.5 years) and high lithiasis proportion suggest that many patients are frequently overlooked and pose a question mark about fascioliasis detection in the country. High seroprevalences found in recent random surveys suggest human endemic situations. This analysis highlights that human fascioliasis may have been overlooked in the past and its real epidemiological situation in high risk rural, mainly altitudinal areas, may currently be underestimated. Results provide a valuable baseline on which to design appropriate multidisciplinary studies on humans, animals and lymnaeids to assess up to which level and in which areas, human fascioliasis may represent a health problem in Argentina. PMID- 21663692 TI - A comprehensive transcriptome and immune-gene repertoire of the lepidopteran model host Galleria mellonella. AB - BACKGROUND: The larvae of the greater wax moth Galleria mellonella are increasingly used (i) as mini-hosts to study pathogenesis and virulence factors of prominent bacterial and fungal human pathogens, (ii) as a whole-animal high throughput infection system for testing pathogen mutant libraries, and (iii) as a reliable host model to evaluate the efficacy of antibiotics against human pathogens. In order to compensate for the lack of genomic information in Galleria, we subjected the transcriptome of different developmental stages and immune-challenged larvae to next generation sequencing. RESULTS: We performed a Galleria transcriptome characterization on the Roche 454-FLX platform combined with traditional Sanger sequencing to obtain a comprehensive transcriptome. To maximize sequence diversity, we pooled RNA extracted from different developmental stages, larval tissues including hemocytes, and from immune-challenged larvae and normalized the cDNA pool. We generated a total of 789,105 pyrosequencing and 12,032 high-quality Sanger EST sequences which clustered into 18,690 contigs with an average length of 1,132 bases. Approximately 40% of the ESTs were significantly similar (E <= e-03) to proteins of other insects, of which 45% have a reported function. We identified a large number of genes encoding proteins with established functions in immunity related sensing of microbial signatures and signaling, as well as effector molecules such as antimicrobial peptides and inhibitors of microbial proteinases. In addition, we found genes known as mediators of melanization or contributing to stress responses. Using the transcriptomic data, we identified hemolymph peptides and proteins induced upon immune challenge by 2D-gelelectrophoresis combined with mass spectrometric analysis. CONCLUSION: Here, we have developed extensive transcriptomic resources for Galleria. The data obtained is rich in gene transcripts related to immunity, expanding remarkably our knowledge about immune and stress-inducible genes in Galleria and providing the complete sequences of genes whose primary structure have only partially been characterized using proteomic methods. The generated data provide for the first time access to the genetic architecture of immunity in this model host, allowing us to elucidate the molecular mechanisms underlying pathogen and parasite response and detailed analyses of both its immune responses against human pathogens, and its coevolution with entomopathogens. PMID- 21663693 TI - Reduced renal function is associated with progression to AIDS but not with overall mortality in HIV-infected Kenyan adults not initially requiring combination antiretroviral therapy. AB - BACKGROUND: The World Health Organization (WHO) has recently recommended that antiretrovirals be initiated in all individuals with CD4 counts of less than 350 cells/mm3. For countries with resources too limited to expand care to all such patients, it would be of value to able to identify and target populations at highest risk of HIV progression. Renal disease has been identified as a risk factor for disease progression or death in some populations. METHODS: Times to meeting combination antiretroviral therapy (cART) initiation criteria (developing either a CD4 count < 200 cells/mm3 or WHO stage 3 or 4 disease) and overall mortality were evaluated in cART-naive, HIV-infected Kenyan adults with CD4 cell counts >=200/mm3 and with WHO stage 1 or 2 disease. Cox proportional hazard regression models were used to evaluate the associations between renal function and these endpoints. RESULTS: We analyzed data of 7383 subjects with a median follow-up time of 59 (interquartile range, 27-97) weeks. In Cox regression analyses adjusted for age, sex, WHO disease stage, CD4 cell count and haemoglobin, estimated creatinine clearance (CrCl) < 60 mL/min was significantly associated with shorter times to meeting cART initiation criteria (HR 1.34; 95% CI, 1.23-1.52) and overall mortality (HR 1.73; 95% CI, 1.19-2.51) compared with CrCl >=60 mL/min. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 was associated with shorter times to meeting cART initiation criteria (HR 1.39; 95% CI, 1.22-1.58), but not with overall mortality. CrCl and eGFR remained associated with shorter times to cART initiation criteria, but neither was associated with mortality, in weight-adjusted analyses. CONCLUSIONS: In this large natural history study, reduced renal function was strongly associated with faster HIV disease progression in adult Kenyans not initially meeting cART initiation criteria. As such, renal function measurement in resource-limited settings may be an inexpensive method to identify those most in need of cART to prevent progression to AIDS. The initial association between reduced CrCl, but not reduced eGFR, and greater mortality was explained by the low weights in this population. PMID- 21663695 TI - Production of viable male unreduced gametes in Brassica interspecific hybrids is genotype specific and stimulated by cold temperatures. AB - BACKGROUND: Unreduced gametes (gametes with the somatic chromosome number) may provide a pathway for evolutionary speciation via allopolyploid formation. We evaluated the effect of genotype and temperature on male unreduced gamete formation in Brassica allotetraploids and their interspecific hybrids. The frequency of unreduced gametes post-meiosis was estimated in sporads from the frequency of dyads or giant tetrads, and in pollen from the frequency of viable giant pollen compared with viable normal pollen. Giant tetrads were twice the volume of normal tetrads, and presumably resulted from pre-meiotic doubling of chromosome number. Giant pollen was defined as pollen with more than 1.5 * normal diameter, under the assumption that the doubling of DNA content in unreduced gametes would approximately double the pollen cell volume. The effect of genotype was assessed in five B. napus, two B. carinata and one B. juncea parents and in 13 interspecific hybrid combinations. The effect of temperature was assessed in a subset of genotypes in hot (day/night 30 degrees C/20 degrees C), warm (25 degrees C/15 degrees C), cool (18 degrees C/13 degrees C) and cold (10 degrees C/5 degrees C) treatments. RESULTS: Based on estimates at the sporad stage, some interspecific hybrid genotypes produced unreduced gametes (range 0.06 to 3.29%) at more than an order of magnitude higher frequency than in the parents (range 0.00% to 0.11%). In nine hybrids that produced viable mature pollen, the frequency of viable giant pollen (range 0.2% to 33.5%) was much greater than in the parents (range 0.0% to 0.4%). Giant pollen, most likely formed from unreduced gametes, was more viable than normal pollen in hybrids. Two B. napus * B. carinata hybrids produced 9% and 23% unreduced gametes based on post-meiotic sporad observations in the cold temperature treatment, which was more than two orders of magnitude higher than in the parents. CONCLUSIONS: These results demonstrate that sources of unreduced gametes, required for the triploid bridge hypothesis of allopolyploid evolution, are readily available in some Brassica interspecific hybrid genotypes, especially at cold temperatures. PMID- 21663694 TI - Bone turnover in passive smoking female rat: relationships to change in bone mineral density. AB - BACKGROUND: Many studies have identified smoking as a risk factor for osteoporosis, but it is unclear whether passive smoking has an effect on bone mineral density and bone turnover and if such an effect could cause osteoporosis.The purpose of the study was to investigate the effect of passive smoking on bone mineral density (BMD) and bone turnover and the relationship between BMD and bone turnover in female rat. METHODS: Forty-eight female Wistar rats were randomized into six groups: 2-month, 3-month,4-month smoke-exposed rats and their controls. A rat model of passive cigarette smoking was prepared by breeding female rats in a cigarette-smoking box for 2, 3 or 4 months. Serums were analyzed for levels of osteocalcin, bone-specific alkaline phosphatase (b-ALP) and Tartrate-resistant acid phosphatase 5b (TRACP 5b). BMD was assessed at lumbar vertebrae and femur by dual energy X-ray absorptiometry in passive smoking rats and in control rats. RESULTS: BMD of lumbar spine and femur was lower in 4-month smoke-exposed female rats than that in controls. However, there was no significant difference in serum osteocalcin levels between smoke-exposed rats and controls. Significantly lower b-ALP and higher TRACP 5b were found in the 3-month or 4-month smoke-exposed rats compared to controls. Subsequent analysis showed that b-ALP positively correlated with BMD of the lumbar vertebrae(r = 0.764, P = 0.027) and femur(r = 0.899, P = 0.002) in 4-month smoke-exposed female rats. Furthermore, TRACP 5b levels negatively correlated with BMD of lumbar vertebrae (r = -0.871, P = 0.005) and femur (r = -0.715, P = 0.046) in 4-month smoke exposed female rats. CONCLUSION: Our data suggest that smoke exposure can inhibit bone formation and increase bone resorption. The hazardous effects of passive smoking on bone status are associated with increased bone turnover in female rat. PMID- 21663696 TI - Pragmatic randomised controlled trial of preferred intensity exercise in women living with depression. AB - BACKGROUND: Exercise may be effective in treating depression, but trials testing its effect in depressed women are rare. AIM: To compare the effect of exercise of preferred intensity with exercise of prescribed intensity in thirty-eight women living with depression. METHODS: A Pragmatic RCT of 12 sessions of exercise at preferred intensity compared with 12 sessions at prescribed intensity. Beck Depression Inventory (BDI), Rosenberg Self Esteem Scale (RSES), General Health Questionnaire 12 (GHQ-12), heart rate (HR), Rating of Perceived Exertion Scale (RPE), Quality of Life in Depression Scale (QLDS), Multi-Dimensional Scale of Perceived Social Support (MDSPSS), SF12 Health Survey and exercise participation rates were compared between groups. RESULTS: Intervention participants had statistically better BDI (t = 2.638, df = 36, p = 0.006, 95% mean (SD) 26.5 (10.7), CI-20.4 to -2.7, d = 0.86), GHQ-12 (t = 3.284, df = 36, p = 0.001, mean (SD) 8.3 (3.7) 95% CI -6.5 to -1.5, d = 1.08), RSES (t = 2.045, df = 36, p = 0.024, mean (SD) 11.3 (5.8), 95% CI 0.3 -6.4, d = 0.25), QLDS (t = 1.902, df = 36, p = 0.0325, mean (SD) 15.5 (7.9), 95% CI -12.2 -0.4, d = 0.27) RPE scores (t = 1.755, df = 36, p = 0.0475, mean (SD) 9.2 (3.2), 95% CI -.5 - 5.2, d = 0.77) and attended more exercise sessions (t = 1.781, df = 36, p = 0.0415, number of sessions 8 (65%), 95% CI-0.3 -4.8, d = 0.58). SF-12, MSPSS and HR did not differ significantly between groups. CONCLUSIONS: Exercise of preferred intensity improves psychological, physiological and social outcomes, and exercise participation rates in women living with depression. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00546221. PMID- 21663697 TI - A minor role of CD4+ T lymphocytes in the control of a primary infection of cattle with Mycoplasma mycoides subsp. mycoides. AB - Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides, is an important livestock disease in Africa. The current control measures rely on a vaccine with limited efficacy and occasional severe side effects. Knowledge of the protective arms of immunity involved in this disease will be beneficial for the development of an improved vaccine. In previous studies on cattle infected with M. mycoides subsp. mycoides, a correlation was detected between the levels of mycoplasma-specific IFN-gamma-secreting CD4+ T lymphocytes and reduced clinical signs. However, no cause and effect has been established, and the role of such cells and of protective responses acquired during a primary infection is not known.We investigated the role of CD4+ T lymphocytes in CBPP by comparing disease patterns and post mortem findings between CD4+ T cell depleted and non-depleted cattle. The depletion was carried out using several injections of BoCD4 specific murine monoclonal antibody on day 6 after experimental endotracheal infection with the strain Afade. All cattle were monitored clinically daily and sacrificed 28-30 days post-infection. Statistically significant but small differences were observed in the mortality rate between the depleted and non-depleted animals. However, no differences in clinical parameters (fever, signs of respiratory distress) and pathological lesions were observed, despite elimination of CD4+ T cells for more than a week. The slightly higher mortality in the depleted group suggests a minor role of CD4+ T cells in control of CBPP. PMID- 21663698 TI - Efficacy of a referral and physical activity program for survivors of prostate cancer [ENGAGE]: rationale and design for a cluster randomised controlled trial. AB - BACKGROUND: Despite evidence that physical activity improves the health and well being of prostate cancer survivors, many men do not engage in sufficient levels of activity. The primary aim of this study (ENGAGE) is to determine the efficacy of a referral and physical activity program among survivors of prostate cancer, in terms of increasing participation in physical activity. Secondary aims are to determine the effects of the physical activity program on psychological well being, quality of life and objective physical functioning. The influence of individual and environmental mediators on participation in physical activity will also be determined. METHODS/DESIGN: This study is a cluster randomised controlled trial. Clinicians of prostate cancer survivors will be randomised into either the intervention or control condition. Clinicians in the intervention condition will refer eligible patients (n=110) to participate in an exercise program, comprising 12 weeks of supervised exercise sessions and unsupervised physical activity. Clinicians allocated to the control condition will provide usual care to eligible patients (n=110), which does not involve the recommendation of the physical activity program. Participants will be assessed at baseline, 12 weeks, 6 months, and 12 months on physical activity, quality of life, anxiety, depression, self efficacy, outcome expectations, goals, and socio-structural factors. DISCUSSION: The findings of this study have implications for clinicians and patients with different cancer types or other chronic health conditions. It will contribute to our understanding on the potential impact of clinicians promoting physical activity to patients and the long term health benefits of participating in physical activity programs. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000609055Deakin University Human Research Ethics Approval 2011-085. PMID- 21663699 TI - Rapeseed oil fortified with micronutrients reduces atherosclerosis risk factors in rats fed a high-fat diet. AB - BACKGROUND: Micronutrients polyphenols, tocopherols and phytosterols in rapeseed exert potential benefit to cardiovascular system, but most of these micronutrients are removed by the refining process. The aim of this study was to determine the effect of rapeseed oil fortified with these micronutrients on the atherosclerosis risk factors in rats fed a high-fat diet. METHODS: The rodent diet contained 20% fat whose source was refined rapeseed oil (RRO) or fortified refined rapeseed oil with low, middle and high quantities of these micronutrients (L-, M- and H-FRRO). Forty male SD rats were divided into four groups. One group received RRO diet and other groups received L-, M- and H-FRRO diet for 10 weeks. RESULTS: Micronutrients supplementation significantly increased plasma antioxidant defense capacities, as evaluated by the significant elevation in the activities of GPx, CAT and SOD as well as the level of GSH, and the significant decline in lipid peroxidation. These micronutrients also reduced the plasma contents of TG, TC and LDL-C and increased the ratio of HDL-C/LDL-C. In addition, in parallel with the enhancement of these micronutrients, plasma levels of IL-6 and CRP declined remarkably. CONCLUSION: Rapeseed oil fortified with micronutrients polyphenols, tocopherols and phytosterols may contribute to prevent atherogenesis by ameliorating plasma oxidative stress, lipid profile and inflammation. PMID- 21663700 TI - PLCbeta1-SHP-2 complex, PLCbeta1 tyrosine dephosphorylation and SHP-2 phosphatase activity: a new part of Angiotensin II signaling? AB - BACKGROUND: Angiotensin II (Ang II) signaling occurs via two major receptors which activate non-receptor tyrosin kinases that then interact with protein tyrosin-phosphatases (PTPs) to regulate cell function. SHP-2 is one such important PTP that also functions as an adaptor to promote downstream signaling pathway. Its role in Ang II signaling remains to be clarified. RESULTS: Using cultured normal human fibroblasts, immunoprecipitation and western blots, we show for the first time that SHP-2 and PLCbeta1 are present as a preformed complex. Complex PLCbeta1 is tyr-phosphorylated basally and Ang II increased SHP-2 PLCbeta1 complexes and caused complex associated PLCbeta1 tyr-phosphorylation to decline while complex associated SHP-2's tyr-phosphorylation increased and did so via the Ang II type 1 receptors as shown by Ang II type 1 receptor blocker losartan's effects. Moreover, Ang II induced both increased complex phosphatase activity and decreased complex associated PLCbeta1 tyr-phosphorylation, the latter response required regulator of G protein signaling (RGS)-2. CONCLUSIONS: Ang II signals are shown for the first time to involve a preformed SHP-2-PLCbeta1 complex. Changes in the complex's PLCbeta1 tyr-phosphorylation and SHP-2's tyr phosphorylation as well as SHP-2-PLCbeta1 complex formation are the result of Ang II type 1 receptor activation with changes in complex associated PLCbeta1 tyr phosphorylation requiring RGS-2. These findings might significantly expand the number and complexity of Ang II signaling pathways. Further studies are needed to delineate the role/s of this complex in the Ang II signaling system. PMID- 21663701 TI - High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease. AB - BACKGROUND: The complexity of chronic diseases is a challenge for investigators conducting randomized trials. The causes for this include the often difficult control for confounding, the selection of outcomes from many potentially important outcomes, the risk of missing data with long follow-up and the detection of heterogeneity of treatment effects. Our aim was to assess such aspects of trial design and analysis for four prevalent chronic diseases. METHODS: We included 161 randomized trials on drug and non-drug treatments for chronic obstructive pulmonary disease, type 2 diabetes mellitus, stroke and heart failure, which were included in current Cochrane reviews. We assessed whether these trials defined a single outcome or several primary outcomes, statistically compared baseline characteristics to assess comparability of treatment groups, reported on between-group comparisons, and we also assessed how they handled missing data and whether appropriate methods for subgroups effects were used. RESULTS: We found that only 21% of all chronic disease trials had a single primary outcome, whereas 33% reported one or more primary outcomes. Two of the fifty-one trials that tested for statistical significance of baseline characteristics adjusted the comparison for a characteristic that was significantly different. Of the 161 trials, 10% reported a within-group comparison only; 17% (n = 28) of trials reported how missing data were handled (50% (n = 14) carried forward last values, 27% (n = 8) performed a complete case analysis, 13% (n = 4) used a fixed value imputation and 10% (n = 3) used more advanced methods); and 27% of trials performed a subgroup analysis but only 23% of them (n = 10) reported an interaction test. Drug trials, trials published after wide adoption of the CONSORT (CONsolidated Standards of Reporting Trials) statement (2001 or later) and trials in journals with higher impact factors were more likely to report on some of these aspects of trial design and analysis. CONCLUSION: Our survey showed that an alarmingly large proportion of chronic disease trials do not define a primary outcome, do not use appropriate methods for subgroup analyses, or use naive methods to handle missing data, if at all. As a consequence, biases are likely to be introduced in many trials on widely prescribed treatments for patients with chronic disease. PMID- 21663703 TI - Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance. AB - Dopamine is an important catecholamine neurotransmitter modulating many physiological functions, and is linked to psychopathology of many diseases such as schizophrenia and drug addiction. Dopamine D1 and D2 receptors are the most abundant dopaminergic receptors in the striatum, and although a clear segregation between the pathways expressing these two receptors has been reported in certain subregions, the presence of D1-D2 receptor heteromers within a unique subset of neurons, forming a novel signaling transducing functional entity has been shown. Recently, significant progress has been made in elucidating the signaling pathways activated by the D1-D2 receptor heteromer and their potential physiological relevance. PMID- 21663704 TI - Abstracts of the 15th International Conference on Human Retroviruses: HTLV and Related Viruses. Leuven and Gembloux, Belgium. June 5-8, 2011. PMID- 21663702 TI - Regulation of opioid receptor signalling: implications for the development of analgesic tolerance. AB - Opiate drugs are the most effective analgesics available but their clinical use is restricted by severe side effects. Some of these undesired actions appear after repeated administration and are related to adaptive changes directed at counteracting the consequences of sustained opioid receptor activation. Here we will discuss adaptations that contribute to the development of tolerance. The focus of the first part of the review is set on molecular mechanisms involved in the regulation of opioid receptor signalling in heterologous expression systems and neurons. In the second part we assess how adaptations that take place in vivo may contribute to analgesic tolerance developed during repeated opioid administration. PMID- 21663705 TI - Dystonia. AB - INTRODUCTION: Dystonia is usually a lifelong condition with persistent pain and disability. Focal dystonia affects a single part of the body; generalised dystonia can affect most or all of the body. It is more common in women, and some types of dystonia are more common in people of European Ashkenazi Jewish descent. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments, surgical treatments, and physical treatments for focal, and for generalised dystonia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 15 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholine release inhibitors (botulinum toxin), acupuncture, anticholinergic/antihistaminic drugs, anticonvulsants, atypical antipsychotic drugs, benzodiazepines, biofeedback, chiropractic manipulation, deep brain stimulation of thalamus and globus pallidus, dopaminergic agonists and antagonists, gamma-aminobutyric acid (GABA) analogues, microvascular decompression, muscle relaxants, myectomy, occupational therapy, osteopathy, pallidotomy, physiotherapy, selective peripheral denervation, serotonergic agonists and antagonists, speech therapy, and thalamotomy. PMID- 21663707 TI - Clusters of infectious diseases in German nursing homes: observations from a prospective infection surveillance study, October 2008 to August 2009. PMID- 21663708 TI - Emergence of carbapenemase-producing Enterobacteriaceae in France, 2004 to 2011. PMID- 21663709 TI - Hepatitis B prevention in Victoria, Australia: the potential to protect. PMID- 21663710 TI - Update on the ongoing outbreak of haemolytic uraemic syndrome due to Shiga toxin producing Escherichia coli (STEC) serotype O104, Germany, May 2011. PMID- 21663713 TI - Suggested guidelines for the practice of arthroscopic surgery. Committee on Ethics and Standards and the Board of Directors of the Arthroscopy Association of North America. PMID- 21663715 TI - Lower price high volume better outcome maximum efficiency minimally invasive: a developing model for health care delivery. PMID- 21663716 TI - We have to eliminate nonanatomic anterior cruciate ligament tunnel placement as a cause of osteoarthritis. PMID- 21663717 TI - Efficacy of augmenting a subacromial continuous-infusion pump with a preoperative interscalene block in outpatient arthroscopic shoulder surgery: a prospective, randomized, blinded, and placebo-controlled study. AB - PURPOSE: This study's purpose was to determine the effectiveness of adding a preoperative interscalene brachial plexus block to standard postoperative management, including oral narcotics and a subacromial bupivacaine infusion pump, after arthroscopic shoulder surgery. METHODS: After performing a prospective power analysis and obtaining institutional board approval, we conducted a randomized placebo-controlled trial of 53 patients separated into a preoperative interscalene brachial plexus group and a control group. Group 1 received an interscalene block with 30 mL of 0.5% ropivacaine. Group 2 received a placebo with 10 mL of saline solution. All patients postoperatively received an arthroscopically placed subacromial infusion pump catheter for 72 hours and oral narcotics. Pain scores on a visual analog scale (VAS) and narcotic pill use were recorded at 6, 12, 20, 32, 40, 52, 60, 72, and 80 hours. RESULTS: Preoperative pain scores between groups were not significant (P > .05). A statistically significant difference was found for decreased pain scores at 6 hours after discharge in patients receiving an interscalene block (P = .001) (VAS of 30.9 in group 1 v 61.8 in group 2). There was also a decrease in the number of narcotic pills taken at the 6-hour time interval (P = .1) (0.6 pills v 1.1 pills). Group 1 had a rebound phenomenon 20 hours after discharge. Pain scores spiked as the effects of the block wore off (P = .08) (net change in VAS score increase, 25.0 v 10.3). No other statistical or clinical differences were observed. CONCLUSIONS: The addition of a preoperative interscalene block to a postoperative subacromial infusion pump provided significant improvement of pain control only at 6 hours after discharge. Twelve hours after discharge, this benefit had disappeared. A rebound phenomenon of increased pain at 20 hours was seen after the interscalene block had worn off. After 20 hours, no statistically significant or clinically applicable differences were found. LEVEL OF EVIDENCE: Level I, randomized controlled trial. PMID- 21663718 TI - Is there an association between SLAP lesions and biceps pulley lesions? AB - PURPOSE: The purpose of this study was to evaluate the prevalence of SLAP and biceps reflection pulley lesions. The hypothesis was that these lesions do not occur concomitantly and they have a different etiology. METHODS: We prospectively analyzed 3,395 shoulder arthroscopies that were independently performed by 2 surgeons between 2004 and 2008 regarding the prevalence of SLAP and biceps pulley lesions. Intraoperative findings were correlated with patient history and clinical examination. Exclusion criteria were type I SLAP lesions, full-thickness rotator cuff tears, and a history of shoulder dislocation. RESULTS: This study included 182 patients with SLAP lesions (prevalence, 5.4%; 138 men; mean age, 47 years) and 87 patients with pulley lesions (prevalence, 2.6%; 63 men; mean age, 49 years). Isolated SLAP lesions were present in 157 cases, and isolated pulley lesions in 62 cases. The concomitant presence of a SLAP lesion and pulley lesion was significantly rare (10%, P = .003). In 55 (35%; 42 men [76%]; mean age, 43 years) of the cases with isolated SLAP lesions and 40 (65%; 27 men [68%]; mean age, 49 years) with isolated pulley lesions, there was a significant association with history of trauma (P < .01). Most SLAP lesions (32 [58%], P = .174 [not significant]) and most pulley lesions (28 [70%], P < .01) resulted from falling on the outstretched arm with external arm rotation in SLAP lesions and internal rotation in pulley lesions (P > .05). CONCLUSIONS: The concomitant presence of biceps tendon-associated lesions in the form of SLAP and pulley lesions is significantly rare. A history of falling on the abducted and externally rotated arm was typical in patients with SLAP lesions, whereas a fall on the arm with internal rotation was often noted in patients with pulley lesions. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 21663719 TI - Response to diagnostic injection in patients with femoroacetabular impingement, labral tears, chondral lesions, and extra-articular pathology. AB - PURPOSE: The purpose of this study was to compare the percent relief from injection among subjects with arthroscopic findings of femoroacetabular impingement (FAI) and labral and chondral pathologies while controlling for coexisting extra-articular pathology. METHODS: We retrospectively reviewed 72 consecutive subjects (54 female and 18 male subjects), aged 29.9 +/- 10.4 years (range, 16 to 55 years), who underwent hip arthroscopy. Three separate analyses of covariance compared the percent relief after injection between groups based on surgically confirmed type of impingement (none, cam, pincer, or combined), labral pathology (none, mild, or torn), and chondral pathology (none, mild acetabular abnormality, acetabular delamination, or femoral lesion) while controlling for the presence of extra-articular pathology (iliotibial band, iliopsoas tendinopathy, or bursitis). RESULTS: The results of analysis 1 (F3,67 = 1.96, P = .128, partial eta2 = .081) and analysis 2 (F2,68 = 0.008, P = .992, partial eta2 = .000) indicated no significant main effect for FAI and labral pathology, respectively, on percent relief from injection. The results for analysis 3 indicated a significant main effect for chondral pathology of the hip on the percent relief from injection (F3,67 = 3.03, P < .05, partial eta2 = .128). Post hoc analysis showed that those with mild chondral pathology of the acetabulum and those with acetabular delamination had significantly greater percent relief compared with those without chondral pathology. Extra-articular pathology did not influence the percent relief from injection in any of the analyses. CONCLUSIONS: Subjects with chondral damage had greater relief from injection than those without, regardless of severity. The presence and severity of FAI and labral pathology did not influence the percent relief from injection. Concurrent extra articular pathology did not alter the interpretation of the percent relief from injection. Therefore the interpretation and diagnostic value of an anesthetic injection in those with primary intra-articular pathology does not need to be altered by the presence of coexisting extra-articular hip pathology. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 21663720 TI - An anatomic arthroscopic description of the hip capsular ligaments for the hip arthroscopist. AB - PURPOSE: To examine and describe the normal anatomic intra-articular locations of the hip capsular ligaments in the central and peripheral compartments of the hip joint. METHODS: Eight paired fresh-frozen human cadaveric hips (mean age, 73.3 years) were carefully dissected free of soft tissue to expose the hip capsule. Needles were placed through the capsule along the macroscopic borders of the hip capsular ligaments. Arthroscopy was performed on each hip, and the relations of the needles, and thus the ligaments, to the arthroscopic portals and other soft tissue and osseous landmarks in the hip were recorded by use of a clock-face reference system. RESULTS: The iliofemoral ligament (ILFL) ran from 12:45 to 3 o'clock. The ILFL was pierced by the anterolateral and anterior portals just within its lateral and medial borders, respectively. The pubofemoral ligament was located from the 3:30 to the 5:30 clock position; the lateral border was at the psoas-U perimeter, and the medial border was at the junction of the anteroinferior acetabulum and the cotyloid fossa. The ischiofemoral ligament (ISFL) ran from the 7:45 to the 10:30 clock position. The posterolateral portal pierced the ISFL just inside its superior/lateral border, and the inferior/lateral border was located at the posteroinferior acetabulum. In the peripheral compartment the lateral ILFL and superior/lateral ISFL borders were in proximity to the lateral synovial fold. The medial ILFL and lateral pubofemoral ligament borders were closely approximated to the medial synovial fold. CONCLUSIONS: The hip capsular ligaments have distinct and consistent arthroscopic locations within the hip joint and are associated with clearly identifiable landmarks in the central and peripheral compartments. The standard hip arthroscopy portals are closely related to the borders of the hip capsular ligaments. CLINICAL RELEVANCE: These findings will help orthopaedic surgeons know which structures are being addressed during arthroscopic surgery and may help in the development of future hip procedures. PMID- 21663721 TI - High complication rate after biplanar open wedge high tibial osteotomy stabilized with a new spacer plate (Position HTO plate) without bone substitute. AB - PURPOSE: We performed a prospective clinical and radiographic evaluation after open wedge high tibial osteotomy (HTO) using the new Position HTO plate (Aesculap, Tuttlingen, Germany) without bone transplantation. METHODS: Thirty five open wedge HTOs with the Position HTO plate were performed without bone wedges. The mean patient age was 44.6 +/- 9.2 years at the time of osteotomy, which was planned with mediCAD II software (Hectec, Niederviehbach, Germany). The Hospital for Special Surgery score, Lysholm-Gillquist score, Tegner activity level, and International Knee Documentation Committee subjective score were used for clinical assessment. We evaluated radiographs obtained preoperatively and at 2, 6, and 12 months postoperatively using full-weight-bearing anteroposterior whole-leg views and anteroposterior and lateral views of the knee. For statistical analyses, JMP 8.0.1 (SAS, Cary, NC) was used. RESULTS: We observed an overall complication rate of 34% and a plate-related complication rate of 23%. Plate-related complications included loss of correction, fracture of the tibial plateau, screw failure, malunion, and fracture of the lateral cortical bone. A significant difference in the mechanical tibiofemoral angle of -1.3 degrees +/- 1.4 degrees (P < .001) was found between the follow-up at 2 and 6 months. The mean Hospital for Special Surgery score was 74.8 +/- 11.7 preoperatively, and it increased to 87.8 +/- 11.0 (P < .001). The mean score on the Lysholm-Gillquist knee functional scoring scale was 55.5 +/- 21.7 preoperatively, and it improved to 73.0 +/- 23.9 (P < .001). The Tegner activity level was 2.6 +/- 0.9 preoperatively, and it improved significantly at final follow-up to 3.7 +/- 1.8 (P < .02). The International Knee Documentation Committee subjective score was 43.0 +/- 14.9 preoperatively, and it increased to 66.1 +/- 21 (P < .001). CONCLUSIONS: We have shown a high plate-related complication rate and a significant loss of correction between 2 and 6 months of follow-up after open wedge HTO using the new Position HTO plate without bone wedges. The preoperatively planned mechanical tibiofemoral angle was not achieved. Despite these complications, the clinical outcome improved significantly. The Position HTO plate cannot be recommended with the presented technique. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 21663722 TI - Anterior cruciate ligament reconstruction using patellar tendon versus hamstring tendon: a prospective comparative study with 9-year follow-up. AB - PURPOSE: To analyze the long-term evaluation of clinical, functional, and magnetic resonance imaging (MRI) results after implant-free press-fit anterior cruciate ligament (ACL) reconstruction with bone-patella tendon (BPT) versus quadrupled hamstring tendon (HT) grafts. METHODS: Sixty-two ACL-insufficient patients were included in a prospective, randomized study (31 BPT and 31 HT). Both surgical procedures were performed without any implants by a press-fit technique by the senior author. The femoral tunnel was drilled through the anteromedial portal for anatomic placement. At 8.8 years after reconstruction, 53 patients (28 BPT and 25 HT) were examined by different clinical and functional tests. Bilateral MRI scans were performed and interpreted by an independent radiologist. RESULTS: On follow-up, the score on the International Knee Documentation Committee evaluation form was significantly better in the HT group. The clinical examination including range of motion, KT-1000 test (MEDmetric, San Diego, CA), and pivot-shift test showed no significant differences. On isokinetic testing, the mean quadriceps strength was close to normal (96%) in both groups, but the hamstring strength was lower in the HT group (100.3%/95.1%). Kneeling (1.5/1.1, P = .002), knee walking (1.72/1.14, P = .002), and single-leg hop test (95.8%/99.1%, P = .057) were better in the HT group. The MRI findings about the mean degree of cartilage lesion (International Cartilage Repair Society protocol) of the operated (2.1/2.1) and nonoperated (1.4/1.8) knee showed no significant differences. No significant difference was found in the grade of medial or lateral meniscal lesion or the number of patients having meniscal lesions when the operated and nonoperated knees were compared. Tunnel measurements, Caton Deschamps Index, and the sagittal ACL angle were similar. CONCLUSIONS: The implant-free press-fit technique for anterior cruciate ligament reconstruction by use of bone-patellar tendon and hamstring grafts with anatomic graft placement is an innovative technique to preserve the cartilage and meniscal status without significant differences between the operated and nonoperated knees in the long term. Significantly less anterior knee pain was noted in the hamstring group, when testing for kneeling and knee walking. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 21663723 TI - A biomechanical comparison of 2 femoral fixation techniques for anterior cruciate ligament reconstruction in skeletally immature patients: over-the-top fixation versus transphyseal technique. AB - PURPOSE: The purpose of this study was to compare knee kinematics and in situ forces of the graft between 2 femoral fixation techniques of anterior cruciate ligament (ACL) reconstruction: the over-the-top (OTT) fixation and transphyseal (TP) techniques. METHODS: ACL reconstruction in skeletally immature patients is a challenging procedure. Regarding the femoral fixation techniques, 2 methods are commonly used: the OTT fixation and TP techniques. Ten cadaveric knees (mean age, 57 years; range, 48 to 65 years) were tested with the robotic/universal force moment sensor system by use of (1) an 89-N anterior tibial load at full extension and 15 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion and (2) a combined 7-Nm valgus torque and 5-Nm internal tibial rotation torque at 15 degrees and 30 degrees of knee flexion. RESULTS: Both OTT and TP ACL reconstruction techniques closely restored the intact knee kinematics and had a significant reduction in anterior tibial translation under an anterior tibial load and in coupled anterior tibial translation under a combined rotatory load when compared with an ACL-deficient knee. When both ACL reconstruction techniques were compared, the only difference found was that the in situ force of the ACL graft reconstructed with the OTT technique in response to a combined rotatory load at 30 degrees of flexion was significantly lower than the ACL graft reconstructed with the TP technique (5.3 +/- 3.3 N and 10.7 +/- 6.0 N, respectively; P = .013). CONCLUSIONS: This time 0 testing showed that both ACL reconstruction techniques, OTT and TP, can reproduce the kinematics of the intact knee in response to an anterior tibial load and a combined rotatory load. CLINICAL RELEVANCE: Both femoral fixation techniques exhibited comparable time 0 kinematics when subjected to simulated clinical examination loading conditions. PMID- 21663724 TI - Failure of operative treatment for glenohumeral instability: etiology and management. AB - Failure of primary shoulder stabilization procedures is often related to uncorrected anatomic pathology. Orthopaedic surgeons must recognize excessive capsular laxity or large glenohumeral bone defects preoperatively to avoid recurrence of instability. When history, physical examination, and radiographic evaluation are used in conjunction, patients at risk for failure can be identified. The instability severity index score permits precise identification of patients at risk. When treating patients in whom prior surgical intervention has failed, the success of revision procedures correlates to the surgeon's ability to identify the essential pathology and use lesion-specific treatment strategies. Revision procedures remain technically demanding. Keen preoperative and intraoperative judgment is required to avoid additional recurrence of instability after revision procedures, particularly because results deteriorate with each successive operation. Glenoid or humeral defects with greater than 25% bone loss compromise stability provided through the mechanism of concavity compression. These defects must be specifically addressed to avoid recurrence of instability. We prefer anatomic reconstruction techniques combined with capsulolabral repair and, if bone defects are present, anatomic reconstruction with osteochondral allograft. PMID- 21663725 TI - The use of radiofrequency energy for arthroscopic chondroplasty in the knee. AB - We present a review of the current literature surrounding the use of radiofrequency energy for arthroscopic chondroplasty in the knee. This review article summarizes basic science, clinical efficacy, and recent advances in the understanding of radiofrequency energy use for the treatment of chondral lesions. Laboratory evidence of increased mechanical stability and decreased release of inflammatory mediators associated with the use of radiofrequency energy chondroplasty is described with clinical evidence of decreased pain and increased functional scores when compared with mechanical chondroplasty. We re-examine concerns about the immediate side effects of radiofrequency energy use, including damage to local structures, in light of new potentially contradictory results, as well as the progression of techniques and probe design. However, although reported complications are few, because the quality of clinical evidence about safety and efficacy remains low, we suggest cautious and judicious use of this technology until future research has clearly defined the long-term clinical outcomes and risks. PMID- 21663726 TI - All-inside anterior cruciate ligament graft-link technique: second-generation, no incision anterior cruciate ligament reconstruction. AB - We describe an anatomic, single-bundle, all-inside anterior cruciate ligament (ACL) graft-link technique using second-generation Flipcutter guide pins (Arthrex, Naples, FL), which become retrograde drills, and second-generation cortical suspensory fixation devices with adjustable graft loop length: femoral TightRope (Arthrex) and tibial ACL TightRope-Reverse Tension (Arthrex). The technique is minimally invasive using only four 4-mm stab incisions. Graft choice is no-incision allograft or gracilis-sparing, posteriorly harvested semitendinosus material. The graft is sutured 4 times through each strand in a loop and linked, like a chain, to femoral and tibial adjustable TightRope graft loops. With this method, graft tension can be increased even after graft fixation. The technique may be modified for double-bundle ACL reconstruction. PMID- 21663727 TI - Tibial plateau fracture after primary anatomic double-bundle anterior cruciate ligament reconstruction: a case report. AB - Tibial plateau fracture after primary anatomic double-bundle anterior cruciate ligament (ACL) reconstruction is rare. To our knowledge, this is the first case report of a tibial plateau fracture after primary anatomic double-bundle ACL reconstruction. In our patient the tibial plateau fracture occurred after a torsional injury to the involved extremity. The fracture occurred 4.5 years after the ACL reconstruction. The fracture was intra-articular Schatzker type IV and had a significant displacement. The patient was treated operatively by open reduction-internal fixation. He recovered well. PMID- 21663729 TI - MMP-9 activity is induced by Leishmania braziliensis infection and correlates with mucosal leishmaniasis. AB - Infection of humans with Leishmania braziliensis typically results in localized cutaneous leishmaniasis (LCL). Rarely, after months or years of apparent clinical cure, some patients develop the destructive mucosal leishmaniasis (ML). ML results from L. braziliensis dissemination, probably via phagocytic cells. As the preferred cells for Leishmania spp. colonization, macrophages are critical to infection control, and may contribute to parasite dissemination. However, the host factors that determine this outcome are unknown. Matrix metalloproteinase 9 (MMP-9) is known to be important for immune cell migration, macrophage recruitment, and effective granuloma formation. Moreover, MMP-9 has been involved in Mycobacterium tuberculosis dissemination. Here, we demonstrate that in vitro infection of human macrophages with L. braziliensis increased the secretion and activation of MMP-9. We also demonstrate that macrophages from healthy cured individuals with previous history of ML had increased MMP-9 activity compared to LCL cured individuals. These findings may represent a fundamental difference in host innate immunity that could contribute to the clinical leishmaniasis presentation. PMID- 21663730 TI - Monomeric RC-LH1 core complexes retard LH2 assembly and intracytoplasmic membrane formation in PufX-minus mutants of Rhodobacter sphaeroides. AB - In the model photosynthetic bacterium Rhodobacter sphaeroides domains of light harvesting 2 (LH2) complexes surround and interconnect dimeric reaction centre light-harvesting 1-PufX (RC-LH1-PufX) 'core' complexes, forming extensive networks for energy transfer and trapping. These complexes are housed in spherical intracytoplasmic membranes (ICMs), which are assembled in a stepwise process where biosynthesis of core complexes tends to dominate the early stages of membrane invagination. The kinetics of LH2 assembly were measured in PufX mutants that assemble monomeric core complexes, as a consequence of either a twelve-residue N-terminal truncation of PufX (PufXDelta12) or the complete removal of PufX (PufX(-)). Lower rates of LH2 assembly and retarded maturation of membrane invagination were observed for the larger and less curved ICM from the PufX(-) mutant, consistent with the proposition that local membrane curvature, initiated by arrays of bent RC-LH1-PufX dimers, creates a favourable environment for stable assembly of LH2 complexes. Transmission electron microscopy and high resolution atomic force microscopy were used to examine ICM morphology and membrane protein organisation in these mutants. Some partitioning of core and LH2 complexes was observed in PufX(-) membranes, resulting in locally ordered clusters of monomeric RC-LH1 complexes. The distribution of core and LH2 complexes in the three types of membrane examined is consistent with previous models of membrane curvature and domain formation (Frese et al., 2008), which demonstrated that a combination of crowding and asymmetries in sizes and shapes of membrane protein complexes drives membrane organisation. PMID- 21663731 TI - Selective permeabilization of lipid membranes by photodynamic action via formation of hydrophobic defects or pre-pores. AB - To gain insight into mechanisms of photodynamic modification of biological membranes, we studied an impact of visible light in combination with a photosensitizer on translocation of various substances across artificial (vesicular and planar) bilayer lipid membranes (BLMs). Along with induction of carboxyfluorescein leakage from liposomes, pronounced stimulation of lipid flip flop between the two monolayers was found after photosensitization, both processes being prevented by the singlet oxygen quencher sodium azide. On the contrary, no enhancement of potassium chloride efflux from liposomes was detected by conductometry under these conditions. Illumination of planar BLMs in the presence of a photosensitizer led to a marked increase in membrane permeability to amphiphilic 2-n-octylmalonic acid, but practically no change in the permeability to ammonia, which agreed with selective character of the photosensitized leakage of fluorescent dyes from liposomes (Pashkovskaya et al., Langmuir, 2010). Thus, the effect on transbilayer movement of molecules elicited by the photodynamic treatment substantially depended on the kind of translocated species, in particular, on their lipophilicity. Based on similarity with results of previous electroporation studies, we hypothesized about photodynamic induction of "pre-pores" or "hydrophobic defects" permeable to amphiphilic compounds and less permeable to hydrophilic substances and inorganic ions. PMID- 21663732 TI - Involvement of TRP channels in the signal transduction of bradykinin in human osteoblasts. AB - Bradykinin (BK), a mediator of pain and inflammation, is involved in bone metabolism. We have previously reported that BK increased the synthesis of interleukin-6 and prostaglandin E(2) via phosphorylation of ERK1/2 in human osteoblasts, SaM-1. In the present study, we investigated the signal transduction pathway of BK focusing on intracellular Ca(2+) kinetics in SaM-1 cells. Bath applied BK increased intracellular Ca(2+) concentration through the activation of B(2) receptors. Removal of extracellular Ca(2+) attenuated the effects of BK. Additionally, thapsigargin, endoplasmic reticulum Ca(2+) pump inhibitor, completely inhibited BK-induced increase of intracellular Ca(2+). These results suggested that bath-applied BK activated store-operated Ca(2+) channels (SOCCs) following Ca(2+) store depletion via B(2) receptor. Although the molecular components of SOCCs have yet to be conclusively identified in all cell types, recent studies demonstrated that transient receptor potential canonical (TRPC) channels are candidates for them. TRPC1, TRPC3, TRPC4 and TRPC6 were expressed in SaM-1 cells and inhibitors of TRP channel, 2-aminoethoxydiphenyl borate, GdCl(3), LaCl(3) and flufenamic acid, inhibited the effects of BK. These findings suggested that BK activated SOCCs and induced Ca(2+) influx via B(2) receptor in human osteoblasts. Molecular components of the SOCCs are suggested to be TRPC channels. PMID- 21663733 TI - Paradoxical facilitation of exocytosis by inhibition of L-type calcium channels of bovine chromaffin cells. AB - Ca(2+) entry through the L-subtype (alpha(1D), Ca(v)1,3) of voltage-dependent calcium channels (VDCCs) seems to selectively regulate the endocytotic response after the application of a single depolarizing pulse to voltage-clamped bovine chromaffin cells. Here we have found that L channel blockade with nifedipine transformed the exocytotic responses elicited by a double-pulse protocol, from depression to facilitation. This apparent paradoxical effect was mimicked by pharmacological interventions that directly block endocytosis namely, dynasore, calmidazolium, GTP-gammaS and GDP-betaS. This reinforces our view that Ca(2+) entry through PQ channels (alpha(1A); Ca(v)2.1) regulates fast exocytosis while Ca(2+) entry through L channels preferentially controls rapid endocytosis. PMID- 21663734 TI - Piperine ameliorates the severity of cerulein-induced acute pancreatitis by inhibiting the activation of mitogen activated protein kinases. AB - Piperine is a phenolic component of black pepper (Piper nigrum) and long pepper (Piper longum), fruits used in traditional Asian medicine. Our previous study showed that piperine inhibits lipopolysaccharide-induced inflammatory responses. In this study, we investigated whether piperine reduces the severity of cerulein induced acute pancreatitis (AP). Administration of piperine reduced histologic damage and myeloperoxidase (MPO) activity in the pancreas and ameliorated many of the examined laboratory parameters, including the pancreatic weight (PW) to body weight (BW) ratio, as well as serum levels of amylase and lipase and trypsin activity. Furthermore, piperine pretreatment reduced the production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 during cerulein induced AP. In accordance with in vivo results, piperine reduced cell death, amylase and lipase activity, and cytokine production in isolated cerulein-treated pancreatic acinar cells. In addition, piperine inhibited the activation of mitogen-activated protein kinases (MAPKs). These findings suggest that the anti inflammatory effect of piperine in cerulein-induced AP is mediated by inhibiting the activation of MAPKs. Thus, piperine may have a protective effect against AP. PMID- 21663735 TI - Klotho KL-VS genotype is involved in blood pressure regulation. AB - BACKGROUND AND AIMS: Genome-wide linkage analysis studies reported the importance of the long arm of chromosome 13 in systolic blood pressure regulation. Therefore, isolating a genetic variant related to this chromosomal region could be challenging. Klotho KL-VS allele is located on this chromosomal region and its relationships with cardio-vascular risk factors need extensive investigations. The aim of the present study is to examine whether the klotho KL-VS genotype is associated with cardio-vascular risk factors, more particularly hypertension, in two independent cohorts. A secondary objective was to investigate relationships with antihypertensive treatment, arterial stiffness and carotid artery parameters. METHODS AND RESULTS: A total of 1023 French individuals were genotyped for klotho KL-VS. Participants were part of the French ERA and STANISLAS cohorts. In both cohorts, klotho KL-VS/KL-VS genotype was significantly associated with lower systolic blood pressure and pulse pressure when compared to homozygous and heterozygous more frequent (WT) allele carriers (p=0.003 and p<0.001 respectively). Antihypertensive treatment stratification confirmed the previous significant associations, while a significant interaction between klotho KL-VS genotype and antihypertensive treatment was also interestingly found (0.019 for p interaction). CONCLUSION: Klotho KL-VS/KL-VS genotype may be associated with decreased cardio-vascular risk and may interact with antihypertensive treatment in order to reduce blood pressure. This finding could lead to identify subgroups of hypertensive adults who might benefit antihypertensive drug therapies. PMID- 21663736 TI - WT1 regulates epicardial epithelial to mesenchymal transition through beta catenin and retinoic acid signaling pathways. AB - An epithelial sheet, the epicardium, lines the surface of the heart. In the developing embryo, the epicardium expresses the transcriptional regulator Wilm's Tumor Gene 1 (Wt1). Through incompletely understood mechanisms, Wt1 inactivation derails normal heart development. We investigated mechanisms by which Wt1 regulates heart development and epicardial epithelial to mesenchymal transition (EMT). We used genetic lineage tracing approaches to track and isolate epicardium and epicardium derivatives in hearts lacking Wt1 (Wt1(KO)). Wt1(KO) hearts had diminished proliferation of compact myocardium and impaired coronary plexus formation. Wt1(KO) epicardium failed to undergo EMT. Wt1(KO) epicardium expressed reduced Lef1 and Ctnnb1 (beta-catenin), key components of the canonical Wnt/beta catenin signaling pathway. Wt1(KO) epicardium expressed decreased levels of canonical Wnt downstream targets Axin2, Cyclin D1, and Cyclin D2 and exhibited decreased activity of the Batgal Wnt/beta-catenin reporter transgene, suggestive of diminished canonical Wnt signaling. Hearts with epicardium-restricted Ctnnb1 loss of function resembled Wt1(KO) hearts and also failed to undergo epicardial EMT. However, Ctnnb1 inactivation did not alter WT1 expression, positioning Wt1 upstream of canonical Wnt/beta-catenin signaling. Wnt5a, a prototypic non canonical Wnt with enriched epicardial expression, and Raldh2, a key regulator of retinoic acid signaling confined to the epicardium, were also markedly downregulated in Wt1(KO) epicardium. Hearts lacking Wnt5a or Raldh2 shared phenotypic features with Wt1(KO). Although Wt1 has been proposed to regulate EMT by repressing E-cadherin, we detected no change in E-cadherin in Wt1(KO) epicardium. Collectively, our study shows that Wt1 regulates epicardial EMT and heart development through canonical Wnt, non-canonical Wnt, and retinoic acid signaling pathways. PMID- 21663737 TI - Carvedilol inhibits Kir2.3 channels by interference with PIP2-channel interaction. AB - Carvedilol, a beta- and alpha-adrenoceptor blocker, is used to treat congestive heart failure, mild to moderate hypertension, and myocardial infarction. It has been proposed to block K(ATP) channels by binding to the bundle crossing region at a domain including cysteine at position 166, and thereby plugging the pore region. However, carvedilol was reported not to affect Kir2.1 channels, which lack 166 Cys. Here, we demonstrate that carvedilol inhibits Kir2.3 carried current by an alternative mechanism. Carvedilol inhibited Kir2.3 channels with at least 100 fold higher potency (IC(50)=0.49 MUM) compared to that for Kir2.1 (IC(50)>50 MUM). Kir2.3 channel inhibition was concentration-dependent and voltage-independent. Increasing Kir2.3 channel affinity for PIP(2), by a I213L point mutation, decreased the inhibitory effect of carvedilol more than twentyfold (IC(50)=11.1 MUM). In the presence of exogenous PIP(2), Kir2.3 channel inhibition by carvedilol was strongly reduced (80 vs. 2% current inhibition). These results suggest that carvedilol, as other cationic amphiphilic drugs, inhibits Kir2.3 channels by interfering with the PIP(2)-channel interaction. PMID- 21663738 TI - Agonist-dependent effects of mutations in the sphingosine-1-phosphate type 1 receptor. AB - The sphingosine-1-phosphate type 1 (S1P(1)) receptor is a new target in the treatment of auto-immune diseases as evidenced by the recent approval of FTY720 (Fingolimod). The ligand-binding pocket of the S1P(1) receptor has been generally characterised but detailed insight into ligand-specific differences is still lacking. The aim of the current study is to determine differences in ligand induced S1P(1) receptor activation using an in silico guided site-directed mutagenesis strategy. S1P(1) mutant receptors (modifications of residues Y98(2.57), R120(3.28), F125(3.33)) were probed with a chemically diverse set of S1P(1) agonists (S1P, dihydro-S1P (dhS1P), R-, S- and racemic FTY720-P, VPC24191, SEW2871). Mutation of the R(3.28) residue generally results in a reduction of the potency of all ligands although the synthetic ligands including FTY720-P are less sensitive to these mutations. The Y(2.57)F mutation does not affect the potency of any of the ligands tested, but for all ligands except FTY720-P a significant decrease in potency is observed at the Y(2.57)A mutant. The F(3.33)A mutation significantly decreased the potency of FTY720-P and is detrimental for SEW2871 and VPC24191. The non-aromatic endogenous ligands S1P and dhS1P are less affected by this mutation. Our in silico guided mutagenesis studies identified new molecular determinants of ligand-induced S1P(1) receptor activation: 1) the flexibility of the polar head of the agonist to maintain a tight H-bond network with R(3.28) and 2) the ability of the agonist to make aromatic pi-stacking interactions with F(3.33). Interestingly, FTY720-P has both chemical properties and is the only ligand that can efficiently activate the Y(2.57)A mutant. PMID- 21663739 TI - beta(2)-Adrenergic activity of 6-methoxykaempferol-3-O-glucoside on rat uterus: in vitro and in silico studies. AB - 6-Methoxykaempferol-3-O-glucoside (6-MKG) was isolated from a Sudanese herb (El hazha). The pharmacological effects of 6-MKG were tested on isolated non-pregnant or late-pregnant rat uteri in vitro, whilst docking studies were carried out modelling of the binding of 6-MKG to the rat beta(2)-adrenoceptor in silico. In vitro studies revealed that 6-MKG was able to relax both the non-pregnant and the late-pregnant uterine contractility with 50% of the E(max) of terbutaline, whilst the EC(50) for 6-MKG was at least half than that of terbutaline. The beta(2) adrenoceptors antagonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2 ol(ICI118,551) competitively antagonised the relaxing effect of 6-MKG. Radioligand binding and cAMP studies confirmed the beta(2)-adrenoceptors agonistic property of the compound. In in silico docking studies, 6-MKG bound to rat beta(2)-adrenoceptors with low ?G(bind) value (-11.53+/-0.06 kcal/mol) and it interacted with four residues of the active site (Asp(113), Asn(312), Cys(191)and Tyr(316)). It is concluded that 6-MKG exerts weak beta(2)-adrenoceptor agonistic activity and can be considered a natural compound with potential therapeutic significance in the field of premature pregnant uterine contractions and asthmatic problems. PMID- 21663740 TI - Cytotrienin A, a translation inhibitor that induces ectodomain shedding of TNF receptor 1 via activation of ERK and p38 MAP kinase. AB - Cytotrienin A, a member of the triene-ansamycin family, was initially identified to be an inducer of apoptosis and recently shown to be an inhibitor of translation that interferes with eukaryotic elongation factor 1A function. In human lung carcinoma A549 cells, cytotrienin A was found to inhibit more strongly the cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor (TNF)-alpha than the expression induced by interleukin (IL)-1alpha. Cytotrienin A induced the ectodomain shedding of TNF receptor 1 by TNF-alpha-converting enzyme (TACE). The TACE inhibitor TAPI-2 antagonized the selective inhibitory effect of cytotrienin A on inhibitor of nuclear factor kappaB-alpha (IkappaBalpha) degradation as well as ICAM-1 expression in TNF-alpha stimulated cells. The MEK inhibitor U0126 and the p38 MAP kinase inhibitor SB203580, but not the JNK inhibitor SP600125, prevented the ectodomain shedding of TNF receptor 1 induced by cytotrienin A and reversed the inhibitory effects of cytotrienin A on the TNF-alpha-induced IkappaBalpha degradation. In the presence of both U0126 and SB203580, cytotrienin A inhibited TNF-alpha- and IL-1alpha induced ICAM-1 expression at almost equivalent concentrations. Thus, our present results demonstrate that cytotrienin A is a translation inhibitor that triggers ribotoxic stress response and selectively inhibits the TNF-alpha-induced ICAM-1 expression by inducing the ectodomain shedding of TNF receptor 1 via the activation of ERK and p38 MAP kinase. PMID- 21663741 TI - Impairment of protein trafficking by direct interaction of gliadin peptides with actin. AB - Intestinal celiac disease (CD) is triggered by peptic-tryptic digest of gluten, known as Frazer's Fraction (FF), in genetically predisposed individuals. Here, we investigate the immediate effects of FF on the actin cytoskeleton and the subsequent trafficking of actin-dependent and actin-independent proteins in COS-1 cells. Morphological alterations in the actin filaments were revealed concomitant with a drastic reduction in immunoprecipitated actin from cells incubated with FF. These alterations elicit impaired protein trafficking of intestinal sucrase isomaltase, a glycoprotein that follows an actin-dependent vesicular transport to the cell surface. However, the actin-independent transport of intestinal lactase phlorizin hydrolase remains unaffected. Moreover, the morphological alteration in actin is induced by direct interaction of this protein with gliadin peptides carrying the QQQPFP epitope revealed by co-immunoprecipitation utilizing a monoclonal anti-gliadin antibody. Finally, stimulation of cells with FF directly influences the binding of actin to Arp2. Altogether, our data demonstrate that FF directly interacts with actin and alters the integrity of the actin cytoskeleton thus leading to an impaired trafficking of intestinal proteins that depend on an intact actin network. This direct interaction could be related to the endocytic segregation of gliadin peptides as well as the delayed endocytic vesicle trafficking and maturation in gliadin-positive intestinal epithelial cells and opens new insights into the pathogenesis of CD. PMID- 21663742 TI - Tissue-specific promoter methylation and histone modification regulate CYP19 gene expression during folliculogenesis and luteinization in buffalo ovary. AB - Aromatase, the key enzyme of estrogen biosynthesis, is encoded by the CYP19 gene. The expression of CYP19 gene is regulated in species- and tissue-specific manner by alternate use of different promoters. We have previously, cloned and characterized the tissue-specific promoter and tissue-specific transcripts in preovulatory (granulosa cells) and postovulatory (corpus luteum) structure of buffalo ovary. The present study was aimed to understand if epigenetic gene regulation through DNA methylation and histone modifications is involved in tissue-specific CYP19 gene regulation during folliculogenesis and luteinization in buffalo ovary. Methylation analysis of five CpG dinucleotides of ovary specific proximal promoter II showed hypo-methylation in large follicle while hyper-methylation in corpus luteum. However, PI.1, the exclusive promoter responsible for residual CYP19 gene expression in corpus luteum, was found to be hypermethylated. Analysis of histone modifications using ChIP assay revealed that the distal promoter (PI.1) of CYP19 gene is ~40-fold more enriched with acetylated Histone H3 in corpus luteum than in the large follicle. This indicates that PI.1 chromatin was more accessible for transcription in corpus luteum as compared to large follicles. The chromatin accessibility for the proximal promoter (PII) in the preovulatory stage tends to be higher than the luteal tissue. However, the difference was not found to be significant. In vitro experiments showed the similar results. In conclusion, results of the present study suggests that tissue-specific methylation status of PII and chromatin remodeling through histone modifications of PI.1, coincides with the changes in expression of CYP19 gene and thus are the regulatory mechanism controlling its tissue-specific expression and promoter activity during folliculogenesis and luteinization. PMID- 21663743 TI - Differential regulation of the luteinizing hormone genes in teleosts and tetrapods due to their distinct genomic environments--insights into gonadotropin beta subunit evolution. AB - The pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are essential for the control of vertebrate reproduction. Although the molecular structures of these two hormones are well conserved from teleosts to mammals, some studies report differences in their regulatory mechanisms of gene expression between teleosts and tetrapods. In the present study, we examined the molecular evolution of the gonadotropin gene loci in vertebrates and found that there is a syntenic conservation among the teleost fshb and tetrapod fshb and lhb loci. However, the teleost lhb locus has no syntenic homology to either tetrapod lhb or teleost fshb; this fact suggests that an extensive genome-wide rearrangement of the lhb locus, caused by an accelerated genome evolution speed after the third round of genome-wide duplication, occurred in the teleost lineage. We subsequently demonstrated by double labeling in situ hybridization using a teleost medaka that the fshb and lhb genes in teleosts are expressed in completely separate cellular populations in the pituitary, which is different in tetrapods. Furthermore, the expression analysis in ovariectomized and steroid treated medaka revealed that, under breeding conditions, the expression of the medaka LHbeta was down-regulated by ovariectomy and recovered by treatment with gonadal steroids; this result is also completely opposite in mammals, where the steroids have negative-feedback effects on LHbeta expression. We suggest that these differences between teleosts and mammals in the cellular expression pattern and dynamic expressional changes of the lhb gene are the result of the drastic changes in the genomic environment of the lhb gene that occurred early in teleost evolution. PMID- 21663744 TI - Female tail wagging enhances sexual performance in male goats. AB - Preference testing has shown that sexually experienced male goats choose females that are tail wagging, a behavior that may function as both attractivity and proceptivity, over those that are not. We hypothesized that exposure to females expressing high rates of tail wagging would arouse males, increasing sexual performance. Tail wagging rate could be manipulated because we have shown previously that flutamide treatment increases the frequency of tail wagging in estrous goats. Sexually experienced males observed different stimuli for 10 min before a 20 min sexual performance test (SPT). The stimuli were an empty pen (MT), or groups of three females that were all estrous (E), non-estrous (NE), estrous+flutamide (E(F)) or non-estrous+flutamide (NE(F)). During the stimulus observation period, tail wagging was recorded. During SPT, frequencies and latencies of sexual behaviors were recorded. E(F) females displayed the most tail wagging. Viewing E(F) females before SPT increased the number of ejaculations attained by males and decreased the latencies to first and second ejaculation, as well as the inter-ejaculatory interval. Viewing estrous females (E and E(F)) before SPT decreased the latency to first mount, as compared to non-estrous females (NE and NE(F)). We conclude that male goats are sexually aroused by tail wagging. This study and previous work demonstrate that tail wagging functions as both attractivity and proceptivity in goats. PMID- 21663745 TI - A concerted mechanism for opening the GDP binding pocket and release of the nucleotide in hetero-trimeric G-proteins. AB - G-protein hetero-trimers play a fundamental role in cell function. Their dynamic behavior at the atomic level remains to be understood. We have studied the Gi hetero-trimer through a combination of molecular dynamics simulations and normal mode analyses. We showed that these big proteins could undergo large-amplitude conformational changes, without any energy penalty and with an intrinsic dynamics centered on their GDP binding pocket. Among the computed collective motions, one of the modes (mode 17) was particularly able to significantly open both the base and the phosphate sides of the GDP binding pocket. This mode describing mainly a motion between the Ras-like and the helical domains of G(alpha) was in close agreement with some available X-ray data and with many other biochemical/biophysical observations including the kink of helix alpha5. The use of a new protocol, which allows extraction of the GDP ligand along the computed normal modes, supported that the exit of GDP was largely coupled to an opening motion along mode 17. We propose for the first time a "concerted mechanism" model in which the opening of the GDP pocket and the kink of the alpha5 helix occur concomitantly and favor GDP release from G(alphabetagamma) complexes. This model is discussed in the context of the G-protein-coupled receptor/G-protein interaction close to the cell membrane. PMID- 21663746 TI - Nascent peptide side chains induce rearrangements in distinct locations of the ribosomal tunnel. AB - Although we have numerous structures of ribosomes, none disclose side-chain rearrangements of the nascent peptide during chain elongation. This study reports for the first time that rearrangement of the peptide and/or tunnel occurs in distinct regions of the tunnel and is directed by the unique primary sequence of each nascent peptide. In the tunnel mid-region, the accessibility of an introduced cysteine to a series of novel hydrophilic maleimide reagents increases with increasing volume of the adjacent chain residue, a sensitivity not manifest at the constriction and exit port. This surprising result reveals molecular movements not yet resolvable from structural studies. These findings map solvent accessible volumes along the tunnel and provide novel insights critical to our understanding of allosteric communication within the ribosomal tunnel, translational arrest, chaperone interaction, folding, and rates of elongation. PMID- 21663747 TI - Crystallographic snapshots of the complete catalytic cycle of the unregulated aspartate transcarbamoylase from Bacillus subtilis. AB - Here, we report high-resolution X-ray structures of Bacillus subtilis aspartate transcarbamoylase (ATCase), an enzyme that catalyzes one of the first reactions in pyrimidine nucleotide biosynthesis. Structures of the enzyme have been determined in the absence of ligands, in the presence of the substrate carbamoyl phosphate, and in the presence of the bisubstrate/transition state analog N phosphonacetyl-L-aspartate. Combining the structural data with in silico docking and electrostatic calculations, we have been able to visualize each step in the catalytic cycle of ATCase, from the ordered binding of the substrates, to the formation and decomposition of the tetrahedral intermediate, to the ordered release of the products from the active site. Analysis of the conformational changes associated with these steps provides a rationale for the lack of cooperativity in trimeric ATCases that do not possess regulatory subunits. PMID- 21663748 TI - Evolutionary connections between coding and splicing regulatory regions in the fibronectin EDA exon. AB - Research on exonic coding sequences has demonstrated that many substitutions at the amino acid level may also reflect profound changes at the level of splicing regulatory regions. These results have revealed that, for many alternatively spliced exons, there is considerable pressure to strike a balance between two different and sometimes conflicting forces: the drive to improve the quality and production efficiency of proteins and the maintenance of proper exon recognition by the splicing machinery. Up to now, the systems used to investigate these connections have mostly focused on short alternatively spliced exons that contain a high density of splicing regulatory elements. Although this is obviously a desirable feature in order to maximize the chances of spotting connections, it also complicates the process of drawing straightforward evolutionary pathways between different species (because of the numerous alternative pathways through which the same end point can be achieved). The alternatively spliced fibronectin extra domain A exon (also referred to as EDI or EIIIA) does not have these limitations, as its inclusion is already known to depend on a single exonic splicing enhancer element within its sequence. In this study, we have compared the rat and human fibronectin EDA exons with regard to RNA structure, exonic splicing enhancer strengths, and SR protein occupancy. The results gained from these analyses have then been used to perform an accurate evaluation of EDA sequences observed in a wide range of animal species. This comparison strongly suggests the existence of an evolutionary connection between changes at the nucleotide levels and the need to maintain efficient EDA recognition in different species. PMID- 21663749 TI - Self-regulation in tip-growth: the role of cell wall ageing. AB - We develop a model to describe the effect of cell wall ageing on the local expansion rate of tip-growing cells. Starting from an exact equation for the stationary age-distribution of the wall material, we propose a generic measure for the local expansion propensity of the wall if the ageing process is described by a constant rate Poissonian decay process. This ageing process may be either interpreted as biochemical in nature describing the finite lifetime of regulatory proteins, or as mechanical in nature describing the gradual "hardening" of the wall through cross-linking or gelation of the wall polymers. In this way we can construct models for tip-growth in which material deposition, evolving wall properties and surface expansion are self-consistently intertwined. As a proof of principle, we implement our ageing approach in two different idealised models of tip-growth, obtaining the stationary tip shapes as a function of the ageing parameter. In the first, the spatial distribution of delivery of growth material is determined by the local curvature of the cell and the growth mode is orthogonal. In the second, the growth material originates from a Vesicle Supply Center, a point-like representation of the Spitzenkorper as found in fungal hyphae, and the growth mode is isometric. PMID- 21663750 TI - An individual-based approach to SIR epidemics in contact networks. AB - Many approaches have recently been proposed to model the spread of epidemics on networks. For instance, the Susceptible/Infected/Recovered (SIR) compartmental model has successfully been applied to different types of diseases that spread out among humans and animals. When this model is applied on a contact network, the centrality characteristics of the network plays an important role in the spreading process. However, current approaches only consider an aggregate representation of the network structure, which can result in inaccurate analysis. In this paper, we propose a new individual-based SIR approach, which considers the whole description of the network structure. The individual-based approach is built on a continuous time Markov chain, and it is capable of evaluating the state probability for every individual in the network. Through mathematical analysis, we rigorously confirm the existence of an epidemic threshold below which an epidemic does not propagate in the network. We also show that the epidemic threshold is inversely proportional to the maximum eigenvalue of the network. Additionally, we study the role of the whole spectrum of the network, and determine the relationship between the maximum number of infected individuals and the set of eigenvalues and eigenvectors. To validate our approach, we analytically study the deviation with respect to the continuous time Markov chain model, and we show that the new approach is accurate for a large range of infection strength. Furthermore, we compare the new approach with the well-known heterogeneous mean field approach in the literature. Ultimately, we support our theoretical results through extensive numerical evaluations and Monte Carlo simulations. PMID- 21663751 TI - Micro-encapsulated secretory leukocyte protease inhibitor decreases cell-mediated immune response in autoimmune orchitis. AB - AIMS: We previously reported that recombinant human Secretory Leukocyte Protease Inhibitor (SLPI) inhibits mitogen-induced proliferation of human peripheral blood mononuclear cells. To determine the relevance of this effect in vivo, we investigated the immuno-regulatory role of SLPI in an experimental autoimmune orchitis (EAO) model. MAIN METHODS: In order to increase SLPI half life, poly epsilon-caprolactone microspheres containing SLPI were prepared and used for in vitro and in vivo experiments. Multifocal orchitis was induced in Sprague-Dawley adult rats by active immunization with testis homogenate and adjuvants. Microspheres containing SLPI (SLPI group) or vehicle (control group) were administered s.c. to rats during or after the immunization period. KEY FINDINGS: In vitro SLPI-release microspheres inhibited rat lymphocyte proliferation and retained trypsin inhibitory activity. A significant decrease in EAO incidence was observed in the SLPI group (37.5%) versus the control group (93%). Also, SLPI treatment significantly reduced severity of the disease (mean EAO score: control, 6.33+/-0.81; SLPI, 2.72+/-1.05). In vivo delayed-type hypersensitivity and ex vivo proliferative response to testicular antigens were reduced by SLPI treatment compared to control group (p<0.05). SIGNIFICANCE: Our results highlight the in vivo immunosuppressive effect of released SLPI from microspheres which suggests its feasible therapeutic use. PMID- 21663752 TI - Differential effects of amisulpride and haloperidol on dopamine D2 receptor mediated signaling in SH-SY5Y cells. AB - Dopamine D(2) receptors (D(2)R) are the primary target of antipsychotic drugs and have been shown to regulate Akt/glycogen synthase kinase-3beta (GSK-3beta) signaling through scaffolding protein beta-arrestin 2. Amisulpride, an atypical antipsychotic drug, and haloperidol, a typical antipsychotic drug, are both potent D(2)R antagonists, but their therapeutic effects differ. In the present study, we compared the effects of amisulpride and haloperidol on the beta arrestin 2-mediated Akt/GSK-3beta pathway in SH-SY5Y cells. To determine whether these drugs affected neuronal morphology in SH-SY5Y cells, we investigated the effects of amisulpride and haloperidol on neurite outgrowth using immunostaining. We examined the effects of these drugs on Akt and GSK-3beta and its well-known downstream regulators, cAMP response element-binding protein (CREB), brain derived neurotrophic factor (BDNF), and Bcl-2 levels using Western blot analysis. Amisulpride, but not haloperidol, was found to enhance neurite outgrowth. Small interfering RNA (siRNA) for beta-arrestin 2 knockdown blocked the increase in amisulpride-induced neurite outgrowth. Furthermore, amisulpride increased the levels of Akt and GSK-3beta phosphorylation, while haloperidol had no effect. The elevation of Akt phosphorylation induced by amisulpride was reduced by beta arrestin 2 siRNA. Moreover, amisulpride effectively increased the levels of phospho-CREB, BDNF, and Bcl-2. However, haloperidol had no effect on the levels of these proteins. Additionally, wortmannin, a phosphatidylinositol 3-kinase (PI3 K) inhibitor, blocked the stimulatory effect of amisulpride on phosphorylated Akt. Together, these results suggest that regulation of the beta-arrestin 2 dependent pathway via blockade of the D(2)R in SH-SY5Y cells is one mechanism underlying the neuroprotective effect of amisulpride, but not haloperidol. PMID- 21663754 TI - Longevity. The allostatic load of dietary restriction. AB - Restriction of food intake by 10-50% of ad libitum on a per unit of weight or energy content basis can extend the lifespan of a wide variety of species and prevent or delay age-related disease. This review first briefly summarizes the data delineating mortality trajectories of various species' populations maintained on restricted diets to provide insight into the effects of nutrient deprivation on distinct components of the aging process. Next, I discuss a number of important studies that have addressed the question whether it is the lack of calories and/or specific nutrients that determines the longevity response to dietary restriction. Finally, I review the evidence for hormesis as a proximate mechanism underpinning the impact of dietary restriction on lifespan. In aggregate, the currently available demographic data suggest that dietary restriction can both slow the age-related progressive accumulation of cellular damage and also enhance the ability of organisms to cope with irreversible injury. Restriction of essential nutrients as well as calories may affect life expectancy, perhaps in a species specific fashion. Hormesis, i.e. an evolutionary conserved stress response routine providing protection against a wide variety of (other) hazards in response to low levels of stress, is very likely to contribute to the beneficial health effects of dietary restriction. PMID- 21663755 TI - Analysis of head position used by myopes and emmetropes when performing a near vision reading task. AB - The aim of the study was to compare head posture in young, adult emmetropes and corrected myopes during a reading task. Thirty-two (32) myopes (mean spherical equivalent: -3.46+/-2.35 D) and 22 emmetropes (mean spherical equivalent: -0.03+/ 0.36 D) participated in the study. Of the myopes, 16 were progressing (rate of progression ?-0.5D over the previous 2 years), 12 were stable (changes of -0.25 D or less over 2 years) and four could not be classified. Seated subjects were asked to read a text binocularly in their habitual posture. To measure head posture, two simultaneous images were recorded from different directions. In a separate study with the same subjects and conditions, a motion monitor was used to track head posture for 1 min. The habitual reading distance was measured in both studies, together with the stereoscopic acuity and fixation disparity for each subject. The results of the photographic study showed no significant differences in head posture or reading distance between the myopic and emmetropic groups (p>0.05) but there was some evidence that downward pitch angles were greater in progressing myopes than in non-progressing myopes (p=0.03). No correlations were observed between the binocular parameters and head posture. Reading distances were systematically shorter with the helmet-mounted eye tracker and it was concluded that posture was affected by the weight of the equipment. With this reservation, it appeared that the rate of change of downward pitch angle over the 1-min recording session increased with the subject's rate of myopia progression (correlation between myopia progression and slope of pitch: r(2)=-0.69, p=0.001), implying a greater reliance on head movements when reading down a page. Overall, while no differences in mean head posture were found between myopes and emmetropes, there was some evidence that head posture and movement during reading may differ in progressing myopes. PMID- 21663753 TI - Prism adaptation differently affects motor-intentional and perceptual-attentional biases in healthy individuals. AB - Prism adaptation (PA) has been shown to affect performance on a variety of spatial tasks in healthy individuals and neglect patients. However, little is still known about the mechanisms through which PA affects spatial cognition. In the present study we tested the effect of PA on the perceptual-attentional "where" and motor-intentional "aiming" spatial systems in healthy individuals. Eighty-four participants performed a line bisection task presented on a computer screen under normal or right-left reversed viewing conditions, which allows for the fractionation of "where" and "aiming" bias components (Schwartz et al., 1997). The task was performed before and after a short period of visuomotor adaptation either to left- or right-shifting prisms, or control goggles fitted with plain glass lenses. Participants demonstrated initial leftward "where" and "aiming" biases, consistent with previous research. Adaptation to left-shifting prisms reduced the leftward motor-intentional "aiming" bias. By contrast, the "aiming" bias was unaffected by adaptation to the right-shifting prisms or control goggles. The leftward "where" bias was also reduced, but this reduction was independent of the direction of the prismatic shift. These results mirror recent findings in neglect patients, who showed a selective amelioration of right motor-intentional "aiming" bias after right prism exposure (Fortis et al., 2009; C.L. Striemer & J. Danckert, 2010). Thus, these findings indicate that prism adaptation primarily affects the motor-intentional "aiming" system in both healthy individuals and neglect patients, and further suggest that improvement in neglect patients after PA may be related to changes in the aiming spatial system. PMID- 21663756 TI - Structural and functional characterization of pseudopodocyte, a shaggy immune cell produced by two Drosophila species of the obscura group. AB - We recently reported that most of the Drosophila species of the obscura group were unable to mount cellular capsules and no lamellocyte was ever found in the hemolymph of any of the tested species. Only three species were able to encapsulate, despite lacking lamellocytes. Their encapsulation ability was always associated with the presence of an unpreviously described kind of capsule-forming immunocytes designated as "atypical hemocytes". Here, we describe the ultrastructural and functional characteristics of this type of hemocyte. We show that these cells share many ultrastructural and morphological features with Drosophila melanogaster plasmatocytes, although they are involved in the formation of the external layers of the cellular capsule, a functional property exhibited by lamellocytes in D. melanogaster. Due to the high number of pseudopodes in these cells, we suggest to name them "pseudopodocytes". After structural and functional characterization of these atypical hemocytes, their ambiguous status between plasmatocytes and lamellocytes is discussed. PMID- 21663757 TI - Identification of a lineage negative cell population in bovine peripheral blood with the ability to mount a strong type I interferon response. AB - Lineage negative dendritic cells, or natural interferon-producing cells (NIPC), also referred to as plasmacytoid dendritic cells (pDC) constitute a small population of leukocytes secreting high levels of type I interferon (IFNalpha/beta) in response to certain danger signals. Here, we provide initial data towards the identification of so far uncharacterised circulating bovine pDC like cells. A lineage negative cell population (LIN(-) cells) was isolated from PBMC which showed characteristics similar to that of pDC in other species. Isolated LIN(-) cells presented lymphoid morphology with a semi-crescent nucleus, extensive ER and Golgi network; indicative of pDC. In addition phenotypic analysis of LIN(-) cells described them as distinct from other bovine DC subsets; expressing both lymphoid and myeloid surface markers. LIN(-) cells did not express lineage specific markers, but were MHC class II(+), CD45RO(+), CD80/86(+), CD6(+), WC1(+), CD26(+) and expressed the myeloid markers CD205, CD172a and CD11a. In keeping with pDC, LIN(-) cells express TLR7 mRNA transcripts; however, in a resting state do not express TLR8 or TLR9. Functionally, LIN(-) cells, but not PBMC, monocytes and monocyte derived DC produce large amounts of IFNalpha/beta in response to different CpG oligonucleotides. Taken together, we present data suggesting that an enriched circulating population of bovine LIN(-) cells are uniquely capable of producing IFNalpha/beta in response to CpG oligonucleotides and thus this population likely contain the functional equivalent of bovine pDC. PMID- 21663758 TI - Bioinformatic and molecular characterization of beta-defensins-like peptides isolated from the green lizard Anolis carolinensis. AB - The high resistance of lizards to infections indicates that anti-microbial peptides may be involved. Through the analysis of the green lizard (Anolis carolinensis) genome and the expressed sequence tag (EST) libraries 32 beta defensin-like-peptides have been identified. The level of expression of some of these genes in different tissues has been determined by semi-quantitative RT-PCR. Gene expression and structure analysis suggest the presence of alternative splicing mechanisms, with a number of exons ranging from two to four, similar to that for beta-defensins genes in mammals. Lizard beta-defensin-like peptides present the characteristic cysteine-motif identified in mammalian and avian beta defensins. Phylogenetic analysis indicates that some lizard beta-defensins-like peptides are related to crotamine and crotamin-like peptides of snakes and lizards suggesting that beta-defensins and venomous peptides have a common ancestor gene. PMID- 21663759 TI - Evolution of the thioester-containing proteins (TEPs) of the arthropoda, revealed by molecular cloning of TEP genes from a spider, Hasarius adansoni. AB - The thioester-containing protein (TEP) family of genes, found in most Eumetazoan genomes, is classified into two subfamilies: the alpha-2-macroglobulin (A2M) subfamily and the C3 subfamily. Many A2M subfamily members, including insect TEP (iTEP), have been reported from the Arthropoda, whereas the C3 subfamily members have been reported only from two horseshoe crab species thus far. To elucidate the evolution of these genes among the Arthropoda, TEP genes were isolated from a spider, Hasarius adansoni (Chelicerata), by reverse transcription polymerase chain reaction (RT-PCR) amplification using universal degenerate primers specific for the thioester region. Four different TEP genes were identified. Phylogenetic analysis using the entire amino acid sequences of these and various other TEP sequences from the Eumetazoa indicated that two of the spider genes are type C3 (HaadC3-1 and HaadC3-2), one is type A2M (HaadA2M) and the other is closely related to iTEP (HaadiTEP). These results suggest that the common ancestor of the Arthropoda possessed at least three TEP genes, C3, A2M and iTEP and that they were lost differentially in the Crustacean and Hexapodan lineages. PMID- 21663760 TI - Heterogeneous nuclear ribonucleoprotein hrp36 acts as an alternative splicing repressor in Litopenaeus vannamei Dscam. AB - Heterogeneous nuclear ribonucleoproteins (hnRNPs) are highly conserved from nematode to mammal because they play an important role in several aspects of pre mRNA maturation, including RNA packaging and alternative splicing. In Drosophila, the hnRNP A1 homolog hrp36 regulates alternative splicing in several genes, including the Down syndrome cell adhesion molecule (Dscam), which produces tens of thousands of isoforms from one locus. In this study, the first hrp36 gene was identified and characterized from Litopenaeus vannamei (Lvhrp36). Its open reading frame (ORF) contains 1101 bp encoding 366 amino acids. The deduced Lvhrp36 protein includes two copies of the RNA recognition motif (RRM), a C terminal glycine-rich domain (GRD), the highly degenerate RNP consensus sequences RNP-1 and RNP-2, and two RGG boxes. Tissue tropism analysis indicated that Lvhrp36 is expressed ubiquitously and at high levels in most tissues. dsRNA silencing of shrimp Lvhrp36 in vivo induced abnormal exon inclusions in LvDscam, especially in the Ig3 variable region. In the Ig3 region, a total of 14 different combinations were arranged in three different types of abnormal inclusion pattern. This compares to a single combination (one abnormal pattern) in Ig2 and three different combinations (one abnormal pattern) in Ig7. This is the first evidence to suggest that hrp36 may be involved in the regulation of the Ig7 variable region, and it is noteworthy because, at least in Drosophila, there are no hrp36 binding sequences in the Ig7 exon cluster. The above aberrant events were not observed in all of the Lvhrp36-silenced shrimp, and even when they occurred, the normal patterns of inclusion were far more common. We hypothesize that this continued prevalence of normal inclusions was probably due to other unsilenced proteins that were able to rescue Lvhrp36's functionality. Taken together, our results suggest that Lvhrp36 acts as a splicing repressor that regulates alternative splicing events in the Ig2, Ig3 and Ig7 variable regions of shrimp L. vannamei Dscam. PMID- 21663761 TI - Kinetics of the avian influenza-specific humoral responses in lung are indicative of local antibody production. AB - The role and kinetics of respiratory immunoglobulins in AIV infection has not been investigated. In this study we determined the numbers of both total antibody secreting cells (ASC) and virus-specific ASC in lung, spleen, blood and bone marrow (BM) following low-pathogenic AIV infection. Antiviral humoral immune responses were induced both locally in the lung and systemically in the spleen. Responses in the lung and BM preceded responses in the spleen and in blood, with virus-specific IgY ASC already detected in lung and BM from 1 week post-primary inoculation, indicating that respiratory immune responses are not induced in the spleen, but locally in the lung. ASC present in the blood of the lungs and co isolated during lymphocyte isolation from the lungs have no major impact on the ASC detected in the lungs based on statistical correlation. PMID- 21663762 TI - Comparison of BACTECTM plus Aerobic/F and VersaTREK REDOX((r)) blood culture media for the recovery of Staphylococcus aureus from patients with suspected persistent bacteremia. PMID- 21663763 TI - Rapid influenza A detection and quantitation in birds using a one-step real-time reverse transcriptase PCR and High Resolution Melting. AB - Efficient influenza A viral surveillance of wild and domestic birds requires rapid viral detection and quantitation of high and low quality samples. Current influenza A qPCR-based detection protocols specified by CDC, OIE and USDA utilize fluorogenic hydrolysis probe based real-time reverse transcription PCR (RRT-PCR) assays for detection and quantitation. The sequence diversity of this virus, even in the conserved matrix gene M1, makes primer and probe designs challenging. In this report it was determined that false RRT-PCR positives are possible with this method. This is particularly problematic when surveying non-cultured or inactivated avian tracheal and cloacal mucosal samples with low concentrations of virus and large proportions of background nucleic acids. This report presents a modification of a one-step RRT-PCR detection method for influenza A using SYBR green intercalating dye-based target amplification detection. High Resolution Melting (HRM), amplicon size quantitation and sequence verification is used to screen for non-target amplification (false positives). The resulting protocol has the sensitivity of hydrolysis probe methods, allows for flexible primer design and verification of target amplification, and provides high confidence in positive results. A multiplex subtype detection method using the RRT-PCR HRM assay is also demonstrated. Overall, this method is both time and cost effective while providing an extra measure of confidence in surveillance results through the implementation of target verification. PMID- 21663764 TI - Evaluation of a fluorogenic real-time reverse transcription-polymerase chain reaction method for the specific detection of all known serotypes of porcine teschoviruses. AB - Performance of a real-time reverse-transcription polymerase chain reaction method for the rapid, simple and reliable detection of porcine teschovirus (PTV) was assessed. The method was based on the use of a set of oligonucleotides consisting of two specific primers and a fluorogenic TaqMan-MGB probe. Reverse transcription and PCR reactions were performed sequentially in one step. As a result the whole procedure was simple and rapid, taking less than 3h for completion. The method reacted in a dose-dependent manner with prototype strains for the eleven known PTV serotypes (PTV1-11), with higher analytical sensitivity than other gel-based RT-PCR methods described, which were performed in parallel to allow for a comparison. The assay did not cross-react with other related viruses or porcine viruses tested. The diagnostic performance of the method was analyzed using a panel of field samples consisting of pig fecal and pig slurry samples. As a conclusion, this technique is adequate and convenient for porcine teschovirus detection, both for diagnosis as well as in environmental investigations. PMID- 21663765 TI - Rapid discrimination of Tomato chlorosis virus, Tomato infectious chlorosis virus and co-amplification of plant internal control using real-time RT-PCR. AB - Tomato chlorosis virus (ToCV) and Tomato infectious chlorosis virus (TICV) (genus: Crinivirus, family: Closteroviridae) are two emergent whitefly transmitted viruses that have been associated with yellowing symptoms of tomato crops during the last two decades. A real-time, one-step reverse transcription (RT) TaqMan((r)) polymerase chain reaction (PCR) assay was developed and optimized for the multiplex detection of TICV, ToCV and an internal control of mitochondrion cytochrome oxidase subunit I (mtCOXI) gene from plants. The plant mtCOXI assay can be used as an internal control in at least 77 plant species from 28 different families. The one-step RT TaqMan PCR assay successfully detected and discriminated the two virus species in infected tomato plants, other host plants and their whitefly vectors. In direct comparison, the assay was approximately 10,000-fold and 100-fold more sensitive than conventional one-step RT-PCR and two step nested RT-PCR, respectively. The increased sensitivity allowed the use of alternative template preparation methods that do not require RNA purification. The assay can be performed either by the direct addition of crude plant extract into the real-time reaction mixture or alternatively, the sap extract can be blotted on a positively charged nylon membrane, eluted and added in the reaction mixture. The developed assay allows the simple, fast and cost-effective testing of a large number of samples and can be easily applied in surveys and certification schemes. PMID- 21663766 TI - Enhanced detection of infectious airborne influenza virus. AB - Current screening methodologies for detecting infectious airborne influenza virus are limited and lack sensitivity. To increase the sensitivity for detecting infectious influenza virus in an aerosol sample, the viral replication assay was developed. With this assay, influenza virus is first amplified by replication in Madin-Darby canine kidney (MDCK) cells followed by detection with quantitative PCR (qPCR). Spanning a 20-h replication period, matrix gene expression levels from infectious virus were measured at several time points using qPCR and found to exponentially increase. Compared with the traditional culture-based viral plaque assay, the viral replication assay resulted in a 4.6 * 10(5) fold increase in influenza virus detection. Furthermore, viral replication assay results were obtained in half the time of the viral plaque assay. To demonstrate that the viral replication assay is capable of detecting airborne influenza virus, dilute preparations of strain A/WS/33 were loaded into a nebulizer, aerosolized within a calm-air settling chamber and subsequently collected using NIOSH Two-Stage Bioaerosol Samplers. At the most diluted concentration corresponding to a chicken embryo infectious dose 50% endpoint (CEID(50)) of 2.8E+02/ml, the viral replication assay was able to detect infectious influenza virus that was otherwise undetectable by viral plaque assay. The results obtained demonstrate that the viral replication assay is highly sensitive at detecting infectious influenza virus from aerosol samples. PMID- 21663767 TI - Development and preliminary application of an immunochromatographic strip for rapid detection of infection with porcine reproductive and respiratory syndrome virus in swine. AB - A "strip test" to detect porcine reproductive and respiratory syndrome virus (PRRSV) was established using a monoclonal antibody (MAb) 2D7 conjugated with colloidal gold. Two MAbs binding to protein N at different epitopes, 2D7 and 1G7 were obtained. In the test, samples of PRRSV bound to colloidal gold-conjugated MAb 2D7. The complex was then captured by MAb 1G7 at the test line (T) on the nitrocellulose membrane, presenting a purple band. If the sample did not contain PRRSV or if the quantity of PRRSV was less than that required for the kit, only the control line (C), in which goat anti-mouse antibody was added as the capture antibody, was present. Results from the sensitivity test of the kit demonstrated that the lowest detected quantity of PRRSV is 2.9 * 10(3)TCID(50)/ml. In clinical trials, the specificity and the sensitivity of this kit are 98.1% and 88.4%, respectively, compared with RT-PCR. Furthermore, this kit was found to be efficient in three areas of China and appears to have better results in practical applications than in empirical studies. In summary, this kit has not only high rates of specificity and sensitivity but also has the beneficial features such as efficiency, convenience and speed. PMID- 21663768 TI - Transmission of HIV drug resistance and non-B subtype distribution in the Spanish cohort of antiretroviral treatment naive HIV-infected individuals (CoRIS). AB - CoRIS is an open multicentre cohort of HIV seroprevalent ARV-naive subjects who began treatment at 32 Spanish healthcare centres from January 2004. Up to November 2008, a total of 683 FASTA format sequences, encoding the HIV protease and reverse transcriptase (RT) derived from plasma samples at entry into the cohort, had been obtained for examination of transmitted drug resistance (TDR) and HIV clade. TDR was found in 8.5% of the patients (4.4% NRTIs, 4% NNRTIs, 2.2% PIs). The most prevalent resistance mutations were: T215 revertants (3.8%), D67NG (1.3%), K219QENR (1.2%) and M41L (1%), for NRTIs; K103N (3.2%), for NNRTIs; I54VLMSAT, M46I and L90M (0.7%), for PIs. Non-B subtypes were recognized in 104 patients (15.2%) and were more common in Sub-Saharan Africans (15/17, 88.2%), Eastern Europeans (7/12, 58.3%) and Northern Africans (8/16, 50%) than among Spaniards (53/479, 11%) (p<0.001). The most prevalent non-B subtype was CRF02_AG (4.4%), followed by subtype D (1.9%), CRF03_AB (1.5%), CRF07_BC and subtype F1 (1%). A trend was observed for the transmission of non-B subtypes to increase and for TDR to decrease. PMID- 21663769 TI - Physico-mechanical characterisation of cells using atomic force microscopy - Current research and methodologies. AB - Atomic force microscopy (AFM) is a technique that has long been employed in materials science, but is now increasingly being used in the biological sciences. AFM provides excellent topographical information on prokaryotic and eukaryotic cell surfaces, and the extracellular material produced by the cells. It helps to generate important data on the mechanical properties of cells, such as hardness and elasticity. AFM can also be used to measure the strength of adhesion, attraction, and repulsion forces between cells and surfaces or even between individual molecules. Additionally, by combining AFM with other complementary techniques such as fluorescence microscopy or Raman spectroscopy, the chemistry of given surface structures can be identified. This review aims to provide an update on the AFM techniques currently used in cell biology studies, along with a description of the range of recently developed research methodologies in which AFM plays a key role. PMID- 21663770 TI - Rapid detection of "highly virulent" Group B Streptococcus ST-17 and emerging ST 1 clones by MALDI-TOF mass spectrometry. AB - MALDI-TOF MS identified a 6250-Da protein specific to Sequence Type-1 (ST-1) strains and a 7625-Da protein specific to ST-17 strains when used for identification of Group B streptococci. The strains of these STs are major causes of meningitis and late-onset-disease in neonates. This rapid method of identification could thus be valuable in the evaluation of risk of neonatal diseases. PMID- 21663771 TI - Survey of bromodeoxyuridine uptake among environmental bacteria and variation in uptake rates in a taxonomically diverse set of bacterial isolates. AB - Incorporation of 5-Bromo-2'-Deoxyuridine (BrdU) into DNA can be used to target replicating bacteria in the environment, but differential uptake capacity is a potential bias. Among 23 bacterial isolates commonly found in soils, most took up BrdU, but at up to 10-fold different cell-specific rates. Combined with results from an in silico analysis of 1000 BrdU-labeled 16S rRNA gene sequences, our results demonstrate a BrdU uptake bias with no apparent relationship between taxa affiliation and ability to incorporate BrdU. PMID- 21663772 TI - Spatial memory deficits and oxidative stress damage following exposure to lipopolysaccharide in a rodent model of Parkinson's disease. AB - Stimulation of the immune system has been found to enhance, impair, or have no effect on various memory tasks. In the present study, male Wistar rats received saline, lipopolysaccharide (LPS, 250MUg/kg in saline, 7 consecutive days), intranigral 6-hydroxydopamine (6-OHDA, 2MUg/MUl saline; 5MUl/site) and intranigral 6-OHDA plus 7 consecutive days of LPS injections and then tested in two cognitive tasks (Y-maze and radial arm-maze). Altered behavioral responses in Y-maze and radial arm-maze tasks were observed in LPS- and LPS+6-OHDA-treated rats compared to control group. Notably, positive correlations were detected among LPS and LPS+6-OHDA-treated rats when behavioral deficits were correlated with indicators of oxidative stress. Taken together, we demonstrated that activation of the immune system with LPS administration induced memory impairment and brain oxidative stress, significantly correlated with nigral lesion promoted by 6-OHDA. PMID- 21663773 TI - Stem cells and growth factor delivery systems for cardiovascular disease. AB - Coronary (CAD) and peripheral (PAD) artery diseases are major causes of morbidity and mortality, and millions of CAD and PAD patients are treated by various medications, bypass surgery or angioplasty around the world. Such patients might benefit from novel stem cells and tissue engineering strategies aimed at accelerating natural processes of postnatal collateral vessel formation and repairing damaged tissues. By combining three fundamental "tools", namely stem cells, biomaterials and growth factors (GFs), such strategies may enhance the efficacy of cell therapy in several ways: (a) by supplying exogenous stem cells or GFs that stimulate resident cardiac stem cell (CSC) migration, engraftment and commitment to cardiomyocytes, and that induce and modulate arterial response to ischemia; (b) by supporting the maintenance of GFs and transplanted stem cells in the damaged tissues through the use of biocompatible and biodegradable polymers for a period of time sufficient to allow histological and anatomical restoration of the damaged tissue. This review will discuss the potential of combining stem cells and new delivery systems for growth factors, such as vehicle-based delivery strategies or cell-based gene therapy, to facilitate regeneration of ischemic tissues. These approaches would promote the ability of resident CSCs or of exogenous multipotent stem cells such as adipose tissue-derived mesenchymal stem cells (AT-MSCs) to induce the healing of damaged tissue, by recruiting and directing these cells into the damage area and by improving angiogenesis and reperfusion of ischemic tissues. PMID- 21663774 TI - Enhanced UDP-glucose and UDP-galactose by homologous overexpression of UDP glucose pyrophosphorylase in Lactobacillus casei. AB - UDP-sugars are widely used as substrates in the synthesis of oligosaccharides catalyzed by glycosyltransferases. In the present work a metabolic engineering strategy aimed to direct the carbon flux towards UDP-glucose and UDP-galactose biosynthesis was successfully applied in Lactobacillus casei. The galU gene coding for UDP-glucose pyrophosphorylase (GalU) enzyme in L. casei BL23 was cloned under control of the inducible nisA promoter and it was shown to be functional by homologous overexpression. Notably, about an 80-fold increase in GalU activity resulted in approximately a 9-fold increase of UDP-glucose and a 4 fold increase of UDP-galactose. This suggested that the endogenous UDP-galactose 4-epimerase (GalE) activity, which inter-converts both UDP-sugars, is not sufficient to maintain the UDP-glucose/UDP-galactose ratio. The L. casei galE gene coding for GalE was cloned downstream of galU and the resulting plasmid was transformed in L. casei. The new recombinant strain showed about a 4-fold increase of GalE activity, however this increment did not affect that ratio, suggesting that GalE has higher affinity for UDP-galactose than for UDP-glucose. The L. casei strains constructed here that accumulate high intracellular levels of UDP-sugars would be adequate hosts for the production of oligosaccharides. PMID- 21663775 TI - The development of a cisgenic apple plant. AB - Cisgenesis represents a step toward a new generation of GM crops. The lack of selectable genes (e.g. antibiotic or herbicide resistance) in the final product and the fact that the inserted gene(s) derive from organisms sexually compatible with the target crop should rise less environmental concerns and increase consumer's acceptance. Here we report the generation of a cisgenic apple plant by inserting the endogenous apple scab resistance gene HcrVf2 under the control of its own regulatory sequences into the scab susceptible apple cultivar Gala. A previously developed method based on Agrobacterium-mediated transformation combined with a positive and negative selection system and a chemically inducible recombination machinery allowed the generation of apple cv. Gala carrying the scab resistance gene HcrVf2 under its native regulatory sequences and no foreign genes. Three cisgenic lines were chosen for detailed investigation and were shown to carry a single T-DNA insertion and express the target gene HcrVf2. This is the first report of the generation of a true cisgenic plant. PMID- 21663776 TI - Coupling single base extension to a spectral codification tool for increased throughput screening. AB - We report a new strategy that combines a Forster Resonance Energy Transfer (FRET) based spectral codification tool with a single base extension (SBE) reaction for rapid and medium-throughput analysis of single nucleotide polymorphisms (SNPs). This strategy is based on the spectral codification - a donor (fluorophore labeled probe complementary to the region adjacent to an SNP) is used to induce specific FRET signatures from an acceptor fluorophore revealing the SNP variant. Using an SBE reaction and differently labeled ddNTPs, we can directly question each donor probe and retrieve information about which allele variant is present at that locus. The potential of the method is demonstrated by application to simultaneous questioning of two loci in the same reaction tube. Following calibration with all possible combinations of FRET pairs, an evaluation algorithm was calibrated so as to optimize base calling and allow unequivocal allele scoring with more than 80% confidence (for two simultaneous loci being questioned, one homo- and one heterozygous). In conclusion, this spectral codification approach may constitute a solution towards increasing throughput capability of single base extension based assays. PMID- 21663777 TI - Controlled release of thymosin beta4 using collagen-chitosan composite hydrogels promotes epicardial cell migration and angiogenesis. AB - Rapid vascularization at the infarcted site is crucial for cardiac repair following myocardial infarction. Thymosin beta4 (Tbeta4), a 43-amino acid peptide, is both angiogenic and cardioprotective. Tbeta4 in soluble form was previously shown to promote cell migration from quiescent adult cardiac explants. Here we developed a collagen-chitosan hydrogel for the encapsulation of Tbeta4, which allowed its controlled release over 28days to elicit localized and prolonged effects. Contrastingly, Tbeta4 was fully released over 3days when encapsulated in collagen-only hydrogels due to charge repulsion and lack of interconnected pores as shown by SEM. The charge of encapsulated molecules affected their release from collagen-chitosan hydrogels. While the release of neutral polyalanine was size-controlled diffusion, that of negatively-charged Tbeta4 and positively-charged polylysine was affected by electrostatic interactions of peptides with collagen/chitosan molecules. Hydrogels with encapsulated Tbeta4 significantly increased cell migration and outgrowth of CD31 positive capillaries from mouse and rat epicardial explants in vitro, compared to Tbeta4-free and soluble controls. Potential advantage of Tbeta4 over commonly used angiogenic growth factors is that it can induce recruitment and differentiation of both endothelial and smooth muscle cells necessary for vascular stability. Importantly, Tbeta4-encapsulated collagen-chitosan hydrogels promoted angiogenesis in vivo upon subcutaneous injection, compared to collagen only hydrogels. PMID- 21663779 TI - Measuring salient food attitudes and food-related values. An elaborated, conflicting and interdependent system. AB - Consumer food choice behaviour in post-industrial countries is complex and influenced by a multitude of interacting variables. This study looked at the antecedents of behaviour and examined salient food-related values and attitudes. To discover personal meanings and patterns of everyday food choices across different situations we used a qualitative approach in the form of repertory grid interviews. An analysis of the personal constructs elicited from a representative sample of 100 Swiss consumers revealed elaborated value systems. The food-related values can be summarised as: authenticity/naturalness, conviviality, health, quality/indulgence, convenience, and price. The salience of these values and their negatively evaluated counterparts differed for various social eating situations and product categories. Consumers' personal values also differed significantly from their perception of current trends in eating culture. In every day food choices interdependent food-related values compete and are thus a possible cause of ambivalence and conflicts. The findings offer explanations of discrepancies between values/attitudes and behaviour that may be due to situational constraints and habits. Implications for companies include the need for strategic realignment to regain consumers' trust by providing comprehensive value-congruent food solutions that also consider health and ethical criteria. PMID- 21663780 TI - Refined information on alleles belonging to the C*07:01/07:06/07:18 group in the Korean population. AB - Alleles of the C*07:01/07:06/07:18 group is distinguished by polymorphisms in exons 5-6. In a previous study, we focused on exons 2-3 of the gene and showed that 6.8% of Koreans express alleles in this group. In this study, we identified allelic and haplotypic diversities of the C*07:01/07:06/07:18 group in Koreans. Among 118 C*07:01/07:06/07:18-positive, unrelated, healthy samples, 96.6% were C*07:06 and 3.4% were C*07:01. Each allele was exclusively associated with a specific set of other alleles consisting of the conserved haplotypes A*01:01 C*07:01-B*08:01-DRB1*03:01-DQB1*02:01 (100%) and A*33:03-C*07:06-B*44:03 DRB1*07:01-DQB1*02:02 (95.6%), respectively. None carried C*07:18. With the continuous discovery of novel alleles, periodic updates with testing for newer alleles will be useful to support related research and clinical settings in each population. PMID- 21663778 TI - Targeted drug delivery to tumors: myths, reality and possibility. PMID- 21663781 TI - Human leukocyte antigen class I haplotypes of human immunodeficiency virus-1 infected persons on Likoma Island, Malawi. AB - Human leukocyte antigen (HLA) allele frequencies vary between different human populations, with implications both for the evolutionary pressures shaping those populations as well as for the outcome of new infectious epidemics. We defined HLA class I types in a well-described cohort of persons on Likoma Island in Malawi, a population for which there are lacking data on allelic frequencies. The profile of HLA frequencies was similar but phylogenetically distinct from those of other sub-Saharan African populations in neighboring regions. The most common A alleles included A30, A23, A28 (A*68), and A2, and the most common B alleles included B15 (group), B53, B58, and B44. Notably, the frequency of B53, which is protective against malaria, was similar to that of other malaria-endemic African countries, and higher than that in countries with less malaria. This is the first reported significant dataset of HLA class I allelic frequencies in Malawians. PMID- 21663782 TI - Association of FCRL3 -169T/C polymorphism with endometriosis and identification of a protective haplotype against the development of the disease in Brazilian population. AB - An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Fc receptor-like 3 gene (FCRL3) has been proposed as a novel autoimmune predisposing factor. The authors have hypothesized a possible relationship between endometriosis, infertility, and FCRL3 polymorphisms. This was a case-control study that included 170 women with endometriosis-related infertility, 91 women with idiopathic infertility, and 166 controls. Detection of FCRL3 polymorphisms (-169C/T, -110G/A, +358C/G and +1381 A/G) was performed using TaqMan PCR. The results were analyzed statistically and a p value <0.05 was considered significant. Results Single-marker analysis revealed that FCRL3 -169C/T was significantly associated with endometriosis (p = 0.004), regardless of the stage of the disease, p = 0.011 and p = 0.035, respectively to minimal/mild and to moderate/severe endometriosis. No association was found considering -110A/G, +358C/G, and +1381 A/G polymorphisms either for the endometriosis-related infertility group or the idiopathic infertility group. Haplotype analysis of four FCRL3 polymorphisms identified a haplotype GGGC associated with endometriosis (p = 0.026). The haplotype AGAT was associated with protection against endometriosis (p = 0.011) and infertility (p = 0.041). The data from this study point to a possible association of the FCRL3 -169C/T polymorphisms with endometriosis, especially minimal/mild endometriosis, and the haplotype AGAT may be protective against the development of the disease, in Brazilian women. However, these findings clearly need to be replicated in an independent sample and in different populations. PMID- 21663783 TI - Soluble human leukocyte antigen-G serum levels in patients with acquired immune deficiency syndrome affected by different disease-defining conditions before and after antiretroviral treatment. AB - We have previously reported that the serum levels of soluble human leukocyte antigen (HLA)-A, -B, -C, and -G antigens are elevated in human immunodeficiency virus (HIV)-infected subjects and decrease after antiretroviral therapy. In this study, we measured soluble HLA-G serum levels in patients with acquired immune deficiency syndrome (AIDS) affected by different AIDS-defining conditions before and during antiretroviral therapy and correlated them with virologic and immunologic parameters of response to treatment. Soluble HLA-G levels were significantly higher in AIDS patients before treatment as compared with healthy controls and significantly decreased after 36 months of therapy. The decrease of soluble HLA-G correlated with the decrease of plasma HIV-RNA level and CD8(+) T lymphocytes number and with the increase of CD4(+) T-lymphocytes number. Soluble HLA-G levels were significantly higher in patients with opportunistic infections and Kaposi's sarcoma compared with patients with the wasting syndrome. These data suggest that infections and neoplasms may trigger the shedding of soluble HLA-G molecules, and confirm that the level of soluble HLA-G in serum might represent a surrogate marker to monitor virologic response and immune reconstitution in HIV positive individuals. PMID- 21663784 TI - Treating the periphery to ameliorate neurodegenerative diseases. AB - Abnormalities in the kynurenine pathway are associated with neurodegenerative disorders. Zwilling et al. (2011) show that inhibition of kynurenine 3 monooxygenase in the body's periphery leads to an increase in kyneuric acid, a neuroprotective compound, in the brain. This intervention ameliorates neurodegeneration in mouse models of Alzheimer's disease and Huntington's disease. PMID- 21663785 TI - Rolling ES cells down the Waddington landscape with Oct4 and Sox2. AB - Embryonic stem cell (ESC) pluripotency is maintained by core transcriptional circuits whereby critical factors sustain their own expression while preventing the expression of genes required for differentiation. Thomson et al. (2011) now show that two core components of the pluripotency circuit, Oct4 and Sox2, are also critical for germ layer fate choice. PMID- 21663786 TI - A kinesin in command of primary ciliogenesis. AB - Primary cilia sense extracellular cues and in response transmit signals required for development and tissue homeostasis. A new study by Kobayashi et al. (2011) reports that the kinesin Kif24 controls the formation of primary cilia by restricting the nucleation of cilia at centrioles. PMID- 21663787 TI - Democracy derived? New trajectories in pluripotent stem cell research. AB - How has the development of human induced pluripotent stem cells (hiPSCs) modified the trajectory of stem cell research? Here, coauthorship networks of stem cell research articles and analysis of cell lines used in stem cell research indicate that hiPSCs are not replacing human embryonic stem cells, but instead, the two cell types are complementary, interdependent research tools. Thus, we conclude that a ban on funding for embryonic stem cell research could have unexpected negative ramifications on the nascent field of hiPSCs. PMID- 21663788 TI - Cell fate plug and play: direct reprogramming and induced pluripotency. AB - Building on the discovery that MyoD expression reprograms fibroblasts into muscle, three papers (Vierbuchen et al., 2010; Ieda et al., 2010; Szabo et al., 2010) recently reported the reprogramming of fibroblasts into neurons, cardiomyocytes, and blood cell progenitors without first passing the cells through a pluripotent state. Here we discuss the advantages and challenges of harnessing this direct reprogramming method for regenerative medicine. PMID- 21663789 TI - The human brain in a dish: the promise of iPSC-derived neurons. AB - Induced pluripotent stem cell-derived neurons from patients promise to fill an important niche between studies in humans and model organisms in deciphering mechanisms and identifying therapeutic avenues for neurologic and psychiatric diseases. Recent work begins to tap this potential and also highlights challenges that must be overcome to be fully realized. PMID- 21663790 TI - Chromatin connections to pluripotency and cellular reprogramming. AB - The pluripotent state of embryonic stem cells (ESCs) provides a unique perspective on regulatory programs that govern self-renewal and differentiation and somatic cell reprogramming. Here, we review the highly connected protein and transcriptional networks that maintain pluripotency and how they are intertwined with factors that affect chromatin structure and function. The complex interrelationships between pluripotency and chromatin factors are illustrated by X chromosome inactivation, regulatory control by noncoding RNAs, and environmental influences on cell states. Manipulation of cell state through the process of transdifferentiation suggests that environmental cues may direct transcriptional programs as cells enter a transiently "plastic" state during reprogramming. PMID- 21663791 TI - Strategies for homeostatic stem cell self-renewal in adult tissues. AB - In adult tissues, an exquisite balance exists between stem cell proliferation and the generation of differentiated offspring. Classically, it has been argued that this balance is obtained at the level of a single stem cell, which divides strictly into a new stem cell and a progenitor. However, recent evidence suggests that balance can also be achieved at the level of the stem cell population. Some stem cells might be lost due to differentiation or damage, whereas others divide symmetrically to fill this gap. Here, we consider the general strategies for stem cell self-renewal and review the evidence for stochastic stem cell fate in adult tissues across a range of tissue types and organisms. PMID- 21663792 TI - Pluripotency factors in embryonic stem cells regulate differentiation into germ layers. AB - Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells. PMID- 21663793 TI - The RNA helicase Mtr4p modulates polyadenylation in the TRAMP complex. AB - Many steps in nuclear RNA processing, surveillance, and degradation require TRAMP, a complex containing the poly(A) polymerase Trf4p, the Zn-knuckle protein Air2p, and the RNA helicase Mtr4p. TRAMP polyadenylates RNAs designated for decay or trimming by the nuclear exosome. It has been unclear how polyadenylation by TRAMP differs from polyadenylation by conventional poly(A) polymerase, which produces poly(A) tails that stabilize RNAs. Using reconstituted S. cerevisiae TRAMP, we show that TRAMP inherently suppresses poly(A) addition after only 3-4 adenosines. This poly(A) tail length restriction is controlled by Mtr4p. The helicase detects the number of 3'-terminal adenosines and, over several adenylation steps, elicits precisely tuned adjustments of ATP affinities and rate constants for adenylation and TRAMP dissociation. Our data establish Mtr4p as a critical regulator of polyadenylation by TRAMP and reveal that an RNA helicase can control the activity of another enzyme in a highly complex fashion and in response to features in RNA. PMID- 21663794 TI - Translational control via protein-regulated upstream open reading frames. AB - Analysis of the regulation of msl-2 mRNA by Sex lethal (SXL), which is critical for dosage compensation in Drosophila, has uncovered a mode of translational control based on common 5' untranslated region elements, upstream open reading frames (uORFs), and interaction sites for RNA-binding proteins. We show that SXL binding downstream of a short uORF imposes a strong negative effect on major reading frame translation. The underlying mechanism involves increasing initiation of scanning ribosomes at the uORF and augmenting its impediment to downstream translation. Our analyses reveal that SXL exerts its effect controlling initiation, not elongation or termination, at the uORF. Probing the generality of the underlying mechanism, we show that the regulatory module that we define experimentally functions in a heterologous context, and we identify natural Drosophila mRNAs that are regulated via this module. We propose that protein-regulated uORFs constitute a systematic principle for the regulation of protein synthesis. PMID- 21663795 TI - Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. AB - The epithelial-mesenchymal transition (EMT) has been associated with the acquisition of motility, invasiveness, and self-renewal traits. During both normal development and tumor pathogenesis, this change in cell phenotype is induced by contextual signals that epithelial cells receive from their microenvironment. The signals that are responsible for inducing an EMT and maintaining the resulting cellular state have been unclear. We describe three signaling pathways, involving transforming growth factor (TGF)-beta and canonical and noncanonical Wnt signaling, that collaborate to induce activation of the EMT program and thereafter function in an autocrine fashion to maintain the resulting mesenchymal state. Downregulation of endogenously synthesized inhibitors of autocrine signals in epithelial cells enables the induction of the EMT program. Conversely, disruption of autocrine signaling by added inhibitors of these pathways inhibits migration and self-renewal in primary mammary epithelial cells and reduces tumorigenicity and metastasis by their transformed derivatives. PMID- 21663796 TI - Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. AB - Melanocyte stem cells (McSCs) intimately interact with epithelial stem cells (EpSCs) in the hair follicle bulge and secondary hair germ (sHG). Together, they undergo activation and differentiation to regenerate pigmented hair. However, the mechanisms behind this coordinated stem cell behavior have not been elucidated. Here, we identified Wnt signaling as a key pathway that couples the behavior of the two stem cells. EpSCs and McSCs coordinately activate Wnt signaling at the onset of hair follicle regeneration within the sHG. Using genetic mouse models that specifically target either EpSCs or McSCs, we show that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes, while EpSC Wnt signaling not only dictates hair follicle formation but also regulates McSC proliferation during hair regeneration. Our data define a role for Wnt signaling in the regulation of McSCs and also illustrate a mechanism for regeneration of complex organs through collaboration between heterotypic stem cell populations. PMID- 21663797 TI - Interlocked feedforward loops control cell-type-specific Rhodopsin expression in the Drosophila eye. AB - How complex networks of activators and repressors lead to exquisitely specific cell-type determination during development is poorly understood. In the Drosophila eye, expression patterns of Rhodopsins define at least eight functionally distinct though related subtypes of photoreceptors. Here, we describe a role for the transcription factor gene defective proventriculus (dve) as a critical node in the network regulating Rhodopsin expression. dve is a shared component of two opposing, interlocked feedforward loops (FFLs). Orthodenticle and Dve interact in an incoherent FFL to repress Rhodopsin expression throughout the eye. In R7 and R8 photoreceptors, a coherent FFL relieves repression by Dve while activating Rhodopsin expression. Therefore, this network uses repression to restrict and combinatorial activation to induce cell type-specific expression. Furthermore, Dve levels are finely tuned to yield cell type- and region-specific repression or activation outcomes. This interlocked FFL motif may be a general mechanism to control terminal cell-fate specification. PMID- 21663798 TI - Riboneogenesis in yeast. AB - Glucose is catabolized in yeast via two fundamental routes, glycolysis and the oxidative pentose phosphate pathway, which produces NADPH and the essential nucleotide component ribose-5-phosphate. Here, we describe riboneogenesis, a thermodynamically driven pathway that converts glycolytic intermediates into ribose-5-phosphate without production of NADPH. Riboneogenesis begins with synthesis, by the combined action of transketolase and aldolase, of the seven carbon bisphosphorylated sugar sedoheptulose-1,7-bisphosphate. In the pathway's committed step, sedoheptulose bisphosphate is hydrolyzed to sedoheptulose-7 phosphate by the enzyme sedoheptulose-1,7-bisphosphatase (SHB17), whose activity we identified based on metabolomic analysis of the corresponding knockout strain. The crystal structure of Shb17 in complex with sedoheptulose-1,7-bisphosphate reveals that the substrate binds in the closed furan form in the active site. Sedoheptulose-7-phosphate is ultimately converted by known enzymes of the nonoxidative pentose phosphate pathway to ribose-5-phosphate. Flux through SHB17 increases when ribose demand is high relative to demand for NADPH, including during ribosome biogenesis in metabolically synchronized yeast cells. PMID- 21663800 TI - SnapShot: stem cell niches of the Drosophila testis and ovary. PMID- 21663799 TI - Metazoan operons accelerate recovery from growth-arrested states. AB - Existing theories explain why operons are advantageous in prokaryotes, but their occurrence in metazoans is an enigma. Nematode operon genes, typically consisting of growth genes, are significantly upregulated during recovery from growth arrested states. This expression pattern is anticorrelated to nonoperon genes, consistent with a competition for transcriptional resources. We find that transcriptional resources are initially limiting during recovery and that recovering animals are highly sensitive to any additional decrease in transcriptional resources. We provide evidence that operons become advantageous because, by clustering growth genes into operons, fewer promoters compete for the limited transcriptional machinery, effectively increasing the concentration of transcriptional resources and accelerating recovery. Mathematical modeling reveals how a moderate increase in transcriptional resources can substantially enhance transcription rate and recovery. This design principle occurs in different nematodes and the chordate C. intestinalis. As transition from arrest to rapid growth is shared by many metazoans, operons could have evolved to facilitate these processes. PMID- 21663801 TI - Sophiology, vaccinology, and the healing professions - a warning from ancient Greece? PMID- 21663802 TI - Genetics, health care, family and kinship in a global perspective: situated processes of co-construction. PMID- 21663803 TI - Worry, worry attacks, and PTSD among Cambodian refugees: a path analysis investigation. AB - Among traumatized Cambodian refugees, this article investigates worry (e.g., the types of current life concerns) and how worry worsens posttraumatic stress disorder (PTSD). To explore how worry worsens PTSD, we examine a path model of worry to see whether certain key variables (e.g., worry-induced somatic arousal and worry-induced trauma recall) mediate the relationship between worry and PTSD. Survey data were collected from March 2010 until May 2010 in a convenience sample of 201 adult Cambodian refugees attending a psychiatric clinic in Massachusetts, USA. We found that worry was common in this group (65%), that worry was often about current life concerns (e.g., lacking financial resources, children not attending school, health concerns, concerns about relatives in Cambodia), and that worry often induced panic attacks: in the entire sample, 41% (83/201) of the patients had "worry attacks" (i.e., worry episodes that resulted in a panic episode) in the last month. "Worry attacks" were highly associated with PTSD presence. In the entire sample, generalized anxiety disorder was also very prevalent, and was also highly associated with PTSD. Path analysis revealed that the effect of worry on PTSD severity was mediated by worry-induced somatic arousal, worry-induced catastrophic cognitions, worry-induced trauma recall, inability to stop worry, and irritability. The final model accounted for 75% of the variance in PTSD severity among patients with worry. The public health and treatment implications of the study's findings that worry may have a potent impact on PTSD severity in severely traumatized populations are discussed: worry and daily concerns are key areas of intervention for these worry-hypersensitive (and hence daily-stressor-hypersensitive) populations. PMID- 21663804 TI - Utilization of adzuki bean extract as a natural antioxidant in cured and uncured cooked pork sausages. AB - A commercial adzuki bean extract (AE) was evaluated for antioxidant effectiveness in cured and uncured cooked pork sausages. TBARS values, instrumental color evaluation and sensory panel scores were assessed. For uncured sausages, AE at 0.2% was equally effective as 0.1% butylated hydroxytoluene (BHT) in reducing TBARS values. Similarly, AE at 0.2% significantly (P<0.01) reduced the TBARS in cured sausages. Incorporation of 0.2% AE into sausages produced higher (P<0.05) CIE lab color a* value and lower (P<0.05) L* and b* values. Sensory panels did not detect any difference in color, odor, taste, flavor, and overall acceptance in uncured pork sausages with addition of 0.2% AE. However, there were adverse changes in the color and odor of cured sausages, even though the taste, flavor, and overall acceptance were similar. Therefore, the results suggest that AE is a potential antioxidant. PMID- 21663805 TI - High post-mortem temperature combined with rapid glycolysis induces phosphorylase denaturation and produces pale and exudative characteristics in broiler Pectoralis major muscles. AB - This study investigated the effect of early post-mortem temperature on broiler protein characteristics and meat quality. Muscles were kept at different temperatures (0, 20 and 40 degrees C) until 4h post-mortem and then stored at 4 degrees C. Rapid degradation of ATP and glycogen, thus inducing a high rate of lactate formation and pH drop, were found in the 40 degrees C group during incubation. When extracting proteins, a lower protein content of the sarcoplasmic fraction and a higher protein content of the myofibrillar fraction were found in the 40 degrees C group at 24h post-mortem; SDS-PAGE and western-blotting results revealed that phosphorylase was associated with the myofibrillar fraction. Furthermore, the 40 degrees C group had paler surfaces, higher drip loss and lower processing properties. These data suggest that elevated temperature during early post-mortem period, resulting in rapid glycolysis, induced phosphorylase denaturation and association with myofibrillar proteins thus generating pale and exudative characteristics. PMID- 21663806 TI - Effects of succinate on ground beef color and premature browning. AB - The objective of this experiment was to determine the effects of succinate on raw and cooked ground beef color. Chubs (n=10) were divided in half and assigned to either succinate (final w/w concentration of 2.5%) or distilled water. Patties (n=14 per chub half) were assigned to initial day 0 color and each of 6 treatment combinations, created by crossing 3 packaging types (vacuum, high-oxygen/80% O(2), and PVC) with 2 storage times (days 1 and 3). After storage, patties were cooked to either 66 degrees C or 71 degrees C. Succinate increased (P<0.05) ground beef pH and metmyoglobin reducing activity but had no effect (P>0.05) on raw a* and chroma values. Moreover, succinate decreased (P<0.05) raw L* values, lipid oxidation, and premature browning for patties packaged in PVC and high oxygen. Succinate may increase cooked patty redness via its influence on meat pH. PMID- 21663807 TI - Proximate composition and energy content of beef steaks as influenced by USDA quality grade and degree of doneness. AB - This study evaluated the influence of various degrees of doneness on proximate composition and energy content of beef. Ten steaks were obtained from each of five USDA Prime, five USDA Choice, and five USDA Select strip loins and assigned to one of five degree of doneness treatments (two sets of treatments per strip loin): raw, medium rare (63 degrees C), medium (71 degrees C), well done (77 degrees C), and very well done (82 degrees C). After cooking, steaks were dissected into separable tissue components consisting of lean, fat, and refuse. Lean tissue was used to obtain proximate analyses of protein, moisture, fat, and ash. Degree of doneness did influence (P<0.05) the nutrient composition of beef steaks. As the degree of doneness increased, percent fat and protein increased, while percent moisture decreased. Cooking steaks to a higher degree of doneness resulted in a higher caloric value when reported per 100g basis. PMID- 21663808 TI - Can't buy me love? Financial incentives and sub-specialization in anesthesiology. PMID- 21663809 TI - Pain on injection of propofol: a comparison of methylene blue and lidocaine. AB - STUDY OBJECTIVE: To investigate whether methylene blue, given before injection of propofol, was effective in reducing the frequency and severity of pain associated with propofol injection. DESIGN: Prospective, randomized, double-blinded clinical study. SETTING: Operating room of a university hospital. PATIENTS: 90 adult, ASA physical status 1 and 2 patients undergoing elective surgery. INTERVENTIONS: Patients were randomly allocated to one of three groups of 30 patients each. Group I received 50 mg of methylene blue, Group II received 40 mg of lidocaine, and Group III, the control group, was given normal saline. All drugs were given as a 2.0 mL bolus 45 seconds before propofol administration. MEASUREMENTS: Injection pain using vocal responses, facial grimacing, arm withdrawal, tears, and questioning of the patient were noted. A 4-point scale was used for documenting pain. MAIN RESULTS: Pain frequency was 90% in the saline group, whereas the frequencies were significantly lower in the lidocaine and methylene blue groups (26.7% and 40%, respectively). CONCLUSIONS: Intravenous pretreatment with methylene blue appears to be effective in reducing the pain during propofol injection. PMID- 21663810 TI - Who teaches surgical airway management and how do they teach it? A survey of United States anesthesiology training programs. AB - STUDY OBJECTIVE: To determine the methods used to teach surgical airway management to residents. DESIGN: Electronic mail survey instrument. SETTING: Academic medical center. PARTICIPANTS: 82 (of a possible 132) United States residency program directors. MEASUREMENTS: Data including whether instruction in surgical airway management was provided, which methods were used, whether these teaching methods have changed since the subject was first examined, were recorded. The number of residents in each program represented by a respondent also was recorded. MAIN RESULTS: The survey response rate was 62% (82 of 132). Seventy-two respondents (88%) reported that education in surgical airway management was part of their curriculum. Practice on a mannequin was the most common form of instruction (57%), followed by traditional didactic teaching (31%), a cadaver workshop or a large animal laboratory (29%), human patient simulator training (24%), and supply of subject-specific reading materials alone (3%). Forty-seven programs (65%) taught surgical airway management using a single method, whereas the remainder (35%) incorporated more than one approach. Training experience was dependent on the program size. The top one quarter of the programs in size (67 +/- 10 residents) were more likely to use a multimodal approach (48%) and a cadaver workshop or large animal laboratory (38%). CONCLUSIONS: The majority of anesthesiology training programs accredited by the Accreditation Council for Graduate Medical Education provide some form of skill-based instruction in surgical airway management for their residents. PMID- 21663811 TI - Indirect versus direct laryngoscopy for routine nasotracheal intubation. AB - STUDY OBJECTIVE: To compare the effectiveness of the indirect laryngoscopes, Airtraq (A) and GlideScope (G), with the Macintosh (M) laryngoscope in routine nasotracheal intubation. DESIGN: Randomized, single-blinded study. SETTING: University-affiliated, tertiary-care hospital. PATIENTS: 62 adult, ASA physical status 1 and 2 patients with normal airways requiring nasotracheal intubation for dental or maxillofacial surgery. INTERVENTION: Patients in Groups A and G underwent nasal intubation with the Airtraq and GlideScope, respectively, while laryngoscopy in Group M was performed with the Macintosh blade. MEASUREMENTS: Performance of the intubating tools was judged by the ease [Intubation Difficulty Scale (IDS) and numeric rating scale (NRS)] and time to intubation (laryngoscopy and endotracheal tube advancement). In addition, hemodynamic parameters, severity of postoperative sore throat, and posture of the intubator were recorded. MAIN RESULTS: IDS score was significantly lower with the Airtraq and GlideScope than with the Macintosh laryngoscope (mean +/- SD: A 0.1 +/- 0.3, G 0.3 +/- 0.6, M 0.8 +/- 1.0; P = 0.013). NRS reported by the intubators showed a similar preference for indirect over direct laryngoscopy (A 0.9 +/- 0.7, G 1.1 +/- 0.6, M 1.9 +/- 1.1; P = 0.001). Duration of laryngoscopy and endotracheal tube insertion was similar in all groups. No significant intergroup differences in hemodynamic parameters were recorded. Postoperative sore throat was significantly reduced using the GlideScope compared with the other devices (P = 0.048). CONCLUSION: The Airtraq and GlideScope facilitated nasotracheal intubation more so than the Macintosh laryngoscope in adults with apparently normal airways. PMID- 21663812 TI - Remifentanil for the insertion and removal of long-term central venous access during monitored anesthesia care. AB - STUDY OBJECTIVE: To determine the analgesic efficacy of three different rates of remifentanil infusion in patients undergoing insertion or removal of long-term central venous access devices during monitored anesthesia care and local anesthetic field infiltration. DESIGN: Double-blinded, randomized, controlled study. SETTING: Operating theatre of an University hospital. PATIENTS: 44 unpremedicated, ASA physical status 1 and 2 patients, aged 18-65 years, undergoing insertion or removal of a Port-a-Cath or Hickman catheter. INTERVENTIONS: Patients sedated with a propofol target-controlled infusion were randomly allocated to three groups: Group R25 (n = 14), Group R50 (n = 15), and Group R75 (n = 15), to receive remifentanil 0.025, 0.05, and 0.075 MUg/kg/min, respectively. Rescue remifentanil 0.5 MUg/kg was administered for pain scores > 3. The remifentanil infusion rate was maintained constant unless respiratory and/or cardiovascular unwanted events occurred, whereupon the rate was adjusted in 0.01 MUg/kg/min decrements as necessary. MEASUREMENTS: Pain scores (primary outcome), sedation, and movement scores (secondary outcomes) were assessed during local anesthetic infiltration of the anterior chest wall and 5 other procedural steps. MAIN RESULTS: All infusion rates had equal analgesic efficacy, as shown by comparable pain scores, number of rescue boluses, and number of patients requiring rescue analgesia. Excessive sedation was associated with the highest remifentanil rate such that Group R75 patients were significantly more sedated than Groups R25 or R50 at selective procedural steps (P < 0.05). More Group R75 patients (6/15) required remifentanil rate reduction than did patients from Group R50 (1/15) or Group R25 (0/14), P < 0.01, most commonly because of respiratory depression. CONCLUSIONS: For the insertion or removal of long-term central venous access devices, all three remifentanil infusion rates proved to be equally analgesic-efficient. However, the excessive sedation and tendency to respiratory and cardiovascular events associated with the highest remifentanil infusion rate renders such a rate less desirable for this purpose. PMID- 21663813 TI - Intravenous landiolol, a novel beta(1)-adrenergic blocker, reduces the minimum alveolar concentration of sevoflurane in women. AB - STUDY OBJECTIVE: To investigate the effect of intravenous (IV) landiolol, a novel beta(1)-adrenergic blocker, on the minimum alveolar concentration (MAC) of sevoflurane in adult women. DESIGN: Prospective, randomized study. SETTING: University hospital. PATIENTS: 42 ASA physical status 1 and 2 women, aged 24-57 years, who were scheduled to undergo elective abdominal surgery. INTERVENTIONS: Anesthesia was induced in all patients by vital capacity rapid inhalation induction of sevoflurane. In the landiolol group, administration of landiolol began when patients took a vital-capacity breath: 0.125 mg/kg/min for one minute and then 0.04 mg/kg/min. Normal saline was administered in the control group. MEASUREMENTS: MAC was determined by a technique adapted from the conventional up down method. MAIN RESULTS: The MAC of sevoflurane was 2.2% +/- 0.2% in the control group and 1.7% +/- 0.2% in the landiolol group, a statistically significant difference (P = 0.0005). CONCLUSIONS: IV landiolol reduces the MAC of sevoflurane in women by approximately 20%. PMID- 21663814 TI - 5 HT(3)-receptor antagonists and cardiac repolarization time in patients expressing a novel genetic target associated with baseline QTc interval abnormalities. AB - STUDY OBJECTIVE: To investigate whether a common single nucleotide polymorphism (SNP), rs10494366, is associated with significant prolongation of the QTc interval following administration of 5-HT(3)-receptor antagonists in the perioperative setting. DESIGN: Post-hoc analysis of deoxyribonucleic acid (DNA) samples and electrocardiographic (ECG) data from an established perioperative genomics database. SETTING: University teaching hospital. MEASUREMENTS: DNA samples of 132 ASA physical status 1, 2, and 3 patients were obtained from an established genomic database of surgical patients who had received either granisetron or dolasetron as part of their general anesthesia plan. ECG recordings were collected on all subjects before administration of antiemetic medication, then 10 minutes after drug injection. DNA analysis was performed using TaqMan real-time PCR genotyping assay. Results from the TaqMan real-time PCR assay were used to calculate relative frequencies of the T (major) and G (minor) alleles, in addition to calculating the genotype frequencies. QTc intervals were calculated according to Bazett's formula. RESULTS: Relative frequencies for T and G alleles were 0.63 and 0.37, respectively. The relative frequencies of the pertinent genotypes were TT 39.4%, TG 46.9%, and GG 13.7%. No significant difference was noted in QTc interval pre-antiemetic or post antiemetic drug administration for the homozygous carriers of the minor allele GG (P = 0.059), but a significant difference was seen in the pre-drug and post-drug QTc intervals in the heterozygous and homozygous carriers of the major allele TG and TT (P = 0.003 and P = 0.017, respectively). Compared with homozygous carriers of the minor allele, absolute risk increase for QTc interval prolongation after antiemetic administration was 0.08 and 0.15 in heterozygous and homozygous carriers of the major allele, respectively. CONCLUSION: Homozygous and heterozygous carrier status for the major SNP, rs10494366 allele (T), in intron 1 of the human NOSA1P gene may be associated with an increased risk of QTc interval prolongation following administration of 5-HT(3)-receptor antagonists in the perioperative setting, when compared with homozygotes for the minor (G) allele. PMID- 21663815 TI - Ultrasound-guided transversus abdominis plane (TAP) block: a useful adjunct in the management of postoperative respiratory failure. AB - The ultrasound-guided transversus abdominis plane (TAP) block is a useful tool in controlling postoperative pain following abdominal surgery. The bilateral ultrasound-guided TAP blocks successfully managed the pain of a patient presenting with hypoxemia and respiratory failure in the Post-anesthesia Care Unit, following a laparotomy for small bowel obstruction during general anesthesia. The TAP block reduced systemic opioid requirements and opioid-induced sedation and respiratory depression, improved patient compliance with non invasive positive pressure ventilation, and prevented the need for intubation and ventilation in the intensive care unit. PMID- 21663816 TI - Psoas compartment block for operative reduction of hip fracture in a patient with increased intracranial pressure due to inoperable brain tumor. AB - General and neuraxial anesthesia in patients with increased intracranial pressure (ICP) who present for non-neurosurgical surgery may cause life-threatening changes in ICP, with possible fatal outcome. Peripheral nerve blocks may be a safe alternative technique for limb surgery. The successful use of psoas compartment block for operative reduction of a hip fracture in a patient with increased ICP due to an inoperable brain tumor is presented. PMID- 21663817 TI - A case of posterior reversible encephalopathy syndrome in a 52 year old woman after cardiac arrest. AB - A 52 year old woman who suffered a cardiac arrest was treated in a local hospital with cardiopulmonary resuscitation. Following transfer to our hospital, she developed renal failure, hypertension, impaired consciousness, headache, and visual disturbances. Magnetic resonance imaging (MRI) showed high signal intensity areas in the periventricular deep cerebral white matter and subcortical white matter (mainly in the parieto-temporo-occipital lobes), findings typical of posterior reversible encephalopathy syndrome. After the MRI findings, her nitroglycerin infusion was stopped, and antihypertensive therapy was initiated using beta blockers and alpha-agonists. She was also treated with continuous venovenous hemofiltration. PMID- 21663818 TI - Severe back pain following epidural analgesia in patients with spinocerebellar ataxia: a report of two cases. AB - Two patients with spinocerebellar ataxia received epidural analgesia with no exacerbation of their symptoms. The patients developed transient, but extremely severe, low back pain as a result of the epidural analgesia. PMID- 21663819 TI - Perioperative management of partial face transplantation involving a heparin antibody-positive donor. AB - Heparin-induced thrombocytopenia (HIT) is an immunologic condition that may lead to thrombosis. We present a case of face transplantation from a donor who had suffered a severe stroke, possibly from HIT, during cardiac surgery. The procedure was planned to include full heparinization. The anesthesia team was involved in the early planning phase and had detailed access to the donor's medical history; alternative anticoagulation for the donor and recipient was suggested so as to avoid a possible complication. PMID- 21663820 TI - Delayed awakening following inadvertent high-dose remifentanil infusion in a 13 year old patient. AB - We report the case of a 13 year old patient who received 3.0 mg of remifentanil during a 50-minute surgical procedure as a result of a dosage miscalculation. The patient failed to awaken at the conclusion of the procedure and showed signs of opioid overdose. She recovered spontaneously two hours later. PMID- 21663821 TI - Axillary arterial catheter use associated with hand ischemia in a multi-trauma patient: case report and literature review. AB - A case of hand ischemia associated with use of an axillary arterial catheter in a multi-trauma patient is presented. Despite removal of the arterial catheter and limb salvage procedures, distal hand gangrene developed. Simple measures such as minimizing dressings, use of distal continuous pulse oximetry, placement of invasive arterial catheters in the nondominant extremity, and avoiding their use whenever possible may prevent complications and minimize morbidity. PMID- 21663822 TI - Carcinoid syndrome and perioperative anesthetic considerations. AB - Carcinoid tumors are uncommon, slow-growing neoplasms. These tumors are capable of secreting numerous bioactive substances, which results in significant potential challenges in the management of patients afflicted with carcinoid syndrome. Over the past two decades, both surgical and medical therapeutic options have broadened, resulting in improved outcomes. The pathophysiology, clinical signs and symptoms, diagnosis, treatment options, and perioperative management, including anesthetic considerations, of carcinoid syndrome are presented. PMID- 21663823 TI - Successful difficult airway management for a rare case of iatrogenic tracheal foreign body. PMID- 21663824 TI - Tonsillar injury caused by the Airtraq optical laryngoscope in children. PMID- 21663825 TI - Fiberoptic tracheal intubation through a Boussignac valve to maintain continuous oxygenation during intubation in severely obese patients: 11 cases. PMID- 21663827 TI - Epigenetic drug discovery special issue. PMID- 21663828 TI - Enhancing recovery and performance in sport. PMID- 21663829 TI - Young elite cross-country skiers and low back pain-A 5-year study. AB - OBJECTIVES: To evaluate possible changes in spinal curvature over a period of 5 years of an elite cross-country skiing squad, and to study whether there are any differences in this respect between individuals who report low back pain and those how do not. PARTICIPANTS: Fifteen young cross-country skiers (M age=13.6+/ 0.9) participated voluntarily throughout the entire study period. MAIN OUTCOME MEASURES: Debrunner's kyphometer was used for measuring the difference between thoracic kyphosis and lumbar lordosis of the spine. All subjects also answered a questionnaire including questions about ski-related low back pain, the amount of ski training, and participation in other sports. RESULTS: The results at the end of the 5-year period comprise data from 15 skiers (M age=18.5+/-0.9 years). The relationship between thoracic kyphosis and lumbar lordosis increased from 3.5 degrees to 13.1 degrees , respectively (p=0.0001). Of the 15 elite cross-country skiers, seven reported low back pain at the 5-year examination. At the 5-year follow-up, skiers with low back pain showed significantly higher relationship between thoracic kyphosis and lumbar lordosis than did those skiers without low back pain, 18.2 degrees and 10.5 degrees , respectively (p=0.035). Of the eight elite cross-country skiers without low back pain, seven were also involved in other sports (p=0.005). CONCLUSIONS: Based on these findings, our advice is that adolescent cross-country skiers also should participate in other physical activities besides cross-country skiing. PMID- 21663830 TI - Repeated single-limb postural stability testing elicits a practice effect. AB - OBJECTIVE: To document the effects of repeated testing on the single-leg stance balance task. DESIGN: Single cohort repeated measures. SETTING: Laboratory in an educational institution. SUBJECTS: Thirty-two healthy males and females. OUTCOME MEASURE: The number of errors (deviations from the required posture) during each 20-s trial summed over the eight conditions recorded on six occasions. RESULTS: There was a statistically significant (p=.0013) decrease in the number of errors recorded over the six sessions, from 26.8 (95% CI: 23.1-30.5) to 19.7 (95% CI: 16.3-23.1). Linear regression confirmed a systematic decrease of 1.5 errors per session on average (95% CI: 1.0-1.9; p<.0001). CONCLUSION: The decreased number of errors (increased performance) with repeated testing alerts clinicians to the need for care when using this test protocol to measure rehabilitation interventions. PMID- 21663832 TI - Acute changes in passive stiffness and range of motion post-stretching. AB - PURPOSE: To investigate the change in passive hamstring stiffness and knee joint range of motion (ROM) following a single bout of passive hamstring stretching with or without active movement post-stretch. METHODS: A Kincom dynamometer was used to measure knee joint ROM and passive stiffness in nine participants. Each participant completed three conditions: (1) a baseline test of knee extension ROM and passive stiffness, 4*20 second static stretches of the hamstring muscles and repeat testing immediately post-stretch and at 5min intervals for 20min; (2) the same procedure with the addition of 90s of isotonic knee flexion and extension between tests over the 20min post-stretching period; (3) the control condition involving repeat tests only over 20min. RESULTS: Knee joint ROM increased by 4-5 degrees post-stretch in both intervention conditions, relative to the control condition, but there was no clear evidence of the ROM increase lasting longer than 5min. Both intervention conditions showed a small decrease in passive stiffness post-stretch and it is likely this effect lasted for at least 20min. CONCLUSIONS: An isolated bout of stretching produced a small, short-lived change in ROM and stiffness. This has implications for the design of warm-up protocols. PMID- 21663831 TI - Assessing dynamic knee joint range of motion using siliconcoach. AB - OBJECTIVE: Compared to measuring static range of motion (ROM) the assessment of dynamic ROM has received very little research attention. The purpose of this study therefore was to determine the reliability of the siliconCOACH motion analysis system for assessing dynamic ROM of the knee joint. DESIGN: Test-retest reliability. SETTING: Laboratory. PARTICIPANTS: Ten male subjects unable to fully extend their knee at 90 degrees of hip flexion. MAIN OUTCOME MEASURES: Static and dynamic ROM over four separate occasions using a video camera and siliconCOACH digitized footage. RESULTS: The variation between days for both static and dynamic measurements was minimal (CV<2.1%). With regards to test retest reliability, the ICC values, were high (ICC?0.89) for both assessment techniques and the static and dynamic ROM measurements did not differ significantly (p<0.05) on any given testing occasion. CONCLUSIONS: The high ICC and low CVs indicate a high degree of stability between testing days for the procedures used in this study to assess dynamic ROM. Software programmes such as siliconCOACH seem ideal for determining the end range of a movement for both static and dynamic ROM and would seem to offer a functional and cost effective assessment strategy for those practitioners and clinicians interested in the effects of various interventions on ROM. PMID- 21663833 TI - The physiotherapy management of muscle haematomas. AB - Muscle haematomas may present in athletes following a muscle tear or contusion injury. The objective of this literature review was to examine the literature pertaining to the physiotherapeutic management of muscle haematomas. An electronic literature search was performed of the databases AMED, Cinahl, Embase, PEDro and Ovid Medline from their inception to April 2006. Human and animal subject, clinical trials, written in English, which could assist in the assessment of this topic, were included. Seventeen (of 7794) papers met the inclusion criteria and were reviewed. The review concluded that few clinical trials have been published assessing the efficacy of these strategies. Furthermore, since numerous methodological weaknesses plagued the limited evidence-base, it was not possible to support or refute the application of different physiotherapy modalities, for the treatment of muscle haematomas. Further study is recommended to identify the best therapeutic interventions to treat muscle haematomas. PMID- 21663834 TI - Endocrine disease in HIV infection. PMID- 21663835 TI - The effects of HIV-1 infection on endocrine organs. AB - Early in the HIV epidemic, multiple endocrine and metabolic abnormalities were observed in HIV-infected patients. These abnormalities were either related glandular infection or infiltration with opportunistic diseases or the effects of systemic inflammation and severe illness on hormonal function and metabolic homeostasis. This review describes the epidemiology and pathogenesis of dyslipidemia, disorders of bone homeostasis, and dysfunction of the adrenal, gonadal, and thyroid axes in the untreated HIV-infected patient. While this review is most applicable to the HIV epidemic in the developing world where effective antiretroviral therapy is not available, understanding the effect of systemic inflammation on endocrine and metabolic function in the untreated HIV infected person has valuable lessons for the pathogenesis of endocrine disease in HIV-infected patients receiving antiretroviral treatment. PMID- 21663836 TI - Disorders of fat partitioning in treated HIV-infection. AB - HIV-associated lipodystrophy is clinically characterized by body fat changes including subcutaneous fat loss (lipoatrophy) with or without truncal fat accumulation (lipohypertrophy). Thymidine nucleoside reverse transcriptase inhibitors, stavudine and to a lesser extent zidovudine, are major contributors for lipoatrophy. Drug factors are not clear for lipohypertrophy. Restoration to health with effective viral suppression and weight gain may be factors playing significant roles in lipohypertrophy. Mitochondrial dysfunction and inflammation in subcutaneous adipose tissue are key factors in the pathogenesis of HIV associated lipoatrophy. The pathogenesis of lipohypertrophy is less well understood. Switching from thymidine nucleoside reverse transcriptase inhibitors restores subcutaneous fat in patients with HIV-associated lipoatrophy, but improvement is slow and limited. Surgical filling cosmetically improves facial lipoatrophy. Exercise and diet may reduce increased visceral adipose tissue. Liposuction may be useful to remove superficial, localized fat accumuli. PMID- 21663837 TI - Lipid metabolism in treated HIV Infection. AB - Patients infected with the human immunodeficiency virus (HIV) are prone to a great number of lipid and lipoprotein disturbances, as a result of both the infection itself and direct effects on lipid metabolism from the drugs used to treat HIV infection. These lipid disorders account for at least part of the increased risk of cardiovascular disease seen in this population. In general, evaluation and interventions for dyslipidemia in HIV-infected individuals should follow guidelines established for the general population. Special consideration, however, must be given to the potential for adverse drug interactions between lipid lowering drugs and the agents used to treat HIV infection. In this review, we summarize what is known about the relative tendency of different antiretroviral drugs to alter lipid levels, and suggest an approach to intervention for dyslipidemia in this population. PMID- 21663838 TI - Insulin resistance in treated HIV infection. AB - Insulin resistance (IR) was one of the first metabolic complications reported with highly active antiretroviral therapy for HIV infection. It continues to be of concern despite the introduction of newer antiretrovirals with safer metabolic profiles and is associated with inflammation and the development of diabetes mellitus. As the HIV-infected population ages, the prevalence of IR is likely to rise. Specific antiretrovirals can increase insulin resistance through two principal mechanisms, either directly by interfering with insulin signalling at the cellular level or indirectly as a consequence of defects in lipid metabolism (lipotoxocity) arising from antiretroviral toxicities such as the IR observed in those with HIV-associated lipodystrophy. There is considerable overlap between different antiretrovirals in their propensity to cause IR making it more difficult to attribute development of IR to a particular antiretroviral medication. In addition, in the setting of a generalised epidemic of obesity that exists in many populations worldwide, HIV-infected patients may be more prone to the consequences of antiretroviral-induced insulin resistance and diabetes mellitus. Optimal screening and treatment strategies for IR in treated HIV infection have not been established. In this article we review current opinion on insulin resistance in HIV and identify potential areas for future research. PMID- 21663840 TI - The prevalence and pathogenesis of diabetes mellitus in treated HIV-infection. AB - HIV-associated morbidity and mortality have declined significantly since the introduction of highly active antiretroviral therapy (HAART). These developments have allowed an increased focus on associated adverse metabolic effects, such as dyslipidemia, diabetes mellitus, and insulin resistance, which are risk factors for cardiovascular disease and other adverse outcomes. The pathophysiologic mechanisms underlying the metabolic changes are complicated and not yet fully elucidated due to the difficulty of separating the effects of HIV infection from those of HAART, co-morbidities, or individual patient vulnerabilities. This article reviews studies concerning the prevalence and incidence of diabetes mellitus and HIV, HIV-specific effects on diabetes mellitus complications, and HIV-specific diabetes mellitus treatment considerations. PMID- 21663839 TI - Molecular mechanisms for insulin resistance in treated HIV-infection. AB - Identification and characterization of the molecular mechanisms contributing to the high incidence of insulin resistance in HIV infected patients treated with combined antiretroviral therapy remains a critically important goal in the quest to improve the safety of antiretroviral treatment regimens. The use of in vitro model systems together with the investigation of drug-mediated effects on glucose homeostasis in animals and healthy human volunteers has provided important insight into the contribution of individual drugs to insulin resistance and affected cellular pathways. HIV protease inhibitor mediated blockade of glucose transport and nucleoside reverse transcriptase inhibitor mediated mitochondrial toxicity have been well characterized. Together with growing understanding of mediators of insulin resistance in non-HIV metabolic syndrome, additional cellular effects including the induction of endoplasmic reticulum and oxidative stress, altered adipocytokine secretion, and lipotoxicity have been integrated into this developing picture. Further elucidation of these mechanisms provides potential for the continued development of safer antiviral drugs and targeted treatment of insulin resistance in affected patients. PMID- 21663841 TI - The metabolic syndrome in HIV. AB - The metabolic syndrome (MS) is a term used to describe the clustering of risk factors for cardiovascular disease (CVD), including elevated triglyceride (TG), low high density lipoprotein cholesterol (HDL), hypertension, hyperglycemia/ insulin resistance and intra-abdominal obesity. This paper discusses why the prevalence of MS in the setting of HIV has been reported to range from 7-45% and how antiretroviral drugs might contribute to the development of MS. The MS has been reported to be a 'CVD risk enhancer', and much debate is ongoing on the independent risk of CVD associated with the MS. Based on a limited number of studies on MS in HIV with clinical end-points, there is no data to support that the MS is independently associated with an increased risk of CVD. PMID- 21663842 TI - Adipose tissue biology and HIV-infection. AB - HIV-1/highly active antiretroviral therapy-associated lipodystrophy syndrome (HALS) is an adipose tissue redistribution disorder characterized by subcutaneous adipose tissue lipoatrophy, sometimes including visceral adipose tissue hypertrophy and accumulation of dorsocervical fat ('buffalo hump'). The pathophysiology of HALS appears to be multifactorial and several key pathophysiological factors associated with HALS have been identified. These include mitochondrial dysfunction, adipocyte differentiation disturbances, high adipocyte lipolysis, and adipocyte apoptosis. These alterations in adipose tissue biology expand to involve systemic metabolism through alterations in endocrine functions of adipose tissue (via disturbed adipokine release), enhanced production of pro-inflammatory cytokines and excessive free fatty-acid release due to lipolysis. The deleterious action of some antiretroviral drugs is an important factor in eliciting these alterations in adipose tissue. However, HIV-1 infection-related events and HIV-1-encoded proteins also contribute directly to the complex development of HALS through effects on adipocyte biology, or indirectly through the promotion of local inflammation in adipose tissue. PMID- 21663843 TI - Endocrine complications of human immunodeficiency virus infection: hypogonadism, bone disease and tenofovir-related toxicity. AB - Treatment with highly active antiretroviral therapy (HAART) has revolutionized care of patients with HIV infection. The cost of increased survival has been antiretroviral toxicity and increasing age-related co-morbidities that include significant metabolic issues. Hypogonadism was first described in the setting of advanced AIDS and can be primary or secondary. Data regarding treatment largely concern patients with wasting. Varied syndromes involving bone have been described in patients with HIV including osteonecrosis, low bone mineral density (BMD) and osteoporosis, and rarely osteomalacia. Low BMD leading to osteoporosis is the most common bone pathology and may be as a result of HIV infection, drug toxicity or co-morbidities. However, increasingly fragility fractures are reported in HIV-infected patients, suggesting bone demineralization in this population is of clinical relevance. Further research is required to understand its pathogenesis and determine effective management; however, initiation of antiretroviral therapy seems to accelerate (in the short-term) bone demineralization. One particular antiretroviral agent, tenofovir is widely used and is potentially implicated as having a greater role in long-term bone and renal dysfunction. As this population ages, screening for low BMD will become increasingly more important. PMID- 21663844 TI - Growth hormone and HIV infection: contribution to disease manifestations and clinical implications. AB - In untreated HIV patients growth hormone deficiency contributes to loss of lean and fat mass. Pharmacologic doses of growth hormone successfully reverse this wasting process. In patients responding to antiretroviral therapies several non AIDS-related complications usually common among older, uninfected persons now occur more frequently in younger HIV patients. Among these conditions are cardiovascular disease and metabolic disorders. Although their etiology is multifactorial, changes in growth hormone biology reflecting relative growth hormone deficiency occur and may be involved. In these patients truncal obesity, and associated dyslipidemia and glucose homeostasis changes contribute to impaired quality of life and increased cardiovascular risk. Treatment with growth hormone and growth hormone releasing factor leads to short-term improvement of some of these abnormalities. This paper will review abnormalities of growth hormone biology and the use of growth hormone and growth hormone releasing factor as therapeutic agents in HIV patients. PMID- 21663845 TI - Editorial. PMID- 21663846 TI - Epidemiological aspects of studying work-related musculoskeletal disorders. AB - There are many challenges to conducting valid epidemiological research of work related musculoskeletal disorders and interpreting reports describing the results. In particular, these concern the basic study design, selection of subjects, measurement of exposure and outcome, control of confounding and the limitations of workers' compensation data systems. Researchers and people interested in the research results need to be aware of the major potential problems and pay careful attention to them when designing, conducting and using the results of such research. PMID- 21663848 TI - Hand pain other than carpal tunnel syndrome (CTS): the role of occupational factors. AB - Some occupational factors have been implicated in the development of disorders manifested as hand pain. The associations seem to be well documented in processes such as hand-arm vibration syndrome (HAVS) or writer's cramp. There are contradictory data in the literature about the relationships of trigger finger, De Quervain's tenosynovitis (DQT) and tenosynovitis of the wrist with occupational factors. In this article, we review current knowledge about clinical manifestations, case definition, implicated occupational factors, diagnosis and treatment of the most relevant hand pain disorders that have been associated with occupational factors, excluding carpal tunnel syndrome (CTS). PMID- 21663847 TI - Carpal tunnel syndrome: the role of occupational factors. AB - Carpal tunnel syndrome (CTS) is a fairly common condition in working-aged people, sometimes caused by physical occupational activities, such as repeated and forceful movements of the hand and wrist or use of hand-held, powered, vibratory tools. Symptoms may be prevented or alleviated by primary control measures at work, and some cases of disease are compensable. Following a general description of the disorder, its epidemiology and some of the difficulties surrounding diagnosis, this review focusses on the role of occupational factors in causation of CTS and factors that can mitigate risk. Areas of uncertainty, debate and research interest are emphasised where relevant. PMID- 21663849 TI - Lateral and medial epicondylitis: role of occupational factors. AB - Epicondylitis is a common upper-extremity musculoskeletal disorder. It is most common at the age of 40-60 years. Epicondylitis seems to affect women more frequently than men. Diagnosis of epicondylitis is clinical and based on symptoms and findings of physical examination. The prevalence of lateral epicondylitis in the general populations is approximately 1.0-1.3% in men and 1.1-4.0% in women and that of medial epicondylitis is nearly 0.3-0.6% in men and 0.3-1.1% in women. The incidence rate of medical consultations has been estimated at 0.3-1.1 for lateral and 0.1 for medial epicondylitis per year per 100 subjects of general practice populations. Of occupational risk factors, forceful activities, high force combined with high repetition or awkward posture and awkward postures are associated with epicondylitis. The number of studies is limited to work-related psychosocial factors and the effects are not as consistent as those of physical load factors. Topical non-steroidal anti-inflammatory drugs, corticosteroid injections and acupuncture provide short-term beneficial effects. Workload modification should be considered, especially in manually strenuous jobs. According to clinical case series, surgical treatment has shown fair to good results; however, the efficacy of surgical treatment has not been evaluated in randomised controlled trials. Poorer prognosis of epicondylitis has been reported for individuals with high level of physical strain at work, non-neutral wrist postures during work activity and for those with the condition on the dominant elbow. Modification of physical factors could reduce the risk or improve the prognosis of epicondylitis. PMID- 21663850 TI - Shoulder pain at the workplace. AB - Shoulder pain is among the most common of regional musculoskeletal complaints in the work environment. It is also a very common problem in the broader community. A challenge to health professionals working in this area is that only a small proportion of shoulder pain at work can be explained by conditions that are readily identifiable (such as rotator cuff disease) and can be adequately managed in a medical model. A greater proportion of shoulder pain at work cannot be understood in this way, and standard medical management is unlikely to offer the best chance of recovery. Furthermore, current research suggests that traditional work-related associations and risk factors only explain a minor part of the total problem and that ergonomic approaches focusing on primary prevention are also unlikely to adequately address the problem. This article examines recent research in the area of work-associated shoulder pain. It focuses on the recent literature examining classification of shoulder pain, and the assessment, management and prognosis of this challenging, regional musculoskeletal pain problem and argues for a more encompassing approach to its management. PMID- 21663851 TI - Neck and back pain and intervertebral disc degeneration: role of occupational factors. AB - Back pain is a near-universal human experience at some time during life, and neck pain is also common. The overwhelming majority of low back and cervical pain is considered to be due to unspecified mechanical factors or disc degeneration, which is a common with ageing and, hence, in people of working age. Back pain and disc disease appear to have significant heritability, based upon twin studies, but environmental factors also contribute - including physical occupational activities in some studies - although the strength of this association remains uncertain. This article examines the contribution of genetic and environmental factors to back pain and disc disease, with a specific focus on occupational exposures. PMID- 21663852 TI - Hip and knee pain: role of occupational factors. AB - Many people rely economically on occupations involving high loading of the hip or knee joints for lengthy periods, possibly placing them at increased risk of developing chronic pain in these joints. There is a growing body of evidence from large longitudinal cohort studies, case-control studies and population-based surveys that certain occupations, or having work involving considerable heavy lifting, kneeling or squatting, may be associated with increased risk of symptomatic hip or knee osteoarthritis and joint replacement surgery. Only a few studies have evaluated the effectiveness of specific workplace strategies to reduce this risk. Identifying modifiable workplace risk factors and implementing feasible and accessible preventative strategies will be of great public health significance in the next decade. PMID- 21663853 TI - Factors that affect the occurrence and chronicity of occupation-related musculoskeletal disorders. AB - The components that affect the occurrence and chronicity of musculoskeletal disease are multifactorial. The return to work process and prevention of future chronic disability commences at the time of the initial assessment. The clinician can identify, at an early stage, patients with negative expectations of return to work and adopt a care plan oriented to functional adaptation. Medical and psychosocial treatment plans taking account of coping preferences, beliefs and practices are more likely to help prevent chronic disability. Other factors that can influence the long-term disability rate include medically discretionary or unnecessary time off work and litigation itself. Workplace factors can result in unnecessary absenteeism and poorly managed presenteeism. PMID- 21663854 TI - Management of occupation-related musculoskeletal disorders. AB - Occupation-related musculoskeletal disorders are a common clinical problem. Management presents challenges in understanding the factors that give rise to work loss and disability. To improve outcomes, practitioners need to screen for risk factors, understand the demands of work and workplaces and be prepared to actively assist the process of work return. There are limitations with regard to many therapeutic modalities commonly used, though there are many useful adjuncts for the physician in achieving improved outcomes. PMID- 21663855 TI - Clinical trials of vascular disrupting agents in advanced non--small-cell lung cancer. AB - Tumor vascular disrupting agents (VDAs), such as the flavonoid compound ASA404 and the tubulin-binding compound combretastatin, selectively disrupt established tumor blood vessels, inhibit tumor blood flow, and induce extensive necrosis at the core of solid tumors. A rationale for combining tumor VDAs with standard chemotherapy for treating advanced non-small-cell lung cancer (NSCLC) includes their complementary actions on different spatial regions of solid tumors and their additive or synergistic preclinical activity in animal models of lung cancer. A randomized, phase II, multicenter, open-label trial with a single-arm extension phase evaluated outcomes in a total of 104 patients (> 18 years of age) with histologically confirmed stage IIIb or stage IV, previously untreated NSCLC that in this trial was treated with ASA404 plus standard chemotherapy vs. standard chemotherapy alone. Adding ASA404 to standard chemotherapy numerically improved tumor response, time to disease progression, and overall survival in this phase II trial, without significantly increasing the incidence or severity of side effects. Other randomized phase II and phase III clinical trials of ASA404 and combretastatin combined with standard chemotherapy in advanced NSCLC are currently ongoing or will be reported shortly. PMID- 21663856 TI - Scar carcinoma of the lung: a historical perspective. AB - Lung scar carcinoma (SC) was first described by Friedrich in 1939 as a type of lung cancer that originates around peripheral scars in the lung. Scarring in the lung can result from a variety of infections, injuries, and lung diseases. Scars can also be due to repeated episodes of tumor necrosis and healing. SCs are typically found as subpleural adenocarcinomas with retraction or puckering of the overlying pleura. They were considered a histologic curiosity that was promoted for decades until doubts about their existence were raised in the 1980s. Finding type III collagen, type V collagen, and myofibroblasts characteristic of fibrosis in the scars, finally reversed the original SC concept. The presence of type III collagen and extracellular matrix suggested an ongoing fibrosing process secondary to host response to the neoplasm. The high concentration of type III collagen in SC indicates that the fibrous tissue is in an active immature state compared with noneuplastic fibrous tissue, which is mature and contains type I and type V collagen. A recent cohort analysis of data from the PLCO (Prostate, Lung, Colorectal and Ovarian) cancer screening trial demonstrated a correlation between the presence of scar and the development of carcinoma, but the causation of this association has to be determined by future studies. The role of inflammation, infections, and smoking in the development of cancer is discussed in this article. Additional research is necessary to determine if lung scarring detected by imaging requires clinical monitoring in the context of the development of lung cancer when a defined set of risk factors is identified. PMID- 21663858 TI - A phase II study of carboplatin and irinotecan in extensive stage small-cell lung cancer. AB - OBJECTIVES: Our study set out to determine the antitumor efficacy of carboplatin and irinotecan as assessed by response rate in persons with chemotherapy-naive extensive-disease, small-cell lung cancer (ED-SCLC). Secondary objectives included progression-free survival (PFS), overall survival, and toxicity findings. METHODS: Patients with previously untreated ED-SCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2, life expectancy >= 3 months, and adequate organ function were eligible. Patients were treated with carboplatin AUC 5 intravenously over 30-60 minutes on day 1, followed by CPT 11(irinotecan) 50 mg/m(2) intravenously over 30-90 minutes on days 1 and 8 every 3 weeks for 4-6 cycles at the discretion of the treating physician. RESULTS: Fifty-six patients were enrolled, and 50 patients were eligible. The median age of patients was 60.1 years. The most common toxicities were neutropenia, thrombocytopenia, nausea/vomiting, and dehydration. The overall response rate was 58%. Median PFS was 5.3 months, median overall survival was 9.7 months, and 1 year overall survival was 28.7%. CONCLUSIONS: Carboplatin and irinotecan is a safe and reasonable combination for the treatment of patients with ED-SCLC. PMID- 21663857 TI - Docetaxel vs. vinorelbine in elderly patients with advanced non--small-cell lung cancer: a hellenic oncology research group randomized phase III study. AB - BACKGROUND/PURPOSE: This study compared front-line treatment with docetaxel or vinorelbine in elderly patients with advanced/metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with inoperable stage IIIB and stage IV NSCLC who were > 65 years of age with performance status (PS) of 0-2 were enrolled. Patients were assigned to receive either docetaxel 38 mg/m(2) or vinorelbine 25 mg/m(2) by intravenous (I.V.) infusion on days 1 and 8 every 3 weeks. RESULTS: One hundred thirty elderly patients were enrolled in the study (docetaxel n = 66 and vinorelbine n = 64 patients). The objective response rate was 12.1% and 14.1% in patients treated with docetaxel and vinorelbine, respectively (2P = .799). The median time to tumor progression (TTP) was 2.33 and 1.9 months (2P = .298) and the median overall survival (OS) was 6.07 and 3.87 months (2P = .090) in the docetaxel and vinorelbine arms, respectively. Grade 3/4 neutropenia occurred in 4.5% and 29.7% of patients in the docetaxel arm and vinorelbine arm, respectively (2P < .001). Febrile neutropenia occurred in 1.5% and 1.6% of patients in the docetaxel arm and the vinorelbine arm, respectively (2P = .950) and the use of granulocyte colony-stimulating factor (G-CSF) was more frequent in patients treated with vinorelbine (37.1% vs. 22.5%; 2P < .001). There were no deaths from toxicity. Nonhematologic toxicity was mild. CONCLUSIONS: Docetaxel has an efficacy comparable to that of vinorelbine as first-line treatment in elderly patients with NSCLC and has an acceptable toxicity profile. The trial was closed prematurely because of low accrual, thus limiting the strength of the conclusions derived. PMID- 21663859 TI - The role of NF-E2-related factor 2 in predicting chemoresistance and prognosis in advanced non-small-cell lung cancer. AB - BACKGROUND: NF-E2-related factor 2 (Nrf2) plays an important role in platinum chemoresistance by activating transcription of target genes through binding to the antioxidant response element (ARE) in gene promoters, moreover it could stimulate tumor growth in non-small-cell lung cancer (NSCLC). The objective of this study was to elucidate the correlation between Nrf2 expression and platinum based chemotherapy response as well as the prognostic significance of Nrf2 levels. PATIENTS AND METHODS: Immunohistochemical analysis of Nrf2 in tumor specimens was performed in a total of 60 patients with stage IIIB or IV NSCLC. RESULTS: Positive staining for Nrf2 was found in nearly all cases, just at different levels. High Nrf2 expression was noted in 34 of 60 patients (56.7%). The expression of Nrf2 correlated with age (P = .014), stage (P = .017), and performance status (P = .014). The response rate of platinum-based chemotherapy in patients with < 75% positive staining was significantly higher than that in patients with 75%-100% positive staining (P = .003; r = 0.447). Furthermore, a high percentage of Nrf2 staining was the independent prognostic factor in progression survival (P = .000) analysis. CONCLUSION: We suggest that the assessment of Nrf2 expression may be useful for evaluating chemoresistance and tumor progression in patients with advanced stage NSCLC. PMID- 21663860 TI - Serum tumor markers CEA, CYFRA21-1, and CA-125 are associated with worse prognosis in advanced non-small-cell lung cancer (NSCLC). AB - BACKGROUND: Serum tumor markers are considered a negative prognostic factor in early-stages NSCLC but its role in advanced disease is controversial. The aim of this study is to analyze the prognostic value of tumor markers in advanced NSCLC. PATIENTS AND METHODS: Two hundred and seventy seven patients diagnosed in our institution were retrospectively reviewed. Baseline prognostic factors analyzed were gender, histology and brain metastases. RESULTS: Baseline patients characteristics: median age 63 years (30-81 years); males 84.4%, stage IV: 61.7%; adenocarcinoma 38.6%, squamous carcinoma 22.4%. High levels of CEA, CYFRA21-1, and CA125 levels were detected in 179 (55.9%), 119 (65%), and 129 (46.6%) patients respectively. Significant higher levels of CEA and CA125 at baseline were present in adenocarcinoma (P < .05). PFS in patients with elevated CEA, CYFRA21-1, and CA125 was 5.3 months (m), 3.5 m and 4.6 m versus 7.4 m, 6.2 m and 7.5 m in patients with normal levels (P < .05). The OS in patients with high and normal levels of tumor markers was 10.0 m vs 14.0 m (P = 0.085) for CEA; 5.6 vs 12.1 m for CYFRA21-1 (P = .002), and 8.7 vs 14.0 (P = .03) for CA125. In the multivariate analysis high levels of tumor markers, histology and clinical stage were significant correlated with worse prognostic. Patients with all the tumor markers elevated presented the worst prognosis (3.6 m for PFS and 7.1 m for OS, P < .001). CONCLUSION: In our analysis, high levels of tumor markers at baseline are correlated with worse survival in stage III-IV NSCLC patients. PMID- 21663861 TI - Frameless image-guided stereotactic body radiation therapy for lung tumors with 4 dimensional computed tomography or 4-dimensional positron emission tomography/ computed tomography. AB - BACKGROUND/PURPOSE: To augment the accuracy of stereotactic body radiation therapy (SBRT), a variety of image guidance systems are used for patient positioning and target localization. Clinical outcomes evaluating these systems, especially frameless image-guided systems, are still limited. This article aims to describe and evaluate our frameless image-guided SBRT technique for lung tumors. METHODS: Between 2007 and 2009, 85 pulmonary tumors (50 primaries and 35 metastases) were treated with SBRT using daily image guidance for patient positioning and target localization in lieu of a body frame. Four-dimensional computed tomography (4DCT) or an in-house protocol for integrated 4D positron emission computed tomography (4DPET/CT) was used for planning simulation. RESULTS: Median follow-up was 17 months (range, 4-42). Median overall survival (OS) was 31 months (95% CI, 26-34), and median local failure-free survival was 30 months (95% CI, 18-32). At last follow-up, 9 of 83 evaluable lesions failed locally. Actuarial local control at 24 months was 87% (95% CI, 75-98) and was significantly worse for metastatic lesions (95% vs. 74%; P = .045; log-rank test). No acute or late toxicities (grade >= 4) were observed. CONCLUSIONS: Frameless image-guided SBRT is a feasible, safe, and effective treatment for lung tumors. PMID- 21663863 TI - Clinical value of assaying tumor supplied group of factor/tumor specific growth factor in patients with solitary pulmonary nodule. AB - OBJECTIVE: This pilot study was designed to evaluate the clinical value of assaying tumor supplied group of factor/tumor specific growth factor (TSGF) in solitary pulmonary nodule (SPN). PATIENTS AND METHODS: The study was conducted from March 2007 to September 2010 and included 33 patients with SPN and 28 healthy volunteers. TSGF was assayed in preoperative serum, intraoperative pleural lavage fluid (IPLF), and postoperative serum. RESULTS: At operation, 20 patients were diagnosed with malignancy and 13 patients were diagnosed with nonmalignancy and placed in group A and group B, respectively. In group A, pathologic staging demonstrated 8 patients (group A1) with stage T1N0M0, 7 patients (group A2) with stage T1N1M0 and 53 patients (group A) with stage T1N2M0 disease. In group B, 8 patients were diagnosed with tuberculoma (group B1) and 5 patients were diagnosed with inflammatory pseudotumor (group B2). Before operation, levels of TSGF in peripheral blood were significantly higher in group A compared with group B and the control group (98.8 +/- 29.9 vs. 62.1 +/- 24.9 and 50.1 +/- 17.9, Student-Newman-Keuls test; P < .05). The percentage of patients with positive serum TSGF results was significantly higher in group A than in group B or the control group (90.0% vs. 30.8% and 17.9%, chi(2) test; P < .05). With respect to the diagnostic value of serum TSGF in malignant SPN, we found sensitivity to be 90%, specificity to be 69.2%, positive forecast rate to be 74.5%, negative forecast rate to be 87.4%, and accurate diagnosed rate to be 79.5%. The TSGF level in IPLF in group A was significantly higher than that in group B (132.2 +/- 51.9 vs. 84.6 +/- 12.6, Student t test, P < .05). Additionally, TSGF in group A2 and group A3 was significantly higher compared with group A1 (162.2 +/- 52.3 and 176.4 +/- 17.8 vs. 100.2 +/- 35.8, Student Newman-Keuls test; P < .05). Postoperative serum TSGF in the patients diagnosed with lung cancer decreased significantly after operation. TSGF returned to a normal threshold level (71 U/mL) in the sixth month postoperatively. In addition, there was no appreciable change in the patients in group B. CONCLUSION: Serum TSGF is conducive to discriminating between benign and malignant features of SPN. Additionally, investigation of IPLF TSGF can potentially offer a new approach to predict the existence of lymph node metastases. PMID- 21663862 TI - A phase II study of higher dose weekly topotecan in relapsed small-cell lung cancer. AB - BACKGROUND: Five-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m(2) intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR) < 10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity. PATIENTS AND METHODS: This multicenter phase II trial sought a 25% ORR (alpha = 0.04; beta = 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m(2) I.V. for 6 weeks) and were restaged every 8 weeks. RESULTS: Baseline characteristics were N = 38, enrolled 5/2006 10/2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (> 10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment related deaths. CONCLUSION: Weekly topotecan (6 mg/m(2) I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC. PMID- 21663864 TI - Prognostic implications of parathyroid hormone-related protein in males and females with non--small-cell lung cancer. AB - BACKGROUND: Non-small-cell lung carcinoma immunoreactivity for parathyroid hormone-related protein has been associated with increased survival in female patients but not in male patients. The current investigation attempted to substantiate this finding in 2 new patient groups. METHODS: Patients were divided into groups with and without immunoreactivity for a carboxyl-terminal parathyroid hormone-related protein epitope assessed in deparaffinized sections by a blinded observer. One group included 85 female patients with stage I lung cancer, and the second group had 48 female and 66 male patients with stage I-IV lung cancer. Survival times were compared by the log-rank test between groups separated by tumor parathyroid hormone-related protein status. RESULTS: Parathyroid hormone related protein was present in 70%-80% of the patients, independent of sex, stage, and smoking history. In the females with stage I lung cancer, parathyroid hormone-related protein increased median survival from 25 to 60 months (P < .05). In the second group, parathyroid hormone-related protein expression increased 48 month disease-free survival of female lung cancer patients from 44% to 63% (P < .05), but had no effect in male patients. Parathyroid hormone-related protein remained a significant, independent predictor when evaluated together with other covariates by Cox multivariate regression. CONCLUSION: This study verifies that parathyroid hormone-related protein is a sex-dependent survival factor for non small-cell lung carcinoma, that it correlates with disease-free survival, and that the association with survival holds for women with early-stage disease as well as more advanced cancer. Thus, the protein could find use as a prognostic indicator and could be a target for therapy. PMID- 21663865 TI - DNA profiling and forensic dentistry--a review of the recent concepts and trends. AB - BACKGROUND: Teeth are amongst the hardest structures of the human body which are resistant to adverse conditions such as incineration, immersion, trauma, mutilation, decomposition and hence, used in forensic investigations. It is also a valuable source of DNA as other parts of the body gets destroyed or degraded in mass disasters. The fast technological advancements in DNA research have revolutionized the field of forensic medicine and the present work was undertaken to provide an insight in to the recent concepts of DNA profiling in Forensic dentistry. METHODS: Articles were identified by searches in PubMed and Embase electronic databases from 1980 through July 2010. RESULTS: DNA profiling provides an exact identification of an individual in mass disasters, identification of culprits in crime scene investigations and solving paternity issues as well. It also provides information regarding the physical characteristics, ethnicity and sex determination. CONCLUSION: Teeth should be considered for DNA analysis as they are rich sources of quality DNA which can be utilised in all forensic investigations. From variable number tandem repeats (VNTRs) to single nucleotide polymorphism (SNP), the field of forensic DNA research has been true to the characteristics of any scientific process and it has never been static but represents a continuous evolution of technological development. PMID- 21663866 TI - Pesticide use and related health problems among greenhouse workers in Batinah Coastal Region of Oman. AB - Pesticide practices and the health problems associated with pesticide exposure among 74 greenhouse workers in the Batinah Coastal Region of Oman were investigated. The workers were mostly migrant workers from India (37.8%), Bangladesh (28.4%), Nepal (14.9%), Sri Lanka (8.1%) and Pakistan (5.4%). Majority of the workers (44%) had some primary education, were between 31 and 40 years of age (50%), were married (85.1%) and had been applying pesticides for over 10 years (32.4%). Occupational and phytosanitary practices among the pesticide workers were poor, as most of the workers (59.5%) did not wash their hands after pesticide application, many (43.2%) did not shower and some (20.3%) did not change their clothes. Their methods of handling of partly used pesticides were questionable, with 81.1% storing them in other rooms in the house and 14.9% storing them in their bedrooms. Personal protective equipment (PPE) such as nose mask, overall and eye goggles were hardly used during pesticide application. Some of the reported health symptoms due to pesticide exposure were skin irritation (70.3%), burning sensation (39.2%), headache (33.8%), vomiting (29.7%) and salivation (21.6%). It was suggested that a provision be included in the Pesticide Laws of Oman that makes it mandatory for greenhouse owners to provide their workers with PPE. Also, regular training programs should be organized for the greenhouse pesticide workers to improve their ability to handle hazardous chemicals. PMID- 21663867 TI - Medical ethics educational improvement, is it needed or not?! Survey for the assessment of the needed form, methods and topics of medical ethics teaching course amongst the final years medical students Faculty of Medicine Ain Shams University (ASU), Cairo, Egypt 2010. AB - INTRODUCTION: In the process of our faculty gaining accreditation, the debate concerning the necessity for initiating an integrated course in which medical ethics course is implemented have arouse. Arguments concerning what should this course include, the best timing for this course to be applied, how it should be taught, planned for and mostly for what the students are interested to get out of it. GOAL: The main purpose of this work is to identify the ethical needs and ethical dilemmas freshly graduated medical students face at the beginning of their training and their suggestions to seek better educational approaches that can be applied in teaching medical ethics proposed by the medical students themselves throughout the teaching process and after graduation. METHODS: It seemed rather appropriate at this stage to carry out an evaluation survey assessing the needs for medical ethics teaching course through the exploration of the opinions of medical students and freshly graduated doctors on ethical issues through a simple survey by using an open ended question questionnaire designed to fulfil the study targeted requirements. RESULTS: 100 volunteers (n = 100) randomly chosen from the fifth year students of our faculty of medicine ASU who had recently studied ethics course in the fourth year (n = 20), interns both junior and senior residents in El Demerdash hospitals (n = 80). 25 questionnaires were excluded due to inappropriate or missing answers resulting in 75% response rate. 60% of the surveyed group favored an integrated ethics course taught throughout the whole academic years study. 56% chose the practical teaching method with problem solving strategies for the daily arising confusing ethical issues to be the best way to teach the course. While 53.4% thought that stuff specialized in medico legal issues were best to teach this course. As regards the highly confusing ethical dilemmas in which they were interested in getting updated feedback about: Confidentiality, doctor-patient relationship and informed consent came first by 69.3%. CONCLUSIONS: This study revealed the essential need for a model medical ethics curriculum that responds to students' concerns in addition to providing basic training in moral reasoning and ethical decision making to be applied both horizontally and vertically across the whole years of medical school. RECOMMENDATIONS: A Simple booklet containing recent version of the Egyptian code of ethics, common ethical dilemmas and recently evolving ethical issues should be available for all newly graduated health professionals. PMID- 21663868 TI - Sex determination using mandibular ramus flexure: a preliminary study on Indian population. AB - Determination of sex by morphological assessment has been one of the oldest approaches in forensic anthropology. Loth and Henneberg(6) introduced a morphological trait "Mandibular Ramus Flexure" for sex identification with a high accuracy of 99% in African Blacks. However, the population specificity of sexually dimorphic features is well known. The purpose of this study is to test the reliability of this trait in Indian population. A total number of 112 adult mandibles (88 males and 24 females) were studied from the Department of Forensic Medicine, Institute of Medical Sciences, Banaras Hindu University, India. The mandibles were scored according to the original method by two observers in three different sessions. This was done to test inter and intra-observer errors in identifying the trait. The result shows that this trait can be used to diagnose sex with an average accuracy of upto 82%. Though, inter and intra-observer errors were present but could be minimized with extended practice. So, the trait has the potential to be relied upon as a single morphological trait for determination of sex in Indian population. PMID- 21663869 TI - Biomarkers of recent drinking, retrograde extrapolation of blood-alcohol concentration and plasma-to-blood distribution ratio in a case of driving under the influence of alcohol. AB - This case report describes the police investigation of a road-traffic accident involving a collision at night (01.00 am) between a car and a truck in which a passenger in the car was killed. The driver of the truck was found responsible for the crash although a roadside breath-alcohol test was negative (<0.1 mg/L breath or 20 mg/100 mL blood). Because of injuries sustained in the crash, the female driver of the car was not breath-tested at the time but was transported to a local hospital for emergency treatment. After swabbing the skin with isopropanol an indwelling catheter was inserted at 01.40 am. A blood sample was taken at 02.10 am and the plasma portion contained 8 mmol/L ethanol according to analysis at the hospital clinical laboratory using a gas chromatographic method. Another blood sample was taken at 05.45 am for analysis of ethanol at a forensic toxicology laboratory, although the result was negative (<10 mg/100 mL). The police authorities wanted an explanation for the discrepancy between the clinical and forensic laboratory results and inquired whether the driver of the car was above the legal alcohol limit (>20 mg/100 mL) at the time of the crash. The scientific basis for converting a plasma-ethanol concentration into a blood ethanol concentration and back extrapolation of the driver's blood-alcohol concentration (BAC) is explained. The risk of contaminating a blood sample by swabbing the skin with isopropanol is discussed along with the use of alcohol biomarkers (ethyl glucuronide and ethyl sulphate) as evidence of recent drinking. PMID- 21663870 TI - Rupture of the left ventricle due to blunt trauma--a pediatric case study and literature review. AB - Tamponade due to rupture of the chambers of the heart, in particular the left ventricle, after blunt thoracic trauma is described only sparsely in the literature. Most cases involve multiple thoracic trauma following motor vehicle accidents. We present the case study of a five-year old victim of a household accident, in which two concrete basins apparently fell on him. He died rapidly, despite attempted resuscitation. The autopsy showed essentially a hemorrhagic extravasation of the diaphragm and mediastinum, hemopericardium, and massive damage to the apex of the left ventricle. Pathological exam confirmed the traumatic origin of the cardiac rupture, with no underlying pathology. We will discuss the mechanisms described in the literature that result in such lesions, the mechanism which we believe most probable in this case, and the importance of background information. In our case study, lack of specific information concerning the accident prevents a definitive conclusion of the exact mechanism that caused this massive trauma particularly due to the fact that the external examination couldn't find any lesion in favor of a thoracic or abdominal traumatism. To our knowledge, in context of a household accident, such an isolated lesion causing almost immediate death has not previously been described in the literature. PMID- 21663871 TI - Non-fatal gunshot wounds in the context of intimate partner violence. The importance of a multidisciplinary approach: a case report. AB - According to Portuguese law, if a case of intimate partner violence is noticed or suspected by a professional working in public services, reporting it to the police, medico-legal services or directly to the public prosecutor is mandatory. However, in most cases, reporting does not take place, despite its vital importance in triggering the multidisciplinary intervention that will ensure the correct and timely diagnosis and protection of the victim. In the present case, the victim, a 37 year-old woman, was sexually and physically abused by her husband in their home, and was physically abused again at the victim's mother's house. The victim mentioned that her husband struck her in the head with a hammer and shot a handgun while in her mother's house. However, she denied having a gunshot wound. The couple's daughter was also slapped in the face by her father. The police took the victim to the emergency room of a central hospital to receive medical attention, while the medical examiner on duty was called to the same emergency room to perform a medico-legal evaluation in the context of the intimate partner violence reported to the police. Medico-legal assessment revealed scalp injuries that had not been detected during the first inspection by the emergency room attending physicians who had performed a neurological examination, which revealed no neurological dysfunction. A cranial computed tomography with three-dimensional reconstitution and virtual dissection, requested by the medical examiner, revealed two projectiles trapped in between the inner and the outer table of the cranium, with linear fractures only in the inner table and no brain injuries. Gynecological examination with the collection of biological evidence, also performed by the medical examiner, made it possible to identify a male DNA profile matching her husband's. The victim was subjected to neurosurgery and a follow-up, and was released one month after the traumatic event. A forensic psychological evaluation, performed one month after the traumatic event, revealed the presence of reactive symptoms to the occurrence. This multidisciplinary intervention and the use of modern diagnosis imaging techniques allowed for a timely diagnosis and treatment, adequate protection of the victim and her family, as well as the identification of the aggressor, who was arrested. PMID- 21663872 TI - Leda and the Swan--and other myths about rape. AB - In his David Jenkins Memorial Lecture, Dr Norfolk discusses rape and some of the myths that surround the topic, exploring the research evidence about conviction rates, false allegations, clinician gender preferences of rape victims and the role of sexual assault referral centres in service delivery. PMID- 21663873 TI - Methadone & heroin use: a survey of prisoners in police custody. PMID- 21663874 TI - First description of gastroenteritis viruses in Lebanese children: a pilot study. AB - Human enteric viruses are important causes of acute gastroenteritis in infants and children. The role of rotaviruses, adenoviruses, human caliciviruses and astroviruses in the development of severe acute gastroenteritis requiring hospitalization of infants and young children in North Lebanon was investigated. Stool specimens collected between April and May 2010 from 79 Lebanese infants and children hospitalized for severe acute gastroenteritis, were screened for enteric viruses by immunoassays and internally controlled multiplex PCR assay. Out of 79 stool samples, 38 (48%) were positive for rotavirus, and 5 (6%) were positive for norovirus genogroup II. Enteric adenoviruses, sapoviruses and human astroviruses were not detected. Children with severe rotavirus gastroenteritis were younger than those with severe norovirus gastroenteritis. These results highlight the importance of rotavirus and norovirus as causes of severe gastroenteritis in Lebanese children, and the need to incorporate routine screening tests for norovirus infection in clinical settings. PMID- 21663875 TI - Antimicrobial susceptibility and pulsed: field Gel Electrophoretic analysis of Salmonella in a tertiary hospital in northern Malaysia. AB - BACKGROUND AND AIMS: Salmonella infections remain a major public health problem in developing countries. The occurrence of infections caused by antimicrobial resistant Salmonella has been on the rise complicating the available therapeutic options. The study aimed to determine the antibiograms and genotypes of prevalent Salmonella serotypes. METHODS: A retrospective study involving 80 stool and extra intestinal Salmonella strains collected over a 18-month period (January 2005-June 2006) from a tertiary hospital in Penang, Malaysia was conducted. Isolates were examined for resistance to 14 antimicrobial drugs and the clonality of the strains was determined by PFGE. RESULTS: Twenty-one serotypes were identified, the most common being S. enteritidis (42.5%) followed by S. corvallis (11.25%) and S. braenderup (11.25%). S. enteritidis was significantly more common amongst the extra-intestinal isolates compared to stool isolates (74.2% versus 22.4%, p<0.0001). Overall, the highest resistance was observed for tetracycline (66.3%), sulphonamides (56.3%), streptomycin (32.5%), trimethoprim (28.8%) and nalidixic acid (27.5%). Amongst the 31 invasive extra-intestinal isolates, resistance towards therapeutically relevant antibiotics was as follows: co-trimoxazole (38.7%), ampicillin (29%) and ceftriaxone (3.2%). Although there was no detectable resistance towards chloramphenicol and ciprofloxacin, 29% strains showed nalidixic acid resistance. About 41% of the 80 isolates were multidrug resistant. PFGE subtyped the 78 Salmonella isolates to 33 distinct XbaI pulsotypes. Isolates within the serotypes S. enteritidis, S. corvallis, S. branderup and S. fasta were more homogeneous while S. typhi and S. weltervden were genetically more diverse. CONCLUSIONS: The high percentage of multidrug resistant Salmonella strains is worrying and is of public health concern. PFGE was a useful and discriminative method for assessing the genetic diversity of Salmonellae. PMID- 21663876 TI - Evaluation of syndromic management of sexually transmitted infections in Saudi Arabia. AB - BACKGROUND: STIs can lead to acute symptoms, chronic infection and serious delayed consequences such as infertility, ectopic pregnancy, cervical cancer and the untimely death of infants and adults. OBJECTIVES: To identify the points of strength and weakness in the system for management of sexually transmitted infections (STIs) and pattern of distribution of reported cases in Saudi Arabia. METHODS: Data of 5377 reported cases of STIs from all regions of the kingdom during the year 2009 were collected. The original data collection sheets were collected from primary health care centers in all regions of the kingdom, entered into Epi-Info software computer program, organized and statically analyzed. RESULTS: Average monthly reporting was variable between 163.4 cases and 3.3 cases. Age group of 20-40 represented 70.7% of reported cases with the majority Saudis (92%), females (92.9%), literate (59.2%) and married (91.0%). Housewives represented 62% followed by the unemployed (17.3%). The age at first sexual experience ranged from 15 to 25 (81.0%) which was mostly with other sex (95.1%). HIV testing was performed by only 3.0% of reported cases. Vaginal discharge was the most frequent diagnosis (77.6%) followed by lower abdominal pain (42.3%). Urethral discharge and lower abdominal pain differed significantly in relation to sex while scrotal swelling and lower abdominal pain were statistically different in relation to nationality. Vaginal discharge, cervical inflammation and abdominal pain differed significantly in relation to age. CONCLUSION: Syndromic surveillance of STIs is essential to decrease STIs and control human immunodeficiency virus (HIV) infections. There is a need to build capacity of primary health care workers to collect accurate and valid data. Monitoring and evaluation activities are essential to promote program activities. PMID- 21663877 TI - Importance of structured training programs and good role models in hand hygiene in developing countries. AB - The aim of this study is to identify the beliefs and perceptions associated with hand hygiene performance in two different institutions with limited resources and recently established infection control programme later than developed institutions. The study was conducted in two different hospitals (University Hospital-U-hospital and Community Hospital-C-hospital) in the same city by a self administered questionnaire. Most questions were drawn from questionnaires used previously in other studies from "industrialized" countries based on "The Theory of Planned Behavior". All nurses, nurse students (last class), physicians and intern medical students in the U-hospital, and all nurses in the C-hospital were included into the study. Of 1764 questionnaires, 941 (41%) were returned. The return rate was highest for nurses in C-hospital (63.8% [303 of 475]) and lowest for senior physicians in U-hospital (7.5% [16 of 212]). Out of the respondent a total of 16 (1.7%) were senior physicians, 110 (11.6%) were physician assistants, 400 (42.6%) were nurses in the U-hospital, 303 (32%) were nurses in the C hospital, 66 (7%) were medical students and 46 (4.9%) were nurse students. Seven hundred and ninety five (85.9%) of 926 respondents were female. Respondents provided demographic information and data about various behavioral, normative, and control beliefs that determined their intentions with respect to performing hand hygiene. Among individuals from the other professional categories, a greater percentage of U-hospital nurses (57.6% vs. 53.9%, respectively) believed that healthcare-associated infections to be greater than 20%, and mortality rate among infected patients to be greater than 5%. C-hospital nurses generally believed the frequency, severity, and impact of healthcare-associated infections to be lower than U-hospital nurses and other individuals. However, all professional categories believed that good hand hygiene effectively prevents infections (98%). In univariate analysis, receipt of structured training in hand hygiene, perceived colleagues adherence's as good, adherence models good practices for others, having been observed for their adherence (normative beliefs), the perception that hand hygiene is relatively easy to perform and high workload (control beliefs) was associated with good hand hygiene. However, in multivariate analysis, high self reported adherence to hand hygiene was independently associated with receipt of structured training in hand hygiene, perceived good adherence by colleagues, the perception that hand hygiene is relatively easy to perform and having been observed for their adherence. In a country with limited resources, intention to comply was associated with training and strong normative and control beliefs. Also, in two different kinds of institution with the similar hand hygiene promotion campaign in the same city, the believes of nurses were different. In developing countries, more resources have to be allocated for training of HCWs and easy access for hand hygiene products. PMID- 21663878 TI - Plasmodium vivax malaria: is it actually benign? AB - Plasmodium vivax (Pv) malaria is being increasingly recognized as a cause of severe malaria in children. OBJECTIVES: To describe the various severe manifestations associated with vivax malaria by retrospective analysis of records. METHODS: Children between the ages of 0 and 18 years with a confirmed diagnosis of Pv malaria monoinfection done by peripheral blood film (PBF) and/or rapid diagnostic test (RDT) admitted between June and September 2009 were included. Their clinical, hematological and biochemical manifestations were analyzed. RESULTS: Twenty-three patients of Pv malaria were retrospectively analyzed. Thrombocytopenia was present in 22 (96%) patients with counts less than 50,000/ MUL in 9 patients. Severe anemia (hgb<5mg/dl) was present in 8 (34%) patients. Cerebral malaria was present in 3 patients. Liver enzymes were elevated (>3 times normal) in 4 (17.3%) patients while jaundice (bilirubin>2.5mg/dl) was present in 2 patients (total bilirubin 5.2mg/dl and 14.3mg/dl). Renal dysfunction (creatinine>3mg/dl) was present in 6 (26%) patients with 2 patients showing severely deranged renal functions (blood urea 168 mg/dl, 222 mg/dl and serum creatinine 5.0mg/dl, 5.6 mg/dl, respectively). Hypernatremia was present in one patient. One patient expired within 12h of presentation because of severely deranged hepatic and renal dysfunction. CONCLUSION: Pv malaria can lead to unusual and fatal complications. All new guidelines should include "Severe Vivax malaria" as a clinical entity. Further research into the etiopathogenesis and treatment would be important. PMID- 21663879 TI - Cerebral phaeohyphomycosis due to Rhinocladiella mackenziei (formerly Ramichloridium mackenziei): case presentation and literature review. AB - Rhinocladiella mackenziei (formerly Ramichloridium mackenziei), a causative agent of cerebral phaeohyphomycosis, is extremely rare and it is geographically limited to the Middle East. The organism has a predilection to cause brain infections and results in a grave prognosis with a high mortality rate. The current patient was admitted to a long term care facility with chronic respiratory failure and dependence on a mechanical ventilator. She later developed left sided weakness and a CT-scan of the brain revealed multiple variable sized hypodense, well defined lesions with ring enhancement. A stereotactic needle aspiration of the largest lesion showed fungal hyphae. The final culture grew R. mackenzie. The patient was initially started on liposomal amphotericin B, then voriconazole and caspofungin intravenously as posaconazole was not available. The patient failed to respond to antifungal therapy and finally she died 34 days after the start of the treatment. R. mackenziei is a highly virulent agent, and should be considered in the differential diagnosis of central nervous system disease in patients from the Middle East. PMID- 21663880 TI - BK virus neurotropism. PMID- 21663882 TI - Motor planning and execution in left- and right-handed individuals during a bimanual grasping and placing task. AB - The issue of handedness has been the topic of great interest for researchers in a number of scientific domains. It is typically observed that the dominant hand yields numerous behavioral advantages over the non-dominant hand during unimanual tasks, which provides evidence of hemispheric specialization. In contrast to advantages for the dominant hand during motor execution, recent research has demonstrated that the right hand has advantages during motor planning (regardless of handedness), indicating that motor planning is a specialized function of the left hemisphere. In the present study we explored hemispheric advantages in motor planning and execution in left- and right-handed individuals during a bimanual grasping and placing task. Replicating previous findings, both motor planning and execution was influenced by object end-orientation congruency. In addition, although motor planning (i.e., end-state comfort) was not influenced by hand or handedness, motor execution differed between left and right hand, with shorter object transport times observed for the left hand, regardless of handedness. These results demonstrate that the hemispheric advantages often observed in unimanual tasks do not extend to discrete bimanual tasks. We propose that the differences in object transport time between the two hands arise from overt shifting visual fixation between the two hands/objects. PMID- 21663883 TI - The air quality index: a tool for managing patients with cardiopulmonary disease. PMID- 21663884 TI - Health care-associated pneumonia: an evidence-based review. AB - Health care-associated pneumonia is a relatively new classification of pneumonia that includes community-dwelling pneumonia patients having contact with the health care system. Current data indicate that health care-associated pneumonia patients present with more severe disease, are more likely to be infected with drug-resistant pathogens, and suffer increased mortality compared with community acquired pneumonia patients. Guidelines recommend that these patients receive empiric antibiotics similar to those recommended for nosocomial pneumonia; however, it is not currently known if outcomes are improved when health care associated pneumonia patients are treated with these therapies. In addition, the individual health care-associated pneumonia risk factors are based on limited data and are a poor predictor of patients likely to be infected with drug resistant pathogens. Many questions remain on how to most appropriately care for this growing group of pneumonia patients. This review is an evidence-based discussion of current health care-associated pneumonia data, the individual health care-associated pneumonia risk factors, and limitations and additional considerations for the health care-associated pneumonia classification system. PMID- 21663885 TI - Hand-carried echocardiography by hospitalists: a randomized trial. AB - BACKGROUND: Hospitalists can use hand-carried echocardiography for accurate point of-care information, but patient outcome data for its application are sparse. METHODS: We performed an unblinded, parallel-group randomized trial between July 2008 and March 2009 at one teaching hospital in Chicago, Illinois. We randomly assigned adult general medicine inpatients referred for standard echocardiography with indications investigatable by hand-carried echocardiography to care guided by hand-carried echocardiography or usual care. The main outcome measure was length of stay on the referring hospitalist's service. Secondary outcomes included a before-after analysis of reported changes in management due to hand carried echocardiography and the diagnostic accuracy of hand-carried echocardiography. RESULTS: The difference in length of stay between 226 participants randomized to care guided by hand-carried echocardiography (geometric mean 46.1 hours, interquartile range 29.0-70.9 hours) and 227 participants randomized to usual care (46.9 hours, interquartile range 34.1-68.3 hours) corresponded to a 1.7% reduction in length of stay that was not statistically significant (95% confidence interval, -12.1 to 9.8%). In post hoc subgroup analyses, care guided by hand-carried echocardiography reduced length of stay in participants who were referred for heart failure (P=.0008). Among participants who underwent both hand-carried and standard echocardiography, hospitalists changed management due to hand-carried echocardiography in 37%. Despite the favorable diagnostic accuracy of hand-carried echocardiography, most changes to the timing of hospital discharge occurred after standard echocardiography. CONCLUSION: Hospitalist care guided by hand-carried echocardiography for unselected general medicine patients does not meaningfully affect length of stay. Whether or not it affects care quality remains unstudied. PMID- 21663886 TI - Beating to a different drum. PMID- 21663887 TI - Constipation and risk of cardiovascular disease among postmenopausal women. AB - BACKGROUND: Constipation is common in Western societies, accounting for 2.5 million physician visits/year in the US. Because many factors predisposing to constipation also are risk factors for cardiovascular disease, we hypothesized that constipation may be associated with increased risk of cardiovascular events. METHODS: We conducted a secondary analysis in 93,676 women enrolled in the observational arm of the Women's Health Initiative. Constipation was evaluated at baseline by a self-administered questionnaire. Estimates of the risk of cardiovascular events (cumulative end point including mortality from coronary heart disease, myocardial infarction, angina, coronary revascularization, stroke, and transient ischemic attack) were derived from Cox proportional hazards models adjusted for demographics, risk factors, and other clinical variables (median follow-up 6.9 years). RESULTS: The analysis included 73,047 women. Constipation was associated with increased age, African American and Hispanic descent, smoking, diabetes, high cholesterol, family history of myocardial infarction, hypertension, obesity, lower physical activity levels, lower fiber intake, and depression. Women with moderate and severe constipation experienced more cardiovascular events (14.2 and 19.1 events/1000 person-years, respectively) compared with women with no constipation (9.6/1000 person-years). After adjustment for demographics, risk factors, dietary factors, medications, frailty, and other psychological variables, constipation was no longer associated with an increased risk of cardiovascular events except for the severe constipation group, which had a 23% higher risk of cardiovascular events. CONCLUSION: In postmenopausal women, constipation is a marker for cardiovascular risk factors and increased cardiovascular risk. Because constipation is easily assessed, it may be a helpful tool to identify women with increased cardiovascular risk. PMID- 21663888 TI - Racial and regional differences in age at menopause in the United States: findings from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. AB - OBJECTIVE: We sought to examine regional and black-white differences in mean age at self-reported menopause among community-dwelling women in the United States. STUDY DESIGN: This was a cross-sectional survey conducted in the context of the REasons for Geographic And Racial Differences in Stroke and Myocardial Infarction study. RESULTS: We studied 22,484 menopausal women. After controlling for covariates, Southern women reported menopause 10.8 months earlier than Northeastern women, 8.4 months earlier than Midwestern women, and 6.0 months earlier than Western women (P < .05 for all). No difference was observed in menopausal age between black and white women after controlling for covariates (P = .69). CONCLUSION: Women in the South report earlier menopause than those in other regions, but the cause remains unclear. Our study's large sample size and adjustment for multiple confounders lends weight to our finding of no racial difference in age at menopause. More study is needed of the implications of these findings with regard to vascular health. PMID- 21663889 TI - The microbial load with genital mycoplasmas correlates with the degree of histologic chorioamnionitis in preterm PROM. AB - OBJECTIVE: We sought to determine whether there is an association between bacterial load of genital mycoplasmas and histologic chorioamnionitis (HCA) in women with preterm premature rupture of membranes (PPROM). STUDY DESIGN: A total of 103 women with PPROM between 24-36 weeks of gestation were included in the study. Amniocenteses were performed, and the amounts of target genital mycoplasma DNA in amniotic fluid samples were evaluated using real-time polymerase chain reaction. The bacterial load of the genital mycoplasmas was relatively assessed using the threshold cycle value. RESULTS: The presence of genital mycoplasmas in amniotic fluid was found in 38% (39/103) of the women. The presence of HCA was associated with lower threshold cycle values (median 21.3, interquartile range, 16.5-28.5, vs median 29.4, interquartile range, 27.0-30.5; P = .005). CONCLUSION: HCA in PPROM is associated with a higher bacterial load of genital mycoplasmas. PMID- 21663890 TI - [Distal coronary thrombosis during L-asparaginase treatment for an acute lymphoblastic leukaemia]. AB - A 53-year-old man is treated by L-asparaginase for an acute lymphoblastic leukaemia. He received anti thrombin infusions. A systematic electrocardiogram showed an asymptomatic subepicardium ischemia without troponin elevation. Echocardiography and heart magnetic resonance imaging showed an apical thrombus facing a zone of myocardial necrosis. A thrombus regression was observed under anticoagulation. Atypical and asymptomatic coronary thrombosis may occur following L-asparaginase treatment. Regular electrocardiogram monitoring is proposed along this treatment. Arterial thrombosis associated with anti tumor chemotherapies are reviewed. PMID- 21663891 TI - [About an implantable cardioverter-fibrillator]. AB - A 61-year-old man has been implanted with a Ventritex Profile MD V-186 HV3 ICD for ischemic cardiomyopathy with sustained inducible VT. Three years later, this patient received several inappropriate shocks during the device's interrogation. These shocks provoked ventricular fibrillation. They were caused by a failing soldering between the system random accessory memory (SRAM) module and the hybrid circuit of the device. The device was explanted in emergency. PMID- 21663892 TI - [Cardiovascular disease prevention and life style modifications]. AB - Cardiovascular diseases are mainly caused by atherosclerosis, the development of which is highly dependent on our Western lifestyle. Slowing this pathology depends on the reduction of risk factors such as hypercholesterolemia, high blood pressure, smoking, lack of physical activity, excess weight and diabetes. Drug treatment exists and is very effective, but too often they treat the immediate abnormality such as diabetes, high blood pressure and hypercholesterolemia and not the underlying causes: poor eating habits, lack of physical activity and excess weight. These have a negative impact on endothelial function, oxidative stress, and can trigger inflammation, arrythmias and thrombosis. Cardiovascular prevention must therefore target sedentary lifestyle, excess weight, and favor low-calorie, low-salt food and Mediterranean diet. The way this diet works begins to be understood and goes beyond simple cardiovascular prevention. Therapeutic education holds a growing and complementary role in the Public Health system which should call upon the strengths of all healthcare professionals. PMID- 21663893 TI - [Syphilitic aortic regurgitation: a sexually transmissible cardiopathy]. AB - Syphilitic cardiovascular complications are currently rare. It concerns the tertiary phase of the disease and results in sacciform aneurysm of the thoracic aorta or ostial coronary artery stenosis. Syphilitic aortic regurgitation is even more rare. We illustrate it by a clinical observation and discuss its diagnosis and its treatment. PMID- 21663894 TI - [Epidemiological study of the idiopathic dilated cardiomyopathy in Tunisia]. AB - AIMS OF THE STUDY: Idiopathic dilated cardiomyopathy (IDC) is a complex disease. The interest of this study were to investigate the epidemiology characteristics of the disease and to evaluate the prognostic echocardiographic markers by region in order to highlight the existence of genetic risk factors and/or environmental and to identify those patients who could benefit from early treatment and better care to avoid further complications of the disease. PATIENTS AND METHODS: This is a retrospective study based on the Fischer exact and bilateral Mann-Whitney test. RESULTS: We included 526 patients with dilated cardiomyopathies of them we detected 50 cases of IDC including 12 families: The average age was 39,3+/-15.2 years. The sex ratio was 2.6. Mean left ventricular end-diastolic diameter (DIVGd) was higher in patients from the North East region (44.3+/-6.2mm/m(2)). Using Receiver Operating Characteristics (ROC) curve, we found a threshold value of 40mm/m(2). The odds ratio associated with this cutoff was 9.2. CONCLUSION: Our results suggest that the prevalence and severity of IDC were higher in the North East region of Tunisia. Furthermore, large-scale prospective studies are needed to confirm these findings. In confirmation of a higher prevalence, a genetic study should be undertaken in this region. PMID- 21663895 TI - Gender differences in visual reflexive attention shifting: evidence from an ERP study. AB - Attention is considered a central component of cognitive functioning. While many studies have demonstrated that eye direction can trigger reflexive attention shifting, there have been few studies on gender differences in attention shifting. To explore this issue we present results from an event-related potential (ERP) experiment using the spatial cueing task, in which females show larger ERP component amplitude. We suggest this result may be because women have a larger cueing effect in the visual spatial attention task, which leads women to use more attention resources to complete the task. The result may also be because women mature earlier than men in the major brain areas for visual spatial attention, and therefore women have the more mature activation patterns with enhanced amplitude in these regions. Gender differences in visual attention shifting may moderate or contribute to gender differences in other cognitive activities, such as memory, thought, and speech. Future studies of cognitive ability and cognitive processes should pay more attention to the possible effects of gender. PMID- 21663896 TI - Short-term sleep deprivation increases intrinsic excitability of prefrontal cortical neurons. AB - Short-term sleep deprivation (SD) has been shown to enhance cortical activity. However, alterations in the cellular excitability of cortical neurons following SD are not yet fully understood. The present study investigated the effects of 4 hour SD on pyramidal neurons in the prefrontal cortex (PFC) of rats using whole cell patch-clamp recording. SD led to an increase in the initial slope of firing frequency-current curve and a decrease in frequency adaptation, which were reversed by recovery sleep (RS). Correspondingly, the total afterhyperpolarization (AHP) was reduced in the SD group and returned in the RS group. Furthermore, the component of AHP changed after SD seemed to be sensitive to Ca(2+). These observations indicate an enhancement in intrinsic excitability due to short-term SD, and suggest a role for Ca(2+)-dependent AHP in this change. The findings of the present study may provide a possible explanation for the SD induced increase in cortical activity. PMID- 21663898 TI - The cristal (right superior septal) coronary artery and its relationship to anomalous left coronary origin. AB - The cristal artery is an occasional finding, being visible in around 3% of coronary angiograms, arising from the proximal right coronary artery (RCA) and passing downwards and forwards through the muscle of the crista superventricularis. It supplies a variable volume of the superior interventricular septum, and can contribute to collateralization of the other septal vessels. When part or all of the left coronary artery (LCA) arises anomalously from the right coronary sinus, its passage to the left may be in the same pathway as a cristal artery, bearing a tell-tale septal vessel arising from its proximal segment. This helps to differentiate it from one that has a higher pathway, running between the great vessels, and which may have a greater correlation with sudden cardiac death. PMID- 21663897 TI - Expeditious oligosaccharide synthesis via selective, semi-orthogonal, and orthogonal activation. AB - Traditional strategies for oligosaccharide synthesis often require extensive protecting and/or leaving group manipulations between each glycosylation step, thereby increasing the total number of synthetic steps while decreasing the efficiency of the synthesis. In contrast, expeditious strategies allow for the rapid chemical synthesis of complex carbohydrates by minimizing extraneous chemical manipulations. Oligosaccharide synthesis by selective activation of one leaving group over another is one such expeditious strategy. Herein, the significant improvements that have recently emerged in the area of the selective activation are discussed. The development of orthogonal strategy further expands the scope of the selective activation methodology. Surveyed in this article, are representative examples wherein these excellent innovations have been applied to the synthesis of various oligosaccharide sequences. PMID- 21663899 TI - In the assessment of supratentorial glioma grade: the combined role of multivoxel proton MR spectroscopy and diffusion tensor imaging. AB - AIM: To detect a difference in the parameters derived from proton magnetic resonance spectroscopy ((1)H-MRS) and diffusion tensor imaging (DTI) between low grade and high-grade gliomas, and to evaluate whether the combination of these two techniques can improve the diagnostic accuracy of conventional magnetic resonance imaging (MRI) in supratentorial glioma grading. MATERIALS AND METHODS: Thirty patients with histologically proved supratentorial brain gliomas (12 low grade, 18 high grade) were prospectively evaluated with contrast material enhanced MRI, DTI, and multivoxel (1)H-MRS (135 ms echo time). The tumour grades determined using the three methods were then compared with those obtained at histopathology. Receiver operating characteristic (ROC) analyses were performed to determine the optimum thresholds for glioma grading. Independent sample t test, Spearman's rank correlation, and the Fisher's exact test were also carried out for statistical analysis. p<0.05 was considered statistically significant. RESULTS: Statistically significant differences were found between the low-grade and high-grade gliomas for the choline (Cho)/creatine (Cr), N-acetylaspartate (NAA)/Cr, NAA/Cho ratio in the tumours (p<0.01), apparent diffusion coefficient (ADC) value (p<0.01), and fractional anisotropy (FA) value (p<0.05) in the tumours. The NAA/Cr and NAA/Cho ratios and the calculated ADC value significantly correlated with the histological grading of the gliomas (p<0.01). Using a threshold value of 0.66 for tumour NAA/Cr, 0.265 for NAA/Cho, 1118.1*10(-6) mm(2)/s for the calculated ADC value, corresponding to the maximum Youden index from the ROC curve of the above-selected parameters, the resultant sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Kappa values were all higher and the fraction of misclassified tumour was lower when compared with conventional MRI. However, only NAA/Cho and ADC calculation contributed to the significant difference (p<0.01) in the assessment of glioma grade compared to conventional MRI alone, and the grading results of statistical tests comparing those two parameters were highly consistent (kappa value=0.798). CONCLUSION: Thresholds for NAA/Cho and calculated ADC values, corresponding to maximum Youden index from ROC curve analyses, helped to improve the accuracy of supratentorial glioma grading when compared with conventional MRI alone. In addition, a combination of NAA/Cho and ADC calculation were more useful together than each alone in a clinical setting to evaluate glioma grade preoperatively and provide a means for guiding treatment. PMID- 21663900 TI - Frontal callosal disconnection syndromes. AB - The interhemispheric connections of the cortical areas of the human brain are distributed within the corpus callosum according to a topographic order which is being studied in detail by novel imaging techniques. Total section of the corpus callosum is followed by a variety of interhemispheric disconnection symptoms each of which can be attributed to the interruption of fibers in a specific callosal sector. Disconnection symptoms deriving from posterior callosal sections, disconnecting parietal, temporal and occipital lobes across the midline, are more apparent than those following anterior callosal sections disconnecting the frontal lobes. In spite of the massive bulk of the frontal callosal connections in man, ascertained consequences of their interruption are limited to disorders of motor control, with particular regard to bimanual coordination. Technical advances in brain imaging and the design of appropriate tests are expected to reveal so far undetected deficits in the domain of executive and higher cognitive functions, resulting from callosal disconnection of the prefrontal cortices. PMID- 21663901 TI - Lead levels in new residential enamel paints in Taipei, Taiwan and comparison with those in mainland China. AB - Five brands of new enamel household paints from Taiwan were analyzed: two multi nationals and three local. The median lead concentration of 2574 parts per million (ppm) dry weight was more than 30 times the current US standard of 90ppm for new paints and was more than 4 times the former standard of 600ppm. Lead levels ranged from below detection (4.5ppm) to 158,000ppm. Lead concentrations varied significantly by color of paint and paint brand but not by price per liter. Fifty-six percent of Taiwan paints had lead levels above the 90ppm US limit. One of the multi-national brands and two of the local brands had high levels of lead with the averages ranging from 12,890 to 53,640ppm. Concentrations were less than 90ppm in each of the samples from the other two brands. One of the two multi-national paint brands was imported as the house brand for its big box store in Taipei and had lead levels above 600ppm in four of five samples. Comparison of the lead concentrations of paints from Taiwan with those that we previously analyzed from mainland China revealed higher levels in Taiwan where the median level was 2574ppm compared to 46ppm in mainland China. PMID- 21663904 TI - Ovarian reserve and oocyte maturity in cancer patients. PMID- 21663902 TI - Serum PBDEs and age at menarche in adolescent girls: analysis of the National Health and Nutrition Examination Survey 2003-2004. AB - BACKGROUND: Polybrominated diphenyl ethers (PBDEs), widely used as flame retardants since the 1970s, have exhibited endocrine disruption in experimental studies. Tetra- to hexa-BDE congeners are estrogenic, while hepta-BDE and 6-OH BDE-47 are antiestrogenic. Most PBDEs also have antiandrogenic activity. It is not clear, however, whether PBDEs affect human reproduction. OBJECTIVES: The analysis was designed to investigate the potential endocrine disruption of PBDEs on the age at menarche in adolescent girls. METHODS: We analyzed the data from a sample of 271 adolescent girls (age 12-19 years) in the National Health and Nutrition Examination Survey (NHANES), 2003-2004. We estimated the associations between individual and total serum BDEs (BDE-28, -47, -99, -100, -153, and -154, lipid adjusted) and mean age at menarche. We also calculated the risk ratios (RRs) and 95% confidence intervals (CI) for menarche prior to age 12 years in relation to PBDE exposure. RESULTS: The median total serum BDE concentration was 44.7ng/g lipid. Higher serum PBDE concentrations were associated with slightly earlier ages at menarche. Each natural log unit of total BDEs was related to a change of -0.10 (95% CI: -0.33, 0.13) years of age at menarche and a RR of 1.60 (95% CI: 1.12, 2.28) for experiencing menarche before 12 years of age, after adjustment for potential confounders. CONCLUSION: These data suggest high concentrations of serum PBDEs during adolescence are associated with a younger age of menarche. PMID- 21663905 TI - Endoscopic submucosal dissection with or without snaring for colorectal neoplasms. AB - BACKGROUND: Despite a high en bloc resection rate, its technical difficulty and risk of complications limit the widespread use of colorectal endoscopic submucosal dissection (ESD). OBJECTIVE: To analyze outcomes after colorectal ESD and ESD with snaring (ESD-S), a simplified modification of ESD. DESIGN: A retrospective observational study. SETTING: A single, tertiary-care, referral center. PATIENTS AND INTERVENTION: ESD was performed on 163 lesions in 162 patients and ESD-S on 74 lesions in 71 patients. All lesions were nonpedunculated colorectal neoplasms of 15 mm or larger. MAIN OUTCOME MEASUREMENTS: We analyzed procedure-related variables such as en bloc resection rate, procedure time, and complications. Histopathologic results were reviewed. Follow-up data were analyzed. RESULTS: The en bloc resection rate was higher for ESD than for ESD-S (87% vs 64%, P < .01). The histologically complete resection rate was also higher for ESD. However, both rates for resection of lesions of <20 mm were not different between ESD and ESD-S groups. The rates of perforation and bleeding were similar for both groups. Submucosal cancers were present in 21% and 31% of the ESD and ESD-S groups, respectively. One patient from each group developed a local adenoma recurrence. LIMITATIONS: Retrospective design. CONCLUSION: Both ESD and ESD-S were safe and effective for resection of colorectal neoplasms. The higher en bloc resection rate for ESD suggests that it should be the first option for resection of suspected superficial submucosal cancers in the colorectum. ESD S can be a good alternative to ESD for en bloc resection of colorectal lesions of <20 mm. PMID- 21663906 TI - Endoscopic submucosal dissection for gastric neoplasms by using a novel attachment device-a one-sided, expandable balloon. PMID- 21663907 TI - Matching colonoscopy and pathology data in population-based registries: development of a novel algorithm and the initial experience of the New Hampshire Colonoscopy Registry. AB - BACKGROUND: The quality of polyp-level data in a population-based registry depends on the ability to match each polypectomy recorded by the endoscopist to a specific diagnosis on the pathology report. OBJECTIVE: To review impediments encountered in matching colonoscopy and pathology data in a population-based registry. DESIGN: New Hampshire Colonoscopy Registry data from August 2006 to November 2008 were analyzed for prevalence of missing reports, discrepancies between colonoscopy and pathology reports, and the proportion of polyps that could not be matched because of multiple polyps submitted in the same container. SETTING: New Hampshire Colonoscopy Registry. PATIENTS: This study involved all consenting patients during the study period. INTERVENTION: Develop an algorithm for capturing number, size, location, and histology of polyps and for defining and flagging discrepancies to ensure data quality. MAIN OUTCOME MEASUREMENTS: The proportion of polyps with no assumption or discrepancy, the proportion of patient records eligible for determining the adenoma detection rate (ADR), and the number of patients with >=3 adenomas. RESULTS: Only 50% of polyps removed during this period were perfectly matched, with no assumption or discrepancy. Records from only 69.9% and 29.7% of eligible patients could be used to determine the ADR and the number of patients with >=3 adenomas, respectively. LIMITATIONS: Rates of missing reports may have been higher in the early phase of establishment of the registry. CONCLUSION: This study highlights the impediments in collecting polyp level data in a population-based registry and provides useful parameters for evaluating the quality and accuracy of data obtained from such registries. PMID- 21663908 TI - Incidence and predictors of missed injuries in trauma patients in the initial hot report of whole-body CT scan. AB - BACKGROUND: Whole-body CT scan is the cornerstone of trauma-related injury assessment. Several lines of evidence indicate that significant number of injuries may remain undetected after the initial hot report of CT. Missed injuries (MI) represent an important issue in trauma patients, for they may increase morbidity, mortality and costs. The aim of this study was to examine incidence and predictors of MI in trauma patients undergoing whole-body CT scan. METHODS: 177 CT scan performed upon admission of trauma patients during year 2005 were reviewed by a radiologist blinded to patient's initial data. MI was defined as injuries not written in the initial report. Patients with and without MI were compared to determine predictors of MI by multivariable analysis. RESULTS: 157 MI were diagnosed in 85 (47%) patients. MI was predominantly encoded AIS 2 (57%) or 3 (29%). Patients with MI had significantly higher SAPSII, higher ISS and were more frequently sedated. Age over 50 years (OR: 4.37, p=0.003) and ISS over 14 (OR: 4.17, p<0.0001) were independent predictors of MI. Median ISS after encoding MI was significantly higher than initial ISS (22 vs. 20 p<0.0001). After adjustment for severity, mortality and length of stay were not different between patients with or without MI. CONCLUSION: Trauma patients, especially aged and severe, experienced a high rate of missed injuries in the initial hot report which appeared to be predominantly minor and musculoskeletal, advocating a CT scan second reading. PMID- 21663909 TI - Combination of interfragmentary screws and locking plates in distal meta diaphyseal fractures of the tibia: a retrospective, single-centre pilot study. AB - If distal tibia fractures cannot be treated with intramedullary nails, locking compression plates, such as the LCP Medial Distal Tibia Plate of Synthes, are used. Bridge plating with interfragmentary movement is the strategy for such osteosynthesis. Interfragmentary movement is difficult to predict. Too much movement leads to formation of more, but less stable callus; longer time until complete fracture healing has been reported. Interfragmentary movement can be controlled by the stability and flexibility of the osteosynthesis construct. We used interfragmentary screws to limit interfragmentary movement in certain cases. We noticed a tendency of faster fracture healing in patients with interfragment lag screw compared with those with sole bridge plating. We therefore retrospectively assessed our patients for time until clinical fracture healing (i.e., pain-free weight bearing and visible callus in both layers on conventional plain film radiographs) and callus formation. METHODS: Data (from patient chart and from regular visits) of 52 patients with fracture of the distal tibia were reviewed, of which 11 were lost to follow-up. After surgery, weight bearing was limited to 20 kg for 6 weeks and then increased in weekly intervals to the pain threshold. X-rays were taken after 3 days, 6, 12 and 24 weeks and when achieving full weight bearing. Time from surgery until ability to full weight bearing was measured and compared. Callus index was measured as quotient of callus thickness and diameter of corticalis both in a.p. and sagittal direction. Statistical evaluation was done with the Mann-Whitney U-test. RESULTS: A total of 41 patients could be analysed; of them, 30 patients had extra-articular fractures. Four patients had 43-B and seven patients had 43-C fractures. As many as 13/30 extra articular fractures were treated with interfragmentary screws: In this group (n=11, without considering one patient with plate failure and one with pseudarthrosis) time to full weight bearing was 11.38 weeks versus 14.9 weeks without screw (n=14; without two pseudarthrosis and one deep infection) (p=0.044). Callus index at full weight bearing was significantly lesser in patients with screw compared with those without. CONCLUSION: Though interfragmentary screws seem to block necessary interfragmentary movement, we see callus formation as a sign of secondary fracture healing. The osteosynthesis construct with interfragmentary screw seems to be more stable and less flexible than sole bridge plating, leading to faster fracture healing. Interfragmentary screws might help to control and limit interfragmentary movement in certain cases. PMID- 21663910 TI - Three-dimensional ultrasound imaging for the evaluation of carotid atherosclerosis. AB - INTRODUCTION: Emerging data suggests that 3-dimensional (D) ultrasound (US) may provide us with a new tool for the identification of the vulnerable carotid plaque. METHODS: A systematic review of the PubMed, Scopus and Cochrane databases regarding the reproducibility and effectiveness of 3D US in evaluation of carotid plaque disease (CPD) was performed. RESULTS: Seven studies on the reproducibility of 3D ultrasound evaluation of plaque volume (PV) were identified. All studies reported good intra- and inter-observer reproducibility ranging from 2.8-6.0% to 4.2-7.6%, respectively. In addition, ten studies evaluating 3D carotid plaque progression with and without treatment were retrieved. In the 4 studies where 2D and 3D US features were compared, PV rather than intima media thickness (IMT) was a more sensitive marker of plaque change as a response to treatment. However, there were no studies evaluating changes in plaque morphology or specific composition features post-treatment with both 2 and 3D US. Finally, only one study was identified regarding the 3D composition differences of CPD between symptomatic and asymptomatic patients. CONCLUSION: The current evidence supports the good reproducibility of the 3D US on the evaluation of carotid plaque volume, however with high heterogeneity between studies. There is also preliminary evidence that PV measurements may be more sensitive than IMT in the identification of plaque change post-treatment, though, more plaque-related evidence is necessary. Further research is needed to establish if 3D is superior to 2D US in the identification of the vulnerable carotid plaque in clinical settings. PMID- 21663911 TI - Leptin: the missing link between obesity and heart disease? PMID- 21663912 TI - Association of increased S100B, S100A6 and S100P in serum levels with acute coronary syndrome and also with the severity of myocardial infarction in cardiac tissue of rat models with ischemia-reperfusion injury. AB - OBJECTIVE: We aim to check if serum levels of receptor for advanced glycation endproduct (RAGE) ligands S100B, S100A6 and S100P were related to myocardial injury in acute coronary syndrome (ACS). METHODS: Serum levels of S100B, S100A6, S100P, and soluble RAGE (sRAGE) were analyzed in 882 patients. Based upon clinical and laboratory findings, they were assigned into control (n=251), stable angina (n=211), and ACS (n=420). To verify clinical data of ACS, forty Sprague Dawley rats were subjected to cardiac ischemia-reperfusion (I/R) injury by occluding proximal (large infarct size; n=20) or distal (small infarct size; n=20) left anterior descending coronary artery, and another 20 rats were in sham operation group. The expressions of S100B, S100A6, S100P and RAGE in the myocardium were analyzed. RESULTS: Serum levels of S100B, S100A6 and S100P were higher in ACS group than in stable angina and control groups, and sRAGE levels were higher in ACS patients versus controls (all p<0.01). S100B and S100P levels correlated significantly with CK-MB and troponin I levels in ACS group (all p<0.05). In multivariable regression analysis, S100B, S100A6, S100P and conventional risk factors were independently associated with ACS. In animal models, the expressions of S100B, S100A6 and S100P were closely related to infarct size (all p<0.05). CONCLUSION: This study indicates that serum levels of S100B, S100A6 and S100P are associated with ACS, and serum levels and myocardial expression of these proteins are related to infarct size. PMID- 21663913 TI - Autopsy investigation and Bayesian approach to coronary artery disease in victims of motor-vehicle accidents. AB - BACKGROUND: Each year, 1.2 million people die worldwide as a result of motor vehicle accidents (MVA), representing a tremendous burden to healthcare. The aim of this study was to define the prevalence of coronary disease and its possible role in motor-vehicle accidents. METHODS AND RESULTS: We examined consecutive cases of non-hospital sudden death autopsies in the area of West Quebec during the period of 2002-2006, and we focused on those victims of MVA. Severe coronary artery disease (CAD) was defined as a narrowing of >= 75% of a cross-sectional area or the presence of acute plaque events in major epicardial coronary arteries. From a total cohort of 1260 autopsies, MVA were responsible for 123 deaths, 100 of whom were men and 23 were women. Significant CAD was documented in approximately 37% of these cases. In individuals older than 60 years, the prevalence of significant CAD and ischemia were 86.2% and 19.8%, respectively. A percentage of 40% of the coronary patients showed erratic driving before the accident, as observed by witnesses. Statistical analysis showed that an individual affected by CAD has 9% probability of suffering a motor-vehicle accident. CONCLUSIONS: The prevalence of severe CAD and acute myocardial ischemia is very high among individuals who have suffered a MVA. Our data suggest the hypothesis that acute CAD could be the cause of accidents in a large group of the drivers affected by coronary disease. For these reasons CAD could be investigated in drivers above 50 years old, as a possible preventive measure and determinant of individual risk stratification. PMID- 21663914 TI - Circulating Dickkopf-1 in acute ischemic stroke and clinically stable cerebrovascular disease. AB - OBJECTIVES: Previous data suggest that Dickkopf-1 (Dkk-1), an inhibitor of the canonical/beta-catenin cascade of the Wnt pathway, is upregulated in carotid atherosclerosis and acute myocardial ischemia. It is currently unclear if such upregulation also occurs in cerebral ischemia. METHODS: We measured plasma levels of Dkk-1 in patients with acute ischemic stroke (n=57) within 24h from symptom onset, in patients with clinically stable cerebrovascular disease (n=29) and in healthy controls (n=29). Stroke severity on admission was determined by the National Institutes of Stroke Scale (NIHSS). The modified Rankin Scale (mRS) served to define outcome at day 90. Ischemic stroke subtype and cause was determined by the Oxfordshire Community Stroke Project (OCSP) criteria and the Causative Classification of Stroke System (CCS). RESULTS: Dkk-1 plasma levels were significantly higher in acute stroke patients (median 727.1 pg/ml) as compared to patients with stable cerebrovascular disease (median 534.2 pg/ml; p=0.017) or healthy controls (median 371.3 pg/ml; p<0.001). The difference of Dkk 1 levels between patients with stable cerebrovascular disease and healthy controls was also significant (p=0.005). No significant differences in Dkk-1 plasma levels were found between different causes or subtypes of ischemic stroke. No correlation of Dkk-1 levels was found with stroke severity on admission and outcome at day 90. CONCLUSION: Our study provides for the first time evidence for a release of Dkk-1 into the circulation in patients with acute ischemic stroke and also in patients with clinically stable cerebrovascular disease. PMID- 21663915 TI - Cross-correlations of center of mass and center of pressure displacements reveal multiple balance strategies in response to sinusoidal platform perturbations. AB - Compared to static balance, dynamic balance requires a more complex strategy that goes beyond keeping the center of mass (COM) within the base of support, as established by the range of foot center of pressure (COP) displacement. Instead, neuromechanics must accommodate changing support conditions and inertial effects. Therefore, because they represent body's position and changes in applied moments, relative COM and COP displacements may also reveal dynamic postural strategies. To investigate this concept, kinetics and kinematics were recorded during three 12 cm, 1.25 Hz, sagittal perturbations. Forty-one individual trials were classified according to averaged cross-correlation lag between COM and COP displacement (lag(COM:COP)) and relative head-to-ankle displacement (Delta(head)/Delta(ankle)) using a k-means analysis. This process revealed two dominant patterns, one for which the lag(COM:COP) was positive (Group 1 (n=6)) and another for which it was negative (Group 2 (n=5)) . Group 1 (G1) absorbed power from the platform over most of the cycle, except during transitions in platform direction. Conversely, Group 2 (G2) participants applied power to the platform to maintain a larger margin between COM and COP position and also had larger knee flexion and ankle dorsiflexion, resulting in a lower stance. By the third repetition, the only kinematic differences were a slightly larger G2 linear knee displacement (p=0.008) and an antiphasic relationship of pelvis (linear) and trunk (angular) displacements. Therefore, it is likely that the strategy differences were detected by including COP in the initial screening method, because it reflects the pattern of force application that is not detectable by tracking body movements. PMID- 21663916 TI - Effect of chemical cross-linking on the mechanical properties of elastomeric peptides studied by single molecule force spectroscopy. AB - Mechanical properties of animal tissues are mainly provided by the assembly of single elastomeric proteins into a complex network of filaments. Even if the overall elastic properties of such a reticulated structure depend on the mechanical characteristics of the constituents, it is not the only aspect to be considered. In addition, the aggregation mechanism has to be clarified to attain a full knowledge of the molecular basis of the elastic properties of natural nanostructured materials. This aim is even more crucial in the process of rational design of biomaterials with selected mechanical properties, in which not only the mechanics of single molecules but also of their assemblies has to be cared of. In this study, this aspect was approached by means of single molecule stretching experiments. In particular, the effect of chemical cross-linking on the mechanical properties of a naturally inspired elastomeric peptide was investigated. Accordingly, we observed that, in order to preserve the elastic properties of the single filament, the two strands of the dimer have to interact with each other. The results thus confirm that the influence of the aggregation process on the mechanical properties of a molecular assembly cannot be neglected. PMID- 21663917 TI - "Reperfusion ST-elevation peak": an interesting phenomenon that needs to be studied and implemented further. PMID- 21663918 TI - Predictors of children's prosocial lie-telling: Motivation, socialization variables, and moral understanding. AB - Children tell prosocial lies for self- and other-oriented reasons. However, it is unclear how motivational and socialization factors affect their lying. Furthermore, it is unclear whether children's moral understanding and evaluations of prosocial lie scenarios (including perceptions of vignette characters' feelings) predict their actual prosocial behaviors. These were explored in two studies. In Study 1, 72 children (36 second graders and 36 fourth graders) participated in a disappointing gift paradigm in either a high-cost condition (lost a good gift for a disappointing one) or a low-cost condition (received a disappointing gift). More children lied in the low-cost condition (94%) than in the high-cost condition (72%), with no age difference. In Study 2, 117 children (42 preschoolers, 41 early elementary school age, and 34 late elementary school age) participated in either a high- or low-cost disappointing gift paradigm and responded to prosocial vignette scenarios. Parents reported on their parenting practices and family emotional expressivity. Again, more children lied in the low cost condition (68%) than in the high-cost condition (40%); however, there was an age effect among children in the high-cost condition. Preschoolers were less likely than older children to lie when there was a high personal cost. In addition, compared with truth-tellers, prosocial liars had parents who were more authoritative but expressed less positive emotion within the family. Finally, there was an interaction between children's prosocial lie-telling behavior and their evaluations of the protagonist's and recipient's feelings. Findings contribute to understanding the trajectory of children's prosocial lie-telling, their reasons for telling such lies, and their knowledge about interpersonal communication. PMID- 21663919 TI - Noise on, voicing off: Speech perception deficits in children with specific language impairment. AB - Speech perception of four phonetic categories (voicing, place, manner, and nasality) was investigated in children with specific language impairment (SLI) (n=20) and age-matched controls (n=19) in quiet and various noise conditions using an AXB two-alternative forced-choice paradigm. Children with SLI exhibited robust speech perception deficits in silence, stationary noise, and amplitude modulated noise. Comparable deficits were obtained for fast, intermediate, and slow modulation rates, and this speaks against the various temporal processing accounts of SLI. Children with SLI exhibited normal "masking release" effects (i.e., better performance in fluctuating noise than in stationary noise), again suggesting relatively spared spectral and temporal auditory resolution. In terms of phonetic categories, voicing was more affected than place, manner, or nasality. The specific nature of this voicing deficit is hard to explain with general processing impairments in attention or memory. Finally, speech perception in noise correlated with an oral language component but not with either a memory or IQ component, and it accounted for unique variance beyond IQ and low-level auditory perception. In sum, poor speech perception seems to be one of the primary deficits in children with SLI that might explain poor phonological development, impaired word production, and poor word comprehension. PMID- 21663921 TI - Novel de novo large deletion in cystic fibrosis transmembrane conductance regulator gene results in a severe cystic fibrosis phenotype. AB - We identified c.1521_1523delCTT and c.1679+94_2619+986del8118 in trans in a 6 year-old boy with a severe cystic fibrosis phenotype. The first deletion was inherited maternally, but the latter had arisen de novo. PMID- 21663920 TI - Learning to learn: From within-modality to cross-modality transfer during infancy. AB - One critical aspect of learning is the ability to apply learned knowledge to new situations. This ability to transfer is often limited, and its development is not well understood. The current research investigated the development of transfer between 8 and 16 months of age. In Experiment 1, 8- and 16-month-olds (who were established to have a preference to the beginning of a visual sequence) were trained to attend to the end of a sequence. They were then tested on novel visual sequences. Results indicated transfer of learning, with both groups changing baseline preferences as a result of training. In Experiment 2, participants were trained to attend to the end of a visual sequence and were then tested on an auditory sequence. Unlike Experiment 1, only older participants exhibited transfer of learning by changing baseline preferences. These findings suggest that the generalization of learning becomes broader with development, with transfer across modalities developing later than transfer within a modality. PMID- 21663923 TI - [Prognostic factors and long-term survival after initial diagnosis of heart failure]. AB - BACKGROUND AND OBJECTIVE: To assess long-term mortality and prognostic factors after initial diagnosis of heart failure (HF), to analyze the differences in function of the left ventricular ejection fraction (preserved [HFPEF] vs. systolic dysfunction [HFSD]) and to compare the results with the main series of incident cases of HF published. PATIENTS AND METHODS: Retrospective cohort study including patients first diagnosed of heart failure (Framingham criteria), between 1-01-1997 and 31-12-2001, classified according to a left ventricle ejection fraction (LVEF) above or equal to 50% (HFPEF) or below 50% (HFSD). Follow-up of patients was conducted during ten years. RESULTS: Out of 400 incident cases of heart failure, 231 patients (57,7%) presented with HFPEF. At 10 years, mortality rates were higher in the HFSD group (64,5 vs. 55,4%, p=0,04). Following a multi-variant analysis, HFPEF mortality was related with age, diabetes mellitus, ischemic heart disease, and chronic renal failure. Treatment with statins and beta-blockers was associated with improved prognosis. Among patients with HFSD, mortality predictors were similar, although patients treated with statins did not show higher survival rates. For other series of incident cases, there were differences in variables related to prognosis and mortality of patients. CONCLUSIONS: After an initial diagnosis of HF, more than half of patients die within 10 years of monitoring. Age, diabetes mellitus, ischemic heart disease and chronic renal failure are all associated with worse prognosis in these patients, whereas the use of beta-blockers and statins is associated with a better prognosis. PMID- 21663922 TI - Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium. AB - OBJECTIVE: To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinson's disease (PD). METHODS: The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. RESULTS: Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0-2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African-Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2-0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95% CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. CONCLUSIONS: DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster. PMID- 21663924 TI - Mitochondrial bioenergetics is not impaired in nonobese subjects with type 2 diabetes mellitus. AB - Although mitochondrial dysfunction has been well documented in obese people with type 2 diabetes mellitus, its presence or absence in nonobese subjects with type 2 diabetes mellitus has not been well studied so far. The aim of the present study was to assess the status of mitochondrial oxidative phosphorylation in subcutaneous adipose tissue of nonobese type 2 diabetes mellitus subjects in comparison to control, obese nondiabetic, and obese type 2 diabetes mellitus subjects. Mitochondria were isolated from subcutaneous white adipose tissue obtained from the abdominal region of control, obese nondiabetic, nonobese type 2 diabetes mellitus, and obese type 2 diabetes mellitus subjects. The activities of complex I, I to III, II to III, and IV; transmembrane potential; and inorganic phosphate utilization of mitochondria from different groups were measured. Mitochondrial transmembrane potential, inorganic phosphate utilization, and the activities of respiratory chain complexes were significantly reduced in obese nondiabetic and obese type 2 diabetes mellitus patients compared with those in control subjects. No detectable change in mitochondrial functional parameters was observed in case of nonobese type 2 diabetes mellitus subjects compared with control subjects. Furthermore, a significant difference was noticed in mitochondrial phosphate utilization and activities of respiratory complexes, for example, I, I to III, and II to III, between obese type 2 diabetes mellitus subjects and obese nondiabetic subjects. Obesity modulates mitochondrial dysfunction associated with type 2 diabetes mellitus. PMID- 21663925 TI - Prophylactic vitamin D in healthy infants: assessing the need. AB - The objective was to evaluate the need for vitamin D prophylaxis in healthy infants. This was a prospective and randomized study performed at primary care clinics. Eighty-eight full-term 1-month-old healthy infants were randomly assigned to receive (n = 41) or not (n = 47) 402 IU/d of vitamin D for 1 year. Primary outcome measures were serum 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) concentrations at 3, 6, and 12 months of age; secondary measures included data on feeding, habitat, season of birth, sun exposure, and physical examination. At 3 and 6 months of age, serum 25OHD levels (+/-SD) were significantly higher (P < .001) in the prophylaxis group. In the group without prophylaxis, serum 25OHD increased with age; and breast-fed infants aged 3 months had the lowest value (20.2 +/- 9.4 ng/mL), which was significantly (P = .001) lower than that of formula-fed infants (35.0 +/- 9.7 ng/mL). The PTH levels were not influenced by the prophylaxis or feeding. No influence of either the habitat or season of birth on serum 25OHD concentrations was demonstrated. No infant had clinical signs of vitamin D deficiency. Serum 25OHD and PTH concentrations were weakly but significantly correlated (r = -0.29, P = .009) at 3 months of age. Healthy infants without vitamin D prophylaxis had lower circulating concentrations of 25OHD at 3 and 6 months of age, the lowest value being found in 3-month breast-fed infants. The clinical relevance of these findings is probably negligible because serum 25OHD levels spontaneously increased with age and were not associated with high serum PTH. Clinical manifestations of rickets were not observed. PMID- 21663927 TI - A method for determining the concentration of haptoglobin in cattle blood following haemolysis caused at collection. AB - This study aimed to develop an in-house assay for haptoglobin determination in bovine blood samples, assess the effect of haemolysis on the reported haptoglobin concentration and develop a method to correct for haemolysis interference. The assay developed is highly repeatable (92.3% across plates and 94.8% between assays). A correction equation (Hp(corrected)=Hp(raw)-Hp(endogenous activity) Hp(due to Hb); where Hp(due to Hb)=0.118*Hb(free)+0.015) was developed based around the linear relationship of haptoglobin and haemoglobin (by-product of haemolysis) and endogenous interference, tested and validated for use with haemolysed samples. The method described in this paper allows samples inadvertently haemolysed at collection to be analysed, with the reported haptoglobin concentration being an accurate reflection of the physiological levels in the animal's blood at the time of collection. PMID- 21663926 TI - Telomere length measurement-caveats and a critical assessment of the available technologies and tools. AB - Studies of telomeres and telomere biology often critically rely on the detection of telomeric DNA and measurements of the length of telomere repeats in either single cells or populations of cells. Several methods are available that provide this type of information and it is often not clear what method is most appropriate to address a specific research question. The major variables that need to be considered are the material that is or can be made available and the accuracy of measurements that is required. The goal of this review is to provide a comprehensive summary of the most commonly used methods and discuss the advantages and disadvantages of each. Methods that start with genomic DNA include telomere restriction fragment (TRF) length analysis, PCR amplification of telomere repeats relative to a single copy gene by Q-PCR or MMQPCR and single telomere length analysis (STELA), a PCR-based approach that accurately measures the full spectrum of telomere lengths from individual chromosomes. A different set of methods relies on fluorescent in situ hybridization (FISH) to detect telomere repeats in individual cells or chromosomes. By including essential calibration steps and appropriate controls these methods can be used to measure telomere repeat length or content in chromosomes and cells. Such methods include quantitative FISH (Q-FISH) and flow FISH which are based on digital microscopy and flow cytometry, respectively. Here the basic principles of various telomere length measurement methods are described and their strengths and weaknesses are highlighted. Some recent developments in telomere length analysis are also discussed. The information in this review should facilitate the selection of the most suitable method to address specific research question about telomeres in either model organisms or human subjects. PMID- 21663928 TI - Evaluation of variables to describe the shape of volumetric capnography curves during bronchoconstriction in dogs. AB - The aim of the study was to investigate changes in volumetric capnography (V(C)) variables during bronchoconstriction in dogs and compare it with total respiratory resistance (R(L)) measured with a Fleisch pneumotachograph. Six dogs were challenged with increasing concentrations of carbachol until obvious signs of bronchoconstriction were seen. All V(C) parameters were obtained before, directly after, 10 and 20 min after maximal bronchoconstriction. The slope of phase III (SIII) and airway and alveolar dead space parameters were significantly different from baseline directly after the challenge. The V(C) curve obtained a typical shape at the time of maximal bronchoconstriction and a trend to return to baseline shape was seen over time. A significant correlation was found for all aforementioned parameters with R(L). We conclude that the shape of the V(C) curve in combination with dead space calculation can be used to verify bronchoconstriction on a breath-to-breath basis. PMID- 21663930 TI - Wave propagation of functionally graded material plates in thermal environments. AB - The wave propagation of an infinite functionally graded plate in thermal environments is studied using the higher-order shear deformation plate theory. The thermal effects and temperature-dependent material properties are both taken into account. The temperature field considered is assumed to be a uniform distribution over the plate surface and varied in the thickness direction only. Material properties are assumed to be temperature-dependent, and graded in the thickness direction according to a simple power law distribution in terms of the volume fractions of the constituents. Considering the effects of transverse shear deformation and rotary inertia, the governing equations of the wave propagation in the functionally graded plate are derived by using the Hamilton's principle. The analytic dispersion relation of the functionally graded plate is obtained by solving an eigenvalue problem. Numerical examples show that the characteristics of wave propagation in the functionally graded plate are relates to the volume fraction index and thermal environment of the functionally graded plate. The influences of the volume fraction distributions and temperature on wave propagation of functionally graded plate are discussed in detail. The results carried out can be used in the ultrasonic inspection techniques and structural health monitoring. PMID- 21663929 TI - Increased accumulation of paclitaxel and doxorubicin in proliferating capillary cells and prostate cancer cells following ultrasound exposure. AB - INTRODUCTION: We have previously reported enhanced cytotoxic effects of both doxorubicin and antisense oligonucleotides using an optimized ultrasound regime of a single 10s exposure in burst-mode (4 MHz, 32 W/cm(2)(SaTa), 50 ms burst period) in both PC3 (prostate cancer) cells and angiogenic Huvec (human umbilical cord endothelial cells). The objective of this study was to investigate the effect of ultrasound on the cellular uptake of both hydrophilic agents (rhodamine R123, doxorubicin hydrochloride and mannitol) and hydrophobic agents (rhodamine R6G and paclitaxel) using the same 4 MHz ultrasound exposure system. METHODS: PC3 cells and Huvec were incubated with solutions of radioactive or fluorescent compounds for 1h and ultrasound was then applied to cells. Following washing and lysis of cells, the degree of drug uptake was measured using liquid scintillation counting or fluorescence spectroscopy. RESULTS: Ultrasound exposure resulted in the enhanced uptake of both hydrophilic and hydrophobic compounds into cells. For paclitaxel, approximately 100% increased uptake was observed when the drug was encapsulated in a nanoparticulate micellar formulation compared to approximately 50% for free drug. CONCLUSIONS: The 4 MHz, 32 W/cm(2) ultrasound exposure regime (using burst-mode with 50 ms burst period) allows for the enhanced uptake of both water soluble and insoluble compounds into proliferating cancer and angiogenic cells. PMID- 21663931 TI - Application of SH surface acoustic waves for measuring the viscosity of liquids in function of pressure and temperature. AB - Viscosity measurements were carried out on triolein at pressures from atmospheric up to 650 MPa and in the temperature range from 10 degrees C to 40 degrees C using ultrasonic measuring setup. Bleustein-Gulyaev SH surface acoustic waves waveguides were used as viscosity sensors. Additionally, pressure changes occurring during phase transition have been measured over the same temperature range. Application of ultrasonic SH surface acoustic waves in the liquid viscosity measurements at high pressure has many advantages. It enables viscosity measurement during phase transitions and in the high-pressure range where the classical viscosity measurement methods cannot operate. Measurements of phase transition kinetics and viscosity of liquids at high pressures and various temperatures (isotherms) is a novelty. The knowledge of changes in viscosity in function of pressure and temperature can help to obtain a deeper insight into thermodynamic properties of liquids. PMID- 21663932 TI - Patterns of mercury and methylmercury bioaccumulation in fish species downstream of a long-term mercury-contaminated site in the lower Ebro River (NE Spain). AB - Since the 19th century, large amounts of industrial waste were dumped in a reservoir adjacent to a chlor-alkali plant in the lower Ebro River (NE Spain). Previous toxicological analysis of carp populations inhabiting the surveyed area have shown that the highest biological impact attributable to mercury pollution occurred downstream of the discharge site. However, mercury speciation in fish from this polluted area has not been addressed yet. Thus, in the present study, piscivorous European catfish (Silurus glanis) and non-piscivorous common carp (Cyprinus carpio) were selected, to investigate the bioavailability and bioaccumulation capacities of both total mercury (THg) and methylmercury (MeHg) at the discharge site and downstream points. Multiple Correspondence Analysis (MCA) was applied to reduce the dimensionality of the data set, and Multiple Linear Regression (MLR) models were fitted in order to assess the relationship between both Hg species in fish and different variables of interest. Mercury levels in fish inhabiting the dam at the discharge site were found to be approximately 2-fold higher than those from an upstream site; while mercury pollution progressively increased downstream of the hot spot. In fact, both THg and MeHg levels at the farthest downstream point were 3 times greater than those close to the waste dump. This result clearly indicates downstream transport and increased mercury bioavailability as a function of distance downstream from the contamination source. A number of factors may affect both the downstream transport and increased Hg bioavailability associated with suspended particulate matter (SPM) and dissolved organic carbon (DOC). PMID- 21663933 TI - Human maternal and umbilical cord blood concentrations of polybrominated diphenyl ethers. AB - Polybrominated diphenyl ethers (PBDEs), widely used as flame retardants in commercial products, have become ubiquitous environmental contaminants. Although adult human exposure to PBDEs is well documented, developmental exposure is less well characterized. The objectives of this study were to measure maternal and fetal exposure to nine PBDE congeners and to investigate potential associations with birth weight. PBDE congeners were quantified in maternal serum at 24-28 weeks of pregnancy, delivery, and umbilical cord serum (UCS) by gas chromatography-mass spectrometry (GC/MS/MS). Complete blood sample sets were obtained from 97 pregnant women (mean age 33.1+/-0.5 years). PBDE-28, -47 and -99 were quantified in all samples tested and PBDE-47 was the most abundant congener measured in both maternal (mid-pregnancy and delivery samples geometric mean=26.9 and 26.9, respectively) and UCS (GM=56.0 ng g(-1) lipid). The UCS concentration for all congeners with the exception of PBDE-153 was higher vs. maternal delivery samples (p<0.001). Only the UCS concentration of PBDE-17 and -99 were significantly associated (beta=-49.860, p=0.032, and beta=-3.645, p=0.05) with birth weight. However, after adjustment for potential confounders only the association between PBDE-99 and birth weight remained significant (beta=-3.951 and p=0.016). We conclude that: the fetus is exposed to PBDEs from at least the second trimester of pregnancy onward; PBDE congeners are higher in UCS compared to maternal serum samples collected at delivery; and that developmental PBDE exposure is potentially associated with lower birth weight. PMID- 21663934 TI - Unusual polar metabolites in the groundwater of a contaminated waste site indicate a new pathway of mononitrotoluene transformation. AB - At a mononitrotoluene-contaminated waste disposal site, the groundwater was screened for polar transformation products of mononitrotoluenes, by means of HPLC MS, HPLC-NMR and further off-line NMR and MS techniques. Besides expected metabolites such as aminotoluenes (ATs) and nitrobenzoic acids (NBAs), three unknowns (di- and tetrahydro-derivatives of (2-oxo-quinolin-3-yl) acetic acid) could be identified which, in the context of explosives and related compounds, are new metabolites. Evidence could be provided by microcosm experiments with 2 nitrotoluene (2-NT) that these metabolites are microbial transformation products of 2-NT under anaerobic conditions. The NMR and MS data are presented and the possible pathway for the formation of these metabolites after addition of 2-NT to fumarate is discussed. PMID- 21663935 TI - Identification of various laccases induced by anthracene and contribution to its degradation in a Mediterranean coastal pine litter. AB - Mediterranean coastal ecosystems are known to be highly subject to natural and anthropic environmental stress. In this study, we examine the effects of anthracene as a common pollutant on the total microbial communities from a Pinus halepensis litter of a typical Mediterranean coastal site (Les Calanques, Marseille). The main objective was to identify the microbial factors leading the resilience of this ecosystem. Two questions were addressed: (i) how lignin degrading enzymes (Laccase, Lignin-peroxidase and Mn-peroxidase) are affected by the presence of this molecule, (ii) whether the indigenous consortia are involved in its degradation in mesocosms under favorable incubation conditions (25 degrees C, 60% WHC) and after different time intervals (1 and 3 month(s)). We found a strong increase in laccase production in the presence of anthracene after 3 months, together with anthracene degradation (28%+/-5). Moreover 9,10 anthraquinone is detected as the product of anthracene oxidation after 3 months. However neither lignin-peroxidase activity nor Mn-peroxidase activity is detected. Laccase proteins directly extracted from litter were sequenced via Nano LC-MS/MS and reveal twelve different peptide sequences induced by the presence of anthracene in the mesocoms. Our study confirms the major detoxification role of this enzymatic system and highlights the high degradation potential of fungal species inhabiting P. halepensis litter, a factor in the resilience of Mediterranean ecosystems. PMID- 21663936 TI - Endobronchial metastatic breast cancer with pagetoid histology mimicking bronchial pagetoid squamous cell carcinoma in situ. AB - We report a case of a 56-year-old woman with endobronchial breast cancer metastasis of unusual histology. The patient presented with persistent cough, and a lesion was noted in the left mainstem bronchus on bronchoscopic examination. Biopsy revealed extensive squamous metaplasia of bronchial epithelium along with large, atypical cells exhibiting pagetoid intraepithelial spread within squamous mucosa. Immunohistochemical stains were compatible with a diagnosis of metastatic breast adenocarcinoma with pagetoid spread. To our knowledge, this is the first reported case of endobronchial breast cancer metastasis with this histologic presentation. In this report, we describe the clinical, radiographic, bronchoscopic, histologic, and immunohistochemical characteristics of this case. We provide a brief review of existing literature on endobronchial breast cancer metastasis. In addition, we discuss the principal differential diagnosis of bronchial pagetoid lesions. This report raises awareness of this uncommon manifestation of metastatic breast cancer. PMID- 21663937 TI - PAX8 immunostaining of anaplastic thyroid carcinoma: a reliable means of discerning thyroid origin for undifferentiated tumors of the head and neck. AB - Anaplastic thyroid carcinoma can be difficult to diagnose because it does not show thyroid differentiation morphologically or immunohistochemically. Depending on the histologic variant, anaplastic thyroid carcinoma may be confused with sarcoma or squamous cell carcinoma of the head and neck. PAX8 is a transcription factor expressed in normal and neoplastic thyroid follicular epithelium and only a few other tissues. This restricted expression suggests that PAX8 staining could be useful when dealing with spindled or squamoid tumors of the neck. The purposes of this study were to determine the frequency of PAX8 staining in anaplastic thyroid carcinoma and to evaluate PAX8 immunohistochemistry as a means of distinguishing its squamoid variant from head and neck squamous cell carcinoma. PAX8 immunohistochemical staining was performed on 34 anaplastic thyroid carcinomas and 118 head and neck squamous cell carcinomas. PAX8 staining was present in 26 (76%) anaplastic thyroid carcinomas including 16 (100%) of 16 squamoid variants, 7 (58%) of 12 giant cell/pleomorphic variants, and 3 (50%) of 6 spindled variants. All head and neck squamous cell carcinomas were negative for PAX8. PAX8 expression is often retained in anaplastic thyroid carcinomas including the squamoid variant, but it is not expressed in head and neck squamous cancers. PAX8 staining is an excellent marker for carcinomas of follicular epithelial origin, including those carcinomas that are undifferentiated in other respects. The tissue specificity of PAX8 expression may be useful in resolving the differential diagnosis of anaplastic thyroid carcinoma such as the distinction between its squamoid variant and squamous cell carcinoma of the head and neck. PMID- 21663938 TI - Benign lymphoid hyperplasia (pseudolymphoma) of soft tissue. AB - Benign lymphoid hyperplasia (pseudolymphoma) has been reported in the skin, lungs, orbit, and gastrointestinal tract, but only rarely in soft tissues. These lesions mimic lymphoma both clinically and histologically. We describe a case of a pseudolymphoma of the deep soft tissues of the lower extremity. The lesion was composed of nonencapsulated lymphoid tissue with involvement of adjacent fat and connective tissues and multiple variably sized well-polarized germinal centers. Immunohistochemical staining, flow cytometry, chromogenic in situ hybridization for kappa/lambda light-chain restriction, and polymerase chain reaction for T- and B-cell gene rearrangements all revealed a polyclonal population of T and B cells, consistent with a benign reactive process. So far as we know, pseudolymphoma of the deep soft tissues has been described only once previously in the medical literature. PMID- 21663939 TI - Intraglomerular crescentic metastases of malignant melanoma. AB - We describe here a patient with a metastatic malignant melanoma displaying crescentic lesions in the glomeruli. A 64-year-old woman was referred to our hospital because of a sudden increase of serum creatinine. Clinical diagnosis suggested rapidly progressive glomerulonephritis. Renal biopsy revealed diffuse crescentic lesions containing metastatic melanoma cells. These cells were also seen in the glomerular capillary lumina and tubules, and a few scattered tumor cells were also present in the interstitium. Glomerular metastasis is a very rare entity. To the best of our knowledge, this patient is the first to be described in the English language literature showing intraglomerular metastasis of malignant melanoma as demonstrated by needle biopsy and is only the second patient with intraglomerular metastasis presenting with acute renal failure. PMID- 21663940 TI - Parakeratosis in skin is associated with loss of inhibitor of differentiation 4 via promoter methylation. AB - Parakeratosis refers to incomplete maturation of epidermal keratinocytes, resulting in abnormal retention of nuclei in the stratum corneum. It occurs in many diseases of the skin, particularly in psoriasis. Down-regulation of inhibitor of differentiation 4 messenger RNA has been demonstrated in psoriatic skin, but the specificity and mechanism for this finding are unknown. In this study, we addressed specificity by immunohistochemical staining for inhibitor of differentiation 4 protein in skin disorders showing parakeratosis, including: psoriasis (n = 9), chronic eczema (n = 6), and squamous cell carcinoma (n = 7). In these conditions, parakeratotic keratinocytes in the upper layers of the skin lacked inhibitor of differentiation 4 protein expression, whereas keratinocytes in the lower layers were densely stained, in contrast to diffuse expression in normal skin. Because promoter hypermethylation of inhibitor of differentiation 4 has been described in several cancers, we determined the methylation pattern of the inhibitor of differentiation 4 promoter in psoriasis and compared this with squamous cell carcinoma. We found a novel methylation pattern of the inhibitor of differentiation 4 promoter in both conditions. Inhibitor of differentiation 4 promoter methylation was significantly increased in psoriasis (34.8%) and squamous cell carcinoma (21.8%), compared with normal skin (0%). Moreover, cells in the upper and lower parts of psoriatic epidermis were, respectively, hypermethylated and nonmethylated, at the inhibitor of differentiation 4 promoter. Comparable studies in several cell lines confirmed that hypermethylation of the promoter was associated with loss of inhibitor of differentiation 4 messenger RNA and protein expression. Our study demonstrates a previously unreported link between gene-specific promoter hypermethylation and abnormal cellular differentiation in several skin diseases. This mechanism might provide clues for novel therapies for skin disorders characterized by parakeratosis. PMID- 21663941 TI - Breast cancer multifocality, disease extent, and survival. AB - The prognostic information implied in subgross morphologic parameters such as lesion distribution (unifocal, multifocal, or diffuse) and disease extent in breast cancer has remained largely unexplored in the literature. We aimed to test whether these parameters influence survival in breast carcinoma. The parameters were assessed in a series of 574 cases, all documented in large-format histology sections. We used Cox proportional hazards regression accompanied by Kaplan-Meyer survival curves, with P < .05 regarded as significant. The invasive component was unifocal in 62% (311/499), multifocal in 24% (122/499), and diffuse in 5% (26/499) of the cases. Combining the in situ and invasive tumor components resulted in 48% (274/574) unifocal, 25% (141/574) multifocal, and 20% (117/574) diffuse tumors. Sixty percent (347/574) of the tumors were categorized as having limited extent (occupying an area <40 mm in largest dimension) and 29% (164/574) as extensive. Highly significant (P < .0001) differences were observed in 10-year disease-specific cumulative survival among the cases with unifocal, multifocal, and diffuse invasive (89.6%, 76.0%, and 63.6%, respectively) and combined (92.3%, 82.3%, and 75.7%, respectively) lesion distribution. Patients with extensive tumors exhibited a significantly lower cumulative survival (P < .0001) compared with those with limited extent (91.6% and 75.5%) and a statistically significantly 1.89-fold (95% confidence interval, 1.07-3.37; P = .03) risk for breast cancer death after controlling for tumor attributes, type of surgery, and adjuvant therapy. The hazard ratio for breast cancer death for mutifocal and/or diffuse tumors versus unifocal ones was 1.96 (95%; 1.11-3.48; P = .02) after controlling for the same factors. Lesion distribution and disease extent represent important independent survival-related prognostic parameters in breast carcinoma. PMID- 21663942 TI - Benign mesothelial cells as confounders when cytokeratin immunohistochemistry is used in sentinel lymph nodes. PMID- 21663943 TI - Expression of nitric oxide synthases in primary ciliary dyskinesia. AB - Nitric oxide is believed to play a central role in nonspecific defense of upper airways. Patients with primary ciliary dyskinesia have very low concentration of nasal nitric oxide, which may contribute to the chronic upper airway diseases encountered by these patients. The mechanisms underlying this drop of nasal nitric oxide in primary ciliary dyskinesia are still unknown. The goal of the present work was to study nitric oxide synthases expression in upper airway tissues from patients with primary ciliary dyskinesia. For this purpose, 5 patients with primary ciliary dyskinesia and 10 nonallergic age-matched patients without primary ciliary dyskinesia undergoing nasal polypectomy were included. Nasal nitric oxide concentration was measured before polypectomy, and nitric oxide synthase expression and function were studied in nasal polyps. The nasal nitric oxide in patients with primary ciliary dyskinesia was lower than that in patients without primary ciliary dyskinesia (13 [9-16] ppb versus 210 [167-254] ppb, P < .0001). Nitric oxide synthase 2 immunostaining was prominent at the apical part of the ciliated epithelial cells and was similar in both groups. Nitric oxide synthase 3 staining was restricted to endothelial cells in both groups. In addition, reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity was superimposable to nitric oxide synthases 2 and 3 immunostaining, suggesting a preserved NADPH-activity of nitric oxide synthase. We therefore conclude that the drop in nasal nitric oxide in patients with primary ciliary dyskinesia is not secondary to the loss of nitric oxide synthase expression. PMID- 21663944 TI - Environmental and health hazard ranking and assessment of plastic polymers based on chemical composition. AB - Plastics constitute a large material group with a global annual production that has doubled in 15 years (245 million tonnes in 2008). Plastics are present everywhere in society and the environment, especially the marine environment, where large amounts of plastic waste accumulate. The knowledge of human and environmental hazards and risks from chemicals associated with the diversity of plastic products is very limited. Most chemicals used for producing plastic polymers are derived from non-renewable crude oil, and several are hazardous. These may be released during the production, use and disposal of the plastic product. In this study the environmental and health hazards of chemicals used in 55 thermoplastic and thermosetting polymers were identified and compiled. A hazard ranking model was developed for the hazard classes and categories in the EU classification and labelling (CLP) regulation which is based on the UN Globally Harmonized System. The polymers were ranked based on monomer hazard classifications, and initial assessments were made. The polymers that ranked as most hazardous are made of monomers classified as mutagenic and/or carcinogenic (category 1A or 1B). These belong to the polymer families of polyurethanes, polyacrylonitriles, polyvinyl chloride, epoxy resins, and styrenic copolymers. All have a large global annual production (1-37 million tonnes). A considerable number of polymers (31 out of 55) are made of monomers that belong to the two worst of the ranking model's five hazard levels, i.e. levels IV-V. The polymers that are made of level IV monomers and have a large global annual production (1-5 million tonnes) are phenol formaldehyde resins, unsaturated polyesters, polycarbonate, polymethyl methacrylate, and urea-formaldehyde resins. This study has identified hazardous substances used in polymer production for which the risks should be evaluated for decisions on the need for risk reduction measures, substitution, or even phase out. PMID- 21663945 TI - Awake at the switch: improving fish consumption advisories for at-risk women. AB - Eating fish provides health benefits; however, nearly all fish contain at least some methylmercury which can impair human health. While government agencies have been issuing fish consumption advisories for 40 years, recent evaluation efforts highlight their poor performance. The benefit of an advisory can be measured by its ability to inform consumers as to both the positive and negative attributes of their potential choices, leading to appropriate changes in behavior. Because of the health benefits, fish advisories should not reduce fish consumption, even among at-risk individuals, but should lead consumers to switch away from highly contaminated fish toward those less contaminated. Although studies document how advisories reduce fish consumption (a negative outcome), no study indicates whether they lead to switching behavior (a positive outcome). We explore the effects of Maine Center of Disease Control and Prevention's advisory aimed at informing women who may become pregnant, nursing mothers and pregnant women about the benefits and risks of fish consumption. We examine how the advisory changes consumption, especially related to switching behavior. We demonstrate such changes in behavior both during and after pregnancy and compare the advisory induced changes with those induced by other information sources. Although we find the advisory reduced some women's consumption of fish, we find the decrease is short-lived. Most importantly, the advisory induced appropriate switching behavior; women reading the advisory decreased their consumption of high-risk fish and increased their consumption of low-risk fish. We conclude a well designed advisory can successfully transform a complex risk/benefit message into one that leads to appropriate knowledge and behavioral changes. PMID- 21663946 TI - Fluctuation analysis-based risk assessment for respiratory virus activity and air pollution associated asthma incidence. AB - Asthma is a growing epidemic worldwide. Exacerbations of asthma have been associated with bacterial and viral respiratory tract infections and air pollution. We correlated the asthma admission rates with fluctuations in respiratory virus activity and traffic-related air pollution, namely particulate matter with an aerodynamic diameter <= 10 MUm (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3). A probabilistic risk assessment framework was developed based on a detrended fluctuation analysis to predict future respiratory virus and air pollutant associated asthma incidence. Results indicated a strong association between asthma admission rate and influenza (r=0.80, p<0.05) and SO2 level (r=0.73, p<0.05) in Taiwan in the period 2001-2008. No significant correlation was found for asthma admission and PM10, O3, NO2, and CO. The proposed fluctuation analysis provides a simple correlation exponent describing the complex interactions of respiratory viruses and air pollutants with asthma. This study revealed that there was a 95% probability of having exceeded 2987 asthma admissions per 100,000 population. It was unlikely (30% probability) that the asthma admission rate exceeded 3492 per 100,000 population. The probability of asthma admission risk can be limited to below 50% by keeping the correlation exponent of influenza to below 0.9. We concluded that fluctuation analysis based risk assessment provides a novel predictor of asthma incidence. PMID- 21663947 TI - Similar expression to FGF (Sef) reduces endometrial adenocarcinoma cells proliferation via inhibiting fibroblast growth factor 2-mediated MAPK/ERK signaling pathway. AB - OBJECTIVE: Fibroblast growth factors (FGF) axis, and in particular FGF2 axis, is an important mitogenic stimulus in endometrial carcinogenesis. hSef is a key inhibitory regulator of FGF signaling and aberrant hSef expression is reported to be present in various human carcinomas. The objective of this study was to investigate the role of hSef in the growth and proliferation of endometrial adenocarcinoma cells and to explore the mechanism that may be involved. METHODS: Using western blot analysis, we determined the expression of hSef in Ishikawa cells under different conditions. Using luciferase reporter assays and western blot analysis, we detected the effect of hSef on MAPK/ERK-mediated FGF2 signaling. Using MTT, cell counting and colony formation assays, we analyzed the growth and proliferation of Ishikawa cells under different conditions. RESULTS: We found that the hSef expression was positively regulated by FGF2-induced MAPK/ERK signaling and inversely, hSef expression efficiently inhibited the activity of FGF2-induced MAPK/ERK signaling, indicating the presence of hSef mediated negative feedback mechanism for FGF signaling in endometrial cancer cells. In addition, we found that MAPK/ERK signaling was essential for the growth and proliferation of endometrial cancer cells in vitro, and hSef expression significantly reduced the cell proliferation. CONCLUSIONS: hSef expression can inhibit the growth and proliferation of endometrial cancer cells via acting on the FGF2/MAPK/ERK signaling. PMID- 21663948 TI - Identity in university students: the role of parental and romantic attachment. AB - In this study with 236 Portuguese university students, we examined two competing models for understanding identity. In the first model, the direct independent effects of parental and romantic attachment on identity were tested. The second model examined the mediating role of romantic attachment representations in the link between parental attachment and identity. The participants completed measures of parental and romantic attachment at the beginning of the freshman year (Wave 1), and a measure of identity development 18 months later (Wave 2). Structural equation modeling for the independent model indicated that identity is exclusively predicted by romantic attachment at this life stage, and not by parental attachment. Regarding the second model, our mediational hypothesis was supported, since the association between parental attachment and identity was totally mediated by romantic attachment representations. Both models presented adequate indices of adjustment, and provided a complementary understanding of the differential role that romantic relations play in contributing to explaining identity development. PMID- 21663950 TI - SHARP: a stab in the right direction in chronic kidney disease. PMID- 21663951 TI - Is health still global? A new approach from the UK Government. PMID- 21663952 TI - Open letter to Ulf Wiinberg, Chief Executive of Lundbeck Pharmaceuticals. PMID- 21663955 TI - The effect of purity upon the triple-helical stability of collagenous peptides. AB - Collagen is the fundamental structural protein, comprising 25-35% of the total body protein, its rod-like triple helix providing support in many tissues. Our laboratory has synthesised 113 Toolkit peptides, each 63 residues long, covering the entirety of the homotrimeric helix sequence of collagen II and collagen III. These are used primarily to investigate protein-collagen interactions, from which biomedical applications are under development. Upon increasing the temperature of a Toolkit peptide solution, a novel low temperature transition (LTT) as well as a broadening of the helix unfolding higher temperature transition (HTT) was observed. Here, we hypothesized that unfolding of imperfect helices can account for the LTT. Peptides of various purities were isolated by HPLC or gel filtration, and their unfolding measured by polarimetry, CD, and DSC. The resulting temperature transitions were fitted to a kinetic unfolding equation, allowing comparison of the data, and explanation of the observed melting curve complexity as due to peptide imperfections. Finally, using a mathematical model, this data can be replicated by setting a parameter that quantifies the mutual stabilization conferred by helices on each side of a peptide defect within a triple helix. PMID- 21663954 TI - Determinants of the thrombogenic potential of multiwalled carbon nanotubes. AB - Multiwalled carbon nanotubes (MWCNTs) are cylindrical tubes of graphitic carbon with unique physical and electrical properties. MWCNTs are being explored for a variety of diagnostic and therapeutic applications. Successful biomedical application of MWCNTs will require compatibility with normal circulatory components, including constituents of the hemostatic cascades. In this manuscript, we compare the thrombotic activity of MWCNTs in vitro and in vivo. We also assess the influence of functionalization of MWCNTs on thrombotic activity. In vitro, MWCNT activate the intrinsic pathway of coagulation as measured by activated partial thromboplastin time (aPTT) assays. Functionalization by amidation or carboxylation enhances this procoagulant activity. Mechanistic studies demonstrate that MWCNTs enhance propagation of the intrinsic pathway via a non-classical mechanism strongly dependent on factor IX. MWCNTs preferentially associate with factor IXa and may provide a platform that enhances its enzymatic activity. In addition to their effects on the coagulation cascade, MWCNTs activate platelets in vitro, with amidated MWCNTs exhibiting greater platelet activation than carboxylated or pristine MWCNTs. However, contrasting trends are obtained in vivo, where functionalization tends to diminish rather than enhance procoagulant activity. Thus, following systemic injection of MWCNTs in mice, pristine MWCNTs decreased platelet counts, increased vWF, and increased D-dimers. In contrast, carboxylated MWCNTS exhibited little procoagulant tendency in vivo, eliciting only a mild and transient decrease in platelets. Amidated MWCNTs elicited no statistically significant change in platelet count. Further, neither carboxylated nor amidated MWCNTs increased vWF or D-dimers in mouse plasma. We conclude that the procoagulant tendencies of MWCNTs observed in vitro are not necessarily recapitulated in vivo. Further, functionalization can markedly attenuate the procoagulant activity of MWCNTs in vivo. This work will inform the rational development of biocompatible MWCNTs for systemic delivery. PMID- 21663956 TI - Nanosheet-based titania microspheres with hollow core-shell structure encapsulating horseradish peroxidase for a mediator-free biosensor. AB - Nanosheet-based titania (TiO(2)) microspheres with a hollow core-shell structure have been synthesized and employed to immobilize horseradish peroxidase (HRP) in order to fabricate a mediator-free biosensor. The morphology and structure of the TiO(2) microspheres were characterized by X-ray diffraction, scanning electron microscopy and transmission electronic microscopy. A possible growth mechanism has been proposed. Spectroscopic and electrochemical measurements revealed that the TiO(2) microspheres are an immobilization support with biocompatibility for enzymes, affording good enzyme stability and bioactivity. Due to the nanosheet based hollow core-shell structure of the TiO(2) microspheres, the direct electron transfer of HRP is facilitated and the resulting biosensor displayed good performance for the detection of H(2)O(2), with both a low detection limit of 0.05 MUM and a wide linear range of 0.4-140 MUM, as well as a fast response and excellent long-term stability. The nanosheet-based TiO(2) microspheres with hollow core-shell structure, can be used for the efficient entrapment of other redox-active proteins and have wide potential applications in biosensors, biocatalysis, biomedical devices and bioelectronics. PMID- 21663958 TI - The role of pore size on vascularization and tissue remodeling in PEG hydrogels. AB - Vascularization is influenced by the physical architecture of a biomaterial. The relationship between pore size and vascularization has been examined for hydrophobic polymer foams, but there has been little research on tissue response in porous hydrogels. The goal of this study was to examine the role of pore size on vessel invasion in porous poly(ethylene glycol) (PEG) hydrogels. Vascularized tissue ingrowth was examined using three-dimensional cell culture and rodent models. In culture, all porous gels supported vascular invasion with the rate increasing with pore size. Following subfascial implantation, porous gels rapidly absorbed wound fluid, which promoted tissue ingrowth even in the absence of exogenous growth factors. Pore size influenced neovascularization, within the scaffolds and also the overall tissue response. Cell and vessel invasion into gels with pores 25-50 MUm in size was limited to the external surface, while gels with pores larger pores (50-100 and 100-150 MUm) permitted mature vascularized tissue formation throughout the entire material volume. A thin layer of inflammatory tissue was present at all PEG-tissue interfaces, effectively reducing the area available for tissue growth. These results show that porous PEG hydrogels can support extensive vascularized tissue formation, but the nature of the response depends on the pore size. PMID- 21663957 TI - The influence of Leucine-rich amelogenin peptide on MSC fate by inducing Wnt10b expression. AB - Amelogenin is the most abundant protein of the enamel organic matrix and is a structural protein indispensable for enamel formation. One of the amelogenin splicing isoforms, Leucine-rich Amelogenin Peptide (LRAP) induces osteogenesis in various cell types. Previously, we demonstrated that LRAP activates the canonical Wnt signaling pathway to induce osteogenic differentiation of mouse ES cells through the concerted regulation of Wnt agonists and antagonists. There is a reciprocal relationship between osteogenic and adipogenic differentiation in bone marrow mesenchymal stem cells (BMMSCs). Wnt10b-mediated activation of canonical Wnt signaling has been shown to regulate mesenchymal stem cell fate. Using the bipotential bone marrow stromal cell line ST2, we have demonstrated that LRAP activates the canonical Wnt/beta-catenin signaling pathway. A specific Wnt inhibitor sFRP-1 abolishes the effect of LRAP on the stimulation of osteogenesis and the inhibition of adipogenesis of ST2 cells. LRAP treatment elevates the Wnt10b expression level whereas Wnt10b knockdown by siRNA abrogates the effect of LRAP. We show here that LRAP promotes osteogenesis of mesenchymal stem cells at the expense of adipogenesis through upregulating Wnt10b expression to activate Wnt signaling. PMID- 21663959 TI - Enhancement of the photostability and retention time of indocyanine green in sentinel lymph node mapping by anionic polyelectrolytes. AB - Sentinel lymph node (SLN) biopsy techniques have been widely used in the diagnosis of cancer metastasis because lymph node metastasis is one of the most important prognostic signs. Indocyanine green (ICG) has potential application as a molecular imaging probe for SLN mapping due to its fluorescent properties emitting in the near-infrared (NIR) region, where light transmission through biological tissue is maximized. However, its low photostability in an aqueous solution at the physiological temperature and its rapid diffusion behavior through SLN into the second lymph node have limited its wide use in real clinical fields. In this study, we developed a new NIR imaging contrast system consisting of ICG and poly (gamma-glutamic acid) (gamma-PGA) polymers for efficient sentinel lymph node mapping. By a combination of clinically used ICG and the biocompatible anionic polyelectrolyte, gamma-PGA, the photostabilities of aqueous ICG solutions at room and body temperatures were drastically enhanced. When the ICG/gamma-PGA complex was injected subcutaneously into the front paw of a mouse, it entered the lymphatics and migrated to the axillary sentinel lymph node (SLN) within 2 min. Furthermore, the NIR fluorescent signal intensity and retention time of ICG/gamma PGA complex in lymph node were superior to those of ICG only. In addition, a histofluorescentstudy of the SLN resected under NIR imaging revealed that ICG and gamma-PGA were co-localized in the lymph node.Taken together, the experimental results on the enhanced photostability and retention time of the ICG/gamma-PGA complex provide strong evidence that it has promising potential for improved sentinel lymph node mapping. PMID- 21663960 TI - Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging. AB - We report on the fabrication of multifunctional polymeric unimolecular micelles as an integrated platform for cancer targeted drug delivery and magnetic resonance imaging (MRI) contrast enhancement under in vitro and in vivo conditions. Starting from a fractionated fourth-generation hyperbranched polyester (Boltorn H40), the ring-opening polymerization of E-caprolactone (CL) from the periphery of H40 and subsequent terminal group esterification with 2 bromoisobutyryl bromide afforded star copolymer-based atom transfer radical polymerization (ATRP) macroinitiator, H40-PCL-Br. Well-defined multiarm star block copolymers, H40-PCL-b-P(OEGMA-co-AzPMA), were then synthesized by the ATRP of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and 3-azidopropyl methacrylate (AzPMA). This was followed by the click reaction of H40-PCL-b P(OEGMA-co-AzPMA) with alkynyl-functionalized cancer cell-targeting moieties, alkynyl-folate, and T(1)-type MRI contrast agents, alkynyl-DOTA-Gd (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid), affording H40-PCL-b P(OEGMA-Gd-FA). In aqueous solution, the amphiphilic multiarm star block copolymer exists as structurally stable unimolecular micelles possessing a hyperbranched polyester core, a hydrophobic PCL inner layer, and a hydrophilic P(OEGMA-Gd-FA) outer corona. H40-PCL-b-P(OEGMA-Gd-FA) unimolecular micelles are capable of encapsulating paclitaxel, a well-known hydrophobic anticancer drug, with a loading content of 6.67 w/w% and exhibiting controlled release of up to 80% loaded drug over a time period of ~120 h. In vitro MRI experiments demonstrated considerably enhanced T(1) relaxivity (18.14 s(-1) mM(-1)) for unimolecular micelles compared to 3.12 s(-1) mM(-1) for that of the small molecule counterpart, alkynyl-DOTA-Gd. Further experiments of in vivo MR imaging in rats revealed good accumulation of unimolecular micelles within rat liver and kidney, prominent positive contrast enhancement, and relatively long duration of blood circulation. The reported unimolecular micelles-based structurally stable nanocarriers synergistically integrated with cancer targeted drug delivery and controlled release and MR imaging functions augur well for their potential applications as theranostic systems. PMID- 21663961 TI - Layer-by-layer co-immobilization of soluble complement receptor 1 and heparin on islets. AB - Early graft loss due to instant blood-mediated inflammatory reactions (IBMIRs) is a major obstacle of clinical islet transplantation; inhibition of blood coagulation and complement activation is necessary to inhibit IBMIRs. Here, human soluble form complement receptor 1 (sCR1) and heparin were co-immobilized onto the surfaces of islet cells. sCR1 molecules carrying thiol groups were immobilized through maleimide-poly(ethylene glycol)-phospholipids anchored in the lipid bilayers of islet cells. Heparin was immobilized on the sCR1 layer via the affinity between sCR1 and heparin, and additional layers of sCR1 and heparin were formed layer-by-layer. The sCR1 and heparin molecules in these layers maintained anti-complement activation and anti-coagulation activities, respectively. This promising method could be employed to reduce the number of islet cells required to reverse hyperglycemia and prolong graft survival in both allo- and xeno-islet transplantation. PMID- 21663962 TI - The effect of scaffold architecture on odontogenic differentiation of human dental pulp stem cells. AB - Previous studies have shown the superiority of nanofibrous (NF) poly(l-lactic acid) (PLLA) scaffolds in supporting the osteogenic differentiation of a few cell types and bone regeneration. The aim of the current study was to investigate whether NF-PLLA scaffolds are advantageous for the odontogenic differentiation and mineralization of human dental pulp stem cells (DPSCs) over solid-walled (SW) PLLA scaffolds. The in vitro studies demonstrated that, compared with SW scaffolds, NF scaffolds enhanced attachment and proliferation as well as odontogenic differentiation of human DPSCs. The alkaline phosphatase (ALP) activity and the expression of odontogenic genes of human DPSCs were increased on NF scaffolds compared with that on SW scaffolds. In addition, more mineral deposition was observed on the NF scaffolds, as demonstrated by von Kossa staining, calcium content measurement and scanning electron microscopy. Consistent with the in vitro studies, NF scaffolds promoted odontogenic differentiation and hard tissue formation compared with SW scaffolds after 8 weeks of ectopic transplantation in nude mice, as confirmed by von Kossa staining, Masson's trichrome staining and immunohistochemical staining for dentin sialoprotein. In conclusion, NF-PLLA scaffolds enhanced the odontogenic differentiation of human DPSCs and mineralization both in vitro and in vivo, and are promising scaffolds for dentin regeneration. PMID- 21663963 TI - Cardioprotective action of urocortin in postconditioning involves recovery of intracellular calcium handling. AB - Ischemia/reperfusion (I/R) damage in the heart occurs mainly during the first minutes of reperfusion. Urocortin (Ucn) is a member of the corticotrophin releasing factor that has been identified as a potent endogenous cardioprotector peptide when used in pre- and postconditioning protocols. However, the underlying mechanisms are not completely elucidated. Here, we focused on intracellular calcium ([Ca(2+)](i)) handling by Ucn when applied in early reperfusion. We used Langendorff-perfused rat hearts to determine hemodynamic parameters, and confocal microscopy to study global [Ca(2+)](i) transients evoked by electrical stimulation in isolated cardiomyocytes loaded with fluorescence Ca(2+) dye fluo 3AM. We found that the acute application of Ucn at the onset of reperfusion, in isolated hearts submitted to ischemia, fully recovered the hearts contractility and relaxation. In isolated cardiac myocytes, following ischemia we observed that the diastolic [Ca(2+)](i) was increased, the systolic [Ca(2+)](i) transients amplitude were depressed and sarcoplasmic reticulum (SR) Ca(2+) load was reduced. These effects were correlated to a decrease in the Na(+)/Ca(2+) exchanger (NCX) activity. Importantly, Ucn applied at reperfusion produced a complete recovery in diastolic [Ca(2+)](i) and global [Ca(2+)](i) transient amplitude, which were due to NCX activity improvement. In conclusion, we demonstrated that [Ca(2+)](i) handling play an essential role in postconditioning action of Ucn. PMID- 21663964 TI - The ancient cell death suppressor BAX inhibitor-1. AB - Bax inhibitor-1 (BI-1) was initially identified for its ability to inhibit BAX induced apoptosis in yeast cells and is the founding member of a family of highly hydrophobic proteins localized in diverse cellular membranes. It is evolutionarily conserved and orthologues from plants can substitute for mammalian BI-1 in regard to its anti-apoptotic function suggesting a high degree of functional conservation. BI-1 interacts with BCL-2 and BCL-XL and, similar to these two anti-apoptotic proteins, the effect of BI-1 on cell death involves changes in the amount of Ca(2+) releasable from intracellular stores. However, BI 1 is also a negative regulator of the endoplasmic reticulum stress sensor IRE1 alpha, it interacts with G-actin and increases actin polymerization, enhances cancer metastasis by altering glucose metabolism and activating the sodium hydrogen exchanger, and reduces the production of reactive oxygen species through direct interaction with NADPH-P450 reductase. In this contribution, we summarize what is known about the expression, intracellular localization and structure of BI-1 and specifically illuminate its effects on the intracellular Ca(2+) homeostasis and how this might relate to its other functions. We also present a thorough phylogenetic analysis of BI-1 proteins from major phyla together with paralogues from all BI-1 family members. PMID- 21663965 TI - Calcium-dependence of Donnan potentials in glycerinated rabbit psoas muscle in rigor, at and beyond filament overlap; a role for titin in the contractile process. AB - In glycerinated rabbit psoas muscle, Donnan potential measurements demonstrated that the net electric charge on the actin-myosin matrix undergoes a sharp switch like transition at pCa(50) = 6.8. The potentials are 2 mV less negative at the lower pCa(2+) (P < 0.001). If ATP is present, the muscle contracts and breaks the microelectrode. Therefore the rigor state was studied. There is no reason to suppose a priori that a similar voltage switch does not occur during contraction, however. Calcium dependence is still apparent in muscles stretched beyond overlap (sarcomere length>3.8 MUm) and is also seen in the gap filaments between the A- and I-band ends; further stretching abolishes the dependence. These experiments strongly suggest that calcium dependence is controlled initially by the titin component, and that this control is lost when titin filaments break. We suppose that that effect is mediated by the titin kinase in the M-line region and may involve the extensible PEVK region of titin. There is great interest in the electric charge on proteins in muscle within the structural system. We suggest how changes in these charges may control the calcium activation process. We also suggest some simple experimental approaches that could clarify these effects. PMID- 21663967 TI - Saliva is a reliable and practical source of germline DNA for genome-wide studies in chronic lymphocytic leukemia. AB - High-throughput genomics requires tumor DNA matched to germline DNA, that cannot be easily obtained in the context of leukemia. Using chronic lymphocytic leukemia as a model, saliva DNA was frequently devoid of tumor DNA also during overt disease, and passed quality controls for SNP-array (77/102, 75.4%) and next generation sequencing (71/102, 69.6%). Compared to saliva, urine provides germline DNA of similar quality but in lower amounts. Saliva DNA was successfully run on SNP 6.0 arrays, and passed quality control call rate thresholds. On these bases, saliva represents a useful source of germline DNA for high-throughput genomic studies of hematologic neoplasia. PMID- 21663968 TI - Macrocyclic fragrance materials--a screening-level environmental assessment using chemical categorization. AB - A screening-level aquatic environmental risk assessment for macrocyclic fragrance materials using a "group approach" is presented using data for 30 macrocyclic fragrance ingredients. In this group approach, conservative estimates of environmental exposure and ecotoxicological effects thresholds for compounds within two subgroups (15 macrocyclic ketones and 15 macrocyclic lactones/lactides) were used to estimate the aquatic ecological risk potential for these subgroups. It is reasonable to separate these fragrance materials into the two subgroups based on the likely metabolic pathway required for biodegradation and on expected different ecotoxicological modes of action. The current volumes of use for the macrocyclic ketones in both Europe and North America ranges from <1 (low kg quantities) to no greater than 50 metric tonnes in either region and for macrocyclic lactones/lactides the volume of use range for both regions is <1 to no greater than 1000 metric tonnes in any one region. Based on these regional tonnages, biodegradability of these two subgroups of materials, and minimal in stream dilution (3:1), the conservatively predicted exposure concentrations for macrocyclic ketones would range from <0.01 to 0.05 MUg/L in Europe and from <0.01 to 0.03 MUg/L in North America. For macrocyclic lactones/lactides, the concentration within the mixing zone would range from <0.01 to 0.7 MUg/L in Europe and from <0.01 to 1.0 MUg/L in North America. The PNECs derived for the macrocyclic ketones is 0.22 MUg/L and for macrocyclic lactones/lactides is 2.7 MUg/L. The results of this screening-level aquatic ecological risk assessment indicate that at their current tonnage, often referred to as volumes of use, macrocyclic fragrance materials in Europe and North America, pose a negligible risk to aquatic biota; with no PEC/PNEC ratio exceeding 1 for any material in any subgroup. PMID- 21663966 TI - Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Abeta) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the 'amyloid hypothesis' of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca(2+)) handling and may contribute to AD pathogenesis, an idea termed the 'calcium hypothesis' of AD. Mutations in presenilin proteins account for the majority of FAD cases. Presenilins function as catalytic subunits of gamma-secretase involved in the generation of Abeta peptide. Recently, we discovered that presenilns function as low-conductance, passive ER Ca(2+) leak channels, independent of gamma-secretase activity. We further discovered that many FAD mutations in presenilins results in the loss of ER Ca(2+) leak function activity and Ca(2+) overload in the ER. These results provided potential explanation for abnormal Ca(2+) signaling observed in FAD cells with mutations in presenilns. The implications of these findings for understanding AD pathogenesis are discussed in this article. PMID- 21663970 TI - Impact of diabetes and poor glycaemic control on risk of bacteraemia with haemolytic streptococci groups A, B, and G. AB - BACKGROUND: Diabetes has been associated with bacteraemia due to haemolytic streptococci but epidemiological evidence is limited. METHODS: We conducted a 15 year population-based case-control study of all adults with first-time bacteraemia with groups A, B, and G haemolytic streptococci and matched population controls. The study setting was Northern Denmark between 1992 and 2006. We computed odds ratios (ORs) for streptococcal bacteraemia according to diabetes and glycaemic control, using regression analysis for confounder adjustment. RESULTS: We identified 397 adult patients with bacteraemia due to haemolytic streptococci (median age 67 years, 51% women), of which 63 (17%) had diabetes. Persons with diabetes had a 2.1-fold increased risk of streptococcal bacteraemia compared with population controls (adjusted odds ratio (OR) 2.1; 95% confidence interval (CI), 1.5-2.9). For persons with type 1 diabetes, the adjusted OR was 14.8 (2.4-91.2). Longer diabetes duration and poor glycaemic control conferred higher risk estimates: adjusted OR 1.5 (0.8-3.0) for HbA(1c) level <7%, and OR 3.6 (1.6-8.1) for HbA(1c) level >=9%. The association between diabetes and HS bacteraemia was independent of the underlying foci of infection and was strongest for group B streptococcal bacteraemia (OR 3.5; 1.8-7.0) and for group G streptococcal bacteraemia (OR 2.6; 1.6-4.4). There was no clear increase in risk for group A streptococcal bacteraemia (OR 1.2; 0.7-2.2). CONCLUSIONS: Diabetes is a strong risk factor for group B and group G, but not group A, haemolytic streptococcal bacteraemia. The risk increase is particularly high for type 1 diabetes, long diabetes duration, and poor long-term glycaemic control. PMID- 21663969 TI - Differential STIM1 expression in T and B cell subsets suggests a role in determining antigen receptor signal amplitude. AB - Ca(2+) acts ubiquitously as a second messenger in transmembrane signal transduction. In lymphocytes, calcium mobilization is triggered by antigen and chemokine receptors, among others, and controls cell functions ranging from proliferation to migration. The primary mechanism of extracellular Ca(2+) entry in lymphocytes is the CRAC influx. STIM1 is a crucial component of the CRAC influx mechanism in lymphocytes, acting as a sensor of low Ca(2+) concentration in the ER and an activator of the Ca(2+) selective channel ORAI1 in the plasma membrane. While STIM1 function has been studied extensively, little is known regarding whether it is differentially expressed and thereby affects the magnitude of calcium mobilization responses. We report here that STIM1 expression differs in murine T and B lymphocytes, and in respective subsets. For example, mature T cells express ~4 times more STIM1 than mature B cells. Furthermore, we show that through the physiologic range of expression, STIM1 levels determine the magnitude of Ca(2+) influx responses that follow BCR-induced intracellular store depletion. Considered in view of previous reports that differences in amplitude of lymphocyte Ca(2+) mobilization determine alternate biological responses, these findings suggest that differential STIM1 expression may be important determinant of biological responses. PMID- 21663971 TI - Periprosthetic joint infection following Staphylococcus aureus bacteremia. AB - OBJECTIVES: The incidence of haematogenous periprosthetic joint infections (PJI) among patients with remote infections has been reported to be less than 1%. This incidence may be much higher in cases after documented Staphylococcus aureus bacteremia (SAB). We evaluated the incidence of haematogenous PJI following SAB in patients with previously uninfected arthroplasties. METHODS: A retrospective analysis of our cohort including patients with SAB and prosthetic joints at the Basel University Medical Clinic Liestal from 1998 to 2008. RESULTS: We identified 31 patients with 45 uninfected prosthetic joints in situ at the time of SAB. In 12 patients (39%) and 13 arthroplasties (29%), SAB caused PJI. In comparison to nosocomial SAB, infections occurred only in cases with community-acquired SAB (p=0.002). PJI was diagnosed within a median time of 2.5 days (IQR 1-3.5) after admission. The comparison between patients with and without PJI revealed no significant difference in gender, age, comorbidities and number of prostheses per patient and age of the prosthesis. CONCLUSIONS: The rate of PJI after SAB is high, ranging from 30% to 40%, and clearly higher than rates reported for bacteremia with other pathogens. PJIs were observed in community-onset bacteremia, in which there is a typically delay from symptoms to antimicrobial treatment. PMID- 21663972 TI - Possible association between ubiquitin-specific peptidase 46 gene and major depressive disorders in the Japanese population. AB - BACKGROUND: Several investigations have reported that abnormalities in circadian rhythms might be related to the pathophysiology of major depressive disorder (MDD) and the therapeutic response to selective serotonin reuptake inhibitors (SSRIs). Recently, ubiquitin-specific peptidase 46 (USP46), a new molecule related to the circadian clock system, has been described. We conducted a case control study between seven tagging SNPs (rs10517263, rs17675844, rs6554557, rs12646800, rs2244291, rs10034164, rs346005) in the USP46 gene, MDD, and the SSRI therapeutic response in MDD in the Japanese population. METHOD: We recruited 432 MDD patients (202 males and 230 females) and 792 healthy controls (319 males and 473 females). Two hundred sixty-one of 432 MDD patients were treated with SSRIs (fluvoxamine, sertraline or paroxetine). RESULT: We detected an association between the USP46 gene and MDD in a haplotype analysis (rs2244291-rs10034164 rs346005 and rs12646800-rs2244291-rs10034164-rs346005). However, we did not find any association between the USP46 gene and SSRI response or remission in MDD in the Japanese population. LIMITATIONS: A replication study using larger samples may be required for conclusive results, since our sample size was small. CONCLUSIONS: Our results suggest that the USP46 gene might play a role in the pathophysiology of MDD in the Japanese population. PMID- 21663973 TI - Type D personality is independently associated with major psychosocial stressors and increased health care utilization in the general population. AB - BACKGROUND: Type D is considered as a non pathological personality trait and propensity for mental distress. Its relationship with mental distress has been mainly studied in cardiovascular patients and with respect to depression. The knowledge about the relationship of Type D with mental disorders, psychosocial stressors and health care utilization in the general population is insufficient. Therefore the present study sought to determine the associations of Type D with mental distress, major psychosocial stressors, health status, and health care utilization in the general population. METHODS: Cross-sectional analysis in a representative population based sample of n = 2495 subjects (mean age 49 years, range 14-92 years) of whom 33.1% had Type D personality. RESULTS: Individuals with Type D had an increased risk for clinically significant depression, panic disorder, somatization and alcohol abuse. After adjustment for these mental disorders Type D was still robustly associated with all major psychosocial stressors. The strongest associations emerged for feelings of social isolation and for traumatic events. After comprehensive adjustment Type D still remained associated with increased help seeking behavior and utilization of health care, especially of mental health care. LIMITATIONS: The main limitation is the reliance on self-report measures and the lack of information about the medical history and clinical diagnosis of the participants. CONCLUSION: Type D identifies persons with severely increased risk for mental distress, major psychosocial stressors and increased health care utilization. As a frequent disposition, Type D is assumed to be of high relevance for health care. PMID- 21663974 TI - To the editor: association of ZNF804A polymorphisms with schizophrenia and antipsychotic drug efficacy in a Chinese Han population. PMID- 21663975 TI - Measurement invariance of the Schizotypal Personality Questionnaire-Brief across gender and age. AB - The purpose of this study was to examine the dimensional structure and measurement invariance of the Schizotypal Personality Questionnaire-Brief (SPQ-B) (Raine and Benishay, 1995) across sex and age in a representative sample of nonclinical adolescents and young adults. The sample consisted of 1789 adolescents and young adults (42.1% males), with a mean age of 17.1years (S.D.=2.9). The results indicated that the Likert version of the SPQ-B showed adequate psychometric properties (alpha total score 0.89). The schizotypal personality models that presented the best fit indices were Raine et al.'s (1994) three-factor model and Stefanis et al.'s (2004) four-factor model. In addition, the results support the measurement invariance of the SPQ-B across sex and age. When the latent means of the schizotypal dimensions were compared across sex and age, statistically significant differences were found. Consistent with previous literature, schizotypal personality is a multidimensional construct whose structure appears invariant across sex and age. Future studies should examine the invariance of schizotypal personality across cultures, as well as using the SPQ-B as a screening method in the general population to detect individuals at risk for schizophrenia-spectrum disorders, given its rapid and easy administration. PMID- 21663976 TI - Measuring motor activity in major depression: the association between the Hamilton Depression Rating Scale and actigraphy. AB - Despite the use of actigraphy in depression research, the association of depression ratings and quantitative motor activity remains controversial. In addition, the impact of recurring episodes on motor activity is uncertain. In 76 medicated inpatients with major depression (27 with a first episode, 49 with recurrent episodes), continuous wrist actigraphy for 24h and scores on the Hamilton Depression Rating Scale (HAMD) were obtained. In addition, 10 subjects of the sample wore the actigraph over a period of 5 days, in order to assess the reliability of a 1-day measurement. Activity levels were stable over 5 consecutive days. Actigraphic parameters did not differ between patients with a first or a recurrent episode, and quantitative motor activity failed to correlate with the HAMD total score. However, of the motor-related single items of the HAMD, the item activities was associated with motor activity parameters, while the items agitation and retardation were not. Actigraphy is consistent with clinical observation for the item activities. Expert raters may not correctly rate the motor aspects of retardation and agitation in major depression. PMID- 21663977 TI - Immunophenotype-related microRNA expression in canine chronic lymphocytic leukemia. AB - MicroRNAs (miRNAs) are posttranscriptional regulatory noncoding RNAs used to profile human hematopoietic tumors. In this study, some mature miRNAs was quantitated in peripheral blood from dogs with chronic lymphocytic leukemia (CLL). Relative expression data were normalised against four endogenous controls (let-7a, miR-17-5p, miR-26b, and miR-223) selected by geNorm analysis. The results revealed distinct miRNA patterns in CLL depending on the immunophenotype. Also in dogs, the different miRNAs expression could reflect developmental lineage and tumor differentiation. The similar genetics, physiology and exposure to environment in dogs and humans make the miRNA expression study in canine CLL attractive for comparative oncology. PMID- 21663978 TI - Fiberoptic Endoscopic Evaluation of Swallowing in children: feeding outcomes related to diagnostic groups and endoscopic findings. AB - OBJECTIVE: Fiberoptic Endoscopic Evaluation of Swallowing (FEES) is used as an adjunct to assess swallowing function in children with complex feeding disorders. We report the feeding outcomes of patients who underwent FEES to determine whether associations exist between clinical diagnoses or FEES findings and feeding outcomes. METHODS: Retrospective review of children who underwent FEES for dysphagia or aspiration from 2003 to 2009. The clinical diagnoses and initial FEES findings were compared to follow up feeding status for associations. RESULTS: 79 patients were included (44 males and 35 females). The change from initial to final status: total oral feeding (42-67%), NPO +/- minimal tastes (39 21%) and oral feeding with tube feeding (19-12%). Of the clinical diagnoses, tonsillar hypertrophy was associated with ultimately obtaining total oral feeding status (p = 0.046) while the inability to obtain total oral feeding status was associated with neurologic (p < 0.001). The initial FEES findings showed no significant associations with long-term feeding status. CONCLUSION: Many children overcome their dysphagia but those with neurologic disorders are less likely to achieve total oral feeding status. In children with dysphagia evaluated by FEES, the long-term feeding status is not significantly associated with the initial FEES findings. PMID- 21663980 TI - Mid-arm and calf circumferences (MAC and CC) are better than body mass index (BMI) in predicting health status and mortality risk in institutionalized elderly Taiwanese. AB - The study was to compare the ability of BMI, MAC and CC in predicting nutritional status, functional ability and follow-up mortality risk of older adults. The study purposively recruited 160 of 320 residents of a nursing home in Central Taiwan to serve as subjects. Residents who were >=65 years old, cognitively normal, without acute conditions and non-hospitalized were qualified to participate. All subjects signed an informed consent. Each was interviewed with a structured questionnaire for sociodemographic, lifestyle and health-related information; evaluated with the Mini Nutritional Assessment (MNA) and the Activities of Daily Living (ADL) scales; measured for weight, height, MAC and CC; and assayed for nutrition-related biochemical values. Results showed that CC was the best, followed by MAC and then BMI in predicting the nutritional status and health conditions. CC and MAC were also more effective than BMI in predicting 12 month follow-up mortality. Overall, CC is the most capable in predicting nutritional status, functional activity and general health conditions; MAC is the most capable in predicting 12-month follow-up mortality risk whereas BMI is the weakest in all functions. These results should have practical implication in geriatric health measurements. PMID- 21663979 TI - Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases. AB - The past decade has seen great progress in the understanding of the molecular pharmacology, physiological function and therapeutic potential of G-protein coupled receptors (GPCRs). Free fatty acids (FFAs) have been demonstrated to act as ligands of several GPCRs including GPR40, GPR43, GPR84, GPR119 and GPR120. We have recently shown that GPR120 acts as a physiological receptor of omega3 fatty acids in macrophages and adipocytes, which mediate potent anti-inflammatory and insulin sensitizing effects. The important role GPR120 plays in the control of inflammation raises the possibility that targeting this receptor could have therapeutic potential in many inflammatory diseases including obesity and type 2 diabetes. In this review paper, we discuss lipid-sensing GPCRs and highlight potential outcomes of targeting such receptors in ameliorating disease. PMID- 21663981 TI - A case of hypertrophic cardiomyopathy with mid-ventricular obstruction (MVO) -- dramatic long-term improvement with a DDD pacemaker as assessed by diastolic paradoxical jet flow velocity. PMID- 21663982 TI - Predicting 30-day major adverse cardiovascular events after primary percutaneous coronary intervention. The RISK-PCI score. AB - BACKGROUND: Identification of patients at risk for major adverse cardiovascular events (MACE) might help selecting candidates for aggressive treatment or early discharge after primary percutaneous coronary intervention (pPCI). METHODS: The RISK-PCI is an observational trial of 2096 consecutive patients who underwent pPCI between 2006 and 2009, randomly allocated to derivation and validation sets with a set ratio of 80% to 20%. Thirty-day MACE comprising death, nonfatal reinfarction and stroke was the primary end point. Multivariable logistic regression was used to determine the independent predictors of outcome. A sum of weighted points for specific predictors was calculated to define the final score. RESULTS: The RISK-PCI score comprised 12 independent predictors of 30-day MACE, with a graded 125-fold increase in the primary end point with increasing risk score from <= 1 to >= 15. The model showed good discrimination and calibration for the prediction of 30-day MACE (c-statistic 0.83, goodness-of-fit p = 0.72) and 30-day death (c-statistic 0.87, goodness-of-fit p = 0.56). Bootstrapping with 1000 resample confirmed the stability of the model's performance. Patients were classified into risk classes, with the observed incidence of 30-day MACE of 1.9, 5.9, 13.3 and 39.4% in the low, intermediate, high and very high-risk classes, respectively. An 18-fold graded increase in the primary end point was observed between patients in a low risk class and those in a very high risk class. CONCLUSION: We derived a novel risk model to predict 30-day MACE after pPCI, which might help clinician decide the most appropriate treatment in accordance with the patient's risk profile. PMID- 21663983 TI - Clopidogrel up-titration versus standard dose in patients with high residual platelet reactivity after percutaneous coronary intervention: a single-center pilot randomised study. PMID- 21663984 TI - The delayed activation wave in non-ST-elevation myocardial infarction. AB - BACKGROUND: Little is known about the relationship between the electrocardiographic characteristics and the infarct related artery (IRA) in non ST-elevation myocardial infarction (NSTEMI). We found a curious phenomenon in electrocardiograms of patients with acute occlusion of left circumflex artery in NSTEM: A notch or deflection was often present in the terminal QRS complex in leads II,III and aVF or I,aVL . The objective of this study was to determine whether the previously unreported ECG phenomenon that we have found in NSTEMI could identify the culprit artery in non-ST-elevation myocardial infarction. METHODS AND RESULTS: Our study included 218 NSTEMI patients who presented to our institution and underwent coronary angiography within 24 hours of admission. For convenience, 'N' wave was defined as a notch or deflection in the terminal QRS complex of the surface ECG. The duration of QRS with N wave before PCI was more prolonged than the duration of QRS without N wave (121 +/- 12 ms vs 106 +/- 11 ms, P<0.01). In the LCX group, 66(77%) patients had N wave in leads II, III and aVF, whereas only 5(6%) patients in the LAD group and 9(18%) patients in the RCA group had such ECG feature (P<0.001). A greater proportion of patients in the LCX group also had N waves in leads I and aVL (P<0.001). N wave in leads II, III and aVF was associated with 77% sensitivity and 89% specificity, respectively. N wave in leads I and aVL was associated with 64% sensitivity and 96% specificity, respectively. CONCLUSION: The abnormal waveform in terminal QRS complex in NSTEMI ,which is described above, is the delayed activation wave of left ventricular basal region which the left circumflex artery supplies. It is associated with a higher specificity and higher sensitivity for culprit LCX in non-ST-elevation myocardial infarction. The delayed activation wave is a new pattern of ischemia in ECG. PMID- 21663985 TI - Non-triggered Takotsubo-syndrome in metabolic myopathy. PMID- 21663986 TI - Cardiac remodeling induced by 13-cis retinoic acid treatment in acne patients. AB - BACKGROUND: Currently, 13-cis-retinoic acid (13-cis-RA) is the most effective therapy for acne. Isotretinoin, a first-generation synthetic 13-cis-RA compound, is associated with numerous adverse effects. To investigate the cardiac effects of 13-cis-RA, acne patients receiving 13-cis-RA were studied. METHODS: Twenty male patients with acne were enrolled in the study. Patients were treated with a dose of 0.5 mg/kg/d of isotretinoin. All participants were assessed prior to treatment and after 10 weeks of therapy with Doppler-echocardiogram. RESULTS: Patients showed reductions in right atrium vertical diameter, left atrium longitudinal diameter, left atrium volume and left ventricular diastolic diameter over the course of treatment. Significant increases in interventricular septum diastolic thickness, posterior wall diastolic thickness, relative wall relative thickness and left ventricle (LV) mass were observed. The LV mass index showed an increase in ventricular mass and a decrease in the cavity size. Examining LV systolic function, a decrease was observed for the cardiac index. CONCLUSION: In this study, 10 weeks of 13-cis-RA therapy at a dose of 0.5 mg/kg/d was found to promote concentric-type heart remodeling due to the occurrence of two associated events: heart hypertrophy and hypovolemia. PMID- 21663987 TI - Treating cancer with genetically engineered T cells. AB - Administration of ex vivo cultured, naturally occurring tumor-infiltrating lymphocytes (TILs) has been shown to mediate durable regression of melanoma tumors. However, the generation of TILs is not possible in all patients and there has been limited success in generating TIL in other cancers. Advances in genetic engineering have overcome these limitations by introducing tumor-antigen targeting receptors into human T lymphocytes. Physicians can now genetically engineer lymphocytes to express highly active T-cell receptors (TCRs) or chimeric antigen receptors (CARs) targeting a variety of tumor antigens expressed in cancer patients. In this review, we discuss the development of TCR and CAR gene transfer technology and the expansion of these therapies into different cancers with the recent demonstration of the clinical efficacy of these treatments. PMID- 21663988 TI - Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. AB - BACKGROUND AND PURPOSE: Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN. MATERIALS AND METHODS: Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n=40 plans) and dose-volume histograms were generated. RESULTS: The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p=0.020) and mean doses to the contralateral parotid gland (p=0.049) and larynx (p=0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lowered the maximum doses to the spinal cord (p<0.002 for both) and brainstem (p<0.002 for both) and mean doses to the larynx (p<0.002 for both) and ipsilateral (p=0.004 IMRT, p=0.050 adaptive) and contralateral (p<0.002 IMRT, p=0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT. CONCLUSIONS: Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage. PMID- 21663989 TI - Single vocal cord irradiation: a competitive treatment strategy in early glottic cancer. AB - INTRODUCTION: The treatment of choice for early glottic cancer is still being debated; ultimately it relies on the functional outcome. This paper reports on a novel sparing 4D conformal technique for single vocal cord irradiation (SVCI). MATERIAL AND METHODS: The records of 164 T1a patients with SCC of the vocal cord, irradiated in the Erasmus MC between 2000 and 2008, were analyzed for local control and overall survival. The quality of life was determined by EORTC H&N35 questionnaires. Also the VHI (voice handicap index), and the TSH (thyroid stimulating hormone) blood levels, were established. On-line image guided SVCI, using cone beam CT or stereotactic radiation therapy (SRT) techniques, were developed. RESULTS: A LC rate at five-years of 93% and a VHI of 12.7 (0-63) was determined. It appeared feasible to irradiate one vocal cord within 1-2mm accuracy. This way sparing of the contralateral (CL) vocal cord and CL normal tissues, could be achieved. CONCLUSIONS: Given the accuracy (1-2mm) and small volume disease (CTV limited to one vocal cord), for the use of stereotactic RT techniques SVCI with large fraction sizes is currently being investigated in clinic. It is argued that hypofractionated SVCI can be a competitive alternative to laser surgery. PMID- 21663990 TI - Aflatoxigenic fungi and aflatoxin in cocoa. AB - This paper reports the occurrence of aflatoxigenic fungi and the presence of aflatoxins in 226 cocoa samples collected on Brazilian farms. The samples were taken at various stages of fermentation, drying and storage. A total of 819 potentially aflatoxigenic fungi were isolated using Dichloran 18% Glycerol agar after surface disinfection, and identified by standard techniques. The ability of the fungi to produce aflatoxins was determined using the agar plug technique and TLC. The presence of aflatoxins in cocoa samples was determined by HPLC using post-column derivatization with bromide after immunoaffinity column clean up. The aflatoxigenic fungi isolated were Aspergillus flavus, A. parasiticus and A. nomius. A considerable increase in numbers of these species was observed during drying and storage. In spite of the high prevalence of aflatoxigenic fungi, only low levels of aflatoxin were found in the cocoa samples, suggesting the existence of limiting factors to the accumulation of aflatoxins in the beans. PMID- 21663991 TI - Development of a green fluorescent tagged strain of Aspergillus carbonarius to monitor fungal colonization in grapes. AB - An enhanced green fluorescent protein has been used to tag an OTA-producing strain of Aspergillus carbonarius (W04-40) isolated from naturally infected grape berries. Transformation of the fungus was mediated by Agrobacterium tumefaciens. The most efficient transformation occurred when the co-cultivation was done with 10(4) conidia due to higher frequency of resistance colonies (894 per 10(4) conidia) and lower background obtained. To confirm the presence of the hph gene in hygromycin resistant colonies, 20 putative transformants were screened by PCR analysis. The hph gene was identified in all the transformants. Variation on the expression levels of the eGFP was detected among the transformants and 50% of them appeared bright green fluorescent under the microscope. Microscopic analysis of all the bright fluorescent transformants revealed homogeneity of the fluorescent signal, which was clearly visible in the hyphae as well as in the conidia. eGFP expression in A. carbonarius was shown to be stable in all transformants. Confocal Laser scanning microscopy images of grape berries infected with the eGFP transformant demonstrated fungal penetration into the berry tissues. OTA production was importantly increased in the eGFP transformant in comparison with the wild type strain and pathogenicity on grape berries was slightly decreased after four days of inoculation. However, no differences in virulence were found after seven days of inoculation, thus allowing utilization of this eGFP mutant for in situ analysis of A. carbonarius infection of grape berries. To our knowledge, this is the first report describing the construction of a GFP-tagged strain belonging to Aspergillus section Nigri for monitoring Aspergillus rot on grape berries. PMID- 21663992 TI - The impact of endosymbionts on the evolution of host sex-determination mechanisms. AB - The past years have revealed that inherited bacterial endosymbionts are important sources of evolutionary novelty for their eukaryotic hosts. In this review we discuss a fundamental biological process of eukaryotes influenced by bacterial endosymbionts: the mechanisms of sex determination. Because they are maternally inherited, several endosymbionts of arthropods, known as reproductive parasites, have developed strategies to convert non-transmitting male hosts into transmitting females through feminization of genetic males and parthenogenesis induction. Recent investigations have also highlighted that endosymbionts can impact upon host sex determination more subtly through genetic conflicts, resulting in selection of host nuclear genes resisting endosymbiont effects. Paradoxically, it is because of their selfish nature that reproductive parasites are such powerful agents of evolutionary change in their host sex-determination mechanisms. They might therefore represent excellent models for studying transitions between sex-determining systems and, more generally, the evolution of sex-determination mechanisms in eukaryotes. PMID- 21663993 TI - Automated approaches for analysis of multimodal MRI acquisitions in a study of cognitive aging. AB - In this work we describe an integrated and automated workflow for a comprehensive and robust analysis of multimodal MR images from a cohort of more than hundred subjects. Image examinations are done three years apart and consist of 3D high resolution anatomical images, low resolution tensor-valued DTI recordings and 4D resting state fMRI time series. The integrated analysis of the data requires robust tools for segmentation, registration and fiber tracking, which we combine in an automated manner. Our automated workflow is strongly desired due to the large number of subjects. Especially, we introduce the use of histogram segmentation to processed fMRI data to obtain functionally important seed and target regions for fiber tracking between them. This enables analysis of individually important resting state networks. We also discuss various approaches for the assessment of white matter integrity parameters along tracts, and in particular we introduce the use of functional data analysis (FDA) for this task. PMID- 21663994 TI - Preoperative pulmonary rehabilitation before lung cancer resection: results from two randomized studies. AB - Complete surgical resection is the most effective curative treatment for lung cancer. However, many patients with lung cancer also have severe COPD which increases their risk of postoperative complications and their likelihood of being considered "inoperable." Preoperative pulmonary rehabilitation (PR) has been proposed as an intervention to decrease surgical morbidity but there is no established protocol and no randomized study has been published to date. We tested two preoperative PR interventions in patients undergoing lung cancer resection and with moderate-severe COPD in a randomized single blinded design. Outcomes were length of hospital stay and postoperative complications. The first study tested 4 weeks of guideline-based PR vs. usual care: that study proved to be very difficult to recruit as patients and providers were reluctant to delay surgery. Nine patients were randomized and no differences were found between arms. The second study tested ten preoperative PR sessions using a customized protocol with nonstandard components (exercise prescription based on self efficacy, inspiratory muscle training, and the practice of slow breathing) (n=10) vs. usual care (n=9). The PR arm had shorter length of hospital stay by 3 days (p=0.058), fewer prolonged chest tubes (11% vs. 63%, p=0.03) and fewer days needing a chest tube (8.8 vs. 4.3 days p=0.04) compared to the controlled arm. A ten-session preoperative PR intervention may improve post operative lung reexpansion evidenced by shorter chest tube times and decrease the length of hospital stay, a crude estimator of post operative morbidity and costs. Our results suggest the potential for short term preoperative pulmonary rehabilitation interventions in patients with moderate-severe COPD undergoing curative lung resection. 4 weeks of conventional preoperative PR seems non feasible. PMID- 21663995 TI - Different efficacy of CT screening for lung cancer according to histological type: analysis of Japanese-smoker cases detected using a low-dose CT screen. AB - The efficacy of CT screening for lung cancers is still a controversial issue, although one of the recently publicized large randomized controlled trials of this methodology, the National Lung Screening Trial (NLST), reported a decrease in the lung cancer-specific mortality for heavy smokers. We here performed case matched comparative analyses, as a retrospective study, of three lung cancer arms detected by CT screen, X-ray screen, and by individual analysis of the clinicopathological features and outcomes in smokers from a symptomatic-prompted group of patients. We also considered the impacts of various potential biases in this cohort. The total study cohort comprised 136 patients in the CT screen group, 263 in the X-ray screen group and 254 in the symptomatic-prompted group. The ratio of stage IA cancers in the CT screen group was 67.7% and the ratio of advanced cases (i.e. stages IIIB+IV) was 12.5%. The percentage of bronchioloalveolar carcinoma (BAC) was 28.7% in the CT screen group. The 5-year survival rates were 82.4% in the CT screen group, 38.0% in the X-ray screen group and 17.8% in the symptomatic-prompted group. CT screening was found to be an independent prognostic factor for lung cancer even when BAC cases were eliminated (HR 0.35, P<0.01). Based on our sub-analysis by individual histological sub-type, CT screen lung cancer cases had a better survival rate than non-screened patients, which included adenocarcinoma, squamous cell carcinoma and large/small cell carcinoma. However, by multi-variant analysis a CT scan would not be expected to reduce the risk of lung cancer mortality in patients with large/small cell carcinoma, although would be expected to reduce the risk of lung cancer death by 80% in cases of both adenocarcinoma and squamous cell carcinoma. In conclusion, our current findings indicate that CT screening for lung cancer is an effective strategy for smokers and that patients with adenocarcinoma and squamous cell carcinoma of all variant histological types may benefit from this test. In this regard, early stage large/small cell carcinomas are insufficiently detected by the existing annual screening system. PMID- 21663996 TI - Mesothelioma at era of helical tomotherapy: results of two institutions in combining chemotherapy, surgery and radiotherapy. AB - PURPOSE: There is a scarce clinical experience about adjuvant helical tomotherapy (HT) in patients affected by malignant pleural mesothelioma (MPM) even though it appears as a useful technique to treat complex volume as the pleural cavity, and seems to have better dose distribution than the "classic" intensity modulated radiotherapy (IMRT). METHODS AND MATERIALS: Twenty-four patients received adjuvant radiotherapy (RT) by HT from August 1st, 2007 to December 1st, 2009 at Curie Institute (Paris) and Rene Gauducheau Cancer Center (Nantes). Thirteen patients had neoadjuvant chemotherapy. Extrapleural pleuropneumonectomy (EPP) was done in 23 patients. Median dose to PTV was 50Gy [48.7-55.9Gy] (2Gy/fraction). Acute and long term toxicities, disease free survival (DFS), overall survival (OS) and relapses are presented. RESULTS: Average follow up after RT was 7 months. The disease was staged mostly as T2-T3, N1-N2. Nineteen patients had epithelial type histology. Most patients tolerated radiotherapy with grade 1-2 side effects: redness of the skin, light cough or dyspnea, fatigue, nausea and odynophagia, mild increase of the post-operative thoracic pain. Grade 3 pneumonitis was suspected in 2 patients. Two grade 5 pneumonitis were also suspected. Eleven patients had a follow up of more than 6 months and no long term side effects related with HT were noted. At 24 months, 51.8% of patients were free of disease. Thirty percent of patients relapsed, with 2 patients presenting local relapses. Two patients died from recurrence. CONCLUSION: With limited follow up, HT has comparable toxicity to those observed with traditional IMRT. Higher radiation dose and good coverage results in excellent local control. PMID- 21663997 TI - Efficacy of CT screening for lung cancer in never-smokers: analysis of Japanese cases detected using a low-dose CT screen. AB - CT-screening for lung cancer is fairly widely used for both smokers and never smokers in East Asia because the mortality rate for never-smokers due to this cancer is relatively high in this region. We performed comparative analyses, as a retrospective study, on three lung cancer arms detected by CT-screen, X-ray screen, and via analysis of clinicopathological features and outcomes in never smokers from a symptomatic-prompted group of patients. The total study cohort comprised 218 patients in CT group, 160 in X-ray group, and 82 in symptomatic prompted group. The percentage of bronchioloalveolar carcinoma (BAC) was 65.1% in CT-screen group. The ratio of stage IA tumors in CT-screen group was 88.5% and the ratio of advanced cases (i.e. stages IIIB+IV) was 2.3%. The 5-year-survival rates were 95.0% in CT-screen, 73.0% in X-ray-screen and 40.0% in symptomatic prompted group. We performed further sub-analysis which excluded pure BACs (i.e. Noguchi types A and B) or pure GGOs within a 10mm diameter because this is indicative of a very favorable prognosis. Based on this sub-analysis the number of the subjects in each group became 76 in CT group; 140 in X-ray group and 77 in symptomatic-prompted group. The principal characteristics of the patients such as age and sex became almost even in the three arms. In CT-screen subgroup, the ratio of stage IA cancer was 69.7% and of advanced cases was 6.6%. This advanced ratio was lower than both X-ray-screen (22.1%) and symptomatic-prompted (61.9%) groups. The 5-year-survival rates were 89.9% among CT-screen group patients, 72.6% for X-ray screen cases and 39.1% in symptomatic-prompted group. A CT-screen was found to be one of the independent prognostic factors for lung cancer (HR, 0.28; 95% CI, 0.12-0.72) and based on this would be expected to reduce the risk of lung cancer death by 78% compared with non-screened cases. In conclusion, CT will improve the survival rate and decrease the rate of advanced cancers in never smokers via the existing annual screening system. CT-screening is also an independent prognostic improvement factor in never-smokers, and will therefore reduce the risk of lung cancer death. PMID- 21663998 TI - The combined effect of salt stress and heat shock on proteome profiling in Suaeda salsa. AB - Under natural conditions or in the field, plants are often subjected to a combination of different stresses such as salt stress and heat shock. Although salt stress and heat shock have been extensively studied, little is known about how their combination affects plants. We used proteomics, coupled with physiological measurements, to investigate the effect of salt stress, heat shock, and their combination on Suaeda salsa plants. A combination of salt stress and heat shock resulted in suppression of CO(2) assimilation and the photosystem II efficiency. Approximately 440 protein spots changed their expression levels upon salt stress, heat shock and their combination, and 57 proteins were identified by MS. These proteins were classified into several categories including disease/defense, photosynthesis, energy production, material transport, and signal transduction. Some proteins induced during salt stress, e.g. choline monooxygenase, chloroplastic ATP synthase subunit beta, and V-type proton ATPase catalytic subunit A, and some proteins induced during heat shock, e.g. heat shock 70kDa protein, probable ion channel DMI1, and two component sensor histidine kinase, were either unchanged or suppressed during a combination of salt stress and heat shock. In contrast, the expression of some proteins, including nucleoside diphosphate kinase 1, chlorophyll a/b binding protein, and ABC transporter I family member 1, was specifically induced during a combination of salt stress and heat shock. The potential roles of the stress-responsive proteins are discussed. PMID- 21663999 TI - [Clinical and paraclinical course of melanocytoma of the optic disk. Contribution of spectral- and time-domain OCT in the study of 10 patients]. AB - INTRODUCTION: Melanocytoma of the optic disk is a rare, benign, slow-growing tumor. We analyzed the clinical and paraclinical features of melanocytomas followed at the Fort-de-France University Hospital to expose and compare characteristics from new clinical imaging. PATIENTS AND METHOD: This was a prospective study of 10 patients with a melanocytoma of the optic disk. The principal features studied were the ophthalmoscopic findings, the visual field defects, fluorescein angiography features, and the comparison between standard time-domain optical coherence tomography (OCT) characteristics and the latest spectral-domain OCT findings. RESULTS: The mean age of the patients at diagnosis was 49.2 years. All the patients were from the French West Indies. The lesion was discovered incidentally in 90% of the cases. Visual acuity was normal in 70% of the cases. Visual field defects were present at the first visit in 80% of the cases. Tumor growth was monitored in 50% of the cases during a mean follow up of 4.8 years. The in-depth extension into chorioretina and laterally into the retina were better visualized in spectral-domain OCT than in time-domain OCT as hyperreflective granular dots. CONCLUSION: Optic disk melanocytoma appears to be a singular benign tumor that is seen more frequently in dark-skinned patients. Most melanocytomas do not cause significant visual impairment but can show substantial growth in size for many years of follow-up. A malignant transformation is always to fear in case of atypical development. Spectral domain OCT seems to be an important tool in the assessment of extension and follow-up. PMID- 21664001 TI - Practically speaking: rethinking hand hygiene improvement programs in health care settings. AB - BACKGROUND: Hand hygiene is widely recognized as the single most effective means of reducing health care-associated infections. Implementing a credible hand hygiene program and maintaining high compliance among staff is both expected and required of hospitals. However, beyond general guidelines, few resources are available for establishing an institution-wide hand hygiene program that is both successful and sustainable over the long term. METHODS: Beginning in 2008, we completely overhauled the approach to hand hygiene at our institution. We created small teams consisting of a representative from Quality Assessment, an Infection Prevention Practitioner, and staff from a particular unit. Teams began by discussing the current barriers to hand hygiene success. They then set their own goals for hand hygiene compliance. Staff learned the World Health Organization (WHO) hand hygiene guidelines, which recently had been adopted as part of hospital infection prevention policy. Using the WHO guidelines, teams diagrammed detailed workflows for several of their most common patient care tasks. Wherever hand hygiene was indicated, the workflow was marked with a number corresponding to one or more of the WHO's "5 moments for hand hygiene." At the end of the 12 week period, staff members were trained to observe each other and began officially collecting and submitting data to Infection Prevention. RESULTS: Between 2006 and 2008, our average institutional hand hygiene compliance held steady at 60%-70%. After the new program was launched in 2008, compliance reached 97% and has been maintained at this level ever since. In addition to the 19 areas of the hospital that were observed previously, 15 ambulatory facilities and 5 regional sites are now included in the data. CONCLUSION: This article describes a novel approach to measuring, monitoring, and ultimately increasing hand hygiene compliance at our hospital. Our objective is to provide concrete, practical strategies for other institutions faced with the challenge of building or revamping their own hand hygiene programs. PMID- 21664000 TI - Do contact precautions cause depression? A two-year study at a tertiary care medical centre. AB - Contact precautions, used to reduce the transmission of infectious diseases, include the wearing of gowns and gloves for room entry. Previous small studies have shown an association between contact precautions and increased symptoms of depression and anxiety. A retrospective cohort of all patients admitted to a tertiary care centre over two years was studied to assess the relationship between contact precautions and depression or anxiety. During the two-year period, there were 70,275 admissions including 28,564 unique non-intensive-care unit (ICU), non-psychiatric admissions. After adjusting for potential confounders, contact precautions were associated with depression [odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2-1.5] but not with anxiety (OR 0.8, 95% CI 0.7-1.1) in the non-ICU population. Depression was 40% more prevalent among general inpatients on contact precautions. PMID- 21664002 TI - Outbreak of Burkholderia cepacia complex among ventilated pediatric patients linked to hospital sinks. AB - We investigated a cluster of Burkholderia cepacia complex colonization in ventilated pediatric patients. Isolates from 15 patients, 2 sink drains, and several ventilator components were found to belong to a single B cenocepacia clone. Hospital tap water used during oral and tracheostomy care was identified as the most likely mechanism for transmission. PMID- 21664003 TI - A controlled crossover human volunteer study of the in vivo filtration efficacy of a high-efficiency particulate air-filtering oxygen mask. AB - Nosocomial airborne disease transmission can be important in some epidemics. An oxygen mask incorporating a high-efficiency particulate (HEPA) filter may reduce the chance of inhaling airborne particles. In a randomized controlled crossover volunteer study, the median ratio of ambient:intramask 0.02 to 1-MU particles was significantly higher for the HEPA oxygen mask than for a Hudson-type mask (P < .001), and was >=100 in 59%-64% of subjects. The use of HEPA masks may protect patients receiving supplementary oxygen against airborne pathogens. PMID- 21664004 TI - A comparative study to evaluate surface microbial contamination associated with copper-containing and stainless steel pens used by nurses in the critical care unit. AB - A clinical study was undertaken to compare the surface microbial contamination associated with pens constructed of either a copper alloy or stainless steel used by nurses on intensive care units. A significantly lower level of microbial contamination was found on the copper alloy pens. PMID- 21664005 TI - Clinical characteristics and outcomes of hospitalized patients with 2009 H1N1 influenza in a large acute care tertiary hospital, Singapore. AB - This study describes the clinical characteristics and outcomes of hospitalized patients with 2009 H1N1 influenza in a large, acute care, tertiary hospital in Singapore. Of the 265 hospitalized patients with laboratory-confirmed 2009 influenza A (H1N1) during the height of the H1N1 flu pandemic, 13% (35) suffered severe outcomes including a mortality rate of 4.5% (12). Severe outcomes were associated with patients aged 40 years or more, underlying comorbidities, and complicated by pneumonia. PMID- 21664006 TI - Attempts to change culture in a line-obsessed pediatric world: the Riley Heart Center line initiative. AB - Interventions to reduce central line-associated bloodstream infections in pediatric patients have not yet been validated. Unique approaches to reducing infection rates may be warranted in this population. PMID- 21664007 TI - Learning capabilities and CA1-prefrontal synaptic plasticity in a mice model of accelerated senescence. AB - SAMP8 mice represent a suitable model of accelerated senescence as compared with SAMR1 animals presenting normal aging. Five-month-old SAMP8 mice presented reflex eyelid responses like those of SAMR1 controls, but were incapable of acquiring classically-conditioned eye blink responses in a trace (230 milliseconds [ms] of interstimulus interval) paradigm. Although SAMP8 mice presented a normal paired pulse facilitation of the hippocampal CA1-medial prefrontal synapse, an input/output curve study revealed smaller field excitatory postsynaptic potentials (fEPSPs) in response to strong stimulations of the CA1-prefrontal pathway. Moreover, SAMP8 mice did not show any activity-dependent potentiation of the CA1-prefrontal synapse across the successive conditioning sessions shown by SAMR1 animals. In addition, SAMP8 mice presented a functional deficit during an object recognition test, continuing to explore the familiar object when controls moved to the novel one. Alert behaving SAMP8 mice presented a significant deficit in long-term potentiation (LTP) at the CA1-medial prefrontal synapse. According to the present results, SAMP8 mice present noticeable functional deficits in hippocampal and prefrontal cortical circuits directly related with the acquisition and storage of new motor and cognitive abilities. PMID- 21664008 TI - [Bone scan findings in a North African ethnic group and relation to PSA level and Gleason score of the biopsy]. AB - OBJECTIVE: A number of large-scaled studies carried out in western countries have proven a positive relationship between serum prostate specific antigen (PSA) level and prevalence of positive bone scan findings, in newly diagnosed prostate cancer patients. The aim of our study is to verify that the tendency occurs as well in north-african population, as well as to establish a possible correlation between PSA level, bone scan result, and Gleason score. MATERIAL AND METHODS: Records of 348 patients diagnosed to have prostatic adenocarcinoma were reviewed retrospectively for bone scan results, PSA levels, and Gleason score. Statistical analyses were performed using the Fisher exact test, by a statistical software (statistical package for the social sciences "SPSS", version 11.5.1, Chicago, IL) with differences at P<0,05 considered significant. RESULTS: Based on positive bone scintigraphy 102 patients were proven to have bone metastases. None of these patients had a PSA level of less than 10 ng/ml. Six metastatic patients had PSA level between 11 and 20 ng/ml. 45 metastatic cases had serum PSA between 21 and 100. Concerning PSA level over 101 ng/ml, 51 men had positive bone scan. CONCLUSION: Based on the PSA level, the likelihood of positive bone scan result can be postulated. According to PSA levels, staging investigations can be more selective for our patients. The risk of positive bone scan is so low that it is not required for patients with PSA level less than 10 ng/ml. On the other hand, on studying the correlation between Gleason score and PSA level or bone scan results, no statistically significant relationship was established. PMID- 21664009 TI - [Health information is hampered by an antiquated computer system]. PMID- 21664010 TI - Synthesis and antiviral evaluation of alpha-L-2'-deoxythreofuranosyl nucleosides. AB - The synthesis of a series of alpha-L-2'-deoxythreofuranosyl nucleosides featuring the nucleobases A, T, C and U is described in seven steps from 1,2-O isopropyledene-alpha-L-threose, involving a Vorbruggen coupling and a Barton McCombie deoxygenation protocol as the key steps. All analogues, including a phosphoramidate nucleoside phosphate prodrug of the T analogue, were evaluated against a broad panel of different viruses but found inactive, while also lacking notable cellular toxicity. The thymidine analogue showed inhibition to mitochondrial thymidine kinase-2 (TK-2), herpes simplex virus type 1 (HSV-1) TK, varicella-zoster virus (VZV) TK and Mycobacterium tuberculosis thymidylate kinase. PMID- 21664011 TI - A novel and efficient one-pot synthesis of symmetrical diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates and evaluation of their biological activities. AB - A novel and efficient method for the one-pot synthesis of diamide (bis-amidate) prodrugs of acyclic nucleoside phosphonates, starting from free phosphonic acids or phosphonate diesters is reported. The approach from phosphonate diesters via their bis(trimethylsilyl) esters is highly convenient, eliminates isolation and tedious purification of the phosphonic acids, and affords the corresponding bis amidates in excellent yields (83-98%) and purity. The methodology has been applied to the synthesis of the potent anticancer agent GS-9219, and symmetrical bis-amidates of other biologically active phosphonic acids. Anti-HIV, antiproliferative, and immunomodulatory activities of the compounds are discussed including the bis-amidate prodrugs 14 and 17 that exhibited anti-HIV activity at submicromolar concentrations with minimal cytotoxicity. PMID- 21664012 TI - Synthesis, trypanocidal activity and molecular modeling studies of 2 alkylaminomethylquinoline derivatives. AB - Research and development of new drugs effective in the treatment of Trypanosoma cruzi infections are a real need for the 16 million people infected in the Americas. In a previous work, a quinoline derivative substituted by a 2 piperidylmethyl moiety showed to be active against Chagas disease and was considered a lead compound for further optimization. A series of ten analogous derivatives were tested against epimastigotes as a first approach. In view of their promising results, six of them were evaluated against the blood and intracellular replicative forms of the parasite in humans. Among them, compound 12 which possesses a 6-acetamidohexylamino substituent showed remarkable improvement in activity against epimastigotes, trypomastigotes and amastigotes compared with the structure lead, as well as a good selectivity index for the two parasite stages present in humans. In addition, treatment of infected mice with compound 12 induced a significant reduction in parasitemia compared with non treated mice. Molecular modeling studies were performed by computational methods in order to elucidate the factors determining these experimental bioactivities. PMID- 21664013 TI - Single step synthesis of new fused pyrimidine derivatives and their evaluation as potent Aurora-A kinase inhibitors. AB - A simple, facile, efficient and one pot three-component procedure for the synthesis of pyrazolo[1,5-a]pyrimidines, triazolo[1,5-a]pyrimidines and pyrimido[1,2-a]benzimidazoles ring systems incorporating phenylsulfonyl moiety was developed via the reaction of 1-aryl-2-(phenylsulfonyl)ethanone derivatives 1a-d with the appropriate heterocyclic amine and triethyl orthoformate and evaluated as Aurora-A kinase inhibitors. The cytotoxic activity of the newly synthesized compounds against HST116 colon tumor cell line was investigated. 2,7 Diphenyl-6-(phenylsulfonyl)pyrazolo[1,5-a]pyrimidine (4b) and its p-methoxy analogue 4c were found to be equipotent to Doxorubicin as a reference drug. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results. PMID- 21664014 TI - Evaluation of practical exercises using an intravenous simulator incorporating virtual reality and haptics device technologies. AB - This study confirmed the educational effectiveness of practical exercises (PE) using intravenous (IV) simulators incorporating virtual reality (VR)/haptics (based on the sense of touch) device technologies. First-year nursing students (n=114) were randomly divided into three PE groups: Group A, utilizing a conventional arm model (IV arm); Group B, utilizing a VR/Haptics IV Simulator (IV sim); and Group C, utilizing both the IV arm and IV sim. Group C scored highest on procedures for conducting venipuncture. Group B was more successful in performing injections than Groups A and C. Group C required significantly less time than Group B to complete a venipuncture injection and was faster than Group A, although this difference was not significant. In conclusion, a new paradigm of PE is suggested using both IV sim and IV arm. PMID- 21664015 TI - Assisting undergraduate nursing students to learn evidence-based practice through self-directed learning and workshop strategies during clinical practicum. AB - To equip undergraduate nursing students with basic knowledge and skills and foster positive attitudes toward evidence-based practice (EBP), a pilot learning program during their clinical practicum was developed in a teaching hospital in China. This article describes the specific learning process through which self directed learning and workshop strategies were used, and a pre- and post intervention survey were conducted to evaluate the effectiveness of the learning strategies. The findings show a significant improvement in their perceptions of EBP knowledge, attitudes and beliefs, and behavior levels. Beginning competencies in EBP were achieved. Participants reported great satisfaction and have found this program helpful in promoting their analytical and problem-solving abilities, independent learning ability, and cooperative and communication abilities as well. PMID- 21664016 TI - Effects of a nationwide predialysis educational program on modality choice, vascular access, and patient outcomes. AB - BACKGROUND: Patients' education about transplant, hemodialysis (HD), peritoneal dialysis (PD), and conservative care often is provided by nephrologists as needed and occurs as time allows. STUDY DESIGN: Quality improvement report. SETTING & PARTICIPANTS: Attendees of a national treatment options program (TOPs) who initiated long-term dialysis therapy (median, 3.4 months) at Fresenius Medical Care, North America facilities throughout 2008 were compared with period prevalent incident patients receiving usual care. QUALITY IMPROVEMENT PLAN: Standardized predialysis treatment options education. OUTCOMES: Rates of opting for PD modality, arteriovenous HD access at initiation, and early (90-day) mortality risk. MEASUREMENTS: Logistic regression (for choice of PD and HD access type) and Cox models (for early mortality) were constructed, including a 1:1 matched cohort. A post hoc sensitivity analysis also compared a propensity score matched cohort. RESULTS: 3,165 TOPs attendees (10.5% of 30,217 incident patients admitted between January 1 and December 31, 2008), were younger, more likely to be white, and had slightly larger body surface area. The unadjusted OR for TOPs attendees for selecting PD therapy was 8.45 (95% CI, 7.63-9.37) with a case-mix plus laboratory-adjusted OR of 5.13 (95% CI, 3.58-7.35). For patients who opted for in-center HD therapy, the OR was 2.14 (95% CI, 1.96-2.33) and adjusted OR was 2.06 (95% CI, 1.88-2.26) for starting with a fistula or graft. The unadjusted early mortality HR was 0.51 (95% CI, 0.43-0.60) and case-mix plus laboratory adjusted adjusted HR was 0.61 (95% CI, 0.50-0.74) for TOPs attendees (all outcomes, P < 0.001). These results were consistent in the 1:1 matched analysis and propensity score-matched analysis. LIMITATIONS: It is possible that physicians who referred to these programs were more likely to prescribe PD therapy or place arteriovenous accesses. Motivated, treatment-adherent patients (who would have better outcomes) may have self-selected to attend education sessions. CONCLUSION: Attending an options class predialysis was associated with more frequent selection of home dialysis, fewer tunneled HD catheters, and lower mortality risk during the first 90 days of dialysis therapy. PMID- 21664018 TI - Eliciting ethical and social values in health technology assessment: A participatory approach. AB - Despite a growing consensus that ethical and social values should be addressed in health technology assessment (HTA) processes, there exist a variety of methods for doing so. There is growing interest in involving citizens in policy development to ensure that decisions are legitimate, and reflect the broad social values of the public. We sought to bring these issues together by employing a participatory approach to elicit ethical and social values in HTA. Our primary objective was to elicit a set of ethical and social values from citizens that could be used to guide Ontario's HTA evidentiary review and appraisal process. A secondary objective was to explore the feasibility of using participatory approaches to elicit these values. A 14-person Citizens' Reference Panel on Health Technologies was established to provide input to the Ontario Health Technology Advisory Committee in developing its recommendations. A mixed methods approach was used where informed, deliberative discussions were combined with pre and post-questionnaires, which assessed the relative importance of various ethical and social values as well as their stability over time. Over the course of five meetings, panel members progressed toward the identification of a set of core values -universal access, choice and quality care. These values were consistently prioritized as the core values that should be considered in the evaluation of health technologies and ensuing recommendations. Sustained and deliberative methods, like a citizens' panel, offer a promising approach for eliciting ethical and social values into HTA. PMID- 21663949 TI - The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. AB - BACKGROUND: Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. METHODS: This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. FINDINGS: 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/L (SE 0.02; with about two-thirds compliance) during a median follow-up of 4.9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs 619 [13.4%] placebo; rate ratio [RR] 0.83, 95% CI 0.74-0.94; log-rank p=0.0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs 230 [5.0%]; RR 0.92, 95% CI 0.76-1.11; p=0.37) and there were significant reductions in non-haemorrhagic stroke (131 [2.8%] vs 174 [3.8%]; RR 0.75, 95% CI 0.60-0.94; p=0.01) and arterial revascularisation procedures (284 [6.1%] vs 352 [7.6%]; RR 0.79, 95% CI 0.68-0.93; p=0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10,000 patients per year of treatment with this combination (9 [0.2%] vs 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs 18 [0.4%]), gallstones (106 [2.3%] vs 106 [2.3%]), or cancer (438 [9.4%] vs 439 [9.5%], p=0.89) and there was no significant excess of death from any non-vascular cause (668 [14.4%] vs 612 [13.2%], p=0.13). INTERPRETATION: Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. FUNDING: Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council. PMID- 21664017 TI - Smoking in dialysis patients: a systematic review and meta-analysis of mortality and cardiovascular morbidity. AB - BACKGROUND: Cigarette smoking is associated with increased cardiovascular morbidity and mortality in the general population, but the effect of smoking on these outcomes in the dialysis population is less well studied. STUDY DESIGN: Systematic review and meta-analysis of cohort studies. SETTING & POPULATION: Adults treated with long-term hemodialysis or peritoneal dialysis. SELECTION CRITERIA FOR INCLUDED STUDIES: Cohort studies of unselected dialysis patients reporting the association between smoking status and cardiovascular morbidity and/or mortality. PREDICTOR: Smoking status (determined using patient report). OUTCOMES: (1) All-cause or cardiovascular mortality; (2) incident cardiovascular events. RESULTS: We identified 34 studies that fulfilled all inclusion criteria. Of these, 26 studies provided data for smoking and mortality and 10 (n = 6,538) were included in a meta-analysis. The pooled HR for all-cause mortality in smokers compared with nonsmokers was 1.65 (95% CI, 1.26-2.14; P < 0.001). 11 studies provided data for smoking and incident cardiovascular events; 5 (pooled n = 845) were included in a meta-analysis. The pooled HR for composite cardiovascular events in smokers compared with nonsmokers was 1.01 (95% CI, 0.98 1.05; P = 0.4). LIMITATIONS: Data for these meta-analyses were heterogeneous. Few individual studies assessed smoking as the primary variable of interest. CONCLUSIONS: Active smoking is associated with a significant increase in all cause mortality in dialysis patients, although there was no corresponding increased risk of cardiovascular events. PMID- 21664019 TI - Electronic prescriptions and disruptions to the jurisdiction of community pharmacists. AB - The practice of community pharmacists is being challenged by the appearance of electronic prescription (e-Rx) technology. This article examines the disruptions caused by e-Rx technology to the jurisdiction of community pharmacists based on a model developed from work by Abbott (1988). The main disruptions to professional activities were investigated by qualitative methods in a series of interviews with pharmacists and physicians separated in two groups: practitioners who tested a typical e-Rx technology and stakeholders involved in the implementation of this large-scale e-Rx project in Quebec, Canada. The findings suggest that the technology may disrupt the jurisdiction of community pharmacists, mainly by changing the distribution of information among physicians and community pharmacists. More specifically, the technology represents both a threat to community pharmacists - by supporting the dominant position held by physicians if it gives them access to information held exclusively by pharmacists - and an opportunity - by redistributing information to the pharmacists' benefit, allowing them to improve the quality of their inferences about medication. However, it would appear that the opportunities offered by the technology generate concerns and tensions, both between physicians and pharmacists and between the pharmacists themselves. This phenomenon may well work against the implementation and use of available tools. PMID- 21664020 TI - Comparing social determinants of self-rated health across the United States and Canada. AB - A large body of research shows that social determinants of health have significant impact on the health of Canadians and Americans. Yet, very few studies have directly compared the extent to which social factors are associated with health in the two countries, in large part due to the historical lack of comparable cross-national data. This study examines differences in the effect of a wide-range of social determinants on self-rated health across the two populations using data explicitly designed to facilitate comparative health research-Joint Canada/United States Survey of Health. The results show that: 1) sociodemographic and socioeconomic factors have substantial effects on health in each country, though the size of the effects tends to differ-gender, nativity, and race are stronger predictors of health among Americans while the effects of age and marital status on health are much larger in Canada; the income gradient in health is steeper in Canada whereas the education gradient is steeper in the U.S.; 2) Socioeconomic status (SES) mediates or links sociodemographic variables with health in both countries-the observed associations between gender, race, age, and marital status and health are considerably weakened after adjusting for SES; 3) psychosocial, behavioural risk and health care access factors are very strong determinants of health in each country, however being severely/morbidly obese, a smoker, or having low life satisfaction has a stronger negative effect on the health of Americans, while being physically inactive or having unmet health care needs has a stronger effect among Canadians; and 4) risk and health care access factors together play a relatively minor role in linking social structural factors to health. Overall, the findings demonstrate the importance of social determinants of health in both countries, and that some determinants matter more in one country relative to the other. PMID- 21664021 TI - Regulating diagnosis in post-genomic medicine: re-aligning clinical judgment? AB - In recent years, genomic technologies have entered oncology. In particular, so called tumor signatures are now commercially available for diagnosing breast cancer. These new diagnostic tools have expanded the content and meaning of diagnosis, by adding a distinctive prognostic (will the disease recur?) and predictive (how will the disease react to treatment?) dimension to this activity, and modifying the relations between diagnosis and therapy. In particular, they raise the issue of the locus of clinical judgment and clinical decision-making insofar as they involve a re-alignment of the biological and clinical components of medical activities. Using as a case study a debate over the regulation of tests for genomic signatures by the US FDA, this paper examines how the actors problematize the issues related to the introduction of molecular diagnostics into clinical settings. PMID- 21664022 TI - [Cardiac amyloidosis presenting as recurrent syncope]. PMID- 21664024 TI - Ventricular perforation and active fixation leads: new entity? PMID- 21664023 TI - Transapical access closure of a mechanical mitral prosthesis leak. PMID- 21664025 TI - Evacuation from the restricted zone of the damaged Fukushima nuclear power plant: Facing with the reality. PMID- 21664026 TI - Rescuing A Patient In Deteriorating Situations (RAPIDS): A simulation-based educational program on recognizing, responding and reporting of physiological signs of deterioration. AB - AIM: To describe the development, implementation and evaluation of an undergraduate nursing simulation program for developing nursing students' competency in assessing, managing and reporting of patients with physiological deterioration. METHOD: A full-scale simulation program was developed and implemented in a pre-registered nursing curriculum. A randomized controlled study was performed with 31 third year nursing students. After a baseline evaluation of all participants in a simulated environment, the intervention group underwent four simulation scenarios in a 6h education session. All participants were then re-tested. The baseline and post-test simulation performances were scored using a validated tool. The students completed a survey to evaluate their learning experiences. RESULTS: The clinical performances mean scores for assessment and management of deteriorating patients improved significantly after the training program compared to baseline scores (t=9.26; p<0.0001) and to post-test mean scores of the control group (F=77.28; p<0.0001). The post-test mean scores of the intervention group in reporting deterioration was significantly higher than the baseline mean scores (t=4.24; p<0.01) and the post-test means scores of the control group (F=8.98; p<0.01). The participants were satisfied with their simulation experiences, rated positively on features of the simulation and valued the program in developing their self-confidence. CONCLUSION: The nursing students' competency in assessing, managing and reporting of deteriorating patient can be enhanced through a systematic development and implementation of a simulation-based educational program that utilized mnemonics to help students to remember key tasks. PMID- 21664027 TI - Predisposition of subtle endometriotic lesions predominantly on the left side assessed by transvaginal hydrolaparoscopy (THL). AB - OBJECTIVE: Endometriosis is one of the most frequent gynaecological disorders being associated with infertility. Hence, the early detection of endometriosis in infertility patients is of importance for the treatment modalities in infertility. Transvaginal hydrolaparoscopy (THL) offers an accurate, safe and quick diagnostic tool, not only for the evaluation of the fallopian tubes but also for the detection of very subtle endometriotic lesions in the early stages of endometriosis. STUDY DESIGN: Between January 2008 and January 2010, we conducted a study in order to evaluate the prevalence, extent and localisation of endometriosis via the new technique of THL in infertility patients. 239 patients with a mean age of 33.9 years underwent THL after having given informed consent. RESULTS: In 237 patients, access to the cul-de-sac was successfully achieved. Endometriosis was detected in 77 of 237 cases (32.5%). In 85.7% of cases, the endometriotic lesions were classified as very small (ASRM stage I degrees ). Predominantly, the small lesions were found merely on the left side of the patient's peritoneal cavity: in 43 cases (55.8%), endometriosis was detected strictly on the left side, whereas the disease was detected on the right side in only 5 patients (6.5%). In 29 patients, endometriosis could be detected in both sides of the pelvis (37.7%). The differences in the side-dependent distribution were statistically highly significant (p<0.0001). In most of the cases, the subtle endometriotic lesions affected the ovarian surface superficially (53.5%) or the peritoneum of the lateral pelvic wall (25.6%). CONCLUSIONS: These data clearly indicate that there is a high prevalence of endometriosis in patients with infertility. THL is an accurate, safe and quick method for a thorough examination of the female pelvis besides the patency of the fallopian tubes. The high prevalence of left-sided subtle endometriotic lesions must be interpreted that during THL a very early process in the development of endometriosis can be observed. Even minimal to mild endometriosis might lead to a significant restriction in uterotubal transport capacity whose integrity is directly correlated to normal pregnancy rates. The extent of the accompanying adenomyosis is directly correlated to the loss of intact uterotubal transport capacity. PMID- 21664028 TI - The prevalence and factors associated with previous surgery for pelvic organ prolapse and/or urinary incontinence in a cross-sectional study in The Netherlands. AB - OBJECTIVE: To estimate the prevalence and identify the factors associated with previous pelvic organ prolapse (POP) and/or incontinence surgery. STUDY DESIGN: In a cross-sectional study, all women who were aged 45-85 years and registered in eight general practices were invited to participate. They completed standardised questionnaires (the urinary distress inventory (UDI) and the defaecatory distress inventory (DDI)) and answered questions on previous pelvic floor surgery. RESULTS: Out of 2979 women eligible for this study, 1380 women were included. Previous surgery had been performed in 119 women. The prevalence of surgery increased with age, with a prevalence of 20.3% in the age group 76-85 years. Pelvic floor symptoms were more prevalent in women who had undergone previous surgery, with higher UDI and DDI scores. Factors associated with previous surgery were age, higher BMI, POP symptoms during pregnancy and previous hernia surgery. CONCLUSION: In The Netherlands, approximately one in five women will undergo surgery for POP and/or incontinence during her lifetime. The women who underwent surgery were more likely to have symptoms of pelvic floor dysfunction than those who did not undergo surgery. PMID- 21664029 TI - The effect of adenomyosis on in vitro fertilisation and intra-cytoplasmic sperm injection treatment outcome. AB - OBJECTIVE: To investigate the effect of uterine adenomyosis diagnosed by transvaginal ultrasound on IVF/ICSI treatment outcome. STUDY DESIGN: A retrospective cohort study of all women aged <= 42 years with infertility who underwent IVF/ICSI treatment at IVF Australia-East between January 2000 and June 2006. Patients were divided into two groups according to findings on a baseline pre-treatment transvaginal pelvic ultrasound: group A consisted of women with adenomyosis and group NA consisted of women without adenomyosis. The primary outcome measure was live birth rate per patient (cycle). RESULTS: A total of 201 patients (37 patients in Group A, 164 patients in group NA) undergoing a single stimulated cycle of IVF/ICSI were included in the data analysis. There was no difference in live birth rate per patient (cycle) between the two groups with both raw and logistic regression adjusted data (29.7%V 26.1%; p=0.395; OR 1.45 with 95% CI 0.61-3.43). There were no other differences in ovarian response, embryological parameters or clinical outcomes between the two groups. CONCLUSIONS: The presence of transvaginal ultrasound diagnosed adenomyosis did not adversely affect outcome in women undergoing IVF/ICSI treatment at our unit. However, the results are not conclusive and further large, well-designed prospective cohort studies are required in order to confirm our findings. PMID- 21664030 TI - Exploring the psychosexual drive, before genital cosmetic surgery. PMID- 21664031 TI - Does metformin influence the insulin-, IGF I- and IGF II-receptor gene expression and Akt phosphorylation in human decidualized endometrial stromal cells? AB - OBJECTIVE: To assess the effects of metformin on insulin-, IGF I-, and IGF II receptor gene expression and Akt phosphorylation in decidualized human endometrial stromal cells (ESC) after stimulation with insulin, IGF I and II. STUDY DESIGN: ESC were isolated from healthy, regularly cycling women and after two passages decidualized with estrogen/progesterone+/-metformin. Cells were incubated with insulin, IGF I or IGF II for 1, 5, and 10 min to assess Akt phosphorylation by Western blot. To investigate the insulin-, IGF I- and IGF II receptor gene expression ESC were incubated with insulin, IGF I or IGF II for 6 and 24h. RESULTS: Insulin- and IGF I-receptor gene expression in ESC changed significantly after incubation with insulin, IGF I or IGF II. This was further augmented in metformin pretreated cells, while IGF II-receptor gene expression changed particularly after pretreatment with metformin. Akt phosphorylation peaked after 5 min insulin, IGF I and IGF II stimulation in ESC in both control (control 0.08 +/- 0.03 vs. insulin 0.74 +/- 0.19, IGF I 0.68 +/- 0.22, IGF II 0.53 +/- 0.13, p<0.05) and metformin pretreated cells (control 0.03 +/- 0.01 vs. insulin 0.75 +/- 0.11, IGF I 0.74 +/- 0.15, IGF II 0.67 +/- 0.09, p<0.005). However, there was no significant difference between the control and metformin pretreated group. CONCLUSION: Insulin, IGF I and IGF II lead to changes in their receptor gene expression and induced Akt phosphorylation in ESC. These effects were further highlighted in the presence of metformin. PMID- 21664032 TI - Microparticles (MPs), tissue factor (TF) and tissue factor inhibitor (TFPI) in cord blood plasma. A preliminary study and literature survey of procoagulant properties of MPs. AB - OBJECTIVES: In the working hypothesis we assumed that the procoagulant activity of microparticles (MPs) is associated with the concentration of tissue factor (TF) and its inhibitor (TFPI), and that these three components together affect fetal hemostasis. The aim of the study was to check whether MPs are present in the cord blood, to compare their concentration with that in the maternal blood, as well as to measure the concentrations of TF antigen and TFPI antigen in the cord blood and maternal blood. STUDY DESIGN: The study group consisted of 28 healthy parturient women who gave normal delivery, and their 28 babies. Blood from the umbilical vein was collected immediately after delivery, still prior to omphalotomy, whereas mother's blood was obtained from the antecubital vein. The concentration of MPs as well as TF antigen and TFPI antigen were measured using ELISA method. RESULTS: The level of MPs in cord blood plasma was found to be 6.25 times higher than in the mother's blood plasma (median: 26.76 nM PS; range: 22.90 34.41 nM PS vs. median: 4.26 nM PS; range: 2.68-5.37 nM PS respectively, p=0.0022), whereas the level of TF antigen was 1.94 times higher in the fetus than in the mother (median: 238.03 pg/ml; range: 192.25-283.10 pg/ml vs. median: 122.4 pg/ml, range: 52.71-176.74 pg/ml, respectively, p=0.0012). On the other hand, the level of TFPI antigen was lower in cord blood plasma than in maternal blood plasma, accounting for 33.95% of the value noted in the mother (median: 30.04 ng/ml, range: 24.84-35.12 ng/ml vs. median: 88.48 ng/ml; range: 78.64 107.20 ng/ml, respectively, p<0.0001). There was no correlation between MP concentration and the levels of TF as well as TFPI in fetal blood and maternal blood. CONCLUSIONS: Microparticles (MPs) are constituent components of cord blood plasma; their concentration is significantly higher than that in mother's blood plasma. In the fetus, MPs may play a role of a powerful procoagulant, thus facilitating thrombin generation (TF-dependent thrombin generation, which may take place on their surface); this hypothesis is based on literature data and our own evidence. PMID- 21664033 TI - Fetal microchimerism: benevolence or malevolence for the mother? AB - For a long time, the conventional view was that the fetus and maternal vascular system are kept separate. In fact there is a two way traffic of cells through the placenta and the transplacental passage of cells is in fact the norm. The fetal cells can persist in a wide range of woman's tissues following a pregnancy or an abortion and she becomes a chimera. Fetal cells have been found in the maternal circulation and they were shown to persist for the entire life in humans, thus demonstrating long-term engraftment and survival capabilities. Microchimerism is a subject of much interest for a number of reasons. Studies of fetal microchimerism during pregnancy may offer explanations for complications of pregnancy, such as preeclampsia, as well as insights into the pathogenesis of autoimmune diseases which usually ameliorate during pregnancy. The impact of the persistence of allogenic cells of fetal origin and of the maternal immunological response to them on the mother's health is still not clear. On the beneficial side, it has been proposed that genetically disparate fetal microchimerism provides protection against some cancers, that fetal microchimerism can afford the mother new mechanisms of protection to some diseases, that fetal microchimerism can enlarge the immunological repertoire of the mother improving her defense against aggressor. Fetal cells are often present at sites of maternal injury and may have an active role in the repair of maternal tissues. PMID- 21664034 TI - Laparoscopic-assisted vaginal hysterectomy vs abdominal hysterectomy for benign disease: a meta-analysis of randomized controlled trials. AB - The objective of this meta-analysis was to assess whether laparoscopic-assisted vaginal hysterectomy achieves better clinical results compared with abdominal hysterectomy. Medline (PubMed), EMBASE, Web of Science, ProQuest, Cochrane Library and China Biological Medicine Database were searched to identify randomized controlled trials that compared laparoscopic-assisted vaginal hysterectomy with abdominal hysterectomy. Twenty-three trials were studied and the analysis was performed using Review Manager Version 5 and R Version 2.11.1. The results showed that laparoscopic-assisted vaginal hysterectomy was associated with a longer operation time, less blood loss, shorter hospital stay, smaller haemoglobin drop, less postoperative pain, quicker return to normal activities and fewer peri-operative complications. Quality of life is likely to be the key outcome to evaluate the approach for hysterectomy, but further research is needed. For suitable patients and surgeons, laparoscopic-assisted vaginal hysterectomy is a better choice than abdominal hysterectomy. PMID- 21664035 TI - Assessing conservation opportunity on private land: socio-economic, behavioral, and spatial dimensions. AB - This study presents a method for assessing conservation opportunity on private land based on landholders' socio-economic, behavioral, and farm characteristics. These characteristics include age, gender, education, level of off-farm income, farm size, proportion of remnant native vegetation on-farm, and ecological value of native vegetation on-farm. A sample of landholders who own greater than 2 ha of land in the South Australian Murray-Darling Basin region were sent a mail based survey about their values and preferences for environmental management (N = 659, 52% response). Cross-tabulations and ANOVA statistical analysis techniques were used to compare the socio-economic attributes across three landholder classes: disengaged, moderately engaged, and highly engaged in native vegetation planting. Results indicate that highly engaged landholders were more likely to be female, formally educated, hobby farmers who managed small parcels of land and have high off-farm incomes, whereas disengaged landholders held significantly stronger farming connections (more farming experience, family have lived on the farm for more generations). Spatial analysis revealed area-specific differences in conservation opportunity and conservation priority. In some areas, properties of high ecological value were managed by highly engaged landholders, but nearby properties of high value were managed by moderately engaged or disengaged landholders. Environmental managers therefore cannot assume areas of high conservation priority will be areas of high conservation opportunity. At the regional scale, the potential for revegetation seems most promising within the moderately engaged landholder group considering the vast amount of land managed by this group in areas of high ecological value, particularly within the less represented Mallee and Coorong and Rangelands sub-regions. We suggest that incentive schemes which purchase conservation need to be targeted at disengaged landholders; mentoring schemes led by commercial farmers highly engaged in native vegetation planting should be directed at moderately engaged landholders, and; awards programs which acknowledge conservation successes should be targeted at highly engaged landholders. PMID- 21664036 TI - The role of power line rights-of-way as an alternative habitat for declined mire butterflies. AB - Habitat loss is one of the greatest threats for biodiversity. In Finland, two thirds of natural mires have been drained for silviculture, which transforms open wetlands into dense forests. However, vegetation management of power line rights of-way (ROW) maintain the drained mires as open areas. The aim of this study was to determine the effect of the power line ROW vegetation management on butterfly abundance, species richness and community structure by comparing the managed power line ROWs to unmanaged drained control sites and to natural mires. The species richness or abundance of mire butterflies did not differ between the power line ROWs and natural mires. In contrast, both species richness and abundance of butterflies was low on the unmanaged control sites. Tree canopy cover had a negative effect on mire butterflies and this is most likely related to changes in microclimate. The results indicate that the active vegetation removal in the power line ROWs maintain alternative habitats for mire butterflies; yet, the power line ROWs cannot substitute the natural mires. PMID- 21664038 TI - Re: Didem Sunay, Melih Sunay, Yasin Aydogmus, et al. Acupuncture versus paroxetine for the treatment of premature ejaculation: a randomized, placebo controlled clinical trial. Eur Urol 2011;59:765-71. PMID- 21664037 TI - Study of boron behaviour in two Spanish coal combustion power plants. AB - A full-scale field study was carried out at two Spanish coal-fired power plants equipped with electrostatic precipitator (ESP) and wet flue gas desulfurisation (FGD) systems to investigate the distribution of boron in coals, solid by products, wastewater streams and flue gases. The results were obtained from the simultaneous sampling of solid, liquid and gaseous streams and their subsequent analysis in two different laboratories for purposes of comparison. Although the final aim of this study was to evaluate the partitioning of boron in a (co )combustion power plant, special attention was paid to the analytical procedure for boron determination. A sample preparation procedure was optimised for coal and combustion by-products to overcome some specific shortcomings of the currently used acid digestion methods. In addition boron mass balances and removal efficiencies in ESP and FGD devices were calculated. Mass balance closures between 83 and 149% were obtained. During coal combustion, 95% of the incoming boron was collected in the fly ashes. The use of petroleum coke as co combustible produced a decrease in the removal efficiency of the ESP (87%). Nevertheless, more than 90% of the remaining gaseous boron was eliminated via the FGD in the wastewater discharged from the scrubber, thereby causing environmental problems. PMID- 21664039 TI - Mortality among men with locally advanced prostate cancer managed with noncurative intent: a nationwide study in PCBaSe Sweden. AB - BACKGROUND: There are limited prognostic data for locally advanced prostate cancer PCa to guide in the choice of treatment. OBJECTIVE: To assess mortality in different prognostic categories among men with locally advanced PCa managed with noncurative intent. DESIGN, SETTING, AND PARTICIPANTS: We conducted a register based nationwide cohort study within the Prostate Cancer DataBase Sweden. The entire cohort of locally advanced PCa included 14 908 men. After the exclusion of 2724 (18%) men treated with curative intent, 12 184 men with locally advanced PCa either with local clinical stage T3 or T4 or with T2 with serum levels of prostate-specific antigen (PSA) between 50 and 99 ng/ml and without signs of metastases remained for analysis. MEASUREMENTS: We followed up the patient cohort in the Cause of Death Register for <= 11 yr and assessed cumulative incidence of PCa -specific death stratified by age and clinical characteristics. RESULTS AND LIMITATIONS: The PCa -specific mortality at 8 yr of follow-up was 28% (95% confidence interval [CI], 25-32%) for Gleason score (GS) 2-6, 41% (95% CI, 38 44%) for GS 7, 52% (95% CI, 47-57%) for GS 8, and 64% (95% CI, 59-69%) for GS 9 10. Even for men aged >85 yr at diagnosis with GS 8-10, PCa was a major cause of death: 42% (95% CI, 37-47%). Men with locally advanced disease and a PSA<4 ng/ml at diagnosis were at particularly increased risk of dying from PCa. One important limitation is the lack of bone scans in 42% of the patient cohort, but results remained after exclusion of patients with unknown metastasis status. CONCLUSIONS: The PCa-specific mortality within 8 yr of diagnosis is high in locally advanced PCa, suggesting undertreatment, particularly among men in older age groups. Our results underscore the need for more studies of treatment with curative intent for locally advanced tumors. PMID- 21664040 TI - Contemporary management of small renal masses. AB - CONTEXT: An increasing number of small renal masses (SRMs) with heterogeneous histology and clinical behaviour are being detected with modern radiologic imaging. Although surgical removal is the standard of care for small renal tumours, alternative minimally invasive and conservative treatment options are possible in selected patients with shorter life expectancy. OBJECTIVE: To systematically review indications, techniques, and outcomes of surgical and conservative treatments of SRMs. EVIDENCE ACQUISITION: A literature search of English-language publications was performed using the Medline database from January 2000 to February 2011 using the terms renal mass and renal carcinoma in conjunction with the evaluated management options. The articles that provided the highest level of evidence were selected with the consensus of all the authors and reviewed. EVIDENCE SYNTHESIS: Only one randomised controlled trial comparing the results of elective nephron-sparing surgery and radical nephrectomy for low-stage renal tumours is available. Few comparative studies of different treatment options for SRMs have been published. The assessment of oncologic outcomes is therefore based mainly on observational studies. Most series of nonsurgical therapies have strong selection biases and relatively short follow-up. Treatment selection is based on the clinical and histologic characteristics of SRMs, on patient age and comorbidities, and on personal preferences and experience of the urologist. CONCLUSIONS: Partial nephrectomy (PN) is the standard treatment for solitary SRMs whenever it is technically feasible. Laparoscopic PN is an alternative to open PN in experienced hands. The rationale of ablative treatments is to treat incidental cortical SRMs in patients at high surgical risk with potentially reduced morbidity. Active surveillance is considered an appropriate strategy for the elderly or for patients with significant comorbidity who have a shorter life expectancy. Percutaneous biopsies are increasingly being used to establish histology of SRMs and support treatment decisions, especially for patients who are candidates for nonsurgical treatment. PMID- 21664041 TI - Long-term cancer-specific survival in patients with high-risk, non-muscle invasive bladder cancer and tumour progression: a systematic review. AB - CONTEXT: Some studies report that tumour progression in patients with non-muscle invasive bladder cancer (NMIBC) is associated with a poor prognosis. However, no systematic evidence is available. OBJECTIVE: The aim of the study was to systematically review literature to determine the long-term cancer-specific survival in patients with high-risk NMIBC (T1G3, multifocal, highly recurrent, or carcinoma in situ) having tumour progression. EVIDENCE ACQUISITION: A systematic review was conducted by searching PubMed and the Cochrane library for studies published between 2006 and 2011. Additional studies were identified by scanning reference lists of relevant papers. We attempted to retrieve missing data by contacting the corresponding author. Keywords used included bladder cancer, high risk, high grade, carcinoma in situ, non-muscle invasive bladder cancer, progression, and survival. Studies were included when they met the following criteria: inclusion of at least 75 patients having high-risk NMIBC, patients were initially treated conservatively with transurethral resection of the bladder tumour and intravesical instillations, a median follow-up of at least 48 mo, and reporting data on progression to muscle-invasive bladder cancer (MIBC) and death resulting from bladder cancer (BCa). EVIDENCE SYNTHESIS: Literature was systematically reviewed, and 19 trials were included, producing a total of 3088 patients, of which 659 (21%) showed progression to MIBC and 428 (14%) died as a result of BCa after a median follow-up of 48-123 mo. Survival after progression from high-risk NMIBC to MIBC was 35%. Progression to MIBC and BCa-related death in high-risk NMIBC were found to be relatively early events, occurring mainly within 48 mo. Finally, even in cases of early cystectomy in patients with high risk NMIBC, a relevant proportion of these patients appear not be cured of their disease. CONCLUSIONS: This study provides systematically gathered evidence showing a poor prognosis for patients with high-risk NMIBC and tumour progression. PMID- 21664042 TI - miR-17-92 cluster microRNAs confers tumorigenicity in multiple myeloma. AB - miRNAs play important roles in the regulation of cell proliferation, differentiation and apoptosis. The deregulation of miRNAs expression contributes to tumorigenesis by modulating oncogenic and tumor suppressor signaling pathways. Oncogenic transcription factor Myc can control expression of a large set of microRNAs (miRNAs). Previous studies have shown that the expression of miR-17-92 cluster, a polycistron encoding six microRNAs (miRNA), has close relationship with the expression of Myc. In current study, silencing Myc in multiple myeloma (MM)cells induced cell death and growth inhibition, and downregulated expression of miR-17-92 cluster. Overexpression of miR-17 or miR-18 could partly abrogated Myc-knockdown-induced MM cell apoptosis. One of the mechanism of Myc inhibiting MM cell apoptosis is through Myc activates miR-17-92 cluster and subsequently down-modulates proapoptotic protein Bim. Although miR-17-92 cluster are located at 13q31.3, the expression of miR-18, miR-19 and miR-20 (especially miR-19) in patients with del(13q14) was higher than those without del(13q14). Patients with miR-17, miR-20 and miR-92 high-expression had shorter PFS compared to those with miR-17, miR-20 and miR-92 low-expression. These results suggest the Myc-inducible miR-17-92 cluster miRNAs contribute to tumorigenesis and poor prognosis in multiple myeloma. PMID- 21664044 TI - Gel-hydrothermal synthesis of carbon and boron co-doped TiO2 and evaluating its photocatalytic activity. AB - Carbon and boron co-doped TiO(2) photocatalysts were prepared firstly by the gel hydrothermal method, that is, synthesized through sol-gel process followed by hydrothermal in the glucose solution. The prepared photocatalysts were characterized by XRD, Raman spectra, TEM, N(2) physical adsorption, XPS, and UV vis absorption spectra. It was found that the co-doped TiO(2) has a larger BET surface areas and a narrower band gap than undoped TiO(2). The experimental results show that the coke carbon generated on the carbon doped TiO(2) surface act as a photosensitizer and has the photosensitization effect under the visible light. Except for carbon sensitization effect, the boron and carbon co-doped TiO(2) has synergistic effect which is responsible for effective photo degradation of 2,4-dichlorophenol in the visible light irradiation. PMID- 21664043 TI - GDC-0941 sensitizes breast cancer to ABT-737 in vitro and in vivo through promoting the degradation of Mcl-1. AB - The present study showed that GDC-0941 potently sensitized breast cancer to ABT 737 in vitro and in vivo. ABT-737 exhibited limited lethality in breast cancer cells; however, when combined with GDC-0941, it displayed strong synergistic cytotoxicity and enhanced caspase-mediated apoptosis. GDC-0941 promoted proteasomal degradation of Mcl-1, of which the overexpression has been validated to confer ABT-737 resistance, thereby enhanced the anticancer efficacy of ABT 737. Furthermore, the combination of GDC-0941 and ABT-737 exerted increased anti tumor efficacy on MDA-MB-231 xenograft models. Overall, our data described unprecedentedly the promising therapeutic potential and underlying mechanisms of combining GDC-0941 with ABT-737 in treating breast cancer. PMID- 21664045 TI - Effect of sulfide concentration on the location of the metal precipitates in inversed fluidized bed reactors. AB - The effect of the sulfide concentration on the location of the metal precipitates within sulfate-reducing inversed fluidized bed (IFB) reactors was evaluated. Two mesophilic IFB reactors were operated for over 100 days at the same operational conditions, but with different chemical oxygen demand (COD) to SO(4)(2-) ratio (5 and 1, respectively). After a start up phase, 10mg/L of Cu, Pb, Cd and Zn each were added to the influent. The sulfide concentration in one IFB reactor reached 648 mg/L, while it reached only 59 mg/L in the other one. In the high sulfide IFB reactor, the precipitated metals were mainly located in the bulk liquid (as fines), whereas in the low sulfide IFB reactor the metal preciptiates were mainly present in the biofilm. The latter can be explained by local supersaturation due to sulfide production in the biofilm. This paper demonstrates that the sulfide concentration needs to be controlled in sulfate reducing IFB reactors to steer the location of the metal precipitates for recovery. PMID- 21664046 TI - Degradation of organothiophosphorous extractant Cyanex 301. AB - The resistance of extractants to light is important during industrial extraction processes. A photodegradation of the organothiophosphorous extractant Cyanex 301 in toluene and hexane as organic diluent and the identification of possible degradation products using FT-IR and GC-MS techniques were performed. The influence of copper(II) and cobalt(II) ions on the stability of the extractant under UV-vis light exposure was also studied. The changes in the percentage composition of individual components of the extractant depended on the types of organic diluents and copper or cobalt ions. During this process, copper complex irradiation precipitation of black powder and photooxidation of toluene were observed. Based on these results we proposed a hypothetical mechanism of photodegradation of extractant Cyanex 301. PMID- 21664047 TI - Diclofenac photodegradation under simulated sunlight: Effect of different forms of nitrogen and kinetics. AB - A synthetic non-steroidal anti-inflammatory drug diclofenac is one of the most frequently detected pharmaceuticals in various water samples. One of the most important degradation processes relating to diclofenac is its photodegradation in the aquatic environment. This paper studies the kinetic model for diclofenac degradation in water and the variation of the photodegradation of diclofenac in the presence of different forms of nitrogen changes with different pE values in the aquatic environment under simulated sunlight. The results demonstrate that degradation pathways proceed via pseudo first-order kinetics in all cases and the photodegradation of diclofenac is the sum of the degradation by direct photolysis and self-sensitization. NO(3)(-) and NO(2)(-) have inhibiting effects on the photodegradation of diclofenac. The different forms of nitrogen changes with different pE values and this has a significant influence on the photodegradation of diclofenac. The results show that when NH(4)(+) and NO(2)(-) coexist in the aquatic environment, the inhibiting effect on the photodegradation diclofenac is less than the sum of the partial inhibiting effects. The results indicated that NO(2)(-) had an obvious antagonistic action for NH(4)(+). When NO(3)(-) and NO(2)(-) coexisted in the aquatic environment, a similar antagonistic action between NO(3)(-) and NO(2)(-) was observed. PMID- 21664048 TI - Photocatalytic activities of Mo-doped Bi2WO6 three-dimensional hierarchical microspheres. AB - The Mo-doped Bi(2)WO(6) three-dimensional (3D) hierarchical microspheres from nanoplates have been synthesized by a hydrothermal route. The products were characterized in detail by multiform techniques: X-ray diffraction (XRD), energy dispersive X-ray analysis (EDS), scanning electron microscopy (SEM), and UV-vis absorption spectrum. The results of the photocatalytic degradation of Rhodamine-B (RhB) in aqueous solution showed that molybdenum ions doping greatly improved the photocatalytic efficiency of Bi(2)WO(6) 3D hierarchical microspheres. The Mo doped Bi(2)WO(6) microspheres with atomic ratio of Mo-W of 0.05 had the best activity in photodegradation of RhB in aqueous solution under 500 W Xe lamp light irradiation. PMID- 21664049 TI - Phytoremediatory effect and growth of two species of Ocimum in endosulfan polluted soil. AB - Endosulfan is a hazardous organochlorine pesticide banned or restricted in several countries. However, it has been found in the environment and in animal samples. To study a potential way to bioremediate soils contaminated with this pesticide, two plant species of the genus Ocimum were studied: Ocimum basilicum L. and Ocimum minimum L., since they are economically feasible and well adapted to the climatic conditions of the Nayarit zone (Mexican pacific coast). Young plants were transplanted into soil experimentally polluted with endosulfan. Growth of both species was not affected by endosulfan, the plants grew, flourished, and produced seeds; 30 days later, endosulfan concentration was lower in the soil with O. basilicum than in the soil without plants. On day 90, no differences in endosulfan concentrations were found between soil with or without O. minimum. At day 1, plants in the polluted soil showed lipoperoxidation, as measured by thiobarbituric acid-reactive species (TBARS). Interestingly, a higher TBARS value was observed at day 3 in transplanted plants as compared to non transplanted plants. In conclusion, both species can endure endosulfan pollution (as high as 1 g kg(-1)) in soils. O. basilicum seems to be an adequate candidate for bioremediation of soils polluted with endosulfan. PMID- 21664050 TI - Synthesis of sulfated Y-doped zirconia particles and effect on properties of polysulfone membranes for treatment of wastewater containing oil. AB - Polysulfone (PSF) membranes are broadly applied in many fields owing to good physicochemical stability, resistance to oxidation and chlorine. But when treated with wastewater containing oil, PSF membranes are easily contaminated due to their hydrophilicity, causing declining flux and lifespan of the membranes thereby limiting their large scale applications. In order to enhance the hydrophilic and anti-fouling capability of PSF membranes for treating wastewater containing oil, sulfated Y-doped zirconia particles (SO(4)(2-)/ZrO(2)-Y(2)O(3) or SZY particles) were firstly synthesized and then doped into polysulfone to fabricate a novel hybrid membrane (SZY/PSF). The optimum preparation conditions of SZY particles were studied and determined. SZY particles were characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR), specific surface area and transmission electron microscopy (TEM). Wastewater containing oil (80mg/L) was used to investigate the separation properties of SZY/PSF membranes. The results show that the oil concentration in the permeation is 0.67mg/L, which meets the recycle standard of the Chinese oil-field (SY/T 5329-94, oil concentration <10mg/L). It is concluded that doping SZY particles into polysulfone can reasonably resist membrane fouling and SZY/PSF membranes can be considered feasible in treating wastewater containing oil. PMID- 21664051 TI - Eugenol reverses mechanical allodynia after peripheral nerve injury by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. AB - Mechanical allodynia is a common symptom found in neuropathic patients. Hyperpolarization-activated cyclic nucleotide-gated channels and their current, I(h), have been suggested to play an important role in neuropathic pain, especially in mechanical allodynia and spontaneous pain, by involvement in spontaneous ectopic discharges after peripheral nerve injury. Thus, I(h) blockers may hold therapeutic potential for the intervention of mechanical allodynia under diverse neuropathic conditions. Here we show that eugenol blocks I(h) and abolishes mechanical allodynia in the trigeminal system. Eugenol produced robust inhibition of I(h) with IC(50) of 157 MUM in trigeminal ganglion (TG) neurons, which is lower than the dose of eugenol that inhibits voltage-gated Na channels. Eugenol-induced I(h) inhibition was not mediated by G(i/o)-protein activation, but was gradually diminished by an increase in intracellular cAMP concentration. Eugenol also inhibited I(h) from injured TG neurons which were identified by retrograde labeling with DiI and reversed mechanical allodynia in the orofacial area after chronic constriction injury of infraorbital nerve. We propose that eugenol could be potentially useful for reversing mechanical allodynia in neuropathic pain patients. PMID- 21664052 TI - Ultrastructural features of Tritrichomonas mobilensis and comparison with Tritrichomonas foetus. AB - Tritrichomonas mobilensis is an intestinal parasite of squirrel monkeys. There are few reports concerning the morphological aspects of this parasite. In addition, the taxonomic relationship between T. mobilensis and Tritrichomonas foetus, a serious pathogen that causes bovine and feline trichomonosis, has been questioned. For this reason, in the present study, we examined and compared both tritrichomonads with regard to their morphology, ultrastructure, endocytic activity and cytotoxicity when in the presence of host cells. Electron microscopy demonstrated consistent morphological differences between the hydrogenosomes of both parasites. Moreover, T. mobilensis and T. foetus had striking differences in their endocytic behavior. Thus, this work provides additional data that support the hypothesis that T. mobilensis is a distinct species from T. foetus. PMID- 21664053 TI - Prevalence pattern and biology of Sarcocystis capracanis infection in the Egyptian goats: a light and ultrastructural study. AB - Cysts of Sarcocystis capracanis obtained from infected goats were examined to clarify the effect of the parasite on the host. Muscle tissues from fresh oesophagus, tongue, diaphragm and skeletal muscles of 680 goats were slaughtered in the main abattoir of Cairo, Egypt and they were examined microscopically for Sarcocystis infection for the first time in Egypt. 540 out of 680 (79.4%) of examined goats were found to be infected with Sarcocystis sp. The infection was recorded firstly by light microscopy as spindle shaped cysts embedded in the muscle tissues. The validity of this species as S. capracanis was confirmed by means of ultrastructural characteristics of the primary cyst wall which revealed the presence of thick-radially striated wall with finger like projections, underlined by a thick layer of ground substance enclosing the developing metrocytes and merozoites that usually contain nearly all the structures of the apical complex and fill the interior cavity of the cyst. The cyst cavity is divided by many septa extending from the ground substance and producing large number of chambers. An experimental infection using the highly infected muscles was carried out to determine the final host, which is dog. Smears of intestinal epithelium were taken to examine the endogenous stages (gamogony and sporogony) by means of light microscopy. These stages were mainly observed as to infect the lamina propria of the posterior third of the small intestine. Gamogony and zygote formation (fertilization) occurred 2-8 days post infection, while sporulation took place within the final host 13-15 days and sporocysts were passed within faeces of the infected puppies at that time. The prepatent period of S. capracanis was 12-15 days, while the patent period was extended to 37 days. In goats, infection with S. capracanis led to the loss of weight, anaemia, abortion and even death in cases of heavy infection. While bleeding, watery faeces filled with mucous on 5th and 8th day p.i. as well as intestinal lesions are the pathogenic effects occurred in puppies after experimental infection. PMID- 21664054 TI - A theoretical model of efficacy of concentrative meditation for cognitive rehabilitation of dementia. AB - The positive effects of various types of meditation on health have been one of the well documented evidences of past decade. However, the effects of meditation on one specific domain of human cognition-attention have been understudied. This becomes an especially important issue in cases of dementia, where attention deterioration is an important component in addition to the memory problems. Here we appraise some theories of attention deterioration in aging individuals. We next proceed to build a model of the effects of concentrative meditation practice on various domains of attention in aging individuals, backed up with the evidences from literature. For this we also present the results of our own studies conducted on the concentrative meditation of Vihangam Yoga to highlight the fact that with long-term meditation practice, attention can be improved in various domains. Finally we propose that the effects of meditation can be especially tried on minimal cognitive deficit patients to explore if it helps further deterioration in such patients. This line of study could have important implication for future treatments of attention related problems in dementia patients. PMID- 21664055 TI - Quality traits of wild boar mould-ripened salami manufactured with different selections of meat and fat tissue, and with and without bacterial starter cultures. AB - Quality traits of wild boar mould-ripened salami were assessed in eight batches produced from two different assortments of meat (hind leg vs. shoulder), fat tissue (backfat from domestic pigs vs. fat tissue from wild boar), and with and without addition of a commercial bacterial starter culture. Chemical composition of finished products (day 35) were in compliance with national food codex. Batches produced with a bacterial starter culture were generally preferred by taste panels, had significantly lower concentrations of TBARS (<1.5 mgmalondialdehyde/kg) and peroxide values (POVs) and lower concentrations of cadaverine (<50 mg/kg), histamine (<10 mg/kg) and putrescine (<60 mg/kg). TBARS and POVs were inversely related to sensory preference scores (r(2)=0.84 and 0.88). Batches produced from shoulder muscles contained significantly higher concentrations of cadaverine, histamine and putrescine. TBARS were highest in batches manufactured with fat tissue from wild boars. These findings should be considered when guides to good practice for the manufacture of game meat products are developed. PMID- 21664056 TI - Incubation of curing brines for the production of ready-to-eat, uncured, no nitrite-or-nitrate-added, ground, cooked and sliced ham. AB - Salt concentration, vegetable juice powder (VJP) concentration and temperature were investigated to determine necessary conditions for incubation of curing brines including VJP and a starter culture containing Staphylococcus carnosus prior to production of naturally cured, no-nitrate/nitrite-added meat products. Subsequently, incubated brines were utilized to produce no-nitrate/nitrite-added sliced ham in which quality characteristics and residual nitrite concentrations were measured to determine feasibility of brine incubation for nitrate conversion prior to injection. Two ham treatments (one with VJP and starter culture; one with pre-converted VJP) and a nitrite-added control were used. No differences (P>0.05) were found for color in the VJP treatments. Control sliced ham was redder after 42 days of storage, retaining significantly (P<0.05) greater a* (redness) than either of the VJP treatments. Residual nitrite concentration was greater (P<0.05) in the control hams during the first week of storage. While the nitrite-added control retained greater red color and initially had more residual nitrite than the VJP treatments, the two VJP treatments did not differ from each other. PMID- 21664057 TI - Meningocerebral angiodysplasia with metanephric induction failure: Broadening the spectrum of an emerging maldevelopmental syndrome. AB - The uncommon simultaneous occurrence of an exuberant, angioma-like proliferation of superficial cerebral microvessels along with absence of the kidneys has been proposed to constitute a syndromic complex for which the term "meningocerebral angiodysplasia (or angiomatosis) with renal agenesis" (MCA-RA) is being descriptively used. We observed this constellation in one of a pair of dichorionic male twins following postpartal death in the 38th week of pregnancy. General autopsy revealed rudimentary metanephric anlagen made up of few residual glomeruli, cysts lined by flattened tubular epithelium, and islands of cartilage corresponding to renal aplastic dysplasia. Largely inconspicuous with respect to its gyral pattern, as well as the configuration of the ventricular system, the brain microscopically showed extensive replacement of the cortex by a lattice of proliferating capillaries with necrosis of the intervening parenchyma. Minute foci of calcified necrosis were scattered in the deep subcortical white matter as well, while the ventricular ependyma and the subventricular germ cell layer remained remarkably intact. The cerebellum and brain stem appeared unaffected as well. Karyotyping of skin fibroblasts indicated a normal chromosome set of 46XY without gross structural anomalies. We interpret these findings as ones apt to being reasonably accommodated within the spectrum of MCA-RA. Although exceedingly rare, accurate identification of individual cases of MCA-RA is relevant both to differential diagnosis from its prognostically different look-alike "proliferative vasculopathy and hydranencephaly-hydrocephaly" (PVHH), and to refine the nosology of unconventional pediatric vascular malformations, for which the rather nonspecific label "angiodysgenetic necrotizing encephalopathy" is still commonly used. PMID- 21664058 TI - Mutational and expressional analyses of ATG5, an autophagy-related gene, in gastrointestinal cancers. AB - There is mounting evidence that alterations of cell death processes are involved in cancer pathogenesis. ATG5 is a key regulator of autophagic and apoptotic cell death. The aim of this study was to see whether alterations of ATG5 protein expression and somatic mutation of ATG5 gene are features of human gastrointestinal cancers. In this study, we analyzed ATG5 somatic mutation in 45 gastric, 45 colorectal, and 45 hepatocellular carcinomas by single-strand conformation polymorphism (SSCP). Also, we analyzed ATG5 protein expression in 100 gastric, as well as in 95 colorectal and hepatocellular carcinomas using immunohistochemistry. Overall, we detected two somatic missense mutations of ATG5 gene in the coding sequences p.Leu112Phe and p.His41Tyr. The mutations were observed in one gastric and one hepatocellular carcinoma. Immunohistochemically, ATG5 protein was well expressed in normal stomach, colon, and liver epithelial cells, while it was lost in 21 (21%) of the gastric carcinomas, in 22 (23%) of the colorectal carcinomas, and in 5 (10%) of the hepatocellular carcinomas. Our data suggest that ATG5 gene could be altered in gastrointestinal cancers at the mutational or expressional level. Despite the low incidences of the alterations, our data led us to conclude that somatic mutation and loss of expression of ATG5 gene might play a role in gastrointestinal cancer pathogenesis by altering autophagic and apoptotic cell death. PMID- 21664059 TI - The benefits of including clinical factors in rectal normal tissue complication probability modeling after radiotherapy for prostate cancer. AB - PURPOSE: To study the impact of clinical predisposing factors on rectal normal tissue complication probability modeling using the updated results of the Dutch prostate dose-escalation trial. METHODS AND MATERIALS: Toxicity data of 512 patients (conformally treated to 68 Gy [n = 284] and 78 Gy [n = 228]) with complete follow-up at 3 years after radiotherapy were studied. Scored end points were rectal bleeding, high stool frequency, and fecal incontinence. Two traditional dose-based models (Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) and a logistic model were fitted using a maximum likelihood approach. Furthermore, these model fits were improved by including the most significant clinical factors. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminating ability of all fits. RESULTS: Including clinical factors significantly increased the predictive power of the models for all end points. In the optimal LKB, RS, and logistic models for rectal bleeding and fecal incontinence, the first significant (p = 0.011-0.013) clinical factor was "previous abdominal surgery." As second significant (p = 0.012-0.016) factor, "cardiac history" was included in all three rectal bleeding fits, whereas including "diabetes" was significant (p = 0.039-0.048) in fecal incontinence modeling but only in the LKB and logistic models. High stool frequency fits only benefitted significantly (p = 0.003-0.006) from the inclusion of the baseline toxicity score. For all models rectal bleeding fits had the highest AUC (0.77) where it was 0.63 and 0.68 for high stool frequency and fecal incontinence, respectively. LKB and logistic model fits resulted in similar values for the volume parameter. The steepness parameter was somewhat higher in the logistic model, also resulting in a slightly lower D(50). Anal wall DVHs were used for fecal incontinence, whereas anorectal wall dose best described the other two endpoints. CONCLUSIONS: Comparable prediction models were obtained with LKB, RS, and logistic NTCP models. Including clinical factors improved the predictive power of all models significantly. PMID- 21664060 TI - Brain tumor therapy-induced changes in normal-appearing brainstem measured with longitudinal diffusion tensor imaging. AB - PURPOSE: To characterize therapy-induced changes in normal-appearing brainstems of childhood brain tumor patients by serial diffusion tensor imaging (DTI). METHODS AND MATERIALS: We analyzed 109 DTI studies from 20 brain tumor patients, aged 4 to 23 years, with normal-appearing brainstems included in the treatment fields. Those with medulloblastomas, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors (n = 10) received postoperative craniospinal irradiation (23.4-39.6 Gy) and a cumulative dose of 55.8 Gy to the primary site, followed by four cycles of high-dose chemotherapy. Patients with high-grade gliomas (n = 10) received erlotinib during and after irradiation (54 59.4 Gy). Parametric maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and spatially registered to three-dimensional radiation dose data. Volumes of interest included corticospinal tracts, medial lemnisci, and the pons. Serving as an age-related benchmark for comparison, 37 DTI studies from 20 healthy volunteers, aged 6 to 25 years, were included in the analysis. RESULTS: The median DTI follow-up time was 3.5 years (range, 1.6-5.0 years). The median mean dose to the pons was 56 Gy (range, 7-59 Gy). Three patterns were seen in longitudinal FA and apparent diffusion coefficient changes: (1) a stable or normal developing time trend, (2) initial deviation from normal with subsequent recovery, and (3) progressive deviation without evidence of complete recovery. The maximal decline in FA often occurred 1.5 to 3.5 years after the start of radiation therapy. A full recovery time trend could be observed within 4 years. Patients with incomplete recovery often had a larger decline in FA within the first year. Radiation dose alone did not predict long term recovery patterns. CONCLUSIONS: Variations existed among individual patients after therapy in longitudinal evolution of brainstem white matter injury and recovery. Early response in brainstem anisotropy may serve as an indicator of the recovery time trend over 5 years after radiation therapy. PMID- 21664061 TI - Long-term outcome and patterns of failure in primary ocular adnexal mucosa associated lymphoid tissue lymphoma treated with radiotherapy. AB - PURPOSE: To evaluate the long-term treatment outcome and disease behavior of primary ocular adnexal MALT (mucosa-associated lymphoid tissue) lymphoma (POAML) after treatment with radiotherapy. METHODS AND MATERIALS: Seventy-eight patients (42 male, 36 female) diagnosed with stage I POAML between 1991 and 2010 at Kobe University Hospital were included. The median age was 60 years (range, 22-85 years). The median radiation dose administered was 30.6 Gy. Rituximab-based targeted therapy and/or chemotherapy was performed in 20 patients (25.6%). Local control (LC), recurrence-free survival (RFS), and overall survival (OS) rates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up duration was 66 months. Major tumor sites were conjunctiva in 37 patients (47.4%), orbita in 29 (37.2%), and lacrimal glands in 12 (15.4%). The 5- and 10 year OS rates were 98.1% and 95.3%, respectively. The 5- and 10-year LC rates were both 100%, and the 5- and 10-year RFS rates were 88.5% and 75.9%, respectively. Patients treated with a combination of radiotherapy and targeted therapy and/or chemotherapy had a trend for a better RFS compared with those treated with radiotherapy alone (p = 0.114). None developed greater than Grade 2 acute morbidity. There were 14 patients who experienced Grade 2 morbidities (cataract: 14; retinal disorders: 7; dry eye: 3), 23 patients who had Grade 3 morbidities (cataract: 23; dry eye: 1), and 1 patient who had Grade 4 glaucoma. CONCLUSIONS: Radiotherapy for POAML was shown to be highly effective and safe for LC and OS on the basis of long-term observation. The absence of systemic relapse in patients with combined-modality treatment suggests that lower doses of radiation combined with targeted therapy may be worth further study. PMID- 21664062 TI - Imaging for stereotactic spine radiotherapy: clinical considerations. AB - There is growing interest in the use of stereotactic body radiation therapy (SBRT) for spinal metastases. With the need for accurate target definition and conformal avoidance of critical normal structures, high-quality multimodal imaging has emerged as a key component at each stage of the treatment process. Multidisciplinary collaboration is necessary to optimize imaging protocols and implement imaging advances into routine patient care. PMID- 21664063 TI - Ductal carcinoma in situ--the influence of the radiotherapy boost on local control. AB - PURPOSE: Local recurrence (LR) of ductal carcinoma in situ (DCIS) is reduced by whole-breast irradiation after breast-conserving surgery (BCS). However, the benefit of adding a radiotherapy boost to the surgical cavity for DCIS is unclear. We sought to determine the impact of the boost on LR in patients with DCIS treated at the McGill University Health Centre. METHODS AND MATERIALS: A total of 220 consecutive cases of DCIS treated with BCS and radiotherapy between January 2000 and December 2006 were reviewed. Of the patients, 36% received a radiotherapy boost to the surgical cavity. Median follow-up was 46 months for the boost and no-boost groups. Kaplan-Meier survival analyses and Cox regression analyses were performed. RESULTS: Compared with the no-boost group, patients in the boost group more frequently had positive and <0.1-cm margins (48% vs. 8%) (p < 0.0001) and more frequently were in higher-risk categories as defined by the Van Nuys Prognostic (VNP) index (p = 0.006). Despite being at higher risk for LR, none (0/79) of the patients who received a boost experienced LR, whereas 8 of 141 patients who did not receive a boost experienced an in-breast LR (log-rank p = 0.03). Univariate analysis of prognostic factors (age, tumor size, margin status, histological grade, necrosis, and VNP risk category) revealed only the presence of necrosis to significantly correlate with LR (log-rank p = 0.003). The whole breast irradiation dose and fractionation schedule did not affect LR rate. CONCLUSIONS: Our results suggest that the use of a radiotherapy boost improves local control in DCIS and may outweigh the poor prognostic effect of necrosis. PMID- 21664064 TI - Potential impact of preoperative magnetic resonance imaging of the breast on patient selection for accelerated partial breast irradiation. AB - PURPOSE: Accelerated partial breast irradiation (APBI) after breast-conserving therapy is currently under investigation in prospective randomized studies. Multifocality and multicentricity are exclusion criteria for APBI. Preoperative breast magnetic resonance imaging (MRI) can detect ipsilateral and contralateral invasive tumor foci or ductal carcinoma in situ in addition to conventional diagnostic methods (clinical examination, mammography, and ultrasonography). The objective of this retrospective study was to evaluate the impact of preoperative MRI on patient selection for APBI. METHODS AND MATERIALS: From 2002 to 2007, a total of 579 consecutive, nonselected patients with newly diagnosed early-stage breast cancer received preoperative breast MRI in addition to conventional imaging studies at the Bonn University Breast Cancer Center. In retrospect, 113 patients would have met the criteria for APBI using conventional imaging workup (clinical tumor size <=3 cm; negative axillary lymph node status; unifocal disease; no evidence of distant metastases; no invasive lobular carcinoma, ductal and lobular carcinoma in situ, or Paget's disease). We analyzed the amount of additional ipsilateral and contralateral tumor foci detected by MRI. RESULTS: MRI detected additional tumor foci in 8.8% of patients eligible for APBI (11 tumor foci in 10 of 113 patients), either ipsilateral (n = 7, 6.2%) or contralateral (n = 4, 3.5%). In 1 patient, MRI helped detect additional tumor focus both ipsilaterally and contralaterally. CONCLUSIONS: Preoperative breast MRI is able to identify additional tumor foci in a clinically relevant number of cases in this highly selected group of patients with low-risk disease and may be useful in selecting patients for APBI. PMID- 21664065 TI - Multimodality local therapy for retroperitoneal sarcoma. AB - PURPOSE: Soft-tissue sarcomas of the retroperitoneum are rare tumors comprising less than 1% of all malignancies. Although surgery continues as the mainstay of treatment, the large size of these tumors coupled with their proximity to critical structures make resection with wide margins difficult to achieve. The role and timing of radiotherapy are controversial. This study updates our institutional experience using multimodality local therapy for resectable retroperitoneal sarcoma and identifies prognostic factors impacting disease control and survival. METHODS AND MATERIALS: Between 1974 and 2007, 58 patients with nonmetastatic retroperitoneal sarcoma were treated with surgery and radiation at the University of Florida. The median age at radiotherapy was 57 years old (range, 18-80 years). Forty-two patients received preoperative radiotherapy and 16 received postoperative radiotherapy. Nineteen patients received 1.8 Gy once daily and 39 patients received 1.2 Gy twice daily. Variables analyzed for prognostic value included age, grade, kidney involvement, histology, de novo versus recurrent presentation, tumor diameter, margin status, radiotherapy sequencing (preoperative vs. postoperative), total radiation dose, fractionation scheme, and treatment era. RESULTS: The 5-year overall survival, cause-specific survival, and local control rates were 49%, 58%, and 62%, respectively. Nearly two-thirds of disease failures involved a component of local progression. On multivariate analysis, only margin status was significantly associated with improved 5-year local control (85%, negative margins; 63%, microscopic positive margins; 0%, gross positive margins; p < 0.0001) and 5-year overall survival (64%, negative margins; 56%, microscopic positive margins; 13%, gross positive margins; p = 0.0012). Thirty-one Grade 3 or greater toxicities were observed in 22 patients, including two treatment-related deaths (3%). CONCLUSION: For retroperitoneal sarcoma, local control remains a challenge and combined-modality therapy may be associated with significant acute and late morbidity. Our patterns of failure data suggest that improvements in local control may translate into a survival benefit. PMID- 21664066 TI - Distant metastases following permanent interstitial brachytherapy for patients with clinically localized prostate cancer. AB - PURPOSE: Recent publications have suggested high-risk patients undergoing radical prostatectomy have a lower risk of distant metastases and improved cause-specific survival (CSS) than patients receiving definitive external beam radiation therapy (XRT). To date, none of these studies has compared distant metastases and CSS in brachytherapy patients. In this study, we evaluate such parameters in a consecutive cohort of brachytherapy patients. METHODS AND MATERIALS: From April 1995 to June 2007, 1,840 consecutive patients with clinically localized prostate cancer were treated with brachytherapy. Risk groups were stratified according to National Comprehensive Cancer Network (www.nccn.org) guidelines. Subgroups of 658, 893, and 289 patients were assigned to low, intermediate, and high-risk categories. Median follow-up was 7.2 years. Along with brachytherapy implantation, 901 (49.0%) patients received supplemental XRT, and 670 (36.4%) patients received androgen deprivation therapy (median duration, 4 months). The mode of failure (biochemical, local, or distant) was determined for each patient for whom therapy failed. Cause of death was determined for each deceased patient. Multiple parameters were evaluated for impact on outcome. RESULTS: For the entire cohort, metastases-free survival (MFS) and CSS at 12 years were 98.1% and 98.2%, respectively. When rates were stratified by low, intermediate, and high-risk groups, the 12-year MFS was 99.8%, 98.1%, and 93.8% (p < 0.001), respectively. CSS rates were 99.8%, 98.0%, and 95.3% (p < 0.001) for low, intermediate, and high-risk groups, respectively. Biochemical progression-free survival was 98.7%, 95.9% and 90.4% for low, intermediate, and high-risk patients, respectively (p < 0.001). In multivariate Cox-regression analysis, MFS was mostly closely related to Gleason score and year of treatment, whereas CSS was most closely associated with Gleason score. CONCLUSIONS: Excellent CSS and MFS rates are achievable with high-quality brachytherapy for low, intermediate, and high-risk patients. These results compare favorably to alternative treatment modalities. In particular, our MFS and CSS rates for high-risk patients appear superior to those of published radical prostatectomy series. PMID- 21664067 TI - Influence of antiflatulent dietary advice on intrafraction motion for prostate cancer radiotherapy. AB - PURPOSE: To evaluate the effect of an antiflatulent dietary advice on the intrafraction prostate motion in patients treated with intensity-modulated radiotherapy (IMRT) for prostate cancer. METHODS AND MATERIALS: Between February 2002 and December 2009, 977 patients received five-beam IMRT for prostate cancer to a dose of 76 Gy in 35 fractions combined with fiducial markers for position verification. In July 2008, the diet, consisting of dietary guidelines to obtain regular bowel movements and to reduce intestinal gas by avoiding certain foods and air swallowing, was introduced to reduce the prostate motion. The intrafraction prostate movement was determined from the portal images of the first segment of all five beams. Clinically relevant intrafraction motion was defined as >=50% of the fractions with an intrafraction motion outside a range of 3 mm. RESULTS: A total of 739 patients were treated without the diet and 105 patients were treated with radiotherapy after introduction of the diet. The median and interquartile range of the average intrafraction motion per patient was 2.53 mm (interquartile range, 2.2-3.0) without the diet and 3.00 mm (interquartile range, 2.4-3.5) with the diet (p < .0001). The percentage of patients with clinically relevant intrafraction motion increased statistically significant from 19.1% without diet to 42.9% with a diet (odds ratio, 3.18; 95% confidence interval, 2.07-4.88; p < .0001). CONCLUSIONS: The results of the present study suggest that antiflatulent dietary advice for patients undergoing IMRT for prostate cancer does not reduce the intrafraction movement of the prostate. Therefore, antiflatulent dietary advice is not recommended in clinical practice for this purpose. PMID- 21664068 TI - Comparison of prophylactic naftopidil, tamsulosin, and silodosin for 125I brachytherapy-induced lower urinary tract symptoms in patients with prostate cancer: randomized controlled trial. AB - PURPOSE: To compare the efficacy of three alpha(1A)/alpha(1D)-adrenoceptor (AR) antagonists--naftopidil, tamsulosin, and silodosin--that have differing affinities for the alpha(1)-AR subtypes in treating urinary morbidities in Japanese men with (125)I prostate implantation (PI) for prostate cancer. METHODS AND MATERIALS: This single-institution prospective randomized controlled trial compared naftopidil, tamsulosin, and silodosin in patients undergoing PI. Patients were randomized and received either naftopidil, tamsulosin, or silodosin. Treatment began 1 day after PI and continued for 1 year. The primary efficacy variables were the changes in total International Prostate Symptom Score (IPSS) and postvoid residual urine (PVR). The secondary efficacy variables were changes in IPSS storage score and IPSS voiding score from baseline to set points during the study (1, 3, 6, and 12 months). RESULTS: Two hundred twelve patients were evaluated in this study between June 2006 and February 2009: 71, 70, and 71 patients in the naftopidil, tamsulosin, and silodosin groups, respectively. With respect to the primary efficacy variables, the mean changes in the total IPSS at 1 month after PI in the naftopidil, tamsulosin, and silodosin groups were +10.3, +8.9, and +7.5, respectively. There were significantly greater decreases with silodosin than naftopidil at 1 month in the total IPSS. The mean changes in the PVR at 6 months were +14.6, +23.7, and +5.7 mL in the naftopidil, tamsulosin, and silodosin groups, respectively; silodosin showed a significant improvement in the PVR at 6 months vs. tamsulosin. With respect to the secondary efficacy variables, the mean changes in the IPSS voiding score at 1 month in the naftopidil, tamsulosin, and silodosin groups were +6.5, +5.6, and +4.5, respectively; silodosin showed a significant improvement in the IPSS voiding score at 1 month vs. naftopidil. CONCLUSIONS: Silodosin has a greater impact on improving PI induced lower urinary tract symptoms than the other two agents. PMID- 21664069 TI - Comparative toxicity and dosimetric profile of whole-pelvis versus prostate bed only intensity-modulated radiation therapy after prostatectomy. AB - PURPOSE: To assess whether whole-pelvis (WP) intensity modulated radiation therapy (IMRT) for prostate cancer (PCa) after prostatectomy is associated with increased toxicity compared to prostate-bed only (PB) IMRT. METHODS AND MATERIALS: All patients (n = 67) undergoing postprostatectomy IMRT to 70.2 Gy at our institution from January 2006 to January 2009 with minimum 12-month follow-up were divided into WP (n = 36) and PB (n = 31) comparison groups. WP patients received initial pelvic nodal IMRT to 45 Gy. Pretreatment demographics, bladder and rectal dose-volume histograms, and maximum genitourinary (GU) and gastrointestinal (GI) toxicities were compared. Logistic regression models evaluated uni- and multivariate associations between pretreatment demographics and toxicities. RESULTS: Pretreatment demographics including age and comorbidities were similar between groups. WP patients had higher Gleason scores, T stages, and preoperative prostate-specific antigen (PSA) levels, and more WP patients underwent androgen deprivation therapy (ADT). WP minimum (Dmin) and mean bladder doses, bladder volumes receiving more than 5 Gy (V5) and V20, rectal Dmin, and PB bladder and rectal V65 were significantly increased. Maximum acute GI toxicity was Grade 2 and was increased for WP (61%) vs. PB (29%) patients (p = 0.001); there was no significant difference in acute Grade >=2 GU toxicity (22% WP vs. 10% PB; p = 0.193), late Grade >=2 GI toxicity (3% WP vs. 0% PB; p = 0.678), or late Grade >=2 GU toxicity (28% WP vs. 19% PB; p = 0.274) with 25 month median follow-up (range, 12-44 months). On multivariate analysis, long-term ADT use was associated with Grade >=2 late GU toxicity (p = 0.02). CONCLUSION: Despite dosimetric differences in irradiated bowel, bladder, and rectum, WP IMRT resulted only in clinically significant increased acute GI toxicity in comparison to that with PB IMRT, with no differences in GU or late GI toxicity. PMID- 21664070 TI - Comparison of IGRT registration strategies for optimal coverage of primary lung tumors and involved nodes based on multiple four-dimensional CT scans obtained throughout the radiotherapy course. AB - PURPOSE: To investigate the impact of primary tumor and involved lymph node (LN) geometry (centroid, shape, volume) on internal target volume (ITV) throughout treatment for locally advanced non-small cell lung cancer using weekly four dimensional computed tomography (4DCT). METHODS AND MATERIALS: Eleven patients with advanced non-small cell lung cancer were treated using image-guided radiotherapy with acquisition of weekly 10-Phase 4DCTs (n = 51). Initial ITV was based on planning 4DCT. Master-ITV incorporated target geometry across the entire treatment (all 4DCTs). Geographic miss was defined as the % Master-ITV positioned outside of the initial planning ITV after registration is complete. Registration strategies considered were bony (B), primary tumor soft tissue alone (T), and registration based on primary tumor and involved LNs (T_LN). RESULTS: The % geographic miss for the primary tumor, mediastinal, and hilar lymph nodes based on each registration strategy were (1) B: 30%, 30%, 30%; (2) T: 21%, 40%, 36%; and (3) T_LN: 26%, 26%, 27%. Mean geographic expansions to encompass 100% of the primary tumor and involved LNs were 1.2 +/- 0.7 cm and 0.8 +/- 0.3 cm, respectively, for B and T_LN. Primary and involved LN expansions were 0.7 +/- 0.5 cm and 1.1 +/- 0.5 cm for T. CONCLUSION: T is best for solitary targets. When treatments include primary tumor and LNs, B and T_LN provide more comprehensive geographic coverage. We have identified high % geographic miss when considering multiple registration strategies. The dosimetric implications are the subject of future study. PMID- 21664071 TI - Reconstructive treatment of soft tissue sarcoma of the upper extremity. AB - Limb-sparing surgery is currently the cornerstone of treatment for most patients with soft-tissue sarcoma of the upper extremity. To achieve the best outcome, the reconstructive surgeon must be part of a multidisciplinary team and is required to have a thorough understanding of the whole treatment concept. This article provides an update for the current surgical management of patients with soft tissue sarcoma of the upper extremity. Relevant nonsurgical aspects are also highlighted. PMID- 21664072 TI - Flexor tendon repair with a knotless barbed suture: a comparative biomechanical study. AB - PURPOSE: To test the hypothesis that a flexor tendon repair with only a knotless barbed suture technique provides a repair with a greater maximal load to failure and 2-mm gapping resistance than a traditional technique using a 4-strand core plus a running-locking epitendinous suture. METHODS: We assigned 41 fresh-frozen cadaveric flexor digitorum profundus tendons for repair by either a traditional technique using a 4-strand core (Tajima and horizontal mattress) plus a running locking epitendinous suture (n = 20) or a bidirectional barbed suture technique using a knotless, 4-strand core secured with 3 transverse passes (n = 21). A biomechanical study was performed on each tendon-suture construct and the tendons were linearly distracted to failure at 100 mm/min. The maximal tensile load to failure, 2-mm gapping tensile load, and mode of failure were determined and statistically compared. RESULTS: The average maximal load to failure was not significantly different between the traditional repair (48 +/- 12 N) and the barbed suture repair (50 +/- 14 N). The average 2-mm gapping load was also insignificantly different between the traditional repair (42 +/- 12 N) and the barbed suture repair (32 +/- 9 N). The traditional repair failed by knot unraveling and suture rupture 35% and 65% of the time, respectively. The barbed suture repair failed by suture pull-out and rupture 67% and 33% of the time, respectively. The average load to failure by suture rupture was insignificantly different between the traditional repair (51 +/- 13 N) and the barbed suture repair (63 +/- 16 N). The average load to failure by knot unraveling using the traditional repair was 43 +/- 11 N, whereas the average load to failure by suture pull-out using the barbed suture repair was 43 +/- 8 N. CONCLUSIONS: The barbed suture repair did not demonstrate a significant difference in maximal load to failure and 2-mm gapping resistance compared with the traditional method of repair. CLINICAL RELEVANCE: This study examines the biomechanical differences between 2 types of flexor-tendon repair, which can help guide the surgical management for these injuries. PMID- 21664073 TI - Computed tomography osteoabsorptiometry alterations in stress distribution patterns through the wrist after radial shortening osteotomy for Kienbock disease. AB - PURPOSE: The distribution pattern of subchondral bone density is considered to closely reflect the stress distribution across a joint under physiological loading conditions. Our purpose was to determine alterations in the distribution pattern of subchondral bone density across the distal articular surfaces of the radius and the ulna in patients with Kienbock disease after radial shortening. METHODS: We collected preoperative and postoperative computed tomography (CT) image data from 7 wrists of 7 patients who had undergone radial shortening for Kienbock disease. We measured the distribution of subchondral bone density through the distal articular surface of the radius and the ulna using a CT osteoabsorptiometry method. The obtained data were quantitatively assessed by calculating the high-density area ratio of the entire radiocarpal joint surface, scaphoid fossa, lunate fossa, and distal ulnar surface. RESULTS: At the mean postoperative period of 27 months, the mean high-density area ratio in the entire distal articular surface of the radius significantly decreased from 0.413 preoperatively to 0.141 postoperatively. The postoperative value in each fossa demonstrated a significant reduction from 0.253 to 0.096 in the scaphoid fossa and from 0.160 to 0.045 in the lunate fossa. No significant alteration in the value was found in the distal ulna at follow-up. CONCLUSIONS: Our CT osteoabsorptiometry analysis suggests that the distribution of subchondral bone density in both scaphoid and lunate fossae notably decreases after radial shortening. This indicates that radial shortening unloads the lunate by reducing the actual stress across the distal articular surface of the radius in subjects with Kienbock disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 21664074 TI - Pasteurella multocida lipopolysaccharide: the long and the short of it. AB - Pasteurella multocida is a capsulated, gram-negative cocco-bacillus that can cause serious disease in a wide range of mammals and birds. P. multocida strains are classified into 16 serovars based on lipopolysaccharide (LPS) antigens. LPS is an essential virulence factor of P. multocida; mutants expressing severely truncated LPS are completely attenuated in chickens. LPS is also a major immunogen of P. multocida and protection against infections caused by P. multocida is generally considered to be serovar specific. In this review we summarize current knowledge of the structure and genetics of LPS assembly of P. multocida strains belonging to five different serovars. These include strains belonging to serovars 1 and 3, the most common serovars found in the poultry industry, and strains belonging serovars 2 and 5, the serovars associated with bovine haemorrhagic septicaemia outbreaks. A number of the serovars are genetically related; serovars 1 and 14 share the same LPS outer core biosynthesis locus, but due to a mutation within the phosphocholine biosynthesis gene, pcgA, the serovar 14 strain produces a truncated LPS structure. Similarly serovars 2 and 5 share an identical LPS outer core locus and express near-identical LPS structures. However, due to a single point mutation in the phosphoethanolamine (PEtn) transferase gene, lpt_3, the serovar 2 strain does not elaborate a PEtn residue on heptose II. Knowledge of the genetic basis for the LPS structures expressed by P. multocida will facilitate the development of rapid molecular methods for typing and diagnosis and will be essential for a rational approach to vaccine formulation. PMID- 21664075 TI - Expression and secretion of the RTX-toxin GtxA among members of the genus Gallibacterium. AB - Strains from genus Gallibacterium colonize and occasionally cause disease in a range of bird species. The seven species identified vary with respect to haemolytic activity: Gallibacterium genomospecies 1 and 2 are haemolytic, while G. anatis comprise both haemolytic and nonhaemolytic strains. The remaining species are all non-haemolytic. We previously reported that G. anatis strain 12656-12 expresses an atypical RTX-toxin (repeat in toxin), GtxA, responsible for the haemolytic activity and likely to be a major virulence factor. The aim of this study was to investigate the basis of the variation in haemolytic activity observed among Gallibacterium species and strains. Using PCR and dot blotting we found that the gtxA gene was absent from non-haemolytic Gallibacterium species, but present in Gallibacterium genomospecies 1 and 2. Surprisingly, gtxA was present in both haemolytic and non-haemolytic strains of G. anatis. However, in two out of seven of the non-haemolytic G. anatis strains, gtxA was interrupted by an insertion sequence. We identified a new type I secretion system locus (gtxEBD) and showed that this locus is required for export of GtxA. The gtxEBD locus was identified in all strains possessing gtxA, thus, lack of export system genes cannot explain the non-haemolytic phenotype. Instead we examined expression of gtxA at both the transcript- and protein level by Northern- and Western blotting and found that expression of gtxA varied significantly between strains. In conclusion, we have shown that differences in haemolytic properties among strains of Gallibacterium may be explained by both genotypic differences and by differential expression. PMID- 21664076 TI - HtpG is involved in the pathogenesis of Edwardsiella tarda. AB - Hsp90 is a molecular chaperone that is involved in diverse cellular processes including protein folding/repairing and signal transduction. Edwardsiella tarda is a serious fish pathogen that affects fish aquaculture worldwide. The aim of this study was to investigate the potential importance of HtpG, the prokaryotic homologue of Hsp90, in the pathogenesis of E. tarda. E. tarda HtpG is 627-residue in length and contains domain structures that are conserved among Hsp90 family members. Quantitative real time RT-PCR analysis indicated that expression of htpG is induced by heat shock and oxidative stress. Recombinant HtpG (rHtpG) purified from Escherichia coli exhibits apparent ATPase activity, which is optimal at 40 degrees C. Mutation of htpG (i) affects bacterial growth at elevated temperature and renders the cells more sensitive to stress induced by reactive oxygen species, (ii) causes dramatic reduction in blood dissemination and general bacterial virulence, (iii) weakens the ability of E. tarda to block head kidney macrophage activation and to resist against the bactericidal effect of macrophages, and (iv) upregulates the expression of pro-inflammatory cytokines in macrophages. Taken together, these results indicate that HtpG is a biologically active protein that is required for E. tarda to cope with various stress conditions especially that encountered in vivo the host system during infection. PMID- 21664077 TI - Effects of tetracycline and zinc on selection of methicillin-resistant Staphylococcus aureus (MRSA) sequence type 398 in pigs. AB - An in vivo experiment was conducted to evaluate the effects of tetracycline and zinc on pig colonization and transmission of methicillin-resistant Staphylococcus aureus (MRSA) sequence type (ST) 398. Eight piglets naturally colonized with MRSA ST398 and 8 MRSA-negative piglets of the same age and breed were assigned to three groups treated with tetracycline and zinc (Group 1), zinc (Group 2) or tetracycline alone (Group 3) and one non-treated group (Group 4), each containing two MRSA-positive and two MRSA-negative animals. Two additional non-treated control groups composed of only MRSA-positive (Group 5) and MRSA-negative (Group 6) animals were used to check for stability of MRSA carriage status. Nasal swabs and environmental wipes were collected on Days 0, 7, 14, and 21, and the occurrence of MRSA in each sample was quantified by bacteriological counts on BrillianceTM MRSA agar. Significantly higher nasal MRSA counts were observed in the zinc-treated (p=0.015) and tetracycline-treated (p=0.008) animals compared to the non-treated animals. Environmental MRSA counts appeared to increase over time in Groups 1 and 2 but such an increase was not statistically significant. MRSA negative animals housed with MRSA-positive animals became positive in all groups, whereas the carriage status of the animals in Groups 5 and 6 did not change. This study demonstrates that feed supplemented with tetracycline or zinc increases the numbers of MRSA ST398 in the nasal cavity of pigs. Transmission of MRSA from positive to negative animals housed within the same pen was not influenced by exposure to these agents. PMID- 21664078 TI - Efficacy of a pandemic (H1N1) 2009 virus vaccine in pigs against the pandemic influenza virus is superior to commercially available swine influenza vaccines. AB - In April 2009 a new influenza A/H1N1 strain, currently named "pandemic (H1N1) influenza 2009" (H1N1v), started the first official pandemic in humans since 1968. Several incursions of this virus in pig herds have also been reported from all over the world. Vaccination of pigs may be an option to reduce exposure of human contacts with infected pigs, thereby preventing cross-species transfer, but also to protect pigs themselves, should this virus cause damage in the pig population. Three swine influenza vaccines, two of them commercially available and one experimental, were therefore tested and compared for their efficacy against an H1N1v challenge. One of the commercial vaccines is based on an American classical H1N1 influenza strain, the other is based on a European avian H1N1 influenza strain. The experimental vaccine is based on reassortant virus NYMC X179A (containing the hemagglutinin (HA) and neuraminidase (NA) genes of A/California/7/2009 (H1N1v) and the internal genes of A/Puerto Rico/8/34 (H1N1)). Excretion of infectious virus was reduced by 0.5-3 log(10) by the commercial vaccines, depending on vaccine and sample type. Both vaccines were able to reduce virus replication especially in the lower respiratory tract, with less pathological lesions in vaccinated and subsequently challenged pigs than in unvaccinated controls. In pigs vaccinated with the experimental vaccine, excretion levels of infectious virus in nasal and oropharyngeal swabs, were at or below 1 log(10)TCID(50) per swab and lasted for only 1 or 2 days. An inactivated vaccine containing the HA and NA of an H1N1v is able to protect pigs from an infection with H1N1v, whereas swine influenza vaccines that are currently available are of limited efficaciousness. Whether vaccination of pigs against H1N1v will become opportune remains to be seen and will depend on future evolution of this strain in the pig population. Close monitoring of the pig population, focussing on presence and evolution of influenza strains on a cross border level would therefore be advisable. PMID- 21664079 TI - Embryo transfer and sex determination following superovulated hinds inseminated with frozen-thawed sex-sorted Y sperm or unsorted semen in Wapiti (Cervus elaphus songaricus). AB - The aim of this study was to evaluate embryo production in superovulated wapiti hinds inseminated with either Y-sorted or unsorted semen. Eighteen hinds were allocated to three treatment groups: AI following multiple ovulation (CIDR/FSH) with 10*10(6) Y-sorted frozen-thawed semen (Y group, n=6), or 10*10(6) and 100*10(6) unsorted frozen-thawed semen for the unsorted (n=6) and the control group (n=6). The embryos from the sixth day following insemination were collected and classified. Fifteen embryos from the unsorted or the control group, and four embryos from the Y group were sex determinated based on DNA analysis of the amelogenin gene. Twenty-one embryos from the Y group and 42 embryos from the unsorted or the control group were transferred into 21 and 42 synchronized recipients via standard procedures on 6th day post estrus, respectively. There were no significant differences in the number of recovered eggs, transferable embryos, degenerated embryos or unfertilized oocytes per hind among the three groups of the control (9.2+/-3.6, 4.7+/-1.9, 3.0+/-2.0, 1.5+/-1.4), the unsorted (8.2+/-1.9, 4.8+/-0.7, 1.7+/-1.0, 1.7+/-1.0) and the Y group (8.8+/-4.2, 4.2+/ 1.8, 2.2+/-1.2, 2.5+/-2.1), respectively (P>0.05). The sex ratio of embryos from the Y group (4M/0F) was significantly (P<0.05) distinct from that of the unsorted and control group (8M/7F). The sex ratio of the offspring from sexed embryos (8M/0F) was deviated significantly (P<0.05) from that of the non-sexed embryos (11M/9F). In conclusion, the results suggested that the male embryos of predicted sex can be achieved with AI of sex-sorted cryopreserved sperm. PCR amplification using the amelogenin gene primers can be applied to DNA analysis of micro samples from wapiti embryo biopsies for sex identification. The male offspring can be produced after transferred with the male embryos of predicted sex. PMID- 21664080 TI - Application of capillary electrophoresis to examination of color inkjet printing inks for forensic purposes. AB - In the process of questioned document examination, the discrimination of inkjet printing inks is becoming more necessary due to increasingly frequent counterfeiting of documents printed by inkjet printers. Therefore, a method based on micellar electrophoretic capillary chromatography (MECC) has been developed and applied to analysis of such inks extracted from paper. With the use of an optimized and validated analytical procedure, multielectropherograms of inks taken from various models of printers made by various producers (Hewlett-Packard, Epson, Brother, Lexmark and Canon) were created. It was shown that effective differentiation of individual inks was possible in terms of migration time, order and specific shapes of characteristic peaks. By comparison of recorded UV-Vis spectra, the identification of main dyes was also achievable. The usefulness of the method was confirmed by an intralaboratory test of utility, in which several forged printouts were successfully examined. The obtained results proved that the proposed procedure is a useful tool that could be applied to ink discrimination and group identification of dyes originating from inkjet printing inks. Consequently, the developed method can be applied in the forensic field, including investigation of the authenticity of documents. PMID- 21664081 TI - The unique histology of methamphetamine cardiomyopathy: a case report. AB - This report describes the histological changes observed in the heart a young methamphetamine abuser who died of heart failure. Most of the microscopic changes in the heart have previously been described in experimental animals, but never clearly illustrated in man. Gross examination of the heart revealed concentric myocardial hypertrophy (heart weight 470 g versus median predicted weight of 312 g). Areas of old myocardial infarction were also evident, along with enzymatic evidence indicating that a new infarct had occurred. Myocardial remodeling was extensive with perivascular and interstitial fibrosis, cellular vacuolization, and ongoing myocyte destruction with proliferation of fibromyocytes in the intestitum. Of note were the widespread, bizarre looking, distorted, cell nuclei. They were reminiscent of those seen in viral-induced dilated congestive cardiomyopathy. Clinical chemical measurements also showed unequivocal evidence of both evolving infarction and profound heart failure, with a BNP > 5000. This pattern has not previously been reported in humans, probably because forensic pathologists rarely examine the hearts of methamphetamine abusers microscopically. If the pattern observed here is typical for methamphetamine induced cardiotoxicity, it could well explain increasing reports of heart failure in methamphetamine abusers. It might also be diagnostic for the disorder. PMID- 21664082 TI - Usefulness of post mortem determination of serum tryptase, histamine and diamine oxidase in the diagnosis of fatal anaphylaxis. AB - The diagnosis of fatal anaphylaxis can be difficult for clinical features may not always be evident in necropsy. Therefore post mortem determination of tryptase and other blood parameters can be helpful in verifying the diagnosis. We compared post mortem tryptase, histamine and diamine oxidase (DAO) serum levels of two patients who had died after a Hymenoptera sting and one patient who died of bronchospasm during anaesthesia with data obtained from 55 control subjects who had died from other causes than anaphylaxis. In the three anaphylactic cases, serum tryptase level was 880, 68 and 200 MUg/l (normal range in living subjects: <11.4 MUg/l), histamine was 37.5, 8.5 and 23.2 ng/ml (normal range: <0.3 ng/ml) and DAO was 1, 30 and 4 U/ml (normal range 10-30 U/ml), respectively. Values in the control group were as follows: tryptase 1-340 MUg/l (mean 24.2 +/- 58.2), histamine 5.0-22.0 ng/ml (mean 14.7 +/- 3.9) and DAO 0-114 U/ml (mean 21.1 +/- 27.8). 19/55 (34.5%) of the controls had elevated tryptase levels >11.4 MUg/l, with four of them showing values >45 MUg/ml. Significantly higher histamine levels were seen in blood samples taken more than 24h post mortem (p<0.05), whereas the timing of blood collection had no effect on tryptase and DAO levels. While moderately elevated tryptase levels are common in post mortem sera, values above 45 MUg/l may support the diagnosis of fatal anaphylaxis. Strongly elevated histamine levels might give an additional clue on fatal anaphylaxis, whereas DAO does not seem to be helpful. PMID- 21664083 TI - Spatially offset Raman spectroscopy (SORS) for the analysis and detection of packaged pharmaceuticals and concealed drugs. AB - Spatially offset Raman spectroscopy (SORS) is a powerful new technique for the non-invasive detection and identification of concealed substances and drugs. Here, we demonstrate the SORS technique in several scenarios that are relevant to customs screening, postal screening, drug detection and forensics applications. The examples include analysis of a multi-layered postal package to identify a concealed substance; identification of an antibiotic capsule inside its plastic blister pack; analysis of an envelope containing a powder; and identification of a drug dissolved in a clear solvent, contained in a non-transparent plastic bottle. As well as providing practical examples of SORS, the results highlight several considerations regarding the use of SORS in the field, including the advantages of different analysis geometries and the ability to tailor instrument parameters and optics to suit different types of packages and samples. We also discuss the features and benefits of SORS in relation to existing Raman techniques, including confocal microscopy, wide area illumination and the conventional backscattered Raman spectroscopy. The results will contribute to the recognition of SORS as a promising method for the rapid, chemically specific analysis and detection of drugs and pharmaceuticals. PMID- 21664084 TI - Reducing the radiation dose for low-dose CT of the paranasal sinuses using iterative reconstruction: feasibility and image quality. AB - PURPOSE: To evaluate image quality of dose-reduced CT of the paranasal-sinus using an iterative reconstruction technique. METHODS: In this study 80 patients (mean age: 46.9+/-18 years) underwent CT of the paranasalsinus (Siemens Definition, Forchheim, Germany), with either standard settings (A: 120 kV, 60 mAs) reconstructed with conventional filtered back projection (FBP) or with tube current-time product lowering of 20%, 40% and 60% (B: 48 mAs, C: 36 mAs and D: 24 mAs) using iterative reconstruction (n=20 each). Subjective image quality was independently assessed by four blinded observers using a semiquantitative five point grading scale (1=poor, 5=excellent). Effective dose was calculated from the dose-length product. Mann-Whitney-U-test was used for statistical analysis. RESULTS: Mean effective dose was 0.28+/-0.03 mSv(A), 0.23+/-0.02 mSv(B), 0.17+/ 0.02 mSv(C) and 0.11+/-0.01 mSv(D) resulting in a maximum dose reduction of 60% with iterative reconstruction technique as compared to the standard low-dose CT. Best image quality was observed at 48 mAs (mean 4.8; p<0.05), whereas standard low-dose CT (A) and maximum dose reduced scans (D) showed no significant difference in subjective image quality (mean 4.37 (A) and 4.31 (B); p=0.72). Interobserver agreement was excellent (kappa values 0.79-0.93). CONCLUSION: As compared to filtered back projection, the iterative reconstruction technique allows for significant dose reduction of up to 60% for paranasal-sinus CT without impairing the diagnostic image quality. PMID- 21664085 TI - The value of MDCT in diagnosis of hyaline-vascular Castleman's disease. AB - PURPOSE: Castleman's disease (CD) is an uncommon entity characterized by a massive growth of lymphoid tissue. There are two types: the hyaline-vascular (HV) type and the plasma cell (PC) type. The purpose of this study was to evaluate the clinical value of multiple detector computed tomography (MDCT) in the diagnosis and planning of treatment for hyaline-vascular CD. MATERIALS AND METHODS: Fifty two cases of confirmed hyaline-vascular CD were retrospectively reviewed. Unenhanced and contrast-enhanced MDCT scans had been performed in all patients, followed by surgery and pathological analysis of the lesion. Original MDCT transverse and reconstructed images were used for image interpretation. Features of the lesion and its adjacent structures were identified. RESULTS: The lesion was present in the thorax of 24 patients and the abdomen in 28. Obvious features of hyaline-vascular CD (especially feeding vessels and draining veins) and its adjacent structures were demonstrated on 52 patients. CONCLUSION: On MDCT imaging, original MDCT transverse and reconstructed images provide an excellent tool for diagnosis of hyaline-vascular CD and have high value in the determination of a treatment plan. PMID- 21664086 TI - Calcified plaque resorptive status as determined by high-resolution ultrasound is predictive of successful conservative management of calcific tendinosis. AB - OBJECTIVE: In patients with calcific tendinosis, the morphology of calcified plaques is associated with response to conservative management. We aimed to determine changes in pain and morphology of plaques in patients with calcific tendinosis and non-arc-shaped plaques identified by high-resolution ultrasonography who received only conservative treatment. METHODS: A total of 33 patients with a mean age of 63.3+/-10.3 years were included. Pain scores at the time of first and follow-up ultrasound were recorded, and the degree of plaque resolution was calculated. RESULTS: At follow-up, 90.9% (30 of 33) of patients reported improvement in pain, and 84.8% (28 of 33) patient had more than 50% elimination of plaques. Most of increased vascularity observed in color Doppler ultrasonography during 1st visit disappeared at follow-up. CONCLUSIONS: In patients with calcific tendinosis, non-arc-shaped plaques determined by high resolution ultrasonography are likely to resolve and conservative management is warranted. PMID- 21664087 TI - The effect of a gadolinium-based contrast agent on diffusion tensor imaging. AB - OBJECTIVE: The aim of this study was to investigate in detail the effect of gadolinium contrast on diffusion tensor imaging scans. As the present literature offers conflicting results, we have included a large selection of indices in the analysis. MATERIALS AND METHODS: Sixteen patients harboring an intra-axial contrast enhancing brain tumor were included in this study. Two diffusion tensor imaging scans were performed-one natively, and the second following a gadolinium contrast agent application. Maps of the invariant indices fractional anisotropy (FA), linear, planar, and spherical indices, trace, eigenvalues lambda(1), lambda(2), lambda(3) as well as of the components of the diffusion tensor matrix Dxx, Dyy, Dzz, Dxy, Dxz and Dyz were co-registered and compared statistically with matching ROI pairs in the contrast enhancing areas, peritumoral edema and the normal appearing white matter. RESULTS: We have observed a significant increase in the FA and disproportional decrease of the eigenvalues in the post contrast scans. In accordance with these findings, the spherical index was decreased and the linear and planar indices were increased. There was a significant decrease of all diagonal components of the diffusion tensor matrix. These changes have been strongest in the contrast enhancing areas, but there were also significant changes in the peritumoral edema and the normal appearing white matter. CONCLUSION: Diffusion tensor imaging scans performed after gadolinium contrast agent administration may display artificially increased FA values due to disproportional changes of the measured eigenvalues. The distortion of the diffusion measurement is strongest in, but not limited to the contrasting areas. PMID- 21664088 TI - Sweeping under controlled electroosmotic flow and micellar electrokinetic chromatography for on-line concentration and determination of trace phlorizin and quercitrin in urine samples. AB - A novel sweeping under controlled electroosmotic flow scheme was developed for preconcentration and determination of neutral compounds by micellar electrokinetic chromatography (MEKC). An anionic surfactant, sodium dodecyl sulfate (SDS), was added into the buffer for sweeping and separation. By controlled electroosmotic flow (EOF) equal to the counter electrophoretic flow, the surfactants were at an immobile state in capillary. The neutral analytes with sample solution was injected electroosmotically into capillary and swept by SDS micelle for essentially an unlimited volume. The injected sample plug lengths for phlorizin and quercitrin under 18 kV for 70 min were experimentally estimated as 1532 cm, corresponding to 51-fold the effective capillary length. The sweeping under controlled EOF scheme resulted in increased detection factors for phlorizin and quercitrin of 2.3 * 104 and 2.1 * 104 using 70 min injection relative to a traditional pressure injection. The proposed method has been adopted to analyze trace phlorizin and quercitrin in urine samples successfully. PMID- 21664089 TI - Investigation and structural elucidation of a process related impurity in candesartan cilexetil by LC/ESI-ITMS and NMR. AB - Four impurities were detected in candesartan cilexetil bulk drug samples by HPLC and LC/MS. These impurities were marked as CDC-I, II, III and IV. One of the impurities CDC-II was unknown and has not been reported previously. An optimized method using liquid chromatography coupled with electrospray ionization ion trap mass spectrometry (LC/ESI-ITMS) in positive ion mode has been developed to carry out structural identification of unknown impurity. Based on mass spectrometric data and synthetic specifics the structure of CDC-II was proposed as 2-ethoxy-1 [[2'-(1-ethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 carboxylic acid ethyl ester. The impurity was isolated by semi-preparative HPLC and structure was confirmed by NMR spectroscopy. The plausible mechanism for the formation of impurities is also discussed. PMID- 21664090 TI - Incidence of asymptomatic intracranial embolic events after pulmonary vein isolation: comparison of different atrial fibrillation ablation technologies in a multicenter study. AB - OBJECTIVES: We compared the safety of different devices by screening for subclinical intracranial embolic events after pulmonary vein isolation with either conventional irrigated radiofrequency (RF) or cryoballoon or multielectrode phased RF pulmonary vein ablation catheter (PVAC). BACKGROUND: New devices specifically designed to facilitate pulmonary vein isolation procedures have recently been introduced. METHODS: This prospective, observational, multicenter study included patients with symptomatic atrial fibrillation referred for pulmonary vein isolation. Ablation was performed using 1 of the 3 catheters. Strict periprocedural anticoagulation, with intravenous heparin during ablation to achieve an activated clotting time >300 s, was ensured in all patients. Cerebral magnetic resonance imaging was performed before and after ablation. RESULTS: Seventy-four patients were included in the study: 27 in the irrigated RF group, 23 in the cryoballoon group, and 24 in the PVAC group. Total procedure times were 198 +/- 50 min, 174 +/- 35 min, and 124 +/- 32 min, respectively (p < 0.001 for PVAC vs. irrigated RF and cryoballoon). Findings on neurological examination were normal in all patients before and after ablation. Post-procedure magnetic resonance imaging detected a single new embolic lesion in 2 of 27 patients in the irrigated RF group (7.4%) and in 1 of 23 in the cryoballoon group (4.3%). However, in the PVAC group 9 of 24 patients (37.5%) demonstrated 2.7 +/- 1.3 new lesions each (p = 0.003 for the presence of new embolic events among the 3 groups). CONCLUSIONS: The PVAC is associated with a significantly higher incidence of subclinical intracranial embolic events. Further study of the causes and significance of these emboli is required to determine the safety of the PVAC. PMID- 21664091 TI - Shock bowel caused by neurogenic shock: computed tomography findings. PMID- 21664092 TI - Sex-based outcomes after endovascular repair of thoracic aortic aneurysms. AB - INTRODUCTION: Unlike with abdominal aortic aneurysms (AAA), women appear to have an almost comparable incidence as men for thoracic aortic aneurysms (TAA). However, the extent to which a patient's sex influences endograft treatment of TAA has not been reported. The current study analyzes the influence of sex on the endovascular management of TAAs. METHODS: A total of 421 patients (265 men and 156 women) were identified as part of the TAG (W. L. Gore and Associates, Flagstaff, Ariz) thoracic stent graft trials. Preoperative risk factors, intraoperative events, and 365-day follow-up data were analyzed. RESULTS: Among 18 different preoperative risk factors evaluated, women were less likely to have prior vascular procedures (38.9% vs 55.3%; P = .004). A trend was noted toward lower rates of coronary artery disease (41.3% vs 51.2%; P = .09) and smoking (77.8% vs 85.6%; P = .08). Women were also more likely to be nonwhite (81.4% vs 87.9%; P = .007). Women had a smaller mean external iliac vessel diameter (7.1 vs 9.0 mm; P < .001), resulting in 24.4% vs 6.0% conduit use (P < .001) for device delivery. Local access site complications were significantly higher in women (14.1% vs 4.5%; P < .001). No difference was noted between sexes in the technical success rate (device delivery and successful aneurysm exclusion) or the major adverse event rate at 30 days (26.3% vs 20.4%; P = .18). The overall length of stay was 5.5 +/- 6.2 days for female patients vs 4.8 +/- 13.0 days (P < .001). No sex-related difference was noted in endoleak rate, aneurysm rupture, prosthetic migration, or aneurysm diameter change at 365 days. CONCLUSIONS: No significant differences in major outcomes were noted between men and women treated with endovascular repair of TAA at 1 month and 1 year. Women have more vascular complications, which are associated with smaller access vessels. A lower threshold for using conduits in women may be a more prudent approach. PMID- 21664094 TI - Technical endovascular highlights for crossing the difficult aortic bifurcation. AB - Effective endovascular treatment requires successful vascular access to reach the targeted lesion. When the targeted lesion is infrainguinal in location, the vascular access options include the ipsilateral antegrade femoral approach, the contralateral retrograde femoral approach, or the transbrachial approach. The contralateral retrograde femoral route remains the most commonly used approach but may be challenging, particularly in the settings of a scarred groin or a difficult aortic bifurcation. The purpose of this article is to provide technical tips for the challenges encountered in obtaining contralateral femoral access for peripheral interventions with a difficult aortic bifurcation. PMID- 21664093 TI - Low lifetime recreational activity is a risk factor for peripheral arterial disease. AB - BACKGROUND: The relationship between lifetime physical activity and the risk of developing peripheral arterial disease (PAD) is not known. METHODS: We studied 1381 patients referred for elective coronary angiography in a point prevalence analysis. PAD was defined as ankle-brachial index (ABI) <0.9 at the time or a history of revascularization of the lower extremities regardless of ABI measure. We used a validated physical activity questionnaire to retrospectively measure each patient's lifetime recreational activity (LRA). Multivariate and logistic regression analyses were used to assess the independent association of LRA to ABI and the presence of PAD. RESULTS: PAD was present in 19% (n = 258) of all subjects. Subjects reporting no regular LRA had greater diastolic blood pressure and were more likely to be female. They had lower average ABI, and a higher proportion had PAD (25.6%). In a regression model, including traditional risk factors and LRA, multivariate analysis showed that age (P < .001), female gender (P < .001), systolic blood pressure (P = .014), fasting glucose (P < .001), serum triglycerides (P = .02), and cumulative pack years (P < .001) were independent negative predictors of ABI, and LRA was a positive predictor of ABI (P < .001). History of sedentary lifestyle independently increased the odds ratio for PAD (odds ratio, 0.46; 95% confidence interval, 1.01-2.10) when assessed by logistic regression. Intriguingly, there is a correlation between physical activity and gender, such that women with low LRA are at greatest risk. CONCLUSION: Recalled LRA is positively correlated to ABI and associated with PAD. Whereas the mechanism for this effect is not clear, LRA may be a useful clinical screening tool for PAD risk, and strategies to increase adult recreational activity may reduce the burden of PAD later in life. PMID- 21664095 TI - Efficacy of covered stent placement for central venous occlusive disease in hemodialysis patients. AB - OBJECTIVES: Covered stents have been proposed as an endovascular option for recalcitrant cases of hemodialysis-related central venous occlusive disease (CVOD). This study evaluated the efficacy and durability of covered stents in treating CVOD to preserve a functional dialysis access circuit. METHODS: A retrospective review was performed of all patients with clinically significant CVOD who were treated by placement of covered stents from April 2007 to September 2010. Demographics, lesion locations and anatomic characteristics, stent graft, and access patency rates were determined. Complications, reinterventions, and factors influencing their outcomes were examined. RESULTS: In 25 patients (56% men; mean age, 57 +/- 29 years) with CVOD, covered stents were used in 20 to treat symptomatic venous hypertension or in 5 at the time of access creation to enable functionality. The target lesion was accessed via the dialysis access site or the common femoral vein. The Viabahn endoprosthesis (W. L. Gore and Associates, Flagstaff, Ariz) was used in 24 patients (average size and length, 11 mm * 5 cm) and a 13-mm * 5-cm Fluency covered stent (Bard Peripheral Vascular, Tempe, Ariz) was implanted in 1 patient. Technical success was 100%, and resolution of arm edema occurred after covered stent deployment in symptomatic patients. Two postprocedural cases (8%) of thrombosis occurred, one within 30 days and another at 3 months. Both required percutaneous thrombectomy and percutaneous transluminal angioplasty (PTA). Three additional patients (12%) required PTA due to restenosis in one of the ends of the device. Covered stent primary patency (PP), assisted primary patency (APP), and secondary patency (SP) were 56%, 86%, and 100% at 12 months, respectively. Access patency rates at 12 months were 29%, 85%, and 94% for PP, APP, and SP, respectively, in patients that received a covered stent for access salvage; patency rates were 74%, 85%, and 94% for PP, APP, and SP, respectively, in patients in whom the access was created after the venous outflow restoration. CONCLUSIONS: Placement of covered stents for hemodialysis-related CVOD is safe, effective in relieving symptoms, and enabled functionality of new dialysis access circuits. Further prospective and randomized studies are necessary to determine whether covered stents provide superior long-term results to those achieved with PTA and bare metal stents. PMID- 21664097 TI - Factors influencing survival in patients with breast cancer and single or solitary brain metastasis. AB - AIM: To perform a comprehensive analysis of patients with breast cancer and solitary or single brain metastasis and to analyze factors influencing survival from brain metastasis. METHODS: One hundred consecutive patients with single or solitary brain metastasis were treated in one institution in the years 2003-2009. Brain lesions were diagnosed by magnetic resonance imaging (MRI). A total of 57% of patients underwent resection of brain metastasis, 95% of patients received whole-brain radiation therapy (WBRT) and 67% were treated systemically after WBRT. RESULTS: Median survival from the detection of brain metastasis was 13 months and 28% of patients survived for 2 years. In 29 patients with solitary brain metastasis, median survival was 20 months (2-80 months) and in 71 patients with single brain metastasis it was 11 months (1-79 months) p = 0.01. Median survival from brain metastasis in patients with Recursive Partitioning Analysis Radiation Therapy Oncology Group (RPA RTOG) prognostic class I, II and III was 22 months (4-80 months), 13 months (2-79 months) and 6 months (0.4-28 months), respectively, p < 0.0001. Median survival from brain metastasis in triple negative, HER2, luminal B and luminal A subtypes was 11 months, 13 months, 16 months and 15 months, respectively (p = 0.60). Multivariate analysis revealed that RPA RTOG prognostic class I, neurosurgery and systemic therapy after WBRT were factors that correlated with survival. CONCLUSIONS: In patients with one metastatic lesion in the brain, affiliation to RPA RTOG prognostic class I and intensive local and systemic treatment had a strong correlation with survival. There was no significant correlation between biological subtype of cancer and survival. PMID- 21664098 TI - Expression of cysteine-rich 61 is correlated with poor prognosis in patients with esophageal squamous cell carcinoma. AB - INTRODUCTION: Cysteine-rich 61 (Cyr61), a secreted protein belonged to the CCN family, was involved in the progression of many cancers. The purpose of this study was to explore the clinical significance of Cyr61 expression in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: Cyr61 expression was detected on tissue microarrays of ESCC samples in 372 cases by using immunohistochemical staining. Survival analysis was assessed by the Kaplan-Meier analysis. Relative risk was evaluated by the multivariate Cox proportional hazards model. RESULTS: The staining pattern of Cyr61 was heterogeneous and varied from negative to intense expression in a cytoplasmic distribution. Kaplan Meier analysis revealed that expression of Cyr61 was related to poor survival of ESCC patients (P = 0.001). Further analysis revealed that Cyr61 high-expression was related to poorer overall survival of patients in stage I/II (P = 0.001); but did not effect the overall survival of patients in stage III/IV. Univariate and multivariate analysis suggested that Cyr61 expression status was an independent prognostic factor for ESCC (P = 0.001). DISCUSSION: Cyr61 might play important roles in the progression of ESCC. Cyr61 is a new biomarker to predict the prognosis of ESCC patients. PMID- 21664099 TI - Two-year quality of life after breast cancer surgery: a comparison of three surgical procedures. AB - PURPOSE: To analyze longitudinal changes in each subscale of a quality of life (QOL) measure and to explore their relationships to effective QOL predictors in breast cancer surgery patients. PATIENTS AND METHODS: This prospective study analyzed 172 patients at two tertiary academic hospitals. All patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its supplementary breast cancer measure (QLQ BR23) at baseline and at 1 and 2 years postoperatively. The 95% confidence intervals for differences in responsiveness estimates were derived by bootstrap estimation. Scores derived by these instruments were interpreted by generalized estimating equation (GEE) before and after surgery. RESULTS: A 2-year follow-up survey of the examined population revealed significant (P < 0.05) improvement in each QOL subscale. In both postoperative surveys, effect size was largest in the QLQ subscales for patients who had received mastectomy with reconstruction and lowest in those who had received modified radical mastectomy. After adjusting for time effects and baseline predictors, GEE approaches revealed the following explanatory variables for QOL: time, type of surgical procedure, age, chemotherapy, radiotherapy, hormone therapy, and preoperative functional status. CONCLUSIONS: When evaluating QOL after breast cancer surgery, several factors other than the surgery itself should be considered. Patients should also be advised that their postoperative QOL might depend not only on the success of their operations, but also on their preoperative functional status. PMID- 21664100 TI - Economic evaluation of palivizumab in children with congenital heart disease: a Canadian perspective. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of bronchiolitis in infants. In children with congenital heart disease (CHD), it is associated with significant morbidity and mortality. Palivizumab is a monoclonal antibody that reduces the number of RSV-associated hospitalizations in children with CHD. We sought to assess cost savings and cost-effectiveness of palivizumab in children < 2 years old with hemodynamically significant CHD in a provincially administered RSV prophylaxis program. METHODS: A cohort of children who received palivizumab (N = 292) from 2003-2007 was compared to a historical cohort of children (N = 412) from 1998-2003 who met the eligibility criteria for palivizumab prior to initiation of the prophylaxis program. Direct and indirect costs and benefits were determined. RESULTS: The direct and indirect costs in the historical cohort were $838 per patient season compared to $9130 per patient season in the palivizumab cohort. Risk of admission was reduced by 42%, and days in hospital were reduced by 83%. The incremental cost of the RSV prophylaxis program was $8292 per patient for 1 RSV season. The incremental cost to prevent 1 day of hospitalization was $15,514. The cost of palivizumab accounted for 87.9% of the cost of prophylaxis. CONCLUSIONS: Palivizumab is clinically effective; however, the cost was exceptionally high relative to the outcomes in this population. Given the financial constraints in a public health care setting, more strict criteria for patient selection or reduced drug costs would improve the cost-effectiveness of RSV prophylaxis. PMID- 21664101 TI - [Undernutrition and quality of life in non small cell lung cancer patients]. AB - Cancer is related to a deterioration of nutritional status and quality of life (QoL), but the extent of these conditions in patients with Non Small Cell Lung Cancer (NSCLC) has not been studied. The aim of the present study was to assess the association between QoL and undernutrition in NSCLC patients. Nutritional status was evaluated with Patient Generated - Subjective Global Assessment and QoL using the European Organization for Research and Treatment of Cancer Quality of Life - C30 and also with the specific module for lung cancer patients. A consecutive sample of fifty six patients diagnosed with NSCLC was evaluated. A high proportion of patients is undernourished (35.7%), 1.8% in early stages vs 33.9% in advanced stages of disease. Undernutrition is related to measured dimensions of QoL: lack of appetite (rho=0.70), fatigue (rho=0.54), nausea and vomiting (rho=0.52) and constipation (rho=0.56). Undernourished patients have worse global health status, physical, emotional, social and role functioning. Patients with NSCLC have high frequency of undernutrition in advanced stages of disease. Undernourished patients present more symptoms, a worse global health status/QoL, physical, role, emotional and social functioning than patients without undernutrition. Undernutrition is associated with worse QoL, specifically in the parameters: appetite loss, nausea and vomiting, constipation and fatigue. PMID- 21664102 TI - Renal replacement therapy in prolonged mechanical ventilation patients with renal failure in Taiwan. AB - BACKGROUND: Renal failure requiring renal replacement therapy (RRT) is associated with a high mortality rate in intensive care unit (ICU) patients. Little information is available on the outcomes of patients having prolonged mechanical ventilation (PMV) in addition to RRT. The purpose of this study was to investigate the impact of RRT in PMV patients. METHODS: This was an observational, retrospective study in the 24-bed respiratory care center (RCC) of Chang Gung Memorial Hospital, Taiwan, between May 2001 and April 2007. The end points were weaning rate and survival rate at the RCC. RESULTS: Of the 1301 RCC patients, 157 patients (13.7%) underwent RRT. The RRT patients had lower successful weaning rate (39.5% vs 58.4%, P < .001) and RCC survival rate (45.9% vs 71.9%, P < .001) compared with without-RRT patients. The successful weaning rates of end-stage renal disease (ESRD) patients, patients with RRT initiated at the ICU and continued at RCC, and patients whose RRT was initiated at the RCC were 49.2%, 39.1%, and 22.2%, respectively. The RCC survival rates were 50.8%, 47.8%, and 29.6%, respectively. The odds ratios of successful weaning rate and survival rate were 0.295 (95% confidence interval, 0.105-0.833; P = .021) and 0.407 (95% confidence interval, 0.155-1.021; P = .069) for patients whose RRT was initiated at the RCC vs ESRD patients. CONCLUSION: The present study demonstrates that the need for RRT had a negative impact on weaning and mortality in PMV patients compared with patients without RRT. Patients who had RRT initiated at the RCC had a significantly lower weaning rate compared with ESRD patients. PMID- 21664103 TI - Differences between early and late drop-outs from treatment for obsessive compulsive disorder. AB - To examine characteristics of drop-outs from treatment for obsessive-compulsive disorder (OCD), we studied 121 participants who underwent exposure or cognitive treatment, either alone or with fluvoxamine. OCD symptoms were assessed at pre treatment, post-treatment, and at every session. No differences in attrition were found between treatment conditions. Drop-outs from treatment (n=31) were divided into early (before session 6) and late (session 6 or after) drop-outs. We found that early drop-outs had more severe OCD symptoms at termination compared to completers, whereas late drop-outs did not differ from treatment completers. Higher levels of depressive symptoms were associated with early drop-outs, and lower levels with completers. These findings suggest that individuals with high levels of pretreatment depression are at risk for early drop-out with elevated OCD symptoms. Conversly, late drop-outs may be treatment responders who drop out after experiencing substantial improvement. Implications for allocation of resources for attrition prevention are discussed. PMID- 21664105 TI - The Autism Spectrum Screening Questionnaire (ASSQ)-Revised Extended Version (ASSQ REV): an instrument for better capturing the autism phenotype in girls? A preliminary study involving 191 clinical cases and community controls. AB - We wanted to develop and validate an extension of the Autism Spectrum Screening Questionnaire (ASSQ)-the ASSQ Revised Extended Version (ASSQ-REV)--for better capturing the female phenotype of autism spectrum disorders (ASD). Clinic girls and Clinic boys, most of whom with ASD and/or attention-deficit/hyperactivity disorder (ADHD), and Community girls without a clinical diagnosis of any kind of neuropsychiatric disorder were compared on the results of the parent-rated ASSQ and on a new set of items (ASSQ-GIRL). The ASSQ-REV discriminated well between cases and non-cases. Certain single ASSQ-GIRL items were much more typical of girls than of boys with ASD. The most striking of these were "avoids demands", "very determined", "careless with physical appearance and dress" and "interacts mostly with younger children". The issue of whether or not there is a gender specific ASD for phenotype is discussed. PMID- 21664104 TI - Massive transfusion protocols for patients with substantial hemorrhage. AB - Transfusion medicine for the resuscitation of patients with massive hemorrhage has recently advanced from reactive, supportive treatment with crystalloid and red blood cell therapy to use of standardized massive transfusion protocols (MTPs). Through MTPs, medical facilities are able to standardize the most effective posthemorrhage treatments and execute them rapidly while reducing potential waste of blood products. Damage control resuscitation is an example of an MTP, where patients are (1) allowed more permissive hypotension, (2) spared large volumes of crystalloid/colloid therapy (through low volume resuscitation), and (3) transfused with blood products preemptively using a balanced ratio of plasma and platelets to red blood cells. This focused approach improves the timely availability of blood components during resuscitation. However, the use of MTPs remains controversial. This review describes published experiences with MTPs and illustrates the potential value of several MTPs currently utilized by academic transfusion services. PMID- 21664106 TI - Cutting edge assessment of the impact of autoimmunity on female reproductive success. AB - There, likely, is no more controversial issue in reproductive medicine than the effects of autoimmunity on female reproductive success. Published studies are, therefore, often biased. We performed PubMed, Google Scholar and Medline searches for the years 2000-2010 under various key words and phrases, referring to effects of autoimmunity/autoimmune diseases on pregnancy/pregnancy outcomes/pregnancy rates/reproduction/reproductive outcomes/fertility/infertility/fertility treatments/infertility treatments, and a number of similar terms. Reference lists of selected manuscripts were evaluated for additional, potential references. All selected manuscripts were reviewed by at least one author (N.G.). Opinions were reached based on preferential review of only selected studies, which offered data, primarily developed in pursuit of unrelated scientific questions. Data from various medical fields point, surprisingly effectively, toward significant impacts of autoimmunity on female reproductive success. Autoimmunity not only increases miscarriage risks but also reduces female fecundity and infertility treatment success. A, likely, reason why differences of opinion have persisted is that effects are primarily observed in genetically predisposed women, with specific fragile X mental retardation 1 (FMR1) genotypes. This discovery coincides with recently increasing appreciation of the importance of the long arm of the X chromosome (Xq) in control of functional ovarian reserve (reflective of female fertility) and autoimmunity, with FMR1at Xq27.3, located at cross roads of both. Autoimmune effects on female reproductive success deserve recognition. Further investigations must not ignore patient stratification, based on ovarian FMR1 genotypes. Genetic definition of high-risk patients should lead to development of successful therapeutic interventions. PMID- 21664108 TI - ASIC1a polymorphism is associated with temporal lobe epilepsy. AB - Recent in vitro and in vivo data show that acid-sensing ion channel 1a (ASIC1a) activation enhances neuronal excitability in the hippocampus and neocortex, indicating that ASIC1a might play a role in the generation and maintenance of epileptic seizures. The aim of this study was to investigate association of the ASIC1a gene with temporal lobe epilepsy (TLE) for the first time. Six tag single nucleotide polymorphisms (SNPs) of the ASIC1a gene were selected and genotyped using polymerase chain reaction-restriction fragment length polymorphism in 560 TLE patients and 401 healthy controls. There was a significant allelic and genotypic association between rs844347:A>C and TLE compared with controls. The rs844347-A allele frequency was 88.1% in the patients and 83.0% in control subjects (OR=1.516, 95% CI 1.142-2.013, p=0.004). Furthermore, the haplotype analysis revealed a significant association with TLE. The results of this study demonstrate for the first time an association between an ASC1a variant allele and TLE in a Han Chinese population. PMID- 21664109 TI - Laser-induced primary and secondary hemostasis dynamics and mechanisms in relation to selective photothermolysis of port wine stains. AB - BACKGROUND: Superficial vascular anomalies such as port wine stains are commonly treated by selective photothermolysis (SP). The endovascular laser-tissue interactions underlying SP are governed by a photothermal response (thermocoagulation of blood) and a hemodynamic response (thrombosis). Currently it is not known whether the hemodynamic response encompasses both primary and secondary hemostasis, which platelet receptors are involved, and what the SP induced thrombosis kinetics are in low-flow venules. OBJECTIVES: To (1) define the role and kinetics of primary and secondary hemostasis in laser-induced thrombus formation and (2) determine which key platelet surface receptors are involved in the hemodynamic response. METHODS: 532-nm laser-irradiated hamster dorsal skin fold venules were studied by intravital fluorescence microscopy following fluorescent labeling of platelets with 5(6)-carboxyfluorescein. Heparin and fluorescently labeled anti-glycoprotein Ib-alpha (GPIbalpha) and anti-P selectin antibodies were administered to investigate the role of coagulation and platelet receptors, respectively. Lesional sizes were quantified by software. RESULTS: Laser irradiation consistently produced sub-occlusive thermal coagula. Thrombosis was triggered in all irradiated venules in a thermal coagulum independent manner and peaked at 6.25min post-irradiation. Heparin decreased the maximum thrombus size and caused thrombosis to reach a maximum at 1.25min. Immunoblocking of GPIbalpha abated the extent of thrombosis, whereas immunoblocking of P-selectin had no effect. CONCLUSIONS: The hemodynamic response ensues the photothermal response in a thermal coagulum-independent manner and involves primary and secondary hemostasis. Primary hemostasis is mediated by constitutively expressed GPIbalpha but not by activation-dependent P-selectin. PMID- 21664110 TI - Non-susceptibility to tigecycline in enterococci from hospitalised patients, food products and community sources. AB - In this study, the in vitro activity of tigecycline against 1140 enterococci collected from humans, food products, animals and the environment in Portugal (1996-2008) was analysed. Ten isolates (seven Enterococcus faecalis and three Enterococcus spp.) non-susceptible to tigecycline (minimum inhibitory concentrations of 0.5-1.0 mg/L), which were also resistant to tetracycline and minocycline, were mostly observed in samples collected before the introduction of tigecycline in the therapeutic arsenal. The E. faecalis isolates were recovered from hospitalised patients (n=2; ST319/CC2 and ST34), healthy humans (n=2; ST21/CC21), chicken meat (n=1; ST260) as well as from two swine samples. The remaining isolates were also recovered from chicken meat (n=1; Enterococcus gallinarum) and swine (n=2; Enterococcus hirae and Enterococcus spp.). Recovery of enterococcal isolates with reduced susceptibility to tigecycline amongst different reservoirs, including animals for food consumption, suggests that selection of tigecycline-resistant isolates by antibiotics other than tigecycline might occur in non-clinical settings. PMID- 21664111 TI - Polymeric emulsion and crosslink-mediated synthesis of super-stable nanoparticles as sustained-release anti-tuberculosis drug carriers. AB - This study focused on evaluating four emulsion-based processing strategies for polymeric nanoparticle synthesis to explicate the mechanisms of nanoparticle formation and the influence on achieving sustained-release of two anti tuberculosis drugs, isoniazid and rifampicin. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were formulated with and without sorbitan mono-oleate as a stabilizer using emulsion-solvent-surfactant-evaporation (ESSE) and emulsion solvent-evaporation (ESE) approaches. An alginate solution gelled by ionic crosslinking with calcium chloride was employed to prepare alginate hydrogel nanoparticles via reverse-emulsion-cationic-gelification (RECG) and reverse emulsion-surfactant-cationic-gelification (RESCG) approaches. In vitro drug release analysis was performed. The size, zeta potential and morphology of the nanoparticles were analyzed. Molecular mechanics energy relationships (MMER) were employed to explore the spatial disposition of alginate and PLGA with respect to the emulsifying profile of sorbitan monooleate and to corroborate the experimental findings. Results revealed that particle size of the PLGA nanoparticles was influenced by the stabilizer concentration. Nanoparticles synthesized by the ESSE approach had smaller sizes of 240+/-8.7 nm and 195.5+/ 5.4 nm for rifampicin- and isoniazid-loaded nanoparticles, respectively. This was a substantial size reduction from nanoparticles generated by the ESE approach (>1000 nm). The RESCG approach produced stable and higher nanoparticle yields with desirable size (277+/-1.0 nm; 289+/-1.2 nm), a low polydispersity index (27.1+/-0.3 mV; 28.5+/-0.5 mV) and drug entrapment efficiency of 73% and 75% for isoniazid and rifampicin, respectively. Drug release from the ESSE and RESCG synthesized nanoparticles displayed desirable release of the two anti-TB drugs with sustained zero-order kinetics over a period of 8h. MMER supported the mechanisms of nanoparticle formation with a sphericalized interlaced network configuration. PMID- 21664112 TI - The effects of cyclophosphamide, melatonin and carvedilol on neural tube and skeletal system of mice fetuses in prenatal period. AB - Cyclophosphamide (CP) as an alkylating agent is used for treatment of cancer and to prevent rejection of tissue transplantation. There are many reports that the teratogenic effects of cyclophosphamide can be prevented by application of antioxidant drugs and stimulation of the maternal immune system. Also, there is some evidence that melatonin and carvedilol are antioxidant.Therefore, in this study, the prophylactic effects of melatonin and carvedilol on teratogenic effects of CP was compared. This study was performed on 31 pregnant mice that were divided into six groups. The control group received normal saline and test groups received CP (20mg/kg), carvedilol (5mg/kg), melatonin (10mg/kg), CP (20mg/kg) pluscarvedilol (5mg/kg) and CP (20mg/kg) plus melatonin (10mg/kg) intraperitoneally on the 10th day of gestation, respectively. Fetuses were collected on the 19th day of gestation and after determination of weight and length; they were stained by Alizarin red-Alcian blue method. Cleft palate, spina bifida and exencephalyincidence were 62.79%, 62.79% and 30.23% in fetuses of mice that received only CP. Cleft palate,spina bifida, exencephaly, and incidence were 45.45%, 9.09% and 0% in group which received CP plus carvedilol (5mg/kg), respectively.However, cleft palate, spina bifida and exencephalyincidence were 62.5%, 45.83% and 4.16% range in the group which received CP plus melatonin (10mg/kg), respectively. In addition, theincidence of skeletal anomalies including limb, vertebral, and sternaldefects were decreased by melatonin and carvedilol. The mean weight and length of animal fetuses that had received melatonin and carvedilol were significantly greater than those receiving only CP. It is concluded; carvedilol has a significant effect in preventing CP-induced malformations and in cases like CP-induced exencephaly, cleft palate and spina bifidahas better prophylactic effect than melatonin, but this improvement is not significant. PMID- 21664113 TI - Anti-depression effects of Danggui-Shaoyao-San, a fixed combination of Traditional Chinese Medicine, on depression model in mice and rats. AB - Anti-depression effects of Danggui-Shaoyao-San (DSS, 1.8-7.2g/kg, orally), a famous Chinese compound prescription with a fixed combination, on forced swimming test (FST) and chronic unpredictable mild stress (CUMS) model were investigated. DSS (7.2g/kg, orally, 7 days) shortened immobility time in FST model and DSS (3.6 or 7.2g/kg, orally, 21 days) increased the open-field activities and the percentage of sugar preference in CUMS model. DSS (7.2g/kg, orally, 21 days) also decreased the content of arginine vasopressin (AVP) in the pituitary and the expression of AVP mRNA in hypothalamus compared with the stress control group. These results demonstrated for the first time DSS has anti-depression effect and it may be influencing the central AVP system. PMID- 21664115 TI - Aging of hematopoietic stem cells: Intrinsic changes or micro-environmental effects? AB - During development hematopoietic stem cells (HSCs) expand in number and persist throughout life by undergoing self-renewing divisions. Nevertheless, the hematopoietic system does not escape the negative effects of aging, suggesting that self-renewal is not complete. A fundamental issue in stem cell biology relates to such age-dependent loss of stem cell activity. Both stem cell intrinsic factors and extrinsic factors associated with an aging micro environment could contribute to aging of the hematopoietic system. Recently, changes in the clonal composition of the HSC compartment during aging have been put forward as a key factor. Here, we discuss these recent developments and speculate how they may be of clinical relevance. PMID- 21664114 TI - Brain protection by rapeseed oil in magnesium-deficient mice. AB - Diets given for 30 days with various mono-(MUFA) and poly-(PUFA) unsaturated fatty acid contents were evaluated for brain protection in magnesium-deficient mice: a commercial and three synthetic diets (n-6PUFA, n-3PUFA and MUFA-based chows enriched with 5% corn/sunflower oils 1:3, with 5% rapeseed oil and with 5% high oleic acid sunflower oil/sunflower oil 7:3, respectively). Unlike magnesium deprivation, they induced significant differences in brain and erythrocyte membrane phospholipid fatty acid compositions. n-3PUFA but not other diets protected magnesium-deficient mice against hyperactivity and moderately towards maximal electroshock- and NMDA-induced seizures. This diet also inhibited audiogenic seizures by 50%, preventing animal deaths. Because, like n-6PUFA diet, matched control MUFA diet failed to induce brain protections, alpha-linolenate (ALA) rather than reduced n-6 PUFA diet content is concluded to cause n-3PUFA neuroprotection. Present in vivo data also corroborate literature in vitro inhibition of T type calcium channels by n-3 PUFA, adding basis to ALA supplementation in human anti-epileptic/neuroprotective strategies. PMID- 21664116 TI - Exploration of the specific structural characteristics of thiol-modified single stranded DNA self-assembled monolayers on gold by a simple model. AB - This paper proposed a simple hexagonal model to explore the specific structural characteristics of thiol-modified single-stranded DNA (ss-DNA) self-assembled monolayers (SAMs) on gold substrate. The calibrated gyration diameter d'(g)(d'(g)=rd(g)) was used to quantify the size of ss-DNA molecules on gold by introducing a calibrating factor r, where d(g) was ss-DNA gyration diameter in solution. Based on the model, the interfacial parameters of ss-DNA-SAMs on gold assembled under different ionic strength were obtained theoretically. The ss-DNA SAMs were assembled on gold under different concentrations of C(NaCl) and six important electrochemical parameters were used to validate the model experimentally, which include surface coverage (Gamma(m)), interfacial capacitance (C), phase angle (F(1 Hz)), ions transfer resistance (R(it)(*)), current density difference (Deltaj) and charge transfer resistance (R(ct)) from chronocoulometry (CC), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Three main aspects were included in this paper: (1) construction of a simple hexagonal model to describe the specific structural characteristics of ss-DNA-SAMs on gold; (2) calculation of the calibrating factor r by CC experiments and several important conclusions from the simple model; and (3) confirmation of the simple model by our experimental results and literature reports. The simple model may provide an important reference for optimizing the design of DNA sensor. PMID- 21664117 TI - Electrochemical immunosensor detection of antigliadin antibodies from real human serum. AB - The determination of antigliadin antibodies from human serum samples is of vital importance for the diagnosis of an autoimmune disease such as celiac disease. An electrochemical immunosensor that mimics traditional ELISA type architecture has been constructed for the detection of antigliadin antibodies with control over the orientation and packing of gliadin antigen molecules on the surface of gold electrodes. The orientation of the antigen on the surface has been achieved using a carboxylic-ended bipodal alkanethiol that is covalently linked with amino groups of the antigen protein. The bipodal thiol presents a long poly(ethyleneglycol)-modified chain that acts as an excellent non-specific adsorption barrier. The bipodal nature of the thiol ensured a good spacing and hence good diffusion properties of electroactive species through the self assembled monolayer, which is vital for the efficiency of the constructed electrochemical immunosensor. The electrochemical immunosensor was characterized using surface plasmon resonance as well as electrochemical impedance spectroscopy. Amperometric evaluation of the sensor with polyclonal antigliadin antibodies showed stable and reproducible low limits of detection (46 ng/mL; % RSD = 8.2, n = 5). The behaviour and performance of the electrochemical immunosensor with more complex matrixes such as reference serum solutions and real patient samples was evaluated and compared with commercial ELISA kits demonstrating an excellent degree of correlation in thirty minutes total assay time; the electrochemical immunosensor not only delivers a positive or negative result, it allows the estimation of semi-quantitative antibody contents based on the comparison against clinical reference solutions. PMID- 21664118 TI - Direct surface plasmon resonance immunosensor for in situ detection of benzoylecgonine, the major cocaine metabolite. AB - In this paper the development of the first direct surface plasmon resonance (SPR) immunoassay for the detection of benzoylecgonine (BZE) is described. Immunosensor chips consisting of a high affinity monoclonal anti-BZE-antibody (anti-BZE-Ab) immobilized at high density to a sensor chip were prepared. First, BZE detection in Hepes buffer was achieved by direct, real time monitoring of the binding between BZE in solution and the surface bound antibody. The detection protocol was based on calibration curves obtained from reaction rate data and end point data analysis of sensorgrams registered after injection of a series of known BZE concentrations over the chips. Moreover, immunosensor accuracy, reproducibility, stability and robustness were tested to demonstrate their good performance as reusable devices. The immunosensor was used for BZE detection in oral fluid (OF) showing that, within 180 s, our immunoassay detects BZE concentrations as low as 4 MUg/L in filtered OF-buffer (1:4) samples. This value is remarkably lower than current cut off levels established by the Substance Abuse and Mental Health Services Administration. These results manifest the potential use of this direct SPR immunoassay for the in situ sensitive detection of recent cocaine abuse, of utility in roadside drug OF testing. Moreover, it exemplifies the high potential of direct SPR immunoassays for the rapid, sensitive detection of small molecules in contrast with the more established indirect methods. PMID- 21664119 TI - A bio-inspired two-layer multiple-walled carbon nanotube-polymer composite sensor array and a bio-inspired fast-adaptive readout circuit for a portable electronic nose. AB - We report a fully integrated, portable, battery-operated electronic nose system comprising a bio-inspired two-layer multiple-walled carbon nanotube (MWNT) polymer composite sensor array, a bio-inspired fast-adaptive readout circuit, and a microprocessor embedded with a pattern recognition algorithm. The two-layer MWNT-polymer composite sensor is simple to operate, and the membrane quality can be easily controlled. These two-layer membranes have improved sensitivity and stability. The fast-adaptive readout circuit responds to the sensor response, while tuning out the long-term constant background humidity, temperature, and odors. This portable electronic nose system successfully classified four complex alcohol samples 40 times for each sample; these samples were sake, sorghum liquor, medical liquor, and whisky. PMID- 21664120 TI - Poly(HEMA) brushes emerging as a new platform for direct detection of food pathogen in milk samples. AB - Surface plasmon resonance (SPR) biosensors capable of in real time detection of Cronobacter at concentrations down to 106 cells mL-1 in samples of consumer fresh whole fat milk, powder whole-fat milk preparation, and powder infant formulation were developed for the first time. Antibodies against Cronobacter were covalently attached onto polymer brushes of poly(2-hydroxyethyl methacrylate) (poly(HEMA)) grafted from the SPR chip surface. The lowest detection limit, 104 cells mL-1, was achieved in phosphate buffered saline (pH 7.4) with sensors prepared by covalent immobilization of the same antibodies onto a self assembled monolayer (SAM) of hexa(ethylene glycol) undecanethiol (EG6). However, when the EG6 based sensors were challenged with milk samples the non-specific response due to the deposition of non-targeted compounds from the milk samples was much higher than the specific response to Cronobacter hampering the detection in milk. Similar interfering fouling was observed on antifouling polymer brushes of hydroxy-capped oligoethylene glycol methacrylate and even a 10 times higher fouling was observed on the widely used SAM of mixed hydroxy- and carboxy-terminated alkanethiols. Only poly(HEMA) brushes totally suppressed the fouling from milk samples. The robust well-controlled surface initiated atom transfer radical polymerization of HEMA allowed the preparation of highly dense brushes with a minimal thickness so that the capture of antigens by the antibodies immobilized on the brush layer could take place close to the gold SPR surface to provide a stronger optical response while the fouling was still suppressed. A minimum thickness of 19 nm of poly(HEMA) brush layer was necessary to suppress completely non-specific sensor response to fouling from milk. PMID- 21664121 TI - A new set up for multi-analyte sensing: at-line bio-process monitoring. AB - A multi-analyte sensing device is described, for simultaneous at-line monitoring of glucose, ethanol, pO2-value and cell density. It consists of a dual biosensor, a modified microscope and a fiber optical pO2-sensor that are integrated into a flow analysis (FA) system. The biosensor is based on a conventional thin layer flow-through cell equipped with a gold (Au) dual electrode (serial configuration). The biosensors with no cross-talking were produced by modifying the electrochemical transducers. Each Au surface was initially modified by self assembled monolayer (SAM) of cysteamine. Alcohol oxidase (AOx) and pyranose oxidase (PyOx) were immobilized each onto a gold surface by means of PAMAM (polyamidoamine) dendrimer via glutaraldehyde cross-linking. The responses for glucose and ethanol were linear up to 0.5 mM. The operational stability of the biosensors was very promising, after 11 h continuous operation, only 6.0% of the initial activity was lost. The potential of the described biosensor was demonstrated by parallel determination of ethanol and glucose in yeast fermentation process. Simultaneously the cell density of the culture was monitored with an in situ microscope (ISM), which was integrated into the FA system. Both the used in situ microscope and the image processing algorithm used for the analysis of the acquired image data are described. Furthermore the pO2 value was monitored using a fiber optical sensor, which was embedded in a flow cell. The multi-sensor device allows the at-line monitoring of several process values without the need for further sampling or time consuming offline measurements. PMID- 21664122 TI - Simple colorimetric sensing of trace bleomycin using unmodified gold nanoparticles. AB - A simple colorimetric sensing platform for trace bleomycin (BLM) was proposed with the unmodified gold nanoparticles (AuNPs) as the sensing element. BLM has multiple N-donor functionality and exhibited strong coordination effect on AuNPs, which made it possible for the occurrence of ligand exchange of BLM with the weakly surface-bound citrate ions on AuNPs. Meanwhile, the positively charged BLM molecules further neutralized the surface charge, leading to increased van der Waals attractive force among AuNPs for rapid aggregation. This was reflected by the obvious color change from wine red to blue and rapid aggregation kinetics within 7.5 min. The BLM sensing based on unmodified AuNPs can be seen with the naked eye and monitored by UV-vis extinction spectra. The linear range of the colorimetric sensor for BLM was from 2 to 150 nM. The as-established colorimetric strategy opened a new avenue for trace BLM determination. PMID- 21664124 TI - Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas. AB - Human mesenchymal stem cells (hMSCs) have emerged as attractive cellular vehicles for gene therapy against brain malignancy because of their targeted tropism for cancer and the intrinsic attribute of autologous transplantation. We evaluated the characteristics and therapeutic potential of human adipose tissue-derived MSCs (hAT-MSCs) and prodrug gene therapy against diffuse pontine gliomas. The hAT MSCs were isolated from human adipose tissue and characterised for morphology, surface markers and potential to differentiate into mesenchymal and neuronal lineages. We genetically modified hAT-MSCs to express rabbit carboxylesterase (rCE) enzyme, which can efficiently convert the prodrug CPT-11 (irinotecan-7 ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin), into the active drug SN-38 (7-ethyl-10-hydroxycamptothecin). The migratory capacity of hAT-MSCs expressing rCE (hAT-MSC.rCE), their ability to convert CPT-11 to SN-38 and cytotoxic effect on F98 cells were evaluated in vitro. The therapeutic potential of hAT-MSC.rCE was confirmed using a rat brainstem glioma model. The hAT-MSCs showed fibroblast-like morphology and expressed hMSC-specific markers including CD73, CD90 and CD105. The hAT-MSCs could differentiate into a mesenchymal lineage and transdifferentiate into a neuronal lineage under optimum culture conditions. The hAT-MSC.rCE converted CPT-11 to SN-38 and preserved the tumour tropism of hAT MSCs. Brainstem glioma-bearing rats treated with hAT-MSC.rCE and CPT-11 survived 5d more than rats treated with CPT-11 only (p=0.0018). Our study demonstrates that hAT-MSCs can be easily prepared and genetically modified as cellular vehicles for prodrug gene therapy and that they have therapeutic potential against brainstem gliomas. PMID- 21664123 TI - Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial. AB - BACKGROUND: To evaluate the safety and efficacy of pre-operative chemoradiation, using capecitabine, oxaliplatin and bevacizumab with standard doses of radiation, in patients with high-risk rectal cancer. METHODS: Patients with locally advanced or low rectal cancer were treated with capecitabine 825 mg/m(2) twice daily on days 1-14 and 22-35, oxaliplatin 50mg/m(2) on days 1, 8, 22 and 29, bevacizumab 5mg/kg on days 14, 1, 15 and 29, and radiation 50.4 Gy in 28 fractions including boost. Total mesorectal excision was performed 7-9 weeks after chemoradiation. The primary end-point was complete tumour regression (ypT0NX) by central review. FINDINGS: Forty-two evaluable patients were enrolled, and 38 proceeded to definitive surgery. Eighteen patients (43%) had clinical T4 tumours and/or N2 tumours. Mean relative dose intensity was >90% for all systemic agents, and 97% for radiation. Grade 3/4 diarrhoea occurred in 10 patients (24%) and pain in 4 patients (10%) pre-operatively, while grade 3/4 pain, fatigue and infection were each reported among 5 patients (13%) post-operatively. Re-operation due to complications occurred in 4 patients (11%). Complete tumour regression (ypT0) was seen in 9 patients (23.7%) of which two had N1 disease and the pathological complete response (pCR) rate (ypT0N0) was 18.4%. Central review changed pathologic stage in six cases (16%). INTERPRETATION: In this study, pre-operative bevacizumab added to oxaliplatin, capecitabine and radiation was safe and resulted in a promising tumour regression rate. Surgical complications were closely monitored and occurred with the expected frequency. Central pathology review should be considered for trials with pathologic response as the primary end-point. FUNDING: British Columbia Cancer Agency, Hoffmann-La Roche Canada and Sanofi-Aventis. PMID- 21664125 TI - Poly-ethers from Winogradskyella poriferorum: Antifouling potential, time-course study of production and natural abundance. AB - A sponge-associated bacterium, Winogradskyella poriferorum strain UST030701-295T was cultured up to 100l for extraction of antifouling bioactive compounds. Five poly-ethers were isolated and partially characterized based on nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS); two of them showed inhibitory effects on biofilm formation of marine bacteria and larval settlement of macro-foulers but did not produce any adverse effects on the phenotypes of zebra fish embryos at a concentration of 5MUg ml(-1). The effect of culture duration on the production of the poly-ethers and the bioactivity of the relevant extracts was monitored over a period of 12 days. The total crude poly-ether production increased from day 2 to day 5 and the highest bioactivity was observed on day 3. The poly-ethers were found to be localized in the cellular fraction of the extracts, implying their natural occurrence. The potent bioactivity of these poly-ethers together with their high natural abundance in bacteria makes them promising candidates as ingredients in antifouling applications. PMID- 21664126 TI - Kinetics investigation on the reduction of NO using straw char based on physicochemical characterization. AB - NO reduction using straw-char has been investigated in a fixed bed, and the effects of char-preparation temperature, reduction temperature, char concentration C(char) and NO concentration C(NO) were considered. Straw char was prepared at three temperatures, 873, 1073 and 1273K. The characterization was conducted by employing SEM-EDS, XRD, BET and TGA. Results show that the char prepared at 1073K holds the most developed pore structure and surface area, the best combustion activity, and the highest NO reduction rate. The reduction rate of NO linearly increases with increasing char concentration, but decreases with increasing NO concentration following a power-function relation. A transition temperature region from dynamic-control to diffusion-control is found to be around 1173K. In the dynamic-control region, the apparent activation energy E of char-NO reaction is in the range of 89.78-95.41kJ mol(-1), affected inconspicuously by the char-preparation temperature. The reaction rate between NO and straw-char is given by r(NO)=k(0).exp(-11,069/T).C(NO)(0.89).C(char). PMID- 21664127 TI - Study on the flocs poly-beta-hydroxybutyrate production and process optimization in the bio-flocs technology system. AB - The bio-flocs technology (BFT) was applied in the sequencing batch reactor (SBR) to treat aquaculture wastewater for flocs poly-beta-hydroxybutyrate (PHB) accumulation with alternant anaerobic and aerobic conditions. The statistical modeling approach was used to evaluate system performance and to optimize the flocs PHB yield at batch mode. The results show that all variables have significant impact on the response objective, as well as the interactions of the C/N ratio with the flocs biomass concentration (VSS) and anaerobic time, respectively. By process optimization, approximately 150-200 PHB/VSS (mg.g) of flocs PHB yield was achieved in the range of 4-7g/l of flocs biomass concentration, 15-18 of the C/N ratio and 50-85min of anaerobic time in the BFT systems. The results demonstrated that a suitable flocs PHB yield can be obtained via optimizing the ex-situ operating strategy, which have potential prebiotic value and practical implication for the sustainable aquaculture. PMID- 21664128 TI - Effectiveness of microbial pretreatment by Ceriporiopsis subvermispora on different biomass feedstocks. AB - Different types of feedstocks, including corn stover, wheat straw, soybean straw, switchgrass, and hardwood, were tested to evaluate the effectiveness of fungal pretreatment by Ceriporiopsis subvermispora. After 18-d pretreatment, corn stover, switchgrass, and hardwood were effectively delignified by the fungus through manganese peroxidase and laccase. Correspondingly, glucose yields during enzymatic hydrolysis reached 56.50%, 37.15%, and 24.21%, respectively, which were a 2 to 3-fold increase over those of the raw materials. A further 10-30% increase in glucose yields was observed when pretreatment time extended to 35d. In contrast, cellulose digestibility of wheat straw and soybean straw was not significantly improved by fungal pretreatment. When external carbon sources and enzyme inducers were added during fungal pretreatment of wheat straw and soybean straw, only glucose and malt extract addition improved cellulose digestibility of wheat straw. The cellulose digestibility of soybean straw was not improved. PMID- 21664129 TI - Performance and spatial community succession of an anaerobic baffled reactor treating acetone-butanol-ethanol fermentation wastewater. AB - An anaerobic baffled reactor with four compartments (C1-C4) was successfully used for treatment of acetone-butanol-ethanol fermentation wastewater and methane production. The chemical oxygen demand (COD) removal efficiency was 88.2% with a CH(4) yield of 0.25L/(g COD(removed)) when organic loading rate (OLR) was 5.4kg CODm(-3)d(-1). C1 played the most important role in solvents (acetone, butanol and ethanol) and COD removal. Community structure of C2 was similar to that in C1 at stage 3 with higher OLR, but was similar to those in C3 and C4 at stages 1-2 with lower OLR. This community variation in C2 was consistent with its increased role in COD and solvent removal at stage 3. During community succession from C1 to C4 at stage 3, abundance of Firmicutes (especially OTUs ABRB07 and ABRB10) and Methanoculleus decreased, while Bacteroidetes and Methanocorpusculum became dominant. Thus, ABRB07 coupled with Methanoculleus and/or acetogen (ABRB10) may be key species for solvents degradation. PMID- 21664130 TI - Synthesis of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide as anticancer and anti-inflammatory agents. AB - Thirteen new 2-pyrazoline derivatives bearing benzenesulfonamide moiety (2a-m) were synthesized by condensing appropriate chalcones with 4 hydrazinonbenzenesulfonamide hydrochloride and tested for anticancer and anti inflammatory actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay compounds 2b, 2c, 2e, 2f and 2g exhibited considerable antitumor activities against the entire tested tumor cell lines and showed effective growth inhibition GI(50) (MG-MID) values of 2.63, 2.57, 6.61, 3.31 and 2.57MUM, respectively, beside a cyclostatic activity TGI (MG-MID) 9.54, 8.51, 24.0, 19.9 and 8.71MUM, respectively. Two compounds 2g and 2k showed more potent anti-inflammatory activity than celecoxib at 5h in carrageenan-induced rat paw edema bioassay. These compounds (2g and 2k) proved to have superior gastrointestinal safety profiles as compared to celecoxib, when tested for their ulcerogenic effects. Compounds 2g and 2k showed no inhibition against the enzymatic activity of bovine COX-2 (in vitro). PMID- 21664131 TI - Synthesis and evaluation of highly potent GABA(A) receptor antagonists based on gabazine (SR-95531). AB - A selection of highly potent analogues based on the gabazine structure is described. Their syntheses are carried out in just four steps, and their potencies for antagonism at the GABA(A) receptor were measured. All antagonists showed significantly higher potencies compared to the parent competitive antagonist, gabazine. PMID- 21664132 TI - Thiophenyl oxime-derived phosphonates as nano-molar class C beta-lactamase inhibitors reducing MIC of imipenem against Pseudomonas aeruginosa and Acinetobacter baumannii. AB - The preparation and characterization of a series of thiophenyl oxime phosphonate beta-lactamase inhibitors is described. A number of these analogs were potent and selective inhibitors of class C beta-lactamases from Pseudomonas aeruginosa and Enterobacter cloacae. Compounds 3b and 7 reduced the MIC of imipenem against an AmpC expressing strain of imipenem-resistant P. aeruginosa. A number of the title compounds retained micromolar potency against the class D OXA-40 beta-lactamase from Acinetobacter baumannii and at high concentrations compound 3b was shown to reduce the MIC of imipenem against a highly imipenem-resistant strain of A. baumanii expressing the OXA-40 beta-lactamase. In mice compound 3b exhibited phamacokinetics similar to imipenem. PMID- 21664134 TI - Atomic force microscopy: a nanoscopic window on the cell surface. AB - Atomic force microscopy (AFM) techniques provide a versatile platform for imaging and manipulating living cells to single-molecule resolution, thereby enabling us to address pertinent questions in key areas of cell biology, including cell adhesion and signalling, embryonic and tissue development, cell division and shape, and microbial pathogenesis. In this review, we describe the principles of AFM, and survey recent breakthroughs made in AFM-based cell nanoscopy, showing how the technology has increased our molecular understanding of the organization, mechanics, interactions and processes of the cell surface. We also discuss the advantages and limitations of AFM techniques, and the challenges remaining to be addressed in future research. PMID- 21664135 TI - Conducting a large survey of critical care nurses in Canada: lessons learnt. AB - INTRODUCTION: Survey research provides information regarding clinician opinion, adherence to evidence-based recommendations and practice variation. Yet, the conduct of large surveys can present numerous challenges. Practical challenges such as establishing a sampling strategy consistent with a population's distribution may be anticipated. Additional unanticipated challenges may emerge during survey implementation that require troubleshooting and result in additional costs. OBJECTIVE: Our objective is to inform nurse clinicians and researchers of our experiences in the conduct of a large, Canadian survey of critical care nurses. Specifically, we describe administrative, financial and logistical considerations and challenges. RESULTS: Administrative challenges included negotiation with each provincial/territorial nursing association to facilitate survey distribution. Financial considerations included anticipated and unanticipated costs such as postage, nursing association fees, translation, printing, shipping and research assistant time. Logistical challenges included systematizing survey mail outs and tracking, and translating survey materials and responses for bilingual provinces. CONCLUSION: Conduct of this large national survey required considerable financial resources, time, energy and coordination. We anticipate greater understanding of the work and cost associated with planning and implementing such surveys may inform researchers as well as critical care nurses considering responding to future survey invitations. PMID- 21664133 TI - pRB, a tumor suppressor with a stabilizing presence. AB - The product of the retinoblastoma tumor-susceptibility gene (RB1) is a key regulator of cell proliferation and this function is thought to be central to its tumor suppressive activity. Several studies have demonstrated that inactivation of pRB not only allows inappropriate proliferation but also undermines mitotic fidelity, leading to genome instability and ploidy changes. Such properties promote tumor evolution and correlate with increased resistance to therapeutics and tumor relapse. These observations suggest that inactivation of pRB could contribute to both tumor initiation and progression. Further characterization of the role of pRB in chromosome segregation will provide insight into processes that are misregulated in human tumors and could reveal new therapeutic targets to kill or stall these chromosomally unstable lesions. We review the evidence that pRB promotes genome stability and discuss the mechanisms that probably contribute to this effect. PMID- 21664136 TI - Assessment of minute-by-minute stepping rate of physical activity under free living conditions in female adults. AB - BACKGROUND: The minute-by-minute stepping rate (MMSR) is a unique index of the walking speed. The MMSR under free-living conditions remains unclear. PURPOSE: The purpose of the present investigation was to clarify the physical activity (PA) levels based on MMSR under free-living conditions. METHODS: A total of 85 female volunteers, age from 21 to 91 year, wore a pedometer with a uni-axial accelerometer (Lifecorder, Kenz, Japan) for 7 days consecutively in order to determine the number of steps, the intensity of PA (light intensity PA; LPA, moderate intensity PA; MPA, and vigorous intensity PA; VPA), and the MMSR. Thereafter, the daily time spent in PA at <100, 100 to 129, and 130 steps min(-1) (min day(-1)) was calculated. All experiments were conducted in March 2007. RESULTS: The number of steps, the time spent in LPA, MPA, VPA, PA at <100, 100 to 129, and 130 steps min(-1) were 9275+/-3453 steps day(-1), 71+/-25 min day(-1), 34+/-22 min day(-1), 4+/-6 min day(-1), 295+/-88 min day(-1), 16+/-12 min day( 1), and 4+/-6 min day(-1). The time spent in PA at <100 steps min(-1) positively associated with age (p<0.05). The time spent in PA at 100 to 129 steps min(-1) negatively associated with age (p<0.01). CONCLUSION: The time spent in PA at <130 of steps min(-1) MMSR differs across different age-groups under free-living conditions in female adults. The clinical significance with regards to the age associated changes in MMSR remains unclear. PMID- 21664137 TI - Structure and genetics of circular bacteriocins. AB - Circular bacteriocins are antimicrobial peptides produced by a variety of Gram positive bacteria. They are part of a growing family of ribosomally synthesized peptides with a head-to-tail cyclization of their backbone that are found in mammals, plants, fungi and bacteria and are exceptionally stable. These bacteriocins permeabilize the membrane of sensitive bacteria, causing loss of ions and dissipation of the membrane potential. Most circular bacteriocins probably adopt a common 3D structure consisting of four or five alpha-helices encompassing a hydrophobic core. This review compares the various structures, as well as the gene clusters that encode circular bacteriocins, and discusses the biogenesis of this unique class of bacteriocins. PMID- 21664138 TI - New microtubule polymerization inhibitors comprising a nitrooxymethylphenyl group. AB - We have designed cancer antiproliferative compounds, starting from aniline or phenol derivative, which comprise one or two nitrooxymethylphenyl groups as do the hybrid drugs NCX4040 and NCX530. Compound 2a with p-nitrooxymethylbenzoyl-oxy and -amino groups as well as 8a with a p-nitrooxymethylbenzoylamino group showed more promising effects than NCX4040 against human colon and breast cancer cells. Since 2a and 8a, but not NCX4040, arrested human colon carcinoma HCT116 cells in the M phase, the former two compounds may inhibit cell growth differently from NCX4040. Merged images of immunofluorescence-stained alpha-tubulin and Hoechst stained nuclei in human fibrosarcoma HT1080 cells showed that 2a and 8a disrupted microtubule formation just as did vincristine, the tubulin polymerization inhibitor. In experiments in vivo, the intraperitoneal administration of 8a at 80 mg/kg/day reduced the growth of HCT116 xenografts in nude mice to T/C 55%. PMID- 21664139 TI - Left ventricular pseudoaneurysm after apicoaortic bypass. PMID- 21664140 TI - Lymph node involvement in T1 non-small-cell lung cancer: do not miss radical lymphadenectomy. PMID- 21664141 TI - Evaluation of platelet count after isolated biological aortic valve replacement with Freedom Solo bioprosthesis. AB - OBJECTIVE: The risk of thrombocytopenia in patients undergoing aortic valve replacement (AVR) with the Freedom Solo (FS) bioprosthesis is controversial. The aim of our study was to evaluate the postoperative evolution of platelet count and function after AVR in patients undergoing isolated biological AVR with FS. METHODS: Between May 2005 and June 2010, 322 patients underwent isolated biological AVR. Of these, 116 patients received FS and were compared with 206 patients who received biological valves. Platelet count, mean platelet volume (MPV), and platelet distribution width (PDW) were evaluated at baseline (T0), first (T1), second (T2), and fifth (T3) postoperative days, respectively. RESULTS: Overall in-hospital mortality was 1.5% with no difference between the two groups. Thirty-seven (11.5%) patients developed thrombocytopenia. FS implantation was associated with a higher incidence of thrombocytopenia compared with the control group (24.1% vs 4.4%, p<0.0001). Patients in the FS group showed a lower platelet count than the control group at T1 (99.4+/-38*10(3) MUl(-1) vs 122.5+/-41.6*10(3) MUl(-1), p<0.001), T2 (79.7+/-36.3*10(3) MUl(-1) vs 122.5+/ 43.3*10(3) MUl(-1), p<0.001) and T3 (86.6+/-57.4*10(3) MUl(-1) vs 158.4+/ 55.8*10(3) MUl(-1), p<0.001). Moreover, the FS group also had a higher MPV (11.6+/-0.9 fl vs 11+/-1 fl, p<0.001) and higher PDW (15.1+/-2.3 fl vs 13.9+/-2.1 fl, p<0.001) at T3. In a multivariable analysis, FS (p<0.0001), body surface area (p<0.0001), cardiopulmonary bypass time (p=0.003), and lower preoperative platelet counts (p=0.006) were independent predictors of thrombocytopenia. CONCLUSIONS: The FS valve might increase the risk of thrombocytopenia and platelet activation, in the absence of adverse clinical events. Prospective randomized studies on platelet function need to confirm our data. PMID- 21664143 TI - Editorial comment: Surgery after MitraClip therapy: you can't win them all. PMID- 21664145 TI - Cardiac transplantation with a donor heart rescued from deep hypothermia. PMID- 21664144 TI - Low-dose, once-daily, intraclot injections of alteplase for treatment of acute deep venous thrombosis. AB - PURPOSE: To evaluate the safety and efficacy of once-daily intraclot injections of low doses (<= 10 mg) of tissue plasminogen activator (tPA) for thrombolysis of venous thrombosis. MATERIALS AND METHODS: In prospective studies, 33 patients with subclavian, jugular, and central venous thrombosis (SJ-CVT) (all but two cases associated with central catheters) were treated once a day with <= 4 mg/day of tPA, and 30 patients with acute deep vein thrombosis of the lower extremity (DVT-LE) < 14 days old were treated once a day with <= 10 mg/leg/day of tPA by intraclot "lacing" of thrombus without continuous infusions of tPA. RESULTS: Patency was restored in 26 (79%) of 33 patients with SJ-CVT using an average total dose of 7.1 mg of tPA/per patient and average of 2.1 treatments or days of therapy. Five patients received thrombolytic therapy for SJ-CVT as outpatients. Initial patency was restored in 29 (97%) of 30 patients with acute DVT-LE using an average total dose of 20 mg of tPA per patient over an average of 2.7 treatments/or days per patient. Follow-up imaging examinations at 6 months showed continued patency in 27 (96%)/of 28 patients. There were no major bleeding complications, and no patient required a blood transfusion. CONCLUSIONS: Intraclot injection of low doses of alteplase is effective for acute venous thrombosis, and pharmacokinetic data suggest potentially greater safety. PMID- 21664146 TI - Patients with bipolar disorder show a selective deficit in the episodic simulation of future events. AB - A substantial body of evidence suggests that autobiographical recollection and simulation of future happenings activate a shared neural network. Many of the neural regions implicated in this network are affected in patients with bipolar disorder (BD), showing altered metabolic functioning and/or structural volume abnormalities. Studies of autobiographical recall in BD reveal overgeneralization, where autobiographical memory comprises primarily factual or repeated information as opposed to details specific in time and in place and definitive of re-experiencing. To date, no study has examined whether these deficits extend to future event simulation. We examined the ability of patients with BD and controls to imagine positive, negative and neutral future events using a modified version of the Autobiographical Interview (Levine, Svoboda, Hay, Winocur, & Moscovitch, 2002) that allowed for separation of episodic and non episodic details. Patients were selectively impaired in imagining future positive, negative, and neutral episodic details; simulation of non-episodic details was equivalent across groups. PMID- 21664147 TI - Visible homonyms are ambiguous, subliminal homonyms are not: a close look at priming. AB - Homonyms, i.e. ambiguous words like 'score', have different meanings in different contexts. Previous research indicates that all potential meanings of a homonym are first accessed in parallel before one of the meanings is selected in a competitive race. If these processes are automatic, these processes of selection should even be observed when homonyms are shown subliminally. This study measured the time course of subliminal and supraliminal priming by homonyms with a frequent (dominant) and a rare (subordinate) meaning in a neutral context, using a lexical decision task. In the subliminal condition, priming across prime-target asynchronies ranging from 100 ms to 1.5 s indicated that the dominant meaning of homonyms was facilitated and the subordinate meaning was inhibited. This indicates that selection of meaning was much faster with subliminal presentation than with supraliminal presentation. Awareness of a prime might decelerate an otherwise rapid selection process. PMID- 21664149 TI - Detection of incidental carotid artery calcifications during dental examinations: panoramic radiography as an important aid in dentistry. AB - OBJECTIVE: This study aimed to determine the diagnostic reliability of panoramic radiographs (PRs) in the detection of carotid artery calcifications (CACs) during routine dental examination by comparing them with color Doppler ultrasound (CDUS) examination as the criterion standard. The correlations between CAC formation and systemic diseases, body mass index, smoking, and age were also examined. STUDY DESIGN: A total of 70 patients >40 years old diagnosed with CACs from PRs obtained during routine dental examination between January 2008 and September 2009 and 35 patients with no CACs (control group) were referred for further ultrasound examination. RESULTS: Compared with CDUS examination of 210 carotid arteries in 105 patients, PRs were found to have sensitivity, specificity, and accuracy rates of 79.8%, 81.1%, and 80.5%, respectively, in the diagnosis of CACs. CACs were found to be significantly correlated with chronic diseases, such as hypertension, hyperlipidemia, and heart disease, but not with diabetes mellitus or renal disease. In addition, correlations were found between CACs and smoking and beween CACs and menopause. CONCLUSIONS: The findings of PRs and ultrasound are consistent enough to warrant the referral of patients prediagnosed with suspected CACs from PRs for further medical evaluation. PMID- 21664151 TI - Comparison of Endovac irrigation system with conventional irrigation for removal of intracanal smear layer: an in vitro study. AB - AIM: This study comparatively evaluated the efficacy of Endovac irrigation system with conventional needle irrigation in removing smear layer from the root canal. STUDY DESIGN: Thirty permanent maxillary central incisors were divided into 3 groups of 10 teeth each. In group I, the teeth were instrumented and irrigated by conventional irrigation using 27-gauge irrigation needle. In group II, irrigation was done using Endovac irrigation system. In group III (negative control) chemomechanical preparation was performed using saline solution. Scanning electron microscope evaluation was done for assessment of smear layer removal in the coronal, middle, and apical thirds. RESULTS: Data were analyzed using post hoc test and Kruskal-Wallis test for significance at P < .05. Statistically significant difference was seen between the 2 test groups in smear layer removal from the apical third (3 mm) of the root canal, although no significant difference was seen in the coronal and middle thirds. The most efficient smear layer removal was seen in group II (Endovac) compared with other groups (P < .05). CONCLUSIONS: The study showed significantly better removal of smear layer from the apical third of root canal using Endovac compared with conventional needle irrigation. PMID- 21664153 TI - Comparison between multislice and cone-beam computerized tomography in the volumetric assessment of cleft palate. AB - The aim of this study was to determine the applicability of multislice and cone beam computerized tomography (CT) in the assessment of bone defects in patients with oral clefts. Bone defects were produced in 9 dry skulls to mimic oral clefts. All defects were modeled with wax. The skulls were submitted to multislice and cone-beam CT. Subsequently, physical measurements were obtained by the Archimedes principle of water displacement of wax models. The results demonstrated that multislice and cone-beam CT showed a high efficiency rate and were considered to be effective for volumetric assessment of bone defects. It was also observed that both CT modalities showed excellent results with high reliability in the study of the volume of bone defects, with no difference in performance between them. The clinical applicability of our research has shown these CT modalities to be immediate and direct, and they is important for the diagnosis and therapeutic process of patients with oral cleft. PMID- 21664155 TI - Evaluation of radicular dentin erosion and smear layer removal capacity of Self Adjusting File using different concentrations of sodium hypochlorite as an initial irrigant. AB - OBJECTIVE: The aim of this study was to evaluate Self-Adjusting File (SAF) in the removal of smear layer and impact on the dentin surface using sodium hypochlorite (NaOCl) as an initial irrigation solution at 3 different concentrations combined with 1% EDTA. In addition, the erosive effect of this dual irrigation regime was examined. STUDY DESIGN: Root canal preparations were performed in 30 teeth using the SAF with a continuous irrigation device (Vatea) in a closed system in which the apical foramen was sealed. The vibration mode was on for 5 minutes during the preparation. Three different concentrations of NaOCl (1.3%, 2.6%, and 5.25%) and 1% EDTA were used for continuous irrigation. The final flush was also performed using NaOCl with the vibration mode on. The roots were split longitudinally and subjected to scanning electron microscopy (SEM). The presence of the smear layer was scored using a 5-point scoring system, and the erosive capacity of the irrigants were scored using a 3-point scoring system. RESULTS: The results showed no significant difference in smear layer removal among different concentrations of NaOCl and among the regions. Clean dentin surfaces were observed in 80%, 70%, and 70% with a score of 1 or 2 of the apical thirds using 1.3%, 2.6%, and 5.25% NaOCl, respectively. The 1.3% and 2.6% NaOCl solutions showed similar erosion patterns on the root canal walls (P > .05); however, 5.25% NaOCl caused severe erosion (P < .05). CONCLUSIONS: When using the SAF with continuous irrigation and vibration, lower concentrations of NaOCl and EDTA can be recommended for efficient clinical removal of the smear layer even in the apical thirds and to avoid excessive erosion of root dentin. PMID- 21664154 TI - Differential impairment of vascularization and angiogenesis in bisphosphonate associated osteonecrosis of the jaw-related mucoperiosteal tissue. AB - OBJECTIVES: Impaired vascularization in the etiopathology of aminobisphosphonate associated osteonecrosis of the jaw (BONJ) is assumed, but evidence is lacking. This immunohistochemical study differentiated vascularization and angiogenesis in BONJ-adjacent mucoperiosteal tissue. STUDY DESIGN: Twenty BONJ (after zoledronate treatment) and 20 control mucoperiosteal tissue samples were processed with an autostaining-based alkaline phosphatase-antialkaline phosphatase staining kit. Vascularization was assessed by CD31 staining and angiogenesis-related neovessels by CD105 staining. The ratio of stained capillary area to total area of visible field was assessed. Statistics included Bonferroni adjustment. RESULTS: CD31 stained microvessels were detected in each section and CD105-stained neovessels in each control. BONJ-adjacent mucoperiosteal tissue showed significantly fewer CD105-positive vessels in capillary areas (P < .05) than control samples. CD31 stained capillary area was not significantly reduced in mucoperiosteal BONJ samples. CONCLUSIONS: Angiogenesis is impaired in BONJ-related mucoperiosteal tissue, but vascularization remains unaffected. Vessel remodeling and neovessel formation is delayed in BONJ, resulting in impaired tissue regeneration of bisphosphonate-exposed oral mucosa. PMID- 21664156 TI - Potential of fluid-attenuated inversion recovery (FLAIR) in identification of temporomandibular joint effusion compared with T2-weighted images. AB - OBJECTIVE: The purpose of this study was to determine the potential of fluid attenuated inversion recovery (FLAIR) sequence images in the identification of joint effusion (JE) compared with T2-weighted images. STUDY DESIGN: A total of 31 joints (28 patients) with JE were investigated by magnetic resonance imaging (MRI). Regions of interest were placed over JE, cerebrospinal fluid (CSF), and gray matter (GM) on T2-weighted and FLAIR images and their signal intensities compared. The signal intensity ratios (SIRs) of JE and CSF were calculated with GM as the reference point. The Pearson product-moment correlation coefficient was used for the statistical analysis. RESULTS: The SIR of JE showed a strong correlation between T2-weighted and FLAIR images. However, no correlation was observed for CSF. The average suppression ratio for JE was lower than that for CSF. CONCLUSIONS: MRI using FLAIR sequences revealed that JE was not just water content, but a fluid accumulation containing elements such as protein. Further studies are needed, and FLAIR sequences could be useful for the diagnosis of pain and symptoms of the temporomandibular joint (TMJ). PMID- 21664158 TI - Self-criticism interacts with the affective component of pain to predict depressive symptoms in female patients. AB - This longitudinal study examined the role of the trait of self-criticism as a moderator of the relationship between the affective and sensory components of pain, and depression. One hundred and sixty-three chronic pain patients treated at a specialty pain clinic completed self-report questionnaires at two time points assessing affective and sensory components of pain, depression, and self criticism. Hierarchical linear regression analysis revealed a significant 3-way interaction between self-criticism, affective pain and gender, whereby women with high affective pain and high self-criticism demonstrated elevated levels of depression. Our findings are the first to show within a broad, comprehensive model, that selfcriticism is activated by the affective, but not sensory component of pain in leading to depressive symptoms, and highlight the need to assess patients' personality as part of an effective treatment plan. PMID- 21664157 TI - Genotype and phenotype characterizations in a large cohort of beta-thalassemia heterozygote with different forms of alpha-thalassemia in northeast Thailand. AB - In order to update the molecular basis of beta-thalassemia and describe hematological features among different mutations and the concurrent of alpha- and beta-thalassemias, 849 unrelated beta-thalassemia heterozygotes recruited in northeast Thailand during a prevention and control program were studied. beta- and alpha-thalassemia mutations were investigated using the polymerase chain reaction (PCR)-based technologies and hematological parameters were recorded using standard methods. Seventeen different mutations including both beta(0)- and beta(+) -thalassemias were identified. Eight of these 17 beta-thalassemia alleles accounted for 97.4%, others were found at lower frequencies (<1.0%). Of the 849 cases, 626 were investigated for common alpha-thalassemia mutations and 155 (24.8%) were found to be co-inherited with different forms of alpha-thalassemia. Comparison of the hematological parameters among different beta-thalassemia mutations revealed an increasing trend of MCV and MCH in a group of heterozygous states for the 3.4kb deletion and the A-G substitution at nucleotide (NT) -28. Hb A(2) and Hb F levels in individuals with the 3.4kb deletion were significantly higher than those with other mutations. Interaction of each beta-thalassemia mutation with alpha-thalassemia did not affect the diagnostic ranges of Hb A(2) and Hb F, though the significantly increased MCV and MCH was noted. These findings underline the heterogeneity of beta-thalassemia and the importance of hematological and molecular analyses of both alpha-and beta-thalassemias in the diagnosis and genetic counseling of the couples at-risk of having babies with severe thalassemia diseases in the region. PMID- 21664159 TI - Fast high-resolution 2D correlation spectroscopy in inhomogeneous fields via Hadamard intermolecular multiple quantum coherences technique. AB - Recently, a method based on intermolecular multiple quantum coherences (iMQCs) has been proposed to obtain high-resolution 2D COSY spectra in inhomogeneous fields via 3D acquisitions. However, the very long acquisition time prevents its practical application. To overcome this shortage, the Hadamard technique was applied for the iMQC method in this paper. For the new pulse sequence, the direct frequency-domain excitation is used in the first indirect detection dimension, so the 3D acquisition was replaced by an array of 2D acquisitions. The acquisition time can be reduced to 10 min. The resulting spectra retain useful structural information including chemical shifts and multiplet patterns of J coupling even when the inhomogeneous line broadening leads to overlap of neighboring diagonal resonances in the conventional COSY spectrum. The experimental results are consistent with the theoretical predictions and computer simulations. The new sequence may provide a time-efficient way for the studies of chemical solution in inhomogeneous fields. PMID- 21664160 TI - Investigation of the effect of a variety of pulse errors on spin I=1 quadrupolar alignment echo spectroscopy. AB - We report on an analysis of a well known three-pulse sequence for generating and detecting spin I=1 quadrupolar order when various pulse errors are taken into account. In the situation of a single quadrupolar frequency, such as the case found in a single crystal, we studied the potential leakage of single and/or double quantum coherence when a pulse flip error, finite pulse width effect, RF transient or a resonance offset is present. Our analysis demonstrates that the four-step phase cycling scheme studied is robust in suppressing unwanted double and single quantum coherence as well as Zeeman order that arise from the experimental artifacts, allowing for an unbiased measurement of the quadrupolar alignment relaxation time, T(1Q). This work also reports on distortions in quadrupolar alignment echo spectra in the presence of experimental artifacts in the situation of a powdered sample, by simulation. Using our simulation tool, it is demonstrated that the spectral distortions associated with the pulse artifacts may be minimized, to some extent, by optimally choosing the time between the first two pulses. We highlight experimental results acquired on perdeuterated hexamethylbenzene and polyethylene that demonstrate the efficacy of the phase cycling scheme for suppressing unwanted quantum coherence when measuring T(1Q). It is suggested that one employ two separate pulse sequences when measuring T(1Q) to properly analyze the short time behavior of quadrupolar alignment relaxation data. PMID- 21664161 TI - Growth hormone treatment for two years is safe and effective in adults with Prader-Willi syndrome. AB - OBJECTIVE: Prader-Willi syndrome (PWS) shares similarities with the growth hormone (GH) deficiency syndrome in regards to reduced lean body mass and increased fat mass and several short-term trials with GH treatment have demonstrated beneficial effects on body composition. The aim of the present study was to evaluate the effects and safety of two years of GH therapy in adults with PWS. DESIGN: Forty-three adults (24 women) with genetically verified PWS were included. Blood samples, body composition as measured by computed tomography (CT) and dual-energy x-ray absorptiometry (DXA) were performed at baseline and during two years of continued GH treatment. RESULTS: Thirty-nine patients completed treatment for two years. The GH dosage averaged 0.61 mg/day (range 0.2-1.6). Based upon CT, body composition improved at two years; thigh muscle volume increased 6.7 mL (3.7 to 9.7; P<0.001) whereas abdominal subcutaneous fat volume decreased by 53.3 mL (13.8 to 92.9; P=0.01). By DXA, lean body mass improved 2.8 kg (1.9 to 3.6; P<0.001), whereas fat mass decreased by 3.0 kg (1.1 to 4.8; P=0.003). Lung function as evaluated by peak expiratory flow increased 12% (p<0.001) - indicating improved muscle function. Adverse effects were few. Fifteen out of 39 patients had diabetes (DM; n=4) or impaired glucose tolerance (IGT; n=11) prior to GH treatment. Among the 11 patients with IGT, three reverted to normal glucose tolerance, while three progressed to overt DM at two years of GH treatment. CONCLUSION: The known beneficial effects of GH treatment upon body composition in PWS are maintained during two years continuous treatment. With appropriate control, GH is a safe treatment option in adults with PWS. PMID- 21664162 TI - Case report: low circulating IGF-I levels due to Acid-Labile Subunit deficiency in adulthood are not associated with early development of atherosclerosis and impaired heart function. AB - OBJECTIVE: Decreased insulin-like growth factor-I (IGF-I) levels in adults have been associated with an increased risk of ischemic heart disease and heart failure. It is currently unknown whether patients with low circulating IGF-I levels due to a homozygous acid-labile subunit (IGFALS) gene mutation also have increased risk of cardiovascular disease. Therefore, we evaluated atherosclerotic burden in a 27 year old male patient who was diagnosed with a homozygous IGFALS mutation and consequently had extremely low circulating IGF-I levels. METHODS: Ten year's cardiovascular risk was calculated using the Framingham risk score. Presence of (subclinical) atherosclerosis was assessed using a 64-slice CT scan of the coronary arteries. Cardiac performance was measured by conventional echocardiographic measurements, three dimensional (3D)-echocardiography, and tissue deformation imaging. RESULTS: Despite his extremely low circulating IGF-I levels due to Acid-Labile Subunit (ALS) deficiency, our patient had a low Framingham risk score and no signs of coronary atherosclerosis. Adjusted for physical height, cardiac performance was not impaired compared with healthy subjects. CONCLUSION: The present case report does not lend support to routine cardiovascular screening in patients with extremely low circulating IGF-I levels due to a homozygous IGFALS mutation, when cardiovascular risk is low. PMID- 21664163 TI - [Acknowledged risks in transfusion and impact of taken measures on those risks]. AB - Transfusion is indeed associated with risks that are diverse in nature. Besides, the society expects a risk- and vice-exempt transfusion. During the recent past years, there have been three levels of safety implementation in transfusion: a generalized risk assessment policy; a mastering of processes; standard quality engineering. However, these safety measures have impacts in several ways, such as management and organization, inventory, economics and possibly ethics. All these issues are addressed in the present essay as well as the possible effect of pathogen reduction procedures. PMID- 21664164 TI - Effect of NF-kappaB decoy on insulin resistance of adipocytes from patients with type 2 diabetes mellitus. AB - AIM: This study aimed to investigate whether NF-kappaB contributes to insulin resistance in type 2 diabetes (T2DM). METHODS: Subcutaneous abdominal adipose tissue was obtained from T2DM patients and non-diabetic control subjects. Pre adipocytes were cultured and differentiated into adipocytes in vitro. Upon insulin stimulation, IRS-1 tyrosine and AKT (Ser473) phosphorylation were examined by immunoprecipitation and immunoblotting, while levels of inflammatory mediators IL-6 and MCP-1, and the DNA-binding activity of NF-kappaB, were examined by ELISA and electrophoretic mobility shift assay (EMSA), respectively. NF-kappaB decoy molecules were introduced into T2DM adipocytes, and their effects on all these molecular events evaluated. RESULTS: Compared with cells from non diabetic subjects, adipocytes from T2DM patients showed signs of insulin resistance, with significantly reduced IRS-1 tyrosine and AKT (Ser 473) phosphorylation levels in response to insulin stimulation. At the same time, T2DM cells displayed elevated levels of IL-6 and MCP-1, and NF-kappaB activity. Introduction of NF-kappaB decoy molecules significantly inhibited both IL-6 secretion and NF-kappaB activity, while enhancing insulin-stimulated IRS-1 tyrosine and AKT (Ser473) phosphorylation in T2DM adipocytes. CONCLUSION: Abdominal subcutaneous fat cells from T2DM patients display signs of insulin resistance and microinflammatory status. NF-kappaB decoy molecules inhibited NF kappaB overactivation and also partly reversed insulin resistance. These results provide evidence of a link between inflammation and insulin resistance in T2DM cells, suggesting a potential contribution of inflammation to the mechanism of insulin resistance. PMID- 21664165 TI - [Cancer stem cells: a new target for lung cancer treatment]. AB - Lung cancer remains the leading cause of cancer death. Understanding lung tumours physiopathology should provide opportunity to prevent tumour development or/and improve their therapeutic management. Cancer stem cell theory refers to a subpopulation of cancer cells also named tumour initiating cells that can drive cancer development. Cells presenting these characteristics have been identified and isolated from lung cancer. Exploring cell markers and signalling pathways specific to lung cancer stem cells may lead to progress in therapy and improve the prognosis of patients with lung cancer. Continuous efforts in developing in vitro and in vivo models may yield reliable tools to better understand cancer stem cell abilities and to test new therapeutic targets. Even if some data are in favour of a higher chemo and radioresistance of cancer stem cells this issue remains disputed. Preclinical data on putative cancer stem cell targets are emerging by now. These preliminary studies are critical for the next generation of lung cancer therapies. PMID- 21664166 TI - [Non-Hodgkin lymphoma of the nasopharynx: a report of four cases]. AB - We report four cases of non-Hodgkin lymphoma involving the nasopharynx. Clinical, radiological, histological and treatment modalities are described. The four patients were male and aged 20, 42, 71 and 77 years. The symptoms were nasal obstruction with epistaxis in three cases and a cervical node in the fourth case. The histological type was a non-Hodgkin lymphoma of phenotype B with large cells CD20+ in the four cases. The treatment consisted in radiotherapy and chemotherapy. PMID- 21664167 TI - Functional hypoparathyroidism in postmenopausal women with fragility fracture. AB - INTRODUCTION: Secondary hyperparathyroidism sometimes is lacking despite authentic vitamin D insufficiency (VDI) and the concept of functional hypoparathyroidism with a protective role on bone status has been proposed. Therefore, we tested the hypothesis that its prevalence was very low in a population of women with a peripheral fragility fracture. METHODS: We conducted our study in postmenopausal women, admitted for such a fracture in our Fracture Liaison Service. All had bone mineral density (BMD), biochemical assessment and a medical visit. RESULTS: Two hundred and thirty seven women (72.9+/-11.6-year-old) were included and 90.4% had VDI (25[OH]D<=30 ng/mL). Yet, 87.9% of the latter had normal PTH levels less or equal to 64 ng/L. In this population with VDI (n=214), we found no PTH plateau level related to 25(OH)D. Since a recent study reported an increase in the risk of fracture only when 25(OH)D was below 15 ng/mL, we then used this value as a new threshold. We observed a significant difference in hip BMD between patients with 25(OH)D either less or equal to or greater than 15 ng/mL. However, 81.2% of the formers were still with normal PTH with no difference in BMD whether PTH level was above or within normal range. CONCLUSION: In a population of postmenopausal women with a fragility fracture, we found that 25(OH)D less or equal to 15 ng/mL was associated with significantly lower hip BMD. Even using this low threshold, we found a high prevalence of functional hypoparathyroidism and it was not associated with any difference in hip or spine BMD. Overall, our results do not support the hypothesis of a protective effect of this biological profile. PMID- 21664168 TI - Application of ultrasound as pretreatment for extraction of podophyllotoxin from rhizomes of Podophyllum peltatum. AB - The effect of high-power ultrasound pretreatment on the extraction of podophyllotoxin from Podophyllum peltatum was investigated. Direct sonication by an ultrasound probe horn was applied at 24 kHz and a number of factors were investigated: particle size (0.18-0.6 mm), type of solvent (0-100% aqueous ethanol), ultrasonic treatment time (2-40 min), and power of ultrasound (0-100% power intensity, maximum power: 78 W). The optimal condition of ultrasound was achieved with 0.425-0.6 mm particle size, 10 min sonication time, 35 W ultrasound power, and water as the medium. There was no obvious degradation of podophyllotoxin with ultrasound under the applied conditions, and an improvement in extractability was observed. The SEM microscopic structure change of treated samples disclosed the effect of ultrasound on the tissue cells. The increased pore volume and surface area after ultrasonic treatment also confirmed the positive effect of ultrasound pretreatment on the extraction yield of podophyllotoxin from the plant cells. PMID- 21664169 TI - Enhanced sonochemical degradation of azure B dye by the electroFenton process. AB - The degradation of azure B dye (C15H16ClN3S; AB) has been studied by Fenton, sonolysis and sono-electroFenton processes employing ultrasound at 23 kHz and the electrogeneration of H2O2 at the reticulated vitreous carbon electrode. It was found that the dye degradation followed apparent first-order kinetics in all the degradation processes tested. The rate constant was affected by both the pH of the solution and initial concentration of Fe2+, with the highest degradation obtained at pH between 2.6 and 3. The first-order rate constant decreased in the following order: sono-electroFenton>Fenton>sonolysis. The rate constant for AB degradation by sono-electroFenton is ~10-fold that of sonolysis and ~2-fold the one obtained by Fenton under silent conditions. The chemical oxygen demand was abated ~68% and ~85% by Fenton and sono-electroFenton respectively, achieving AB concentration removal over 90% with both processes. PMID- 21664170 TI - Increased levels of endothelial progenitor cells in Parkinson's disease. PMID- 21664171 TI - Behavioural problems and bullying at school: can cognitive neuroscience shed new light on an old problem? PMID- 21664172 TI - Label free biochemical 2D and 3D imaging using secondary ion mass spectrometry. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) provides a method for the detection of native and exogenous compounds in biological samples on a cellular scale. Through the development of novel ion beams the amount of molecular signal available from the sample surface has been increased. Through the introduction of polyatomic ion beams, particularly C(60), ToF-SIMS can now be used to monitor molecular signals as a function of depth as the sample is eroded thus proving the ability to generate 3D molecular images. Here we describe how this new capability has led to the development of novel instrumentation for 3D molecular imaging while also highlighting the importance of sample preparation and discuss the challenges that still need to be overcome to maximise the impact of the technique. PMID- 21664173 TI - Importance of weak interactions in developing 1,3-bis(4,6-dimethyl-1H nicotinonitrile-1-yl)1,3-dioxy propane polymorphs. AB - The structure of 1,3-bis(4,6-dimethyl-1H-nicotinonitrile-1-yl)1,3-dioxy propane polymorphs has been characterized by X-ray diffraction, FT-IR, 1H and 13C NMR spectroscopies. The influence of intra and intermolecular weak interactions is thoroughly studied in solid state using single crystal X-ray diffraction and FT IR. These polymorphs belong to monoclinic space group 'P2(1/n)' and 'P2(1/c)'. These polymorphs have C-H?n (lone pair), hydrogen bonds, C-N?pi, C-H?pi and pi?pi intermolecular non-covalent interactions. These polymorphs are the result of weak interactions and solvent used in crystallization. The FT-IR spectra have been recorded in the solid phase and NMR has been recorded in solvent. The optimized geometry has been calculated by B3LYP methods using different basis sets. The FT IR and NMR spectra of 1st polymorphs has been calculated at B3LYP/6-31G (d) level. The scaled theoretical wave number showed good agreement with the experimental values. These two polymorphs as well as other stereomers are studied by DFT calculations. PMID- 21664174 TI - Structural, thermal and optical characterization of a Schiff base as a new organic material for nonlinear optical crystals and films with reversible noncentrosymmetry. AB - Macroscopic single crystals of (E)-5-(diethylamino)-2-((3,5 dinitrophenylimino)methyl)phenol (DNP) were obtained from slow cooling of chloroform or dichlorometane saturated solutions at controlled temperature. X-ray diffraction analysis showed that this compound crystallizes in a noncentrosymmetric space group (P2(1)2(1)2(1)). Thermal analysis was performed and indicated that the crystals are stable until 260 degrees C. Second-order nonlinear optical properties of DNP were experimentally investigated in solution through EFISH technique and in solid state through the Kurtz-Perry powder technique. Crystals of compound DNP exhibited a second-harmonic signals 39 times larger than of the technologically useful potassium dihydrogenphosphate (KDP) under excitation at infrared wavelengths. In addition, the second-order nonlinear optical properties of DNP were also studied at visible wavelengths through the photorefractive effect and applied to demonstrate dynamic holographic reconstruction. PMID- 21664175 TI - Synthesis of CdSe quantum dots using selenium dioxide as selenium source and its interaction with pepsin. AB - A novel method has been developed for the synthesis of thioglycolic acid (TGA) capped CdSe quantum dots (QDs) in an aqueous medium when selenium dioxide worked as a selenium source and sodium borohydride acted as a reductant. The interaction between CdSe QDs and pepsin was investigated by fluorescence spectroscopy. It was proved that the fluorescence quenching of pepsin by CdSe QDs was mainly a result of the formation of CdSe-pepsin complex. Based on the fluorescence quenching results, the Stern-Volmer quenching constant (Ksv), binding constant (KA) and binding sites (n) were calculated. According to the Foster's non-radiative energy transfer theory, the binding distance (r) between pepsin and CdSe QDs was obtained. The influence of CdSe QDs on the conformation of pepsin has been analyzed by synchronous fluorescence spectra, which provided that the secondary structure of pepsin has been changed by the interaction of CdSe QDs with pepsin. PMID- 21664176 TI - Simultaneous determination of Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+ by using second derivative spectrophotometry method. AB - A new method of simultaneous determination of Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+ is proposed here by using the second-derivative spectrophotometry method. In pH=10.35 Borax-NaOH buffer, using meso-tetra (3-methoxyl-4-hydroxylphenyl) porphyrin ([T-(3-MO-4-HP)P]) as chromomeric reagent, micelle solution was formed after Tween-80 surfactant was added into the solution containing Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+ ions. The original absorption spectrum of the above complexes was obtained after heating in the boiling water for 25 min. The second-derivative absorption peaks of five metal-porphyrin complexes can be separated from the original absorption spectrum by using chemometric tool. In this way, Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+ ions can be determined simultaneously. Under the optimal conditions, the linear ranges of the calibration curve were 0-0.60, 0-0.60, 0 0.40, 0-0.80 and 0-0.48 MUg mL(-1) for Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+, respectively. The molar absorptivity of these color systems were 1.38*10(5), 1.01*10(5), 3.24*10(5), 1.07*10(5) and 1.29*10(5)Lmol(-1)cm(-1). The method developed in this paper has advantages in selectivity, sensitivity, operation and can effectively resolve spectra overlapping problem. This method has been applied to determine the real samples with satisfactory results. PMID- 21664177 TI - Vibrational spectra, tautomerism and thermodynamics of anticarcinogenic drug: 5 fluorouracil. AB - The FT-IR and FT-Raman spectra of 5-Fluorouracil were recorded in the solid phase in the regions 400-4000 cm(-1) and 50-4000 cm(-1), respectively. The vibrational spectra were analysed and the observed fundamentals were assigned to different normal modes of vibration. The experimental wavenumbers were compared with the scaled vibrational values using DFT methods: the Ar matrix data were related to gas phase calculations, while the values of the solid state spectra were compared to those with dimer simulations. The study indicates that some features that are characteristic of vibrational spectra of uracil and its derivatives are retained in the spectrum of 5-fluorouracil and it exists in ketonic form in the solid phase. The tautomerism was also studied and the spectra of the two most stable forms were simulated. The calculated wavenumbers have been employed to yield thermodynamic properties. PMID- 21664179 TI - A closer functional look at the utricular balance pathway: a neuroanatomical and clinical perspective. PMID- 21664178 TI - Activity-dependent changes in impulse conduction of single human motor axons: a stimulated single fiber electromyography study. AB - OBJECTIVE: The aim of this study is to develop a novel method to assess activity dependent hyperpolarization in human single motor axons at a constant stimulus frequency by using intra-muscular axonal stimulating single fiber electromyography (s-SFEMG). METHODS: We performed s-SFEMG in the extensor digitorum communis (EDC) muscle of 10 normal subjects, and measured changes in latencies for single muscle fiber action potentials (MAPs) during 500 stimuli delivered at 5, 10 and 20 Hz. The data were analyzed with a repeated measurement analysis, and multiple comparisons were performed. RESULTS: A total of 585 MAPs were examined at 5 Hz (n=190), 10 Hz (n=210), and 20 Hz (n=185) steady stimulation. There was a progressive linear prolongation of latencies, as the stimulus rate increased (F=95.6, p<0.001); the least square means (SEM) of latency change were 100.7 (0.28)% at 5 Hz, 102.3 (0.27)% at 10 Hz and 105.3 (0.28)% at 20 Hz. There were statistically significant differences between frequencies by Tukey-Kramer's method. Despite the significant latency prolongation, no activity-dependent conduction block developed. A 20 Hz electric stimulation to intramuscular axons was well-tolerated in all the subjects. CONCLUSIONS: Tetanic stimulation at a constant rate results in significant latency increase in single human motor axons, the extent of which depends on the stimulus frequency. The findings imply that physiological discharge rates will activate the Na(+)/K(+) pump and thereby produce axonal hyperpolarization in single motor axons. SIGNIFICANCE: This technique may detect activity-dependent conduction block if the safety margin of impulse transmission is significantly reduced by demyelination or increased branching due to collateral sprouting in a variety of neuromuscular disorders. PMID- 21664180 TI - Predication of Japanese green tea (Sen-cha) ranking by volatile profiling using gas chromatography mass spectrometry and multivariate analysis. AB - The sensory quality ranking of Japanese green tea (Sen-cha) was evaluated and predicted using volatile profiling and multivariate data analyses. The volatile constituents were extracted from tea infusion using vacuum hydrodistillation and analyzed using GC/MS. A quality of green tea could be discriminated to a high or low grade regarding the volatile profile by partial least squares discriminant analysis (PLS-DA). A quality ranking predictive model was developed from the relationship between subjective attributes (sensory quality ranking) and objective attributes (volatile profile) using partial least squares projections to latent structures together with the preprocessing filtering technique, orthogonal signal correction (OSC). Several volatile compounds highly contributed to model prediction were identified as various odor-active compounds, including geraniol, indole, linalool, cis-jasmone, dihydroactinidiolide, 6-chloroindole, methyl jasmonate, coumarin, trans-geranylacetone, linalool oxides, 5,6-epoxy-beta ionone, phytol, and phenylethyl alcohol. The whole fingerprints of these volatile compounds could be possible markers for the overall quality evaluation of green tea beverage. PMID- 21664181 TI - Excessive daytime sleepiness among attending physicians: a pilot survey study at an academic institution. AB - The purpose of this study is to assess excessive daytime sleepiness (EDS) among attending physicians. Emails with an embedded link to an IRB approved questionnaire were sent to attending physicians of two closely affiliated academic institutions. An online hospital directory was used to compile a list of active attending physicians who practiced clinical medicine. Two additional reminder emails, about 2 weeks apart, were also sent. Data were collected anonymously and participation was voluntary. Three hundred fifteen responses out of 506 emails were returned (responder rate of 62.2%). The average age was 47 years and the majority was married with children. The mean Epworth Sleepiness Scale score was six and only 50 (15.9%) physicians were sleepy with a score of >10. Only working longer hours (p=0.014), habitual napping (p=0.01) and the feeling of not getting enough sleep (p=0.01) significantly correlated with daytime sleepiness. Hours at work, however, did not correlate with hours of sleep, and the latter surprisingly did not correlate with sleepiness. Physicians in our sample were slightly more sleep deprived than the general population but not as sleep deprived as resident physicians. PMID- 21664182 TI - Fatty-acid binding protein 4 gene polymorphisms and plasma levels in children with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is associated with increased risk for metabolic syndrome in both adults and children. In adults with OSA, serum levels of fatty acid binding protein 4 (FABP4) are elevated and associated with the degree of metabolic insulin resistance, independent of obesity. Therefore, we assessed plasma FABP4 levels and FABP4 allelic variants in obese and non-obese children with and without OSA. METHODS: A total of 309 consecutive children ages 5-8years were recruited. Children were divided into those with OSA and without OSA (NOSA) based on the apnea-hypopnea index (AHI). Subjects were also subdivided into obese (OB) and non-obese (NOB) based on BMI z score. Morning fasting plasma FABP4 levels were assayed using ELISA, and 11 single-nucleotide polymorphisms (SNPs) within the FABP4 region were genotyped. RESULTS: Morning plasma FABP4 levels were increased in all children with OSA, even in NOB children. However, plasma FABP4 levels were strongly associated with BMI z score. Of the 11 SNPs tested, the frequency of rs1054135 (A/G) minor allele (A) was significantly increased in OSA. This SNP was also associated with increased plasma FABP4 levels in both OSA and obese subjects. The minor allele frequency of all other SNPs was similar in OSA and NOSA groups. CONCLUSIONS: Childhood obesity and OSA are associated with higher plasma FABP4 levels and thus promote cardiometabolic risk. The presence of selective SNP (e.g., rs1054135) in the FABP4 gene may account for increased plasma FABP4 levels in the context of obesity and OSA in children. PMID- 21664183 TI - Effects of cigarette smoke residues from textiles on fibroblasts, neurocytes and zebrafish embryos and nicotine permeation through human skin. AB - Toxic substances from cigarette smoke can attach to carpets, curtains, clothes or other surfaces and thus may pose risks to affected persons. The phenomenon itself and the potential hazards are discussed controversially, but scientific data are rare. The objective of this study was to examine the potential of textile-bound nicotine for permeation through human skin and to assess the effects of cigarette smoke extracts from clothes on fibroblasts, neurocytes and zebrafish embryos. Tritiated nicotine from contaminated cotton textiles penetrated through adult human full-thickness skin as well as through a 3D in vitro skin model in diffusion chambers. We also observed a significant concentration-dependent cytotoxicity of textile smoke extracts on fibroblast viability and structure as well as on neurocytes. Early larval tests with zebrafish embryos were used as a valid assay for testing acute vertebrate toxicity. Zebrafish development was delayed and most of the embryos died when exposed to smoke extracts from textiles. Our data show that textiles contaminated with cigarette smoke represent a potential source of nicotine uptake and can provoke adverse health effects. PMID- 21664184 TI - G-protein-coupled receptors in control of natural killer cell migration. AB - Natural killer (NK) cells are highly motile cells that patrol lymphoid and non lymphoid organs, and are poised to react to infectious or other inflammatory situations. Several NK cell subsets equipped with different sets of chemotactic G protein-coupled receptors, and which display distinct distribution across lymphoid and non-lymphoid organs, have been described. These receptors detect various guidance cues including sphingosine-1-phosphate and chemokines that orchestrate NK cell trafficking. Here, we highlight recent advances regarding the receptors involved in NK cell migration, with a focus on bone marrow egress, entry into activated lymph nodes, extravasation into inflamed tissues, and motility within lymph nodes or tumors. Understanding NK cell migration could provide a rational basis for the design of novel therapies in various clinical conditions. PMID- 21664186 TI - The naming of genes. PMID- 21664187 TI - Using constructive alignment theory to develop nursing skills curricula. AB - Constructive alignment theory has been used to underpin the development of curricula in higher education for some time (Biggs and Tang, 2007), however, its use to inform and determine skills curricula in nursing is less well documented. This paper explores the use of constructive alignment theory within a study of undergraduate student nurses undertaking clinical skill acquisition in the final year of a BSc (Hons) Nursing course. Students were followed up as newly qualified nurses (NQN) (n = 58) to ascertain the impact of skill acquisition in this way. Comparisons were made with newly qualified nurses who did not participate in a constructively aligned curriculum. This mixed methods study reported skill identification within the immediate post-registration period and evaluated the constructively aligned curriculum as having positive benefits for NQNs in terms of confidence to practice. This was supported by preceptors' views. The study recommends two process models for nursing skills curriculum development and reports that constructive alignment is a useful theoretical framework for nurse educators. PMID- 21664185 TI - Monocyte trafficking in acute and chronic inflammation. AB - Environmental signals at the site of inflammation mediate rapid monocyte mobilization and dictate differentiation programs whereby these cells give rise to macrophages or dendritic cells. Monocytes participate in tissue healing, clearance of pathogens and dead cells, and initiation of adaptive immunity. However, recruited monocytes can also contribute to the pathogenesis of infection and chronic inflammatory disease, such as atherosclerosis. Here, we explore monocyte trafficking in the context of acute inflammation, relying predominantly on data from microbial infection models. These mechanisms will be compared to monocyte trafficking during chronic inflammation in experimental models of atherosclerosis. Recent developments suggest that monocyte trafficking shares common themes in diverse inflammatory diseases; however, important differences exist between monocyte migratory pathways in acute and chronic inflammation. PMID- 21664188 TI - Health, sustainability and student travel. AB - A survey of 246 pre-registration nursing students in a University in the South West of England was carried out to explore the impact of course related travel on the student experience. Results from the survey indicated that students' main mode of transport to practice placements was by car which reflects the rural nature of the South West and the relative paucity of public transport. Long distances that many students travel to their study centre and to placements, and the concurrent financial strain that this creates, impacted negatively on the student experience. Students recognised the need to travel to a place of study and clinical placements and suggestions of minimising the negative impact of travel were offered. These included the increased use of electronic delivery of lectures, attendance at local university premises, the provision of shared transport to placements and placements closer to the student's home. Few students, however, considered the environmental impact of travel. Higher Education Institutions need to address issues of sustainability through promoting student wellbeing and taking steps to reduce greenhouse gas emissions. It is therefore important that student awareness of sustainability related issues is increased as well as focusing on reducing the environmental impact through organisational change. PMID- 21664189 TI - Time for proper support for the next-of-kin of a patient who has suffered a cardiac event. PMID- 21664191 TI - MAP3738c and MptD are specific tags of Mycobacterium avium subsp. paratuberculosis infection in type I diabetes mellitus. AB - Mycobacterium avium subsp. paratuberculosis (Map) is the causative agent of Johne's disease, a chronic inflammation of ruminants' intestine. Recent studies have linked Map to type I Diabetes mellitus (T1DM). We searched the presence of antibodies against two specific proteins of Map (MptD and MAP3738c) in sera of patients affected by T1DM and type II Diabetes mellitus (T2DM). MptD protein (MAP3733c) has been recognized as a Map virulent factor whereas MAP3738c has not yet been studied. Both proteins are encoded by genes belonging to a Map specific pathogenicity island. Forty three T1DM patients' sera, 56 T2DM patients' sera and 48 healthy subjects' sera were screened by ELISA to evaluate the immunoresponse against MptD or MAP3738c recombinant proteins. Results showed a positive response to both proteins in T1DM patients whereas no difference with controls was found for T2DM patients. Results suggest a potential relation between T1DM and the bacterial infection. PMID- 21664192 TI - Challenges for emerging neurostimulation-based therapies for real-time seizure control. AB - In step with the worthwhile aim of this special issue, two junior investigators impart their insights on the therapeutic challenges imposed by pharmacoresistant epilepsies and offer viable approaches to improvement of treatment outcomes. Sunderam's comprehensive perspective addresses issues of critical importance for the design of efficacious therapies. Talathi delves into the thorny roles of so called "interictal" spikes in ictio- and epileptogenesis, roles that are central to understanding the dynamics of these phenomena and implicitly of how to prevent them or abort them. First, however, Osorio and co-workers illustrate the complex behavior of the epileptogenic network and point to the importance of real-time intraindividual adaptation and optimization of therapies for seizures originating from the same epileptogenic network. PMID- 21664193 TI - Racial disparities in quality of medication use in older adults: findings from a longitudinal study. AB - BACKGROUND: The quality of medication use in older adults is suboptimal, with a large percentage of individuals not receiving recommended care. Most efforts to evaluate the quality of medication use target high-risk drugs, appropriate treatment of prevalent chronic disease states, or a set of predefined quality indicators of medication use rather than the patient. It is also suggested that racial differences in the quality of medication use may exist in older adults. OBJECTIVE: This study was conducted to determine the prevalence, number, and types of medication-related problems in older adults, examining the impact of race on quality medication use. METHODS: This was a prospective cohort study involving in-home interviews and medical record reviews of community-residing older adults, stratified by race, conducted 3 times over 1 year. No intervention to address medication-related problems was performed. The quality of medication use was reported as medication-related problems by clinical pharmacists. RESULTS: Of the 200 participants (100 blacks, 100 whites), mean age was 78.3 (whites) and 75.5 (blacks), and the majority of patients were female. Although whites used more medications than blacks (mean, 11.6 vs 9.7; P < 0.01), blacks had more medication-related problems per person than whites (mean, 6.3 vs 4.9; P < 0.01). All patients had at least 1 medication-related problem. Common problems at baseline, 6 months, and 12 months for both whites and blacks were undertreatment, suboptimal drug use, suboptimal dosing, nonadherence, and less costly alternative available. Blacks had significantly higher rates of nonadherence than whites (68% vs 42%; P < 0.01). Over the 12-month study, the number of medication-related problems not only persisted but increased (adjusted P = 0.0168). CONCLUSIONS: Medication-related problems were prevalent in both black and white older adults and persisted over 1 year. Blacks had more medication-related problems than whites, including higher rates of nonadherence. These findings require further study to better understand racial disparities in the quality of medication use in older adults and the impact of race on specific medication-related problems. PMID- 21664194 TI - Enhanced expression of plasminogen activator inhibitor may prevent cardiac rupture in female and castrated mice after myocardial infarction. AB - OBJECTIVE: The objective of this study was to test the hypothesis that gender has a significant impact on cardiac inflammation, fibrosis, and survival after myocardial infarction (MI) in a murine model of left coronary artery ligation (CAL) by investigating the underlying cellular-molecular mechanisms. METHODS: Age matched male and female mice were randomly assigned into 6 groups: sham-operated males, sham-operated females, intact males with CAL, intact females with CAL, castrated males with CAL, and oophorectomized females with CAL. The animals were sacrificed 14 days postoperatively. The hearts from each group were harvested for morphologic studies (n = 6) (infarct and fibrotic area, inflammatory cell markers CD40 and CD68) and mRNA expression analyses (n = 6) of pro- and antiinflammatory molecules, including matrix metalloproteinase (MMP)-9, plasminogen activator inhibitor (PAI)-1, interleukin (IL)-10, transforming growth factor (TGF)-beta, and endothelial nitric oxide synthase (eNOS). RESULTS: Intact males with CAL had significantly lower 14-day survival compared with intact females with CAL. Similarly, the infarct areas in intact males with CAL were largest compared with other CAL animals. The fibrotic area was also larger in intact males with CAL than in intact females with CAL. Numbers of CD40(+)/CD68(+) cells and MMP-9 expression were higher in intact males with CAL than in intact females with CAL and castrated males with CAL. IL-10, eNOS, and TGF-beta were significantly suppressed in oophorectomized females with CAL compared with intact females with CAL. Intact females with CAL and castrated males with CAL exhibited notably enhanced post-MI PAI-1 expression. CONCLUSIONS: Male gender (compared with female) may be an unfavorable prognostic factor after MI in terms of enhanced inflammation and fibrosis in a murine model. Although castration seemed to be significantly antiinflammatory and antifibrotic after MI, oophorectomy had no significant impact on survival, suggesting that factors other than estrogen may account for favorable outcome after MI in the female gender. Furthermore, enhanced postinfarct PAI-1 expression in castrated and female mice may contribute to suppressed MMP-9 expression and survival advantage. PMID- 21664196 TI - Does bacterial density in cystic fibrosis sputum increase prior to pulmonary exacerbation? AB - BACKGROUND: Cystic Fibrosis (CF) lung disease is characterised by an inexorable decline in lung function, punctuated by periods of symptomatic worsening known as pulmonary exacerbations (referred to here as CFPE). Despite their clinical significance, the cause of CFPE remains undetermined. It has been suggested that an increase in bacterial density may be a trigger, although this has not been shown empirically. METHODS: Here, a previously validated quantitative PCR-based approach was used to assess numbers of Pseudomonas aeruginosa and of total bacteria in respiratory secretions from patients during the period leading up to CFPE. Sputum samples collected from 12 adult CF patients were selected retrospectively to fall approximately 21, 14, 7 and 0 days prior to CFPE diagnosis. In addition, the relationships between clinical parameters (FEV(1), temperature and patient reported outcome measures) and microbiological data were investigated. RESULTS: No significant changes either in total bacterial or P. aeruginosa numbers were identified prior to CFPE. Of all the correlations tested, only temperature showed a significant correlation with total bacterial numbers in the period leading to CFPE. CONCLUSIONS: These findings strongly suggest that CFPE do not generally result from increased bacterial density within the airways. Instead, data presented here are consistent with alternative models of pulmonary exacerbation. PMID- 21664197 TI - Metastatic 5-mm rectal neuroendocrine carcinoma. PMID- 21664195 TI - Pharmacological investigations of the cellular transduction pathways used by cholecystokinin to activate nodose neurons. AB - Cholecystokinin (CCK) directly activates vagal afferent neurons resulting in coordinated gastrointestinal functions and satiation. In vitro, the effects of CCK on dissociated vagal afferent neurons are mediated via activation of the vanilloid family of transient receptor potential (TRPV) cation channels leading to membrane depolarization and an increase in cytosolic calcium. However, the cellular transduction pathway(s) involved in this process between CCK receptors and channel opening have not been identified. To address this question, we monitored CCK-induced cytosolic calcium responses in dissociated nodose neurons from rat in the presence or absence of reagents that interact with various intracellular signaling pathways. We found that the phospholipase C (PLC) inhibitor U-73122 significantly attenuated CCK-induced responses, whereas the inactive analog U-73433 had no effect. Responses to CCK were also cross desensitized by a brief pretreatment with m-3M3FBS, a PLC stimulator. Together these observations strongly support the participation of PLC in the effects of CCK on vagal afferent neurons. In contrast, pharmacological antagonism of phospholipase A(2), protein kinase A, and phosphatidylinositol 3-kinase revealed that they are not critical in the CCK-induced calcium response in nodose neurons. Further investigations of the cellular pathways downstream of PLC showed that neither protein kinase C (PKC) nor generation of diacylglycerol (DAG) or release of calcium from intracellular stores participates in the response to CCK. These results suggest that alteration of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)) content by PLC activity mediates CCK-induced calcium response and that this pathway may underlie the vagally-mediated actions of CCK to induce satiation and alter gastrointestinal functions. PMID- 21664198 TI - Comment to "current applications of evolving methodologies in gastroesophageal reflux disease testing". PMID- 21664199 TI - The effect of priming a thin ideal on the subsequent perception of conceptually related body image words. AB - Our research examined the effects of thin ideal priming on the perception of body image words in participants without an eating disorder. Half of the participants were primed by viewing thin models, and half were primed with gender-neutral shoes. Subsequently, all participants (N=56) completed a Stroop task for three categories of words: neutral (BOOKS), shoe (CLOGS), and body (THIGHS). Lastly, all participants completed a body dissatisfaction questionnaire. We predicted that body dissatisfaction scores would be correlated with the Stroop effect. We found a significant correlation between body dissatisfaction and the body effect of slower color naming times for the body related words compared to the neutral words. Our study demonstrates that body dissatisfaction and a brief priming with thin models results in subsequent differences in performing a Stroop task in a non clinical population of female participants. PMID- 21664200 TI - Measuring dysmorphic concern in Italy: psychometric properties of the Italian Body Image Concern Inventory (I-BICI). AB - The present research evaluated an Italian version of the Body Image Concern Inventory (I-BICI). A total of 412 Italian volunteers from Central and Southern Italy completed the measure (M=27.05 years, range=13-66 years) and the basic psychometric properties (factor structure, internal consistency, convergent validity) were assessed. The total measure demonstrated good internal consistency. Significant correlations were found between the I-BICI and measures of eating disorder (EDI-2) and obsessive-compulsive symptomatology (PI). Confirmatory factor analysis replicated the mesaure's proposed factor structure. Directions for future research are discussed. PMID- 21664201 TI - Assessing anti-fat bias in preschoolers: a comparison of a computer generated line-drawn figure array and photographic figure array. AB - This study examined differences in preschoolers' ratings of anti-fat bias and identification of current body size depending on the realism of the figure array used: computer generated line-drawn or photographic. Children reported strong anti-fat bias with both arrays. However, less extreme bias was elicited with the photographic figure array. In addition, children were inaccurate reporters of their current body size when both figure arrays were used. However, children were consistent in their selection of figures that were thinner than their actual body size. Children's consistent selection of thinner figures as representative of their current body size may be an additional indicator of anti-fat bias. Overall, these results suggest that some of the anti-fat bias observed in preschoolers is attributable to less realistic figure arrays. Therefore, photographic figure arrays are proposed as a better measurement tool in the assessment of anti-fat bias in preschoolers. PMID- 21664202 TI - The impact of weight, sex, and race/ethnicity on body dissatisfaction among urban children. AB - The purpose of the current study was to examine the relative contributions of weight status, race/ethnicity, sex, and age on body dissatisfaction in a large group of diverse children. Participants were 4th-6th graders (N=1212) in ten inner-city schools who participated in an obesity prevention study previously published. Children completed the body dissatisfaction subscale of the Eating Disorder Inventory-2 (EDI-2), and weight status was assessed by measured weights and heights. Multiple regression analyses were conducted. Relative weight status was the strongest predictor of body dissatisfaction, followed by race/ethnicity, and sex. Body dissatisfaction was greatest in obese, Asian, and female children. Overall, results indicated that children's body dissatisfaction varies based on relative weight status, as well as race/ethnicity and sex among urban children. Results highlight the strong need for additional research so that more definitive conclusions may be drawn regarding the development of body image among diverse groups of children. PMID- 21664203 TI - Myth: gastroesophageal reflux is a pathological entity in the preterm infant. AB - There is concern about possible consequences of gastroesophageal reflux (GER) in preterm infants. GER is perceived to be a frequent condition in these infants, often causing an exhaustive investigation and expensive therapy. We review current evidence for and against an association between GER and apnea, failure to thrive, wheezing and respiratory diseases. Although there are some limitations to the methodologies currently used for detecting GER, there is clearly a lack of unequivocal evidence supporting a causal relationship between GER and its assumed consequences, particularly in preterm infants. Despite physiologic data that stimulation of laryngeal efferents by GER may induce apnea, there is little evidence for a causal relationship between GER and apnea. Studies on preterm infants with failure to thrive have also not demonstrated an association between the latter and GER in most cases, and there is equally little evidence for a casual relationship with respiratory problems. Therefore, we believe that GER in preterm infants is only rarely associated with serious consequences and existing evidence does not support the widespread use of anti-reflux medications for treatment of these signs in this age group. An improvement of methods to identify the few preterm infants at risk for developing serious consequences of GER is urgently needed. PMID- 21664204 TI - Tunneling of a leech into a free flap breast reconstruction. AB - Leeches are well known to migrate over the surface of the treated tissues. At times, they can be located in remote locations once they become engorged and detach. We report the first case of a leech tunneling through a dermal bite wound on a breast free flap. PMID- 21664205 TI - Free flap microcirculatory monitoring correlates to free flap temperature assessment. AB - INTRODUCTION: Salvage rates of free flaps have been reported to be inversely related to the time interval between the onset of ischaemia and its clinical recognition. Consecutively, monitoring of free flaps remains of major importance. The aim of this study was to analyse the correlation of postoperative free flap microcirculation and free flap skin temperature as a potential tool of postoperative flap monitoring. HYPOTHESIS: Free flap skin temperature correlates to free flap capillary microcirculation. METHODS: Fifty-four free flaps were prospectively monitored during the study. Postoperative flap monitoring was performed using a regular digital infrared surface thermometer (Medisana FTD, Germany) simultaneously to microcirculatory assessment using combined Laser Doppler and photospectrometry (Oxygen-to-see, Lea Medizintechnik, Germany). RESULTS: Mean microcirculatory blood flow was 105+/-35 arbitrary units (AU). Mean temperature was 34.9+/-2.2 degrees C. We found a significant correlation between free flap temperature and free flap capillary blood flow (Pearson correlation r=0.48; p<0.001) and postcapillary venous filling pressure (r=-0.32; p=0.021) in 54 free flaps. A 1 degrees C less free flap temperature was associated with a decrease of the mean microcirculatory capillary blood flow by 37 relative units. CONCLUSION: Our study demonstrates free flap skin temperature related to capillary microcirculation. Our primary hypothesis was confirmed. We postulate an acute temperature drop of 3 degrees C at the centre of the skin island as indicative of arterial thrombosis, whereas a 1-2 degrees C uniform temperature drop of the flap is indicative of venous compromise. Consecutively, free flap skin temperature assessment might be a reliable and inexpensive adjunct monitoring method in plastic reconstructive surgery to improve patients' safety. PMID- 21664206 TI - Treatment of a large congenital melanocytic nevus with dermabrasion and autologous cell suspension (ReCELL(r)): a case report. AB - Congenital melanocytic naevi (CMN) are present at birth in between 1 and 6% of all neonates. They are caused by malformations of the neuroectoderm that are comprised of melanocytes and occasionally neural elements, following dysregulated growth and arrest of melanocytes during migration from the neural crest to the skin. Most commonly they are sub-classified according to size. They are at risk of malignant transformation, but the psychological impact of prominent CMN's is arguably of greater potential concern to the parent and child. Treatment modalities to date have included complete surgical excision with defect reconstruction, as well as less invasive methods such as dermabrasion, curretage, chemical peels and laser therapy. We present an illustrated case of a healthy, term, 4 week-old male neonate with a large CMN on his face. The lesion was dermabraded, and non-cultured epithelial autograft harvested from the right post auricular area was applied. Dressings were no longer required by the 8th post operative day, and excellent skin pigmentation and texture was achieved by 5 months post-op. PMID- 21664207 TI - A canthopexy to begin with. PMID- 21664208 TI - What are the facilitators, inhibitors, and implications of birth positioning? A review of the literature. AB - BACKGROUND: From the historical literature it is apparent that birthing in an upright position was once common practice while today it appears that the majority of women within Western cultures give birth in a semi-recumbent position. AIM: To undertake a review of the literature reporting the impact of birth positions on maternal and perinatal wellbeing, and the factors that facilitate or inhibit women adopting various birth positions throughout the first and second stages of labour. METHODS: A search strategy was designed to identify the relevant literature, and the following databases were searched: CINAHL, CIAP, the Cochrane Database of Systematic Reviews, Medline, Biomed Central, OVID and Google Scholar. The search was limited to the last 15 years as current literature was sought. Over 40 papers were identified as relevant and included in this literature review. RESULTS: The literature reports both the physical and psychological benefits for women when they are able to adopt physiological positions in labour, and birth in an upright position of their choice. Women who utilise upright positions during labour, have a shorter duration of the first and second stage of labour, experience less intervention, and report less severe pain and increased satisfaction with their childbirth experience than women in a semi recumbent or supine/lithotomy position. Increased blood loss during third stage is the only disadvantage identified but this may be due to increased perineal oedema associated with upright positions. There is a lack of research into factors and/or practices within the current health system that facilitate or inhibit women to adopt various positions during labour and birth. Upright birth positioning appears to occur more often within certain models of care, and birth settings, compared to others. The preferences for positions, and the philosophies of health professionals, are also reported to impact upon the position that women adopt during birth. CONCLUSION: Understanding the facilitators and inhibitors of physiological birth positioning, the impact of birth settings and how midwives and women perceive physiological birth positions, and how beliefs are translated into practice needs to be researched. PMID- 21664209 TI - Allele frequencies for the new European Standard Set (ESS) loci and D1S1677 in the Belgian population. PMID- 21664210 TI - Durability of peel bond of resilient denture liners to acrylic denture base resin. AB - PURPOSE: The purpose of this study was to determine the durability of the peel bond of commercial resilient denture liners to a denture base resin using a thermal cycling test. METHODS: Eight commercial resilient denture liners (five silicone and three acrylic) were used in the study. The samples were exposed to thermal cycles between 5 degrees C and 55 degrees C for 1 min for 0, 1,250, 2,500, 5,000 and 10,000 cycles. The test samples were placed under tension until failure in a materials testing machine using a crosshead speed of 20 mm/min. The modes of debonding were characterized as tear, peel or snap. Statistical analysis was performed using one-way and two-way analysis of variance and Student-Newman Keuls multiple comparison tests (alpha=.05). RESULTS: A significant difference was found between different resilient denture liners for peel bond strength at 0 cycles. No extreme influence on the peel bond strength was observed under any of the thermal cycles. The snap mode of debonding was observed in most samples of all materials for all cycles. CONCLUSION: All resilient denture liners tested had a sufficiently strong bond to the denture base resin. Within the limitations of this study, the results show that all of the materials were acceptable for clinical use, having met the accepted adequate bond strength for resilient denture liners of 0.45 MPa. PMID- 21664211 TI - Day-to-day variations in salivary cortisol measurements. AB - PURPOSE: The purpose of this study was to clarify the day-to-day variations of salivary cortisol to discuss the appropriate timing for collecting saliva in a day for stress evaluation. MATERIALS AND METHODS: Saliva samples from twelve healthy adults were collected by means of Salivette((r)) (SARSTEDT Co.) three times per day, immediately after awakening (Time1), 6:00 PM (Time2) and 30 min before going to bed (Time3), on 5 nonconsecutive days. Cortisol concentration was measured using a radioimmunoassay. RESULTS: Salivary cortisol concentration showed the larger value at Time1 than that at Time2. The mean value of %CV for day-to-day variation showed the smallest value at Time1 (mean: 43.1%) and the largest value at Time3 (mean: 100.3%). There were significant differences in %CV value between Time1 and Time3, Time2 (mean: 64.1%) and Time3. CONCLUSIONS: There are considerable day-to-day variations in salivary cortisol concentration measurements. From the viewpoint of day-to-day variation, collecting saliva immediately after awakening in the morning is thought to be more advantageous for evaluating cortisol concentration. PMID- 21664212 TI - Small bowel ischemia after angiographic embolization for angiodysplasia of lower gastrointestinal tract: the case for conservative management. AB - However, transarterial embolization for angiodysplasia has become widely used, the possibility of complications such as bowel ischemia and infarction still exists. We experienced a 60-year-old woman of small bowel ischemia after angiographic embolization for the angiodysplasia of cecum treated with conservative management. We should consider the possibility of recovery via the rich intramural vascular networks of the lower GI tract before deciding to operate. PMID- 21664213 TI - Increased expression of cytochrome P450 2E1 in nonalcoholic fatty liver disease: mechanisms and pathophysiological role. AB - Due to the worldwide surge in obesity and type 2 diabetes, the increased incidence of nonalcoholic fatty liver disease (NAFLD) is a major concern for the public health. Indeed, NAFLD encompasses a large spectrum of conditions ranging from fatty liver to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis in some patients. A better understanding of the mechanisms involved in fatty liver and its progression into NASH is important in order to develop efficient drugs able to alleviate these liver diseases. Although numerous investigations pointed to reactive oxygen species (ROS) as key players in the progression of fatty liver to NASH, their exact source is still uncertain. Besides the mitochondrial respiratory chain, cytochrome P450 2E1 (CYP2E1) has recently emerged as another potentially important cause of ROS overproduction. Indeed, higher hepatic CYP2E1 expression and activity have been frequently observed in the context of obesity and NAFLD. It is currently unknown why CYP2E1 is enhanced in these dysmetabolic diseases, although increased hepatic levels of fatty acids and insulin resistance might play a role. Nonetheless, higher hepatic CYP2E1 could play a significant role in the pathophysiology of NASH by inducing lipid peroxidation and oxidative damage of key cellular components. Moreover, CYP2E1-mediated overproduction of ROS could promote hepatic insulin resistance, which can further aggravate fatty liver. Since a significant amount of CYP2E1 can be located within liver mitochondria, higher levels of CYP2E1 in NAFLD could also have detrimental effects on mitochondrial function. Finally, increased CYP2E1 activity during NAFLD could enhance the susceptibility of some patients to the hepatotoxicity of different xenobiotics through the CYP2E1-mediated generation of harmful reactive metabolites. PMID- 21664214 TI - Routine gastrostomy tube for gastric decompression in 55 consecutive pylorus conserving pancreatoduodenectomy: retrospective analysis of the efficacy and tolerance. PMID- 21664215 TI - Impact of the type of seasonal influenza vaccine on immune responses to the 2009 pandemic influenza A (H1N1) vaccine. PMID- 21664216 TI - Complete protection against a H5N2 avian influenza virus by a DNA vaccine expressing a fusion protein of H1N1 HA and M2e. AB - Most influenza vaccines target hemagglutinin (HA) in order to protect the host against infection. However, theses vaccines are strain-specific due to major antigenic variations of HA. Since it is difficult to predict epidemic and pandemic strains of influenza virus, the development of effective vaccines against divergent influenza viruses is urgently needed. Although M2e-based vaccines are associated with weaker protection than HA-based vaccines that induce neutralizing antibodies against challenge virus matched-strain, the extracellular domain of Matrix 2 protein (M2e) is one of a potential broad-spectrum immunogen because it contains highly conserved sequences among influenza A viruses. In this study, M2e sequence was fused to H1N1 HA DNA (M2e-HA) and the immunogenicity and antiviral efficacy of this DNA vaccine was evaluated in response to challenge with a heterosubtypic H5N2 avian influenza virus. Compared to vaccination with HA or M2e DNA alone, vaccination with M2e-HA DNA or combination of M2e DNA and HA DNA (M2e DNA+HA DNA) induced a broad immunity without evidence of immune interference. In addition, HA-specific CD8(+) and M2e-specific T cell responses elicited by M2e-HA DNA vaccination were significantly higher than those of HA or M2e DNA vaccine alone, respectively. Following challenge with a heterosubtypic influenza virus infection, vaccination with M2e-HA DNA conferred complete protection against mortality. In combination, these results suggest that DNA vaccines expressing a fusion protein, M2e-HA, may provide an attractive approach for the development of broad-spectrum influenza vaccines. PMID- 21664217 TI - The epidemiologic evidence underlying recommendations for use of pneumococcal polysaccharide vaccine among American Indian and Alaska Native populations. AB - Alaska Native and some American Indian (AI/AN) populations suffer disproportionately high rates of invasive pneumococcal disease (IPD) in both the pediatric and adult populations compared to the general U.S. population. Two pneumococcal vaccines are currently available in the U.S.: a 23-valent pneumococcal polysaccharide vaccine (PPSV23), available since 1983 and recommended for the elderly and those over 2 years of age with underlying medical conditions, and a 13-valent pneumococcal conjugate vaccine (PCV13), used in the routine infant immunization schedule since 2010. The U.S. Advisory Committee on Immunization Practice (ACIP) previously recommended use of PPSV23 for persons living in special environments or social settings, including AN and certain AI persons 2-64 years of age, on the basis of higher disease rates. The recommendation for routine PPSV23 use among AI/AN persons <65 years of age, regardless of underlying conditions, was removed in 2008, although the option for use among those 50-64 years of age living in areas with high pneumococcal disease rates was maintained. The rationale for the revised recommendations lay in the recognition that much of the excess disease burden occurs among those with an existing medical indication for PPSV23. Other considerations for the change were the potential risks of giving multiple PPSV23 doses and the considerable heterogeneity in pneumococcal disease risk among American Indian populations requiring a more tailored approach to local recommendations based on local epidemiology. PMID- 21664219 TI - The influence of molecular adjuvants in the cutaneous response to antigen after topical vaccination. AB - A micro-emulsion (ME), previously shown to enable topical delivery of therapeutic amounts of protein, was used for immunisation of multiple strains of mice with tetanus toxoid (TT). Topical vaccination with TT alone induced low levels of serum antibody in the BALB/c and A/J strains, with C57Bl/6 the only strain capable of a significant TT-specific antibody response. Topical vaccination with TT in combination with murabutide and monophosphoryl lipid A adjuvant generated high humoral and cellular responses in both C57Bl/6 and the non-responsive strain, BALB/c, comparable to intramuscular injection with TT adsorbed to Alum adjuvant. High level immunity after topical administration with chemical adjuvants suggested that the poor response to TT alone in some strains was not due to a low bioavailability of protein. Weak immunity with TT alone may instead be related to passive absorption of antigen into skin that did not result in detectable inflammation or tissue damage. Immune mice given a booster vaccination also showed weak responses to topical TT alone; a further indication that the adaptive response to cutaneous antigen was highly dependent on adequate induction of innate immunity within local tissue. Our data supported the potential for high level adaptive immunity after cutaneous immunisation but only when combined with potent activators of the innate immune system. PMID- 21664218 TI - Enhancement of immune response to an antigen delivered by vaccinia virus by displaying the antigen on the surface of intracellular mature virion. AB - Vaccinia virus (VACV) is the vaccine for smallpox and a widely used vaccine vector for infectious diseases and cancers. The majority of the antibodies elicited by live VACV vaccination respond to virion structural proteins, including many integral membrane proteins on the intracellular mature virion (MV). Here, we showed that antibody response to an exogenous antigen delivered by VACV was greatly enhanced by incorporating the antigen as an integral membrane protein of MV. We constructed recombinant VACV expressing a Yersinia pestis protective antigen, LcrV, unmodified or fused with either a signal peptide or with the transmembrane domain of VACV D8 protein (LcrV-TM). Electron microscopy showed that LcrV-TM was displayed on the surface of MV. Importantly, VACV expressing LcrV-TM elicited a significantly higher titer of anti-LcrV antibody in mice than viruses expressing other forms of LcrV. Only mice immunized with LcrV TM-expressing VACV were protected from lethal Y. pestis and VACV WR challenges. Antigen engineering through fusion with D8 transmembrane domain may be broadly applicable for enhancing the immune response to antigens delivered by a VACV vector. The recombinant virus described here could also serve as the basis for developing a vaccine against both smallpox and plague. PMID- 21664220 TI - Aberrant emotional processing in posterior cortical midline structures in bipolar II depression. AB - Bipolar II depression is a serious and disabling illness associated with significant impairment and high rates of suicide attempts. However, mechanisms underlying emotional dysregulation in this condition are poorly characterized. The goal of this work was to investigate one component of emotional processing in this disorder, brain activation associated with exposure to emotional faces. Functional MRI was used to study 16 unmedicated male subjects with bipolar II depression and 19 healthy male controls. The activation paradigm exposed subjects to happy, fearful and neutral faces. The two key findings of this study were as follows. First, bipolar subjects demonstrated significantly decreased activation in response to happy facial expression in the left posterior cortical midline structures (CMS) and frontal cortex. Second, depression severity was positively correlated with activation of the posterior CMS and other regions. Our results suggest that mechanisms involving CMS dysfunction may play a role in the neurobiology of bipolar II depression as has been demonstrated for unipolar illness. Further investigations of CMS function in bipolar spectrum disorders are warranted. PMID- 21664221 TI - Edible wild vegetable, Gymnaster koraiensis protects retinal ganglion cells against oxidative stress. AB - This study was conducted to determine whether Gymnaster koraiensis is effective at blunting the negative influence of N-methyl-D-aspartate (NMDA) on the retinas of rats and on oxidative stress induced cell death in transformed retinal ganglion cells (RGC-5). The ethyl acetate fraction of G. koraiensis (EAGK) and the isolated compound, 3,5-di-O-caffeoylquinic acid (3,5-DCQA), were shown to significantly attenuate the negative effect of H(2)O(2) on the RGC-5 cells tested by various procedures. The inclusion of EAGK or 3,5-DCQA in the culture reduced the reactive oxygen species (ROS) and replenished the reduced glutathione levels caused by various radical species such as H(2)O(2,) O(2)()(-) or ()OH. Moreover, EAGK or 3,5-DCQA inhibited lipid peroxidation caused by sodium nitroprusside (SNP) in rat brain homogenates. From in vivo experiments, the presence of NMDA in the retina affected the thickness of the inner plexiform layer (IPL) and the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) in positive ganglion cells. EAGK or 3,5-DCQA protected the thinning of the IPL and increased TUNEL positive cells in the ganglion cell layer (GCL). Our results clearly demonstrate the neuroprotective effect of EAGK both in vitro and in vivo. Moreover, 3,5-DCQA is suggested to be the active compound of EAGK. PMID- 21664222 TI - Inhibition of acrolein-stimulated MUC5AC expression by Platycodon grandiflorum root-derived saponin in A549 cells. AB - Mucin overproduction is a hallmark of chronic airway diseases such as chronic obstructive pulmonary disease. In this study, we investigated the inhibition of acrolein-induced expression of mucin 5, subtypes A and C (MUC5AC) by Changkil saponin (CKS) in A549 cells. Acrolein, a known toxin in tobacco smoke and an endogenous mediator of oxidative stress, increases the expression of airway MUC5AC, a major component of airway mucus. CKS, a Platycodon grandiflorum root derived saponin, inhibited acrolein-induced MUC5AC expression and activity, through the suppression of NF-kappaB activation. CKS also repressed acrolein induced phosphorylation of ERK1/2, JNK1/2, and p38MAPK, which are upstream signaling molecules that control MUC5AC expression. In addition, the MAPK inhibitors PD98059 (ERK1/2), SP600125 (JNK1/2), and SB203580 (p38 MAPK), and a PKC delta inhibitor (rottlerin; PKCdelta) inhibited acrolein-induced MUC5AC expression and activity. CKS repressed acrolein-induced phosphorylation of PKCdelta. Moreover, a reactive oxygen species (ROS) inhibitor, N-acetylcysteine, inhibited acrolein-induced MUC5AC expression and activity through the suppression of PKCdelta and MAPK activation, and CKS repressed acrolein-induced ROS production. These results suggest that CKS suppresses acrolein-induced MUC5AC expression by inhibiting the activation of NF-kappaB via ROS-PKCdelta-MAPK signaling. PMID- 21664223 TI - Anandamide and its congeners inhibit human plasma butyrylcholinesterase. Possible new roles for these endocannabinoids? AB - Butyrylcholinesterase (BChE), a serine hydrolase biochemically related to the cholinergic enzyme Acetylcholinesterase (AChE), is found in many mammalian tissues, such as serum and central nervous system, but its physiological role is still unclear. BChE is an important human plasma esterase, where it has detoxifying roles. Furthermore, recent studies suggest that brain BChE can have a role in Alzheimer's disease (AD). The endocannabinoid arachidonoylethanolamide (anandamide) and other acylethanolamides (NAEs) are almost ubiquitary molecules and are physiologically present in many tissues, including blood and brain, where they show neuroprotective and anti-inflammatory properties. This paper demonstrates that they are uncompetitive (oleoylethanolamide and palmitoylethanolamide) or non competitive (anandamide) inhibitors of BChE (Ki in the range 1.32-7.48 nM). On the contrary, NAEs are ineffective on AChE kinetic features. On the basis of the X-ray crystallographic structure of human BChE, and by using flexible docking procedures, an hypothesis on the NAE-BChE interaction is formulated by molecular modeling studies. Our results suggest that anandamide and the other acylethanolamides studied could have a role in the modulation of the physiological actions of BChE. PMID- 21664224 TI - Nucleic acids targeted to drugs: SELEX against a quadruplex ligand. AB - A number of small molecules demonstrate selective recognition of G-quadruplexes and are able to stabilize their formation. In this work, we performed the synthesis of two biotin-tagged G4 ligands and analyzed their interactions with DNA by two complementary techniques, FRET and FID. The compound that exhibited the best characteristics (a biotin pyridocarboxamide derivative with high stabilization of an intramolecular quadruplex and excellent duplex-quadruplex specificity) was used as bait for in vitro selection (SELEX). Among 80 DNA aptamer sequences selected, only a small minority (5/80) exhibited G4-prone motifs. Binding of consensus candidates was confirmed by SPR. These results indicate that G4 ligands that appear highly specific when comparing affinities or stabilization for one quadruplex against one duplex, do not only bind quadruplex sequences but may also recognize other nucleic motifs as well. This observation may be relevant when whole genome or transcriptome analysis of binding sites is seeked for, as unexpected binding sites may also be present. PMID- 21664225 TI - Structural and functional insights into IkappaB-alpha/HIV-1 Tat interaction. AB - Protein-protein interactions play fundamental roles in physiological and pathological biological processes. The characterization of the structural determinants of protein-protein recognition represents an important step for the development of molecular entities able to modulate these interactions. We have recently found that IkappaB-alpha (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) blocks the HIV-1 expression and replication in a NF-kappaB-independent manner by directly binding to the virus-encoded Tat transactivator. Here, we report the evaluation of the entity of binding of IkappaB-alpha to Tat through in vitro Surface Plasmon Resonance assay. Moreover, by designing and characterizing a set of peptides of the C-terminus region of IkappaB-alpha, we show that the peptide corresponding to the IkappaB-alpha sequence 262-287 was able to bind to Tat with high affinity (300 nM). The characterization of a number of IkappaB-alpha-based peptides also provided insights into their intrinsic folding properties. These findings have been corroborated by mutagenesis studies on the full-length IkappaB-alpha, which unveil that different IkappaB-alpha residues are involved in NF-kappaB or Tat recognition. PMID- 21664226 TI - Hallmarks of the channelopathies associated with L-type calcium channels: a focus on the Timothy mutations in Ca(v)1.2 channels. AB - Within the voltage-gated calcium channels (Cav channels) family, there are four genes coding for the L-type Cav channels (Cav1). The Cav1 channels underly many important physiological functions like excitation-contraction coupling, hormone secretion, neuronal excitability and gene transcription. Mutations found in the genes encoding the Cav channels define a wide variety of diseases called calcium channelopathies and all four genes coding the Cav1 channels are carrying such mutations. L-type calcium channelopathies include muscular, neurological, cardiac and vision syndromes. Among them, the Timothy syndrome (TS) is linked to missense mutations in CACNA1C, the gene that encodes the Ca(v)1.2 subunit. Here we review the important features of the Cav1 channelopathies. We also report on the specific properties of TS-Ca(v)1.2 channels, which display non-inactivating calcium current as well as higher plasma membrane expression. Overall, we conclude that both electrophysiological and surface expression properties must be investigated to better account for the functional consequences of mutations linked to calcium channelopathies. PMID- 21664227 TI - Identification of new protein complexes of Escherichia coli inorganic pyrophosphatase using pull-down assay. AB - Inorganic pyrophosphatase (PPase) is a conserved and essential enzyme catalyzing the hydrolysis of pyrophosphate PP(i). Its activity is required to promote a lot of thermodynamically unfavorable reactions including biosynthesis of activated precursors of sugars and amino acids. Several protein partners of PPase were found so far in Escherichia coli by large-scale approaches. Functional role of these interactions was not studied. In this paper we report the identification of three protein partners of E. coli PPase not found earlier. Pull-down assay on the Ni(2+)-chelating column using 6His-tagged PPase as bait was used to isolate PPase complexes from stationary-phase cells. Of several isolated protein components, five were identified by MALDI-TOF mass-spectrometry: two chaperones (DnaK and GroEL) and three enzymes of carbohydrate and amino acid metabolism (FbaB, fructose-1,6-bisphosphate aldolase, class I; GadA, l-glutamate decarboxylase; and KduI, 5-keto-4-deoxyuronate isomerase). These three proteins were cloned, expressed and purified in 6His-tagged and/or tag-free forms. Their binary interactions with PPase were verified by independent approaches. Initial characterization of the complexes indicates that PPase may stabilize its protein partners against unfolding or degradation. Comparative analysis of the PPase protein partners allowed an insight into its possible involvement in the cell metabolic regulation. PMID- 21664228 TI - Substantial changes in synaptic firing frequencies induced by glial ATP hysteresis. AB - Recent experimental studies strongly suggest the influence of glial purinergic transmission in the modulation of synaptic dynamics. By releasing adenosine triphosphate (ATP), which accumulates as adenosine, astrocytes tonically suppressed synaptic transmission. The delayed multi-step feedback of the glial ATP with the neuron suggests the existence of a discrete hysteresis phenomena. By integration of this hysteretic behavior into a delayed leaky integrate-and-fire model for the tripartite synapses, a significant sensitivity of the pre- and postsynaptic firing frequency patterns to the adenosine feedback-delays is observed that might be of importance for adenosine-related neurological deficits, such as sleep disorders. PMID- 21664229 TI - Monte Carlo simulation from proton slip to "coupled" proton flow in ATP synthase based on the bi-site mechanism. AB - ATP synthase couples proton flow to ATP synthesis, but is leaky to protons at very low nucleotide concentration. Based on the bi-site mechanism, we simulated the proton conduction from proton slip to "coupled" proton flow in ATP synthase using the Monte Carlo method. Good agreement is obtained between the simulated and available experimental results. Our model provides deeper insight into the nucleotide dependence of ATP catalysis, and the kinetic cooperativity in three catalysis subunits. The results of simulation support the bi-site mechanism in ATP synthesis. PMID- 21664230 TI - Vitamin D metabolism within bone cells: effects on bone structure and strength. AB - The endocrine activity of 1,25-dihydroxyvitamin D (1,25(OH)(2)D(3)) contributes to maintaining plasma calcium and phosphate homeostasis through actions on the intestine, kidney and bone. A significant body of evidence has been published over the last 10 years indicating that all major bone cells have the capacity to metabolise 25-hydroxyvitamin D (25(OH)D(3)) to 1,25(OH)(2)D(3), which in turn exerts autocrine/paracrine actions to regulate bone cell proliferation and maturation as well as bone mineralisation and resorption. In vivo and in vitro studies indicate that these autocrine/paracrine activities of 1,25(OH)(2)D(3) in bone tissue contribute to maintaining bone mineral homeostasis and enhancing skeletal health. PMID- 21664231 TI - The effects of vitamin D on brain development and adult brain function. AB - A role for vitamin D in brain development and function has been gaining support over the last decade. Multiple lines of evidence suggest that this vitamin is actually a neuroactive steroid that acts on brain development, leading to alterations in brain neurochemistry and adult brain function. Early deficiencies have been linked with neuropsychiatric disorders, such as schizophrenia, and adult deficiencies have been associated with a host of adverse brain outcomes, including Parkinson's disease, Alzheimer's disease, depression and cognitive decline. This review summarises the current state of research on the actions of vitamin D in the brain and the consequences of deficiencies in this vitamin. Furthermore, we discuss specific implications of vitamin D status on the neurotransmitter, dopamine. PMID- 21664232 TI - Adipose circadian rhythms: translating cellular and animal studies to human physiology. AB - Emerging links between circadian rhythms and metabolism promise much for the understanding of metabolic physiology and pathophysiology, in which white adipose tissue (WAT) plays a prominent role. Many WAT endocrine molecules, termed adipokines, display rhythmic plasma concentration. Moreover, similar to most other tissues, WAT exhibits widespread 24-h variation in gene expression, with approximately 20% of the murine adipose transcriptome estimated to undergo daily variation. A major limitation to human chronobiology research is the availability of physiologically defined peripheral tissues. To date most analyses of in vivo human peripheral clocks has been limited to blood leucocytes. However, subcutaneous adipose tissue represents a novel opportunity to study peripheral molecular rhythms that are of clearly defined metabolic relevance. This review summarises basic concepts of circadian and metabolic physiology before then comparing alternative protocols used to analyse the rhythmic properties of human adipose tissue. PMID- 21664233 TI - Aldosterone resistance: structural and functional considerations and new perspectives. AB - Aldosterone plays an essential role in the maintenance of fluid and electrolyte homeostasis in the distal nephron. Loss-of-function mutations in two key components of the aldosterone response, the mineralocorticoid receptor and the epithelial sodium channel ENaC, lead to type 1 pseudohypoaldosteronism (PHA1), a rare genetic disease of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia and metabolic acidosis. This review describes the clinical, biological and genetic characteristics of the different forms of PHA1 and highlights recent advances in the understanding of the pathogenesis of the disease. We will also discuss genotype-phenotype correlations and new clinical and genetic entities that may prove relevant for patient's care in neonates with renal salt losing syndromes and/or failure to thrive. PMID- 21664234 TI - New genetic factors implicated in human GnRH-dependent precocious puberty: the role of kisspeptin system. AB - Human puberty is triggered by the reemergence of GnRH pulsatile secretion with progressive activation of the gonadal function. A number of genes have been identified in the complex regulatory neuroendocrine network that controls puberty initiation. KISS1 and KISS1R genes, which encode kisspeptin and its cognate receptor, respectively, are considered crucial factors for acquisition of normal reproductive function. Recently, rare missense mutations and single nucleotide polymorphisms (SNPs) of the kisspeptin system were associated with puberty onset. Two gain-of-function mutations of the KISS1 and KISS1R genes were implicated in the pathogenesis of GnRH-dependent precocious puberty, previously considered idiopathic. These discoveries have yielded significant insights into the physiology and pathophysiology of this important life transition time. Here, we review the current molecular defects that are implicated in human GnRH-dependent precocious puberty. PMID- 21664235 TI - The road less traveled: new views of steroid receptor action from the path of dose-response curves. AB - Conventional studies of steroid hormone action proceed via quantitation of the maximal activity for gene induction at saturating concentrations of agonist steroid (i.e., A(max)). Less frequently analyzed parameters of receptor-mediated gene expression are EC(50) and PAA. The EC(50) is the concentration of steroid required for half-maximal agonist activity and is readily determined from the dose-response curve. The PAA is the partial agonist activity of an antagonist steroid, expressed as percent of A(max) under the same conditions. Recent results demonstrate that new and otherwise inaccessible mechanistic information is obtained when the EC(50) and/or PAA are examined in addition to the A(max). Specifically, A(max), EC(50), and PAA can be independently regulated, which suggests that novel pathways and factors may preferentially modify the EC(50) and/or PAA with little effect on A(max). Other approaches indicate that the activity of receptor-bound factors can be altered without changing the binding of factors to receptor. Finally, a new theoretical model of steroid hormone action not only permits a mechanistically based definition of factor activity but also allows the positioning of when a factor acts, as opposed to binds, relative to a kinetically defined step. These advances illustrate some of the benefits of expanding the mechanistic studies of steroid hormone action to routinely include EC(50) and PAA. PMID- 21664236 TI - Vitamin D metabolism and function in the skin. AB - The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but in possessing the enzymatic machinery to metabolize vitamin D to its active metabolite 1,25(OH)(2)D. Furthermore, these cells also express the vitamin D receptor (VDR) that enables them to respond to the 1,25(OH)(2)D they produce. Numerous functions of the skin are regulated by 1,25(OH)(2)D and/or its receptor. These include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, and promotion of the hair follicle cycle. Regulation of these actions is exerted by a number of different coregulators including the coactivators DRIP and SRC, the cosuppressor hairless (Hr), and beta catenin. This review will examine the regulation of vitamin D production and metabolism in the skin, and explore the various functions regulated by 1,25(OH)(2)D and its receptor. PMID- 21664237 TI - Steroid receptor coactivators 1, 2, and 3: critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy. AB - Coactivators are a diverse group of non-DNA binding proteins that induce structural changes in agonist-bound nuclear receptors (NRs) that are essential for NR-mediated transcriptional activation. Once bound, coactivators function to bridge enhancer binding proteins to the general transcription machinery, as well as to recruit secondary coactivators that modify promoter and enhancer chromatin in a manner permissive for transcriptional activation. In the following review article, we focus on one of the most in-depth studied families of coactivators, the steroid receptor coactivators (SRC) 1, 2, and 3. SRCs are widely implicated in NR-mediated diseases, especially in cancers, with the majority of studies focused on their roles in breast cancer. We highlight the relevant literature supporting the oncogenic activity of SRCs and their future as diagnostic and prognostic indicators. With much interest in the development of selective receptor modulators (SRMs), we focus on how these coactivators regulate the interactions between SRMs and their respective NRs; and, importantly, the influence that coactivators have on the functional output of SRMs. Furthermore, we speculate that coactivator-specific inhibitors could provide powerful, all encompassing treatments that target multiple modes of oncogenic regulation in cancers resistant to typical anti-endocrine treatments. PMID- 21664238 TI - Corepressor effect on androgen receptor activity varies with the length of the CAG encoded polyglutamine repeat and is dependent on receptor/corepressor ratio in prostate cancer cells. AB - The response of prostate cells to androgens reflects a combination of androgen receptor (AR) transactivation and transrepression, but how these two processes differ mechanistically and influence prostate cancer risk and disease outcome remain elusive. Given recent interest in targeting AR transrepressive processes, a better understanding of AR/corepressor interaction and responses is warranted. Here, we used transactivation and interaction assays with wild-type and mutant ARs, and deletion AR fragments, to dissect the relationship between AR and the corepressor, silencing mediator for retinoic acid and thyroid hormone receptors (SMRT). We additionally tested how these processes are influenced by AR agonist and antagonist ligands, as well as by variation in the polyglutamine tract in the AR amino terminal domain (NTD), which is encoded by a polymorphic CAG repeat in the gene. SMRT was recruited to the AR ligand binding domain by agonist ligand, and as determined by the effect of strategic mutations in activation function 2 (AF-2), requires a precise conformation of that domain. A distinct region of SMRT also mediated interaction with the AR-NTD via the transactivation unit 5 (TAU5; residues 315-538) region. The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT:AR molar ratio. These data suggest that the extent to which the CAG encoded polyglutamine repeat influences AR activity represents a balance between corepressor and coactivator occupancy of the same ligand-dependent and independent AR interaction surfaces. Changes in the homeostatic relationship of AR to these molecules, including SMRT, may explain the variable penetrance of the CAG repeat and the loss of AR signaling flexibility in prostate cancer progression. PMID- 21664240 TI - Isolated cryptorchidism: no evidence for involvement of genes underlying isolated hypogonadotropic hypogonadism. AB - Mutations in FGFR1, GNRHR, PROK2, PROKR2, TAC3, or TACR3 underlie isolated hypogonadotropic hypogonadism (IHH) with clinically variable phenotypes, and, by causing incomplete intrauterine activation of the hypothalamic-pituitary-gonadal axis, may lead to cryptorchidism. To investigate the role of defects in these genes in the etiology of isolated cryptorchidism, we screened coding exons and exon-intron boundaries of these genes in 54 boys or men from 46 families with a history of cryptorchidism. Control subjects (200) included 120 males. None of the patients carried mutation(s) in FGFR1, PROK2, PROKR2, TAC3 or TACR3. Two of the 46 index subjects with unilateral cryptorchidism were heterozygous carriers of a single GNRHR mutation (Q106R or R262Q), also present in male controls with a similar frequency (3/120; p=0.62). No homozygous or compound heterozygous GNRHR mutations were found. In conclusion, cryptorchidism is not commonly caused by defects in genes involved in IHH. PMID- 21664239 TI - Genome-wide principles of gene regulation by the vitamin D receptor and its activating ligand. AB - The vitamin D receptor (VDR) mediates virtually all of the known biological actions of the hormonal ligand 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). These actions are directed toward the nucleus, where the VDR binds to the regulatory regions of target genes and modulates their transcriptional output. Recent technological advances have enabled the study of transcription factor binding on a genome-wide scale in cells and tissues that are major targets of vitamin D action. In this review, the results of several of these studies are discussed wherein overarching principles of gene regulation by the vitamin D hormone are beginning to emerge. In addition, several specific genes that are regulated by 1,25(OH)(2)D(3) and which provide new insight into the increasingly complex mechanism whereby the receptor functions to modulate gene expression are considered. These studies suggest that while many of the principles that are now accepted regarding the regulation of gene expression by hormones and other regulatory factors are well grounded, others require extensive modification. PMID- 21664241 TI - Triiodothyronine modulates initiation of spermatogenesis in rats depending on treatment timing and blood level of the hormone. AB - Triiodothyronine (T3) stimulates spermatogenic onset but the influence of T3 on spermatogonia development is unknown. The aim of the study was to investigate the role of T3 for both processes simultaneously. Male rats were given daily injections of 100 MUg T3/kg body weight or vehicle from birth until postnatal day (pnd) 5 and euthanized on pnd 6 (short T3-sT3). Other rats, euthanized on pnd 16, were treated either transiently with T3 (tT3) during the initial 5 days or continuously until pnd 15 (cT3). sT3 was found to increase gonocyte differentiation, spermatogonia number, cell degeneration and proliferation. tT3 increased serum T3 level and spermatogonial development to adult values precociously, but cell degeneration or proliferation were not affected. cT3 increased serum T3 together with cell degeneration and proliferation, but cell number was not affected. In conclusion, T3 may modulate spermatogonial development quantitatively depending on treatment timing and blood level of the hormone. PMID- 21664242 TI - Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo. AB - A well established functional polymorphism of the human androgen receptor (hAR) is the length of AR's N-terminal glutamine tract (Q-tract). This tract is encoded by a CAG trinucleotide repeat and varies from 8 to 33 codons in the healthy population. Q-tract length is inversely correlated with AR transcriptional activity in vitro, but whether endogenous androgen action is affected is not consistently supported by results of clinical and epidemiological studies. To test whether Q-tract length influences androgen sensitivity in vivo, we examined effects of controlled androgen exposure in "humanized" mice with hAR knock-in alleles bearing 12, 21 or 48 CAGs. Mature male mice were analyzed before or 2weeks after orchidectomy, with or without a subdermal dihydrotestosterone (DHT) implant to attain stable levels of this non-aromatizable androgen. The validity of this DHT clamp was demonstrated by similar serum levels of DHT and its two primary 3alphaDiol and 3betaDiol metabolites, regardless of AR Q-tract length. Q tract length was inversely related to DHT-induced suppression of castrate serum LH (p=0.005), as well as seminal vesicle (SV) weight (p=0.005) and prostate lobe weights (p<0.006). This confirms that the hAR Q-tract polymorphism mediates in vivo tissue androgen sensitivity by impacting negative hypothalamic feedback and trophic androgen effects on target organs. In this manner, AR Q-tract length variation may influence numerous aspects of male health, from virilization to fertility, as well as androgen-dependent diseases, such as prostate cancer. PMID- 21664244 TI - Loss of APC function in mesenchymal cells surrounding the Mullerian duct leads to myometrial defects in adult mice. AB - The WNT signal transduction pathway plays a rate limiting role in early development of many different organs. To study the functional consequences of constitutive activation of the canonical WNT pathway in the developing uterus, we generated a novel mouse model where loss of the tumor suppressor gene Apc was induced. A mouse model was generated and evaluated where Amhr2(Cre/+) driven loss of Apc exon 15 was induced. The Apc recombination was detected mainly in the myometrial layer of the adult uterus. A significant loss of muscle fibers in myometrium was apparent, though with very few muscle cells earmarked by nuclear beta-catenin. The finding was confirmed in the Pgr(Cre/+);Apc(15lox/15lox) mouse model. Loss of APC function in mesenchymal cells surrounding the fetal Mullerian ducts results in severe defects in the myometrial layers of the uterus in adult mice, suggesting that the WNT signaling pathway plays important roles in maintaining myometrial integrity. PMID- 21664243 TI - 1,25-Dihydroxyvitamin D(3) regulates PTHrP expression via transcriptional, post transcriptional and post-translational pathways. AB - Parathyroid hormone-related protein (PTHrP) increases the growth and osteolytic potential of prostate cancer cells, making it important to control PTHrP expression. PTHrP expression is suppressed by 1,25-dihydroxyvitamin D(3) (1,25D). The aim of this study was to identify the pathways via which 1,25D exerts these effects. Our main findings are that 1,25D regulates PTHrP levels via multiple pathways in PC-3 and C4-2 (human prostate cancer) cell lines, and regulation is dependent on VDR expression. The human PTHrP gene has three promoters (P); PC-3 cells preferentially utilize P2 and P3, while C4-2 cells preferentially utilize P1. 1,25D regulates PTHrP transcriptional activity from both P1 and P3. The 1,25D mediated decrease in PTHrP mRNA levels also involves a post-transcriptional pathway since 1,25D decreases PTHrP mRNA stability. 1,25D also suppresses PTHrP expression directly at the protein level by increasing its degradation. Regulation of PTHrP levels is dependent on VDR expression, as using siRNAs to deplete VDR expression negates the 1,25D-mediated downregulation of PTHrP expression. These results indicate the importance of maintaining adequate 1,25D levels and VDR status to control PTHrP levels. PMID- 21664245 TI - VDR activation of intracellular signaling pathways in skeletal muscle. AB - The purpose of this article is to review the activation of signal transduction pathways in skeletal muscle cells by the hormone 1alpha,25(OH)(2)-vitamin D(3) [1alpha,25(OH)(2)D(3)], focusing on the role of the vitamin D receptor (VDR). The hormone induces fast, non transcriptional responses, involving stimulation of the transmembrane second messenger systems adenylyl cyclase/cAMP/PKA, PLC/DAG+IP(3)/PKC, Ca(2+) messenger system and MAPK cascades. Short treatment with 1alpha,25(OH)(2)D(3) induces reverse translocation of the VDR from the nucleus to plasma membranes. Accordingly, a complex is formed in the caveolae between the VDR and TRCP3, integral protein of capacitative Ca(2+) entry (CCE), suggesting an association between both proteins and a functional role of the VDR in 1alpha,25(OH)(2)D(3) activation of CCE. Stimulation of tyrosine phosphorylation cascades by 1alpha,25(OH)(2)D(3) have demonstrated the formation of complexes between Src and the VDR. Through these mechanisms, 1alpha,25(OH)(2)D(3) plays an important function in contractility and myogenesis. PMID- 21664246 TI - Inhibins and activins in blood: predictors of female reproductive health? AB - Inhibins A and B are gonadal factors which are important in fertility. Their use as predictors of female reproductive health has centred on their application to ovarian cancer, Anorexia Nervosa, Down Syndrome and preeclampsia. Inhibin B also provides an index of the endocrine feedback relationship between the ovary and pituitary particularly when the ovarian follicle reserve is low. These applications are relevant in monitoring the onset of the menopause transition, ovarian recovery following chemotherapy and disturbances in pubertal development. Currently, these applications have only found widespread use in Down Syndrome and ovarian cancer. Activins, on the other hand, appear to have a limited application. PMID- 21664247 TI - Vitamin D metabolism and activity in the parathyroid gland. AB - Parathormone (PTH) and vitamin D are two critical hormonal regulators of calcium homeostasis. An important cross-talk exists between the PTH and vitamin D hormonal systems. PTH enhances vitamin D hydroxylation on carbon 1 in kidney cells thereby allowing the systemic release of 1-25-dihydroxy-vitamin D, which represents the fully active hormone. Conversely, parathyroid gland represents a direct target for vitamin D. Parathyroid cells express the vitamin D receptor and the 1-alpha-hydroxylase enzyme, which allows the local formation of 1-25 dihydroxy-vitamin D. Because of its potential implication in several diseases, including osteoporosis or chronic kidney disease, the interplay between PTH and vitamin D has received considerable attention these last two decades. The aim of this review is to summarize our current understanding of the molecular basis of vitamin D action and metabolism in parathyroid cells. The potential clinical implications of the recent advances made in this field will also be discussed. PMID- 21664248 TI - Mimecan in pituitary corticotroph cells may regulate ACTH secretion and the HPAA. AB - Mimecan is a protein of unknown function that is expressed in the pituitary tissues of mouse and human. In this study, we observed the function of mimecan on the proopiomelanocortin (POMC) gene in the pituitary and the hypothalamo pituitary-adrenal axis (HPAA). Incubating pituitary corticotroph AtT-20 cells with recombinant mimecan protein stimulated adrenocorticotrophic hormone (ACTH) secretion without significantly up-regulating POMC gene expression. In addition, pituitary corticotroph AtT-20 cell corticotropin-releasing hormone receptor 1 (CRHR1) gene expression was induced by mimecan. Interestingly, long-term mimecan overexpression in corticotroph cells increased CRHR1 mRNA levels while slightly decreasing POMC mRNA expression and ACTH secretion. Using mimecan knockout mice, we found that, although the serum ACTH concentration was not significantly different between wild type and mimecan knockout mice under basal conditions, the serum ACTH level was relatively lower in mimecan knockout mice after treatment with corticotropin-releasing hormone (CRH). Meanwhile, we observed that POMC and CRHR1 gene expression decreased in primary cultured knockout mouse pituitary cells compared with wild type cells. Taken together, these data suggest that mimecan expressed in pituitary corticotroph cells mainly regulates ACTH secretion in the pituitary and coordinates the HPAA. PMID- 21664250 TI - The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes. AB - Recently fibroblast growth factor 21 (FGF21) has been identified as a potent regulator in glucose and lipid homeostasis. Here, we firstly investigated the metabolic role of FGF21 in human liver-derived HepG2 cells, and suggested that overexpression of FGF21 suppressed triglyceride accumulation by inhibiting the transcription of the gene necessary for de novo lipogenesis. The potential mechanism of FGF21 regulating lipogenesis was also explored, which revealed that FGF21 repressed the transcription of sterol regulatory element binding protein 1c (SREBP1c), an essential transcription factor promoting expression of lipogenesis related genes. Overexpression of FGF21 ameliorated the up-regulation of SREBP1c and fatty acid synthase (FAS) in HepG2 cells elicited by FFAs treatment. Moreover, FGF21 could inhibit the transcriptional levels of the key genes involved in processing and nuclear translocation of SREBP1c, and decrease the protein amount of mature SREBP1c. Unexpectedly, overexpression of SREBP1c in HepG2 cells could also inhibit the endogenous FGF21 transcription. Further experiments demonstrated that SREBP1c could significantly attenuate the promoter activity of FGF21. In conclusion, our data identifies a clear link between FGF21 and SREBP1c during lipogenesis in hepatocyte in culture. PMID- 21664251 TI - A novel aspect of GNAS imprinting: higher maternal expression of Galphas in human lymphoblasts, peripheral blood mononuclear cells, mammary adipose tissue, and heart. AB - The human GNAS gene is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in pituitary, thyroid, renal proximal tubules, and gonads, but is supposed to be biallelically expressed with an equal allelic expression in most other tissues. We analysed allelic expression of Galphas using Pyrosequencing. By genotyping the GNAS T393C polymorphism we quantified mRNA transcripts in lymphoblasts (Ly, n=11), peripheral blood mononuclear cells (PBMC, n=18), mammary adipose tissue (MAT, n=23) and heart tissue (HT, n=44). Allelic expression analysis revealed an unequal allelic expression (ratio maternal/total*100+/-SEM: 55.7+/-1% (95% CI 53.4-58.1%) in Ly, 56.1+/-0.8 (95% CI 54.5-57.7%) in PBMC, 54.5+/-0.8% (95% CI 53-56.1%) in MAT and 54.1+/-0.6% (95% CI 53-55.3%) in HT). Maternal ratio differed significantly from the mean (p<0.0001). This phenomenon may be a general feature existing in all tissues. PMID- 21664249 TI - Vitamin D metabolism and action in the prostate: implications for health and disease. AB - Prostate cancer (PCa) is the second most common cancer in men worldwide. Epidemiological, molecular, and cellular studies have implicated vitamin D deficiency as a risk factor for the development and/or progression of PCa. Studies using cell culture systems and animal models suggest that vitamin D acts to reduce the growth of PCa through regulation of cellular proliferation and differentiation. However, although preclinical studies provide a strong indication for anti-cancer activity, proof of therapeutic benefits in men is still lacking. The anti-proliferative and pro-differentiating properties of vitamin D have been attributed to calcitriol [1,25(OH)(2)D(3)], the hormonally active form of vitamin D, acting through the vitamin D receptor (VDR). Metabolism of vitamin D in target tissues is mediated by two key enzymes: 1alpha-hydroxylase (CYP27B1), which catalyzes the synthesis of calcitriol from 25(OH)D and 24 hydroxylase (CYP24), which catalyzes the initial step in the conversion of calcitriol to less active metabolites. Many factors affect the balance of calcitriol synthesis and catabolism and several maneuvers, like combination therapy of calcitriol with other drugs, have been explored to treat PCa and reduce its risk. The current paper is an overview addressing some of the key factors that influence the biological actions of vitamin D and its metabolites in the treatment and/or prevention of PCa. PMID- 21664252 TI - Transcriptome analysis of aldosterone-regulated genes in human vascular endothelial cell lines stably expressing mineralocorticoid receptor. AB - A series of studies have demonstrated that endothelial cell is one of the target tissues of aldosterone. Here, we have conducted a transcriptome analysis of aldosterone-inducible genes in human endothelial cell lines stably expressing human mineralocorticoid receptor (MR) by retroviral system (MR-EAhy). We found that aldosterone in physiologic concentrations robustly induced MR-dependent transcriptional response in MR-EAhy. By DNA microarray analysis, we validated 12 aldosterone-up-regulated genes among which at least seven were concomitantly associated with increased protein expression. We also found five aldosterone-down regulated genes. Among 11 aldosterone-up-regulated genes tested, mRNA expressions of three (ESM1, SNF1LK, ANGPTL4) were significantly up-regulated in aortic tissue from aldosterone-induced hypertensive rats compared to those from control rats, suggesting their potential pathophysiologic significance in vivo. In conclusion, using MR stably expressed human endothelial cell lines, we identified a variety of aldosterone-inducible genes, suggesting their possible roles in the development and/or the protection for aldosterone-induced vascular injury. PMID- 21664253 TI - Vitamin D metabolism, cartilage and bone fracture repair. AB - The 1,25-(OH)(2)D metabolite mediates the endocrine actions of vitamin D by regulating in the small intestine the expression of target genes that play a critical role in intestinal calcium absorption. The major role of the vitamin D hormone on bone is indirect and mediated through its endocrine function on mineral homeostasis. However, genetic manipulation of the expression of Cyp27b1 or the VDR in chondrocytes strongly support a direct role for locally synthesized 1,25(OH)(2)D, acting through the VDR, in vascular invasion and osteoclastogenesis during endochondral bone development. Cells from the growth plate respond to the 24,25-(OH)(2)D and 1,25-(OH)(2)D metabolites in a cell maturation-dependent manner and the effects of 1,25-(OH)(2)D are thought to be mediated through binding to the membrane-associated receptor PDIA3 (protein disulfide isomerase associated 3). The physiological relevance of membrane-mediated 1,25-(OH)(2)D signaling is emerging and is discussed. Finally, preliminary results suggest that mice deficient for Cyp24a1 exhibit a delay in bone fracture healing and support a role for 24,25-(OH)(2)D in mammalian fracture repair. PMID- 21664254 TI - The level of arousal modulates P50 peak amplitude. AB - We aimed to evaluate the effect of arousal level in healthy subjects on P50 potential, as the variation in the level of arousal may be a source of variance in the recordings as well as it may provide additional information about the pathology under study. Eleven healthy volunteers participated in the study. A standard auditory P50 potential paradigm was applied. Two stimulation conditions were selected: eyes-open, i.e., high arousal level condition and eyes-closed, i.e., low arousal level condition. P50 component amplitudes in response to both the first (S1) and second stimulus (S2) of the pair, their ratio and difference were evaluated. P50 amplitude in response to S1 was significantly higher during the low arousal closed eyes condition as compared to high arousal open eyes condition. There was no P50 amplitude difference in response to S2 and no arousal effect on gating measures. This prompts for more careful evaluation of patients' arousal level when performing P50 studies and interpreting the results. PMID- 21664256 TI - Novelty-induced activity-regulated cytoskeletal-associated protein (Arc) expression in frontal cortex requires serotonin 2A receptor activation. AB - Many psychiatric disorders are characterized by cognitive and emotional alterations that are related to abnormal function of the frontal cortex (FC). FC is involved in working memory and decision making and is activated following exposure to a novel environment. The serotonin 2A receptor (5-HT(2A)R) is highly expressed in the FC where its activation induces hallucinations, while blockade of 5-HT(2A)Rs contributes to the therapeutic effects of atypical antipsychotic drugs. The purpose of the present study was to investigate the involvement of 5 HT(2A)R in FC activation following exposure to a novel environment. As an output of FC activation we measured expression of activity-regulated cytoskeletal associated protein (Arc). Novelty-exposure (open-field arena) robustly up regulated FC Arc mRNA expression (~160%) in mice compared to home-cage controls. This response was inhibited with the 5-HT(2A)R antagonists ketanserin and MDL100907, but not with the selective 5-HT(2C)R antagonist SB242084. Novelty exposure also induced Arc mRNA expression in hippocampus (~150%), but not in cerebellum or brainstem. Pretreatment with 5-HT(2A)R antagonist ketanserin did not repress the Arc induction in hippocampus, indicating that the involvement of 5-HT(2A)R in this response is restricted to the FC. Similarly, the novelty induced stress as determined by increasing levels of plasma corticosterone, was not influenced by 5-HT(2A)R antagonism suggesting that Arc mRNA and stress are activated via distinct mechanisms. Taken together, our results demonstrate that the induction of Arc in the FC following exposure to a novel environment is dependent on the 5-HT(2A)R, and that the simultaneous release of corticosterone is regulated via another system independent of 5-HT(2A)R activation. PMID- 21664255 TI - Interactive effects of age and estrogen on cortical neurons: implications for cognitive aging. AB - In the past few decades it has become clear that estrogen signaling plays a much larger role in modulating the cognitive centers of the brain than previously thought possible. We have developed a nonhuman primate (NHP) model to investigate the relationships between estradiol (E) and cognitive aging. Our studies of cyclical E treatment in ovariectomized (OVX) young and aged rhesus monkeys have revealed compelling cognitive and synaptic effects of E in the context of aging. Delayed response (DR), a task that is particularly dependent on integrity of dorsolateral prefrontal cortex (dlPFC) area 46 revealed the following: (1) that young OVX rhesus monkeys perform equally well whether treated with E or vehicle (V), and (2) that aged OVX animals given E perform as well as young adults with or without E, whereas OVX V-treated aged animals display significant DR impairment. We have analyzed the structure of layer III pyramidal cells in area 46 in these same monkeys. We found both age and treatment effects on these neurons that are consistent with behavioral data. Briefly, reconstructions of pyramidal neurons in area 46 from these monkeys showed that cyclical E increased the density of small, thin spines in both young and aged monkeys. However, this effect of E was against a background of age-related loss of small, thin spines, leaving aged V-treated monkeys with a particularly low density of these highly plastic spines, and vulnerable to cognitive decline. Our current interpretation is that E not only plays a critically important role in maintaining spine number, but also enables synaptic plasticity through a cyclical increase in small highly plastic spines that may be stabilized in the context of learning. Interestingly, recent studies demonstrate that chronic E is less effective at inducing spinogenesis than cyclical E. We have begun to link certain molecular attributes of excitatory synapses in area 46 to E effects and cognitive performance in these monkeys. Given the importance of synaptic estrogen receptor alpha (ER-alpha) in rat hippocampus, we focused our initial studies on synaptic ER-alpha in area 46. Three key findings have emerged from these studies: (1) synaptic ER-alpha is present in axospinous synapses in area 46; (2) it is stable across treatment and age groups (which is not the case in rat hippocampus); and (3) the abundance and distribution of synaptic ER-alpha is a key correlate of individual variation in cognitive performance in certain age and treatment groups. These findings have important implications for the design of hormone treatment strategies for both surgically and naturally menopausal women. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. PMID- 21664258 TI - Reelin deficiency causes specific defects in the molecular composition of the synapses in the adult brain. AB - The extracellular protein Reelin regulates radial neuronal migration in the embryonic brain, promotes dendrite outgrowth in the developing postnatal forebrain, and strengthens synaptic transmission in the adult brain. Heterozygous reeler mice expressing reduced levels of Reelin are grossly normal but exhibit behavioral and physiological abnormalities. We previously demonstrated that dendritic spine density is reduced in the developing hippocampus of these mice. In this study, we investigated the consequence of Reelin deficiency on synapse formation in adult heterozygous reeler mice using imaging and biochemical approaches. Using a reeler colony that expresses yellow fluorescent protein in selected neurons, we analyzed spine density in hippocampal area CA1 by confocal microscopy and found modest abnormalities in heterozygous reeler mice. However, biochemical analysis of synaptic composition revealed specific postsynaptic defects in scaffolding proteins, neurotransmitter receptors, and signaling proteins. Using whole brain homogenates and purified pre- and postsynaptic fractions, we found that the defects were localized to the postsynaptic compartment of heterozygous reeler synapses. Decreased levels of postsynaptic density-95 (PSD-95), the N-methyl d-aspartate (NMDA) receptor subunits NR2A and NR2B, and the phosphatase PTEN were found specifically in the postsynaptic density fraction obtained from these mice. Furthermore, we found that PSD-95, NR2A, and PTEN interact with each other at the synapse. Finally, we show that levels of NR2A are reduced in conditional Pten knock out mice, demonstrating that the PTEN phosphatase regulates NMDA receptor expression at the synapse in vivo. These studies may provide insights into the etiology of cognitive disorders associated with deficiencies in Reelin signaling and PTEN dysfunction. PMID- 21664257 TI - Ethanol alters calcium signaling in axonal growth cones. AB - Calcium (Ca2+) channels are sensitive to ethanol and Ca2+ signaling is a critical regulator of axonal growth and guidance. Effects of acute and chronic exposure to ethanol (22, 43, or 87 mM) on voltage-gated Ca2+ channels (VGCCs) in whole cells, and KCl-induced Ca2+ transients in axonal growth cones, were examined using dissociated hippocampal cultures. Whole-cell patch-clamp analysis in neurons with newly-formed axons (Stage 3) revealed that rapidly inactivating, low-voltage activated (LVA) and non-inactivating, high-voltage activated (HVA) currents were both inhibited in a dose-dependent manner by acute ethanol, with relatively greater inhibition of HVA currents. When assessed by Fluo-4-AM imaging, baseline fluorescence and Ca2+ response to ethanol in Stage 3 neurons was similar compared to neurons without axons, but peak Ca2+ transient amplitudes in response to bath applied KCl were greater in Stage 3 neurons and were decreased by acute ethanol. The amplitude of Ca2+ transients elicited specifically in axonal growth cones by focal application of KCl was also inhibited by acute exposure to moderate-to-high concentrations of ethanol (43 or 87 mM), whereas a lower concentration (22 mM) had no effect. When 43 or 87 mM ethanol was present continuously in the medium, KCl-evoked Ca2+ transient amplitudes were also reduced in growth cones. In contrast, Ca2+ transients were increased by continuous exposure to 22 mM ethanol. Visualization using a fluorescent dihydropyridine analog revealed that neurons continuously exposed to ethanol expressed increased amounts of L-type Ca2+ channels, with greater increases in axonal growth cones than cell bodies. Thus, acute ethanol reduces Ca2+ current and KCl-induced Ca2+ responses in whole cells and axonal growth cones, respectively, and chronic exposure is also generally inhibitory despite apparent up-regulation of L-type channel expression. These results are consistent with a role for altered growth cone Ca2+ signaling in abnormal neuromorphogenesis associated with fetal alcohol spectrum disorders. PMID- 21664259 TI - Unusual signatures of highly adaptable R-loci in closely-related Arabidopsis species. AB - Plant resistance genes (R-genes) evolve rapidly in response to changing environments. What are the most remarkable signatures of fast adaptive genes, besides the commonly revealed rapid divergence and high non-synonymous substitution rate? Here we investigated these changes in five R-loci following recent differentiation between Arabidopsis thaliana and Arabidopsis lyrata. Extreme differences in evolutionary rates were observed: e.g., an overall 5.46 9.83-fold different nucleotide diversity at two R-loci between species, ten-fold higher non-synonymous substitution rates within one species versus the other, significantly different Ka/Ks ratios between species for the same R-gene, and high interspecific divergence at one R-locus. Particularly, we observed an elevated level of trans-specific polymorphism at one R-locus and a differentially maintained presence/absence polymorphism at another. The high frequency of ancestral polymorphisms amongst R-genes suggests that the persistence of some functional variation is an important evolutionary mechanism shaping genetic variation in R-genes, while the variation of presence/absence polymorphisms provides a potential mechanism for malleable activation of adaptive resistance response pathways. The distinct patterns among R-genes suggest that the same R gene ortholog can be quickly shaped by different evolutionary processes, e.g., purifying selection in one species but positive selection in a closely-related species. PMID- 21664260 TI - Differential gene expression in silkworm in response to Beauveria bassiana infection. AB - Host-pathogen interactions are complex processes, and revealing these interactions is challenging. Beauveria bassiana is a destructive pathogen to the economically beneficial silkworm, Bombyx mori, but is also a good pathogenic material for investigating insect responses to fungal infection. For better understanding of the molecular regulation of immune response and the interactive mechanism between the silkworm and B. bassiana, suppression subtractive hybridization was employed to identify differentially expressed genes in the pathogen-stimulated silkworm larvae. Complementary DNA libraries were constructed, in which 240 clones were sequenced. A total of 77 genes were found to be involved in the infection process, among which 55 were known genes and 22 were novel. Expression profiling of 6 genes by quantitative PCR showed that they were induced by fungal challenge. This study establishes the first step to understanding the molecular mechanisms by which silkworm responds to fungal infection. PMID- 21664261 TI - Regulation of gene expression at the fission yeast Schizosaccharomyces pombe urg1 locus. AB - The lack of a rapid and efficient system to regulate transcriptional induction in the fission yeast Schizosaccharomyces pombe is currently a limitation of this model eukaryote. The commonly used nmt1 promoter has excellent dynamic range and a low "off-state" transcription, but takes 14-16 hours to induce upon thiamine withdrawal. Conversely, other induction systems have rapid response times, but suffer from a limited dynamic range and/or relatively high levels of off-state transcription. Recently, the urg1 gene was identified as a rapidly induced transcript, responding to uracil addition in ~30 min and exhibiting low off-state transcription and high dynamic range. However, attempts to reproduce this ectopically result in a significant increase in off-state transcription, severely limiting utility. To overcome this, we have adapted the Cre/lox recombination mediated cassette exchange (RCME) system to facilitate easy insertion of sequences at the urg1 locus. We show that the P(urg1) induction kinetics are maintained when ectopic open reading frames (ORFs) replace the native urg1 ORF. As proof of principle, we characterise HO-endonuclease expression in cells harbouring a novel S. pombe single-strand annealing (SSA) assay. After 60 min induction we observe clear double-strand breaks, demonstrate >90% of cells are committed to SSA and show that the Rad22(Rad52) repair protein associates robustly with sequences adjacent to the DSB. This inducible system will be a valuable tool for future studies in S. pombe. PMID- 21664262 TI - Molecular diagnosis of two families with classic congenital adrenal hyperplasia. AB - We investigated the genetic defects in two families with classic congenital adrenal hyperplasia (CAH). Clinical data and vein blood of the family members were collected, hormonal evaluation, karyotype analysis, ultrasound and CT scans were performed, and a direct-sequencing of PCR products of the candidate genes was used to identify the mutations. In family A, Patients A-II:1 and A-II:2 were found to be in a compound heterozygous state for mutations of p.I172N (g.1004T>A) in exon 4 and IVS2-13A/C>G (g.659A/C>G) in intron 2 in CYP21A2 gene, their father A-I:1 and mother A-I:2 were found to carry a heterozygous mutation of IVS2 13A/C>G (g.659A/C>G) and p.I172N (g.1004T>A) respectively. In family B, Patient B II:1 was detected to carry only one heterozygous mutation of p.I172N; no other mutations in CYP11B1, CYP17A1 or HSD3B2 genes were detected. Her father B-I:1 carried a heterozygous mutation of p.I172N (g.1004T>A) and her mother B-I:2 was found to be a wild type in all the candidate genes. Obviously, patients A-II:1 and A-II:2 inherited the p.I172N (g.1004T>A)-bearing maternal allele and the IVS2 13A/C>G (g.659A/C>G)-bearing paternal allele. And this kind of compound heterozygous mutations caused simple virilising (SV) CAH. While patient B-II:1, whose phenotype was SV CAH too, was found to carry only one heterozygous mutation of the p.I172N (g.1004T>A)-bearing paternal allele, and needed further studies. PMID- 21664264 TI - Activation of presynaptic GABAB receptors modulates GABAergic and glutamatergic inputs to the medial geniculate body. AB - The medial geniculate body (MGB) receives ascending inputs from the inferior colliculus and descending inputs from the auditory cortex. In the present study, we intended to determine whether activation of presynaptic GABA(B) receptors modulates GABAergic and glutamatergic inputs to the MGB with whole-cell patch clamp recordings in brain slices of the rat. To evoke a synaptic response, we electrically stimulated the ascending and descending inputs to MGB neurons with bipolar electrodes placed on the brachium of the inferior colliculus and the superior thalamic radiation. To isolate presynaptic mechanisms, we blocked the effects of postsynaptic GABA(B) receptors by filling recording electrodes with the internal solution containing cesium and QX-314. The activation of presynaptic GABA(B) receptors by exogenous agonist was shown to modulate synaptic inputs to the MGB as demonstrated by that (1) baclofen, a GABA(B) receptor agonist, reversibly suppressed both inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) and this suppressive effect could be blocked by CGP35348, a GABA(B) receptor antagonist, (2) baclofen significantly increased the ratio of IPSCs or EPSCs elicited by paired-pulse stimulation, and (3) baclofen depressed EPSCs and IPSCs in response to repetitive stimulation. The activation of presynaptic GABA(B) receptors by endogenously released GABA was shown to modulate the synaptic transmission as demonstrated by that CGP55845, another GABA(B) receptor antagonist, increased the ratio of IPSCs to paired-pulse stimulation in young (P8-10) rats, although not in juvenile (P15-18) rats. Our study provides electrophysiological evidence for the presence of functional presynaptic GABA(B) receptors in the MGB and suggests an age-dependent role of these receptors in the synaptic transmission in this central auditory region. PMID- 21664263 TI - Impaired perception of temporal fine structure and musical timbre in cochlear implant users. AB - Cochlear implant (CI) users demonstrate severe limitations in perceiving musical timbre, a psychoacoustic feature of sound responsible for 'tone color' and one's ability to identify a musical instrument. The reasons for this limitation remain poorly understood. In this study, we sought to examine the relative contributions of temporal envelope and fine structure for timbre judgments, in light of the fact that speech processing strategies employed by CI systems typically employ envelope extraction algorithms. We synthesized "instrumental chimeras" that systematically combined variable amounts of envelope and fine structure in 25% increments from two different source instruments with either sustained or percussive envelopes. CI users and normal hearing (NH) subjects were presented with 150 chimeras and asked to determine which instrument the chimera more closely resembled in a single-interval two-alternative forced choice task. By combining instruments with similar and dissimilar envelopes, we controlled the valence of envelope for timbre identification and compensated for envelope reconstruction from fine structure information. Our results show that NH subjects utilize envelope and fine structure interchangeably, whereas CI subjects demonstrate overwhelming reliance on temporal envelope. When chimeras were created from dissimilar envelope instrument pairs, NH subjects utilized a combination of envelope (p = 0.008) and fine structure information (p = 0.009) to make timbre judgments. In contrast, CI users utilized envelope information almost exclusively to make timbre judgments (p < 0.001) and ignored fine structure information (p = 0.908). Interestingly, when the value of envelope as a cue was reduced, both NH subjects and CI users utilized fine structure information to make timbre judgments (p < 0.001), although the effect was quite weak in CI users. Our findings confirm that impairments in fine structure processing underlie poor perception of musical timbre in CI users. PMID- 21664265 TI - Motile responses of cochlear outer hair cells stimulated with an alternating electrical field. AB - The goal of the present study was to evaluate and characterize the motile responses of guinea pig OHCs, stimulated at frequencies varying from 50 Hz to 4 kHz, using high-definition, high-speed video recording and fully automatic image analysis software. Cells stimulated in continuous, burst and sweeping modes with an external alternating electrical field showed robust fast and slow motility, which were dependent on frequency, mode and intensity of stimulation. In response to continuous stimulation, electromotile amplitude ranged from 0.3% to 3.2% of total cell length, whereas cell length usually decreased in amounts varying from 0.1% to 4.3%. Electromotile amplitude in OHCs stimulated with square wave's sweeps was near constant up to 200 Hz, progressively decreased between 200 Hz and 2 kHz, and then remained constant up to 4 kHz. In continuous and burst modes electromotility followed cycle-by-cycle the electrical stimulus, but it required 1-2 s to fully develop and reach maximal amplitude. Instead, slow cell length changes started about 0.6 s after the beginning and continuously developed up to 3 s after the end of electrical stimulation. Incubation of OHCs with 10 mM salicylate affected electromotility but not slow motility, whereas incubation with 3 mM gadolinium affected both. Thus, combination of external electrical stimulation, high-speed video recording and advanced image analysis software provides information about OHC motile responses at acoustic frequencies with an unprecedented detail, opening new areas of research in the field of OHC mechanics. PMID- 21664266 TI - Production and harvesting of microalgae for wastewater treatment, biofuels, and bioproducts. AB - The integration of microalgae-based biofuel and bioproducts production with wastewater treatment has major advantages for both industries. However, major challenges to the implementation of an integrated system include the large-scale production of algae and the harvesting of microalgae in a way that allows for downstream processing to produce biofuels and other bioproducts of value. Although the majority of algal production systems use suspended cultures in either open ponds or closed reactors, the use of attached cultures may offer several advantages. With regard to harvesting methods, better understanding and control of autoflocculation and bioflocculation could improve performance and reduce chemical addition requirements for conventional mechanical methods that include centrifugation, tangential filtration, gravity sedimentation, and dissolved air flotation. There are many approaches currently used by companies and industries using clean water at laboratory, bench, and pilot scale; however, large-scale systems for controlled algae production and/or harvesting for wastewater treatment and subsequent processing for bioproducts are lacking. Further investigation and development of large-scale production and harvesting methods for biofuels and bioproducts are necessary, particularly with less studied but promising approaches such as those involving attached algal biofilm cultures. PMID- 21664269 TI - Major determinants of photoinduced cell death: Subcellular localization versus photosensitization efficiency. AB - We present a study on whether and to what extent subcellular localization may compete favorably with photosensitization efficiency with respect to the overall efficiency of photoinduced cell death. We have compared the efficiency with which two cationic photosensitizers, namely methylene blue (MB) and crystal violet (CV), induce the photoinduced death of human cervical adenocarcinoma (HeLa) cells. Whereas MB is well known to generate singlet oxygen and related triplet excited species with high quantum yields in a variety of biological and chemical environments (i.e., acting as a typical type II photosensitizer), the highly mitochondria-specific CV produces triplet species and singlet oxygen with low yields, acting mostly via the classical type I mechanism (e.g., via free radicals). The findings described here indicate that the presumably more phototoxic type II photosensitizer (MB) does not lead to higher degrees of cell death compared to the type I (CV) photosensitizer. In fact, CV kills cells with the same efficiency as MB, generating at least 10 times fewer photoinduced reactive species. Therefore, subcellular localization is indeed more important than photochemical reactivity in terms of overall cell killing, with mitochondrial localization representing a highly desirable property for the development of more specific/efficient photosensitizers for photodynamic therapy applications. PMID- 21664271 TI - Anxiety-like behaviour in mice exposed to tannery wastewater: The effect of photoelectrooxidation treatment. AB - The leather industry is a major producer of wastewaters and releases large quantities of many different chemical agents used in hide processing into the environment. Since the central nervous system is sensitive to many different contaminants, our aim was to investigate the neurobehavioral effects of exposure of mice to tannery effluents using animal models of depression and anxiety, namely forced swim and elevated plus-maze. In order to propose a clean technology for the treatment of this effluent, we also investigated the exposure of mice to effluents treated by photoelectrooxidation process (PEO). Adult male Swiss albino mice (CF1 strain) were given free access to water bottles containing an effluent treated by a tannery (non-PEO) or PEO-treated tannery wastewater (0.1 and 1% in drinking water). Exposure to tannery wastewater induced behavioural changes in the mice in elevated plus-maze. Exposure to non-PEO 1% decreased the percentage of time spent in the open arms, indicating anxiety-like behaviour. Exposure to tannery wastewater did not alter immobility time in the forced swim test, suggesting that tannery effluents did not induce depression-like behaviour in the mice. These behavioural data suggest that non-PEO tannery effluent has an anxiogenic effect, whereas PEO-treated tannery effluents do not alter anxiety levels. PMID- 21664270 TI - The rate of oxygen utilization by cells. AB - The discovery of oxygen is considered by some to be the most important scientific discovery of all time--from both physical-chemical/astrophysics and biology/evolution viewpoints. One of the major developments during evolution is the ability to capture dioxygen in the environment and deliver it to each cell in the multicellular, complex mammalian body-on demand, i.e., just in time. Humans use oxygen to extract approximately 2550 calories (10.4 MJ) from food to meet daily energy requirements. This combustion requires about 22 mol of dioxygen per day, or 2.5*10(-4) mol s(-1). This is an average rate of oxygen utilization of 2.5*10(-18) mol cell(-1) s(-1), i.e., 2.5 amol cell(-1) s(-1). Cells have a wide range of oxygen utilization, depending on cell type, function, and biological status. Measured rates of oxygen utilization by mammalian cells in culture range from <1 to >350 amol cell(-1) s(-1). There is a loose positive linear correlation of the rate of oxygen consumption by mammalian cells in culture with cell volume and cell protein. The use of oxygen by cells and tissues is an essential aspect of the basic redox biology of cells and tissues. This type of quantitative information is fundamental to investigations in quantitative redox biology, especially redox systems biology. PMID- 21664272 TI - Adaptor protein Nck1 interacts with p120 Ras GTPase-activating protein and regulates its activity. AB - Adaptor protein Nck1 binds a number of intracellular proteins and influences various signaling pathways. Here we show that Nck1 directly binds and activates the GTPase-activating protein of Ras (RasGAP), which is responsible for the down regulation of Ras. The first and the third SH3 domains of Nck1 and the NH(2) terminal proline-rich sequence of RasGAP contribute most to the complex formation causing direct molecular interaction between the two proteins. Cell adhesion to the substrate is obligatory for the Nck1 and RasGAP association, as cell detachment makes RasGAP incapable of associating with Nck1. This leads to the complex dissipation, decrease of RasGAP activity and the increase of H-Ras-GTP level in the detached cells. Our findings reveal unexpected feature of adaptor protein Nck1 as the regulator of RasGAP activity. PMID- 21664268 TI - Vitamins C and E: beneficial effects from a mechanistic perspective. AB - The mechanistic properties of two dietary antioxidants that are required by humans, vitamins C and E, are discussed relative to their biological effects. Vitamin C (ascorbic acid) is an essential cofactor for alpha-ketoglutarate dependent dioxygenases. Examples are prolyl hydroxylases, which play a role in the biosynthesis of collagen and in down-regulation of hypoxia-inducible factor (HIF)-1, a transcription factor that regulates many genes responsible for tumor growth, energy metabolism, and neutrophil function and apoptosis. Vitamin C dependent inhibition of the HIF pathway may provide alternative or additional approaches for controlling tumor progression, infections, and inflammation. Vitamin E (alpha-tocopherol) functions as an essential lipid-soluble antioxidant, scavenging hydroperoxyl radicals in a lipid milieu. Human symptoms of vitamin E deficiency suggest that its antioxidant properties play a major role in protecting erythrocyte membranes and nervous tissues. As an antioxidant, vitamin C provides protection against oxidative stress-induced cellular damage by scavenging of reactive oxygen species, by vitamin E-dependent neutralization of lipid hydroperoxyl radicals, and by protecting proteins from alkylation by electrophilic lipid peroxidation products. These bioactivities bear relevance to inflammatory disorders. Vitamin C also plays a role in the function of endothelial nitric oxide synthase (eNOS) by recycling the eNOS cofactor, tetrahydrobiopterin, which is relevant to arterial elasticity and blood pressure regulation. Evidence from plants supports a role for vitamin C in the formation of covalent adducts with electrophilic secondary metabolites. Mechanism-based effects of vitamin C and E supplementation on biomarkers and on clinical outcomes from randomized, placebo-controlled trials are emphasized in this review. PMID- 21664273 TI - Cloning, expression, purification, and characterization of the membrane protein UncI from Escherichia coli. AB - The Escherichia coli unc-operon encodes the genes for the subunits of the F0F1 ATP synthase and an integral membrane protein of unknown function called UncI. UncI influences the cell-growth and activity of F0F1, but its exact function is still unknown. The expression level is too low to extract milligram amounts of UncI from E. coli membranes and the existing purification protocol based on methanol/chloroform is not suitable for structural and functional studies. Here we present protocols to increase the expression level, to purify UncI in a detergent where UncI is monodisperse, and we characterize its oligomeric state. PMID- 21664274 TI - The gamma-chain cytokine/receptor system in fish: more ligands and receptors. AB - The mammalian gamma-chain (gammaC) cytokine family consists of interleukin (IL) 2, IL-4, IL-7, IL-9, IL-15 and IL-21. They signal through a receptor complex containing the common gammaC and a private alpha chain, and in the case of IL-2 and IL-15 an additional common IL-2/15Rbeta chain. Deficiency of gammaC signalling in mammals prevents CD4+ T cells from developing effector functions and CD8+ T cells from developing immunological memory. Thus gammaC cytokines are critical for the generation and peripheral homeostasis of naive and memory T cells. This review will give an update on the gammaC ligands and receptor subunits in fish, and also present some new data on the cloning and expression of a second gammaC and two IL-2Rbeta chains in rainbow trout Oncorhynchus mykiss. In recent years, aided by the availability of sequenced fish genomes and expressed sequence tag databases, five of the six mammalian gammaC cytokines and their cognate receptors have been discovered in fish, with only the IL-9/IL-9R homologues apparently absent. Paralogues have been discovered in diploid fish and all the receptors described in the tetraploid rainbow trout, including gammaC itself, IL-2Rbeta, IL-4Ralpha, IL-13Ralpha1, IL-13Ralpha2 and IL-2/15Ralpha, have duplicates. As a consequence of the teleost and salmonid whole genome duplications, even more paralogues may yet be discovered. Some of the paralogues have changes in domain structures and show differential expression and modulation, suggesting the potential for a change in function. Functional characterisation of fish gammaC cytokines is beginning but made more difficult by the co-existence of so many paralogues of the ligands and their receptors. Initial functional studies have shown that fish gammaC cytokines can modulate the expression of key cytokines (e.g. interferon-gamma, IL-10 and IL-22) of the adaptive immune response, and may thus have promise as adjuvants to improve vaccination efficiency in fish. PMID- 21664277 TI - Higher or lower? The functional anatomy of perceived allocentric social hierarchies. AB - The perception and judgement of social hierarchies forms an integral part of social cognition. Hierarchical judgements can be either self-referential or allocentric (pertaining to two or more external agents). In psychiatric conditions such as dissocial personality disorder and schizophrenia, the impact of hierarchies may be problematic. We sought to elucidate the brain regions involved in judging allocentric social hierarchies. Twenty-two healthy male subjects underwent three fMRI scans. During scanning, subjects answered questions concerning visually-presented target pairs of human individual's relative superiority within a specific social hierarchy or their perceived degree of social alliance (i.e., whether they were "friends or enemies"). Subjects also made judgements relating to target pairs' age, gender and fame to control for confounding factors and performed a baseline numerical task. Response times increased in line with hypothesized ascending executive load. Both social hierarchy and social alliance judgements activated left ventrolateral prefrontal cortex (VLPFC), left dorsal inferior frontal gyrus (IFG) and bilateral fusiform gyri. In addition, social alliance judgements activated right dorsal IFG and medial prefrontal cortex. When compared directly with social alliance, social hierarchy judgements activated left orbitofrontal cortex. Detecting the presence of social hierarchies and judging other's relative standing within them implicates the cognitive executive, in particular the VLPFC. Our finding informs accounts of 'normal' social cognition but our method also provides a means of probing the dissocial brain in personality disorder and schizophrenia where executive function may be dysfunctional. PMID- 21664276 TI - Functional neuroimaging of the baboon during concurrent image-guided transcranial magnetic stimulation. AB - Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. However the underlying mechanisms of TMS-induced alterations in brain function are not well understood. As a result, treatment design parameters are determined ad hoc and not informed by any coherent theory or model. Once the mechanisms underlying TMS's modulatory effects on brain systems are better understood and modeled, TMS's potential as a therapeutic and/or investigative tool will be more readily explored and exploited. An animal model is better suited to study different TMS variables, therefore we developed a baboon model to facilitate testing of some of the current theoretical models of TMS interactions with brain regions. We have demonstrated the feasibility of this approach by successfully imaging cerebral blood flow (CBF) changes with H(2)(15)O positron emission tomography imaging during high-frequency, suprathreshold repetitive TMS in the primary motor cortex of five healthy, adult baboons. PMID- 21664278 TI - Differential roles of caudate nucleus and putamen during instrumental learning. AB - The dorsal striatum is crucial for the acquisition and consolidation of instrumental behaviour, but the underlying computations and internal dynamics remain elusive. To address this issue, we combined a model of key computations supporting decision-making during instrumental learning with human behavioural and functional magnetic resonance imaging (fMRI) data. The results showed that the associative and sensorimotor dorsal striatum host complementary computations that, we suggest, may differentially support goal-directed and habitual processes. The anterior caudate nucleus integrates information about performance and cognitive control demands, whereas the putamen tracks how likely the conditioning stimuli lead to correct response. Contrary to current models, the putamen is recruited during initial acquisition. As the exploratory phase proceeds, the relative contribution of the caudate nucleus becomes dominant over the putamen. During early consolidation, caudate nucleus and putamen settle to asymptotic values and share control. We then investigated how dorsal striatal computations may affect decision-making. We found that portion of reaction times' variance parallels the combined cost associated with the dorsal striatal computations. Overall, our findings provide a deeper insight into the functional heterogeneity within the dorsal striatum and suggest that the dynamic interplay between caudate nucleus and putamen, rather than their serial recruitment, underlies the acquisition and early consolidation of instrumental behaviours. PMID- 21664275 TI - On the context-dependent nature of the contribution of the ventral premotor cortex to speech perception. AB - What is the nature of the interface between speech perception and production, where auditory and motor representations converge? One set of explanations suggests that during perception, the motor circuits involved in producing a perceived action are in some way enacting the action without actually causing movement (covert simulation) or sending along the motor information to be used to predict its sensory consequences (i.e., efference copy). Other accounts either reject entirely the involvement of motor representations in perception, or explain their role as being more supportive than integral, and not employing the identical circuits used in production. Using fMRI, we investigated whether there are brain regions that are conjointly active for both speech perception and production, and whether these regions are sensitive to articulatory (syllabic) complexity during both processes, which is predicted by a covert simulation account. A group of healthy young adults (1) observed a female speaker produce a set of familiar words (perception), and (2) observed and then repeated the words (production). There were two types of words, varying in articulatory complexity, as measured by the presence or absence of consonant clusters. The simple words contained no consonant cluster (e.g. "palace"), while the complex words contained one to three consonant clusters (e.g. "planet"). Results indicate that the left ventral premotor cortex (PMv) was significantly active during speech perception and speech production but that activation in this region was scaled to articulatory complexity only during speech production, revealing an incompletely specified efferent motor signal during speech perception. The right planum temporal (PT) was also active during speech perception and speech production, and activation in this region was scaled to articulatory complexity during both production and perception. These findings are discussed in the context of current theories of speech perception, with particular attention to accounts that include an explanatory role for mirror neurons. PMID- 21664279 TI - Brain activation during audiovisual exposure anticipates future perception of ambiguous speech. AB - In modern perceptual neuroscience, the focus of interest has shifted from a restriction to individual modalities to an acknowledgement of the importance of multisensory processing. One particularly well-known example of cross-modal interaction is the McGurk illusion. It has been shown that this illusion can be modified, such that it creates an auditory perceptual bias that lasts beyond the duration of audiovisual stimulation, a process referred to as cross-modal recalibration (Bertelson et al., 2003). Recently, we have suggested that this perceptual bias is stored in auditory cortex, by demonstrating the feasibility of retrieving the subjective perceptual interpretation of recalibrated ambiguous phonemes from functional magnetic resonance imaging (fMRI) measurements in these regions (Kilian-Hutten et al., 2011). However, this does not explain which brain areas integrate the information from the two senses and represent the origin of the auditory perceptual bias. Here we analyzed fMRI data from audiovisual recalibration blocks, utilizing behavioral data from perceptual classifications of ambiguous auditory phonemes that followed these blocks later in time. Adhering to this logic, we could identify a network of brain areas (bilateral inferior parietal lobe [IPL], inferior frontal sulcus [IFS], and posterior middle temporal gyrus [MTG]), whose activation during audiovisual exposure anticipated auditory perceptual tendencies later in time. We propose a model in which a higher-order network, including IPL and IFS, accommodates audiovisual integrative learning processes, which are responsible for the installation of a perceptual bias in auditory regions. This bias then determines constructive perceptual processing. PMID- 21664280 TI - Beyond acute social stress: increased functional connectivity between amygdala and cortical midline structures. AB - Whereas we know a fair amount on the role of the amygdala in the acute stress response, virtually nothing is known about its role during the recovery period after the stress has waned. Functional connectivity analysis of the amygdala during this period might be useful in revealing brain circuits promoting adaptive recovery from a stressful event, as well as consolidation of emotionally relevant information in preparing for future challenges. Healthy participants were randomly assigned to either a psychosocial stress task (n=18; stress group) or a comparable non-stressful control procedure (n=20; controls). To study the prolonged effects of stress on amygdala functional connectivity, resting-state fMRI scans were acquired an hour after the stress task. Amygdala functional connectivity with other brain regions was assessed using seed-based correlations. The stress group exhibited a strong physiological and behavioral reaction to psychosocial stress exposure. Compared with controls the stress group showed increased amygdala functional connectivity with three cortical midline structures: the posterior cingulate cortex and precuneus (p<.05, corrected), and the medial prefrontal cortex (p<.05, small volume corrected). An hour after psychosocial stress, changes in amygdala functional connectivity were detected with cortical midline structures involved in the processing and regulation of emotions, as well as autobiographical memory. It is hypothesized that these effects could relate to top-down control of the amygdala and consolidation of self-relevant information after a stressful event. These results on functional connectivity in the recovery phase after stress might provide an important new vantage point in studying both sensitivity and resilience to stress. PMID- 21664281 TI - Emotion modulates the effects of endogenous attention on retinotopic visual processing. AB - A fundamental challenge for organisms is how to focus on perceptual information relevant to current goals while remaining able to respond to goal-irrelevant stimuli that signal potential threat. Here, we studied how visual threat signals influence the effects of goal-directed spatial attention on the retinotopic distribution of processing resources in early visual cortex. We used a combined blocked and event-related functional magnetic resonance imaging paradigm with target displays comprising diagonal pairs of intact and scrambled faces presented simultaneously in the four visual field quadrants. Faces were male or female and had fearful or neutral emotional expressions. Participants attended covertly to a pair of two diagonally opposite stimuli and performed a gender-discrimination task on the attended intact face. In contrast to the fusiform face area, where attention and fearful emotional expression had additive effects, neural responses to attended and unattended fearful faces were indistinguishable in early retinotopic visual areas: When attended, fearful face expression did not further enhance responses, whereas when unattended, fearful expression increased responses to the level of attended face stimuli. Remarkably, the presence of fearful stimuli augmented the enhancing effect of attention on retinotopic responses to neutral faces in remote visual field locations. We conclude that this redistribution of neural activity in retinotopic visual cortex may serve the purpose of allocating processing resources to task-irrelevant threat-signaling stimuli while at the same time increasing resources for task-relevant stimuli as required for the maintenance of goal-directed behavior. PMID- 21664282 TI - Phylogeny and character evolution in the jelly fungi (Tremellomycetes, Basidiomycota, Fungi). AB - The Tremellomycetes (Agaricomycotina, Basidiomycota, Fungi) are a nutritionally heterogeneous group comprising saprotrophs, animal parasites, and fungicolous species (fungal-inhabiting, including lichen-inhabiting). The relationships of many species, particularly those with a lichenicolous habit, have never been investigated by molecular methods. We present a phylogeny of the Tremellomycetes based on three nuclear DNA ribosomal markers (nSSU, 5.8S and nLSU), representing all main taxonomic groups and life forms, including lichenicolous taxa. The Cystofilobasidiales, Filobasidiales, Holtermanniales, and Tremellales (including the Trichosporonales) are recovered as monophyletic, but this is not the case for the Tremellomycetes. We suggest, however, that the Cystofilobasidiales tentatively continue to be included in the Tremellomycetes. As currently circumscribed, the Filobasidiaceae, Sirobasidiaceae, Syzygosporaceae and Tremellaceae are non-monophyletic. Cuniculitremaceae, Sirobasidiaceae and Tetragoniomycetaceae are nested within Tremellaceae. The lichenicolous species currently included within the Tremellomycetes belong in this group, distributed across the Filobasidiales and Tremellales. Lichen-inhabiting taxa do not form a monophyletic group; they are distributed in several clades and sometimes intermixed with taxa of other nutritional habits. Character state reconstruction indicates that two morphological traits claimed to characterize groups in the Tremellomycetes (the basidium habit and basidium septation) are highly homoplastic. Comparative phylogenetic methods suggest that the transitions between single and catenulate basidia in the Tremellales are consistent with a punctuational model of evolution whereas basidium septation is likely to have evolved under a graduational model in the clade comprising the Holtermanniales, Filobasidiales, and Tremellales. PMID- 21664283 TI - Human aggrecanase generated synovial fluid fragment levels are elevated directly after knee injuries due to proteolysis both in the inter globular and chondroitin sulfate domains. AB - OBJECTIVE: To examine different aggrecanase generated fragments in synovial fluid (SF) from patients with acute and chronic knee injuries and from knee healthy subjects. METHODS: We prepared SF-D1 samples from acute (n=35) and chronic (n=35) knee injury patients and knee healthy subjects (n=10). Aggrecan fragments were analyzed in the SF-D1 samples by quantitative (G1, ARGS, KEEE and G3 antibodies) and non-quantitative (GRGT and AGEG antibodies) Western blot. RESULTS: ARGS-SELE, ARGS-chondroitin sulfate (CS)1, GRGT-, GLGS- and AGEG-G3 fragments were the main ARGS and G3 fragments in injured and reference samples. In the acute injury samples the concentrations of these fragments were increased compared to the reference, and the level of the ARGS-SELE remained elevated for at least 2 years after the joint injury. Both SF ARGS fragments and aggrecanase generated G3 fragments had high sensitivity and specificity as biomarkers in distinguishing injured from healthy knee joints, although the ARGS fragments had higher area under the receiver operating characteristic curve (AUC) values for injuries (74 86%) than the G3 fragments (AUC values 63-68%). CONCLUSION: Our results suggest that during the acute phase after knee injury there is an increased aggrecanase activity against both the interglobular domain (IGD) and the CS2 cleavage sites of joint cartilage aggrecan. This increase in SF aggrecanolytic fragments is present for several years after the injury. SF ARGS fragments are better biomarkers than the aggrecanase generated G3-fragments in distinguishing injured from healthy knee joints. PMID- 21664284 TI - Epidemiological characteristics of infections caused by Bacteroides, Prevotella and Fusobacterium species: a prospective observational study. AB - In order to investigate differences among infections due to Gram-negative anaerobic bacteria (Bacteroides, Prevotella and Fusobacterium spp.), clinical, epidemiological, and microbiological data were collected and evaluated from 206 anaerobic infections. The most frequently isolated species was Bacteroides fragilis. The majority of the cases were intra-abdominal infections (49%) followed by skin and soft tissue infections (24.7%). Logistic regression analysis showed that Bacteroides spp. strains were more often isolated from intra abdominal infections (p = 0.002), whereas Prevotella spp. were isolated more frequently from cases with shorter duration of hospitalization (p = 0.026), and less frequently from bloodstream infections (p = 0.049). In addition, Bacteroides spp. were associated with coinfection due to Enterobacteriaceae species (p = 0.007), whereas Prevotella spp. were associated with coinfection due to Staphylococcus spp. (p = 0.002). Patients with an infection due to B. fragilis, were more frequently admitted in a general surgical ward (p = 0.017), or have been treated with a 2nd generation cephalosporin before anaerobic infection onset (p = 0.05). Total mortality was 10.9% and was associated with bacteremia (p = 0.026), and hematological (p = 0.028), or solid organ malignancy (p = 0.007). Metronidazole resistance was detected only among Prevotella spp. (16.2%) and B. fragilis group (0.8%) isolates. In conclusion, this study indicated differences between infections due to the most frequently isolated Gram-negative anaerobic species, differences that may affect the design and implementation of empirical antimicrobial chemotherapy guidelines. PMID- 21664285 TI - Clinicopathological and immunological studies on toxoids vaccine as a successful alternative in controlling clostridial infection in broilers. AB - The present study was conducted to evaluate the efficacy and safety of three vaccination regimes of Clostridium perfringens (C. perfringens) type A, C and combined A&C toxoids based on their clinical signs and immunological effects. The vaccines were administered two times at two weeks interval (7 & 21 days old), then the birds were challenged (35 days old) with virulent strains of C. perfringens type A, C and combined A&C. Blood samples were taken one week after the first and second vaccination as well as after challenge. The evaluated parameters in this study included: clinical signs, gross intestinal lesions, complete blood count (CBC), serum protein, liver profiles, and enzyme-linked immunosorbent assay (ELISA) test for detecting serum antibody titers. The results revealed that immunization of broilers with C. perfringens type A, C and combined A&C toxoids resulted in a significant decrease in numbers of chickens with intestinal lesions particularly with the A&C toxoids vaccine. Results of the CBC values were significantly increased in all treated groups and challenged groups. Total leukocytic count decreased in challenged non vaccinated group while increased in challenged vaccinated birds. Results of biochemical assays implicated that there were a significant increase in serum protein and liver profiles. ELISA results explored a significant increase in antibody titers after immunization of broilers with C. perfringens type A, C and combined A&C toxoids particularly after the second dose of vaccination. We concluded that immunization of broilers with toxoid vaccines particularly the combined type A & C is safe, well-tolerated and can protect broiler chickens against necrotic enteritis particularly after the second booster dose of the vaccine. PMID- 21664286 TI - Cytomegalovirus viral load and virus-specific immune reconstitution after peripheral blood stem cell versus bone marrow transplantation. AB - Peripheral blood stem cell (PBSC) products contain more T cells and monocytes when compared with bone marrow (BM), leading to fewer bacterial and fungal infections. Cytomegelovirus (CMV) viral load and disease as well as CMV-specific immune reconstitution were compared in patients enrolled in a randomized trial comparing PSBC and BM transplantation. There was a higher rate of CMV infection and disease during the first 100 days after transplantation among PBSC recipients (any antigenemia/DNAemia: PBSC, 63% vs BM, 42%, P = .04; CMV disease: PBSC, 17% vs BM, 4%, P = .03). By 2 years, CMV disease rates were similar. The early increase in CMV events correlated temporarily with lower CMV-specific CD4(+) T helper and CD8(+) cytotoxic T lymphocyte function at 30 days after transplantation in PBSC recipients. By 3 months after transplantation and thereafter, CMV-specific immune responses were similar between BM and PBSC recipients. In conclusion, higher CMV infection and disease rates occurred in PBSC transplant recipients early after transplantation. These differences may be because of a transient delay in CMV-specific immune reconstitution following PBSC transplantation. PMID- 21664287 TI - Tubular GFP uptake pattern in the rat and frog kidneys. AB - The renal tubular uptake of green fluorescent protein (GFP) after its bolus intravenous injection was studied in both frogs and rats. GFP fluorescence in the proximal tubule (PT) was revealed by fluorescent and confocal microscopy. Granular GFP fluorescence was observed nearby in the apical membrane of PT cells featuring distribution over the cytoplasm. GFP was internalized into endosomes and lysosomes as determined by immunocytochemistry in frogs. The tubular uptake and accumulation of GFP were dose- and time-dependent in both rats and frogs. Intralymphatic sac injection of arginine vasotocin (AVT) decreased the uptake of GFP in hydrated frogs. A high negative correlation between the AVT dose and the uptake of GFP was revealed. The effect of AVT was inhibited by a V(1)-receptor antagonist. A noted decrease in the average number of fluorescent PT profiles per kidney section and their irregular distribution after AVT injections suggest that not all of the glomeruli or preglomerular vessels are equally responsive to AVT. GFP may serve as a good marker for tubular uptake and intracellular traffic in the amphibian kidney for use in in vivo studies. PMID- 21664288 TI - Evidence for placental transfer of maternal corticosterone in a viviparous lizard. AB - In mammals, there is experimental evidence that circulating maternal cortisol is transferred to the embryos across the placenta during gestation. Direct effects of this maternal cortisol may allow embryos to display phenotypic plasticity to cope with postnatal environments (i.e., pre-programming). The potential for maternal hormone induced-adaptation may be of considerable evolutionary significance in viviparous animals. However, to date, there is no such direct evidence that circulating maternal corticosterone passes through the placenta and into the embryos of viviparous reptiles. In this study, we assessed the transfer of (3)H-corticosterone injected into females of the lizard Pseudemoia entrecasteauxii into maternal blood, maternal liver, the embryo, the yolk and the amniotic fluid during mid-to-late gestation. We provide direct evidence that circulating maternal corticosterone passes through the placenta into the embryos in this species. Transfer of maternal corticosterone into the embryos significantly decreased at the end of embryonic development. We discuss these results in terms of the relationships between the degree of corticosterone transfer and embryonic stage. These results demonstrate the potential for direct effects of maternal corticosterone, including endocrine pre-programming, upon the developing embryos in viviparous lizards. PMID- 21664289 TI - Acute myeloid leukemia: a central role for the ETS factor ERG. AB - Acute myeloid leukemia is a cancer of the myeloid lineage, characterized by the rapid proliferation of immature progenitor cells which accumulate in the bone marrow and interfere with the production of normal blood cells. Aberrant regulation of E-twenty-six (ETS) specific transcription factors such as PU.1 (SPI1) is thought to play a major role in this type of leukemia. The importance of these factors in normal blood development is highlighted by the fact that numerous studies showed a direct link between hematopoietic defects and aberrant regulation of ETS factor expression or expression of mutant forms. Apart from PU.1, another ETS factor, ERG, has emerged as a key player in normal hematopoiesis. Here, the role of this protein in normal and aberrant blood development will be discussed as well as the possibilities to therapeutically target this ETS factor. PMID- 21664290 TI - Adenomatous polyposis coli protein regulates the cellular response to DNA replication stress. AB - The adenomatous polyposis coli (APC) tumor suppressor traffics between nucleus and cytoplasm to perform distinct functions. Here we identify a specific role for APC in the DNA replication stress response. The silencing of APC caused an accumulation of asynchronous cells in early S phase and delayed S phase progression in cells released from hydroxyurea-mediated replication arrest. Immunoprecipitation assays revealed a selective binding of APC to replication protein A 32kDa subunit (RPA32), and the APC-RPA32 complex increased at chromatin after hydroxyurea treatment. Interestingly, APC knock-down prevented accumulation at chromatin of the stress-induced S33- and S29-phosphorylated forms of RPA32, and reduced the expression of ATR-phosphorylated forms of S317-phospho-Chk1 and gamma-H2AX. Using RPA32-inducible cells we showed that reconstitution of RPA32 diminished the S-phase delay caused by loss of APC. In contrast to full-length APC, the truncated APC mutant protein expressed in SW480 colon cancer cells was impaired in its binding and regulation of RPA32, and failed to regulate cell cycle after replication stress. We propose that APC associates with RPA at stalled DNA replication forks and promotes the ATR-dependent phosphorylation of RPA32, Chk1 and gamma-H2AX in response to DNA replication stress, thereby influencing the rate of re-entry into the cell cycle. PMID- 21664292 TI - Influence of gender, feeding regimen, and exposure duration on gene expression associated with xenobiotic metabolism in fathead minnows (Pimephales promelas). AB - Little is known about how gender and diet affect the metabolism of environmental contaminants in fish. This study was undertaken to compare these differences in hepatic mRNA expression of two genes associated with xenobiotic metabolism: the pregnane x-receptor (PXR) and cytochrome P450 3A4 (CYP3A4). PXR is an ideal receptor to study xenobiotic metabolism as it binds to a vast array of anthropogenic compounds and induces transcription of genes involved in metabolizing xenobiotic compounds, such as CYP3A4. In this study FHM were separated by gender and feeding regimen (fed versus unfed), and injected with control (corn oil), clotrimazole, or pregnene-16alpha-olone, and expression monitored after 2- and 5-days of treatment. Our research indicates that there are gender- and diet-specific differences in the expression of PXR and CYP3A4, the most striking of which was a significant increase in the expression of PXR and CYP3A4 in unfed females as compared to all other groups. Understanding the relationship among xenobiotic metabolism, gender and diet would be of particular interest in the study of contaminated habitats, where fish may have to adapt to reductions in food quantity or quality while being exposed to toxic compounds. PMID- 21664293 TI - A high-throughput histoarray for quantitative molecular profiling of multiple, uniformly oriented medaka (Oryzias latipes) embryos. AB - Embryos of aquatic animal model fish have proven to be useful organisms for developmental biology and for early life stage toxicity tests. By virtue of their transparent chorions, imaging of normal and abnormal development can be detected and related to exposure or to alterations due to environmental factors. However, the detection of changes at sub-individual levels of organization is hampered by time required to detect important events within cells and tissues of affected organisms. We describe herein development of a highly cost effective embryo chip enabling stringent inter-individual comparisons and multiplex detection in embryos and eleutheroembryos. As a proof of principle we examine cell proliferation and controlled cell death in normoxic and hypoxic conditions and relate these to tissue turnover in individual organisms. Coupled with a recently developed whole adult animal platform, we can now move beyond the common approach focusing on single target organ to the detection and characterization of systemic phenomena (syndromes) affecting the organism. Taken together, we can now determine adult consequences of early life stage exposure and assess ability of exposed individuals to respond to stresses superimposed along the axis of time. PMID- 21664291 TI - Lipid imaging with time-of-flight secondary ion mass spectrometry (ToF-SIMS). AB - Fundamental advances in secondary ion mass spectrometry (SIMS) now allow for the examination and characterization of lipids directly from biological materials. The successful application of SIMS-based imaging in the investigation of lipids directly from tissue and cells are demonstrated. Common complications and technical pitfalls are discussed. In this review, we examine the use of cluster ion sources and cryogenically compatible sample handling for improved ion yields and to expand the application potential of SIMS. Methodological improvements, including pre-treating the sample to improve ion yields and protocol development for 3-dimensional analyses (i.e. molecular depth profiling), are also included in this discussion. New high performance SIMS instruments showcasing the most advanced instrumental developments, including tandem MS capabilities and continuous ion beam compatibility, are described and the future direction for SIMS in lipid imaging is evaluated. PMID- 21664294 TI - Cardiovascular effects of DPP-4 inhibition: beyond GLP-1. AB - Dipeptydil-peptidase-4 (DPP-4) inhibitors are available as oral anti hyperglycemic drugs for the treatment of type 2 diabetes. Their metabolic effect is mediated through sparing incretin hormones (such as glucagon-like peptide-1, GLP-1) from the rapid degradation by DPP-4. In turn, GLP-1 improves meal stimulated insulin secretion by pancreatic beta-cells thus reducing hyperglycemia. It has been shown that GLP-1 signaling is also active in the cardiovascular system, where it may exert beneficial effects. However, DPP-4 has several non-incretin substrates, and its immunomodulatory activity is known from decades. DPP-4 physiologically cleaves cytokines, chemokines and neuropeptides involved in inflammation, immunity, and vascular function. Owing to these off target mechanisms, DPP-4 inhibitors hold promise for cardiovascular protection, but may also face unexpected side effects. Herein, we review available data on the cardiovascular effects of DPP-4 inhibitors, with a special interest in GLP-1 independent mechanisms. The modulation of endothelial progenitor cells, inflammatory pathway and ischemic response emerges as the major cardiovascular target of DPP-4 inhibitors. PMID- 21664295 TI - Targeted delivery of a combination therapy consisting of combretastatin A4 and low-dose doxorubicin against tumor neovasculature. AB - The present study demonstrates the applicability of a novel strategy that employs targeted delivery of combined treatment against tumor neovasculature. Briefly, a ligand of integrins, cyclic arginine-glycine-aspartic acid-tyrosine-lysine pentapeptide (cRGDyK), was conjugated to the PEG end of polyethylene glycol-b poly lactic acid (PEG-b-PLA), and doxorubicin was chemically linked to the PLA end of PEG-b-PLA. The targeted dual-drug micelle system was prepared by mixing combretastatin A4 (an antivascular agent), PEG-b-PLA, and the above two conjugates using a solution-casting method. The targeted micelles significantly enhanced cellular uptake of the drug by B16-F10 cells and human umbilical vein endothelial cells through a receptor-mediated endocytosis. The cRGDyK-modified dual-drug system achieved an optimal antitumor effect, lifespan increase, antineovasculature, antiproliferation, and apoptosis induction, revealing the advantage of active targeting and the modified combination therapy. In conclusion, the integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment. FROM THE CLINICAL EDITOR: A ligand of integrins was conjugated to PEG-b-PLA, and doxorubicin was chemically linked to the PLA. Efficiency was demonstrated in a cancer model. The integration of targeted delivery and combination therapy against tumor neovasculature represents a promising approach for cancer treatment. PMID- 21664297 TI - Analysis of the compliance of informed consent documents with good clinical practice guideline. AB - BACKGROUND: Informed consent document plays an integral part in the process of obtaining informed consent. Although India is fast gaining repute as a preferred clinical trial destination, only few studies have evaluated the compliance of informed consent documents with the Indian Good Clinical Practice guideline. METHODS: Retrospective analysis of consent documents submitted to the institutional ethics committee during the periods January 2007-July 2008 and August 2008-December 2009, for the inclusion of 14 essential information elements outlined in the Indian Good Clinical Practice guideline was carried out. Cumulative scores were given for compliance with the guideline and for vernacular translations of the consent documents. RESULTS: Majority of the informed consent documents analyzed were for academic projects in both periods. There was marked improvement in the documents in terms of compliance with Indian GCP in the period 2008-09. The mean cumulative score for consent documents for academic projects increased significantly from 7.00 +/- 0.25 in 2007-08 to 8.57 +/- 0.16 in 2008 09. The mean score for consent documents for pharmaceutical sponsored studies also increased from 10.23 +/- 0.17 in 2007-08 to 11.31 +/- 0.32 in 2008-09. Additionally, greater number of consent documents had been translated into vernacular language in the period 2008-29. CONCLUSIONS: The increased compliance with the good clinical practice guideline and improvement in the mean cumulative scores in 2008-09 was probably the outcome of greater awareness amongst the clinical researchers within the institute. PMID- 21664296 TI - Coordination and management of multisite complementary and alternative medicine (CAM) therapies: experience from a multisite reflexology intervention trial. AB - BACKGROUND: Multisite randomized clinical trials allow for increased research collaboration among investigators and expedite data collection efforts. As a result, government funding agencies typically look favorably upon this approach. As the field of complementary and alternative medicine (CAM) continues to evolve, so do increased calls for the use of more rigorous study design and trial methodologies, which can present challenges for investigators. PURPOSE: To describe the processes involved in the coordination and management of a multisite randomized clinical trial of a CAM intervention. METHODS: Key aspects related to the coordination and management of a multisite CAM randomized clinical trial are presented, including organizational and site selection considerations, recruitment concerns and issues related to data collection and randomization to treatment groups. Management and monitoring of data, as well as quality assurance procedures are described. Finally, a real world perspective is shared from a recently conducted multisite randomized clinical trial of reflexology for women diagnosed with advanced breast cancer. RESULTS: The use of multiple sites in the conduct of CAM-based randomized clinical trials can provide an efficient, collaborative and robust approach to study coordination and data collection that maximizes efficiency and ensures the quality of results. CONCLUSIONS: Multisite randomized clinical trial designs can offer the field of CAM research a more standardized and efficient approach to examine the effectiveness of novel therapies and treatments. Special attention must be given to intervention fidelity, consistent data collection and ensuring data quality. Assessment and reporting of quantitative indicators of data quality should be required. PMID- 21664298 TI - The GoodNEWS (Genes, Nutrition, Exercise, Wellness, and Spiritual Growth) Trial: a community-based participatory research (CBPR) trial with African-American church congregations for reducing cardiovascular disease risk factors- recruitment, measurement, and randomization. AB - INTRODUCTION: Although cardiovascular diseases (CVD) are the leading cause of death among Americans, significant disparities persist in CVD prevalence, morbidity, and mortality based on race and ethnicity. However, few studies have examined risk factor reduction among the poor and ethnic minorities. METHODS: Community-based participatory research (CBPR) study using a cluster randomized design--African-American church congregations are the units of randomization and individuals within the congregations are the units of analysis. Outcome variables include dietary change (Diet History Questionnaire), level of physical activity (7-Day Physical Activity Recall), lipoprotein levels, blood pressure, fasting glucose, and hemoglobin A1c. RESULTS: Eighteen (18) church congregations were randomized to either a health maintenance intervention or a control condition. Complete data were obtained on 392 African-American individuals, 18 to 70 years of age, predominantly employed women with more than a high school diploma. Treatment and intervention groups were similar at baseline on saturated fat intake, metabolic equivalent of tasks (METS) per day, and other risk factors for CVD. CONCLUSIONS: The GoodNEWS trial successfully recruited and evaluated CVD related risk among African-American participants using a CBPR approach. Several logistical challenges resulted in extending the recruitment, preliminary training, and measurement periods. The challenges were overcome with the assistance of a local community consultant and a professional event planner. Our experience supports the need for incorporating non-traditional community-based staff into the design and operational plan of CBPR trials. PMID- 21664299 TI - GRIM-19 function in cancer development. AB - Cancer development involves multiple genetic changes, which can occur in tumor suppressor genes and lead to loss of function in a recessive manner. Recent findings have identified a novel tumor suppressor gene named GRIM-19. Similar to what has been observed for other known tumor suppressor proteins such as p53, GRIM-19 gene mutations and loss of protein expression have been observed in several tumor types. In this review, we perform a detailed description on the current understanding of GRIM-19 function in carcinogenesis. PMID- 21664300 TI - Functional evidence for nitric oxide production by skeletal-muscle mitochondria from lipopolysaccharide-treated mice. AB - The possible existence of a mitochondrially localized nitric oxide (NO) synthase (mtNOS) is controversial. To clarify this, we studied the ability of intact mitochondria to generate NO and the effect of mitochondrial NO on respiration. Respiratory rates and oxygen kinetics (P(50) values) were determined by high resolution respirometry in skeletal-muscle mitochondria from control mice and mice injected with Escherichia coli lipopolysaccharide (LPS). In the presence of the NOS substrate L-arginine, mitochondria from LPS-treated mice had lower respiration rates and higher P(50) values than control animals. These effects were prevented by the NOS inhibitor L-NMMA. Our results suggest that mitochondrially derived NO is generated by an LPS-inducible NOS protein other than iNOS and modulates oxygen consumption in mouse skeletal muscle. PMID- 21664301 TI - Evaluation of basic mitochondrial functions using rat tissue homogenates. AB - The primary attempt in diagnostic and experimental studies of numerous pathological states associated with mitochondrial dysfunction is a precise evaluation of changes in function, content and structure of mitochondrial OXPHOS system. The analysis of rat heart, liver, brain and kidney by oxygraphy, enzyme activities, membrane potential, and BN/SDS-PAGE western blotting demonstrated that tissue homogenates can substitute for isolated mitochondria, providing comparable qualitative mitochondrial parameters. The use of homogenate avoids the loss of the majority of mitochondria during their isolation. Only 50-100mg of the tissue is required for the complex OXPHOS analysis, i.e. five times less as compared with isolated mitochondria. PMID- 21664302 TI - Chondroitin sulphate proteoglycans: extracellular matrix proteins that regulate immunity of the central nervous system. AB - The extracellular matrix (ECM) is a complex network of scaffolding molecules that also plays an important role in cell signalling, migration and tissue structure. In the central nervous system (CNS), the ECM is integral to the efficient development/guidance and survival of neurons and axons. However, changes in distribution of the ECM in the CNS may significantly enhance pathology in CNS disease or following injury. One group of ECM proteins that is important for CNS homeostasis is the chondroitin sulphate proteoglycans (CSPGs). Up-regulation of these molecules has been demonstrated to be both desirable and detrimental following CNS injury. Taking cues from arthritis, where there is a strong anti CSPG immune response, there is evidence that suggests that CSPGs may influence immunity during CNS pathological conditions. This review focuses on the role of CSPGs in CNS pathologies as well as in immunity, both from a viewpoint of how they may inhibit repair and exacerbate damage in the CNS, and how they are involved in activation and function of peripheral immune cells, particularly in multiple sclerosis. Lastly, we address how CSPGs may be manipulated to improve disease outcomes. PMID- 21664303 TI - Structure-process-property relationship of the polar graphene oxide-mediated cellular response and stimulated growth of osteoblasts on hybrid chitosan network structure nanocomposite scaffolds. AB - We here describe the structure-process-property relationship of graphene oxide mediated proliferation and growth of osteoblasts in conjunction with the physico chemical, mechanical, and structural properties. Chitosan-graphene network structure scaffolds were synthesized by covalent linkage of the carboxyl groups of graphene oxide with the amine groups of chitosan. The negatively charged graphene oxide in chitosan scaffolds was an important physico-chemical factor influencing cell-scaffold interactions. Furthermore, it was advantageous in enhancing the biocompatibility of the scaffolds and the degradation products of the scaffolds. The high water retention ability, hydrophilic nature, and high degree of interconnectivity of the porous structure of chitosan-graphene oxide scaffolds facilitated cell attachment and proliferation and improved the stability against enzymatic degradation. The cells infiltrated and colonized the pores of the scaffolds and established cell-cell interactions. The interconnectivity of the porous structure of the scaffolds helps the flow of medium throughout the scaffold for even cell adhesion. Moreover, the seeded cells were able to infiltrate inside the pores of chitosan-graphene oxide scaffolds, suggesting that the incorporation of polar graphene oxide in scaffolds is promising for bone tissue engineering. PMID- 21664304 TI - In vitro and in vivo characteristics of core-shell type nanogel particles: optimization of core cross-linking density and surface poly(ethylene glycol) density in PEGylated nanogels. AB - The biocompatibility and body distribution of PEGylated polyamine nanogels composed of chemically cross-linked poly(2-N,N-(diethylamino)ethyl methacrylate) (PEAMA) gel cores surrounded by poly(ethylene glycol) (PEG) chains were investigated to evaluate their feasibility as drug nanocarriers for systemic administration. PEGylated nanogels with different cross-linking densities (1, 2, and 5mol.%) were prepared to evaluate their biocompatibilities by in vitro cytotoxicity assay, hemolysis assay, and in vivo acute toxicity assay. The toxic effect of the PEGylated nanogels derived from polyamine gel cores was significantly reduced when the cross-linking density was increased, and those with a cross-linking density of 5mol.% showed a remarkably high median lethal dose (LD(50)) value >200mgkg(-1),despite the abundance of amino groups in the core. One hour after intravenous injection the PEGylated nanogels were found to have been eliminated from the systemic circulation, and less than 1% of the injected dose (ID) remained in the bloodstream. To improve the blood circulation time by increasing the surface PEG density of the PEGylated nanogels post PEGylation of the PEGylated nanogels (via the Menschutkin reaction between tertiary amines of the PEAMA gel core and bromobenzyl-terminated short PEG) was carried out. A biodistribution study of these post-PEGylated nanogels revealed that the blood circulation time of the nanogels was definitely prolonged as the PEG content was increased. Therefore, the precise design of PEGylated nanogels with increased cross-linking densities in their polyamine gel cores and increased surface PEG densities seems promising for systemic applications. PMID- 21664305 TI - Oligo(trimethylene carbonate)-poly(ethylene glycol)-oligo(trimethylene carbonate) triblock-based hydrogels for cartilage tissue engineering. AB - A triblock co-polymer of oligo(trimethylene carbonate)-block-poly(ethylene glycol) 20000-block-oligo(trimethylene carbonate) diacrylate (TMC20) was used as a photo-polymerizable precursor for the encapsulation of primary articular chondrocytes. The efficacy of TMC20 as a biodegradable scaffold for cartilage tissue engineering was compared with non-degradable poly(ethylene glycol) 20000 diacrylate (PEG20) hydrogel. Chondrocytes encapsulated in PEG hydrogels containing oligo(trimethylene carbonate) (OTMC) moieties underwent spontaneous aggregation during in vitro culture, which was not observed in the PEG hydrogel counterparts. The aggregation of cells was found to be dependent on the initial cell density, as well as the mesh size of the hydrogels. Similarly, cell aggregation was also found in biodegradable PEG hydrogels containing caprolactone moieties. The aggregation of cells in TMC20 hydrogels resulted in enhanced cartilage matrix production compared with their PEG20 counterparts over 3 weeks of culture. Taken together, these results indicate that PEG hydrogels containing degradable OTMC moieties promote the aggregation and biosynthetic activity of encapsulated chondrocytes, indicating their potential as scaffolds for the repair of cartilage tissue. PMID- 21664306 TI - Modulation of alignment, elongation and contraction of cardiomyocytes through a combination of nanotopography and rigidity of substrates. AB - The topographic and mechanical characteristics of engineered tissue constructs, simulating native tissues, should benefit tissue engineering. Previous studies reported that surface topography and substrate rigidity provide biomechanical cues to modulate cellular responses such as alignment, migration and differentiation. To fully address this issue, the present study aimed to examine the influence of nanogrooved substrates with different stiffnesses on the responses of rat cardiomyocytes. Nanogrooved substrates (450nm in groove/ridge width; 100 or 350nm in depth) made of polystyrene and polyurethane were prepared by imprinting from polydimethylsiloxane molds. The morphology and orientation of cardiomyocytes attached to the substrates were found to be influenced mainly by the nanogrooved structures, while the contractile function of the cells was regulated by the coupled effect of surface topography and substrate stiffness. The distribution of intracellular structural proteins such as vinculin and F actin showed that the surface topography and substrate stiffness regulated the organization of the actin cytoskeleton and focal adhesion complexes, and consequently the contractile behavior of the cardiomyocytes. The beating rates of the cultured cardiomyocytes were dependent on both the surface topography and the substrate stiffness. The study provides insights into the interaction between cardiomyocytes and biomaterials, and benefits cardiac tissue engineering. PMID- 21664307 TI - Dasatinib, imatinib and staurosporine capture compounds - Complementary tools for the profiling of kinases by Capture Compound Mass Spectrometry (CCMS). AB - Capture Compound Mass Spectrometry (CCMS) is a platform technology for the functional isolation of subproteomes. Here we report the synthesis of two new kinase Capture Compounds (CCs) based on the tyrosine-kinase specific inhibitors dasatinib and imatinib and compare their interaction profiles to that of our previously reported staurosporine-CCs. CCs are tri-functional molecules: they comprise a sorting function (e.g. the small molecule or drug of interest) which interacts with target proteins, a photo-activatable reactivity function to covalently trap the interacting proteins, and a sorting function to isolate the CC-protein conjugates from complex biological samples for protein identification by liquid chromatography/mass spectrometry (LC-MS/MS). We present data of CCMS experiments from human HepG2 cells and compare the profiles of the kinases isolated with dasatinib, imatinib and staurosporine CC, respectively. Dasatinib and imatinib have a more selective kinase binding profile than staurosporine. Moreover, the new CCs allow isolation and identification of additional kinases, complementing the staurosporine CC. The family of kinase CCs will be a valuable tool for the proteomic profiling of this important protein class. Besides sets of expected kinases we identified additional specific interactors; these off-targets may be of relevance in the view of the pharmacological profile of dasatinib and imatinib. PMID- 21664308 TI - SET domain proteins in plant development. AB - Post-translational methylation of lysine residues on histone tails is an epigenetic modification crucial for regulation of chromatin structure and gene expression in eukaryotes. The majority of the histone lysine methyltransferases (HKMTases) conferring such modifications are proteins with a conserved SET domain responsible for the enzymatic activity. The SET domain proteins in the model plant Arabidopsis thaliana can be assigned to evolutionarily conserved classes with different specificities allowing for different outcomes on chromatin structure. Here we review the present knowledge of the biochemical and biological functions of plant SET domain proteins in developmental processes. This article is part of a Special Issue entitled: Epigenetic control of cellular and developmental processes in plants. PMID- 21664309 TI - Borage and fish oils lifelong supplementation decreases inflammation and improves bone health in a murine model of senile osteoporosis. AB - Fats are prevalent in western diets; they have known deleterious effects on muscle insulin resistance and may contribute to bone loss. However, relationships between fatty acids and locomotor system dysfunctions in elderly population remain controversial. The aim of this study was to analyze the impact of fatty acid quality on the age related evolution of the locomotor system and to understand which aging mechanisms are involved. In order to analyze age related complications, the SAMP8 mouse strain was chosen as a progeria model as compared to the SAMR1 control strain. Then, two months old mice were divided in different groups and subjected to the following diets : (1) standard "growth" diet - (2) "sunflower" diet (high omega6/omega3 ratio) - (3) "borage" diet (high gamma linolenic acid) - (4) "fish" diet (high in long chain omega3). Mice were fed ad libitum through the whole protocol. At 12 months old, the mice were sacrificed and tissues were harvested for bone studies, fat and muscle mass measures, inflammation parameters and bone cell marker expression. We demonstrated for the first time that borage and fish diets restored inflammation and bone parameters using an original model of senile osteoporosis that mimics clinical features of aging in humans. Therefore, our study strongly encourages nutritional approaches as relevant and promising strategies for preventing aged-related locomotor dysfunctions. PMID- 21664310 TI - Eldecalcitol, a second-generation vitamin D analog, drives bone minimodeling and reduces osteoclastic number in trabecular bone of ovariectomized rats. AB - To elucidate the histological events that follow administration of eldecalcitol, a second-generation of vitamin D analog currently awaiting approval as a drug for treatment of osteoporosis, we employed the ovariectomy (OVX) rat model. OVX rats received vehicle or 30ng/kg of eldecalcitol, and sham-operated animals received vehicle only. Rats were sacrificed after 12weeks and had their femora and tibiae removed and processed for histochemical and histomorphometrical analyses. When compared with OVX group, osteoclastic number and bone resorption parameters were significantly reduced in eldecalcitol-treated rats, accompanied by decreased bone formation parameters. The preosteoblastic layer, with which osteoclastic precursors interact for mutual differentiation, was poorly developed in the eldecalcitol group, indicating less cell-to-cell contact between preosteoblasts and osteoclast precursors. Interestingly, eldecalcitol did promote a type of focal bone formation that is independent of bone resorption, a process known as bone minimodeling. While the number of ED-1-positive macrophages was higher in the bone marrow of treated rats, though osteoclastic number was deceased. Taken together, our findings suggest that eldecalcitol stimulates preosteoblastic differentiation rather than their proliferation, which in turn may prevent or diminish cell-to-cell contact between preosteoblasts and osteoclastic precursors, and therefore, lead to lower osteoclast numbers and decreased bone resorption. PMID- 21664338 TI - Comparative effectiveness of perineal versus retropubic and minimally invasive radical prostatectomy. PMID- 21664339 TI - A meta-analysis of the relation of intolerance of uncertainty to symptoms of generalized anxiety disorder, major depressive disorder, and obsessive-compulsive disorder. AB - Intolerance of uncertainty (IU) has been suggested to reflect a specific risk factor for generalized anxiety disorder (GAD), but there have been no systematic attempts to evaluate the specificity of IU to GAD. This meta-analysis examined the cross-sectional association of IU with symptoms of GAD, major depressive disorder (MDD), and obsessive-compulsive disorder (OCD). Random effects analyses were conducted for two common definitions of IU, one that has predominated in studies of GAD (56 effect sizes) and another that has been favored in studies of OCD (29 effect sizes). Using the definition of IU developed for GAD, IU shared a mean correlation of .57 with GAD, .53 with MDD, and .50 with OCD. Using the alternate definition developed for OCD, IU shared a mean correlation of .46 with MDD and .42 with OCD, with no studies available for GAD. Post-hoc significance tests revealed that IU was more strongly related to GAD than to OCD when the GAD specific definition of IU was used. No other differences were found in the magnitude of associations between IU and the three syndromes. We discuss implications of these findings for models of shared and specific features of emotional disorders and for future research efforts. PMID- 21664340 TI - A novel real-time PCR assay for the detection of Plasmodium falciparum and Plasmodium vivax malaria in low parasitized individuals. AB - The rapid, accurate diagnosis of Plasmodium spp. is essential for the effective control of malaria, especially in asymptomatic infections. In this study, we developed a sensitive, genus-specific, real-time quantitative PCR assay. It was compared with the microscopic examination of Giemsa-stained blood smears and two different molecular diagnostic techniques: nested PCR and multiplex PCR. For the effective quantitative detection of malaria parasites, all reagents were designed with a lyophilized format in one tube. Plasmodium was detected successfully in all 112 clinically suspected malaria patients, including 32 individuals with low parasitemia (1-100 parasites/MUl). The sensitivity threshold was 0.2 parasites/MUl and no PCR-positive reaction occurred when malaria parasites were not present. This may be a useful method for detecting malaria parasites in endemic areas. PMID- 21664311 TI - Unraveling the role of FoxOs in bone--insights from mouse models. AB - The FoxO subfamily of forkhead transcription factors plays a critical role in a variety of physiological processes including metabolism, differentiation, proliferation, apoptosis and protection from stress. FoxO activity is inhibited by growth factors and the insulin signaling pathways and stimulated by nutrient depletion and a plethora of reactive oxygen species (ROS)-induced post translational modifications. Recent studies have uncovered a fundamental role for FoxOs in skeletal homeostasis. In cells of the osteoblast lineage, FoxOs modulate redox balance, protein synthesis, and differentiation through the activation of specific gene programs and interaction with other transcription factors and co factors such as beta-catenin, ATF-4, and Runx2. FoxO activation also attenuates osteoclastogenesis through both cell autonomous and indirect mechanisms. In this review I discuss recent advances in the understanding of FoxO specific actions in osteoblast progenitors, osteoblasts, and osteoclast, as well as the implications of FoxO activation for age-related skeletal involution. PMID- 21664341 TI - Redox reactions of the FAD-containing apoptosis-inducing factor (AIF) with quinoidal xenobiotics: a mechanistic study. AB - Mitochondrial apoptosis-inducing factor (AIF) is a FAD-containing protein that under certain conditions translocates to the nucleus and causes a programmed cell death, apoptosis. The apoptogenic action of AIF is redox controlled as the NADH reduced AIF dimer has lower affinity for DNA than the oxidized monomer. To gain further insights into the mechanism of AIF, we investigated its interaction with a series of quinone oxidants, including a number of anticancer quinones. Our data indicate that the NADH:quinone oxidoreduction catalyzed by AIF follows a "ping pong" scheme, with the reductive half-reaction being rate-limiting and the FADH( )-NAD(+) charge-transfer complex serving as an electron donor. AIF is equally reactive toward benzo- and naphthoquinones, but may discriminate structures with a higher number of aromatic rings. The reactivity of quinones is mainly defined by their one-electron reduction potential, whereas the size and nature of the substituents play a minor role. AIF is unlikely to significantly contribute to bioreductive activation of low-potential quinoidal anticancer quinones. However, high-potential quinones, e.g. a toxic natural compound naphthazarin, maintain AIF in the oxidized state when a significant excess of NADH is present. Thus, these compounds may prevent the accumulation of the reduced form of AIF in vivo, and enhance AIF-mediated apoptosis. PMID- 21664342 TI - Human HOXA5 homeodomain enhances protein transduction and its application to vascular inflammation. AB - Cellular protein delivery is an emerging technique by which exogenous recombinant proteins are delivered into mammalian cells across the membrane. We have developed an Escherichia coli expression vector including human specific gene sequences for protein cellular delivery. The plasmid was generated by ligation the nucleotides 770-817 of the homeobox A5 mRNA sequence which was matched with protein transduction domain (PTD) of homeodomain protein A5 (HOXA5) into pET expression vector. The cellular uptake of HOXA5-PTD-EGFP was detected in 1min and its transduction reached a maximum at 1h within cell lysates. The cellular uptake of HOXA5-EGFP at 37 degrees C was greater than in 4 degrees C. For study for the functional role of human HOXA5-PTD, we purified HOXA5-APE1/Ref-1 and applied it on monocyte adhesion. Pretreatment with HOXA5-APE1/Ref-1 (100nM) inhibited TNF alpha-induced monocyte adhesion to endothelial cells, compared with HOXA5-EGFP. Taken together, our data suggested that human HOXA5-PTD vector provides a powerful research tools for uncovering cellular functions of proteins or for the generation of human PTD-containing proteins. PMID- 21664343 TI - Hepatoblasts comprise a niche for fetal liver erythropoiesis through cytokine production. AB - In mammals, definitive erythropoiesis first occurs in fetal liver (FL), although little is known about how the process is regulated. FL consists of hepatoblasts, sinusoid endothelial cells and hematopoietic cells. To determine niche cells for fetal liver erythropoiesis, we isolated each FL component by flow cytometry. mRNA analysis suggested that Dlk-1-expressing hepatoblasts primarily expressed EPO and SCF, genes encoding erythropoietic cytokines. EPO protein was detected predominantly in hepatoblasts, as assessed by ELISA and immunohistochemistry, and was not detected in sinusoid endothelial cells and hematopoietic cells. To characterize hepatoblast function in FL, we analyzed Map2k4(-/-) mouse embryos, which lack hepatoblasts, and observed down-regulation of EPO and SCF expression in FL relative to wild-type mice. Our observations demonstrate that hepatoblasts comprise a niche for erythropoiesis through cytokine secretion. PMID- 21664344 TI - Fluorinated cholesterol retains domain-forming activity in sphingomyelin bilayers. AB - Lipid rafts are cholesterol (Chol)-rich microdomains floating in a sea of lipid bilayers. Chol is thought to interact preferentially with sphingolipids such as sphingomyelin (SM) rather than with glycerophospholipids, and this putative SM Chol interaction is generally recognized as a requirement for raft formation. However, the presence of the specific interaction is still controversial, primarily because of the lack of useful molecular probes for scrutinizing this interaction. Recently, we reported that the dynamic properties of 6-F-Chol in DMPC bilayers are similar to those of unmodified Chol. Hence, in the present study, we first compared the roles of 6-F-Chol and Chol in SM bilayers through detergent insolubility, fluorescence polarization, and (2)H NMR experiments. The results demonstrated that 6-F-Chol and Chol behave similarly in SM bilayers, whereas, in SM-DOPC membranes, 6-F-Chol is less effective in domain formation. Then, we analyzed the molecular orientation of 6-F-Chol in SM bilayers using solid-state NMR, and found that the dynamics and orientation of 6-F-Chol in SM bilayers are almost identical to those in DMPC bilayers. This supports the notion of the lack of a putative specific interaction between SM and Chol. Thus, this study demonstrates the utility of 6-F-Chol as a molecular probe for understanding molecular recognition in lipid rafts. PMID- 21664345 TI - Performance of the CRAFTi portable fluorometer comparing with the HPLC method for determining serum retinol. AB - OBJECTIVE: To determine the performance of a portable fluorometer for measuring serum retinol (SR) concentration. DESIGN AND METHODS: Serum samples were obtained from 75 factory worker women and 143 school children. SR concentration was quantified using a portable fluorometer ('CRAFTi') and HPLC analysis. RESULTS: SR by HPLC (1.23 +/- 0.43 MUmol/L) and CRAFTi (1.16 +/- 0.46 MUmol/L) was significantly correlated. Sensitivity and specificity were 85.3% and 78.0% (cutoff of 1.05 MUmol/L). Kappa statistics showed moderate agreement. CONCLUSIONS: CRAFTi portable fluorometer is a promising field-friendly tool for screening vitamin A deficiency. PMID- 21664346 TI - Lack of association between genetic variations in the KALRN region and ischemic stroke. AB - OBJECTIVES: To investigate whether KALRN gene variation is associated with ischemic stroke (IS). DESIGN AND METHODS: Associations to overall IS and IS subtypes were investigated in SAHLSIS, which comprises 844 patients with IS and 668 controls. RESULTS: Associations between KALRN SNPs and overall IS and cardioembolic stroke were detected. Associations for overall IS were investigated in two additional Swedish samples, but could not be replicated. CONCLUSION: KALRN gene variation is not associated with overall IS. PMID- 21664347 TI - Introductory comment on six papers from a Symposium on experimental and historical aspects of evolutionary bioscience. PMID- 21664349 TI - Dramatic changes in patterning gene expression during metamorphosis are associated with the formation of a feather-like antenna by the silk moth, Bombyx mori. AB - Many moths use sex pheromones to find their mates in the dark. Their antennae are well developed with lateral branches to receive the pheromone efficiently. However, how these structures have evolved remains elusive, because the mechanism of development of these antennae has not been studied at a molecular level. To elucidate the developmental mechanism of this type of antenna, we observed morphogenesis, cell proliferation, cell death and antennal patterning gene expression in the branched antenna of the silk moth, Bombyx mori. Region-specific cell proliferation and almost ubiquitous apoptosis occur during early pupal stages and appear to shape the lateral branch cooperatively. Antennal patterning genes are expressed in a pattern largely conserved among insects with branchless antennae until the late 5th larval instar but most of them change their expression dramatically to a pattern prefiguring the lateral branch during metamorphosis. These findings imply that although antennal primordium is patterned by conserved mechanisms before metamorphosis, most of the antennal patterning genes are reused to form the lateral branch during metamorphosis. We propose that the acquisition of a new regulatory circuit of antennal patterning genes may have been an important event during evolution of the sensory antenna with lateral branches in the Lepidoptera. PMID- 21664348 TI - Stem cell-based growth, regeneration, and remodeling of the planarian intestine. AB - Although some animals are capable of regenerating organs, the mechanisms by which this is achieved are poorly understood. In planarians, pluripotent somatic stem cells called neoblasts supply new cells for growth, replenish tissues in response to cellular turnover, and regenerate tissues after injury. For most tissues and organs, however, the spatiotemporal dynamics of stem cell differentiation and the fate of tissue that existed prior to injury have not been characterized systematically. Utilizing in vivo imaging and bromodeoxyuridine pulse-chase experiments, we have analyzed growth and regeneration of the planarian intestine, the organ responsible for digestion and nutrient distribution. During growth, we observe that new gut branches are added along the entire anteroposterior axis. We find that new enterocytes differentiate throughout the intestine rather than in specific growth zones, suggesting that branching morphogenesis is achieved primarily by remodeling of differentiated intestinal tissues. During regeneration, we also demonstrate a previously unappreciated degree of intestinal remodeling, in which pre-existing posterior gut tissue contributes extensively to the newly formed anterior gut, and vice versa. By contrast to growing animals, differentiation of new intestinal cells occurs at preferential locations, including within newly generated tissue (the blastema), and along pre-existing intestinal branches undergoing remodeling. Our results indicate that growth and regeneration of the planarian intestine are achieved by co-ordinated differentiation of stem cells and the remodeling of pre-existing tissues. Elucidation of the mechanisms by which these processes are integrated will be critical for understanding organogenesis in a post-embryonic context. PMID- 21664350 TI - Neuroprotection with a new kynurenic acid analog in the four-vessel occlusion model of ischemia. AB - Global forebrain ischemia results in damage to the pyramids in the CA1 hippocampal subfield, which is particularly vulnerable to excitotoxic processes. Morphological and functional disintegration of this area leads to a cognitive dysfunction and neuropsychiatric disorders. Treatment with N-methyl-d-aspartate receptor antagonists is a widely accepted method with which to stop the advance of excitotoxic processes and concomitant neuronal death. From a clinical aspect, competitive glycine- and polyamine-site antagonists with relatively low affinity and moderate side-effects are taken into account. Endogenous kynurenic acid acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. In the present study, we estimated the neuroprotective capability of a novel kynurenic acid analog in transient global forebrain ischemia, measuring the rate of hippocampal CA1 pyramidal cell loss and the preservation of long-term potentiation at Schaffer collateral-CA1 synapses. The neuroprotective potential was reflected by a significantly diminished hippocampal CA1 cell loss and preserved long-term potentiation expression. The neuroprotective effect was robust in the event of pretreatment, and also when the drug was administered at the time of reperfusion. This result is beneficial since a putative neuroprotectant proven to be effective as post-treatment is of much greater benefit. PMID- 21664351 TI - Citrulline malate supplementation increases muscle efficiency in rat skeletal muscle. AB - Citrulline malate (CM; CAS 54940-97-5, Stimol(r)) is known to limit the deleterious effect of asthenic state on muscle function, but its effect under healthy condition remains poorly documented. The aim of this longitudinal double blind study was to investigate the effect of oral ingestion of CM on muscle mechanical performance and bioenergetics in normal rat. Gastrocnemius muscle function was investigated strictly non-invasively using nuclear magnetic resonance techniques. A standardized rest-stimulation- (5.7 min of repeated isometric contractions electrically induced by transcutaneous stimulation at a frequency of 3.3 Hz) recovery-protocol was performed twice, i.e., before (t(0)-24 h) and after (t(0)+48 h) CM (3 g/kg/day) or vehicle treatment. CM supplementation did not affect PCr/ATP ratio, [PCr], [Pi], [ATP] and intracellular pH at rest. During the stimulation period, it lead to a 23% enhancement of specific force production that was associated to significant decrease in both PCr (28%) and oxidative (32%) costs of contraction, but had no effect on the time-courses of phosphorylated compounds and intracellular pH. Furthermore, both the rate of PCr resynthesis during the post-stimulation period (VPCr(rec)) and the oxidative ATP synthesis capacity (Q(max)) remained unaffected by CM treatment. These data demonstrate that CM supplementation under healthy condition has an ergogenic effect associated to an improvement of muscular contraction efficiency. PMID- 21664352 TI - P43-dependent mitochondrial activity regulates myoblast differentiation and slow myosin isoform expression by control of Calcineurin expression. AB - We have previously shown that mitochondrial protein synthesis regulates myoblast differentiation, partly through the control of c-Myc expression, a cellular oncogene regulating myogenin expression and myoblast withdrawal from the cell cycle. In this study we provide evidence of the involvement of Calcineurin in this regulation. In C2C12 myoblasts, inhibition of mitochondrial protein synthesis by chloramphenicol decreases Calcineurin expression. Conversely, stimulation of this process by overexpressing the T3 mitochondrial receptor (p43) increases Calcineurin expression. Moreover, expression of a constitutively active Calcineurin (DeltaCN) stimulates myoblast differentiation, whereas a Calcineurin antisense has the opposite effect. Lastly, DeltaCN expression or stimulation of mitochondrial protein synthesis specifically increases slow myosin heavy chain expression. In conclusion, these data clearly suggest that, partly via Calcineurin expression, mitochondrial protein synthesis is involved in muscle development through the control of myoblast differentiation and probably the acquisition of the contractile and metabolic phenotype of muscle fibres. PMID- 21664353 TI - Tumor-produced, active interleukin-1beta regulates gene expression in carcinoma associated fibroblasts. AB - Recently we described a co-culture model of periodontal ligament (PDL) fibroblasts and SCC-25 lingual squamous carcinoma cells, which resulted in conversion of normal fibroblasts into carcinoma-associated fibroblasts (CAFs), and in epithelial-mesenchymal transition (EMT) of SCC-25 cells. We have found a constitutive high interleukin-1beta (IL1-beta) expression in SCC-25 cells in normal and in co-cultured conditions. In our hypothesis a constitutive IL1-beta expression in SCC-25 regulates gene expression in fibroblasts during co-culture. Co-cultures were performed between PDL fibroblasts and SCC-25 cells with and without dexamethasone (DEX) treatment; IL1-beta processing was investigated in SCC-25 cells, tumor cells and PDL fibroblasts were treated with IL1-beta. IL1 beta signaling was investigated by western blot and immunocytochemistry. IL1-beta regulated genes were analyzed by real-time qPCR. SCC-25 cells produced 16kD active IL1-beta, its receptor was upregulated in PDL fibroblasts during co culture, which induced phosphorylation of interleukin-1 receptor-associated kinase-1 (IRAK-1), and nuclear translocalization of NFkappaBalpha. Several genes, including interferon regulatory factor 1 (IRF1) interleukin-6 (IL-6) and prostaglandin-endoperoxide synthase 2 (COX-2) were induced in CAFs during co culture. The most enhanced induction was found for IL-6 and COX-2. Treatment of PDL fibroblasts with IL1-beta reproduced a time- and dose-dependent upregulation of IL1-receptor, IL-6 and COX-2. A further proof was achieved by DEX inhibition for IL1-beta-stimulated IL-6 and COX-2 gene expression. Constitutive expression of IL1-beta in the tumor cells leads to IL1-beta-stimulated gene expression changes in tumor-associated fibroblasts, which are involved in tumor progression. PMID- 21664354 TI - Cell type-specific transcriptional regulation of the gene encoding importin alpha1. AB - Importin-alpha1 belongs to a receptor family that recognizes classical nuclear localization signals. Encoded by Kpna2, this receptor subtype is highly expressed in mouse embryonic stem (ES) cells. In this study, we identified a critical promoter region in Kpna2 and showed that the expression of this gene is differentially regulated in ES cells and NIH3T3 cells. Conserved CCAAT boxes are required for Kpna2 promoter activity in both ES and NIH3T3 cells. Interestingly, deletion of the region from nucleotide position -251 to -179 bp resulted in a drastic reduction in Kpna2 transcriptional activity only in ES cells. This region contains Kruppel-like factor (Klf) binding sequences and is responsible for transactivation of the gene by Klf2 and Klf4. Accordingly, endogenous Kpna2 mRNA levels decreased in response to depletion of Klf2 and Klf4 in ES cells. Our results suggest that Klf2 and Klf4 function redundantly to drive high level of Kpna2 expression in ES cells. PMID- 21664355 TI - NAADP mediates ATP-induced Ca2+ signals in astrocytes. AB - Intracellular Ca(2+) signals provide astrocytes with a specific form of excitability that enables them to regulate synaptic transmission. In this study, we demonstrate that NAADP-AM, a membrane-permeant analogue of the new second messenger nicotinic acid-adenine dinucleotide phosphate (NAADP), mobilizes Ca(2+) in astrocytes and that the response is blocked by Ned-19, an antagonist of NAADP signalling. We also show that NAADP receptors are expressed in lysosome-related acidic vesicles. Pharmacological disruption of either NAADP or lysosomal signalling reduced Ca(2+) responses induced by ATP and endothelin-1, but not by bradykinin. Furthermore, ATP increased endogenous NAADP levels. Overall, our data provide evidence for NAADP being an intracellular messenger for agonist-mediated calcium signalling in astrocytes. PMID- 21664357 TI - Molecular cloning and characterization of the porcine Ero1L and ERp44 genes: potential roles in controlling energy metabolism. AB - Disulfide bond formation is a pivotal step in the maturation and release of secretory proteins that is controlled by specific endoplasmic reticulum (ER) resident enzymes. An important element in this process is Ero (ER oxidoreduction), a glycosylated flavoenzyme tightly associated with oxidative protein folding that lacks the known ER retention motifs. ER resident protein 44kDa (ERp44) is an ER resident protein that mediates ERo1 localization in ER and also prevents the secretion of unassembled cargo proteins with unpaired cysteine. These proteins are not only the key participants in the disulfide-bond formation process, but they also control the secretory pathway on both qualitative and quantitative levels. Here, we cloned full-length cDNA sequences of the porcine Ero1L (1448bp) and ERp44 (1361bp) genes. Isolation and characterization of their genomic sequences revealed that Ero1L contains 16 exons and 15 introns almost 150 kp in length, whereas ERp44 contains 12 exons and 11 introns more than 140 kp in length, and they are located on porcine chromosome 1q21 and 1q29, respectively. Tissue distribution analysis of the two genes revealed extremely high expression in adipose tissue, and the topology of their phylogenic tree indicates a high degree of conservation among different species. We looked at transcription factors binding sites in the 5'-flanking regions of Ero1L and ERp44, and many adipose differentiations related factors reflect the tight relationship to energy metabolism. PMID- 21664356 TI - Radiographic response to locoregional therapy in hepatocellular carcinoma predicts patient survival times. AB - BACKGROUND & AIMS: It is not clear whether survival times of patients with hepatocellular carcinoma (HCC) are associated with their response to therapy. We analyzed the association between tumor response and survival times of patients with HCC who were treated with locoregional therapies (LRTs) (chemoembolization and radioembolization). METHODS: Patients received LRTs over a 9-year period (n = 463). Patients with metastases, portal venous thrombosis, or who had received transplants were excluded; 159 patients with Child-Pugh B7 or lower were analyzed. Response (based on European Association for the Study of the Liver [EASL] and World Health Organization [WHO] criteria) was associated with survival times using the landmark, risk-of-death, and Mantel-Byar methodologies. In a subanalysis, survival times of responders were compared with those of patients with stable disease and progressive disease. RESULTS: Based on 6-month data, in landmark analysis, responders survived longer than nonresponders (based on EASL but not WHO criteria: P = .002 and .0694). The risk of death was also lower for responders (based on EASL but not WHO criteria: P = .0463 and .707). Landmark analysis of 12-month data showed that responders survived longer than nonresponders (P < .0001 and .004, based on EASL and WHO criteria, respectively). The risk of death was lower for responders (P = .0132 and .010, based on EASL and WHO criteria, respectively). By the Mantel-Byar method, responders had longer survival than nonresponders, based on EASL criteria (P < .0001; P = .596 with WHO criteria). In the subanalysis, responders lived longer than patients with stable disease or progressive disease. CONCLUSIONS: Radiographic response to LRTs predicts survival time. EASL criteria for response more consistently predicted survival times than WHO criteria. The goal of LRT should be to achieve a radiologic response, rather than to stabilize disease. PMID- 21664358 TI - Galanin antagonist increases insulin resistance by reducing glucose transporter 4 effect in adipocytes of rats. AB - Seeing that galanin increases animal body weight on the conditions of inhibiting insulin secretion and animals with metabolic disorder of galanin easily suffer from diabetes, we postulate that endogenous galanin is necessary to reduce insulin resistance in adipocytes. To test this hypothesis, we compared four groups of rats to examine whether an increase in galanin secretion stimulated by swimming may reduce insulin resistance. The rats from sedentary and trained drug groups were injected by M35, a galanin antagonist. The rats from trained control and trained drug groups swam after each injection for four weeks. We found that exercise significantly elevated plasma galanin contents and glucose transporter 4 (GLUT4) mRNA levels in adipocytes. Meanwhile, M35 treatment reduced GLUT4 and GLUT4 mRNA levels, and glucose infusing rates in euglycemic-hyperinsulinemic clamp tests. The ratios of GLUT4 concentrations at plasma membranes to total cell membranes in both drug groups were lower compared with each control group, respectively. These observations suggest that endogenous galanin reduces insulin resistance by increasing GLUT4 contents and promoting GLUT4 transportation from intracellular membranes to plasma membranes in adipocytes. Galanin is an important hormone to reduce insulin resistance in rats. PMID- 21664360 TI - Increased consistency and efficiency in routine potency testing by bioassay with direct use of cryopreserved (ready-to-plate) cells. AB - The use of cells as a cryopreserved, readily available reagent has facilitated high-throughput screening of new drug candidates by bioassay. This practice is considerably less labor intensive and allows more flexibility in laboratory testing than traditional continuous cell culture. We have shown that this practice can be adapted to cell proliferation and reporter gene assay formats used in routine sample testing for determination of relative potency of commercial product in a Quality Control Laboratory. The ability to use the same, optimized population of cells provides consistency in an assay over time. Measures of assay performance to indicate maintenance of the validated state of a method and to determine benefit on variation in potency results were compared between cultured and cryopreserved (frozen ready-to-plate) cells. Control of the cellular component, which is the most variable aspect of most cell based potency assays, allowed detection of more minor contributors to variability. In a cell proliferation assay format, the final result was a highly precise bioassay (repeatability CV of 2%). An improvement in process capability (Cp) was noted when ready-to-plate cells were used in the studies completed over long periods of time. PMID- 21664359 TI - 2D:4D ratios in the first 2 years of life: Stability and relation to testosterone exposure and sensitivity. AB - The relative lengths of the 2nd and 4th digits (2D:4D) may provide an easily measurable and stable anthropometric index of prenatal androgen exposure, but no study has examined the development of 2D:4D in infancy and the potential impact of neonatal testosterone levels. We collected 2D:4D ratios from 364 children between 0 and 2 years of age. Saliva samples were collected from 236 of these children 3 months after birth and analyzed for testosterone. In addition, 259 children provided DNA samples which were genotyped for the CAG repeat polymorphism in the androgen receptor. There was substantial variability across age in 2D:4D. Sex differences were small compared to adults and did not consistently reach statistical significance. This suggests that 2D:4D may not function well as a proxy measure of prenatal testosterone exposure in infancy. In addition, the interaction of salivary T and CAG repeats predicted right hand digit ratio at 12 months and left hand digit ratio at 12 months and 24 months in males. The interaction of salivary testosterone and CAG repeat length also predicted change in left hand 2D:4D from 2 weeks to 12 months in males. This suggests that 2D:4D in adults may reflect, in part, neonatal testosterone exposure. No significant relationships were observed within females. No significant relationships were observed when salivary testosterone and CAG repeats were examined independent of each other. Results have important implications for the design and interpretation of studies which use 2D:4D as a proxy measure of prenatal testosterone exposure. PMID- 21664361 TI - Folding of AcrB Subunit Precedes Trimerization. AB - AcrB and its homologues are major players in the efflux of anti-microbials out of Gram-negative bacteria. The structural and functional unit of AcrB is a homo trimer. The assembly process of obligate membrane protein oligomers, including AcrB, remains elusive. It is not clear if an individual subunit folds into a monomeric form first followed by association (three-stage pathway) or if association occurs simultaneously with subunit folding (two-stage pathway). To answer this question, we investigated the feasibility of creating a folded monomeric AcrB mutant. The existence of well-folded monomers in the cell membrane would be an evidence of a three-stage pathway. A monomeric AcrB mutant, AcrB(Deltaloop), was created through the truncation of a protruding loop that appeared to contribute to the stability of an AcrB trimer. AcrB(Deltaloop) expressed at a level similar to that of wild-type AcrB. The secondary structure content and tertiary conformation of AcrB(Deltaloop) were very similar to those of wild-type AcrB. However, when expressed in an acrB-deficient strain, AcrB(Deltaloop) failed to complement its defect in drug efflux. Results from blue native polyacrylamide gel electrophoresis and chemical cross-linking experiments suggested that AcrB(Deltaloop) existed as a monomer. The expression of this monomeric mutant in a wild-type Escherichia coli strain did not have a significant dominant-negative effect, suggesting that the mutant could not effectively co-assemble with genomic AcrB. AcrB(Deltaloop) is the first monomeric mutant reported for the intrinsically trimeric AcrB. The structural characterization results of this mutant suggest that the oligomerization of AcrB occurs through a three-stage pathway involving folded monomers. PMID- 21664362 TI - Generation of bivalent and bispecific kringle single domains by loop grafting as potent agonists against death receptors 4 and 5. AB - Bivalent or bispecific binding activity of proteins has been mainly achieved by assembling two or more domains in a single molecule. Here we report bivalent/bispecific single-domain proteins based on the kringle domain (KD), which has a cystine knot structural motif and is highly tolerant of sequence modifications. KD has seven loops protruding from the core fold into two largely opposite directions, dubbed loop cluster regions (LCRs) 1 and 2. Mutational analysis of previously isolated agonistic KD variants against human death receptors (DRs) 4 and 5 revealed that they can simultaneously recognize two target molecules of DR4 and/or DR5 via the two independent binding sites of LCR1 and LCR2. Binding loop mapping of yeast-surface-displayed KD mutants identified high-affinity target binding loops in LCR2, which were then grafted into conformationally compatible loops located on the opposite side of LCR1 within the same or different KD variants to generate bivalent/bispecific KD variants against DR4 and/or DR5 with improved affinity. The loop-grafted bivalent/bispecific KD variants showed enhanced cell-death-inducing activity of tumor cells compared with their monovalent/monospecific and bivalent/monospecific counterparts, demonstrating an advantage of bispecific targeting to both DR4 and DR5 over the targeting of only one of the two pro-apoptotic receptors. Our results suggest that the KD with the two independent binding surfaces for target recognition is an appropriate scaffold for the development of bivalency and/or bispecificity by loop grafting on the single domain, which offers a distinct advantage over other protein scaffolds with a single binding surface. PMID- 21664363 TI - Arg149 is involved in switching the low affinity, open state of the binding protein AfProX into its high affinity, closed state. AB - The substrate binding protein AfProX from the Archaeoglobus fulgidus ProU ATP binding cassette transporter is highly selective for the compatible solutes glycine betaine (GB) and proline betaine, which confer thermoprotection to this hyperthermophilic archaeon. A detailed mutational analysis of the substrate binding site revealed the contribution of individual amino acids for ligand binding. Replacement of Arg149 by an Ala residue displayed the largest impact on substrate binding. The structure of a mutant AfProX protein (substitution of Tyr111 with Ala) in complex with GB was solved in the open liganded conformation to gain further insight into ligand binding. In this crystal structure, GB is bound differently compared to the GB closed liganded structure of the wild-type AfProX protein. We found that a network of amino acid side chains communicates the presence of GB toward Arg149, which increases ligand affinity and induces domain closure of AfProX. These results were corroborated by molecular dynamics studies and support the view that Arg149 finalizes the high-affinity state of the AfProX substrate binding protein. PMID- 21664364 TI - LYP, a bestatin dimethylaminoethyl ester, inhibited cancer angiogenesis both in vitro and in vivo. AB - Our previous study revealed that LYP, a bestatin dimethylaminoethyl ester, inhibited the growth of human ovarian carcinoma ES-2 xenografts in mice and suppressed aminopeptidase N (APN/CD13) activity more potently than bestatin. In this study, we examined the inhibitory effect of LYP on migration and formation of capillary tube of human umbilical vascular endothelial cells (HUVECs) in vitro and anti-angiogenesis in ES-2 xenografts in mice. LYP did not possess cytotoxicity to HUVEC proliferation according to the MTT assay and trypan blue exclusion assay. However, APN/CD13 activity on cell surface of HUVECs was suppressed in the presence of LYP as measured by quantifying the enzymatic cleavage of the substrate l-leucine-p-nitroanilide. The assays of scratch and transwell chamber showed that LYP significantly inhibited HUVEC migration and invasion through Matrigel coated polycarbonate filters. Capillary tube formation assay revealed that the number of branch points formed by HUVECs on 3-D Matrigel was reduced after incubation with LYP. The anti-angiogenesis of LYP was verified in ES-2 xenografts in mice. The mean vascular density (MVD) and mean vascular luminal diameter (MVLD) were markedly reduced by LYP after two weeks of intravenous injection as evaluated by CD34 immunohistochemical staining. LYP suppression of cancer angiogenesis was greater than that of bestatin. The inhibition of angiogenic molecules may involve in anti-angiogenesis of LYP. The levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF-alpha) were decreased in HUVECs and ES-2 xenografts after treatment with LYP as determined by Western blot analysis. These results indicated that the high efficacy of LYP may partially relate to the inhibition of angiogenesis. PMID- 21664366 TI - Ginsenoside Rd attenuates redox imbalance and improves stroke outcome after focal cerebral ischemia in aged mice. AB - We previously found that ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, protects against ischemic brain damage induced by oxygen glucose deprivation in vitro and middle cerebral artery occlusion (MCAO) in vivo. Considering stroke happens frequently in aged individuals, we herein sought to further define the protective effects of Rd in the aged mice. 16-18-month-old mice administered with Rd (0.1-200 mg/kg) or vehicle were subjected to transient MCAO. Rd at the doses of 10-50 mg/kg significantly reduced both cortical and striatal infarct volume. This protection was associated with an improvement in neurological function and was sustained for at least 2 weeks after the insult. Importantly, Rd was effective even when administered up to 4 h after recirculation. To evaluate the underlying mechanisms, oxidative DNA damage was identified by 8-hydroxy-deoxyguanosine immunostaining, oxidative protein damage was identified by the assessment of protein carbonyl, and lipid peroxidation was estimated by determining the malondialdehyde formation. Rd significantly suppressed the accumulations of DNA, protein and lipid peroxidation products at 24 h post-ischemia. Rd also protected mitochondria at 4 and 24 h after reperfusion as indicated by preserved respiratory chain complex activities and aconitase activity, lowered mitochondrial hydrogen peroxide production, and hyperpolarized mitochondrial membrane potential. Furthermore, Rd partly enhanced endogenous antioxidant activities following MCAO. Collectively, these findings demonstrated that Rd exerts neuroprotection against transient focal ischemia in the aged brain, which may be associated with the attenuation of redox imbalance. PMID- 21664365 TI - Emerging interventions for PTSD: future directions for clinical care and research. AB - Efficacious therapeutic approaches for treating Posttraumatic Stress Disorder (PTSD) are needed given the significant psychosocial and physical impairment associated with the disorder (e.g., Hidalgo and Davidson, 2000; Jaycox and Foa, 1999; Stein et al., 2000). Although variations of cognitive behavioral therapy (CBT) effectively treat PTSD, non-response rates and dropout rates remain relatively high (Bradley et al., 2005; Schottenbauer et al., 2008). Thus, treatment outcome research is needed to improve the effectiveness of existing protocols, particularly within specific populations, develop new approaches for treating individuals who cannot access or do not benefit from traditional treatments, and evaluate the types of treatment that may be effective for particular individuals. The present review provides an overview of emerging treatment approaches for PTSD that attempt to address these remaining issues in the treatment outcome literature. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. PMID- 21664367 TI - 250 ms to code for action affordance during observation of manipulable objects. AB - It is well known that viewing graspable tools (but not other objects) activates motor-related brain regions, but the time course of affordance processing has remained relatively unexplored. In this study, EEG was continuously recorded from 128 scalp sites in 15 right-handed university students while they received stimuli in the form of 150 pictures of familiar non-tool objects and 150 pictures of manipulable tools, matched for size, luminance and perceptual familiarity. To select the 300 images for the study, a wider set of preliminary stimuli was screened for motoric content by 20 judges using a 3-point scale (0=absent; 2=strong); pictures that scored below 1.5 or above 0.6 were excluded from the tool and non-tool categories, respectively. Tools and non-tools were presented in random order, interspersed with 25 photos of live plants. Each slide was presented for 1000 ms, with an interval ranging from 1500 to 1900 ms. The task consisted of responding to the photos of plants while ignoring the other stimuli. Both an anterior negativity (210-270 ms) and a centroparietal P300 (550-600 ms) were larger in response to tools than objects, particularly in the left hemisphere. swLORETA inverse solution identified the occipito-temporal cortex (BA19 and BA37) as the most significant source of activity (in the 210-270-ms time window) for both types of visual objects and the left postcentral gyrus (BA3) and the left and right premotor cortex (BA6) as the most significant source of activity for tools only. These data hint at an automatic access to motoric object properties even under conditions in which attention is devoted to other stimulus categories. PMID- 21664368 TI - Synthesis of modified steroids as a novel class of non-ulcerogenic, anti inflammatory and anti-nociceptive agents. AB - The identification of compounds able to treat both pain and inflammation with limited side effects is one of the prominent goals in biomedical research. This study aimed at the synthesis of new modified steroids with structures justifying non-ulcerogenic, anti-inflammatory and anti-nociceptive activities. The steroid derivatives were synthesized via straightforward and efficient methods and their structures were established based on the analytical and spectral data. The in vivo anti-inflammatory, anti-nociceptive and anti-ulcerogenic activities of some of these compounds were studied. The newly synthesized compounds 8b, 19b, 24 and 31a showed anti-inflammatory, anti-nociceptive and anti-ulcerogenic activity with various intensities. Oedema was significantly reduced by either dose 25 or 50 mg/kg of all tested compounds at 3 and 4 h post-carrageenan. Compound 19b was the most effective in alleviating thermal pain. The analgesic activity of either dose of the compounds 8b, 24, 31a as well as the high dose 19b was significantly higher than that for indomethacin (IND). Gastric mucosal lesions caused in the rats by the administration of 96% EtOH and IND were inhibited by all tested compounds administered at (50 mg/kg) dose in the study. PMID- 21664369 TI - Associations between social ecological factors and self-reported short physical activity breaks during work hours among desk-based employees. AB - OBJECTIVE: To examine the associations between potential social ecological correlates and self-reported short physical activity breaks during work hours (defined as any interruption in sitting time during a typical work hour) among a sample of employees who commonly sit for working tasks. METHODS: 801 employed adults aged 18-70 years from metropolitan Melbourne, Australia were surveyed in 2009 about their short physical activity breaks from sitting during work hours and potential social ecological correlates of this behaviour. RESULTS: Men reported significantly more short physical activity breaks per work hour than did women (2.5 vs. 2.3 breaks/h, p=0.02). A multivariable linear regression analysis adjusting for clustering and meeting the public health physical activity recommendations showed that the factors associated with frequency of short physical activity breaks per work hour were perceptions of lack of time for short physical activity breaks for men (-0.31 breaks/h, 95% confidence intervals [CI] 0.52, -0.09) and lack of information about taking short physical activity breaks for women (-0.20 breaks/h, CI -0.47, -0.05). CONCLUSION: These findings suggest that providing male employees with support for short physical activity breaks during work hours, and female employees with information on benefits of this behaviour may be useful for reducing workplace sedentary time. PMID- 21664370 TI - Cytotoxicity and genotoxicity of chitooligosaccharides upon lymphocytes. AB - Two COS mixtures and a low molecular weight chitosan (LMWC) were tested for potential cytotoxicity and genotoxicity upon human lymphocytes. Genotoxicity was evaluated in vitro by cytokinesis-blocked micronucleus and alkaline comet assays, while cytotoxicity was assessed by flow cytometry analysis. Our results suggest that COS do not exhibit any genotoxicity upon human lymphocytes, independently of MW or concentration. However, above 0.07mg/mL COS induced strong cytotoxic effects. According to the concentration used, such cytotoxicity will induce cell death, essentially by necrosis (>0.10mg/mL) and/or apoptosis (<0.10mg/mL). The level of necrosis/apoptosis induced by high COS concentrations, suggests a promising use as apoptosis inducers in specific cancer situations. PMID- 21664371 TI - Development and characterization of a chitosan-supported immunoaffinity chromatography column for the selective extraction of methandrostenolone from food and feed samples. AB - The development of a chitosan-supported immunoaffinity chromatography (IAC) column and its application to the selective extraction of methandrostenolone (MA) from food and feed samples were described in this paper. Using hybridoma technique, a monoclonal antibody (mAb) against MA was produced. The IAC column was prepared by coupling the produced antibody with crosslinked chitosan. Scanning electron microscopy and IR spectroscopy was used to characterize the chitosan crosslinking and antibody coupling. 2% and 90% methanol were respectively selected as loading and eluting solution by optimization. The maximum capacity of the column for MA was 1790ng/mL gel. The extraction recoveries of the column for MA at three different spiked concentrations ranged from 83.7 to 98.5%. After 2 cycles of usage, the column capacity and extraction recovery still remained 84.6% and 80.5%. To further verify the effect of matrix on the IAC cleanup, MA-fortified food and feed samples were extracted using the prepared IAC column, and MA recovery rates were found to be 86.2% and 70.4%, respectively. PMID- 21664372 TI - Effect of gamma irradiation on rheological properties of polysaccharides exuded by A. fluccosus and A. gossypinus. AB - In this study, Iranian gum tragacanth (GT) exudates from Astragalus fluccosus (AFG) and Astragalus gossypinus (AGG) were irradiated at 3, 7, 10 and 15 kGy. Fourier transform infrared spectroscopy (FTIR) data showed that irradiation did not induce changes in the chemical structure of either type of gum. Although particle size distribution and both steady shear and dynamic rheological properties were considerably affected by the irradiation process, the magnitude of the effect of irradiation on each of the rheological and size variables was different for the hydrocolloids. For instance, for AGG, increasing the irradiation dose from 3 to 10 kGy, the d(0.5) and D[3,2] values were reduced by one-sixth to one-eighth fold. Colour measurement revealed that the radiation process led to an increase in the yellow index and b* values for both types of GT in powder form, but it was more pronounced for AGG samples. Irradiation led to an approximate 13-fold increase in redness in AFG. Surface and shape changes of the gum crystals were studied by scanning electron microscope (SEM) and a smoother surface for irradiated samples was detected. The notable changes in functional properties of each variety of irradiated gum should be taken into consideration before using the radiation technology as a commercial tool for sterilisation. PMID- 21664373 TI - The role of gap junctions in the brain in health and disease. AB - Gap junctions connect the cytosolic compartments of adjacent cells for direct electrotonic and metabolic cell-to-cell communication. Gap junctions between glial cells or neurons are ubiquitously expressed in the brain and play a role in brain development including cell differentiation, cell migration and survival, tissue homeostasis, as well as in human diseases including hearing loss, skin disease, neuropathies, epilepsy, brain trauma, and cardiovascular disease. Furthermore, gap junctions are involved in the synchronization and rhythmic oscillation of hippocampal and neocotical neuronal ensembles which might be important for memory formation and consolidation. In this review the accumulated evidence from mouse mutant and pharmacological studies using gap junction blockers is summarized and the progress made in dissecting the physiological, pathophysiological and behavioral roles of gap junction mediated intercellular communication in the brain is discussed. PMID- 21664376 TI - Management of the no-reflow phenomenon. AB - The lack of reperfusion of myocardium after prolonged ischaemia that may occur despite opening of the infarct-related artery is termed "no reflow". No reflow or slow flow occurs in 3-4% of all percutaneous coronary interventions, and is most common after emergency revascularization for acute myocardial infarction. In this setting no reflow is reported to occur in 30% to 40% of interventions when defined by myocardial perfusion techniques such as myocardial contrast echocardiography. No reflow is clinically important as it is independently associated with increased occurrence of malignant arrhythmias, cardiac failure, as well as in-hospital and long-term mortality. Previously the no-reflow phenomenon has been difficult to treat effectively, but recent advances in the understanding of the pathophysiology of no reflow have led to several novel treatment strategies. These include prophylactic use of vasodilator therapies, mechanical devices, ischaemic postconditioning and potent platelet inhibitors. As no reflow is a multifactorial process, a combination of these treatments is more likely to be effective than any of these alone. In this review we discuss the pathophysiology of no reflow and present the numerous recent advances in therapy for this important clinical problem. PMID- 21664374 TI - ALDH2 in alcoholic heart diseases: molecular mechanism and clinical implications. AB - Alcoholic cardiomyopathy is manifested as cardiac hypertrophy, disrupted contractile function and myofibrillary architecture. An ample amount of clinical and experimental evidence has depicted a pivotal role for alcohol metabolism especially the main alcohol metabolic product acetaldehyde, in the pathogenesis of this myopathic state. Findings from our group and others have revealed that the mitochondrial isoform of aldehyde dehydrogenase (ALDH2), which metabolizes acetaldehyde, governs the detoxification of acetaldehyde formed following alcohol consumption and the ultimate elimination of alcohol from the body. The ALDH2 enzymatic cascade may evolve as a unique detoxification mechanism for environmental alcohols and aldehydes to alleviate the undesired cardiac anomalies in ischemia-reperfusion and alcoholism. Polymorphic variants of the ALDH2 gene encode enzymes with altered pharmacokinetic properties and a significantly higher prevalence of cardiovascular diseases associated with alcoholism. The pathophysiological effects of ALDH2 polymorphism may be mediated by accumulation of acetaldehyde and other reactive aldehydes. Inheritance of the inactive ALDH2*2 gene product is associated with a decreased risk of alcoholism but an increased risk of alcoholic complications. This association is influenced by gene environment interactions such as those associated with religion and national origin. The purpose of this review is to recapitulate the pathogenesis of alcoholic cardiomyopathy with a special focus on ALDH2 enzymatic metabolism. It will be important to dissect the links between ALDH2 polymorphism and prevalence of alcoholic cardiomyopathy, in order to determine the mechanisms underlying such associations. The therapeutic value of ALDH2 as both target and tool in the management of alcoholic tissue damage will be discussed. PMID- 21664377 TI - Timbre discrimination in cochlear implant users and normal hearing subjects using cross-faded synthetic tones. AB - The identification and discrimination of timbre are essential features of music perception in cochlear implant users. As timbre differences appear as multidimensional cues, the spectral shape, the spectral fluctuation, and the rise time are the most dominating parameters of timbre in normal hearing listeners. Recently, a psychoacoustical test was developed to determine the timbre discrimination abilities using only the spectral shape difference as a cue. Therefore, a synthetically generated tone continuum was used in an adaptive alternative forced choice paradigm. The spectral shape was modified by cross fading the tones adaptively, depending on the listeners' response which allows very precise determinations of the just noticeable difference (JND). With this behavioral test, the spectral shape JND for complex tones with different fundamental frequencies was measured in cochlear implant users and compared to normal hearing listeners. The results confirm the applicability of the test to measure timbre discrimination in cochlear implant users. The resulting individual spectral shape JND profiles reveal a maximum with a fundamental frequency of 525 Hz, whereas the JND profiles were rather flat in the normal hearing individuals. PMID- 21664375 TI - Pharmacotherapy of autonomic failure. AB - The clinical picture of autonomic failure is characterized by severe and disabling orthostatic hypotension. These disorders can develop as a result of damage of central neural pathways or peripheral autonomic nerves, caused either by a primary autonomic neurodegenerative disorder or secondary to systemic illness. Treatment should be focused on decreasing pre-syncopal symptoms instead of achieving blood pressure goals. Non-pharmacologic strategies such as physical counter-maneuvers, dietary changes (i.e. high salt diet, rapid water drinking or compression garments) are the first line therapy. Affected patients should be screened for co-morbid conditions such as post-prandial hypotension and supine hypertension that can worsen orthostatic hypotension if not treated. If symptoms are not controlled with these conservative measures the next step is to start pharmacological agents; these interventions should be aimed at increasing intravascular volume either by promoting water and salt retention (fludrocortisone) or by increasing red blood cell mass when anemia is present (recombinant erythropoietin). When pressor agents are needed, direct pressor agents (midodrine) or agents that potentiate sympathetic activity (atomoxetine, yohimbine, pyridostigmine) can be used. It is preferable to use short-acting pressor agents that can be taken on as needed basis in preparation for upright activities. PMID- 21664378 TI - Use of SNARF-1 to measure murine T cell proliferation in vitro and its application in a novel regulatory T cell suppression assay. AB - The green fluorescent dye carboxyfluorescein diacetate succinimidyl ester (CFSE) has been used to track the proliferation of T cells in vitro. Such assays often incorporate more than one population of cells, but the paucity of alternative, spectrally distinct dyes suitable for measuring proliferation has hampered the simultaneous tracking of multiple cell populations; furthermore, CFSE is not compatible with green fluorescent protein (GFP), used to identify T cells in various transgenic mice. We have therefore validated the use of the far red dye seminaphthorhodafluor-1 (SNARF)-1 - originally developed to measure intracellular pH - to track murine T cell proliferation in vitro, demonstrating its ability to distinguish multiple cycles of proliferation over three days in a similar fashion to CFSE. The small changes in fluorescence emission attributed to intracellular alkalinisation of proliferating T cells have minimal impact on the ability of SNARF-1 to track cell division and this dye induces minimal cell death at the concentration used in this application. On the basis of these results, we have developed a novel in vitro murine T cell suppression assay, in which the proliferation of both conventional T cells (Tcons) stained with SNARF-1 and regulatory T cells (Tregs) stained with CFSE can be measured simultaneously. We have also demonstrated that SNARF-1 may be used to stain Tcons in assays of suppression involving 'designer' Tregs, generated by the transduction of CD4(+) T cells with constructs encoding the Foxp3(gfp) fusion protein. PMID- 21664379 TI - Evaluation of hollow-fiber ultrafiltration primary concentration of pathogens and secondary concentration of viruses from water. AB - Tangential flow hollow-fiber ultrafiltration (HFUF) was evaluated for virus and Cryptosporidium parvum concentration from water. Recovery of viruses at a low filtration rate was found to be significantly greater than at a higher filtration rate, with the recoveries of bacteriophage MS2 at high and low filtration rates shown to be 64.7% and 98.7%, respectively. Poliovirus recoveries from tap water were similar to MS2, with recoveries of 62.9% and 104.5% for high and low filtration rates, respectively. C. parvum, which was only tested at high filtration rates, had an average recovery was 105.1%. In addition to the optimization of the primary concentration technique, this study also compared several secondary concentration procedures. The highest recovery (89.5%) of poliovirus from tap water concentrates was obtained when a beef extract-celite method was used and the virus was eluted from the celite with phosphate buffered saline, pH 9.0. When HFUF primary concentration and the optimal secondary concentration methods were combined, an average recovery of 97.0 +/- 35.6% or 89.3 +/- 19.3%, depending on spike level, was achieved for poliovirus. This study demonstrated that HFUF primary concentration method is effective at recovering MS2, poliovirus and C. parvum from large volumes of water and that beef extract celite method is an effective secondary concentration method for the poliovirus tested. PMID- 21664380 TI - Effects on subjective and objective alertness and sleep in response to evening light exposure in older subjects. AB - Evening bright light exposure is reported to ameliorate daytime sleepiness and age-related sleep complaints, and also delays the timing of circadian rhythms. We tested whether evening light exposure given to older adults with sleep-wake complaints would delay the timing of their circadian rhythms with respect to their sleep timing, thereby reducing evening sleepiness and improving subsequent sleep quality. We examined the impact of evening light exposure from two different light sources on subjective alertness, EEG activity during wakefulness, and sleep stages. Ten healthy older adults with sleep complaints (mean age=63.3 years; 6F) participated in a 13-day study. After three baseline days, circadian phase was assessed. On the evening of days 5-8 the subjects were exposed for 2h to either polychromatic blue-enriched white light or standard white fluorescent light, and on the following day circadian phase was re-assessed. Subjects were allowed to leave the laboratory during all but the two days when the circadian phase assessment took place. Evening assessments of subjective alertness, and wake and sleep EEG data were analyzed. Subjective alertness and wake EEG activity in the alpha range (9.75-11.25 Hz) were significantly higher during light exposures when compared to the pre-light exposure evening (p<0.05). The light exposures produced circadian phase shifts and significantly prolonged latency to rapid eye-movement (REM) sleep for both light groups (p<0.05). The increase in wake EEG alpha activity during the light exposures was negatively correlated with REM sleep duration (p<0.05). Evening light exposure could benefit older adults with early evening sleepiness, without negatively impacting the subsequent sleep episode. PMID- 21664381 TI - Breeder and batch-dependent variability in the acquisition and performance of a motor skill in adult Long-Evans rats. AB - Reaching tasks are popular tools for investigating the neural mechanisms of motor skill learning and recovery from brain damage in rodents, but there is considerable unexplained variability across studies using these tasks. We investigated whether breeder, batch effects, experimenter, time of year, weight and other factors contribute to differences in the acquisition and performance of a skilled reaching task, the single pellet retrieval task, in adult male Long Evans hooded rats. First, we retrospectively analyzed task acquisition and performance in rats from different breeding colonies that were used in several studies spanning a 3 year period in our laboratory. Second, we compared reaching variables in age-matched rats from different breeders that were trained together as a batch by the same experimenters. All rats had received daily training on the reaching task until they reached a criterion of successful reaches per attempt. We found significant breeder-dependent differences in learning rate and final performance level. This was found even when age-matched rats from different breeders were trained together by the same experimenters. There was also significant batch-to-batch variability within rats from the same breeder trained by the same experimenter. Other factors, including weight, paw preference and the experimenter, were not as strong or consistent in their contributions to differences across studies. The breeder and batch effects found within the same rat strain may reflect genetic and environmental influences on the neural substrates of motor skill learning. This is an important consideration when comparing baseline performance across studies and for controlling variability within studies. PMID- 21664382 TI - Reversed light-dark cycle and cage enrichment effects on ethanol-induced deficits in motor coordination assessed in inbred mouse strains with a compact battery of refined tests. AB - The laboratory environment existing outside the test situation itself can have a substantial influence on results of some behavioral tests with mice, and the extent of these influences sometimes depends on genotype. For alcohol research, the principal issue is whether genotype-related ethanol effects will themselves be altered by common variations in the lab environment or instead will be essentially the same across a wide range of lab environments. Data from 20 inbred strains were used to reduce an original battery of seven tests of alcohol intoxication to a compact battery of four tests: the balance beam and grip strength with a 1.25 g/kg ethanol dose and the accelerating rotarod and open field activation tests with 1.75 g/kg. The abbreviated battery was then used to study eight inbred strains housed under a normal or reversed light-dark cycle, or a standard or enriched home cage environment. The light-dark cycle had no discernable effects on any measure of behavior or response to alcohol. Cage enrichment markedly improved motor coordination in most strains. Ethanol-induced motor coordination deficits were robust; the well-documented strain-dependent effects of ethanol were not altered by cage enrichment. PMID- 21664383 TI - TSIDER1, a short and non-autonomous Salivarian trypanosome-specific retroposon related to the ingi6 subclade. AB - Retroposons of the ingi clade are the most abundant transposable elements identified in the trypanosomatid genomes. Some are long autonomous elements (ingi, L1Tc) while others, such as RIME and NARTc, are short non-coding elements that parasitize the retrotransposition machinery of the active autonomous ones for their own mobilization. Here, we identified a new family of short non autonomous retroposons of the ingi clade, called TSIDER1, which are present in the genome of Salivarian (African) trypanosomes, Trypanosoma brucei, T. congolense and T. vivax, but absent in the T. cruzi and Leishmania spp. genomes and, as such, TSIDER1 is the only retroposon subfamily conserved at the nucleotide level between African trypanosome species. We identified three TvSIDER1 families within the genome of T. vivax and the high level of sequence conservation within the TvSIDER1a and TvSIDER1b groups suggests that they are still active. We propose that TvSIDER1a/b elements are using the Tvingi retrotransposition machinery, as they are preceded by the same conserved pattern characteristic of the ingi6 subclade, which corresponds to the retroposon-encoded endonuclease binding site. In contrast, TcoSIDER1, TbSIDER1 and TvSIDER1c are too divergent to be considered as active retroposons. The relatively low number of SIDER elements identified in the T. congolense (70 copies), T. vivax (32 copies) and T. brucei (22 copies) genomes confirms that trypanosomes have not expanded short transposable elements, which is in contrast to Leishmania spp. (~2000 copies), where SIDER play a role in the regulation of gene expression. PMID- 21664384 TI - Nasal administration of a novel recombinant human parathyroid hormone (1-34) analog for the treatment of osteoporosis of ovariectomized rats. AB - Synthetic human parathyroid (1-34) (hPTH (1-34)) is known to have the full biological activity of the holohormone for osteoporosis. This study is about designing a novel analog of hPTH (1-34) which is more suitable for intranasal administration. We likewise evaluate effectiveness of the nasal drops against osteoroporosis. Through fusion expression of combining gene, cell disruption, inclusion body washing, ethanol fraction precipitation, acid hydrolysis, and CM 52 ion exchange column chromatography Pro-Pro-[Arg11] hPTH (1-34)-Pro-Pro was designed and produced. Nasal drops of Pro-Pro-[Arg11] hPTH (1-34)-Pro-Pro were prepared and administrated to ovariectomized rats. After 12 weeks of raising, Bone Material Densities (BMD) of vertebrae were examined by Dual Energy X-Ray Absorptiometry (DEXA). The average BMD of these groups treated with nasal drops of the peptide were 28.0%-47.2% (P<0.01) higher than that of the group treated with normal saline (NS). The subchondral bone plates of the femoral heads were examined by scanning electron microscopy and a defined planar section was photographed. Percentage of the area of the cancellous bone was calculated. Percentages of the groups treated with nasal drops of the peptide increased; values were significantly different to that of the group treated with NS (P<0.001) and were even equivalent to that of normal groups. These results show that nasal drops of Pro-Pro-[Arg11] hPTH (1-34)-Pro-Pro are effective against osteoporosis. PMID- 21664385 TI - Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. AB - Glucocorticoids are major regulators of a plethora of cellular functions, acting on target cells through glucocorticoid receptors (GR) and modulation of gene transcription, among other mechanisms. One main site of action of glucocorticoids is the hepatocyte, which responds to the hormonal stimulus with induction of several proteins among them enzymes of oxidative phosphorylation (OXPHOS), both nuclearly and mitochondrially encoded. The induction of OXPHOS is regarded as a result of a nuclear action of the receptor on the respective nuclear genes and on genes encoding mitochondrial transcription factors. The presence of GR in mitochondria and of sequences in the mitochondrial genome similar to glucocorticoid responsive elements, suggested a direct action of GR on mitochondrial transcription. We demonstrate in HepG2 hepatocarcinoma cells specific binding of GR to the regulatory D-loop region of the mitochondrial genome and show that dexamethasone induces the mitochondrial transcription factors A, B1, and B2, the mitochondrial ribosomal RNA, and several mitochondrially encoded OXPHOS genes. Applying alpha-amanitin, the specific inhibitor of DNA-dependent RNA polymerase II, the dexamethasone-induced transcription of the mitochondrial genes can still proceeds, whereas the DEX effect on transcription of the mitochondrial transcription factors is suppressed. Moreover, HepG2 cells overexpressing mitochondrial targeted GR showed increased RNA synthesis, cytrochrome oxidase subunit I protein expression, and mitochondrial ATP production. We conclude that glucocorticoids can stimulate directly mitochondrial transcription by the mitochondrially localized GR, affecting OXPHOS enzyme biosynthesis. This takes place in addition to their action on mitochondrial genes by way of induction of the nuclearly encoded mitochondrial transcription factors. PMID- 21664386 TI - Development and validation of ELISA for detection of antibodies to Legionella pneumophila serogroup 1, 3 and 6 in human sera. AB - The aim of this study was to determine whether separate measurement of immunoglobulin (Ig) M and G antibodies to Legionella (L.) pneumophila serogroups (sg) 1, 3 and 6 as single antigens can facilitate an early diagnosis of Legionnaires' disease. The developed ELISA was evaluated and compared with an in house indirect Legionella immunofluorescence antibody test (IFAT) measuring Total Ig. A total of 193 sera from 128 patients with confirmed L. pneumophila infections were used to assess the sensitivity of the developed ELISA. The sensitivity was assessed in different time-periods after onset of symptoms. It was found that the sensitivity of the test increased during the first month of infection, IgM being the most sensitive; ranging from 13% in the first week after onset of symptoms, 45% in the second week to 84% in the third week; in the fourth (and beyond) week a drop to 67% was observed. The IFAT detecting L. pneumophila sg 1-6 had a sensitivity of 11%, 27%, 80% and 59%, respectively, during these time-periods. The test with the lowest sensitivity was the IgG ELISA (0%, 21%, 36% and 52%), but by combining the IgG results with the IgM results, the overall sensitivity of the assay was improved (13%, 48%, 88% and 70%). This study confirms that detection of IgG and IgM antibodies by ELISA is an important diagnostic tool especially during the initial phase of the disease, when supported by other tests like the urinary antigen test, PCR or culture. Furthermore, we showed that the ELISA is suitable for the detection of significant changes in antibody levels in paired serum samples. It was found that the sensitivity was higher for the ELISA assays than for the IFAT. Both the in house IgM ELISA and the IFAT had a low false positive rate, while a 14% false positive rate was found for the IgG ELISA among serum samples from patients with other infections. PMID- 21664387 TI - Biofilm formation by five species of Candida on three clinical materials. AB - Most recalcitrant infections are associated with colonization and microbial biofilm development. These biofilms are difficult to eliminate by the immune response mechanisms and the current antimicrobial. Fungi can form biofilms on biomaterials commonly used in clinical practice (intravascular catheters, dentures, heart valves, implanted devices, contact lenses and other devices) and are associated with infections. A variety of in vitro models using different substrates/devices have been described. These models have been used to investigate the effect of different variables, including flow, growth time, nutrients and physiological conditions on fungal biofilm formation, morphology and architecture. The purpose of our study is to analyze biofilm formation capacity by 84 strains of Candida spp. (23C. albicans, 23C. parapsilosis, 16C. tropicalis, 17C. glabrata and 5C. krusei) on three materials used in medical devices and its quantification using a method based on viable cell count. Under the conditions of our study, all assayed Candida strains have been able to form biofilms. All species showed greater biofilm formation capacity on TeflonTM, with the exception of C. glabrata which displayed higher biofilm formation capacity on PVC. Biofilm formation by Candida spp. varies depending on the type of material on which it grows and on the species and strain of Candida. The method we propose could be of great use to deepen scientific knowledge on this subject of remarkable clinical significance, considering the absence of standard biofilm formation and quantification techniques on the catheters and the level of difficulty associated to those available. PMID- 21664388 TI - The improvement of a phenotype microarray protocol for the chemical sensitivity analysis of Streptococcus thermophilus. AB - Phenotype MicroArray (PM) permits the characterisation of bacteria under nearly 2000 culture conditions. The PM standard procedure for the chemical sensitivity analysis of Gram-positive bacteria failed in the analysis of Streptococcus thermophilus. Therefore, we developed an efficient and reproducible protocol to obtain a chemically sensitive profile of S. thermophilus using PM. PMID- 21664389 TI - A time-dependent effect of caffeine upon lesion-induced plasticity. AB - During a critical period, unilateral retinal lesions induce rapid axonal sprouting of intact axons into denervated territories within the collicular visual layers. We investigated the effect of caffeine, a non-selective A(1) and A(2a) antagonist, upon the lesion-induced plasticity of retinotectal axons. Pigmented rats submitted to a temporal retinal lesion received either caffeine (30mg/kg, ip) or saline treatment. The anterograde tracing revealed that caffeine treatment during the critical period resulted in a clear reduction on the sprouting of ipsilateral fibers but to an amplification of the plasticity after PND21, thus revealing opposite effects depending on the developmental time window. PMID- 21664390 TI - DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway. AB - Disrupted-in-Schizophrenia 1 (DISC1) is a susceptibility gene for major mental illnesses, including bipolar disorder and schizophrenia. Although the roles of DISC1 in nervous system development and functions are increasingly recognized, pathophysiological mechanisms underlying a range of neuropsychiatric symptoms caused by DISC1 mutations remain unclear. Here we show that DISC1 enhances synaptic vesicle transport along microtubules. Knocking down DISC1 expression results in attenuated vesicle transport in primary cortical neurons. Likewise, expressing the dominant-negative, breakpoint mutant version of DISC1 causes defective vesicle transport, by disrupting the assembly between the kinesin-1 adaptor FEZ1 and the cargo protein Synaptotagmin-1 (Syt-1). In addition, lithium, a mood-stabilizing agent used for the treatment of bipolar disorder, can restore the assembly of FEZ1 and Syt-1, and normalizes the defective transport caused by the dominant-negative DISC1. Thus, this study addresses a new role of DISC1 in organelle transport in neurons, and suggests that this cellular pathway could be therapeutically targeted for the treatment against neuropsychiatric diseases. PMID- 21664391 TI - PEGylation improves pharmacokinetic profile, liver uptake and efficacy of Interferon gamma in liver fibrosis. AB - Interferon gamma (IFNgamma) is a potent cytokine that displays a variety of anti viral, anti-proliferative, immunomodulatory, apoptotic and anti-fibrotic functions. However, its clinical use is limited to the treatment of few diseases due to the rapid clearance from the body. PEGylated IFN-alpha formulations are shown to be beneficial in viral hepatitis, but PEGylation of IFNgamma to enhance its therapeutic effects in liver fibrosis is not yet explored. Liver fibrosis is characterized by the extensive accumulation of an abnormal extracellular matrix and is the major cause of liver-related morbidity and mortality worldwide. To date, there is no pharmacotherapy available for this disease. We modified IFNgamma with different-sized linear PEG molecules (5, 10 and 20kDa) and assessed the biological activity in vitro and in vivo. All PEGylated IFNgamma constructs were biologically active and activated IFNgamma signaling in vitro as determined with a nitric oxide release assay and a pGAS-Luc reporter plasmid assay, respectively. Similar to IFNgamma, all PEGylated IFNgamma induced a significant reduction of fibrotic parameters in mouse NIH3T3 fibroblasts as shown with immunohistochemical staining and quantitative PCR analyses. In vivo, the pharmacokinetic profile of radiolabeled (125)I-IFNgamma-PEG conjugates revealed a decreased renal clearance and an increased plasma half-life with an increase of PEG size. Moreover, the liver accumulation of PEGylated IFNgamma constructs was significantly higher than the unmodified IFNgamma, which was also confirmed by increased MHC-II expression in the livers. Furthermore, in a CCl(4)-induced acute liver injury model in mice, PEGylated constructs reduced the early fibrotic parameters more drastically than unmodified IFNgamma. Of note, these effects were stronger with higher PEG-sized IFNgamma constructs. These data nicely correlated with the pharmacokinetic data. In conclusion, PEGylation significantly improved the pharmacokinetics, liver uptake and anti-fibrotic effects of IFNgamma. This study opens new opportunities to exploit the therapeutic applications of PEGylated IFNgamma for the treatment of liver fibrosis and other diseases. PMID- 21664392 TI - Advances in assay of complement function and activation. AB - The main function of the complement system is pattern recognition of danger. Typical exogenous danger signals are pathogen associated molecular patterns inducing a protective inflammatory response. Other examples are exposure to foreign surfaces of biomedical materials including nanoparticles, which principally induce the same inflammatory response. If a surface is "foreign" to the host, it induces complement activation. Development of monoclonal antibodies to neoepitopes on complement activation products introduced an entirely new set of methods for assay of complement activation. Activation of complement by a surface occurs by impairment of the fine balance of the control system, e.g. by preferred binding of factor B at the expense of factor H. Sensitive methods to detect complement activation on surfaces and in the fluid phase are a prerequisite for investigation of the biocompatibility of artificial materials. This information can be used to develop new materials with enhanced biocompatibility. Here we review available methods to study human and animal complement function and activation in vitro and in vivo. PMID- 21664393 TI - Adrenomedullin protects against fructose-induced insulin resistance and myocardial hypertrophy in rats. AB - Adrenomedullin (ADM) has been recognized as a multipotent multifunctional peptide. To explore the pathophysiological roles of ADM in insulin resistance (IR), we studied the changes in ADM mRNA level in the myocardium and vessels and the effect of ADM supplementation on rats with IR induced by fructose feeding. Rats were fed 4% fructose in drinking water for 8 weeks, and ADM was administered subcutaneously in pure water through an Alzet Mini-osmotic Pump at 300 ng/kg/h for the last 4 weeks. Compared with controls, rats with IR showed increased levels of fasting blood sugar and serum insulin, by 95% and 67%, respectively (all P<0.01), and glycogen synthesis and glucose transport activity of the soleus decreased by 54% and 55% (all P<0.01). mRNA level and content of brain natriuretic peptide (BNP) in myocardial were all increased significantly. Fructose-fed rats showed increased immunoreactive-ADM content in plasma by 110% and in myocardia by 55% and increased mRNA level in myocardia and vessels (all P<0.01). ADM administration ameliorated the induced IR and myocardial hypertrophy. The glycogen synthesis and glucose transport activity of the soleus muscle increased by 41% (P<0.01) and 32% (P<0.05). ADM therapy attenuated myocardial and soleus lipid peroxidation injury and enhanced the antioxidant ability. Our results showed upregulation of endogenous ADM during fructose induced IR and the protective effect of ADM on fructose-induced IR and concomitant cardiovascular hypertrophy probably by its antioxidant effect, which suggests that ADM could be an endogenous protective factor in IR. PMID- 21664394 TI - Inhibitory effects and mechanisms of physiological conditions on the activity of enantiomeric forms of an alpha-helical antibacterial peptide against bacteria. AB - Enantiomeric amphipathic alpha-helical antibacterial peptides were synthesized and their biophysical and biological properties under different physiological conditions were studied. In the absence of physiological factors, the L- and D peptides exhibited similar antimicrobial activities against a broad spectrum of bacteria, even against clinical isolates with resistance to traditional antibiotics. However, in the presence of NaCl, CaCl2 or human serum albumin (HSA) at physiological concentrations, the enantiomers revealed bacterium-species dependent attenuations in antibacterial activity. In the presence of salts the electrostatic interaction between the peptides and the biomembrane was inhibited. Salts, especially CaCl2 weakened the ability of the peptides to permeabilize the outer membrane of Gram-negative bacteria, as determined by a 1-N phenylnaphthylamine uptake assay. HSA exhibited variable inhibitory effects on the activity of the peptides when incubated with different bacterial strains. The peptides showed different binding association abilities to HSA at different molar ratios, regardless of their chirality, resulting in reduced peptide biological activity. The D-peptide performed better than its L-enantiomer in all conditions tested because of its resistance to proteolysis, and may therefore represent a promising candidate for development as a therapeutic agent. PMID- 21664395 TI - Peptidomic analysis of skin secretions demonstrates that the allopatric populations of Xenopus muelleri (Pipidae) are not conspecific. AB - Mueller's clawed frog Xenopus muelleri (Peters 1844) occupies two non-contiguous ranges in east and west Africa. The phylogenetic relationship between the two populations is unclear and it has been proposed that the western population represents a separate species. Peptidomic analysis of norepinephrine-stimulated skin secretions from X. muelleri from the eastern range resulted in the identification of five antimicrobial peptides structurally related to the magainins (magainin-M1 and -M2), xenopsin-precursor fragments (XPF-M1) and caerulein-precursor fragments (CPF-M1 and -M2) previously found in skin secretions of other Xenopus species. A cyclic peptide (WCPPMIPLCSRF.NH2) containing the RFamide motif was also isolated that shows limited structural similarity to the tigerinins, previously identified only in frogs of the Dicroglossidae family. The components identified in skin secretions from X. muelleri from the western range comprised one magainin (magainin-MW1), one XPF peptide (XPF-MW1), two peptides glycine-leucine amide (PGLa-MW1 and -MW2), and three CPF peptides (CPF-MW1, -MW2 and -MW3). Comparison of the primary structures of these peptides suggest that western population of X. muelleri is more closely related to X. borealis than to X. muelleri consistent with its proposed designation as a separate species. The CPF peptides showed potent, broad-spectrum activity against reference strains of bacteria (MIC 3-25 MUM), but were hemolytic against human erythrocytes. PMID- 21664396 TI - CD4+CD25+Foxp3+IFN-gamma+ human induced T regulatory cells are induced by interferon-gamma and suppress alloresponses nonspecifically. AB - Interferon-gamma (IFN-gamma)-producing CD3(+)CD4(+)CD25(+)Foxp3(+) peripheral blood lymphocytes (PBL) are more frequently detectable in patients with good than in patients with impaired long-term kidney graft function, suggesting an immunoregulatory role of this induced T regulatory (iTreg) subtype. Herein, the in vitro function of separated CD3(+)CD4(+)CD25(+)Foxp3(+)IFN-gamma(+) PBL that were induced by phorbol 12-myristate 13-acetate (PMA)/ionomycin or alloantigenic stimulation was investigated using cell coculture techniques and flow cytometry. CD4(+)CD25(+)Foxp3(+) PBL with intracellular IFN-gamma production increased to 26% in cell cultures stimulated with PMA/ionomycin for 6 hours. Recombinant IFN gamma augmented and anti-IFN-gamma monoclonal antibody blocked induction of CD4(+)CD25(+)Foxp3(+)IFN-gamma(+) PBL, suggesting their IFN-gamma-dependent induction. In addition, CD4(+)CD25(+)Foxp3(+)IFN-gamma(+) PBL produced immunosuppressive interleukin (IL)-10, transforming growth factor-beta, and IL-4 intracellularly and expressed both IFN-gamma and IFN-gamma receptors (CD119) on the cell surface, allowing separation of CD4(+)CD25(+)IFN-gamma(+) PBL with 98% purity. Addition of enriched CD4(+)CD25(+)IFN-gamma(+) PBL to autologous PMA/ionomycin stimulated PBL decreased blast formation (p < 0.05), indicating suppression of cell proliferation by CD4(+)CD25(+)IFN-gamma(+) PBL. CD4(+)CD25(+)IFN-gamma(+) PBL separated from primary mixed leukocyte cultures (MLC) and added to autologous or third-party secondary MLC suppressed allogeneic T-cell activation nonspecifically (p < 0.05). We conclude that CD4(+)CD25(+)Foxp3(+)IFN-gamma(+) PBL are induced by IFN-gamma, making them sensors for IFN-gamma and initial immune responses. Circulating CD4(+)CD25(+)Foxp3(+)IFN-gamma(+) PBL could suppress allogeneic T-cell responses in patients and may be involved in inhibition of the posttransplant alloresponse. PMID- 21664397 TI - Blinded, controlled field trial of two commercially available Mycoplasma bovis bacterin vaccines in veal calves. AB - Mycoplasma bovis is an etiologic agent of pneumonia, arthritis, and otitis in young calves, such as those found in the special-fed veal industry. We conducted a blinded, controlled trial of two commercially available M. bovis bacterin vaccines for the prevention of respiratory disease in calves associated with M. bovis infection. Calves were randomly assigned to a subcutaneous treatment of vaccine A (n=50), adjuvant A (n=50), vaccine B (n=50), or 0.9% sterile saline solution (n=50) beginning at 27 days of age. Upper-respiratory tract colonization was not impacted by vaccination status. Vaccine A significantly reduced the presence of lung lesions (p=0.0325), however there was no significant reduction of M. bovis in lung lesions. Vaccine B did not significantly reduce total lung lesions or M. bovis-specific lung lesions. The relative risk was determined to be 0.56, 1.0, and 1.36 for vaccine A, adjuvant A, and vaccine B, respectively. There was no association between the total specific antibody isotype (IgM, IgG1, IgG2, IgA) concentrations or M. bovis antibodies and the M. bovis-associated morbidity in the veal calves. Under the field conditions of this study, observed vaccine efficacy for vaccine A and vaccine B was 44% and less than 1%, respectively. PMID- 21664398 TI - Three CpG oligodeoxynucleotide classes differentially enhance antigen-specific humoral and cellular immune responses in mice. AB - Synthetic oligodeoxynucleotides containing unmethylated CpG-dinucleotides (CpG ODNs) are immunostimulatory in a broad spectrum of species. Extensive studies provide evidence that CpG-ODNs are effective as immunotherapeutics and vaccine adjuvants in various clinical settings. Three major classes of immunostimulatory CpG-ODNs are well characterized according to their in vitro activities and chemical compositions. However, it remains largely unclear whether and how these differences translate in vivo and in particular when used as vaccine adjuvants. In the present study, a panel of CpG-ODNs, including four representative sequences respectively from each class, was used to characterize their adjuvant activities in mice. The results demonstrated that three CpG-ODN classes can differentially affect antigen-specific humoral and cellular immune responses. Specifically, the B- and C-class CpG-ODNs induce a potent Th1-biased immunity with comparable antibody levels as well as CD4+ and CD8+ T cell responses. In contrast, although the A-class CpG-ODNs can weakly enhance antibody titers and CD8+ T cell response regarding cytotoxic activity, they are not able to change the IgG1/IgG2a ratio or elicit antigen-specific, IFN-gamma-secreting CD4+ and CD8+ T cells. Consistent with this, three CpG-ODN classes provide differential antigen-specific protection against Listeria monocytogenes, an intracellular bacterial infection. In conclusion, our study provides not only better knowledge about the adjuvant activities of three CpG-ODN classes but also implications for the rational design of CpG-ODN adjuvants. PMID- 21664399 TI - Cysteine proteases as potential antigens in antiparasitic DNA vaccines. AB - Cysteine proteases in parasites are potent inducers of vertebrate host immune responses and may under certain circumstances take part in the pathogen's immune evasion strategies. These capacities place these parasite molecules as interesting candidate antigens in antiparasitic vaccines for use in vertebrates. Parasite cysteine proteases are able to skew the Th1/Th2 profile in mammals towards a response which allows sustainable parasite burdens in the host. DNA vaccines are also able to skew the Th1/Th2 profile by different administration techniques and the use of cysteine proteases in these genetic immunizations open perspectives for manipulation of the host immune response towards higher protection. PMID- 21664400 TI - Safety and efficacy of Rift Valley fever Smithburn and Clone 13 vaccines in calves. AB - Two modified live attenuated vaccines against the disease Rift Valley fever (RVF) have been tested for safety and efficacy in young calves. The RVF Smithburn vaccine produced in South Africa and used successfully to prevent and control the disease in endemic sub-Saharan countries was compared to the candidate vaccine RVF Clone 13. Five sero-negative calves per vaccine group were vaccinated with a single dose of each vaccine and tested for antibody response. All vaccinated calves were challenged with a highly virulent RVF virus together with five unvaccinated calves used as control of the challenge. Protection was confirmed in all vaccinated animals as they did not show any clinical signs typical of RVF. A good neutralizing antibody response was induced post-vaccination and no viraemia could be detected post-challenge in calves of both vaccine groups. All non vaccinated control animals showed clinical symptoms of RVF, high viraemia and were euthanized. This study reported the first case of blindness in cattle resulting from virulent RVF virus infection in unvaccinated calves used as negative controls. PMID- 21664401 TI - Single chain variable fragment antibodies against Shiga toxins isolated from a human antibody phage display library. AB - Shiga toxins (Stxs) are involved in the pathogenesis of hemolytic-uremic syndrome and other severe systemic complications following enterohemorrhagic Escherichia coli infection in humans. Passive immunotherapies using monoclonal antibodies have been shown to be effective for neutralizing the toxic effects of Stxs. However, animal-derived monoclonal antibodies are sometimes immunogenic and their production is both laborious and expensive. We here report the isolation of single-chain variable fragment antibodies against Stxs by screening a phage display library constructed from a naive human repertoire. An antibody among the selected clones designated B22 bound to the binding subunits of both Stx-1 and Stx-2, and strongly neutralized the cytotoxicity of Stx-1. This is the first example of a monovalent antibody showing Stx-neutralizing activity. The B22 antibody is also completely naturally occurring in human, which reduces the possibility of adverse immunological effects, and can be easily produced using bacterial protein synthesis systems. PMID- 21664402 TI - The burden of hospitalizations for meningococcal infection in Spain (1997-2008). AB - All hospital discharges and deaths related to invasive meningococcal disease, meningococcal meningitis and meningococcemia in the general population from 1997 to 2008 in Spain were obtained. Among the 11,611 meningococcal infection related discharges 53% were meningococcal meningitis and 55% were meningococcemia. The annual hospitalization rate was 2.33, 1.23 and 1.29 cases per 100,000 for invasive meningococcal disease, meningococcal meningitis and meningococcemia, respectively. 846 deaths for invasive meningococcal disease, 235 for meningococcal meningitis and 605 for meningococcemia were reported. Although an important decrease in meningococcal infections related morbidity and mortality has occurred in the last twelve years in Spain, they still continue being major causes of hospitalization and death, especially in the children up to 2 years of age. Future preventive measures, such as vaccination with vaccines covering new conjugated serogroups (B and ACYW135), could further improve population health. PMID- 21664403 TI - Isolation of phytate from Jatropha curcas kernel meal and effects of isolated phytate on growth, digestive physiology and metabolic changes in Nile tilapia (Oreochromis niloticus L.). AB - Jatropha curcas seeds are rich in oil and protein. The oil is used for biodiesel production. The defatted Jatropha kernel meal obtained after oil extraction is rich in protein (58-66%) and phytate (9-11%). The phytate rich fraction was isolated from defatted kernel meal using organic solvents (acetone and carbon tetracholride). It had 66% phytate and 22% crude protein. The fingerlings (n=50, 16.2 +/- 0.64 g) were randomly distributed into five groups containing 10 replicates and fed iso-nitrogenous diets (crude protein 36%): control diet containing casein and gelatin as proteins; control diet containing 1.5% and 3% Jatropha phytate (PWP(1.5) and PWP(3), respectively); and control diet containing 1.5% and 3% Jatropha phytate supplemented with phytase (1500 FTU/kg) (PWP(1.5+Phytase) and PWP(3+Phytase), respectively). Significantly lower (P<0.05) growth and feed utilization in PWP(1.5) and PWP(3) groups than for control and both phytase containing groups were observed; whereas feed gain ratio exhibited opposite trend. Protein and lipid digestibilities of the diets, amylase and protease enzyme activities in the intestine were significantly higher (P<0.05) in PWP(1.5+Phytase) and PWP(3+Phytase) groups than for PWP(1.5) and PWP(3) groups. Lowest red blood cell counts, and hemoglobin and hematocrit concentrations were observed in PWP(3) group which were not statistically different to those for PWP(1.5) group, but were significantly (P<0.05) lower than those for all other groups. Highest albumin, globulin and total protein concentrations were observed in PP(3+Phytase) group and lowest in PWP(1.5) group; and values for the latter were statistically similar to those for control group. Calcium, phosphorus and glucose concentrations in blood and cholesterol concentration in plasma were significantly lower (P<0.05) in the phytate enriched groups compared with control and phytase treated groups (PP(1.5+Phytase) and PP(3+Phytase)). Higher (P<0.05) alkaline phosphatase activity was observed in phytase supplemented groups compared with that in non-supplemented groups which (PP(1.5+Phytase)) was statistically similar to that in control group, whereas alanine transaminase activity in blood exhibited opposite trend. In conclusion, Jatropha phytate present in DJKM is an antinutrient and addition of phytase in the diet containing DJKM is recommended. PMID- 21664404 TI - Disruption of spermatogenesis and differential regulation of testicular estrogen receptor expression in mice after polychlorinated biphenyl exposure. AB - The testicular toxicity of polychlorinated biphenyls (PCBs) has been extensively studied. However, the detailed mechanism is still obscure. In the present study, male C57 mice were treated with different doses of Aroclor 1254 (a commercial PCB mixture) once every 3 days by oral gavage. After exposure to Aroclor 1254 for 50 days, the sperm count decreased in a dose-dependent manner. Cell proliferation and apoptosis are key processes regulating development of the testis, and alterations in these processes may underlie testicular dysgenesis. Our results showed that the germ cell proliferation was inhibited and the apoptosis of the germ cell was induced in a dose-dependent manner after treatment with Aroclor 1254. Although there was no significant change in serum testosterone levels and androgen receptor expression levels after treatment with different dosages of Aroclor 1254, the estradiol levels decreased and the expression of estrogen receptor (ER) beta increased in a dose-dependent manner, whereas an elevation of the expression of ERalpha was only observed in the 50MUg/kg group. The data as a whole suggested that inhibited proliferation and induced apoptosis in germ cells, and a differential regulation of ER, may be involved in the testicular toxicity of PCBs. PMID- 21664405 TI - Interplay of early biochemical manifestations by cadmium insult in sertoli-germ coculture: an in vitro study. AB - Cadmium is a common environmental and occupational hazard and its adverse effect on reproductive organ has been well documented. The present study is planned to delineate the mechanism of Cd toxicity in rat testes. Our study shows that Cd causes apoptosis in sertoli-germ cells which is governed by oxidative stress. We assayed ROS, GSH and MMP to ensure the role of oxidative stress, further confirmed it by thiol modulators. The initial biochemical response shown in sertoli-germ cells was a significant rise in intracellular calcium followed by a drastic fall in MMP and then ROS generation. The downstream events included cytochrome c release leading to caspase-3 activation and culminating in cell death via apoptosis. Furthermore Cd disrupted the spermatogenic pathway as evident by suppression in tesmin and LDH-X levels. PMID- 21664406 TI - In vivo hydroquinone exposure alters circulating neutrophil activities and impairs LPS-induced lung inflammation in mice. AB - Hydroquinone (HQ) is an environmental contaminant which causes immune toxicity. In this study, the effects of exposure to low doses of HQ on neutrophil mobilization into the LPS-inflamed lung were investigated. Male Swiss mice were exposed to aerosolized vehicle (control) or 12.5, 25 or 50ppm HQ (1h/day for 5 days). One hour later, oxidative burst, cell cycle, DNA fragmentation and adhesion molecules expressions in circulating neutrophils were determined by flow cytometry, and plasma malondialdehyde (MDA) levels were measured by HPLC. Also, 1h later the last exposures, inflammation was induced by LPS inhalation (0.1mg/ml/10min) and 3h later, the numbers of leukocytes in peripheral blood and in the bronchoalveolar lavage fluid (BALF) were determined using a Neubauer chamber and stained smears; adhesion molecules expressed on lung microvessel endothelial cells were quantified by immunohistochemistry; myeloperoxidase (MPO) activity was measured in the lung tissue by colorimetric assay; and cytokines in the BALF were determined by ELISA. In vivo HQ exposure augmented plasma MDA levels and oxidative activity of neutrophils, but did not cause alterations in cell cycle and DNA fragmentation. Under these conditions, the number of circulating leukocytes was not altered, but HQ exposure reduced LPS-induced neutrophil migration into the alveolar space, as these cells remained in the lung tissue. The impaired neutrophil migration into BALF may not be dependent on reduced cytokines secretions in the BALF and lung endothelial adhesion molecules expressions. However, HQ exposure increased the expression of beta(2) and beta(3) integrins and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in neutrophils, which were not further enhanced by fMLP in vitro stimulation, indicating that HQ exposure activates circulating neutrophils, impairing further stimulatory responses. Therefore, it has been shown, for the first time, that neutrophils are target of lower levels of in vivo HQ exposure, which may be considered in host defense in infectious diseases. PMID- 21664407 TI - Purification and partial characterization of a novel phosphodiesterase from the venom of Trimeresurus stejnegeri: inhibition of platelet aggregation. AB - The phosphodiesterases (PDEs) are a superfamily of enzymes that have multiple roles in extracellular nucleotide metabolism and in the regulation of nucleotide based intercellular signaling. Here we describe for the first time the isolation and partial characterization of a novel phosphodiesterase from Trimeresurus stejnegeri venom, named TS-PDE, using ion exchange and gel filtration chromatography. The purified TS-PDE is shown to be homogeneous as judged by SDS PAGE and capillary isoelectric focusing. TS-PDE is a glycoprotein which contains 2.48% carbohydrate. Unlike other PDEs which are usually single polypeptide chain proteins with isoelectric points between 7.5 and 10.5, TS-PDE is a disulfide linked heterodimer with an isoelectric point of 5.1 and a molecular mass of 100 kDa. The N-terminal amino acids of two chains are valine and serine, respectively. Furthermore, among all identified PDEs, only TS-PDE contains both of endogenous Cu(2+) and Zn(2+) which are essential for its phosphodiesterase activity. The purified TS-PDE exhibits broad phosphodiesterase substrate range with the order of specificity: nicotinamide guanine dinucleotide > ATP > nicotinamide adenine dinucleotide > ADP. The purified TS-PDE shows an exonuclease activity and no contamination with either alkaline phosphatase or 5'-nucleotidase activity. TS-PDE strongly inhibits ADP-induced platelet aggregation in human platelet-rich plasma by hydrolyzing ADP. Altogether, these results indicate that the novel TS-PDE is a unique phosphodiesterase with different structure from the known PDEs. PMID- 21664408 TI - Bifunctional transfer-messenger RNA. AB - Transfer-messenger RNA (tmRNA) is a bifunctional RNA that has properties of a tRNA and an mRNA. tmRNA uses these two functions to release ribosomes stalled during translation and target the nascent polypeptides for degradation. This concerted reaction, known as trans-translation, contributes to translational quality control and regulation of gene expression in bacteria. tmRNA is conserved throughout bacteria, and is one of the most abundant RNAs in the cell, suggesting that trans-translation is of fundamental importance for bacterial fitness. Mutants lacking tmRNA activity typically have severe phenotypes, including defects in viability, virulence, and responses to environmental stresses. PMID- 21664410 TI - S100 and S100 fused-type protein families in epidermal maturation with special focus on S100A3 in mammalian hair cuticles. AB - Epithelial Ca(2+)-regulation, which governs cornified envelope formation in the skin epidermis and hair follicles, closely coincides with the expression of S100A3, filaggrin and trichohyalin, and the post-translational modification of these proteins by Ca(2+)-dependent peptidylarginine deiminases. This review summarizes the current nomenclature and evolutional aspects of S100 Ca(2+) binding proteins and S100 fused-type proteins (SFTPs) classified as a separate protein family with special reference to the molecular structure and function of S100A3 dominantly expressed in hair cuticular cells. Both S100 and SFTP family members are identified by two distinct types of Ca(2+)-binding loops in an N terminal pseudo EF-hand motif followed by a canonical EF-hand motif. Seventeen members of the S100 protein family including S100A3 are clustered with seven related genes encoding SFTPs on human chromosome 1q21, implicating their association with epidermal maturation and diseases. Human S100A3 is characterized by two disulphide bridges and a preformed Zn(2+)-pocket, and may transfer Ca(2+) ions to peptidylarginine deiminases after its citrullination-mediated tetramerization. Phylogenetic analysis utilizing current genome databases suggests that divergence of the S100A3 gene coincided with the emergence of hair, a defining feature of mammals, and that the involvement of S100A3 in epithelial Ca(2+)-cycling occurred as a result of a skin adaptation in terrestrial mammals. PMID- 21664409 TI - From snoRNA to miRNA: Dual function regulatory non-coding RNAs. AB - Small nucleolar RNAs (snoRNAs) are an ancient class of small non-coding RNAs present in all eukaryotes and a subset of archaea that carry out a fundamental role in the modification and processing of ribosomal RNA. In recent years, however, a large proportion of snoRNAs have been found to be further processed into smaller molecules, some of which display different functionality. In parallel, several studies have uncovered extensive similarities between snoRNAs and other types of small non-coding RNAs, and in particular microRNAs. Here, we explore the extent of the relationship between these types of non-coding RNA and the possible underlying evolutionary forces that shaped this subset of the current non-coding RNA landscape. PMID- 21664411 TI - I-mfa domain proteins specifically interact with SERTA domain proteins and repress their transactivating functions. AB - The I-mfa domain proteins I-mfa and HIC are considered to be candidate tumor suppressor genes and have been shown to be involved in transcriptional regulation. We show here that I-mfa and HIC specifically interact with SEI-1 through their C-terminal I-mfa domains in vivo. This interaction affects the intracellular localization of I-mfa and requires the region of SEI-1 between 30 and 90 amino acids, which includes its SERTA domain, and results in repression of its intrinsic transcriptional activity. I-mfa also decreases the levels of the SEI-1.DP-1 complex and endogenous Fbxw7 mRNA, the expression of which is coregulated by E2F.DP-1 and SEI-1 in an interaction-dependent manner in vitro. In addition, I-mfa also specifically interacts with other SERTA domain-containing proteins, including SEI-2, SEI-3, SERTAD3 and SERTAD4, through its I-mfa domain in vivo. This interaction also affects the intracellular localization of I-mfa and represses the intrinsic transcriptional activities of SEI-2 and SERTAD3, which are also involved in the E2F-dependent transcription. These data reveal for the first time that I-mfa domain proteins interact with SERTA domain proteins and negatively regulate their transcriptional activity. Because SEI-1, SEI-2 and SERTAD3, whose intrinsic transcriptional activities are repressed by I-mfa, are suggested to be oncogenes, I-mfa domain proteins may be involved in their oncogenic functions by negatively regulating their transcriptional activities. PMID- 21664412 TI - Salivary alpha-amylase response to acute psychosocial stress: the impact of age. AB - The impact of stress on health varies across the different stages of human life. Aging is associated with psychobiological changes that could limit our ability to cope with stressors. Therefore, it is crucial to clarify the physiological mechanisms that underlie the stress response and the changes that occur in them as we age. Our aim was to investigate age differences in the salivary alpha amylase (sAA) response to stress, and its relationship with other typical stress biomarkers such as cortisol and heart rate (HR). Sixty-two participants divided into two age groups (younger group: N=31, age range: 18-35 years; older group: N=31, age range: 54-71 years) were exposed to the Trier Social Stress Test and a control condition in a crossover design. No age differences were found in the sAA or HR responses to stress. However, the sAA global output was higher in older than younger adults. Additionally, in the stress condition, the total amount of cortisol released was positively related to the total sAA released, while the HR increase was positively related to the sAA increase. Our results do not support the existence of an attenuated autonomic nervous system response to stress in older adults, but rather a heightened sympathetic tone. Furthermore, we found further evidence of the coordination between the hypothalamus-pituitary-adrenal system and the autonomic nervous system in their response to acute psychosocial stress. PMID- 21664413 TI - Vitamin D and intestinal calcium absorption. AB - The principal function of vitamin D in calcium homeostasis is to increase calcium absorption from the intestine. Calcium is absorbed by both an active transcellular pathway, which is energy dependent, and by a passive paracellular pathway through tight junctions. 1,25Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) the hormonally active form of vitamin D, through its genomic actions, is the major stimulator of active intestinal calcium absorption which involves calcium influx, translocation of calcium through the interior of the enterocyte and basolateral extrusion of calcium by the intestinal plasma membrane pump. This article reviews recent studies that have challenged the traditional model of vitamin D mediated transcellular calcium absorption and the crucial role of specific calcium transport proteins in intestinal calcium absorption. There is also increasing evidence that 1,25(OH)(2)D(3) can enhance paracellular calcium diffusion. The influence of estrogen, prolactin, glucocorticoids and aging on intestinal calcium absorption and the role of the distal intestine in vitamin D mediated intestinal calcium absorption are also discussed. PMID- 21664414 TI - The puzzles of the prokineticin 2 pathway in human reproduction. AB - Prokineticin, 1 (PROK1) and prokineticin 2 (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. MIT-1 was initially identified as a non-toxic constituent in the venom of the black mamba snake (Dendroaspis polylepis) (Joubert and Strydom, 1980) while Bv8 was identified in the skin secretion of the toad, Bombina variegate (Mollay et al., 1999). All three homologs stimulate gastrointestinal motility thus accounting for their family name "prokineticins" (Schweitz et al., 1990, 1999). However, since its initial description, both PROK1 and PROK2 have been found to regulate a dazzling array of biological functions throughout the body. In particular, PROK1 acts as a potent angiogenic mitogen on endocrine vascular epithelium, thus earning its other name, Endocrine gland-vascular endothelial factor (EG-VEGF) (LeCouter et al., 2002). In contrast, the PROK2 signaling pathway is a critical regulator of olfactory bulb morphogenesis and sexual maturation in mammals and this function is the focus of this review. PMID- 21664415 TI - Genetic counseling for isolated GnRH deficiency. AB - As our understanding of the complexities of the various etiologies and complex genetic architecture of GnRH deficiency grows, so too does the need to apply newly-developed genetic tools in a way that: (a) is meaningful to individuals and their families; (b) integrates all of the phenotypic features of this syndrome into a rationale; and (c) provides up-to-date diagnostic technologies in a cost effective algorithm of genetic testing. Genetic counseling aims to accomplish these goals through ascertainment of detailed family histories, targeted comprehensive phenotypic evaluations, informed selection of genetic testing, interpretation of genetic test results, and the provision of highly specific risk assessments and psychological support to individuals diagnosed with this reproductive condition. This chapter offers a guide to incorporating this rapidly evolving state of knowledge of the pedigree and phenotypes into the process of selecting and prioritizing genetic testing. In addition, the provision of risk assessment that accounts for nuanced genetic concepts such as variable expressivity, incomplete penetrance, and oligogenicity, all of which are emerging features of the genetics of this clinical syndrome, is considered. Beyond translating genetic information, genetic counseling should address the psychological impact of embarrassment, shame, anxiety, and guilt that are often seen among individuals with reproductive disorders. PMID- 21664416 TI - Coordination of mitochondrial biogenesis by thyroid hormone. AB - Thyroid hormone (TH) has profound influence on metabolism that is closely linked to its effect on mitochondrial biogenesis and function. After a single injection of TH into mammals, physiological alterations (e.g. changes in oxygen consumption rates) are detectable after a lag period of ~48h. This characteristic lag period is somewhat surprising since non-genomic responses are already detectable within minutes, and first genomic responses within some hours after administration of TH. This review provides a model to explain the characteristic lag period: TH regulates a first series of TH target genes via classical activation of gene expression by binding to thyroid hormone response elements. Some directly regulated target genes serve as intermediate factors and subsequently regulate a second series of indirect TH target genes. Intermediate factors are transcription factors (such as NRF-1, NRF-2 and PPARgamma) and transcriptional coactivators (such as PGC-1alpha and PGC-1beta). In concert with several post-translational modifications, these intermediate factors orchestrate the physiological response to thyroid hormone in vivo. PMID- 21664418 TI - Functional interaction of fibroblast growth factor-8, bone morphogenetic protein and estrogen receptor in breast cancer cell proliferation. AB - Estrogen is involved in the development and progression of breast cancer. Here we investigated the effect of fibroblast growth factor (FGF)-8 on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptor (ER)alpha, ERbeta, FGF receptors, and Smad signaling molecules. Estradiol stimulated MCF-7 cell proliferation in a concentration-responsive manner, whereas BSA-bound estradiol had a weak effect on MCF-7 cell mitosis compared with the effect of free estradiol. It is notable that estrogen-induced cell proliferation was enhanced in the presence of FGF-8 and that the combined effects were reversed in the presence of an FGF-receptor kinase inhibitor or an ER antagonist. It was also revealed that FGF-8 increased the expression levels of ERalpha, ERbeta and aromatase mRNAs, while estradiol reduced the expression levels of ERs, aromatase and steroid sulfatase in MCF-7 cells. FGF 8-induced phosphorylation of FGF receptors was augmented by estradiol, which was reversed by an ER antagonist. FGF-8-induced activation of MAPKs and AKT signaling was also upregulated in the presence of estrogen. On the other hand, FGF-8 suppressed BMP-7 actions that are linked to mitotic inhibition by activating the cell cycle regulator cdc2. FGF-8 was revealed to inhibit BMP receptor actions including Id-1 promoter activity and Smad1/5/8 phosphorylation by suppressing expression of BMP type-II receptors and by increasing expression of inhibitory Smads. Collectively, the results indicate that FGF-8 acts to facilitate cell proliferation by upregulating endogenous estrogenic actions as well as by suppressing BMP receptor signaling in ER-expressing breast cancer cells. PMID- 21664419 TI - Stress and glucocorticoids regulated corticotropin releasing factor in rat prefrontal cortex. AB - Corticotropin releasing factor (CRF) is considered as the central driving force in the stress response and plays a key role in the pathogenesis of depression. CRF neurons have been identified to locate in most regions of the prefrontal cortex (PFC), a brain region that is highly associated with the control of emotion and cognition. However, little is known on the regulation of CRF in this region. In this study, we aimed to identify the regulatory effect of acute restraint stress and glucocorticoid on PFC CRF and characterize the possible function of CRF in the PFC. We found that acute restraint stress increased and glucocorticoid decreased PFC CRF mRNA expression. The expression of glucocorticoid receptor (GR) was found to colocalize with CRF neurons in the PFC. In addition, recruitment of GR by the CRF promoter was observed in vivo. Specific attention was paid to the effect of CRF on CRF receptor 1 (CRFR1) expression in primary PFC cultures. The results showed that CRF increased CRFR1 expression through the MEK-ERK1/2 pathway. In summary, this study may contribute to the better understanding of CRF functions in the PFC. PMID- 21664417 TI - Central regulation of blood pressure by the mineralocorticoid receptor. AB - Addition of mineralocorticoid receptor (MR) antagonists to standard therapy for heart failure, kidney disease, metabolic syndrome, and diabetes is increasing steadily in response to clinical trials demonstrating clear benefits. In addition to blocking deleterious activity of MR within the heart, vessels and kidneys, MR antagonists target MR in hemodynamic regulatory centers in the brain, thereby decreasing excessive sympathetic nervous system drive, vasopressin release, abnormal baroreceptor function, and circulating and tissue pro-inflammatory cytokines. However, brain MR are also involved with cognition, memory, affect and functions yet to be determined. Understanding specific central mechanisms involved in blood pressure regulation by MR is necessary for the development of agents to target downstream events specific to central hemodynamic regulation, not only to avoid the hypokalemia caused by inhibition of renal tubular MR, but also to avoid untoward long term effects of inhibiting brain MR that are not involved in blood pressure control. PMID- 21664420 TI - Melanocortin 4 receptor is a transcriptional target of nescient helix-loop-helix 2. AB - Melanocortin 4 receptor (Mc4r/MC4R) is a G-Protein coupled receptor that is expressed in the hypothalamus and implicated in body weight control. Mutations in MC4R are the most frequent cause of monogenetic forms of human obesity. Despite its importance, the MC4R signaling pathways and transcriptional regulation underlying the melanocortin pathway are far from being fully understood. The transcription factor nescient helix-loop-helix 2 (Nhlh2) influences the melanocortin pathway through transcriptional regulation of prohormone convertase I, which influences the production of melanocortin peptides. In the present study, Nhlh2's role as a transcriptional regulator of Mc4r has been demonstrated. Nhlh2 knockout mice have reduced hypothalamic expression of Mc4r mRNA, suggesting that it could be a direct or indirect transcriptional regulator of the Mc4r promoter. To demonstrate direct transcriptional regulation, chromatin immunoprecipitation and electrophoretic gel shift assays show that Nhlh2 binds to the E-Boxes located at -551, -366 and +54 on the Mc4r promoter. Leptin-induced transactivation of the Mc4r promoter is significantly higher in the presence of exogenously added Nhlh2. siRNA knockdown of Nhlh2 leads to significantly reduced endogenous Mc4r mRNA expression levels in N29/2 cell line. Transactivation using promoters with mutations in each of the E-Boxes results in significantly reduced transactivation efficiency compared to the WT Mc4r promoter, suggesting that Nhlh2 regulates Mc4r transcription through these sites. Findings from these studies, combined with previous work implicating Nhlh2 as a transcriptional regulator of both the Mc4r gene and the melanocortin pathway, suggest that Nhlh2's transcriptional activity directly influences the human and rodent body weight control pathways. PMID- 21664421 TI - The role of clock genes and rhythmicity in the liver. AB - The liver is the important organ to maintain energy homeostasis of an organism. To achieve this, many biochemical reactions run in this organ in a rhythmic fashion. An elegant way to coordinate the temporal expression of genes for metabolic enzymes relies in the link to the circadian timing system. In this fashion not only a maximum of synchronization is achieved, but also anticipation of daily recurring events is possible. Here we will focus on the input and output pathways of the hepatic circadian oscillator and discuss the recently found flexibility of its circadian transcriptional networks. PMID- 21664422 TI - Intra-ovarian roles of activins and inhibins. AB - Granulosa cells are the main ovarian source of inhibins, activins and activin binding protein (follistatin) while germ (oogonia, oocytes) and somatic (theca, granulosa, luteal) cells express activin receptors, signaling components and inhibin co-receptor (betaglycan). Activins are implicated in various intra ovarian roles including germ cell survival and primordial follicle assembly; follicle growth from preantral to mid-antral stages; suppression of thecal androgen production; promotion of granulosa cell proliferation, FSHR and CYP19A1 expression; enhancement of oocyte developmental competence; retardation of follicle luteinization and/or atresia and involvement in luteolysis. Inhibins (primarily inhibin A) are produced in greatest amounts by preovulatory follicles (and corpus luteum in primates) and suppress FSH secretion through endocrine negative feedback. Together with follistatin, inhibins act locally to oppose auto /paracrine activin (and BMP) signaling thus modulating many of the above processes. The balance between activin-inhibin shifts during follicle development with activin signalling prevailing at earlier stages but declining as inhibin and betaglycan expression rise. PMID- 21664423 TI - Interleukin-6: a multifunctional targetable cytokine in human prostate cancer. AB - Several cytokines are involved in regulation of cellular events in prostate cancer. Interleukin-6 (IL-6) was frequently investigated in prostate cancer models because of its increased expression in cancer tissue at early stages of the disease. In patients with metastatic prostate cancer, it is well-known that IL-6 levels increase in serum. High levels of IL-6 were measured in the supernatants of cells which do not respond to androgenic stimulation. IL-6 expression in prostate cancer increases due to enhanced expression of transforming growth factor-beta, and members of the activating protein-1 complex, and loss of the retinoblastoma tumour suppressor. IL-6 activation of androgen receptor (AR) may contribute to progression of a subgroup of prostate cancers. Results obtained with two prostate cancer cell lines, LNCaP and MDA PCa 2b, indicate that IL-6 activation of AR may cause either stimulatory or inhibitory responses on proliferation. Interestingly, prolonged treatment with IL-6 led to establishment of an IL-6 autocrine loop, suppressed signal transducer and activator of transcription (STAT)3 activation, and increased mitogen-activated protein kinase phosphorylation. In several cell lines IL-6 acts as a survival molecule through activation of the signalling pathway of phosphotidylinositol 3 kinase. Expression of suppressors of cytokine signalling (SOCS) has been studied in prostate cancer. SOCS-3 prevents phosphorylation of STAT3 and is an important anti-apoptotic factor in AR-negative prostate cancer cells. Experimental therapy against IL-6 in prostate cancer is based on the use of the monoclonal antibody siltuximab which may be used for personalised therapy coming in the future. PMID- 21664424 TI - A truncated, activin-induced Smad3 isoform acts as a transcriptional repressor of FSHbeta expression in mouse pituitary. AB - The receptor-regulated protein Smad3 is key player in the signaling cascade stimulated by the binding of activin to its cell surface receptor. Upon phosphorylation, Smad3 forms a heterocomplex with Smad2 and Smad4, translocates to the nucleus and acts as a transcriptional co-activator. We have identified a unique isoform of Smad3 that is expressed in mature pituitary gonadotropes. 5' RACE revealed that this truncated Smad3 isoform is transcribed from an ATG site within exon 4 and consists of 7 exons encoding half of the linker region and the MH2 region. In pituitary cells, the truncated Smad3 isoform was phosphorylated upon activin treatment, in a manner that was temporally distinct from the phosphorylation of full-length Smad3. Activin-induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA mediated knockdown of Smad3. The truncated Smad3 isoform antagonized Smad3 mediated, activin-responsive promoter activity. We propose that the pituitary gonadotrope contains an ultra-short, activin-responsive feedback loop utilizing two different isoforms of Smad3, one which acts as an agonist (Smad3) and another that acts as an intracrine antagonist (truncated Smad3 isoform) to regulate FSHbeta production. PMID- 21664426 TI - The glucokinase activator GKA50 causes an increase in cell volume and activation of volume-regulated anion channels in rat pancreatic beta-cells. AB - Glucokinase plays a key role in the metabolism of glucose by pancreatic beta cells. In this study the effects of the glucokinase activator GKA50 on cell volume and electrical activity in rat beta-cells were examined. One micro molar GKA50 caused an increase in beta-cell volume in the presence of 4mM glucose. GKA50 also caused a depolarisation of beta-cell membrane potential and increased electrical activity. These changes were associated with the activation of inward whole-cell currents, and were attenuated by the anion channel inhibitor 5-nitro-2 (3-phenylpropylamino) benzoic acid. In single channel experiments, the open probability of volume-regulated anion channels (VRAC) was increased from 0.03+/ 0.01 to 0.19+/-0.04 (n=3) by the GKA50. The data suggest that a GKA50-evoked increase in glucose metabolism causes an increase in beta-cell volume. This in turn activates VRAC leading to a depolarisation of the cell membrane potential. PMID- 21664427 TI - Effects of the thyroid hormone derivatives 3-iodothyronamine and thyronamine on rat liver oxidative capacity. AB - Thyronamines T(0)AM and T(1)AM are naturally occurring decarboxylated thyroid hormone derivatives. Their in vivo administration induces effects opposite to those induced by thyroid hormone, including lowering of body temperature. Since the mitochondrial energy-transduction apparatus is known to be a potential target of thyroid hormone and its derivatives, we investigated the in vitro effects of T(0)AM and T(1)AM on the rates of O(2) consumption and H(2)O(2) release by rat liver mitochondria. Hypothyroid animals were used because of the low levels of endogenous thyronamines. We found that both compounds are able to reduce mitochondrial O(2) consumption and increase H(2)O(2) release. The observed changes could be explained by a partial block, operated by thyronamines, at a site located near the site of action of antimycin A. This hypothesis was confirmed by the observation that thyronamines reduced the activity of Complex III where the site of antimycin action is located. Because thyronamines exerted their effects at concentrations comparable to those found in hepatic tissue, it is conceivable that they can affect in vivo mitochondrial O(2) consumption and H(2)O(2) production acting as modulators of thyroid hormone action. PMID- 21664425 TI - Vitamin D metabolism and innate immunity. AB - Effects of vitamin D on the immune system have been recognized for over 30 years and stemmed in part from analysis of the dysregulated vitamin D metabolism associated with granulomatous diseases. However, it is only in more recent years that a role for interaction between vitamin D and normal immune function has been proposed. As with the original studies, the basis for this new perspective on immunomodulation by vitamin D stems from studies of vitamin D metabolism by immune cells. In particular, induction of the vitamin D-activating enzyme CYP27B1 in monocytes via pathogen recognizing receptors has highlighted an entirely new function for vitamin D as a potent inducer of antibacterial innate immune responses. This has prompted a new potential role for vitamin D in protecting against infection in a wide range of tissues but has also prompted revision of the parameters for adequate vitamin D status. The following review describes some of the key developments in innate immune responses to vitamin D with particular emphasis on the role of key metabolic enzyme as determinants of localized immune activity of vitamin D. PMID- 21664429 TI - Prolactin signaling mechanisms in ovary. AB - Prolactin is a hormone that is essential for normal reproduction and signals through two types of receptors. Not only is the classical long form of the prolactin receptor identified, but so are many short form receptors in rodents and human tissues. Mouse mutagenesis studies have offered insight into the biology of prolactin family, providing compelling evidence that the different isoforms have independent biological activity. The possibility that short forms mediate cell proliferation is important for a variety of tissues including mammary gland and ovarian follicles. This review summarizes our current knowledge about prolactin signaling and its role in reproduction through either long or short isoform receptors. PMID- 21664428 TI - Role of fibroblast growth factor (FGF) signaling in the neuroendocrine control of human reproduction. AB - Fibroblast growth factor (FGF) signaling is critical for a broad range of developmental processes. In 2003, Fibroblast growth factor receptor 1 (FGFR1) was discovered as a novel locus causing both forms of isolate GnRH Deficiency, Kallmann syndrome [KS with anosmia] and normosmic idiopathic hypogonadotropic hypogonadism [nIHH] eventually accounting for approximately 10% of gonadotropin releasing hormone (GnRH) deficiency cases. Such cases are characterized by a broad spectrum of reproductive phenotypes from severe congenital forms of GnRH deficiency to reversal of HH. Additionally, the variable expressivity of both reproductive and non-reproductive phenotypes among patients and family members harboring the identical FGFR1 mutations has pointed to a more complex, oligogenic model for GnRH deficiency. Further, reversal of HH in patients carrying FGFR1 mutations suggests potential gene-environment interactions in human GnRH deficiency disorders. PMID- 21664430 TI - Functional connectivity analysis of steady-state visual evoked potentials. AB - In this paper, functional connectivity of steady-state visual evoked potential (SSVEP) was investigated. Directed transfer function (DTF) was applied to cortical signals recorded from electroencephalography (EEG) in order to obtain connectivity patterns. Flow gain was proposed to assess the role of the specific brain region involved in the information transmission process. We found network connections exist in many regions beyond occipital region. Flow gain mapping both in 8-12Hz and 13-30Hz showed that parietal region seemed to serve as the sole hub of information transmission. Further studies of flow gain obtained from channel Pz showed two distinct peaks centered at about 12Hz low frequency and 20Hz medium frequency respectively. The low frequency region had a larger value of flow gain. The present study introduced functional connectivity into SSVEP. Furthermore, we put forward the concept of flow gain for the first time to explore the exchange and processing of brain information during SSVEP. PMID- 21664431 TI - A HA2-Fusion tag limits the endosomal release of its protein cargo despite causing endosomal lysis. AB - BACKGROUND: Protein transduction domains (PTDs) can be fused to a protein to render it cell-permeable. The delivery efficiencies of PTDs are, however, often poor because PTD-protein conjugates cannot escape from endosomes. A potential solution to this problem consists in adding HA2 analogs to the PTD-protein construct as these peptides can cause endosomal lysis upon acidification of the endosomal lumen. To date, however, the utility of HA2-based PTDs has not been clearly established. METHODS: We investigate the biophysical and cellular properties of the glutamate-rich HA2 analog E5 fused to the model protein TAT mCherry. RESULTS: E5-TAT-mCherry causes the release of fluorescent dextrans trapped with the protein inside endosomes. Yet, E5-TAT-mCherry itself is not released in the cytosol of cells, indicating that the protein remained trapped inside endosomes even after endosomal lysis takes place. Cytosolic delivery of the protein could be achieved, however, by insertion of a disulfide bond between E5 and its cargo. CONCLUSIONS: These results show that E5 causes the retention of its fused protein inside endosomes even after lysis takes place. GENERAL SIGNIFICANCE: These data establish that HA2 analogs might not be useful PTDs unless cleavable linkers are engineered between PTD and protein cargo. PMID- 21664432 TI - Upregulation of neuronal nitric oxide synthase in the periphery promotes pain hypersensitivity after peripheral nerve injury. AB - Peripheral nerve injury often results in neuropathic pain that is manifested as hyperalgesia, and allodynia. Several studies suggest a functional role for neuronal nitric oxide synthase (nNOS) in the development or maintenance of neuropathic pain, but such a contribution remains unclear. In our current study, we found that intraplantar injection of the NOS substrate L-arginine or NO donor 3-morpholino-synonimine (SIN-1) produced mechanical hypersensitivity that lasted more than 24 h. Following L5 spinal nerve ligation (L5 SNL), immunoreactivity for nNOS in the ipsilateral L5 but not L4 dorsal root ganglion (DRG) was dramatically increased in mainly small- and medium-sized neurons and non-neuronal cells. L5 SNL caused increased nNOS immunoreactivity in the ipsilateral sciatic nerve, mainly in Schwann cells and the ipsilateral glabrous hind paw skin, mainly on the basement membrane. Furthermore, total nNOS protein and mRNA in the ipsilateral sciatic nerve and hind paw skin were markedly upregulated following nerve injury. Intraplantar injection of the NOS inhibitor 7-nitroindazole (7-NI) or the non specific NOS inhibitor L-N(G)-nitro-arginine methyl ester (L-NAME) effectively suppressed SNL-induced mechanical allodynia. Collectively, these data suggest that in the periphery nNOS upregulation induced by peripheral nerve injury contributes to mechanical hypersensitivity during the maintenance phase of neuropathic pain. Blocking nNOS signaling in the periphery may thus be a novel therapeutic strategy for the treatment of neuropathic pain. PMID- 21664433 TI - GABAergic neural activity involved in salicylate-induced auditory cortex gain enhancement. AB - Although high doses of sodium salicylate impair cochlear function, it paradoxically enhances sound-evoked activity in the auditory cortex (AC) and augments acoustic startle reflex responses, neural and behavioral metrics associated with hyperexcitability and hyperacusis. To explore the neural mechanisms underlying salicylate (SS)-induced hyperexcitability and "increased central gain," we examined the effects of GABA receptor agonists and antagonists on SS-induced hyperexcitability in the AC and startle reflex responses. Consistent with our previous findings, local or systemic application of SS significantly increased the amplitude of sound-evoked AC neural activity, but generally reduced spontaneous activity in the AC. Systemic injection of SS also significantly increased the acoustic startle reflex. S-baclofen or R-baclofen, GABA-B agonists, which suppressed sound-evoked AC neural firing rate and local field potentials, also suppressed the SS-induced enhancement of the AC field potential and the acoustic startle reflex. Local application of vigabatrin, which enhances GABA concentration in the brain, suppressed the SS-induced enhancement of AC firing rate. Systemic injection of vigabatrin also reduced the SS-induced enhancement of acoustic startle reflex. Collectively, these results suggest that the sound-evoked behavioral and neural hyperactivity induced by SS may arise from a SS-induced suppression of GABAergic inhibition in the AC. PMID- 21664434 TI - Activation of peripheral delta-opioid receptors leads to anti-hyperalgesic responses in the masseter muscle of male and female rats. AB - In this project, we examined peripheral delta-opioid receptor (DOR)-mediated anti hyperalgesic responses in the context of an acute orofacial muscle pain condition in both male and female rats. We also investigated whether the ATP-sensitive K+ channel (KATP), a downstream target of OR signaling, contributes to DOR-mediated anti-hyperalgesic responses. Local pretreatment of the masseter with a DOR agonist, [D-Pen2, D-Pen6]-enkephalin (DPDPE), dose-dependently attenuated capsaicin-induced mechanical hypersensitivity in both male and female rats. However, there were sex differences in the potency of local DPDPE in that a 10 fold higher dose of DPDPE was required in female rats to produce the level of anti-hyperalgesia achieved in male rats. The sex differences in the DPDPE effect may not be fully explained by DOR expression level since there was no significant sex difference in DOR mRNA levels in trigeminal ganglia (TG). Finally, pretreatment of the masseter with the KATP antagonist, glibenclamide, significantly blocked the effects of DPDPE in male rats suggesting that the peripheral DOR effect is mediated by the KATP. These studies revealed novel information about sex differences with regards to peripherally localized DOR mediated anti-hyperalgesia under an orofacial muscle pain condition. PMID- 21664435 TI - Proliferation zones in the brain of adult fish Austrolebias (Cyprinodontiform: Rivulidae): a comparative study. AB - In contrast with mammals, adult fish brains exhibit an enormous potential to produce new cells. Proliferation zones, however, have been described in only a few species, hindering comparisons among genuses and orders. Here we analyzed brain cell proliferation in annual teleostean fishes Austrolebias (Cyprinodontiform: Rivulidae). Immunocytochemistry against 5-bromo-2' deoxyuridine (BrdU) was quantitated and mapped 24 h after injection in three species with different phylogenetic positions or habitats. All species had similar brain anatomy and total volume, but olfactory bulbs, torus longitudinalis and cerebellum were of different sizes in different species. Cell proliferation was found throughout the brain. Three-D reconstructions provided evidence for contiguity along the rostro-caudal axis and concentration in the vicinity of the ventricles. Brain regions analyzed exhibited high mitotic activity, and the torus longitudinalis had the highest volume-normalized proliferation index. A. affinis exhibited the highest normalized proliferation indexes in visual regions but the lowest in olfactory bulb. A. reicherti showed an inverse pattern, suggesting that these species have a different hierarchy of sensorial modalities that could be related to phylogeny or habitat. Double immunostaining against BrdU and cell-type specific markers was performed to determine the fate of proliferating cells. A widespread gliogenesis was evidenced. Few cells positive for both BrdU and the neuronal marker HuC/D were found in the brain of the three species, demonstrating neurogenesis in the adult Austrolebias brain. Summarizing, adult members of the three species showed similar brain anatomy and cell proliferation patterns. Among species, volume-normalized proliferation indexes varied in regions involved in different sensory modalities. To our knowledge, this is the first report showing proliferating cells with neuronal markers as earlier as 24 h after BrdU injection. PMID- 21664436 TI - Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats. AB - Cysteinyl leukotrienes (CysLTs), potent inflammatory mediators, are released from ischemic brain, and may regulate ischemic injury through activating CysLT1 and CysLT2 receptors. The CysLT1 receptor is closely associated with ischemic injury and post-ischemic repair; however, the CysLT2 receptor-mediated responses remain unknown. Here, we investigated the spatiotemporal profiles and implications of CysLT2 receptor expression and localization in rat brain after focal cerebral ischemia. CysLT2 receptors were normally localized in astrocytes in the cortex and around the ventricles. After focal cerebral ischemia, CysLT2 receptor expression was up-regulated in concert with neuronal and glial responses. In the acute phase (6-24 h), up-regulated CysLT2 receptors were restricted to injured neurons in the ischemic core; while in the late phase (3-28 days), the up regulation was restricted to hypertrophic microglia (ischemic core) and mainly localized in hypertrophic astrocytes (boundary zone). Thus, the spatiotemporal profiles of CysLT2 receptor expression suggest that it plays regulatory roles in acute neuron injury, and astrocytosis and microgliosis in the late phase. PMID- 21664437 TI - Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test. AB - There is considerable evidence suggesting genetic factors play an important role in the pathophysiology of depression, possibly by increasing susceptibility to repeated environmental stressors. Recent linkage studies have associated a polymorphism of the gene coding for the P2X7 receptor (P2X7R) with both major depressive disorder and bipolar disorder. Here we assessed whether P2X7 deletion affected the behavioural and neural response to repeated stress. P2X7R knockout (P2X7-/-) mice were subjected to the forced swim test for three consecutive days and neuronal activation in response to the third exposure was assessed using c Fos immunohistochemistry. In addition, anxiety was evaluated in another group of P2X7-/- mice using the elevated plus maze (EPM) and light dark emergence (LDE) tests. Equivalent levels of immobility were observed in P2X7-/- mice and wild type (WT) mice on the first exposure to forced swim, but much greater immobility was seen in WT mice on second and third exposures. This suggests that P2X7-/- mice exhibit an impaired adaptive coping response to repeated stress. Reinforcing this view, c-Fos expression in the dentate gyrus of the hippocampus and in the basolateral amygdala was seen in WT mice but not P2X7-/- mice following repeated forced swim. In addition, decreased locomotor activity was detected in P2X7-/- mice without any specific effects on anxiety in the LDE test. However, P2X7-/- mice showed greater anxiety-like behaviour in the EPM. These data suggest that the P2X7R may be involved in the adaptive mechanisms elicited by exposure to repeated environmental stressors that leads to the development of depression-like behaviours. This suggests that P2X7R antagonists may be useful therapeutics for the treatment of major depression, possibly by increasing resilience in the face of repeated stress. PMID- 21664438 TI - Fear conditioning is associated with dynamic directed functional interactions between and within the human amygdala, hippocampus, and frontal lobe. AB - The current model of fear conditioning suggests that it is mediated through modules involving the amygdala (AMY), hippocampus (HIP), and frontal lobe (FL). We now test the hypothesis that habituation and acquisition stages of a fear conditioning protocol are characterized by different event-related causal interactions (ERCs) within and between these modules. The protocol used the painful cutaneous laser as the unconditioned stimulus and ERC was estimated by analysis of local field potentials recorded through electrodes implanted for investigation of epilepsy. During the prestimulus interval of the habituation stage FL>AMY ERC interactions were common. For comparison, in the poststimulus interval of the habituation stage, only a subdivision of the FL (dorsolateral prefrontal cortex, dlPFC) still exerted the FL>AMY ERC interaction (dlFC>AMY). For a further comparison, during the poststimulus interval of the acquisition stage, the dlPFC>AMY interaction persisted and an AMY>FL interaction appeared. In addition to these ERC interactions between modules, the results also show ERC interactions within modules. During the poststimulus interval, HIP>HIP ERC interactions were more common during acquisition, and deep hippocampal contacts exerted causal interactions on superficial contacts, possibly explained by connectivity between the perihippocampal gyrus and the HIP. During the prestimulus interval of the habituation stage, AMY>AMY ERC interactions were commonly found, while interactions between the deep and superficial AMY (indirect pathway) were independent of intervals and stages. These results suggest that the network subserving fear includes distributed or widespread modules, some of which are themselves "local networks." ERC interactions between and within modules can be either static or change dynamically across intervals or stages of fear conditioning. PMID- 21664439 TI - TGF-beta signaling is required for maintenance of retinal ganglion cell differentiation and survival. AB - PURPOSE: To determine the role of TGF-beta1 in the maintenance of retinal ganglion cell line (RGC-5) differentiation and integrity. METHODS: RGC-5 cells were differentiated in media conditioned by human non-pigmented ciliary epithelial cells (HNPE) for 4 days before treatment with TGF-beta1 for 24 h. Cells were examined for morphological changes and harvested for western blot and real-time PCR analysis. For study of apoptosis, differentiated RGC-5 cells were grown in serum-free medium for 24 h in the presence or absence of TGF-beta1 and collected for Annexin V/Propidium iodide FACs analysis. The role of MAPK pathways in TGF-beta1-dependent signaling was determined by treatment with specific inhibitors of ERK, JNK and p38. RESULTS: Differentiation of RGC-5 cells in HNPE conditioned media (CM) increased the neural cell markers, Brn-3c, NF-160, Thy1.2, Tau and PGP9.5. Treatment with TGF-beta1 significantly increased the length of neurites extended by differentiated RGC-5s, concomitant with increased expression of NF-160 and PGP9.5, but not Brn-3c, Thy1.2 or Tau. TGF-beta1 also decreased RGC 5 cell apoptosis in serum-free medium. p38 phosphorylation, but not smad2/3, JNK or ERK phosphorylation, was increased in TGF-beta1 treated cells. Specific inhibition of p38 signaling reversed TGF-beta1 induced neurite growth. CONCLUSIONS: These findings demonstrate the induction of RGC-5 cell differentiation by HNPE-derived CM and illustrate a role for TGF-beta1 in maintaining RGC-5 cell survival and promoting neurite outgrowth through p38 MAPK. PMID- 21664441 TI - Microinjection of histamine into the cerebellar vermis impairs emotional memory consolidation in mice. AB - The biogenic amine histamine is an important neurotransmitter in the central nervous system that has been implicated in learning and memory processes. Experimental evidence indicates that the role of the cerebellum may be more complex than the simple regulation of motor responses, and recent studies have demonstrated significant involvement of the cerebellum in emotional memory consolidation. This study investigated the effect of histamine microinjected into the cerebellar vermis on emotional memory consolidation in mice in the elevated plus-maze (EPM). The cerebellar vermis of male mice (Swiss Albino) were implanted with guide cannulae. The mice weighed between 25 and 30 g. After three days of recovery, behavioral tests in the EPM were performed on two consecutive days; the testing periods were called, Trial 1 and Trial 2. Immediately after Trial 1, the animals received microinjections of histamine in the cerebellar vermis (0.54, 1.36, 2.72, and 4.07 nmol/0.1 MUl). On both days, the test sessions were recorded to enable analysis of behavioral measures. The decrease in open arm exploration (% entries and % time spent in the open arms) in Trial 2 relative to Trial 1 was used as a measure of learning and memory. The data were analyzed using One-way Analysis of Variance (ANOVA) and Duncan's tests. The percentage of open arm entries (%OAE) and the percentage of time spent in the open arms (%OAT) were reduced in Trial 2 relative to Trial 1 for the control group; the same was true for the group that was microinjected with histamine at doses of 0.54 (%OAE and %OAT) and 1.36 nmol (%OAT). However, when the animals received histamine at doses of 2.72 and 4.07 nmol, their open arm exploration did not decrease. No significant changes were observed in the number of enclosed arm entries (EAE), an EPM index of general exploratory activity. These results suggest that there is a dose-dependent inhibitory effect of histamine microinjected into the cerebellar vermis on emotional memory consolidation. PMID- 21664440 TI - Autoradiographic analysis of GABAA receptor binding in the neural anxiety network of postpartum and non-postpartum laboratory rats. AB - Postpartum female rats exhibit a suppression of anxiety-related behaviors when compared to diestrous virgin females, pregnant females, and males. This blunted anxiety promotes optimal maternal care and involves elevated GABA neurotransmission, possibly including greater density of GABA(A) and benzodiazepine receptors in the postpartum brain. We here examined autoradiographic binding of [(3)H]muscimol to measure the total population of GABA(A) receptors and [(3)H]flunitrazepam to assess density of benzodiazepine sites in the medial prefrontal cortex, bed nucleus of the stria terminalis, amygdala, hippocampus, and periaqueductal gray of female rats sacrificed on day 7 postpartum, day 10 of pregnancy, or as diestrous virgins. A group of sexually naive male rats was also included. We found that [(3)H]muscimol binding did not differ among groups in any site but that diestrous virgin females had greater [(3)H]flunitrazepam binding in the CA1 and dentate gyrus of the hippocampus compared to mid-pregnant females and males. Notably, postpartum and diestrous virgin females did not significantly differ in binding of either ligand in any site examined. This is the first study to evaluate the densities of GABA(A) and benzodiazepine binding sites simultaneously across three female reproductive states and sex with a focus on brain sites influencing anxiety-related behaviors. The results suggest that changes in other GABA(A) receptor characteristics such as subunit composition, or increased presynaptic GABA release during interactions with offspring, must instead play a greater role in the postpartum suppression of anxiety in laboratory rats. PMID- 21664442 TI - Conditioning of sexual proceptivity in female quail: measures of conditioned place preference. AB - The present experiments were conducted to explore the nature of conditioned sexual proceptivity in female quail. Females exposed to males subsequently approached the area where the males were previously housed (Experiment 1). This increased preference for the male's area reflected an increase in female sexual proceptivity and not an increase in non-directed locomotor activity (Experiment 2). These findings provide the first evidence that female quail show conditioned responses that may be considered to be proceptive responses toward male conspecifics. The proceptive responses are expressed as tonic changes in preference for areas where males have been observed in the past rather than as specific phasic conditioned responses. PMID- 21664443 TI - Assessment of biological half life using in silico QSPkR approach: a self organizing molecular field analysis (SOMFA) on a series of antimicrobial quinolone drugs. AB - The quinolones belong to a family of synthetic potent broad-spectrum antibiotics and particularly active against gram-negative organisms, especially Pseudomonas aeruginosa. A 3D-QSPkR approach has been used to obtain the quantitative structure pharmacokinetic relationship for a series of quinolone drugs using SOMFA. The series consisting of 28 molecules have been investigated for their pharmacokinetic performance using biological half life (t(1/2)). A statistically validated robust model for a diverse group of quinolone drugs having flexibility in structure and pharmacokinetic profile (t(1/2)) obtained using SOMFA having good cross-validated correlation coefficient r(cv)(2) (0.6847), non cross validated correlation coefficient r(2) values (0.7310) and high F-test value (33.9663). Analysis of 3D-QSPkR models through electrostatic and shape grids provide useful information about the shape and electrostatic potential contributions on t(1/2). The analysis of SOMFA results provide an insight for the generation of novel molecular architecture of quinolones with optimal half life and improved biological profile. PMID- 21664444 TI - Determination of parameters for successful spray coating of silicon microneedle arrays. AB - Coated microneedle patches have demonstrated potential for effective, minimally invasive, drug and vaccine delivery. To facilitate cost-effective, industrial scale production of coated microneedle patches, a continuous coating method which utilises conventional pharmaceutical processes is an attractive prospect. Here, the potential of spray-coating silicon microneedle patches using a conventional film-coating process was evaluated and the key process parameters which impact on coating coalescence and weight were identified by employing a fractional factorial design to coat flat silicon patches. Processing parameters analysed included concentration of coating material, liquid input rate, duration of spraying, atomisation air pressure, gun-to-surface distance and air cap setting. Two film-coating materials were investigated; hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC). HPMC readily formed a film-coat on silicon when suitable spray coating parameter settings were determined. CMC films required the inclusion of a surfactant (1%, w/w Tween 80) to facilitate coalescence of the sprayed droplets on the silicon surface. Spray coating parameters identified by experimental design, successfully coated 280MUm silicon microneedle arrays, producing an intact film-coat, which follows the contours of the microneedle array without occlusion of the microneedle shape. This study demonstrates a novel method of coating microneedle arrays with biocompatible polymers using a conventional film-coating process. It is the first study to indicate the thickness and roughness of coatings applied to microneedle arrays. The study also highlights the importance of identifying suitable processing parameters when film coating substrates of micron dimensions. The ability of a fractional factorial design to identify these critical parameters is also demonstrated. The polymer coatings applied in this study can potentially be drug loaded for intradermal drug and vaccine delivery. PMID- 21664445 TI - Effects of mitochondrial mutations on hearing and cochlear pathology with age. AB - Age-related hearing loss is a multi-factorial process involving genetic and environmental factors, including exposure to noise and ototoxic agents, as well as pathological processes. Among these is the accumulation of mitochondrial DNA mutations and deletions. The creation of a transgenic mouse with a loss-of function deletion of the nuclear gene that encodes the polymerase required to repair damaged mitochondrial DNA (PolgA) enabled evaluation of age-related cochlear pathology associated with random mitochondrial DNA deletions that accrue over the lifespan of the mouse. In comparison with their wild-type or heterozygous counterparts, animals with mutated DNA polymerase gamma developed hearing loss most rapidly. Any loss of mitochondrial DNA polymerase function however, resulted in detrimental effects, as evidenced by hearing tests and histological investigation of transgenic heterozygotes. Cochlear pathology in transgenic animals at 10 months of age included loss of neurons and clumping of surviving neurons in the apical turn of the spiral ganglion. Mitochondrial mutations in young animals, on the other hand, were protective against the development of temporary threshold shift in response to relatively low level noise exposure. This supports the idea that temporary threshold shifts are the result of an active process involving mitochondria and respiratory chain activity. Our results indicate that mitochondrial mutation and deletion can certainly contribute to the development of an aging phenotype, specifically age related hearing loss. PMID- 21664446 TI - The adequate stimulus for mammalian linear vestibular evoked potentials (VsEPs). AB - Short latency linear vestibular sensory evoked potentials (VsEPs) provide a means to objectively and directly assess the function of gravity receptors in mammals and birds. The importance of this functional measure is illustrated by its use in studies of the genetic basis of vestibular function and disease. Head motion is the stimulus for the VsEP. In the bird, it has been established that neurons mediating the linear VsEP respond collectively to the rate of change in linear acceleration during head movement (i.e. jerk) rather than peak acceleration. The kinematic element of motion responsible for triggering mammalian VsEPs has not been characterized in detail. Here we tested the hypothesis that jerk is the kinematic component of head motion responsible for VsEP characteristics. VsEP amplitudes and latencies changed systematically when peak acceleration level was held constant and jerk level was varied from ~0.9-4.6 g/ms. In contrast, responses remained relatively constant when kinematic jerk was held constant and peak acceleration was varied from ~0.9 to 5.5 g in mice and ~0.44 to 2.75 g in rats. Thus the mammalian VsEP depends on jerk levels and not peak acceleration. We conclude that kinematic jerk is the adequate stimulus for the mammalian VsEP. This sheds light on the behavior of neurons generating the response. The results also provide the basis for standardizing the reporting of stimulus levels, which is key to ensuring that response characteristics reported in the literature by many laboratories can be effectively compared and interpreted. PMID- 21664447 TI - A comparison of proliferative capacity and passaging potential between neural stem and progenitor cells in adherent and neurosphere cultures. AB - Neural stem and progenitor cells (NSPCs) can be isolated from the fetal or adult brain and expanded in culture for potential use in basic research, drug discovery and cell therapy. In the present study, two culture systems have been commonly used to maintain and expand NSPCs isolated from mammalian CNS: neurosphere and adhesive substrate-bound monolayer culture. NSPCs were isolated from the neuroepithelium of E14 embryonic rat cerebral cortex and maintained and expanded on fibronectin substrates or within neurospheres in serum-free medium. Ultrastructural study under transmission electron microscope revealed similar characteristics of immature morphology of NSPCs in adherent and neurosphere cultures. NSPCs cultured on adherent substrates and within neurospheres shared the properties of self-renewal and multipotency, but little is known about proliferation capacity and passaging potential of adherent NSPCs compared to neurosphere culture. We found that the self-renewal capacity of NSPCs in adherent culture was higher than that in neurosphere culture in the P1 and P3 passages, and reduced after the P5 passage. At the same time, comparative analysis using BrdU incorporation and immunostaining for nestin indicated that NSPCs grew significantly faster in primary cultures on adherent substrates than within neurospheres. Whereas, NSPCs in adherent culture could not maintain such robust growth for more than 6 passages. The growth of NSPCs within neurospheres was slower than that in adherent culture, but increased steadily and could be maintained for more than 10 passages. These data provide useful information for large scale in vitro expansion of NSPCs required by potential drug screening and cell therapy. PMID- 21664448 TI - Alcohol-induced neuronal death in central extended amygdala and pyriform cortex during the postnatal period of the rat. AB - Mothers who consume alcohol during pregnancy may cause a neurotoxic syndrome defined as fetal alcohol spectrum disorder (FASD) in their offspring. This disorder is characterized by reduction in brain size, cognitive deficits and emotional/social disturbances. These alterations are thought to be caused by an alcohol-induced increase in apoptosis during neurodevelopment. Little is known about neuroapoptosis in the central extended amygdala and the pyriform cortex, which are key structures in emotional/social behaviors. The goal of this study was to determine the vulnerability of neuroapoptotic alcohol effects in those areas. Rats were administered alcohol (2.5g/kg s.c. at 0 and 2h) or saline on postnatal day (PND) 7, 15 and 20. The Amino-cupric-silver technique was used to evaluate neurodegeneration and immunohistochemistry to detect activated caspases 3-8 and 9 at 2h, 4, 6, 8, 12 and 24h after drug administration. We measured blood alcohol levels each hour, from 2 to 8h post second administration of alcohol in each of the ages studied. Results showed alcohol induced apoptotic neurodegeneration in the central extended amygdala on PND 7 and 15, and pyriform cortex on PND 7, 15 and 20. These structures showed activation of caspase 3 and 9 but not of caspase 8 suggesting that alcohol-induced apoptosis could occur by the intrinsic pathway. The pharmacokinetic differences between ages did not associate with the neurodegeneration age dependence. In conclusion, these limbic areas are damaged by alcohol, and each one has their own window of vulnerability during the postnatal period. The possible implications in emotional/social features in FASD are discussed. PMID- 21664449 TI - The Mycoplasma gallisepticum alpha-enolase is cell surface-exposed and mediates adherence by binding to chicken plasminogen. AB - The alpha-enolase protein is reported to be an adhesin in several pathogenic bacterial species, but its role in Mycoplasma gallisepticum is unknown. In this study, the M. gallisepticum alpha-enolase gene was adapted to heterologous expression in Escherichia coli by performing overlapping polymerase chain reaction with site-directed mutagenesis to introduce A960G and A1158G mutations in the nucleotide sequence. The full-length mutated gene was cloned into a pGEM-T Easy vector and subcloned into the expression vector pET32a(+) to construct the pET-rMGEno plasmid. The expression of rMGEno in E. coli strain DE3 was confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis with Coomassie blue staining. Purified rMGEno exhibited alpha-enolase catalytic activity that it could reflect the conversion of NADH to NAD(+). Mouse antiserum to alpha-enolase was generated by immunization with rMGEno. Immunoblotting and immunofluorescence assay with the antiserum identified alpha-enolase on the surface of M. gallisepticum cells. Enzyme-linked immunosorbent assay characterized rMGEno as a chicken plasminogen binding protein. An adherence inhibition assay on immortalized chicken fibroblasts (DF-1) demonstrated more than 77% inhibition of adhesion in the presence of mouse antiserum, suggesting that alpha-enolase of M. gallisepticum participates in bacterial adhesion to DF-1 cells. PMID- 21664451 TI - Anti-inflammatory signaling in schizophrenia. AB - A great deal of interest has been centered upon activated inflammatory processes in schizophrenia and their contribution to disease-relevant brain and behavioral impairment. In contrast, the role of anti-inflammatory signaling has attracted somewhat less attention in this context. The present article focuses on the emerging role of anti-inflammatory signaling in schizophrenia and discusses the potential influence of altered anti-inflammatory activity on progressive inflammatory processes, physical and metabolic functions, and treatment effects related to the use of conventional antipsychotic drugs and immunomodulatory agents in the pharmacotherapy of schizophrenia. By reviewing existing evidence, it appears that enhanced anti-inflammatory activity has many faces in schizophrenia: On the one hand, it may effectively limit potentially harmful inflammatory processes and may contribute to the improvement of psychopathological symptoms, especially when the anti-inflammatory system is boosted at early stages of the disease. On the other hand, enhanced anti inflammatory activity may render affected individuals more susceptible to distinct physiological abnormalities such as cardiovascular disease, and may further impede the resistance to specific infectious agents. Therefore, an enhancement of anti-inflammatory signaling in schizophrenia might not simply be said to be either advantageous or disadvantageous, but rather should be interpreted and dealt with in a context-dependent manner. Increased awareness of the multiple roles of anti-inflammatory signaling may readily help to reduce additional health burdens in schizophrenia, and at the same time, may provide opportunities to further explore the benefits associated with anti-inflammatory strategies in the symptomatological and/or preventive treatment of this disorder. PMID- 21664450 TI - Analysis for the potential of polystyrene and TiO2 nanoparticles to induce skin irritation, phototoxicity, and sensitization. AB - The human skin equivalent model (HSEM) is well known as an attractive alternative model for evaluation of dermal toxicity. However, only limited data are available on the usefulness of a HSEM for nanotoxicity testing. This study was designed to investigate cutaneous toxicity of polystyrene and TiO2 nanoparticles using cultured keratinocytes, a HSEM, and an animal model. In addition, we also evaluated the skin sensitization potential of nanoparticles using a local lymph node assay with incorporation of BrdU. Findings from the present study indicate that polystyrene and TiO2 nanoparticles do not induce phototoxicity, acute cutaneous irritation, or skin sensitization. Results from evaluation of the HSEMs correspond well with those from animal models. Our findings suggest that the HSEM might be a useful alternative model for evaluation of dermal nanotoxicity. PMID- 21664452 TI - Immunology meets neuroscience--opportunities for immune intervention in neurodegenerative diseases. AB - Neuroinflammatory changes are characteristic of many, if not all, neurodegenerative diseases but the extent to which the immune system is involved in the pathogenesis of these diseases is unclear. The findings of several studies during the past decade has established that there is a well-developed communication between the central nervous system (CNS) and the peripheral immune system, but also has revealed that the immune system in the CNS is much more sophisticated that previously acknowledged. In this mini-review, we discuss two major neurodegenerative disorders, Alzheimer's disease (AD) and multiple sclerosis (MS), and consider whether the therapies most likely to succeed are those that are identified by studying the marriage of neuroscience and immunology. PMID- 21664453 TI - Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology. AB - Toxicogenomic evaluations may improve toxicity prediction of in vitro-based developmental models, such as whole embryo culture (WEC) and embryonic stem cells (ESC), by providing a robust mechanistic marker which can be linked with responses associated with developmental toxicity in vivo. While promising in theory, toxicogenomic comparisons between in vivo and in vitro models are complex due to inherent differences in model characteristics and experimental design. Determining factors which influence these global comparisons are critical in the identification of reliable mechanistic-based markers of developmental toxicity. In this study, we compared available toxicogenomic data assessing the impact of the known teratogen, methylmercury (MeHg) across a diverse set of in vitro and in vivo models to investigate the impact of experimental variables (i.e. model, dose, time) on our comparative assessments. We evaluated common and unique aspects at both the functional (Gene Ontology) and gene level of MeHg-induced response. At the functional level, we observed stronger similarity in MeHg response between mouse embryos exposed in utero (2 studies), ESC, and WEC as compared to liver, brain and mouse embryonic fibroblast MeHg studies. These findings were strongly correlated to the presence of a MeHg-induced developmentally related gene signature. In addition, we identified specific MeHg induced gene expression alterations associated with developmental signaling and heart development across WEC, ESC and in vivo systems. However, the significance of overlap between studies was highly dependent on traditional experimental variables (i.e. dose, time). In summary, we identify promising examples of unique gene expression responses which show in vitro-in vivo similarities supporting the relevance of in vitro developmental models for predicting in vivo developmental toxicity. PMID- 21664454 TI - The HPV16 transcriptome in cervical lesions of different grades. AB - Infections with high-risk human papillomaviruses (HPV), mainly HPV type 16, can cause malignant transformation of the human cervical epithelium and cervical cancer (CxCa). Very little is known about the quantitative expression of HPV16 transcripts in cervical lesions of different grades. We have analysed the viral transcriptome in 80 HPV16 DNA positive cervical smears including lesions of different cytological grades, using nucleic acid sequence-based amplification (NASBA)-Luminex hybridisation assays quantifying spliced and unspliced HPV16 transcripts. Based on the quantitative analysis of single transcripts, highly significant changes in transcript levels were observed between different grades of cervical lesions. In conclusion, quantitative expression changes of HPV16 transcript markers may be involved in tumour progression. This study provides a basis for selection of candidate RNA markers for diagnostics of HPV16-related disease. PMID- 21664455 TI - Serotonin innervation of basal ganglia in monkeys and humans. AB - This review paper summarizes our previous contributions to the study of serotonin (5-hydroxytryptamine; 5-HT) innervation of basal ganglia in human and nonhuman primates under normal conditions. We have visualized the 5-HT neuronal system in squirrel monkey (Saimiri sciureus) and human postmortem materials with antibodies directed against either 5-HT, 5-HT transporter (SERT) or 5-HT synthesizing enzyme tryptophan hydroxylase (TPH). Confocal microscopy was used to compare the distribution of 5-HT and dopamine (DA; tyrosine hydroxylase-immunolabeled) axons in human, while the ultrastructural features of 5-HT axon terminals in monkey subthalamic nucleus were characterized at electron microscopic level. In monkeys and humans, midbrain raphe neurons emit axons that traverse the brainstem via the transtegmental system, ascend within the medial forebrain bundle and reach their targets by coursing along the major output pathways of the basal ganglia. These 5 HT axons arborize in virtually all basal ganglia components with the substantia nigra receiving the densest innervation and the striatum the most heterogeneous one. Although the striatum - the major basal ganglia input structure - appears to be a common termination site for many of 5-HT ascending axons, our results reveal that the widely distributed 5-HT neuronal system can also act directly upon neurons located within the two major output structures of the basal ganglia, namely the internal pallidum and the substantia nigra pars reticulata in monkeys and humans. This system also has a direct access to neurons of the DA nigrostriatal pathway, a finding that underlines the importance of the 5-HT/DA interactions in the physiopathology of basal ganglia. PMID- 21664456 TI - Nox2-derived ROS in PPARgamma signaling and cell-cycle progression of lung alveolar epithelial cells. AB - Reactive oxygen species (ROS) play important roles in peroxisome proliferator activated receptor gamma (PPARgamma) signaling and cell-cycle regulation. However, the PPARgamma redox-signaling pathways in lung alveolar epithelial cells remain unclear. In this study, we investigated the in vivo and in vitro effects of PPARgamma activation on the levels of lung ROS production and cell-cycle progression using C57BL/6J wild-type and Nox2 knockout mice (n=10) after intraperitoneal injection of a selective PPARgamma agonist (GW1929, 5 mg/kg body wt, daily) for 14 days. Compared to vehicle-treated mice, GW1929 increased significantly the levels of ROS production in wild-type lungs, and this was accompanied by significant up-regulation of PPARgamma, Nox2, PCNA, and cyclin D1 and phosphorylation of ERK1/2 and p38MAPK. These effects were absent in Nox2 knockout mice. In cultured alveolar epithelial cells, GW1929 (5 MUM for 24 h) increased ROS production and promoted cell-cycle progression from G0/G1 into S and G2/M phases, and these effects were abolished by (1) adding a PPARgamma antagonist (BADGE, 1 MUM), (2) knockdown of PPARgamma using siRNA, or (3) knockout of Nox2. In conclusion, PPARgamma activation through Nox2-derived ROS promotes cell-cycle progression in normal mouse lungs and in cultured normal alveolar epithelial cells. PMID- 21664457 TI - Inhibition of surgical trauma-enhanced peritoneal dissemination of tumor cells by human catalase derivatives in mice. AB - Surgical trauma, which is inevitably associated with the surgical removal of cancer, has been reported to accelerate tumor metastasis. The close association of reactive oxygen species with the trauma and tumor metastasis supports the possibility of using antioxidants for the inhibition of metastasis. To inhibit surgical trauma-enhanced peritoneal dissemination, human catalase (hCAT) derivatives, i.e., hCAT-nona-arginine peptide (hCAT-R9) and hCAT-albumin-binding peptide (hCAT-ABP), were designed to increase the retention time of the antioxidant enzyme in the abdominal cavity after intraperitoneal administration. Both (125)I-labeled derivatives showed significantly prolonged retention in the cavity compared to (125)I-hCAT. Cauterization of the cecum of mice with a hot iron, an experimental model of surgical trauma, induced abdominal adhesions. In addition, cauterization followed by colon26 tumor cell inoculation increased lipid peroxidation in the cecum and mRNA expression of molecules associated with tissue repair/adhesion and inflammation in the peritoneum. hCAT derivatives significantly suppressed the increased mRNA expression. The cauterization also increased the number of tumor cells in the abdominal organs, and the number was significantly reduced by hCAT-R9 or hCAT-ABP. These results indicate that hCAT-R9 and hCAT-ABP, both of which have a long retention time in the peritoneal cavity, can be effective at inhibiting surgery-induced peritoneal metastasis. PMID- 21664458 TI - SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells. AB - Free fatty acid (FFA)-mediated renal lipotoxicity is associated with the progression of tubulointerstitial inflammation in proteinuric kidney disease. SIRT3 is an antiaging molecule regulated by calorie restriction and mitochondria localized NAD(+)-dependent deacetylase. In this study, we investigated whether SIRT3 reversed renal lipotoxicity-mediated ROS and inflammation. In the kidney of the FFA-bound BSA-overloaded mouse, which is a well-established experimental model of FFA-associated tubulointerstitial inflammation, mRNA expression of SIRT3 was significantly decreased and negatively correlated with mRNA expression of an inflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1). In cultured proximal tubular (mProx) cells, the saturated FFA palmitate stimulated ROS accumulation and expression of MCP-1. These effects were ameliorated by retrovirus-mediated overexpression of SIRT3, whereas they were exacerbated by either overexpression of a dominant-negative form of SIRT3(N87A) lacking deacetylase activity or knockdown of SIRT3 by siRNA transfection. Furthermore, we showed that SIRT3 positively regulated both mitochondrial oxidative capacity and antioxidant gene expression, thereby reducing ROS accumulation in mProx cells, which suggests a mechanism that underlies SIRT3-mediated reversal of palmitate induced inflammation. In conclusion, these results highlight a new role for SIRT3 in lipotoxicity/ROS-related inflammation, reveal a new molecular mechanism underlying calorie restriction-mediated antioxidant and anti-inflammatory effects, and could aid in the design of new therapies for the prevention of tubulointerstitial lesions in proteinuric kidney disease. PMID- 21664459 TI - A novel nitroxide is an effective brain redox imaging contrast agent and in vivo radioprotector. AB - Individuals are exposed to ionizing radiation during medical procedures and nuclear disasters, and this exposure can be carcinogenic, toxic, and sometimes fatal. Drugs that protect individuals from the adverse effects of radiation may therefore be valuable countermeasures against the health risks of exposure. In the current study, the LD(50/30) (the dose resulting in 50% of exposed mice surviving 30 days after exposure) was determined in control C3H mice and mice treated with the nitroxide radioprotectors Tempol, 3-CP, 16c, 22c, and 23c. The pharmacokinetics of 22c and 23c were measured with magnetic resonance imaging (MRI) in the brain, blood, submandibular salivary gland, liver, muscle, tongue, and myocardium. It was found that 23c was the most effective radioprotector of the five studied: 23c increased the LD(50/30) in mice from 7.9+/-0.15Gy (treated with saline) to 11.47+/-0.13Gy (an increase of 45%). Additionally, MRI-based pharmacokinetic studies revealed that 23c is an effective redox imaging agent in the mouse brain, and that 23c may allow functional imaging of the myocardium. The data in this report suggest that 23c is currently the most potent known nitroxide radioprotector, and that it may also be useful as a contrast agent for functional imaging. PMID- 21664460 TI - Prenatal exposure to multiple toxic heavy metals and neonatal neurobehavioral development in Shanghai, China. AB - BACKGROUND: Epidemiological studies examining the effects of prenatal toxic heavy metals exposure on neonatal development at the population-based level are limited. OBJECTIVE: To explore prenatal exposure levels to toxic heavy metals and examine whether exposure is associated with neonatal development. METHODS: A stratified multi-stage cluster sampling methodology was used to investigate 1652 mother-infant pairs from 2008 through 2009 in Shanghai. Cord blood concentrations of Pb, Hg, Cd, As, Tl and NBNA (Neonatal Behavioral Neurological Assessments) were tested. We defined three different exposure levels (low, medium and high) according to the considered safe values. RESULTS: The median blood Pb, Hg, Cd, As and Tl concentrations were 41 MUg/L, 1.88 MUg/L, 0.03 MUg/L, 0.86 MUg/L and 0.02 MUg/L, respectively, which all were in the level considered safe. Increasing exposure to Cd, Hg, As and Tl during pregnancy was associated with decreasing NBNA scores. High level-exposure (exceeding the level considered safe) of Hg, Cd and Tl had lower NBNA scores compared to medium and low levels (both in the level considered safe), which implied that the level considered safe of these heavy metals was safe for the newborns' development. The mean decreasing scores of NBNA was 0.61, 1.50 and 0.84 (total score = 40) with high-level exposure of Hg, Cd and Tl, respectively. The medium-level exposure (in the level considered safe) to As had lower NBNA scores compared to low-level exposure, which implied that level of considered safe for As was not safe to the newborns' development. However, prenatal Pb high-exposure did not affect NBNA scores either by single or multiple factor analysis. In addition, important contribution factors for heavy metals pollutants were diet, lifestyle and housing renovation. CONCLUSIONS: Prenatal heavy metals except Pb exposures were associated with NBNA. The adverse effect of medium-level As warrants the need to further investigate the safe range of As. PMID- 21664461 TI - Reactive oxygen species regulate M-CSF-induced monocyte/macrophage proliferation through SHP1 oxidation. AB - Macrophage colony-stimulating factor (M-CSF) stimulation results in the production of reactive oxygen species (ROS) that participate in the proliferation of monocyte/macrophage. However, the molecular mechanisms whereby ROS modulate the signaling processes of M-CSF remain poorly defined. We report here that the redox-sensitive Src homology region 2 domain-containing phosphatase 1 (SHP1) is a critical regulator of M-CSF-mediated signaling in bone marrow monocyte/macrophage lineage cells (BMMs). Application of diphenylene iodonium (DPI) inhibited the responses of BMMs to M-CSF, including ROS production, cell proliferation, and phosphorylation of c-Fms as well as Akt kinase, but not of MAP kinases such as ERK, p38, and JNK. Dysregulation of SHP1 by overexpression or RNA interference in BMMs showed that SHP1 specifically regulates PI3 kinase (PI3K)/Akt signaling, but not MAP kinases in a redox-dependent manner, thereby regulating proliferation of BMMs through cyclins D1 and D2. These findings demonstrate that M-CSF-mediated ROS generation leads to SHP1 oxidation, which promotes cell proliferation through the PI3K/Akt-dependent signaling pathway. PMID- 21664462 TI - Encapsulation of Cwp84 into pectin beads for oral vaccination against Clostridium difficile. AB - We have designed an oral vaccine against Clostridium difficile infection. The virulent factor Cwp84, that is a cystein protease highly immunogenic in patients with C. difficile-associated disease, was entrapped within pectin beads. Beads encapsulating Cwp84 were shown to be stable in the simulated intestinal medium and to release the cystein protease once in the simulated colonic medium. Three groups of hamsters were immunized, the first receiving pectin beads encapsulating Cwp84, the second unloaded beads and the third one free Cwp84. After three immunizations by the intragastric route, all groups received clindamycine. Post challenge survival with a strain of C. difficile showed that 2 days after infection, all hamsters treated with unloaded beads and all hamsters treated with free Cwp84 have deceased after 7 days, whereas about 40% of hamsters administered with Cwp84-loaded beads survived 10 days after challenge, proving that oral vaccination provides partial protection. These first data obtained with an oral vaccine against C. difficile appear promising for preventing this infection. PMID- 21664463 TI - In vitro penetration properties of solid lipid nanoparticles in intact and barrier-impaired skin. AB - Treatment of skin diseases implies application of a drug to skin with an impaired epidermal barrier, which is likely to affect the penetration profile of the drug substance as well as the carrier into the skin. To elucidate this, the effect of skin barrier damage on the penetration profile of a corticosteroid applied in solid lipid nanoparticles (SLN) composed of different lipids, varying in polarity, was studied. The studies were carried out in vitro using impaired and intact porcine ear skin, and the SLN were compared with a conventional ointment. It was shown that a significantly higher amount of corticosteroid remained in the skin, intact as well as barrier impaired, when SLN was used as a vehicle. In general, the penetration profile of the drug substance into the skin was affected by the type of lipid used in the formulation and related to lipid polarity and drug substance solubility. When formulated in SLN and applied to intact skin, the permeation of the drug substance across the skin was significantly reduced, as compared to the ointment. Altogether, in both barrier-impaired and intact skin, a higher amount of drug substance remained in the skin during application of SLN for 6, 16, and 24h, as compared to the ointment. These results emphasize the applicability of SLN to create a drug reservoir in skin, with the drug localized distinctively in the stratum corneum. PMID- 21664464 TI - An anti-juvenile hormone agent, ethyl 4-(2-benzylhexyloxy)benzoate, inhibits juvenile hormone synthesis through the suppression of the transcription of juvenile hormone biosynthetic enzymes in the corpora allata in Bombyx mori. AB - Ethyl 4-[(S)-2-benzylhexyloxy)]benzoate (KF-13S), derived from ethyl 4-[2-(tert butylcarbonyloxy)butoxy]benzoate (ETB), has strong anti-juvenile hormone (JH) activity which causes precocious metamorphosis in Bombyx mori, and the mode of action of this compound was studied. Application of KF-13S inhibited JH biosynthesis by the corpora allata (CA) in a reversible manner, and in vitro culture experiments showed that this inhibition was due to the direct action of this compound on the CA. When mRNA expression of the JH biosynthetic enzymes were studied, KF-13S strongly suppressed those of HMG Co-A synthase and HMG Co-A reductase. mRNA levels of other mevalonate enzymes and JH acid O methyltransferase were also suppressed but were less sensitive to the compound. These studies showed that KF-13S prevents the transcription of many of the JH biosynthetic enzymes so that JH synthesis is suppressed. PMID- 21664465 TI - Real-time cardiac synchronization with fixed volume frame rate for reducing physiological instabilities in 3D FMRI. AB - Although 2D echo-planar imaging (EPI) remains the dominant method for functional MRI (FMRI), 3D readouts are receiving more interest as these sequences have favorable signal-to-noise ratio (SNR) and enable imaging at a high isotropic resolution. Spoiled gradient-echo (SPGR) and balanced steady-state free precession (bSSFP) are rapid sequences that are typically acquired with highly segmented 3D readouts, and thus less sensitive to image distortion and signal dropout. They therefore provide a powerful alternative for FMRI in areas with strong susceptibility offsets, such as deep gray matter structures and the brainstem. Unfortunately, the multi-shot nature of the readout makes these sequences highly sensitive to physiological fluctuations, and large signal instabilities are observed in the inferior regions of the brain. In this work a characterization of the source of these instabilities is given and a new method is presented to reduce the instabilities observed in 3D SPGR and bSSFP. Rapidly acquired single-slice data, which critically sampled the respiratory and cardiac waveforms, showed that cardiac pulsation is the dominant source of the instabilities. Simulations further showed that synchronizing the readout to the cardiac cycle minimizes the instabilities considerably. A real-time synchronization method was therefore developed, which utilizes parallel-imaging techniques to allow cardiac synchronization without alteration of the volume acquisition rate. The implemented method significantly improves the temporal stability in areas that are affected by cardiac-related signal fluctuations. In bSSFP data the tSNR in the brainstem increased by 45%, at the cost of a small reduction in tSNR in the cortical areas. In SPGR the temporal stability is improved by approximately 20% in the subcortical structures and as well as cortical gray matter when synchronization was performed. PMID- 21664466 TI - Measuring the effects of manipulating stimulus presentation time on sensorimotor alpha and low beta reactivity during hand movement observation. AB - The present study addresses three methodological questions that have been ignored in previous research on EEG indices of the human mirror neuron system (hMNS), particularly in regard to autistic individuals. The first question regards how to elicit the EEG indexed hMNS during movement observation: Is hMNS activation best elicited using long stimulus presentations or multiple short repetitions? The second question regards what EEG sensorimotor frequency bands reflect sensorimotor reactivity during hand movement observation? The third question regards how widespread is the EEG reactivity over the sensorimotor cortex during movement observation? The present study explored sensorimotor alpha and low beta reactivity during hand movement versus static hand or bouncing balls observation and compared two experimental protocols (long exposure vs. multiple repetitions) in the same participants. Results using the multiple repetitions protocol indicated a greater low beta desynchronisation over the sensorimotor cortex during hand movement compared to static hand and bouncing balls observation. This result was not achieved using the long exposure protocol. Therefore, the present study suggests that the multiple repetitions protocol is a more robust protocol to use when exploring the sensorimotor reactivity induced by hand action observation. In addition, sensorimotor low beta desynchronisation was differently modulated during hand movement, static hand and bouncing balls observation (non biological motion) while it was not the case for sensorimotor alpha and that suggest that low beta may be a more sensitive index of hMNS activation during biological motion observation. In conclusion the present study indicates that sensorimotor reactivity of low beta during hand movement observation was found to be more widespread over the sensorimotor cortex than previously thought. PMID- 21664467 TI - Enhanced brain connectivity in long-term meditation practitioners. AB - Very little is currently known about the cerebral characteristics that underlie the complex processes of meditation as only a limited number of studies have addressed this topic. Research exploring structural connectivity in meditation practitioners is particularly rare. We thus acquired diffusion tensor imaging (DTI) data of high angular and spatial resolution and used atlas-based tract mapping methods to investigate white matter fiber characteristics in a well matched sample of long-term meditators and controls (n=54). A broad field mapping approach estimated the fractional anisotropy (FA) for twenty different fiber tracts (i.e., nine tracts in each hemisphere and two inter-hemispheric tracts) that were subsequently used as dependent measures. Results showed pronounced structural connectivity in meditators compared to controls throughout the entire brain within major projection pathways, commissural pathways, and association pathways. The largest group differences were observed within the corticospinal tract, the temporal component of the superior longitudinal fasciculus, and the uncinate fasciculus. While cross-sectional studies represent a good starting point for elucidating possible links between meditation and white matter fiber characteristics, longitudinal studies will be necessary to determine the relative contribution of nature and nurture to enhanced structural connectivity in long term meditators. PMID- 21664469 TI - Update on resistance of Bacteroides fragilis group and related species with special attention to carbapenems 2006-2009. AB - The susceptibility trends for the species of the Bacteroides fragilis group against various antibiotics were determined using data from 4 years [2006-2009] on 1957 isolates referred by 8 medical centers participating in a National Survey for the Susceptibility of B. fragilis. The antibiotic test panel included doripenem, ertapenem, imipenem, meropenem, ampicillin:sulbactam, piperacillin:tazobactam, cefoxitin, clindamycin, moxifloxacin, tigecycline, chloramphenicol and metronidazole. MICs were determined using agar dilution methods following CLSI recommendations. Genetic analysis of isolates from 2008 with elevated MICs (>2 MUg/mL) to one or more of the carbapenems to detect presence of the cfiA gene was performed using PCR methodology. The results showed an increase in the resistance rates to the beta-lactam antibiotics. High resistance rates were seen for clindamycin and moxifloxacin (as high as 60% for clindamycin and >80% for moxifloxacin), with relatively stable low resistance (5.4%) for tigecycline. For carbapenems, resistance in B. fragilis was 1.1%-2.5% in 2008-9. One isolate resistant to metronidazole (MIC 32 MUg/mL) was observed as well as isolates with elevated MICs to chloramphenicol (16 MUg/mL). Genetic analysis indicated that the cfiA gene was present in some but not all of the isolates with high MICs to the carbapenems. These data indicate that there continue to be changes in susceptibility over time, and that resistance can be seen among the carbapenems. High antibiotic resistance rates tend to be associated with specific species. PMID- 21664468 TI - In vivo lysogenization of a Clostridium difficile bacteriophage FCD119. AB - Clostridium difficile is a nosocomial pathogen identified as the cause of antibiotic-associated diarrhea and colitis. In this study, we have documented the lysogeny of a C. difficile bacteriophage in hamsters during C. difficile infection. The lysogens isolated from the hamsters were toxin typed and their phage integration site was confirmed by PCR. Through toxin ELISA it was found that the toxin production in the in vivo isolated lysogens was affected due to FCD119 lysogenization as in the case of in vitro isolated FCD119 lysogens. Together our findings indicate that a baceriophage can lysogenize its C. difficile host even during the infection process and highlights the importance of lysogeny of C. difficile phages as an evolutionary adaptation for survival. PMID- 21664470 TI - The human commensal Bacteroides fragilis binds intestinal mucin. AB - The mammalian gastrointestinal tract harbors a vast microbial ecosystem, known as the microbiota, which benefits host biology. Bacteroides fragilis is an important anaerobic gut commensal of humans that prevents and cures intestinal inflammation. We wished to elucidate aspects of gut colonization employed by B. fragilis. Fluorescence in situ hybridization was performed on colonic tissue sections from B. fragilis and Escherichia coli dual-colonized gnotobiotic mice. Epifluorescence imaging reveals that both E. coli and B. fragilis are found in the lumen of the colon, but only B. fragilis is found in the mucosal layer. This observation suggests that physical association with intestinal mucus could be a possible mechanism of gut colonization by B. fragilis. We investigated this potential interaction using an in vitro mucus binding assay and show here that B. fragilis binds to murine colonic mucus. We further demonstrate that B. fragilis specifically and quantitatively binds to highly purified mucins (the major constituent in intestinal mucus) using flow cytometry analysis of fluorescently labeled purified murine and porcine mucins. These results suggest that interactions between B. fragilis and intestinal mucin may play a critical role during host-bacterial symbiosis. PMID- 21664471 TI - Cord blood transplantation from unrelated donors for children with acute lymphoblastic leukemia in Japan: the impact of methotrexate on clinical outcomes. AB - Cord blood transplantation (CBT) from an unrelated donor is recognized as one of the major treatment modalities in allogeneic stem cell transplantation (SCT) for children with hematologic malignancies. We analyzed the clinical outcomes of CBT for children with acute lymphoblastic leukemia (ALL) in Japan and identified the risk factors for the transplant outcomes. From 1997 to 2006, 332 children with ALL underwent CBT from unrelated donors, 270 of which had no prior transplant. Their disease statuses at transplant were first complete remission (CR) (n = 120), second CR (n = 71), and more advanced stages (n = 75). As preconditioning for SCT, total body irradiation (TBI) was given to 194 patients and, for the prophylaxis of graft-versus-host disease (GVHD), methotrexate (MTX) was given to 159 patients. The cumulative incidents of neutrophil and platelet recovery (>20 K) were 88.5% and 78.4%, respectively. The incidents of grade II-IV, III-IV acute GVHD (aGVHD), and chronic GVHD (cGVHD) were 45.6%, 20.4%, and 19.2%, respectively, and treatment-related mortality was 22.6%. The 5-year event-free survival (EFS) and overall survival (OS) at CR1, CR2, and advanced status were 47.4%, 45.5%, 15.0%, and 63.7%, 59.7%, and 20.7%, respectively. Multivariate analysis revealed that MTX with calcineurin inhibitor (CNI) was associated with decreased incidence of grade II-IV GVHD (CNI alone: hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.06-2.83, P = .027; CNI + prednisolone (PSL), HR = 1.61, 95% CI = 1.03-2.50, P = .036), III-IV aGVHD (CNI alone: HR = 3.02, 95% CI = 1.55-5.91, P = 0.001; CNI + PSL, HR = 1.89, 95% CI = 0.93-3.83, P = .078), or cGVHD (CNI alone: HR = 1.78, 95% CI = 0.83-3.82, P = .143; CNI + PSL, HR = 2.44, 95% CI = 1.24-4.82, P = .01), compared with CNI alone or CNI + PSL. At an advanced stage of disease, GVHD prophylaxis with MTX + CNI is associated with improved OS compared with CNI alone (CNI alone: HR = 3.20, 95% CI = 1.43-7.15, P = .005; CNI + PSL, HR = 1.47, CI = 0.67-3.20, P = .332). Our retrospective study showed that CBT for children with ALL is feasible and GVHD prophylaxis with MTX + CNI is associated with significant favorable outcomes in prevention of aGVHD and cGVHD as well as survival advantage in advanced cases. PMID- 21664472 TI - Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. AB - Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 * 10(7) CD3(+) cells/kg (n = 4), 5 * 10(7) CD3(+) cells/kg (n = 6), and 1 * 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated in vitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations. PMID- 21664473 TI - Rationale and design of the chronic GVHD cohort study: improving outcomes assessment in chronic GVHD. AB - In 2005, the National Institutes of Health sponsored a Consensus Development Project on Criteria for Clinical Trials in chronic graft-versus-host (cGVHD) to achieve consensus about key elements of cGVHD research, including definitions for diagnosis, severity scoring, and response measures. To test these proposed definitions, a multicenter prospective cohort study of people with cGVHD is ongoing. This study will evaluate the performance of proposed prognostic factors, measures of disease activity, and surrogate endpoints for therapeutic response. Data are collected at 6-month intervals in a heterogeneous population of patients reflecting modern transplant techniques and posttransplantation clinical management (target enrollment 672 with cGVHD from 10 transplantation centers). This report describes the rationale, design, and methods of the cGVHD cohort study, and invites other investigators to collaborate with the Consortium to analyze data or specimens. PMID- 21664474 TI - Pyridoxine supply in human development. AB - Vitamin B(6) has an important role in the function of the human nervous system. Experimental data are not generally available on the role in human development, but significant conclusions may be made from studies of the effect of disorders of B(6) vitamer metabolism. Vitamin B(6) comprises seven compounds - pyridoxal, pyridoxine, pyridoxamine and their respective 5' phosphates. The common active form in human tissue is the 5'-phosphate form of pyridoxal (PLP) most of which is found in muscle bound to phosphorylase. Like many vitamins, B(6) can function both as a co-enzyme and as a chaperone. Pyridoxal-5'-phosphate is the metabolically active form and is involved in 100 enzymatic reactions including carbohydrate, amino acid, and fatty acid metabolism. There is evidence that in some situations B(6) vitamers can function as antioxidants. The fetus is dependent on the placenta for supply of vitamin B(6) and the demand correlates with amino acid metabolism. Few reports are available on the role of B(6) in embryogenesis. Studies of human disorders where B(6) metabolism is blocked show a major role in neurotransmitter function with secondary cerebral and cerebellar hypoplasia. Pyridoxine potentiates vitamin A teratogenicity and an excess leads to peripheral nerve cell degeneration. The key role of vitamin B(6) in the developing human is in metabolism, especially of the neurotransmitters. PMID- 21664475 TI - Fluorescent and bimolecular-fluorescent protein tagging of genes at their native loci in Neurospora crassa using specialized double-joint PCR plasmids. AB - The double-joint polymerase chain reaction (DJ-PCR) is a technique that can be used to construct vectors for targeted genome integration without laborious subcloning steps. Here we report the availability of plasmids that facilitate DJ PCR-based construction of Neurospora crassa tagging vectors. These plasmids allow the creation of green or red fluorescent protein (GFP or RFP) tagging vectors for protein localization studies, as well as split-yellow fluorescent protein (YFP) tagging vectors for bimolecular fluorescence complementation (BiFC) analyses. We have demonstrated the utility of each plasmid with the tagging of known meiotic silencing proteins. Microscopic analysis of the tagged strains indicates that SMS 2 and QIP form macromolecular complexes in the perinuclear region during meiosis. PMID- 21664476 TI - Sinusoidal electromagnetic field stimulates rat osteoblast differentiation and maturation via activation of NO-cGMP-PKG pathway. AB - Nitric oxide (NO) is an important intracellular and intercellular messenger, critically affecting bone metabolism. The purpose of this research is to investigate whether the effect of sinusoidal electromagnetic field (SEMF) on the differentiation and maturation of osteoblasts is mediated by the NO-cGMP-PKG signal pathway. We examined the impact of SEMF on nitric oxide synthase (NOS) activity, and found that L-NAME, nitric oxide synthase's inhibitor, prevents SEMF mediated increase in NOS activity and NO levels. We showed that an inhibitor of soluble guanylyl cyclase (ODQ) blocks the increase in cGMP levels triggered by exposure to SEMF. The inhibitor PDE5, which hydrolyzes 3',5'-cyclic-GMP to 5' GMP, prevents the SEMF's stimulation of PKG activity. We also blocked the NO-cGMP PKG pathway to determine whether the maturation and mineralization of osteoblasts, stimulated by SEMF, would be inhibited. This was evaluated by measuring alkaline phosphatase (ALP) activity, osterix gene expression and mineralized bone modulus. After treatment with SEMF, the NOS activity increases in comparison with the control group (P<0.01), reaching the highest level after 0.5h. Osterix gene expression, ALP activity and mineralized bone nodules in the SEMF experimental group also increase significantly. However, these effects are partially blocked in the L-NAME treated cultures. Surprisingly, all the osteogenic markers in the SEMF+L-NAME group were slightly higher than in the control culture, but lower than in the cells exposed to SEMF only. We conclude that the NO-cGMP-PKG signal pathway is activated by SEMF treatment, the stimulatory effect of SEMF on the differentiation and mineralization of osteoblasts is attenuated when the pathway is blocked. PMID- 21664477 TI - Endothelin increases the ciliary beat frequency of ovine airway epithelium via its interaction with endothelin a receptors. AB - Ovine airway epithelial explants, cultured at an air-liquid interface, were used to determine whether endothelin (ET-1) acts via ET(A)- or ET(B)-receptors to increase ciliary beat frequency (CBF). Further, the role of prostanoids and nitric oxide (NO) downstream of receptor activation was explored. CBF was measured using an image analysis system with a sampling rate of 224 frames s(-1). At 37 degrees C, baseline CBF was 14.90 +/- 3.49 Hz (n = 116 cells). ET-1 dose dependently stimulated CBF (EC(50) = 60.98 +/- 27.99 nM). The stimulatory effect of ET-1 (1 MUM) could be mimicked by the ET(A)-receptor agonist sarafotoxin S6b (100 nM) but not the ET(B)-receptor agonist sarafotoxin S6c (100 nM) and was completely abolished by the ET(A)-receptor antagonist BQ-123 (1 MUM). Thus the ciliostimulatory effect of ET-1 appears to be via its interaction with ET(A) receptors. Application of a combination of the cyclo-oxygenase (COX) inhibitors indomethacin (30 MUM) and ibuprofen (10 MUM) did not alter baseline CBF but prevented ciliostimulation by ET-1. Incubation of the explants with the nitric oxide synthase (NOS) inhibitor L-NMMA (100 MUM) caused a significant decrease in CBF relative to baseline (p < 0.01) which developed over 20 min and remained stable thereafter. Subsequent perfusion of the explant with ET-1 was unable to increase CBF above the new baseline. These results suggest a role for both prostanoids and nitric oxide in ET-1-stimulated CBF. This study has shown, for the first time, that ET-1 stimulates CBF via its interaction with ET(A) receptors. Inhibition of both COX and NOS inhibited the effect of ET-1 suggesting a role for both these enzymes in the ET-1 response downstream from the ET(A) receptor. PMID- 21664478 TI - Fundulus heteroclitus acutely transferred from seawater to high salinity require few adjustments to intestinal transport associated with osmoregulation. AB - The common killifish, Fundulus heteroclitus, has historically been a favorite organism for the study of euryhalinity in teleost fish. Despite the species' large range of salinity tolerance, studies of osmoregulation in high salinity are rare, with most previous studies focused on fish transferred between freshwater and seawater. Similarly, while branchial transport properties have been studied extensively, there are relatively few studies investigating the role of the intestine in osmoregulation in killifish. This study sought to characterize the fluid and ion transport occurring in the intestinal tract of killifish adapted to seawater, and furthermore to investigate the adjustments that occur to these mechanisms following acute transfer to high salinity (70ppt). In vivo samples of blood plasma and intestinal fluids of seawater-acclimated killifish indicated absorption of Na(+), Cl(-), and water, the relative impermeability of the intestine to Mg(2+) and SO(4)(2-), and active secretion of HCO(3)(-) into the intestinal lumen. The details of these processes were investigated further using in vitro techniques of isolated intestinal sac preparations and an Ussing chamber pH-stat titration system. However, these methods were discovered to be of limited utility under physiologically relevant conditions due to tissue deterioration. Results that could be validly interpreted suggested that there are few changes to intestinal transport following transfer to high salinity, and that adjustments to epithelial permeability occur in the first 24h post-transfer. PMID- 21664479 TI - Mechanisms associated with cellular desiccation tolerance of Artemia encysted embryos from locations around the world. AB - Using differential scanning calorimetry we demonstrated the presence of biological glasses and measured the glass transition temperatures (Tg) in dry encysted gastrula embryos (cysts) of the brine shrimp, Artemia, from eleven different locations, two of which provided cysts from parthenogenetic animals. Values for Tg were highest, by far, in Artemia franciscana cysts from the Mekong Delta, Vietnam (VN), these cysts having been produced from previous sequential inoculations into growth ponds of cysts from the San Francisco Bay, California, USA. Tg values for three groups of A. franciscana cysts were significantly higher than those of other cysts (except those of Artemia persimilis) studied here, as well as all other desiccation-tolerant animal systems studied to date. We also measured three stress proteins (hsc70, artemin and p26) in all these cysts as well as the total alcohol soluble carbohydrates (ASC), about 90% of which is the disaccharide trehalose, a known component of biological glasses. We interpret the results in terms of mechanisms involved with desiccation tolerance and, to some extent, with thermal conditions at the sites of cyst collection. PMID- 21664480 TI - Heat shock protein expression in relation to reproductive cycle in land snails: Implications for survival. AB - Land snails are subject to daily and seasonal variations in temperature and in water availability and use heat shock proteins (HSPs) as part of their survival strategy. We tested whether the reproductive cycle of land snails affects the endogenous levels of HSPs, and their involvement in the reproductive process. We examined HSP levels in the foot tissue of two Sphincterochila species, S. cariosa and S. zonata, before and after laying eggs, and analyzed the albumen gland (reproductive organ) of both species and eggs of S. cariosa for the presence and quantity of various HSPs. Our study shows reduction in the expression level of Hsp70 isoforms and Hsp90 in S. zonata foot and of Hsp74 in S. cariosa foot during the period preceding egg laying compared to the post-reproductive stage. Hsp70 isoforms and Hsp25 were highly expressed in both large albumen glands and in freshly laid eggs of S. cariosa, whereas large albumen glands of S. zonata expressed mainly Hsp70 isoforms. We conclude that a trade-off between survival and fertility is responsible for the expression level of HSPs in the foot tissue of Sphincterochila snails. Our study shows that HSPs are involved in the reproductive process. We propose that parental provision of HSPs may be part of a "be prepared" strategy of Sphincterochila snails, and that HSPs may play important roles in the survival strategy of land snails during the early life stages. Our observations also highlight the importance of the reproductive status in study of whole organisms, especially when assessing the HSP response to stress. PMID- 21664481 TI - Isolation and characterization of the CYP17A1 gene and its processed pseudogene in Rana rugosa. AB - CYP17A1 expression is up-regulated in the gonad in Rana (Glandirana) rugosa tadpoles treated with androgens to induce female-to-male sex-reversal. In this study, we isolated the CYP17A1 gene and its processed pseudogene from R. rugosa. The former was found to consist of 8 exons, and the latter a single-exon gene, designated CYP17A1P. The sequence of the promoter region of CYP17A1 differed from that of CYP17A1P. We found several consensus binding-sites for candidate transcription factors including androgen receptor (AR), Sox and FoxL2 in the CYP17A1 promoter region, but an AR-binding site was absent from CYP17A1P. When AR was over-expressed in Xenopus A6 cells, it did not increase CYP17A1 transcription in luciferase assays. CYP17A1 was strongly expressed in indifferent male gonads during sex determination and exclusively in testis, among eight adult tissues of R. rugosa. By contrast, CYP17A1P was expressed at very low, and similar levels in the adult tissues of both sexes. Fluorescent In-Situ Hybridization (FISH) analysis showed that CYP17A1P is localized to chromosome 4, while CYP17A1 is on chromosome 9. These results collectively suggest that CYP17A1, but not CYP17A1P is involved in male sex-determination in R. rugosa, and that androgens may not have a direct effect on the CYP17A1 transcription. PMID- 21664482 TI - Isozymes from the herbivorous gecarcinid land crab, Gecarcoidea natalis that possess both lichenase and endo-beta-1,4-glucanase activity. AB - Three isozymes with both lichenase and endo-beta-1,4-glucanase activity were purified and characterised from the midgut gland of the herbivorous gecarcinid land crab, Gecarcoidea natalis. The three isozymes, termed 1a, 1b and 2, had respective molecular masses of 53 +/- 0 (3), 43 +/- 0 (3) and 47.4 +/- 0(3) kDa. All isozymes possessed similar V(max) values and thus hydrolysed both carboxy methyl cellulose and lichenan equally. Furthermore the chromatography profiles for lichenase activities mirrored that for endo-beta-1,4-glucanase activities suggesting that the same enzyme possessed both activities. Given this, the endo beta-1,4-glucanase enzymes described for other animals, may, like the isozymes described in this study, may be able to hydrolyse lichenan. However this ability needs to be confirmed. The main digestive function of these isozymes may be to hydrolyse hemicelluloses such as lichenan and mixed beta-D-glucan. All three isozymes randomly hydrolysed internal glycosidic bonds within carboxy methyl cellulose and lichenan to release short oligomers of 4-5 glucose units in length. They also hydrolysed cellotetraose to either two units of cellobiose or cellotriose and glucose. Cellotriose was hydrolysed to cellobiose and glucose. All three enzymes lacked beta-1,4-glucosidase activity as they could not hydrolyse cellobiose. PMID- 21664483 TI - Lysophosphatidic acid and calcitriol co-operate to promote human osteoblastogenesis: requirement of albumin-bound LPA. AB - Lysophosphatidic acid (LPA), a pleiotropic signalling lipid is assuming growing significance in osteoblast biology. Although committed osteoblasts from several mammalian species are receptive to LPA far less is known about the potential for LPA to influence osteoblast formation from their mesenchymal progenitors. An essential factor for both bone development and post-natal bone growth and homeostasis is the active metabolite of vitamin D3, calcitriol (D3). Previously we reported how a combination of LPA and D3 synergistically co-operated to enhance the differentiation of immature human osteoblasts. Herein we provide evidence for the formation of human osteoblasts from multiple, primary human bone marrow derived stromal (stem) cells (hBMSCs). Importantly osteoblast development from hBMSCs only occurred when LPA was administered as a complex with albumin, its natural carrier. Collectively our findings support a co-operative role of LPA and D3 in osteoblastogenesis, findings which may aid the development of novel treatment strategies for bone repair. PMID- 21664485 TI - Chromatin modifying agents - the cutting edge of anticancer therapy. AB - Chromatin modifying compounds are emerging as the next generation of anticancer therapies. By altering gene expression they could be able to correct uncontrolled proliferation and, in certain cases, aberrant apoptotic pathways, which are hallmarks of malignant cells. The modulation of gene expression is regulated via chromatin remodelling processes that include DNA methylation and chromatin modifications. The identification of aberrant methylation of genes and dysregulated histone acetylation status in cancer cells provides a basis for novel epigenetic therapies. Currently available chromatin modifying agents, a group that includes DNA methyltransferase and histone deacetylase inhibitors, exert anticancer effects by reactivating tumour suppressor genes, inhibiting proliferation and inducing apoptosis. It is anticipated that massive parallel sequencing will identify new epigenetic targets for drug development. PMID- 21664484 TI - On diphtheria toxin fragment A release into the cytosol--cytochalasin D effect and involvement of actin filaments and eukaryotic elongation factor 2. AB - Diphtheria toxin has been well characterized in terms of its receptor binding and receptor mediated endocytosis. However, the precise mechanism of the cytosolic release of diphtheria toxin fragment A from early endosomes is still unclear. Various reports differ regarding the requirement for cytosolic factors in this process. Here, we present data indicating that the distribution of actin filaments due to cytochalasin D action enhances the retention of diphtheria toxin in early endosomes. Treating cells with cytochalasin D reduces the cytosolic fragment A activity and leads to changes in the intracellular distribution and size of early endosomes with toxin cargo. F-actin and eukaryotic elongation factor 2 can promote fragment A release from toxin-loaded early endosomes in an in vitro translocation system. Moreover, these proteins bind to toxin-loaded early endosomes in vitro and promote each other's binding. They are thus thought to be involved in the cytosolic release of fragment A. Finally, ADP-ribosylation of eukaryotic elongation factor 2 is shown to inhibit fragment A release and, via a feed-back mechanism, to account for the minute amounts of fragment A normally found in the cytosol. PMID- 21664486 TI - Association of HLA and post-schistosomal hepatic disorder: a systematic review and meta-analysis. AB - Several human genetic variants, HLA antigens and alleles are reportedly linked to post-schistosomal hepatic disorder (PSHD), but the results from these reports are highly inconclusive. In order to estimate overall associations between human genetic variants, HLA antigens, HLA alleles and PSHD, we systematically reviewed and performed a meta-analysis of relevant studies in both post-schistosomal hepatic disorder and post-schistosomal non-hepatic disorder patients. PubMed, Scopus, Google Scholar, The HuGE Published Literature database, Cochrane Library, and manual search of reference lists of articles published before July 2009 were used to retrieve relevant studies. Two reviewers independently selected articles and extracted data on study characteristics and data regarding the association between genetic variants, HLA antigens, HLA alleles and PSHD in the form of 2*2 tables. A meta-analysis using fixed-effects or random-effects models to pooled odds ratios (OR) with corresponding 95% confidence intervals were calculated only if more than one study had investigated particular variation. We found 17 articles that met our eligibility criteria. Schistosoma mansoni and Schistosoma japonicum were reported as the species causing PSHD. Since human genetic variants were only investigated in one study, these markers were not assessed by meta analysis. Thus, only HLA-genes (a total of 66 HLA markers) were conducted in the meta-analysis. Our meta-analysis showed that human leucocyte antigens HLA DQB1*0201 (OR=2.64, P=0.018), DQB1*0303 (OR=1.93, P=0.008), and DRB1*0901 (OR=2.14, P=0.002) alleles and HLA-A1 (OR=5.10, P=0.001), A2 (OR=2.17, P=0.005), B5 (OR=4.63, P=0.001), B8 (OR=2.99, P=0.02), and B12 (OR=5.49, P=0.005) serotypes enhanced susceptibility to PSHD, whereas HLA-DQA1*0501 (OR=0.29, P<=0.001) and DQB1*0301 (OR=0.58, P=0.007) were protective factors against the disease. We further suggested that the DRB1*0901-DQB1*0201, DRB1*0901-DQB1*0303 and A1-B8 haplotypes enhanced susceptibility to PSHD, whereas DQA1*0501-DQB1*0301 linkage decreased the risk of PSHD. The result improved our understanding of the association between the HLA loci and PSHD with regard to pathogenic or protective T-cells and provided novel evidence that HLA alleles may influence disease severity. PMID- 21664487 TI - Identification of robust hypoxia biomarker candidates from fin of medaka (Oryzias latipes). AB - Aquatic hypoxia caused by organic pollution and eutrophication is a pressing worldwide water pollution problem. Better methods for monitoring oxygen levels are needed to assist efforts to maintain and protect the health of natural aquatic environments. In this project, we used a Japanese ricefish (medaka, Oryzias latipes) 8K oligonucleotide array as a platform to identify potential hypoxic biomarkers in different organs (fin, gill, liver and brain) upon exposure to hypoxia. The microarray results were validated by qRT-PCR employing a subset of candidate biomarkers. Interestingly, the largest number and most significant of hypoxia responding array features were detected in hypoxia exposed fin tissues. We identified 173 array features that exhibited a significant response (over 2 fold change in expression) upon exposure to hypoxic conditions and validated a subset of these by quantitative RT-PCR. These gene targets were subjected to annotation and gene ontology mining. Positively identifiable gene targets that may be useful for development of a rapid and accurate biomarker test using fin clips are discussed in relation to previous reports on hypoxia responsive genes. PMID- 21664488 TI - Cloning of estrogen receptor alpha and aromatase cDNAs and gene expression in turtles (Chrysemys picta and Pseudemys scripta) exposed to different environments. AB - Reproductive changes have been observed in painted turtles (Chrysemys picta) from a site with known contamination located on Cape Cod, MA, USA. We hypothesize that these changes are caused by exposure to endocrine-disrupting compounds and that genes playing a significant role in reproduction are affected. cDNA sequences were determined for estrogen receptor alpha and aromatase in the painted turtle. These genes were measured in our study animals using quantitative PCR. Adult turtles were trapped from our study site (Moody Pond, MP) or a reference site (Washburn Pond) and exposed to laboratory environments containing soil from either site. The red-eared slider (Pseudemys scripta), a pond turtle closely related to the painted turtle, was used to assess neonatal exposure to soil and water from the sites. Our results show an increase in hepatic estrogen receptor, which suggests exposure to estrogenic contaminants. Female turtles from MP appear to have a long-term effect on hepatic ER. Other findings were apparent age dependent differences in expression of aromatase and ER in the brains of neonate and year-old juvenile turtles. Phylogenetic analyses of the cDNA sequences further support the hypothesis that turtles are in a sister clade to birds and crocodilians. PMID- 21664489 TI - ZnO nanorod-induced apoptosis in human alveolar adenocarcinoma cells via p53, survivin and bax/bcl-2 pathways: role of oxidative stress. AB - Zinc oxide (ZnO) nanoparticles (NPs) are increasingly recognized for their utility in biological applications, including biosensor and medicine. However, little is known about the toxicity mechanisms of ZnO nanorods in human cells. This study was designed to investigate the possible mechanisms of apoptosis induced by ZnO nanorods in human alveolar adenocarcinoma (A549) cells. ZnO nanorod was found to induce cytotoxicity, reactive oxygen species (ROS) generation, oxidative stress and activities of caspase-3 & caspase-9 in a dose- and time-dependent manner. Western blot results showed that ZnO nanorods induced the expression of heat shock protein 70, a first-tier marker of cell damage and a cell-cycle checkpoint protein p53. Moreover, pro-apoptotic protein bax was upregulated and the antiapoptotic proteins, survivin and bcl-2, were downregulated in ZnO nanorod exposed cells. In conclusion, our data demonstrates that ZnO nanorod induced apoptosis in A549 cells through ROS and oxidative stress via p53, survivin, bax/bcl-2 and caspase pathways. FROM THE CLINICAL EDITOR: This study describes the mechanisms of apoptosis induced by ZnO nanorods in human alveolar adenocarcinoma cells. PMID- 21664490 TI - A peptide derived from herpes simplex virus type 1 glycoprotein H: membrane translocation and applications to the delivery of quantum dots. AB - Cell membranes are impermeable to most molecules that are not actively imported by living cells, including all macromolecules and even small molecules whose physiochemical properties prevent passive membrane diffusion. However, recently, we have seen the development of increasingly sophisticated methodology for intracellular drug delivery. Cell-penetrating peptides (CPPs), short peptides believed to enter cells by penetrating cell membranes, have attracted great interest in the hope of enhancing gene therapy, vaccine development and drug delivery. Nevertheless, to achieve an efficient intracellular delivery, further strategies to bypass the endocytotic pathway must be investigated. We report on a novel peptide molecule derived from glycoprotein gH of herpes simplex type I virus that is able to traverse the membrane bilayer and to transport a cargo into the cytoplasm with novel properties in comparison with existing CPPs. We use as cargo molecule quantum dots that do not significantly traverse the membrane bilayer on their own. FROM THE CLINICAL EDITOR: Cell-penetrating peptides have recently attracted great interest in optimizing gene therapy, vaccine development and drug delivery. In this study, a peptide derived from glycoprotein gH of herpes simplex I is investigated from this standpoint. PMID- 21664491 TI - Development of tool for the assessment of comprehension of informed consent form in healthy volunteers participating in first-in-human studies. AB - Informed consent is a process that involves providing all pertinent study information to the potential study participant. The information imparted in the form gives all such information as would enable a potential participant to come to a decision regarding his/her participation in the study. Various study related aspects are outlined in the participant information leaflet including the background of the study, the benefits and risks, treatment alternatives; the methodology of the study, follow up schedules, confidentiality of the data, compensations and remunerations and right to not participate or withdraw from the study. We have continued a similar exercise for a phase I, first-in-human study, conducted by our center. Here, the volunteers were asked certain questions pertaining to the trial background, design, patients' rights and miscellaneous categories. They were then assessed and the scores compared to come up with certain conclusions. The median (range) for the entire comprehension score was calculated and statistically analyzed on various aspects. Readability of the ease of reading of the consent form was also analyzed on a Flesch-Kinkaid reading scale. A total of 69 volunteers were screened out of which 50 were enrolled in the study. The median (range) score was 27 (19 to 33) and the mean (S.D.) score was 28.9 (3.1). The maximum correct responses were observed for the questions falling under the volunteers' rights category. The Flesch reading ease score was 54 and the Flesch-Kincaid Grade level score was 9.8. Investigators may be encouraged to incorporate such tools in their informed consent process. PMID- 21664492 TI - Cholecystokinin octapeptide inhibits immunoglobulin G1 production of lipopolysaccharide-activated B cells. AB - Cholecystokinin octapeptide (CCK-8) is a typical brain-gut peptide that exerts a variety of physiological actions in both the peripheral and central nervous systems. Our laboratory has previously reported that CCK-8 produces immunoregulatory action through activating CCK receptor (CCK1R/CCK2R) expression on immune cell surfaces. In the present study, we investigated the effect of CCK 8 on immunoglobulin G1 (IgG1) production in lipopolysaccharide (LPS)-activated B cells in vitro. CCK-8 inhibited the proliferation and IgG1 mRNA expression of LPS activated B cells and therefore inhibited IgG1 production. The mechanism may be associated with the regulation of CCK-8 on transcription factors Blimp1, Pax5, Xbp1 and Bcl6. CCK-8 inhibited the expression of Blimp1, while the effect on Pax5, Xbp1 and Bcl6 varied with time, suggesting that CCK-8 acted as a complex regulator of LPS-activated B cells. The inhibitory action of CCK-8 was mainly mediated through the CCK2R pathway. These studies indicate that CCK-8 attenuates humoral immune responses and acts as endogenous immune deactivators in autoimmune diseases. PMID- 21664493 TI - Successful expression of heterologous egfp gene in the mitochondria of a photosynthetic eukaryote Chlamydomonas reinhardtii. AB - The efficient expression of exogenous gene in mitochondria of photosynthetic organism has been an insurmountable problem. In this study, the pBsLPNCG was constructed by inserting the egfp gene into a site between TERMINVREP-Left repeats and the cob gene in a fragment of mitochondrial DNA of Chlamydomonas reinhardtii CC-124 and introduced into the mitochondria of respiratory deficient dum-1 mutation of C. reinhardtii CC-2654. Sequencing and DNA Southern analyses revealed that egfp gene had been integrated into the mitochondrial genome of transgenic algae as expected and no other copy of egfp existed in their nucleic genome. Both the fluorescence detection and Western blot analysis confirmed the presence of eGFP protein in the transgenic algae; it indicated that the egfp gene was successfully expressed in the mitochondria of C. reinhardtii. PMID- 21664494 TI - The antioxidant Trolox helps recovery from the familial Parkinson's disease specific mitochondrial deficits caused by PINK1- and DJ-1-deficiency in dopaminergic neuronal cells. AB - The nature of mitochondrial dysfunction in dopaminergic neurons in familial Parkinson's disease (PD) is unknown. We characterized the pathophenotypes of dopaminergic neuronal cells that were deficient in PINK1 or DJ-1, genes with mutations linked to familial PD. Both PINK1- and DJ-1-deficient dopaminergic neurons had the increased production of ROS, severe mitochondrial structural damages and complex I deficits. A striking decrease in complex IV activity was also prominent by the PINK1-deficiency. The complex I deficits were relatively PD specific and were significantly improved by an antioxidant Trolox. These data suggest that mitochondrial deficits are severe in dopaminergic neurons in familial PD and antioxidant-mediated functional recovery is feasible. PMID- 21664495 TI - Mitochondrial enzymes discriminate between mitochondrial disorders and chronic fatigue syndrome. AB - We studied the extent of mitochondrial involvement in chronic fatigue syndrome (CFS) and investigated whether measurement of mitochondrial respiratory chain complex (RCC) activities discriminates between CFS and mitochondrial disorders. Mitochondrial content was decreased in CFS compared to healthy controls, whereas RCC activities corrected for mitochondrial content were not. Conversely, mitochondrial content did not discriminate between CFS and two groups of mitochondrial disorders, whereas ATP production rate and complex I, III and IV activity did, all with higher activities in CFS. We conclude that the ATP production rate and RCC activities can reliably discriminate between mitochondrial disorders and CFS. PMID- 21664496 TI - Increased availability of endogenous and dietary oleic acid contributes to the upregulation of cardiac fatty acid oxidation. AB - In the present study, we tested the hypothesis that cardiac substrate utilization is affected by oleic acid originating from the endogenous conversion of stearate by stearoyl-CoA desaturase and from the diet. Here, we show that the cardiac oleate content is increased in tristearate (TS)- and trioleate (TO)-fed rats when compared with chow-fed rats. TS or TO feeding increases mitochondrial fatty acid oxidation via activation of expression of the oxidative genes, activation of the AMP-activated protein kinase pathway, and a decrease in glucose uptake. These results suggest that oleic acid, both dietary and de novo synthesized, affects substrate utilization in the heart. Furthermore, our data show that the endogenous synthesis of oleate in the heart can compensate for a deficiency of this fatty acid in the diet. PMID- 21664497 TI - Idiopathic inflammatory myopathies: definition and management of refractory disease. AB - Adult idiopathic inflammatory myopathies, commonly referred to as myositis, are a heterogeneous group of diseases with an autoimmune etiology. In this review, the authors are going to focus on myositis excluding inclusion body myositis. They will review the prognostic factors (for mortality and response to steroids), define refractory disease, introduce a new concept (presumed refractory disease), analyze definitions of active disease, damage and improvement criteria, and summarize therapeutic alternatives for refractory patients, based on different disease phenotypes. PMID- 21664498 TI - A corrosion model for bioabsorbable metallic stents. AB - In this study a numerical model is developed to predict the effects of corrosion on the mechanical integrity of bioabsorbable metallic stents. To calibrate the model, the effects of corrosion on the integrity of biodegradable metallic foils are assessed experimentally. In addition, the effects of mechanical loading on the corrosion behaviour of the foil samples are determined. A phenomenological corrosion model is developed and applied within a finite element framework, allowing for the analysis of complex three-dimensional structures. The model is used to predict the performance of a bioabsorbable stent in an idealized arterial geometry as it is subject to corrosion over time. The effects of homogeneous and heterogeneous corrosion processes on long-term stent scaffolding ability are contrasted based on model predictions. PMID- 21664499 TI - Solvothermal synthesis of cobalt ferrite nanoparticles loaded on multiwalled carbon nanotubes for magnetic resonance imaging and drug delivery. AB - Multiwalled carbon nanotube (MWCNT)/cobalt ferrite (CoFe(2)O(4)) magnetic hybrids were synthesized by a solvothermal method. The reaction temperature significantly affected the structure of the resultant MWCNT/CoFe(2)O(4) hybrids, which varied from 6nm CoFe(2)O(4) nanoparticles uniformly coated on the nanotubes at 180 degrees C to agglomerated CoFe(2)O(4) spherical particles threaded by MWCNTs and forming necklace-like nanostructures at 240 degrees C. Based on the superparamagnetic property at room temperature and high hydrophilicity, the MWCNT/CoFe(2)O(4) hybrids prepared at 180 degrees C (MWCNT/CoFe(2)O(4)-180) were further investigated for biomedical applications, which showed a high T(2) relaxivity of 152.8 Fe mM(-1)s(-1) in aqueous solutions, a significant negative contrast enhancement effect on cancer cells and, more importantly, low cytotoxicity and negligible hemolytic activity. The anticancer drug doxorubicin (DOX) can be loaded onto the hybrids and subsequently released in a sustained and pH-responsive way. The DOX-loaded hybrids exhibited notable cytotoxicity to HeLa cancer cells due to the intracellular release of DOX. These results suggest that MWCNT/CoFe(2)O(4)-180 hybrids may be used as both effective magnetic resonance imaging contrast agents and anticancer drug delivery systems for simultaneous cancer diagnosis and chemotherapy. PMID- 21664500 TI - Three new cases with a mosaicism involving a normal cell line and a cryptic unbalanced autosomal reciprocal translocation. AB - Mosaicism involving a normal cell line and an unbalanced autosomal translocation are rare. In this study we present three new cases with such a mosaicism, which were detected by Single Nucleotide Polymorphism (SNP) array analysis in our routine diagnostic setting. These cases were further characterized using Fluorescence in situ Hybridisation (FISH) analysis and conventional karyotyping. The first case is a mentally retarded male who carries an unbalanced translocation in 87% of his cells. The phenotypically normal mother carries the balanced form of the translocation in all her cells. The second case is a phenotypically normal female who has an unbalanced translocation in 52% of her cells. The inheritance could not be determined. The third case is a female referred for Rubinstein-Taybi syndrome who carries an unbalanced translocation in 60% of her cells. Both parents of this case showed a normal karyotype. The mechanisms that might be responsible for these mosaic karyotypes are discussed. Furthermore, we demonstrate that high-resolution whole-genome SNP array is a powerful tool to reveal cryptic unbalanced translocations and mosaicisms, including the more rare cases. PMID- 21664501 TI - Increased plasma plant sterol concentrations and a heterozygous amino acid exchange in ATP binding cassette transporter ABCG5: a case report. AB - Whilst conducting a scientific study, an elevated plasma plant sterol concentration of 3.07 mg/dL was established in one proband. Similar levels found in his mothers plasma (2.73 mg/dL) were suggestive of a heterozygous sitosterolemia. The resulting gene analysis for ATP binding cassette transporter G5/G8 (ABCG5/G8) revealed a heterozygous polymorphism in ABCG8 (Thr400Lys, rs4148217), which the proband had inherited from his father. However, a heterozygous amino acid exchange (Arg406Gln) in exon 9 of ABCG5 was revealed, which was inherited from his mother. Although not sufficient evidence exists to regard this sequence variation as a mutation, this previously unreleased sequence variation occurred in a "hot spot" area for sitosterolemia of the ABCG5 gene (exon 9) and the similar increased plasma plant sterol concentrations of the heterozygous mother contribute to the notion, that this very likely presents an inactivating mutation. PMID- 21664502 TI - Bacterial tyrosinases: old enzymes with new relevance to biotechnology. AB - Tyrosinases are copper-containing dioxygen activating enzymes found in many species of bacteria and are usually associated with melanin production. These proteins have a strong preference for phenolic and diphenolic substrates and are somewhat limited in their reaction scope, always producing an activated quinone as product. Despite this fact they have potential in several biotechnological applications, including the production of novel mixed melanins, protein cross linking, phenolic biosensors, production of l-DOPA, phenol and dye removal and biocatalysis. Although most studies have used Streptomyces sp. enzymes, there are several other examples of these proteins that are also of potential interest. For instance a solvent tolerant enzyme has been described, as well as an enzyme with both tyrosinase and laccase activities, enzymes with altered substrate preferences, an enzyme produced as an inactive zymogen as well as examples which do not require auxiliary proteins for copper insertion (unlike the Streptomyces sp. enzymes which do require such a protein). This article will summarise the reports on the biotechnological applications of bacterial tyrosinases as well as the current information available on the different types of this enzyme. PMID- 21664503 TI - Establishment of a luciferase assay-based screening system for detecting estrogen receptor agonists in plant extracts. AB - In order to effectively treat osteoporosis and other bone-loss disorders, small compounds that could induce bone formation are needed. The present study attempted to establish a screening system for detecting estrogenic activity of compounds, which probably have anti-osteoporosis effects. For this purpose, we established osteoblastic-like MG63 cells stably transfected with the PGL3 reporter gene driven by a promoter consisting of three estrogen response elements (EREs). Using this system, we screened numerous plant extracts, and found several which displayed bioactivity. We conclude that the MG63 cells with estrogen specific reporter plasmids (MG63-pERE) are useful for high-throughput screening of estrogen receptor agonists from plants which may have favorable potency and could be developed into novel anti-osteoporosis drugs. PMID- 21664504 TI - Guest editorial & introduction to the special issue. PMID- 21664505 TI - Bringing it home: our imperative to translate reproductive health research into real practice change. PMID- 21664506 TI - Clinical guidelines. Labor induction abortion in the second trimester. AB - Labor induction abortion is effective throughout the second trimester. Patterns of use and gestational age limits vary by locality. Earlier gestations (typically 12 to 20 weeks) have shorter abortion times than later gestational ages, but differences in complication rates within the second trimester according to gestational age have not been demonstrated. The combination of mifepristone and misoprostol is the most effective and fastest regimen. Typically, mifepristone 200 mg is followed by use of misoprostol 24-48 h later. Ninety-five percent of abortions are complete within 24 h of misoprostol administration. Compared with misoprostol alone, the combined regimen results in a clinically significant reduction of 40% to 50% in time to abortion and can be used at all gestational ages. However, mifepristone is not widely available. Accordingly, prostaglandin analogues without mifepristone (most commonly misoprostol or gemeprost) or high dose oxytocin are used. Misoprostol is more widely used because it is inexpensive and stable at room temperature. Misoprostol alone is best used vaginally or sublingually, and doses of 400 mcg are generally superior to 200 mcg or less. Dosing every 3 h is superior to less frequent dosing, although intervals of up to 12 h are effective when using higher doses (600 or 800 mcg) of misoprostol. Abortion rates at 24 h are approximately 80%-85%. Although gemeprost has similar outcomes as compared to misoprostol, it has higher cost, requires refrigeration, and can only be used vaginally. High-dose oxytocin can be used in circumstances when prostaglandins are not available or are contraindicated. Osmotic dilators do not shorten induction times when inserted at the same time as misoprostol; however, their use prior to induction using misoprostol has not been studied. Preprocedure-induced fetal demise has not been studied systematically for possible effects on time to abortion. While isolated case reports and retrospective reviews document uterine rupture during second-trimester induction with misoprostol, the magnitude of the risk is not known. The relationship of individual uterotonic agents to uterine rupture is not clear. Based on existing evidence, the Society of Family Planning recommends that, when labor induction abortion is performed in the second trimester, combined use of mifepristone and misoprostol is the ideal regimen to effect abortion quickly and completely. The Society of Family Planning further recommends that alternative regimens, primarily misoprostol alone, should only be used when mifepristone is not available. PMID- 21664507 TI - The evolution of combined oral contraception: improving the risk-to-benefit ratio. AB - Since its introduction in 1960, the combined oral contraceptive (COC) pill has become one of the most widely and frequently used methods of contraception worldwide. Although highly effective, early COC formulations were associated with significant adverse effects and unacceptable cardiovascular risk. Improvements in tolerability and safety have been achieved, without compromises in effectiveness, primarily via hormone dosage reductions and the development of several new progestins. Multiphasic COCs and extended-/continuous-cycle COCs have also been introduced, although the clinical advantages of these formulations vs. traditional COCs have yet to be established. Inclusion of natural estrogens such as estradiol valerate and 17beta-estradiol with selective progestins in new combinations that maintain good cycle control is the most recent evolutionary step designed to improve COC tolerability and safety. Vigorous research needs to continue to help guarantee that the unmet need for safe and effective contraception is satisfied in future generations. PMID- 21664508 TI - Effect on pregnancy rates of the delay in the administration of levonorgestrel for emergency contraception: a combined analysis of four WHO trials. AB - BACKGROUND: Levonorgestrel is an effective method for emergency contraception (EC) and is used worldwide. Consistent with its mechanism of action in delaying ovulation, the earlier it is administered within 72 h of an unprotected act of intercourse, the more effective it is. There is uncertainty, however, about its effectiveness after 72 h. This analysis explores the effect of 24-h intervals of delay in levonorgestrel administration on pregnancy rates when used until 120 h of an unprotected act of intercourse. STUDY DESIGN: Data were analyzed from 6794 women participating in four World Health Organization randomized trials and receiving 1.5 mg of levonorgestrel for EC in a single dose or split into two doses 12 h apart, within 48, 72 or 120 h of an act of unprotected intercourse. The pregnancy rates among women in successive days after an unprotected act of intercourse and odds ratios of pregnancy were calculated using logistic regression with the first day as the reference. RESULTS: For the four trials combined, odds ratios for pregnancy in the second, third and fourth day with respect to the first day were not significantly different from 1 at the 5% level of significance. On the fifth day, the odds ratio of pregnancy compared to the first day was almost 6. CONCLUSIONS: Levonorgestrel for EC should be administered as soon as possible after unprotected intercourse. Delaying levonorgestrel administration until the fifth day after unprotected intercourse increases the risk of pregnancy over five times compared with administration within 24 h. It is uncertain whether levonorgestrel administration on the fifth day still offers some protection against unwanted pregnancy. PMID- 21664509 TI - Is the oral contraceptive pill associated with fracture in later life? New evidence from the Royal College of General Practitioners Oral Contraception Study. AB - BACKGROUND: Several studies, including an earlier analysis from the Royal College of General Practitioners (RCGP) Oral Contraception Study, have suggested that ever users of oral contraceptives have an increased risk of fracture when compared with never users. In this paper, we examined a subset of women in the RCGP study living in Scotland to determine whether this risk has persisted. STUDY DESIGN: A nested case-control study was carried out using data collected prospectively for the RCGP Oral Contraception Study. Cases were women with a first ever diagnosis of fracture (n=651), age-matched to two controls (n=1302). Adjustments were made for smoking, social class and parity. RESULTS: There was not a significant association between ever use of oral contraception and fracture (adjusted odds ratio 1.05, 95% confidence interval 0.86-1.29), compared with never users. Neither were significant associations found between fracture and smoking, social class and parity. The findings did not vary materially with age or type of fracture. CONCLUSION: Ever use of oral contraception was not associated with fracture in this study. PMID- 21664510 TI - Effectiveness of a theory-based postpartum sexual health education program on women's contraceptive use: a randomized controlled trial. AB - BACKGROUND: The aim of this study was to evaluate the effectiveness of a refined theory-based Interactive Postpartum Sexual Health Education Program to enhance postpartum women's effective contraceptive behavior. STUDY DESIGN: Participants (N=250) were randomized to three groups. Experimental Group A received our intervention program via strategies that matched participants' learning preparedness, as determined by the transtheoretical model. Experimental Group B received only a pamphlet. The control group received routine education. Only Group A received health education. Data were collected at baseline, 3 days, 2 months and 3 months postpartum. RESULTS: Women who received theory-based postpartum sexual health education program had significantly greater contraceptive self-efficacy and were more likely to choose more effective contraceptive methods at 2 months postpartum than women in the routine teaching and interactive pamphlet-only groups. CONCLUSION: Our theory-based Interactive Postpartum Sexual Health Education Program enhanced postpartum women's contraceptive self-efficacy and effective contraceptive behavior. PMID- 21664511 TI - Unintended pregnancy and postpartum contraceptive use in women with and without chronic medical disease who experienced a live birth. AB - BACKGROUND: Maternal chronic medical disease and unintended pregnancies increase the risk of maternal and infant morbidity and mortality. Little is known regarding the relationship between chronic medical disease status and pregnancy intendedness or contraceptive use. STUDY DESIGN: We compared pregnancy intention and postpartum contraception use in women with and without chronic medical disease who experienced a live birth using data from the Florida Pregnancy Risk Assessment Monitoring System 2004-2005. RESULTS: Women aged >=20 years with chronic medical disease were more likely to report that the index pregnancy was unintended (odds ratio [OR]=1.56, 95% confidence interval [CI] 1.28-2.03) and reported similar postpartum contraception nonuse (OR=0.85, 95% CI 0.60-1.19) compared to those without chronic medical disease. Women aged <20 years with chronic medical disease were less likely to report that the index pregnancy was unintended (OR=0.50, 95% CI 0.28-0.88) and reported similar postpartum contraception nonuse (OR=0.99, 95% CI 0.54-1.82) compared to those without chronic medical disease. CONCLUSIONS: In our study population, age and chronic medical disease were associated with different risks of pregnancy intention in the index pregnancy. Women with and without chronic disease in both age groups reported similar postpartum contraception use. PMID- 21664512 TI - Effects of low-dose mifepristone administration in two different 14-day regimens on the menstrual cycle and endometrial development: a randomized controlled trial. AB - BACKGROUND: This study was conducted to evaluate the effects of treatment with mifepristone 5 mg given every day or every other day for 14 days, starting 15 days after menses started for endometrial development. STUDY DESIGN: Ten women recruited to the study were given mifepristone 5 mg beginning 15 days after initiation of menses. In Group A, five women were administered mifepristone every day for three cycles; in Group B, five women were administered mifepristone every other day for three cycles. The effects on the menstrual cycle and endometrial development were investigated. RESULTS: Following these treatments with mifepristone 5 mg, there was slight suppression of ovulation in both treatment cycles compared with control cycles. The follicular phase in subsequent cycles was prolonged after daily treatment with mifepristone, which was not observed after administration every other day. In addition, continuous treatment increased progesterone receptor (PR) expression and reduced leukemia inhibitory factor (LIF) expression in the endometrial epithelium. CONCLUSION: Treatment with low dose mifepristone every day or every other day starting 15 days after initiation of menses retards endometrial development and impairs endometrial receptivity but has minor effects on the menstrual cycle. PMID- 21664513 TI - Attitudes and prescribing patterns of extended-cycle oral contraceptives. AB - BACKGROUND: The survey was conducted to assess attitudes and patterns of health care providers (HCPs) prescribing extended regimen oral contraceptives (OCs). STUDY DESIGN: A prospective, anonymous, written survey that assessed attitudes and prescribed preferences of extended-cycle OCs was distributed at six educational conferences. RESULTS: An estimated 90% of the conference attendees participated in the survey. Of the 799 HCPs surveyed, 92% have recommended extended-cycle regimens with ob/gyn practitioners most likely to recommend their use (p<.05). The most commonly prescribed extended regimen remains an 84-day active pill cycle followed by a 7-day hormone-free interval (49%). The majority of HCPs (73.5%) continue to prescribe OCs which induce monthly withdrawal bleeds as their most common regimen. CONCLUSION: While HCPs appear to be recommending extended OC regimens more often, monthly cyclic regimens are the most commonly prescribed. PMID- 21664514 TI - Predictors of intimate partner violence in women seeking medication abortion. AB - BACKGROUND: High rates of intimate partner violence (IPV) have been reported among women seeking surgical abortion. Women seeking medication abortion differ from surgical abortion patients on many measures. The rate of IPV among medication abortion patients is unknown. STUDY DESIGN: The Modified Abuse Assessment Questionnaire was administered to 1128 women at enrollment into a prospective, multicenter medication abortion trial. RESULTS: Twenty-three percent of subjects reported ever experiencing IPV. Women reporting IPV were significantly more likely to be white and less likely to be married. They were more likely to have had previous spontaneous and induced abortions, and were more likely to incorrectly estimate their gestational age (GA). CONCLUSION: The rate of IPV in this study was similar to the background US rate. Few demographic variables are predictive of IPV among women seeking medication abortion. Gynecologic variables associated with IPV are consistent with less control over reproductive health. PMID- 21664515 TI - Premenstrual dysphoric disorder symptom cluster improvement by cycle with the combined oral contraceptive ethinylestradiol 20 mcg plus drospirenone 3 mg administered in a 24/4 regimen. AB - BACKGROUND: A combined oral contraceptive comprising ethinylestradiol (EE) 20 mcg/drospirenone 3 mg in a 24/4 regimen has been clinically shown to alleviate the symptoms associated with premenstrual dysphoric disorder (PMDD). However, previous studies did not report data according to cycle-by-cycle improvement. STUDY DESIGN: This was a subanalysis of a Phase III, double-blind, multicenter, United States-based study. Women with confirmed PMDD were randomized to EE 20 mcg/drospirenone 3 mg 24/4 or placebo for three treatment cycles. Ten of the 21 emotional and physical items on the Daily Record of Severity of Problems scale were grouped to define three symptom clusters: (a) negative emotions, (b) food cravings and (c) water retention-related symptoms. The change from baseline at each treatment cycle was compared between groups using a weighted analysis of covariance model. RESULTS: The full analysis set comprised 449 women. Daily Record of Severity of Problems scores for each symptom cluster were significantly reduced from baseline with both EE 20 mcg/drospirenone 3 mg 24/4 and placebo (p<.0001 for all). The greatest symptom improvements were achieved within the first cycle of treatment and continued throughout cycles 2 to 3. The mean between treatment difference was significant in favor of EE 20 mcg/drospirenone 3 mg 24/4 for all three symptom clusters in all three treatment cycles (p<=.0001 vs. placebo in percent change from baseline). CONCLUSION: Ethinylestradiol 20 mcg/drospirenone 3 mg 24/4 improved commonly recognizable PMDD symptom clusters relating to negative emotions, food cravings and water retention-related symptoms to a significantly greater extent than placebo during all three cycles of treatment. PMID- 21664517 TI - Contraception choices in a cohort of HIV+ women in the era of highly active antiretroviral therapy. AB - BACKGROUND: The study was conducted to determine whether increased desire for fertility coupled with increased awareness of reduction in mother-to-child HIV transmission (MTCT) with increased availability and use of highly active antiretroviral therapy (HAART) has been associated with reduction in use of tubal sterilization as a form of contraception among women infected with HIV. STUDY DESIGN: One hundred HIV+ women, 18 to 45 years of age, receiving care at university-affiliated HIV facilities between October 2008 and February 2009, were surveyed about their contraceptive knowledge and practices. We performed descriptive analysis of population characteristics to determine contraception choices and fertility desires following initiation of HAART. RESULTS: The study group was composed of women with median age of 35 years, 55% African American, 18% Caucasians, 19% Hispanic and 8% "other". Most (63%) were single; 36% were married. Contraception choices were condom 61%, injectable contraceptive 7%, pills 6% and only 3% said they used female sterilization. Thirty-four percent of respondents said that their choice of contraception was based primarily on ease of use, 19% said that their choice was primarily based on convenience and only 9% said that their choice was primarily based on provider recommendation. Desire for future childbearing increased to 19% following knowledge that MTCT can be reduced by taking antiretroviral therapy (ARV) and to 22% following initiation of ARV. CONCLUSIONS: Initiation of ARV and awareness that maternal treatment can reduce MTCT may explain lower use of female sterilization as a form of contraception among a cohort of HIV+ women in the post HAART era. PMID- 21664516 TI - A comparison of women with induced abortion, spontaneous abortion and ectopic pregnancy in Ghana. AB - BACKGROUND: Despite having one of the most liberal abortion laws in sub-Saharan Africa, complications from induced abortion are the second leading cause of maternal mortality in Ghana. STUDY DESIGN: The sample is composed of patients with pregnancy termination complications in Ghana between June and July 2008. The majority of patients report having had a spontaneous abortion (75%; n=439), while 17% (n=100) and 8% (n=46) report having had an induced abortion or an ectopic pregnancy, respectively. Factors associated with women in each of the three groups were explored using multinomial logistic regression. RESULTS: When compared to women with spontaneous abortions, women with induced abortions were younger, poorer, more likely to report no religious affiliation, less likely to be married, more likely to report making the household decisions and more likely to fail to disclose this pregnancy to their partners. Within the induced abortion subsample, failure to disclose the most recent pregnancy was associated with already having children and autonomous household decision making. CONCLUSION: Identifying the individual and relationship characteristics of induced abortion patients is the first step toward targeted policies and programs aimed at reducing unsafe abortion in Ghana. PMID- 21664518 TI - Evaluation of reversible contraceptive activities of Cuminum cyminum in male albino rats. AB - BACKGROUND: The aim of the present study was to evaluate the contraceptive efficacy of Cuminum cyminum (jeera) seeds in male albino rats. STUDY DESIGN: C. cyminum methanol extract (CcMtE) at dose levels of 100 and 200 mg/rat/day was orally administered to male rats for 60 days. The effect of the treatment on reproductive organs and fertility was investigated. Recovery and toxicity studies were also carried out. RESULTS: C. cyminum methanol extract fed to male rats for 60 days did not cause any alterations in the body weight, whereas the weight of testes, epididymides, seminal vesicles and ventral prostate were significantly reduced (p<=.001). Animals treated with CcMtE showed a marked reduction in sperm density in the cauda epididymis and testes and sperm motility in the cauda epididymis. Reduction in fertility was 69.0% and 76.0% in 100 and 200 mg/rat/day dose levels, respectively. The circulatory hormones were also reduced significantly. Testicular biochemical analysis of protein, sialic acid, glycogen, ascorbic acid and fructose indicated a marked decline, whereas testicular cholesterol content was significantly increased, which showed altered biochemistry of the reproductive organs. After CcMtE treatment, significant decreases (p<=.001) were observed in the number of testicular cells (i.e., spermatogonia, primary spermatocytes [preleptotene and pachytene], secondary spermatocytes and round spermatids); nonsignificant change was observed in the Sertoli cell count. The treatment had no effect on levels of serum protein, cholesterol, bilirubin, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea and hematological indices. CONCLUSIONS: The present study shows that C. cyminum treatment resulted in the inhibition of spermatogenesis and fertility without producing apparent toxic effects. PMID- 21664519 TI - Time to trim the loose ends of the tailstring debate. PMID- 21664521 TI - Family planning methods in peripartum cardiomyopathy. PMID- 21664523 TI - Does bupivacaine in laparoscopic ports not reduce postsurgery pain in tubal ligation? PMID- 21664525 TI - Acute disseminated encephalomyelitis and its place amongst other acute inflammatory demyelinating CNS disorders. AB - The diagnosis of acute inflammatory demyelinating CNS conditions is complex and this is reflected in variations in how cohorts are defined across studies. For some conditions the diagnosis relies on whether it is monophasic or relapsing, in others the anatomical site of inflammation is used as a means of categorisation. Clinical features such as precipitants, gender and age may affect the probability of certain diagnoses, but are not highly accurate. Exclusive features for the pathology are identifiable for some but not all conditions, and are seldom available during life. Specific markers such as antibodies are informative and new developments in this area are likely in the near future. This review outlines the features and classification of acute disseminated encephalomyelitis and contrasts it with other related conditions before attempting to define a pragmatic organisation of these conditions based upon present evidence. PMID- 21664526 TI - Technology and the evolution of clinical methods for stuttering. AB - The World Wide Web (WWW) was 20 years old last year. Enormous amounts of information about stuttering are now available to anyone who can access the Internet. Compared to 20 years ago, people who stutter and their families can now make more informed choices about speech-language interventions, from a distance. Blogs and chat rooms provide opportunities for people who stutter to share their experiences from a distance and to support one another. New technologies are also being adopted into speech-language pathology practice and service delivery. Telehealth is an exciting development as it means that treatment can now be made available to many rural and remotely located people who previously did not have access to it. Possible future technological developments for speech-language pathology practice include Internet based treatments and the use of Virtual Reality. Having speech and CBT treatments for stuttering available on the Internet would greatly increase their accessibility. Second Life also has exciting possibilities for people who stutter. EDUCATIONAL OBJECTIVES: The reader will (1) explain how people who stutter and their families can get information about stuttering from the World Wide Web, (2) discuss how new technologies have been applied in speech-language pathology practice, and (3) summarize the principles and practice of telehealth delivery of services for people who stutter and their families. PMID- 21664527 TI - Stuttering severity and educational attainment. AB - PURPOSE: This study investigated the relationship between self-reported stuttering severity ratings and educational attainment. METHOD: Participants were 147 adults seeking treatment for stuttering. At pretreatment assessment, each participant reported the highest educational level they had attained and rated their typical and worst stuttering severity on a 9-point scale for a range of speaking situations. These included: (1) talking with a family member, (2) talking with a familiar person, not a family member, (3) talking in a group of people, (4) talking with a stranger, (5) talking with an authority figure such as a work manager or teacher, (6) talking on the telephone, (7) ordering food or drink, and (8) giving their name and address. RESULTS: There was a significant negative relationship between highest educational achievement and mean self reported stuttering severity rating for the eight situations. CONCLUSIONS: Future research is needed to investigate how this result should be addressed in educational institutions. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe the negative effects of stuttering through childhood to adulthood; (2) identify some of the negative consequences associated with stuttering on peer and teacher relationships, and academic performance at school; and (3) summarise the relationship between stuttering severity and educational attainment. PMID- 21664529 TI - Changing adolescent attitudes toward stuttering. AB - PURPOSE: Live oral or recorded video presentations on stuttering were delivered to high school students in order to determine the extent to which their attitudes toward stuttering could be improved. METHODS: A classroom teacher administered the Public Opinion Survey of Human Attributes-Stuttering (POSHA-S) to two health classes before and after an oral live presentation by a person who stutters. She also gave the POSHA-S to two other similar classes before and after a True Life((r)): I Stutter video presentation. The stuttering person in the oral condition was one of three people featured in the video. Also, following the video condition, students filled out the POSHA-S a third time after a short oral presentation by the same person who stutters. RESULTS: Measured attitudes improved overall on the POSHA-S and on selected items. CONCLUSIONS: High school students hold similar attitudes toward stuttering and stutterers as adults, and these attitudes can be improved, at least temporarily, by a presentation on stuttering but more via a live presentation than a professionally prepared video. EDUCATIONAL OBJECTIVES: (1) The reader will identify different ways to improve attitudes toward stuttering in high school students. (2) The reader will list advantages and disadvantages of live oral presentations and recorded video presentations as strategies to change attitudes toward stuttering. (3) The reader will identify characteristics of a speaker that can assist in attitude changes of high school students. PMID- 21664528 TI - Systematic studies of modified vocalization: speech production changes during a variation of metronomic speech in persons who do and do not stutter. AB - The most common way to induce fluency using rhythm requires persons who stutter to speak one syllable or one word to each beat of a metronome, but stuttering can also be eliminated when the stimulus is of a particular duration (e.g., 1 second [s]). The present study examined stuttering frequency, speech production changes, and speech naturalness during rhythmic speech that alternated 1s of reading with 1s of silence. A repeated-measures design was used to compare data obtained during a control reading condition and during rhythmic reading in 10 persons who stutter (PWS) and 10 normally fluent controls. Ratings for speech naturalness were also gathered from naive listeners. Results showed that mean vowel duration increased significantly, and the percentage of short phonated intervals decreased significantly, for both groups from the control to the experimental condition. Mean phonated interval length increased significantly for the fluent controls. Mean speech naturalness ratings during the experimental condition were approximately "7" on a 1-9 scale (1=highly natural; 9=highly unnatural), and these ratings were significantly correlated with vowel duration and phonated intervals for PWS. The findings indicate that PWS may be altering vocal fold vibration duration to obtain fluency during this rhythmic speech style, and that vocal fold vibration duration may have an impact on speech naturalness during rhythmic speech. Future investigations should examine speech production changes and speech naturalness during variations of this rhythmic condition. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe changes (from a control reading condition) in speech production variables when alternating between 1s of reading and 1s of silence, (2) describe which rhythmic conditions have been found to sound and feel the most natural, (3) describe methodological issues for studies about alterations in speech production variables during fluency-inducing conditions, and (4) describe which fluency-inducing conditions have been shown to involve a reduction in short phonated intervals. PMID- 21664530 TI - Mindfulness training in stuttering therapy: a tutorial for speech-language pathologists. AB - The use of mindfulness training for increasing psychological well-being in a variety of clinical and nonclinical populations has exploded over the last decade. In the area of stuttering, it has been widely recognized that effective long-term management often necessitates treatment of cognitive and affective dimensions of the disorder in addition to behavioral components. Yet, mindfulness based strategies and their possible usefulness in stuttering management have not been described in detail in the literature. This article seeks to engage professionals who treat stuttering in a conversation about the possible usefulness of incorporating mindfulness training into stuttering management. A review of the literature reveals that there is a substantial overlap between what is required for effective stuttering management and the benefits provided by mindfulness practices. Mindfulness practice results in decreased avoidance, increased emotional regulation, and acceptance in addition to improved sensory perceptual processing and attentional regulation skills. These skills are important for successful long-term stuttering management on both psychosocial and sensory-motor levels. It is concluded that the integration of mindfulness training and stuttering treatment appears practical and worthy of exploration. Mindfulness strategies adapted for people who stutter may help in the management of cognitive, affective, and behavioral challenges associated with stuttering. EDUCATIONAL OBJECTIVES: Readers should be able to: (1) describe what mindfulness is and how it is cultivated; (2) identify the benefits that can be produced from mindfulness practice; (3) summarize how the benefits of mindfulness practice parallel what is often required for effective long-term stuttering management; and (4) identify specific mindfulness techniques that can be taught in stuttering therapy and explain their rationale. PMID- 21664531 TI - Stuttering treatment control using P300 event-related potentials. AB - Positron emission tomography studies during speech have indicated a failure to show the normal activation of auditory cortical areas in stuttering individuals. In the present study, P300 event-related potentials were used to investigate possible effects of behavioral treatment on the pattern of signal amplitude and latency between waves. In order to compare variations in P300 measurements, a control group paired by age and gender to the group of stutterers, was included in the study. Findings suggest that the group of stutterers presented a significant decrease in stuttering severity after the fluency treatment program. Regarding P300 measurements, stutterers and their controls presented results within normal limits in all testing situations and no significant statistical variations between pre and post treatment testing. When comparing individual results between the testing situations, stutterers presented a higher average decrease in wave latency for the right ear following treatment. The results are discussed in light of previous P300 event-related potentials and functional imaging studies with stuttering adults. EDUCATIONAL OBJECTIVES: The reader will learn about and be able to describe the: (1) use of P300 event-related potentials in the study of stuttering; (2) differences between stuttering and non-stuttering adults; and (3) effects of behavioral fluency treatment on cerebral activity in stuttering speakers. PMID- 21664532 TI - Regulatory and Metabolic Networks for Amino Acid Production by Corynebacterium glutamicum. PMID- 21664533 TI - Disinfection: is it time to reconsider Spaulding? AB - The Spaulding classification, originally proposed in 1957, is a widely used system for matching the disinfection and sterilization of surfaces, particularly those of re-usable medical/surgical devices, with available processes. It presents a ranking, from simple disinfection through to sterilization, that should be considered in the reprocessing of devices, based on the risks associated with their use, ranging from 'critical' (presenting a high risk), through 'semi-critical' to 'non-critical' (presenting a low risk). The different levels of disinfection are based on demonstrating antimicrobial activity against established marker micro-organisms representing a range of pathogens. Although this classification system is probably as valid today as it was in 1957, the understanding of microbiology and micro-organisms has changed. This article discusses some examples of disinfection studies with viruses, bacteria, protozoa and prions that challenge the current definitions and expectations of high-, intermediate- and low-level disinfection. In many of these examples, the test micro-organisms demonstrate atypical tolerance or resistance profiles to disinfection processes. In addition to laboratory-based studies, there is now clinical evidence for at least some of these micro-organisms that biocide resistance can lead to infection outbreaks due to unexpected disinfection failure. These reports should encourage the reader to challenge current dogma, and reconsider the expectations of disinfection and sterilization practices. PMID- 21664534 TI - Comparative biocidal activity of peracetic acid, benzalkonium chloride and ortho phthalaldehyde on 77 bacterial strains. AB - Despite numerous reports on biocide activities, it is often difficult to have a reliable and relevant overview of bacterial resistance to disinfectants because each work challenges a limited number of strains and tested methods are often different. The aim of this study was to evaluate the bactericidal activity of three different disinfectants commonly used in industrial or medical environments (peracetic acid, benzalkonium chloride and ortho-phthalaldehyde) against 77 bacterial strains from different origins using one standard test method (NF EN 1040). Results highlight the existence of high interspecific variability of resistance to disinfectants and, contrary to widespread belief, Gram-positive strains generally appeared more resistant than Gram-negative strains. Resistance was also variable among strains of the same species such as Bacillus subtilis to peracetic acid, Pseudomonas aeruginosa to benzalkonium chloride and Staphylococcus aureus to ortho-phthalaldehyde. PMID- 21664535 TI - Letter to the editor concerning Fritsche et al. Prevention of medication overuse in patients with migraine. Pain 2010;151:404-13. PMID- 21664538 TI - Coadsorption of lithium and oxygen on W(1 1 2): nanosized facets versus single crystals. AB - Coadsorption of lithium and oxygen on a nanosized W-tip is studied using field ion appearance energy spectroscopy (FIAES). Binding energies of coadsorbed Li adatoms are derived locally for chosen atomic sites on (1 1 2) facets for different oxygen and Li-coverages. Independently, the binding energies of Li adatoms in coadsorbed Li/oxygen layers are determined for macroscopic W(1 1 2) single crystal samples from the adsorption isobars in adsorption-desorption equilibrium experiments and compared with the local nm-scale measurements. The comparison reveals a very good agreement of results obtained by two different methods on differing length scales. PMID- 21664539 TI - Macroscopic electrical field distribution and field-induced surface stresses of needle-shaped field emitters. AB - One major concern since the development of the field ion microscope is the mechanical strength of the specimens. The macroscopic shape of the imaging tip greatly influences field-induced stresses and there is merit in further study of this phenomenon from a classical perspective. Understanding the geometrical, as opposed to localized electronic, factors that affect the stress might improve the quality and success rate of atom probe experiments. This study uses macroscopic electrostatic principles and finite element modelling to investigate field induced stresses in relation to the shape of the tip. Three two-dimensional idealized models are considered, namely hyperbolic, parabolic and sphere-on orthogonal-cone; the shapes of which are compared to experimental tips prepared by electro-polishing. Three dimensional morphologies of both a nano-porous and single-crystal aluminium tip are measured using electron tomography to quantitatively test the assumption of cylindrical symmetry for electro-polished tips. The porous tip was prepared and studied to demonstrate a fragile specimen for which such finite element studies could determine potential mechanical failure, prior to any exhaustive atom probe investigation. PMID- 21664540 TI - Measurement of z-direction component of electron spins field-emitted from a single-crystal magnetite whisker. AB - A 90 degrees sector type spin rotator was developed for measurement of the z direction component of a spin polarization, which is parallel to the emitter axis. The rotator enables us to measure all components of electron spins field emitted from a single crystalline magnetite. In-plane component of spin polarization dominated of field-emitted electrons from single crystalline magnetite whisker, thus it is suggested that the magnetization of the magnetite whisker results from the anisotropy of crystalline structure rather than its shape. PMID- 21664541 TI - The influence of voxel size on atom probe tomography data. AB - A methodology for determining the optimal voxel size for phase thresholding in nanostructured materials was developed using an atom simulator and a model system of a fixed two-phase composition and volume fraction. The voxel size range was banded by the atom count within each voxel. Some voxel edge lengths were found to be too large, resulting in an averaging of compositional fluctuations; others were too small with concomitant decreases in the signal-to-noise ratio for phase identification. The simulated methodology was then applied to the more complex experimentally determined data set collected from a (Co(0.95)Fe(0.05))(88)Zr(6)Hf(1)B(4)Cu(1) two-phase nanocomposite alloy to validate the approach. In this alloy, Zr and Hf segregated to an intergranular amorphous phase while Fe preferentially segregated to a crystalline phase during the isothermal annealing step that promoted primary crystallization. The atom probe data analysis of the volume fraction was compared to transmission electron microscopy (TEM) dark-field imaging analysis and a lever rule analysis of the volume fraction within the amorphous and crystalline phases of the ribbon. PMID- 21664542 TI - Detecting density variations and nanovoids. AB - A combination of simulated and experimental data has been used to investigate the size range of nanovoids that can be detected in atom probe tomography data. Simulated atom probe tomography data have revealed that nanovoids as small as 1 nm in diameter can be detected in atom probe tomography data with the use of iso density surfaces. Iso-density surfaces may be used to quantify the size, morphology and number density of nanovoids and other variations in density in atom probe tomography data. Experimental data from an aluminum-yttrium-iron metallic glass ribbon have revealed the effectiveness of this approach. Combining iso-density surfaces with atom maps also permits the segregation of solute to the nanovoids to be investigated. Field ion microscopy and thin section atom maps have also been used to detect pores and larger voids. PMID- 21664543 TI - APT analysis of WC-Co based cemented carbides. AB - A method for quickly producing sharp and site-specific atom probe specimens from WC-Co based cemented carbides was developed using a combination of electropolishing, controlled back-polishing and FIB milling. Also, a method for measuring the amount of segregated atoms to an interface between two phases with a big difference in field needed for field evaporation was developed. Using atom probe tomography, the interface chemistry of WC/WC grain boundaries, WC/(M,W)C phase boundaries and WC/binder phase boundaries was analysed. In addition, the transition metal solubility in WC was determined. PMID- 21664544 TI - Quantitative APT analysis of Ti(C,N). AB - A specially produced Ti(C,N) standard material, with a known nominal composition, was investigated with laser assisted atom probe tomography. The occurrence of molecular ions and single/multiple events was found to be influenced by the laser pulse energy, and especially C related events were affected. Primarily two issues were considered when the composition of Ti(C,N) was determined. The first one is connected to detector efficiency, due to the detector dead-time. The second one is connected to peak overlap in the mass spectrum. A method is proposed for quantification of the C content in order to establish the C/N ratio. A correction was made to the major C peaks, C at 6 and 12 Da, with the (13)C isotopes, at 6.5 and 13 Da, according to the known natural abundance. In addition, a correction of the peak at 24 Da, where C and Ti overlap, is proposed based on the occurrence of single/multiple events for respective element. The results were compared to the results from other techniques such as electron energy loss spectroscopy, chemical analysis and X-ray diffraction. After applying the corrections, atom probe tomography results were satisfactory. Furthermore, the content of dissolved O in Ti(C,N) was successfully quantified. PMID- 21664545 TI - Time evolution of morphology in mechanically alloyed Fe-Cu. AB - Being widely accessible as well as already utilised in many applications, Fe-Cu acts as an ideal binary model alloy to elaborate the enforced nonequilibrium enhanced solubility in such a solution system that shows a limited regime of miscibility and characterised by a large positive heat of mixing. In addition to the detailed analysis of ball milled Fe-Cu powders by means of Atom Probe Tomography (APT), site specific structural analysis has been performed in this study using Transmission Electron Microscopy (TEM). In this contribution results on powders with low Cu concentrations (2.5-10 at%) are presented. Combining a ductile element (Cu, fcc) and a brittle one (Fe, bcc), striking differences in morphology were expected and found on all length-scales, depending on the mixing ratio of the two elements. However, not only could the atomic mixing of Fe and Cu be evaluated, but also the distribution of impurities, mostly stemming from the fabrication procedure. The combination of APT and TEM enables a correlation between the structural evolution and the chemical mixing during the milling process. For the first time, a clear distinction can be drawn between the morphological evolution at the surface and in the interior of the powder particles. This became possible owing to the site specific sample preparation of TEM lamellae by Focussed Ion Beam (FIB). Surprisingly, the texture arising from the ball milling process can directly be related to the classical rolling texture of cold rolled Fe. In addition, full homogeneity can be achieved even on the nano scale for this material as shown by APT, resulting in an extended miscibility region in comparison to the equilibrium phase diagram. Grain sizes were determined by means of XRD and TEM. The strain corrected XRD results are in very good agreement with the values derived by TEM, both confirming a truly nanocrystalline structure. PMID- 21664547 TI - Introduction to the special issue in honor of Regents' Prof. John C.H. Spence in occasion of his 65th birthday. PMID- 21664548 TI - Mask-assisted deterministic phase-amplitude retrieval from a single far-field intensity diffraction pattern: two experimental proofs of principle using visible light. AB - We recently developed a simple closed-form algorithm, which allows one to reconstruct the complex scalar wavefield at the exit surface of a sample, from the intensity of its far-field coherent diffraction pattern which is obtained in the presence of a suitable object-plane mask. In the first variant of this algorithm, the sample is contained within a uniformly illuminated sharp rectangular aperture in which at least one transverse dimension is at least twice that of the object. In the second variant, the sample is uniformly illuminated and is transversely displaced from an opaque rectangular mask in the object plane. For both variants, the far-field diffraction pattern is first Fourier transformed and then differentiated with respect to both transverse coordinates, in order to deterministically yield a series of independent reconstructions of the sample. Here we give an experimental demonstration of each of these two variants of our technique, using visible light. PMID- 21664549 TI - A new approach to structure amplitude determination from 3-beam convergent beam electron diffraction patterns. AB - The intensity distribution in three-beam CBED patterns from centrosymmetric crystals can be inverted analytically to enable the direct measurement of crystal structure amplitudes and three-phase invariants. The accuracy of the measurements depends upon the accuracy and precision with which specific loci within the discs can be identified. The present work exploits the equivalence in form of the intensity distribution along these loci to provide an algorithm for their automated location, enabling the rapid and unequivocal identification of their position. Moreover, it demonstrates how the loci can be used to determine directly the relative magnitudes of structure amplitudes with superior accuracy and without recourse to complex pattern-matching calculations. PMID- 21664550 TI - A holographic biprism as a perfect energy filter? AB - It has often been stated that a holographic biprism represents a near perfect energy filter and only elastically scattered electrons can participate in the interference fringes. This is based on the assumption that the reference wave does not contain inelastically scattered electrons. In this letter we show that this is not exactly true because of the delocalised inelastic interaction of the reference wave with the sample. We experimentally and theoretically show that inelastic scattering plays a role in the fringe formation, but it is shown that this contribution is small and can usually be neglected in practice. PMID- 21664551 TI - Persistent misconceptions about incoherence in electron microscopy. AB - Incoherence in electron microscopic imaging occurs when during the observation the microscope and the object are subject to fluctuations. In order to speed up the computer simulation of the images, approximations are used that are considered as valid. In this paper we will question the validity of these approximations and show that in specific cases they can lead to erroneous results. It is shown in particular in the case of one single vibrating atom that the thermal diffuse scattering that causes the signal in HAADF STEM is not only dependent on Z but also on the mean square displacement of the atom so that it can even be large for light atoms in soft matter, provided the right HAADF aperture is used. In HREM imaging the diffuse scattering leaks out of the coherent (elastic) wave and is redistributed in the background. This might explain the mismatch in elastic contrast (Stobbs factor) especially for crystals with a thickness beyond the extinction distance, where also the HAADF signal saturates and the elastic (coherent) component vanishes. PMID- 21664552 TI - Applying an information transmission approach to extract valence electron information from reconstructed exit waves. AB - The knowledge of the valence electron distribution is essential for understanding the properties of materials. However this information is difficult to obtain from HREM images because it is easily obscured by the large scattering contribution of core electrons and by the strong dynamical scattering process. In order to develop a sensitive method to extract the information of valence electrons, we have used an information transmission approach to describe the electron interaction with the object. The scattered electron wave is decomposed in a set of basic functions, which are the eigen functions of the Hamiltonian of the projected electrostatic object potential. Each basic function behaves as a communication channel that transfers the information of the object with its own transmission characteristic. By properly combining the components of the different channels, it is possible to design a scheme to extract the information of valence electron distribution from a series of exit waves. The method is described theoretically and demonstrated by means of computer simulations. PMID- 21664553 TI - REPRINT OF: Aberration measurement in HRTEM: Implementation and diagnostic use of numerical procedures for the highly precise recognition of diffractogram patterns. AB - The precise characterisation of the instrumental imaging properties in the form of aberration parameters constitutes an almost universal necessity in quantitative HRTEM, and is underlying most hardware and software techniques established in this field. We focus in this paper on the numerical analysis of individual diffractograms as a first preparatory step for further publications on HRTEM aberration measurement. The extraction of the defocus and the 2-fold astigmatism from a diffractogram is a classical pattern recognition problem, which we believe to have solved in a near-optimum way concerning precision, speed, and robustness. The newly gained measurement precision allows us to resolve fluctuations of the defocus and the 2-fold astigmatism and to assess thereby the optical stability of electron microscopes. Quantitative stability criteria are elaborated, which may serve as helpful guidelines for daily work as well as for microscope acceptance tests. PMID- 21664554 TI - Fabrication and electric measurements of nanostructures inside transmission electron microscope. AB - Using manipulation holders specially designed for transmission electron microscope (TEM), nanostructures can be characterized, measured, modified and even fabricated in-situ. In-situ TEM techniques not only enable real-time study of structure-property relationships of materials at atomic scale, but also provide the ability to control and manipulate materials and structures at nanoscale. This review highlights in-situ electric measurements and in-situ fabrication and structure modification using manipulation holder inside TEM. PMID- 21664555 TI - Histological evaluation of patients with gastritis at high risk of developing gastric cancer using a conventional index. AB - Although gastric cancer (GCa) is strongly associated with Helicobacter pylori infection, only some H. pylori-positive subjects develop gastric cancer. The aim of this study is to identify H. pylori-positive subjects at high risk of developing GCa by assessment of the histopathological findings in the non-cancer containing mucosa of patients with and without GCa. The subjects were 35 patients with diffuse-type gastric cancer (D-GCa), 55 with intestinal-type gastric cancer (I-GCa), and 99 H. pylori-positive controls without GCa. Two specimens were taken from the greater curvature of the antrum and the middle body. Histopathological gradings were evaluated using the updated Sydney System, and the risk of GCa was evaluated using a modified Meining's gastric cancer risk index (GCRI). Among the H. pylori-positive controls, corpus gastritis was seen in 98.0% (97/99) and corpus atrophic gastritis in 78.8% (78/99). The mean GCRI for the D-GCa (5.514+/ 2.03) and I-GCa (6.836+/-2.08) groups was significantly greater than that for the H. pylori-positive controls (4.071+/-2.07; p=0.0005, p<0.0001). In addition, the mean GCRI for the I-GCa group was significantly greater than that for the D-GCa group (p<0.005). The GCRI-positive rate was significantly higher in subjects with GCa than in H. pylori-positive controls (D-GCa: p<0.005, I-GCa: p<0.0001). Many H. pylori-positive Japanese still carry a high risk for gastric cancer. However, H. pylori-positive patients at high risk of developing GCa (not only intestinal type but also diffuse-type) may be detected using a simple GCRI. PMID- 21664556 TI - Preface: a special issue on nuclear receptors with a special view on the molecular basis of disease. PMID- 21664557 TI - Ataxia is still an important clinical finding in severe high altitude illness. PMID- 21664558 TI - Plasma adipokine and hormone changes in mountaineers on ascent to 5300 meters. AB - OBJECTIVE: The current study evaluated multiple metabolic and inflammatory hormone responses in recreational climbers (7 men and 3 women, age 26-49 years) over 9 days. In particular, acylation-stimulating protein (ASP), which influences fat storage in adipose tissue, has not been measured at high altitude. METHODS: Serial measurements were taken at sea level (SL), or 353 m, on day 0, 4000 m on day 3, 4750 m on day 6, and 5300 m on day 9 of the expedition. RESULTS: Body mass index (BMI) decreased upon ascent to 5300 m from SL (SL 23.2 +/- 1.5 kg/m(2); 4000 m 23.2 +/- 1.4 kg/m(2); 4750 m 22.9 +/- 1.3 kg/m(2); 5300 m 22.3 +/- 1.2 kg/m(2); P<.001). Similarly, plasma non-esterified fatty acids and triglycerides increased, while HDL cholesterol decreased (P<.05 to <.001) from SL to 5300 m. Acylation-stimulating protein (SL 42.2 +/- 40.2 nm; 4000 m 117.0 +/- 69.6 nm; 4750 m 107.9 +/- 44.5 nm; 5300 m 82.2 +/- 20.2 nm; P=.019) and adiponectin (SL 10.4 +/- 6.5 ng/mL, 4000 m 13.9 +/- 8.5 ng/mL, 4750 m 18.3 +/- 8.3 ng/mL, 5300 m 14.7 +/- 8.0 ng/mL; P=.015) increased, as did insulin and Interleukin-6 (IL-6) levels (up to 71% and 168%, respectively; P<.05) with no change in leptin, complement C3 (C3), high sensitivity C-reactive protein (hsCRP) or cortisol levels throughout the mountain ascent from SL to 5300 m. CONCLUSION: Acylation stimulating protein and adiponectin are increased during a 9-day period of high altitude (SL to 5300 m) exposure despite weight loss in healthy mountaineers. PMID- 21664559 TI - Infectious diseases associated with caves. AB - In recent times, caving has become increasingly popular, with almost 2 million people visiting national park caves each year in the United States. Although the 2 million tourist visits are extremely low risk, smaller numbers of sport cavers are at risk for some high risk conditions, and expedition cavers are at risk for some obscure infections. Infectious diseases like histoplasmosis, rabies, leptospirosis, and tick-borne relapsing fever may be transmitted by the underground fauna. To reduce the risk of illness or injury while caving, knowledge of potential risks before engaging in this activity is important. Caving preparation needs to be carefully planned and executed, including vaccinations, prophylactic medications, and advice regarding safe conduct and behaviors. PMID- 21664560 TI - High work output combined with high ambient temperatures caused heat exhaustion in a wildland firefighter despite high fluid intake. AB - The purpose of this case study is to examine the physiological/behavioral factors leading up to heat exhaustion in a male wildland firefighter during wildland fire suppression. The participant (24 years old, 173 cm, 70 kg, and 3 years firefighting experience) experienced heat exhaustion following 7 hours of high ambient temperatures and arduous work on the fire line during the month of August. At the time of the heat-related incident (HRI), core temperature was 40.1 degrees C (104.2 degrees F) and skin temperature was 34.4 degrees C (93.9 degrees F). His work output averaged 1067 counts.min(-1) (arbitrary units for measuring activity) for the 7 hours prior to the HRI, a very high rate of work over an extended time period during wildfire suppression. In the 2.5 hours leading up to the heat incident, he was exposed to a mean ambient temperature of 44.6 degrees C (112.3 degrees F), with a maximum temperature of 59.7 degrees C (139.5 degrees F). He consumed an average of 840 mL.h(-1) in the 7 hours leading up to the incident and took an average of 24 +/- 11 drinks.h(-1) (total of 170 drinks). The combined effects of a high work rate and high ambient temperatures resulted in an elevated core temperature and a higher volume and frequency of drinking than typically seen in this population, ultimately ending in heat exhaustion and removal from the fire line. The data demonstrate that heat-related incidents can occur even with aggressive fluid intake during wildland fire suppression. PMID- 21664561 TI - Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite. AB - The Wilderness Medical Society convened an expert panel to develop a set of evidence-based guidelines for the prevention and treatment of frostbite. We present a review of pertinent pathophysiology. We then discuss primary and secondary prevention measures and therapeutic management. Recommendations are made regarding each treatment and its role in management. These recommendations are graded based on the quality of supporting evidence and balance between the benefits and risks/burdens for each modality according to methodology stipulated by the American College of Chest Physicians. PMID- 21664562 TI - High altitude ataxia--its assessment and relevance. AB - Ataxia at altitude is reviewed in relation to acute mountain sickness (AMS). The cause of ataxia occurring at altitude is unknown but may be hypoxia affecting basal ganglia and hindbrain activity. Ataxia is an important sign of high altitude cerebral edema (HACE) but is less well-established as a clinical feature of AMS. Assessment of ataxia is part of the Environmental Systems and the Lake Louise questionnaires, together with a heel-to-toe measurement. More precise measures of ataxia include the Sharpened Romberg Test (SRT) and the use of unstable platforms. Isolated ataxia at altitude may not be related to AMS or HACE. Age affects ataxia and careful baseline measurements are essential in older subjects before results at high altitude can be interpreted. Testing for ataxia needs to be standardized with sufficient learning time. Ataxia should be distinguished from weakness or fatigue occurring at altitude. Specialized tests have not been shown to be clinically important. Our results above 5000 m showed that an abnormal SRT may be specific for AMS but with relatively poor sensitivity. Wobble board results have not correlated with AMS scores consistently. Other authors using an unstable platform in a chamber and static posturography during 3 days of exposure to 4559 m also found no relationship with AMS scores. Ataxia is a common and important clinical feature of HACE but is unhelpful in the assessment of mild or even moderate AMS in the absence of an altered mental state. The simple heel-to-toe test remains a useful part of the assessment of more severe AMS bordering on HACE. PMID- 21664563 TI - The honey, the poison, the weapon. PMID- 21664565 TI - Do medical physicists have a role in case of a nuclear or radiological emergency? PMID- 21664567 TI - Secondary prevention: why does it seem to be so hard? PMID- 21664570 TI - Moving right along: how PP1 helps clear the checkpoint. AB - Spindle checkpoint silencing is crucial for cell-cycle progression, but mechanisms underlying this process remain mysterious. Two papers, one in this issue of Developmental Cell (Meadows et al., 2011) and one in Current Biology (Rosenberg et al., 2011), begin to show how phosphatase PP1-gamma connects chromosome-microtubule attachment with anaphase entry. PMID- 21664571 TI - Balancing parental contributions in plant embryonic gene activation. AB - Little is known about chromatin remodeling events immediately after fertilization. A recent report by Autran et al. (2011) in Cell now shows that chromatin regulatory pathways that silence transposable elements are responsible for global delayed activation of gene expression in the early Arabidopsis embryo. PMID- 21664572 TI - Viperin turns coat in cytomegalovirus infection. AB - Cytomegalovirus infection is associated with cytoskeletal alterations and cell swelling (cytomegaly), which have been attributed to the viral mitochondria localized inhibitor of apoptosis (vMIA) protein. In a recent issue of Science, Seo et al. (2011) showed that the antiviral host protein viperin is co-opted to function with vMIA for facilitating infection. PMID- 21664573 TI - Spindle checkpoint silencing requires association of PP1 to both Spc7 and kinesin 8 motors. AB - The spindle checkpoint is the prime cell-cycle control mechanism that ensures sister chromatids are bioriented before anaphase takes place. Aurora B kinase, the catalytic subunit of the chromosome passenger complex, both destabilizes kinetochore attachments that do not generate tension and simultaneously maintains the spindle checkpoint signal. However, it is unclear how the checkpoint is silenced following chromosome biorientation. We demonstrate that association of type 1 phosphatase (PP1(Dis2)) with both the N terminus of Spc7 and the nonmotor domains of the Klp5-Klp6 (kinesin-8) complex is necessary to counteract Aurora B kinase to efficiently silence the spindle checkpoint. The role of Klp5 and Klp6 in checkpoint silencing is specific to this class of kinesin and independent of their motor activities. These data demonstrate that at least two distinct pools of PP1, one kinetochore associated and the other motor associated, are needed to silence the spindle checkpoint. PMID- 21664574 TI - GGA3 functions as a switch to promote Met receptor recycling, essential for sustained ERK and cell migration. AB - Cells are dependent on correct sorting of activated receptor tyrosine kinases (RTKs) for the outcome of growth factor signaling. Upon activation, RTKs are coupled through the endocytic machinery for degradation or recycled to the cell surface. However, the molecular mechanisms governing RTK recycling are poorly understood. Here, we show that Golgi-localized gamma ear-containing Arf-binding protein 3 (GGA3) interacts selectively with the Met/hepatocyte growth factor RTK when stimulated, to sort it for recycling in association with "gyrating" clathrin. GGA3 loss abrogates Met recycling from a Rab4 endosomal subdomain, resulting in pronounced trafficking of Met toward degradation. Decreased Met recycling attenuates ERK activation and cell migration. Met recycling, sustained ERK activation, and migration require interaction of GGA3 with Arf6 and an unexpected association with the Crk adaptor. The data show that GGA3 defines an active recycling pathway and support a broader role for GGA3-mediated cargo selection in targeting receptors destined for recycling. PMID- 21664575 TI - Sonic hedgehog shedding results in functional activation of the solubilized protein. AB - All Hedgehog (Hh) proteins are released from producing cells despite being synthesized as N- and C-terminally lipidated, membrane-tethered molecules. Thus, a cellular mechanism is needed for Hh solubilization. We previously suggested that a disintegrin and metalloprotease (ADAM)-mediated shedding of Sonic hedgehog (ShhNp) from its lipidated N and C termini results in protein solubilization. This finding, however, seemed at odds with the established role of N-terminal palmitoylation for ShhNp signaling activity. We now resolve this paradox by showing that N-palmitoylation of ShhNp N-terminal peptides is required for their proteolytic removal during solubilization. These peptides otherwise block ShhNp zinc coordination sites required for ShhNp binding to its receptor Patched (Ptc), explaining the essential yet indirect role of N-palmitoylation for ShhNp function. We suggest a functional model in which membrane-tethered multimeric ShhNp is at least partially autoinhibited in trans but is processed into fully active, soluble multimers upon palmitoylation-dependent cleavage of inhibitory N terminal peptides. PMID- 21664576 TI - Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. AB - Secreted Hedgehog (HH) ligands signal through the canonical receptor Patched (PTCH1). However, recent studies implicate three additional HH-binding, cell surface proteins, GAS1, CDO, and BOC, as putative coreceptors for HH ligands. A central question is to what degree these coreceptors function similarly and what their collective requirement in HH signal transduction is. Here we provide evidence that GAS1, CDO, and BOC play overlapping and essential roles during HH mediated ventral neural patterning of the mammalian neural tube. Specifically, we demonstrate two important roles for these molecules: an early role in cell fate specification of multiple neural progenitors and a later role in motor neuron progenitor maintenance. Most strikingly, genetic loss-of-function experiments indicate an obligatory requirement for GAS1, CDO, and BOC in HH pathway activity in multiple tissues. PMID- 21664577 TI - Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. AB - Hedgehog (Hh) proteins regulate important developmental processes, including cell proliferation and differentiation. Although Patched acts as the main Hh receptor in Drosophila, Hh signaling absolutely requires the additional Hh-binding proteins Ihog and Boi. Here we show that, unexpectedly, cerebellar granule neuron progenitors (CGNPs) lacking Boc and Cdon, the vertebrate orthologs of Ihog and Boi, still proliferate in response to Hh. This is because in their absence, Gas1, an Hh-binding protein not present in Drosophila, mediates Hh signaling. Consistently, only CGNPs lacking all three molecules-Boc, Cdon, and Gas1-have a complete loss of Hh-dependent proliferation. In a complementary manner, we find that a mutated Hh ligand that binds Patched1 but not Boc, Cdon, or Gas1 cannot activate Hh signaling. Together, this demonstrates an absolute requirement for Boc, Cdon, and Gas1 in Hh signaling and reveals a distinct requirement for ligand binding components that distinguishes the vertebrate and invertebrate Hh receptor systems. PMID- 21664578 TI - Hedgehog activates fused through phosphorylation to elicit a full spectrum of pathway responses. AB - In flies and mammals, extracellular Hedgehog (Hh) molecules alter cell fates and proliferation by regulating the levels and activities of Ci/Gli family transcription factors. How Hh-induced activation of transmembrane Smoothened (Smo) proteins reverses Ci/Gli inhibition by Suppressor of Fused (SuFu) and kinesin family protein (Cos2/Kif7) binding partners is a major unanswered question. Here we show that the Fused (Fu) protein kinase is activated by Smo and Cos2 via Fu- and CK1-dependent phosphorylation. Activated Fu can recapitulate a full Hh response, stabilizing full-length Ci via Cos2 phosphorylation and activating full-length Ci by antagonizing Su(fu) and by other mechanisms. We propose that Smo/Cos2 interactions stimulate Fu autoactivation by concentrating Fu at the membrane. Autoactivation primes Fu for additional CK1-dependent phosphorylation, which further enhances kinase activity. In this model, Smo acts like many transmembrane receptors associated with cytoplasmic kinases, such that pathway activation is mediated by kinase oligomerization and trans phosphorylation. PMID- 21664579 TI - PDGFRbeta signaling regulates mural cell plasticity and inhibits fat development. AB - Mural cells (pericytes and vascular smooth muscle cells) provide trophic and structural support to blood vessels. Vascular smooth muscle cells alternate between a synthetic/proliferative state and a differentiated/contractile state, but the dynamic states of pericytes are poorly understood. To explore the cues that regulate mural cell differentiation and homeostasis, we have generated conditional knockin mice with activating mutations at the PDGFRbeta locus. We show that increased PDGFRbeta signaling drives cell proliferation and downregulates differentiation genes in aortic vascular smooth muscle. Increased PDGFRbeta signaling also induces a battery of immune response genes in pericytes and mesenchymal cells and inhibits differentiation of white adipocytes. Mural cells are emerging as multipotent progenitors of pathophysiological importance, and we identify PDGFRbeta signaling as an important in vivo regulator of their progenitor potential. PMID- 21664581 TI - Dynamic coordination of innate immune signaling and insulin signaling regulates systemic responses to localized DNA damage. AB - Metazoans adapt to changing environmental conditions and to harmful challenges by attenuating growth and metabolic activities systemically. Recent studies in mice and flies indicate that endocrine signaling interactions between insulin/IGF signaling (IIS) and innate immune signaling pathways are critical for this adaptation, yet the temporal and spatial hierarchy of these signaling events remains elusive. Here, we identify and characterize a program of signaling interactions that regulates the systemic response of the Drosophila larva to localized DNA damage. We provide evidence that epidermal DNA damage induces an innate immune response that is kept in check by systemic repression of IIS activity. IIS repression induces NFkappaB/Relish signaling in the fat body, which is required for recovery of IIS activity in a second phase of the systemic response to DNA damage. This systemic response to localized DNA damage thus coordinates growth and metabolic activities across tissues, ensuring growth homeostasis and survival of the animal. PMID- 21664582 TI - Inositol trisphosphate-induced Ca2+ signaling modulates auxin transport and PIN polarity. AB - The phytohormone auxin is an important determinant of plant development. Directional auxin flow within tissues depends on polar localization of PIN auxin transporters. To explore regulation of PIN-mediated auxin transport, we screened for suppressors of PIN1 overexpression (supo) and identified an inositol polyphosphate 1-phosphatase mutant (supo1), with elevated inositol trisphosphate (InsP(3)) and cytosolic Ca(2+) levels. Pharmacological and genetic increases in InsP(3) or Ca(2+) levels also suppressed the PIN1 gain-of-function phenotypes and caused defects in basal PIN localization, auxin transport and auxin-mediated development. In contrast, the reductions in InsP(3) levels and Ca(2+) signaling antagonized the effects of the supo1 mutation and disrupted preferentially apical PIN localization. InsP(3) and Ca(2+) are evolutionarily conserved second messengers involved in various cellular functions, particularly stress responses. Our findings implicate them as modifiers of cell polarity and polar auxin transport, and highlight a potential integration point through which Ca(2+) signaling-related stimuli could influence auxin-mediated development. PMID- 21664580 TI - SLIT/ROBO1 signaling suppresses mammary branching morphogenesis by limiting basal cell number. AB - In the field of breast biology, there is a growing appreciation for the "gatekeeping function" of basal cells during development and disease processes yet mechanisms regulating the generation of these cells are poorly understood. Here, we report that the proliferation of basal cells is controlled by SLIT/ROBO1 signaling and that production of these cells regulates outgrowth of mammary branches. We identify the negative regulator TGF-beta1 upstream of Robo1 and show that it induces Robo1 expression specifically in the basal layer, functioning together with SLIT2 to restrict branch formation. Loss of SLIT/ROBO1 signaling in this layer alone results in precocious branching due to a surplus of basal cells. SLIT2 limits basal cell proliferation by inhibiting canonical WNT signaling, increasing the cytoplasmic and membrane pools of beta-catenin at the expense of its nuclear pool. Together, our studies provide mechanistic insight into how specification of basal cell number influences branching morphogenesis. PMID- 21664583 TI - Perinuclear cohibin complexes maintain replicative life span via roles at distinct silent chromatin domains. AB - Heterochromatin, or silent chromatin, preferentially resides at the nuclear envelope. Telomeres and rDNA repeats are the two major perinuclear silent chromatin domains of Saccharomyces cerevisiae. The Cohibin protein complex maintains rDNA repeat stability in part through silent chromatin assembly and perinuclear rDNA anchoring. We report here a role for Cohibin at telomeres and show that functions of the complex at chromosome ends and rDNA maintain replicative life span. Cohibin binds LEM/SUN domain-containing nuclear envelope proteins and telomere-associated factors. Disruption of Cohibin or the envelope proteins abrogates telomere localization and silent chromatin assembly within subtelomeres. Loss of Cohibin limits Sir2 histone deacetylase localization to chromosome ends, disrupts subtelomeric DNA stability, and shortens life span even when rDNA repeats are stabilized. Restoring telomeric Sir2 concentration abolishes chromatin and life span defects linked to the loss of telomeric Cohibin. Our work uncovers roles for Cohibin complexes and reveals relationships between nuclear compartmentalization, chromosome stability, and aging. PMID- 21664584 TI - Gene regulation by MAPK substrate competition. AB - Developing tissues are patterned by coordinated activities of signaling systems, which can be integrated by a regulatory region of a gene that binds multiple transcription factors or by a transcription factor that is modified by multiple enzymes. Based on a combination of genetic and imaging experiments in the early Drosophila embryo, we describe a signal integration mechanism that cannot be reduced to a single gene regulatory element or a single transcription factor. This mechanism relies on an enzymatic network formed by mitogen-activated protein kinase (MAPK) and its substrates. Specifically, anteriorly localized MAPK substrates, such as Bicoid, antagonize MAPK-dependent downregulation of Capicua, a repressor that is involved in gene regulation along the dorsoventral axis of the embryo. MAPK substrate competition provides a basis for ternary interaction of the anterior, dorsoventral, and terminal patterning systems. A mathematical model of this interaction can explain gene expression patterns with both anteroposterior and dorsoventral polarities. PMID- 21664585 TI - Age, race, weight, and gender impact normative values of bone mineral density. AB - BACKGROUND: Osteoporosis and fractures represent a major public health issue. Accurate normative reference bone mineral density (BMD) values are vital for diagnosing osteoporosis. The generalizability of the T-score method across gender, race, and age in clinic decision-making has been debated. Our aim was to identify the best statistical model to derive normative BMD values in both men and women in the multiethnic United States population. METHODS: The Third National Health and Nutrition Examination Survey was used as a data source. Gender- and race/ethnicity-stratified data analyses and modeling were conducted on 9779 persons (ages 20 to 65 years) who reported no conditions or medications likely to affect bone metabolism. Sampling and design effects were addressed using STATA 10. Model comparisons were conducted by partial F tests and residual plots. RESULTS: Polynomial regression provided a statistically significant better fit than linear regression in predicting normative BMD in both men and women. Age centered polynomial models provided the best model for predicting normative BMD values. CONCLUSION: The gender- and race-specific lower limit of normal values obtained created a new classification method of low BMD, which might mitigate some of the T-score limitations in men and minority populations. PMID- 21664586 TI - Gender-specific differences in fetal cardiac troponin T in pregnancies complicated by placental insufficiency. AB - BACKGROUND: Placental insufficiency and fetal growth restriction may lead to fetal hypoxia and acidemia, which result in fetal cardiac injury. OBJECTIVE: The goal of this study was to compare the levels of fetal cardiac troponin T (cTnT) at birth and fetal Doppler parameters according to fetal gender in pregnancies complicated by placental insufficiency before 34 weeks' gestation. METHODS: Between March 2007 and November 2010, singleton pregnancies with placental insufficiency characterized by abnormal umbilical artery Doppler results were prospectively studied. All the patients delivered by cesarean section, and Doppler examinations were performed up to 48 hours before birth. Immediately after delivery, umbilical artery blood samples were obtained for fetal cTnT measurements. RESULTS: Fifty high-risk pregnant women met the study criteria. The study groups were as follows: group 1 consisted of 23 male fetuses (46%) and group 2 consisted of 27 female fetuses (54%). cTnT levels were significantly higher in the group of male fetuses (median, 0.14; range, 0.01-0.85) compared with the group of female fetuses (median, 0.05; range, 0.01-0.27) (P = 0.039). In the group of male fetuses, Doppler results of the ductus venosus assessment revealed values of pulsatility index for veins >=1.0 in 15 male fetuses (65.2%) and 9 female fetuses (33.3%) (P = 0.032). CONCLUSIONS: Fetal gender was associated with cTnT level at birth in pregnancies complicated by placental insufficiency before 34 weeks' gestation, although the Doppler findings did not support gender differences. The fetal cardiac compromise and cardiac injury may be influenced by fetal gender, suggesting differences in the cardiovascular response to fetal hypoxia. PMID- 21664587 TI - Diagnosis and referral delay in women with Parkinson's disease. AB - BACKGROUND: Gender differences in Parkinson's disease may be attributable to biological and environmental factors as well as health care-seeking behaviors and diagnosis bias. OBJECTIVE: The goal of this pilot study was to determine whether there are gender discrepancies in diagnosis and time to present to a movement disorder specialist, and to assess whether clinical and referral factors account for these differences. METHODS: We report data on diagnosis, health care-seeking patterns, and clinical features in men and women with early Parkinson's disease treated at a tertiary care center. RESULTS: A total of 109 patients with Parkinson's disease (53 women and 56 men; median age at onset, 60.3 years) were included in this study. Although men and women did not differ in time from symptom onset to first physician visit, duration from symptom onset to movement disorder specialist visit was longer in women than in men. The expected duration from onset to movement disorder specialist visit for women was 61% greater than for men in the unadjusted model (P = 0.002). CONCLUSION: There were gender differences in time to present to a movement disorder specialist in these patients with early Parkinson's disease, and further study in larger samples is warranted. PMID- 21664588 TI - Postural configuration affects the perception of earth-based space during pitch tilt. AB - This study investigates the relative contribution of body parts in the elaboration of a whole-body egocentric attraction phenomenon previously observed during earth-based judgments. This was addressed through a particular earth-based task requiring estimating the possibility of passing under a projected line, imagining a forward horizontal displacement. Different postural configurations were tested, involving whole-body tilt, trunk tilt alone or head tilt alone. Two legs positions relative to the trunk were manipulated. Results showed systematic deviations of the subjective "passability" toward the tilt, linearly related to the tilt magnitude. For each postural configuration, the egocentric influence appeared to be highly dependent on the position of trunk and head axes, whereas the legs position appeared not relevant. When compared to the whole-body tilt condition, tilting the trunk alone consistently reduced the amount of the deviation toward the tilt, whereas tilting the head alone consistently increased it. Our results suggest that several specific effects from multiple body parts can account for the global deviation of the estimates observed during whole-body tilt. Most importantly, we support that the relative contribution of the body segments could mainly depend on a reweighting process, probably based on the reliability of sensory information available for a particular postural set. PMID- 21664589 TI - Epidemiology and quality of life of patients with psoriasis in Chile. AB - BACKGROUND: Clinical characteristics of psoriasis vary between different races and climates. There are few data on Latin American and even fewer on Chilean patients with psoriasis. OBJECTIVES: To assess that clinical characteristics and quality of life (QoL) of a group of Chilean patients with psoriasis. METHODS: A cross-sectional, observational and analytic study was conducted at the Dermatology Department of the Clinical Hospital of the University of Chile between July 2006 and December 2008 applying an epidemiological and QoL-related survey to psoriatic patients. RESULTS: One hundred fifty-three patients with psoriasis were included in the study. The mean (SD) age was 42.7 (14.9) years and 60.1% of the patients were male. The most frequent disease subtype was plaque psoriasis (71.9%), followed by "guttatiform" (guttate morphology without confirmed streptococcal infection) psoriasis (17.7%). In 38.6% of patients, less than 10% of body surface area (BSA) was affected. Joint involvement was reported in 28.8% of patients. Those with early onset of disease (before 30 years of age) were more likely to have a positive family history of psoriasis. Hypertension and diabetes were present in 20.3% and 11.1% of patients, respectively. The mean Dermatology Life Quality Index was 14. Greater impact of the disease on QoL was associated with male sex, young age of onset, newly diagnosed disease, facial involvement, and widespread disease. CONCLUSION: Chilean patients with psoriasis have clinical characteristics and QoL comparable to patients in other countries. A notable difference, however, was the greater impact of psoriasis on the QoL of Chilean men compared to women. PMID- 21664590 TI - Risk of suicide and bariatric surgery. PMID- 21664592 TI - Comparison of pars plana vitrectomy with and without scleral buckle for the repair of primary rhegmatogenous retinal detachment. AB - PURPOSE: To compare pars plana vitrectomy (PPV) with combined PPV and scleral buckle (SB) for the repair of noncomplex primary rhegmatogenous retinal detachment (RRD). DESIGN: Retrospective, nonrandomized, interventional case series. METHODS: We reviewed 181 consecutive cases of vitrectomy for primary RRD at 2 major medical centers in Israel. The follow-up was at least 3 months. There were 96 eyes in the PPV group and 85 eyes in the PPV plus SB group. Main outcome measures were single-surgery anatomic success (SSAS) and final visual acuity (VA). RESULTS: SSAS was achieved in 81.3% and 87.1% in the PPV and PPV plus SB groups, respectively (P=.29). Final anatomic success rate was 98.9% and 98.8%, respectively (P=.61). Final VA was 0.41 (20/51) in the PPV group and 0.53 (20/68) in the PPV plus SB group (P=.13). The final VA was significantly better than the preoperative VA in both groups (P<.0001). In detachments caused by inferior tears, SSAS rates were 80.9% and 81.5% in the PPV and PPV plus SB groups, respectively (P=.74). In phakic eyes, SSAS rates were 92% and 87.5%, respectively, and in pseudophakic eyes, SSAS rates were 77.5% and 86.7%, respectively, in the PPV and PPV plus SB groups (P=.29). CONCLUSIONS: The reattachment rate and the final VA were similar in both groups. The addition of SB did not improve the results and was associated with slightly lower VA than with PPV alone. Tear location or lens status had no significant effect on success rates. It is likely that in eyes undergoing PPV for primary RRD, addition of a SB is not warranted. PMID- 21664593 TI - Ocular complications after anti-vascular endothelial growth factor therapy in Medicare patients with age-related macular degeneration. AB - PURPOSE: To determine longitudinal rates of ocular complications after anti vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD) in a nationally representative longitudinal sample. DESIGN: Retrospective, longitudinal case-control study. METHODS: Using the Medicare 5% claims database, diagnoses of neovascular AMD and anti-VEGF injections of ranibizumab, bevacizumab, or pegaptanib were identified from International Classification of Diseases and Current Procedural Terminology procedure codes. Six thousand one hundred fifty-four individuals undergoing anti VEGF treatment for neovascular AMD (total of 40 903 injections) were compared with 6154 matched controls with neovascular AMD who did not undergo anti-VEGF treatment. Propensity score matching was used to match individuals receiving anti VEGF injections with controls. Rates of postinjection adverse outcomes (endophthalmitis, rhegmatogenous retinal detachment, retinal tear, uveitis, and vitreous hemorrhage) were analyzed by cumulative incidence and Cox proportional hazards model to control for demographic factors and ocular comorbidities. RESULTS: At the 2-year follow-up, the rates of endophthalmitis per injection (0.09%; P<.01), uveitis (0.11%; P<.01), and vitreous hemorrhage per injection (0.23%; P < .01) were significantly higher in the anti-VEGF treatment group. With Cox proportional hazards modeling, the anti-VEGF treatment group had a 102% higher risk of severe ocular complications overall and a 4% increased risk per injection, both of which were statistically significant (P<.01). CONCLUSIONS: Rates of endophthalmitis, uveitis, and vitreous hemorrhage were higher in the group treated with anti-VEGF injection than in the control group, although these nevertheless were rare in both groups. The overall risk of severe ocular complications was significantly higher in the anti-VEGF treatment group. PMID- 21664594 TI - Long-term development of significant visual field defects in highly myopic eyes. AB - PURPOSE: To identify the characteristics that are associated significantly with visual field (VF) defects in highly myopic eyes. DESIGN: Retrospective, observational series. METHODS: The medical records of 492 eyes of 308 patients with high myopia (myopic refractive error > 8 diopters or axial length >= 26.5 mm) with a follow-up of 5 years or more were reviewed. The VFs were determined by Goldmann kinetic perimetry, and the VFs were quantified in 100 sectors within the V4 isopter. Eyes with loss of 10% or more of the sectors were classified as having significant VF defects, and a further loss of 10% or more during the follow-up period was classified as a significant progression. To avoid the influence of the posterior fundus changes resulting from the high myopia, eyes with any type of myopic macular or peripheral lesions that could cause visual field defects were excluded. RESULTS: Significant VF defects were newly developed in 13.2% of these selected highly myopic eyes during a mean follow-up +/- standard deviation of 11.6 +/- 5.5 years. The incidence of significant VF defects in myopic eyes was significantly higher in eyes with an oval optic disc than that in eyes with a round optic disc. An oval optic disc was present significantly more frequently in the myopic eyes with VF defects. Temporal and nasal VF defects were present in the same eye. Among the eyes with significant VF defect, the temporal VF defects were observed in 61.5% of the eyes with round discs, in 75.0% of the eyes with vertically oval discs, and in 68.2% of the eyes with obliquely oval discs. During a mean follow-up +/- standard deviation of 10.2 +/- 3.4 years, 73.8% of the eyes showed a significant progression of the VF defects. An abrupt change of the scleral curvature (types VII and IX staphyloma by Curtin) was the only factor significantly associated with a progression of the VF defects. CONCLUSIONS: Because the VF defects are progressive, we suggest that high myopia is a high risk factor for VF defects and that these eyes be examined at least once yearly. The combination of stretching and distortion of the optic nerve fibers resulting from an abrupt change of scleral curvature may be the factors that lead to the damage of the optic nerve fibers in highly myopic eyes. PMID- 21664595 TI - Natural course of adult-onset foveomacular vitelliform dystrophy: a spectral domain optical coherence tomography analysis. AB - PURPOSE: To describe the natural course of adult-onset foveomacular vitelliform dystrophy using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Retrospective study. METHODS: We reviewed the charts of all consecutive patients with adult-onset foveomacular vitelliform dystrophy who underwent SD-OCT at baseline and at least 12 months later (last visit). Main outcome measures were changes of clinical and SD-OCT features over time. RESULTS: Forty-six eyes (31 patients, 15 male and 16 female; mean age 74.6 +/- 8.2 years) were included. Follow-up was 16.2 +/- 6 (range, 12-30) months. Visual acuity (VA) reduced from 0.32 +/- 0.22 logMAR at baseline to 0.39 +/- 0.28 logMAR at last visit (P=.03). The stage of the disease was vitelliform in 28 eyes (60.8%), pseudohypopyon in 7 eyes (15.2%), vitelliruptive in 11 eyes (23.9%) at baseline; vitelliform in 23 eyes (50%), pseudohypopyon in 5 eyes (10.9%), vitelliruptive in 13 eyes (28.2%), and atrophic in 5 eyes (10.9%) at last visit. Stabilization of the disease stage, inner segment/outer segment (IS/OS) interface status, and lesion reflectivity on SD-OCT determined no VA changes (P>.05), while their worsening determined a reduction of VA (P=.03). In eyes that presented a progression of the disease stage, mean central macular thickness, maximal thickness of the lesion, and maximal width of the lesion showed a significant change (from 404.1 +/- 107.6 MUm to 246.1 +/- 74.0 MUm, P = .004; from 277.0 +/- 80.8 MUm to 105.3 +/- 92.3 MUm, P=.001; from 2324.2 +/- 1250.3 MUm to 1751.0 +/- 858.3 MUm, P = .04, respectively). CONCLUSIONS: In adult-onset foveomacular vitelliform dystrophy, progression of the lesion stage (partial/complete resorption of the material) is generally accompanied by IS/OS interface disruption/loss and visual impairment. PMID- 21664596 TI - Ultra-thin donor tissue preparation for endothelial keratoplasty with a double pass microkeratome. AB - PURPOSE: To quantify and describe practically a novel technique for donor tissue preparation in Descemet stripping endothelial keratoplasty to approach the superior visual outcomes of Descemet membrane endothelial keratoplasty. DESIGN: Experimental laboratory investigation. METHODS: SETTING: Institutional. STUDY POPULATION: Eleven human donor corneas. INTERVENTION: Double-pass of microkeratome over donor corneas-first with a thicker cutting depth and subsequently with a thinner cutting depth. MAIN OUTCOME MEASURES: Donor tissue profiles and residual bed thicknesses. RESULTS: After the first pass of the microkeratome, the average cut thickness using the 250-MUm cutting head was 342.5 +/- 14.8 MUm (range, 332 to 353 MUm), that using the 300-MUm head was 343.8 +/- 39.2 MUm (range, 315 to 411 MUm), and that with the 350-MUm head was 467.7 +/- 50.1 MUm (range, 419 to 519 MUm). We used the 200-MUm cutting head only once with a cut depth of 210 MUm. For the second pass, when using the 110-MUm head, the cutting depth averaged to 167.8 +/- 28.8 MUm (range, 133 to 203 MUm). The 130-MUm cutting head yielded a cut depth of 199.7 +/- 24.4 MUm (range, 180 to 227 MUm). Two corneas were perforated during the second pass. The average final thickness of the residual bed was 121 +/- 32.2 MUm (range, 52 to 160 MUm). CONCLUSIONS: Double-pass harvest for ultra-thin Descemet stripping automated endothelial keratoplasty could improve optical outcomes by obtaining donor Descemet stripping automated endothelial keratoplasty tissue with thinner residual beds. Further studies are needed with larger sample sizes to establish algorithms for appropriate cutting head thickness in each pass. Potential additional endothelial cell loss with the second pass of the microkeratome also should be evaluated. PMID- 21664597 TI - Risk factors for primary open-angle glaucoma and pseudoexfoliative glaucoma in the Thessaloniki eye study. AB - PURPOSE: To investigate risk factors for primary open-angle glaucoma (POAG) and pseudoexfoliative glaucoma (PEXG) in the Thessaloniki Eye Study. DESIGN: Cross sectional, population-based study. METHODS: Randomly selected subjects 60 years of age and older (n=2554) participated in the Thessaloniki Eye Study. Glaucomatous damage and presence of pseudoexfoliation (PEX) were defined according to specific criteria. Open-angle glaucoma (OAG) subjects were compared with nonglaucoma subjects (controls), POAG subjects were compared with controls without PEX, and PEXG subjects were compared with controls with PEX for demographic, lifestyle, ophthalmic, and systemic factors. Factors with P < .2 in the univariate analysis were retained for multivariate analyses. RESULTS: In multivariate analysis restricted to persons who participated in clinic visits and who had at least 1 phakic eye (n=2078), intraocular pressure (odds ratio [OR], 1.21 per 1 mm Hg; P<.001), PEX (OR, 2.81; P<.001), history of coronary artery bypass or vascular surgery (OR, 1.95; P=.017), and moderate-to-high myopia (>= -3 diopters; OR, 2.40; P=.009) were associated with higher odds for OAG. In analysis including all clinic visits (n=2261), age became significantly associated (OR, 1.05; P=.004). In multivariate analysis for POAG (n=1840), associations were found for age (OR, 1.04 per year; P=.048), IOP (OR, 1.19 per 1 mm Hg; P<.001), history of coronary artery bypass or vascular surgery (OR, 2.09; P=.01), and history of diabetes treated with insulin (OR, 3.05; P=.045). In multivariate analysis for PEXG (n=238), the latter was associated with increased IOP (OR, 1.25 per 1 mm Hg; P<.001). CONCLUSIONS: IOP was the only factor associated with both POAG and PEXG, whereas moderate-to-high myopia showed borderline significance in both. Vascular systemic diseases and their treatment were associated only with POAG. The implications of these differences for the pathogenesis between the 2 common types of OAG should be explored further. PMID- 21664598 TI - [Acute myocarditis complicating Mediterranean spotted fever. A case report]. AB - Mediterranean spotted fever (MSF) due to Rickettsia conorii is the most important tick-borne disease occurring in North Africa. The first description of MSF was made by Conor and Brush in 1910 in Tunisia. Clinical diagnosis relies on the association of fever, rash and inoculation's scar during summertime. Prognosis in MSF is usually good, however malignant forms were described. These forms occur in patients with comorbidities. G6PD deficiency is a classic ground for severe forms of MSF. Myocarditis is an uncommon complication in MSF; only few cases were reported in the literature. We report a new case of myocarditis complicating MSF in a 15-year-old patient with G6PD deficiency. The patient presented with fever and rash, evocative of MSF; he reported chest pain and the electrocardiogram showed ST segment elevation in anterior leads. Troponin level was elevated. Echocardiogram showed left ventricular dysfunction with 40% ejection fraction. Serologic tests confirmed R. conorii recent infection. Antibiotic treatment with vibramycine and rifadine was started. Patient also received classic treatment of myocarditis with left ventricular dysfunction associating CEI, beta-bloquers and diuretics. Evolution was favourable with complete recovery of left ventricular function. Myocarditis is an uncommon but severe complication of MSF. Early diagnosis and treatment allow favorable evolution. PMID- 21664599 TI - [Accessory pathway ablation in children: indications and results]. AB - INTRODUCTION: Radiofrequency ablation of accessory pathways (AP) has become a first-line treatment, except in young children where the indications are discussed because of radiation risks and complications of catheterization. The purpose of the study was to evaluate the indications and results of radiofrequency AP ablation in children and teenagers. METHODS: Electrophysiological study (EPS) was performed in 145 patients aged from 5 to 18 years (13.5+/-3) with a preexcitation syndrome (PS). RESULTS: AP ablation was indicated in 66 children (group 1); others represent the group I. Group I was older and less frequently asymptomatic. All children with a spontaneous malignant form had an ablation. Group 1 has a faster conduction through the AP than group 2. The induction of reentrant tachycardia (RT), atrial fibrillation and the presence of a malignant form is more common in group 1. Failures or reappearances of WPW after ablation were frequent (20, 26%) related to a younger age (15+/-3 vs 17+/-4) (<0.05). In group 2, one 18-year-old teenager with untreated RT died before ablation. Asymptomatic children are well with disappearance of PS in two. Medically treated symptomatic children are well. CONCLUSION: If spontaneous malignant forms, symptoms with drugs or practice of competitive sport are indications of AP ablation, it is recommended to wait for adolescence in other children. PMID- 21664600 TI - [Coronary embolism due to an adherent right atrium thrombus through a patent foramen ovale]. AB - This observation relates to the discovery of native coronary paradoxical embolism secondary to thrombus adherent to the right atrium through a patent foramen ovale (PFO). A patient of 64 years, with a history of mitral regurgitation not followed, was hospitalized for acute respiratory distress due to a mitral insufficiency (MI) with a ruptured chordae and pulmonary embolism. Coronary angiography was performed and revealed two typical images of coronary embolism associated to a non-atheromatous coronary tree. The patient underwent a mitral valve replacement. After the establishment of cardiopulmonary bypass, adherent fibrin and cruoric thrombus of the right atrium and a PFO were found. The analysis of the valves did not reveal any arguments for infective endocarditis. A CT scan, performed as the patient remained unconscious after surgery, showed several cerebral infarcts. Paradoxical embolism coronary was diagnosed in front of the combination of adherent thrombus in the right atrium, pulmonary embolism and systemic coronary and cerebral embolism with a PFO. Coronary embolism rarely happens. It is mainly due to three causes: iatrogenic origin in most cases, direct causes due to micro emboli, particularly from infectious endocarditis and paradoxical embolic origin. There are two types of right atrial thrombus; the most common is the mobile thrombus from the peripheral venous system. The other one, which is more rare, is the adherent thrombus, which occurs in situ. Coronary embolism of paradoxical origin represents a small proportion of the causes of coronary embolism. However, this diagnosis must be considered. PMID- 21664601 TI - Acute pericarditis after dengue fever. AB - A 63-year-old woman was admitted for acute chest pain and asthenia worsening for one week. Clinical examination was normal. ECG revealed widespread T waves depression. Echocardiography, cardiac MR-scan, biological examinations and coronary angiogram were normal except positive dengue fever serologies. She had suffered from dengue fever recently. Clinical and ECG outcomes were good under treatment. Cardiac complications are scarce in case of dengue fever. In this case report, clinical and especially ECG presentation are typical of acute pericarditis. This pericarditis is due to dengue fever. PMID- 21664602 TI - What is the origin of this arrhythmia? AB - PURPOSE: The existence of inter-atrial epicardial connections bridging the two atria at different levels has well been described and their implication in some forms of supraventricular arrhythmias is a known fact. However, up to date, little data exists in the literature showing their role in the mechanisms of focal atrial tachycardias, providing at the same time clear electroanatomical and activation maps using a three-dimensional, non-fluoroscopic mapping system. PATIENTS AND METHODS: We present the case of a 29-year-old woman with a focal atrial tachycardia with the origin in a pulmonary vein, manifested as a right atrial origin due to the conduction of the electrical impulse form the right inferior pulmonary vein (RIPV) to the postero-inferior right atrium (RA) via inter-atrial epicardial connections. Using a three-dimensional, non-fluoroscopic mapping system (CARTO, Biosense Webster), an RA activation map was created during tachycardia. RESULTS: Radiofrequency (RF) application at the earliest endocardial breakthrough site situated in the postero-inferior RA changed the right atrial depolarization sequence without terminating the arrhythmia. Subsequently, a left atrium activation map was created showing the earliest endocardial breakthrough site at the level of the RIPV ostium and RF application at this level abolished the atrial tachycardia. CONCLUSION: Inter-atrial epicardial connections can be part of the substrate of some forms of supraventricular arrhythmias. Awareness of their existence is important to the electrophysiologist, since a better understanding of transseptal activation can avoid, in some cases, unnecessary RF applications at the level of the postero-septal right atrium, with a subsequent increase in procedural risk. PMID- 21664603 TI - Effects of prismatic glasses including optometric correction on head and neck kinematics, perceived exertion and comfort during dental work in the oral cavity- a randomised controlled intervention. AB - AIM: To quantify the effects of using prismatic glasses including optometric correction, on head and neck kinematics, perceived exertion and comfort, during work in the oral cavity. METHODS: The study population consisted of forty-five participants. After a basic ergonomic education, baseline measurements of head and neck kinematics were made using inclinometers. Perceived exertion and comfort were rated by the participants. An intervention group (n = 25), selected at random from the participants, received prismatic glasses and optometric correction when needed and were compared with a control group (n = 20). Follow up assessments were made after the intervention. RESULTS: At follow up there was a reduction in both the intervention group (8.7 degrees ) and in the control group (3.6 degrees ) regarding head flexion. Neck flexion was reduced by 8.2 degrees in the intervention group and 3.3 degrees in the control group. The difference between the intervention and the control groups, i.e. the effect of the intervention, was statistically significant for both head (5.1 degrees ; p = 0.009) and neck (4.9 degrees ; p = 0.045) flexion. No effect of the intervention was seen regarding perceived exertion and comfort. CONCLUSION: The reduction in head and neck flexion achieved by the prismatic glasses is likely to reduce the risk of neck pain during dental work. The effect of the prismatic lenses could not be separated from the effect of the optometric correction. The possible effect of the ergonomic education was not evaluated. PMID- 21664604 TI - Conserved interneuron-specific ErbB4 expression in frontal cortex of rodents, monkeys, and humans: implications for schizophrenia. AB - BACKGROUND: Neuregulin-1 and ErbB4 are genetically associated with schizophrenia, and detailed knowledge of the cellular and subcellular localization of ErbB4 is important for understanding how neuregulin-1 regulates neuronal network activity and behavior. Expression of ErbB4 is restricted to interneurons in the rodent hippocampus and cortex. However, controversy remains about the cellular expression pattern in primate brain and its subcellular distribution in postsynaptic somatodendritic locations versus presynaptic terminals. METHODS: ErbB4 expression was analyzed in pyramidal cells and interneurons in the frontal cortex of five species: C57BL6 mice (n = 3), ErbB4-/- mice (n = 2), Sprague Dawley rats (n = 3), two macaque species (n = 3 + 2), and humans (normal control subjects, n = 2). We investigated 1) messenger RNA in mice, macaques, and humans; 2) protein expression in all species using highly specific monoclonal antibodies; and 3) specificity tests of several ErbB4 antibodies on brain samples (mouse, macaque, human). RESULTS: ErbB4 RNA is restricted to interneurons in the frontal cortex of mice. ErbB4 protein is undetectable in pyramidal cells of rodents, macaques, and human frontal cortex, whereas most interneurons positive for parvalbumin, calretinin, or cholecystokinin, but only a minority of calbindin positive cells, co-express ErbB4 in macaques. Importantly, no presynaptic ErbB4 expression was detected in any species. CONCLUSIONS: The interneuron-selective somatodendritic expression of ErbB4 is consistent with a primary role of neuregulin-ErbB4 signaling in the postsynaptic modulation of gamma-aminobutyric acidergic function in rodents and primates. Our data validate the use of rodents to analyze effects of abnormal ErbB4 function as a means to model endophenotypes of psychiatric disorders. PMID- 21664605 TI - Methylphenidate normalizes frontocingulate underactivation during error processing in attention-deficit/hyperactivity disorder. AB - BACKGROUND: Children with attention-deficit/hyperactivity disorder (ADHD) have deficits in performance monitoring often improved with the indirect catecholamine agonist methylphenidate (MPH). We used functional magnetic resonance imaging to investigate the effects of single-dose MPH on activation of error processing brain areas in medication-naive boys with ADHD during a stop task that elicits 50% error rates. METHODS: Twelve medication-naive boys with ADHD were scanned twice, under either a single clinical dose of MPH or placebo, in a randomized, double-blind design while they performed an individually adjusted tracking stop task, designed to elicit 50% failures. Brain activation was compared within patients under either drug condition. To test for potential normalization effects of MPH, brain activation in ADHD patients under either drug condition was compared with that of 13 healthy age-matched boys. RESULTS: During failed inhibition, boys with ADHD under placebo relative to control subjects showed reduced brain activation in performance monitoring areas of dorsomedial and left ventrolateral prefrontal cortices, thalamus, cingulate, and parietal regions. MPH, relative to placebo, upregulated activation in these brain regions within patients and normalized all activation differences between patients and control subjects. During successful inhibition, MPH normalized reduced activation observed in patients under placebo compared with control subjects in parietotemporal and cerebellar regions. CONCLUSIONS: MPH normalized brain dysfunction in medication-naive ADHD boys relative to control subjects in typical brain areas of performance monitoring, comprising left ventrolateral and dorsomedial frontal and parietal cortices. This could underlie the amelioration of MPH of attention and academic performance in ADHD. PMID- 21664606 TI - Methodology for rapid measures of glutamate release in rat brain slices using ceramic-based microelectrode arrays: basic characterization and drug pharmacology. AB - Excessive excitability or hyperexcitability of glutamate-containing neurons in the brain has been proposed as a possible explanation for anxiety, stress-induced disorders, epilepsy, and some neurodegenerative diseases. However, direct measurement of glutamate on a rapid time scale has proven to be difficult. Here we adapted enzyme-based microelectrode arrays (MEA) capable of detecting glutamate in vivo, to assess the effectiveness of hyperexcitability modulators on glutamate release in brain slices of the rat neocortex. Using glutamate oxidase coated ceramic MEAs coupled with constant voltage amperometry, we measured resting glutamate levels and synaptic overflow of glutamate after K(+) stimulation in brain slices. MEAs reproducibly detected glutamate on a second-by second time scale in the brain slice preparation after depolarization with high K(+) to evoke glutamate release. This stimulus-evoked glutamate release was robust, reproducible, and calcium dependent. The K(+)-evoked glutamate release was modulated by ligands to the alpha(2)delta subunit of voltage sensitive calcium channels (PD-0332334 and PD-0200390). Meanwhile, agonists to Group II metabotropic glutamate (mGlu) receptors (LY379268 and LY354740), which are known to alter hyperexcitability of glutamate neurons, attenuated K(+)-evoked glutamate release but did not alter resting glutamate levels. This new MEA technology provides a means of directly measuring the chemical messengers involved in glutamate neurotransmission and thereby helping to reveal the role multiple glutamatergic system components have on glutamate signaling. PMID- 21664607 TI - [One-step nucleic acid amplification (OSNA) assay for sentinel lymph node metastases as an alternative to conventional postoperative histology in breast cancer: A cost-benefit analysis]. AB - INTRODUCTION: Intraoperative molecular analysis for sentinel lymph node (SLN) metastases using the OSNA (one-step nucleic acid amplification) method has been already validated in breast cancer. The authors compared the cost of OSNA versus the conventional postoperative histopathologic evaluation in patients with breast cancer. METHODOLOGY: Patients with operable breast cancer and clinically and sonographic negative evaluation of the axilla, and who subsequently were operated on between the 15th of October 2008 and the 15th of December 2009 were included in this retrospective cost-benefit analysis. The SLN was assessed by conventional postoperative histological evaluation in Group 1 (45 patients), and by OSNA in Group 2 (35 patients). The following variables were analysed: age, tumour size, histological type, number of SLNs, biopsy result, duration of surgery, days in hospital, postoperative complications, positive lymph nodes in the case of axillary lymphadectomy, cost per patient, hospitalisation cost, and cost per operation. RESULTS: The duration of surgery of the first operation in Group 1 was significantly shorter, but the total time was also higher in this group. The mean hospital stay was longer in Group 1 (P<.001). The mean cost of the hospital stay was higher in Group 1 compared to Group 2 (P<.001), with a mean difference of 199.69 ?. The mean cost of the surgery was higher in Group 1 (P<.001), with a mean difference of 157.49 ?. The mean cost per SLN analysis was significantly higher in Group 1, with a mean difference of 162.5 ?. The cost per patient was significantly higher in Group 1 (P<.005). A mean saving of 439.67 ? per patient was achieved by using the OSNA method. CONCLUSION: Intraoperative molecular analysis for SLN metastases using the OSNA method reduces the number of admission days, duration of surgery, and achieves a saving of 439.67 ? per patient. PMID- 21664608 TI - Association between tobacco smoking and bipolar affective disorder: clinical, epidemiological, cross-sectional, retrospective study in outpatients. AB - PURPOSE: Although high rates of smoking have been reported among psychiatric patients, only a few studies examined the prevalence of smoking in bipolar disorder, and findings are inconsistent. We investigated smoking among bipolar patients. METHODS: We examined the prevalence of smoking in of 102 patients that met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for bipolar I disorder in Israel and evaluated the relationship between smoking and demographic and clinical data. RESULTS: Fifty-five of the bipolar patients (53.9%) smoked, with a rate that is 2.36 times higher than among the general population in Israel (22.8%). Significant relationships were revealed between smoking and lifetime history of alcohol dependence/abuse (P = .02), between smoking and history of drug use (P <= .01), and between smoking and age of illness onset (P = .04). LIMITATIONS: The cross-sectional nature of the study and the relatively small sample size preclude generalization of the findings. Nicotine levels were not measured; thus, the information regarding smoking was subjective. CONCLUSIONS: Bipolar patients smoke more than the general population. Bipolar patients that are moderate or heavy smokers are more likely than nonsmokers to consume alcohol and abuse psychoactive substances. Contrary to findings of previous studies, no association was found between clinical variables of bipolar patients and smoking. PMID- 21664609 TI - Protein remote homology detection based on auto-cross covariance transformation. AB - Protein remote homology detection is a critical step toward annotating its structure and function. Supervised learning algorithms such as support vector machine are currently the most accurate methods. The position-specific score matrices (PSSMs) contain wealthy information about the evolutionary relationship of proteins. However, the PSSMs often have different lengths, which are difficult to be used by machine-learning methods. In this study, a simple, fast and powerful method is presented for protein remote homology detection, which combines support vector machine with auto-cross covariance transformation. The PSSMs are converted into a series of fixed-length vectors by auto-cross covariance transformation and these vectors are then input to a support vector machine classifier for remote homology detection. The sequence-order effects can be effectively captured by this scheme. Experiments are performed on well established datasets, and the remote homology is simulated at the superfamily and the fold level, respectively. The results show that the proposed method, referred to as ACCRe, is comparable or even better than the state-of-the-art methods in terms of detection performance, and its time complexity is superior to those of other profile-based SVM methods. The auto-cross covariance transformation provides a novel way for the usage of evolutionary information, which can be widely used for protein-level studies. PMID- 21664610 TI - Simultaneous recording of electroencephalographic data in musicians playing in ensemble. AB - Here we describe a methodological approach for the simultaneous electroencephalographic (EEG) recording in musicians playing in ensemble. Four professional saxophonists wore pre-wired EEG caps (30 electrodes placed according to an augmented 10-20 system; cephalic reference and ground). Each cap was connected to a single multi-channel amplifier box [Brain Explorer (BE), EB Neuro((c))]. The four boxes converged to a single workstation equipped with a software (GALILEO NT, EB-Neuro((c))) allowing the simultaneous recording of sounds, digital trigger, and EEG-electrooculographic (EOG)-electromyographic (EMG) data, and providing a separate output file for each individual. Noteworthy, the subjects were electrically decoupled to satisfy international safety guidelines. The quality of the EEG data was confirmed by the rate of artifact free EEG epochs (about 80%) and by EEG spectral features. During the resting state, dominant EEG power density values were observed at alpha band (8-12Hz) in posterior cortex. The quality of EMG can be used to identify "on" and "off" states of the musicians' motor performance, thus potentially allowing the investigation of the relationships between EEG dynamics and different characteristics of the specific performance. During the music performance, alpha power density values decreased in amplitude in several cortical regions, whereas power density values enhanced within narrow high-frequency bands. In conclusion, the present methodological approach appeared to be suitable for simultaneous EEG recordings in musicians playing in ensemble. PMID- 21664611 TI - Tracking the impact of neuroethics. PMID- 21664612 TI - Maternal folic acid supplement intake and semen quality in Danish sons: a follow up study. AB - OBJECTIVE: To examine whether maternal folic acid supplement intake during pregnancy is related to better semen quality in male offspring. DESIGN: A follow up study. SETTING: Two major Danish municipalities, Aalborg and Odense. PATIENT(S): The study population included 347 singleton sons of mothers enrolled into the Healthy Habits for Two cohort when pregnant in 1984-87. INTERVENTION(S): Information on maternal folic acid supplement intake during pregnancy was provided by self-administered questionnaire in the 36th week of gestation. MAIN OUTCOME MEASURE(S): Semen characteristics and serum concentrations of sex hormones. RESULT(S): The distribution of semen characteristics among sons whose mothers took folic acid supplement during pregnancy (n = 88, 25%) did not differ from the distributions among those without (n = 75, 22%) or with unknown folic acid supplement intake (n = 84, 53%). On the contrary, serum levels of FSH and LH were significantly higher in the folic acid supplement group. CONCLUSION(S): The hypothesis that folic acid supplement intake during pregnancy will improve semen quality in male offspring was not corroborated by a follow-up study in young Danish men. PMID- 21664613 TI - Bicycle-related injuries requiring hospitalization in the United Arab Emirates. AB - OBJECTIVES: To study the anatomical distribution, severity, and outcome of bicycle-related injuries requiring hospitalization in Al-Ain city, United Arab Emirates in order to improve preventive measures. METHODS: All patients with bicycle-related injuries who were admitted to Al-Ain Hospital or who died after arrival were studied. Data were prospectively collected over a period of six years (October 2001-October 2007). Demography of patients, Glasgow Coma Scale (GCS), Injury Severity Score (ISS), hospital stay, and mortality were analysed. RESULTS: There were 130 patients (126 males). Mean (SD) age was 27.1 (14.5) years. 17.7% were United Arab Emirates (UAE) nationals. None of the patients was wearing a helmet. The percentage of UAE nationals of less than 15 years old was significantly higher (65.2%) than non-UAE nationals (14.3%) (p<0.0001, Fisher's Exact Test). The most common mechanism of injury for UAE nationals was falling from a bicycle (73.7%) whilst for non-UAE nationals was hitting a moving vehicle (66.7%). 96 (73.9%) patients had head and face injuries whilst 91 patients (70%) had extremity injuries. On arrival to the hospital, the median (range) ISS was 4 (1-41) and the median (range) GCS was 15 (3-15). The median (range) of total hospital stay was 4 (1-95) days. 17 patients (13.1%) were admitted to the Intensive Care Unit. Two patients died because of head injury (overall mortality was 1.5%). CONCLUSIONS: The majority of hospitalized injured cyclists in our study were low income adults using cycling as a cheap transportation method. Compulsory helmet use by bicycle riders and subsidising helmet cost should be adopted so as to reduce morbidity and mortality of bicycle-related injuries. PMID- 21664614 TI - Balloon Foley catheter compression as a treatment for intercostal vessel bleeding. PMID- 21664615 TI - Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. AB - OBJECTIVES AND DESIGN: Epidemiological studies have suggested a role of nonalcoholic fatty liver disease (NAFLD) in the development of cardiovascular disease. We evaluated liver mRNA expression of 84 genes encoding proteins involved in the atherosclerosis pathway in patients with NAFLD proven through biopsy in a case-control design, and examined the putative role of the histological disease severity in the molecular events associated with the atherogenic profile. RESULTS: Nonalcoholic steatohepatitis (NASH), when compared with simple steatosis (SS), significantly increases the expression of TGFB1 (6.8, p<0.005), angiotensin I-converting enzyme (ACE) (2.1, p<0.007), LAMA1 (2.1, p<0.007), SERPINB2 (2.1, p<0.007), CSF2 (2.5, p<0.002), IL1A (2.5, p<0.005), IL3 (2.1, p<0.007), IL4 (2.1, p<0.007), LIF (2.1, p<0.007), and MMP1 (2.1, p<0.007), and decreases the transcript levels of genes involved in the negative regulation of cell-death pathways. A post hoc analysis of liver biopsies of NASH patients who were treated with enalapril monotherapy because of arterial hypertension showed a significant association with lower fibrosis scores in comparison with untreated patients. BIRC3, a severe hypoxia-activated gene, was significantly increased in SS (8.2, p<0.004), when compared with the controls. NASH, but not SS, was also associated with a significant increase in platelet abundance of TGFB1 mRNA. Systems biology analysis revealed highly scored pathways involved in the regulation of programmed cell death, angiogenesis, and immune system, in which TGFB1 was mostly involved. CONCLUSION: NASH, but not SS, may increase atherosclerotic and cardiovascular risk by local overexpression of mediators of atherogenesis, endothelial damage, and regulators of blood pressure; this observation may have therapeutic implications, because ACE inhibitors may improve both cardiovascular outcomes and liver fibrosis. Hepatocyte hypoxia seems to have an important role in the molecular events activated by liver steatosis. PMID- 21664616 TI - Globographic visualisation of three dimensional joint angles. AB - Three different methods for describing three dimensional joint angles are commonly used in biomechanics. The joint coordinate system and Cardan/Euler angles are conceptually quite different but are known to represent the same underlying mathematics. More recently the globographic method has been suggested as an alternative and this has proved particularly attractive for the shoulder joint. All three methods can be implemented in a number of ways leading to a choice of angle definitions. Very recently Rab has demonstrated that the globographic method is equivalent to one implementation of the joint coordinate system. This paper presents a rigorous analysis of the three different methods and proves their mathematical equivalence. The well known sequence dependence of Cardan/Euler is presented as equivalent to configuration dependence of the joint coordinate system and orientation dependence of globographic angles. The precise definition of different angle sets can be easily visualised using the globographic method using analogues of longitude, latitude and surface bearings with which most users will already be familiar. The method implicitly requires one axis of the moving segment to be identified as its principal axis and this can be extremely useful in helping define the most appropriate angle set to describe the orientation of any particular joint. Using this technique different angle sets are considered to be most appropriate for different joints and examples of this for the hip, knee, ankle, pelvis and axial skeleton are outlined. PMID- 21664617 TI - In-vivo determination of 3D muscle architecture of human muscle using free hand ultrasound. AB - Muscle architecture is an important parameter affecting the muscle function. Most of the previous studies on in-vivo muscle architecture have used in 2D ultrasound. The importance of the third dimension has not been much explored due to lack of appropriate methods. DT-MRI has been used to study muscle architecture in 3D, however, due to long scan times of about 15 min DT-MRI has not been suitable to study active muscle contractions. The purpose of this study was to develop and validate methods to determine in-vivo muscle fascicle orientations in 3D using ultrasound. We have used 2D ultrasound and a 3D position tracker system to find the 3D fascicle orientation in 3D space. 2D orientations were obtained by using automated methods developed in our previous studies and we have extended these in the current study to obtain the 3D muscle fascicle orientation in 3D space. The methods were validated using the physical phantom and we found that the mean error in the measurement was less than 0.5 degrees in each of the three co-ordinate planes. These methods can be achieved with short scan times (less than 2 min for the gastrocnemii) and will thus enable future studies to quantify 3D muscle architecture during sub-maximal voluntary contractions. PMID- 21664619 TI - Mass transfer kinetics, band broadening and column efficiency. AB - Important progress was recently made in our understanding of the physico-chemical aspects of mass transfer kinetics in chromatographic columns, in methods used for accurate determination of the different contributions to the height equivalent to a theoretical plate (HETP), and in the application of these advances to the elucidation of mass transfer mechanisms in columns packed with recent chromatographic supports (sub-2 MUm fully porous particles, sub-3 MUm core-shell particles, and monoliths). The independent contributions to the HETP are longitudinal diffusion, eddy dispersion, liquid-solid mass transfer (including trans-particle or trans-skeleton mass transfer and external film mass transfer), and the contributions caused by the thermal heterogeneity of the column. The origin and importance of these contributions are investigated in depth. This work underlines the areas in which improvements are needed, an understanding of the contribution of the external film mass transfer term, a better design of HPLC instruments providing a decrease of the extra-column band broadening contributions to the apparent HETP, the development of better packing procedures giving more radially homogeneous column beds, and new packing materials having a higher thermal conductivity to eliminate the nefarious impact of heat effects in very high pressure liquid chromatography (vHPLC) and supercritical fluid chromatography (SFC). PMID- 21664618 TI - High-sensitivity capillary electrophoresis method for monitoring purine nucleoside phosphorylase and adenosine deaminase reactions by a reversed electrode polarity switching mode. AB - A simple, efficient, and highly sensitive in-line CE method was developed for the characterization and for inhibition studies of the nucleoside-metabolizing enzymes purine nucleoside phosphorylase (PNP) and adenosine deaminase (ADA) present in membrane preparations of human 1539 melanoma cells. After filling the running buffer (50 mM borate buffer, 100 mM SDS, pH 9.10) into a fused-silica capillary (50 cm effective length * 75 MUm), a large sample volume was loaded by hydrodynamic injection (5 psi, 36 s), followed by the removal of the large plug of sample matrix from the capillary using polarity switching (-20 kV). The current was monitored and the polarity was reversed when 95% of the current had been recovered. The separation of the neutral analytes (nucleosides and nucleobases) was performed by applying a voltage of 15 kV. An about 10-fold improvement of sensitivity for the five investigated analytes (adenosine, inosine, adenine, hypoxanthine, xanthine) was achieved by large-volume stacking with polarity switching when compared with CE without stacking. For inosine and adenine detection limits as low as 60 nM were achieved. To the best of our knowledge, this represents the highest sensitivity for nucleoside and nucleobase analysis using CE with UV detection reported so far. The Michaelis-Menten constants (K(m)) for PNP and ADA and the inhibition constants (K(i)) for standard inhibitors determined with the new method were consistent with literature data. PMID- 21664620 TI - Adsorption of tetracycline onto goethite in the presence of metal cations and humic substances. AB - Adsorption of tetracycline, one of the most widely used antibiotics, onto goethite was studied as a function of pH, metal cations, and humic acid (HA) over a pH range 3-10. Five background electrolyte cations (Li(+), Na(+), K(+), Ca(2+), and Mg(2+)) with a concentration of 0.01 M showed little effect on the tetracycline adsorption at the studied pH range. While the divalent heavy metal cation, Cu(2+), could significantly enhance the adsorption and higher concentration of Cu(2+), stronger adsorption was found. The results indicated that different adsorption mechanisms might be involved for the two types of cations. Background electrolyte cations hardly interfere with the interaction between tetracycline and goethite surfaces because they only form weak outer sphere surface complexes. On the contrary, Cu(2+) could enhance the adsorption via acting as a bridge ion to form goethite-Cu(2+)-tetracycline surface complex because Cu(2+) could form strong and specific inner-sphere surface complexes. HA showed different effect on the tetracycline sorption under different pH condition. The presence of HA increased tetracycline sorption dramatically under acidic condition. Results indicated that heavy metal cations and soil organic matters have great effects on the tetracycline mobility in the soil environment and eventually affect its exposure concentration and toxicity to organisms. PMID- 21664621 TI - Effect of hydrophobicity on the stability of the wetting films of water formed on gold surfaces. AB - We have developed a methodology that can be used to determine disjoining pressures (Pi) in both stable and unstable wetting films from the spatial and temporal profiles of dynamic wetting films. The results show that wetting films drain initially by the capillary pressure created by the changes in curvature at the air/water interface and subsequently by the disjoining pressure created by surface forces. The drainage rate of the film formed on a gold surface with a receding contact angle (theta(r)) of 17 degrees decreases with film thickness due to a corresponding increase in positive Pi, resulting in the formation of a stable film. The wetting film formed on a hydrophobic gold with theta(r)=81 degrees drains much faster due to the presence of negative Pi in the film, resulting in film rupture. Analysis of the experimental data using the Frumkin Derjaguin isotherm suggests that short-range hydrophobic forces are responsible for film rupture and long-range hydrophobic forces accelerate film thinning. PMID- 21664622 TI - Developmental differences in working memory: Where do they come from? AB - Several models assume that working memory development depends on age-related increases in efficiency and speed of processing. However, age-related increases in the efficiency of the mechanisms that counteract forgetting and restore memory traces may also be important. This hypothesis was tested in three experiments by manipulating both the processing duration within a working memory task and the time available to restore memory traces. Third- and sixth-grade children performed a complex span task in which they maintained series of letters while adding numbers to series of digits. When we equated processing and restoration times between ages, the developmental difference in working memory span was reduced but remained significant. However, this residual difference was eliminated when the time available to reactivate memory traces was tailored to the processing speed of each age group. This indicates that children employ active mechanisms for maintenance and restoration of memory traces that develop with age. PMID- 21664623 TI - Lack of neurologic improvement after aortic repair for acute type A aortic dissection complicated by cerebral malperfusion: predictors and association with survival. AB - BACKGROUND: Surgical treatment of acute type A aortic dissection complicated by cerebral malperfusion remains challenging. This study evaluated predictors of lack of neurologic improvement after aortic repair for acute type A dissection complicated by cerebral malperfusion and assessed relationship with survival. METHODS: We retrospectively reviewed 41 consecutive patients operated on between 1999 and 2008 for acute type A dissection complicated by cerebral malperfusion. Lack of postoperative neurologic improvement was defined as a difference between baseline and postoperative National Institutes of Health Stroke Scale scores of 3 points or less. RESULTS: Lack of neurologic improvement was seen in 15 patients (37%). Logistic regression analysis, baseline National Institutes of Health Stroke Scale score (odds ratio, 6.7; 95% confidence interval, 1.4-32.4; P = .02), and time to surgery (odds ratio, 14.6; 95% confidence interval, 2.7-8.5; P = .002) were significantly associated with lack of neurologic improvement. In receiver operating characteristic analysis, National Institutes of Health Stroke Scale score greater than 11 and time to surgery longer than 9.1 hours were best cutoffs for predicting lack of neurologic improvement. Thirty-day mortality was 14.6%. All early deaths were caused by large hemispheric infarction. Postoperative computed tomography or magnetic resonance imaging revealed cerebral infarction in 21 patients (51%). Five-year survival was significantly lower in patients without neurologic improvement (33% +/- 12% vs 84% +/- 7%, log-rank P <.001). CONCLUSIONS: Time to surgery and baseline National Institutes of Health Stroke Scale score were predictors of lack of improvement, which was associated with poor survival. PMID- 21664624 TI - Do higher-risk patients benefit from off-pump coronary artery bypass grafting? Evidence from an ecologic analysis of randomized trials. AB - OBJECTIVE: It is commonly believed that especially higher-risk patients benefit from off-pump coronary artery bypass grafting. However, analyses from several registries give different results. A common shortcoming of all those analyses is the fact that they concentrate on evidence from nonrandomized trials. METHODS: In an ecologic analysis, we included all randomized trials comparing the on- and off pump techniques until January 2011. By logistic regression, we investigated whether the effect of off-pump surgery on mortality, myocardial infarction, stroke, and atrial fibrillation is modified across the range of the 3 risk factors: age, proportion of women, and ejection fraction. RESULTS: Eighty-six studies with a total population of 9906 patients reported on at least 1 risk factor and 1 outcome. We found a superiority of the off-pump technique in patients with lower ejection fraction values for the outcomes mortality and atrial fibrillation. No effect modification was seen for the risk factors age and proportion of women. CONCLUSIONS: Our ecologic analysis of nearly 10,000 patients from 86 randomized trials found a superiority of the off-pump technique in patients with lower ejection fraction values, especially for the most valid outcome of mortality. As every ecologic analysis is prone to ecologic bias, a definite answer on the benefit of the off-pump technique in higher-risk patients can only be given by meta-analyses using individual patient data. PMID- 21664625 TI - Annular intimal tear of the aortic root misdiagnosed as aortic regurgitation. PMID- 21664626 TI - Reduction of air leaks in a canine model of pulmonary resection with a new staple line buttress. AB - OBJECTIVE: Recently, linear staplers have been used frequently in thoracic surgery; however, air leakage from the staple line is still unresolved. Various buttress materials have been developed to prevent air leakage, but performance is still not satisfactory. We are therefore developing a new material, consisting of calcium alginate nonwoven fabric covered with sodium alginate sponge. METHODS: Thirty-three beagle dogs were divided into 7 groups, and each underwent thoracotomy. Right middle lobe incision was performed with a linear stapler and 1 of the following buttress methods: group A, no buttress; group B, polyglycolic acid nonwoven fabric; group C, fibrin glue alone; group D, polyglycolic acid nonwoven fabric with fibrin glue; group E, polyglycomer sheet; group F, new alginate material; and group G, polyglycolic acid nonwoven fabric plus new alginate material. Burst pressures were measured under mechanical ventilation management. RESULTS: Burst pressures were 12.0 +/- 6.8 cm H(2)O in group A, 31.3 +/- 6.6 cm H(2)O in group B, 13.9 +/- 3.8 cm H(2)O in group C, 26.9 +/- 2.8 cm H(2)O in group D, 24.8 +/- 1.8 cm H(2)O in group E, 48.5 +/- 4.9 cm H(2)O in group F, and 54.2 +/- 12.4 cm H(2)O in group G. F and G group pressures reached the target of 40 to 50 cm H(2)O and were significantly higher than those of the 5 conventional groups (P < .0005) CONCLUSIONS: This alginate buttress should be effective for preventing air leakage during operations because it has both sealant and bolster effects working in conjunction. PMID- 21664627 TI - Impact of preoperative left ventricular function and time from infarction on the long-term benefits after intramyocardial CD133(+) bone marrow stem cell transplant. AB - OBJECTIVE: Our objective was to elucidate long-term clinical and functional effects of intramyocardial stem cell transplant and to identify patients who will show sustained benefit. METHODS: Long-term outcomes of 35 patients after intramyocardial CD133(+) bone marrow stem cell transplant during coronary artery bypass grafting were compared with those of a control group of 20 patients after coronary artery bypass grafting alone. Clinical effects were assessed with the New York Heart Association classification system and the Minnesota Living With Heart Failure questionnaire. Electrocardiography, 24-hour Holter monitoring, echocardiography, myocardial perfusion scanning, magnetic resonance imaging, and computed tomography were performed. Logistic regression analyses were used to identify prognostic factors for improvement in long-term left ventricular ejection fraction after stem cell treatment. RESULTS: The stem cell group revealed similar New York Heart Association and life quality scores to the control group. Myocardial perfusion score at the area of risk was significantly increased in the stem cell group after 36-month follow-up (P = .024 vs control). Multivariate logistic regression analysis revealed a 44-fold higher probability of at least 5% improvement in left ventricular ejection fraction for patients with preoperative left ventricular ejection fraction not greater than 40% than for patients with preoperative ejection fraction greater than 40% (P = .018). Furthermore, patients operated on between 7 and 12 weeks after myocardial infarction had a 56-fold higher chance of at least 5% improvement in left ventricular ejection fraction than patients treated later than 12 weeks after infarction (P = .023). CONCLUSIONS: Intramyocardial stem cell therapy was safe but lacked significant lasting benefits beyond 6 months in our study cohort with a limited number of patients. Preoperative left ventricular ejection fraction and time since myocardial infarction may be critical parameters for selection of patients who can benefit most from intramyocardial stem cell treatment during coronary artery bypass grafting. PMID- 21664628 TI - Effects of environmental stresses on the responses of mangrove plants to spent lubricating oil. AB - The influence of different environmental stresses, including salinity (5-350/00), tidal cycle (6/6, 12/12 and 24/24 h of high/low tidal regimes) and nutrient addition (1-6 times background nitrogen and phosphorus content) on Bruguiera gymnorrhiza and Aegiceras corniculatum grown in sediment contaminated with spent lubricating oil (7.5 L m(-2)) were investigated. The oil-treated 1-year-old mangrove seedlings subject to low (50/00) and high (350/00) salinity had significantly more reduction in growth, more release of superoxide radical (O2.-) and higher activity of superoxide dismutase (SOD) than those subject to moderate salinity (150/00). Extended flooding (24/24 h of high/low tidal regime) enhanced O2.- release and malondialdehyde (MDA) content in both oil-treated species but had little negative effects on biomass production (P>0.05) except the stem of A. corniculatum (P=0.012). The addition of nutrients had no beneficial or even posed harmful effects on the growth and cellular responses of the oil-treated seedlings. PMID- 21664629 TI - Nicotinic acid induces apolipoprotein A-I gene expression in HepG2 and Caco-2 cell lines. AB - The objective was to test the effect of nicotinic acid on apolipoprotein A-I (apo A-I) gene expression in hepatic (HepG2) and intestinal (Caco-2) cell lines. HepG2 and Caco-2 cells were treated with 0.1, 0.3, 1.0, 3.0, and 10 mmol/L of nicotinic acid; and apo A-I concentrations in conditioned media were measured with Western blots. Relative apo A-I messenger RNA (mRNA) levels, normalized to glyceraldehyde 3-phosphate dehydrogenase mRNA, were measured with quantitative real-time polymerase chain reaction method. The nicotinic acid response element in the apo A-I promoter was identified using a series of apo A-I reporter plasmids containing deletion constructs of the promoter. In other experiments, HepG2 cells were also transfected with the apo A-I reporter plasmid and the hepatocyte nuclear factors 3alpha and beta expression plasmids. The apo A-I levels in conditioned media from HepG2 cells, apo A-I mRNA levels, and apo A-I promoter activity increased significantly following treatment with 1.0, 3.0, and 10 mmol/L nicotinic acid. Nicotinic acid-induced promoter activity required a region of the apo A-I gene located between -170 and -186 base pairs. Exogenous overexpression of the hepatocyte nuclear factors 3alpha and beta had no additive effect on apo A I promoter. Apolipoprotein A-I concentrations in conditioned media and the apo A I promoter activity were also significantly increased in Caco-2 intestinal cells. Nicotinic acid may increase apo A-I protein synthesis in the liver and small intestine. Induction of apo A-I gene by nicotinic acid requires a nicotinic acid responsive element in the apo A-I promoter. PMID- 21664630 TI - Involvement of visfatin in palmitate-induced upregulation of inflammatory cytokines in hepatocytes. AB - Free fatty acids (FFAs) lead to the activation of inflammatory pathways related to the induction of insulin resistance. Visfatin is known to play a role in obesity-related metabolic diseases and inflammatory conditions. Here, the role of visfatin in FFA-induced inflammation was investigated in hepatocytes. The following factors were examined: (1) the protein and messenger RNA (mRNA) expression of visfatin in the liver tissue of insulin-resistant rats and in (2) in HepG2 cells treated with palmitate, (3) the palmitate-induced mRNA expression and protein synthesis of interleukin-6 and tumor necrosis factor-alpha in HepG2 cells transfected with visfatin-specific small interfering RNA, and (4) the expression of visfatin in HepG2 cells treated with a nuclear factor-kappaB (NF kappaB) inhibitor (SN50) and infected with Ad-IkappaBalpha. The protein and mRNA levels of visfatin were significantly higher in insulin-resistant rat liver tissue compared with the control group. Visfatin expression and protein synthesis significantly increased in HepG2 cells treated with palmitate in a time- and concentration-dependent manner. Visfatin-specific small interfering RNA significantly decreased the palmitate-induced mRNA expression and protein synthesis of interleukin-6 and tumor necrosis factor-alpha. A NF-kappaB inhibitor induced the downregulation of visfatin in HepG2 cells following treatment with palmitate. HepG2 cells infected with Ad-IkappaBalpha showed decreased expression of visfatin following treatment with palmitate. The expression of visfatin is closely associated with the expression of proinflammatory cytokines in FFA induced inflammation and is significantly decreased by NF-kappaB inhibition in HepG2 cells. Visfatin may play a role in FFA-induced inflammation in hepatocytes through the NF-kappaB pathway. PMID- 21664631 TI - Higher ratio of triglyceride to high-density lipoprotein cholesterol may predispose to diabetes mellitus: 15-year prospective study in a general population. AB - The aims of the study were to examine whether the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) could predict future diabetes mellitus (DM) in a general population during a 15-year follow-up. The data were collected in 1992 and then again in 2007 from the same group of 711 individuals. Because 24 of them were found to be diabetic in 1992, our analysis was eventually based on the usable data collected from the remaining 687 individuals (male, 58.1%). During the period 1992-2007, 74 individuals were found to have developed DM (10.8%). After adjusting the associated variables, it was found that TG and TG/HDL-C were independent DM risk factors, with the odds ratios being 1.292 (P = .047) and 1.341 (P = .010), respectively, although they were poor in their DM discriminatory power (area under the receiver operating characteristic curve, 0.662 and 0.672, respectively). Combined with other risk factors (fasting plasma glucose, waist circumference, and family history of DM), the DM discriminatory power of TG and TG/HDL-C was improved (area under the receiver operating characteristic curve, 0.764 and 0.767, respectively). The DM incidence increased with ascending risk score. Single HDL-C seems unable to predict future DM. Triglycerides and TG/HDL-C were independent DM risk factors; and of the two, TG/HDL-C was a stronger risk factor. The DM discriminatory power of TG and TG/HDL C was poor; therefore, it is recommended that they be used in combination with other risk factors. Diabetes mellitus incidence increased with ascending risk score. PMID- 21664632 TI - Hormonal appetite control is altered by shift work: a preliminary study. AB - Shift work has been associated with a higher propensity for developing nutritional problems and obesity. However, the possible changes in leptin and ghrelin (2 hormones that contribute importantly to the central regulation of food intake) concentrations in this population are poorly described. The objective of the study was to evaluate the daily concentrations of leptin, nonacylated ghrelin, and acylated ghrelin and the appetite ratings in men working different shift schedules. Daily concentrations of nonacylated ghrelin, acylated ghrelin, and leptin and appetite were measured in 3 groups of subjects: workers on fixed night shifts (n = 9), fixed early morning shifts (n = 6), and fixed day shifts (n = 7). Appetite was evaluated by a validated questionnaire. Blood samples were collected every 4 hours over the course of 24 hours for a total of 6 samples. When comparing the 3 groups, leptin concentrations at 8:00 am and 4:00 pm for those workers on the day shift were significantly lower than for those on the early morning shift; and concentrations at noon for those workers on the day shift were significantly lower than for those on the night shift. Nonacylated and acylated ghrelin concentrations were significantly lower for those workers on the early morning shift than for those on the day shift. In general, appetite was the lowest in those working the early morning shift. Shift workers on the early morning shift have lower appetites and concentrations of leptin and nonacylated and acylated ghrelin than the workers on other shifts. Further studies are required to better understand the detailed needs of these individuals. PMID- 21664633 TI - Adipose tissue depot-specific differences in adipocyte apolipoprotein E expression. AB - Important differences in gene expression have been documented in adipocytes derived from specific adipose tissue depots. We have previously documented an important role for adipocyte apolipoprotein E (apoE) in modulating adipocyte and adipose tissue triglyceride and lipoprotein metabolism. We now evaluate the endogenous expression of apoE in adipocytes isolated from unique adipose tissue depots in 4 different species. Adipocyte apoE expression is higher in subcutaneous fat compared with visceral fat in humans, mice, rats, and baboons. In baboons, evaluation of apoE expression in 5 adipose tissue depots (subcutaneous abdominal, subcutaneous gluteal, visceral, pericardial, epicardial) showed that, compared with subcutaneous abdominal adipocytes, the level of apoE expression is similar in subcutaneous gluteal, lower in visceral and pericardial, and higher in epicardial adipocytes. Consistent with previously demonstrated suppression of adipocyte apoE by adipose tissue inflammation, adipose tissue depots with lower apoE expression demonstrated greater infiltration of macrophages and an increased expression of tumor necrosis factor-alpha messenger RNA. Depot-specific differences in apoE expression were maintained after in vitro differentiation. Adipocytes isolated from depots with lower apoE expression manifested lower rates of triglyceride synthesis in the absence and presence of triglyceride-rich lipoproteins. Adenoviral-mediated increase of apoE expression in omental adipocytes increased triglyceride synthesis in these cells. Our results demonstrate significant heterogeneity in adipocyte apoE expression across adipose tissue depots in several species. Because of its role in modulating adipocyte triglyceride and lipoprotein metabolism, depot-specific differences in endogenous adipocyte apoE could have important implications for modulating the accumulation of lipid in these depots. PMID- 21664634 TI - Triterpenes and neolignans from the roots of Nannoglottis carpesioides. AB - Seven oleanane-type triterpenes and two 8-O-4'-neolignans, along with five known compounds (three 28-noroleanane-type triterpenes, one sarratane triterpene, and one neolignan), were isolated from roots of Nannoglottis carpesioides. Their structures were elucidated by spectroscopic methods, including 1D and 2D NMR, HRMS, and CD. The absolute configurations of two triterpenes were determined by experimental and calculated circular dichroism (CD) and optical rotation values. Ten compounds were evaluated for their cytotoxicity against human promyelocytic leukaemia (HL-60) and human hepatoma (Hep-G2) cells using the MTT assay. The antioxidant activities of these compounds were assessed by ABTS radical scavenging assays. Among the tested compounds, three compounds exhibited moderate radical-scavenging activity against ABTS.+, with IC50 values of 22.4, 17.4, and 23.2 MUM, respectively. PMID- 21664635 TI - Tackling men's health: a research, policy and practice perspective. PMID- 21664636 TI - Evaluation of anti-Moraxella bovis pili immunoglobulin-A in tears following intranasal vaccination of cattle. AB - Infectious bovine keratoconjunctivitis (IBK) is a highly contagious ocular disease of cattle caused by Moraxella bovis (Mb). Parenterally administered immunogens used to prevent the disease do not offer complete protection possibly because they stimulate a poor ocular mucosal secretory response, in which locally secreted immunoglobulin-A (sIgA) is one of the main components. The principal aim of this study was to evaluate by an indirect enzyme linked immunosorbent assay (ELISA), the local ocular mucosal sIgA response against Mb purified pili, produced after intranasal inoculation of experimental vaccines. Pili were adjuvanted by several different adjuvants (QuilA, Marcol Arlacel, Marcol Span, microencapsulated pili with PLGA polymers). Results were compared to sIgA response produced by adjuvant placebo inoculations and by IBK natural infection. Significantly higher anti-pili IgA response (p<0.05) was detected in calves vaccinated intranasally with pili QuilA and pili Marcol Span compared to control calves, although this specific immune response did not seem to be related to protection against Mb infection or typical IBK lesion development. PMID- 21664638 TI - Low-temperature (7 degrees C) anaerobic treatment of a trichloroethylene contaminated wastewater: microbial community development. AB - The feasibility of low-temperature (7 degrees C) anaerobic digestion for the treatment of a trichloroethylene (TCE) contaminated wastewater was investigated. Two expanded granular sludge bed (EGSB) bioreactors (R1 and R2) were employed for the mineralisation of a synthetic volatile fatty acid based wastewater at an initial organic loading rate (OLR) of 3 kg COD m(-3) d(-1), and an operating temperature of 15 degrees C. Successive reductions in OLR to 0.75 kg COD m(-3) d(-1), and operational temperature to 7 degrees C, resulted in stable bioreactor operation by day 417, with COD removal efficiency and biogas CH(4) content >= 74%, for both bioreactors. Subsequently, the influent to R1 was supplemented with increasing concentrations (10, 20, 30 mg l(-1)) of TCE, while R2 acted as a control. At an influent TCE concentration of 30 mg l(-1), although phase average TCE removal rates of 79% were recorded, a sustained decrease in R1 performance was observed, with COD removal of 6%, and % biogas CH(4) of 3% recorded on days 595 and 607, respectively. Specific methanogenic activity (SMA) assays identified a general shift from acetate- to hydrogen-mediated methanogenesis in both R1 and R2 biomass, while toxicity assays confirmed an increased sensitivity of the acetoclastic community in R1 to TCE and dichloroethylene (DCE), which contributed to acetate accumulation. Quantitative Polymerase Chain Reaction (qPCR) analysis of the methanogenic community confirmed the dominance of hydrogenotrophic methanogens in both R1 and R2, representing 71-89% of the total methanogenic population, however acetoclastic Methanosaeta were the dominant organisms, based on 16S rRNA gene clone library analysis of reactor biomass. The greatest change in the bacterial community, as demonstrated by UPGMA analysis of DGGE banding profiles, was observed in R1 biomass between days 417 and 609, although 88% similarity was retained between these sampling points. PMID- 21664637 TI - Long-distance kissing loop interactions between a 3' proximal Y-shaped structure and apical loops of 5' hairpins enhance translation of Saguaro cactus virus. AB - Circularization of cellular mRNAs is a key event prior to translation initiation. We report that efficient translation of Saguaro cactus virus (SCV) requires a 3' translational enhancer (PTE) located partially in coding sequences. Unlike a similar PTE reported in the 3' UTR of Pea enation mosaic virus that does not engage in an RNA:RNA interaction (Wang Z. et al., J. Biol. Chem. 284, 14189 14202, 2009), the SCV PTE participates in long distance RNA:RNA interactions with hairpins located in the p26 ORF and in the 5' UTR of one subgenomic RNA. At least two additional RNA:RNA interactions are also present, one of which involves the p26 initiation codon. Similar PTE can be found in six additional carmoviruses that can putatively form long-distance interactions with 5' hairpins located in comparable positions. PMID- 21664639 TI - Pesticides removal from waste water by activated carbon prepared from waste rubber tire. AB - Waste rubber tire has been used for the removal of pesticides from waste water by adsorption phenomenon. By applying successive chemical and thermal treatment, a basically cabonaceous adsorbent is prepared which has not only a higher mesopore, macropore content but also has a favorable surface chemistry. Presence of oxygen functional groups as evidenced by FTIR spectra along with excellent porous and surface properties were the driving force for good adsorption efficiency observed for the studied pesticides: methoxychlor, methyl parathion and atrazine. Batch adsorption studies revealed maximum adsorption of 112.0 mg g(-1), 104.9 mg g(-1) and 88.9 mg g(-1) for methoxychlor, atrazine and methyl parathion respectively occurring at a contact time of 60 min at pH 2 from an initial pesticide concentration of 12 mg/L. These promising results were confirmed by column experiments; thereby establishing the practicality of the developed system. Effect of various operating parameters along with equilibrium, kinetic and thermodynamic studies reveal the efficacy of the adsorbent with a higher adsorption capacity than most other adsorbents. The adsorption equilibrium data obey Langmuir model and the kinetic data were well described by the pseudo-first order model. Applicability of Bangham's equation indicates that diffusion of pesticide molecules into pores of the adsorbent mainly controls the adsorption process. Spontaneous, exothermic and random characteristics of the process are confirmed by thermodynamic studies. The developed sorbent is inexpensive in comparison to commercial carbon and has a far better efficiency for pesticide removal than most other adsorbents reported in literature. PMID- 21664640 TI - Removal of bisphenol A and 17alpha-ethinyl estradiol from landfill leachate using single-walled carbon nanotubes. AB - In this study, the adsorption of bisphenol A (BPA) and 17alpha-ethinyl estradiol (EE2) from landfill leachate onto single-walled carbon nanotubes (SWCNTs) was investigated. Different leachate solutions were prepared by altering the pH, ionic strength, and dissolved organic carbon (DOC) in the solutions to mimic the varying water conditions that occur in leachate during the various stages of waste decomposition. The youngest and oldest leachate solutions contained varying DOC and background chemistry and were represented by leachate Type A (pH = 5.0; DOC = 2500 mg/L; conductivity = 12,500 MUS/cm; [Ca(2+)] = 1200 mg/L; [Mg(2+)] = 470 mg/L) and Type E (pH = 7.5; DOC = 250 mg/L; conductivity = 3250 MUS/cm; [Ca(2+)] = 60 mg/L; [Mg(2+)] = 180 mg/L). These solutions were subsequently combined in different ratios to produce intermediate solutions, labeled B-D, to replicate time-dependent changes in leachate composition. Overall, a larger fraction of EE2 was removed as compared to BPA, consistent with its higher log K(OW) value. The total removal of BPA and EE2 decreased in older leachate solutions, with the adsorptive capacity of SWCNTs decreasing in the order of leachate Type A > Type B > Type C > Type D > Type E. An increase in the pH from 3.5 to 11 decreased the adsorption of BPA by 22% in young leachate and by 10% in old leachate. The changes in pH did not affect the adsorption of EE2 in the young leachate, but did reduce adsorption by 32% in the old leachate. Adjusting the ionic strength using Na(+) did not significantly impact adsorption, while increasing the concentration of Ca(2+) resulted in a 12% increase in the adsorption of BPA and a 19% increase in the adsorption of EE2. DOC was revealed to be the most influential parameter in this study. In the presence of hydrophilic DOC, represented by glucose in this study, adsorption of the endocrine disrupting compounds (EDCs) onto the SWCNTs was not affected. In the absence of SWCNTs, hydrophobic DOC (i.e., humic acid) adsorbed 15-20% of BPA and EE2. However, when the humic acid and SWCNTs were both present, the overall adsorptive capacity of the SWCNTs was reduced. Hydrophobic (pi-pi electron donor acceptor) interactions between the EDCs and the constituents in the leachate, as well as interactions between the SWCNTs and the EDCs, are proposed as potential adsorption mechanisms for BPA and EE2 onto SWCNTs. PMID- 21664641 TI - Geochemical and microbiological processes contributing to the transformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in contaminated aquifer material. AB - Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a potential human carcinogen, and its contamination of subsurface environments is a significant threat to public health. This study investigated abiotic and biological degradation of RDX in contaminated aquifer material. Anoxic batch systems were started with and without pre-aeration of aquifer material to distinguish initial biological RDX reduction from abiotic RDX reduction. Aerating the sediment eliminated chemical reductants in the native aquifer sediment, primarily Fe(II) sorbed to mineral surfaces. RDX (50 MUM) was completely reduced and transformed to ring cleavage products when excess concentrations (2mM) of acetate or lactate were provided as the electron donor for aerated sediment. RDX was reduced concurrently with Fe(III) when acetate was provided, while RDX, Fe(III), and sulfate were reduced simultaneously with lactate amendment. Betaproteobacteria were the dominant microorganisms associated with RDX and Fe(III)/sulfate reduction. In particular, Rhodoferax spp. increased from 21% to 35% and from 28% to 60% after biostimulation by acetate and lactate, respectively. Rarefaction analyses demonstrated that microbial diversity decreased in electron-donor-amended systems with active RDX degradation. Although significant amounts of Fe(III) and/or sulfate were reduced after biostimulation, solid-phase reactive minerals such as magnetite or ferrous sulfides were not observed, suggesting that RDX reduction in the aquifer sediment is due to Fe(II) adsorbed to solid surfaces as a result of Fe(III)-reducing microbial activity. These results suggest that both biotic and abiotic processes play an important role in RDX reduction under in situ conditions. PMID- 21664642 TI - Evaluation of the presence of drugs of abuse in tap waters. AB - A total of seventy samples of drinking water were tested for non-controlled and illicit drugs. Of these, 43 were from Spanish cities, 15 from seven other European countries, three from Japan and nine from seven different Latin American countries. The most frequently detected compounds were caffeine, nicotine, cotinine, cocaine and its metabolite benzoylecgonine, methadone and its metabolite EDDP. The mean concentrations of non-controlled drugs were: for caffeine 50 and 19 ng L(-1), in Spanish and worldwide drinking water respectively and for nicotine 13 and 19 ng L(-1). Illicit drugs were sparsely present and usually at ultratrace level (<1 ng L(-1)). For example, cocaine has mean values of 0.4 (Spain) and 0.3 ng L(-1) (worldwide), whereas for benzoylecgonine, these mean values were 0.4 and 1.8 ng L(-1), respectively. Higher concentrations of benzoylecgonine were found in Latin American samples (up to 15 ng L(-1)). No opiates were identified in any sample but the presence of methadone and EDDP was frequently detected. Total mean values for EDDP were 0.4 ng L(-1) (Spain) and 0.3 ng L(-1) (worldwide). Very few samples tested positive for amphetamines, in line with the reactivity of chlorine with these compounds. No cannabinoids, LSD, ketamine, fentanyl and PCP were detected. PMID- 21664643 TI - Reduction of selenite to red elemental selenium by moderately halotolerant Bacillus megaterium strains isolated from Bhitarkanika mangrove soil and characterization of reduced product. AB - Two Gram (+) bacterial strains, BSB6 and BSB12, showing resistance and potential for Se(IV) reduction among 26 moderately halotolerant isolates from the Bhitarkanika mangrove soil were characterized by biochemical and 16S rDNA sequence analyses. Both of them were strictly aerobic and able to grow in a wide range of pH (4-11), temperature (4-40 degrees C) and salt concentration (4-12%) having an optimum growth at 37 degrees C, pH ~7.5 and 7% salt (NaCl). The biochemical characteristics and 16S rDNA sequence analysis of BSB6 and BSB12 showed the closest phylogenetic similarity with the species Bacillus megaterium. Both the strains effectively reduced Se(IV) and complete reduction of selenite (up to 0.25 mM) was achieved within 40 h. SEM with energy dispersive X-ray and TEM analyses revealed the formation of nano size spherical selenium particles in and around the bacterial cells which were also supported by the confocal micrograph study. The UV-Vis diffuse reflectance spectra and XRD of selenium precipitates revealed that the selenium particles are in the nanometric range and crystalline in nature. These bacterial strains may be exploited further for bioremediation process of Se(IV) at relatively high salt concentrations and green synthesis of selenium nanoparticles. PMID- 21664644 TI - Determining pesticide foliar half-lives from soil half-life value: not so "cut and-dry". PMID- 21664645 TI - Toxicity of 58 substituted anilines and phenols to algae Pseudokirchneriella subcapitata and bacteria Vibrio fischeri: comparison with published data and QSARs. AB - A congeneric set of 58 substituted anilines and phenols was tested using the 72-h algal growth inhibition assay with Pseudokirchneriella subcapitata and 15-min Vibrio fischeri luminescence inhibition assay. The set contained molecules substituted with one, two or three groups chosen from -chloro, -methyl or -ethyl. For 48 compounds there was no REACH-compatible algal toxicity data available before. The experimentally obtained EC50 values (mg L(-1)) for algae ranged from 1.43 (3,4,5-trichloroaniline) to 197 (phenol) and for V. fischeri from 0.37 (2,3,5-trichlorophenol) to 491 (aniline). Only five of the tested 58 chemicals showed inhibitory effect to algae at concentrations >100 mg L(-1), i.e. could be classified as "not harmful", 32 chemicals as "harmful" (10-100 mg L(-1)) and 21 as "toxic" (1-10 mg L(-1)). The occupied para-position tended to increase toxicity whereas most of the ortho-substituted congeners were the least toxic. As a rule, the higher the number of substituents the higher the hydrophobicity and toxicity. However, in case of both assays, the compounds of similar hydrophobicity showed up to 30-fold different toxicities. There were also assay/organism dependent tendencies: phenols were more toxic than anilines in the V. fischeri assay but not in the algal test. The comparison of the experimental toxicity data to the data available from the literature as well as to QSAR predictions showed that toxicity of phenols to algae can be modeled based on hydrophobicity, whereas the toxicity of anilines to algae as well as toxicity of both anilines and phenols to V. fischeri depended on other characteristics in addition to log K(ow). PMID- 21664646 TI - Systematic analysis of proteins from different signaling pathways in the tumor center and the invasive front of colorectal cancer. AB - In colorectal cancer, the functional impact of proteins from different signaling pathways varies between tumor center and tumor front. Our objective was to identify differential protein expression profiles between the tumor center and the tumor front of colorectal cancer. Twenty proteins from different signaling pathways (epidermal growth factor receptor [EGFR], phosphorylated extracellular signal regulated kinase [pERK], receptor for hyalouronic acid mediated motility [RHAMM], Raf-1 kinase inhibitor protein [RKIP], beta-catenin, E-cadherin, phosphorylated AK transforming [pAKT], p16, p21, Ki-67, B-cell Lymphoma-2 [BCL2], vascular endothelial growth factor, apoptosis protease activating factor 1 [APAF 1], mucin1 [MUC1], ephrin B2 receptor [EphB2], matrix metalloproteinase 7 [MMP7], phosphorylated mothers against decapentaplegic 2 [pSMAD2], caudal type homeobox transcription factor 2 [CDX2], Laminin5gamma2, and mammalian sterile 20-like kinase 1 [MST1]) involved in colorectal cancer progression were studied immunohistochemically on 220 well-characterized patients using a multiple-punch tissue microarray including 437 and 430 samples from the tumor center and the invasive front, respectively. Mean expression between the tumor center and the tumor front varied statistically significantly for pSMAD2, pERK, Raf-1 kinase inhibitor protein, E-cadherin, pAKT, BCL2, vascular endothelial growth factor, EphB2, matrix metalloproteinase 7, CDX2, Laminin5gamma2, MST1, and APAF-1. Overexpression of pAKT, BCL2, vascular endothelial growth factor, APAF-1, pERK, EphB2, Raf-1 kinase inhibitor protein, CDX2, E-cadherin, MST1 (P < .001 each), and pSMAD2 (P = .002) was more frequently observed in the tumor center, whereas matrix metalloproteinase 7 and Laminin5gamma2 (P < .001 each) overexpression was associated with the invasive front. In multivariate analysis, vascular endothelial growth factor (P < .001), Raf-1 kinase inhibitor protein (P = .009), and Laminin5gamma2 (P < .001) were the most relevant proteins with the multimarker phenotypes positive/positive/negative and negative/negative/positive being most discriminating between the tumor center and the tumor front. Moreover, the combination negative/negative/positive vascular endothelial growth factor/Raf 1 kinase inhibitor protein/Laminin5gamma2 at the tumor front was associated with vascular/lymphatic invasion (P = .014), distant metastasis (P = .019), higher tumor grade (P < .001), and poorer survival (P = .05). Our findings show that, in colorectal cancer progression, vascular endothelial growth factor overexpression seems to play a role in the tumor center, whereas Laminin5gamma2-positivity combined with Raf-1 kinase inhibitor protein loss is associated with tumor invasion at the front. PMID- 21664647 TI - Intratumoral budding as a potential parameter of tumor progression in mismatch repair-proficient and mismatch repair-deficient colorectal cancer patients. AB - In colorectal cancer, tumor budding at the invasive front (peritumoral budding) is an established prognostic parameter and decreased in mismatch repair-deficient tumors. In contrast, the clinical relevance of tumor budding within the tumor center (intratumoral budding) is not yet known. The aim of the study was to determine the correlation of intratumoral budding with peritumoral budding and mismatch repair status and the prognostic impact of intratumoral budding using 2 independent patient cohorts. Following pancytokeratin staining of whole-tissue sections and multiple-punch tissue microarrays, 2 independent cohorts (group 1: n = 289; group 2: n = 222) with known mismatch repair status were investigated for intratumoral budding and peritumoral budding. In group 1, intratumoral budding was strongly correlated to peritumoral budding (r = 0.64; P < .001) and less frequent in mismatch repair-deficient versus mismatch repair-proficient cases (P = .177). Sensitivity and specificity for lymph node positivity were 72.7% and 72.1%. In mismatch repair-proficient cancers, high-grade intratumoral budding was associated with right-sided location (P = .024), advanced T stage (P = .001) and N stage pN (P < .001), vascular invasion (P = .041), infiltrating tumor margin (P = .003), and shorter survival time (P = .014). In mismatch repair-deficient cancers, high intratumoral budding was linked to higher tumor grade (P = .004), vascular invasion (P = .009), infiltrating tumor margin (P = .005), and more unfavorable survival time (P = .09). These associations were confirmed in group 2. High-grade intratumoral budding was a poor prognostic factor in univariate (P < .001) and multivariable analyses (P = .019) adjusting for T stage, N stage distant metastasis, and adjuvant therapy. These preliminary results on 511 patients show that intratumoral budding is an independent prognostic factor, supporting the future investigation of intratumoral budding in larger series of both preoperative and postoperative rectal and colon cancer specimens. PMID- 21664648 TI - Speciation, diversity, and Mode 1 technologies: the impact of variability selection. AB - Over geological timescales, organisms encounter periodic shifts in selective conditions driven by environmental change. The variability selection hypothesis suggests that increases in environmental fluctuation have led to the evolution of complex, flexible behaviours able to respond to novel and unpredictable adaptive settings. This hypothesis is tested via the framework of a single locus genetic model in which an invading 'versatilist' allele competes with two opposed specialists in a selection regime driven by a fluctuating environment, modelled initially as a sine wave and subsequently as an empirical climate curve covering the past 5 million years. Results demonstrate that generalist alleles achieve fixation in the sine wave environment, whilst versatilist alleles do so in the empirical environment, even at a range of very low fitness advantages over the basic generalist template. Variability selection is found to be a particularly strong force between approximately 2.5 and 1.2 Ma (millions of years ago). These results are discussed in relation to the spread of Oldowan lithics and the patterns of speciation and extinction documented in the hominin fossil record. It is suggested that the flexibility required for survival in a variable climatic regime may have been a stimulus to the development of the first stone tool technologies, whilst the ecological opportunities provided by heightened variability may have been a factor in prompting the hominin adaptive radiation evidenced during this period. PMID- 21664649 TI - The Roc de Marsal Neandertal child: a reassessment of its status as a deliberate burial. AB - Whether Neandertals buried their dead has considerable bearing on the debate concerning the nature of their cultural behavior. Among the claims for intentional Neandertal burial in Europe, the child from Roc de Marsal has long been one of the less contentious examples because its articulated skeleton was found in what has become widely accepted as an intentionally excavated pit. However, what is known about the context of the Roc de Marsal remains from the original descriptions, coupled with new stratigraphic, sedimentological, and archaeological data on the site from recent excavations, cast serious doubt on this interpretation. PMID- 21664650 TI - Left transperitoneal laparoscopic partial nephrectomy in the presence of a left sided inferior vena cava. AB - OBJECTIVES: To report a case and the surgical techniques of transperitoneal laparoscopic partial nephrectomy (LPN) in a patient with a small left renal mass and an aberrant left-sided inferior vena cava (IVC). METHODS: An otherwise healthy 49-year-old man with a body mass index of 23.1 kg/m(2) was diagnosed with a 5 * 6-cm mass in the left kidney. A transperitoneal LPN was performed in the presence of a left-sided IVC. The procedure was completed using standard laparoscopic instruments. The left renal vein was identified, with the gonadal vein used as an anatomic landmark. Slightly rostral to the location where the renal vein emptied into the left-sided IVC, 2 renal arteries were dissected and clamped individually using laparoscopic bulldog clamps. A standard LPN was then completed. RESULTS: The duration of the surgery was 182 minutes, and there was an estimated blood loss of 100 mL. The warm ischemic time was 31 minutes. The postoperative recovery was uneventful, and the patient was discharged to his home on postoperative day 7. A pathologic examination revealed a renal oxyphilic adenoma, which is a benign lesion. At the follow-up visits that were 1 month and 3 months after surgery, the patient was determined to be clinically healthy. CONCLUSIONS: The anomaly of a left-sided IVC is not an impediment to performing a transperitoneal LPN; however, the correct identification of the anatomical landmarks and the use of meticulous intraoperative techniques are of paramount importance during this procedure. PMID- 21664651 TI - Inclusion of erectile domain to UPOINT phenotype does not improve correlation with symptom severity in men with chronic prostatitis/chronic pelvic pain syndrome. AB - OBJECTIVE: To evaluate the addition of an erectile dysfunction (ED) domain to the UPOINT (Urinary, Psychosocial, Organ-specific, Infection, Neurologic/systemic, and Tenderness) system in our patients. The UPOINT system classifies men with chronic prostatitis/chronic pelvic pain syndrome into 6 domains. The domain number correlates with the symptom severity, and UPOINT-guided therapy has been shown to significantly improve symptoms. This was recently confirmed in a large Italian cohort, but was only true in a German cohort if an ED domain was added ("S," resulting in "UPOINTS"). METHODS: A total of 100 recent patients with chronic prostatitis/chronic pelvic pain syndrome were classified using the UPOINT system. An additional "S" domain was retrospectively added for men with bothersome ED. Symptom severity was assessed using the National Institutes of Health Chronic Prostatitis Symptom Index. RESULTS: The "S" domain was positive in 28% of the patients. A stepwise positive correlation was found between the number of positive UPOINT domains and symptom severity (Pearson r=.27, P=.006). The "S" domain reduced this correlation (Pearson r=.25, P=.01). ED had no effect on the total Chronic Prostatitis Symptom Index (24.8 vs 24.7) or on the subscores for pain (11.5 vs 11.6) or quality of life (8.8 vs 8.9). On multivariate analysis, the number of UPOINT domains was the strongest predictor of the total Chronic Prostatitis Symptom Index (relative increase 4.1, 95% confidence interval 1.5 6.7, P=.002), a relationship lost with UPOINTS (relative increase 1.0, 95% confidence interval -2.1-4.2, P=.53). CONCLUSION: In our patients, ED did not independently affect the chronic pelvic pain syndrome symptom severity or quality of life. Although ED should be elicited and appropriately treated in men with chronic prostatitis/chronic pelvic pain syndrome, our data do not support the utility of using ED as an independent UPOINT domain. PMID- 21664652 TI - Effect of renal function on urinary mineral excretion and stone composition. AB - OBJECTIVE: To determine the effect of renal function on urinary mineral stone excretion and composition of kidney stones in patients undergoing urologic intervention for nephrolithiasis. METHODS: We performed a retrospective analysis of 158 patients with 193 kidney stones who underwent endourologic intervention for nephrolithiasis. The patients were grouped by the estimated glomerular filtration rate (eGFR). The kidney stone composition and results of the 24-hour urinalysis were reported for each group. Statistical analysis was performed using the chi-square test, Kruskal-Wallis test, and analysis of variance. RESULTS: The kidney stone composition profile differed significantly between the groups, with uric acid stones associated with a lower eGFR and calcium phosphate stones associated with a greater eGFR. A lower eGFR correlated with lower urine pH, lower calcium excretion, and greater oxalate excretion. Excretion of uric acid and the body mass index did not differ between groups. CONCLUSION: Different degrees of renal function correlated with certain types of kidney stones. The urine pH was lower in patients with impaired renal function. Renal function might be an underappreciated factor that affects kidney stone composition and urinary mineral excretion. PMID- 21664653 TI - Percutaneous nephrolithotomy versus extracorporeal shock wave lithotripsy for moderate sized kidney stones. AB - OBJECTIVE: To compare the outcomes of percutaneous nephrolithotomy (PNL) and extracorporeal shock wave lithotripsy (ESWL) for moderate sized (1-2 cm) upper and middle pole renal calculi in regards to stone clearance rate, morbidity, and quality of life. METHODS: All patients diagnosed with moderate sized upper and middle pole kidney stones by computed tomography (CT) were offered enrollment. They were randomized to receive either ESWL or PNL. The SF-8 quality of life survey was administered preoperatively and at 1 week and 3 months postoperatively. Abdominal radiograph at 1 week and CT scan at 3 months were used to determine stone-free status. All complications and outcomes were recorded. RESULTS: PNL established a stone-free status of 95% and 85% at 1 week and 3 months, respectively, whereas ESWL established a stone-free status of 17% and 33% at 1 week and 3 months, respectively. Retreatment in ESWL was required in 67% of cases, with 0% retreatment in PNL. Stone location, stone density, and skin-to stone distance had no impact on stone-free rates at both visits, irrespective of procedure. Patient-reported outcomes, including overall physical and mental health status, favored a better quality of life for patients who had PNL performed. CONCLUSION: PNL more often establishes stone-free status, has a more similar complication profile, and has similar reported quality of life at 3 months when compared with ESWL for moderate-sized kidney stones. PNL should be offered as a treatment option to all patients with moderate-sized kidney stones in centers with experienced endourologists. PMID- 21664654 TI - Retroperitoneal hibernoma in a 28-year-old man. AB - Retroperitoneal hibernomas are rare, with only a handful of cases reported in the literature. These benign lesions are composed primarily of brown fat and can include varying amounts of white fat, myxoid material, and spindled cells, which makes their imaging characteristics highly variable. Here we present a series of images taken in a 28-year-old-man with pathologically confirmed retroperitoneal hibernoma. Surgical excision was undertaken and resulted in complete removal of the lesion. PMID- 21664655 TI - Variable prostate-specific antigen management patterns by nonurologist providers at a tertiary care medical center. AB - OBJECTIVES: To determine prostate-specific antigen (PSA) management patterns of nonurologist providers. Urologists are involved in the management of men's prostate health. In practice, nonurology providers are more likely to see patients in the screening setting. METHODS: Survey questions were designed to evaluate a nonurologist's approach to PSA screening. The survey instrument was distributed to physicians and physician extenders in fields of internal medicine and family practice at a tertiary-care medical center. RESULTS: Of 116 nonurologist providers, 86 (74%) completed the survey. There was variability with respect to the age at which to screen the index patient (asymptomatic white man without a prostate cancer family history): 16% initiated screening at 41-50 years of age and 77% at 51-60 years. Additionally, heterogeneity was found with regard to categorizing an elevated PSA level, with 62% of providers using an absolute PSA cutoff of >4 ng/mL and only 27% citing age-specific criteria. When diagnosing an asymptomatic man with an elevated PSA level, most providers will recheck PSA in 3-6 months (38%) or initiate a trial of empiric antibiotics (30%). Only a smaller fraction will refer the patient to a urologist (21%) or repeat PSA test immediately within 2-4 weeks (11%). CONCLUSIONS: We noted variability in PSA management patterns by nonurologists. Only 27% of providers used age-specific criteria, and almost 70% managed an elevated value by rechecking at a delayed interval or initiating a trial of antibiotics. This suggests that education might be necessary to create uniformity in PSA screening amongst nonurologists. PMID- 21664656 TI - Abnormal distribution of hDlg and PTEN in premalignant lesions and invasive cervical cancer. AB - OBJECTIVE: The aim of the present study was to evaluate differences in expression levels and localization status of PTEN, p53 and hDlg suppressor proteins in premalignant lesions and cervical cancer, and to analyze the possible correlation between them. METHODS: Expression levels (positivity/intensity) and localization (nuclear, membrane or cytoplasmic) of PTEN, hDlg and p53 were analyzed by immunohistochemistry in 43 cases with different stages of cervical intraepithelial neoplasia (CIN) and 105 invasive cervical carcinomas (ICC) (91 squamous carcinoma, 14 adenocarcinoma). Differences between proportions were evaluated. RESULTS: We found a decreased expression of PTEN in ICC that correlated with a loss of hDlg from the cell membrane. In contrast, no changes were found in p53 protein levels or localization in CIN and ICC. CONCLUSIONS: These results suggest that the abnormal expression and localization of PTEN during cervical carcinogenesis may be a consequence of modifications in the expression patterns of hDlg. PMID- 21664657 TI - Phase II trial of intraperitoneal cisplatin combined with intravenous paclitaxel in patients with ovarian, primary peritoneal and fallopian tube cancer. AB - BACKGROUND.: The objective of this study was to determine the toxicity of cisplatin-based intraperitoneal (IP)/intravenous (IV) treatment using a modified version of the IP/IV arm of GOG 172. METHODS.: Patients with stage IC-IV and recurrent ovarian cancer were treated with D1 paclitaxel (IV at 135 mg/m2, 3-h infusion) and cisplatin (IP at 50 mg/m2) and D8 cisplatin (IP at 50 mg/m2) every 21 days for 6 cycles. The primary outcome measure was completion of 6 cycles. Toxicity was assessed using the CTCAE, v.3.0 as well as subjective reporting by patients after each cycle. RESULTS.: Twenty-one patients completed 87 cycles of chemotherapy with IP cisplatin and intravenous (IV) paclitaxel. Eleven patients (52%) were able to complete all 6 cycles. Reasons for failing to complete treatment: progression of disease (n=3), grade 3-4 ototoxicity (n=2), IP port complication (n=1), grade 4 fatigue (n=1), small bowel obstruction (n=1), severe paclitaxel reaction (n=1) and one patient refused further treatment (n=1). Dose reductions of paclitaxel (135 mg/m2 to 110 mg/m2) were implemented per protocol for neutropenia (n=3) at a frequency of 3.75%. Dose delays were noted prior to 9 cycles for neutropenia (n=6), thrombocytopenia (n=1), elevated creatinine (n=1), and grade 3 rash (n=1) at a frequency of 10%. CONCLUSIONS.: Although only 52% of patients were able to complete 6 cycles of cisplatin-based IP chemotherapy, significant reductions in cisplatin-related metabolic toxicity and catheter related complications were noted. PMID- 21664658 TI - Circulating tumor cells predict progression free survival and overall survival in patients with relapsed/recurrent advanced ovarian cancer. AB - OBJECTIVE: Serial circulating tumor cell (CTC) counts have demonstrated predictive and prognostic value in patients with metastatic breast, colorectal, and prostate cancer. In a phase III study of pegylated liposomal doxorubicin (PLD) with trabectedin vs. PLD for relapsed ovarian cancer, we evaluated the correlation, if any, between numbers of CTCs and progression free survival, (PFS) and overall survival (OS). METHODS: CTCs were isolated from peripheral blood (10 mL) using the CellSearch system and reagents (Veridex). A CTC is defined as EpCAM+, cytokeratin+, CD45-, and is positive for the nuclear stain DAPI. The normal reference range for CellSearch is <2 CTC/7.5 mL of blood. Hazard ratios adjusted for known prognostic factors were estimated by Cox regression. RESULTS: Two-hundred sixteen patients had baseline CTC measurements of which 111 (51.4%) were randomized to the trabectedin+PLD arm; 143/216 patients (66.2%) were platinum-sensitive. Thirty-one of 216 patients (14.4%) had 2 or more CTCs detected prior to the start of therapy (range 2-566). Univariate Cox regression analyses indicated that patients with >=2 CTCs prior to therapy had 1.89- (p=0.003) and 2.06-fold (p=0.003) higher risk for progression and death respectively. Multivariate analyses that include baseline CA-125, platinum sensitivity status, largest diameter lesion, number of tumor lesions, ECOG PS, and tumor grade show that patients with elevated baseline CTC had 1.58- (p=0.058) and 1.54-fold (p=0.096) higher risk for progression and death respectively. CONCLUSIONS: Results from this study indicate that elevated numbers of CTCs impart an unfavorable prognosis for ovarian cancer patients. PMID- 21664659 TI - The revolving door: hospital readmissions of gynecologic oncology patients. AB - OBJECTIVE: Rehospitalization within 30 days of discharge was identified by the Obama Administration as a target for reducing health care spending. We examined readmissions to our gynecologic oncology service to determine: 1) rates of readmission, 2) indication for readmissions, 3) whether the admission was planned, and 4) costs. METHODS: IRB approval was obtained for this 5-year retrospective review (2004-2008). Gynecologic oncology patients were included if they were readmitted within 30 days of discharge at a single academic hospital. Abstracted data included: demographics, dates of hospitalizations, cancer history, indication for admission, and cost. A series of admissions was any number of admissions that occurred within 30 days of discharge. An index admission was the first admission in a series. RESULTS: In the study period, 2455 unique patients were admitted to Gynecologic Oncology. 324 unique patients (13.2%) were readmitted within 30 days, with 37 experiencing >1 series of admission. 87.3% were readmitted to Gynecologic Oncology. Within a series of admissions, patients were admitted on average 1.5 times following the index admission, up to 9 admissions. The median cost of index admission was $9820; for readmissions, $8059. The total cost of readmissions over 5 years was $6,421,733. Unplanned readmissions accounted for the majority of this cost. CONCLUSIONS: Hospital readmissions affect the cost of care, but also the quality of care delivered to our patients. When extrapolated across institutions and across the country, unplanned readmissions are a costly expenditure to patients and the health system, deserving of attention. PMID- 21664660 TI - Laparoscopic adrenalectomy for isolated adrenal metastasis from cervical squamous cell carcinoma and endometrial adenocarcinoma. PMID- 21664661 TI - Adjuvant treatment for stage IIIC endometrial cancer: options and controversies. AB - Endometrial cancer is the most common gynecologic malignancy. Locally advanced and high risk endometrial cancer encompasses a heterogeneous group of patients and optimal treatment for various sub-groups of these patients remains controversial. Stage IIIC is the most common sub-stage of patients with locally advanced endometrial carcinoma. This article reviews retrospective and prospective data of various adjuvant treatment approaches involving chemotherapy, radiation therapy, or combined modality therapy, including the recently proposed "sandwich" regimens that have yielded encouraging results. Areas of controversy are also discussed to assist clinicians in identifying the most effective adjuvant treatment regimens for patients with locally advanced disease. On-going randomized trials are briefly discussed. PMID- 21664662 TI - Relevance of gamma-glutamyltransferase--a marker for apoptotic balance--in predicting tumor stage and prognosis in cervical cancer. AB - INTRODUCTION: Recent large epidemiologic population-based studies identified gamma-glutamyltransferase (GGT) as a marker for increased cervical cancer incidence. Furthermore, high levels of GGT seem to increase the risk of progression of high-grade cervical dysplasia to invasive carcinoma. Therefore, we evaluated the association between pre-therapeutic serum GGT levels, tumor stage and prognosis in patients with cervical cancer. MATERIALS AND METHODS: In this multi-center trial, pre-therapeutic GGT levels were examined in 692 patients with cervical cancer. GGT levels were correlated with clinico-pathological parameters. Patients were assigned to previously described GGT risk groups and uni- and multivariable survival analyses were performed. RESULTS: GGT serum levels were associated with FIGO stage (p<0.0001) and age (r=0.2, p<0.0001) but not with lymph node involvement (p=0.85), and histological type (p=0.98). High-risk GGT group affiliation (p=0.01 and p<0.0001) was associated with poor disease-free and overall survival in a univariate analysis, but not in a multivariable Cox regression model (p=0.59 and p=0.171). We further investigated the association between prognosis and GGT and observed a linear correlation between GGT and prognosis. Therefore we were not able to identify a clear prognostic cut-off value for GGT in patients with cervical cancer. CONCLUSIONS: High GGT--a marker for apoptosis and cervical cancer risk--is associated with advanced tumor stage in patients with cervical cancer. PMID- 21664663 TI - Surgical cytoreduction in stage IV endometrioid endometrial carcinoma. AB - OBJECTIVE: To evaluate the role of surgical cytoreduction and the amount of residual disease in patients with newly diagnosed stage IV endometrioid endometrial carcinoma (EC). METHODS: Patients with stage IV EC of endometrioid histology who underwent surgery at our institution from 1977 to 2003 were identified. Patients with microscopic stage IV disease were excluded. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier method and compared with log-rank test. RESULTS: A total of 58 patients were identified, of which 9 (15.5%) had no gross residual (NGR) after surgery, 11 (19.0%) had residual disease <=1 cm, 32 (55.1%) had residual disease >1 cm, and 6 (10.3%) had no cytoreduction attempted. The median PFS was 11.1 months (95% CI, 9.8-12.3) and the median OS was 19.2 months (95% CI, 8.5-29.9) for the cohort. The median PFS was 40.3 months (95% CI, 0-93.9) for patients with NGR disease, 11 months (95% CI, 9.9-12.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients who did not have attempted cytoreduction (P<0.001). The median OS was 42.2 months (95% CI, not estimable) for patients with NGR disease, 19 months (95% CI, 13.9-24.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients that did not have attempted cytoreduction (P<0.001). CONCLUSION: Though stage IV endometrioid EC has a poor prognosis, surgical cytoreduction to no gross residual disease in a highly select group of patients is associated with improved survival. PMID- 21664665 TI - Cryopreservation of turkey semen by the pellet method: effects of variables such as the extender, cryoprotectant concentration, cooling time and warming temperature on sperm quality determined through principal components analysis. AB - This study was designed to identify the best pellet cryopreservation procedure for the cryosurvival of turkey semen among 192 different treatments established by variations and permutations of seven conditions used in the freezing/thawing process. These conditions were: diluent (IGGKPh, SPh or Tselutin); dilution rate (1:3 vs. 1:4); cooling time (45 vs. 60 min); dimethylacetamide (DMA) concentration as cryoprotectant (6 vs. 8%); equilibration time in DMA (1 vs. 5 min); semen drop volume (50 vs. 80 MUL) and thawing temperature (60 vs. 75 degrees C). Through principal components analysis (PCA), post-thaw sperm quality data (mobility, viability and membrane functional integrity) were reduced to a single output variable (Sperm Quality) indicating overall post-thaw semen quality. All treatments induced a significant reduction in semen quality after warming (P < 0.01), though one set of seven conditions, or treatment, was identified by PCA to generate the highest Sperm Quality score and a further five treatments yielded a score not significantly different (P > 0.05) from this best score. Although still not fulfilling the requirements for commercial application, our findings serve to identify the critical steps in turkey sperm cryopreservation that need to be assessed in future studies. PMID- 21664664 TI - In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. AB - Neurogenesis and gliogenesis continue in discrete regions of the adult mammalian brain. A fundamental question remains whether cell genesis occurs from distinct lineage-restricted progenitors or from self-renewing and multipotent neural stem cells in the adult brain. Here, we developed a genetic marking strategy for lineage tracing of individual, quiescent, and nestin-expressing radial glia-like (RGL) precursors in the adult mouse dentate gyrus. Clonal analysis identified multiple modes of RGL activation, including asymmetric and symmetric self renewal. Long-term lineage tracing in vivo revealed a significant percentage of clones that contained RGL(s), neurons, and astrocytes, indicating capacity of individual RGLs for both self-renewal and multilineage differentiation. Furthermore, conditional Pten deletion in RGLs initially promotes their activation and symmetric self-renewal but ultimately leads to terminal astrocytic differentiation and RGL depletion in the adult hippocampus. Our study identifies RGLs as self-renewing and multipotent neural stem cells and provides novel insights into in vivo properties of adult neural stem cells. PMID- 21664666 TI - Flow cytometric assessment of fresh and frozen-thawed Canada goose (Branta canadensis) semen. AB - The present study was conducted to investigate spermatozoal membrane integrity, acrosome integrity, mitochondrial activity, and chromatin structure in fresh and frozen-thawed Canada goose (Branta canadensis) semen with the use of the flow cytometry. The experiment was carried out on ten, 2-year-old, Canada goose ganders. The semen was collected twice a week, by a dorso-abdominal massage method, then pooled and subjected to cryopreservation in straws, in a programmable freezing unit with the use of dimethyloformamide (DMF) as a cryoprotectant. Frozen samples were thawed in a water bath at 60 degrees C. The freezing procedure was performed ten times. For the cytometric analysis the fresh and the frozen-thawed semen was extended with EK extender to a final concentration of 50 million spermatozoa per mL. Sperm membrane integrity was assessed with SYBR-14 and propidium iodide (PI), acrosomal damage was evaluated with the use of PNA-Alexa Fluor(r)488 conjugate, mitochondrial activity was estimated with Rhodamine 123 (R123), and spermatozoal DNA integrity was measured by the sperm chromatin structure assay (SCSA). The cryopreservation of Canada goose semen significantly decreased the percentage of live cells, from 76.3 to 50.4% (P < 0.01). Moreover, we observed the significant decrease in the percentage of live spermatozoa with intact acrosomes (P < 0.01), but we did not detect significant changes in the percentage of live spermatozoa with ruptured acrosomes. However, after thawing 50% of Canada goose live spermatozoa retained intact acrosomes. Furthermore, the percentage of live spermatozoa with active mitochondria was significantly lower in the frozen-thawed semen than in the fresh semen (P < 0.05). Nevertheless, after thawing the mitochondria remained active in almost 50% of live cells. In the present study, we observed no changes in the percentage of sperm with fragmented DNA after freezing-thawing of Canada goose semen. In conclusion, the present study indicates that even the fresh Branta canadensis semen might have poor quality, the cryopreservation of its semen did not provoke spermatozoal DNA defragmentation and half of the spermatozoa retained intact acrosomes and active mitochondria after freezing-thawing. PMID- 21664667 TI - Does storage time in LN2 influence survival and pregnancy outcome of vitrified rabbit embryos? AB - Vitrification is one of the most widely used techniques for embryo cryopreservation. The aim of this work was to study the effect of storage time in liquid nitrogen on vitrified rabbit embryos. A total of 1467 vitrified rabbit embryos were transferred into 174 females. The embryos had been maintained in liquid nitrogen during 3 different periods, A) < 1 year (98 transfers, 827 embryos); B) 2-5 years (44 transfers, 360 embryos) and C) > 15 years (32 transfers, 280 embryos). A generalized linear model was used to determine the effect of period on pregnancy and birth rates. A Bayesian approach was applied to analyze the survival rate of the vitrified embryos. In all analyses the number of transferred embryos was included as covariate. It was observed that neither the period of storage nor the number of transferred embryos affected pregnancy rate, and all periods presented similar pregnancy rates (0.85 +/- 0.04; 0.86 +/- 0.05; 0.78 +/- 0.07 for A, B and C). Fertility at birth was affected by the number of transferred embryos, but non-significant differences between periods were detected (0.77 +/- 0.04, 0.75 +/- 0.07; 0.69 +/- 0.08 for A, B and C). Also, the posterior means (highest posterior density intervals at 95%) of embryo survival at birth from pregnant females were similar between the different periods (47 [41 53]; 47 [38 56]; 42 [31 54]; for A, B and C). Results obtained in the present experiment point out that vitrified embryos could be stored in liquid nitrogen during at least fifteen years, achieving good pregnancy rate, fertility and survival at birth. PMID- 21664668 TI - A comparative study on efficiency of adult fibroblast, putative embryonic stem cell and lymphocyte as donor cells for production of handmade cloned embryos in goat and characterization of putative ntES cells obtained from these embryos. AB - The main purpose of the experiment was to compare the efficiency of three cell types, namely adult fibroblast, putative embryonic stem (ES) cell, and lymphocyte, as donor cells for somatic cell nuclear transfer by handmade cloning in goats. The outcome clearly shows that putative embryonic stem cells, with a cleavage and blastocyst production rate of 74.69% +/- 3.92 and 39.75% +/- 3.86, respectively, performs better in comparison to adult fibroblast cell and lymphocyte. Between adult fibroblast cell and lymphocyte no statistically significant difference exists at P < 0.05. An overall cleavage and blastocyst formation rate of 67.41% +/- 3.92 and 26.96% +/- 3.86 was obtained using adult fibroblast donor cells. The study establishes beyond doubt the reprogrammability of lymphocyte by handmade cloning (HMC) protocol with a cleavage and blastocyst production rate of 56.47% +/- 3.92 and 24.70% +/- 3.86, respectively. PCR analysis of highly polymorphic 286 bp fragment of MHC II DRB genes of cloned embryos and three donor cells were performed to verify the cloned embryos. The amplified PCR products were subjected to SSCP to confirm their genetic identity. The karyotyping of the cloned embryos showed normal chromosomal status as expected in goat. Significantly, in the second stage of the experiment, the produced cloned embryos were successfully used to derive ntES-like cells. The rate of primary colony formation rate was 62.50% +/- 4.62 for fibroblast donor cell derived embryos. The same was 60.60% +/- 4.62 for putative ES donor cell derived embryos and 66.66% +/- 4.62 for lymphocyte donor cell derived embryos, respectively. The putative ntES colonies were positively characterized for alkaline phosphatase, Oct-4, TRA-1-60, TRA-1-81, Sox-2, and Nanog by Immunocytochemistry and Reverse Transcription PCR. To further validate the stem ness, the produced putative ntES colonies were differentiated to embryoid bodies. Immunocytochemistry revealed that embryoid bodies expressed NESTIN specific for ectodermal lineage; GATA-4 for endodermal lineage and smooth muscle actin-I, and troponin-I specific for mesodermal lineage. The study has established an efficient protocol for putative ntES cell derivation from HMC embryos. It could be of substantial significance as patient specific ntES cells have proven therapeutic significance. PMID- 21664669 TI - Chemotactic activity of cotyledons for mononuclear leukocytes related to occurrence of retained placenta in dexamethasone induced parturition in cattle. AB - Induction of parturition with glucocorticosteroids in cattle is used for research purposes, in diseased or injured pregnant cows, and as a management tool to time parturition. A negative side effect of induction of parturition with glucocorticosteroids is the high incidence of retained placenta that occurs after these calvings. Reaction of the maternal immune system against the 'foreign' foetal membranes contributes to the breakdown of the foetal-maternal attachment. Several studies indicate that failure of this immune assisted detachment increases the occurrence of retained placenta. We hypothesized that retained placenta occurring after induction of parturition with glucocorticosteroids is caused by failure of immune assisted detachment of the foetal membranes. The chemotactic activity of cotyledons for mononuclear leukocytes was used as a parameter to see whether immune assisted detachment of the foetal membranes had occurred. Cotyledons were collected from spontaneously calving non-retained placenta cows and from dexamethasone induced non-retained placenta and retained placenta cows. The study showed that the chemotactic activity of cotyledons for mononuclear leukocytes was lower (P < 0.001) in cotyledons obtained from retained placenta cows in which parturition was induced with dexamethasone compared to the chemotactic activity of cotyledons obtained from spontaneously calving non retained placenta cows, whereas the chemotactic activity of cotyledons obtained from induced non-retained placenta cows was not lower (P = 0.10) than the chemotactic activity of cotyledons obtained from spontaneously calving non retained placenta cows. We concluded that induction of parturition with dexamethasone causes a failure of immune assisted detachment of the foetal membranes and the accompanying release of chemotactic factors. As a result, the chemotactic activity of cotyledons for mononuclear leukocytes is lower in induced retained placenta cows than in cotyledons from non-retained placenta cows in which successful immune assisted detachment of the foetal membranes occurs. PMID- 21664670 TI - The reproductive performance of female Forest musk deer (Moschus berezovskii) in captivity. AB - Reproductive performance of 750 adult female Forest musk deer (FMD, Moschus berezovskii) was monitored (from 2005 to 2009) on two Forest musk deer farms in Sichuan province, China. The mean (+/- SEM) lengths of the estrous cycle, pregnancy, and consecutive fawning intervals were 17.5 +/- 0.8 d (n = 64), 182.9 +/- 0.8 d (n =190), and 363.2 +/- 2.4 d (n = 120), respectively. Copulation occurred from the end of October to early March, with the majority (84.1 +/- 1.9%) during November and December (P < 0.05). The fawning rate was 68.7 +/- 2.2% in yearling hinds and 73.3 +/- 1.3% in adult hinds. Fawning occurred from the end of April to early September, with the majority (88. 9 +/- 2.2%) during May and June (P < 0.005), including a peak in May (52.0 +/- 1.0%). Yearling hinds fawned later (7.3 +/- 1.8 d) than adult hinds. Rates of premature delivery and dystocia were 2.7 +/- 0.4 and 2.0 +/- 0.3%, respectively. There was a 1.07:1 female-to male ratio at birth (P > 0.05), with 67.7% twins, but only two cases of triplets and one set of quadruplets among 537 fawns. Birth weight averaged 518.7 +/- 10.3 g, ranging from 304 to 775 g (n = 240), with male fawns slightly heavier than females (521.1 +/- 14.8 vs 516.9 +/- 14.3 g). Postnatal and pre-weaning mortality rates were 25.0 +/- 1.2 and 17.9 +/- 3.1%, respectively. Postnatal mortality and urinary calculus were much more common in male fawns (P < 0.01). The mortality rate due to suppuration and dyspepsia were different (P < 0.001) between postnatal and pre-weaning periods. Due to higher mortality of male fawns, the adult sex ratio was significantly female-biased. In conclusion, captive FMD had similar seasonal patterns of copulation and fawning as wild FMD and other musk deer species. PMID- 21664671 TI - Characterization of bovine transcripts preferentially expressed in testis and with a putative role in spermatogenesis. AB - Although the number of genes known to be associated with bovine spermatogenesis has increased in the past few years, regulation of this biological process remains poorly understood. Therefore, discovery of new male fertility genetic markers is of great value for assisted selection in commercially important cattle breeds, e.g., Nelore, that have delayed reproductive maturation and low fertility rates. The objective of the present study was to identify sequences associated with spermatogenesis that could be used as fertility markers. With RT-PCR, the following five transcripts preferentially expressed in adult testis were detected: TET(656) detected only in adult testis; TET(868) and TET(515) expressed preferentially in adult testis but also detected in fetal gonads of both sexes; and TET(456) and TET(262,) expressed primarily in the testis, but also present in very low amounts in somatic tissues. Based on their homologies and expression profiles, we inferred that they had putative roles in spermatogenesis. Detection of sequences differentially expressed in testis, ovary, or both, was a useful approach for identifying new genes related to bovine spermatogenesis. The data reported here contributed to discovery of gene pathways involved in bovine spermatogenesis, with potential for prediction of fertility. PMID- 21664672 TI - Assessment of freezing procedures for rat immature testicular tissue. AB - Fertility preservation has been included in the management of childhood cancer treatment. Cryopreservation of immature testicular tissue is the only available solution for pre-pubertal boys. Different freezing protocols have been developed in several species but without a clearly identified procedure. We tried to evaluate several protocols for cryopreservation of rat immature testicular tissue. Twelve different freezing protocols using different (i) cryoprotectant (dimethylsulphoxide [DMSO] or 1,2-propanediol [PROH]), (ii) cryoprotectant concentration (1.5M or 3M), (iii) equilibration time (30 or 60 min), (iv) equilibration temperature (4 degrees C or room temperature), (v) size of testicular fragment (7.5mg or 15 mg), (vi) package (straws or cryovials), were compared using cord morphological damage evaluation. A testicular tissue piece of 7.5mg cryopreserved in cryovial using 1.5M DMSO, an equilibration time of 30 min at 4 degrees C showed fewer morphological alterations than the other protocols tested. The selected freezing protocol was able to maintain rat immature testicular tissue architecture, functionality after testicular pieces organotypic culture, and could be proposed in a human application. PMID- 21664673 TI - Ultrasonographic and laparoscopic evaluation of the reproductive tract of the captive female African lion (Panthera leo). AB - The use of transabdominal ultrasonography to assess the oestrous cycle has not been previously described in the African lion (Panthera leo). Twelve sexually mature lionesses and five female cubs had their reproductive organs assessed by transabdominal ultrasound. Ovarian findings were compared to laparoscopic findings while performing laparoscopic ovariectomy or salpingectomy. Vaginal cytology was performed and serum progesterone levels were determined. By combining all data the oestrous cycle stage of each lion was determined. One lion was far pregnant and was not operated on. In adults a uterine body could be seen ultrasonographically in 67% of lions while mural structures could be distinguished in 44% of lions. Five uterine horns could be seen in 3 lions. In 12 adults 10 ovaries were found of which eight had discernable follicles or luteal structures. During laparoscopy 12 active ovaries were seen with luteal structures seen in 11 ovaries and follicles in 2 ovaries. Using laparoscopy as the gold standard, ultrasonography had a sensitivity of 66% and specificity of 83% to detect ovarian reproductive activity. Two uterine cysts and a cluster of periovarian cysts were seen in three different lions. Three lions were pregnant, two were in oestrus, three in a luteal phase (dioestrus), and four were in anoestrus. Transabdominal ultrasound in combination with serum progesterone levels and vaginal cytology can be used to assess ovarian cyclical activity with reasonable accuracy in captive bred lions. PMID- 21664674 TI - Comparing ethylene glycol with glycerol for cryopreservation of buffalo bull semen in egg-yolk containing extenders. AB - The objective of this work was to evaluate the possibility of substituting glycerol for ethylene glycol when cryopreserving buffalo semen. Semen of eight buffalo bulls was mixed, pooled, and frozen in one of these four diluents: centrifuged Tris egg yolk glycerol; centrifuged Tris egg yolk ethylene glycol; centrifuged Milk egg yolk glycerol; or centrifuged Milk egg yolk ethylene glycol. Semen quality parameters assessed after thawing were motility, survivability, livability, sperm abnormality, acrosome integrity, and plasma membrane integrity. Conception rate and pregnancy rate were calculated after insemination of 104 buffaloes by straws of different groups (26 female/extender). Improvement in livability, sperm abnormality, acrosome integrity, plasma membrane integrity, conception rate, and pregnancy rate were seen when using ethylene glycol to replace glycerol when freezing buffalo bull semen in centrifuged TRIS egg yolk 61.15 +/- 0.73, 24.85 +/- 0.41, 69.10 +/- 0.81, 71.75 +/- 0.72, 46.2%, and 46.2%, respectively, followed by centrifuged milk egg yolk extenders. PMID- 21664675 TI - How much do resin-based dental materials release? A meta-analytical approach. AB - OBJECTIVES: Resin-based dental materials are not inert in the oral environment, and may release components, initially due to incomplete polymerization, and later due to degradation. Since there are concerns regarding potential toxicity, more precise knowledge of the actual quantity of released eluates is necessary. However, due to a great variety in analytical methodology employed in different studies and in the presentation of the results, it is still unclear to which quantities of components a patient may be exposed. The objective of this meta analytical study was to review the literature on the short- and long-term release of components from resin-based dental materials, and to determine how much (order of magnitude) of those components may leach out in the oral cavity. METHODS: Out of an initial set of 71 studies, 22 were included. In spite of the large statistical incertitude due to the great variety in methodology and lack of complete information (detection limits were seldom mentioned), a meta-analytical mean for the evaluated eluates was calculated. To relate the amount of potentially released material components with the size of restorations, the mean size of standard composite restorations was estimated using a 3D graphical program. RESULTS: While the release of monomers was analyzed in many studies, that of additives, such as initiators, inhibitors and stabilizers, was seldom investigated. Significantly more components were found to be released in organic than in water-based media. Resin-based dental materials might account for the total burden of orally ingested bisphenol A, but they may release even higher amounts of monomers, such as HEMA, TEGDMA, BisGMA and UDMA. Compared to these monomers, similar or even higher amounts of additives may elute, even though composites generally only contain very small amounts of additives. A positive correlation was found between the total quantity of released eluates and the volume of extraction solution. SIGNIFICANCE: There is a clear need for more accurate and standardized analytical research to determine the long-term release from resin-based materials. Several guidelines for standardization are proposed. PMID- 21664676 TI - The future of immunisation policy, implementation, and financing. AB - Vaccines have already saved many lives and they have the potential to save many more as increasingly elaborate technologies deliver new and effective vaccines against both infectious diseases--for which there are currently no effective licensed vaccines--such as malaria, tuberculosis, and HIV and non-infectious diseases such as hypertension and diabetes. However, these new vaccines are likely to be more complex and expensive than those that have been used so effectively in the past, and they could have a multifaceted effect on the disease that they are designed to prevent, as has already been seen with pneumococcal conjugate vaccines. Deciding which new vaccines a country should invest in requires not only sound advice from international organisations such as WHO but also a well informed national immunisation advisory committee with access to appropriate data for local disease burden. Introduction of vaccines might need modification of immunisation schedules and delivery procedures. Novel methods are needed to finance the increasing number of new vaccines that have the potential to save lives in countries that are too poor to afford them. Here, we discuss some options. PMID- 21664677 TI - Is immunisation child protection? PMID- 21664678 TI - Making new vaccines affordable: a comparison of financing processes used to develop and deploy new meningococcal and pneumococcal conjugate vaccines. AB - Mechanisms to increase access to health products are varied and controversial. Two innovative mechanisms have been used to accelerate the development of low price supply lines for conjugate vaccines. The Meningitis Vaccine Project is a so called push mechanism that facilitated technology transfer to an Indian company to establish capacity to manufacture a vaccine. The Advanced Market Commitment for pneumococcal vaccines is a so-called pull mechanism that guarantees companies a supplement paid in addition to the purchase price for vaccines for a specific period. We compare these approaches, identifying key dimensions of each and considering their potential for replication. We also discuss issues that the Global Alliance for Vaccines and Immunisation (GAVI) face now that these new vaccines are available. Progress towards GAVI's strategic aims is needed and funding is crucial. Approaches that decrease the financial pressure on GAVI and greatly increase political and financial engagement by low-income countries should also be considered. PMID- 21664679 TI - Addressing the vaccine confidence gap. AB - Vaccines--often lauded as one of the greatest public health interventions--are losing public confidence. Some vaccine experts have referred to this decline in confidence as a crisis. We discuss some of the characteristics of the changing global environment that are contributing to increased public questioning of vaccines, and outline some of the specific determinants of public trust. Public decision making related to vaccine acceptance is neither driven by scientific nor economic evidence alone, but is also driven by a mix of psychological, sociocultural, and political factors, all of which need to be understood and taken into account by policy and other decision makers. Public trust in vaccines is highly variable and building trust depends on understanding perceptions of vaccines and vaccine risks, historical experiences, religious or political affiliations, and socioeconomic status. Although provision of accurate, scientifically based evidence on the risk-benefit ratios of vaccines is crucial, it is not enough to redress the gap between current levels of public confidence in vaccines and levels of trust needed to ensure adequate and sustained vaccine coverage. We call for more research not just on individual determinants of public trust, but on what mix of factors are most likely to sustain public trust. The vaccine community demands rigorous evidence on vaccine efficacy and safety and technical and operational feasibility when introducing a new vaccine, but has been negligent in demanding equally rigorous research to understand the psychological, social, and political factors that affect public trust in vaccines. PMID- 21664681 TI - The last mile in global poliomyelitis eradication. PMID- 21664680 TI - Vaccine production, distribution, access, and uptake. AB - For human vaccines to be available on a global scale, complex production methods, meticulous quality control, and reliable distribution channels are needed to ensure that the products are potent and effective at the point of use. The technologies used to manufacture different types of vaccines can strongly affect vaccine cost, ease of industrial scale-up, stability, and, ultimately, worldwide availability. The complexity of manufacturing is compounded by the need for different formulations in different countries and age-groups. Reliable vaccine production in appropriate quantities and at affordable prices is the cornerstone of developing global vaccination policies. However, to ensure optimum access and uptake, strong partnerships are needed between private manufacturers, regulatory authorities, and national and international public health services. For vaccines whose supply is insufficient to meet demand, prioritisation of target groups can increase the effect of these vaccines. In this report, we draw from our experience of vaccine development and focus on influenza vaccines as an example to consider production, distribution, access, and other factors that affect vaccine uptake and population-level effectiveness. PMID- 21664682 TI - A call to action for the new decade of vaccines. PMID- 21664683 TI - Will the Decade of Vaccines mean business as usual? PMID- 21664684 TI - The vaccine paradox. PMID- 21664685 TI - The next decade of vaccines: societal and scientific challenges. AB - Vaccines against microbial diseases have improved the health of millions of people. In the next decade and beyond, many conceptual and technological scientific advances offer extraordinary opportunities to expand the portfolio of immunisations against viral and bacterial diseases and to pioneer the first vaccines against human parasitic and fungal diseases. Scientists in the public and private sectors are motivated as never before to bring about these innovations in immunisation. Many societal factors threaten to compromise realisation of the public health gains that immunisation can achieve in the next decade and beyond--understanding these factors is imperative. Vaccines are typically given to healthy individuals and safety issues loom high on the list of public concerns. The public needs to regain confidence in immunisation and trust the organisations responsible for the research, development, and implementation of vaccines. In the past, by use of a judicious amalgam of knowledge and empiricism, successful vaccines were largely developed by microbiologists who identified antigens that induced immune responses to conserved pathogen components. In the future, vaccines need to be developed against deadly diseases for which this strategy is often not feasible because of the extensive antigenic variability of relevant pathogens. High microbial diversity means that immunity after natural infection is often ineffective for prevention of disease on subsequent exposure, for example in HIV infection and malaria. Additionally, vaccines need to be generated to protect the people who are most vulnerable because of age or underlying diseases. Thus, in the future, a much deeper understanding of the immunological challenges--including the diversifying role of host genetics and environmental factors, leading perhaps to more personalised approaches-will be the touchstone for rational design and development of adjuvants that result in novel safe and effective vaccines. PMID- 21664686 TI - Public-private collaboration in vaccine research. PMID- 21664687 TI - Vaccine discovery and translation of new vaccine technology. AB - An unprecedented increase in new vaccine development has occurred over the past three decades. This activity has resulted in vaccines that protect against an increased range of vaccine-preventable diseases, vaccines that reduce the number of required injections, and vaccines with improved safety and purity. New methods of discovery, such as reverse vaccinology, structural biology, and systems biology, promise new vaccines for different diseases and efficient development pathways for these vaccines. We expect development of vaccines not only for infectious diseases in children but also for healthy adults, pregnant women, and elderly people, and for new indications such as autoimmune disease and cancer. We have witnessed a concomitant development of new technology for assessment of vaccine safety to rapidly identify potential safety issues. Success of these new approaches will depend on effective implementation of vaccination programmes, creative thinking on the part of manufacturers and regulators as to how best to ensure that safe and effective vaccines are available in a timely manner, and improvement of public awareness about the benefits and risks of new vaccines in a way that encourages confidence in vaccines. PMID- 21664688 TI - Response to short term starvation of growth, haematological, biochemical and non specific immune parameters in European sea bass (Dicentrarchus labrax) and blackspot sea bream (Pagellus bogaraveo). AB - Growth, haematological (haematocrit), biochemical (serum cortisol and glucose), and non-specific immune (lysozyme, serum haemolytic and haemagglutinating activities, extracellular respiratory burst activity) parameters, were monitored in European sea bass Dicentrarchus labrax and blackspot sea bream Pagellus bogaraveo subjected to a 31 days starvation compared to fed fish, to assess the responses to feed deprivation of these health status indicators. While haematocrit, serum cortisol, glucose and haemolytic activity of both species did not undergo significant variation following starvation, probably due to the short period applied, some non-specific immune parameters were affected significantly. In the starved sea bass, mucus lysozyme content doubled (1.8 U/mL) compared to the initial value. Haemagglutinating activity was significantly lower in starved sea bass than in fed fish after 31 days. In blackspot sea bream, a slight, not significant, reduction in haemagglutinating activity occurred 11 days after starvation. Respiratory burst activity decreased significantly in the starved fish. In spite of the limited number of examined parameters, the opportunity to use a panel of several indicators to obtain a more complete picture of health status in fish was underlined. PMID- 21664689 TI - Enhanced siRNA delivery into cells by exploiting the synergy between targeting ligands and cell-penetrating peptides. AB - We have developed a polymer nanoparticle-based siRNA delivery system that exploits a cell surface binding synergism between targeting ligands and cell penetrating peptides. Nanoparticles were coated with folate and penetratin via a PEGylated phospholipid linker (DSPE-PEG): the combination of both of these ligands represents a strategy for enhancing intracellular delivery of attached polymer nanoparticles. Nanoparticles were characterized for size, morphology, density of surface modification, and ligand association and retention. The surface coverage achieved on DSPE-PEG-coated nanoparticles is as high as (or higher than) obtained with other ligand-modified nano-scale particulate systems (~0.5-5 pmol ligand/cm2). Additionally, these nanoparticles were loaded with a high density of siRNA (~130-140 pmol siRNA/mg nanoparticles), which is slowly released upon incubation in water. Synergies between the activity of surface binding and cell internalizing ligands on these siRNA-loaded nanoparticles impart delivery enhancements that improve their gene silencing efficacy both in culture and in tumor models. Traditionally, targeting ligands function by binding to cell surface receptors, while cell-penetrating peptides function by nonspecifically transporting across cell membranes. Interestingly, we have observed that improved delivery of these dual-functionalized nanoparticles was in part, a result of increased cell surface avidity afforded by both ligands. This siRNA delivery system presents an approach to surface modification of nanovehicles, in which multiple ligands function in parallel to enhance cell binding and uptake. PMID- 21664690 TI - Role of low placental share in twin-twin transfusion syndrome complicated by intrauterine growth restriction. AB - OBJECTIVES: Prior studies have demonstrated that donor twin survival following treatment of twin-twin transfusion syndrome (TTTS) was highly associated with donor intrauterine growth restriction (IUGR). Here, we hypothesized that donor IUGR may be attributed in part to low placental share. STUDY DESIGN: The study population consisted of all patients who underwent laser treatment for TTTS at a single institution between 2006-2010. Only those pregnancies with dual survival at birth were included so that placental share information could be interpreted. We examined the relationships between Quintero Stage (with separate analysis of Stage III patients with critically abnormal donor Doppler findings) and low placental share (defined as <= 30%) with IUGR (<10th percentile) using chi-square analysis and multivariable logistic regression modeling. RESULTS: Of 210 patients treated, 159 (75.7%) had dual survivors at birth. Of these, placental share was documented in 90 cases (56.6%). Twenty-seven (30.0%) had low placental share, and 37 (41.1%) had IUGR. IUGR was associated with low placental share (63.0% vs. 31.7%, P = 0.0116). IUGR was also associated with Stage III patients (57.4% vs. 23.3%, P = 0.0021), and in particular with Stage III patients with donor involvement (77.8% vs. 25.4%, P < 0.0001). In logistic regression modeling, both low placental share and Stage III with donor involvement were independent risk factors for IUGR (OR = 3.5 [1.2-10.3], P = 0.0206, and OR = 10.1 [3.3-30.6], P < 0.0001, respectively). CONCLUSIONS: Donor IUGR in TTTS pregnancies appears to be associated, in part, with low placental share. PMID- 21664691 TI - In vitro synergism between LFA-1 targeting leukotoxin (LeukotheraTM) and standard chemotherapeutic agents in leukemia cells. AB - Leukotoxin (LeukotheraTM; LtxA) is a bacterial protein and experimental therapeutic that binds leukocyte function antigen (LFA-1) on white blood cells (WBCs) and induces cell death via apoptosis or necrosis. We previously found that LtxA preferentially targets WBCs with high levels of activated LFA-1, which is characteristic of many leukemias and lymphomas, and showed that LtxA exhibits significant anti-leukemia activity in vivo using the humanized SCID mouse model. In this report, we demonstrate that LtxA induces very rapid (1h) apoptosis in acute monocytic leukemia THP-1 cells characterized by binding of annexin V to cells, loss of mitochondrial membrane potential, depletion of cellular ATP, and fragmentation of chromosomal DNA. We tested the activity of LtxA in combination with the standard chemotherapeutic agents, etoposide, mitoxantrone, daunorubicin, busulfan, and imatinib against several leukemia cell lines, including THP-1, GDM 1, HL-60, and KU-812 cells. LtxA exhibited synergism with all the drugs, and the levels of synergy were dependent on the doses used and cell lines examined. In general, the greatest level of synergy was observed with LtxA and etoposide or imatinib. Combination index (CI) values were less than 0.1 for many of the combinations, indicating very strong synergism. In addition, LtxA alone was cytotoxic to primary cells from newly diagnosed, relapsed, and refractory patients with different hematological malignancies. Thus, LtxA is highly effective at inducing rapid apoptosis both as a single agent and in combination with approved leukemia therapies. PMID- 21664692 TI - A comparative study of different diets to optimize cultivation of Hyalella azteca in the laboratory. AB - The aim of this study was to assess the influence of four diets on the laboratory cultivation of H. azteca, seeking to improve production of young specimens through reduced mortality and better growth and number of offspring per couple. The best diet was composed of a mixture of diluted commercial fish food, diluted yeast and primrose oil, associated with fish food flakes containing spirulina. With this diet the maximum mortality was 25 percent (at the end of 28 days), the average number of offspring/couple was 11.4 +/- 2.8 (at the end of twelve days) and the peak weight and length of the males (at the end of 40 days) were 0.930 MUg and 5.26 +/- 1.1mm, respectively. PMID- 21664693 TI - Determination of polybrominated diphenyl ethers in human semen. AB - Some persistent organic pollutants (POPs) have been found in human semen but until this point it was unclear whether polybrominated diphenyl ethers (PBDEs) could be detected in human semen. In this study, PBDEs were found for the first time in human semen samples (n=101) from Taizhou, China. The concentrations of total PBDEs (?PBDEs) varied from 15.8 to 86.8 pg/g ww (median=31.3 pg/g ww) and 53.2 to 121 pg/g ww (median=72.3 pg/g ww) in semen and blood samples, respectively. The ?PBDE level in semen was about two times lower than in human blood, which was different in the distribution in the two matrices from other POPs. A correlation of ?PBDE concentration was found between paired semen and in blood. The results suggest that semen could be used to detect PBDE burden in human body as a non-invasive matrix. In addition, the levels of BDE-209 and BDE 153, especially the latter, were much higher in blood than in semen, while the levels of BDE-28, BDE-47 and BDE-99 were comparable in the two matrices, suggesting that low brominated congeners could be more easily transferred to semen than high brominated congeners. Considering different toxicities among the PBDE congeners, it might be more significant to measure PBDEs in semen than in blood for evaluating male reproduction risks of PBDEs. PMID- 21664695 TI - Impact of therapeutic choices on outcome of osteomyelitis caused by MRSA. PMID- 21664694 TI - Leishmania mexicana promastigotes inhibit macrophage IL-12 production via TLR-4 dependent COX-2, iNOS and arginase-1 expression. AB - The effects of Leishmania mexicana metacyclic promastigotes upon MAP kinase signalling in mouse bone marrow macrophages and subsequent expression of the disease regulatory proteins iNOS and COX-2 were studied. At a ratio of 5:1, promastigotes caused a marked increase in phosphorylation of the three major MAP kinases, ERK, p38 and JNK. MAP kinase signalling was substantially reduced in TLR 4(-/-) but not TLR-2(-/-) deficient macrophages and completely abolished in double TLR-2/4(-/-) macrophages. A similar outcome was observed using cysteine peptidase B deficient amastigotes. Furthermore, whilst promastigotes had no independent effect on iNOS or COX-2 expression, they prolonged the induction of these proteins stimulated by LPS and enhanced PGE(2) and NO production. Induction of COX-2 and iNOS was also TLR-4 dependent. Blockade of either PGE(2) or NO production with indomethacin or l-NAME reversed promastigote inhibition of LPS induced IL-12 production. Promastigotes also increased macrophage arginase-1 expression and enhanced arginase activity, both of which were substantially reduced in TLR-4 but not TLR-2 deficient macrophages. Surprisingly, arginase inhibition by Nor-NOHA also caused a reversal of promastigote mediated inhibition of macrophage IL-12 production. These data demonstrate for the first time the role of TLR-4 in mediating the effects of L. mexicana promastigotes on MAP kinase activation, up-regulation of COX-2, iNOS as well as arginase-1 expression in macrophages and further shows that PGE(2), NO and arginase activity all contribute substantially to the inhibition of host cell IL-12 production. PMID- 21664697 TI - Does Toxoplasma gondii play a role in obsessive-compulsive disorder? PMID- 21664696 TI - Common mental disorders and subsequent work disability: a population-based Health 2000 Study. AB - BACKGROUND: Work disability due to common mental disorders has increased in Western countries during the past decade. The contribution of depressive, anxiety, and alcohol use disorders to all disability pensions at the population level is not known. METHODS: Epidemiological health data from the Finnish Health 2000 Study, gathered in 2000-2001, was linked to the national register on disability pensions granted due to the ICD-10 diagnoses up to December 2007. Mental health at baseline was assessed using the Composite International Diagnostic Interview (CIDI). Sociodemographic, clinical, and work-related factors, health behaviors, and treatment setting were used as covariates in the logistic regression analyses among the 3164 participants aged 30-58 years. RESULTS: Anxiety, depressive, and comorbid common mental disorders predicted disability pension when adjusted for sex and age. In the fully adjusted multivariate model, comorbid common mental disorders, as well as physical illnesses, age over 45 years, short education, high job strain, and previous long term sickness absence predicted disability pension. LIMITATIONS: The study population included persons aged 30 or over. Sub groups according to mental disorders were quite small which may have diminished statistical power in some sub groups. Baseline predictors were measured only once and the length of exposure could not be determined. The systems regarding financial compensation to employees differ between countries. CONCLUSIONS: Comorbid mental disorders pose a high risk for disability pension. Other independent predictors of work disability include socio-demographic, clinical, work-related, and treatment factors, but not health behavior. More attention should be paid to work-related factors in order to prevent chronic work disability. PMID- 21664698 TI - Redefining phenotypes in eating disorders based on personality: a latent profile analysis. AB - To conduct a latent profile analysis (LPA) in eating disorder (ED) patients using temperament and character (TCI-R) measures as indicators. 1312 ED patients including those with anorexia nervosa (AN), bulimia nervosa (BN) and EDNOS were assessed. The final LPA solution was validated using demographics, clinical variables, ED symptomatology (EDI-2) and impulsive behaviors. The best-fitting model consisted of a six-profile solution using the seven subscales of the TCI-R. These profiles were labeled: "self-focused", "inhibited", "average", "impulsive", "adaptive" and "maladaptive". Validation analyses indicated that the "inhibited" and "maladaptive" profiles generally presented with the highest values for ED symptomatology and impulsive behaviors. Whereas high levels of Harm Avoidance and low levels of Novelty Seeking and Persistence characterized the "inhibited" profile, the "maladaptive" profile presented with low levels of Reward Dependence, Self-Directedness and Cooperativeness. The most favorable results on the other hand were exhibited by the "adaptive" profile, characterized by high scores on Reward Dependence, Self-Directedness, Cooperativeness and low levels on Novelty Seeking. Finally, when our six-profile solution was compared with the DSM IV ED diagnoses, significant differences among profiles and ED diagnoses were observed. Our study shows that ED patients can be meaningfully grouped according to temperament and character. PMID- 21664699 TI - Cannabinoids improve driving ability in a Tourette's patient. PMID- 21664700 TI - An association between high birth weight and schizophrenia in a Finnish schizophrenia family study sample. AB - Longitudinal cohort studies have implicated an association between both low and high birth weight and schizophrenia. It has been suggested that schizophrenia associated genes could augment an individual's susceptibility to adverse prenatal and perinatal environmental events. We investigated the association between birth weight and schizophrenia in a large Finnish schizophrenia family study sample. We utilized the birth weight data of 1051 offspring from 315 Finnish families with at least one offspring with a diagnosis of schizophrenia. We used a multivariate COX frailty model to analyze the effect of birth weight on the risk of developing schizophrenia within the families. Using information from the Medication Reimbursement Register and patient interviews, we further investigated the association of maternal type 2 diabetes and schizophrenia risk among offspring. High birth weight (>4000g) was associated with a 1.68-fold increase in schizophrenia susceptibility. Maternal diabetes at the time of data collection, a proxy for gestational diabetes, was associated with a 1.66-fold increase in the risk of developing schizophrenia among offspring. Our results corroborate recent findings showing an association between high birth weight and schizophrenia. Our results also point to a potential birth-weight independent association between maternal type 2 diabetes and schizophrenia among offspring. PMID- 21664701 TI - Comparison of humoral and cellular immune responses to inactivated swine influenza virus vaccine in weaned pigs. AB - Humoral and cellular immune responses to inactivated swine influenza virus (SIV) vaccine were evaluated and compared. Fifty 3-week-old weaned pigs were randomly divided into the non-vaccinated control group and vaccinated group containing 25 pigs each. Pigs were vaccinated intramuscularly twice with adjuvanted UV inactivated A/SW/MN/02011/08 (MN/08) H1N2 SIV vaccine at 6 and 9 weeks of age. Whole blood samples for multi-parameter flow cytometry (MP-FCM) and serum samples for hemagglutination inhibition (HI) assay were collected at 23 and 28 days after the second vaccination, respectively. A standard HI assay and MP-FCM were performed against UV-inactivated homologous MN/08 and heterologous pandemic A/CA/04/2009 (CA/09) H1N1 viruses. While the HI assay detected humoral responses only to the MN/08 virus, the MP-FCM detected strong cellular responses against the MN/08 virus and significant heterologous responses to the CA/09 virus, especially in the CD4+CD8+ T cell subset. The cellular heterologous responses to UV-inactivated virus by MP-FCM suggested that the assay was sensitive and potentially detected a wider range of antigens than what was detected by the HI assay. Overall, the adjuvanted UV-inactivated A/SW/MN/02011/08 H1N2 SIV vaccine stimulated both humoral and cellular immune responses including the CD4-CD8+ T cell subset. PMID- 21664702 TI - Cytokine mRNA expression of pulmonary macrophages varies with challenge but not with disease state in horses with heaves or in controls. AB - Heaves in horses is characterized by lower airway neutrophilic inflammation, and reversible airflow obstruction. Pulmonary macrophages contribute to the inflammation observed in a number of human and animal pulmonary diseases, and it has been postulated that they are responsible for the neutrophilic inflammation present in heaves by the release of cytokines and chemokines. To test this hypothesis, the mRNA expression of TNF-alpha, IL-1beta, IL-8, and MIP-2 by macrophages isolated from bronchoalveolar lavage cells was quantified using real time RT-PCR in horses with heaves (n-6) and controls (n-6). Animals were studied after being pastured for 3 months to induce clinical remission of heaves, and after 24h, and 9 days of a continuous natural antigen challenge consisting of hay feeding and straw bedding. The study was performed during 2 consecutive summers, when 3 horses with heaves and 3 control horses were evaluated. As expected, airway obstruction developed with the challenge only in horses with heaves, while airway neutrophilia was observed in both groups of horses. Stabling resulted in an increased expression of IL-8/beta-actin and MIP-2/beta-actin after 24h of stabling in both groups of horses. Further analyses revealed that compared to pasture, the expression of these chemokines was significantly increased after 24h of stabling only in Year 1, while the IL-8 expression was significantly decreased at 9 days in Year 2. No significant group, time, or year differences in IL 1beta/beta-actin and TNF-alpha/beta-actin ratio were observed. The expression of IL-1beta was strongly correlated with neutrophil percentages, although at different time points in the two study-years. These results suggest that alveolar macrophages can contribute to the airway inflammation resulting from stabling in horses by the release of IL-8 and MIP-2, but that the release of these chemokines is unlikely to be responsible for the marked airway neutrophilia observed in heaves. The variable expression of IL-8 and MIP-2 by alveolar macrophages between the two-study years are additional novel findings highlighting the complexity of the inflammatory pathways associated with airway inflammation and the importance of evaluating concurrently horses with heaves and controls to ensure identical environmental challenges. PMID- 21664703 TI - Reply to: Long-term follow-up of children after submucosal diathermy to the inferior turbinate for rhinitis. PMID- 21664704 TI - Cardiac resynchronization therapy for critically ill patients with left ventricular systolic dysfunction. AB - BACKGROUND: The experience of cardiac resynchronization therapy (CRT) in critically ill patients with cardiogenic shock or advanced heart failure is limited and inadequately described in literature. METHODS: CRT implants performed in patients on the cardiothoracic intensive care unit (ICU) at a tertiary cardiac centre during 2007-2010 were retrospectively studied. RESULTS: We identified 24 patients, 17 male, of median age 76 years (IQR 11) treated with a CRT pacemaker (n=10) or CRT defibrillator (n=14). Prior to implantation median left ventricular ejection fraction (LVEF) was 26% (IQR 13) and median QRS duration 146 ms (IQR 29). Eleven (46%) patients were post elective cardiac surgery and 8 (33%) post emergency cardiac surgery or intervention with high prevalence of co-morbidities. Nineteen patients required inotropic support pre-implantation, 8 patients were on mechanical circulatory support and 18 were on mechanical ventilation. Post CRT LVEF improved from 26% to 39% (p=0.027) and the estimated glomerular filtration rate increased from 42 ml/min/1.73 m(2) (IQR 26) to 63 ml/min/1.73 m(2) (IQR 48, p=0.001). All but one patient were successfully weaned from inotropic support within a median of 4 days (IQR 5) post CRT and 22/24 (92%) survived to hospital discharge. After a median follow up of 392 days (IQR 538), 7 (33%) patients died. In-hospital and one year mortality rates were 8.3% and 29.4% respectively. Ten out of 12 patients (83%) were alive at long-term (22 +/- 9 months) follow up. CONCLUSIONS: CRT may assist weaning from circulatory and respiratory support in critically ill patients with left ventricular systolic dysfunction. PMID- 21664705 TI - Effects of vascular nitric oxide pathway on vascular smooth muscle cell proliferation. PMID- 21664706 TI - Sudden cardiac arrest and syncope triggered by coronary spasm. AB - BACKGROUND: Patients with coronary spasm generally have a good prognosis, although it can result in sudden cardiac arrest (SCA) and syncope. We hypothesized that the nature of coronary spasm triggering lethal arrhythmias may be different from that which induces angina-only. METHODS: Clinical characteristics were examined in patients who had experienced SCA (n = 18) or syncope (n = 28) triggered by coronary spasm. These characteristics were compared to those of patients who had coronary spastic angina-only (n = 52). RESULTS: SCA and syncope occurred frequently during daytime in 57% and 68%, respectively. Spontaneous ST-segment changes during daytime were recorded more often in patients with SCA (50%) and syncope (39%) than angina-only patients (4%, p < 0.01 for each). Nocturnal angina occurred less frequently in patients with SCA (33%) and syncope (32%) than angina-only patients (83%, p < 0.01 for each). Severe multivessel spasm, daytime ST-segment changes, and younger age were significant predictors of SCA. Daytime ST-segment changes and active smoking were related to syncope. CONCLUSIONS: The circadian variance of coronary spasm triggering SCA or syncope may be different from that inducing typical coronary spastic angina. The coronary spasm should be evaluated for patients with aborted SCA or recurrent syncope of unknown cause, even though the patients have not experienced the typical nocturnal angina. PMID- 21664708 TI - Genetic lotteries within families. AB - Drawing on findings from the biomedical literature, this paper introduces the idea that specific exogenously inherited differences in the genetic code between full biological siblings can be used to test within-family estimators and potentially improve our understanding of economic relationships. These points are illustrated with an application to identify the causal impact of several poor health conditions on academic outcomes. We present evidence that family fixed effects estimators by themselves cannot fully account for the endogeneity of poor health when estimating education production functions. Further, our analysis elucidates the situations under which genetic markers can serve as instrumental variables for specific health conditions. PMID- 21664707 TI - Right ventricular ejection fraction <20% is an independent predictor of mortality but not of hospitalization in older systolic heart failure patients. AB - BACKGROUND: Reduced right ventricular ejection fraction (RVEF) is associated with poor outcomes in patients with chronic systolic heart failure (HF). Although most HF patients are older adults, little is known about the relationship between low RVEF and outcomes in older adults with systolic HF. METHODS: Of the 2008 Beta Blocker Evaluation of Survival Trial (BEST) participants with systolic HF (left ventricular ejection fraction <= 35%) 822 were >= 65 years and had data on baseline RVEF estimated by gated-equilibrium radionuclide ventriculography. Using RVEF >= 40% (n = 308) as reference, we examined association of RVEF 30-39% (n = 214), 20-29% (n = 206) and <20% (n = 94) with outcomes using Cox regression models. RESULTS: All-cause mortality occurred in 36%, 40%, 39% and 56% of patients with RVEF >= 40%, 30-39%, 20-29% and <20% respectively. Compared with RVEF >= 40%, unadjusted hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality associated with RVEF 30-39%, 20-29% and <20% were 1.19 (0.90 1.57; P = 0.220), 1.13 (0.84-1.51; P = 0.423) and 1.97 (1.43-2.73; P<0.001) respectively. Respective multivariable-adjusted HR's (95% CI's) for all-cause mortality were 1.19 (0.88-1.60; P = 0.261), 1.00 (0.73-1.39; P = 0.982) and 1.70 (1.14-2.53; P = 0.009). Adjusted HR's (95% CI's) associated with RVEF <20% (versus >= 40%) for cardiovascular mortality and HF mortality were 1.79 (1.17 2.76; P = 0.008) and 1.97 (1.02-3.83; P = 0.045) respectively. RVEF had no independent association with sudden cardiac death, all-cause or HF hospitalization. CONCLUSIONS: Abnormally low RVEF is a significant independent predictor of mortality, but not of HF hospitalization, in older adults with systolic HF. PMID- 21664709 TI - Emerging roles of engineered nanomaterials in the food industry. AB - Nanoscience is the study of phenomena and the manipulation of materials at the atomic or molecular level. Nanotechnology involves the design, production and use of structures through control of the size and shape of the materials at the nanometre scale. Nanotechnology in the food sector is an emerging area with considerable research and potential products. There is particular interest in the definition and regulation of engineered nanomaterials. This term covers three classes of nanomaterials: natural and processed nanostructures in foods; particulate nanomaterials metabolized or excreted on digestion; and particulate nanomaterials not broken down on digestion, which accumulate in the body. This review describes examples of these classes and their likely status in the food industry. PMID- 21664710 TI - Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. AB - PURPOSE: This multicentre, prospective, randomised-controlled trial compared efficacy and toxicity of differing radiotherapy doses in non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Patients with any histological subtype of NHL, requiring radiotherapy for local disease control, whether radical, consolidative or palliative, were included. Three hundred and sixty one sites of indolent NHL (predominantly follicular NHL and marginal zone lymphoma) were randomised to receive 40-45Gy in 20-23 fractions or 24Gy in 12 fractions. Six hundred and forty sites of aggressive NHL (predominantly diffuse large B cell lymphoma as part of combined-modality therapy) were randomised to receive 40-45Gy in 20-23 fractions or 30Gy in 15 fractions. Patients with all stages of disease, having first-line and subsequent therapies were included; first presentations of early-stage disease predominated. RESULTS: There was no difference in overall response rate (ORR) between standard and lower-dose arms. In the indolent group, ORR was 93% and 92%, respectively, (p=0.72); in the aggressive group, ORR was 91% in both arms (p=0.87). With a median follow-up of 5.6years, there was no significant difference detected in the rate of within-radiation field progression (HR=1.09, 95%CI=0.76-1.56, p=0.64 in the indolent group; HR=0.98, 95%CI=0.68-1.4, p=0.89 in the aggressive group). There was also no significant difference detected in the progression free or overall survival. There was a trend for reduced toxicities in the low-dose arms; only the reduction in reported erythema reached significance. CONCLUSION: In a large, randomised trial, there was no loss of efficacy associated with radiotherapy doses of 24Gy in indolent NHL and 30Gy in aggressive NHL, compared with previous standard doses of 40-45Gy. PMID- 21664711 TI - Delineation of organs at risk involved in swallowing for radiotherapy treatment planning. AB - BACKGROUND AND PURPOSE: Radiotherapy, alone or combined with chemotherapy, is a treatment modality used frequently in head and neck cancer. In order to report, compare and interpret the sequelae of radiation treatment adequately, it is important to delineate organs at risk (OARs) according to well-defined and uniform guidelines. The aim of this paper was to present our institutional Computed Tomography (CT)-based delineation guidelines for organs in the head and neck at risk for radiation-induced swallowing dysfunction (SWOARs). MATERIAL AND METHODS: After analyses of the human anatomy of the head and neck area and literature review, CT-based guidelines for delineation of the most relevant SWOARs were described by a panel of experts. RESULTS AND CONCLUSIONS: This paper described institutional guidelines for the delineation of potential SWOARs, accompanied by CT-based illustrations presenting examples of the delineated structures and their corresponding anatomic borders. This paper is essential to ensure adequate interpretation of future reports on the relationship between dose distribution in these SWOARs and different aspects of post-treatment swallowing dysfunction. PMID- 21664712 TI - Verification of the effectiveness of SCAR (sequence characterized amplified region) primers for the identification of Polish strains of Fusarium culmorum and their potential ability to produce B-trichothecenes and zearalenone. AB - Rapid and sensitive methods to detect Fusarium culmorum and trichothecene and zearalenone producing strains in food and feed are valuable in predicting potential contamination. In this study the effectiveness of primers, recommended in the literature, for species identification of F. culmorum and basic genes encoding for mycotoxin production was tested. A total of 68 isolates of F. culmorum were collected from cereals and potato between 2005 and 2008 from different Polish provinces. It was shown that from among the four primer pairs enabling the identification of F. culmorum, and therefore also to establish its presence in the material, only primers Fc01F/Fc01R seem to be fully effective in the case of Polish strains. Determination of material contamination by F. culmorum, however, is only a first step in determining food safety. It is also extremely important to identify genes encoding the potential ability to produce mycotoxins. It was shown that three pairs of primers (tox5-1/tox5-2, HATriF/HATriR and Tri5F/Tri5R) enable a fully effective identification of the presence of the Tri5 gene responsible for producing trichothecenes. Determination of the DON-chemotype, and thus identification of the strains of F. culmorum potentially producing deoxynivalenol, is enabled equally by MinusTri7F/MinusTri7F, Tri7F/Tri7DON and Tri13F/Tri13DONR. However, a determination of the NIV-chemotype, and thus identification of the strains potentially producing nivalenol, is enabled by Tri7F/Tri7R, Tri7F/Tri7NIV and Tri13NIVF/Tri13R. The potential ability of isolates to produce ZEA can be determined to the same degree in assay with PKS4-PS.1/PKS4-PS.2 and F1/R1. PMID- 21664713 TI - Time and dose-related changes in radiological lung density after concurrent chemoradiotherapy for lung cancer. AB - Radiation pneumonitis is an important cause of morbidity after concurrent thoracic chemoradiotherapy (CCRT). However, asymptomatic changes in lung density on computed tomography (CT)-scans occur more commonly, and correspond to regions of inflammatory changes. Characterization of dose- and time-related changes in radiological lung density (RLD) may facilitate improved radiation planning, and allow for a more objective measure for assessing damage. We studied changes in RLD following CCRT with cisplatin-etoposide, using deformable registration to co register follow-up scans. All CT-scans performed for up to 24 months post treatment were evaluated in 25 patients treated with CCRT for stage III non-small cell lung cancer. A total of 104 scans (median of 3 per patient) were co registered with planning scans using a deformable registration tool (VelocityAI, Atlanta, USA). Last follow-up scan was at median 9.4 months (range 3.4-22.6 months). Seven patients developed clinical radiation pneumonitis. RLD changes (in Hounsfield units) were measured in regions receiving 3-66Gy. Linear mixed models were used to study dose-density changes over time. No significant changes in RLD were observed in the first 3 months post-treatment. Increases in RLD were observed at 3-6 months (p<0.0001) and 6-12 months (p=0.006), but stabilized at 1 year. Increases were most evident in regions receiving >30Gy, with only minor density changes at lower dose levels. Planning target volume size was significantly associated with RLD changes (p=0.03). Limiting lung doses to <=30Gy during CCRT may limit sub-clinical damage, and the time-course of RLD changes may allow for early quantification of pulmonary damage when evaluating novel treatment strategies. PMID- 21664714 TI - Nickel speciation in the xylem sap of the hyperaccumulator Alyssum serpyllifolium ssp. lusitanicum growing on serpentine soils of northeast Portugal. AB - Nickel speciation was studied in the xylem sap of Alyssum serpyllifolium ssp. lusitanicum, a Ni-hyperaccumulator endemic to the serpentine soils of northeast Portugal. The xylem sap was collected from plants growing in its native habitat and characterized in terms of carboxylic and amino acids content. The speciation of nickel was studied in model and real solutions of xylem sap by voltammetric titrations using Square Wave Voltammetry (SWV). The results showed that Ni transport in the xylem sap occurs mainly as a free hydrated cation (about 70%) and complexed with carboxylic acids, mainly citric acid (18%). Altogether, oxalic acid, malic acid, malonic acid and aspartic acid complexed less than 13% of total Ni. A negligible amount bounded to the amino acids, like glutamic acid and glutamine (<1%). Histidine did not play a role in Ni translocation in the xylem sap of A. serpyllifolium under field conditions. Amino acids are one of the main forms of N transport in the xylem sap, and under field conditions, N is usually a limited nutrient. We hypothesize that the translocation of Ni in the xylem sap as a free ion or chelated with carboxylic acids is 'cheaper' in terms of N resources. PMID- 21664715 TI - [Comparison of the depth predictability of intra corneal ring segment implantation by mechanical versus femtosecond laser-assisted techniques using optical coherence tomography (OCT Visante((r)))]. AB - Comparison of the depth predictability of intracorneal ring segment implantation by mechanical versus femtosecond laser-assisted techniques using optical coherence tomography (OCT Visante((r))). PURPOSE: To compare the depth predictability of intracorneal ring segment implantation by mechanical versus femtosecond laser-assisted techniques using OCT Visante((r)). METHODS: This observational prospective study included, after patients' consent, 76 keratoconic eyes, of which 31 eyes (group 1) were operated using the mechanical technique and 45 eyes (group 2) with the femtosecond laser-assisted technique. The target depth was two-thirds of the peripheral corneal thickness, ranging from 5 to 7 mm in diameter. Every patient underwent high-resolution anterior segment OCT (OCT Visante((r))) measurement preoperatively and for the implant depth, 1 month postoperatively. Then two different sites were used to determine the segment depth, at the segment site and tangentially, at a distance of 700 MUm central to the segment's inner edge. RESULTS: Both measurement techniques demonstrated that targeted implantation depth of 66% of the corneal thickness was not observed in either group. The mean difference between the preoperative expected depth and final segment implantation was 76.64 +/- 48.76 MUm in the manual technique and 85.85 +/- 33.02 MUm in the femtosecond-assisted technique, with no statistically significant difference between the groups. Comparison between the measurement sites showed implantation depth to be shallower, 54.93+/-6.03%, at the tangential site compared to 55.14 +/- 8.08% at the implant site in group 1 and 56.17 +/- 5.82% versus 58.88 +/- 6.06%, respectively, in group 2. CONCLUSION: Both mechanical and femtosecond laser-assisted techniques showed a more superficial Intacs((r)) placement than predicted. No statistically significant difference was observed in implantation depth between the two groups. PMID- 21664716 TI - [When the pupil becomes the teacher]. AB - OBJECTIVE: To evaluate the theoretical teaching provided to ophthalmology residents in Toulouse during the 2006-2007 academic year using the PowerVote((r)) system. PUPILS AND METHOD: This was a prospective study concerning all ophthalmology residents in Toulouse. Classes were given by the house doctors and senior registrars as PowerPoint presentations lasting about 45 min. Just before each lecture, the house doctors took a 5 min test comprising five multiple choice questions. There were two lectures per month on average. One month after the course of lectures ended, the course as a whole was evaluated using the PowerVote((r)) tool, on objectives given to the house doctors in advance. The teaching concerned the macula. RESULTS: Ten residents took part in the final evaluation in 2007. The residents who had given lectures obtained significantly better results, not only in the initial test but also in the final one. DISCUSSION: Teaching can take many forms. We evaluated teaching by the students themselves. The more involved a house doctor was in teaching, the better he remembered the lesson. CONCLUSION: Giving a theoretical lecture enables residents to reach a higher level, which is further improved if they are involved in the teaching. The use of PowerVote((r)) is an interesting pedagogical tool. PMID- 21664717 TI - [Reconstruction of anophthalmic socket]. AB - PURPOSE: Evaluate different surgical techniques in the management of the contracted anophthalmic socket. PATIENTS AND METHODS: A retrospective study including 12 patients with acquired anophthalmic socket presenting inadequate fornices and/or orbital volume loss. The surgeries performed were conjunctival suture to the periosteum (mild fornix contraction), buccal mucosa graft (moderate fornix retraction), auricular cartilage graft (severe fornix retraction), and dermis-fat graft (loss of orbital volume). RESULTS: Fornix retraction was mild in two patients, moderate in three patients, and severe in two patients. We observed five patients with loss of orbital volume. Successful correction was achieved in all patients with fornix retraction who were able to wear an external prosthesis. One patient with orbital volume loss developed graft atrophy. CONCLUSION: Autologous grafts are useful in the rehabilitation of the contracted socket. PMID- 21664719 TI - Increased risk of infectious disease requiring hospitalization among patients with psoriasis: a population-based cohort. AB - BACKGROUND: Immunologic alterations caused by psoriasis and/or its therapies may affect the risk of serious infections. OBJECTIVE: For patients with psoriasis, we explored the overall and therapy-related risk of contracting an infectious disease (ID) requiring hospitalization in a large population-based cohort. METHODS: The incidence of ID was compared between patients with psoriasis and a randomly selected cohort (ratio 1:5) using hospital and pharmacy databases covering 2.5 million Dutch residents between 1997 and 2008. First and multiple IDs were defined and categorized into 20 groups based on primary International Classification of Diseases, Ninth Revision, Clinical Modification discharge diagnoses. Multivariate Cox regression and Poisson event-count models were used to test the risk difference of IDs between patients with psoriasis and reference cohort. RESULTS: A total of 25,742 patients with psoriasis and 128,710 reference subjects were followed up for approximately 6 years. The likelihood of IDs in patients with psoriasis was twice as high as the reference population (908 vs 438 events/100,000 person-years, crude hazard ratio 2.08, 95% confidence interval 1.96-2.22). In a multivariate model the hazard ratio decreased to 1.54 (95% confidence interval 1.44-1.65). This risk was highest for patients with more severe psoriasis (adjusted hazard ratio 1.81, 95% confidence interval 1.57-2.08), but was not associated with recent systemic antipsoriatic drug dispensing. Respiratory tract, abdominal, and skin infections occurred most frequently in patients with psoriasis. Multiple event analysis that counted the total number of infectious discharge diagnoses gave similar results. LIMITATIONS: No data were available on lifestyle factors. CONCLUSION: The risk of severe infections was significantly higher for patients with psoriasis compared with control subjects and could not be explained by exposure to systemic antipsoriatic drugs. PMID- 21664718 TI - Supplement use and risk of cutaneous squamous cell carcinoma. AB - BACKGROUND: Laboratory and epidemiologic studies suggest that certain dietary supplements may alter risk of cutaneous squamous cell carcinoma (SCC). OBJECTIVE: We sought to examine the association between supplement use and SCC risk. METHODS: Cases (n = 415) were defined as Kaiser Permanente Northern California members with a pathology-verified SCC in 2004 and control subjects (n = 415) were age-, sex-, and race-matched members with no history of skin cancer. Supplement use and SCC risk factors were ascertained by questionnaire. Associations of SCC with use of multivitamins; vitamins A, C, D, and E; and grape seed extract were estimated as odds ratios and 95% confidence intervals using conditional logistic regression. Models were adjusted for SCC risk factors and other supplement use. RESULTS: Grape seed extract users had a significantly decreased risk of cutaneous SCC (adjusted odds ratio 0.26, confidence interval 0.08-0.89, P = .031). Multivitamin use was associated with a borderline significant reduction in SCC risk (adjusted odds ratio 0.71, confidence interval 0.51-1.00, P = .049). Use of vitamins A, C, D, and E was not associated with SCC risk. LIMITATIONS: The data may be prone to recall and selection bias because of the case-control design. No information was obtained on dose or duration of supplement use. CONCLUSIONS: Use of grape seed extract may be associated with a decreased risk of cutaneous SCC. The other supplements included in our study did not reveal clear associations with SCC risk. PMID- 21664720 TI - A bundle of care to reduce colorectal surgical infections: an Australian experience. AB - Use of 'bundles of care' to improve patient outcomes is becoming more widespread; however, their use is more common internationally than in Australia. The objective of this study was to assess the feasibility of implementing a bundle of care for patients undergoing colorectal surgery with the aim of reducing surgical site infections. Each component of the bundle was evidence based, focusing on normothermia, normoglycaemia, oxygen delivery and use of appropriate antibiotics. Implementation required extensive consultation and education, together with a checklist to accompany patients and record whether processes were followed and outcomes achieved. Difficulties were experienced with achieving compliance with processes, although some improvements were seen. There was a link between the use of warming devices and improved maintenance of normothermia. The infection rate fell from 15% [95% confidence interval (CI) 10.4-20.2] before the project to 7% (95% CI 3.4-12.6) 12 months after the project. While the small sample size does not allow definitive conclusions to be drawn, the results are promising. Potential reasons for low compliance with individual components of the bundle of care are discussed. In conclusion, introduction of a bundle of care for patients undergoing colorectal surgery into an Australian hospital was only modestly successful. Despite this, infection rates decreased over the 12 months following introduction of the bundle. PMID- 21664721 TI - Decline and fall of epidemic meticillin-resistant Staphylococcus aureus-16. AB - Epidemic meticillin-resistant Staphylococcus aureus-16, which was widespread throughout the UK and the rest of the world, has declined markedly in recent years. The reasons for this are not clear. PMID- 21664723 TI - Improving central venous catheter insertion documentation to facilitate electronic surveillance of bundle compliance. AB - We developed an electronic surveillance system and modified electronic medical record and documentation practices to allow automated tracking of the central line bundle documentation with the insertion of central venous catheters. Despite significant improvements in documented use of the central line bundle in >80% of insertions, our central line-associated bloodstream infection rate remained unchanged, suggesting the need to further improve compliance toward a goal of 100% of central line insertions, as well as training and education on proper line maintenance for catheters that are medically required for prolonged periods. PMID- 21664722 TI - Adherence to hand hygiene and risk factors for poor adherence in 13 Ontario acute care hospitals. AB - Multicenter studies assessing hand hygiene adherence and risk factors for poor performance are scarce. In an observational study involving 13 hospitals across Ontario, Canada, we found a mean adherence rate of 31.2%, and that adherence was positively associated with nurses, single rooms, contact precautions, and the availability of alcohol hand rub dispensers. PMID- 21664724 TI - A home health agency's pandemic preparedness and experience with the 2009 H1N1 pandemic. AB - BACKGROUND: Adequate pandemic preparedness is imperative for home health agencies. METHODS: A 23-item pandemic preparedness survey was administered to home health agencies in the spring of 2010. The Kruskal-Wallis (KW) test was used to evaluate the relationships between agency size and preparedness indicators. Significant findings were further analyzed by the Mann-Whitney (MW) U post hoc test. RESULTS: The response rate was 25% (526/2,119). Approximately one-third of respondents (30.4%; n = 131) reported experiencing trouble obtaining supplies during the 2009 H1N1 pandemic. Small agencies were significantly more likely (Krusal-Wallis [KW] = 9.2; P < .01) to report having trouble obtaining supplies than larger-sized agencies (Mann-Whitney [MW] = 14,080; P < .01). Most home health agencies (87.3%; n = 459) reported having a pandemic influenza plan. One third (33.5%; n = 176) reported having no surge capacity; only 27.0% (n = 142) reported having at least a 20% surge capacity. The largest agencies were significantly more likely (KW = 138; P < .001) to report having at least 20% surge capacity than medium-sized agencies (MW = 7,812; P = .001) or small agencies (MW = 8,306; P < .001). Approximately 80% (n = 414) reported stockpiling personal protective equipment. Three-quarters (71.3%; n = 375) reported fit testing staff, and half (49.2%; n = 259) reported participating in disaster drills. The majority of home health professionals (75.1%; n = 395) reported having a personal/family disaster plan in place. CONCLUSION: There are gaps in US home health agency pandemic preparedness, including surge capacity and participation in disaster drills, that need to be addressed. PMID- 21664725 TI - [Bone metabolism changes in 100 patients with inflammatory bowel disease]. AB - OBJECTIVES: To evaluate the prevalence of osteopenia and osteoporosis in patients with inflammatory bowel disease (IBD) and to study the factors involved in their pathogenesis. METHODS: One hundred consecutive patients with IBD (57 women, mean age 41 years) were included in this study. Data were collected about their life habits, disease characteristics of medication use (mainly corticosteroids). Bone turnover markers were analyzed and the presence of osteoporosis or osteopenia was assessed with total hip and lumbar spine bone densitometry (DXA). RESULTS: Osteopenia percentages ranged from 37% (t-score measured by lumbar spine DXA) to 39% (hip DXA t-score). The prevalence of osteoporosis ranged from 2% (t-score measured by hip DXA) to 15% (lumbar spine DXA t-score). In the multivariate analysis, diagnosis of Crohn's disease (vs. ulcerative colitis; odds ratio 2.9, 95% CI 1-8.7) and the number of flares controlled by the cumulative dose of steroids (number of flares >= 3: odds ratio 8.7; 95%CI 1.6-45) were associated with a higher risk of osteopenia/osteoporosis. None of the analytical parameters significantly correlated with bone mineral density values. CONCLUSIONS: The prevalence of osteopenia/osteoporosis is higher in patients with IBD (mainly those with Crohn's disease) than in the general population. Changes in bone metabolism seem to be more closely related to the inflammatory activity of IBD than to the steroid dose per se. Bone turnover markers did not correlate with the presence of osteopenia and osteoporosis. PMID- 21664727 TI - [Economic evaluation of rituximab added to fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide for the treatment of chronic lymphocytic leukemia]. AB - OBJECTIVES: We evaluated the cost-effectiveness of rituximab added to the chemotherapy regimen of fludarabine plus cyclophosphamide (R-FC) versus fludarabine plus cyclophosphamide (FC) for the treatment of patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). METHODS: Two Markov models were built, using published results on progression free survival (PFS) in patients receiving first- or second-line therapy with R-FC vs FC, rates of disease progression and mortality rates in Spain. Patient elicited utilities were applied to PFS and progressed health states. The cost of drugs, supportive care, and quality-adjusted life years (QALY) were estimated over a 10-year period. Univariate and probabilistic (Monte Carlo) sensitivity analyses were performed. RESULTS: The addition of rituximab to chemotherapy in first- and second-line therapy increased life-years gained (LYG) and QALYs compared with chemotherapy. The incremental cost per LYG and QALY gained was ?20,703 and ?19,343 for first-line treatment and was ?23,183 and ?24,781 for second-line treatment. CONCLUSION: In patients with previously untreated or relapsed/refractory CLL, the addition of rituximab to the FC regimen increased life expectancy and quality-adjusted life expectancy. In both types of patient, the treatment was cost-effective. PMID- 21664728 TI - [Hospital admissions in Bahia de Algeciras (Cadiz, Spain). Comparison with the rest of Andalusia and Spain (2001-2005)]. AB - OBJECTIVES: To describe hospital admissions data in the Bay of Algeciras from 2001 to 2005 compared with the rest of Andalusia and Spain and to analyze the relationship between these data and the most frequent diagnoses leading to excessive premature mortality in this area. METHODS: We carried out a cross sectional study. The study population consisted of the residents of the municipalities of the Bay of Algeciras, obtained from the Population and Household Census of 2001. Age-adjusted annual average hospital admission rates were compared between the Bay of Algeciras (2001-2005) and the rest of Andalusia and Spain using the relative and attributable risk. Hospital admissions and premature mortality rates were compared by means of the relative risk of the most important causes. RESULTS: Hospital admissions in the Bay of Algeciras were significantly lower for most of the diagnoses studied. There was also excessive premature mortality, especially for circulatory diseases (RR for hospital admissions: 0.79 in men and 0.87 in women; RR for premature mortality: 1.39 in men and 1.70 in women). Notable specific diseases were diabetes in both genders and cerebrovascular disease and liver cirrhosis in men. CONCLUSIONS: This study found a lower use of healthcare services and a higher risk of premature mortality due to severe diseases in this region. Further studies analyzing the potential socioeconomic and environmental determinants of the area are required. PMID- 21664729 TI - Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones. AB - Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A(1) and A(2A) receptors. Selected compounds were additionally investigated for affinity to the human A(1), A(2A), A(2B) and A(3) receptor subtypes. The results of the radioligand binding assays at adenosine A(1) and A(2A) receptors showed that most of the compounds exhibited adenosine A(2A) receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A(2A) affinity. The most potent A(2A) ligands of the present series were compounds 6 (K(i) 0.33 MUM rat A(2A), 0.31 MUM human A(2A)), 8 (K(i) 0.98 MUM rat A(2A), 0.42 MUM human A(2A)) and 15 (K(i) 0.24 MUM rat A(2A), 0.61 MUM human A(2A)) with the latter one showing high A(2A) selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A(2A) receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q(2) = 0.88) for A(2A) AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A(2A) antagonists with good water-solubility. PMID- 21664730 TI - Stereoselective synthesis and antimicrobial activity of steroidal C-20 tertiary alcohols with thiazole/pyridine side chain. AB - Stereoselective synthesis of novel steroidal C-20 tertiary alcohols with thiazole and pyridine side chain using Grignard reaction of steroidal ketones and thiazole/pyridine magnesium bromide have been realized. These molecules were evaluated in vitro for their antifungal and antibacterial activities. Most of the compounds exhibited significant antifungal and antibacterial activity against all the tested strains. PMID- 21664731 TI - Synthesis and screening of galactose-linked nitroimidazoles and triazoles against Mycobacterium tuberculosis. AB - A series of galactose-linked nitroimidazoles/triazoles were synthesised and screened against Mycobacterium tuberculosis H(37)Rv. Preliminary results were promising with MIC values in the range 1.56-12.5 MUg/mL. Most importantly they are active under aerobic condition under which metronidazole is inactive. PMID- 21664732 TI - Midwifery early labour series--call for papers. PMID- 21664733 TI - Upper limb kinetic analysis of three sitting pivot wheelchair transfer techniques. AB - BACKGROUND: The objective of this study was to investigate differences in shoulder, elbow and hand kinetics while performing three different SPTs that varied in terms of hand and trunk positioning. METHODS: Fourteen unimpaired individuals (8 male and 6 female) performed three variations of sitting pivot transfers in a random order from a wheelchair to a level tub bench. Two transfers involved a forward flexed trunk (head-hips technique) and the third with the trunk remaining upright. The two transfers involving a head hips technique were performed with two different leading hand initial positions. Motion analysis equipment recorded upper body movements and force sensors recorded hand reaction forces. Shoulder and elbow joint and hand kinetics were computed for the lift phase of the transfer. FINDINGS: Transferring using either of the head hips techniques compared to the trunk upright style of transferring resulted in reduced superior forces at the shoulder (P<0.002), elbow (P<0.004) and hand (P<0.013). There was a significant increase in the medial forces in the leading elbow (P=0.049) for both head hip transfers and the trailing hand for the head hip technique with the arm further away from the body (P<0.028). The head hip techniques resulted in higher shoulder external rotation, flexion and extension moments compared to the trunk upright technique (P<0.021). INTERPRETATION: Varying the hand placement and trunk positioning during transfers changes the load distribution across all upper limb joints. The results of this study may be useful for determining a technique that helps preserve upper limb function overtime. PMID- 21664734 TI - Transvenous cardiac device wires and vascular access in hemodialysis patients. PMID- 21664736 TI - Guidelines for the older adult with CKD. PMID- 21664735 TI - Trends in the use and outcomes of implantable cardioverter-defibrillators in patients undergoing dialysis in the United States. AB - BACKGROUND: Sudden cardiac death constitutes the leading cause of death in patients receiving dialysis. Little is known about the trends in implantable cardioverter-defibrillator (ICD) use and the outcomes of such device placement. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: US long-term dialysis patients who received an ICD in 1994-2006. PREDICTORS, OUTCOMES, & MEASUREMENTS: ICD utilization rates and incident rates of all-cause mortality, device infections, and other device-related procedures were measured. We compared mortality between recipients and otherwise similar patients who did not receive such a device using high-dimensional propensity score matching. We also examined the associations of demographics, dialysis type, baseline comorbid conditions, cardiovascular events at the time of admission, and recent infection with the study outcomes. RESULTS: 9,528 patients received an ICD in 1994-2006, with >88% placed after 2000. Almost all ICD use in the 1990s was for secondary prevention, however, half the patients received ICDs for apparent primary prevention in 2006. Mortality rates after implantation were high (448 deaths/1,000 patient-years) and most deaths were cardiovascular. Postimplantation infection rates were high, especially in the first year after implantation (988 events/1,000 patient-years) and were predicted by diabetes and recent infection. Patients receiving ICDs for secondary prevention had an overall 14% (95% CI, 9%-19%) lower mortality risk compared with propensity-matched controls, but these benefits seemed to be restricted to the early postimplantation time. LIMITATIONS: Lack of clinical data, especially for laboratory and heart function studies. Residual confounding by indication. CONCLUSIONS: ICD use in dialysis patients is increasing, but rates of all-cause and cardiovascular mortality remain high in dialysis patients receiving these devices. Device infections are common, particularly in patients with recent infections. Randomized trials of ICDs are needed to determine the efficacy, safety, and risk-benefit ratio of these devices in dialysis patients. PMID- 21664737 TI - Culture, gender and health care stigma: Practitioners' response to facial masking experienced by people with Parkinson's disease. AB - Facial masking in Parkinson's disease is the reduction of automatic and controlled expressive movement of facial musculature, creating an appearance of apathy, social disengagement or compromised cognitive status. Research in western cultures demonstrates that practitioners form negatively biased impressions associated with patient masking. Socio-cultural norms about facial expressivity vary according to culture and gender, yet little research has studied the effect of these factors on practitioners' responses toward patients who vary in facial expressivity. This study evaluated the effect of masking, culture and gender on practitioners' impressions of patient psychological attributes. Practitioners (N = 284) in the United States and Taiwan judged 12 Caucasian American and 12 Asian Taiwanese women and men patients in video clips from interviews. Half of each patient group had a moderate degree of facial masking and the other half had near normal expressivity. Practitioners in both countries judged patients with higher masking to be more depressed and less sociable, less socially supportive, and less cognitively competent than patients with lower masking. Practitioners were more biased by masking when judging the sociability of the American patients, and American practitioners' judgments of patient sociability were more negatively biased in response to masking than were those of Taiwanese practitioners. Practitioners were more biased by masking when judging the cognitive competence and social supportiveness of the Taiwanese patients, and Taiwanese practitioners' judgments of patient cognitive competence were more negatively biased in response to masking than were those of American practitioners. The negative response to higher masking was stronger in practitioner judgments of women than men patients, particularly American patients. The findings suggest local cultural values as well as ethnic and gender stereotypes operate on practitioners' use of facial expressivity in clinical impression formation. PMID- 21664738 TI - Taxing sin and saving lives: Can alcohol taxation reduce female homicides? AB - With costs exceeding $5.8 billion per year, violence against women has significant ramifications for victims, their families, the health care systems that treat them, and the employers who depend on their labor. Prior research has found that alcohol abuse contributes to violence against both men and women, and that stringent alcohol control policies can reduce alcohol consumption and in turn some forms of violence. In this paper, we estimate the direct relationship between an important alcohol control measure, excise taxes, and the most extreme form of violence, homicide. We use female homicide rates as our measure of severe violence, as this measure is consistently and accurately reported across multiple years. Our results provide evidence that increased alcohol taxes reduce alcohol consumption and that reductions in alcohol consumption can reduce femicide. Unfortunately, a direct test of the relationship does not have the power to determine whether alcohol taxes effectively reduce female homicide rates. We conclude that while alcohol taxes have been shown to effectively reduce other forms of violence against women, policy makers may need alternative policy levers to reduce the most severe form of violence against women. PMID- 21664739 TI - Life satisfaction and age: Dealing with underidentification in age-period-cohort models. AB - Recent literature typically finds a U shaped relationship between life satisfaction and age. Age profiles, however, are not identified without forcing arbitrary restrictions on the cohort and/or time profiles. In this paper we report what can be identified about the relationship between life satisfaction and age without applying such restrictions. Also, we identify the restrictions needed to conclude that life satisfaction is U shaped in age. For the case of Germany, we find that the relationship between life satisfaction and age is indeed U shaped, but only under the untestable condition that the linear time trend is negative and that the linear trend across birth cohorts is practically flat. PMID- 21664740 TI - Correlation between volume of herniated orbital contents and the amount of enophthalmos in orbital floor and wall fractures. AB - PURPOSE: To analyze the correlation between the volume of herniated orbital contents and the amount of enophthalmos in orbital floor and wall fractures. MATERIALS AND METHODS: Patients with secondary enophthalmos due to unilateral orbital floor and wall fractures were recruited. Computed tomography-assisted measurements of both orbits as well as of the amount of enophthalmos were performed. The following volumes were calculated: 1) the overall volume of both the healthy and fractured orbit, 2) the volume of herniated orbital contents at the orbital walls, 3) the volume of herniated orbital contents anterior and posterior to the vertical eyeball equator. The amount of enophthalmos was also measured by computed tomography. Multifactor linear regression analysis was performed to obtain correlations between the amount of enophthalmos and the measured volumes. RESULTS: Twenty-three patients were included. The average enophthalmos was 4.0 mm (SD = 1.49). Although correlation between volume differences of healthy and fractured sides was not statistically significant, the overall volume of the herniated orbital contents was significantly correlated (P < .05) with the amount of enophthalmos. Regarding the specific orbital sites of herniation, the orbital floor was detected to be most significantly correlated to the amount of enophthalmos (P < .05), although only the herniation posterior to the vertical eyeball equator. CONCLUSION: The overall volume of herniated orbital contents correlated significantly with the amount of enophthalmos. The orbital floor was detected to be the site most significantly correlated with the amount of enophthalmos (although only if herniation occurred posterior to the vertical eyeball equator). Only the volume of herniated soft tissues posterior to the eyeball equator showed correlation with the amount of enophthalmos. PMID- 21664741 TI - Retrospective analysis of use of buccal fat pad as an interpositional graft in temporomandibular joint ankylosis: preliminary study. AB - PURPOSE: To evaluate the feasibility and usefulness of buccal fat pad as an interpositional graft in the treatment of temporomandibular joint (TMJ) ankylosis. MATERIALS AND METHODS: A retrospective study of 10 patients with TMJ ankylosis (9 unilateral and 1 bilateral) was performed with follow-up of 6 months to 2 years. RESULTS: In the present study, patients had a maximum interincisal opening of 32 to 41 mm (mean, 35.1 mm) at the latest follow-up. Mean deviation to the affected side on mouth opening was 1.6 mm (range, 0 to 4 mm), but chewing function was good and all the patients were satisfied. No major occlusal changes were observed and all the patients had satisfactory occlusion at the follow-up periods. No facial paresis of temporal and zygomatic branch of facial nerve was observed in any case. Periodic panoramic radiographs showed well-maintained intra articular space because of the interposed tissue, with no signs of relapse. CONCLUSION: The findings of this study showed the short-term successful management of TMJ ankylosis using buccal fat pad as an interpositional graft. PMID- 21664742 TI - Effectiveness of buccal fat in closing residual midpalatal and posterior palatal fistulas in patients previously treated for clefts. AB - PURPOSE: The present retrospective study assessed the outcome and effectiveness of the buccal fat pad flap for closure of postoperative midpalatal fistulas and fistulas of the posterior palate in patients previously treated for cleft palate. PATIENTS AND METHODS: The charts of 29 patients with residual midpalatal and posterior palatal fistulas treated using buccal fat pad flaps were assessed. Of the 29 patients, 18 were males and 11 were females, aged 2.5 to 19 years. The fistula size was 10 to 20 mm. RESULTS: Full epithelialization of the flap had occurred within 4 weeks in all 29 patients. The fistulas had completely closed in 28 patients. In 1 patient, a 2-mm defect was noted in the anterior part of the fistula repair that had healed after 2 months without intervention. CONCLUSION: The buccal fat pad flap can be used to repair any remaining postoperative palatal fistulas that are 10 to 20 mm in size. PMID- 21664743 TI - Traumatic orbital floor fractures: repair with autogenous bone grafts in a tertiary trauma center. AB - PURPOSE: To evaluate the outcome of autologous bone grafts in the reconstruction of orbital floor fractures. A retrospective interventional case series was performed at a tertiary trauma center. MATERIALS AND METHODS: All patients with traumatic orbital floor fractures that had been reconstructed using calvarial or iliac autogenous bone grafts from August 2006 to January 2010 were included in the present study. The operations were performed by the same team of maxillofacial and oculoplastic surgeons. The patients were evaluated pre- and postoperatively for the presence of enophthalmus and diplopia. The surgical technique was tailored to best fit the patient's clinical characteristics, with attention to the cosmetic and functional outcomes and the preferred use of a sutureless transconjunctival technique, when applicable. The main outcome measures were residual enophthalmus, diplopia, and the complication rate. RESULTS: A total of 16 patients (11 males and 5 females), with an average age of 34.4 years, underwent orbital floor reconstruction using an autologous bone graft. Calvarial and iliac bone grafts were used in 11 and 5 patients, respectively. A transconjunctival approach was applied in 10 patients. All patients achieved good cosmetic and functional outcomes, with improvement in enophthalmus. Three patients had residual diplopia postoperatively that was probably due to traumatic muscular injury. No significant perioperative or long term complications were noted during a mean follow-up of 12.5 months. CONCLUSION: Reconstruction of orbital floor fractures after trauma using autologous bone grafts is safe and associated with a low rate of complications. Combining the appropriate surgical approach with multidisciplinary teamwork results in excellent cosmetic and functional outcomes and allows for efficient and comprehensive postoperative management. PMID- 21664744 TI - Causes of persistent joint pain after arthrocentesis of temporomandibular joint. AB - PURPOSE: The present study was undertaken to elucidate the factors responsible for the failure of arthrocentesis to cure persistent joint pain in patients with nonreducing articular disc displacement in the temporomandibular joint (TMJ). PATIENTS AND METHODS: Thirty-six patients with internal derangement of the TMJ were selected. Magnetic resonance imaging was used to examine the configuration and position of the articular discs, cortical changes, and bone marrow abnormalities in the condyle and the presence of joint effusion. Arthrocentesis was then performed, and the patients were followed for 6 weeks. The results were then classified as poor or improved. RESULTS: The effects of arthrocentesis did not depend on the configuration of the disc, disc position and motion, or bone marrow abnormalities. Joints with no or minimal amounts of joint effusion achieved a good response to arthrocentesis. Joints with erosive cortical changes of the condyle were less responsive to arthrocentesis. CONCLUSION: Persistent joint pain after arthrocentesis is generally associated with extensive amounts of joint effusion or erosive cortical changes of the condyle. PMID- 21664745 TI - Cervicofacial necrotizing fasciitis and steroids: case report and literature review. PMID- 21664746 TI - Endoscope-assisted transoral reduction and internal fixation versus closed treatment of mandibular condylar process fractures--a prospective double-center study. AB - PURPOSE: The aim of this international AO-study was to compare the functional outcome after open versus closed treatment of mandibular condylar neck fractures. PATIENTS AND METHODS: A prospective comparative study with two follow-ups (FU) at 8-12 weeks and 1 year was undertaken in two clinics, which exclusively privileged either surgical or conservative treatment due to different therapeutic agendas. Patients from clinic 1 (ENDO group) received endoscope-assisted transoral open reduction and internal fixation, whereas patients from clinic 2 (CONS group) were treated conservatively without surgery. Patients with unilateral condylar neck fractures showing one or more of the following conditions were included: displacement of the condyle with an inclination >30 degrees and/or severe functional impairment such as malocclusion or open bite, with or without dislocation of the condylar fragment; severe pain upon palpation or movement, and/or vertical shortening of the ascending ramus. High or intracapsular condylar neck fractures were excluded. RESULTS: 75 patients (44 CONS and 31 ENDO patients) with condylar neck fractures were included in this study. The Asymmetric Helkimo Dysfunction Score (A-HDS) was slightly lower in the CONS group than in the ENDO group at the 8-12-week FU, corresponding to better function on the short-term. At the 1-year FU, however, there were slightly better values in the ENDO group. For the Clinical Dysfunction Index (Di) and the Anamnestic Dysfunction Index (Ai), CONS patients had a better outcome than ENDO patients at the 8-12 week FU, ie, a higher proportion of ENDO patients had severe symptoms due to the operative trauma. Yet these symptoms improved by one year, finishing with a significant higher proportion of symptom-free patients in the ENDO group. In addition, these patients had better values for the Index for Occlusion and Articulation Disturbance (Oi) at both FU examinations, ie, the proportion of patients without any occlusal disturbances was significantly higher in the ENDO group. On average, the duration of postoperative maxillo-mandibular fixation (MMF) was 3 times longer for the CONS group than for the ENDO group (33 vs. 11 days). CONCLUSION: Both treatment options may yield acceptable results for displaced condylar neck fractures. Especially in patients with severe malocclusion directly after trauma, however, endoscope-assisted transoral open reduction and fixation seems to be the appropriate treatment for prevention of occlusal disturbances during FU. PMID- 21664747 TI - 9 is always on top: assessing the automaticity of synaesthetic number-forms. AB - For number-form synaesthetes, digits occupy idiosyncratic spatial locations. Atypical to the mental number line that extends horizontally, the synaesthete (L) experiences the numbers 1-10 vertically. We used a spatial cueing task to demonstrate that L's attention could be automatically directed to locations within her number-space - being faster to detect targets appearing in synaesthetically cued locations. We sought to eliminate any influence of strategy on L's performance by: (a) shortening the cue-target onset to 150 ms, (b) making the cues counterpredictive, and (c) instructing L to use an opposing strategy. If L's performance was attributable to intentionally using the cue to predict target location, these manipulations should eliminate any cuing effects consistent with her synaesthesia. However, L showed an attentional bias compatible with her number-form, except when explicitly instructed of the opposing strategy and given enough time (800 ms). Therefore, we attribute L's resilient cueing effects to the automaticity of her number-form. PMID- 21664748 TI - [Heart failure in a patient with Wolff-Parkinson-White syndrome]. PMID- 21664749 TI - Simultaneous replacement of complete thoracic aorta. PMID- 21664751 TI - [Problems of a teenager's heart]. PMID- 21664752 TI - [Dual coronary artery fistulas as a cause of unstable angina]. PMID- 21664753 TI - [Contrast echocardiography and ST-segment elevation]. PMID- 21664754 TI - [Usefulness of the Tornus(r) catheter in nondilatable coronary chronic total occlusion]. AB - The treatment of coronary chronic total occlusions (CTO) remains a challenge for the interventional cardiologist. Failure of balloon angioplasty is the second more common cause of an unsuccessful procedure. We describe our experience with the use of the new Tornus(r) catheter (Asahi Intecc, Aichi, Japan) designed specifically for the treatment of "nondilatable" CTO. Between November 2008 and March 2010, 17 patients (age 62 years, 88% men, 82% dyslipidemia, 52% hypertension, 29% diabetes) were treated in whom balloon dilatation had failed after crossing the lesion with the guide. The use of Tornus(r) catheter was successful without complications in 15. All patients underwent clinical follow-up (median, 573 days) with no documented major adverse events. The use of the Tornus(r) catheter is safe and feasible in those patients with CTO lesions in whom balloon angioplasty has been unsuccessful. PMID- 21664755 TI - [Diagnostic accuracy of NT-proBNP compared with electrocardiography in detecting left ventricular hypertrophy of hypertensive origin]. AB - Electrocardiography (ECG) is the most widely used method for diagnosing left ventricular hypertrophy (LVH) in hypertensive patients. We assessed the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) determination compared with ECG for detecting LVH in 336 consecutive hypertensive patients with preserved systolic function. We found a significant correlation between NT-proBNP levels and left ventricular mass adjusted for body surface area (r=.41; P<.001). The area under the receiver operating characteristic curve was 0.75 (95% CI, 0.7 0.8). A cut-off of 74.2 pg/mL had a greater sensitivity than ECG (76.6% vs 25.5%; P<.001) and a higher negative predictive value (87.8% vs 76.6%; P<.001) in the identification of LVH. NT-proBNP determination may be a useful tool for LVH screening in hypertensive patients. PMID- 21664756 TI - [Congenital heart failure in a nonagenarian patient]. PMID- 21664757 TI - Positive impact of crisis resource management training on no-flow time and team member verbalisations during simulated cardiopulmonary resuscitation: a randomised controlled trial. AB - OBJECTIVES: To evaluate the impact of video-based interactive crisis resource management (CRM) training on no-flow time (NFT) and on proportions of team member verbalisations (TMV) during simulated cardiopulmonary resuscitation (CPR). Further, to investigate the link between team leader verbalisation accuracy and NFT. METHODS: The randomised controlled study was embedded in the obligatory advanced life support (ALS) course for final-year medical students. Students (176; 25.35+/-1.03 years, 63% female) were alphabetically assigned to 44 four person teams that were then randomly (computer-generated) assigned to either CRM intervention (n=26), receiving interactive video-based CRM-training, or to control intervention (n=18), receiving an additional ALS-training. Primary outcomes were NFT and proportions of TMV, which were subdivided into eight categories: four team leader verbalisations (TLV) with different accuracy levels and four follower verbalisation categories (FV). Measurements were made of all groups administering simulated adult CPR. RESULTS: NFT rates were significantly lower in the CRM-training group (31.4+/-6.1% vs. 36.3+/-6.6%, p=0.014). Proportions of all TLV categories were higher in the CRM-training group (p<0.001). Differences in FV were only found for one category (unsolicited information) (p=0.012). The highest correlation with NFT was found for high accuracy TLV (direct orders) (p=0.06). CONCLUSIONS: The inclusion of CRM training in undergraduate medical education reduces NFT in simulated CPR and improves TLV proportions during simulated CPR. Further research will test how these results translate into clinical performance and patient outcome. PMID- 21664758 TI - Is it possible to predict para-aortic lymph node metastasis in endometrial cancer? AB - OBJECTIVE: The purpose of this study was to determine the histopathologic risk factors for pelvic lymph node (PLN) and para-aortic lymph node (PALN) metastasis in endometrial cancer (EC) and to identify in which patients PALN dissection should be performed. STUDY DESIGN: A total of 204 consecutive patients, with EC and underwent systematic pelvic and para-aortic lymphadenectomy extending to the renal vessels, were studied retrospectively. Statistical significance between risk factors was examined using multivariant logistic regression analysis. RESULTS: Cell type, depth of myometrial invasion and tumor size were found to be independently related to PLN metastasis. PLN metastasis in any site and lymphovascular invasion (LVSI) were independent prognostic factors for predicting PALN metastasis. The sensitivity, specificity and the NPV of PLN metastasis for detecting PALN metastasis were 80.8%, 89.3% and 97%, respectively. Furthermore, the 204 patients were divided into two groups according to the presence of one of these following factors: (1) non-endometrioid cell type, (2) PLN metastasis, (3) LVSI, (4) adnexal metastasis and (5) serosal involvement. Among these 204 patients, 104 had one or more of these factors (group A), and 100 patients had none of these factors (group B). PALN metastasis was significantly greater in group A, compared to group B. The sensitivity and the NPV of these combined prognostic factors for predicting PALN metastasis were 96.2% and 99%, respectively. CONCLUSIONS: Presence of non-endometrioid cell type, PLN metastasis, LVSI, adnexal metastasis or serosal involvement diagnosed by frozen section (FS) seem to be poor prognostic factor for PALN metastasis in EC. Also, PALN dissection should be extended to the level of the renal vessels in all patients who will undergo PALN dissection, due to frequent involvement of the supramesenterial region. PMID- 21664760 TI - Neurologic symptoms and diagnosis in adults with mast cell disease. AB - OBJECTIVE: To identify complications of mastocytosis that impact the nervous system across a large cohort. PATIENTS AND METHODS: In this retrospective series, we reviewed the electronic medical records of adult patients with a diagnosis of mastocytosis who were referred to a Neurologist at Mayo Clinic in Rochester, MN from January 1, 1999 to December 31, 2008. RESULTS: Thirty patients were identified who presented to a Neurologist with symptoms potentially related to the mast cell disease. Twelve of these patients presented with complex spells involving syncope, which frequently preceded a formal diagnosis of mastocytosis. Nine individuals presented with acute back pain which was ultimately deemed symptomatic of vertebral compression fractures. One individual experienced spinal cord compression from a vertebral mast cell infiltrate. Headaches were reported in 78/223 (35%) total patients with mastocytosis. Although details of headaches were insufficiently ascertained to diagnose most, the five individuals in our referral cohort met International Headache Society (IHS) criteria for migraine. Finally, three individuals (1.3%) were identified with multiple sclerosis occurring at variable times after the mast cell diagnosis. CONCLUSION: Symptoms related to mastocytosis may be encountered by neurologists and mimic many common, often idiopathic syndromes including, syncopal spells, back pain, and headache. In our cohort, multiple sclerosis may be over-represented. Mastocytosis should be considered in patients with these presentations, especially when also accompanied by flushing, abdominal cramping or diarrhea. PMID- 21664761 TI - Depression in relation to anxiety, obsessionality and phobia among neurosurgical patients with a primary brain tumor: a 1-year follow-up study. AB - Depression is found to be present in up to 44% of brain tumor patients during their illness process. Anxiety as a comorbid psychiatric disorder with depression has formerly been studied, but phobia or obsessive-compulsive symptoms among brain tumor patients have not yet been noticed. By using a clinical prospective database of primary brain tumor patients (n=77) we studied the level of depression, anxiety, obsessionality (traits and symptoms) and phobic anxiety symptoms. Psychiatric symptoms were assessed before tumor operation as well as at three months and at one year after operation. The presence of comorbid anxiety, obsessionality and phobic anxiety symptoms was assessed before operation and at follow-ups in depressed and non-depressed patients, separately. Before tumor operation 16% of the patients had depression according to Beck Depression Inventory (BDI), while 10% had depression at three months and 15% at one year after operation. The depressed patients had statistically significantly higher anxiety scores and phobic scores at all three measurement points compared to corresponding scores among non-depressed brain tumor patients. The mean obsessionality scores among depressed brain tumor patients were significantly higher when measured before operation and at one year after the operation compared to non-depressed patients. To our knowledge, this is the first study so far in which comorbidity of psychiatric symptoms has been shown among depressive brain tumor patients. Concurrent comorbid conditions have been shown to be associated with increased severity, morbidity and chronicity of depression. It is recommended that treatment of depressive patients complicated with comorbid psychiatric disorders be planned by psychiatric units. PMID- 21664759 TI - The functional role of reactive stroma in benign prostatic hyperplasia. AB - The human prostate gland is one of the only internal organs that continue to enlarge throughout adulthood. The specific mechanisms that regulate this growth, as well as the pathological changes leading to the phenotype observed in the disease benign prostatic hyperplasia (BPH), are essentially unknown. Recent studies and their associated findings have made clear that many complex alterations occur, involving persistent and chronic inflammation, circulating hormonal level deregulation, and aberrant wound repair processes. BPH has been etiologically characterized as a progressive, albeit discontinuous, hyperplasia of both the glandular epithelial and the stromal cell compartments coordinately yielding an expansion of the prostate gland and clinical symptoms. Interestingly, the inflammatory and repair responses observed in BPH are also key components of general wound repair in post-natal tissues. These responses include altered expression of chemokines, cytokines, matrix remodeling factors, chronic inflammatory processes, altered immune surveillance and recognition, as well as the formation of a prototypical 'reactive' stroma, which is similar to that observed across various fibroplasias and malignancies of a variety of tissue sites. Stromal tissue, both embryonic mesenchyme and adult reactive stroma myofibroblasts, has been shown to exert potent and functional regulatory control over epithelial proliferation and differentiation as well as immunoresponsive modulation. Thus, the functional biology of a reactive stroma, within the context of an adult disease typified by epithelial and stromal aberrant hyperplasia, is critical to understand within the context of prostate disease and beyond. The mechanisms that regulate reactive stroma biology in BPH represent targets of opportunity for new therapeutic approaches that may extend to other tissue contexts. Accordingly, this review seeks to address the dissection of important factors, signaling pathways, genes, and other regulatory components that mediate the interplay between epithelium and stromal responses in BPH. PMID- 21664762 TI - Cranial subarachnoid hemorrhage as an unusual complication of epidural blood patch. PMID- 21664763 TI - Biological sex and social setting affects pain intensity and observational coding of other people's pain behaviors. AB - This experiment examines the impact of biological sex and audience composition on laboratory-induced ischemic pain intensity and observational coding of other people's pain behaviors. Situational context was manipulated by varying the sex and number of audience stimuli in the laboratory setting during the pain task and during observational evaluations of other people's pain suffering. The analyses revealed sex differences in felt pain intensity and observable pain behaviors, with male subjects reporting lower pain intensity and evidencing fewer pain behaviors than female subjects on average. Follow-up analyses revealed that, after controlling for social anxiety, audience composition was linked to felt pain intensity, and this relation was moderated by participant sex and audience sex, such that only male subjects showed decreased pain intensity with increasing number of female audience members. Sex differences were also found in the rating of other people's pain behaviors, with male observers rating the pain of others lower than female observers. Composition of the audience influenced observers' pain ratings such that the presence of more male subjects in the audience correlated with lower observer ratings, whereas the presence of more female subjects correlated with higher observer ratings. This is the first study to show that the sex and the composition of the social context in which pain is experienced affects the intensity of felt pain and the evaluation of other people's pain suffering. Implications of the findings for measuring and interpreting pain suffering in male and female patients by male and female treatment providers in health care settings are discussed. PMID- 21664764 TI - High mortality and lesions of the central nervous system in trypanosomosis by Trypanosoma vivax in Brazilian hair sheep. AB - Here, we report an outbreak of Trypanosoma vivax-induced trypanosomosis in Brazilian hair sheep on a farm in Paraiba state, a non-endemic region in northeastern Brazilian. Of 306 total sheep, 240 showed clinical signs and 216 died. Clinical signs included anorexia, lethargy, anemia, rough hair coat, weight loss, submandibular edema, abortion, and in some cases, neurological signs such as head pressing, lateral recumbence, paddling movements and muscle tremors. T. vivax was identified by blood smear analysis and polymerase chain reaction (PCR). At necropsy, animals exhibited watery blood, pale tissue coloring, and the presence of liquid in the peritoneal cavity and pericardial sac. Histologically, nonsuppurative myocarditis and meningoencephalitis with areas of malacia were observed. After treatment, no parasites were detected by blood smear analysis or PCR. Cattle and buffalo that remained in the same pasture were also infected but presented with asymptomatic infections. Epidemiological data suggest that T. vivax was introduced to the farm and the susceptible flock by buffalos that were asymptomatic carriers of the infection; T. vivax was most likely transmitted by Tabanus spp. bites and also iatrogenically. PMID- 21664765 TI - SSRIs and placental dysfunction. PMID- 21664766 TI - Carpal coalition: symptomatic incomplete bony coalition of the capitate and trapezoid--case report. AB - We present a case of symptomatic, incomplete bony carpal coalition between capitate and trapezoid. We describe previous case reports and possible therapeutic options. PMID- 21664767 TI - Gliding resistance and triggering after venting or A2 pulley enlargement: a study of intact and repaired flexor tendons in a cadaveric model. AB - PURPOSE: This study compared the effect of 2 techniques of pulley management- venting and pulley enlargement (complete A2 incision with pulley repair and sheath closure using a retinacular graft)--on gliding resistance and on the incidence of triggering following zone 2 flexor tendon repairs in human cadaver specimens. METHODS: In vitro gliding resistance and the incidence of triggering were determined in 10 human cadaver specimens under 5 progressive conditions: (1) intact, (2) tendon repair (both tendons cut and repaired with the sheath intact), (3) condition 2 plus 50% venting of the distal A2 pulley, (4) condition 2 with venting extended to 66% of distal A2, and (5) condition 4 plus pulley enlargement. Triggering was determined in the same specimens by 2 computational algorithms that detected force changes in the load cells used to measure gliding resistance. RESULTS: Tendon repair increased gliding resistance from the intact condition by an average of 229%. Gliding resistance was reduced in conditions 3, 4, and 5 from the repair condition by 15%, 25%, and 22%, respectively. Triggering commenced with tendon repair in some specimens, and its incidence increased with 50% venting. Further venting reduced triggering, but not as effectively as pulley enlargement did. CONCLUSIONS: In this cadaveric study, venting and pulley enlargement reduce gliding resistance by equivalent amounts. Triggering persisted despite venting. The surgeon should carefully examine tendon repairs for free gliding. Pulley enlargement might be more effective than venting in reducing the incidence of triggering. PMID- 21664768 TI - The relationship between industry and surgery. AB - This article examines industry's involvement in medicine, particularly with respect to surgeons and clinical research, as well as continuing medical education. We describe some historical events involving industry and how these events have led to guidelines by various organizations to handle conflicts of interest. We also review the advantages and disadvantages of collaborating with industry and provide practical guides for interactions with industry in terms of clinical research, continuing medical education, and clinical practice. With careful consideration to protect all parties involved, collaboration with industry can be advantageous to surgeons, industry, and patients. PMID- 21664769 TI - Osteoarthritis of the elbow. PMID- 21664770 TI - Drug dealing cessation among a cohort of drug users in Vancouver, Canada. AB - INTRODUCTION: Drug dealing among drug users has been associated with elevated risk-taking and negative health outcomes. However, little is known about the cessation of drug dealing among this population. METHODS: We assessed time to cessation of drug dealing using Cox regression. We also used generalized estimating equation (GEE) analysis and chi-square analysis to examine factors associated with willingness to cease drug dealing. RESULTS: In total, 868 participants reported drug dealing between November 2005 and March 2009. Among 381 participants dealing drugs at baseline, 194 (51%) ceased dealing. Incidence of dealing cessation was positively associated with spending less than $50 per day on drugs (Adjusted Hazard Ratio [AHR]=1.88, 95% confidence interval [CI]: 1.14-3.10) and negatively associated with buying drugs from the same source (AHR=0.60, 95% CI: 0.37-0.98). In a GEE analysis, willingness to cease dealing was positively associated with older age (Adjusted Odds Ratio [AOR]=1.02, 95% CI: 1.01-1.03), crack use (AOR=2.00, 95% CI: 1.44-2.79), public injecting (AOR=1.95, 95% CI: 1.55-2.43), and reporting that police presence affects drug purchases (AOR=1.53, 95% CI: 1.22-1.91), and negatively associated with crystal methamphetamine injection (AOR=0.62, 95% CI: 0.47-0.83). DISCUSSION: Intensity of drug use and acquisition method were predictive of dealing cessation. Willingness to cease dealing was associated with a range of risky drug-related activities. Interventions to reduce drug dealing should be conceived in tandem with addiction treatment strategies. PMID- 21664771 TI - Self-reported drug use and mortality among a nationwide sample of Swedish conscripts - a 35-year follow-up. AB - BACKGROUND: Drug users in clinical samples have elevated mortality compared with the general population, but little is known about mortality among users of drugs within the general population. AIM: To determine whether self-reported use of illicit drugs and non-prescribed sedatives/hypnotics among young men in the general population is related to mortality. METHODS: A 35-year follow-up of 48024 Swedish men, born 1949-1951 and conscripted in 1969/1970, among whom drug use was reported by 8767 subjects. Cross-record linkage was effected between individual data from the Swedish conscription and other national registers. Deaths and causes of death/1000 person-years were calculated. Cox PH regression was used to estimate hazard ratios (HRs) for death with 95% confidence intervals (95% CIs). An HR was calculated for users of different dominant drugs at conscription compared with non-users by age interval, after adjusting for confounders and hospitalisation with a drug-related diagnosis. RESULTS: Drug users showed elevated mortality (HR 1.61, p<0.05) compared with non-users. After adjusting for risk factors, users of stimulants (HR 4.41, p<0.05), cannabis (HR 4.27, p<0.05), opioids (HR 2.83, p>0.05), hallucinogens (HR 3.88, p<0.05) and unspecified drugs (HR 4.62, p<0.05) at conscription with a drug-related diagnosis during follow-up showed an HR approaching the standard mortality ratios in clinical samples. Among other drug users (95.5%), only stimulant users showed statistically significantly increased mortality (HR 1.96, p<0.05). CONCLUSIONS: In a life-time perspective, drug use among young men in the general population was a marker of premature death, even a long time after exposure. PMID- 21664772 TI - Prevention of deformational plagiocephaly in neonates. AB - BACKGROUND: Since the early 90s a striking rise in deformational plagiocephaly (DP) has been reported, and a causal link between the "back to sleep" position recommended to reduce the risk of sudden infant death syndrome. Recent data suggested that supine position is a risk factor only when combined with other environmental factors OBJECTIVE: To evaluate the impact of early intervention in the newborn environment on the prevalence of DP at 4 months of life. METHODS: A multicentric, prospective, controlled study in healthy term neonates. Within 72 h of birth, all parents received the usual recommendations for positioning their infants to prevent sudden infant death syndrome. In the Intervention group, recommendations were also given to encourage spontaneous and unhindered physical movement. At 1, 2 and 4 months, we looked for plagiocephaly and collected information on the infants' environment. RESULTS: The environment of the Intervention group (n = 88) was significantly more favorable to unhindered movement than in the control group (n = 51) (lower immobility score, p < 0.01). The prevalence of DP was significantly lower in the Intervention group than in the control group (13% vs. 31%, p < 0.001). For each supplementary hour of immobility during the third and fourth months of life, the risk of DP at four months doubled (OR:2.1[1.4-3.2]). CONCLUSION: Early postnatal intervention on the maternity ward reduces the prevalence of DP. The recent rise in the incidence of DP could be related to a lack of stimulation and encouragement to physical movement rather than to supine positioning proposed for prevention of sudden infant death syndrome. PMID- 21664773 TI - Falls, injuries from falls, health related quality of life and mortality in older adults with vision and hearing impairment--is there a gender difference? AB - BACKGROUND: Vision and hearing decline with age. Loss of these senses is associated with increased risk of falls, injuries from falls, mortality and decreased health-related quality of life (HRQOL). Our objective was to determine if there are gender differences in the associations between visual and hearing impairment and these outcomes. METHODS: 2340 men and 3014 women aged 76-81 years from the Health in Men Study and the Australian Longitudinal Study on Women's Health were followed for an average of 6.36 years. Dependent variables were self reported vision and hearing impairment. Outcome variables were falls, injuries from falls, physical and mental components of HRQOL (SF-36 PCS and MCS) and all cause mortality. RESULTS: Vision impairment was more common in women and hearing impairment was more common in men. Vision impairment was associated with increased falls risk (odds ratio (OR)=1.77, 95% CI=1.35-2.32 in men; OR=1.82, 95% CI=1.44-2.30 in women), injuries from falls (OR=1.69, 95% CI=1.23-2.34 in men, OR=1.79, 95% CI=1.38-2.33 in women), and mortality (hazard ratio (HR)=1.44; 95% CI=1.17-1.77 in men; HR=1.50, 95% CI=1.24-1.82 in women) and declines in SF-36 PCS and MCS. Hearing impairment was associated with increased falls risk (OR=1.38, 95% CI=1.08-1.78 in men; OR=1.45, 95% CI=1.08-1.93 in women) and declines in SF-36 PCS and MCS. Overall there were no gender differences in the association between vision and hearing impairment and the outcomes. CONCLUSION: In men and women aged 76-81 years, there were no gender differences in the association between self-reported vision and hearing impairment and the outcomes of falls, mortality and HRQOL. PMID- 21664774 TI - Regional neuropathology referral practice before and after new organ retention legislation. AB - AIMS: Previous organ retention controversies in the United Kingdom have resulted in public concern in relation to the retention of organs following post mortem examination. Therefore, protocols were devised and implemented to facilitate adequate sampling for diagnostic purposes for neuropathology autopsy referrals, without the need for organ retention. We have examined various aspects of referral practice before and after the introduction of these new sampling protocols. METHODS: All neuropathology autopsy referral cases were reviewed between 1993 and 1995, and 2003 and 2005 and data such as: referral source, nature of samples (whether whole organ or limited sampling) and final diagnosis were recorded. RESULTS: Overall, the number of autopsy cases referred for neuropathology opinion reduced, particularly those originating from hospital consented autopsies. Forensic referrals also reduced, with a shift in practice from referrals of whole fixed brains, to both whole brains and sampled brain slices. Within the referrals from forensic practice, whilst cases of 'natural deaths' and head injury cases secondary to road traffic accidents or falls reduced, cases involving inflicted, traumatic head injury and sudden unexpected death in epilepsy and infancy remained static. CONCLUSION: The introduction of protocols to facilitate sampling of brains at autopsy, so minimising organ retention, proved successful and, whilst there has been a reduction in neuropathology referrals, cases in which neuropathology input is deemed best practice remained static. PMID- 21664775 TI - Determining dental sex dimorphism in South Indians using discriminant function analysis. AB - Dental forensics forms a vital branch of forensic science which deals with proper handling, examination and evaluation of dental evidences for identification of victims of crime, accidents or calamities. Therefore skull and teeth often provide the identification material. The aim of the study was to investigate the accuracy of odontometric methods in sex determination of permanent teeth and to compute new formula to differentiate male and female teeth using discriminant function analysis for South Indian population. A total of 100 subjects were selected for the study from a parent population of 4800 students by simple random sampling method. Alginate impressions of the upper dental arch were made and casts were poured immediately. A digital vernier calliper was used for the measurement of all upper anteriors. Twelve different tooth measurements were recorded and from those two indexes have been computed. Statistical analysis was performed using the SPSS version 17.0 software. All the predictor variables were subjected to stepwise discriminant function analysis which optimally separates the genders and a best discriminant function was generated. In all the observed mean dimensions, male values exceed the female values. Student's 't' test for the different predictor variables of all teeth selected between male and females were found significant (p < 0.05). Very high significance was found in mean MD of 11, 12 and 13 and |c| of 23. The variables exhibiting best discriminant powers were mesiodistal width of both upper central incisors, DB-ML of 13 and canine crown module of 13. Sexual dimorphism in the size of permanent teeth differs from one population to the other and hence the standards set for one population could not be applied for another population. Hence this technique would be a simple, quick, cost effective, reliable and accurate for sex determination. PMID- 21664776 TI - Recent misconceptions about the 'database search problem': a probabilistic analysis using Bayesian networks. AB - This paper analyses and discusses arguments that emerge from a recent discussion about the proper assessment of the evidential value of correspondences observed between the characteristics of a crime stain and those of a sample from a suspect when (i) this latter individual is found as a result of a database search and (ii) remaining database members are excluded as potential sources (because of different analytical characteristics). Using a graphical probability approach (i.e., Bayesian networks), the paper here intends to clarify that there is no need to (i) introduce a correction factor equal to the size of the searched database (i.e., to reduce a likelihood ratio), nor to (ii) adopt a propositional level not directly related to the suspect matching the crime stain (i.e., a proposition of the kind 'some person in (outside) the database is the source of the crime stain' rather than 'the suspect (some other person) is the source of the crime stain'). The present research thus confirms existing literature on the topic that has repeatedly demonstrated that the latter two requirements (i) and (ii) should not be a cause of concern. PMID- 21664778 TI - Diagnostic performance of combined cardiac MRI for detection of coronary artery disease. AB - OBJECTIVE: To evaluate the diagnostic performance of stress perfusion cardiac MR (CMR) for detecting significant CAD (>=70% narrowing) in comparison with invasive coronary angiography (ICA) as a reference standard. METHODS: Examinations of 54 patients who underwent both stress perfusion CMR and ICA for investigation of CAD between 2007 and 2009 were evaluated. The CMR protocol included dipyridamole stress and rest perfusion, stress and rest cine MRI for assessment of ventricular function and delayed gadolinium enhancement for assessment of myocardial viability and detection of infarction. CMR interpretation was performed by 2 observers blinded to the results of ICA and the clinical history. RESULTS: From a total of 54 patients, 37 (68.5%) showed significant CAD in 71 coronary territories. A perfusion defect was detected in 35 patients and in 69 coronary territories. Individual stress perfusion CMR evaluation showed the highest accuracy (83%) of the CMR techniques. The combined analysis using all sequences increased the overall accuracy of CMR to 87%. CONCLUSION: Combination of perfusion and cine-MR during stress/rest, associated to delayed enhancement in the same protocol improves CMRI diagnostic accuracy and sensitivity for patients with significant coronary stenosis, and may therefore be helpful for risk stratification and defining treatment strategies. PMID- 21664777 TI - Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. AB - OBJECTIVES: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a gamma aminobutyric acid (GABA) degradative defect. Epilepsy affects half of patients. The murine model is associated with a transition from absence to convulsive seizures in the third week, with fatal status epilepticus. METHODS: The clinical phenotype is reported from a patient database. Flumazenil-Positron Emission Topography (FMZ-PET) and Transcranial Magnetic Stimulation (TMS) were used to study GABA neurotransmission. Electrocorticography, single cell electrophysiology, and radioligand binding studies are reported from animal studies. RESULTS: Generalized seizures predominate, including tonic-clonic, atypical absence, and myoclonic. EEG discharges are typically generalized spike wave. MRI shows a dentatopallidoluysian pattern. Sudden Unexpected Death in Epilepsy Patients (SUDEP) has occurred and the associated neuropathology reveals chronic excitotoxic injury in gloubus pallidus. Investigations using FMZ-PET and TMS support downregulation of GABA(A) and GABA(B) activity, respectively, in patients. Gamma-hydroxybutyrate (GHB) induces spike-wave discharges in homozygous null mice via GHB and GABA(B)-mediated mechanisms. These resemble absence seizures and are abolished by a GABA(B) receptor antagonist. Decreased binding of GABA(A) and GABA(B) receptor antagonists has been demonstrated in P19 and P14 null mice, respectively. Downregulation of GABA(A) and GABA(B) receptor subunits is observed by P14. GABA(A) and GABA(B) mediated potentials are reduced from P8 P14. CONCLUSION: Generalized epilepsy and epileptiform discharges are characteristic of SSADH deficiency. Spontaneous absence seizures appear in null mice by the third week, which may be induced by GHB or GABA(B) activity. Subsequent overuse dependent downregulation of GABA(A) and GABA(B) receptor activity may be associated with hyperexcitability concomitant with the transition to generalized seizures. PMID- 21664779 TI - MRI evaluation of residual tumor size after neoadjuvant endocrine therapy vs. neoadjuvant chemotherapy. AB - AIM: To investigate if there is any difference in evaluation of residual tumor size after neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NAE). METHODS: Seventy-eight tumors in 57 patients were prospectively enrolled. Residual tumor sizes in contrast-enhanced MRI after NAC and NAE were compared with those measured on surgical specimen by using linear regression analyses. The line slope values >1 indicates overestimation by MRI. Differences in types of shrinkage patterns: concentric shrinkage (CS) and dendritic shrinkage (DS) were also investigated. RESULTS: Fifty lesions were treated with NAC and 28 lesions were treated with NAE. Shrinkage patterns were CS in 33 lesions and in 45 lesions. The slopes values were 0.75 (R=0.92) and 0.70 (R=0.90) for NAC and NAE, respectively, and no significant difference was observed (p=0.46). However, they were 1.02 (R=0.92) and 0.68 (R=0.92), respectively for CS and DS with significant difference (p<0.01). The difference between CS and DS was found only in a subgroup with size by MRI >20 mm. CONCLUSION: Contrast enhanced MRI enabled fairly accurate measurement in NAE as well as in NAC. PMID- 21664780 TI - Diagnosis of right-sided varicocele: a retrospective comparative study between clinical examination, Doppler findings, US imaging and vascular anatomy at phlebography. AB - Historically varicocele is diagnosed almost exclusively on the left side. The introduction of new imaging techniques has allowed the identification and characterization of right varicocele. This study aims to compare the diagnostic accuracy of various imaging techniques to data obtained using phlebography in the diagnosis of right varicocele. Patients treated for isolated right varicocele between 1992 and 2010 were retrospectively identified. Data from clinical examination, Doppler-USS, Color-Doppler-USS and Retrograde Phlebography were collected for each patient. 133 out of 4305 patients (3.1%) presented with an isolated right varicocele. 34 of these patients (25.6%) presented with palpable right varicocele. Doppler-USS identified various degrees of type I right venous reflux in 90 patients (67.7%). Phlebography showed venous reflux in all the patients (133), although with variability in terms of internal spermatic vein anatomy. Right varicocele is characterized by predictable anatomic features. Identification and characterization of these features is useful in guiding percutaneous treatment, allowing to optimize radiological display and reducing failure rate. PMID- 21664782 TI - Bilateral filtering of magnetic resonance phase images. AB - High-pass filtering is required for the removal of background field inhomogeneities in magnetic resonance phase images. This high-pass filtering smooths across boundaries between areas with large differences in phase. The most prominent boundary is the surface of the brain where areas with large phase values inside the brain are located close to areas outside the brain where the phase is, on average, zero. Cortical areas, which are of great interest in brain MRI, are therefore often degraded by high-pass filtering. Here, we propose the use of the bilateral filter for the high-pass filtering step. The bilateral filter is essentially a Gaussian filter that stops smoothing at boundaries. We show that the bilateral filter improves image quality at the brain's surface, without sacrificing contrast within the brain. PMID- 21664781 TI - Realignment strategies for awake-monkey fMRI data. AB - Functional magnetic resonance imaging (fMRI) experiments with awake nonhuman primates (NHPs) have recently seen a surge of applications. However, the standard fMRI analysis tools designed for human experiments are not optimal for NHP data collected at high fields. One major difference is the experimental setup. Although real head movement is impossible for NHPs, MRI image series often contain visible motion artifacts. Animal body movement results in image position changes and geometric distortions. Since conventional realignment methods are not appropriate to address such differences, algorithms tailored specifically for animal scanning become essential. We have implemented a series of high-field NHP specific methods in a software toolbox, fMRI Sandbox (http://kyb.tuebingen.mpg.de/~stoewer/), which allows us to use different realignment strategies. Here we demonstrate the effect of different realignment strategies on the analysis of awake-monkey fMRI data acquired at high field (7 T). We show that the advantage of using a nonstandard realignment algorithm depends on the amount of distortion in the dataset. While the benefits for less distorted datasets are minor, the improvement of statistical maps for heavily distorted datasets is significant. PMID- 21664783 TI - Principal eigenvector field segmentation for reproducible diffusion tensor tractography of white matter structures. AB - The study was aimed to test the feasibility of utilizing an algorithmically determinable stable fiber mass (SFM) map obtained by an unsupervised principal eigenvector field segmentation (PEVFS) for automatic delineation of 18 white matter (WM) tracts: (1) corpus callosum (CC), (2) tapetum (TP), (3) inferior longitudinal fasciculus (ILF), (4) uncinate fasciculus (UNC), (5) inferior fronto occipital fasciculus (IFO), (6) optic pathways (OP), (7) superior longitudinal fasciculus (SLF), (8) arcuate fasciculus (AF), (9) fornix (FX), (10) cingulum (CG), (11) anterior thalamic radiation (ATR), (12) superior thalamic radiation (STR), (13) posterior thalamic radiation (PTR), (14) corticospinal/corticopontine tract (CST/CPT), (15) medial lemniscus (ML), (16) superior cerebellar peduncle (SCP), (17) middle cerebellar peduncle (MCP) and (18) inferior cerebellar peduncle (ICP). Diffusion tensor imaging (DTI)-derived fractional anisotropy (FA) and the principal eigenvector field have been used to create the SFM consisting of a collection of linear voxel structures which are grouped together by color coding them into seven natural classes to provide PEVFS signature segments which greatly facilitate the selection of regions of interest (ROIs) for fiber tractography using just a single mouse click, as compared with a manual drawing of ROIs in the classical approach. All the 18 fiber bundles have been successfully reconstructed, in all the subjects, using the single ROIs provided by the SFM approach, with their reproducibility characterized by the fact that the ROI selection is user independent. The essentially automatic PEVFS method is robust, efficient and compares favorably with the classical ROI methods for diffusion tensor tractography (DTT). PMID- 21664784 TI - Authentication of Senecio scandens and S. vulgaris based on the comprehensive secondary metabolic patterns gained by UPLC-DAD/ESI-MS. AB - A secondary metabolic pattern using ultra-performance liquid chromatography (UPLC)-DAD/ESI-MS was constructed to gain chemical information for authentication of Senecio scandens (SS) and Senecio vulgaris (SV), the two representative species containing hepatotoxic pyrrolizidine alkaloids (HPAs). The metabolic pattern showed three groups of bioactive constituents: phenolic/aromatic acids, flavonoid glycosides and the HPAs. 47 peaks were identified including 19 phenolic/aromatic acids, 10 flavonoid glycosides and 18 PAs by direct comparison with the available reference compounds or deduced from the UV absorption and their ESI-MS fragmentation patterns. The two species could be authenticated diagnostically by their metabolic profiling of the three chromatographic fingerprints. Although both SS and SV contain PAs as the characteristic constituents, only 2 PAs, adonifoline and adonifoline N-oxide were detected in SS, while other 16 PAs were detected in SV, including the highly toxic senecionine, retrorsine, seneciphylline and their corresponding N-oxides. The concentration of PAs in SV is also higher than that in SS. The number and concentration of the phenolic compounds in SS were higher than in SV. Jacaranone derivatives were only detected in SS and jacaranone ethyl ester was detected as the predominant constituent. In the fingerprint of the n-butanol extracts, 10 quercetin and kaempferol glycosides derivatives were detected. 9 were found in SS and only 2 in SV. PAs, jacaranone derivatives and flavonoid glycosides can serve as the metabolic markers to distinguish the Senecio plants from each other, and provide evidence for their clinical application in the consideration of safety and efficacy. PMID- 21664785 TI - A strategy for the detection of quality fluctuation of a Chinese herbal injection based on chemical fingerprinting combined with biological fingerprinting. AB - Herbal injections are powerful preparations of traditional Chinese medicines. However, the quality control (QC) of these formulations is difficult to establish. Recently, chemical fingerprinting (CF) has been recommended as a potential strategy for the QC of herbal injections. However, some constituents cannot be detected by chromatographic methods. To establish a comprehensive QC process, biological fingerprinting (BF) was combined with CF to detect the fluctuation in quality of a herbal injection from chemical and biological aspects. Yinzhihuang injection was selected as a representative herbal injection. Ten batches of normal samples and six batches of artificially abnormal samples were collected. High-performance liquid chromatography and thermal activity monitoring were applied to develop CF and BF, respectively. The CF and BF of normal samples were similar, with good stability and consistency, but the abnormal samples were not. The results were analyzed by hierarchical clustering analysis: all abnormal samples could be correctly distinguished when CF and BF were combined. The recognition ratio was higher for CF (87.5%) than for BF (93.75%). The key factors of quality fluctuation were bacterial contamination, high temperature, lighting, and sterilizing conditions. The described method could be used for early prediction of adverse drug events, which could help improve the safety of herbal injections. PMID- 21664786 TI - A support vector machine based pharmacodynamic prediction model for searching active fraction and ingredients of herbal medicine: Naodesheng prescription as an example. AB - The complex chemical composition of herbal medicine leads to the lack of appropriate method for identifying active compounds and optimizing the formulation of herbal medicine. One of the most commonly used method is bioassay guided fractionation. However, if the herbal medicine was divided into many fractions, it would cost much money and time in carrying out such a full bioassay. So, can we just perform the bioassay of a few fractions, and then develop a method to predict the bioactivities of other fractions? This study is designed to try to answer the question. In this work, a support vector machine (SVM) pharmacodynamic prediction model was introduced to search active fraction and ingredients of Naodesheng prescription. The prescription was first divided into five extracts, yielding a total of 25=32 combinations. Anti-platelet aggregation experiment with SD rats was just carried out on 16 combinations. The effects of the remained 32-16=16 combinations were then predicted by the SVM model. The prediction quality was evaluated by both the rigorous jackknife test and the independent dataset validation test. Furthermore, the present method was compared with the frequently used MLR, PCR and PLSR. The present method outperforms the other 3 methods, yielding: RMSECV=2.40, R=0.895 by the jackknife test and RMSEP=7.41, R=0.910 by the independent dataset test. It indicates that the SVM prediction model has good accuracy and generalization ability. The active fraction and ingredients of Naodesheng prescription were then predicted by the model. It is believed that the present model can be extended to help search the active fraction and ingredients of other herbal medicines. PMID- 21664787 TI - Determination of isotretinoin in human plasma by high performance liquid chromatography-electrospray ionization mass spectrometry. AB - A rapid, sensitive and specific high performance liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) method for the quantification of 13-cis-retinoic acid (isotretinoin) in human plasma has been developed. Acitretin was employed as the internal standard (IS). The analytes were chromatographically separated on a Shimadzu Shim-pack VP-ODS C18 column (150 mm * 2.0 mm I.D.) with a mobile phase consisting of acetonitrile and water (90:10, v/v). Detection was performed on a single quadrupole mass spectrometer using an electrospray ionization interface with the selected-ion monitoring (SIM) mode. The method showed excellent linearity (r=0.9989) over the concentration range of 10-1500 ng/mL with good accuracy and precision. The intra- and inter batch precisions were within 10% relative standard deviation. The recoveries were more than 80%. The validated method was successfully applied to a preliminary bioequivalence study of isotretinoin in 20 Chinese healthy male volunteers. PMID- 21664788 TI - Information needs and preferences of women as they proceed through radiotherapy for breast cancer. AB - OBJECTIVE: While radiotherapy is commonly employed in the treatment of breast cancer, many women know little about treatment and experience treatment related anxiety. The aims of this study were to: Prioritise breast cancer patients' radiotherapy related information needs and concerns; determine unmet information needs; ascertain which information sources patients prefer to receive; and explore whether information provision reduces anxiety and depression. METHODS: A longitudinal survey was administered at four time points: after initial consultation with radiation oncologist, after the planning appointment, within first week of treatment and after treatment completion. Data was analysed using generalised estimating equations. RESULTS: 123 women participated. Women were most concerned about the impact treatment would have on their health in the future. Women identified high information needs prior to treatment planning and commencing treatment. Women's anxiety at baseline (mean=6.07, SD=3.89) did not significantly drop until after treatment commencement (mean=5.33, SD=4.15). CONCLUSION: This study demonstrates that women's information needs and anxiety levels are high until treatment commencement. PRACTICE IMPLICATIONS: In order to reduce patients' psychological distress, information needs and concerns we recommend that a greater focus is placed on providing information to patients prior to treatment planning and prior to treatment. PMID- 21664789 TI - Efficacy of continuing medical education to reduce the risk of buprenorphine diversion. AB - As office-based opioid dependence treatment (OBOT) has grown in the United States, postmarketing surveillance data reveal increased reports of buprenorphine misuse and diversion. It is important that doctors understand buprenorphine clinical pharmacology and engage in practices to decrease risk of misuse, diversion, and other adverse events. This study evaluated the efficacy of continuing medical education (CME) in two U.S. regions with surveillance signals of buprenorphine misuse/diversion. Four surveys (before, on-site, and 1 and 3 months post CME) evaluated physician characteristics, practice behaviors, and buprenorphine pharmacology and legislative knowledge. The results show that physicians had limited addictions training. Knowledge and practice behaviors significantly improved after the CME, which should enhance the quality of OBOT and may decrease risk of buprenorphine misuse and diversion from their practices. Mandatory CME targeting OBOT-certified physicians could have a positive impact on patient and public health outcomes. PMID- 21664790 TI - If substance use disorder treatment more than offsets its costs, why don't more medical centers want to provide it? A budget impact analysis in the Veterans Health Administration. AB - Given that many studies have reported that the costs of substance use disorder (SUD) treatment are more than offset by other savings (e.g., in health care, in criminal justice, in foster care), why haven't health care system managers rushed to expand treatment? This article attempts to explain this puzzling discrepancy by analyzing 1998-2006 data from the national Veterans Affairs (VA) health care system. The main outcome measures were annual cost and utilization for VA SUD diagnosed patients. The key independent variable was the medical centers' annual spending for SUD treatment. There was no evidence that SUD spending was associated with lower medical center costs over time within the medical center that paid for the treatment. Health care system managers may not be influenced by research suggesting that the costs of SUD treatment are more than fully offset because they bear the cost of providing treatment while the savings largely accrue to other systems. PMID- 21664791 TI - Technical failure of medial patellofemoral ligament reconstruction. AB - In patients with chronic patellofemoral instability who have normal alignment and deficient proximal medial restraints, medial patellofemoral ligament (MPFL) reconstruction is a good option to treat patellar instability. However, medial subluxation, medial patellofemoral articular overload, and recurrent lateral instability are possible when the graft is positioned non-anatomically. The clinical presentation of MPFL femoral tunnel malpositioning has not been highlighted in the literature. We have had 5 patients referred to us after a malpositioned femoral MPFL graft led to disabling symptoms and a need for revision surgery. This report highlights the effects of a malpositioned graft and describes strategies to identify the anatomic MPFL insertion during surgery. PMID- 21664792 TI - Sport-specific outcomes after anterior cruciate ligament reconstruction. AB - PURPOSE: Although anterior cruciate ligament (ACL) reconstruction has been studied extensively in the literature, sport-specific outcomes have not been well documented. The purpose of this systematic review was to assess sport-specific outcomes after ACL reconstruction in the literature. METHODS: We performed a systematic review of the literature to identify studies reporting sport-specific outcomes after primary ACL reconstruction. Included studies were required to have reported standardized outcomes after primary ACL reconstruction for a single sport or comparing between different sports. RESULTS: In total 8 studies conformed to all inclusion criteria: 2 Level II studies, 1 Level III study, and 5 Level IV case series. Only 1 study reported comparisons of standardized outcomes between different sports, whereas 7 studies reported standardized outcomes in a single sport. Return to activity was the most common sport-specific outcome reported and varied from 19% (soccer) to 100% (bicycling and rugby), although the methods of measuring this outcome differed. CONCLUSIONS: Whereas return to activity after ACL reconstruction appears more likely for bicycling and jogging than for cutting and pivoting sports such as soccer and football, the literature on sport-specific outcomes from ACL reconstruction is limited with minimal data. Further studies are needed to report sport-specific outcomes and return to play after ACL reconstruction. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV studies. PMID- 21664793 TI - [Letter on the article "Number of deaths attributable to benfluorex"]. PMID- 21664794 TI - [Recent advances in the treatment of HCV cryoglobulinemia vasculitis]. PMID- 21664795 TI - Reoperative minimally invasive mitral valve replacement for bovine pericardial valve thrombosis secondary to idiopathic hypereosinophilic syndrome. AB - Bioprosthetic mitral valves rarely obstruct. We present an older woman who presented with rapidly progressive dyspnea 4 years after bovine mitral replacement. Investigations demonstrated severe mitral stenosis with large, obstructive masses within the previous mitral prosthesis and an elevated eosinophil count. She underwent urgent reoperative mitral replacement and tricuspid valve repair through a 4-cm right minithoracotomy under hypothermic, fibrillatory arrest. Pathologic analysis revealed eosinophilic infiltrates in the obstructive masses and normal endomyocardial biopsies. She made an uneventful recovery and was discharged on steroids to suppress the eosinophilia. Repeat echocardiography demonstrated a well-functioning porcine valve without leaflet restriction or obstruction. PMID- 21664796 TI - Pulmonary function tests and respiratory symptoms among smokers in the city of Mashhad (north east of Iran). AB - The prevalence of smoking was studied using a questionnaire. Pulmonary function tests and respiratory symptoms were evaluated in 176 smokers. The total studied population with family and co-workers were 13289. The number of smokers among studied population was 11.7%. The rate of smoking among male subjects was 17.2% and in female 2.5%. All values of PFTs in smokers were significantly lower (p<0.001) and respiratory symptoms higher than in non smokers (p<0.05 for cough and p<0.001 for wheeze and tightness). There were significant negative correlations between smoking duration and rate with values of PFT (p<0.05 p<0.001). In this study the prevalence of smoking in population of Mashhad city was shown. The prevalence of smoking was higher among male than females. Smoking leads to increased respiratory symptoms and reduction of PFTs values. PMID- 21664797 TI - Pain disrupts sleep in children and youth with intellectual and developmental disabilities. AB - Both chronic pain and sleep problems are common for children with intellectual and developmental disabilities (IDD). Although one study has revealed a relationship between having a medical condition and sleep problems in this population, the role of pain was not examined independently. Thus, the goal of this study was to clarify the specific role of pain in children's sleep problems. Caregivers of 123 children with IDD (67 male; mean age = 10 years, 7 months (SD = 49.7 months)) completed the Children's Sleep Habits Questionnaire (CHSQ) and provided information about children's pain, function and demographic characteristics. Children were grouped as having: No Pain (86), Treated Pain (21), or Untreated Pain (16). A Multivariate Analysis of Variance (MANOVA) indicated children who had pain had significantly more sleep problems overall (F(16, 222) = 2.2, p = .005), and more Night Wakings (F(2, 118) = 3.1, p = .05), Parasomnias (F(2, 118) = 5.0, p = .009) and Sleep Disordered Breathing (F(2, 118) = 5.1, p = .008) in particular. The pattern of sleep problems varied due to whether the child was taking pain medication. Children with pain also had significantly shorter typical sleep duration (F(2, 112) = 3.5, p = 0.035). The presence of sleep problems did not vary due to functional level or whether children were taking sleep medications. However, parents of children who were taking sleep medications reported that both Bedtime Resistance (F(1, 121) = 5.7, p = .019) and Sleep Duration (F(1, 121) = 6.0, p = .016) were more problematic for them. This data indicates pain disrupts sleep in children with IDD even when it is being managed pharmacologically, suggesting pain treatment may not be effective. These results suggest that pain should be considered during evaluation and management of sleep problems in children with IDD. PMID- 21664799 TI - Normal values for left ventricular volume in infants and young children: questions for the authors. PMID- 21664800 TI - Smoking and psoriasis: A meta-analysis of case-control studies. PMID- 21664801 TI - Early psychosis treatment in an integrated model within an adult mental health service. AB - OBJECTIVE: To compare the treatment of patients with early psychosis, 2 years after the introduction of an integrated model of enhanced management within a public adult mental health service, with an historic cohort from the same service. METHOD: Variables examined in the 2001 cohort were compared with 2008 patients. Computer database review and a file audit were conducted for all patients with early psychosis across the first 2 years of the program. RESULTS: Compared to the historic cohort, patients in the current cohort were 24% less likely to have been admitted (P=0.004). There were statistically significant reductions in involuntary status and use of a locked unit. Rates of police involvement in admission and use of seclusion were also reduced, though this trend was not significant. Average length of stay was reduced. Median duration of untreated psychosis was 3 months in both 2001 and 2008 cohorts. CONCLUSIONS: The introduction of an integrated model of management within an area mental health service for patients with early psychosis contributed to significant reductions in admissions, involuntary status and use of a locked ward. The data suggests that enhanced treatment of early psychosis patients can be offered within generic services. PMID- 21664802 TI - Sequential patterning of two fluorescent streptavidins assisted by photoactivatable biotin on an aminodextran-coated surface. AB - Sequential patterning of two fluorescent streptavidins (SAvs) was carried out using photopatterning of photoactivatable biotin (photobiotin) on an aminodextran surface, which was crucial for the minimization of non-specific binding. Photobiotin was bound by photoreaction to the amine groups of aminodextran. Water contact angle at each step during the preparation of the aminodextran surface was measured to investigate the hydrophilicity of the surfaces. The specific and nonspecific binding of a fluorescent SAv was investigated for the aminodextran surface and the amine-silane surface. The aminodextran surface almost entirely prevented nonspecific binding of a fluorescent SAv and was successfully used for sequential patterning of two fluorescent SAvs. The addition of ethanolamine (40 mM) in the photobiotin solution diminished blurring of pattern shape. To decrease pattern size, the UV light was focused on the aminodextran surface in an inverted microscope system. Under optimized conditions, two fluorescent SAvs array of approximately 25 MUm size was obtained using a shadow mask of 100 MUm hole size in the inverted microscope system. PMID- 21664803 TI - [Vancomycin: what dosages are needed to achieve efficacy in paediatric hematology/oncology?]. AB - INTRODUCTION: In children and infants, the determination of optimal dosages is essential from the beginning of treatments with vancomycin because of the high risk of inadequate serum concentrations and bacterial resistance. Bayesian pharmacokinetic methods can be used to adjust dosages according to serum vancomycin concentrations and the patients' physiopathological characteristics. The aim of this retrospective study was to review the effective dosages of vancomycin in paediatric hematology/oncology, using a bayesian pharmacokinetic method. PATIENTS AND METHODS: One hundred and sixty-one patients in paediatric hematology/oncology units, aged from 1 month to 18 years, who were treated with vancomycin in continuous infusion, were selected between 2000 and 2010. The influence of initial vancomycin dosages on serum steady-state concentrations (S(sc)) before bayesian adaptation was studied on the basis of dosing recommendations in children and infants (i.e., 40 mg/kg/day). In addition, the S(sc) before bayesian adaptation and the effective dosages determined after bayesian adaptation (E(db)) were analysed according to the patients' age, for an identical dosage of 40 mg/kg/day (+/- 10%). RESULTS: The percentage of patients with low S(sc) (i.e.,<10mg/L) was 28.6%, 16%, and 0 when treatment was initiated at less than 40 mg/kg/day (+/- 10%), at 40 mg/kg/day (+/- 10%), and at more than 40 mg/kg/day (+/- 10%), respectively. For an identical initial dosage of 40 mg/kg/day (+/- 10%), the S(sc) gradually increased as the patients' age increased. The S(sc) were optimal (i.e., between 15 and 20mg/L) in adolescents and children from 6 to 12 years of age, but less than 15 mg/L in children from 2 to 6 years of age and infants. The E(db) gradually increased as the patients' age decreased. DISCUSSION AND CONCLUSIONS: The choice of initial dosages of vancomycin treatment must take greater account of the patient's age in order to reduce the frequency of inadequate S(sc) before titration. In the absence of nephrotoxic cofactors, we suggest an increase in initial vancomycin dosages in continuous infusion between 40 and 45 mg/kg/day in children from 6 to 12 years old, between 45 and 50mg/kg/day in children from 2 to 6 years old, and between 50 and 55 mg/kg/day in infants, in hematology/oncology. For teenage patients, the standard dosage (i.e., 40 mg/kg/d) seems appropriate. PMID- 21664804 TI - [Antibiotic resistance of pneumococci and H. influenzae isolated from the nasopharyngeal flora of children with acute otitis media between 2006 and 2010]. AB - OBJECTIVES: The choice of antibiotics (ATB) to treat acute otitis media (AOM) has to take into account the level of resistance of bacteria species implicated. The aim of this study was to evaluate in France, ATB resistance of pneumococci and H. influenzae isolated from the nasopharyngeal flora, in children with AOM, vaccinated with 7 valent pneumococcal conjugate vaccine (PCV7). METHODS: From 2006 to 2010, 66 pediatricians performed nasopharyngeal specimens of children 6 to 24 months with AOM. Demographic characteristics, history, vaccination status and symptoms were reported on a case report form transmitted to ACTIV. RESULTS: Of the 3,501 children included (mean age 13.5 +/- 5 months), over 98% were PCV7 vaccinated and 41.1% were cared in day care center. A total of 47.3% of children had received ATB within 3 months before inclusion (cephalosporins, 22.6% and amoxicillin clavulanate, 19.2%). Pneumococcus and H. influenzae carriage was respectively 57.9% and 48.2%. Pneumococcal strains with reduced susceptibility to penicillin represented 46.3% of cases (3.9% highly resistant strains and 42.4% intermediate resistant strains). Factors that increased the risk of carrying these strains were: day care center (OR: 1.5, 95% CI: [1.2, 1.9]) and two courses or more of ATB before inclusion (OR: 2.6 (95% CI: [2.0, 3.4]). For H. influenzae strains the proportion of betalactamases+ producing strains was 17.1% and those with reduced susceptibility due to penicillin binding protein changes (BLNAR+ strains+) accounted for 7.7% of cases. Three factors increased the risk of carriage BLNAR+ betalactamase+ producing strains: age equal or greater than 12 months (OR: 3.5, 95% CI: [1.2, 10.3]), cephalosporin use (OR: 2.5, 95% CI: [1.0, 6.1]) and two courses or more of ATB before inclusion (OR: 3.1, 95% CI: [1.2, 8.0]). CONCLUSION: The data in this study (reduction of betalactamase producing H. influenzae strains and increase of intermediate penicillin pneumococcal strains) should help to change the choice of antibiotics for AOM in children in France, by reducing the role of oral cephalosporins and secondly, by giving frontline amoxicillin +/- clavulanic acid. PMID- 21664805 TI - [Parapneumonic pleural effusion incidence in a French region before and during the antipneumococcal vaccine era]. AB - BACKGROUND AND AIMS: The aim of the study was to compare the incidence of parapneumonic pleural effusion in the Limousin region of France, based on the comparison of pre- and postvaccination periods. METHODS: Subjects, 0-18-years old, were retrospectively identified by searching in computerized databases of coded discharge diagnosis for patients with a diagnosis of pleural effusion and/or empyema and/or pulmonary infection in all the pediatric departments in Limousin hospitals. Medical records were reviewed by one of the authors and those with parapneumonic effusion and confirmed or suspected pneumococcal infection were included in the study. Data from the children hospitalized for parapneumonic pleural effusion were collected for two periods: period A, from July 2000 to July 2006, and period B, from July 2006 to July 2009 (before and after the generalization of the antipneumococcal vaccination). The main endpoint was the number of parapneumonic pleural effusion cases in each period in order to calculate the incidence within each period. RESULTS: A total of 35 children were included: nine during period A and 26 during period B. The incidence was 1 per 100,000 children for period A and 5.8 per 100,000 for period B. Bacteriological tests allowed us to serotype eight S. pneumoniae over the two periods. All serotypes were non-vaccine serotypes (1, 3, and 19A). CONCLUSION: This study demonstrates the increase in parapneumonic pleural effusion in the Limousin region. PMID- 21664806 TI - Visual pattern mining in histology image collections using bag of features. AB - OBJECTIVE: The paper addresses the problem of finding visual patterns in histology image collections. In particular, it proposes a method for correlating basic visual patterns with high-level concepts combining an appropriate image collection representation with state-of-the-art machine learning techniques. METHODOLOGY: The proposed method starts by representing the visual content of the collection using a bag-of-features strategy. Then, two main visual mining tasks are performed: finding associations between visual-patterns and high-level concepts, and performing automatic image annotation. Associations are found using minimum-redundancy-maximum-relevance feature selection and co-clustering analysis. Annotation is done by applying a support-vector-machine classifier. Additionally, the proposed method includes an interpretation mechanism that associates concept annotations with corresponding image regions. The method was evaluated in two data sets: one comprising histology images from the different four fundamental tissues, and the other composed of histopathology images used for cancer diagnosis. Different visual-word representations and codebook sizes were tested. The performance in both concept association and image annotation tasks was qualitatively and quantitatively evaluated. RESULTS: The results show that the method is able to find highly discriminative visual features and to associate them to high-level concepts. In the annotation task the method showed a competitive performance: an increase of 21% in f-measure with respect to the baseline in the histopathology data set, and an increase of 47% in the histology data set. CONCLUSIONS: The experimental evidence suggests that the bag-of features representation is a good alternative to represent visual content in histology images. The proposed method exploits this representation to perform visual pattern mining from a wider perspective where the focus is the image collection as a whole, rather than individual images. PMID- 21664807 TI - CD8+ T cell differentiation in the aging immune system: until the last clone standing. AB - A substantial deterioration of the naive CD8(+) T cell pool occurs regularly in humans beyond the age of 65 years. While recall responses to pathogens encountered during youth or adulthood are largely uncompromised, the de novo generation of memory responses by aged naive CD8(+) T cells is perturbed. In recent years evidence has accumulated that the diminished responsiveness of naive CD8(+) T cells in aged humans and other mammals coincides with a progressive loss of naive T cell receptor (TCR) repertoire diversity. In this review we focus on thymic involution and chronic latent viral infections as key factors driving the reduction in naive TCR repertoire diversity. We present novel insights gained by studying the antigen-driven differentiation of single CD8(+) T cells in young hosts and discuss possible implications of these insights for therapeutic support of the thinned-out clonal T cell repertoire of the elderly by vaccination or adoptive cell therapy. PMID- 21664809 TI - Rationally engineering natural protein assemblies in nanobiotechnology. AB - Multimeric protein assemblies are essential components in viruses, bacteria, eukaryotic cells, and organisms where they act as cytoskeletal scaffold, storage containers, or for directional transport. The bottom-up structures can be exploited in nanobiotechnology by harnessing their built-in properties and combining them with new functional modules. This review summarizes the design principles of natural protein assemblies, highlights recent progress in their structural elucidation, and shows how rational engineering can create new biomaterials for applications in vaccine development, biocatalysis, materials science, and synthetic biology. PMID- 21664810 TI - Whole-body diffusion-weighted magnetic resonance imaging: current evidence in oncology and potential role in colorectal cancer staging. AB - Tumour staging in cancer patients generally entails a multimodality imaging approach. Whole-body (WB) imaging techniques may, however, be more time- and cost effective than a multimodality approach. 2-fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET), computed tomography (CT) and hybrid positron emission tomography and computed tomography (PET/CT) are the most established WB modalities, although new techniques, amongst which diffusion weighted magnetic resonance imaging (DWI), are emerging. This review aims to evaluate the current evidence for WB-DWI in oncology, to discuss its potential for the WB staging of (colo)rectal cancer and to relate it to the established WB techniques. PMID- 21664808 TI - Protein folding and quality control in the endoplasmic reticulum: Recent lessons from yeast and mammalian cell systems. AB - The evolution of eukaryotes was accompanied by an increased need for intracellular communication and cellular specialization. Thus, a more complex collection of secreted and membrane proteins had to be synthesized, modified, and folded. The endoplasmic reticulum (ER) thereby became equipped with devoted enzymes and associated factors that both catalyze the production of secreted proteins and remove damaged proteins. A means to modify ER function to accommodate and destroy misfolded proteins also evolved. Not surprisingly, a growing number of human diseases are linked to various facets of ER function. Each of these topics will be discussed in this article, with an emphasis on recent reports in the literature that employed diverse models. PMID- 21664812 TI - Effects of biodrying process on municipal solid waste properties. AB - In this paper, the effect of biodrying process on municipal solid waste (MSW) properties was studied. The results obtained indicated that after 14d, biodrying reduced the water content of waste, allowing the production of biodried waste with a net heating value (NHV) of 16,779+/-2,074kJ kg(-1) wet weight, i.e. 41% higher than that of untreated waste. The low moisture content of the biodried material reduced, also, the potential impacts of the waste, i.e. potential self ignition and potential odors production. Low waste impacts suggest to landfill the biodried material obtaining energy via biogas production by waste re moistening, i.e. bioreactor. Nevertheless, results of this work indicate that biodrying process because of the partial degradation of the organic fraction contained in the waste (losses of 290g kg(-1) VS), reduced of about 28% the total producible biogas. PMID- 21664811 TI - Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. AB - BACKGROUND: In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. METHODS: Patients (n=458) with unresectable HCC, Child-Pugh class A cirrhosis and >=25% tumour necrosis/shrinkage 1-3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). FINDINGS: Baseline characteristics in the two groups were similar; >50% of patients started sorafenib>9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70-1.09; P=0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69-1.64; P=0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed. INTERPRETATION: This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses. PMID- 21664813 TI - WITHDRAWN: Comparative Data on Effects of Leading Pretreatments and Enzyme Loadings and Formulations on Sugar Yields from Different Switchgrass Sources. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21664814 TI - Mild hydrogenolysis of in-situ and isolated Pinus radiata lignins. AB - The Pd/C-catalysed hydrogenolysis of in-situ and isolated lignins from Pinus radiata wood was investigated to gain a more complete understanding of the factors affecting yield and composition of the hydrogenolysis products. Such hydrogenolysis products could potentially be refined into aromatic feedstock chemicals providing sustainable alternatives to petroleum-derived phenols. Lignins were converted into solvent-soluble oils composed of monomeric, dimeric and oligomeric products in high yields, up to 89% of the original lignin. The main monomer products were dihydroconiferyl alcohol and 4-n-propyl guaiacol. Dimeric and oligomeric compounds constituted 75% of the hydrogenolysis oils and were mainly composed of dihydroconiferyl alcohol and 4-n-propyl guaiacol units linked by beta-5, 5-5, 4-O-5 and beta-1 linkages. Hydrogenolysis of steam exploded wood gave lower yields of lignin hydrogenolysis products compared to unmodified wood due to fewer reactive aryl-ether linkages in the lignin. PMID- 21664815 TI - DNA-instructed acyl transfer reactions for the synthesis of bioactive peptides. AB - We present a method which allows for the translation of nucleic acid information into the output of molecules that interfere with disease-related protein-protein interactions. The method draws upon a nucleic acid-templated reaction, in which adjacent binding of reactive conjugates triggers the transfer of an aminoacyl or peptidyl group from a donating thioester-linked PNA-peptide hybrid to a peptide PNA acceptor. We evaluated the influence of conjugate structures on reactivity and sequence specificity. The DNA-triggered peptide synthesis proceeded sequence specifically and showed catalytic turnover in template. The affinity of the formed peptide conjugates for the BIR3 domain of the X-linked inhibitor of apoptosis protein (XIAP) is discussed. PMID- 21664816 TI - Late onset painful cold-aggravated myotonia: three families with SCN4A L1436P mutation. AB - We describe three Belgian families with a L1436P mutation in the SCN4A gene, causing a sodium channel myotonia with an atypical clinical presentation, characterized by late onset painful cold-aggravated myotonia. These families represent a distinct phenotype within the spectrum of sodium channel myotonia. PMID- 21664817 TI - TARDIS-based microbial metabolomics: time and relative differences in systems. AB - Metabolomics can play a particularly important role in elucidating novel anabolic and catabolic pathways in bacteria and fungi, and in understanding the dynamics of metabolism. In these approaches, an isotopically labelled substrate, with an artificially high abundance of isotopic label, is fed to the microorganism under study. The products become isotopically labelled, and can be measured using a combination of mass spectrometry and nuclear magnetic resonance spectroscopy. This mass isotopomer analysis is referred to as time and relative differences in systems (TARDIS)-based analysis, as it measures and quantifies the temporal sequential emergence of these labelled products. In this review, we cover this topic from an experimental point of view in relation to the study of metabolism, and summarise how the application of radioactive and stable isotopes is being used in pathway elucidation and metabolic flux determination (fluxomics). PMID- 21664818 TI - Biosensors and their applications in microbial metabolic engineering. AB - Many metabolic pathways in microbial hosts have been created, modified and engineered to produce useful molecules. The titer and yield of a final compound is often limited by the inefficient use of cellular resources and imbalanced metabolism. Engineering sensory-regulation devices that regulate pathway gene expression in response to the environment and metabolic status of the cell have great potential to solve these problems, and enhance product titers and yields. This review will focus on recent developments in biosensor design, and their applications for controlling microbial behavior. PMID- 21664819 TI - Pseudomonas aeruginosa: all roads lead to resistance. AB - Pseudomonas aeruginosa is often resistant to multiple antibiotics and consequently has joined the ranks of 'superbugs' due to its enormous capacity to engender resistance. It demonstrates decreased susceptibility to most antibiotics due to low outer membrane permeability coupled to adaptive mechanisms and can readily achieve clinical resistance. Newer research, using mutant library screens, microarray technologies and mutation frequency analysis, has identified very large collections of genes (the resistome) that when mutated lead to resistance as well as new forms of adaptive resistance that can be triggered by antibiotics themselves, in in vivo growth conditions or complex adaptations such as biofilm growth or swarming motility. PMID- 21664820 TI - Light helps bacteria make important lifestyle decisions. AB - Until recently, bacterial responses to changes in light environments were regarded as specialized adaptations in a small number of phototrophs. However, the genomes of many photosynthetic and chemotrophic bacteria not known to have photophysiological responses also encode photoreceptor proteins. What new trends in the biological responses triggered by these photoreceptors are emerging? Here, we review several instances where members of different blue-light receptor classes (LOV, BLUF and PYP) photoregulate a lifestyle choice between the motile single-cellular state and the multicellular surface-attached community state (biofilm) by a range of mechanisms including bacterial two-component systems, the second messenger cyclic di-GMP and direct interactions of photoreceptors with transcription factors. We also discuss how 'seeing' helps some pathogenic bacteria make another important choice, i.e. between environmental and host associated lifestyles. PMID- 21664821 TI - Bioenergetic challenges of microbial iron metabolisms. AB - Before cyanobacteria invented oxygenic photosynthesis and O(2) and H(2)O began to cycle between respiration and photosynthesis, redox cycles between other elements were used to sustain microbial metabolism on a global scale. Today these cycles continue to occur in more specialized niches. In this review we focus on the bioenergetic aspects of one of these cycles - the iron cycle - because iron presents unique and fascinating challenges for cells that use it for energy. Although iron is an important nutrient for nearly all life forms, we restrict our discussion to energy-yielding pathways that use ferrous iron [Fe(II)] as an electron donor or ferric iron [Fe(III)] as an electron acceptor. We briefly review general concepts in bioenergetics, focusing on what is known about the mechanisms of electron transfer in Fe(II)-oxidizing and Fe(III)-reducing bacteria, and highlight aspects of their bioenergetic pathways that are poorly understood. PMID- 21664822 TI - Muscle power and function two years after unicompartmental knee replacement. AB - Unicompartmental knee replacement (UKR) is a commonly performed procedure, suitable for one in four patients requiring knee replacement for end-stage osteoarthritis. Recovery and return of function is quicker than with total knee replacement (TKR), but little information is known about the recovery of muscle power. We prospectively studied a cohort of forty four patients undergoing medial UKR to document their functional recovery and leg extensor power. Muscle power was measured using a Leg Extensor Power rig preoperatively and at 1 and 2 years after surgery. Function was self reported using the Oxford Knee Score (OKS) and Tegner Activity Scale (TAS). At 1 year all patients had made significant improvements on all functional measures, with a mean gain in OKS of 15.9 and TAS of 0.84. There were also significant increases in leg extensor power (LEP) of both legs. The mean change in LEP of the operated leg at 1 year was 0.50 W/kg and the non-operated leg was 0.10 W/kg. Between 1 and 2 years there were very slight improvements in strength in both legs, but these were not significant. Compared with healthy age matched normative values, the UKR LEP values at 2 years after surgery were decreased. The recovery of strength and function following UKR had stabilised by 1 year and during the following year further improvements were minimal. PMID- 21664823 TI - Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti platelet activity of morpholino-substituted-1,3-naphth-oxazines. AB - A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin 3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55+/-4 and 85+/-4 MUM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA PK) activity. The most active compounds were 18 IC(50)=0.091 MUM, 24 IC(50)=0.191 MUM, and 22 IC(50)=0.331 MUM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity. PMID- 21664824 TI - Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2 a]benzimidazoles. AB - A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2 a]benzimidazole analogue to directly inhibit the lytic activity of the pore forming protein perforin. A series of analogues were prepared to study structure activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors. PMID- 21664825 TI - Modulation of the 6-position of benzopyran derivatives and inhibitory effects on the insulin releasing process. AB - The synthesis of different series of 4- and 6-substituted R/S-3,4-dihydro-2,2 dimethyl-2H-1-benzopyrans is described. All of these new benzopyran derivatives were bearing, at the 4-position, a phenylthiourea moiety substituted on the phenyl ring by a meta or a para-electron-withdrawing group such as Cl or CN. The study aimed at exploring the influence of the nature of the substituent at the 6 position in order to develop new benzopyran-type K(ATP) channel activators exhibiting an improved selectivity towards the insulin secreting cells. The original compounds were examined in vitro on rat pancreatic islets (inhibition of insulin release) as well as on rat aorta rings (vasorelaxant effect) and their activity was compared to that of the reference K(ATP) channel activators (+/-) cromakalim, (+/-)-pinacidil, diazoxide and to previously synthesized cromakalim analogues. Structure-activity relationships indicated that the inhibitory effect on the insulin secreting cells was related to the lipophilicity of the molecules and to the size of the substituent located at the 6-position. A marked inhibitory activity on the insulin secretory process was obtained with molecules bearing a bulky tert-butyloxycarbonylamino group at the 6-position (20-23). The latter compounds were found to have the same efficacy on the pancreatic endocrine tissue than some previously described molecules. Lastly, radioisotopic experiments further identified R/S-N-4-chlorophenyl-N'-(6-tert-butyloxycarbonylamino-3,4 dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)thiourea (23) as a K(ATP) channel opener. PMID- 21664826 TI - Effects of molecular structures on reduction properties of formyl groups in chlorophylls and pheophytins prepared from oxygenic photosynthetic organisms. AB - Reduction of the 7-formyl groups in chlorophyll (Chl) b and its demetalated compound pheophytin (Phe) b was kinetically analyzed by using tert-butylamine borane complex (t-BuNH(2).BH(3)), and was compared with that of the 3-formyl groups in Chl d and Phe d. Reduction kinetics of the 7-formyl group in Chl b was similar to that in Phe b in dichloromethane containing 5mM t-BuNH(2).BH(3). Little difference of the reduction kinetics of the 7-formyl groups between Chl b and Phe b was in sharp contrast to the reduction kinetics of the 3-formyl groups in Chl d and Phe d: the 3-formyl group in Phe d was reduced 5.3-fold faster than that in Chl d. The 7-formyl groups in Chl b and Phe b were reduced more slowly than the 3-formyl groups in Chl d and Phe d, respectively. The difference of the reactivity between the 3- and 7-formyl groups was in line with (13)C NMR measurements of chlorophyllous pigments, in which the chemical shifts of carbon atoms in the 7-formyl groups of Chl b and Phe b were high-field shifted compared with those in the 3-formyl groups of Chl d and Phe d, respectively. These indicate that the 7-formyl groups in chlorophyllous pigments were less reactive for reduction to the corresponding hydroxymethyl groups than the 3-formyl groups due to the difference in electronic states of the formyl groups in the A- and B rings of the chlorin macrocycle. PMID- 21664827 TI - Synthesis of [3beta-acetoxy-urs-12-en-28-oyl]-1-monoglyceride and investigation on its anti tumor effects against BGC-823. AB - Ursolic acid (UA) as the leader compound was designed to prepare a series of derivatives (three novel compounds UA-1a, UA-1b and UA-2) by modification at the C3 and C28 positions. Their chemical structures were confirmed by IR, (1)H NMR and MS. The cytotoxic activity of the derivatives was evaluated against HepG2, BGC-823 and HT-29 by the MTT assay. The novel derivative UA-1a, [3beta-acetoxy urs-12-en-28-oyl]-1-monoglyceride showed significant anti-growth ability against the assayed cancer cell lines, particularly against BGC-823, while low cytotoxicity to human normal gastric cell line GES-1. Further investigation revealed that UA-1a could induce apoptotic events of the treated BGC-823 cells, such as comet-like DNA bend, sub-G0/G1 phase accumulation and phosphatidylserine externalization. The activity of Caspase-3 was found to be up-regulated, while the expression of Bcl-2 and Survivin were down-regulated in UA-1a treated cells. UA-1a might trigger the death of BGC-823 cells by inducing apoptosis via the mitochondria pathway. UA-1a exerted stronger ability than Taxol to retard tumor growth in nude mice without leaving apparent toxicity to the hosts. The experimental data suggested that UA-1a would have a therapeutic potential in the treatment of gastric cancer. PMID- 21664828 TI - Effects of Choukroun's platelet-rich fibrin on bone regeneration in combination with deproteinized bovine bone mineral in maxillary sinus augmentation: a histological and histomorphometric study. AB - PURPOSE: The potential effect of Choukroun's platelet-rich fibrin (PRF) in combination with allograft on promoting bone regeneration has been discussed in previous publications. This study aims to evaluate an influence of PRF on bone regeneration in sinus augmentation in combination with a xenograft, deproteinised bovine bone. MATERIALS AND METHODS: Eleven sinuses from 10 patients with posterior maxillary bone atrophy were selected for the study. As a test group, six sinus floor elevations were grafted with a Bio-Oss and PRF mixture, and as control group, five sinuses were treated with Bio-Oss alone. Clinical and radiographic examinations were performed pre- and postoperatively. After 6 months of sinus augmentation, bone biopsies were obtained from the grafted posterior maxilla, and un-decalcified ground sections were prepared. Bone characteristics were evaluated using histological observation and histomorphometric analyses. RESULTS: No adverse effect was observed in any case within the follow-up period of 6 months after sinus augmentation. Histological observation showed similar morphological characteristics for both the PRF and control groups. The percentage of new bone formation in the PRF group was about 1.4 times of that in control (18.35%+/-5.62% vs. 12.95%+/-5.33%), while the percentage of residual bone substitute in the control group was about 1.5 times higher as that in the PRF group (28.54%+/-12.01% vs. 19.16%+/-6.89%). The percentage of contact length between newly formed bone and bone substitute in the PRF group was 21.45%+/ 14.57% vs. 18.57%+/-5.39% in the control. No significant statistical differences between the two groups were found in these observed parameters. CONCLUSIONS: Our preliminary result demonstrated neither an advantage nor disadvantage of the application of PRF in combination with deproteinised bovine bone mineral in sinus augmentation after a healing period of 6 months. PMID- 21664831 TI - Aortic dissection with sheared-off intimal flap. PMID- 21664829 TI - Management of mitral regurgitation during left ventricular reconstruction for ischemic heart failure. AB - OBJECTIVE: Remodeling of the left ventricle (LV) in ischemic cardiomyopathy frequently leads to functional mitral regurgitation (MR). The indication for correcting MR in patients undergoing LV reconstruction (LVR) is unclear. In this study, we evaluated our strategy of correcting MR>=grade 2+ by restrictive mitral annuloplasty (RMA) during LVR. METHODS: We studied 92 consecutive patients (76 men, mean age 61+/-10 years) who underwent LVR for ischemic heart failure (IHF). RMA was performed in all patients with MR>=grade 2+ on preoperative echocardiography and in patients who showed increased MR to >=grade 2+ immediately after LVR. Patients were attributed to a RMA and no-RMA group, depending on whether or not concomitant RMA had been performed. Mean clinical and structured echocardiographic follow-up was 47+/-20 months and was 100% complete. RESULTS: In 38 out of 40 patients (95%) with preoperative MR>=grade 2+, concomitant RMA was planned and performed. In 17 out of 52 patients (33%) with MR=grade 2+ leading to additional RMA during a second period of aortic cross-clamping. Early mortality in the RMA group (n=55) was 12.7% and survival at 36 months 78.2+/-11.2%. Early mortality in the no-RMA group (n=37) was 5.4% and survival at 36 months 81.1+/ 12.8%. Patients in the RMA group had significantly more reduced LV function with greater LV dimensions and volumes preoperatively. Echocardiography demonstrated sustained improvement in LVEF with reduction of LV volumes in both patient groups. Recurrence of MR at late follow-up was observed in 2 patients (1 patient per group). CONCLUSIONS: Patients with IHF eligible for LV reconstruction have MR>=grade 2+ in 44% of cases. In one-third of IHF patients with MR=grade 2+ after LVR. Concomitant mitral valve repair for MR>=grade 2+, on either preoperative echocardiography or immediately after LVR, results in favorable late clinical and echocardiographic outcome that proved to be similar to patients without concomitant mitral valve repair, despite more advanced disease. PMID- 21664832 TI - Feasibility of the use of ELISA in an immunogenicity-based potency test of anthrax vaccines. AB - Complexities of lethal challenge animal models have prompted the investigation of immunogenicity assays as potency tests of anthrax vaccines. An ELISA was used to measure the antibody response to protective antigen (PA) in mice immunized once with a commercially available (AVA) or a recombinant PA vaccine (rPAV) formulated in-house with aluminum hydroxide. Results from the anti-PA ELISA were used to select a single dose appropriate for the development of a potency test. Immunization with 0.2 mL of AVA induced a measurable response in the majority of animals. This dose was located in the linear range of the vaccine dose-antibody response curve. In the case of rPAV, practical limitations prevented the finding of the best single dose for the potency testing of purified vaccines. In additional immunogenicity experiments neither the magnitude of the response to a single dose of vaccine, nor the estimation of the dose necessary to induce a measurable response were able to consistently detect brief exposure of vaccines to potentially damaging temperatures. However, differences detected for rPAV in the proportion of mice responding to the same dose of treated and untreated vaccine suggested that further assay development to increase the sensitivity of the latter design may be warranted. PMID- 21664833 TI - Degeneration of sensory afferent nerves enhances pulmonary inflammatory alterations in acute myocardial infarction in rats. AB - BACKGROUND: Evidence suggests proinflammatory changes in the lungs during acute myocardial infarction and a participation of neural mechanisms and substance P in the pathology. This study was undertaken to investigate the role and the mechanisms by which sensory afferent degeneration at neonatal stages exacerbates the pulmonary inflammatory responses to acute myocardial infarction in the adult rats. METHODS: The degeneration of capsaicin-sensitive afferent nerves was induced by administration of capsaicin to neonatal rats. The pulmonary inflammatory changes following coronary artery occlusion (CAO) were assessed by the analysis of the infiltration of neutrophils and tissue morphology in the lungs. RESULTS: Significant increases in the pulmonary infiltration of neutrophils, up to 240% and 218% of the sham controls at 3 and 6 h, respectively, after CAO (P<.05) and marked pulmonary edema were observed. Degeneration of capsaicin-sensitive afferent nerves or antagonism of endogenous neurokinin (NK)-1 receptor exacerbated the pulmonary infiltration of neutrophils (up to 214% and 254% of the controls, respectively) and pulmonary tissue edema following the CAO. CONCLUSION: The findings indicate that degeneration of sensory afferent nerves enhances the pulmonary inflammatory changes in acute myocardial infarction, in which the endogenous NK may play a role. PMID- 21664834 TI - Handheld computers to run ACASI to assess HIV risk and deliver tailored soap opera video feedback: acceptability among young adult urban women. PMID- 21664835 TI - Correction of longitudinal epiphyseal bracket disease with external fixation: a case report with 6-year follow-up period. AB - Longitudinal epiphyseal bracket disease is a rare congenital abnormality of the tubular bones. This syndrome eventually leads to progressive shortening and angular deformity of the involved bone. When longitudinal epiphyseal bracket disease affects the first metatarsal, a short trapezoidal shaped metatarsal is noted radiographically. We present the case of a 9-year-old patient with longitudinal epiphyseal bracket disease of the first metatarsal. The abnormality was surgically treated by bracket osteotomy with callus distraction before physeal closure. At 6 years of follow-up, the patient displayed a relatively normal looking cosmetic foot compared with the contralateral foot. A mild residual hallux varus was noted, with maintenance of the forefoot parabola. Surgical correction resulted in alteration of the first intermetatarsal angle and the first metatarsophalangeal angle. The first intermetatarsal angle decreased from a preoperative value of -30 degrees to a postoperative value of 10 degrees . The first metatarsophalangeal angle decreased from a preoperative value of 36 degrees of hallux varus to a postoperative value of 4 degrees . The length of the first metatarsal was restored compared with that of the contralateral limb and was slightly elongated. The present case study demonstrates that early surgical correction with callus distraction of an ossified abnormal bracket before physeal closure, a relatively simple procedure, can restore longitudinal growth and correct the angular deformity. PMID- 21664836 TI - Use of remodeled femoral head allograft for tarsal reconstruction in the treatment of muller-weiss disease. AB - Muller-Weiss disease (MWD), spontaneous avascular necrosis of the navicular in adults, is rare. Without treatment, it can result in permanent disability. Operative treatment is often required. MWD was suspected in a 51-year-old woman with spontaneous pain in her right foot. The radiologic tests showed a comma shaped deformed navicular and severe talonavicular necrosis and sclerosis. After excision of the necrotic navicular, a 5 * 5 * 3-cm defect appeared. A femoral head bone allograft was remodeled to fit this defect precisely. Autologous cancellous bone was also used. The allograft interposition arthrodesis was stabilized with a low contact plate. The histopathologic results showed avascular osteonecrosis, supporting the diagnosis of MWD. After 12 weeks of non-weight bearing plaster cast immobilization, the radiographs showed consolidation and no osteolysis. At 6 months after surgery, she was fully weight-bearing. The low contact plate was removed, because it impeded exercise. After 10 months, she was walking pain free. At 14 months after surgery, her radiographs still showed good consolidation, with no sign of osteolysis. The use of a bone allograft to cover a tarsal defect could be a safe and effective operative treatment of MWD that has not yet been reported in English-language studies. This treatment also results in minimal donor site morbidity. PMID- 21664837 TI - "Paroperative" pantheon. PMID- 21664838 TI - Preoperative characteristics of men with unfavorable high-Gleason prostate cancer at radical prostatectomy. AB - INTRODUCTION: Some men with Gleason sum 8-10 prostate cancer (PC) at RP have favorable outcomes: Biochemical recurrence free (BFS) and prostate cancer specific survival (CSS) are improved for such men with pT2 or pT3a disease compared with pT3b or N1 disease at radical prostatectomy (RP). We examine biopsy characteristics of men with high-grade PC at RP to better select those who may benefit from surgery. MATERIALS AND METHODS: A total of 1,174 men from our Institutional Database (1982-2010) had Gleason 8-10 cancer at RP. Their demographic and prostate biopsy characteristics were compared among those with disease defined as favorable (pT2 or pT3a) vs. unfavorable (pT3b or N1). Logistic regression was used to determine predictors of unfavorable disease. Kaplan-Meier analysis was used to determine survival outcomes. RESULTS: Biopsy data were available for 1,157 men (median cores 12 [2-20]); 779 (66.4%) favorable, 394 (33.6%) unfavorable; 102 (8.7%), 515 (44.1%), and 552 (47.2%) were low, intermediate, and high-risk. For favorable and unfavorable cases, 10-year BFS was 40.0% and 5.7% (P < 0.001) and CSS was 84.9% and 60.3% (P < 0.001). Multivariate logistic regression revealed that PSA >= 20 and perineural invasion (PNI) at biopsy increased the likelihood of unfavorable, high-grade disease. Considering PSA >= 20 and PNI as adverse features, 23.7%, 40.1%, and 71.4% of patients with none, 1, or 2 adverse features had unfavorable, high-Gleason PC (P < 0.001). CONCLUSIONS: High-Gleason PC was not uniformly associated with poor outcomes after RP, though men with unfavorable (pT3b/N1) disease fared poorly. Preoperative predictors of high-Gleason, unfavorable disease in a cohort of predominantly intermediate and high-risk patients were PSA >= 20 and PNI. PMID- 21664839 TI - Prognostic value of carbonic anhydrase IX expression in penile squamous cell carcinoma: a pilot study. AB - OBJECTIVES: To determine whether carbonic anhydrase IX (CA IX) has prognostic value of lymph node metastases and cancer-specific survival in penile squamous cell carcinoma treated with surgery. MATERIALS AND METHODS: CA IX expression was detected in the primary disease of 73 penile cancer patients using the method of immunohistochemistry. The expression levels of CA IX were categorized into 2 groups according to the cutoff of 10% of positively stained tumor cells. Associations between CA IX expression and clinicopathologic characteristics, immunoreactivity of p53 and Ki-67, and outcomes were analyzed. RESULTS: High CA IX expression was observed in 31 (42.5%) of cases. CA IX expression was not associated with patient age, T stage, grade, lymphovascular invasion, and Ki-67 expression, but was associated with p53 expression (P = 0.015). Both univariate and multivariate analysis failed to show CA IX expression was a statistically significant predictor of lymph node metastases and cancer-specific survival. CONCLUSIONS: Immunohistochemical expression of CA IX did not associate with lymph node metastases and cancer-specific survival in penile squamous cell carcinoma. A panel of prognostic markers that reflect the characteristic of tumor cell and organ microenvironment may be more suitable for prognostication in penile cancer. PMID- 21664840 TI - Primary central carcinoma ex pleomorphic adenoma of the mandible: report of a rare case and literature review. AB - We report a rare case of primary carcinoma ex pleomorphic adenoma (CXPA) of the mandible. A 13-year-old girl presented with a large mass, measuring about 30 cm in its greatest dimension, involving the mandible. She was referred to our department for surgery, and her postoperative course was uneventful; she is currently free from the disease 48 months after surgery. Primary CXPAs located centrally within the jawbones are rare with only 10 cases reported in the English and Chinese literature. This case illustrates 2 key facts regarding the diagnosis and therapy of CXPA. First, clinicians should be aware of this possibility and should emphasize the need for submission of so-called cystic lytic lesions for histopathologic analysis. Second, tumors should be excised en bloc with adjuvant postoperative radiotherapy when local recurrence and regional metastasis are suspected clinically. PMID- 21664841 TI - The effect of aging on luminance of standard liquid crystal display (LCD) monitors. AB - OBJECTIVES: The aim of this study was to evaluate the luminance level of monitors as a function of the burning time of the lamp in the monitor and further to evaluate if different areas of the monitor varied in luminance levels at a specific time. MATERIAL AND METHODS: Nine standard liquid crystal display (LCD) monitor models, in total 180 monitors, were evaluated. The monitors' maximal luminance levels were measured, and the burning times of the lamps were noted. The estimated function between burning time and luminance was calculated. On 11 monitors, 9 areas distributed over the full screen were measured to evaluate the extent to which different areas had different luminance levels. RESULTS: Over time, the luminance decreased in all monitor models. No difference was found among the monitor models in how rapidly the luminance levels decreased. Different luminance values were found for different areas on the monitors, but no area deteriorated faster than another. CONCLUSIONS: Standard liquid crystal display monitors undergo gradual deteriorations in luminance levels over time, and these deteriorations are correlated with the time that the monitors have been switched on. The degradation in luminance is similar over all areas of the monitors. PMID- 21664845 TI - Laminitis epidemiology data: still severely lacking.... PMID- 21664846 TI - Nociceptive trigeminal reflexes in non-sedated horses. AB - Electrically induced reflexes can be used to investigate the physiology and pathophysiology of the trigeminal system in humans. Similarly, the assessment of the trigemino-cervical (TCR) and blink reflexes (BR) may provide a new diagnostic tool in horses. The aim of this study was to evoke nociceptive trigeminal reflexes and describe the electrophysiological characteristics in non-sedated horses. The infraorbital (ION) and supraorbital nerves (SON) were stimulated transcutaneously in 10 adult Warmblood horses in separate sessions using train-of five electrical pulses. The current was increased gradually until the TCR threshold was found. The stimulus-response curve of the TCR was evaluated. At the same time as TCR, the BR response was also assessed. Surface electromyographic (EMG) responses were recorded from the orbicularis oculi, splenius and cleidomastoideus muscles. Latency, duration, amplitude of the reflexes and behavioural responses were analysed. Noxious electrical stimulation of the ION or SON evoked reflex EMG responses, with similar features regardless of the nerve that had been stimulated. Stimulations of increasing intensity elicited reflexes of increasing amplitude and decreasing latency, accompanied by stronger behavioural reactions, therefore confirming the nociceptive nature of the TCR. These findings provide a reference for the assessment of dysfunction of the equine trigeminal system. PMID- 21664847 TI - Association of clinical findings of temporomandibular disorders (TMD) with self reported musculoskeletal pains. AB - BACKGROUND AND AIMS: Temporomandibular disorders (TMD) can be related to self reported musculoskeletal pains. The aim of the study was to investigate the association of clinical findings of TMD with self-reported pain in other parts of the body, and to discriminate pain clusters according to definite profiles of pain conditions including TMD among subjects in general population. METHODS: A nationally representative Health 2000 Survey was carried out in 2000-2001 in Finland. The data were obtained from 6227 subjects aged ?30years. Information about pain in different parts of the body was collected from a questionnaire. The associations between clinically assessed TMD findings and pain in other areas were analyzed using chi-square test and logistic regression analyses. Latent class analysis (LCA) was used to form natural clusters, i.e., groups in which the individuals had similar profiles of pain conditions. RESULTS: Masticatory muscle pain on palpation associated with back, neck and shoulder pain and pain in joints. Temporomandibular joint (TMJ) pain on palpation associated with back, neck, shoulder and other joint pain. These associations did not change essentially after adjustment for confounders. After clustering of the study population with the LCA, 5.8% of the study population showed a multiple pain condition linked with TMD findings. Female gender, intermediate/poor self reported health and presence of a longstanding illness increased the probability to belong to this cluster. CONCLUSIONS: TMD findings associate with pain in several locations. Female gender and presence of impaired health were particularly related to occurrence of multiple pain conditions. PMID- 21664848 TI - Rapid frequency scan EPR. AB - In rapid frequency scan EPR with triangular scans, sufficient time must be allowed to insure that the magnetization in the x, y plane decays to baseline at the end of the scan, which typically is about 5T(2) after the spins are excited. To permit relaxation of signals excited toward the extremes of the scan the total scan time required may be much longer than 5T(2). However, with periodic, saw tooth excitation, the slow-scan EPR spectrum can be recovered by Fourier deconvolution of data recorded with a total scan period of 5T(2), even if some spins are excited later in the scan. This scan time is similar to polyphase excitation methods. The peak power required for either polyphase excitation or rapid frequency scans is substantially smaller than for pulsed EPR. The use of an arbitrary waveform generator (AWG) and cross loop resonator facilitated implementation of the rapid frequency scan experiments reported here. The use of constant continuous low B(1), periodic excitation waveform, and constant external magnetic field is similar to polyphase excitation, but could be implemented without the AWG that is required for polyphase excitation. PMID- 21664849 TI - Molecular characterization of methicillin-resistant Staphylococcus aureus obtained from the anterior nares of healthy Korean children attending daycare centers. AB - OBJECTIVES: This study was performed to investigate the molecular characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolated from the anterior nares of Korean children attending daycare centers. METHODS: During September and October 2008, a survey of nasal carriage of MRSA was conducted among healthy children who were attending daycare centers in Seoul, Korea. Nasal swab samples were cultured to isolate S. aureus, and antimicrobial susceptibility was assessed using a disk diffusion test. All MRSA isolates were archived for subsequent molecular tests, including multilocus sequence typing, Panton-Valentine leukocidin (PVL) genes polymerase chain reaction (PCR), and staphylococcal cassette chromosome mec (SCCmec) typing. RESULTS: Among 428 preschool-aged children enrolled, 9.3% (40/428) were colonized with MRSA. Among the 40 MRSA isolates, antibiotic susceptibilities to clindamycin and erythromycin were 97.5% (39/40) and 45% (18/40), respectively. All of the 21 strains susceptible to clindamycin and resistant to erythromycin had MLS(B)-inducible phenotypes. Sequence type (ST) 72-SCCmec type IV was the predominant clone (n=23; 57.5%), followed by ST72-SCCmec type II (n=6; 15%), ST1765-SCCmec type IV (n=4; 10%), ST1765-SCCmec type II (n=2; 5%), and ST1-SCCmec type IV (n=2; 5%). No clone was positive for PVL genes. CONCLUSIONS: ST72 strains, which were previously found in hospital-associated MRSA, are now widely distributed in healthy Korean children. In addition, the prevalence of inducible resistance of clindamycin should be considered when selecting empirical antibiotics for community associated MRSA infections in Korea. PMID- 21664850 TI - [Radiotherapy for cutaneous cancers with xeroderma pigmentosum]. AB - PURPOSE: To analyze the therapeutic results of cutaneous cancers on xeroderma pigmentosum through a series of 15 patients treated by radiotherapy. PATIENTS AND METHODS: Between 1993 and 2006, 15 patients with xeroderma pigmentosum and having cutaneous cancers were treated in the Radiotherapy Department of university hospital Habib-Bourguiba of Sfax in Tunisia. Seventy-three percent of the cases occurred in male patients and the mean age of appearance of the first tumour was 18.2 years. Tumour histology was squamous cell carcinoma in 74% of the cases. The total number of cutaneous tumours was 84. Ten patients had a surgical resection. Four patients did not respond to chemotherapy. The modality of irradiation was decided according to the size, thickness and localization of the tumour. The dose of radiotherapy was 60Gy or equivalent with classic irradiation. RESULTS: The total number of lesions treated with radiotherapy was 64. Forty-three lesions were treated with contact therapy, ten with brachytherapy and 11 with cobalt therapy. The following acute complications were observed: cutaneous infection (53.3% of patients), radioepithelite (80% of patients) and necroses (33.3% of patients). Evaluation after treatment showed a clinical complete remission in 73% of the cases. Late effects were noted in seven cases: telangiectasy and cutaneous atrophy. A recurrence in the irradiated zone was observed in one case. A nodal metastasis was observed in two cases. Another patient presented lung metastases. After a median follow up of 37.2 months, four patients died, seven are alive with cutaneous cancer and four are alive with complete remission. CONCLUSION: Radiotherapy is a possible and effective therapeutic alternative. Dose and methods are not defined for xeroderma pigmentosum. PMID- 21664851 TI - [New perspectives for radiosensitization in pancreatic carcinoma: a review of mechanisms involved in pancreatic tumorigenesis]. AB - Pancreatic carcinoma is the fifth leading cause of cancer-related mortality. The 5-year overall survival is less than 5 %. This very poor prognosis can be explained both by late diagnosis and by treatment resistance, including resistance to radiation therapy. A better understanding of the pancreatic tumorigenesis and knowledge of the most frequent mutations in pancreatic adenocarcinoma (KRAS, p16, TP53, Smad4) open new perspectives for the development of more effective treatments. This review presents the major genetic and molecular alterations in pancreatic cancer that could be targeted to improve radiosensitization. PMID- 21664852 TI - [Dosimetry comparison of irradiation with conformal radiotherapy, intensity modulated radiotherapy, conformal radiotherapy in stereotactic conditions and robotic stereotactic radiotherapy for benign brain tumours]. AB - PURPOSE: To compare several techniques in order to determine the best treatment for benign brain tumours. METHODS AND PATIENTS: A retrospective study was performed for five patients who received 3D-conformal radiotherapy, intensity modulated radiotherapy or CyberKnife((r)). These patients had a meningioma, a pituitary tumour, a craniopharyngioma or a neurinoma. In each case, these treatment plans were optimised and compared with the three other dosimetries. Radiobiological or positioning parameters were evaluated, as well as dosimetric parameters, in order to compare treatments with different characteristics. RESULTS: The dosimetric parameters showed that the choice of treatment seemed to be determined mostly by tumour size, shape and proximity with organs at risk (not tumour localisation). Whereas the results showed no significant deviations with regards to the radiobiological parameters. Therefore, with these parameters, it was difficult to give priority to a treatment. CONCLUSIONS: With regards to benign brain tumours of medium or large size, intensity modulated radiotherapy seemed the recommended treatment. It enabled to obtain a good ratio between efficacy and toxicity for tumours that are really close to organs at risk. Concerning small benign brain tumours, the CyberKnife((r)) was probably the best treatment. PMID- 21664853 TI - Serum resistin level is associated with radiographic changes in hand osteoarthritis: cross-sectional study. AB - OBJECTIVE: The aim of this study was to determine whether adipokines such as adiponectin and resistin were related to radiographic outcomes in patients with hand osteoarthritis (OA). METHODS: A total of 156 female subjects (46 controls, 60 non-radiographic hand OA, and 50 radiographic hand OA) were enrolled. We measured serum adiponectin and resistin concentrations using an enzyme-linked immunosorbent assay (ELISA). Radiographic hand OA was defined by the presence of a >=2 Kellgren-Lawrence radiological grade after assessment for 20 joints of both hands. The association between radiographic hand OA and each adipokine was assessed using multivariate logistic regression models controlling for confounding clinical parameters. RESULTS: Serum resistin levels in radiographic hand OA patients were higher than in non-radiographic hand OA and controls (p(adj)=0.020 and p(adj)=0.019, respectively), whereas there were no significant differences in serum adiponectin levels. The presence of radiographic changes in hand OA was shown to be dependent on serum resistin levels (p(adj)=0.028). Specifically, subchondral erosion in radiographic hand OA was associated with serum resisitin (p(adj)=0.028). However, there were no associations of serum adipokines with joint space narrowing, bony ankylosis, and cortical destruction. CONCLUSIONS: This study suggests that resistin is involved in radiographic changes in hand OA, and that adipokines contribute to pathogenesis in radiographic outcomes in hand OA. PMID- 21664854 TI - Pathophysiology of bone loss in disuse osteoporosis. AB - Osteoporosis, or rather the localised bone loss observed in patients with spinal cord injury, as well as during any type of immobilisation involves various processes and structures including the direct response of the musculoskeletal system to unloading, the central and peripheral nervous systems and their effects on bone cells and on the vascular system, the bone remodelling unit in its marrow compartment and a number of local factors controlling cell-cell cross-talk as well as calciotropic hormones. The authors present a detailed review of these different mechanisms which are all involved regardless of the type of immobilisation: pathological, environmental, or experimental. These factors are interconnected and put bone at the centre of the regulation of body homeostasis. A better knowledge of these mechanisms should promote the development of preventive therapies for the often neglected osteoporotic fractures that occur in patients with spinal cord injury. PMID- 21664855 TI - Serotonin and dopamine striatal innervation in Parkinson's disease and Huntington's chorea. AB - In contrast to our vast knowledge of the dopamine (DA) system, much less is known about the involvement of serotonin (5-HT) in neurodegenerative diseases affecting the basal ganglia. Therefore, we designed a study that aimed at characterizing the status of the striatal DA and 5-HT systems in patients who suffered from either Parkinson's (PD) or Huntington's disease (HD), compared to age-matched controls. Antibodies against tyrosine hydroxylase (TH) and 5-HT transporter (SERT) were used as markers of DA and 5-HT axonal profiles, respectively. The density and pattern of TH+ and SERT + innervation were determined by optical density measurements as well as by direct stereological estimates of labeled axon varicosities. The results reveal a significant decrease in TH immunoreactivity and TH + axon terminals throughout the striatum in both PD and HD, whereas the intensity of SERT immunostaining and the density of SERT + axon varicosities were found to be slightly increased in the striatum of PD and HD patients compared to controls. These findings reveal that the nigrostriatal DA system is significantly impaired in both PD and HD compared to the striatal 5-HT innervation, which is slightly increased in these two conditions. The striatal 5-HT augmentation observed in PD might be the result of a neural mechanism designed to compensate for DA denervation, whereas the marked atrophy of the striatum might explain the increase in the 5-HT innervation noted in HD. These findings underline the importance of the complex interplay between DA and 5-HT striatal afferents in the elaboration of appropriate motor behaviour. PMID- 21664856 TI - Fitting an MSD (mini scleral design) rigid contact lens in advanced keratoconus with INTACS. AB - Keratoconus is a bilateral degenerative disease characterized by a non inflammatory, progressive central corneal ectasia (typically asymmetric) and decreased vision. In its early stages it may be managed with spectacles and soft contact lenses but more commonly it is managed with rigid contact lenses. In advanced stages, when contact lenses can no longer be fit, have become intolerable, or corneal damage is severe, a penetrating keratoplasty is commonly performed. Alternative surgical techniques, such as the use of intra-stromal corneal ring segments (INTACS) have been developed to try and improve the fit of rigid contact lenses in keratoconic patients and avoid penetrating keratoplasties. This case report follows through the fitting of rigid contact lenses in an advanced keratoconic cornea after an INTACS procedure and discusses clinical findings, treatment options, and the use of mini-scleral and scleral lens designs as they relate to the challenges encountered in managing such a patient. Mini-scleral and scleral lenses are relatively easy to fit, and can be of benefit to many patients, including advanced keratoconic patients, post-INTAC patients and post-penetrating keratoplasty patients. PMID- 21664857 TI - ACR appropriateness criteria(r) adjuvant therapy for resected squamous cell carcinoma of the head and neck. AB - Locoregional recurrence following surgical resection alone for stage III/IV head and neck cancer is common. Adjuvant radiotherapy has been shown to improve post operative locoregional control when compared to pre-operative radiotherapy for head and neck cancers. Following surgical resection, adverse pathological features determine the need for adjuvant therapy. High-risk pathologic features include extranodal tumor spread and involved surgical margins. Other adverse pathologic features include T 3-4 tumors, perineural invasion, lymphovascular space invasion, low neck adenopathy, and multiple tumor involved cervical lymph nodes. The standard adjuvant therapies are post-operative radiation therapy or post-operative chemoradiotherapy. Post-operative chemoradiotherapy yields superior locoregional control, progression-free survival, and in some studies, overall survival compared to post-operative radiotherapy for high-risk patients in multiple randomized studies. Pooled analyses of randomized data demonstrate that post-operative concurrent chemoradiotherapy is associated with overall survival benefits for patients with involved surgical margins as well as those with extranodal tumor spread. Post-operative radiotherapy concurrent with cisplatin at 100 mg/m(2) every 21 days is the current standard chemoradiotherapy platform adjuvant head and neck cancer treatment. Post-operative radiotherapy and post-operative chemoradiotherapy radiation treatment volumes are not standardized and should be designed based on the risk of recurrence and clinically occult involvement of head and neck subsites and nodal regions. Evidence supports a post operative radiotherapy and chemoradiotherapy radiation dose of at least 63 Gy for high-risk patients and at least 57 Gy for low risk patients. PMID- 21664858 TI - Significance of tumor satellite variables in reflecting the epithelial mesenchymal transition of tongue cancer. AB - The epithelial-mesenchymal transition (EMT) is important in determining the biological behaviors and clinical prognosis of tongue cancer. However, the heterogeneous nature of the cancer populations renders clinical grading controversial. The main purpose of EMT analysis is to identify the cell population with the greatest metastatic potentials. Therefore, tumor satellites that form at the invasive front of tongue cancer may be the optimal target for EMT evaluation. From 1999 to 2002, surgical samples of 117 consecutive tongue cancer patients diagnosed and treated at the National Taiwan University Hospital were collected. EMT-related biomarkers, including E-cadherin and vimentin, were analyzed in tongue cancer specimens to verify the association with tumor satellite variables. The results showed that the down-regulation of epithelial markers, manifested by E-cadherin loss, was significantly different compared to the pattern of invasion (p=0.011), tumor satellite formation (p=0.019), and tumor satellite size (p=0.019). For mesenchymal phenotype acquisition, vimentin expression significantly differs in groups stratified by tumor satellite distance (TSD) (p=0.018). EMT positive immunoreaction was more frequent in the cases with tumor satellite formation (p=0.042) and in those with greater TSD (p=0.023). In addition, in the EMT positive cases, the average TSD was 0.79+/-1.20mm compared to 0.36+/-0.52mm in the EMT-negative cases (p=0.010). The results demonstrated the correlation between tumor satellite variables and EMT. Loss of epithelial features contributes to tumor satellite formation, whereas acquisition of the mesenchymal phenotype is beneficial to tumor satellite spreading. The current results indicate the importance of evaluating tumor satellite variables in assessing the EMT of tongue cancer. PMID- 21664859 TI - Vibrational spectra of the Ga(III) complexes with oxine and clioquinol. AB - The FTIR and FT-Raman spectra of the gallium(III) complexes of 8-hydroxyquinoline (oxine) and 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol), were recorded and briefly discussed by comparison with the spectra of the uncoordinated ligands and with some related species. PMID- 21664860 TI - Quantum chemical studies of FT-IR and Raman spectra of methyl 2,5 dichlorobenzoate. AB - In this paper, experimental and theoretical studies on the molecular structure and vibrational spectra of methyl 2,5-dichlorobenzoate (MDCB) are presented. Fourier transform infrared and Raman spectra of the title molecule in the solid phase were recorded and analyzed. The geometrical parameters were calculated using DFT (B3LYP) with 6-311G(d,p) and 6-311++G(d,p) basis sets, and compared with the experimental data. The vibrational frequencies, infrared intensities and Raman scattering activities were also reported. The detailed assignments were given based on the total energy distribution of the vibrational modes, calculated with scaled quantum mechanics method. The observed and calculated frequencies are found to be in good agreement. PMID- 21664861 TI - Vibrational study of tolazoline hydrochloride by using FTIR-Raman and DFT calculations. AB - Quantum mechanical (QM) calculations have been carried out in order to study the tolazoline hydrochloride theoretical structure and vibrational properties. This compound was characterized by infrared and Raman spectroscopies in the solid phase. For a complete assignment of the IR and Raman spectra, the density functional theory (DFT) calculations were combined with Pulay's Scaled Quantum Mechanics Force Field (SQMFF) methodology in order to fit the theoretical frequency values to the experimental ones. An agreement between theoretical and available experimental results was found. Three intense bands in the infrared spectrum characteristic of the protonated species of the compound were detected. Also, the possible charge-transfer and the topological properties for both benzyl and imidazoline rings were studied by means of Natural Bond Orbital (NBO) and Atoms in Molecules theory (AIM) investigation. PMID- 21664862 TI - FT-IR and XRD analysis of natural Na-bentonite and Cu(II)-loaded Na-bentonite. AB - Na-bentonite has been studied extensively because of its strong adsorption capacity and complexation ability. In this work, surface area, total pore volume, mean pore diameter, TG, DTA, FT-IR and XRD were carried out in order to reveal the characteristics of natural Na-bentonite. XRD and FT-IR of natural Na bentonite (China) and Cu-loaded Na-bentonite as a function of Na-bentonite dosage and temperature using batch technique were characterized in detail, respectively. PMID- 21664863 TI - Characterization of pentacarbonyl(4-methylpyridine)chromium(0) complex using density functional theory (DFT) and Hartree-Fock (HF) computational methods. AB - The optimized molecular structure, atomic charges, vibrational frequencies, thermodynamic properties, nuclear magnetic resonance (NMR) and ultraviolet visible (UV-Vis) spectral data of pentacarbonyl(4-methylpyridine)chromium(0) complex have been investigated by performing ab initio Hartree-Fock (HF) and density functional theory, B3LYP, B3PW91 and BE1PBE methods with 6-311G, 6 311+G(3d,3p) and 6-31G(d,p) basis set. The calculated NMR data at 6-311G basis set, vibrational frequencies at 6-311+G(3d,3p) basis set and the optimized geometric bond lengths and bond angles at 6-31G(d,p) basis set are in good agreement with the corresponding experimental values. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) have been simulated. In addition, the transition state and energy band gap and infrared intensities have also been reported. PMID- 21664864 TI - Promoting use-dependent plasticity with externally-paced training. AB - OBJECTIVE: To evaluate use-dependent plasticity (UDP) before and after training under metronome-paced and self-paced conditions. METHODS: Twelve healthy adults were recruited to this cross-over, pseudo-randomized, repeated measures study. Participants performed wrist extension training that was either self-paced, or externally-paced to an auditory metronome at their preferred movement frequency or at a more demanding frequency. Motor evoked potentials from transcranial magnetic stimulation of left primary motor cortex were recorded in right extensor carpi radialis (ECR) and flexor carpi radialis (FCR) to assess corticomotor excitability. The direction and velocity of TMS-evoked wrist movement (stimulus evoked velocity, SEV) were measured before and after training to evaluate UDP. RESULTS: The most persistent UDP occurred when training was metronome-paced at the participant's preferred movement frequency. This training protocol produced spatially selective modulation of resting ECR and FCR corticomotor excitability and directional tuning of TMS-evoked wrist movement toward the trained direction. Metronome-paced training at a more demanding frequency resulted in nonspecific facilitation of resting corticomotor excitability, and did not alter TMS-evoked wrist movement. CONCLUSIONS: These novel findings indicate that externally-paced training at the individual's preferred frequency facilitates UDP. SIGNIFICANCE: UDP underpins motor recovery after stroke. Externally-paced training may be a useful adjunct to movement rehabilitation therapy. PMID- 21664865 TI - Antioxidant treatment with quercetin ameliorates erectile dysfunction in streptozotocin-induced diabetic rats. AB - Oxidative stress is demonstrated to be involved in the pathophysiological mechanism of erectile dysfunction (ED). Quercetin, a potent bioflavonoid, has been reported to have the antioxidant role. In the present study, we examined the effect of quercetin on ED and oxidative stress in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in Sprague-Dawley rats with a single intravenous injection of STZ. The diabetic rats were then randomized to diabetic group and quercetin therapy groups which were treated with quercetin at different doses of 5, 20 and 50mg/kg per day respectively. At the end of the 8th week, erectile function was assessed by measuring the rise in intracavernous pressure (ICP) following cavernous nerve electrostimulation. Superoxide dismutase (SOD) activity, thiobarbituric acid-reacting substance (TBARS) and nitrite and nitrate (NOx) levels were measured in cavernosum tissue. Endothelial NO synthase (eNOS) expression was determined using Western blot method. ICP in diabetic rats was significantly decreased than that in controls. After treatment with quercetin at the doses of 20 and 50mg/kg, ICP was significantly increased compared to that in untreated diabetic rats. Decreased levels of SOD activity, NOx and eNOS expression, as well as elevated levels of TBARS were found in diabetic group compared with control group. Treatment with 20 and 50mg/kg quercetin improved SOD activity, NOx and TBARS levels in corpus cavernosum of diabetic rats. Decreased expression of eNOS in diabetic rats was only ameliorated by 50mg/kg quercetin treatment. Quercetin could ameliorate ED in diabetic rats by inhibiting oxidative stress. PMID- 21664866 TI - Potentially human pathogenic vibrios in marine and fresh bathing waters related to environmental conditions and disease outcome. AB - In 2009, four bathing sites in The Netherlands were monitored for potentially human pathogenic Vibrio species to observe possible associations with environmental conditions and health complaints. Three slightly different enrichment procedures were used to isolate Vibrio species with different growth requirements. Waters were generally positive for Vibrio from May until October; median Vibrio concentrations ranged from 4 to 383 MPN per litre (maximum 10(5) MPN per litre). Isolated Vibrio species included V. alginolyticus (50.6%) and V. parahaemolyticus (8.5%) from bathing sites with salinities ranging between 2.8 and 3.5% and V. cholerae non-O1/O139 (6.9%) from sites with salinities ranging between 0.007 and 0.08%. Although more samples were positive for Vibrio at elevated water temperatures, a quantitative relation between Vibrio numbers in water samples and the water temperature was not observed which may be explained by maximum water temperatures of 21 degrees C. Active surveillance yielded one case of a recreational water related Vibrio infection. V. cholerae non-O1/O139 was cultured from the patient's wound and the implicated recreational water; PFGE profiles of the water and patient isolates were not identical. The number of patients that contract a Vibrio infection through exposure to Dutch recreational waters seems low, but may be underestimated. The common occurrence of Vibrio species in these waters stresses the need for providing information on Vibrio to risk groups to prevent infections. PMID- 21664868 TI - Combination therapy in metastatic renal cell carcinoma. PMID- 21664869 TI - Multiple myeloma and the road to personalised medicine. PMID- 21664867 TI - Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. AB - BACKGROUND: Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma. METHODS: TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov, number NCT00619268. FINDINGS: Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29.5% (26 of 88 patients, 95% CI 20.0-39.1) in group A, 35.7% (15 of 42, 21.2-50.2) in group B, and 61.0% (25 of 41, 46.0-75.9) in group C. Median PFS was 8.2 months (95% CI 7.0 9.6) in group A, 8.2 months (5.5-11.7) in group B, and 16.8 months (6.0-26.0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively. INTERPRETATION: The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma. FUNDING: French Ministry of Health and Wyeth Pharmaceuticals. PMID- 21664870 TI - Central nervous system control of cough: pharmacological implications. AB - For many years the idea of a cough center in the brain dominated discussions in the field without any substantial progress in defining what this cough center is or how it functions. Substantial progress has now been made and many of the central neural elements involved in coughing are being described. Furthermore, hypothesis driven research into the function of these neural elements is providing exciting new leads for possible therapeutic targets. The concept of a specific, centrally acting drug for cough suppression is fast becoming a reality. This review summarizes the key findings from the past few years and provides a perspective on future directions for the development of novel antitussives. PMID- 21664871 TI - DNA polymorphism of Mycobacterium tuberculosis PE_PGRS33 gene among clinical isolates of pediatric TB patients and its associations with clinical presentation. AB - In vitro and in animal studies have suggested an important role for the Mycobacterium tuberculosis PE_PGRS33 protein in the pathogenesis of TB. A significant level of PE_PGRS33 gene DNA polymorphism among clinical isolates from adult tuberculosis (TB) patients and its association with clinical and epidemiological phenotypes of the disease has been found. To better understand the role of PE_PGRS33 protein in the pathogenesis pediatric TB, we investigated DNA polymorphism of the PE_PGRS33 gene among 101 of pediatric TB patients' isolates and assessed the relationship between the PE_PGRS33 sequence variation and clinical characteristics of TB. Twelve different PE_PGRS33 sequence variations representing 12 different alleles were observed among the 101 M. tuberculosis clinical isolates investigated. Of these 101 isolates, 62(59.41%) had PE_PGRS33 alleles that would result in a change in the amino acid sequence of the PE_PGRS33 protein. The degree of DNA polymorphism within individual M. tuberculosis isolates from pediatric TB patients was remarkably lower than that previously found in M. tuberculosis isolates from adults TB patients. The frequency distribution of isolates having PE_PGRS33 gene sequence variations was similar between Beijing and non-Beijing families of the pathogen. Patients having TB meningitis and negative PPD skin test results appeared to be more likely to be infected by isolates having a mutant type of the PE_PGRS33 gene than patients who had no TB meningitis (OR 2.54, 95% CI [1.11-5.84]) and patients who had positive PPD-skin test results (OR 4.26, 95% CI [1.14-12.86]), respectively. This study provides new insight into the molecular pathogenesis of pediatric TB. PMID- 21664872 TI - Influence of previous tuberculin skin test on serial IFN-gamma release assays. AB - Tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) have been proposed for serial testing in tuberculosis. In the present study, we assessed the effect of TST on subsequent QuantiFERON-TB Gold In-Tube (QFT-GIT) results by monitoring the evolution of responses during a follow-up period of 6 weeks. One hundred and two subjects were initially tested with QFT-GIT and subsequently with TST; then the QFT-GIT was performed serially 1, 2, 4, and 6 weeks after the TST. A subgroup of 40 subjects was also assessed by older version of the QuantiFERON TB Gold (QFT-G) assay. The results showed no significant variation in IFN-gamma response over time in the tested patients, although two TST-positive subjects showed evidence of possible boosting effect. In addition, a direct comparison between the QFT-G and QFT-GIT test showed no significant differences at any time point with excellent agreement between two tests. No significant differences were seen in IFN-gamma responses between BCG-unvaccinated and BCG-vaccinated patients at each time point. In conclusion, our findings indicate that TST does not influence the outcome of subsequent IGRAs testing in individuals with negative TST results, but it can boost the IFN-gamma response in subjects sensitized to TB antigens and not detected by IGRA. PMID- 21664873 TI - Blunt pediatric anterior and posterior urethral trauma: 32-year experience and outcomes. AB - OBJECTIVE: To analyze our experience with delayed repair of pediatric urethral trauma. MATERIALS AND METHODS: From 1978 to 2007, 26 boys <18 years old (mean age 15.0) presented for delayed repair of urethral stricture after blunt trauma. Anterior and posterior urethral injuries were separately stratified. RESULTS: There were 8 anterior and 18 posterior urethral strictures. All patients presented in a delayed fashion. Mean follow up of the anterior cohort was 2.9 years. All repairs were performed via a ventral onlay buccal graft or anastomotic approach. The mean follow up of the posterior cohort was 1.1 years, and all posterior urethral injuries were repaired via an anastomotic approach. Overall success for anterior stricture disease was 88.9% and for posterior stricture disease was 89.5%. All three urethroplasty failures responded favorably to internal urethrotomy; however, one failed anterior repair and one of the two failed posterior repairs required two internal urethrotomy operations for success. No secondary urethroplasty operations were required and ultimately all patients were voiding per urethra without need for urethral dilation. CONCLUSION: Delayed, definitive repair of pediatric urethral trauma via open urethroplasty has a high success rate. PMID- 21664874 TI - Non-invasive vesicoureteral reflux detection: heating risk studies for a new device. AB - OBJECTIVE: To investigate a novel non-invasive device developed to warm bladder urine and to measure kidney temperature to detect vesicoureteral reflux. MATERIALS AND METHODS: Microwave antennas focused energy within the bladder. Phantom experiments measured the results. The heating protocol was optimized in an in-vivo porcine model, and then tested once, twice and three times consecutively in three pigs followed by pathologic examinations. RESULTS: Computer simulations showed a dual concentric conductor square slot antenna to be the best. Phantom studies revealed that this antenna easily heated a bladder phantom without over heating intervening layers. In-vivo a bladder heating protocol of 3 min with 30 W each to two adjacent antennas 45 s on 15 s off followed by 15 min of 15 s on and 45 s off was sufficient. When pigs were heated once, twice and three times with this heating protocol, pathologic examination of all tissues in the heated area showed no thermal changes. More intensive heating in the animal may have resulted in damage to muscle fibers in the anterior abdominal wall. CONCLUSIONS: Selective warming of bladder urine was successfully demonstrated in phantom and animals. Localized heating for this novel vesicoureteral reflux device requires low-power levels and should be safe for humans. PMID- 21664875 TI - Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency. AB - Hypomorphic mutations in genes associated with severe combined immunodeficiency (SCID) or Omenn syndrome can also cause milder immunodeficiencies. We report 10 new patients with such "atypical" SCID and summarize 63 patients from the literature. The patient groups with T(low)B(low) (n=28), T(low)B(+) (n=16) and ADA (n=29) SCID variants had similar infection profiles but differed in the frequency of immune dysregulation, which was observed predominantly in patients with recombination defects. Most immunological parameters were remarkably similar in the three groups. Of note, 19/68 patients with "atypical" SCID had normal T cell counts, 48/68 had normal IgG and 23/46 had at least one normal specific antibody titer. Elevated IgE was a characteristic feature of ADA deficiency. This overview characterizes "atypical" SCID as a distinct disease with immune dysregulation in addition to infection susceptibility. Lymphopenia, reduced naive T cells and elevated IgE are suggestive, but not consistent features of the disease. PMID- 21664876 TI - New technologies and advances in colposcopic assessment. AB - To have a good grasp of clinical colposcopy, it is necessary to understand the histopathologic structure of the normal and dysplastic cervical epithelium. Previous meta-analyses had indicated high overall sensitivity of colposcopy in detecting dysplastic lesions, but recent studies have suggested that the technique has much lower sensitivity in detecting high-grade intraepithelial neoplasia. The best practice in colposcopy relies on accurately taking a biopsy from the correct (i.e. most morphological abnormal) site, and by taking more than one biopsy, the sensitivity for detection of high-grade cervical intraepithelial neoplasia can be increased. Cytological screening programmes of proven and maintained high quality will enhance the predictive colposcopic accuracy for high grade cervical intraepithelial neoplasia after referral. With the advent of computerised colposcopy and the Internet, digital imaging can be transmitted in real-time for instant viewing, facilitating distant consultation and education. This form of 'telemedicine' will allow family practice and remote areas to have access to colposcopy expertise. Of all the currently available technological adjuncts to colposcopy, spectroscopy devices have demonstrated relatively high sensitivities, and seem to have the best potential to become the technique of choice in future routine clinical practice in developed countries following the human papillomavirus vaccination. Other alternatives may need to be used in parts of the globe with high disease incidence and without organised screening or vaccination programmes. Opportunities remain for global collaboration in research, education and training to promote more effective and affordable cervical screening, and to enhance the skills of colposcopists worldwide. PMID- 21664877 TI - Validity and reliability of the Portuguese version of the Epilepsy Medication Treatment Complexity Index for Brazil. AB - We evaluated the reliability and validity of a Brazilian-Portuguese version of the Epilepsy Medication Treatment Complexity Index (EMTCI). Interrater reliability was evaluated with the intraclass correlation coefficient (ICC), and validity was evaluated by correlation of mean EMTCI scores with the following variables: number of antiepileptic drugs (AEDs), seizure control, patients' perception of seizure control, and adherence to the therapeutic regimen as measured with the Morisky scale. We studied patients with epilepsy followed in a tertiary university-based hospital outpatient clinic setting, aged 18 years or older, independent in daily living activities, and without cognitive impairment or active psychiatric disease. ICCs ranged from 0.721 to 0.999. Mean EMTCI scores were significantly correlated with the variables assessed. Higher EMTCI scores were associated with an increasing number of AEDs, uncontrolled seizures, patients' perception of lack of seizure control, and poorer adherence to the therapeutic regimen. The results indicate that the Brazilian-Portuguese EMTCI is reliable and valid to be applied clinically in the country. The Brazilian Portuguese EMTCI version may be a useful tool in developing strategies to minimize treatment complexity, possibly improving seizure control and quality of life in people with epilepsy in our milieu. PMID- 21664878 TI - Comparison of cellular damage response to low-dose-rate 125I seed irradiation and high-dose-rate gamma irradiation in human lung cancer cells. AB - PURPOSE: To investigate the difference of cellular response between low-dose-rate (LDR) 125I seed irradiation and high-dose-rate (HDR) gamma-irradiation in human lung cancer cells. METHODS AND MATERIALS: A549 and NCI-H446 cells with or without wortmannin (WM) treatment were exposed to 125I seeds and gamma-rays, respectively. Cell survival, micronuclei (MN) formation, and the expressions of Ku70/Ku80 proteins were measured. RESULTS: There was a strong negative correlation between survival and MN formation for both irradiations, and the MN inductions of NCI-H446 were about twofolds of those of A549, and the survival of NCI-H446 was lower than that of A549, indicating the radiosensitivity of NCI-H446 cells was greater than that of A549 cells. Interestingly, at 4-Gy radiation, NCI H446 cells were more sensitive to LDR irradiation than HDR irradiation. WM treatment enhanced the radiosensitivity of A549 cells evenly to (125I seed and gamma-irradiation, but this treatment led NCI-H446 cells to be more sensitive to LDR 125I. Further results revealed that the expression of phosphorylated Ku80 protein was enhanced in irradiated A549, but in contrast, it was markedly decreased in NCI-H446 cells after 4-Gy LDR 125I irradiation as that compared with gamma-irradiated and nonirradiated cells. CONCLUSION: NCI-H446 cells were more sensitive to LDR 125I irradiation than HDR irradiation, and this sensitivity could be further enhanced by WM treatment. But no obvious differences of cellular response to both irradiations were observed in A549. Ku as molecular markers together with cell proliferation rate can be used to predict the radiosensitivity of tumor cells to LDR 125I seed irradiation. PMID- 21664879 TI - Accelerated partial breast irradiation via brachytherapy: a patterns-of-care analysis with ASTRO consensus statement groupings. AB - PURPOSE: The 2002 Food and Drug Administration approval of the MammoSite catheter (Hologic, Inc., Beford, MA) led to a surge of interest in accelerated partial breast irradiation (APBI). Until recently, guidelines as to the optimal candidates for this treatment were unavailable. We performed a patterns-of-care analysis for patients undergoing breast brachytherapy and compared these results with the American Society for Radiation Oncology (ASTRO) consensus statement. METHODS AND MATERIALS: The Surveillance, Epidemiology, and End Results database was used to examine female breast cancer patients treated with brachytherapy between 2002 and 2007. The patients were then categorized into suitable, cautionary, and unsuitable groups based on the ASTRO guidelines. RESULTS: We identified 4172 female breast cancer patients treated within the stated years. The number of brachytherapy cases increased nearly 10-fold over the time period studied from 163 in 2002 to 1427 in 2007 (p<0.0001). Patients with data missing were excluded, leaving a total of 3593 patients available for analysis. The mean patient age was 64 years. Most patients had small (<2cm in 80.9%) estrogen receptor-positive (86.7%) invasive (88.6%) tumors. The percentage of patients treated for ductal carcinoma in situ increased with time (p<0.001), whereas the percentage of patients treated with positive lymph nodes decreased with time (p<0.001). Using the data available, 1369 (38.1%), 1563 (43.5%), and 661 (18.3%) patients were characterized as suitable, cautionary, and unsuitable, respectively. CONCLUSIONS: More than 60% of patients who received APBI via brachytherapy would fall into the ASTRO cautionary or unsuitable groupings. This is the largest patterns-of-care analysis for APBI patients and serves as a baseline for future comparison. PMID- 21664880 TI - The effect of varenicline on heart rate variability in healthy smokers and nonsmokers. AB - Varenicline is an alpha4beta2 nicotinic acetylcholine receptor partial agonist. In this study, we assessed the effects of varenicline on heart rate variability (HRV). Thirty subjects were included in the randomized, double-blind, placebo controlled, crossover study. Varenicline or placebo was administered in two different testing sessions. Time domain parameters and power spectral analysis of HRV were assessed in the supine position and during handgrip exercise before and after the participants were given placebo or varenicline. Fifteen healthy non smokers (NS) and fifteen healthy smokers (S) were included in the study. There were no statistically significant differences among any of the time domain parameters obtained before and after placebo administration or between the S and NS groups with respect to varenicline administration. In frequency domain analyses, normalized HF (high-frequency) powers were significantly higher in the S group than in the NS group (before placebo, NS:6.57+/-3.58 vs. S:13.85+/-7.50, p=0.002, after placebo, NS:6.33+/-3.89 vs. S:10.82+/-4.88, p=0.007). After varenicline administration, the normalized HF power was significantly higher (NS:6.65+/-4.34 vs. S:11.06+/-4.52, p=0.01), and the ratio of LF (low-frequency) to HF was significantly lower (NS:8.44+/-5.89 vs. S:4.97+/-4.60, p=0.02) in the S group than in the NS group. Administration of a single dose of varenicline significantly increased the LF/HF ratio (5.83+/-2.69 vs. 8.44+/-5.89) in the NS group, but in the S group, there were no significant differences related to any of the time or frequency domain parameters. We concluded that a single dose of varenicline does not affect HRV in healthy smokers but that it may alter HRV when administered at a therapeutic dose to healthy non-smokers during mild sympathetic stimulation. PMID- 21664881 TI - A novel H(2)O(2) amperometric biosensor based on gold nanoparticles/self-doped polyaniline nanofibers. AB - A new kind of gold nanoparticles/self-doped polyaniline nanofibers (Au/SPAN) with grooves has been prepared for the immobilization of horseradish peroxidase (HRP) on the surface of glassy carbon electrode (GCE). The ratio of gold in the composite nanofibers was up to 64%, which could promote the conductivity and biocompatibility of SPAN and increase the immobilized amount of HRP molecules greatly. The electrode exhibits enhanced electrocatalytic activity in the reduction of H(2)O(2) in the presence of the mediator hydroquinone (HQ). The effects of concentration of HQ, solution pH and the working potential on the current response of the modified electrode toward H(2)O(2) were optimized to obtain the maximal sensitivity. The proposed biosensor exhibited a good linear response in the range from 10 to 2000 MUM with a detection limit of 1.6 MUM (S/N=3) under the optimum conditions. The response showed Michaelis-Menten behavior at larger H(2)O(2) concentrations, and the apparent Michaelis-Menten constant K(m) was estimated to be 2.21 mM. The detection of H(2)O(2) concentration in real sample showed acceptable accuracy with the traditional potassium permanganate titration. PMID- 21664882 TI - Colon cancer in lung transplant recipients with CF: increased risk and results of screening. AB - OBJECTIVE: To determine the incidence of colon cancer in lung transplant recipients with cystic fibrosis (CF) and review screening colonoscopic findings in other recipients with CF. METHODS: A retrospective chart review was performed for all patients with CF transplanted at the University of Wisconsin Hospital and Clinics (January 1994 through December 2010). RESULTS: Four of 70 transplant recipients with CF developed fatal colon carcinoma following transplantation, and the cancer was advanced in all 4 recipients (age 31, 44, 44, 64) at the time of diagnosis. In contrast, only one of 287 recipients transplanted for non-CF indications developed colon cancer. Of all recipients with CF who did not develop colon cancer, 20 recipients underwent screening colonoscopy at 1 to 12 years following transplantation. Seven (35%) of the screened transplant recipients (ages 36, 38, 40, 41, 43, 49, 51) had colonic polyps in locations ranging from cecum to sigmoid colon and up to 3 cm in diameter. CONCLUSIONS: In contrast to non-CF recipients, patients with CF displayed a significant incidence of colon cancer (4 of 70 recipients; 5.7%) with onset ranging from 246 days to 9.3 years post-transplant, which may be due to a combination of their underlying genetic disorder plus intense, sustained immunosuppression following lung transplantation. Colonoscopic screening may identify patients with pre-malignant colonic lesions and prevent progression to colonic malignancy. PMID- 21664883 TI - Pharmacokinetics of ergosterol in rats using rapid resolution liquid chromatography-atmospheric pressure chemical ionization multi-stage tandem mass spectrometry and rapid resolution liquid chromatography/tandem mass spectrometry. AB - Rapid resolution liquid chromatography/tandem multi-stage mass spectrometry (RRLC MS(n)) and rapid resolution liquid chromatography/tandem mass spectrometry (RRLC/MS/MS) methods were developed for the identification and quantification of ergosterol and its metabolites from rat plasma, urine and faeces. Two metabolites (ERG1 and ERG2) were identified by RRLC/MS(n). The concentrations of the ergosterol were determined by RRLC/MS/MS. The separation was performed on an Agilent Zorbax SB-C18 with the mobile phase consisting of methanol and water (containing 0.1% formic acid). The detection was carried out by means of atmospheric pressure chemical ionization mass spectrometry in positive ion mode with multiple reaction monitoring (MRM). Linear calibration curves were obtained in the concentration range of 7-2000, 6-2000 and 8-7500 ng/mL for plasma, urine and faecal homogenate, respectively. The intra- and inter-day precision values (RSD) were below 10%. The method was applied to the pharmacokinetic properties and elimination pathway of ergosterol in rats. PMID- 21664884 TI - Theory-guided efficient strategy to maximize speed and resolution in rapid gradient LC-MS/MS bioanalysis. AB - Reversed-phase gradient LC-MS/MS bioanalytical methods of 5-100% organic solvent in a 1-3 min gradient time are common in today's bioanalytical laboratory. The goal of this work was to develop a theory-guided systematic strategy for maximizing resolution and speed in rapid gradient LC-MS/MS bioanalysis. We studied the effect of gradient time (t(G)), initial and final eluent strength (% B=% organic), and flow rate (F) on the separation of multiple critical pairs (R(s)) and peak capacity (n(c)) in a gradient elution of a mixture of five structurally related compounds. By optimizing the gradient time t(G), the initial and final percentages of the organic component of the mobile phase, comparable resolution and peak capacity could be achieved in a shorter run time. More importantly, we demonstrated that higher flow rates improved resolution, peak capacity and reduced run time in rapid gradient separations on a 5 MUm particle column. A straightforward mathematical explanation of the phenomenon was provided applying basic resolution equations in gradient elution theory. A systematic approach to execute a rapid gradient LC-MS/MS bioanalytical method to shorten run time and improve resolution is proposed, taking into consideration not only the analytes of interest but also potential matrix effects from the dosing vehicle and biological matrix. PMID- 21664885 TI - LC-MS/MS method for simultaneous determination of valproic acid and major metabolites in human plasma. AB - A rapid and sensitive method using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was developed and validated for simultaneous quantitative determination of valproic acid and three major metabolites (3-OH-valproic acid, 4 ene-valproic acid and 5-OH-valproic acid) in human plasma. The analytes and internal standard were isolated from 200 MUL samples by solid phase extraction using a ZORBAX SB-C8 column (3.5 MUm, 2.1*100 mm) with an isocratic mobile phase consisting of methanol-10mM ammonium acetate (80:20, v/v) containing 0.1% formic acid at a flow rate of 0.3 mL/min. The method had a chromatographic total run time of 2.0 min. The lower limit of quantification of valproic acid, 3-OH valproic acid, 4-ene-valproic acid and 5-OH-valproic acid of the method was 2030, 51.5, 50.15 and 51.25 ng/mL, respectively. The method was linear for valproic acid and the three metabolites with correlation coefficients >0.995 for all analytes. The intra-day and inter-day accuracy and precision of the assay were less than 15.0%. This analytical method was successfully used to assay plasma concentrations of valproic acid and the three metabolites in human plasma from epileptic patients. PMID- 21664886 TI - Refinement of the tripartite influence model for men: dual body image pathways to body change behaviors. AB - Although muscularity and body fat concerns are central to conceptualizing men's body image, they have not been examined together within existing structural models. This study refined the tripartite influence model (Thompson, Heinberg, Altabe, & Tantleff-Dunn, 1999) by including dual body image pathways (muscularity and body fat dissatisfaction) to engagement in muscular enhancement and disordered eating behaviors, respectively, and added dating partners as a source of social influence. Latent variable structural equation modeling analyses supported this quadripartite model in 473 undergraduate men. Nonsignificant paths were trimmed and two unanticipated paths were added. Muscularity dissatisfaction and body fat dissatisfaction represented dual body image pathways to men's engagement in muscularity enhancement behaviors and disordered eating behaviors, respectively. Pressures to be mesomorphic from friends, family, media, and dating partners made unique contributions to the model. Internalization of the mesomorphic ideal, muscularity dissatisfaction, and body fat dissatisfaction played key meditational roles within the model. PMID- 21664887 TI - An exploration of the tripartite influence model of body dissatisfaction and disordered eating among Australian and French college women. AB - The aim of the study was to compare levels of body dissatisfaction, disordered eating and risk factors, and to examine the tripartite influence model of body image and eating disturbance among French and Australian young adult females. Participants were 188 Australian (mean age=19.6 years, SD=1.0) and 190 French (mean age=20.7 years, SD=2.6) students. Media, peer and family influences, internalisation of media ideals, appearance comparison, body dissatisfaction, drive for thinness, bulimia and self-esteem were assessed. Australian participants reported perceiving more peer and media influence, and higher levels of appearance comparison, internalisation of media ideals and bulimic symptoms than French participants (p<.001). Path analyses revealed that the tripartite model was a good fit in both samples, with similarities and differences. Findings suggest the importance of identifying cultural specificities, and developing a global framework of body image and eating disturbance with a view to prevention. PMID- 21664888 TI - On being victimized by peers in the advent of adolescence: prospective relationships to objectified body consciousness. AB - Previous research indicates that peer victimization is tied to children's negative appearance evaluations. The current study examines whether early peer victimization is also prospectively related to objectified body consciousness. Six-hundred-and-two Swedish boys and girls answered questionnaires at age 10, and again at age 18. Main findings showed that being the target of peer victimization at age 10 was related to more habitual appearance monitoring and body shame at age 18. Gender moderated the relations between victimization and body shame, with victimized girls experiencing stronger body shame than victimized boys. Additionally, whereas boys experienced less body shame than girls, they were equally likely to monitor their appearance. In sum, this study provides preliminary support to the notion that peer victimization is involved in the processes by which young adolescents' self-objectify. Future studies are warranted to further validate these findings. PMID- 21664889 TI - Atypical fibroxanthoma and malignant fibrous histiocytoma. AB - BACKGROUND: Atypical fibroxanthoma (AFX) and malignant fibrous histiocytoma (MFH) are soft-tissue tumours with variable aggressiveness. There is considerable debate about the relationship between these lesions, as histological and immunochemical differentiation is difficult. METHODS: Current opinions and evidence for diagnostic differences between AFX and MFH were reviewed. Consecutive cases of AFX and MFH were identified from our non-melanoma skin cancer (NMSC) database 1996-2007 for the Central Region of New Zealand. RESULTS: Of the 50,411 NMSC lesions excised surgically from 26,138 patients, there were 101 AFX and 15 MFH cases. Three MFH cases were originally diagnosed as AFX. AFX and MFH share similar patient demographics, size and location and histological and immunohistochemical features. Most diagnostic biopsies of AFX were not followed by formal excision. Incomplete excision occurred in a large proportion of patients with AFX, which often did not proceed to re-excision, resulting in local recurrence. Cases of MFH generally underwent definitive treatment including re-excision if incompletely excised, and postoperative adjuvant radiotherapy. CONCLUSIONS: The failure to treat AFX adequately may have resulted from the lack of appreciation of its aggressiveness. Contrary to the literature, we found few clinical differences between AFX and MFH. AFX and MFH also share similar histologic features and there are no immunohistochemical markers that reliably distinguish them. AFX is best considered a distinct entity with MFH, now reclassified as an undifferentiated pleomorphic sarcoma. PMID- 21664890 TI - Cutting bipolar diathermy: introducing a felt coat. PMID- 21664891 TI - The segmental gastrocnemius muscles' flap: a cadaveric study. AB - The aim of this study was to evaluate the feasibility of splitting each head of the gastrocnemius muscle into two segments. This prospective study was conducted on 35 fresh cadavers with injection of radio-opaque contrast material in the popliteal artery. Seventy medial gastrocnemius and 70 lateral gastrocnemius muscle specimens were obtained. Gastrocnemius intramuscular arterial anatomy was analysed by using the digital X-ray technique. The most common vascular pattern found in this study was both bellies supplied by individual sural arteries, which shows distal bifurcation. The medial sural artery always showed bifurcation in the medial gastrocnemius muscle in both lower limbs, whereas this bifurcation of the lateral sural artery was present in only 87% cases and 13% of cases showed a single lateral sural artery without bifurcation in the lateral gastrocnemius muscle. The mean pedicle length of the medial sural artery in the right lower limb was 2.1 cm, and in left lower limb 2.3 cm. The mean pedicle length of the lateral sural artery in the right lower limb was 2.44 cm and in the left lower limb 3.21 cm. The segmental vascular pattern of the medial belly of the gastrocnemius is constant, and, thus, it can be divided safely for coverage of multiple wound defects around the knee joint. The short length of the median sural artery allows for high division of the medial gastrocnemius muscle belly. The segmental vascular anatomy is not constant in the lateral belly of the gastrocnemius muscle and, hence, division of the lateral belly is not advocated without prior preoperative colour Doppler. PMID- 21664892 TI - European College of Orthodontics: Commission of Affiliation and Titularisation. AB - Date of birth: 24/2/1975; gender: female. A. PRETREATMENT RECORDS: (12/2005; 30 yrs). DIAGNOSIS: Adult patient presenting Angle Class II,1 malocclusion. TREATMENT: Extraction of 14-24 fixed lingual appliance on both arches. B. POST TREATMENT RECORDS: (9/2008; 33 yrs). RETENTION: Bonded lingual wires 13 to 23 and 33 to 43. C. POST-RETENTION RECORDS: (9/2009; 34 yrs). PMID- 21664894 TI - Y-STR genetic diversity in autochthonous Andalusians from Huelva and Granada provinces (Spain). AB - Seventeen Y-chromosomal short tandem repeats (STRs) were analyzed in 347 healthy, unrelated, autochthonous males from the Andalusian provinces of Huelva (N=167) and Granada (N=180). AmpFlSTR Y-filer PCR Amplification kit (Applied Biosystems) was used to type the Y-STR markers. A total of 156 and 166 different haplotypes for the 17 Y-STR set were detected in Huelva, and Granada, respectively. The same haplotype diversity was found for both samples (0.998+/-0.001), and the overall discrimination capacity was 0.904. The most common minimal haplotype (DYS19, DYS389 I, DYS389 II, DYS390, DYS391, DYS392, DYS393) in both subpopulations was 14-13-16-24-11-13-13, which is also the most frequent haplotype among Atlantic European populations. Comparison analysis using pairwise R(ST) values and Analysis of Molecular Variance (AMOVA) revealed a significant genetic distance between our Andalusian samples and other ones from the northern Iberian fringe (including Basque and Pyrenean populations). However, results from the multi dimensional scaling analysis (MDS) yielded a well-defined group of Iberian populations separated from the other Mediterranean clusters observed. PMID- 21664895 TI - Right ventricular outflow tract pseudoaneurysm: two cases. AB - Right ventricular pseudoaneurysm is a rare complication following repair of Tetralogy of Fallot. Presented are two patients, both with history of Tetralogy of Fallot, successful repair and pseudoaneurysms discovered on symptomatic follow up. Because surgical intervention is often required, the location and characteristics of the pseudoaneurysm are critical determinants of successful outcomes. Cardiac gated CT provides physicians with an invaluable tool in evaluating pseudoaneurysms. PMID- 21664896 TI - Epigenetic regulation of CIITA expression in human T-cells. AB - In humans, T-cells accomplish expression of MHC-II molecules through induction of CIITA upon activation. Here we show that CIITA promoter accessibility in T-cells is epigenetically regulated. In unstimulated T-cells, CIITA-PIII chromatin displays relative high levels of repressive histone methylation marks (3Me-K27-H3 and 3Me-K20-H4) and low levels of acetylated histones H3 (Ac-H3) and H4 (Ac-H4). These repressive histone marks are replaced by histone methylation marks associated with transcriptional active genes (3Me-K4-H3) and high levels of Ac-H3 and Ac-H4 in activated T-cells. This is associated with concomitant recruitment of RNA polymerase II. In T-leukemia cells, devoid of CIITA expression, similar repressive histone methylation marks and low levels of acetylated histone H3 correlated with lack of CIITA expression. This in contrast to CIITA expressing T lymphoma cells, which display high levels of Ac-H3 and 3Me-K4-H3, and relative low levels of the 3Me-K27-H3 and 3Me-K20-H4 marks. Of interest was the observation that the levels of histone acetylation and methylation modifications in histones H3 and H4 were also noted in chromatin of the downstream CIITA-PIV promoter as well as the upstream CIITA-PI and CIITA-PII promoters both in normal T-cells and in malignant T-cells. Together our data show that CIITA chromatin in T-cells expressing CIITA display similar histone acetylation and methylation characteristics associated with an open chromatin structure. The opposite is true for T-cells lacking CIITA expression, which display histone modifications characteristic of condensed chromatin. PMID- 21664897 TI - Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: delineation of anti-leukemic mechanisms of action. AB - Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would solely interfere with aberrant tyrosine kinase activation in malignant cells. Nevertheless, preclinical and clinical studies demonstrated that TKI also exhibit "off-target" effects, that is effects not mediated by the assumed mechanisms of action. We and others showed that the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib exert potent antineoplastic effects on EGFR-negative myeloblasts from patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Here, we undertook a side-by-side comparison of the anti-leukemic efficacy of four different TKI in MDS and AML. Besides the EGFR inhibitor erlotinib, which served as a point of reference, we employed the dual EGFR/HER2 TKI lapatinib, as well as the multikinase inhibitors dasatinib and sorafenib. All four drugs had anti-leukemic effects on cell line models of MDS/AML in vitro as well as on malignant blasts from MDS/AML patients ex vivo. We explored the biological phenomena underlying this anti-leukemic efficacy. Since it is established that a therapeutic benefit in MDS/AML can be conveyed by induction of cell cycle arrest, apoptosis and/or differentiation, we deciphered the individual contribution of these three phenomena to the anti leukemic action of each of the four TKI. The concomitant assessment of the panel of TKI enables us thus to define (and quantify) their differential capacity to impact on the three biological phenomena, and provide further evidence that these mechanisms are not solely explained by on-target effects. PMID- 21664898 TI - Sterically stable liposomes improve the therapeutic effect of hepatic stimulator substance on fulminant hepatic failure in rats. AB - BACKGROUND AND AIMS: Few drugs have been confirmed to be effective for fulminant hepatic failure (FHF). The purpose of this study was to prepare sterically stable liposomes (SSL) encapsulating hepatic stimulator substance (HSS) and determine their therapeutic effect on FHF. METHODS: HSS were encapsulated into SSL (HSS SSL). FHF was induced in rats by thioacetamide (TAA) injection (400mg/kg, three times with a 24-h interval). The agents, including HSS-SSL, SSL, HSS, and sodium chloride (NS), were each injected intravenously 2h after the second and the third TAA injection. RESULTS: Freshly prepared HSS-SSL had a mean size of 93.59nm and the average encapsulation efficiency was 37.20%. HSS encapsulated in SSL showed a longer half life and more potent target to injured livers than free HSS. Twenty four hours after the third TAA-injection, the survival rate of HSS-SSL-treated rats (80%) was significantly higher than that of rats treated with NS (20%), SSL (25%), or HSS (50%). Histopathologic examination showed that there was the least necrosis and inflammation in the livers of HSS-SSL-treated rats. The incidence of stage 3 or 4 hepatic encephalopathy in HSS-SSL-treated rats was significantly lower than that in rats treated with other agents. The serum pro-inflammatory cytokine levels and hepatic lipid peroxidation levels were both markedly reduced, while hepatocyte proliferative rate was markedly increased after HSS-SSL treatment. CONCLUSION: Encapsulation by SSL markedly improved the therapeutic effect of HSS on FHF in rats. Encapsulation by SSL may be an effective approach to enhance the therapeutic potency of drugs for FHF. PMID- 21664899 TI - Evaluation of two automated capillary electrophoresis systems for human serum protein analysis. AB - OBJECTIVES: We compared automated capillary electrophoresis (CE) systems Capillarys 2 from Sebia and V8 from Helena Biosciences Europe (Elitech) with the semi-automated Hydrasys-Hyrys agarose gel electrophoresis (AGE) from Sebia. DESIGN AND METHODS: We evaluated analytical performances and compared 129 fresh routine sera (group A) to 164 frozen pathologic samples with suspicion or antecedent of monoclonal component (MC) (group B). Immunofixation was then compared with immunotyping provided by both CE systems. RESULTS: Analytical performances from both CE systems have proven suitable results for clinical use, with within-run and between-run coefficients of variation inferior or equal to 5.2% and 7.7%, respectively. A good correlation was found between AGE and CE with r-value ranging from 0.81 to 0.96 for both CE systems. We observed high MC detection sensitivities (>85%) of in electrophoretogram readings for both CE systems. MC identification using CE systems provided suitable concordance with immunofixation, although failing to detect some IgM proteins or free light chains. CONCLUSIONS: Both Capillarys 2 and V8 are reliable automated CE systems for patient care. PMID- 21664900 TI - Heart-type fatty acid binding protein in elective cardioversion of atrial fibrillation. AB - OBJECTIVES: We sought to investigate whether heart-type fatty acid binding protein (H-FABP), a new marker of myocardial necrosis, increases in relation to elective cardioversion of atrial fibrillation (AF). METHODS: We studied 25 consecutive patients (61 +/- 16 years old, 21 men) admitted to our hospital for elective cardioversion of AF. Peripheral venous samples were drawn immediately before cardioversion, one hour and 24h after the procedure and assayed for H FABP. RESULTS: A mean of 309 +/- 183 J was used for cardioversion. Successful cardioversion in sinus rhythm was achieved in 18 patients (72%). Serum levels of H-FABP did not change significantly either in relation to the procedure [1385 (256-17,127)pg/mL at baseline, 1125 (290-15,238)pg/mL 1h post and 1045.5 (66 2981)pg/mL 24 h post cardioversion, p=0.37] or to the success of the procedure. CONCLUSION: H-FABP does not significantly change following elective cardioversion for AF and we, therefore, speculate that myocardial necrosis does not occur during cardioversion. PMID- 21664902 TI - Neurotransmitters, more than meets the eye--neurotransmitters and their perspectives in cancer development and therapy. AB - The neurotransmitter/receptor system has been shown to modulate various aspects of tumor development including cell proliferation, angiogenesis, invasion, migration and metastasis. It has been found that tumor tissues can not only synthesize and release a wide range of neurotransmitters but also produce different biological effects via respective receptors. These tissues are also innervated by nerve fibers but the biological significance is unknown. Nevertheless neurotransmitters can produce either stimulatory or inhibitory effect in normal and tumor tissues. These effects are dependent on the types of tissues and the kinds of neurotransmitter as well as the subtypes of corresponding receptors being involved. These findings clearly extend the conventional role of neurotransmitters in nervous system to the actions in oncogenesis. In this regard, intervention or stimulation of these neuronal pathways in different cancer diseases would have significant clinical implications in cancer treatments. Here, we summarize the influences of various well-characterized neurotransmitters and their receptors on tumor growth and further discuss the respective possible strategies and perspectives for cancer therapy in the future. PMID- 21664901 TI - Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development. AB - Heart development requires contributions from, and coordinated signaling interactions between, several cell populations, including splanchnic and pharyngeal mesoderm, postotic neural crest and the proepicardium. Here we report that Fgf3 and Fgf10, which are expressed dynamically in and near these cardiovascular progenitors, have redundant and dosage sensitive requirements in multiple aspects of early murine cardiovascular development. Embryos with Fgf3( /+);Fgf10(-/-), Fgf3(-/-);Fgf10(-/+) and Fgf3(-/-);Fgf10(-/-) genotypes formed an allelic series of increasing severity with respect to embryonic survival, with double mutants dead by E11.5. Morphologic analysis of embryos with three mutant alleles at E11.5-E13.5 and double mutants at E9.5-E11.0 revealed multiple cardiovascular defects affecting the outflow tract, ventricular septum, atrioventricular cushions, ventricular myocardium, dorsal mesenchymal protrusion, pulmonary arteries, epicardium and fourth pharyngeal arch artery. Assessment of molecular markers in E8.0-E10.5 double mutants revealed abnormalities in each progenitor population, and suggests that Fgf3 and Fgf10 are not required for specification of cardiovascular progenitors, but rather for their normal developmental coordination. These results imply that coding or regulatory mutations in FGF3 or FGF10 could contribute to human congenital heart defects. PMID- 21664903 TI - Histamine H(4) receptor antagonist reduces dermal inflammation and pruritus in a hapten-induced experimental model. AB - Effects of the histamine H(4) receptor antagonist 1-[(5-chloro-1H-indol-2 yl)carbonyl]-4-methylpiperazine (JNJ7777120) were examined for 99 days in a long term experimental model of pruritic dermatitis induced by repeated challenge with 2,4,6-trinitrochlorobenzene (TNCB) in HR-1 mice. Repeated application of TNCB to the back skin of mice elicited frequent scratching behavior and skin lesions at 24 h after challenge and beyond. JNJ7777120 (10 and 30 mg/kg) reduced this scratching behavior and ameliorated the skin lesions in a dose-dependent manner, whereas the histamine H(1) receptor antagonist fexofenadine had no such effect and did not reduce the inflammation score, even though dexamethasone reduced the scratching bouts. Each of the three agents reduced the increase in the serum IgE concentration induced by TNCB, but only JNJ7777120 reduced the number of mast cells in the skin lesions elicited by repeated application of TNCB. These results indicate that treatment with a H(4) receptor antagonist may be effective for amelioration of both skin inflammation and pruritus in patients with allergic dermatitis such as atopic dermatitis. PMID- 21664904 TI - Multiple signalling pathways underlie the protective effect of levosimendan in cardiac myocytes. AB - Levosimendan is a cardiovascular drug for the treatment of acute and decompensated heart failure. The current weight of evidence on the cardioprotective effects of levosimendan originates from whole heart models and there is no information on the mechanism whereby signalling pathways are activated. In the present study, we investigated the effect of levosimendan on ischaemia/reperfusion injury and the underlying mechanism in cardiac myocytes. Pretreatment with levosimendan reversed the effects of ischaemia and ischaemia/reperfusion on cell viability and enhanced phosphorylation of Akt, p38 mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinases 1/2 (ERK1/2). Inhibitors of these kinases and the blocker of the mitochondrial K(ATP) channels, 5-hydroxydecanoate, completely abolished the protection afforded by levosimendan. Levosimendan stimulated the phosphorylation of Akt, ERK1/2 and p38-MAPK with different kinetics and the activation of these pathways was dependent on the opening of the mitochondrial K(ATP) channels and the production of oxygen free radicals. The levosimendan-induced phosphorylation of ERK1/2 and Akt was reduced by inhibitors of epidermal growth factor receptor and Src. On the other hand, inhibition of the protein kinase A (PKA) pathway reduced phosphorylation of p38-MAPK. Furthermore, p38-MAPK was activated when a phosphodiesterase inhibitor or a selective PKA activator was used. Overall, our results suggest that levosimendan regulates the wiring of the natural salvaging pathways to execute the prosurvival signals. This network includes Akt, ERK1/2 and p38-MAPK. Opening of mitochondrial K(ATP) channels and the subsequent production of oxygen free radicals, the epidermal growth factor receptor/Src, and the cAMP/PKA pathways seem to mediate this response. PMID- 21664905 TI - Could maternal perinatal atypical antipsychotic treatments program later metabolic diseases in the offspring? AB - An association is established between schizophrenia and the development of metabolic alterations including cardiovascular diseases, type 2 diabetes and obesity. Perinatal insults, such as undernutrition, have been shown to increase the propensity to develop these pathologies, reinforcing the idea that schizophrenia may have a neurodevelopmental origin. Moreover, the use of second generation antipsychotics (SGAs) also known as "atypical" neuroleptics has also been demonstrated to exacerbate metabolic anomalies in patients with schizophrenia. SGAs are able to cross the placental barrier and have been detected in milk from women receiving atypical neuroleptics treatment during the perinatal period. To date, the consequences of such treatment have only been examined on the birth weight and the cognitive capacities of the child from women with schizophrenia, but no data is available concerning the putative long-term effects of SGAs on their body weight and metabolic parameters. We have recently reported that rat offspring from prenatally undernourished mothers exhibit a low birth weight associated with modified sensitivity to clozapine and aripiprazole in adulthood reinforcing the idea that some forms of schizophrenia may be acquired during early development. In view of these observations, the risks of perinatal exposure to SGAs must be weighed against the growing evidence that maternal psychiatric illness poses risks to the fetus/newborn as well as for long term susceptibility to diseases. Thus, metabolic follow-up of children born from mothers treated by SGAs during the perinatal period will be clearly recommended, in particular if they exhibit alterations of their body weight during this early critical period. PMID- 21664906 TI - The carbohydrate ligands on the host embryo mediate intercellular migration of the parasitic wasp embryo. AB - Invasive stage embryos of the parasitic wasp Copidosoma floridanum transmigrate through the epithelium of phylogenetically distant host embryos in a manner that is similar to mammalian leukocyte infiltration. Host embryonic cells appear to recognize the invading wasp embryo by components on the cell surface. We developed an in vitro wasp entry inhibition assay and found that C-type lectins of the wasp embryo bound to N-linked carbohydrate chains with fucose residues on the surface of host embryo. This is the first report showing a receptor-ligand interaction between heterologous multicellular organisms. PMID- 21664907 TI - Apoptosis-inducing factor is a target gene of C/EBPalpha and participates in adipocyte differentiation. AB - Besides the contribution in cell death, apoptosis-inducing factor (AIF) also exerts roles in other cellular activities, which are largely unknown. The CCAAT enhancer binding protein alpha (C/EBPalpha) is required for differentiation of adipocytes and granulocytes. Here we report that, during 3T3-L1 adipocyte differentiation, AIF expression is robustly upregulated via transcriptional regulation by C/EBPalpha. The upregulated effect is also confirmed by knockdown and ectopic expression of C/EBPalpha in U937 and MCF-7 cells respectively with and without endogenous expression of C/EBPalpha protein. We also reveal that AIF knockdown attenuates 3T3-L1 adipocyte differentiation, presumably due to the mitochondrial respiratory chain deficiency. These results provide evidence for the role of AIF in adipocyte differentiation. PMID- 21664908 TI - Identification of the substrate binding site in the N-terminal TBP-like domain of RNase H3. AB - Ribonuclease H3 from Bacillus stearothermophilus (Bst-RNase H3) has the N terminal TBP-like substrate-binding domain. To identify the substrate binding site in this domain, the mutant proteins of the intact protein and isolated N domain, in which six of the seventeen residues corresponding to those involved in DNA binding of TBP are individually mutated to Ala, were constructed. All of them exhibited decreased enzymatic activities and/or substrate-binding affinities when compared to those of the parent proteins, suggesting that the N-terminal domain of RNase H3 uses the flat surface of the beta-sheet for substrate binding as TBP to bind DNA. This domain may greatly change conformation upon substrate binding. PMID- 21664909 TI - PANcreatic-DERived factor: novel hormone PANDERing to glucose regulation. AB - PANcreatic-DERived factor (PANDER, FAM3B) is a member of the FAM3 family of cytokine molecules that were initially described in 2002. PANDER expression is primarily localized to the endocrine pancreas and is secreted from both pancreatic alpha and beta-cells. Initial characterization of PANDER revealed a potential role in pancreatic islet apoptosis. However, recent animal models have indicated PANDER functions as a hormone by regulating glucose levels via interaction with both the liver and the endocrine pancreas. An understanding of the function of PANDER can further the insight into the mechanisms of glucose regulation and potentially provide additional therapeutic targets for the treatment of diabetes. This review details the supporting data demonstrating PANDER has a biological function in glycemic regulation. PMID- 21664910 TI - Melatonin elevates intracellular free calcium in human platelets by inositol 1,4,5-trisphosphate independent mechanism. AB - Several studies have indicated the existence of direct effects of melatonin on platelets. Here we show that, melatonin at high concentration is capable of significantly raising platelet intracellular calcium even in the absence of an agonist. The effect of melatonin on platelets was abolished by luzindole, a melatonin receptor blocker, and rotenone, while it was unaffected by cell permeable antagonists of either inositol 1,4,5-trisphosphate (IP(3)) receptor, phospholipase C (PLC), or bafilomycin A1, which discharges acidic calcium stores. Melatonin-induced manganese entry provided evidence for activation of bivalent cation entry. Thus, our data suggest that melatonin evoked the elevation of platelet intracellular calcium through depletion of mitochondrial Ca(2+) stores and store-operated calcium entry (SOCE), while the action was independent of the PLC-IP(3) axis. PMID- 21664911 TI - A ternary mechanism for NADH oxidation by positively charged electron acceptors, catalyzed at the flavin site in respiratory complex I. AB - The flavin mononucleotide in complex I (NADH:ubiquinone oxidoreductase) catalyzes NADH oxidation, O(2) reduction to superoxide, and the reduction of several 'artificial' electron acceptors. Here, we show that the positively-charged electron acceptors paraquat and hexaammineruthenium(III) react with the nucleotide-bound reduced flavin in complex I, by an unusual ternary mechanism. NADH, ATP, ADP and ADP-ribose stimulate the reactions, indicating that the positively-charged acceptors interact with their negatively-charged phosphates. Our mechanism for paraquat reduction defines a new mechanism for superoxide production by complex I (by redox cycling); in contrast to direct O(2) reduction the rate is stimulated, not inhibited, by high NADH concentrations. PMID- 21664912 TI - The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks. AB - DNA double-strand breaks (DSBs) represent the most destructive type of chromosomal lesion and trigger rapid chromatin restructuring accompanied by accumulation of proteins in the vicinity of the DSB. Non-proteolytic ubiquitylation of chromatin surrounding DSBs, mediated by the RNF8/RNF168 ubiquitin ligase cascade, has emerged as a key mechanism for restoration of genome integrity by licensing the DSB-modified chromatin to concentrate genome caretaker proteins such as 53BP1 and BRCA1 near the lesions. In parallel, SUMOylation of upstream DSB regulators is also required for execution of this ubiquitin-dependent chromatin response, but its molecular basis is currently unclear. Here, we discuss recent insights into how ubiquitin- and SUMO-dependent signaling processes cooperate to orchestrate protein interactions with sites of DNA damage to facilitate DSB repair. PMID- 21664913 TI - Interaction of calmodulin with L-selectin at the membrane interface: implication on the regulation of L-selectin shedding. AB - The calmodulin (CaM) hypothesis of ectodomain shedding stipulates that CaM, an intracellular Ca2+-dependent regulatory protein, associates with the cytoplasmic domain of L-selectin to regulate ectodomain shedding of L-selectin on the other side of the plasma membrane. To understand the underlying molecular mechanism, we have characterized the interactions of CaM with two peptides derived from human L selectin. The peptide ARR18 corresponds to the entire cytoplasmic domain of L selectin (residues Ala317-Tyr334 in the mature protein), and CLS corresponds to residues Lys280-Tyr334, which contains the entire transmembrane and cytoplasmic domains of l-selectin. Monitoring the interaction by fluorescence spectroscopy and other biophysical techniques, we found that CaM can bind to ARR18 in aqueous solutions or the L-selectin cytoplasmic domain of CLS reconstituted in the phosphatidylcholine bilayer, both with an affinity of approximately 2 MUM. The association is calcium independent and dynamic and involves both lobes of CaM. In a phospholipid bilayer, the positively charged L-selectin cytoplasmic domain of CLS is associated with anionic phosphatidylserine (PS) lipids at the membrane interface through electrostatic interactions. Under conditions where the PS content mimics that in the inner leaflet of the cell plasma membrane, the interaction between CaM and CLS becomes undetectable. These results suggest that the association of CaM with L-selectin in the cell can be influenced by the membrane bilayer and that anionic lipids may modulate ectodomain shedding of transmembrane receptors. PMID- 21664914 TI - Sample entropy of laser Doppler flowmetry signals increases in patients with systemic sclerosis. AB - Associated to reactivity tests, laser Doppler flowmetry (LDF) emphasizes abnormal skin microvascular function in diseases affecting digits, such as Raynaud's phenomenon (RP) and systemic sclerosis (SSc). However, baseline perfusion value does not discriminate between disease states. We study if LDF sample entropy (SampEn) allows distinguishing healthy subjects, RP and SSc patients. LDF measurements were performed on finger pad and forearm of 108 subjects (27 controls, 28 RP patients, 53 SSc patients), before and after local thermal hyperemia. We also assessed the reproducibility of SampEn [expressed as within subject coefficients of variation (CV) and intra-class correlation coefficients (ICC)]. Baseline SampEn is significantly increased in patients with SSc compared to RP and controls on finger pad [0.49 (0.19), 0.38 (0.14) and 0.36 (0.15), respectively; P<0.002], but not on forearm. However, local thermal hyperemia increased SampEn at all sites and for all groups. Finally, reproducibility of SampEn computed on two baseline segments was acceptable (CV=26%, ICC=0.63). SampEn of skin blood flow at rest is increased on finger pad of patients with SSc but not on forearm. This is consistent with the pathophysiology of the disease, which predominantly affects digital microcirculation in most patients. SampEn of LDF signal could be a reproducible tool to predict digital microvascular impairment. PMID- 21664915 TI - Noradrenergic regulation of itch transmission in the spinal cord mediated by alpha-adrenoceptors. AB - It has recently been shown that clonidine suppresses itch-related responses via its action on alpha(2)-adrenoceptors in the spinal cord, raising the possibility that the descending noradrenergic system regulates itch signaling in the spinal cord. In this study, we investigated whether the transmission of itch signals in the spinal cord is under tonic inhibition by the descending noradrenergic system. An intraplantar injection of serotonin in mice induced biting of the treated paw (an itch-related response). An intrathecal injection of 6-hydroxydopamine (catecholaminergic neurotoxin) enhanced the itch-related response. There was a significant inverse correlation between the response and noradrenaline content. An intrathecal injection of phentolamine (alpha-adrenoceptor antagonist) enhanced serotonin-induced biting, although prazosin (alpha(1)-, alpha(2B)-, and alpha(2C) adrenoceptor antagonist) and yohimbine (alpha(2)-adrenoceptor antagonist) had no effects. Intrathecal injections of phenylephrine (alpha(1)-adrenoceptor agonist) and clonidine (alpha(2)-adrenoceptor agonist) inhibited serotonin-induced biting. The action of phenylephrine was antagonized by intrathecal prazosin but not 5 methylurapidil (alpha(1A)-adrenoceptor antagonist), cyclazosin (alpha(1B) adrenoceptor antagonist), and BMY 7378 (alpha(1D)-adrenoceptor antagonist). mRNAs encoding alpha(1A)-, alpha(1B)-, alpha(2A)-, alpha(2B)-, and alpha(2C) adrenoceptor subtypes were expressed in the dorsal root ganglion and spinal dorsal horn. These results suggest that the descending noradrenergic system exerts tonic inhibition on itch signaling in the spinal cord. Both alpha(1)- and alpha(2)-adrenoceptors may be involved in the tonic inhibition of itch signaling and the stimulation of either alpha-adrenoceptor subtype may result in the inhibition of itch. PMID- 21664916 TI - Food anticipation depends on oscillators and memories in both body and brain. AB - Despite the importance of learning and circadian rhythms to feeding, there has been relatively little effort to integrate these separate lines of research. In this review, we focus on how light and food entrainable oscillators contribute to the anticipation of food. In particular, we examine the evidence for temporal conditioning of food entrainable oscillators throughout the body. The evidence suggests a shift away from previous notions of a single locus or neural network of food entrainable oscillators to a distributed system involving dynamic feedback among cells of the body and brain. Several recent advances, including documentation of peroxiredoxin metabolic circadian oscillation and anticipatory behavior in the absence of a central nervous system, support the possibility of conditioned signals from the periphery in determining anticipatory behavior. Individuals learn to detect changes in internal and external signals that occur as a consequence of the brain and body preparing for an impending meal. Cues temporally near and far from actual energy content can then be used to optimize responses to temporally predictable and unpredictable cues in the environment. PMID- 21664917 TI - Emotionality in growing pigs: is the open field a valid test? AB - The ability to assess emotionality is important within animal welfare research. Yet, for farm animals, few tests of emotionality have been well validated. Here we investigated the construct validity of behavioural measures of pig emotionality in an open-field test by manipulating the experiences of pigs in three ways. In Experiment One (pharmacological manipulation), pigs pre-treated with Azaperone, a drug used to reduce stress in commercial pigs, were more active, spent more time exploring and vocalised less than control pigs. In Experiment Two (social manipulation), pigs that experienced the open-field arena with a familiar companion were also more exploratory, spent less time behaviourally idle, and were less vocal than controls although to a lesser degree than in Experiment One. In Experiment Three (novelty manipulation), pigs experiencing the open field for a second time were less active, explored less and vocalised less than they had done in the first exposure to the arena. A principal component analysis was conducted on data from all three trials. The first two components could be interpreted as relating to the form (cautious to exploratory) and magnitude (low to high arousal) of the emotional response to open-field testing. Based on these dimensions, in Experiment One, Azaperone pigs appeared to be less fearful than saline-treated controls. However, in Experiment Two, exposure to the arena with a conspecific did not affect the first two dimensions but did affect a third behavioural dimension, relating to oro-nasal exploration of the arena floor. In Experiment Three, repeat exposure altered the form but not the magnitude of emotional response: pigs were less exploratory in the second test. In conclusion, behavioural measures taken from pigs in an open-field test are sensitive to manipulations of their prior experience in a manner that suggests they reflect underlying emotionality. Behavioural measures taken during open-field exposure can be useful for making assessments of both pig emotionality and of their welfare. PMID- 21664919 TI - Search asymmetries: parallel processing of uncertain sensory information. AB - What is the mechanism underlying search phenomena such as search asymmetry? Two stage models such as Feature Integration Theory and Guided Search propose parallel pre-attentive processing followed by serial post-attentive processing. They claim search asymmetry effects are indicative of finding pairs of features, one processed in parallel, the other in serial. An alternative proposal is that a 1-stage parallel process is responsible, and search asymmetries occur when one stimulus has greater internal uncertainty associated with it than another. While the latter account is simpler, only a few studies have set out to empirically test its quantitative predictions, and many researchers still subscribe to the 2 stage account. This paper examines three separate parallel models (Bayesian optimal observer, max rule, and a heuristic decision rule). All three parallel models can account for search asymmetry effects and I conclude that either people can optimally utilise the uncertain sensory data available to them, or are able to select heuristic decision rules which approximate optimal performance. PMID- 21664920 TI - Dissociating spatial and letter-based word length effects observed in readers' eye movement patterns. AB - In previous eye movement research on word length effects, spatial width has been confounded with the number of letters. McDonald (2006) unconfounded these factors by rendering all words in sentences in constant spatial width. In the present study, the Arial font with proportional letter spacing was used for varying the number of letters while equating for spatial width, while the Courier font with monospaced letter spacing was used to measure the contribution of spatial width to the observed word length effect. Number of letters in words affected single fixation duration on target words, whereas words' spatial width determined fixation locations in words and the probability of skipping a word. The results support the existence of distinct subsystems for deciding where and when to move eyes in text (Rayner & McConkie, 1976). The number-of-letters effect in fixation duration may be explained by visual acuity, visual crowding, and/or serial letter processing. PMID- 21664921 TI - Point mutation at the Nbs1 Threonine 278 site does not affect mouse development, but compromises the Chk2 and Smc1 phosphorylation after DNA damage. AB - NBS1, mutated in Nijmegen breakage syndrome (NBS), senses the DNA double strand breaks (DSBs) and initiates the DNA damage response (DDR) by activating ATM kinase. Meanwhile, NBS1 is phosphorylated by ATM at Serine 278 and Serine 343 and thereby assists the activation of the ATM downstream targets. To study the physiological function of the Nbs1 phosphorylation, we have knocked in a point mutation in the moue genome that results in the replacement of Threonine 278 (equivalent to the human Serine 278) by Alanine. The Nbs1(T278A) knock-in mice develop normally and show no gross defects. The mutation of this phosphorylation site does not affect the proliferation or genomic stability. Ionizing radiation (IR) of primary Nbs1(T278A) MEFs reveals no obvious defects in the Chk2 phosphorylation at 1Gy, but a delayed phosphorylation of Chk2 and Smc1 only at intermediate (4.5Gy) and high (10Gy) doses, respectively. In contrast to Serine 343 mutant, Threonine 278 mutation has no effect on the HU-induced ATR-Chk1 activation. Our study thus shows that Nbs1 phosphorylation at the Threonine 278 is dispensable for mouse development and plays a differential function in assisting the DDR of downstream effectors in vivo, depending on the doses of DNA damage. PMID- 21664918 TI - Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism. AB - The atypical antipsychotics (AAPs) are associated with weight gain and an increased incidence of metabolic disease including type 2 diabetes mellitus. Epidemiological, cross-sectional and prospective studies suggest that two of the AAPs, olanzapine and clozapine, cause the most dramatic weight gain and metabolic impairments including increased fasting glucose, insulin and triglycerides. Relative to the other AAPs, both olanzapine and clozapine exhibit a particularly high antagonistic affinity for histamine and muscarinic receptors which have been hypothesized as mediators of the reported increase in weight and glucose abnormalities. In this article, we review the current evidence for the AAP associated weight gain and abnormal glucose metabolism. We postulate that the effects of the AAPs on food intake and peripheral metabolism are initially independently regulated but with increasing body adiposity, the early AAP-induced impairments in peripheral metabolism will be exacerbated, thereby establishing a vicious cycle such that the effects of the AAP are magnified by the known pathophysiological consequences of obesity. Furthermore, we examine how inhibition of the histaminergic pathway may mediate increases in food intake and the potential role of the vagus nerve in the reported peripheral metabolic effects. PMID- 21664922 TI - Synergistic anti-allodynic effects of nociceptin/orphanin FQ and cannabinoid systems in neuropathic mice. AB - Combinations of analgesics from different classes are commonly used in the management of chronic pain. The goal is to enhance pain relief together with the reduction of side effects. The present study was undertaken to examine the anti allodynic synergy resulting from the combination of WIN 55,212-2, a cannabinoid CB1 receptor agonist, and JTC-801, a nociceptin/orphanin FQ receptor antagonist, on neuropathic pain. Mice were tested for behavioral effects before and 2-4 weeks after the surgery, in which a partial tight ligation of the sciatic nerve was made. Nerve injury-induced mechanical allodynia was assessed with Dynamic Plantar Aesthesiometer, and a hot/cold plate was used to assess cold allodynia. Both WIN 55,212-2 and JTC-801 produced dose-dependent mechanical and cold anti-allodynic effects. As shown by isobolographic analysis, WIN 55,212-2/JTC-801 combinations interacted synergistically at all three ratios studied in the mechanical allodynia assay. In conclusion, co-administration of a cannabinoid with a nociceptin/orphanin FQ receptor antagonist resulted in a synergistic interaction, which may have utility in the pharmacological treatment of neuropathic pain. PMID- 21664923 TI - The extraction process optimization and physicochemical properties of polysaccharides from the roots of Euphorbia fischeriana. AB - Response surface methodology (RSM) was used to determine the optimum extraction conditions for polysaccharides (EFP) from the roots of Euphorbia fischeriana. A Box-Behnken design (BBD) with four independent variables was investigated, such as extraction temperature ( degrees C), water/solid ratio, extraction number (n), and extraction time (h). The results indicated optimum extraction conditions were extraction temperature of 97 degrees C, water/solid ratio of 9:1, extraction number of 2 and extraction time of 2.4h, respectively. Under these conditions, the experimental value was 24.6+/-0.62, which was well in close agreement with value predicted by the model. The preliminary chemical analysis of EFP revealed the EFP contained 25.43% polysaccharides, 20.42% uronic acids, 2.54% sulfate radical and 23.41% proteins. And the neutral polysaccharides were mainly composed of glucose, arabinose, rhamnose, galactose, xylose, mannose in the ratio of 21:8:5:3:1:1. PMID- 21664924 TI - Physico-chemical characterization, antioxidant and anticancer activities in vitro of a novel polysaccharide from Melia toosendan Sieb. Et Zucc fruit. AB - A novel water-soluble polysaccharide pMTPS-3, obtained from Melia toosendan Sieb. Et Zucc fruit by hot-water extraction and ethanol precipitation, was fractionated by DEAE-52 cellulose anion-exchange and Sephadex G-100 gel filtration chromatography. Its primary structural features and molecular weight were characterized by Fourier infrared spectrometry (FTIR), gel permeation chromatography (GPC) and gas chromatography (GC). And the antioxidant activities of pMTPS-3 in vitro were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay, superoxide radical scavenging assay and hydroxyl radical scavenging assay. The results suggested that pMTPS-3 was a heteropolysaccharide, composed of arabinose, glucose, mannose, and galactose in the molar ratio of 17.3:28.3:41.6:12.6 with molecular weight 26100Da. The purified pMTPS-3 was revealed to have notable scavenging activity against DPPH radical in a concentration-dependent manner and present a moderate inhibition of superoxide radicals with an IC(50) (5.6mg/ml), and potent inhibiting power for hydroxyl radical compared with crude polysaccharide. Further, it exhibited strong inhibition effect in vitro on the growth of human gastric cancer BGC-823 cells. It is strongly evidenced that pMTPS-3 purified from the crude polysaccharides of Melia toosendan Sieb. Et Zucc could be explored as a potential antioxidant and therapeutics. PMID- 21664925 TI - Iron/dextran sulfate multilayered microcapsules for controlled release of 10 hydroxycamptothecin. AB - Stable 10-hydroxycamptothecin (HCPT) microcrystals with a length of about 5-10MUm and a zeta-potential of -38.5mV were produced by pH-induced reprecipitation in presence of a stabilizer hydroxypropylmethylcellulose. Sequential layer growth was achieved by the layer-by-layer (LbL) assembly of Fe(3+) and dextran sulfate (DS) on the surface of HCPT microcrystals via both electrostatic interaction and chemical complexation process. The satisfactory drug loading content (67.2+/ 0.82%) as well as high encapsulation efficiency (60.56+/-0.82%) for four bilayers of Fe(3+)/DS coating was achieved. Both in vitro and in vivo release study revealed that the release time increased as the number of deposited Fe(3+)/DS bilayers increased. These results indicated that such iron-polysaccharide multilayered microcapsules can be a promising approach for the construction of an effective controlled release delivery system of HCPT as well as other drugs with potential cytotoxicity or short half-life time. PMID- 21664926 TI - Homology modeling, docking, molecular dynamics simulation, and structural analyses of coxsakievirus B3 2A protease: an enzyme involved in the pathogenesis of inflammatory myocarditis. AB - 2A protease of the pathogenic coxsackievirus B3 is key to the pathogenesis of inflammatory myocarditis and, therefore, an attractive drug target. However lack of a crystal structure impedes design of inhibitors. Here we predict 3D structure of CVB3 2A(pro) based on sequence comparison and homology modeling with human rhinovirus 2A(pro). The two enzymes are remarkably similar in their core regions. However they have different conformations at the N-terminal. A large number of N terminal hydrophobic residues reduce the thermal stability of CVB3 2A(pro), as we confirmed by fluorescence, western blot and turbidity measurement. Molecular dynamic simulation revealed that elevated temperature induces protein motion that results in frequent movement of the N-terminal coil. This may therefore induce successive active site changes and thus play an important role in destabilization of CVB3 2A(pro) structure. PMID- 21664927 TI - A novel globular protein electrospun fiber mat with the addition of polysilsesquioxane. AB - The aim of this work has been to elaborate well defined gliadin nanofibers with incorporation of inorganic molecules, such as polyhedral oligomeric silsesquioxane (POSS). Nanofibers were obtained by electrospinning processing, controlling the relevant parameters such as tip-to-collector distance, voltage and feed rate. The fiber mats were characterized by SEM, confocal images, DSC, viscosity, FTIR and conductivimetry analysis. FTIR spectra showed characteristic absorption bands related to the presence of POSS-NH(2) within the matrices. SEM micrographs showed that gliadin fibers decreased their dimensions as the amount of POSS-NH(2) increased in the spinning solution. The electrical conductivity of gliadin solutions diminished as the concentration of POSS-NH(2) was increased. Besides, confocal micrographs revealed that POSS-NH(2) might be dispersed as nanocrystals into gliadin and gluten fibers. The dimension of gluten nanofibers was also affected by the POSS-NH(2) concentration, but conversely, this dependence was not proportional to the POSS-NH(2) amount. Somehow, the interaction between gliadin and POSS-NH(2) in aqueous TFE affected the solution viscosity and, as a consequence, higher jet instabilities and thinner fiber dimensions were obtained. PMID- 21664928 TI - Extraction of polysaccharides and the antioxidant activity from the seeds of Plantago asiatica L. AB - The extraction conditions of polysaccharides from Plantago asiatica L. seeds were investigated. Four parameters affecting the polysaccharides extraction, extraction times, water to sample, extraction temperature and single extraction time, were determined by orthogonal experiments. Under the optimized conditions, the polysaccharides yield of P. asiatica L. seeds was 2.467%. The antioxidant activities of the polysaccharides were investigated. The reducing power of the polysaccharides was dose dependent, and the reducing capacity of the polysaccharides was inferior to butylated hydroxytoluene, which is known to be a strong reducing agent. The scavenging rates of the polysaccharides on superoxide and 1,1-diphenyl-2-picrylhydrazyl radicals were 79.7% and 81.4%, at polysaccharides concentration of 0.75 mg/mL, respectively, a scavenging rates approximately similar to that of 0.75 mg/mL ascorbic acid (83.5% and 85.1%, respectively). Furthermore, it exhibited a moderate concentration-dependent ABTS radical scavenging activity, ferrous ion chelating potency and H(2)O(2) scavenging activity. The data obtained in the in vitro models clearly establish the antioxidant potency of the polysaccharides extracted from Semen Plantaginis. PMID- 21664929 TI - Identification and cloning of a selenophosphate synthetase (SPS) from tiger shrimp, Penaeus monodon, and its transcription in relation to molt stages and following pathogen infection. AB - Complementary (c)DNA encoding selenophosphate synthetase (SPS) messenger (m)RNA of the tiger shrimp Penaeus monodon, designated PmSPS, was obtained from the hepatopancreas by a reverse-transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The 1582-bp cDNA contained an open reading frame (ORF) of 1248 bp, a 103-bp 5'-untranslated region (UTR), and a 231 bp 3'-UTR, which contained a conserved selenocysteine insertion sequence (SECIS) element, a conventional polyadenylation signal, and a poly A tail. The molecular mass of the deduced amino acid (aa) sequence (416 aa) was 45.5 kDa with an estimated pI of 4.85. It contained a putative selenocysteine residue which was encoded by the unusual stop codon, (275)TGA(277), which formed at the active site with residues Sec(58) and Lys(61). A comparison of amino acid sequences showed that PmSPS was more closely related to invertebrate SPS1, such as those of Heliothis virescens and Drosophila melanogaster a and b. PmSPS cDNA was synthesized in all tested tissues, especially in the hepatopancreas. PmSPS in the hepatopancreas of shrimp significantly increased after an injection with either Photobacterium damsela or white spot syndrome virus (WSSV) in order to protect cells against damage from oxidation, and enhance the recycling of selenocysteine or selenium metabolism, indicating that PmSPS is involved in the disease resistance response. The PmSPS expression by hemocytes significantly increased in stage C, and then gradually decreased until stage A, suggesting that the cloned PmSPS in hemocytes might play a role in viability by renewing hemocytes and antioxidative stress response for new exoskeleton synthesis during the molt cycle of shrimp. PMID- 21664930 TI - Complete nucleotide sequence of a quinolone resistance gene (qnrS2) carrying plasmid of Aeromonas hydrophila isolated from fish. AB - Aeromonas hydrophila strain AO1 isolated from an infected fish was found to be resistant to several quinolones. A plasmid isolated from the strain AO1, termed pBRST7.6, was cloned and sequenced and shown to be 7621bp in length with a GC content of 60%. Further analysis confirmed that it contained a gene with 100% identity to qnrS2 genes described in plasmids associated with other Aeromonas species, the product of which usually confers increased resistance to quinolones. The plasmid backbone contained a replication initiation module (repA repC) belonging to the IncQ-family and two genes (mobC and mobB), the products of which are putatively involved in plasmid mobilization. Putative iteron-based origin of replication and characteristic oriT like sequences were also present in the plasmid. The result suggests that Aeromonas spp. carrying plasmids with quinolone resistance genes are potential reservoirs of antimicrobial resistance determinants in the environment. PMID- 21664931 TI - Clostridium difficile in children: colonisation and disease. AB - Clostridium difficile is the commonest cause of hospital acquired diarrhoea in adults and is associated with significant mortality and morbidity. The clinical significance of C. difficile in children, however, is less certain. In this article we discuss colonisation and infection and describe C. difficile in childhood in terms of risk factors, epidemiology and management. PMID- 21664932 TI - Evolving controversies and challenges in the management of opportunistic infections in HIV-seropositive individuals. AB - The British HIV Association, in association with the British Infection Association, has produced guidelines on the management of opportunistic infections in individuals living with HIV. Opportunistic infections remain a major clinical challenge emphasising the key role of early testing and getting individuals on antiretroviral therapy before their CD4 T-cell count drops to levels that put individuals at risk of opportunistic infection. We emphasise the changing pattern of opportunistic infections and the importance of considering what constitutes an opportunistic infection in the era of effective combination antiretroviral therapy as well as the increasing burden of geographically restricted infections. Key areas of when to safely stop prophylaxis against opportunistic infection and when to start antiretroviral therapy after treatment of an opportunistic infection are discussed. PMID- 21664933 TI - Osteomyelitis as a manifestation of perinatal Human Immunodeficiency Virus disease. AB - We report a premature neonate born of Human Immunodeficiency Virus (HIV)-1 positive mother presenting with extensive osteomyelitis and massive periosteal reaction involving both femurs and left tibia. There was no collection of fluid in soft tissue or joints in ultrasonography and Doppler examination showed normal venous return in both the lower limbs. Blood culture revealed growth of Candida albicans sensitive to fluconazole. The mother did not take any antenatal care and her HIV status was evident only after delivery during routine screening. DNA PCR for HIV-1 of the neonate done on day 45 and day 48 were positive with a viral load of 12 million copies/mL and his CD4 count was 24%. He was diagnosed as severe HIV-associated clinical disease with severe immunosuppression as per WHO classification and was put on combination antiretroviral therapy, Pneumocystis chemoprophylaxis and fluconazole. He responded well to treatment, repeat x-ray done at 4 months was normal except mild bowing of both the femurs. In the present case we wanted to emphasize the need of proper antenatal care and universal HIV testing as the key to prevent mother-to-child transmission and severe HIV disease as in this case. PMID- 21664934 TI - Flow detection of propagating waves with temporospatial correlation of activity. AB - Voltage-sensitive dye imaging (VSDI) allows population patterns of cortical activity to be recorded with high temporal resolution, and recent findings ascribe potential significance to these spatial propagation patterns--both for normal cortical processing and in pathologies such as epilepsy. However, analysis of these spatiotemporal patterns has been mostly qualitative to date. In this report, we describe an algorithm to quantify fast local flow patterns of cortical population activation, as measured with VSDI. The algorithm uses correlation of temporal features across space, and therefore differs from conventional optical flow algorithms which use correlation of spatial features over time. This alternative approach allows us to take advantage of the characteristics of fast optical imaging data, which have very high temporal resolution but less spatial resolution. We verify the method both on artificial and biological data, and demonstrate its use. PMID- 21664936 TI - The P4pc: an electrophysiological marker of attentional disengagement? AB - The processing of successive targets requires that attention be engaged and disengaged. Whereas attentional engagement can be studied by means of the N2pc component of the event-related potential (ERP), no ERP component has been linked to attentional disengagement. Here, we report the finding of such a component using an RSVP paradigm with multiple, successive targets and with a spatial-cuing paradigm. In both experiments, disengagement of attention was necessary to attend to subsequent targets. A distinct waveform following the N2pc, which we call the P4pc (Positivity 400 ms post-target posterior contralateral), was found. The P4pc was found when a lateralized cue indicated that attention would be needed for the processing of a target at either the same or a different location as the cue, but not when only the cue was to be responded to, indicating that the need to disengage attention is a prerequisite for the P4pc to occur. We expect the P4pc to provide a valuable addition to the set of electrophysiological measures used to study the dynamics and mechanisms of visual attention and visual search. PMID- 21664935 TI - Gender effects on amygdala morphometry in adolescent marijuana users. AB - Adolescent developments in limbic structures and the endogenous cannabinoid system suggest that teenagers may be more vulnerable to the negative consequences of marijuana use. This study examined the relationships between amygdala volume and internalizing symptoms in teenaged chronic marijuana users. Participants were 35 marijuana users and 47 controls ages 16-19 years. Exclusions included psychiatric (e.g., mood and anxiety) or neurologic disorders. Substance use, internalizing (anxiety/depression) symptoms and brain scans were collected after 28 days of monitored abstinence. Reliable raters manually traced amygdala and intracranial volumes on high-resolution magnetic resonance images. Female marijuana users had larger right amygdala volumes and more internalizing symptoms than female controls, after covarying head size, alcohol, nicotine and other substance use (p<0.05), while male users had similar volumes as male controls. For female controls and males, worse mood/anxiety was linked to smaller right amygdala volume (p<0.05), whereas more internalizing problems was associated with bigger right amygdala in female marijuana users. Gender interactions may reflect marijuana-related interruptions to sex-specific neuromaturational processes and staging. Subtle amygdala development abnormalities may underlie particular vulnerabilities to sub-diagnostic depression and anxiety in teenage female marijuana users. PMID- 21664938 TI - A novel GLP-1 analog exhibits potent utility in the treatment of type 2 diabetes with an extended half-life and efficient glucose clearance in vivo. AB - The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. Therefore, the stabilization of GLP-1 is critical for its utility in drug development. Based on our previous research, a GLP-1 analog that contained an intra-disulfide bond exhibited a prolonged biological half-life. In this study, we improved upon previous analogs with a novel GLP-1 analog that contained a tryptophan cage-like sequence for an improved binding affinity to the GLP-1 receptor. The binding capacities and the stabilities of GLP715a were investigated, and the physiological functions of the GLP715a were compared to those of the wild-type GLP-1 in animals. The results demonstrated that the new GLP-1 analog (GLP715a) increased its biological half life to approximately 48h in vivo; GLP715a also exhibited a higher binding affinity to the GLP-1 receptor than the wild-type GLP-1. The increased binding capacity of GLP715a to its receptor resulted in a quick response to glucose administration. The long-acting anti-diabetic property of GLP715a was revealed by its increased glucose tolerance, higher HbA(1c) reduction, more efficient glucose clearance and quicker insulin stimulation upon glucose administration compared to the wild-type GLP-1 in rodents. The improved physiological characterizations of GLP715a make it a possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus. PMID- 21664939 TI - Characterization of the major histocompatibility complex class I chain-related gene B (MICB) polymorphism in a northern Chinese Han population: the identification of a new MICB allele, MICB*023. AB - Major histocompatibility complex class I chain-related gene B (MICB) has only been characterized for allelic variation in very few human populations. The MICB polymorphism remains largely unknown in Chinese populations. In this study, 104 healthy unrelated Han subjects recruited from central Inner Mongolia Autonomous Region, northern China, were investigated by sequence-based typing for MICB allelic variation, the association of MICB alleles with AluyMICB insertion/deletion dimorphism located in MICB intron 1, linkage disequilibrium of MICB with human leukocyte antigen (HLA)-B and MICA, and HLA-A-C-B-MICA-MICB haplotypic diversity. Ten kinds of MICB alleles were observed, among which MICB*005:02/010, MICB*002:01, and MICB*004:01 were the most frequent alleles with frequencies of 51.44, 16.35, and 11.54%, respectively. Significant linkage disequilibrium (LD) was observed for 9 of the 21 HLA-B-MICB haplotypes and 6 of the 17 MICA-MICB haplotypes with a frequency >1.5%. In particular, HLA-B*13:01 and HLA-B*13:02, both of which were frequently represented in this population, exhibited a distinct LD pattern with the MICB allele. A new MICB allele, MICB*023, was identified, which differed from MICB*005:02/010 by a single mutation of G to A at position 86 in exon 2, resulting in an amino acid change from arginine to histidine at codon 6. HLA-A*30-C*06-B*13:02-MICA*008:01 MICB*005:02/010 was the most common haplotype, with a frequency of 8.64% in this population. HLA-A*02-C*08-B*48-MICA*Del-MICB*009N demonstrated a frequency of 2.4% in this population. Our results provide for the first time data regarding the MICB genetic polymorphism in northern Chinese Han populations and will form the basis for future studies of the potential role of MICB in allogeneic organ transplantation and disease association in related ethnic groups. PMID- 21664940 TI - Major histocompatibility complex class I-related chain A allele mismatching, antibodies, and rejection in renal transplantation. AB - Even when kidney allografts are well matched for human leukocyte antigen (HLA) and anti-HLA antibodies are not detected, graft rejection can still occur. There is evidence that some patients who lose their graft have antibodies specific for major histocompatibility complex (MHC) class I-related chain A (MICA) antigens. We investigated whether mismatching MICA alleles associates with MICA antibody production and graft rejection or dysfunction. MICA and HLA antibody screening in 442 recipients was performed, and specificities were confirmed in a subgroup of 227 recipients using single-antigen multiplex technology. For assignment of MICA antibody specificity, we used three independent assays. In addition, MICA alleles of 227 recipients and donors were determined by DNA sequencing. In all, 17 patients (7.5%) had MICA antibodies, and 13 patients (6%) developed MICA donor specific antibodies (DSA). Multivariate analysis revealed MICA mismatching, as an independent significant factor associated with the presence of MICA antibodies (p = 0.009), and 14 mismatched MICA residues significantly correlated with MICA antibody production. MICA and HLA antibodies significantly associated with acute rejection (AR) and MICA DSA and HLA DSA correlated with decreased graft function by univariate and multivariate analysis. We conclude that mismatching for MICA epitopes in renal transplantation is a mechanism leading to production of MICA antibodies that associate with AR and graft dysfunction. PMID- 21664937 TI - Targeting tumor cell motility to prevent metastasis. AB - Mortality and morbidity in patients with solid tumors invariably result from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID- 21664941 TI - Human leukocyte antigen-B (-Bw6/-Bw4 I80, T80) and human leukocyte antigen-C ( C1/-C2) subgrouping using pyrosequence analysis. AB - Specific combinations of killer immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA) class I molecules characterized by a particular residue 80 are significantly associated with outcomes in different pathologic conditions, such as autoimmunity, pathogenic infection, cancer, and reproductive failure. Thus, a simplified method for HLA typing used in association with the analysis of KIR genotype (Kirotype) is of particular interest to extend the analysis of larger series. Here, we describe a quick and inexpensive method that allows use of pyrosequencing, a helpful subtyping of HLA class I molecules, into HLA-Bw6, Bw4 I(80) or -Bw4 T(80), HLA-C1, or -C2 groups and HLA-A allotypes sharing Bw4+ epitope or the rare HLA-B allotypes displaying the C1 motif. In particular, this analysis is focused on the amino acids around residue 80, known to be relevant in defining the affinity of KIR/HLA interaction and in the functional effects. This method was demonstrated to have good sensitivity, specificity, and reproducibility of detection and it was validated using a panel of HLA-typed International Histocompatibility Workshop (IHW) cell lines and clinical isolates. Using an allele quantitative acquisition mode, the method permitted us to obtain an accurate sequencing as required in heterozygous and/or homozygous sample definition. PMID- 21664942 TI - Organochlorine pesticides residues in feed and muscle of farmed Nile tilapia from Brazilian fish farms. AB - Organochlorine pesticide (OCP) concentrations were determined in fish muscle and feed collected from four different fish farms in Brazil. Nile tilapia from two growth stages, juveniles and adults, collected at two intensive tanks farms (IT1 and IT2) and two net cage farms (NC1 and NC2), were analyzed by High Resolution Gas Chromatography/High Resolution Mass Spectrometry. Pesticides were detected in almost all samples, but no samples exceeded international maximum limits for safe fish consumption. SigmaDDT was the predominant pesticide in fish muscle, found in all fish samples, and endosulfan was the most predominant pesticide in feed, found in all feed samples. No significant correlation (p>0.05) was observed between the different growth stages and OCP concentrations, although slightly higher OCP concentrations were observed in adults. Among the rearing systems, NC farmed fish presented higher lipid levels and, consequently, higher OCP concentrations than fish from IT farms. Some OCPs (SigmaHCH, aldrin, dieldrin and endrin) presented strong positive correlations (p<0.05) between feed and fish muscle concentrations, while others (SigmaDDT, mirex, chlordane, SigmaHCB and endosulfan) presented no correlation. However, the low levels of the sum of contaminants found in most of the feed samples may explain the low contaminant levels in fish tissue. PMID- 21664943 TI - Discovery and development of integrative biological markers for schizophrenia. AB - Schizophrenia is one of the most disabling forms of mental illness. One of the most important challenges is to establish biological markers which can accurately identify at-risk individuals in preclinical stages and thus improve the effects of early intervention strategies. Here, we review recent findings in the field of molecular genetics, CSF (cerebrospinal fluid) based markers as well as structural and functional neuroimaging in the light of their relevance for schizophrenia biomarker research. We also examine evidence supporting the hypothesis that schizophrenia and neurodegenerative disorders such as Alzheimer's disease may share certain pathophysiological features, e.g. chronic inflammation and oxidative stress, and discuss their possible role in schizophrenia. The heterogeneous, multifaceted and multifactorial nature of the traditionally clinically operationalized entity "schizophrenia" presents an enormous challenge towards the identification of single diagnostic or surrogate markers. We propose that abnormal neural coordination is a major point of convergence of a number of crucial pathophysiological pathways. Therefore, functional markers reflecting disturbed neural coordination might be particularly attractive biomarker candidates, because of their ability to integrate the influence of diverse pathophysiological mechanisms. Similarly, combinatorial and multimodal approaches may be a promising way to more accurately capture the complex biological underpinnings schizophrenia. We consider the development of such integrative biomarkers to be essential in order to facilitate a timely diagnosis of schizophrenia. They should also advance our understanding of the subtle and intricate biological nature of schizophrenia. PMID- 21664944 TI - Enzyme maintenance effort as criterion for the characterization of alternative pathways and length distribution of isofunctional enzymes. PMID- 21664945 TI - Structural features discriminate androgen receptor N/C terminal and coactivator interactions. AB - Human androgen receptor (AR) transcriptional activity involves interdomain and coactivator interactions with the agonist-bound AR ligand binding domain (LBD). Structural determinants of the AR NH(2)- and carboxyl-terminal interaction between the AR NH(2)-terminal FXXLF motif and activation function 2 (AF2) in the LBD were shown previously by crystallography. In this report, we provide evidence for a region in AR LBD helix 12 outside the AF2 binding cleft that facilitates interactions with the FXXLF and LXXLL motifs. Mutagenesis of glutamine 902 to alanine in AR LBD helix 12 (Q902A) disrupted AR FXXLF motif binding to AF2, but enhanced coactivator LXXLL motif binding. Functional compensation for defective FXXLF motif binding by AR-Q902A was suggested by the slower dissociation rate of bound androgen. Functional importance of glutamine 902 was indicated by the charged residue germline mutation Q902R that caused partial androgen insensitivity, and a similar somatic mutation Q902K reported in prostate cancer, both of which increased the androgen dissociation rate and decreased AR transcriptional activity. High affinity equilibrium androgen binding was retained by alanine substitution mutations at Tyr-739 in AR LBD helix 5 or Lys-905 in helix 12 structurally adjacent to AF2, whereas transcriptional activity decreased and the androgen dissociation increased. Deleterious effects of these loss of function mutations were rescued by the helix stabilizing AR prostate cancer somatic mutation H874Y. Sequence NH(2)-terminal to the AR FXXLF motif contributed to the AR NH(2)- and carboxyl-terminal interaction based on greater AR-2-30 FXXLF motif peptide binding to the agonist-bound AR LBD than a shorter AR-20-30 FXXLF motif peptide. We conclude that helix 12 residues outside the AF2 binding cleft modulate AR transcriptional activity by providing flexibility to accommodate FXXLF or LXXLL motif binding. PMID- 21664946 TI - Upregulation of pancreatic derived factor (FAM3B) expression in pancreatic beta cells by MCP-1 (CCL2). AB - Pancreatic derived factor (PANDER, FAM3B) is a peptide mainly synthesized and secreted by pancreatic beta-cells. PANDER is proposed to be involved in regulation of beta-cell function under physiological conditions and impairment of beta-cell function under pathological conditions. MCP-1 (CCL2) is expressed by normal pancreatic islets and has been implicated in inflammation related pancreatic disorders. We examined the effect of MCP-1 on PANDER expression by using murine pancreatic beta-cell line MIN6 and pancreatic islets. We found that MCP-1 induced PANDER mRNA transcription and protein synthesis in MIN6 cells and islets. By using calcium chelator (EGTA); inhibitors for PKC (Go6976), MEK1/2 (PD98059) or c-Jun-N-terminal kinase (JNK) (SP600125); c-Jun dominant-negative construct; PANDER promoter luciferase constructs; and islets isolated from Fos knockout mice; we demonstrated that MCP-1 induced PANDER gene expression in beta cells through Ca(2+)-ERK1/2-AP-1 and PKC-JNK-AP-1 signaling pathways. Our findings suggest a new link between the endocrine and immune systems and provide useful information for further investigating the physiological functions of PANDER and its involvement in inflammation-related pancreatic disorders. PMID- 21664947 TI - The effects of human chorionic gonadotrophin, progesterone and oestradiol on trophoblast function. AB - Remodelling of the uterine vasculature during the first trimester of human pregnancy requires invasion of trophoblast from the placenta into decidual spiral arterioles. The pregnancy-associated hormones human chorionic gonadotropin (hCG), progesterone (P(4)) and oestradiol (E(2)) are present at high concentrations at the maternal-fetal interface during the remodelling period and thus may contribute to the regulation of trophoblast movement. This study examined the effects of these hormones on trophoblast functions. HTR8/SVneo cells were treated with hCG (5-100mIU/mL), P(4) (20nM-20MUM) or E(2) (0.07-734nM). hCG significantly stimulated migration and MMP-9 activity but did not affect cell numbers. P(4) significantly inhibited migration, MMP-2 and -9 activity and reduced cell numbers. E(2) had no effect on migration, MMP activity or cell numbers. We conclude that hCG and P(4), but not E(2), play direct roles in controlling trophoblast invasion, acting as positive and negative stimuli respectively to regulate trophoblast movement during vascular remodelling in early pregnancy. PMID- 21664949 TI - Cancers and the NSD family of histone lysine methyltransferases. AB - Both genetic and epigenetic alterations are responsible for the stepwise initiation and progression of cancers. Only epigenetic aberrations can be reversible, allowing the malignant cell population to revert to a more benign phenotype. The epigenetic therapy of cancers is emerging as an effective and valuable approach to both the chemotherapy and the chemoprevention of cancer. The utilization of epigenetic targets that include histone methyltransferase (HMTase), Histone deacetylatase, and DNA methyltransferase, are emerging as key therapeutic targets. The nuclear receptor binding SET domain (NSD) protein is a family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1, and plays a critical part in chromatin integrity as evidenced by a growing number of conditions linked to the alterations and/or amplification of NSD1, NSD2, and/or NSD3. NSD1, NSD2 and NSD3 are associated with multiple cancers. The amplification of either NSD1 or NSD2 triggers the cellular transformation and thus is key in the early carcinogenesis events. In most cases, reducing the levels of NSD proteins would suppress cancer growth. NSD1 and NSD2 were isolated as genes linked to developmental diseases, such as Sotos syndrome and Wolf-Hirschhorn syndrome, respectively, implying versatile aspects of the NSD proteins. The NSD pathways, however, are not well understood. It is noteworthy that the NSD family is phylogenetically distinct compared to other known lysine-HMTases, Here, we review the current knowledge on NSD1/NSD2/NSD3 in tumorigenesis and prospect their special value for developing novel anticancer drugs. PMID- 21664948 TI - Ubiquitin-independent proteasomal degradation during oncogenic viral infections. AB - Most eukaryotic proteins destined for imminent destruction are first tagged with a chain of ubiquitin molecules and are subsequently dismantled by the proteasome. Ubiquitin-independent degradation of substrates by the proteasome, however, also occurs. The number of documented proteasome-dependent, ubiquitin-independent degradation events remains relatively small but continues to grow. Proteins involved in oncogenesis and tumor suppression make up the majority of the known cases for this type of protein destruction. Provocatively, viruses with confirmed or suspected oncogenic properties are also prominent participants in the pantheon of ubiquitin-independent proteasomal degradation events. In this review, we identify and describe examples of proteasome-dependent, ubiquitin-independent protein degradation that occur during tumor virus infections, speculate why this type of protein destruction may be preferred during oncogenesis, and argue that this uncommon type of protein turnover represents a prime target for antiviral and anticancer therapeutics. PMID- 21664950 TI - Effects of endogenous and exogenous estrogen exposures in midlife and late-life women on episodic memory and executive functions. AB - Cognitive aging affects episodic memory and executive functions, and these vulnerable domains are postulated to be modulated by endogenous and exogenous estrogen exposures. In midlife and late-life women without dementia, estrogen effects on cognition can be examined through associations with concentrations of serum estrone and estradiol and through clinical trials of estrogen-containing hormone therapy. To this end, we reviewed published studies including at least 100 women (larger studies are less prone to publication bias) addressing associations between estrogen levels and performance on neuropsychological tests of episodic memory or executive functions (including working memory; seven studies), or that reported results of placebo-controlled clinical trials of hormone therapy with objective measures within these cognitive domains (eight studies). Results were considered separately for midlife and late-life (age>=65 years) women. There were no consistent associations between endogenous serum estrogen concentrations and episodic memory or executive functions in naturally menopausal midlife women or in older postmenopausal women. Clinical trial findings suggested no substantial impact of exogenous estrogens on episodic memory or executive functions over time frames of up to several years. A quantitative synthesis of clinical trial results supported the inference of absence of effect. This overall conclusion of no substantial effect on episodic memory or executive functions might reassure women concerned by potential adverse cognitive consequences of menopause or of relatively short-term midlife hormone therapy. There was no apparent window of opportunity during which exogenous hormones might benefit near-term cognition, but included studies provided limited power to identify such a window. Conclusions are tempered by small numbers of studies, imprecise estimates of long-term estrogen exposures, and narrow range of neuropsychological tests. Long-term (late-life) cognitive consequence of midlife estrogen exposures are poorly addressed by current data, as are cognitive consequences of surgical menopause and cognitive consequences of exogenous estrogens during the menopause transition. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. PMID- 21664951 TI - I.c.v administration of an endothelin ET(B) receptor agonist stimulates vascular endothelial growth factor-A production and activates vascular endothelial growth factor receptors in rat brain. AB - Vascular endothelial growth factors (VEGFs), a family of angiogenic factors, are upregulated by nerve injuries. To clarify the extracellular signals involved in VEGF production in the brain, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined. I.c.v. administration of 500 pmol/d Ala(1,3,11,15)-ET-1, an ET(B) receptor agonist, increased the level of VEGF-A mRNA in the rat cerebrum, whereas those of VEGF-B, placental growth factor (PLGF), angiopoietin (ANG)-1, and ANG-2 mRNAs were not largely affected by Ala(1,3,11,15)-ET. The ET-induced increases in cerebrum VEGF-A mRNA were reduced by coadministration of 1 nmol/d BQ788, an ET(B) antagonist. Ala(1,3,11,15)-ET-1 also stimulated the production of VEGF-A proteins in the cerebrum. Immunohistochemical observations in the cerebrum of Ala(1,3,11,15)-ET-1-infused rats showed that glial fibrillary acidic protein (GFAP)-positive astrocytes had VEGF-A immunoreactivity. Neurons, microglia, and brain capillary endothelial cells in the Ala(1,3,11,15)-ET-1-infused rats did not show VEGF-A reactivity. The i.c.v. administration of Ala(1,3,11,15)-ET-1 stimulated tyrosine phosphorylations of VEGF-R1 and R2 receptors in the rat cerebrum, whereas expression levels of total VEGF-R1 and R2 proteins were not largely changed. Immunoreactivity of tyrosine-phosphorylated VEGF-R1 was selectively shown in GFAP-positive astrocytes in the cerebrum of Ala(1,3,11,15)-ET-1-infused rats. Tyrosine-phosphorylated VEGF R2 proteins were present in astrocytes and brain capillary endothelial cells. These findings indicate that activation of brain ET(B) receptors increases production of VEGF-A and stimulates VEGF receptor signaling in the brain. PMID- 21664952 TI - Event-related potential correlates of the interaction between attention and spatiotemporal context regularity in vision. AB - Visual perception is influenced at early processing stages by geometric spatiotemporal context regularities (consistent with the "vision-as-inference" view) and by attention, yet little is known about the interaction between these two influences on visual processing. Here, we investigate the temporal dynamics of the interaction between attention and spatiotemporal context regularity in target detection using event-related potentials (ERP). Spatial attention was withdrawn from the context by a secondary task in Experiment 1, and the role of task-relevance was explored in Experiment 2 by including a passive viewing condition. The ERP correlates of spatiotemporal regularity reported in an earlier study were replicated in single task (Experiment 1) and active viewing (Experiment 2): P1 and N1 peak-latency was shorter when the target was preceded by a context. Latency first differentiated between the two context conditions at N1, where latency was shortest for targets preceded by a context with both spatial and temporal regularities (compared with temporal regularity only). In dual task and passive viewing, this N1 latency-shift was abolished. Comparisons of "low-attention" (dual task or passive viewing) with "high-attention" conditions (single task or active viewing) revealed that attention only shortened N1 peak-latency when the target was preceded by stimulus sequences with spatial and temporal regularity. P1 latency was unaffected by manipulation of top-down attention factors. Attentional factors are likely to modulate influences of spatiotemporal context through re-afferent projections at later stages of visual processing in regions of extrastriate cortex associated with the generators of the N1 waveform. PMID- 21664953 TI - Growth hormone and prolactin regulate human neural stem cell regenerative activity. AB - We have previously shown that the growth hormone (GH)/prolactin (PRL) axis has a significant role in regulating neuroprotective and/or neurorestorative mechanisms in the brain and that these effects are mediated, at least partly, via actions on neural stem cells (NSCs). Here, using NSCs with properties of neurogenic radial glia derived from fetal human forebrains, we show that exogenously applied GH and PRL promote the proliferation of NSCs in the absence of epidermal growth factor or basic fibroblast growth factor. When applied to differentiating NSCs, they both induce neuronal progenitor proliferation, but only PRL has proliferative effects on glial progenitors. Both GH and PRL also promote NSC migration, particularly at higher concentrations. Since human GH activates both GH and PRL receptors, we hypothesized that at least some of these effects may be mediated via the latter. Migration studies using receptor-specific antagonists confirmed that GH signals via the PRL receptor promote migration. Mechanisms of receptor signaling in NSC proliferation, however, remain to be elucidated. In summary, GH and PRL have complex stimulatory and modulatory effects on NSC activity and as such may have a role in injury-related recovery processes in the brain. PMID- 21664954 TI - Simultaneous micronization and surface modification for improvement of flow and dissolution of drug particles. AB - Simultaneous micronization and surface modification of drug particles is considered in order to mitigate disadvantages of micronization, e.g., agglomeration, poor flowability, marginal increase in surface area and low bulk density. Particles of ibuprofen (102 MUm), a model drug, pre-blended with hydrophilic nano-silica, are micronized down to 10 and 5 MUm in a continuous fluid energy mill (FEM) to obtain fine surface modified particles. The solid feeding rate and the grinding pressure are shown as critical parameters for achieving the desired particle size and size distribution. The powder properties were characterized via SEM, laser scattering, powder rheometer with shear-cell, and dissolution test. Significant improvement in flow properties and dissolution rate was observed when micronization accompanied surface modification. Additionally, co-grinding with water-soluble polymer during micronization led to further increase in bulk density and more enhanced dissolution rate improvement, which is attributed to improved wettability. XRD, DSC and Raman were used to examine crystallinity, indicating minimal detectable physical transformation with FEM processed ibuprofen. The surface modified, micronized powders also showed improved dispersion, higher bulk densities (>0.4 g/ml), reduced electrostatic, and higher flowability (FFC >= 6) compared to just micronized powder (0.19 g/ml, FFC=1.0), indicating they may be used in high drug loaded formulations amenable to direct compression. PMID- 21664955 TI - Oral peptide delivery by tetraether lipid liposomes. AB - The aim of this study is to improve of oral peptide delivery by a novel type of liposomes containing tetraether lipids (TELs) derived from archaea bacteria. Liposomes were used for the oral delivery of the somatostatin analogue octreotide. TELs were extracted from Sulfolobus acidocaldarius and subsequently purified to single compounds. Liposomes were prepared by the film method followed by extrusion. Vesicles in size between 130 and 207 nm were obtained as confirmed by photon correlation spectroscopy. The pharmacokinetics of radiolabeled TELs in liposomes was investigated after oral administration to rats. 1.6% of the applied radioactivity in fed and 1.5% in fasted rats was recovered in the blood and inner organs after 2h, while most of the radioactivity remained in the gastro intestinal tract. After 24h the percentage of radioactivity in inner organs was reduced to 0.6% in fed rats, respectively 1.0% in fasted animals. Several liposomal formulations containing dipalmitoyl phosphatidylcholine (DPPC) and TELs in different ratios were loaded with octreotide and orally administered. Liposomes with 25% TEL could improve the oral bioavailability of octreotide 4.1 fold and one formulation with a cationic TEL derivative 4.6-fold. TEL-liposomes probably act by protecting the peptide in the gastro-intestinal tract. PMID- 21664956 TI - Effect of physical ageing on the performance of dexamethasone loaded PLGA microspheres. AB - The phenomenon of physical ageing or structural relaxation and its effect on the performance of dexamethasone loaded poly(lactide-co-glycolide) (PLGA) microspheres was evaluated. Microspheres were incubated at temperatures (-20 (control), 4 and 25 degrees C) below their glass transition temperature for 12 months. Physical ageing occurred in microspheres incubated at 25 degrees C due to structural relaxation of the polymer chains which occurs to achieve a lower equilibrium energy state. Significant physical ageing was not observed in microspheres incubated at 4 degrees C due to the lower molecular mobility of PLGA. The rate of structural relaxation (at 25 degrees C) was a function of free volume which decreased with time. The microspheres incubated at 25 degrees C for 12 months resulted in a slower release profile after day 25 when compared to the control microspheres. This was speculated to be due to a reduction in free volume upon physical ageing which in turn may reduce water absorption and retention of acidic degradation products in the PLGA matrix, hence reducing the degradation rate of PLGA. Therefore, exposure to ambient temperature during storage, shipping or handling may cause physical ageing in PLGA microspheres and hence, their performance may be affected. Storage temperatures of 4 degrees C or lower may be considered appropriate for PLGA microspheres. PMID- 21664957 TI - Hereditary hearing loss: from human mutation to mechanism. AB - The genetic heterogeneity of hereditary hearing loss is thus far represented by hundreds of genes encoding a large variety of proteins. Mutations in these genes have been discovered for patients with different modes of inheritance and types of hearing loss, ranging from syndromic to non-syndromic and mild to profound. In many cases, the mechanisms whereby the mutations lead to hearing loss have been partly elucidated using cell culture systems and mouse and other animal models. The discovery of the genes has completely changed the practice of genetic counseling in this area, providing potential diagnosis in many cases that can be coupled with clinical phenotypes and offer predictive information for families. In this review we provide three examples of gene discovery in families with hereditary hearing loss, all associated with elucidation of some of the mechanisms leading to hair cell degeneration and pathology of deafness. PMID- 21664958 TI - Separable developmental trajectories for the abilities to detect auditory amplitude and frequency modulation. AB - Amplitude modulation (AM) and frequency modulation (FM) are inherent components of most natural sounds. The ability to detect these modulations, considered critical for normal auditory and speech perception, improves over the course of development. However, the extent to which the development of AM and FM detection skills follow different trajectories, and therefore can be attributed to the maturation of separate processes, remains unclear. Here we explored the relationship between the developmental trajectories for the detection of sinusoidal AM and FM in a cross-sectional design employing children aged 8-10 and 11-12 years and adults. For FM of tonal carriers, both average performance (mean) and performance consistency (within-listener standard deviation) were adult-like in the 8-10 y/o. In contrast, in the same listeners, average performance for AM of wideband noise carriers was still not adult-like in the 11-12 y/o, though performance consistency was already mature in the 8-10 y/o. Among the children there were no significant correlations for either measure between the degrees of maturity for AM and FM detection. These differences in developmental trajectory between the two modulation cues and between average detection thresholds and performance consistency suggest that at least partially distinct processes may underlie the development of AM and FM detection as well as the abilities to detect modulation and to do so consistently. PMID- 21664959 TI - Stimulus level effects on neural excitation and eCAP amplitude. AB - The common assumption that the electrically evoked compound action potential (eCAP) has a linear relationship with the number of excited nerve fibres is derived from the acoustical unitary response concept. This study tests the validity of this hypothesis for electrical stimulation. Five guinea pigs were implanted with the tip of a human HiFocus electrode. eCAPs were measured with the forward masking paradigm, using anodic- and cathodic-leading biphasic current pulses and the inter-pulse interval was varied. Masker and probe amplitudes were varied either individually or simultaneously. Surprisingly, at high levels decreasing eCAP amplitudes were measured with increasing stimulus current. In search for an explanation, the experimental conditions were implemented in our 3D computational model of the implanted guinea pig cochlea to perform a functional comparison. In the final experiment, with fixed inter-pulse interval (IPI) and anodic-leading pulses, increasing stimulus currents showed growing numbers of excited nerve fibres and decreasing eCAP amplitudes at high levels, again. While simulating the relative contribution of single fibres to the overall eCAP, an explanation for this could be found in a waveform change in the modelled single fibre action potentials at high levels. We conclude that highly stimulated nerve fibres have another contribution to the eCAP response than lower stimulated fibres, which leads to a reduction of the eCAP amplitude at high levels. PMID- 21664960 TI - Antinociceptive effect of the essential oil of Zingiber zerumbet in mice: possible mechanisms. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zingiber zerumbet (L.) Smith, a wild edible ginger species or locally known as "lempoyang", commonly used in the Malays traditional medicine as an appetizer or to treat stomachache, toothache, muscle sprain and as a cure for swelling sores and cuts. AIM: The present study was conducted to investigate the possible mechanism of actions underlying the systemic antinociception activity of the essential oil of Zingiber zerumbet (EOZZ) in chemical-induced nociception tests in mice. MATERIALS AND METHODS: Acetic acid-induced abdominal constriction, capsaicin-, glutamate- and phorbol 12 myristate 13-acetate-induced paw licking tests in mice were employed in the study. In all experiments, EOZZ was administered systemically at the doses of 50, 100, 200 and 300 mg/kg. RESULTS: It was shown that EOZZ given to mice via intraperitoneal and oral routes at 50, 100, 200 and 300 mg/kg produced significant dose dependent antinociception when assessed using acetic acid induced abdominal writing test with calculated mean ID(50) values of 88.84 mg/kg (80.88-97.57 mg/kg) and 118.8 mg/kg (102.5-137.8 mg/kg), respectively. Likewise, intraperitoneal administration of EOZZ at similar doses produced significant dose dependent inhibition of neurogenic pain induced by intraplantar injection of capsaicin (1.6 MUg/paw), glutamate (10 MUmol/paw) and phorbol 12-myristate 13 acetate (1.6MUg/paw) with calculated mean ID(50) of 128.8 mg/kg (118.6-139.9 mg/kg), 124.8 mg/kg (111.4-139.7 mg/kg) and 40.29 (35.39-45.86) mg/kg, respectively. It was also demonstrated that pretreatment with l-arginine (100mg/kg, i.p.), a nitric oxide precursor significantly reversed antinociception produced by EOZZ suggesting the involvement of l-arginine/nitric oxide pathway. In addition, methylene blue (20mg/kg, i.p.) significantly enhanced antinociception produced by EOZZ. Administration of glibenclamide (10mg/kg, i.p.), an ATP-sensitive K(+) channel antagonist significantly reversed antinociceptive activity induced by EOZZ. CONCLUSION: Together, the present results suggested that EOZZ-induced antinociceptive activity was possibly related to its ability to inhibit glutamatergic system, TRPV1 receptors as well as through activation of l-arginine/nitric oxide/cGMP/protein kinase C/ATP-sensitive K(+) channel pathway. PMID- 21664961 TI - Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists. AB - Early recognition of invading bacteria by the innate immune system has a crucial function in antibacterial defense by triggering inflammatory responses that prevent the spread of infection and suppress bacterial growth. Toll-like receptor 4 (TLR4), the innate immunity receptor of bacterial endotoxins, plays a pivotal role in the induction of inflammatory responses. TLR4 activation by bacterial lipopolysaccharide (LPS) is achieved by the coordinate and sequential action of three other proteins, LBP, CD14 and MD-2 receptors, that bind lipopolysaccharide (LPS) and present it to TLR4 by forming the activated (TLR4-MD-2-LPS)(2) complex. Small molecules active in modulating the TLR4 activation process have great pharmacological interest as vaccine adjuvants, immunotherapeutics or antisepsis and anti-inflammatory agents. In this review we present natural and synthetic molecules active in inhibiting TLR4-mediated LPS signalling in humans and their therapeutic potential. New pharmacological applications of TLR4 antagonists will be also presented related to the recently discovered role of TLR4 in the insurgence and progression of neuropathic pain and sterile inflammations. PMID- 21664962 TI - Reactive oxygen species-independent rapid initiation of mitochondrial apoptotic pathway by chelerythrine. AB - Chelerythrine, formerly identified as a protein kinase C inhibitor, has also been shown to inhibit the anti-apoptotic Bcl-2 family proteins. However, recent studies have now demonstrated that chelerythrine can induce the loss of mitochondrial membrane potential (DeltaPsim), a membrane permeability transition (MPT), and the subsequent activation of the mitochondrial apoptotic pathway, even in the cells deficient in Bax and Bak. This suggests the existence of an alternative Bax/Bak-independent pathway for apoptosis. The generation of reactive oxygen species (ROS) from the mitochondrial electron transport chain (ETC) is also implicated in the cytotoxity elicited by chelerythrine. In our current study, we show that chelerythrine induces the rapid apoptotic death of H9c2 cardiomyocyte-derived cells within 8 min of treatment. The proteolytic activation of caspase9 and caspase3, crucial mediators of the mitochondrial apoptotic pathway, are also observed within 6 min of exposure to this drug. The generation of ROS is detected but at only marginal levels in the treated cells. The inhibition of the mitochondrial ETC by rotenone and malonate had almost no effects on ROS generation but in both cases effectively inhibited both cell death and the caspase activation induced by chelerythrine. Hence, chelerythrine initiates the rapid mitochondrial apoptotic death of H9c2 cardiomyoblastoma cells in a manner that is likely independent of the generation of ROS from mitochondria. PMID- 21664963 TI - Vitamin D receptor (VDR) gene SNPs influence VDR expression and modulate protection from multiple sclerosis in HLA-DRB1*15-positive individuals. AB - Multiple sclerosis (MS) is an autoimmune disease with a multifactorial etiology. The HLA-DRB1*15 allele, is the main genetic risk factor for MS in Caucasians; recent findings showed that the transcription of this molecule is regulated by the vitamin D/vitamin D receptor (VDR) complex. We analyzed SNPs within the VDR gene in association with the HLA-DRB1 locus in 641 MS patients diagnosed according to McDonald criteria and 558 age- and sex-matched healthy controls, to verify possible correlations between the vitamin D/VDR complex, HLA-DRB1, and susceptibility to MS. Results confirmed that HLA-DRB1*15 is a strong predisposing allele (p<1*10(-7); OR: 3.04; 95% CI: 2.02-4.60) for MS. Cosegregation analyses of VDR SNPs with HLA-DRB1*15 indicated a reduction of risk for MS given by the presence of the -DRB1*15-rs731236 T VDR haplotype (p=9.5*10(-5); OR: 2.52; 95% CI: 1.56-4.06) and, conversely, an augmented risk for disease associated with the -DRB1*15-rs731236 C VDR haplotype. Analyses performed on HLA-DRB1*15-positive MS patients and HC alone confirmed the protective role of rs731236 TT VDR genotype (p(y)=0.004; OR: 0.53; 95% CI: 0.33-0.83); notably, FACS, PCR, and confocal microscopy analyses showed that rs731236 TT genotype is associated with an augmented VDR expression in MBP-stimulated PBMC from patients. In conclusion, rs731236 TT VDR genotype modulates VDR expression and confers protection against MS in HLA-DRB1*15-positive individuals. Results herein offer a model justifying the interaction between the major genetic (HLA-DRB*15) and environmental (vitamin D) factors associated with MS onset. PMID- 21664964 TI - The methoxychlor metabolite, HPTE, inhibits rat luteal cell progesterone production. AB - The methoxychlor metabolite, HPTE, was shown to inhibit P450-cholesterol side chain cleavage (P450scc) activity resulting in decreased progesterone production by cultured ovarian follicular cells in previous studies. It is not known whether HPTE has any effect on progesterone formation by the corpus luteum. RESULTS: Exposure to 100 nM HPTE reduced progesterone production by luteal cells with progressive declines to <22% of control at 500 nM HPTE. Similarly, HPTE progressively inhibited progesterone formation and P450scc catalytic activity of hCG- or 8 Br-cAMP-stimulated luteal cells. However, HPTE did not alter mRNA and protein levels of P450scc. Compounds acting as estrogen (17 beta-estradiol, bisphenol-A or octylphenol), antiestrogen (ICI) or antiandrogen (monobutyl phthalate, flutamide or M-2) added alone to luteal cells did not mimic the action of HPTE on progesterone and P450scc activity. These results suggest that HPTE directly inhibits P450scc catalytic activity resulting in reduced progesterone formation, and this action was not mediated through estrogen or androgen receptors. PMID- 21664965 TI - Polymorphisms in genes encoding leptin, ghrelin and their receptors in German multiple sclerosis patients. AB - Multiple sclerosis (MS) is a neuro-inflammatory, autoimmune disease influenced by environmental and polygenic components. There is growing evidence that the peptide hormone leptin, known to regulate energy homeostasis, as well as its antagonist ghrelin play an important role in inflammatory processes in autoimmune diseases, including MS. Recently, single nucleotide polymorphisms (SNPs) in the genes encoding leptin, ghrelin and their receptors were evaluated, amongst others, in Wegener's granulomatosis and Churg-Strauss syndrome. The Lys656Asn SNP in the LEPR gene showed a significant but contrasting association with these vasculitides. We therefore aimed at investigating these polymorphisms in a German MS case-control cohort. Twelve SNPs in the LEP, LEPR, GHRL and GHSR genes were genotyped in 776 MS patients and 878 control subjects. We found an association of a haplotype in the GHSR gene with MS that could not be replicated in a second cohort. Otherwise, no significant differences in allele or genotype frequencies were observed between patients and controls in this particular cohort. Thus, the present results do not support the hypothesis that genetic variation in the leptin/ghrelin system contributes substantially to the pathogenesis of MS. However, a modest effect of GHSR variation cannot be ruled out and needs to be further evaluated in future studies. PMID- 21664966 TI - Plaque oxysterols induce unbalanced up-regulation of matrix metalloproteinase-9 in macrophagic cells through redox-sensitive signaling pathways: Implications regarding the vulnerability of atherosclerotic lesions. AB - An imbalance in the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) contributes to atherosclerotic plaque destabilization and rupture. Here we determined whether oxysterols accumulating in advanced atherosclerotic lesions play a role in plaque destabilization. In human promonocytic U937 cells, we investigated the effects of an oxysterol mixture of composition similar to that in advanced human carotid plaques on the expression and synthesis of MMP-9 and its endogenous inhibitors TIMP-1 and TIMP 2. A marked increment of MMP-9 gene expression, but not of its inhibitors, was observed by real-time RT-PCR; MMP-9 gelatinolytic activity was also found increased by gel zymography. Consistently, a net increment of MMP-9 protein level was also observed by immunoblotting. Using antioxidants or specific inhibitors or siRNAs, we demonstrated that the oxysterol mixture induces MMP-9 expression through: (i) overproduction of reactive oxygen species, probably by NADPH-oxidase and mitochondria; (ii) up-regulation of mitogen-activated protein kinase signaling pathways via protein kinase C; and (iii) up-regulation of activator protein-1- and nuclear factor-kappaB-DNA binding. These results suggest, for the first time, that oxysterols accumulating in advanced atherosclerotic lesions significantly contribute to plaque vulnerability by promoting MMP-9/TIMP-1/2 imbalance in phagocytic cells. PMID- 21664967 TI - Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a critical role in the development of TGFbeta resistance of H460 cell. AB - The primary goal of the study was to investigate how peroxisome proliferator activated receptor gamma (PPARgamma) played a critical role in the protection of H460 cell, one of the non-small cell lung cancer (NSCLC) cells with multidrug resistance, from transforming growth factor beta (TGFbeta)-mediated mitoinhibition. In the study, TGFbeta resistance of H460 cell was first confirmed by analyses of PPARgamma expression, its interaction with TGFbeta-induced Smad3 and phospho-Smad3 (p-Smad3) and survival of H460. Results showed that enable to escape from G2/M phase arrest, H460 cell had higher resistance to TGFbeta mediated mitoinhibition than CH27 (a drug sensitive control). TGFbeta significantly increased PPARgamma expression of H460 but not of CH27 cell whereas nuclear accumulation of p-Smad3 was only limited to CH27, the latter was believed to contribute to the induction of P(21 waf1/cip1) and cyclin B1, cell cycle arrest at G2/M phase and TGFbeta-mediated mitoinhibition of CH27 cell. TGFbeta induced PPARgamma of H460 cell was further demonstrated to bind to Smad3 and p Smad3, and GW9662 (PPARgamma inhibitor) or PPARgamma-specific shRNA could disrupt the binding. GW9662 also increased the nuclear accumulation of p-Smad3 that eventually led to the reduction of TGFbeta resistance of H460. A transient knockdown of PPARgamma with shRNA revealed a similar effect as GW9662. In addition, activation of P(38) instead of ERK played a critical role in TGFbeta induced expression of PPARgamma, which subsequently activated RhoA in H460 cell. PMID- 21664968 TI - Substituted 2-aminothiazoles are exceptional inhibitors of neuronal degeneration in tau-driven models of Alzheimer's disease. AB - A novel series of 2-aminothiazoles with strong protection in an Alzheimer's disease (AD) model comprising tau-induced neuronal toxicity is disclosed. These derivatives can be synthesized in one-pot and a small SAR of the substitution within these series afforded several compounds that counteracted tau-induced cell toxicity at nanomolar concentrations. These congeners therefore have strong potential as possible treatment for Alzheimer's disease and other related tauopathies. PMID- 21664969 TI - The use of in situ near infrared spectroscopy to provide mechanistic insights into gel layer development in HPMC hydrophilic matrices. AB - In this study, near infrared (NIR) spectroscopy has been used to track the spatial and temporal movement of a model drug (Compound A) while monitoring in situ the gel layer development in hydrophilic matrices based on hydroxypropyl methylcellulose (HPMC). To validate the NIR experimental set-up, Compound A was formulated in "slow" and "fast" drug releasing formulations with high (56% w/w) and low (18% w/w) levels of HPMC K100M, respectively. NIR microscopy was used to (i) define the extent of HPMC pseudo-gel swelling, (ii) elucidate the movement of the polymer swelling front and (iii) track movement of the drug through the gel layer. Dissolution testing (USP I) allowed correlation of mechanistic details ascertained using NIR with the rate and extent of drug release. Several critical differences were observable between "fast" and "slow" formulations. In the "fast" formulation, HPMC swelling front movement occurred at a slower rate and to a lesser extent compared to drug release, suggestive of inadequate gel layer formation and a partial loss of extended release characteristics. In contrast, the "slow" formulation exhibited a similar rate of HPMC swelling front movement compared to drug release, suggesting a release mechanism predominately controlled by polymer erosion, supported by an apparent zero order drug dissolution curve in USP I. In conclusion, the study suggests the potential future value of using NIR in situ to elucidate mechanistic insights in drug release rate from pharmaceutical formulations. PMID- 21664970 TI - Mechanistic modelling of fluidized bed drying processes of wet porous granules: a review. AB - Fluidized bed dryers are frequently used in industrial applications and also in the pharmaceutical industry. The general incentives to develop mechanistic models for pharmaceutical processes are listed, and our vision on how this can particularly be done for fluidized bed drying processes of wet granules is given. This review provides a basis for future mechanistic model development for the drying process of wet granules in pharmaceutical processes. It is intended for a broad audience with a varying level of knowledge on pharmaceutical processes and mathematical modelling. Mathematical models are powerful tools to gain process insight and eventually develop well-controlled processes. The level of detail embedded in such a model depends on the goal of the model. Several models have therefore been proposed in the literature and are reviewed here. The drying behaviour of one single granule, a porous particle, can be described using the continuum approach, the pore network modelling method and the shrinkage of the diameter of the wet core approach. As several granules dry at a drying rate dependent on the gas temperature, gas velocity, porosity, etc., the moisture content of a batch of granules will reside in a certain interval. Population Balance Model (ling) (PBM) offers a tool to describe the distribution of particle properties which can be of interest for the application. PBM formulation and solution methods are therefore reviewed. In a fluidized bed, the granules show a fluidization pattern depending on the geometry of the gas inlet, the gas velocity, characteristics of the particles, the dryer design, etc. Computational Fluid Dynamics (CFD) allows to model this behaviour. Moreover, turbulence can be modelled using several approaches: Reynolds-averaged Navier-Stokes Equations (RANS) or Large Eddy Simulation (LES). Another important aspect of CFD is the choice between the Eulerian-Lagrangian and the Eulerian-Eulerian approach. Finally, the PBM and CFD frameworks can be integrated, to describe the evolution of the moisture content of granules during fluidized bed drying. PMID- 21664971 TI - Iodine-131-lipiodol therapy in hepatic tumours. AB - The incidence of hepatocellular carcinoma (HCC) is worldwide sharply on the rise and patients with advanced disease carry a poor prognosis. HCC is the sixth most common cancer and the third leading cause of cancer associated deaths in the world. Intra-arterially administered (131)I-Lipiodol is selectively retained by hepatocellular carcinomas, and has been used as a vehicle for delivery of therapeutic agents to these tumours. In this review we focus on the therapeutic indications, usefulness and methods of treatment with 131-Iodine Lipiodol. The effectiveness of (131)I-Lipiodol treatment is proven both in the treatment of HCC with portal thrombosis and also as an adjuvant to surgery after the resection of HCCs. It is at least as effective as chemoembolization and is tolerated much better. Severe liver dysfunction represents theoretic contraindication for radioembolization as well as for TACE. In such cases (131)I-Lipiodol is an alternative therapy option especially in tumours smaller than 6cm. PMID- 21664972 TI - Expression and purification of the C-terminal fragments of TRPV5/6 channels. AB - The transient receptor potential vanniloid 5 and 6 (TRPV5 and TRPV6) Ca(2+)-ion channels are crucial for the regulation of minute-to-minute whole body calcium homeostasis. They act as the gatekeepers of active Ca(2+) reabsorption in kidney and intestine, respectively. In spite of the great progress in the TRP channels characterization, very little is known at the atomic level about their structure and interactions with other proteins. To the major extent it is caused by difficulties in obtaining suitable samples. Here, we report expression and purification of 36 intracellular C-terminal fragments of TRPV5 and TRPV6 channels, for which no structural information is reported thus far. We demonstrate that these proteins contain intrinsically disordered regions and identify fragments suitable for biophysical characterization. By combining bioinformatic predictions and experimental results, we propose several criteria that may aid in designing a scheme for large-scale production of difficult proteins. PMID- 21664973 TI - Heterologous expression and purification of membrane-bound pyrophosphatases. AB - Membrane-bound pyrophosphatases (M-PPases) are enzymes that couple the hydrolysis of inorganic pyrophosphate to pumping of protons or sodium ions. In plants and bacteria they are important for relieving stress caused by low energy levels during anoxia, drought, nutrient deficiency, cold and low light intensity. While they are completely absent in mammalians, they are key players in the survival of disease-causing protozoans making these proteins attractive pharmacological targets. In this work, we aimed at the purification of M-PPases in amounts suitable for crystallization as a first step to obtain structural information for drug design. We have tested the expression of eight integral membrane pyrophosphatases in Saccharomyces cerevisiae, six from bacterial and archaeal sources and two from protozoa. Two proteins originating from hyperthermophilic organisms were purified in dimeric and monodisperse active states. To generate M PPases with an increased hydrophilic surface area, which potentially should facilitate formation of crystal contacts, phage T4 lysozyme was inserted into different extramembraneous loops of one of these M-PPases. Two of these fusion proteins were active and expressed at levels that would allow their purification for crystallization purposes. PMID- 21664974 TI - D-Xylulose kinase from Saccharomyces cerevisiae: isolation and characterization of the highly unstable enzyme, recombinantly produced in Escherichia coli. AB - The Saccharomyces cerevisiae gene encoding xylulose kinase (XKS1) was over expressed to an abundance of >= 10% intracellular protein in Escherichia coli. Instability of XKS1, not pointed out in previous reports of the enzyme, prevented isolation of active enzyme in native or "tagged" form under a wide range of purification conditions. A fusion protein haboring C-terminal Strep-tag II (XKS1 Strep) displayed activity (~20 U/mg) as isolated. However, the half-life time of purified XKS1-Strep was only ~1.5h at 4 degrees C and could not be enhanced substantially by an assortment of extrinsic stabilizers (osmolytes, protein, substrates). Peptide mass mapping and N-terminal sequencing showed that the recombinant protein was structurally intact, ruling out proteolytic processing and chemical modifications as possible factors to compromise the stability of the enzyme as isolated. Partial functional complementation of a largely inactive XKS1 preparation by the high-molecular mass fraction (>= 10kDa) of cell extract prepared from an E. coli BL21 (DE3) expression host suggests a possible role for heterotropic protein-XKS1 interactions in conferring activity/stability to the enzyme. Michaelis-Menten constants of XKS1-Strep were determined: d-xylulose (210 +/- 40 MUM) and Mg(2+)-ATP (1.70 +/- 0.10 mM). PMID- 21664975 TI - Affinity purification of a chimeric nicotinic acetylcholine receptor in the agonist and antagonist bound states. AB - Nicotinic acetylcholine receptors (nAChRs) form ligand-gated ion channels that mediate fast signal transmission at synapses. These receptors are members of a large family of pentameric ion channels that are of active medical interest. An expression system utilizing a chimerical construct of the N-terminal extracellular ligand binding domain of alpha7 type nAChR and the C-terminal transmembrane portion of 5HT3 type receptor resulted high level of expressions. Two ligand affinity chromatography purification methods for this receptor have been developed. One method relies on the covalent immobilization of a high affinity small molecule alpha7 nAChR agonist, (R)-5-(4-aminophenyl)-N (quinuclidin-3-yl) furan-2-carboxamide, and the other uses mono biotinylated alpha-bungarotoxin, an antagonist, that forms a quasi-irreversible complex with alpha7 nAChR. Detergent solubilized alpha7/5HT(3) chimeric receptors were selectively retained on the affinity resins and could be eluted with free ligand or biotin. The proteins purified by both methods were characterized by gel electrophoresis, mass spectra, amino acid composition analysis, and N-terminal sequence determination. These analyses confirmed the isolation of a mature alpha7/5HT(3) receptor with the signal peptide removed. These results suggest a scalable path forward to generate multi-milligram amounts of purified complexes for additional studies including protein crystallization. PMID- 21664976 TI - Two hepcidin-like antimicrobial peptides in Barramundi Lates calcarifer exhibit differing tissue tropism and are induced in response to lipopolysaccharide. AB - Genes encoding two hepcidin-like antimicrobial peptides were discovered in Barramundi, Lates calcarifer (barramundi, Giant sea perch). Analysis of the coding regions indicated that genes for each hepcidin comprised 3 exons and 2 introns. The deduced amino acid sequences for each molecule resulted in a protein comprising a signal sequence of 24 aa in each case, coupled to a prepropeptide of 75 aa for hepcidin 1 and 78 aa for hepcidin 2. A cleavage site was identified in each prepropetide at amino acid 64 with the cleavage motif--QKR/QS--resulting in mature peptides of 25 and 28 amino acids respectively. Each mature peptide contained 8 conserved cysteine residues and 3 dimensional modeling predicted a beta-hairpin and beta-sheet structure characteristic of human Liver Expressed Antimicrobial Peptide (LEAP). Analysis of the deduced amino acid sequences by BLAST with phylogenetic supported indicated that hepcidin 1 was a HAMP1-type peptide closely related to hepcidins identified in other Perciformes (Micropterus and Pseudosciaena), whilst hepcidin 2 was a HAMP2-type peptide most similar to a hepcidin previously identified in black rock fish (Sebastes schlegeli). Both hepcidin genes were inducible in barramundi following intraperitoneal injection with lipopolysaccharide, with elevated expression detected in liver and head kidney 3 h post IP injection for hepcidin 1 and in liver only for hepcidin 2. The elevated expression was transient with return to normal levels within 24-48 h. No significant expression of either peptide was detected in spleen, skin or gill following IP injection with LPS. PMID- 21664977 TI - In vitro effects of noradrenaline on Akoya pearl oyster (Pinctada imbricata) haemocytes. AB - Exposure to fluctuating environmental conditions in bivalve molluscs can lead to physiological stress and up-regulated production of stress-associated hormones, such as noradenaline (NA). Since environmental stressors have been found to have an immunosuppressive effect on Pinctada imbricata, we investigated the in vitro affects of NA exposure on their defensive haemocytes, focussing specifically on markers of apoptosis. Terminal dUTP nick-end (TUNEL) labelling was used to detect cells displaying DNA fragmentation within tissue exposed to NA. DNA fragmentation was most significant when haemocytes were exposed to 10.0 ng NA/MUg protein relative to non-treated controls. Similarly, Annexin V-FITC staining, a marker of early apoptotic events, was evident in cells exposed to 5.0 and 10.0 ng NA/MUg protein after 120 min (p<0.05), and haemocyte adhesion to glass slides declined significantly when cells were exposed to 10.0 ng NA/MUg protein (p<0.05). A number of morphological and ultrastructural changes in NA-exposed haemocytes were also identified using transmission and scanning electron microscopy. These alterations included chromatin and cytoplasmic condensation, the formation of apoptotic bodies, vacuolisation and blebbing. In NA-treated cells, polymerisation of F-actin was observed around the periphery of the cytoplasm. All of these data suggest that NA induces apoptosis in P. imbricata haemocytes. PMID- 21664978 TI - Climate changes, environment and infection: facts, scenarios and growing awareness from the public health community within Europe. AB - Climate change is a current global concern and, despite continuing controversy about the extent and importance of causes and of its effects, it seems likely that it will affect the incidence and prevalence of both residual and imported infections in Europe. Climate affects mainly the range of infectious diseases, whereas weather affects the timing and intensity of outbreaks. Climate change scenarios include a change distribution of infectious diseases with warming and changes in outbreaks associated with weather extremes. The largest health impact from climate change for Europe doesn't come from vector borne infectious diseases. This does not mean that these types of health impacts will not arise in Europe. The ranges of several vector-borne diseases or their vectors are already changing in altitude due to warming. In addition, more intense weather events create conditions conductive to outbreaks of infectious diseases: Heavy rains leave insect breeding sites, drive rodents from burrows, and contaminate clean water systems. The incidence of mosquito-borne parasitic and viral diseases, are among those diseases most sensitive to climate. Climate change affect disease transmission by shifting the vector's geographic range and by shortening the pathogen incubation period. climate-related increases in temperature in sea surface and level would lead to higher incidence of waterborne infectious and toxin-related illnesses, such as cholera and seafood intoxication. Climate changes all around the world with impact in Europe are demonstrated by the fact that recent cases of cholera have been imported to Europe from Kenya, where spreading epidemic has been linked to the El Nino phenomenon, originated from the Pacific Ocean. Human migration and damage to health infrastructures from aberrant climate changes could indirectly contribute to disease transmission. Human susceptibility to infections might be further compounded by alterations in the human immune system caused by increased exposure to ultraviolet radiation and malnutrition due to alterations in agricultural products. Different kind of incidents in Europe with extreme weather events demonstrated effects on public health. The recent outbreak of the insect-borne Chikungunya virus in Italy in 2007 is an example of the kind of new health threat that the EU must be vigilant to confront. In addition, health effects of flooding, have been related to an excess cases of leptospirosis and campylobacter enteritis. Such examples have been demonstrated reported after flooding in the Czech Republic. Similarly, an increase of cryptosporidiosis in the United Kingdom has been related to flooding. Changing vector distributions associated with tickborne encephalitis and malaria have also been demonstrated in EU. A recently reported case of malaria in Italy in June 2008, suspected to be indigenously acquired, has shown how easily malaria could be reintroduced into several countries in the region. Another case of malaria in Greece in May 2010 affecting a young man living in a forestry region was claimed at KEELPNO-the Greek Center for disease control. Would this latest case be considered closely related to the one from Italy? If yes, then Public Health Services should elaborate plans to affront possible tickborne diseases. Heat waves are important causes of mortality on mortality are important. The deaths seen in France in 2003 from a heat wave are projected to be repeated, as heat waves become more severe. However, heat waves impacts on the transmission and severity of infectious diseases have not been elucidated. Finally scientific challenges include the elucudation of climate changes and extreme weather condition impact on infection transmission and outcome, human immune system changes and infection response, outbreak scenarios, animal and plant health and public health preparedness. European action plans to affront climate changes related health and infection problems are developed by the EU Commission at different levels and jointly by different DGs. In a few words within the EU the following points on human, animal and plant health are considered a priority: * Strengthening cooperation between the services of these three branches of health (human, animals, plants); * Developing action plans in the event of extreme weather conditions, in order to be better prepared and to react in the best way; * Gathering more reliable information on the risks of climate change whilst maintaining international cooperation, in particular with the WHO, as cooperation beyond that between Member States will be required to be more effective; * Providing additional effort to identify the most effective measures; * Improving the surveillance and the control of the animal diseases. The European Commission has decided to consider climate change, and the consequences it has on health, with greater importance whilst being aware that it is at the root of numerous diseases. PMID- 21664979 TI - Safety and immunogenicity of the live attenuated varicella vaccine following T replete or T cell-depleted related and unrelated allogeneic hematopoietic cell transplantation (alloHCT). AB - There are limited studies assessing the live attenuated varicella vaccine following allogeneic hematopoietic cell transplantation (alloHCT). Because of the morbidity of varicella acquired after childhood, we immunized and retrospectively analyzed the safety and immunogenicity of this vaccine in 46 varicella zoster virus (VZV) seronegative patients <20 years old at HCT who achieved a CD4 cell count >=200/MUL, were off immunosuppression, and responded to >=1 post-HCT vaccines. Two vaccinated patients lacking follow-up titers were excluded from analysis. Stem cells were derived from an HLA-matched sibling (n = 18) or an alternative (HLA mismatched related or unrelated) donor (n = 26). Median time to vaccination was 4 years. Sixty-four percent of patients seroconverted following 1 immunization. There was no significant difference in response between recipients of a matched related or alternative donor graft (P = .2) or between those given a T cell-depleted or T-replete alternative donor graft (P = .27). Three of 44 patients developed a self-limited varicella-like rash within 2.5 weeks of immunization. With a median follow-up of 29.1 (range: 6.9-167.1) months, there were no subsequent cases of varicella-like rashes. No patient developed shingles. This study suggests that this vaccine is safe and immunogenic when given according to preset clinical and immunologic milestones, warranting larger prospective studies in patients >=24 months following HCT as outlined in current post-HCT vaccine guidelines. PMID- 21664980 TI - B12 in fetal development. AB - Vitamin B12 (cobalamin) is necessary for development of the fetus and child. Pregnant women who are vegetarian or vegan, have Crohn's or celiac disease, or have undergone gastric bypass surgery are at increased risk of B12 deficiency. Low serum levels of B12 have been linked to negative impacts in cognitive, motor, and growth outcomes. Low cobalamin levels also may be related to depression in adults. Some studies indicate that B12 supplementation may improve outcomes in children, although more research is needed in this area. Overall, the mechanisms of B12 action in development remain unclear. Further studies in this area to elucidate the pathways of cobalamin influence on development, as well as to prevent B12 deficiency in pregnant women and children are indicated. PMID- 21664981 TI - Vitamin D in fetal brain development. AB - In this review we will provide a concise summary of the evidence implicating a role for vitamin D in the developing brain. Vitamin D is known to affect a diverse array of cellular functions. Over the past 10 years data has emerged implicating numerous ways in which this vitamin could also affect the developing brain including its effects on cell differentiation, neurotrophic factor expression, cytokine regulation, neurotransmitter synthesis, intracellular calcium signaling, anti-oxidant activity, and the expression of genes/proteins involved in neuronal differentiation, structure and metabolism. Dysfunction in any of these processes could adversely affect development. Although there are many ways to study the effects of vitamin D on the developing CNS in vivo, we will concentrate on one experimental model that has examined the impact of the dietary absence of vitamin D in utero. Finally, we discuss the epidemiological data that suggests that vitamin D deficiency either in utero or in early life may have adverse neuropsychiatric implications. PMID- 21664982 TI - Foraging behavior adjustments related to changes in nectar sugar concentration in phyllostomid bats. AB - Nectar-feeding bats regulate their food ingestion in response to changes in sugar concentration as a way to achieve a constant energy intake. However, their digestive capability to assimilate sugars can limit their total energy intake, particularly when sugar concentration in nectar is low. Our experimental study evaluated the effect that changes in sugar concentration of nectar have on the foraging behavior of the nectar-feeding bats Glossophaga soricina and Leptonycteris yerbabuenae in captivity. We measured foraging behavior and food intake when bats fed at different concentrations of sucrose (5, 15, 25 and 35%wt/vol.). To compensate for low-energy intake, both bat species reduced their flight time, and increased feeding time when sugar concentration decreased. Our results suggest that nectar-feeding bats in nature confront two scenarios with complementary ecological effects: 1) bats feeding on dilute nectars (i.e. <=15%wt/vol.) should increase the number of flowers visited per night enhancing pollination, and 2) bats feeding on concentrated nectars could spend more time flying, including long- and short-distance-flights increasing food patch exploration for use during subsequent nights, and thus enhancing plant gene flow. Further studies on foraging behavior of nectarivorous bats under natural conditions are necessary to corroborate these hypotheses. PMID- 21664983 TI - Autophagy facilitates an IFN-gamma response and signal transduction. AB - Autophagy, that is directly triggered by invaded pathogens and indirectly triggered by IFN-gamma, acts as a defense by mediating intracellular microbial recognition and clearance. In addition, autophagy contributes to inflammation by facilitating an IFN-gamma response and signal transduction. For immune escape, downregulated autophagy may be a strategy used by microbes. PMID- 21664984 TI - Multilocus microsatellite typing shows three different genetic clusters of Leishmania major in Iran. AB - Ten polymorphic microsatellite markers were used to analyse 25 strains of Leishmania major collected from cutaneous leishmaniasis cases in different endemic areas in Iran. Nine of the markers were polymorphic, revealing 21 different genotypes. The data displayed significant microsatellite polymorphism with rare allelic heterozygosity. Bayesian statistic and distance based analyses identified three genetic clusters among the 25 strains analysed. Cluster I represented mainly strains isolated in the west and south-west of Iran, with the exception of four strains originating from central Iran. Cluster II comprised strains from the central part of Iran, and cluster III included only strains from north Iran. The geographical distribution of L. major in Iran was supported by comparing the microsatellite profiles of the 25 Iranian strains to those of 105 strains collected in 19 Asian and African countries. The Iranian clusters I and II were separated from three previously described populations comprising strains from Africa, the Middle East and Central Asia whereas cluster III grouped together with the Central Asian population. The considerable genetic variability of L. major might be related to the existence of different populations of Phlebotomus papatasi and/or to differences in reservoir host abundance in different parts of Iran. PMID- 21664985 TI - Construction of amphiphilic copolymer nanoparticles based on hyperbranched poly (amine-ester) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine as drug carriers for cancer therapy. AB - Novel amphiphilic copolymer nanoparticles (HPAE-co-PLA-DPPE) composed of hyperbranched poly (amine-ester), polylactide and 1,2-dipalmitoyl-sn-glycero-3 phosphoethanolamine (DPPE) segments were designed and synthesized that provided high encapsulation efficiency. These nanoparticles (NPs) were used to encapsulate an antitumor model drug, doxorubicin (DOX). The resulting NPs exhibited high encapsulation efficiency to DOX under an appropriate condition. In vitro release experiments revealed that the release of DOX from NPs was faster at pH 4.5 than that at pH 7.4 or pH 6.0. Confocal microscopy observation indicated that the DOX loaded NPs can enter cells and localize in lysosomes that can be released quickly into the cytoplasm. The DOX-loaded NPs showed comparable anticancer efficacy with the free drug both in vivo and in vitro. These results demonstrate a feasible application of the hyperbranched copolymer, HPAE-co-PLA-DPPE, as a promising nanocarrier for intracellular delivery of antitumor drugs. FROM THE CLINICAL EDITOR: In this paper, the development of novel amphiphilic copolymer nanoparticles is discussed with the goal of establishing high encapsulation efficiency for chemotherapy drugs. PMID- 21664986 TI - Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 2: Statistical considerations. AB - If the primary objective of a trial is to learn about the ability of a new treatment to help future patients without sacrificing the safe and effective treatment of the current patients, then a Bayesian design with frequent assessments of the accumulating data should be considered. Unfortunately, Bayesian analyses typically do not have standard approaches, and because of the subjectivity of prior probabilities and the possibility for introducing bias, statisticians have developed other methods for statistical inference that only depend on deductive probabilities. However, these frequentist probabilities are just theories about how certain relative frequencies will develop over time. They have no real meaning in a single experiment. Designed to work well in the long run, p-values become hard to explain for individual experiments. Fortunately, the controversy surrounding Bayes' theorem comes, not from the representation of evidence, but from the use of probabilities to measure belief. A prior distribution is not necessary. The likelihood function contains all of the information in a trial relevant for making inferences about the parameters. Monitoring clinical trials is a dynamic process which requires flexibility to respond to unforeseen developments. Likelihood ratios allow the data to speak for themselves, without regard for the probability of observing weak or misleading evidence, and decisions to stop, or continue, a trial can be made at any time, with all of the available information. A likelihood based method is needed. PMID- 21664987 TI - Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 1: Ethical considerations. AB - The protection of patient safety is the principal responsibility of clinical trial investigators, and must be assured even if that were to prevent successful completion of a trial. Yet, the decision to prematurely stop a blinded, randomized controlled clinical trial can be extremely complicated, involving a tangle of ethical, statistical, and practical issues. Questions are quickly answered when conclusive evidence of harm has been established for trial participants, or when the potential for harm exceeds an acceptable limit of comfort for an oversight body. Less readily addressed are those situations in which early alarms warn of possible harm, but the data are too preliminary or incomplete to reach a satisfactory decision as to whether or not to stop the study. Early study termination without sufficient evidence disallows the study question from being answered and may allow an inferior treatment to remain in use, or prevent a superior one from being discovered. Even without early stopping, as a study proceeds, worrisome trends may lead to overzealous (or overly cautious) looks at study data which could jeopardize the integrity of the findings. Trial investigators and safety monitoring groups, aided by objective statistical rules and thoughtful deliberations, share responsibility for patient welfare. Statistical guidelines must not frustrate ethical concerns, but, rather, should be designed to promote the highest ethical and scientific outcomes possible, safeguarding both trial participants and the public - the ultimate beneficiaries of clinical trials. PMID- 21664988 TI - Continuous safety monitoring for randomized controlled clinical trials with blinded treatment information. Part 3: Design considerations. AB - Ongoing safety monitoring of clinical trials of investigational treatments must operate at levels that range from the minute and detailed - namely, mathematical treatment of trial data - to the philosophical and societal - namely, ethical concerns for individuals and populations. Between those two poles lies a realm of environmental and pragmatic considerations that reflect the goals, biases, risk tolerance, and constraints of study sponsors and organizers. These factors, while more difficult to quantify or, at times, to justify, also have a meaningful impact on the approach to safety monitoring and the resulting actions and outcomes. This paper considers the influence and interaction of two such factors, study design and statistical framework, on continuous safety monitoring procedures. Group sequential designs have been generally preferred for clinical trials over continuous sequential designs because of practical considerations. The group means and greater time for deliberation when using a group sequential procedure, as opposed to a continuous sequential procedure, can improve the quality of the analyses with minimal loss in sensitivity. However, undertaking any sequential analysis within a frequentist framework provokes considerable theoretical and practical difficulties. Continuous monitoring with a likelihood based method, on the other hand, has the advantages that all available information, including new data, can be used; sample sizes need not be fixed; and decisions can be made at any time without statistical penalty, irrespective of trial design. Such responsive statistical rules are needed to provide guidance to the human beings charged with trial monitoring. PMID- 21664989 TI - Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: two genes, five proteins and many functions? AB - The lectin pathway of the complement system is activated following the binding of carbohydrate-based ligands by recognition molecules such as mannose-binding lectin (MBL) or ficolins. Engagement of the recognition molecules causes activation of associated MBL-associated serine proteases or MASPs, which in turn activate downstream complement molecules to activate the system. Two MASP genes are alternatively spliced during expression to yield 5 proteins, including three proteases (MASP-1, -2 and -3) and two truncated proteins, MAp19 and MAp44. Here we discuss what is currently known about these proteins in terms of their structure and function. MASP-2 is autoactivated following the initial binding events of the pathway and is able to subsequently activate the C4 and C2 substrates required to activate the rest of the pathway. MASP-1 is able to augment MASP-2 activation, but also appears to play other roles, although the physiological significance of these is not yet clear. The roles of the truncated Map19 and Map44 proteins and the MASP-3 protease are currently unknown. The proteases form an interesting sub-family of proteins that clearly should be the focus of future research in order to establish their biological roles. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21664991 TI - Emerging roles of cathepsin E in host defense mechanisms. AB - Cathepsin E is an intracellular aspartic proteinase of the pepsin superfamily, which is predominantly expressed in certain cell types, including the immune system cells and rapidly regenerating gastric mucosal and epidermal keratinocytes. The intracellular localization of this protein varies with different cell types. The endosomal localization is primarily found in antigen presenting cells and gastric cells. The membrane association is observed with certain cell types such as erythrocytes, osteoclasts, gastric parietal cells and renal proximal tubule cells. This enzyme is also found in the endoplasmic reticulum, Golgi complex and cytosolic compartments in various cell types. In addition to its intracellular localization, cathepsin E occurs in the culture medium of activated phagocytes and cancer cells as the catalytically active enzyme. Its strategic expression and localization thus suggests the association of this enzyme with specific biological functions of the individual cell types. Recent genetic and pharmacological studies have particularly suggested that cathepsin E plays an important role in host defense against cancer cells and invading microorganisms. This review focuses emerging roles of cathepsin E in immune system cells and skin keratinocytes, and in host defense against cancer cells. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21664992 TI - CTAB, Triton X-100 and freezing-thawing treatments of Candida guilliermondii: effects on permeability and accessibility of the glucose-6-phosphate dehydrogenase, xylose reductase and xylitol dehydrogenase enzymes. AB - Cells of Candida guilliermondii (ATCC 201935) were permeabilised with surfactant treatment (CTAB or Triton X-100) or a freezing-thawing procedure. Treatments were monitored by in situ activities of the key enzymes involved in xylose metabolism, that is, glucose-6-phosphate dehydrogenase (G6PD), xylose reductase (XR) and xylitol dehydrogenase (XD). The permeabilising ability of the surfactants was dependent on its concentration and incubation time. The optimum operation conditions for the permeabilisation of C. guilliermondii with surfactants were 0.41 mM (CTAB) or 2.78 mM (Triton X-100), 30 degrees C, and pH 7 at 200 rpm for 50 min. The maximum permeabilisation measured in terms of the in situ G6PD activity observed was, in order, as follows: CTAB (122.4+/-15.7U/g(cells)) > freezing-thawing (54.3 +/- 1.9U/g(cells))>Triton X-100 (23.5 +/- 0.0U/g(cells)). These results suggest that CTAB surfactant is more effective in the permeabilisation of C. guilliermondii cells in comparison to the freezing-thawing and Triton X-100 treatments. Nevertheless, freezing-thawing was the only treatment that allowed measurable in situ XR activity. Therefore, freezing thawing permeabilised yeast cells could be used as a source of xylose reductase for analytical purposes or for use in biotransformation process such as xylitol preparation from xylose. The level of in situ xylose reductase was found to be 13.2 +/- 0.1 U/g(cells). PMID- 21664990 TI - Controlling reaction specificity in pyridoxal phosphate enzymes. AB - Pyridoxal 5'-phosphate enzymes are ubiquitous in the nitrogen metabolism of all organisms. They catalyze a wide variety of reactions including racemization, transamination, decarboxylation, elimination, retro-aldol cleavage, Claisen condensation, and others on substrates containing an amino group, most commonly alpha-amino acids. The wide variety of reactions catalyzed by PLP enzymes is enabled by the ability of the covalent aldimine intermediate formed between substrate and PLP to stabilize carbanionic intermediates at Calpha of the substrate. This review attempts to summarize the mechanisms by which reaction specificity can be achieved in PLP enzymes by focusing on three aspects of these reactions: stereoelectronic effects, protonation state of the external aldimine intermediate, and interaction of the carbanionic intermediate with the protein side chains present in the active site. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology. PMID- 21664993 TI - The effect of the symbiosis between Tagetes erecta L. (marigold) and Glomus intraradices in the uptake of Copper(II) and its implications for phytoremediation. AB - Phytoremediation is an environmental biotechnology that seeks to remediate pollution caused by bioaccumulative toxins like copper (Cu). Symbiotic mycorrhizal associations can increase the uptake and delivery of low mobility nutrients and micronutrients to the host plant because they solubilize these substances and increase their catchment area. To analyze the effect of mycorrhizae on the phytoaccumulation of Cu, we studied their ability to solubilize Cu(II) and enhance its absorption by the plant Tagetes erecta L. colonized with the arbuscular mycorrhizal fungus Glomus intraradices. Plants were grown for nine weeks in a growth chamber under controlled conditions of temperature, relative humidity and photoperiod. Cu was added in the insoluble form of CuO to simulate the insoluble Cu-O affixed species in soil. The biotic and abiotic parameters of colonization, foliar area, biomass and the pH of leachates were determined as functions of the Cu concentration that was measured in the roots, shoots and leachates by AAS. The results of Cu absorption showed that the colonized plants accumulated more Cu in the roots as well as the whole plant and that both the colonized and non-colonized plants displayed the typical behavior of Cu excluders. Mycorrhizal colonization of the roots resulted in a proliferation of vesicles and this was observed to scale with root tissue Cu concentrations. Also, the G. intraradices-T. erecta system displayed a higher resistance to the toxicity induced by Cu while nonetheless improving the indices of phytoaccumulative yields. These results suggest that G. intraradices possibly accumulates Cu in its vesicles thereby enhancing the Cu tolerance of T. erecta even while increasing root Cu accumulation. The parameters of bioconcentration factor and translocation factor measured in this work suggest that the system T. erecta-G. intraradices can potentially phytostabilize Cu in contaminated soils. PMID- 21664994 TI - Recombinant protein purification using complementary peptides as affinity tags. AB - Affinity tags have become highly popular tools for purifying recombinant proteins from crude extracts by affinity chromatography. Besides, short peptides are excellent ligands for affinity chromatography, as they are not likely to cause an immune response in case of leakage into the product, they are more stable than antibodies to elution and cleaning conditions and they usually have very acceptable selectivity. Hydropathically complementary peptides designed de novo show enough selectivity to be used successfully as peptide ligands for protein purification from crude extracts. Recognition specificity and selectivity in the interaction between the complementary peptide pair His-Leu-Leu-Phe-Pro-Ile-Ile Ile-Ala-Ala-Ser-Leu and Lys-Asn-Tyr-Pro-Lys-Lys-Lys-Met-Glu-Lys-Arg-Phe have been demonstrated by other authors. In this work, we designed a recombinant protein purification method using a peptide affinity tag that binds to a peptide-binding partner immobilized on a chromatographic matrix. The enhanced green fluorescent protein expressed (EGFP) in Escherichia coli was used as the model. The peptide Gly-Gly-Gly-His-Leu-Leu-Phe-Pro-Ile-Ile-Ile-Ala-Ala-Ser-Leu was synthesized by solid phase using the Fmoc chemistry and immobilized in NHS-Sepharose (PC Sepharose). Gly residues were added as a spacer arm at the N terminus. The EGFP was expressed either with the fusion tag Lys-Asn-Tyr-Pro-Lys-Lys-Lys-Met-Glu-Lys Arg-Phe on the C terminus (EGFP-CPTag) or without any fusion tag. After cell disruption, the extract was directly applied to the PC-Sepharose column equilibrated with 20mM sodium phosphate buffer, pH 7.0. The adsorbed EGFP-CPTag was then eluted with 1M Tris. The yield was 98% and the purification factor 4.6. By contrast, EGFP without tag pass through without interacting with the PC Sepharose column. The method designed can be applied for the purification of other recombinant proteins. PMID- 21664995 TI - Polycomb-group mediated epigenetic mechanisms through plant evolution. AB - Polycomb Group (PcG) proteins form an epigenetic "memory system", conserved in both plants and animals, controlling global gene expression during development via histone modifications. The role of PcG proteins in plants was primarily explored in Arabidopsis thaliana, where PcG regulation of developmental processes was demonstrated throughout the plant life cycle. Our knowledge about the PcG machinery in terrestrial plants other than Arabidopsis began to accumulate only in recent years. In this review we summarize recent emerging data on the evolution and diversification of PcG mechanisms in various phyla, from early diverging plants, including members of the Chlorophyte algae, through bryophytes and flowering plants. We describe the compositions of the PcG gene families, their so-far studied expression profiles, and finally summarize commonalities vs. differences among PcG functions across the various species. This article is part of a Special Issue entitled: Epigenetic control of cellular and developmental processes in plants. PMID- 21664996 TI - Disease-causing mutations in genes of the complement system. AB - Recent studies have revealed profound developmental consequences of mutations in genes encoding proteins of the lectin pathway of complement activation, a central component of the innate immune system. Apart from impairment of immunity against microorganisms, it is known that hereditary deficiencies of this system predispose one to autoimmune conditions. Polymorphisms in complement genes are linked to, for example, atypical hemolytic uremia and age-dependent macular degeneration. The complement system comprises three convergent pathways of activation: the classical, the alternative, and the lectin pathway. The recently discovered lectin pathway is less studied, but polymorphisms in the plasma pattern-recognition molecule mannan-binding lectin (MBL) are known to impact its level, and polymorphisms in the MBL-associated serine protease-2 (MASP-2) result in defects of complement activation. Recent studies have described roles outside complement and immunity of another MBL-associated serine protease, MASP-3, in the etiology of 3MC syndrome, an autosomal-recessive disorder involving a spectrum of developmental features, including characteristic facial dysmorphism. Syndrome causing mutations were identified in MASP1, encoding MASP-3 and two additional proteins, MASP-1 and MAp44. Furthermore, an association was discovered between 3MC syndrome and mutations in COLEC11, encoding CL-K1, another molecule of the lectin pathway. The findings were confirmed in zebrafish, indicating that MASP-3 and CL-K1 underlie an evolutionarily conserved pathway of embryonic development. Along with the discovery of a role of C1q in pruning synapses in mice, these recent advances point toward a broader role of complement in development. Here, we compare the functional immunologic consequences of "conventional" complement deficiencies with these newly described developmental roles. PMID- 21664997 TI - Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations. AB - Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geographically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3-4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spectrum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria. PMID- 21664998 TI - The orphan disease networks. AB - The low prevalence rate of orphan diseases (OD) requires special combined efforts to improve diagnosis, prevention, and discovery of novel therapeutic strategies. To identify and investigate relationships based on shared genes or shared functional features, we have conducted a bioinformatic-based global analysis of all orphan diseases with known disease-causing mutant genes. Starting with a bipartite network of known OD and OD-causing mutant genes and using the human protein interactome, we first construct and topologically analyze three networks: the orphan disease network, the orphan disease-causing mutant gene network, and the orphan disease-causing mutant gene interactome. Our results demonstrate that in contrast to the common disease-causing mutant genes that are predominantly nonessential, a majority of orphan disease-causing mutant genes are essential. In confirmation of this finding, we found that OD-causing mutant genes are topologically important in the protein interactome and are ubiquitously expressed. Additionally, functional enrichment analysis of those genes in which mutations cause ODs shows that a majority result in premature death or are lethal in the orthologous mouse gene knockout models. To address the limitations of traditional gene-based disease networks, we also construct and analyze OD networks on the basis of shared enriched features (biological processes, cellular components, pathways, phenotypes, and literature citations). Analyzing these functionally-linked OD networks, we identified several additional OD-OD relations that are both phenotypically similar and phenotypically diverse. Surprisingly, we observed that the wiring of the gene-based and other feature-based OD networks are largely different; this suggests that the relationship between ODs cannot be fully captured by the gene-based network alone. PMID- 21665000 TI - A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak Syndrome type 9. AB - Hermansky-Pudlak Syndrome (HPS) is an autosomal-recessive condition characterized by oculocutaneous albinism and a bleeding diathesis due to absent platelet delta granules. HPS is a genetically heterogeneous disorder of intracellular vesicle biogenesis. We first screened all our patients with HPS-like symptoms for mutations in the genes responsible for HPS-1 through HPS-6 and found no functional mutations in 38 individuals. We then examined all eight genes encoding the biogenesis of lysosome-related organelles complex-1, or BLOC-1, proteins in these individuals. This identified a homozygous nonsense mutation in PLDN in a boy with characteristic features of HPS. PLDN is mutated in the HPS mouse model pallid and encodes the protein pallidin, which interacts with the early endosomal t-SNARE syntaxin-13. We could not detect any full-length pallidin in our patient's cells despite normal mRNA expression of the mutant transcript. We could detect an alternative transcript that would skip the exon that harbored the mutation, but we demonstrate that if this transcript is translated into protein, although it correctly localizes to early endosomes, it does not interact with syntaxin-13. In our patient's melanocytes, the melanogenic protein TYRP1 showed aberrant localization, an increase in plasma-membrane trafficking, and a failure to reach melanosomes, explaining the boy's severe albinism and establishing his diagnosis as HPS-9. PMID- 21664999 TI - Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. AB - Extreme corneal fragility and thinning, which have a high risk of catastrophic spontaneous rupture, are the cardinal features of brittle cornea syndrome (BCS), an autosomal-recessive generalized connective tissue disorder. Enucleation is frequently the only management option for this condition, resulting in blindness and psychosocial distress. Even when the cornea remains grossly intact, visual function could also be impaired by a high degree of myopia and keratoconus. Deafness is another common feature and results in combined sensory deprivation. Using autozygosity mapping, we identified mutations in PRDM5 in families with BCS. We demonstrate that regulation of expression of extracellular matrix components, particularly fibrillar collagens, by PRDM5 is a key molecular mechanism that underlies corneal fragility in BCS and controls normal corneal development and maintenance. ZNF469, encoding a zinc finger protein of hitherto undefined function, has been identified as a quantitative trait locus for central corneal thickness, and mutations in this gene have been demonstrated in Tunisian Jewish and Palestinian kindreds with BCS. We show that ZNF469 and PRDM5, two genes that when mutated cause BCS, participate in the same regulatory pathway. PMID- 21665001 TI - Hereditary leukonychia, or porcelain nails, resulting from mutations in PLCD1. AB - Hereditary leukonychia (porcelain nails or white nails) is a rare nail disorder with an unknown genetic basis. To identify variants in a gene underlying this phenotype, we identified four families of Pakistani origin showing features of hereditary leukonychia. All 20 nails of each affected individual were chalky and white in appearance, consistent with total leukonychia, with no other cutaneous, appendageal, or systemic findings. By using Affymetrix 10K chip, we established linkage to chromosome 3p21.3-p22 with a LOD score (Z) of 5.1. We identified pathogenic mutations in PLCD1 in all four families, which encodes phosphoinositide-specific phospholipase C delta 1 subunit, a key enzyme in phosphoinositide metabolism. We then identified localization of PLCD1 in the nail matrix. It was recently shown that PLCD1 is a component of the human nail plate by proteomic analysis and is localized in the matrix of human nails. Furthermore, mutations detected in PLCD1 resulted in reduced enzymatic activity in vitro. Our data show that mutations in PLCD1 underlie hereditary leukonychia, revealing a gene involved in molecular control of nail growth. PMID- 21665002 TI - A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. AB - Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain. PMID- 21665004 TI - American Heart Association guidelines for depression screening in heart disease: call to action for the research community? PMID- 21665003 TI - Mutations in Frizzled 6 cause isolated autosomal-recessive nail dysplasia. AB - Inherited and isolated nail malformations are rare and heterogeneous conditions. We identified two consanguineous pedigrees in which some family members were affected by isolated nail dysplasia that suggested an autosomal-recessive inheritance pattern and was characterized by claw-shaped nails, onychauxis, and onycholysis. Genome-wide SNP array analysis of affected individuals from both families showed an overlapping and homozygous region of 800 kb on the long arm of chromosome 8. The candidate region spans eight genes, and DNA sequence analysis revealed homozygous nonsense and missense mutations in FZD(6), the gene encoding Frizzled 6. FZD(6) belongs to a family of highly conserved membrane-bound WNT receptors involved in developmental processes and differentiation through several signaling pathways. We expressed the FZD(6) missense mutation and observed a quantitative shift in subcellular distribution from the plasma membrane to the lysosomes, where the receptor is inaccessible for signaling and presumably degraded. Analysis of human fibroblasts homozygous for the nonsense mutation showed an aberrant response to both WNT-3A and WNT-5A stimulation; this response was consistent with an effect on both canonical and noncanonical WNT-FZD signaling. A detailed analysis of the Fzd(6)(-/-) mice, previously shown to have an altered hair pattern, showed malformed claws predominantly of the hind limbs. Furthermore, a transient Fdz6 mRNA expression was observed in the epidermis of the digital tips at embryonic day 16.5 during early claw morphogenesis. Thus, our combined results show that FZD6 mutations can result in severe defects in nail and claw formation through reduced or abolished membranous FZD(6) levels and several nonfunctional WNT-FZD pathways. PMID- 21665005 TI - Is routine screening a parachute for heart disease patients with depression? PMID- 21665006 TI - Depression screening in patients with coronary heart disease: a critical evaluation of the AHA guidelines. AB - OBJECTIVE: We lack evidence that routine screening for depression in patients with coronary heart disease (CHD) improves patient outcome. This lack has challenged the advisory issued by the American Heart Association (AHA) to routinely screen for depression in CHD patients. We assess the AHA advisory in the context of well-established criteria of screening for diseases. METHODS: Using principles and criteria for screening developed by the World Health Organization and the United Kingdom National Screening Committee, we generated criteria pertinent to screening for depression in CHD patients. To find publications relevant to these criteria and clinical setting, we performed a broadly based literature search on "depression and CHD," supplemented by more focused literature searches. RESULTS: Evidence for an association between depression and CHD is strong. Despite this, the AHA advisory has several limitations. It did not account for the complexity of the association between depression and CHD. It acknowledged there was no evidence that screening for depression leads to improved outcomes in cardiovascular populations but still recommended routine screening without providing an alternative evidence-based explanation. It ignored the paucity of literature about the safety and cost effectiveness of routine screening for depression in CHD and failed to define the nature and extent of resources needed to implement such a program effectively. CONCLUSION: We conclude that the AHA advisory is premature. We must first demonstrate the efficacy, safety, and cost-effectiveness of screening and define the resources necessary for its implementation and monitoring. Meanwhile, organizations representing cardiologists, psychiatrists, and general practitioners must coordinate efforts to manage depression and CHD through collaborative care, and work with the policy makers to develop the necessary infrastructure and services delivery system needed to optimize the outcome of depressed and at-risk-for-depression patients suffering from CHD. PMID- 21665008 TI - A systematic review of non-pharmacological treatments for depression in people with chronic physical health problems. AB - OBJECTIVE: To review the efficacy of non-pharmacological treatment for depression in people with depression and chronic physical health problems. METHOD: Five electronic databases were searched including EMBASE, Medline and PsycINFO for randomized controlled trials (RCTs). Each paper was assessed for quality, data extracted and, where possible, the data meta-analyzed. The overall quality of each meta-analysis was assessed. RESULTS: 35 studies met our inclusion criteria and 22 were meta-analyzed using a random-effects model. The largest and strongest evidence base supports individual- and group-based cognitive and behavioral interventions (18 trials). The evidence was strongest for those interventions aimed solely at reducing depression in comparison to those aimed more broadly at reducing the psychosocial stress associated with having a chronic physical health problem. CONCLUSION: Overall, the efficacy of certain types of non pharmacological interventions for people with depression and chronic physical health problems has been demonstrated. The overall impression is that their efficacy in this population is comparable to that in people with depression without chronic physical health problems but the evidence-base is currently inadequate and larger trials with long-term follow-up are required. PMID- 21665007 TI - Inflammation and treatment response to sertraline in patients with coronary heart disease and comorbid major depression. AB - OBJECTIVE: Treatment-resistant depression has recently emerged as a marker of increased risk for morbidity and mortality in patients with coronary heart disease (CHD). Studies in depressed patients without CHD suggest that elevated markers of inflammation predict poor response to treatment. This may help to explain the increased risk of cardiac events associated with depression. We therefore studied the relationship between pretreatment markers of inflammation and treatment response in patients with CHD and major depression. METHODS: This was a planned, secondary analysis of a clinical trial in which 122 patients with CHD and comorbid major depression were randomly assigned to 50 mg of sertraline plus 2 g/day omega-3 fatty acids or to 50 mg of sertraline plus 2 g/day corn oil placebo capsules for ten weeks. Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II). Blood samples were collected at baseline to determine levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha). The primary outcome was the post-treatment BDI-II depression score. RESULTS: Baseline levels of hs-CRP, IL-6, and TNF-alpha were not associated with the 10-week post-treatment depression score (P=.89, P=.88, and P=.31, respectively). Treatment responders (>50% reduction from baseline BDI-II score) did not differ from non-responders in either baseline hs-CRP, IL-6, or TNF-alpha (P=.83, P=.93, and P=.24, respectively). Similarly, depression remitters (BDI-II <=8 at post-treatment) did not differ from non-remitters on the three baseline inflammation markers. CONCLUSION: These findings do not support the hypothesis that elevated baseline inflammatory markers predict poor response to sertraline in patients with CHD and major depression. The explanation for the increased risk of cardiac events associated with poor response to depression treatment remains unclear. PMID- 21665010 TI - Depressive symptoms predict long-term mortality after liver transplantation. AB - OBJECTIVE: Depressive symptoms are common after liver transplantation (LT). We studied whether depressive symptoms affect long-term survival after LT. METHODS: In a prospective cohort study, 134 liver transplant patients were assessed for depressive symptoms using the Beck Depression Inventory-short form (BDI), focusing on the 3 months post-LT score and on the score change from the waiting list period. They were followed up for long-term survival. The median duration of the follow-up period was 43 months post-LT. None of the 134 patients was lost to follow-up for survival. RESULTS: A total of 33.6% of the LT patients had mild to moderate depressive symptoms 3 months post-LT. Eighteen (13.4%) patients died during the follow-up. Using Cox proportional hazards analysis, depressive symptoms were significantly associated with mortality (hazard ratio [HR] 1.22, 95% confidence interval (CI) 1.07-1.40, P<.003), one more point in the BDI score being associated with a 17% increase in mortality risk. Other predictive factors of mortality were older age and hepatitis C virus with recurrence 3 months post LT. Similarly, an increase in depressive symptoms between the waiting list and 3 months post-LT periods predicted mortality (HR 1.18, 95% CI 1.01-1.38, P=.03), especially for patients without depressive symptoms on waiting list (HR 1.56, 95% CI 1.16-2.12, P=.004). CONCLUSION: Depressive symptoms after LT and an increase in depressive symptoms between the waiting list and post-LT are associated with an increased risk of long-term mortality. Interventions that could reduce depressive symptoms could potentially decrease long-term mortality after LT. PMID- 21665009 TI - History of depressive episodes as a risk factor for illness severity in early inflammatory arthritis. AB - OBJECTIVE: Psychosocial research in arthritis consistently demonstrates a relationship between depression and disease characteristics such as severity of illness and physical disability. In this study, we examine how a history of clinical depression identified through diagnostic interviews influences disease outcome measures in patients with early inflammatory arthritis (EIA) in the absence of current depression. METHODS: Patients in the early phase (more than 6 weeks, less than 1-year duration) of inflammatory arthritis were recruited from a larger EIA registry, which recorded sociodemographic data, current depressive symptoms and measures of disease severity. Current and history of major depression was assessed by a structured clinical interview. Eighty-one patients without current major depression were divided into two groups: 28 with and 53 without a history of depression. RESULTS: There were no significant differences between the two groups in age, sex, education, income, or level of current depressive symptoms. Compared with patients with no history of major depression, those with a history of depressive episodes had higher self-ratings of disease activity and were assessed as having more severe disease and poorer physical functioning by their physicians. CONCLUSION: This study indicates that a history of major depression represents a risk factor for disease severity in EIA. This may reflect an enduring physiological effect of depression that influences subsequent inflammatory arthritis or an underlying shared process between these two disease entities. PMID- 21665011 TI - Are medically unexplained symptoms and functional disorders predictive for the illness course? A two-year follow-up on patients' health and health care utilisation. AB - OBJECTIVE: To investigate whether the general practitioners' (GP) diagnosis of medically unexplained symptoms (MUS) and/or the diagnosis functional disorders (FD) can predict the patients' 2-year outcome in relation to physical and mental health and health care utilisation. Furthermore, to identify relevant clinical factors which may help the GP predict the patient's outcome. METHOD: The study included 38 GPs and 1785 consecutive patients who presented a new health problem. The GPs completed a questionnaire on diagnosis for each patient. Patients completed the Common Mental Disorder Questionnaire (CMDQ) and the SF-36 questionnaire at baseline and after 24 months. A stratified sample of 701 patients was diagnosed with a psychiatric research interview. Data on health cost was obtained from national registers. RESULTS: A FD diagnosis following the research interview was associated with a decline in physical health (OR 3.27(95%CI 1.84-5.81)), but this was not the case with MUS diagnosed by the GP. MUS was associated with a poor outcome on mental health (OR 2.16 (95%CI 1.07 4.31)). More than 4 symptoms were associated with a poor outcome on physical health (OR 5.35 (95%CI 2.28-12.56)) and on mental health (OR 2.17(95%CI 1.02 4.59)). Neither FD nor MUS were associated with higher total health care use. However, FD (OR 2.31(95%CI 1.24-4.31)) and MUS (OR 1.98(95%CI 1.04-3.75)) was associated with increased cost in primary care. CONCLUSION: Our current diagnoses of MUS show limitations in their prediction of the patients' illness course. Although, the ICD-10 diagnoses of functional disorders was not developed for the primary care setting, our results indicate that some of its elements would be useful to bring in when rethinking the diagnosis for MUS in primary care, elements that are easily obtainable for the GP in a normal consultation. Our results may contribute to the construction of a more useful diagnostic for these patients in primary care. PMID- 21665012 TI - Association of change in depression and anxiety symptoms with functional outcomes in pulmonary rehabilitation patients. AB - OBJECTIVE: Pulmonary rehabilitation (PR) has emerged over the last decade as an essential component of an integrated approach to managing patients with chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD). We sought to examine how depression and anxiety symptom changes relate to disease specific quality of life outcomes following PR. METHODS: We performed a cohort study of 81 patients with COPD who completed PR at a Veterans Administration Medical Center. Pulmonary rehabilitation consisted of supervised exercise training and education twice weekly for 8 weeks. Beck Depression and Anxiety Inventories (BDI and BAI) assessed symptom burden at baseline and completion of PR. We measured change in disease-specific quality of life using the dyspnea, mastery, emotion and fatigue domains of the Chronic Respiratory Questionnaire Self-Reported (CRQ-SR) from baseline to completion of PR. RESULTS: Participants were 69.8+/-9.1 years old and all male. Forced expiratory volume in 1 s (FEV1) was 1.23+/-0.39 L. The CRQ-SR scores improved significantly: dyspnea (P<.0001), mastery (P=.015) and fatigue (P=.017). The BDI scores improved significantly (13.1+/-10.5 to 10.8+/-9.9, P=.003; BAI: 13.1+/-10.1 to 12.1+/-11.7). Multivariate regression models controlling for age, FEV1, depression treatment and anxiety treatment showed that improvement in depressive symptoms were associated with improvement in fatigue (P=.003), emotion (P=.003) and mastery (P=.01). Anxiety symptom change was not significantly associated with change in disease-specific quality of life domains. CONCLUSION: Addressing anxiety symptoms in PR patients may be indicated because disease-specific quality of life improvement appears to be associated with mood. PMID- 21665013 TI - Mini Mental State Examination over time in chronic hemodialysis patients. AB - OBJECTIVE: Cognitive impairment is relatively common in end-stage renal disease patients on chronic hemodialysis, but the course of cognitive function deterioration in hemodialysis patients is essentially unknown. The present study aimed to evaluate if changes in Mini Mental State Examination (MMSE) over time in hemodialysis (HDP) and elderly (EP) patients differ significantly and determine the variables associated with such possible changes. METHODS: In 80 HDP and 160 EP, the MMSE was assessed at baseline and after 1 year. Patients were stratified at baseline and at 1 year into three groups according to the MMSE: normal cognitive function >23; mild-moderate cognitive dysfunction: 18-23; severe cognitive dysfunction: <18. Univariate and multivariate analyses were performed to determine the variables associated with MMSE change over time RESULTS: One year median reduction of MMSE was greater in HDP (from 24 to 21) than in EP (from 26 to 25) (P<.0001). A higher percentage of HDP than EP switched from normal to mild-moderate or severe MMSE group (P<.0001). At baseline, MMSE was negatively correlated with hypertension (P=.013), angina (P=.007) and Beck Depression Inventory (P=.041) and positively correlated with education (P=.017) and male gender (P=.015). No factors were found to be significantly associated with change of MMSE between baseline and month 12 in HDP. CONCLUSION: One-year MMSE reduction was greater in HDP that in EP. No factors were associated with MMSE reduction in HDP. However, it remains likely that cardiovascular comorbidities and low haemoglobin levels are related to such decline. PMID- 21665014 TI - Symptoms of postsurgical distress following total knee replacement and their relationship to recovery outcomes. AB - OBJECTIVE: Prior research has suggested that posttraumatic stress symptoms may occur in the context of medical events. Further, these symptoms are often comorbid with conditions associated with pain. Therefore, the current study examined the occurrence of distress following arthroplastic surgery and the relationship of these symptoms to postoperative recovery. METHODS: Patients (N =110) undergoing unilateral, total knee replacement (TKR) surgery were assessed at three time points proximal to their surgery: approximately 2 weeks prior to surgery (T1), 1 month following surgery (T2) and 3 months following surgery (T3). Patients completed survey assessments of recovery outcomes (Western Ontario and McMaster Universities Osteoarthritis Index) and distress (The Impact of Event Scale [IES]) following surgery (T2 and T3). RESULTS: A significant percentage (20%) of patients undergoing TKR reported noteworthy levels of postsurgical stress 1 and 3 months following surgery. Further, this distress was associated with a more difficult recovery following TKR, characterized by more severe pain and greater functional limitations. After controlling for potential confounding variables, regression analyses suggested that postsurgical stress was cross sectionally related to pain perception and longitudinally predicted subsequent functional limitations and global assessments of recovery. DISCUSSION: To our knowledge, this is the first study to examine postoperative distress (using the IES) following TKR. The present study adds to the growing body of literature documenting the impact of psychological processes on postoperative recovery. PMID- 21665015 TI - Marine mammals and debris in coastal waters of British Columbia, Canada. AB - Entanglement in and ingestion of synthetic marine debris is increasingly recognized worldwide as an important stressor for marine wildlife, including marine mammals. Studying its impact on wildlife populations is complicated by the inherently cryptic nature of the problem. The coastal waters of British Columbia (BC), Canada provide important habitat for marine mammal species, many of which have unfavorable conservation status in the US and Canada. As a priority-setting exercise, we used data from systematic line-transect surveys and spatial modeling methods to map at-sea distribution of debris and 11 marine mammal species in BC waters, and to identify areas of overlap. We estimated abundance of 36,000 (CIs: 23,000-56,600) pieces of marine debris in the region. Areas of overlap were often far removed from urban centers, suggesting that the extent of marine mammal debris interactions would be underestimated from opportunistic sightings and stranding records, and that high-overlap areas should be prioritized by stranding response networks. PMID- 21665016 TI - Listening to the Deep: live monitoring of ocean noise and cetacean acoustic signals. AB - The development and broad use of passive acoustic monitoring techniques have the potential to help assessing the large-scale influence of artificial noise on marine organisms and ecosystems. Deep-sea observatories have the potential to play a key role in understanding these recent acoustic changes. LIDO (Listening to the Deep Ocean Environment) is an international project that is allowing the real-time long-term monitoring of marine ambient noise as well as marine mammal sounds at cabled and standalone observatories. Here, we present the overall development of the project and the use of passive acoustic monitoring (PAM) techniques to provide the scientific community with real-time data at large spatial and temporal scales. Special attention is given to the extraction and identification of high frequency cetacean echolocation signals given the relevance of detecting target species, e.g. beaked whales, in mitigation processes, e.g. during military exercises. PMID- 21665018 TI - The influence of biofilms on the migration of uranium in acid mine drainage (AMD) waters. AB - The uranium mine in Konigstein (Germany) is currently in the process of being flooded. Huge mass of Ferrovum myxofaciens dominated biofilms are growing in the acid mine drainage (AMD) water as macroscopic streamers and as stalactite-like snottites hanging from the ceiling of the galleries. Microsensor measurements were performed in the AMD water as well as in the biofilms from the drainage channel on-site and in the laboratory. The analytical data of the AMD water was used for the thermodynamic calculation of the predominance fields of the aquatic uranium sulfate (UO(2)SO(4)) and UO(2)(++) speciation as well as of the solid uranium species Uranophane [Ca(UO(2))(2)(SiO(3)OH)(2)?5H(2)O] and Coffinite [U(SiO(4))(1-x)(OH)(4x)], which are defined in the stability field of pH>4.8 and Eh<960 mV and pH>0 and Eh<300 mV, respectively. The plotting of the measured redox potential and pH of the AMD water and the biofilm into the calculated pH-Eh diagram showed that an aqueous uranium(VI) sulfate complex exists under the ambient conditions. According to thermodynamic calculations a retention of uranium from the AMD water by forming solid uranium(VI) or uranium(IV) species will be inhibited until the pH will increase to >4.8. Even analysis by Energy filtered Transmission Electron Microscopy (EF-TEM) and electron energy loss spectroscopy (EELS) within the biofilms did not provide any microscopic or spectroscopic evidence for the presence of uranium immobilization. In laboratory experiments the first phase of the flooding process was simulated by increasing the pH of the AMD water. The results of the experiments indicated that the F. myxofaciens dominated biofilms may have a substantial impact on the migration of uranium. The AMD water remained acid although it was permanently neutralized with the consequence that the retention of uranium from the aqueous solution by the formation of solid uranium species will be inhibited. PMID- 21665017 TI - Relationship between serum concentrations of polychlorinated biphenyls and organochlorine pesticides and dietary habits of pregnant women in Shanghai. AB - The use of most polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) has been restricted in China; however, their use remains a concern because of their adverse effects on human health, especially on fetuses and infants. To date, there is no data regarding the exposure levels of pregnant women to PCBs and OCPs in Shanghai. In order to evaluate PCB and OCP exposure levels and the contribution of dietary habits to these levels, we determined the concentrations of 8 PCBs and 14 OCPs in the umbilical cord blood serum of healthy pregnant women in Shanghai. Dietary habits of the pregnant women were obtained from a self administered questionnaire. Results showed that p, p'-DDE, HCB and beta-HCH were the major pollutants present in the serum samples; PCBs were detected in a few samples at low concentrations. Age, weight and body mass index before delivery were positively associated with serum levels of p, p'-DDE and beta-HCH. Women and their husbands who had higher education levels, higher income levels, tended to have higher levels of p, p'-DDE and beta-HCH. Spearman correlation analysis results suggested that consumption of foods such as milk, eggs, meat, fish, and shrimp may contribute to higher serum levels of p, p'-DDE and beta-HCH. Furthermore, multiple linear regression analyses indicated that the age and educational levels of the pregnant women and their intake of fried/flamed food and shellfish were positively associated with beta-HCH levels, and that the age and educational levels of the pregnant women and their intake of parity, beef, pork, mutton, and shrimp were positively associated with p, p'-DDE levels. This is the first study to investigate the exposure levels of pregnant women to PCBs and OCPs in Shanghai, and it should provide useful information for future related research. PMID- 21665020 TI - World report on disability. PMID- 21665019 TI - Estimation of daily inhalation rate in preschool children using a tri-axial accelerometer: a pilot study. AB - The activity of 5- to 6-year-old Japanese children (n=29) was monitored for 3 consecutive days, including one weekend day, using an ActivTracer tri-axial accelerometer. The daily inhalation rate and time spent in sedentary, light, or moderate to vigorous levels of physical activity (MVPA) were estimated from the accelerometer measurements based on previously developed regression equations. The 3-day mean daily inhalation rate (STPD) was estimated at 8.3+/-1.4 m(3) day( 1) in 10 subjects who completed 3 days of monitoring. The time spent in sedentary, light, or MVPA each day was 320, 415, and 81 min day(-1), respectively. Analysis of between-day reliability indicated that 3 days of monitoring with the ActivTracer tri-axial accelerometer provided an acceptable estimate of daily inhalation rate (intra-class correlation coefficient [ICC]=0.892), but low to moderate reliability for the time spent in different levels of activities (ICC=0.43 to 0.58). We observed a significant difference in the daily inhalation rate between weekdays and the weekend day, possibly due to differences in time spent in MVPA. This finding suggests that a weekend day should be included to obtain more reliable estimates of daily inhalation rate using an accelerometer. PMID- 21665021 TI - Responding to disease outbreaks in Europe. PMID- 21665022 TI - Global CO2 emissions: time to mitigate and adapt. PMID- 21665024 TI - Bill Roedy. PMID- 21665025 TI - Costing lives. PMID- 21665026 TI - Helen Rees on the quest for global equity. PMID- 21665027 TI - The health of prisoners. PMID- 21665028 TI - The health of prisoners. PMID- 21665029 TI - The health of prisoners. PMID- 21665030 TI - Mediator: who's to blame? PMID- 21665031 TI - The health of prisoners. PMID- 21665032 TI - Mediator: who's to blame? PMID- 21665033 TI - Mediator: who's to blame? PMID- 21665034 TI - Non-communicable diseases in southeast Asia. PMID- 21665035 TI - Non-communicable diseases in southeast Asia. PMID- 21665038 TI - Use of systematic reviews in WHO recommendations. PMID- 21665036 TI - Prevention of elder abuse. PMID- 21665039 TI - Learning from Haiti. PMID- 21665040 TI - Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus. AB - BACKGROUND: Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes. OBJECTIVES: The aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM. METHODS: Relevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data. RESULTS: Pharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited beta-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%-44%), vomiting (13%-17%), and diarrhea (11%-17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%-6% vs 3%-4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo). CONCLUSION: The 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term beta-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined. PMID- 21665041 TI - Clinical pharmacology of incretin therapies for type 2 diabetes mellitus: implications for treatment. AB - BACKGROUND: Increased understanding of the role of incretin hormones in maintaining glucose homeostasis has enabled the development of pharmacotherapies that target deficient incretin activity in type 2 diabetes mellitus (T2DM). Incretin therapies are premised on 1 of 2 approaches: (1) augmenting the activity of the hormone glucagon-like peptide (GLP)-1 (GLP-1 receptor agonists) and (2) inhibiting the degradation of GLP-1 by dipeptidyl peptidase (DPP)-4 (DPP-4 inhibitors). OBJECTIVE: This review discusses the pharmacokinetic properties and clinical profiles of the GLP-1 receptor agonists (exenatide twice daily, liraglutide once daily, exenatide once weekly, taspoglutide, and albiglutide) and the DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, and alogliptin) available for use or in late-stage development. METHODS: A search of PubMed for literature published between 2000 and mid-2010 was conducted using the names of each agent as key words. Phase III and IV studies were included in the review of efficacy and tolerability. Supplemental searches of abstracts from major diabetes conferences provided additional information on pharmacokinetic properties. Searches of all reference lists were performed to identify additional references of interest. RESULTS: The PubMed search identified multiple randomized, controlled clinical studies of the GLP-1 receptor agonists and the DPP-4 inhibitors administered as monotherapy or in combination regimens. Reductions from baseline in glycosylated hemoglobin ranged from 0.4% to 1.5% with exenatide 5 to 10 MUg/d (7 studies), 0.6% to 1.5% with liraglutide 0.6 to 1.8 mg/d (6 studies), 0.3% to 1.0% with sitagliptin 25 to 200 mg/d (9 studies), 0.5% to 0.9% with saxagliptin 2.5 to 10 mg/d (3 studies), 0.4% to 1.0% with vildagliptin 50 to 100 mg/d (6 studies), and 0.4% to 0.8% with alogliptin 12.5 to 25 mg/d (4 studies). Dosage adjustments and caution in prescribing incretin therapies are recommended in patients with renal disease, with those recommendations varying based on the agent and the degree of dysfunction. Incretin therapies have been associated with few interactions with commonly used antihyperglycemic and cardiovascular therapies. CONCLUSION: Based on the pharmacokinetic and therapeutic characteristics described in previously published Phase III and IV studies of incretin therapies, these agents may provide an option for the management of T2DM. PMID- 21665042 TI - What comes after producing the evidence? The importance of external validity to translating science to practice. PMID- 21665043 TI - A pharmacoepidemiologic analysis of the impact of calendar packaging on adherence to self-administered medications for long-term use. AB - BACKGROUND: Calendar blister packaging (CBP) that incorporates a day or date feature is a simple medication packaging technology that is designed to improve medication adherence and persistence. OBJECTIVE: This study was conducted to assess the effect of a new calendar packaging technology on prescription refill adherence and persistence for daily, self-administered, long-term medication use. METHODS: Anonymized pharmacy dispensing data from a large US mass merchandiser were analyzed. This retrospective cohort study included people aged 18 to 75 years who filled prescriptions for oral lisinopril or enalapril (control group) at a study pharmacy during 1 year before and after the switch of lisinopril packaging from vials to CBP. Cohorts were stratified into new and prevalent medication users. We used linear and logistic regression modeling and propensity score matching to assess the impact of CBP on refill adherence, using medication possession ratio (MPR) and proportion of days covered (PDC), and persistence using length of therapy (LOT). RESULTS: Our sample comprised 76,321 new users and 249,040 prevalent users. Across all user, medication, and packaging groups, the mean unadjusted LOT decreased in the follow-up year, possibly due to economic recession. The LOT decline was attenuated in the CBP cohort. After adjustment for covariates, CBP use in new and prevalent medication users was associated with significantly higher LOT and PDC but not MPR. The odds of achieving PDC >=80% were higher by 15% in new users (odds ratio [OR] = 1.15; 95% CI, 1.09-1.21) and 12% in prevalent users (OR = 1.12; 95% CI, 1.09-1.15) who switched to CBP, compared with continued vial use. CONCLUSIONS: CBP of medication prescribed for daily, self-administered, long-term use was associated with modest improvement in prescription refill adherence and persistence. An adherence strategy of even small effect size that is broadly implemented on a population level could significantly leverage therapeutic effect and provide substantial cumulative public health benefit. Clinical benefit, or harm, associated with use of CBP should be investigated. Usability assessments of CBP in patient subgroups may provide insight about differential impact on adherence and persistence. PMID- 21665044 TI - Retrospective evaluation of the impact of copayment increases for specialty medications on adherence and persistence in an integrated health maintenance organization system. AB - BACKGROUND: Specialty drugs are generally defined as high-cost injectable, infused, oral, or inhaled drugs that require close monitoring. Specialty drugs account for an increasing percentage of total drug expenditures, and management of specialty drugs has become a priority. A Central Texas-based integrated health maintenance organization system implemented a specialty drug benefit to manage expensive specialty drug costs. OBJECTIVES: Our objective was to measure and compare the change in adherence and persistence after implementation of copayment increases for select specialty medications used on a long-term basis (at least 2 years). METHODS: Patients who were long-term users of anti-inflammatory, immunosuppressant, cancer, and multiple sclerosis medications were selected. The intervention group consisted of those whose out-of-pocket payment for specialty medications increased, and the control group consisted of those whose out-of pocket costs did not change. Adherence, defined by proportion of days covered, was measured every 3 months for 12 months before and after the change. Individual growth model analysis evaluated the changes in adherence. Cox regression analysis determined the difference in persistence between groups. RESULTS: There were 178 and 202 patients in the intervention and control groups, respectively. The growth model showed a small but statistically significant decrease in proportion of days covered of 0.040 after copay changes in the intervention versus control group (P < 0.001) for immunosuppressants. The Cox regression analysis indicated a higher probability of intervention patients on anti-inflammatory drugs (hazard ratio [HR] = 2.53; 95% CI, 1.38-4.62) and immunosuppressants (HR = 3.01; 95% CI, 1.20 7.56) would be nonpersistent compared with those in their control groups. CONCLUSIONS: The move to the specialty formulary allows for closer scrutiny of specialty utilization by pharmacists, who actively monitor utilization and access. Despite the minimal adherence decrease and significant persistence changes with certain drug types, the results indicated relatively more stability with specialty drug use than reported with traditional pharmaceuticals. PMID- 21665045 TI - Associations between prescription copayment levels and beta-blocker medication adherence in commercially insured heart failure patients 50 years and older. AB - BACKGROUND: High prescription copayments may create barriers to care, resulting in medication nonadherence. Although many studies have examined these associations in commercially insured patients with chronic disease, few have examined beta-blocker effects in heart failure patients. OBJECTIVE: Associations between beta-blocker prescription copayment levels and medication nonadherence were examined within commercially insured beneficiaries with a diagnosis of heart failure. METHODS: Heart failure patients were identified as those with at least 1 inpatient claim or 2 outpatient claims with an associated International Classification of Diagnosis, 9th Edition (ICD-9) code of 428.x, in addition to those with at least 2 beta-blocker claims. Copayment levels were defined in using $5.00 (USD) interval categories, and adherence was defined using the medication possession ratio (MPR). Ordinary least squares (OLS), fixed effects (FE), and random effect (RE) models were used to estimate associations between copayment level and MPR. Logistic regression was used to estimate the probability of nonadherence (MPR < 0.80) conditional upon copayment level. Regressions controlled for patient demographics, health status, prior hospitalizations, and concomitant medication use. RESULTS: The highest beta-blocker copayment level ($26+) had an average MPR that was 0.07 (95% CI, -0.11 to -0.03), 0.08 (95% CI, 0.12 to -0.04), and 0.09 (95% CI, -0.17 to -0.02) units lower than beta-blocker copayment level ($0 to $1) in the OLS, RE, and FE models, respectively. Copayment levels $21-$25 and $26+ were significantly associated with an increased risk of medication nonadherence (OR = 1.64; 95% CI, 1.1-2.4; and OR = 2.5; 95%, CI 1.6-4, respectively). CONCLUSIONS: Commercially insured heart failure patients aged >=50 years who are prescribed higher costing beta-blockers may have up to an average 9% decrease in annual beta-blocker medication supply as well as an increased risk of nonadherence (MPR <0.80). Results need to be interpreted with caution given the potential of selection bias due to selective prescribing. Associations between copayment levels and nonadherence need to be further explored given the adverse health consequences of nonadherence to beta-blockers. PMID- 21665046 TI - Subjects at risk of discontinuation of lipid-lowering agents: a 6-month cohort study among 12,875 patients in a chinese population. AB - BACKGROUND: Dyslipidemia is a significant health problem, and persistent use of lipid-lowering agents among dyslipidemic patients is clinically important. However, few studies have evaluated the profiles of medication discontinuation among ethnic Chinese patients. OBJECTIVE: The objective of this study was to evaluate the level of medication adherence among Chinese patients who were prescribed a lipid-lowering drug and to investigate factors that could help physicians identify patients at risk for discontinuing their medication. METHODS: All patients who attended any primary care clinic in 1 territory of Hong Kong and were prescribed at least 1 lipid-lowering agent from January 2004 to June 2007 were included. The incidences of drug discontinuation within 180 days after drug prescriptions were measured, and the factors associated with discontinuation using binary logistic regression analyzes were evaluated. RESULTS: Of the 12,875 eligible patients, the majority were prescribed fibrates (54.4%) and statins (45.1%). Among the patients, 17.0% discontinued their medication. Older patients (adjusted odds ratio [aOR] = 0.72-0.79 for patients >50 years), male subjects (aOR = 0.87; 95% CI, 0.78-0.97; P = 0.009), fee payers (aOR = 0.88; 95% CI, 0.78 0.99; P = 0.029), attendees in family medicine specialist clinics (aOR = 0.82; 95% CI, 0.70-0.96; P = 0.013), residents in rural districts (aOR = 0.52; 95% CI, 0.44-0.60; P < 0.001), follow-up visitors (aOR = 0.60; 95% CI, 0.54-0.66; P < 0.001), patients with comorbidities (aOR = 0.39; 95% CI, 0.35-0.44; P < 0.001 for 1 comorbidity and aOR = 0.28; 95% CI, 0.25-0.33; P < 0.001 for at least 2 comorbidities), and persons who use fibrates (aOR = 0.56; 95% CI, 0.49-0.64; P < 0.001) were significantly less likely to discontinue their medication. CONCLUSIONS: The findings of these associated factors were new for ethnic Chinese patients. These findings could help physicians identify patients who had been prescribed a lipid-lowering agent who were at higher risk of discontinuing their medication. Their medication-taking behavior should be monitored more closely, and future studies should evaluate the reasons of drug discontinuation. PMID- 21665047 TI - Comparison of the pharmacokinetics of a new 15-mg modified-release tablet formulation of metoclopramide versus a 10-mg immediate-release tablet: a single- and multiple-dose, randomized, open-label, parallel-group study in healthy Mexican male volunteers. AB - BACKGROUND: Metoclopramide is a prokinetic and antiemetic agent. OBJECTIVE: The goal of this study was to assess the pharmacokinetics of a new, modified-release metoclopramide tablet and compare it with an immediate-release tablet to obtain marketing approval from the Mexican regulatory agency. METHODS: This was a single center, randomized, open-label, parallel-group, single- and multiple-dose, pharmacokinetic study. Investigational products were administered to healthy Mexican male volunteers for 3 consecutive days: one 15-mg modified-release tablet every 12 hours or one 10-mg immediate-release tablet every 8 hours. Multiple blood samples were collected after the first and last doses of metoclopramide over a 24-hour period. Plasma metoclopramide concentrations were determined by using a validated HPLC method. Safety and tolerability were assessed by measurement of vital signs, clinical evaluations, and spontaneous reports from study subjects. RESULTS: All 26 subjects were included in the analyses (mean [SD] age: 25 [6] years [range, 18-40 years]; body mass index, 23.44 [2.31] kg/m(2) [range, 18.26-27.49 kg/m2]). Peak plasma concentrations were lower (C(max), 33.13 [7.25] vs 46.04 [17.27] ng/mL after the first dose [P < 0.05]; C(max,ss), 48.60 [8.52] vs 75.23 [21.27] ng/mL after the last dose [P < 0.05]) and occurred later (P < 0.05) with the modified-release formulation. In terms of average plasma concentrations (C(avgtau), 20.98 [3.94] vs 23.38 [7.35] ng/mL after the first dose; C(avg,ss), 22.20 [5.64] vs 23.02 [7.77] ng/mL after the last dose), differences did not reach the level of statistical significance (P > 0.05). Four adverse events were reported in the test group (abdominal distention [n = 2], epigastric pain [n = 1], and somnolence [n = 1]), and 3 were reported in the reference group (epigastric pain [n = 1], diarrhea [n = 1], and hiccups [n = 1]). CONCLUSIONS: This study in a sample of selected healthy Mexican male volunteers suggests that the metoclopramide15-mg modified-release tablets have features compatible with the slow-release formulation (lower C(max) and longer T(max)) compared with immediate-release tablets. PMID- 21665049 TI - Effect of organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphism on the single- and multiple-dose pharmacokinetics of enalapril in healthy Chinese adult men. AB - BACKGROUND: Enalapril is an angiotensin-converting enzyme (ACE) inhibitor approved for the treatment of mild to severe hypertension and congestive heart failure. There is evidence that enalapril may be an organic anion-transporting polypeptide 1B1 (OATP1B1) substrate, suggesting that genetic polymorphisms of the OATP1B1 gene may play a role in causing the interindividual pharmacokinetic differences of this drug. OBJECTIVE: The purpose of this study was to investigate the functional significance of the OATP1B1 genetic polymorphism on the pharmacokinetics of enalapril and its active metabolite enalaprilat in healthy Chinese adult male participants. METHODS: This was a single-center, open-label, single- and multiple-dose study conducted in healthy Chinese male participants. Each participant received a single oral dose of 10 mg enalapril under fasting conditions, followed by enalapril 10 mg/d for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 24 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7; on day 7, samples were collected from 0 to 72 hours after drug administration. An HPLC-MS/MS method was used to determine plasma concentrations of enalapril and enalaprilat. A polymerase chain reaction technique was used for genotyping of 2 single nucleotide polymorphisms (SNPs) of the OATP1B1 gene: T521C and A388G. The pharmacokinetic parameters of enalapril and enalaprilat were then compared according to genotype groups, using 1-way ANOVA, except for T(max) in which the Mann-Whitney test or Kruskal-Wallis test was used. RESULTS: The study included 32 healthy Han Chinese male participants (age range, 18-28 years; weight range, 50.0-80.0 kg; height range,159-182.0 cm). Twenty-six were OATP1B1*15 noncarriers (homozygous for 521TT), the others were *15 carriers with at least one 521 T>C mutant allele. After single and multiple oral doses of 10 mg enalapril, plasma concentrations of enalapril in *15 noncarriers were lower than that in *15 carriers, with significant difference in area under the curve at steady state (AUC(ss)) between *15 noncarriers and *15 carriers (P = 0.048) in the multiple-dose phase. There were no significant differences in enalapril's AUC(0-24), C(max), or the ratio of the AUC(0-24h) in the single-dose study to the AUC(ss) (R(ac)) between the *15 carriers and noncarriers. In contrast to enalapril, the mean AUC(0-24h) and C(max) of enalaprilat in *15 noncarriers was significantly higher than those in *15 carriers (P = 0.040 and P = 0.027, respectively) in the single-dose phase. There were no significant differences in enalaprilat's AUC(ss) or C(maxss) between the 2 groups in the multiple-dose phase. For the 3 groups classified according to the effect of A388G variant in all subjects homozygous for 521T (TT), *1a/*1a, *1a/*1b, and *1b/*1b, no significant difference was found in AUC(0-24h), C(max), and T(max) of enalapril and enalaprilat. CONCLUSIONS: In this small population of healthy Chinese men, the OATP1B1*15 allele and T521C variant appeared to be an important determinant of the pharmacokinetics of enalapril. There were significant differences between the *15 carriers and noncarriers in enalapril's AUC(ss) and enalaprilat's AUC(0-24h), C(max), and R(ac). However, there were no significant differences in enalapril's AUC(0-24), C(max), or enalaprilat's AUC(ss), C(maxss) between the *15 carriers and noncarriers. PMID- 21665050 TI - Enterprise policy evaluation: is there a 'new' way of doing it? AB - Given that most economies are now in recession, policymakers are looking to small firms to act as engines of economic growth; this has led to a revived interest in the role of enterprise policy. The 'new' enterprise policy is systemic, promoting and shaping externalities and capabilities. At its core are R&D, innovation and education. It encapsulates a shift from direct intervention towards creating an enabling environment for small firms and entrepreneurship. At present there is a research lacuna regarding the evaluation of such policies. The aim of this paper is to fill this gap by making two key contributions. First, I demonstrate that traditional enterprise evaluation metrics are too narrow: they focus almost exclusively on private firm impacts, rather than broader societal impacts caused by the pervasive nature of 'new' enterprise policies. Second, I illustrate how logic models could be expanded to account for these broader impacts. PMID- 21665048 TI - Orally formulated artemisinin in healthy fasting Vietnamese male subjects: a randomized, four-sequence, open-label, pharmacokinetic crossover study. AB - BACKGROUND: Artemisinin derivatives are used in antimalarial drug combination therapy. Artemisinin and piperaquine have recently been proven to be prospective candidates for combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. OBJECTIVE: The goal of this study was to evaluate the relative bioavailability and to characterize the pharmacokinetic properties of a new micronized powder formulation of artemisinin against the previous standard Vietnamese formulation when administered as a single oral dose or in combination with piperaquine. METHODS: This was a single-center, randomized, 4-sequence, open label, crossover study conducted in 15 healthy male Vietnamese volunteers under fasting conditions with a washout period of 3 weeks between study visits. A single oral dose of 160 or 500 mg of artemisinin was administered alone or in combination with piperaquine. Potential adverse events were monitored daily by the clinician and by using laboratory test results. Frequent blood samples were drawn for 12 hours after dose. Artemisinin was quantified in plasma using LC MS/MS. Pharmacokinetic parameters were computed from the plasma concentration time profiles using a noncompartmental analysis method. RESULTS: Pharmacokinetic parameters T(max), C(max), AUC(0-infinity), V(d)/F, CL/F, and t(1/2) (mean [SD]) for the new formulation of artemisinin were 1.83 (0.88) hours, 178 (97) ng/mL, 504 (210) h * ng/mL, 1270 (780) L, 401 (260) L/h, and 2.21 (0.29) hours, respectively. The mean percentage of the test/reference formulation ratio for the logarithmically transformed values of C(max), AUC(0-last,) and AUC(0-infinity) were 121% (90% CI, 92.5-158), 122% (90% CI, 101-148), and 120% (90% CI, 98.0 146), respectively. CONCLUSIONS: This single-dose study found that the dose normalized C(max), AUC(0-last), and AUC(0-infinity) mean geometric differences between the test and reference formulations were relatively small (<40%) and will probably not have a clinical impact in the treatment of malaria infections. PMID- 21665051 TI - Targeting the worst-off for free health care: a process evaluation in Burkina Faso. AB - Effective mechanisms to exempt the indigent from user fees at health care facilities are rare in Africa. A State-led intervention (2004-2005) and two action research projects (2007-2010) were implemented in a health district in Burkina Faso to exempt the indigent from user fees. This article presents the results of the process evaluation of these three interventions. Individual and group interviews were organized with the key stakeholders (health staff, community members) to document the strengths and weaknesses of key components of the interventions (relevance and uptake of the intervention, worst-off selection and information, financial arrangements). Data was subjected to content analysis and thematic analysis. The results show that all three intervention processes can be improved. Community-based targeting was better accepted by the stakeholders than was the State-led intervention. The strengths of the community-based approach were in clearly defining the selection criteria, informing the waiver beneficiaries, using a participative process and using endogenous funding. A weakness was that using endogenous funding led to restrictive selection by the community. The community-based approach appears to be the most effective, but it needs to be improved and retested to generate more knowledge before scaling up. PMID- 21665052 TI - Optimizing an immersion ESL curriculum using analytic hierarchy process. AB - The main purpose of this study is to fill a substantial knowledge gap regarding reaching a uniform group decision in English curriculum design and planning. A comprehensive content-based course criterion model extracted from existing literature and expert opinions was developed. Analytical hierarchy process (AHP) was used to identify the relative importance of course criteria for the purpose of tailoring an optimal one-week immersion English as a second language (ESL) curriculum for elementary school students in a suburban county of Taiwan. The hierarchy model and AHP analysis utilized in the present study will be useful for resolving several important multi-criteria decision-making issues in planning and evaluating ESL programs. This study also offers valuable insights and provides a basis for further research in customizing ESL curriculum models for different student populations with distinct learning needs, goals, and socioeconomic backgrounds. PMID- 21665053 TI - Pd-Fe nanoparticles stabilized by chitosan derivatives for perchloroethene dechlorination. AB - A series of chitosan-stabilized Pd-NZVI (nano-zero-valent-iron) catalysts for dechlorination with variation in their composition and in the nature of the polymer has been prepared. The synthesis procedures and palladium and chitosan contents were optimized. It was demonstrated by the XPS method that Fe and Pd in Fe-Pd/chitosan samples exist in the metallic state. The positive shift of the binding energy as compared with the bulk metal shows that the iron metal in the surface layers exists as very small nanoparticles. The prepared materials were characterized also by the XAS method. The presence of O and N atoms in the first coordination shell of the central Fe atom in the Fe-Pd/chitosan samples certifies the binding of the Fe metal particles with the chitosan surface via OH and NH(2) groups. The samples are characterized by the high stability of the nanoparticles as compared to unstabilized Pd-NZVI. The materials were tested to evaluate their catalytic activity in the perchloroethene (PCE) dechlorination reaction. Some samples of chitosan-stabilized Pd-NZVI revealed a good performance in PCE degradation as compared to unstabilized Pd-NZVI. PMID- 21665054 TI - Lanthanum cobaltite perovskite supported onto mesoporous zirconium dioxide: nature of active sites of VOC oxidation. AB - Novel catalytic nano-sized materials based on LaCoO(x) perovskite nanoparticles incapsulated in the mesoporous matrix of zirconia were prepared, characterized by physicochemical methods and tested in complete methanol oxidation. LaCoO(x) nanoparticles were prepared inside the mesopores of ZrO(2) by decomposition of bimetallic La-Co glycine precursor complexes. The catalysts have been studied by diffuse-reflectance FTIR-spectroscopy using such probe molecules as CO, CD(3)CN and CDCl(3) to test low-coordinated metal ions. At low temperatures of decomposition of complexes (up to 400 degrees C), low-coordinated Co(3+) ions predominate in the LaCoO(x) nanoparticles, whereas basically Co(2+) ions are found upon increasing the decomposition temperature to 600 degrees C. The novel nano-sized perovskite catalysts exhibit a very high catalytic activity in the abatement of volatile organic compounds present in air, like methanol and light hydrocarbons. PMID- 21665055 TI - Need for unbiased computation of the moderate-intensity physical activity of youth in epidemiologic studies. PMID- 21665057 TI - Effects of healthcare reforms on coverage, access, and disparities: quasi experimental analysis of evidence from Massachusetts. AB - BACKGROUND: The 2010 Patient Protection and Affordable Care Act (PPACA) has been controversial. The potential impact of national healthcare reform may be considered using a similar set of state-level reforms including exchanges and a mandate, enacted in 2006 in Massachusetts. PURPOSE: To evaluate the effects of reforms on healthcare access, affordability, and disparities. DESIGN: Interrupted time series with comparison series. SETTING/PARTICIPANTS: Longitudinal survey data from 2002 to 2009 from the Behavioral Risk Factor Surveillance System including 178,040 nonelderly adults residing in Massachusetts, Vermont, New Hampshire, Rhode Island, and Connecticut. Analysis was conducted from January to August 2010. INTERVENTION: Massachusetts 2006 healthcare reform, which included an individual health insurance mandate. MAIN OUTCOME MEASURES: Being uninsured, having no personal doctor, and forgoing care because of cost, evaluated in Massachusetts and four comparison states before (2002-2005) and after (2007-2009) the healthcare reform. Effects on disparities defined by race, education, income, and employment also were assessed. RESULTS: Living in Massachusetts in 2009 was associated with a 7.6 percentage point (95% CI=3.9, 11.3) higher probability of being insured; 4.8 percentage point (-0.9, 10.6) lower probability of forgoing care because of cost; and a 6.6 percentage point (1.9, 11.3) higher probability of having a personal doctor, compared to expected levels in the absence of reform, defined by trends in control states and adjusting for socioeconomic factors. The effects of the reform on insurance coverage attenuated from 2008 to 2009. In a socioeconomically disadvantaged group, the reforms had a greater effect in improving outcomes on the absolute but not relative scale. CONCLUSIONS: Healthcare reforms in Massachusetts, which included a health insurance mandate, were associated with significant increases in insurance coverage and access. The absolute effects of the reform were greater for disadvantaged populations. This is important evidence to consider as debate over national healthcare reform continues. PMID- 21665058 TI - The effectiveness of the FLU-FOBT program in primary care a randomized trial. AB - BACKGROUND: The FLU-FOBT Program is an intervention in which nurses provide home fecal occult blood tests (FOBTs) to eligible patients during annual influenza vaccination (FLU) campaigns. The effectiveness of the FLU-FOBT Program when implemented during primary care visits has not been extensively studied. PURPOSE: The effectiveness of the FLU-FOBT Program was tested as adapted for use during primary care visits in community clinics serving multiethnic patients with low baseline colorectal cancer (CRC) screening rates. DESIGN: Randomized clinical trial. During intervention weeks, nurses routinely initiated the offering of FOBT to eligible patients who were given FLU (FLU-FOBT group). During control weeks, nurses provided FOBT with FLU only when ordered by the primary care clinician during usual care (FLU-only group). SETTING/PARTICIPANTS: The study was conducted in six community clinics in San Francisco. Participants were patients aged 50-75 years who received FLU during primary care visits during an 18-week intervention beginning on September 28, 2009. MAIN OUTCOME MEASURES: The primary outcome was the change in CRC screening rates in the FLU-FOBT group compared to the FLU-only group at the end of the study period, on March 30, 2010. Multivariate logistic regression analysis was used to determine predictors of becoming up-to-date with CRC screening. RESULTS: Data were analyzed in 2010. A total of 695 participants received FLU on FLU-FOBT dates, and 677 received FLU on FLU-only dates. The CRC screening rate increased from 32.5% to 45.5% (+13.0 percentage points) in the FLU FOBT group, and from 31.3% to 35.6% (+4.3 percentage points) in the FLU-only group (p=0.018 for change difference). For those due for CRC screening, the OR for completing CRC screening by the end of the measurement period was 2.22 (95% CI=1.24, 3.95) for the FLU-FOBT group compared to the FLU-only group. CONCLUSIONS: FLU-FOBT Program participants were twice as likely to complete CRC screening as those receiving usual care. The FLU-FOBT Program is a practical strategy to increase CRC screening in community clinics. TRIAL REGISTRATION #: NCT01211379. PMID- 21665059 TI - Support-person promotion of a smoking quitline: a randomized controlled trial. AB - BACKGROUND: Quitlines and other evidence-based cessation treatments are greatly underutilized by smokers, limiting their public health impact. Social support is correlated with successful cessation. Thus, efforts targeting the social network of smokers could be a potential avenue to promote quitline utilization. PURPOSE: This study examined the efficacy of an intervention for nonsmokers interested in helping a smoker (i.e., support people) to promote smoker utilization of the Minnesota QUITPLAN((r)) Helpline. Data were collected from 2007 to 2010, and analyses were conducted from 2010 to 2011. DESIGN: Two-group randomized design evaluating the support-person intervention (n=267) compared with a control condition (written materials, n=267). SETTING/PARTICIPANTS: Enrolled were 534 support people (91% female, 93% Caucasian) residing in Minnesota. INTERVENTION: Written materials plus three weekly telephone sessions lasting 10-30 minutes each. Based on Cohen's theory of social support, the intervention provided participants with information and skills needed to encourage their smoker to call the QUITPLAN Helpline. MAIN OUTCOME MEASURES: Participants completed the Support Provided Measure (SPM) by mail at baseline and Week 4 (end-of-treatment). Helpline intake staff documented smoker calls to the Helpline through 6 months of follow-up. RESULTS: The proportion of calls to the Helpline was significantly (p=0.012) greater for smokers linked to support people in the intervention group (16.1%, 43/267) than in the control group (8.6%, 23/267). The treatment effect remained significant after adjusting for support person residing with the smoker (OR=2.04, 95% CI=1.19, 3.49, p=0.010). Among support people randomly assigned to the intervention group, greater number of sessions completed was associated with increased smokers' calls to the Helpline (p=0.004). After adjusting for the baseline score, the M+/-SD SPM score at Week 4 was significantly higher for support people in the intervention group (16.4+/-3.3) than for those in the control group (15.3+/-3.6), p=0.002. CONCLUSIONS: A support-person intervention is effective in increasing smoker utilization of the QUITPLAN Helpline. There is potential for increasing the reach of quitlines by targeting the social network of smokers. TRIAL REGISTRATION #: NCT01311830. PMID- 21665060 TI - Pediatricians' and family physicians' weight-related care of children in the U.S. AB - BACKGROUND: Few national data exist to assess primary care physicians' (PCPs') clinical practices with regard to childhood obesity. PURPOSE: To survey pediatricians and family practice physicians regarding their assessment, counseling, and management of diet, physical activity, and weight status among pediatric patients in the primary care setting. METHODS: A nationally representative cross-sectional survey of pediatricians and family practice physicians sampled from the American Medical Association (AMA) Masterfile was conducted in 2008 and analyzed in 2010. Outcomes included physicians' self reported practice behaviors regarding assessments of pediatric patients' weight status, counseling of diet and physical activity, and referrals and follow-ups. RESULTS: Response rate excluding physicians listed as "no-contact" by the AMA was 73.7% among pediatricians and 66.9% among family physicians. Less than 50% of all PCPs assessed BMI percentiles regularly in children. Eighteen percent of all PCPs reported referring children for further evaluation or management. Fifty-eight percent of all PCPs reported never, rarely, or only sometimes tracking patients over time concerning weight or weight-related behaviors. Pediatricians were more likely than family physicians to assess weight status and provide behavioral counseling (p's<0.001). CONCLUSIONS: Active PCP participation in assessing or managing childhood obesity in the primary care setting appears low relative to the frequency of the problem in the U.S. Interventions to reduce the barriers to physician engagement in the assessment and management of healthy lifestyles are needed to prevent and control childhood obesity. PMID- 21665061 TI - U.S. primary care physicians' diet-, physical activity-, and weight-related care of adult patients. AB - BACKGROUND: Overweight and obesity are substantial problems in the U.S., but few national studies exist on primary care physicians' (PCPs') clinical practices regarding overweight and obesity. PURPOSE: To profile diet, physical activity, and weight control practice patterns of PCPs who treat adults. METHODS: A nationally representative survey of 1211 PCPs sampled from the American Medical Association's Masterfile was conducted in 2008 and analyzed in 2010. Outcomes included PCPs' assessment, counseling, referral, and follow-up of diet, physical activity, and weight control in adult patients with and without chronic disease and PCPs' use of pharmacologic treatments and surgical referrals for overweight and obesity. RESULTS: The survey response rate was 64.5%. Half of PCPs (49%) reported recording BMI regularly. Fewer than 50% reported always providing specific guidance on diet, physical activity, or weight control. Regardless of patients' chronic disease status, <10% of PCPs always referred patients for further evaluation/management and <22% reported always systematically tracking patients over time concerning weight or weight-related behaviors. Overall, PCPs were more likely to counsel on physical activity than on diet or weight control (p's<0.05). More than 70% of PCPs reported ever using pharmacologic treatments to treat overweight and 86% had referred for obesity-related surgery. CONCLUSIONS: PCPs' assessment and behavioral management of overweight and obesity in adults is at a low level relative to the magnitude of the problem in the U.S. Further research is needed to understand barriers to providing care and to improve physician engagement in tracking and managing healthy lifestyles in U.S. adults. PMID- 21665063 TI - Physical activity in 22 African countries: results from the World Health Organization STEPwise approach to chronic disease risk factor surveillance. AB - BACKGROUND: Baseline physical activity data are needed to effectively plan programs and policies to prevent noncommunicable diseases, but for many African countries these data are lacking. PURPOSE: To describe and compare levels and patterns of physical activity among adults across 22 African countries. METHODS: Data from 57,038 individuals from 22 countries (11 national and 11 subnational samples) that participated in the STEPwise approach to chronic disease risk factor surveillance (2003-2009) were analyzed in 2010. The validated Global Physical Activity Questionnaire (GPAQ) was used to assess days and duration of physical activity at work, for transport, and during leisure time in a typical week. RESULTS: Overall, 83.8% of men and 75.7% of women met WHO physical activity recommendations (at least 150 minutes of moderate activity per week or equivalent). Country prevalence ranged from 46.8% (Mali) to 96.0% (Mozambique). Physical activity, both at work and for transport, including walking, had large contributions to overall physical activity, while physical activity during leisure time was rare in the analyzed countries. CONCLUSIONS: Physical activity levels varied greatly across African countries and population subgroups. Leisure time activity was consistently low. These data will be useful to inform policymakers and to guide interventions to promote physical activity. PMID- 21665062 TI - The influence of neighborhood food stores on change in young girls' body mass index. AB - BACKGROUND: As the prevalence of childhood obesity has risen in past decades, more attention has been given to how the neighborhood food environment affects children's health outcomes. PURPOSE: This exploratory study examined the relationship between the presence of neighborhood food stores within a girl's neighborhood and 3-year risk of overweight/obesity and change in BMI, in girls aged 6 or 7 years at baseline. METHODS: A longitudinal analysis of participants in the Cohort Study of Young Girls' Nutrition, Environment and Transitions (CYGNET) was conducted from 2005 to 2008. Neighborhood food stores were identified from a commercial database and classified according to industry codes in 2006. Generalized linear and logistic models were used to examine how availability of food stores within 0.25-mile and 1.0-mile network buffers of a girl's residence were associated with BMI z-score change and risk of overweight or obesity, adjusting for baseline BMI/weight and family sociodemographic characteristics. Data were analyzed in 2010. RESULTS: Availability of convenience stores within a 0.25-mile network buffer of a girl's residence was associated with greater risk of overweight/obesity (OR=3.38, 95% CI=1.07, 10.68) and an increase in BMI z-score (beta=0.13, 95% CI=0.00, 0.25). Availability of produce vendors/farmer's markets within a 1.0-mile network buffer of a girl's residence was inversely associated with overweight/obesity (OR=0.22, 95% CI=0.05, 1.06). A significant trend was observed between availability of produce vendors/farmer's markets and lower risk of overweight/obesity after 3 years. CONCLUSIONS: Although food store inventories were not assessed and food store indices were not created, the availability of neighborhood food stores may affect a young girl's weight trajectory over time. PMID- 21665064 TI - The epidemiology of fatal occupational traumatic brain injury in the U.S. AB - BACKGROUND: Although traumatic brain injury (TBI) is one of the leading causes of death and disability in the U.S., work-related TBI has not been well documented. PURPOSE: The aim of this study was to describe the epidemiologic characteristics and temporal trends of fatal occupational TBI in the U.S between 2003 and 2008. METHODS: A cross-sectional analysis of the Census of Fatal Occupational Injury database was performed. Both the Occupational Injury and Illness Classification System nature of injury codes and body part codes were used to define TBIs. Fatality rates were calculated using denominators derived from the Current Population Survey. Fatality rates were compared among industries, cause of death, and demographics with rate ratios (RRs) and 95% CIs. Poisson regression was used to assess trends in fatality rates. Data were analyzed in 2009-2010. RESULTS: Nearly 7300 occupational TBI deaths occurred between 2003 and 2008, for an average fatality rate of 0.8 per 100,000 workers per year. The leading causes of occupational TBI death were as follows: motor vehicle (31%); falls (29%); assaults and violent acts (20%); and contact with objects/equipment (18%). Fatality rates were 15 times higher in men compared with women (RR=15, 95% CI=13.7, 16.3). Workers aged >=65 years experienced the highest TBI fatality rate of all age groups (2.5 per 100,000 per year). Construction, transportation, and agriculture/forestry/fishing industries recorded nearly half of all TBI fatalities (n=1828, n=825, n=761, respectively). Occupational TBI death rates declined 23% over the 6-year period (p<0.0001). CONCLUSIONS: This study provides the first national profile of fatal TBIs occurring in the U.S. workplace. Prevention efforts should be directed at those industries with the highest frequency and/or highest risk. The construction industry had the highest number of TBIs, and the agriculture, forestry, and fishing industry had the highest rates. Additionally, workers aged >65 years in all industries would be a good target for future prevention efforts. PMID- 21665065 TI - Ultraviolet B and incidence rates of leukemia worldwide. AB - BACKGROUND: Recent research has suggested a relationship between vitamin D deficiency and risk of leukemia. PURPOSE: Using data from the UN cancer database, GLOBOCAN, this study will determine whether a relationship exists for latitude and ultraviolet B (UVB) irradiance with incidence rates of leukemia in 175 countries. METHODS: Multiple regression was used to analyze the independent association between UVB and age-adjusted incidence rates of leukemia in 139 countries in 2002. This study controlled for dietary data on intake of energy from animal sources and per capita healthcare expenditures. The analyses were performed in 2009. RESULTS: People residing in the highest-latitude countries had the highest rates of leukemia in both men (R(2)=0.34, p<0.0001) and women (R(2)=0.24, p<0.0001). In men, UVB was independently inversely associated with leukemia incidence rates (p<=0.001), whereas animal energy consumption (p=0.02) and per capita healthcare expenditures (p<=0.0001) were independently positively associated (R(2) for model=0.61, p<=0.0001). In women, UVB adjusted for cloud cover was independently inversely associated with leukemia incidence rates (p<=0.01), whereas animal energy consumption (p<=0.05) and per capita healthcare expenditures (p=0.0002) were independently positively associated (R(2) for model=0.51, p<0.0001). CONCLUSIONS: Countries with low UVB had higher age adjusted incidence rates of leukemia. This suggests the possibility that low serum 25-hydroxyvitamin D status, because of lower levels of UVB, somehow might predict the development of leukemia. PMID- 21665066 TI - Impact of communication on preventive services among deaf American Sign Language users. AB - BACKGROUND: Deaf American Sign Language (ASL) users face communication and language barriers that limit healthcare communication with their providers. Prior research has not examined preventive services with ASL-skilled clinicians. PURPOSE: The goal of this study was to determine whether provider language concordance is associated with improved receipt of preventive services among deaf respondents. METHODS: This cross-sectional study included 89 deaf respondents aged 50-75 years from the Deaf Health Survey (2008), a Behavioral Risk Factor Surveillance System survey adapted for use with deaf ASL users. Association between the respondent's communication method with the provider (i.e., categorized as either concordant-doctor signs or discordant-other) and preventive services use was assessed using logistic regression adjusting for race, gender, income, health status, health insurance, and education. Analyses were conducted in 2010. RESULTS: Deaf respondents who reported having a concordant provider were more likely to report a greater number of preventive services (OR=3.42, 95% CI=1.31, 8.93, p=0.0122) when compared to deaf respondents who reported having a discordant provider even after adjusting for race, gender, income, health status, health insurance, and education. In unadjusted analyses, deaf respondents who reported having a concordant provider were more likely to receive an influenza vaccination in the past year (OR=4.55, p=0.016) when compared to respondents who had a discordant provider. CONCLUSIONS: Language-concordant patient-provider communication is associated with higher appropriate use of preventive services by deaf ASL users. PMID- 21665067 TI - Use of a new public bicycle share program in Montreal, Canada. AB - BACKGROUND: Cycling contributes to physical activity and health. Public bicycle share programs (PBSPs) increase population access to bicycles by deploying bicycles at docking stations throughout a city. Minimal research has systematically examined the prevalence and correlates of PBSP use. PURPOSE: To determine the prevalence and correlates of use of a new public bicycle share program called BIXI (name merges the word BIcycle and taXI) implemented in May 2009 in Montreal, Canada. METHODS: A total of 2502 adults were recruited to a telephone survey in autumn 2009 via random-digit dialing according to a stratified random sampling design. The prevalence of BIXI bicycle use was estimated. Multivariate logistic regression allowed for identification of correlates of use. Data analysis was conducted in spring and summer 2010. RESULTS: The unweighted mean age of respondents was 47.4 (SD=16.8) years and 61.4% were female. The weighted prevalence for use of BIXI bicycles at least once was 8.2%. Significant correlates of BIXI bicycle use were having a BIXI docking station within 250 m of home, being aged 18-24 years, being university educated, being on work leave, and using cycling as the primary mode of transportation to work. CONCLUSIONS: A newly implemented public bicycle share program attracts a substantial fraction of the population and is more likely to attract younger and more educated people who currently use cycling as a primary transportation mode. PMID- 21665068 TI - Differential effects of depression on smoking cessation in a diverse sample of smokers in treatment. AB - BACKGROUND: Recent cross-sectional evidence suggests that the effect of depression on smoking prevalence and quit ratios differs by race/ethnicity. PURPOSE: This study prospectively examined the main and interactive effects of race/ethnicity and depressive symptoms on smoking cessation during a specific quit attempt among smokers receiving cessation treatment. METHODS: Data from a longitudinal study of smokers in treatment were examined using continuation ratio logit modeling. Continuous abstinence across Weeks 1, 2, and 4 post-quit was the outcome variable. Data were collected between March 2005 and November 2007, and the current study analyses were conducted in April 2010. RESULTS: Depressive symptoms predicted significantly lower cessation rates for whites and African Americans. In contrast, among Latinos there was no relationship between depression and cessation. CONCLUSIONS: This research is the first to prospectively demonstrate a racially/ethnically differentiated effect of depressive symptoms on smoking cessation, and it has implications for targeted smoking-cessation treatments as it indicates that depression may not be a key treatment target for Latinos. PMID- 21665070 TI - Public health services and systems research: entering adolescence? PMID- 21665069 TI - A neighborhood wealth metric for use in health studies. AB - BACKGROUND: Measures of neighborhood deprivation used in health research are typically based on conventional area-based SES. PURPOSE: The aim of this study is to examine new data and measures of SES for use in health research. Specifically, assessed property values are introduced as a new individual-level metric of wealth and tested for their ability to substitute for conventional area-based SES as measures of neighborhood deprivation. METHODS: The analysis was conducted in 2010 using data from 1922 participants in the 2008-2009 survey of the Seattle Obesity Study (SOS). It compared the relative strength of the association between the individual-level neighborhood wealth metric (assessed property values) and area-level SES measures (including education, income, and percentage above poverty as single variables, and as the composite Singh index) on the binary outcome fair/poor general health status. Analyses were adjusted for gender, categoric age, race, employment status, home ownership, and household income. RESULTS: The neighborhood wealth measure was more predictive of fair/poor health status than area-level SES measures, calculated either as single variables or as indices (lower DIC measures for all models). The odds of having a fair/poor health status decreased by 0.85 (95% CI=0.77, 0.93) per $50,000 increase in neighborhood property values after adjusting for individual-level SES measures. CONCLUSIONS: The proposed individual-level metric of neighborhood wealth, if replicated in other areas, could replace area-based SES measures, thus simplifying analyses of contextual effects on health. PMID- 21665071 TI - Growth of a scientific community of practice public health services and systems research. AB - BACKGROUND: Public health services and systems research (PHSSR) is an emerging discipline that examines the organization, financing, and delivery of public health services. PURPOSE: The objective of this descriptive study is to provide insight into the discipline's growth by examining the researchers, practitioners, and policymakers who are engaged in PHSSR and their expertise, sources of funding, collaboration patterns, productivity, and challenges. METHODS: A 27-item online survey was conducted and analyzed in 2010. It targeted 2067 individuals who had participated in PHSSR groups, meetings, and events since 2004. The response rate was 41%. Descriptive statistics characterized demographics, expertise and mentoring, funding, publication, and collaboration. RESULTS: Half of the community members became involved in 2004 or after. More than 40% of the community collaborates in some form. Challenges include knowledge distribution, an agenda to secure ongoing funding, and translating research evidence to public health practice. CONCLUSIONS: A clear resource for the community is a nucleus of productive and engaged members who foster its growth. PMID- 21665072 TI - Mapping the multidisciplinary field of public health services and systems research. AB - CONTEXT: Public health services and systems research (PHSSR) is the field of study charged with evaluating the public health system. PHSSR currently lacks a clear identity integrating the many theories, approaches, and disciplines contributing to the field. EVIDENCE ACQUISITION: Experts in PHSSR were consulted to identify 11 key published PHSSR studies. With these articles as a starting point, a newly developed citation data collection system was used to collect a sample of 2986 documents connected to the key articles through citation linkages. Data were collected in October 2009. EVIDENCE SYNTHESIS: Citation network methods and latent position cluster modeling were used to examine the network of documents. A subset of 108 documents comprising the backbone of the network was identified through main-path analysis. Four unique clusters were identified within the main path. The core cluster consisted of older articles focused on local health department activities, partnerships, and effectiveness. The three non-core clusters focused on public health law, behavioral interventions, and national performance standards. Although all non-core clusters cited the core, there was little crosstalk among the non-core clusters, a pattern consistent with multidisciplinary fields. CONCLUSIONS: PHSSR appears to be a multidisciplinary field with research happening in silos across different research areas. Developing transdisciplinary research connections across PHSSR is necessary to meet national PHSSR goals. PMID- 21665073 TI - Evolution of coauthorship in public health services and systems research. AB - CONTEXT: Public health services and systems research (PHSSR) focuses on the structure, organization, and legal basis of domestic public health activities and their effect on population health. An accurate description of the field is needed to empower funding agencies and other stakeholders to coordinate PHSSR activities and to foster the development of the field. The purpose of the study is to characterize the emerging community of researchers engaged in PHSSR. This study (1) describes dynamics of this growing community and (2) identifies research themes, subgroups within the field, and collaboration among groups. EVIDENCE ACQUISITION: Coauthorship network visualization of selected research publications in the MEDLINE bibliographic database between 1988 and May 2010. EVIDENCE SYNTHESIS: PHSSR has emerged gradually with noticeable growth after 1994 and after 2004. The network of PHSSR research has a core-periphery structure. The core includes highly collaborative researchers focusing on topics pertaining directly to PHSSR, such as workforce, quality improvement and performance, law, and information infrastructure. The periphery consists of groups publishing either on general health services research topics or on epidemiologic and clinical topics. CONCLUSIONS: Although a nucleus group of productive and engaged individuals participate in PHSSR, most also publish broadly on health services research and population health. This trend suggests that this emerging field cannot yet support a singular focus on PHSSR. Lack of funding sources and defined career paths likely contribute to this pattern. An overview of collaboration in PHSSR is an important step in advancing a coordinated research agenda and attracting sustainable funding streams for this field. PMID- 21665075 TI - [Incidence of venous thromboembolism in men admitted to a pneumology unit for acute respiratory disease]. AB - BACKGROUND: Venous thromboembolism (VTE) is a major source of morbidity and mortality all over the world. It is one of the complications arising in a hospital environment. The main aim of this study is to estimate the incidence of VTE in respiratory inpatients. METHOD: The authors carried out a prospective study on acute respiratory disease inpatients. A medical analytical index card was used. An echo-venous Doppler of lower limbs was practiced on D1 and D10 of hospitalization. The Wells scored was used to estimate the clinical probability of the occurrence of VTE. RESULTS: Seven of 100 patients studied developed VTE (95% CI : 2-12%), four of which presented a pulmonary embolism. The patients with VTE are 60-years-old+/-11.67. The incidence of VTE includes 20% (95% CI : 12.2 27.8%) of the patients hospitalized for bronchial cancer, 7.14% (95% CI : 2.1 12.18) of the patients presenting pulmonary tuberculosis and 4.54% (95% CI : 0.46 8.62%) of the patients hospitalized for exacerbation of chronic obstructive pulmonary disease (COPD). The duration of hospitalization was prolonged for the treatment of VTE (21+/-4.41 days for these patients compared with 12+/-5 days in the absence of VTE (P<0.001)). The analysis of the various risk factors shows that a Performance Status>2 (P=0.005) and lung cancer (P=0.028) are the factors most incriminated in the occurrence of VTE. It is associated with a mortality of 2%. CONCLUSION: VTE is a reality which is necessary to prevent in respiratory inpatients in situations at risk, especially in patients with lung cancer and with a PS>2. PMID- 21665077 TI - [Comorbidities in COPD: a new challenge in clinical practice]. AB - Today it is a recognised fact that chronic obstructive pulmonary disease (COPD) is a real systemic disease that is respiratory-based. Recently, the focus has been on the importance of the comorbidities that are associated with COPD, such as all the cardiovascular diseases, lung cancer, diabetes, metabolic syndrome, peripheral muscular dysfunction, depression, anxiety, osteoporosis and anaemia, etc. These comorbidities constitute a new medical and therapeutic challenge with regard to COPD; their high frequency and considerable impact on the quality of life and the prognosis for survival of the patients make them a key element. The aims of this focus are to present the spectrum and prevalence of comorbidities in COPD, to obtain an objective view as to why and how these comorbidities should be systematically assessed and treated in patients, and subsequently to discuss the impact of this new data in clinical practice and in research. This recent data is another positive step in understanding the disease, optimising the diagnosis, and assessing and caring for COPD patients. PMID- 21665076 TI - [Flexible bronchoscopy as it is lived by the patient]. AB - INTRODUCTION: Flexible bronchoscopy is an indispensable complementary exam in respiratory medicine for both diagnosis of many pulmonary diseases and their treatment. Only a few studies in literature have been conducted to evaluate the safety and acceptability of this act. PATIENTS AND METHODS: Prospective, mono center, non-comparative study involving 120 patients who underwent a flexible bronchoscopy for diagnostic. RESULTS: During the study, flexible bronchoscopy has caused neither deaths nor major complications. However, minor incidents have been deplored: hemoptysis (13.3%), epistaxis (3.3%), desaturation less than 90% (4.2%), laryngospasm (3.3%) and vagal discomfort (1.7%). 56.7% of patients were anxious before the exam and 24% of patients preferred to have general anesthesia. The patients reported cough in 78.3% of cases, difficulty in breathing in 55% of cases and pain in 13.3% of cases. The occurrence of nausea, noted in 15.8% of cases, was correlated with the pathway of the bronchoscope (P=0.002). At the end of the endoscopy, 67.5% of patients agreed to repeat the examination, if necessary, under the same conditions. CONCLUSION: The results of our study confirm that many complications during a flexible bronchoscopy are rare and generally mild failing in life-threatening. However, the occurrence of discomfort (cough, pain, vomiting, dyspnea) or incidents (asphyxia, vagal discomfort, laryngeal spasm) are likely to alter patient comfort during the exam. PMID- 21665078 TI - [18-FDG PET-scan of intrathoracic gossypiboma during the monitoring of lung cancer]. AB - The 18-FDG PET-scan is today used to monitor patients operated for non small-cell lung cancer. The presence of an intrathoracic gossypiboma (or textiloma) can be responsible for intense enhancement in a PET-scan because of inflammatory phenomenon. The authors report the case of a patient who underwent surgery for lung cancer nine years ago, where a newly discovered intrathoracic mass with intensive enhancement on PET-scan, led to concern about a local recurrence in spite of the fine-needle transthoracic biopsy identifying textile fibers in the histological examination. PMID- 21665079 TI - [Unusual alveolar proteinosis]. AB - Pulmonary alveolar proteinosis (PAP), a rare infiltrative disease of unknown aetiology, is characterized by an accumulation of abnormal lung surfactant in the alveoli. The diagnosis is based on the results of the bronchoalveolar lavage (BAL) and sometimes on the lung biopsy. The authors report the case of a 49-year old woman who was hospitalized for chronic expectoration of the membranes. The chest X-ray revealed alveolar opacities in the lowest part of the right lung. The chest CT scan detected alveolar ground glass opacities with interlobular thickening involving the middle lobe. The BAL was opaque with periodic acid Schiff stain-positive acellular material. The anatomopathology analysis of the membranes concludes as to the presence of granular eosinophilic material and the absence of neoplasic cells or hydatidous membranes. The diagnosis of PAP was established. Since functional deterioration was not detected, therapy was based on physiotherapy alone. The evolution was favourable, with the disappearance of the symptomatology and the normalisation of the chest X-ray. This observation shows an unusual presentation of PAP based on membrane expectoration and unusual localized lesions. PMID- 21665080 TI - [Pleomorphic carcinoma of the lung: a case report]. AB - Pleomorphic carcinoma is a rare malignancy belonging to the family of nonsmall cell lung cancers. A 40-year-old man, a smoker, was hospitalized for thoracic pain and dry cough with a deteriorating general condition. The imaging showed a "drop ball" of both lungs. The pathological evidence was obtained by lung biopsy under scanographic control. The presence of supraclavicular and abdominal nodes classified the tumour as stage IV. The patient received six cycles of first-line chemotherapy associating cisplatin and vinorelbine. However, the disease continued to progress and distant metastases were observed. The patient died 6 months after the diagnosis. Pleomorphic carcinoma is identified by purely histological criteria: the concomitant presence of malignant epithelial and homologous sarcomatoid spindle-cell components. Like the other nonsmall cell lung cancers, the treatment is primarily surgical, and the invasive nature of this tumour makes it very difficult. Pleomorphic carcinoma has a poorer prognosis than conventional nonsmall cell lung cancers despite surgery, irradiation and chemotherapy, because relapse occurs early. PMID- 21665081 TI - [Clonal eosinophilia revealed by recurrent Staphylococcus aureus infection]. AB - Acquired eosinophilia is currently classified into secondary (reactional to underlying diseases), clonal (presence of a bone marrow histological, cytogenetic or molecular marker of a myeloid malignancy) and idiopathic (neither secondary nor clonal) categories. We report the case of a 47-year-old male who was admitted to the hospital for Staphylococcus aureus recurring infections. An hypereosinophilia was discovered and led to molecular analysis. The identification of FIP1L1-PDGFRA fusion gene permitted the diagnostic of clonal eosinophilia. Treatment by imatinib mesylate induced an haematological remission, the control of the infection and thoracotomy cicatrization. This case is original because of its infectious presentation and the efficacy of imatinib mesylate to control the infectious process. PMID- 21665082 TI - [Contribution of the surgical treatment of drug-resistant tuberculosis during medical follow-up (experience of the pneumology department of the CHU of Cocody, in connection with five observations)]. AB - Multidrug resistance is defined as a resistance to two major antituberculosis drugs, which are isoniazid and rifampicin. The aim of the study was to specify the place of the thoracic surgery during the medical follow-up of the TB-MDR. Five files were kept over six years during this retrospective study. On the clinical and radiological level, localised lesions and a negative HIV serology were noted in the five patients. The completion date of the surgery varied between the third month and the 22nd after the beginning of the medical treatment. This delay in carrying out the surgery was encouraged by the social conditions of the patients. Three series of expectoration culture post-surgery were all negative. After surgery, the medical treatment was drawn out over six and 12 months depending on the clinical condition of the patient. No recurrence was observed. Only one patient died one year after the surgery from hemoptysis in relation to pulmonary sequelae. PMID- 21665083 TI - [Six cases of pulmonary MALT lymphoma: a heterogeneous therapeutic management]. AB - Pulmonary mucosa-associated lymphoid tissue lymphomas (PMALT) account for around 1% of lymphomas. Clinical and radiological presentations, and the treatment of six PMALT were collected from 1993 to 2008. All patients received chemotherapy before disease progression. Two patients had a lobectomy and one received thoracic radiotherapy. In 2008, all the patients were alive and three were in remission. A "watch and wait" strategy is widely accepted for stable, asymptomatic patients and patients with low tumour mass. Surgery may be proposed for symptomatic patients who have localised PMALT. When a chemotherapy treatment is to be suggested, chlorambucil-based chemotherapy is preferred. There may be room for rituximab alone or in combination, but this remains to be precisely defined. Several larger studies are currently ongoing to assess the role of monoclonal antibodies and chemotherapy in MALT lymphomas. Subgroup analysis should help us to define the optimal treatment for PMALT. PMID- 21665084 TI - [Unusual pulmonary tumour]. PMID- 21665085 TI - [Fast worsening of a solitary fibrous tumor of the pleura watched over 10 years]. PMID- 21665086 TI - RNA Nanotechnology: methods for synthesis, conjugation, assembly and application of RNA nanoparticles. PMID- 21665087 TI - MRI of cartilage. PMID- 21665088 TI - MRI appearance of normal articular cartilage. AB - At each joint, the extracellular matrix of cartilage is arranged in a complex and characteristic organization that is specific for that joint. This structure exerts a strong influence on the appearance of magnetic resonance (MR) images through orientation-related alterations in T2 decay. As a result, the MR appearance of cartilage at each joint is predictable and specific for that joint. The diagnostic utility of MR imaging for evaluating cartilage is enhanced when the acquisition and review of the images is informed by an understanding of this relationship between normal structure and the MR appearance of cartilage. PMID- 21665089 TI - Morphologic imaging of articular cartilage. AB - Magnetic resonance (MR) imaging plays an integral role in the assessment of articular cartilage. This article discusses the role of MR imaging in the evaluation of articular cartilage, the appearance of cartilage lesions on MR imaging, and the currently available MR imaging techniques for evaluating cartilage morphology. A limitation of currently available sequences is their inability to consistently detect superficial degenerative and posttraumatic cartilage lesions that may progress to more advanced osteoarthritis. In the future, improved image quality may allow for better evaluation of articular cartilage and earlier detection of cartilage lesions. PMID- 21665091 TI - Rapidly progressive osteoarthritis: biomechanical considerations. AB - An underlying hypothesis for rapid cartilage loss in patients with osteoarthritis (OA) is that perturbation from normal joint mechanics produces locally high biomechanical strains that exceed the material properties of the tissue, leading to rapid destruction. Several imaging findings are associated with focally high biomechanical forces and thus are potential candidates for predictive biomarkers of rapid OA progression. This article focuses on 3 aspects of knee biomechanics that have potential magnetic resonance imaging correlates, and which may serve as prognostic biomarkers: knee malalignment, meniscal dysfunction, and injury of the osteochondral unit. PMID- 21665092 TI - Magnetic resonance imaging in knee osteoarthritis research: semiquantitative and compositional assessment. AB - Semiquantitative assessment of the knee by expert magnetic resonance imaging readers is a powerful research tool for understanding the natural history of osteoarthritis (OA). Several reliable semiquantitative scoring systems have been applied to large observational cross-sectional and longitudinal epidemiologic studies and interventional clinical trials. Such evaluations have enabled understanding of the relevance of disease in structures within the knee joint to explain pain and progression of OA. Compositional imaging of cartilage has added to our ability to detect early degeneration before morphologic changes are present, which may help to prevent the permanent morphologic changes commonly seen in knee OA. PMID- 21665094 TI - MR imaging assessment of inflammatory, crystalline-induced, and infectious arthritides. AB - The role of magnetic resonance imaging in evaluating patients with inflammatory arthritides has evolved with the recent introduction of drugs capable of modifying disease activity and natural history. In conditions like rheumatoid arthritis, active synovitis and bone marrow inflammation precede and predict bone and cartilage erosion. These imaging findings identify patients who can be treated early and aggressively to prevent future morbidity. Similarly, in gout and other crystalline disorders, specific diagnosis aided by imaging may lead to earlier medical and surgical management. Infected joints need the most rapid identification to institute immediate therapy and prevent irreversible cartilage destruction. PMID- 21665095 TI - MR imaging of early hip joint degeneration. AB - MR imaging is one of the most commonly used imaging techniques to evaluate patients with hip pain. Intra-articular abnormalities of the hip joint are better assessed with recent advances in MR imaging technology, such as high-field strength scanners, improved coils, and more signal-to-noise ratio-efficient sequences. This article discusses the causes of early hip joint degeneration and the current use of morphologic and physiologic MR imaging techniques for evaluating the articular cartilage of the hip joint. The article also discusses the role of MR arthrography in clinical cartilage imaging. PMID- 21665093 TI - MR imaging assessment of articular cartilage repair procedures. AB - Because articular cartilage is avascular and has no intrinsic capacity to heal itself, physical damage to cartilage poses a serious clinical problem for orthopedic surgeons and rheumatologists. No medication exists to treat or reconstitute physical defects in articular cartilage, and pharmacotherapy is limited to pain control. Developments in the field of articular cartilage repair include microfracture, osteochondral autografting, osteochondral allografting, repair with synthetic resorbable plugs, and autologous chondrocyte implantation. MR imaging techniques have the potential to allow in vivo monitoring of the collagen and proteoglycan content of cartilage repair tissue and may provide useful additional metrics of cartilage repair tissue quality. PMID- 21665096 TI - MR imaging of the articular cartilage of the knee and ankle. AB - Cartilage abnormalities in the knee and ankle are a common source of pain and are often difficult to diagnose clinically or radiographically. MR imaging is a valuable tool for diagnosing and characterizing cartilage lesions of both the knee and ankle. An understanding of the appearance of cartilage, and an understanding of how and when to report cartilage injury in the knee and ankle based on current grading systems allows the radiologist to provide the most helpful reports to referring clinicians. This article presents the range of cartilage pathologies in the knee and ankle and provides clinically relevant guidelines. PMID- 21665097 TI - The current state of imaging the articular cartilage of the upper extremity. AB - MR imaging has increasingly been used to image joints since its inception. Historically, there has been more emphasis on the evaluation of internal derangement rather than cartilaginous disease. This article reviews cartilaginous diseases of the upper extremity emphasizing those that can be assessed using current clinical MR imaging protocols and addresses the limitations of current imaging techniques in evaluating the articular cartilage of smaller joints. It also provides a brief overview of novel techniques that may be instituted in the future to improve the diagnostic performance of MR imaging in the evaluation of the articular cartilage of the upper extremity. PMID- 21665090 TI - MR imaging of articular cartilage physiology. AB - The newer magnetic resonance (MR) imaging methods can give insights into the initiation, progression, and eventual treatment of osteoarthritis. Sodium imaging is specific for changes in proteoglycan (PG) content without the need for an exogenous contrast agent. T1rho imaging is sensitive to early PG depletion. Delayed gadolinium-enhanced MR imaging has high resolution and sensitivity. T2 mapping is straightforward and is sensitive to changes in collagen and water content. Ultrashort echo time MR imaging examines the osteochondral junction. Magnetization transfer provides improved contrast between cartilage and fluid. Diffusion-weighted imaging may be a valuable tool in postoperative imaging. PMID- 21665098 TI - Third International Fascia Research Congress 2012. PMID- 21665099 TI - Re: The Fall of the postural-structural-biomechanical model in manual therapy: exemplified by lower back pain. A response to reviewers and further thoughts. PMID- 21665100 TI - Re: Is a postural-structural-biomechanical model, within manual therapy, viable? A JBMT debate. PMID- 21665101 TI - Consideration of sleep dysfunction in rehabilitation. AB - The physiology of sleep is not completely understood but it is widely accepted that sleep is important to the human body in the recovery of metabolic and neurological processes. This paper summarizes the effects of sleep dysfunction on different systems and considers implications in the context of rehabilitation. When sleep is experimentally completely or partially curtailed important brain functions are impacted leading to psychological and neurological disturbances. Increased cortisol levels, reduction of glucose tolerance, and increased sympathetic nervous system activity have also been identified in healthy subjects under such conditions. Several studies show that 50-80% of patients with chronic pain suffer from sleep dysfunction. It has been suggested that on the one hand pain can cause sleep dysfunction and on the other hand that sleep dysfunction can aggravate pain. The physiologic mechanism behind this interaction is not completely clear; although most authors describe the relationship between pain and sleep dysfunction as aberrant processing of tactile-cutaneous sensory inputs at the meso-encephalic level and in the trigeminal nucleus both when asleep and awake. Decreased duration of sleep also increases heart rate, blood pressure and sympathetic activity magnifying the individual's response to stressful stimuli. Possible causal mechanisms for the established connection between short sleep cycles and coronary pathology include sympathetic nervous system hyperactivity, increased blood pressure increase or reduced glucose tolerance. Finally, sleep and fatigue have traditionally been linked. Fatigue can have a physical etiology but is also associated with depression. Sleep alterations are also considered an important risk factor for psychological dysfunction and also mental illness. However, despite the noted repercussions of sleep dysfunction, studies investigating interventions to improve sleep have been limited in number. Benefits of exercise programs on sleep habits have been controversial with some have finding positive effects, whereas others did not find any significant effect. It is possible that the dose or intensity of exercise programs may have an important influence in the outcomes. It is our opinion that based on the multi system repercussions of different sleep dysfunctions, evaluation of sleep habits should be considered fundamental in the context of rehabilitation and should be included as part of the clinical history of each patient attending physical therapy. PMID- 21665102 TI - Pandiculation: nature's way of maintaining the functional integrity of the myofascial system? AB - Pandiculation is the involuntary stretching of the soft tissues, which occurs in most animal species and is associated with transitions between cyclic biological behaviors, especially the sleep-wake rhythm (Walusinski, 2006). Yawning is considered a special case of pandiculation that affects the musculature of the mouth, respiratory system and upper spine (Baenninger, 1997). When, as often happens, yawning occurs simultaneously with pandiculation in other body regions (Bertolini and Gessa, 1981; Lehmann, 1979; Urba-Holmgren et al., 1977) the combined behavior is referred to as the stretch-yawning syndrome (SYS). SYS has been associated with the arousal function, as it seems to reset the central nervous system to the waking state after a period of sleep and prepare the animal to respond to environmental stimuli (Walusinski, 2006). This paper explores the hypothesis that the SYS might also have an auto-regulatory role regarding the locomotor system: to maintain the animal's ability to express coordinated and integrated movement by regularly restoring and resetting the structural and functional equilibrium of the myofascial system. It is now recognized that the myofascial system is integrative, linking body parts, as the force of a muscle is transmitted via the fascial structures well beyond the tendonous attachments of the muscle itself (Huijing and Jaspers, 2005). It is argued here that pandiculation might preserve the integrative role of the myofascial system by (a) developing and maintaining appropriate physiological fascial interconnections and (b) modulating the pre-stress state of the myofascial system by regularly activating the tonic musculature. The ideas presented here initially arose from clinical observations during the practice of a manual therapy called Muscular Repositioning (MR) (Bertolucci, 2008; Bertolucci and Kozasa, 2010a; Bertolucci, 2010b). These observations were supplemented by a review of the literature on the subject. A possible link between MR and SYS is presented: The neural reflexes characteristically evoked through MR are reminiscent of SYS, which both suggests that MR might stimulate parts of the SYS reaction, and also points to one of MR's possible mechanisms of action. PMID- 21665103 TI - The effects of the Bowen technique on hamstring flexibility over time: a randomised controlled trial. AB - The hamstring muscles are regularly implicated in recurrent injuries, movement dysfunction and low back pain. Links between limited flexibility and development of neuromusculoskeletal symptoms are frequently reported. The Bowen Technique is used to treat many conditions including lack of flexibility. The study set out to investigate the effect of the Bowen Technique on hamstring flexibility over time. An assessor-blind, prospective, randomised controlled trial was performed on 120 asymptomatic volunteers. Participants were randomly allocated into a control group or Bowen group. Three flexibility measurements occurred over one week, using an active knee extension test. The intervention group received a single Bowen treatment. A repeated measures univariate analysis of variance, across both groups for the three time periods, revealed significant within-subject and between-subject differences for the Bowen group. Continuing increases in flexibility levels were observed over one week. No significant change over time was noted for the control group. PMID- 21665104 TI - Breathing and temporomandibular joint disease. AB - Temporomandibular joint disease (TMD) refers to a collection of pain related conditions in the masticatory muscles and temporomandibular joint. Occlusal factors have been implicated in TMD pathogenesis, yet despite decades of research no causal relationship between occlusion and TMD has been found. The significance of psychosocial factors in both the assessment and the long-term management of patients with TMD is receiving increased recognition. The teaching of relaxation skills and coping strategies are effective, proven TMD therapies. The role of breathing re-education in temporomandibular joint (TMJ) disorders is rarely mentioned. A focus on breathing patterns and their disorders potentially explains how biomechanical factors associated with psychosocial influences might lead to pathophysiological changes within the TMJ as well as in the associated muscles. Attention to factors such as breathing and postural rehabilitation provides health professionals valuable, additional tools to help care for patients with TMD. PMID- 21665105 TI - The effect of close proximity holographic wristbands on human balance and limits of stability: a randomised, placebo-controlled trial. AB - The purpose of this study was to investigate the effect of holographic technology wristbands on human balance and stability performance. Forty-two individuals volunteered to participate in the study. A performance technology silicone wristband containing two holograms was utilised as the 'Device'. A 'placebo' performance technology silicone wristband was utilised where the two holograms were removed and replaced with two stainless steel discs to the same dimensions and weight as the Device. Each participant was randomly allocated into two different testing protocol groups: Protocol 1 (Device-baseline-placebo) and Protocol 2 (placebo-baseline-Device). One week following the initial testing, the Protocol 1 group was tested under the conditions of Protocol 2, and vice versa, so that all participants were taken through both protocols. Results indicated that there was no statistically significant mean change in balance performance brought about by either the placebo or the Device. Notably, the sample data indicated an overall decrease in balance and stability. However, these mean changes are still within the bounds of what would be expected assuming the Device had no overall effect. The findings of this study indicate that holographic technology wristbands have no effect on human balance and stability performance. PMID- 21665106 TI - A pilot study of the prevalence of leg pain among women with endometriosis. AB - Radiating leg pain is a common symptom presenting in manual therapy practices. Although this symptom has been reported as a complication of endometriosis, its prevalence and characteristics have not been studied. We surveyed members of a national endometriosis support group with endometriosis using a self administered, mailed questionnaire. The main outcome measures were the prevalence and characteristics of leg pain. Of 94 respondents, leg pain was reported by 48 women (51%), and was bilateral in 59% of these symptomatic women. The likelihood of experiencing leg pain was related to weight gain since age 18, age, and height. The most common treatments tried included exercise, over-the-counter medications, and massage therapy, all with variable results. These data support leg pain as a prevalent complication of endometriosis, and that the disease may affect multiple peripheral nerves. Manual therapists should remain aware to this possible etiology for radiating pain. PMID- 21665107 TI - Pain relief due to physiotherapy doesn't change the motor function of the shoulder. AB - OBJECTIVE: The purpose of this study is to evaluate the effect of different training methods in physiotherapy on pain relief and change in proprioception and kinesthesia of the shoulder. Further, the connections between pain relief and change in motor function of the shoulder will be investigated. DESIGN: Randomised trial. SETTING: Ambulatory care. PARTICIPANTS: Two groups of unspecific shoulder pain patients (group1 n = 12, group2 n = 10). One group (n = 8) of non symptomatic subjects. INTERVENTION: The first shoulder-pain group was trained using flexible foil, whilst flexible bands were used to train the patients in the second group. Training period was 12 weeks. MAIN OUTCOME MEASURES: Pain of the shoulder was evaluated through functional pain assessment (Constant-Murley score) before, halfway through and after intervention. Proprioceptive and kinaesthetic ability was measured by an active-active angle-replication test for the shoulder before and after intervention. The data of the shoulder patients was compared to the group of non-symptomatic subjects. RESULTS: Pain was reduced significantly in both groups (p < .05) whereas no changes were measured for the ability to replicate angles of the shoulder. CONCLUSION: This suggests that pain relief in the shoulder is not associated with enhancement of the investigated parameters in motor function. PMID- 21665108 TI - Effect of ischemic pressure using a Backnobber II device on discomfort associated with myofascial trigger points. AB - OBJECTIVE: The purpose of this study was to assess the effectiveness of ischemic pressure on myofascial trigger point (MTrP) sensitivity. DESIGN: Randomized, controlled study with the researcher assessing MTrP sensitivity blinded to the intervention. PARTICIPANTS: Twenty-eight people with two MTrPs in the upper back musculature. INTERVENTION: The sensitivity of two MTrPs in the upper back was assessed with a JTECH algometer. One of the two MTrPs was randomly selected for treatment with a Backnobber II, while the other served as a control. OUTCOME MEASURES: Pre- and post-test pressure-pain thresholds of the MTrPs RESULTS: There was a significant difference between the pre- and post-test sensitivities of the treated and non-treated MTrPs (p=0.04). CONCLUSIONS: The results of this study confirm that the protocol of six repetitions of 30-s ischemic compression with the Backnobber II rendered every other day for a week was effective in reducing MTrP irritability. PMID- 21665109 TI - The effect of rhythmic exercises on cognition and behaviour of maltreated children: a pilot study. AB - OBJECTIVES: This study assesses the effect of rhythmic exercises using Rhythmex((r)) program on the cognitive function and behaviour of maltreated children living in a group residential facility. METHOD: School age children (ages 6-9) participated in the study, one group of 23 children exercised with Rhythmex rhythmic exercise program for eight weeks, 2-3 times a week, for 5 min, while a second group of 14 children did not exercise. Both groups took the Visual Motor Integration (VMI) test pre- and post-intervention and social workers evaluated their behaviour on the Achenbach's Child Behaviour Checklist (CBCL) pre intervention and then 12 months later. RESULTS: Improvement of 12 months on average in the VMI scores from pre- to post-intervention among the exercise group participants was observed compared with the control group. Aggressive behaviour was significantly lower on the Achenbach's CBCL aggression subscale among the exercise group participants compared with the control group. CONCLUSION: Rhythmic exercises for 5 min, 2-3 times a week for 8 weeks appear to be effective in improving VMI scores and lowering aggressive behaviour among maltreated children when compared to children of the same age who did not participate in the rhythmic exercises program. PMID- 21665110 TI - The presence of physiological stress shielding in the degenerative cycle of musculoskeletal disorders. AB - The health of physiological tissue is governed by the continuous conversion of mechanical stimulus (stress) to bio-chemical response, a concept known as mechanical homeostasis. If this regulatory imperative becomes flawed, it may be detrimental, and consequently invoke or encourage the progression of various musculoskeletal disorders. This notion is corroborated by the quantification of altered function and irregular mechanical properties found within the articulations of such phenotypes as cerebral palsy. Although the divergence from healthy to irregular tissue behavior is likely multifactorial, the presence of imbalanced mechanical properties may promote the concept of physiological stress shielding. Extrapolating upon the stress shielding phenomenon may allow inferences to be drawn with respect to the pathomechanisms of progressive disorders. Further, recognition of this association may also provide a new platform from which to interpret the impact of conventional treatments aimed at such syndromes and, in turn, perhaps support new therapeutic avenues. PMID- 21665111 TI - Acute effects of Surya Namaskar on the cardiovascular & metabolic system. AB - With the recent rise in obesity awareness and the increased understanding of the importance of physical activity in promoting overall health, greater emphasis has been placed on improving physical fitness to enhance quality of life. Surya Namaskar, a component of Hatha Yoga, has been practiced by Asian Indians for hundreds of years and is often used in place of a typical fitness program. It consists of a series of postures (asanas) that are repeated 12 times per round. Only one published study has looked specifically at Surya Namaskar, measuring the energy cost of individual asanas (Sinha et al., 2004). However, practitioners typically perform several rounds of the asanas during a session. PURPOSE: To assess the cardiorespiratory and metabolic responses of four rounds of Surya Namaskar, a typical amount performed by practitioners, to determine its potential as a training and weight loss tool. METHODS: Six healthy Asian Indian men and women (18-22 years) who had trained in Surya Namaskar for over two years participated in the study. Testing was completed in a single session lasting about 30 min. To measure heart rate and oxygen consumption while performing the four rounds, participants were connected to a heart rate monitor and the Oxycon Mobile Metabolic System. RESULTS: Participants exercised at 80% of age-predicted maximal heart rate (HRmax) during Round 2, 84% during Round 3, and 90% during Round 4. Average intensity during the four rounds was 80% HRmax, sufficient to elicit a cardiorespiratory training effect. Oxygen consumption averaged 26 ml/kg/min during each round, resulting in an energy expenditure of 230 kcals during a 30 min session for a 60 kg individual. CONCLUSION: Regular practice of Surya Namaskar may maintain or improve cardiorespiratory fitness, as well as promote weight management. PMID- 21665112 TI - Immediate effect of electric point stimulation (TENS) in treating latent upper trapezius trigger points: a double blind randomised placebo-controlled trial. AB - OBJECTIVE: The purpose of this study was to investigate the immediate effect of electric point stimulation in treating latent upper trapezius trigger points compared to placebo. DESIGN: Double blind randomised placebo-controlled trial. SETTING: Anglo-European College of Chiropractic. PARTICIPANTS: Sixty participants with latent upper trapezius trigger points. INTERVENTIONS: Electric point stimulator type of TENS, or detuned (inactive) electric point stimulator type of TENS. MAIN OUTCOME MEASURES: The three outcome measures were pressure pain threshold at the trigger point, a numerical rating scale for pain elicited over the trigger point, and lateral cervical flexion to the side opposite the trigger point. RESULTS: On the outcome of pressure pain threshold the electric point stimulator group had a mean change of 0.49 (0.99) kg/cm(2), while the placebo group had a mean change of 0.45 (0.98) kg/cm(2) (t = 0.16, df = 58, p = 0.88). For change in pain over the trigger point, the electric point stimulator group had a mean decrease of 0.93 (0.87) points, while the placebo group had a mean decrease of 0.23 (0.97) points (t = 0.70, df = 58, p = 0.005). On the outcome of change in lateral cervical flexion the electric point stimulator group had a mean increase of 2.87 (4.55) degrees, while the placebo group had a mean increase of 1.99 (2.49) degrees (t = 0.92, df = 58, p = 0.36). CONCLUSION: Electric point stimulator type of TENS is superior to placebo only in reduction of pain for treating latent upper trapezius trigger points. PMID- 21665113 TI - Six weeks of aerobic dance exercise improves blood oxidative stress status and increases interleukin-2 in previously sedentary women. AB - This study evaluated the change in blood oxidative stress, blood interleukin-2, and physical performance following 6 weeks of moderate intensity and duration aerobic dance exercise in 24 sedentary women. Blood samples were collected at rest twice before (baseline) and after the 6-week intervention for analysis of protein hydroperoxide (PrOOH), malondialdehyde (MDA), total anti-oxidant capacity (TAC), and interleukin-2 (IL-2) levels. Maximal treadmill run time (Time(max)) and maximal oxygen consumption (VO(2max)) were also measured. All variables were statistically analyzed with a repeated measurement ANOVA and Tukey post hoc. No differences were noted in any variable during the baseline period (p > 0.05). After aerobic dance exercise, VO(2max), Time(max), TAC and IL-2 were significantly increased, whereas MDA levels were decreased significantly (p < 0.05). PrOOH did not change either between baseline measures or after exercise. It can be concluded that aerobic dance exercise at a moderate intensity and duration can improve physical fitness, decrease MDA, and increase TAC and IL-2 in previously sedentary women. PMID- 21665114 TI - The effect of cetylated fatty esters and physical therapy on myofascial pain syndrome of the neck. AB - Participants with Myofascial Pain Syndrome (MPS) of the neck were randomly assigned into 2 groups of the double-blinded study: topical cetylated fatty ester complex (CFEC) cream application plus physical therapy (CF-PT; n=37), and placebo cream application plus physical therapy (PL-PT; n=35). There were 3 visits during 4 weeks of treatment. Physical Therapy (PT), given twice/week, included Ischaemic Compression, Deep Pressure Trigger Point Massage and Myofascial Releases. Topical cream [CFEC cream (5.6%) and 1.5% menthol] or placebo cream [1.5% menthol, in a cream base] was applied twice/day. CF-PT provided the fastest and most effective study treatment modality. The addition of CFEC cream to PT resulted in statistically significant improvements, compared to PL-PT, for reduction of pain, neck disability and life quality indicators. Our results indicate that cetylated derivatives of fatty acids can effectively reduce pain and symptoms associated with neck MPS, when combined with physical therapy. PMID- 21665115 TI - Anatomy in 3D. PMID- 21665117 TI - Successful rehabilitation of a recreational endurance runner: initial validation for the Bunkie test. AB - This case report details the musculoskeletal evaluation and the successful rehabilitation of a 24-year-old female recreational distance runner who self referred to physical therapy with an acute bout of low back pain (LBP). Her LBP was provoked during each distance run. The patient's musculoskeletal evaluation revealed core weakness, especially on the left. A recently reported functional test, the Bunkie test, was administered as part of the physical evaluation. The scores from the Bunkie test correlated with other quantitative and qualitative findings. A therapeutic exercise program emphasizing core stabilization was prescribed. The patient was able to shortly return to running pain-free. PMID- 21665116 TI - Rhythmic stabilization versus conventional passive stretching to prevent injuries in indoor soccer athletes: a controlled clinical trial. AB - OBJECTIVE: Indoor soccer is a sport that exposes the athletes to muscle and joint lesions. The effect of rhythmic stabilization (RS) technique to prevent these kinds of lesions in indoor soccer athletes is largely unknown and its use in athletes is controversial. Nevertheless, empiric evidence suggests that RS might be effective to prevent lesions in indoor soccer athletes. A controlled clinical trial of efficacy was performed to test this hypothesis. METHODS: Athletes were randomly divided into two groups: a RS group (7 athletes) and passive stretching (PS) group (7 athletes). At the beginning and at the end of the experiment (after four months) all athletes were subjected to clinical evaluation. Assessments were performed by subjective pain intensity, clinical evaluation and measurements of the range of maximal lower limb flexion movement. RESULTS: Athletes of both groups had lower limb injuries during the four months. The athletes submitted to RS technique had fewer injuries than those subjected to the PS technique although the difference was not significant. CONCLUSIONS: Although no significant difference was found between RS and PS, a trend suggests RS may be more effective than PS to prevent muscular and ankle joint lesions in indoor soccer athletes, but more research is needed. PMID- 21665118 TI - Y exercises for correcting the most common faulty movement pattern of the shoulder/neck region. PMID- 21665119 TI - Transfusion medicine. PMID- 21665120 TI - The global burden of musculoskeletal conditions - why is it important? PMID- 21665121 TI - How to measure the impact of musculoskeletal conditions. AB - Musculoskeletal conditions are universally prevalent among all age and gender groups, across all socio-demographic strata of society. Their impact is pervasive yet this is not widely recognised at the level of health policy and priority. Musculoskeletal conditions are a diverse group of disorders with regard to pathophysiology but are linked anatomically and by their association with pain and impaired physical function; encompassing a spectrum of conditions, including inflammatory diseases such as rheumatoid arthritis or gout; age-related conditions such as osteoporosis and osteoarthritis; common conditions of unclear aetiology such as back pain and fibromyalgia; and those related to activity or injuries such as occupational musculoskeletal disorders, sports injuries or the consequences of falls and major trauma. The increasing number of older people and the changes in lifestyle throughout the world with increasing obesity and reduced physical activity mean that the burden on people and society will increase dramatically. The growing awareness of the burden increases the need for accurate measurement and assessment of the burden as well as measurement of the impact of any public health action. This chapter considers theoretical and practical issues relevant to measuring the buden of musculoskeltal conditions in populations, societies and individuals. PMID- 21665122 TI - Rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a complex disease that affects approximately 0.5% of the adult population worldwide, and occurs in 20-50 cases per 100 000 annually, mainly in women after their 40s. The onset of the disease has important diagnostic, prognostic and therapeutic implications and is yet to be defined. The distribution of the disease, in terms of both occurrence and clinical expression, has unclear geographical borders that may reflect differences in genetic admixture, environmental factors and socio-demographic determinants. Some diseases co-occur more frequently than expected with RA, as it is the case of cardiovascular disease, infections or lymphoma, but others in lower frequency than expected, such as cancer or schizophrenia. RA is associated with increased mortality rates compared with the general population in the majority of cohorts published, and the expected survival of RA patients is likely to decrease 3-10 years. As in the general population, the leading cause of death among patients with RA is cardiovascular disease, and deaths due to malignancy occur at a comparable incidence; however, patients with RA are at greater risk of mortality due to infection. Many genes have been implicated in the susceptibility of RA, all of which with a modest effect on isolation. Gene-environment interactions appear as the most plausible underlying cause of RA. Age, sex, smoking, shared epitope and others correlate with its RA. The most important determinants of prognosis in RA are the severity at presentation and the management of the disease, both of which are subject to inequalities. PMID- 21665123 TI - Seronegative spondyloarthritis. AB - Seronegative spondyloarthritis (SpA) is a group of inflammatory rheumatic diseases with common clinical and aetiological features, including axial and peripheral inflammatory arthritis, enthesitis, extra-articular manifestations and a close link to the presence of the human leucocyte antigen (HLA)-B27 epitope. Ankylosing spondylitis is the most common of the SpA diseases, with prevalence in the Caucasian population ranging between 0.15% and 1.8%, generally higher in populations with a higher background prevalence of HLA-B27 positivity. Incidence has been estimated between 0.49 (Japan) and 10 (Norway) per 100,000. The prevalence of psoriatic arthritis ranges from 0.02% to 0.2%, and the incidence in the normal population is 7.2 per 100,000 per year. In patients with existing psoriasis, the prevalence of psoriatic arthritis rises to 6-42%. The prevalence of reactive arthritis is dependent on the background incidence of gastrointestinal or genitourinary infections; incidence has been described as up to 30-40 per 100,000. SpA symptoms are present in up to 50% of patients with inflammatory bowel disease. PMID- 21665124 TI - Osteoarthritis. AB - Internationally, prevalence estimates for osteoarthritis show wide variability depending on the age and sex of the studied population, the method of case identification used, and the specificity of joint sites included. Currently, there is no generally agreed "gold standard" for identifying cases of osteoarthritis in epidemiologic studies. Despite this lack of standardisation, it is consistently demonstrated in population-based studies, worldwide, that osteoarthritis prevalence is positively associated with increasing age and that the greatest disease burden is attributable to involvement of the hip or knee joints. To estimate the true burden of osteoarthritis involving the hips or knees, comprehensive accounting of all associated morbidity is required. The identification of modifiable risk factors for disease incidence and progression is needed. PMID- 21665125 TI - The Epidemiology of low back pain. AB - Low back pain is an extremely common problem that most people experience at some point in their life. While substantial heterogeneity exists among low back pain epidemiological studies limiting the ability to compare and pool data, estimates of the 1 year incidence of a first-ever episode of low back pain range between 6.3% and 15.4%, while estimates of the 1 year incidence of any episode of low back pain range between 1.5% and 36%. In health facility- or clinic-based studies, episode remission at 1 year ranges from 54% to 90%; however, most studies do not indicate whether the episode was continuous between the baseline and follow-up time point(s). Most people who experience activity-limiting low back pain go on to have recurrent episodes. Estimates of recurrence at 1 year range from 24% to 80%. Given the variation in definitions of remission and recurrence, further population-based research is needed to assess the daily patterns of low back pain episodes over 1 year and longer. There is substantial information on low back pain prevalence and estimates of the point prevalence range from 1.0% to 58.1% (mean: 18.1%; median: 15.0%), and 1 year prevalence from 0.8% to 82.5% (mean: 38.1%; median: 37.4%). Due to the heterogeneity of the data, mean estimates need to be interpreted with caution. Many environmental and personal factors influence the onset and course of low back pain. Studies have found the incidence of low back pain is highest in the third decade, and overall prevalence increases with age until the 60-65 year age group and then gradually declines. Other commonly reported risk factors include low educational status, stress, anxiety, depression, job dissatisfaction, low levels of social support in the workplace and whole-body vibration. Low back pain has an enormous impact on individuals, families, communities, governments and businesses throughout the world. The Global Burden of Disease 2005 Study (GBD 2005) is currently making estimates of the global burden of low back pain in relation to impairment and activity limitation. Results will be available in 2011. Further research is needed to help us understand more about the broader outcomes and impacts from low back pain. PMID- 21665126 TI - The epidemiology of neck pain. AB - Neck pain is becoming increasingly common throughout the world. It has a considerable impact on individuals and their families, communities, health-care systems, and businesses. There is substantial heterogeneity between neck pain epidemiological studies, which makes it difficult to compare or pool data from different studies. The estimated 1 year incidence of neck pain from available studies ranges between 10.4% and 21.3% with a higher incidence noted in office and computer workers. While some studies report that between 33% and 65% of people have recovered from an episode of neck pain at 1 year, most cases run an episodic course over a person's lifetime and, thus, relapses are common. The overall prevalence of neck pain in the general population ranges between 0.4% and 86.8% (mean: 23.1%); point prevalence ranges from 0.4% to 41.5% (mean: 14.4%); and 1 year prevalence ranges from 4.8% to 79.5% (mean: 25.8%). Prevalence is generally higher in women, higher in high-income countries compared with low- and middle-income countries and higher in urban areas compared with rural areas. Many environmental and personal factors influence the onset and course of neck pain. Most studies indicate a higher incidence of neck pain among women and an increased risk of developing neck pain until the 35-49-year age group, after which the risk begins to decline. The Global Burden of Disease 2005 Study is currently making estimates of the global burden of neck pain in relation to impairment and activity limitation, and results will be available in 2011. PMID- 21665127 TI - Osteoporosis and fragility fractures. AB - The prevalence of osteoporosis is expected to increase with the ageing of the world's population. This article reviews the epidemiology, risk factors and health burden of osteoporosis. In the Global Burden of Disease (GBD) Study 2005, osteoporosis is studied as a risk factor for fracture by considering the bone mineral-density (BMD) measurement as the continuous exposure variable. We have performed a systematic review seeking population-based studies with BMD data measured by dual-X-ray absorptiometry (DXA). The femoral neck was selected as the unique location and all values were converted into Hologic((r)) to enable inclusion of worldwide data for analysis. Provisional results on mean BMD values for different world regions are shown in age breakdowns for males and females 50 years or over, as well as mean T-scores using the young, white, female reference of National Health and Nutrition Examination Survey (NHANES) III. Results show remarkable geographical differences and a time trend towards improvement of the BMD values in Asian and European populations. PMID- 21665128 TI - Epidemiology of gout: an update. AB - Gout is the most common inflammatory joint disease in men, characterised by formation of monosodium urate (MSU) crystals in the synovial fluid of joints and in other tissues. The epidemiology of gout provides us with the understanding of the disease distribution and its determinants. In an attempt to update the knowledge on the topic, more recent research reports on the descriptive epidemiology of gout are reviewed in this article. The review describes clinical characteristics and case definitions of gout, including the Rome and New York diagnosis criteria of gout, '1977 American Rheumatism Association (ARA) criteria' and the 10 key propositions of the European League Against Rheumatism (EULAR) recommendations. Gout incidence, prevalence, morbidity and mortality, geographical variation of the disease, relevant risk factors for both the occurrence and outcome of gout and trends of the disease over time are then described. Difficulties in obtaining the information and data reported are also discussed. PMID- 21665129 TI - Generalised musculoskeletal pain syndromes. AB - The study of the descriptive epidemiology of chronic widespread pain (CWP) in several countries is of interest, as the occurrence of this condition varies among different populations. However, reports of pain prevalence are not consensual: it is clear that chronic musculoskeletal pain is frequent all over the world, varying from 4.2% to 13.3%. The reasons for the prevalence differences in CWP might include genetic and/or environmental factors. Multifactorial aetiopathogenesis of CWP and fibromyalgia syndrome (FMS) certainly includes genetic susceptibility and environmental influences. The risk factors for the occurrence and maintenance of CWP/FMS include female gender, increasing age, family history of chronic pain, several causes of distress, obesity and poorest mental and/or physical status. On the other hand, risk factors that negatively influence the outcome of CWP/FMS are: high levels of psychological distress, presence of somatisation, presence of fatigue, poor sleep, higher number of painful sites and pain intensity, poorest mental status and functional capacity, presence of co-morbid conditions and highest number of primary-care consultations. Mild alcohol consumption and individualised social support seem to have a protective effect on the outcome of CWP/FMS. PMID- 21665130 TI - Systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is one of the most diverse autoimmune diseases as it may affect any organ in the body and display a broad spectrum of clinical and immunological manifestations. Epidemiological studies have identified marked differences in the prevalence and course of SLE between genders, and across different ages, races and geographic locations. Methodological differences between studies may account for some of the disparity seen. Additionally, some insights into possible environmental risk factors for SLE have also been provided. As this condition is relatively uncommon, multifactorial, and largely influenced by genetic predisposition, it is inherently difficult to confirm or exclude infectious or environmental contributors to its etiology. Movement of people between communities and defining specific exposures can also be problematic. Despite these limitations, ongoing observation of SLE cohorts in multiple countries and settings, along with large international cooperative efforts in recent years, have helped clarify the risks of SLE in various groups and have defined marked differences in the worldwide occurrence of the disease. PMID- 21665131 TI - Epidemiology of systemic sclerosis. AB - Systemic sclerosis (SSc) is a multisystem auto-immune disease. The two main subtypes of SSc (limited and diffuse) typically have differing courses and prognoses. New classification criteria have been proposed to identify SSc in the earliest stages, before skin involvement. Over the past three decades, there has been an apparent increase in the incidence of SSc to approximately 20 per million, possibly due to improved diagnosis. The most extensively studied environmental associations of SSc are organic solvents and silica but no single risk factor has emerged. Recent genetic studies have identified new susceptibility factors including human leucocyte antigen (HLA) haplotypes and polymorphisms in immune regulatory genes. Despite earlier disease recognition and effective treatment for some of its complications, SSc still carries a high mortality, particularly due to cardiorespiratory complications. Although some predictors of organ involvement and outcomes have been identified, novel biomarkers are greatly needed. Due to low disease prevalence, large multicentre research collaborations are required. PMID- 21665132 TI - Epidemiology of large-vessel vasculidities. AB - The systemic vasculitides are multisystem disorders characterised by the inflammation of blood vessels and tissue necrosis. Classified by the size of the vessels affected, the large vessel vasculitides include giant cell arteritis (GCA) and Takayasu's arteritis (TA). These are anatomically, epidemiologically and clinically distinct conditions. They are often associated with considerable morbidity and mortality. The classification of vasculitis has been an area of controversy for many years and current classification criteria remain suboptimal. Although intensive efforts are under way to improve them, a further understanding of the aetiology and pathogenesis of these diseases is required to develop more sensitive and specific diagnostic tests. These efforts, however, have been hampered by the low prevalence of these diseases. The establishment of national and international registries is encouraged to enhance valuable data collection. These are anatomically, epidemiologically and clinically distinct conditions. This article summarises the current classification systems for systemic vasculitis and their limitations. We also review the presently known epidemiology, risk factors and morbidity and mortality associated with GCA and TA. PMID- 21665133 TI - Ixabepilone: clinical role in metastatic breast cancer. AB - Ixabepilone has shown promising clinical data in metastatic breast cancer (MBC) and may be particularly valuable in patients showing progression after treatment with standard chemotherapy. This article reviews the developing clinical profile of ixabepilone in MBC. Unlike taxanes and anthracyclines, ixabepilone has low susceptibility to multiple mechanisms of tumor cell resistance and has activity against tumors resistant to taxanes and/or anthracyclines. In phase II studies, single-agent ixabepilone resulted in objective response rates ranging from 11.5% to 57% in patients who had locally advanced or metastatic breast cancer, including patients who were treated as first-line therapy or in resistant patients who had received multiple lines of previous treatment. In two large phase III studies in women who had locally advanced or MBC pretreated with or resistant to taxanes and/or anthracyclines, a combination of ixabepilone plus capecitabine was superior to capecitabine alone in terms of progression-free survival and response rates. The efficacy of ixabepilone has also been shown in subsets, including patients with poor prognosis, the first-line metastatic setting, and in triple-negative disease. Studies are underway to investigate this agent in combination with biologics. A recent three-arm study has shown the activity and tolerability of ixabepilone plus bevacizumab; however, comparative data are not yet available. The toxicity profile of ixabepilone is generally manageable and predictable. The most common adverse events associated with ixabepilone include peripheral neuropathy and neutropenia. Ixabepilone appears to offer a promising alternative chemotherapeutic agent for patients with MBC who progress on various taxanes, anthracyclines, and capecitabine. PMID- 21665134 TI - Hormonal therapy plus bevacizumab in postmenopausal patients who have hormone receptor-positive metastatic breast cancer: a phase II Trial of the Sarah Cannon Oncology Research Consortium. AB - PURPOSE: Preclinical models suggest that addition of anti-vascular endothelial growth factor therapy may improve the efficacy of anti-estrogens in hormone sensitive breast cancer. This phase II trial evaluated the feasibility and efficacy of bevacizumab added to either anastrozole or fulvestrant in the first line treatment of patients who have hormone receptor-positive metastatic breast cancer. METHODS: Women who had newly diagnosed metastatic hormone receptor positive breast cancer were eligible. Patients who had relapsed while receiving, or <= 12 months after receiving, adjuvant aromatase inhibitor therapy were treated with bevacizumab (10 mg/kg intravenously every 2 weeks) and fulvestrant (loading dose 500 mg intramuscularly [IM], then 250 mg IM 2 weeks later, then 250 mg IM every 4 weeks). All other patients received fulvestrant/bevacizumab or anastrozole (1 mg orally daily)/bevacizumab. Patients who were HER2-positive could also receive trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Patients were reevaluated after 8 weeks of therapy; responding or stable patients continued treatment until disease progression or unacceptable toxicity. RESULTS: Seventy-nine patients were enrolled (38 were administered anastrozole 41 fulvestrant). Median treatment duration was 8 months in the anastrozole group and 5.5 months in the fulvestrant group. Both regimens were efficacious: overall response rate and median progression-free survival for the entire group were 28% and 13.5 months, respectively. Both regimens were well-tolerated; toxicity was consistent with the known toxicity profiles of each single agent. CONCLUSION: Bevacizumab combined with either anastrozole or fulvestrant was feasible and active in the first-line treatment of patients who have hormone receptor-positive metastatic breast cancer. Phase III trials evaluating the efficacy of bevacizumab added to endocrine therapy are in progress. PMID- 21665135 TI - Human epidermal growth factor receptor 2-positive breast cancer relapsing post adjuvant trastuzumab: pattern of recurrence, treatment and outcome. AB - BACKGROUND: The purpose of this study is to evaluate the response to and benefit of first-line metastatic treatment (including re-exposure to trastuzumab) for patients relapsing after exposure to adjuvant trastuzumab (AT). PATIENTS AND METHODS: All HER2-positive breast cancer cases relapsing after exposure to AT at our institutions were identified. Clinico-pathologic details, pattern of relapse, and treatment in the metastatic setting were documented. Response to treatment and outcome were assessed. RESULTS: Twenty-nine relapses were recorded. The median time to relapse was 18.4 months from diagnosis, and 8.7 months from AT initiation. At a median time of observation of 9.9 months, 18 patients had progressed on first-line therapy. The median time-to-progression (TTP) was 8.6 months. Fifteen patients received trastuzumab as first-line treatment, with no statistical difference in TTP between this group and those not re-exposed to trastuzumab. TTP was not statistically different between those relapsing on or after AT. Overall survival was longer for those who relapsed after completion of 1 year of AT as well as those who received further trastuzumab at relapse; however, this did not reach statistical significance. CONCLUSION: Overall survival was longer in patients who relapse after completion of AT and who received further trastuzumab at progression. PMID- 21665137 TI - Reirradiation as a component of the multidisciplinary management of locally recurrent breast cancer. AB - BACKGROUND AND PURPOSE: Our intent was to review a modern multidisciplinary institutional experience involving reirradiation of the breast, chest wall, and lymphatics for locoregional recurrences of breast cancer and report toxicity and clinical outcomes. MATERIALS AND METHODS: Between 1995 and 2009, 12 locoregional recurrences were reirradiated in 8 patients. The mean dose of initial radiotherapy was 57.1 Gy (range, 50.4-60.6 Gy), and the mean dose of reirradiation was 46.7 Gy (range, 30-62.1 Gy). The second course of radiotherapy was delivered using daily radiotherapy to 5 recurrences, twice-daily radiotherapy to 5 recurrences (1 with mold brachytherapy boost), and a combination of once- and twice-daily radiotherapy to 2 recurrences. RESULTS: The median follow-up from time of completion of reirradiation was 30 months (range, 1.5-67 months). Local control was achieved in 7 of 8 patients and 11 of 12 recurrences. Regional control was achieved in 5 of 8 patients and 6 of 12 recurrences. Distant control was achieved in 5 of 8 patients. At time of analysis, 5 of 8 patients were alive. Median survival since reirradiation completion was 36 months (range, 4.5-47 months). Acute toxicity included grade 2 dermatitis in 4 patients, ipsilateral shoulder pain in 1 patient, and ipsilateral pleurisy in 1 patient. Late skin and soft tissue toxicity manifested as fibrosis in 4 patients, hyperpigmentation in 3 patients, and telangiectasia in 3 patients. Three patients reported lymphedema, 1 patient reporting chest wall pain and 1 patient with an ipsilateral rib fracture. CONCLUSIONS: Multidisciplinary management of locoregional recurrence of breast cancer using reirradiation is well tolerated as salvage treatment and provides durable locoregional control. PMID- 21665136 TI - Effects of Tai Chi Chuan on insulin and cytokine levels in a randomized controlled pilot study on breast cancer survivors. AB - BACKGROUND: Tai Chi Chuan (TCC) is an integrative medicine mind-body practice with a physical activity component that has positive effects on aerobic capacity, muscular strength, and quality of life among cancer survivors, similar to the effects elicited by other modes of moderate-intensity exercise. Inflammatory cytokines and insulin and insulin-related signaling molecules may contribute to weight gain and affect cancer recurrence rates and survival; exercise can curb cancer- and treatment-related weight gain, increase survival, and reduce levels of insulin and inflammatory cytokines. Despite knowing the beneficial effects of conventional exercise interventions on these mediators, little is known about the physiologic effects of TCC on these pathways in breast cancer survivors. METHODS: We assessed the effects of a 12-week, moderately intense, TCC intervention (n = 9) compared with a non-physical activity control (n = 10) consisting of psychosocial support therapy (PST), on levels of insulin, insulin-like growth factor (IGF)-1, insulin growth factor-like binding protein (IGFBP)-1, IGFBP-3, and cytokines interleukin (IL)-6, IL-2, and interferon (IFN)-gamma in breast cancer survivors. RESULTS: Levels of insulin are significantly different in TCC and PST groups; levels remained stable in the TCC group but increased in the PST control group (P = .099). Bivariate analysis revealed novel and significant correlations (all r > 0.45, all P <= .05) of both decreased fat mass and increased fat-free mass with increased IL-6 and decreased IL-2 levels. CONCLUSIONS: This pilot study shows that TCC may be associated with maintenance of insulin levels and changes in cytokine levels that may be important for maintenance of lean body mass in breast cancer survivors. PMID- 21665138 TI - Treatment persistence with monthly zoledronic acid is associated with lower risk and frequency of skeletal complications in patients with breast cancer and bone metastasis. AB - BACKGROUND: Zoledronic acid (ZA) reduces skeletal complications in breast cancer patients with bone metastases. This study explored relationships between ZA treatment persistence and patient outcomes. METHODS: Two thousand three hundred ninety-four female patients with breast cancer and bone metastasis were identified from the PharMetrics((r)) Integrated Database between January 2003 and October 2006. Of these women, 714 (29.7%) received ZA; the remainder received no intravenous (IV) bisphosphonate (untreated). ZA treatment persistence was measured from first treatment to the first treatment gap > 45 days. Treatment persistence was categorized as short (<= 90 days, n = 230), medium (91-180 days, n = 171), or long (> 180 days, n = 313). Relationships between ZA treatment and persistence on outcomes were assessed in regression models adjusted for age, comorbidities, and propensity to receive treatment. RESULTS: Compared with untreated patients, after multivariate adjustment, ZA-treated patients experienced a 25% lower rate of skeletal complications (P < .05), were at lower risk for skeletal complications or loss to follow-up (hazard ratio [HR] = 0.67; P < .001), and had 41% longer follow-up time (P < .001). The skeletal complication risk was lower in the long-persistence group than in the short-persistence group (HR = 0.576; P < .05). In patients with >= 1 skeletal complication, the long persistence group had 39% fewer skeletal complications than the short-persistence group (P < .01). The medium- and long-persistence groups had 40% and 139% longer follow-up than the short-persistence group (both P < .001). CONCLUSIONS: ZA treatment was associated with lower risk and frequency of skeletal complications and longer follow-up time. Greater persistence with ZA treatment was associated with better outcomes. PMID- 21665139 TI - Accelerated partial breast intensity-modulated radiotherapy in women who have prior breast augmentation. AB - PURPOSE: To examine the outcome of breast cancer patients who have prior breast augmentation treated with lumpectomy followed by accelerated partial breast external intensity-modulated radiotherapy (APBIMRT) with image-guided radiotherapy (IGRT). METHODS AND MATERIALS: Four patients with previous elective subpectoral breast augmentation were enrolled on this APBIMRT trial. These four patients were treated with 10 equal twice daily 3.85 Gy fractions over 5 consecutive days (total dose of 38.5 Gy) using APBIMRT and IGRT. Patients were assessed for pain and cosmetic outcome (physician and a patient self-assessment). RESULTS: At last follow-up, two patients reported an excellent cosmetic results (at 2 years and at 8 months, respectively), one reported good cosmetic results (at 2 years), and one reported poor cosmetic results (at 20 months). Physicians rated the cosmetic outcomes as excellent in two (CEL; at 2 years and 8 months, respectively), good in one (CEL; at 20 months) and excellent in one (KTH; at 2 years). Three patients reported no breast/chest wall pain (two at 2 years and one at 1 year) and the fourth reported mild pain (at 20 months). The mean percent volume of ipsilateral breast receiving 100%, 75%, 50%, and 25% of the prescribed dose was 7.28%, 17.55%, 24.33%, and 33.1%, respectively. The mean breast, planning target volume (PTV), and implant volumes were 399.88 cc, 43.55 cc, and 313.36 cc, respectively. The mean breast prosthesis/total volume (breast tissue plus prosthesis) ratio was 44.55%. The mean PTV/ipsilateral breast and PTV/total volume ratios were 11.1% and 6.1%, respectively. CONCLUSION: The results show that a regimen of APBIMRT with IGRT is possible in patients who have prior breast augmentation. PMID- 21665140 TI - Isolated sternal involvement in breast cancer: is it truly stage IV disease? AB - PURPOSE: There is no consensus regarding treatment for patients with breast cancer and isolated sternal involvement. Though classified as AJCC stage IV, this group of patients may have prolonged distant disease free survival. PATIENTS AND METHODS: Retrospective case series of 8 patients with isolated sternal recurrence. Information regarding age, menopausal status, hormonal receptor status, HER2 status, initial treatment, time to sternal recurrence, treatment of sternal involvement, and outcome was obtained. RESULTS: Median follow-up, 6 years. Seven of 8 diagnosed with metachronous sternal recurrence at a median of 3 years from initial breast cancer diagnosis, 1 with sternal involvement at initial diagnosis. Seven of 8 are alive, with one death from metastatic breast cancer 10 years after sternal recurrence. Six of 8 are without evidence of distant spread, 2 in continuous complete remission (CR) at 7 and 14 years from sternal recurrence. CONCLUSION: While a small cohort, the excellent survival of the group identifies this as a distinct subset of metastatic disease, requiring special treatment considerations. Isolated sternal involvement could represent direct local-regional extension rather than systemic spread. PMID- 21665141 TI - Oncogene-induced mitotic stress: p53 and pRb get mad too. AB - Oncogenic signaling frequently results in unscheduled overexpression of cell cycle proteins and replicative stress. In this issue of Cancer Cell, Schvartzman et al. show that inactivation of p53 or pRb induces Mad2, and the overexpression of this mitotic checkpoint protein is a necessary event during oncogene-induced mitotic stress. PMID- 21665142 TI - A lipid kinase cousin cooperates to promote cancer. AB - Phosphoinositide 3-kinases (PI3Ks) are considered promising drug targets in oncology. In this issue of Cancer Cell, Schmid et al. demonstrate that the PI3Kgamma isoform is required for inflammatory myeloid cells to traffic to tumors. Though tumor cells do not express PI3Kgamma, selective inhibition of this isoform suppresses tumor growth and angiogenesis. PMID- 21665143 TI - ROCK-driven actomyosin contractility induces tissue stiffness and tumor growth. AB - The tumor environment consists of tumor-associated cells, such as macrophages, fibroblasts, and extracellular matrix, and has an important impact on tumor progression. In this issue of Cancer Cell, Samuel et al. show that ROCK-driven actomyosin contractility increases tissue stiffness affecting epidermal homeostasis, as well as tumor growth and progression. PMID- 21665144 TI - Turning reciprocal feedback regulation into combination therapy. AB - Two recent Cancer Cell articles report the discovery of reciprocal feedback regulation between androgenic and PTEN loss/PI3K-AKT signaling in prostate cancer. Both studies link endocrine regulation with a common oncogenic pathway, which led to the development of a combination therapeutic approach with immediate application in prostate cancer. PMID- 21665145 TI - Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. AB - Multiple mechanisms have been proposed to explain how Rb and p53 tumor suppressor loss lead to chromosome instability (CIN). It was recently shown that Rb pathway inhibition causes overexpression of the mitotic checkpoint gene Mad2, but whether Mad2 overexpression is required to generate CIN in this context is unknown. Here, we show that CIN in cultured cells lacking Rb family proteins requires Mad2 upregulation and that this upregulation is also necessary for CIN and tumor progression in vivo. Mad2 is also repressed by p53 and its upregulation is required for CIN in a p53 mutant tumor model. These results demonstrate that Mad2 overexpression is a critical mediator of the CIN observed upon inactivation of two major tumor suppressor pathways. PMID- 21665147 TI - Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. AB - Pancreatic acinar cells of adult mice (>=P60) are resistant to transformation by some of the most robust oncogenic insults including expression of K-Ras oncogenes and loss of p16Ink4a/p19Arf or Trp53 tumor suppressors. Yet, these acinar cells yield pancreatic intraepithelial neoplasias (mPanIN) and ductal adenocarcinomas (mPDAC) if exposed to limited bouts of non-acute pancreatitis, providing they harbor K-Ras oncogenes. Pancreatitis contributes to tumor progression by abrogating the senescence barrier characteristic of low-grade mPanINs. Attenuation of pancreatitis-induced inflammation also accelerates tissue repair and thwarts mPanIN expansion. Patients with chronic pancreatitis display senescent PanINs, providing they have received antiinflammatory drugs. These results support the concept that antiinflammatory treatment of people diagnosed with pancreatitis may reduce their risk of developing PDAC. PMID- 21665146 TI - Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. AB - Tumor inflammation promotes angiogenesis, immunosuppression, and tumor growth, but the mechanisms controlling inflammatory cell recruitment to tumors are not well understood. We found that a range of chemoattractants activating G protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and Toll-like/IL-1 receptors (TLR/IL1Rs) unexpectedly initiate tumor inflammation by activating the PI3-kinase isoform p110gamma in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110gamma in a Ras/p101-dependent manner, RTKs and TLR/IL1Rs directly activate p110gamma in a Ras/p87-dependent manner. Once activated, p110gamma promotes inside-out activation of a single integrin, alpha4beta1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110gamma suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology. PMID- 21665148 TI - Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1(+) leukemia. AB - Imatinib has revolutionized the treatment of Bcr-Abl1(+) chronic myeloid leukemia (CML), but, in most patients, some leukemia cells persist despite continued therapy, while others become resistant. Here, we report that PlGF levels are elevated in CML and that PlGF produced by bone marrow stromal cells (BMSCs) aggravates disease severity. CML cells foster a soil for their own growth by inducing BMSCs to upregulate PlGF, which not only stimulates BM angiogenesis, but also promotes CML proliferation and metabolism, in part independently of Bcr-Abl1 signaling. Anti-PlGF treatment prolongs survival of imatinib-sensitive and resistant CML mice and adds to the anti-CML activity of imatinib. These results may warrant further investigation of the therapeutic potential of PlGF inhibition for (imatinib-resistant) CML. PMID- 21665149 TI - Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. AB - Small cell lung cancer (SCLC) is one of the most lethal human malignancies. To investigate the cellular origin(s) of this cancer, we assessed the effect of Trp53 and Rb1 inactivation in distinct cell types in the adult lung using adenoviral vectors that target Cre recombinase to Clara, neuroendocrine (NE), and alveolar type 2 (SPC-expressing) cells. Using these cell type-restricted Adeno Cre viruses, we show that loss of Trp53 and Rb1 can efficiently transform NE and SPC-expressing cells leading to SCLC, albeit SPC-expressing cells at a lesser efficiency. In contrast, Clara cells were largely resistant to transformation. The results indicate that although NE cells serve as the predominant cell of origin of SCLC a subset of SPC-expressing cells are also endowed with this ability. PMID- 21665150 TI - Impairment of cytoplasmic eIF6 activity restricts lymphomagenesis and tumor progression without affecting normal growth. AB - Eukaryotic Initiation Factor 6 (eIF6) controls translation by regulating 80S subunit formation. eIF6 is overexpressed in tumors. Here, we demonstrate that eIF6 inactivation delays tumorigenesis and reduces tumor growth in vivo. eIF6(+/ ) mice resist to Myc-induced lymphomagenesis and have prolonged tumor-free survival and reduced tumor growth. eIF6(+/-) mice are also protected by p53 loss. Myc-driven lymphomas contain PKCbetaII and phosphorylated eIF6; eIF6 is phosphorylated by tumor-derived PKCbetaII, but not by the eIF4F activator mTORC1. Mutation of PKCbetaII phosphosite of eIF6 reduces tumor growth. Thus, eIF6 is a rate-limiting controller of initiation of translation, able to affect tumorigenesis and tumor growth. Modulation of eIF6 activity, independent from eIF4F complex, may lead to a therapeutical avenue in tumor therapy. PMID- 21665151 TI - Actomyosin-mediated cellular tension drives increased tissue stiffness and beta catenin activation to induce epidermal hyperplasia and tumor growth. AB - Tumors and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen. beta-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters. PMID- 21665152 TI - PI3Kgamma mediates kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. AB - Angioproliferative tumors induced by the Kaposi's sarcoma-associated herpesvirus (KSHV) have been successfully treated with rapamycin, which provided direct evidence of the clinical activity of mTOR inhibitors in human malignancies. However, prolonged mTOR inhibition may raise concerns in immunocompromised patients, including AIDS-Kaposi's sarcoma (KS). Here, we explored whether KSHV oncogenes deploy cell type-specific signaling pathways activating mTOR, which could be exploited to halt KS development while minimizing immune suppressive effects. We found that PI3Kgamma, a PI3K isoform exhibiting restricted tissue distribution, is strictly required for signaling from the KSHV-encoded vGPCR oncogene to Akt/mTOR. Indeed, by using an endothelial-specific gene delivery system modeling KS development, we provide genetic and pharmacological evidence that PI3Kgamma may represent a suitable molecular target for therapeutic intervention in KS. PMID- 21665153 TI - Climate change and the Emergency Nurse Practitioner role. PMID- 21665154 TI - Caring assessment in the Swedish ambulance services relieves suffering and enables safe decisions. AB - This study has a health care science approach and explores pre-hospital emergency care with emphasis on assessment. Health care science is focused on the patient with the general aim to describe care that strengthens and supports health. Assessment in the ambulance services has not been explored earlier from this perspective, despite the emphasis on 'coming close' to the acute suffering patient. The aim of the study is to describe and analyse assessment in caring situations. Data was collected by participant observations. The major findings point out the importance of professional carers' recognition of the patient's lifeworld as an essential part of assessment. The carers' openness to the situation and to the patient's suffering and needs vary from being of minor interest to complete focus of the assessment. It seems that assessments that focus solely on a patient's medical condition can be an obstacle to a full understanding of the individual, and thereby the illness per se. A caring assessment based on an encounter and a dialogue between patient and carer, characterised by inviting the patient to participate, adds further dimensions to the objective data. Therefore, the inclusion of the patient perspective relieves suffering and enables more safe decisions. PMID- 21665155 TI - The ability of emergency nurses to detect simulated long bone fractures with portable ultrasound. AB - Fractures are a common emergency department (ED) diagnosis. Ultrasound is a useful tool to evaluate for the presence of long bone fractures and can be performed by minimally trained individuals. We examined the ability of ED nurses to sonographically detect long bone fractures using a recently described training model. The fracture model consisted of a turkey long bone within a firm gelatin matrix. Emergency nurses examined five fracture models with a portable ultrasound machine to determine the presence or absence of a fracture. Overall accuracy was compared via chi-square analysis to the ability of physicians to complete the same assessment. Thirty nurses sonographically assessed the models. An overall sensitivity of 98% (95% confidence interval: 92-99%) and specificity of 93% (95% confidence interval: 76-99%) was observed for the detection of a fractured model. No difference in fracture detection accuracy (p>0.05) was revealed compared to an evaluation by 30 ED physicians. While the clinical impact of this ability remains uncertain, future utilization of nursing ability to detect fractures by ultrasound may improve patient care in ways such as more efficient triaging of radiographs and the mobilization of resources for fracture reduction. PMID- 21665156 TI - Evaluating new roles within emergency care: a literature review. AB - INTRODUCTION: In recent years economic and political drivers have strongly influenced the development and introduction of new roles such as medical substitution roles within emergency care in the National Health Service (NHS) in the United Kingdom (UK). AIMS: The aims of this literature review were to establish the national and international evidence available which examine the scope of practice of emergency nurse practitioners, emergency care practitioners and extended scope physiotherapists; to establish the national and international evidence which explores patient satisfaction with non-medical roles in emergency care; to establish the national and international evidence which explores the acceptability of emergency nurse practitioner, emergency care practitioner and extended scope physiotherapists services from a healthcare professional perspective. METHODS: A search of the literature was undertaken using BNI, CINAHL plus, International Bibliography of the Social Sciences, MEDLINE and SPORTDiscus databases combined with searches of the Cochrane library collection, NICE and the grey literature. Critical assessment of the literature is presented. RESULTS: A high level of patient satisfaction was found with all the new roles. Interestingly the scope of practice of Emergency nurse practitioners appears to be most limited in the UK. Five major themes were identified from healthcare professionals' perceptions of these new roles. CONCLUSION: There is general agreement that non-medical roles help to reduce waiting times in emergency departments, as well as attracting a high level of patient satisfaction, confidence and acceptance of these roles. Several issues were identified which warrant further study; including the current UK evidence surrounding the limited scope of practice of these roles. PMID- 21665157 TI - Is alcohol more dangerous than heroin? The physical, social and financial costs of alcohol. AB - A recent paper claimed in its classification of harmful substances, that alcohol is more dangerous than heroin. This paper aims to weigh up some of the evidence in the literature on the physical, social and financial effects of alcohol and the associated disease burden. We will also explore alcohol within the context of emergency department (ED) presentations. Reasons for ED attendance can be overtly and directly alcohol related such as alcohol intoxication, assaults, injuries and falls and indirectly such as child neglect, psychological problems and chronic diseases. Alcohol is often viewed as an isolated incident or factor for ED presentations but there are data that refute this perception. In ED, the priority is to treat the patient and their primary complaint, however it may be appropriate to screen for alcohol use, give advice and potentially offer an intervention to the patient. With the recent UK and Australian guidelines on reducing health risks from drinking alcohol, the ED has the ability to play an active role in reducing the harmful effects of alcohol through screening, advising and undertaking intervention as appropriate. However this cannot be achieved in isolation but within the broader political and health policy framework. There is now a growing body of literature supporting the need to make alcohol less affordable, less easy to buy and reducing alcohol advertising. Although alcohol is a legal substance, this paper concludes that examining the wider effects in physical, social and financial terms, alcohol is more dangerous than heroin. It has become an endemic problem in society affecting the individual and the whole community. PMID- 21665158 TI - Meeting the needs of people with a learning disability in the emergency department. AB - Nurses in the emergency department will regularly encounter individuals with a learning disability in their day to day work. Admission to hospital and especially the emergency department can be very problematic for people with a learning disability. For a number of reasons the health, safety and welfare of this group of patients may be seriously compromised. An awareness of the risks associated with hospital care for these patients, along with an understanding of their specific needs, will help to minimise the potential for problems to occur. PMID- 21665159 TI - What every emergency nurse needs to know about aspirin: an update. AB - In 2005, we presented a manuscript about the use of aspirin (ASA) in the setting of the Emergency Department (ED). We now write to report recent developments in our understanding about ASA and individual responses to the medication. The phenomenon of aspirin resistance is explored. PMID- 21665160 TI - IENJ research review - April 2011:. PMID- 21665161 TI - Strategies to overcome cancer survivorship care barriers. PMID- 21665162 TI - Accuracy of ultrasound-guided and palpation-guided knee injections by an experienced and less-experienced injector using a superolateral approach: a cadaveric study. AB - OBJECTIVES: To evaluate the accuracy of ultrasound (US)-guided and palpation guided knee injections by an experienced and a less-experienced clinician with use of a superolateral approach. DESIGN: Single-blinded, prospective study. SETTING: Academic institution procedural skills laboratory. PARTICIPANTS: Twenty cadaveric knee specimens without trauma, surgery, or major deformity. INTERVENTION: US-guided and palpation-guided knee injections of colored liquid latex were performed in each specimen by an experienced and a less-experienced clinician with use of a superolateral approach. The order of injections was randomized. The specimens were subsequently dissected by a blinded investigator and assessed for accuracy. MAIN OUTCOMES: Accuracy was divided into 3 categories: (1) accurate (all of the injectate was within the joint), (2) partially accurate (some of the injectate was within the joint and some was within the periarticular tissues), and (3) inaccurate (none of the injectate was within the joint). The accuracy rates were calculated for each clinician and guidance method. RESULTS: US-guided knee injections that used a superolateral approach were 100% accurate for both clinicians. Palpation-guided knee injections that used a superolateral approach were significantly influenced by experience, with the less-experienced investigator demonstrating an accuracy rate of 55% (95% confidence interval = 34% 74%) and the more experienced investigator demonstrating an accuracy rate of 100% (95% confidence interval = 81%-100%). CONCLUSIONS: US-guided knee injections that use a superolateral approach are very accurate in a cadaveric model, whereas the accuracy of palpation-guided knee injections that use the same approach is variable and appears to be significantly influenced by clinician experience. These findings suggest that US guidance should be considered when one performs knee injections with a superolateral approach that require a high degree of accuracy. PMID- 21665163 TI - Baseline severity of upper limb hemiparesis influences the outcome of low frequency rTMS combined with intensive occupational therapy in patients who have had a stroke. AB - OBJECTIVE: To clarify whether the efficacy of combined low-frequency repetitive transcranial magnetic stimulation (rTMS) and intensive occupational therapy (OT) depends on baseline severity of upper limb hemiparesis after stroke. DESIGN: Retrospective comparative study. SETTING: Department of Rehabilitation Medicine at a university hospital. SUBJECTS: Fifty-two patients who had sustained a stroke and had upper limb hemiparesis (age: 57 +/- 13 years; time after onset: 50 +/- 33 months). Based on the Brunnstrom stage for hand-fingers at admission, patients were divided into a Stage 3 group (n = 13), a Stage 4 group (n = 20), and a Stage 5 group (n = 19). INTERVENTIONS: During a 15-day hospitalization, each patient underwent 22 sessions of 20-minute low-frequency rTMS that was applied to the non lesional hemisphere and 120 minutes of intensive OT (one-on-one training and self training). MAIN OUTCOME MEASURES: Motor function of the affected upper limb was evaluated with the Fugl-Meyer Assessment and the Wolf Motor Function Test (WMFT) on the days of admission and discharge. WMFT performance time data were log transformed. RESULTS: The Fugl-Meyer Assessment score increased significantly in all patients (from 40.2 +/- 12.2 to 43.4 +/- 11.8 points, P < .001), but the score increase was significantly larger in the Stage 4 group than in the other two groups (2.1 +/- 2.3 points in the Stage 3 group, 5.1 +/- 2.9 points in the Stage 4 group, and 2.3 +/- 1.8 points in the Stage 5 group, all P < .05). Similarly, the WMFT performance time decreased significantly in all patients (from 3.27 +/- 0.90 to 2.96 +/- 1.10, P < .001), but the difference in the extent of the decrease was significant between Stage 3 and Stage 4 groups and between Stage 3 and Stage 5 groups (0.04 +/- 0.07 in the Stage 3 group, 0.41 +/- 0.29 in the Stage 4 group, and 0.35 +/- 0.31 in the Stage 5 group, all P < .01). CONCLUSIONS: Our 15-day protocol of low-frequency rTMS and intensive OT is potentially promising in improving motor function of the affected upper limb. The extent of motor improvement by the intervention seemed to be influenced by the severity of upper limb hemiparesis at study entry. PMID- 21665164 TI - Characterization of injuries during hardcourt bike polo participation: a descriptive survey. AB - OBJECTIVE: To describe injury rates and patterns in the emerging sport of hardcourt bike polo (HBP). DESIGN: Descriptive survey. SETTING: HBP playing areas (urban flat concrete surfaces). PARTICIPANTS: Twenty-two adult (>=18 years) HBP players who presented to a routine thrice-weekly playing site completed the survey. MAIN OUTCOME MEASUREMENTS: Participants completed a survey that was used to evaluate demographics; frequency of play; rate, localization, and severity of injuries sustained in the past 1 year; and use of medical care. RESULTS: The incidence of sustaining an injury in 1 year was 0.86. The main sites of injury involved the knee, elbow, wrist, and hand. Medical attention was sought by 15% of the injured players. CONCLUSION: HBP is a rapidly evolving urban sport in which participants are at risk for trauma-related injury, some of which may be preventable by the addition of appropriate safety equipment. PMID- 21665165 TI - A new functional outcome assessment tool for military musculoskeletal rehabilitation: a pilot validation study. AB - OBJECTIVE: To examine the construct and concurrent validity of a new occupational military outcome measure (the Functional Activity Assessment [FAA]). DESIGN: A validation study. SETTING: British Defence rehabilitation facilities. PARTICIPANTS: A total of 141 service personnel who attended a musculoskeletal injury assessment clinic. METHODOLOGY: The association among the Short Form 36 (SF-36), Physical Workload Questionnaire, and the FAA was examined. Agreement and correlation with an actual medical category also was examined. MAIN OUTCOME MEASURES: FAA, SF-36 and Physical Workload Questionnaire scores. RESULTS: The FAA was significantly correlated with heavy physical workload and all SF-36 subscale and component scores, in line with predictions. The regression model retained 3 variables that accounted for 49% of the variation in FAA, most of which was accounted for by the role-physical subscale score of the SF-36. The FAA was well correlated with actual medical category. CONCLUSIONS: The FAA is a valid measure of physical health in relation to physical workload. PMID- 21665166 TI - Confirmatory factor analysis of the Patient Health Questionnaire-9: a study of the participants from the spinal cord injury model systems. AB - OBJECTIVE: To examine the factor structure of the Patient Health Questionnaire-9, a measure of depression, in persons with spinal cord injury (SCI). DESIGN: Cross sectional, confirmatory factor analytic study. SETTING: Community. PARTICIPANTS: Data for 7296 persons with an SCI who had sustained their injury at least 1 year prior to assessment and who had complete Patient Health Questionnaire-9 data collected at a follow-up interview were drawn from the National Spinal Cord Injury Statistical Center Database. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Factor structure of the Patient Health Questionnaire-9. RESULTS: Confirmatory factor analysis indicated a marginal fit for the single factor solution (root mean square error of approximation [RMSEA] = 0.086), whereas the solution with 5 somatic items and 4 nonsomatic items had the best fit (RMSEA = 0.054) among 2 factor models that used all 9 items. Of the models that used fewer than 9 items, the best fit was for the 6-item solution with 3 somatic items (sleep, appetite, and fatigue) and 3 nonsomatic items (feeling down, feeling bad about self, and suicidal ideation; RMSEA = 0.043). Similar results were found across the strata except for the Hispanic group (for whom no model fit well). CONCLUSIONS: Given the results of this analysis that support a 2-factor structure of the Patient Health Questionnaire-9 in persons with SCI, the next step in this line of research is to validate each of these dimensions against other ways of measuring depression. PMID- 21665167 TI - Comparison of self-reported knee injury and osteoarthritis outcome score to performance measures in patients after total knee arthroplasty. AB - OBJECTIVE: To characterize patient outcomes after total knee arthroplasty (TKA) by (1) examining changes in self-report measures (Knee Injury and Osteoarthritis Outcome Score [KOOS]) and performance measures over the first 6 months after TKA, (2) evaluating correlations between changes in KOOS self-report function (activities of daily living [ADL] subscale) and functional performance (6-minute walk [6MW]), and (3) exploring how changes in pain correlate with KOOS ADL and 6MW outcomes. DESIGN: Retrospective cohort evaluation. SETTING: Clinical research laboratory. PATIENTS (OR PARTICIPANTS): Thirty-nine patients scheduled for a unilateral, primary TKA for end-stage unilateral knee osteoarthritis. METHODS: Patients were evaluated 2 weeks before surgery and 1, 3, and 6 months after surgery. MAIN OUTCOME MEASUREMENTS: KOOS, 6MW, timed-up-and-go (TUG), and stair climbing tests (SCT), quadriceps strength. RESULTS: Three of 5 KOOS subscales significantly improved by 1 month after TKA. All 5 KOOS subscales significantly improved by 3 and 6 months after TKA. In contrast, performance measures (6MW, TUG, SCT, and quadriceps strength) all significantly declined from preoperative values by 1 month after TKA and significantly improved from preoperative values by 3 and 6 months after TKA; yet, improvements from preoperative values were not clinically meaningful. Pearson correlations between changes in the KOOS ADL subscale and 6MW from before surgery were not statistically significant at 1, 3, or 6 months after TKA. In addition, KOOS Pain was strongly correlated with KOOS ADL scores at all times, but KOOS Pain was not correlated with 6MW distance at any time. CONCLUSIONS: Patient self-report by using the KOOS did not reflect the magnitude of performance deficits present after surgery, especially 1 month after TKA. Self-report KOOS outcomes closely paralleled pain relief after surgery, whereas performance measures were not correlated with pain. These results emphasize the importance of including performance measures when tracking recovery after TKA as opposed to solely relying on self-reported measures. PMID- 21665168 TI - Iliotibial band syndrome: soft tissue and biomechanical factors in evaluation and treatment. AB - Muscle performance factors and altered loading mechanics have been linked to a variety of lower extremity musculoskeletal disorders. In this article, biomechanical risk factors associated with iliotibial band syndrome (ITBS) are described, and a strategy for incorporating these factors into the clinical evaluation of and treatment for that disorder is presented. Abnormal movement patterns in runners and cyclists with ITBS are discussed, and the pathophysiological characteristics of this syndrome are considered in light of prior and current studies in anatomy. Differential diagnoses and the use of imaging, medications, and injections in the treatment of ITBS are reviewed. The roles of hip muscle strength, kinematics, and kinetics are detailed, and the assessment and treatment of muscle performance factors are discussed, with emphasis on identifying and treating movement dysfunction. Various stages of rehabilitation, including strengthening progressions to reduce soft-tissue injury, are described in detail. ITBS is an extremely common orthopedic condition that presents with consistent dysfunctional patterns in muscle performance and movement deviation. Through careful assessment of lower quarter function, the clinician can properly identify individuals and initiate treatment. PMID- 21665169 TI - Understanding study design. PMID- 21665170 TI - Venous thromboembolism prophylaxis in the pediatric population. PMID- 21665171 TI - Acute inpatient rehabilitation after left ventricular assist device implantation for congestive heart failure. PMID- 21665172 TI - Focal spinal epidural lipomatosis after a single epidural steroid injection. PMID- 21665173 TI - Magnetic resonance imaging of the brain: are findings suggestive of amyotrophic lateral sclerosis of any diagnostic utility? PMID- 21665175 TI - Lumbar fractures more common in multiple myeloma. PMID- 21665176 TI - Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. AB - The study of cancer predisposition syndromes leads to identification and understanding of mutations in genes coding for proteins and cellular pathways leading to cancer development, as well as normal cell growth and death regulators. Many patients with cancer predisposition syndromes experience excess toxicity with standard therapeutic regimens and are at lifelong risk for development of additional cancers and must be followed closely; early diagnosis is crucial for appropriate management of these patients. This review describes specific leukemia-predisposing conditions, including the clinical and historical findings that should trigger testing for these syndromes, and discusses recent insights into the management of these disorders. Disorders are organized by mechanism: (1) DNA damage repair defects, including Fanconi anemia, ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome; (2) cell cycle and differentiation defects, such as neurofibromatosis type 1, Noonan and Noonan like syndromes, and severe congenital neutropenia; (3) the hereditary transcription factor syndromes familial platelet disorder with predisposition to myeloid malignancy and CEBPA deficiency; and (4) aneuploidy-associated leukemia predisposition, exemplified by Down syndrome. Identifying the specific mechanisms underlying these relatively rare conditions allows for better understanding of leukemogenesis and development of targeted therapies that benefit a much broader population than simply those with genetic predispositions to leukemia. PMID- 21665177 TI - Correlation of polypoid colorectal adenocarcinoma with pre-existing adenomatous polyps and KRAS mutation. AB - Cetuximab is an anti-epidermal growth factor receptor that helps effectively treat patients with advanced colorectal adenocarcinoma without KRAS activating mutations. KRAS mutations are associated with 16% to 50% of isolated villous adenomas and approximately 30% of colorectal cancer. Correlation between the gross and histological subset of colorectal adenocarcinoma with KRAS mutation is unknown. Archived surgical resection specimens of colorectal adenocarcinoma (n = 42) and villous adenoma (n = 9) were collected. The gross appearance and histopathological features of these lesions were thoroughly reviewed, including the presence of a pre-existing adenomatous polyp. DNA was extracted from formalin fixed, paraffin-embedded tissue sections and then subjected to TaqMan real-time polymerase chain reaction to detect the seven most common KRAS mutations. KRAS mutations were found in 13 of 42 cases (31%) of colorectal adenocarcinoma and 7 of 9 cases (78%) of villous adenoma. All 13 cases of colorectal carcinoma with a KRAS mutation showed a gross polypoid configuration, compared to no KRAS mutation in the colorectal carcinomas with ulcerative configuration. In addition, 13 of 17 of these cases (76%) had histological features of adenocarcinoma with a persistent preexisting adenomatous polyp with villous architecture. In summary, grossly polypoid colorectal adenocarcinomas with a persistent pre-existing adenomatous polyp with villous architecture are strongly associated with KRAS mutations. PMID- 21665178 TI - Expression of HOXB genes is significantly different in acute myeloid leukemia with a partial tandem duplication of MLL vs. a MLL translocation: a cross laboratory study. AB - In acute myeloid leukemia (AML), the mixed lineage leukemia (MLL) gene may be rearranged to generate a partial tandem duplication (PTD), or fused to partner genes through a chromosomal translocation (tMLL). In this study, we first explored the differentially expressed genes between MLL-PTD and tMLL using gene expression profiling of our cohort (15 MLL-PTD and 10 tMLL) and one published data set. The top 250 probes were chosen from each set, resulting in 29 common probes (21 unique genes) to both sets. The selected genes include four HOXB genes, HOXB2, B3, B5, and B6. The expression values of these HOXB genes significantly differ between MLL-PTD and tMLL cases. Clustering and classification analyses were thoroughly conducted to support our gene selection results. Second, as MLL-PTD, FLT3-ITD, and NPM1 mutations are identified in AML with normal karyotypes, we briefly studied their impact on the HOXB genes. Another contribution of this study is to demonstrate that using public data from other studies enriches samples for analysis and yields more conclusive results. PMID- 21665179 TI - Molecular characterization of a t(2;7) translocation linking CDK6 to the IGK locus in CD5(-) monoclonal B-cell lymphocytosis. AB - The term monoclonal B-cell lymphocytosis (MBL) is used to characterize individuals with a circulating population of clonal B-cells and no other features of a lymphoproliferative disorder. Although several recent studies have examined the molecular basis of this condition, the subgroup of MBL lacking CD5 expression has been largely overlooked. In this study, we sequenced a t(2;7) in a patient with persistent but non-progressing CD5(-) MBL. This revealed a breakpoint at 2p11.2 localized to the recombination signal sequence (RSS) of the immunoglobulin kappa (IGK) variable gene IGKV3-15, and a breakpoint at 7q21.2 located 520 base pairs (bp) upstream of the transcription start site of cyclin-dependent kinase 6 (CDK6 ). The 7q breakpoint showed perfect sequence homology to the immunoglobulin RSS heptamer, and was located within 3 bp of a t(2;7) junction previously characterized in splenic marginal zone lymphoma (SMZL). These findings highlight a genetic link between CD5(-) MBL and SMZL, and implicate the dysregulation of CDK6 in the emergence of this preclinical disorder. PMID- 21665180 TI - An insertion/deletion polymorphism in the 3' untranslated region of type I collagen a2 (COL1A2) is associated with susceptibility for hepatocellular carcinoma in a Chinese population. AB - Hepatocellular carcinoma (HCC) is one of the most common and severe diseases in the world. Besides the influence of environmental factors, such as viral infection, an increasing number of novel genetic components identified by genome wide association studies have been associated with predisposition to HCC. Thus, studies focusing on functional variants in these findings are indispensable. In the present study, based on in-silico analysis, we carried out a case-control study in a Chinese population (207 cases and 245 controls) to investigate the association between HCC susceptibility with a 7 base pair (bp) insertion/deletion polymorphism (rs3917) in the 3'UTR of COL1A2. Our results showed that the ins/del + del/del genotype had an odds ratio of 1.76 (95% C.I.=1.03-3.01; P=0.028) for developing HCC compared to the ins/ins genotype. Carriers for the "del" allele of rs3917 were associated with a 1.73-fold increased risk for HCC (95% C.I.=1.06 2.84; P(trend)=0.02). Computational modeling suggests that this polymorphism is located in the hsa-let-7 g potential target sequence in the COL1A2 3' untranslated region. Our data suggest that most likely, common genetic changes in COL1A2 may influence HCC risk, at least in part by let-7 g-mediated regulation, which is possibly involved in the pathogenesis of HCC. The replication of our studies in other populations will further strengthen our understanding of this association. PMID- 21665181 TI - The effect of TP53 codon 72 and RNASEL codon 462 polymorphisms on the development of cervical cancer in Argentine women. AB - Epidemiological evidence suggests that genetic factors, such as variants in cancer suppressor genes, may play an important role in the etiology of cervical carcinoma. TP53 is an outstanding cell cycle regulator, mutated in most human cancers, and RNASEL is thought to be involved in antiviral and apoptotic responses. To determine whether TP53 Arg72Pro and RNASEL Arg462Gln polymorphisms are associated with susceptibility to cervical cancer, a case-control study of 98 cancer patients and 123 healthy controls was conducted. Cervical samples were genotyped for both polymorphisms by pyrosequencing technology. The association between cervical cancer risk and the studied SNPs was evaluated by logistic regression, and potential gene-gene interactions were studied by Multifactor Dimensionality Reduction analysis. In the single-locus analysis, only the heterozygous TP53 Arg72Pro genotype was significantly associated with the risk of developing a cervical carcinoma, while the RNASEL polymorphism showed no association after age adjustment. In addition, the combination of both polymorphisms gives near-null information gain. Consequently, the effect provided by each single nucleotide polymorphism individually is considered higher than the effect resulting from the interaction between these two genes in cervical cancer risk. These results suggest that a heterozygous TP53 Arg72Pro genotype may contribute to cervical cancer susceptibility. PMID- 21665182 TI - Increased sperm aneuploidy in two male carriers of germline TP53 mutations. AB - Li-Fraumeni syndrome is a rare autosomal dominant cancer predisposition syndrome characterized by a broad spectrum of tumors. The disorder is caused by germline mutations in the TP53 gene. We studied chromosomes in the sperm of two male carriers of TP53 mutations. We observed increased sperm aneuploidy, mainly concerning the gonosomes when compared to four normal male controls. This observation may correlate with the involvement of the p53 protein in spermatogenesis, with its role in aneuploidy in cancer, and with the occurrence of two cases of Turner syndrome in families with germline TP53 mutations reported in the literature. PMID- 21665183 TI - Glioblastoma specimens with TP53 mutations do not show EGFRvIII amplification. PMID- 21665184 TI - Foreword: bisphosphonates. PMID- 21665185 TI - [Interest of coronary flow reserve of the LAD during dobutamine stress echocardiography]. AB - AIM OF THE STUDY: To assess the value of the coronary flow reserve (CFR) in the left anterior descending artery (LAD) during dobutamine stress echocardiography in the diagnosis of significant LAD stenosis (more than 70%). METHOD: Retrospective study of 81 patients with a positive stress echocardiography who underwent a coronarography. RESULTS: Measurement of coronary flow reserve was able in half echocardiographic exams. Medium Pic diastolic velocity was 0.33 m/s (SD 0.20), medium maximal diastolic velocity during stress was 0.62 m/s (SD 0.20), medium CFR was 2.25 (SD 0.65). In 50 patients LAD was not seen; in five of them LAD was occluded. The predictive positive value (PPV) of a low coronary flow reserve to detect LAD stenosis is 66.7% and the negative predictive value (NPV) is 65.4%. An abnormal anterior contraction during stress echo with a low reserve has a PPV of 75% for the diagnosis of significant IVA stenosis and a normal contraction during stress with normal coronary flow reserve means a NPV of 65%. We did not show a significant correlation between low coronary flow and abnormal contraction during stress echocardiography (kappa 0.51). CONCLUSION: Coronary flow reserve of LAD during stress echo is feasible but does not really improve exam performance to detect significant IVA stenosis. This measurement remains to be clear in coronary patients management. PMID- 21665186 TI - [Associated factors for sleep apnea in heart failure]. AB - OBJECTIVE: Genesis of sleep apnoea syndrome (SAS) in chronic heart failure (CHF) is not well known. The aim of our study was to find associated factors to SAS in heart failure (HF) and to look for differences between central sleep apnea (CSA) and obstructive sleep apnea (OSA). PATIENTS AND METHODS: We realised a cross sectional and retrospective study. Thirty patients with stable heart failure under medical optimal therapy were included. Polygraphy, echocardiography and cardiopulmonary exercise were systematically performed. RESULTS: Men were predominant (80%) in the group. Mean age, left ventricular ejection fraction (LVEF) were respectively 64.1+/-13.8years and 40+/-9.8%. SAS was present in 60% of patients (33.3% were classified as central sleep apnoea [CSA] and 26.7% as obstructive sleep apnoea [OSA]). Body mass index, blood pressure and left ventricular pressures estimated by the E/Ea ratio were significantly higher in the group with SAS (P<0.05) compared to the non SAS group. New York Heart Association class was significantly higher (P=0.04) and the predicted peak VO(2) was significantly lower in CSA patients compared to OSA patients. CONCLUSION: High left ventricular pressures estimated by the E/Ea are significantly associated with SAS in heart failure. CSA patients tend to have a worse functional state than OSA patients. PMID- 21665187 TI - [Malignant fascicular ventricular tachycardia degenerating into ventricular fibrillation in a patient with early repolarization syndrome]. AB - A 45-year-old man was hospitalized for syncope due to fascicular ventricular tachycardia degenerating into ventricular fibrillation (VF). The electrocardiogram showed an early repolarization syndrome. The arrhythmia was repetitive and disappeared after oral hydroquinidine. An implantable cardioverter defibrillator (ICD) was implanted; subsequently, the patient was arrhythmia free at 9 months follow-up. PMID- 21665188 TI - [Flaccid paraplegia revealing an adenoma of Conn: a case report]. AB - We report the case of Conn's adenoma in a 36-year-old woman, revealed by low extremities weakness. The patient had hypertension at 170/90 mmHg. Her initial potassium level was low i.e., 1.5 mmol/L. The diagnosis, confirmed by hormonal investigation, showed an elevation of plasma aldosterone and lower plasma renin activity. Abdominal MRI revealed a lesion in left adrenal gland, measuring 1.8 cm in diameter and taking contrast in periphery, compatible with an adrenal adenoma. The patient underwent a left laparoscopic adrenalectomy and microscopic examination confirmed the diagnosis. The postoperative course was uneventful with normalization of serum potassium level and blood pressure. PMID- 21665189 TI - The development of a tool to predict team performance. AB - The paper describes the development of a tool to predict quantitatively the success of a team when executing a process. The tool was developed for the UK defence industry, though it may be useful in other domains. It is expected to be used by systems engineers in initial stages of systems design, when concepts are still fluid, including the structure of the team(s) which are expected to be operators within the system. It enables answers to be calculated for questions such as "What happens if I reduce team size?" and "Can I reduce the qualifications necessary to execute this process and still achieve the required level of success?". The tool has undergone verification and validation; it predicts fairly well and shows promise. An unexpected finding is that the tool creates a good a priori argument for significant attention to Human Factors Integration in systems projects. The simulations show that if a systems project takes full account of human factors integration (selection, training, process design, interaction design, culture, etc.) then the likelihood of team success will be in excess of 0.95. As the project derogates from this state, the likelihood of team success will drop as low as 0.05. If the team has good internal communications and good individuals in key roles, the likelihood of success rises towards 0.25. Even with a team comprising the best individuals, p(success) will not be greater than 0.35. It is hoped that these results will be useful for human factors professionals involved in systems design. PMID- 21665190 TI - Air conditioner operation behaviour based on students' skin temperature in a classroom. AB - A total of 25 college students participated in a study to determine when they would use an air conditioner during a lecture in a university classroom. The ambient temperature and relative humidity were measured 75 cm above the floor every minute. Skin temperatures were measured every minute at seven points, according to the recommendation of Hardy and Dubois. The average clothing insulation value (CLO) of subjects was 0.53 +/- 0.07 CLO. The mean air velocity in the classroom was 0.13 +/- 0.028 m/s. When the subjects turned the air conditioner both on and off, the average ambient temperatures, relative humidity and mean skin temperatures were 27.4 and 23.7 degrees C (p = 0.000), 40.9 and 40.0% (p = 0.528) and 32.7 and 32.2 degrees C (p = 0.024), respectively. When the status of the air conditioner was changed, the differences of skin temperatures in core body parts (head, abdomen and thigh) were not statistically significant. However, in the extremities (mid-lower arm, hand, shin and instep), the differences were statistically significant. Subjects preferred a fluctuating environment to a constant temperature condition. We found that a changing environment does not affect classroom study. PMID- 21665191 TI - A talking control for use in evaluating the effectiveness of cognitive-behavioral therapy. AB - OBJECTIVE: Common factors predict outcome in psychotherapy, but there is a dearth of research defining and standardising control conditions. A description and evaluation of a talking control (TC) used in a randomized controlled trial (RCT) of cognitive-behavioral therapy (CBT) for older people with depression in primary care is presented. METHODS: Two hundred and four older people participated in a RCT of CBT for people with a Geriatric Mental State diagnosis of Depression (Serfaty et al., 2009). One in 10 session of CBT or TC were evaluated using the Cognitive Therapy Scale (CTS) to examine common and specific factors in therapy. RESULTS: 1005 therapy sessions were delivered; 508 for TC and 497 CBT. There were higher total CTS scores (P<0.001) for CBT (median 55.0; QR 52.0-55.0) than TC (median 23.0; QR 21.0-24.0). CBT scored better than TC for specific techniques (median 23.7; IQR 21.0-24.0 versus median 0.70.0; IQR 0.0-0.0, P<0.001). Both interventions scored highly for interpersonal effectiveness, but no difference was observed. The TC was easily delivered, deemed acceptable by patients and was not associated with harm. CONCLUSIONS: Development, standardization and measurement of a TC intervention is possible and provides a useful comparator in evaluations of effectiveness of CBT. PMID- 21665192 TI - The effects of estradiol on 17beta-hydroxysteroid dehydrogenase type IV and androgen receptor expression in the developing zebra finch song system. AB - Recent work in zebra finches suggests that genes and hormones may act together to masculinize the brain. This study tested the effects of exogenous estradiol (E2) on 17beta-hydroxysteroid dehydrogenase type IV (HSD17B4) and the co-localization of HSD17B4 and androgen receptor (AR) mRNA. We asked three primary questions: First, how does post-hatching E2 treatment affect HSD17B4 mRNA expression in males and females? Second, is this gene expressed in the same cells as AR. Third, if so does E2 modulate co-expression? Female finches implanted with 50 MUg of E2 on the third day post-hatching showed a significant increase in the density of cells expressing HSD17B4 and AR in HVC at day 25. Co-localization of AR cells that also expressed HSD17B4 was high across groups (>81%). We found significant sex differences in co-localization in both the HVC and Area X of control animals, with males showing a higher percentage of cells expressing AR mRNA that also expressed HSD17B4 in comparison to females. However, although E2 treatments significantly increased the number of cells expressing HSD17B4 mRNA and AR mRNA in the HVC of females, the percentage of HSD17B4 cells co-expressing AR was reduced in HVC and Area X in E2-treated animals. These results lend support to the hypothesis that genes and hormones may act in concert to modulate the sexually differentiation of the zebra finch song system. Further, the data suggest that a single hormonal mechanism cannot mimic the complex development of male singing behavior and associated song nuclei. PMID- 21665193 TI - Electrocortical activity in the near-term ovine fetus: automated analysis using amplitude frequency components. AB - We have designed an automated method for analyzing electrocortical (ECoG) activity in the near-term ovine fetus to process and quantitatively classify large amounts of data rapidly and objectively. Seven chronically catheterized fetal sheep were studied for 8h each at ~0.9 of gestation with continuous recording of ECoG activity using a computerized data acquisition system. Multiple ECoG amplitude and frequency parameters were scored from which we established animal specific parameter cut-off values as well as population based duration cut off values to distinguish low-voltage/high frequency (LV/HF) and high-voltage/low frequency (HV/LF) state epochs, and indeterminate voltage/frequency (IV/F) and transition period activities. We have shown that the incidence of the predominant LV/HF and HV/LF activity states at 45% and 36% of the time, respectively, is comparable to that previously reported using semi-quantitative techniques with visual analysis. However, the duration of these state epochs is considerably shorter due to the detection of brief periods of IV/F activity which would be difficult to capture using visual analysis. Importantly, our findings in the healthy ovine fetus near-term using this automated ECoG scoring methodology now provide a framework from which to study maturational events in younger animals, and under adverse pregnancy conditions. PMID- 21665194 TI - Bis(12)-hupyridone, a novel multifunctional dimer, promotes neuronal differentiation more potently than its monomeric natural analog huperzine A possibly through alpha7 nAChR. AB - The cause of many neurodegenerative disorders can be ascribed to the loss of functional neurons, and thus agents capable of promoting neuronal differentiation may have therapeutic benefits to patients of these disorders. In this study, the effects and underlying mechanisms of bis(12)-hupyridone (B12H), a novel dimeric acetylcholinesterase inhibitor modified from huperzine A (HA), on neuronal differentiation were investigated using both the rat PC12 pheochromocytoma cell line and adult rat hippocampus neural stem cells. B12H (3-30 MUM), characterized by morphological changes and expression of GAP-43, induced neurite outgrowth in a concentration- and time-dependent manner, with almost 3-fold higher efficacy than that of HA in PC12 cells. Furthermore, B12H (2.5-10 MUM), but not HA, promoted neuronal differentiation as shown by the percentage increase of betaIII-tubulin positive neurons in neural stem cells. The activities of extracellular signal regulated kinase (ERK), as well as its downstream transcription factors Elk-1 and cAMP response element-binding protein (CREB) were elevated in the B12H-treated PC12 cells. Mitogen-activated protein kinase kinase inhibitors and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) antagonist blocked the neurite outgrowth and the activation of ERK induced by B12H. All these findings suggest that B12H potently induces pro-neuronal cells into differentiated neurons by activating the ERK pathway possibly via regulating alpha7nAChR. These findings support the recent proposition that alpha7nAChR is required for the neuronal dendritic arborization and differentiation in the adult mice hippocampus, and provide insights into the possible therapeutic potential of B12H in treating neurodegenerative disorders. PMID- 21665195 TI - Structures and genetics of Kdo-containing O-antigens of Cronobacter sakazakii G2706 and G2704, the reference strains of serotypes O5 and O6. AB - Cronobacter sakazakii G2706 and G2704 are the reference strains of serotypes O5 and O6 in the serological classification of this species proposed recently. Mild acid degradation of the lipopolysaccharides of both strains resulted in cleavage of the O-polysaccharide chains at the acid-labile linkage of 3-deoxy-d-manno-oct 2-ulosonic acid (Kdo) to yield oligosaccharides representing repeating units of the O-polysaccharides. The oligosaccharides and alkali-degraded lipopolysaccharides were studied by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy, and the following O-polysaccharide structures were established: The structure of strain G2706 is unique among the known bacterial polysaccharide structures, whereas that of strain G2704 is identical to the structure of Cronobacter malonaticus 3267 [MacLean, L. L.; Vinogradov, E.; Pagotto, F.; Farber, J. M.; Perry, M. B. Biochem. Cell Biol.2009, 87, 927-932], except for that the latter lacks O-acetylation. Putative functions of the genes in the O-antigen gene clusters of C. sakazakii strains studied are in agreement with the O-polysaccharide structures. PMID- 21665196 TI - Keto-fluorothiopyranosyl nucleosides: a convenient synthesis of 2- and 4-keto-3 fluoro-5-thioxylopyranosyl thymine analogs. AB - A novel series of fluorinated keto-beta-d-5-thioxylopyranonucleosides bearing thymine as the heterocyclic base have been designed and synthesized. Deprotection of 3-deoxy-3-fluoro-5-S-acetyl-5-thio-d-xylofuranose (1) and selective acetalation gave the desired isopropylidene 5-thioxylopyranose precursor 3. Acetylation and isopropylidene removal followed by benzoylation led to 3-deoxy-3 fluoro-1,2-di-Omicron-benzoyl-4-O-acetyl-5'-thio-d-xylopyranose (6). This was condensed with silylated thymine and selectively deacetylated to afford 1-(2' Omicron-benzoyl-3'-deoxy-3'-fluoro-5'-thio-beta-d-xylopyranosyl)thymine (8). Oxidation of the free hydroxyl group in the 4'-position of the sugar led to the formation of the target 4'-keto compound together with the concomitant displacement of the benzoyl group by an acetyl affording, 1-(2'-O-acetyl-3'-deoxy 3'-fluoro-beta-d-xylopyranosyl-4'-ulose)thymine (9). Benzoylation of 3 and removal of the isopropylidene group followed by acetylation, furnished 3-deoxy-3 fluoro-1,2-di-Omicron-acetyl-4-O-benzoyl-5'-thio-d-xylopyranose (12). Condensation of thiosugar 12 with silylated thymine followed by selective deacetylation led to the 1-(4'-Omicron-benzoyl-3'-fluoro-5'-thio-beta-d xylopyranosyl)thymine (14). Oxidation of the free hydroxyl group in the 2' position and concomitant displacement of the benzoyl group by an acetyl gave target 1-(4'-O-acetyl-3'-deoxy-3'-fluoro-beta-d-xylopyranosyl-2'-ulose)thymine (15). PMID- 21665197 TI - Characterization of cyclic beta-glucans of Bradyrhizobium by MALDI-TOF mass spectrometry. AB - Periplasmic, cyclic beta-glucans isolated from Bradyrhizobium elkanii, Bradyrhizobium liaoningense, and Bradyrhizobium yuanmingense strains have been investigated by means of Matrix-Assisted Laser Desorption/Ionization Time-of Flight Mass Spectrometry (MALDI-TOF MS), 1D and 2D nuclear magnetic resonance (NMR), as well as standard chemical methods. These compounds are built of 10-13 d glucose residues. The main fractions contain molecules assembled of 12 hexose units (M(w)=1945.363Da). Glucose monomers are linked by beta-(1->3) or beta-(1 >6) glycosidic bonds. The ratio of beta-(1->3) to beta-(1->6) linked glucose is approximately 1:2. Moreover, methylation analysis demonstrated the presence of terminal, non-reducing, as well as branched (i.e., 3- and 6-substituted) glucoses. Thus, the basic structure of the investigated compounds is similar to that of periplasmic oligosaccharides from Bradyrhizobium japonicum and Azorhizobium caulinodans strains. The analyzed cyclic beta-glucans are substituted by phosphocholine (PC) (one or two residues per ring) and highly decorated with acetate and succinate. The substituents are arranged diversely in the population of cyclic beta-glucan molecules. The concentrations of cyclic beta glucans in Bradyrhizobium periplasmic space are osmotically regulated and increase in response to a decrease of medium osmolarity. PMID- 21665198 TI - Investigating joint attention mechanisms through spoken human-robot interaction. AB - Referential gaze during situated language production and comprehension is tightly coupled with the unfolding speech stream (Griffin, 2001; Meyer, Sleiderink, & Levelt, 1998; Tanenhaus, Spivey-Knowlton, Eberhard, & Sedivy, 1995). In a shared environment, utterance comprehension may further be facilitated when the listener can exploit the speaker's focus of (visual) attention to anticipate, ground, and disambiguate spoken references. To investigate the dynamics of such gaze following and its influence on utterance comprehension in a controlled manner, we use a human-robot interaction setting. Specifically, we hypothesize that referential gaze is interpreted as a cue to the speaker's referential intentions which facilitates or disrupts reference resolution. Moreover, the use of a dynamic and yet extremely controlled gaze cue enables us to shed light on the simultaneous and incremental integration of the unfolding speech and gaze movement. We report evidence from two eye-tracking experiments in which participants saw videos of a robot looking at and describing objects in a scene. The results reveal a quantified benefit-disruption spectrum of gaze on utterance comprehension and, further, show that gaze is used, even during the initial movement phase, to restrict the spatial domain of potential referents. These findings more broadly suggest that people treat artificial agents similar to human agents and, thus, validate such a setting for further explorations of joint attention mechanisms. PMID- 21665199 TI - Cognitive effects of language on human navigation. AB - Language has been linked to spatial representation and behavior in humans, but the nature of this effect is debated. Here, we test whether simple verbal expressions improve 4-year-old children's performance in a disoriented search task in a small rectangular room with a single red landmark wall. Disoriented children's landmark-guided search for a hidden object was dramatically enhanced when the experimenter used certain verbal expressions to designate the landmark during the hiding event. Both a spatial expression ("I'm hiding the sticker at the red/white wall") and a non-spatial but task-relevant expression ("The red/white wall can help you get the sticker") enhanced children's search, relative to uncued controls. By contrast, a verbal expression that drew attention to the landmark in a task-irrelevant manner ("Look at this pretty red/white wall") produced no such enhancement. These findings provide further evidence that language changes spatial behavior in children and illuminate one mechanism through which language exerts its effect: by helping children understand the relevance of landmarks for encoding locations. PMID- 21665200 TI - When two and too don't go together: a selective phonological deficit sparing number words. AB - We report the case of an Italian speaker (GBC) with classical Wernicke's aphasia syndrome following a vascular lesion in the left posterior middle temporal region. GBC exhibited a selective phonological deficit in spoken language production (repetition and reading) which affected all word classes irrespective of grammatical class, frequency, and length. GBC's production of number words, in contrast, was error free. The specific pattern of phonological errors on non number words allows us to attribute the locus of impairment at the level of phonological form retrieval of a correctly selected lexical entry. These data support the claim that number words are represented and processed differently from other word categories in language production. PMID- 21665201 TI - Sensitive periods in human development: evidence from musical training. AB - One of the primary goals of cognitive neuroscience is to understand the interaction between genes, development and specific experience. A particularly fascinating example of this interaction is a sensitive period - a time during development when experience has a differential effect on behavior and the brain. Behavioral and brain imaging studies in musicians have provided suggestive evidence for a possible sensitive period for musical training; showing that musicians who began training early show better task performance and greater changes in auditory and motor regions of the brain. However, these studies have not controlled for likely differences between early- (ET) and late-trained (LT) musicians in the number of years of musical experience. This review presents behavioral work from our laboratory comparing the performance of ET (before age seven) and LT musicians who were matched for years of experience on the ability to tap in synchrony with auditory and visual rhythms. The results demonstrate the existence of a possible sensitive period for musical training that has its greatest impact on measures of sensorimotor integration. Work on motor learning in children and how this might relate to the observed sensitive period effect is also reviewed. These studies are described in the context of what is currently known about sensitive periods in animals and humans; drawing on evidence from anatomy and physiology, studies of deafness, as well as structural and functional neuroimaging studies in trained musicians. The possible mechanisms underlying sensitive periods for musical training are discussed based on current theories describing the influence of both low-level features of sensory experience and higher-level cognitive processing. PMID- 21665202 TI - The development of aesthetic responses to music and their underlying neural and psychological mechanisms. AB - In the field of psychology, the first studies in experimental aesthetics were conducted approximately 140 years ago. Since then, research has mainly concentrated on aesthetic responses to visual art. Both the aesthetic experience of music and, especially, its development have received rather limited attention. Moreover, until now, very little attention has been paid to the investigation of the aesthetic experience of music using neuroscientific methods. Aesthetic experiences are multidimensional and include inter alia sensory, perceptual, affective, and cognitive components. Aesthetic processes are usually experienced as pleasing and rewarding and are, thus, important and valuable experiences for many people. Because of their multidimensional nature, these processes employ several brain areas. In the present review, we examine important psychological and neural mechanisms that are believed to contribute to the development of aesthetic experiences of music. We also discuss relevant research findings. With the present review, we wish to provoke further discussion and possible future investigations as we consider the investigation of aesthetic experiences to be important both scientifically and with respect to potential clinical applications. PMID- 21665203 TI - Brain imaging in psychosis and psychopathy--ethical considerations. PMID- 21665204 TI - The countervailing forces of binding and selection in vision. AB - Evidence indicates that when one feature of an object is specifically attended, other task-irrelevant features of that object also receive enhanced processing, presumably as a result of automatic binding processes. On the other hand, evidence also shows that attention can be selectively biased in favor of processing one feature at the expense of processing others. Thus, binding invokes combinatorial processing of related features whereas selective attention emphasizes differential processing. We hypothesized that binding and selective feature-based attention depend on a common resource and therefore might show interference effects. The current study tested this by manipulating binding demands while human participants directed their attention to the color or motion of moving random dot stimuli. Response time measures showed that effects of biased attention were reduced when binding demands were increased. This finding supports the thesis that binding relies, at least in part, upon the same mechanisms invoked by preparatory biasing of selective attention. PMID- 21665205 TI - Cigarette smoking influences the clinical and occupational outcome of patients with tibial shaft fractures. AB - Tibial shaft fracture is one of the most common types of bone fracture in young patients. In this prospective clinical cohort study, we investigated the effects of cigarette smoking on the clinical, functional, psychosocial and occupational outcomes after isolated lower-leg fracture. We examined 85 patients, including 61 men and 24 women, with a collective mean age of 46 years (range: 18-84 years). Thirty-nine patients had never smoked (G1) and 45 patients were current or previous smokers (G2). The G2 group displayed a significantly increased risk for delayed union or nonunion (G1=3 patients, G2=18 patients; P=0.0007) and increased time required for fracture healing (mean times: G1=11.9 weeks, G2=17.4 weeks; p=0.003) and a markedly increased time out of work (mean times: G1=16.1 weeks, G2=21.5 weeks; p=0.1177 (not significant)). The 18 negatively affected patients in G2 displayed a significant increase in the time required for fracture healing and time out of work (26 weeks (p=0.02) and 31 weeks (p=0.03), respectively). G2 group members had a 3- to 18-fold higher risk of impaired bone healing. The mean Short Form 36 (SF-36) was similar in both groups. The physical-function scores were G1=49.6 and G2=48.6; the mental scores were G1=52.7 and G2=52.8. These findings indicate that smoking significantly increases the risk of impaired fracture healing, which has clinical and occupational consequences for the affected patients. Based on our data, we developed a score to estimate the individual risk of impaired fracture healing. These types of patients must be informed and closely monitored to determine the need for timely re-intervention with additional therapy, such as BMP s or ultrasound. PMID- 21665206 TI - Skin autofluorescence is inversely related to HDL anti-oxidative capacity in type 2 diabetes mellitus. AB - OBJECTIVE: High density lipoprotein (HDL) particles protect apolipoprotein B containing lipoproteins from oxidative modification. An impaired anti-oxidative functionality of HDL in type 2 diabetes mellitus (T2DM) may contribute to enhanced formation of oxidative stress products, such as Advanced Glycation Endproducts (AGEs). We tested whether in T2DM the HDL anti-oxidative capacity is related to the accumulation of AGEs in the skin. METHODS: Skin autofluorescence (AF), a non-invasive read-out for AGEs, and HDL anti-oxidative capacity, i.e. the ability of HDL to protect against LDL oxidation in vitro, were assessed in 67 non smoking T2DM patients without complications (median age: 60 (53-65), 60% males, 6.5 (5.2-8.5) years of diabetes duration). RESULTS: In univariate analysis, skin AF correlated inversely with HDL anti-oxidative capacity (r=-0.305, P<0.02), but not with HDL cholesterol or apolipoprotein A-I. HDL anti-oxidative capacity correlated inversely with glucose, HbA(1c), triglycerides, and insulin resistance (homeostasis model assessment) (P<0.05 to P <= 0.001). Multiple linear regression showed that skin AF remained inversely related to HDL anti-oxidative capacity (partial r=-0.314, P=0.015) taking account of age, plasma glucose, non-HDL cholesterol, triglycerides, HOMA(ir), and CRP. CONCLUSION: These findings suggest that skin AF is inversely related to the HDL anti-oxidative capacity rather than to the HDL cholesterol concentration in T2DM. Impaired anti-oxidative functionality of HDL could contribute to tissue accumulation of AGEs. PMID- 21665207 TI - Genetic variants of 11 telomere-pathway gene loci and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study. AB - OBJECTIVE: Leukocyte telomere length shortening has recently been associated with type 2 diabetes mellitus (T2D). Whether this observation was modulated by genetic variation within the telomere-pathway genes remains elusive. To date, no prospective epidemiological data on the relationship of telomere-pathway gene variation with T2D are available. METHODS: The association between 150 tagging SNPs (tSNPs) of 11 telomere-pathway genes (TERC, UCP1, TERT, POT1, TNKS, TERF1, TNKS2, TEP1, ACD, TERF2 and TERF2IP) and incident T2D was investigated in 22,715 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease, cancer and diabetes at baseline. During a 13-year follow-up period, 1445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk assuming an additive genetic model. Haplotype block analysis was also performed. RESULTS: A total of eleven tSNPs within TERF1, TNKS, TEP1, ACD, and TERF2 were associated with T2D risk (all p uncorrected <0.050). Further investigation using the haplotype-block analysis again revealed an association of several prespecified haplotypes of TERF1, and TEP1 with T2D risk (all p-uncorrected <0.040). CONCLUSION: If corroborated in other prospective studies, the present findings suggest that genetic variation within the telomere-pathway gene loci examined may be useful predictor for T2D risk assessment. PMID- 21665208 TI - Fluid flow induced calcium response in osteoblasts: mathematical modeling. AB - Fluid flow in the bone lacuno-canalicular network can induce dynamic fluctuation of intracellular calcium concentration ([Ca(2+)](i)) in osteoblasts, which plays an important role in bone remodeling. There has been limited progress in the mathematical modeling of this process probably due to its complexity, which is controlled by various factors such as Ca(2+) channels and extracellular messengers. In this study we developed a mathematical model to describe [Ca(2+)](i) response induced by fluid shear stress (SS) by integrating the major factors involved and analyzed the effects of different experimental setups (e.g. [Ca(2+)](i) baseline, pretreatment with ATP). In this model we considered the ATP release process and the activities of multiple ion channels and purinergic receptors. The model was further verified quantitatively by comparing the simulation results with experimental data reported in literature. The results showed that: (i) extracellular ATP concentration has more significant effect on [Ca(2+)](i) baseline (73% increase in [Ca(2+)](i) with extracellular ATP concentration varying between 0 and 10 MUM), as compared to that induced by SS (25% variation in [Ca(2+)](i) with SS varying from 0 to 3.5 Pa); (ii) Pretreatment with ATP-medium results in different [Ca(2+)](i) response as compared to the control group (ATP-free medium) under SS; (iii) Relative [Ca(2+)](i) fluctuation over baseline is more reliable to show the [Ca(2+)](i) response process than the absolute [Ca(2+)](i) response peak. The developed model may improve the experimental design and facilitate our understanding of the mechanotransduction process in osteoblasts. PMID- 21665209 TI - High-efficiency high performance liquid chromatographic analysis of red wine anthocyanins. AB - The analysis of anthocyanins in natural products is of significant relevance in recent times due to the recognised health benefits associated with their consumption. In red grapes and wines in particular, anthocyanins are known to contribute important properties to the sensory (colour and taste), anti-oxidant- and ageing characteristics. However, the detailed investigation of the alteration of these compounds during wine ageing is hampered by the challenges associated with the separation of grape-derived anthocyanins and their derived products. High performance liquid chromatography (HPLC) is primarily used for this purpose, often in combination with mass spectrometric (MS) detection, although conventional HPLC methods provide incomplete resolution. We have previously demonstrated how on-column inter-conversion reactions are responsible for poor chromatographic efficiency in the HPLC analysis of anthocyanins, and how an increase in temperature and decrease in particle size may improve the chromatographic performance. In the current contribution an experimental configuration for the high efficiency analysis of anthocyanins is derived using the kinetic plot method (KPM). Further, it is shown how analysis under optimal conditions, in combination with MS detection, delivers much improved separation and identification of red wine anthocyanins and their derived products. This improved analytical performance holds promise for the in-depth investigation of these influential compounds in wine during ageing. PMID- 21665210 TI - Effect of cyclization of N-terminal glutamine and carbamidomethyl-cysteine (residues) on the chromatographic behavior of peptides in reversed-phase chromatography. AB - N-terminal loss of ammonia is a typical peptide modification chemical artifact observed in bottom-up proteomics experiments. It occurs both in vivo for N terminal glutamine and in vitro following enzymatic cleavage for both N-terminal glutamine and cysteine alkylated with iodoacetamide. In addition to a mass change of -17.03 Da, modified peptides exhibit increased chromatographic retention in reversed-phase (RP) HPLC systems. The magnitude of this increase varies significantly depending on the peptide sequence and the chromatographic condition used. We have monitored these changes for extensive sets (more than 200 each) of tryptic Gln and Cys N-terminated species. Peptides were separated on 100 A pore size C18 phases using identical acetonitrile gradient slopes with 3 different eluent compositions: 0.1% trifluoroacetic acid; 0.1% formic acid and 20 mM ammonium formate at pH 10 as ion-pairing modifiers. The observed effect of this modification on RP retention is the product of increased intrinsic hydrophobicity of the modified N-terminal residue, lowering or removing the effect of ion pairing formation on the hydrophobicity of adjacent residues at acidic pHs; and possibly the increased formation of amphipathic helical structures when the positive charge is removed. Larger retention shifts were observed for Cys terminated peptides compared to Gln, and for smaller peptides. Also the size of the retention increase depends on the eluent conditions: pH 10?trifluoroacetic acid90%) used on the hydrophilic polymethacrylate-based monoliths reported previously. Additionally, a mixed mode of hydrophilic interaction (HI) and strong cation-exchange (SCX) could be also obtained in the analysis of charged peptides, and high column efficiency up to 80,000 plates/m was achieved without peak tailing. The prepared hydrophilic stationary phase might provide a potential environmental friendly separation media for polar solutes as it consumes a low volume of organic solvents. PMID- 21665215 TI - Development of magnetic multiwalled carbon nanotubes combined with near-infrared radiation-assisted desorption for the determination of tissue distribution of doxorubicin liposome injects in rats. AB - For the first time, magnetic multiwalled carbon nanotubes (MWNTs) combined with near-infrared radiation-assisted desorption (NIRAD) was successfully developed for the determination of tissue distribution of doxorubicin liposome injects (DOXLI) in rats. The magnetic MWNTs nanomaterials were synthesized via a simple hydrothermal process. Magnetic Fe(3)O(4) beads, with average diameters of ca. 200 nm and narrow size distribution, were decorated along MWNTs to form octopus-like nanostructures. The hybrid nanocomposites provided an efficient way for the extraction and enrichment of doxorubicin (DOX) via pi-pi stacking of DOX molecules onto the polyaromatic surface of MWNTs. DOX adsorbed with magnetic MWNTs could be simply and rapidly isolated through a magnetic field. In addition, due to the near-infrared radiation (NIR) absorption property of MWNTs, irradiation with NIR laser was employed to induce photothermal conversion, which could trigger rapid DOX desorption from DOX-loaded magnetic MWNTs. Extraction conditions such as amount of magnetic MWNTs added, pH values, adsorption time, desorption solvent and NIR time were investigated and optimized. Method validations including linear range, detection limit, precision, and recovery were also studied. The results showed that the proposed method based on magnetic MWNTs coupled to NIRAD was a simple, rapid and high efficient approach for the analysis of DOXLI in rat tissues. PMID- 21665216 TI - Partial-filling affinity capillary electrophoresis of glycoprotein oligosaccharides derivatized with 8-aminopyrene-1,3,6-trisulfonic acid. AB - Partial-filling affinity capillary electrophoresis has been applied to the simultaneous analysis of interactions between glycoprotein oligosaccharides and certain plant lectins. A lectin solution and a mixture of glycoprotein-derived oligosaccharides labeled with 8-aminopyrene-1,3,6-trisulfonic acid were introduced to a neutrally coated capillary in this order, and separated by application of a negative voltage. Interaction of a lectin with each oligosaccharide in the mixture was observed as the specific retardation or dissipation of peaks, in addition to the size/charge separation of oligosaccharides by zone electrophoresis in the remainder (~90%) of the capillary. The strength of the interaction with lectin was controlled by introducing an appropriate volume of lectin solution. Application of various specificities of lectins indicated characteristic migration profiles of the oligosaccharides. Moreover, sequential injection of four lectins (Maachia amurensis mitogen, Sambucus sieboldiana agglutinin, Erythrina cristagalli agglutinin, Aleuria aurantia lectin) induced complete dissipation of complex-type oligosaccharides and enabled specific determination of the presence of high mannose oligosaccharides without the interference or alteration of the electropherogram in porcine thyroglobulin. This method was also applied to determine the binding constants of ovalbumin-derived oligosaccharides to wheat germ agglutinin. PMID- 21665217 TI - Direct separation and detection of biogenic amines by ion-pair liquid chromatography with chemiluminescent nitrogen detector. AB - Analysis of biogenic amines is critical to pharmaceutical and food industry due to their biological importance. For many years, the determination of biogenic amines has relied on high performance liquid chromatography (HPLC) coupling with pre-, on-, or post-column derivatization procedures to enable UV or fluorescent detections. In this study, 14 biogenic amines were separated on a Phenomenex Luna Phenyl-Hexyl column by an ion-pair liquid chromatography method using perfluorocarboxylic acids as ion-pair reagents and detected by a chemiluminescent nitrogen detector (CLND). This direct separation and detection HPLC method eliminated the time consuming and cumbersome derivatization procedures. Compared with HPLC-UV (post-column derivatization with ninhydrin) and HPLC-charged aerosol detector (CAD) methods, this HPLC-CLND technique provided narrower peaks, better baselines, and improved separations and detections. Excellent linearity was acquired by CLND for each of the 14 biogenic amines ranging from less than 1 ng to about 1000 ng (on-column weights). The relative response factors determined by this LC-CLND method were proportional to the numbers of nitrogen atoms in each compound, which has been the characteristic of the equimolar determinations by CLND. In addition, a number of samples including beer, dairy beverage, herb tea, and vinegar were analyzed by the LC-CLND method with satisfactory precision and accuracy. PMID- 21665218 TI - Effect of salt additives on partition of nonionic solutes in aqueous PEG-sodium sulfate two-phase system. AB - Partition of 12 nonionic organic compounds in aqueous PEG-8000-Na(2)SO(4) two phase system was examined. Effects of four salt additives (NaCl, NaSCN, NaClO(4), and NaH(2)PO(4)) in the concentration range from 0.027 up to ca. 1.9 M on binodal curve of PEG-sulfate two-phase system and solute partitioning were explored. It was found that different salt additives at the relatively high concentrations display different effects on both phase separation and partition of various nonionic solutes. Analysis of the results indicates that the PEG-Na(2)SO(4) ATPS with the up to 0.215 M NaCl concentration may be viewed as similar to the ATPS without NaCl in terms of the Collander equation's predictive ability of the partitioning behavior of nonionic compounds. All ATPS with each of the salt additive used at the concentration of 0.027 M may be viewed as similar to each other as the Collander equation holds for partition coefficients of nonionic solutes in these ATPS. Collander equation is valid also for the compounds examined in the ATPS with additives of NaSCN and NaClO(4) at the concentrations up to 0.215 M. The observed similarity between these ATPS might be explained by the similar effects of these two salts on the water structure. At concentrations of the salt additives exceeding the aforementioned values, different effects of salt additives on partitioning of various nonionic solutes are displayed. In order to explain these effects of salt additives it is necessary to examine the intensities of different solute-solvent interactions in these ATPS within the framework of the so-called Linear Solvation Energy Relationship (LSER) model. PMID- 21665219 TI - Speciation analysis of arsenic compounds in edible oil by ion chromatography inductively coupled plasma mass spectrometry. AB - An inductively coupled plasma mass spectrometer (ICP-MS) was used as an ion chromatographic (IC) detector for the speciation analysis of arsenic in edible oil. The arsenic species studied include arsenite, arsenate, monomethylarsonic acid, dimethylarsinic acid, arsenobetaine and arsenocholine. Gradient elution using (NH(4))(2)CO(3) and methanol at pH 8.5 allowed the chromatographic separation of all species in less than 8 min. Effluents from the IC column were delivered to the nebulizer of ICP-MS for the determination of arsenic. The concentrations of arsenic species have been determined in several used and fresh vegetable oil samples. In this study, a microwave-assisted extraction method was used for the extraction of arsenic species from oil samples. The extraction efficiency was better than 92% and the recoveries from spiked samples were in the range of 90-105%. The precision between sample replicates was better than 8% for all determinations. The limits of detection were in the range of 0.008-0.024 ng mL(-1) for various arsenic species based on peak height, which corresponded to 0.08-0.24 ng g(-1) in the original oil sample. The major arsenic species in the used oil samples varied based on the food items cooked. PMID- 21665220 TI - Noninjection, one-pot synthesis of Cu-deficient CuInS2/ZnS core/shell quantum dots and their fluorescent properties. AB - Non-toxic, environment-benign colloidal CuInS(2) (CIS) quantum dots (QDs) were synthesized through a facile noninjection, one-pot approach by reacting Cu and In precursors with dodecanethiol dissolved in 1-octadecence at 220 degrees C. The Cu:In precursor molar ratio was varied from 1:1 to 1:4 to intentionally generate Cu-deficient CIS QDs. Depending on the stoichiometry of the QDs, their emission peak wavelengths were tuned in red-deep red region. More Cu-deficient CIS QDs (Cu:In=1:4) were found to be more efficient than ones with Cu:In=1:1. After successive ZnS shell was overgrown on the surface of core QDs with Cu:In=1:4, the resulting core/shell QDs exhibited a highly efficient yellow emission with a quantum yield of ~50%. A substantially blue-shifted emission from the core/shell QDs versus core ones was described by suggesting an alternative recombination pathway that may be induced by the ZnS shell coating. PMID- 21665221 TI - Controlled self-assembly of hydrophobic quantum dots through silanization. AB - We demonstrate the formation of one-, two-, and three-dimensional nanocomposites through the self-assembly of silanized CdSe/ZnS quantum dots (QDs) by using a controlled sol-gel process. The self-assembly behavior of the QDs was created when partially hydrolyzed silicon alkoxide monomers replaced hydrophobic ligands on the QDs. We examined systematically self-assembly conditions such as solvent components and QD sizes in order to elucidate the formation mechanism of various QD nanocomposites. The QD nanocomposites were assembled in water phase or on the interface of water and oil phase in emulsions. The partially hydrolyzed silicon alkoxides act as intermolecules to assemble the QDs. The QD nanocomposites with well-defined solid or hollow spherical, fiber-like, sheet-like, and pearl-like morphologies were prepared by adjusting the experimental conditions. The high photoluminescence efficiency of the prepared QD nanocomposites suggests partially hydrolyzed silicon alkoxides reduced the surface deterioration of QDs during self assembly. These techniques are applicable to other hydrophobic QDs for fabricating complex QD nanocomposites. PMID- 21665222 TI - Population pharmacokinetics of pentobarbital in neonates, infants, and children after open heart surgery. AB - OBJECTIVES: To determine the pharmacokinetics of pentobarbital in neonates, infants, and young children with congenital heart disease after open-heart surgery. STUDY DESIGN: Thirty-five subjects (3.0 days-4.4 years) after open-heart surgery who received pentobarbital as standard of care were enrolled. Serial pharmacokinetic blood samples were obtained. A population-based, nonlinear mixed effects modeling approach was used to characterize pentobarbital pharmacokinetics. RESULTS: A two-compartment model with weight as a co-variate allometrically expressed on clearance (CL), inter-compartmental clearance, central (V1) and peripheral volume of distributions, bypass grafting time as a co variate on CL and V1, and age and ventricular physiology as co-variates on CL best described the pharmacokinetics. A typical infant (two-ventricle physiology, 6.9 kg, 5.2 months, and bypass grafting time of 60 minutes) had a CL of 0.12 L/hr/kg, V1 of 0.45 L/kg, and peripheral volume of distributions of 0.98 L/kg. The bypass grafting effect was poorly estimated. For subjects <12 months age, an age effect on CL remained after accounting for weight and was precisely estimated. CONCLUSIONS: Pentobarbital pharmacokinetics is influenced by age and weight. Subjects with single-ventricle physiology demonstrated a 15% decrease in clearance when compared with subjects with two-ventricle physiology. PMID- 21665223 TI - The effect of calcium supplementation on blood lead levels in Nigerian children. AB - OBJECTIVE: To determine whether calcium supplementation alters the risk of lead toxicity. STUDY DESIGN: Children aged 12-18 months from 3 communities in Nigeria were assigned to receive daily calcium supplementation, as either calcium carbonate (400 mg) or ground dried fish (529 +/- 109 mg), or placebo. All children received 2500 IU of vitamin A. Levels of blood lead, calcium, and vitamin D metabolites were measured at baseline and after 12-18 months (n = 358). RESULTS: The mean (+/- SD) baseline lead level was 11.1 +/- 7.8 MUg/dL (range, 1 43 MUg/dL; median, 9 MUg/dL); 44.7% of subjects had a lead level >10 MUg/dL. After 12-18 months, the mean lead level was 8.1 +/- 6.3 MUg/dL (range, 1-48 MUg/dL; median, 6 MUg/dL), with 22.6% with a level >10 MUg/dL. Lead levels at baseline varied among communities (P = .01) and were higher in children who used eye cosmetics or lived near a lead-acid battery melter (both P < .001). In a multiple regression model, the decrease in blood lead level was predicted by age, baseline lead level, and time of final lead value at 12-18 months (R(2) = 31%), but not by calcium supplementation (P = .98). CONCLUSIONS: Lead toxicity is common in Nigerian children, but calcium supplementation does not affect blood lead levels. PMID- 21665224 TI - Single-plane compensatory phase shift of head and eye oscillations in infantile nystagmus syndrome. AB - A 43-year-old man with infantile nystagmus syndrome complained of "head tremor" that would occur during attempted reading. Three-dimensional, combined eye and head recordings were performed with the magnetic search coil technique in two conditions: 1) looking straight-ahead under photopic conditions without a particular attentional focus and 2) reading a simple text held one meter away. A mainly vertical-horizontal spontaneous nystagmus was evident in both conditions, whereas head nodding emerged in the second condition. The head oscillated only in the vertical plane and concomitant analysis of eye and head displacement revealed a counterphase, compensatory pattern of the first harmonic of the INS waveform. This was verified by the significant negative peak of the crosscorrelogram at zero lag. Eye-in-space (gaze) displacement during nystagmic oscillations was thereby reduced suggesting a central adaptive behavior that may have evolved to partly compensate for the abnormal eye movements during reading. PMID- 21665225 TI - The impact of smoking on the severity of acute ischemic stroke. AB - OBJECTIVES: This study investigated the impact of smoking on the initial severity of acute ischemic stroke and examined its subsequent outcome. METHODS: Patient data was collected from the Stroke Registry in the Chang Gung Healthcare System (SRICHS). A total of 2650 patients admitted for acute ischemic stroke from January to December 2009 were included. Baseline characteristics were compared between smokers and non-smokers. Factors affecting the initial severity and the recovery from neurological deficit were examined by logistic regression analysis. The patients were further divided according to stroke mechanism for subgroup analysis. RESULTS: The total number of smokers and non-smokers was 817 (31.9%) and 1833 (69.1%), respectively. Univariate analysis showed that smokers had lower NIHSS scores on admission than did non-smokers (P<0.001). In subgroup analysis, smokers with small-vessel occlusions frequently had higher NIHSS scores on admission than did non-smokers (P=0.001). However, smokers with cardioembolic stroke had lower NIHSS scores on admission as compared to non-smokers (P=0.024). No subgroup had smoking as a significant factor for neurological recovery during hospitalization. CONCLUSIONS: Smoking correlated with higher NIHSS scores on admission for small-vessel occlusion. Conversely, it was associated with lower NIHSS scores on admission for cardioembolism. PMID- 21665226 TI - Treatment with rtPA of stroke associated with intravenous immunoglobulins perfusion. AB - Information about the security of intravenous recombinant tissue type plasminogen activator (rtPA) in immunoglobulins related stroke can only be ascertained from singular cases as it was not assessed in clinical trials. Only two cases of stroke associated with IVIg treated with rtPA were described in literature. We report the outcome of two patients with IVIg associated stroke that were treated with rtPA. In our patients there were hemorrhagic complications - remote cerebral haemorrhage and diffuse cutaneous hematomas. PMID- 21665227 TI - Natalizumab and drug holiday in clinical practice: an observational study in very active relapsing remitting multiple sclerosis patients. AB - BACKGROUND: In order to reduce the risk of progressive multifocal leucoencephalopathy when using natalizumab for more than 12 months, a 6-month drug holiday has been discussed. However, the consequences on short term disease activity have been poorly assessed. OBJECTIVE: The aim of this study was to assess clinical and radiological disease activity within 6 months after stopping natalizumab in very active relapsing remitting Multiple Sclerosis (RRMS) patients. METHODS: In 8 hospitals from Western France, we retrospectively collected clinical and MRI data from consecutive RRMS patients treated with natalizumab for at least 6 months, and who stopped the drug for various reasons except therapeutic failure. Patients didn't receive any other disease modifying treatment after discontinuing natalizumab. RESULTS: A total of 27 patients with very active RRMS before natalizumab start (mean annualized relapse rate of 2.3, MRI activity in 21 of 27 patients) were studied. Within 6 months after discontinuing natalizumab, 18 patients (67%) experienced clinical relapse and 3 additional patients had radiological activity, without clinical relapse. Four patients (15%) experienced a rebound activity, with severe relapse and 20 or more gadolinium enhancing lesions on MRI. CONCLUSION: Such observational data didn't support the concept of drug holiday when using natalizumab in very active RRMS. PMID- 21665228 TI - A minimally invasive approach is more cost-effective than a traditional sternotomy approach for mitral valve surgery. AB - OBJECTIVE: The aim of this study was to compare the cost and effectiveness of a minimally invasive (MI) versus traditional sternotomy (ST) approach for mitral valve surgery (MVS). METHODS: From January 1, 2003, to December 31, 2008, a total of 847 patients underwent isolated MVS at our institution. Propensity matching on 22 clinical variables was carried out to generate a study cohort of 434 patients (217 matched pairs). Direct and indirect costs from the hospital perspective were retrospectively obtained from our finance department. Total hospital costs were further stratified into 13 standardized institutional billing categories. In addition, data on morbidity, mortality, discharge location, hospital readmissions within 1 year, and freedom from reoperation were obtained. RESULTS: Compared with ST, MIMVS was associated with a $9054 +/- $3302 lower mean total hospital cost (P = .006), driven largely by a reduction in direct (P = .003) versus indirect costs (P = .06). Among the 13 billing categories, MIMVS was associated with a significant reduction in costs of cardiac imaging (P = .004), laboratory tests (P = .005), boarding and nursing (P = .001), and radiology (P = .002). More patients in the ST group required intubation for more than 72 hours (P = .019); however, there were no differences in morbidity or long-term survival (P = .334). A higher proportion of MI patients were discharged home with no nursing services (P = .018), and a higher proportion of ST patients required readmission within 1 year (P = .023). There were no differences in freedom from reoperation between groups (P = .574). CONCLUSIONS: With equivalent efficacy across a range of measures and lower costs compared with ST, MIMVS represents a cost-saving strategy for MVS. PMID- 21665229 TI - Repair of anomalous origin of the left coronary artery from the pulmonary artery in infants and children. AB - OBJECTIVE: Although mortality after direct aortic reimplantation for anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) has significantly decreased, many questions remain unanswered. METHODS: Between 1986 and June 2010, we operated on 27 consecutive pediatric patients with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). All patients underwent reestablishment of a dual coronary system with direct aortic reimplantation of the left coronary artery into the aorta. Postoperative extracorporeal mechanical circulatory support was necessary in 7 cases. In all 7 patients, hemodynamic stability was achieved after 4 to 10 days of support. Mitral valve repair was performed in 9 patients with severe mitral valve incompetence and resulted in stable mitral valve function during follow-up as long as 19 years. RESULTS: There were no early or late deaths. During follow-up (3 months-17.5 years), both early and late improvement of myocardial function was observed in all patients. Reduced left ventricular regional function late after successful surgical correction of ALCAPA was related to the presence of left ventricular myocardial scar tissue, as detected by magnetic resonance imaging. CONCLUSIONS: Despite the absence of early and late mortality, the long-term prognosis for patients after reimplantation of ALCAPA into the aorta is not clear. Scars and perfusion deficits of the left ventricle may not be detected by standard echocardiographic evaluation of global left ventricular function and therefore may be underestimated. We therefore recommend lifelong surveillance of these patients, including magnetic resonance imaging. PMID- 21665230 TI - Spartina densiflora demonstrates high tolerance to phenanthrene in soil and reduces it concentration. AB - The present study was conducted to investigate the tolerance of Spartina densiflora to phenanthrene, and to test its ability in phenanthrene dissipation. A glasshouse experiment was designed to investigate the effect of phenanthrene from 0 to 1000 mg kg(-1) on growth and photosynthetic apparatus of S. densiflora by measuring chlorophyll fluorescence parameters, gas exchange and photosynthetic pigments. We also performed chemical analysis of plant samples, and determined the concentration of phenanthrene remaining in soil. S. densiflora survived to concentrations as high as 1000 mg kg(-1) phenanthrene in soil; in fact, there was no significant difference in RGR among the treatments after 30 days. Otherwise, phenanthrene affected photosynthetic apparatus at 100 and 1000 mg kg(-1); thus, the lower PhiPSII could be explained by the declined photosynthetic pigment concentrations. Soil extraction indicated a more marked rate of phenanthrene disappearance in the soil in the presence of S. densiflora. PMID- 21665231 TI - Trace metals in harbour and slipway sediments from the island of Malta, central Mediterranean. AB - Sediment samples collected from large harbours and public slipways on the island of Malta have been analysed for geochemically important metals (Al, Ca, Fe, Mn) and contaminant metals (As, Cd, Co, Cr, Cu, Ni, Pb, Sn, Zn) following fractionation (<63 MUm) and digestion in aqua regia. Absolute and Al-normalised concentrations of contaminant metals exhibited relatively little dispersion both among different samples from the same location and between samples from different locations, notable exceptions including lower concentrations of Cr and Sn on the slipways than in the harbours. Sources of contaminant metals are attributed to diffuse and specific waste inputs from urban surroundings and boating and shipping activities. Overall, concentrations are similar to those reported for other large harbours in urban settings where equivalent sample fractionation digestion has been performed. Relative to various sediment quality guidelines, Pb is predicted to exert the greatest threat to the marine environment of Malta. PMID- 21665232 TI - Selective and reversible thiol-pegylation, an effective approach for purification and characterization of five fully active ficin (iso)forms from Ficus carica latex. AB - The latex of Ficus carica constitutes an important source of many proteolytic components known under the general term of ficin (EC 3.4.22.3) which belongs to the cysteine proteases of the papain family. So far, no data on the purification and characterization of individual forms of these proteases are available. An effective strategy was used to fractionate and purify to homogeneity five ficin forms, designated A, B, C, D1 and D2 according to their sequence of elution from a cation-exchange chromatographic support. Following rapid fractionation on a SP Sepharose Fast Flow column, the different ficin forms were chemically modified by a specific and reversible monomethoxypolyethylene glycol (mPEG) reagent. In comparison with their un-derivatized counterparts, the mPEG-protein derivatives behaved differently on the ion-exchanger, allowing us for the first time to obtain five highly purified ficin molecular species titrating 1mol of thiol group per mole of enzyme. The purified ficins were characterized by de novo peptide sequencing and peptide mass fingerprinting analyzes, using mass spectrometry. Circular dichroism measurements indicated that all five ficins were highly structured, both in term of secondary and tertiary structure. Furthermore, analysis of far-UV CD spectra allowed calculation of their secondary structural content. Both these data and the molecular masses determined by MS reinforce the view that the enzymes belong to the family of papain-like proteases. The five ficin forms also displayed different specific amidase activities against small synthetic substrates like dl-BAPNA and Boc-Ala-Ala-Gly-pNA, suggesting some differences in their active site organization. Enzymatic activity of the five ficin forms was completely inhibited by specific cysteine and cysteine/serine proteases inhibitors but was unaffected by specific serine, aspartic and metallo proteases inhibitors. PMID- 21665233 TI - Ripening, storage temperature, ethylene action, and oxidative stress alter apple peel phytosterol metabolism. AB - The chilling conditions of apple cold storage can provoke an economically significant necrotic peel disorder called superficial scald (scald) in susceptible cultivars. Disorder development can be reduced by inhibiting ethylene action or oxidative stress as well as intermittent warming. It was previously demonstrated that scald is preceded by a metabolomic shift that results in altered levels of various classes of triterpenoids, including metabolites with mass spectral features similar to beta-sitosterol. In this study, a key class of phytosterol metabolites was identified. Changes in peel tissue levels of conjugates of beta-sitosterol and campesterol, including acylated steryl glycosides (ASG), steryl glycosides (SG) and steryl esters (SE), as well as free sterols (FS), were determined during the period of scald development. Responses to pre-storage treatment with the ethylene action inhibitor, 1 methylcyclopropene, or an antioxidant (diphenylamine), rapid temperature elevation, and cold acclimation using intermittent warming treatments were evaluated. Diphenylamine, 1-MCP, and intermittent warming all reduced or prevented scald development. ASG levels increased and SE levels decreased in untreated control fruit during storage. Removing fruit from cold storage to ambient temperature induced rapid shifts in ASG and SE fatty acyl moieties from unsaturated to saturated. FS and SG levels remained relatively stable during storage but SG levels increased following a temperature increase after storage. ASG, SE, and SG levels did not increase during 6 months cold storage in fruit subjected to intermittent warming treatment. Overall, the results show that apple peel phytosteryl conjugate metabolism is influenced by storage duration, oxidative stress, ethylene action/ripening, and storage temperature. PMID- 21665234 TI - [Diagnosis of atresia of the main left coronary artery using 320-detector volumetric cardiac computed tomography [corrected]]. AB - The congenital absence of the left coronary trunk is one of the rarest anomalies of the coronary artery. We present a case in which this anomaly was suspected at cardiac catheterization and confirmed at volumetric cardiac computed tomography (CT) with a single heart beat. PMID- 21665235 TI - [Osteopathia striata with cranial sclerosis]. AB - Osteopathia striata with cranial sclerosis is a rare disease: fewer than 100 cases have been reported. The radiologic findings of osteopathia striata are characteristic, and once they are identified, they lead to the correct diagnosis. Longitudinal sclerotic striation in long bones and osteosclerosis in facial bones should raise suspicion of osteopathia striata with cranial sclerosis. This is not a serious disease, although it is often associated with other kinds of disorders and extraskeletal malformations that can affect the prognosis. Involvement of cranial and facial bones can lead to facial deformity and marked functional incapacity when the cranial nerves are affected. We present a case of osteopathia striata with cranial sclerosis discovered incidentally in a young woman studied for clinical manifestations unrelated to this disease. PMID- 21665236 TI - Lipotropes (methyl nutrients) inhibit growth of feline lymphoma in vitro. AB - Feline lymphoma is one of the most frequently diagnosed tumors in cats. Lipotropes are dietary methyl donors that may modulate DNA methylation status and the expression of genes involved in growth and apoptosis of feline lymphoma cells. The specific objective of the study was to determine if lipotropes affect the growth of feline lymphoma cells, which entailed examining a correlation between lymphoma cell proliferation and apoptosis. F1B and FeLV-3281 cells were cultured and treated with 20 times the level of lipotropes contained in the basal culture medium. Cell growth and death and caspase 3 and tumor protein p53 activity were measured. Lipotropes were found to significantly reduce cell growth; increased cell death and caspase 3 and p53 activity was seen in F1B cells after 72 h, but the effect was minimal on FeLV-3281. These results could be useful in the development of dietary strategies for treating and preventing feline lymphoma. PMID- 21665237 TI - Epizootic heamorragic disease. AB - Epizootic haemorrhagic disease (EHD) is an infectious non-contagious viral disease transmitted by insects of the genus Culicoides which affects wild and domestic ruminants. The causative agent, the epizootic haemorrhagic disease virus (EHDV), belongs to the family Reoviridae, genus Orbivirus and shares many morphological and structural characteristics with the other members of the genus such as bluetongue, African horse sickness and equine encephalosis viruses. In recent years EHD outbreaks have been reported in countries bordering the European Union. They caused disease in cattle and severe repercussion on the livestock industry of the affected countries. In the light of recent European bluetongue epizootic these events pose an increasing threat to the European Union. This review includes the most recent information regarding the virus and the disease as well as tools for its diagnosis and control. It is our conviction that more attention should be drawn to both EHDV and the disease itself in order to fulfil all these gaps and not to be unprepared in case future possible incursions. PMID- 21665238 TI - [Multiple sclerosis associated with antiphospholipid syndrome: diagnostic and therapeutic difficulties]. AB - Strokes are the main neurological manifestation of antiphospholipid syndrome. Other clinical presentations are possible and may mimic classic symptoms of multiple sclerosis (MS). A 46-year-old woman, with a history of two miscarriages, presented four subacute neurological episodes (optic neuritis, right facial paralysis, paraparesis of the thigh, and right brachial monoparesis). Using McDonald criteria, the diagnosis of multiple sclerosis was retained. Because of the occurrence of thrombocytopenia during a final relapse, we reconsidered the diagnosis of MS. Search for antiphospholipid antibodies was positive. All clinical manifestations and complementary tests were compatible with the diagnosis of antiphospholipid syndrome associated with multiple sclerosis. Given the great similarity of clinical, radiological and biological findings in the two diseases, non-thrombotic neurological manifestations of antiphospholipid syndrome can be difficult to distinguish from MS associated with antiphospholipid syndrome. PMID- 21665239 TI - Virus attenuation by microbial mechanisms during the idle time of a household slow sand filter. AB - The biosand filter (BSF) is a household slow sand filter that is operated intermittently such that an idle time of typically 18-22 h occurs in between daily charges of water. Virus attenuation during the idle time was investigated over repeated daily filtration cycles to capture the effect of media aging that encompasses processes occurring throughout the filter depth rather than restricted to the schmutzdecke at the media surface. A threshold aging period of about one to two weeks was required before virus attenuation began. The observed rates of MS2 and PRD-1 reduction were first-order and reached maxima of 0.061- and 0.053-log per hr, respectively, over seven-to-ten weeks. Suppression of microbial activity by sodium azide eliminated virus reduction during the idle time thus indicating that the operative media aging process was microbially mediated. The mechanism of virus reduction was not modification of media surfaces by physical/chemical or microbial processes. Instead, it appears that the activity of the microbial community within the filter is responsible. The most likely biological pathways are production of microbial exoproducts such as proteolytic enzymes or grazing of bacteria and higher microorganisms on virus particles. Implications of these findings for BSF design and operation and their relevance to other biological filtration technologies are discussed. PMID- 21665240 TI - Enhanced immunological and detoxification responses in Pacific oysters, Crassostrea gigas, exposed to chemically dispersed oil. AB - The aim of this study was to evaluate the effects of chemically dispersed oil on an economically and ecologically important species inhabiting coasts and estuaries, the Pacific oyster Crassostrea gigas. Studies were carried out with juveniles, known to generally be more sensitive to environmental stress than adults. A set of enzyme activities involved in immune defence mechanisms and detoxification processes, i.e. superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), catecholase-type phenoloxidase (PO), laccase-type PO and lysozyme were analysed in different oyster tissues, i.e. the gills, digestive gland and mantle, and in the plasma and the haemoycte lysate supernatant (HLS) of the haemolymph. Results indicated that total PAH body burdens were 2.7 times higher in the presence than in the absence of the chemical dispersant. After 2 days of exposure to chemically dispersed oil, alkylated naphthalenes accounted for 55% of the total PAH body burden, whereas alkylated fluorenes and alkylated dibenzothiophenes accounted for 80% when the chemical dispersant was absent. Importantly, a higher number of enzyme activities were modified when oil was chemically dispersed, especially in the plasma and gills. Moreover, independently of the presence or absence of chemical dispersant, oil exposure generally inhibited enzyme activities in the gills and plasma, while they were generally activated in the mantle and haemocytes. These results suggest that the gills and plasma constitute sensitive compartments in C. gigas, and that the mantle and haemocytes may play an important role in protection against xenobiotics. Among the six enzyme activities that were analysed in these body compartments, five were modulated in the chemical dispersion (CD) treatment while only half of the enzyme activities were modulated in the mechanical dispersion treatment. Furthermore, CD treatment effects were often observed following exposure, but also during depuration periods. These results suggest that immune and/or detoxification responses are likely to be affected when dispersants are used to treat oil spills in shallow waters. PMID- 21665241 TI - Occurrence and suitability of sucralose as an indicator compound of wastewater loading to surface waters in urbanized regions. AB - Urban watersheds are susceptible to numerous pollutant sources and the identification of source-specific indicators can provide a beneficial tool in the identification and control of input loads, often times needed for a water body to achieve designated beneficial uses. Differentiation of wastewater flows from other urban wet weather flows is needed in order to more adequately address such environmental concerns as water body nutrient impairment and potable source water contamination. Anthropogenic compounds previously suggested as potential wastewater indicators include caffeine, carbamazepine, N,N-diethyl-meta-toluamide (DEET), gemfibrozil, primidone, sulfamethoxazole, and TCEP. This paper compares the suitability of a variety of anthropogenic compounds to sucralose, an artificial sweetener, as wastewater indicators by examining occurrence data for 85 trace organic compounds in samples of wastewater effluents, source waters with known wastewater point source inputs, and sources without known wastewater point source inputs. The findings statistically demonstrate the superior performance of sucralose as a potential indicator of domestic wastewater input in the U.S. While several compounds were detected in all of the wastewater effluent samples, only sucralose was consistently detected in the source waters with known wastewater discharges, absent in the sources without wastewater influence, and consistently present in septic samples. All of the other compounds were prone to either false negatives or false positives in the environment. PMID- 21665242 TI - Distinctive patterns of p53 protein expression and microsatellite instability in human colorectal cancer. AB - Although evidence suggests an inverse relationship between microsatellite instability and p53 alterations in colorectal cancer, no study has thoroughly examined the use of p53 immunohistochemistry in phenotyping colorectal cancers. We investigated the value of p53 immunohistochemistry in microsatellite instability-positive colorectal cancers prescreening and attempted to clarify the relationship between DNA mismatch repair system and p53 pathway. In a series of 104 consecutive colorectal cancers, we performed p53 immunohistochemistry, TP53 mutational analysis, DNA mismatch repair system efficiency evaluation (DNA mismatch repair system immunohistochemistry, microsatellite instability status, MLH1/MSH2 germ line, and BRAF, murine double minute 2, and p21 immunohistochemistry. Microsatellite instability high was observed in 25 of 104 colorectal cancers, with DNA mismatch repair system protein loss (24/25) and germ line (8/25) or BRAF mutations (8/25). p53 immunohistochemistry revealed 3 distinct patterns of expression: complete negative immunostaining associated with truncating TP53 mutations (P < .0001), diffuse overexpression associated with missense TP53 mutations (P < .0001), and restricted overexpression characterized by a limited number of homogenously scattered strongly positive tumor cells in 36.5% of colorectal cancers. This latest pattern was associated with wild-type TP53 and microsatellite instability high colorectal cancers (P < .0001) including all Lynch tumors (8/8), but its presence among 22% of DNA mismatch repair system competent colorectal cancers decreased its positive predictive value (55.2% [95% confidence interval, 45%-65%]). It was also correlated with murine double minute 2 overexpression (P < .0001) and inversely with p21 loss (P = .0002), independently of microsatellite instability status. In conclusion, a restricted pattern of p53 overexpression is preferentially associated with microsatellite instability high phenotype and could, therefore, be of clinical use as signal for microsatellite instability analysis in a large-scale tumor screening. Its association with concomitant murine double minute 2 overexpression suggests an alternative mechanism of p53 pathway deregulation. PMID- 21665243 TI - Bio-magnetostratigraphy and environment of the oldest Eurasian hominoid from the Early Miocene of Engelswies (Germany). AB - The paleobiogeography of hominoids exhibits a puzzling pattern of migrations between and within Africa and Eurasia. A precise dating of hominoid-bearing localities is therefore essential to reveal the timing, direction and possible causes of dispersals. Here, we present a bio-magnetostratigraphic analysis of the section of Engelswies (Southern Germany, Upper Freshwater Molasse, North Alpine Foreland Basin) where the oldest Eurasian hominoid was found. Our paleomagnetic results reveal a very short normal and a reverse magnetic polarity for the entire section. The polarity record is correlated to the Astronomical Tuned Neogene Time Scale using an integrated stratigraphic approach. This approach follows the chronostratigraphic framework for the Upper Freshwater Molasse, which combines magnetostratigraphy with biostratigraphic, lithostratigraphic and (40)Ar/(39)Ar dating results. According to this outcome, the reverse polarity of the Engelswies section most likely correlates to magnetochron C5Cr. The origin of the short normal polarity remains enigmatic. The magnetostratigraphic calibration and the evolutionary level of the Engelswies small mammal fauna suggest an age of 17.1 17.0Ma (Early Karpatian, Early Miocene) for the oldest Eurasian hominoid, and roughly confirm the estimates of Heizmann and Begun (2001). The estimated age suggests that the first hominoids in Eurasia are contemporaneous with Afro Arabian afropithecins, and dispersal may have been facilitated by intra Burdigalian (~18-17Ma) sea-level low stands and the beginning of the Miocene Climate Optimum. The paleoclimatic and environmental reconstruction of the Engelswies locality indicates a lakeshore environment near dense subtropical rain forest vegetation, where paratropical temperatures (mean annual temperature around 20 degrees C) and humid conditions (mean annual precipitation>1.100mm) prevailed. PMID- 21665244 TI - The effect of various temperature indicators on different mortality categories in a subtropical city of Brisbane, Australia. AB - BACKGROUND: The relationship between temperature and mortality has been explored for decades and many temperature indicators have been applied separately. However, few data are available to show how the effects of different temperature indicators on different mortality categories, particularly in a typical subtropical climate. OBJECTIVE: To assess the associations between various temperature indicators and different mortality categories in Brisbane, Australia during 1996-2004. METHODS: We applied two methods to assess the threshold and temperature indicator for each age and death groups: mean temperature and the threshold assessed from all cause mortality was used for all mortality categories; the specific temperature indicator and the threshold for each mortality category were identified separately according to the minimisation of AIC. We conducted polynomial distributed lag non-linear model to identify effect estimates in mortality with one degree of temperature increase (or decrease) above (or below) the threshold on current days and lagged effects using both methods. RESULTS: Akaike's Information Criterion was minimized when mean temperature was used for all non-external deaths and deaths from 75 to 84 years; when minimum temperature was used for deaths from 0 to 64 years, 65-74 years, >= 85 years, and from the respiratory diseases; when maximum temperature was used for deaths from cardiovascular diseases. The effect estimates using certain temperature indicators were similar as mean temperature both for current day and lag effects. CONCLUSION: Different age groups and death categories were sensitive to different temperature indicators. However, the effect estimates from certain temperature indicators did not significantly differ from those of mean temperature. PMID- 21665245 TI - Risk, predictors, and clinical characteristics of lymphoma development in primary Sjogren's syndrome. AB - OBJECTIVE: To assess the risk and predictors of lymphoma development in a large cohort of patients with primary Sjogren's syndrome (pSS). METHODS: Cox-regression analyses were used to study the predictive value of clinical and laboratory findings at pSS diagnosis, and Kaplan-Meier survival curves to compare survival probability between patients who developed lymphoma and the total cohort. Expected risk for lymphoma was calculated by comparison with the background population. RESULTS: Eleven (4.5%) from 244 patients developed a non-Hodgkin lymphoma (NHL). Diffuse large B-cell and mucosa-associated lymphoid tissue lymphomas occurred at a similar frequency. Three (27.3%) patients died: 2 due to transformation from mucosa-associated lymphoid tissue to diffuse large B-cell. Purpura (HR 8.04, 95% confidence interval [CI] 2.33-27.67), parotidomegaly (HR 6.75, 95%CI 1.89-23.99), anemia (HR 3.43, 95%CI 1.04-11.35), leukopenia (HR 8.70, 95%CI 2.38-31.82), lymphocytopenia (HR 16.47, 95%CI 3.45-78.67), hypergammaglobulinemia (HR 4.06, 95%CI 1.06-15.58), low C3 (HR 36.65, 95%CI 10.65 126.18), and low C4 (HR 39.70, 95%CI 8.85-126.18) levels at pSS diagnosis were significant predictors of NHL development, but only hypocomplementemia and lymphocytopenia were independent risk factors. Hypocomplementemia was related to earlier development of NHL and higher mortality. The cumulative risk of developing lymphoma ranged from 3.4% in the first 5 years to 9.8% at 15 years. Standardized incidence ratio (95%CI) for NHL development was 15.6 (95%CI 8.7 28.2). CONCLUSIONS: Patients with pSS have a 16-fold increased risk of developing lymphoma. This risk increases with time. Hypocomplementemia and lymphocytopenia at pSS diagnosis are the strongest predictors. Survival is clearly reduced in patients with hypocomplementemia. Indolent lymphomas tend to evolve over time toward a more aggressive histologic type. PMID- 21665246 TI - Changing trends in the epidemiology of pyogenic vertebral osteomyelitis: the impact of cases with no microbiologic diagnosis. AB - OBJECTIVES: The observed higher incidence of pyogenic vertebral osteomyelitis (PVO) may entail an increasing number of patients with no microbiologic diagnosis. The true incidence of these cases, how exhaustive the etiologic diagnostic efforts must be, and the usefulness of an empirical antibiotic therapy are not well defined. METHODS: Retrospective analysis of all cases of vertebral osteomyelitis in our center (1991-2009) and retrospective analysis of cases of PVO (2005-2009). Clinical data, diagnostic procedures, treatment, and outcome were reviewed. A comparative analysis between microbiologically confirmed PVO (MCPVO) and probable PVO (PPVO) was performed. RESULTS: Increasing incidence of PVO (+0.047 episodes/100,000 inhabitants-year). During the last decade, there was an increase of PPVO (+0.059 episodes/100,000 inhabitants-year) with stable incidence of MCPVO. During 2005-2009, there were 72 patients [47 (65%) MCPVO and 25 (35%) PPVO]. 60% men; mean age was 66 years. Bacteremia was found in 59%. Computed tomographic guided vertebral biopsy, positive in 7/36 (19%), was more successful among patients with bacteremia. Among MCPVO, there was an increasing proportion of less virulent bacteria. Cases of MCPVO presented more frequently with sepsis, fever, and high acute-phase reactants, and PPVO cases were mostly treated with oral fluoroquinolones plus rifampin. No differences were found between both groups in outcome (93% success, 22% sequelae). CONCLUSIONS: An epidemiologic change of PVO is suggested by a higher incidence of PPVO and the isolation of less virulent microorganisms among MCPVO. In this setting, the availability of an oral and effective empirical antibiotic therapy may challenge an exhaustive prosecution of the etiology. PMID- 21665247 TI - The effect of TNF-alpha blocking therapy on lipid levels in rheumatoid arthritis: a meta-analysis. AB - OBJECTIVES: Changes in the lipid profile have been described in patients with rheumatoid arthritis (RA) following therapy with tumor necrosis factor (TNF) alpha blocking agents. However, thus far, results have been inconsistent. Therefore, we investigated changes in lipid levels after TNF-alpha blocking therapy using meta-analysis of published data. METHODS: The literature was searched to identify studies assessing changes in total cholesterol (TC), high density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol, triglycerides, atherogenic index (ie, TC/HDLc ratio), and apolipoprotein levels in response to TNF-alpha blocking therapy. Weighted mean levels of lipids at different time points and subsequent changes in these lipid levels between these time points were calculated with multivariate linear mixed models. RESULTS: Data were available on TC in 15 studies encompassing 766 RA patients and on HDLc in 14 studies encompassing 736 RA patients. TC increased significantly (maximum increase of 10%) and HDLc increased significantly in the first 2 to 6 weeks of therapy (maximum increase of 7%), after which it remained more or less stable. The atherogenic index did not significantly change over time. There was too limited information to evaluate changes in other lipids and apolipoproteins. CONCLUSIONS: TNF-alpha blocking therapy has a modest effect on TC and HDLc levels in RA patients with no significant overall effect on the atherogenic index. Whether TNF-alpha blocking effects on qualitative lipid changes (structure and function) are more relevant to their presumed vascular benefits requires further study. PMID- 21665248 TI - New concepts in pain research and pain management of the rheumatic diseases. AB - OBJECTIVES: To provide an update on advances in pain research and practical guidelines for pain management in the rheumatic diseases. METHODS: A selected literature review and authors' conference consensus. RESULTS: There is emerging evidence that augmented pain regulation, as found in fibromyalgia, is important in rheumatoid arthritis and osteoarthritis. These findings are applicable to optimal management paradigms in the rheumatic diseases. CONCLUSIONS: Fibromyalgia and other forms of chronic widespread pain have taught us important lessons about pain epidemiology and pain pathways. PMID- 21665249 TI - Cytoplasmic expression of estrogen receptor beta (ERbeta) predicts poor clinical outcome in advanced serous ovarian cancer. AB - OBJECTIVE: In this study we investigated the prognostic value of estrogen receptor alpha (ERalpha), ERbeta and progesterone receptor (PR) expression in 58 untreated advanced serous ovarian cancer patients. The study also included 12 macroscopically and histopathologically normal ovaries. MATERIALS AND METHODS: Protein expression was evaluated by immunohistochemistry, and antibody staining detected in both the nuclear and cytoplasmic compartments was taken into account. Immunopositivity was analyzed in relation to tumor clinicopathological variables, disease-free survival (DFS), and overall survival (OS). RESULTS: Epithelial cells in ovarian cancer tissue showed significantly lower levels of nuclear ERbeta and PR, but not ERalpha, than in normal ovarian tissue. In the case of ERbeta, however, while normal ovarian epithelium exhibited almost exclusively strong nuclear staining, ovarian cancer tissue mostly showed cytoplasmic immunopositivity. Nuclear ERalpha and ERbeta expression were not associated with clinical outcome. Conversely, any cytoplasmic ERbeta expression was an independent unfavorable prognostic factor for DFS, a finding approaching statistical significance also for OS. These data suggest that, in advanced serous ovarian cancer, cytoplasmic ERbeta signaling may be more important for patient survival than its nuclear signaling. In the case of PR, positivity was an independent favorable prognostic factor for DFS. CONCLUSIONS: These novel findings, that need to be confirmed in a large prospective trial, suggest that additional prognostic, and possibly therapeutic opportunities may be available in advanced serous ovarian cancer. PMID- 21665250 TI - Consolidation paclitaxel is more cost-effective than bevacizumab following upfront treatment of advanced epithelial ovarian cancer. AB - INTRODUCTION: Randomized trials have demonstrated significant improvements in progression-free survival (PFS) with consolidation paclitaxel (P) and bevacizumab (B) following cytoreduction and adjuvant carboplatin/paclitaxel (CP) for advanced epithelial ovarian cancer (EOC). We sought to evaluate the cost-effectiveness (C/E) of these consolidation strategies. METHODS: A decision model was developed based on Gynecologic Oncology Group (GOG) protocols #178 and #218. Arm 1 is 6 cycles of CP. Arm 2 is 6 cycles of CP followed by 12 cycles of P (CP+P). Arm 3 is 1 cycle of CP, 5 cycles of CPB, and 16 cycles of B (CPB+B). Parameters include PFS, overall survival (OS), cost, complications (neuropathy for P and bowel perforation for B), and quality-of-life utility values. Sensitivity analyses were performed. RESULTS: The incremental cost-effectiveness ratio (ICER) for CT+T is $13,402/quality adjusted life year (QALY) gained compared to CP. For CPB+B compared to CP, the ICER is $326,530/QALY. When compared simultaneously, CPB+B is dominated, i.e. is more costly and less effective than CP+P. Results were robust to parameter variation. At a willingness to pay threshold of $100,000/QALY, CP+P was the preferred option throughout most of the decision space. Sensitivity analyses suggest that CPB+B would become the preferred option if it were to improve OS by 6.1 years over CP+P. CONCLUSIONS: In this model, B consolidation for advanced EOC was associated with a modest improvement in effectiveness that is less than that with P consolidation and more costly. A statistically significant improvement in survival may improve the value of B consolidation. PMID- 21665252 TI - Intraperitoneal administration of novel doxorubicin loaded polymeric delivery systems against peritoneal carcinomatosis: experimental study in a murine model of ovarian cancer. AB - OBJECTIVE: Peritoneal spread is an adverse outcome in ovarian cancer. Despite clinical efficiency, intraperitoneal (i.p.) chemotherapy after cytoreductive surgery is associated with high systemic and local toxicity. Two polymer-drug delivery systems (P-HYD1-DOX and P-HYD2-DOX) were developed for i.p. administration by conjugating doxorubicin (DOX) to a poly(l-Lysine citramide) polymer carrier with a hydrazone-based degradable spacer. The aim of this study was to assess the antitumoral efficacy of these two conjugates in a xenograft model of human ovarian carcinomatosis. METHODS: Peritoneal carcinomatosis was generated in athymic mice by i.p. injection of SKOV3-Luc cells. Free DOX, P-HYD1 DOX and P-HYD2-DOX solutions were administered i.p. at the same dose of 10 mg/kg (DOX eq.). For each treatment, tumor load and therapeutic efficacy were compared to untreated mice and assessed by bioluminescence imaging and survival rates. Toxicity profiles in each group and biodistribution of P-HYD2-DOX after i.p. administration were also determined. RESULTS: P-HYD-1-DOX and P-HYD-2-DOX demonstrated significant antitumoral efficacy against peritoneal carcinomatosis. Compared to untreated group, P-HYD1-DOX improved median survival times from 58 to 105 days. For P-HYD2-DOX, median survival was not reached after a follow-up of 120 days. Bioluminescence showed high efficacy of P-HYD-2-DOX compared to free DOX but the difference was not significant. Biodistribution study confirmed that free and active DOX were successively released from P-HYD2-DOX in vivo. P-HYD-DOX conjugates were well tolerated by mice after i.p. injection. CONCLUSION: P-HYD DOX conjugates demonstrated significant activity against peritoneal carcinomatosis in a xenograft model of ovarian carcinomatosis and their ability to release active DOX in i.p. deposits and tumor. These features are of clinical interest for i.p. administration in the treatment of ovarian peritoneal carcinomatosis after cytoreductive surgery. PMID- 21665253 TI - Human papillomavirus DNA and mRNA positivity of the anal canal in women with lower genital tract HPV lesions: predictors and clinical implications. AB - OBJECTIVE: Women with HPV related pathology of the lower genital tract are at higher risk for AIN and anal cancer than the general population. A strategy to identify anal disease in these women has not been formulated. The aim of this study is to examine the feasibility of HPV related biomarker testing on anal smears, to identify the risk factors for anal HPV positivity and to provide information of the clinical implications of anal HPV infection in this population. METHODS: In women referred for colposcopy because of HPV related pathology of the lower genital tract (cervical cancer, CIN, VIN, warts) a detailed questionnaire, an anal smear and a cervical smear were taken. On each sample morphological cytology, flow cytometric evaluation of E6&7 mRNA, and HPV DNA detection and typing were performed. Women with a positive anal result were referred for high resolution anoscopy. RESULTS: So far 235 women have been included (mean age 34.3). HPV DNA, high-risk HPV DNA, high-risk mRNA was detected in 45%, 31% and 8% of the anal smears and in 56%, 39% and 25% of the cervical smears respectively. Absolute or partial concordance of the types between the cervix and the anus was seen in 74%. Positivity for mRNA was significantly lower in the anus than the cervix (8% vs 25%). Logistic regression analysis revealed risk factors for the presence of anal HPV DNA (>3 lifetime sexual partners and presence of cervical HPV DNA), hr HPV DNA (presence of cervical hr HPV DNA), and hr mRNA (presence of cervical hr mRNA). Twelve months after LLETZ 53% of women were cervical HPV negative, but 25% of those were still HPV positive in the anus. CONCLUSIONS: HPV infection of the anus is common in this group and is interlinked with the cervical infection. Anal HPV E6&7 mRNA expression is less common than in the cervix. Possible clinical implications of anal infection could be the development of AIN and recurrence of CIN after treatment due to cervical reinfection from the anal reservoir. The use of HPV biomarkers is feasible in anal smears, although especially DNA testing as triage method for referral to anoscopy is probably inappropriate due to high positivity rate. PMID- 21665254 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: multi-institutional phase-II trial. AB - OBJECTIVE: The primary end-point of this multi-institutional phase-II trial was to assess results in terms of overall survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in treatment-naive epithelial ovarian cancer (EOC) with advanced peritoneal involvement. Secondary end-points were treatment morbi-mortality and outcome effects of time to subsequent adjuvant systemic chemotherapy (TTC). METHODS: Twenty-six women with stage III-IV EOC were prospectively enrolled in 4 Italian centers to undergo CRS and closed-abdomen HIPEC with cisplatin and doxorubicin. Then they received systemic chemotherapy with carboplatin (AUC 6) and paclitaxel (175 mg/m(2)) for 6 cycles. RESULTS: Macroscopically complete cytoreduction was achieved in 15 patients; only minimal residual disease (<=2.5 mm) remained in 11. Major complications occurred in four patients and postoperative death in one. After a median follow-up of 25 months, 5-year overall survival was 60.7% and 5-year progression-free survival 15.2% (median 30 months). Excluding operative death, all the patients underwent systemic chemotherapy at a median of 46 days from combined treatment (range: 29-75). The median number of cycles per patient was 6 (range: 1-8). The time to chemotherapy did not affect the OS or PFS. CONCLUSIONS: In selected patients with advanced stage EOC, upfront CRS and HIPEC provided promising results in terms of outcome. Morbidity was comparable to aggressive cytoreduction without HIPEC. Postoperative recovery delayed the initiation of adjuvant systemic chemotherapy but not sufficiently to impact negatively on survival. These data warrant further evaluation in a randomized clinical trial. PMID- 21665255 TI - Prevalence of asthma in young children. PMID- 21665258 TI - Clarification concerning amoxicillin skin testing. PMID- 21665261 TI - Sublingual immunotherapy: allergen specific or placebo effect? PMID- 21665262 TI - Reducing "white rush" use: emergency department and multidisciplinary community agency collaboration. PMID- 21665263 TI - Non-invasive quantification of resin-dentin interfacial gaps using optical coherence tomography: validation against confocal microscopy. AB - OBJECTIVES: Regardless of the cause, gap formation at the tooth-restoration interface may result in treatment failure; non-destructive assessment and monitoring of these defects are important. The aim of this in vitro study is to assess the tooth-restoration interface using a non-invasive technique; swept source optical coherence tomography (SS-OCT) and to confirm the findings with confocal laser scanning microscope (CLSM). METHODS: Cylindrical class-I cavities (3mm in diameter and 1.5mm in depth) were prepared in the occlusal surface of human premolars. Each cavity was restored using an all-in-one adhesive system (Clearfil Tri-S Bond) and one of the three types of composites placed in bulk; Majesty Posterior, AP-X and Majesty LV (all by Kuraray Medical, Japan). Ten serial cross-sectional images of the whole restored cavity were obtained by SS OCT at 1319 nm center wave length, to which locations the specimens were later trimmed, polished and observed under CLSM. An image analysis software was used to detect significant peaks in the signal intensity at the resin-dentin interface of the cavity floor. The presence and dimensions of gaps at the interface were also confirmed by CLSM. RESULTS: Increased SS-OCT signal intensity along the interface corresponded well to the interfacial gaps detected by CLSM. The actual gap size detected ranged from 26 MUm to 1.9 mm in length, and the universal composite APX showed lowest interfacial gaps. CONCLUSION: SS-OCT imaging technology can be used to non-invasively detect and quantify micrometer gaps at the bottom of composite restorations, and potentially become a monitoring tool for composite restorations both in the laboratory research, and in the clinics. PMID- 21665264 TI - Antithrombotics and stent type for primary PCI. PMID- 21665265 TI - Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. AB - BACKGROUND: Primary results of the HORIZONS-AMI trial have been previously reported. In this final report, we aimed to assess 3-year outcomes. METHODS: HORIZONS-AMI was a prospective, open-label, randomised trial undertaken at 123 institutions in 11 countries. Patients aged 18 years or older were eligible for enrolment if they had ST-segment elevation myocardial infarction (STEMI), presented within 12 h after onset of symptoms, and were undergoing primary percutaneous coronary intervention. By use of a computerised interactive voice response system, we randomly allocated patients 1:1 to receive bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI; pharmacological randomisation; stratified by previous and expected drug use and study site) and, if eligible, randomly allocated 3:1 to receive a paclitaxel-eluting stent or a bare metal stent (stent randomisation; stratified by pharmacological group assignment, diabetes mellitus status, lesion length, and study site). We produced Kaplan-Meier estimates of major adverse cardiovascular events at 3 years by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00433966. FINDINGS: Compared with 1802 patients allocated to receive heparin plus a GPI, 1800 patients allocated to bivalirudin monotherapy had lower rates of all-cause mortality (5.9%vs 7.7%, difference -1.9% [-3.5 to -0.2], HR 0.75 [0.58 0.97]; p=0.03), cardiac mortality (2.9%vs 5.1%, -2.2% [-3.5 to -0.9], 0.56 [0.40 0.80]; p=0.001), reinfarction (6.2%vs 8.2%, -1.9% [-3.7 to -0.2], 0.76 [0.59 0.99]; p=0.04), and major bleeding not related to bypass graft surgery (6.9%vs 10.5%, -3.6% [-5.5 to -1.7], 0.64 [0.51-0.80]; p=0.0001) at 3 years, with no significant differences in ischaemia-driven target vessel revascularisation, stent thrombosis, or composite adverse events. Compared with 749 patients who received a bare-metal stent, 2257 patients who received a paclitaxel-eluting stent had lower rates of ischaemia-driven target lesion revascularisation (9.4%vs 15.1%, -5.7% [-8.6 to -2.7], 0.60 [0.48-0.76]; p<0.0001) after 3 years, with no significant differences in the rates of death, reinfarction, stroke or stent thrombosis. Stent thrombosis was high (>=4.5%) in both groups. INTERPRETATION: The effectiveness and safety of bivalirudin monotherapy and paclitaxel-eluting stenting are sustained at 3 years for patients with STEMI undergoing primary percutaneous coronary intervention. FUNDING: Boston Scientific and The Medicines Company. PMID- 21665266 TI - UN High-Level Meeting on Non-Communicable Diseases: addressing four questions. AB - Non-communicable diseases (NCDs), principally heart disease, stroke, cancer, diabetes, and chronic respiratory diseases, are a global crisis and require a global response. Despite the threat to human development, and the availability of affordable, cost-effective, and feasible interventions, most countries, development agencies, and foundations neglect the crisis. The UN High-Level Meeting (UN HLM) on NCDs in September, 2011, is an opportunity to stimulate a coordinated global response to NCDs that is commensurate with their health and economic burdens. To achieve the promise of the UN HLM, several questions must be addressed. In this report, we present the realities of the situation by answering four questions: is there really a global crisis of NCDs; how is NCD a development issue; are affordable and cost-effective interventions available; and do we really need high-level leadership and accountability? Action against NCDs will support other global health and development priorities. A successful outcome of the UN HLM depends on the heads of states and governments attending the meeting, and endorsing and implementing the commitments to action. Long-term success requires inspired and committed national and international leadership. PMID- 21665257 TI - Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. AB - BACKGROUND: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity. The course of the disease is characterized by neurologic manifestations, infections, and cancers. OBJECTIVE: We studied A-T progression and investigated whether manifestations were associated with the ATM genotype. METHODS: We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers. RESULTS: Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality. Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations. CONCLUSION: Morbidity and mortality among patients with A-T are associated with ATM genotype. This information could improve our prognostic ability and lead to adapted therapeutic strategies. PMID- 21665267 TI - Delivery of calf thymus DNA to tumor by folate receptor targeted cationic liposomes. AB - Calf thymus DNA (ctDNA) has been shown to stimulate macrophages to produce cytokines both in vitro and in vivo when complexed with cationic liposomes. In addition, direct cytotoxicity of ctDNA has been found in tissue culture and in mice. In this study, ctDNA and folate receptor targeted cationic liposome complexes (ctDNA-F-CLs) were prepared and evaluated in FR (+) tumors. In addition, the underlying mechanism for the anti-cancer activity of ctDNA-F-CLs was investigated. Selective uptake of ctDNA-F-CLs was observed in FR (+) KB and L1210JF cells using flow cytometry. In RAW264.7 cells and DBA/2 mice, ctDNA-F-CLs and ctDNA-N-CLs significantly induced TNF-alpha and IL-6 production compared to free ctDNA. However, no significant difference in cytokine production was observed between ctDNA-N-CLs and ctDNA-F-CLs. In tumor bearing DBA/2 mice, ctDNA F-CLs significantly increased INF-gamma and IL-6 production compared to ctDNA-N CLs. Furthermore in L1210JF cells, ctDNA-F-CLs had significantly increased cytotoxicity compared to ctDNA-N-CLs. Tumor cell apoptosis was also found in co culture of RAW264.7 cells and ctDNA-F-CLs treated L1210JF cells. In L1210JF tumor bearing mice, ctDNA-F-CLs were found to significantly inhibit tumor growth and prolong the median survival time (MeST). In contrast, ctDNA-N-CLs and free ctDNA showed similar activities for tumor inhibition and animal survival. Moreover, the anti-cancer effect of ctDNA-F-CL was further enhanced by combination with anti cancer drug doxorubicin. These results suggest that ctDNA-F-CLs are a promising agent for treatment of FR-positive tumors. PMID- 21665268 TI - Quantification of in vitro and in vivo angiogenesis stimulated by ovine forestomach matrix biomaterial. AB - Ovine forestomach matrix (OFM) biomaterial acts as a biomimetic of native extracellular matrix (ECM) by providing structural and functional cues to orchestrate cell activity during tissue regeneration. The ordered collagen matrix of the biomaterial is supplemented with secondary ECM-associated macromolecules that function in cell adhesion, migration and communication. As angiogenesis and vasculogenesis are critical processes during tissue regeneration we sought to quantify the angiogenic properties of the OFM biomaterial. In vitro studies demonstrated that soluble OFM components stimulated human umbilical vein endothelial cell (HUVEC) migration and increased vascular sprouting from an aorta. Blood vessel density and branch points increased in response to OFM in an ex ovo chicken chorioallantoic membrane (CAM) assay. The OFM biomaterial was shown to undergo remodeling in a porcine full-thickness excisional model and gave rise to significantly more blood vessels than wounds treated with small intestinal submucosa decellularized ECM or untreated wounds. PMID- 21665269 TI - Spatio-temporal detachment of single cells using microarrayed transparent electrodes. AB - This paper describes a dynamic cell manipulation approach by which cells can be selectively detached from transparent indium tin oxide (ITO) electrodes via electrochemical desorption of a self-assembled monolayer (SAM) of alkanethiol. Changes in the surface properties of ITO following modification and electrical desorption of the SAM were characterized. By using these reactions on ITO, cells were readily attached and then detached from ITO electrodes in a very rapid manner, with greater than 90% of the cells being detached within 5 min. Furthermore, we fabricated micropatterns of ITO electrodes using photolithography. Cells on the micropatterned ITO electrodes could be detached with single-cell resolution. This approach could potentially lead to on-demand harvesting or elimination of one population from others under microscopy, for a wide range of purposes. PMID- 21665270 TI - MicroRNA regulation associated chondrogenesis of mouse MSCs grown on polyhydroxyalkanoates. AB - Microbial polyhydroxyalkanoates (PHA) including poly(3-hydroxybutyrate-co-3 hydroxyhexanoate) (PHBHHx) were found to induce chondrogenesis of mesenchymal stem cells (MSCs) and preserve chondrocytic phenotype as well as support chondrocytes-specific extracellular matrix (ECM) secretion. In this study, mouse MSCs cultured on the PHBHHx films for 24 h showed up-regulated expression of chondrogenic marker genes including aggrecan, col2, sox9, col10 and pthrp. To further illustrate this phenomonon, chondrogenesis-related microRNA expression profiling was examined by quantitative real-time PCR (RT-PCR) based on results of microRNA array obtained from comparison between mouse MSCs and mature mouse chondrocytes. Among 44 microRNAs related to chondrogenesis on microrray studies, considering only broadly-conserved microRNAs, seven differentially-expressed microRNAs were selected to study their target genes related to chondrogenesis. Two microRNAs out of the seven, namely, miR-29a and miR-29b, were revealed to directly target 3' UTR of col2a1 encoding type II collagen by dual-luciferase assay, and their activity was under the regulation of Sox9, the SRY-related high mobility group-box gene 9. For the first time microRNAs were shown to regulate the stem cell differentiation processes mediated by cell-material interactions. PMID- 21665271 TI - Drug carrier nanoparticles that penetrate human chronic rhinosinusitis mucus. AB - No effective therapies currently exist for chronic rhinosinusitis (CRS), a persistent inflammatory condition characterized by the accumulation of highly viscoelastic mucus (CRSM) in the sinuses. Nanoparticle therapeutics offer promise for localized therapies for CRS, but must penetrate CRSM in order to avoid washout during sinus cleansing and to reach underlying epithelial cells. Prior research has not established whether nanoparticles can penetrate the tenacious CRSM barrier, or instead become trapped. Here, we first measured the diffusion rates of polystyrene nanoparticles and the same nanoparticles modified with muco inert polyethylene glycol (PEG) coatings in fresh, minimally perturbed CRSM collected during endoscopic sinus surgery from CRS patients with and without nasal polyp. We found that uncoated polystyrene particles, previously shown to be mucoadhesive in a number of human mucus secretions, were immobilized in all CRSM samples tested. In contrast, densely PEGylated particles as large as 200 nm were able to readily penetrate all CRSM samples from patients with CRS alone, and nearly half of CRSM samples from patients with nasal polyp. Based on the mobility of different sized PEGylated particles, we estimated the average pore size of fresh CRSM to be at least 150 +/- 50 nm. Guided by these studies, we formulated mucus-penetrating particles composed of poly(lactide-co-glycolide) (PLGA) and Pluronics, two materials with a long history of safety and use in humans. We showed that these biodegradable particles are capable of rapidly penetrating CRSM at average speeds up to only 20-fold slower than their theoretical speeds in water. Our findings strongly support the development of mucus-penetrating nanomedicines for the treatment of CRS. PMID- 21665272 TI - Characterization of the pattern of ischemic stroke induced by artificial particle embolization in the rat brain. AB - Embolism is responsible for half of cerebral infarctions, yet few animal models were developed due to the unpredictability of the embolus-induced infarcts. We manufactured artificial embolic particles by blending chitin and poly(D,L-Lactide co-glycolide) (chitin/PLGA) for their good biocompatibility and rapid hydration expansion property. We subdivided the chitin/PLGA microparticles into 10 size groups (from 38-45 MUm to 255-350 MUm) and injected them through the external carotid artery toward the bifurcation of the common carotid artery in the rat. Reduced blood flow of the ipsilateral hemisphere was evident immediately after the injection of particles. The spherical appearance of the particle was critical in occluding the cerebral vessels. Particle(212-250 MUm) produced the greatest diffuse infarction in the ipsilateral hemisphere, including the cortex, hippocampus, basal ganglion, thalamus, midbrain and cerebellum. Particle(75-90 MUm) induced single or sparse isolated infarcts mainly located in the subcortical region, resembling lacunar stroke observed in humans. Particle(38-45 MUm) frequently crossed to the contralateral hemisphere and induced diffuse infarctions in both hemispheres. The cortex infarct volumes were positively correlated to neurologic score and seizure incidence. In conclusion, we have established embolic stroke animal models, including a novel model that mainly expresses lacunar infarction, by intravenous injection of chitin/PLGA microparticles. PMID- 21665274 TI - ORAI-mediated calcium influx in T cell proliferation, apoptosis and tolerance. AB - Ca(2+) homeostasis controls a diversity of cellular processes including proliferation and apoptosis. A very important aspect of Ca(2+) signaling is how different Ca(2+) signals are translated into specific cell functions. In T cells, Ca(2+) signals are induced following the recognition of antigen by the T cell receptor and depend mainly on Ca(2+) influx through store-operated CRAC channels, which are mediated by ORAI proteins following their activation by STIM proteins. The complete absence of Ca(2+) influx caused by mutations in Stim1 and Orai1 leads to severe immunodeficiency. Here we summarize how Ca(2+) signals are tuned to regulate important T cell functions as proliferation, apoptosis and tolerance, the latter one being a special state of immune cells in which they can no longer respond properly to an otherwise activating stimulus. Perturbations of Ca(2+) signaling may be linked to immune suppressive diseases and autoimmune diseases. PMID- 21665273 TI - How does variability of immune system genes affect placentation? AB - Formation of the placenta is a crucial step in mammalian pregnancy. Apart from its function in ensuring an optimal supply of nutrients and oxygen to the fetus, the placenta is also the interface at which allo-recognition of invading trophoblast cells by the maternal immune system can potentially occur. We summarise here the "state of the art" on how variability of immune system genes that code for major histocompatibility complex (MHC) molecules and natural killer receptors (NKR) may impact on human placentation. MHC and NKR are the most polymorphic human genes. Our recent reports point out that specific combinations of fetal MHC and maternal NKR genes in humans correlate with the risk of pre eclampsia, recurrent miscarriage (RM) and fetal growth restriction (FGR). Research in this field is still at an early stage and future studies in mouse and humans will be needed before the results can be translated to clinical applications. We discuss our recent work, as well as the opportunities offered by mouse genetics, to understand the cellular and molecular mechanisms underlying immune interactions at the maternal-fetal interface. PMID- 21665275 TI - Adaptation of the plasma inhibitory activity assay to detect Aurora, ABL and FLT3 kinase inhibition by AT9283 in pediatric leukemia. AB - Non-invasive assessment of biomarker modulation is important for evaluating targeted therapeutics, particularly in pediatrics. The plasma inhibitory activity (PIA) assay is used clinically to assess FLT3 inhibition ex vivo and guide dosing. AT9283 is a novel Aurora kinase inhibitor with secondary activity against FLT3 and ABL. We adapted the PIA assay to simultaneously detect inhibition of Aurora and FLT3 in AML, and Aurora and ABL in CML by AT9283. Furthermore, we optimized the assay for children, where limited blood volumes are available for pharmacodynamic studies. Simultaneously detecting multiple kinase inhibition may identify important mechanisms of action for novel anti-leukemic drugs. PMID- 21665276 TI - Using the theory of planned behavior to predict the use of incentive spirometry among cardiac surgery patients in Taiwan. AB - OBJECTIVE: The use of incentive spirometry (IS) is reported to prevent and treat postoperative pulmonary complications. This study sought to use the theory of planned behavior to predict the use of IS in this population. METHODS: The study used a prospective design, with convenience sampling, to recruit a total of 116 postcardiac-surgery patients from 2 medical centers in Taipei, Taiwan, from November 2008 to May 2009. Data were collected through 2 instruments: a demographic questionnaire, and an IS questionnaire. Descriptive analysis, independent t test, one-way analysis of variance, binary regression, and liner regression were used to analyze the data. RESULTS: Perceived behavioral control, but not intention, was a predictor of the use of IS. CONCLUSION: Our findings provide partial support for the utility of the theory of planned behavior in explaining the use of IS behavior for cardiac surgery patients. PMID- 21665277 TI - Identification of novel innate immune genes by transcriptional profiling of macrophages stimulated with TLR ligands. AB - Toll-like receptors (TLRs) are key receptors in innate immunity and trigger responses following interaction with pathogen-associated molecular patterns (PAMPs). TLR3, TLR4 and TLR9 recognize double stranded RNA, lipopolysaccharide (LPS) and CpG DNA, respectively. These receptors differ importantly in downstream adaptor molecules. TLR4 signals through MyD88 and TRIF; in contrast, the TLR3 pathway involves only TRIF while TLR9 signals solely through MyD88. To determine how differences in downstream signaling could influence gene expression in innate immunity, gene expression patterns were determined for the RAW264.7 macrophage cell line stimulated with LPS, poly (I:C), or CpG DNA. Gene expression profiles 6 and 24h post-stimulation were analyzed to determine genes, pathways and transcriptional networks induced. As these experiments showed, the number and extent of genes expressed varied with stimulus. LPS and poly (I:C) induced an abundant array of genes in RAW264.7 cells at 6h and 24h following treatment while CpG DNA induced many fewer. By analyzing data for networks and pathways, we prioritized differentially expressed genes with respect to those common to the three TLR ligands as well as those shared by LPS and poly (I:C) but not CpG DNA. The importance of changes in gene expression was demonstrated by experiments indicating that RNA interference-mediated inhibition of two genes identified in this analysis, PLEC1 and TPST1, reduced IL-6 production by J774A.1 and RAW264.7 macrophages stimulated with LPS. Together, these findings delineate macrophage gene response patterns induced by different PAMPs and identify new genes that have not previously been implicated in innate immunity. PMID- 21665278 TI - Killer cell immunoglobulin-like receptor genes in Spanish multiple sclerosis patients. AB - Killer cell immunoglobulin-like receptors (KIRs) are regulators of cytolytic activity of natural killer and certain T cells through interactions with human leukocyte antigen (HLA) class I ligands. KIRs have been shown to contribute to the pathogenesis of several autoimmune diseases, but their role in multiple sclerosis (MS) is still unclear. Here we determined the influence of KIR genes and their HLA class I ligands on susceptibility to MS and on the response to interferon-beta treatment in a Spanish population. KIR and HLA genotyping were performed in 200 MS patients and 200 controls. Significantly higher frequencies were found for KIR2DL5 and KIR3DS1 genes in MS patients and the carriage of the KIR2DL1 gene was associated with a higher progression index. Moreover, the frequency of the HLA-Bw4 motif was significantly reduced in MS patients. The KIR2DL1 and HLA-C2 matches were more frequent in MS patients, whereas the KIR3DL1 and HLA-Bw4 matches were more frequent in healthy controls. Nevertheless, non significant associations were found between all the KIR genes and therapeutic response to interferon-beta. Our results confirm that the carriage of HLA-Bw4 is a protective factor in MS and suggest that KIR2DL5 and KIR3DS1 may have a predisposing role in the disease. PMID- 21665279 TI - Corneal refractive power and its associations with ocular and general parameters: the Central India Eye and Medical Study. AB - PURPOSE: To investigate the normal distribution of corneal refractive power (CRP) and its associations with other ocular and systemic parameters in the Central Indian population. DESIGN: Population-based study. PARTICIPANTS: The Central India Eye and Medical Study is a population-based study performed in a rural region of Central India. The study comprised 4711 subjects aged 30+ years. METHODS: A detailed ophthalmic and medical examination was performed. Horizontal and vertical CRP were measured using a non-automatic keratometer. MAIN OUTCOME MEASURES: Corneal refractive power. RESULTS: After excluding pseudophakic or aphakic eyes, keratometric measurements were available on 9024 eyes of 4617 study participants (98.0%) with a mean age of 49.1+/-13.2 years (range, 30-100 years) and a mean refractive error of -0.20+/-1.52 diopters (D). Mean horizontal CRP was 44.60+/-1.68 D (mean +/- standard deviation; range, 36.5-52.0 D), and vertical CRP was 44.62+/-1.74 D (range, 37.75-52.0 D) with no significant difference between both parameters (P=0.27). In multivariate analysis, CRP was significantly (P < 0.001) associated with the systemic parameters of increasing age (P < 0.001), lower level of education (P=0.02), and lower body height (P < 0.001), and with the ocular parameters of thinner central corneal thickness (P < 0.001), deeper anterior chamber (P < 0.001), shorter axial length (P < 0.001), and myopic refractive error (P < 0.001). The results remained unchanged if eyes with CRP >=48 D were excluded. CONCLUSIONS: Horizontal CRP increased with higher age, lower level of education, lower body height, thinner central cornea, deeper anterior chamber, shorter axial length, and myopic refractive error. The association with age may be of importance for refractive surgery. The association of a steeper cornea with a shorter body stature and a shorter axial length parallels an association between shorter body length and shorter axial length without association with refractive error. The association among steeper cornea, shorter body length, and lower educational level complements the association between shorter body length and lower educational level. The correlation between steeper cornea and deeper anterior chamber may be explained geometrically. PMID- 21665280 TI - Prevalence and characteristics of abnormal head posture in children with Down syndrome: a 20-year retrospective, descriptive review. AB - PURPOSE: To characterize the abnormal head posture (AHP) in children with Down syndrome (DS). The study had 3 aims: to estimate the prevalence of AHP, to describe the distribution of different causes for AHP, and to evaluate the long term outcomes of AHP in children with DS evaluated at the University of Iowa Hospitals and Clinics between 1989 and 2009. DESIGN: Retrospective chart review. PARTICIPANTS: Two hundred fifty-nine patient records. METHODS: The study data were analyzed using chi-square tests (the Fisher exact test when appropriate) to describe the relationship between the outcome of interest and each study covariate. A predictive logistic regression model for AHP was constructed including all the significant covariates. MAIN OUTCOME MEASURES: Abnormal head posture. RESULTS: Over the study period, 259 records of patients with DS were identified. Of these, 64 (24.7%) patients had AHP. The most frequent cause of AHP was incomitant strabismus in 17 (26.6%) of 64 patients. The second most frequent cause of AHP was nystagmus, in 14 (21.8%) of 64 patients. For a substantial number of patients with AHP, the cause could not be determined. They represented 12 (18.8%) of all the patients with AHP in this study and 12 (4.6%) of all patients with DS examined. When compared with patients with AHP from a determined cause, this subgroup has a statistically significantly (P = 0.027, Fisher exact test) higher percentage of atlantoaxial instability. In the study population, 9 (14.1%) of 64 patients with AHP had more than 1 cause for AHP. Refractive errors, ptosis, unilateral hearing loss, and neck and spine musculoskeletal abnormalities were responsible for AHP in a small percentage of patients. Of all the patients with AHP, 23 (35.9%) improved their head posture with treatment (glasses or surgery). An additional 6 (9.4%) patients improved their posture spontaneously, over time and without treatment. CONCLUSIONS: The prevalence of AHP in the children with DS evaluated was 24.7%. From this analysis, having strabismus of any kind and particularly incomitant strabismus, nystagmus, or both is highly correlated with the development of an AHP. Almost 19% of DS patients with AHP had no definitive cause that could be determined. PMID- 21665281 TI - Invasive aspergillosis of orbit in immunocompetent patients: treatment and outcome. AB - OBJECTIVE: Invasive sino-orbital aspergillosis in immunocompetent patients is a rare clinical entity and often misdiagnosed. Invasive sino-orbital aspergillosis is potentially fatal; however, mortality may be avoided with timely treatment. Presently, there are no universal guidelines for its treatment. We present the clinical features, treatment, and outcome in 15 cases of invasive sino orbital/orbital aspergillosis in healthy individuals. DESIGN: Retrospective case series. PARTICIPANTS: Fifteen cases of invasive sino-orbital/orbital aspergillosis in immunocompetent individuals. METHODS: We retrospectively analyzed all patients with sino-orbital/orbital aspergillosis who were treated at the Dr. Rajendra Prasad Center for Ophthalmic Sciences between June 1999 and September 2009. Diagnosis was based on histopathologic documentation of tissue invasion by septate fungal hyphae with acute angle branching and presence of granulomatous inflammation. MAIN OUTCOME MEASURES: Treatment outcome in terms of patient survival, resolution of symptoms, and resolution of orbital mass on imaging. RESULTS: Fifteen patients (11 male and 4 female) were studied. Mean age of patients was 35 years. One patient declined treatment. Surgery was performed for orbital disease in 6 patients. Medical therapy consisted of intravenous amphotericin B followed by itraconazole in 10 patients, itraconazole alone in 2 patients, and voriconazole followed by itraconazole in 2 patients. Eleven patients are alive without recurrence at a median follow-up of 20 months. Of these patients, 5 had residual mass on imaging at last follow-up. One patient died of progressive disease. CONCLUSIONS: This is a large case series of orbital aspergillosis reported in healthy individuals. The role of orbital surgery is not clear in treatment of this entity and requires further evaluation. Newer antifungal agents alone seem to be effective in controlling the infection. PMID- 21665282 TI - The influence of tilt, decentration, and pupil size on the higher-order aberration profile of aspheric intraocular lenses. AB - PURPOSE: To characterize the influence of tilt angle, decentration, and pupil size on the higher-order aberration (HOA) profile of 3 aspheric intraocular lenses (IOLs) using a physical model eye. DESIGN: A 4-factor (model, pupil, angle, decentration) in vitro experimental design comparing 3 aspheric IOLs using a physical model eye. METHODS: Measurements of HOA were obtained using the Zywave aberrometer (Bausch & Lomb, Rochester, NY) and a purpose-built physical model eye. The following IOLs were assessed with various levels and combinations of pupil diameter, decentration, and tilt angle: the AcrySof IQ SN60WF aspheric (Alcon, Hunenberg, Switzerland), Technis ZA9003 aspheric (Advanced Medical Optics, Santa Ana, CA), and Adapt Advanced Optics (Bausch & Lomb). Fifteen Zernike modes were compared using multivariate analysis of variance, canonical discrimination, and regression analysis. Four identical IOLs of each IOL model were assessed at all possible combinations of 3 pupil sizes, 4 levels of decentration, and 4 tilt angles. MAIN OUTCOME MEASURES: Individual HOA from z200 to z550. RESULTS: Pupil size, decentration, model, and tilt angle all had statically significant effects on the HOA profile. Pupil size contributed most to observed total variability (54.9%), followed by decentration (22.7%), then model (16.6%), and finally tilt angle (5.7%). All factors demonstrated significant interaction terms with respect to HOA. Intraocular lenses with increased aspheric properties inherent in the design of the optic were more sensitive to decentration and change in pupil size. CONCLUSIONS: The 3 IOL models demonstrated significant differences in HOAs in response to changes in pupil size, decentration, and tilt angle. All IOL models assessed in this study demonstrated minimal HOA at small pupil diameters. The IOL models with lower, or an absence of, negative spherical aberration were most robust to displacement with increased decentration and tilt angle. PMID- 21665283 TI - Initial parafoveal versus peripheral scotomas in glaucoma: risk factors and visual field characteristics. AB - OBJECTIVE: To assess risk factors for an initial parafoveal scotoma (IPFS) compared with an initial nasal step (INS) in glaucoma. DESIGN: Retrospective, observational study. PARTICIPANTS: Sixty-nine patients with glaucoma with an isolated IPFS and 53 patients with an isolated INS. METHODS: On the basis of 2 reliable, consistent 24-2 Swedish interactive threshold algorithm standard visual fields (VFs), 2 groups of patients with glaucoma were studied: those with an IPFS in 1 hemifield (>=3 adjacent points with P<5% within the central 10 degrees of fixation, >=1 point with P<1% lying at the innermost paracentral points, and no VF abnormality outside the central 10 degrees) and those with an INS in 1 hemifield (>=3 adjacent points with P<5% in the nasal periphery outside 10 degrees of fixation, the nasal-most point with P<1%, and no VF abnormality within the central 10 degrees). Clinical characteristics and systemic factors were recorded from charts and compared between the 2 groups. MAIN OUTCOME MEASURES: Maximum untreated intraocular pressure (IOP), disc hemorrhage (DH) detection during follow-up, systemic risk factors, and VF mean deviation (MD) and pattern standard deviation (PSD). RESULTS: Maximum untreated IOP (21.6+/-4.5 vs. 28.3+/ 9.6 mmHg; P<0.001) was significantly lower, and frequency of DH detection (44% vs. 17%; P=0.001) and systemic risk factors (hypotension, migraine, Raynaud's phenomenon, and sleep apnea; 16%, 23%, 24%, and 9% vs. 0%, 4%, 9%, and 0%; P=0.001, 0.002, 0.025, and 0.030, respectively) were significantly higher in patients with an IPFS than in patients with an INS. There were no significant differences in age, gender, family history of glaucoma, refractive error, central corneal thickness, and disc area between the 2 groups (all P>0.1). Mean deviation was similar between the 2 groups (P=0.346), but PSD was significantly greater in the IPFS group than in the INS group (P=0.043). CONCLUSIONS: Eyes with an IPFS differ from those with an INS. These findings may help clinicians identify patients at higher risk of early central field loss. PMID- 21665284 TI - Experience matters: 11-month-old infants can learn to use material information to predict the weight of novel objects. AB - In contrast to previous findings, this study demonstrates that 11-month-old infants are able to learn the relationship between object material and object weight when exploring different objects that provided a systematic covariation of both object features. This guides their action in a subsequent preferential reaching task. PMID- 21665285 TI - Seasonality of Chinese rural young suicide and its correlates. AB - BACKGROUND: There had been few studies on seasonality of Chinese suicide especially for Chinese rural youths. In this research, we wanted to find the seasonal pattern and the relationship between personal and behavioral characteristics and seasonal variation of suicide. METHOD: We examined Chinese rural young adults aged 15 to 34 years who died by suicide using Psychological Autopsy method to gather information from the informants of suicide victims. Altogether 330 suicide victims were collected among which 144 were female and 186 were male. The chi(2) test was used for comparison, and the multiple logistic regressions and Odds Ratios were adopted to analyze the seasonal preferences of suicide victims. RESULT: Seasonal summer peak of suicide emerged in total population and in each subgroup. Four logistic regression models were constructed: in spring, six variables were included in the regression model, which were Gender (OR = 1.627), Pesticide Used (OR = 1.622), Life Events (OR = 2.764), Suicide Intent (OR = 1.641), Marital Status (OR = 0.574) and Family Conflicts (OR = 0.590); in summer, only Marital Status (OR = 1.927) was accepted; in autumn, four variables including Marital Problems (OR = 1.924), Trait Anxiety (OR = 1.758), Gender (OR = 0.518) and Religion (OR = 0.534) were retained; in winter, Pesticide Used (OR = 0.486) and Suicide Intent (OR = 0.614) were retained. CONCLUSION: Seasonal variations of personal and behavioral characteristics, combined with social activities, might also play very important roles in suicide seasonality. PMID- 21665286 TI - Socioeconomic status and risk of psychological distress and depression in the Stockholm Public Health Cohort: a population-based study. AB - BACKGROUND: There is limited evidence whether the association between low socioeconomic status and risk of common mental disorders varies with symptom severity, type of socioeconomic indicator or gender. METHODS: A population-based survey was conducted among a random sample of Stockholm County residents aged 18 84 years in 2002. Respondents were reassessed via a follow-up questionnaire in 2007. Participants in both surveys (n = 23794) were categorized according to socioeconomic status at baseline and followed up for onset of psychological distress (according to the twelve-item general health questionnaire) and depression (according to health data registers). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Occupational class was not associated with risk of psychological distress, regardless of severity or gender. Occupational class was strongly associated with onset of depression in men (OR 3.0 [95% CI 1.5-5.9], comparing unskilled manual workers with higher non-manual workers) but not women. Income was associated with risk of onset of all outcomes, and risks increased with symptom severity. Belonging to the highest household income category was particularly protective of depression in women. Education was unrelated to either outcome in men and women overall. LIMITATIONS: Retention rate at follow-up was 76% and depression was ascertained via health service use. CONCLUSION: Low socioeconomic position is associated with onset of depression but not mild distress. Attributes of occupational class and household income may be respectively more relevant for the development of depression in men and women. PMID- 21665287 TI - What goes up can come down? A preliminary investigation of emotion reactivity and emotion recovery in bipolar disorder. AB - BACKGROUND: How is emotion disrupted in bipolar disorder? Two studies are presented that adopt a multi-method approach to investigate emotion reactivity and emotion recovery in bipolar I disorder. METHODS: Across both studies, individuals with inter-episode bipolar disorder and healthy controls were shown three emotion-eliciting films (neutral, happy, and sad) and experiential and physiological responses were measured. In Study 1, bipolar (BD; n=23) and non clinical control (NC; n=24) participants' emotional reactivity during film clips was assessed. In Study 2, a separate sample of BD (n=23) and NC (n=25) participants' emotion recovery was assessed after the film clips were assessed. RESULTS: Results indicated that the BD group exhibited increased self-reported positive emotion and respiratory sinus arrhythmia across all films compared to the NC group. There were no group differences in emotion recovery. DISCUSSION: Taken together, these results suggest that bipolar disorder is associated with increased positive emotion reactivity, but not emotion recovery, across contexts. PMID- 21665288 TI - Screening for depression with the Patient Health Questionnaire-2 (PHQ-2) among the general population in Hong Kong. AB - BACKGROUND: This study investigates the psychometric properties of the Patient Health Questionnaire-2 (PHQ-2) in the general population of Hong Kong. METHODS: Random sampling was used to recruit 6028 participants aged 15 years or over. Among them, 203 were surveyed twice within a two-week period. Participants completed the Chinese version of the PHQ-9 (including 2 items of the PHQ-2), the Chinese Health Questionnaire, the Happiness Scale, the SF-12, and questions about diagnosis and health service utilization. Internal consistency, test-retest reliability, construct and discriminant validity of the PHQ-2 were assessed. RESULTS: Cronbach's alpha was 0.76. The test-retest reliability over two weeks calculated by intraclass correlation was 0.70. Spearman correlation results showed that the PHQ-2 score was associated with the remaining seven items of the PHQ-9 (r = 0.53), the Chinese Health Questionnaire (r = 0.37), and the Happiness scale (r = -0.32). As expected, the strength of the correlation between the PHQ-2 and the SF-12 Physical Component Summary was lower (r = -0.29) than that with the SF-12 Mental Component Summary (r = -0.50). Participants with higher PHQ-2 scores more frequently reported having received a depression diagnosis made by a doctor, having chronic illness, using medicine, and utilizing health services. Using the cutoff point >= 3, 4.2% of participants screened positive for Major Depressive Disorder. LIMITATIONS: We did not use diagnostic interviews or other depression measures to test the PHQ-2's relative performance in screening for depression. CONCLUSIONS: This study provides evidence for the PHQ-2 as a reliable and valid screening tool for depressive symptoms among a randomly recruited community sample in Hong Kong. PMID- 21665290 TI - Impulsivity in anxiety disorder patients: is it related to comorbid cyclothymia? AB - OBJECTIVE: The relationship between anxiety and impulsivity is controversial and not well explored. In a previous study we compared impulsivity, measured by different rating tools, in patients with anxiety disorders vs. healthy controls. In the same sample we now explore the influence of comorbid soft bipolar spectrum disorders on the relationship between anxiety disorders and impulsivity. METHOD: A sample including 47 subjects with anxiety disorder(s) and 45 control subjects matched for demographic, educational and work characteristics underwent a diagnostic evaluation by the Mini Neuropsychiatric Interview (MINI); a symptomatological evaluation by the Bech-Rafaelsen Depression and Mania Scale (BRDMS), the State-Trait Anxiety Inventory (STAI), the Hypomania Check List (HCL 32) and the Clinical Global Impression (CGI); a temperamental and personological evaluation by the Questionnaire for the Affective and Anxious Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Modified (TEMPS-M), the Separation Anxiety Symptoms Inventory (SASI), the Interpersonal Sensitivity Symptoms Inventory (ISSI); and, finally, a psychometric and a neuro-cognitive evaluation of impulsivity by the Barratt Impulsiveness Scale (BIS) and the Immediate and Delayed Memory Task (IMT/DMT). The initial sample of patients with anxiety disorders was then subdivided into two subgroups depending on the presence of comorbid cyclothymia (Cyclo+, n=26 and Cyclo-, n=21). For the diagnosis of cyclothymic disorder, we used both the DSM-IV-TR criteria and also a modified threshold for hypomania with a duration of 2 days. We compared symptomatological, temperamental, personological and impulsivity measures in Cyclo+, Cyclo- and controls. RESULTS: The comparison between Cyclo+, Cyclo- and controls showed that Cyclo+ are the most impulsive subjects in all the investigated measures and are characterized by greatest symptomatological impairment, highest scores in temperamental scales, and highest levels of interpersonal sensitivity and separation anxiety. Cyclo- subjects resulted to be more impulsive compared to controls concerning the retrospective trait measures, but not in the neuro-cognitive test. LIMITATIONS: Correlational cross-sectional study. CONCLUSION: In our patients with anxiety disorders, without lifetime comorbidity with major mood episodes, trait and state impulsivity resulted to be greater than in controls. In particular impulsivity was highest in patients with both anxiety disorders and cyclothymia. In anxious-cyclothymic patients also separation anxiety and interpersonal sensitivity were more severe than in anxious patients without cyclothymia and controls. Our findings suggest that impulsivity, rather than being directly related to the presence of the anxiety disorder, could be associated with comorbidity with cyclothymia. PMID- 21665289 TI - Rural-urban differences in stigma against depression and agreement with health professionals about treatment. AB - OBJECTIVES: To determine if levels of personal stigma towards depression and agreement with health professionals about treatment differ between rural-urban populations. METHODS: Data from a telephone survey conducted in Alberta (n = 3047, response rate = 75.2%) was analyzed. Participants responded to a case vignette describing a depressed individual and questionnaires assessing attitudes towards treatments, and personal stigma against depression. The relation between rural-urban status and agreement with health professionals about treatment was assessed using logistic regression. Stigma scores in relation to rural-urban status were analyzed using multivariate linear regression. RESULTS: Urban respondents were more likely than rural participants to agree with health professionals about depression treatments. This was found overall, and in women. After adjustment for income and education, rural-urban status was no longer significant. Urban participants had lower stigma scores in overall analysis. After adjustment for income and education, stigma scores remained higher among rural men. Education was associated with lower stigma scores among both men and women in fully adjusted models. The ability to recognize depression was associated with lower stigma scores. CONCLUSIONS: Differences exist in rural urban population about treatments for depression and stigma towards depression. The rural-urban differences in stigma and agreement with health professionals about treatment may be largely explained by educational levels. PMID- 21665291 TI - Chronic prostatitis and depressive disorder: a three year population-based study. AB - BACKGROUND: There is limited research on the relationship between chronic prostatitis (CP) and the subsequent risk of depressive disorders (DD). This population-based study aims to prospectively examine the relationship between a history of CP and the risk of developing DD in Taiwan. METHODS: A total of 3051 adult patients, newly diagnosed with CP during 2001 to 2005, were recruited, together with 15,255 matched enrollees without a history of CP as a comparison cohort. All patients were tracked for a three year period from their index healthcare encounters to identify those who had subsequent DD. The Cox proportional hazards models were carried out to compute the risk of DD in the study and comparison cohorts, after adjustment for socio-demographic characteristics. RESULTS: Of a total of 18,306 patients, 163 (5.34%) from the CP group and 494 (3.24%) from the comparison group had a subsequent diagnosis of DD during the follow-up period. Stratified Cox proportional analysis shows that, after adjusting for monthly income, geographic region, and urbanization level of the community in which the patient resided, hypertrophy (benign) of prostate, and urinary incontinence, the hazard ratio of DD during the three year follow-up period is 1.63 for patients with chronic prostatitis (95% CI = 1.36-1.96) than those without chronic prostatitis. The differences are most significant in the younger group, aged less than 30 years (hazard ratio, 2.50; 95% CI = 1.18-4.51). CONCLUSIONS: These results suggest that CP patients experience an increased risk of DD compared to non-CP patients during a three year follow-up period. PMID- 21665292 TI - Impulsivity and internalizing disorders in childhood. AB - Impulsivity has often been related to externalizing disorders, but little is known about how it is related to symptoms of internalizing disorders. This study aims to examine the relationship between impulsivity and depression and anxiety symptoms of depression and anxiety in childhood, and compare it with its relationship with a measure of aggressive behavior, which is present in many externalizing disorders. We administered the Barratt Impulsiveness Scale-11 for children, the Children's Depression Inventory and the Screen for Children's Anxiety Related Emotional Disorders to a case-control sample of 562 children aged between 9 and 13 who were selected from an epidemiological study of anxiety and depression and whose teachers provided information about their proactive and reactive aggression. Impulsivity was related to measures of anxiety, depression and aggressive behavior, and showed higher relationships with measures of internalizing symptoms than with aggression. Motor impulsivity, a component of impulsivity related to inhibition deficits, was the component most related to anxiety and depression. Cognitive impulsivity, on the other hand, was negatively related to anxiety and depression. The relationships between impulsivity and symptoms of internalizing disorders seem to indicate that impulsivity should be taken into account not only in externalizing problems, but also in depression and anxiety in children and adolescents. PMID- 21665293 TI - Clinical correlates of maltreatment and traumatic experiences in childhood and adolescence among predominantly African American, socially disadvantaged, hospitalized, first-episode psychosis patients. AB - Associations among maltreatment and traumatic experiences in childhood and adolescence, later substance use, and subsequent mental health outcomes for individuals with schizophrenia-spectrum disorders have been initially explored in previous studies; however, research on these factors in socially disadvantaged patients with first-episode psychosis is unavailable. This exploratory, correlational analysis examined associations between maltreatment and trauma related variables (e.g., traumatic experiences, parental harsh discipline, violence exposure) and: social variables (years of education attained and extent of Axis IV psychosocial problems at initial hospitalization), substance abuse (age at initiation of alcohol and cannabis use, as well as estimates of lifetime intake of both), and positive and negative symptom severity. Rates of childhood abuse and traumatic events were remarkably high in the sample. Years of educational attainment and number of Axis IV psychosocial problems were substantially correlated with several domains of childhood abuse/traumatic events. Age at initiation of alcohol and cannabis use, and lifetime alcohol and cannabis intake, were correlated with a number of trauma domains. Whereas positive symptom severity was correlated with four of the trauma variables, negative symptom severity was correlated only with prior emotional neglect. These results provide insights into the relations among childhood traumatic events, substance use, and clinical features of first-episode psychosis, creating hypotheses for future research. PMID- 21665294 TI - Molecular cloning, tissue expression, and subcellular localization of porcine peptidoglycan recognition proteins 3 and 4. AB - Peptidoglycan recognition proteins (PGRPs) are innate immune molecules that are present in most invertebrates and vertebrates. Mammals have four PGRPs, PGLYRP1 4. In the present study, we cloned the cDNAs encoding porcine PGLYRP3 and 4 from the esophagus of adult swine. The length of the complete open reading frames of porcine PGLYRP3 and 4 are identical and contain 1125bp encoding 374 amino acid residues. The amino acid sequences of these two proteins were more similar to their human orthologs (78.9% [PGLYRP3] and 73.9% [PGLYRP4]) than to their mouse orthologs (71.3% [PGLYRP3] and 67.9% [PGLYRP4]). Expression analysis revealed that both PGLYRP3 and 4 were more strongly expressed in digestive tract, especially the esophagus, than in immune organs such as spleen or mesenteric lymph nodes in both newborn and adult swine. To analyze the subcellular distribution of porcine PGLYRP1-4, we constructed transfectant cell lines. Western blot and flow cytometric analyses revealed that porcine PGLYRP3 and 4 are not only secreted, but also expressed on the cell surface, unlike PGLYRP1 and 2. These results should help contribute to the understanding of PGLYRP3- and 4 mediated immune responses via their recognition of intestinal microorganisms in newborn and adult swine. PMID- 21665295 TI - Antioxidant status and biomarkers of oxidative stress in bovine leukemia virus infected dairy cows. AB - Bovine leukemia virus (BLV) is among the most widespread livestock pathogens in many countries. Despite advances in understanding the pathogenesis of this disease, little is known about the involvement of oxidative stress. Therefore, this study examined the antioxidant status and the markers of oxidative stress in BLV-infected dairy cows. BLV infection was associated with an increase in triacylglycerol levels, a decrease in glutathione peroxidase (GSH-Px) activity and a tendency toward lower superoxide dismutase activity in the infected animals. No significant difference was observed in other markers of oxidative stress (i.e., conjugated dienes, hydroperoxides and malondialdehyde) in the infected animals compared to controls. A novel method for the analysis of oxidative stress, Z-scan based on the measurement of the mean-value of theta in low density lipoprotein indicated that the infected animals had low-density lipoprotein particles that were slightly less modified than those from the healthy group. Thus, we conclude that BLV infection is associated with a selective decrease in GSH-Px activity without any alteration in the common plasma markers of oxidative stress. PMID- 21665296 TI - Cholinergic modulation of dendritic cell function. AB - Dendritic cells (DCs) are highly specialized antigen-presenting cells with a unique ability to activate resting T lymphocytes. Acetylcholine (ACh) is the primary parasympathetic neurotransmitter and also a non-neural paracrine factor produced by different cells. Here, we analyzed the expression of the cholinergic system in DCs. We found that DCs express the muscarinic receptors M(3), M(4) and M(5), as well as the enzymes responsible for the synthesis and degradation of ACh, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), respectively. Differentiation of DCs in the presence of the cholinergic agonist carbachol, the synthetic analog of ACh, resulted in an increased expression of HLA-DR and CD86 and the stimulation of TNF-alpha and IL-8 production. All these effects were prevented by atropine, a muscarinic ACh receptor (mAChR) antagonist. Carbachol, was also able to modulate the function of DCs when added after the differentiation is accomplished; it increased the expression of HLA-DR, improved the T cell priming ability of DCs, and stimulated the production of TNF-alpha but not IL-12 or IL-10. By contrast, carbachol significantly inhibited the stimulation of HLA-DR expression and the enhancement in the T cell priming ability of DCs triggered by LPS. Interestingly, the TNF-alpha antagonist etanercept completely prevented the increased expression of HLA-DR induced by carbachol, suggesting that it promotes the phenotypic maturation of DCs by stimulating the production of TNF-alpha. ACh induced similar effects than carbachol; it stimulated the expression of HLA-DR and the production of TNF alpha, while inhibiting the stimulation of HLA-DR expression and IL-12 production triggered by LPS. Similarly, neostigmine, an inhibitor of AChE, also stimulated the expression of HLA-DR and the production of TNF-alpha by DCs while inhibiting the production of TNF-alpha and IL-12 triggered by LPS. These results support the existence of an autocrine/paracrine loop through which ACh modulates the function of DCs. PMID- 21665297 TI - Epidemiology of acute otitis media in children of Latin America and the Caribbean: a systematic review and meta-analysis. AB - BACKGROUND: Acute otitis media (AOM) is one of the most common childhood diseases requiring antimicrobial prescription in pre-school children. This systematic review aimed to estimate the AOM incidence, bacterial etiology and use of resources in children aged <6 years in Latin America and the Caribbean (LA&C). METHODS: A systematic search using keywords otitis or middle ear and inflammation was performed for articles published during 1988-2008 in MEDLINE, Cochrane Library, EMBASE, LILACS, generic and academic internet searches, Ministries of Health, PAHO, regional proceedings, reference lists and consulting experts. Pairs of reviewers independently selected articles and assessed their methodological quality with a checklist of essential items from the STROBE statement according to pre-specified criteria. Studies involving immune-competent children with AOM were considered. Arcsine transformations were used for proportion meta-analyses. RESULTS: Annual AOM incidence in four studies in children aged <5 years ranged from 1,171-36,000 episodes/100,000 children. Meta-analysis on etiology and pneumococcal serotypes included 18 studies and 125, 519 children with AOM from six LA&C countries. Meta-analysis per serotype showed that Streptococcus pneumoniae (32.4%; 95%CI=27.1-38.0%) and Haemophilus influenzae (26%; 95%CI=19.5 33.1%), including non-typeable H. influenzae (18.3%; 95%CI=9.5-33.1%) were the most prevalent. The most commonly observed pneumococcal serotype was 19F (24.0%; 95% CI 17.0-32.0%). Data on use of health resources were scarce. CONCLUSIONS: Streptococcus pneumoniae and H. influenzae were the most frequent AOM bacterial pathogens, consistent with the international literature from other regions. Future studies on AOM incidence and health resources usage will help better define the impact of this disease. PMID- 21665299 TI - Risk factors for the presence and extent of Developmental Orthopaedic Disease in the limbs of young horses: Insights from a count model. AB - Developmental Orthopaedic Disease (DOD) in limb joints is frequent, can cause lameness and is a major cause of economic losses for the horse breeding industry. Studies on risk factors for DOD usually dichotomise the outcome to presence/absence without considering the extent of the disease, which can be appreciated by the number or the severity of the lesions. The aim of this study was to assess the effects of growth, exercise conditions and feeding practices on the number of radiographic findings (RF) of DOD in a cohort of horses, assuming that the risk factors associated with the presence of the disease and the number of RF may differ. We recruited broodmares on 21 stud farms in the Normandy region, France in 2002-2004. The stud farms were visited regularly to collect growth, exercise conditions, and feeding practices data from the end of the gestation to the weaning of the foal. The carpus, the front and hind digits, the tarsus and the stifle of the foals were radiographed at approximately six months of age. Each foal was classified according to the absence (no RF) or presence (>=1 RF) of DOD and to the number of RF. A zero-inflated Poisson model was used to simultaneously determine risk factors for presence/absence and for the number of RF of the disease. The convenience sample consisted of 378 foals, 53.1% of which did not have any RF. The mean number of RF per foal was 1.25 and the variance was 2.80. Comparing to the Poisson, negative binomial, and zero-inflated negative binomial regressions, the zero-inflated Poisson model was found to be best suited for these data. Of the 295 foals with complete data, three risk factors were significantly associated with a higher risk of being affected by DOD: high wither height increase, large group size in pasture and large pasture size. Seven risk factors were associated with the number of RF: wither height at 30 days of age, age of the mare, breed, regularity of exercise, Ca/P level in the mare and foal rations, group size in pasture, and the type and frequency of handling. This study shows that risk factors vary for the presence and extent of DOD, and that the use of a count model achieves a more detailed determination of risk factors for the presence of DOD and for the number of RF of DOD compared to the more conventional dichotomy presence/absence of the disease. PMID- 21665300 TI - Where would you go for your next hospitalization? AB - We examine the effects of diverse dimensions of hospital quality - including consumers' perceptions of unobserved attributes - on future hospital choice. We utilize consumers' stated preference weights to obtain hospital-specific estimates of perceptions about unmeasured attributes such as reputation. We report three findings. First, consumers' perceptions of reputation and medical services contribute substantially to utility for a hospital choice. Second, consumers tend to select hospitals with high clinical quality scores even before the scores are publicized. However, the effect of clinical quality on hospital choice is relatively small. Third, satisfaction with a prior hospital admission has a large impact on future hospital choice. Our findings suggest that including measures of consumers' experience in report cards may increase their responsiveness to publicized information, but other strategies are needed to overcome the large effects of consumers' beliefs about other quality attributes. PMID- 21665298 TI - Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. AB - The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this review we will highlight recent advances in our knowledge of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism. PMID- 21665301 TI - Recombinant lactic acid bacteria as mucosal biotherapeutic agents. AB - The safety status of lactic acid bacteria (LAB) and their capacity to survive the passage through the gastrointestinal tract (GI tract) have rendered them excellent candidates for the production of therapeutic proteins and their delivery in situ to the GI tract. During the past two decades, major health benefits of mucosally administered recombinant LAB have been successfully demonstrated, predominantly using animal models. However, the field has recently moved into the era of human clinical trials. In this review, we provide a timely update on the recent important advances made in this field, and outline the potential of recombinant LAB as therapeutic tools for their safe and efficient use in human health. PMID- 21665303 TI - A personal philosophy of a radiation oncologist. AB - All humans are of one species and are near identical genetically, viz. >99.5%. Also note, the Chimp is >96% genetically identical to humans. There has been extremely rapid increase in information and knowledge and this is accelerating. Several points: time is absolutely equalitarian. There is and has not been an unnatural event in this universe. Luck is the dominant factor in an individual's success in life. At birth, the infant has zero choice of genes, parents, siblings, relatives, era and site of birth. In addition, the young child has essentially no choice in school [if any], health, etc. The key to advancing knowledge is asking decisive questions, proceeding to investigate and generate answers to the question posed and publishing the investigation, data and interpretation. The number 1 interest and concern of the physician is the care of the individual patient. The potential of "humanized experimental animals" for selected Phase III clinical trial within 2-3 decades is judged feasible. Physicians should view our current best treatment as obsolete and use this as a provocation for active effort to develop superior management strategies. PMID- 21665302 TI - Potential of plant proteins for medical applications. AB - Various natural and synthetic polymers are being explored to develop biomaterials for tissue engineering and drug delivery. Although proteins are preferable over carbohydrates and synthetic polymers, biomaterials developed from proteins lack the mechanical properties and/or biocompatibilities required for medical applications. Plant proteins are widely available, have low potential to be immunogenic and can be made into fibers, films, hydrogels and micro- and nano particles for medical applications. Studies, mostly with zein, have demonstrated the potential of using plant proteins for tissue engineering and drug delivery. Although other plant proteins such as wheat gluten and soyproteins have also shown biocompatibility using in vitro studies, fabricating biomaterials such as nano-fibers and nano-particles from soy and wheat proteins offers considerable challenges. PMID- 21665304 TI - Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expression. AB - PURPOSE: To compare functional effects of combined irradiation and EGFR inhibition in different HNSCC tumour models in vivo with the results of molecular evaluations, aiming to set a basis for the development of potential biomarkers for local tumour control. MATERIAL AND METHODS: In five HNSCC tumour models, all wild-type for EGFR and KRAS, the effect of radiotherapy alone (30 fractions/6 weeks) and with simultaneous cetuximab or erlotinib treatment on local tumour control were evaluated and compared with molecular data on western blot, immunohistochemistry and fluorescence-in situ-hybridisation (FISH). RESULTS: Erlotinib and cetuximab alone significantly prolonged tumour growth time in 4/5 tumour models. Combined irradiation and cetuximab treatment significantly improved local tumour control in 3/5 tumour models, whereas erlotinib did not alter local tumour control in any of the tumour models. The amount of the cetuximab-effect on local tumour control significantly correlated with the EGFR/CEP-7 ratios obtained by FISH. CONCLUSION: Both drugs prolonged growth time in most tumour models, but only application of cetuximab during irradiation significantly improved local tumour control in 3/5 tumour models. The significant correlation of this curative effect with the genetic EGFR expression measured by FISH will be further validated in preclinical and clinical studies. PMID- 21665305 TI - Elevated radiation-induced gammaH2AX foci in G2 phase heterozygous BRCA2 fibroblasts. AB - BACKGROUND AND PURPOSE: About 5-10% of all breast cancer cases are associated with heterozygous germ-line mutations in the genes encoding BRCA1 and BRCA2. Carriers of such mutations are highly predisposed for developing breast or ovarian cancer and, thus, are advised to undergo regular radio-diagnostic examinations. BRCA1 and BRCA2 are involved in multiple cellular processes including the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) and different studies addressing the DSB repair capacity of BRCA1+/- or BRCA2+/- cells led to contradictory results. MATERIALS AND METHODS: Using the sensitive method of gammaH2AX foci analysis in combination with cell cycle markers, we specifically measured DSB repair in confluent G0 as well as in exponentially growing G1 and G2 phase primary WT, BRCA1+/- and BRCA2+/- fibroblasts. RESULTS: Both BRCA1+/- and BRCA2+/- cells displayed normal DSB repair in G0 and in G1. In contrast, in G2, BRCA2+/- but not BRCA1+/- cells exhibited a decreased DSB repair capacity which was in between that of WT and that of a hypomorphic BRCA2-/- cell line. CONCLUSIONS: The residual amount of normal BRCA1 seems to be sufficient for efficient DSB repair in all cell cycle phases, while the decreased DSB repair capacity of heterozygous BRCA2 mutations suggests gene dosage effects in G2. PMID- 21665306 TI - In tumor cells regulation of DNA double strand break repair through EGF receptor involves both NHEJ and HR and is independent of p53 and K-Ras status. AB - PURPOSE: The purpose of this study was to examine whether the epidermal growth factor receptor (EGFR) may be used as a general target to modulate DNA double strand break (DSB) repair in tumor cells. MATERIAL AND METHODS: Experiments were performed with human tumor cell lines A549, H1299 and HeLa and primate cell line CV1. EGF, ARG and TGFalpha were used for EGFR activation, cetuximab or erlotinib for inhibition. Overall DSB repair was assessed by gammaH2AX/53BP1 co immunostaining and non-homologous end-joining (NHEJ) and homologous recombination (HR) by using NHEJ and HR reporter cells; cell cycle distribution was determined by flow cytometry and protein expression by Western blot. RESULTS: EGFR activation was found to stimulate overall DSB repair as well as NHEJ regardless of the ligand used. This stimulation was abolished when EGFR signaling was blocked. This regulation was found for all cell lines tested, irrespective of their p53 or K-Ras status. Stimulation and inhibition of EGFR were also found to affect HR. CONCLUSIONS: Regulation of DSB repair by EGFR involves both the NHEJ and HR pathway, and appears to occur in most tumor cell lines regardless of p53 and K-Ras mutation status. PMID- 21665307 TI - Deregulation of cap-dependent mRNA translation increases tumour radiosensitivity through reduction of the hypoxic fraction. AB - BACKGROUND AND PURPOSE: Tumour hypoxia is an important limiting factor in the successful treatment of cancer. Adaptation to hypoxia includes inhibition of mTOR, causing scavenging of eukaryotic initiation factor 4E (eIF4E), the rate limiting factor for cap-dependent translation. The aim of this study was to determine the effect of preventing mTOR-dependent translation inhibition on hypoxic cell survival and tumour sensitivity towards irradiation. MATERIAL AND METHODS: The effect of eIF4E-overexpression on cell proliferation, hypoxia tolerance, and radiation sensitivity was assessed using isogenic, inducible U373 and HCT116 cells. RESULTS: We found that eIF4E-overexpression significantly enhanced proliferation of cells under normal conditions, but not during hypoxia, caused by increased cell death during hypoxia. Furthermore, eIF4E-overexpression stimulated overall rates of tumour growth, but resulted in selective loss of hypoxic cells in established tumours and increased levels of necrosis. This markedly increased overall tumour sensitivity to irradiation. CONCLUSIONS: Our results demonstrate that hypoxia induced inhibition of translational control through regulation of eIF4E is an important mediator of hypoxia tolerance and radioresistance of tumours. These data also demonstrate that deregulation of metabolic pathways such as mTOR can influence the proliferation and survival of tumour cells experiencing metabolic stress in opposite ways of nutrient replete cells. PMID- 21665309 TI - Metabolism of tumors under treatment: mapping of metabolites with quantitative bioluminescence. AB - BACKGROUND AND PURPOSE: The metabolic switch to aerobic glycolysis (Warburg effect) and enhanced lactate production is characteristic for aggressive tumor cells and is a co-determining factor for tumor response and treatment outcome. Thus analysis of the metabolic status under treatment is important to understand and improve treatment modalities. MATERIALS AND METHODS: Metabolite concentrations were determined by the immersion of tumor sections in an ATP, lactate or glucose-depending luciferase-containing buffer system. Integrated light output is detected in a bioluminescent detection system. RESULTS: Mice carrying tumor xenografts derived from A549 lung cancer cells were treated with the microtubule stabilizing agent patupilone, ionizing radiation or in combination. Lactate levels were significantly reduced and glucose levels drastically increased in comparison to untreated tumors. Interestingly, these changes were only minimal in tumors derived from patupilone-resistant but otherwise isogenic A549EpoB40 cells. ATP levels of all tumors tested did not change under any treatment. When compared with histological endpoints, basal and treatment-dependent changes of lactate levels in the different tumors mainly correlated with the proliferative activity and the tumor growth response to treatment. CONCLUSIONS: This study shows that the tumor metabolism is responsive to different treatment modalities and could eventually be used as an early surrogate marker for treatment response. PMID- 21665308 TI - Correlation between metabolic tumor volume and pathologic tumor volume in squamous cell carcinoma of the oral cavity. AB - PURPOSE: To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer. MATERIALS AND METHODS: Twenty-three patients with squamous cell carcinoma of the oral tongue had PET-CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET-CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques. RESULTS: Multiple MTV's were associated with pathologic tumor volume; however the correlation was poor (R(2) range 0.29-0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV (p=0.0005) and tumor grade (p=0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume (R(2)=0.63). CONCLUSIONS: Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET-CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV. PMID- 21665310 TI - Epithelial-mesenchymal-transition induced by EGFR activation interferes with cell migration and response to irradiation and cetuximab in head and neck cancer cells. AB - BACKGROUND AND PURPOSE: The role of epithelial-mesenchymal transition (EMT) in the poor outcome of EGFR-overexpressing SCCHN was evaluated. MATERIAL AND METHODS: SCCHN cell lines were characterized for their cell morphology and expression of EGFR and the EMT-associated factors E-cadherin, vimentin and Snail1. The migratory potential of cells was assessed in motility assays. Response to irradiation and cetuximab was determined using clonogenic survival assays. RESULTS: High basal expression of E-cadherin but low to absent vimentin expression could be observed in all SCCHN cell lines. Although E-cadherin expression levels did not change after treatment with EGF we observed a significant change in cell morphology resembling EMT. SCCHN cells with high basal levels of Snail1 resulting from constitutive EGFR activation were characterized by mesenchymal-like morphology, elevated migratory potential, reduced sensitivity to irradiation and cetuximab but increased sensitivity to the combined treatment. CONCLUSIONS: Autocrine activation of EGFR leading to EMT is associated with a metastatic phenotype and reduced sensitivity of SCCHN cells to single-modality treatment with cetuximab or irradiation. The potential of Snail1 as biomarker for selection of patients who will mostly benefit from a combination of cetuximab and radiotherapy has to be evaluated in future clinical studies. PMID- 21665311 TI - Pathogenic potential of Salmonella Typhimurium DT104 following sequential passage through soil, packaged fresh-cut lettuce and a model gastrointestinal tract. AB - From a quantitative microbial risk assessment perspective it is important to know whether certain food environments influence the pathogenic potential of pathogens and to what extent. The purpose of the present study was to examine the pathogenic potential of S. Typhimurium DT104, measured as the capability to survive a simulated gastrointestinal tract system and the capability of adhering to and invading differentiated Caco-2 cells, after sequential incubation (without intermediate culturing) into soil, lettuce and cut lettuce stored under modified atmosphere (MAP) conditions. Two S. Typhimurium DT104 strains were used, one isolated from a pig carcass and one isolated from lettuce. The most important result of the present study is that the sequential incubation of S. Typhimurium in soil and lettuce slightly increased the capability of surviving the simulated gastric fluid, increased the capability to grow in the simulated intestinal fluid but decreased the capability of epithelial attachment and invasion and decreased the overall survival probability of the gastrointestinal tract system. Some variation in responses between the strains was observed, with the lettuce strain maintaining higher epithelial attachment capability and the carcass strains maintaining higher epithelial invasion capability. This study provided quantitative data on the effect of environmental and food matrices on the pathogenic potential of S. Typhimurium DT104 using a realistic system of sequential incubations in environmental and food matrices, followed by simulated gastrointestinal tract passage without intermediate culturing. These results could aid the development of more realistic quantitative microbial risk assessments. PMID- 21665312 TI - Molecular survey of trichothecene genotypes of Fusarium graminearum species complex from barley in southern Brazil. AB - Fusarium head blight is a disease of primary concern to small-grain cereals of Brazil, including barley. Its main causal agent, Fusarium graminearum species complex (Fg complex) is able to produce mycotoxins, especially deoxynivalenol (DON) and nivalenol (NIV), that usually contaminate grain. Strains that produce DON may also produce its acetylated derivatives: 3-acetyl-DON (3-ADON) and 15 acetyl-DON (15-ADON). Ninety two isolates were obtained from samplings of barley grain during three years (2007, 2008 and 2009) from several fields in both southern and northern production regions of Rio Grande do Sul state, Brazil. These isolates were examined for polymerase chain-reaction-based (PCR) trichothecene genotype based on the amplification of portions of Tri3 and Tri12. There was no effect of year or region on the proportion of trichothecene genotypes. Overall, 66% of the strains (61/92) were 15-ADON, 4.4% (4/92) were 3 ADON and 29.3% (27/92) were NIV. The overall NIV/DON ratio estimated (0.41) was five times higher than that found in previous studies with strains from wheat grown in the same region. Species identification of nine strains representing the trichothecene genotypes, based on comparisons of DNA sequences of portions of the PHO, RED and URA genes with sequences from curated reference isolates of Fusarium from GenBank, revealed that they belong to F. graminearum sensu stricto (four 15 ADON and one 3-ADON strain), F. meridionale (three NIV strains) and F. austroamericanum (one 3-ADON strain). These results add to the current regional knowledge of trichothecene genotypes and species within the Fg complex affecting barley in the region. PMID- 21665313 TI - Psychological screening in adolescents with type 1 diabetes predicts outcomes one year later. AB - AIMS: Adolescents with type 1 diabetes are at increased risk for depression and anxiety, which can adversely affect diabetes management, glycemic control, and quality of life (QOL). However, systematic psychological screening is rarely employed. We hypothesized that higher depression and anxiety screener scores would predict higher HbA1c, less frequent blood glucose monitoring (BGM), and poorer QOL one year later. Raw screener scores were expected to be more robust predictors than cutoff scores. METHODS: 150 adolescents age 13-18 with type 1 diabetes completed depression and anxiety screeners. One year later, blood glucose meters were downloaded to assess BGM frequency, HbA1c values were obtained, and caregivers rated the participants' QOL. Separate regressions were conducted for each outcome, including demographic and medical covariates. RESULTS: Higher depression scores predicted less frequent BGM (b=-0.05, p<.05) and poorer QOL (b=-0.71, p<.01), and higher state anxiety scores predicted higher HbA1c (b=0.07, p<.05). Continuous screener scores identified risk for 12-month outcomes more robustly than clinical cut-off scores. CONCLUSIONS: Psychological screeners predict diabetes outcomes one year later. Future clinical research studies should explore whether psychological screening and referral for appropriate intervention can prevent deteriorations in diabetes management and control commonly seen during adolescence. PMID- 21665314 TI - TyG index performs better than HOMA in a Brazilian population: a hyperglycemic clamp validated study. AB - The TyG index was evaluated as a surrogate method for estimation of insulin resistance (IR). TyG index correlated with adiposity, metabolic and atherosclerosis markers related to IR and presented a moderate degree of agreement with hyperglycemic clamp. TyG index represents an accessible tool for assessment of IR in clinical practice. PMID- 21665316 TI - Cisplatin and irinotecan combination chemotherapy for advanced thymic carcinoma: evaluation of efficacy and toxicity. AB - BACKGROUND: Thymic carcinoma is a rare, malignant mediastinal tumor that is definitively distinguished from thymoma by its wide extensiveness and poor prognosis. At present, cisplatin-based triplet or quartet chemotherapy with the second generation antitumor agents, referred to as Einhorn's protocol for germ cell tumors, is used as first-line chemotherapy for advanced thymic carcinoma, though an optimal chemotherapeutic regimen has not yet been established. In this retrospective study, the effectiveness and toxicity of cisplatin and irinotecan combination chemotherapy were evaluated over a nine-year period. PATIENTS AND METHODS: Patients with advanced thymic carcinoma who were treated with cisplatin and irinotecan combination chemotherapy between January 1, 2002 and December 31, 2010, were retrospectively identified from our database and medical records. The endpoints in this study were disease control, response rate, progression-free survival (PFS), and overall survival (OS). Significant hematological and non hematological toxicities were also assessed. RESULTS: Among identified nine patients, disease control was achieved in 8 patients (88.9%), and a clinical response was achieved in 5 (55.6%). The median PFS was 7.9 months, and the median OS was 33.8 months. One- and two-year OS were 77.7% and 55.6%, respectively. Grade 3/4 hematological toxicities were observed in 2 patients (22.2%), and Grade 3/4 non-hematological toxicities were seen in 2 patients (22.2%). No febrile neutropenia or toxic death was recorded. CONCLUSION: Cisplatin and irinotecan combination chemotherapy appears to be acceptable for advanced thymic carcinoma as first-line chemotherapy with respect to efficacy, toxicity, and usage in the clinical setting. PMID- 21665317 TI - Suggested time to perform DTP FDG-PET scan in the evaluation of SPNs with an initial SUV less than 2.5. PMID- 21665315 TI - Type 2 diabetes: identifying high risk Asian American subgroups in a clinical population. AB - AIMS: We compared the prevalence and treatment of type 2 diabetes across Asian American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese) and Non-Hispanic Whites (NHWs) in a Northern California healthcare system. METHODS: A three-year, cross-sectional sample of patient electronic health records was accessed to compare diabetes prevalence in 21,816 Asian and 73,728 NHWs aged 35+ years. Diabetes was classified through ICD-9 codes, abnormal laboratory values, or use of oral anti-diabetic medication. Multivariate adjusted prevalence rates for each Asian subgroup, and adjusted odds ratios (OR) relative to NHWs, were compared. RESULTS: Age-adjusted prevalence ranged from 5.8% to 18.2% (women) and 8.1 to 25.3% (men). Age-adjusted ORs of Asian subgroups ranged 1.11-3.94 (women) and 1.14-4.56 (men). The odds of diabetes were significantly higher in Asian Indians (women OR 3.44, men OR 3.54) and Filipinos (women OR 3.94, men OR 4.56), compared to NHWs. Results for Asian Indians and Filipinos were similar with age-and-BMI adjustment. Treatment rates across subgroups were 59.7-82.0% (women) and 62.9-79.4% (men). CONCLUSIONS: Heterogeneity exists in the prevalence of diabetes across Asian subgroups, independent of obesity prevalence. Asian Indian and Filipino subgroups had particularly high prevalence of diabetes when compared to NHWs. Future studies should explore these clinically important differences among Asian subgroups. PMID- 21665319 TI - Biodiversity databases should gain support from journals. PMID- 21665320 TI - Stepwise superposition approach for the analytical solutions of multi-dimensional contaminant transport in finite- and semi-infinite aquifers. AB - Analytical solutions of contaminant transport in multi-dimensional media are significant for theoretical and practical purposes. However, due to the problems for which the solutions are sought which are complex in most of the cases, most available analytical solutions in multi-dimensional media are not given in their closed forms. Integrals are often included in the solution expressions, which may limit the practitioners to use the solutions. In addition, available multi dimensional solutions for the third-type sources in bounded media are fairly limited. In this paper, a stepwise superposition approach for obtaining approximate multi-dimensional transport solutions is developed. The approach is based on the condition that the one-dimensional solution along the flow direction is known. The solutions are expressed in their closed forms without integrals. The transport media to the solutions are flexible and can be finite, semi infinite, or infinite in the transverse directions. The solutions subject to the first- and third-type boundary conditions at the inlet with a distributed source over the domain are obtained. The integrals in some known solutions can also be evaluated by the approach if they can be derived to include known longitudinal integrals with respect to time. The accuracy and efficiency of the solutions proposed in this paper are verified through test problems and calculation examples. PMID- 21665318 TI - Combined alpha-tocopherol and ascorbic acid protects against smoke-induced lung squamous metaplasia in ferrets. AB - Many epidemiological studies show the benefit of fruits and vegetables on reducing risk of lung cancer, the leading cause of cancer death in the United States. Previously, we demonstrated that cigarette smoke exposure (SM)-induced lung lesions in ferrets were prevented by a combination of low dose of beta carotene, alpha-tocopherol (AT), and ascorbic acid (AA). However, the role of a combination of AT and AA alone in the protective effect on lung carcinogenesis remains to be examined. In the present study, we investigated whether the combined AT (equivalent to ~100 mg/day in the human) and AA (equivalent to ~210 mg/day) supplementation prevents against SM (equivalent to 1.5 packs of cigarettes/day) induced lung squamous metaplasia in ferrets. Ferrets were treated for 6 weeks in the following three groups (9 ferrets/group): (i) Control (no SM, no AT+AA), (ii) SM alone, and (iii) SM+AT+AA. Results showed that SM significantly decreased concentrations of retinoic acid, AT, and reduced form of AA, not total AA, retinol and retinyl palmitate, in the lungs of ferrets. Combined AT+AA treatment partially restored the lowered concentrations of AT, reduced AA and retinoic acid in the lungs of SM-exposed ferrets to the levels in the control group. Furthermore, the combined AT+AA supplementation prevented SM induced squamous metaplasia [0 positive/9 total ferrets (0%) vs. 5/8 (62%); p<0.05] and cyclin D1 expression (p<0.05) in the ferret lungs, in which both were positively correlated with expression of c-Jun expression. Although there were no significant differences in lung microsomal malondialdehyde (MDA) levels among the three groups, we found a positive correlation between MDA levels and cyclin D1, as well as c-Jun expressions in the lungs of ferrets. These data indicate that the combination of antioxidant AT+AA alone exerts protective effects against SM induced lung lesions through inhibiting cyclin D1 expression and partially restoring retinoic acid levels to normal. PMID- 21665321 TI - HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system. AB - Although most autoimmune diseases are connected to major histocompatibility complex (MHC) class II alleles, a small number of these disorders exhibit a variable degree of association with selected MHC class I genes, like certain human HLA-A and HLA-B alleles. The basis for these associations, however, has so far remained elusive. An understanding might be obtained by comparing functional, biochemical, and biophysical properties of alleles that are minimally distinct from each other, but are nevertheless differentially associated to a given disease, like the HLA-B*27:05 and HLA-B*27:09 antigens, which differ only by a single amino acid residue (Asp116His) that is deeply buried within the binding groove. We have employed a number of approaches, including X-ray crystallography and isotope-edited infrared spectroscopy, to investigate biophysical characteristics of the two HLA-B27 subtypes complexed with up to ten different peptides. Our findings demonstrate that the binding of these peptides as well as the conformational flexibility of the subtypes is greatly influenced by interactions of the C-terminal peptide residue. In particular, a basic C-terminal peptide residue is favoured by the disease-associated subtype HLA-B*27:05, but not by HLA-B*27:09. This property appears also as the only common denominator of distinct HLA class I alleles, among them HLA-B*27:05, HLA-A*03:01 or HLA-A*11:01, that are associated with diseases suspected to have an autoimmune etiology. We postulate here that the products of these alleles, due to their unusual ability to bind with high affinity to a particular peptide set during positive T cell selection in the thymus, are involved in shaping an abnormal T cell repertoire which predisposes to the acquisition of autoimmune diseases. PMID- 21665323 TI - Mutation of the transcription factor LEAFY COTYLEDON 2 alters the chemical composition of Arabidopsis seeds, decreasing oil and protein content, while maintaining high levels of starch and sucrose in mature seeds. AB - The transcription factor LEAFY COTYLEDON 2 (LEC2; At1g28300) is preferentially expressed in developing seeds of Arabidopsis. Detailed biochemical analysis of a loss-of-function lec2 mutant was carried out in seeds 6-21 days after flowering (DAF). In comparison to wild type controls, lec2 seeds had 15% less protein and 30% less oil, but accumulated 140% more sucrose and >5-fold more starch. We also quantified biomass and carbohydrates in the seed coat and embryo. The lec2 mutant had smaller seeds and an altered proportion of dry weight (bigger seed coat and smaller embryos). Mutant plants produced less mature seeds per silique and the harvest index was reduced. Soluble sugars (glucose, fructose and sucrose) was accumulated in the seed coat of the lec2 mutant, whereas the opposite effect was observed in the embryos (decrease in comparison to wild type). The rate of starch synthesis increased during early development, whereas the rate of starch degradation was diminished during late development, leading to higher residual starch in mature seed of the mutant. Starch accumulated in both seed coat and embryo. Homozygous mutant plants produced seeds that could germinate well if they were harvested immaturely, whereas seeds that became dry during maturity lost their germination efficiency very rapidly. We conclude that the LEC2 transcription factor not only controls cotyledon identity and morphology as previously reported, but also alters: (1) the delivery of photosynthates from the seed coat to the embryo (sink strength), (2) carbon partitioning towards different storage compounds (oil, proteins and carbohydrates), (3) the rate of starch synthesis and degradation in developing seeds and (4) germination capacity of dry seeds. PMID- 21665322 TI - Roles of intracellular hydrogen peroxide accumulation in abscisic acid signaling in Arabidopsis guard cells. AB - Reactive oxygen species (ROS), including hydrogen peroxide (H(2)O(2)), are among the important second messengers in abscisic acid (ABA) signaling in guard cells. In this study, to investigate specific roles of H(2)O(2) in ABA signaling in guard cells, we examined the effects of mutations in the guard cell-expressed catalase (CAT) genes, CAT1 and CAT3, and of the CAT inhibitor 3-aminotriazole (AT) on stomatal movement. The cat3 and cat1 cat3 mutations significantly reduced CAT activities, leading to higher basal level of H(2)O(2) in guard cells, when assessed by 2',7'-dichlorodihydrofluorescein, whereas they did not affect stomatal aperture size under non-stressed condition. In addition, AT-treatment at concentrations that abolish CAT activities, showed trivial affect on stomatal aperture size, while basal H(2)O(2) level increased extensively. In contrast, cat mutations and AT-treatment potentiated ABA-induced stomatal closure. Inducible ROS production triggered by ABA was observed in these mutants and wild type as well as in AT-treated guard cells. These results suggest that ABA-inducible cytosolic H(2)O(2) elevation functions in ABA-induced stomatal closure, while constitutive increase of H(2)O(2) do not cause stomatal closure. PMID- 21665324 TI - Antioxidant response of Arabidopsis plants to gamma irradiation: Genome-wide expression profiling of the ROS scavenging and signal transduction pathways. AB - Arabidopsis presumably has few sensors for gamma-rays and few signal transduction systems that respond to them. In an effort to assess their radiation sensitivity, wild-type (Ler) Arabidopsis plants were irradiated with various doses of gamma rays at the vegetative (VE) and reproductive (RE) stages. 100Gy treatment induced the higher production of siliques during both the VE and RE stages compared with non-irradiation. Treatments at doses over 200Gy repressed shoot growth, and the plants perished under 800Gy treatment. The results of physiological analysis using electron spin resonance (ESR) and transmission electron microscopy (TEM) revealed that increased doses of gamma-rays induce greater ROS generation. To establish the gene expression profiles after gamma irradiation and for an analysis of the antioxidant response, we employed an oligonucleotide microarray system. Different responses of genes related with ROS scavenging and signal transduction pathways by a gamma irradiation were observed. At least 33 and 42 out of all genes with significantly altered expression were associated with ROS scavenging and signal transduction pathways having an induction or repression ratio cutoff of at least 2-fold, respectively. CAT3 (At1g20620), Ferritin1 (At5g01600), Blue copper binding protein (At5g20230), and AOX putative (At1g32350) were up-regulated regardless of dosage at the VE stage. Reactive oxygen species signaling genes encoding phospholipase, zinc finger protein, WRKY DNA-binding protein, and calcium binding protein were highly expressed, evidencing changes greater than 2-fold. Our transcriptomic profile of the responses of Arabidopsis genes to gamma irradiation showed that plants evidenced altered expressions of many signal transduction and antioxidant genes, as have been seen with other environmental stresses. PMID- 21665325 TI - Heritable alteration in DNA methylation induced by nitrogen-deficiency stress accompanies enhanced tolerance by progenies to the stress in rice (Oryza sativa L.). AB - Cytosine methylation is responsive to various biotic- and abiotic-stresses, which may produce heritable epialleles. Nitrogen (N)-deficiency is an abiotic stress being repeatedly experienced by plants. To address possible epigenetic consequences of N-deficiency-stress, we investigated the stability of cytosine methylation in rice (Oryza sativa L.) subsequent to a chronic (a whole generation) N-deficiency at two levels, moderate (20mg/L) and severe (10mg/L), under hydroponic culture. MSAP analysis revealed that locus-specific methylation alteration occurred in leaf-tissue of the stressed plants (S(0)) experiencing either level of N-deficiency, which was validated by gel-blotting. Analysis on three non-stressed self-fed progenies (S(1), S(2) and S(3)) by gel-blotting indicated that ca. 50% of the altered methylation patterns in somatic cells (leaf) of the stressed S(0) plants were recaptured in S(1), which were then stably inherited to S(2) and S(3). Bisulfite sequencing of two variant MSAP loci with homology to low-copy retrotransposons on one stressed plant (S(0)) and its non-stressed progenies (S(1) and S(2)) showed that whereas one locus exhibited limited and non-heritable CHH methylation alteration, the other locus manifested dramatic heritable hypermethylation at nearly all cytosine sites within the assayed region. Intriguingly, when two groups of S(2) plants descended from the same N-deficiency-stressed S(0) plant were re-subjected to the stress, the group inheriting the modified methylation patterns showed enhanced tolerance to the N deficiency-stress compared with the group bearing the original patterns. Our results thus demonstrate heritability of an acquired adaptive trait in rice, which was accompanied by epigenetic inheritance of modified cytosine methylation patterns, implicating an epigenetic basis underlying the inheritance of an acquired trait in plants. PMID- 21665326 TI - K252a-sensitive protein kinases but not okadaic acid-sensitive protein phosphatases regulate methyl jasmonate-induced cytosolic Ca2+ oscillation in guard cells of Arabidopsis thaliana. AB - Methyl jasmonate (MeJA) induces stomatal closure similar to abscisic acid (ABA), and MeJA signaling in guard cells shares some signal components with ABA signaling. As part of this process, MeJA as well as ABA induce the elevation and oscillation of cytosolic free-calcium concentrations ([Ca(2+)](cyt)) in guard cells. While abscisic acid-induced [Ca(2+)](cyt) oscillation has been extensively studied, MeJA-induced [Ca(2+)](cyt) oscillation is less well understood. In this study, we investigated the effects of K252a (a broad-range protein kinase inhibitor) and okadaic acid (OA, a protein phosphatase 1 and 2A inhibitor) on MeJA-induced [Ca(2+)](cyt) oscillation in guard cells of Arabidopsis thaliana ecotype Columbia expressing the Ca(2+) reporter yellow cameleon 3.6. The protein kinase inhibitor K252a abolished MeJA-induced stomatal closure and reduced MeJA elicited [Ca(2+)](cyt) oscillation. The protein phosphatase inhibitor OA, on the other hand, did not inhibit these processes. These results suggest that MeJA signaling involves activation of K252a-sensitive protein kinases upstream of [Ca(2+)](cyt) oscillation but not activation of an OA-sensitive protein phosphatase in guard cells of A. thaliana ecotype Columbia. PMID- 21665327 TI - [Unilateral congenital ptosis with ipsilateral superior rectus muscle overaction]. AB - Congenital ptosis may be frequently accompanied by weakness of the ipsilateral superior rectus muscle. We report a case of ptosis with ipsilateral superior rectus muscle overaction. The 45-year-old patient presented with unilateral congenital ptosis. Ipsilateral superior rectus muscle overaction was found in the upgaze, with an inferior sclera show. This can be found in 40% of congenital ptosis. The authors give two possible causes: either an exaggerated Bell reflex or misdirection innervations of the superior rectus muscle by the superior division of the oculomotor nerve, initially innervating the upper eyelid elevator muscle. Histological or electrophysiological studies can be useful to determine the physiopathology of this association. PMID- 21665328 TI - [Foreword. Innovations of retinal therapy]. PMID- 21665329 TI - A national collaborative for reducing health care-associated infections: current initiatives, challenges, and opportunities. AB - There has been increasing interest and an upsurge in efforts to prevent hospital associated infections (HAIs), a leading cause of death in the United States. This study was conducted to assess current strategies and efforts of HAI reduction initiatives in hospitals. HAI reduction initiatives and factors influencing institutional participation in these initiatives were categorized. Data were collected via open-ended questions on surveys performed in 5 different HAI collaboratives. Thematic analysis of the coded qualitative data was conducted. A total of 1,212 health care professionals from 33 different hospitals participated. Improving hand hygiene was the most frequently mentioned HAI reduction initiative implemented in the previous year. Initiatives for reducing central line or central venous catheter infections and ventilator-associated pneumonia also were commonly cited. The most frequently mentioned challenges to implementing HAI reduction initiatives included poor adherence, insufficient resources, staffing problems, lack of culture change, no impetus to change, and issues related to staff and patient education. Many respondents identified engaging physicians as particularly challenging.These findings suggest that consistently improving hand hygiene remains a widespread problem for reducing HAIs and sustaining this type of behavioral change is difficult. Furthermore, ensuring staff and physician engagement and compliance in HAI reduction efforts remains challenging for most hospitals. PMID- 21665330 TI - [Ustekinumab in a patient with Crohn's disease and anti-TNF-alpha-induced psoriasis]. AB - Treatment with anti-tumor necrosis factor (TNF)-alpha for Crohn's disease is relatively safe, although various cutaneous adverse effects have been reported such as the development or exacerbation of anti-TNF- alpha-induced psoriasis, which can sometimes lead to treatment withdrawal. Therefore, new alternative treatments with new mechanisms of action are required. Ustekinumab, a monoclonal antibody against the p40 subunit of interleukin 12/23, could induce response in patients with Crohn's disease and has demonstrated efficacy in patients with psoriasis. We present the case of a woman with Crohn's disease who developed psoriasis after treatment with two anti-TNF- alpha drugs (infliximab and adalimumab). The patient was subsequently treated with ustekinumab with resolution or psoriasis lesions and maintenance of remission of Crohn's disease. PMID- 21665331 TI - [Spanish opinions on tobacco smoke-free areas]. AB - OBJECTIVE: To determine the number of passive smokers, the environments where exposure to second-hand smoke (SHS) is higher, the opinion of smokers and non smokers with regard to these spaces and their influence on smoking. DESIGN: Descriptive and cross-sectional observational study of a convenience sample. LOCATION: Multi-centre, Spanish Health-care Centres. PARTICIPANTS: A total of 9733 people older than 16 years who were seen or were working in Spanish Health care Centres in April 2008. MAIN MEASUREMENTS: Smoker condition, gender, profession and their opinion with regard to second-hand smoke (SHS) exposure. RESULTS: A total of 42.4% of participants considered themselves second-hand (passive) smokers in public places and 96.8% in indoor areas. Almost all of them (91.8%) considered SHS exposure harmful for non-smokers, Smoke-free environments were considered to be good for discouraging people from starting to smoke (70.3%), and for quitting smoking (71.8%). Smoke-free environments were preferred by 81.1%. They felt more exposed SHS inside a car (79.8%) and in cafes (34.7%). Non-smokers, both men and women, shared these opinions significantly (P<.05). CONCLUSIONS: Altogether, those surveyed considered themselves as second-hand smokers and think that smoke-free environments reduce the impact of smoking and help in quitting smoking. Besides, they prefer living in those environments. Considering the preferences of most of the population, this stresses the need to urge governments to establish legislative measures promoting smoke-free environments. PMID- 21665332 TI - A new nitrosyl ruthenium complex: synthesis, chemical characterization, in vitro and in vivo antitumor activities and probable mechanism of action. AB - This study describes the synthesis of a new ruthenium nitrosyl complex with the formula [RuCl(2)NO(BPA)] [BPA = (2-hydroxybenzyl)(2-methylpyridyl)amine ion], which was synthesized and characterized by spectroscopy, cyclic voltammetry, X ray crystallography, and theoretical calculation data. The biological studies of this complex included in vitro cytotoxic assays, which revealed its activity against two different tumor cell lines (HeLa and Tm5), with efficacy comparable to that of cisplatin, a metal-based drug that is administered in clinical treatment. The in vivo studies showed that [RuCl(2)NO(BPA)]is effective in reducing tumor mass. Also, our results suggest that the mechanism of action of [RuCl(2)NO(BPA)] includes binding to DNA, causing fragmentation of this biological molecule, which leads to apoptosis. PMID- 21665333 TI - Evaluation of doctoral nursing education in Japan by students, graduates, and faculty: a comparative study based on a cross-sectional questionnaire survey. AB - Evaluation of doctoral education in nursing is needed with the rapid increase in doctoral nursing programs in Japan. This study aimed to compare the evaluations of doctoral nursing education by students, graduates, and faculty. All 46 doctoral nursing programs in Japan were target settings. 127 students who had been in the doctoral program, 24 graduates and 87 faculty members had responded to the survey. A questionnaire with 17 items for program evaluation, 12 items for faculty evaluation, 9 items for resource evaluation, and 3 for overall evaluations was distributed in November and December 2008. Responses to 1 program evaluation item, 2 faculty evaluation items and 4 resource evaluation items indicated significant differences among evaluators. While 79.2% of graduates responded positively that the number of faculty members was sufficient to facilitate learning, only 36.1% of faculty members and 49.6% of students responded affirmatively. Graduates' ratings were the most positive and faculty members were the least positive, especially for infrastructure or equipment such as libraries, computers, and the number of technical and support staff. The significant differences among the evaluators suggested that having evaluators in various roles is important to evaluate the quality of doctoral nursing education. PMID- 21665334 TI - The 'one dimensional' state of UK (nursing) education. PMID- 21665335 TI - Graduating Finnish nurse students' interest in gerontological nursing--a survey study. AB - This study aimed to examine nurse students' interest in gerontological nursing and the factors enhancing and decreasing that interest. The quantitative data was collected in the autumn of 2009 using a structured instrument with a Visual Analogue Scale (VAS), which was developed for this study based on the literature review. Graduating nurse students (n=183) from three polytechnics in Southern Finland participated in the study. The data was analysed statistically using descriptive statistics and t-test for independent samples to indicate statistical significance. The students did not clearly state if they are interested in gerontological nursing as a future career choice or not. Students who had prior gerontological nursing work experience, women, and students who had learned about gerontological nursing through an independent course were the most interested in the field. The factors that enhance interest are the quality of gerontological nursing, the challenging aspects of the field and the opportunities for career advancement, the gerontological nursing education and the practical training in gerontological nursing. On the basis of the results, it seems that it is possible to enhance nurse students' interest in gerontological nursing as a future career choice. PMID- 21665336 TI - Validity of abbreviated oral fat tolerance tests for assessing postprandial lipemia. AB - BACKGROUND & AIMS: Postprandial lipemia is assessed using the oral fat tolerance test (OFTT), a six-hour procedure requiring hourly blood sampling. In order to simplify the test, we investigated whether a) a single postprandial triacylglycerol concentration, b) an OFTT lasting less than six hours or c) an OFTT requiring fewer blood samples, may accurately assess postprandial lipemia under various conditions. METHODS: Seventy-two subjects underwent a conventional OFTT. Predictability of single-point concentrations and time-shortened tests was assessed using linear regression and re-sampling analysis. Validity of reduced sampling tests was assessed using Pearson's correlation coefficients and Bland Altman analysis. RESULTS: a) A single-point triacylglycerol concentration (3 or 4h postprandially) did not present significant correlation with postprandial lipemia in the hypetriacylglycerolemic, exercise and energy restriction groups (P>0.05), b) Time-shortened OFTT (4h) was able to predict postprandial lipemia in every group studied (R(2)=0.707-0.970, P<0.01), except the hypertriacylglycerolemics (P=0.338), c) Reduced-sampling OFTT (3 or 4 samples) was able to assess postprandial lipemia in every group as well as in the overall sample (r=0.874-0.997, P<0.05). CONCLUSIONS: A more convenient, reduced-sampling OFTT may be used alternatively to the conventional OFTT, whereas a time-shortened OFTT may be appropriate only for healthy people. PMID- 21665337 TI - Development and validation of a dynamical atmosphere-vegetation-soil HTO transport and OBT formation model. AB - A numerical model simulating transport of tritiated water (HTO) in atmosphere soil-vegetation system, and, accumulation of organically bound tritium (OBT) in vegetative leaves was developed. Characteristic of the model is, for calculating tritium transport, it incorporates a dynamical atmosphere-soil-vegetation model (SOLVEG-II) that calculates transport of heat and water, and, exchange of CO(2). The processes included for calculating tissue free water tritium (TFWT) in leaves are HTO exchange between canopy air and leaf cellular water, root uptake of aqueous HTO in soil, photosynthetic assimilation of TFWT into OBT, and, TFWT formation from OBT through respiration. Tritium fluxes at the last two processes are input to a carbohydrate compartment model in leaves that calculates OBT translocation from leaves and allocation in them, by using photosynthesis and respiration rate in leaves. The developed model was then validated through a simulation of an existing experiment of acute exposure of grape plants to atmospheric HTO. Calculated TFWT concentration in leaves increased soon after the start of HTO exposure, reaching to equilibrium with the atmospheric HTO within a few hours, and then rapidly decreased after the end of the exposure. Calculated non-exchangeable OBT amount in leaves linearly increased during the exposure, and after the exposure, rapidly decreased in daytime, and, moderately nighttime. These variations in the calculated TFWT concentrations and OBT amounts, each mainly controlled by HTO exchange between canopy air and leaf cellular water and by carbohydrates translocation from leaves, fairly agreed with the observations within average errors of a factor of two. PMID- 21665338 TI - Surgical (open) gastrostomy and repair of the radial forearm donor site. PMID- 21665339 TI - Heavy metal pollution exerts reduction/adaptation in the diversity and enzyme expression profile of heterotrophic bacteria in Cochin estuary, India. AB - Over the past three decades heavy metal pollution has increased substantially in Cochin estuary, south west coast of India. Here we studied the distribution, diversity and enzyme expression profile of culturable microbial population along a pollution gradient. The distribution of resistance against 5 mM concentration of Zn, Co, Ni and Cu was observed among 90-100% of bacterial isolates retrieved from highly polluted Eloor, whereas it was less than 40% in Vypin and Munambam. Similarly, there was a difference in the distribution and diversity of bacterial phyla with predominance of Proteobacteria in Eloor and Firmicutes in Munambam and Vypin. We observed that 75-100% of the organisms retrieved from Eloor had low levels of expression for hydrolytic enzyme. In conclusion, the heavy metal pollution in Cochin estuary brought in reduction/adaptation in the distribution, diversity and enzyme expression profile of bacteria, which may impart adverse impacts on ecosystem functioning. PMID- 21665340 TI - 'Non-compliance' as illness management: Hemodialysis patients' descriptions of adversarial patient-clinician interactions. AB - With only 50% of patients in developed countries following the therapies prescribed for them by health professionals, "non-compliance" is commonly described as causing increases in morbidity, hospital visits, and overall healthcare costs. A plethora of non-compliance studies have failed to identify consistent predictors for, or solutions to, patients' non-compliance. Our longitudinal (September 2006-September 2008) participatory action research (PAR) focused on (a) understanding hemodialysis patients' perspectives on the challenges and solutions to living well with their chronic illness and (b) taking action to improve this population's quality of life. The study's participants included seven purposefully sampled patients in two hospital hemodialysis units in Canada. A small sample size was essential to accommodate our commitment to conducting a PAR study with this patient population whose unpredictable health status presented significant challenges to recruitment, follow-up interviews, and participation in data analysis. Data collection and analysis over 2 years included over 100 h of ethnographic field observation, bi-weekly unrecorded and 12 audio-recorded in-dialysis interviews, five video-recorded life-history interviews, two video-recorded focus groups, and five video-recorded dialysis treatment sessions. Thematic content analysis drew attention to patients' descriptions of adversarial interactions with health professionals. In these interactions, three points of tension were identified: (a) between whole person care and "assembly line" treatment, (b) between patient knowledge and medical expertise, and (c) between shared decision-making and "digging to find out". The article concludes that these adversarial relationships are indicative of a lack of trust stemming from health professionals' failure to interact with patients as whole persons with unique expertise on their bodies, their experience of illness, and their lives. PMID- 21665341 TI - The effect of outpatient dialysis global budget cap on healthcare utilization by end-stage renal disease patients. AB - Controlling the cost of chronic diseases remains one of the vexing problems of developed and developing nations alike. Taiwan, faced with rapidly escalating healthcare costs associated with End Stage Renal Disease (ESRD) services utilization, imposed an outpatient dialysis global budget (ODBG) on outpatient dialysis care. This study, using a before and after study design with a comparison group, assessed the impact of this policy innovation on outpatient, inpatient and emergency room utilization. Using a difference in difference (DID) strategy and the generalized estimating equation (GEE) approach, this study found providers responded to these changes through cost reduction and revenue enhancement strategies. This study extends our understanding of provider responses to changes in reimbursement policies that target one segment of the continuum of care required by chronic disease patients. PMID- 21665342 TI - Sakit Hati: A state of chronic mental distress related to resentment and anger amongst West Papuan refugees exposed to persecution. AB - There has been an increasing interest in the role of gross injustices in generating pathological states of anger. The goal of this study amongst 41 West Papuan refugees conducted in Australia between 2007 and 2010 was to explore the phenomenology of Sakit Hati, a condition in which there appeared to be a close link between human rights violations and anger. West Papuan refugee participants made repeated reference to the condition of Sakit Hati in the early phase of the study so that the remainder of the study focused specifically on this construct. The qualitative approach involved an iterative process including focus groups, in depth interviews, and semi-structured confirmatory interviews. The research revealed that Sakit Hati included elements of chronic brooding, resentment and anger attributed to experiences of injustice, a state that created vulnerability to episodes of explosive rage and aggression in response to reminders of persecution. Sakit Hati was distinguished from a depression-loss constellation, Susah Hati, although the two reactions overlapped. Sakit Hati led to substantial personal suffering and interpersonal difficulties. The intractable political conditions in West Papua made it difficult to achieve a durable resolution for the condition. Sakit Hati provides a cross-cultural illustration of the nexus between injustice and chronic anger, demonstrating how this dynamic interaction can be perpetuated by ongoing social and political forces. Greater attention may be warranted by psychiatric classification systems to the recognition of anger as an affective state that may be provoked and maintained by experiences of injustice. PMID- 21665343 TI - Seven-year retrospective clinical study evaluating efficacy of stainless steel mesh in mandibular fractures. AB - PURPOSE: The use of titanium mesh in communited mandibular fractures has been substantially documented. However, the use of stainless steel mesh for routine fixation in mandibular fractures has not been widely reported. The aim of the present study was to evaluate the efficacy of stainless steel mesh for routine osteosynthesis of mandibular fractures. MATERIALS AND METHODS: A total of 252 patients who had been diagnosed with 287 single or multiple mandibular fractures at Guru Nanak Institute of Dental Science and Research from 2002 to 2009 were selected for the present study. Those with condylar fractures and other maxillofacial injuries were excluded from the study. The patients were evaluated preoperatively, intraoperatively, and postoperatively at 1 day, 6 weeks, and 3 and 6 months. The local complications, occlusion (for static function), and chewing (for dynamic function) were evaluated postoperatively. RESULTS: The intraoperative time taken for implant fixation (from site exposure to fixation of the last screw) was 32 minutes. Of the 252 patients, 40 (15.8%) had local complications and 24 patients required implant removal. Of the 252 patients, 82% had bilaterally satisfactory occlusion according to the surgeon at 6 months postoperatively. Discomfort in chewing unilaterally or bilaterally was reported by 17% of the patients. CONCLUSION: The results of our study have shown that stainless steel mesh has acceptable complication rates and the ability to maintain occlusion and chewing postoperatively compared with the present standards of care of mandibular fractures using miniplates. The lower cost and versatile placement of screws were the principal advantages. However, placement near the mental foramen with an extraoral approach for certain sites is the primary disadvantage. PMID- 21665344 TI - Comparison of 1-point fixation with 2-point fixation in treating tripod fractures of the zygoma. AB - PURPOSE: Zygomatic tripod fracture is relatively common and generally requires open reduction-internal fixation through several incisions. However, lateral eyebrow incisions have sometimes left unsightly scars, and thus we have used 1 point fixation through a buccogingival incision so as not to leave scars in selected cases. The aim of this study was to compare 1-point fixation in the zygomaticomaxillary (ZM) area with 2-point fixation in the ZM and frontozygomatic (FZ) areas in tripod fractures. MATERIALS AND METHODS: This study is retrospective and was approved by the institutional review board of our hospital. From November 2005 to March 2010, 30 patients were enrolled in this study. We investigated 14 patients with 1-point fixation in the ZM area (group 1), 1 of whom had bilateral tripod fractures, and 16 patients with 2-point fixation in the ZM and FZ area (group 2). We postoperatively checked for 1) unfavorable scars; 2) bony movement, pain, and palpability in the FZ area; 3) satisfaction with surgical outcomes; 4) presence or absence of surgeries for plate removal; and 5) anxiety about no fixation of the FZ area. RESULTS: Of 16 patients in group 2, 10 (63%) complained of unsightly scars in the lateral eyebrow incision site, whereas none of the patients in group 1 complained of external scarring. None of the patients complained of bony movement and pain in the FZ area in either group. In group 2, 4 of 16 patients (25%) complained of palpability in the FZ area, whereas none in group 1 complained of palpability. The satisfaction score for surgery was 9.4 +/- 1.6 in group 1 and 7.7 +/- 2.6 in group 2 (P < .05). Two patients underwent surgery for plate removal in group 2. None of the patients in group 1 complained of any cosmetic problems, with no fixation in the FZ area. CONCLUSIONS: One-point fixation in the ZM area in zygomatic tripod fractures can avoid unsightly scars and give high satisfaction with surgical outcomes in selected patients with tripod fractures. PMID- 21665345 TI - Incidence and consequences of bur breakage in orthognathic surgery: a retrospective study with discussion of 2 interesting clinical situations. AB - PURPOSE: To determine the incidence of bur breakage in routine orthognathic surgery, as well as its postsurgical sequela, and to illustrate 2 cases with more than 6 months' follow-up. PATIENTS AND METHODS: We performed a retrospective evaluation of case records of 76 consecutive orthognathic surgical procedures performed by a team of 2 surgeons over a period of 16 months, between January 2009 and July 2010, at a single center. RESULTS: Surgical bur breakage was reported in 5 patients in the series. Of these, 3 were retrieved whereas 2 were not, 1 of which caused a foreign body reaction in the patient, which persisted for a duration of almost 1 year. CONCLUSION: Instrument breakage may be a relatively common occurrence with the use of surgical burs in orthognathic surgery but its incidence is seldom recorded or reported. This study gives insight into the probability of postoperative sequela of these instruments when left in situ and a protocol for management of broken instruments. PMID- 21665346 TI - A comparison of motorcycle and bicycle accidents in oral and maxillofacial trauma. AB - PURPOSE: The aim of this study was to present a large series of motorcycle- and bicycle-related traumas to the face in an attempt to identify the injury pattern in motorcyclists and bicyclists. PATIENTS AND METHODS: Data were collected from patients during a 10-year period (1999 through 2009), which included demographic data, diagnosis of facial fractures, use of protective devices, dentoalveolar trauma, and facial soft tissue injuries. RESULTS: There were 556 patients with bicycle accidents and 367 with motorcycle accidents. Men were involved in 79% (436) of bicycles accidents and 82% (299) of motorcycle accidents. Young male patients were more frequent in bicycle and motorcycle accidents. Two hundred fifty bicyclists showed 311 maxillofacial fractures. Two hundred twenty-one motorcyclists showed 338 maxillofacial fractures. Motorcycle accidents caused multiple fractures in more patients. Seventy-six percent of motorcyclists were using helmets at the time of the accidents, whereas 6% of cyclists were using helmets. Motorcyclists showed a larger number of lacerations, whereas bicyclists showed a larger number of abrasions. Avulsion was the most common dentoalveolar injury for these accident types. Hospital stays were 3.8 days for motorcyclists and 1.3 days for bicyclists. CONCLUSIONS: The high-impact collisions typically observed in motorcycle accidents is directly related to larger percentages of soft tissue lacerations and facial fractures. The low-impact trauma that is observed in bicycle accidents is more commonly associated with soft tissue abrasion, hematoma, and dentoalveolar fractures. This stresses the need for compulsory legislation for helmet use with face-guards for cyclists and motorcyclists. It is important to take measures to alert the public regarding the severity of injuries likely to occur in bicycle- and motorcycle-related accidents and ways to prevent them. PMID- 21665348 TI - Giant retroperitoneal abscess caused by extraperitoneal bladder rupture after instrumental vaginal delivery. PMID- 21665347 TI - [Management of upper obstetrical brachial plexus palsy. Long-term results of non operative treatment in 22 children]. AB - INTRODUCTION: Treatment of obstetrical brachial plexus palsy (OBPP) is always debated, especially for upper plexus palsy. Some authors perform early surgical treatment in case of absence of biceps contraction at the age of 3 months. Others prefer to wait until the age of 6 months before considering a surgical procedure when no suspicion of root avulsion is found. We think that a conservative approach with intensive rehabilitation program can obtain good functional outcome for patients who will recover biceps function spontaneously between 3 and 6 months, and that it is not necessary to perform surgery at 3 months. To argue our choice, we have compared the long-term outcome of two groups of children with upper OBPP conservatively treated regarding the age of biceps recovery (before or after 3 months). PATIENTS AND METHODS: Twenty-two patients with non operated upper roots birth palsy, followed in Timone's Hospital of Marseille by a multidisciplinary team, have recovered a biceps contraction between 1 and 8 months and were retrospectively included in this study. All children underwent an intensive rehabilitation program since birth, performed by a specialized physiotherapist. Patients were reviewed, and their shoulder function was assessed using Mallet score. The score was analysed regarding the age of biceps recovery. RESULTS: The mean follow up was 8.2 years. Nine children recovered a biceps contraction at 3 months of age or before; the mean global Mallet score was 4.11. Thirteen children recovered a biceps contraction after 3 months of age (between 3 and 8 months); the mean global Mallet score was 3.92. The difference was not statistically significant. CONCLUSION: This study shows that global shoulder function is comparable for two groups. The children who did not recover a biceps contraction at 3 months of age had a global shoulder function as good as the one who recovered biceps function earlier. We think our intensive rehabilitation program allowed us to avoid a useless early surgery. Surgical plexus treatment was indicated for children who did not have biceps contraction after 6 months of age. PMID- 21665349 TI - Structure of hydration water in proteins: a comparison of molecular dynamics simulations and database analysis. AB - Hydration layer water molecules play important structural and functional roles in proteins. Despite being a critical component in biomolecular systems, characterizing the properties of hydration water poses a challenge for both experiments and simulations. In this context we investigate the local structure of hydration water molecules as a function of the distance from the protein and water molecules respectively in 188 high resolution protein structures and compare it with those obtained from molecular dynamics simulations. Tetrahedral order parameter of water in proteins calculated from previous and present simulation studies show that the potential of bulk water overestimates the average tetrahedral order parameter compared to those calculated from crystal structures. Hydration waters are found to be more ordered at a distance between the first and second solvation shell from the protein surface. The values of the order parameter decrease sharply when the water molecules are located very near or far away from the protein surface. At small water-water distance, the values of order parameter of water are very low. The average order parameter records a maximum value at a distance equivalent to the first solvation layer with respect to the water-water radial distribution and asymptotically approaches a constant value at large distances. Results from present analysis will help to get a better insight into structure of hydration water around proteins. The analysis will also help to improve the accuracy of water models on the protein surface. PMID- 21665350 TI - Heightened stability of polcalcin Phl p 7 is correlated with strategic placement of apolar residues. AB - Phl p 7 exhibits atypical conformational stability and a diminutive denaturational heat capacity increment, DeltaC(p). Because exposure of apolar surface largely dictates the magnitude of DeltaC(p), a depressed value could signify an unusually compact unfolded state. The volume of the denatured state ensemble (DSE) is evidently inversely correlated with mean hydrophobicity [Pace et al., Protein Sci. 19 (2010) 929-943]. Interestingly, apolar residues replace more polar ones at four positions in Phl p 7. We herein examine the consequences of replacing those residues with the corresponding ones from Bra n 1, a related isoform. All four mutations - M4H, L21A, I60T, and C63A - destabilize Phl p 7. Our analysis suggests that the DSE of Phl p 7 is indeed highly compact and that the substitutions act by increasing its volume and solvent-accessibility. All four mutations increase the urea m value; L21A, I60T, and C63A also yield a perceptible increase in DeltaC(p). PMID- 21665351 TI - A comparative analysis of the folding and misfolding pathways of the third PDZ domain of PSD95 investigated under different pH conditions. AB - Equilibrium unfolding at neutral pH of the third PDZ domain of PSD95 is well described by the presence of a partly unfolded intermediate that presents association phenomena. After some days' incubation annular and fibrillar structures form from the oligomers. At pH values below 3, however, differential scanning calorimetry shows that PDZ3 seems to unfold under a two-state scheme. Kinetic measurements followed by dynamic light scattering, ThT and ANS fluorescence reveal that the misfolding pathway still exists despite the absence of any populated intermediates and shows an irreversible assembling of the supramacromolecular structures as well as an appreciable lag-phase, contrary to what is found in similar experiments at neutral pH. Moreover, as shown by transmission-electron-microscopy images, the annular structures seen at neutral pH completely disappear from incubated solutions. According to the structural information, this titration behavior appears to be the consequence of a conformational equilibrium that depends on the protonation of some Glu residues located at the C-terminal alpha3 helix and at the hairpin formed by strands beta2 and beta3. Our calculations suggest that the enthalpic contribution of these interactions may well be as much as 40kJ.mol(-1). The possible regulatory role of this equilibrium upon PDZ3 functionality and amyloid formation is briefly discussed. PMID- 21665352 TI - An Assessment of U(VI) removal from groundwater using biochar produced from hydrothermal carbonization. AB - The ever-increasing growth of biorefineries is expected to produce huge amounts of lignocellulosic biochar as a byproduct. The hydrothermal carbonization (HTC) process to produce biochar from lignocellulosic biomass is getting more attention due to its inherent advantage of using wet biomass. In the present study, biochar was produced from switchgrass at 300 degrees C in subcritical water and characterized using X-ray diffraction, fourier transform infra-red spectroscopy, scanning electron micrcoscopy, and thermogravimetric analysis. The physiochemical properties indicated that biochar could serve as an excellent adsorbent to remove uranium from groundwater. A batch adsorption experiment at the natural pH (~3.9) of biochar indicated an H-type isotherm. The adsorption data was fitted using a Langmuir isotherm model and the sorption capacity was estimated to be ca. 2.12 mg of U g(-1) of biochar. The adsorption process was highly dependent on the pH of the system. An increase towards circumneutral pH resulted in the maximum adsorption of ca. 4 mg U g(-1) of biochar. The adsorption mechanism of U(VI) onto biochar was strongly related to its pH-dependent aqueous speciation. The results of the column study indicate that biochar could be used as an effective adsorbent for U(VI), as a reactive barrier medium. Overall, the biochar produced via HTC is environmentally benign, carbon neutral, and efficient in removing U(VI) from groundwater. PMID- 21665353 TI - Application of a cave inventory system to stimulate development of management strategies: the case of west-central Florida, USA. AB - The active management of air-filled cave systems is virtually non-existent within the karst landscape of west-central Florida. As in every karst landscape, caves are important because they contain a wide variety of resources (e.g., biota, speleothems) and can act as direct connections between surface and subsurface hydrological processes, potentially exacerbating the pollution of groundwater. Before sound management policies can be drafted, implemented, and enforced, stakeholders must first have knowledge of the management requirements of each cave. However, there is an informational disconnect between researchers, stakeholders, and the recreational caving community. Here, we present a cave inventory system that simplifies the dissemination of resource knowledge to stakeholders so that cave management and protection policies can be drafted and implemented at the state and local level. We inventoried 36 caves in west-central Florida, located on both public and private land, and analyzed cave resource data to provide insights on cave sensitivity and disturbance using two standardized indices. The data revealed that both public and private caves exhibit a wide range of sensitivity and disturbance, and before management strategies can be drafted, the ownership of each cave must be considered. Our inventory geodatabase serves as a link between researchers, landowners, and the public. To ensure the conservation and protection of caves, support from county or state government, combined with cave inventory data, is crucial in developing sound management policy. PMID- 21665354 TI - The performance of constructed wetlands treating primary, secondary and dairy soiled water in Ireland (a review). AB - In Ireland, no database detailing the design, influent loading rates or performance of constructed wetlands (CWs) exists. On account of this, they are designed without any protocol based on empirical data. The aim of this paper was to provide the first published data on the performance of free-water surface flow (FWSF) CWs treating primary and secondary-treated municipal wastewater, and agricultural dairy soiled water (DSW) in Ireland. In total, the performance of thirty-four FWSF CWs, comprising fourteen CWs treating primary-treated municipal wastewater, thirteen CWs treating secondary-treated municipal wastewater, and seven CWs treating DSW, were examined. In most CWs, good organic, suspended solids (SS) and nutrient removal was measured. At an average organic loading rate (OLR) of 10 and 9 g biochemical oxygen demand (BOD) m(-2) d(-1), CWs treating primary and secondary wastewater removed 95 and 84% of influent BOD. Constructed wetlands treating DSW had an average BOD removal of 98%. At average SS loading rates of 6 and 14 g m(-2) d(-1), CWs treating primary and secondary wastewater had a 96 and an 82% reduction, and produced a final effluent with a concentration of 14 and 13 mg L(-1). Constructed wetlands treating DSW produced a final effluent of 34 mg L(-1) (94% reduction). Similar to other studies, all CWs examined had variable performance in ammonium-N (NH(4)(+)-N) removal, with average removals varying between 37% (for CWs treating secondary wastewater) and 88% (for CWs treating DSW). Variable ortho-phosphorus (PO(4)(3-)-P) removal was attributable to different durations of operation, media types and loading rates. PMID- 21665355 TI - En bloc mobilization of the spleen, pancreas, and colon during hand-assisted laparoscopic left donor nephrectomy. PMID- 21665356 TI - Ureteral and multifocal tumours have worse prognosis than renal pelvic tumours in urothelial carcinoma of the upper urinary tract treated by nephroureterectomy. AB - BACKGROUND: It is not known whether the primary tumour location of upper urinary tract urothelial carcinoma (UUT-UC) is associated with prognosis. OBJECTIVE: To evaluate the impact of initial primary tumour location on survival in patients who had undergone radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS: Using a multi-institutional, retrospective database, we identified 609 patients with UUT-UC who had undergone RNU between 1995 and 2010. Tumour location was categorised as renal pelvis, ureter, or multifocal. INTERVENTION: All patients had undergone RNU. MEASUREMENTS: Tumour location was tested as a prognostic factor for survival through univariate and multivariable Cox regression analysis. RESULTS AND LIMITATIONS: Tumour location was renal pelvis in 317 cases (52%), ureter in 185 cases (30%), and multifocal in 107 cases (18%). Compared to renal pelvic and ureteral tumours, multifocal tumours were more likely to be associated with advanced stages (pT3/pT4; 39%, 30%, and 54%, respectively; p<0.001) and high-grade disease (53%, 56%, and 76%, respectively; p<0.001). On multivariable analysis, tumour location was an independent prognostic factor for cancer-specific death, disease recurrence, and metastasis (p<0.05). The 5-yr cancer-specific death-free survival probability was 86.8% for renal pelvic tumours, 68.9% for ureteral tumours, and 56.8% for multifocal tumours (p<0.001). The retrospective design of this study was its main limitation. CONCLUSIONS: Ureteral and multifocal tumours had a worse prognosis than renal pelvic tumours. These findings are not in line with recently published data and should be investigated in a prospective assessment to obtain a definitive statement regarding this matter. PMID- 21665358 TI - Stage pT0 after radical cystectomy: are all patients equal? PMID- 21665357 TI - The surgical learning curve for artificial urinary sphincter procedures compared to typical surgeon experience. AB - BACKGROUND: The artificial urinary sphincter (AUS) is a well-established treatment for male stress urinary incontinence. OBJECTIVE: We aimed to characterize the surgical learning curve for reoperation rates after AUS implantation. DESIGN, SETTING, AND PARTICIPANTS: The study cohort consisted of 65 602 adult males who received an AUS between 1988 and 2008, constituting close to 90% of all operations conducted during that time. Data on reoperations were obtained from the manufacturer, which requires documentation for warranty coverage. MEASUREMENTS: Surgeon experience was calculated as the number of original AUS implants performed prior to the index patient's surgery. Multivariable logistic regression models were used to examine the association between experience and reoperative rates, adjusted for case mix. RESULTS AND LIMITATIONS: There was a slow but steady decrease in reoperative rates with increasing surgeon experience (p=0.020), showing no plateau through 200 procedures. The risk of reoperation for a surgeon with five prior cases was 24.0%, which decreased to 18.1% for a surgeon with 100 prior implants (absolute risk difference [ARD]: 5.9%; 95% confidence interval [CI], 1.3-10.1%) and to 13.2% for a surgeon with 200 prior implants (ARD: 10.7%; 95% CI, 2.6-16.6%). Two thirds of contemporary patients (having AUS procedure between years 2000 and 2008) saw a surgeon who had done <=25 prior AUS implants; only 9% saw a surgeon with >=100 prior procedures. CONCLUSIONS: The learning curve for AUS surgery appears to be very long and without an obvious plateau. This is in contrast to typical surgeon experience, suggesting a considerable burden of avoidable reoperations. Efforts to flatten the learning are urgently needed. PMID- 21665359 TI - Cerebral vasospasm after auditory brainstem implantation in a patient with hyperostosis cranialis interna. PMID- 21665360 TI - Segmental ballism due to acute ischemic lesions of the caudate nucleus and parietal lobe: case report and review of the literature. PMID- 21665361 TI - CDH4 as a novel putative tumor suppressor gene epigenetically silenced by promoter hypermethylation in nasopharyngeal carcinoma. AB - We investigated the transcription levels, promoter methylation status and role as a tumor suppressor gene (TSG) of the cadherin CDH4 in nasopharyngeal carcinoma (NPC). The expression of CDH4 was decreased in NPC cell lines, xenografts and primary tumor biopsies. Promoter hypermethylation of CDH4 was detected in all five NPC cell lines, both NPC xenograft lines and 94.3% of primary tumors but not in any of the 12 normal epithelial samples. Loss of CDH4 expression could be restored by the methyltransferase inhibitor 5-aza-2'-deoxycytidine in NPC cell lines. Ectopic expression of CDH4 in the NPC cell lines inhibits cell proliferation, colony formation, migration and elicit cell communication. CDH4 may be a novel putative TSG that can be frequently and tumor-specifically inactivated by its promoter methylation in NPC. PMID- 21665362 TI - A large proportion of esophageal cancer cases and the incidence difference between regions are attributable to lifestyle risk factors in China. AB - A population-based case-control study was conducted in a high-risk area (Dafeng) and a low-risk area (Ganyu) of Jiangsu province, China. In this analysis, the population attributable fraction (PAF) was calculated to quantify the etiology of risk factors; the relative attributable risk (RAR) was applied to explore how much of the incidence difference could be explained by variations in the distribution of risk factors. Results showed that unhealthy lifestyles accounted for a high fraction of esophageal cancer in China. Dissimilar distribution of several lifestyle factors, together with hereditary variations may be largely responsible for the incidence difference between areas. PMID- 21665363 TI - Ethylene removal evaluation and bacterial community analysis of vermicompost as biofilter material. AB - Biofiltration of ethylene provides an environmentally friendly and economically beneficial option relative to physical/chemical removal, where selection of appropriate bed material is crucial. Here the vermicompost with indigenous microorganisms as bed material was evaluated for ethylene removal through batch test and biofilter experiment. Temporal and spatial dynamics of bacterial community in the vermicompost-biofilter under different ethylene loads were characterized by culture and denaturing gradient gel electrophoresis (DGGE) methods. The results showed that ethylene was effectively degraded by the vermicompost under conditions of 25-50% moisture content and 25-35 degrees C temperature. The vermicompost-biofilter achieved nearly 100% ethylene removal up to an inlet load of 11mg m(-3)h(-1). Local nitrogen lack of the vermicompost in the biofilter was observed over operation time, but the change of pH was slight. DGGE analysis demonstrated that the bacterial abundance and community structure of vermicompost-biofilter varied with the height of biofilter under different ethylene loads. Pseudomonads and Actinobacteria were predominant in the biofilter throughout the whole experiment. PMID- 21665364 TI - Aerobic degradation of 2,4-dinitrotoluene by individual bacterial strains and defined mixed population in submerged cultures. AB - The degradation efficiencies of isomeric mononitrotoluenes (2- and 4-NTs) and dinitrotoluenes (2,4-DNT and 2,6-DNT) by either individual bacterial strains (Bacillus cereus NDT4, Pseudomonas putida NDT1, Pseudomonas fluorescens NDT2, and Achromobacter sp. NDT3) or their mixture were compared in submerged batch cultivations. The mixed culture degraded 2,4-DNT nearly 50 times faster than any of the individual strains. The mixed culture also demonstrated significantly shorter lag periods in 2,4-DNT degradation, a lack of nitrite or organic intermediates accumulation in the liquid medium and the ability to degrade a broader spectrum of nitrotoluenes over a wider concentration range. The presence of both readily degradable 2-NT (or 4-NT) and poorly degradable 2,6-DNT in the medium negatively affected 2,4-DNT biodegradation. However, the mixed bacterial culture still effectively degraded 2,4-DNT with only slightly lower rates under these unfavorable conditions, thus showing potential for the remediation of 2,4 DNT contaminated sites. PMID- 21665365 TI - Sex differences in perceived pain are affected by an anxious brain. AB - Decades of research confirm that women have greater pain sensitivity than men. Women also show greater overall anxiety sensitivity than men. Given these differences, we hypothesized that sex differences in anxiety would explain sex differences in experienced pain and physiological responses to pain (at both spinal and cortical levels). By measuring subjective pain, state/trait anxiety, nociceptive flexion reflexes, and somatosensory evoked potentials (SEPs), it was possible to test the effects of anxiety on the processing of painful drives at different levels of the neuraxis while also documenting the role played by anxiety on sex differences in experienced pain. Results confirm that women are indeed more sensitive to pain than men. Importantly, this difference was accompanied by a significant sex difference in cortical activity (SEP amplitude) but not spinal nociceptive activity, suggesting that much of the sex difference in experienced pain is attributable to variations in thalamocortical processing and to ensuing changes in the appraisal of and/or emotional response to noxious insult. In support of this claim, we found that sex differences in cortical activity and subjective pain disappeared when trait anxiety was controlled for. This means that stable predispositions to respond with heightened apprehension contribute to baseline pain sensitivity differences between the sexes. These results indicate that the modulatory effect of affect on pain-related brain processes may explain why men and women experience painful shocks so differently. In our study, the mediating role of anxiety on sex differences in pain was tested and confirmed using path analysis. PMID- 21665367 TI - Parasites of cetaceans stranded on the Pacific coast of Costa Rica. AB - Information regarding parasitic fauna of cetaceans from Costa Rica is provided for the first time. A total of 25 stranded dolphins and whales were examined between 2001 and 2009, including striped dolphin (Stenella coeruleoalba) (n=19), pantropical spotted dolphin (S. attenuata) (n=2), spinner dolphin (S. longirostris) (n=1), bottlenose dolphin (Tursiops truncatus) (n=1), dwarf sperm whale (Kogia sima) (n=1) and Cuvier's beaked whale (Ziphius cavirostris) (n=1). Pathological findings associated with the parasites are also presented. In the most representative dolphin species, S. coeruleoalba, the prevalence of parasites was 89.5%; moreover, all examined specimens of S. attenuata, S. longirostris, T. truncatus and Z. cavirostris presented parasites. No parasites were recovered from K. sima. Fourteen helminth taxa were identified, including six species of cestodes (Strobilocephalus triangularis, Tetrabothrius forsteri, Trigonocotyle sp., Phyllobothrium delphini, Monorygma grimaldi, Tetraphyllidea gen. sp. plerocercoid), four digeneans (Nasitrema globicephalae, Brachycladium palliatum, B. pacificum and Oschmarinella albamarina) and four nematodes (Anisakis spp., Halocercus lagenorhynchi, Halocercus sp. and Crassicauda anthonyi). A commensal crustacean, Xenobalanus globicipitis, was also identified. All identified parasites representing new geographic records for the Pacific coast of Central America and new host records are presented. Parasitological information is valuable for conservation of cetaceans in Pacific coast of Costa Rica. PMID- 21665366 TI - Pain symptomatology and pain medication use in civilian PTSD. AB - The comorbidity of pain syndromes and trauma-related syndromes has been shown to be high. However, there have been limited data, especially in civilian medical populations, on the role of trauma-related disorders such as posttraumatic stress disorder (PTSD) on chronic pain and pain medication use. We analyzed 647 general hospital patients in primary care and obstetrics and gynecological waiting rooms for the experience of trauma and PTSD-related stress disorders. PTSD symptoms were found to be significantly positively correlated with pain ratings (r=.282, P<0.001) and pain-related functional impairment (r=0.303, P<0.001). Those with a current PTSD diagnosis had significantly higher subjective pain and pain-related impairment ratings than those with no PTSD. Furthermore, those with a current diagnosis of PTSD were significantly more likely to have used opioid analgesics for pain control compared to those without a diagnosis of PTSD (chi(2)=8.98, P=0.011). When analyzing the separate PTSD symptom subclusters (re-experiencing, avoidance, and hyperarousal), all symptom clusters were significantly related to pain and pain-related impairment ratings, but only the avoidance cluster was significantly related to prior opioid pain medication use. We conclude that PTSD and trauma-related disorders are common in impoverished medical populations and that their presence should be examined in patients with pain syndromes. Furthermore, these data suggest that PTSD and pain may share a vulnerability pathway, including the endogenous opioid neurotransmission systems. PMID- 21665368 TI - A survey on hydatidosis in livestock in Northern Iran based on data collected from slaughterhouses from 2004 to 2008. AB - Data have been collected from slaughterhouses in three provinces across the Northern Iran (Gilan, Mazandaran and Golestan) from March 2004 to March 2008. These data were collected to evaluate the prevalence of hydatidosis in slaughtered cattle, sheep and goats. During the study, 3,347,797 animals were slaughtered. These included 621,686 cattle, 1,719,725 sheep and 1,006,386 goats. The prevalence of infection in cattle, sheep and goats was 12%, 14.6% and 10.1%, respectively. The association of condemnation rates with seasons was not proven statistically. PMID- 21665369 TI - Selected impulsivity facets with alcohol use/problems: the mediating role of drinking motives. AB - Impulsivity is associated with alcohol use and related problems, yet limited research has examined the different facets of impulsivity with these outcomes. This study aimed to examine whether sensation seeking, positive urgency, and negative urgency, as separate constructs, would differentially predict alcohol use/problems, and to investigate whether specific drinking motives would mediate these relationships. Self-reported data from an online survey of undergraduate drinkers (n=317) was used in the current study. Findings indicate that sensation seeking and the urgency traits represent unique personality constructs in the prediction of alcohol use/problems, and should be considered separately in future research and when designing prevention and intervention strategies. PMID- 21665370 TI - The role of executive function in bridging the intention-behaviour gap for binge drinking in university students. AB - BACKGROUND: Alcohol consumption contributes to a significant proportion of disease and the high prevalence amongst young adults is a worldwide health concern. PURPOSE: To determine which aspects of executive function (EF) distinguish binge-drinkers from non binge-drinkers and to establish the role of EF in predicting behaviour. METHODS: Self-report questionnaires, four tests of self-regulation and a behaviour measure were administered to 153 students. RESULTS: The Theory of Planned Behaviour model was significant in predicting both intentions and behaviour. Although binge-drinkers and non binge-drinkers were found to differ on three of the four measures of EF, none predicted additional variance in behaviour. Planning ability and inhibition control moderated the relationship between intention and behaviour such that for individuals who intended to binge-drink, those with high planning ability or high inhibitory control were more likely to avoid doing so. CONCLUSIONS: Interventions targeting binge-drinking behaviour should aim to develop planning skills and inhibitory control. PMID- 21665371 TI - Alcohol, violence, and the Alcohol Myopia Model: preliminary findings and implications for prevention. AB - This experiment provided a preliminary test of whether the Alcohol Myopia Model (AMM; Steele & Josephs, 1990) would provide a guiding framework for the prevention of alcohol-related violence. The model contends that alcohol has a "myopic" effect on attentional capacity that presumably facilitates violence by focusing attention onto more salient provocative, rather than less salient inhibitory, cues in hostile situations. Participants were 16 intoxicated male social drinkers who completed a laboratory task in which electric shocks were received from, and administered to, a fictitious opponent under the guise of a competitive reaction-time task while they were exposed to either violence promoting (n=8) or violence-inhibiting (n=8) cues. Aggression was operationalized as the intensity and duration of shocks administered by the participant to his "opponent." Despite being equally intoxicated, participants exposed to violence inhibiting cues were dramatically less aggressive (d=1.65) than those exposed to the violence-promoting cues. Our data suggest that the AMM holds a great deal of promise to help develop effective prevention interventions for alcohol-related violence. PMID- 21665372 TI - Alcohol policy support among mandated college students. AB - BACKGROUND: Alcohol consumption on college campuses is high, and often dangerous. College administrators have created policies to control alcohol consumption, but student body support or opposition of specific policies has been relatively unexplored. METHOD: The current study examined the relations of alcohol policy support with gender and alcohol consumption. Mandated students (N=229; 44% women) completed self-report assessments of alcohol policy support and alcohol consumption. RESULTS: Women supported policies to a greater extent than did men, as did lighter drinkers relative to heavier drinkers. Drinks per drinking day fully mediated the relation between gender and alcohol policy support. CONCLUSION: While alcohol policy support differs by gender, this covariation is explained by differences in alcohol consumption. Findings have implications for addressing alcohol policy support among mandated college students. PMID- 21665373 TI - To drink or not to drink: motives and expectancies for use and nonuse in adolescence. AB - Drinking motives have a prominent role in cognitive models of adolescent and adult alcohol decision-making (Cooper, Russell, Skinner, & Windle, 1992; Cooper, 1994). The complementary construct of motivation not to drink has received less attention (Epler, Sher & Piasecki, 2009). We examined how abstinence motives interacted with drinking motives and alcohol expectancies to predict alcohol consumption in samples of US high school students (N>2500). Nondrinking motives predicted lower rates of lifetime and current alcohol use. Motives not to drink interacted with specific drinking motives, like social and coping motives, and alcohol expectancies to predict certain aspects of drinking behavior. For example, motives not to drink had the greatest impact on youth with weaker social motivations. Findings highlight the distinction between motives not to drink and other alcohol-related cognitions in predicting adolescent alcohol consumption. This work not only supports the utility of this construct in developing models of youth alcohol-related decision-making but also has implications for prevention programming. PMID- 21665374 TI - Learning from prion-derived peptides for designing novel phosphorylation sensitive peptide probes. AB - Novel catalytic peptides highly active in conversion of hydrogen peroxide to superoxide are newly designed and proposed as novel probes for assessing the cellular protein phosphorylation/dephosphorylation events possibly available for future clinical applications. One of model peptide was invented by fusing the copper-binding catalytic peptide and Erk1/2 MAP kinase kinase substrate peptide. In order to demonstrate that this type of probes is phosphorylation-sensitive, preliminary data was obtained with non-phosphorylated and phosphorylated peptides at two phosphorylation sites, namely, threonine and tyrosine residues. As expected, model phosphorylations effectively lowered the catalytic activity of the peptide. This is the first implication that phosphorylation-controllable enzyme mimics could be artificially invented. In addition, the author propose a possible application of this type of peptides as the tools or components for constructing a simplified in vitro signaling system processing the phosphorylation signals into the oxidative signals possibly affecting the fate of the living cells. PMID- 21665375 TI - Is the ataxia of Charlevoix-Saguenay a developmental disease? AB - The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is considered a neurodegenerative disease caused by mutations in the SACS gene, located on chromosome 13q12.12. It is a syndrome that comprises skeletal, retinal and neurological manifestations, among which feature spasticity, cerebellar ataxia and peripheral neuropathy. Five patients with a molecular diagnosis of ARSACS underwent clinical, radiological, and ophthalmologic examinations. Every one of the identified causal mutations was novel. Spastic ataxia, peripheral neuropathy, pes cavus, and hammertoes were found in every case. T2 and T2-fluid attenuation inversion recovery-weighted MRI sequences demonstrated cerebellar atrophy and a hypointense linear striation at the pons. Tensor diffusion sequences revealed that the hypointense striation corresponded with hyperplasia of the pontocerebellar fibres, which gave place to abnormally thick middle cerebellar peduncles. Stereophotographs of the optic discs showed an increased number of retinal fibres, and ocular coherence tomography, increased thickness of the retinal nerve fibre layer. The authors suggest that the hyperplasic pontocerebellar fibres compress the pyramidal tracts at the pons since a very early stage of central nervous system development, causing spasticity, and may also cause cerebellar atrophy by means of glutamate-induced excitotoxicity. The abnormal amount of retinal fibres traversing the optic discs could have caused the detected mild peripheral visual field defects. Taken together, these facts point to a developmental cause in ARSACS, as it does not exhibit the tissue atrophy characteristic of degenerative diseases. Clinical deterioration in ARSACS seems to be mediated by phenomena (compression of the pyramidal tracts and cerebellar glutamate-mediated excitotoxicity) derived from the developmental anomalies referred to, while the neuromuscular symptoms are caused by a peripheral neuropathy with pathologic features suggestive of a similar origin. These observations should be taken into account when research about the origin of ARSACS is undertaken. PMID- 21665376 TI - Angiogenesis and lymphangiogenesis in sporadic hepatic angiomyolipoma. AB - Angiogenesis and lymphangiogenesis are critical processes for tumor growth, invasion, and metastasis. The present study aimed to investigate the distribution and clinical significance of angiogenesis and lymphangiogenesis in hepatic angiomyolipoma (AML). We performed immunohistochemical staining for endothelial cell markers (CD34 and podoplanin) on 80 cases of sporadic hepatic AMLs. Microvessel density (MVD) and lymphatic vessel density (LVD) were determined in intratumoral and peritumoral regions and adjacent non-tumorous liver tissues. All hepatic AMLs showed positive staining for CD34 and podoplanin. Intratumoral and peritumoral MVDs and LVDs were significantly higher than those in adjacent liver tissues (P<0.001). No statistical difference in both MVD and LVD was found between intratumoral and peritumoral areas. Large tumors (>5cm) had a significantly increased MVD and LVD as compared with smaller tumors. A significant positive correlation was found between average LVDs and MVDs (r=0.567, P<0.001), and LVDs were a relatively lower event as compared with MVDs. Double immunostaining revealed that no neoplastic cells positive for HMB-45, an antibody reacting with melanosome-associated antigen, were concurrently immunoreactive for endothelial cell markers. In conclusion, intratumoral and peritumoral angiogenesis and lymphangiogenesis commonly occur in hepatic AMLs, thus representing potential therapeutic targets for this disease. PMID- 21665377 TI - Low concentrations of alendronate increase the local invasive potential of osteoblastic sarcoma cell lines via connexin 43 activation. AB - Bisphosphonates (BPs) are agents used for treating disorders of excessive bone resorption. In addition, due to their cell-killing activity, BPs were potent candidates for adjuvant cancer therapy. On the other hand, low-concentrations of BPs have been reported to increase cellular viability in several types of tumor cells. Therefore, we focused on the effect of BPs on cellular aggressiveness of malignant bone tumors at low concentrations. MTS assay was performed using osteosarcoma cell lines MG63 and HOS, fibrosarcoma cell line HT1080, and prostate cancer cell line PC3. All the cell lines showed toxicity at high concentrations. On the other hand, at lower concentrations, the cellular viabilities of HOS and MG63 were rather higher than those of untreated controls. Since this tendency was most evident, HOS was used for further assays, including cellular motility, bone resorption activity, and cathepsin K activity. The low-concentration of alendronate enhanced cellular viability and motility, which correlated with the expression of connexin 43 at the mRNA and protein levels. Interestingly, oleamide, a potent connexin 43 inhibitor, had an inhibitory effect on the enhanced proliferation. Our data suggest that alendronate may enhance the proliferation of osteoblastic cell line through connexin 43 activation. PMID- 21665378 TI - Radiation pneumopathy in the rat after intravenous application of (188)Re-labeled microspheres. AB - PURPOSE: To determine the dose dependence and kinetics of pneumopathy after systemic administration of rhenium-188 ((188)Re)-labeled microspheres in a rat model. METHODS AND MATERIALS: (188)Re-microspheres were injected intravenously into adult Wistar rats (n = 54, age, 8 +/- 2 months). The rats were divided into 6 groups according to the intended absorbed dose in the lung (maximum 60 Gy). Gamma camera scans were used to estimate the individual whole lung doses. One control group (n = 5) received nonlabeled microspheres. The breathing rate was measured before and weekly after the treatment using whole body plethysmography until 24 weeks. An increase in the breathing rate by 20% compared with the individual pretreatment control value was defined as the quantal endpoint for dose-effect analyses. RESULTS: A biphasic increase in the breathing rate was observed. The first impairment of lung function occurred in Weeks 3-6. For late changes, the interval to onset was clearly dose dependent and was 17 weeks (10-30 Gy) and 10 weeks (50-60 Gy), respectively. The incidence of the response was highly dependent on the estimated lung dose. The median effective dose for an early and late response was virtually identical (19.9 +/- 0.6 Gy and 20.4 +/- 3.1 Gy, respectively). A significant correlation was found between the occurrence of an early and a late effect in the same rat, suggesting a strong consequential component. CONCLUSIONS: The effects of radiolabeled microspheres can be studied longitudinally in a rat model, using changes in the breathing rate as the functional, clinically relevant response. The isoeffective doses from the present study using radionuclide administration and those from published investigations of homogeneous external beam radiotherapy are almost similar. PMID- 21665379 TI - Redefining high-risk prostate cancer based on distant metastases and mortality after high-dose radiotherapy with androgen deprivation therapy. AB - PURPOSE: Modern outcomes of high-dose external beam radiotherapy (EBRT) with androgen deprivation therapy (ADT) for high-risk (HR) prostate cancer are not well described. METHODS AND MATERIALS: We identified 585 patients who met HR criteria by 2010 National Comprehensive Cancer Network guidelines, who were treated with EBRT consisting of >=74 Gy from 1996 to 2008 at Cleveland Clinic, of whom 95% received ADT. We analyzed biochemical relapse-free survival (bRFS), distant metastases-free survival (DMFS), and prostate cancer-specific mortality (PCSM). RESULTS: The median EBRT dose was 78 Gy, and median ADT duration was 6 months. At 10 years, the bRFS was 50.2%, the DMFS was 71.6%, and the PCSM was 14.4%. On multivariate analysis, significant predictors of bRFS were biopsy Gleason score (bGS) of 8 to 10, stage T3, and prostate-specific antigen (PSA) concentration; predictors of DMFS were bGS of 8 to 10 and stage T3; the only predictor of PCSM was bGS of 8 to 10. The duration of ADT was not predictive of any endpoint. We identified an unfavorable high-risk (UHR) group of stage T1-T2 tumors consisting of bGS of 8 with PSA of >10 ng/ml or bGS of 9 to 10 with any PSA level; the remaining clinically localized cancers comprised the favorable high-risk (FHR) group. Comparing FHR, UHR, and stage T3 groups, the DMFS rates were 81.4%, 57.8%, and 59.1% (p < 0.0001), and the PCSM rates were 7.5%, 28.4%, and 20.6% at 10 years, respectively (p = 0.006). CONCLUSION: A bGS of 8 to 10 is the strongest predictor of bRFS, DMFS, and PCSM after high-dose EBRT with ADT. The duration of ADT did not correlate with outcome. Future studies should account for the heterogeneity in HR prostate cancer. PMID- 21665380 TI - Determinants of toxicity, patterns of failure, and outcome among adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with greater than conventional doses of perioperative high-dose-rate brachytherapy and external beam radiotherapy. AB - PURPOSE: The present study was undertaken to determine factors predictive of toxicity, patterns of failure, and survival in 60 adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with combined perioperative high-dose-rate brachytherapy and external beam radiotherapy. METHODS AND MATERIALS: The patients were treated with surgical resection and perioperative high-dose-rate brachytherapy (16 or 24 Gy) for negative and close/microscopically positive resection margins, respectively. External beam radiotherapy (45 Gy) was added postoperatively to reach a 2-Gy equivalent dose of 62.9 and 72.3 Gy, respectively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with advanced high-grade tumors. RESULTS: Grade 3 toxic events were observed in 18 patients (30%) and Grade 4 events in 6 patients (10%). No Grade 5 events were observed. A location in the lower limb was significant for Grade 3 or greater toxic events on multivariate analysis (p = .013), and the tissue volume encompassed by the 150% isodose line showed a trend toward statistical significance (p = .086). The local control, locoregional control, and distant control rate at 9 years was 77.4%, 69.5%, and 63.8%, respectively. On multivariate analysis, microscopically involved margins correlated with local control (p = .036) and locoregional control (p = .007) and tumor size correlated with distant metastases (p = .004). The 9-year disease-free survival and overall survival rate was 47.0% and 61.5%, respectively. Multivariate analysis showed poorer disease-free survival rates for patients with tumors >6 cm (p = .005) and microscopically involved margins (p = .043), and overall survival rates decreased with increasing tumor size (p = .011). CONCLUSIONS: Grade 3 or greater wound complications can probably be decreased using meticulous treatment planning to decrease the tissue volume encompassed by the 150% isodose line, especially in lower limb locations. Microscopically involved margins remain a predictor of local and locoregional failure, despite radiation doses >70 Gy. Patients with tumors >=6 cm and microscopically involved margins are at high risk of treatment failure and death from the development of distant metastases. PMID- 21665381 TI - Single fraction versus fractionated linac-based stereotactic radiotherapy for vestibular schwannoma: a single-institution experience. AB - PURPOSE: To evaluate and compare outcomes for patients with vestibular schwannoma (VS) treated in a single institution with linac-based stereotactic radiosurgery (SRS) or by fractionated stereotactic radiotherapy (SRT). METHODS AND MATERIALS: One hundred and nineteen patients (SRS = 78, SRT = 41) were treated. For both SRS and SRT, beam shaping is performed by a mini-multileaf collimator. For SRS, a median single dose of 12.5 Gy (range, 11-14 Gy), prescribed to the 80% isodose line encompassing the target, was applied. Of the 42 SRT treatments, 32 treatments consisted of 10 fractions of 3-4 Gy, and 10 patients received 25 sessions of 2 Gy, prescribed to the 100% with the 95% isodose line encompassing the planning target volume. Mean largest tumor diameter was 16.6 mm in the SRS and 24.6 mm in the SRT group. Local tumor control, cranial nerve toxicity, and preservation of useful hearing were recorded. Any new treatment-induced cranial nerve neuropathy was scored as a complication. RESULTS: Median follow-up was 62 months (range, 6-136 months), 5 patients progressed, resulting in an overall 5 year local tumor control of 95%. The overall 5-year facial nerve preservation probability was 88% and facial nerve neuropathy was statistically significantly higher after SRS, after prior surgery, for larger tumors, and in Koos Grade >=3. The overall 5-year trigeminal nerve preservation probability was 96%, not significantly influenced by any of the risk factors. The overall 4-year probability of preservation of useful hearing (Gardner-Robertson score 1 or 2) was 68%, not significantly different between SRS or SRT (59% vs. 82%, p = 0.089, log rank). CONCLUSION: Linac-based RT results in good local control and acceptable clinical outcome in small to medium-sized vestibular schwannomas (VSs). Radiosurgery for large VSs (Koos Grade >=3) remains a challenge because of increased facial nerve neuropathy. PMID- 21665382 TI - Intraoperative localization of tantalum markers for proton beam radiation of choroidal melanoma by an opto-electronic navigation system: a novel technique. AB - PURPOSE: External beam proton radiation therapy has been used since 1975 to treat choroidal melanoma. For tumor location determination during proton radiation treatment, surgical tantalum clips are registered with image data. This report introduces the intraoperative application of an opto-electronic navigation system to determine with high precision the position of the tantalum markers and their spatial relationship to the tumor and anatomical landmarks. The application of the technique in the first 4 patients is described. METHODS AND MATERIALS: A navigated reference base was attached noninvasively to the eye, and a navigated pointer device was used to record the spatial position of the tantalum markers, the tumor, and anatomical landmarks. Measurement accuracy was assessed on ex vivo porcine eye specimen by repetitive recording of the tantalum marker positions. The method was applied intraoperatively on 4 patients undergoing routine tantalum clip surgery. The spatial position information delivered by the navigation system was compared to the geometric data generated by the EYEPLAN software. RESULTS: In the ex vivo experiments, the maximum repetition error was 0.34 mm. For the intraoperative application, the root mean square error of paired-points matching of the marker positions from the navigation system and from the EYEPLAN software was 0.701-1.25 mm. CONCLUSIONS: Navigation systems are a feasible tool for accurate localization of tantalum markers and anatomic landmarks. They can provide additional geometric information, and therefore have the potential to increase the reliability and accuracy of external beam proton radiation therapy for choroidal melanoma. PMID- 21665383 TI - [Do couples who procreate through sperm donation inform their children?]. AB - OBJECTIVES: An amendment to the French bioethics law allowing children conceived by gamete donation to know the identity of donors is proposed, while no study can assess the proportion of parents in France that disclose the nature of conception to their donor conceived offspring. The aim of our study was to know whether couples who wish to inform their offspring actually did it. PATIENTS AND METHODS: We sent a questionnaire to parents who had expressed an intention to disclose the nature of conception to their future offspring conceived by sperm donation. This allowed us to evaluate the number of couples who inform their offspring, and the couple and offspring feelings when information was given. RESULTS: Among 38 questionnaires sent, 20 couples answered. Fourteen informed their offspring about the nature of conception, most having lived serenely this moment. 47% of offspring have reacted with indifference. While 19 couples informed their friends or family, six couples did not inform their offspring, and two of them no longer want to disclose anymore. CONCLUSION: Careful thought before the beginning of assisted reproductive technology and support after birth are needed to help couples communicate information to their offspring. Without this communication, any policy of openness to know donor related data seems vain. PMID- 21665384 TI - Characteristics associated with the diversion of controlled medications among adolescents. AB - BACKGROUND: The objective of this study was to estimate the lifetime prevalence of diversion (i.e., trading, selling, giving away or loaning) of four classes of controlled medications (pain, stimulant, anti-anxiety, and sleeping) among adolescents, and to identify demographic and behavioral characteristics of adolescents who divert their own controlled medications. METHODS: A web-based survey was self-administered by 2744 secondary school students from two southeastern Michigan school districts in 2009-2010. The sample consisted of 51% females, 65% Whites, 29% African-Americans, 4% Asians, 1% Hispanics and 1% from other racial categories. RESULTS: Thirty-three percent of the students had ever been prescribed at least one controlled pain, stimulant, anti-anxiety, or sleeping medication. Approximately 13.8% (n=117) of lifetime prescribed users of controlled medications (n=848) had ever traded, sold, given away or loaned their medications. Multiple logistic regression analyses indicated that being approached to divert medications, nonmedical use of prescription medications, externalizing behaviors, and being non-White were significantly associated with the diversion of controlled medications. Multiple logistic regression analysis indicated that the odds of substance use and abuse for lifetime prescribed users who diverted their controlled medications were significantly greater than prescribed users who never diverted. CONCLUSIONS: The findings indicate that approximately one in seven prescribed users had diverted their controlled medications in their lifetimes. Being approached to divert medications and substance use are more prevalent among adolescents who diverted their controlled medications. Careful assessments, diligent prescribing and monitoring of controlled medications, and continual patient education could be useful in reducing medication diversion. PMID- 21665385 TI - Contingency management for alcohol use reduction: a pilot study using a transdermal alcohol sensor. AB - BACKGROUND: Contingency management (CM) has not been thoroughly evaluated as a treatment for alcohol abuse or dependence, in part because verification of alcohol use reduction requires frequent in-person breath tests. Transdermal alcohol sensors detect alcohol regularly throughout the day, providing remote monitoring and allowing for rapid reinforcement of reductions in use. METHODS: The purpose of this study was to evaluate the efficacy of CM for reduction in alcohol use, using a transdermal alcohol sensor to provide a continuous measure of alcohol use. Participants were 13 heavy drinking adults who wore the Secure Continuous Remote Alcohol Monitoring (SCRAM) bracelet for three weeks and provided reports of alcohol and drug use using daily web-based surveys. In Week 1, participants were asked to drink as usual; in Weeks 2 and 3, they were reinforced on an escalating schedule with values ranging from $5 to $17 per day on days when alcohol use was not reported or detected by the SCRAM. RESULTS: Self reports of percent days abstinent and drinks per week, and transdermal measures of average and peak transdermal alcohol concentration and area under the curve declined significantly in Weeks 2-3. A nonsignificant but large effect size for reduction in days of tobacco use also was found. An adjustment to the SCRAM criteria for detecting alcohol use provided an accurate but less conservative method for use with non-mandated clients. CONCLUSION: Results support the efficacy of CM for alcohol use reductions and the feasibility of using transdermal monitoring of alcohol use for clinical purposes. PMID- 21665386 TI - Effect of the US3 protein of bovine herpesvirus 5 on the actin cytoskeleton and apoptosis. AB - The US3 protein is a unique protein kinase only present in the Alphaherpesvirinae subfamily of the herpesviruses. Studies performed with several alphaherpesviruses demonstrated that the US3 protein is involved in cytoskeleton modifications during viral infection and displays anti-apoptotic activity. However, the US3 protein of BoHV-5 has not been studied up to now. As reported for other alphaherpesviruses, our results showed that BoHV-5 US3 confers resistance against apoptosis and induces cytoskeletal reorganization leading to cell rounding, actin stress fiber breakdown and cell projections that interconnect cells. The expression of a kinase-dead version of BoHV-5 US3 showed that the anti-apoptotic activity and the induction of cell projections are kinase-dependent whereas kinase activity is not absolutely required for actin stress fiber breakdown. Besides, the kinase-dead version of US3, but not the wild type protein, was found excluded from the nucleus. These results constitute the first report on the BoHV 5 US3 functions, and highlight that there are functional differences and similarities among US3 proteins of different alphaherpesviruses. PMID- 21665387 TI - Evidence for recombination in neboviruses. AB - Neboviruses are bovine enteric caliciviruses (genus Nebovirus) associated with enteric diseases in calves. By screening the stools of calves collected from Italian herds using primers targeted to a conserved stretch in calicivirus RNA dependent RNA-polymerase (RdRp), nebovirus RNA was detected in calves with enteritis (13.1%) but not in overtly health animals. Upon sequence analysis of the RdRp fragment, the Italian viruses formed a tightly conserved group and resembled closely the nebovirus prototype Nebraska/80/US. The sequence of a 2.2kb ORF1 fragment, spanning the 3' end of the RdRp and the full-length capsid coding region, of two nebovirus strains was determined, revealing marked genetic heterogeneity in the capsid protein, as the two Italian viruses were classified into two distinct capsid lineages, and suggesting a recombination event downstream the highly conserved shell (S) domain. PMID- 21665388 TI - Pathogenicity in quails and mice of H5N1 highly pathogenic avian influenza viruses isolated from ducks. AB - In our study, the pathogenicity of H5N1 influenza A viruses circulating in waterfowls in Southern China was investigated. Three H5N1 highly pathogenic avian influenza (HPAI) viruses isolated from ducks, A/Duck/Guangdong/383/2008(DK383), A/Duck/Guangdong/378/2008(DK378) and A/Duck/Guangdong/212/2004(DK212) were inoculated at 10(6) fifty-percent egg infectious doses (EID(50)) into ducks, quails and mice and showed varying levels of pathogenicity. In ducks, the mortality rates ranged from 0 to 60% and the mean death time (MDT) was 0-6.7 days post-inoculation (DPI). While the viruses were highly pathogenic in quails, resulting in 83.3-100% mortality and the MDT of 2.3-3 DPI, they were completely lethal in mice (100% mortality). The viruses replicated in many organs of ducks and quails and were found in the brain, and kidney, lung and spleen of the mice. Phylogenetic analysis revealed that DK383 and DK378 viruses of clade 2.3.2 belonged to genotype 11, while DK212 virus of clade 9 was genotype 3. Our study illustrated H5N1 influenza viruses within Clade 2.3.2 and 9 from duck in Southern China had very highly pathogenicity to Japanese quails and BALB/c mice, but viruses within Clade 2.3.2 had more highly lethality than those of clade 9 to Muscovy ducks. Therefore, they had posed a continued challenge for disease control and public health. PMID- 21665389 TI - Exogenous DNA uptake by South American catfish (Rhamdia quelen) spermatozoa after seminal plasma removal. AB - Sperm from different species shows biological differences, determining the success or failure of the sperm-mediated gene transfer (SMGT) technique. There is evidence that exogenous DNA uptake by the spermatozoa is a species-specific and highly regulated phenomenon. Problems involving SMGT procedures might be related to activation of defenses in spermatozoa and in seminal plasma such as DNase enzymes. The objective in the present study was to transfect South American catfish spermatozoa after seminal plasma removal. Seminal plasma had a strong DNase activity that is reduced after sperm washes in isosmotic solution, in which Western blot analysis demonstrated a reduction in the DNase content after washes and Southern blot evaluations show the presence of plasmid after sperm washes. The seminal plasma DNase digests exogenous DNA in a few minutes and has an optimal activity at 43 degrees C. Also, EDTA at 30 mM concentration inhibits the DNase activity. Using PCR the pEGFP vector was internalized by sperm cells even at lesser concentrations (5-40 ng/10(6) spermatozoa) without motility loss after seminal plasma removal. Conversely, using greater pEGFP concentrations (100 ng/10(6) spermatozoa), there were no motile cells, suggesting toxicity of exogenous DNA for sperm cells. These results are interpreted to provide information that can improve the protocol for generation of transgenic South American catfish. PMID- 21665390 TI - The impact of chocolate on cardiovascular health. AB - Cardiovascular disease is the leading determinant of mortality and morbidity in women. Functional foods are attracting interest as potential regulators of the susceptibility to disease. Supported by epidemiological evidence, chocolate has emerged as a possible modulator of cardiovascular risk. Chocolate, or cocoa as the natural source, contains flavanols, a subclass of flavonoids. The latter years have witnessed an increasing number of experimental and clinical studies that suggest a protective effect of chocolate against atherogenesis. Oxidative stress, inflammation, and endothelial function define three biological mechanisms that have shown sensitivity to chocolate. Moreover, the consumption of chocolate has been involved in the protective modulation of blood pressure, the lipid profile, the activation of platelets, and the sensitivity to insulin. Dark chocolate seems more protective than milk or white chocolate. Despite this array of benefits, there is a lack of well designed clinical studies demonstrating cardiovascular benefit of chocolate. The high caloric content of chocolate, particularly of some less pure forms, imposes caution before recommending uncontrolled consumption. PMID- 21665391 TI - Sturdivan's formula revisited: MRI assessment of anterior chest wall thickness for injury risk prediction of blunt ballistic impact trauma. AB - BACKGROUND: The thickness and composition of the chest wall are important quantities in multiparametric trauma models for the assessment of injury severity due to blunt ballistic chest impact. While ballistic parameters of non penetrating projectiles can routinely be measured with high accuracy, data on the thickness of the anterior chest wall is unreliable. Therefore, it is the aim of this work to provide data on the thickness and composition of the anterior chest wall based on MRI examinations of healthy volunteers and to compare these measurements with different empirical estimation rules for the chest wall thickness. METHODS: The study encompassed consecutive male patients from an ongoing population-based cohort study. Each subject underwent standardized whole body MRI (1.5Tesla). Thickness of total chest wall (CWT) and of adipose tissue (AT) were measured by two independent readers at ten anatomic locations on two cross-sectional planes over the centre of the left ventricle and over the tracheal bifurcation. For each subject, chest wall thickness was estimated based on ten different empirical estimation rules and percent errors were calculated. RESULTS: The study encompassed 250 male volunteers (average age 55.5 years, range 21-84 years, SD 13.6 years). Mean intraclass correlation coefficient of the two readers was 0.90 (range 0.59-1.0, SD 0.08). Average CWT was 31.2mm (range 17.3 51.6mm, SD 5.8mm) while average thickness of AT was 13.1mm (range 3.6-26.7mm, SD 4.6mm). Relative adiposity was 0.41 on average (range 0.19-0.61, SD 0.09). There was significant correlation between CWT and body weight and between CWT and body mass index. Sturdivan's approximation formula showed strong correlation with the measured values (percent error 3.58%, SD 16.26%). CONCLUSION: In this population, Sturdivan's equation formula which is based on the individual's body weight provides valid approximation values for the chest wall thickness and may be used for the optimal design of protective devices and personal body armor as well as for the development of anthropomorphic based test methodologies. PMID- 21665392 TI - The incidence of drugs of impairment in oral fluid from random roadside testing. AB - Oral fluid (OF) has become a popular specimen to test for presence of drugs, particularly in regards to road safety. In Victoria, OF specimens from drivers have been used to test for the presence of methylamphetamine (MA) and Delta(9) tetrahydrocannabinol (THC) since 2003 and 3,4-methylenedioxy-N-methylamphetamine (MDMA) since 2006. LC-MS/MS has been used to test the most recent 853 submitted OF specimens from Victoria Police for 31 drugs of abuse including those listed in the Australian Standard AS4760-2006. At least one proscribed drug was detected in 96% of drivers, of which MA was the most common (77%), followed by THC (42%), MDMA (17%) and the combination of all three (3.9%). Opioids were detected in 14% of drivers of which 4.8% were positive for 6-acetylmorphine and 3.3% for methadone. The incidence of the opioids tramadol (1.2%) and oxycodone (1.1%) were relatively low. Cocaine (8.0%) was as commonly detected as benzodiazepines (8.0%), and was almost always found in combination with MA (7.9%). Samples positive to benzodiazepines were largely due to diazepam (3.5%) and alprazolam (3.4%), with only 0.2% of drivers combining the two. Ketamine was also detected in 1.5% of cases. While the incidences of the proscribed drugs itself are concerning, it is clear that many drivers are also using other drugs capable of causing impairment. PMID- 21665393 TI - Toxicological investigations of drivers killed in road traffic accidents in Norway during 2006-2008. AB - AIM: To study the results from the toxicological investigations of drivers of cars and vans who were fatally injured in road traffic accidents in 2006-2008 and discuss the findings in relation to the proposed legal limits and impairment thresholds for drugs. METHODS: Analyses for alcohol, illegal drugs and psychoactive medicinal drugs were performed by the Norwegian Institute of Public Health. Information on type of accident (single or multiple vehicles) and type of road (urban or rural) was obtained from Statistics Norway. RESULTS: Toxicological analyses were requested for 59% of the fatally injured drivers. Drivers involved in single vehicle accidents were more often subject to toxicological investigations, so were also young male drivers and drivers killed on urban roads. Alcohol or drugs were found in concentrations above the current (for alcohol) or proposed (for drugs) legal limits in samples from 37.8% of the drivers; from 64.3% those killed in single-vehicle accidents and 17.9% of those killed in multiple-vehicle accidents. In total, alcohol was found in 25.0%, illicit drugs in 10.2%, and psychoactive medicinal drugs in 13.8% of the samples. Combinations of alcohol and drugs were found in 5.1% and multiple drugs without alcohol in 6.1% of the samples. The prevalence of alcohol or drugs was higher in samples from males than females, higher in samples from young drivers, and higher in samples from drivers killed during weekends. Two thirds of the drivers with alcohol or drug concentrations above the current or proposed legal limits had concentrations above the proposed high impairment threshold. About 60% of the latter ones were impaired by alcohol only, 20% by drugs in combination with alcohol, and 20% by drugs only, mainly due to multi-drug use. CONCLUSION: The use of alcohol or drugs before driving was a significant contributing factor in fatal road traffic accidents, particularly in single vehicle accidents, and particularly among young male drivers. Alcohol was the most significant intoxicant, but multi-substance use was also significantly prevalent. The majority of the drivers with alcohol or drug findings were strongly impaired. PMID- 21665394 TI - Efficacy of fluoro-2-deoxy-D-glucose positron emission tomography to evaluate responses to concurrent chemoradiotherapy for head and neck squamous cell carcinoma. AB - OBJECTIVE: This study evaluates the utility of fluorodeoxyglucose-positron emission tomography (FDG-PET) in patients with head and neck squamous cell carcinoma (HNSCC) who received concurrent chemoradiotherapy (CCRT). METHODS: Sixty-five patients were recruited for this study between November 2002 and April 2007. The FDG-PET scan was performed before treatment and 4-6 weeks after treatment. RESULTS: The mean of maximum standardized uptake value (SUVmax) before treatment at the primary tumor site was 8.1 (range, 2-22). The sensitivity of FDG PET for the diagnosis of primary tumor site was 98%. The mean of SUVmax after treatment was 2.6 (range, 2-5). The sensitivity, specificity, and accuracy of FDG PET for the diagnosis of primary tumor site after treatment were 100%, 40%, and 46%, respectively. The mean of SUVmax before treatment at the nodal site was 4.7 (range, 2-16). The mean of SUVmax after treatment was 2.0 (range, 2-6.7). The pre treatment SUVmax of T2, T3, and T4 stages were significantly higher than that of the T1 stage. The N stage had no correlation in terms of the pre-treatment nodal site SUVmax. CONCLUSION: Our results indicate that FDG-PET is a useful imaging method for evaluating the response of CCRT in patients with HNSCC. However, performing FDG-PET 4-6 weeks after treatment may be too early as it may give false-positive results due to fibrosis and scarring. PMID- 21665395 TI - Image quality and dose in mammography in 17 countries in Africa, Asia and Eastern Europe: results from IAEA projects. AB - PURPOSE: The objective is to study mammography practice from an optimisation point of view by assessing the impact of simple and immediately implementable corrective actions on image quality. MATERIALS AND METHODS: This prospective multinational study included 54 mammography units in 17 countries. More than 21,000 mammography images were evaluated using a three-level image quality scoring system. Following initial assessment, appropriate corrective actions were implemented and image quality was re-assessed in 24 units. RESULTS: The fraction of images that were considered acceptable without any remark in the first phase (before the implementation of corrective actions) was 70% and 75% for cranio caudal and medio-lateral oblique projections, respectively. The main causes for poor image quality before corrective actions were related to film processing, damaged or scratched image receptors, or film-screen combinations that are not spectrally matched, inappropriate radiographic techniques and lack of training. Average glandular dose to a standard breast was 1.5 mGy (mean and range 0.59-3.2 mGy). After optimisation the frequency of poor quality images decreased, but the relative contributions of the various causes remained similar. Image quality improvements following appropriate corrective actions were up to 50 percentage points in some facilities. CONCLUSIONS: Poor image quality is a major source of unnecessary radiation dose to the breast. An increased awareness of good quality mammograms is of particular importance for countries that are moving towards introduction of population-based screening programmes. The study demonstrated how simple and low-cost measures can be a valuable tool in improving of image quality in mammography. PMID- 21665397 TI - Comparison of 3T and 7T MRI clinical sequences for ankle imaging. AB - The purpose of this study was to compare 3T and 7T signal-to-noise and contrast to noise ratios of clinical sequences for imaging of the ankles with optimized sequences and dedicated coils. Ten healthy volunteers were examined consecutively on both systems with three clinical sequences: (1) 3D gradient-echo, T(1) weighted; (2) 2D fast spin-echo, PD-weighted; and (3) 2D spin-echo, T(1) weighted. SNR was calculated for six regions: cartilage; bone; muscle; synovial fluid; Achilles tendon; and Kager's fat-pad. CNR was obtained for cartilage/bone, cartilage/fluid, cartilage/muscle, and muscle/fat-pad, and compared by a one-way ANOVA test for repeated measures. Mean SNR significantly increased at 7T compared to 3T for 3D GRE, and 2D TSE was 60.9% and 86.7%, respectively. In contrast, an average SNR decrease of almost 25% was observed in the 2D SE sequence. A CNR increase was observed in 2D TSE images, and in most 3D GRE images. There was a substantial benefit from ultra high-field MR imaging of ankles with routine clinical sequences at 7T compared to 3T. Higher SNR and CNR at ultra-high field MR scanners may be useful in clinical practice for ankle imaging. However, carefully optimized protocols and dedicated extremity coils are necessary to obtain optimal results. PMID- 21665396 TI - Coronary computer tomographic angiography for preoperative risk stratification in patients undergoing liver transplantation. AB - The assessment of the cardiovascular risk profile in patients with end-stage liver disease is essential prior to liver transplantation (LT) as cardiovascular diseases are major causes of morbidity and mortality in the posttransplant course. The aim of this study was to evaluate the accuracy of a 64-slice coronary computed tomographic angiography (CTA) and coronary calcium scoring (CCS) to predict the postoperative cardiovascular risk of patients assessed for LT. In this single center, observational study we included 54 consecutive patients who were assessed for LT and consequently transplanted. Twenty-four patients (44%) presented with a high CCS above 300 and/or a significant stenosis (>50% percent narrowing due to stenotic plaques) and were further referred to coronary angiography. Three of these patients had a more than 70% LAD stenosis with subsequent angioplasty (n=1) or conservative therapy (n=2). The other patients showed only diffuse CAD without significant stenosis. The remaining 30 patients with normal CTA findings were listed for LT without further tests. None of the 54 patients developed cardiovascular events peri- and postoperatively. This study indicated that CTA combined with CCS is a useful non-invasive imaging technique for pre-LT assessment of coronary artery disease and safe tool in the risk assessment of peri- and postoperative cardiovascular events in patients undergoing LT. PMID- 21665398 TI - Diversity and abundance of ammonia-oxidizing archaea and bacteria in polluted mangrove sediment. AB - Ammonia oxidation by microorganisms is a critical process in the nitrogen cycle. Recent research results show that ammonia-oxidizing archaea (AOA) are both abundant and diverse in a range of ecosystems. In this study, we examined the abundance and diversity of AOA and ammonia-oxidizing beta-proteobacteria (AOB) in estuarine sediments in Hong Kong for two seasons using the ammonia monooxygenase A subunit gene (amoA) as molecular biomarker. Relationships between diversity and abundance of AOA and AOB and physicochemical parameters were also explored. AOB were more diverse but less abundant than AOA. A few phylogenetically distinct amoA gene clusters were evident for both AOA and AOB from the mangrove sediment. Pearson moment correlation analysis and canonical correspondence analysis (CCA) were used to explore physicochemical parameters potentially important to AOA and AOB. Metal concentrations were proposed to contribute potentially to the distributions of AOA while total phosphorus (TP) was correlated to the distributions of AOB. Quantitative PCR estimates indicated that AOA were more abundant than AOB in all samples, but the ratio of AOA/AOB (from 1.8 to 6.3) was smaller than most other studies by one to two orders. The abundance of AOA or AOB was correlated with pH and temperature while the AOA/AOB ratio was with the concentrations of ammonium. Several physicochemical factors, rather than any single one, affect the distribution patterns suggesting that a combination of factors is involved in shaping the dynamics of AOA and AOB in the mangrove ecosystem. PMID- 21665399 TI - Identification and control of impurities in streptomycin sulfate by high performance liquid chromatography coupled with mass detection and corona charged aerosol detection. AB - For the control of impurities in streptomycin sulfate a reversed phase ion-pair high performance liquid chromatography (HPLC) method using charged aerosol detection (CAD) was developed. With this method, 21 impurities could be separated and tentatively identified using a combination of exact mass measurement by TOF MS and MS/MS experiments with a triple quadrupole MS. For three impurities the suggested structures could be confirmed by in situ formation. The CAD detector response was found to be linear over 2 orders of magnitude allowing a straightforward quantification of all impurities. A limit of quantification of 0.09% for streptomycin sulfate and of 0.008% for streptidine sulfate (referred to the concentration of the 5mg/ml test solution) could be achieved. The HPLC method was applied to the purity testing of 12 samples of commercially available streptomycin sulfate from different manufacturers. Impurity levels between 4.6% and 16.0% were found. The current European Pharmacopoeia monograph for streptomycin sulfate only limits streptomycin B by a TLC test to 3.0%. Therefore, the results of this study underline the importance of introducing a state-of-the art test for the control of impurities in the monograph. The new HPLC-CAD method is considered suitable for this purpose. PMID- 21665400 TI - Simultaneous qualitative and quantitative analysis of triterpenic acids, saponins and flavonoids in the leaves of two Ziziphus species by HPLC-PDA-MS/ELSD. AB - The leaves of Ziziphus jujuba and Z. jujuba var. spinosa have been utilized as crude drugs for their health benefits in China for thousands of years. To control their quality, a reliable method based on high-performance liquid chromatography coupled with photo diode array and electrospray ionization tandem mass spectrometry detection (HPLC-PDA-ESI-MS/MS) was developed for exploration of the chemical profiles of these jujube leaves. As the results, fourteen constituents including three flavonoids, two saponins and nine triterpenic acids were identified or tentatively characterized. Then, twelve of them such as quercetin-3 O-rutinoside, zizyphus saponins I and II, ceanothic acid, alphitolic acid, maslinic acid, 2alpha-hydroxyursolic acid, zizyberanalic acid, epiceanothic acid, ceanothenic acid, betulinic acid, and oleanolic acid were selected as the chemical markers and were determined using an HPLC coupled with evaporative light scattering detection (ELSD) method. The separation was carried out on a Waters Sunfire C18 column with 0.2 % acetic acid and acetonitrile as the mobile phase under gradient elution. The operating conditions of ELSD were set as 80 degrees C for drift tube temperature and 2.7 l/min for nitrogen flow rate. The developed method was fully validated in terms of linearity, sensitivity, precision, repeatability as well as recovery, and subsequently applied to evaluate the quality of eight batches of Z. jujuba and Z. jujuba var. spinosa leaves from different collections. PMID- 21665402 TI - Binding studies of phloridzin with human serum albumin and its effect on the conformation of protein. AB - In this study, the binding mode of phloridzin with human serum albumin (HSA) was established under physiological condition. The binding study is important to understand the pharmacokinetics and toxicity of phloridzin. The results proved the mechanism of fluorescence quenching of HSA by phloridzin was due to the formation of HSA-phloridzin complex. The binding constants, the number of binding sites and thermodynamic parameters were calculated. In addition, the alterations of HSA secondary structure in the presence of phloridzin were confirmed by the evidences from Fourier transform infrared (FT-IR), UV-visible absorption, circular dichroism (CD), synchronous and three-dimensional fluorescence spectroscopy. Alterations of protein conformation were observed with reduction of alpha-helix from 54% (free HSA) to 50% in the HSA-phloridzin complexes, indicating a partial protein unfolding. The distance between phloridzin and HSA was 3.74 nm according to fluorescence resonance energy transfer theory. In addition, the effects of common ions on the constants of HSA-phloridzin complex were also discussed. PMID- 21665401 TI - A fast ultra high pressure liquid chromatographic method for qualification and quantification of pharmaceutical combination preparations containing paracetamol, acetyl salicylic acid and/or antihistaminics. AB - A fully validated UHPLC method for the identification and quantification of pharmaceutical preparations, containing paracetamol and/or acetyl salicylic acid, combined with anti-histaminics (phenylephrine, pheniramine maleate, diphenhydramine, promethazine) and/or other additives as quinine sulphate, caffeine or codeine phosphate, was developed. The proposed method uses a Waters Acquity BEH C18 column (2 mm * 100 mm, 1.7 MUm) with a gradient using an ammonium acetate buffer pH 4.0 as aqueous phase and methanol as organic modifier. The obtained method was fully validated based on its measurement uncertainty (accuracy profile) and robustness tests. Calibration lines for all components were linear within the studied ranges. The relative bias and the relative standard deviations for all components were respectively smaller than 1.5% and 2%, the beta-expectation tolerance limits did not exceed the acceptance limits of 10% and the relative expanded uncertainties were smaller than 5% for all of the considered components. A UHPLC method was obtained for the identification and quantification of these kind of pharmaceutical preparations, which will significantly reduce analysis times and workload for the laboratories charged with the quality control of these preparations. PMID- 21665403 TI - A systematic approach to development of liquid chromatographic impurity methods for pharmaceutical analysis. AB - A strategy for developing chromatographic methods designed to determine impurities and degradation products in active pharmaceutical ingredients and drug products is presented. Selectivity is achieved by evaluating a chromatographic space comprised of 12 stationary/mobile phase combinations. Stationary phases predicted to be orthogonal based on their hydrophobic subtraction model parameters used. The particle sizes, column dimensions, and gradient times chosen provide high peak capacities and allow operation at backpressures that can be achieved with standard instrumentation. The mobile phases utilized are compatible with MS detection and cover a wide range of pH, solvent strength, and solvent selectivity. Analyte detection is accomplished using a combination of diode array and mass spectroscopic detectors which allow mixtures of project compounds to be injected and selectively detected. Automation of data acquisition and processing is accomplished using AutoChrom software from ACD?Labs. The strategy is illustrated with detailed data from two case studies and summary data from nineteen pharmaceutical projects. PMID- 21665404 TI - Compatibility study between ketoprofen and pharmaceutical excipients used in solid dosage forms. AB - Thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC) techniques were used for assessing the compatibility between ketoprofen (KT) and several excipients as: corn starch, microcrystalline cellulose (PH 101 and PH 102), colloidal silicon dioxide, lactose (monohydrate and anhydre), polyvinylpyrrolidone K30, magnesium stearate and talc, commonly used in the pharmaceutical form. In order to investigate the possible interactions between the components, the thermal curves of KT and each selected excipients were compared with those of their 1:1 (w/w) physical mixtures. For KT, the DSC curves have shown a sharp endothermic peak at 96.8 degrees C which corresponds to the melting process (literature value: 94-97 degrees C), respectively the TG curves demonstrated a simple stage of mass loss in the temperature range of 235-400 degrees C. FT-IR spectroscopy and X-ray powder diffraction (XRPD) were used as complementary techniques to adequately implement and assist in interpretation of the DSC results. On the basis of thermal results, a possible interaction was found between the KT with polyvinylpyrrolidone K30 and magnesium stearate, which could influence the stability of the KT in the binary mixtures. These possible incompatibilities were confirmed by FT-IR and X-ray analysis. PMID- 21665405 TI - Resolution of left ventricular thrombus with lepirudin after failed treatment with heparin. AB - A 49-year-old man was admitted with high-risk left ventricular thrombosis and systemic embolization. Prompt and complete resolution of the thrombus was achieved under intravenous lepirudin administration but not under full-dose heparin treatment. Medical physicians, including emergency medicine physicians, cardiologists, cardiac surgeons, and hematologists, should become more aware of these alternative anticoagulant treatments, especially in cases when other therapeutic options (such as thrombolysis or cardiac surgery) may be associated with high morbidity or mortality. PMID- 21665406 TI - On-site pharmacists in the ED improve medical errors. AB - OBJECTIVE: The objective of the study was to compare errors in the emergency department (ED) with pharmacists present (PPs) for resuscitations and traumas vs with pharmacists absent (PAs). Our hypothesis was that errors would be significantly fewer during PP than PA times. We also hypothesized that times with PP would affect patients greater when disposition was to more critical areas (intensive care unit, or ICUs). METHODS: The study was conducted during a 3-month period in 2009 in a level 1 trauma center with an emergency medicine residency. This was a cross-sectional cohort study comparing a prospective analysis of patients during the time (10 hour/day) with PP and a retrospective review of the time on the same days (14 hours/day) with PA. Demographics of age, race, and sex were recorded. Patient disposition was either ICU, operating room, non-ICU wards, observation unit, or discharge. Main outcome was errors recorded including medications given but not ordered, medication ordered but not given, and time delays for medications. For demographics and prevalence, descriptive statistics and percentages were used. Percent differences and 95% confidence intervals (CIs) and chi2 were derived. Logistic regression used predictor variables of age, race, sex, disposition, and presence or absence of pharmacists. An a priori power analysis was performed. The study was powered at 80% with 186 subjects per group (PP vs PA), to find a difference of 20% between the 2 groups in percent of medical errors. RESULTS: There were 694 patients included in the 3-month period. A total of 242 presented during PP times and 452 during PA times. There were 383 (55%) male, 301 (43%) female, and 10 (2%) unknown sex. Mean age was 45+/-18 years in PP group and 48+/-20 years in PA group (P, nonsignificant). There was no difference in ethnicity between groups. There were 6 (3%) patients with errors recorded during PP times and 137 (30%) with errors recorded during PA times (difference, 27%; 95% CI, 23-32). Controlling for age, race, sex, and disposition, medical errors were 13.5 times more likely during PA than during PP times (adjusted odds ratio, 13.5; 95% CI, 5.7-31.9). CONCLUSION: With pharmacists absent, over 13 times more errors are recorded in our ED than with pharmacists present. An on-site pharmacist in the ED may be helpful in reducing medical errors. PMID- 21665407 TI - Trepopnea may explain right-sided pleural effusion in patients with decompensated heart failure. AB - BACKGROUND: Physicians often overlook trepopnea as a symptom, and its prevalence and clinical repercussions are not usually described. We propose that trepopnea is a common symptom in heart failure (HF) and, because of patient avoidance of left lateral decubitus position, contributes to the greater prevalence of right sided pleural effusion in patients with HF. Accordingly, this study aimed to determine trepopnea prevalence and to evaluate the association of trepopnea and the laterality of pleural effusion in decompensated HF. METHODS: Consecutive patients (n = 37) with decompensated HF and evidence of pleural effusion by chest x-ray were included. Data were collected at the emergency department by a standard clinical examination in which patients were specifically asked about the presence of trepopnea and preferred decubitus position while recumbent. Chest x ray and echocardiographic parameters were recorded. RESULTS: Of the 37 patients, 19 (51%) reported trepopnea. Most patients presented with right-sided pleural effusion; only 2 patients (5.4%) presented with left-sided pleural effusion. Patients who reported trepopnea had predominant right-sided pleural effusion more frequently than patients without this symptom (73.7% vs 26.3%; P = .049). The participants that reported trepopnea or avoidance of left lateral decubitus position while recumbent or both had a greater probability of having predominant right-sided pleural effusion (likelihood ratio, 1.85; 95% confidence interval, 1.02-3.35). CONCLUSIONS: Trepopnea is a common symptom in patients with decompensated HF and is associated with predominant right-sided pleural effusion in this population. Our results indicate that trepopnea may be a contributory factor for pleural effusion laterality in patients with decompensated HF. PMID- 21665408 TI - Inferior vena cava assessment in the bedside diagnosis of acute heart failure. AB - OBJECTIVES: The objective of this study was to determine the test characteristics of the caval index and caval-aortic ratio in predicting the diagnosis of acute heart failure in patients with undifferentiated dyspnea in the emergency department (ED). METHODS: This prospective observational study was performed at an urban ED that enrolled patients, 50 years or older, with acute dyspnea. A sonographic caval index was calculated as the percentage decrease in the inferior vena cava (IVC) diameter during respiration. A caval-aortic ratio was defined by the maximum IVC diameter divided by the aortic diameter. The sensitivity, specificity, and likelihood ratios of these measurements associated with heart failure were estimated. RESULTS: Eighty-nine patients were enrolled in the study with a mean age of 68 years. A caval index of less than 33% had 80% sensitivity (95% confidence interval [CI], 63%-91%) and 81% specificity (95% CI, 68%-90%) in diagnosing acute heart failure, whereas an index of less than 15% had a 37% sensitivity (95% CI, 22%-55%) and 96% specificity (95% CI, 86%-99%). The sensitivity of a caval-aortic ratio of more than 1.2 was 33% (95% CI, 18%-52%) and the specificity was 96% (95% CI, 86%-99%). Positive likelihood ratios were 10 for a caval index of less than 15%, 4.3 for an index of less than 33%, and 8.3 for a caval-aortic ratio of more than 1.2. CONCLUSION: Bedside assessments of the caval index or caval-aortic ratio may be useful clinical adjuncts in establishing the diagnosis of acute heart failure in patients with undifferentiated dyspnea. PMID- 21665409 TI - Estimation of glomerular filtration rate and assessment of risk of stroke in an emergency setting. PMID- 21665410 TI - Extracorporeal membrane oxygenation for refractory, life-threatening, and herpes simplex virus 1-induced acute respiratory distress syndrome. Our experience and literature review. AB - We report our first experience of treating an immunocompetent adult patient with acute respiratory distress syndrome (ARDS) due to type 1 herpes simplex (HSV1) pneumonitis, using extracorporeal membrane oxygenation (ECMO). Similar cases reported in literature are reviewed as well. The therapeutic options for this particular complication are discussed. Pneumonia caused by HSV1 is a rare finding in immunocompetent individuals; it occurs more often in immunosuppressed and ventilated patients. It is a severe illness; therefore, early diagnosis and initiation of treatment are imperative. Diagnosis is based on cytologic and histologic findings, viral cultures, or serologic methods. This condition can be reversible; however, often, it can progress into refractory ARDS with limited therapeutic options available. We demonstrate the causative role of HSV1 in refractory ARDS of a previously healthy 18-year-old man who presented to the intensive care unit with acute respiratory distress after a week of flulike syndrome. Due to severe hypoxemia and hypercarbia, the patient required mechanical ventilation and later emergent blood oxygenation with extracorporeal support. For the first time in this condition, we used venovenous ECMO management, to rest the lung, sustain blood oxygenation and end-organ oxygen delivery, and promote potential lung recovery. During ECMO and after our etiologic diagnosis, specific therapy was introduced. After viral negativization, corticosteroid therapy (Meduri protocol) was initiated. Extracorporeal membrane oxygenation allowed us to initiate therapy while maintaining end-organ oxygenation and support the patient until lung recovery. After 18 days of ECMO, our patient recovered completely. Near-normal lung structures and functions were documented on a chest x-ray/computed tomography, thoracic ultrasonography, and pulmonary functional tests at hospital discharge and at a 1-year follow-up. Data suggest that severe pulmonary involvement in HVS1 infection associated with septicemia/shock is a rare but often fatal in immunocompetent adult as well. We suggest that ECMO might be the selected treatment for severe refractory ARDS in this clinical scenario. It seems to be an effective and useful ultimate therapeutic strategy for preventing death and furthermore permitting near-full pulmonary function recovery. PMID- 21665411 TI - The double lung point. PMID- 21665412 TI - Gang members in the ED: what you believe may not be true. PMID- 21665413 TI - The "Code Drugs in Cardiac Arrest"--the use of cardioactive medications in cardiac arrest resuscitation. AB - In October of 2010, the American Heart Association (AHA) published the 2010 Guidelines on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. These guidelines place significant emphasis on 5 major areas of therapy in patient with cardiac arrest, including immediate recognition and activation of the emergency response team, effective chest compressions, rapid defibrillation, effective advanced life support (ALS), and integrated postresuscitation care. "Effective ALS" includes the placement of an advanced airway, establishment of parenteral access, and the administration of cardioactive medications. Advanced life support encompasses only 1 of these 5 major areas of cardiac arrest intervention-in sharp contrast to past renditions of the AHA guidelines in which ALS was significantly emphasized. In fact, recent research and the AHA guidelines note that ALS therapy is less important than previously thought. This article will briefly review the evidence regarding the use of the 5 principal medications -epinephrine, vasopressin, atropine, lidocaine, and amiodarone--used in Advanced Cardiac Life Support cardiac arrest algorithm. PMID- 21665414 TI - Rate control medications for atrial fibrillation in the setting of hypercalcemia. PMID- 21665415 TI - Therapeutic hypothermia induction via an esophageal route--a computer simulation. AB - OBJECTIVES: Mild therapeutic hypothermia has been shown to improve outcomes after adult cardiac arrest but remains underused. Development of easier methods than currently exist to induce therapeutic hypothermia may help increase use of this treatment. We developed a mathematical model to evaluate the potential to induce mild therapeutic hypothermia through the esophagus. METHODS: Using a finite element mathematical modeling software package incorporating Pennes Bioheat equation, we predicted the changes in body temperature that would occur with placement of an esophageal cooling device containing recirculating chilled water at 10 degrees C. RESULTS: Patient temperature under the simulated conditions decreased from 37 degrees C to 33 degrees C in approximately 40 minutes. Distribution of body temperature was not uniform in our model, with the skin surface and extremities showing a greater temperature decrease than in the patient's core. CONCLUSIONS: Our computer simulations suggest that inducing mild therapeutic hypothermia via an esophageal route is feasible. PMID- 21665416 TI - Volar subluxation of the metacarpal-phalangeal joint: a case report. AB - Dislocations and subluxations at the metacarpal-phalangeal joint are rare and volar or palmar subluxations represent a small fraction of these. A 54-year-old man presented with an injury to his right hand; he had heard a pop while putting down a weight. He had normal vital signs, and his examination revealed a deformity at the third metacarpal-phalangeal joint. Plain radiographs did not reveal a fracture. The diagnosis of volar subluxation was made after consultation with a hand surgeon. Attempts at closed reduction in the emergency department were unsuccessful, and he was splinted with plans for follow-up. There are several characteristics of this injury that present a diagnostic challenge: most patients are able to make a fist due to intact flexor mechanism, the deformity is subtle and may be masked by swelling, and lateral radiographs tend not to image the joint well. Recognition of this injury and hand surgery consultation are essential because most described cases required open reduction. PMID- 21665417 TI - Potassium status should be evaluated also when diabetic ketoacidosis is complicated by heart failure. PMID- 21665418 TI - Noninvasive detection of elevated intracranial pressure using a portable ultrasound system. AB - OBJECTIVE: The aim of this study is to prospectively compare the accuracies of transcranial color-coded sonography (TCCS) and transcranial Doppler (TCD) in the diagnosis of elevated intracranial pressure. METHODS: A prospective, blinded, head-to-head comparison of TCD and TCCS methods using intracranial pressure (ICP) measured continuously via an intraparenchymal catheter as the reference standard in 2 groups of 20 neurocritical care patients each: high ICP (group 1) and normal ICP (group 2). Middle cerebral artery (MCA) pulsatility index (PI) recordings from all patients' sonographic reports were selected based on the highest left or right recorded MCA PI. Transcranial Doppler was performed using a dedicated TCD device, and TCCS was performed using a portable ultrasound system. RESULTS: The PI values obtained did not differ significantly between the 2 methods (group 1, P = .46; group 2, P = .11). Linear regression analysis identified a significant relationship between PI obtained with both methods (r = 0.897; P < .0001). The duration of PI measurement was statistically longer with TCCS than TCD (group 1, P < .01; group 2, P < .01). Diagnostic accuracies were good and similar for both methods (TCD area under curve, 0.901; TCCS area under curve 0.870; P = .69). CONCLUSIONS: This work is a pilot study comparing TCCS and TCD in the detection of elevated ICP. This study suggests that a bedside portable ultrasound system may be useful to determine MCA PI with accuracy similar to that of a dedicated TCD device. PMID- 21665419 TI - The resilience of the human body. PMID- 21665420 TI - Impact of decision aids in a sustained implementation at a breast care center. AB - OBJECTIVE: We examined the reach and impact of five decision aids (DAs) routinely distributed to breast cancer patients as part of a shared decision making demonstration project. METHODS: From 2005 to 2008, we surveyed patients' change in knowledge and decisional conflict (DC) before and after their review of DAs. Using bivariate tests, we identified significant predictors of change in knowledge or decisional conflict and entered significant predictors into a multivariate regression model. RESULTS: We distributed 1553 DAs to 1098 patients and received 549 completed surveys. The DAs were associated with increased knowledge and decreased DC. For knowledge, significant predictors of above average change included: lower baseline knowledge and viewing the surgery decision aid. For decisional conflict, significant predictors of above-average change included: higher decisional conflict; viewing any of the early-stage cancer DAs; and Hispanic ethnicity. CONCLUSIONS: DAs used in routine care were associated with significant knowledge gains and reductions in decisional conflict. Some subsets of patients (those reporting low baseline knowledge, high DC, or Hispanic ethnicity) may benefit more than others. PRACTICE IMPLICATIONS: Breast cancer patients benefit overall from routine distribution of DAs. Our exploratory findings may be useful in generating hypotheses to identify target populations who would most benefit from reviewing DAs. PMID- 21665421 TI - Phase III randomized equivalence trial of early breast cancer treatments with or without axillary clearance in post-menopausal patients results after 5 years of follow-up. AB - BACKGROUND: Axillary lymph node clearance (ALNC) improves locoregional control and provides prognostic information for early breast cancer treatment, but effects on survival are controversial. This multicentre, randomized pragmatic equivalence trial compares outcomes for post-menopausal early invasive breast cancer patients after locoregional treatment with ALNC and adjuvant therapies to outcomes after locoregional treatment without ALNC and adjuvant therapies. METHODS: From 1995-2005, women aged >= 50 years with early breast cancer (tumor <= 10 mm) and clinically-negative axillary nodes were randomized to receive treatment with ALNC (Ax) or without (no-Ax). Adjuvant therapies were prescribed according to hormonal receptor status and individual histological results. The primary endpoint was overall survival (OS); secondary endpoints were event-free survival (EFS) and functional outcomes. The trial was terminated due to lack of equivalence and low accrual after first interim analyses. TRIAL REGISTRATION: NCT00210236. RESULTS: Of 625 patients, 297 no-Ax and 310 Ax patients were maintained for final per-protocol analyses. OS and EFS at five years were not equivalent (Ax vs. no-Ax: 98% vs. 94% and 96% vs. 90% respectively). Recurrence was higher for no-Ax, particularly in the first five years after surgery. Axillary nodes were positive for 14% Ax patients but only 2% no-Ax patients experienced axillary node recurrence. Functional impairments were greater after ALNC. CONCLUSION: Our results fail to demonstrate equivalence of outcomes when ALNC is omitted from post-menopausal early breast cancer patient treatment. However the low locoregional recurrence rates warrant further examination over a longer duration, in particular to consider whether these would impact on survival. PMID- 21665422 TI - Longitudinal follow-up study using the distress and impact thermometer in an outpatient chemotherapy setting. AB - CONTEXT: Although the combined use of the Impact Thermometer (IT) with the Distress Thermometer (DT), DIT, is reported to be a validated screening tool for clinically significant psychological distress in cancer patients, its longitudinal changes in the outpatient chemotherapy setting have not been examined. OBJECTIVES: The objective was to clarify the longitudinal changes in distress evaluated by the DIT and effects of coexisting physical symptoms in an outpatient chemotherapy setting. METHODS: A total of 297 patients who underwent chemotherapy for any malignancy on an outpatient basis were included. All the participants completed a questionnaire that included the DIT and intensities of seven physical symptoms (pain, somnolence, fatigue, dyspnea, appetite loss, abdominal distention, and nausea) at the initial and follow-up visit. RESULTS: Although 109 patients had moderate or severe distress (the DT >=4 and IT >=3) at the initial visit, 46.8% of these patients improved their distress (DIT score below the cutoff of moderate distress) at their follow-up visit. Also, 85 patients had severe distress (DT >=5 and IT >=4) at the initial visit, and 43.5% of these patients improved their distress (DIT score below the cutoff of severe distress) at their follow-up visit. In a subgroup of patients who had no severe physical symptoms at the initial visit, 69.0% and 68.4% of the patients with moderate or severe distress and severe distress at the initial visit, respectively, improved their distress (DIT scores below the cutoff of moderate and severe distress) at the follow-up visit. CONCLUSION: The distress evaluated by DIT can change on sequential measurements within short time intervals. Further study is needed to determine the appropriate use of the DIT for the screening and monitoring of psychological distress in an outpatient chemotherapy setting. PMID- 21665423 TI - A retrospective review of Palmaz stenting of the aortic neck for endovascular aneurysm repair. AB - BACKGROUND: To review the aortic neck characteristics, graft types, and technical results of Palmaz stent placement as an adjunct to endovascular aneurysm repair (EVAR). METHODS: A retrospective review of 110 consecutive EVAR cases identified 18 cases in which Palmaz stents were placed as an adjunct to EVAR. Graft types, hostile aortic neck features (neck diameter: >26 mm, length: <15 mm, angulation: >60 degrees , reverse taper necks), and treatment success were identified. RESULTS: Technical success in the placement of a proximal Palmaz stent was achieved in 17 of 18 cases. Palmaz stenting was attempted for the treatment of type I endoleak in 17 of 18 patients. One prophylactic stent was deployed in the setting of hostile neck anatomy. Proximal stent deployment resulted in immediate treatment success of type I endoleaks in 16 of 17 patients-one failure occurred in a patient who presented with a delayed type I endoleak. Analysis of aortic neck anatomy revealed that two of 18 patients had no criteria for a hostile neck, seven had one criterion, and nine met at least two criteria. With respect to stent-graft types, nine of 18 (50%) cases used the Endologix Powerlink, six used Gore Excluder, two used Cook Zenith, and one used Medtronic Talent. With a mean follow-up of 254 days, 16 of 17 type I endoleaks remain resolved. CONCLUSIONS: With proper patient selection and additional adjunctive treatments, Palmaz stenting can effectively treat proximal type I endoleaks. PMID- 21665424 TI - Management and urgent repair of ruptured visceral artery aneurysms. AB - Five patients were treated for ruptured visceral artery aneurysms during the last 9 years, including two splenic and three pancreaticoduodenal aneurysms. The average size of aneurysm was 2.6 cm (range: 1.5-5 cm). All patients underwent open surgical treatment. There was one operative death. After a mean follow-up of 46.6 months, there were no cases of mortality or secondary complications. The authors conclude that operative treatment of ruptured visceral artery aneurysms is durable. PMID- 21665425 TI - Intermediate and long-term outcomes after treating symptomatic persistent sciatic artery using different techniques. AB - Persistent sciatic artery (PSA) is a rare congenital vascular malformation. In this article, we have described the case of a 66-year-old woman presenting with a pulsatile mass in the left buttock and bilateral lower limb ischemia, who underwent surgical therapy. Preoperative computed tomography scanning showed a left thrombosed PSA aneurysm (PSAA) with concomitant occlusion of bilateral iliac, bilateral common femoral, and left popliteal arteries. After recanalization of the left common femoral artery occlusion with a systemic heparin treatment, the patient underwent bypass surgery (left femoropopliteal bypass, right iliofemoral bypass) and PSAA exclusion. Postoperative computed tomography scanning 20 months after surgery revealed that the excluded PSAA was thrombosed with no refilling collateral flow, and that the bypass grafts were patent in both legs. In addition to this case report, a literature review of PubMed articles published between 1965 and 2009 that included the treatment and intermediate/long-term management of symptomatic PSAs was conducted. We found 45 articles (67 limbs), of which 24 (29 limbs) described the intermediate/long-term outcomes in patients treated for symptomatic PSA. Regardless of the method of arterial reconstruction or PSAA repair, intermediate/long-term outcomes of different treatments for lower limb ischemia and PSAAs were satisfactory, and the patients were asymptomatic during the follow-up period which ranged from 2 months to 10 years. PMID- 21665426 TI - Targeted duplex ultrasound in a one-stop dialysis vascular access assessment clinic. AB - BACKGROUND: Many duplex detectable factors have been shown to correlate with upper limb arteriovenous fistula (AVF) outcomes, and many practitioners now request preoperative duplex vessel mapping routinely before AVF surgery. We report outcomes from a "one stop" AVF assessment clinic in which the operating surgeons perform their own targeted preoperative ultrasound examinations. METHODS: All patients undergoing assessment for formation of a new AVF were included in this prospective observational study. A plan was made for surgery based on the results of the physical examination performed by the surgeon and then reviewed in light of the findings from a targeted duplex ultrasound (DUS) that was performed by the surgeon in the clinic on portable ultrasound equipment. Ultimate choice of surgical site and the influence of the DUS were recorded along with postoperative outcomes. RESULTS: In all, 39 patients were included. Four (10%) of the patients received a more distal AVF and eight (20%) were converted to more proximal AVF because of unexpected adverse findings after targeted DUS. In one patient, no site could be confidently selected by physical examination alone. There was a 13% early failure rate with cumulative patency rates of 86% and 73% at 3 and 6 months, respectively. CONCLUSION: Targeted DUS identified findings that might adversely affect fistula function in one of four patients in this series, whereas one in 10 patients was able to have more distal fistulae formed because of improved confidence in the quality of distal vessels. Early failure and patency rates are comparable with those in units using formal routine ultrasound. These results would suggest that routine targeted DUS, performed quickly by surgeons in an outpatient clinic, can alter surgical planning in one of the three patients and is therefore advocated as a quick, relatively inexpensive and important adjunct to AVF planning. PMID- 21665427 TI - Popliteal entrapment syndrome caused by fibular osteochondroma. AB - Osteochondromas are the most common tumors of bone. In adolescence, they usually present as a painless growing mass. Femoropopliteal vascular complications associated with an osteochondroma are rare, with most cases involving pseudoaneurysms. This report describes an exceptional case of a popliteal entrapment syndrome caused by a proximal fibular osteochondroma. PMID- 21665428 TI - On the road to invariant recognition: explaining tradeoff and morph properties of cells in inferotemporal cortex using multiple-scale task-sensitive attentive learning. AB - Visual object recognition is an essential accomplishment of advanced brains. Object recognition needs to be tolerant, or invariant, with respect to changes in object position, size, and view. In monkeys and humans, a key area for recognition is the anterior inferotemporal cortex (ITa). Recent neurophysiological data show that ITa cells with high object selectivity often have low position tolerance. We propose a neural model whose cells learn to simulate this tradeoff, as well as ITa responses to image morphs, while explaining how invariant recognition properties may arise in stages due to processes across multiple cortical areas. These processes include the cortical magnification factor, multiple receptive field sizes, and top-down attentive matching and learning properties that may be tuned by task requirements to attend to either concrete or abstract visual features with different levels of vigilance. The model predicts that data from the tradeoff and image morph tasks emerge from different levels of vigilance in the animals performing them. This result illustrates how different vigilance requirements of a task may change the course of category learning, notably the critical features that are attended and incorporated into learned category prototypes. The model outlines a path for developing an animal model of how defective vigilance control can lead to symptoms of various mental disorders, such as autism and amnesia. PMID- 21665429 TI - An information-theoretic analysis of return maximization in reinforcement learning. AB - We present a general analysis of return maximization in reinforcement learning. This analysis does not require assumptions of Markovianity, stationarity, and ergodicity for the stochastic sequential decision processes of reinforcement learning. Instead, our analysis assumes the asymptotic equipartition property fundamental to information theory, providing a substantially different view from that in the literature. As our main results, we show that return maximization is achieved by the overlap of typical and best sequence sets, and we present a class of stochastic sequential decision processes with the necessary condition for return maximization. We also describe several examples of best sequences in terms of return maximization in the class of stochastic sequential decision processes, which satisfy the necessary condition. PMID- 21665430 TI - Deterioration of myocardial function in paradoxical low-flow severe aortic stenosis: two-dimensional strain analysis. AB - BACKGROUND: The diagnosis and management of paradoxical low-flow (PLF) aortic stenosis (AS) is challenging in clinical practice. In addition, its pathophysiology has not been fully understood. The aim of this study was to test the hypothesis that left ventricular (LV) myocardial function is deteriorated in PLF AS and that it is closely related to global LV afterload. METHODS: Echocardiographic data from 103 patients with severe AS (aortic valve area < 1.0 cm(2)) with normal LV ejection fractions were prospectively collected. Global longitudinal and circumferential myocardial strain was analyzed using two dimensional speckle-tracking imaging. PLF AS was defined as a stroke volume index < 35 mL/m(2). RESULTS: Sixteen patients were classified as having PLF AS. Compared with those with normal-flow AS, patients with PLF AS were more likely to have worse functional status (mean New York Heart Association functional class, 2.38 +/- 0.70 vs 1.96 +/- 0.62; P = .02), worse global longitudinal strain (GLS) (-12.6 +/- 4.4% vs -16.4 +/- 4.0%, P < .01), lower aortic valve area (0.53 +/- 0.15 vs 0.78 +/- 0.19 cm(2), P < .01), and higher valvuloarterial impedance (5.62 +/- 1.33 vs 3.65 +/- 0.83 mm Hg . m(2)/mL, P < .01). GLS showed a significant negative linear relationship with stroke volume index (r = -0.324, P = .001) and a positive relationship with E/E' ratio (r = 0.367, P < .001). Multivariate analysis showed that age (beta = 0.08, P = .07) and valvuloarterial impedance (beta = 1.54, P < .01) were significant predictors of GLS. CONCLUSIONS: GLS is depressed in patients with PLF AS. This implies that subclinical myocardial dysfunction may be more prominent in PLF AS compared with normal-flow AS and suggests the possible diagnostic and prognostic value of two-dimensional global strain in identifying PLF AS. In addition, global LV afterload is an important determinant of myocardial dysfunction in patients with severe AS. PMID- 21665431 TI - Early detection of left atrial strain abnormalities by speckle-tracking in hypertensive and diabetic patients with normal left atrial size. AB - BACKGROUND: Systemic hypertension and type 2 diabetes mellitus are associated with impaired left atrial (LA) function, but whether LA functional abnormalities also occur in patients with hypertension and diabetes who have normal LA sizes is unknown. The aim of this study was to explore LA strain using speckle-tracking echocardiography in patients with hypertension or diabetes and normal LA size. METHODS: LA strain was studied by speckle-tracking echocardiography in 155 patients with hypertension or diabetes with LA volume indexes < 28 mL/m(2) (83 with hypertension, 34 with diabetes, and 38 with both diabetes and hypertension) and 36 age-matched controls. The following indexes were measured: peak atrial longitudinal strain, time to peak atrial longitudinal strain, atrial longitudinal strain during early diastole and late diastole, and peak LA strain rate during ventricular systole, early diastole, and late diastole. RESULTS: Peak atrial longitudinal strain was lower in patients with hypertension (29.0 +/- 6.5%) and those with diabetes (24.7 +/- 6.4%) than in controls (39.6 +/- 7.8%) and further reduced in patients with diabetes and hypertension (18.3 +/- 5.0%) (P < .0001). Similar results were found for atrial longitudinal strain during early diastole, atrial longitudinal strain during late diastole, and peak LA strain rate during ventricular systole and early diastole (P < .0001 for all). An inverse trend was found for time to peak atrial longitudinal strain, whereas no differences in peak LA strain rate during late diastole were observed. Two-way analysis of variance showed no interactions between hypertension and diabetes. In multivariate analyses, hypertension and diabetes were both independently associated with decreases in all LA strain and strain rate indexes, with the exception of peak LA strain rate during late diastole. CONCLUSIONS: LA deformation mechanics are impaired in patients with hypertension or diabetes with normal LA size. The coexistence of both conditions further impairs LA performance in an additive fashion. Speckle-tracking echocardiography may be considered a promising tool for the early detection of LA strain abnormalities in these patients. PMID- 21665432 TI - Feasibility of intraoperative three-dimensional transesophageal echocardiography in the evaluation of right ventricular volumes and function in patients undergoing cardiac surgery. AB - BACKGROUND: The aim of this study was to test the feasibility of the assessment of right ventricular (RV) volumes and function using real-time three-dimensional (3D) transesophageal echocardiographic (TEE) imaging in patients undergoing cardiac surgery. METHODS: One hundred-fifty surgical patients were enrolled: 65 undergoing mitral valve repair, 10 undergoing mitral valve and tricuspid valve repair, four with congenital heart disease, two undergoing Jarvik implantation, 13 undergoing aortic valve surgical replacement, and 56 undergoing transcatheter aortic valve implantation. Real-time 3D TEE acquisition for RV evaluation was performed before and after the surgical procedure and compared with standard two dimensional multiplane TEE measurements. In a subgroup of 81 patients, 3D transthoracic echocardiographic imaging was also performed. RV volumetric quantification was performed for all data using dedicated software. RESULTS: Three-dimensional RV analysis was feasible in 98.7% in the preoperative TEE data set and in 92.7% in the postoperative TEE data set. Agreement between 3D transthoracic and transesophageal echocardiography for end-diastolic volume (r = 0.98; 95% confidence interval [CI], -0.2 +/- 13.6 mL), end-systolic volume (r = 0.97; 95% CI, -2.1 +/- 10.2 mL), ejection fraction (r = 0.77; 95% CI, 1.8 +/- 8.2%), and stroke volume (r = 0.91; 95% CI, 2.0 +/- 12.9 mL) was significant. RV parameters were highly reproducible in patients with both normal and dilated RV volumes. CONCLUSIONS: Intraoperative 3D TEE assessment of RV volumes and function is feasible in patients with normal and dilated right ventricles, with good correlation between 3D transthoracic echocardiographic and TEE RV parameters. These measurements could improve the quantitative evaluation of RV function during cardiac surgery. PMID- 21665434 TI - Screening should be a program, not just a strategy. PMID- 21665437 TI - Study of mandible bone mineral density of Chinese adults by dual-energy X-ray absorptiometry. AB - The objective of this study was to measure the bone mineral density (BMD) of mandible and study the correlation between the BMD of the mandible and the lumbar vertebrae. 224 healthy volunteers were recruited in China and divided into 6 age groups: 20-29, 30-39, 40-49, 50-59, 60-69, and over 70 years. Dual-energy X-ray absorptiometry (DXA) was used to measure the BMD of the lumbar vertebrae and the mandible of each volunteer. The BMD of mandibular chin, mandibular angle and the lumbar vertebrae (L1-L4) was 1.3013+/-0.2576 g/cm(2), 1.0484+/-0.1087 g/cm(2) and 1.1195+/-0.1373 g/cm(2), respectively. The BMD of mandibular angle and lumbar vertebrae decreased significantly beyond the age of 50 years. There was a significant difference between males and females in the BMD of the mandibular angle and lumbar vertebrae in the 50-59, 60-69 and over 70 year age groups. The authors found that the BMD of mandibular angles correlates with that of lumbar vertebrae. This study suggests that measurement of mandible BMD could be used to predict osteoporosis. PMID- 21665436 TI - TLR7/9-mediated monocytosis and maturation of Gr-1(hi) inflammatory monocytes towards Gr-1(lo) resting monocytes implicated in murine lupus. AB - Circulating monocytes are divided into two major, phenotypically and functionally distinct subsets: Gr-1(hi) "inflammatory" and Gr-1(lo) "resting" monocytes. One of the unique cellular abnormalities in lupus-prone mice is monocytosis, which is characterized by a selective expansion of Gr-1(lo) monocytes and dependent on the expression of stimulatory IgG Fc receptors (FcgammaR). We speculated that IgG immune complexes containing nuclear antigens could stimulate Gr-1(hi) monocytes through interaction with FcgammaRs and then TLR7 and TLR9, thereby promoting the maturation towards Gr-1(lo) monocytes. In the present study, we assessed this hypothesis by analyzing effects of TLR9 or TLR7 agonist on monocytes in vivo. The analysis of various surface markers differentially expressed on both subsets of monocytes in combination with selective depletion of either subset revealed that within 48 h after injection of the TLR9 agonist CpG, approximately one third of Gr-1(hi) monocytes became phenotypically identical to Gr-1(lo) monocytes. In addition, we observed approximately two-fold increases in the total monocyte population 8-24 h after injection of CpG. Moreover, the activation of TLR9 resulted in an increased expression of stimulatory FcgammaRIV relative to inhibitory FcgammaRIIB on monocytes, thereby enhancing their responsiveness to IgG immune complexes. Essentially identical results were obtained after stimulation of TLR7 with a synthetic agonist (1V136). Our results indicate that the activation of TLR7 and TLR9 not only induced the maturation of a fraction of Gr-1(hi) monocytes towards Gr-1(lo) monocytes but also promoted the overall generation of monocytes, thereby supporting the critical role of TLR7 and TLR9 for the development of monocytosis in lupus-prone mice. PMID- 21665435 TI - To B or not to B: role of B cells in pathogenesis of arthritis in HLA transgenic mice. AB - Population studies have shown that amongst all the genetic factors linked with autoimmune disease development, MHC class II genes are the most significant. Experimental autoimmune arthritis resembling human rheumatoid arthritis (RA) can be induced in susceptible strains of mice following immunization with type II collagen (CIA). We generated transgenic mice lacking endogenous class II molecules and expressing various HLA genes including RA-associated, HLA-DRB1*0401 and HLA-DQ8, and RA-resistant, DRB1*0402, genes. The HLA molecules in these mice are expressed on the cell surface and can positively select CD4+ T cells expressing various Vbeta T cell receptors. Endogenous class II invariant chain is required for proper functioning of the class II transgene. Arthritis development in transgenic mice is CD4+ and B cells dependent. Studies in humanized mice showed that B cells are required as antigen presenting cells in addition to antibody producing cells for the development of CIA. The transgenic mice expressing *0401 and *0401/DQ8 genes developed sex-biased arthritis with predominantly females being affected, similar to that of human RA. Further, the transgenic mice produced autoantibodies like rheumatoid factor and anti-cyclic antibodies. Antigen presentation by B cells leads to a sex-specific immune response in DRB1*0401 mice suggesting a role of B cells and HLA-DR in rendering susceptibility to develop arthritis in females. PMID- 21665438 TI - Coexistence of idiopathic generalized epilepsy among surgically treated patients with drug-resistant temporal lobe epilepsy. AB - INTRODUCTION: Failure to identify the association antiepileptic drug (AED) resistant temporal lobe epilepsy (TLE) with idiopathic generalized epilepsy (IGE) can interfere with decision for anterior temporal lobectomy (ATL) and prediction of post-ATL seizure outcome. METHODS: Out of the 664 consecutive patients who underwent ATL between March 1995 and December 2007, 12 (1.8%) had coexisting IGE. The decision for ATL was made after a thorough discussion in the multidisciplinary patient management conference based upon the concordance between the clinical, electroencephalographic and magnetic resonance imaging data. All of them underwent epilepsy surgery for AED-resistant TLE. RESULTS: In seven of the 12 patients, IGE was not identified until post-ATL. During a median follow-up period of 8.5 years, 8 of our 12 patients were seizure-free; the remaining 4 patients only had infrequent myoclonus. In two them, AEDs were discontinued; others were on montherapy for IGE. CONCLUSIONS: Our study highlights the rare association of IGE with TLE, the most common AED-resistant focal epilepsy syndrome. As the seizure outcome following ATL is similar in AED resistant TLE patients with and without IGE, their co-existence is not a contraindication for ATL. Future studies should explore the molecular genetic basis of the rare association between these two epilepsy syndromes. PMID- 21665439 TI - cAMP-dependent protein kinase A activity modulates topiramate potentiation of GABA(A) receptors. AB - Activation of cAMP-dependent protein kinase A (PKA) prevents inhibition of non NMDA glutamate receptors by the anticonvulsant topiramate. Using two-electrode voltage-clamp techniques, we demonstrate that PKA activity also modulates topiramate potentiation of recombinant GABA(A) receptors expressed in Xenpus laevis oocytes. PKA activators, dibutyryl-cAMP and forskolin, attenuate topiramate potentiation, whereas the PKA inhibitor H-89 increases topiramate potentiation. Thus, endogenous PKA activity and receptor phosphorylation states may contribute to topiramate treatment efficacy. PMID- 21665440 TI - The place of observational studies in assessing the effectiveness of depot antipsychotics. PMID- 21665441 TI - Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. AB - Major depressive disorder (MDD) is often accompanied by significant cognitive impairment, and there are limited interventions specific to this particular symptom. S-adenosylmethionine (SAMe), a naturally occurring molecule which serves as a major methyl-donor in human cellular metabolism, is required for the synthesis and maintenance of several neurotransmitters that have been implicated in the pathophysiology and treatment of cognitive dysfunction in MDD. OBJECTIVES: This study is a secondary analysis of a clinical trial involving the use of adjunctive SAMe for MDD. METHODS: Forty-six serotonin-reuptake inhibitor (SRI) non-responders with MDD enrolled in a 6-week, double-blind, randomized trial of adjunctive oral SAMe were administered the self-rated cognitive and physical symptoms questionnaire (CPFQ), a validated measure of cognitive as well as physical symptoms of MDD, before and after treatment. RESULTS: There was a greater improvement in the ability to recall information (P=0.04) and a trend towards statistical significance for greater improvement in word-finding (P=0.09) for patients who received adjunctive SAMe than placebo. None of the remaining five items reached statistical significance. CONCLUSIONS: These preliminary data suggest that SAMe can improve memory-related cognitive symptoms in depressed patients, and warrant replication. PMID- 21665442 TI - Nanocapsule of cationic liposomes obtained using "in situ" acrylic acid polymerization: stability, surface charge and biocompatibility. AB - In this work, didecyldimethylammonium bromide (DDAB) and 1,2-dioleoyl-sn-glycero 3-phosphatidylethanolamine (DOPE) (2.5:1) were used to prepare liposomes coated with polyacrylic acid (PAA) using "in situ" polymerization with 2.5, 5 and 25 mM of acrylic acid (AA). The PAA concentrations were chosen to achieve partially to fully covered capsules, and the polymerization reaction was observed with real time monitoring using dynamic light scattering (NanoDLS). The DDAB:DOPE liposomes showed stability in the tested temperature range (25-70 degrees C), whereas the results confirmed the success of the polymerization according to superficial charge (zeta potential of +66.7+/-1.2 mV) results and AFM images. For the liposomes that were fully coated with PAA (zeta potential of +0.3+/-3.9 mV), cytotoxicity was independent of the concentration of albumin. Cationic liposomes and nanocapsules of the stable liposomes coated with PAA were obtained by controlling the surface charge, which was the most important factor related to cytotoxicity. Thus, a potential, safe drug nanocarrier was successfully developed in this work. PMID- 21665443 TI - [Ophthalmologic manifestations of congenital rubella]. AB - Congenital rubella is a rare and serious disease including auditory neurological, cardiac, urinary, and ocular abnormalities. The eye complaints are often congenital cataract, congenital glaucoma, microphthalmia, and oculomotor disorders. We report the case of a 6-year-old girl presenting with a unilateral congenital cataract associated with congenital rubella. She was referred for complaints of high myopia in her right eye. She had a family history of cardiac and urogenital malformations, and presented deafness at birth. The ophthalmologic examination showed a microcornea and a unilateral dense congenital cataract in the right eye. B-scan ophthalmic ultrasound revealed a posterior microphthalmos. The anterior segment examination of the left eye was normal. Funduscopy revealed a salt-and-pepper appearance. Laboratory tests revealed a positive serology, confirming the congenital rubella. Given her complaints of loss of visual acuity in the right eye, the patient was operated on with a phacoaspiration implant in the capsular bag. The postoperative course was uneventful. The prevention of congenital rubella is based on routine vaccination of children. The association of cataract, congenital heart defects, and deafness must be systematically investigated as it may be more serious in association with systemic manifestations. PMID- 21665444 TI - [Urachal remnant infection: keep it in mind during atypical abdominal pain in children]. AB - Etiological diagnosis of abdominal pain is delicate due to its many possible causes. Those that are less frequent are consequently less known and can lead to a trickier diagnosis. We report on a rare case of a 2.5-year-old female patient presenting with abdominal pain in association with secondary dysuria due to an urachal remnant infection. Knowledge of the anatomical pathway of the urachal channel can discriminate its role during an atypical clinical case. The diagnosis is then based on ultrasound scans, which localize and characterize its contents. PMID- 21665445 TI - Prediction of intraoperative complexity from preoperative patient data for laparoscopic cholecystectomy. AB - OBJECTIVE: Different reasons may cause difficult intraoperative surgical situations. This study aims to predict intraoperative complexity by classifying and evaluating preoperative patient data. The basic prediction problem addressed in this paper involves the classification of preoperative data into two classes: easy (Class 0) and complex (Class 1) surgeries. METHODS AND MATERIAL: preoperative patient data were collected from 337 patients admitted to the Klinikum rechts der Isar hospital in Munich, Germany for laparoscopic cholecystectomy (LAPCHOL) in the period of 2005-2008. The data include the patient's body mass index (BMI), sex, inflammation, wall thickening, age and history of previous surgery, as well as the name and level of experience of the operating surgeon. The operating surgeon was asked to label the intraoperative complexity after the surgery: '0' if the surgery was easy and '1' if it was complex. For the classification task a set of classifiers was evaluated, including linear discriminant classifier (LDC), quadratic discriminant classifier (QDC), Parzen and support vector machine (SVM). Moreover, feature-selection was applied to derive the optimal preoperative patient parameters for predicting intraoperative complexity. RESULTS: Classification results indicate a preference for the LDC in terms of classification error, although the SVM classifier is preferred in terms of results concerning the area under the curve. The trained LDC or SVM classifier can therefore be used in preoperative settings to predict complexity from preoperative patient data with classification error rates below 17%. Moreover, feature-selection results identify bias in the process of labelling surgical complexity, although this bias is irrelevant for patients with inflammation, wall thickening, male sex and high BMI. These patients tend to be at high risk for complex LAPCHOL surgeries, regardless of labelling bias. CONCLUSIONS: Intraoperative complexity can be predicted before surgery according to preoperative data with accuracy up to 83% using an LDC or SVM classifier. The set of features that are relevant for predicting complexity includes inflammation, wall thickening, sex and BMI score. PMID- 21665446 TI - Palliative radiotherapy for bone metastases in the last 3 months of life: worthwhile or futile? AB - AIMS: To determine the efficacy of radiotherapy for the palliation of pain from bone metastases among patients in their last 3 months of life. MATERIALS AND METHODS: Mutually exclusive, prospectively gathered Edmonton Symptom Assessment System and Brief Pain Inventory databases compiled from patients with bone metastases receiving palliative radiotherapy were reviewed. Demographic information and response rates from patients dying within 3 months of beginning radiotherapy were analysed. RESULTS: From a total of 918 patients, 232 dying within 3 months of beginning treatment were identified. There were 148 men and 84 women. Their median age was 69 years and their median Karnofsky Performance Status was 60. The three most common primary cancers were lung (34%), prostate (18%) and gastrointestinal (14%). Fifty-eight percent of patients received single fraction treatment. A pain response was evaluable for the 109 (47%) patients with available follow-up information. The overall response rates were 70% at 1 month and 63% at 2 months, which included complete and partial responses in accordance with the International Bone Metastases Consensus definitions. CONCLUSIONS: Despite their limited lifespan, patients reported pain relief after palliative radiotherapy. Patients suffering from painful bone metastases with an estimated survival of 3 months should still be considered for palliative radiotherapy. PMID- 21665447 TI - Spontaneous amphophilic focus in the liver of a young Sprague-Dawley rat. AB - Altered hepatocellular focus was histopathologically observed in the liver of a 6 week-old Sprague-Dawley rat. The hepatocytes within this lesion had diffusely eosinophilic cytoplasm with scattered basophilia and slightly enlarged nuclei with prominent nucleoli. Based on these cytological characteristics, the lesion of these hepatocytes was classified as an amphophilic focus. This is the first report to describe spontaneous amphophilic focus in a young rat. PMID- 21665448 TI - Diversity of free-living nitrogen-fixing microorganisms in the rhizosphere and non-rhizosphere of pioneer plants growing on wastelands of copper mine tailings. AB - The composition of free-living nitrogen-fixing microbial communities in rhizosphere and non-rhizosphere of pioneer plants growing on wastelands of copper mine tailings was studied by the presence of nifH genes using Polymerase Chain Reaction-Denatured Gradient Gel Electrophoresis (PCR-DGGE) approach. Eleven rhizosphere tailing samples and nine non-rhizosphere tailing samples from six plant communities were collected from two wastelands with different discarded periods. The nested PCR method was used to amplify the nifH genes from environmental DNA extracted from tailing samples. Twenty-two of 37 nifH gene sequences retrieved from DGGE gels clustered in Proteobacteria (alpha Proteobacteria and beta-Proteobacteria) and 15 nifH gene sequences in Cyanobacteria. Most nifH gene fragments sequenced were closely related to uncultured bacteria and cyanobacteria and exhibited less than 90% nucleotide acid identity with bacteria in the database, suggesting that the nifH gene fragments detected in copper mine tailings may represent novel sequences of nitrogen fixers. Our results indicated that the non-rhizosphere tailings generally presented higher diversity of nitrogen-fixers than rhizosphere tailings and the diversity of free-living nitrogen-fixers in tailing samples was mainly affected by the physico-chemical properties of the wastelands and plant species, especially the changes of nutrient and heavy metal contents caused by the colonization of plant community. PMID- 21665450 TI - Chemical composition and antimicrobial activity of Cymbopogon citratus and Cymbopogon giganteus essential oils alone and in combination. AB - As part of ongoing research on the chemical composition and the antimicrobial properties of Burkinabe plants essential oils alone and in combination, essential oils (EOs) from leaves of Cymbopogon citratus and Cymbopogon giganteus from Burkina Faso were analyzed by GC-FID and GC-MS. Five constituents, which accounted for 96.3% of the oil, were identified in the EO of C. citratus. Geranial (48.1%), neral (34.6%) and myrcene (11.0%) were the major constituents. For C. giganteus a total of eight compounds were identified which represented 86.0% of the oils extracted. The dominant compounds were limonene (42%) and a set of monoterpene alcohols: trans-p-mentha-1(7),8-dien-2-ol (14.2%), cis-p-mentha 1(7),8-dien-2-ol (12%), trans-p-mentha-2,8-dien-1-ol (5.6%) and cis-p-mentha-2,8 dien-1-ol (5.2%). The EOs were tested against nine bacteria by using disc diffusion and microdilution methods. C. giganteus EO showed antimicrobial effects against all microorganisms tested whereas C. citratus EO failed to inhibit Pseudomonas aeruginosa. The antimicrobial activity of combinations of the two EOs was quantified by the checkerboard method. Combinations of the two EOs exerted synergistic, additive and indifferent antimicrobial effects. Results of the present investigation provide evidence that the combinations of plant EOs could be assessed for synergistic activity in order to reduce their minimum effective dose. PMID- 21665449 TI - Pre-clinical validation of a vaginal cream containing copaiba oil (reproductive toxicology study). AB - The aims of this study was to evaluate the effects of oil-resin of Copaiba (Copaifera duckei Dwyer), aired in vaginal cream on the reproductive performance of female rats (Rattus norvegicus). To determine the components of the C. duckei oleoresin, gas chromatography coupled with mass spectrometry (CG-MS) was used, and considering the trans-caryophyllene sesquiterpene as a phytochemical marker in the oleoresin. Due to the extensive use of copaiba oleoresin in the suppository form for gynecological infections, an evaluation was carried out on the effects of copaiba oleoresin (Copaifera duckei Dwyer), delivered in a vaginal cream, on the reproductive performance of female Wistar rats. For this purpose, three groups (n=5-6/group) of female rats were treated as follows: 1--vaginal cream of copaiba oleoresin (28.6 mg/kg), 2--base vaginal cream and 3--control (physiological saline 0.9%), administered intravaginally, for 30 days before pregnancy, and from day zero to day 20 during pregnancy. Laparotomy was performed on the 21st day of pregnancy, followed by the determination of reproductive variables: number of live and dead fetuses, mass of the fetuses and placentas, number of implantations and resorptions, number of corpora lutea, pre- and post implantation loss, and analyses of the fetuses with regard to external and internal anomalies and/or malformations (skeletal and visceral). The trans caryophyllene present in the sample is suggested as a phytochemical marker and the results of this study demonstrate an absence of maternal toxicity and foetotoxicity embryofoetotoxicity at the dose administered, corresponding to ten times the recommended dose for use in humans. Accordingly, no significant statistical difference was observed between the treated and control groups, for the variables analyzed. Thus, it is concluded that the vaginal cream containing 2.5% copaiba oleoresin is safe during gestation, in female rats (Rattus norvegicus) of the Wistar strain. PMID- 21665451 TI - Hypoglycemic activity of alkaloidal fraction of Tinospora cordifolia. AB - The stem of Tinospora cordifolia (TC) is widely used in the therapy of diabetes in traditional folk medicine of India. In the present study, isoquinoline alkaloid rich fraction (AFTC) derived from stem of TC and three alkaloids viz., palmatine, jatrorrhizine and magnoflorine were evaluated for insulin-mimicking and insulin-releasing effect in vitro and in vivo. Their effect on hepatic gluconeogenesis was examined in rat hepatocytes. Insulin releasing effect was detected in vitro using rat pancreatic beta-cell line, RINm5F. Furthermore, effects of AFTC and isolated alkaloids on serum glucose and insulin level were studied in fasted and glucose challenged normal rats. AFTC significantly decreased gluconeogenesis in rat hepatocytes as insulin did and it increases insulin secretion in RINm5F cells similar to tolbutamide. In acute 30 min test in vitro, AFTC, palmatine, jatrorrhizine and magnoflorine stimulated insulin secretion from the RINm5F cell line. As in vivo results, administration of AFTC (50, 100, and 200 mg/kg), palmatine, jatrorrhizine and magnoflorine (10, 20 and 40 mg/kg each) orally significantly decreased fasting serum glucose, and suppressed the increase of blood glucose levels after 2 g/kg glucose loading in normal rats. In vivo study further justified their insulin secreting potential by raising the serum insulin level in glucose fed rats. These results demonstrate the alkaloid present in TC contributed for antihyperglycemic activity. AFTC may have hypoglycemic effects via mechanisms of insulin releasing and insulin mimicking activity and thus improves postprandial hyperglycemia. PMID- 21665452 TI - Protective effect of tetramethylpyrazine isolated from Ligusticum chuanxiong on nephropathy in rats with streptozotocin-induced diabetes. AB - PURPOSE: This study was designed to investigate the protective effect of tetramethylpyrazine isolated from Ligusticum chuanxiong, a traditional Chinese medicine, on diabetic nephropathy in a rat model, and to explore the possible mechanism involved in a protective function. MATERIALS: Diabetes was induced in male Sprague-Dawley rats by a single intraperitoneal injection of 70mg/kg of streptozotocin. One week later, 200mg/kg/day of tetramethylpyrazine was administered intragastric gavage daily for 8 weeks. Renal functions and expression of vascular endothelial growth factor were examined at 4 and 8 weeks after tetramethylpyrazine administration. RESULTS: Blood glucose and renal function were significantly improved in the tetramethylpyrazine-treated group compared to the untreated diabetic rats. Diabetic nephropathy resulted in an increase in the expression of vascular endothelial growth factor, while tetramethylpyrazine administration greatly decreased the expression. CONCLUSIONS: Our results suggest that administration of tetramethylpyrazine may reduce kidney damage caused by diabetes. This protective effect may be mediated, in part, by downregulated expression of vascular endothelial growth factor in the kidney. PMID- 21665453 TI - Photodynamic activity of anthraquinones isolated from Heterophyllaea pustulata Hook f. (Rubiaceae) on MCF-7c3 breast cancer cells. AB - Searching for agents that could be effective in the treatment of cancer, special highlight has focused on the study of numerous plant-derived compounds. We previously demonstrated that anthraquinones (AQs) isolated from a vegetal species: Heterophyllaea pustulata Hook f. (Rubiaceae), such as rubiadin, rubiadin 1-methyl ether, soranjidiol, soranjidiol-1-methyl ether exhibit photosensitizing properties without antecedents as photodynamic agents in malignant cells. In the present study, we investigated the potential role of these AQs as a phototoxic agent against human breast carcinoma using MCF-7c3 cells. All AQs exhibited significant photocytotoxicity on cancer cells at the concentration of 100 MUM with 1 J/cm(2) light dose, resulting soranjidiol-1-methyl ether in complete cell destruction. The observed cellular killing by photoactivated AQs exhibited close relation with singlet oxygen production, except for soranjidiol-1-methyl ether, where cell viability decrease is in relation to uptake by tumor cells. PMID- 21665454 TI - Antioxidant and cardioprotective effects of Danshensu (3-(3, 4-dihydroxyphenyl)-2 hydroxy-propanoic acid from Salvia miltiorrhiza) on isoproterenol-induced myocardial hypertrophy in rats. AB - Myocardial hypertrophy has been linked to the development of a variety of cardiovascular diseases, and is a risk factor for myocardial ischemia, arrhythmias, and sudden cardiac death. The objective of the present study was to evaluate the cardioprotective effects of Danshensu (DSS), a water-soluble active component of Danshen, on cardiac hypertrophy in rats. We are the first to report that DSS reversed Cx43 down-regulation in ventricular tissue. Cardiomyopathy in rats was produced using isoproterenol (Iso) treatment (2.5 mg/kg/d, s.c.) for seven days. DSS (3 and 10 mg/kg/d, i.p.) and Valsartan (Val) (10 mg/kg, i.g.) were administered on days 4-7 of Iso-treatment. Heart weight index, hemodynamic parameters, and ECG II parameters were monitored and recorded; protein expression of left ventricular connexin 43 (Cx43) and the activity of the redox system were assayed, and arrhythmias were produced using a coronary ligation/reperfusion procedure. The results demonstrated that DSS treatment significantly decreased heart weight/body weight (HW/BW) and left ventricular weight/body weight (LVW/BW) ratios. The protective role of DSS against Iso-induced myocardial hypertrophy was further confirmed using ECG. The incidences of ventricular tachycardia and ventricular fibrillation (VT, VF) and arrhythmic scores were higher in the model group and were suppressed by DSS. DSS decreased the serum and myocardium levels of creatine kinase, lactate dehydrogenase, and malondialdehyde (CK, LDH, and MDA) and increased serum activity of superoxide dismutase (SOD) in a dose-dependent manner. Cx43 expression in the left ventricle was down-regulated, and there was significant oxidative stress in this model of cardiomyopathy. DSS reversed the down-regulated Cx43 protein levels and showed potent anti-oxidative activities and cellular protection. These data demonstrate that DSS can prevent cardiac I/R injury and improve cardiac function in a rat model of hypertrophy, the effects partially resulting from antioxidants and the protection from Cx43 expression. PMID- 21665455 TI - Signaling clusters in the cell membrane. AB - Large-scale molecular assemblies, or signaling clusters, at the cell membrane are emerging as important regulators of cell signaling. Here, we review new findings and describe shared characteristics common to signaling clusters from a diverse set of cellular systems. The well-known T cell receptor cluster serves as our paradigmatic model. Specifically, each cluster initiates recruitment of hundreds of molecules to the membrane, interacts with the actin cytoskeleton, and contains a significant fraction of the entire signaling process. Probed by recent advancements in patterning and microscopy techniques, the signaling clusters display functional outcomes that are not readily predictable from the individual components. PMID- 21665456 TI - Cross-talk between calcium and protein kinase A in the regulation of cell migration. AB - Calcium (Ca(2+)) and the cAMP-dependent protein kinase (PKA) are pleiotropic cellular regulators and both exert powerful, diverse effects on cytoskeletal dynamics, cell adhesion, and cell migration. Localization, by A-kinase-anchoring proteins (AKAPs), of PKA activity to the protrusive leading edge, integrins, and other regulators of cytoskeletal dynamics has emerged as an important facet of its role in cell migration. Additional recent work has firmly established the importance of Ca(2+) influx through mechanosensitive transient receptor potential (TRP) channels and through store-operated Ca(2+) entry (SOCE) in cell migration. Finally, there is considerable evidence showing that these mechanisms of Ca(2+) influx and PKA regulation intersect--and often interact--and thus may work in concert to translate complex extracellular cues into the intracellular biochemical anisotropy required for directional cell migration. PMID- 21665457 TI - Multi-sample acoustic biosensing microsystem for protein interaction analysis. AB - The current work describes a novel setup for multi-sample biomolecular analysis. It is based on the assembly of a dual acoustic device chip with a four-channel microfluidic module, forming an array of eight available domains for experiments. Initially, multiple detection was demonstrated via the specific interaction of neutravidin with four different biotinylated proteins, namely protein G, protein A, bovine serum albumin, and immunoglobulin G; results revealed a reproducibility between the microchannel domains better than 90%. Real-time analysis of the binding interactions was used to calculate the affinity and kinetic constants of the four biotinylated molecules binding to surface-immobilized neutravidin; this was the first time that this information was derived using a biosensing device and four biotinylated molecules. Interestingly, all calculated kinetic and affinity constants resemble those typical of antibody-antigen interactions, although the investigated specific binding was of avidin-biotin nature. Finally, under device pre-functionalization conditions, it was possible to probe eight interactions all together, exploiting the full capacity of the microsystem and reducing significantly the analysis time, contrary to the use of the standard acoustic device configuration. The outcome of this full-scale validation opens the way for the integrated acoustic platform to be implemented in even higher throughput detection for future diagnostic/biomedical applications, as well as in fundamental research studies regarding biomolecular interaction investigation and characterization. PMID- 21665458 TI - A novel and simple route to prepare a Pt nanoparticle-loaded carbon nanofiber electrode for hydrogen peroxide sensing. AB - A facile wet-chemical method was developed to prepare a novel Pt nanoparticle loaded carbon nanofiber (Pt/CNF) electrode. Without using any stabilizer or pretreatment procedure, large amounts of Pt nanoparticles could be well deposited on the surface of the electrospun CNF electrode at room temperature, as revealed by scanning electron microscopy (SEM). The effect of the precursor concentration on the formation of Pt catalysts was investigated to optimize the performance of the proposed hybrid electrode. When applied to the electrochemical detection of hydrogen peroxide (H2O2), the Pt/CNF electrode exhibited low overpotential, fast response and high sensitivity. A low detection limit of 0.6 MUM with wide linear range of 1-800 MUM (R=0.9991) was achieved at the Pt/CNF electrode, which was superior to that obtained with other H2O2 electrochemical sensors reported previously. In addition, the Pt/CNF electrode showed good selectivity for H2O2 detection in the presence of ascorbic acid (AA), acetaminophenol (AP) and uric acid (UA) under physiological pH condition. The attractive analytical performances and facile preparation method made this novel hybrid electrode promising for the development of effective H2O2 sensors. PMID- 21665459 TI - A Sexually Transmitted Disease (STD) DNA chip for the diagnosis of genitourinary infections. AB - The results of an investigation aimed at the development of a DNA chip for the detection of genitourinary infections are described. Through analysis of over 35,000 clinical cases, 14 pathogens which are most abundantly found among Koreans were selected and candidate sequences for capture probes were accordingly chosen by considering their sequences and beta-globin house-keeping gene. Among this group, the most suitable capture probe sequences were selected by employing repeated chip tests in which they are immobilized on a glass chip by using a recently developed novel gold nanoparticles-based method. A multiplex PCR method was established to generate fluorescence-labeled sequences for all 14 pathogens along with the beta-globin gene. By using optimized hybridization conditions, the final chip was constructed and employed to diagnose reliably both single and multiple infections in clinical human samples for 14 target pathogens. The results show that the novel chip methodology serves as a highly reliable and convenient tool for the diagnosis of Sexually Transmitted Diseases (STDs). Furthermore, this study has its great significance in that it demonstrates the entire process from statistical analysis of a large number of clinical cases to the final development of STD DNA chip just ready to be applied or commercialized in the clinical diagnostic field. PMID- 21665460 TI - Ultra trace analysis of small molecule by label-free impedimetric immunosensor using multilayer modified electrode. AB - A multilayer electrode modified with a self-assembled thiourea monolayer (SATUM) followed by gold nanoparticles (AuNPs), mercaptosuccinic acid (MSA) and antibody was investigated for the detection of ultra trace amount of a small molecule (chloramphenicol) in an impedimetric system. The formation of the antibody antigen complex at the electrode surface caused the impedance to increase. Under optimum conditions three modified electrodes were compared the SATUM/AuNPs/MSA electrode provided a wide linear range (0.50-10) * 10-16 M, and a very low determination limit of 1.0 * 10-16 M. This determination limit was much lower than the SATUM/AuNPs electrode, 1.0 * 10-15 M, and SATUM electrode, 4.7 * 10-14 M. The modified electrode provided good selectivity for chloramphenicol detection and can be reused up to 45 times with a relative standard deviation of lower than 4%. When applied to determine chloramphenicol in shrimp samples, the results agreed well with those obtained by the high-performance liquid chromatography coupled with a photo diode array detector (P > 0.05). The developed system can be applied to detect other small molecules using appropriate affinity binding pairs. PMID- 21665461 TI - Cerebellar supervised learning revisited: biophysical modeling and degrees-of freedom control. AB - The biophysical models of spike-timing-dependent plasticity have explored dynamics with molecular basis for such computational concepts as coincidence detection, synaptic eligibility trace, and Hebbian learning. They overall support different learning algorithms in different brain areas, especially supervised learning in the cerebellum. Because a single spine is physically very small, chemical reactions at it are essentially stochastic, and thus sensitivity longevity dilemma exists in the synaptic memory. Here, the cascade of excitable and bistable dynamics is proposed to overcome this difficulty. All kinds of learning algorithms in different brain regions confront with difficult generalization problems. For resolution of this issue, the control of the degrees of-freedom can be realized by changing synchronicity of neural firing. Especially, for cerebellar supervised learning, the triangle closed-loop circuit consisting of Purkinje cells, the inferior olive nucleus, and the cerebellar nucleus is proposed as a circuit to optimally control synchronous firing and degrees-of-freedom in learning. PMID- 21665463 TI - A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer. AB - AIM: To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet(r)) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet(r) 50 mg/m2 (day 1), docetaxel 30 mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF). RESULTS: The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline>15%. LVEF median values remained stable from baseline to the end of the study (60%). CONCLUSIONS: The combination of Myocet(r), docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC. PMID- 21665462 TI - Single-agent irinotecan or FOLFIRI as second-line chemotherapy for advanced colorectal cancer; results of a randomised phase II study (DaVINCI) and meta analysis [corrected]. AB - BACKGROUND: Second-line treatment with irinotecan for advanced or metastatic colorectal cancer prolongs survival. It is uncertain whether irinotecan is better administered with 5-fluorouracil or alone in patients previously treated with a fluoropyrimidine. We compared toxicity (particularly diarrhoea), quality of life, and efficacy of combination chemotherapy and irinotecan in these patients. METHODS: In DaVINCI, a randomised phase II trial, patients with advanced colorectal cancer were randomly allocated to: Combination therapy (FOLFIRI), irinotecan (180 mg/m(2) IV over 90 min, day 1), 5-fluorouracil (400mg/m(2) IV bolus and 2400 mg/m(2) by 46-hour infusion from day 1) and folinic acid (20mg/m(2) IV bolus, day 1), 2-weekly; or Single-agent, irinotecan (350 mg/m(2) IV over 90 min), 3-weekly. Toxicity was evaluated every treatment cycle; QOL and response 6-weekly. Analysis was by intention to treat. The trial, amended from a larger factorial design, was terminated early due to slow recruitment. Results were also combined with other second-line irinotecan trials. FINDINGS: We randomised 44 patients to combination and 45 to single agent. Eight patients in the irinotecan arm and 4 in the combination arm had grade 3/4 diarrhoea (P=0.24). Treatment groups did not differ significantly in overall QOL changes, response rate or progression free or overall-survival. In a systematic review of 29 trials of second-line irinotecan-based treatment, single-agent irinotecan was associated with more diarrhoea and alopecia than the combination but efficacy was similar. INTERPRETATION: Combination treatment compared with single-agent irinotecan reduces alopecia and diarrhoea without compromising efficacy on clinical outcomes. Both regimens remain as reasonable treatment options. FUNDING: Research grant (Pfizer). PMID- 21665465 TI - Studying the effects of laccase-catalysed grafting of ferulic acid on sisal pulp fibers. AB - Functionalization of sisal specialty pulp fibers by laccase-catalysed grafting of ferulic acid (FRC) was investigated. To this end, the extent of phenol coupling to fibers under different reaction conditions (laccase and FRC rates, and time) was evaluated in terms of pulp properties including kappa number (expressed as the combined contributions of lignin and hexenuronic acids), brightness, Klason lignin and surface anionic charge after Soxhlet extraction of acetone-treated pulp. The specific treatment resulting in the highest degree of grafting was then used in a comparative study of the effects of applying the laccase-FRC system to refined and unrefined pulp with a view to confirming whether the increased surface area obtained by effect of fibrillation would lead to enhanced grafting. Based on the results, refining the pulp prior to the enzyme treatment resulted in increased grafting which in turn led to handsheets with improved strength-related properties (particularly wet tensile strength) relative to control samples. PMID- 21665464 TI - Resection of perihilar biliary schwannoma. AB - INTRODUCTION: Schwannomas are usually benign nerve sheath tumors, which typically arise in the head, neck, spinal cord and extremities. Schwannoma of the biliary tract is an extremely rare finding. Patients generally lack symptoms and seek medical attention when tumor growth causes obstructive jaundice. Preoperative diagnosis is difficult and resection is the treatment of choice. METHODS: A 54 year-old female with history of back and right labia minor melanoma for which she underwent complete excision and right inguinal lymph node dissection more than 10 years ago, was evaluated for new onset gastroesophageal reflux symptoms and found to have markedly abnormal liver enzymes. Imagining studies revealed intrahepatic ductal dilatation and a 5.2 cm mass in the porta hepatis that was not consistent with cholangiocarcinoma or hepatocellular carcinoma. Multiple percutaneous biopsies of the mass failed to provide a definitive diagnosis. With a high clinical suspicion of metastatic melanoma and no other evident sites of disease, operative intervention was undertaken for diagnosis and definitive treatment. RESULTS: Diagnostic laparoscopy was performed initially, but access to the mass was difficult, given its location. Subsequently, the patient underwent laparotomy, with tumor excision, common bile duct resection and hepato jejunostomy. Pathologic examination and analysis were consistent with cellular schwannoma. Postoperatively, the patient recovered uneventfully, and liver function studies returned to normal. CONCLUSION: Schwannomas are uncommon tumors, which very rarely arise from the biliary tract and cause biliary obstruction. Exploration is indicated in order to establish the diagnosis and to render definitive treatment. PMID- 21665466 TI - The role of phase separation and feed cycle length in leach beds coupled to methanogenic reactors for digestion of a solid substrate (Part 2): Hydrolysis, acidification and methanogenesis in a two-phase system. AB - The effect of phase separation and batch duration on the trophic stages of anaerobic digestion was assessed for the first time in leach beds coupled to methanogenic reactors digesting maize (Zea mays). The system was operated for consecutive batches of 7, 14 and 28 days for ~120 days. Hydrolysis rate was higher the shorter the batch, reaching 8.5 gTS(destroyed)d(-1) in the 7-day system. Phase separation did not affect acidification but methanogenesis was enhanced in the short feed cycle leach beds. Phase separation was inefficient on the 7-day system, where ~89% of methane was produced in the leach bed. Methane production rate increased with shortening the feed cycle, reaching 3.523ld(-1) average in the 7-day system. Low strength leachate from the leach beds decreased methanogenic activity of methanogenic reactors' sludges. Enumeration of cellulolytic and methanogenic microorganisms indicated a constant inoculation of leach beds and methanogenic reactors through leachate recirculation. PMID- 21665468 TI - Quantitative structure-activity relationship study of phloroglucinol-terpene adducts as anti-leishmanial agents. AB - Phloroglucinol class of natural products occur widely in Myrtaceae family and possess variety of biological activities viz. antimicrobial, antimalarial, cancer chemopreventive, anti-HIV and anti-leishmanial. In the present article, quantitative structure-activity relationship (QSAR) study was carried out for a series of phloroglucinol-terpene adducts exhibiting anti-leishmanial activity to find out the structural features which are crucial for the biological activity. The QSAR study was carried out using JChem for Excel and the best QSAR model was derived by multiple regression analysis. The best model of four descriptors yields squared correlation coefficient of 0.930 (s=0.096, F=65.93, P<0.0001) based on stepwise multiple regression method. The predictive ability of model was checked by cross validation method. The study indicated that the lipophilic character (CLogP), isoelectric point, Haray index and Platt index play important role in anti-leishmanial activity of compounds. Anti-leishmanial activity of several structurally similar naturally occurring euglobals has also been predicted using developed QSAR model. PMID- 21665467 TI - Optimization of the production of poly-gamma-glutamic acid by Bacillus amyloliquefaciens C1 in solid-state fermentation using dairy manure compost and monosodium glutamate production residues as basic substrates. AB - Poly-gamma-glutamic acid (gamma-PGA) is a polymer with uses in foods, cosmetics, medicine and agriculture. The medium for the production of gamma-PGA by Bacillusamyloliquefaciens C1 was optimized by response surface methodology using agro-industrial wastes in solid-state fermentation (SSF). The optimal SSF medium (20g substrates with 50% initial moisture) for producing gamma-PGA was determined to contain 5.51g dairy manure compost, 1.91g soybean cake, 0.57g corn flour, 2.15g monosodium glutamate production residues, 1.5g wheat bran, 0.5g rapeseed cake, 0.1g citric acid, 0.05g MgSO(4).7H(2)O and 0.03g MnSO(4).H(2)O. In this medium the strain produced up to 0.0437g gamma-PGA per gram of substrates when cultured for 48h at 37 degrees C. SDS-PAGE showed that the molecular weight of the gamma-PGA was more than 130kDa. Due to the high-yields observed and the low cost nature of the optimal medium, this study indicates a possibility to establish economical large-scale production of gamma-PGA. PMID- 21665469 TI - Synthesis and antitubercular evaluation of amidoalkyl dibenzofuranols and 1H benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones. AB - A new class of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5 e][1,3]oxazin-3(2H)-ones was synthesized in very good yields through polyphosphoric acid supported on silica (PPA-SiO(2)) catalyzed one-pot three component condensation of 2-dibenzofuranol; aromatic aldehydes and acetamide or benzamide or urea under solvent free conditions. At 125 degrees C the reaction led to the formation of amidoalkyl dibenzofuranols 5a-k where as at 160 degrees C cyclization take place to give oxazin-3(2H)-one analogues 6a-e. Screening all the 16 compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) resulted 1-((4-chlorophenyl)(2 hydroxydibenzo[b,d]furanyl)methyl)urea 5h; 1-((4-bromophenyl)(2 hydroxydibenzo[b,d]furanyl)methyl)urea 5i; 1-phenyl-1H-benzo[2,3]benzo furo[4,5 e][1,3]oxazin-3(2H)-one 6a (MIC 3.13MUg/mL) and 1-(4-chlorophenyl)-1H benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-one 6b; 1-(4-bromophenyl)-1H benzo[2,3]benzofuro [4,5-e][1,3]oxazin-3(2H)-one 6c (MIC 1.56MUg/mL) as most active antitubercular agents. PMID- 21665470 TI - Inhibition of a prolyl hydroxylase domain (PHD) by substrate analog peptides. AB - Oxygen dependent degradation of hypoxia-inducible factor (HIF)-1alpha is triggered with hydroxylation by proline hydroxylase domain 2 (PHD2) under normoxic conditions. Some of previously developed PHD2 inhibitors show a considerable potency against factor inhibiting HIF (FIH), the HIF asparagine hydroxylase. For specific inhibition of PHD2, we have synthesized peptides containing 556-575 residues of HIF-1alpha with modifications at the Pro-564 and examined their inhibitory effect against PHD2. Adopting fluorescence polarization based assays, we evaluated inhibitory potency of the peptides and selected potent inhibitors. These PHD2 inhibitor peptides showed no significant potency against FIH, demonstrating their specific inhibitory effect on PHD2. PMID- 21665471 TI - Influence of histology on the effectiveness of adjuvant chemotherapy in patients with hormone receptor positive invasive breast cancer. AB - INTRODUCTION: To investigate the effect of adjuvant chemotherapy on long term survival in addition to hormonal therapy in the systemic treatment of hormonal receptor positive breast cancer patients. METHODS: All patients with primary non metastatic hormonal receptor positive invasive lobular (mixed) (=ILC) and invasive ductal (=IDC) breast cancer operated on between 1986 and 2007 were identified from a population based cohort. Four hundred ninety-eight patients with lobular (mixed) and sixteen hundred seventeen with ductal cancer were eligible. Both groups were divided in patients receiving adjuvant hormonal treatment with or without systemic chemotherapy. RESULTS: Overall survival was not statistically different in patients with ILC treated with adjuvant hormonal and chemotherapy compared to hormonal treatment alone (5-year survival 85.2% vs 82.8%, P = .68). In contrast, patients with IDC receiving adjuvant hormonal and chemotherapy had a significantly better overall survival compared to hormonal therapy alone (5-year survival rate 87.6% vs 80.8%, P < .001). In the multivariate analysis however, this significance disappeared suggesting that the data are possibly too small, too unbalanced, or influenced by other confounding factors to come to definitive conclusions. CONCLUSIONS: There are good reasons to consider ductal and lobular breast cancers as different entities in future studies. Patients with hormone receptor positive ILC seem to benefit differently from additional adjuvant chemotherapy to hormonal therapy as compared with patients with IDC. PMID- 21665472 TI - Microfluidic devices for studying chemotaxis and electrotaxis. AB - Directed cell migration plays important roles in physiological processes such as host defense, wound healing, cancer metastasis and embryogenesis. Many organisms are capable of directional migration, which can be guided by diverse cellular factors including chemical and electrical cues. Recently, microfluidic devices that consist of small channels with micrometer dimensions are being developed for cell migration studies. These devices can precisely configure and flexibly manipulate chemical concentration gradients and electric fields, and thus can be used to study the complex guiding mechanisms for cell migration. In this paper we highlight recent applications of microfluidic devices for cell migration research, with a focus on electric field-directed cell migration, to provide important and timely updates of this rapidly developing research field. PMID- 21665473 TI - The utility and futility of non-invasive ventilation in non-designated areas: can critical care outreach nurses influence practice? AB - OBJECTIVE: To explore the practice of delivering non-invasive ventilation (NIV) in non-designated areas within a large university teaching hospital by critical care outreach nurses. METHODS: Local audit was prospectively conducted over a five-month period of all patients commenced on NIV in non-designated areas. The audit was repeated a year later and again four years later. MAIN OUTCOME MEASURES: Documentation of patient diagnosis and management plan including whether they were suitable for attempted cardiopulmonary resuscitation and endotracheal intubation as per British Thoracic Society guidelines (2002). Patient outcome (to hospital discharge) and arterial blood gas results pre and post commencement of NIV. RESULTS: 115 patients received NIV for the treatment of acute respiratory failure. The mortality rate for the first 2 years data combined (n75) was 57% and attributed to the fact that patients were elderly, acidotic and had diagnoses associated with a poor response to NIV. 86% of patients had a documented resuscitation status and management plan. Resuscitation status (p=0.01) and arterial blood gas improvement within two hours of therapy had a significant effect on patient outcome (p=0.001). Four years later the mortality rate had reduced to 35% possibly due to appropriate patient selection. More patients were deemed suitable for resuscitation, were transferred to designated areas and electively ventilated. CONCLUSION: Inappropriate use of NIV in non designated areas is associated with a high mortality. Critical care outreach nurses can play a pivotal role in influencing appropriate patient selection for NIV. PMID- 21665474 TI - An evaluation of serum albumin and the sub-scores of the Waterlow score in pressure ulcer risk assessment. AB - BACKGROUND: From previous work serum albumin is predictive of pressure ulcers over and above the Waterlow score. However the sub-scores of the Waterlow score were not available, and the accuracy of calculation of the total score was poor. This study has used sub-scores and is an order of magnitude larger. OBJECTIVES: To compare serum albumin with Waterlow score as a predictive measure for pressure ulcers. DESIGN: Retrospective analysis of hospital information support system. SETTINGS: A district general hospital in Staffordshire. PARTICIPANTS: Adult non elective in-patients. METHODS: Logistic regression and receiver operating characteristic. RESULTS: The sub-scores of the Waterlow score were explored. While they constitute a multi-dimensional dataset, many were not found relevant to pressure ulcer risk in this population (non-elective in-patients). Some sub scores were not recorded correctly, and body mass index (BMI) was particularly badly reported. Age was found to be as predictive of pressure ulcer as the more complex Waterlow score. Serum albumin was at least as good as the Waterlow score in risk assessment of pressure ulcers. Matching patients with pressure ulcers to patients with none, who had identical Waterlow sub-scores, confirmed serum albumin as a robust predictive value in pressure ulcers. CONCLUSION: Risk assessing patients based on their age is as good as the more complex Waterlow score. Additional risk information can be gained from knowing the serum albumin value. PMID- 21665475 TI - Why is walker-assisted gait metabolically expensive? AB - Walker-assisted gait is reported to be ~200% more metabolically expensive than normal bipedal walking. However, previous studies compared different walking speeds. Here, we compared the metabolic power consumption and basic stride temporal-spatial parameters for 10 young, healthy adults walking without assistance and using 2-wheeled (2W), 4-wheeled (4W) and 4-footed (4F) walker devices, all at the same speed, 0.30m/s. We also measured the metabolic power demand for walking without any assistive device using a step-to gait at 0.30m/s, walking normally at 1.25m/s, and for repeated lifting of the 4F walker mimicking the lifting pattern used during 4F walker-assisted gait. Similar to previous studies, we found that the cost per distance walked was 217% greater with a 4F walker at 0.30m/s compared to unassisted, bipedal walking at 1.25m/s. Compared at the same speed, 0.30m/s, using a 4F walker was still 82%, 74%, and 55% energetically more expensive than walking unassisted, with a 4W walker and a 2W walker respectively. The sum of the metabolic cost of step-to walking plus the cost of lifting itself was equivalent to the cost of walking with a 4F walker. Thus, we deduce that the high cost of 4F walker assisted gait is due to three factors: the slow walking speed, the step-to gait pattern and the repeated lifting of the walker. PMID- 21665476 TI - Primary intraosseous paraganglioma of the sacrum. AB - Primary intraosseous sacral paraganglioma is a rare case of location for spinal paragangliomas, which generally manifest as intradural extramedullary tumors of the cauda equina region. The diagnosis can be elusive considering the rarity of sacral paragangliomas. The clinical importance of recognizing this relatively benign tumor cannot be overemphasized as the outcome, extent of surgery and management differs significantly from other common bony sacral tumors which are generally malignant. We report a rare case of sacral paraganglioma that was diagnosed only after histopathological examination, along with a relevant review of the literature. PMID- 21665477 TI - An episode mimicking a versive seizure in acute bilateral pontine stroke. AB - Pontine ischemia usually results in focal deficits such as hemiparesis, facial palsy, dysarthria, disorders of eye movements or vertigo. Although rarely described, involuntary abnormal movements and "convulsions" due to pontine lesions can also occur. Here we describe a 67-year-old woman with hypertension who presented with a tonic movement mimicking a versive seizure in the acute phase of bilateral pontine ischemia. Post-stroke movement disorders are well known. They are usually associated with supratentorial lesions and rarely occur in the acute phase, but "seizure-like" episodes can be seen in pontine ischemia. Awareness of this rare phenomenon is useful for the management of acute stroke patients. PMID- 21665478 TI - A single neurosurgical center's experience of the resolution of cervical radiculopathy after dorsal foraminotomy and ventral discectomy. AB - Monosegmental cervical disc herniation can be removed either by dorsal foraminotomy and sequesterectomy (Frykholm's method) or by a ventral approach with extensive removal of the affected disc with subsequent segmental fusion (modified Cloward's method). The choice of method largely depends on the surgeon's individual preference and experience. We evaluated the neurological outcomes of both surgical methods in a retrospective series of 100 consecutive patients (50 male, 50 female; mean age=47.7 years) who underwent surgery within a 3-year period. Fifty-one patients (30 male, 21 female; mean age=50.1 years) underwent a dorsal foraminotomy and 49 patients (20 male, 29 female; mean age=45.3 years) underwent surgery by the ventral approach with consecutive segmental fusion. We identified demographic data and analysed the postoperative neurological performance (motor and sensory activity) and the resolution of the radiating and local pain during the in-hospital stay. Patients in the Cloward Group recovered significantly better from cervicobrachialgia (p=0.02), neck pain (p=0.01) and sensory deficits (p=0.003). Furthermore, the Cloward Group showed a trend towards better outcomes for paresis. Complete removal of the affected cervical disc via a ventral approach and segmental fusion results in a superior neurological performance in the short-term compared to a dorsal foraminotomy and nerve root decompression by sequestrectomy. However, assessment of the long-term outcome is required and further studies are required to confirm our results. PMID- 21665479 TI - Severe phenotypes of paralysis periodica paramyotonia are associated with the Met1592Val mutation in the voltage-gated sodium channel gene (SCN4A) in a Chinese family. AB - Paralysis periodica paramyotonia (PPP) is caused by mutation of the adult skeletal muscle sodium channel gene's alpha (alpha)-subunit (SCN4A). Here, we report four generations of a Chinese family affected by a remarkably severe form of PPP with progressive myopathy. Routine electromyograms (EMG) showed myotonic discharge and after a long exercise test, compound motor action potential amplitudes were markedly decreased by 40-55%. Muscle biopsy revealed obvious vacuolar changes. Moreover, genetic analysis revealed the Met1592Val mutation in the alpha-subunit, SCN4A. The patients showed a striking clinical and electrophysiological improvement during treatment with acetazolamide. Thus, our findings showed that mutation of Met1592Val in the SCN4A gene is associated with aggressive development of PPP characterized by severe vacuolar myopathy. PMID- 21665480 TI - Paediatric ganglioglioma of the conus medullaris. AB - Gangliogliomas of the conus medullaris are very rare, with only 12 patients reported so far. We report a 6-year-old male who presented with a painless numbness of the left lower limb and with bladder dysfunction. MRI revealed an intramedullary lesion at the T11-T12 vertebral levels. The tumour was subtotally removed. Histopathological examination demonstrated ganglioglioma. PMID- 21665481 TI - Anterior-posterior stability of the knee by an MR image subtraction method. AB - The purpose of our study was to test the hypothesis that when a shear force was applied posteriorly to the loaded knee in vivo, there would be no relative motion between the tibia and the medial femoral condyle. Siemens 7 Tesla high-resolution MRI machine was used to scan eight healthy male volunteers with the knee at 15 degrees of flexion. Two scans were obtained: the first with a compressive force of 660 N along the tibial long axis and a second with the compressive force and a posterior shear force of 36 N applied to the tibia. Solid models were created of the femur, tibia, and menisci for both loading conditions. The tibial models were superimposed enabling the displacements of the femur and menisci to be determined, relative to a fixed tibia. On average, the lateral femoral condyle displaced anteriorly by 0.66 mm but the medial femoral condyle displaced posteriorly by 0.36 mm. This indicated an axial rotation with a center between the lateral and medial condyles, but closer to the medial. The menisci displaced with the femoral condyles, but there was no indication that the medial meniscus was contributing to the pivoting action. This study supported the concept of medial anterior-posterior stability under weight-bearing conditions, but with structures other than the medial meniscus providing the stability. This study has application to the treatment of knee injuries and to knee arthroplasty design. PMID- 21665482 TI - Facile fabrication of promising protein tyrosine phosphatase (PTP) inhibitor entities based on 'clicked' serine/threonine-monosaccharide hybrids. AB - Protein tyrosine phosphatases (PTPs) are well-validated therapeutic targets for many human major diseases. The development of their potent inhibitors has therefore become a main focus of both academia and the pharmaceutical industry. We report herein a facile strategy toward the fabrication of new and competent PTP inhibitor entities by simply 'clicking' alkynyl amino acids onto diverse azido sugar templates. Triazolyl glucosyl, galactosyl, and mannosyl serine and threonine derivatives were efficiently synthesized via click reaction, which were then identified as potent CDC25B and PTP1B inhibitors selective over a panel of homologous PTPs tested. Their inhibitory activity and selectivity were found to largely lie on the structurally and configurationally diversified monosaccharide moieties whereon serinyl and threoninyl residues were introduced. In addition, MTT assay revealed the triazole-connected sugar-amino acid hybrids may also inhibit the growth of several human cancer cell lines including A549, Hela, and especially HCT-116. On the basis of such compelling evidence, we consider that this compound series could furnish promising chemical entities serving as new CDC25B and PTP1B inhibitors with potential cellular activity. Furthermore, the 'click' strategy starting from easily accessible and biocompatible amino acids and sugar templates would allow the modular fabrication of a rich library of new PTP inhibitors efficaciously and productively. PMID- 21665483 TI - Evaluation of NTF1836 as an inhibitor of the mycothiol biosynthetic enzyme MshC in growing and non-replicating Mycobacterium tuberculosis. AB - The mycothiol biosynthesis enzyme MshC catalyzes the ligation of cysteine with the pseudodisaccharide GlcN-Ins and has been identified as an essential enzyme in Mycobacterium tuberculosis. We now report on the development of NTF1836 as a micromolar inhibitor of MshC. Using commercial libraries, we conducted preliminary structure-activity relationship (SAR) studies on NTF1836. Based on this data, NTF1836 and five structurally related compounds showed similar activity towards clinical strains of M. tuberculosis. A gram scale synthesis was developed to provide ample material for biological studies. Using this material, we determined that inhibition of M. tuberculosis growth by NTF1836 was accompanied by a fall in mycothiol and an increase in GlcN-Ins consistent with the targeting of MshC. We also determined that NTF1836 kills non-replicating M. tuberculosis in the carbon starvation model of latency. PMID- 21665484 TI - Discovery of novel c-Met kinase inhibitors bearing a thieno[2,3-d]pyrimidine or furo[2,3-d]pyrimidine scaffold. AB - A series of thieno[2,3-d]pyrimidines and furo[2,3-d]pyrimidines were synthesized and evaluated for the c-Met inhibition. Thieno[2,3-d]pyrimidine 6b stood out as the most potent showing an IC(50) of 35.7 nM. This compound displayed high inhibitory effect on cell proliferation in BaF3-TPR-Met cells and showed high selectivity for c-Met family against other 14 tested kinases. However, compound 6b was found ineffective in the c-Met-dependent U-87MG human gliobastoma xenograft model that may be relevant to its poor PK profile. PMID- 21665485 TI - Synthesis and evaluation of fluorescent heterocyclic aminoadamantanes as multifunctional neuroprotective agents. AB - A series of fluorescent heterocyclic adamantane amines were synthesised with the goal to develop novel fluorescent ligands for neurological assay development. These derivatives demonstrated multifunctional neuroprotective activity through inhibition of the N-methyl-d-aspartate receptor/ion channel, calcium channels and the enzyme nitric oxide synthase. It also exhibited a high degree of free radical scavenging potential. N-(1-adamantyl)-2-oxo-chromene-3-carboxamide (8), N adamantan-1-yl-5-dimethyl-amino-1-naphthalenesulfonic acid (11) and N-(1-cyano-2H isoindol-2-yl) adamantan-1-amine (12) were found to possess a high degree of multifunctionality with favourable physical-chemical properties for bioavailability and blood-brain barrier permeability. The ability of these heterocyclic adamantane amine derivatives as nitric oxide synthase inhibitors, calcium channel modulators, NMDAR inhibitors and effective antioxidants, indicate that they may find application as multifunctional drugs in neuroprotection. PMID- 21665486 TI - Benzoxazolin-2(3H)-one (BOA) induced changes in leaf water relations, photosynthesis and carbon isotope discrimination in Lactuca sativa. AB - The effects are reported here of Benzoxazolin-2(3H)-one (BOA), an allelopathic compound, on plant water relations, growth, components of chlorophyll fluorescence, and carbon isotope discrimination in lettuce (Lactuca sativa L.). Lettuce seedlings were grown in 1:1 Hoagland solution in perlite culture medium in environmentally controlled glasshouse. After 30 days, BOA was applied at concentration of 0.1, 0.5, 1.0 and 1.5 mM and distilled water (control). BOA, in the range (0.1-1.5 mM), decreased the shoot length, root length, leaf and root fresh weight. Within this concentration range, BOA significantly reduced relative water content while leaf osmotic potential remained unaltered. Stress response of lettuce was evaluated on the basis of six days of treatment with 1.5 mM BOA by analyzing several chlorophyll fluorescence parameters determined under dark adapted and steady state conditions. There was no change in initial fluorescence (F0) in response to BOA treatment while maximum chlorophyll fluorescence (F(m)) was significantly reduced. BOA treatment significantly reduced variable fluorescence (F(v)) on first, second, third, fourth, fifth and sixth day. Quantum efficiency of open PSII reaction centers (F(v)/F(m)) in the dark-adapted state was significantly reduced in response to BOA treatment. Quantum yield of photosystem II (PhiPSII) electron transport was significantly reduced because of decrease in the efficiency of excitation energy trapping of PSII reaction centers. Maximum fluorescence in light-adapted leaves (F'(m)) was significantly decreased but there was no change in initial fluorescence in light-adapted state (F'0) in response to 1.5 mM BOA treatment. BOA application significantly reduced photochemical fluorescence quenching (qP) indicating that the balance between excitation rate and electron transfer rate has changed leading to a more reduced state of PSII reaction centers. Non photochemical quenching (NPQ) was also significantly reduced by BOA treatment on third, fourth and fifth day. BOA had dominant effect on C isotope ratios (delta13C) that was significantly less negative (-26.93) at 1.0 mM concentration as compared to control (-27.61). Carbon isotope discrimination (Delta13C) values were significantly less (19.45) as compared to control (20.17) at 1.0 mM. BOA also affect ratio of intercellular to air CO2 concentration (ci/ca) that was significantly less (0.66) as compared to control (0.69) when treated with 1.0 mM BOA. Protein content of lettuce leaf tissue decreased under BOA treatment at 1.5 mM concentration as compared to control. PMID- 21665487 TI - Acute renal failure following lung transplantation: risk factors, mortality, and long-term consequences. AB - OBJECTIVE: Acute renal failure (ARF) frequently complicates lung transplantation. This study determined the prevalence, predictive factors, and consequences of ARF on long-term renal function and survival. METHODS: One hundred and seventy-four lung transplantation recipients were divided into two groups based on the presence or absence of ARF defined as a 50% decrease in creatinine clearance from baseline (group I: 67 patients with ARF; group II: 107 patients without ARF). Multivariate analysis compared pre-operative, operative, and post-operative risk factors to assess predictive factors. Renal function over time was assessed by two-way repeated measures analysis of variance (ANOVA). RESULTS: ARF developed in 67 (39%) of patients. Multivariate analysis identified aprotinin (OR 2.20 (1.11; 4.36), p=0.02) and double lung transplantation (OR 2.61 (1.32; 5.15), p=0.006) as risk factors for post-operative renal failure. At 5 years following transplant, creatinine clearance was similar between the two groups (group I CrCl: 73 ml s( 1); group II CrCl: 53 ml s(-1); p=0.54). Survival at 5 years was the same in the two groups. Multivariate analysis associated age at the time of transplantation (HR 1.030 (1.004; 1.057), p=0.02) and intensive care unit (ICU) length of stay (HR 1.029 (1.008; 1.051), p=0.007) with decreased survival. CONCLUSIONS: The use of aprotinin and double lung transplantation are associated with ARF following lung transplantation. Age at the time of transplantation and a longer intensive care stay predict decreased survival. ARF after lung transplantation is not predictive of late renal dysfunction or decreased long-term survival. PMID- 21665488 TI - Clarithromycin and telithromycin increases interleukin-10 expression in the rat endometriosis model. AB - Endometriosis is a common gynecological disorder associated with infertility. However, treatment options remain limited at present. Since the pathogenesis involves immune responses, the immunomodulatory effect of macrolide on endometriosis has been the focus of much research. A previous study showed that clarithromycin decreased stromal proliferation and promoted apoptosis of fibroblasts in an endometriosis model in rats; however, the mechanism of the effect remains unknown. The aim of this study is to investigate the effect of clarithromycin, one of the major macrolides, and telithromycin, one of the antibiotics belonging to a macrolide group (ketolide), on IL6, IL10 and Ccl2 expression in a rat endometriosis model induced by the surgical transplantation of endometrium onto the peritoneum in 8-week-old female Sprague-Dawley rats. After autotransplantation, the rats were given daily administration of clarithromycin (16 mg/kg/day or telithromycin (12 mg/kg/day) for 3 days. The induced lesions were examined 4 days after autotransplantation. After treatment, IL10 expression in the lesions was increased in rats treated with clarithromycin (1.70-fold) and telithromycin (2.88-fold). The drugs attenuated proliferative stromal lesion of the endometriosis model. The results showed that in the endometriosis model, the drugs enhanced expression of IL10, which may play a role in inhibiting excess inflammatory reaction with its therapeutic effect on the lesion. Macrolide and ketolide therapy may have significant value for the treatment of human endometriosis. PMID- 21665489 TI - A comparison of a maximum exertion method and a model-based, sub-maximum exertion method for normalizing trunk EMG. AB - The problem with normalizing EMG data from patients with painful symptoms (e.g., low back pain) is that such patients may be unwilling or unable to perform maximum exertions. Furthermore, the normalization to a reference signal, obtained from a maximal or sub-maximal task, tends to mask differences that might exist as a result of pathology. Therefore, we presented a novel method (GAIN method) for normalizing trunk EMG data that overcomes both problems. The GAIN method does not require maximal exertions (MVC) and tends to preserve distinct features in the muscle recruitment patterns for various tasks. Ten healthy subjects performed various isometric trunk exertions, while EMG data from 10 muscles were recorded and later normalized using the GAIN and MVC methods. The MVC method resulted in smaller variation between subjects when tasks were executed at the three relative force levels (10%, 20%, and 30% MVC), while the GAIN method resulted in smaller variation between subjects when the tasks were executed at the three absolute force levels (50 N, 100 N, and 145 N). This outcome implies that the MVC method provides a relative measure of muscle effort, while the GAIN-normalized data gives an estimate of the absolute muscle force. Therefore, the GAIN-normalized data tends to preserve the differences between subjects in the way they recruit their muscles to execute various tasks, while the MVC-normalized data will tend to suppress such differences. The appropriate choice of the EMG normalization method will depend on the specific question that an experimenter is attempting to answer. PMID- 21665490 TI - Medium-term outcome after lung transplantation is comparable between brain-dead and cardiac-dead donors. AB - BACKGROUND: Donation after cardiac death (DCD) to overcome the donor organ shortage is now moving into the clinical setting, but the medium-term outcome after DCD lung transplantation (LTx) remains largely unknown. METHODS: In this retrospective study, DCD LTx recipients (n = 21) were compared with a cohort of donation-after-brain-death (DBD) LTx recipients (n = 154) transplanted between February 2007 and July 2010. Immediate (post)operative outcome was evaluated by assessing need for peri-operative extracorporeal membrane oxygenation (ECMO), time to extubation, hospital discharge and primary graft dysfunction (PGD) within the first 48 hours. Survival, incidence of bronchiolitis obliterans syndrome (BOS), acute rejection (AR) and inflammatory markers in blood and in bronchoalveolar lavage (BAL) were assessed and compared over a median follow-up of 327 days for DCD and 531 days for DBD, showing no statistically significant difference (NS). RESULTS: There were no differences between groups with regard to patient characteristics except for a higher number of patients transplanted for obliterative bronchiolitis in the DCD group (4 of 21 vs 7 of 154; p < 0.05). In the DCD group, 2 of 21 patients died, vs 23 of 154 patients in the DBD group (NS). Actuarial survival rates at 6 months, 1 year and 3 years are 95%, 95% and 71% for the DCD group and 96%, 91% and 75% for the DBD group (NS). Three patients (14%) in the DCD group developed BOS vs 15 patients (10%) in the DBD group (NS). Survival and freedom from BOS were not different between the groups. AR, inflammatory markers and immediate (post)operative outcome also did not differ. CONCLUSIONS: In our experience, both early- and medium-term outcome in DCD lung recipients is comparable to that of DBD lung recipients. Use of lungs recovered from controlled donors after cardiac death is a safe option for expansion of the donor pool. PMID- 21665492 TI - Septic arthritis of the adult ankle joint secondary to Salmonella enteritidis: a case report. AB - Salmonella septic arthritis in healthy individuals is a rare phenomenon. However, septic arthritis of the native adult ankle joint in healthy patients has not been previously described in the published data. This is a case report of a 70-year old farmer who presented with a 2-week history of a painful, swollen right ankle and an inability to bear weight. He had no history of ankle injury or any predisposing conditions. Joint aspirations were positive for Salmonella enteritidis that was successfully treated with right ankle arthrotomy and washout, along with a 6-week course of intravenous antibiotic therapy. PMID- 21665493 TI - A risk-adapted strategy of radiotherapy or cisplatin-based chemotherapy in stage II seminoma. AB - OBJECTIVES: Indications for radiotherapy and chemotherapy in stage II seminoma are currently debated. MATERIALS AND METHODS: Since 1980, the policy at Institut Gustave Roussy was to treat patients with stage IIA-B disease with external radiotherapy and patients with stage IIB-C with cisplatin-based chemotherapy. In stage IIB disease, 3 cm was the usual tumor size threshold above which individual patients were considered for chemotherapy. RESULTS: During the period 1980-2001, 67 patients with stage II seminoma were treated: stage IIA (n = 5), stage IIB (n = 31), and stage IIC (n = 31). The median age was 40 years (range: 23-64). Among 37 patients who received radiotherapy, 5, 28, and 4 had a stage IIA, IIB, and IIC, respectively. Among 30 patients who received chemotherapy, 27 had a stage IIC. With a median follow-up of 9.4 years, 19 relapses (28%) occurred, including 11 and 8 cases treated with radiotherapy (30%) and chemotherapy (27%), respectively. The 5-year relapse-free survival was 71% (95% CI: 59-80). All but three relapses were salvaged with chemotherapy followed in selected cases by surgical resection of residual masses. Only 3 patients died of seminoma. The 5 year overall survival rate is 97% (95% CI: 89-99). Five patients subsequently developed a non-germ-cell second cancer, which occurred within the radiation field in 3 cases. CONCLUSION: With an overall survival rate of 97%, the overall outcome of patients with stage II seminoma managed according to this risk-adapted strategy is good. The possibility of extending the indications for chemotherapy to selected stage IIB seminoma patients needs to be further evaluated as potentially beneficial in terms of relapse risk. PMID- 21665494 TI - Predictors for response to intermittent androgen deprivation (IAD) in prostate cancer cases with biochemical progression after surgery. AB - OBJECTIVE: To define characteristics of the first cycle of intermittent androgen deprivation (IAD) that would predict for outcomes in a long term follow-up. MATERIAL AND METHODS: In 1996 we started a prospective study of IAD for the treatment of biochemical progression (BP) after radical prostatectomy (RP) for prostate cancer (PC). The end-points of the trial were time to clinical progression (CP) and time to castration resistance PC (CRPC). Eighty-four cases were included in the study. In all cases, after an initial induction period, an acceptable nadir to switch from on-to-off-phase of IAD was considered to be a serum PSA < 1.0 ng/ml. MEASUREMENTS: As possible predictors for time to CP and CRPC, we analyzed pretreatment parameters such as age, Gleason Score, serum PSA, testosterone, chromogranina A (CgA) levels, and characteristics from the first cycle of IAD. RESULTS: Mean follow-up during IAD was 88.6 +/- 16.7 months; 29.7% of patients developed CRPC and 14.2% of cases showed a CP with a mean time of 88.4 +/- 14.3 months and 106.5 +/- 20.6 months, respectively. At univariate and multivariate analysis, the PSA nadir during the first on-phase period and the first off-phase interval resulted in significant and independent predictors (P < 0.001) of the time to CRPC and CP. In particular for cases with a PSA nadir > 0.4 ng/ml and for those with an off-phase interval <= 24 weeks, the risk of CRPC and CP during IAD was 2.7-2.5 and 3.0-3.1 times that for patients with a PSA nadir <= 0.1 ng/ml and with an off-phase interval > 48 weeks, respectively. CONCLUSIONS: Cases with BP after RP selected to IAD that show at the first cycle a PSA nadir <= 0.1 ng/ml and a off-phase interval >= 48 weeks may identify candidates who will experience better response to IAD treatments and delayed CP or CRPC development. PMID- 21665495 TI - Concordance of preoperative prostate endorectal MRI with subsequent prostatectomy specimen in high-risk prostate cancer patients. AB - OBJECTIVE: Endorectal MRI (ER-MRI) may identify areas suspicious for prostate cancer. We evaluated the accuracy of ER-MRI compared with subsequent pathology specimen from prostatectomy. MATERIALS AND METHODS: We reviewed 309 open radical retropubic prostatectomy cases (RRP) from 2003 to 2008 to identify 94 men with a preoperative ER-MRI, which was obtained in patients with high-risk factors suspicious for local extension (Gleason grade >= 4+3, PSA >= 10 ng/ml, abnormal rectal exam, or extensive biopsy core involvement). Findings of extracapsular extension (ECE), seminal vesicle invasion (SVI), and lymphadenopathy (LAD) on ER MRI were compared with subsequent findings on pathology specimens. RESULTS: Ninety-four men underwent preoperative ER-MRI. No tumor was seen on ER-MRI in 9 men (10%). Of 94 ER-MRIs, 4% showed SVI, and 12% had ECE. At prostatectomy, lymph nodes were pathologically positive in 10 men, none of which were enlarged on ER MRI. RRP was aborted in 3 of these 10 patients due to positive nodes confirmed on frozen section. Comparing ER-MRI results to subsequent prostatectomy specimen the results for accuracy, positive predictive value, negative predictive value, sensitivity, specificity were 70%, 27%, 76%, 14%, 88% for ECE and 93%, 75%, 94%, 38%, 99% for SVI. The accuracy of ECE prediction was 86% in abnormal rectal exam vs. 66% in normal exam (P < 0.05). CONCLUSIONS: Endorectal MRI in the evaluation of high-risk prostate cancer was moderately accurate for SV involvement but inaccurate for ECE and insensitive for metastatic lymph node involvement. The predictive accuracy of ER-MRI improved in patients with an abnormal rectal exam. PMID- 21665497 TI - Three-dimensional cephalometric norms of Chinese adults in Hong Kong with balanced facial profile. AB - OBJECTIVE: The objectives of this study were (1) to develop a 3D cephalometric analysis scheme applicable to assessing dentofacial deformities; and (2) to create a normative database of 3D cephalometric measurements for adult Chinese in Hong Kong. STUDY DESIGN: A cross-sectional study was conducted on 50 male and 50 female adults with normal balanced facial profile and occlusion. Cone-beam computed tomography and stereo photogrammetry imaging were performed on all subjects. Three-dimensional virtual models were generated from imaging data, and cephalometric analysis was performed using specialized software. A new 3D cephalometric analysis scheme appropriate for orthognathic surgery as well as a new reference plane (supraorbital margin plane) for midfacial assessment was used in this study. RESULTS: The cephalometric norms generated in this study were comparable with those reported in the literature for conventional 2D cephalometric analysis and the unique features of Chinese faces. The results also showed significant differences between males and females in most of the facial height measurements (P < .01). CONCLUSIONS: This is the first database of 3D cephalometric norms based on CBCT and 3D photogrammetry of the Chinese population in Hong Kong. This can be a useful reference for characterizing facial deformities in 3 dimensions. Moreover, 3D cephalometric analysis has the potential of incorporating new measurement methods that are difficult if not impossible in 2D cephalometric analysis. PMID- 21665496 TI - A comparative study of extra- and intraluminal sigmoid colonic tonometry to detect colonic hypoperfusion after operation for abdominal aortic aneurysm. AB - OBJECTIVES: There is no ideal method to monitor colonic perfusion after abdominal aortic aneurysm (AAA) repair. The aim was to evaluate extraluminal sigmoid colon tonometry, comparing with the established intraluminal method. METHODS: Eighteen patients were monitored with both methods, 10 after elective and eight after ruptured AAA repair. One tonometric catheter was placed inside the sigmoid colon (intraluminal) and another extraluminally in close contact with the serosa of the sigmoid colon (extraluminal). Intra- and extraluminal partial pressure of carbon dioxide (pCO(2)) were measured every 10 min during 48 h postoperatively, 1536 simultaneous measurements. Intraluminal pH (pHi) and extraluminal pH (pHe) were calculated, and intra-abdominal pressure (IAP) was measured, every 4 h. Colonic ischaemia was defined as pHi <= 7.1. RESULTS: Mean pHi was 7.18 +/- 0.11 and mean pHe was 7.28 +/- 0.09. With a pHe cut-off value of <= 7.2, the sensitivity and specificity to detect colonic ischaemia were 95% and 95%, respectively. Accuracy was 95% and the positive and negative predictive values 0.80 and 0.99, respectively. The positive likelihood ratio was 19 and the negative likelihood ratio 0.05. CONCLUSION: Extraluminal tonometry may serve as a screening test: A pHe-value < 7.2 indicates suspected colonic ischaemia, meriting further investigation. It was not able to evaluate the severity of ischaemia. PMID- 21665498 TI - Frequency of equine laminitis: a systematic review with quality appraisal of published evidence. AB - Equine laminitis is a highly debilitating disease of the foot. Despite its perceived importance, epidemiological characteristics are poorly understood and the true frequency of the disease remains unclear. The objective of this study was to retrospectively assess previous research to identify publications which provide the best evidence of the frequency of naturally-occurring equine laminitis. A systematic review of English language publications was conducted using MEDLINE (1950-2010), CAB Direct (1910-2010) and IVIS (1997-2010). Additional publications were included by searching bibliographies. Search terms included laminitis, equine, frequency, prevalence and incidence. Studies that allowed frequency estimations to be made for naturally-occurring equine laminitis were included. Information was extracted using predefined data fields, including 13 study quality indicators. Sixty-nine publications were appraised. Ten were considered to provide the most reliable information, estimating the frequency of equine laminitis ranging from 1.5% to 34%. Previous publications estimating laminitis frequency were generally poor quality. Laminitis frequency varied across publications however the publications included in this review focussed on many of the different underlying laminitis aetiologies and comparison of the frequencies between groups would be inappropriate. High-quality evidence-based studies are needed to estimate the true disease frequency in different equine populations. PMID- 21665500 TI - Concurrent presentation of aniridia and megalocornea without glaucoma. AB - We report an 18-month-old boy who presented with aniridia and megalocornea but no evidence of glaucoma. In children with aniridia, glaucoma often does not present with buphthalmos; because, it typically manifests in preadolescence or adolescence, as progressive changes occur in the drainage angle. Megalocornea, however, in the presence of aniridia strongly suggests glaucoma in early infancy. This case represents a previously unreported association of aniridia and megalocornea in an otherwise-healthy child with good vision. PMID- 21665499 TI - The evaluation of new and isotopically labeled isoindoline nitroxides and an azaphenalene nitroxide for EPR oximetry. AB - Isoindoline nitroxides are potentially useful probes for viable biological systems, exhibiting low cytotoxicity, moderate rates of biological reduction and favorable Electron Paramagnetic Resonance (EPR) characteristics. We have evaluated the anionic (5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl; CTMIO), cationic (5-(N,N,N-trimethylammonio)-1,1,3,3-tetramethylisoindolin-2-yloxyl iodide, QATMIO) and neutral (1,1,3,3-tetramethylisoindolin-2-yloxyl; TMIO) nitroxides and their isotopically labeled analogs ((2)H(12)- and/or (2)H(12) (15)N-labeled) as potential EPR oximetry probes. An active ester analogue of CTMIO, designed to localize intracellularly, and the azaphenalene nitroxide 1,1,3,3-tetramethyl-2,3-dihydro-2-azaphenalen-2-yloxyl (TMAO) were also studied. While the EPR spectra of the unlabeled nitroxides exhibit high sensitivity to O(2) concentration, deuteration resulted in a loss of superhyperfine features and a subsequent reduction in O(2) sensitivity. Labeling the nitroxides with (15)N increased the signal intensity and this may be useful in decreasing the detection limits for in vivo measurements. The active ester nitroxide showed approximately 6% intracellular localization and low cytotoxicity. The EPR spectra of TMAO nitroxide indicated an increased rigidity in the nitroxide ring, due to dibenzo annulation. PMID- 21665501 TI - The effect of surgical preparation technique on the bacterial load of surgical needles and suture material used during strabismus surgery. AB - PURPOSE: To investigate the effectiveness of 3 surgical preparation techniques in decreasing bacterial contamination of needles and suture material during strabismus surgery. METHODS: Consecutive patients requiring 2-muscle strabismus surgery were randomized into 1 of 3 groups. In Group A, patients' periocular skin and bulbar conjunctivae underwent preparation with 5% povidone-iodine; the drape was placed without regard to eyebrows; and an open wire-loop lid speculum was used. Group B patients underwent the same preparation as Group A patients; however, the eyelashes and eyebrows were scrubbed with 5% povidone-iodine on cotton tip applicators, and the drape was placed to exclude the eyebrows from the surgical field. Group C patients underwent the same preparation as Group B patients; however, a bladed lid speculum was used during surgery to exclude some of the eyelashes from the surgical field. After the procedure, all needles and suture materials were sent separately for aerobic culture. The data were analyzed for differences in contamination rates between the groups. RESULTS: Of 77 patients, 24 (31.4%) had either a needle and/or suture contaminant. Groups A, B, and C had mean contamination rates of 29.6%, 34.6%, and 29.2%, respectively. There was no significant statistical variation in contamination among the 3 groups. The most common organism identified was a coagulase-negative staphylococcus strain. CONCLUSIONS: More meticulous sterile preparation of the surgical field did not result in a meaningful reduction in suture or needle contamination rates during strabismus surgery. PMID- 21665502 TI - Initial postoperative deviation as a predictor of long-term outcome after surgery for intermittent exotropia. AB - PURPOSE: To determine the relationship between initial postoperative deviation and long-term results after surgery for intermittent exotropia. METHODS: A nonrandomized, retrospective case series. The records of patients who underwent surgery for intermittent exotropia between 2002 and 2006 and had 2 or more years of follow-up were evaluated. Distance alignment at postoperative week 1 was used to predict long-term surgical outcomes. A successful outcome was defined as no recurrence of exodeviation (exotropia/phoria >15(Delta)) at last follow-up. RESULTS: A total of 81 patients with mean age of 7.2 years at surgery (range, 1.3 16.9) were included. Bilateral lateral rectus recession was performed in 24 patients, unilateral recession and resection in 48, and unilateral lateral rectus recession in 9. At postoperative week 1, 41 patients had orthophoria or undercorrection (0(Delta)-18(Delta) exotropia/phoria; Group A), 28 had esotropia/phoria <=10(Delta) (Group B), and 12 had esotropia/phoria >10(Delta) (Group C) at distance. At 2 years after surgery, 12 patients (29%) in Group A, 3 patients (11%) in Group B, and none (0%) in Group C had recurrent exotropia. The recurrence rates within 2 years of surgery significantly differed between groups (P = 0.03). The long-term recurrence rates did not significantly differ in the 3 groups after a mean of 51 +/- 23 months' follow-up. CONCLUSIONS: Although initial overcorrection after intermittent exotropia surgery may be associated with lower probability of recurrence within 2 years after surgery, it cannot predict long term motor outcomes. PMID- 21665503 TI - Superior oblique tendon expansion with Achilles tendon allograft for treating Brown syndrome. AB - PURPOSE: To report the results of treatment of Brown syndrome using Achilles tendon allograft as a superior oblique tendon expander. METHODS: Achilles tendon allografts were prepared from the tissue bank. Five eyes of 3 patients with congenital Brown syndrome (mean age, 6 years) were enrolled in the study. Surgery was performed with a superotemporal conjunctival fornix approach. The superior oblique tendon was exposed and severed; then a 2- to 3-mm-wide strip of Achilles tendon (with a thickness of 1-2 mm) was trimmed and sutured between the cut ends using double-armed 5-0 Mersilene sutures. The length of the expander ranged from 7 mm to 8 mm, depending on the severity of the disease. RESULTS: The preoperative hypotropia in primary position ranged from 15(Delta) to 30(Delta), with abnormal head position in 1 patient. Nine months after the operation, 2 eyes with moderate Brown syndrome showed an improvement in the hypotropia to <3(Delta), and 2 eyes with severe disease had residual hypotropia of 5(Delta). Another eye with severe Brown syndrome had a residual hypotropia of 20(Delta). The elevation in adduction improved by 1 grade in 1 eye and resolved in the other 4 eyes. The amount of correction in the deviation improved with time. None of the patients developed secondary superior oblique palsy, rejection, infection, extrusion, prolonged ocular inflammation, or foreign body sensation. CONCLUSIONS: Superior oblique tendon elongation with Achilles tendon allograft had acceptable short-term results in 4 of 5 eyes treated for Brown syndrome. PMID- 21665504 TI - Intravitreal bevacizumab for posttraumatic choroidal neovascularization in a child. AB - Choroidal neovascularization, an uncommon occurrence in children, may complicate up to 20% of cases of closed-globe blunt trauma with Bruch's membrane rupture. Visual outcome in untreated eyes is usually poor, and there is no consensus on the management of this complication. Treatment options include observation, surgical removal of the membrane, photocoagulation, or photodynamic therapy. Antivascular endothelial growth factor therapy has recently been proposed in sporadic adult cases. We report a case of post-traumatic choroidal neovascularization in a boy that has was successfully treated with intravitreal bevacizumab. PMID- 21665505 TI - Ophthalmic manifestations of tetrasomy 18p. AB - PURPOSE: To characterize ophthalmic findings in patients with tetrasomy 18p, a rare chromosomal anomaly that has been previously associated with strabismus. METHODS: All subjects underwent a complete eye examination to screen for ocular pathology. RESULTS: A total of 25 subjects (13 female) were examined after they were diagnosed with tetrasomy 18p. The average age of subjects was 8.2 years (range, 13 months to 22 years). Of the 25 subjects, 18 (72% of examined subjects, 42% of the cohort) showed evidence of strabismus; 16 had esotropia (8 uncategorized, 5 infantile, and 3 accommodative), 1 had esophoria, and 1 was diagnosed with intermittent exotropia. CONCLUSIONS: The coincidence of esotropia with tetrasomy 18p indicates the need to routinely screen these patients for strabismus at the time of diagnosis. PMID- 21665506 TI - The relationships among cycloplegic refraction, keratometry, and axial length in children with refractive accommodative esotropia. AB - PURPOSE: To explore the relationships among cycloplegic refraction, keratometry, and axial length in children with refractive accommodative esotropia and to evaluate the feasibility of axial length estimation from the other 2 parameters. METHODS: This is a prospective case series of children ages 4-12 years who were diagnosed with refractive accommodative esotropia, cooperative for keratometry and optical biometry by the IOLMaster, and without amblyopia in the right eye. The right eyes of the first group of patients were used to generate a linear regression formula from cycloplegic refraction, keratometry, and axial length. This formula was used in the second group of patients to estimate axial length from cycloplegic refraction and keratometry. RESULTS: A total of 100 children were enrolled. Cycloplegic refraction ranged from +2.25 D to +8.25 D, keratometry ranged from 38.34 D to 48.37 D, and measured axial length ranged from 19.34 mm to 23.66 mm. Estimated and measured axial lengths were strongly correlated (Pearson coefficient = 0.9; 95% CI, 0.83-0.94) with the former values having a greater mean by the paired t test (2-sided P < 0.0001; difference between means, 0.27 mm). Estimated and measured values differed by <0.5 mm for most eyes (33/50, 66%) and were within 1 mm for all eyes. CONCLUSIONS: In children with refractive accommodative esotropia, there exists a constant mathematical relationship among cycloplegic refraction, keratometry, and axial length. This relationship allows reasonable estimation of axial length from the other 2 parameters. PMID- 21665507 TI - Adult renal cell carcinoma with rhabdoid morphology represents a neoplastic dedifferentiation analogous to sarcomatoid carcinoma. AB - Renal cell carcinoma (RCC) with rhabdoid morphology (RCC-RM) is a recently described variant of RCC, which has an aggressive biologic behavior and poor prognosis, akin to sarcomatoid RCC. The current World Health Organization classification of RCC does not include the rhabdoid phenotype as a distinct histologic entity. The aim of this study is to investigate whether RCC-RM represents a dedifferentiation of a classifiable-type World Health Organization RCC or a carcinosarcoma with muscle differentiation. We reviewed 168 cases of RCC obtained between 2003 and 2008. From these cases, 10 (6%) were found to have areas of classic rhabdoid morphology. Immunohistochemistry for cytokeratin, epithelial membrane antigen, desmin, CD10, and CD117 was performed in each case using the labeled streptavidin-biotin method. Rhabdoid differentiation was identified in association with conventional-type RCC (9) and with unclassifiable type RCC with spindle cell morphology (1). In all cases, both the rhabdoid and nonrhabdoid tumoral areas were positive for cytokeratin and epithelial membrane antigen and negative for desmin. Cytokeratin positivity in the rhabdoid areas was focal. In cases associated with conventional-type RCC, CD10 was positive in both the rhabdoid and nonrhabdoid foci. CD117 was negative in these tumors. The unclassifiable-type RCC with spindle cell morphology was negative for both CD10 and CD117. The similar immunophenotype between the rhabdoid and nonrhabdoid tumoral foci supports the origin of the rhabdoid cells from the classifiable-type RCC. Areas of rhabdoid morphology do not represent muscle metaplastic differentiation. Renal cell carcinoma with rhabdoid morphology may represent a dedifferentiation of a classifiable-type RCC, similar to that of sarcomatoid differentiation. The recognition of RCC-RM is important as it allows for the inclusion of these high-grade malignancies into a category associated with poor prognosis despite lacking the spindle cell component classically identified as sarcomatoid change. PMID- 21665508 TI - Auxology-based cut-off values for biochemical testing of GH secretion in childhood. AB - OBJECTIVE: The diagnosis of GH deficiency (GHD) in childhood requires GH tests with arbitrary cut-offs. We aimed to define GH cut-offs based on auxology. DESIGN: From a total of 349 children diagnosed with GHD between 1985 and 2005 at our hospital, we excluded all children who had additional characteristics likely to interfere with growth velocity. Age at start of therapy was defined as 4 to 8/9 years (girls/boys). Auxological inclusion criteria were pathological growth velocity, height at start of therapy >1.5 SD below the target, and efficient catch-up growth during GH therapy. Basal IGF-I/IGFBP-3, GH response to arginine and spontaneous GH secretion at night had been measured by the same polyclonal RIA. The reference was a group of 108 normally growing age-matched children with Turner syndrome or born small for gestational age tested during the same time period. RESULTS: We identified 52 children with GHD who fulfilled the inclusion criteria. ROC analysis showed the best diagnostic accuracy at a peak GH cut-off for arginine of 6.6 MUg/L (sensitivity, 84.3%; specificity, 75.5%; AUC=0.83) and at a peak GH cut-off during spontaneous secretion at night of 7.3 MUg/L (sensitivity, 96.8%; specificity, 82.4%; AUC=0.93). Our arbitrarily defined GH cut-offs had been higher. Children diagnosed with GHD in the past with GH test values above the new cut-offs were less responsive to GH therapy (P=0.007). CONCLUSIONS: Here we provide a new rational approach which allows the substitution of arbitrarily defined GH cut-offs by those based on auxology. PMID- 21665509 TI - Association of PNPLA3 SNP rs738409 with liver density in African Americans with type 2 diabetes mellitus. AB - AIM: Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in patients with obesity and type 2 diabetes mellitus (T2DM), and has been associated with the single nucleotide polymorphism (SNP) rs738409 in the PNPLA3 gene. This association remains to be investigated in African Americans with T2DM, a group at lower risk for hepatic steatosis relative to European Americans with T2DM. METHODS: We examined 422 African Americans with T2DM (40.3% male; age: 56.4+/-9.6 years; Body Mass Index: 35.2+/-8.2 kg/m(2)), all with measures of liver density reflecting hepatic fat content on abdominal computed tomography, and blood glucose and lipid profiles. Associations between rs738409 and phenotypes of interest were determined using SOLAR, assuming an additive model of inheritance with covariates age, sex, BMI and use of lipid-lowering medications. RESULTS: Mean+/-SD liver density was 55.4+/-10.2 Hounsfield Units. SNP rs738409 in PNPLA3 was significantly associated with liver density (P=0.0075) and hepatic steatosis (P=0.0350), but not with blood glucose, HbA(1c), total cholesterol, triglycerides, high-density or low-density lipoprotein levels or liver function tests (P=0.15-0.96). CONCLUSION: These findings provide evidence that the PNPLA3 SNP rs738409 contributes to risk for increased liver fat content in African Americans with T2DM, an effect that appears to be independent from serum lipids. Although African Americans are less susceptible to fatty liver than European Americans, PNPLA3 appears to be a risk locus for hepatic steatosis in diabetic African Americans. PMID- 21665510 TI - Analysis of semibatch emulsion polymerization: role of ultrasound and initiator. AB - In this work semibatch miniemulsion was carried out wherein the effect of free radicals produced by ultrasound and an external addition of initiator was examined. Influence of different variables on polymerization rate and polymer particle size has also been investigated. Over a range of 0-4% (by wt) initiator, the polymerization rate was found to increase over a range of 0.56-1.33 g L(-1) min(-1). Similarly monomer concentration range (7.2-15 wt.%) changed the polymerization rate from 1.33 to 2.61 g L(-1) min(-1). Under optimum parametric conditions polymer particle size 50 nm were obtained with a narrow size distribution. Syndiotactic phase of PMMA was observed by controlling the formulation recipe. Although, number of reports could be found in the literature [9,13,17,18,20,22] related to batch emulsion polymerization, this experimental data could be useful for the production of large scale monodispersed PMMA latex as all of the scale-up and design parameters have been qualitatively addressed. PMID- 21665511 TI - Zinc oxide nano-particles--sonochemical synthesis, characterization and application for photo-remediation of heavy metal. AB - Zinc oxide nanoparticles have been synthesized sonochemically from zinc acetate solution in aqueous methanol, ethanol and iso-propanol containing about 5 volume% of alcohol. Characterization with FESEM, XRD, AFM and BET surface area shows that the synthesized particles differ in shape and size. ZnO synthesized using isopropanol was observed to be the most crystalline one. The synthesized nanoparticles were used for the photocatalytic reduction of hexavalent chromium in aqueous medium under solar radiation. It was observed that the initial reduction rates varied with the difference in morphology of ZnO crystallites. PMID- 21665512 TI - A review of clinical ventricular assist devices. AB - Given the limited availability of donor hearts, ventricular assist device (VAD) therapy is fast becoming an accepted alternative treatment strategy to treat end stage heart failure. The field of mechanical ventricular assistance is littered with novel and unique ideas either based on volume displacement or rotary pump technology, which aim to sufficiently restore cardiac output. However, only a select few have made the transition to the clinical arena. Clinical implants were initially dominated by the FDA approved volume displacement Thoratec HeartMate I, IVAD, and PVAD, whilst Berlin Heart's EXCOR, and Abiomed's BVS5000 and AB5000 offered suitable alternatives. However, limitations associated with an inherently large size and reduced lifetime of these devices stimulated the development and subsequent implantation of rotary blood pump (RBP) technology. Almost all of the reviewed RBPs are clinically available in Europe, whilst many are still undergoing clinical trial in the USA. Thoratec's HeartMate II is currently the only rotary device approved by the FDA, and has supported the highest number of patients to date. This pump is joined by MicroMed Cardiovascular's Heart Assist 5 Adult VAD, Jarvik Heart's Jarvik 2000 FlowMaker and Berlin Heart's InCOR as the axial flow devices under investigation in the USA. More recently developed radial flow devices such as WorldHeart's Levacor, Terumo's DuraHeart, and HeartWare's HVAD are increasing in their clinical trial patient numbers. Finally CircuLite's Synergy and Abiomed's Impella are two mixed flow type devices designed to offer partial cardiac support to less sick patients. This review provides a brief overview of the volume displacement and rotary devices which are either clinically available, or undergoing the advanced stages of human clinical trials. PMID- 21665513 TI - Cervical spine response in frontal crash. AB - Predicting neck response and injury resulting from motor vehicle accidents is essential to improving occupant protection. A detailed human cervical spine finite element model has been developed, with material properties and geometry determined a priori of any validation, for the evaluation of global kinematics and tissue-level response. Model validation was based on flexion/extension response at the segment level, tension response of the whole ligamentous cervical spine, head kinematic response from volunteer frontal impacts, and soft tissue response from cadaveric whole cervical spine frontal impacts. The validation responses were rated as 0.79, assessed using advanced cross-correlation analysis, indicating the model exhibits good biofidelity. The model was then used to evaluate soft tissue response in frontal impact scenarios ranging from 8G to 22G in severity. Disc strains were highest in the C4-C5-C6 segments, and ligament strains were greatest in the ISL and LF ligaments. Both ligament and disc fiber strain levels exceeded the failure tolerances in the 22G case, in agreement with existing data. This study demonstrated that a cervical spine model can be developed at the tissue level and provide accurate biofidelic kinematic and local tissue response, leading to injury prediction in automotive crash scenarios. PMID- 21665514 TI - Disrupted thalamocortical connectivity in PSP: a resting-state fMRI, DTI, and VBM study. AB - Progressive supranuclear palsy (PSP) is associated with pathological changes along the dentatorubrothalamic tract and in premotor cortex. We aimed to assess whether functional neural connectivity is disrupted along this pathway in PSP, and to determine how functional changes relate to changes in structure and diffusion. Eighteen probable PSP subjects and 18 controls had resting-state (task free) fMRI, diffusion tensor imaging and structural MRI. Functional connectivity was assessed between thalamus and the rest of the brain, and within the basal ganglia, salience and default mode networks (DMN). Patterns of atrophy were assessed using voxel-based morphometry, and patterns of white matter tract degeneration were assessed using tract-based spatial statistics. Reduced in-phase functional connectivity was observed between the thalamus and premotor cortex including supplemental motor area (SMA), striatum, thalamus and cerebellum in PSP. Reduced connectivity in premotor cortex, striatum and thalamus were observed in the basal ganglia network and DMN, with subcortical salience network reductions. Tract degeneration was observed between cerebellum and thalamus and in superior longitudinal fasciculus, with grey matter loss in frontal lobe, premotor cortex, SMA and caudate nucleus. SMA functional connectivity correlated with SMA volume and measures of cognitive and motor dysfunction, while thalamic connectivity correlated with degeneration of superior cerebellar peduncles. PSP is therefore associated with disrupted thalamocortical connectivity that is associated with degeneration of the dentatorubrothalamic tract and the presence of cortical atrophy. PMID- 21665515 TI - Obesity among working age adults: the role of county-level persistent poverty in rural disparities. AB - Little research has investigated the relationship between county-level poverty and obesity rates. We examined the factors related to obesity among residents of Rural Persistent Poverty counties, finding that these counties had a larger proportion of obese residents (34.5%) than Other Rural (28.4%) or Urban counties (24.9%). In adjusted analysis, the statistically significant association between persistent poverty and obesity was attenuated. Both individual characteristics (race, age) and county-level food availability and access factors were found to be significantly related to obesity. Improved access to quality food may be beneficial to residents of impoverished areas. PMID- 21665516 TI - Prototype cell-to-cell auxin transport mechanism by intracellular auxin compartmentalization. AB - Carrier-dependent, intercellular auxin transport is central to the developmental patterning of higher plants (tracheophytes). The evolution of this polar auxin transport might be linked to the translocation of some PIN auxin efflux carriers from their presumably ancestral localization at the endoplasmic reticulum (ER) to the polar domains at the plasma membrane. Here we propose an eventually ancient mechanism of intercellular auxin distribution by ER-localized auxin transporters involving intracellular auxin retention and switch-like release from the ER. The proposed model integrates feedback circuits utilizing the conserved nuclear auxin signaling for the regulation of PIN transcription and a hypothetical ER-based signaling for the regulation of PIN-dependent transport activity at the ER. Computer simulations of the model revealed its plausibility for generating auxin channels and localized auxin maxima highlighting the possibility of this alternative mechanism for polar auxin transport. PMID- 21665517 TI - The flip side: scientists who rock. AB - Many scientists play music. I'm one. I'm the rhythm guitar player, song writer, and singer in The Amygdaloids. We play original music about mind and brain and mental disorders. The songs are inspired by research that I do, as well as general ideas in the brain and cognitive sciences, and the philosophy of mind. For me, playing music is not a distraction to other life obligations. It makes me better at everything else I do. PMID- 21665518 TI - Different states in visual working memory: when it guides attention and when it does not. AB - Recent studies have revealed a strong relationship between visual working memory and selective attention, such that attention is biased by what is currently on our mind. However, other data show that not all memorized items influence the deployment of attention, thus calling for a distinction within working memory: whereas active memory items function as an attentional template and directly affect perception, other, accessory items do not. We review recent evidence that items compete for the status of 'attentional template' that contains only one object at a time. Neurophysiological results provide insight into these different memory states by revealing a more intricate organization of working memory than was previously thought. PMID- 21665519 TI - Scanning slit topography: diagnostic boon in presumed unilateral Terrien's marginal degeneration. AB - PURPOSE: To describe the scanning slit topography in two children with presumed unilateral Terrien's marginal degeneration. METHODS: Two girls aged 9 and 12 years presented with redness and reduced vision in their right eyes. The younger patient had scarring adjacent to the superior limbus, with vessels coursing across, and lipid deposition. Visual acuity improved to 20/20 from 20/400 with +1.0 -3.5*90 degrees . The older patient had similar features inferiorly. Her visual acuity improved to 20/20 from 20/40 with -3.5*65 degrees . Their left eyes were normal. A diagnosis of unilateral Terrien's Marginal Degeneration (TMD) was made. RESULTS: Scanning slit topography (Orbscan IITM, Orbscan Inc., Salt Lake City, UT) of the right eyes revealed high against-the-rule astigmatism. The left eyes showed elevations of anterior and posterior corneal surface above the best fit-sphere, skewing of principal meridians and increased astigmatism from 3.0 to 5.0mm zones. Based on these findings bilateral asymmetric TMD was diagnosed. CONCLUSION: Though the diagnosis of TMD is mainly clinical, scanning slit topography findings in TMD have not been described earlier and are useful in establishing the diagnosis of bilateral asymmetric TMD. PMID- 21665520 TI - Protein interactions with surfaces: Computational approaches and repellency. AB - Study of protein adsorption to solid surfaces continues to be substantial because of its role in cellular responses to biomaterials, interest in molecular aspects such as conformation and orientation, new methods for making protein repellent surfaces, and new application areas such as nanoparticles and microfluidics. This brief review is based only on very recent articles of particular interest to the authors, who each have worked in this area for some time. Simulations of protein interactions with surfaces and protein repellent surfaces are the only subtopics reviewed here. PMID- 21665521 TI - Molecular complexity and fragment-based drug discovery: ten years on. AB - We review the concept of molecular complexity in the context of the very simple model of molecular interactions that we introduced over ten years ago. A summary is presented of efforts to validate this simple model using screening data. The relationship between the complexity model and the problem of sampling chemical space is discussed, together with the relevance of these theoretical concepts to fragment-based drug discovery. PMID- 21665522 TI - Protein interactions with surfaces: cellular responses, complement activation, and newer methods. PMID- 21665523 TI - Risk subset of the survival for nasopharyngeal carcinoma patients with bone metastases: who will benefit from combined treatment? AB - Bone metastasis from nasopharyngeal carcinoma (NPC) is the most frequent type of distant metastasis (DM). The purpose of this study was to elucidate survival, prognostic factors, and significant of treatment in NPC patients with bone metastasis. A total of 221 patients who developed single type of DM from NPC at the first failure after primary treatment were retrospectively recruited from January 1998 to October 2000. The correlation between disease-free interval (DFI) and clinicopathologic features was assessed by the Chi-square test. Univariate and multivariate analyses of clinicopathologic variables were performed using Cox proportional hazards regression models. Actuarial survival rates were plotted against time using the Kaplan-Meier method, and log-rank testing was used to compare the differences between the curves. The median overall survival (OS) of the whole cohort and bone metastatic NPC patients were 38.5 and 33.3months, respectively. After univariate and multivariate analyses of clinicopathologic variables, age, local recurrence, subsequent metastasis, DFI and treatment modality were independently significant prognostic factors. The outcomes of bone metastatic NPC patients in low- and high-risk subset were significantly different (49.5 vs. 19.4months, P<0.001). In stratified survival analysis, compared to chemotherapy alone, chemoradiotherapy (CRT) could benefit the patients in low risk subset (P<0.001), but not those in high-risk subset (P=0.135). Our findings indicated that clinicopathologic variables could provide easily available prognostic factors for survival in NPC patients with bone metastasis. A subset of bone metastatic NPC patients would benefit from aggressive combined treatment and receive a long-term survival. PMID- 21665525 TI - Selective fluorescent probes based on CN isomerization and intramolecular charge transfer (ICT) for zinc ions in aqueous solution. AB - As the second most abundant transition-metal ion in the human body, Zn2+ plays crucial roles in many important biological processes; while in the environment, an excessive concentration of Zn2+ may reduce the soil microbial activity resulting in phytotoxic effects. Therefore, developing effective and sensitive detection method for Zn2+ has become crucially important and necessary both in life and environment science. Two new fluorescence probes, 2-((2 hydroxynaphthalen-1-yl)methyleneamino)-3-(1H-imidazol-5-yl) propanoic acid (2) and 2-hydroxy-2-((2-hydroxynaphthalen-1-yl) methyleneamino) acetic acid (3), were easily prepared by a one step reaction between 2-hydroxy-1-naphthaldehyde with histidine and serine, respectively, in ethanol. The optical properties of them were investigated by fluorescence spectra, which displayed specific and sensitive recognition to Zn2+ and especially avoided the interference of Cd2+ when they were tested against a range of physiological and environmentally relevant metal ions in aqueous solution. The responsive mechanism of the two probes to Zn2+ were involved both the CN isomerization and ICT, which were clarified by NBO charge analysis and the HOMO-LUMO energy gap calculation by using B3LYP/6-31G density functional theory. PMID- 21665524 TI - Co(II), Ni(II) and Cu(II) complexes with coumarin-8-yl Schiff-bases: spectroscopic, in vitro antimicrobial, DNA cleavage and fluorescence studies. AB - A new series of Co(II), Ni(II) and Cu(II) complexes of the type ML.2H2O of Schiff bases derived from m-substituted thiosemicarbazides and 8-acetyl-7-hydroxy-4 methylcoumarin have been synthesized and characterized by spectroscopic studies. Schiff-bases exhibit thiol-thione tautomerism wherein sulphur plays an important role in the coordination. The coordination possibility of the Schiff-bases towards metal ions have been proposed in the light of elemental analyses, spectral (IR, UV-vis, FAB-mass, ESR and fluorescence), magnetic and thermal studies. The low molar conductance values in DMF indicate that, the metal complexes are non-electrolytes. The cyclic voltammetric studies suggested that, the Cu(II) and Ni(II) complexes are of single electron transfer quasi-reversible nature. The Schiff-bases and its metal complexes have been evaluated for their in vitro antibacterial (Escherichia coli, Staphilococcus aureus, Bascillus subtilis and Salmonella typhi) and antifungal activities (Candida albicans, Cladosporium and Aspergillus niger) by MIC method. The Schiff-base I and its metal complexes exhibited DNA cleavage activity on isolated DNA of A. niger. PMID- 21665526 TI - Studies of the spin-Hamiltonian parameters and defect structures for Gd3+ ions in zircon-structure silicates MSiO4 (M=Zr, Hf, Th). AB - The spin-Hamiltonian parameters (g factors g?, g? and zero-field splittings b2(0), b4(0), b4(4), b6(0), b6(4)) for 4f7 ion Gd3+ at the tetragonal M4+ site of zircon-structure silicates MSiO4 (M=Zr, Hf, Th) are calculated from a diagonalization (of energy matrix) method. The Hamiltonian concerning this energy matrix contains the free-ion, crystal-field interaction and Zeeman interaction terms and the 56*56 energy matrix is constructed by considering the ground multiplet 8S7/2 and the excited multiplets 6L7/2 (L=P, D, F, G, H, I). The defect structures of Gd3+ centers in the three MSiO4 crystals are yielded from the calculation. The results are discussed. PMID- 21665527 TI - Two copper(II) complexes with 4-benzoylpyridine ligand: synthesis, crystal structure and luminescent properties. AB - Two new copper(II) complexes Cu(NCS)2(4-Bzpy)2 (1) and Cu(NO3)2(4-Bzpy)4 (2) (4 Bzpy=4-benzoylpyridine) have been synthesized and characterized by IR, UV, elemental analysis and X-ray crystallography. Cu(II) atom has a square planar environment for 1 and an distorted octahedral environment for 2, respectively. In solid state there are C-H?pi interactions and C-H?S hydrogen bonds between adjacent molecules in complex 1. The molecule of complex 2 is further connected by multiform pi-pi interactions, C-H?pi interactions and C-H?O hydrogen bonds to form a three-dimensional supramolecular structure. The luminescent properties of the complexes 1 and 2 were both investigated in H2O solution and in solid state at room temperature, respectively. PMID- 21665528 TI - Synthesis, experimental and theoretical characterization of palladium(II) and platinum(II) saccharinate complexes with 2-(2-pyridyl)benzimidazole. AB - New palladium(II) and platinum(II) complexes of saccharinate (sac) with 2-(2 pyridyl)benzimidazole (pybim) have been synthesized and characterized by elemental analysis and spectroscopic techniques. From the experimental studies, these complexes were formulated as [Pd(pybim)(sac)2] (1), and [Pt(pybim)(sac)2].4H2O (2). The ground-state geometries of both complexes were optimized using density functional theory (DFT) methods at the B3LYP level. A bidentate pybim ligand together with two N-coordinated sac ligands form the square-planar MN4 coordination geometry around the palladium(II) and platinum(II) ions. The calculated IR and UV-vis spectral data have been correlated to the experimental results. Thermal analysis data support the molecular structures of both complexes. PMID- 21665529 TI - Theoretical investigation for the EPR g-factors of the mixed ground state in NaCl: Ag2+ crystals. AB - In this paper, it is considered that the local structure of the (AgCl6)4- cluster for the NaCl: Ag2+ crystal is of the axially elongational D4h symmetry which possesses the weaker rhombic distortion at <001> lattice site. The mechanism for an admixture of the 2A1g into the ground state 2B1g is taken into account. The electron paramagnetic resonance (EPR) g factors of NaCl: Ag2+ are studied by using the double spin-orbit coupling model and an approximation of a semiempirical molecular orbit. The EPR g factors for the NaCl: Ag2+ crystals are reasonably explained as well as the good agreement between the calculated values and the experimental data is obtained. PMID- 21665530 TI - Quantification of complex precore mutations of hepatitis B virus by SimpleProbe real time PCR and dual melting analysis. AB - BACKGROUND: Hepatitis B virus (HBV) precore G1896A mutation is associated with Hepatitis B e antigen (HBeAg) seroconversion. This mutation and the adjacent G1899A mutation also appear to associate with increased risk of hepatocellular carcinoma. Quantitative mutant dynamics may help determine the potential of these mutants as clinical biomarkers. However, a reliable method to quantify either mutant is not available, partly because the viral genome has polymorphisms in general and the precore mutations are complex. OBJECTIVES: (1) To develop a reliable and ultrasensitive assay for the quantification of HBV G1896A and/or G1899A mutants. (2) To obtain preliminary data on the quantities of the precore mutants in patients. STUDY DESIGN: A SimpleProbe real time PCR assay was developed to quantify the HBV precore mutants. Dual melting analysis and a primer probe partial overlap approach were used to increase detection accuracy. A wild type selective PCR blocker was also developed to increase mutant detection sensitivity. RESULTS: The assay correctly identified the precore sequence from all 62 patient samples analyzed. More than 97% of precore sequences in the GenBank can be recognized. Mutant detection sensitivity reached 0.001% using a wild type-selective PCR blocker. At least one precore mutant can be detected from all 20 HBeAg-positive individuals who were negative for precore mutations by DNA sequencing. CONCLUSIONS: The reliability of this ultrasensitive mutation quantification assay was demonstrated. The same approaches may be useful for the detection of other clinically significant mutations. Evolution of the precore mutants warrants further studies. PMID- 21665531 TI - Effect of reassortment on the nucleotide and amino acid changes of human A/H3N2 RNP subunits during 1998-2009. AB - BACKGROUND: The ribonucleoprotein (RNP) complex of influenza virus consists of four subunits PB2, PB1, PA, and NP, which are essential for replication. While reassortment plays an important role in the evolution and virulence of influenza viruses, limited studies have investigated the effect of reassortment on the evolution of the internal RNP subunits. OBJECTIVE: To examine the effect of reassortment on the nucleotide and amino acid changes of human A/H3N2 RNP subunits during the period 1998-2009. STUDY DESIGN: A total of 240 A/H3N2 RNP subunit sequences were obtained from 23 clinical isolates in Australia and 217 isolates from National Centre for Biotechnology Information (NCBI) database. Rates of nucleotide change, amino acid substitution profile and phylogenetic analysis of each subunit during the 12-year period were determined using MEGA5. RESULT: A major reassortment event within the A/H3N2 RNP subunits occurred in 2003. The rates of nucleotide change for PB2, PB1 and PA differed significantly before and after 2003, and were low compared to surface protein haemagglutinin (HA). No change was observed for NP. The amino acid substitution profile of the RNP subunits during the 12-year period showed the presence of simultaneous amino acid fixations in a pattern similar to HA, with an average amino acid fixation rate of 1.57 years. CONCLUSION: Reassortment can affect the evolution of the influenza RNP subunits. Monitoring the amino acid substitution profile and evolution of the RNP subunits is necessary for the surveillance of future reassortments and emergence of potential virulence markers in the population. PMID- 21665533 TI - Dis-regulation of response inhibition in adult Attention Deficit Hyperactivity Disorder (ADHD): an ERP study. AB - OBJECTIVE: To define the brain activity involved in impaired response inhibition of Attention Deficit Hyperactivity Disorder (ADHD) in adults. METHODS: Performance measures and brain activity of 14 adult ADHD subjects and 14 controls, matched for age, gender, and overall intelligence were compared in an auditory Go-NoGo paradigm to tones. The task required a button press (Go) to 80% and inhibition of response (NoGo) to 20% of the tones, according to the tone's pitch. RESULTS: In NoGo trials ADHD subjects made significantly more commission errors compared to controls. ERPs of ADHD subjects showed smaller amplitudes of P3 (but not N2), and longer latencies of both N2 and P3. Source current density estimation revealed reduced activity in the right frontal dorsolateral cortex and in the posterior cingulate of the ADHD group. In addition, ADHD subjects showed an unexpected significantly enhanced response inhibition in Go trials, with excessive omission errors associated with significantly larger N2 amplitudes. CONCLUSION: In ADHD the neural networks sub-serving response inhibition are impaired. SIGNIFICANCE: ADHD is a general dis-regulation of behavioral inhibition, not limited to response inhibition. PMID- 21665532 TI - Extensive oral herpes simplex virus type 1 infection in a haematopoietic stem cell transplant recipient not responding to aciclovir. PMID- 21665534 TI - Improving working memory: exploring the effect of transcranial random noise stimulation and transcranial direct current stimulation on the dorsolateral prefrontal cortex. AB - OBJECTIVE: The aim of this study was to determine if working memory (WM) performance is significantly improved after the delivery of transcranial random noise stimulation (tRNS) to the left dorsolateral prefrontal cortex (DLPFC), compared to an active comparator or sham. METHODS: Ten participants undertook three experimental sessions in which they received 10 min of anodal tDCS (active comparator), tRNS or sham tDCS whilst performing the Sternberg WM task. Intra stimulation engagement in a WM task was undertaken as this has been previously shown to enhance the effects of tDCS. Experimental sessions were separated by a minimum of 1 week. Immediately prior to and after each stimulation session the participants were measured on speed and accuracy of performance on an n-back task. RESULTS: There was significant improvement in speed of performance following anodal tDCS on the 2-back WM task; this was the only significant finding. CONCLUSIONS: The results do not provide support for the hypothesis that tRNS improves WM. However, the study does provide confirmation of previous findings that anodal tDCS enhances some aspects of DLPFC functioning. Methodological limitations that may have contributed to the lack of significant findings following tRNS are discussed. SIGNIFICANCE: Anodal tDCS may have significant implications for WM remediation in psychiatric conditions, particularly schizophrenia. PMID- 21665535 TI - Essential involvement of the Bacillus subtilis ABC transporter, EcsB, in genetic transformation of purified DNA but not native DNA from protoplast lysates. AB - Involvement of the Bacillus subtilis ABC transporter EcsB in genetic transformation with native DNA from protoplast lysate (LP transformation) was investigated using an ecsB deletion mutant constructed by fusion polymerase chain reaction. In these experiments, the non-transformability phenotype of the ecsB mutant was reversed and high numbers of transformants generated (1.5*10(5)/MUg DNA). The relative efficiency of transformation (RET) of ecsB to wild type (1.2*10(-2)) was a thousand times higher using native chromosomal DNA than the RET obtained from purified DNA (<8.6*10(-6)). Similar transformation efficiencies were observed using native plasmid DNA. These results rule out a primary role for EcsB as a competence gene regulator. DNA-binding proteins attached to native DNA are not present in purified DNA preparations, and it is possible that such proteins could account for the transformability of the ecsB mutant. Because EcsB may play a role in protein(s) export, we tested exogenous proteins to identify functional replacements. We found that bovine serum albumin (fraction V) partially suppressed the phenotype of the ecsB mutation, leading to transformability with purified DNA. Linkage analysis of the ecsB mutant by LP co transformation produced a higher co-transformation ratio (42% and 20%) at a distance of 34kb and 121kb in the ecsB mutant, compared to the wild-type strain, AYG2 (30.5% and 12.3%). The stimulatory linkage effect observed could be derived from a regulating gene involved in homologous recombination. PMID- 21665536 TI - The impact of blue space on human health and well-being - Salutogenetic health effects of inland surface waters: a review. AB - Water is one of the most important physical, aesthetic landscape elements and possesses importance e.g. in environmental psychology, landscape design, and tourism research, but the relationship between water and health in current literature is only investigated in the field of environmental toxicology and microbiology, not explicitly in the research field of blue space and human well being. Due to the lack of a systematic review of blue space and well-being in the various fields of research, the aim of this review is to provide a systematic, qualitative meta-analysis of existing studies that are relevant to this issue. Benefits for health and well-being clearly related to blue space can be identified with regard to perception and preference, landscape design, emotions, and restoration and recreation. Additionally, direct health benefits have already been stated. The studies included in the review are mostly experimental studies or cross-sectional surveys, focusing on students as the subject group. There is a need for more qualitative and multi-faceted, interdisciplinary studies, using triangulation as a method to achieve a resilient image of reality. A broader study design considering all age groups would contribute to identifying benefits for the whole of society. The inattentiveness to blue space makes it difficult to measure long-term effects of blue space on well-being. There is still little respect for water and health in planning issues, although salutogenetic health benefits can be identified. To close the gap regarding missing systematic concepts, a concept for assessing salutogenetic health effects in blue space is provided. Blue space is considered therein as a multi-dimensional term including four dimensions of appropriation, as well as at least five ontological dimensions of substantiality. The aim of the concept is to support researchers and practitioners analysing health effects in blue space. PMID- 21665537 TI - High prevalence of enteric viruses in untreated individual drinking water sources and surface water in Slovenia. AB - Waterborne infections have been shown to be important in outbreaks of gastroenteritis throughout the world. Although improved sanitary conditions are being progressively applied, fecal contaminations remain an emerging problem also in developed countries. The aim of our study was to investigate the prevalence of fecal contaminated water sources in Slovenia, including surface waters and groundwater sources throughout the country. In total, 152 water samples were investigated, of which 72 samples represents groundwater from individual wells, 17 samples from public collection supplies and 63 samples from surface stream waters. Two liters of untreated water samples were collected and concentrated by the adsorption/elution technique with positively charged filters followed by an additional ultracentrifugation step. Group A rotaviruses, noroviruses (genogroups I and II) and astroviruses were detected with real-time RT-PCR method in 69 (45.4%) out of 152 samples collected, of which 31/89 (34.8%) drinking water and 38/63 (60.3%) surface water samples were positive for at least one virus tested. In 30.3% of drinking water samples group A rotaviruses were detected (27/89), followed by noroviruses GI (2.2%; 2/89) and astroviruses (2.2%; 2/89). In drinking groundwater samples group A rotaviruses were detected in 27 out of 72 tested samples (37.5%), genogroup I noroviruses in two (2.8%), and human astroviruses in one (1.4%) samples. In surface water samples norovirus genogroup GII was the most frequently detected (41.3%; 26/63), followed by norovirus GI (33.3%; 21/63), human astrovirus (27.0%; 17/63) and group A rotavirus (17.5%; 11/63). Our study demonstrates relatively high percentage of groundwater contamination in Slovenia and, suggests that raw groundwater used as individual drinking water supply may constitute a possible source of enteric virus infections. In the future, testing for enteric viruses should be applied for drinking water sources in waterborne outbreaks. PMID- 21665538 TI - Lack of risk-awareness and reporting behavior towards HIV infection through needlestick injury among European medical students. AB - Medical students are at risk for occupational needlestick injuries (NSIs) which can result in substantial health consequences and psychological stress. Therefore, an open online survey among final year medical students from Austria, Germany, and the United Kingdom (UK) was conducted. The aim of the study was to evaluate risk-awareness and reporting behavior regarding needlestick injury (NSI), post-exposure prophylaxis, and level of education regarding the transmission of HIV through NSIs. Of 674 medical students, 226 (34%) reported at least one NSI during medical school. Respondents from Austria and Germany experienced a significantly higher number of NSIs in comparison to respondents from the UK. Seventy-six respondents (34%) did not report their most recent injury to an employee health office. Almost one third were not familiar with reporting procedures in case of a NSI and 45% of the study population feared that reporting an injury might have an adverse effect on their study success. 176 respondents (78%) who had suffered a NSI were not aware of the patient's HIV status. Education regarding NSIs and HIV transmission reduced the actual risk of experiencing a NSI significantly. These data indicate that medical students are at high risk of suffering NSIs during medical school. The rate of nonreporting of such injuries to an employee health service is alarmingly high. Improved medical curricula including precise recommendations may contribute to a more efficient prevention of occupational HIV infection in medical students. PMID- 21665539 TI - New insights into an ancient insect nose: the olfactory pathway of Lepismachilis y-signata (Archaeognatha: Machilidae). AB - Hexapods most likely derived from an aquatic ancestor, which they shared with crustaceans. During the transition from water to land, their sensory systems had to face the new physiological demands that terrestrial conditions impose. This process also concerns the sense of smell and, more specifically, detection of volatile, air-borne chemicals. In insects, olfaction plays an important role in orientation, mating choice, and food and host finding behavior. The first integration center of odor information in the insect brain is the antennal lobe, which is targeted by the afferents from olfactory sensory neurons on the antennae. Within the antennal lobe of most pterygote insects, spherical substructures called olfactory glomeruli are present. In order to gain insights into the evolution of the structure of the central olfactory pathway in insects, we analyzed a representative of the wingless Archaeognatha or jumping bristletails, using immunocytochemistry, antennal backfills and histological section series combined with 3D reconstruction. In the deutocerebrum of Lepismachilis y-signata, we found three different neuropil regions. Two of them show a glomerular organization, but these glomeruli differ in their shape from those in all other insect groups. The connection of the glomerular neuropils to higher brain centers remains unclear and mushroom bodies are absent as reported from other archaeognathan species. We discuss the evolutionary implications of these findings. PMID- 21665540 TI - Effects of cryopreservation and density-gradient washing on phospholipase C zeta concentrations in human spermatozoa. AB - Cryopreservation and density-gradient washing (DGW) are routinely used in infertility treatment. This study used quantitative immunofluorescence analysis to report how these techniques affect concentrations of the oocyte activation factor, phospholipase C zeta (PLCzeta) in spermatozoa from fertile men. DGW significantly elevated the proportion of spermatozoa in which PLCzeta could be detected (by 25-81%; P < 0.0001). In contrast, in four donors, cryopreservation significantly reduced PLCzeta concentrations (by 20-56%; P < 0.0001). These findings indicate that while DGW positively selects spermatozoa with detectable PLCzeta, cryopreservation has significant detrimental effects upon PLCzeta concentrations. Since reduced PLCzeta concentrations have been implicated in deficient oocyte activation and infertility, further study is highly warranted. PMID- 21665541 TI - Corifollitropin alfa doses based on body weight: clinical overview of drug exposure and ovarian response. AB - Corifollitropin alfa is a new recombinant gonadotrophin with a different pharmacokinetic profile but similar pharmacodynamic properties to conventional recombinant FSH. A single dose of corifollitropin alfa sustains multiple follicular development during the first 7 days of ovarian stimulation. This review is based on results of phase II and III trials testing the selected dose of 150 MUg corifollitropin alfa in subjects >60 kg and 100 MUg in subjects <=60 kg. Exposure to corifollitropin alfa is inversely related to bodyweight. The selected doses of 100 and 150 MUg in subjects weighing <=60 and >60 kg, respectively, provide, on average, equal drug exposure producing similar ovarian responses in terms of the number of growing follicles, serum oestradiol, inhibin B and number of oocytes retrieved. Clinicians treating IVF patients with corifollitropin alfa should alter their treatment paradigm as a lower or higher dose than recommended according to body weight does not affect the ovarian response, which depends mainly on the ovarian reserve. After decades of daily dosing with FSH preparations, corifollitropin alfa allows a simpler IVF treatment regime with fewer injections. Successful use of corifollitropin alfa requires assessment of patient suitability and dosing before the start of stimulation. PMID- 21665542 TI - Conventional ovarian stimulation no longer exists: welcome to the age of individualized ovarian stimulation. AB - The prediction of extremes of ovarian response to stimulation and the irreversibility of reduced ovarian reserve remain important clinical and basic science research issues of IVF treatment. Recommending commencement of ovarian stimulation using any of the available exogenous compounds without knowledge of individual ovarian potentials is simplistic and dangerous because of the possible adverse consequences for the woman. The identification of groups of patients likely to benefit from one protocol than another is central to the workup process of IVF. Determining the agents for ovarian stimulation as well as the combination of them, the daily dose and duration according to some background information should be seen as the way to enhance safety and cost-effectiveness. This discussion paper aims to introduce the concept of individualized ovarian stimulation in routine clinical practice and to generate interest for tailored stimulation protocols. PMID- 21665543 TI - The fine structure of human germ layers in vivo: clues to the early differentiation of embryonic stem cells in vitro. AB - The fine structure of the three germ layers in human ectopic embryos (stage 7) have been documented by digital light and electron microscopy. The formation of ectoderm, endoderm and mesoderm and notochordal cells, and also the extraembryonic membranes, amnion and yolk sac, are imaged. The germ layers give rise to all the cells and tissues of the human body. Possible clues to the early differentiation of embryonic stem cells (ESC) in vitro were obtained, since these events are more or less mimicked in cultures of ESC derived from the inner cell mass of human blastocysts. The findings are discussed with reference to previous studies on the fine structure of ESC using the same technique. PMID- 21665544 TI - Histidine-rich glycoprotein polymorphism and pregnancy outcome: a pilot study. AB - Histidine-rich glycoprotein (HRG) is involved in fibrinolysis and coagulation, the immune system and angiogenesis. These processes are all crucial in establishing and maintaining pregnancy. The primary aim of this pilot study was to determine if HRG affects pregnancy outcome. The secondary aim was to investigate if a specific genetic polymorphism (rs9898 C/T) in the HRG gene is associated with pregnancy results. The polymorphism leads to expression of either a serine or proline residue at position 186 in the protein sequence. In this study, women undergoing IVF were included. The genetic polymorphism in the HRG gene was analysed by Western blot and single nucleotide polymorphism analysis. None of the women homozygous for the serine at residue 186 became pregnant whereas the women homozygous for proline at residue 186 had higher than expected pregnancy rates. As far as is known,this is the first study to show that a specific genetic polymorphism in the HRG gene of a woman affects her chances of becoming pregnant after IVF. The results may be essential in improving advice and IVF treatment for couples with unexplained infertility. PMID- 21665545 TI - Adverse effects of hepatitis B virus on sperm motility and fertilization ability during IVF. AB - The consequences of hepatitis B virus (HBV) infection for fertility are still unclear. Spermatozoa with decreased motility have been reported in HBV-infected patients. It has been demonstrated in vitro that HBV S protein has adverse effects on human sperm function with consequences for fertilization. In a case control study design, 32 IVF cycles in couples with male HBV infection were compared with 64 cycles in non-infected couples, matched for age, time period, cycle rank and sperm parameters on the day of oocyte retrieval. Sperm motility before selection was significantly reduced in the HBV group (36.3 +/- 11.6% versus 45.3 +/- 14.4%,P = 0.003). A low fertilization rate (LFR) was more frequently observed in the HBV group (34.4% versus 15.6%, P = 0.036) and was associated with a decreased number of embryos available for transfer, although embryo quality on day 2 or 3 was not different.Implantation and pregnancy rates were comparable between groups. This study shows that HBV has a deleterious effect on sperm motility in vivo and that couples whose male partner is infected have a higher risk of LFR after IVF, a risk which is independent from the initial sperm motility. PMID- 21665546 TI - Preovulatory progesterone concentration associates significantly to follicle number and LH concentration but not to pregnancy rate. AB - Using data from a large prospective randomized controlled trial that evaluated the effect of recombinant LH (rLH)co-administration for ovarian stimulation, the present study assessed whether progesterone concentration on the day of human chorionic gonadotrophin (HCG) administration was associated with pregnancy outcome. Progesterone concentration was measured on stimulation day 1 and on the day of HCG administration in 475 patients who underwent IVF/intracytoplasmic sperm injection treatment following ovarian stimulation with gonadotrophin releasing hormone (GnRH) agonist and recombinant FSH with or without rLH administration from day 6 of stimulation. There was no significant association between the late-follicular-phase progesterone concentration and the clinical pregnancy rate. However, progesterone concentration was strongly associated with the number of follicles and retrieved oocytes. Late-follicular-phase LH concentration also showed a significant positive association with progesterone concentration (P = 0.018). Administration of rLH during ovarian stimulation did not affect progesterone concentration. The present study does not support an association between progesterone concentration on the day of HCG administration and the probability of clinical pregnancy in women undergoing ovarian stimulation with GnRH agonists and gonadotrophins for assisted reproduction treatment.Instead, late-follicular-phase progesterone concentration appears to be governed by the number of preovulatory follicles and LH concentration. PMID- 21665547 TI - Gonadotrophin ovulation induction and enhancement outcomes: analysis of more than 1400 cycles. AB - Ovulation induction (OI) or ovulation enhancement (OE) with gonadotrophins can be a reasonable treatment option for patients with a variety of infertility diagnoses. It must be used with extensive monitoring and management given the risk of multiple pregnancy,especially high-order multiples. This retrospective study evaluated per cycle outcomes of a large cohort of 1452 gonadotrophin OI/OE cycles at an academic infertility centre, and the efficacy of specific guidelines in limiting multiple pregnancy. The lowest possible gonadotrophin doses were used and cycle cancellation was recommended if more than three dominant follicles were present, and/or ifserum oestradiol was above 1500 pg/ml. Overall, pregnancy rate (PR) was 12% and live birth rate was 7.7%, with an increasing trend in younger patients (P = 0.0002 and <0.0001, respectively). Multiple clinical PR was 2.6% with 1.9% twins and 0.7% triplets and above.The birthweight of a singleton from a vanishing twin pregnancy (n = 8)was significantly lower than other singletons (2882 g versus 3250 g,P = 0.013). Reducing multiple pregnancies from OI/OE cycles remains an important and challenging goal. In this large cohort, high-order multiple clinical PR was limited to 0.7% per cycle by using specific management strategies while maintaining a reasonable PR. PMID- 21665548 TI - Methodology matters: IVF versus ICSI and embryonic gene expression. AB - The use of assisted reproduction treatment, especially intracytoplasmic sperm injection (ICSI), is now linked to a range of adverse consequences, the aetiology of which remains largely undefined. Our objective of this study was to determine differences in gene expression of blastocysts generated by ICSI as well as ICSI with artificial oocyte activation (ICSI-A) versus the less manipulative IVF, providing fundamental genetic information that can be used to aid in the diagnosis or treatment of those adversely affected by assisted reproduction treatment, as well as stimulate research to further refine these techniques. Murine blastocysts were generated by ICSI, ICSI-A and IVF, and processed for a microarray-based analysis of gene expression. Ten blastocysts were pooled for each procedure and three independent replicates generated. The data were then processed to determine differential gene expression and to identify biological pathways affected by the procedures. In blastocysts derived by ICSI versus IVF, the expression of 197 genes differed (P < 0.01). In blastocysts derived by ICSI-A versus IVF and ICSI-A versus ICSI, the expression of 132 and 65 genes differed respectively (P < 0.01). Procedural-induced changes in genes regulating specific biological pathways revealed some consistency to known adverse consequences. Detailed investigation of procedure-specific dysfunction is therefore warranted. PMID- 21665549 TI - Measuring perceived barriers to healthful eating in obese, treatment-seeking adults. AB - OBJECTIVE: To characterize perceived barriers to healthful eating in a sample of obese, treatment-seeking adults and to examine whether changes in barriers are associated with energy intake and body weight. DESIGN: Observational study based on findings from a randomized, controlled behavioral weight-loss trial. PARTICIPANTS: Participants were 113 women and 100 men, mean age 48.8 years, 67% white, and mean body mass index at baseline 34.9 kg/m(2). VARIABLES MEASURED: Perceived diet barriers were assessed using a 39-item questionnaire. Energy intake was assessed with the Block Food Frequency Questionnaire. Body weight (kg) and height (cm) were measured. ANALYSIS: Factor-based scales constructed from exploratory factor analysis. Linear regression models regressed 12-month energy intake and body weight on baseline to 12-month factor-based score changes (alpha = .05). RESULTS: Exploratory factor analysis yielded 3 factors: lack of knowledge, lack of control, and lack of time. Reported declines in lack of knowledge and lack of control from baseline to 12 months were associated with significantly greater energy restriction over 12 months, whereas reported declines in lack of control and lack of time were associated with significantly greater weight loss. CONCLUSIONS AND IMPLICATIONS: Results suggest that declines in perceived barriers to healthful eating during treatment are associated with greater energy restriction and weight loss. PMID- 21665550 TI - Adolescent weight status and receptivity to food TV advertisements. AB - OBJECTIVE: This study examined the relationship between adolescent weight status and food advertisement receptivity. DESIGN: Survey-based evaluation with data collected at baseline (initial and at 2 months), and at follow-up (11 months). SETTING: New Hampshire and Vermont. PARTICIPANTS: Students (n = 2,281) aged 10-13 in 2002-2005. MAIN OUTCOME MEASURE: Overweight. ANALYSIS: Generalized estimating equations to model the relationship between identifying a food advertisement as their favorite and being overweight. RESULTS: Overall, 35.9% of the adolescents were overweight. Less than one fifth named a food advertisement as their favorite (16.1%). Most of the food advertisements were for less-healthful food (89.6%). After controlling for school, age, sex, sociodemographics, physical activity, number of TV sessions watched, and having a TV in the bedroom, overweight adolescents were significantly less likely to be receptive to food advertisements (relative risk = 0.83, 95% confidence interval 0.70, 0.98) compared to non overweight adolescents. CONCLUSIONS AND IMPLICATIONS: This study provides preliminary evidence that normal-weight adolescents are receptive to unhealthful food advertisements. Longitudinal studies are needed to evaluate whether consistent exposure to advertisements for unhealthful food, particularly if they are promoted with healthful behaviors such as being physically active, influence adolescents' food choices, and ultimately their body mass index, over the long term. PMID- 21665551 TI - Sudden unexpected death in epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) has an incidence ranging between 0.09 and 9 per 1000 patient-years depending on the patient population and the study methodology. It is the commonest cause of death directly attributable to epilepsy, and occurs at or around the time of a seizure. The principal risk factor for SUDEP is poorly controlled generalized tonic-clonic seizures. Other risk factors include polytherapy, male sex, early age at onset of epilepsy, symptomatic etiology, and, possibly, treatment with lamotrigine. The mechanisms underlying SUDEP are poorly understood, but autonomic dysfunction, central apnea, cerebral depression, and cardiac arrthymias have all been described in animal models of SUDEP and during human seizures. Prevention of this fatal event should be aimed at optimizing control of seizures, including prompt referral for consideration of epilepsy surgery. All patients should be told about the risks of SUDEP and informed that complete seizure control appears to be the one proven way of preventing the phenomenon. PMID- 21665552 TI - Vibration-induced afferent activity augments delayed onset muscle allodynia. AB - Evidence suggests large diameter afferents, presumably in response to centrally mediated changes, augment the mechanical allodynia or hyperalgesia seen in delayed onset muscle soreness (DOMS) conditions. Healthy males aged 18 to 30 (n = 16) performed eccentric exercise eliciting DOMS in the tibialis anterior muscle of a randomly assigned exercised leg. The contralateral leg served as a control. Mechanosensitivity was assessed on the exercised and control legs prior to and 24 hours postexercise via pressure pain thresholds (PPTs). PPTs were assessed at the muscle site, and at a distant segmentally related site, either without vibration or with vibration concurrently applied to the distant muscle, segmentally related, or control extra-segmentally related site. Participants completed a 6 point Likert scale providing a subjective measure of DOMS 5 days postexercise. Baseline mechanosensitivity was not significantly different at any site between the exercised and control legs prior to the exercise. Soreness ratings were higher 24 to 48 hours postexercise (P < .05), and baseline PPTs at the exercised legs muscle site decreased postexercise (P < .001). On day 1 following exercise, segmentally related site PPTs reduced significantly when vibration was applied concurrently to the DOMS affected tibialis anterior muscle (P < .04) compared to baseline mechanosensitivity or extrasegmental control vibration. PERSPECTIVE: Further evidence is presented by this article indicating that large diameter afferents, presumably via centrally mediated mechanisms, augment the mechanical hyperalgesia seen in DOMS conditions. Future research examining eccentric activity in individuals with likely centrally sensitized conditions may be warranted. PMID- 21665553 TI - Three-dimensional image-based high-dose-rate interstitial brachytherapy for vaginal cancer. AB - PURPOSE: To evaluate dosimetric and clinical outcomes of three-dimensional (3D) image-based high-dose-rate (HDR) interstitial brachytherapy (HDRB) in patients with vaginal cancers. METHODS AND MATERIALS: Thirty patients with vaginal cancers were treated with HDRB using Syed-Neblett template. CT scan was done after placement of needles for confirmation of placement and treatment planning. The target volume and organs at risk, including clinical target volume (CTV), rectum, bladder, and sigmoid colon, were contoured on CT scans. Twenty-eight (93.3%) patients received external beam radiation therapy at a median 45 (24.0-50.4)Gy in 12-28 fractions, followed by HDRB at 3.75-5.0Gy per fraction in five fractions. Total doses for CTV and organs at risk from external beam radiation therapy and HDRB were summated and normalized to a biologically equivalent dose of 2Gy per fraction. RESULTS: Seventeen patients (56.7%) with primary vaginal cancer and 13 patients (43.3%) with recurrent vaginal cancers were treated with 3D HDRB. The mean CTV was 39.3+/-25.7 cm(3), and the median tumor diameter was 3.3 (1.3 8.0)cm. The median biologically equivalent dose of 2Gy per fraction for 2cc of bladder, rectum, and sigmoid was 55.0, 56.3, 50.0Gy, respectively. The median D(90) for high-risk CTV was 74.3 (36.3-81.1)Gy. The mean volume receiving 100%, 150%, and 200% of prescribed dose was 90.7+/-10.0%, 41.3+/-14.6%, and 17.7+/ 8.3%, respectively. With a median followup of 16.7 months, the respective 1-/2 year locoregional and overall survival rates were 84.4%/78.8% and 82.1%/70.2%, respectively. There were no Grade >=3 gastrointestinal complications. Late complications of Grade 3 vaginal ulceration and Grade 4 vaginal necrosis were seen in two cases. CONCLUSIONS: Initial results of 3D HDRB using our fractionation schedule in the treatment of vaginal cancers showed good local response with acceptable morbidities. PMID- 21665554 TI - Presymptomatic apolipoprotein E genotyping for Alzheimer's disease risk assessment and prevention. AB - Current practice guidelines advocate apolipoprotein E (APOE) genotyping in cases of dementia and mild cognitive impairment and also in asymptomatic participants within the context of clinical/epidemiological research. APOE genotyping is not recommended for prognostication in cognitively intact persons outside the research arena. On the basis of emerging developments, in this article, we revisit the notion that presymptomatic APOE testing might be medically appropriate and ethical for the purpose of Alzheimer's disease (AD) risk assessment and prevention. In support of this thesis, recent evidence is adduced indicating that (i) the potency of potentially modifiable AD determinants and responsiveness to intervention may be affected by the presence or absence of the epsilon4 allele, (ii) disclosure of APOE status to asymptomatic individuals seeking AD risk assessment is well tolerated when appropriate safeguards are in place, and (iii) awareness of personal AD risk in general, and APOE status in particular, may motivate individuals to engage in beneficial, risk-lowering behaviors. PMID- 21665555 TI - RP-HPLC method for quantitative determination of cystathionine, cysteine and glutathione: An application for the study of the metabolism of cysteine in human brain. AB - The RP-HPLC method for a simultaneous separation and quantitation of the dinitrophenyl derivative of cystathionine (N,N'-di-DNP) in biological samples together with GSH, GSSG, cysteine and cystine, provides a very useful tool for investigation of the transsulfuration pathway in biological samples, at the same providing results which reflect the redox status (GSH/GSSG ratio) and the potential of the generation of H2S. An application of the method for the study of the process of transsulfuration in various human brain regions shows the presence of cystathionine in all the investigated regions; it also demonstrates that cystathionine levels vary greatly between particular regions. The highest level in the thalamus and the lowest in the cerebellum were associated with respectively a low or high gamma-cystathionase activity, and at the same time, a high cysteine and GSH level in the thalamus and a low value in the cerebellum. Based on the above results, one may suggest a regulatory mechanism responsible for inhibition of the CGL activity at high concentration values of cysteine and/or GSH. Simultaneous determinations of GSH and GSSG levels allow for determining the GSH/GSSG ratio, which reflects tissue redox status. The method may be also employed in determining the activity of gamma-cystathionase and cystathionine-beta synthase. PMID- 21665556 TI - Simultaneous analysis of chlorpyrifos and cypermethrin in cord blood plasma by online solid-phase extraction coupled with liquid chromatography-heated electrospray ionization tandem mass spectrometry. AB - Chlorpyrifos and cypermethrin are the most used insecticides in Taiwan. Exposure to both pesticides has been associated with reproductive and developmental health effects in humans and animals. This study describes an online solid-phase extraction coupled with liquid chromatography-heated electrospray ionization tandem mass spectrometry (online SPE-LC/HESI/MS/MS) method to analyze chlorpyrifos and cypermethrin in cord blood of pregnant women. Calibration curves showed good linearity (r2 > 0.998) for both pesticides within the range of 0.1 100 ppb. Limits of detection (LODs) were 0.01 and 0.05 ppb and recoveries in cord blood were 97.2 +/- 4.8% and 93.5 +/- 9.5% for chlorpyrifos and cypermethrin respectively. After analysis of 396 samples, the mean concentrations of chlorpyrifos and cypermethrin were 0.38 and 1.08 ppb respectively. These results demonstrate that LC/HESI/MS/MS is effective for the simultaneous analysis of chlorpyrifos and cypermethrin in cord blood with excellent sensitivity and specificity and may also be effective for high throughput assay in future epidemiology studies. PMID- 21665557 TI - An HPLC method for the pharmacokinetic study of vincristine sulfate-loaded PLGA PEG nanoparticle formulations after injection to rats. AB - The aim of this study is to develop a simple and applicable HPLC method for the detection of vincristine in rat plasma after administration of poly(lactic-co glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles loaded with vincristine sulfate (VCR). Vincristine was extracted from rat plasma and vinblastine sulfate was chosen as the internal standard (IS). Chromatographic separation of VCR and IS was achieved by a Dikma Dimonsil C18 column (200 mm*4.6 mm) with the mobile phase consisting of 0.02 M sodium dihydrogen phosphate methanol (36:64, v/v, pH=4.7) at a flow rate of 1.0 mL/min. The ultraviolet detection wavelength was set at 276 nm. The calibration curve was linear over a concentration range of 0.05-5.0 MUg/mL. The intra-day and inter-day accuracy for three quality controls (QC) samples was 93.48-107.74% and 92.61-96.58%, respectively; the precision was less than 9%. The average method recoveries for vincristine from spiked plasma at all QC levels were over 83%; and extraction recoveries were between 66 and 70%. Vincristine was stable in rat plasma for one month at -80 degrees C, for 8 h at room temperature, as well as during three freeze-thaw cycles. This HPLC method was applied successfully to the pharmacokinetic study of vincristine in rats after a single intravenous injection of VCR in physiological saline (F-VCR) solution, VCR-loaded PLGA-mPEG nanoparticles with (NP1) and PLGA-PEG-folate nanoparticles (NP2) suspension, respectively. There were significant differences in main pharmacokinetic parameters between F-VCR and the nanoparticles. Both kinds of VCR-loaded nanoparticles displayed improved pharmacokinetic profiles. PMID- 21665558 TI - Coeliac disease and suicide risk: facts or artefacts? PMID- 21665559 TI - Endoscopic ultrasound fine needle aspiration of pancreatic lesions: is a smaller needle safer and better? PMID- 21665560 TI - Mitochondrial disorders in the perinatal period. PMID- 21665561 TI - Islanded pedicled superior epigastric artery perforator flaps for bilateral breast augmentation with mastopexy after massive weight loss. AB - OBJECTIVE: To present a surgical technique of recruiting tissue from the abdominal wall, based on the superior epigastric artery perforators, in order to provide autologous augmentation of the breasts with mastopexy in patients after massive weight loss. CASE REPORT: A 39-year-old woman presented to the plastic surgery outpatient clinic with significant bilateral breast deformity following massive weight loss of 85.5 kg. She was dissatisfied with the appearance of her breasts and abdomen despite previous Fleur-de-lis abdominoplasty. On examination, the patient had major ptosis with a deflated breast skin envelope and near-total absence of breast volume. She had insignificant brachial skin excess and limited excess of the lateral chest wall. There was a large element of residual skin redundancy in her upper abdomen. SURGICAL TECHNIQUE: Bilaterally, islanded superior epigastric artery perforator flaps were harvested from the epigastric region. In addition, turnover flaps were raised from the lateral chest wall. Inferior pedicled mastopexy was performed and the flaps were secured to the anterior chest wall in order to augment the breasts. CONCLUSIONS: The islanded pedicled superior epigastric artery perforator flap is a useful technique for utilising the upper epigastric abdominal excess to augment the breasts following previous massive weight loss, obviating the need for implants and therefore eliminating potential implant-related complications. PMID- 21665562 TI - The effects of topically applied silicone gel and its silver derivative on the prevention of hypertrophic scarring in two rabbit ear-scarring models. AB - Topically applied silicone gel is an effective treatment in the management of hypertrophic scars. This early study of silicone gel predates other well controlled scientific studies that demonstrate these findings. Our well established rabbit ear scarring model creates 7 mm punch wounds down to the bare cartilage, including the removal of the perichondrium. In this study, we employ a new model that creates 10 mm punch wounds that leaves the perichondrium intact. Both the 7 mm and new 10 mm scar models were used to study the effectiveness of silicone gel and silicone gel silver respectively on hypertrophy and the inhibition of scar formation. All samples were harvested at post-wounding day 35 for histological analysis. Silicone gel significantly reduced scar area (p=0.005), scar elevation index (p=0.03), and epidermal area (p=0.016). Silicone gel silver significantly reduced scar elevation index (p=0.004). The new 10 mm scar model resulted in more hypertrophic scarring than the typical, 7 mm wound scar model (p=0.0001). In conclusion, silicone gel and its silver derivative are effective in preventing hypertrophic scarring and scar models that leave the perichondrium intact causes scars with more hypertrophy. PMID- 21665563 TI - A lupus-like syndrome induced by infliximab treatment. PMID- 21665565 TI - Ambient particulate matter induces interleukin-8 expression through an alternative NF-kappaB (nuclear factor-kappa B) mechanism in human airway epithelial cells. AB - BACKGROUND: Exposure to ambient air particulate matter (PM) has been shown to increase rates of cardiopulmonary morbidity and mortality, but the underlying mechanisms are still not well understood. OBJECTIVE: We examined signaling events involved in the expression of the inflammatory gene interleukin-8 (IL-8) in human airway epithelial cells (HAECs) exposed to ambient PM collected in an urban area of Mexicali, Mexico. METHODS: We studied IL-8 expression and regulatory signaling pathways in cultured HAECs exposed to Mexicali PM suspended in media for 0-4 hr. RESULTS: Exposure resulted in a dose-dependent, 2- to 8-fold increase in IL-8 mRNA expression relative to controls. PM exposure induced IL-8 transcriptional activity in BEAS-2B cells that was dependent on the nuclear factor-kappa B (NF kappaB) response element in the IL-8 promoter. Chromatin immunoprecipitation (ChIP) assays showed a 3-fold increase in binding of the p65 (RelA) NF-kappaB isoform to the IL-8 promoter sequence in HAECs exposed to PM. Western blot analyses showed elevated levels of phosphorylation of p65 but no changes in IkappaBalpha phosphorylation or degradation. IL-8 expression was blunted in a dose-dependent manner in BEAS-2B cells transduced with a lentivirus encoding a dominant negative p65 mutant in which phosphorylation sites were inactivated. CONCLUSION: Taken together, these findings show that the increase in IL-8 mRNA expression in HAECs exposed to PM10 (PM <= 10 MUm in aerodynamic diameter) is mediated through an NF-kappaB-dependent signaling mechanism that occurs through a pathway involving direct phosphorylation of the transcription factor p65 in the absence of IkappaBalpha degradation. These data show that exposure to PM10 in ambient air can induce inflammatory responses by activating specific signaling mechanisms in HAECs. PMID- 21665566 TI - Serum perfluorinated compound concentration and attention deficit/hyperactivity disorder in children 5-18 years of age. AB - BACKGROUND: Perfluorinated compounds (PFCs) are persistent environmental pollutants. Toxicology studies demonstrate the potential for perfluorooctanoic acid (PFOA) and other PFCs to affect human growth and development. Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder with suspected environmental and genetic etiology. OBJECTIVES: We examined the cross-sectional association between serum PFC concentration and parent or self-report of doctor diagnosed ADHD with and without current ADHD medication. METHODS: We used data from the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community highly exposed to PFOA through contaminated drinking water, to study non-Hispanic white children 5-18 years of age. Logistic regression models were adjusted for age and sex. RESULTS: Of the 10,546 eligible children, 12.4% reported ADHD and 5.1% reported ADHD plus ADHD medication use. We observed an inverted J-shaped association between PFOA and ADHD, with a small increase in prevalence for the second quartile of exposure compared with the lowest, and a decrease for the highest versus lowest quartile. The prevalence of ADHD plus medication increased with perfluorohexane sulfonate (PFHxS) levels, with an adjusted odds ratio of 1.59 (95% confidence interval, 1.21-2.08) comparing the highest quartile of exposure to the lowest. We observed a modest association between perfluorooctane sulfonate and ADHD with medication. CONCLUSIONS: The most notable finding for PFOA and ADHD, a reduction in prevalence at the highest exposure level, is unlikely to be causal, perhaps reflecting a spurious finding related to the geographic determination of PFOA exposure in this population or to unmeasured behavioral or physiologic correlates of exposure and outcome. Possible positive associations between other PFCs and ADHD, particularly PFHxS, warrant continued investigation. PMID- 21665567 TI - Additivity of pyrethroid actions on sodium influx in cerebrocortical neurons in primary culture. AB - BACKGROUND: Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Although previous work has tested the additivity of pyrethroids in vivo, this has not been assessed directly at the primary molecular target using a functional measure. OBJECTIVES: We investigated the potency and efficacy of 11 structurally diverse food-use pyrethroids to evoke sodium (Na+) influx in neurons and tested the hypothesis of dose additivity for a mixture of these same 11 compounds. METHODS: We determined pyrethroid-induced increases in Na+ influx in primary cultures of cerebrocortical neurons using the Na+-sensitive dye sodium-binding benzofuran isophthalate (SBFI). Concentration-dependent responses for 11 pyrethroids were determined, and the response to dilutions of a mixture of all 11 compounds at an equimolar mixing ratio was assessed. Additivity was tested assuming a dose additive model. RESULTS: Seven pyrethroids produced concentration-dependent, tetrodotoxin-sensitive Na+ influx. The rank order of potency was deltamethrin > S bioallethrin > beta-cyfluthrin > lambda-cyhalothrin > esfenvalerate > tefluthrin > fenpropathrin. Cypermethrin and bifenthrin produced modest increases in Na+ influx, whereas permethrin and resmethrin were inactive. When all 11 pyrethroids were present at an equimolar mixing ratio, their actions on Na+ influx were consistent with a dose-additive model. CONCLUSIONS: These data provide in vitro relative potency and efficacy measurements for 7 pyrethroid compounds in intact mammalian neurons. Despite differences in individual compound potencies, we found the action of a mixture of all 11 pyrethroids to be additive when we used an appropriate statistical model. These results are consistent with a previous report of the additivity of pyrethroids in vivo. PMID- 21665568 TI - In-traffic air pollution exposure and CC16, blood coagulation, and inflammation markers in healthy adults. AB - BACKGROUND: Exposure to traffic-related air pollution is a risk factor for cardiovascular events, probably involving mechanisms of inflammation and coagulation. Little is known about effects of the short exposures encountered while participating in traffic. OBJECTIVES: The objective of the study was to examine effects of exposure of commuters to air pollution on cardiovascular biomarkers. METHODS: Thirty-four healthy adult volunteers commuted for 2 hr by bus, car, or bicycle during the morning rush hour. During the commute, exposure to particle number, particulate matter (PM) <= 2.5 um in aerodynamic diameter (PM2.5), PM <= 10 um in diameter (PM10), and soot was measured. We estimated inhaled doses based on heart rate monitoring. Shortly before exposure and 6 hr after exposure, blood samples were taken and analyzed for CC16 (Clara cell protein 16), blood cell count, coagulation markers, and inflammation markers. Between June 2007 and June 2008, 352 pre- and postexposure blood samples were collected on 47 test days. We used mixed models to analyze the associations between exposure and changes in health parameters. RESULTS: We observed no consistent associations between the air pollution exposures and doses and the various biomarkers that we investigated. CONCLUSIONS: Air pollution exposure during commuting was not consistently associated with acute changes in inflammation markers, blood cell counts, or blood coagulation markers. PMID- 21665570 TI - Experimental inoculation of day-old ducks with Brachyspira pilosicoli and B. alvinipulli. AB - Two groups of one-day-old Peking ducklings (Groups I and II, 12 birds/group) were inoculated orally with Brachyspira pilosicoli and two groups with B. alvinipulli (Groups III and IV, 12 birds/group). T-2 toxin was added to the feed of Groups II and IV in a dose of 1 mg/kg of feed. Groups V and VI served as uninfected control groups (ducks of Group VI received T-2 toxin). The body weight gain of the ducks was measured and clinical signs were monitored continuously. The birds were sacrificed and necropsied on days 7, 14, 21, and 28 post infection (PI). The liver, spleen, kidney, thymus, bursa of Fabricius, ileum, caecum and colon were examined histologically. Culturing of Brachyspira spp. and immunohistochemistry were performed from the sampled parts of the intestines as well. No gross pathological or histological lesions that could be associated with B. pilosicoli or B. alvinipulli were detectable in the intestinal mucous membrane including the colonised intestinal glands. Mortality did not occur during the experimental period. Decrease in body weight gain was significant in the T-2-toxin-treated groups, and it was slight (not significant) in the Brachyspira-infected groups. Crust on the beaks, necrosis, crusting and ulceration in the mucous membrane of the oral cavity and on the skin of the feet, atrophy of the thymus and bursa of Fabricius due to the effect of T-2 toxin, accompanied by lymphocyte depletion, were observed. These lesions were most prominent on days 14 and 21 PI but were seen on day 28 PI as well. Immunohistochemical detection and reisolation of B. pilosicoli and B. alvinipulli were successful on days 7, 14, 21 and 28 days from different segments of the intestine of certain birds, but no significant difference was observed in the colonisation rate between the T-2-toxin-treated and the untreated groups. PMID- 21665569 TI - Detection of Vibrio parahaemolyticus in Mediterranean mussels (Mytilus galloprovincialis) in Slovenia. AB - The aim of this study was to determine the prevalence of Vibrio parahaemolyticus in shellfish samples harvested along the Slovenian coast. Shellfish samples of Mediterranean mussels (Mytilus galloprovincialis) were collected along the Slovenian coast at four locations (Seca, Piran, Strunjan and Debeli Rtic) between 2006 and 2008. Samples were examined and analysed for the presence of V. parahaemolyticus by conventional and molecular methods. The presence of Vibrio in the samples was examined by conventional methods on plate grown bacterial cells before and after enrichment in alkaline saline peptone water (ASPW). PCR methods were used for the detection of V. parahaemolyticus-specific toxR and tlh genes and of the virulence-associated tdh and trh genes. Out of 168 samples examined, 24 were positive for toxR and tlh genes by PCR from enrichment broth. Five out of 62 (8.1%), 4 out of 32 (12.5%) and 15 out of 74 (20.2%) samples were positive in 2006, 2007 and 2008, respectively. Colonies of V. parahaemolyticus were isolated from only one sample positive for V. parahaemolyticus by PCR. PMID- 21665571 TI - Intraoperative echocardiography and surgical treatment of traumatic pericarditis in a pregnant cow. AB - Traumatic pericarditis is one of the most significant bovine cardiac diseases. The authors describe the use of intraoperative echocardiography and successful surgical treatment of a case of traumatic pericarditis. A seven-year-old Hungarian Simmental dairy cow in late pregnancy showed severe oedema of the throat region and brisket, as well as jugular distension. Cardiac auscultation demonstrated tachycardia with a normal cardiac rhythm. The heart sounds were muffled, but no cardiac murmur or splashing sounds were heard. A large amount of echogenic fluid with some strands of fibrin was seen in the pericardial and right pleural cavities by ultrasonography. Ultrasound-guided pericardiocentesis demonstrated the presence of a thick, fetid and purulent exudate. Pericardiotomy was performed in standing position with sedation and local anaesthesia. After costal resection, intraoperative echocardiography was performed. It showed an echogenic tract between the caudal pericardium and diaphragm, but no foreign body was seen. Two weeks after the surgery, the cow delivered a healthy bull-calf. Intraoperative echocardiography - not reported earlier - can be applied to evaluate the entire bovine pericardial sac and heart. The report also demonstrates that surgical treatment of traumatic pericarditis can be successful in carefully selected cases. PMID- 21665572 TI - Peritonitis in horses: 55 cases (2004-2007). AB - Factors associated with the outcome of peritonitis in horses are seldom described. The objectives of this study were to determine the common clinical signs and clinicopathologic findings and to reveal prognostic factors associated with the outcome of peritonitis in equine patients. Data were examined in a retrospective manner in 55 horses diagnosed with and treated for peritonitis. The most common clinical and clinicopathologic findings were tachycardia (94%), increased amount of peritoneal fluid on ultrasound (84%), altered mucous membranes (82%), bacteria noted on the direct smear (67%), hyperfibrinogenaemia (58%) and left shift (40%). The most commonly isolated organism was E. coli (37%). Survival rates were as follow: 78% in the whole study, 81% in the abdominal lavage group, 93% in the medically and 46% in the surgically managed groups. Complications were more common in the non-survivor group (P < 0.001). Initial haematocrit and surgical interventions were strongly associated with non survival in the multivariate logistic regression model (P = 0.049, OR: 1.07 and P = 0.01, OR: 9.87, respectively). Prognosis of peritonitis without gastrointestinal rupture depends on the initial hydration status, surgical interventions and development of secondary complications, while other clinical and clinicopathologic findings do not appear to correlate with survival. Prospective evaluation of hydration and perfusion parameters and abdominal lavage warrants further investigation. PMID- 21665573 TI - Effect of diets with different inclusion levels of distillers dried grain with solubles combined with lysine and methionine supplementation on the lipid peroxidation and glutathione status of chickens. AB - To study the possible effects of different inclusion levels of distillers dried grain with solubles (DDGS) on the lipid peroxidation and glutathione redox status of chickens, 200 three-week-old Ross 308 cockerels were assigned to four treatment groups of 50 birds each. The groups were fed a control and three experimental, isocaloric and isonitrogenous grower diets containing 15, 20 and 25% DDGS, respectively, combined with lysine (Lys) and methionine (Met) supplementation until 6 weeks of age. It was found that DDGS inclusion increased the ether extract content of the diets which resulted in higher reduced glutathione (GSH) content and elevated glutathione peroxidase activity (GSHPx) in the liver. However, DDGS addition with Lys and Met supplementation did not influence the malondialdehyde content of the blood and the liver. The oleic acid proportion of the diet showed a close positive correlation with GSH content of the liver. A smaller ratio of methionine and cysteine in the diet with DDGS resulted in significantly higher liver GSH content. GSHPx activity increased parallel with the elevated GSH content of the liver homogenate, suggesting that the enzyme is activated by the actual supply of its co-substrate. In conclusion, the results show that DDGS, even at a high inclusion level combined with Lys and Met supplementation, has no initiative effect on lipid peroxidation in the blood and liver of broiler chickens. PMID- 21665574 TI - Detection of Leishmania amastigotes in peripheral blood from four dogs--Short communication. AB - The authors carried out microscopic examination of blood smears of 1438 dogs infected with Leishmania infantum. Unusual findings of leishmaniosis associated with circulating parasitised cells are described in four dogs. Most of the dogs presented severe illness, with lethargy, dysorexia, emaciation and alterations of the haematological pattern (anaemia, thrombocytopenia, neutrophilia and monocytosis). In three cases, leishmaniosis was associated with ehrlichiosis. On examination of peripheral blood smears, Leishmania sp. amastigotes were observed both in various circulating leukocytes (neutrophil, monocyte, macrophage) and free. In conclusion, parasites can rarely be detected in blood smears (in 0.28% of the animals examined); thus, the time-consuming microscopic search for amastigotes can make only a weak contribution to the conventional diagnosis of canine leishmaniosis. PMID- 21665575 TI - Molecular evidence of vector-borne pathogens coinfecting dogs from Poland. AB - Ticks of the genus Ixodes are vectors for many pathogens, including Borrelia burgdorferi sensu lato, Anaplasma phagocytophilum and Rickettsia spp., and may also serve as vectors for Bartonella spp. However, the role of ticks in Bartonella transmission requires additional studies. The aim of this study was to investigate whether coinfection with two or more vector-borne pathogens can occur in the following three groups of dogs: I - dogs with suspected borreliosis (N = 92), II - dogs considered healthy (N = 100), and III - dogs with diagnosed babesiosis (N = 50). Polymerase chain reactions were performed to detect DNA of Anaplasma phagocytophilum, Rickettsia spp. and Bartonella spp. in the blood of dogs. In dogs of Group I, the DNA of both A. phagocytophilum and Bartonella sp. was detected (14% and 1%, respectively). In eight dogs, coinfection was indicated: A. phagocytophilum or Bartonella sp. with B. burgdorferi s.l. (the presence of antibodies against and/or DNA B. burgdorferi s.l.). In the case of five dogs positive for A. phagocytophilum DNA, no coinfection with B. burgdorferi s.l. was shown. In Group II, the DNA of A. phagocytophilum was detected in four dogs. In Group III, no pathogenic agents possibly transmitted by ticks were confirmed. No DNA of R. helvetica was detected in any of the groups studied. PMID- 21665576 TI - First report of an endometrial adenoacanthoma in a dog. AB - Uterine adenoacanthoma, a subtype of primary endometrial adenocarcinoma, was found in a tissue specimen removed during ovariohysterectomy from an 8-year-old German Shepherd dog. Multifocal, benign squamous metaplastic islands were identified in the parenchyma of the malignant endometrial tumour. The tumour was highly infiltrative but did not metastasise to other organs. Detailed immunohistochemical analyses were carried out in order to characterise the immunophenotype of the tumour. PMID- 21665577 TI - Effect of recombinant interleukin-10 on some haematological and biochemical parameters in a rat endotoxaemic model. AB - Recombinant interleukin-10 (rIL10) has been found to suppress the synthesis of tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6) and tissue factor and to improve survival from experimental sepsis. The aim of this study was to evaluate the protective effect of rIL-10 on lipopolysaccharide-(LPS ) induced haematological and biochemical disturbances in rats. In the present study, 40 rats were used and divided equally into four groups. Group 1 (control group, C) was treated with 0.9% saline. Group 2: LPS was injected intravenously (1.6 mg/100 g), Group 3 received rIL10 treatment (125 MUg/kg) 2 min before 0.9% saline injection, Group 4 received rIL10 treatment 2 min before endotoxin treatment. When compared with the controls, platelet count, leukocyte count (with a marked neutrophilia and lymphopenia) and fibrinogen were decreased, while activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged in the endotoxaemic rats. In addition, LPS caused statistically significant increases in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as creatinine, cholesterol and triglyceride concentrations, while it caused a statistically significant decrease in glucose, total protein and albumin levels as compared to the control group. On the other hand, rIL10 significantly suppressed disturbances in the haematological and biochemical parameters associated with endotoxaemia. As a result, rIL10 may be efficacious in preventing haematological disorders, tissue damage and changes in lipid, protein and carbohydrate metabolism in endotoxaemia. PMID- 21665578 TI - Strategy for the treatment of puerperal metritis and improvement of reproductive efficiency in cows with retained placenta. AB - The objective of this study was to improve the reproductive efficiency of dairy cows with puerperal metritis (PM) subsequent to retained placenta (RP) using a two-step treatment strategy. A total of 188 postpartum cows, aged from 2 to 8 years, were utilised for 2 experiments. In Experiment 1, cows affected with RP/PM were randomly assigned to two treatment groups. Cows in Group A (n = 17) were treated with 600 mg of ceftiofur intramuscularly for 3 days followed by intrauterine lavage with 0.1% chlorhexidine and infusion with 0.5% povidoneiodine, while cows in Group B (n = 16) received two intrauterine infusions, first with 5 g of oxytetracycline and then with 0.5% povidone-iodine. Cows with normal postpartum findings were regarded as the healthy control group (n = 26). Ultrasonographic examination revealed that the ovarian activities including the appearance of a dominant follicle and days to first ovulation of the cows in Group A during the early postpartum period differed from those of Group B (P < 0.05), which coincided with the results of uterine swabbing for bacteriology. In Experiment 2, cows with normal postpartum findings were allocated to Group D (n = 78), which received an ovulation protocol (GnRH - 7 d PGF2alpha - 48 h hCG - 24 h AI) on day 50 +/- 2 postpartum. Cows affected with PM were randomly divided into two groups, Group E (n = 25) combined the treatments applied in Groups A and D, while Group F (n = 26) repeated the treatment administered in Group E except for uterine lavage. The results indicated that the pregnancy rate within 150 days postpartum and the mean days open in Group E (76.0% and 106.3 +/- 4.6 days, respectively) were significantly different from those in Group F (38.5% and 137.9 +/- 10.9 days, respectively) (P < 0.05). This study suggests that reproductive efficiency could be improved by using the two step treatment to regulate uterine involution and an early resumption of ovarian function in cows with RP/PM. PMID- 21665579 TI - Reproductive function of Hungarian Mangalica boars: effect of seasons. AB - Seasonal changes in testis volume, testosterone (T) productivity (GnRH test) and semen characteristics of Mangalica boars were studied. The biggest testis volume was measured in autumn and the smallest in winter. Significant differences were demonstrated between autumn-winter (P = 0.012) and autumn-spring (P = 0.015) in testis volume. The highest basic T concentration (Tb) was observed in autumn and the lowest in summer. The provoked T concentration (Tincr) was significantly higher in autumn than in spring (P = 0.0007). A strong correlation was observed between T concentrations and testis volume in spring. The highest ejaculate volume was measured in winter while the lowest in autumn. Significant differences were found in semen concentration as well as in the total number of spermatozoa per ejaculate between seasons. The highest number of abnormal sperm cells was observed in spring while the lowest in summer. It can be concluded that the ejaculate of the Mangalica breed tends to be of lower volume and higher sperm concentration as compared to most pig breeds. Seasonal differences could be observed in testicular measurements, testosterone production capacity and sperm morphological features; however, sperm motility remained constantly high during the study. PMID- 21665580 TI - Effects of prolactin receptor genotype on the litter size of Mangalica. AB - The aim of this study was to detect different alleles of the prolactin receptor (PRLR) gene and to examine their effects on the litter size of the indigenous Hungarian pig, the Mangalica. G1789A single nucleotide polymorphism (SNP) was investigated as a candidate for litter size. Samples from 80 purebred Mangalica sows and data of their 335 litters were provided by Olmos & Toth Ltd. Hair follicles were used to isolate the required DNA. Allelic discrimination was performed by means of the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method using the AluI restriction enzyme and agarose gel electrophoresis. In the population examined, the A allele was found to be preferable in the Mangalica breed group. The most advantageous AA genotype was the least prevalent (8.75%), while the frequencies of AB and BB were 40% and 51.25%, respectively. Remarkably, the average number of piglets born alive per litter was 1.11 +/- 0.39 higher in sows with AA as compared to those with BB genotype. By raising the frequency of the AA genotype, the litter size is likely to increase. However, the effect of PRLR genotypes can differ among pig breeds and even lines. Further studies may be required to observe and estimate possible pleiotropic effects of this polymorphism on other traits. PMID- 21665581 TI - Partial sequence of the DNA-dependent DNA polymerase gene of fowl adenoviruses: a reference panel for a general diagnostic PCR in poultry. AB - Adenoviruses are frequent infectious agents in different poultry species. The traditional, serological typing of new isolates by virus neutralisation tests is now in transition to be replaced by PCR and sequencing. The first PCRs, recommended for the detection of adenoviruses, had been designed to target the gene of the major capsid protein, the hexon. In birds, members of three different genera of the family Adenoviridae may occur. Accordingly, three specific hexon PCRs had to be elaborated for the detection of adenoviruses in poultry. A significantly more sensitive PCR, targeting the viral DNA-dependent DNA polymerase gene, has been described recently. This method proved to be an efficient alternative for the general detection of adenoviruses irrespective of their genus affiliation. Fowl adenoviruses (FAdVs), isolated from chicken to date, comprise twelve serotypes classified into five virus species (FAdV-A to E). The polymerase gene sequence has been determined yet only from three FAdV types representing three species. In the present work, the panel of polymerase gene sequences was completed with those of the rest of FAdVs. The newly determined sequences will facilitate the identification of new FAdV isolates as an existing species or as a putative new FAdV. Once the polymerase sequence is known, more specific PCRs for the amplification of the hexon and other genes can be designed and performed according to the preliminary species classification. PMID- 21665582 TI - Floral ontogeny of Lecointea, Zollernia, Exostyles, and Harleyodendron (Leguminosae: Papilionoideae: Swartzieae s.l). AB - Floral initiation and development were examined using scanning electron microscopy in Exostyles venusta, Harleyodendron unifoliolatum, Lecointea hatschbachii, and Zollernia ilicifolia. Common features include (1) unidirectional sepal initiation, (2) simultaneous petal initiation, (3) unidirectional initiation of each stamen whorl (except in the antesepalous whorl in Lecointea and Exostyles), (4) overlap in time of initiation of the two stamen whorls, and (5) initiation of the carpel concurrently with petals. Significant developmental features include (1) the first sepal median abaxial in all except Lecointea where it is non-median abaxial; (2) intraspecific variation in petal aestivation in Exostyles, Harleyodendron, and Lecointea; (3) initiation of antepetalous stamens before the antesepalous ones in Zollernia, Exostyles, and Lecointea; and (4) ovule initiation before the carpel margins are fused in Exostyles. The stamen sequence has not been found in any other legumes. The following late developmental events distinguish the four genera from each other: copious hairs hold the anthers together as a domelike structure at anthesis in Harleyodendron; zygomorphy in Zollernia results from differing petal reflexion; late hypanthium in Exostyles, Lecointea, and Holocalyx (no hypanthium in Harleyodendron or Zollernia); and reflexed sepal lobes in Exostyles, Harleyodendron, and Zollernia but not in Holocalyx and Lecointea. The genera studied here are ontogenetically more similar to taxa of Sophoreae than to other Swartzieae that have been investigated. None of the taxa studied here has a ring meristem, the structure that characterizes the remaining swartzioid taxa studied elsewhere. PMID- 21665583 TI - Censusing natural microgametophyte populations: variable spatial mosaics and extreme fine-graininess in winter-flowering Helleborus foetidus (Ranunculaceae). AB - Little is known about patterns and correlates of variation in microgametophyte populations for naturally pollinated plants, yet this information is critical for evaluating the prevalence and potential evolutionary significance of gametophyte competition in the wild. This paper analyzes spatial and temporal variation in microgametophyte populations (= number of pollen tubes per style) for the winter flowering, perennial herb Helleborus foetidus (Ranunculaceae), based on data from 29 populations in three regions of the Iberian Peninsula collected over two consecutive years. Mean size of microgametophyte populations varied significantly at a wide range of spatial scales, including among regions, among populations within regions, among individual plants within populations, among flowers of the same plant, and among pistils of the same flower (H. foetidus flowers are apocarpous). Differences between regions were quantitatively negligible. Differences between populations in the same region were moderate to low, and their sign and magnitude were inconsistent between years. Roughly half of total variance in microgametophyte numbers was accounted for by variation within individual plants, and the largest part of this component was due to differences between the pistils of the same flower. These results reveal extreme spatial fine graininess and marked stochasticity in the spatial variation of H. foetidus microgametophyte populations and suggest that opportunities for consistent selection on male gametophyte competitive ability are probably negligible in this species. PMID- 21665584 TI - The consequences of rewardlessness in orchids: reward-supplementation experiments with Anacamptis morio (Orchidaceae). AB - Pollinators are expected to respond to low reward availability in an inflorescence by visiting fewer flowers before departure, thus potentially causing reduced visitation, but also reduced geitonogamous selfing. I tested this hypothesis using Anacamptis morio, an orchid that does not reward its pollinators. Supplementation of inflorescences with artificial nectar did not result in an increase in fruit set on supplemented inflorescences compared to control inflorescences and tended to reduce pollinia removal. Supplementation resulted in reduced fruit quality, but there was no evidence that this was as a result of inbreeding depression. Behavioral experiments showed that pollinating bumble bees, as predicted, visited more flowers on supplemented inflorescences. Bumble bees also deposited more self-pollen on supplemented inflorescences, but this was marginally significant. Bumble bee queens removed significantly more pollinia from control inflorescences, while Bombus terrestris and B. lucorum workers did not. I conclude that while pollinators behaved as predicted, there was weak evidence that pollinia removal, pollen deposition, and fruit set followed the predictions of the hypothesis. I argue that this was probably because some pollinators were more efficient at removing and depositing pollen on control inflorescences, while others were not. PMID- 21665585 TI - Temporal changes in floral nectar production, reabsorption, and composition associated with dichogamy in annual caraway (Carum carvi; Apiaceae). AB - The dynamics of nectar production were studied in perfect florets of two varieties (Karzo, Moran) of annual caraway (Carum carvi L., Apiaceae). Florets were protandrous and strongly dichogamous, lasting 7-15 d but producing nectar from the stylopodia for 4-12 d, in an interrupted fashion. Nectar secretion began during a floret's phase of stamen elongation and anther dehiscence. After reabsorption of uncollected nectar, at which point nectary surfaces were completely dry, the two styles elongated and a second bout of secretion commenced during the female phase, up to 5 d later, when a floret became receptive to pollination. During the male and female phases, respectively, 0.392 +/- 0.064 MUL and 1.083 +/- 0.261 MUL of nectar of similar solute concentration (844 mg/mL) was produced per ten florets. On a daily basis, florets yielded 1.5-fold more nectar in the female than during the male phase. First-time nectar removal throughout the female phase did not match the sum of nectar quantities from male and female phases combined, suggesting that under natural conditions, any uncollected male phase nectar, once reabsorbed, is not made available to visitors of the same florets when in the female phase. Nectar-sugar composition differed between bouts of secretion; it was hexose-rich (59.6% fructose, 26.9% glucose, 13.6% sucrose) initially, but hexose-dominant (70.2, 26.8, 3.1) during the female phase. A 5.7 fold difference in mean nectar production per floret occurred among plants. PMID- 21665586 TI - Why does the flower stalk of Pulsatilla cernua (Ranunculaceae) bend during anthesis? AB - Flower stalks of Pulsatilla cernua, an early spring herb in north temperate Asia, changed position from erect to pendulous and back to erect during 6-10 d anthesis. We tested three possible explanations for this movement. Our results showed that (1) this movement is unlikely to be a mechanism to attract pollinators or enhance pollen output, because no pollinator preference was observed between erect and pendulous flowers and we found no buzz-pollination in this species; (2) hand self-pollination yielded higher seed set than open pollination in the field, but spontaneous selfing rarely occurred. Among open pollinated flowers, seed set was depressed by emasculation, indicating that in the presence of insects, self-pollen provided reproductive assurance in this protogynous and self-compatible species. However, the change in flower orientation cannot be explained as reproductive assurance in that even self pollination largely depended on pollinator visits rather than gravity. (3) A pollen germination experiment indicated that pollen damage by water is serious in this species. We deduced that the bending of the flower stalk during anthesis was to avoid rain damage to pollen grains in this species. During the 3-6 d period of pollen presentation, the petals elongated and were covered with unwettable hairs. Together with flower stalk movement, this was enough to protect the organs inside the flower from rain. This movement of the flower stalk seems to be important to maintain pollen viability in a rainy habitat with a scarcity of pollinators. PMID- 21665587 TI - Quantifying latitudinal clines to light responses in natural populations of Arabidopsis thaliana (Brassicaceae). AB - Evidence of adaptation in Arabidopsis thaliana (Brassicaceae) phenotypic traits has rarely been shown. We demonstrate latitudinal clines in two A. thaliana traits: hypocotyl responses to red and far-red light. Natural populations of A. thaliana were sampled along a latitudinal gradient from southern to northern Norway. Seeds from maternal families within each population were subjected to 1 wk of constant red, far-red, blue, white, and dark treatments. Hypocotyl lengths were measured for each maternal family within each population. Significant variability within and among populations in hypocotyl responses for the various treatments was found. There was a significant latitudinal cline in hypocotyl responses for red and far-red treatments, with northern populations being more de etiolated than southern populations. These results suggest that northern populations are more responsive to red and far-red light than southern populations. Thus, differentiation of seedling traits in natural populations of A. thaliana seems in part to be mediated by the phytochrome pathway. There was no correlation between hypocotyl responses and flowering time for any treatment. This suggests that flowering time variability and variability in hypocotyl responses may not be governed by genes shared between the pathways, such as those involved in photoreception or the circadian clock. PMID- 21665588 TI - Interactive effects of lateral shade and wind on stem allometry, biomass allocation, and mechanical stability in Abutilon theophrasti (Malvaceae). AB - The effects of lateral shade and wind on stem allometry, whole-plant biomass allocation, and mechanical stability were examined for Abutilon theophrasti in a fully factorial glasshouse experiment. Lateral shade from neighboring plants increased stem height by 33% relative to control plants grown individually, despite a decrease in plant dry mass. Intermittent wind decreased stem height by 18% in unshaded plants, but by only 3% in shaded plants. Surprisingly, both lateral shade and wind caused decreases in stem diameter, even with diameter controlled for height, resulting in low diameter : height ratios in wind-treated plants relative to untreated plants. Under shade, wind-treated plants had higher root allocation than untreated plants, which allowed wind-treated shade plants to compensate for a low diameter : height ratio. This did not occur in the absence of shade, where stem tissue density and root allocation of wind-treated plants did not exceed that of untreated plants. Nevertheless, wind-treated plants experienced low drag relative to untreated plants due to a lower leaf area. Consequently, stem deflections of wind-treated plants did not exceed those of untreated plants at any given windspeed. Our results document a complex interaction between shade and wind on plant morphology and suggest that the nature of this interaction is generally that lateral shade acts to reduce or eliminate thigmomorphogenic responses. PMID- 21665589 TI - Recruitment potential of two perennial grasses with different growth forms at a semiarid-arid transition zone. AB - The objective of this study was to quantify differences in recruitment potential (seed production, seed presence in the soil) for two congeneric perennial grasses (Bouteloua gracilis, Bouteloua eriopoda [Poaceae]) that dominate adjacent arid and semiarid grassland biomes. It was hypothesized that these species have different recruitment strategies at the biome transition zone that are related to differences in their growth form and longevity. Recruitment potential for each Bouteloua species was compared in patches dominated by one or both species or codominated by the invasive shrub, Larrea tridentata (Zygophyllaceae). Regional variation in recruitment was examined for B. gracilis for cases in which comparable data were available in the literature for a site located within the semiarid grassland biome. The short-lived stoloniferous species B. eriopoda produced more seeds per plant than the long-lived bunchgrass B. gracilis, yet seed viability (<60%) and presence in the soil were lower. Mean viability of B. gracilis was higher (>90%) than that of B. eriopoda, and a greater percentage of seeds produced on a square meter basis was found in the soil (10-25%). Similar patterns were found for both species in all grass-dominated patches. Bouteloua eriopoda plants growing in patches codominated by L. tridentata produced fewer seeds per plant with lower viability, and fewer seeds were found in the soil compared to grass-dominated patches. Regional comparisons found greater seed production per square meter and more seeds in the soil for B. gracilis at the transitional site compared with a cooler, wetter site located within the semiarid grassland biome. These differences in recruitment potential along with published differences in rates of seedling establishment and vegetative spread may explain, at least in part, localized patterns in species dominance. PMID- 21665590 TI - Phenology and demography of two species of Botrychium (Ophioglossaceae). AB - Temporal and demographic aspects of the growth of Botrychium gallicomontanum and B. mormo were studied for 2 yr. A total of 219 B. gallicomontanum and 412 B. mormo plants were monitored in a prairie and maple-basswood forest, respectively. Growth events were divided into four stages: leaf emergence, leaf separation, spore release, and senescence. Botrychium gallicomontanum emerged in April, peaked during the first week of June, and declined rapidly. The largest plants were found in late June and early July with a mean peak trophophore size of 4.0 +/- 1.8 cm. Botrychium mormo emerged in June, and the population size peaked in early July. The largest plants occurred late in August with a mean peak trophophore size of 3.0 +/- 1.1 cm. The mean season span, or period of emergence aboveground annually, for B. gallicomontanum and B. mormo was 7.7 +/- 2.4 and 11.9 +/- 3.5 wk, respectively. Late-emerging plants produced spores in shorter periods. The separation stage was prolonged in B. gallicomontanum plants, whereas B. mormo plants had a much longer separation stage. Phenological differences are related to different habitat parameters of grassland and forest. Understanding the phenology of these rare species will help us more accurately predict the impact of management practices. PMID- 21665591 TI - Variation in grazing tolerance among three tallgrass prairie plant species. AB - Three tallgrass prairie plant species, two common perennial forbs (Artemisia ludoviciana and Aster ericoides [Asteraceae]) and a dominant C(4) perennial grass (Sorghastrum nutans) were studied under field and greenhouse conditions to evaluate interspecific variation in grazing tolerance (compensatory growth capacity). Adaptation to ungulate grazing was also assessed by comparing defoliation responses of plants from populations with a 25-yr history of no grazing or moderate ungulate grazing. Under field conditions, all three species showed significant reductions in shoot relative growth rates (RGR), biomass, and reproduction with defoliation. In the two forbs, clipping resulted in negative shoot RGR and reductions in both number and length of shoot branches per ramet. Sorghastrum nutans maintained positive RGR under defoliation due to a compensatory increase in leaf production. Defoliation reduced rhizome production in A. ericoides and S. nutans, but not in A. ludoviciana. Clipping significantly reduced sexual reproductive allocation in all three species, although S. nutans showed a smaller reduction than the forbs. All three species showed similar responses to defoliation in burned and unburned sites. Under greenhouse conditions, a similar clipping regimen resulted in smaller reductions in growth and reproduction than those observed in the field. For all three species, the grazing tolerance indices calculated under natural field conditions were significantly lower than those estimated from greenhouse-grown plants, and the interspecific patterns of grazing tolerance were different. Aster ericoides exhibited the highest overall defoliation tolerance under greenhouse conditions, followed by S. nutans. Artemisia ludoviciana, the only study species that is typically not grazed by ungulates in the field, showed the lowest grazing tolerance. In the field experiment S. nutans showed the highest grazing tolerance and the two forbs had similar low tolerance indices. These patterns indicate that, despite high compensatory growth potential, limited resource availability and competition in the field significantly reduce the degree of compensation and alter interspecific differences in grazing tolerance among prairie plants. In all three species, defoliation suppressed sexual reproduction more than growth or vegetative reproduction. Significant interactions between plant responses to defoliation and site of origin (historically grazed or ungrazed sites) for some response variables (root/shoot ratios, rhizome bud initiation, and reproductive allocation) indicated some degree of population differentiation and genetic adaptation in response to a relatively short history of ungulate grazing pressure. The results of this study indicate that patterns of grazing tolerance in tallgrass prairie are both genetically based and also environmentally dependent. PMID- 21665592 TI - Soil seed bank and seed dormancy in wild populations of lima bean (Fabaceae): considerations for in situ and ex situ conservation. AB - Seed dormancy and its impact on the soil seed bank for wild Lima bean (Phaseolus lunatus) populations were studied in the Central Valley of Costa Rica. Five populations were selected in contrasted environments. In all cases, distribution of seeds in the soil was limited to 3 cm depth. No innate dormancy was observed but combination of hard seed coat and hilum opening controlled by environmental conditions were responsible for an induced dormancy and the constitution of a persistent seed bank. Breaking of this dormancy was obtained by a brief elevation of temperature from 25 degrees to 45 degrees C. Impacts of this phenomenon concern both genetic and demographic aspects of in situ conservation of the species. Consequences on ex situ conservation are mainly related with the regeneration of the seed collection. PMID- 21665593 TI - Group II introns as phylogenetic tools: structure, function, and evolutionary constraints. AB - Group II introns comprise the majority of noncoding DNA in many plant chloroplast genomes and include the commonly sequenced regions trnK/matK, the rps16 intron, and the rpl16 intron. As demand increases for nucleotide characters at lower taxonomic levels, chloroplast introns may come to provide the bulk of plastome sequence data for assessment of evolutionary relationships in infrageneric, intergeneric, and interfamilial studies. Group II introns have many attractive properties for the molecular systematist: they are confined to organellar genomes in eukaryotes and the majority are single-copy; they share a well-defined and empirically tested secondary and tertiary structure; and many are easily amplified due to highly conserved sequence in flanking exons. However, structure linked mutation patterns in group II intron sequences are more complex than generally supposed and have important implications for aligning nucleotides, assessing mutational biases in the data, and selecting appropriate models of character evolution for phylogenetic analysis. This paper presents a summary of group II intron function and structure, reviews the link between that structure and specific mutational constraints in group II intron sequences, and discusses strategies for accommodating the resulting complex mutational patterns in subsequent phylogenetic analyses. PMID- 21665594 TI - Phylogeny of seed plants based on evidence from eight genes. AB - Relationships among the five groups of extant seed plants (cycads, Ginkgo, conifers, Gnetales, and angiosperms) remain uncertain. To explore relationships among groups of extant seed plants further and to attempt to explain the conflict among molecular data sets, we assembled a data set of four plastid (cpDNA) genes (rbcL, atpB, psaA, and psbB), three mitochondrial (mtDNA) genes (mtSSU, coxI, and atpA), and one nuclear gene (18S rDNA) for 19 exemplars representing the five groups of living seed plants. Analyses of the combined eight-gene data set (15 772 base pairs/taxon) with maximum parsimony (MP), maximum likelihood (ML), and Bayesian approaches reveal a gymnosperm clade that is sister to angiosperms. Within the gymnosperms, a conifer clade includes Gnetales as sister to Pinaceae. Cycads and Ginkgo are either successive sisters to this conifer clade (including Gnetales) or a clade that is sister to conifers and Gnetales. All analyses of the mtDNA partition and ML analyses of the nuclear partition yield very similar topologies. However, MP analyses of the combined cpDNA genes place Gnetales as sister to all other seed plants with strong bootstrap support, whereas ML and Bayesian analyses of the cpDNA data set place Gnetales as sister to Pinaceae. Maximum parsimony and ML analyses of first and second codon positions of the cpDNA partiation also place Gnetales as sister to Pinaceae. In contrast, MP analyses of third codon positions place Gnetales as sister to other seed plants, although ML analyses of third codon positions place Gnetales with Pinaceae. Thus, most of the discrepancies in seed plant topologies involve third codon positions of cpDNA genes. The likelihood ratio (LR) and Shimodaira-Hasegasa (SH) tests were applied to the cpDNA data. The preferred topology based on the LR test is that Gnetales are sister to Pseudotsuga. The SH test based on first and second codon and all three codon positions indicated that there is no significant difference between the best topology (Gnetales sister to Pseudotsuga) and Gnetales sister to a conifer clade. However, there is a significant difference between the best topology and topologies in which Gnetales are sister to the rest of the seed plants or Gnetales sister to angiosperms. PMID- 21665595 TI - The phylogeny and a new classification of the gingers (Zingiberaceae): evidence from molecular data. AB - The pantropical Zingiberaceae is the largest family in the order Zingiberales with 53 genera and over 1200 species. Classifications of the family first proposed in 1889 and refined by others since that time recognize four tribes (Globbeae, Hedychieae, Alpinieae, and Zingibereae) based on morphological features, such as number of locules and placentation in the ovary, development of staminodia, modifications of the fertile anther, and rhizome-shoot-leaf orientation. New phylogenetic analyses based on DNA sequences of the nuclear internal transcribed spacer (ITS) and plastid matK regions suggest that at least some of these morphological traits are homoplasious and three of the tribes are paraphyletic. The African genus Siphonochilus and Bornean genus Tamijia are basal clades. The former Alpinieae and Hedychieae for the most part are monophyletic taxa with the Globbeae and Zingibereae included within the latter. The results of these phylogenetic investigations are used to propose a new classification of the Zingiberaceae that recognizes four subfamilies and four tribes: Siphonochiloideae (Siphonochileae), Tamijioideae (Tamijieae), Alpinioideae (Alpinieae, Riedelieae), and Zingiberoideae (Zingibereae, Globbeae). Morphological features congruent with this classification and the taxonomic status of various monotypic genera are discussed. PMID- 21665596 TI - The phylogenetic utility of nucleotide sequences of sorbitol 6-phosphate dehydrogenase in Prunus (Rosaceae). AB - Sequences from s6pdh, a gene that encodes sorbitol-6-phosphate dehydrogenase in the Rosaceae, are used to reconstruct the phylogeny of 22 species of Prunus. The s6pdh sequences alone and in combination with previously published sequences of the internal transcribed spacer (ITS) and the cpDNA trnL-trnF spacer are analyzed using parsimony and maximum likelihood methods. Both methods reconstructed the same phylogeny when s6pdh sequences are used alone and in combination with ITS and trnL-trnF, and the topology is in agreement with previous studies that used a larger sample size. The s6pdh sequences have about twice as many informative sites as ITS. A molecular clock is rejected for s6pdh, most likely due to greater rates of evolution in subgenera Padus and Laurocerasus than in the rest of the genus. Phylogenetic reconstruction of Prunus as determined by analysis of the combined data set suggests an early split into two clades. One is composed of subgenera Cerasus, Laurocerasus, and Padus. The second includes subgenera Amygdalus, Emplectocladus, and Prunus. Species of section Microcerasus (formerly in subgenus Cerasus) are nested within subgenus Prunus. The order of branching and relationships among early diverging lineages is weakly supported, as a result of very short branches that may indicate rapid radiation. PMID- 21665597 TI - Origin of the Hawaiian endemic mints within North American Stachys (Lamiaceae). AB - The Hawaiian endemic mints constitute a major island radiation, displaying a remarkable diversity of floral, fruit, and vegetative features. Haplostachys and Phyllostegia have flowers associated with insect pollination, whereas Stenogyne has flowers typical of bird pollination. The three genera had been thought to be closely related to East Asian members of Lamioideae tribe Prasieae because of the fleshy nutlets borne by Phyllostegia and Stenogyne. We evaluated the origins of the Hawaiian mints using phylogenetic analyses of DNA sequence data from the plastid rbcL and trnL intron loci and the nuclear ribosomal 5S nontranscribed spacer. The Hawaiian genera were found to be monophyletic but deeply nested inside another lamioid genus, Stachys. In particular, they were found to be most closely related to a group of temperate North American Stachys from the Pacific coast, suggesting that the Hawaiian mints derived from a single colonization event from western North America to the Hawaiian Islands. Furthermore, Stachys, which contains amphiatlantic and transberingian clades, was found to be polyphyletic, with some species more closely related to Gomphostemma, Phlomidoschema, Prasium, and Sideritis than to other species of Stachys. Based on chromosomal evidence and our phylogenetic analyses, we hypothesize that the Hawaiian mints may be polyploid hybrids whose reticulate genomes predate the Hawaiian dispersal event and are derived from Stachys lineages with flowers exhibiting insect- vs. bird-pollination characteristics. Thus, the Hawaiian endemic mints may provide yet another insular system for the combined study of polyploidy, hybrid cladogenesis, and adaptive radiation. PMID- 21665598 TI - Occurrence and phylogenetic significance of latex in the Malpighiaceae. AB - Latex and laticifers are reported for the first time in the genera Galphimia and Verrucularia (Malpighiaceae), with description and illustration of the leaf and stem anatomy of both genera. Those genera and the other two in which latex is known (Lophanthera and Spachea) constitute a single tribe, Galphimieae, that is at or near the base of the family's phylogeny, which suggests that latex in the Malpighiaceae may indicate an ancestor shared with the Euphorbiaceae. PMID- 21665599 TI - Inflorescence development in a high-altitude annual Mexican teosinte (Poaceae). AB - Some have postulated that highland Mexican maize was derived from an ancient high altitude teosinte and that later introgression between the two taxa occurred. We used scanning electron microscopy to examine the inflorescence development in both the tassel and ear of a high-altitude Toluca teosinte. One of the most interesting observations was the presence of atypical multiranked orthostiches in the central spike of some male Toluca teosinte inflorescences. Most tassels exhibited a central spike with a pure, four-ranked, tetrastichous phyllotaxy or an intermediate (distichous/tetrastichous) phyllotaxy. A few A(1) tassels had a more typical distichous (two-ranked) central spike. Most ears showed the two-rank condition expected for teosintes. However, three ears displayed an intermediate (distichous/tristichous or distichous/ tetrastichous) phyllotaxy and one ear was tetrastichous. Our analysis of spikelet and floret development in all Toluca inflorescences revealed a pattern similar to that in landrace and U.S. maize, as well as to their close relatives, the teosintes. We suggest that this investigation may reveal inflorescence development in a natural maize-teosinte hybrid. This study further supports our hypothesis that both maleness and femaleness in the Zea inflorescences are derived from a common developmental pathway and underpins a proposal that andropogonoid grasses share a common pattern of inflorescence development. PMID- 21665600 TI - In situ development of the foliicolous lichen Phyllophiale (Trichotheliaceae) from propagule germination to propagule production. AB - The vegetative cycle of the foliicolous lichen Phyllophiale, from propagule germination to propagule production, was studied by light microscope observation of thalli colonizing plastic cover slips placed within a lowland tropical forest. Discoid propagules germinated by growth of radially arranged fungal cells and developed directly into lichen thalli. The young lichen comprised a single disc of closely branched, radiating filaments of the algal symbiont Phycopeltis, covered by a network of fungal hyphae extending onto the substrate as a prothallus. The prothallic hyphae incorporated additional Phycopeltis thalli encountered on the substrate. The phycobiont formed a single layer, with individual algal thalli clearly distinguishable within the lichen. Radial growth ceased at points of contact between adjacent phycobiont thalli. The visible shape of the crustose lichen thallus corresponded to the perimeter of the phycobiont thalli within. Propagules were initiated at points corresponding to the margins of the phycobiont thalli, by vertical reorientation of horizontal algal filaments surrounded by fungal hyphae. The lichenized alga produced intercalary gametangia. Degeneration of propagules unsuccessful in lichen establishment sometimes resulted in free growth of the phycobiont. The alga generally maintained its shape, growth pattern, and reproductive independence within the lichen, while also participating in the formation of unique symbiotic propagules. PMID- 21665601 TI - The evolution of anther morphology in orchids: incumbent anthers, superposed pollinia, and the vandoid complex. AB - The anther is the source of several of the principal characters traditionally used for classification in Orchidaceae, especially in Epidendroideae. In particular, anther and pollinium orientation are important, but little-studied characters; it is not known whether various instances of these states are achieved in the same way. We examined variation in anther and pollinium orientation in Epidendroideae and Vanilloideae using anatomical sections of columns at successive ontogenetic stages and related the observed changes to the final anther morphology to reexamine our homology hypotheses for these characters. Anther bending in vanilloids is achieved primarily by massive expansion of the connective. In nonvandoid epidendroids it is the result of column elongation and tipping of the mature anther, while in vandoids it is due to a redirection of growth in very early ontogenetic stages. Superposed pollinia result from a reorientation of developing thecae; those is Sobralia result from incurving of the thecae, while vandoids have thecae that are directed outward (latrorse). Contrasting ontogenetic and phylogenetic patterns suggest heterochronic changes in these characters, especially in vandoids. These observations allow us to further refine character states that are crucial to our understanding of orchid relationships. PMID- 21665602 TI - Novel morphology in Enteromorpha (Ulvophyceae) forming green tides. AB - "Green tides" are vast accumulations of unattached green macroalgae associated with eutrophicated marine environments. They have major ecological and economic impacts globally, so an understanding of their origin and persistence is required in order to make management decisions. Blooms predominantly consist of two common fouling genera of the Ulvales, Ulva (distromatic sheets) and Enteromorpha (monostromatic tubes). In the Baltic Sea and elsewhere green tides have increased over the last few decades. On the west coast of Finland, summer blooms consist of monostromatic sheets resembling Monostroma (Codiolales). We identified these as Enteromorpha intestinalis by comparative analyses of rDNA internal transcribed spacer 1 (ITS1), 5.8S, and ITS2 sequences, the first time monostromatic sheets have been found in the genus Enteromorpha. Ordinary attached E. intestinalis sporulated freely in culture, but the sheets reproduced only by cell regeneration into typical tubular thalli. The ITS sequences were identical to those of attached E. intestinalis populations in southwestern Finland, but differed by two substitutions from other Baltic sequences. We infer that this bloom originated from local attached populations and now reproduces clonally by fragmentation. This study provides further evidence of radical changes in gross morphology of green algae under eutrophicated conditions and the need for molecular identification. PMID- 21665603 TI - Is auxin the repressor signal of branch growth in apical control? AB - "Apical control" is the repression of branch growth by a higher dominating branch or shoot. There has been some confusion in the literature concerning the meaning and causal mechanisms of this correlative phenomenon with those of "apical dominance," which term is often used in a strict sense to connote the repression of the initiation of axillary bud outgrowth by an active shoot apex. Although the term "apical control" is most commonly employed with respect to woody species, this phenomenon also widely occurs in herbaceous plants. Because of the strong evidence for a role of auxin as a repressor signal in apical dominance and partly because of this lack of distinction in terminology, a similar role for auxin in apical control is often assumed in spite of the obvious acropetal auxin transport difficulty and the lack of direct evidence for the acropetal transport of any inhibitor influence. In the present study with the herbaceous Ipomoea nil, it has been clearly demonstrated that while exogenous auxin (1% NAA) strongly restores apical dominance in the Thimann-Skoog experiment, auxin treatments to decapitated dominant shoots do not, in any observable way, restore apical control in lower dominated branches. Hence, in this fast-growing species, the hypothesis for the role of auxin as a repressor signal for apical control is not supported. PMID- 21665604 TI - Variation in floral scent composition within and between populations of Geonoma macrostachys (Arecaceae) in the western Amazon. AB - In geonomoid palms floral scent is both an important pollinator attractant and an important factor in reproductive isolation. However, little is known about intraspecific variation in floral scent composition in these as well as in other plants. In this study the level of variation in floral scent composition found within and among five populations of Geonoma macrostachys var. macrostachys in the western Amazon is documented. Floral scent samples were collected using head space adsorption and were analyzed by gas chromatography-mass spectrometry. Most of the 108 compounds recorded were of isoprenoid origin, but only 28 of the compounds were found in all 62 samples analyzed. No differentiation was found between the studied populations, confirming that G. macrostachys var. macrostachys is outbreeding and indicating that the individual populations are part of a metapopulation linked by sufficient gene flow to avoid local differentiation. However, a negative correlation between distance and similarity of floral scent chemistry indicates a case of clinal variation within the distribution area of G. macrostachys. Male euglossine bees are infrequent visitors to G. macrostachys, while other groups of insects are abundant. However, the level of variation and the chemical composition lend support to a suggested importance of male euglossine bees in long-distance pollen flow in G. macrostachys. Other insect groups are probably important in securing pollination of most flowers with pollen from nearby sources. PMID- 21665605 TI - Ecophysiology of seed germination in Erythronium japonicum (Liliaceae) with underdeveloped embryos. AB - Erythronium japonicum (Liliaceae) (Japanese name, katakuri) is indigenous to Japan and adjacent Far East regions. We examined their embryo elongation, germination, and seedling emergence in relationship to the temperature. In incubators, seeds did not germinate at 20 degrees /10 degrees (light 12 h/dark 12 h alternating temperature), 20 degrees , 15 degrees , 5 degrees , or 0 degrees C with a 12-h light photoperiod for 200 d. They germinated at 15 degrees /5 degrees or 10 degrees C, starting on day 135. If seeds were kept at 20 degrees or at 25 degrees /15 degrees C before being exposed to 5 degrees C, the seeds germinated, but if kept at 25 degrees or 30 degrees C they did not. Embryos at 25 degrees /15 degrees C grew to half the seed length without germinating; at 0 degrees or 5 degrees C, embryos elongated little. Embryos grew and seeds germinated when kept at 25 degrees /15 degrees C for 90 d and then at 5 degrees C. In the field, seeds are dispersed in mid-June in Hokkaido and in Honshu, mid May to mid-June. Seeds do not germinate immediately after dispersal because the embryo is underdeveloped. Embryos elongated at medium temperatures in autumn after summer heat, and germination ends in November at 8 degrees /0 degrees C. After germination, seedling emergence was delayed, and most seedlings were observed in early April around the snowmelt when soil cover was 2-3 mm. PMID- 21665606 TI - Limited seed dispersal and microspatial population structure of an agamospermous grass of West African savannahs, Hyparrhenia diplandra (Poaceae). AB - We studied the microspatial population structure of the perennial tussock grass, Hyparrhenia diplandra (Poaceae), a facultative agamospermous species of West African savannahs. The microspatial population structure of H. diplandra was investigated by choosing two 100-m(2); quadrats at random from which all individuals were mapped. The genotype of every individual was determined using two highly polymorphic microsatellite loci. A chloroplast locus was also used to investigate the role of seed dispersal on the genetic structure of populations. The genetic diversity index (0.85) was high for a clonal species. Significant genetic differentiation over short distances was detected by F statistics, and spatial autocorrelation analyses within both quadrats showed significant isolation-by-distance patterns, both with the cytoplasmic locus and the nuclear loci. Some clones formed large patches (up to 5 m in diameter) whereas others were more scattered. However, the genetic differentiation between quadrats was much higher when studied with the cytoplasmic locus than with the nuclear loci, indicating that gene flow via pollen, but not seeds, may frequently occur between quadrats. The maintenance of genetic diversity in this facultative agamospermous species most likely results from several factors, such as low seed dispersal ability, nonnegligible gene flow through pollen, and selective pressures induced by regularly occurring fires in this ecosystem. PMID- 21665607 TI - Limited hybridization between Quercus lobata and Quercus douglasii (Fagaceae) in a mixed stand in central coastal California. AB - Many oak species are interfertile, and morphological and genetic evidence for hybridization is widespread. Here we use DNA microsatellite markers to characterize hybridization between two closely related oak species in a mixed stand in central coastal California, Quercus lobata (valley oak) and Q. douglasii (blue oak) (Fagaceae). Genotypes from four microsatellite loci indicate that many alleles are shared between the two species. However, each species harbors unique alleles, and allele frequencies differ significantly. A Bayesian analysis of genetic structure in the stand identified two highly differentiated genetic clusters, essentially corresponding to species assignment based on morphology. Data from the four loci were sufficient to assign all 135 trees to one of the two species. In addition, five putative hybrid individuals having intermediate morphologies could be assigned genetically to one or the other species, and all but one had low probability of hybrid ancestry. Overally, only six (4.6%) trees showed >0.05 probability of hybrid ancestry, in all cases their probabilities for nonhybrid ancestry were substantially higher. We conclude that adult hybrids of Q. douglasii * Q. lobata are rare at this site and plasticity in morphological characters may lead to overestimates of hybridization among Quercus species. PMID- 21665608 TI - Additional observations on Rhynchosperma quinnii (Medullosaceae): a permineralized ovule from the Chesterian (Upper Mississippian) Fayetteville Formation of Arkansas. AB - New ovules from the Fayetteville Formation (Upper Mississippian) of Arkansas expand our knowledge of the morphology and anatomy of Rhynchosperma and suggest it was produced by a medullosan seed fern. Rhynchosperma has been described as radially symmetrical with a two-layered integument and vascularization in the integument only. The apical portion of the integument is ribbed; the nucellus is fused to the integument and apically differentiated into a dome-shaped pollen chamber. The vascular system is incompletely known and apparently restricted to the base of the integument. The new specimens are like Rhynchosperma in external shape, size, number of ribs, and numerous histological features. However, new data reveal that the nucellus is vascularized by a sheath of tracheids, the integument is vascularized by discrete bundles, the pollen chamber has a nucellar beak, and the nucellus is attached to the integument for a variable distance from the base. In addition, the integument is tripartite with an elaborate apical region; ribs formed by the integument are more pronounced at the apex; and internally open, hollow lobes form a stellate micropylar canal. The presence of a tripartite integument, the nature of the vascular system, the nucellus-integument attachment, the pollen chamber structure, symmetry, and the association with medullosan vegetative remains suggest medullosan affinity for these ovules and strengthens the evidence for the origin of the family before the end of the Lower Carboniferous. PMID- 21665609 TI - Molecular data place Hydnoraceae with Aristolochiaceae. AB - Utilization of molecular phylogenetic information over the past decade has resulted in clarification of the position of most angiosperms. In contrast, the position of the holoparasitic family Hydnoraceae has remained controversial. To address the question of phylogenetic position of Hydnoraceae among angiosperms, nuclear SSU and LSU rDNA and mitochondrial atp1 and matR sequences were obtained for Hydnora and Prosopanche. These sequences were used in combined analyses that included the above four genes as well as chloroplast rbcL and atpB (these plastid genes are missing in Hydnoraceae and were hence coded as missing). Three data sets were analyzed using maximum parsimony: (1) three genes with 461 taxa; (2) five genes with 77 taxa; and (3) six genes with 38 taxa. Analyses of separate and combined data partitions support the monophyly of Hydnoraceae and the association of that clade with Aristolochiaceae sensu lato (s.l.) (including Lactoridaceae). The latter clade is sister to Piperaceae and Saururaceae. Despite over 11 kilobases (kb) of sequence data, relationships within Aristolochiaceae s.l. remain unresolved, thus it cannot yet be determined whether Aristolochiaceae, Hydnoraceae, and Lactoridaceae should be classified as distinct families. In contrast to most traditional classifications, molecular phylogenetic analyses do not suggest a close relationship between Hydnoraceae and Rafflesiaceae. A number of morphological features is shared by Hydnoraceae and Aristolochiaceae; however, a more resolved phylogeny is required to determine whether these represent synapomorphies or independent acquisitions. PMID- 21665610 TI - A comparison of the taxonomic richness of temperate plants in East Asia and North America. AB - The taxonomic richness of seed plants at different taxonomic levels was compared between temperate East Asia and North America at both continental and semi continental scales. In each comparison, land area and latitude range were adjusted to a comparable level between the two continental regions. East Asia is significantly more diverse than North America. In general, differences in taxonomic diversity arise at and below the genus level. At the continental scale, East Asia has 1.3 and 1.5 times as many genera and species, respectively, as North America. The northern part of East Asia has 1.1 times as many species as the northern part of North America. At the genus level, the northern part of East Asia is less diverse than the northern part of North America by a factor of 0.94. This pattern indicates that the diversity bias between the two continental regions results from the flora of southern East Asia. The diversity differences between East Asia and North America are not homogenously distributed across different plant groups. At the species level, East Asia had significantly more species than expected in magnoliids, alismatids, Liliidae, ranunculids, and rosids and had significantly less species in the Commelinidae, Caryophyllidae, and euasterids than North America. PMID- 21665611 TI - Phylogeny of Capparaceae and Brassicaceae based on chloroplast sequence data. AB - Capparaceae and Brassicaceae have long been known to be closely related families, with the monophyly of Capparaceae more recently questioned. To elucidate the relationship between Brassicaceae and Capparaceae as well as to address infrafamilial relationships within Capparaceae, we analyzed sequence variation for a large sampling, especially of Capparaceae, of these two families using two chloroplast regions, trnL-trnF and ndhF. Results of parsimony and likelihood analyses strongly support the monophyly of Brassicaceae plus Capparaceae, excluding Forchhammeria, which is clearly placed outside the Brassicaceae and Capparaceae clade and suggest the recognition of three primary clades-Capparaceae subfamily (subf.) Capparoideae, subf. Cleomoideae, and Brassicaceae. Capparaceae monophyly is strongly contradicted with Cleomoideae appearing as sister to Brassicaceae. Two traditionally recognized subfamilies of Capparaceae, Dipterygioideae and Podandrogynoideae, are embedded within Cleomoideae. Whereas habit and some fruit characteristics demarcate the three major clades, floral symmetry, stamen number, leaf type, and fruit type all show homoplasy. Clades within Capparoideae show a biogeographical pattern based on this sampling. These results are consistent with several alternative classification schemes. PMID- 21665612 TI - Response of an allergenic species, Ambrosia psilostachya (Asteraceae), to experimental warming and clipping: implications for public health. AB - We examined the responses of an allergenic species, western ragweed (Ambrosia psilostachya DC.), to experimental warming and clipping. The experiment was conducted in a tallgrass prairie in Oklahoma, USA, between 1999 and 2001. Warming increased ragweed stems by 88% when not clipped and 46% when clipped. Clipping increased ragweed stems by 75% and 36% in the control and warmed plots, respectively. In 2001, warming resulted in a 105% increase in ragweed aboveground biomass (AGB), and the ratio of ragweed AGB to total AGB increased by 79%. Dry mass per ragweed stem in the warmed plots was 37% and 38% greater than that in the control plots in 2000 and 2001, respectively. Although warming caused no difference in pollen production per stem, total pollen production increased by 84% (P < 0.05) because there were more ragweed stems. Experimental warming significantly increased pollen diameter from 21.2 MUm in the control plots to 23.9 MUm in the warmed plots (a 13% increase). The results from our experiment suggest that global warming could aggravate allergic hazards and thereby jeopardize public health. PMID- 21665613 TI - Delayed and carryover effects of salinity on flowering in Iris hexagona (Iridaceae). AB - Saltwater intrusion into wetland ecosystems has destroyed or damaged many native plant populations. Iris hexagona is a salt-sensitive species that exhibits intraspecific variation in salinity tolerance. To investigate the effect of salinity on flowering, we exposed I. hexagona collected from natural populations to salt treatments in a common garden. Experimental salinity additions strongly delayed flowering phenology, but the effect was not apparent until the second year, when less than 4 g/L NaCl delayed flowering up to 3 d. In the field, soil salinity and flowering phenology varied substantially within I. hexagona populations. Iris flowers are receptive to pollinators for 2 d or less, therefore a 3-d delay could affect outcrossing dynamics, and ultimately, the evolutionary ecology of iris populations. Salinity also had a carryover effect; prior salinity exposure delayed flowering in irises that had been replanted in freshwater conditions for 6 mo. This is an important result because it suggests that episodic stress (such as tropical storms) can influence performance well after the stress has disappeared. Our research further underscores the importance of long-term studies because a 1-yr experiment would have failed to reveal the strong effects of salinity that emerged in the second year. PMID- 21665614 TI - Diversity and host specificity of endophytic Rhizoctonia-like fungi from tropical orchids. AB - All orchids have an obligate relationship with mycorrhizal symbionts. Most orchid mycorrhizal fungi are classified in the form-genus Rhizoctonia. This group includes anamorphs of Tulasnella, Ceratobasidium, and Thanatephorus. Rhizoctonia can be classified according to the number of nuclei in young cells (multi-, bi-, and uninucleate). From nine Puerto Rican orchids we isolated 108 Rhizoctonia-like fungi. Our isolates were either bi- or uninucleate, the first report of uninucleate Rhizoctonia-like fungi as orchid endophytes. We sequenced the internal transcribed spacer (ITS) region of nuclear ribosomal DNA from 26 isolates and identified four fungal lineages, all related to Ceratobasidium spp. from temperate regions. Most orchid species hosted more than one lineage, demonstrating considerable variation in mycorrhizal associations even among related orchid species. The uninucleate condition was not a good phylogenetic character in mycorrhizal fungi from Puerto Rico. All four lineages were represented by fungi from Tolumnia variegata, but only one lineage included fungi from Ionopsis utricularioides. Tropical epiphytic orchids appear to vary in degree of specificity in their mycorrhizal interactions more than previously thought. PMID- 21665615 TI - A QTL controlling stem morphology and vascular development in Lycopersicon esculentumxLycopersicon hirsutum (Solanaceae) crosses is located on chromosome 2. AB - The vascular tissue of higher plants is organized into a continuous and unified system that undergoes a transition between two highly differentiated structures, the root and the shoot. This transition was studied in tomato by investigating the genetic basis of morphological variation between Lycopersicon esculentum and L. hirsutum LA407. Our analysis concentrated on morphology in stem cross sections, and we detected heritable genetic differences in an inbred backcross population having L. esculentum as the recurrent parent and LA407 as the donor parent. Inbred backcross line (IBL) 2353 contained a donor segment from chromosome 2 and retained features of the LA407 stem vascular morphology. Marker trait analysis of vascular structure in a cross between IBL 2353 and L. esculentum showed significant (0.0001 <= P <= 0.0375) associations between markers on chromosome 2 and the size of primary vascular bundles, the shape of the vascular system, and the thickness of the secondary vascular tissue. Families with LA407 DNA for the markers on chromosome 2 had larger primary vascular bundles, more developed secondary vascular tissue, and a triangular vascular shape. These results suggest that the distal portion of chromosome 2 in LA407 contains a locus or loci affecting vascular morphology and development. PMID- 21665616 TI - Floral anatomy and systematics of Alliaceae with particular reference to Gilliesia, a presumed insect mimic with strongly zygomorphic flowers. AB - The floral structure of Alliaceae is assessed in relation to the systematics of the family, especially the nature of the component parts of the remarkably insect like flower of Gilliesia graminea. Both presence of solid styles and possession of tenuinucellate ovules represent consistent synapomorphies for Alliaceae and support the separation of Agapanthus and Themidaceae from Alliaceae. Within Alliaceae, absence of septal nectaries (i.e., complete fusion of carpel margins) is a synapomorphy for the sister genera Gilliesia and Gethyum; septal nectaries are present in all other Alliaceae. A gynobasic style and reduced ovule number are probable synapomorphies for the genus Allium. In contrast to most other Alliaceae, in Gethyum and Gilliesia only three (abaxial) stamens (A1, a1, a2) are expressed, as in the apostasioid orchid Neuwiedia, but the perianth of Gethyum is only slightly bilaterally symmetric (zygomorphic), whereas Gilliesia graminea shows bilateral symmetry in all three floral whorls: perianth (suppression of the inner adaxial tepal in most flowers), androecium (suppression of three adaxial stamens), and gynoecium (slight bilateral symmetry, evident in transverse section). The precise relationships of Miersia and Solaria, the other two genera of Alliaceae with bilaterally symmetric flowers, are unknown, but their morphology indicates a close relationship with Gilliesia and Gethyum. Appendages of tepaline origin occur in Gethyum, Gilliesia, and Miersia; their papillate epidermis suggests that they function as osmophores. Their presence in Miersia, which has six stamens, indicates that these novel structures, which develop late in floral ontogeny, evolved independently from stamen suppression in this group. Within Gilliesia graminea, the genetic mechanisms controlling tepal number and shape are apparently unstable, resulting in fluctuating asymmetry. In G. graminea the possession of insect mimicry, presence of osmophores and absence of nectar together indicate a deceitful pollination mechanism similar to that of some Orchidaceae; this would make Gilliesia highly unusual among non-orchid monocots, given that pollination by sexual deceit is normally regarded as exclusive to orchids. PMID- 21665617 TI - Developmental morphology and structural homology of corolla-androecium synorganization in the tribe Amorpheae (Fabaceae: Papilionoideae). AB - Comparative developmental morphology was used to assess structural homology of flowers in Dalea, Marina, and Psorothamnus of the tribe Amorpheae (Fabaceae: Papilionoideae). Dalea, Marina, and some species of Psorothamnus have an unusual petal-stamen synorganization (stemonozone) in which free petals are inserted on a region that is continuous with fused stamen filaments. Developmental studies of these three genera demonstrated similarity during organogenesis. Zonal growth results in several synorganized regions, including the stemonozone of Dalea, Marina, and some Psorothamnus. Psorothamnus species that lack a stemonozone have fused stamens and free petals inserted on the hypanthium, as in most other papilionoid legumes. We concluded that the stemonozone is not strictly homologous to either androecium or receptacle, but that it is the product of a modified androecial developmental program. In the prairie clover daleas, petaloid structures positioned between the stamens have been variously interpreted as petals or as staminodes; we infer that they have an extreme form of the daleoid stemonozone, on which five petals (no staminodes) and five stamens are inserted. Assessing structural homology of these flowers allows us to characterize accurately daleoid morphology for evolutionary studies in the tribe Amorpheae. PMID- 21665618 TI - The influence of light on paternal plants in Campanula americana (Campanulaceae): pollen characteristics and offspring traits. AB - Offspring trait expression is determined by the combination of parental genes and parental environments. Although maternal environmental effects have been widely characterized, few studies have focused on paternal environmental effects. To determine whether light availability influences pollen and offspring traits in the woodland herb Campanula americana, we reared clones of 12 genotypes in two light levels. In the parental generation we measured pollen number and size. Plants grown under high light produced more pollen grains per flower than those grown under low light. However, the response was genotype specific; some individuals responded little to changes in light availability while others substantially reduced pollen production. As a consequence, paternity ratios may vary between light environments if more pollen is associated with greater siring success. We crossed a subset of these plants to produce the offspring generation. The paternal and maternal light environments influenced offspring seed mass, percentage germination, and days to germination, while only maternal light levels influenced later life traits, such as leaf number and size. Maternal and paternal environmental effects had opposite influences on seed mass, percentage germination and days to germination. Finally, there was no direct relationship between light effects on pollen production and offspring trait expression. PMID- 21665619 TI - The transition to gender dimorphism on an evolutionary background of self incompatibility: an example from Lycium (Solanaceae). AB - Populations of three North American species of Lycium (Solanaceae) are morphologically gynodioecious and consist of male-sterile (i.e., female) and hermaphroditic plants. Marked individuals were consistent in sexual expression across years and male sterility was present throughout much of the species' ranges. Controlled pollinations reveal that L. californicum, L. exsertum, and L. fremontii are functionally dioecious. Fruit production in females ranged from 36 to 63%, whereas hermaphrodites functioned essentially as males. Though hermaphrodites were mostly male, investigation of pollen tube growth reveals that hermaphrodites of all dimorphic species were self-compatible. Self-fertilization and consequent inbreeding depression are commonly invoked as important selective forces promoting the invasion of male-sterile mutants into cosexual populations. A corollary prediction of these models is that gender dimorphism evolves from self-compatible ancestors. However, fruit production, seed production, and pollen tube number following outcross pollination were significantly higher than following self-pollination for three diploid, cosexual species that are closely related to the dimorphic species. The data presented here on incompatibility systems are consistent with the hypothesis that polyploidy disrupted the self incompatibility system in the gynodioecious species leading to the evolution of gender dimorphism. PMID- 21665620 TI - The vulnerability to freezing-induced xylem cavitation of Larrea tridentata (Zygophyllaceae) in the Chihuahuan desert. AB - The temperature dependence of freezing-induced xylem cavitation was studied in a Chihuahuan desert population of Larrea tridentata (Zygophyllaceae). Field measurements of wood temperature and xylem embolism were combined with anatomical studies and laboratory measurements of embolism in stem and root samples frozen under controlled conditions. Our laboratory experiments corroborated the previously observed relationship between minimum freezing temperature and embolism. The area of the low-temperature exotherms produced during the freezing treatments was correlated with the resulting embolism, suggesting that the freezing of water inside parenchyma cells is associated with the occurrence of xylem embolism. In the laboratory experiments, embolism in stems increased only at temperatures below -14 degrees C. Although this meant that the studied population was more resistant to freezing-induced xylem embolism than a previously studied population from the Sonoran desert, the impact of freezing was nevertheless greater because of much lower environmental temperatures. This result suggests that dieback associated with periodic extreme freezes may contribute to limiting the present distribution of L. tridentata in central New Mexico. Although laboratory experiments showed that root xylem embolism increased after freezing to less negative minimum temperatures than stems (significant effects at T = -7 degrees C), root embolism in the field was lower than shoot embolism in accordance with measured soil temperatures throughout the study. PMID- 21665621 TI - Decline of photosynthetic capacity with leaf age and position in two tropical pioneer tree species. AB - The effect of leaf age on photosynthetic capacity, a critical parameter in the theory of optimal leaf longevity, was studied for two tropical pioneer tree species, Cecropia longipes and Urera caracasana, in a seasonally dry forest in Panama. These species continuously produce short-lived leaves (74 and 93 d, respectively) during the rainy season (May-December) on orthotropic branches. However, they differ in leaf production rate, maximum number of leaves per branch, light environment experienced by the leaves, leaf mass per unit area, and nitrogen content. Light-saturated photosynthetic rates for marked leaves of known ages (+/-1 wk) were measured with two contrasting schemes (repeated measurements vs. chronosequence within branch), which overall produced similar results. In both species, photosynthetic rates and nitrogen use efficiency were negatively correlated with leaf age and positively correlated with light availability. Photosynthetic rates declined faster with leaf age in Cecropia than in Urera as predicted by the theory. The rate of decline was faster for leaves on branches with faster leaf turnover rates. Nitrogen per unit leaf area decreased with leaf age only for Urera. Leaf mass per unit area increased with leaf age, either partly (in Cecropia) or entirely (in Urera) due to ash accumulation. PMID- 21665622 TI - Root deployment and shoot growth for two desert species in response to soil rockiness. AB - Soil texture, as well as the presence of rocks, can determine the water status, growth, and distribution of plants in arid environments. The effects of soil rockiness and soil particle size distribution on shoot and root growth, root system size, rooting depth, and water relations were therefore investigated for the Crassulacean acid metabolism leaf succulent Agave deserti and the C(4) bunchgrass Pleuraphis rigida after precipitation events during the summer and winter/spring rainfall periods in the northwestern Sonoran Desert. The soils at the field site varied from sandy (<3% rocks by volume) to rocky (up to 35% rocks), with greater water availability at higher water potentials for sandy than for rocky soils. Although A. deserti was absent from the sandiest sites, its shoot and root growth during both rainfall periods were greatest in comparatively sandier sites and decreased as the soil rock content increased. Furthermore, A. deserti had twofold greater root surface area, root : leaf area ratio, and mean rooting depth at sandier than at rocky sites. As for A. deserti, shoot growth was greater for P. rigida at the sandier sites than at the rockier sites, even though its root surface area and mean rooting depth did not vary significantly. After early spring rainfall events, the leaf water potential for A. deserti did not differ between rocky and sandy sites, but transpiration rates were almost twofold greater at rocky than at sandy sites. During the same period, P. rigida had lower leaf water potentials and 25% lower transpiration rates at rocky than at sandy sites. The greater variability in the deployment of the root systems of A. deserti in response to soil rockiness may reflect its evergreen habit and slower growth, which allow it to endure periods of lower water availability than does P. rigida, whose leaves die during drought. PMID- 21665623 TI - Triuridaceae fossil flowers from the Upper Cretaceous of New Jersey. AB - We report here on a series of fossil flowers exhibiting a mosaic of characters present in the extant monocot family Triuridaceae. Phylogenetic analyses of morphological data from a broad sample of extant monocots confirm the affinities of the fossils with modern Triuridaceae. The fossil flowers were collected from outcrops of the Raritan Formation (Upper Cretaceous, ~90 million years before present), New Jersey, USA. These are the oldest known unequivocal monocot flowers. Because other reports of "earliest" monocots are all based on equivocal character suites and/or ambiguously preserved fossil material, the Triuridaceae fossils reported here should also be considered as the oldest unequivocal fossil monocots. Flowers are minute and unisexual (only male flowers are known); the perianth is composed of six tepals, lacking stomata. The unicyclic androecium is of three stamens with dithecal, monosporangiate, extrorse anthers that open by longitudinal slits. The endothecium has U-shaped type thickenings. Pollen grains are monosulcate. The triurid fossil flowers can be separated into three distinctive species. On the basis of phylogenetic analyses of morphological characters, the fossil taxa nest within the completely saprophytic achlorophyllous Triuridaceae supporting the interpretation that the extinct plants were also achlorophyllous and saprophytic. If so, this represents the earliest known fossil occurrence of the saprophytic/mycotrophic habit in angiosperms. PMID- 21665624 TI - Hapsidoxylon terpsichorum gen. et sp. nov., a stem with unusual anatomy from the Triassic of Antarctica. AB - The Middle Triassic flora of the Fremouw Formation in the central Transantarctic Mountains consists of conifers, cycads, ferns, pteridosperms, and sphenophytes. Stems with an unusual anatomy have been discovered within silicified peat from the same locality. The diameters of the stems range from 1.4 to 1.7 cm; the longest specimen is approximately 12 cm. In transverse section the vascular system consists of segments that occur as single traces or are connected in the center and anastomose at varying levels within the stem. Each segment contains a bifacial vascular cambium. Secondary tissues of each segment surround a central area of parenchyma and small tracheids presumed to represent primary xylem. Surrounding the stem is a periderm. Traces are produced near the periphery of the axis and consist of radially arranged secondary xylem and a thick periderm. The absence of leaves and reproductive organs leads to uncertain phylogenetic relationships. We are unaware of any Triassic plants with this type of vascular tissue organization, and those plants with a similar type of arrangement occur only in the Devonian and Carboniferous. Possible phylogenetic affinities with the Cladoxylales and Lycophyta are examined, but the anatomical differences, along with stratigraphic age, preclude formal assignment to any known taxon at this time. Therefore, we have assigned it to a new taxon: Hapsidoxylon terpsichorum gen. et sp. nov. PMID- 21665625 TI - A phylogeny of the rice tribe Oryzeae (Poaceae) based on matK sequence data. AB - Phylogenetic relationships were inferred using nucleotide sequences of the chloroplast gene matK for 26 species representing 11 genera of the tribe Oryzeae and three outgroup species. The sequenced fragments varied from 1522 base pairs (bp) to 1534 bp in length with 15.4% variable and 7.9% phylogenetically informative sites when the outgroups were excluded. The aligned sequences were analyzed by maximum parsimony and neighbor-joining methods. Analyses of the sequence data indicated that species of Oryzeae form a strongly supported monophyletic group, concordant with previous morphological and anatomical evidence. The tribe Oryzeae can be divided into two monophyletic lineages, corresponding to the traditionally recognized subtribes Oryzinae and Zizaniinae. The first subtribe consists of Oryza and Leersia, while the subtribe Zizaniinae includes the remaining genera. The matK sequence data did not support the close affinities of the monoecious genera in Oryzeae, implying the possibility of multiple origins of the floral structures in the tribe. It is noteworthy that Porteresia coarctata is closely related to Oryza species, suggesting that it should be treated as a member in the genus Oryza rather than a separate monotypic genus. PMID- 21665626 TI - Experimental hybridizations of Eriophyllum annuals (Asteraceae, Helenieae). AB - Seven of the eight annual species of Eriophyllum, a western North American genus, were studied in greenhouse and garden. Eriophyllum congdonii and E. nubigenum proved to be self-compatible; E. ambiguum, E. multicaule, E. pringlei, and E. wallacei were self-incompatible; E. lanosum was not studied. All combinations of artificial hybridizations were attempted except E. congdonii * E. lanosum. Among the species with n = 7, fertile hybrids came from E. congdonii * E. nubigenum and sterile hybrids from E. ambiguum var. ambiguum * E. pringlei, E. ambiguum var. paleaceum * E. congdonii, E. multicaule, E. nubigenum, and E. pringlei, as well as E. multicaule * E. congdonii and E. multicaule * E. pringlei. The other homoploid combinations failed, as did heteroploid combinations involving the annual species with n = 7 and either E. wallacei (n = 5) or E. lanosum (n = 4). Sterile hybrids were generated in crosses of E. congdonii to the perennial E. lanatum (x = 8). PMID- 21665627 TI - Phylogeny of the Macaronesian endemic Crambe section Dendrocrambe (Brassicaceae) based on internal transcribed spacer sequences of nuclear ribosomal DNA. AB - The 14 species of Crambe L. sect. Dendrocrambe DC. (Brassicaceae) form a monophyletic group endemic to the Canary and Madeira archipelagos. Both parsimony and maximum likelihood analyses of sequence data from the two internal transcribed spacer regions of nuclear ribosomal DNA were used to estimate phylogenetic relationships within this section. These analyses support the monophyly of three major clades. No clade is restricted to a single island, and therefore it appears that inter-island colonization has been the main avenue for speciation in these two archipelagos. The two species endemic to Fuerteventura (C. sventenii) and Madeira (C. fruticosa) comprise a clade, providing the first evidence for a floristic link between the Eastern Canary Islands and the archipelago of Madeira. Both maximum likelihood and weighted parsimony analyses show that this clade is sister to the two other clades, although bootstrap support for this relationship is weak. Parsimony optimizations of ecological zones and island distribution suggest a colonization route from the low-altitude areas of the lowland scrub toward the high-elevation areas of the laurel and pine forests. In addition, Tenerife is likely the ancestral island for species endemic to the five westernmost islands of Gran Canaria, La Gomera, El Hierro, La Palma, and Tenerife. PMID- 21665628 TI - Relationships among seed plants inferred from highly conserved genes: sorting conflicting phylogenetic signals among ancient lineages. AB - Phylogenetic studies based on different types and treatment of data provide substantially conflicting hypotheses of relationships among seed plants. We conducted phylogenetic analyses of sequences of two highly conserved chloroplast genes, psaA and psbB, for a comprehensive taxonomic sample of seed plants and land plants. Parsimony analyses of two different codon position partitions resulted in well-supported, but significantly conflicting, phylogenetic trees. First and second codon positions place angiosperms and gymnosperms as sister clades and Gnetales as sister to Pinaceae. Third positions place Gnetales as sister to all other seed plants. Maximum likelihood trees for the two partitions are also in conflict. Relationships among the main seed plant clades according to first and second positions are similar to those found in parsimony analysis for the same data, but the third position maximum likelihood tree is substantially different from the corresponding parsimony tree, although it agrees partially with the first and second position trees in placing Gnetales as the sister group of Pinaceae. Our results document high rate heterogeneity among lineages, which, together with the greater average rate of substitution for third positions, may reduce phylogenetic signal due to long-branch attraction in parsimony reconstructions. Whereas resolution of relationships among major seed plant clades remains pending, this study provides increased support for relationships within major seed plant clades. PMID- 21665629 TI - Glacial history of the alpine herb Rumex Nivalis (Polygonaceae): a comparison of common phylogeographic methods with nested clade analysis. AB - The glacial history of the alpine herb Rumex nivalis was investigated using amplified fragment length polymorphisms (AFLPs) and restriction fragment length polymorphisms with polymerase chain reaction (PCR-RFLPs) of cpDNA. Both traditional statistical methods widely applied in phylogeographic research and nested clade analysis were used. The AFLPs indicated little geographic structure probably due to the wind-pollinated reproductive system of the dioecious R. nivalis. Because cpDNA haplotypes exhibited distinct distributional patterns, correlation between AFLPs and PCR-RFLPs was low. The results of common statistical methods and of nested clade analysis were largely congruent. Both supported in situ survival of one group of common haplotypes in the Central Alps. For another group of common haplotypes, classical phylogeographic analyses gave strong evidence for survival in peripheral refugia at the northern alpine border, whereas this conclusion was not as clearly supported in the nested clade analysis. Nested clade analysis provided several detailed insights on past and ongoing populational demographic processes. Thus, it is a valuable tool in the phylogeographical analysis of haplotype data, but it should preferably be combined with other statistical analyses. In situations with low genetic variation in cpDNA, classical phylogeographic analytical tools on nuclear DNA will still be the methods of choice. PMID- 21665630 TI - Hybridization in the section Mentha (Lamiaceae) inferred from AFLP markers. AB - The amplified fragment length polymorphism (AFLP) method was used to evaluate genetic diversity and to assess genetic relationships within the section Mentha in order to clarify the taxonomy of several interspecific mint hybrids with molecular markers. To this end, genetic diversity of 62 Mentha accessions from different geographic origins, representing five species and three hybrids, was assessed. Three EcoRI/MseI AFLP primer combinations generated an average of 40 AFLP markers per primer combination, ranging in size from 50 to 500 base pairs (bp). The percentage of markers polymorphic ranged from 50% to 60% across all accessions studied. According to phenetic and cladistic analysis, the 62 mint accessions were grouped into two major clusters. Principal coordinates analysis separated species into well-defined groups, and clear relationships between species and hybrids could be described. Our AFLP analysis supports taxonomic classification established among Mentha species by conventional (morphological, cytological, and chemical) methods. It allows the assessment of phenetic relationships between species and the hybrids M. spicata and M. * piperita, largely cultivated all over the world for their menthol source, and provides new insights into the subdivision of M. spicata, based for the first time on molecular markers. PMID- 21665631 TI - Saponaria pumila (caryophyllaceae) and the ice age in the European alps. AB - The polymerase chain reaction (PCR)-based amplified fragment length polymorphism (AFLP) technique was applied to elucidate the glacial history of the alpine cushion plant Saponaria pumila in the European Alps. Special emphasis was given to a dense sampling of populations. Our data support a survival of S. pumila during the last ice age in at least three refugia, which are characterized by unique marker sets. Patterns of genetic diversity and divergence can be explained by survival in peripheral refugia and additional in situ survival within the ice sheet on peripheral nunataks. A nunatak survival in interior parts of the Alps needs not be postulated to explain our results. The level of genetic diversity is dramatically different between populations (Shannon's diversity index: 0.87 19.86). Some peripheral populations are characterized by a high number of rare fragments indicating long isolation, but not necessarily by a high level of genetic diversity. Parts of the present distributional area were recolonized via recent long-distance dispersal, leading to severely bottlenecked populations lacking private or rare fragments. The combination of our data with palaeogeological and palaeoclimatological evidence allows us to confine Pleistocene refugia to certain regions and to draw a detailed scenario of the glacial and postglacial history of S. pumila. PMID- 21665632 TI - Thigmo responses in plants and fungi. AB - Thigmo mechanisms are adaptations that permit a plant to alter growth rates, change morphology, produce tropisms, avoid barriers, control germination, cling to supporting structures, infect a host plant, facilitate pollination, expedite the movement of pollen, spores, or seeds, and capture prey. Through these varied functions, plant thigmo systems have evolved impressive controls of cell differentiation, localized growth rates, regulated synthesis of novel products, and some elegant traps and projectile systems. For most thigmo events, there will be a dependence upon transmission of a signal from the cell wall through the plasmalemma and into the cytoplasm. We propose the possible involvement of integrin-like proteins, Hechtian strands, and cytoskeletal structures as possible transduction components. Many thigmo mechanisms may use some modification of the calcium/calmodulin signal transduction system, though the details of transduction systems are still poorly understood. While transmission of thigmo signals to remote parts of a plant is associated with the development of action potentials, hormones may also play a role. Thigmo mechanisms have facilitated an enormous array of plant and fungal adaptations that make major contributions to their success despite their relatively sessile or immobile states. PMID- 21665633 TI - Comparative anatomical analysis of the cotyledonary region in three Mediterranean Basin Quercus (Fagaceae). AB - Anatomical changes at the cotyledonary node from the embryo to the seedling stage in Quercus coccifera, Q. ilex, and Q. humilis were investigated by light and scanning electron microscopy techniques. Mature embryos of Q. humilis possess 2-3 pairs of leaf primordia and a pair of cotyledonary buds, whereas in Q. coccifera and Q. ilex there are two incipient primordia, and cotyledonary buds are not observed until 1 wk after germination. In all three species the cotyledonary buds multiply, forming bud clusters, and a vascular connection is well established within 5-6 wk after germination. As development proceeds, the cotyledonary region becomes woody, but buds, which are exogenous in origin, never become embedded in the periderm. In comparison with Q. suber, another native Mediterranean Basin oak, the cotyledonary node is short and axillary buds are not present below the insertion of cotyledons. In addition, starch accumulation in the cotyledonary region is not observed from histological analysis in the three oaks. Therefore, in Q. coccifera, Q. ilex, and Q. humilis seedlings the cotyledonary node can be considered to be an important regenerative structure enabling them to resprout after the elimination of the shoot above the cotyledons, despite the absence of a lignotuberous structure. PMID- 21665634 TI - Correlated variation in microtubule distribution, callose deposition during male post-meiotic cytokinesis, and pollen aperture number across Nicotiana species (Solanaceae). AB - In most flowering plants, a single cytokinesis follows the two meiotic divisions during pollen-grain ontogeny. Aperture pattern (i.e., aperture number and distribution on pollen surface) ontogeny could be linked to the processes ensuring the apportionment of the cytoplasm to the four microspores.This apportionment is achieved by radial arrays of microtubules organized around the nuclei. The cleavage planes are defined in the overlapping regions of opposing arrays extending from different nuclei. We followed the establishment of these arrays in two different lines of plants belonging to the genus Nicotiana that produce pollen grains with different aperture numbers. Different distributions of the microtubules have been observed, which can be interpreted as resulting from variation in the interactions between nuclei; these distributions appear to be correlated with aperture number.As a consequence, we propose that simultaneous cytokinesis allows the formation of multiple pollen morphologies. This mechanism is consistent with aperture number distribution within angiosperms and provides clues to help our understanding of the evolution of aperture number. PMID- 21665635 TI - Slow heating of barley aleurone layers to heat-shock temperature preserves heat shock-sensitive cellular properties. AB - In barley (Hordeum vulgare L. cv. Himalaya) aleurone layers, heat shock causes the selective suppression of alpha-amylase synthesis by destabilizing this secretory protein's mRNA. The lamellar stacks of the endoplasmic reticulum (ER), which serve as the site of alpha-amylase mRNA translation, are dissociated by heat shock, suggesting that heat-shock-induced changes in ER may be important in selectively targeting alpha-amylase mRNAs for destabilization. We have found that samples maintained at heat-shock temperature (40 degrees C) for 18 h recover the ability to synthesize alpha-amylase and that the ER membranes in these samples contain membrane phospholipids with enhanced levels of fatty acid saturation. This present study investigated whether gradual warming to 40 degrees C over 3-6 h (ramping) would preserve alpha-amylase synthesis by permitting ER membrane phospholipid retailoring during the gradual temperature increase. Analyses by sodium dodecyl-sulfate polyacrylamide gel electrophoresis revealed that alpha amylase synthesis was markedly increased in ramped samples. Furthermore, northern hybridization analyses and transmission electron microscopy showed that these samples had increased alpha-amylase mRNA levels and stacks of ER lamellae, respectively. Gas chromatographic analyses of ER membrane phospholipids indicated that the fatty acids of ramped samples were more saturated than their heat shocked counterparts. These data indicate that heat-induced increases in aleurone ER membrane phospholipid fatty acid saturation may be important in maintaining secretory protein expression at normally nonpermissive heat-shock temperatures. PMID- 21665636 TI - Weedy adaptation in Setaria spp. V. Effects of gaseous environment on giant foxtail (Setaria faberii) (Poaceae) seed germination. AB - The effects that naturally occurring gases (oxygen, nitrogen, carbon monoxide) may cause in dormant giant foxtail (Setaria faberii) seed germination under favorable temperature and moisture conditions were investigated. The germination responses to gas mixtures supported the hypothesis that S. faberii germination behavior is regulated by the amount of oxygen taken into hydrated seed over time. Setaria faberii seed germination was markedly affected by O(2) concentration (in N(2)) above and below that of air (20% O(2)): the largest increase in germination (from 37 to 60%) occurred between 20-25% O(2); between 0-10% O(2), germination increased from 0-30%; and surprisingly germination at 10 and 20% O(2) was similar. These observations reveal an asymmetrical response to incremental changes in O(2) above and below that typically found in agricultural soils. Carbon monoxide had opposite effects on S. faberii germination in air depending on concentration, stimulation, and inhibition: germination increased from 37 to 56% with the addition of 1% CO, but decreased from 37 to 14% with 75% added CO. An explanation may be that there are two separate effects of CO, each occurring in different physiological systems of dormant seeds at the same time. At high concentrations (75%) in air CO inhibited seed germination, probably by inhibiting mitochondrial respiration. But low CO concentrations (0.1 or 1%) in air stimulated seed germination. It was not apparent which physiological system(s) CO and O(2) affected. It seems unlikely that CO-stimulated germination arises from effects on the respiratory apparatus, but may be a consequence of CO interactions with an as yet unknown physiological factor in the seed. We provide a model of Setaria spp. dormancy consistent with its seed morphology, the gas-germination data, and the hypothesized second physiological factor that may be involved in CO stimulated germination. PMID- 21665637 TI - Microscopy of a cytoplasmic male-sterile soybean from an interspecific cross between Glycine max and G. soja (Leguminosae). AB - Cytoplasmic male sterility has been found independently in soybean three times since 1995, but no microscopic investigation has been published. The purpose of this microscopic study was to establish the developmental sequence leading to sterility in a cytoplasmic male-sterile soybean line that has been found to be stable under all environmental conditions tested and to demarcate the temporal and spatial parameters that result in degeneration of the microspores and pollen grains. Light microscopy showed an abnormal development and/or premature degeneration of the tapetum after meiosis II, but some pollen grains persisted until after microspore mitosis. The pollen grains never completely filled with reserves. Premature formation of the endothecium also was evident. Histochemical staining for water-insoluble carbohydrates revealed an abnormal pattern of starch deposition in anther walls that coincided with lack of pollen filling. Electron microscopy showed degeneration of the inner mitochondrial membrane in the tapetal cells as the first detectable change leading to cell degeneration. Subsequently, the tapetal endoplasmic reticulum exhibited atypical concentric rings. Pollen grains displayed mitochondria with unusually enlarged inner mitochondrial spaces, degraded plastids, a rudimentary intine, and no starch or lipid reserves. Results link mitochondrial degeneration, premature formation of the endothecium, and energy deprivation to male sterility. PMID- 21665638 TI - Effects of crossing distance and genetic relatedness on pollen performance in Alstroemeria aurea (Alstroemeriaceae). AB - Prezygotic barriers may represent effective mechanisms to avoid the deleterious effects of inbreeding. This study reports the existence of distance-dependent prezygotic barriers in self-compatible Alstroemeria aurea, a clonal herb native to temperate forests of the southern Andes. We analyzed pollen germination and tube growth as indicators of donor-recipient affinity using crossing distances of 1, 10, and 100 m. We used allozyme electrophoresis to determine the actual genetic relatedness between donor and recipient ramets. Pollen germination was not affected by distance between mates, but the number of pollen tubes reaching the base of the style increased strongly with distance between donor and recipient. This pattern was related to an increase in genetic dissimilarity with distance between mates. In contrast, pollen tube-style interactions did not change with distance when we restricted analysis to individuals at different distances that appeared to be genetically identical. This test implied genetic dissimilarity as the critical factor affecting pollen performance. We propose that the existence of prezygotic barriers might contribute to the high degree of genetic mixing exhibited by some clonal species. PMID- 21665639 TI - Diurnal and nocturnal pollination of Silene alba (Caryophyllaceae). AB - Flowers that are open for >12 h may be visited by both diurnal and nocturnal pollinators. I compared the effectiveness (measured as seed production and pollen movement distance) of diurnal and nocturnal pollinators of Silene alba, a species whose flowers open in evening but close by midmorning the following day. By bagging flowers either during evening hours or during daylight hours or both day and night, I compared seed production caused by diurnal and nocturnal pollinators. Flowers exposed only to nocturnal visitors (mostly sphingid and noctuid moths) produced significantly more seeds than flowers exposed only to diurnal visitors (bees, flies, and wasps). Fluorescent dye applied to anthers moved significantly further and to more stigmas at night than during the day. In both measures of pollination effectiveness, nocturnal-visiting moths are better pollinators of S. alba than are the diurnal-visiting bees, flies, and wasps. These data support the hypothesis that floral phenology is an adaptation to expose flowers to the most effective pollinators. PMID- 21665640 TI - Temporal variation in floral display size and individual floral sex allocation in racemes of Narthecium asiaticum (Liliaceae). AB - We analyzed the effects of temporal variation in floral display size (number of flowers open at one time on a plant) on the rate of pollen removed and receipt of individual flowers for the sequential blooming plant Narthecium asiaticum (Liliaceae). Because of the acropetal blooming of this species, the display sizes when upper flowers opened was much greater than the display sizes when lower flowers opened. Our experiments revealed that large displays lead to a high rate of pollen removal from individual flowers, though they do not lead to a high rate of ovule fertilization. Consequently, the rate of pollen grains removed per flower by pollinators was greater in upper flowers than in lower flowers. The pattern of sex allocation in individual flowers within a raceme was consistent with such variation. Namely, both maleness [stamen mass/(stamen mass + pistil mass)] and pollen : ovule ratio were larger in upper flowers. We suggest that the temporal variation in display size, in addition to such factors as dichogamy and pollinator directionality, also produces variation in the probability of successful pollen transfer from individual flowers that may cause the variation in the sex allocation of individual flowers. PMID- 21665641 TI - Population genetics of Intsia palembanica (Leguminosae) and genetic conservation of Virgin Jungle Reserves in Peninsular Malaysia. AB - A field survey of Virgin Jungle Reserve (VJR) compartments in Peninsular Malaysia allowed us to identify six populations of Intsia palembanica for this study. These were Pasoh Forest Reserve (FR) (Pasoh), Sungai Lalang FR (Lalang), Bukit Lagong FR (Lagong), Bubu FR (Bubu), Bukit Kinta FR (Kinta), and Bukit Perangin FR (Perangin). About 40 adult individuals were sampled in each population. In addition, progeny arrays were collected from nine mother plants at Lagong for a mating system study. A total of nine allozymes, encoded by 14 putative gene loci, were consistently resolved in I. palembanica. The mating system study showed that the species exhibited a mixed-mating system, with multilocus outcrossing rate of 0.766. The levels of diversity were comparably high (mean number of alleles per polymorphic locus = 2.4, mean effective number of alleles per polymorphic locus = 1.64, and mean expected heterozygosity (H(e)) = 0.242), and the majority of the diversity was partitioned within population (G(ST) = 0.040 and F(ST) = 0.048). Significant levels of inbreeding were detected in Bubu and Perangin. Probability tests of recent effective population size reduction using the Infinite Allele Model showed the occurrence of genetic bottlenecks on Lalang and Kinta. Two genetically unique populations (Pasoh and Perangin) were inferred using jackknife analysis. By using the neutral mutation rates, effective population size (N(e)) to maintain the H(e) was 80-800 000 individuals. A simulation study based on pooled samples, however, circumscribed the N(e) to 200 and 210 individuals. Implications of the study for managing the species and the VJRs are discussed. PMID- 21665642 TI - A comparison of two methods of calculating GST, a genetic measure of population differentiation. AB - G(ST) is a genetic statistic describing differentiation of populations and has frequently been compared with Hamrick and Godt's (1989) review of the plant literature. We show here that some comparisons may be inappropriate if G(ST) was calculated in a different way than that used by Hamrick and Godt (HG). An alternative method advocated by Nei is mathematically different from the HG technique, occasionally resulting in different G(ST) values. We reviewed 695 studies that appeared between 1990 and September 1999 that cited Hamrick and Godt (1989) and found that many of these calculated G(ST) according to Nei's method (46%), with the majority of these papers (61%) including comparisons to Hamrick and Godt's review. We suggest that if G(ST) estimates are compared across studies, it is most appropriate to calculate them the same way. However, we found that in most cases, the magnitude of difference in G(ST) values was small, suggesting that qualitative comparisons of G(ST) estimates between most studies are probably valid. Nevertheless, we have identified theoretical and empirical situations in which large differences in G(ST) values are likely to arise. Thus, we advise future investigators to carefully consider which method to use in calculating G(ST) for a given data set. PMID- 21665643 TI - Probability of tree seedling establishment changes across a forest-old field edge gradient. AB - Forest edges affect many aspects of plant communities, causing changes in microclimate, species composition, and community structure. However, the direct role of edges in regulating forest regeneration is relatively unknown. The pattern of tree establishment across a forest-old field edge was experimentally examined to determine the response of three tree species to the edge gradient. We placed 100 1-m(2) plots in a 90 * 90 m grid that began 30 m inside the forest, extended across the edge, and ended at 60 m into the old field. Into each plot, we planted seeds of Acer rubrum, Acer saccharum, and Quercus palustris. Emergence increased with distance into the field for both A. saccharum and Q. palustris. Emergence for A. rubrum increased from forest to field, reaching a maximum near 20 m into the field, and then declined with further distance. Nearly all A. rubrum seedlings died shortly after emergence. Survival of A. saccharum increased with distance into the old field, while survivorship of Q. palustris did not respond to the edge gradient. Establishment probabilities increased with distance into the old field for both A. saccharum and Q. palustris. Growth of Q. palustris and allocation patterns of A. saccharum also varied across the edge gradient. These results suggest that edges have complex, species-specific effects on tree establishment and growth that can influence the spatial pattern and species composition of regenerating forests. PMID- 21665644 TI - Habitat divergence between a homoploid hybrid sunflower species, Helianthus paradoxus (Asteraceae), and its progenitors. AB - The diploid hybrid species Helianthus paradoxus is restricted to salt marshes with sodium concentrations that exceed those found in the habitats of its progenitors, H. annuus and H. petiolaris. The observed association with saline habitats has led to the hypothesis that H. paradoxus is more salt tolerant than its progenitors. This hypothesis was tested by growing all three species in three NaCl treatments (0 mmol/L, 100 mmol/L, and 200 mmol/L). Helianthus paradoxus treated with NaCl was found to be more than five times as fit, in terms of biomass and survivorship, than its progenitors. Selection for salt tolerance in early generation hybrids may have contributed to the formation of H. paradoxus because theory predicts that homoploid hybrid speciation is feasible even when selection favoring hybrid genotypes is much weaker. Additionally, we show that H. paradoxus is significantly different from its parental species for several traits that often distinguish salt-tolerant species and suggest a mechanistic basis for the elevated salt tolerance expressed by H. paradoxus. PMID- 21665645 TI - Factors responsible for Honckenya peploides (Caryophyllaceae) and Leymus mollis (Poaceae) spatial segregation on subarctic coastal dunes. AB - Low water and nutrient availability and significant sand movement, salt spray, and soil salinity are typical of coastal dunes. These conditions are generally unfavorable for the various life stages of plants and especially for seedlings. However, the intensity of these stresses decreases landward, even over short distances, with significant effects on community composition. On coastal dunes in subarctic Quebec, Canada, Honckenya peploides (Caryophyllaceae) colonizes the upper beach where it forms small mounds called embryo dunes. Leymus mollis (Poaceae) is mostly restricted to the foredune; however, a few individuals successfully establish on the upper beach, particularly on embryo dunes. We hypothesized that this differential distribution is associated with differences in the tolerance of the two species' seedlings to physical stresses. Honckenya peploides and L. mollis seedling tolerance to sand burial, salt spray, soil salinity, and nutrient and water availability was assessed in greenhouse experiments. Unexpectedly, our results showed that tolerance to sand burial, salt spray, and soil salinity was lower for H. peploides than for L. mollis. If seeds are available and seedlings tolerate the conditions prevailing on the upper beach well, why are mature L. mollis individuals rare in this habitat? We suggest that massive abrasion events (e.g., violent storm waves and ice thrust) restrict the presence of the species on the upper beach. PMID- 21665646 TI - Role of warm stratification in promoting germination of seeds of Empetrum hermaphroditum (Empetraceae), a circumboreal species with a stony endocarp. AB - The broad objective of this research was to define the role of warm (>=15 degrees C) stratification in breaking dormancy in seeds with stony endocarps that require warm-plus-cold (~0 degrees -10 degrees C) stratification for germination. This question was addressed using seeds (true seed + endocarp, hereafter called seeds) of Empetrum hermaphroditum. Only 2-5% of freshly matured seeds collected in September and October at five sites in Sweden germinated in light at daily alternating temperature regimes of 15 degrees /6 degrees , 20 degrees /10 degrees , and 25 degrees /15 degrees C. Dormancy was not due to impermeability of the stony endocarp surrounding each seed, and embryos did not grow prior to radicle emergence. Thus, seeds did not have physical, morphological, or morphophysiological dormancy. Long periods of either cold stratification (20 or 32 wk) or warm stratification (16 wk) resulted in a maximum of 22-38 and 10% germination, respectively, in light at 25 degrees /15 degrees C. After 12 wk warm stratification plus 20 wk cold stratification, 83-93% of the seeds germinated in light at the three temperature regimes. For a cold stratification period of 20 wk, germination increased with increase in length of the preceding warm stratification treatment. Gibberellic acid (GA(3)) promoted germination of 77-87% of the seeds. Based on dormancy-breaking requirements and response to GA(3), 62 78% of the seeds had intermediate physiological dormancy; the others had nondeep physiological dormancy. Contrary to suggestions of several other investigators that warm stratification is required to make the endocarp permeable to water via its breakdown by microorganisms, our results with E. hermaphroditum show that this is not the case. In this species, warm stratification is part of the dormancy-breaking requirement of embryos in seeds with intermediate physiological dormancy. PMID- 21665647 TI - Does clonal integration improve competitive ability? A test using aspen (Populus tremuloides [Salicaceae]) invasion into prairie. AB - Many clonal plants consist of many connected individual ramets, allowing them to share water and nutrients via physiological integration. Integration among ramets may also improve the ability of clonal plants to tolerate abiotic stress or improve the competitive ability of individual ramets. Here I use a field experiment to determine whether clonal integration improves ramet performance for a widespread clonal tree species invading into native prairie. Aspen (Populus tremuloides) dominates the southern treeline in western Canada, has long-lived belowground connections between mother and daughter ramets, and reproduces vegetatively via resprouting rhizomes after disturbance. I applied two competition treatments (neighbors present or absent) and two clonal integration treatments (belowground rhizomes between mother and daughter ramets either severed or left intact) to 12 replicate Populus daughter ramets at each of three sites. Neighbors improved the survivorship of Populus ramets by 25-35% after 2 yr, but decreased growth by ~20%. Clonal integration tended to improve ramet survival and growth, but these trends were often not significant. Clonal integration did not alter the effects of competition from neighboring vegetation, suggesting that connections between ramets do not necessarily improve the competitive ability of Populus invading into native prairie. PMID- 21665648 TI - Impact of tree leaf phenology on growth rates and reproduction in the spring flowering species Trillium erectum (Liliaceae). AB - We investigated the impact of overstory tree leaf phenology on growth rates, carbon allocation pattern, and fruit characteristics in the spring flowering species, Trillium erectum (Liliaceae). Air temperature, overstory canopy closure, and T. erectum phenology were monitored at three locations following a latitudinal gradient in Quebec, Canada. Northern sugar maple trees leaf out at cooler temperatures than more southern populations, while Trillium development was initiated at the same soil temperature irrespective of the latitude. Therefore, in northern areas, the time between initiation of T. erectum leaf expansion and canopy closure was shorter than in southern areas, which left less time for northern plants to accumulate reserves before canopy closure. Differences in growth patterns were noted between T. erectum populations. From a south-north gradient, investment to reproduction, total plant biomass, and annual growth rate decreased, while specific leaf area and stem height increased, indicating shade acclimation. The length of the high light period in early spring seems to be a determinant for spring flowering plants' growth and reproduction and may explain the northern distribution limit of some of these species. PMID- 21665650 TI - Erratum. PMID- 21665649 TI - Phylogenetic relationships in Selaginellaceae based on RBCL sequences. AB - A phylogenetic framework is developed for the clubmoss family Selaginellaceae based on maximum parsimony analyses of molecular data. The chloroplast gene rbcL was sequenced for 62 species, which represent nearly 10% of living species diversity in the family. Taxa were chosen to reflect morphological, geographical, and ecological diversity. The analyses provide support for monophyly of subgenera Selaginella and Tetragonostachys. Stachygynandrum and Heterostachys are polyphyletic. Monophyly of Ericetorum is uncertain. Results also indicate a large number of new groupings not previously recognized on morphological grounds. Some of these new groups seem to have corresponding morphological synapomorphies, such as the presence of rhizophores (distinctive root-like structures), aspects of rhizophore development, and leaf and stem morphology. Others share distinctive ecological traits (e.g., xerophytism). For many groups, however, no morphological, ecological, or physiological markers are known. This could reflect patchy sampling and a lack of detailed knowledge about many species. Despite a lengthy fossil record dating from the Carboniferous Period, cladogram topology indicates that most of the living tropical species are probably the products of more recent diversifications. Resurrection plants, extreme xerophytes characterized by aridity-driven inrolling of branches and rapid revival on rehydration, have evolved at least three times in quite different clades. PMID- 21665651 TI - Chloroplast DNA evidence for the roles of island colonization and extinction in Tolpis (Asteraceae: Lactuceae). AB - Tolpis consists of ~13 species native to Africa, Europe, and Macaronesia, with at least one species endemic to each of the four major archipelagos of the Azores, Madeira Islands, Canary Islands, and Cape Verde Islands. All but two of these species develop woody stems by maturity. Chloroplast DNA restriction site variation was analyzed for all species of Tolpis and four outgroups in order to understand the patterns of island colonization and evolution of woodiness in this genus. Parsimony analyses revealed a strongly supported monophyletic Tolpis. Within the genus, the following three well-supported groups were detected: all species from the Canary Islands and Cape Verde Islands, both Azorean species, and both continental species. The Canary Island/Cape Verde clade was sister to the two continental species, and the Azorean clade was sister to this group. The two Madeiran species of Tolpis occupied the basalmost positions within the genus. When biogeography was mapped onto this phylogeny, nine equally parsimonious reconstructions (five steps each) of dispersal history were detected, which fell into two groups: eight reconstructions implied that Tolpis colonized Madeira from the continent, followed by continental extinction and subsequent continental recolonization, while one reconstruction implied that Tolpis colonized Macaronesia four times. Two of the reconstructions involving continental extinction required the least amount of overall dispersal distance. The cpDNA phylogeny also suggests that woodiness arose in the common ancestor of all extant Tolpis, followed by two independent reversals to an herbaceous habit. Assuming that one of the eight reconstructions favoring continental extinction and recolonization is true, our results suggest that Tolpis may represent the first documented example of a woody plant group in Macaronesia that has recolonized the mainland in herbaceous form. PMID- 21665652 TI - Aristolochia spp. (Aristolochiaceae) pollinated by flies breeding on decomposing flowers in Panama. AB - This study presents breeding and pollination systems of Aristolochia maxima and A. inflata in a seasonal tropical forest of Panama. Aristolochia is the most diverse genus of Aristolochiaceae, with ~120 species distributed throughout the tropics and subtropics. All the Aristolochia species studied so far are pollinated by saprophagous flies of different families, which are presumably deceived by floral odor. Flowers of many species have trap-and-release mechanisms. The flowers attract and imprison pollinators during the female stage first day of flowering and release them after anther dehiscence. Pollination systems of A. maxima and A. inflata are different from those of other Aristolochia in lacking trap mechanisms. Furthermore, the pollinators oviposit in the flowers, and their larvae grow on the fallen, decaying flowers on the ground. Therefore, the plants have a mutualistic relationship with their pollinators. Self-compatible A. inflata is pollinated by Megaselia sakaiae (Phoridae, Diptera). The pollinator may be specialized to Aristolochia flowers, which is the only substrate for larval development. On the other hand, self-incompatible A. maxima is pollinated by Drosophila spp. (Drosophilidae, Diptera), which utilize Aristolochia flowers as a breeding site only occasionally. This pollination mutualism might have evolved from deceit pollination. PMID- 21665653 TI - A diverse assemblage of Anacardiaceae from Oligocene sediments, Tepexi de Rodriguez, Puebla, Mexico. AB - Among the plants collected from the Pie de Vaca Formation of the Oligocene, of Tepexi de Rodriguez, Puebla, Mexico are five plants of Anacardiaceae, Haplorhus medranoensis, Rhus toxicodendron, Rhus sp., Comocladia intermedia, and Pistacia marquezii represented by their leaves and/or leaflets. The past and present diversity and geographic distribution of one of these genera, Rhus, demonstrate its capability to adapt and diversify in a wide variety of environments. Leaf architecture characters of this taxon overlap with those of other genera in the family, suggesting a high degree of phenotypic plasticity. The presence in the Pie de Vaca Formation of a type of Pistacia with leaf architecture characters similar to those of Asian plants further supports a long history of exchange between low-latitude North America and Asia. Links between low-latitude North and South America and the Caribbean are suggested by the presence of Comocladia and Haplorhus. Whereas Comocladia highlights the long history of regional endemics in the area, Haplorhus, today an endemic monotypic genus of Peru, suggests exchange mechanisms between North and South America. The morphologic characters of these taxa, and those of Pseudosmodingium (Anacardiaceae), some Rosaceae, Leguminosae, and Berberidaceae, suggest that the Pie de Vaca community was established and evolved in harsh environmental conditions. The Pie de Vaca flora thus provides significant new insights into the biogeographic relationships of the low latitude vegetation of North America. PMID- 21665654 TI - Erratum. PMID- 21665655 TI - Karyotypic studies in Turnera sidoides complex (Turneraceae, Leiocarpae). AB - Turnera sidoides, with the most southerly distribution of all Turnera species in America, is a complex of obligately outcrossing perennial herbs. Karyotypes of the five subspecies of T. sidoides (x = 7) are described for the first time utilizing root-tip mitotic metaphases. Different ploidy levels were found for all of the subspecies, ranging from diploid to octoploid. The results obtained, coupled with available meiotic and preliminary biosystematic data, support the hypothesis of autopolyploidy within this species complex. Although detailed karyotype analysis shows a high degree of intraspecific uniformity, subspecies may be differentiated by the number, type, and position of satellites, suggesting that chromosome rearrangements may also be involved in the karyotypic evolution of T. sidoides. Karyotype data, coupled with morphological and anatomical features, suggest the removal of T. sidoides from series Leiocarpae. PMID- 21665656 TI - Molecular mapping of the fasciation mutation in soybean, Glycine max (Leguminosae). AB - The spontaneous fasciation mutation generates novel developmental diversity in cultivated soybean, Glycine max (L.) Merrill. An increased apical dominance in the mutant inhibits axillary buds, causes a branchless phenotype, and restricts reproduction to shoot apices. The fasciation mutation is encoded by a recessive (f) allele at a single locus. The mutation, despite its importance in soybean development, has no locus assignment on previously reported molecular maps of soybean. A population of 70 F(2) progeny was derived from a cross between 'Clark 63' and the fasciation mutant. More than 700 molecular markers (amplified restriction fragment length polymorphisms [AFLPs], random amplified polymorphic DNAs [RAPDs], restriction fragment length polymorphisms [RFLPs], and simple sequence repeats [SSRs]) were used in mapping of the fasciation phenotype. Twenty linkage groups (LGs) corresponding to the public soybean molecular map are represented on the Clark 63 * fasciation mutant molecular map that spans 3050 centimorgans (cM). The f locus was mapped on LG D1b+W and linked with two AFLPs and four SSR markers (Satt005, Satt141, Satt600, and Satt703). No linkage was found between the f locus and several cDNA polymorphic loci between the wild type and the mutant. The known map position of the f locus and demonstration of the mutant phenotype from early postembryonic throughout reproductive stages provide an excellent resource for investigations of molecular mechanisms affecting soybean ontogeny. PMID- 21665657 TI - Genetic variation at allozyme and RAPD markers in Pinus longaeva (Pinaceae) of the White Mountains, California. AB - We compared genetic diversity estimated from allozymes and from random amplified polymorphic DNA (RAPDs) in a sample of 210 Great Basin bristlecone pines (Pinus longaeva Bailey) from three groves in the White Mountains, California, USA. The White Mountains are the most westerly extension of bristlecone pine and home to the oldest known living trees. We assayed two forks of each tree to determine whether they originated from multiple seed caches of the Clark's nutcracker. Despite the limited and fragmented distribution of bristlecone pine, its level of genetic diversity was comparable to that of other pines, but lower than that reported for eastern populations of Great Basin bristlecone pine. Twenty-six of 36 allozymes were polymorphic (p(95) = 38.9%; p = 63.0%), with observed heterozygosity (H(o)) of 0.122 and expected heterozygosity (H(e)) of 0.134. The proportion of the total variation among populations (G(ST)) was only 0.011. The high proportion of trees with multiple stems was not due to germination in seed caches; only six of 210 forked trees had multiple allozyme genotypes. Of the 42 RAPD loci scored, 27 were monomorphic. Genetic diversity for RAPDs was nearly the same as that for allozymes (p(95) = 34.1%, H(e) = 0.130). However, the estimates of diversity and differentiation were much higher (H(e) = 0.321, G(ST) = 0.039) after excluding monomorphic loci. PMID- 21665658 TI - Application of methyl jasmonate on Picea abies (Pinaceae) stems induces defense related responses in phloem and xylem. AB - Application of 100 mmol/L methyl jasmonate (MJ) to the intact bark of 30-yr-old Norway spruce induced anatomical reactions related to defense. Within 30 d, a single MJ treatment induced swelling of existing polyphenolic parenchyma cells (PP cells) and an increase in their phenolic contents and formation of additional PP cells and of traumatic resin ducts (TDs) at the cambial zone. These changes occurred up to 7 cm away from the application zone. Treatment enhanced resin flow and increased resistance to the blue-stain fungus, Ceratocystis polonica. Methyl jasmonate application to the oldest internode of 2-yr-old saplings also induced TD formation, and, more surprisingly, TDs were formed in the untreated internode. Traumatic ducts were not formed in branches, ruling out an effect of volatile MJ on the upper internode. Methyl jasmonate application never gave rise to a hypersensitive response, cell death, tissue necrosis, or wound periderm, indicating the amount of MJ transported across the periderm was very low relative to the application concentration. This is the first report of a single compound giving rise to major cellular features related to acquired resistance and previously shown to be induced by wounding, fungal infection, and bark beetles in Norway spruce. PMID- 21665659 TI - Floral longevity in Campanula americana (Campanulaceae): a comparison of morphological and functional gender phases. AB - Plastic responses to pollination and/or pollen removal may shift a flower's realized longevity closer to an optimal longevity that maximizes reproductive output per unit resource input. In particular, conditional responses to pollen removal and pollen deposition are expected in flowers of protandrous species in which the lengths of the male and female phases may be adjusted independently. We investigated plasticity in floral longevity in Campanula americana, a protandrous, insect-pollinated herb. In greenhouse studies, we found that the longevity of the morphological male phase was shortened by pollen removal and that the longevity of the morphological female phase was shortened by pollen deposition. In a natural population, male and female sexual functions saturated within a few hours of morphological gender phase onset. In contrast to theory, morphological gender phases did not terminate immediately upon saturation of sexual function. These findings are discussed in the context of current floral longevity theory. PMID- 21665660 TI - Maintenance of sexually dimorphic preadult traits in Marchantia inflexa (Marchantiacae). AB - Marchantia inflexa, a dioecious thallose liverwort, is sexually dimorphic in clonal expansion traits. We used selection analyses to measure the magnitude and direction of selection on clonal fitness to uncover possible mechanisms for the maintenance of preadult sexually dimorphic characters. We planted replicates of genotypes of female and male M. inflexa in two light environments in a greenhouse and measured morphological and phenological characters associated with growth and asexual reproduction. Timing to onset of asexual reproduction and plant size early in development were under sex-specific selection in a low light environment. Additionally, females exhibited a sex-specific cost of plasticity in the timing of their onset of asexual reproduction in high light. Selection on asexual fitness tended to shift traits toward monomorphism rather than sexual dimorphism, whereas the expressed phenotype of females was congruent with patterns of selection acting on sexual fitness. We detected negative trade-offs between asexual and sexual fitness components in females in one light environment. Opposing selective forces acting on asexual and sexual fitness components may explain how sexual dimorphisms persist in the face of selection for monomorphism in the preadult phase. PMID- 21665661 TI - Genetic variation in Bromus tectorum (Poaceae): differentiation in the eastern United States. AB - Bromus tectorum, a devastating plant invader in western North America, had entered Pennsylvania by 1790. Although rare, or extirpated, in the east until the 1850s, it was collected with increasing frequency after 1859 from Vermont to Virginia. Using enzyme electrophoresis, we analyzed 38 populations of this grass in the eastern U.S. to determine their genetic variation and structure as well as assess their relatedness to populations in the west. Genetic variation among eastern U.S. populations is low: mean number of alleles per locus (A), percent polymorphic loci per population (%P), and expected heterozygosity (H(exp)) are 1.01, 1.05%, and 0.002, respectively. No heterozygotes were detected. The eastern populations are genetically similar: mean genetic identity for all populations was 0.990 with values among population pairs ranged from 0.913 to 1.000. Thirteen populations in eastern and western North America shared Pgm-1a and Pgm-2a, while eight populations shared Mdh-2b and Mdh-3b. Other alleles detected in western North America (Got-4c, Got-4d, and Pgi-2b) were not, however, found in eastern U.S. populations. The invasion of North America by B. tectorum occurred through multiple introductions on both coasts; results from historical and genetic evidence suggest that eastern populations stem from a minimum of two introductions. The 19th century westward spread of B. tectorum from the East appears to be plausible. PMID- 21665662 TI - Genetic diversity in Delphinium variegatum (Ranunculaceae): a comparison of two insular endemic subspecies and their widespread mainland relative. AB - Delphinium variegatum is subdivided into three subspecies: D. v. variegatum is widespread in central and northern California, while D. v. kinkiense (an endangered taxon) and D. v. thornei are endemic to San Clemente Island off the coast of southern California. Electrophoretic data for 19 loci were collected from 7 populations of the mainland subspecies and all 24 known populations of the two insular endemic subspecies. Populations of the widespread mainland subspecies have more polymorphic loci (33.6% vs. 24.5%) and more alleles per polymorphic locus (2.61 vs. 2.15) than the insular endemic subspecies. However, observed heterozygosities are lower in the mainland subspecies (0.041 vs. 0.071), presumably due to lower levels of outcrossing (t = 0.464 vs. 0.895). Expected heterozygosities are similar (0.064 vs. 0.074) due to lower alternative allele frequencies in populations of the mainland subspecies (mean q = 0.075 vs. 0.190). Populations of the two insular subspecies are almost equivalent genetically (mean I = 0.997) regardless of taxonomic designation or geographic location. In contrast, one of the mainland populations is genetically well differentiated from the others. If this exceptional population is excluded, the mainland subspecies partitions genetic diversity similarly to the island subspecies, with most variation being found within populations (G(ST) = 0.073 vs. 0.030). PMID- 21665663 TI - Saltwater spray as an agent of natural selection: no evidence of local adaptation within a coastal population of Triplasis purpurea (Poaceae). AB - An ability to tolerate airborne saltwater spray is critical for plant populations in coastal environments. The opportunity for continued microevolution for improved salt tolerance can exist if there is variation in the response of genetic families to saltwater spray. Our objective was to determine whether or not there was differentiation among subpopulations near (15 m) and far (80 m) from shore and among families within subpopulations in relation to the effects of salt spray on life history traits in a population of the dunegrass Triplasis purpurea. In this annual, most seeds are matured in cleistogamous spikelets on axillary, leaf-sheath enclosed panicles and show poor dispersal capacity. Plants were reared in the greenhouse from seeds of 13 and 11 families from the near and far subpopulations, respectively. Fifty percent of plants in a family were subjected to 6 seawater sprays/wk, resulting in weekly salt deposition of 213 MUg/cm(2); the others were sprayed with distilled water. Data were recorded on life span, tiller numbers, root and shoot dry mass, and seed production. There was no effect of subpopulation on any measured trait and, hence, no evidence for local adaptation to salt spray. Final tiller numbers, but not dry mass or seed production, were reduced by salt spray. However, for most traits there were significant family (within subpopulation) effects, indicating genetic substructuring. Life span and mean seed mass showed a significant family by treatment interaction, indicating genetic variation in phenotypic responses to salt spray. Life span and mean seed mass were reduced by salt spray in some, but not all, families. Path analysis revealed that an increase in life span or tiller number indirectly increased seed production via direct effects on vegetative mass. For this relatively salt-tolerant T. purpurea population on the south shore of Staten Island, New York, USA, salt sprays may not be a significant agent of natural selection. However, there are pronounced phenotypic differences among inbred family groups and opportunity for genetic substructuring within these subpopulations. Variable effects of salt spray among families could result in microevolutionary changes in life span and mean seed mass, both of which impact annual fitness in this dunegrass. PMID- 21665664 TI - Propagation mechanisms in Agave macroacantha (Agavaceae), a tropical arid-land succulent rosette. AB - Agave macroacantha can sexually reproduce by seeds and propagate vegetatively by aerial bulbils and ground-level basal shoots and rhizomes. It forms compact patches apparently generated by the multiplication of ground-level offshoots. We experimentally evaluated the establishment and survival of bulbils and seedlings of A. macroacantha in the Tehuacan Valley, Mexico, between 1991 and 1994 and studied comparatively the effectiveness of sexual reproduction against vegetative propagation.Seedlings showed low survival rates. Cohorts placed outside nurse plants died in less than 1 yr, while 1-10% of cohorts under nurse plants survived for more than 2 yr. Herbivores negatively affected seedling survival in non nursed plots. In rainy years, survival rates increased. Bulbils showed higher survival rates than seedlings.The excavation of rosettes showed that most are derived from vegetative shoots, as indicated by remains of rhizomes in their base. Most rosettes had ground-level vegetative offspring totaling almost three shoots per rosette.In A. macroacantha, the establishment of seedlings and bulbils is a rare event that possibly only occurs under nurse plants in rainy years, while ground-level cloning is highly effective as a propagation mechanism. These results are consistent with the aggregated spatial pattern of the species. PMID- 21665665 TI - Clonal structure and hybrid susceptibility to a smut pathogen in microscale hybrid zones of northern wetland Carex (Cyperaceae). AB - Interspecific hybrid taxa, especially those with the potential for clonal spread, may play important roles in community dynamics and plant-pathogen interactions. This study combines the mapping of clonal structure for two rhizomatous sedges (Carex limosa, C. rariflora) and their nearly sterile interspecific hybrid with an investigation of the relationship between these taxa and a nonsystemic floral smut pathogen (Anthracoidea limosa) in six subarctic fens in Nouveau-Quebec, Canada. We used allozyme polymorphisms in 14 of 18 putative loci to confirm hybrid identification and to distinguish among genotypes for mapping. The incidence of A. limosa was 5-20 times greater on hybrids than on parental taxa across all sites at two spatial scales (intensive extent = 10.5 m(2), extensive extent = entire fens). Spatial autocorrelation was detected in smut incidence; however, its statistical removal did not alter the strong association between hybrids and smut infection. Smut incidence on both C. limosa and hybrids was greater when they were growing in areas of high hybrid density. Our study provides evidence that disease can help maintain boundaries between species. We suggest explanations for hybrid susceptibility and provide evidence for a model in which hybrids act as a source for reinfection for all three taxa during subsequent years. PMID- 21665666 TI - Evolution of phenotypic integration in Brassica (Brassicaceae). AB - Phenotypic integration is a necessary characteristic of living organisms that results from genetic, developmental, and functional relationships among traits. The nature of these relationships can be influenced by the environment. We examined patterns of phenotypic integration of six species of rapid cycling Brassica and of Raphanus sativus within a phylogenetic context. Specifically, we tested the hypothesis that hybrid species show intermediate levels of integration in morphological and life-history characters compared to their putative parentals. We used matrix correlation tests to examine if cytogenetic relationships or ecological similarities among species partially explained the patterns of phenotypic integration. There was a significant negative relationship between the ecological and cytogenetic matrices, suggesting that more closely related species were ecologically dissimilar. However, neither ecological nor cytogenetic matrices significantly explained differences among species in the pattern of their phenotypic correlations. Set correlation analysis indicated that important traits within the modules and the strength of the correlations within modules differed across species. We also found that there were a greater number of significant correlations between modules than within modules. Hybrid species were more integrated (had greater number of significant trait correlations) than either of their parents, both within and between modules. However, univariate analyses of character means of the hybrid species were not significantly different from the combined mean of their putative parents for 5, 6, or 7 of the 11 phenotypic characters (for Brassica napus, B. juncea and B. carinata, respectively); for the remaining characters, the hybrids were more similar to one of the parents. PMID- 21665667 TI - Anatomy of umkomasia (corystospermales) from the triassic of antarctica. AB - The permineralized, corystosperm, cupulate, ovule-bearing organ Umkomasia resinosa is described from the early Middle Triassic of Antarctica. This is the first description of anatomically preserved Umkomasia, which consists of a determinate cupulate branch with helically arranged, recurved, pedicellate megasporophylls, each of which bears one or two abaxially attached unitegmic ovules. Cupules are ovoid, bilobed with elongate ventral and dorsal openings or unlobed with a single ventral opening, and have a two-zoned parenchymatous cortex and abundant secretory cavities. Ovules are small, orthotropous, and possess a thin integument that contains numerous secretory cavities. The ovules are broadly attached at the base, with a bifid integumentary apex that extends past the cupule lobes. The cupulate branch displays stem-like anatomy, producing paired traces into each cupule stalk. These structurally preserved ovulate organs can be related to other corystosperm organs from Antarctica, particularly the pollen organ Pteruchus fremouwensis. Both anatomical and morphological features support interpretation of corystosperm reproductive structures as branching systems rather than as compound sporophylls. As a result of an increased understanding of the organization of Umkomasia, it appears doubtful that any direct relationship exists between the corystosperm and angiosperm lineages. PMID- 21665668 TI - Phylogenetic relationships in the order Ericales s.l.: analyses of molecular data from five genes from the plastid and mitochondrial genomes. AB - Phylogenetic interrelationships in the enlarged order Ericales were investigated by jackknife analysis of a combination of DNA sequences from the plastid genes rbcL, ndhF, atpB, and the mitochondrial genes atp1 and matR. Several well supported groups were identified, but neither a combination of all gene sequences nor any one alone fully resolved the relationships between all major clades in Ericales. All investigated families except Theaceae were found to be monophyletic. Four families, Marcgraviaceae, Balsaminaceae, Pellicieraceae, and Tetrameristaceae form a monophyletic group that is the sister of the remaining families. On the next higher level, Fouquieriaceae and Polemoniaceae form a clade that is sister to the majority of families that form a group with eight supported clades between which the interrelationships are unresolved: Theaceae Ternstroemioideae with Ficalhoa, Sladenia, and Pentaphylacaceae; Theaceae Theoideae; Ebenaceae and Lissocarpaceae; Symplocaceae; Maesaceae, Theophrastaceae, Primulaceae, and Myrsinaceae; Styracaceae and Diapensiaceae; Lecythidaceae and Sapotaceae; Actinidiaceae, Roridulaceae, Sarraceniaceae, Clethraceae, Cyrillaceae, and Ericaceae. PMID- 21665669 TI - Using RPB1 sequences to improve phylogenetic inference among mushrooms (Inocybe, Agaricales). AB - An investigation of mushroom phylogeny using the largest subunit of RNA polymerase II gene sequences (RPB1) was conducted in comparison with nuclear ribosomal large subunit RNA gene sequences (nLSU) for the same set of taxa in the genus Inocybe (Agaricales, Basidiomycota). The two data sets, though not significantly incongruent, exhibit conflict among the placement of two taxa that exhibit long branches in the nLSU data set. In contrast, RPB1 terminal branch lengths are rather uniform. Bootstrap support is increased for clades in RPB1. Combined data sets increase the degree of confidence for several relationships. Overall, nLSU data do not yield a robust phylogeny when independently assessed by RPB1 sequences. This multigene study indicates that Inocybe is a monophyletic group composed of at least four distinct lineages-subgenus Mallocybe, section Cervicolores, section Rimosae, and subgenus Inocybe sensu Kuhner, Kuyper, non Singer. Within subgenus Inocybe, two additional lineages, one composed of species with smooth basidiospores (clade I) and a second characterized by nodulose-spored species (clade II), are recovered by RPB1 and combined data. The nLSU data recover only clade I. The genera Astrosporina and Inocybella cannot be recognized phylogenetically. "Supersections" Cortinatae and Marginatae are not monophyletic groups. PMID- 21665670 TI - Madagasikaria (Malpighiaceae): a new genus from Madagascar with implications for floral evolution in Malpighiaceae. AB - Madagasikaria andersonii is described here as a new genus and species of Malpighiaceae from Madagascar. The phylogenetic placement of Madagasikaria was estimated by using combined data from ndhF and trnL-F chloroplast sequences and phytochrome (PHYC) and ITS nuclear sequences. It forms a strongly supported clade with the Malagasy endemic genera Rhynchophora and Microsteira. Despite nearly identical floral morphology among species in this clade (here called the madagasikarioid clade), these genera are easily distinguishable on the basis of their fruits. The schizocarpic fruits of Madagasikaria have distinctive mericarps. Each mericarp has a lateral wing, which completely encircles the nut, and a peculiar dorsal wing, which folds over on itself. The morphology of this fruit suggests that the homology of the unusual wing in Rhynchophora is lateral in nature and represents a reduced wing similar to the lateral wing in Madagasikaria. Taxa in the madagasikarioid clade all appear to be morphologically androdioecious and functionally dioecious, producing both staminate and "bisexual" (i.e., functionally carpellate) individuals. This condition appears to be exceedingly rare in flowering plants and has important implications for floral evolution within Malpighiaceae. Neotropical Malpighiaceae are pollinated by specialized oil-collecting anthophorine bees of the tribe Centridini and exhibit highly conserved floral morphology despite tremendous diversity in fruit morphology and habit. These oil-collecting bees are absent from the paleotropics, where most members of the Malpighiaceae lack both the oil glands and the typical floral orientation crucial to pollination by neotropical oil-collecting bees. The madagasikarioids represent one shift from the neotropical pollination syndrome among Old World Malpighiaceae. PMID- 21665671 TI - Rapid diversification of the cotton genus (Gossypium: Malvaceae) revealed by analysis of sixteen nuclear and chloroplast genes. AB - Previous molecular phylogenetic studies have failed to resolve the branching order among the major cotton (Gossypium) lineages, and it has been unclear whether this reflects actual history (rapid radiation) or sampling properties of the genes evaluated. In this paper, we reconsider the phylogenetic relationships of diploid cotton genome groups using DNA sequences from 11 single-copy nuclear loci (10 293 base pairs [bp]), nuclear ribosomal DNA (695 bp), and four chloroplast loci (7370 bp). Results from individual loci and combined nuclear and chloroplast DNA partitions reveal that the cotton genome groups radiated in rapid succession following the formation of the genus. Maximum likelihood analysis of nuclear synonymous sites shows that this radiation occurred within a time span equivalent to 17% of the time since the separation of Gossypium from its nearest extant relatives in the genera Kokia and Gossypioides. Chloroplast and nuclear phylogenies differ significantly with respect to resolution of the basal divergence in the genus and to interrelationships among African cottons. This incongruence is due to limited character evolution in cpDNA and either previously unsuspected hybridization or unreliable phylogenetic performance of the cpDNA characters. This study highlights the necessity of using multiple, independent data sets for resolving phylogenetic relationships of rapidly diverged lineages. PMID- 21665672 TI - Discovery of an endophytic alga in Ginkgo biloba. AB - Although intracellular associations with mycorrhizal fungi are known for Ginkgo biloba, no other endosymbiotic relationships have ever been reported for this "living fossil." A protoplast culture derived from haploid explants has now revealed the existence of a green alga in vitro, whose eukaryotic status was confirmed by transmission electron microscopic studies. Phylogenetic 18S rDNA sequence analyses showed this alga to be closely related to the lichen photobiont Coccomyxa. Algae, which in host cells exist as more or less undifferentiated "precursor" forms, proliferated within necrosing G. biloba cells of a subculture derived from a zygotic embryo and were finally released into the medium. Light and electron microscopic observations showed that G. biloba cells rapidly filled up with countless green particles whose number increased up to the bursting of the hypertrophic host cells. At the beginning of reproduction no algae were visible in the nutritive medium, demonstrating that the proliferation started inside the G. biloba cells and excluding the possibility of an exogenous contamination. Occasionally, mature algae together with their precursor forms were detected by transmission electron microscopy in intact host cells of a green callus. The algae were easily identified by their similarity to the cultured algae. Eukaryotic algae have never been reported to date to reside inside higher plant cells, whereas several algal associations are well known from the animal kingdom. PMID- 21665673 TI - Tetrad pollen formation in Annona (Annonaceae): proexine formation andbinding mechanism. AB - Meiotic tetrads of Annona glabra and A. montana build up a well-developed proexine (protectum, probaculum, and pronexine) at the proximal side but only a thin pronexine at the distal side during the tetrad stage. The callosic envelope is only partially digested by the end of tetrad stage. The remaining, undigested part is composed of the intersporal mass and thin peripheral layers, and the latter is conjunct with the distal pronexine of the microspore. In this remaining callosic structure celluloses are also present. Later on, due to the continuous slow decomposition of this callose-cellulose structure and microspore expansion, microspores break up the callose-cellulose envelope. Because all the four microspores are bound together by the callose-cellulose structure, they move out of the chamber in rotation. Eventually the thin pronexine is pulled toward the center of the tetrad and the well-developed proexine becomes the distal wall. These descriptions of the partial digestion of callosic envelope, the transformation from a callose-cellulose structure to the binding system of tetrad pollen, and microspore rotation in Annona are unusual in the angiosperms. PMID- 21665674 TI - Floral ontogeny in Sophoreae(Leguminosae: Papilionoideae). III. Radial symmetry and random petal aestivation in Cadia Purpurea. AB - Floral organogeny and development are described in Cadia purpurea, a legume with radial symmetry, unstable petal aestivation, and free organs, all unusual features among papilionoids. Flowers are usually solitary or, rarely, in few flowered racemes. No bracteoles are formed. The order of organ initiation is unidirectional in each whorl, and the carpel initiates directly after petal initiation.The petal primordia remain small until all other floral organs have initiated, enlarged, and differentiated. Petal aestivation is variable, unlike the great majority of papilionoid flowers. Petal margins of Cadia grow straight outward rather than some petal margins curving inward inside the adjacent petal as is the case in other papilionoids. When adjacent growing petal margins of Cadia meet, chance determines which petal becomes positioned inside the other. Hence, the pattern of petal aestivation is random. PMID- 21665675 TI - Chimeric patterns in Juniperus chinensis 'Torulosa Variegata' (Cupressaceae) expressed during leaf and stem formation. AB - Juvenile leaves of the variegated Hollywood juniper, Juniperus chinensis 'Torulosa Variegata', have sectorial chimeras of variable widths and lengths. Sectors extend over several nodes often as small as 1/24 the circumference of the leaf. Other chimeras appear as light green to yellow streaks but are actually internal, dark green corpus sectors often occupying less than 1/20 of the cross sectional area of a leaf. On the basis of the sizes of these two types of sectors, there seems to be ideally about 168 founder cells comprising 63 tunica cells and 105 corpus cells; 49 of the latter are contiguous with the tunica and 66 are located deeper in the corpus. Similarly, sectoring in axillary branches of original chimeric sprays have the same types of sectoring. It is hypothesized that the outer rings of founder cells form two arcs of 12 cells around the stem apex, one for each of two leaves at a node of the decussate shoot, of a circumference of about 50 cells. PMID- 21665676 TI - Induction of vivipary in Arabidopsis by silique culture: implications for seed dormancy and germination. AB - Culture of excised fruits (siliques) of different ages of Arabidopsis thaliana in a solidified mineral salt medium supplemented with vitamins, myo-inositol, and 3% sucrose induces vivipary. Whereas early stage and immature embryos complete their full development before germinating viviparously in seeds enclosed in the silique, mature green embryos enclosed in green ovules germinate without further growth in culture. Vivipary is not observed in cultured siliques enclosing brown ovules with yellowish mature embryos inside. Suggestive of a role for abscisic acid in preventing vivipary on the mother plant, addition of the hormone to the culture medium is found to inhibit vivipary in cultured siliques. Although dried green ovules enclosing mature embryos require a cold treatment for germination, undried ovules of the same age do not germinate even after a cold treatment. This indicates that mature embryos enclosed in green ovules that germinate viviparously are cold resistant and have not become dormant at the time of culture of siliques. The circumvention by silique culture of a cold treatment and light exposure normally required for germination of isolated seeds of A. thaliana provides new possibilities to study the molecular biology of vivipary and seed germination in this model plant. PMID- 21665677 TI - Chromosome-specific desynapsis in the n = 2 race of Haplopappus gracilis (Compositae). AB - During cytological screening for pollen sterility in a wild population of Haplopappus gracilis (n = 2), several partially sterile plants were found that had good pachytene pairing but varying numbers of univalents. Some plants had chromosome A bivalents or A univalents, while in the same cells chromosome B had only bivalents. In other plants the reverse condition occurred; the B chromosome had B bivalents or B univalents and only A bivalents. This demonstrates a chromosome-specific effect for the desynapsis genes. Hybridization between the two homozygous mutant genotypes produced only normal bivalents; this indicates the two mutants are not alleles and each is recessive. An F2 generation showed independent assortment of the desynaptic mutations. The chromosome A bivalent is the larger of the two and normally has one or two chiasmata; the B bivalent normally has a single chiasma. Chiasmata distribution was tested in the desynaptic mutant A bivalents and showed an acceptable fit to a binomial distribution. This occurs also in heterozygous, asynaptic pairing control gene mutations. Analysis of the NOR bivalent in two hologenomic desynaptic mutations in tomato also showed a good fit to a binomial distribution of chiasmata. This indicates the same methods are applicable to diverse species. PMID- 21665678 TI - Genetic variation and population structure in central and isolated populations of balsam fir, Abies balsamea (Pinaceae). AB - Genetic variation and spatial genetic structure in balsam fir (Abies balsamea) were examined in two isolated populations in Iowa and Minnesota thought to be paleorefugia and in two ecologically central populations in old-growth forests of Upper Michigan. Overall levels of genetic variability at 22 allozyme loci were lower than that found in most conifer species (H(o) values ranged from 0.005 in the isolated populations to 0.025 in the central populations). The mean F(IS) value (0.154) was larger than usually found in conifers and suggests moderate levels of inbreeding. The mean F(ST), an estimate of genetic diversity among populations, was 3.7% of the total diversity, a value lower than the mean for conifers. Nm, the number of migrants per generation, was 6.5, suggesting either some gene flow among populations or a lack of genetic differentiation. Spatial autocorrelation analysis revealed a moderately patchy structure, with gene flow distances of 30-70 m in the central populations and at least 10 m in the isolated populations. The future of the ecologically central populations depends on maintenance of an intact forest mosaic. The low genetic variability in the small, isolated populations suggests that habitat fragmentation has led to a reduction in evolutionary potential and that the future viability of these populations will likely require active management in the face of global climate change. PMID- 21665679 TI - Regional patterns of genetic diversity in Pinus flexilis (Pinaceae) reveal complex species history. AB - Pinus flexilis (limber pine) is patchily distributed within its large geographic range; it is mainly restricted to high elevations in the Rocky Mountains and the Basin and Range region of western North America. We examined patterns of allozyme diversity in 30 populations from throughout the species' range. Overall genetic diversity (H(e) = 0.186) was high compared with that of most other pine species but was similar to that of other pines widespread in western North America. The proportion of genetic diversity occurring among populations (G(ST) = 0.101) was also high relative to that for other pines. Observed heterozygosity was less than expected in 28 of the 30 populations. When populations were grouped by region, there were notable differences. Those in the Basin and Range region had more genetic diversity within populations, a higher proportion of genetic diversity among populations, and higher levels of inbreeding within populations than populations from either the Northern or Utah Rocky Mountain regions. Patterns of genetic diversity in P. flexilis have likely resulted from a complex distribution of Pleistocene populations and subsequent gene flow via pollen and seed dispersal. PMID- 21665680 TI - Isozyme variability of the wetland specialist Swertia perennis (Gentianaceae) in relation to habitat size, isolation, and plant fitness. AB - We examined the effects of size and spatial isolation of fens on the isozyme variability of 17 populations of Swertia perennis. This long-lived perennial is a locally abundant fen specialist in Switzerland, where wetlands have been strongly fragmented. Isozyme variability was comparable to other outcrossing plants (A = 1.53, AP(p) = 2.01, P(p) = 42.5, H(o) = 0.113, H(e) = 0.139). F statistics indicated both inbreeding within and differentiation between populations (F(IS) = 0.076, F(IT) = 0.194, F(ST) = 0.128), with moderate gene flow between populations (N(e)m = 1.703). Populations in small, isolated fens had reduced genetic variability and the highest within-population inbreeding coefficients (F(IS)). Isozyme variability was significantly associated with vegetative fitness traits (MANOVA), and the magnitude of leaf herbivory decreased as the percentage of polymorphic loci increased. These data suggest that the reduced genetic variability of S. perennis in small, isolated populations may reduce plant fitness, thereby increasing susceptibility to herbivore damage. Our study also shows that habitat fragmentation can reduce the genetic variability of populations of fairly common habitat specialists, which so far have attracted less conservation attention than rare species. PMID- 21665681 TI - Canonical rules for plant organ biomass partitioning and annual allocation. AB - Here we review a general allometric model for the allometric relationships among standing leaf, stem, and root biomass (M(L), M(S), and M(R), respectively) and the exponents for the relationships among annual leaf, stem, and root biomass production or "growth rates" (G(L), G(S), and G(R), respectively). This model predicts that M(L) ? M(S)(3/4) ? M(R)(3/4) such that M(S) ? M(R) and that G(L) ? G(S) ? G(R). A large synoptic data set for standing plant organ biomass and organ biomass production spanning ten orders of magnitude in total plant body mass supports these predictions. Although the numerical values for the allometric "constants" governing these scaling relationships differ between angiosperms and conifers, across all species, standing leaf, stem, and root biomass, respectively, comprise 8%, 67%, and 25% of total plant biomass, whereas annual leaf, stem, and root biomass growth represent 30%, 57%, and 13% of total plant growth. Importantly, our analyses of large data sets confirm the existence of scaling exponents predicted by theory. These scaling "rules" emerge from simple biophysical mechanisms that hold across a remarkably broad spectrum of ecologically and phyletically divergent herbaceous and tree-sized monocot, dicot, and conifer species. As such, they are likely to extend into evolutionary history when tracheophytes with the stereotypical "leaf," "stem," and "root" body plan first appeared. PMID- 21665682 TI - Shoot dieback during prolonged drought in Ceanothus (Rhamnaceae) chaparral of California: a possible case of hydraulic failure. AB - Progressive diebacks of outer canopy branchlets of Ceanothus crassifolius were repeatedly observed after rainless periods up to 9 mo in duration in the Santa Monica Mountains of southern California. Mean xylem pressures of branchlets near the end of drought were as low as -11.2 MPa (N = 22) with a mean of about 60 dead branchlets per shrub. Inoculation (N = 15) with three species of fungi previously isolated from the same population of C. crassifolius did not promote dieback, suggesting that the observed decline was not fungal induced, as had been proposed. Further, at least 50% of healthy-appearing twigs, without symptoms of dieback, contained isolatible endophytic fungi. We used a centrifugal force method to determine the range of xylem pressure causing cavitation (vulnerability curves) for branchlets (N = 12) and roots (N = 16). We combined vulnerability curves with soil texture data (N = 6) into a water transport model that estimated the critical values (P(Lcrit)) of leaf xylem pressure associated with the loss of water from soil to foliage. Maximum P(Lcrit) was between -10 and -11 MPa and within the range of minimum measured xylem pressures of branchlets during drought and dieback. Branchlet dieback correlated with seasonal declines in xylem pressure in concert with declining safety margins from hydraulic failure. Symptoms of dieback were duplicated in the field by partially severing stem xylem that normally supplied branchlets with water. Taken together, these results indicate that loss of hydraulic conductance to foliage was the probable cause of the observed dieback in C. crassifolius. Partial dieback of peripheral branchlets, and its attendant reduction in evaporative surface area, may be a last-resort mechanism for whole-plant water conservation and drought survival in this species. PMID- 21665683 TI - Seed germination ecophysiology of the Asian species Osmorhiza aristata (Apiaceae): comparison with its North American congeners and implications for evolution of types of dormancy. AB - Osmorhiza aristata is an herbaceous perennial that grows primarily in Japan, through southern China, to the Himalayas. It closely resembles the eastern North American species O. claytonii and O. longistylis, and, together, the three species are an example of the well-known North American-Asian pattern of disjunction. Requirements for dormancy break and embryo growth were determined for seeds of O. aristata collected in Japan during the summers of 1998-2000. Embryos in fresh seeds were ca. 0.5 mm long, and they had to grow to 9 mm before the radicle emerged from the mericarp. Embryo growth and germination occurred during cold stratification at 5 degrees C, the optimum temperature for germination. Gibberellic acid did not substitute for cold stratification. Thus, O. aristata seeds have deep complex morphophysiological dormancy (MPD). The type of MPD in O. aristata is similar to that in two western North American congeners but different from that in eastern North American congeners (nondeep complex MPD). Mapping the types of MPD onto a phylogeny of the genus suggests that nondeep complex MPD is derived from deep complex MPD. Although eastern North American-Asian disjuncts often exhibit morphological stasis, the taxa may differ greatly in physiological traits, such as seed dormancy. PMID- 21665684 TI - Reproductive phenology, life-forms, and habitats of the Venezuelan Central Plain. AB - Reproductive phenology of 171 plant species belonging to 57 families of angiosperms was studied according to life-forms in four habitat types in a savanna-forest mosaic on the Venezuelan Central Plain. Flowering, unripe fruit, and mature fruit patterns were affected significantly according to life-forms and habitats respectively. Production of flowers, unripe fruits, and mature fruits showed marked seasonality for all habitats except for the forest. Flowering peaked during the rainy season, and fruiting peaked toward the end of the rainy season. The savanna and the disturbed area had similar proportions of species that flowered over the year. The percentage of species with unripe fruits produced throughout the year was more seasonal for the disturbed area than for the other habitats. Mature fruit patterns showed an increase during the late rainy season for the ecotone and savanna. A large number of herbaceous (annual and perennial) and liana species flowered during the wet season, and a smaller fraction flowered during the dry season; and trees, shrubs, and epiphytes increased flowering activity during the dry season. Unripe fruit patterns were similar to those of flowering for all life-forms, however, tree species were less seasonal. Mature fruit production by shrubs peaked in the period of maximum rainfall, while the peak for perennial herbs was in the late rainy season and the peak for annual herbs was during the transition between the rainy season and the dry season. The largest proportion of tree and liana species with ripe fruits occurred during the dry season. Differences among phenological patterns in habitats were caused mainly by life-forms and promote a wider distribution of reproductive events in habitats and overall community in the Venezuelan Central Plain. PMID- 21665685 TI - First comparative phenetic studies of Argentinean species of Acacia (Fabaceae), using morphometric, isozymal, and RAPD approaches. AB - Morphological and genetic diversity among Acacia aroma, A. macracantha, A. caven, and A. furcatispina were studied with morphometric, isozymal, and RAPD approaches. The analysis of seven isozyme systems revealed 21 loci, and RAPD analysis showed 34 loci. Most of these loci allowed us to differentiate the species, with the exception of A. aroma and A. macracantha, the two most similar species. The levels of genetic variability estimated by isozymes were higher than those obtained from RAPD analyses. Morphometric characters showed highly significant differences among the species, although A. aroma and A. macracantha are differentiated only by thorn length. The phenogram obtained from isozyme data is consistent with morphological data. The RAPD phenogram based on allelic frequencies showed agreement with morphological and isozymal approaches only at the intraspecific levels, while the RAPD phenogram based on Nei and Li's similarity measures agreed with the phenograms constructed from isozyme and morphological data. High similarities and high indirect gene flow were found between A. aroma and A. macracantha, results that call the relationship between them into question. PMID- 21665686 TI - Different fates of island brooms: contrasting evolution in Adenocarpus, Genista, and Teline (Genisteae, Fabaceae) in the Canary Islands and Madeira. AB - Analysis of sequence data from the internal transcribed spacers (ITS) and 5.8S region of nuclear ribosomal DNA show that Canarian and Madeiran brooms (Genisteae) of the genera Teline, Adenocarpus, and Genista are related to Mediterranean species and not to species from adjacent parts of Morocco. Each separate colonization of the islands has resulted in contrasting patterns of adaptation and radiation. The genus Teline is polyphyletic, with both groups (the "T. monspessulana group" and the "T. linifolia group") separately nested within Genista. Genista benehoavensis (La Palma) and G. tenera (Madeira) form, with G. tinctoria of Europe, a single clade characterized by vestigially arillate seeds. The Canarian species of Adenocarpus have almost identical sequence to the Mediterranean A. complicatus and are likely to be the result of island speciation after a very recent colonization event. This Canarian/Mediterranean A. complicatus group is sister to the afrotropical montane A. mannii which is probably derived from an earlier colonization from the Mediterranean, possibly via the Red Sea hills. The independent colonization and subsequent radiation of the two Teline groups in the Canary Islands make an interesting comparison: the phylogenies both show geographical structuring, each with a central and western island division of taxa. Within the "T. monspessulana group" there is some evidence that both continental and Madeiran taxa could be derived from the Canary Islands, although it is likely that near contemporaneous speciation occurred via rapid colonization of the mainland and islands. The finding of two groups within Teline also has implications for patterns of hybridization in those parts of the world where Teline species are invasive; in California members of the T. monspessulana group hybridize readily, but no hybrids have been recorded with T. linifolia which has been introduced in the same areas. PMID- 21665687 TI - Patterns of diversification in New Zealand Stylidiaceae. AB - Phylogenetic analysis of ITS and rbcL sequences show that New Zealand Stylidiaceae fall into two distinct lineages differing in species richness. Each lineage represents a unique dispersal event to New Zealand occurring at different times during the evolutionary history of the family. One lineage comprises seven species of Forstera and Phyllachne, while the other consists solely of Oreostylidium subulatum. The origin of the Forstera/Phyllachne lineage in New Zealand is equivocal; either a South American or a Tasmanian origin is equally parsimonious. Possible sister groups are F. bellidifolia in Tasmania and P. uliginosa in South America. Oreostylidium subulatum has an Australian origin. In our analyses O. subulatum is nested in a clade composed entirely of species of Stylidium, almost all of which are endemic to Australia. Species of Phyllachne share a cushion habit with the outgroup Donatia (Donatiaceae) that may have preadapted them to alpine environments in New Zealand. The New Zealand Stylidiaceae have small, white, actinomorphic flowers that are well adapted to the unspecialized pollinator fauna. Forstera and Phyllachne share this trait with Donatia; however, the small, white flowers of Oreostylidium are a dramatic departure from the colorful, highly specialized flowers of Stylidium. PMID- 21665688 TI - Comparative floral ontogeny in Detarieae (Leguminosae: Caesalpinioideae). 1. Radially symmetrical taxa lacking organ suppression. AB - Flowers in detarioid legume taxa (Isoberlinia angolensis, Microberlinia brazzavillensis, M. bisulcata, Hymenostegia klainii) initiate all 21 floral organs, are radially symmetrical, and have little or no organ suppression. All share a narrow, "Omega"-shaped floral apex and massive bracteoles at initiation. All have helical sepal initiation, starting abaxially. They differ in whether the first sepal initiates medianly (Microberlinia brazzavillensis, M. bisulcata) or nonmedianly (Isoberlinia angolensis, Hymenostegia klainii), and in petal order: helical (I. angolensis) or unidirectional (M. brazzavillensis, M. bisulcata, H. klainii). Stamens initiate in unidirectional order in each whorl except in M. brazzavillensis, which has a bidirectional outer whorl. An unusual feature is the ring meristem in M. bisulcata, on which petals and stamens are initiated. Overlap in time of organ initiation between whorls occurs in I. angolensis, M. brazzavillensis, and M. bisulcata but not in H. klainii. The carpel initiates concurrently with petals in all except H. klainii, in which it initiates with the outer stamens. The carpel remains open at ovule initiation in both species of Microberlinia. These detarioid taxa represent elements of the tribe having essentially radially symmetrical flowers, with all organs initiated and persisting to anthesis, but their specialized "Omega" character-state complex is shared with specialized taxa that have zygomorphic flowers and some organs suppressed. PMID- 21665689 TI - Comparative floral ontogeny in Detarieae (Leguminosae: Caesalpinioideae). 2. Zygomorphic taxa with petal and stamen suppression. AB - Marked floral zygomorphy and a reduced number of petals and/or stamens are the character traits that distinguish the taxa described (species of Afzelia, Berlinia, Gilbertiodendron, Macrolobium, Neochevalierodendron, Paramacrolobium, Phyllocarpus, and Tetraberlinia). All have an "Omega"-shaped floral apex after bracteole initiation, bracteoles large when initiated, helical sepal initiation, unidirectional petal initiation (simultaneous in Afzelia, not determinable in Tetraberlinia), and unidirectional stamen initiation. Floral zygomorphy is expressed primarily by one petal being much larger than the others and by suppression of several of the stamens. Five petals are initiated in all; suppression begins in late development. Either two petals (Neochevalierodendron, Phyllocarpus) or four petals (Afzelia, Berlinia, Macrolobium, Tetraberlinia) are suppressed. All ten stamens are initiated; at midstage, suppression begins in either three stamens (Afzelia) or seven stamens (Gilbertiodendron, Macrolobium, Paramacrolobium). Other expressions of zygomorphy may include diadelphy, stamen filament connation late in development, or displacement of the carpel from a central position to the adaxial side of the hypanthium. There is no loss of organs similar to that which occurs in some other Detarieae. PMID- 21665690 TI - Apical organization and maturation of the cortex and vascular cylinder inArabidopsis thaliana (Brassicaceae) roots. AB - Developmental and physiological studies of roots are frequently limited to a post germination stage. In Arabidopsis, a developmental change in the root meristem architecture during plant ontogenesis has not previously been studied and is addressed presently. Arabidopsis thaliana have closed root apical organization, in which all cell file lineages connect directly to one of three distinct initial tiers. The root meristem organization is dynamic and changes as the root ages from 1 to 4 wk post-germination. During the ontogeny of the root, the number of cells within the root apical meristem (RAM) increases and then decreases due to changes in the number of cortical layers and number of cell files within a central cylinder. The architecture of the initial tiers also changes as the root meristem ages. Included in the RAM's ontogeny is a pattern associated with the periclinal divisions that give rise to the middle cortex and endodermis; the three-dimensional arrangement of periclinally dividing derivative cells resembles one gyre of a helix. Four- or 5-wk-old roots exhibit a disorganized array of vacuolated initial cells that are a manifestation of the determinate nature of the meristem. Vascular cambium is formed via coordinated divisions of vascular parenchyma and pericycle cells. The phellogen is the last meristem to complete its development, and it is derived from pericycle cells that delineate the outer boundary of the root. PMID- 21665691 TI - The origin of tobacco's T genome is traced to a particular lineage within Nicotiana tomentosiformis (Solanaceae). AB - Nicotiana tabacum (tobacco) is a natural allotetraploid. The maternal genome donor is not controversial and is probably derived from an ancestor of N. sylvestris. The paternal, T-genome donor has been less clear, with N. tomentosiformis, N. otophora, or an introgression hybrid proposed. Here we provide evidence that the T genome of N. tabacum is derived from a particular lineage of N. tomentosiformis. We show that the repetitive sequences of geminiviral origin, GRD53 and GRD3, are present in the genomes of N. tabacum cultivars, a tobacco cell suspension culture TBY-2, and N. tomentosiformis ac. NIC 479/84. Surprisingly, they are not present in another three varieties of N. tomentosiformis. A detailed cytogenetic analysis also revealed that N. tomentosiformis ac. NIC 479/84 most closely resembles the N. tabacum T genome in the location of other tandem repetitive sequences. Thus, tobacco formed after divergence within N. tomentosiformis, and the spectrum of potential donors of the paternal genome can be narrowed to a genotype of N. tomentosiformis characterized by the presence of GRD53 and GRD3 repeats. It is clear that future paternity studies in tobacco should use N. tomentosiformis ac. NIC 479/84 rather than any other accession. PMID- 21665692 TI - Tackling speciose genera: species composition and phylogenetic position of Senecio sect. Jacobaea (Asteraceae) based onplastid and nrDNA sequences. AB - The molecular phylogeny of Senecio sect. Jacobaea (Asteraceae; Senecioneae) was studied to clarify species composition and interspecific relationships of Senecio sect. Jacobaea. This information is necessary for studies seeking explanations of the evolutionary success of Senecio, in terms of high species numbers and the evolution of chemical defense mechanisms. Parsimony analyses with 60 species of the tribe Senecioneae, representing 23 genera and 11 sections of Senecio, based on DNA sequence data of the plastid genome (the trnT-L intergenic spacer, the trnL intron, and two parts of the trnK intron, flanking both sides of the matK gene) and nuclear genome (ITS1, 5.8S, and ITS2 gene and spacers) show that sect. Jacobaea is a strongly supported monophyletic group. Fifteen species have been identified as members of section Jacobaea, including three species that have been consistently ascribed to this section in taxonomic literature and 12 species that were either placed in other sections of Senecio or not exclusively ascribed to sect. Jacobaea. This section was traditionally circumscribed as a group of European, biennial, or perennial herbs with pinnately incised leaves, but the results of this study show that one annual species, a species from northeastern Asia, and a species growing in the Himalayas are members of sect. Jacobaea as well. Furthermore, not all species in the section have pinnately incised leaves. The genera Emilia, Packera, and Pseudogynoxys form the sister clade of sect. Jacobaea, but this relationship lacks strong bootstrap support and thus remains provisional. PMID- 21665693 TI - Phylogeny of Chloranthus (Chloranthaceae) based on nuclear ribosomal ITS and plastid TRNL-F sequence data. AB - The internal transcribed spacers (ITS) of the nuclear ribosomal DNA and trnL-F region of the chloroplast DNA were sequenced for all ten species of Chloranthus and the outgroup Sarcandra (Chloranthaceae). Parsimony analyses of separate and combined data sets strongly suggest that Chloranthus is monophyletic and can be divided into two major clades: one containing C. erectus, C. spicatus, C. serratus, C. henryi, C. sessilifolius, and C. oldhamii (Clade A), and the other comprising C. angustifolius, C. fortunei, C. nervosus, and C. japonicus (Clade B). Taxonomically, these two clades correspond to Bentham and Hooker's sections Euchloranthus and Tricercandra. Within Clade A, two subclades, corresponding to Solms-Laubach's sections Triandri and Brachyuri, can be recognized. Solms Laubach's subgenera Fruticosi and Herbacei, however, were resolved as paraphyletic, and thus the traditional division of Chloranthus on the basis of growth habit was not supported. Evidence from ITS and trnL-F sequences, in agreement with morphology, anatomy, and cytology, strongly suggest that Chloranthus consists of two groups that morphologically may be distinguished by their androecial characters. The present study also supports the hypothesis that the tripartite androecium of Chloranthus may have arisen by splitting of a single stamen with two marginal thecae. PMID- 21665694 TI - Reclassification of landrace populations of cultivated potatoes (Solanum sect. Petota). AB - Cultivated potatoes have been classified as species under the International Code of Botanical Nomenclature (ICBN) and as cultivar-groups under the International Code of Nomenclature of Cultivated Plants (ICNCP); both classifications are still widely used. This study examines morphological support for the classification of landrace populations of cultivated potatoes, using representatives of all seven species and most subspecies as outlined in the latest taxonomic treatment. These taxa are S. ajanhuiri, S. chaucha, S. curtilobum, S. juzepczukii, S. phureja subsp. phureja, S. stenotomum subsp. stenotomum, S. stenotomum subsp. goniocalyx, S. tuberosum subsp. andigenum, and S. tuberosum subsp. tuberosum. The results show some phenetic support for S. ajanhuiri, S. chaucha, S. curtilobum, S. juzepczukii, and S. tuberosum subsp. tuberosum, but little support for the other taxa. Most morphological support is by using a suite of characters, all of which are shared with other taxa (polythetic support). These results, combined with their likely hybrid origins, multiple origins, evolutionary dynamics of continuing hybridization, and our classification philosophy, leads us to recognize all landrace populations of cultivated potatoes as a single species, S. tuberosum, with the eight cultivar-groups: Ajanhuiri Group, Andigenum Group, Chaucha Group, Chilotanum Group, Curtilobum Group, Juzepczukii Group, Phureja Group, and Stenotomum Group. We defer classification of modern cultivars, traditionally classified in Tuberosum Group, to a later study. PMID- 21665695 TI - Discordance of chloroplast and nuclear ribosomal DNA data in Osmorhiza (Apiaceae). AB - Phylogenetic studies were conducted to evaluate interspecific relationships in Osmorhiza (Apiaceae: Apioideae) using sequences of the ITS regions of nuclear ribosomal DNA, the chloroplast ndhF gene, and two noncoding regions (trnL intron, and trnL [UAA] 3' exon-trnF [GAA] intergenic spacer). All data sets suggest the monophyly of the New World taxa and showed that Osmorhiza aristata from Asia is relatively divergent from other members of the genus, even though it is morphologically similar to the eastern North American O. claytonii and O. longistylis. The ITS and chloroplast DNA trees differ in the relationships among the New World taxa, especially the phylogenetic position of O. occidentalis, O. glabrata, and O. depauperata. The lack of congruence between the two data sets may be a result of hybridization or introgression. Although there is high discordance between nrITS and two chloroplast DNA data sets, the latter two show similar topologies. PMID- 21665696 TI - Conservation implications of the reproductive ecology of Agalinis acuta (Scrophulariaceae). AB - Reproductive ecology of Agalinis acuta was investigated by examining potential for self-fertilization before and at anthesis, reproductive output from outcrossed vs. selfed matings, and effects of browsing, plant size, and conspecific plant density on seed and fruit production. These features of a plant species can provide indirect information pertinent to conservation such as patterns and maintenance of genetic diversity, risk associated with inbreeding depression, and changes in pollinator abundance or effectiveness. The species is self-compatible, with 97% of selfed flowers setting fruit; pollinators were not required for reproduction. However, seed set in self-pollinated fruits averaged 17-20% less than that in open-pollinated fruits. Geitonogamous and facilitated selfing are possible throughout anthesis and autonomous selfing is possible late in anthesis as corollas abscise. Delaying self-pollination until after outcrossing opportunities likely limits selfing rates and thus reduces risks associated with inbreeding but allows reproduction in absence of pollinators. Supplementing pollen on open-pollinated flowers yielded no additional seed set over controls. Neither early-season browsing of primary stems nor conspecific plant density had significant effects on number of fruits per plant, on fruit size, or on number of seeds from open-pollinated flowers. Currently, reproduction appears to be high (about 2400 seeds/plant), and future risks due to lack of genetic diversity are likely low. PMID- 21665697 TI - Cottonwood hybrids gain fitness traits of both parents: a mechanism for theirlong term persistence? AB - Using surveys of natural populations, experimental crosses, and common garden trials, we tested the hypothesis that hybrid cottonwoods (Populus fremontii * P. angustifolia) from the Weber River in northern Utah would produce as many viable offspring as their parental species. We found that both F(1) generations and backcross generations can be just as fit as the parent taxa. First, F(1) hybrids produced as many viable seed as P. angustifolia (but less than P. fremontii), and backcross genotypes produced as many viable seeds as both parent taxa. Second, hybrids produced nearly two times as many ramets from root sprouts as P. angustifolia and four times as many ramets as P. fremontii. Third, the high mortality of germinated seedlings of all tree types (i.e., >90%) and very low mortality of asexually derived ramets provide hybrids with equal sexual reproduction and enhanced asexual reproduction, especially since backcross hybrids exhibit transgressive segregation in ramet production. Our findings suggest that the introgression of P. fremontii seed traits into the hybrid genome is responsible for their equivalent performance (at least to one parent) in sexual reproduction, while the contributions of asexual traits from P. angustifola results in hybrids having equal or greater fitness. PMID- 21665698 TI - The interaction between pollinator size and the bristle staminode of Penstemon digitalis (Scrophulariaceae). AB - Penstemon digitalis, a prairie species whose flowers possess a large bristle staminode, is visited by eight bee species of varying size. Two sets of field experiments involving staminode removal were performed to test pollination efficiency in relation to bee size. Our data indicate that bristle staminode presence and function are influenced by size-dependent selection on bee body size and associated pollen transporting attributes. The first experiment compared staminode presence and removal in open-pollinated flowers. Staminode removal significantly reduced total pollen deposition but had no effect on total pollen removal. The second experiment utilized single bee visits to assess the interaction between pollinator size and staminode presence on the rate of pollen deposition and removal. This experiment indicated that staminode removal resulted in fewer pollen grains deposited on stigmas and less pollen removed from anthers for both large and small bees (the contrary was true for medium bees). Although the number of pollen grains deposited was greatly reduced for large bees, staminode removal reduced deposition efficiency most notably for small bees by 41.3%, reducing female reproductive success. Staminode removal increased pollen removal efficiency most notably for medium bees by 22.7%, reducing male reproductive success. Mechanisms of staminode function are discussed. PMID- 21665699 TI - The defensive role of Ni hyperaccumulation by plants: a field experiment. AB - Hyperaccumulation of Ni by plants is hypothesized to function as an elemental defense against herbivores and pathogens. Laboratory experiments have documented toxic effects to herbivores consuming high-Ni plant tissues, but this paper reports the first experiment to examine the defensive effectiveness of Ni hyperaccumulation under field conditions. The experiment was conducted at an ultramafic soil site naturally inhabited by the Ni hyperaccumulator Streptanthus polygaloides (Brassicaceae). Experimental treatments examined the response of herbivores to hyperaccumulated Ni, using exclosure and insecticide treatments to divide herbivores into groups based primarily upon herbivore size. Three soils (Ni-amended greenhouse soil, unamended greenhouse soil, ultramafic soil), three exclosure treatments (exclosure, control exclosure, no exclosure), and a systemic insecticide treatment were combined in a fractional factorial experimental design. Streptanthus polygaloides plants were grown in a greenhouse for 2 mo, transplanted into the field by inserting potted plants into holes dug on the experimental site, and periodically examined for herbivore damage during a 41-d period. Initial surveys showed greater amounts of insect damage to plants with low tissue Ni levels, confirming the defensive effect of Ni against some insect herbivores, but large herbivores (probably vertebrates) later consumed entire plants regardless of plant Ni status. We concluded that Ni was not an effective defense against these large herbivores, probably because their diets mix high-Ni S. polygaloides foliage with that of associated non-hyperaccumulating species. We suggest that such dietary dilution is one mechanism whereby some herbivores can circumvent elemental plant defenses. PMID- 21665700 TI - Morphologically complex plant macrofossils from the Late Silurian of Arctic Canada. AB - In addition to vegetative remains, fertile remains from ten plants, representing seven distinct taxa whose size and complexity are much greater than most contemporaneous fossils, are reported from late Ludlow (Ludfordian) sediments of Bathurst Island in Nunavut, Canada. Evidence for the age of these beds is gathered from stratigraphic relationships and index fossils including conodonts, graptolites, and brachiopods. Zosterophylls dominate the collection, some of which constitute the earliest record of fertile structures arranged in dense clusters and longitudinal rows along axes. Representatives include a plant that resembles Bathurstia, one species of Zosterophyllum, and two specimens that bear affinity to this genus. Distichophytum is also represented, as is a new zosterophyll named Macivera gracilis. The prevalence of sporangial clustering and reduced sporangial stalks in this flora leads to a discussion of the origins and significance of these morphological features. Following a review of some of the other Silurian floras, particularly the Baragwanathia-bearing Lower Plant Assemblage of Victoria, Australia, which also shows morphological advancement over the rhyniophytoid-dominated floras common to Laurussia, it is concluded that the Bathurst Island flora presents the best evidence to date of substantial morphological diversity, complexity, and stature of vascular land plants in this period. PMID- 21665701 TI - Silver enhances stamen development in female white campion (Silene latifolia [Caryophyllaceae]). AB - Sex expression in the dioecious plant white campion (Silene latifolia Poiret subsp. alba) appears to be insensitive to exogenous applications of auxins, cytokinins, gibberellic acid, and ethylene; however, silver thiosulfate (Ag(2)S(2)O(3)), an ethylene inhibitor, enhanced stamen development in female white campion. In wild-type females, stamen development is arrested before the microspore mother cells are formed. In contrast, stamens of Ag(2)S(2)O(3)-treated females completed meiosis and produced microspores. Stamen development for these females was incomplete, however, and pollen did not mature. Ag(2)S(2)O(3) stimulated stamen development to the same extent in asexual white campion mutants that retained a Y chromosome but had lost Y-linked genes needed for early stages of stamen development. Although Ag(2)S(2)O(3) can inhibit ethylene signaling, the enhancement of stamen development in female white campion cannot be explained as a loss of ethylene response because no other ethylene inhibitor tested (1 methylcyclopropene, trans-cyclooctene, aminoethoxyvinylglycine, and cobalt chloride) caused stamens to develop in female plants. In addition, application of other metal ions could not enhance stamen development. Therefore, the effect we observed on female white campion was specifically caused by silver ions but not by their action on ethylene signaling. PMID- 21665702 TI - A method to estimate pollen viability from pollen size variation. AB - The mean diameter of viable pollen grains is approximately 13 MUm greater than the mean diameter of inviable grains in Mimulus guttatus. We show that this difference is large enough to be detected by particle counters and that these machines can be used to obtain a rapid estimate of pollen viability. While requiring a separate calibration, a size-based statistic is also strongly correlated with pollen viability in Collinsia verna. These results suggest that statistics derived from the size distribution of pollen grains may provide an alternative to more labor-intensive methods for estimating pollen viability, particularly in cases where inviability results from inbreeding depression or hybrid failure. PMID- 21665703 TI - Seed dispersal and seedling establishment of Sarracenia purpurea (Sarraceniaceae). AB - Plant ecologists continue to grapple with Reid's paradox, the observation that dispersal distances of most herbs and trees are too limited to account for their recolonization of northern latitudes following glacial recession. As global climate changes and natural habitats become increasingly fragmented, understanding patterns of seed dispersal and the potential for long-distance colonization takes on new importance. We studied the dispersal and establishment of the northern pitcher plant Sarracenia purpurea, which grows commonly in isolated bogs throughout Canada and eastern North America. Median dispersal distance of S. purpurea is only 5 cm, which is insufficient to explain its occurrence throughout formerly glaciated regions of North America. Establishment probability of seeds in the field is approximately 5%, and juveniles are normally found clustered around adult plants. The large-scale population genetic structure of this species can be accounted for by rare long-distance dispersal events, but its predictable occurrence in isolated habitats requires additional explanation. Reid's paradox remains an open question, and predicting long-range colonization into fragmented habitats by species with limited dispersal ability is a novel challenge. PMID- 21665704 TI - Phylogeny and classification of Naucleeae s.l. (Rubiaceae) inferred from molecular (ITS, rBCL, and tRNT-F) and morphological data. AB - Parsimony analyses of the tribe Naucleeae sensu lato (s.l.) using the noncoding internal transcribed spacer (ITS) regions of nuclear rDNA, the protein-coding rbcL and noncoding trnT-F regions of chloroplast DNA, and morphological data were performed to construct new intratribal classification, test the monophyly of previous subtribal circumscriptions, and evaluate the generic status of Naucleeae s.l. Fifty-two ITS, 45 rbcL, and 55 trnT-F new sequences are published here. Our study supports the monophyly of the subtribes Anthocephalidae, Mitragynae, Uncariae all sensu Haviland and Naucleinae sensu Ridsdale. There was no support for Cephalanthidae sensu Haviland and Adininae sensu Ridsdale. Naucleeae can be subdivided into six highly supported and morphologically distinct subtribes, Breoniinae, Cephalanthinae, Corynantheinae, Naucleinae, and Mitragyninae, Uncarinae, plus one, Adininae, which is poorly supported. The relationships among these subtribes were largely unresolved. We maintain the following 22 genera: Adina, Adinauclea, Breonadia, Breonia, Burttdavya, Cephalanthus, Gyrostipula, Haldina, Janotia, Ludekia, Metadina, Mitragyna, Myrmeconauclea, Nauclea, Neolamarckia, Neonauclea, Ochreinauclea, Pausinystalia, Pertusadina, Sarcocephalus, Sinoadina, and Uncaria. Pseudocinchona is reestablished. Corynanthe is restricted to C. paniculata and Hallea is reincluded in Mitragyna. Our results were inconclusive for assessing the relationships among Adina, Adinauclea, Metadina, and Pertusadina due to lack of resolution. PMID- 21665705 TI - Origins of domestication and polyploidy in oca (Oxalis Tuberosa: Oxalidaceae). 2. Chloroplast-expressed glutamine synthetase data. AB - In continuing study of the origins of the octoploid tuber crop oca, Oxalis tuberosa Molina, we used phylogenetic analysis of DNA sequences of the chloroplast-active (nuclear encoded) isozyme of glutamine synthetase (ncpGS) from cultivated oca, its allies in the "Oxalis tuberosa alliance," and other Andean Oxalis. Multiple ncpGS sequences found within individuals of both the cultigen and a yet unnamed wild tuber-bearing taxon of Bolivia were separated by molecular cloning, but some cloned sequences appeared to be artifacts of polymerase chain reaction (PCR) recombination and/or Taq error. Nonetheless, three classes of nonrecombinant sequences each joined a different part of the O. tuberosa alliance clade on the ncpGS gene tree. Octoploid oca shares two sequence classes with the Bolivian tuber-bearing taxon (of unknown ploidy level). Fixed heterozygosity of these two sequence classes in all ocas sampled suggests that they represent homeologous loci and that oca is allopolyploid. A third sequence class, found in eight of nine oca plants sampled, might represent a third homeologous locus, suggesting that oca may be autoallopolyploid, and is shared with another wild tuber-bearing species, tetraploid O. picchensis of southern Peru. Thus, ncpGS data identify these two taxa as the best candidates as progenitors of cultivated oca. PMID- 21665706 TI - Divergent and reticulate species relationships in Leucaena (Fabaceae) inferred from multiple data sources: insights into polyploid origins and nrDNA polymorphism. AB - Previous analyses of species relationships and polyploid origins in the mimosoid legume genus Leucaena have used chloroplast DNA (cpDNA) restriction site data and morphology. Here we present an analysis of a new DNA sequence data set for the nuclear ribosomal DNA (nrDNA) 5.8S subunit and flanking ITS 1 and ITS 2 spacers, a simultaneous analysis of the morphology, ITS and cpDNA data sets for the diploid species, and a detailed comparison of the cpDNA and ITS gene trees, which include multiple accessions of all five tetraploid species. Significant new insights into species relationships and polyploid origins, including that of the economically important tropical forage tree L. leucocephala, are discussed. Heterogeneous ITS copy types, including 26 putative pseudogene sequences, were found within individuals of four of the five tetraploid and one diploid species. Potential pseudogenes were identified using two pairwise comparison approaches as well as a tree-based method that compares observed and expected proportions of total ITS variation contributed by the 5.8S subunit optimized onto branches of one of the ITS gene trees. Inclusion of putative pseudogene sequences in the analysis provided evidence that some pseudogenes in allopolyploid L. leucocephala are not the result of post-allopolyploidization gene silencing, but were inherited from its putative diploid maternal progenitor L. pulverulenta. PMID- 21665707 TI - Molecular phylogenetics of the Espeletia complex (Asteraceae): evidence from nrDNA ITS sequences on the closest relatives of an Andean adaptive radiation. AB - The subtribe Espeletiinae (Asteraceae, Heliantheae) comprises morphologically and ecologically diverse plants endemic to the tropical montane paramos of the Andes of Venezuela, Colombia, and Ecuador. Though the ecophysiology and ecology of this adaptive radiation have been well studied, relationships among taxa in the subtribe and between the subtribe and other taxa in the Heliantheae are poorly known. In this study, sequences from the internal transcribed spacer (ITS) region of nuclear ribosomal DNA are used to test previous hypotheses about the phylogenetic position of the Espeletiinae within the Heliantheae and to determine which taxa are the subtribe's closest relatives. Gene phylogenies based on maximum parsimony analyses reveal that the Espeletiinae clade is nested well within the subtribe Melampodiinae and thus should be considered a monophyletic complex of species, not a separate subtribe. The most parsimonious gene trees suggest that the genus Ichthyothere may be the sister taxon to the Espeletia complex and that the genus Smallanthus and a species of Rumfordia are likely among the complex's other closest living relatives. These data offer preliminary insights into the origins of this adaptive radiation and the broader phylogenetic context in which it occurred. PMID- 21665708 TI - Phylogenetic origins of Lophocereus (Cactaceae) and the senita cactus-senita moth pollination mutualism. AB - Recent ecological research has revealed that the Sonoran Desert columnar cactus Lophocereus and the pyralid moth Upiga virescens form an obligate pollination mutualism, a rare but important case of coevolution. To investigate the phylogenetic origins of this unusual pollination system, we used molecular sequence data to reconstruct the phylogeny of the four taxa within the genus Lophocereus and to determine the phylogenetic position of Lophocereus within the North American columnar cacti (tribe Pachycereeae). Our analysis included Lophocereus, six Pachycereus species, Carnegiea gigantea, and Neobuxbaumia tetetzo within the subtribe Pachycereinae, and Stenocereus thurberi as an outgroup within the Stenocereinae. Extensive screening of chloroplast and mitochondrial genomes failed to reveal sequence variation within Lophocereus. At a deeper phylogenetic level, however, we found strong support for the placement of Lophocereus within Pachycereus as sister group to the hummingbird-pollinated P. marginatus. We discuss possible hypotheses that may explain the transition from bat pollination (ancestral) to moth and hummingbird pollination in Lophocereus and P. marginatus, respectively. Additional phylogenetic analyses suggest that the genus Pachycereus should be expanded to include Lophocereus, Carnegiea, Neobuxbaumia, and perhaps other species, whereas P. hollianus may need to be excluded from this clade. Future study will be needed to test taxonomic distinctions within Lophocereus, to test for parallel cladogenesis between phylogroups within Lophocereus and Upiga, and to fully delineate the genus Pachycereus and relationships among genera in the Pachycereinae. PMID- 21665709 TI - Redefining Phrymaceae: the placement of Mimulus, tribe Mimuleae, and Phryma. AB - Chloroplast trnL/F and nuclear ribosomal ITS and ETS sequence data were used to analyze phylogenetic relationships among members of tribe Mimuleae (Scrophulariaceae) and other closely related families in Lamiales. The results of these analyses led to the following conclusions. (1) The Australian genera Glossostigma and Peplidium and the taxonomically isolated Phryma join four genera of tribe Mimuleae to form a well-supported clade that is distinct from other families in the Lamiales. We refer to that clade as the subfamily Phrymoideae. (2) The genera Mazus and Lancea (tribe Mimuleae) together form a well-supported clade that we recognize as the subfamily Mazoideae. Mazoideae is weakly supported as sister to Phrymoideae. We assign Mazoideae and Phrymoideae to a redefined family Phrymaceae. (3) Mimulus is not monophyletic, because members of at least six other genera have been derived from within it. In light of the molecular evidence, it is clear that species of Phrymaceae (about 190 species) have undergone two geographically distinct radiations; one in western North America (about 130 species) and another in Australia (about 30 species). Phylogenetic interpretations of morphological evolution and biogeographical patterns are discussed. PMID- 21665710 TI - Cryptic goldfields: a molecular phylogenetic reinvestigation of Lasthenia californica sensu lato and close relatives (Compositae: Heliantheae sensu lato). AB - Maximum parsimony analysis of DNA sequence data from the internal and external transcribed spacer (ITS and ETS) regions of 18S-26S nuclear ribosomal DNA and the 3' trnK intron of chloroplast DNA from over 60 populations of Lasthenia sect. Amphiachaenia yielded a well-supported tree showing that the most common species of Lasthenia, L. californica sensu lato (s.l.), is not monophyletic. Members of Lasthenia californica s.l. belong to two well-supported but morphologically cryptic clades. One clade includes members of L. macrantha; the other represents a basally divergent lineage in L. sect. Amphiachaenia. Members of each clade can be diagnosed by pappus morphology and by geographic distribution, except for epappose plants that occur in a broad region of sympatry in central California. Overall diversification in the clade corresponding to L. sect. Amphiachaenia has been accompanied by minimal morphological divergence, which has resulted in previously underappreciated cryptic diversity. PMID- 21665711 TI - Allelopathic effects and root distribution of Ceratiola ericoides (Empetraceae) on seven rosemary scrub species. AB - We studied the root distribution and the effects of leachates from the dominant shrub in rosemary scrub, Florida rosemary (Ceratiola ericoides), on germination of seven subordinate rosemary scrub species. For rosemary scrub specialists, (Eryngium cuneifolium and Hypericum cumulicola), germination was suppressed by the leaf and litter leachates. For species that are not found exclusively in rosemary scrub (Liatris ohlingerae, Polygonella basiramia, Paronychia chartacea, and Palofoxia feayi) litter and leaf leachate did not suppress germination significantly. Species limited to gaps in rosemary scrub (E. cuneifolium, H. cumulicola, and Lechea deckertii) showed reduced germination from rosemary leachates while species not limited to rosemary-free gaps (L. ohlingerae and P. feayi) were not affected by rosemary leachates. Rosemary root abundance was greatest near shrubs, at a shallow depth, and at sites not recently burned. As rosemary scrub patches age, rosemary roots are more likely to interact with herbaceous species in gaps. PMID- 21665712 TI - Diffusivity in a marine macrophyte canopy: implications for submarine pollination and dispersal. AB - The dispersion and capture of differently shaped particles within a Zostera marina L. (eelgrass; Zosteraceae) bed were examined to understand submarine pollination and other dispersals. During periods of moderate flow in the canopy, the capture rate of "spherical" (the shape of ancestral pollen) and "filamentous" (the shape of eelgrass pollen) particles was greater for particles released at the top of the canopy (3.07 and 4.53% * 10(-5) cm(-2) of collector; i.e., percentage of particles captured normalized to collector area) and greater for filamentous than for spherical particles (4.51% * 10(-5) cm(-2) vs. 2.01% * 10( 5) cm(-2)). Estimates of the horizontal P (Joseph-Sendner diffusion velocity) and the vertical diffusivity (Gaussian K) of filamentous particles were small (P ~ 4 * 10(-4) m/s; K ~ 10(-4) m(2)/s) compared to theoretical values that do not consider plant canopies. These findings support the concept that eelgrass canopies modify the fluid dynamics (i.e., reduced turbulent mixing) within their canopies. These results indicate that 1000-10 000 Z. marina pollen are required to pollinate a single flower. Similarly, it was estimated that under some conditions, the probability of particle impaction on eelgrass vegetation approaches certainty. These results provide insight into the evolution of filamentous pollen and submarine pollination, as well as dispersal and other mass transport phenomena within macrophyte canopies. PMID- 21665713 TI - Developmental features of the discontinuous stem vascular system in the rattan palm Calamus (Arecaceae-Calamoideae-Calamineae). AB - Calamus is a climbing palm marked by considerable internodal extension and limited stem-thickening growth, but with a surprisingly discontinuous axial vascular system. Stem bundles end blindly in a basipetal direction and are connected to each other only by narrow and late-developing transverse commissures. Vascular connection via leaf traces between stem and leaf is made over about nine plastochrons (P), but the dominant central system is completed by about P(7), with subsequent bundles forming the crowded fibrous peripheral system, which has reduced or no vascular tissues. The stem internode below a leaf completes its extension and maturation only by P(10) to P(11). Axial stem bundles originate as procambial strands that are discontinuous apically for up to 15 plastochrons before being "captured" by a developing leaf. Their distal unconnected ends arise by dedifferentiation of ground parenchyma cells. Protoxylem is initiated as short overlapping initials that differentiate progressively during extension growth, which ruptures all but the last-formed elements. Their form, with tapered ends, means that they mature as tracheids. Metaxylem appears only late in shoot development, shortly before internodal elongation ceases (P(8)) and always unconnected to the late-differentiating protoxylem. In each axial bundle protophloem differentiates as a single strand, subsequently and much later appearing as two separate metaphloem strands as the early initials, ruptured by extension growth, are replaced by fibers. It is suggested that the unique features of this stem can be ascribed to the absence of a "meristematic cap," which otherwise typifies palms of normal habit, and that discontinuity is causally related to the pronounced late stem extension growth. PMID- 21665714 TI - Multilocus genetic structure at contrasted spatial scales of the endangered water fern Marsilea strigosa Willd. (Marsileaceae, Pteridophyta). AB - Marsilea strigosa (Marsileaceae, Pterydophyta) is a rare water fern found in the Mediterranean basin, in temporary flooded habitats only. We analyzed the level and the distribution of genetic variation at seven microsatellite loci, both at the Mediterranean scale and at a narrower scale within a highly fragmented French metapopulation. Genetic diversity among individuals within each pond suggests that M. strigosa reproduces predominantly through selfing. The very high population differentiation at the Mediterranean scale indicates that gene flow (if any) is highly restricted. Similar differentiation is also found at the scale of a single metapopulation. The distribution of multilocus genotypes suggests that the genetic variation in this species is maintained mainly through the interplay of mutation and low recombination. PMID- 21665715 TI - Genetic structure and indirect estimates of gene flow in three taxa of Cucurbita (Cucurbitaceae) in western Mexico. AB - Cultivated squash (Cucurbita argyrosperma ssp. argyrosperma and C. moschata) are important in the Mexican traditional agroecosystem. They are typically cultivated within maize fields where adjacent populations of a wild, close relative, C. argyrosperma ssp. sororia, occur. Consequently, there are ample opportunities for gene flow between domesticated and free-living Cucurbita populations. We used allozymes to examine genetic variation and gene flow among these three Cucurbita taxa in the state of Jalisco in Western Mexico. Twelve polymorphic allozyme loci were used to calculate genetic diversity for 16 populations of Cucurbita. We found high levels of genetic variation: polymorphism of 0.96, mean allelic diversity of 2.08, average expected heterozygosity 0.407, and little differentiation among conspecific populations (D = 0.081; F(ST) = 0.087; N(e)m = 5.22). These findings indicate that Cucurbita possess a high pollen dispersal potential, a somewhat surprising result considering they have specialist pollinators. Unweighted pair group method with arithmetic means (UPGMA) analysis of allozymes suggests the existence of at least two distinct groups of populations, one consisting of both subspecies of C. argyrosperma and another consisting of C. moschata. PMID- 21665716 TI - Floral biology and unique pollination system of root holoparasites, Balanophora kuroiwai and B. tobiracola (Balanophoraceae). AB - We investigated the floral and pollination biology of two monoecious root holoparasites, Balanophora kuroiwai and B. tobiracola (Balanophoraceae), in the subtropical forests of southern Japan. Both species secrete nectar from extrafloral nectaries distributed among the flowers, which is mainly consumed by ants, cockroaches, and pyralid moths. Pollen grains were found attached to the bodies of these insects. Pyralid moths of the genera Assara and Nacoleia were observed laying eggs on the inflorescences of B. kuroiwai. In both Balanophora species, pyralid larvae were found feeding on vegetative tissue without exploiting the seeds, and adults emerged from the fruited infructescences. In B. kuroiwai, we assessed pollination success under different experimental conditions by estimating the percentage of styles that had pollen tubes reaching the ovules. This revealed that: (1) the plants were at least sporophytically self-compatible; (2) they were generally pollinated within an inflorescence (geitonogamy); (3) outcrossing occurred, but the rates varied greatly among inflorescences; and (4) ants were probably responsible for the geitonogamy. While ants and flightless cockroaches were the most likely contributors to geitonogamous self-pollination, we consider pyralid moths to be the most likely cross-pollinators of Balanophora species. This is a new example of pollination mutualism involving a plant and its pollinating parasite. PMID- 21665717 TI - Vulnerability and determinants of reproductive success in the narrow endemic Antirrhinum microphyllum (Scrophulariaceae). AB - The breeding system and flowering phenology of the narrow endemic Antirrhinum microphyllum (Scrophulariaceae) were studied in order to assess the main factors affecting female reproductive success and to identify existing or potential threats to the viability of its populations. Hand-pollination experiments showed that A. microphyllum is an allogamous self-incompatible species. In both populations studied, the flowering season was 4 mo long and mean flowering duration per plant was about 1 mo. Peak flower production took place between mid April and mid-May and overlapped with the period of activity of the main pollinator, Rhodanthidium sticticum (Megachilidae). Estimated mean number of seeds produced per plant was 9391, showing that population viability is not presently limited by seed output. The study of the direct and indirect effects of plant size, phenological traits (first flowering date, flowering duration, and flowering synchrony), and distance to neighbor plants on reproductive success was performed using structural equation modeling (SEM). In both populations, number of flowers and plant size were the main factors that determined the total number of fruits produced by a plant. First flowering date and flowering synchrony also affected fruit production. Multisample comparison of path coefficients for the two populations rejected the possibility that reproductive patterns could be described by one single model. PMID- 21665718 TI - Synchronization of growth, branching and flowering processes in the South American tropical tree Cecropia obtusa (Cecropiaceae). AB - Cecropia obtusa Trecul (Cecropiaceae) is a pioneer species associated with the initial phases of regeneration of tropical South American forests. A comparison of the succession of morphological events associated with each node (inflorescences or branches developed or aborted and underlying internode length) making up the axes of 30 trees helped to establish a link between their architecture and the regularity and synchronicity of their expression of growth, flowering, and branching processes over time on an individual and stand level. For a given individual, new nodes are emitted at the same rate on all the axes, irrespective of their branching order. Flowering and branching alternate, and these processes occur in all the axes of the tree synchronously. On a stand level, flowering and branching occur regularly every 35 nodes or so, which apparently corresponds to an annual rhythm. Under nonlimiting conditions, a single branch tier would be emitted each year, and it is thus possible to determine a posteriori the age of a crown accurately. The merits of the method, the possibility of estimating the age of natural Cecropia obtusa regrowth by observing tree architecture, and the possible applications in the field of ecology are discussed. PMID- 21665719 TI - Root starch storage and allocation patterns in seeder and resprouter seedlings of two Cape Erica (Ericaceae) species. AB - Post-fire sprouting of dormant buds in resprouter plants is facilitated by stored carbohydrate reserves, with starch being the critical reserve. Starch is mainly stored in xylem parenchyma ray tissue of woody underground organs, such as burls, lignotubers, and roots. We carried out a comparative analysis of the pattern of starch storage and the proportion of parenchymatic ray tissue in the upper root or cotyledonary region of seedlings from seeder and resprouter forms within two Cape Erica (Ericaceae) species: E. coccinea L. and E. calycina L., which were raised in the greenhouse under controlled irrigation. We also explored the root to-shoot allocation patterns of seeder and resprouter seedlings in these two species. Resprouter seedlings of both species showed higher relative amounts of upper-root starch and upper-root storage tissue as well as a higher root-to-shoot allocation than their seeder counterparts. Pronounced swelling of the upper root region suggests ontogenetic development of a lignotuber in the resprouter forms of the two Erica species. The distinct allocation of starch in roots seems to be genetically determined and would account for the apparent differences in the root to-shoot allocation patterns between both regeneration forms from the early seedling stage. PMID- 21665720 TI - Frequency of spontaneous amphiploids in Gilia (Polemoniaceae) hybrids. AB - This paper reports the frequency of spontaneous amphiploids or neopolyploids in experimental interspecific hybrids in two annual sections of Gilia (Polemoniaceae, sects. Arachnion and Gilia, x = 9). In each section the species were intercrossed in numerous hybrid combinations to obtain an array of F1 hybrid types; seven of the hybrid types spontaneously produced new amphiploid progeny in F2. In sect. Arachnion the parental species and F1s were all diploids and the amphiploids were tetraploid; in sect. Gilia the parental species were diploids or tetraploids and the amphiploids were tetraploid or hexaploid. Two measures were used to express the frequency of spontaneous amphiploid formation. The first is the proportion of the F1 hybrid combinations that yielded any amphiploid progeny at all. In sect. Arachnion this proportion is 3/39 or 7.7%; in sect. Gilia it is 4/16 or 25%. A second measure is needed to express the variation in productivity among the seven amphiploid-producing hybrid types. The measure adopted is the mean number of new amphiploids per single F1 hybrid plant. The productivity numbers for the three hybrid combinations in sect. Arachnion are 0.25, 0.67, and 2.0; and those for four hybrid combinations in sect. Gilia are 0.15, 0.62, 2.25, and 12.62. There are large differences from one hybrid combination to another in rate of amphiploid formation, and the rate is quite high in some hybrids. The factors affecting these differences are discussed. PMID- 21665721 TI - Inflorescence diversification in the panicoid "bristle grass" clade (Paniceae, Poaceae): evidence from molecular phylogenies and developmental morphology. AB - Grasses exhibit a great variety of inflorescence forms and these appear homoplasious when mapped onto cladograms. The overall pattern is sufficiently complex that it is difficult to analyze inflorescence evolution. We have reduced the complexity of the problem by examining one group of grasses, the panicoid "bristle clade," which exhibits a less complex pattern of variation. The clade is morphologically defined by inflorescences bearing both spikelets and sterile bristles and is monophyletic in both morphological and molecular phylogenetic analyses. We have constructed a chloroplast DNA phylogeny of the three main genera, which finds three well-supported clades, two comprising species placed in Setaria and one of Pennisetum + Cenchrus. In this tree Cenchrus is monophyletic, but both Setaria and Pennisetum are paraphyletic. Developmental morphology of these groups is very similar at early stages. Changes in axis ramification, primordial differentiation, and axis elongation account for most variation in mature inflorescence morphology. Characters derived from comparisons of developmental sequences were optimized onto one of the most parsimonious trees. Most developmental characters were congruent with the molecular phylogeny except for three reversals in the subclade containing S. barbata, S. palmifolia, and two accessions of S. poiretiana. Changes in just a handful of developmental events account for inflorescence evolution in the bristle clade, and similar changes may account for inflorescence diversity in the grasses as a whole. PMID- 21665722 TI - Population genetic analysis of European Prunus spinosa (Rosaceae) using chloroplast DNA markers. AB - Chloroplast DNA diversity in Prunus spinosa, a common shrub of European deciduous forests, was assessed using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Thirty-two haplotypes were detected in 25 populations spread across the European continent. Ten haplotypes were shared by two or more populations, and 22 were private. The major proportion of the total cpDNA diversity (H(T) = 0.73) was located within the populations (H(S) = 0.49), and differentiation between populations was low (G(ST) = 0.33) compared with other forest species. Haplotype diversity was higher in southern Europe than in northern Europe, indicating probable localization of glacial refugia in southern Europe. The minimum-length spanning tree of haplotypes showed incongruency between the phylogeny of haplotypes and their geographic locations. This might be the result of intensive seed movements following recolonization, which thereby erased the phylogeographic structure in P. spinosa. PMID- 21665723 TI - Landscape-level spatial genetic structure in Quercus acutissima (Fagaceae). AB - Quercus acutissima (Fagaceae), a deciduous broad-leaved tree, is an important forest element in hillsides of South Korea. We used allozyme loci, Wright's F statistics, and multilocus spatial autocorrelation statistics to examine the distribution of genetic diversity within and among three local populations and the spatial genetic structure at a landscape scale (15 ha, 250 * 600 m) on Oenaro Island, South Korea. Levels of genetic diversity in Q. acutissima populations were comparable to mean values for other oak species. A moderate but significant deficit of heterozygotes (mean F(IS) = 0.069) was detected within local populations and low but significant differentiation was observed among populations (F(ST) = 0.010). Spatial autocorrelation analyses revealed little evidence of significant genetic structure at spatial scales of 100-120 m. The failure to detect genetic structure within populations may be due to intraspecific competition or random mortality among saplings, resulting in extensive thinning within maternal half-sib groups. Alternatively, low genetic differentiation at the landscape scale indicates substantial gene flow among local populations. Although wind-borne pollen may be the primary source of gene flow in Q. acutissima, these results suggest that acorn movement by animals may be more extensive than previously anticipated. Comparison of these genetic data for Oenaro Island with a disturbed isolated inland population suggests that population-to-population differences in internal genetic structure may be influenced by local variation in regeneration environment (e.g., disturbance). PMID- 21665724 TI - The effects of stigma age on receptivity in Silene alba (Caryophyllaceae). AB - Silene alba, a perennial, dioecious plant, produces flowers that open in the evening and can remain open and receptive to pollination for up to 5 d, though in hot and dry conditions the flowers will wilt during the day only to reopen night after night. In the field, it is visited by two different kinds of pollinators with differential success: moths visit the flowers at night, and their movements result in broad pollen dispersal and large seed production, whereas bees, wasps, and flies visit the flowers in the mornings and have decreased pollination effectiveness. However, this differential success may be due to a decrease in stigmatic receptivity soon after the flowers open. We performed controlled pollinations to determine the effect of stigma age on pollen germination and seed set. We pollinated flowers at 12-h intervals up to 120 h and divided these into two sets: from one set, we removed stigmas 24 h after pollination to examine percentage of pollen germination. The second set of flowers was allowed to produce fruits, and the seeds were counted and weighed. Pollen germination declined significantly with stigma age, but there was no significant effect of stigma age at pollination on the number or mass of resulting seeds. Thus, the decreased pollination success of bees is not due to a decrease in stigmatic receptivity but is most likely a result of pollinator inefficiency. PMID- 21665725 TI - Evolutionary maintenance of stigma-height dimorphism in Narcissus papyraceus (Amaryllidaceae). AB - Stigma-height dimorphism is a sexual polymorphism in which plant populations are composed of two floral morphs that differ significantly in style length but not anther position. The morphs exhibit approach and reverse herkogamy, floral designs that in most species typically occur as monomorphic conditions. We investigated the floral biology of stigma-height dimorphism in the Mediterranean geophyte Narcissus papyraceus (Amaryllidaceae) in an effort to understand the evolutionary forces maintaining stylar polymorphism. Our survey of 66 populations in Spain, Portugal, and Morocco indicated that 56% were dimorphic with the long styled morph at an average frequency of 0.79. The remaining 44% of populations sampled were monomorphic for the long-styled morph. In dimorphic populations there was a significant positive relation between population size and the frequency of the short-styled morph. Controlled pollinations demonstrated that N. papyraceus is self-sterile with no significant differences in female fertility between intra- and intermorph crosses. Prior self-pollination reduced seed set in flowers that were subsequently cross-pollinated. Estimates of mating patterns using allozyme markers in eight populations indicated that N. papyraceus is largely outcrossing (mean t(m) = 0.81) with no significant differences between monomorphic and dimorphic populations or style morphs. Stigma-height dimorphism in N. papyraceus is maintained in populations by insect-mediated cross pollination with biased morph ratios and stylar monomorphism likely resulting from the combined influence of the inheritance of the polymorphism, morph specific differences in assortative mating and founder effects. PMID- 21665726 TI - Effects of population size and pollen diversity on reproductive success and offspring size in the narrow endemic Cochlearia bavarica (Brassicaceae). AB - In small, fragmented populations of self-incompatible plant species, genetic drift and increasingly close relationships between plants may restrict the number of genetically different pollen donors, the availability of compatible mates, and the opportunity for pollen competition and selection. These restrictions may reduce the siring success or increase the probability of inbreeding depression in the offspring. To test if this was the case, we hand-pollinated maternal plants in small and large populations of the rare, endemic plant Cochlearia bavarica (Brassicaceae) with pollen from one, three, or nine donors from the same population or with nine donors from a different population. In one additional population of intermediate size, maternal plants were hand-pollinated with ten donors located at a distance of 1, 10, 100, or 1000 m. We then recorded seed and offspring characters. On average, offspring from small populations were smaller than normal and fewer survived to maturity. Increasing the number of pollen donors had a positive effect on reproductive success in small and large populations, but at the highest pollen diversity this occurred at the expense of slightly reduced offspring fitness. Because the total amount of transferred pollen was held constant, these effects could not be attributed to increasing pollen load. Rather, the increasing pollen diversity may have increased the chances of selecting a particularly "good" donor for fertilization-an example of a sampling effect of diversity. Pollen from outside a population or from 10-100 m away resulted in higher reproductive success and greater offspring size. Effects of population size and pollination treatments on reproductive success and offspring fitness were additive. Apparently, there is no obvious size threshold above which the potential of inbreeding depression can be ignored in C. bavarica. PMID- 21665727 TI - Floral variation in the generalist perennial herb Paeonia broteroi (Paeoniaceae): differences between regions with different pollinators and herbivores. AB - This paper investigates the differences in floral phenotype in Paeonia broteroi (Paeoniaceae) in four populations at two distant mountainous regions in southern Spain. Paeonia broteroi flowers exhibit traits of a highly generalized pollination system, but previous studies have revealed that not all flower visitors are effective at pollen delivery. Plants differed between regions in the number of flowers per plant, petal size, number of stamens per flower, and ovules per carpel. Differences between regions could not be attributable to differences in the size structure of the plants. Flower visitors in the two regions differed in assemblage and body size at all the spatiotemporal scales. Larger visitors were more effective as pollinators in the region with the largest and more rewarding (as measured by the number of stamens) flowers, suggesting that pollinators may create opportunities for selection of certain floral traits. In contrast, the two regions did not differ in the probability of damage by herbivores, which did not select flowers based on any of the measured traits, nor affected maternal fecundity. Despite the differences in flower phenotype, potential maternal fecundity, and pollinator effectiveness, plants did not differ between regions in seed production. The role of pollinators as determinants of the differences between regions in floral phenotype, through male and female reproductive success, is discussed. Also, alternative explanations to divergence are addressed, with special reference to the patterns of resource allocation between sexual functions and genetic drift. PMID- 21665728 TI - Do floral herbivores respond to variation in flower characteristics in Gelsemium sempervirens (Loganiaceae), a distylous vine? AB - We tested the hypothesis that traits traditionally thought to function in pollination can also influence attack by floral herbivores. Because distylous species produce two different flower types, we used Gelsemium sempervirens, a distylous vine of southeastern USA, to examine the frequency and pattern of floral herbivory in relation to floral characteristics. Flowers of the short styled morph had larger corollas but showed no difference in the volume or concentration of nectar produced. Over the 2 yr of this study, 20-30% of plants suffered floral herbivory. The pattern of damage was morph-specific. Long-styled flowers were more likely to have damaged pistils, while stamens were more often damaged in short-styled flowers. In this distylous species, exserted flower organs were more likely to be eaten. Such differential herbivory based on the position of floral organs within a flower may result in reduced fitness via either male (short-styled morph) or female function (long-styled morph). PMID- 21665729 TI - Convergence in light capture efficiencies among tropical forest understory plants with contrasting crown architectures: a case of morphological compensation. AB - Leaf and crown characteristics were examined for 24 tree and herbaceous species of contrasting architectures from the understory of a lowland rainforest. Light capture efficiency was estimated for the crowns of the different species with a three-dimensional geometric modeling program. Causal relationships among traits affecting light absorption at two hierarchical levels (leaf and whole crown) were quantified using path analysis. Light-capture and foliage display efficiency were found to be very similar among the 24 species studied, with most converging on a narrow range of light absorption efficiencies (ratio of absorbed vs. available light of 0.60-0.75). Exceptionally low values were found for the climber vines and, to a lesser extent, for the Bromeliad Aechmea magdalenae. Differences in photosynthetic photon flux density (PFD) absorbed per unit leaf area by individual plants were mostly determined by site to site variation in PFD and not by the differences in crown architecture among individuals or species. Leaf angle, and to a lesser extent also supporting biomass, specific leaf area, and internode length, had a significant effect on foliage display efficiency. Potential constraints on light capture such as the phyllotactic pattern were generally offset by other compensatory adjustments of crown structure such as internode length, arching stems, and plagiotropy. The variety of shoot morphologies capable of efficiently capturing light in tropical forest understories is greater than initially thought, extending over species with very different phyllotactic patterns, crown architectures, leaf sizes, and morphologies. PMID- 21665730 TI - The 120-yr period for Dr. Beal's seed viability experiment. AB - After 120 yr of burial in moist, well-aerated sand, 23 seeds of Verbascum blattaria and two seeds of a Verbascum sp. germinated and produced normal plants (50% germination for Verbascum). After a 6-wk cold treatment, a single seed of Malva rotundifolia germinated also, producing a normal plant (2% germination). Plants were grown to maturity in a greenhouse, and flowering was induced by exposure to a 6-wk cold treatment. Flowers were artificially pollinated to produce seed of both Verbascum blattaria and Malva rotundifolia. The Verbascum sp. failed to set seed. Collected seeds were subsequently germinated, producing normal plants. F(1) seeds of V. blattaria had a germination of 64%. Seeds (6%) of M. rotundifolia germinated after a cold treatment. PMID- 21665731 TI - Lateral root function and root overlap among mycorrhizal and nonmycorrhizal herbs in a Florida shrubland, measured using rubidium as a nutrient analog. AB - Lateral root spread is an important indicator of the area over which plants forage belowground and has implications for individual plant fitness, belowground competition, and ultimately both population dynamics and community structure. Because fine lateral roots are difficult to excavate and measure, we used rubidium (Rb), an analog for potassium that occurs at very low levels in soils and plants, as a tracer of root activity. We injected Rb into sandy soils of a xeric Florida shrubland and examined uptake by four small herbaceous species that generally do not overlap aboveground. All four species took up Rb at distances of up to 97 cm (with an average lateral root spread of 51 cm), indicating that belowground neighborhoods are larger than aboveground. The arbuscular mycorrhizal species exhibited greater Rb enrichment without any change in lateral spread. The spatial arrangement of plants with elevated levels of Rb relative to Rb patches was consistent with root and mycorrhizal systems that are radially discontinuous and asymmetric. Furthermore, many individuals acquired Rb from the same patches, suggesting overlap in root function and the potential for belowground competition, although small-scale spatial and/or temporal segregation could have occurred. PMID- 21665732 TI - Reproductive effort and herbivory timing in a perennial herb: fitness components at the individual and population levels. AB - We experimentally investigated how pollinator- and herbivore-induced changes influence the performance of the long-lived herb Primula veris. Eight treatments that corresponded to natural factors normally affecting this species were designed to enhance or reduce reproductive success and resource availability (flower removal, supplementary pollination, defoliation). During the experimental season and in the following year we quantified responses in terms of survival, growth, and seed production of reproductive plants. Matrix population models were used to calculate population growth rate using the demographic parameters recorded in permanent plots and respective treatment groups. Seed production was not limited by pollen availability, and we found no evidence of a cost of reproduction. Leaf removal had either no effect or a negative effect on future performance, depending on the timing of removal. Defoliation early in the season reduced current seed production and future growth, whereas removal during fruit development affected performance in the following year. Demographic models suggest that leaf damage has a smaller negative impact than flower removal on overall performance in this population. Our results suggest that the source-sink paths vary over the season and that the timing of herbivory may influence the extent to which effects are carried over to subsequent reproductive seasons. PMID- 21665733 TI - Architecture of coastal and desert Encelia farinosa (Asteraceae): consequences of plastic and heritable variation in leaf characters. AB - The shrub Encelia farinosa (Asteraceae) exhibits geographic variation in aboveground architecture and leaf traits in parallel with environmental variation in temperature and moisture. Measurements of plants occurring across a natural gradient demonstrated that plants in desert populations produce smaller, more pubescent leaves and are more compact and branched than plants in more mesic coastal environments. This phenotypic variation is interpreted in part as adaptive genetic differentiation; small size and pubescence reduce leaf temperature and thus increase water-use efficiency but at the cost of lower photosynthetic rate, which results in slower growth and more compact growth form. We explored the basis of phenotypic variation by planting seed offspring from coastal and desert populations in common gardens in both environments. Phenotypic differences among populations persisted in both common gardens, suggesting a genetic basis for trait variation. Desert offspring outperformed coastal offspring in the desert garden, suggesting superior adaptation to hot, dry conditions. Herbivore damage was greater for all offspring in the coastal garden. Phenotypic characters also showed plastic responses; all offspring had smaller, more pubescent leaves and more compact growth form in the desert garden. Our results confirm that leaf size and pubescence are heritable characters associated with pronounced variation in plant architecture. PMID- 21665734 TI - Historical biogeography and the origin of stomatal distributions in Banksia and Dryandra (Proteaceae) based on their cpDNA phylogeny. AB - Banksia and Dryandra have undergone extensive speciation and adaptive radiation, especially in Australia's isolated Southwest Botanical Province. We derive a phylogeny for these groups based on cpDNA sequences and use it to reconstruct their historical biogeography and evolution of leaf traits thought to be adapted to drought and/or nutrient poverty. Slowly evolving regions (trnL intron, trnL/trnF spacer) are used to resolve large-scale relationships; faster evolving regions (rp116 intron, psbA/trnH and trnT/trnL spacers) are used to resolve relationships among closely related species. Banksia is paraphyletic with respect to Dryandra. The lineage underwent a basal split into two clades (here named /Cryptostomata and /Phanerostomata), and four infrageneric taxa supported by morphological cladistic analyses (series Spicigerae, Abietinae, Tetragonae, and Banksia) are not monophyletic. Dispersal-vicariance analysis resolves a southwestern Australian origin for the lineage, with two later expansions to the east followed by vicariance events. Stomatal crypts arose with the /Cryptostomata, which is characterized by tough, long-lived leaves and common in southwestern Australia. Sequestering of stomata also arose multiple times in /Phanerostomata, which is characterized by softer, short-lived leaves and common in moister coastal areas, via inrolling of the margins of narrow leaves and restricting stomata to shallow pits. The hypothesis that sclerophylly preadapted the plants to xeromorphy is supported in the case of shallow stomatal pits and deep stomatal crypts, but not narrow, needle-like leaves. PMID- 21665735 TI - A chloroplast DNA phylogeny of eastern Phlox (Polemoniaceae): implications of congruence and incongruence with the ITS phylogeny. AB - The comparison of independent phylogenies is a valuable approach to the study of evolutionary pattern and process. Available data on eastern North American Phlox, including our recent ITS phylogeny, suggest that relationships are complicated in the group and that hybridization may have been a contributing factor. We used restriction site data from the chloroplast genome to develop a second phylogeny for eastern Phlox. Sampling was the same as that for the ITS study and consisted of 79 samples (including all 22 eastern Phlox species and most eastern subspecies, as well as multiple populations of many taxa). The resulting cpDNA phylogeny agrees with the ITS phylogeny in many respects, strengthening earlier conclusions. Nevertheless, incongruence between the trees is noteworthy: many samples, particularly of members of the P. pilosa and P. glaberrima complexes, are placed in different clades. A variety of tests were carried out to assess congruence in terms of topological patterns, character congruence, and homogeneity of data sets. Significant conflict between the phylogenies is discussed in light of the hypothesis that hybridization has affected relationships in this genus. PMID- 21665736 TI - Subfamilial relationships within Caryophyllaceae as inferred from 5' ndhF sequences. AB - DNA sequences of the 5' end of the chloroplast ndhF gene for 15 species of Caryophyllaceae have been analyzed by parsimony and neighbor-joining analyses. Three major clades are identified, with little or no support for monophyly of traditionally recognized subfamilies. The first of the three major clades identified (Clade I) is constituted by part of the subfamily Paronychioideae. It includes members of the tribe Paronychieae and members of tribe Polycarpeae. The second (Clade II) contains members of the Paronychieae exclusively. Tribe Paronychieae is thus apparently polyphyletic and tribe Polycarpeae is at least paraphyletic. The third clade (Clade III) includes members of subfamilies Alsinoideae and Caryophylloideae along with the genus Spergularia. The genus Scleranthus is also part of Clade III, while Drymaria groups with the other genera of tribe Polycarpeae in Clade II. We conclude that morphological characters previously used to delimit subfamilial groupings in the Caryophyllaceae are apparently unreliable estimators of phylogeny. PMID- 21665737 TI - A phylogenetic evaluation of a biosystematic framework: Brodiaea and related petaloid monocots (Themidaceae). AB - Phylogenetic analyses of plastid DNA sequences of ndhF, trnL-F intron and spacer regions, and rpl16 are presented separately and combined for 41 taxa from all 12 genera of the Themidaceae and for 20 taxa from nine related families in the higher Asparagales. The results from the combined analysis are the most resolved and provide a high level of support for the monophyly of Themidaceae. Within Themidaceae, the Milla complex of Mexico is supported as monophyletic within a paraphyletic Brodiaea complex of western North America. Four major clades are identified in each of the individual and combined analyses: (1) the Milla complex; (2) Brodiaea, Dichelostemma, and Triteleiopsis; (3) Triteleia, Bloomeria, and Muilla clevelandii; and (4) Androstephium and the other species of Muilla. These well-defined clades suggest that morphological characters (e.g., an extended perianth tube) that have been traditionally used to circumscribe the genera within the Brodiaea complex have evolved independently at least twice. In addition, common biogeographic distribution patterns (e.g., Brodiaea and Triteleia having centers of diversity in northern California and the Pacific Northwest) appear to be the result of separate evolutionary radiations. PMID- 21665738 TI - The formation of adventitious roots on root axes is a widespread occurrence in field-grown dicotyledonous plants. AB - The formation of adventitious branch roots in the secondary tissues of parental root axes is a widespread and frequent occurrence under field conditions. Anatomical features diagnostic for the recognition of adventitious roots were utilized to confirm the occurrence of adventitious roots on roots of 22 species from 12 families in nine orders of dicotyledonous plants. Adventitious roots may play an important role in generating the population of fine roots as part of root turnover in the soil. PMID- 21665739 TI - Subdioecy in Consolea spinosissima (Cactaceae): breeding system and embryological studies. AB - The breeding system and the embryology of Consolea spinosissima, a tree-like opuntioid endemic to Jamaica, were investigated. Morphological and embryological studies revealed that the species is subdioecious, with three sexual morphs present in the 150 * 120 m plot studied at Hellshire Hills, Jamaica. The female morph has pistillate flowers with open stigma lobes, no pollen grains, and sets fruit. The male morph has cryptic staminate flowers with closed stigma lobes, viable pollen grains, and a nonfunctional gynoecium that does not set seed. The weak hermaphrodite morph has low fruit set and "perfect" flowers that superficially resemble the functionally staminate flowers of the male morph. These perfect flowers reach anthesis with viable pollen grains, with no or only a few functional ovules, and with the style supporting pollen tube growth. Embryological studies showed that the critical stage for sex determination occurs earlier in pistillate than in staminate and perfect flowers. Anthers of pistillate flowers abort prior to microspore tetrad formation, whereas ovules of the staminate and perfect flowers degenerate after the complete maturation of the embryo sac. Based on flower structure and embryological data, we hypothesize that the ancestor of C. spinosissima is/was hermaphroditic. PMID- 21665740 TI - Responses of carbon acquisition traits to irradiance and light quality in Mercurialis annua (Euphorbiaceae): evidence for weak integration of plastic responses. AB - It is often suggested that traits will be integrated, either because of pleiotropy or because natural selection may favor suites of integrated traits. Plant responses to different environments can provide evidence of such integration. We grew Mercurialis annua plants in high-density stands in high irradiance, in neutral shade, and in high red to far-red (R:FR) shade, resulting in environments of high irradiance, low R:FR; low irradiance, low R:FR; and low irradiance, high R:FR. We measured gas exchange, leaf morphology, stem elongation, and biomass traits and tested the prediction that traits within each functional group would show higher trait integration, as evidenced by high correlations among traits within environments, higher correlations of trait plasticity, and lower plasticity of trait correlations. Overall, we found evidence of only moderate integration for some groups of traits. Functionally related groups of traits, or pairs of traits, could be strongly integrated by one criterion but weakly integrated by another of the criteria. Stem elongation traits, though often observed to be strongly integrated in other taxa, showed little evidence of integration. Internode traits exhibited a novel pattern of responses to low R:FR, with increased elongation of the hypocotyl, decreased elongation of the first internode, and no change in the second internode. We propose that these responses to light are more likely to be the result of natural selection than the consequence of constraints imposed by pleiotropy. PMID- 21665741 TI - Separate effects of human visitation and touch on plant growth and herbivory in an old-field community. AB - Although animal scientists have long been aware that methods used to measure an experimental system can affect the subject of measurement, similar confounding effects of commonly used field methods have only recently been acknowledged by plant ecologists. Here we demonstrate significant effects of weekly visitation (walking up to a focal plant) and handling (taking morphological measures) on plant growth and herbivory in an old-field community. Of the three species examined, Apocynum cannabinum was the most severely affected by our treatments. For Apocynum, weekly visitations resulted in a positive relationship between initial and final size, which did not occur in the unvisited plants. Visitation also increased leaf herbivory, resulting in a reduced leaf:stem biomass ratio. Handling the plants nearly doubled the proportion of individuals with a stem borer emergence hole. Growth of the other species in this study, Potentilla recta and Erigeron philadelphicus, was altered by either visitation or visitation plus handling. Visiting plants in order to observe them and touching them as one would when making morphological measurements can have important biological consequences. We suggest that plant ecologists treat repeated entry into a natural system as a research method, subject to the same scrutiny and justification as all other experimental methods. PMID- 21665742 TI - Genetic and environmental effects on morphology in clonal sedges in the Eurasian Arctic. AB - We studied the variation in morphological characters of importance for resource acquisition and storage in 21 populations of four clonal sedge taxa in arctic Eurasia, Carex bigelowii, C. ensifolia subsp. arctisibirica, C. lugens, and C. stans, and the response to transplantation to a common garden in Tromso, Norway. The morphology of C. stans was distinct from the other three taxa, all of which belong to the C. bigelowii species complex. However, differences among populations within taxa were even greater than differences among taxa, and environmental variables explained 40-50% of the among-population variation in the morphological characters. Stomatal size decreased with temperature while stomatal density increased. Shoot height and leaf width were smaller at peak lemming population phase, while rhizome length was shorter at higher longitudes. Transplantation to a common garden affected stomatal density in all taxa, stomatal size and shoot height only in some taxa, while leaf width was not affected. We found a weak, but highly significant correlation between geographical, morphological, and genetic distances. We concluded that although genotypic differentiation in arctic rhizomatous Carex species is reflected in their morphology, they are also capable of plastic morphological responses to the environment and that these responses are specific for each taxon. PMID- 21665743 TI - Variation in the expression of chemical defenses in Alliaria petiolata (Brassicaceae) in the field and common garden. AB - I examined glucosinolates, trypsin inhibitors (TI), and peroxidase (POD) activity in garlic mustard (Alliaria petiolata) plants growing naturally in Wright State University's Forest Preserve and in a common garden experiment in plants from the same populations conducted in the greenhouse. In the field, first-year plants expressed each defense, but defense levels varied significantly in plants from different sites in the forest. Patterns in site variation were consistent for glucosinolate and POD, but not for TI. The TI and POD levels were increased by mechanical wounding, but glucosinolate levels were unaffected. In the greenhouse, plants expressed each defense at higher levels than in the field, but defense levels did not vary among plants collected from each site in the field. The POD activity was increased by wounding, but glucosinolate and TI levels where unaffected. Plants from each site varied in height and leaf length when measured shortly after transplantation, but site differences substantially diminished after 4 wk. Site-based variation in defense expression in the field, which disappeared in the greenhouse, was presumably related to differences in environmental quality among the sites. Sites were shown to vary in soil moisture content, soil pH, nutrient levels, and presumably light quantity or quality. Despite an apparent lack of genetic variation in defense across sites in the field, the constitutive expression of these three chemical defenses, increases due to wounding, and phenotypic variation across sites could reduce herbivore success on garlic mustard individuals and slow the rate of herbivore adaptation to garlic mustard populations. PMID- 21665744 TI - Photosynthetic characteristics of invasive and noninvasive species of Rubus (Rosaceae). AB - The prolific amount of growth and reproduction in invasive plants may be achieved by greater net photosynthesis and/or resource-use efficiency. I tested the hypotheses that leaf-level photosynthetic capacity and resource-use efficiency were greater in two invasive species of Rubus as compared with two noninvasive species that have overlapping distributions in the Pacific Northwest. The invasive species had significantly higher photosynthetic capacity and maintained net photosynthesis (A) over a longer period of the year than the noninvasive species. The construction cost (CC) of leaf tissue per unit leaf mass was comparable among the four species, but the invasive species allocated less nitrogen (N) per unit leaf mass. On a leaf area basis, both leaf CC and N were higher for the invasive species. The specific leaf area (SLA) was also lower in the invasive species, indicating less photosynthetic area per gram leaf tissue. The invasive species achieved high A at lower resource investments than the noninvasive species, including having higher maximum photosynthetic rate (A(max)) per unit dark respiration (R(d)), greater A(max) per unit leaf N (photosynthetic nitrogen-use efficiency), and greater water-use efficiency as measured by instantaneous rates of A per unit transpiration (A/E) and by integrated A/E inferred from stable carbon isotope ratios (delta(13)C). Using discriminant analysis, these photosynthetic characteristics were found to be powerful in distinguishing between the invasive and noninvasive Rubus. A(max) and A/E were identified as the most useful variables for distinguishing between the species, and therefore, may be important factors contributing to the success of these invasive species. PMID- 21665745 TI - Divergent phenologies may facilitate the coexistence of arbuscular mycorrhizal fungi in a North Carolina grassland. AB - Interest in the diversity of arbuscular mycorrhizal (AM) fungal communities has been stimulated by recent data that demonstrate that fungal communities influence the competitive hierarchies, productivity, diversity, and successional patterns of plant communities. Although natural communities of AM fungi are diverse, we have a poor understanding of the mechanisms that promote and maintain that diversity. Plants may coexist by inhabiting disparate temporal niches; plants of many grasslands are either warm or cool season specialists. We hypothesized that AM fungi might be similarly seasonal. To test our hypothesis, we tracked the sporulation of individual AM fungal species growing within a North Carolina grassland. Data were collected in 1996 and 1997; in 1997, sampling focused on two common species. We found that AM fungi, especially Acaulospora colossica and Gigaspora gigantea, maintained different and contrasting seasonalities. Acaulospora colossica sporulated more frequently in the warm season, but Gi. gigantea sporulated more frequently in the cool season. Moreover, AM fungal species were spatially aggregated at a fine scale. Contrasting seasonal and spatial niches may facilitate the maintenance of a diverse community of AM fungi. Furthermore, these data may illuminate our understanding of the AM fungal influence on plant communities: various fungal species may preferentially associate with different plant species and thereby promote diversity in the plant community. PMID- 21665746 TI - Anatomically preserved Cycadeoidea (Cycadeoidaceae), with a reevaluation of systematic characters for the seed cones of Bennettitales. AB - Four anatomically preserved ovulate cycadeoid cones have been recovered from three localities in Upper Cretaceous (Turonian/Coniacian-Late Campanian) sediments of Vancouver and Hornby Islands, British Columbia, Canada. All of the specimens are preserved by calcareous cellular permineralization and are quite similar to seed cones described as several species of Cycadeoidea and Bennettites. These cones, described as Cycadeoidea maccafferyi sp. nov., consist of tightly packed interseminal scales and ovulate sporophylls with terminal ovules. Two specimens also preserve remains of a small receptacle. Interseminal scales and ovulate sporophylls are oriented parallel to one another. Ovules are distinctly stellate at the base of the micropylar tube, and the sarcotesta consists of both longitudinally oriented tubular cells and large radially elongated cells attached to the sclerotesta. The vascular strand below each ovule is highly contorted in a pattern that is characteristic of contractile tissue in the roots of living plants. These specimens are the most recent anatomically preserved cycadeoid cones yet discovered, revealing details of the reproductive biology shortly before extinction of the clade. Superb preservation of the British Columbia cones confirms that Bennettitales lack a cupule, have radial seeds, and have a vascularized nucellus (but no integumentary tracheids), and that no pollen chamber is produced. Together with a new species of Williamsonia preserved at one of the same localities, these specimens reveal a clear set of contrasting systematic characters for differentiating between isolated seed cones of Williamsoniaceae and Cycadeoidaceae. PMID- 21665747 TI - Morphometric analysis of pollen grains for paleoecological studies: classification of Picea from eastern North America. AB - Little is known about the paleoecological histories of the three spruce species (white spruce, Picea glauca; black spruce, P. mariana; and red spruce P. rubens) in eastern North America, largely because of the difficulty of separating the three species in the pollen record. We describe a novel and effective classification method of distinguishing pollen grains on the basis of quantitative analysis of grain attributes. The method is illustrated by an analysis of a large sample of modern pollen grains (522 grains from 38 collections) of the three Picea species, collected from the region where the three species co-occur today. For each species X we computed a binary regression tree that classified each grain either as X or as not-X; these three determinations for each grain were then combined as Hamming codes in an error/uncertainty detection procedure. The use of Hamming codes to link multiple binary trees for error detection allowed identification and exclusion of problematic specimens, with correspondingly greater classification certainty among the remaining grains. We measured 13 attributes of 419 reference grains of the three species to construct the regression trees and classified 103 other reference grains by testing. Species-specific accuracies among the reliably classified grains were 100, 77, and 76% for P. glauca, P. mariana, and P. rubens, respectively, and 21, 30, and 22% of the grains by species, respectively, were problematic. The method is applicable to any multi-species classification problem for which a large reference sample is available. PMID- 21665748 TI - An anatomically preserved arborescent lycopsid, Sublepidodendron songziense (Sublepidodendraceae), from the Late Devonian of Hubei, China. AB - Sublepidodendron is a common megafossil plant in the Late Devonian of China, but historically the generic delimitation based on leaf bases masked its true systematic position. A reinvestigation of S. songziense from the Late Devonian Hsiehchingssu Formation, Hubei, China, provides new insights into its internal anatomy and reproductive morphology. This arborescent lycopsid is characterized by small, vertically elongated leaf bases arranged in spirals, presence of false leaf scars, possibly bearing separate cones, and association with a stigmarian rhizomorph. The potential for organic connections of these detached organ genera has been noted for other Sublepidodendron species. The anatomy of S. songziense axes from two levels reveals that the thinner axis may bear an ectophloic siphonostele with a filamentous pith and an outer cortex. The thicker axis has a siphonostele with a branch gap, two-zoned pith with secondary thickenings, multiseriate rays across secondary xylem, a thick periderm, and primary and secondary tracheid walls characterized by "Williamson's striations." Similarities to synapomorphies of Diaphorodendraceae and Lepidodendraceae suggest that S. songziense bears a closer affinity to Lepidodendrales rather than Protolepidodendrales, as formerly thought. Widespread occurrence of Sublepidodendron implies that phylogenetically advanced arborescent lycopsids must have diverged by the Late Devonian. PMID- 21665749 TI - The origin of the apple subfamily (Maloideae; Rosaceae) is clarified by DNA sequence data from duplicated GBSSI genes. AB - For 70 yr the leading hypothesis for the origin of the Maloideae has involved wide hybridization between ancestors of two other subfamilies. The basis of this hypothesis is that Maloideae have a base chromosome number of 17, whereas other Rosaceae are mostly x = 7, 8, or 9. To investigate this hypothesis we cloned and sequenced approximately 1.8 kilobases from the 5' portion of granule-bound starch synthase (GBSSI, or waxy) genes for 89 clones from 32 Rosaceae genera. Previous studies demonstrate the presence of two copies in all Rosaceae (GBSSI-1 and GBSSI 2) and four in Maloideae (GBSSI-1A, GBSSI-1B, GBSSI-2A, and GBSSI-2B). Parsimony and maximum likelihood analyses nest Gillenia, a genus of the southeastern United States with a base chromosome number of 9, within either Maloideae GBSSI-1 or GBSSI-2. Monophyly of Maloideae plus Gillenia is well supported by bootstrap values, loss of the sixth intron in all GBSSI-1 sequences, intron alignability between genera, and numerous nonmolecular characters. Our results falsify the wide-hybridization hypothesis and are consistent with a polyploid origin involving only members of a lineage that contained the ancestors of Gillenia. Under this hypothesis, the subfamily originated in North America, and the high Maloideae chromosome number arose via aneuploidy from x = 18. PMID- 21665750 TI - Rediscovery of Pedilanthus coalcomanensis (Euphorbiaceae), a threatened endemic Mexican species. AB - Pedilanthus coalcomanensis was described from specimens collected by George B. Hinton in 1941 but was not collected again until 1999, when we found it in a tropical deciduous forest near Tehuantepec, in Chinicuila, Michoacan, Mexico. After analyzing Hinton's original collection notes, we concluded that this is the type locality. Based on the reduced geographic distribution presently known for this species (11 km(2)), the level of disturbance of its habitat, and the use of the method for the assessment of extinction risk in Mexican wild species (MER), we propose that P. coalcomanensis be covered by the appropriate Mexican legislation as a threatened species and be included in the Red List of Threatened Plants of the International Union for the Conservation of Nature. Our results help justify and delimit a local biosphere reserve in northwestern Michoacan, an area that is considered a center of endemism and that has largely been deforested. Our findings have implications for research on other historical specimens collected by Hinton in this region. PMID- 21665751 TI - Phenetic and phylogenetic analysis of Reinhardtia (Palmae). AB - Principal component analysis and cluster analysis of morphometric data divide specimens of Reinhardtia into six groups, corresponding to the six species recognized in the most recent revisions. Discriminant analysis classifies specimens into these six species with 100% success. Five species occur in lowland to montane moist forests in Central America, from Mexico to Panama, and just reach Colombia; one species occurs in montane moist forests in Hispaniola. Three species have large stems and are rare, patchily distributed, and seldom collected. The other three species have small stems, are common and frequently collected, but also patchily distributed. One species of small plants, R. gracilis, exhibits considerable variability. Within this species, seven distinct groups can be recognized, although sample size is limited. Among species, there is a phyletic decrease in size of plants, from the basal species with large stems to derived species with small stems. For leaves and inflorescences there is also an associated decrease in size, but one species does not follow this trend. In this species, R. latisecta, there is evidence of a large ontogenetic change in leaf development. Phyletic decrease in size corresponds to a latitudinal and elevational gradient suggesting speciation has taken place from north to south and from high to low elevation. However, this pattern is obscured disjunct distributions in some species. PMID- 21665752 TI - Molecular evidence for the common origin of snap-traps among carnivorous plants. AB - The snap-trap leaves of the aquatic waterwheel plant (Aldrovanda) resemble those of Venus' flytrap (Dionaea), its distribution and habit are reminiscent of bladderworts (Utricularia), but it shares many reproductive characters with sundews (Drosera). Moreover, Aldrovanda has never been included in molecular phylogenetic studies, so it has been unclear whether snap-traps evolved only once or more than once among angiosperms. Using sequences from nuclear 18S and plastid rbcL, atpB, and matK genes, we show that Aldrovanda is sister to Dionaea, and this pair is sister to Drosera. Our results indicate that snap-traps are derived from flypaper-traps and have a common ancestry among flowering plants, despite the fact that this mechanism is used by both a terrestrial species and an aquatic one. Genetic and fossil evidence for the close relationship between these unique and threatened organisms indicate that carnivory evolved from a common ancestor within this caryophyllid clade at least 65 million years ago. PMID- 21665753 TI - Monophyly of the Convolvulaceae and circumscription of their major lineages based on DNA sequences of multiple chloroplast loci. AB - Convolvulaceae, a large family of worldwide distribution, exhibit a rich diversity of morphological characteristics and ecological habitats. Previous efforts to systematize this diversity without a cladistic phylogenetic framework have disagreed on the circumscription of the family as well as tribal composition and relationship. In order to circumscribe the family and assess the relationships among its major lineages, a broad data set was constructed containing representatives of all ten recognized tribes of Convolvulaceae plus representatives of putatively related families within Asteridae. This is done by using four chloroplast regions: rbcL, atpB, psbE-J operon, and trnL-trnF intron/spacer. The results indicate that Convolvulaceae are monophyletic and sister to Solanaceae. Two of the three groups that have been proposed previously as separate families, Cuscuta and Dichondreae, are nested within the Convolvulaceae in this analysis, and the third, Humbertia, is the sister to all other members of the family. The exact position of Cuscuta could not be ascertained, but some alternatives were rejected with confidence. The study identified several distinct monophyletic groups, some of which correspond to earlier taxonomic treatments. Close relationships of tribes Hildebrandtieae with Cresseae and Ipomoeeae with Argyreieae (forming Echinoconieae) were confirmed. The polyphyly of Merremieae, Convolvuleae, Poraneae, and Erycibeae is first identified in this study. PMID- 21665754 TI - Comparison of Eudorina/Pleodorina ITS sequences of isolates from nature with those from experimental hybrids. AB - Internal transcribed spacer (ITS) regions of nuclear ribosomal repeats were compared among 50 Eudorina and Pleodorina isolates and two Volvox species known to clade with Eudorina species. Of the six major subclades found, four containing Eudorina and Pleodorina illinoisensis isolates, one containing Eudorina and Pleodorina indica, and one containing Volvox gigas and V. powersii, the basal branching order remains uncertain, but the positioning of isolates known to mate was always as nearest neighbors on the terminal branches of the tree. Four hybrid clones from a cross of E. elegans with P. illinoisensis, known from chromosome counts to be products of the failure of meiosis at zygote germination, contain both parental ITS repeat regions, as expected. However, they have in addition both crossover and other variant ITS cistrons among their many repeats of ITS. Such variation is limited to terminal regions of helices, as recognized from knowledge of RNA transcript secondary structure. Proper alignment then utilizes all of the nucleotide positions; the hybrid variants appear in positions intermediate between their parents in the tree. In fact, such variants seem to be hallmarks of recent hybridization events, since they were not found in any of the other 50 isolates. PMID- 21665755 TI - Urticalean rosids: circumscription, rosid ancestry, and phylogenetics based on rbcL, trnL-F, and ndhF sequences. AB - To address the composition of the urticalean rosids, the relationships of the component families (maximally Cannabaceae, Cecropiaceae, Celtidaceae, Moraceae, Ulmaceae, and Urticaceae) and analyze evolution of morphological characters, we analyzed sequence variation for a large sampling of these families and various rosid outgroups using rbcL, trnL-F, and ndhF plastid regions. Urticalean rosids are derived out of a lineage including Barbeyaceae, Dirachmaceae, Elaeagnaceae, and Rhamnaceae, with Rosaceae less closely related; thus, they are imbedded within Rosales. Ulmaceae are the sister to all remaining families. Cannabaceae are derived out of a subclade of Celtidaceae; this expanded family should be called Cannabaceae. Cecropiaceae are derived within Urticaceae and are polyphyletic with Poikilospermum derived elsewhere within Urticaceae; this expanded family should be called Urticaceae. Monophyletic Moraceae are sister to this expanded Urticaceae. Support for these relationships comes from a number of morphological characters (floral sexuality, presence or absence of hypanthium, stamen type and dehiscence, pollen pore number, ovule position, and embryo alignment) and chromosome numbers. Most fruit types, in terms of ecological dispersal, are derived independently multiple times and are strongly correlated with habitat. PMID- 21665756 TI - Evidence of carpinus (betulaceae) in the late tertiary (pliocene) of alabama. AB - Carpinus is a common and widespread element of the modern North American forest vegetation, but its scant fossil record on the continent is perplexing, especially considering the abundant and relatively continuous record of the genus in the Tertiary of Europe and Asia. Despite earlier claims of Tertiary Carpinus remains, recent reviews have indicated that a definitive post-Eocene Tertiary record of the genus in North America is lacking. Therefore, it remains uncertain if Carpinus was present but left no clear fossil record or if the genus became extinct in North America and migrated back to the continent more recently. A reinvestigation of the Citronelle Formation paleoflora has yielded conclusive evidence for the presence of Carpinus in the Gulf Coastal Plain of Alabama during the Pliocene based upon the discovery of a nutlet bract. Carpinus bracts are distinctive and consist of a central bract fused basally with two lateral bractlets. This specimen provides proof of the existence of Carpinus on this continent by the Pliocene Epoch, and any future research on the biogeography of the genus must consider this as the earliest, post-Eocene record of the genus in North America based on unequivocal reproductive structures. PMID- 21665757 TI - The potential for gene flow between cultivated and wild sunflower (Helianthus annuus) in the United States. AB - The transfer of genes from crop plants to their wild relatives via hybridization has emerged as one of the primary risks associated with the commercialization of genetically engineered crops. Although previous studies have revealed relatively high levels of hybridization when crop plants come into contact with their wild relatives, the frequency of such contact across the range of cultivation of any crop taxon is unknown. Here we report the results of a multi-year, range-wide survey of the potential for reproductive contact between cultivated and common sunflower (Helianthus annuus). The results of this work indicate that the opportunity for crop-wild hybridization exists throughout the range of sunflower cultivation. Approximately two-thirds of all cultivated fields occurred in close proximity to, and flowered coincidentally with, common sunflower populations. In these populations, the phenological overlap was extensive, with 52-96% of all wilds flowering coincidentally with the adjacent cultivar field. Moreover, there was morphological evidence of hybridization in 10-33% of the populations surveyed within a given year. These findings indicate that crop-wild hybridization is likely across the range of sunflower cultivation in the USA. PMID- 21665758 TI - Not just another evidence-based practice column! PMID- 21665759 TI - Psychiatric mental health evidence-based practice. AB - This article is the first in a new column focusing on evidence-based practice (EBP) in psychiatric mental health nursing. The EBP movement was strongly influenced by a British epidemiologist, Dr. Cochrane, who advocated care based on randomized clinical controlled trials in the late 1900s. Although the majority of the EBP movement is directed toward developing clinical guidelines, the critical element focuses on the therapeutic relationship and clinical judgment associated with providing care. This column will address a clinical problem, define PICO questions, report knowledge base searches, and present existing evidence. Recommendations will be offered for potential interventions and suggestions for evaluating clinical outcomes. Nurses can no longer view clinical studies as academic exercises discarded on graduation and not applied to the clinical setting. Conscientiously applying what is known about treatments and interventions of ethical, if not legal, value is consistent with the professional definition of care. J Am Psychiatr Nurses Assoc, 2008; 14(2), 107-111. DOI: 10.1177/1078390308315798. PMID- 21665760 TI - Tobacco intervention training in graduate psychiatric nursing education programs. AB - BACKGROUND: Tobacco use is the leading cause of preventable death, with the highest rate of cigarette smoking seen in mentally ill people. OBJECTIVE: This study assessed the content, amount of time, and educational techniques used in tobacco education training for graduate psychiatric nurses. STUDY DESIGN: A national mail survey of all graduate psychiatric nursing education programs. RESULTS: One-third of programs offered detailed (>1 hr) information on stages of change, the 5 A's and 5 R's. The majority of basic science tobacco topics were not covered or were covered briefly, and the 6 sociopolitical topics were not covered by the majority of programs. Training was by the traditional didactic method using scientific literature reviews. CONCLUSIONS: This study provides evidence of the need to improve the education of psychiatric nurses as tobacco interventionists at both the individual level and the legislative and policy formulation level. J Am Psychiatr Nurses Assoc, 2008; 14(2), 117-124. DOI: 10.1177/1078390307311973. PMID- 21665761 TI - Factors associated with perceived burden, resourcefulness, and quality of life in female family members of adults with serious mental illness. AB - BACKGROUND: Each year, 54 million American adults are affected by serious mental illness. Most of these persons depend on female family members for support or assistance, and unless these women are resourceful, they may experience considerable burden, stigma by association, depressive thoughts, and poor quality of life. OBJECTIVE: In this study, we examined the associations between characteristics of female family members (age, race, education), adults with serious mental illness (age, diagnosis), and the family situation (relationship, living arrangements, care provided) and caregivers' burden, stigma, depressive cognitions, resourcefulness, and quality of life. STUDY DESIGN: In this descriptive, cross-sectional study, a convenience sample of 60 female relatives of adults with serious mental illness provided demographic information and completed established measures of the study variables. RESULTS: We discuss associations between contextual variables and process regulators, resourcefulness, and quality of life. CONCLUSIONS: The results highlight the importance of targeting interventions for caregivers of adults with serious mental illness who are parents, caregivers of younger seriously mentally ill persons in earlier stages of diagnosis, and caregivers of persons who have bipolar disorder. J Am Psychiatr Nurses Assoc, 2008; 14(2), 125-135. DOI: 10.1177/1078390308315612. PMID- 21665763 TI - Psychopharmacologic first-line strategies in the treatment of major depression and psychosis: a survey of advanced practice nurses. AB - BACKGROUND: Developments in psychopharmacology have led to a broad range of medication choices for prescribing clinicians. Although there have been advances in drug development, less is known about the prescribing strategies used by psychiatric-mental health advanced practice nurses or the extent to which these practices reflect existing practice guidelines. OBJECTIVES: This study examined the prescribing practices of advanced practice nurses attending a psychopharmacology continuing education program. Participants were surveyed about (a) first-line strategies for the treatment of major depression and first-episode psychosis and (b) choices for managing insomnia and the side effect of weight gain. STUDY DESIGN: Participants completed an onsite questionnaire regarding advanced practice characteristics and management of specific clinical situations. RESULTS: The majority of prescribing advanced practice nurses surveyed were psychiatric-mental health specialists. Approximately two thirds (65.9%) of the advanced practice nurses prescribed psychotropic medications, most often for depression. First-choice agents for depression and first-episode psychosis were selective serotonin reuptake inhibitors (97.3%) and atypical antipsychotics (93.9%), respectively. Interventions for insomnia and medication-related weight gain were more varied. CONCLUSIONS: For the advanced practice nurses surveyed, first-line strategies for depression and first-episode psychosis appear consistent with literature and practice guidelines. Future studies and educational offerings would benefit from addressing dosing and switching strategies and optimizing approaches for managing side effects. J Am Psychiatr Nurses Assoc , 2008; 14(2), 144-151. DOI: 10.1177/1078390308316124. PMID- 21665762 TI - Hildegard Peplau's Theory and the Health Care Encounters of Survivors of Sexual Violence. AB - BACKGROUND: Individuals who experience sexual violence often seek services in a variety of health care settings. Although research indicates that survivors often report that interactions with health care professionals are distressing, little is known about what renders these encounters helpful or hurtful. OBJECTIVE: The purpose of this study was to use Hildegard Peplau's (1952) conceptualization of nurses' helping roles (i.e., stranger, resource person, teacher, leadership, surrogate, counselor, technical expert) in nurse-client interactions to explore how survivors of sexual violence perceive their encounters with health care professionals. STUDY DESIGN: Content analysis was conducted on the transcripts of 60 minimally structured interviews in which participants discussed their experiences of sexual violence. RESULTS: The results revealed that the helping roles of counselor and technical expert, as identified by Peplau, were most important to survivors of sexual violence. Regardless of role, participants perceived health care professionals to be helpful when they exhibited interpersonal sensitivity, especially in regard to the participants' experiences with violence. CONCLUSIONS: The findings indicate that health care professionals need to maintain an attentive and compassionate stance when working with survivors of sexual violence. Those who serve in a counselor role need to create an atmosphere of trust so that clients may explore in depth how violence has affected their lives. J Am Psychiatr Nurses Assoc, 2008; 14(2) , 136-143. DOI: 10.1177/1078390308315613. PMID- 21665764 TI - Evidence-based practice in psychiatric care: defining levels of evidence. AB - Identification and application of the current research evidence to a clinical problem is a goal reflected in professional codes and institutional mission statements. The use of expert opinions and traditions is no longer clinically or legally defensible in an era of using emerging evidence. Application of current research evidence is the emerging standard of care for all health care personnel, including psychiatric mental health care. The emergence of evidence-based practice as the new standard of care obliges all health care providers to use the latest research evidence. The need to make an intervention based on the highest level of evidence mandates that clinicians understand levels of research evidence and how the different classification systems of evidence compare. In this article, the levels of research evidence are reviewed to provide a framework for determining the best evidence to use as a basis for clinical interventions. J Am Psychiatr Nurses Assoc, 2008; 14(3), 181-187. DOI: 10.1177/1078390308321220. PMID- 21665765 TI - Factors contributing to depression in latinas of mexican origin residing in the United States: implications for nurses. AB - BACKGROUND: Latinas experience more depression and are less likely to receive mental health support than White women or African American women. OBJECTIVE: This article synthesizes the research on depression in adult Latinas of Mexican origin residing in the United States. STUDY DESIGN: MEDLINE (PubMed), The Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO databases for the years 2000 through 2008 were searched using the keywords Latina, Latino, Hispanic, Mexican American, Mexican immigrant, women, and depression. RESULTS: The process of acculturation and associated stressors may have a negative effect on the mental health of women of Mexican origin residing in the United States. Separation from family, harmful interpersonal relationships, unmet economic needs, conflict, and isolation may contribute to depression in this population. CONCLUSIONS: More research is needed on the influence of family and economic strain as well as the effectiveness of assessments and interventions for depression in Mexican and Mexican American women, especially for those living in emerging Latina/o immigrant communities. J Am Psychiatr Nurses Assoc, 2008; 14(3), 193-204. DOI: 10.1177/1078390308319034. PMID- 21665766 TI - Amenorrhea as a diagnostic criterion for anorexia nervosa: a review of the evidence and implications for practice. AB - Amenorrhea is currently a criterion in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., Text rev. [DSM-IV-TR]) for the diagnosis of anorexia nervosa (AN). Recently, there has been increased interest in examining the utility of this criterion. This article reviews the historical rationale for inclusion of amenorrhea in the DSM criteria for AN, clinical evidence evaluating amenorrhea as a diagnostic criterion for AN, and the nursing practice implications of amenorrhea as a diagnostic criterion for AN. Data suggest there is limited support for amenorrhea as a diagnostic criterion for AN. J Am Psychiatr Nurses Assoc, 2008; 14(3), 209-215. DOI: 10.1177/1078390308320288. PMID- 21665767 TI - Telenursing intervention increases psychiatric medication adherence in schizophrenia outpatients. AB - BACKGROUND: Promoting medication adherence is a critical issue in optimizing both physical and mental health in persons with schizophrenia. Average antipsychotic medication adherence is only 50%; few studies have examined nonpsychiatric medication adherence. Psychosocial interventions with components of problem solving and motivation have shown promise in improving adherence behaviors. OBJECTIVES: This study examines telephone intervention problem solving (TIPS) for outpatients with schizophrenia. TIPS is a weekly, provider-initiated, proactive telenursing intervention designed to help persons with schizophrenia respond to a variety of problems, including adherence problems. STUDY DESIGN: The authors completed objective measures of adherence to psychiatric and nonpsychiatric medications in 29 community-dwelling persons with schizophrenia, monthly for 3 months. STUDY RESULTS: Persons receiving TIPS had significantly higher objective adherence to psychiatric medications throughout the study period, F(1, 20) = 5.47, p = .0298. CONCLUSIONS: Clinicians should consider using TIPS as an adjunct to face-to-face appointments to support adherence in persons at risk. J Am Psychiatr Nurses Assoc, 2008; 14(3), 217-224. DOI: 10.1177/1078390308318750. PMID- 21665768 TI - HIPAA's Preconsent: Impact on Study Validity. AB - The Health Insurance Portability and Accountability Act (HIPAA) regulations added potential validity threats to clinical studies. The HIPAA regulations, using the principle of patient autonomy were designed to increase patient's control over the all health related information. The Department of Health and Human Services did not identify rules related to research regulations believing HIPAA regulations facilitate investigations through use of de-identified information. Yet, under HIPAA guidelines, health care agencies can not allow access because of the need to obtain a patient's prior permission to release raw data. The problem of how to conduct investigations in the face of the HIPAA "Privacy Rule" raises concerns for effects on subject recruitment and selection. This paper examines the impact of obtaining a HIPAA preconsent on subject recruitment, selection, and subject characteristics, and offers strategies for addressing the validity threats associated with the HIPAA regulations. J Am Psychiatr Nurses Assoc, 2008; 14(3), 225-230. DOI: 10.1177/1078390308319224. PMID- 21665769 TI - In memoriam: ida jean orlando pelletier. PMID- 21665770 TI - The Time to Act Is Now: APNA's Commitment to Smoking Cessation in Persons With Major Mental Illness. PMID- 21665771 TI - Ecological salivary cortisol specimen collection--part 1: methodological consideration of yield, error, and effects of sampling decisions in a perinatal mental health study. AB - BACKGROUND: Current health research strives to integrate biological, psychological, and social factors consistent with ecological models. Home-based biomarker specimens are consistent with an ecological approach, but deviations from laboratory norms could affect validity of results. OBJECTIVE: This article uses salivary cortisol specimens collected early in a perinatal mental health study to describe (a) return rate and returner characteristics, (b) adherence to procedures, (c) sources of laboratory error, (d) effects of deleting specimens with "nuisance" factors, and (e) effects that selection bias could have on cortisol concentration distribution. STUDY DESIGN: This includes methodological analysis of collection, assay, and preanalysis decision components. RESULTS: Rates of return do not differ by participants' sociodemographic, perinatal, or psychiatric characteristics. Excluding smokers affects representativeness. Selection bias in favor of more or less disadvantaged participants affects cortisol distribution. CONCLUSIONS: The large yield of useable specimens permits multivariate modeling of cortisol level in association with health outcomes, potentially enhancing ecological validity. J Am Psychiatr Nurses Assoc, 2008; 14(4), 273-284. DOI: 10.1177/1078390308322944. PMID- 21665773 TI - School-based support groups for adolescents with a substance-abusing parent. AB - BACKGROUND Adolescents with substance-abusing parents need interventions to reduce their risk for a variety of problems. School-based support groups (SBSGs) have been proposed to increase resilience in this population. OBJECTIVE The purpose of this study was to evaluate a SBSG for adolescents with substance abusing parents. STUDY DESIGN The randomized, controlled study was conducted with high-school students (n = 109) to evaluate the impact of SBSGs on resiliency. Resiliency was operationalized as positive physical health, mental health, and risk behaviors in the presence of adverse life events. Data were collected pre- and postintervention. RESULTS Significant improvements in knowledge of substance abuse were noted. Findings suggested gender differences in coping and health outcomes and positive trends in substance use. CONCLUSIONS SBSGs may increase resilience in this at-risk population. However, there were gender differences in response to the intervention, and group facilitators should be aware that participants' gender may influence response to the groups. J Am Psychiatr Nurses Assoc, 2008; 14(4), 297-309. DOI: 10.1177/1078390308321223. PMID- 21665772 TI - Ecological salivary cortisol analysis-- part 2: relative impact of trauma history, posttraumatic stress, comorbidity, chronic stress, and known confounds on hormone levels. AB - BACKGROUND: Although bio-psycho-social health research is an ideal, samples adequate for complex modeling require biomarker specimens from hundreds of participants. Ecological sampling departs from laboratory study norms, with implications for analysis. OBJECTIVE: To inform ecological study designs, this article compares salivary cortisol levels and effect sizes of "focal" psychiatric factors, such as trauma history, posttraumatic stress diagnosis, comorbidity, and chronic stress, and "nuisance" factors, including endocrine disorders and medications and physiological factors such as gestational age and smoking. STUDY DESIGN: This is a descriptive analysis of ecologically collected cortisol specimens, assayed in an ongoing perinatal psychobiological study, addressing methodological considerations. RESULTS: Focal and nuisance factors are often interdependent with similar effect sizes. Careful specimen deletion decisions and model specification are needed to achieve the hoped-for external validity while maintaining internal validity. CONCLUSIONS: Results of multivariate models lend support to the validity and usefulness of an ecological approach to incorporating biomarkers in health research. J Am Psychiatr Nurses Assoc, 2008; 14(4), 285-296. DOI: 10.1177/1078390308321939. PMID- 21665775 TI - Access and creativity in the master of science in nursing. PMID- 21665776 TI - Meta-analysis as a basis for evidence-based practice: the question is, why not? PMID- 21665774 TI - Motivators of HIV Risk-Taking Behavior of Young Gay Latino Men. AB - BACKGROUND: Latinos have been disproportionately affected by HIV, placing young Latino men who have sex with men (MSM) at increased risk within this ethnic community. OBJECTIVES: The study explored the lived experience of growing up as a young Latino MSM and motivators to HIV risk behaviors. DESIGN: Five young Latino MSM ages 18 to 25 years were enrolled in a qualitative, phenomenological study using semistructured interviews followed by a HIV risk-taking behavior survey. RESULTS: A relationship was identified between patterns of belonging and self acceptance of sexual orientation and motivators of HIV sexual risk-taking behavior. La familia, machismo, hiding, and guilt were themes related to belonging and self-acceptance. CONCLUSIONS: The need to belong and be accepted by the family and self-acceptance of sexual orientation are related to the HIV sexual risk-taking behavior of young Latino MSM. J Am Psychiatr Nurses Assoc, 2008; 14(4), 310-316. DOI: 10.1177/1078390308321926. PMID- 21665777 TI - Magnet forces: a structure for a transformation in inpatient psychiatric nursing. AB - Recovery is a cornerstone of the federal government's transformation vision for mental health care. Recovery is most often depicted as a process by which people with serious mental illness reengage with activities that create a meaningful existence and a purpose in life. Psychiatric nurses are expected to partner with patients in the recovery process during inpatient treatment. This may prove difficult given the current emphasis on medical models of care and the state of the science in inpatient psychiatric nursing. In this article, the authors describe how magnet forces that focus on empowering nurses, empowering evidence based care, and strengthening unit-based leadership have the potential for generating transformational change at the point of service. Engaging in the recovery movement within the magnet structure may generate innovations critical to the growth of the specialty. J Am Psychiatr Nurses Assoc, 2008; 14(5), 346 352. PMID- 21665778 TI - Exploring the experience of hallucinations from a perspective of self: surviving and persevering. AB - BACKGROUND: Despite improved treatment, little is understood about how clients view their hallucinations from a perspective of self, and few studies address the meaning of hallucinations or the relationship of hallucinations to the individual sense of being. OBJECTIVE: To understand hallucinations from an individual perspective of self. STUDY DESIGN: Heideggerian and hermeneutics-guided thematic analysis. Twelve individuals described their experiences of hallucinations. All interviews were recorded (with consent) and transcribed verbatim. RESULTS: Four themes described surviving and persevering: (a) Are they who they are? (b) a not so-certain life; (c) finding strength in the broken places; and (d) I am still me. Although experiencing hallucinations was analogous to living with loss, participants recalled hallucinations as providing something positive in how they cared for and related to others. CONCLUSIONS: Practitioners can incorporate a language of caring that meets the needs of their clients, rather than the language of empowerment, which proved overwhelming for participants already overwhelmed by the "business of getting better." J Am Psychiatr Nurses Assoc, 2008; 14(5), 353-362. PMID- 21665779 TI - From traditional inpatient to trauma-informed treatment: transferring control from staff to patient. AB - Mental health professionals worldwide realize the imperative for reducing inpatient restraints and seclusion. The high incidence of posttraumatic stress disorder for inpatients and the resulting symptoms support the creation of a trauma-informed approach. The objective of the current article is to describe the experience of staff in a 20-bed unit transitioning from traditional inpatient care to a trauma-informed approach. The study comprised a qualitative design using content analysis (n = 10). The patterns clustered into the following categories: changing perspective, developing collaborative relationships, implementing safety measures, and prescribing educational resources. Staff underwent a deep cultural change that subsequently won state recognition for the reduction of seclusion and restraints. PMID- 21665780 TI - Lessons Learned in Clinical Research: Using the MMSE With Older Mexican American Nursing Home Residents. AB - This authors examined the utility of the Mini-Mental State Examination (MMSE) in a pilot study to measure cognitive function in older Mexican American nursing home residents. Many of the lessons learned are transferable to the community: Cognitive screening instruments must be carefully examined for validity and utility, they may need to be administered in Spanish, certain items may need alteration in the questions or expected responses, phrases to be repeated must be culturally appropriate, cutoff scores may need adjustment, "serial sevens" must be used, and education and socioeconomic status must be considered in interpretation of results. Consequently, the MMSE may not be an appropriate measure to use to assess cognitive functioning in older Hispanic populations whose educational levels or literacy is low or unknown. Instead, clinicians should seek other ways to assess mental status, such as other instruments normed for those populations or measures that do not require literacy. J Am Psychiatr Nurses Assoc, 2008; 14(5), 373-378. PMID- 21665781 TI - Letter to the editor of the evidence-based practice column: evidence-based practice in psychiatric care--facing the future now! PMID- 21665782 TI - Evidence-based practice in psychiatric and mental health nursing: qualitative meta-synthesis. PMID- 21665783 TI - The intersection of violence, crime, and mental health. PMID- 21665784 TI - Multiple perspectives on assault: the 360-degree interview. AB - Workplace violence is common in health care settings. The authors review various models of this violence that have developed over time. From a linear model, understanding progressed to an interactional and then to a contextual model of assault that examines interactions of the aggressor, victim, and the environment. To date, there has not been a satisfactory research methodology to explore the complexities of the contextual model. This article proposes the 360-degree evaluation as an appropriate methodology for examination of multiple perspectives on assault. The 360-degree model allows comparison of perspectives of the assailant, victim, victim's peers, and victim's supervisor. J Am Psychiatr Nurses Assoc, 2009; 14(6), 413-420. PMID- 21665785 TI - Struggling to Reconnect: Women's Perspectives on Alcohol Dependence, Violence, and Sexual Function. AB - Until recently, substance use disorders and sexual function were two areas in which women received comparatively less attention then men. Recent studies have challenged sexual stereotypes about women who drink and use other substances. This study explores the experiences of women dependent on alcohol and/or other substances who have stopped their use. These women were subjected to significant abuse during both childhood and adulthood. A pattern of using alcohol and other substances as a means of managing negative feelings, disconnecting from abuse, reconnecting to form new relationships, and disconnecting from subsequent abuse was prominent in the women's stories. The women in this study also experienced problems with sexual function both while using and following cessation of use. Findings highlight the complex relationships among substance abuse, trauma, and sexual problems as well as the importance of routinely assessing for sexual problems. Suggestions for treatment and future research are offered. J Am Psychiatr Nurses Assoc, 2009; 14(6), 421-428. PMID- 21665786 TI - Leadership, education, achievement, and development: a nursing intervention for prevention of youthful offending behavior. AB - PURPOSE: This 3-year study examines a theoretically designed community-based program aimed to reduce the risk of first-time involvement by minority youth with the juvenile justice system. METHODS: A quasi-experimental design with a nonrandomized sample of 146 African American youth test an expressive art curriculum with an after school control group. Outcome measures include protective factors, behavioral self-control, self-esteem, and resilience. FINDINGS: Ninety males and 56 females participated over the 3 years. All four of the outcomes were statistically significant or the LEAD group over the control group. Youth evaluate the LEAD program higher. CONCLUSION: LEAD can be viewed as a promising prevention program. Plans for replication, with larger samples and a longitudinal design are needed to examine the effects of the development of African American youth along with other variables that relate to later acquisition of offending behaviors. J Am Psychiatr Nurses Assoc, 2009; 14(6), 429 441. PMID- 21665787 TI - Pornography use as a risk marker for an aggressive pattern of behavior among sexually reactive children and adolescents. AB - Sexually reactive children and adolescents (SRCAs), sometimes referred to as juvenile sexual offenders, may be more vulnerable and likely to experience damaging effects from pornography use because they are a high-risk group for a variety of aggressive behaviors. The purpose of this study is to describe the characteristics of those who use pornography and those who do not and to examine the associations between pornography use and aggressive behaviors among SRCAs. This secondary analysis used a descriptive, exploratory design to study 160 SRCAs. Chi-square and individual odds ratio analyses were employed to examine the associations between use of pornography and aggressive behaviors. SRCAs who used pornography were more likely to display aggressive behaviors than their nonusing cohort. Recommendations for nurses and mental health professionals encountering these children and adolescents are offered. J Am Psychiatr Nurses Assoc, 2009; 14(6), 442-453. PMID- 21665788 TI - Male-on-Male Rape of an Adult Man: A Case Review and Implications for Interventions. AB - Male-on-male rape is a critical and timely topic for mental health nurses as they continue to improve their value to society. Only recently have scholars begun to address adult male sexual assault and rape survivorship. A reality for some of the men mental health nurses encounter in practice, male sexual assault and rape causes despair and suffering for which mental health nurses can help facilitate health and healing. As illustrated in a case review of male-on-male rape and selected literature, quality humanistic interpersonal relationships are deemed important for the survivor's health. J Am Psychiatr Nurses Assoc, 2009; 14(6), 454-461. PMID- 21665789 TI - Human trafficking: implications for the role of the advanced practice forensic nurse. AB - Human trafficking is internationally recognized as a widespread violation of human rights. This article defines and gives a detailed historical account of the political and social issues surrounding human trafficking. The article explains the role of the advanced practice forensic nurse in recognizing and addressing the needs of victims of human trafficking. The developing roles of the advanced practice psychiatric forensic nurse in collaboration with law enforcement and health care professionals are described with the ultimate goal of restoring the lives of victims of human trafficking. J Am Psychiatr Nurses Assoc, 2009; 14(6), 462-470. PMID- 21665790 TI - A call to action: smoking cessation curriculum. PMID- 21665791 TI - Psychiatric nurses as champions for smoking cessation. PMID- 21665792 TI - Tobacco quitlines and persons with mental illnesses: perspective, practice, and direction. AB - The prevalence of tobacco use among persons with mental illnesses is 2 to 3 times that of the general population, and these individuals suffer significant related health disparities. Many people with mental illnesses contact tobacco quitlines for cessation assistance. With free telephone counseling and in some cases nicotine replacement therapy, quitlines offer a potentially effective resource for this population. However, quitlines are still trying to determine how best to meet these callers' unique needs. The authors discuss emerging practices regarding quitline services for persons with mental illnesses, as well as expert opinion for enhancing work with these individuals. PMID- 21665793 TI - Windows of opportunity for culture change around tobacco use in mental health settings. AB - BACKGROUND: Smoking rates among individuals with mental illnesses are significantly higher than in the general population and contribute to increased rates of morbidity and mortality. OBJECTIVE: The purpose of this study was to generate a theory of the process by which to lower the prevalence of smoking in this population. STUDY DESIGN: Grounded theory methods, including constant comparison and theoretical sampling, were used to uncover the emerging process of addressing tobacco use in mental health settings from the perspective of national leaders. RESULTS: Participants suggested that the culture in mental health settings around tobacco use significantly contributes to the high rates of smoking and described barriers to and opportunities for culture change. CONCLUSIONS: The findings highlight several windows of opportunity that have begun to be explored. Leaders described current signs of change within mental health settings and expressed optimism about the possibility to lower future rates of smoking among mental health consumers and staff members. PMID- 21665794 TI - Training psychiatrists and advanced practice nurses to treat tobacco dependence. AB - The lack of availability of continuing medical education programs on tobacco dependence for psychiatrists and psychiatric nurses is profound. We developed a 2 day curriculum delivered in November 2006 and March 2007 to 71 participants. Ninety-three percent ( n = 66) completed a pretest/posttest, and 91% (n = 65) completed the attitudes and beliefs survey. Scores on the pretest were low (M = 47% correct). Paired t tests found significant increases in raw scores from 6.7 to 13.6, t(65) = -22.8, p < .0001. More than 90% of psychiatrists and nurses indicated that motivating and helping patients to stop smoking and discussing smoking behavior were part of their professional role. Although 80% reported that they usually ask about smoking status, fewer reported recommending nicotine replacement (34%), prescribing pharmacotherapy (29%), or referring smokers to a telephone quit line (26%). Trainings are repeated twice a year because of ongoing demand. Further follow-up should evaluate changes in practices after training. PMID- 21665795 TI - Smoking among psychiatric nurses: does it hinder tobacco dependence treatment? AB - BACKGROUND: Data on tobacco dependence treatment for patients with mental illness are limited. OBJECTIVE: Describe factors associated with psychiatric nurses' tobacco interventions. STUDY DESIGN: Survey of 100 psychiatric nurses. RESULTS: The majority "always/usually" asked (87%), advised (70%), and assessed (74%) tobacco use. A minority (49%) assisted with quit attempts, and arranged (21%) for follow-up. Former (56%, odds ratio [OR] = 0.13, 95% confidence interval [CI] = 0.02, 0.88) and current smokers (20%, OR = .08, 95% CI = 0.01, 0.72) were less likely to ask about tobacco use than never smokers. CONCLUSIONS: Efforts are needed to promote tobacco cessation and to support nurses who smoke to quit. PMID- 21665796 TI - Moving forward in smoking cessation: issues for psychiatric nurses. PMID- 21665798 TI - National survey of psychiatric mental health advanced practice nursing: development, process, and finding. AB - A survey was sent to all Psychiatric Mental Health (PMH) Advanced Practice Registered Nurses (APRNs) who had a registered e-mail address with the American Nurses Credentialing Center, resulting in 1,899 usable surveys. The practice of two groups of APRNs was examined and contrasted: those certified to treat children and adolescents and PMH-APRNs certified only to treat adults. Our findings raise concerns about the numbers of PMH-APRNs treating children. Considering the national demand for mental health professionals prepared to treat children, the specialty must move to increase the number of qualified APRN child providers. PMID- 21665799 TI - A comparison of the practices of psychiatric clinical nurse specialists and nurse practitioners who are certified to provide mental health care for children and adolescents. AB - BACKGROUND: A task force of the American Psychiatric Nurses Association and the International Society of Psychiatric Mental Health Nurses initiated a survey to identify how advanced practice psychiatric nurses were addressing the mental health needs of children and adolescents. OBJECTIVES: Practice patterns of Child and Adolescent Psychiatric-Mental Health Nurses (CACNSs) and Family Psychiatric Nurse Practitioners (FPNPs) were compared. DESIGN: An electronic survey was completed by 234 CACNSs and 170 FPNPs from a national database. Group data were compared using descriptive and inferential statistics. RESULTS: Both groups spent the greatest percentage of their time in medication management, with depression being the most frequent problem they treated. However, CACNSs treated more school aged children and provided more psychotherapy. FPNPs frequently merged prescribing and therapy when seeing patients. CONCLUSIONS: Findings indicate more commonalities than differences in the practices of the two certification groups but suggest the need for standards that will inform educational programs and certification examinations. PMID- 21665800 TI - The clinical nurse leader: helping psychiatric mental health nurses transform their practice. AB - The national movement to transform the health care delivery systems must include a focus on mental health treatment. To address similar deficits across other practice domains, the Clinical Nurse Leader (CNL) role has been created. The CNL is a master's degree that prepares a nurse to use a systems perspective to improve outcomes for a cohort of patient, deliver care based on best practices, and coordinate care in a multidisciplinary team. Applying the CNL role to mental health care could help psychiatric mental health nursing be at the forefront in the transformation of mental health care delivery. PMID- 21665801 TI - Applying Benner's Model to Psychiatric Mental Health Nurse Practitioner Self Ratings of Role Competence. AB - BACKGROUND: Cross-sectional survey research elicited self-perceptions of role competence from practicing psychiatric mental health nurse practitioners (PMHNPs) and new PMHNP graduates. OBJECTIVES: Examine relationships between PMHNP perceptions of competence, prior basic-level nursing experience, and years of PMHNP practice. STUDY DESIGN: Self-ratings of competence were elicited by a questionnaire designed from Benner's model. The relationship between prior nursing experience and perceptions of competence was examined by chi-square analysis. Changes in PMHNP competence rankings over years of practice were examined with Kruskal-Wallis and Mann-Whitney procedures. RESULTS: Self perceptions of competence increased in seven role dimensions as PMHNPs progressed through years of practice (p < .000). Gains in perceptions of competence occurred between career entry and 3 to 5 years of practice in all but one role dimension. Prior nursing experience did not significantly increase perceptions of competence among PMHNP graduates. CONCLUSIONS: Self-perceptions of competence progressively and significantly increased over years of PMHNP practice among participants in this study. PMID- 21665802 TI - Effect size in psychiatric evidence-based practice care. AB - Developing evidence-based practice skills requires a familiarity with the language and terminology of clinical research. Few articles discuss concepts, such as effect size, that must be understood to determine if the findings of studies are clinically meaningful. Clinically meaningful results of studies are determined by the effect size of an intervention. The effect size of an intervention, such as cognitive-behavioral therapy, can be calculated from the findings of different studies using different designs and populations. However, the determination and use of an effect size is important to clinicians using research findings to guide practice. PMID- 21665803 TI - Evidence-based psychiatric and mental health nursing: responsibilities and their distribution. PMID- 21665804 TI - Report from a national tobacco dependence survey of psychiatric nurses. AB - BACKGROUND: Persons with mental illness smoke proportionately more cigarettes and die earlier than the general population. Yet compared with other clinicians, psychiatric professionals have intervened slowly with smoking patients. To assess psychiatric nurses' perspectives concerning tobacco dependence interventions, the American Psychiatric Nurses Association (APNA) Tobacco Dependence Task Force surveyed email-accessible APNA members (N = 1,365). OBJECTIVES: This paper reports survey results and implications for psychiatric nursing. STUDY DESIGN: Cross-sectional analysis of a 29-item online survey conducted in early 2008. RESULTS: Most nurses asked if patients smoked but fewer advised against smoking, referred to cessation resources, or delivered intensive interventions. Nurses referred to resources if they felt motivated, knowledgeable, and/or confident in their skills and rated highly their patients' ability and/or motivation to quit smoking. Workplace characteristics were related to nurses' behaviors. Nursing curricula lack tobacco dependence content. CONCLUSIONS: Findings will guide efforts to support nurses in reducing/eliminating smoking by their patients through practice, education, research, and policy initiatives. PMID- 21665805 TI - Estimating person--environment transactions on intention to change drug-using behaviors. AB - The community attachment model of addiction is an ecologically based social process model that suggests social context referents (peers, family, neighbors, etc.) will influence attachment to addiction or recovery communities, via cognitive, affective, and behavioral commitments. This study examined the influence of social context referents on intention to change drug using behavior, and examined moderating effects of three contextual indicators (labor market attachment, educational attainment, and family poverty status) on these relationships. The study sample consisted of 302 adults in inpatient and outpatient substance abuse treatment facilities, who completed a set of instruments that included the Ecological Assessment of Substance Abuse Experiences (EASE), a new instrument designed to measure the influence of social context referents on addiction and recovery attachment processes. Results showed that all three contextual indicators moderated relationships among social context referenced attitudes, drug use concern, and intention to change drug using behaviors. Findings suggest that practitioners should attend to both microlevel orientations to social context and macrolevel contextual dimensions (e.g., labor force attachment), as both may influence behavioral change opportunities. PMID- 21665806 TI - Mental health patients' experiences of being misunderstood. AB - BACKGROUND: Mental health patients describe "being understood" as an experience that evokes feelings of importance, worthiness, and empowerment. However, the experience of "being misunderstood" is more prevalent in patients' relationships with health care providers. Negative consequences such as vulnerability, dehumanization, and frustration reveal that being misunderstood has the potential to damage or destroy therapeutic relationships. OBJECTIVE: The purpose of this secondary analysis was to examine mental health patients' experiences of being misunderstood. STUDY DESIGN: Data consisted of transcripts from 20 interviews with community-dwelling adults with mental illness, which were analyzed using an existential phenomenological approach. RESULTS: Four figural themes expressed the experiences of being misunderstood: protection from vulnerability, an object to be fixed, treated like a child, and relentless frustration. CONCLUSIONS: Nurses and other caregivers can use the findings of this study to promote understanding, strengthen therapeutic relationships, and improve the quality of mental health care. PMID- 21665807 TI - The Importance of Qualitative Research to EBP. PMID- 21665808 TI - Evidence-based practice: critical appraisal of qualitative evidence. AB - One of the key steps of evidence-based practice is to critically appraise evidence to best answer a clinical question. Mental health clinicians need to understand the importance of qualitative evidence to their practice, including levels of qualitative evidence, qualitative inquiry methods, and criteria used to appraise qualitative evidence to determine how implementing the best qualitative evidence into their practice will influence mental health outcomes. The goal of qualitative research is to develop a complete understanding of reality as it is perceived by the individual and to uncover the truths that exist. These important aspects of mental health require clinicians to engage this evidence. PMID- 21665809 TI - Boundaries: the nurse scientist and care provider. PMID- 21665810 TI - Evaluating Differential Item Functioning of the CES-D Scale According to Caregiver Status and Cultural Context in Korean Women. AB - BACKGROUND: Proper evaluation of the generalizability of an instrument is critical for its use across different social contexts such as caregiver status. OBJECTIVE: To examine the differential item functioning of the Center for Epidemiologic Studies Depression (CES-D) Scale, patterns of response to each item of the CES-D Scale attributable to caregiver status was assessed. STUDY DESIGN: Using a cross-study comparison method, a sample of 58 matched pairs of Korean American caregivers and noncaregivers was used for matched moderated regression analysis on the CES-D Scale. RESULTS: The authors identified three items that vary according to caregiver status in the present study: Item 2 (My appetite was poor), Item 4 (I felt that I was as good as other people), and Item 14 (I felt lonely). CONCLUSIONS: Beyond assessing the level of depression through total CES D scores, it is important to examine variations in the items of the CES-D Scale across different social contexts. J Am Psychiatr Nurses Assoc, 2009; 15(4), 240 248. DOI: 10.1177/1078390309343713. PMID- 21665811 TI - Meeting the "Now" Need: PMH-APRN-- Interpreter Teams Provide In-Home Mental Health Intervention for Depressed Latina Mothers With Limited English Proficiency. AB - Latina mothers of infants and toddlers are at high risk for developing serious depressive symptoms if they are newly immigrated and have limited English proficiency (LEP). Depressive symptoms compromise these mothers and result in severe consequences for their U.S.-born children. A randomized clinical trial of a short-term, in-home psychotherapy intervention for symptomatic mothers in an area of the United States where bilingual mental health providers were scarce used teams of English-speaking advanced practice psychiatric mental health nurses and bilingual community interpreters who were trained in a conduit, consecutive model of interpretation. The article describes the development of a theoretically congruent interpreter model, the training program that supported it, the challenges that surfaced and lessons learned during successful implementation in the field. Future refinements in progress and uses of the model are discussed. PMID- 21665812 TI - Executive-level reviews of seclusion and restraint promote interdisciplinary collaboration and innovation. AB - Elimination of seclusion and restraint requires support at all levels of an organization, especially from leaders who visibly champion and communicate their vision. Nurses, physicians, educators, and administrators at New Hampshire Hospital, an acute psychiatric inpatient facility, have established a standard meeting time and place for an executive-level review of every episode of seclusion and restraint. The standing meeting demonstrates the organization's commitment to caring for both patients and staff. The daily meetings foster a spirit of interdisciplinary collaboration, where direct care staff have the opportunity to tell their stories and share their ideas and concerns in an environment that is caring, supportive, and devoid of criticism or blame. Narrative descriptions of emergency interventions, including what was learned from debriefings with patients and staff involved, provide data about factors that may contribute to the use of seclusion or restraint. This forum provides visible administrative and clinical support that promotes creative thinking, collaborative problem solving, and the exploration of new ideas recommended by those directly involved in providing patient care. It has fostered exploration and development of strategies that have minimized episodes of aggressive behavior as well as seclusion and restraint. PMID- 21665813 TI - An interview with dr. Carole shea: on becoming an academic nursing leader. PMID- 21665814 TI - Vertebrate sickness behaviors: Adaptive and integrated neuroendocrine immune responses. AB - Vertebrate sickness behaviors, which include lethargy, anorexia, and decreased libido, can facilitate defense against pathogens by conserving energy for use in other immune responses and by limiting parasites' access to nutrients. Such benefits come with considerable costs, however, as lethargy decreases the time available for other fitness-enhancing activities and dampened libido directly reduces reproductive prospects. While the degree of sickness behaviors expressed varies among individuals, populations, and species, the ecological and physiological factors driving this diversity remain unclear. Here, we consider how an organism's ecological context and life-history strategy may impact the ways in which it balances the costs and benefits of sickness behaviors to enable or suppress its expression. Striking an appropriate balance requires physiological assimilation of information about external ecological conditions as well as about the status of infection and host nutrition. This integration requires multi-directional communication among the endocrine, nervous, and immune systems, the purview of the field of psychoneuroimmunology. This discipline portrays cytokines, signaling molecules originally characterized solely by their roles within the immune system, as key mediators of a brain-immune network that ensures the adaptive expression of sickness behaviors. Study of these molecules and the behaviors they coordinate in an ecological context will greatly augment our understanding of the natural variation in immune function found among wild animals. PMID- 21665815 TI - A hassle a day may keep the pathogens away: The fight-or-flight stress response and the augmentation of immune function. AB - Stress is known to suppress or dysregulate immune function and increase susceptibility to disease. Paradoxically, the short-term fight-or-flight stress response is one of nature's fundamental defense mechanisms that galvanizes the neuroendocrine, cardiovascular, and musculoskeletal systems into action to enable survival. Therefore, it is unlikely that short-term stress would suppress immune function at a time when it may be critically required for survival (e.g., in response to wounding and infection by a predator or aggressor). In fact, studies have shown that stress can enhance immune function under certain conditions. Several factors influence the direction (enhancing versus suppressive) of the effects of stress on immune function: (1) DURATION: acute or short-term stress experienced at the time of activation of an immune response enhances innate and adaptive immune responses. Chronic or long-term stress can suppress or dysregulate immune function. (2) Leukocyte distribution: compartments (e.g., skin), that are enriched with immune cells during acute stress show immuno enhancement, while those that are depleted of leukocytes (e.g., blood), show immuno-suppression. (3) The differential effects of physiologic versus pharmacologic stress hormones: Endogenous hormones in physiological concentrations can have immuno-enhancing effects. Endogenous hormones at pharmacologic concentrations, and synthetic hormones, are immuno-suppressive. (4) Timing: immuno-enhancement is observed when acute stress is experienced during the early stages of an immune response while immuno-suppression may be observed at late stages. The type of immune response (protective, regulatory/inhibitory, or pathological) that is affected determines whether the effects of stress are ultimately beneficial or harmful for the organism. Arguments based on conservation of energy have been invoked to explain potential adaptive benefits of stress-induced immuno-suppression, but generally do not hold true because most mechanisms for immuno-suppression expend, rather than conserve, energy. We propose that it is important to study, and if possible, to clinically harness, the immuno-enhancing effects of the acute stress response that evolution has finely sculpted as a survival mechanism, just as we study its maladaptive ramifications (chronic stress) that evolution has yet to resolve. PMID- 21665816 TI - Postnatal programming of the innate immune response. AB - A host's defensive response to a pathogen is a phylogenetically ancient reaction that consists of a CNS-mediated series of autonomic, hormonal and behavioral responses that combine to combat infection. The absence of such defense results in greater morbidity and mortality and thus, these responses are essential for survival. The postnatal period represents a malleable phase in which the long term behavior and physiology of the developing organism, including its immune responses, can be influenced. Postnatal challenge of the immune system by introduction of live replicating infections, or administration of bacterial and viral mimetics, can result in a multidomain alteration to the defenses of the adult host. Findings from our laboratory and others' indicate that the postnatal administration of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (PolyI:C), which mimic bacterial and viral infections respectively, can influence the neuroimmune response (generation of fever and production of cytokines) to a second challenge to the immune system in adulthood. This long-lasting alteration in the innate immune response is associated with myriad other effects on the animal's physiology and appears to be primarily mediated by a sensitized hypothalamic-pituitary-adrenal axis. Thus, a transient immunological perturbation to a developing animal may program the organism for subsequent health complications as an adult. In this review we discuss some of the potential mechanisms for these phenomena. PMID- 21665817 TI - Ecological immunology: The organism in context. AB - A major challenge in integrative biology is understanding the mechanisms by which organisms regulate trade-offs among various functions competing for limiting resources. Key among these competing processes is the maintenance of health and the production of offspring. Optimizing both, given limited resources, can prove challenging. The physiological and behavioral changes that occur during reproduction have been shown to greatly influence an organism's immune system, which can have consequences for susceptibility to disease. Likewise, investing in costly immunological defenses can impair reproductive function. However, the precise nature of these physiological and behavioral interactions appears to be greatly dependent upon the environmental context in which they occur. Here we take a comparative look at interactions between the reproductive and immune systems, including current immunological approaches, and discuss how similar studies can reveal vastly disparate results. Specifically, we highlight results from the ornate tree lizard (Urosuarus ornatus) and the Siberian hamster (Phodopus sungorus) model systems, which provide an example of current research in the field. Collectively, these results emphasize the importance of resource availability and an individual's energy stores for the existence of life-history trade-offs and the efficiency of physiological processes in general. Akin to Dobzhansky's famous line, like other aspects of biology, nothing in ecoimmunology seems to make sense except in the context of an organism's environment. PMID- 21665819 TI - PharmEcology: A pharmacological approach to understanding plant-herbivore interactions: an introduction to the symposium. AB - A central goal in understanding the ecology and evolution of animals is to identify factors that constrain or expand breadth of diet. Selection of diet in many animals is often constrained by chemical deterrents (i.e., secondary metabolites) in available food items. The integration of chemistry and ecology has led to a significant understanding of the chemical complexity of prey (e.g., animals, plants, and algae) and the resultant foraging behavior of consumers. However, most of the literature on chemical defenses of marine and terrestrial prey lacks a mechanistic understanding of how consumers tolerate, or avoid, chemically-defended foods. In order to understand ecological patterns of foraging and co-evolutionary relationships between prey and consumers, we must advance our understanding of the physiological mechanisms responsible for chemical interactions. Such mechanistic studies require the integration of the discipline of pharmacology with ecology, which we call "PharmEcology." Pharmacology provides the tools and insight to investigate the fate (what the body does to a chemical) and action (what a chemical does to the body) of chemicals in living organisms, whereas ecology provides the insight into the interactions between organisms (e.g., herbivores) and their environment (e.g., plants). Although, the general concepts of pharmacology were introduced to ecologists studying plant-herbivore interactions over 30 years ago, the empirical use of pharmacology to understand mechanisms of chemical interactions has remained limited. Moreover, many of the recent biochemical, molecular and technical advances in pharmacology have yet to be utilized by ecologists. The PharmEcology symposium held at a meeting of the Society for Integrative and Comparative Biology in January of 2009 was developed to define novel research directions at the interface of pharmacology and ecology. PMID- 21665820 TI - Revisiting the dietary niche: When is a mammalian herbivore a specialist? AB - Understanding dietary specialization in herbivores has theoretical and practical implications in ecology, yet defining niche breadth consistently has been problematic. To increase clarity and communication among ecologists and among disciplines (i.e., chemists, pharmacologists), we propose a specialization key for mammalian herbivores that assigns "obligatory" and "facultative" modifiers to the terms "specialist" and "generalist". These modifiers are assigned based on (1) relative breadth of the animal's realized niche and diet (what it eats), (2) relative breadth of the fundamental niche and available diet (what it could eat), (3) the extent of chemical or physical characteristics, termed "difficulty", that make food items either low in value or unpalatable to most herbivores, and (4) relevant temporal and spatial scales at which diets and niche breadth were measured. Obligatory specialists always have a narrow realized niche consisting of difficult food items, and morphological adaptations and/or the loss of redundant behavioral flexibility that effectively limit their fundamental niches, precluding them from expanding their diet under changed environmental conditions. Facultative specialists have a consistently narrow realized niche for difficult foods during at least one spatial or temporal scale, but have a broad enough fundamental niche to allow them to expand their diet to include less difficult foods when environmental conditions allow. Facultative generalists have the broadest fundamental niche, allowing them to consume a wide variety of foods. However, they may occasionally demonstrate a narrow realized niche, focused on less difficult plants than is the case with specialists. Finally, the obligatory generalists always have a wide realized niche because of a relatively narrow fundamental niche, precluding them from eating much of any difficult plant. We summarize hypothesized characteristics of mammalian herbivores in each of the four categories of specialization. We demonstrate the need for further work on defining the realized and fundamental niches, comparing among herbivores across categories conducted under similar conditions, and understanding the nature of trade-offs required for specialization and generalization for both community and phylogenetically based analyses. PMID- 21665818 TI - Immune and behavioral consequences of microglial reactivity in the aged brain. AB - Bidirectional communication between the immune system and the brain is essential for mounting the appropriate immunological, physiological, and behavioral responses to immune activation. Aging, however, may impair this important bi directional interaction. In support of this notion, peripheral infection in the elderly is associated with an increased frequency of behavioral and cognitive complications. Recent findings in animal models of aging and neurodegenerative disease indicate that microglia, innate immune cells of the brain, become primed or reactive. Understanding age- and disease-associated alterations in microglia is important because glia (microglia and astrocytes) play an integral role in propagating inflammatory signals that are initiated in the periphery. In this capacity, brain glia produce inflammatory cytokines that target neuronal substrates and elicit a sickness-behavior syndrome that is normally beneficial to the host organism. Increased reactivity of microglia sets the stage for an exaggerated neuroinflammatory cytokine response following activation of the peripheral innate immune system, which may underlie subsequent long-lasting behavioral and cognitive deficits. In support of this premise, recent findings indicate that stimulation of the peripheral immune system in aged rodents causes exaggerated neuroinflammation that is paralleled by cognitive impairment, prolonged sickness, and depressive-like complications. Therefore, the purpose of this review is to discuss the new evidence that age-associated priming of microglia could play a pathophysiological role in exaggerated behavioral and cognitive sequelae to peripheral infection. PMID- 21665821 TI - The emerging role of pharmacology in understanding consumer-prey interactions in marine and freshwater systems. AB - Within our lakes, streams, estuaries, and oceans, there is an astounding chemodiversity of secondary metabolites produced by microbes, algae, and invertebrates. Nearly 30 years of study have yielded hundreds of examples in which secondary metabolites alter the foraging behavior or fitness of aquatic consumers, or both. However, our understanding of the mechanisms that mediate the fate and consequences of these metabolites in aquatic consumers remains in its infancy. Interactions between metabolites and consumers at the molecular and biochemical level are the purview of modern pharmacology, which is rooted in the long history of human-drug interactions and can be adopted for ecological studies. Here, we argue that a pharmacological approach to consumer-prey interactions will be as productive within aquatic systems as it has been for understanding terrestrial systems. We review the diversity of secondary metabolites in aquatic organisms, their known effects on the feeding behaviors and performance of aquatic consumers, and the few studies that have attempted to describe their biochemical manipulation within consumer tissues, i.e., their absorption, distribution, metabolism (including detoxification), and excretion. We then highlight vexing issues in the ecology and evolution of aquatic consumer prey interactions that would benefit from a pharmacological approach, including specialist-versus-generalist feeding strategies, dietary mixing, nutrient-toxin interactions, and taste. Finally, we argue that a pharmacological approach could help to predict how consumer-prey interactions are altered by global changes in pH, water temperature and ultraviolet radiation, or by pollution. Arguably, the state of knowledge of aquatic consumer-prey interactions is equivalent to that faced by ecologists studying terrestrial herbivores in the 1970s; the literature documents profound variation among consumers in their feeding tolerances for secondary metabolites without a thorough understanding of the mechanisms that underlie that variation. The subsequent advancement in our understanding of terrestrial herbivores in the intervening decades provides confidence that applying a pharmacological approach to aquatic consumers will prove equally productive. PMID- 21665822 TI - Exploitation of secondary metabolites by animals: A response to homeostatic challenges. AB - We propose that the exploitation of the bioactive properties of secondary metabolites (SMs) by animals can provide a "treatment" against various challenges that perturb homeostasis in animals. The unified theoretical framework for the exploitation of SMs by animals is based on a synthesis of research from a wide range of fields and although it is focused on providing generalized predictions for herbivores that exploit SMs of plants, predictions can be applied to understand the exploitation of SMs by many animals. In this review, we argue that the probability of SM exploitation is determined by the relative difference between the cost of a homeostatic challenge and the toxicity of the SM and we provide various predictions that can be made when considering behavior under a homeostatic perspective. The notion that animals experience and respond to costly challenges by exploiting therapeutic SMs provides a relatively novel perspective to explain foraging behavior in herbivores, specifically, and behavior of animals in general. We provide evidence that animals can exploit the biological activity of SMs to mitigate the costs of infection by parasites, enhance reproduction, moderate thermoregulation, avoid predation, and increase alertness. We stress that a better understanding of animal behavior requires that ecologists look beyond their biases that SMs elicit punishment and consider a broader view of avoidance or selection of SMs relative to the homeostatic state. Finally, we explain how understanding exploitation of SMs by animals could be applied to advance practices of animal management and lead to discovery of new drugs. PMID- 21665823 TI - Nutritional PharmEcology: Doses, nutrients, toxins, and medicines. AB - The synthesis of pharmacological techniques and concepts into ecology holds considerable promise for gaining new insights into old questions, uncovering new priorities for research and, ultimately, for consolidating a new sub-discipline within the ecological sciences-PharmEcology. We argue that this potential will best be realized if the boundaries of PharmEcology are drawn broadly to encompass not only toxins and medicines, but also nutrients. The hub of our argument is that PharmEcology shares with the established discipline of nutritional ecology an organismal focus, at the core of which is the notion of evolutionary function. From this functional viewpoint the dividing lines between chemicals traditionally considered as "toxins," "medicines," and "nutrients" are often thin, vague, heavily contingent and non-stationary, and thus provide a poor footing for an emerging sub-discipline. We build our argument around three points: nutrients and toxins are not so different, medicines and nutrients are not so different, and even in cases in which nutrients, medicines and toxins can be categorically distinguished, the biological actions of these compounds are heavily interdependent. PMID- 21665824 TI - Comparative endocrinology in the 21st century. AB - Hormones coordinate developmental, physiological, and behavioral processes within and between all living organisms. They orchestrate and shape organogenesis from early in development, regulate the acquisition, assimilation, and utilization of nutrients to support growth and metabolism, control gamete production and sexual behavior, mediate organismal responses to environmental change, and allow for communication of information between organisms. Genes that code for hormones; the enzymes that synthesize, metabolize, and transport hormones; and hormone receptors are important targets for natural selection, and variation in their expression and function is a major driving force for the evolution of morphology and life history. Hormones coordinate physiology and behavior of populations of organisms, and thus play key roles in determining the structure of populations, communities, and ecosystems. The field of endocrinology is concerned with the study of hormones and their actions. This field is rooted in the comparative study of hormones in diverse species, which has provided the foundation for the modern fields of evolutionary, environmental, and biomedical endocrinology. Comparative endocrinologists work at the cutting edge of the life sciences. They identify new hormones, hormone receptors and mechanisms of hormone action applicable to diverse species, including humans; study the impact of habitat destruction, pollution, and climatic change on populations of organisms; establish novel model systems for studying hormones and their functions; and develop new genetic strains and husbandry practices for efficient production of animal protein. While the model system approach has dominated biomedical research in recent years, and has provided extraordinary insight into many basic cellular and molecular processes, this approach is limited to investigating a small minority of organisms. Animals exhibit tremendous diversity in form and function, life-history strategies, and responses to the environment. A major challenge for life scientists in the 21st century is to understand how a changing environment impacts all life on earth. A full understanding of the capabilities of organisms to respond to environmental variation, and the resilience of organisms challenged by environmental changes and extremes, is necessary for understanding the impact of pollution and climatic change on the viability of populations. Comparative endocrinologists have a key role to play in these efforts. PMID- 21665825 TI - Hormonal regulation of whole-animal performance: Implications for selection. PMID- 21665826 TI - Steroid use and human performance: Lessons for integrative biologists. AB - While recent studies have begun to address how hormones mediate whole-animal performance traits, the field conspicuously lags behind research conducted on humans. Recent studies of human steroid use have revealed that steroid use increases muscle cross-sectional area and mass, largely due to increases in protein synthesis, and muscle fiber hypertrophy attributable to an increased number of satellite cells and myonuclei per unit area. These biochemical and cellular effects on skeletal muscle morphology translate into increased power and work during weight-lifting and enhanced performance in burst, sprinting activities. However, there are no unequivocal data that human steroid use enhances endurance performance or muscle fatigability or recovery. The effects of steroids on human morphology and performance are in general consistent with results found for nonhuman animals, though there are notable discrepancies. However, some of the discrepancies may be due to a paucity of comparative data on how testosterone affects muscle physiology and subsequent performance across different regions of the body and across vertebrate taxa. Therefore, we advocate more research on the basic relationships among hormones, morphology, and performance. Based on results from human studies, we recommend that integrative biologists interested in studying hormone regulation of performance should take into account training, timing of administration, and dosage administered when designing experiments or field studies. We also argue that more information is needed on the long-term effects of hormone manipulation on performance and fitness. PMID- 21665828 TI - Hormonal regulation of energy metabolism in insects as a driving force for performance. AB - Since all life processes depend on energy, the endocrine control of energy metabolism is one of the driving forces for the performance of an individual. Here, we review the literature on the key players in the endocrine regulation of energy homeostasis in insects, the adipokinetic hormones. These pleiotropic peptides not only control dynamic performance traits (flight, swimming, walking) but also regulatory performance traits (egg production, larval growth, and molting). Adipokinetic hormone is released into the hemolymph during intense muscular activity (flight) and also during apparently less energy-demanding locomotory activities, such as swimming and even walking, and, finally, activates the catabolic enzymes phosphorylase and/or triacylglycerol lipase that mobilize carbohydrates and/or lipids and proline, respectively. At the same time, anabolic processes such as the synthesis of protein, lipid, and glycogen are inhibited. Furthermore, adipokinetic hormones affect locomotory activity via neuromodulatory mechanisms that apparently employ biogenic amines. During oogenesis, it is thought that adipokinetic hormone performs similar tasks, because energetic substrates have to be mobilized and transported from the fat body to the ovaries in order to support oocyte growth. Inhibition of anabolic processes by exogenous adipokinetic hormone results in females that lay fewer and smaller eggs. Much less is known about the role of adipokinetic hormones during larval development and during molting but in this case energy homeostasis has to be tightly regulated as well: in general, during the early phase of a larval instar intake of food prevails and the energy stores of the fat body are established, whereas, prior to the molt, insects stop feeding and mobilize energy stores in the fat body, thereby fueling energy-demanding processes such as the formation of the new cuticle and the emergence from the old one. From the few data available to date, it is clear that adipokinetic hormones are involved in the regulation of these events in larvae. PMID- 21665827 TI - Phenotypic integration and independence: Hormones, performance, and response to environmental change. AB - Hormones coordinate the co-expression of behavioral, physiological, and morphological traits, giving rise to correlations among traits and organisms whose parts work well together. This article considers the implications of these hormonal correlations with respect to the evolution of hormone-mediated traits. Such traits can evolve owing to changes in hormone secretion, hormonal affinity for carrier proteins, rates of degradation and conversion, and interaction with target tissues to name a few. Critically, however, we know very little about whether these changes occur independently or in tandem, and thus whether hormones promote the evolution of tight phenotypic integration or readily allow the parts of the phenotype to evolve independently. For example, when selection favors a change in expression of hormonally mediated characters, is that alteration likely to come about through changes in hormone secretion (signal strength), changes in response to a fixed level of secretion (sensitivity of target tissues), or both? At one extreme, if the phenotype is tightly integrated and only the signal responds via selection's action on one or more hormonally mediated traits, adaptive modification may be constrained by past selection for phenotypic integration. Alternatively, response to selection may be facilitated if multivariate selection favors new combinations that can be easily achieved by a change in signal strength. On the other hand, if individual target tissues readily "unplug" from a hormone signal in response to selection, then the phenotype may be seen as a loose confederation that responds on a trait-by-trait basis, easily allowing adaptive modification, although perhaps more slowly than if signal variation were the primary mode of evolutionary response. Studies reviewed here and questions for future research address the relative importance of integration and independence by comparing sexes, individuals, and populations. Most attention is devoted to the hormone testosterone (T) and a songbird species, the dark-eyed junco (Junco hyemalis). PMID- 21665829 TI - Hormones, performance and fitness: Natural history and endocrine experiments on a lizard (Sceloporus undulatus). AB - We used the "morphology-performance-fitness" paradigm (Arnold, 1983) as our framework to investigate endocrine control of performance and fitness in Sceloporus undulatus (Eastern Fence Lizard). Focusing on males, we used the "natural experiments" of seasonal, sexual, and developmental variation in growth and in exercise endurance to identify testosterone and corticosterone as potential modulators of performance and related traits of interest. We followed with experimental manipulations of testosterone to investigate functional relationships, both in the laboratory and in the field. Further, we used focal observations and demographic studies, coupled with genetic determination of paternity, to test associations between performance and fitness, measured as reproductive success. We found that in males, endurance and plasma concentrations of testosterone and corticosterone are at their peaks in the spring breeding season, when lizards are most actively engaged in patrolling home ranges and in reproductive behavior. At that time, plasma concentrations of testosterone are correlated with body size; plasma concentrations of corticosterone and parameters of home range, including area and the number of overlapped females, are correlated with home-range overlap between males and females. During prereproductive development, males (but not females) experience a maturational increase in plasma testosterone. At about the same time, they become more active, expand their home ranges, and grow less quickly than do females, suggesting a trade-off in the allocation of energy, mediated by testosterone. Experimentally, testosterone has positive effects on fitness by stimulating endurance and reproductive activity and increasing home-range area, but it exacts costs in fitness by increasing ectoparasitism, decreasing growth, and decreasing survivorship. We found evidence of selection on body size, endurance, and home range size (and thus access to potential mates). Despite having positive effects on performance traits, plasma concentrations of testosterone were not correlated with number of offspring sired by males. However, we found a strong correlation between the level of plasma corticosterone and the number of offspring sired. We also found evidence of size-assortative mating, indicating that for males, both the number and the size (and thus, fecundity) of their mates increase with body size. Our studies exemplify the power of natural history combined with experimental endocrine manipulations to identify hormonal regulators of performance and linkages to fitness. Furthermore, our results illustrate ecological and evolutionary significance of individual variation in endocrine traits. PMID- 21665830 TI - Evolution of the hormonal control of animal performance: Insights from the seaward migration of salmon. AB - The endocrine system is the key mediator of environmental and developmental (internal) information, and is likely to be involved in altering the performance of animals when selection has favored phenotypic plasticity. The endocrine control of performance should be especially pronounced in animals that undergo a developmental shift in niche, such as occurs in migratory species. By way of example, I review the developmental and environmental control of the preparatory changes for seawater entry of juvenile salmon (known as smolting) and its hormonal regulation. There is a size threshold for smolt development in juvenile Atlantic salmon that results in greater sensitivity of the growth hormone and cortisol axes to changes in daylength. These hormones, in turn, have broad effects on survival, ion homeostasis, growth and swimming performance during entry into seawater. Migratory niche shifts and metamorphic events are extreme examples of the role of hormones in animal performance and represent one end of a continuum. A framework for predicting when hormones will be involved in performance of animals is presented. Endocrine involvement in performance will be more substantial when (1) selection differentials on traits underlying performance are high and temporally discontinuous over an animal's lifetime, (2) the energetic and fitness costs of maintaining performance plasticity are less than those of constant performance, (3) cues for altering performance are reliable indicators of critical environmental conditions, require neurosensory input, and minimize effects of lag, and (4) the need for coordination of organs, tissues and cells to achieve increased performance is greater. By examining these impacts of selection, endocrinologists have an opportunity to contribute to the understanding of performance, phenotypic plasticity, and the evolution of life history traits. PMID- 21665831 TI - Social behavior in context: Hormonal modulation of behavioral plasticity and social competence. AB - In social species animals should fine-tune the expression of their social behavior to social environments in order to avoid the costs of engaging in costly social interactions. Therefore, social competence, defined as the ability of an animal to optimize the expression of its social behavior as a function of the available social information, should be considered as a performance trait that impacts on the Darwinian fitness of the animal. Social competence is based on behavioral plasticity which, in turn, can be achieved by different neural mechanisms of plasticity, namely by rewiring or by biochemically switching nodes of a putative neural network underlying social behavior. Since steroid hormones respond to social interactions and have receptors extensively expressed in the social behavioral neural network, it is proposed that steroids play a key role in the hormonal modulation of social plasticity. Here, we propose a reciprocal model for the action of androgens on short-term behavioral plasticity and review a set of studies conducted in our laboratory using an African cichlid fish (Oreochromis mossambicus) that provide support for it. Androgens are shown to be implicated as physiological mediators in a wide range of social phenomena that promote social competence, namely by adjusting the behavioral response to the nature of the intruder and the presence of third parties (dear enemy and audience effects), by anticipating territorial intrusions (bystander effect and conditioning of the territorial response), and by modifying future behavior according to prior experience of winning (winner effect). The rapid behavioral actions of socially induced short-term transient changes in androgens indicate that these effects are most likely mediated by nongenomic mechanisms. The fact that the modulation of rapid changes in behavior is open to the influence of circulating levels of androgens, and is not exclusively achieved by changes in central neuromodulators, suggests functional relevance of integrating body parameters in the behavioral response. Thus, the traditional view of seeing neural circuits as unique causal agents of behavior should be updated to a brain-body-environment perspective, in which these neural circuits are embodied and the behavioral performance (and outcomes as fitness) depends on a dynamic relationship between the different levels. In this view hormones play a major role as behavioral modulators. PMID- 21665832 TI - Interactions and trade-offs among physiological determinants of performance and reproductive success. AB - How an animal performs in its natural environment ultimately plays a key role in its reproductive success. While a number of studies have investigated how selection acts on performance-related traits, far fewer studies have examined the mechanisms responsible for variation in performance. Among mechanisms, variable morphology has received the most attention. Although physiological traits have received less attention, they are intrinsically related to performance and ultimately to reproductive success. We present a framework whereby investigators can link some basic physiological functions with organismal performance and ultimately with reproductive success. We propose that performance and ultimately reproductive success are strongly influenced by hormones, immune functions, and energetics. We further argue that no physiological function can be considered in isolation and thus our model emphasizes interactions and trade-offs both within each physiological function as well as among them. Some of the most commonly studied trade-offs are between reproduction and immune functions, with energetics as one of the key common currencies for these trade-offs. From an evolutionary perspective, the largest gaps in our knowledge lie in how these interactions and trade-offs influence reproductive success. We believe that a full understanding of how hormones, immune functions, and energetics influence performance traits related to reproduction and, ultimately, lifetime reproductive success requires recognition of the complex relationships, interactions, and trade-offs among these processes. PMID- 21665833 TI - Hormones and acoustic communication in anuran amphibians. AB - Circulating hormone levels can mediate changes in the quality of courtship signals by males and/or mate choice by females and may thus play an important role in the evolution of courtship signals. Costs associated with shifts in hormone levels of males, for example, could effectively stabilize directional selection by females on male signals. Alternatively, if hormone levels affect the selection of mates by females, then variation in hormone levels among females could contribute to the maintenance of variability in the quality of males' signals. Here, I review what is known regarding the effects of hormone levels on the quality of acoustic signals produced by males and on the choice of mates by females in anuran amphibians. Surprisingly, despite the long history of anuran amphibians as model organisms for studying acoustic communication and physiology, we know very little about how variation in circulating hormone levels contributes to variation in the vocal quality of males. Proposed relationships between androgen levels and vocal quality depicted in recent models, for example, are subject to the same criticisms raised for similar models proposed in relation to birds, namely that the evidence for graded effects of androgens on vocal performance is often weak or not rigorously tested and responses seen in one species are often not observed in other species. Although several studies offer intriguing support for graded effects of hormones on calling behavior, additional comparative studies will be required to understand these relationships. Recent studies indicate that hormones may also mediate changes in anuran females' choice of mates, suggesting that the hormone levels of females can influence the evolution of males' mating signals. No studies to date have concurrently addressed the potential complexity of hormone-behavior relationships from the perspective of sender as well as receiver, nor have any studies addressed the costs that are potentially associated with changes in circulating hormone levels in anurans (i.e., life-history tradeoffs associated with elevations in circulating androgens in males). The mechanisms involved in hormonally induced changes in signal production and selectivity also require further investigation. Anuran amphibians are, in many ways, conducive to investigating such questions. PMID- 21665834 TI - Grand challenges in organismal biology: The need to develop both theory and resources. AB - This contribution is fifth in a series of articles in Integrative and Comparative Biology that was initiated by Schwenk et al. (2009) and followed by Satterlie et al. (2009), Denny and Helmuth (2009), and Denver et al. (2009). Here, our intent is to be provocative and to stimulate further discourse. Like other contributors we have our own biases, and as it should be clear to the readers, we approach this task as evolutionary biologists, specifically systematists. PMID- 21665835 TI - Food supplementation experiments: A tool to reveal mechanisms that mediate timing of reproduction. AB - Food supplementation of free-living animals has been used to address the role of availability of resources in the timing of reproduction. A meta-analysis by Schoech and Hahn suggested that responsiveness of the reproductive axis to the supplementary cue of food is lessened at higher latitudes, presumably because the brief time during which conditions are appropriate to rear offspring has led to an evolved resistance to supplementary cues with a primary reliance on photoperiod. Unfortunately, few investigators have examined the potential underlying mechanisms that mediate this differential responsiveness to supplemental food across latitudes. Considerable research, however, links nutritional state and plasma glucocorticoid levels, both of which impinge upon the reproductive axis. Long-term research on Florida scrub-jays (Aphelocoma coerulescens) in my laboratory shows that suburban birds with access to ad libitum supplemental food express early breeding and lower plasma corticosterone (CORT) levels in comparison to jays in nearby natural habitat. Furthermore, supplementation in natural habitat advances laying, with the largest effects occurring in bad years (i.e., years defined by late breeding and poor reproductive output by non-supplemented controls). Similarly, reproductive output of supplemented jays is greater and exhibits considerably less variance than do controls, suggesting fitness benefits of supplementation that are tied to advanced breeding. Generally, CORT levels in early-breeding supplemented jays are lower than are those of controls. Also, regression analysis suggests that clutch initiation dates of non-supplemented female breeders are predicted by baseline CORT levels. Although these data are not conclusive and trends can be obscured by year-effects, they suggest a role for CORT in timing of breeding. Whether this link might help to explain the above-referenced latitudinal trends remains to be characterized. PMID- 21665836 TI - Proximate control and adaptive potential of protandrous migration in birds. AB - Migration determines where, when, and in which order males and females converge for reproduction. Protandry, the earlier arrival of males relative to females at the site of reproduction, is a widespread phenomenon found in many migratory organisms. Detailed knowledge of the determinants of protandry is becoming increasingly important for predicting how migratory species and populations will respond to rapid phenological shifts caused by climatic change. Here, we review and discuss the potential mechanisms underlying protandrous migration in birds, focusing on evidence from passerine species. Latitudinal segregation during the non-breeding period and differences in the initiation of spring migration are probably the key determinants of protandrous arrival at the breeding sites, while sexual differences in speed of migration appear to play a minor role. Experimental evidence suggests that differences between the sexes in the onset of spring migratory activity are caused by differences in circannual rhythmicity or by photoperiodic responsiveness. Both of these mechanisms are hardwired and could prevent individuals from responding plastically to chronic changes in temperature at the breeding grounds. As a consequence, adaptive changes in both the timing of arrival in spring and of reproduction will require evolutionary (genetic) changes of the cue-response systems underlying the initiation and extent of migration in both males and females. PMID- 21665837 TI - Comparative analysis of the molecular basis of photoperiodic signal transduction in vertebrates. AB - In temperate zones, the reproductive physiology of most vertebrates is controlled by changes in photoperiod. Mechanisms for the regulation of photoperiodic gonadal responses are known to differ between mammals and birds: in mammals, melatonin is the photoperiodic signal messenger, whereas in birds, photoperiodic information is received by deep brain photoreceptors. Recently, the molecular mechanism of photoperiodism has been revealed by studies on Japanese quail, which exhibit a most remarkable responsiveness to photoperiod among vertebrates, and molecular cascades involved in photoperiodism have been elucidated. Long-day stimulus induces expression of the beta-subunit of thyroid stimulating hormone (TSH-beta) in the pars tuberalis (PT) of the pituitary gland, and TSH derived from the PT regulates reciprocal switching of genes encoding types 2 and 3 deiodinases (Dio2 and Dio3, respectively) in the mediobasal hypothalamus (MBH) by retrograde action. Dio2 locally converts prohormone thyroxine (T(4)) to bioactive triiodothyronine (T(3)) in the MBH, which subsequently stimulates the gonadal axis. These events have been confirmed to occur in mammals with seasonal breeding, such as hamsters and sheep, suggesting that similar mechanisms are involved among various vertebrates. In addition, nonphotoperiodic mice also appeared to possess the same molecular mechanisms at the hypothalamo-hypophysial level. It has been noted that melatonin regulates the above-mentioned key genes (Dio2, Dio3, and TSH-beta) in mammals, while photoperiod directly regulates these genes in birds. Thus, the input pathway of photoperiod is different between mammals and birds (i.e., melatonin versus light); however, the essential mechanisms are conserved among these vertebrates. PMID- 21665838 TI - Proximate mechanisms driving circadian control of neuroendocrine function: Lessons from the young and old. AB - Circadian rhythms impact a variety of behavioral and physiological functions contributing to longevity and successful reproduction. In their natural environments, individuals of a species are faced with a multitude of challenges and the coordination of internal processes and behavior with external pressures has been hypothesized to be an important target of natural selection. Several lines of evidence from cyanobacteria, Drosophila, and plants provide strong support for an important role of the circadian clock in survival and reproductive success. Similarly in mammals, disruptions in circadian function markedly impact reproduction and lifespan. The present review discusses research outlining the proximate and ultimate mechanisms responsible for the central and peripheral control of the reproductive axis. Because precise temporal coordination of the endocrine system is particularly crucial for reproduction by females, the present overview focuses on the role of circadian timing in this sex. PMID- 21665839 TI - Opportunism, photoperiodism, and puberty: Different mechanisms or variations on a theme? AB - There are many parallels between the neural regulation of seasonal breeding in birds and puberty in primates, but most studies of the regulation of puberty in vertebrates involve the use of rodents. The findings from rodent studies are often perceived as being typical of mammals and therefore pertinent to human reproductive biology and in many cases, rodent models have a great deal to offer in terms of an understanding of the regulation of puberty and reproductive biology. However, knowledge available from comparative work perhaps highlights mechanistic similarities that may not exist between rodent and primate systems. In this short review, we highlight some of the advantages of studying avian reproductive biology in this regard. We discuss disparities between rodent puberty and primate puberty, and similarities between primates and birds. Thus, understanding the mechanisms regulating avian puberty and seasonal breeding might in some cases provide greater insight into the mechanistic control of puberty in nonrodent mammals. We also describe in detail the neuroendocrine regulation of reproduction in birds and aim to provoke discussion of the possible roles of thyroid hormones and multiple forms of gonadotropin-releasing hormone in avian and mammalian reproduction. PMID- 21665840 TI - Microevolution of neuroendocrine mechanisms regulating reproductive timing in Peromyscus leucopus. AB - A key question in the evolution of life history and in evolutionary physiology asks how reproductive and other life-history traits evolve. Genetic variation in reproductive control systems may exist in many elements of the complex inputs that can affect the hypothalamic-pituitary-gonadal (HPG) or reproductive axis. Such variation could include numbers and other traits of secretory cells, the amount and pattern of chemical message released, transport and clearance mechanisms, and the number and other traits of receptor cells. Selection lines created from a natural population of white-footed mice (Peromyscus leucopus) that contains substantial genetic variation in reproductive inhibition in response to short winter daylength (SD) have been used to examine neuroendocrine variation in reproductive timing. We hypothesized that natural genetic variation would be most likely to occur in the inputs to GnRH neurons and/or in GnRH neurons themselves, but not in elements of the photoperiodic pathway that would have pleiotropic effects on nonreproductive functions as well as on reproductive functions. Significant genetic variation has been found in the GnRH neuronal system. The number of GnRH neurons immunoreactive to an antibody to mature GnRH peptide under conditions maximizing detection of stained neurons was significantly heritable in an unselected control (C) line. Furthermore, a selection line that suppresses reproduction in SD (photoperiod responsive, R) had fewer IR-GnRH neurons than a selection line that maintains reproduction in SD (photoperiod nonresponsive, NR). This supports the hypothesis that genetic variation in characteristics of GnRH neurons themselves may be responsible for the observed phenotypic variation in reproduction in SD. The R and NR lines differ genetically in food intake and iodo melatonin receptor binding, as well as in other characteristics. The latter findings are consistent with the hypothesis that genetic variation occurs in the nutritional and hormonal inputs to GnRH neurons. Genetic variation also exists in the phenotypic plasticity of responses to two combinations of treatments, (1) food and photoperiod, and (2) photoperiod and age, indicating genetic variation in individual norms of reaction within this population. Overall, the apparent multiple sources of genetic variation within this population suggest that there may be multiple alternative combinations of alleles for both the R and NR phenotypes. If that interpretation is correct, we suggest that this offers some support for the evolutionary "potential" hypothesis and is inconsistent with the evolutionary "constraint" and "symmorphosis" hypotheses for the evolution of complex neuroendocrine pathways. PMID- 21665841 TI - Geographically distinct reproductive schedules in a changing world: Costly implications in captive Stonechats. AB - With progressively faster global change, shifts in phenology, and distributional ranges are reported for an increasing number of species. The success of organisms at coping with novel seasonal conditions depends on the mechanisms that determine their schedules. Species that rely on fixed schedules and those that time their activities by predictive cues may be particularly constrained in their ability to accommodate changes. The present study examines rigid scheduling and its implications for breeding in captivity in an avian model taxon, the Stonechat (Saxicola torquata). Within their extensive breeding range, Stonechats differ geographically in migratory behavior and reproduce and molt under a wide range of daylengths (10-17 h). Stonechats time their activities by programs that involve circannual rhythms and photoperiodism. The study reports reproductive timing of four taxa (central European, Irish, Siberian, and Kenyan), relates it to laydates in the field, and investigates modifying influences of housing conditions and of social context. Reproductive consequences of timing programs were then tested by crossbreeding of taxa with different schedules. The study revealed persistent, population-specific breeding windows in captivity. Resident Stonechats from equatorial Kenya synchronized their reproductive cycles with the European summer, presumably in response to local photoperiod, and bred at similar times as northern migrants. In all other taxa schedules matched those in the field, but were timed slightly earlier in captivity and advanced by indoor keeping conditions. Influences of social context were negligible. In pairs with clutches, testes regressed slightly later than in pairs without clutches, but presence of a mate per se had no influence on breeding cycles. Accordingly, crossbreeding Stonechats were predicted to have limited capacity to adjust schedules to those of their mates. This prediction was tested by crossbreeding of single-clutched Siberian long-distance migrants with multiple-clutched European short-distance migrants. Males and females of both taxa retained their characteristic breeding schedules, regardless of their mate's activities. This led to dramatic loss of reproductive success in the population with the longer breeding season, European Stonechats. Siberian Stonechats were unable to profit from the presence of a sexually active mate, but they suffered no disadvantage from crossbreeding. In a changing world, inherited timing programs may severely constrain responses to novel conditions, impose schedule-dependent, asymmetric costs of hybridization, and contribute to directional gene flow or to reproductive isolation. PMID- 21665842 TI - The evolution of photoperiod response systems and seasonal GnRH plasticity in birds. AB - Animals' lives are typically subdivided into distinct stages, some of which (e.g. breeding) contribute to fitness through enhancing current reproductive success, and some of which (e.g. molting and migration in birds; hibernation in mammals) contribute to fitness through enhancing survival and, therefore, future reproductive opportunities. There is often a trade-off between these two kinds of processes, either because they are temporally incompatible with one another (e.g. migration precludes simultaneous nesting in birds) or because they are energetically incompatible with one another (e.g. successful molting appears to be incompatible with simultaneous nesting in many birds). Consequently, adaptations facilitating appropriate timing and coordination of different life cycle stages are arguably as important to fitness as are more obvious adaptations such as feeding morphologies and predator avoidance. Mechanisms that facilitate coordination of life-cycle events with the annual cycle of changes in the environment are therefore expected to evolve in response to selection imposed by different environmental challenges. This article focuses on how mechanisms affecting the timing of, and transitions between, life-cycle stages, particularly breeding, have evolved in birds. Through comparative analyses, we show that photorefractoriness and one neuroendocrine correlate of it-plasticity of the gonadotropin releasing hormone system-have evolved in ways that facilitate different degrees of flexibility in timing of the transition from breeding to molting in different environments. We argue that the nature of the mechanistic adaptations will affect the capacity for adaptive adjustments to changing environmental conditions both in the short term (plasticity inherent in individuals) and in the long term (evolutionary responses of populations to selection). PMID- 21665843 TI - Episodes in insect evolution. AB - This article derives from a society-wide symposium organized by Timothy Bradley and Adriana Briscoe and presented at the 2009 annual meeting of the Society for Integrative and Comparative Biology in Boston, Massachusetts. David Grimaldi provided the opening presentation in which he outlined the major evolutionary events in the formation and subsequent diversification of the insect clade. This presentation was followed by speakers who detailed the evolutionary history of specific physiological and/or behavioral traits that have caused insects to be both ecologically successful and fascinating as subjects for biological study. These include a review of the evolutionary history of the insects, the origins of flight, osmoregulation, the evolution of tracheal systems, the evolution of color vision, circadian clocks, and the evolution of eusociality. These topics, as covered by the speakers, provide an overview of the pattern and timing of evolutionary diversification and specialization in the group of animals we know as insects. PMID- 21665844 TI - Genomics and vertebrate adaptive radiation: A celebration of the first cichlid genome. PMID- 21665845 TI - Cichlid genomics and phenotypic diversity in a comparative context. AB - Cichlid fishes provide an excellent natural system for integrating studies of genomics and adaptive radiation. Cichlids are unique in comprising a substantial fraction of all vertebrate species, possessing unique jaw structures, displaying an exceptional range of breeding systems, and exhibiting rampant phenotypic convergence. The rate of divergence in cichlid jaws, teeth, color patterns, visual systems, reproductive biology, and mating behaviors is unparalleled among vertebrates. I discuss ways rapid divergence in cichlids and other adaptive radiations make understanding the genomic basis of adaptive divergence more tractable. Then, I briefly overview some major findings and insights into vertebrate adaptation that have been gained through cichlid genetic studies. Finally, I discuss the extensive evolutionary replication provided by cichlid adaptive radiations and their potential for studies of genotype-to-phenotype mapping. PMID- 21665846 TI - Gene duplication and differential gene expression play an important role in the diversification of visual pigments in fish. AB - Sensory systems provide crucial information about an organism's external environment and, thus, are often subject to strong natural selection. Because of the large variation in the intensity and spectral quality of light in aquatic environments, studies of sensory adaptation have focused on the visual systems of fish for over a half a century. Recently, the molecular genetic mechanisms that determine the spectral sensitivity of visual pigments have been characterized in several fishes including zebrafish, guppies, medaka, killifish, bream, and cichlids. The results of these studies suggest that teleost fish have incredibly diverse visual systems. In this paper, we review the role that opsin duplication and differential gene expression have played in the diversification of visual pigments. We compare our findings in cichlids to five other taxonomic groups and highlight the ways that their similarities and differences may provide new insights into the molecular genetic basis of sensory adaptation and diversification. PMID- 21665847 TI - Interspecific profiling of gene expression informed by comparative genomic hybridization: A review and a novel approach in African cichlid fishes. AB - Modern genomic approaches have facilitated great progress in our understanding of the molecular and genetic underpinnings of ecological and evolutionary processes. Analysis of gene expression through heterologous hybridization in particular has enabled genome-scale studies in many ecologically and evolutionarily interesting species. However, these studies have been hampered by the difficulty of comparing on a common array platform-gene-expression profiles across species due to sequence divergence altering the dynamics of hybridization. All too often, comparisons of expression profiles across species were limited to contrasting lists of gene or even of just functional categories. Here we review these issues and propose a novel solution. Exploiting the diverse cichlid lineages of East Africa as our model-system, we then present results from an experimental case study that compares the neural gene-expression profiles of males and females of two species that differ in mating system. Using a single microarray platform that contains genes from one species, Astatotilapia burtoni, we conducted a total of 16 direct comparisons for neural gene-expression level between individual males and females from a pair of sister species, the polygynous Enantiopus melanogenys and the monogamous Xenotilapia flavipinnis. Next, we conducted a meta-analysis with previously published data from two different intra-specific expression studies to determine whether sex-specific neural gene expression is more closely associated with behavioral phenotype than it is with gonadal sex. Our results indicate that the gene expression profiles are species-specific to a large extent, as relatively few genes show conserved expression patterns associated with either sex. Finally, we describe how competitive genomic DNA hybridizations between the two focal species allow us to assess the degree to which divergence of sequences biases the results. We propose a masking technique that correlates interspecific expression ratios obtained with cDNA with hybridization ratios obtained with genomic DNA for the same set of species and determines threshold sequence divergence to reduce false positives. Our approach should be applicable to a wide range of interesting questions related to the evolution and ecology of gene expression. PMID- 21665848 TI - Maternal care and altered social phenotype in a recently collected stock of Astatotilapia burtoni cichlid fish. AB - For over 30 years, the African cichlid fish, Astatotilapia burtoni, has been an important model system for studying the mechanisms underlying socially mediated behavioral change, with the focus being the dominance behavior of males. A recently collected wild-stock (WS) of this species invigorates interest in parallel studies of females' behavior. Here, we describe a robust 'good-mother' phenotype, increased maternal affiliation in fry, and subtle differences in males' behavior that are exhibited by this new stock. While the females of both the laboratory-stock (LS) and the WS brood the developing fry in their buccal cavity, only the WS continues to provide maternal care after initial release of the fry while the LS engage in filial cannibalism. We show that weight loss during starvation, either during brooding or with restriction of food, is greater in the LS than in the WS; thus, the observed behavioral differences may be tied to metabolic differences. The WS also exhibits a robust androgen response to challenge during the maternal care phase. Given the increasing power of genomic tools available for this species, the comparison of these two stocks will offer the opportunity to investigate the genetic and genomic basis of behavioral differences. PMID- 21665849 TI - Using Drosophila for studying fundamental processes in hearing. AB - Apart from detecting sounds, vertebrate ears occasionally produce sounds. These spontaneous otoacoustic emissions are the most compelling evidence for the existence of the cochlear amplifier, an active force-generating process within the cochlea that resides in the motility of the hair cells. Insects have neither a cochlea nor hair cells, yet recent studies demonstrate that an active process that is equivalent to the cochlear amplifier occurs in at least some insect ears; like hair cells, the chordotonal sensory neurons that mediate hearing in Drosophila actively generate forces that augment the minute vibrations they transduce. This neuron-based force-generation, its impact on the ear's macroscopic performance, and the underlying molecular mechanism are the topics of this article, which summarizes some of the recent findings on how the Drosophila organ of hearing works. Functional parallels with vertebrate auditory systems are described that recommend the fly for the study of fundamental processes in hearing. PMID- 21665850 TI - Active touch, exploratory movements, and sensory prediction. AB - The relation between somatosensory input and motor output is asymmetric. Somatosensation is associated with every movement an animal makes, but movement is not required for somatosensation. This symposium paper proposes a classification scheme for movement, in which movements are placed along a continuum that describes the role that somatosensory information plays during the movement. Fine sensorimotor control-manipulation and exploration-are found to fall to one extreme of the spectrum, and exploratory movements in particular are shown to possess characteristics that clearly distinguish them from other varieties of movement. Specifically, the exploratory process must permit animals to extract an object's features independently of the sequence of movements executed to explore the object. Based in part on our work on the rat vibrissal system, we suggest that exploration of objects may consist of two complementary levels of sensorimotor prediction operating in parallel. At the cognitive level, the animal might move so as to perform hypothesis testing about the identity or nature of the object. The particular hypothesis tests chosen by the animal might be implemented through sequences of control-level predictions that could be generated at the level of the brainstem and cerebellum. PMID- 21665851 TI - The influence of viscous hydrodynamics on the fish lateral-line system. AB - Fish exhibit many behaviors that involve sensing water flows with their lateral line system. In many situations, viscosity affects how the flow interacts with the body of the fish and the neuromasts of the lateral line. Here we discuss how viscosity influences the stimulus to the fish lateral-line system. The movement of a fish's body creates flows that can interfere with the detection of external signals, but these flows can also serve as a source of information about nearby obstacles and the fish's own hydrodynamic performance. The viscous boundary layer on the surface of the skin alters external signals by attenuating the low frequency components of stimuli. The stimulus to each neuromast depends on the interaction of the fluid surrounding the neuromast and the structural properties of that neuromast, including the number of mechanosensory hair cells it contains. A consideration of the influences of viscosity on flow, at both the whole-body and receptor levels, offers the promise of a more comprehensive understanding of the signals involved in behaviors mediated by the lateral-line system. PMID- 21665852 TI - Environmental influences in the evolution of tetrapod hearing sensitivity and middle ear tuning. AB - Vertebrates inhabit and communicate acoustically in most natural environments. We review the influence of environmental factors on the hearing sensitivity of terrestrial vertebrates, and on the anatomy and mechanics of the middle ears. Evidence suggests that both biotic and abiotic environmental factors affect the evolution of bandwidth and frequency of peak sensitivity of the hearing spectrum. Relevant abiotic factors include medium type, temperature, and noise produced by nonliving sources. Biotic factors include heterospecific, conspecific, or self produced sounds that animals are selected to recognize, and acoustic interference by sounds that other animals generate. Within each class of tetrapods, the size of the middle ear structures correlates directly to body size and inversely to frequency of peak sensitivity. Adaptation to the underwater medium in cetaceans involved reorganization of the middle ear for novel acoustic pathways, whereas adaptation to subterranean life in several mammals resulted in hypertrophy of the middle ear ossicles to enhance their inertial mass for detection of seismic vibrations. The comparative approach has revealed a number of generalities about the effect of environmental factors on hearing performance and middle ear structure across species. The current taxonomic sampling of the major tetrapod groups is still highly unbalanced and incomplete. Future expansion of the comparative evidence should continue to reveal general patterns and novel mechanisms. PMID- 21665853 TI - Physician home visits by palliative medicine fellow. AB - BACKGROUND: Physician home visits (HVs) are an important model of care for the terminally ill. Hospice and palliative medicine (HPM) fellows make a minimum of 25 HVs. OBJECTIVE: To describe HPM fellow hospice HVs in an academic palliative medicine practice. METHODS: Retrospective chart review of HVs conducted by 1 HPM fellow. RESULTS: Twenty-five HVs were made to 21 hospice patients. Nineteen had advanced cancer. Indications for visits were symptom management (22) and education (21). On average 2.8 symptoms (+/- SD 1) were addressed on each visit, usually pain. Medications were reviewed at every visit. CONCLUSIONS: HVs are an important part for patient care and fellow education, which provided an opportunity for medication revision and symptom education. PMID- 21665854 TI - End-of-life issues in caring for patients with dementia: the case for palliative care in management of terminal dementia. AB - The number of people suffering with dementia is increasing in the general population and the trend is projected to continue as people live longer, especially in countries with developed economies. The most common cause of dementia (among the many other causes) is Alzheimer's dementia, which is considered a terminal illness. The disease could eventually lead to death, or death could occur as a consequence of co-morbid physical complications. The problem of end of life (EOL) care for patients suffering from dementia though spoken of and written about, does not get the attention and system support as for example patients suffering from cancer receive. Many reasons have been advanced for the current state of affairs where EOL issues for patients suffering from dementia are concerned. This article attempts to revisit the issues, and the reasons, that may contribute to this. Some guidelines on palliative management in cases of patients suffering from severe dementia exist; the evidence base for these guidelines though is relatively weak. The ethical and legal issues that may influence or impact on the decision to initiate the palliative care pathway in the management of EOL issues for dementia patients in the terminal or end stage of the illness is highlighted. Initiatives by the department of health in England and Wales, and other bodies with interest in dementia issues and palliative care in the United Kingdom to ensure good and acceptable EOL pathways for patients with dementia are mentioned. PMID- 21665855 TI - Ethics and palliative care: which consultant and when? AB - Over the past 30 years, and increasingly over the past decade, palliative care services characteristically address the complexity of communication, decision making, and management of end-of-life issues for patients and families of all ages. Clinical ethics services have a parallel 30-plus year history in the United States-so much so that some have offered that clinical ethics has "cut its teeth" on issues attendant to the beginning and end of life. The authors propose considerations necessary in determining the appropriateness of consultation with palliative care, clinical ethics, or both, and when either may be necessary but perhaps not sufficient for patient and family management. A resolution for any encountered tension and identification of common or overlapping domains for both consultants is presented. PMID- 21665856 TI - Victimization in off-street sex industry work. AB - The victimization experienced by street-based sex workers has led many observers to argue that prostitution is inherently dangerous. However, street-based workers form the minority of sex workers in Canada. Can their experiences validly be generalized to other types of prostitution? The research presented in this article examines whether female off-street sex workers face the same degree of victimization as female street-based sex workers in Vancouver, British Columbia. The results of a victimization survey examining interpersonal violence and other forms of victimization indicate that although violence and exploitation do occur in the off-street industry, some women sell sex without experiencing violence. PMID- 21665857 TI - Exploring the intersection of partner stalking and sexual abuse. AB - This study examined a range of sexually abusive acts women with protective orders against violent partners experienced using three groups: (a) women who never experience stalking or rape by the violent partner; (b) women who experienced stalking but who had never been raped by the violent partner; and (c) women who were stalked and raped by the violent partner. Findings suggest that women in violent relationships experienced a wide range of sexually abusive experiences and that there is a significant association of partner stalking and partner sexual abuse beyond rape. Implications for practice and future research are discussed. PMID- 21665858 TI - A qualitative analysis of sexual victimization narratives. AB - The current study examined qualitatively 78 sexual victimization narratives to (a) investigate variability within Sexual Experiences Survey (SES) categories to determine whether these events shared contextual features, (b) investigate variability between SES categories to determine whether these events were contextually distinct, and (c) identify emerging contextual features of victimization experiences. Results revealed considerable variation in both within and between-SES severity categories. Qualitative analysis also identified several emerging contextual features of victimization narratives, such as the after-party situation. Findings suggest that qualitative research may expose contextual variability in sexual victimization experiences not currently captured by quantitative measures of sexual victimization. PMID- 21665859 TI - True colors. PMID- 21665860 TI - Spontaneous complete regression of gastric large-cell neuroendocrine carcinoma: mediated by cytomegalovirus-induced cross-autoimmunity? AB - Spontaneous regression of malignant tumour is a rare phenomenon. This report describes such an occurrence in a gastric large cell neuroendocrine carcinoma of a 77-year-old man. The patient presented with dyspepsia, and biopsy of the fungating mass in the cardia showed a high grade neuroendocrine carcinoma. The pre-operative biopsy taken after 3 months showed chronic inflammation and cytomegalovirus inclusions, but no tumour. In the gastrectomy specimen, no residual tumour was found. Instead, there were foamy histiocytes, chronic inflammatory cells and fibrovascular tissue splitting apart the muscularis propria. In addition, there was ganglionitis involving the myenteric plexus, even in areas of the stomach away from the inflamed site. Chemotherapy, radiotherapy or alternative medicine (including herbal medicine) had not been given. We postulate that cytomegalovirus infection initiated a cross-autoimmune reaction against neuronal cells, and this reaction "unintentionally" eliminated the carcinoma cells which also expressed neural antigens. PMID- 21665861 TI - Source of anti-cytokeratin CAM 5.2 reagent. PMID- 21665865 TI - Editorial changes at JECH. PMID- 21665866 TI - Public health evaluation: which designs work, for whom and under what circumstances? PMID- 21665867 TI - All-cause, liver-related, and non-liver-related mortality among HCV-infected individuals in the general US population. AB - BACKGROUND: Liver-related mortality among those infected with hepatitis C virus (HCV) has been described, but little is known about non-liver-related mortality. Our objective was to determine HCV-associated all-cause, liver-, and non-liver related mortality in the general US population. METHODS: A prospective cohort study of 9378 nationally representative adults aged 17-59 years was performed utilizing the Third National Health and Nutrition Examination Survey (NHANES III) Linked Mortality File that was made publicly available in 2010. HCV status was assessed from 1988 to 1994, with mortality follow-up of the same individuals through 2006. RESULTS: There were 614 deaths over a median follow-up of 14.8 years. After adjusting for all covariate risk factors, HCV chronic infection had a 2.37 times higher all-cause mortality rate ratio [MRR] (95% CI: 1.28-4.38; P = .008), a 26.46 times higher liver-related MRR (95% CI: 8.00-87.48; P < .001), and 1.79 times higher non-liver-related MRR (95% CI: .77-4.19; P = .18), compared with being HCV-negative. This represents an estimated 2.46 million US adults aged 17-59 years with chronic HCV infection who had an estimated 31,163 deaths from all causes per year, of which 57.8% (95% CI: 21.9%-77.2%) were attributable to HCV. Among those, there was an estimated 9569 liver-related deaths per year, of which 96.2% (95% CI: 87.5-98.9%) were attributable to HCV. Non-liver-related deaths were not significantly associated with HCV status. CONCLUSIONS: Chronic HCV all-cause mortality is more than twice that of HCV-negative individuals. This suggests that those with chronic HCV infection are at a higher risk of death even after accounting for liver-related morbidity and should be closely monitored. PMID- 21665868 TI - Assessment of applicability and transferability of evidence-based antenatal interventions to the Australian indigenous setting. AB - There is a need for public health interventions to be based on the best available evidence. Unfortunately, well-conducted studies from settings similar to that in which an intervention is to be implemented are often not available. Therefore, health practitioners are forced to make judgements about proven effective interventions in one setting and their suitability to make a difference in their own setting. The framework of Wang et al. has been proposed to help with this process. This paper provides a case study on the application of the framework to a decision-making process regarding antenatal care in Aboriginal and Torres Strait Islander communities in Queensland. This method involved undertaking a systematic search of the current available evidence, then conducting a second literature search to determine factors that may affect the applicability and transferability of these interventions into these communities. Finally, in consideration of these factors, clinical judgement decisions on the applicability and transferability of these interventions were made. This method identified several interventions or strategies for which there was evidence of improving antenatal care or outcomes. By using the framework, we concluded that several of these effective interventions would be feasible in Aboriginal and Torres Strait Islander communities within Queensland. PMID- 21665869 TI - Alcohol attenuates activation in the bilateral anterior insula during an emotional processing task: a pilot study. AB - AIMS: Alcohol acutely reduces agitation and is widely used in social situations, but the neural substrates of emotion processing during its intoxication are not well understood. We examine whether alcohol's social stress dampening effect may be via reduced activity in the cortical systems that subserve awareness of bodily sensations, and are associated with affective distress. METHODS: Blood oxygen level-dependent activation was measured through 24 functional magnetic resonance imaging sessions in 12 healthy volunteers during an emotional face-processing task following ingestion of a moderate dose of alcohol and a placebo beverage. RESULTS: Results revealed that bilateral anterior insula response to emotional faces was significantly attenuated following consumption of alcohol, when compared with placebo (clusters >1472 MUl; corrected P < 0.05). CONCLUSION: Attenuated response in the anterior insula after alcohol intake may explain some of the decreased interoceptive awareness described during intoxication. PMID- 21665870 TI - Hazardous drinking concepts, limits and methods: low levels of awareness, knowledge and use in the Swedish population. AB - AIMS: To investigate the awareness and knowledge of hazardous drinking limits among the general population in Sweden and the extent to which people estimate their alcohol consumption in standard drinks to assess their level of drinking. METHODS: A population-based study involving 6000 individuals selected from the total Swedish population was performed. Data were collected by means of a postal questionnaire. The mail survey response rate was 54.3% (n = 3200) of the net sample of 5891 persons. RESULTS: With regard to drinking patterns, 10% of the respondents were abstainers, 59% were sensible drinkers and 31% were classified as hazardous drinkers. Most of the abstainers (80%), sensible drinkers (64%) and hazardous drinkers (56%) stated that they had never heard about the standard drink method. Familiarity with the hazardous drinking concept also differed between the three categories although ~61% of sensible and hazardous drinkers expressed awareness of the concept (46% of the abstainers). Knowledge about the limits for sensible drinking was very poor. Between 94 and 97% in the three categories did not know the limit. There was a statistically significant association between having visited health care within the last 12 months and being aware of the standard drink method and the hazardous drinking concept, but not with knowing the hazardous drinking limits. Similarly, there was a significant association between having had at least one alcohol conversation in health care within the last 12 months and being aware of the standard drink method and the hazardous drinking concept, but not with knowing the hazardous drinking limits. CONCLUSION: The results can be seen as a major challenge for the health-care system and public health authorities because they imply that a large proportion of the Swedish population does not know when alcohol consumption becomes a threat to their health. The current strategy to disseminate knowledge about sensible drinking limits to the population through the health-care system seems to have failed and new means of informing the population are warranted. PMID- 21665871 TI - Electrophoretic sperm isolation: optimization of electrophoresis conditions and impact on oxidative stress. AB - BACKGROUND: The purpose of this study was to optimize the electrophoretic conditions that should be used for the effective isolation of functional human spermatozoa and to determine whether this method of isolating cells was associated with oxidative stress and DNA damage. METHODS: Human spermatozoa were prepared by repeated centrifugation, discontinuous density gradient centrifugation and electrophoresis followed by assessments of sperm quality. RESULTS: Systematic analysis of optimal electrophoresis conditions demonstrated that field strength was positively correlated with sperm recovery rates but negatively correlated with sperm movement, irrespective of whether the current or the voltage was held constant. This loss of functionality observed at high power settings was not associated with a major increase in superoxide generation or the induction of oxidative DNA damage. In contrast, discontinuous Percoll gradient centrifugation was shown to produce a significant rise in oxidative DNA base adduct expression in live cells (P < 0.05). As a result of these analyses, optimized electrophoretic conditions were defined that permitted sperm recovery rates of around 20%. These electrophoretically isolated cells were not only free of oxidative stress but exhibited significantly enhanced motility (P < 0.01) and vitality (P < 0.001) compared with the original samples. CONCLUSIONS: We conclude that while field strength is positively correlated with sperm recovery rates; it is negatively associated with sperm motility. Optimized conditions are described that represent a balance between these opposing forces and permit the isolation of highly motile, vital sperm populations, free from the oxidative DNA damage associated with conventional density gradient centrifugation technologies. PMID- 21665872 TI - Selective karyotyping in recurrent miscarriage: are recommended guidelines adopted in daily clinical practice? AB - BACKGROUND: Couples with recurrent miscarriage (RM) have an increased risk of one of the partners carrying a structural chromosome abnormality. On the basis of four independent risk factors, an evidence-based model was developed, which allows limiting karyotyping to high-risk couples. The aim of this study was to assess the level of adoption of selective karyotyping, its clinical consequences and the factors at the patient and hospital level that determine adoption. METHODS: A retrospective cohort study was performed in nine Departments of Obstetrics and Gynaecology, the Netherlands, in 2006. Selective karyotyping was defined as offering karyotyping to high-risk couples and refraining from karyotyping in low-risk couples. Data were collected for risk factors as described in the model for selective karyotyping, cytogenetic results as a measure for clinical consequences, and information about determinants and costs. RESULTS: A total of 530 couples were included; 252 (48%) high-risk couples and 278 (52%) low-risk couples. Among the high-risk couples, 186 (74%) were offered karyotyping. Although not advised, karyotyping was still performed in 198 (71%) low-risk couples. Overall, selective karyotyping was offered to 50% of the couples. The main determinants for adoption of the model were maternal age, obstetric history, treatment by specialists in RM and the number of patients per centre. If selective karyotyping was adopted adequately, a potential reduction of 34% of all karyotyping tests performed is possible. CONCLUSION: Selective karyotyping is applied in only half of the couples with RM in daily practice. Implementation of selective karyotyping should be a topic of future research. PMID- 21665873 TI - Patients' and professionals' barriers and facilitators of tailored expectant management in subfertile couples with a good prognosis of a natural conception. AB - BACKGROUND: European guidelines on fertility care emphasize that subfertile couples should receive information about their chances of a natural conception and should not be exposed to unnecessary treatments and risks. Prognostic models can help to estimate their chances and select couples with a good prognosis for tailored expectant management (TEM). Nevertheless, TEM is not always practiced. The aim of this study was to identify any barriers or facilitators for TEM among professionals and subfertile couples. METHODS: A qualitative study was performed with semi-structured in-depth interviews of 21 subfertile patients who were counselled for TEM and three focus-group interviews of 21 professionals in the field of reproductive medicine. Two theoretical models were used to guide the interviews and the analyses. The primary outcome was the set of identified barriers and facilitators which influence implementation of TEM. RESULTS: Among the subfertile couples, main barriers were a lack of confidence in natural conception, a perception that expectant management is a waste of time, inappropriate expectations prior to the first consultation, misunderstanding the reason for expectant management and overestimation of the success rates of treatment. Both couples and professionals saw the lack of patient information materials as a barrier. Among professionals, limited knowledge about prognostic models leading to a decision in favour of treatment was recognized as a main barrier. A main facilitator mentioned by the professionals was better management of patients' expectations. CONCLUSIONS: We identified several barriers and facilitators which can be addressed to improve the implementation of TEM. These should be taken into account when designing future implementation strategies. PMID- 21665874 TI - The competence of germinal vesicle oocytes is unrelated to nuclear chromatin configuration and strictly depends on cytoplasmic quantity and quality in the cat model. AB - BACKGROUND: Chromatin configuration of the germinal vesicle (GV) and quality of the cytoplasm are critical factors in achieving oocyte meiotic and developmental capacity during folliculogenesis. Besides gaining new insights into the timing and cellular mechanisms associated with the acquisition and regulation of GV oocyte competence, the domestic cat model was used to examine (i) the relation between GV chromatin configuration and oocyte functionality during folliculogenesis and (ii) the role of the cytoplasmic environment on the GV competence and stability. METHODS: Structural and functional properties of GV oocytes were characterized after isolation from different follicle stages of non stimulated cat ovaries. GV transfers, artificial chromatin compaction and oocyte vitrification were used to demonstrate the respective roles of GV and cytoplasm on the oocyte functionality. RESULTS: GVs acquired the intrinsic capability to resume meiosis during the pre-antral follicle stage, whereas the capacity to support embryo development occurred while the antrum started to form. Chromatin configuration of the GV did not undergo extensive modification during the acquisition of competence or during the arrest of transcriptional activity at the large antral follicle stage. However, the quality and quantity of the cytoplasm regulated and enhanced GV functionality. This finding also held for GVs transferred from incompetent or subpar oocytes into the cytoplasm of good quality oocytes or when chromatin was artificially modified or vitrified. CONCLUSIONS: The cat model provides a new insight into GV oocyte structure and function during folliculogenesis while challenging current concepts about oocyte quality criteria based on the GV morphology. This suggests alternative evaluative approaches for oocytes from other species too, including humans. Cat GVs also appear competent at an early follicle stage and are resilient to perturbations which designate this organelle as an attractive target for developing novel fertility preservation tactics. PMID- 21665875 TI - The fertility quality of life (FertiQoL) tool: development and general psychometric properties. AB - BACKGROUND: To develop the first international instrument to measure fertility quality of life (FertiQoL) in men and women experiencing fertility problems, to evaluate the preliminary psychometric properties of this new tool and to translate FertiQoL into multiple languages. METHOD: We conducted a survey, both online and in fertility clinics in USA, Australia/New Zealand, Canada and UK. A total of 1414 people with fertility problems participated. The main outcome measure was the FertiQoL tool. RESULTS: FertiQoL consists of 36 items that assess core (24 items) and treatment-related quality of life (QoL) (10 items) and overall life and physical health (2 items). Cronbach reliability statistics for the Core and Treatment FertiQoL (and subscales) were satisfactory and in the range of 0.72 and 0.92. Sensitivity analyses showed that FertiQoL detected expected relations between QoL and gender, parity and support-seeking. FertiQoL was translated into 20 languages by the same translation team with each translation verified by local bilingual fertility experts. CONCLUSIONS: FertiQoL is a reliable measure of the impact of fertility problems and its treatment on QoL. Future research should establish its use in cross-cultural research and clinical work. PMID- 21665876 TI - Systems modeling in integrative oncology. AB - Systems modeling provides an integrated framework to capture and analyze diverse and multidisciplinary data in a standardized manner. The authors present the Integrative Oncology Systems Model (IOSM) to help assess the impact of behavior modification and various therapeutic interventions on cancer development and progression and the resultant effect on survival and quality of life outcomes. PMID- 21665877 TI - Gypenosides suppress growth of human oral cancer SAS cells in vitro and in a murine xenograft model: the role of apoptosis mediated by caspase-dependent and caspase-independent pathways. AB - PURPOSE: Gypenosides (Gyp) are the major components of Gynostemma pentaphyllum Makino. The authors investigated the effects of Gyp on cell morphology, viability, cell cycle distribution, and induction of apoptosis in human oral cancer SAS cells and the determination of murine SAS xenograft model in vivo. EXPERIMENTAL DESIGN: Flow cytometry was used to quantify the percentage of viable cells; cell cycle distribution; sub-G1 phase (apoptosis); caspase-3, -8, and -9 activity; reactive oxygen species (ROS) production, intracellular Ca(2+) determination; and the level of mitochondrial membrane potential (DeltaPsi(m)). Western blotting was used to examine levels of apoptosis-associated proteins, and confocal laser microscopy was used to examine the translocation of proteins in cells. RESULTS: Gyp induced morphological changes, decreased the percentage of viable cells, caused G0/G1 phase arrest, and triggered apoptotic cell death in SAS cells. Cell cycle arrest induced by Gyp was associated with apoptosis. The production of ROS, increased intracellular Ca(2+) levels, and the depolarization of DeltaPsi(m) were observed. Gyp increased levels of the proapoptotic protein Bax but inhibited the levels of the antiapoptotic proteins Bcl-2 and Bcl-xl. Gyp also stimulated the release of cytochrome c and Endo G. Translocation of GADD153 to the nucleus was stimulated by Gyp. Gyp in vivo attenuated the size and volume of solid tumors in a murine xenograft model of oral cancer. CONCLUSIONS: Gyp induced cell death occurs through caspase-dependent and caspase-independent apoptotic signaling pathways, and the compound reduced tumor size in a xenograft nu/nu mouse model of oral cancer. PMID- 21665878 TI - The chiropractic care of patients with cancer: a systematic review of the literature. AB - BACKGROUND AND SIGNIFICANCE: Cancer is the leading cause of death worldwide and accounted for 7.4 million deaths in 2004. By 2030, deaths from cancer have been estimated at 12 million with 30% being preventable. Complementary and alternative medicine remains popular among cancer patients; particularly with chiropractic services. However, the nature of the chiropractic clinical encounter and its reported benefits remains to be fully investigated. Towards these efforts, we begin with a systematic review of the literature on the chiropractic care of patients with cancer. METHODS: The following electronic databases were searched: MANTIS [1965-2010]; Index to Chiropractic Literature [1984-2010]; Pubmed [1966 2010]; Medline [1965-2010] EMBASE [1974-2010], AMED [1975-2010], CINAHL Plus [1965-2010], Alt-Health Watch [1965-2010] and PsychINFO [1965-2010]. Key words used were "cancer" and "neoplasm" in Boolean combination with "chiropractic." Primary investigation/reports in peer-reviewed English journals involving chiropractic care were reviewed. RESULTS: Our review revealed 60 case reports, 2 case series, 21 commentaries, 2 survey studies, and 2 literature reviews. The case reports were diagnostic with commentaries highlighting the importance of recognizing the patient presenting with NMS complaints due to an underlying neoplasm. The chiropractic clinical encounter prior to cancer diagnosis and subsequent medical referral is poorly characterized in the literature. CONCLUSION: Patients with cancer seek the care of chiropractors. The literature does not reflect or describe the totality of the chiropractic clinical encounter. We encourage further research in this field. PMID- 21665880 TI - Effects of a motor and multisensory-based approach on residents with moderate-to severe dementia. AB - Involving institutionalized people with dementia in their routines may be challenging, particularly in advanced stages of the disease. Motor and multisensory stimulation may help to maintain or improve residents' remaining abilities such as communication and self-care. This study examines the effects of a motor and multisensory-based approach on the behavior of 6 residents with moderate-to-severe dementia. A single-group, pre- and post test design was conducted. Motor and multisensory stimulation strategies were implemented in residents' morning care routines by staff, after the provision of training and assistance. Twelve video recordings of morning care (6 pre- and 6 post interventions) were coded for the type of residents' behavior. Results showed a tendency toward improvements in residents' levels of caregiver-direct gaze, laughing and engagement, and a reduction of closed eyes, during morning care. The introduction of a motor and multisensory-based approach in care routines may improve residents' engagement and attention to the environment. PMID- 21665879 TI - Nomilin inhibits metastasis via induction of apoptosis and regulates the activation of transcription factors and the cytokine profile in B16F-10 cells. AB - Nomilin is a triterpenoid present in common edible citrus fruits with putative anticancer properties. In this study, the authors investigated the antimetastatic potential of nomilin and its possible mechanism of action. Metastasis was induced in C57BL/6 mice through the lateral tail vein using highly metastatic B16F-10 melanoma cells. Administration of nomilin inhibited tumor nodule formation in the lungs (68%) and markedly increased the survival rate of the metastatic tumor bearing animals. These results correlated with the biochemical parameters and histopathological analysis. Nomilin showed an inhibition of tumor cell invasion and activation of matrix metalloproteinases. Treatment with nomilin induced apoptotic response, characterized by an increase in the sub-G1 fraction of cells with chromatin condensation and membrane blebbing, a typical ladder of DNA fragmentation, and detection of apoptotic cells by TUNEL assay. Nomilin treatment also exhibited a downregulated Bcl-2 and cyclin-D1 expression and upregulated p53, Bax, caspase-9, caspase-3, p21, and p27 gene expression in B16F-10 cells. Proinflammatory cytokine production and gene expression were found to be downregulated in nomilin-treated cells. The study also reveals that nomilin could inhibit the activation and nuclear translocation of antiapoptotic transcription factors such as nuclear factor (NF)-kappaB, CREB, and ATF-2 in B16F-10 cells. PMID- 21665881 TI - One-year test-retest reliability of the Inventory of Statements about Self-Injury (ISAS). AB - Nonsuicidal self-injury (NSSI) is a growing public health problem among adolescents and young adults. The Inventory of Statements About Self-Injury (ISAS) is a self-report measure designed to assess NSSI behaviors and functions. The current study examines the one-year test-retest reliability of the ISAS in a sample of young adult self-injurers. Results indicate that the ISAS behavioral and functional scales demonstrate good stability over one year. For the behavioral scales, test-retest correlations ranged from .52 (biting) to .83 (burning), with a median of .68. For the functional scales, test-retest correlations were .60 for the superordinate intrapersonal functions scale and .82 for the superordinate interpersonal functions scale. Regarding individual functions, test-retest correlations ranged from .35 (affect regulation) to .89 (peer bonding), with a median of .59. Findings suggest the ISAS has good test retest reliability and contributes to the growing literature on the psychometric properties of the ISAS. PMID- 21665882 TI - How much power and speed is measured in this test? AB - An old issue in psychological assessment is to what extent power and speed each are measured by a given intelligence test. Starting from accuracy and response time data, an approach based on posterior time limits (cut-offs of recorded response time) leads to three kinds of recoded data: time data (whether or not the response precedes the cut-off), time-accuracy data (whether or not a response is correct and precedes the cut-off), and accuracy data (as time-accuracy data, but coded as missing when not preceding the time cut-off). Each type of data can be modeled as binary responses. Speed and power are investigated through the effect of posterior time limits on two main aspects: (a) the latent variable that is measured: whether it is more power-related or more speed-related; (b) how well the latent variable (of whatever kind) is measured through the item(s). As empirical data, we use responses and response times for a verbal analogies test. The main findings are that, independent of the posterior time limit, basically the same latent speed trait was measured through the time data, and basically the same latent power trait was measured through the accuracy data, while for the time-accuracy data the nature of the latent trait moved from power to speed when the posterior time limit was reduced. It was also found that a reduction of the posterior time limit had no negative effect on the reliability of the latent trait measures (of whatever kind). PMID- 21665883 TI - A comparison of Agreeableness scores from the Big Five Inventory and the NEO PI R: consequences for the study of narcissism and psychopathy. AB - Despite being significantly correlated, there is evidence to suggest that the scales measuring Agreeableness from the Big Five Inventory (BFI) and the Revised NEO Personality Inventory (NEO PI-R) do not capture identical constructs. More specifically, NEO PI-R Agreeableness contains content related to "honesty and humility" that is not contained by the BFI. In a sample of undergraduates (N = 290), the authors compared the correlations between these two measures of Agreeableness with traits from the HEXACO-PI-R as well as measures of narcissism, narcissistic personality disorder, and psychopathy. As expected, the two scores were significantly correlated but NEO PI-R Agreeableness manifested stronger correlations with the domains/facets of Honesty-Humility, narcissism/NPD, and aspects of psychopathy; these differences appear to be due primarily to the inclusion of the NEO PI-R facets of Straightforwardness and Modesty. These differences have important implications for the assessment and conceptualization of personality and personality disorder. PMID- 21665884 TI - Clarifying the construct of perfectionism. AB - The construct of perfectionism is related to many important outcome variables. However, the term perfectionism has been defined in many different ways, and items comprising the different existing scales appear to be very different in content. The overarching aim of the present set of studies was to help clarify the specific unidimensional personality constructs that contribute to perfectionistic behavior. First, trained raters reliably sorted items from existing measures of perfectionism into nine dimensions. An exploratory factor analysis, followed by a confirmatory factor analysis on an independent sample, resulted in a 9-scale, 61-item measure, called the Measure of Constructs Underlying Perfectionism. The nine scales were internally consistent and stable across time, and they were differentially associated with relevant measures of personality in theoretically meaningful ways. PMID- 21665886 TI - Focusing on the adult attachment style in schizophrenia in community mental health centres: validation of the Psychosis Attachment Measure (PAM) in a German speaking sample. AB - BACKGROUND: Assessing attachment style in people with schizophrenia may be important to identify a risk factor in building a strong therapeutic relationship and so indirectly to understand the development of mal-compliance as one of the major obstacles in the treatment of schizophrenia. AIMS: The present study analysed the psychometric properties of the German version of the Psychosis Attachment Measure (PAM), which assesses avoidant and anxious attachment style. METHODS: A sample of 127 patients suffering from chronic schizophrenia or schizoaffective disorder participated in this study. In testing discriminant validity, we assessed psychopathology, depression, therapeutic relationship and service engagement. Internal consistency, test-retest reliability and factor structure were analysed. RESULTS: The German version of PAM exhibited acceptable to good internal and test-retest reliabilities and the two-factor structure of the English version could be replicated. Avoidant attachment style was related to higher levels of positive symptoms and to a poorer therapeutic relationship. In the context of external validation, a regression analysis revealed that a poor therapeutic relationship correlated with avoidant attachment style, independent of anxious attachment style and depressive symptoms. Anxious attachment was associated with higher treatment adherence. Both insecure attachment styles (avoidant and anxious) were found to be correlated with higher levels of depression, but only attachment anxiety had an independent predictive value for self-reported depression in regression analysis. CONCLUSIONS: The German version of PAM displayed satisfactory psychometric properties and seems to be a reliable measure for assessing attachment style in individuals with schizophrenia. Validation of PAM led to the finding that only the avoidant attachment style might be a risk factor when building a strong therapeutic relationship in schizophrenia. In future studies, other factors influencing therapeutic relationship should be taken into account. Anxious attachment style may be a risk factor for depression, but it also has an enhancing effect on treatment adherence. PMID- 21665885 TI - High-density lipoprotein cholesterol as a predictor of clinical outcomes in patients achieving low-density lipoprotein cholesterol targets with statins after percutaneous coronary intervention. AB - BACKGROUND: A low level of high-density lipoprotein cholesterol (HDL-C) is strongly associated with cardiovascular events. However, the significance of HDL C after statin therapy on the outcome of patients who have undergone percutaneous coronary intervention (PCI) with drug eluting stents (DES) is unclear. OBJECTIVES: To investigate the significance of HDL-C after statin therapy on cardiovascular events in patients with coronary artery disease after DES implantation. METHODS: Patients who underwent PCI with DES from January 2004 to December 2009 were prospectively enrolled. The follow-up lipid panel of 2693 patients (median lab follow-up duration 225 days) who had continued using statins after PCI and who attained low-density lipoprotein cholesterol (LDL-C) <100 mg/dl was analysed. Major adverse cardiac events (MACE), including all-cause death, non fatal myocardial infarction, and target vessel revascularisation according to follow-up HDL-C level (40 mg/dl for men or 50 mg/dl for women) were compared with the use of propensity scores matching. RESULTS: Median follow-up duration was 832 days. 1585 (58.9%) patients had low follow-up HDL-C and 1108 had high follow-up HDL-C. The low follow-up HDL-C group had significantly higher rates of MACE. Low follow-up HDL-C was a significant independent predictor of MACE (adjusted HR 1.404, 95% CI 1.111 to 1.774, p=0.004). In further analysis with propensity scores matching, overall findings were consistent. CONCLUSIONS: Raising HDL-C levels may be a subsequent goal after achieving target LDL-C levels in patients with DES implantation. PMID- 21665887 TI - The EMT regulator slug and lung carcinogenesis. AB - Lung cancer is the leading cause of cancer death worldwide. Cancer metastasis and resistance to treatment (including radiotherapy, chemotherapy and targeted therapy) are two major causes for the poor survival of lung cancer patients. Epithelial-mesenchymal transition (EMT) is involved in cancer cell invasion, resistance to apoptosis and stem cell features. The process of EMT is controlled by a group of transcriptional factors, zinc finger proteins and basic helix-loop helix factors. Signaling pathways activated by intrinsic or extrinsic stimuli converge on these transcriptional factors and regulated the phenotypic changes of cancer cells. These EMT regulators may play an important role in cancer progression. In lung cancer, Slug is the most thoroughly investigated EMT regulator. The expression of Slug is associated with lung cancer invasion and resistance to target therapy. In this review, we focus on the current understanding of the role of Slug in the carcinogenesis and progression of lung cancer. PMID- 21665888 TI - Hepatitis B virus X protein activates CD59 involving DNA binding and let-7i in protection of hepatoma and hepatic cells from complement attack. AB - Emerging evidence has shown that hepatitis B virus (HBV) X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma. Complement regulatory proteins including CD46, CD55 and CD59 contribute to escape of tumor cells from complement-dependent cytotoxicity (CDC). However, little is known about the potential role of HBx in anti-CDC activity during hepatocarcinogenesis. In the present study, we for the first time report that HBx decreases the sensitivity of hepatoma and hepatic cells to CDC. Coincidentally, we demonstrated that HBx increased the promoter activity of CD59, as well as their messenger RNA and protein levels. Moreover, flow cytometry showed the increased expression level of CD59 protein on the surface of HBx-positive cells. Of interest, we found that HBx up-regulated CD59 by binding with cAMP response element-binding to the promoter region of the CD59 gene using chromatin immunoprecipitation assay. In addition, we showed that HBx up-regulated CD59 by let-7i at post-transcriptional regulation level. Our data showed that the deposition of C5b-9 were decreased on the cell surface in HepG2-X cells relative to HepG2 cells, suggesting that increased CD59 mediated by HBx prevents the formation of functional membrane attack complex. Furthermore, we demonstrated that down-regulation of CD59 was sufficient to abolish the resistance capability of CDC in HBx-positive cells by RNA interference (siRNA) in vitro and in vivo. Thus, we conclude that HBx contributes to cells resistance to CDC through CD59. Therapeutically, CD59 may serve as a target in HBV-associated hepatoma patients. PMID- 21665889 TI - Proteins as binding targets of isothiocyanates in cancer prevention. AB - Isothiocyanates are versatile cancer-preventive compounds. Evidence from animal studies indicates that the anticarcinogenic activities of ITCs involve all the major stages of tumor growth: initiation, promotion and progression. Epidemiological studies have also shown that dietary intake of ITCs is associated with reduced risk of certain human cancers. A number of mechanisms have been proposed for the chemopreventive activities of ITCs. To identify the molecular targets of ITCs is a first step to understand the molecular mechanisms of ITCs. Studies in recent years have shown that the covalent binding to certain protein targets by ITCs seems to play an important role in ITC-induced apoptosis and cell growth inhibition and other cellular effects. The knowledge gained from these studies may be used to guide future design and screen of better and more efficacious compounds. In this review, we intend to cover all potential protein targets of ITCs so far studied and summarize what are known about their binding sites and the potential biological consequences. In the end, we also offer discussions to shed light onto the relationship between protein binding and reactive oxygen species generation by ITCs. PMID- 21665890 TI - Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells. AB - Estrogens are major risk factors for the development of breast cancer; they can be metabolized to catechols, which are further oxidized to DNA-reactive quinones and semiquinones (SQs). These metabolites are mutagenic and may contribute to the carcinogenic activity of estrogens. Redox cycling of the SQs and subsequent generation of reactive oxygen species (ROS) is also an important mechanism leading to DNA damage. The SQs of exogenous estrogens have been shown to redox cycle, however, redox cycling and the generation of ROS by endogenous estrogens has never been characterized. In the present studies, we determined whether the catechol metabolites of endogenous estrogens, including 2-hydroxyestradiol, 4 hydroxyestradiol, 4-hydroxyestrone and 2-hydroxyestriol, can redox cycle in breast epithelial cells. These catechol estrogens, but not estradiol, estrone, estriol or 2-methoxyestradiol, were found to redox cycle and generate hydrogen peroxide (H(2)O(2)) and hydroxyl radicals in lysates of three different breast epithelial cell lines: MCF-7, MDA-MB-231 and MCF-10A. The generation of ROS required reduced nicotinamide adenine dinucleotide phosphate as a reducing equivalent and was inhibited by diphenyleneiodonium, a flavoenzyme inhibitor, indicating that redox cycling is mediated by flavin-containing oxidoreductases. Using extracellular microsensors, catechol estrogen metabolites stimulated the release of H(2)O(2) by adherent cells, indicating that redox cycling occurs in viable intact cells. Taken together, these data demonstrate that catechol metabolites of endogenous estrogens undergo redox cycling in breast epithelial cells, resulting in ROS production. Depending on the localized concentrations of catechol estrogens and enzymes that mediate redox cycling, this may be an important mechanism contributing to the development of breast cancer. PMID- 21665891 TI - Caloric restriction reduces growth of mammary tumors and metastases. AB - We investigated the effects of caloric restriction (CR) on growth of tumors and metastases in the 4T1 mammary tumor model and found that CR, compared with normal diet, reduced the growth of mammary tumors and metastases and the total number of metastases that originated both spontaneously from the primary tumor and also experimentally from i.v. injection of the tumor cells. CR also decreased proliferation and angiogenesis and increased apoptosis in tumors. CR reduced levels of insulin, leptin, insulin-like growth factor 1, insulin-like growth factor binding protein 3 and increased adiponectin in tumors. We also demonstrated that tumors from CR mice possessed lower levels of transforming growth factor-beta, lower intratumor deposition of collagen IV and reduced invasiveness due to a decrease in tumor secretion of active matrix metalloproteinase 9. Our results suggest that CR-induced metabolic and signaling changes affect the stroma and the tumor cells resulting in a microenvironment that prevents proliferation of breast tumors and their metastases. PMID- 21665892 TI - Hepatocellular carcinoma: the point of view of the hepatitis B virus. PMID- 21665893 TI - A protein kinase C/protein kinase D pathway protects LNCaP prostate cancer cells from phorbol ester-induced apoptosis by promoting ERK1/2 and NF-{kappa}B activities. AB - Phorbol esters such as phorbol 12-myristate 13-acetate (PMA) induce apoptosis in many tumor cells including the androgen-sensitive LNCaP prostate cancer cells. Although phorbol ester-induced apoptotic pathways have been well characterized, little is known of the pro-survival pathways modulated by these agents. We now provide experimental evidence to indicate that protein kinase D (PKD) promotes survival signals in LNCaP cells in response to PMA treatment. Knockdown of endogenous PKD1 or PKD2 decreased extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor-kappaB (NF-kappaB)-dependent transcriptional activities and potentiated PMA-induced apoptosis, whereas overexpression of wild-type PKD1 enhanced ERK1/2 activity and suppressed PMA-induced apoptosis. PMA caused rapid activation, followed by progressive downregulation of endogenous PKD1 in a time- and concentration-dependent manner. The downregulation of PKD1 was dependent on the activity of protein kinase C (PKC), but not that of PKD. Selective depletion of endogenous PKC isoforms revealed that both PKCdelta and PKCepsilon were required for PKD1 activation and subsequent downregulation. Further analysis showed that the downregulation of PKD1 was mediated by a ubiquitin-proteasome degradation pathway, inhibition of which correlated to increased cell survival. In summary, our data indicate that PKD1 is activated and downregulated by PMA through a PKC-dependent ubiquitin-proteasome degradation pathway, and the activation of PKD1 or PKD2 counteracts PMA-induced apoptosis by promoting downstream ERK1/2 and NF-kappaB activities in LNCaP prostate cancer cells. PMID- 21665894 TI - Downregulation of miR-132 by promoter methylation contributes to pancreatic cancer development. AB - MicroRNAs (miRNAs), which regulate gene expression by partial complementarity to the 3' untranslated region of their target genes, have been implicated in cancer initiation and progression. However, the molecular mechanism underlying the regulation of miRNA expression during pancreatic tumorigenesis has not been extensively reported. In this study, we first compared the miRNA expression in human pancreatic cancers and adjacent normal tissues by miRNA array and identified 12 differentially expressed miRNAs. miR-132, which is downregulated in tumors, was further studied in greater detail. Decreased expression of miR-132 was confirmed in 16 of 20 pancreatic carcinomas (P < 0.0001), compared with their respective benign tissues by TaqMan miRNA assays. miR-132 expression was remarkably influenced by promoter methylation in PANC1 and SW1990 cells. Promoter hypermethylation was observed in tumor samples but not in the normal counterparts, and the expression of miR-132 negatively correlated with its methylation status (P = 0.013). miR-132 was transcribed by RNA polymerase II, and Sp1 played a major role in miR-132 transcription. The expression of Sp1 correlated with that of miR-132 in tissues. Moreover, cancerous tissues showed significantly lower Sp1-binding affinity to the miR-132 promoter, relative to non tumor samples. Proliferation and colony formation of pancreatic cancer cells were suppressed in cells transfected with miR-132 mimics and enhanced in cells transfected with miR-132 inhibitor by negatively regulating the Akt-signaling pathway. Our present findings illustrate the mechanism driving miR-132 downregulation and the important role of miR-132 in pancreatic cancer development. PMID- 21665895 TI - MicroRNA 345, a methylation-sensitive microRNA is involved in cell proliferation and invasion in human colorectal cancer. AB - Aberrant methylation has been shown to trigger the inactivation of tumor suppressor genes during tumorigenesis. MicroRNAs (miRNAs) have been found deregulated in human colorectal cancer (CRC), and some of them may function as tumor suppressor genes. Here, we investigated CpG island promoter hypermethylation as a potential mechanism underlying miRNA disruption and identifed methylation-sensitive miRNAs that might repress CRC development. We compared differential expression of miRNAs after 5-aza-2'-deoxycitidine (5-aza dC) treatment using microarrays. DNA methylation status of the candidate miRNA was analyzed. The candidate miRNA was transfected into CRC cells and growth suppressive mechanisms were explored. Luciferase reporter assay and western blot were used to identify the target genes of the candidate miRNA. The expression of mir-345 was significantly increased after 5-aza-dC treatment. DNA methylation analyses of mir-345 showed high methylation levels in tumor versus normal tissues. Expression of mir-345 was significantly down-regulated in 51.6% of CRC tissues compared with corresponding non-cancerous tissues. Low expression of mir 345 was associated with lymph node metastasis and worse histological type. Increased mir-345 function was sufficient to suppress colon cancer cell proliferation and invasiveness in vitro. Furthermore, we identified BCL2 associated athanogene 3 (BAG3), an anti-apoptosis protein, to be a target of mir 345. These results suggested as a methylation-sensitive miRNA in CRC, mir-345 may play an important role of antineoplastic as a growth inhibitor in the development of CRC. PMID- 21665896 TI - Linkage of patient records from disparate sources. AB - We review ideas, approaches and progress in the field of record linkage. We point out that the latent class models used in probabilistic matching have been well developed and applied in a different context of diagnostic testing when the true disease status is unknown. The methodology developed in the diagnostic testing setting can be potentially translated and applied in record linkage. Although there are many methods for record linkage, a comprehensive evaluation of methods for a wide range of real-world data with different data characteristics and with true match status is absent due to lack of data sharing. However, the recent availability of generators of synthetic data with realistic characteristics renders such evaluations feasible. PMID- 21665897 TI - Pressure monitoring during neuroendoscopy: new insights. AB - BACKGROUND: Significant increases in intracranial pressure (ICP) may occur during neuroendoscopic procedures. To detect and prevent serious and sustained increases, ICP should be monitored. At present, controversy exists on the optimal location of the monitoring sensor. Therefore, we conducted an in vitro study to estimate the pressure gradients between the ventricle, the 'gold standard' site, and the rinsing inlet and outlet. METHODS: A head model and a standard endoscope were used. Rinsing was enforced by using a pressurized infusion bag. Using clinically relevant flow rates, pressure was measured at the rinsing inlet and outlet, in the ventricle, and at the distal end of the rinsing channel using a tip sensor or a capillary tube. RESULTS: At a flow of 61 ml min(-1), the steady state pressures measured at the rinsing inlet, in the ventricle, and at the rinsing outlet were 38, 26, and 12 mm Hg, respectively. At 135 ml min(-1), these increased to 136, 89, and 42 mm Hg. Transendoscopic pressure measurements were always within 1 mm Hg of the ventricular pressure. CONCLUSIONS: During endoscopy, measurements at the rinsing inlet overestimated the ventricular pressure by ~50 mm Hg during heavy rinsing, whereas measurements at the rinsing outlet underestimated the pressure by ~50 mm Hg. An electronic tip sensor or a pressure capillary tube placed at the distal end of the lumen of the rinsing channel of the endoscope did not interfere with rinsing flow and produced measurements that were equal to ventricular pressures. PMID- 21665898 TI - Does manual anaesthetic record capture remove clinically important data? AB - BACKGROUND: Numerous studies have shown smoothing and inaccuracies in handwritten anaesthetic records, but the clinical relevance of these findings is unclear. We therefore sought to determine whether the behaviour of anaesthetists differed in assessing anaesthetic records re-synthesized from either handwritten or automated records. METHODS: In a recent New Zealand study (ACTRN12608000068369), both manual and automated records were acquired from the same anaesthetics. Manual records were digitized using digital callipers. Selected data (systolic, diastolic, and mean arterial pressure; heart rate; Sp(O(2)); E'(CO(2))) were replayed in a computerized anaesthetic record-keeping system with which the participants were familiar, to present manual and corresponding automated anaesthetic records. Ten anaesthetists, randomly selected from participants in this study, assessed 24 replayed records (a manual and an automated record from each of 10 anaesthetics, with two of each displayed twice). They indicated where and how they would have intervened if administering these anaesthetics. We compared the number of interventions for each pair of anaesthetics and subjective measures of anaesthetic quality. RESULTS: In our selected sample of unstable anaesthetics, the mean (SD) number of interventions per anaesthetic was 4.0 (2.9) vs 5.2 (3.4) for manual and automated records, respectively (P=0.013). Subjective measures did not differ significantly between record types. Assessors identified 32 artifacts in six manual records (0.32/record assessment) and 105 artifacts in eight automated records (1.05/record assessment), P=0.14. Replicability was moderate (COV 39.8%). CONCLUSIONS: In comparison with computerized record keeping, manual record-keeping resulted in loss of clinically relevant information. PMID- 21665899 TI - Respiratory resistance during anaesthesia with isoflurane, sevoflurane, and desflurane: a randomized clinical trial. AB - BACKGROUND: To investigate whether the effects of desflurane on inspiratory resistance are similar to those of isoflurane and sevoflurane during 30 min administration at 1 and 1.5 MAC in patients with healthy lungs. METHODS: Seventy one patients undergoing elective surgery were randomly assigned to receive isoflurane, sevoflurane, or desflurane. Baseline inspiratory resistance was obtained after intubation and establishment of volume control ventilation. Anaesthesia was maintained with desflurane, isoflurane, or sevoflurane at 1 MAC for 30 min followed by 1.5 MAC for another 30 min. Tidal volume, flow, and inspiratory pressures were continuously recorded with a pneumotachograph. Total inspiratory resistance (R(rs)), minimal resistance (R(min)), and effective resistance (D(Rrs)) were calculated every 5 min using the end-inspiratory occlusion technique. RESULTS: No significant differences of the evaluated parameters (R(rs), R(min) and D(Rrs)) were observed during administration of the three agents at 1 MAC for 30 min. At 1.5 MAC, desflurane caused a maximum increase in R(rs) by 26% and in R(min) by 30% above baseline, in contrast to isoflurane and sevoflurane which did not display a significant effect on R(rs) (+3.7% by isoflurane and +7.6% by sevoflurane) and R(min) (+4.7% by isoflurane and +9.6% by sevoflurane). All parameters returned to baseline after discontinuation of the volatile agent. CONCLUSIONS: In healthy adults, neither sevoflurane nor isoflurane produced bronchodilation at 1 and 1.5 MAC. Desflurane did not affect respiratory resistance at 1 MAC, but at 1.5 MAC caused significant increase in both total and airway resistance with return to near baseline values after discontinuation of the agent. PMID- 21665900 TI - Hand-hygiene practices in the operating theatre: an observational study. AB - BACKGROUND: The current prevalence of healthcare-associated infections (HCAIs) is a major public health concern. Patient contact in the operating theatre (OT) can contribute to HCAI via microbial contamination. The application of hand hygiene is effective in reducing infection rates. Limited data are available on adherence to hand-hygiene guidelines by OT staff. METHODS: Covert direct observations of OT staff at an academic medical centre were performed by a single, trained observer. The primary outcome was the frequency of hand-hygiene application by OT staff, including anaesthesiologists, anaesthesia nurses, surgeons, surgical nurses, and medical students. 'Sterile' scrubbed staff members were excluded. The following hand-hygiene opportunities were monitored: (i) entering or leaving the OT; and (ii) before patient contact. Furthermore, the frequency of 'potential contamination' was recorded (touching OT implements after contact with patient/patient body fluids without the subsequent application of hand hygiene). We recorded non-surgical glove usage for invasive procedures, for example, intubation or insertion of intravascular devices. Finally, we collected qualitative data on incentives for hand hygiene. RESULTS: A total of 28 operations were observed (60 h of observations). On average, 0.14 hand-hygiene applications per hour per staff member were witnessed. Upon entering or leaving the OT, hand hygiene was performed in 2% (7/363) and 8% (28/333) of opportunities. CONCLUSIONS: Frequent interactions between patient, staff, and OT environment were observed. Adherence to hand-hygiene guidelines by OT staff was extremely low. This potentially exposes patients to microbial transmission, HCAIs, and patient harm. PMID- 21665901 TI - Comparison between an uncalibrated pulse contour method and thermodilution technique for cardiac output estimation in septic patients. AB - BACKGROUND: The purpose of this study was to evaluate the reliability of a new uncalibrated pulse contour method, the MostCare, in determining cardiac output (CO) in septic patients. METHODS: Thirty patients with septic shock admitted to an intensive care unit, receiving a norepinephrine infusion and requiring haemodynamic monitoring with a pulmonary artery catheter, were prospectively enrolled. Thermodilution measurements of CO (ThD-CO) were considered as the 'gold standard'. MostCare was connected to the monitoring system of the radial arterial pressure waveform to obtain a continuous CO calculation (MostCare-CO). ThD-CO and MostCare-CO measurements were recorded at three different haemodynamic states: baseline (T1), after raising mean arterial pressure (MAP) to 90 mm Hg by increasing the norepinephrine infusion (T2), and after returning the MAP to baseline value by decreasing vasopressor therapy (T3). A Bland-Altman and linear regression analyses were performed. RESULTS: A total of 90 paired ThD-CO and MostCare-CO measures were obtained (range 4.1-13.9 litre min(-1) for ThD-CO and 4.5-13.5 litre min(-1) for MostCare-CO). A good correlation between ThD-CO and MostCare-CO was observed (R = 0.93). The mean bias between the two techniques was -0.26 litre min(-1) (sd 0.98 litre min(-1)) and the 95% limits of agreement were 2.22 to 1.70 litre min(-1). The percentage of error was 25%. Pearson's R was 0.94, 0.92, and 0.93 at T1, T2, and T3, respectively. CONCLUSIONS: MostCare-CO and ThD-CO showed a good agreement at each time of the study. The reliability of the MostCare system was not affected by the vascular tone changes produced by a norepinephrine infusion. PMID- 21665902 TI - Photoprotective effect of flax seed oil (Linum usitatissimum L.) against ultraviolet C-induced apoptosis and oxidative stress in rats. AB - The aim of this study is to determine antioxidant and antiapoptotic effects of flax seed oil (FSO) on rats exposed to ultraviolet C (UVC). Malondialdehyde (MDA), protein carbonyl (PC) and reduced glutathione (GSH) levels as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were measured in lens, skin and serum. In addition, beta-carotene, vitamin A, C and E contents were measured in serum, while apoptosis was determined in retina. Rats were divided into three groups as control, UVC and UVC + FSO. UVC and UVC + FSO groups were exposed to UVC light for 1 h twice a day for 4 weeks. FSO (4 ml/kg bw) was given by gavage before each irradiation period to the UV + FSO group. While MDA and PC levels of the UVC group increased compared to the control group, their levels decreased in the UVC + FSO group compared with the UVC group in skin, lens and serum. Skin GSH level decreased significantly in the UVC and UVC + FSO groups. As GPx and SOD activities of the UVC group were lower, their activities were higher in the UVC + FSO group in skin, lens and serum. There was only marked elevation of vitamin A level in the UVC group compared to the control group. Apoptosis increased in the UVC group and the UVC + FSO groups in retina. However, retinal apoptosis were lower in the UVC + FSO group compared with the UVC group. This investigation demonstrated that UVC exposure led to oxidative stress and apoptosis in rats as reflected by increased MDA, PC contents and decreased enzymatic and nonenzymatic antioxidant levels, FSO may be useful for preventing photoreactive damage. PMID- 21665903 TI - Lead hepatotoxicology: a study in an animal model. AB - The increasing use of lead (Pb) for industrial purposes has resulted in the significant increase in environmental contamination of our planet especially in concern to water and food. In this study using the electron scanning microscopy (SEM), the authors showed the effects of this metal as a result of a chronic and cumulative process. As a primary method of detection of Pb in situ, SEM was chosen, coupled with a detection system Noran Voyager of basic microanalysis X ray (SEM-XRM), with detection system energy dispersive spectrometry. Mice BALB/c was used as a study model. An animal model of inflammation was used, that consisted in the formation of a subcutaneous pocket of air. It was observed that 75% of Pb stock was captured by the liver, the main target organ in the capture of the metal, the kidney was the second organ to capture the Pb stock and the third was the spleen. It was verified that a low deposition of Pb was found in the lungs and the brain. The main results of this study showed how Pb is captured by different organs. We also demonstrated the vulnerability to inflammation of this metal. PMID- 21665904 TI - Chronic toxicity of pesticides to the mRNA expression levels of metallothioneins and cytochrome P450 1A genes in rainbow trout. AB - The hazardous effects of pesticides on various metabolic pathways are a great problem for environmental health and should be well determined. In the present study, the authors treated rainbow trout with 0.6 MUg/L deltamethrin for 28 days and 1.6 mg/L 2,2-dichlorovinyl dimethyl phosphate for 21 days. After this time period, the authors observed alterations in mRNA expression levels of MT-A, MT-B and CYP-1A. Chronic exposure to low levels of pesticides may have a more significant effect on fish populations than acute poisoning. While both pesticides caused a significant increase on mRNA levels of MT-A and CYP-1A, MT-B mRNA levels were increased significantly only upon deltamethin administration. The significant increase in mRNA levels of the corresponding genes may be considered as a defence mechanism in addition to the antioxidants against oxidative stress, as well as a detoxification mechanism against adverse effects of pesticides. PMID- 21665905 TI - Changing epidemiology of central venous catheter-related bloodstream infections: increasing prevalence of Gram-negative pathogens. AB - OBJECTIVES: Gram-positive microorganisms have been the predominant pathogens in central venous catheter-related bloodstream infections (CRBSIs). Recent guidelines recommend empirical therapy according to this and restrict coverage for Gram-negatives to specific circumstances. This study aimed to analyse the epidemiological changes in CRBSIs over the 1991-2008 period and to analyse predictors of Gram-negative CRBSIs. PATIENTS AND METHODS: A prospectively collected cohort of patients with confirmed CRBSIs was analysed. Strains isolated and antimicrobial susceptibility, as well as clinical and demographic variables were recorded. Differences observed during the study period were analysed by means of a chi2 trend test and factors associated with Gram-negative CRBSIs by means of multivariable analysis. RESULTS: Between 1991 and 2008, 1129 episodes of monomicrobial CRBSIs were recorded. There was an increase in the incidence of CRBSIs, from 0.10 (1991-92) to 0.31 (2007-08) episodes/1000 patient-days. A significant increase in the number of Gram-negative strains among the total isolates was also found, from 3 (4.7%) in 1991-92 to 70 (40.23%) in 2007-08, with a parallel decrease in the percentage of Gram-positives. Solid organ transplantation, prior use of penicillins and hospital stay longer than 11 days were independently associated with a significantly higher risk of Gram-negative CRBSIs, while cirrhosis, diabetes and use of quinolones were associated with a higher risk of Gram-positives. CONCLUSIONS: Gram-negative strains are an increasing cause of CRBSIs, reaching a prevalence of 40% in the 2007-08 period in our hospital. If this trend is confirmed in other centres, a broad-spectrum empirical therapy should be considered in managing these infections. PMID- 21665906 TI - Ceftazidime-hydrolysing beta-lactamase OXA-145 with impaired hydrolysis of penicillins in Pseudomonas aeruginosa. AB - OBJECTIVES: To describe a novel extended-spectrum oxacillinase, named OXA-145, differing from narrow-spectrum OXA-35 (from the OXA-10 group) by deletion of residue Leu-165. The genetic environment of bla(OXA-145) and the biochemical properties of OXA-145 are reported. We also assessed the impact of the Leu-165 deletion on the hydrolysis spectrum of the ancestor OXA-10. METHODS: Extended spectrum beta-lactamase OXA-145 was identified in the multidrug-resistant clinical Pseudomonas aeruginosa 08-056, and characterized by isoelectric focusing, PCR and DNA sequencing. Antibiotic susceptibility tests were performed by agar dilution. The resistance profiles conferred by cloned bla(OXA-10), bla(OXA-35), bla(OXA-145) and a bla(OXA-10) derivative obtained by site-directed mutagenesis were determined in Escherichia coli. Kinetic parameters of OXA-35 and OXA-145 were established after purification of His-tagged proteins. RESULTS: The sequence of OXA-145, encoded by a class 1 integron-borne gene in strain 08-056, differed from that of narrow-spectrum penicillinase OXA-35 by a single amino acid deletion (Leu-165) located in the highly conserved omega loop. Deletion of Leu 165 from OXA-35 (yielding OXA-145) or OXA-10 (the progenitor of OXA-35) extended the hydrolysis spectrum to third-generation cephalosporins and to monobactams, while reducing that for penicillins. OXA-145 showed biphasic hydrolysis curves for all the substrates tested. Its activity against nitrocefin was 10-fold higher in the presence of sodium hydrogen carbonate. CONCLUSIONS: OXA-145 is a new extended-spectrum beta-lactamase from the OXA-10 group. The deletion of Leu-165 is responsible for a shift in the hydrolysis spectrum from penicillins to third generation cephalosporins, as well as monobactams. The loss of penicillin hydrolysis was due to a non-carboxylated Lys-73. PMID- 21665907 TI - Neoadjuvant gemcitabine plus cisplatin for muscle-invasive bladder cancer. AB - OBJECTIVE: Downstaging by neoadjuvant chemotherapy improves the survival of patients with muscle-invasive bladder cancer. In salvage setting, gemcitabine plus cisplatin has demonstrated an efficacy similar to that of methotrexate, vinblastine, doxorubicin and cisplatin with less toxicity. Therefore, the application of neoadjuvant gemcitabine plus cisplatin is also being anticipated. METHODS: Twenty-two patients who received neoadjuvant gemcitabine plus cisplatin were evaluated. The rate of downstaging, chemotherapy delivery profile and toxicity data were assessed. As comparator group, nine patients who were administered with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were evaluated. RESULTS: A mean of 1.9 cycles of neoadjuvant gemcitabine plus cisplatin were performed. Achieved drug intensity for gemcitabine and cisplatin was 83.8 and 95.4%. Downstaging to pT0 and 160 min) cTnI peak value was higher in CB patients (p=0.044). HTK and CB cardioplegic solutions assure similar myocardial protection in patients undergoing thoracic aorta operations. In long cross-clamp times, the lower post-operative cTnI release detected using HTK may be indicative of a better myocardial protection in these extreme conditions. PMID- 21665912 TI - Relationships between antithrombin activity, anticoagulant efficacy of heparin therapy and perioperative variables in patients undergoing cardiac surgery requiring cardiopulmonary bypass. AB - INTRODUCTION: A study on 149 cardiopulmonary bypass (CPB) patients was performed to elucidate possible relationships between antithrombin (AT) activity and a subject's clinical profile or surgery characteristics. METHODS: An initial dose (300 IU/kg) of heparin was administered before CPB. Additional boluses (100 IU/kg) were administered if the activated clotting time (ACT)<=460 s. AT activity and hematological parameters were determined preoperatively, during and after CPB, and at 12, 24, 36, and 48 hours post-intervention. RESULTS: 29.5% patients required an additional dose of heparin during CPB. Preoperative AT was 96.5 +/- 13.9% in all but 4 patients. AT was significantly lower during CPB and upon leaving the operating room (59.7%-80.0%). A small, but significant, inverse correlation was observed between AT at the end of CPB and the patient's age, as well as between basal preoperative AT and total heparin administered. CONCLUSIONS: Patient's age could be a moderate indicator of AT activity drop and low preoperative AT activity could be a sign of reduced anticoagulant efficacy of heparin during CPB. PMID- 21665913 TI - Global profiling of signaling networks: study of breast cancer stem cells and potential regulation. AB - There is overwhelming evidence that breast cancer may be driven by a small subset of breast cancer stem cells (BCSCs) that display stem/progenitor cell properties. In the present study, we identified the rare population of BCSCs, the so-called side population (SP) cells, using flow cytometry. Then, we used microarray analysis to study the differential gene expression profiles between SP and non-SP cells. Sixty-three probe sets showed a more than fourfold difference. Next, we compared the levels of proteins with Pathway Array using 154 antibodies, focusing on the proteins and phosphorylation sites that differed among SP cells, malignant mammary cells, and breast cancer tissues. Our results revealed that 40 proteins and phosphorylation sites were more than 1.5-fold different in SP cells than in non-SP cells. By comparing SP cells, MCF7 cells, and nontumorigenic MCF10A cells, we found 12 proteins that were significantly upregulated in SP cells; these proteins-cAMP-response element binding protein (CREB), cyclic AMP-dependent transcription factor 1, mesothelin, thyroid transcription factor 1, phosphorylated (p)-focal adhesion kinase, p38, Bad, p-CREB, p-protein kinase C (PKC)delta, Wee1, cell division cycle 42, and Twist-were more likely to play important roles in the signaling regulation of BCSCs. Further, 16 proteins and phosphoproteins showed differential expression in SP cells and tumor tissues. beta-catenin, p-PKCalpha, and p-CREB were upregulated in both SP cells and breast tumors. Finally, we filtered the differential expression proteins, summarized the pathway interactions of these proteins, and rebuilt Path-Net in order to determine molecular mechanisms and core regulators. This process will allow us to identify signature patterns and mechanisms of signaling networks in BCSCs. PMID- 21665914 TI - Potential prognostic biomarkers for bone metastasis from hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) most commonly develops in patients who have a viral infection, especially in the case of hepatitis B virus (HBV), and in patients with a chronic liver disease. HCC patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. Identification of patients who are at high risk for BM after undergoing potentially curative treatment for HCC remains challenging. Here, we aimed to identify HCC BM-related genes and proteins to establish prediction biomarkers. METHODS: RNA was extracted from 48 pairs of intratumoral and peritumoral formalin fixed, paraffin-embedded tissue from HCC patients with and without BM. A cDNA mediated annealing, selection, extension and ligation assay containing 502 cancer related genes was used to identify novel BM-associated genes. An additional independent study with 350 HCC patients who had undergone hepatectomy was conducted to evaluate the expression of candidate genes at the protein level using immunohistochemistry on tissue microarrays (TMAs). Of the 350 patients, 273 (78.0%) were infected with HBV. RESULTS: Seven intratumoral genes and 17 peritumoral genes were overexpressed in patients with BM, whereas 15 intratumoral genes and 28 peritumoral genes were underexpressed in patients with BM. We selected the following four genes for further analysis because they were differentially expressed in the cancer gene-specific microarray and were previously reported to be associated with BM: connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), transforming growth factor beta1 (TGF beta1), and interleukin-11 (IL-11). We assessed the protein expression of these selected genes using immunohistochemistry on TMAs including 350 HCC patient specimens. We determined that expression of intratumoral CTGF, intratumoral IL 11, and peritumoral MMP-1 were independent prognostic factors for developing BM in HCC patients. Combining intratumoral CTGF and IL-11 expression was also an independent risk factor for BM development. CONCLUSIONS: Sixty-seven genes were differentially expressed in HCC patients with and without BM. High intratumoral CTGF, positive IL-11, and high peritumoral MMP-1 expression were associated with BM after hepatectomy. Intratumoral CTGF expression combined with IL-11 expression may serve as a useful predictive biomarker for HCC BM. PMID- 21665915 TI - Localization of the Arabidopsis senescence- and cell death-associated BFN1 nuclease: from the ER to fragmented nuclei. AB - Plant senescence- or PCD-associated nucleases share significant homology with nucleases from different organisms. However, knowledge of their function is limited. Intracellular localization of the Arabidopsis senescence- and PCD associated nuclease BFN1 was investigated. Analysis of BFN1-GFP localization in transiently transformed tobacco protoplasts revealed initial localization in filamentous structures spread throughout the cytoplasm, which then clustered around the nuclei as the protoplasts senesced. These filamentous structures were identified as being of ER origin. In BFN1-GFP-transgenic Arabidopsis plants, similar localization of BFN1-GFP was observed in young leaves, that is, in filamentous structures that reorganized around the nuclei only in senescing cells. In late senescence, BFN1-GFP was localized with fragmented nuclei in membrane-wrapped vesicles. BFN1's postulated function as a nucleic acid-degrading enzyme in senescence and PCD is supported by its localization pattern. Our results suggest the existence of a dedicated compartment mediating nucleic acid degradation in senescence and PCD processes. PMID- 21665916 TI - Plant cell and signaling biology blooms in the Wuyi mountain. PMID- 21665917 TI - Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes. AB - OBJECTIVE: To analyse clinicoepidemiological features of neuromyelitis optica in a large cohort and to compare the differences between onset age, gender and clinical phenotypes. METHODS: Antiaquaporin-4 antibody (AQP4-ab) levels were tested in 2366 serum samples of patients diagnosed as having central nervous system inflammatory demyelinating disorders by their referring physicians. AQP4 ab was measured by indirect immunofluorescence staining using human AQP4 transfected HEK 293 cells. A blinded analysis was performed and was combined with clinical information. RESULTS: A total of 583 patients (91.4% women) were AQP4-ab positive. The average onset age was 42.9+/-15.9 years. According to MRI studies, spinal-cord lesions were detected in 85.3% of the patients, longitudinally extensive transverse myelitis in 72.7% and cerebral lesions in 51.1%. Unilateral or bilateral blindness was observed in 16.2% of patients, 19.8% were associated with Sjogren syndrome, and 13.6% were associated with thyroid diseases. Myelin basic protein was detected in the cerebrospinal fluid of 57.5% patients. In addition, men presented with an older onset age, a greater number of brainstem MRI lesions and positive myelin basic protein in the cerebrospinal fluid. All child-onset patients (<15 years, n=9) presented with optic neuritis as the first symptom, while older-onset patients presented with myelitis. Twenty patients initially developed limited brain lesions, and seven of these patients did not develop optic or spinal lesions during the 1-5-year follow-up period. CONCLUSIONS: The clinical characteristics of AQP4-ab-positive patients were similar. However, optic neuritis was more common in paediatric patients, while myelitis was more common in older patients. A small number of patients exhibited only cerebral, brainstem, or cerebellar lesions during the initial several years and lower Extended Disability Status Scale scores. PMID- 21665918 TI - Hypofractionated stereotactic radiotherapy with CyberKnife for nonfunctioning pituitary adenoma: high local control with low toxicity. AB - The aim was to evaluate the clinical outcome of hypofractionated stereotactic radiotherapy (SRT) with CyberKnife for nonfunctioning pituitary adenoma. From October 2000 to March 2009, 100 patients with nonfunctioning pituitary adenoma were treated with hypofractionated SRT. Forty-three patients were male, and 57 were female. The patient's ages ranged from 16 to 82 years (median, 59 years). Five patients were medically inoperable, and 1 refused surgery; the remaining 94 were recurrent cases or those receiving postoperative adjuvant SRT. No patients had a history of previous cranial radiotherapy. Tumor volume ranged from 0.7 to 64.3 mL (median, 5.1 mL). The marginal doses were 17.0 to 21.0 Gy for the 3 fraction schedule and 22.0 to 25.0 Gy for the 5-fraction schedule. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events version 4.0. The median follow-up period for living patients was 33 months (range, 18 118.5 months). The 3-year overall survival and local control rates were 98% and 98%, respectively. In-field and out-field tumor regrowth were observed in 3 and 2 patients, respectively. Transient cyst enlargement occurred in 3 cases. A post SRT grade 2 visual disorder occurred in 1 patient. Symptomatic post-SRT hypopituitarism was observed in 3 of 74 patients who had not received hormone replacement therapy after surgery. CyberKnife SRT involving 21 Gy in 3 fractions or 25 Gy in 5 fractions is safe and effective for surgical treatment of nonfunctioning pituitary adenoma. Hypofractionated SRT appears useful for protecting the visual nerve and neuroendocrine function, especially for tumors located near the optic pathways and large tumors. PMID- 21665919 TI - Risk markers of late high-degree atrioventricular block in patients with left ventricular dysfunction after an acute myocardial infarction: a CARISMA substudy. AB - AIMS: High-degree atrioventricular block (HAVB) after acute myocardial infarction (AMI) is associated with increased risk of mortality. Risk markers and predictors of HAVB occurring after AMI are largely unknown. The aim of this study was to assess the predictive value of risk markers derived from a series of non-invasive and invasive tests for the development of HAVB documented by an implantable loop recorder (ILR) in late convalescent phases of an AMI. METHODS AND RESULTS: The study included 292 patients with AMI and subsequent left ventricular dysfunction without prior HAVB or implanted pacemaker. An ILR was implanted for continuous arrhythmia surveillance. Risk stratification testing was performed at inclusion and 6 weeks after AMI. The tests included echocardiography, electrocardiogram (ECG), 24 h Holter monitoring, and an invasive electrophysiological study. High degree atrioventricular block was documented in 28 (10%) patients during a median follow-up of 2.0 (0.4-2.0) years. Heart rate variability (HRV) measures and non sustained ventricular tachycardia occurring at the week 6 Holter monitoring were highly predictive of HAVB. Power law slope <-1.5 ms(2)/Hz was the most powerful HRV parameter (HR = 6.02 [2.08-17.41], P < 0.001). CONCLUSION: Late HAVB development in post-AMI patients with left ventricular dysfunction can be predicted by risk stratification tests. Measures of HRV reflecting autonomic dysfunction revealed the highest predictive capabilities. PMID- 21665921 TI - Taking the plunge: California Grunion embryos emerge rapidly with environmentally cued hatching. AB - The process of hatching has been well studied in some model species of teleosts: the medaka Oryzias latipes, the mummichog Fundulus heteroclitus, and the zebrafish Danio rerio. These models are compared to the California Grunion, Leuresthes tenuis that has some unique features of reproduction related to tidal synchrony of spawning and environmentally cued hatching (ECH). During oviposition at spring tides, this marine teleost spawns out of water to bury its clutches on sandy beaches in the high intertidal zone. After embryos of L. tenuis reach hatching competence, hatching can be triggered at any time. Incubation above the water line inhibits hatching until ECH is triggered by rising tides during the following lunar phase, and hatching occurs within a few seconds. We review the embryo's response to environmental cues at hatching and the effects of the surrounding medium on the chorionase and chorion for this form of ECH. Leuresthes tenuis shares some similarities as well as some important differences with the model species. Comparison of hatching across teleostean taxa indicates great variability in stage at hatching and in duration of incubation that suggest hatching plasticity in response to environmental cues may be more widespread than currently appreciated. PMID- 21665920 TI - Relationship between T-wave alternans magnitude and T-wave amplitude before the onset of ventricular tachyarrhythmias during emergent reperfusion in acute coronary syndrome patients. PMID- 21665922 TI - Evaluation of caustics and household detergents exposures in an emergency service. AB - OBJECTIVE: The aim of this study was to analyse the caustic and household detergent exposure cases were admitted to the Department of Emergency Medicine at Dokuz Eylul University Hospital (EMDEU) between 1993 and 2008. METHODS: Age, sex, reason of exposure, clinical signs, rate of endoscopy in oral exposures, treatment attempts, length of hospital stay and outcome were evaluated. A chi square test was used to analyse statistical differences. RESULTS: Caustic exposures accounted for 8.5% (1160 cases) and 4.1% (1988 cases) of all poisonings in children and adults, respectively. Female/male ratio of caustic exposure poisonings was 0.8. Most of the exposures were unintentional (158, 86.8%). Intentional exposures were common in cases between 19 and 29 years old (chi(2) = 25.685, p < 0.001). The most common caustic substance was alkaline (106, 58.3%) followed by acidic (47, 25.8%) and other household detergents (28, 15.4%). Vomiting (35.7%), nausea (14.8%) and sore throat (13.1%) were the most common clinical signs. The patients who had endoscopy, the most frequent finding was first-degree damage (58.7%). A 48-year-old man died from intentional hydrochloric acid ingestion. CONCLUSION: Because of the large number of unintentional caustic exposures, parent education is very important to decrease the caustic exposures in children. PMID- 21665923 TI - Detecting selection in immunoglobulin sequences. AB - The ability to detect selection by analyzing mutation patterns in experimentally derived immunoglobulin (Ig) sequences is a critical part of many studies. Such techniques are useful not only for understanding the response to pathogens, but also to determine the role of antigen-driven selection in autoimmunity, B cell cancers and the diversification of pre-immune repertoires in certain species. Despite its importance, quantifying selection in experimentally derived sequences is fraught with difficulties. The necessary parameters for statistical tests (such as the expected frequency of replacement mutations in the absence of selection) are non-trivial to calculate, and results are not easily interpretable when analyzing more than a handful of sequences. We have developed a web server that implements our previously proposed Focused binomial test for detecting selection. Several features are integrated into the web site in order to facilitate analysis, including V(D)J germline segment identification with IMGT alignment, batch submission of sequences and integration of additional test statistics proposed by other groups. We also implement a Z-score-based statistic that increases the power of detecting selection while maintaining specificity, and further allows for the combined analysis of sequences from different germlines. The tool is freely available at http://clip.med.yale.edu/selection. PMID- 21665924 TI - SA-Mot: a web server for the identification of motifs of interest extracted from protein loops. AB - The detection of functional motifs is an important step for the determination of protein functions. We present here a new web server SA-Mot (Structural Alphabet Motif) for the extraction and location of structural motifs of interest from protein loops. Contrary to other methods, SA-Mot does not focus only on functional motifs, but it extracts recurrent and conserved structural motifs involved in structural redundancy of loops. SA-Mot uses the structural word notion to extract all structural motifs from uni-dimensional sequences corresponding to loop structures. Then, SA-Mot provides a description of these structural motifs using statistics computed in the loop data set and in SCOP superfamily, sequence and structural parameters. SA-Mot results correspond to an interactive table listing all structural motifs extracted from a target structure and their associated descriptors. Using this information, the users can easily locate loop regions that are important for the protein folding and function. The SA-Mot web server is available at http://sa-mot.mti.univ-paris-diderot.fr. PMID- 21665925 TI - AquaSAXS: a web server for computation and fitting of SAXS profiles with non uniformally hydrated atomic models. AB - Small Angle X-ray Scattering (SAXS) techniques are becoming more and more useful for structural biologists and biochemists, thanks to better access to dedicated synchrotron beamlines, better detectors and the relative easiness of sample preparation. The ability to compute the theoretical SAXS profile of a given structural model, and to compare this profile with the measured scattering intensity, yields crucial structural informations about the macromolecule under study and/or its complexes in solution. An important contribution to the profile, besides the macromolecule itself and its solvent-excluded volume, is the excess density due to the hydration layer. AquaSAXS takes advantage of recently developed methods, such as AquaSol, that give the equilibrium solvent density map around macromolecules, to compute an accurate SAXS/WAXS profile of a given structure and to compare it to the experimental one. Here, we describe the interface architecture and capabilities of the AquaSAXS web server (http://lorentz.dynstr.pasteur.fr/aquasaxs.php). PMID- 21665926 TI - The impact of unruptured intracranial aneurysm repair in headache management: putting the data into clinical practice. PMID- 21665927 TI - Cactus: Algorithms for genome multiple sequence alignment. AB - Much attention has been given to the problem of creating reliable multiple sequence alignments in a model incorporating substitutions, insertions, and deletions. Far less attention has been paid to the problem of optimizing alignments in the presence of more general rearrangement and copy number variation. Using Cactus graphs, recently introduced for representing sequence alignments, we describe two complementary algorithms for creating genomic alignments. We have implemented these algorithms in the new "Cactus" alignment program. We test Cactus using the Evolver genome evolution simulator, a comprehensive new tool for simulation, and show using these and existing simulations that Cactus significantly outperforms all of its peers. Finally, we make an empirical assessment of Cactus's ability to properly align genes and find interesting cases of intra-gene duplication within the primates. PMID- 21665929 TI - General Medical Council accuses hospital trust's medical director of dishonesty. PMID- 21665928 TI - Genome-wide detection of novel regulatory RNAs in E. coli. AB - The intergenic regions in bacterial genomes can contain regulatory leader sequences and small RNAs (sRNAs), which both serve to modulate gene expression. Computational analyses have predicted the presence of hundreds of these noncoding regulatory RNAs in Escherichia coli; however, only about 80 have been experimentally validated. By applying a deep-sequencing approach, we detected and quantified the vast majority of the previously validated regulatory elements and identified 10 new sRNAs and nine new regulatory leader sequences in the intergenic regions of E. coli. Half of the newly discovered sRNAs displayed enhanced stability in the presence of the RNA-binding protein Hfq, which is vital to the function of many of the known E. coli sRNAs. Whereas previous methods have often relied on phylogenetic conservation to identify regulatory leader sequences, only five of the newly discovered E. coli leader sequences were present in the genomes of other enteric species. For those newly identified regulatory elements having orthologs in Salmonella, evolutionary analyses showed that these regions encoded new noncoding elements rather than small, unannotated protein-coding transcripts. In addition to discovering new noncoding regulatory elements, we validated 53 sRNAs that were previously predicted but never detected and showed that the presence, within intergenic regions, of sigma(70) promoters and sequences with compensatory mutations that maintain stable RNA secondary structures across related species is a good predictor of novel sRNAs. PMID- 21665930 TI - New gallery celebrates life and work of Britain's first woman doctor. PMID- 21665931 TI - Global health diplomacy: how foreign policy can influence health. AB - Ilona Kickbusch argues that public health experts need to work with diplomats in order to achieve global health goals. PMID- 21665932 TI - Do antidepressants improve negative symptoms in schizophrenia? PMID- 21665933 TI - Diagnosis and management of ectopic pregnancy. PMID- 21665934 TI - World's one billion people with disabilities face widespread barriers to healthcare. PMID- 21665935 TI - Ambulance service puts too much emphasis on response time to detriment of overall care, says National Audit Office. PMID- 21665936 TI - Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. AB - During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E cadherin, with mesenchymal proteins including vimentin, N-cadherin and O cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs. PMID- 21665937 TI - Notch1 inhibition alters the CD44hi/CD24lo population and reduces the formation of brain metastases from breast cancer. AB - Brain metastasis from breast cancer is an increasingly important clinical problem. Here we assessed the role of CD44(hi)/CD24(lo) cells and pathways that regulate them, in an experimental model of brain metastasis. Notch signaling (mediated by gamma-secretase) has been shown to contribute to maintenance of the cancer stem cell (CSC) phenotype. Cells sorted for a reduced stem-like phenotype had a reduced ability to form brain metastases compared with unsorted or CD44(hi)/CD24(lo) cells (P < 0.05; Kruskal-Wallis). To assess the effect of gamma secretase inhibition, cells were cultured with DAPT and the CD44/CD24 phenotypes quantified. 231-BR cells with a CD44(hi)/CD24(lo) phenotype was reduced by about 15% in cells treated with DAPT compared with DMSO-treated or untreated cells (P = 0.001, ANOVA). In vivo, mice treated with DAPT developed significantly fewer micro- and macrometastases compared with vehicle treated or untreated mice (P = 0.011, Kruskal-Wallis). Notch1 knockdown reduced the expression of CD44(hi)/CD24(lo) phenotype by about 20%. In vitro, Notch1 shRNA resulted in a reduction in cellular growth at 24, 48, and 72 hours time points (P = 0.033, P = 0.002, and P = 0.009, ANOVA) and about 60% reduction in Matrigel invasion was observed (P < 0.001, ANOVA). Cells transfected with shNotch1 formed significantly fewer macrometastases and micrometastases compared with scrambled shRNA or untransfected cells (P < 0.001; Kruskal-Wallis). These data suggest that the CSC phenotype contributes to the development of brain metastases from breast cancer, and this may arise in part from increased Notch activity. PMID- 21665939 TI - The N-terminal domain of G3BP enhances cell motility and invasion by posttranscriptional regulation of BART. AB - The regulation of mRNA stability plays an important role in the control of gene expression during cell motility and invasion. We previously reported that GTPase activating protein [Src homology 3 (SH3) domain] binding protein (G3BP), a marker of cytoplasmic stress granules that are formed in stressed cells and regulate mRNA stability, binds and degrades the mRNA of binder of Arl two (BART) that inhibits retroperitoneal invasion and hepatic metastasis of pancreatic cancer cells. Here, we report that overexpression of the amino (N)-terminal region of G3BP, including the binding region for BART mRNA, dominant-negatively inhibits formation of the complex between endogenous G3BP and BART mRNA, and increases the expression of BART. This, in turn, inhibits the invasiveness of pancreatic cancer cells. On the other hand, the carboxy (C)-terminal region of G3BP is associated with phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) that initiates stress granule assembly but does not modulate the posttranscriptional regulation of BART mRNA. N-terminal G3BP also plays a role in regulating secreted matrix metalloproteinases, transcription factors, and a variety of genes involved in cell adhesion and motility. These results suggest that N-terminal G3BP contributes to posttranscriptional regulation of cell motility and invasive capacity of pancreatic cancer. PMID- 21665938 TI - Fibroblast growth factor receptor mediates fibroblast-dependent growth in EMMPRIN depleted head and neck cancer tumor cells. AB - Head and neck squamous cell carcinoma tumors (HNSCC) contain a dense fibrous stroma which is known to promote tumor growth, although the mechanism of stroma mediated growth remains unclear. As dysplastic mucosal epithelium progresses to cancer, there is incremental overexpression of extracellular matrix metalloprotease inducer (EMMPRIN) which is associated with tumor growth and metastasis. Here, we present evidence that gain of EMMPRIN expression allows tumor growth to be less dependent on fibroblasts by modulating fibroblast growth factor receptor-2 (FGFR2) signaling. We show that silencing EMMPRIN in FaDu and SCC-5 HNSCC cell lines inhibits cell growth, but when EMMPRIN-silenced tumor cells were cocultured with fibroblasts or inoculated with fibroblasts into severe combined immunodeficient mice, the growth inhibition by silencing EMMPRIN was blunted by the presence of fibroblasts. Coculture experiments showed fibroblast dependent tumor cell growth occurred via a paracrine signaling. Analysis of tumor gene expression revealed expression of FGFR2 was inversely related to EMMPRIN expression. To determine the role of FGFR2 signaling in EMMPRIN-silenced tumor cells, ligands and inhibitors of FGFR2 were assessed. Both FGF1 and FGF2 enhanced tumor growth in EMMPRIN-silenced cells compared with control vector-transfected cells, whereas inhibition of FGFR2 with blocking antibody or with a synthetic inhibitor (PD173074) inhibited tumor cell growth in fibroblast coculture, suggesting the importance of FGFR2 signaling in fibroblast-mediated tumor growth. Analysis of xenografted tumors revealed that EMMPRIN-silenced tumors had a larger stromal compartment compared with control. Taken together, these results suggest that EMMPRIN acquired during tumor progression promotes fibroblast-independent tumor growth. PMID- 21665940 TI - Control of VEGF expression in triple-negative breast carcinoma cells by suppression of SAF-1 transcription factor activity. AB - Angiogenesis plays a significant role in cancer by providing increased blood supply to the affected tissues and thus bringing in growth factors, cytokines, and various nutrients for tumor growth. VEGF is the most prominent angiogenic agent that is markedly induced in cancer. Induction of VEGF has been widely studied but as cancer cells are quite adept at acquiring new alternative processes to circumvent surrounding environmental pressures, our understanding of the molecular mechanisms regulating VEGF expression in cancer, especially in triple-negative breast cancer cells, remains incomplete. Here, we present evidence of a novel mode of VEGF induction in triple-negative MDA-MB-231 breast cancer cells that is regulated by serum amyloid A activating factor 1 (SAF-1) transcription factor. Inhibition of SAF-1 by antisense short hairpin RNA profoundly reduces VEGF expression along with reduction in endothelial cell proliferation and migration. By both in vitro and in vivo molecular studies, we show that the effect of SAF-1 is mediated through its direct interaction with the VEGF promoter. In correlation, DNA-binding activity of SAF-1 is found to be significantly higher in MDA-MB-231 breast cancer cells. Examination of several breast cancer samples further revealed that SAF-1 is overexpressed in clinical breast cancer tissues. Taken together, these findings reveal that SAF-1 is a hitherto unrecognized participant in inducing VEGF expression in triple-negative breast cancer cells, an aggressive form of breast cancer that currently lacks effective treatment options. Suppression of SAF-1 activity in these cells can inhibit VEGF expression, providing a possible new method to control angiogenesis. PMID- 21665941 TI - Nicotine reduces L-DOPA-induced dyskinesias by acting at beta2* nicotinic receptors. AB - L-DOPA-induced dyskinesias or abnormal involuntary movements (AIMs) are a debilitating adverse complication associated with prolonged L-DOPA administration for Parkinson's disease. Few treatments are currently available for dyskinesias. Our recent data showed that nicotine reduced L-DOPA-induced AIMs in parkinsonian animal models. An important question is the nicotinic acetylcholine receptor (nAChR) subtypes through which nicotine exerts this beneficial effect, because such knowledge would allow for the development of drugs that target the relevant receptor population(s). To address this, we used beta2 nAChR subunit knockout [beta2(-/-)] mice because beta2-containing nAChRs are key regulators of nigrostriatal dopaminergic function. All of the mice were lesioned by intracranial injection of 6-hydroxydopamine into the right medial forebrain bundle. Lesioning resulted in a similar degree of nigrostriatal damage and parkinsonism in beta2(-/-) and wild-type mice. All of the mice then were injected with L-DOPA (3 mg/kg) plus benserazide (15 mg/kg) once daily for 4 weeks until AIMs were fully developed. L-DOPA-induced AIMs were approximately 40% less in the beta2(-/-) mice compared with the wild-type mice. It is interesting to note that nicotine (300 MUg/ml in drinking water) reduced L-DOPA-induced AIMs by 40% in wild-type mice but had no effect in beta2(-/-) mice with partial nigrostriatal damage. The nicotine-mediated decline in AIMs was much less pronounced in wild type mice with near-complete degeneration, suggesting that presynaptic nAChRs on dopaminergic terminals have a major influence. These data demonstrate an essential role for beta2* nAChRs in the antidyskinetic effect of nicotine and suggest that drugs targeting these subtypes may be useful for the management of L DOPA-induced dyskinesias in Parkinson's disease. PMID- 21665943 TI - Therapeutic effect of lecithinized superoxide dismutase on pulmonary emphysema. AB - No medication exists that clearly improves the mortality of chronic obstructive pulmonary disease (COPD). Oxidative molecules, in particular superoxide anions, play important roles in the COPD-associated abnormal inflammatory response and pulmonary emphysema, which arises because of an imbalance in proteases and antiproteases and increased apoptosis. Superoxide dismutase (SOD) catalyzes the dismutation of superoxide anions. Lecithinized human Cu/Zn- SOD (PC-SOD) has overcome a number of the clinical limitations of SOD, including low tissue affinity and low stability in plasma. In this study, we examine the effect of PC SOD on elastase-induced pulmonary emphysema, an animal model of COPD. The severity of the pulmonary inflammatory response and emphysema in mice was assessed by various criteria, such as the number of leukocytes in the bronchoalveolar lavage fluid and the enlargement of airspace. Not only intravenous administration but also inhalation of PC-SOD suppressed elastase induced pulmonary inflammation, emphysema, and dysfunction. Inhalation of PC-SOD suppressed the elastase-induced increase in the pulmonary level of superoxide anions and apoptosis. Inhalation of PC-SOD also suppressed elastase-induced activation of proteases and decreased in the level of antiproteases and expression of proinflammatory cytokines and chemokines. We also found that inhalation of PC-SOD suppressed cigarette smoke-induced pulmonary inflammation. The results suggest that PC-SOD protects against pulmonary emphysema by decreasing the pulmonary level of superoxide anions, resulting in the inhibition of inflammation and apoptosis and amelioration of the protease/antiprotease imbalance. We propose that inhalation of PC-SOD would be therapeutically beneficial for COPD. PMID- 21665942 TI - The soluble guanylyl cyclase activator YC-1 increases intracellular cGMP and cAMP via independent mechanisms in INS-1E cells. AB - In addition to increasing cGMP, the soluble guanylyl cyclase (sGC) activator 3 (5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) can elevate intracellular cAMP levels. This response was assumed to be as a result of cGMP-dependent inhibition of cAMP phosphodiesterases; however, in this study, we show that YC-1 induced cAMP production in the rat pancreatic beta cell line INS-1E occurs independent of its function as a sGC activator and independent of its ability to inhibit phosphodiesterases. This YC-1-induced cAMP increase is dependent upon soluble adenylyl cyclase and not on transmembrane adenylyl cyclase activity. We previously showed that soluble adenylyl cyclase-generated cAMP can lead to extracellular signal-regulated kinase activation and that YC-1-stimulated cAMP production also stimulates extracellular signal-regulated kinase. Although YC-1 has been used as a tool for investigating sGC and cGMP-mediated pathways, this study reveals cGMP-independent pharmacological actions of this compound. PMID- 21665944 TI - Cross-reactivity of ryanodine receptors with plasma membrane ion channel modulators. AB - Various pharmacological agents designed to modulate plasma membrane ion channels seem to significantly affect intracellular Ca2+ signaling when acting on their target receptor. Some agents could also cross-react (modulate channels or receptors beyond their putative target) with intracellular Ca2+ transporters. This study investigated the potential of thirty putative modulators of either plasma membrane K+, Na+, or transient receptor potential (TRP) channels to cross react with intracellular Ca2+ release channels [i.e., ryanodine receptors (RyRs)] from skeletal muscle sarcoplasmic reticulum (SR). Screening for cross-reactivity of these various agents was performed by measuring the rate of spontaneous Ca2+ leak or caffeine-induced Ca2+ release from SR microsomes. Four of the agents displayed a strong cross-reactivity and were further evaluated with skeletal RyR (RyR1) reconstituted into planar bilayers. 6,12,19,20,25,26-Hexahydro 5,27:13,18:21,24-trietheno-11,7-metheno-7H-dibenzo [b,n][1,5,12,16]tetraazacyclotricosine-5, 13-diium dibromide (UCL 1684; K+ channel antagonist) and lamotrigine (Na+ channel antagonist) were found to significantly inhibit the RyR1-mediated caffeine-induced Ca2+ release. TRP channel agonists anandamide and (-)menthol were found to inhibit and activate RyR1, respectively. High concentrations of nine other agents produced partial inhibition of RyR1-mediated Ca2+ release from SR microsomes. Various pharmacological agents, especially TRP modulators, also inhibited a minor RyR1 independent component of the SR Ca2+ leak. Overall, ~43% of the agents selected cross-reacted with RyR1-mediated and/or RyR1-independent Ca2+ leak from intracellular stores. Thus, cross-reactivity should be considered when using these classes of pharmacological agents to determine the role of plasmalemmal channels in Ca2+ homeostasis. PMID- 21665945 TI - Ubp15p, a ubiquitin hydrolase associated with the peroxisomal export machinery. AB - Peroxisomal matrix protein import is facilitated by cycling receptors shuttling between the cytosol and the peroxisomal membrane. One crucial step in this cycle is the ATP-dependent release of the receptors from the peroxisomal membrane. This step is facilitated by the peroxisomal AAA (ATPases associated with various cellular activities) proteins Pex1p and Pex6p with ubiquitination of the receptor being the main signal for its export. Here we report that the AAA complex contains dislocase as well as deubiquitinating activity. Ubp15p, a ubiquitin hydrolase, was identified as a novel constituent of the complex. Ubp15p partially localizes to peroxisomes and is capable of cleaving off ubiquitin moieties from the type I peroxisomal targeting sequence (PTS1) receptor Pex5p. Furthermore, Ubp15p-deficient cells are characterized by a stress-related PTS1 import defect. The results merge into a picture in which removal of ubiquitin from the PTS1 receptor Pex5p is a specific event and might represent a vital step in receptor recycling. PMID- 21665946 TI - Characterization of sparstolonin B, a Chinese herb-derived compound, as a selective Toll-like receptor antagonist with potent anti-inflammatory properties. AB - Blockade of excessive Toll-like receptor (TLR) signaling is a therapeutic approach being actively pursued for many inflammatory diseases. Here we report a Chinese herb-derived compound, sparstolonin B (SsnB), which selectively blocks TLR2- and TLR4-mediated inflammatory signaling. SsnB was isolated from a Chinese herb, Spaganium stoloniferum; its structure was determined by NMR spectroscopy and x-ray crystallography. SsnB effectively inhibited inflammatory cytokine expression in mouse macrophages induced by lipopolysaccharide (LPS, a TLR4 ligand), Pam3CSK4 (a TLR1/TLR2 ligand), and Fsl-1 (a TLR2/TLR6 ligand) but not that by poly(I:C) (a TLR3 ligand) or ODN1668 (a TLR9 ligand). It suppressed LPS induced cytokine secretion from macrophages and diminished phosphorylation of Erk1/2, p38a, IkappaBalpha, and JNK in these cells. In THP-1 cells expressing a chimeric receptor CD4-TLR4, which triggers constitutive NF-kappaB activation, SsnB effectively blunted the NF-kappaB activity. Co-immunoprecipitation showed that SsnB reduced the association of MyD88 with TLR4 and TLR2, but not that with TLR9, in HEK293T cells and THP-1 cells overexpressing MyD88 and TLRs. Furthermore, administration of SsnB suppressed splenocyte inflammatory cytokine expression in mice challenged with LPS. These results demonstrate that SsnB acts as a selective TLR2 and TLR4 antagonist by blocking the early intracellular events in the TLR2 and TLR4 signaling. Thus, SssB may serve as a promising lead for the development of selective TLR antagonistic agents for inflammatory diseases. PMID- 21665947 TI - Mitotic modulation of translation elongation factor 1 leads to hindered tRNA delivery to ribosomes. AB - Translation elongation in eukaryotes is mediated by the concerted actions of elongation factor 1A (eEF1A), which delivers aminoacylated tRNA to the ribosome; elongation factor 1B (eEF1B) complex, which catalyzes the exchange of GDP to GTP on eEF1A; and eEF2, which facilitates ribosomal translocation. Here we present evidence in support of a novel mode of translation regulation by hindered tRNA delivery during mitosis. A conserved consensus phosphorylation site for the mitotic cyclin-dependent kinase 1 on the catalytic delta subunit of eEF1B (termed eEF1D) is required for its posttranslational modification during mitosis, resulting in lower affinity to its substrate eEF1A. This modification is correlated with reduced availability of eEF1A.tRNA complexes, as well as reduced delivery of tRNA to and association of eEF1A with elongating ribosomes. This mode of regulation by hindered tRNA delivery, although first discovered in mitosis, may represent a more globally applicable mechanism employed under other physiological conditions that involve down-regulation of protein synthesis at the elongation level. PMID- 21665948 TI - Quantitative transcriptomic profiling of branching in a glycosphingolipid biosynthetic pathway. AB - Cellular biosynthesis of macromolecules often involves highly branched enzyme pathways, thus cellular regulation of such pathways could be rather difficult. To understand the regulatory mechanism, a systematic approach could be useful. We genetically analyzed a branched biosynthetic pathway for glycosphingolipid (GSL) GM1 using correlation index-based responsible enzyme gene screening (CIRES), a novel quantitative phenotype-genotype correlation analysis. CIRES utilizes transcriptomic profiles obtained from multiple cells. Among a panel of B cell lines, expression of GM1 was negatively correlated with and suppressed by gene expression of CD77 synthase (CD77Syn), whereas no significant positive correlation was found for enzymes actually biosynthesizing GM1. Unexpectedly, a GM1-suppressive phenotype was also observed in the expression of catalytically inactive CD77Syn, ruling out catalytic consumption of lactosylceramide (LacCer) as the main cause for such negative regulation. Rather, CD77Syn seemed to limit other branching reaction(s) by targeting LacCer synthase (LacCerSyn), a proximal enzyme in the pathway, because they were closely localized in the Golgi apparatus and formed a complex. Moreover, turnover of LacCerSyn was accelerated upon CD77Syn expression to globally change the GSL species expressed. Collectively, these data suggest that transcriptomic assessment of macromolecule biosynthetic pathways can disclose a global regulatory mechanism(s) even when unexpected. PMID- 21665949 TI - Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase. AB - Lysyl oxidase (LOX), a matrix cross-linking protein, is known to be selectively expressed and to enhance a fibrotic phenotype. A recent study of ours showed that LOX oxidizes the PDGF receptor-beta (PDGFR-beta), leading to amplified downstream signaling. Here, we examined the expression and functions of LOX in megakaryocytes (MKs), the platelet precursors. Cells committed to the MK lineage undergo mitotic proliferation to yield diploid cells, followed by endomitosis and acquisition of polyploidy. Intriguingly, LOX expression is detected in diploid tetraploid MKs, but scarce in polyploid MKs. PDGFR-BB is an inducer of mitotic proliferation in MKs. LOX inhibition with beta-aminopropionitrile reduces PDGFR BB binding to cells and downstream signaling, as well as its proliferative effect on the MK lineage. Inhibition of LOX activity has no influence on MK polyploidy. We next rationalized that, in a system with an abundance of low ploidy MKs, LOX could be highly expressed and with functional significance. Thus, we resorted to GATA-1(low) mice, where there is an increase in low ploidy MKs, augmented levels of PDGF-BB, and an extensive matrix of fibers. MKs from these mice display high expression of LOX, compared with control mice. Importantly, treatment of GATA 1(low) mice with beta-aminopropionitrile significantly improves the bone marrow fibrotic phenotype, and MK number in the spleen. Thus, our in vitro and in vivo data support a novel role for LOX in regulating MK expansion by PDGF-BB and suggest LOX as a new potential therapeutic target for myelofibrosis. PMID- 21665950 TI - Soluble oligomers of amyloid-beta peptide disrupt membrane trafficking of alpha amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor contributing to early synapse dysfunction. AB - beta-Amyloid (Abeta), a peptide generated from the amyloid precursor protein, is widely believed to underlie the pathophysiology of Alzheimer disease (AD). Emerging evidences suggest that soluble Abeta oligomers adversely affect synaptic function, leading to cognitive failure associated with AD. The Abeta-induced synaptic dysfunction has been attributed to the synaptic removal of alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (AMPARs). However, the molecular mechanisms underlying the loss of AMPAR induced by Abeta at synapses are largely unknown. In this study we have examined the effect of Abeta oligomers on phosphorylated GluA1 at serine 845, a residue that plays an essential role in the trafficking of AMPARs toward extrasynaptic sites and the subsequent delivery to synapses during synaptic plasticity events. We found that Abeta oligomers reduce basal levels of Ser-845 phosphorylation and surface expression of AMPARs affecting AMPAR subunit composition. Abeta-induced GluA1 dephosphorylation and reduced receptor surface levels are mediated by an increase in calcium influx into neurons through ionotropic glutamate receptors and activation of the calcium-dependent phosphatase calcineurin. Moreover, Abeta oligomers block the extrasynaptic delivery of AMPARs induced by chemical synaptic potentiation. In addition, reduced levels of total and phosphorylated GluA1 are associated with initial spatial memory deficits in a transgenic mouse model of AD. These findings indicate that Abeta oligomers could act as a synaptic depressor affecting the mechanisms involved in the targeting of AMPARs to the synapses during early stages of the disease. PMID- 21665951 TI - Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. AB - Hypokalemic periodic paralysis (hypoKPP) is characterized by episodic flaccid paralysis of muscle and acute hypokalemia during attacks. Familial forms of hypoKPP are predominantly caused by mutations of either voltage-gated Ca(2+) or Na(+) channels. The pathogenic gene mutation in non-familial hypoKPP, consisting mainly of thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP), is largely unknown. Recently, mutations in KCNJ18, which encodes a skeletal muscle-specific inwardly rectifying K(+) channel Kir2.6, were reported in some TPP patients. Whether mutations of Kir2.6 occur in other patients with non-familial hypoKPP and how mutations of the channel predispose patients to paralysis are unknown. Here, we report one conserved heterozygous mutation in KCNJ18 in two TPP patients and two separate heterozygous mutations in two SPP patients. These mutations result in V168M, R43C, and A200P amino acid substitution of Kir2.6, respectively. Compared with the wild type channel, whole cell currents of R43C and V168M mutants were reduced by ~78 and 43%, respectively. No current was detected for the A200P mutant. Single channel conductance and open probability were reduced for R43C and V168M, respectively. Biotinylation assays showed reduced cell surface abundance for R43C and A200P. All three mutants exerted dominant negative inhibition on wild type Kir2.6 as well as wild type Kir2.1, another Kir channel expressed in the skeletal muscle. Thus, mutations of Kir2.6 are associated with SPP as well as TPP. We suggest that decreased outward K(+) current from hypofunction of Kir2.6 predisposes the sarcolemma to hypokalemia-induced paradoxical depolarization during attacks, which in turn leads to Na(+) channel inactivation and inexcitability of muscles. PMID- 21665952 TI - Importin-alpha protein binding to a nuclear localization signal of carbohydrate response element-binding protein (ChREBP). AB - Carbohydrate response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in the glucose-mediated induction of genes involved in hepatic glycolysis and lipogenesis. Circulating blood glucose levels affect ChREBP activity in hepatocytes largely by post translational mechanisms that include phosphorylation-dependent subcellular localization. Previously, we showed that ChREBP is retained in the cytosol by phosphorylation-dependent binding to 14-3-3 protein dimers and identified the alpha2 helix (residues 125-135) phospho-Ser(140) domain as the primary 14-3-3 binding site (Sakiyama, H., Wynn, R. M., Lee, W. R., Fukasawa, M., Mizuguchi, H., Gardner, K. H., Repa, J. J., and Uyeda, K. (2008) J. Biol. Chem. 283, 24899 24908). To enter the nucleus in response to high glucose, ChREBP must bind importin-alpha; this heterodimer then forms a complex with importin-beta to interact with the nuclear pore complex. In this work, we recharacterized the importin-alpha binding nuclear localization signal (NLS) of rat ChREBP, identifying it as an extended classical bipartite NLS encompassing minimally residues 158-190. Replacing Lys(159)/Lys(190) residues of ChREBP with alanine resulted in loss of importin-alpha binding, glucose-stimulated transcriptional activity and nuclear localization. A secondary 14-3-3 protein binding site also was identified, the alpha3 helix (residues 170-190) phospho-Ser(196) domain. Importin-alpha and 14-3-3 were found to bind competitively to this secondary site. These results suggest an important mechanism by which importin-alpha and 14 3-3 control movement of ChREBP in and out of the nucleus in response to changes in glucose levels in liver and thus further suggest that the extended NLS of ChREBP is a critical glucose-sensing, glucose-responsive site. PMID- 21665953 TI - Dual inhibition of alpha/beta-hydrolase domain 6 and fatty acid amide hydrolase increases endocannabinoid levels in neurons. AB - Agonists at cannabinoid receptors, such as the phytocannabinoid Delta(9) tetrahydrocannabinol, exert a remarkable array of therapeutic effects but are also associated with undesirable psychoactive side effects. Conversely, targeting enzymes that hydrolyze endocannabinoids (eCBs) allows for more precise fine tuning of cannabinoid receptor signaling, thus providing therapeutic relief with reduced side effects. Here, we report the development and characterization of an inhibitor of eCB hydrolysis, UCM710, which augments both N arachidonoylethanolamine and 2-arachidonoylglycerol levels in neurons. This compound displays a unique pharmacological profile in that it inhibits fatty acid amide hydrolase and alpha/beta-hydrolase domain 6 but not monoacylglycerol lipase. Thus, UCM710 represents a novel tool to delineate the therapeutic potential of compounds that manipulate a subset of enzymes that control eCB signaling. PMID- 21665954 TI - Facilitation and Ca2+-dependent inactivation are modified by mutation of the Ca(v)1.2 channel IQ motif. AB - The heart muscle responds to physiological needs with a short-term modulation of cardiac contractility. This process is determined mainly by properties of the cardiac L-type Ca(2+) channel (Ca(v)1.2), including facilitation and Ca(2+) dependent inactivation (CDI). Both facilitation and CDI involve the interaction of calmodulin with the IQ motif of the Ca(v)1.2 channel, especially with Ile 1624. To verify this hypothesis, we created a mouse line in which Ile-1624 was mutated to Glu (Ca(v)1.2(I1624E) mice). Homozygous Ca(v)1.2(I1624E) mice were not viable. Therefore, we inactivated the floxed Ca(v)1.2 gene of heterozygous Ca(v)1.2(I1624E) mice by the alpha-myosin heavy chain-MerCreMer system. The resulting I/E mice were studied at day 10 after treatment with tamoxifen. Electrophysiological recordings in ventricular cardiomyocytes revealed a reduced Ca(v)1.2 current (I(Ca)) density in I/E mice. Steady-state inactivation and recovery from inactivation were modified in I/E versus control mice. In addition, voltage-dependent facilitation was almost abolished in I/E mice. The time course of I(Ca) inactivation in I/E mice was not influenced by the use of Ba(2+) as a charge carrier. Using 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid as a chelating agent for intracellular Ca(2+), inactivation of I(Ca) was slowed down in control but not I/E mice. The results show that the I/E mutation abolishes Ca(2+)/calmodulin-dependent regulation of Ca(v)1.2. The Ca(v)1.2(I1624E) mutation transforms the channel to a phenotype mimicking CDI. PMID- 21665955 TI - Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. AB - BACKGROUND: Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a large group of patients treated with pertuzumab. PATIENTS AND METHODS: A complete database of patients treated with full-dose pertuzumab was used to describe the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) and symptomatic heart failure (HF). RESULTS: Information for 598 unique patients was available for the current analysis. Of the patients treated with pertuzumab alone (n = 331) or pertuzumab in combination with a non-anthracycline-containing cytotoxic (n = 175) or trastuzumab (n = 93), 23 (6.9%), 6 (3.4%), and 6 (6.5%), respectively, developed asymptomatic LVSD and 1 (0.3%), 2 (1.1%), and 1 (1.1%), respectively, displayed symptomatic HF. None of the 15 patients receiving both pertuzumab and erlotinib demonstrated LVSD. CONCLUSIONS: Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects when pertuzumab was given in combination with other anticancer agents. PMID- 21665956 TI - Distinct pathophysiological mechanisms of cardiomyopathy in hearts lacking dystrophin or the sarcoglycan complex. AB - Duchenne muscular dystrophy (DMD) and limb girdle muscular dystrophy (LGMD) 2C-F result from the loss of dystrophin and the sarcoglycans, respectively. Dystrophin, a cytoskeletal protein, is closely associated with the membrane-bound sarcoglycan complex. Despite this tight biochemical association, the function of dystrophin and the sarcoglycan subunits may differ. The loss of dystrophin in skeletal muscle results in muscle that is highly susceptible to contraction induced damage, but the skeletal muscle of mice lacking gamma- or delta sarcoglycan are less susceptible. Using mouse models of DMD, LGMD-2C, and LGMD 2F, we demonstrate that isolated cardiac myocytes from mice lacking either gamma- or delta-sarcoglycan have normal compliance. In contrast, dystrophin-deficient myocytes display poor passive compliance and are susceptible to terminal contracture following mild passive extensions. Mice deficient in dystrophin and, less so, delta-sarcoglycan have reduced survival during in vivo dobutamine stress testing compared to controls. Catheter-based hemodynamic studies show deficits in both baseline and dobutamine-stimulated cardiac function in all of the dystrophic mice compared to control mice, with dystrophin-deficient mice having the poorest function. In contrast, histopathology showed increased fibrosis in the sarcoglycan-deficient hearts, but not in hearts lacking dystrophin. In summary, this study provides important insights into the unique mechanisms of disease underlying these different models of inherited dystrophic cardiomyopathy and supports a model where dystrophin, but not the sarcoglycans, protects the cardiac myocyte against mechanical damage. PMID- 21665957 TI - Molecular basis of the tarantula toxin jingzhaotoxin-III (beta-TRTX-Cj1alpha) interacting with voltage sensors in sodium channel subtype Nav1.5. AB - With conserved structural scaffold and divergent electrophysiological functions, animal toxins are considered powerful tools for investigating the basic structure function relationship of voltage-gated sodium channels. Jingzhaotoxin-III (beta TRTX-Cj1alpha) is a unique sodium channel gating modifier from the tarantula Chilobrachys jingzhao, because the toxin can selectively inhibit the activation of cardiac sodium channel but not neuronal subtypes. However, the molecular basis of JZTX-III interaction with sodium channels remains unknown. In this study, we showed that JZTX-III was efficiently expressed by the secretory pathway in yeast. Alanine-scanning analysis indicated that 2 acidic residues (Asp1, Glu3) and an exposed hydrophobic patch, formed by 4 Trp residues (residues 8, 9, 28 and 30), play important roles in the binding of JZTX-III to Nav1.5. JZTX-III docked to the Nav1.5 DIIS3-S4 linker. Mutations S799A, R800A, and L804A could additively reduce toxin sensitivity of Nav1.5. We also demonstrated that the unique Arg800, not emerging in other sodium channel subtypes, is responsible for JZTX-III selectively interacting with Nav1.5. The reverse mutation D816R in Nav1.7 greatly increased the sensitivity of the neuronal subtype to JZTX-III. Conversely, the mutation R800D in Nav1.5 decreased JZTX-III's IC50 by 72-fold. Therefore, our results indicated that JZTX-III is a site 4 toxin, but does not possess the same critical residues on sodium channels as other site 4 toxins. Our data also revealed the underlying mechanism for JZTX-III to be highly specific for the cardiac sodium channel. PMID- 21665958 TI - Impact of participation in TimeSlips, a creative group-based storytelling program, on medical student attitudes toward persons with dementia: a qualitative study. AB - PURPOSE: To evaluate whether medical student participation in TimeSlips (TS), a creative group-based storytelling program, with persons affected by dementia would improve student attitudes toward this patient population. DESIGN AND METHODS: Fifteen fourth-year medical students from Penn State College of Medicine participated in a month-long regimen of TS sessions at a retirement community. Student course evaluations were analyzed at the conclusion of the program to examine perceived qualitative changes in attitude. FINDINGS: Qualitative data revealed insights into the manner in which student attitudes toward a geriatric patient population became more positive. IMPLICATIONS: This is the first known pilot study to suggest that participation in a creative group-based storytelling program might improve medical student attitudes toward persons with dementia. PMID- 21665959 TI - The 'T-cell-ness' of NK cells: unexpected similarities between NK cells and T cells. AB - NK cells are considered as prototypical innate immune cells. However, recent discoveries have tended to refine the dogmatic concepts of innate and adaptive immunity. In many ways, NK cells are highly related to T cells and represent the closest innate immune cell lineage to adaptive immune cell populations. Here, we review the relationships between NK cells and T cells and discuss the recently described cell-intrinsic-adaptive features of NK cells. PMID- 21665961 TI - Quantitative characterization of postnatal growth trends in proximal pulmonary arteries in rats by phase-contrast magnetic resonance imaging. AB - Malformations of the pulmonary arteries can increase right heart workload and result in morbidity, heart failure, and death. With the increased use of murine models to study these malformations, there is a pressing need for an accurate and noninvasive experimental technique that is capable of characterizing pulmonary arterial hemodynamics in these animals. We describe the growth trends of pulmonary arteries in 13 male Sprague-Dawley rats at 20, 36, 52, 100, and 160 days of age with the introduction of phase-contrast MRI as such a technique. PCMRI results correlated closely with cardiac output measurements by ultrasound echocardiography and with fluorescent microspheres in right-left lung flow split (flow partition). Mean flow, average cross-sectional area, distensibility, and shear rates for the right and left pulmonary arteries (RPA and LPA) were calculated. The RPA was larger and received more flow at all times than the LPA (P < 0.0001). Right-left flow split did not change significantly with age, and arterial distensibility was not significantly different between RPA and LPA, except at 160 days (P < 0.01). Shear rates were much higher for the LPA than the RPA (P < 0.0001) throughout development. The RPA and LPA showed different structure-function relationships but obeyed similar allometric scaling laws, with scaling exponents comparable to those of the main pulmonary artery. This study is the first to quantitatively describe changes in RPA and LPA flows and sizes with development and to apply phase-contrast MRI techniques to pulmonary arteries in rats. PMID- 21665960 TI - Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis. AB - Earlier work from this laboratory demonstrated that apoptosis of alveolar epithelial cells (AECs) requires autocrine generation of angiotensin (ANG) II. More recent studies showed that angiotensin converting enzyme-2 (ACE-2), which degrades ANGII to form ANG1-7, is protective but severely downregulated in human and experimental lung fibrosis. Here it was theorized that ACE-2 and its product ANG1-7 might therefore regulate AEC apoptosis. To evaluate this hypothesis, the AEC cell line MLE-12 and primary cultures of rat AECs were exposed to the profibrotic apoptosis inducers ANGII or bleomycin (Bleo). Markers of apoptosis (caspase-9 or -3 activation and nuclear fragmentation), steady-state ANGII and ANG1-7, and JNK phosphorylation were measured thereafter. In the absence of Bleo, inhibition of ACE-2 by small interfering RNA or by a competitive inhibitor (DX600 peptide) caused a reciprocal increase in autocrine ANGII and corresponding decrease in ANG1-7 in cell culture media (both P < 0.05) and, moreover, induced AEC apoptosis. At baseline (without inhibitor), ANG1-7 in culture media was 10 fold higher than ANGII (P < 0.01). Addition of purified ANGII or bleomycin induced caspase activation, nuclear fragmentation, and JNK phosphorylation in cultured AECs. However, preincubation with ANG1-7 (0.1 MUM) prevented JNK phosphorylation and apoptosis. Moreover, pretreatment with A779, a specific blocker of the ANG1-7 receptor mas, prevented ANG1-7 blockade of JNK phosphorylation, caspase activation, and nuclear fragmentation. These data demonstrate that ACE-2 regulates AEC survival by balancing the proapoptotic ANGII and its antiapoptotic degradation product ANG1-7. They also suggest that ANG1-7 inhibits AEC apoptosis through the ANG1-7 receptor mas. PMID- 21665962 TI - Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries. AB - Hypoxic contraction of pulmonary arterial smooth muscle is thought to require increases in both intracellular Ca(2+) concentration ([Ca(2+)](i)) and myofilament Ca(2+) sensitivity, which may or may not be endothelium-dependent. To examine the effects of hypoxia and endothelium on Ca(2+) sensitivity in pulmonary arterial smooth muscle, we measured the relation between [Ca(2+)](i) and isometric force at 37 degrees C during normoxia (21% O(2)-5% CO(2)) and after 30 min of hypoxia (1% O(2)-5% CO(2)) in endothelium-intact (E+) and -denuded (E-) rat distal intrapulmonary arteries (IPA) permeabilized with staphylococcal alpha toxin. Endothelial denudation enhanced Ca(2+) sensitivity during normoxia but did not alter the effects of hypoxia, which shifted the [Ca(2+)](i)-force relation to higher force in E+ and E- IPA. Neither hypoxia nor endothelial denudation altered Ca(2+) sensitivity in mesenteric arteries. In E+ and E- IPA, hypoxic enhancement of Ca(2+) sensitivity was abolished by the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (30 MUM), which shifted normoxic [Ca(2+)](i)-force relations to higher force. In E- IPA, the Rho kinase antagonist Y-27632 (10 MUM) shifted the normoxic [Ca(2+)](i)-force relation to lower force but did not alter the effects of hypoxia. These results suggest that acute hypoxia enhanced myofilament Ca(2+) sensitivity in rat IPA by decreasing nitric oxide production and/or activity in smooth muscle, thereby revealing a high basal level of Ca(2+) sensitivity, due in part to Rho kinase, which otherwise did not contribute to Ca(2+) sensitization by hypoxia. PMID- 21665963 TI - Organic dust augments nucleotide-binding oligomerization domain expression via an NF-{kappa}B pathway to negatively regulate inflammatory responses. AB - Nucleotide-binding oligomerization domain 2 (NOD2) is involved in innate immune responses to peptidoglycan degradation products. Peptidoglycans are important mediators of organic dust-induced airway diseases in exposed agriculture workers; however, the role of NOD2 in response to complex organic dust is unknown. Monocytes/macrophages were exposed to swine facility organic dust extract (ODE), whereupon NOD2 expression was evaluated by real-time PCR and Western blot. ODE induced significant NOD2 mRNA and protein expression at 24 and 48 h, respectively, which was mediated via a NF-kappaB signaling pathway as opposed to a TNF-alpha autocrine/paracrine mechanism. Specifically, NF-kappaB translocation increased rapidly following ODE stimulation as demonstrated by EMSA, and inhibition of the NF-kappaB pathway significantly reduced ODE-induced NOD2 expression. However, there was no significant reduction in ODE-induced NOD2 gene expression when TNF-alpha was inhibited or absent. Next, it was determined whether NOD2 regulated ODE-induced inflammatory cytokine production. Knockdown of NOD2 expression by small interfering RNA resulted in increased CXCL8 and IL-6, but not TNF-alpha production in response to ODE. Similarly, primary lung macrophages from NOD2 knockout mice demonstrated increased IL-6, CXCL1, and CXCL1, but not TNF-alpha, expression. Lastly, a higher degree of airway inflammation occurred in the absence of NOD2 following acute (single) and repetitive (3 wk) ODE exposure in an established in vivo murine model. In summary, ODE-induced NOD2 expression is directly dependent on NF-kappaB signaling, and NOD2 is a negative regulator of complex, organic dust-induced inflammatory cytokine/chemokine production in mononuclear phagocytes. PMID- 21665965 TI - Different conformations of the kinase-on and kinase-off signaling states in the Aer HAMP domain. AB - HAMP domains are sensory transduction modules that connect input and output domains in diverse signaling proteins from archaea, bacteria, and lower eukaryotes. Here, we employed in vivo disulfide cross-linking to explore the structure of the HAMP domain in the Escherichia coli aerotaxis receptor Aer. Using an Aer HAMP model based on the structure of Archaeoglobus fulgidus Af1503 HAMP, the closest residue pairs at the interface of the HAMP AS-1 and AS-2' helices were determined and then replaced with cysteines and cross-linked in vivo. Except for a unique discontinuity in AS-2, the data suggest that the Aer HAMP domain forms a parallel four-helix bundle that is similar to the structure of Af1503. The HAMP discontinuity was associated with a segment of AS-2 that was recently shown to interact with the Aer-PAS sensing domain. The four-helix HAMP bundle and its discontinuity were maintained in both the kinase-on and kinase-off states of Aer, although differences in the rates of disulfide formation also indicated the existence of different HAMP conformations in the kinase-on and kinase-off states. In particular, the kinase-on state was accompanied by significantly increased disulfide formation rates at the distal end of the HAMP four-helix bundle. This indicates that HAMP signaling may be associated with a tilting of the AS-1 and AS-2' helices, which may be the signal that is transmitted to the kinase control region of Aer. PMID- 21665964 TI - Pulmonary and systemic inflammatory responses to intra-amniotic IL-1alpha in fetal sheep. AB - Clinical and epidemiological studies implicate IL-1 as an important mediator of perinatal inflammation. We tested the hypothesis that intra-amniotic IL-1alpha would induce pulmonary and systemic fetal inflammatory responses. Sheep with singleton fetuses were given an intra-amniotic injection of recombinant sheep IL 1alpha (100 MUg) and were delivered 1, 3, or 7 days later, at 124 +/- 1 days gestation (n=5-8/group). A separate group of sheep were given two intra-amniotic IL-1alpha injections (100 MUg dose each): 7 days and again 1 day prior to delivery. IL-1alpha induced a robust increase in monocytes, neutrophils, lymphocytes, and IL-8 protein in bronchoalveolar lavage fluid. H(2)O(2) secretion was increased in inflammatory cells isolated from lungs of IL-1alpha-exposed lambs upon LPS challenge in vitro compared with control monocytes. T lymphocytes were recruited to the lung. IL-1beta, cyclooxygenase-1, and cyclooxygenase-2 mRNA expression increased in the lung 1 day after intra-amniotic IL-1alpha exposure. Lung volumes increased 7 days after intra-amniotic IL-1alpha exposure, with minimal anatomic changes in air space morphology. The weight of the posterior mediastinal lymph node draining the lung and the gastrointestinal tract doubled, inducible nitric oxide synthase (NOSII)-positive cells increased, and Foxp3 positive T-regulatory lymphocytes decreased in the lymph node after IL-1alpha exposure. In the blood, neutrophil counts and plasma haptoglobin increased after IL-1alpha exposure. Compared with a single exposure, exposure to intra-amniotic IL-1alpha 7 days and again 1 day before delivery had a variable effect (increases in some inflammatory markers, but not pulmonary cytokines). IL-1alpha is a potent mediator of the fetal inflammatory response syndrome. PMID- 21665966 TI - Self-transmissibility of the integrative and conjugative element ICEPm1 between clinical isolates requires a functional integrase, relaxase, and type IV secretion system. AB - Integrative and conjugative elements (ICEs), which are chromosomal mobile elements, can conjugatively transfer between bacteria. Recently, we identified a genomic island of Proteus mirabilis, a common agent of catheter-associated urinary tract infection (UTI), that possesses all the properties consistent with an ICE. This element, designated ICEPm1, is highly conserved in other causative agents of UTI, suggesting its mobility. We demonstrate that ICEPm1 can actively excise from the chromosome in a clonal population of bacteria and that this excision is integrase dependent. Although in P. mirabilis HI4320, ICEPm1 is annotated as integrated into the phenylalanine tRNA gene pheV, we show that ICEPm1 can integrate into either pheV or pheU. We determined that ICEPm1 transfers at a frequency of 1.35 * 10(-5) transconjugants/donor to ICEPm1 deficient P. mirabilis using plate mating assays with clinical isolates. Insertional inactivation of a putative integrase gene on ICEPm1 decreased transfer frequencies of ICEPm1 to below the limit of detection. Mutation of the relaxase of ICEPm1 also eliminates transfer and demonstrates that this element is indeed self-transmissible and not transferred in trans, as are some mobilizable genomic islands. Together, these findings clearly demonstrate that ICEPm1 can actively excise from the chromosome in an integrase-dependent manner, dynamically integrate into both phenylalanine tRNA genes, and transfer into clinical strains using its own conjugation machinery. PMID- 21665967 TI - Genome-wide identification of in vivo binding sites of GlxR, a cyclic AMP receptor protein-type regulator in Corynebacterium glutamicum. AB - Corynebacterium glutamicum GlxR is a cyclic AMP (cAMP) receptor protein-type regulator. Although over 200 GlxR-binding sites in the C. glutamicum genome are predicted in silico, studies on the physiological function of GlxR have been hindered by the severe growth defects of a glxR mutant. This study identified the GlxR regulon by chromatin immunoprecipitation in conjunction with microarray (ChIP-chip) analyses. In total, 209 regions were detected as in vivo GlxR-binding sites. In vitro binding assays and promoter-reporter assays demonstrated that GlxR directly activates expression of genes for aerobic respiration, ATP synthesis, and glycolysis and that it is required for expression of genes for cell separation and mechanosensitive channels. GlxR also directly represses a citrate uptake gene in the presence of citrate. Moreover, ChIP-chip analyses showed that GlxR was still able to interact with its target sites in a mutant with a deletion of cyaB, the sole adenylate cyclase gene in the genome, even though binding affinity was markedly decreased. Thus, GlxR is physiologically functional at the relatively low cAMP levels in the cyaB mutant, allowing the cyaB mutant to grow much better than the glxR mutant. PMID- 21665968 TI - Amino acid precursor supply in the biosynthesis of the RNA polymerase inhibitor streptolydigin by Streptomyces lydicus. AB - Biosynthesis of the hybrid polyketide-nonribosomal peptide antibiotic streptolydigin, 3-methylaspartate, is utilized as precursor of the tetramic acid moiety. The three genes from the Streptomyces lydicus streptolydigin gene cluster slgE1-slgE2-slgE3 are involved in 3-methylaspartate supply. SlgE3, a ferredoxin dependent glutamate synthase, is responsible for the biosynthesis of glutamate from glutamine and 2-oxoglutarate. In addition to slgE3, housekeeping NADPH- and ferredoxin-dependent glutamate synthase genes have been identified in S. lydicus. The expression of slgE3 is increased up to 9-fold at the onset of streptolydigin biosynthesis and later decreases to ~2-fold over the basal level. In contrast, the expression of housekeeping glutamate synthases decreases when streptolydigin begins to be synthesized. SlgE1 and SlgE2 are the two subunits of a glutamate mutase that would convert glutamate into 3-methylaspartate. Deletion of slgE1 slgE2 led to the production of two compounds containing a lateral side chain derived from glutamate instead of 3-methylaspartate. Expression of this glutamate mutase also reaches a peak increase of up to 5.5-fold coinciding with the onset of antibiotic production. Overexpression of either slgE3 or slgE1-slgE2 in S. lydicus led to an increase in the yield of streptolydigin. PMID- 21665969 TI - Crystal structure of the Pseudomonas aeruginosa virulence factor regulator. AB - Virulence factor regulator (Vfr) enhances Pseudomonas aeruginosa pathogenicity through its role as a global transcriptional regulator. The crystal structure of Vfr shows that it is a winged-helix DNA-binding protein like its homologue cyclic AMP receptor protein (CRP). In addition to an expected primary cyclic AMP-binding site, a second ligand-binding site is nestled between the N-terminal domain and the C-terminal helix-turn-helix domain. Unlike CRP, Vfr is a symmetric dimer in the absence of DNA. Removal of seven disordered N-terminal residues of Vfr prevents the growth of P. aeruginosa. PMID- 21665970 TI - Uracil-DNA glycosylase of Thermoplasma acidophilum directs long-patch base excision repair, which is promoted by deoxynucleoside triphosphates and ATP/ADP, into short-patch repair. AB - Hydrolytic deamination of cytosine to uracil in DNA is increased in organisms adapted to high temperatures. Hitherto, the uracil base excision repair (BER) pathway has only been described in two archaeons, the crenarchaeon Pyrobaculum aerophilum and the euryarchaeon Archaeoglobus fulgidus, which are hyperthermophiles and use single-nucleotide replacement. In the former the apurinic/apyrimidinic (AP) site intermediate is removed by the sequential action of a 5'-acting AP endonuclease and a 5'-deoxyribose phosphate lyase, whereas in the latter the AP site is primarily removed by a 3'-acting AP lyase, followed by a 3'-phosphodiesterase. We describe here uracil BER by a cell extract of the thermoacidophilic euryarchaeon Thermoplasma acidophilum, which prefers a similar short-patch repair mode as A. fulgidus. Importantly, T. acidophilumcell extract also efficiently executes ATP/ADP-stimulated long-patch BER in the presence of deoxynucleoside triphosphates, with a repair track of ~15 nucleotides. Supplementation of recombinant uracil-DNA glycosylase (rTaUDG; ORF Ta0477) increased the formation of short-patch at the expense of long-patch repair intermediates, and additional supplementation of recombinant DNA ligase (rTalig; Ta1148) greatly enhanced repair product formation. TaUDG seems to recruit AP incising and -excising functions to prepare for rapid single-nucleotide insertion and ligation, thus excluding slower and energy-costly long-patch BER. PMID- 21665971 TI - Importance of a hydrophobic pocket for peptide binding in lactococcal OppA. AB - Lactococcal oligopeptide-binding protein A (OppA) binds peptides with widely varied lengths and sequences. We previously hypothesized that a hydrophobic pocket in OppA preferentially binds a hydrophobic peptide side chain and thus determines its binding register. Two crystal structures of OppA with different nonapeptides now indeed show binding in different registers. PMID- 21665972 TI - Proteins involved in formation of the outermost layer of Bacillus subtilis spores. AB - To investigate the outermost structure of the Bacillus subtilis spore, we analyzed the accessibility of antibodies to proteins on spores of B. subtilis. Anti-green fluorescent protein (GFP) antibodies efficiently accessed GFP fused to CgeA or CotZ, which were previously assigned to the outermost layer termed the spore crust. However, anti-GFP antibodies did not bind to spores of strains expressing GFP fused to 14 outer coat, inner coat, or cortex proteins. Anti-CgeA antibodies bound to spores of wild-type and CgeA-GFP strains but not cgeA mutant spores. These results suggest that the spore crust covers the spore coat and is the externally exposed, outermost layer of the B. subtilis spore. We found that CotZ was essential for the spore crust to surround the spore but not for spore coat formation, indicating that CotZ plays a critical role in spore crust formation. In addition, we found that CotY-GFP was exposed on the surface of the spore, suggesting that CotY is an additional component of the spore crust. Moreover, the localization of CotY-GFP around the spore depended on CotZ, and CotY and CotZ depended on each other for spore assembly. Furthermore, a disruption of cotW affected the assembly of CotV-GFP, and a disruption of cotX affected the assembly of both CotV-GFP and CgeA-GFP. These results suggest that cgeA and genes in the cotVWXYZ cluster are involved in spore crust formation. PMID- 21665973 TI - Mechanism of citrate metabolism by an oxaloacetate decarboxylase-deficient mutant of Lactococcus lactis IL1403. AB - Citrate metabolism in resting cells of Lactococcus lactis IL1403(pFL3) results in the formation of two end products from the intermediate pyruvate, acetoin and acetate (A. M. Pudlik and J. S. Lolkema, J. Bacteriol. 193:706-714, 2011). Pyruvate is formed from citrate following uptake by the transporter CitP through the subsequent actions of citrate lyase and oxaloacetate decarboxylase. The present study describes the metabolic response of L. lactis when oxaloacetate accumulates in the cytoplasm. The oxaloacetate decarboxylase-deficient mutant ILCitM(pFL3) showed nearly identical rates of citrate consumption, but the end product profile in the presence of glucose shifted from mainly acetoin to only acetate. In addition, in contrast to the parental strain, the mutant strain did not generate proton motive force. Citrate consumption by the mutant strain was coupled to the excretion of oxaloacetate, with a yield of 80 to 85%. Following citrate consumption, oxaloacetate was slowly taken up by the cells and converted to pyruvate by a cryptic decarboxylase and, subsequently, to acetate. The transport of oxaloacetate is catalyzed by CitP. The parental strain IL1403(pFL3) containing CitP consumed oxaloacetate, while the original strain, IL1403, not containing CitP, did not. Moreover, oxaloacetate consumption was enhanced in the presence of L-lactate, indicating exchange between oxaloacetate and L-lactate catalyzed by CitP. Hence, when oxaloacetate inadvertently accumulates in the cytoplasm, the physiological response of L. lactis is to excrete oxaloacetate in exchange with citrate by an electroneutral mechanism catalyzed by CitP. Subsequently, in a second step, oxaloacetate is taken up by CitP and metabolized to pyruvate and acetate. PMID- 21665974 TI - Comparative analysis of the lux operons in Aliivibrio logei KCh1 (a Kamchatka Isolate) and Aliivibrio salmonicida. AB - Here we provide a molecular description of a new psychrophilic strain, KCh11, of marine luminescent bacteria classified as Aliivibrio logei. We sequenced the entire lux operon of A. logei KCh1 and showed that it is substantially similar to the lux operon of Aliivibrio salmonicida. It was demonstrated that the reduced production of bioluminescence in A. salmonicida is most likely defined by a specific defect in its luxD gene. PMID- 21665975 TI - Role of ferredoxin and flavodoxins in Bacillus subtilis fatty acid desaturation. AB - The Bacillus subtilis acyl lipid desaturase (Delta5-Des) is an iron-dependent integral membrane protein able to selectively introduce double bonds into long chain fatty acids. In the last decade since its discovery, the molecular mechanism of Delta5-Des expression has been studied extensively. However, the mechanism of desaturation, which must rely on unknown bacterial proteins for electron transfer, has not yet been explored. The B. subtilis genome encodes three proteins that can act as potential electron donors of Delta5-Des, ferredoxin (Fer) and two flavodoxins (Flds) (YkuN and YkuP), which are encoded by the ykuNOP operon. Here we report that the disruption of either the fer gene or the ykuNOP operon decreases the desaturation of palmitic acid by ~30%. Nevertheless, a fer ykuNOP mutant abolished the desaturation reaction almost completely. Our results establish Fer and the two Flds as redox partners for Delta5-Des and suggest that the Fer and Fld proteins could function physiologically in the biosynthesis of unsaturated fatty acids in B. subtilis. Although Flds have extensively been described as partners in a number of redox processes, this is the first report describing their role as electron donors in the fatty acid desaturation reaction. PMID- 21665976 TI - Taking the Escherichia coli TonB transmembrane domain "offline"? Nonprotonatable Asn substitutes fully for TonB His20. AB - The TonB system of Gram-negative bacteria uses the proton motive force (PMF) of the cytoplasmic membrane to energize active transport of nutrients across the outer membrane. The single transmembrane domain (TMD) anchor of TonB, the energy transducer, is essential. Within that TMD, His20 is the only TMD residue that is unable to withstand alanine replacement without a loss of activity. H20 is required for a PMF-dependent conformational change, suggesting that the importance of H20 lies in its ability to be reversibly protonated and deprotonated. Here all possible residues were substituted at position 20 (H20X substitutions). The His residue was also relocated throughout the TonB TMD. Surprisingly, Asn, a structurally similar but nonprotonatable residue, supported full activity at position 20; H20S was very weakly active. All the remaining substitutions, including H20K, H20R, H20E, and H20D, the obvious candidates to mimic a protonated state or support proton translocation, were inactive. A second site suppressor, ExbB(A39E), indiscriminately reactivated the majority of H20 substitutions and relocations, including H20V, which cannot be made protonatable. These results suggested that the TonB TMD was not on a proton conductance pathway and thus only indirectly responds to PMF, probably via ExbD. PMID- 21665977 TI - Characterization of Staphylococcus aureus cardiolipin synthases 1 and 2 and their contribution to accumulation of cardiolipin in stationary phase and within phagocytes. AB - In many bacteria, including Staphylococcus aureus, progression from the logarithmic to the stationary phase is accompanied by conversion of most of bacterial membrane phosphatidylglycerol (PG) to cardiolipin (CL). Phagocytosis of S. aureus by human neutrophils also induces the conversion of most bacterial PG to CL. The genome of all sequenced strains of S. aureus contains two open reading frames (ORFs) predicting proteins encoded with ~30% identity to the principal CL synthase (cls) of Escherichia coli. To test whether these ORFs (cls1 and cls2) encode cardiolipin synthases and contribute to CL accumulation in S. aureus, we expressed these proteins in a cls strain of E. coli and created isogenic single and double mutants in S. aureus. The expression of either Cls1 or Cls2 in CL deficient E. coli resulted in CL accumulation in the stationary phase. S. aureus with deletion of both cls1 and cls2 showed no detectable CL accumulation in the stationary phase or after phagocytosis by neutrophils. CL accumulation in the stationary phase was due almost solely to Cls2, whereas both Cls1 and Cls2 contributed to CL accumulation following phagocytosis by neutrophils. Differences in the relative contributions of Cls1 and Cls2 to CL accumulation under different triggering conditions suggest differences in the role and regulation of these two enzymes. PMID- 21665978 TI - RcnB is a periplasmic protein essential for maintaining intracellular Ni and Co concentrations in Escherichia coli. AB - Nickel and cobalt are both essential trace elements that are toxic when present in excess. The main resistance mechanism that bacteria use to overcome this toxicity is the efflux of these cations out of the cytoplasm. RND (resistance nodulation-cell division)- and MFS (major facilitator superfamily)-type efflux systems are known to export either nickel or cobalt. The RcnA efflux pump, which belongs to a unique family, is responsible for the detoxification of Ni and Co in Escherichia coli. In this work, the role of the gene yohN, which is located downstream of rcnA, is investigated. yohN is cotranscribed with rcnA, and its expression is induced by Ni and Co. Surprisingly, in contrast to the effect of deleting rcnA, deletion of yohN conferred enhanced resistance to Ni and Co in E. coli, accompanied by decreased metal accumulation. We show that YohN is localized to the periplasm and does not bind Ni or Co ions directly. Physiological and genetic experiments demonstrate that YohN is not involved in Ni import. YohN is conserved among proteobacteria and belongs to a new family of proteins; consequently, yohN has been renamed rcnB. We show that the enhanced resistance of rcnB mutants to Ni and Co and their decreased Ni and Co intracellular accumulation are linked to the greater efflux of these ions in the absence of rcnB. Taken together, these results suggest that RcnB is required to maintain metal ion homeostasis, in conjunction with the efflux pump RcnA, presumably by modulating RcnA-mediated export of Ni and Co to avoid excess efflux of Ni and Co ions via an unknown novel mechanism. PMID- 21665979 TI - Coevolution of ABC transporters and two-component regulatory systems as resistance modules against antimicrobial peptides in Firmicutes Bacteria. AB - In Firmicutes bacteria, ATP-binding cassette (ABC) transporters have been recognized as important resistance determinants against antimicrobial peptides. Together with neighboring two-component systems (TCSs), which regulate their expression, they form specific detoxification modules. Both the transport permease and sensor kinase components show unusual domain architecture: the permeases contain a large extracellular domain, while the sensor kinases lack an obvious input domain. One of the best-characterized examples is the bacitracin resistance module BceRS-BceAB of Bacillus subtilis. Strikingly, in this system, the ABC transporter and TCS have an absolute mutual requirement for each other in both sensing of and resistance to bacitracin, suggesting a novel mode of signal transduction in which the transporter constitutes the actual sensor. We identified over 250 such BceAB-like ABC transporters in the current databases. They occurred almost exclusively in Firmicutes bacteria, and 80% of the transporters were associated with a BceRS-like TCS. Phylogenetic analyses of the permease and sensor kinase components revealed a tight evolutionary correlation. Our findings suggest a direct regulatory interaction between the ABC transporters and TCSs, mediating communication between both components. Based on their observed coclustering and conservation of response regulator binding sites, we could identify putative corresponding two-component systems for transporters lacking a regulatory system in their immediate neighborhood. Taken together, our results show that these types of ABC transporters and TCSs have coevolved to form self-sufficient detoxification modules against antimicrobial peptides, widely distributed among Firmicutes bacteria. PMID- 21665980 TI - The essential beta-barrel assembly machinery complex components BamD and BamA are required for autotransporter biogenesis. AB - Autotransporter biogenesis is dependent upon BamA, a central component of the beta-barrel assembly machinery (BAM) complex. In this report, we detail the role of the other BAM components (BamB-E). We identify the importance of BamD in autotransporter biogenesis and show that BamB, BamC, and BamE are not required. PMID- 21665981 TI - A sulfite respiration pathway from Thermus thermophilus and the key role of newly identified cytochrome c550. AB - Sulfite, produced for instance during amino acid metabolism, is a very reactive and toxic compound. Various detoxification mechanisms exist, but sulfite oxidoreductases (SORs) are one of the major actors in sulfite remediation in bacteria and animals. Here we describe the existence of an operon in the extreme thermophilic bacterium Thermus thermophilus HB8 encoding both a SOR and a diheme c-type cytochrome. The in vitro analysis clearly showed that the newly identified cytochrome c550 acts as an acceptor of the electrons generated by the SOR enzyme during the oxidation of sulfite. The electrons are then rapidly shuttled via cytochrome c552 to the terminal ba3- and caa3-type oxidases, thereby unveiling a novel electron transfer pathway, linking sulfite oxidation to oxygen reduction in T. thermophilus: sulfite -> SOR(HB8) -> cytochrome c550 -> cytochrome c552 -> ba3 oxidase/caa3 oxidase -> O2. The description of the complete pathway reveals that electrons generated during sulfite oxidation by the SOR are funneled into the respiratory chain, participating in the energy production of T. thermophilus. PMID- 21665982 TI - Determination of inadvertent atrial capture during para-Hisian pacing. AB - BACKGROUND: Inadvertent capture of the atrium will lead to spurious results during para-Hisian pacing. We sought to establish whether the stimulation-to atrial electrogram interval at the proximal coronary sinus (stim-PCS) or high right atrium (stim-HRA) could signal inadvertent atrial capture. METHODS AND RESULTS: Para-Hisian pacing with and without intentional atrial capture was performed in 31 patients. Stim-HRA and stim-PCS intervals were measured with atrial capture, His plus para-Hisian ventricular (H+V) capture, and para-Hisian ventricular (V) capture alone. The mean stim-HRA interval was significantly shorter with atrial capture (66 +/- 18 ms) than with H+V (121 +/- 27 ms, P < 0.001) or V capture alone (174 +/- 38 ms, P < 0.001). The mean stim-PCS interval was significantly shorter with atrial capture (51 +/- 16 ms) than with H+V (92 +/ 22 ms, P<0.001) or V capture alone (146 +/- 33 ms, P < 0.001). A stim-PCS < 60 ms (stim-HRA < 70 ms) was observed only with atrial capture. A stim-PCS >90 ms (stim-HRA >100 ms) was observed only in the absence of atrial capture. A stim-HRA of < 85 ms was highly specific and stim-PCS of < 85 ms highly sensitive at identifying atrial capture. Stim-HRA intervals of 75 to 97 ms and stim-PCS intervals of 65 to 88 ms were observed with either atrial, His, or para-Hisian ventricular capture without atrial capture. In this overlap zone, all patients demonstrated a stim-PCS or stim-HRA interval prolongation of at least 20 ms when the catheter was advanced to avoid deliberate atrial pacing. The QRS morphology was of limited value in distinguishing atrial capture due to concurrent ventricular or H+V capture, as observed in 20 of 31 (65%) patients. CONCLUSIONS: Stim-PCS and stim-HRA intervals can be used to monitor for inadvertent atrial capture during para-Hisian pacing. A stim-PCS < 60 ms (or stim-HRA < 70 ms) and stim-PCS > 90 ms (or stim-HRA > 100 ms) were observed only with and without atrial capture, respectively, but there was significant overlap between these values. Deliberate atrial capture and loss of capture reliably identifies atrial capture regardless of intervals. PMID- 21665983 TI - Ablation of ventricular arrhythmias in arrhythmogenic right ventricular dysplasia/cardiomyopathy: arrhythmia-free survival after endo-epicardial substrate based mapping and ablation. AB - BACKGROUND: In patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy, freedom from ventricular arrhythmias (VAs) after endocardial ablation is limited. We compared the long-term freedom from recurrent VAs by using endocardial-alone ablation versus endo-epicardial substrate-based ablation. METHODS AND RESULTS: Forty-nine patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy undergoing ablation of ventricular tachycardia (VT) were divided into 2 groups: endocardial-alone ablation (group 1, n = 23) and endo-epicardial ablation (group 2, n = 26). All patients had an implantable cardioverter-defibrillator (ICD). Conventional and 3D mappings were used to determine the mechanism of induced VTs and to identify area of "scar" or "abnormal" myocardium. All critical sites responsible for VTs and points with "abnormal" potential were targeted for ablation from endocardium (group 1) or from both endocardium and epicardium (group 2). The procedural end point was noninducibility of sustained, monomorphic VT with isoproterenol. The presence of frequent premature ventricular contractions at the end of ablation was recorded. Patients were followed up by ECG, Holter, and ICD interrogation. After a follow up of at least 3 years, freedom from VAs or ICD therapy was 52.2% (12/23) in group 1 and 84.6% (22/26) in group 2 (P = 0.029), with 21.7% (5/23) and 69.2% (18/26) patients off antiarrhythmic drugs (P < 0.001), respectively. Compared with patients with no premature ventricular contractions after ablation, patients with frequent premature ventricular contractions after ablation were more likely to have VA recurrence/ICD therapy [3/33 (9%) versus 12/16 (75%); log-rank P<0.001]. CONCLUSIONS: An endo-epicardial-based ablation strategy achieves higher long-term freedom from recurrent VAs off antiarrhythmic therapy in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy when compared with endocardial-alone ablation. The presence of >= 10 premature ventricular contractions per minute after ablation is associated with more VA recurrence. PMID- 21665984 TI - Owls see in stereo much like humans do. AB - While 3D experiences through binocular disparity sensitivity have acquired special status in the understanding of human stereo vision, much remains to be learned about how binocularity is put to use in animals. The owl provides an exceptional model to study stereo vision as it displays one of the highest degrees of binocular specialization throughout the animal kingdom. In a series of six behavioral experiments, equivalent to hallmark human psychophysical studies, I compiled an extensive body of stereo performance data from two trained owls. Computer-generated, binocular random-dot patterns were used to ensure pure stereo performance measurements. In all cases, I found that owls perform much like humans do, viz.: (1) disparity alone can evoke figure-ground segmentation; (2) selective use of "relative" rather than "absolute" disparity; (3) hyperacute sensitivity; (4) disparity processing allows for the avoidance of monocular feature detection prior to object recognition; (5) large binocular disparities are not tolerated; (6) disparity guides the perceptual organization of 2D shape. The robustness and very nature of these binocular disparity-based perceptual phenomena bear out that owls, like humans, exploit the third dimension to facilitate early figure-ground segmentation of tangible objects. PMID- 21665985 TI - Saccadic eye movements in a high-speed bimanual stacking task: changes of attentional control during learning and automatization. AB - Principles of saccadic eye movement control in the real world have been derived by the study of self-paced well-known tasks such as sandwich or tea making. Little is known whether these principles generalize to high-speed sensorimotor tasks and how they are affected by learning and automatization. In the present study, right-handers practiced the speed-stacking task in 14 consecutive daily training sessions, while their eye movements were recorded. Speed stacking is a high-speed sensorimotor task that requires grasping, moving, rotating, and placing of objects. The following main results emerged. Throughout practice, the eyes led the hands, displayed by a positive eye-hand time span. Moreover, visual information was gathered for the subsequent manual sub-action, displayed by a positive eye-hand unit span. With automatization, the eye-hand time span became shorter, yet it increased when corrected by the decreasing trial duration. In addition, fixations were mainly allocated to the goal positions of the right hand or objects in the right hand. The number of fixations decreased while the fixation rate remained constant. Importantly, all participants fixated on the same task-relevant locations in a similar scan path across training days, revealing a long-term memory-based mode of attention control after automatization of a high-speed sensorimotor task. PMID- 21665986 TI - Acute loading and aging effects on myostatin pathway biomarkers in human skeletal muscle after three sequential bouts of resistance exercise. AB - To determine the influence of age and resistance exercise on myostatin pathway related genes, younger (n = 10; 28 +/- 5 years) and older (n = 10; 68 +/- 6 years) men underwent four testing conditions (T1-T4). A baseline (T1) muscle sample was obtained, whereas the second and third biopsies were obtained 48 hours following the first and second training sessions (T2, T3), and a final biopsy was taken 24 hours following T3. The training sessions consisted of 3 sets of 10 repetitions (80% of one repetition maximum) on leg press, hack squat, and leg extension exercises. Follistatin (FST) messenger RNA was greater in older compared with younger men at T1 and T2 (p < .05). Follistatin-like 3 (FSTL3) messenger RNA was greater in older compared with younger men at T1 and T4 (p < .05). In older men, there was a significant decrease in myostatin (MSTN) messenger RNA at T4 (p < .05). Older men contained less active (Ser-425 phosphorylated) SMAD3 (p-SMAD3) protein than younger men at T3 and T4 (p < .05).Although it is well known that younger individuals possess a greater hypertrophic potential to resistance exercise, it appears that older individuals may paradoxically possess a more favorable resistance exercise response regarding myostatin pathway-related genes and a protein marker of pathway activity. Future research is warranted to examine the physiological significance of this age dependent mechanism. PMID- 21665987 TI - Effect of a combined treatment with growth hormone and melatonin in the cardiological aging on male SAMP8 mice. AB - The effect of a chronic combined treatment with growth hormone (GH) plus melatonin (Mel) on different age-related processes in cytosolic and nuclear fractions of hearts from SAMP8 mice (2 and 10 months) has been investigated. The parameters studied have been messenger RNA expressions of IL-1, IL-10, NFkBp50, NFkBp52, TNFalpha, eNOS, iNOS, HO-1, HO-2, BAD, BAX, and Bcl2 and protein expressions of iNOS, eNOS, TNFalpha, IL-1, IL-10, NFkBp50, NFKbp52, and caspase activity (3 and 9). Our results supported the existence of a proapoptotic and oxidative status together with inflammatory processes in the heart of old mice, with increases of inflammatory cytokines, caspase activity, HO-1, BAX, NFkBp50, and NFkBp52 and decreases of eNOS and Bcl2. Also, we were able to observe the translocation of NFkB to nuclei. The combined treatment was able to partially reduce the incidence of these deleterious changes, showing differences with the separated treatments with GH and Mel as were investigated in previous articles from our group. PMID- 21665988 TI - Genome-wide significance and replication of the chromosome 12p11.22 locus near the PTHLH gene for peripartum cardiomyopathy. AB - BACKGROUND: Peripartum (PP) cardiomyopathy (CM) is a rare condition of unknown etiology that occurs in late pregnancy or early postpartum. Initial evidence suggests that genetic factors may influence PPCM. This study evaluated and replicated genome-wide association of single nucleotide polymorphisms with PPCM. METHODS AND RESULTS: Genome-wide single nucleotide polymorphisms in women with verified PPCM diagnosis (n=41) were compared separately with local control subjects (n=49 postmenopausal age-discordant women with parity >=1 and no heart failure) and iControls (n=654 women ages 30 to 84 years with unknown phenotypes). A replication study of independent population samples used new cases (PPCM2, n=30) compared with new age-discordant control subjects (local2, n=124) and with younger control subjects (n=89) and obstetric control subjects (n=90). A third case set of pregnancy-associated CM cases not meeting strict PPCM definitions (n=29) was also studied. In the genome-wide association study, 1 single nucleotide polymorphism (rs258415) met genome-wide significance for PPCM versus local control subjects (P=2.06*10(-8); odds ratio [OR], 5.96). This was verified versus iControls (P=7.92*10(-19); OR, 8.52). In the replication study for PPCM2 cases, rs258415 (ORs are per C allele) replicated at P=0.009 versus local2 control subjects (OR, 2.26). This replication was verified for PPCM2 versus younger control subjects (P=0.029; OR, 2.15) and versus obstetric control subjects (P=0.013; OR, 2.44). In pregnancy-associated cardiomyopathy cases, rs258415 had a similar effect versus local2 control subjects (P=0.06; OR, 1.79), younger control subjects (P=0.14; OR, 1.65), and obstetric control subjects (P=0.038; OR, 1.99). CONCLUSIONS: Genome-wide association with PPCM was discovered and replicated for rs258415 at chromosome 12p11.22 near PTHLH. This study indicates a role of genetic factors in PPCM and provides a new locus for further pathophysiological and clinical investigation. PMID- 21665989 TI - APC mutations in colorectal tumours from FAP patients are selected for CtBP mediated oligomerization of truncated APC. AB - The germline transmission of a mutation in the adenomatous polyposis coli (APC) gene leads to cancer of the gastro-intestinal tract upon somatic inactivation of the remaining allele in familial adenomatous polyposis (FAP) patients. APC mutations result in truncated products that have primarily lost the ability to properly regulate the level of the transcription factor beta-catenin. However, colorectal cancer cells from FAP patients always retain a truncated APC product and the reasons for this strong selective pressure are not understood. We describe here the surprising property for the transcriptional repressor C terminal binding protein (CtBP) to promote the oligomerization of truncated APC through binding to the 15 amino acid repeats of truncated APC. CtBP can bind to either first, third or fourth 15 amino acid repeats, but not to the second. CtBP mediated oligomerization requires both dimerization domains of truncated APC as well as CtBP dimerization. The analysis of the position of the mutations along the APC sequence in adenomas from FAP patients reveals that the presence of the first 15 amino acid repeat is almost always selected in the resulting truncated APC product. This suggests that the sensitivity of truncated APC to oligomerization by CtBP constitutes an essential facet of tumour development. PMID- 21665990 TI - Common variants near FRK/COL10A1 and VEGFA are associated with advanced age related macular degeneration. AB - Despite significant progress in the identification of genetic loci for age related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21 q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 * 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 * 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD. PMID- 21665991 TI - Mutant Atp13a2 proteins involved in parkinsonism are degraded by ER-associated degradation and sensitize cells to ER-stress induced cell death. AB - Mutations in ATP13A2 (PARK9) have been linked to juvenile parkinsonism with dementia or Kufor-Rakeb syndrome (KRS). The ATP13A2 gene encodes at least three protein isoforms that arise by alternate splicing. A previous study indicated the Atp13a2(Isoform-1) protein is localized to lysosomes, whereas three separate mutations involved in disease cause retention of the protein in the ER. One speculation is that the mutant Atp13a2(Isoform-1) proteins are misfolded and eliminated by the ER-associated degradation pathway (ERAD), which involves the dislocation of proteins from the ER to the cytoplasm for proteasome degradation. We examined whether Atp13a2 proteins are degraded by ERAD and whether the Atp13a2(Isoform-3) protein has similar localization to the Atp13a2(Isoform-1) protein. Through analysis of protein turnover and by disrupting different steps in the ERAD pathway we demonstrate that mutant Atp13a2(Isoform-1) proteins are indeed eliminated by ERAD. Thus, siRNA-mediated knockdown of erasin, a platform for assembly of an ERAD complex, or expression of a dominant negative form of p97/VCP, a protein essential for dislocation of ERAD substrates, or inhibition of the proteasome all slowed degradation of the mutant Atp13a2(Isoform-1) proteins, but not the wild-type Atp13a2(Isoform-1) protein. Immunoprecipitation assays confirmed that the Atp13a2 proteins are ubiquitinated in accord with degradation by ERAD. In contrast to Atp13a2(Isoform-1), we show Atp13a2(Isoform-3) is localized to the ER and rapidly degraded. Lastly, we show Atp13a2 mutants have increased cytotoxicity and predispose cells to ER-stress-induced cell death. These results provide new insight into the properties of wild-type and mutant Atp13a2 proteins involved in KRS. PMID- 21665992 TI - A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P= 9.3 * 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-beta (TGF-beta) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-beta signaling and that decreased ZNF512B expression increases susceptibility to ALS. PMID- 21665993 TI - Association of variants in FRAP1 and PDGFRA with corneal curvature in Asian populations from Singapore. AB - Corneal curvature (CC) is a key determinant of major eye diseases, such as keratoconus, myopia and corneal astigmatism. No prior studies have discovered the genes for CC. Here we report the findings from four genome-wide association studies of CC in 10 008 samples from three population groups in Singapore. Our discovery phase surveyed 2867 Chinese and 3072 Malays, allowing us to identify two loci that were associated with CC variation: FRAP1 on chromosome 1p36.2 and PDGFRA on chromosome 4q12. These findings were subsequently replicated in a validation study involving an additional 2953 Asian Indians and a further collection of 1116 Chinese children. The effect sizes of the identified variants were consistent across all four cohorts, with seven single nucleotide polymorphisms (SNPs) in FRAP1 (lead SNP: rs17036350, meta P-value = 4.06 * 10( 13)) and six SNPs in PDGFRA (lead SNP: rs2114039, meta P-value = 1.33 * 10(-9)) attaining genome-wide significance in the SNP-based meta-analysis of the four studies. This is the first genome-wide survey of CC variation and we have identified two implicated loci in three genetically diverse Asian populations, suggesting the presence of common genetic etiology across multiple populations. PMID- 21665994 TI - Genome-wide association study identifies two loci strongly affecting transferrin glycosylation. AB - Polysaccharide sidechains attached to proteins play important roles in cell-cell and receptor-ligand interactions. Variation in the carbohydrate component has been extensively studied for the iron transport protein transferrin, because serum levels of the transferrin isoforms asialotransferrin + disialotransferrin (carbohydrate-deficient transferrin, CDT) are used as biomarkers of excessive alcohol intake. We conducted a genome-wide association study to assess whether genetic factors affect CDT concentration in serum. CDT was measured in three population-based studies: one in Switzerland (CoLaus study, n = 5181) and two in Australia (n = 1509, n = 775). The first cohort was used as the discovery panel and the latter ones served as replication. Genome-wide single-nucleotide polymorphism (SNP) typing data were used to identify loci with significant associations with CDT as a percentage of total transferrin (CDT%). The top three SNPs in the discovery panel (rs2749097 near PGM1 on chromosome 1, and missense polymorphisms rs1049296, rs1799899 in TF on chromosome 3) were successfully replicated , yielding genome-wide significant combined association with CDT% (P = 1.9 * 10(-9), 4 * 10(-39), 5.5 * 10(-43), respectively) and explain 5.8% of the variation in CDT%. These allelic effects are postulated to be caused by variation in availability of glucose-1-phosphate as a precursor of the glycan (PGM1), and variation in transferrin (TF) structure. PMID- 21665995 TI - Accumulation of noncoding RNA due to an RNase P defect in Saccharomyces cerevisiae. AB - Ribonuclease P (RNase P) is an essential endoribonuclease that catalyzes the cleavage of the 5' leader of pre-tRNAs. In addition, a growing number of non-tRNA substrates have been identified in various organisms. RNase P varies in composition, as bacterial RNase P contains a catalytic RNA core and one protein subunit, while eukaryotic nuclear RNase P retains the catalytic RNA but has at least nine protein subunits. The additional eukaryotic protein subunits most likely provide additional functionality to RNase P, with one possibility being additional RNA recognition capabilities. To investigate the possible range of additional RNase P substrates in vivo, a strand-specific, high-density microarray was used to analyze what RNA accumulates with a mutation in the catalytic RNA subunit of nuclear RNase P in Saccharomyces cerevisiae. A wide variety of noncoding RNAs were shown to accumulate, suggesting that nuclear RNase P participates in the turnover of normally unstable nuclear RNAs. In some cases, the accumulated noncoding RNAs were shown to be antisense to transcripts that commensurately decreased in abundance. Pre-mRNAs containing introns also accumulated broadly, consistent with either compromised splicing or failure to efficiently turn over pre-mRNAs that do not enter the splicing pathway. Taken together with the high complexity of the nuclear RNase P holoenzyme and its relatively nonspecific capacity to bind and cleave mixed sequence RNAs, these data suggest that nuclear RNase P facilitates turnover of nuclear RNAs in addition to its role in pre-tRNA biogenesis. PMID- 21665996 TI - The ubiquitin ligase Rsp5 is required for ribosome stability in Saccharomyces cerevisiae. AB - Rsp5p is a conserved HECT-domain ubiquitin ligase with diverse roles in cellular physiology. Here we report a previously unknown role of Rsp5p in facilitating the stability of the cytoplasmic ribosome pool in budding yeast. Yeast strains carrying temperature-sensitive mutations in RSP5 showed a progressive decline in levels of 18S and 25S rRNAs and accumulation of rRNA decay fragments when cells grown in rich medium were shifted to restrictive temperature. This was accompanied by a decreased number of translating ribosomes and the appearance of ribosomal subunits with an abnormally low sedimentation rate in polysome analysis. Abrogating Rsp5p function affected stability of other tested noncoding RNA species (tRNA and snoRNA), but to a lower extent than that of rRNA, and also inhibited processing of rRNA and tRNA precursors, in agreement with previous studies. The breakdown of cellular ribosomes was not affected by deletion of key genes involved in autophagy, previously implicated in ribosome turnover upon starvation. Our results suggest that functional Rsp5p is required to maintain the integrity of cytoplasmic ribosomes under rich nutrient conditions. PMID- 21665997 TI - Binding and cleavage of unstructured RNA by nuclear RNase P. AB - Ribonuclease P (RNase P) is an essential endoribonuclease for which the best characterized function is processing the 5' leader of pre-tRNAs. Compared to bacterial RNase P, which contains a single small protein subunit and a large catalytic RNA subunit, eukaryotic nuclear RNase P is more complex, containing nine proteins and an RNA subunit in Saccharomyces cerevisiae. Consistent with this, nuclear RNase P has been shown to possess unique RNA binding capabilities. To understand the unique molecular recognition of nuclear RNase P, the interaction of S. cerevisiae RNase P with single-stranded RNA was characterized. Unstructured, single-stranded RNA inhibits RNase P in a size-dependent manner, suggesting that multiple interactions are required for high affinity binding. Mixed-sequence RNAs from protein-coding regions also bind strongly to the RNase P holoenzyme. However, in contrast to poly(U) homopolymer RNA that is not cleaved, a variety of mixed-sequence RNAs have multiple preferential cleavage sites that do not correspond to identifiable consensus structures or sequences. In addition, pre-tRNA(Tyr), poly(U)(50) RNA, and mixed-sequence RNA cross-link with purified RNase P in the RNA subunit Rpr1 near the active site in "Conserved Region I," although the exact positions vary. Additional contacts between poly(U)(50) and the RNase P proteins Rpr2p and Pop4p were identified. We conclude that unstructured RNAs interact with multiple protein and RNA contacts near the RNase P RNA active site, but that cleavage depends on the nature of interaction with the active site. PMID- 21665998 TI - Tunable membrane binding of the intrinsically disordered dehydrin Lti30, a cold induced plant stress protein. AB - Dehydrins are intrinsically disordered plant proteins whose expression is upregulated under conditions of desiccation and cold stress. Their molecular function in ensuring plant survival is not yet known, but several studies suggest their involvement in membrane stabilization. The dehydrins are characterized by a broad repertoire of conserved and repetitive sequences, out of which the archetypical K-segment has been implicated in membrane binding. To elucidate the molecular mechanism of these K-segments, we examined the interaction between lipid membranes and a dehydrin with a basic functional sequence composition: Lti30, comprising only K-segments. Our results show that Lti30 interacts electrostatically with vesicles of both zwitterionic (phosphatidyl choline) and negatively charged phospholipids (phosphatidyl glycerol, phosphatidyl serine, and phosphatidic acid) with a stronger binding to membranes with high negative surface potential. The membrane interaction lowers the temperature of the main lipid phase transition, consistent with Lti30's proposed role in cold tolerance. Moreover, the membrane binding promotes the assembly of lipid vesicles into large and easily distinguishable aggregates. Using these aggregates as binding markers, we identify three factors that regulate the lipid interaction of Lti30 in vitro: (1) a pH dependent His on/off switch, (2) phosphorylation by protein kinase C, and (3) reversal of membrane binding by proteolytic digest. PMID- 21665999 TI - Botrytis cinerea manipulates the antagonistic effects between immune pathways to promote disease development in tomato. AB - Plants have evolved sophisticated mechanisms to sense and respond to pathogen attacks. Resistance against necrotrophic pathogens generally requires the activation of the jasmonic acid (JA) signaling pathway, whereas the salicylic acid (SA) signaling pathway is mainly activated against biotrophic pathogens. SA can antagonize JA signaling and vice versa. Here, we report that the necrotrophic pathogen Botrytis cinerea exploits this antagonism as a strategy to cause disease development. We show that B. cinerea produces an exopolysaccharide, which acts as an elicitor of the SA pathway. In turn, the SA pathway antagonizes the JA signaling pathway, thereby allowing the fungus to develop its disease in tomato (Solanum lycopersicum). SA-promoted disease development occurs through Nonexpressed Pathogen Related1. We also show that the JA signaling pathway required for tomato resistance against B. cinerea is mediated by the systemin elicitor. These data highlight a new strategy used by B. cinerea to overcome the plant's defense system and to spread within the host. PMID- 21666001 TI - De novo telomere formation in Arabidopsis tetraploids. PMID- 21666000 TI - A guideline to family-wide comparative state-of-the-art quantitative RT-PCR analysis exemplified with a Brassicaceae cross-species seed germination case study. AB - Comparative biology includes the comparison of transcriptome and quantitative real-time RT-PCR (qRT-PCR) data sets in a range of species to detect evolutionarily conserved and divergent processes. Transcript abundance analysis of target genes by qRT-PCR requires a highly accurate and robust workflow. This includes reference genes with high expression stability (i.e., low intersample transcript abundance variation) for correct target gene normalization. Cross species qRT-PCR for proper comparative transcript quantification requires reference genes suitable for different species. We addressed this issue using tissue-specific transcriptome data sets of germinating Lepidium sativum seeds to identify new candidate reference genes. We investigated their expression stability in germinating seeds of L. sativum and Arabidopsis thaliana by qRT-PCR, combined with in silico analysis of Arabidopsis and Brassica napus microarray data sets. This revealed that reference gene expression stability is higher for a given developmental process between distinct species than for distinct developmental processes within a given single species. The identified superior cross-species reference genes may be used for family-wide comparative qRT-PCR analysis of Brassicaceae seed germination. Furthermore, using germinating seeds, we exemplify optimization of the qRT-PCR workflow for challenging tissues regarding RNA quality, transcript stability, and tissue abundance. Our work therefore can serve as a guideline for moving beyond Arabidopsis by establishing high-quality cross-species qRT-PCR. PMID- 21666003 TI - Tail docking dairy cattle: responses from an online engagement. AB - Tail docking remains a common practice on dairy farms in the United States. This paper describes the results of an online engagement designed to create discussion on tail docking, to document the reasons participants put forward for and against the practice, and to compare these reasons with the literature available on this topic. A total of 178 people responded; 30% were producers, 23% were veterinarians, 25% had no experience with the dairy industry, and 22% included a mixture of teachers, students, and industry professionals. Approximately 79% of participants were opposed to docking. Responses varied with participant demographics (e.g., females were more likely than males to oppose docking), but in every demographic subgroup (e.g., by sex, age, country of origin, and dairy production experience), the majority of respondents were opposed to tail docking. Common reasons for opposition to docking included the lack of scientific evidence that docking improves cleanliness or udder health, that docking is painful for cows, that docking is unnatural, and that tails are important for controlling flies. Some respondents in favor of docking cited cow cleanliness as an issue, despite the scientific evidence showing no positive effect of docking on cow cleanliness or udder health. Additional reasons included protecting producer safety. These results illustrate the range of reasons that are cited for supporting and opposing tail docking. This approach can be used to better target outreach efforts (e.g., improving farmer education on the lack of positive effects of docking on cleanliness and udder health while addressing concerns about producer safety). More generally, this type of online discussion provides a safe and productive format for discussions about contentious issues in the dairy industry and provides a mechanism for producers, industry professionals, and the public to share perspectives on these topics. PMID- 21666002 TI - Sphingolipids containing very-long-chain fatty acids define a secretory pathway for specific polar plasma membrane protein targeting in Arabidopsis. AB - Sphingolipids are a class of structural membrane lipids involved in membrane trafficking and cell polarity. Functional analysis of the ceramide synthase family in Arabidopsis thaliana demonstrates the existence of two activities selective for the length of the acyl chains. Very-long-acyl-chain (C > 18 carbons) but not long-chain sphingolipids are essential for plant development. Reduction of very-long-chain fatty acid sphingolipid levels leads in particular to auxin-dependent inhibition of lateral root emergence that is associated with selective aggregation of the plasma membrane auxin carriers AUX1 and PIN1 in the cytosol. Defective targeting of polar auxin carriers is characterized by specific aggregation of Rab-A2(a)- and Rab-A1(e)-labeled early endosomes along the secretory pathway. These aggregates correlate with the accumulation of membrane structures and vesicle fragmentation in the cytosol. In conclusion, sphingolipids with very long acyl chains define a trafficking pathway with specific endomembrane compartments and polar auxin transport protein cargoes. PMID- 21666004 TI - Long-term alteration of follicular steroid concentrations in relation to subclinical endometritis in postpartum dairy cows. AB - The focus of this study was to investigate the effect of subclinical endometritis (scEndo) on ovarian follicular steroid concentrations in early postpartum pasture fed dairy cows. Mixed-age lactating dairy cows (n = 169) were examined to ascertain uterine health status on d 21 postpartum (+/-3 d). From this herd, a cohort of scEndo and uninfected cows (n = 47) were selected using uterine cytology to determine scEndo. To ensure cows with scEndo were selected for the study, a conservative threshold [>18% polymorphonuclear (PMN) cells among uterine nucleated cells] was chosen as a selection threshold. Ovarian follicular dynamics were assessed by ultrasonography on d 21, 42, and 63 postpartum. On the latter 2 d, all follicles >4 mm in diameter were ablated, and 4 d later, the largest (F1) and second largest (F2) follicles were measured and their follicular fluid aspirated. Hematological variables and plasma metabolites were measured also on these days to further characterize scEndo cows. On d 21, the prevalence of scEndo was approximately 9% in this herd; by d 42 infections had self-resolved in the majority (81%) of those cows classified as having scEndo on d 21. The scEndo cows had a delayed return to cyclicity; however, no effect was evident on ovarian follicle size or growth rate. Weeks after scEndo had self-resolved and cyclicity was restored, decreased (P = 0.07) testosterone and increased (P = 0.07) cortisol concentrations were evident in F1 follicles of scEndo compared with uninfected cows. Progesterone concentrations of F1 increased (P < 0.05) in 11- to 16-mm diameter follicles of scEndo cows, whereas estradiol, androstendione, and dehydroepiandrosterone concentrations were decreased (P < 0.05) in F1 8- to 10-mm diameter follicles of scEndo cows. These 3 steroids also differed (P < 0.05) between F1 follicle size categories of scEndo but not uninfected cows. On d 21, mean plasma albumin concentration was decreased (P = 0.02) in scEndo cows. In summary, early postpartum scEndo had surprisingly long-term influences on the steroid concentrations of ovarian follicles long after infections had self resolved. This is likely to affect oocyte quality and may partially explain the reduced conception rates and longer interval between calving and conception that are often associated with scEndo, although more detailed investigations are required to substantiate this theory. PMID- 21666005 TI - Effects of mineral-supplement delivery system on frequency, duration, and timing of supplement use by beef cows grazing topographically rugged, native rangeland in the Kansas Flint Hills. AB - The effects of mineral-supplement delivery system on patterns of supplement use by grazing beef cows were measured in 2 studies. Study 1 was conducted on 4 pastures grazed by pregnant, mature beef cows (BW = 562 +/- 38 kg) from February to May. Study 2 was conducted on 4 pastures grazed by lactating beef cows (BW = 579 +/- 54 kg) and their calves from May to September. Treatments were mineral delivered in salt-based, granular form (salty) or mineral provided in a low protein, cooked, molasses-based block (sweet); both were fed ad libitum. The salty supplement was supplied to cattle via a covered mineral feeder; the sweet supplement was supplied via an open-topped barrel. Both salty and sweet supplements were deployed in each pasture. No additional salt was supplied to cattle. Forage use in the vicinity of each supplement-deployment site and the frequency and duration of herd visits to each supplement-deployment site were measured during four 14-d periods during study 1 and seven 14-d periods during study 2. Supplements were moved to new locations within pastures at the beginning of each period. Consumption of the sweet supplement was greater than salty during each data-collection period in study 1; however, relative differences in consumption diminished over time (treatment * time, P = 0.03). In study 2, sweet consumption was greater than salty in periods 1, 6, and 7 but was not different from salty during periods 2, 3, 4, and 5 (treatment * time, P < 0.01). Increased consumption of the sweet supplement in study 1 translated to greater frequency of herd visits to supplement-deployment sites compared with the salty sites (2.82 vs. 2.47 herd visits/d; P = 0.02) and longer herd visits to supplement-deployment sites compared with the salty sites (125.7 vs. 54.9 min/herd visit; P < 0.01). The frequency of herd visits to mineral feeding sites in study 2 was similar (P > 0.10) between treatments for periods 1 through 6; however, herds visited the sweet sites more often than salty during period 7 (P < 0.01). Herd visits to the sweet sites were longer than those to the salty sites in study 2 (83.8 vs. 51.4 min/herd visit; P < 0.01). Forage disappearance within 100 m of supplement deployment sites was not influenced (P >= 0.54) by treatment in either study. Results were interpreted to suggest that the sweet supplement influenced the location of grazing cattle more strongly than the salty supplement and may be more effective for luring cattle into specific areas of pasture during the winter, spring, and early fall but not during summer. PMID- 21666006 TI - Growth, feed intake, carcass characteristics, and eating behavior of feedlot lambs fed high-concentrate diets containing soybean hulls. AB - The objectives of this experiment were to determine the effects of replacing ground corn with soybean hulls (SH) in high-concentrate diets on the growth (56-d period), carcass characteristics, and eating behavior of feedlot lambs. Sixty four Santa Ines ram lambs (18.3 +/- 2.8 kg of BW and 69 +/- 5 d of age) were assigned to a randomized complete block design experiment with 8 blocks and 4 diets. The control diet contained 10% coastcross (Cynodon sp.) hay, 70% corn, and no SH (SH0) in the dietary DM. In the remaining diets, SH replaced corn at the rate of 15 (SH15), 30 (SH30), or 45% (SH45) of the original corn concentration, resulting in 0, 10.5, 21.0, or 31.4% SH in the dietary DM. Dry matter intake increased linearly (P < 0.01) when SH replaced ground corn (1.0, 1.0, 1.1, and 1.1 kg/d for SH0, SH15, SH30, and SH45, respectively). There was no effect on ADG of lambs, with values of 276, 278, 282, and 287 g for SH0, SH15, SH30, and SH45, respectively. Feed efficiency decreased linearly (P < 0.01) with SH inclusion. Carcass measures were not affected by SH as a replacement for ground corn. Eating time, expressed as minutes per day and minutes per gram of NDF, showed a quadratic effect (P < 0.05), whereas no effect was observed when expressed as minutes per gram of DM. Rumination, in minutes per day, was not influenced by dietary SH inclusion, but a linear decrease (P < 0.01) was observed when this variable was expressed as minutes per gram of NDF. Soybean hulls can replace up to 45% of the ground corn (31.4% of SH in the dietary DM) in high-concentrate diets fed to feedlot lambs without negative effects on ADG and carcass measures. The linear decrease in feed efficiency (11.6% reduction from SH0 to SH45) suggests that optimal dietary SH inclusion rates should be dictated by the relative costs of SH and corn. PMID- 21666007 TI - Effects of increasing dietary standardized ileal digestible lysine for gilts grown in a commercial finishing environment. AB - Three experiments were conducted to determine the effects of increasing dietary standardized ileal digestible (SID) Lys on growing and finishing gilts. Diets in all 3 experiments were corn-soybean meal-based and contained 0.15% l-Lys*HCl and 3% added fat from choice white grease. Desired SID Lys concentrations were achieved by altering levels of corn and soybean meal in the diet. Each experiment consisted of 6 treatments with 7 pens per treatment and approximately 27 gilts (PIC 337 * 1050) per pen. In Exp. 1, 1,085 gilts (initially 38.2 kg) were fed diets formulated to contain SID Lys concentrations of 0.7, 0.8, 0.9, 1.0, 1.1, or 1.2% for 28 d, which were analyzed to be total Lys concentrations of 0.78, 0.86, 0.99, 1.06, 1.14, and 1.24%, respectively. As SID Lys increased, ADG and G:F improved (quadratic, P < 0.003) with optimal performance reached at the SID Lys level of 1.1% or SID Lys:ME ratio of 3.16 g/Mcal. Broken-line analysis indicated breakpoints of 1.03 and 1.05% SID Lys for ADG and G:F, respectively. Gilts in this trial required approximately 21.8 g of SID Lys intake per kilogram of BW gain from 38 to 65 kg. In Exp. 2, 1,092 (initially 55.2 kg) gilts were fed diets formulated to contain SID Lys concentrations of 0.66, 0.74, 0.82, 0.90, 0.98, or 1.06% for 28 d, which were analyzed to be total Lys concentrations of 0.75, 0.73, 0.84, 0.90, 0.95, and 0.97%, respectively. Both ADG (quadratic, P = 0.12) and G:F improved (linear, P < 0.001) as SID Lys increased, with broken-line analysis of ADG indicating a requirement estimate of 0.90%, which corresponds to a SID Lys:ME ratio of 2.58 g/Mcal. Gilts in this trial required approximately 19.6 g of SID Lys per kilogram of BW gain from 55 to 80 kg. In Exp. 3, 1,080 gilts (initially 84.1 kg) were fed diets formulated to contain SID Lys concentrations of 0.54, 0.61, 0.68, 0.75, 0.82, or 0.89% for 29 d, which were analyzed to be total Lys concentrations of 0.62, 0.92, 0.79, 0.99, 0.93, and 1.07%, respectively. As the SID Lys concentration increased, ADG and G:F improved (linear, P < 0.001), and performance responses were maximized at the greatest SID Lys level of 0.89% or SID Lys:ME ratio of 2.55 g/Mcal of ME. Gilts in this trial required 23.0 g of SID Lys per kg of BW gain from 85 to 110 kg. The ideal SID Lys:ME ratio was based on the requirement determined by broken-line analysis in Exp. 1, 2, and 3, with the greatest level being tested in Exp. 3. This equation, SID Lys:ME ratio = -0.011 * BW, kg + 3.617, estimates the optimal SID Lys:ME ratios for growth of gilts (PIC 337 * 1050) in this commercial finishing environment. These studies showed growth performance advantages to increasing SID Lys for growing and finishing gilts over previously reported optimal levels, particularly in the later finishing stages. PMID- 21666008 TI - Influence of inducing luteal regression before a modified controlled internal drug-releasing device treatment on control of follicular development. AB - At the initiation of most controlled internal drug-releasing (CIDR) device protocols, GnRH has been used to induce ovulation and reset follicular waves; however, its ability to initiate a new follicular wave is variable and dependent on stage of the estrous cycle. The objectives of the current studies were to determine 1) if inducing luteal regression before the injection of GnRH at time of insertion of a CIDR resulted in increased control of follicular development, and 2) if removing endogenous progesterone by inducing luteal regression before insertion of the CIDR decreased variation in LH pulse frequency. In Exp. 1 and 2, Angus-cross cycling beef heifers (n = 22 and 38, respectively) were allotted to 1 of 2 treatments: 1) heifers received an injection of PGF(2alpha) on d -3, an injection of GnRH and insertion of a CIDR on d 0, and a PGF(2alpha) injection and CIDR removal on d 6 (PG-CIDR) or 2) an injection of GnRH and insertion of a CIDR on d 0 and on d 7 an injection of PGF(2alpha) and removal of CIDR (Select Synch + CIDR). In Exp. 3, Angus-cross beef heifers (n = 15) were assigned to 1 of 3 treatments: 1) PG-CIDR; 2) PGF(2alpha) on d -3, GnRH on d 0, and PGF(2alpha) on d 6 (PG-No CIDR); or 3) Select Synch + CIDR. Follicular development and ovulatory response were determined by transrectal ultrasonography. Across all experiments, more (P = 0.02) heifers treated with PG before GnRH initiated a new follicular wave after the injection of GnRH compared with Select Synch + CIDR-treated heifers. In Exp. 1, after CIDR removal, interval to estrus did not differ (P = 0.18) between treatments; however, the variance for the interval to estrus was reduced (P < 0.01) in PG-CIDR heifers compared with Select Synch + CIDR heifers. In Exp. 3, there was a tendency (P = 0.09) for LH pulse frequency to be greater among PG-CIDR and PG-No CIDR compared with the Select Synch + CIDR, but area under the curve, mean LH concentrations, and mean amplitude did not differ (P > 0.76). In summary, induction of luteal regression before an injection of GnRH increased the percentage of heifers initiating a new follicular wave. Removal of endogenous progesterone tended to increase LH pulse frequency, and the modified treatment increased the synchrony of estrus after CIDR removal. PMID- 21666009 TI - Natural competence and recombination in the plant pathogen Xylella fastidiosa. AB - Homologous recombination is one of many forces contributing to the diversity, adaptation, and emergence of pathogens. For naturally competent bacteria, transformation is one possible route for the acquisition of novel genetic material. This study demonstrates that Xylella fastidiosa, a generalist bacterial plant pathogen responsible for many emerging plant diseases, is naturally competent and able to homologously recombine exogenous DNA into its genome. Several factors that affect transformation and recombination efficiencies, such as nutrient availability, growth stage, and methylation of transforming DNA, were identified. Recombination was observed in at least one out of every 10(6) cells when exogenous plasmid DNA was supplied and one out of every 10(7) cells when different strains were grown together in vitro. Based on previous genomic studies and experimental data presented here, there is mounting evidence that recombination can occur at relatively high rates and could play a large role in shaping the genetic diversity of X. fastidiosa. PMID- 21666010 TI - Role of exopolysaccharides in Pseudomonas aeruginosa biofilm formation and architecture. AB - Pseudomonas aeruginosa is an opportunistic human pathogen and has been established as a model organism to study bacterial biofilm formation. At least three exopolysaccharides (alginate, Psl, and Pel) contribute to the formation of biofilms in this organism. Here mutants deficient in the production of one or more of these polysaccharides were generated to investigate how these polymers interactively contribute to biofilm formation. Confocal laser scanning microscopy of biofilms formed in flow chambers showed that mutants deficient in alginate biosynthesis developed biofilms with a decreased proportion of viable cells than alginate-producing strains, indicating a role of alginate in viability of cells in biofilms. Alginate-deficient mutants showed enhanced extracellular DNA (eDNA) containing surface structures impacting the biofilm architecture. PAO1 DeltapslA Deltaalg8 overproduced Pel, and eDNA showing meshwork-like structures presumably based on an interaction between both polymers were observed. The formation of characteristic mushroom-like structures required both Psl and alginate, whereas Pel appeared to play a role in biofilm cell density and/or the compactness of the biofilm. Mutants producing only alginate, i.e., mutants deficient in both Psl and Pel production, lost their ability to form biofilms. A lack of Psl enhanced the production of Pel, and the absence of Pel enhanced the production of alginate. The function of Psl in attachment was independent of alginate and Pel. A 30% decrease in Psl promoter activity in the alginate-overproducing MucA-negative mutant PDO300 suggested inverse regulation of both biosynthesis operons. Overall, this study demonstrated that the various exopolysaccharides and eDNA interactively contribute to the biofilm architecture of P. aeruginosa. PMID- 21666012 TI - An alkaline phosphatase/phosphodiesterase, PhoD, induced by salt stress and secreted out of the cells of Aphanothece halophytica, a halotolerant cyanobacterium. AB - Alkaline phosphatases (APases) are important enzymes in organophosphate utilization. Three prokaryotic APase gene families, PhoA, PhoX, and PhoD, are known; however, their functional characterization in cyanobacteria largely remains to be clarified. In this study, we cloned the phoD gene from a halotolerant cyanobacterium, Aphanothece halophytica (phoD(Ap)). The deduced protein, PhoD(Ap), contains Tat consensus motifs and a peptidase cleavage site at the N terminus. The PhoD(Ap) enzyme was activated by Ca(2+) and exhibited APase and phosphodiesterase (APDase) activities. Subcellular localization experiments revealed the secretion and processing of PhoD(Ap) in a transformed cyanobacterium. Expression of the phoD(Ap) gene in A. halophytica cells was upregulated not only by phosphorus (P) starvation but also under salt stress conditions. Our results suggest that A. halophytica cells possess a PhoD that participates in the assimilation of P under salinity stress. PMID- 21666011 TI - Common ancestry and novel genetic traits of Francisella novicida-like isolates from North America and Australia as revealed by comparative genomic analyses. AB - Francisella novicida is a close relative of Francisella tularensis, the causative agent of tularemia. The genomes of F. novicida-like clinical isolates 3523 (Australian strain) and Fx1 (Texas strain) were sequenced and compared to F. novicida strain U112 and F. tularensis strain Schu S4. The strain 3523 chromosome is 1,945,310 bp and contains 1,854 protein-coding genes. The strain Fx1 chromosome is 1,913,619 bp and contains 1,819 protein-coding genes. NUCmer analyses revealed that the genomes of strains Fx1 and U112 are mostly colinear, whereas the genome of strain 3523 has gaps, translocations, and/or inversions compared to genomes of strains Fx1 and U112. Using the genome sequence data and comparative analyses with other members of the genus Francisella, several strain specific genes that encode putative proteins involved in RTX toxin production, polysaccharide biosynthesis/modification, thiamine biosynthesis, glucuronate utilization, and polyamine biosynthesis were identified. The RTX toxin synthesis and secretion operon of strain 3523 contains four open reading frames (ORFs) and was named rtxCABD. Based on the alignment of conserved sequences upstream of operons involved in thiamine biosynthesis from various bacteria, a putative THI box was identified in strain 3523. The glucuronate catabolism loci of strains 3523 and Fx1 contain a cluster of nine ORFs oriented in the same direction that appear to constitute an operon. Strains U112 and Schu S4 appeared to have lost the loci for RTX toxin production, thiamine biosynthesis, and glucuronate utilization as a consequence of host adaptation and reductive evolution. In conclusion, comparative analyses provided insights into the common ancestry and novel genetic traits of these strains. PMID- 21666013 TI - Tuning the specificity of the recombinant multicomponent toluene o-xylene monooxygenase from Pseudomonas sp. strain OX1 for the biosynthesis of tyrosol from 2-phenylethanol. AB - Biocatalysis is today a standard technology for the industrial production of several chemicals, and the number of biotransformation processes running on a commercial scale is constantly increasing. Among biocatalysts, bacterial multicomponent monooxygenases (BMMs), a diverse group of nonheme diiron enzymes that activate dioxygen, are of primary interest due to their ability to catalyze a variety of complex oxidations, including reactions of mono- and dihydroxylation of phenolic compounds. In recent years, both directed evolution and rational design have been successfully used to identify the molecular determinants responsible for BMM regioselectivity and to improve their activity toward natural and nonnatural substrates. Toluene o-xylene monooxygenase (ToMO) is a BMM isolated from Pseudomonas sp. strain OX1 which hydroxylates a wide spectrum of aromatic compounds. In this work we investigate the use of recombinant ToMO for the biosynthesis in recombinant cells of Escherichia coli strain JM109 of 4 hydroxyphenylethanol (tyrosol), an antioxidant present in olive oil, from 2 phenylethanol, a cheap and commercially available substrate. We initially found that wild-type ToMO is unable to convert 2-phenylethanol to tyrosol. This was explained by using a computational model which analyzed the interactions between ToMO active-site residues and the substrate. We found that residue F176 is the major steric hindrance for the correct positioning of the reaction intermediate leading to tyrosol production into the active site of the enzyme. Several mutants were designed and prepared, and we found that the combination of different mutations at position F176 with mutation E103G allows ToMO to convert up to 50% of 2-phenylethanol into tyrosol in 2 h. PMID- 21666014 TI - High-resolution amplified fragment length polymorphism typing of Lactococcus lactis strains enables identification of genetic markers for subspecies-related phenotypes. AB - A high-resolution amplified fragment length polymorphism (AFLP) methodology was developed to achieve the delineation of closely related Lactococcus lactis strains. The differentiation depth of 24 enzyme-primer-nucleotide combinations was experimentally evaluated to maximize the number of polymorphisms. The resolution depth was confirmed by performing diversity analysis on 82 L. lactis strains, including both closely and distantly related strains with dairy and nondairy origins. Strains clustered into two main genomic lineages of L. lactis subsp. lactis and L. lactis subsp. cremoris type-strain-like genotypes and a third novel genomic lineage rooted from the L. lactis subsp. lactis genomic lineage. Cluster differentiation was highly correlated with small-subunit rRNA homology and multilocus sequence analysis (MLSA) studies. Additionally, the selected enzyme-primer combination generated L. lactis subsp. cremoris phenotype specific fragments irrespective of the genotype. These phenotype-specific markers allowed the differentiation of L. lactis subsp. lactis phenotype from L. lactis subsp. cremoris phenotype strains within the same L. lactis subsp. cremoris type strain-like genomic lineage, illustrating the potential of AFLP for the generation of phenotype-linked genetic markers. PMID- 21666015 TI - The transcriptional response of Listeria monocytogenes during adaptation to growth on lactate and diacetate includes synergistic changes that increase fermentative acetoin production. AB - The organic acids lactate and diacetate are commonly used in combination in ready to-eat foods because they show synergistic ability to inhibit the growth of Listeria monocytogenes. Full-genome microarrays were used to investigate the synergistic transcriptomic responses of two L. monocytogenes strains, H7858 (serotype 4b) and F6854 (serotype 1/2a), to these two organic acids under conditions representing osmotic and cold stress encountered in foods. Strains were exposed to brain heart infusion (BHI) broth at 7 degrees C with 4.65% water phase (w.p.) NaCl at pH 6.1 with (i) 2% w.p. potassium lactate, (ii) 0.14% w.p. sodium diacetate, (iii) the combination of both at the same levels, or (iv) no organic acids as a control. RNA was extracted 8 h after exposure, during lag phase, to capture gene transcription changes during adaptation to the organic acid stress. Significant differential transcription of 1,041 genes in H7858 and 640 genes in F6854 was observed in at least one pair of the 4 different treatments. The effects of combined treatment with lactate and diacetate included (i) synergistic transcription differences for 474 and 209 genes in H7858 and F6854, respectively, (ii) differential transcription of genes encoding cation transporters and ABC transporters of metals, and (iii) altered metabolism, including induction of a nutrient-limiting stress response, reduction of menaquinone biosynthesis, and a shift from fermentative production of acetate and lactate to energetically less favorable, neutral acetoin. These data suggest that additional treatments that interfere with cellular energy generation processes could more efficiently inhibit the growth of L. monocytogenes. PMID- 21666016 TI - Extent and variation of phage-borne bacterial 16S rRNA gene sequences in wastewater environments. AB - Phage metagenomes isolated from wastewater over a 12-month period were analyzed. The results suggested that various strains of Proteobacteria, Bacteroidetes, and other phyla are likely to participate in transduction. The patterns of 16S rRNA sequences found in phage metagenomes did not follow changes in the total bacterial community. PMID- 21666017 TI - Design and verification of a pangenome microarray oligonucleotide probe set for Dehalococcoides spp. AB - Dehalococcoides spp. are an industrially relevant group of Chloroflexi bacteria capable of reductively dechlorinating contaminants in groundwater environments. Existing Dehalococcoides genomes revealed a high level of sequence identity within this group, including 98 to 100% 16S rRNA sequence identity between strains with diverse substrate specificities. Common molecular techniques for identification of microbial populations are often not applicable for distinguishing Dehalococcoides strains. Here we describe an oligonucleotide microarray probe set designed based on clustered Dehalococcoides genes from five different sources (strain DET195, CBDB1, BAV1, and VS genomes and the KB-1 metagenome). This "pangenome" probe set provides coverage of core Dehalococcoides genes as well as strain-specific genes while optimizing the potential for hybridization to closely related, previously unknown Dehalococcoides strains. The pangenome probe set was compared to probe sets designed independently for each of the five Dehalococcoides strains. The pangenome probe set demonstrated better predictability and higher detection of Dehalococcoides genes than strain-specific probe sets on nontarget strains with <99% average nucleotide identity. An in silico analysis of the expected probe hybridization against the recently released Dehalococcoides strain GT genome and additional KB-1 metagenome sequence data indicated that the pangenome probe set performs more robustly than the combined strain-specific probe sets in the detection of genes not included in the original design. The pangenome probe set represents a highly specific, universal tool for the detection and characterization of Dehalococcoides from contaminated sites. It has the potential to become a common platform for Dehalococcoides-focused research, allowing meaningful comparisons between microarray experiments regardless of the strain examined. PMID- 21666018 TI - Development of a method for markerless gene deletion in Pseudomonas putida. AB - We developed a negative counterselection system for Pseudomonas putida based on uracil phosphoribosyltransferase (UPRTase) and sensitivity against the antimetabolite 5-fluorouracil (5-FU). We constructed a P. putida strain that is resistant to 5-FU and constructed vectors for the deletion of the surface adhesion protein gene, the flagellum biosynthesis operon, and two endonuclease genes. The genes were efficiently disrupted and left a markerless chromosomal in frame deletion. PMID- 21666019 TI - Analysis of insertion sequences in thermophilic cyanobacteria: exploring the mechanisms of establishing, maintaining, and withstanding high insertion sequence abundance. AB - Insertion sequences (ISs) are simple mobile genetic elements capable of relocating within a genome. Through this transposition activity, they are known to create mutations which are mostly deleterious to the cell, although occasionally they are beneficial. Two closely related isolates of thermophilic Synechococcus species from hot spring microbial mats are known to harbor a large number of diverse ISs. To explore the mechanism of IS acquisition within natural populations and survival in the face of high IS abundance, we examined IS content and location in natural populations of Synechococcus by comparing metagenomic data to the genomes of fully sequenced cultured isolates. The observed IS distribution in the metagenome was equivalent to the distribution in the isolates, indicating that the cultured isolates are appropriate models for the environmental population. High sequence conservation between IS families shared between the two isolates suggests that ISs are able to move between individuals within populations and between species via lateral gene transfer, consistent with models for IS family accumulation. Most IS families show evidence of recent activity, and interruption of critical genes in some individuals was observed, demonstrating that transposition is an ongoing mutational force in the populations. PMID- 21666020 TI - Biochemical analyses of multiple endoxylanases from the rumen bacterium Ruminococcus albus 8 and their synergistic activities with accessory hemicellulose-degrading enzymes. AB - Ruminococcus albus 8 is a ruminal bacterium capable of metabolizing hemicellulose and cellulose, the major components of the plant cell wall. The enzymes that allow this bacterium to capture energy from the two polysaccharides, therefore, have potential application in plant cell wall depolymerization, a process critical to biofuel production. For this purpose, a partial genome sequence of R. albus 8 was generated. The genomic data depicted a bacterium endowed with multiple forms of plant cell wall-degrading enzymes. The endoxylanases of R. albus 8 exhibited diverse modular architectures, including incorporation of a catalytic module, a carbohydrate binding module, and a carbohydrate esterase module in a single polypeptide. The accessory enzymes of xylan degradation were a beta-xylosidase, an alpha-l-arabinofuranosidase, and an alpha-glucuronidase. We hypothesized that due to the chemical complexity of the hemicellulose encountered in the rumen, the bacterium uses multiple endoxylanases, with subtle differences in substrate specificities, to attack the substrate, while the accessory enzymes hydrolyze the products to simple sugars for metabolism. To test this hypothesis, the genes encoding the predicted endoxylanases were expressed, and the proteins were biochemically characterized either alone or in combination with accessory enzymes. The different endoxylanase families exhibited different patterns of product release, with the family 11 endoxylanases releasing more products in synergy with the accessory enzymes from the more complex substrates. Aside from the insights into hemicellulose degradation by R. albus 8, this report should enhance our knowledge on designing effective enzyme cocktails for release of fermentable sugars in the biofuel industry. PMID- 21666021 TI - Biodiversity and emerging biogeography of the neutrophilic iron-oxidizing Zetaproteobacteria. AB - Members of the neutrophilic iron-oxidizing candidate class Zetaproteobacteria have predominantly been found at sites of microbially mediated iron oxidation in marine environments around the Pacific Ocean. Eighty-four full-length (>1,400-bp) and 48 partial-length Zetaproteobacteria small-subunit (SSU) rRNA gene sequences from five novel clone libraries, one novel Zetaproteobacteria isolate, and the GenBank database were analyzed to assess the biodiversity of this burgeoning class of the Proteobacteria and to investigate its biogeography between three major sampling regions in the Pacific Ocean: Loihi Seamount, the Southern Mariana Trough, and the Tonga Arc. Sequences were grouped into operational taxonomic units (OTUs) on the basis of a 97% minimum similarity. Of the 28 OTUs detected, 13 were found to be endemic to one of the three main sampling regions and 2 were ubiquitous throughout the Pacific Ocean. Additionally, two deeply rooted OTUs that potentially dominate communities of iron oxidizers originating in the deep subsurface were identified. Spatial autocorrelation analysis and analysis of molecular variance (AMOVA) showed that geographic distance played a significant role in the distribution of Zetaproteobacteria biodiversity, whereas environmental parameters, such as temperature, pH, or total Fe concentration, did not have a significant effect. These results, detected using the coarse resolution of the SSU rRNA gene, indicate that the Zetaproteobacteria have a strong biogeographic signal. PMID- 21666022 TI - Lactobacilli antagonize the growth, motility, and adherence of Brachyspira pilosicoli: a potential intervention against avian intestinal spirochetosis. AB - Avian intestinal spirochetosis (AIS) results from the colonization of the ceca and colorectum of poultry by pathogenic Brachyspira species. The number of cases of AIS has increased since the 2006 European Union ban on the use of antibiotic growth promoters, which, together with emerging antimicrobial resistance in Brachyspira, has driven renewed interest in alternative intervention strategies. Probiotics have been reported as protecting livestock against infection with common enteric pathogens, and here we investigate which aspects of the biology of Brachyspira they antagonize in order to identify possible interventions against AIS. The cell-free supernatants (CFS) of two Lactobacillus strains, Lactobacillus reuteri LM1 and Lactobacillus salivarius LM2, suppressed the growth of Brachyspira pilosicoli B2904 in a pH-dependent manner. In in vitro adherence and invasion assays with HT29-16E three-dimensional (3D) cells and in a novel avian cecal in vitro organ culture (IVOC) model, the adherence and invasion of B. pilosicoli in epithelial cells were reduced significantly by the presence of lactobacilli (P < 0.001). In addition, live and heat-inactivated lactobacilli inhibited the motility of B. pilosicoli, and electron microscopic observations indicated that contact between the lactobacilli and Brachyspira was crucial in inhibiting both adherence and motility. These data suggest that motility is essential for B. pilosicoli to adhere to and invade the gut epithelium and that any interference of motility may be a useful tool for the development of control strategies. PMID- 21666023 TI - Comparative phenotypic and molecular genetic profiling of wild Lactococcus lactis subsp. lactis strains of the L. lactis subsp. lactis and L. lactis subsp. cremoris genotypes, isolated from starter-free cheeses made of raw milk. AB - Twenty Lactococcus lactis strains with an L. lactis subsp. lactis phenotype isolated from five traditional cheeses made of raw milk with no added starters belonging to the L. lactis subsp. lactis and L. lactis subsp. cremoris genotypes (lactis and cremoris genotypes, respectively; 10 strains each) were subjected to a series of phenotypic and genetic typing methods, with the aims of determining their phylogenetic relationships and suitability as starters. Pulsed-field gel electrophoresis (PFGE) analysis of intact genomes digested with SalI and SmaI proved that all strains were different except for three isolates of the cremoris genotype, which showed identical PFGE profiles. Multilocus sequence typing (MLST) analysis using internal sequences of seven loci (namely, atpA, rpoA, pheS, pepN, bcaT, pepX, and 16S rRNA gene) revealed considerable intergenotype nucleotide polymorphism, although deduced amino acid changes were scarce. Analysis of the MLST data for the present strains and others from other dairy and nondairy sources showed that all of them clustered into the cremoris or lactis genotype group, by using both independent and combined gene sequences. These two groups of strains also showed distinctive carbohydrate fermentation and enzyme activity profiles, with the strains in the cremoris group showing broader profiles. However, the profiles of resistance/susceptibility to 16 antibiotics were very similar, showing no atypical resistance, except for tetracycline resistance in three identical cremoris genotype isolates. The numbers and concentrations of volatile compounds produced in milk by the strains belonging to these two groups were clearly different, with the cremoris genotype strains producing higher concentrations of more branched-chain, derived compounds. Together, the present results support the idea that the lactis and cremoris genotypes of phenotypic Lactococcus lactis subsp. lactis actually represent true subspecies. Some strains of the two subspecies in this study appear to be good starter candidates. PMID- 21666024 TI - Molecular characterization of noroviruses and rotaviruses involved in a large outbreak of gastroenteritis in Northern Italy. AB - Noroviruses and rotaviruses from a gastroenteritis outbreak affecting >300 people near Garda Lake (Northern Italy) in 2009 were investigated. Characterization of viruses from 40 patient stool samples and 5 environmental samples identified three distinct rotavirus and five norovirus genotypes; two of the latter were detected in both patient and environmental samples. PMID- 21666025 TI - Addition of genes for cellobiase and pectinolytic activity in Escherichia coli for fuel ethanol production from pectin-rich lignocellulosic biomass. AB - Ethanologenic Escherichia coli strain KO11 was sequentially engineered to contain the Klebsiella oxytoca cellobiose phosphotransferase genes (casAB) as well as a pectate lyase (pelE) from Erwinia chrysanthemi, yielding strains LY40A (casAB) and JP07 (casAB pelE), respectively. To obtain an effective secretion of PelE, the Sec-dependent pathway out genes from E. chrysanthemi were provided on a cosmid to strain JP07 to construct strain JP07C. Finally, oligogalacturonide lyase (ogl) from E. chrysanthemi was added to produce strain JP08C. E. coli strains LY40A, JP07, JP07C, and JP08C possessed significant cellobiase activity in cell lysates, while only strains JP07C and JP08C demonstrated extracellular pectate lyase activity. Fermentations conducted by using a mixture of pure sugars representative of the composition of sugar beet pulp (SBP) showed that strains LY40A, JP07, JP07C, and JP08C were able to ferment cellobiose, resulting in increased ethanol production from 15 to 45% in comparison to that of KO11. Fermentations with SBP at very low fungal enzyme loads during saccharification revealed significantly higher levels of ethanol production for LY40A, JP07C, and JP08C than for KO11. JP07C ethanol yields were not considerably higher than those of LY40A; however, oligogalacturonide polymerization studies showed an increased breakdown of biomass to small-chain (degree of polymerization, <=6) oligogalacturonides. JP08C achieved a further breakdown of polygalacturonate to monomeric sugars, resulting in a 164% increase in ethanol yields compared to those of KO11. The addition of commercial pectin methylesterase (PME) further increased JP08C ethanol production compared to that of LY40A by demethylating the pectin for enzymatic attack by pectin-degrading enzymes. PMID- 21666026 TI - Isolation and characterization of a single-stranded DNA virus infecting Chaetoceros lorenzianus Grunow. AB - Diatoms are one of the most significant primary producers in the ocean, and the importance of viruses as a potential source of mortality for diatoms has recently been recognized. Thus far, eight different diatom viruses infecting the genera Rhizosolenia and Chaetoceros have been isolated and characterized to different extents. We report the isolation of a novel diatom virus (ClorDNAV), which causes the lysis of the bloom-forming species Chaetoceros lorenzianus, and show its physiological, morphological, and genomic characteristics. The free virion was estimated to be ~34 nm in diameter. The arrangement of virus particles appearing in cross-section was basically a random aggregation in the nucleus. Occasionally, distinctive formations such as a ring-like array composed of 9 or 10 spherical virions or a centipede-like array composed of rod-shaped particles were also observed. The latent period and the burst size were estimated to be <48 h and 2.2 * 10(4) infectious units per host cell, respectively. ClorDNAV harbors a covalently closed circular single-stranded DNA (ssDNA) genome (5,813 nucleotides [nt]) that includes a partially double-stranded DNA region (979 nt). At least three major open reading frames were identified; one showed a high similarity to putative replicase-related proteins of the other ssDNA diatom viruses, Chaetoceros salsugineum DNA virus (previously reported as CsNIV) and Chaetoceros tenuissimus DNA virus. ClorDNAV is the third member of the closed circular ssDNA diatom virus group, the genus Bacilladnavirus. PMID- 21666028 TI - Advanced multiplex PCR assay for differentiation of Brucella species. AB - Two new primer sets of a 766- and a 344-bp fragment were introduced into the conventional Bruce-ladder PCR assay. This novel multiplex PCR assay rapidly and concisely discriminates Brucella canis and Brucella microti from Brucella suis strains and also may differentiate all of the 10 Brucella species. PMID- 21666027 TI - In vitro fermentation of linear and alpha-1,2-branched dextrans by the human fecal microbiota. AB - The role of structure and molecular weight in fermentation selectivity in linear alpha-1,6 dextrans and dextrans with alpha-1,2 branching was investigated. Fermentation by gut bacteria was determined in anaerobic, pH-controlled fecal batch cultures after 36 h. Inulin (1%, wt/vol), which is a known prebiotic, was used as a control. Samples were obtained at 0, 10, 24, and 36 h of fermentation for bacterial enumeration by fluorescent in situ hybridization and short-chain fatty acid analyses. The gas production of the substrate fermentation was investigated in non-pH-controlled, fecal batch culture tubes after 36 h. Linear and branched 1-kDa dextrans produced significant increases in Bifidobacterium populations. The degree of alpha-1,2 branching did not influence the Bifidobacterium populations; however, alpha-1,2 branching increased the dietary fiber content, implying a decrease in digestibility. Other measured bacteria were unaffected by the test substrates except for the Bacteroides-Prevotella group, the growth levels of which were increased on inulin and 6- and 70-kDa dextrans, and the Faecalibacterium prausnitzii group, the growth levels of which were decreased on inulin and 1-kDa dextrans. A considerable increase in short-chain fatty acid concentration was measured following the fermentation of all dextrans and inulin. Gas production rates were similar among all dextrans tested but were significantly slower than that for inulin. The linear 1-kDa dextran produced lower total gas and shorter time to attain maximal gas production compared to those of the 70-kDa dextran (branched) and inulin. These findings indicate that dextrans induce a selective effect on the gut flora, short-chain fatty acids, and gas production depending on their length. PMID- 21666029 TI - Calicivirus removal in a membrane bioreactor wastewater treatment plant. AB - To evaluate membrane bioreactor wastewater treatment virus removal, a study was conducted in southwest France. Samples collected from plant influent, an aeration basin, membrane effluent, solid sludge, and effluent biweekly from October 2009 to June 2010 were analyzed for calicivirus (norovirus and sapovirus) by real-time reverse transcription-PCR (RT-PCR) using extraction controls to perform quantification. Adenovirus and Escherichia coli also were analyzed to compare removal efficiencies. In the influent, sapovirus was always present, while the norovirus concentration varied temporally, with the highest concentration being detected from February to May. All three human norovirus genogroups (GI, GII, and GIV) were detected in effluent, but GIV was never detected in effluent; GI and GII were detected in 50% of the samples but at low concentrations. In the effluent, sapovirus was identified only once. An adenovirus titer showing temporal variation in influent samples was identified only twice in effluent. E. coli was always below the limit of detection in the effluent. Overall, the removal of calicivirus varied from 3.3 to greater than 6.8 log units, with no difference between the two main genogroups. Our results also demonstrated that the viruses are blocked by the membrane in the treatment plant and are removed from the plant as solid sludge. PMID- 21666031 TI - Angiotensin-(1-7) induces ovulation and steroidogenesis in perfused rabbit ovaries. AB - A local renin-angiotensin system has been described in several organs, including the ovary; however, data indicating a role for angiotensin II in the induction of ovulation are controversial. We have previously shown the presence of a novel peptide, angiotensin-(1-7) [Ang-(1-7)], in the rat ovary and its effect on steroidogenesis. The objective of the present study was to determine whether Ang (1-7) plays a role in ovulation. We first determined the presence and distribution of Ang-(1-7) and the receptor Mas in rabbit ovaries by immunohistochemistry. Angiotensin-(1-7) and Mas immunoreactivity were observed in interstitial cells and oocytes of immature ovaries. Immunoreactivity for Ang-(1 7) and Mas was also observed in theca and granulosa cells of preovulatory follicles in ovaries of gonadotrophin-stimulated rabbits. To verify the effect of Ang-(1-7) in ovulation and steroidogenesis, we used isolated ovaries from immature rabbits pretreated with equine chorionic gonadotrophin (50 i.u., 48 h before the experiment) and then perfused in vitro. The ovulatory efficiency was determined by the number of oocytes compared with the number of preovulatory follicles present in the ovary. Angiotensin-(1-7) stimulated oestradiol production and enhanced ovulatory efficiency, which was blocked by the specific Ang-(1-7) antagonist, A-779. Ovulation induced by human chorionic gonadotrophin was also antagonized by A-779. These results show, for the first time, the involvement of a novel regulatory peptide system, Ang-(1-7) and Mas, in the ovulatory process. More importantly, because A-779 antagonized hCG-induced ovulation, it may be inferred that Ang-(1-7) plays an important role in ovulation, possibly as a mediator of gonadotrophin action. PMID- 21666030 TI - Marine isolates of Trichoderma spp. as potential halotolerant agents of biological control for arid-zone agriculture. AB - The scarcity of fresh water in the Mediterranean region necessitates the search for halotolerant agents of biological control of plant diseases that can be applied in arid-zone agriculture irrigated with saline water. Among 29 Trichoderma strains previously isolated from Mediterranean Psammocinia sp. sponges, the greatest number of isolates belong to the Trichoderma longibrachiatum-Hypocrea orientalis species pair (9), H. atroviridis/T. atroviride (9), and T. harzianum species complex (7), all of which are known for high mycoparasitic potential. In addition, one isolate of T. asperelloides and two putative new species, Trichoderma sp. O.Y. 14707 and O.Y. 2407, from Longibrachiatum and Strictipilosa clades, respectively, have been identified. In vitro salinity assays showed that the ability to tolerate increasing osmotic pressure (halotolerance) is a strain- or clade-specific property rather than a feature of a species. Only a few isolates were found to be sensitive to increased salinity, while others either were halotolerant or even demonstrated improved growth in increasingly saline conditions. In vitro antibiosis assays revealed strong antagonistic activity toward phytopathogens due to the production of both soluble and volatile metabolites. Two marine-derived Trichoderma isolates, identified as T. atroviride and T. asperelloides, respectively, effectively reduced Rhizoctonia solani damping-off disease on beans and also induced defense responses in cucumber seedlings against Pseudomonas syringae pv. lachrimans. This is the first inclusive evaluation of marine fungi as potential biocontrol agents. PMID- 21666032 TI - Unique spatial distribution of in vivo human muscle activation. AB - The present study examined spatial changes in the muscle activation pattern with different contraction intensity using magnetic resonance imaging (MRI). Transverse relaxation time (T2)-weighted MRI was used to acquire 22 axial slices, which covered the entire medial gastrocnemius muscle, before and immediately after seven sets of 10 plantarflexions with loads that were approximately 20 and 60% of their one-repetition maximum, respectively. Reconstructions of the activated regions from MR images revealed the following: (1) the muscle activation determined by MRI correlated significantly (P < 0.05) with the results of electromyography; (2) the activated area distribution increased with increasing force levels; and (3) differential activation between 20 and 60% load was distributed in a spatially non-uniform manner within the muscle, and some regions indicated reduced activity. These results indicate that at submaximal contraction intensity, activation does not necessarily increase in the whole muscle with increase in contraction intensity. PMID- 21666033 TI - Cytoprotective actions of hydrogen sulfide in ischaemia-reperfusion injury. AB - Hydrogen sulfide (H(2)S) has been known as a highly toxic gas for several centuries. There have been considerable advances made in the H(2)S field regarding its physiological role; however, there is much more work that needs to be done. The biosynthesis of H(2)S has been attributed to three endogenous enzymes: cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CGL or CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes require further investigation to more fully elucidate the cellular expression profile, regulation and precise role of these critical enzymes in the production of H(2)S. In recent years, H(2)S has been demonstrated to have cytoprotective effects in multiple organ systems. In particular, it has been demonstrated that the administration of H(2)S either prior to ischaemia or at reperfusion significantly ameliorates myocardial and hepatic ischaemia-reperfusion injury. Therefore, this review focuses on the cardioprotective and hepatoprotective role of H(2)S. In addition, the review provides a summary of several known molecular targets of H(2)S protection. PMID- 21666034 TI - Hydrogen sulfide and asthma. AB - Asthma is a chronic inflammatory disease, with hyper-responsive bronchoconstriction and airway remodelling, leading to extensive airway narrowing. The regulation of airway responsiveness and inflammation by endogenous hydrogen sulfide (H(2)S) during the pathogenic development of asthma has been suggested. Hydrogen sulfide can be produced in the lung and airway tissues via the actions of two H(2)S-generating enzymes, cystathionine beta-synthase (CBS) and/or cystathionine gamma-lyase (CSE). The abnormal metabolism and function of H(2)S have been reported in experimental animals with asthma, especially ovalbumin-induced rat or mouse models. In patients with asthma, serum H(2)S levels are significantly reduced. Supplementation with exogenous H(2)S has been shown to mitigate the severity of asthma in experimental animals. It is hypothesized that decreased H(2)S production in the lung and airway tissues may be used as an early detection biomarker, and H(2)S-based therapy would represent a new treatment strategy for asthma. Major challenges for establishing the diagnostic and treatment values of H(2)S include the differential expression of CSE and CBS along the airway and their changes during asthma, the effects of H(2)S on bronchoconstriction and airway remodelling, as well as the underlying mechanisms, and the detection of the changes in H(2)S levels in airway tissues and in exhaled air. PMID- 21666035 TI - Structural lesions and changing pattern of expression of genes encoding cardiac muscle proteins are associated with ventricular myocyte dysfunction in type 2 diabetic Goto-Kakizaki rats fed a high-fat diet. AB - Given the clinical prevalence of type 2 diabetes and obesity and their association with high mortality linked to cardiovascular disease, the aim of the study was to investigate the effects of feeding type 2 diabetic Goto-Kakizaki (GK) rats either high- or low-fat diets on cardiomyocyte structure and function. The GK rats were fed either a high-fat diet (HFD) or a low-fat diet (LFD) from the age of 2 months for a period of 7 months. The GK-HFD rats gained more weight, ate less food and drank less water compared with GK-LFD rats. At 7 months, non fasting blood glucose was higher in GK-LFD (334 +/- 35 mg dl(-1)) compared with GK-HFD rats (235 +/- 26 mg dl(-1)). Feeding GK rats with a HFD had no significant effect on glucose clearance following a glucose challenge. Time-to-peak (t(peak)) shortening was reduced in myocytes from GK-HFD (131.8 +/- 2.1 ms) compared with GK-LFD rats (144.5 +/- 3.0 ms), and time-to-half (t(1/2)) relaxation of shortening was also reduced in myocytes from GK-HFD (71.7 +/- 6.9 ms) compared with GK-LFD rats (86.1 +/- 3.6 ms). The HFD had no significant effect on the amplitude of shortening. The HFD had no significant effect on t(peak), t(1/2) decay, amplitude of the Ca(2+) transient, myofilament sensitivity to Ca(2+), sarcoplasmic reticulum Ca(2+) content, fractional release of Ca(2+) and the rate of Ca(2+) uptake. Structurally, ventricular myocytes from GK-HFD rats showed extensive mitochondrial lesions, including swelling, loss of cristae, and loss of inner and outer membranes, resulting in gross vacuolarization and deformation of ventricular mitochondria with a subsequent reduction in mitochondrial density. Expression of genes encoding various L-type Ca(2+) channel proteins (Cacnb2) and cardiac muscle proteins (Myl2 and Atp2a1) were downregulated in GK-HFD compared with GK-LFD rats. Structural lesions and changed expression of genes encoding various cardiac muscle proteins might partly underlie the altered time course of myocyte shortening and relaxation in myocytes from GK-HFD compared with GK-LFD rats. PMID- 21666036 TI - Oxytocin depolarizes mitochondria in isolated myometrial cells. AB - Oxytocin is known to play important roles in uterine contractions, mediated at least in part by increasing intracellular Ca(2+) concentration ([Ca(2+)](i)), through enhancing extracellular Ca(2+) entry and Ca(2+) release from the sarcoplasmic reticulum, processes that are intimately linked with mitochondria. This study examined the effects of oxytocin on mitochondrial function. This was achieved by measuring the ratiometric JC-1 fluorescence signal in isolated myometrial cells, which provides a relative measure of the mitochondrial membrane potential (psi(m)), and also by loading the cells with Oregon Green BAPTA-AM to examine changes in [Ca(2+)](i). Oxytocin (1 nm) depolarized the psi(m) to 73.8 +/ 3.7% of the control value (P < 0.05; perfused for 11 min) and also caused a transient increase in [Ca(2+)](i). The depolarization of mitochondrial membrane potential was effectively reversed by 2-aminoethoxydiphenyl borate, nifedipine, Ca(2+)-free solution or oligomycin, with the ratiometric JC-1 fluorescence signal becoming no different from the control value in all cases (i.e. P > 0.05). The reduction in psi(m) is likely to occur at least in part through the oxytocin induced increase in [Ca(2+)](i), causing enhanced mitochondrial uptake of Ca(2+) and resultant dissipation of the mitochondrial electrochemical gradient. ATP synthase is also stimulated, which would further contribute to a decrease in psi(m). PMID- 21666037 TI - Effect of rosiglitazone on cardiac electrophysiology, infarct size and mitochondrial function in ischaemia and reperfusion of swine and rat heart. AB - Rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist, has been used to treat type 2 diabetes. Despite debates regarding its cardioprotection, the effects of rosiglitazone on cardiac electrophysiology are still unclear. This study determined the effect of rosiglitazone on ventricular fibrillation (VF) incidence, VF threshold (VFT), defibrillation threshold (DFT) and mitochondrial function during ischaemia and reperfusion. Twenty-six pigs were used. In each pig, either rosiglitazone (1 mg kg(-1)) or normal saline solution was administered intravenously for 60 min. Then, the left anterior descending coronary artery was ligated for 60 min and released to promote reperfusion for 120 min. The cardiac electrophysiological parameters were determined at the beginning of the study and during the ischaemia and reperfusion periods. The heart was removed, and the area at risk and infarct size in each heart were determined. Cardiac mitochondria were isolated for determination of mitochondrial function. Rosiglitazone did not improve the DFT and VFT during the ischaemia reperfusion period. In the rosiglitazone group, the VF incidence was increased (58 versus 10%) and the time to the first occurrence of VF was decreased (3 +/- 2 versus 19 +/- 1 min) in comparison to the vehicle group (P < 0.05). However, the infarct size related to the area at risk in the rosiglitazone group was significantly decreased (P < 0.05). In the cardiac mitochondria, rosiglitazone did not alter the level of production of reactive oxygen species and could not prevent mitochondrial membrane potential changes. Rosiglitazone increased the propensity for VF, and could neither increase defibrillation efficacy nor improve cardiac mitochondrial function. PMID- 21666038 TI - Effect of baroreceptor denervation on the autonomic control of arterial pressure in conscious mice. AB - This study evaluated the role of arterial baroreceptors in arterial pressure (AP) and pulse interval (PI) regulation in conscious C57BL mice. Male animals, implanted with catheters in a femoral artery and a jugular vein, were submitted to sino-aortic (SAD), aortic (Ao-X) or carotid sinus denervation (Ca-X), 5 days prior to the experiments. After basal recording of AP, the lack of reflex bradycardia elicited by administration of phenylephrine was used to confirm the efficacy of SAD, and cardiac autonomic blockade with methylatropine and propranolol was performed. The AP and PI variability were calculated in the time and frequency domains (spectral analysis/fast Fourier transform) with the spectra quantified in low- (LF; 0.25-1 Hz) and high-frequency bands (HF; 1-5 Hz). Basal AP and AP variability were higher after SAD, Ao-X or Ca-X than in intact mice. Pulse interval was similar among the groups, whereas PI variability was lower after SAD. Atropine elicited a slight tachycardia in control mice but did not change PI after total or partial denervation. The bradycardia caused by propranolol was higher after SAD, Ao-X or Ca-X compared with intact mice. The increase in the variability of AP was accompanied by a marked increase in the LF and HF power of the AP spectra after baroreceptor denervation. The LF and HF power of the PI were reduced by SAD and by Ao-X or Ca-X. Therefore, both sino aortic and partial baroreceptor denervation in mice elicits hypertension and a remarkable increase in AP variability and cardiac sympathetic tonus. Spectral analysis showed an important contribution of the baroreflex in the power of LF oscillations of the PI spectra. Both sets of baroreceptors seem to be equally important in the autonomic regulation of the cardiovascular system in mice. PMID- 21666039 TI - Nottingham degree gains RCVS recognition. PMID- 21666040 TI - Updated guidance on rabbit keeping. PMID- 21666041 TI - 'A global ambassador for animals'. PMID- 21666043 TI - Protecting pets in hot weather. PMID- 21666042 TI - New MRSA strain in cows and people. PMID- 21666045 TI - Consumers' role in improving animal welfare. PMID- 21666047 TI - FAQs on 'veterinary specials'. PMID- 21666048 TI - One Health: the 21st century challenge. PMID- 21666049 TI - Benzimidazole resistance in Nematodirus battus. PMID- 21666051 TI - Uptake of pet insurance. PMID- 21666052 TI - Cytokinin interplay with ethylene, auxin, and glucose signaling controls Arabidopsis seedling root directional growth. AB - Optimal root architecture is established by multiple intrinsic (e.g. hormones) and extrinsic (e.g. gravity and touch) signals and is established, in part, by directed root growth. We show that asymmetrical exposure of cytokinin (CK) at the root tip in Arabidopsis (Arabidopsis thaliana) promotes cell elongation that is potentiated by glucose in a hexokinase-influenced, G protein-independent manner. This mode of CK signaling requires the CK receptor, ARABIDOPSIS HISTIDINE KINASE4 and, at a minimum, its cognate type B ARABIDOPSIS RESPONSE REGULATORS ARR1, ARR10, and ARR11 for full responsiveness, while type A response regulators act redundantly to attenuate this CK response. Ethylene signaling through the ethylene receptor ETHYLENE RESISTANT1 and its downstream signaling element ETHYLENE INSENSITIVE2 are required for CK-induced root cell elongation. Negative and positive feedback loops are reinforced by CK regulation of the expression of the genes encoding these elements in both the CK and ethylene signaling pathways. Auxin transport facilitated by PIN-FORMED2 as well as auxin signaling through control of the steady-state level of transcriptional repressors INDOLE-3-ACETIC ACID7 (IAA7), IAA14, and IAA17 via TRANSPORT INHIBITOR RESPONSE1/AUXIN SIGNALING F-BOX PROTEIN are involved in CK-induced root cell elongation. This action lies downstream of ethylene and CK induction. Intrinsic signaling in this response operates independently of the extrinsic signal touch, although actin filament organization, which is important in the touch response, may be important for this response, since latrunculin B can induce similar growth. This root growth response may have adaptive significance, since CK responsiveness is inversely related to root coiling and waving, two root behaviors known to be important for fitness. PMID- 21666053 TI - PR-domain-containing Mds1-Evi1 is critical for long-term hematopoietic stem cell function. AB - The Mds1 and Evi1 complex locus (Mecom) gives rise to several alternative transcripts implicated in leukemogenesis. However, the contribution that Mecom derived gene products make to normal hematopoiesis remains largely unexplored. To investigate the role of the upstream transcription start site of Mecom in adult hematopoiesis, we created a mouse model with a lacZ knock-in at this site, termed ME(m1), which eliminates Mds1-Evi1 (ME), the longer, PR-domain-containing isoform produced by the gene (also known as PRDM3). beta-galactosidase-marking studies revealed that, within hematopoietic cells, ME is exclusively expressed in the stem cell compartment. ME deficiency leads to a reduction in the number of HSCs and a complete loss of long-term repopulation capacity, whereas the stem cell compartment is shifted from quiescence to active cycling. Genetic exploration of the relative roles of endogenous ME and EVI1 isoforms revealed that ME preferentially rescues long-term HSC defects. RNA-seq analysis in Lin(-)Sca-1(+)c Kit(+) cells (LSKs) of ME(m1) documents near complete silencing of Cdkn1c, encoding negative cell-cycle regulator p57-Kip2. Reintroduction of ME into ME(m1) LSKs leads to normalization of both p57-Kip2 expression and growth control. Our results clearly demonstrate a critical role of PR-domain-containing ME in linking p57-kip2 regulation to long-term HSC function. PMID- 21666054 TI - Thrombogenicity and cardiovascular effects of ambient air pollution. AB - Exposure to air pollution is associated with adverse effects on health. In particular, a strong epidemiologic association is observed between acute and chronic exposures to particulate matter and the occurrence of cardiovascular events, coronary artery disease, cerebrovascular disease and venous thromboembolism, especially among older people and people with diabetes and previous cardiovascular conditions. Multiple mechanisms have been postulated to cause the increase in atherothrombotic and thromboembolic events, including the activation by particulate matter of inflammatory pathways and hemostasis factors, production of reactive oxygen species through the oxidative stress pathway, alterations in vascular tone, and decreased heart rate variability (a marker of cardiac autonomic dysfunction and a predictor of sudden cardiac death and arrhythmias). Current knowledge on the biologic mechanisms and the clinical effect of short- and long-term exposure to particulate air pollutants is discussed, emphasizing that life expectancy improved significantly in sites where air pollutants were controlled. PMID- 21666055 TI - A critical role for dendritic cells in the formation of lymphatic vessels within tertiary lymphoid structures. AB - Ectopic, or tertiary, lymphoid aggregates often form in chronically inflamed areas. Lymphatic vessels, as well as high endothelial venules, form within these lymphoid aggregates, but the mechanisms underlying their development are poorly understood. Overexpression of the chemokine CCL21 in the thyroid of transgenic mice leads to formation of lymphoid aggregates containing topologically segregated T and B lymphocytes, dendritic cells (DCs), and specialized vasculature, including Lyve-1(+)/Prox-1(+) lymphatic vessels. In this article, we show that adoptive transfer of mature CD4(+) T cells into animals expressing CCL21 in a RAG-deficient background promotes the influx of host NK cells and DCs into the thyroid and the formation of new lymphatic vessels within 10 d. This process is dependent on the expression of lymphotoxin ligands by host cells, but not by the transferred CD4(+) T cells. Ablation of host DCs, but not NK cells, reduces the formation of new lymphatic vessels in the thyroid. Taken together, these data suggest a critical role for CD11c(+) DCs in the induction of lymphangiogenesis in tertiary lymphoid structures. PMID- 21666056 TI - Physical and functional bivalency observed among TCR/CD3 complexes isolated from primary T cells. AB - Unlike BCR and secreted Ig, TCR expression is not thought to occur in a bivalent form. The conventional monovalent model of TCR/CD3 is supported by published studies of complexes solubilized in the detergent digitonin, in which bivalency was not observed. We revisited the issue of TCR valency by examining complexes isolated from primary alphabeta T cells after solubilization in digitonin. Using immunoprecipitation followed by flow cytometry, we unexpectedly observed TCR/CD3 complexes that contained two TCRs per complex. Standard anti-TCR Abs, being bivalent themselves, tended to bind with double occupancy to bivalent TCRs; this property masked the presence of the second TCR per complex in certain Ab binding assays, which may partially explain why previous data did not reveal these bivalent complexes. We also found that the prevalence of bivalency among fully assembled, mature TCR/CD3 complexes was sufficient to impact the functional performance of immunoprecipitated TCRs in binding antigenic peptide/MHC-Ig fusion proteins. Both TCR positions per bivalent complex required an Ag-specific TCR to effect optimal binding to these soluble ligands. Therefore, we conclude that in primary T cells, TCR/CD3 complexes can be found that are physically and functionally bivalent. The expression of bivalent TCR/CD3 complexes has implications regarding potential mechanisms by which Ag may trigger signaling. It also suggests the possibility that the potential for bivalent expression could represent a general feature of Ag receptors. PMID- 21666057 TI - Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization. AB - Although several subsets of intestinal APCs have been described, there has been no systematic evaluation of their phenotypes, functions, and regional localization to date. In this article, we used 10-color flow cytometry to define the major APC subsets in the small and large intestine lamina propria. Lamina propria APCs could be subdivided into CD11c(+)CD11b(-), CD11c(+)CD11b(+), and CD11c(dull)CD11b(+) subsets. CD11c(+)CD11b(-) cells were largely CD103(+)F4/80(-) dendritic cells (DCs), whereas the CD11c(+)CD11b(+) subset comprised CD11c(+)CD11b(+)CD103(+)F4/80(-) DCs and CD11c(+)CD11b(+)CD103(-)F4/80(+) macrophage-like cells. The majority of CD11c(dull)CD11b(+) cells were CD103( )F4/80(+) macrophages. Although macrophages were more efficient at inducing Foxp3(+) regulatory T (T(reg)) cells than DCs, at higher T cell/APC ratios, all of the DC subsets efficiently induced Foxp3(+) T(reg) cells. In contrast, only CD11c(+)CD11b(+)CD103(+) DCs efficiently induced Th17 cells. Consistent with this, the regional distribution of CD11c(+)CD11b(+)CD103(+) DCs correlated with that of Th17 cells, with duodenum > jejunum > ileum > colon. Conversely, CD11c(+)CD11b(-)CD103(+) DCs, macrophages, and Foxp3(+) T(reg) cells were most abundant in the colon and scarce in the duodenum. Importantly, however, the ability of DC and macrophage subsets to induce Foxp3(+) T(reg) cells versus Th17 cells was strikingly dependent on the source of the mouse strain. Thus, DCs from C57BL/6 mice from Charles River Laboratories (that have segmented filamentous bacteria, which induce robust levels of Th17 cells in situ) were more efficient at inducing Th17 cells and less efficient at inducing Foxp3(+) T(reg) cells than DCs from B6 mice from The Jackson Laboratory. Thus, the functional specializations of APC subsets in the intestine are dependent on the T cell/APC ratio, regional localization, and source of the mouse strain. PMID- 21666058 TI - Protein kinase C and NF-kappaB-dependent CD4 downregulation in macrophages induced by T cell-derived soluble factors: consequences for HIV-1 infection. AB - Upon activation, CD4(+) T cells release cytokines, chemokines, and other soluble factors that influence the kinetics of HIV-1 replication in macrophages (M). In this article, we show that activation of human primary T cells suppresses the early stages of HIV-1 replication in human primary Mphi by downregulating the main cellular receptor for the virus CD4. The secreted factors responsible for this effect have a molecular mass greater than conventional cytokines, are independent of Th1 or Th2 polarization, and are not IFN-gamma, IL-16, RANTES, or macrophage inhibitory factor, as revealed by cytokine array analysis and neutralization assays. CD4 downregulation is entirely posttranslational and involves serine phosphorylation of CD4 and its targeting to an intracellular compartment destined for acidification and degradation. CD4 downregulation is dependent on the activities of both protein kinase C and NF-kappaB as well as the proteasomes. Using high-resolution liquid chromatography-tandem mass spectrometry analysis in conjugation with label-free protein quantitation software, we found that proteins that promote Mphi adherence and spreading, such as attractin, fibronectin, and galectin-3-binding protein, were significantly overrepresented in the activated T cell supernatant fractions. These results reveal the existence of previously unreported anti-HIV-1 proteins, released by activated T cells that downregulate CD4 expression, and are of fundamental importance to understand the kinetics of HIV infection in vivo. PMID- 21666059 TI - Ginsenoside Rg1, a novel glucocorticoid receptor agonist of plant origin, maintains glucocorticoid efficacy with reduced side effects. AB - Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, they cause debilitating side effects, which limit the use of these compounds. In the past decade, many researchers have attempted to find so-called dissociated GCs that have separate distinct transactivation and transrepression activities. Anti-inflammation of GCs is a result of glucocorticoid receptor (GR)-mediated transactivation and transrepression in some tissues, similar to their side effects; therefore, the goal to discover a compound that has anti-inflammatory properties, but lacks the negative side effects seen with GCs, has yet to be achieved. In the present study, we introduce a plant-derived compound, ginsenoside Rg1, which possesses GC and estrogen-like activities. In this study, we show that Rg1 downmodulates LPS-induced proinflammatory cytokine release and inhibits NF-kappaB nuclear translocation and DNA binding activity. The negative effects on NF-kappaB activation are due to a decrease in IkappaB phosphorylation and protein stabilization. Furthermore, the inhibitory effect of Rg1 on NF-kappaB is GR-dependent, as small interfering RNA knockdown of GR abrogated this function. Rg1 also displayed profound inhibitory effects on LPS-induced MAPK activation. Importantly, Rg1 did not impair proliferation or differentiation of mouse osteoblasts. Finally, we show that Rg1 can effectively inhibit acute and chronic inflammation in vivo, but it does not cause hyperglycemia or osteoporosis as seen with dexamethasone. These results suggest that ginsenoside Rg1 may serve as a novel anti-inflammatory agent and may exhibit a potential profile for therapeutic intervention in inflammatory diseases. PMID- 21666060 TI - Cholinergic regulatory lymphocytes re-establish neuromodulation of innate immune responses in sepsis. AB - Many anti-inflammatory strategies that are successful in treating sepsis in healthy animals fail in clinical trials, in part because sepsis normally involves immunocompromised patients, and massive lymphocyte apoptosis prevents immunomodulation. In this article, we report a new set of regulatory lymphocytes that are able to re-establish the cholinergic anti-inflammatory modulation and to provide therapeutic advantages in sepsis. The vagus nerve controls inflammation in healthy, but not in septic, mice. Likewise, vagus nerve and cholinergic agonists fail to control inflammation in splenectomized and nude animals. Unlike typical suppressor CD25(+) cells, CD4(+)CD25(-) lymphocytes re-establish the anti inflammatory potential of the vagus nerve and cholinergic agonists in immunocompromised and septic animals. These cholinergic lymphocytes re-establish splenic protection and the potential of cholinergic agonists to rescue immunocompromised animals from established sepsis. The study results revealed these new regulatory lymphocytes as, to our knowledge, the first known physiological target for neuromodulation of the innate immune responses and a potential therapeutic target for sepsis. PMID- 21666061 TI - Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis. AB - Functional NK cell deficiencies are associated with autoimmune diseases, including multiple sclerosis. NK cells can promote or inhibit adaptive immunity via either cytokine production or cytotoxicity toward immature dendritic cells and activated T cells. In humans, this immunoregulatory role resides in the CD56(bright) NK cell subset, which is selectively expanded by daclizumab, a CD25 blocking Ab that suppresses multiple sclerosis-associated inflammation. The objective of this study was to investigate the molecular mechanisms underlying the cytotoxicity of NK cells toward activated T cells. We demonstrated that NK cells induce caspase-independent apoptosis that requires NK cell degranulation and causes mitochondrial dysfunction in activated T cells. Although both granzyme A and granzyme K (GrK) can mediate this form of apoptosis, quantitatively we observed preferential transfer of GrK to target cells. Consequently, gene silencing of GrK in the NK-92 cell line, which retains functional characteristics of CD56(bright) NK cells, profoundly inhibited the ability of NK-92 cells to kill activated syngeneic T cells. Finally, we demonstrated that daclizumab treatment significantly enhanced this newly defined mechanism of cytotoxicity by CD56(bright) NK cells. Our study describes the important physiological role that GrK plays in immunoregulation of adaptive immunity in humans and indicates that therapeutic exploitation of this pathway is beneficial in controlling autoimmunity. PMID- 21666062 TI - Suppression of TLR9 immunostimulatory motifs in the genome of a gammaherpesvirus. AB - Multiple receptors within the innate immune system have evolved to recognize nucleic acids as signatures of viral infection. It is believed that this specificity is essential for viral detection, as viruses often lack other invariant features that can serve as suitable targets for innate receptors. One such innate receptor, TLR9, has been implicated in the detection of many dsDNA viruses. In this study, we investigate the detection of murine gammaherpesvirus 68 (MHV68) by TLR9. We find that the genomic DNA of the murine CMV, a very potent inducer of innate responses. Genome-wide analysis of the number of stimulatory versus nonstimulatory CpG motifs present in the genome of each virus reveals that the MHV68 genome contains only a fraction of the number of immunostimulatory motifs present in murine CMV. Notably, MHV68 appears to have selectively suppressed the number of stimulatory motifs through cytosine to thymine conversion. These data suggest that certain viruses may have evolved and modified their genomic content to avoid recognition by nucleic acid-sensing receptors of the innate immune system. PMID- 21666064 TI - On the inference of function from structure using biomechanical modelling and simulation of extinct organisms. AB - Biomechanical modelling and simulation techniques offer some hope for unravelling the complex inter-relationships of structure and function perhaps even for extinct organisms, but have their limitations owing to this complexity and the many unknown parameters for fossil taxa. Validation and sensitivity analysis are two indispensable approaches for quantifying the accuracy and reliability of such models or simulations. But there are other subtleties in biomechanical modelling that include investigator judgements about the level of simplicity versus complexity in model design or how uncertainty and subjectivity are dealt with. Furthermore, investigator attitudes toward models encompass a broad spectrum between extreme credulity and nihilism, influencing how modelling is conducted and perceived. Fundamentally, more data and more testing of methodology are required for the field to mature and build confidence in its inferences. PMID- 21666063 TI - H2O2: a dynamic neuromodulator. AB - Increasing evidence implicates hydrogen peroxide (H(2)O(2)) as an intracellular and intercellular signaling molecule that can influence processes from embryonic development to cell death. Most research has focused on relatively slow signaling, on the order of minutes to days, via second messenger cascades. However, H(2)O(2) can also mediate subsecond signaling via ion channel activation. This rapid signaling has been examined most thoroughly in the nigrostriatal dopamine (DA) pathway, which plays a key role in facilitating movement mediated by the basal ganglia. In DA neurons of the substantia nigra, endogenously generated H(2)O(2) activates ATP-sensitive K(+) (K-ATP) channels that inhibit DA neuron firing. In the striatum, H(2)O(2) generated downstream from glutamatergic AMPA receptor activation in medium spiny neurons acts as a diffusible messenger that inhibits axonal DA release, also via K-ATP channels. The source of dynamically generated H(2)O(2) is mitochondrial respiration; thus, H(2)O(2) provides a novel link between activity and metabolism via K-ATP channels. Additional targets of H(2)O(2) include transient receptor potential (TRP) channels. In contrast to the inhibitory effect of H(2)O(2) acting via K-ATP channels, TRP channel activation is excitatory. This review describes emerging roles of H(2)O(2) as a signaling agent in the nigrostriatal pathway and basal ganglia neurons. PMID- 21666066 TI - Inappropriate use of D-dimer assay and pulmonary CT angiography in the evaluation of suspected acute pulmonary embolism. AB - The authors question whether the d-dimer assay and pulmonary computed tomography angiography (CTA) are being used appropriately to evaluate suspected acute pulmonary embolism (PE) at their hospital. To answer this question, a retrospective review was performed on all emergency department (ED) patients who underwent d-dimer assay and/or CTA from August 15, 2008, to August 14, 2009. The authors' algorithm for diagnosing PE requires that patients with low or intermediate probability of acute PE undergo a d-dimer assay, followed by CTA if the d-dimer is positive. Patients with high probability of PE should have CTA performed without a d-dimer assay. This result suggests that d-dimer assay and CTA are used inappropriately to evaluate patients with suspected acute PE in our ED. The low threshold for initiating an evaluation for PE decreases the prevalence of PE in this population. PMID- 21666067 TI - An alternative approach for detecting interferences in enzymatic acetaminophen assays. PMID- 21666068 TI - Importance of cystatin C assay standardization. PMID- 21666065 TI - UGT1A6 and UGT2B15 polymorphisms and acetaminophen conjugation in response to a randomized, controlled diet of select fruits and vegetables. AB - Acetaminophen (APAP) glucuronidation is thought to occur mainly by UDP glucuronosyltransferases (UGT) in the UGT1A family. Interindividual variation in APAP glucuronidation is attributed in part to polymorphisms in UGT1As. However, evidence suggests that UGT2B15 may also be important. We evaluated, in a controlled feeding trial, whether APAP conjugation differed by UGT1A6 and UGT2B15 genotypes and whether supplementation of known dietary inducers of UGT (crucifers, soy, and citrus) modulated APAP glucuronidation compared with a diet devoid of fruits and vegetables (F&V). Healthy adults (n = 66) received 1000 mg of APAP orally on days 7 and 14 of each 2-week feeding period and collected saliva and urine over 12 h. Urinary recovery of the percentage of the APAP dose as free APAP was higher (P = 0.02), and the percentage as APAP glucuronide (APAPG) was lower (P = 0.004) in women. The percentage of APAP was higher among UGT1A6*1/*1 genotypes, relative to *1/*2 and *2/*2 genotypes (P = 0.045). For UGT2B15, the percentage of APAPG decreased (P < 0.0001) and that of APAP sulfate increased (P = 0.002) in an allelic dose-dependent manner across genotypes from *1/*1 to *2/*2. There was a significant diet * UGT2B15 genotype interaction for the APAPG ratio (APAPG/total metabolites * 100) (P = 0.03), with *1/*1 genotypes having an approximately 2-fold higher F&V to basal diet difference in response compared with *1/*2 and *2/*2 genotypes. Salivary APAP maximum concentration (C(max)) was significantly higher in women (P = 0.0003), with F&V (P = 0.003), and among UGT1A6*2/*2 and UGT2B15*1/*2 genotypes (P = 0.02 and 0.002, respectively). APAP half-life was longer in UGT2B15*2/*2 genotypes with F&V (P = 0.009). APAP glucuronidation was significantly influenced by the UGT2B15*2 polymorphism, supporting a role in vivo for UGT2B15 in APAP glucuronidation, whereas the contribution of UGT1A6*2 was modest. Selected F&V known to affect UGT activity led to greater glucuronidation and less sulfation. PMID- 21666069 TI - Improving biomarker identification with better designs and reporting. PMID- 21666070 TI - Homocysteine, B vitamins, and the risk of cardiovascular disease. PMID- 21666071 TI - A step toward simplicity for a complex analyte. PMID- 21666072 TI - Identification and characterization of genes required for cell-to-cell fusion in Neurospora crassa. AB - A screening procedure was used to identify cell fusion (hyphal anastomosis) mutants in the Neurospora crassa single gene deletion library. Mutants with alterations in 24 cell fusion genes required for cell fusion between conidial anastomosis tubes (CATs) were identified and characterized. The cell fusion genes identified included 14 genes that are likely to function in signal transduction pathways needed for cell fusion to occur (mik-1, mek-1, mak-1, nrc-1, mek-2, mak 2, rac-1, pp2A, so/ham-1, ham-2, ham-3, ham-5, ham-9, and mob3). The screening experiments also identified four transcription factors that are required for cell fusion (adv-1, ada-3, rco-1, and snf5). Three genes encoding proteins likely to be involved in the process of vesicular trafficking were also identified as needed for cell fusion during the screening (amph-1, ham-10, pkr1). Three of the genes identified by the screening procedure, ham-6, ham-7, and ham-8, encode proteins that might function in mediating the plasma membrane fusion event. Three of the putative signal transduction proteins, three of the transcription factors, the three putative vesicular trafficking proteins, and the three proteins that might function in mediating cell fusion had not been identified previously as required for cell fusion. PMID- 21666073 TI - Genomic characterization of Neoparamoeba pemaquidensis (Amoebozoa) and its kinetoplastid endosymbiont. AB - We have performed a genomic characterization of a kinetoplastid protist living within the amoebozoan Neoparamoeba pemaquidensis. The genome of this "Ichthyobodo related organism" was found to be unexpectedly large, with at least 11 chromosomes between 1.0 and 3.5 Mbp and a total genome size of at least 25 Mbp. PMID- 21666074 TI - The quorum-sensing molecules farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans. AB - Living as a commensal, Candida albicans must adapt and respond to environmental cues generated by the mammalian host and by microbes comprising the natural flora. These signals have opposing effects on C. albicans, with host cues promoting the yeast-to-hyphal transition and bacteria-derived quorum-sensing molecules inhibiting hyphal development. Hyphal development is regulated through modulation of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and it has been postulated that quorum-sensing molecules can affect filamentation by inhibiting the cAMP pathway. Here, we show that both farnesol and 3-oxo-C(12) homoserine lactone, a quorum-sensing molecule secreted by Pseudomonas aeruginosa, block hyphal development by affecting cAMP signaling; they both directly inhibited the activity of the Candida adenylyl cyclase, Cyr1p. In contrast, the 12-carbon alcohol dodecanol appeared to modulate hyphal development and the cAMP signaling pathway without directly affecting the activity of Cyr1p. Instead, we show that dodecanol exerted its effects through a mechanism involving the C. albicans hyphal repressor, Sfl1p. Deletion of SFL1 did not affect the response to farnesol but did interfere with the response to dodecanol. Therefore, quorum sensing in C. albicans is mediated via multiple mechanisms of action. Interestingly, our experiments raise the possibility that the Burkholderia cenocepacia diffusible signal factor, BDSF, also mediates its effects via Sfl1p, suggesting that dodecanol's mode of action, but not farnesol or 3-oxo-C(12) homoserine lactone, may be used by other quorum-sensing molecules. PMID- 21666075 TI - Recombination can either help maintain very short telomeres or generate longer telomeres in yeast cells with weak telomerase activity. AB - Yeast mutants lacking telomerase are able to elongate their telomeres through processes involving homologous recombination. In this study, we investigated telomeric recombination in several mutants that normally maintain very short telomeres due to the presence of a partially functional telomerase. The abnormal colony morphology present in some mutants was correlated with especially short average telomere length and with a requirement for RAD52 for indefinite growth. Better-growing derivatives of some of the mutants were occasionally observed and were found to have substantially elongated telomeres. These telomeres were composed of alternating patterns of mutationally tagged telomeric repeats and wild-type repeats, an outcome consistent with amplification occurring via recombination rather than telomerase. Our results suggest that recombination at telomeres can produce two distinct outcomes in the mutants we studied. In occasional cells, recombination generates substantially longer telomeres, apparently through the roll-and-spread mechanism. However, in most cells, recombination appears limited to helping to maintain very short telomeres. The latter outcome likely represents a simplified form of recombinational telomere maintenance that is independent of the generation and copying of telomeric circles. PMID- 21666076 TI - Interface of Candida albicans biofilm matrix-associated drug resistance and cell wall integrity regulation. AB - Candida albicans frequently infects medical devices by growing as a biofilm, i.e., a community of adherent organisms entrenched in an extracellular matrix. During biofilm growth, Candida spp. acquire the ability to resist high concentrations of antifungal drugs. One recently recognized biofilm resistance mechanism involves drug sequestration by matrix beta-1,3 glucan. Using a candidate gene approach, we investigated potential C. albicans beta-1,3-glucan regulators, based on their homology to Saccharomyces cerevisiae, including SMI1 and protein kinase C (PKC) pathway components. We identified a role for the SMI1 in biofilm matrix glucan production and development of the associated drug resistance phenotype. This pathway appears to act through transcription factor Rlmp and glucan synthase Fks1p. The phenotypes of these mutant biofilms mimicked those of the smi1Delta/smi1Delta biofilm, and overexpression of FKS1 in the smi1Delta/smi1Delta mutant restored the biofilm resistant phenotype. However, control of this pathway is distinct from that of the upstream PKC pathway because the pkc1Delta/pkc1Delta, bck1Delta/bck1Delta, mkk2Delta/mkk2Delta, and mkc1Delta/mkc1Delta biofilms retained the resistant phenotype of the parent strain. In addition, resistance to cell-perturbing agents and gene expression data do not support a significant role for the cell wall integrity pathway during the biofilm formation. Here we show that Smi1p functions in conjunction with Rlm1p and Fks1p to produce drug-sequestering biofilm beta-glucan. Our work provides new insight into how the C. albicans biofilm matrix production and drug resistance pathways intersect with the planktonic cell wall integrity pathway. This novel connection helps explain how pathogens in a multicellular biofilm community are protected from anti-infective therapy. PMID- 21666077 TI - Functional analyses of two acetyl coenzyme A synthetases in the ascomycete Gibberella zeae. AB - Acetyl coenzyme A (acetyl-CoA) is a crucial metabolite for energy metabolism and biosynthetic pathways and is produced in various cellular compartments with spatial and temporal precision. Our previous study on ATP citrate lyase (ACL) in Gibberella zeae revealed that ACL-dependent acetyl-CoA production is important for histone acetylation, especially in sexual development, but is not involved in lipid synthesis. In this study, we deleted additional acetyl-CoA synthetic genes, the acetyl-CoA synthetases (ACS genes ACS1 and ACS2), to identify alternative acetyl-CoA production mechanisms for ACL. The ACS1 deletion resulted in a defect in sexual development that was mainly due to a reduction in 1-palmitoyl-2-oleoyl 3-linoleoyl-rac-glycerol production, which is required for perithecium development and maturation. Another ACS coding gene, ACS2, has accessorial functions for ACS1 and has compensatory functions for ACL as a nuclear acetyl-CoA producer. This study showed that acetate is readily generated during the entire life cycle of G. zeae and has a pivotal role in fungal metabolism. Because ACSs are components of the pyruvate-acetaldehyde-acetate pathway, this fermentation process might have crucial roles in various physiological processes for filamentous fungi. PMID- 21666078 TI - MicroRNA-199a-3p is downregulated in human osteosarcoma and regulates cell proliferation and migration. AB - microRNAs (miRNA, miR) play an important role in cancer cell growth and migration; however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. By applying a miRNA microarray platform and unsupervised hierarchical clustering analysis, we found that several miRNAs have altered expression levels in osteosarcoma cell lines and tumor tissues when compared with normal human osteoblasts. Three miRNAs, miR-199a-3p, miR-127-3p, and miR-376c, were significantly decreased in osteosarcoma cell lines, whereas miR-151-3p and miR-191 were increased in osteosarcoma cell lines in comparison with osteoblasts. Transfection of precursor miR-199a-3p into osteosarcoma cell lines significantly decreased cell growth and migration, thus indicating that the inhibition effect is associated with an increase in the G(1)-phase and a decrease of the S-phase cell population. In addition, we observed decreased mTOR and Stat3 expression in miR-199a-3p transfected cells. This study provides new insights for miRNAs in osteosarcoma and suggests that miR-199a-3p may play a functional role in osteosarcoma cell growth and proliferation. Restoring miR-199a-3p's function may provide therapeutic benefits in osteosarcoma. PMID- 21666080 TI - Pharmacists as mid-level practitioners/providers. AB - With recent changes in health-care delivery, the profession of pharmacy is presented with opportunities for expanded involvement in direct patient care as mid-level practitioners/providers. Will pharmacists be proactive in realizing these opportunities? Expanding current roles to improve medication-related health outcomes for patients will require that pharmacists establish collaborative practice relationships, differentiate our unique services from those of other mid level practitioners/providers, and share these results with the public and other health-care providers. This article encourages pharmacists to advocate for advancing pharmacy practice to meet the needs of society, to continue the dialogue regarding an expanded scope of practice for pharmacists as mid-level practitioners/providers, and to actively engage in developing these new roles. PMID- 21666081 TI - Hemorrhagic and thrombotic events associated with generic substitution of warfarin in patients with atrial fibrillation: a retrospective analysis. AB - BACKGROUND: Substitution of generic warfarin for imprint warfarin (Coumadin; DuPont/Bristol-Myers Squibb) has been a controversial issue due to bioavailability and bioequivalence concerns. OBJECTIVE: To assess the risk of thrombotic and hemorrhagic events following substitution of warfarin formulations in patients with atrial fibrillation (AF). METHODS: Historical cohort analysis was performed using a commercial insurance claims database. Adults with a diagnosis of AF between January 2003 and December 2007, with 16 or more months of continuous eligibility, a warfarin prescription within 30 days after index AF diagnosis, and at least 3 warfarin prescription fills during the follow-up period were included. Individuals with AF diagnosis or warfarin prescription during the pre-index period were excluded. Cox proportional hazard regression models controlling for sex and baseline comorbidities (Charlson comorbidity index, CCI) were used to evaluate the risks of thrombotic and hemorrhagic events following warfarin formulation switches. RESULTS: Of 37,756 subjects included in the analysis (mean age 70.96 years, 42.3% females), 12,996 (34.4%) switched warfarin formulations, 20,292 (53.7%) used only 1 generic product, and 4468 (11.8%) used only Coumadin during follow-up. Compared with continued use of Coumadin, switching from that product to the generic formulation was associated with a significantly higher risk of thrombotic events (HR = 1.81; 95% CI 1.42 to 2.31). Similar findings were observed for switching from generic warfarin to Coumadin (HR = 1.76; 95% CI 1.35 to 2.30), and from 1 generic to another generic product (HR = 1.89; 95% CI 1.57 to 2.29). Similarly, switching from Coumadin to generic warfarin (HR = 1.51; 95% CI 1.17 to 1.93), generic warfarin to Coumadin (HR = 1.60; 95% CI 1.23 to 2.1), and from 1 generic to another generic product (HR = 1.74; 95% CI 1.45 to 2.11) were associated with significantly higher risk of hemorrhage than remaining on Coumadin. CONCLUSIONS: Switching warfarin formulations exposed patients with AF to a higher risk of bleeding events compared to remaining on a single product. Maintaining patients on a product with consistent bioavailability may optimize the risk-benefit balance of anticoagulation therapy. PMID- 21666084 TI - Mirtazapine-induced hepatocellular-type liver injury. PMID- 21666086 TI - Use of recalibrated serum creatinine concentrations for adjustment of drug dosages: determination of values compatible with conventional dosing recommendations. AB - BACKGROUND: Measurement of serum creatinine concentration is central to evaluation of kidney function. Recent efforts to increase the accuracy of this evaluation have led to recalibration of laboratory instruments. Recalibrated creatinine concentrations often are lower than previously reported. OBJECTIVES: To derive a method for converting recalibrated serum creatinine (RSCr) concentrations into values that are compatible with recommended equations for calculation of estimated creatinine clearance. METHODS: Beginning with a proprietary array of recalibrated and corresponding non-recalibrated serum creatinine (NR-SCr) numerical data provided by the instrument manufacturer, relationships were examined with exponential and linear regression analyses. The validity of derived values for NR-SCr obtained through these analyses was tested by comparison of proprietary and derived serum creatinine concentrations and calculated creatinine clearance values. RESULTS: Analyses revealed that relationships between R-SCr and NR-SCr creatinine were essentially linear. Rearranging and solving the equation for a straight line described this relationship as x = (y - b)/m, where x is the derived creatinine value, y is the R-SCr concentration, and, for our laboratory instrument, best parameters for m and b equal to 0.987 and -0.07, respectively. Use of these parameters to derive NR-SCr values was shown to significantly decrease positive bias in subsequent creatinine clearance calculations. CONCLUSIONS: As compared to R-SCr concentrations, use of derived NR-SCr values can improve the predictive performance of conventional equations used to calculate estimated creatinine clearance. PMID- 21666087 TI - Oral ferrous sulfate does not increase preoperative hemoglobin in patients scheduled for hip or knee arthroplasty. AB - BACKGROUND: Low hemoglobin (Hb) concentrations before lower limb joint replacement are associated with the need for blood transfusions and increased mortality. To optimize preoperative Hb, blood conservation protocols often recommend oral iron supplements, even in nonanemic patients. OBJECTIVE: To investigate the impact of ferrous sulfate on the change in Hb prior to hip or knee arthroplasty and evaluate the effect of oral iron on hematocrit, mean corpuscular volume (MCV), ferritin, and transferrin saturation, as well as its tolerability and treatment adherence. METHODS: We conducted a prospective, observational cohort study of adults with Hb concentrations between 10 and 15 g/dL who received iron supplementation prior to hip or knee arthroplasty. Systemic inflammatory diseases, vitamin B(12) or folate deficiency, and current use of iron supplements, intravenous iron, or erythropoietin were exclusion criteria. All participants were prescribed ferrous sulfate 300 mg 3 times daily for a minimum of 3 weeks. Complete blood cell counts and iron studies were performed before therapy and surgery. RESULTS: Eighty-seven patients with a mean (SD) Hb of 13.47 (0.84) g/dL were included in the study. Preoperative Hb decreased after treatment with iron (-0.14 [0.53] g/dL, p = 0.015). Hematocrit also declined (-0.6% [1.8%], p = 0.002), whereas ferritin increased (25.8 [38.6] ng/mL, p < 0.001). No significant change was seen in MCV and transferrin saturation. The most common adverse effects were constipation (33.3%), heartburn (13.8%), and abdominal pain (12.6%). The adherence rate was 67.1%. CONCLUSIONS: Oral ferrous sulfate supplementation is not an effective method to increase preoperative Hb in patients scheduled for hip or knee arthroplasty, and its use is associated with adverse effects. PMID- 21666088 TI - Ulipristal acetate: contraceptive or contragestive? AB - Ulipristal acetate is the first selective progesterone receptor modulator approved for postcoital contraception in the US. It appears to be significantly more effective in inhibition of ovulation than other forms of emergency contraception. However, ulipristal acetate is structurally similar to mifepristone, and several lines of evidence suggest that a postfertilization mechanism of action is also operative. This mechanism of action is considered to be contragestive versus contraceptive. Ulipristal acetate administration is contraindicated in a known or suspected pregnancy; however, it could quite possibly be used as an effective abortifacient. Health-care providers should inform patients of the possibility of both mechanisms of action with use of this drug. PMID- 21666089 TI - Ulipristal acetate for emergency contraception. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of data of ulipristal acetate, a new emergency contraceptive approved for use up to 120 hours after unprotected intercourse. DATA SOURCES: Articles pertaining to the topic were identified and reviewed through searches of PubMed (1994-March 2011) and clinicaltrials.gov, using the key terms ulipristal and CDB-2914. Ella approval documents were obtained and reviewed from Drugs@FDA on the Food and Drug Administration (FDA) Web site. STUDY SELECTION AND DATA EXTRACTION: All published data and FDA approval documents examining pharmacologic, pharmacokinetic, and clinical studies related to ulipristal acetate as an emergency contraceptive were evaluated. Selected studies included 3 randomized trials and 1 meta-analysis. DATA SYNTHESIS: Ulipristal acetate is a progesterone agonist/antagonist emergency contraceptive approved for the prevention of pregnancy to be taken as soon as possible, within 120 hours after unprotected intercourse or a known or suspected contraceptive failure. Based upon results of the Phase 3 clinical trials used to obtain approval, ulipristal acetate administration was at least as effective as levonorgestrel in the reduction of pregnancy rate when studied alone after unprotected intercourse and when taken up to 120 hours after unprotected intercourse. Commonly reported adverse effects associated with ulipristal acetate in trials included headache, breast tenderness, nausea, and abdominal pain. CONCLUSIONS: Ulipristal acetate is effective as an emergency contraceptive for up to 120 hours after unprotected intercourse. Because ulipristal is available only via prescription, it may be covered by insurance. However, the additional factors of travel expenses and time to make and attend a physician appointment must be taken into account when considering use of ulipristal as an emergency contraceptive. Due to the similarity of its structure to mifepristone, controversy regarding ulipristal's mechanism of action has arisen. PMID- 21666090 TI - Substituting warfarin products: what's the source of the problem? AB - Many clinicians have expressed concerns about the bioequivalence of warfarin products, and data suggest that substituting warfarin products may increase the risk of major bleeding and thromboembolic complications. Anecdotal reports and some retrospective studies have reported differences in anticoagulation control after a warfarin product substitution. But the best available evidence prospective, randomized, blinded clinical trials-has failed to validate these observations. Indeed, interpatient and intrapatient variability in anticoagulation control observed before and after warfarin product substitution is very similar. So, while differences in product standardization, bioavailability, and bioequivalence make a convenient explanation, the problem lies elsewhere. Perhaps poor communication, fractionated systems of care, and errors are the culprits. PMID- 21666091 TI - Methadone toxicity due to smoking cessation--a case report on the drug-drug interaction involving cytochrome P450 isoenzyme 1A2. AB - OBJECTIVE: To report the potential clinically significant pharmacokinetic interaction that may result from smoking cessation in patients on methadone maintenance therapy. CASE SUMMARY: A 46-year-old white man was admitted to the step-down intensive care unit with decreased respirations and altered mental status related to methadone toxicity. The patient had been on a stable dose of methadone for chronic back pain, and he reported a 1 pack per day, 33-year history of cigarette smoking. After methadone was held for 3 days, his mental status improved. It was later revealed that he had initiated smoking cessation. He was discharged home on a reduced dose of methadone with no further complications. DISCUSSION: While the potential for toxicity exists for patients who are maintained on methadone and decrease the number of cigarettes they smoke, to our knowledge, there is no recent peer-reviewed literature on this interaction. Methadone is a synthetic opioid primarily metabolized by CYP3A4 and, to a lesser degree, by other isoenzymes, including CYP1A2. Polycyclic aromatic hydrocarbons found in tobacco smoke are known CYP1A2 inducers. Decreased intake of cigarette smoke can lead to a reduction in methadone metabolism, resulting in higher serum concentrations. Our case is an example of methadone toxicity secondary to smoking cessation in a patient on methadone maintenance therapy. An objective causality assessment based on the Horn Drug Interaction Probability Scale revealed the interaction to be probable. CONCLUSIONS: Patients on methadone should be monitored for signs of methadone toxicity upon the start of smoking cessation, and the dose of methadone should be adjusted accordingly. Additional information and reports cautioning clinicians and patients about this potential interaction would be beneficial. PMID- 21666093 TI - Treatment of ciprofloxacin nonsusceptible urinary tract infections with ciprofloxacin. PMID- 21666094 TI - Effectiveness of amlodipine-valsartan single-pill combinations: hierarchical modeling of blood pressure and total cardiovascular disease risk outcomes (the EXCELLENT study). AB - BACKGROUND: Both patient- and physician-related factors have been shown to explain variability in the outcomes of antihypertensive treatment. Total cardiovascular risk (TCVR) is increasingly used as a determinant of treatment effectiveness but has also been proposed as a treatment outcome. To our knowledge, no studies have reported how antihypertensive treatment impacts blood pressure and TCVR outcomes. OBJECTIVE: To examine in patients treated with a regimen including single-pill combinations (SPCs) of amlodipine/valsartan (1) blood pressure (BP) reduction and control, total cardiovascular risk (TCVR) change, and TCVR reduction of 1 class or more; (2) hierarchical patient- and physician-level determinants of these outcomes; and (3) predictors of uncontrolled BP and improved TCVR classification. METHODS: A prospective (90 days), multicenter, multilevel pharmacoepidemiologic study was conducted in 3546 patients with hypertension treated with SPC amlodipine/valsartan by 698 general practitioners. Statistical analysis included hierarchical linear and logistic modeling of BP and TCVR outcomes. RESULTS: Mean (SD) systolic BP (SBP) reductions were 20.1 (15.5) mm Hg and diastolic BP (DBP) reductions were 9.8 (10.3) mm Hg, with higher reductions among high-risk patients. SBP, DBP, and SBP/DBP control rates were 33.3%, 45.3%, and 25.5%, respectively, with lower rates among high risk patients. Mean TCVR improvement was a reduction of 0.73 (0.96) classes (-4 [best] to +4 [worst]), with higher reductions for high-risk patients; 58.2% of patients achieved a TCVR reduction of 1 or more classes, with lower percentages for high-risk patients. Twenty-two percent of systolic variability and 26% of diastolic variability in 90-day BP values were attributable to a physician class effect, as was 16% of TCVR change. CONCLUSIONS: Regimens that include SPC amlodipine/valsartan formulations are effective in reducing BP and TCVR in a real world observational setting. Hierarchical modeling identified patient- and physician-related determinants of BP values and TCVR change, as well as independent predictors of uncontrolled BP and reduced TCVR. TCVR is a scientifically feasible and clinically relevant effectiveness outcome of antihypertensive treatment. PMID- 21666095 TI - High-dose dexmedetomidine for sedation in the intensive care unit: an evaluation of clinical efficacy and safety. AB - BACKGROUND: Dexmedetomidine is an alpha(2)-receptor agonist used for sedation in the intensive care unit (ICU). Although dexmedetomidine is labeled for sedation in critically ill patients at doses up to 0.7 MUg/kg/h, recent studies have used more liberal dosing regimens. However, to our knowledge, no study has assessed the clinical impact of doses greater than 0.7 MUg/kg/h when compared to doses within the Food and Drug Administration--approved labeling. OBJECTIVE: To compare the clinical efficacy and safety of high (HD) and low (LD) doses of dexmedetomidine for sedation in the ICU. METHODS: This retrospective study included a sample of patients who received dexmedetomidine in medical, surgical, medical/surgical, and cardiothoracic ICUs between January 1, 2008, and December 1, 2009. Patients were included in the LD group if their maximum dose was less than 0.7 MUg/kg/h or in the HD group if any dose was more than 0.7 MUg/kg/h. Efficacy was determined by the percentage of Richmond Agitation and Sedation Scale (RASS) scores for each patient maintained at goal sedation (-1 to +1), and safety was determined by the incidence of hypotension and bradycardia. RESULTS: Forty-three of 133 patients received HD dexmedetomidine. Patients in the LD group had a significantly higher percentage of RASS scores at goal (60.0% vs 48.6%; p = 0.03), while those in the HD group experienced a higher percentage of RASS scores classified as undersedated (19.2% vs 4.9%; p = 0.001). There was no significant difference in the incidence of hypotension or bradycardia between groups. CONCLUSIONS: Patients treated with HD dexmedetomidine had fewer RASS scores at goal. Our data suggest that increasing the dose of dexmedetomidine may not enhance sedation efficacy or lead to an increased incidence of adverse effects. Patients who have not achieved goal sedation at doses of 0.7 MUg/kg/h or less may not respond further to increased doses. PMID- 21666096 TI - Unusual strategies for using indium gallium nitride grown on silicon (111) for solid-state lighting. AB - Properties that can now be achieved with advanced, blue indium gallium nitride light emitting diodes (LEDs) lead to their potential as replacements for existing infrastructure in general illumination, with important implications for efficient use of energy. Further advances in this technology will benefit from reexamination of the modes for incorporating this materials technology into lighting modules that manage light conversion, extraction, and distribution, in ways that minimize adverse thermal effects associated with operation, with packages that exploit the unique aspects of these light sources. We present here ideas in anisotropic etching, microscale device assembly/integration, and module configuration that address these challenges in unconventional ways. Various device demonstrations provide examples of the capabilities, including thin, flexible lighting "tapes" based on patterned phosphors and large collections of small light emitters on plastic substrates. Quantitative modeling and experimental evaluation of heat flow in such structures illustrates one particular, important aspect of their operation: small, distributed LEDs can be passively cooled simply by direct thermal transport through thin-film metallization used for electrical interconnect, providing an enhanced and scalable means to integrate these devices in modules for white light generation. PMID- 21666097 TI - Sme4 coiled-coil protein mediates synaptonemal complex assembly, recombinosome relocalization, and spindle pole body morphogenesis. AB - We identify a large coiled-coil protein, Sme4/PaMe4, that is highly conserved among the large group of Sordariales and plays central roles in two temporally and functionally distinct aspects of the fungal sexual cycle: first as a component of the meiotic synaptonemal complex (SC) and then, after disappearing and reappearing, as a component of the spindle pole body (SPB). In both cases, the protein mediates spatial juxtaposition of two major structures: linkage of homolog axes through the SC and a change in the SPB from a planar to a bent conformation. Corresponding mutants exhibit defects, respectively, in SC and SPB morphogenesis, with downstream consequences for recombination and astral microtubule nucleation plus postmeiotic nuclear migration. Sme4 is also required for reorganization of recombination complexes in which Rad51, Mer3, and Msh4 foci relocalize from an on-axis position to a between-axis (on-SC) position concomitant with SC installation. Because involved recombinosome foci represent total recombinational interactions, these dynamics are irrespective of their designation for maturation into cross-overs or noncross-overs. The defined dual roles for Sme4 in two different structures that function at distinct phases of the sexual cycle also provide more functional links and evolutionary dynamics among the nuclear envelope, SPB, and SC. PMID- 21666098 TI - Proactive telephone counseling for smoking cessation: meta-analyses by recruitment channel and methodological quality. AB - BACKGROUND: Systematic reviews demonstrated that proactive telephone counseling increases smoking cessation rates. However, these reviews did not differentiate studies by recruitment channel, did not adequately assess methodological quality, and combined different measures of abstinence. METHODS: Twenty-four randomized controlled trials published before December 31, 2008, included seven of active recruitment, 16 of passive recruitment, and one of mixed recruitment. We rated methodological quality on selection bias, study design, confounders, blinding, data collection methods, withdrawals, and dropouts, according to the Quality Assessment Tool for Quantitative Studies. We conducted random effects meta analysis to pool the results according to abstinence type and follow-up time for studies overall and segregated by recruitment channel, and methodological quality. The level of statistical heterogeneity was quantified by I(2). All statistical tests were two-sided. RESULTS: Methodological quality ratings indicated two strong, 10 moderate, and 12 weak studies. Overall, compared with self-help materials or no intervention control groups, proactive telephone counseling had a statistically significantly greater effect on point prevalence abstinence (nonsmoking at follow-up or abstinent for at least 24 hours, 7 days before follow-up) at 6-9 months (relative risk [RR] = 1.26, 95% confidence interval [CI] = 1.11 to 1.43, P < .001, I(2) = 21.4%) but not at 12-15 months after recruitment. This pattern also emerged when studies were segregated by recruitment channel (active, passive) or methodological quality (strong/moderate, weak). Overall, the positive effect on prolonged/continuous abstinence (abstinent for 3 months or longer before follow-up) was also statistically significantly greater at 6-9 months (RR = 1.58, CI = 1.26 to 1.98, P < .001, I(2) = 49.1%) and 12-18 months after recruitment (RR = 1.40, CI = 1.23 to 1.60, P < .001, I(2) = 18.5%). CONCLUSIONS: With the exception of point prevalence abstinence in the long term, these data support previous results showing that proactive telephone counseling has a positive impact on smoking cessation. Proactive telephone counseling increased prolonged/continuous abstinence long term for both actively and passively recruited smokers. PMID- 21666099 TI - Active vs passive recruitment to quitline studies: public health implications. PMID- 21666102 TI - Re: analysis of pharmaceutical experience with decades of rat carcinogenicity testing. Introduction to article by Sistare et al. PMID- 21666101 TI - Adaptive plasticity of vaginal innervation in term pregnant rats. AB - Changes in reproductive status place varied functional demands on the vagina. These include receptivity to male intromission and sperm transport in estrus, barrier functions during early pregnancy, and providing a conduit for fetal passage at parturition. Peripheral innervation regulates vaginal function, which in turn may be influenced by circulating reproductive hormones. We assessed vaginal innervation in diestrus and estrus (before and after the estrous cycle surge in estrogen), and in the early (low estrogen) and late (high estrogen) stages in pregnancy. In vaginal sections from cycling rats, axons immunoreactive for the pan-neuronal marker protein gene product 9.5 (PGP 9.5) showed a small reduction at estrus relative to diestrus, but this difference did not persist after correcting for changes in target size. No changes were detected in axons immunoreactive for tyrosine hydroxylase (sympathetic), vesicular acetylcholine transporter (parasympathetic), or calcitonin gene-related peptide and transient receptor potential vanilloid type 1 (TRPV-1; sensory nociceptors). In rats at 10 days of pregnancy, innervation was similar to that observed in cycling rats. However, at 21 days of pregnancy, axons immunoreactive for PGP 9.5 and each of the subpopulation-selective markers were significantly reduced both when expressed as percentage of sectional area or after correcting for changes in target size. Because peripheral nerves regulate vaginal smooth muscle tone, blood flow, and pain sensitivity, reductions in innervation may represent important adaptive mechanisms facilitating parturition. PMID- 21666103 TI - An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines. AB - Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety. PMID- 21666104 TI - Grading of lesions. PMID- 21666105 TI - Sliding contact fatigue of graded zirconia with external esthetic glass. AB - Veneer chipping and fracture are common failure modes for porcelain-veneered zirconia dental restorations. We hypothesized that the graded glass/zirconia/glass with external esthetic glass (e-GZG) can increase the lifetime and improve resistance to veneer chipping and fracture relative to porcelain-veneered zirconia, while providing necessary esthetics. Previously, we have demonstrated that a graded glass-zirconia surface possesses excellent resistance to occlusal-like sliding contact fatigue. Here, we investigated the sliding contact fatigue response of this graded glass-zirconia surface with external esthetic glass. This external glass is essential for shade options, for preventing excessive wear of opposing dentition, and for protecting Y-TZP from hydrothermal degradation. e-GZG plates were bonded to composite blocks and subjected to prolonged sliding contact up to 10 million cycles at 200 N in water. The resistance to sliding contact fatigue of e-GZG matches that of monolithic Y TZP, and both of these materials demonstrated lifetimes that were orders of magnitude longer than that of porcelain-veneered zirconia. Graded e-GZG is a promising restorative material. PMID- 21666106 TI - Cold suppresses agonist-induced activation of TRPV1. AB - Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction. PMID- 21666107 TI - Acute rosiglitazone treatment is cardioprotective against ischemia-reperfusion injury by modulating AMPK, Akt, and JNK signaling in nondiabetic mice. AB - Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been demonstrated to possess cardioprotective properties during ischemia-reperfusion. However, this notion remains controversial as recent evidence has suggested an increased risk in cardiac events associated with long term use of RGZ in patients with type 2 diabetes. In this study, we tested the hypothesis that acute RGZ treatment is beneficial during I/R by modulating cardioprotective signaling pathways in a nondiabetic mouse model. RGZ (1 MUg/g) was injected intravenously via the tail vein 5 min before reperfusion. Myocardial infarction was significantly reduced in mice treated with RGZ compared with vehicle controls (8.7% +/- 1.1% vs. 20.2% +/- 2.5%, P < 0.05). Moreover, isolated hearts were subjected to 20 min of global, no-flow ischemia in an ex vivo heart perfusion system. Postischemic recovery was significantly improved with RGZ treatment administered at the onset of reperfusion compared with vehicle (P < 0.001). Immunoblot analysis data revealed that the levels of both phospho-AMP activated protein kinase (Thr(172)) and phospho-Akt (Ser(473)) were significantly upregulated when RGZ was administered 5 min before reperfusion compared with vehicle. On the other hand, inflammatory signaling [phospho-JNK (Thr(183)/Tyr(185))] was significantly downregulated as a result of RGZ treatment compared with vehicle (P < 0.05). Intriguingly, pretreatment with the selective PPAR-gamma inhibitor GW-9662 (1 MUg/g iv) 10 min before reperfusion significantly attenuated these beneficial effects of RGZ on the ischemic heart. Taken together, acute treatment with RGZ can reduce ischemic injury in a nondiabetic mouse heart via modulation of AMP-activated protein kinase, Akt, and JNK signaling pathways, which is dependent on PPAR-gamma activation. PMID- 21666108 TI - IRAG and novel PKG targeting in the cardiovascular system. AB - Signaling by nitric oxide (NO) determines several cardiovascular functions including blood pressure regulation, cardiac and smooth muscle hypertrophy, and platelet function. NO stimulates the synthesis of cGMP by soluble guanylyl cyclases and thereby activates cGMP-dependent protein kinases (PKGs), mediating most of the cGMP functions. Hence, an elucidation of the PKG signaling cascade is essential for the understanding of the (patho)physiological aspects of NO. Several PKG signaling pathways were identified, meanwhile regulating the intracellular calcium concentration, mediating calcium desensitization or cytoskeletal rearrangement. During the last decade it emerged that the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG), an endoplasmic reticulum-anchored 125-kDa membrane protein, is a main signal transducer of PKG activity in the cardiovascular system. IRAG interacts specifically in a trimeric complex with the PKG1beta isoform and the inositol 1,4,5-trisphosphate receptor I and, upon phosphorylation, reduces the intracellular calcium release from the intracellular stores. IRAG motifs for phosphorylation and for targeting to PKG1beta and 1,4,5-trisphosphate receptor I were identified by several approaches. The (patho)physiological functions for the regulation of smooth muscle contractility and the inhibition of platelet activation were perceived. In this review, the IRAG recognition, targeting, and function are summarized compared with PKG and several PKG substrates in the cardiovascular system. PMID- 21666109 TI - A three-dimensional insight into the complexity of flow convergence in mitral regurgitation: adjunctive benefit of anatomic regurgitant orifice area. AB - Mitral effective regurgitant orifice area (EROA) using the flow convergence (FC) method is used to quantify the severity of mitral regurgitation (MR). However, it is challenging and prone to interobserver variability in complex valvular pathology. We hypothesized that real-time three-dimensional (3D) transesophageal echocardiography (RT3D TEE) derived anatomic regurgitant orifice area (AROA) can be a reasonable adjunct, irrespective of valvular geometry. Our goals were to 1) to determine the regurgitant orifice morphology and distance suitable for FC measurement using 3D computational flow dynamics and finite element analysis (FEA), and (2) to measure AROA from RT3D TEE and compare it with 2D FC derived EROA measurements. We studied 61 patients. EROA was calculated from 2D TEE images using the 2D-FC technique, and AROA was obtained from zoomed RT3DE TEE acquisitions using prototype software. 3D computational fluid dynamics by FEA were applied to 3D TEE images to determine the effects of mitral valve (MV) orifice geometry on FC pattern. 3D FEA analysis revealed that a central regurgitant orifice is suitable for FC measurements at an optimal distance from the orifice but complex MV orifice resulting in eccentric jets yielded nonaxisymmetric isovelocity contours close to the orifice where the assumptions underlying FC are problematic. EROA and AROA measurements correlated well (r = 0.81) with a nonsignificant bias. However, in patients with eccentric MR, the bias was larger than in central MR. Intermeasurement variability was higher for the 2D FC technique than for RT3DE-based measurements. With its superior reproducibility, 3D analysis of the AROA is a useful alternative to quantify MR when 2D FC measurements are challenging. PMID- 21666110 TI - Role of Pyk2 in cardiac arrhythmogenesis. AB - Proline-rich tyrosine kinase 2 (Pyk2) is a nonreceptor protein kinase regulated by intracellular Ca(2+), CaMK, and PKC and can be activated by different stress signals involved in heart failure. However, Pyk2 has not been investigated in the human heart, and the functional role of Pyk2 signaling at the whole heart level has not been elucidated. We hypothesize that Ca(2+)-dependent activation of Pyk2 is involved in cardiac electrophysiology. We examined the expression of Pyk2 in nonfailing versus ischemic and nonischemic failing human hearts (n = 6 hearts/group). To investigate Pyk2 function, we optically mapped perfused hearts from wild-type (WT; n = 7) and knockout (Pyk2(-/-); n = 8) mice during autonomic stimulation. Experiments were done in control mice and after 1 wk of transverse aortic constriction. We used the Illumina beadarray approach for transcriptional profiling of WT and Pyk2(-/-) mouse ventricles. Western blot analysis revealed a doubling of Pyk2 activation in nonischemic failing versus nonfailing human hearts. In mouse hearts, we observed a much higher probability of ventricular tachyarrhythmia during ACh perfusion in Pyk2(-/-) versus WT mice. Parasympathetic stimulation resulted in a dose-dependent decrease of atrial action potential duration (APD) in both WT and Pyk2(-/-) mice, whereas in ventricles it induced APD shortening in Pyk2(-/-) mice but not in WT mice. Deficiency of Pyk2 abolished ACh-induced prolongation of atrioventricular delay in Pyk2(-/-) mouse hearts but did not affect heart rate. Lower mRNA and protein levels of sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 and higher mRNA levels of Na(+)/Ca(2+) exchanger 1 were detected in Pyk2(-/-) hearts compared with WT hearts. The transverse aortic constriction protocol did not change the phenotype. In conclusion, our results indicate a protective role of Pyk2 with respect to ventricular tachyarrhythmia during parasympathetic stimulation by regulation of gene expression related to Ca(2+) handling. We hypothesize that activation of Pyk2 in the human heart during heart failure may contribute to protection against arrhythmia. PMID- 21666111 TI - Antecedent hydrogen sulfide elicits an anti-inflammatory phenotype in postischemic murine small intestine: role of heme oxygenase-1. AB - We recently demonstrated that preconditioning with an exogenous hydrogen sulfide donor (NaHS-PC) 24 h before ischemia and reperfusion (I/R) causes postcapillary venules to shift to an anti-inflammatory phenotype in C57BL/6J wild-type (WT) mice such that these vessels fail to support increases in postischemic leukocyte rolling (LR) and leukocyte adhesion (LA). The objective of the present study was to determine whether heme oxygenase-1 (HO-1) is a mediator of these anti inflammatory effects noted during I/R in mice preconditioned with NaHS. Intravital fluorescence microscopy was used to visualize LR and LA in single postcapillary venules of the murine small intestine. I/R induced marked increases in LR and LA, effects that were prevented by NaHS-PC. Treatment with the HO inhibitor tin protoporphyrin IX, but not the inactive protoporphyrin CuPPIX, just before reperfusion prevented the anti-inflammatory effects of antecedent NaHS. The anti-inflammatory effects of NaHS-PC were mimicked by preconditioning with hemin, an agent that induces HO-1 expression. We then evaluated the effect of NaHS as a preconditioning stimulus in mice that were genetically deficient in HO 1 (HO-1(-/-) on an H129 background with appropriate WT strain controls). NaHS-PC was ineffective in HO-1(-/-) mice. Our work indicates that HO-1 serves as an effector of the anti-inflammatory effects of NaHS-PC during I/R 24 h later. PMID- 21666112 TI - Ca2+-induced delayed afterdepolarizations are triggered by dyadic subspace Ca22+ affirming that increasing SERCA reduces aftercontractions. AB - Ca(2+)-induced delayed afterdepolarizations (DADs) are depolarizations that occur after full repolarization. They have been observed across multiple species and cell types. Experimental results have indicated that the main cause of DADs is Ca(2+) overload. The main hypothesis as to their initiation has been Ca(2+) overflow from the overloaded sarcoplasmic reticulum (SR). Our results using 37 previously published mathematical models provide evidence that Ca(2+)-induced DADs are initiated by the same mechanism as Ca(2+)-induced Ca(2+) release, i.e., the modulation of the opening of ryanodine receptors (RyR) by Ca(2+) in the dyadic subspace; an SR overflow mechanism was not necessary for the induction of DADs in any of the models. The SR Ca(2+) level is better viewed as a modulator of the appearance of DADs and the magnitude of Ca(2+) release. The threshold for the total Ca(2+) level within the cell (not only the SR) at which Ca(2+) oscillations arise in the models is close to their baseline level (~1- to 3-fold). It is most sensitive to changes in the maximum sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) pump rate (directly proportional), the opening probability of RyRs, and the Ca(2+) diffusion rate from the dyadic subspace into the cytosol (both indirectly proportional), indicating that the appearance of DADs is multifactorial. This shift in emphasis away from SR overload as the trigger for DADs toward a multifactorial analysis could explain why SERCA overexpression has been shown to suppress DADs (while increasing contractility) and why DADs appear during heart failure (at low SR Ca(2+) levels). PMID- 21666113 TI - Chronic resveratrol treatment restores vascular responsiveness of cerebral arterioles in type 1 diabetic rats. AB - Decreased dilation of cerebral arterioles via an increase in oxidative stress may be a contributing factor in the pathogenesis of diabetes-induced complications leading to cognitive dysfunction and/or stroke. Our goal was to determine whether resveratrol, a polyphenolic compound present in red wine, has a protective effect on cerebral arterioles during type 1 diabetes (T1D). We measured the responses of cerebral arterioles in untreated and resveratrol-treated (10 mg.kg(-1).day(-1)) nondiabetic and diabetic rats to endothelial (eNOS) and neuronal (nNOS) nitric oxide synthase (NOS)-dependent agonists and to a NOS-independent agonist. In addition, we harvested brain tissue from nondiabetic and diabetic rats to measure levels of superoxide under basal conditions. Furthermore, we used Western blot analysis to determine the protein expression of eNOS, nNOS, SOD-1, and SOD-2 in cerebral arterioles and/or brain tissue from untreated and resveratrol-treated nondiabetic and diabetic rats. We found that T1D impaired eNOS- and nNOS dependent reactivity of cerebral arterioles but did not alter NOS-independent vasodilation. While resveratrol did not alter responses in nondiabetic rats, resveratrol prevented T1D-induced impairment in eNOS- and nNOS-dependent vasodilation. In addition, superoxide levels were higher in brain tissue from diabetic rats and resveratrol reversed this increase. Furthermore, eNOS and nNOS protein were increased in diabetic rats and resveratrol produced a further increased eNOS and nNOS proteins. SOD-1 and SOD-2 proteins were not altered by T1D, but resveratrol treatment produced a decrease in SOD-2 protein. Our findings suggest that resveratrol restores vascular function and oxidative stress in T1D. We suggest that our findings may implicate an important therapeutic potential for resveratrol in treating T1D-induced cerebrovascular dysfunction. PMID- 21666114 TI - Persistent sympathoexcitation long after submaximal exercise in subjects with and without coronary artery disease. AB - There is an increased risk of cardiac events after exercise, which may, in part, be mediated by the sympathoexcitation that accompanies exercise. The duration and extent of this sympathoexcitation following moderate exercise is unknown, particularly in those with coronary artery disease (CAD). Twenty control subjects (mean age, 51 years) and 89 subjects with CAD (mean age, 58 years) underwent two 16-min bicycle exercise sessions followed by 30-45 min of recovery. Session 1 was performed under physiological conditions to peak workloads of 50-100 W. In session 2, parasympathetic blockade with atropine (0.04 mg/kg) was achieved at end exercise at the same workload as session 1. RR interval was continually recorded, and plasma catecholamines were measured at rest and selected times during exercise and recovery. Parasympathetic effect, measured as the difference in RR interval with and without atropine, did not differ between controls and CAD subjects in recovery. At 30 and 45 min of recovery, RR intervals were 12% and 9%, respectively, shorter than at rest. At 30 and 45 min of recovery, plasma norepinephrine levels were 15% and 12%, respectively, higher than at rest. A brief period of moderate exercise is associated with a prolonged period of sympathoexcitation extending >45 min into recovery and is quantitatively similar among control subjects and subjects with CAD, with or without left ventricular dysfunction. Parasympathetic reactivation occurs early after exercise and is also surprisingly quantitatively similar in controls and subjects with CAD. The role of these autonomic changes in precipitating cardiac events requires further evaluation. PMID- 21666115 TI - Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. AB - Reactive oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 MUg/ml, 18 h) followed by exposure to physiologic concentrations of H(2)O(2) (1-200 MUM). ARVM hypertrophy was measured by [(3)H]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg.kg(-1).day(-1) for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H(2)O(2)-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H(2)O(2) induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H(2)O(2)-treated ARVM. H(2)O(2)-induced p-ERK activity and NF-kappaB activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-kappaB activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROS induced cardiac remodeling. PMID- 21666116 TI - SPARC regulates collagen interaction with cardiac fibroblast cell surfaces. AB - Cardiac tissue from mice that do not express secreted protein acidic and rich in cysteine (SPARC) have reduced amounts of insoluble collagen content at baseline and in response to pressure overload hypertrophy compared with wild-type (WT) mice. However, the cellular mechanism by which SPARC affects myocardial collagen is not clearly defined. Although expression of SPARC by cardiac myocytes has been detected in vitro, immunohistochemistry of hearts demonstrated SPARC staining primarily associated with interstitial fibroblastic cells. Primary cardiac fibroblasts isolated from SPARC-null and WT mice were assayed for collagen I synthesis by [(3)H]proline incorporation into procollagen and by immunoblot analysis of procollagen processing. Bacterial collagenase was used to discern intracellular from extracellular forms of collagen I. Increased amounts of collagen I were found associated with SPARC-null versus WT cells, and the proportion of total collagen I detected on SPARC-null fibroblasts without propeptides [collagen-alpha(1)(I)] was higher than in WT cells. In addition, the amount of total collagen sensitive to collagenase digestion (extracellular) was greater in SPARC-null cells than in WT cells, indicating an increase in cell surface-associated collagen in the absence of SPARC. Furthermore, higher levels of collagen type V, a fibrillar collagen implicated in collagen fibril initiation, were found in SPARC-null fibroblasts. The absence of SPARC did not result in significant differences in proliferation or in decreased production of procollagen I by cardiac fibroblasts. We conclude that SPARC regulates collagen in the heart by modulating procollagen processing and interactions with fibroblast cell surfaces. These results are consistent with decreased levels of interstitial collagen in the hearts of SPARC-null mice being due primarily to inefficient collagen deposition into the extracellular matrix rather than to differences in collagen production. PMID- 21666117 TI - Enhanced endothelin-1 system activity with overweight and obesity. AB - Endothelin (ET)-1-mediated vasoconstrictor tone contributes to the development and progression of several adiposity-related conditions, including hypertension and atherosclerotic vascular disease. The aims of the present study were to determine 1) whether endogenous ET-1 vasoconstrictor activity is elevated in overweight and obese adults, and, if so, 2) whether increased ET-1-mediated vasoconstriction contributes to the adiposity-related impairment in endothelium dependent vasodilation. Seventy-nine adults were studied: 34 normal weight [body mass index (BMI) < 25 kg/m(2)], 22 overweight (BMI >= 25 and < 30 kg/m(2)), and 23 obese (BMI >= 30 kg/m(2)). Forearm blood flow (FBF) responses to intra arterial infusion of ET-1 (5 pmol/min for 20 min) and selective ET-1 receptor blockade (BQ-123, 100 nmol/min for 60 min) were determined. In a subset of the study population, FBF responses to ACh (4.0, 8.0, and 16.0 MUg.100 ml tissue( 1).min(-1)) were measured in the absence and presence of selective ET-1 receptor blockade. The vasoconstrictor response to ET-1 was significantly blunted in overweight and obese adults (~ 70%) compared with normal weight adults. Selective ET-1 receptor blockade elicited a significant vasodilator response (~ 20%) in overweight and obese adults but did not alter FBF in normal weight adults. Coinfusion of BQ-123 did not affect FBF responses to ACh in normal weight adults but resulted in an ~ 20% increase (P < 0.05) in ACh-induced vasodilation in overweight and obese adults. These results demonstrate that overweight and obesity are associated with enhanced ET-1-mediated vasoconstriction that contributes to endothelial vasodilator dysfunction and may play a role in the increased prevalence of hypertension with increased adiposity. PMID- 21666118 TI - In vivo bioluminescence for tracking cell fate and function. AB - Tracking the fate and function of cells in vivo is paramount for the development of rational therapies for cardiac injury. Bioluminescence imaging (BLI) provides a means for monitoring physiological processes in real time, ranging from cell survival to gene expression to complex molecular processes. In mice and rats, BLI provides unmatched sensitivity because of the absence of endogenous luciferase expression in mammalian cells and the low background luminescence emanating from animals. In the field of stem cell therapy, BLI provides an unprecedented means to monitor the biology of these cells in vivo, giving researchers a greater understanding of their survival, migration, immunogenicity, and potential tumorigenicity in a living animal. In addition to longitudinal monitoring of cell survival, BLI is a useful tool for semiquantitative measurements of gene expression in vivo, allowing a better optimization of drug and gene therapies. Overall, this technology not only enables rapid, reproducible, and quantitative monitoring of physiological processes in vivo but also can measure the influences of therapeutic interventions on the outcome of cardiac injuries. PMID- 21666119 TI - Understanding Guyton's venous return curves. AB - Based on observations that as cardiac output (as determined by an artificial pump) was experimentally increased the right atrial pressure decreased, Arthur Guyton and coworkers proposed an interpretation that right atrial pressure represents a back pressure restricting venous return (equal to cardiac output in steady state). The idea that right atrial pressure is a back pressure limiting cardiac output and the associated idea that "venous recoil" does work to produce flow have confused physiologists and clinicians for decades because Guyton's interpretation interchanges independent and dependent variables. Here Guyton's model and data are reanalyzed to clarify the role of arterial and right atrial pressures and cardiac output and to clearly delineate that cardiac output is the independent (causal) variable in the experiments. Guyton's original mathematical model is used with his data to show that a simultaneous increase in arterial pressure and decrease in right atrial pressure with increasing cardiac output is due to a blood volume shift into the systemic arterial circulation from the systemic venous circulation. This is because Guyton's model assumes a constant blood volume in the systemic circulation. The increase in right atrial pressure observed when cardiac output decreases in a closed circulation with constant resistance and capacitance is due to the redistribution of blood volume and not because right atrial pressure limits venous return. Because Guyton's venous return curves have generated much confusion and little clarity, we suggest that the concept and previous interpretations of venous return be removed from educational materials. PMID- 21666120 TI - Direct regulation of membrane type 1 matrix metalloproteinase following myocardial infarction causes changes in survival, cardiac function, and remodeling. AB - The membrane type 1 matrix metalloproteinase (MT1-MMP) is increased in left ventricular (LV) failure. However, the direct effects of altered MT1-MMP levels on survival, LV function, and geometry following myocardial infarction (MI) and the proteolytic substrates involved in this process remain unclear. MI was induced in mice with cardiac-restricted overexpression of MT1-MMP (MT1-MMPexp; full length human), reduced MT1-MMP expression (heterozygous; MT1-MMP(+/-)), and wild type. Post-MI survival was reduced with MT1-MMPexp and increased with MT1 MMP(+/-) compared with WT. LV ejection fraction was lower in the post-MI MT1 MMPexp mice compared with WT post-MI and was higher in the MT1-MMP(+/-) mice. In vivo localization of MT1-MMP using antibody-conjugated microbubbles revealed higher MT1-MMP levels post-MI, which were the highest in the MT1-MMPexp group and the lowest in the MT1-MMP(+/-) group. LV collagen content within the MI region was higher in the MT1-MMPexp vs. WT post-MI and reduced in the MT1-MMP(+/-) group. Furthermore, it was demonstrated that MT1-MMP proteolytically processed the profibrotic molecule, latency-associated transforming growth factor-1-binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by over fourfold in the post-MI MT1-MMPexp group and reduced in the MT1-MMP(+/-) group, which was directionally paralleled by phospho-Smad-3 levels, a critical signaling component of the profibrotic transforming growth factor pathway. We conclude that modulating myocardial MT1-MMP levels affected LV function and matrix structure, and a contributory mechanism for these effects is through processing of profibrotic signaling molecules. These findings underscore the diversity of biological effects of certain MMP types on the LV remodeling process. PMID- 21666121 TI - Characterization of Ath29, a major mouse atherosclerosis susceptibility locus, and identification of Rcn2 as a novel regulator of cytokine expression. AB - Ath29 is an atherosclerosis susceptibility locus on chromosome 9 identified in an intercross between C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE(-/-)) mice. This locus was subsequently replicated in two separate intercrosses that developed early or advanced atherosclerotic lesions. The objective of this study was to characterize Ath29 through construction and analysis of a congenic strain and identify underlying candidate genes. A congenic line was constructed by introgressing the chromosomal segment harboring Ath29 from C3H.apoE(-/-) into B6.apoE(-/-) mice. Congenic mice developed significantly smaller early and advance atherosclerotic lesions than B6.apoE(-/-) mice. Microarray analysis revealed 317 genes to be differentially expressed in the aorta of congenic mice compared with B6.apoE(-/-) mice. Pathway analysis of these genes suggested the Ca(2+) signaling pathway to be implicated in regulating atherosclerosis susceptibility. Rcn2 is located underneath the linkage peak of Ath29 and involved in Ca(2+) signaling. Multiple single-nucleotide polymorphisms between B6 and C3H mice were detected within and surrounding Rcn2 with one single nucleotide polymorphism falling within an upstream cAMP response element. Immunostaining demonstrated its expression in atherosclerotic lesions. Knockdown of Rcn2 with small interfering RNAs resulted in significant reductions in both baseline and oxidized phospholipid-induced VCAM-1 and monocyte chemoattractant protein-1 expression by endothelial cells. Ath29 is confirmed to be a major atherosclerosis susceptibility locus affecting both early and advanced lesion formation in mice, and Rcn2 is identified as a novel regulator of cytokine expression. PMID- 21666122 TI - Visualizing calcium responses to acetylcholine convection along endothelium of arteriolar networks in Cx40BAC-GCaMP2 transgenic mice. AB - Acetylcholine evokes endothelium-dependent vasodilation subsequent to a rise in intracellular calcium. Despite widespread application in human and animal studies, calcium responses to intravascular ACh have not been visualized in vivo. Microiontophoresis of ACh in tissue adjacent to an arteriole activates abluminal muscarinic receptors on endothelial cells within a "local" region of diffusion, but it is unknown whether ACh released in such fashion gains access to the flow stream resulting in further actions downstream. To test this hypothesis and provide new insight into calcium signaling in vivo, we studied the cremaster muscle microcirculation of anesthetized male Cx40(BAC)-GCaMP2 transgenic mice (n = 22; 5-9 mo; 33 +/- 1 g) expressing the fluorescent calcium sensor GCaMP2 selectively in arteriolar endothelial cells. Submaximal ACh stimuli were delivered using microiontophoresis (1-MUm pipette tip, 500 nA). With stimulus duration <500 ms or with the micropipette positioned within one vessel diameter (~30 MUm) away from an arteriole, endothelial cell calcium fluorescence was restricted to the region of ACh diffusion (<200 MUm). In contrast, with the micropipette tip positioned immediately adjacent to an arteriole or within its lumen, calcium fluorescence encompassed entire networks downstream. The velocity of downstream calcium signaling in response to ACh increased with centerline velocity of fluorescent tracer microbeads (r(2) > 0.99; range: <1 mm/s to >10 mm/s). Diverting arteriolar blood flow into a side branch redirected downstream fluorescence responses to ACh; occluding flow abolished responses. Blocking luminal muscarinic receptors (intravascular glycopyrrolate; 6 MUg/kg) inhibited downstream responses reversibly. Through visualizing the actions of a "local" ACh stimulus on endothelial cell calcium fluorescence in vivo, the present findings illustrate that transmural diffusion and convection of an agonist can activate entire networks of arteriolar endothelial cells concomitant with its delivery in the flow stream. PMID- 21666124 TI - Orientation tuning of the suppressive extraclassical surround depends on intrinsic organization of V1. AB - The intrinsic functional architecture of early cortical areas in highly visual mammals is characterized by the presence of domains and pinwheels, with orientation preference of the inputs to these regions being more and less selective, respectively. We exploited this organizational feature to investigate mechanisms supporting extraclassical surround suppression, a process thought to be critical for figure ground segregation and form vision. Combining intrinsic signal optical imaging and single-unit recording in V1 of anesthetized cats, we show for the first time that the orientation tuning of the suppressive surround is sharper for domain than for pinwheel neurons. This difference depends on high center gain and is more pronounced in superficial cortex. In addition, when we remove the near component of the surround stimulus, the strength of suppression induced by the iso-oriented surround is significantly reduced for domain neurons but is unchanged for orthogonal oriented surrounds. This leads to broader orientation tuning of suppression that renders domain cells indistinguishable from pinwheel cells. Because the limited receptive field of the near surround can be accounted for by the lateral spread of long-range connections in V1, our findings suggest that intrinsic V1 circuits play a key role in the orientation tuning of extraclassical surround suppression. PMID- 21666123 TI - Vascular reactivity to calcitonin gene-related peptide is enhanced in subtotal nephrectomy-salt induced hypertension. AB - In subtotal nephrectomy (SN)- and salt-induced hypertension, calcitonin gene related peptide (CGRP) plays a compensatory role to attenuate the blood pressure increase in the absence of an increase in the neuronal synthesis and release of this peptide. Therefore, the purpose of this study was to determine whether the mechanism of this antihypertensive activity is through enhanced sensitivity of the vasculature to the dilator actions of this neuropeptide. Hypertension was induced in Sprague-Dawley rats by SN and 1% saline drinking water. Control rats were sham-operated and given tap water to drink. After 11 days, rats had intravenous (drug administration) and arterial (continuous mean arterial pressure recording) catheters surgically placed and were studied in a conscious unrestrained state. Baseline mean arterial pressure was higher in the SN-salt rats (157 +/- 5 mmHg) compared with controls (128 +/- 3 mmHg). Administration of CGRP (and adrenomedullin) produced a significantly greater dose-dependent decrease in mean arterial pressure in SN-salt rats compared with controls (~2.0 fold for both the low and high doses). Interestingly, isolated superior mesenteric arterioles from SN-salt rats were significantly more responsive to the dilator effects of CGRP (but not adenomedullin) than the controls (pEC(50), SN salt, 14.0 +/- 0.1 vs. control, 12.0 +/- 0.1). Analysis of the CGRP receptor proteins showed that only the receptor component protein was increased significantly in arterioles from SN-salt rats. These data indicate that the compensatory antihypertensive effects of CGRP result from an increased sensitivity of the vasculature to dilator activity of this peptide. The mechanism may be via the upregulation of receptor component protein, thereby providing a more efficient coupling of the receptor to the signal transduction pathways. PMID- 21666125 TI - Influence of a subtype of inhibitory interneuron on stimulus-specific responses in visual cortex. AB - Inhibition modulates receptive field properties and integrative responses of neurons in cortical circuits. The contribution of specific interneuron classes to cortical circuits and emergent responses is unknown. Here, we examined neuronal responses in primary visual cortex (V1) of adult Dlx1(-/-) mice, which have a selective reduction in cortical dendrite-targeting interneurons (DTIs) that express calretinin, neuropeptide Y, and somatostatin. The V1 neurons examined in Dlx1(-/-) mice have reduced orientation selectivity and altered firing rates, with elevated late responses, suggesting that local inhibition at dendrites has a specific role in modulating neuronal computations. We did not detect overt changes in the physiological properties of thalamic relay neurons and features of thalamocortical projections, such as retinotopic maps and eye-specific inputs, in the mutant mice, suggesting that the defects are cortical in origin. These experimental results are well explained by a computational model that integrates broad tuning from dendrite-targeting and narrower tuning from soma-targeting interneuron subclasses. Our findings suggest a key role for DTIs in the fine tuning of stimulus-specific cortical responses. PMID- 21666127 TI - Threat prompts defensive brain responses independently of attentional control. AB - Negative emotional signals are known to influence task performance, but so far, investigations have focused on how emotion interacts with perceptual processes by mobilizing attentional resources. The attention-independent effects of negative emotional signals are less well understood. Here, we show that threat signals trigger defensive responses independently of what observers pay attention to. Participants were scanned using functional magnetic resonance imaging while watching short video clips of threatening actions and performed either color or emotion judgments. Seeing threatening actions interfered with performance in both tasks. Amygdala activation reflected both stimulus and task conditions. In contrast, threat stimuli prompted a constant activity in a network underlying reflexive defensive behavior (periaqueductal gray, hypothalamus, and premotor cortex). Threat stimuli also disrupted ongoing behavior and provoked motor conflict in prefrontal regions during both tasks. The present results are consistent with the view that emotions trigger adaptive action tendencies independently of task settings. PMID- 21666126 TI - Differential contribution of right and left parietal cortex to the control of spatial attention: a simultaneous EEG-rTMS study. AB - We have recently shown that interference with repetitive transcranial magnetic stimulation (rTMS) of right posterior intraparietal sulcus (IPS) cortex during the allocation of spatial attention leads to abnormal desynchronization of anticipatory (pretarget) electroencephalographic alpha rhythms (8-12 Hz) in occipital-parietal cortex and the detection of subsequently presented visual targets (Capotosto et al. 2009). Since lesion data suggest that lesions of the right frontoparietal cortices produce more severe and long-lasting deficits of visual spatial attention than lesions of the left hemisphere, here, we used the mentioned rTMS-electroencephalographic procedure to test if the control of anticipatory alpha rhythms by IPS is asymmetrically organized in the 2 hemispheres. Results showed that interference with either left or right IPS during covert spatial attention equally disrupted the normally lateralized anticipatory modulation of occipital visual cortex, with stronger alpha desynchronization contralaterally to the attended visual field. In contrast, only interference with right IPS induced a paradoxical pretarget synchronization of alpha rhythms and bilateral deficits of target identification. These results suggest that the control of spatial topography of anticipatory alpha rhythms in occipital-parietal cortex is shared between left and right IPS cortex, but that right IPS uniquely contributes to a bilateral prestimulus activation of occipital visual cortex. PMID- 21666128 TI - Imagery and perception share cortical representations of content and location. AB - Visual imagery allows us to vividly imagine scenes in the absence of visual stimulation. The likeness of visual imagery to visual perception suggests that they might share neural mechanisms in the brain. Here, we directly investigated whether perception and visual imagery share cortical representations. Specifically, we used a combination of functional magnetic resonance imaging (fMRI) and multivariate pattern classification to assess whether imagery and perception encode the "category" of objects and their "location" in a similar fashion. Our results indicate that the fMRI response patterns for different categories of imagined objects can be used to predict the fMRI response patters for seen objects. Similarly, we found a shared representation of location in low level and high-level ventral visual cortex. Thus, our results support the view that imagery and perception are based on similar neural representations. PMID- 21666129 TI - Transcranial magnetic stimulation reveals dissociable mechanisms for global versus selective corticomotor suppression underlying the stopping of action. AB - Stopping an initiated response is an essential function, investigated in many studies with go/no-go and stop-signal paradigms. These standard tests require rapid action cancellation. This appears to be achieved by a suppression mechanism that has "global" effects on corticomotor excitability (i.e., affecting task irrelevant muscles). By contrast, stopping action in everyday life may require selectivity (i.e., targeting a specific response tendency without affecting concurrent action). We hypothesized that while standard stopping engages global suppression, behaviorally selective stopping engages a selective suppression mechanism. Accordingly, we measured corticomotor excitability of the task irrelevant leg using transcranial magnetic stimulation while subjects stopped the hand. Experiment 1 showed that for standard (i.e., nonselective) stopping, the task-irrelevant leg was suppressed. Experiment 2 showed that for behaviorally selective stopping, there was no mean leg suppression. Experiment 3 directly compared behaviorally nonselective and selective stopping. Leg suppression occurred only in the behaviorally nonselective condition. These results argue that global and selective suppression mechanisms are dissociable. Participants may use a global suppression mechanism when speed is stressed; however, they may recruit a more selective suppression mechanism when selective stopping is behaviorally necessary and preparatory information is available. We predict that different fronto-basal-ganglia pathways underpin these different suppression mechanisms. PMID- 21666130 TI - Bidirectional information flow in frontoamygdalar circuits in humans: a dynamic causal modeling study of emotional associative learning. AB - Everyday language is replete with descriptions of emotional events that people have experienced and wish to share with others. Such descriptions presumably rely on pairings of affective words and visual information (such as events and pictures) that have been learnt throughout one's development. To study this kind of affective language learning in the brain, we used functional neuroimaging during associative learning of emotional words and pictures. Brain imaging revealed increased activation of both primary emotional areas such as the amygdala and of higher cognitive areas such as the inferior frontal gyrus (IFG) and medial frontal gyrus. The dynamic causal modeling with Bayesian model selection suggested that the IFG first receives the input and that the connections are bidirectional, suggesting that during such emotional picture-word pair learning, the frontal cortex drives the amygdala activation. Specifically, the interaction between the frontal regions and the amygdala was enhanced by active learning involving both negative and positive emotional stimuli as compared with neutral stimuli. This circuit (especially for negative stimuli) converges with emotion regulation circuits. The enhancement in the connectivity might be responsible for the emotional memory effect in this type of learning. PMID- 21666131 TI - Abnormal structure-function relationship in spasmodic dysphonia. AB - Spasmodic dysphonia (SD) is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. Although recent studies have found abnormal brain function and white matter organization in SD, the extent of gray matter alterations, their structure-function relationships, and correlations with symptoms remain unknown. We compared gray matter volume (GMV) and cortical thickness (CT) in 40 SD patients and 40 controls using voxel-based morphometry and cortical distance estimates. These measures were examined for relationships with blood oxygen level-dependent signal change during symptomatic syllable production in 15 of the same patients. SD patients had increased GMV, CT, and brain activation in key structures of the speech control system, including the laryngeal sensorimotor cortex, inferior frontal gyrus (IFG), superior/middle temporal and supramarginal gyri, and in a structure commonly abnormal in other primary dystonias, the cerebellum. Among these regions, GMV, CT and activation of the IFG and cerebellum showed positive relationships with SD severity, while CT of the IFG correlated with SD duration. The left anterior insula was the only region with decreased CT, which also correlated with SD symptom severity. These findings provide evidence for coupling between structural and functional abnormalities at different levels within the speech production system in SD. PMID- 21666132 TI - Learning the exception to the rule: model-based FMRI reveals specialized representations for surprising category members. AB - Category knowledge can be explicit, yet not conform to a perfect rule. For example, a child may acquire the rule "If it has wings, then it is a bird," but then must account for exceptions to this rule, such as bats. The current study explored the neurobiological basis of rule-plus-exception learning by using quantitative predictions from a category learning model, SUSTAIN, to analyze behavioral and functional magnetic resonance imaging (fMRI) data. SUSTAIN predicts that exceptions require formation of specialized representations to distinguish exceptions from rule-following items in memory. By incorporating quantitative trial-by-trial predictions from SUSTAIN directly into fMRI analyses, we observed medial temporal lobe (MTL) activation consistent with 2 predicted psychological processes that enable exception learning: item recognition and error correction. SUSTAIN explains how these processes vary in the MTL across learning trials as category knowledge is acquired. Importantly, MTL engagement during exception learning was not captured by an alternate exemplar-based model of category learning or by standard contrasts comparing exception and rule following items. The current findings thus provide a well-specified theory for the role of the MTL in category learning, where the MTL plays an important role in forming specialized category representations appropriate for the learning context. PMID- 21666134 TI - Dissociating memory processes in the developing brain: the role of hippocampal volume and cortical thickness in recall after minutes versus days. AB - Retention of information over extended time periods places special demands on the brain. The neural correlates of memory performance after a short delay of 30 min and a long delay of 1 week are likely partly different, but we do not know how structural maturation of the brain contributes to the differential development of these functions. This question was investigated in a sample of 107 children and adolescents aged 8-19 years. Measures used were structural magnetic resonance imaging and the Rey Complex Figure Test copy, organizational strategy, and 30-min and 1-week recall. While the amount of details copied and later recalled after both 30 min and 1 week increased with age, the relative saving over 1 week (1 week/30-min ratio score) did not increase with age. Thirty minutes recall performance was related to thinner left orbitofrontal cortex independently of age and organizational strategy measured during copy, possibly reflecting executive components of retrieval or encoding processes. In contrast, the 1-week/30-min ratio, likely reflecting consolidation of memory traces, was related to larger bilateral hippocampal volume. This indicates that differential developmental effects on memory for short and long periods of time are related to differentially developing brain structures. PMID- 21666136 TI - Psychoanalyisis in the U.S.: recovered memories and new experiences of a former editor. PMID- 21666133 TI - Tangentially migrating transient glutamatergic neurons control neurogenesis and maintenance of cerebral cortical progenitor pools. AB - The relative contribution of intrinsic and extrinsic cues in the regulation of cortical neurogenesis remains a crucial challenge in developmental neurobiology. We previously reported that a transient population of glutamatergic neurons, the cortical plate (CP) transient neurons, migrates from the ventral pallium (VP) over long distances and participate in neocortical development. Here, we show that the genetic ablation of this population leads to a reduction in the number of cortical neurons especially fated to superficial layers. These defects result from precocious neurogenesis followed by a depletion of the progenitor pools. Notably, these changes progress from caudolateral to rostrodorsal pallial territories between E12.5 and E14.5 along the expected trajectory of the ablated cells. Conversely, we describe enhanced proliferation resulting in an increase in the number of cortical neurons in the Gsx2 mutants which present an expansion of the VP and a higher number of CP transient neurons migrating into the pallium. Our findings indicate that these neurons act to maintain the proliferative state of neocortical progenitors and delay differentiation during their migration from extraneocortical regions and, thus, participate in the extrinsic control of cortical neuronal numbers. PMID- 21666137 TI - Investigating merger: subliminal psychodynamic activation and oneness motivation research. AB - Two programs of empirical research have endeavored to explicate some of the unconscious processes involved in adult phenomena of merger, symbiosis, or oneness. Starting in the 1960s under the leadership of Lloyd Silverman (see, e.g., Silverman, Lachmann, and Milich 1982), subliminal psychodynamic activation (SPA) has used subliminal methods to prime and manipulate these processes. Later research into what was termed oneness motivation (OM) posited the existence of a chronic personality variable and explored it independently of priming (see, e.g., Siegel and Weinberger 1998). These lines of research have established links between unconscious processes of oneness and a range of clinical and nonclinical outcomes. PMID- 21666135 TI - The glutamatergic component of the mesocortical pathway emanating from different subregions of the ventral midbrain. AB - The mesocortical pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) plays a critical role in a number of cognitive and emotional processes. While this pathway has been traditionally viewed as dopaminergic, recent data indicate that a considerable proportion of rostromedial VTA neurons possess markers for glutamate transmission. However, the relative density of the glutamatergic projection to the PFC from these rostromedial regions is unknown. In the present study, anterograde tracer injections into 4 ventral midbrain subregions were coupled with immunohistochemical analysis of labeled axons in PFC for markers of dopamine (DA; tyrosine hydroxylase [TH]) and glutamate (vesicular glutamate transporter 2; VGLUT2). We found that while tracer injections into the interfascicular nucleus produced labeled fibers in the PFC that were mainly TH positive, tracer injections into the rostral linear nucleus, rostral VTA, and parabrachial pigmented nucleus produced labeled fibers in PFC that contained mainly VGLUT2-positive rather than TH-positive varicosities. When viewed in the light of the previously documented strong gamma-aminobutyric acidergic component, it would seem that the rostromedial mesocortical projection is actually an amino acid pathway that in addition has a DA component. PMID- 21666138 TI - Design as dream and self-representation: Philip Johnson and the Glass House of Atreus. AB - Philip Johnson's masterpiece--the Glass House--is compared to a dream and conceptualized as containing encrypted and embedded representations of the self. Freud's masterpiece--The Interpretation of Dreams--is the theoretical and methodological model for this approach to design-as-dream. Drawing on Johnson's words and forms set in biographical, historical, and cultural context, interpretive paths are traced from manifest design elements of the Glass House to overdetermined latent meanings, yielding new and surprising insights into the Glass House, its elusive architect, and the process of its design. A mirror that reflects an image, a lens that focuses it, and a prism that reveals its components, the Glass House turns a lucid eye onto its maker. PMID- 21666139 TI - Effectiveness of hybrid assistive neuromuscular dynamic stimulation therapy in patients with subacute stroke: a randomized controlled pilot trial. AB - BACKGROUND AND OBJECTIVE: Hybrid assistive neuromuscular dynamic stimulation (HANDS) therapy was devised to facilitate the use of the hemiparetic upper extremity in daily life by combining assistive neuromuscular electrical stimulation, referred to as the integrated volitional electrical stimulator (IVES), with a splint. The aim of this study is to assess the effectiveness of HANDS therapy for patients with subacute stroke. METHODS: The participants were 24 inpatients receiving rehabilitation for hemiparetic stroke within 60 days of onset. Entry criteria included inability to individuate finger extension. Patients were randomly assigned to 2 groups. The HANDS group (n = 12) used the IVES combined with a wrist splint for 8 hours a day for 3 weeks, and the control group (n = 12) wore a wrist splint alone. All patients received the same daily dose and length of standard poststroke multidisciplinary rehabilitation. Outcome measures were the upper extremity portion of the Fugl-Meyer Assessment (FMA), Action Research Arm Test (ARAT), and Motor Activity Log-14 (MAL). RESULTS: In all, 10 patients in each group completed the interventions. Compared with the control group, the HANDS group showed significantly greater gains in distal (wrist/hand) portion of the FMA (P < .01) and improvement of the ARAT (P < .05). The gains in the MAL did not differ. No adverse effects occurred and the HANDS therapy was well accepted. CONCLUSION: HANDS therapy in addition to conventional therapy may improve hand function in patients with moderate to severe hand impairment during early rehabilitation. PMID- 21666140 TI - Evaluation of the clinical efficacy of minimally invasive procedures for breast cancer screening at a teaching hospital. AB - AIMS: To assess the clinical efficacy of diagnostic procedures for breast cancer at a teaching hospital using internal auditing tools and quality control measures. METHODS: A retrospective assessment of 500 patients who underwent core needle biopsy (wide-bore needle biopsy; WBN) of palpable or non-palpable breast nodes that were submitted for at least one cytological examination (fine needle aspiration (FNA) cytology and/or imprint of a WBN specimen). For statistical analysis the auditing tool and quality control proposed by the National Health Service breast screening programme was utilised. RESULTS: For FNA, full specificity, positive predictive value, inadequate rates and suspicious rates were satisfactory while absolute sensitivity, complete sensitivity, false negatives and false positives were unsatisfactory. For imprint, absolute sensitivity, complete sensitivity, inadequate rate from cancers and suspicious rates were satisfactory, and the remaining indicators were unsatisfactory. WBN displayed the best performance with absolute sensitivity, complete sensitivity, false negative, suspicious rates, full specificity and predictive value showing satisfactory results and only one unsatisfactory result (false positive). CONCLUSIONS: Based on an overall analysis, WBN displayed the highest clinical efficacy compared with FNA and imprint, and demonstrated adequate safety for confirming the appropriate diagnosis and management of patients, ensuring the efficacy of the service. PMID- 21666141 TI - Locked nucleic acid probes for enhanced detection of FLT3 D835/I836, JAK2 V617F and NPM1 mutations. AB - AIMS: Detecting low-level clinically significant cancer-relevant somatic mutations can be difficult. Several technologies exist for detecting minority mutations. One method is locked nucleic acid (LNA) PCR. In this study, LNA probes were used to enhance the sensitivity for detecting FLT3 D835/I836 tyrosine kinase domain (TKD) mutations, the JAK2 V617F mutation and insertion mutations in the nucleophosmin 1 gene. METHODS: PCR was performed with and without LNA probes using DNA known to contain FLT3 D835/I836 TKD, JAK2 V617F and NPM1 mutations. FLT3 D835/I836 TKD mutations were detected following EcoRV restriction enzyme digestion and capillary electrophoresis. The JAK2 V617F mutation was detected by melt-curve analysis. NPM1 insertions were detected by capillary electrophoresis. RESULTS: The detection of FLT3 D835/I836, JAK2 V617F and NPM1 mutations was enhanced approximately 10-50-fold using LNA probes. Rare JAK2 double mutants gave abnormal blocking patterns with the LNA probe. CONCLUSIONS: Adding LNA probes to existing assays is a simple way to enhance and confirm the detection of mutations, especially those at low levels. PMID- 21666142 TI - Rule-based decision support system in the biopsy diagnosis of glomerular diseases. AB - AIMS: To develop a rule-based decision support system (RDSS) to assist in the diagnosis of glomerular diseases on the basis of clinical, histological and immunohistological findings. METHODS: The computer software for the RDSS was written by one of the authors. The prototypical clinical and histomorphological features, including immunofluorescence findings of various glomerular diseases, were selected by three pathologists with experience in renal pathology. For every case included, all the relevant features were fed into the RDSS in the form of one or more vectors. Diagnosis was achieved by the RDSS on the basis of shortest Euclidean distance between the vector of features of a particular 'test' case and vectors of the prototypical features. The diagnoses rendered by the RDSS were compared with the final diagnosis signed out by the renal pathologists; the percentage of correct diagnoses was calculated for the RDSS. RESULTS: A total of 612 cases of glomerular diseases were included in the analysis. The RDSS developed in this study gave the correct diagnosis in 83.2% of the cases included. Of all the cases, membranous glomerulonephritis and lupus nephritis were most frequently diagnosed accurately. However, immunotactoid glomerulonephritis was misdiagnosed due to the lack of ultrastructural findings in the study. CONCLUSION: The decision support system developed in the present study holds promise, given the high accuracy in diagnosis of glomerular diseases on the basis of clinical, histological and immunofluorescence features. Such a system may prove useful not only for diagnosis but also for postgraduate teaching and self-assessment. Results need to be confirmed in further larger studies. PMID- 21666143 TI - Sexual frequency decline from midlife to later life. AB - OBJECTIVE: To examine sexual frequency decline among American men and women between the ages of 44 and 72 born from 1933 to 1948. METHOD: Using data from the National Health and Social Life Survey (NHSLS) and the National Social Life, Health, and Aging Project (NSHAP), the decline in sexual frequency is decomposed into declines due to changes in marital status, physical health, and happiness. We examine the contribution of both changes in the composition of the population with respect to these factors as well as changes in the association between these factors and sexual frequency by age. RESULTS: For women, change in the proportion widowed is a significant factor in sexual frequency decline, as is change in the association between happiness and sexual frequency. Among men, both poorer physical health at older ages and a decrease in its association with frequency are significant factors in the decline. A change in the association between happiness and frequency is also a significant factor for men. Reverse causality may explain the happiness-frequency findings for both men and women. DISCUSSION: Results provide evidence for gendered experiences in the sexual life course. PMID- 21666144 TI - Does self-reported health bias the measurement of health inequalities in U.S. adults? Evidence using anchoring vignettes from the Health and Retirement Study. AB - OBJECTIVES: Measurement of health inequalities based on self-reports may be biased if individuals use response scales in systematically different ways. We use anchoring vignettes to test and adjust for reporting differences by education, race/ethnicity, and gender in self-reported health in 6 domains (pain, sleep, mobility, memory, shortness of breath, and depression). METHOD: Using data from the 2006 U.S. Health and Retirement Study (HRS) and the 2007 Disability Vignette Survey, we estimated generalized ordered probit models of the respondent's rating of each vignette character's health problem, allowing cut points to vary by age, gender, education, and race/ethnicity. We then used one step hierarchical ordered probit (HOPIT) models to jointly estimate the respondent's cut-points from the vignettes and the severity of the respondent's own health problems based on these vignette cut-points. RESULTS: We found strong evidence of reporting differences by age, gender, education, and race/ethnicity, with the magnitude depending on the specific health domain. Overall, traditional models not accounting for reporting differences underestimated the magnitude of health inequalities by education and race/ethnicity. DISCUSSION: These results suggest caution in relying on self-reported health measures to quantify and explain health disparities by socioeconomic status and race/ethnicity/ethnicity in the United States. The findings support expansion of the use of anchoring vignettes to properly account for reporting differences in self-reports of health. PMID- 21666146 TI - Developing a culturally competent workforce through collaborative partnerships. PMID- 21666145 TI - Aging in a cultural context: cross-national differences in disability and the moderating role of personal control among older adults in the United States and England. AB - OBJECTIVES: We investigate cross-national differences in late-life health outcomes and focus on an intriguing difference in beliefs about personal control found between older adult populations in the U.K. and United States. We examine the moderating role of control beliefs in the relationship between physical function and self-reported difficulty with daily activities. METHOD: Using national data from the United States (Health and Retirement Study) and England (English Longitudinal Study on Ageing), we examine the prevalence in disability across the two countries and show how it varies according to the sense of control. Poisson regression was used to examine the relationship between objective measures of physical function (gait speed) and disability and the modifying effects of control. RESULTS: Older Americans have a higher sense of personal control than the British, which operates as a psychological resource to reduce disability among older Americans. However, the benefits of control are attenuated as physical impairments become more severe. DISCUSSION: These results emphasize the importance of carefully considering cross-national differences in the disablement process as a result of cultural variation in underlying psychosocial resources. This paper highlights the role of culture in shaping health across adults aging in different sociopolitical contexts. PMID- 21666147 TI - Response to "Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban". PMID- 21666148 TI - Commentaries on Viewpoint: can muscle size fully account for strength differences between children and adults? PMID- 21666150 TI - A world without measles. PMID- 21666151 TI - The cost-effectiveness of supplementary immunization activities for measles: a stochastic model for Uganda. AB - Supplemental Immunization Activities (SIAs) have become an important adjunct to measles control efforts in countries that endeavor to achieve higher levels of population immunity than can be achieved in a growing routine immunization system. Because SIAs are often supported with funds that have alternative uses, decision makers need to know how cost-effective they are compared with other options. This study integrated a dynamic stochastic model of measles transmission in Uganda (2010-2050) with a cost model to compare a strategy of maintaining Uganda's current (2008) levels of the first dose of routine measles-containing vaccine (MCV1) coverage at 68% with SIAs with a strategy using the same levels of MCV1 coverage without SIAs. The stochastic model was fitted with parameters drawn from district-level measles case reports from Uganda, and the cost model was fitted to administrative data from the Ugandan Expanded Program on Immunization and from the literature. A discount rate of 0.03, time horizon of 2010-2050, and a societal perspective on costs were assumed. Costs expressed in US dollars (2010) included vaccination costs, disease treatment costs including lost productivity of mothers, as well as costs of outbreaks and surveillance. The model estimated that adding on triennial SIAs that covered 95% of children aged 12-59 months to a system that achieved routine coverage rates of 68% would have an incremental cost-effectiveness ratio (ICER) of $1.50 ($US 2010) per disability adjusted life year averted. The ICER was somewhat higher if the discount rate was set at either 0 or 0.06. The addition of SIAs was found to make outbreaks less frequent and lower in magnitude. The benefit was reduced if routine coverage rates were higher. This cost-effectiveness ratio compares favorably to that of other commonly accepted public health interventions in sub-Saharan Africa. PMID- 21666152 TI - Assessing the cost-effectiveness of measles elimination in Uganda: local impact of a global eradication program. AB - BACKGROUND: Measles control has succeeded worldwide, and many countries have substantially reduced incidence and mortality. This has led to consideration of the feasibility of measles elimination in Uganda within the context of global eradication. Before an elimination program is initiated, it is important to consider its potential economic impact, including its cost-effectiveness. METHODS: Incremental cost-effectiveness ratios (ICERs) were estimated for measles mortality reduction and measles elimination in Uganda. A dynamic age-structured compartmental model of measles transmission was used to simulate scenarios and estimate health outcomes and costs. The main outcome measures were costs, measles cases, measles deaths, disability-adjusted life-years (DALYs), and ICERs measured as cost per DALY averted through either the year 2030 or 2050. RESULTS: Measles elimination by 2020 averted 130,232 measles cases, 3520 measles deaths, and 106,330 DALYs through the year 2030, compared with the next best scenario (95% mortality reduction by 2015), and it was the most cost-effective strategy, with ICERs of $556 per DALY averted (2030 time horizon) and $284 per DALY averted (2050 time horizon). CONCLUSIONS: Measles elimination in Uganda, as part of a global eradication program, is projected to be highly cost-effective and should be considered among the available policy options for dealing with the disease. PMID- 21666153 TI - Using cost-effectiveness analysis to support research and development portfolio prioritization for product innovations in measles vaccination. AB - BACKGROUND: Several potential measles vaccine innovations are in development to address the shortcomings of the current vaccine. Funders need to prioritize their scarce research and development resources. This article demonstrates the usefulness of cost-effectiveness analysis to support these decisions. METHODS: This study had 4 major components: (1) identifying potential innovations, (2) developing transmission models to assess mortality and morbidity impacts, (3) estimating the unit cost impacts, and (4) assessing aggregate cost-effectiveness in United Nations Children's Fund countries through 2049. RESULTS: Four promising technologies were evaluated: aerosol delivery, needle-free injection, inhalable dry powder, and early administration DNA vaccine. They are projected to have a small absolute impact in terms of reducing the number of measles cases in most scenarios because of already improving vaccine coverage. Three are projected to reduce unit cost per dose by $0.024 to $0.170 and would improve overall cost effectiveness. Each will require additional investments to reach the market. Over the next 40 years, the aggregate cost savings could be substantial, ranging from $98.4 million to $689.4 million. CONCLUSIONS: Cost-effectiveness analysis can help to inform research and development portfolio prioritization decisions. Three new measles vaccination technologies under development hold promise to be cost saving from a global perspective over the long-term, even after considering additional investment costs. PMID- 21666154 TI - Field effectiveness of live attenuated measles-containing vaccines: a review of published literature. AB - BACKGROUND: Information on measles vaccine effectiveness (VE) is critical to help inform policies for future global measles control goals. METHODS: We reviewed results of VE studies published during 1960-2010. RESULTS: Seventy papers with 135 VE point estimates were identified. For a single dose of vaccine administered at 9-11 months of age and >=12 months, the median VE was 77.0% (interquartile range [IQR], 62%-91%) and 92.0% (IQR, 86%-96%), respectively. When analysis was restricted to include only point estimates for which vaccination history was verified and cases were laboratory confirmed, the median VE was 84.0% (IQR, 72.0% 95.0%) and 92.5% (IQR, 84.8%-97.0%) when vaccine was received at 9-11 and >=12 months, respectively. Published VE vary by World Health Organization region, with generally lower estimates in countries belonging to the African and SouthEast Asian Regions. For 2 doses of measles-containing vaccine, compared with no vaccination, the median VE was 94.1% (IQR, 88.3%-98.3%). CONCLUSIONS: The VE of the first dose of measles-containing vaccine administered at 9-11 months was lower than what would be expected from serologic evaluations but was higher than expected when administered at >=12 months. The median VE increased in a subset of articles in which classification bias was reduced through verified vaccination history and laboratory confirmation. In general, 2 doses of measles-containing vaccine provided excellent protection against measles. PMID- 21666155 TI - The Measles Initiative: moving toward measles eradication. AB - The World Health Assembly should establish a target date for measles eradication based on continued progress toward existing mortality reduction goals. We have a safe, effective, and inexpensive vaccine; a proven elimination strategy; high country demand; and an effective global partnership. Since it was founded in 2001, the Measles Initiative has supported the vaccination of >900 million children in supplementary immunization activities. Largely as a result, global measles deaths decreased by 78% between 2000 and 2008, averting an estimated 4.3 million deaths. The Measles Initiative has exceeded its targets and evolved to address increasingly ambitious goals. The current challenges include a decline in funding and weak routine immunization systems in some countries. Skeptics of measles eradication raise 3 main objections: the yet-to-be-achieved polio eradication goal, the high cost, and the impact on health systems. These are important concerns that can be addressed with judicious program planning. All 6 World Health Organization regions have committed to measles elimination, and 5 have set a target date. The World Health Assembly has endorsed interim targets toward eradication, and an independent global measles advisory group has determined measles can and should be eradicated. A target date for eradication will focus efforts and capitalize on the achievements of the last decade. PMID- 21666156 TI - Persistence of vaccine-induced measles antibody beyond age 12 months: a comparison of response to one and two doses of Edmonston-Zagreb measles vaccine among HIV-infected and uninfected children in Malawi. AB - BACKGROUND: Previously, we demonstrated that measles antibody prevalence was lower at age 12 months among children infected with human immunodeficiency virus (HIV) than uninfected children following measles vaccination (MV) at ages 6 and 9 months. Among HIV-uninfected children, measles antibody prevalence was lower among 1- than 2-dose MV recipients. Here, we report results through age 24 months. METHODS: Children born to HIV-infected mothers received MV at 6 and 9 months, and children of HIV-uninfected mothers were randomized to MV at 6 and 9 months or MV at 9 months. We followed children through age 24 months. The child's HIV status was determined and measles immunoglobulin G (IgG) level was measured by enzyme immunoassay (EIA) and by plaque reduction neutralization (PRN) on a subset. RESULTS: Among HIV-uninfected children, the difference in measles antibody prevalence at age 12 months between one- and two-dose recipients reported previously by EIA was shown to be smaller by PRN. By age 24 months, 84% and 87% of HIV-uninfected children receiving 1 or 2 doses, respectively, were seroprotected. Only 41% of 22 HIV-infected children were measles seroprotected at age 20 months. DISCUSSION: Measles seroprotection persisted through age 24 months among HIV-uninfected children who received 1 or 2 doses of MV. HIV-infected children demonstrated seroprotection through age 12 months, but this was not sustained. PMID- 21666157 TI - International measles incidence and immunization coverage. AB - Measles is exquisitely sensitive to immunization programs. We investigated the decline in measles incidence after immunization with 1 or 2 doses of measles containing vaccine (MCV), with or without supplementary immunization activities (SIAs). Using data from the World Health Organization, we modeled the impact of measles immunization using a negative binomial regression model. All countries offer measles immunization, and 192 of 193 countries offer a second dose of MCV (MCV2), using either a routine second dose, SIAs, or both. The incidence of measles fell from a median of 70.9 cases/100,000/year when coverage with a first dose of MCV (MCV1) was in the range of 0%-39% to a median of .9 cases/100,000/year when MCV1 coverage was 90%-100%, in both cases with no MCV2. Further reductions followed the introduction of MCV2 and SIAs. Modeling showed that each 1% increase in MCV1 coverage was followed by a 2.0% decrease in incidence in the same and following years (95% confidence interval [CI], 2.0% 1.9%, and 2.1%-1.9%, respectively). For a second dose, a rise of 1% in MCV2 coverage was followed by a decrease in measles incidence by .4% (95% CI, .3%-.5%) in the same year and .3% (95% CI, .2%-.5%) in the following year. SIAs were followed by decreases of measles incidence by 40.3% (95% CI, 46.3%-33.8%) in the same year and 45.2% (95% CI, 51.1%-48.7%) in the following year. A herd immunity effect was demonstrated with MCV1 coverage of >80%, and SIAs are an extraordinarily effective strategy for measles control. PMID- 21666158 TI - Measles vaccination in HIV-infected children: systematic review and meta-analysis of safety and immunogenicity. AB - BACKGROUND: Measles control may be more challenging in regions with a high prevalence of HIV infection. HIV-infected children are likely to derive particular benefit from measles vaccines because of an increased risk of severe illness. However, HIV infection can impair vaccine effectiveness and may increase the risk of serious adverse events after receipt of live vaccines. We conducted a systematic review to assess the safety and immunogenicity of measles vaccine in HIV-infected children. METHODS: The authors searched 8 databases through 12 February 2009 and reference lists. Study selection and data extraction were conducted in duplicate. Meta-analysis was conducted when appropriate. RESULTS: Thirty-nine studies published from 1987 through 2008 were included. In 19 studies with information about measles vaccine safety, more than half reported no serious adverse events. Among HIV-infected children, 59% (95% confidence intervals [CI], 46-71%) were seropositive after receiving standard-titer measles vaccine at 6 months (1 study), comparable to the proportion of seropositive HIV-infected children vaccinated at 9 (8 studies) and 12 months (10 studies). Among HIV exposed but uninfected and HIV-unexposed children, the proportion of seropositive children increased with increasing age at vaccination. Fewer HIV-infected children were protected after vaccination at 12 months than HIV-exposed but uninfected children (relative risk, 0.61; 95% CI, .50-.73). CONCLUSIONS: Measles vaccines appear to be safe in HIV-infected children, but the evidence is limited. When the burden of measles is high, measles vaccination at 6 months of age is likely to benefit children of HIV-infected women, regardless of the child's HIV infection status. PMID- 21666159 TI - Safety and immunogenicity of early measles vaccination in children born to HIV infected mothers in the United States: results of Pediatric AIDS Clinical Trials Group (PACTG) protocol 225. AB - BACKGROUND.: ACTG (Pediatric AIDS Clinical Trials Group) 225, a multicenter, randomized, open-label trial in the United States evaluated reactogenicity and immunogenicity of 2 vaccination regimens: monovalent measles vaccine (Attenuvax) at 6 months of age and measles, mumps, and rubella, live attenuated (MMRII) vaccine at 12 months of age (2D), or only MMRII at 12 months of age (1D) in human immunodeficiency virus-infected (HIV-infected) (POS) and uninfected (NEG) children in the pre-highly active antiretroviral therapy (pre-HAART) period. METHODS: Plaque-reduction neutralization (PRN) of measles-neutralizing antibody titers were evaluated at study weeks 0, 6, 26, 32, 52, and 130 (~3 years of age). RESULTS: The 110 subjects included: 65 2DNEG; 30 1DNEG; 7 2DPOS and 8 1DPOS. Vaccinations (n=175) were associated with no adverse experiences >Grade 2 except for Grade 3 fever (n=2, 1 1DPOS and 1 1DNEG). Six weeks after Attenuvax, all 2DPOS subjects (7/7) seroresponded (PRN titers >=120 mIU/mL) with median titers significantly exceeding 2DNEG titers (2115 vs 628 mIU/mL, respectively; P=.023). At ~3 years of age, 67% 1DPOS (4/6) and 83% 2DPOS (4/5) subjects maintained titers >=120 mIU/mL. Prevaccination titers >=25 mIU/mL among 2DNEG subjects correlated inversely with the likelihood of achieving titers >=120 mIU/mL (56% vs 90%; P=.004). CONCLUSIONS: Among HIV-infected children pre-HAART, Attenuvax at 6 months was well tolerated and immunogenic. These data support the current World Health Organization (WHO) recommendation to administer a first dose of measles vaccine at 6 months of age to HIV-infected children. PMID- 21666160 TI - Measles mortality reduction contributes substantially to reduction of all cause mortality among children less than five years of age, 1990-2008. AB - BACKGROUND: The Millennium Development Goal 4 (MDG4) to reduce mortality in children aged <5 years by two-thirds from 1990 to 2015 has made substantial progress. We describe the contribution of measles mortality reduction efforts, including those spearheaded by the Measles Initiative (launched in 2001, the Measles Initiative is an international partnership committed to reducing measles deaths worldwide and is led by the American Red Cross, the Centers for Disease Control and Prevention, UNICEF, the United Nations Foundation, and the World Health Organization). METHODS: We used published data to assess the effect of measles mortality reduction on overall and disease-specific global mortality rates among children aged <5 years by reviewing the results from studies with the best estimates on causes of deaths in children aged 0-59 months. RESULTS: The estimated measles-related mortality among children aged <5 years worldwide decreased from 872,000 deaths in 1990 to 556,000 in 2001 (36% reduction) and to 118,000 in 2008 (86% reduction). All-cause mortality in this age group decreased from >12 million in 1990 to 10.6 million in 2001 (13% reduction) and to 8.8 million in 2008 (28% reduction). Measles accounted for about 7% of deaths in this age group in 1990 and 1% in 2008, equal to 23% of the global reduction in all cause mortality in this age group from 1990 to 2008. CONCLUSIONS: Aggressive efforts to prevent measles have led to this remarkable reduction in measles deaths. The current funding gap and insufficient political commitment for measles control jeopardizes these achievements and presents a substantial risk to achieving MDG4. PMID- 21666161 TI - Measles supplementary immunization activities and GAVI funds as catalysts for improving injection safety in Africa. AB - BACKGROUND: In 2000, reuse of disposable syringes and inadequately sterilized syringes resulted in 39% of all injections being unsafe, causing 22 million infections. We describe the contribution of measles supplemental immunization activities (SIAs) and Global Alliance for Vaccines and Immunisation (GAVI) funding in replacing disposable and sterilizable syringes with auto-disable (AD) syringes to improve injection safety in 39 African countries. METHODS: We assessed trends in nationwide introduction of AD syringes against measles catch up SIAs and GAVI funding using World Health Organization/United Nations Children's Fund (UNICEF) Joint Reporting Form for Immunization and UNICEF supply data. RESULTS: In 19 (49%) of 39 countries, the measles program catalyzed the introduction of injection safety equipment, including AD syringes and safety boxes, training, and procurement of safety equipment during SIAs. GAVI was catalytic through financial support in 14 countries (36%) for including safe injection equipment in routine immunization. Additionally, GAVI funded 21 countries that had already introduced AD syringes in their national program. UNICEF AD syringe shipments to sub-Saharan Africa increased from 11 million to 461 million from 1997 to 2008. All 39 countries stopped using sterilizable syringes by 2004. CONCLUSIONS: The measles mortality reduction program and GAVI complemented each other in improving injection safety. All countries continued with AD syringes for immunization after measles catch-up SIAs and GAVI funding ended. PMID- 21666162 TI - Measles mortality reduction and pre-elimination in the African region, 2001-2009. AB - INTRODUCTION: In 2001, countries in the African region adopted the measles associated mortality reduction strategy recommended by the World Health Organization and the United Nations Children's Fund. With support from partners, these strategies were implemented during 2001-2009. METHODS: To assess implementation, estimates of the first dose of measles vaccination through routine services (MCVI) and reported coverage for measles supplemental immunization activities (SIAs) were reviewed. Measles surveillance data were analyzed. RESULTS: During 2001-2009, regional MCV1 coverage increased from 56% to 69%, and >425 million children received measles vaccination through 125 SIAs. Measles case-based surveillance was established in 40 of 46 countries; the remaining 6 have aggregated case reporting. From 2001 through 2008, reported measles cases decreased by 92%, from 492,116 to 37,010; however, in 2009, cases increased to 83,625. CONCLUSIONS: The implementation of the recommended strategies led to a marked decrease in measles cases in the region; however, the outbreaks occurring since 2008 indicate suboptimal vaccination coverage. To achieve high MCV1 coverage, provide a second dose through either periodic SIAs or routine services, and to ensure further progress toward attaining the regional measles pre-elimination goal by 2012, a renewed commitment from implementing partners and donors is needed. PMID- 21666163 TI - Changing epidemiology of measles in Africa. AB - BACKGROUND: In Africa before the introduction of measles vaccination, measles primarily affected young children. To describe measles epidemiology in Africa since the start of accelerated measles control activities in 2001, we analyzed regional measles case-based surveillance data for 2002-2009. METHODS: Country years were grouped by 10-year moving average of routine measles vaccination coverage (aMCV1). Age was log transformed, and pair-wise comparisons of means were made. A chi(2) test was used to assess association between coverage and age groups. Cumulative percent curves and percentiles of age, dot plots with Loess curve, and Spearman rank correlation coefficient were calculated. RESULTS: Of 180,284 suspected cases, 73,009 (41%) were confirmed as measles. Of these, the mean age was 79 months (median, 36 months; interquartile range, 16-96 months) and significantly younger in country-years with <50% aMCV1 than those with 50%-74% aMCV1 (P=.03) and >=75% (P=.02). With increasing coverage, there was a slight decrease in age in the 10th and 25th and moderate increase in age in the 50th, 75th, and 90th percentiles. CONCLUSIONS: During 2002-2009, the median age of confirmed measles was 36 months. In countries with >=50% aMCV1 coverage compared with low-coverage countries, age shifted to older children and young adults; for infants, age decreased slightly with higher coverage. PMID- 21666165 TI - Measles resurgence following a nationwide measles vaccination campaign in Nigeria, 2005-2008. AB - INTRODUCTION: From 1990 through 2008, routine immunization coverage of measles vaccine in Nigeria ranged from 35% to 70%. Nigeria conducted a nationwide measles vaccination campaign in 2 phases during 2005-2006 that targeted children aged 9 months to 14 years; in 2008, a nationwide follow-up campaign that targeted children aged 9 months to 4 years was conducted in 2 phases. Despite these efforts, measles cases continued to occur. METHODS: This is a descriptive study that reviewed the measles immunization coverage data from administrative, World Health Organization, United Nations Children's Fund, survey, and supplemental immunization activities data. Measles surveillance data were analyzed from case based surveillance reports. RESULTS: Confirmed measles cases increased from 383 in 2006 to 2542 in 2007 and to 9510 in 2008. Of the confirmed cases in 2008, 717 (30%) occurred in children <2 years of age, 1145 (48%) in children 2-4 years of age, and 354 (14%) were in children 5-14 years of age. In 2008, the measles case fatality rate was 1.2%. CONCLUSIONS: Suboptimal routine coverage and the wide interval between the catch-up and follow-up campaigns likely led to an accumulation of children susceptible to measles. PMID- 21666164 TI - Rubella epidemiology in Africa in the prevaccine era, 2002-2009. PMID- 21666166 TI - Progress in measles mortality reduction in Ethiopia, 2002-2009. AB - BACKGROUND: In 2002, Ethiopia adopted the African regional accelerated measles control strategies to reduce measles mortality. Routine measles vaccination is provided for infants at 9 months of age. A second opportunity for measles vaccination through supplementary immunization activities (SIAs) started in 2002, targeting children aged 6 months-14 years; periodic follow-up SIAs were conducted, targeting children aged 6-59 months from 2005 through 2009. METHODS: The administrative coverage data for routine measles vaccination and the respective World Health Organization-United Nations Children's Fund vaccination coverage estimates, as well as administrative coverage during measles SIAs and the measles case-based surveillance data from 2004 through 2009, were reviewed and analyzed. RESULTS: The administrative coverage with routine measles vaccination increased from 37% in 2000 to 76% in 2009. The SIAs coverage was 92% for the catch-up SIAs, 88% for the first follow-up SIAs, and 92% for the second follow-up SIAs. Measles case-based surveillance met the targets set for the 2 main performance indicators during 2005-2009. CONCLUSIONS: Following the adoption of the measles control strategies, a reduction in the number of reported measles cases and measles outbreaks was documented. However, measles outbreaks continued to occur in Ethiopia, mainly because of suboptimal measles vaccination coverage. PMID- 21666167 TI - The epidemiology of rubella disease in Ethiopia: data from the measles case-based surveillance system. AB - BACKGROUND: Rubella is usually a mild rash illness. However, when a woman contracts rubella early in pregnancy, serious consequences may occur, including birth defects known as congenital rubella syndrome (CRS). Information is limited on the epidemiology of rubella and CRS in Ethiopia. METHOD: Rubella cases reported through the measles case-based surveillance system during 2004-2009 were analyzed. RESULTS: A total of 8212 samples were tested for rubella immunoglobulin (Ig) M, and 992 (12.1%) of these specimens had test results that were positive for rubella IgM. The age distribution of patients with rubella-positive cases ranged from 3 months to 44 years. The majority (94.7%) of the cases were in individuals <15 years of age. The proportion of positive specimens from urban areas (19.4%) was higher than that from rural areas (11.6%). CONCLUSIONS: Rubella is endemic in Ethiopia and mainly occurs among children and young adolescents. To better understand the burden of rubella and CRS, and to develop a national strategy for rubella control in Ethiopia, CRS surveillance will need to be established, and appropriate studies need to be conducted. PMID- 21666168 TI - Progress toward control of rubella and prevention of congenital rubella syndrome- worldwide, 2009. AB - Rubella, usually a mild rash illness in children and adults, can cause serious consequences when a pregnant woman is infected, particularly in early pregnancy. These serious consequences include miscarriage, fetal death or an infant born with birth defects (i.e., congenital rubella syndrome (CRS)). The primary purpose for rubella vaccination is the prevention of congenital rubella infection including CRS. Since 1969, several rubella virus vaccines have been licensed for use; however, until the 1990s, use of rubella-containing vaccine (RCV) was limited primarily to developed countries. In 1996, it was estimated that 110,000 infants with CRS were born annually in developing countries. In 2000, the first World Health Organization rubella vaccine position paper was published to guide introduction of RCV in national childhood immunization schedules. From 1996 to 2009, the number of countries that introduced RCV into their national routine childhood immunization programs increased by 57% from 83 countries in 1996 to 130 countries in 2009. In addition, three of the six WHO regions established rubella control and CRS prevention goals: Region of the Americas and Europe rubella elimination by 2010 and 2015, respectively, and Western Pacific Region accelerated rubella control and CRS prevention by 2015. Also, during this time period, the number of rubella cases reported decreased from 670,894 in 2000 to 121,344 in 2009. Rubella control and prevention of CRS can be accelerated by integrating with current global measles mortality reduction and regional elimination activities. PMID- 21666169 TI - A long-lasting measles epidemic in Maroua, Cameroon 2008-2009: mass vaccination as response to the epidemic. AB - BACKGROUND: A measles outbreak occurred in Maroua, Cameroon, from January 2008 to April 2009. In accordance with recent World Health Organization guidelines, an outbreak-response immunization (ORI) was conducted in January 2009. The aim of this study was to investigate the causes of the epidemic in order to guide vaccination strategies. METHODS: We performed a stratified household-based survey using cluster sampling to determine measles vaccination coverage in children aged 9 months to 15 years. We defined 3 strata based on measles incidence. Next, we performed a case-control study to measure vaccine effectiveness (VE). Cases were obtained from health center registries. Controls were selected among respondents to the coverage survey. RESULTS: The vaccination-coverage survey included 2963 children in total. The overall routine vaccination coverage was 74.1% (95% confidence interval [CI]: 70.0%-78.3%). Measles incidence was inversely proportional to routine vaccination coverage, with high incidence associated with coverage of 71% and low incidence associated with coverage of 84%. The overall VE was 94% (95% CI, 86.7%-97.4%). After the ORI in January 2009, the coverage was >90% in all strata and measles incidence declined rapidly. DISCUSSION: Our results confirm that insufficient vaccination coverage was the main reason for this epidemic. The ORI conducted in January 2009 contributed both to control the epidemic and to increase the vaccination coverage to desirable levels. PMID- 21666170 TI - Impact of a measles outbreak response immunization campaign: Maroua, Cameroon, 2009. AB - A large measles outbreak occurred in Maroua, Cameroon during October 2008-April 2009; a nine-day outbreak response immunization (ORI) campaign was initiated 15 weeks after the start of the outbreak during high transmission season. To assess the impact of ORI, we described changes to case counts and characteristics before and after ORI, and the reporting efficiency of measles cases to the surveillance system. A sharp decrease in cases occurred from 555 cases during the period before ORI to 162 cases during the period after ORI; reporting efficiency was 79.5% before ORI and 93.0% after ORI. These findings highlight the potential benefits of rapid implementation of recommended ORI strategies during measles outbreaks in Africa. PMID- 21666171 TI - Preplanned national measles vaccination campaign at the beginning of a measles outbreak--Sierra Leone, 2009-2010. AB - BACKGROUND: Large-scale measles outbreaks occurred throughout Africa from 2008 2010. In Sierra Leone, in November 2009, preceding a measles supplemental immunization activity (SIA), the largest measles outbreak in a decade started. METHODS: We analyzed data from the national measles case-based surveillance system, developed a susceptibility profile of the population, and calculated vaccine effectiveness (VE) among children 12-59 months of age. RESULTS: From November 1, 2009 to July 13, 2010, 1,094 confirmed cases, including 9 deaths, were reported; 716 (66%) were <5 years of age. B3 genotype was identified. Measles attack rates per 100,000 population were highest among infants aged 6-8 months (56.4) and in Bo district (49.4). Districts with higher estimated SIA coverage tended to have lower attack rates (Spearman Correlation Coefficient= 0.63), p=0.07. Among 473 cases with information on vaccination status, 222 (47%) were unvaccinated; estimated VE was 74%. The 2009 measles SIA led to 165,000 fewer estimated susceptible individuals. CONCLUSIONS: The 2009 measles SIA reduced the overall magnitude of the outbreak, though routine and SIA coverage was insufficient to prevent it entirely. Maintaining high coverage through routine services and SIAs in all districts and conducting follow-up SIAs prior to the end of the low transmission season may prevent future outbreaks. PMID- 21666172 TI - The Americas: paving the road toward global measles eradication. AB - BACKGROUND: The Region of the Americas set a goal of interrupting endemic measles virus transmission by the end of 2000. This decision was primarily based on rapid decreases in measles disease burden in pioneering countries that implemented Pan American Health Organization-recommended vaccination and surveillance strategies. Review of these strategies may inform measles elimination efforts in other regions. METHODS: Results from the implementation of the measles elimination strategy in the Americas were compiled and analyzed over a 30-year period, which was divided into 4 phases: the early years of the Expanded Program on Immunization (1980-1986); the start-up phase for elimination (1987-1994); the elimination phase (1995-2002); and the postelimination phase (2003-2010). Factors that contributed to elimination and the challenges confronted during the postelimination phase are discussed. RESULTS: An analysis of vaccination strategies over time highlights the transition from monovalent measles vaccine to the incorporation of measles-mumps-rubella vaccine administered in the routine program. Regional vaccination coverage increased during the period 1987-2010, sustained at >=90% since 1998. Measles elimination efforts led to the implementation of 157 national vaccination campaigns, vaccinating a total of 440 million persons. Endemic measles virus transmission was interrupted in 2002. After elimination, measles importations and associated outbreaks occurred. Measles incidence has remained at <1 case per 1 million population since 2002. CONCLUSIONS: The success of measles elimination strategies in the Americas suggests that global measles eradication is attainable. PMID- 21666173 TI - Measles and rubella elimination initiatives in the Americas: lessons learned and best practices. AB - Countries in the World Health Organization Region of the Americas successfully interrupted endemic measles virus transmission 8 years after setting a regional measles elimination goal and have sustained this achievement since 2002. The vast experience from the region clearly demonstrates that measles elimination can be accomplished and maintained over time. This brief report summarizes the lessons learned and the best practices that evolved in the Americas during 3 measles elimination phases (ie, preelimination, elimination, and postelimination phases), as well as the contribution of rubella elimination to strengthening and maintaining measles elimination. The effective measures that have been implemented and adapted by the countries of the Americas to eliminate endemic measles and rubella will serve as an example to other countries and regions embarking on this endeavor. PMID- 21666174 TI - Strategic planning for measles control: using data to inform optimal vaccination strategies. AB - BACKGROUND: In response to repeated requests for assistance in evaluating the health benefit and cost implications of adjustments to national measles immunization strategies, the World Health Organization (WHO) has developed the Measles Strategic Planning (MSP) tool to harness routinely available data to estimate effectiveness and cost effectiveness of vaccination strategies. METHOD: The MSP tool estimates measles incidence and mortality through a country-specific cohort model, using a probability of infection dependent on population immunity levels. This method approximates measles transmission dynamics without requiring detailed data that would prohibit use in low- and middle-income countries. Coupled with cost data, the tool estimates incremental costs and cost effectiveness of user-defined vaccination strategies over 5-10 year planning periods. RESULTS: The MSP tool produces valid estimates of measles incidence in settings with low to moderate vaccination coverage. Early adopters report that the tool facilitates decision making by minimizing the amount of time required to assess the impact of vaccination strategies on population immunity. CONCLUSIONS: By clearly illustrating what vaccination strategies can effectively protect against measles at the least cost to immunization programs, the MSP tool supports evidence-based decision making for effective and comprehensive measles control. PMID- 21666175 TI - The Caribbean experience in maintaining high measles vaccine coverage. AB - The Caribbean subregion was the first area of the world to eliminate measles. From 1991 through 2010, the 21 countries of the subregion were remarkably successful in maintaining their measles-free status despite importations of the virus from areas where it continues to circulate. This task has been accomplished by ensuring that each country in the subregion maintains measles vaccine coverage of >=95%. The absence of measles is the result of a collaboration between the various national authorities and the Pan American Health Organization in ensuring vaccination campaigns to deliver the second dose of a measles-containing vaccine, estimating and validating vaccine coverage for both the first and second doses of measles vaccine for all local populations; developing detailed plans of action to improve coverage in those populations where coverage is <95%; providing technical assistance for the implementation of the plan; and performing follow-up to confirm that all aspects of the plans were in fact implemented and that the target vaccination level was achieved. These efforts have been extremely successful in maintaining high vaccine coverage and, therefore, in keeping the virus from circulating on those occasions when it has been reintroduced into the subregion. Although sophisticated statistical methods have been used to identify weaknesses in national vaccine programs, the program is basically quite simple and can be systematically implemented in any country that has the desire to eliminate measles from its population. PMID- 21666176 TI - Progress toward measles elimination in the Eastern Mediterranean Region. AB - Since 1997, when the goal of interrupting measles transmission by 2010 was adopted, substantial progress has been made toward the elimination of measles in the Eastern Mediterranean Region (EMR). For the 22 EMR member countries, routine coverage with the first dose of a measles-containing vaccine (MCV) increased from 70% in 1997 to 82% in 2009. All 22 countries conducted measles catch-up vaccination campaigns during 1994-2009, and most conducted follow-up campaigns as needed. Of the 22 EMR countries, 19 have established case-based surveillance for measles with laboratory confirmation. Reported measles cases decreased by 86% during 1998-2008, and estimated measles mortality decreased by 93% during 2000 2008, accounting for 17% of global measles mortality reduction during that period. Despite these successes, several significant challenges remain, and the EMR will not be able to achieve measles elimination by the end of 2010. Achieving and maintaining high population immunity with 2 doses of MCV, improving sensitive case-based surveillance, identifying and vaccinating high-risk subpopulation groups, and appropriately responding to outbreaks are key steps needed to achieve the goal. PMID- 21666177 TI - Toward measles elimination in Bahrain--a Middle East country experience. AB - Measles was a leading cause of infant and child morbidity and mortality in Bahrain before the introduction of measles vaccine in 1974. With the establishment of the Expanded Program on Immunization (EPI) in 1981 and the introduction of a second dose of measles vaccine in 1985, coverage for first and second doses of measles vaccine increased to 94% by 1997 and has been sustained >97% since 2001. Measles, mumps, and rubella (MMR) immunization campaigns targeting 12-year-old students were conducted annually during 1998-2006 and achieved coverage of >95%. As a result, the incidence of measles in Bahrain has declined markedly over the past 4 decades, to 2.7 cases per million persons in 2009. Recent confirmed measles cases have occurred sporadically, in undervaccinated children or in infants too young or adults too old to receive measles vaccine. Bahrain has made significant progress toward measles elimination by sustaining high immunization coverage and strengthening case-based measles surveillance activities. Further success will depend on improved identification and immunization of undervaccinated expatriate workers and their families. PMID- 21666178 TI - Successful control and impending elimination of measles in the Islamic Republic of Iran. AB - Measles is still one of the most common infectious killers of children in the world, especially in developing countries. In Iran, during the prevaccine era, 150,000-500,000 cases of measles were reported annually, with a death rate of 10% 15%. After the establishment of Expanded Program on Immunization program in 1984, vaccination rates for the first and second doses of measles vaccine increased to >90% by the mid-1990s, and the number of measles cases decreased to 2652 in 1996. In response to increased numbers of cases in older age groups during 1996-2002, a nationwide measles-rubella vaccination campaign was conducted in 2003, and 33,100,000 persons (99%) aged 5-25 years were vaccinated. During 2004-2009, 221 laboratory-confirmed measles cases (<1 case per million population) were detected, primarily in rural areas and among migrant groups who traveled to or came from high-incidence countries. High routine immunization coverage, low disease incidence, and surveillance system data suggest that interruption of endemic virus transmission might have already been achieved in Iran, but challenges remain and continued efforts are needed to sustain this accomplishment. PMID- 21666179 TI - Measles control and elimination in Somalia: the good, the bad, and the ugly. AB - Despite enormous challenges, Somalia has been successfully implementing accelerated measles control activities since 2005. Through innovative strategies and with the support of local and international partners, the country has shown potentials of implementing measles mortality reduction activities in complex emergencies. Measles incidence has been reduced by >80% after the measles catch up campaigns of 2005-2007, and national reported measles routine immunization coverage with first dose measles containing vaccine has reached 59% for the first time in 2009. However, the near collapse of the health care system and the ongoing insecurity continue to hamper the implementation of recommended measles control and elimination strategies in some parts of the country, making these achievements fragile. Somalia exemplifies the challenges in meeting measles elimination goals in the World Health Organization Eastern Mediterranean region. As the region is entering its 2010 measles elimination goals, it appears necessary to establish realistic and flexible interim goals for measles control in Somalia that will take into consideration the specificities of the country. Maintaining flexibility in conducting field operations, securing financial resources, multiplying opportunities for measles vaccination, and improving disease monitoring systems will remain vital to sustain and improve current achievements. PMID- 21666181 TI - What will it take to achieve measles elimination in the World Health Organization European Region: progress from 2003-2009 and essential accelerated actions. AB - BACKGROUND: The Member States of the European Region (EUR) of the World Health Organization (WHO) have made great progress towards achieving the goal of measles elimination by 2010. METHODS: Measles surveillance and vaccine coverage data from 2003-2009 reported to WHO were analyzed. A review of feasibility of reaching the elimination goal by the 2010 target date was conducted in 2009. RESULTS: From 2003-2009, the measles incidence decreased dramatically and coverage with 2 doses of measles vaccine increased among wide age groups of susceptible persons. With the decrease of disease incidence and the reduction of outbreaks in the eastern part of EUR, the proportion of reported cases in the western part increased. In 2009, outbreaks in 5 countries accounted for 89.6% of reported cases. Challenges to reach the 2010 goal include ongoing outbreaks with reestablished endemicity in some countries, decreased demand for vaccines with an increased focus on the measles vaccine safety, and population groups with limited access to immunization services. CONCLUSIONS: Measles elimination in EUR is attainable, albeit not by 2010. EUR countries should ensure political commitment and resources to protect the gains made to date and address these challenges to sustain the progress and achieve the elimination goal. PMID- 21666180 TI - Progress toward measles and rubella elimination in Egypt. AB - Measles and rubella were common infectious diseases in Egypt during the prevaccine era. Monovalent measles vaccine was introduced in 1977, and measles vaccination coverage increased from <50% to >90% from 1980 to 1999; however, measles outbreaks continued to occur at 2- to 4-year intervals during this period. After the introduction of a second routine dose of measles vaccine as a combined measles-mumps-rubella (MMR) vaccine in 1999 and the implementation of measles immunization campaigns targeting 6- to 16-year-old children during 2000 2003, reported measles cases dramatically decreased by 2003. In 2002, Egypt established a goal to eliminate measles and rubella and to prevent congenital rubella syndrome (CRS) by 2010. Large-scale rubella and measles outbreaks in 2005 2007, however, led to a revision of the plan of action to achieve the 2010 goals. A nation-wide measles-rubella immunization campaign, targeting children, adolescents, and young adults 2-20 years old, was conducted in 2 phases during 2008-2009 and achieved coverage >95%. With the decrease to record low levels of cases of measles and rubella in 2009 and 2010, Egypt should achieve measles and rubella elimination in the near future, but high coverage(>95%) with 2 doses of measles-rubella vaccine needs to be maintained, measles-rubella surveillance strengthened, and CRS surveillance developed. PMID- 21666182 TI - Molecular genotyping and epidemiology of measles virus transmission in the World Health Organization European Region, 2007-2009. AB - BACKGROUND: In 2002, the World Health Organization (WHO) adopted a goal to eliminate measles in the European Region by 2010. Measles elimination is defined as the interruption of indigenous measles virus (MV) transmission. The molecular epidemiology of MV transmission in the WHO European Region was studied through the investigation of reported cases and outbreaks to monitor the region's progress toward its measles elimination goal. METHODS: National and regional laboratories performed molecular characterization of MV detected between 2007 and 2009 in the WHO European Region. To document indigenous transmission and importations into the region, we analyzed genotyping results and epidemiological data on measles outbreaks reported by the member states. RESULTS: Since 2007, MV genotype D6 has not been reported in the WHO European Region, suggesting that its chains of transmission have been interrupted, whereas several other MV genotypes are still circulating. Although several European countries have already interrupted indigenous MV transmission, genotyping showed that 3 endemic MV transmission chains have been reestablished in other countries. CONCLUSIONS: The WHO European Region 2010 goal will not be met, as indigenous transmission of MV has not been interrupted. As the region begins to document its process of elimination verification to monitor progress toward the goal, countries will need to ensure that genotyping is performed in all measles outbreaks. PMID- 21666183 TI - Supplementary immunization activities to achieve measles elimination: experience of the European Region. AB - BACKGROUND: Supplementary immunization activities (SIAs) using measles-containing vaccine (MCV) have had a substantial impact on reducing mortality associated with measles worldwide. METHODS: To assess impact of SIAs on measles incidence in the World Health Organization European Region and their role at the final stages of measles elimination efforts in Europe, we reviewed information on SIAs, measles surveillance, and routine vaccination coverage during 2000-2009. RESULTS: During 2000-2009, >57 million persons received MCV through SIAs in 16 countries. The Region primarily focused on catch-up campaigns with wider target age groups than in other regions and subsequently relied on routine vaccination rather than periodic follow-up SIAs for the second MCV dose. In addition, the concept of SIAs has been expanded from short-term (<30 days) mass campaigns implemented in other regions to incorporate vaccination efforts over longer periods and outbreak response vaccination. In 2009, 14 of 16 countries that conducted SIAs reported no measles cases or <1 case per 1,000,000 population, reflecting the post-SIA decrease in incidence. CONCLUSIONS: SIAs have made a substantial contribution to the success of measles elimination efforts and will likely remain an important strategy for interrupting measles virus transmission in the European Region, although specific approaches will vary by country. PMID- 21666184 TI - Should outbreak response immunization be recommended for measles outbreaks in middle- and low-income countries? An update. AB - BACKGROUND: Measles caused mortality in >164,000 children in 2008, with most deaths occurring during outbreaks. Nonetheless, the impact and desirability of conducting measles outbreak response immunization (ORI) in middle- and low-income countries has been controversial. World Health Organization guidelines published in 1999 recommended against ORI in such settings, although recently these guidelines have been reversed for countries with measles mortality reduction goals. METHODS: We searched literature published during 1995-2009 for papers reporting on measles outbreaks. Papers identified were reviewed by 2 reviewers to select those that mentioned ORI. World Bank classification of country income was used to identify reports of outbreaks in middle- and low-income countries. RESULTS: We identified a total of 485 articles, of which 461 (95%) were available. Thirty-eight of these papers reported on a total of 38 outbreaks in which ORI was used. ORI had a clear impact in 16 (42%) of these outbreaks. In the remaining outbreaks, we were unable to independently assess the impact of ORI. CONCLUSIONS: These findings generally support ORI in middle- and low-income countries. However, the decision to conduct ORI and the nature and extent of the vaccination response need to be made on a case-by-case basis. PMID- 21666185 TI - Who gets measles in Europe? AB - BACKGROUND: Measles outbreaks continue to occur in Europe as a result of suboptimum vaccination coverage. This article aims to describe individuals susceptible to measles, and provide an overview of affected groups and the public settings in which measles transmission occurred in Europe in 2005-2009. METHODS: Individuals susceptible to measles were described and categorized on the basis of factors leading to nonvaccination and vaccine failure. A literature search was conducted to identify affected groups and public settings in which measles transmission occurred. RESULTS: Most individuals susceptible to measles are previously uninfected and unvaccinated. The reasons for nonvaccination in individuals eligible for vaccination ranged from lack of information to poor access to health care. Several outbreaks have emerged in Roma and Sinti, Traveller, anthroposophic, and ultra-orthodox Jewish communities, and immigrants identifying them as being particularly at risk. Public settings for transmission included mostly educational and health care facilities. CONCLUSIONS: Improved efforts are needed to strengthen immunization programs, identify barriers for measles-containing vaccine uptake, and explore methods to target vulnerable populations that are not being reached with routine immunization delivery services. Specific measures are needed to prevent and control measles in educational and health care facilities. Failure to identify who gets measles and implement the elimination strategies raises concerns for the successful and sustainable elimination of measles in Europe. PMID- 21666186 TI - Progress toward measles elimination in the Russian Federation, 2003-2009. AB - Successful implementation of the Russian Federation's national measles elimination program has been ensured by high vaccine coverage (>95%) of the target population (with 2 doses of measles-containing vaccine), case-based laboratory investigation of measles, and active surveillance of measles cases among patients with rashes and/or fever. As a result, the incidence of measles has decreased to <1 case per 1,000,000 population (2007-2009); no circulation of D6 genotype, which was endemic in the Russian Federation, has been observed since the second half of 2007; and the proportion of imported measles cases of different genotypes increased to 19.8% in 2007 from 1% in 2003. To confirm successful elimination of indigenous measles, a documentation system was initiated in the Russian Federation. PMID- 21666188 TI - Status of rubella and congenital rubella syndrome surveillance, 2005-2009, the World Health Organization European Region. AB - BACKGROUND: The World Health Organization European Region has a goal for rubella elimination and congenital rubella syndrome (CRS) prevention. Although all Member States recommend a rubella-containing vaccine in their national immunization programs, rubella and CRS continue to occur, and surveillance quality varies throughout the region. METHODS: To describe the status of regional rubella and CRS surveillance and assess progress toward elimination, we reviewed surveillance practices by surveying all 53 Member States and analyzed rubella and CRS surveillance data during 2005-2009. RESULTS: Overall, 41 (91%) of 45 responding Member States have nationwide rubella surveillance, and 39 (87%) have nationwide CRS surveillance. During 2005-2009, rubella cases reported in the region decreased by 94% from 206,359 cases to 11,623 cases. The greatest decrease (99%) was observed in newly independent states of the former Soviet Union. In the rest of the region, high rubella incidence was observed in Poland, Romania, Italy, and San Marino during 2005-2008 and in Poland, Bosnia and Herzegovina, and Austria in 2009. A total of 68 CRS cases were reported during 2005-2009. CONCLUSIONS: As the foundation to achieving and verifying rubella elimination, high-quality rubella and CRS surveillance needs to be implemented and sustained in all Member States. PMID- 21666187 TI - Closer to the goal: efforts in measles elimination in Germany 2010. AB - Increasing 2-dose vaccination coverage has led to an interruption of endemic measles virus circulation in Germany. However, outbreaks after virus importation still occur and contribute to international transmission chains. Between 2003 and 2009, annual measles incidence ranged between 0.2 and 2.8 per 100,000 population. Immunization gaps have been identified especially in secondary-school students and young adults, which is also reflected by a shift in age distribution of reported measles cases toward older age groups. Stronger political commitment and standardized guidelines for outbreak containment were put in place in Germany in the past years, but the last step toward measles elimination cannot be made until the number of susceptible individuals has been further reduced. In addition to routine childhood vaccination, supplementary immunization activities are needed targeting school students and young adults to close critical immunization gaps. Intensification of public awareness and sound information on vaccinations are necessary to convince skeptics and remind the forgetful. PMID- 21666189 TI - Toward rubella elimination in Poland: need for supplemental immunization activities, enhanced surveillance, and further integration with measles elimination efforts. AB - BACKGROUND: All Member States of the World Health Organization (WHO) European Region have endorsed rubella elimination and congenital rubella syndrome (CRS) prevention. However, Poland has continued high levels of reported rubella. METHODS: We reviewed rubella incidence in Poland since 1966 and analyzed national aggregated surveillance data from the period 2003-2008 and case-based data from 4 provinces from the period 2006-2008. We described CRS cases since 1997 and assessed maternal receipt of vaccine. We reviewed national vaccination coverage from 1992 through 2008. RESULTS: Since 1966, rubella outbreaks have occurred every 4-6 years in Poland. Aggregate and case-based data from the period 2003 2008 indicate that rubella virus transmission has occurred across wide age ranges (from <1 year to 60 years), with disproportionately higher percentage of cases among adolescent boys. Of 18 children with reported CRS cases from 1997 through 2008, 15 (83%) of their mothers had not been vaccinated. Measles-mumps-rubella dose 1 vaccination coverage ranged from 97% to 99%. CONCLUSIONS: Poland had the highest incidence of rubella in the WHO European Region in 2007 and 2008. Rubella occurs predominantly in age and sex cohorts historically not included in vaccination recommendations. The risk for CRS continues. To achieve rubella elimination, supplemental immunization activities among adolescent boys are needed, as is integration with measles elimination efforts. PMID- 21666190 TI - South-East Asia Regional update on measles mortality reduction and elimination, 2003-2008. AB - In 2005, the World Health Assembly endorsed a global goal of 90% reduction in measles mortality from 2000 to 2010. Substantial progress has been made toward achieving this goal in countries of the South-East Asia Region (SEAR). More than 120 million children received a second dose of measles-containing vaccine during supplemental immunization activities conducted from 2000 to 2008; routine first dose measles-containing vaccine coverage increased from 63% in 2000 to 75% by 2008; and measles surveillance is supported in all countries by the Measles Rubella Laboratory Network. Overall, the estimated number of measles deaths decreased by 46% from 2000 to 2008, and all countries with the exception of India have already achieved the 90% mortality reduction target. Sustained political and financial commitment from SEAR countries is needed to achieve regional measles mortality reduction and elimination. PMID- 21666191 TI - Proceedings of the Global Technical Consultation to assess the feasibility of measles eradication, 28-30 July 2010. PMID- 21666192 TI - Molecular epidemiology of measles in India, 2005-2010. AB - Measles is a childhood disease that causes great morbidity and mortality in India and worldwide. Because measles surveillance in India is in its infancy, there is a paucity of countrywide data on circulating Measles virus genotypes. This study was conducted in 21 of 28 States and 2 of 7 Union Territories of India by MeaslesNetIndia, a national network of 27 centers and sentinel practitioners. MeaslesNetIndia investigated 52 measles outbreaks in geographically representative areas from 2005 through June 2010. All outbreaks were serologically confirmed by detection of antimeasles virus immunoglobulin M (IgM) antibodies in serum or oral fluid samples. Molecular studies, using World Health Organization (WHO)-recommended protocols obtained 203 N-gene, 40 H-gene, and 4 M gene sequences during this period. Measles genotypes D4, D7, and D8 were found to be circulating in various parts of India during the study period. Further phylogenetic analysis revealed 4 lineages of Indian D8 genotypes: D8a, D8b, D8c, and D8d. This study generated a large, countrywide sequence database that can form the baseline for future molecular studies on measles virus transmission pathways in India. This study has created support and capabilities for countrywide measles molecular surveillance that must be carried forward. PMID- 21666193 TI - Stability of the age distribution of measles cases over time during outbreaks in Bangladesh, 2004-2006. AB - Despite recommendations from WHO to conduct measles outbreak response vaccination campaigns based on the age distribution of cases at the beginning of an outbreak, few data exist to specifically examine whether the age distribution of cases remains constant over time in a measles outbreak. This analysis explores this question with use of measles outbreak surveillance data from Bangladesh from the period 2004-2006. Pearson chi(2) tests were conducted of age distributions over 2 periods during 41 large laboratory-confirmed measles outbreaks. Statistically significant changes in age distribution over time were observed in 24% of the outbreaks. No single pattern was detected in the shifts in age distribution; however, an increase in the proportion of cases occurring among infants <9 months of age was evident in 6 outbreaks. These findings suggest a need to consider the possibility of a shift in the age distribution over time when planning an outbreak response vaccination campaign. PMID- 21666194 TI - The heterogeneity of measles epidemiology in India: implications for improving control measures. AB - BACKGROUND: Measles vaccination coverage varies in India. Trainees of the Field Epidemiology Training Programme (FETP) investigated 8 outbreaks from 2004 through 2006 in Himachal Pradesh, Uttaranchal, Tamil Nadu, and West Bengal. We reviewed these outbreaks to contribute to the description of the epidemiology of measles and propose recommendations for control. METHODS: FETP trainees searched for measles cases through stimulated passive surveillance or door-to-door case search; estimated attack rates, case fatality, and the median age of case patients; interviewed mothers about vaccination status of their children; and collected serum samples for immunoglobulin M serological testing whenever possible. For 3 outbreaks, the trainees estimated the vaccine efficacy for children >12 months of age through cohort studies. RESULTS: Six of the 8 outbreaks were serologically confirmed. Compared with outbreaks in other states, outbreaks in states with vaccination coverage of >90% had a higher median age among case patients and a lower median attack rate. Six deaths (case fatality rate, 1.5%) occurred during the 5 outbreaks for which vitamin A was not used. The vaccine efficacy was 84% (95% confidence interval [CI], 74%-91%) in Himachal Pradesh. In West Bengal, it was 66% (95% CI, 44%-80%) in 2005 and 81% (95% CI, 67%-89%) in 2006. CONCLUSIONS: In states with higher coverage, attack rates were lower and case patients were older. Although states with coverage of <90% should increase 1-dose coverage and address coverage in pockets that are poorly reached, a second opportunity for measles vaccination could be considered in states such as Himachal Pradesh and Tamil Nadu. Use of vitamin A for case management needs to be generalized. PMID- 21666195 TI - Measles in rural West Bengal, India, 2005-6: low recourse to the public sector limits the use of vitamin A and the sensitivity of surveillance. AB - BACKGROUND: Measles is often underreported. We evaluated the sensitivity of the measles surveillance in 2 districts of West Bengal in 2005-2006. METHODS: We sampled households with children aged <5 years in village clusters selected with probability proportional to size. We searched households door to door to identify World Health Organization-defined suspected measles cases that had occurred during 12 months in 2004-2005 in Howrah and in 2006 in Purulia. We interviewed mothers about use of health care services during episodes and calculated the proportion of patients seen in the public sector. We reviewed surveillance records at all levels to estimate the proportion of cases seen in public health care facilities that had been reported to the district. We calculated the overall sensitivity of measles surveillance by multiplying these 2 proportions. RESULTS: In Howrah, we identified 240 cases of measles. Of these, 8 (3.3% [95% confidence interval {CI}, 1.5%-6.5%]) had been seen in public facilities and recorded. Of 980 cases identified in 448 public facilities in the periphery, 962 (98%) had been transmitted to the district (overall sensitivity of surveillance, 3.2%). In Purulia, we identified 167 measles cases. Of these, 39 (23.4% [95% CI, = 17.2% 30.5%]) had been seen in public facilities and recorded. Of 418 cases identified in public facilities in the periphery, 414 (99%) had been transmitted to the district (overall sensitivity of surveillance, 23.1%). CONCLUSIONS: Measles surveillance captured a minority of measles cases, but cases captured were transmitted well to the district. Surveillance must engage the private sector. Health education focusing on vitamin A treatment for measles might provide an incentive to seek care, which could increase the sensitivity of surveillance. PMID- 21666196 TI - Developing rubella vaccination policy in Nepal--results from rubella surveillance and seroprevalence and congenital rubella syndrome studies. AB - BACKGROUND: The Government of Nepal is interested in preventing congenital rubella syndrome (CRS). Surveillance data were analyzed and studies conducted to assess the burden of rubella and CRS and aid in developing a rubella vaccination strategy. METHODS: (1) Analysis of rubella cases reported through measles surveillance, 2004-2009; (2) in 2008, rubella seroprevalence among women 15 to 39 years of age was evaluated; and (3) in 2009, children attending a school for the deaf were examined for ocular defects associated with CRS. RESULTS: From 2004 2009, there were 3,710 confirmed rubella cases and more than 95% of these cases were less than 15 years of age. Of 2,224 women of childbearing age (WCBA) tested for anti-rubella IgG, 2,020 (90.8%) were seropositive. Using a catalytic infection model, approximately 1,426 infants were born with CRS (192/100,000 live births) in 2008. Among 243 students attending a school for the deaf, 18 (7.4%) met the clinical criteria for CRS. CONCLUSIONS: Rubella and CRS were documented as significant public health problems in Nepal. A comprehensive approach is necessary, including introducing rubella vaccine in the routine program, assuring immunity among WCBA, strengthening routine immunization, integrating rubella surveillance with measles case-based surveillance, and establishing CRS surveillance. PMID- 21666197 TI - Progress and challenges for measles elimination by 2012 in the Western Pacific Region. AB - BACKGROUND: The 37 countries and areas of the World Health Organization (WHO) Western Pacific Region have targeted measles for elimination by 2012. METHODS: We reviewed routine and supplementary immunization coverage based on 2010 WHO/United Nation's Children's Fund (UNICEF) estimates and Joint Reporting Forms and epidemiologic and laboratory data submitted by the countries and areas. RESULTS: In 2009, 21 of 37 countries and areas had >=90% coverage with a first dose of measles vaccine; 32 countries and areas provided 2 routine doses of measles vaccine with 94% weighted average coverage among those reporting. From 1996 to 2009, 235 million persons received measles vaccine during 94 immunization campaigns in 30 countries and areas. As of 2009, 2.8 suspected cases per 100,000 population were discarded as nonmeasles; however, only 43% of second level administrative units reported at least 1 discarded case per 100,000. Adequate specimen collection rate was 71%. Measles incidence was 34 per million population in 2009, a 58% decrease compared with 2008 and the lowest ever reported. As many as 25 countries and areas already may have eliminated measles. CONCLUSIONS: Achieving the 2012 measles elimination goal is feasible provided political and financial commitments are increased at every level to further improve routine and supplementary immunization activity (SIA) coverage and surveillance in every district. PMID- 21666198 TI - Progress toward measles elimination in the People's Republic of China, 2000-2009. AB - In 2006, China set a goal of measles elimination by 2012. To describe progress toward this goal, we reviewed relevant policies and strategies and analyzed national data for 2000-2009. In response to implementation of these strategies, including increased routine measles vaccination coverage and province-specific supplementary immunization activities (SIAs), reported measles incidence decreased to a historically low level of 39.5 cases per million in 2009. A synchronized nationwide SIA was scheduled in 2010 to further decrease susceptibility to measles. However, reaching and maintaining measles elimination will require strong political commitment and efforts for strengthening surveillance, increasing 2-dose vaccine coverage to >95%, stricter enforcement of the requirement to check immunization status at school entry, and careful attention to measles susceptibility in those aged >=15 years. PMID- 21666199 TI - Impact of supplementary immunization activities in measles-endemic areas: a case study from Guangxi, China. AB - Because of limited resources, each year during the period from 1999 through 2007, only about one-quarter of the 111 counties in Guangxi province were selected by means of risk assessment to participate in Supplementary Immunization Activities (SIAs), targeting children aged 8 months to 14 years during 1999-2003 and 8 months to 10 years during 2004-2007. Approximately 2 million doses of measles vaccines were administrated each year during SIAs. Estimated from the National Notifiable Diseases Surveillance System, with a reliable internal consistency over years, the average annual incidences of measles before SIAs (1993-1998), during the first phase (1999-2003), and during the second phase (2004-2007) were 16.05, 9.10, and 2.46 cases per 100,000, respectively. The overall provincewide annual incidence decreased by 84.67%, from 12.12 cases per 100,000 in 2000 to 2.10 cases per 100,000 in 2007. The percentage of counties with annual incidence >=10 cases per 100,000 decreased from 55% in 1993 to <1% in 2007. Compared with the pre-SIA period, the greatest decrease in annual incidence was 83.93% for the 10-14.9-year-old group and the smallest decrease was 46.16% for children <1 year old. The multiple-year SIAs targeting children in selected high-risk counties were effective in controlling measles in mountainous, impoverished, and multiethnic measles-endemic areas. PMID- 21666200 TI - Innovative use of surveillance data to harness political will to accelerate measles elimination: experience from Guangxi, China. AB - The major challenge for measles elimination is to harness sufficient political will to provide the necessary financial and human resources. This is particularly relevant for local governments (at county and township levels in China) and communities that generally have not accepted measles as a serious health burden and thus have not made its prevention a high priority. An effort has been made to use surveillance data to harness political will and overcome or mitigate the shortage of resources in the impoverished province of Guangxi, one of China's 31 administrative divisions. A comprehensive information system collecting data pertaining to Expanded Program on Immunization (EPI-info) was refined to align with China's political system and translate international and national commitments into sustainable local actions. The EPI-info has proved an effective tool in identifying high-risk areas, strengthening routine immunization services, conducting mass measles immunization campaigns, and catalyzing capacity building at both county and local community levels. We outline the principles and operational features of the EPI-info and the rationale and steps taken to refine it. PMID- 21666201 TI - Biological feasibility of measles eradication. AB - Recent progress in reducing global measles mortality has renewed interest in measles eradication. Three biological criteria are deemed important for disease eradication: (1) humans are the sole pathogen reservoir; (2) accurate diagnostic tests exist; and (3) an effective, practical intervention is available at reasonable cost. Interruption of transmission in large geographical areas for prolonged periods further supports the feasibility of eradication. Measles is thought by many experts to meet these criteria: no nonhuman reservoir is known to exist, accurate diagnostic tests are available, and attenuated measles vaccines are effective and immunogenic. Measles has been eliminated in large geographical areas, including the Americas. Measles eradication is biologically feasible. The challenges for measles eradication will be logistical, political, and financial. PMID- 21666202 TI - Measles outbreak on a college campus transmitted through internet cafes. AB - BACKGROUND: During March 2008, a college in Urumqi, capital of Xinjiang Uygur Autonomous Region in China, reported a measles outbreak, amid a city-wide outbreak involving >2700 cases. METHODS: Suspected case patients were defined as patients with onset of fever (>=38 degrees ) and rash between 7 March and 30 April 2008. Probable case patients were defined as suspected case patients with >3 days of rash or known exposure to someone with laboratory-confirmed measles. Confirmed case patients were defined as suspected or probable case patients with Koplik spots or positive titer for immunoglobulin M antibody. We conducted a case control investigation to identify risk factors for transmission. RESULTS: We identified 162 suspected (attack rate, 1.9%), 99 probable, and 62 confirmed case patients. The epidemic curve indicated a point source initially, followed by person-to-person transmission. Approximately 63% of 90 probable case patients and 27% of 150 asymptomatic student controls randomly selected among classmates of student case patients visited internet cafes during the exposure period (odds ratio [OR], 4.5; 95% confidence interval [CI], 2.6-8.0); 66% of case patients and 45% of student controls reported close contact with a measles case patient (OR, 2.3; 95% CI, 1.3-3.9). In stratified analysis, visiting internet cafes (OR, 4.0; 95% CI, 1.5-11) remained significantly associated with disease, but contact with case patients (OR, 1.9; 95% CI, .79-4.4) became nonsignificant. CONCLUSIONS: This measles outbreak was transmitted in internet cafes, followed by secondary transmission. Chinese universities should require proof of immunity or 2 doses of measles vaccine at college entry. PMID- 21666204 TI - Outbreak of measles in the Republic of Korea, 2007: importance of nosocomial transmission. AB - BACKGROUND: From 2002 through 2006, Republic of Korea conducted extensive measles elimination activities and declared elimination in 2006. An outbreak of measles involving 180 confirmed cases occurred during 2007. METHODS: An outbreak investigation was performed and enhanced surveillance was implemented. Detailed case investigations and laboratory testing included serologic and molecular diagnostic methods. Cases were classified according to World Health Organization and national guidelines. RESULTS: During 2007, 451 suspected cases were reported and 180 (40%) cases were confirmed as measles during epidemiologic weeks 14-42. Incidence during the outbreak was 3.7 cases per million persons, excluding imported cases. Most confirmed cases were reported from Seoul; 137 (76%) cases were among children <24 months old, 124 (69%) case patients had no history of measles vaccination, and 81 (45%) case patients resulted from nosocomial transmission in 6 hospitals. Community members, patients, and health care workers all contributed to measles virus transmission. Limited outbreak control measures were implemented; high population immunity likely accounted for the self-limited transmission during this outbreak. CONCLUSIONS: Limited outbreaks of measles, in which nosocomial transmission can play an important role, may occur after countries have declared elimination. Timely and opportunistic vaccination may help prevent such outbreaks; high-quality surveillance is critical for their detection. PMID- 21666205 TI - Expansion of the global measles and rubella laboratory network 2005-09. AB - Enhancing measles surveillance with integration of epidemiologic and laboratory information is one of the key strategies for accelerated measles control and elimination. The World Health Organization (WHO) Global Measles and Rubella Laboratory Network (LabNet) has been developed since 2000 to currently include 690 laboratories serving 183 countries. The LabNet testing strategy follows well validated, standardized procedures for confirming suspected cases and for monitoring measles and rubella virus transmission patterns. The strength of the LabNet is a strong quality assurance program that monitors the performance of all laboratories through annual proficiency testing and continuous assessment. In the 5-year period 2005-2009, the results of >1 million measles immunoglobulin M (IgM) tests have been reported by the LabNet and, in addition, sequence information on >7000 measles and 600 rubella viruses has been shared. Progress with the development of the LabNet during 2005-2009 is discussed. PMID- 21666203 TI - Epidemiology of a measles epidemic in Vietnam 2008-2010. AB - BACKGROUND: Vietnam conducted a measles catch-up supplementary immunization activity (SIA) during 2002-2003 that targeted children 9 months-10 years of age, followed by subnational SIAs targeting persons up to 20 years of age during 2004 and 2007-2008. A measles epidemic began among young adults in October 2008 in the northern region, spread nationwide during early 2009, and continued during 2010. METHODS: We reviewed national epidemiologic and laboratory surveillance data. Measles cases were defined and classified according to World Health Organization recommendations. RESULTS: From October 2008 through January 2010, 7948 confirmed measles cases were reported from 60 of 63 provinces, an incidence of 93 cases per million population. Incidence was 328 cases per million population among children age 1-4 years, 318 cases per million population among infants, and 271 cases per million population among persons aged 20-24 years. Few cases were reported among persons 7-17 or >27 years of age. Median age of cases trended downward over time in all regions. CONCLUSIONS: The 2002-2003 measles SIA protected its targeted age group, but this epidemic was not prevented by follow-up subnational SIAs in selected provinces during 2007-2008. Transmission began among young adults and was sustained among children. The outcome of Vietnam's 2010 SIA targeting children only and change in routine schedule may influence elimination strategies for other countries. PMID- 21666206 TI - Evaluation of the World Health Organization global measles and rubella quality assurance program, 2001-2008. AB - BACKGROUND: During 2001-2008, the Victorian Infectious Diseases Reference Laboratory (VIDRL) prepared and provided a measles and rubella proficiency test panel for distribution to the World Health Organization (WHO) measles and rubella network laboratories as part of their annual laboratory accreditation assessment. METHODS: Panel test results were forwarded to VIDRL, and results from 8 consecutive years were analyzed. We assessed the type of assays used and results achieved on the basis of the positive and negative interpretation of submitted results, by year and WHO region, for measles and rubella. RESULTS: Over time, there has been a noticeable increase in laboratory and WHO regional participation. For all panels, the proportion of laboratories in all WHO regions using the WHO-validated Dade Behring assay for measles and rubella-specific IgM antibodies ranged from 35% to 100% and 59% to 100%, respectively. For all regions and years, the proportion of laboratories obtaining a pass score ranged from 87% to 100% for measles and 93% to 100% for rubella. CONCLUSIONS: During 2001-2008, a large proportion of laboratories worldwide achieved and maintained a pass score for both measles and rubella. Measles and rubella proficiency testing is regarded as a major achievement for the WHO measles and rubella laboratory program. PMID- 21666207 TI - Improving global virologic surveillance for measles and rubella. AB - An important aspect of laboratory surveillance for measles and rubella is the genetic characterization of circulating wild-type viruses to support molecular epidemiologic studies and to track transmission pathways. Virologic surveillance that is sufficient to document the interruption of transmission of measles and rubella viruses will be an essential criterion for verification of elimination. Laboratories in the World Health Organization (WHO) Measles and Rubella Laboratory Network have worked to improve and expand virologic surveillance as many regions move toward elimination of measles and rubella/congenital rubella syndrome. As countries approach elimination, it will be necessary to obtain genetic information from as many chains of transmission as possible. In addition, baseline virologic surveillance, especially for rubella, needs to be improved in many countries. This report contains a summary of recent improvements to the methods used for virologic surveillance. PMID- 21666208 TI - Global distribution of measles genotypes and measles molecular epidemiology. AB - A critical component of laboratory surveillance for measles is the genetic characterization of circulating wild-type viruses. The World Health Organization (WHO) Measles and Rubella Laboratory Network (LabNet), provides for standardized testing in 183 countries and supports genetic characterization of currently circulating strains of measles viruses. The goal of this report is to describe the lessons learned from nearly 20 years of virologic surveillance for measles, to describe the global databases for measles sequences, and to provide regional updates about measles genotypes detected by recent surveillance activities. Virologic surveillance for measles is now well established in all of the WHO regions, and most countries have conducted at least some baseline surveillance. The WHO Global Genotype Database contains >7000 genotype reports, and the Measles Nucleotide Surveillance (MeaNS) contains >4000 entries. This sequence information has proven to be extremely useful for tracking global transmission patterns and for documenting the interruption of transmission in some countries. The future challenges will be to develop quality control programs for molecular methods and to continue to expand virologic surveillance activities in all regions. PMID- 21666209 TI - Status of global virologic surveillance for rubella viruses. AB - The suspected measles case definition captures rubella cases. Therefore, measles surveillance will be improved in the course of the control and eventual elimination of rubella transmission. One aspect of rubella control, virologic surveillance, is reviewed here. A systematic nomenclature for rubella viruses (RVs) based on 13 genotypes has been established and is updated when warranted by increases in information about RVs. From 2005 through 2010, the genotypes of RVs most frequently reported were 1E, 1G, and 2B, and genotypes 1a, 1B, 1C, 1h, 1j, and 2C were less frequently reported. Virologic surveillance can support rubella control and elimination. Synopses of rubella virologic surveillance in various countries, regions, and globally are given, including characterization of viruses from imported cases in a country that has eliminated rubella and studies of endemic viruses circulating in countries without rubella control objectives. Current challenges are discussed. PMID- 21666210 TI - Genetic characterization of measles vaccine strains. AB - The complete genomic sequences of 9 measles vaccine strains were compared with the sequence of the Edmonston wild-type virus. AIK-C, Moraten, Rubeovax, Schwarz, and Zagreb are vaccine strains of the Edmonston lineage, whereas CAM-70, Changchun-47, Leningrad-4 and Shanghai-191 were derived from 4 different wild type isolates. Nucleotide substitutions were found in the noncoding regions of the genomes as well as in all coding regions, leading to deduced amino acid substitutions in all 8 viral proteins. Although the precise mechanisms involved in the attenuation of individual measles vaccines remain to be elucidated, in vitro assays of viral protein functions and recombinant viruses with defined genetic modifications have been used to characterize the differences between vaccine and wild-type strains. Although almost every protein contributes to an attenuated phenotype, substitutions affecting host cell tropism, virus assembly, and the ability to inhibit cellular antiviral defense mechanisms play an especially important role in attenuation. PMID- 21666211 TI - Comparing measles with previous eradication programs: enabling and constraining factors. AB - BACKGROUND: Five major disease eradication initiatives were initiated during the second half of the 20th century. The enabling and constraining factors-political, social, economic, and other-for these previous and current eradication programs can inform decision making regarding a proposed measles eradication initiative. METHODS: We reviewed the literature on the yaws, malaria, smallpox, guinea worm, and polio eradication programs and compared enabling and constraining factors for each of these programs with the same factors as they relate to a possible measles eradication initiative. RESULTS: A potential measles eradication program would enjoy distinct advantages in comparison with earlier eradication programs, including strong political and societal support, economic analyses demonstrating a high level of cost-effectiveness, and a rigorous upfront process, compared with previous eradication initiatives, that has validated the feasibility of achieving measles eradication. However, increasing population density, urbanization, and wars/civil conflicts will pose serious challenges. CONCLUSIONS: Measles eradication will be very challenging but probably not as difficult to achieve as polio eradication. Measles eradication should be undertaken only if the commitments and resources will be adequate to meet the political, social, economic, and technical challenges. PMID- 21666212 TI - Laboratory characterization of measles virus infection in previously vaccinated and unvaccinated individuals. AB - Waning immunity or secondary vaccine failure (SVF) has been anticipated by some as a challenge to global measles elimination efforts. Although such cases are infrequent, measles virus (MeV) infection can occur in vaccinated individuals following intense and/or prolonged exposure to an infected individual and may present as a modified illness that is unrecognizable as measles outside of the context of a measles outbreak. The immunoglobulin M response in previously vaccinated individuals may be nominal or fleeting, and viral replication may be limited. As global elimination proceeds, additional methods for confirming modified measles cases may be needed to understand whether SVF cases contribute to continued measles virus (MeV) transmission. In this report, we describe clinical symptoms and laboratory results for unvaccinated individuals with acute measles and individuals with SVF identified during MeV outbreaks. SVF cases were characterized by the serological parameters of high-avidity antibodies and distinctively high levels of neutralizing antibody. These parameters may represent useful biomarkers for classification of SVF cases that previously could not be confirmed as such using routine laboratory diagnostic techniques. PMID- 21666213 TI - Two case studies of modified measles in vaccinated physicians exposed to primary measles cases: high risk of infection but low risk of transmission. AB - In 2009, measles outbreaks in Pennsylvania and Virginia resulted in the exposure and apparent infection of 2 physicians, both of whom had a documented history of vaccination with >2 doses of measles-mumps-rubella vaccine. These physicians were suspected of having been infected with measles after treating patients who subsequently received a diagnosis of measles. The clinical presentation was nonclassical in regard to progression, duration, and severity. It is hypothesized that the 2 physicians mounted vigorous secondary immune responses typified by high avidity measles immunoglobulin G antibody and remarkably high neutralizing titers in response to intense and prolonged exposure to a primary measles case patient. Both of the physicians continued to see patients, because neither considered that they could have measles. Despite surveillance for cases among contacts, including unvaccinated persons, no additional cases were identified. PMID- 21666214 TI - Dried blood spots on filter paper as an alternative specimen for measles diagnostics: detection of measles immunoglobulin M antibody by a commercial enzyme immunoassay. AB - BACKGROUND: We compared the results of a serum-based measles immunoglobulin M (IgM) test with results of tests using paired reconstituted dried filter paper blood spot (DBS) samples to assess the feasibility of using DBS samples for measles diagnostic procedures. METHODS: We collected 588 paired serum and DBS samples from 349 children aged 8 months through 12 years at Mulago Hospital in Kampala, Uganda; of these samples, 513 (87%) were collected from children with a clinical diagnosis of measles 0-33 days after rash, and 75(13%) were collected from children hospitalized for other reasons. Eluted DBS and serum samples were tested using a commercial measles IgM enzyme immunoassay. Detection of viral RNA was attempted on a subset of 20 DBS by reverse-transcriptase polymerase chain reaction. RESULTS: Among the 513 sample pairs collected from children with measles, the concordances for samples collected during days 0-6 and >1 week after rash were 95.7% and 100%, respectively (P<.01). The relative sensitivity and specificity of the DBS-based assay during the first week were 98.7% and 88.9%, respectively, and the sensitivity and specificity >1 week after rash were 100% and 100%, respectively. Viral RNA was detected in 5 (26%) of 19 DBS samples tested. Among 75 sample pairs collected from children hospitalized for other reasons, concordance was 94.7%. CONCLUSIONS: DBS samples are a feasible alternative sample for measles diagnostic procedures in high-incidence settings. PMID- 21666215 TI - Is there enough vaccine to eradicate measles? An integrated analysis of measles containing vaccine supply and demand. AB - Responding to regional advancements in combating measles, the World Health Organization in May 2008 called for an assessment of the feasibility of measles eradication, including whether sufficient vaccine supply exists. Interviews with international health officials and vaccine-makers provided data for a detailed model of worldwide demand and supply for measles-containing vaccine (MCV). The study projected global MCV demand through 2025 with and without a global eradication goal. The study found that 5.2 billion MCV doses must be administered during 2010-2025 to maintain current measles programs, and 5.9 billion doses would likely be needed with a 2020 eradication goal; in the most intensive scenario, demand could increase to 7.5 billion doses. These volumes are within existing and planned MCV-manufacturing capacity, although there are risks. In some markets, capacity is concentrated: Supply-chain disruptions could reduce supply or increase prices. Mitigation strategies could include stockpiling, long term contracts, and further coordination with manufacturers. PMID- 21666216 TI - Risk analysis for measles reintroduction after global certification of eradication. AB - BACKGROUND: Measles virus will continue to exist after certification of global eradication as virus stocks and infectious materials held in laboratories, in persistently and chronically infected individuals, and possibly in undetected foci of transmission. A literature search was undertaken to identify and evaluate the main risks for reintroduction of measles transmission in the absence of universal measles immunization. METHODS: A qualitative risk assessment was conducted following a series of literature searches using the PubMed database. RESULTS: If the criteria for global certification of eradication are stringent and require rigorous validation, then the risk of undetected measles transmission after certification is very low. Risk of unintentional reintroduction from any source, including persistent infections and laboratory materials is low to very low but depends on the extent of measles vaccine use. If immunization levels decrease, measles will become a credible agent for bioterrorism through intentional release. CONCLUSIONS: Posteradication risks are low and should not deter any attempt at measles eradication. More information on measles transmission dynamics and the role of atypical infections is required to determine requirements for global certification of eradication. Posteradication risks would be minimized through development and implementation of an international risk management strategy, including requirements for a posteradication vaccine stockpile. PMID- 21666217 TI - How can measles eradication strengthen health care systems? AB - Elimination and eradication initiatives are generally delivered through a vertical approach, which can potentially hamper health systems. We propose 3 approaches by which a measles eradication initiative can ensure that health systems are left strengthened when the eradication goal has been accomplished. First, focus should be placed on strengthening routine vaccination, which could generate positive trickle-up effects on other primary health care services. Second, increased integration with multifunctional health services should be emphasized. Third, efforts should be made to change traditional donor behavior that prioritizes vaccination campaigns and uses uncoordinated staff incentives. PMID- 21666218 TI - Impact of measles elimination activities on immunization services and health systems: findings from six countries. AB - BACKGROUND: One of the key concerns in determining the appropriateness of establishing a measles eradication goal is its potential impact on routine immunization services and the overall health system. The objective of this study was to evaluate the impact of accelerated measles elimination activities (AMEAs) on immunization services and health systems in 6 countries: Bangladesh, Brazil, Cameroon, Ethiopia, Tajikistan, and Vietnam. METHODS: Primary data were collected from key informant interviews and staff profiling surveys. Secondary data were collected from policy documents, studies, and reports. Data analysis used qualitative approaches. RESULTS: This study found that the impact of AMEAs varied, with positive and negative implications in specific immunization and health system functions. On balance, the impacts on immunization services were largely positive in Bangladesh, Brazil, Tajikistan, and Vietnam, while negative impacts were more significant in Cameroon and Ethiopia. CONCLUSIONS: We conclude that while weaker health systems may not be able to benefit sufficiently from AMEAs, in more developed health systems, disruptions to health service delivery are unlikely to occur. Opportunities to strengthen the routine immunization service and health system should be actively sought to address system bottlenecks in order to incur benefits to eradication program itself as well as other health priorities. PMID- 21666219 TI - Impact of measles eradication activities on routine immunization services and health systems in Bangladesh. AB - BACKGROUND: Seroprevalence studies suggest that vaccination coverage of 90%-95% is needed to eliminate measles. In Bangladesh, routine measles vaccination coverage rates have recently reached 80%-85%. The Government of Bangladesh implemented catch-up vaccination through supplementary immunization activities (SIAs). The aim of the present study was to understand the impact of SIAs on immunization services and the health system. METHODS: The study was conducted at 4 sites, all of which had relatively low routine vaccination coverage rates. A document review was performed, followed by interviews of key personnel selected by purposive and snowball sampling. A staff profiling survey was also undertaken. RESULTS: Despite overall high levels of immunization, the expanded program on immunization for measles has not reached the coverage levels targeted by the Government of Bangladesh. The first SIAs vaccinated 35 million children, and the second targeted an additional 20 million. According to data and respondents, implementation of the SIAs was successful with sufficient funds being available, although timely disbursement of funds was inadequate in some areas. Staff were well motivated, and additional training helped boost a positive approach to vaccination. CONCLUSIONS: The SIAs had a positive impact on health and immunization systems and have created a framework on which other health care interventions for bacterial and viral diseases could be based. PMID- 21666220 TI - Global eradication of measles: an epidemiologic and economic evaluation. AB - BACKGROUND: Measles remains an important cause of morbidity and mortality in children in developing countries. Due to the success of the measles mortality reduction and elimination efforts thus far, the WHO has raised the question of whether global eradication of measles is economically feasible. METHODS: The cost effectiveness of various measles mortality reduction and eradication scenarios was evaluated vis-a-vis the current mortality reduction goal in six countries and globally. Data collection on costs of measles vaccination were conducted in six countries in four regions: Bangladesh, Brazil, Colombia, Ethiopia, Tajikistan, and Uganda. The number of measles cases and deaths were projected from 2010 to 2050 using a dynamic, age-structured compartmental model. The incremental cost effectiveness ratios were then calculated for each scenario vis a vis the baseline. RESULTS: Measles eradication by 2020 was the found to be the most cost effective scenario, both in the six countries and globally. Eradicating measles by 2020 is projected to cost an additional discounted $7.8 billion and avert a discounted 346 million DALYs between 2010 and 2050. CONCLUSIONS: In conclusion, the study found that, compared to the baseline, reaching measles eradication by 2020 would be the most cost-effective measles mortality reduction scenario, both for the six countries and on a global basis. PMID- 21666222 TI - Article withdrawal: Disruption of the protein interaction between FAK and IGF-1R inhibits melanoma tumor growth. PMID- 21666221 TI - Superoxide induces endothelial nitric-oxide synthase protein thiyl radical formation, a novel mechanism regulating eNOS function and coupling. AB - An increase in production of reactive oxygen species resulting in a decrease in nitric oxide bioavailability in the endothelium contributes to many cardiovascular diseases, and these reactive oxygen species can oxidize cellular macromolecules. Protein thiols are critical reducing equivalents that maintain cellular redox state and are primary targets for oxidative modification. We demonstrate endothelial NOS (eNOS) oxidant-induced protein thiyl radical formation from tetrahydrobiopterin-free enzyme or following exposure to exogenous superoxide using immunoblotting, immunostaining, and mass spectrometry. Spin trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) followed by immunoblotting using an anti-DMPO antibody demonstrated the formation of eNOS protein radicals, which were abolished by superoxide dismutase and L-NAME, indicating that protein radical formation was due to superoxide generation from the eNOS heme. With tetrahydrobiopterin-reconstituted eNOS, eNOS protein radical formation was completely inhibited. Using mass spectrometric and mutagenesis analysis, we identified Cys-908 as the residue involved in protein radical formation. Mutagenesis of this key cysteine to alanine abolished eNOS thiyl radical formation and uncoupled eNOS, leading to increased superoxide generation. Protein thiyl radical formation leads to oxidation or modification of cysteine with either disulfide bond formation or S-glutathionylation, which induces eNOS uncoupling. Furthermore, in endothelial cells treated with menadione to trigger cellular superoxide generation, eNOS protein radical formation, as visualized with confocal microscopy, was increased, and these results were confirmed by immunoprecipitation with anti-eNOS antibody, followed by immunoblotting with an anti-DMPO antibody. Thus, eNOS protein radical formation provides the basis for a mechanism of superoxide-directed regulation of eNOS, involving thiol oxidation, defining a unique pathway for the redox regulation of cardiovascular function. PMID- 21666223 TI - Aryl hydrocarbon receptor and aryl hydrocarbon nuclear translocator expression in human and rat placentas and transcription activity in human trophoblast cultures. AB - Aryl hydrocarbon receptor (AHR) and its heterodimer aryl hydrocarbon nuclear translocator (ARNT) form a ligand-activated transcription complex that regulates expression of the AHR battery of target genes that includes the most important placental biotransformation enzyme cytochrome CYP1A1. Expression, placental localization, and ontogeny of AHR/Ahr and ARNT/Arnt have not been systematically studied in either human or rat placentas. Moreover, induction of such AHR target genes as CYP1A1, CYP1A2, CYP1B1, UGT1A1, and breast cancer resistance protein (BCRP), as well as of AHR, ARNT, and aryl hydrocarbon receptor repressor (AHRR) genes, after exposure to AHR ligands have not been studied in human placental trophoblast cultures. In this article, we show that only CYP1A1 messenger RNA (mRNA), but not CYP1A2, CYP1B1, UGT1A1, BCRP, AHR, ARNT, and AHRR mRNAs, is significantly induced in human term placental trophoblast cultures after exposure to prototype AHR ligands/activators 2,3,7,8-tetrachlorodibenzo-p-dioxin, 3 methylcholanthrene, omeprazole, and beta-naphthoflavone. We localized AHR/Ahr and ARNT/Arnt in rat placental trophoblasts throughout gestation and in first trimester and term human placental trophoblast, which comprise the crucial component of the maternal-fetal barrier. We demonstrate that rat Ahr and Cyp1a1 reached highest expression during gestation days 15 and 18, which might indicate different response to Ahr ligands in placental Cyp1a1 induction during rat gestation. We also propose the JEG3 choriocarcinoma cell line as a cellular model for human trophoblast induction studies through AHR. In conclusion, we describe expression and ontogeny of AHR/Ahr and ARNT/Arnt and systematically characterize induction of major AHR target genes in human placental trophoblast forming the placental maternal-fetal morphological and metabolic barrier. PMID- 21666224 TI - Reconsidering the criteria for evaluating proposed screening programs: reflections from 4 current and former members of the U.S. Preventive services task force. AB - In 1968, Wilson and Jungner published 10 "principles" for evaluating screening programs (Public Health Papers No. 34. Geneva, Switzerland: World Health Organization), criteria widely used since then. The 4 authors of this review (all current or former members of the U.S. Preventive Services Task Force) have found a different paradigm more useful for evaluating screening programs. This review was written independently of the USPSTF; the authors speak only for themselves and not for the USPSTF. They suggest evaluating screening programs not as a checklist but as a balance between the magnitude of benefits and the magnitude of harms, each estimated from a systematic review of the evidence. To emphasize a focus on health outcomes, the authors suggest reframing the target of screening as an umbrella concept: the "predictor of poor health." Evaluation groups should weigh health benefits and harms to estimate net benefits and then consider whether these net benefits justify the resources required. The final decision about implementation should be made by a democratic process that considers both the panel's evaluation of the evidence and nonevidence factors (e.g., resources available, other priorities, the informed population's preferences). The authors hope these suggestions stimulate further discussion about the optimal way to evaluate proposed screening programs. PMID- 21666225 TI - Mutation rates across budding yeast chromosome VI are correlated with replication timing. AB - Previous experimental studies suggest that the mutation rate is nonuniform across the yeast genome. To characterize this variation across the genome more precisely, we measured the mutation rate of the URA3 gene integrated at 43 different locations tiled across Chromosome VI. We show that mutation rate varies 6-fold across a single chromosome, that this variation is correlated with replication timing, and we propose a model to explain this variation that relies on the temporal separation of two processes for replicating past damaged DNA: error-free DNA damage tolerance and translesion synthesis. This model is supported by the observation that eliminating translesion synthesis decreases this variation. PMID- 21666226 TI - Immunohistochemical detection of blue light-induced phosphorylation of the plasma membrane H+-ATPase in stomatal guard cells. AB - Blue light (BL) receptor phototropins activate the plasma membrane H(+)-ATPase in guard cells through phosphorylation of a penultimate threonine and subsequent binding of the 14-3-3 protein to the phosphorylated C-terminus of H+-ATPase, mediating stomatal opening. To date, detection of the phosphorylation level of the guard cell H+-ATPase has been performed biochemically using guard cell protoplasts (GCPs). However, preparation of GCPs from Arabidopsis for this purpose requires >5,000 rosette leaves and takes >8 h. Here, we show that BL induced phosphorylation of guard cell H+-ATPase is detected in the epidermis from a single Arabidopsis rosette leaf via an immunohistochemical method using a specific antibody against the phosphorylated penultimate threonine of H+-ATPase. BL-induced phosphorylation of the H+-ATPase was detected immunohistochemically in the wild type, but not in a phot1-5 phot2-1 double mutant. Moreover, we found that physiological concentrations of the phytohormone ABA completely inhibited BL induced phosphorylation of guard cell H+-ATPase in the epidermis, and that inhibition by ABA in the epidermis is more sensitive than in GCPs. These results indicate that this immunohistochemical method is very useful for detecting the phosphorylation status of guard cell H+-ATPase. Thus, we applied this technique to ABA-insensitive mutants (abi1-1, abi2-1 and ost1-2) and found that ABA had no effect on BL-induced phosphorylation in these mutants. These results indicate that inhibition of BL-induced phosphorylation of guard cell H+-ATPase by ABA is regulated by ABI1, ABI2 and OST1, which are known to be early ABA signaling components for a wide range of ABA responses in plants. PMID- 21666227 TI - Phytochrome-interacting factor 4 and 5 (PIF4 and PIF5) activate the homeobox ATHB2 and auxin-inducible IAA29 genes in the coincidence mechanism underlying photoperiodic control of plant growth of Arabidopsis thaliana. AB - The plant circadian clock generates rhythms with a period close to 24 h, and it controls a wide variety of physiological and developmental events. Among clock controlled developmental events, the best characterized is the photoperiodic control of flowering time, which is mediated through the CONSTANS (CO)-FLOWERING LOCUS T (FT) pathway in Arabidopsis thaliana. The clock also regulates the diurnal plant growth including the elongation of hypocotyls in a short day (SDs) specific manner. In this mechanism, phytochromes (mainly phyB) and the PHYTOCHROME-INTERACTING FACTOR4 (PIF4) and PIF5, encoding phytochrome-interacting basic helix-loop-helix (bHLH) transcription factors, play crucial roles. The time of day-specific and photoperiodic control of hypocotyl elongation is best explained by the accumulation of the PIF4 and PIF5 proteins during night-time before dawn, especially under SDs, due to coincidence between the internal (circadian rhythm) and external (photoperiod) time cues. However, the PIF4- and/or PIF5-controlled downstream factors have not yet been identified. Here, we provide evidence that ARABIDOPSIS THALIANA HOMEOBOX PROTEIN2 (ATHB2), together with auxin-inducible IAA29, is diurnally expressed with a peak at dawn under the control of PIF4 and PIF5 specifically in SDs. This coincidentally expressed transcription factor serves as a positive regulator for the elongation of hypocotyls. The expression profiles of ATHB2 were markedly altered in certain clock and phytochrome mutants, all of which show anomalous phenotypes with regard to the photoperiodic control of hypocotyl elongation. Taken together, we propose that an external coincidence model involving the clock-controlled PIF4/PIF5-ATHB2 pathway is crucial for the diurnal and photoperiodic control of plant growth in A. thaliana. PMID- 21666229 TI - Hypothalamic-pituitary-adrenal axis stress test in patients with early RA: role of corticotropin-releasing hormone promoter polymorphisms. PMID- 21666230 TI - Distinct ACPA fine specificities, formed under the influence of HLA shared epitope alleles, have no effect on radiographic joint damage in rheumatoid arthritis. AB - OBJECTIVES: Human leucocyte antigen shared epitope (SE) alleles are associated with joint destruction, the presence of anticitrullinated protein antibodies (ACPA) and the ACPA fine specificity repertoire in rheumatoid arthritis (RA). A large variation in joint destruction is seen within the ACPA-positive patient population, and it is conceivable that certain ACPA reactivities contribute to radiological damage. The authors investigated whether ACPA fine specificities, which are formed under the influence of SE alleles, associate with the extent of radiographic joint damage. METHODS: Antibodies recognising six citrullinated epitopes were determined in sera of 330 ACPA-positive RA patients genotyped for SE alleles. The association between SE alleles, ACPA fine specificity and radiographic joint damage was assessed using radiographic follow-up data. A second cohort of 154 RA patients with 5 and 10-year radiographic follow-up was used for replication. RESULTS: SE alleles predisposed to the recognition of certain citrullinated epitopes. However, none of the ACPA fine specificities studied influenced radiographic joint damage. Importantly, although SE alleles associated with radiographic damage in the total RA population, this association was no longer detectable after stratification for the presence of ACPA. CONCLUSIONS: SE alleles are instrumental in shaping the ACPA repertoire. However, ACPA fine specificities formed under the influence of SE alleles do not seem to affect joint destruction. PMID- 21666231 TI - Disruption of emmetropization and high susceptibility to deprivation myopia in albino guinea pigs. AB - PURPOSE: To compare emmetropization in albino and pigmented guinea pigs. METHODS: Distributions of refractive state were examined in 214 albino and 234 pigmented guinea pigs. Albino (A) and pigmented (P) guinea pigs were divided into two groups, hyperopic (H) and myopic (M). Eye development was separately followed in 10 randomly selected animals from each group (AH, AM, PH, PM) from 2 to 10 weeks of age. In addition, deprivation myopia was induced in 36 age-matched albino (18 AH and 18 AM) and 36 pigmented (18 PH and 18 PM) guinea pigs by diffusers that were worn from 2 to 6 weeks of age. Finally, sclera fibril diameters were measured using transmission electron microscopy. RESULTS: Strikingly, the distributions of refractive errors were bimodal at 2 weeks of age, both in albino and pigmented animals, with clearly different averages (-2.86 +/- 5.60 diopters [D] vs. 2.13 +/- 5.27 D respectively; t = 9.712; P < 0.001). Spontaneous myopia was more common in albino animals: 70.1% were myopic (AM) and 29.9% hyperopic (AH), whereas only 28.6% were myopic (PM) and 71.4% hyperopic (PH) in pigmented guinea pigs. Different from PM and AM did not show any recovery from myopia. With diffusers, AH became more myopic (-7.61 +/- 2.71 D and -11.17 +/- 2.55 D) than PH (-4.48 +/- 1.46 D and -8.28 +/- 2.13 D) after 2 and 4 weeks, respectively. Deprivation myopia could still be induced in PM (-1.64 +/- 1.44 D and -5.17 +/- 1.88 D after 2 and 4 weeks, respectively; P < 0.01) but not in AM. Scleral fibril diameters were smaller in myopic animals, both albino and pigmented. CONCLUSIONS: Deprivation myopia could not be induced in spontaneously myopic but only in hyperopic albino guinea pigs, where it was even higher than in pigmented animals. The distinct effects of albinism on emmetropization will help to elucidate the mechanisms underlying the emmetropization. PMID- 21666232 TI - Kappa opioid receptor localization and coupling to nitric oxide production in cells of the anterior chamber. AB - PURPOSE: The present study was designed to determine whether kappa opioid receptors (KORs) are localized to cells of the inflow and outflow pathways of the eye and if activation of these receptors has an effect on nitric oxide (NO) production, because these effects could play a role in KOR agonist-mediated reduction of IOP. METHODS: Human nonpigmented ciliary epithelial (NPCE) and trabecular meshwork (HTM-3) cells were treated with spiradoline (SPR), a selective KOR agonist, or estradiol, for 24 hours. Some cells were pretreated with the selective KOR antagonist norbinaltorphimine (norBNI) or the nonselective NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) for 30 minutes, followed by the addition of SPR. Immunofluorescent localization of KORs was determined in isolated rabbit iris-ciliary bodies (ICBs) and NPCE and HTM-3 cells. RESULTS: Immunohistochemical data show the localization of KORs to the rabbit ICB and more specifically to the ciliary epithelial layer. KORs were also found on cell membranes of NPCE and HTM-3 cells. Treatment of both these cell types with spiradoline caused concentration-dependent increases in the release of NO. Spiradoline-induced release of NO from both cell types was inhibited by pretreatment with norBNI and L-NAME. CONCLUSIONS: Results from this study show the presence of KORs on rabbit ICBs and also on NPCE and HTM cells. Activation of these KORs on both cell types resulted in KOR-mediated increases in NO production. These findings provide evidence that previously demonstrated KOR mediated reduction in IOP could be caused, in part, by NO production in both the ciliary body and the trabecular meshwork. PMID- 21666233 TI - VIP and growth factors in the infected cornea. AB - PURPOSE: Vasoactive intestinal peptide (VIP) is an anti-inflammatory neuropeptide that downregulates proinflammatory cytokines and promotes healing in a susceptible model of P. aeruginosa keratitis. Growth factors also play a role in corneal healing and restoration of tissue homeostasis after wounding. However, whether VIP treatment modulates growth factors to promote healing in the infected cornea remains untested and is the purpose of this study. METHODS: C57BL/6 (B6) mice were injected with VIP and mRNA and protein levels, and immunostaining for EGF, FGF, HGF, and VEGF-A were done. Exogenous treatment with a mixture of the growth factors also was tested and levels of cytokines, defensins, and bacterial counts were determined. RESULTS: Real-time RT-PCR, immunostaining, and ELISA data demonstrated that treatment with VIP enhanced levels of EGF, FGF, and HGF during disease, and that VEGF-A, and associated angiogenic molecules also were increased by VIP. Moreover, immunohistochemical studies confirmed that both epithelial and stromal cells participated in growth factor production. Most notably, treatment with a mixture of EGF, FGF, and HGF after disease onset, prevented corneal perforation when compared with controls. This outcome was associated with downregulation of proinflammatory cytokines such as macrophage inflammatory protein-2 (MIP-2), upregulation of anti-inflammatory cytokines such as TGF-beta, and antimicrobials beta-defensins 2 and 3, as well as decreased plate counts at 1 day postinfection (p.i.) (P = 0.0001). CONCLUSIONS: Collectively, the data provide evidence that VIP treatment modulates growth factors, angiogenic molecules, and defensins in the infected cornea and that this in turn promotes healing and restoration of tissue homeostasis. PMID- 21666234 TI - Automatic detection of diabetic retinopathy and age-related macular degeneration in digital fundus images. AB - PURPOSE: To describe and evaluate the performance of an algorithm that automatically classifies images with pathologic features commonly found in diabetic retinopathy (DR) and age-related macular degeneration (AMD). METHODS: Retinal digital photographs (N = 2247) of three fields of view (FOV) were obtained of the eyes of 822 patients at two centers: The Retina Institute of South Texas (RIST, San Antonio, TX) and The University of Texas Health Science Center San Antonio (UTHSCSA). Ground truth was provided for the presence of pathologic conditions, including microaneurysms, hemorrhages, exudates, neovascularization in the optic disc and elsewhere, drusen, abnormal pigmentation, and geographic atrophy. The algorithm was used to report on the presence or absence of disease. A detection threshold was applied to obtain different values of sensitivity and specificity with respect to ground truth and to construct a receiver operating characteristic (ROC) curve. RESULTS: The system achieved an average area under the ROC curve (AUC) of 0.89 for detection of DR and of 0.92 for detection of sight-threatening DR (STDR). With a fixed specificity of 0.50, the system's sensitivity ranged from 0.92 for all DR cases to 1.00 for clinically significant macular edema (CSME). CONCLUSIONS: A computer aided algorithm was trained to detect different types of pathologic retinal conditions. The cases of hard exudates within 1 disc diameter (DD) of the fovea (surrogate for CSME) were detected with very high accuracy (sensitivity = 1, specificity = 0.50), whereas mild nonproliferative DR was the most challenging condition (sensitivity = 0.92, specificity = 0.50). The algorithm was also tested on images with signs of AMD, achieving a performance of AUC of 0.84 (sensitivity = 0.94, specificity = 0.50). PMID- 21666235 TI - Early corneal wound healing and inflammatory responses after refractive lenticule extraction (ReLEx). AB - PURPOSE: To compare the early corneal wound repair and inflammatory responses after refractive lenticule extraction (ReLEx) and LASIK. METHODS: Eighteen rabbits underwent ReLEx and another 18 underwent LASIK. Each group was divided into three subgroups of six rabbits each and these were subjected to refractive corrections of -3.00 diopters (D), -6.00 D, and -9.00 D. Slit lamp photography, anterior segment optical coherence tomography (AS-OCT), corneal topography, and in vivo confocal microscopy were performed 1 day after surgery. After euthanatization, the corneas were subjected to immunofluorescent staining for fibronectin, CD11b, Ki-67, and TUNEL assay. RESULTS: On slit lamp microscopy, all corneas appeared clear pre- and postoperatively in both ReLEx and LASIK eyes. Corneal topography showed a more significant corneal flattening after LASIK than after ReLEx as the degree of correction was increased (P = 0.916 after -3.00 D correction to P = 0.097 after -9.00 D correction). In vivo confocal microscopy showed less light-scattering particles at the flap interface after ReLEx compared with LASIK. Immunostaining of fibronectin showed a less abundant expression in corneas that underwent ReLEx than LASIK. The differences became more marked as the power of correction was increased. Similar trend was seen in the number of CD11b-positive cells (P = 0.476 after -3.00 D correction to P < 0.001 after 9.00D correction). There was no marked disparity observed in cell death and proliferation between post-ReLEx and -LASIK eyes. CONCLUSIONS: This study has shown that the ReLEx procedure may result in less topographic changes, inflammation, and early extracellular matrix deposition than LASIK, especially at high refractive correction. PMID- 21666236 TI - Gene expression profiling of early-phase Sjogren's syndrome in C57BL/6.NOD Aec1Aec2 mice identifies focal adhesion maturation associated with infiltrating leukocytes. AB - PURPOSE: Despite considerable efforts, the molecular and cellular events in lacrimal gland tissues initiating inflammatory responses leading to keratoconjunctivitis sicca (KCS), autoimmunity, and Sjogren's syndrome (SjS) have yet to be defined. To determine whether altered glandular homeostasis occurs before the onset of autoimmunity, a temporal transcriptome study was carried out in an animal model of primary SjS. METHODS: Using oligonucleotide microarrays, gene expression profiles were generated for lacrimal glands of C57BL/6.NOD Aec1Aec2 mice 4 to 20 weeks of age. Pairwise analyses identified genes differentially expressed, relative to their 4-week expression, during the development of SjS-like disease. Statistical analyses defined differentially and coordinately expressed gene sets. The PANTHER (Protein ANalysis THrough Evolutionary Relationships) classification system was used to define annotated biological processes or functions. RESULTS: Temporal transcript expression profiles of C57BL/6.NOD-Aec1Aec2 lacrimal glands before, or concomitant with, the first appearance of inflammatory cells revealed a highly restricted subset of differentially expressed genes encoding interactive extracellular matrix proteins, fibronectin, integrins, and syndecans. In contrast, genes encoding interepithelial junctional complex proteins defined alterations in tight junctions (TJ), adherens, desmosomes, and gap junctions, suggesting perturbations in the permeability of the paracellular spaces between epithelial barriers. Correlating with this were gene sets defining focal adhesion (FA) maturation and Ras/Raf-Mek/Erk signal transduction. Immunohistochemically, FAs were associated with infiltrating leukocytes and not with lacrimal epithelial cells. CONCLUSIONS: For the first time, FA maturations are implicated as initial biomarkers of impending autoimmunity in lacrimal glands of SjS-prone mice. Changes in TJ complex genes support an increased movement of cells through paracellular spaces. PMID- 21666237 TI - Rapid changes in connexin-43 in response to genotoxic stress stabilize cell-cell communication in corneal endothelium. AB - PURPOSE: To determine how corneal endothelial (CE) cells respond to acute genotoxic stress through changes in connexin-43 (Cx43) and gap junction intercellular communication (GJIC). METHODS: Cultured bovine CE cells were exposed to mitomycin C or other DNA-damaging agents. Changes in the levels, stability, binding partners, and trafficking of Cx43 were assessed by Western blot analysis and immunostaining. Live-cell imaging of a Cx43-green fluorescent protein (GFP) fusion protein was used to evaluate internalization of cell surface Cx43. Dye transfer and fluorescent recovery after photobleaching (FRAP) assessed GJIC. RESULTS: After genotoxic stress, Cx43 accumulated in large gap junction plaques, had reduced zonula occludens-1 binding, and displayed increased stability. Live-cell imaging of Cx43-GFP plaques in stressed CE cells revealed reduced gap junction internalization and degradation compared to control cells. Mitomycin C enhanced transport of Cx43 from the endoplasmic reticulum to the cell surface and formation of gap junction plaques. Mitomycin C treatment also protected GJIC from disruption after cytokine treatment. DISCUSSION: These results show a novel CE cell response to genotoxic stress mediated by marked and rapid changes in Cx43 and GJIC. This stabilization of cell-cell communication may be an important early adaptation to acute stressors encountered by CE. PMID- 21666238 TI - Technetium-99 conjugated with methylene diphosphonate (99Tc-MDP) inhibits experimental choroidal neovascularization in vivo and VEGF-induced cell migration and tube formation in vitro. AB - PURPOSE: To investigate the effects of (99)Tc-MDP, a decay product of (99m)Tc MDP, on the development of choroidal neovascularization (CNV), together with its underlying mechanisms. METHODS: C57BL/6J mice were used to induce CNV by laser photocoagulation. (99)Tc-MDP at the doses of 0.5 * 10(-1), 1 * 10(-1), and 2 * 10(-1) MUg/kg or the same volume of PBS was intraperitoneally injected daily after photocoagulation until the end of the experiment. Seven days after laser injury, mice were perfused with fluorescein-labeled dextran, and areas of CNV were measured. Numbers of infiltrating macrophages, protein levels of VEGF, and inflammation-related molecules including intercellular adhesion molecule (ICAM) 1, tumor necrosis factor (TNF)-alpha, and matrix metalloproteinases (MMPs) in the RPE-choroid complex were detected 3 days after laser photocoagulation. Effects of (99)Tc-MDP on VEGF-induced endothelial cell migration and tube formation were also studied. Toxicity of (99)Tc-MDP was evaluated in vivo and in vitro. RESULTS: Areas of CNV were significantly suppressed by (99)Tc-MDP treatment without toxicity to the retina compared with PBS treatment in a dose-dependent manner: (99)Tc-MDP treatment of 0.5 * 10(-1) MUg/kg (5698.60 +/- 1037.70 MUm(2)), 1 * 10( 1) MUg/kg (3678.34 +/- 1328.18 MUm(2)), and 2 * 10(-1) MUg/kg (2365.78 +/- 923.80 MUm(2)) suppressed the development of CNV by 36.12%, 58.76%, and 73.48%, respectively, compared with that in the PBS treatment group (8920.36 +/- 1097.29 MUm(2); P < 0.001). (99)Tc-MDP treatment led to significant inhibition of macrophages infiltrating to CNV together with downregulated protein expressions of VEGF, ICAM-1, TNF-alpha, and MMP-2. (99)Tc-MDP also showed an inhibitive effect on cell proliferation and VEGF-induced migration and capillary-like tube formation of endothelial cells. CONCLUSIONS: Anti-inflammatory treatment with (99)Tc-MDP has therapeutic potential for CNV-related diseases. PMID- 21666239 TI - Protective effect of intravitreal administration of tresperimus, an immunosuppressive drug, on experimental autoimmune uveoretinitis. AB - PURPOSE: To test the efficiency of locally administrated tresperimus in experimental autoimmune uveoretinitis (EAU). METHODS: EAU was induced in Lewis rats by S-antigen (S-Ag) immunization. Three intravitreal injections of tresperimus (prevention or prevention/treatment protocols) were performed at different time points after immunization. The pharmacokinetics of tresperimus was evaluated in the ocular tissues and plasma. The in vitro effect of tresperimus was evaluated on macrophages. EAU was graded clinically and histologically. Blood ocular barrier permeability was evaluated by protein concentration in ocular fluids. Immune response to S-Ag was examined by delayed type hypersensitivity, the expression of inflammatory cytokines in lymph nodes, ocular fluids and serum by multiplex ELISA, and in ocular cells by RT-PCR. RESULTS: In vitro, tresperimus significantly reduced the production of inflammatory cytokines by lipopolysaccharide-stimulated macrophages. In vivo, in the treatment protocol, efficient tresperimus levels were measured in the eye but not in the plasma up to 8 days after the last injection. Tresperimus efficiently reduced inflammation, retinal damage, and blood ocular barrier permeability breakdown. It inhibited nitric oxide synthase-2 and nuclear factor kappaBp65 expression in ocular macrophages. IL-2 and IL-17 were decreased in ocular media, while IL-18 was increased. By contrast, IL-2 and IL-17 levels were not modified in inguinal lymph nodes draining the immunization site. Moreover, cytokine levels in serum and delayed type hypersensitivity to S-Ag were not different in control and treated rats. In the prevention/treatment protocol, ocular immunosuppressive effects were also observed. CONCLUSIONS: Locally administered tresperimus appears to be a potential immunosuppressive agent in the management of intraocular inflammation. PMID- 21666240 TI - Blockade of insulin receptor substrate-1 inhibits corneal lymphangiogenesis. AB - PURPOSE: To analyze whether insulin receptor substrate (IRS-1) is involved in lymphatic vessel development and whether IRS-1 blockade can inhibit lymphangiogenesis in vivo. METHODS: The impact of IRS-1 blockade by GS-101 (Aganirsen), an antisense oligonucleotide against IRS-1, on lymphatic endothelial cell (LEC) proliferation was assessed by ELISA. Furthermore, the effect of IRS-1 blockade on prolymphangiogenic growth factor expression by LECs and macrophages (peritoneal exudate cells) was tested by real-time PCR. The mouse model of inflammatory corneal neovascularization was used to analyze the effect of IRS-1 blockade in vivo: after corneal suture placement, mice were treated with GS-101 eye drops (twice daily afterwards for 1 week, 5 MUL per drop; 50, 100, or 200 MUM). Afterward, corneal wholemounts were prepared and stained for blood and lymphatic vessels. RESULTS: Blockade of IRS-1 by GS-101 inhibited LEC proliferation dose dependently. GS-101 led to decreased VEGF-A expression levels in LECs, whereas VEGF-C, VEGF-D, and VEGFR3 showed no significant change. In macrophages, VEGF-A expression levels were also inhibited by IRS-1 blockade. Additionally, GS-101 strongly inhibited macrophage-derived VEGF-C, VEGF-D, and VEGFR3 expression. In vivo, corneal hemangiogenesis was significantly inhibited when used at a concentration of 200 MUM (by 17%; P < 0.01). Corneal lymphangiogenesis was significantly inhibited when used at a dose of 100 MUM (by 21%; P < 0.01), and the highest used dose (200 MUM) showed an even stronger inhibition (by 28%; P < 0.001). CONCLUSIONS: Blockade of IRS-1 inhibits not only hemangiogenesis but also lymphangiogenesis. To the authors' knowledge, this is the first evidence that IRS-1 is involved in the molecular pathway leading to lymphangiogenesis. PMID- 21666241 TI - Gene expression and miR profiles of human corneal fibroblasts in response to dexamethasone. AB - PURPOSE: Dexamethasone (DEX) is commonly used as a therapeutic agent for various ocular inflammatory diseases; however, its effect on resident naive cells is unknown. In this study, genome microarray and microRNA (miR) analyses were used to evaluate the global gene and miR expression of human corneal fibroblasts (HKFs) in response to treatment with DEX. METHODS: Primary HKFs from three donors were treated with DEX for 16 hours. Treated and untreated cells were snap frozen for microarray and miR array analyses. Genes with a more than threefold change were classified into gene families using the DAVID web-based classification database, and six of these genes were validated using quantitative real-time PCR. Five miRs were also validated using miR-detection assays. RESULTS: Of the 41,093 genes examined, 261 were upregulated and 123 were downregulated greater than threefold after DEX treatment. Real-time PCR confirmed upregulation of six genes, including oculocutaneous albinism II (OCA2), angiopoietin-like 7 (ANGPTL7), neuron navigator 2 (NAV2), neurofilament light chain polypeptide (NEFL), solute carrier family 16/member 12 (SLC16A12), and serum amyloid A1 (SAA1). Expression of several miR including miR-16, -21, and -29C were upregulated, whereas miR-100 was downregulated in fibroblasts by DEX. CONCLUSIONS: DEX can greatly change the global gene and miR profile of HKFs. DEX not only downregulates inflammatory genes, but can also induce expression of angiogenic and inflammatory genes. In addition, DEX may exert posttranscriptional gene regulation through miRs. These data support a complex role for DEX-induced changes in resident cells that may have implications in the clinical management of corneal inflammation with topical glucocorticoids. PMID- 21666243 TI - Pan-corneal endothelial viability assessment: application to endothelial grafts predissected by eye banks. AB - PURPOSE: To present an experimental method for determining the viable cell pool of corneal endothelia and its application to assessing predissected endothelial grafts. METHODS: The endothelial cell density (ECD) of five pairs of human organ cultured corneas was determined using a standard counting method with a calibrated image analysis system. A thin posterior graft (30-50 MUm) was manually predissected from a cornea chosen at random. Predissected and control corneas were shipped to the remote center, where standard ECD determination was repeated and was immediately followed by a triple Hoechst/ethidium/calcein labeling coupled with image analysis of the whole graft surface. Numeration of nuclei (H+), dead cells (E+), and total area covered by viable cells (C+) allowed the calculation of viable ECD corresponding to the cell density that the cornea may have after redistribution of viable cells over the whole Descemet surface. RESULTS: The median (range) viable ECD was lower than the standard ECD determined immediately earlier in predissected and control corneas: 1628 (1138-2379) and 2065 (1492-2876) cells/mm(2) (P = 0.043), corresponding to -20% (-1%-38%) and 12% (-3%-26%), respectively (P = 0.08). CONCLUSIONS: Standard counting by eye banks overestimates the actual pool of viable endothelial cells. This may be the main explanation for the initially rapid decrease in ECD universally described in patients after all types of keratoplasty. Early low postoperative ECD may indicate that surgeons graft fewer living cells than the eye banks' ECD let suppose, rather than a massive pre- and postoperative cell death. The novel concept of viable ECD can be useful for assessing all types of corneal processing. PMID- 21666242 TI - The application of in vivo confocal scanning laser microscopy in the diagnosis and evaluation of treatment responses in Mooren's ulcer. AB - PURPOSE: To evaluate the extent of corneal inflammation and the response to treatment in patients with Mooren's ulcer, by in vivo confocal microscopy (IVCM). METHODS: Twenty-two eyes of 15 patients with Mooren's ulcer were enrolled in this prospective study. All subjects underwent routine ophthalmic examinations, IVCM, and conjunctival histopathologic examination of specimens in patients undergoing conjunctival excision. Eyes with active ulcer were treated with topical corticosteroids and additional therapy, depending on the signs and symptoms. Eyes in remission continued to receive the previous treatment protocols. The relation between the severity of ulcer and inflammation status as assessed by IVCM was also studied. The endpoints were inflammatory cell density (ICD), counted by IVCM, and the extent of the limbal arc involved with ulcers. RESULTS: Ten eyes had active corneal ulcers, and 12 eyes had been in remission for the past year. The mean ICD of eyes with active ulcers before treatment was 2092.7 +/- 1538.6 cells/mm(2) (range, 835.3-7832.7; 95% CI, 3232.5-952.9). Nine of the eyes improved at 8 weeks, with a decrease in ICD to 249.1 +/- 109.0 cells/mm(2) (range, 100.3-595.3; 95% CI, 329.8-168.3). One eye had corneal perforation, and ICD immediately before perforation was 1677.6 +/- 247.6 cells/mm(2). The mean ICD of 12 eyes in remission was 357.5 +/- 266.8 cells/mm(2) (range, 12.7-1127.0; 95% CI, 555.2-159.8). The correlation of the ICD and the extent of limbal involvement with ulcers was strong (R(2) = 0.8119). CONCLUSIONS: ICD evaluated by IVCM is a useful and promising parameter for evaluation of the degree of inflammation in eyes with Mooren's ulcer and for assessment of response to treatment. PMID- 21666245 TI - Bilateral patching in retinal detachment: fluid mechanics and retinal "settling". AB - PURPOSE: When a patient suffers a retinal detachment and surgery is delayed, it is known clinically that bilaterally patching the patient may allow the retina to partially reattach or "settle." Although this procedure has been performed since the 1860s, there is still debate as to how such a maneuver facilitates the reattachment of the retina. METHODS: Finite element calculations using commercially available analysis software are used to elucidate the influence of reduction in eye movement caused by bilateral patching on the flow of subretinal fluid in a physical model of retinal detachment. RESULTS: It was found that by coupling fluid mechanics with structural mechanics, a physically consistent explanation of increased retinal detachment with eye movements can be found in the case of traction on the retinal hole. Large eye movements increase vitreous traction and detachment forces on the edge of the retinal hole, creating a subretinal vacuum and facilitating increased subretinal fluid. Alternative models, in which intraocular fluid flow is redirected into the subretinal space, are not consistent with these simulations. CONCLUSIONS: The results of these simulations explain the physical principles behind bilateral patching and provide insight that can be used clinically. In particular, as is known clinically, bilateral patching may facilitate a decrease in the height of a retinal detachment. The results described here provide a description of a physical mechanism underlying this technique. The findings of this study may aid in deciding whether to bilaterally patch patients and in counseling patients on pre- and postoperative care. PMID- 21666244 TI - The role of TLR4 activation in photoreceptor mitochondrial oxidative stress. AB - PURPOSE: Herein the authors investigated whether the activation of Toll-like receptors (TLRs) in the innate immune response causes retinal photoreceptor oxidative stress and mitochondrial DNA (mtDNA) damage. METHODS: On day 5 after injection of complete Freund's adjuvant containing heat-killed Mycobacterium tuberculosis (CFA), retinas were submitted to polymerase chain reaction (PCR) array focused on the TLR signaling, or apoptosis, pathway. CFA-mediated TLR4 activation, oxidative stress, and mtDNA damage were determined in B10.RIII and knockout (KO) mice (recombination activation gene [Rag] 1(KO), TLR4(KO), myeloid differentiation primary response gene 88 [MyD88](KO), tumor necrosis factor [TNF] alpha(KO), or caspase 7(KO) mice) using quantitative real-time PCR, enzyme-linked immunosorbent assay, Western blot analysis, and immunohistochemistry. The mycobacterial DNA load on the retina, brain, liver, and spleen was determined by real-time PCR after intracardiac perfusion. RESULTS: PCR array demonstrated the upregulation of TLRs and their signaling molecules in retinas of CFA-injected mice compared with those of control animals without inflammatory cell infiltration in the retina and uvea. Mycobacterial DNA was detected in the retinas of CFA-injected mice. Retinas of CFA-injected animals showed oxidative stress and mtDNA damage, primarily in the photoreceptor inner segments. Upregulated TLR4 was localized with CD11b(+)MHCII(+) cells but not with GFAP(+) astrocytes. This oxidative stress/damage was similar in CFA-injected Rag1(KO) mice compared with wild-type controls. Such damage was absent in the retinas of CFA-injected TLR4(KO), MyD88(KO), and TNF-alpha(KO) mice. CFA-mediated inducible nitric oxide synthase expression in the retina was significantly decreased in TNF alpha(KO) mice. CONCLUSIONS: Retinal photoreceptors are susceptible to mitochondrial oxidative stress/mtDNA damage in robust TLR4-mediated innate immune response. PMID- 21666246 TI - Sustainable construction in rural Guatemala. AB - Waste management is a significant problem in Guatemala, as elsewhere in the developing world. The inappropriate disposal of solid waste produces pollution and places the environment and human health at risk. Environmental risk factors, including inadequate disposal of solid waste, are implicated in 25-30% of disease worldwide with children bearing a disproportionate burden of those diseases. Therefore, economic development which reduces inappropriate disposal of waste and affords economic opportunities may help reduce the global burden of disease on children. In the indigenous highlands of central Guatemala, a community supported non-profit organisation called Long Way Home (http://www.longwayhomeinc.org) is employing alternative construction techniques to build a vocational school complex. The construction of the school from waste materials demonstrates the use and principles of re-purposing materials, helps clean the environment and affords further educational and vocational opportunities. This article will outline the health problems inherent in an indigenous area of a developing country and will offer an alternative solution to reverse environmental risk factors associated with solid waste pollution and also actively improve child health. PMID- 21666247 TI - Amino acid interaction preferences in helical membrane proteins. AB - Membrane proteins are involved in a number of important biological functions. Yet, they are poorly understood from the structure and folding point of view. The external environment being drastically different from that of globular proteins, the intra-protein interactions in membrane proteins are also expected to be different. Hence, statistical potentials representing the features of inter residue interactions based exclusively on the structures of membrane proteins are much needed. Currently, a reasonable number of structures are available, making it possible to undertake such an analysis on membrane proteins. In this study we have examined the inter-residue interaction propensities of amino acids in the membrane spanning regions of the alpha-helical membrane (HM) proteins. Recently we have shown that valuable information can be obtained on globular proteins by the evaluation of the pair-wise interactions of amino acids by classifying them into different structural environments, based on factors such as the secondary structure or the number of contacts that a residue can make. Here we have explored the possible ways of classifying the intra-protein environment of HM proteins and have developed scoring functions based on different classification schemes. On evaluation of different schemes, we find that the scheme which classifies amino acids to different intra-contact environment is the most promising one. Based on this classification scheme, we also redefine the hydrophobicity scale of amino acids in HM proteins. PMID- 21666249 TI - Clinical outcome of renal tubular damage in chronic heart failure. AB - AIMS: Both reduced glomerular filtration and increased urinary albumin excretion independently determine outcome in patients with chronic heart failure (HF). However, tubulo-interstitial injury might indicate renal damage, even in the presence of normal glomerular filtration. We studied the relationship between tubular damage, glomerular filtration, urinary albumin excretion, and outcome in HF patients. METHODS AND RESULTS: In 2130 patients participating in the GISSI-HF trial, we measured urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and three urinary markers of tubular damage: N acetyl-beta-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). We assessed the relationship between the individual tubular damage markers and the combined endpoint of all cause mortality and HF hospitalizations. Mean age was 67 +/- 11 years, and 21% were female. Urinary NAG 13.7 (7.8-22) U/gCr, KIM-1 1939 (671-3871) ng/gCr, and NGAL 36 (14-94) ug/gCr were markedly elevated above normal levels. All individual tubular markers were independently associated with the combined endpoint: NAG: adjusted hazard ratio (HR) 1.22; 95% confidence interval (CI), 1.10-1.36; P< 0.001, KIM-1 HR 1.13; 95% CI, 1.02-1.24; P= 0.018 and NGAL HR 1.10; 95% CI, 1.00 1.20; P= 0.042; all per log standard deviation increase). Even in patients with a normal eGFR, increased tubular markers were related to a poorer outcome. The combination of impaired eGFR, increased UACR, and high NAG was associated with a HR of 3.00; 95% CI, 2.29-3.95; P< 0.001, compared with those without these abnormalities. CONCLUSION: Tubular damage is related to a poor clinical outcome in HF patients even when eGFR is normal. PMID- 21666250 TI - Common carotid artery intima-media thickness is as good as carotid intima-media thickness of all carotid artery segments in improving prediction of coronary heart disease risk in the Atherosclerosis Risk in Communities (ARIC) study. AB - AIMS: Carotid intima-media thickness (CIMT) and plaque information can improve coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF). However, obtaining adequate images of all carotid artery segments (A-CIMT) may be difficult. Of A-CIMT, the common carotid artery intima-media thickness (CCA-IMT) is relatively more reliable and easier to measure. We evaluated whether CCA-IMT is comparable to A-CIMT when added to TRF and plaque information in improving CHD risk prediction in the Atherosclerosis Risk in Communities (ARIC) study. METHODS AND RESULTS: Ten-year CHD risk prediction models using TRF alone, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque were developed for the overall cohort, men, and women. The area under the receiver operator characteristic curve (AUC), per cent individuals reclassified, net reclassification index (NRI), and model calibration by the Gronnesby-Borgan test were estimated. There were 1722 incident CHD events in 12 576 individuals over a mean follow-up of 15.2 years. The AUC for TRF only, TRF + A-CIMT + plaque, and TRF + CCA-IMT + plaque models were 0.741, 0.754, and 0.753, respectively. Although there was some discordance when the CCA-IMT + plaque- and A-CIMT + plaque-based risk estimation was compared, the NRI and clinical NRI (NRI in the intermediate-risk group) when comparing the CIMT models with TRF-only model, per cent reclassified, and test for model calibration were not significantly different. CONCLUSION: Coronary heart disease risk prediction can be improved by adding A-CIMT + plaque or CCA-IMT + plaque information to TRF. Therefore, evaluating the carotid artery for plaque presence and measuring CCA-IMT, which is easier and more reliable than measuring A-CIMT, provide a good alternative to measuring A-CIMT for CHD risk prediction. PMID- 21666251 TI - Candida endocarditis complicating transapical aortic valve implantation. PMID- 21666252 TI - Letter to the editor: SeqXML and OrthoXML: standards for sequence and orthology information. AB - There is a great need for standards in the orthology field. Users must contend with different ortholog data representations from each provider, and the providers themselves must independently gather and parse the input sequence data. These burdensome and redundant procedures make data comparison and integration difficult. We have designed two XML-based formats, SeqXML and OrthoXML, to solve these problems. SeqXML is a lightweight format for sequence records-the input for orthology prediction. It stores the same sequence and metadata as typical FASTA format records, but overcomes common problems such as unstructured metadata in the header and erroneous sequence content. XML provides validation to prevent data integrity problems that are frequent in FASTA files. The range of applications for SeqXML is broad and not limited to ortholog prediction. We provide read/write functions for BioJava, BioPerl, and Biopython. OrthoXML was designed to represent ortholog assignments from any source in a consistent and structured way, yet cater to specific needs such as scoring schemes or meta information. A unified format is particularly valuable for ortholog consumers that want to integrate data from numerous resources, e.g. for gene annotation projects. Reference proteomes for 61 organisms are already available in SeqXML, and 10 orthology databases have signed on to OrthoXML. Adoption by the entire field would substantially facilitate exchange and quality control of sequence and orthology information. PMID- 21666253 TI - Hierarchical regulation of the NikR-mediated nickel response in Helicobacter pylori. AB - Nickel is an essential metal for Helicobacter pylori, as it is the co-factor of two enzymes crucial for colonization, urease and hydrogenase. Nickel is taken up by specific transporters and its intracellular homeostasis depends on nickel binding proteins to avoid toxicity. Nickel trafficking is controlled by the Ni(II)-dependent transcriptional regulator NikR. In contrast to other NikR proteins, NikR from H. pylori is a pleiotropic regulator that depending on the target gene acts as an activator or a repressor. We systematically quantified the in vivo Ni(2+)-NikR response of 11 direct NikR targets that encode functions related to nickel metabolism, four activated and seven repressed genes. Among these, four targets were characterized for the first time (hpn, hpn-like, hydA and hspA) and NikR binding to their promoter regions was demonstrated by electrophoretic mobility shift assays. We found that NikR-dependent repression was generally set up at higher nickel concentrations than activation. Kinetics of the regulation revealed a gradual and temporal NikR-mediated response to nickel where activation of nickel-protection mechanisms takes place before repression of nickel uptake. Our in vivo study demonstrates, for the first time, a chronological hierarchy in the NikR-dependent transcriptional response to nickel that is coherent with the control of nickel homeostasis in H. pylori. PMID- 21666254 TI - Structure-dependent bypass of DNA interstrand crosslinks by translesion synthesis polymerases. AB - DNA interstrand crosslinks (ICLs), inhibit DNA metabolism by covalently linking two strands of DNA and are formed by antitumor agents such as cisplatin and nitrogen mustards. Multiple complex repair pathways of ICLs exist in humans that share translesion synthesis (TLS) past a partially processed ICL as a common step. We have generated site-specific major groove ICLs and studied the ability of Y-family polymerases and Pol zeta to bypass ICLs that induce different degrees of distortion in DNA. Two main factors influenced the efficiency of ICL bypass: the length of the dsDNA flanking the ICL and the length of the crosslink bridging two bases. Our study shows that ICLs can readily be bypassed by TLS polymerases if they are appropriately processed and that the structure of the ICL influences which polymerases are able to read through it. PMID- 21666255 TI - Single Qdot-labeled glycosylase molecules use a wedge amino acid to probe for lesions while scanning along DNA. AB - Within the base excision repair (BER) pathway, the DNA N-glycosylases are responsible for locating and removing the majority of oxidative base damages. Endonuclease III (Nth), formamidopyrimidine DNA glycosylase (Fpg) and endonuclease VIII (Nei) are members of two glycosylase families: the helix hairpin-helix (HhH) superfamily and the Fpg/Nei family. The search mechanisms employed by these two families of glycosylases were examined using a single molecule assay to image quantum dot (Qdot)-labeled glycosylases interacting with YOYO-1 stained lambda-DNA molecules suspended between 5 um silica beads. The HhH and Fpg/Nei families were found to have a similar diffusive search mechanism described as a continuum of motion, in keeping with rotational diffusion along the DNA molecule ranging from slow, sub-diffusive to faster, unrestricted diffusion. The search mechanism for an Fpg variant, F111A, lacking a phenylalanine wedge residue no longer displayed slow, sub-diffusive motion compared to wild type, suggesting that Fpg base interrogation may be accomplished by Phe(111) insertion. PMID- 21666256 TI - PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria. AB - Polyadenylation of mRNA in human mitochondria is crucial for gene expression and perturbation of poly(A) tail length has been linked to a human neurodegenerative disease. Here we show that 2'-phosphodiesterase (2'-PDE), (hereafter PDE12), is a mitochondrial protein that specifically removes poly(A) extensions from mitochondrial mRNAs both in vitro and in mitochondria of cultured cells. In eukaryotes, poly(A) tails generally stabilize mature mRNAs, whereas in bacteria they increase mRNA turnover. In human mitochondria, the effects of increased PDE12 expression were transcript dependent. An excess of PDE12 led to an increase in the level of three mt-mRNAs (ND1, ND2 and CytB) and two (CO1 and CO2) were less abundant than in mitochondria of control cells and there was no appreciable effect on the steady-state level of the remainder of the mitochondrial transcripts. The alterations in poly(A) tail length accompanying elevated PDE12 expression were associated with severe inhibition of mitochondrial protein synthesis, and consequently respiratory incompetence. Therefore, we propose that mRNA poly(A) tails are important in regulating protein synthesis in human mitochondria, as it is the case for nuclear-encoded eukaryotic mRNA. PMID- 21666257 TI - DNA slip-outs cause RNA polymerase II arrest in vitro: potential implications for genetic instability. AB - The abnormal number of repeats found in triplet repeat diseases arises from 'repeat instability', in which the repetitive section of DNA is subject to a change in copy number. Recent studies implicate transcription in a mechanism for repeat instability proposed to involve RNA polymerase II (RNAPII) arrest caused by a CTG slip-out, triggering transcription-coupled repair (TCR), futile cycles of which may lead to repeat expansion or contraction. In the present study, we use defined DNA constructs to directly test whether the structures formed by CAG and CTG repeat slip-outs can cause transcription arrest in vitro. We found that a slip-out of (CAG)(20) or (CTG)(20) repeats on either strand causes RNAPII arrest in HeLa cell nuclear extracts. Perfect hairpins and loops on either strand also cause RNAPII arrest. These findings are consistent with a transcription-induced repeat instability model in which transcription arrest in mammalian cells may initiate a 'gratuitous' TCR event leading to a change in repeat copy number. An understanding of the underlying mechanism of repeat instability could lead to intervention to slow down expansion and delay the onset of many neurodegenerative diseases in which triplet repeat expansion is implicated. PMID- 21666258 TI - GPU.proton.DOCK: Genuine Protein Ultrafast proton equilibria consistent DOCKing. AB - GPU.proton.DOCK (Genuine Protein Ultrafast proton equilibria consistent DOCKing) is a state of the art service for in silico prediction of protein-protein interactions via rigorous and ultrafast docking code. It is unique in providing stringent account of electrostatic interactions self-consistency and proton equilibria mutual effects of docking partners. GPU.proton.DOCK is the first server offering such a crucial supplement to protein docking algorithms--a step toward more reliable and high accuracy docking results. The code (especially the Fast Fourier Transform bottleneck and electrostatic fields computation) is parallelized to run on a GPU supercomputer. The high performance will be of use for large-scale structural bioinformatics and systems biology projects, thus bridging physics of the interactions with analysis of molecular networks. We propose workflows for exploring in silico charge mutagenesis effects. Special emphasis is given to the interface-intuitive and user-friendly. The input is comprised of the atomic coordinate files in PDB format. The advanced user is provided with a special input section for addition of non-polypeptide charges, extra ionogenic groups with intrinsic pK(a) values or fixed ions. The output is comprised of docked complexes in PDB format as well as interactive visualization in a molecular viewer. GPU.proton.DOCK server can be accessed at http://gpudock.orgchm.bas.bg/. PMID- 21666260 TI - Intensive insulin therapy in hospitalised patients increases the risk of hypoglycaemia and has no effect on mortality, infection risk or length of stay. PMID- 21666259 TI - PAComplex: a web server to infer peptide antigen families and binding models from TCR-pMHC complexes. AB - One of the most adaptive immune responses is triggered by specific T-cell receptors (TCR) binding to peptide-major histocompatibility complexes (pMHC). Despite the availability of many prediction servers to identify peptides binding to MHC, these servers are often lacking in peptide-TCR interactions and detailed atomic interacting models. PAComplex is the first web server investigating both pMHC and peptide-TCR interfaces to infer peptide antigens and homologous peptide antigens of a query. This server first identifies significantly similar TCR-pMHC templates (joint Z-value >= 4.0) of the query by using antibody-antigen and protein-protein interacting scoring matrices for peptide-TCR and pMHC interfaces, respectively. PAComplex then identifies the homologous peptide antigens of these hit templates from complete pathogen genome databases (>=10(8) peptide candidates from 864,628 protein sequences of 389 pathogens) and experimental peptide databases (80,057 peptides in 2287 species). Finally, the server outputs peptide antigens and homologous peptide antigens of the query and displays detailed interacting models (e.g. hydrogen bonds and steric interactions in two interfaces) of hitTCR-pMHC templates. Experimental results demonstrate that the proposed server can achieve high prediction accuracy and offer potential peptide antigens across pathogens. We believe that the server is able to provide valuable insights for the peptide vaccine and MHC restriction. The PAComplex sever is available at http://PAcomplex.life.nctu.edu.tw. PMID- 21666262 TI - Parkinson's disease progression at 30 years: a study of subthalamic deep brain stimulated patients. AB - Clinical findings in Parkinson's disease suggest that most patients progressively develop disabling non-levodopa-responsive symptoms during the course of the disease. Nevertheless, several heterogeneous factors, such as clinical phenotype, age at onset and genetic aspects may influence the long-term clinical picture. In order to investigate the main features of long-term Parkinson's disease progression, we studied a cohort of 19 subjects treated with subthalamic nucleus deep brain stimulation after >20 years of disease, reporting clinical and neuropsychological data up to a mean of 30 years from disease onset. This group of patients was characterized by an early onset of disease, with a mean age of 38.63 years at Parkinson's disease onset, which was significantly lower than in the other long-term subthalamic nucleus deep brain stimulation follow-up cohorts reported in the literature. All subjects were regularly evaluated by a complete Unified Parkinson's Disease Rating Scale, a battery of neuropsychological tests and a clinical interview, intended to assess the rate of non-levodopa-responsive symptom progression. Clinical data were available for all patients at presurgical baseline and at 1, 3 and 5 years from the subthalamic nucleus deep brain stimulation surgical procedure, while follow-up data after >7 years were additionally reported in a subgroup of 14 patients. The clinical and neuropsychological performance progressively worsened during the course of follow up; 64% of patients gradually developed falls, 86% dysphagia, 57% urinary incontinence and 43% dementia. A progressive worsening of motor symptoms was observed both in 'medication-ON' condition and in 'stimulation-ON' condition, with a parallel reduction in the synergistic effect of 'medication-ON/stimulation ON' condition. Neuropsychological data also showed a gradual decline in the performances of all main cognitive domains, with an initial involvement of executive functions, followed by the impairment of language, reasoning and memory. Thirty years after the disease onset, most patients presented non levodopa-responsive symptoms, although the effect of both subthalamic nucleus deep brain stimulation and dopaminergic therapies still showed significant efficacy on the main disease cardinal features. Nevertheless, compared with other subthalamic nucleus deep brain stimulation follow-up studies, which included patients with a shorter disease duration at the time of surgery, a higher prevalence of axial and non-levodopa-responsive symptoms was observed in the long term evaluations, confirming that several complex aspects underlie the development of non-motor symptoms and other features of Parkinson's disease progression, even in patients with an early disease onset and a prior long lasting response to dopaminergic therapies. PMID- 21666261 TI - Amygdala responses to averted vs direct gaze fear vary as a function of presentation speed. AB - We examined whether amygdala responses to rapidly presented fear expressions are preferentially tuned to averted vs direct gaze fear and conversely whether responses to more sustained presentations are preferentially tuned to direct vs averted gaze fear. We conducted three functional magnetic resonance imaging (fMRI) studies to test these predictions including: Study 1: a block design employing sustained presentations (1 s) of averted vs direct gaze fear expressions taken from the Pictures of Facial Affect; Study 2: a block design employing rapid presentations (300 ms) of these same stimuli and Study 3: a direct replication of these studies in the context of a single experiment using stimuli selected from the NimStim Emotional Face Stimuli. Together, these studies provide evidence consistent with an early, reflexive amygdala response tuned to clear threat and a later reflective response tuned to ambiguous threat. PMID- 21666264 TI - White matter damage in primary progressive aphasias: a diffusion tensor tractography study. AB - Primary progressive aphasia is a clinical syndrome that encompasses three major phenotypes: non-fluent/agrammatic, semantic and logopenic. These clinical entities have been associated with characteristic patterns of focal grey matter atrophy in left posterior frontoinsular, anterior temporal and left temporoparietal regions, respectively. Recently, network-level dysfunction has been hypothesized but research to date has focused largely on studying grey matter damage. The aim of this study was to assess the integrity of white matter tracts in the different primary progressive aphasia subtypes. We used diffusion tensor imaging in 48 individuals: nine non-fluent, nine semantic, nine logopenic and 21 age-matched controls. Probabilistic tractography was used to identify bilateral inferior longitudinal (anterior, middle, posterior) and uncinate fasciculi (referred to as the ventral pathway); and the superior longitudinal fasciculus segmented into its frontosupramarginal, frontoangular, frontotemporal and temporoparietal components, (referred to as the dorsal pathway). We compared the tracts' mean fractional anisotropy, axial, radial and mean diffusivities for each tract in the different diagnostic categories. The most prominent white matter changes were found in the dorsal pathways in non-fluent patients, in the two ventral pathways and the temporal components of the dorsal pathways in semantic variant, and in the temporoparietal component of the dorsal bundles in logopenic patients. Each of the primary progressive aphasia variants showed different patterns of diffusion tensor metrics alterations: non-fluent patients showed the greatest changes in fractional anisotropy and radial and mean diffusivities; semantic variant patients had severe changes in all metrics; and logopenic patients had the least white matter damage, mainly involving diffusivity, with fractional anisotropy altered only in the temporoparietal component of the dorsal pathway. This study demonstrates that both careful dissection of the main language tracts and consideration of all diffusion tensor metrics are necessary to characterize the white matter changes that occur in the variants of primary progressive aphasia. These results highlight the potential value of diffusion tensor imaging as a new tool in the multimodal diagnostic evaluation of primary progressive aphasia. PMID- 21666263 TI - Olfactocentric paralimbic cortex morphology in adolescents with bipolar disorder. AB - The olfactocentric paralimbic cortex plays a critical role in the regulation of emotional and neurovegetative functions that are disrupted in core features of bipolar disorder. Adolescence is thought to be a critical period in both the maturation of the olfactocentric paralimbic cortex and in the emergence of bipolar disorder pathology. Together, these factors implicate a central role for the olfactocentric paralimbic cortex in the development of bipolar disorder and suggest that abnormalities in this cortex may be expressed by adolescence in the disorder. We tested the hypothesis that differences in olfactocentric paralimbic cortex structure are a morphological feature in adolescents with bipolar disorder. Subjects included 118 adolescents (41 with bipolar disorder and 77 healthy controls). Cortical grey matter volume differences between adolescents with and without bipolar disorder were assessed with voxel-based morphometry analyses of high-resolution structural magnetic resonance imaging scans. Compared with healthy comparison adolescents, adolescents with bipolar disorder demonstrated significant volume decreases in olfactocentric paralimbic regions, including orbitofrontal, insular and temporopolar cortices. Findings in these regions survived small volume correction (P < 0.05, corrected). Volume decreases in adolescents with bipolar disorder were also noted in inferior prefrontal and superior temporal gyri and cerebellum. The findings suggest that abnormalities in the morphology of the olfactocentric paralimbic cortex may contribute to the bipolar disorder phenotype that emerges in adolescence. The morphological development of the olfactocentric paralimbic cortex has received little study. The importance of these cortices in emotional and social development, and support for a central role for these cortices in the development of bipolar disorder, suggest that study of the development of these cortices in health and in bipolar disorder is critically needed. PMID- 21666265 TI - Commentary: breastfeeding and obesity--the 2011 Scorecard. PMID- 21666266 TI - Parent-specific copy number in paired tumor-normal studies using circular binary segmentation. AB - MOTIVATION: High-throughput techniques facilitate the simultaneous measurement of DNA copy number at hundreds of thousands of sites on a genome. Older techniques allow measurement only of total copy number, the sum of the copy number contributions from the two parental chromosomes. Newer single nucleotide polymorphism (SNP) techniques can in addition enable quantifying parent-specific copy number (PSCN). The raw data from such experiments are two-dimensional, but are unphased. Consequently, inference based on them necessitates development of new analytic methods. METHODS: We have adapted and enhanced the circular binary segmentation (CBS) algorithm for this purpose with focus on paired test and reference samples. The essence of paired parent-specific CBS (Paired PSCBS) is to utilize the original CBS algorithm to identify regions of equal total copy number and then to further segment these regions where there have been changes in PSCN. For the final set of regions, calls are made of equal parental copy number and loss of heterozygosity (LOH). PSCN estimates are computed both before and after calling. RESULTS: The methodology is evaluated by simulation and on glioblastoma data. In the simulation, PSCBS compares favorably to established methods. On the glioblastoma data, PSCBS identifies interesting genomic regions, such as copy neutral LOH. AVAILABILITY: The Paired PSCBS method is implemented in an open source R package named PSCBS, available on CRAN (http://cran.r-project.org/). PMID- 21666267 TI - Xwalk: computing and visualizing distances in cross-linking experiments. AB - MOTIVATION: Chemical cross-linking of proteins or protein complexes and the mass spectrometry-based localization of the cross-linked amino acids in peptide sequences is a powerful method for generating distance restraints on the substrate's topology. RESULTS: Here, we introduce the algorithm Xwalk for predicting and validating these cross-links on existing protein structures. Xwalk calculates and displays non-linear distances between chemically cross-linked amino acids on protein surfaces, while mimicking the flexibility and non linearity of cross-linker molecules. It returns a 'solvent accessible surface distance', which corresponds to the length of the shortest path between two amino acids, where the path leads through solvent occupied space without penetrating the protein surface. AVAILABILITY: Xwalk is freely available as a web server or stand-alone JAVA application at http://www.xwalk.org. PMID- 21666268 TI - MGV: a generic graph viewer for comparative omics data. AB - MOTIVATION: High-throughput transcriptomics, proteomics and metabolomics methods have revolutionized our knowledge of biological systems. To gain knowledge from comparative omics studies, strong data integration and visualization features are required. Knowledge gained from these studies is often available in the form of graphs, and their visualization is especially useful in a wide range of systems biology topics, including pathway analysis, interaction networks or gene models. Especially, it is necessary to compare biological models with measured data. This allows the identification of new models and new insights into existing ones. RESULTS: We present MGV, a versatile generic graph viewer for multiomics data. MGV is integrated into Mayday (Battke et al., 2010). It extends Mayday's visual analytics capabilities by integrating a wide range of biological models, high throughput data and meta information to display enriched graphs that combine data and models. A wide range of tools is available for visualization of nodes, data aware graph layout as well as automatic and manual aggregation and refinement of the data. We show the usefulness of MGV applied to several problems, including differential expression of alternative transcripts, transcription factor interaction, cross-study clustering comparison and integration of transcriptomics and metabolomics data for pathway analysis. AVAILABILITY: MGV is a open-source software implemented in Java and freely available as a part of Mayday at www.microarray-analysis.org/mayday. CONTACT: symons@informatik.uni-tuebingen.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21666269 TI - Pathogen detection using short-RNA deep sequencing subtraction and assembly. AB - MOTIVATION: Early and accurate detection of human pathogen infection is critical for treatment and therapeutics. Here we describe pathogen identification using short RNA subtraction and assembly (SRSA), a detection method that overcomes the requirement of prior knowledge and culturing of pathogens, by using degraded small RNA and deep sequencing technology. We prove our approach's efficiency through identification of a combined viral and bacterial infection in human cells. PMID- 21666270 TI - Improving protein fold recognition and template-based modeling by employing probabilistic-based matching between predicted one-dimensional structural properties of query and corresponding native properties of templates. AB - MOTIVATION: In recent years, development of a single-method fold-recognition server lags behind consensus and multiple template techniques. However, a good consensus prediction relies on the accuracy of individual methods. This article reports our efforts to further improve a single-method fold recognition technique called SPARKS by changing the alignment scoring function and incorporating the SPINE-X techniques that make improved prediction of secondary structure, backbone torsion angle and solvent accessible surface area. RESULTS: The new method called SPARKS-X was tested with the SALIGN benchmark for alignment accuracy, Lindahl and SCOP benchmarks for fold recognition, and CASP 9 blind test for structure prediction. The method is compared to several state-of-the-art techniques such as HHPRED and BoostThreader. Results show that SPARKS-X is one of the best single method fold recognition techniques. We further note that incorporating multiple templates and refinement in model building will likely further improve SPARKS-X. AVAILABILITY: The method is available as a SPARKS-X server at http://sparks.informatics.iupui.edu/ PMID- 21666271 TI - Trends in hospitalizations for primary care sensitive conditions following the implementation of Family Health Teams in Belo Horizonte, Brazil. AB - OBJECTIVES: How to provide effective and efficient care to the burgeoning and aging populations of the major cities of low- and middle-income countries constitutes one of the principle public health issues of our times. We evaluated the Family Health Strategy, the Brazilian national health system's public approach to primary health care, in the major city of Belo Horizonte, describing trends and factors associated with hospitalizations for primary care sensitive conditions following the implementation of 506 family health teams, most of which were established in 2002. METHODS: We conducted an ecological study covering 2003 to 2006, using mixed models to investigate time trends in public system hospitalizations as well as their association with social vulnerability and primary care team characteristics. RESULTS: Sensitive conditions accounted for 115,340 (26.4%) hospitalizations. Over the 4-year period, hospitalizations for sensitive conditions declined by 17.9%, vs only 8.3% for non-sensitive ones (P<0.001). Hospitalization for sensitive conditions declined 22% for women in areas of high social vulnerability vs 9% for women in areas of low vulnerability (P<0.001); for men, 17% vs 10% (P=0.11). CONCLUSIONS: Though the ecologic nature of our study limits the confidence with which conclusions can be affirmed, the Family Health Strategy appears to have contributed to a major reduction in hospitalizations due to primary care sensitive conditions in this large Brazilian metropolis, while at the same time promoting greater health equity. PMID- 21666272 TI - Using BioMart as a framework to manage and query pancreatic cancer data. AB - We describe the Pancreatic Expression Database (PED), the first cancer database originally designed based on the BioMart infrastructure. The PED portal brings together multidimensional pancreatic cancer data from the literature including genomic, proteomic, miRNA and gene expression profiles. Based on the BioMart 0.7 framework, the database is easily integrated with other BioMart-compliant resources, such as Ensembl and Reactome, to give access to a wide range of annotations alongside detailed experimental conditions. This article is intended to give an overview of PED, describe its data content and work through examples of how to successfully mine and integrate pancreatic cancer data sets and other BioMart resources. PMID- 21666273 TI - Cytokine-inducing lipoteichoic acids of the allergy-protective bacterium Lactococcus lactis G121 do not activate via Toll-like receptor 2. AB - It was established in a mouse model that the cowshed Gram-positive bacterium Lactococcus lactis G121 modulates the immune system resulting in allergy protection. However, the molecules and mechanisms involved in this process have not been elucidated yet. Lipoteichoic acids (LTAs) represent one major cell envelope component of Gram-positive bacteria that is considered a pathogen associated molecular pattern. In the investigations presented here, the isolation as well as the structural and functional analyses of the LTA of L. lactis G121 were performed. Extraction with butan-1-ol and purification by hydrophobic interaction chromatography yielded pure LTA. Structural investigations included chemical analytical methods, nuclear magnetic resonance spectroscopy and high resolution electrospray ionization Fourier-transformed ion cyclotron mass spectrometry. LTA comprised a heterogeneous mixture of molecules composed of a 1,3-linked poly(glycerol phosphate) backbone which was randomly substituted at C 2 by D-alanine and alpha-D-galactopyranose. The lipid anchor constituents were kojibiose linked to a heterogeneous diglyceride comprising in total six different fatty acid compositions. This LTA preparation possesses Toll-like receptor 2- (TLR2) and TLR4-independent cytokine-inducing activities in human mononuclear cells. PMID- 21666274 TI - Review: most interventions for preventing bone disease in chronic renal failure improved biochemical outcomes. PMID- 21666275 TI - Is there a role for acupuncture in the symptom management of patients receiving palliative care for cancer? A pilot study of 20 patients comparing acupuncture with nurse-led supportive care. AB - PURPOSE: A pilot study to document changes in symptoms after acupuncture or nurse led supportive care in patients with incurable cancer. METHODS: Patients receiving palliative care with estimated survival of at least 3 months were screened with the Edmonton Symptom Assessment System (ESAS). Patients (n=20) with significant symptoms were randomised to receive weekly acupuncture or nurse-led supportive care for 4 weeks. ESAS scores were obtained before and after each treatment, and weekly for 6 weeks after treatment by telephone. RESULTS: 42 of 170 patients screened were eligible. 20 gave consent for recruitment. The compliance rate was 90% for acupuncture and 80% for nurse-led supportive care. Total symptom scores were reduced by an average of 22% after each acupuncture visit and by 14% after each supportive care visit. Compared with baseline, ESAS scores at the end of the follow-up period were reduced by 19% for the acupuncture arm and 26% for nurse-led supportive care. CONCLUSION: Patients appear to benefit from incorporating acupuncture in the treatment of advanced incurable cancer. Acupuncture was well tolerated with no significant or unexpected side effects. Acupuncture had an immediate effect on all symptoms, whereas nurse-led supportive care had a larger impact 6 weeks after the final session. Both interventions appear helpful to this population and warrant further study. PMID- 21666276 TI - Survival among high-risk patients after bariatric surgery. AB - CONTEXT: Existing evidence of the survival associated with bariatric surgery is based on cohort studies of predominantly younger women with a low inherent obesity-related mortality risk. The association of survival and bariatric surgery for older men is less clear. OBJECTIVE: To determine whether bariatric surgery is associated with reduced mortality in a multisite cohort of predominantly older male patients who have a high baseline mortality rate. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of bariatric surgery programs in Veterans Affairs medical centers. Mortality was examined for 850 veterans who had bariatric surgery in January 2000 to December 2006 (mean age 49.5 years; SD 8.3; mean body mass index [BMI] 47.4; SD 7.8) and 41,244 nonsurgical controls (mean age 54.7 years, SD 10.2; mean BMI 42.0, SD 5.0) from the same 12 Veteran Integrated Service Networks; the mean follow-up was 6.7 years. Four Cox proportional hazards models were assessed: unadjusted and controlled for baseline covariates on unmatched and propensity-matched cohorts. MAIN OUTCOME MEASURE: All cause mortality through December 2008. RESULTS: Among patients who had bariatric surgery, the 1-, 2-, and 6-year crude mortality rates were, respectively, 1.5%, 2.2%, and 6.8% compared with 2.2%, 4.6%, and 15.2% for nonsurgical controls. In unadjusted Cox regression, bariatric surgery was associated with reduced mortality (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51-0.80). After covariate adjustment, bariatric surgery remained associated with reduced mortality (HR, 0.80; 95% CI, 0.63-0.995). In analysis of 1694 propensity-matched patients, bariatric surgery was no longer significantly associated with reduced mortality in unadjusted (HR, 0.83; 95% CI, 0.61-1.14) and time-adjusted (HR, 0.94; 95% CI, 0.64-1.39) Cox regressions. CONCLUSION: In propensity score adjusted analyses of older severely obese patients with high baseline mortality in Veterans Affairs medical centers, the use of bariatric surgery compared with usual care was not associated with decreased mortality during a mean 6.7 years of follow-up. PMID- 21666277 TI - Association between ambulance diversion and survival among patients with acute myocardial infarction. AB - CONTEXT: Ambulance diversion, a practice in which emergency departments (EDs) are temporarily closed to ambulance traffic, might be problematic for patients experiencing time-sensitive conditions, such as acute myocardial infarction (AMI). However, there is little empirical evidence to show whether diversion is associated with worse patient outcomes. OBJECTIVE: To analyze whether temporary ED closure on the day a patient experiences AMI, as measured by ambulance diversion hours of the nearest ED, is associated with increased mortality rates among patients with AMI. DESIGN, STUDY, AND PARTICIPANTS: A case-crossover design of 13,860 Medicare patients with AMI from 508 zip codes within 4 California counties (Los Angeles, San Francisco, San Mateo, and Santa Clara) whose admission date was between 2000 and 2005. Data included 100% Medicare claims data that covered admissions between 2000 and 2005, linked with date of death until 2006, and daily ambulance diversion logs from the same 4 counties. Among the hospital universe, 149 EDs were identified as the nearest ED to these patients. MAIN OUTCOME MEASURES: The percentage of patients with AMI who died within 7 days, 30 days, 90 days, 9 months, and 1 year from admission (when their nearest ED was not on diversion and when that same ED was exposed to <6, 6 to <12, and >=12 hours of diversion out of 24 hours on the day of admission). RESULTS: Between 2000 and 2006, the mean (SD) daily diversion duration was 7.9 (6.1) hours. Based on analysis of 11,625 patients admitted to the ED between 2000 and 2005, and whose nearest ED had at least 3 diversion exposure levels (3541, 3357, 2667, and 2060 patients for no exposure, exposure to <6, 6 to <12, and >=12 hours of diversion, respectively), there were no statistically significant differences in mortality rates between no diversion and exposure to less than 12 hours of diversion. Exposure to 12 or more hours of diversion was associated with higher 30-day mortality vs no diversion status (unadjusted mortality rate, 392 patients [19%] vs 545 patients [15%]; regression adjusted difference, 3.24 percentage points; 95% confidence interval [CI], 0.60-5.88); higher 90-day mortality (537 patients [26%] vs 762 patients [22%]; 2.89 percentage points; 95% CI, 0.13-5.64); higher 9 month mortality (680 patients [33%] vs 980 patients [28%]; 2.93 percentage points; 95% CI, 0.15-5.71); and higher 1-year mortality (731 patients [35%] vs 1034 patients [29%]; 3.04 percentage points; 95% CI, 0.33-5.75). CONCLUSION: Among Medicare patients with AMI in 4 populous California counties, exposure to at least 12 hours of diversion by the nearest ED was associated with increased 30 day, 90-day, 9-month, and 1-year mortality. PMID- 21666278 TI - What role for the home learning environment and parenting in reducing the socioeconomic gradient in child development? Findings from the Millennium Cohort Study. AB - BACKGROUND: Early child health and development (ECD) is important for health in later life. Objectives were to (1) examine the extent of socioeconomic inequality in markers of ECD at ages 3 and 5 years; (2) examine whether the ECD-income gap widens between these ages; (3) assess the contribution of the home learning environment, family routines and psychosocial environment to observed inequalities in ECD. METHODS: Data on socioemotional difficulties, and tests of cognitive ability in 3-year-old (n=15 382) and 5-year-old (n=15 042) children from the UK Millennium Cohort Study were used. RESULTS: Children in the highest income group were less likely to have socioemotional difficulties compared with those in the lowest income group at 3 and 5 years (2.4% vs 16.4% and 2.0% vs 15.9%, respectively) and had higher mean scores: age 3 'school readiness' 114 versus 99; verbal ability 54 versus 48, and age 5: verbal ability 60 versus 51, non-verbal ability 58 versus 54 and spatial ability 54 versus 48 (all p<0.001). The income gap in verbal ability scores widened between ages 3 and 5 (Wald test, p=0.04). Statistical adjustment for markers of home learning, family routines and psychosocial environments did more to explain the income gap in socioemotional difficulties than in cognitive test scores. CONCLUSION: Our results suggest that relationships between family income and markers of ECD are amenable to change. The role of home learning, family routines and psychosocial environmental factors are potentially important in closing income gaps in ECD. PMID- 21666279 TI - Notice of redundant publication. PMID- 21666282 TI - RasGrf1 and aging. PMID- 21666283 TI - Cdc14b: a new player in aging. PMID- 21666281 TI - Mutations in the BRCT binding site of BRCA1 result in hyper-recombination. AB - We introduced a K1702M mutation in the BRCA1 BRCT domain known to prevent the binding of proteins harboring pS-X-X-F motifs such as Abraxas-RAP80, BRIP1, and CtIP. Surprisingly, rather than impairing homologous recombination repair (HRR), expression of K1702M resulted in hyper-recombination coinciding with an accumulation of cells in S-G2 and no effect on nonhomologous end-joining. These cells also showed increased RAD51 and RPA nuclear staining. More pronounced effects were seen with a naturally occurring BRCT mutant (M1775R) that also produced elevated levels of ssDNA, in part co-localizing with RPA, in line with excessive DNA resection. M1775R induced unusual, thread-like promyelocytic leukemia (PML) nuclear bodies and clustered RPA foci rather than the typical juxtaposed RPA-PML foci seen with wild-type BRCA1. Interestingly, K1702M hyper recombination diminished with a second mutation in the BRCA1 RING domain (I26A) known to reduce BRCA1 ubiquitin-ligase activity. Thesein vitro findings correlated with elevated nuclear RAD51 and RPA staining of breast cancer tissue from a patient with the M1775R mutation. Altogether, the disruption of BRCA1 (BRCT)-pS-X-X-F protein binding results in ubiquitination-dependent hyper recombination via excessive DNA resection and the appearance of atypical PML-NBs. Thus, certain BRCA1 mutations that cause hyper-recombination instead of reduced DSB repair might lead to breast cancer. PMID- 21666284 TI - Embryonic anti-aging niche. AB - Although functional organ stem cells persist in the old, tissue damage invariably overwhelms tissue repair, ultimately causing the demise of an organism. The poor performance of stem cells in an aged organ, such as skeletal muscle, is caused by the changes in regulatory pathways such as Notch, MAPK and TGF-beta, where old differentiated tissue actually inhibits its own regeneration. This perspective analyzes the current literature on regulation of organ stem cells by their young versus old niches and suggests that determinants of healthy and prolonged life might be under a combinatorial control of cell cycle check point proteins and mitogens, which need to be tightly balanced in order to promote tissue regeneration without tumor formation. While responses of adult stem cells are regulated extrinsically and age-specifically, we put forward experimental evidence suggesting that embryonic cells have an intrinsic youthful barrier to aging and produce soluble pro-regenerative proteins that signal the MAPK pathway for rejuvenating myogenesis. Future identification of this activity will improve our understanding of embryonic versus adult regulation of tissue regeneration suggesting novel strategies for organ rejuvenation. Comprehensively, the current intersection of aging and stem cell science indicates that if the age-imposed decline in the regenerative capacity of stem cells was understood, the debilitating lack of organ maintenance in the old could be ameliorated and perhaps, even reversed. PMID- 21666285 TI - Store-operated Ca(2+) entry (SOCE) contributes to normal skeletal muscle contractility in young but not in aged skeletal muscle. AB - Muscle atrophy alone is insufficient to explain the significant decline in contractile force of skeletal muscle during normal aging. One contributing factor to decreased contractile force in aging skeletal muscle could be compromised excitation-contraction (E-C) coupling, without sufficient available Ca(2+) to allow for repetitive muscle contractility, skeletal muscles naturally become weaker. Using biophysical approaches, we previously showed that store-operated Ca(2+) entry (SOCE) is compromised in aged skeletal muscle but not in young ones. While important, a missing component from previous studies is whether or not SOCE function correlates with contractile function during aging. Here we test the contribution of extracellular Ca(2+) to contractile function of skeletal muscle during aging. First, we demonstrate graded coupling between SR Ca(2+) release channel-mediated Ca(2+) release and activation of SOCE. Inhibition of SOCE produced significant reduction of contractile force in young skeletal muscle, particularly at high frequency stimulation, and such effects were completely absent in aged skeletal muscle. Our data indicate that SOCE contributes to the normal physiological contractile response of young healthy skeletal muscle and that defective extracellular Ca(2+) entry through SOCE contributes to the reduced contractile force characteristic of aged skeletal muscle. PMID- 21666288 TI - Extension of a data-driven gating technique to 3D, whole body PET studies. AB - Respiratory gating can be used to separate a PET acquisition into a series of near motion-free bins. This is typically done using additional gating hardware; however, software-based methods can derive the respiratory signal from the acquired data itself. The aim of this work was to extend a data-driven respiratory gating method to acquire gated, 3D, whole body PET images of clinical patients. The existing method, previously demonstrated with 2D, single bed position data, uses a spectral analysis to find regions in raw PET data which are subject to respiratory motion. The change in counts over time within these regions is then used to estimate the respiratory signal of the patient. In this work, the gating method was adapted to only accept lines of response from a reduced set of axial angles, and the respiratory frequency derived from the lung bed position was used to help identify the respiratory frequency in all other bed positions. As the respiratory signal does not identify the direction of motion, a registration-based technique was developed to align the direction for all bed positions. Data from 11 clinical FDG PET patients were acquired, and an optical respiratory monitor was used to provide a hardware-based signal for comparison. All data were gated using both the data-driven and hardware methods, and reconstructed. The centre of mass of manually defined regions on gated images was calculated, and the overall displacement was defined as the change in the centre of mass between the first and last gates. The mean displacement was 10.3 mm for the data-driven gated images and 9.1 mm for the hardware gated images. No significant difference was found between the two gating methods when comparing the displacement values. The adapted data-driven gating method was demonstrated to successfully produce respiratory gated, 3D, whole body, clinical PET acquisitions. PMID- 21666287 TI - The effect of age on human motor electrocorticographic signals and implications for brain-computer interface applications. AB - Electrocorticography (ECoG)-based brain-computer interface (BCI) systems have emerged as a new signal platform for neuroprosthetic application. ECoG-based platforms have shown significant promise for clinical application due to the high level of information that can be derived from the ECoG signal, the signal's stability, and its intermediate nature of surgical invasiveness. However, before long-term BCI applications can be realized it will be important to also understand how the cortical physiology alters with age. Such understanding may provide an appreciation for how this may affect the control signals utilized by a chronic implant. In this study, we report on a large population of adult and pediatric invasively monitored subjects to determine the impact that age will have on surface cortical physiology. We evaluated six frequency bands--delta (<4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), low gamma band (30-50 Hz), and high gamma band (76-100 Hz)--to evaluate the effect of age on the magnitude of power change, cortical area of activation, and cortical networks. When significant trends are evaluated as a whole, it appears that the aging process appears to more substantively alter thalamocortical interactions leading to an increase in cortical inefficiency. Despite this, we find that higher gamma rhythms appear to be more anatomically constrained with age, while lower frequency rhythms appear to broaden in cortical involvement as time progresses. From an independent signal standpoint, this would favor high gamma rhythms' utilization as a separable signal that could be maintained chronically. PMID- 21666286 TI - Thioaptamer conjugated liposomes for tumor vasculature targeting. AB - Recent developments in multi-functional nanoparticles offer a great potential for targeted delivery of therapeutic compounds and imaging contrast agents to specific cell types, in turn, enhancing therapeutic effect and minimizing side effects. Despite the promise, site specific delivery carriers have not been translated into clinical reality. In this study, we have developed long circulating liposomes with the outer surface decorated with thioated oligonucleotide aptamer (thioaptamer) against E-selectin (ESTA) and evaluated the targeting efficacy and PK parameters. In vitro targeting studies using Human Umbilical Cord Vein Endothelial Cell (HUVEC) demonstrated efficient and rapid uptake of the ESTA conjugated liposomes (ESTA-lip). In vivo, the intravenous administration of ESTA-lip resulted in their accumulation at the tumor vasculature of breast tumor xenografts without shortening the circulation half life. The study presented here represents an exemplary use of thioaptamer and liposome and opens the door to testing various combinations of thioaptamer and nanocarriers that can be constructed to target multiple cancer types and tumor components for delivery of both therapeutics and imaging agent. PMID- 21666290 TI - Implant strategies for endocervical and interstitial ultrasound hyperthermia adjunct to HDR brachytherapy for the treatment of cervical cancer. AB - Catheter-based ultrasound devices provide a method to deliver 3D conformable heating integrated with HDR brachytherapy delivery. Theoretical characterization of heating patterns was performed to identify implant strategies for these devices which can best be used to apply hyperthermia to cervical cancer. A constrained optimization-based hyperthermia treatment planning platform was used for the analysis. The proportion of tissue >=41 degrees C in a hyperthermia treatment volume was maximized with constraints T(max) <= 47 degrees C, T(rectum) <= 41.5 degrees C, and T(bladder) <= 42.5 degrees C. Hyperthermia treatment was modeled for generalized implant configurations and complex configurations from a database of patients (n = 14) treated with HDR brachytherapy. Various combinations of endocervical (360 degrees or 2 * 180 degrees output; 6 mm OD) and interstitial (180 degrees , 270 degrees , or 360 degrees output; 2.4 mm OD) applicators within catheter locations from brachytherapy implants were modeled, with perfusion constant (1 or 3 kg m(-3) s( 1)) or varying with location or temperature. Device positioning, sectoring, active length and aiming were empirically optimized to maximize thermal coverage. Conformable heating of appreciable volumes (>200 cm(3)) is possible using multiple sectored interstitial and endocervical ultrasound devices. The endocervical device can heat >41 degrees C to 4.6 cm diameter compared to 3.6 cm for the interstitial. Sectored applicators afford tight control of heating that is robust to perfusion changes in most regularly spaced configurations. T(90) in example patient cases was 40.5-42.7 degrees C (1.9-39.6 EM(43 degrees C)) at 1 kg m(-3) s(-1) with 10/14 patients >=41 degrees C. Guidelines are presented for positioning of implant catheters during the initial surgery, selection of ultrasound applicator configurations, and tailored power schemes for achieving T(90) >= 41 degrees C in clinically practical implant configurations. Catheter based ultrasound devices, when adhering to the guidelines, show potential to generate conformal therapeutic heating ranging from a single endocervical device targeting small volumes local to the cervix (<2 cm radial) to a combination of a 2 * 180 degrees endocervical and directional interstitial applicators in the lateral periphery to target much larger volumes (6 cm radial), while preferentially limiting heating of the bladder and rectum. PMID- 21666289 TI - A three-dimensional quality-guided phase unwrapping method for MR elastography. AB - Magnetic resonance elastography (MRE) uses accumulated phases that are acquired at multiple, uniformly spaced relative phase offsets, to estimate harmonic motion information. Heavily wrapped phase occurs when the motion is large and unwrapping procedures are necessary to estimate the displacements required by MRE. Two unwrapping methods were developed and compared in this paper. The first method is a sequentially applied approach. The three-dimensional MRE phase image block for each slice was processed by two-dimensional unwrapping followed by a one dimensional phase unwrapping approach along the phase-offset direction. This unwrapping approach generally works well for low noise data. However, there are still cases where the two-dimensional unwrapping method fails when noise is high. In this case, the baseline of the corrupted regions within an unwrapped image will not be consistent. Instead of separating the two-dimensional and one dimensional unwrapping in a sequential approach, an interleaved three-dimensional quality-guided unwrapping method was developed to combine both the two dimensional phase image continuity and one-dimensional harmonic motion information. The quality of one-dimensional harmonic motion unwrapping was used to guide the three-dimensional unwrapping procedures and it resulted in stronger guidance than in the sequential method. In this work, in vivo results generated by the two methods were compared. PMID- 21666291 TI - Estimation of regional hemoglobin concentration in biological tissues using diffuse reflectance spectroscopy with a novel spectral interpretation algorithm. AB - Both in medical research and clinical settings, regional hemoglobin concentrations ([Hb]) in the microcirculation of biological tissues are highly sought. Diffuse reflectance spectroscopy has been proven to be a favorable method by which to detect regional [Hb]. This paper introduces a new algorithm to retrieve [Hb] information from diffuse reflectance spectra. The proposed algorithm utilizes the natural logarithmic operation and the differential wavelet transform to effectively quench the scattering effects, and then employs the concept of isosbestic wavelength in the transformed spectra to reduce the effects of hemoglobin oxygenation. As a result, the intensity at the defined isosbestic wavelength of the transformed spectra is a good indicator of [Hb] estimation. The algorithm was derived and validated using theoretical spectra produced by Monte Carlo simulation of photon migration. Its accuracy was further evaluated using liquid tissue phantoms, and its clinical utility with an in vivo clinical study of brain tumors. The results demonstrate the applicability of the algorithm for real-time [Hb] estimations from diffuse reflectance spectra, acquired by means of a fiber-optic spectroscopy system. PMID- 21666292 TI - Non-invasive estimation and control of inlet pressure in an implantable rotary blood pump for heart failure patients. AB - We propose a dynamical model for mean inlet pressure estimation in an implantable rotary blood pump during the diastolic period. Non-invasive measurements of pump impeller rotational speed (omega), motor power (P), and pulse width modulation signal acquired from the pump controller were used as inputs to the model. The model was validated over a wide range of speed ramp studies, including (i) healthy (C1), variations in (ii) heart contractility (C2); (iii) afterload (C2, C3, C4), and (iv) preload (C5, C6, C7). Linear regression analysis between estimated and extracted mean inlet pressure obtained from in vivo animal data (greyhound dogs, N = 3) resulted in a highly significant correlation coefficients (R(2) = 0.957, 0.961, 0.958, 0.963, 0.940, 0.946, and 0.959) and mean absolute errors of (e = 1.604, 2.688, 3.667, 3.990, 2.791, 3.215, and 3.225 mmHg) during C1, C2, C3, C4, C5, C6, and C7, respectively. The proposed model was also used to design a controller to regulate mean diastolic pump inlet pressure using non invasively measured omega and P. In the presence of model uncertainty, the controller was able to track and settle to the desired input within a finite number of sampling periods and minimal error (0.92 mmHg). The model developed herein will play a crucial role in developing a robust control system of the pump that detects and thus avoids undesired pumping states by regulating the inlet pressure within a predefined physiologically realistic limit. PMID- 21666293 TI - Nucleosome mediated crosstalk between transcription factors at eukaryotic enhancers. AB - A recent study of transcription regulation in Drosophila embryonic development revealed a complex non-monotonic dependence of gene expression on the distance between binding sites of repressor and activator proteins at the corresponding enhancer cis-regulatory modules (Fakhouri et al 2010 Mol. Syst. Biol. 6 341). The repressor efficiency was high at small separations, low around 30 bp, reached a maximum at 50-60 bp, and decreased at larger distances to the activator binding sites. Here, we propose a straightforward explanation for the distance dependence of repressor activity by considering the effect of the presence of a nucleosome. Using a method that considers partial unwrapping of nucleosomal DNA from the histone octamer core, we calculated the dependence of activator binding on the repressor-activator distance and found a quantitative agreement with the distance dependence reported for the Drosophila enhancer element. In addition, the proposed model offers explanations for other distance-dependent effects at eukaryotic enhancers. PMID- 21666294 TI - Mutagenicity associated with O6-methylguanine-DNA damage and mechanism of nucleotide flipping by AGT during repair. AB - Methylated guanine damage at O6 position (i.e. O6MG) is dangerous due to its mutagenic and carcinogenic character that often gives rise to G:C-A:T mutation. However, the reason for this mutagenicity is not known precisely and has been a matter of controversy. Further, although it is known that O6-alkylguanine-DNA alkyltransferase (AGT) repairs O6MG paired with cytosine in DNA, the complete mechanism of target recognition and repair is not known completely. All these aspects of DNA damage and repair have been addressed here by employing high level density functional theory in gas phase and aqueous medium. It is found that the actual cause of O6MG mediated mutation may arise due to the fact that DNA polymerases incorporate thymine opposite to O6MG, misreading the resulting O6MG:T complex as an A:T base pair due to their analogous binding energies and structural alignments. It is further revealed that AGT mediated nucleotide flipping occurs in two successive steps. The intercalation of the finger residue Arg128 into the DNA double helix and its interaction with the O6MG:C base pair followed by rotation of the O6MG nucleotide are found to be crucial for the damage recognition and nucleotide flipping. PMID- 21666295 TI - Comment on 'Shear stiffness in nanolaminar Ti3SiC2 challenges ab initio calculations'. AB - In a recent publication by Kisi et al (2010 J. Phys.: Condens. Matter 22 162202) the authors present experimentally measured elastic constants for the M(n + 1)AX(n) (MAX) phase, Ti(3)SiC(2), that differ from density functional theory calculations. They then conclude that 'prediction [by ab initio calculation] of the full elasticity tensor for Ti(3)SiC(2) has not been successful'. However the authors do not compare with previous experimental work in which Finkel et al measure the elastic moduli (Finkel et al 2000 J. Appl. Phys. 87 1701). The predictions of ab initio calculations (Yu et al 2005 J. Mater. Res. 20 1180) agree with the measurements of Finkel et al as well as with most other experimentally measured elastic moduli for MAX phases (Cover et al 2008 10 935; Cover et al 2009 J. Phys.: Condens. Matter 21 305403). The unrealistically high value of the C(44) constant obtained by Kisi et al, which would mean that Ti(3)SiC(2) is almost as resistant to shear as diamond, undermines confidence in their results. PMID- 21666296 TI - Atomic and electronic structure of amorphous Al-Zr alloy films. AB - Amorphous Al(73)Zr(27) alloy film, grown and then subjected to heat treatments at 400 and 700 degrees C, was studied using a combination of x-ray diffraction and soft x-ray spectroscopic techniques. The Al L(2,3) and Al K x-ray absorption spectroscopy (XAS) and Al L(2,3) x-ray emission spectroscopy (XES) used allowed probing the unoccupied and occupied Al 3s, d states and unoccupied Al 3p states in the sample studied. An irreversible transition from amorphous alloy to a mixture of polycrystalline alloy and amorphous alloy, and then to an amorphous oxide phase was observed. After the annealing at 400 degrees C the Al L(2,3) spectra obtained by XAS could be explained as sums of spectra from amorphous Al(73)Zr(27) alloy and (poly)crystalline Al. This indicates that the sample consists of a mixture of Al-rich crystalline and Zr-enhanced amorphous alloys, as compared to the stoichiometry of the as-deposited Al(73)Zr(27) sample, and that the electronic wavefunctions in the crystalline and amorphous regions can be considered to be confined within the respective regions. The relative amounts of Al atoms were found to be around 1:3 in the crystalline and amorphous phases, respectively, as deduced from the analysis of changes in the electronic structure using Al L(2,3) XAS data. The interpretation was confirmed by the Al K XAS and Al L(2,3) XES. Upon further annealing at 700 degrees C the polycrystalline phase transformed into amorphous oxide, while the amorphous alloy phase underwent gradual oxidation. The important finding was that the greater part of the sample remained in the amorphous state throughout the temperature regimes described. PMID- 21666297 TI - DDFT calibration and investigation of an anisotropic phase-field crystal model. AB - The anisotropic phase-field crystal model recently proposed and used by Prieler et al (2009 J. Phys.: Condens. Matter 21 464110) is derived from microscopic density functional theory for anisotropic particles with fixed orientation. Its morphology diagram is also explored. In particular we have investigated the influence of anisotropy and undercooling on the process of nucleation and microstructure formation from the atomic to the microscale. To that end numerical simulations were performed varying those dimensionless parameters which represent anisotropy and undercooling in our anisotropic phase-field crystal model. The results from these numerical simulations are summarized in terms of a morphology diagram of the stable state phases. These stable phases are also investigated with respect to their kinetics and characteristic morphological features. PMID- 21666299 TI - Computation of heats of transport of vacancies in model crystalline solids: III. AB - This paper extends a previous application of classical molecular dynamics to the computation of the heat of transport, Q(*), of Au atoms in a model of solid gold made at several elevated temperatures above the Debye temperature (Grout and Lidiard 2008 J. Phys.: Condens. Matter 20 425201). That previous paper examined two particular technical points arising in the application of molecular dynamics to this problem, namely (i) the size of the time steps used in the integration of the equations of motion and (ii) the number of vacancy displacements needed to obtain accurate results. In the present paper we examine a third, namely the effect of the size, N, of the periodicity volume (defined as the number of lattice sites within it) on the predicted heats of transport. We show that the necessary size of N decreases as the temperature of the simulation increases. Assuming that the Cherns form of potential may be applied more widely, the present paper also provides a general relation between Q(*) and the heat of activation for vacancy movement in face centred cubic metals. PMID- 21666300 TI - Sr adatoms on As bridge positions on SrFe2As2 observed by scanning tunneling microscopy at 4.2 K. AB - We used a scanning tunneling microscope to image the surface of SrFe(2)As(2) single crystals at 4.2 K. We found, besides the commonly reported row structures and some disordered areas, also maze-like regions. Atomically resolved images of the maze show that the atoms on the surface sit on As bridge positions of the underlying Fe(2)As(2) layer. Examination of the corner positions within the maze like reconstruction reveals the presence of adatoms rather than As dimers. Hence, the surface atoms on these samples are most likely to be Sr atoms. PMID- 21666301 TI - LEED I-V and DFT structure determination of the (?3 * ?3)R30 degrees Pb-Ag(111) surface alloy. AB - The deposition of 1/3 of a monolayer of Pb on Ag(111) leads to the formation of PbAg(2) surface alloy with a long range ordered (?3 * ?3)R30 degrees superstructure. A detailed analysis of this structure using low-energy electron diffraction (LEED) I-V measurements together with density functional theory (DFT) calculations is presented. We find strong correlation between experimental and calculated LEED I-V data, with the fit between the two data sets having a Pendry's reliability factor of 0.21. The Pb atom is found to replace one top layer Ag atom in each unit cell, forming a substitutional PbAg(2) surface alloy, as expected, with the Pb atoms residing approximately 0.4 A above the Ag atoms due to their size difference. DFT calculations are in good agreement with the LEED results. PMID- 21666302 TI - Electronic structure of thermoelectric Zn-Sb. AB - The electronic structures of the two main compounds of the binary zinc antimonides that are stable at room temperature, Zn(1)Sb(1) and beta-Zn(4)Sb(3), were probed with x-ray photoelectron spectroscopy. Additionally, electron energy loss measurements and density functional theory calculations are presented. The compounds are found to share a very similar electronic structure. They both feature only small charge transfers and differ moderately in their screening potentials. These results are in line with recent theoretical works on the Zn-Sb system and are discussed in light of the reported thermoelectric performance of the materials. PMID- 21666303 TI - Size-dependent superconducting state of individual nanosized Pb islands grown on Si(111) by tunneling spectroscopy. AB - By measuring the temperature-dependent tunneling spectroscopy of a set of flat top Pb islands from 3.2 to 15 K, the limiting size of a nine-monolayer-thick Pb island with superconductivity above 3.2 K was determined to be ~ 30 nm(2), in good agreement with the Anderson criterion. Further analysis indicates that the zero-temperature energy gap decreases significantly faster than the transition temperature when the Pb island size approaches this limit. This leads to a decrease of 2Delta(0)/k(B)T(C) from 4.5 to 3.3, thus showing that the Pb island superconductors undergo a change from strong to weak electron-phonon coupling. PMID- 21666304 TI - High-throughput characterization of the Seebeck coefficient of a-(Cr(1-x)Si(x))(1 y)O(y) thin film materials libraries as verification of the extended thermopower formula. AB - In a previous paper (Sonntag 2010 J. Phys.: Condens. Matter 22 235501) the classical thermopower formula has been argued to be incomplete, because it only takes into account the scattering properties of the carriers, but not the temperature dependence of the electrochemical potential MU caused by variation of the carrier density and/or band edge shift with temperature T. This argument is now checked experimentally by high-throughput measurements of the thermopower (Seebeck coefficient) S of a-(Cr(1-x)Si(x))(1-y)O(y) thin film materials libraries. The concentration dependences of S differ depending on whether the measurements are done with the complete film (where x ranges continuously from x~0.3 to 0.8; y~0.1-0.2) or with the separated pieces (each piece with another average value of x). These differences are especially large if, in addition, an oxygen gradient is present. PMID- 21666305 TI - Stationary waves in a superfluid exciton gas in quantum Hall bilayers. AB - Stationary waves in a superfluid magnetoexciton gas in nu = 1 quantum Hall bilayers are considered. The waves are induced by counterpropagating electrical currents that flow in a system with a point obstacle. It is shown that stationary waves can emerge only in imbalanced bilayers in a certain diapason of currents. It is found that the stationary wave pattern is modified qualitatively under a variation of the ratio of the interlayer distance to the magnetic length [Formula: see text]. The advantages of using graphene-dielectric-graphene sandwiches for the observation of stationary waves are discussed. We determine the range of parameters (the dielectric constant of the layer that separates two graphene layers and the ratio d/l) for which the state with superfluid magnetoexcitons can be realized in such sandwiches. Typical stationary wave patterns are presented as density plots. PMID- 21666306 TI - Temperature-dependent local structure of NdFeAsO(1-x)F(x) system using arsenic K edge extended x-ray absorption fine structure. AB - Local structure of NdFeAsO(1-x)F(x) (x = 0.0, 0.05, 0.15 and 0.18) high temperature iron-pnictide superconductor system is studied using arsenic K-edge extended x-ray absorption fine structure measurements as a function of temperature. Fe-As bond length shows only a weak temperature and F-substitution dependence, consistent with the strong covalent nature of this bond. The temperature dependence of the mean square relative displacements of the Fe-As bond length are well described by the correlated Einstein model for all the samples, but with different Einstein temperatures for the superconducting and non superconducting samples. The results indicate distinct local Fe-As lattice dynamics in the superconducting and non-superconducting iron-pnictide systems. PMID- 21666307 TI - Structure and electronic properties of molybdenum monatomic wires encapsulated in carbon nanotubes. AB - Monatomic chains of molybdenum encapsulated in single-walled carbon nanotubes (CNTs) of different chiralities are investigated using density functional theory. We determine the optimal size of the CNT for encapsulating a single atomic wire, as well as the most stable atomic arrangement adopted by the wire. We also study the transport properties in the ballistic regime by computing the transmission coefficients and tracing them back to the electronic conduction channels of the wire and the host. We predict that CNTs of appropriate radii encapsulating a Mo wire have metallic behavior, even if both the nanotube and the wire are insulators. Therefore, encapsulation of Mo wires in CNTs is a way to create conductive quasi-one-dimensional hybrid nanostructures. PMID- 21666308 TI - Toward development of a two-state brain-computer interface based on mental tasks. AB - A recently collected EEG dataset is analyzed and processed in order to evaluate the performance of a previously designed brain-computer interface (BCI) system. The EEG signals are collected from 29 channels distributed over the scalp. Four subjects completed three sessions each by performing four different mental tasks during each session. The BCI is designed in such a way that only one of the mental tasks can activate it. One important advantage of this BCI is its simplicity, since autoregressive modeling and quadratic discriminant analysis are used for feature extraction and classification, respectively. The autoregressive order which yields the best overall performance is obtained during a fivefold nested cross-validation process. The results are promising as the false positive rates are zero while the true positive rates are sufficiently high (67.26% average). PMID- 21666309 TI - From the editor's desk - vasculitis my brief synopsis. PMID- 21666310 TI - Extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type of the ocular adnexa: retrospective single institution review of 95 patients. AB - CONTEXT: There are few reports on the management of extranodal marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type (MALT), which are based on the experience of a single institution, as opposed to large multicenter randomized trials. AIM: The aim of this study was to report on the clinical experience of a single institution. MATERIALS AND METHODS: A retrospective review was undertaken of records of 95 patients with MALT lymphoma of the ocular adnexa. Histologic diagnosis of MALT lymphoma was made according to established criteria, and clinical staging was carried out to determine treatment modalities. All patients were treated by external beam irradiation (30.6-45.0 Gy) after biopsy. Additional chemotherapy was performed in accordance with the clinical stage of the disease. All the patients were treated by the same hemato-oncologist and radio-oncologist. RESULTS: Almost all patients showed complete response, except for four patients who showed partial response. In two of 95 patients, contralateral eye showed recurrence, and they were salvaged by additional radiotherapy. The 3-year overall survival and event-free survival rates were 100 and 97%, respectively, by Kaplan-Meier survival analysis. Moreover, there were no serious radiation-associated complications. CONCLUSIONS: Radiotherapy alone can be an important treatment modality for the local control and survival in patients with localized MALT lymphoma of ocular adnexa. Systemic chemotherapy should be considered in patients with advanced stage disease. PMID- 21666311 TI - Boston ocular surface prosthesis: an Indian experience. AB - CONTEXT: Boston ocular surface prosthesis (BOSP) is a scleral contact lens used in the management of patients who are rigid gas permeable (RGP) failures as with corneal ectasias such as keratoconus and in those patients who have ocular surface disease such as Stevens-Johnson syndrome (SJS). AIM: To report utilization of BOSP in a tertiary eye care center in India. MATERIALS AND METHODS: We retrospectively reviewed charts of 32 patients who received BOSP from July 2008 to May 2009. Indications for fitting these lenses, improvement in visual acuity (VA) before and after lens fitting and relief of symptoms of pain and photophobia were noted. Paired t-test was used for statistical analysis using SPSS version 16.0 for Windows. RESULTS: Thirty-two patients (43 eyes) received these lenses. These consisted of 23 eyes of 17 patients who failed RGP trials for irregular astigmatism and corneal ectasia such as keratoconus and post radial keratotomy and scar and 20 eyes of 15 patients with SJS. Mean age of RGP failures was 27.94 years. Pre- and post-BOSP wear mean LogMAR VA was 1.13 and 0.29, respectively, in RGP failures. The P value was statistically significant (P < 0.001). In patients with SJS, LogMAR VA was 0.84 +/- 0.92 before and 0.56 +/- 0.89 after lens wear. The P value was statistically significant (P < 0.001). VA improved by >2 lines in 7/20 eyes (35%) with SJS, with improvement in symptoms. CONCLUSION: BOSP improves VA in patients who have irregular astigmatism as in ectasias and RGP failures and improves vision and symptoms in patients with SJS. PMID- 21666312 TI - Laser in-situ keratomileusis for refractive error following radial keratotomy. AB - AIM: To evaluate the safety and efficacy of laser in-situ keratomileusis (LASIK) in eyes with residual/induced refractive error following radial keratotomy (RK). DESIGN: Retrospective study. MATERIALS AND METHODS: A retrospective analysis of data of 18 eyes of 10 patients, who had undergone LASIK for refractive error following RK, was performed. All the patients had undergone RK in both eyes at least one year before LASIK. Parameters like uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), contrast sensitivity, glare acuity and corneal parameters were evaluated both preoperatively and postoperatively. STATISTICAL SOFTWARE: STATA-9.0. RESULTS: The mean UCVA before LASIK was 0.16+/ 0.16 which improved to 0.64 +/- 0.22 ( P < 0.001) after one year following LASIK. Fourteen eyes (out of 18) had UCVA of >= 20/30 on Snellen's acuity chart at one year following LASIK. The mean BCVA before LASIK was 0.75 +/- 0.18. This improved to 0.87 +/- 0.16 at one year following LASIK. The mean spherical refractive error at the time of LASIK and at one year after the procedure was -5.37 +/- 4.83 diopters (D) and -0.22 +/- 1.45D, respectively. Only three eyes had a residual spherical refractive error of >= 1.0D at one year follow-up. In two eyes, we noted opening up of the RK incisions. No eye developed epithelial in-growth till 1 year after LASIK. CONCLUSION: LASIK is effective in treating refractive error following RK. However, it carries the risk of flap-related complications like opening up of the previously placed RK incisions and splitting of the corneal flap. PMID- 21666313 TI - Influence of galactose cataract on erythrocytic and lenticular glutathione metabolism in albino rats. AB - CONTEXT: Glutathione depletion has been postulated to be the prime reason for galactose cataract. The current research seeks the prospect of targeting erythrocytes to pursue the lens metabolism by studying the glutathione system. AIMS: To study the activity of the glutathione-linked scavenger enzyme system in the erythrocyte and lens of rats with cataract. MATERIALS AND METHODS: Experiments were conducted in 36 male albino rats weighing 80 +/- 20 g of 28 days of age. The rats were divided into two major groups, viz. experimental and control. Six rats in each group were sacrificed every 10 days, for 30 days. Cataract was induced in the experimental group by feeding the rats 30% galactose (w/w). The involvement of reduced glutathione (GSH) and the linked enzymes was studied in the erythrocytes and lens of cataractous as well as control rats. STATISTICAL ANALYSIS: Parametric tests like one-way ANOVA and Student's 't' test were used for comparison. Correlation linear plot was used to compare the erythrocyte and lens metabolism. RESULTS: The concentration of GSH and the activity of linked enzymes were found decreased with the progression of cataract, and also in comparison to the control. The same linear fashion was also observed in the erythrocytes. CONCLUSION: Depletion of GSH was the prime factor for initiating galactose cataract in the rat model. This depletion may in turn result in enzyme inactivation leading to cross-linking of protein and glycation. The correlation analysis specifies that the biochemical mechanism in the erythrocytes and lens is similar in the rat model. PMID- 21666314 TI - Comparative study on the incidence and outcomes of pigmented versus non pigmented keratomycosis. AB - PURPOSE: To determine the incidence, outcomes and establish factors determining visual prognosis of keratomycosis due to pigmented fungi in comparison with nonpigmented fungi. MATERIALS AND METHODS: All culture-proven cases of fungal keratitis from January 2006 to August 2008 were drawn from a computerized database and cases with adequate documentation were analyzed for predisposing factors, clinical characteristics, microbiology and treatment methods. Outcomes of keratitis due to pigmented and nonpigmented fungi were compared using t-test and chi2 test. RESULTS: Of 373 cases of keratomycosis during the study period, pigmented fungi were etiological agents in 117 eyes (31.3%) and nonpigmented fungi in 256 eyes (68.7%). Eyes with nonpigmented keratitis had significantly larger ulcers (14.96 mm 2 ) and poorer vision (1.42 logMAR) at presentation compared to those with keratomycosis due to pigmented fungi (P=0.01). The characteristic macroscopic pigmentation was seen in only 14.5% in the pigmented keratitis group. Both groups responded favorably to medical therapy (78.1% vs. 69.1%) with scar formation (P=0.32) and showed a significant improvement in mean visual acuity compared with that at presentation (P<0.01). Visual improvement in terms of line gainers and losers in the subgroup of eyes that experienced healing was also similar. Location of the ulcer was the only factor that had significant predictive value for visual outcome (P=0.021). CONCLUSION: Incidence of keratomycosis due to pigmented fungi may be increasing as compared to previous data. These eyes have similar response to medical therapy and similar visual outcome compared to nonpigmented keratitis. Central ulcers have a poor visual outcome. PMID- 21666315 TI - Profile of retinal vasculitis in a tertiary eye care center in Eastern India. AB - AIMS: To provide a fact file on the etiology, clinical presentations and management of retinal vasculitis in Eastern India. MATERIALS AND METHODS: Retrospective, record based analysis of retinal vasculitis cases in a tertiary care center in Eastern India from January 2007 to December 2009 . RESULTS: One hundred and thirteen eyes of 70 patients of retinal vasculitis were included in this study. Sixty (85.7%) patients were male (mean age 33+/- 11.1 years) and 10 (14.3%) were female (mean age 32.4 +/- 13.6 years). Vasculitis was bilateral in 43 (61.4%) and unilateral in 27 (38.6%) patients. Commonest symptoms were dimness of vision (73; 64.6%) and floaters (36; 31.9%). Vascular sheathing (82; 72.6%) and vitritis (51; 45.1%) were commonest signs. Mantoux test was positive in 21 (30%) patients but tuberculosis was confirmed in only four (5.71%) patients. Raised serum angiotensin-converting enzyme level and positive antinuclear antibody level were reported in four (5.71%) patients each. Human leukocyte antigen B5 (HLA B5) marker was present in one (1.4%) patient. However, none of the total 70 patients were found to have a conclusively proven systemic disease attributable as the cause of retinal vasculitis. Oral corticosteroid (60; 85.7%) was the mainstay of treatment. Forty-eight (42.5%) eyes maintained their initial visual acuity and 43 (38%) gained one or more line at mean follow-up of 16.6+/- 6.3 months. CONCLUSION: Retinal vasculitis cases had similar clinical presentations and common treatment plan. There was no systemic disease association with vasculitis warranting a careful approach in prescribing investigations. PMID- 21666316 TI - Role of anterior segment optical coherence tomogram in Descemet's membrane detachment. AB - Descemet's membrane detachment (DD) is a rare but serious complication of intraocular surgery. In rare cases where corneal edema is severe and we may not be able to visualize DD on slit-lamp examination, anterior segment optical coherence tomogram (AS-OCT) would be helpful. We describe two patients with DD, highlighting the role of AS-OCT in early diagnosis and management of patients with DD. One of the patients had DD with rolled in edge, which could only be visualized with AS-OCT. In such a situation, AS-OCT can identify the edge of detachment and show the exact position of the rolled edge, which can allow us to plan the surgical strategy to unroll the DD. PMID- 21666317 TI - Combination treatment of low fluence photodynamic therapy and intravitreal ranibizumab for choroidal neovascular membrane secondary to angioid streaks in Paget's disease - 12 month results. AB - Angioid streaks also called Knapp striae are small breaks in the Bruch's membrane and have been reported with a host of systemic diseases. Rupture of streaks or development of secondary choroidal neovascular membrane (CNVM) carries a dismal visual prognosis. We report the successful treatment of CNVM secondary to Paget's disease using low fluence photodynamic therapy (PDT) and intravitreal ranibizumab. PMID- 21666318 TI - Can we overcome the challenges of sutures in lamellar keratoplasty? AB - Lamellar keratoplasty (LK) is a technique which can be followed for both tectonic and optical purposes. We describe a technique of sutureless anterior LK by fixing the donor lenticule to the recipient bed using fibrin glue. LK was performed in an eye with corneal opacity using the manual dissection method. The donor lenticule was cut with a microkeratome after fixing the corneoscleral rim in an artificial anterior chamber. The size of the donor lenticule was 8.5 mm and fixed to the recipient bed with fibrin glue. The surgical time was reduced significantly with this technique. There was an uneventful postoperative period during the follow-up of 12 months. Best corrected visual acuity improved from hand movement to 20/60. Thus, the use of fibrin glue for fixing the anterior lamellar lenticule is a viable option for both optical and anatomical purposes. PMID- 21666319 TI - Dengue hemorrhagic fever: a rare cause of pituitary tumor hemorrhage and reversible vision loss. AB - Dengue hemorrhagic fever leading to hemorrhage in pituitary adenoma is not reported till date: We herein report the first case of bilateral visual loss secondary to pituitary adenoma hemorrhage associated with dengue hemorrhagic fever. Urgent transnasal trans sphenoidal decompression of the macroadenoma prevented permanent visual loss in this patient. Pituitary apoplexy should be considered as differential diagnosis of visual deterioration apart from retinal hemorrhage, maculopathy, and optic neuropathy in cases of dengue hemorrhagic fever. Early decompression of optic nerves helped in the restoration of vision. PMID- 21666320 TI - Unusual presentation in Axenfeld-Rieger syndrome. AB - We report an unusual presentation of a case of Axenfeld-Rieger (A-R) syndrome. A 14-year-old male presented with gradual dimness of vision for 1 year and redness of left eye for 3 days. The patient had megalocornea with Haab's striae in the right eye and posterior embryotoxon in both the eyes. In the left eye, there was a white cord-like structure traversing the anterior chamber with adhesions to iris tissue along its course. On two antiglaucoma medications, his intraocular pressure (IOP) was 22 mm Hg in the right eye and 18 mm Hg in the left eye. Gonioscopy revealed a cord-like structure originating at the level of Schwalbe's line. He underwent right eye trabeculectomy with mitomycin-C. This case highlights a rare presentation of a strange cord-like structure, a rare presentation of A-R syndrome. PMID- 21666321 TI - Simultaneous bilensectomy and endothelial keratoplasty for angle-supported phakic intraocular lens-induced corneal decompensation. AB - A 40-year-old lady presented with severe endothelial cell loss in both eyes 14 years after angle-supported phakic intraocular lens (AS PIOL) implantation. The left eye had severe corneal edema with bullous keratopathy. The right eye had markedly reduced endothelial cell count (655 cells/mm 2 ) although the cornea was clear. She underwent simultaneous bilensectomy (AS PIOL explantation and phacoemulsification) and Descemet's stripping and endothelial keratoplasty (DSEK) in the left eye. Explanted AS PIOL was identified as ZSAL-4 (Morcher, Stuttgart, Germany) model. Corneal edema cleared completely in 2 months with a best corrected visual acuity (-2.25 D sph) of 20/60. No intervention was done in the right eye. The present case illustrates that AS PIOL-induced endothelial decompensation can be effectively managed by simultaneous bilensectomy and endothelial keratoplasty. PMID- 21666322 TI - Intravitreal ranibizumab for the treatment of choroidal neovascularization secondary to ocular toxoplasmosis. AB - The purpose of the study was to report a case of choroidal neovascularization (CNV) secondary to ocular toxoplasmosis in an 18-year-old female patient. She was treated with a single intravitreal injection of ranibizumab. The CNV resolved as confirmed by fluorescein angiography and optical coherence tomography (OCT). The visual acuity improved to 20/30, which was maintained till the last follow-up visit at two years, without requisition of a repeat injection. PMID- 21666323 TI - Double anterior chamber in a patient with glaucoma and microspherophakia. AB - We report the case of a 16-year-old woman with microspherophakia and secondary open angle glaucoma. The patient presented with a membrane dividing the anterior chamber into two segments without edema or Descemet's membrane detachment. Slit lamp biomicroscopy, Pentacam, and specular microscopy images were obtained. Double anterior chamber is primarily found in patients with anterior chamber anomalies when there is no history of surgery or trauma. PMID- 21666324 TI - Effect of the single-drop mydriatic combination of 0.8% tropicamide with 5% phenylephrine with multiple applications of the same drop: a randomized controlled trial. PMID- 21666325 TI - Inferior trabeculotomy and trabeculectomy for refractory pediatric glaucomas. PMID- 21666326 TI - Optic disc topography in normal Indian eyes using spectral domain optical coherence tomography. PMID- 21666327 TI - Bilateral recurrent dislocation of plate haptic intraocular lens. PMID- 21666328 TI - Crystalline deposition in the cornea and conjunctiva secondary to long-term clofazimine therapy in a leprosy patient. PMID- 21666329 TI - Endogenous endophthalmitis caused by bacteria with unusual morphology in direct microscopic examination of the vitreous. PMID- 21666330 TI - When Goldmann applanation tonometry is not reliable in post Lasik situations. PMID- 21666331 TI - Financing eye care in India - community-assisted and financed eye care project (CAFE). PMID- 21666332 TI - Eye donation: mere awareness and willingness not enough. Only a catalyst can improve corneal harvesting rates. PMID- 21666333 TI - Iris stromal cyst with cataract managed by cyst aspiration and diode laser photocoagulation in a child. PMID- 21666334 TI - Pharmacotherapeutic closure of a uveitic macular hole persisting after vitrectomy. PMID- 21666335 TI - Unilateral, indirect spontaneous caroticocavernous fistula with bilateral abduction palsy. PMID- 21666336 TI - Comments on: clinical profile of cerebral venous sinus thrombosis and role of imaging in its diagnosis in patients with presumed idiopathic intracranial hypertension. PMID- 21666337 TI - Intravitreal bevacizumab for subfoveal choroidal neovascularization complicating active central serous chorioretinopathy. PMID- 21666338 TI - Profiles of atherosclerotic risk factors in gastrectomized men. AB - Postprandial hyperglycemia is an established risk factor for atherosclerotic vascular diseases, and it is frequently observed in gastrectomized subjects. This study sought to examine whether other atherosclerotic risk factors are also common among gastrectomized subjects. The study population comprised of 44 non diabetic men who previously underwent gastrectomy. The age- and body mass index matched control population comprised of 278 non-diabetic men without gastrectomy. In addition to traditional atherosclerotic risk factors for atherosclerosis, high sensitivity C-reactive protein (hsCRP) and brachial-ankle pulse wave velocity (baPWV) were also compared between the groups. Fasting plasma glucose was not different between both groups, while glycated hemoglobin (HbA1c) was significantly higher in the gastrectomized men than in the control men. Systolic and diastolic blood pressures and high density lipoprotein cholesterol (HDL-C) were significantly higher, whereas low density lipoprotein cholesterol (LDL-C) was lower in the gastrectomized men than in the control men. baPWV, hsCRP, triglycerides and insulin resistance (as per the homeostasis model assessment) were not different between groups. While levels of certain atherosclerotic risk factors, including HbA1c and blood pressure are higher among gastrectomized men, HDL-C and LDL-C were actually favorable. Additionally, levels of more emerging risk factors, such as hsCRP and baPWV were not altered among gastrectomized men. PMID- 21666339 TI - Recurrent autoimmune hypophysitis successfully treated with glucocorticoids plus azathioprine: a report of three cases. AB - Recurrent autoimmune hypophysitis is a rare autoimmune endocrine disease involving lymphocytic infiltration and chronic pituitary inflammation. It is even more rare than primary hypophysitis. The objective of the study was to evaluate the efficacy of glucocorticoid treatment combined with azathioprine for treating three cases of recurrent autoimmune lymphocytic hypophysitis encountered within a two-year period. The clinical features and follow-up data of these cases were analyzed, including results of treatment with glucocorticoids combined with azathioprine. All three patients were female and presented with the following clinical characteristics: case 1 was a 22-year-old with headache and diplopia; case 2 was a 70-year-old with dry mouth, polydipsia, and polyuria; case 3, a 32 year-old, with polydipsia, polyuria and menstrual disorders with headache and dizziness. Regarding recurrence, case 1 recurred 4 months after surgery and again 14 months after discontinuing prednisone; case 2 relapsed 16 months after receiving high-dose methylprednisolone pulse therapy; and case 3 recurred during the period of prednisone dose reduction. The patients were treated with glucocorticoids plus azathioprine, and positive responses were seen in all three cases. Symptoms were relieved, and MRI revealed significant reduction of lesions during follow-up. Pituitary function resumed in cases 1 and 3; permanent hypopituitarism was present in case 2. At last follow-up, MRI showed no further recurrence of disease in any patient. Treatment and responses of these patients with autoimmune hypophysitis suggest that glucocorticoid therapy combined with azothioprine is effective treatment for recurrent autoimmune hypophysitis. Endocrine and radiologic studies are an essential part of follow-up. PMID- 21666340 TI - [Lipid metabolism in the central nervous system and neurodegenerative diseases]. PMID- 21666341 TI - [How to determine the absolute purities of target organic compounds-development of quantitative NMR (qNMR)]. PMID- 21666342 TI - [New findings about plasma biomarkers from the research for biomarkers in ischemic stroke. Reverse translational research using multiple clinical biomarkers]. PMID- 21666343 TI - [Molecular target therapeutics of cancer and translational research]. PMID- 21666344 TI - [Pharmacological properties of paliperidone ER (INVEGA((r))) and results of its clinical studies]. PMID- 21666345 TI - Elucidation of the molecular mechanism and exploration of novel therapeutics for spinocerebellar ataxia caused by mutant protein kinase Cgamma. AB - Spinocerebellar ataxia (SCA) is an inherited neurodegenerative disorder that is characterized by cerebellar atrophy and progressive ataxia and is classified into 31 types by the genetic locus. Recently, missense mutations of PRKCG genes that code protein kinase Cgamma (gammaPKC) have been identified as a causal gene of SCA14. To explore the molecular mechanism of SCA14 pathogenesis, we investigated how mutant gammaPKC causes the neurodegeneration of cerebellar Purkinje cells (PCs) by expressing mutant gammaPKC-GFP in cell lines and primary cultured PCs. Mutant gammaPKC was susceptible to aggregation in the cytoplasm, which led to an impairment of the ubiquitin-proteasome system and apoptosis. Furthermore, mutant gammaPKC induced improper dendritic development of cultured PCs in an aggregation independent manner. Stimulation-induced translocation of mutant gammaPKC in PC dendrites was prominently attenuated by the reduced mobility of oligomerized mutant gammaPKC, which resulted in attenuated signal transduction and the improper morphology of PC dendrites. These findings suggested that the oligomerization and aggregation of mutant gammaPKC caused improper dendritic development and apoptosis of PCs, which led to cerebellar dysfunction and SCA14 pathogenesis. We screened the chemicals that improved these cellular dysfunctions and identified several compounds, including trehalose and Congo red, which could be novel therapeutics for SCA14. PMID- 21666346 TI - Possible involvement of glutamatergic signaling machineries in pathophysiology of rheumatoid arthritis. AB - The prevailing view is that L-glutamate (Glu) functions as an excitatory amino acid neurotransmitter through a number of molecular machineries required for the neurocrine signaling at synapses in the brain. These include Glu receptors for signal input, Glu transporters for signal termination, and vesicular Glu transporters for signal output through exocytotic release. Although relatively little attention has been paid to the functional expression of these molecules required for glutamatergic signaling in peripheral tissues, recent molecular biological analyses including ours give rise to a novel function for Glu as an extracellular signal mediator in the autocrine and/or paracrine system in several peripheral and non-neuronal tissues, including bone and cartilage. In particular, a drastic increase is demonstrated in the endogenous levels of both Glu and aspartate in the synovial fluid with intimate relevance to increased edema and sensitization to thermal hyperalgesia in experimental arthritis models. However, to date, there is only limited information about the physiological and pathological significance of glutamatergic signaling machineries expressed by articular synovial tissues. In this review, we have outlined the role of Glu in synovial fibroblasts in addition to the possible involvement of glutamatergic signaling machineries in the pathogenesis of joint diseases such as rheumatoid arthritis. PMID- 21666347 TI - The Dnmt3b splice variant is specifically expressed in in vitro-manipulated blastocysts and their derivative ES cells. AB - Manipulation of preimplantation embryos in vitro, such as in vitro fertilization (IVF), in vitro culture (IVC), intracytoplasmic sperm injection (ICSI), somatic cell nuclear transfer (SCNT) and other assisted reproduction technologies (ART), has contributed to the development of infertility treatment and new animal reproduction methods. However, such embryos often exhibit abnormal DNA methylation patterns in imprinted genes and centromeric satellite repeats. These DNA methylation patterns are established and maintained by three DNA methyltransferases: Dnmt1, Dnmt3a and Dnmt3b. Dnmt3b is responsible for the creation of methylation patterns during the early stage of embryogenesis and consists of many alternative splice variants that affect methylation activity; nevertheless, the roles of these variants have not yet been identified. In this study, we found an alternatively spliced variant of Dnmt3b lacking exon 6 (Dnmt3bDelta6) that is specific to mouse IVC embryos. Dnmt3bDelta6 also showed prominent expression in embryonic stem (ES) cells derived from in vitro manipulated embryos. Interestingly, IVC blastocysts were hypomethylated in centromeric satellite repeat regions that could be susceptible to methylation by Dnmt3b. In vitro methylation activity assays showed that Dnmt3bDelta6 had lower activity than normal Dnmt3b. Our findings suggest that Dnmt3bDelta6 could induce a hypomethylation status especially in in vitro manipulated embryos. PMID- 21666349 TI - [The health of permanent workers and workers with precarious employment: a literature review]. AB - OBJECTIVES: The purpose of this study was to review research articles about the health of workers with precarious employment (precarious workers). METHODS: Articles that compared the health status between permanent and precarious workers were systematically searched. The collected articles are discussed with respect to their study design, data source, sample size, country, health outcome, definition of precarious employment, and primary findings. RESULTS: Sixty-eight articles were identified by the inclusion criteria. Health outcomes were categorized into four types: occupational injuries, physical health, mental health, and alternative health measurements. Precarious employment was associated with a high prevalence of occupational injuries, higher mortality rate, and inferior degree of mental health. For alternative health measures, access to health services were limited among precarious workers. Sickness absence or leave was taken less often by precarious workers than permanent workers. CONCLUSIONS: Unstable employment and the limited welfare of precarious workers might affect their health in relation to a variety of health-related characteristics while several studies concluded that permanent workers had an inferior health status. Therefore, the current social climate, which allows precarious employment with low benefits and diverse work contracts, might be detrimental for workers' health, in general. PMID- 21666352 TI - Development of a microfluidic device for measurement of distribution behavior between supercritical carbon dioxide and water. AB - A measuring method for the distribution behavior between supercritical carbon dioxide and water by a microchip was developed. A surface modification of the microchannel by dichlorodimethylsilane induced a spontaneous phase separation of the supercritical carbon dioxide and aqueous phases in the microchip. The maximum contact time of the aqueous phase to the supercritical carbon dioxide phase was obtained as 0.58 s. This device withstood pressure up to 12.8 MPa. The distribution of tris(acetylacetonato)cobalt(III) (Co(acac)(3)) from the supercritical carbon dioxide phase to the aqueous phase in a microchannel could be measured. The concentration of Co(acac)(3) distributed into the aqueous phase was increased by lengthening the contact time of both phases. These demonstrations showed that the method developed in this study could be used to measure the distribution behavior between supercritical carbon dioxide and water. PMID- 21666350 TI - Aberrant expression of hypoxia-inducible factor 1alpha in the fetal heart is associated with maternal undernutrition. AB - Maternal undernutrition during pregnancy is a risk factor that impairs fetal growth and causes cardiovascular diseases. However, the underlying mechanism is still unknown. In this study, we evaluated the effect of maternal undernutrition on the expression levels of transcription factors in the fetal heart. Female mice were given low protein or regular food from 2 weeks before mating and during their pregnancy. The fetal hearts were collected on day 17.5 of gestation, about 1-2 days before birth. Maternal undernutrition resulted in a significant increase in the relative heart weight (heart weight/body weight) in female fetuses, but not in male fetuses. Microarray analysis revealed that expression levels of mRNAs for 133 transcription factors were changed in the fetal heart under maternal undernutrition. Among them, we focused on hypoxia-inducible factor 1 alpha (HIF1alpha) that is involved in the pathogenesis of cardiovascular diseases on adulthood. Quantitative real-time PCR analysis showed that the expression level of HIF1alpha mRNA was increased about 1.3-fold in male fetal heart under maternal undernutrition, but remained unchanged in female heart. Moreover, maternal undernutrition increased the mRNA level of prolyl hydroxylase 1 (PHD1), which contributes to degradation of HIF1alpha, in male heart but not in female heart. Immunohistochemical analysis showed the accumulation of HIF1alpha protein in the fetal heart of both sexes under maternal undernutrition, without the induction of HIF1alpha mRNA expression in female heart. These results suggest that maternal undernutrition may induce HIF1alpha expression in the fetal heart through the distinct mechanisms depending on the sex. PMID- 21666348 TI - Relationships of survival time, productivity and cause of death with telomere lengths of cows produced by somatic cell nuclear transfer. AB - The reproductive ability, milk-producing capacity, survival time and relationships of these parameters with telomere length were investigated in 4 groups of cows produced by somatic cell nuclear transfer (SCNT). Each group was produced using the same donor cells (6 Holstein (1H), 3 Holstein (2H), 4 Jersey (1J) and 5 Japanese Black (1B) cows). As controls, 47 Holstein cows produced by artificial insemination were used. The SCNT cows were artificially inseminated, and multiple deliveries were performed after successive rounds of breeding and conception. No correlation was observed between the telomere length and survival time in the SCNT cows. Causes of death of SCNT cows included accidents, accident associated infections, inappropriate management, acute mastitis and hypocalcemia. The lifetime productivity of SCNT cows was superior to those of the controls and cell donor cows. All SCNT beef cows with a relatively light burden of lactation remained alive and showed significantly prolonged survival time compared with the cows in the SCNT dairy breeds. These results suggest that the lifetime productivity of SCNT cows was favorable, and their survival time was more strongly influenced by environmental burdens, such as pregnancy, delivery, lactation and feeding management, than by the telomere length. PMID- 21666353 TI - LC-MS/MS analysis of diarrhetic shellfish poisoning (DSP) toxins, okadaic acid and dinophysistoxin analogues, and other lipophilic toxins. AB - Diarrhetic shellfish poisoning (DSP) is a severe gastrointestinal illness caused by consumption of shellfish contaminated with DSP toxins that are originally produced by toxic dinoflagellates. Based on their structures, DSP toxins were initially classified into three groups, okadaic acid (OA)/dinophysistoxin (DTX) analogues, pectenotoxins (PTXs), and yessotoxins (YTXs). Because PTXs and YTXs have been subsequently shown to have no diarrhetic activities, PTXs and YTXs have recently been eliminated from the definition of DSP toxins. Mouse bioassay (MBA), which is the official testing method of DSP in Japan and many countries, also detects PTXs and YTXs, and thus alternative testing methods detecting only OA/DTX analogues are required in DSP monitoring. Electrospray ionization (ESI) liquid chromatography-mass spectrometry (LC-MS) is a very powerful tool for the detection, identification and quantification of DSP and other lipophilic toxins. In the present review, application of ESI LC-MS techniques to the analysis of each toxin group is described. PMID- 21666354 TI - DNA analysis based on the local structural disruption to the duplexes carrying a luminous lanthanide complex. AB - The two DNA conjugates (split probes) carrying a metal chelator form an integrated luminous lanthanide (Ln(3+): Tb(3+) or Eu(3+)) complex on the complementary template DNA (target). The luminous property of this Ln(3+) complex has been used for DNA assay. The intensity of the luminescence was affected by the local structural disruption caused by one-base mispairing around the complex. Among the mispairings systematically introduced around the Ln(3+) center, vicinal mispairings to the center decreased the emission intensity more. This would be a novel nucleobase-discriminating principle, in which the split probes bind the target tightly, yet still retain sequence selectivity. PMID- 21666355 TI - Trypsin-stabilized fluorescent gold nanocluster for sensitive and selective Hg2+ detection. AB - We report on trypsin-stabilized fluorescent gold nanoclusters (Au NCs) for the sensitive and selective detection of Hg(2+) ions. The Au NCs have an average size of 1 nm and show a red emission at 645 nm. The photostable properties of the trypsin-stabilized Au NCs were examined, and their photochemical stability was found to be similar to that of CdSe quantum dots. The fluorescence was particularly quenched by Hg(2+), and therefore the Au NCs can be used as fluorescent sensors for sensitive and selective Hg(2+) detection to a detection limit of 50 +/- 10 nM and the quantitative detection of Hg(2+) in wide and low concentration range of 50-600 nM. PMID- 21666356 TI - Adsorption and desorption dynamics of sodium dodecyl sulfate at the octadecylsilane layer on the pore surface of a mesoporous silica film observed in situ by optical waveguide spectroscopy. AB - The purpose of this study is to apply optical waveguide (OWG) spectroscopy to observe adsorption and desorption dynamics occurring in a surfactant-templated mesoporous silica film. For that purpose, a mesoporous silica (MS) film with open accessible pores (pore diameter, ca. 6 nm) was formed on an aluminum (Al) layer deposited on a glass substrate, and the pore surface of the MS film was modified with octadecylsilane (ODS). The resulting ODS-modified MS (ODS-MS) and Al multilayer film showed a clear waveguide coupling dip in the reflection spectrum. The position of the waveguide coupling dip was red-shifted as the amount of sodium dodecyl sulfate within the ODS-MS layer increases. These results indicate the usefulness of OWG spectroscopy for the study of adsorption/desorption dynamics occurring in MS materials. PMID- 21666357 TI - Carbon-felt-based bioelectrocatalytic flow-detectors: role of ultrasound irradiation during the adsorption of horseradish peroxidase and thionine for a highly sensitive amperometric determination of H2O2. AB - This study reports on the first example, to our knowledge, of the usefulness of an ultrasound (US)-irradiation during an enzyme adsorption step, for enhancing the performance of a redox-enzyme-based amperometric biosensor. Horseradish peroxidase (HRP) and thionine (Th) were coadsorbed from a mixed aqueous solution of HRP and Th onto a carbon-felt (CF) under US-irradiation for 5 min with an ultransonic bath operating at 40 kHz frequency and 55 W of electric power output. The resulting HRP and Th-coadsorbed CF (HRP/Th-CF) was successfully used as a working electrode unit of a bioelectrocatalytic flow-detector for hydrogen peroxide (H(2)O(2)), which detects the cathodic peak currents based on the direct (unmediated) reduction of oxidized HRP intermediates at 0 V vs. Ag/AgCl. Compared with ordinary adsorption without US-irradiation, US-irradiation during the HRP adsorption step was effective to obtain highly sensitive peak current responses to H(2)O(2). The measurements of electrochemical impedance spectroscopy and cyclic voltammetry suggested that the adsorption of HRP and Th under the US irradiation provides a suitable interfacial microenvironment for a favorable orientation and conformation of an enzyme with active site available for both substrates and the electrode, which results in larger bioelectrocatalytic activity. The peak currents for H(2)O(2) increased up to 3 * 10(-6) M (sensitivity, 4.72 uA/uM) with a lower detection limit of 2 * 10(-8) M (S/N = 3; current noise level, 0.03 uA). PMID- 21666358 TI - Direct electrochemistry and electrocatalytic behavior of horseradish peroxidase on attapulgite clay modified electrode. AB - A novel third-generation hydrogen peroxide (H(2)O(2)) biosensor was developed by immobilizing horseradish peroxidase (HRP) on a biocompatible attapulgite (ATP) modified glassy carbon (GC) electrode. The ATP could provide a biocompatible microenvironment for enzyme molecules, greatly amplify the coverage of HRP molecules on the electrode surface, and most importantly facilitate the direct electron transfer between HRP and the electrode. The biosensor construction process was followed by atomic force microscopy (AFM). Cyclic voltammetry was employed to characterize the properties of the biosensor. A linear calibration plot of the enzyme electrode was obtained over the range of 5 uM to 0.3 mM for H(2)O(2) with a detection limit of 5 uM. Furthermore, the biosensor showed high sensitivity, good reproducibility, and fine long-term stability. PMID- 21666359 TI - Polychlorinated aromatic hydrocarbons in a soil sample measured using gas chromatography/multiphoton ionization/time-of-flight mass spectrometry. AB - Gas chromatography/multiphoton ionization/time-of-flight mass spectrometry (GC/MPI/TOF-MS) was applied to a soil sample to survey several groups of polychlorinated aromatic hydrocarbons (polychlorinated dibenzo-p dioxins/dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), polychlorinated naphthalenes (PCNs), polychlorinated diphenylethers (PCDEs), and polychlorinated terphenyls (PCTs)). The signal peaks in the two-dimensional display of GC/MS could be easily and accurately assigned from the intensity distribution of the isotope peaks, even in the presence of numerous interfering species. Using this technology, mutual interferences between organochlorine compounds can be readily recognized from the data of the two-dimensional display after a measurement, although the separation of these compounds is sometimes difficult using high-resolution magnetic-sector-type mass spectrometry. This approach, based on MPI, results in less fragmentation, and is useful for the identification of analytes. Thus, GC/MPI/TOF-MS allows for the simultaneous determination of PCDD/Fs and related compounds in real samples containing numerous interfering species. PMID- 21666360 TI - Quantitative analysis for a color-change of humidity indicator by microscopic absorption spectrometry. AB - A sensitive and easily distinguishable cobalt-free humidity indicator of porphyrin-silica gel-MgCl(2) composite was prepared from pH-induced spectra changeable tetraarylporphyrin, silica gel (SiO(2)), and MgCl(2). The pH change arose from proton release under dry conditions, and proton capture under humid conditions by a reversible reaction between MgCl(2) and a silanol group of SiO(2). A pink-orange porphyrin-Si(OH)(2)-MgCl(2) composite was dried to give a green protonated porphyrin-SiO(2)Mg composite. The optimized concentrations of MgCl(2) to make the concentrations of protonated porphyrin maximum under dry conditions were determined by absorption spectrometry of the green composite using a confocal laser scanning microscope as a microscopic spectrometer. Moreover, the green composite was prepared by heating dichloro(tetraarylporphyrinato)phosphorus chloride with MgCl(2) and SiO(2). The humidity-sensitivity of the green composite was evaluated by the absorption spectra under controlled humidity. A distinguishable color change of the green composite took place below 30% of relative humidity. PMID- 21666361 TI - Development of a multi-mycotoxin analysis in beer-based drinks by a modified QuEChERS method and ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. AB - An analytical method was developed for the identification and quantification of 15 mycotoxins (patulin, nivalenol, deoxynivalenol, aflatoxin B(1), B(2), G(1), G(2), M(1), T-2 toxin, HT-2 toxin, zearalenone, fumonisin B(1), B(2), B(3), and ochratoxin A) in beer-based drinks (beer, low-malt beer, new genre, and nonalcoholic) by a modified QuEChERS method and an ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC/MS/MS). Mycotoxins were extracted from samples using acetonitrile with sodium chloride, anhydrous magnesium sulfate, and sodium citrate, and were then purified with a solid phase extraction (SPE) cartridge including C18. The UHPLC conditions were also examined to establish its optimal conditions for separation. Fifteen mycotoxins were separated in a total of 6.5 min, and were quantified in the optimal mobile phase conditions. Determinations performed using this method produced high correlation coefficients of 15 mycotoxins (R>0.99) and recovery rates ranging from 70.3 to 110.7% with good repeatability (relative standard deviation RSD<14.6%). Further, 24 commercial beer-based drinks in Japan were analyzed using this method, and nivalenol, deoxynivalenol, and fumonisins were detected in several samples, but always under the limit of quantification (<5 ng/mL). These results suggest that the health risk to consumers from beer-based drinks in Japan is relatively low. PMID- 21666362 TI - Rapid determination of mercury species in sewage sludge by high-performance liquid chromatography on-line coupled with cold-vapor atomic-fluorescence spectrometry after ultrasound-assisted extraction. AB - So far, no research has been focused on the determination of organomercuries in sewage sludge. Here, an ultrasonic extraction method for the rapid determination of methylmercury (MeHg) and ethylmercury (EtHg) in sewage sludge after ultrasound assisted extraction is proposed. Using TMA (tetramethylammonium hydroxide) as the extractant with 3.0 g copper powder, ultrasonic extraction for 30 min at 70 degrees C demonstrated to be highly efficient, and was shown a satisfied extraction efficiency for MeHg and EtHg from sewage sludge samples. Determination of mercury species was carried out by high-performance liquid chromatography on line coupled with cold-vapor atomic fluorescence spectrometry (HPLC-CV-AFS). The obtained results from quality control samples were excellent. The proposed method was also validated by the application to five real samples. The results showed that the developed methodology was practicable and highly reliable. Due to the high toxicity of organomercuries and huge amounts of sewage sludge discharged every year, people should pay particular attention to pollutions from sewage sludge. PMID- 21666363 TI - A novel fluorescent probe for copper ions based on polymer-modified CdSe/CdS core/shell quantum dots. AB - Quantum dots (QDs) have become one of the most attractive fields of current research because of their unique optical properties. Novel copper-sensitive fluorescent fluoroionophores based on CdSe/CdS core/shell QDs modified with a polymer of MAO-mPEG were synthesized and characterized in the present work. A pH of 6.47 was optimally selected for measurements. By modifying QDs with MAO-mPEG, significant aqueous fluorescence quenching was observed upon binding with copper ions involving both reduced and oxidized environments, indicating great sensitivity and specificity for copper-ion sensing. No significant interfering effects from other metal ions, such as Ag(+), Al(3+), Ba(2+), Ca(2+), Cd(2+), Co(2+), Cr(3+), Fe(2+), Fe(3+), Hg(2+), K(+), Mg(2+), Mn(2+), Na(+), Ni(2+), Pb(2+), Sn(2+), and Zn(2+), were observed. The linear response range for Cu(2+) was found to be 0.01-0.50 uM, and the limit of detection was evaluated to be 16 nM. The proposed method demonstrated improved sensitivity and selectivity characteristics for Cu(II) determinations based on CdSe/CdS core/shell QDs modified with MAO-mPEG by using a typical liquid-phase quenching assay, showing its potential application to multiplex sensing of different analytes through distinct ligand conjugation and functionalization of individual fluorophores. PMID- 21666364 TI - Oxidation of chromium(III) by free chlorine in tap water during the chlorination process studied by an improved solid-phase spectrometry. AB - The oxidation of Cr(III) at naturally-occurring concentration levels, i.e., ug dm(-3) or lower levels, by free chlorine during the chlorination process of tap water was studied using an improved solid-phase spectrophotometric method, which can be directly applicable to the specific determination of Cr(VI) at ug dm(-3) or lower levels. The effect of the pH on the oxidation kinetics was investigated under three different pH conditions. The results showed that free chlorine oxidized the Cr(III) to Cr(VI), following the pseudo-first-order kinetics with half lifetimes of 3.0, 3.3 and 14.4 h at pH 5.0, 7.0 and 8.0, respectively, if the hypochlorite concentration was maintained at 4 mg Cl dm(-3). PMID- 21666365 TI - Solid-phase extraction of cobalt(II) from lithium chloride solutions using a poly(vinyl chloride)-based polymer inclusion membrane with Aliquat 336 as the carrier. AB - The extraction of cobalt(II) from solutions containing various concentrations of lithium chloride, hydrochloric acid, and mixtures of lithium chloride plus hydrochloric acid is reported using a poly(vinyl chloride) (PVC)-based polymer inclusion membrane (PIM) containing 40% (w/w) Aliquat 336 as a carrier. The extraction from lithium chloride solutions and mixtures with hydrochloric acid is shown to be more effective than extraction from hydrochloric acid solutions alone. The solution concentrations giving the highest amounts of extraction are 7 mol L(-1) for lithium chloride and 8 mol L(-1) lithium chloride plus 1 mol L(-1) hydrochloric acid for mixed solutions. Cobalt(II) is easily stripped from the membrane using deionized water. The cobalt(II) species extracted into the membrane are CoCl(4)(2-) for lithium chloride solutions and HCoCl(4)(-) for mixed solutions; these form ion-pairs with Aliquat 336. It is also shown that both lithium chloride and hydrochloric acid are extracted by the PIM and suppress the extraction of cobalt(II) by forming ion-pairs in the membrane (i.e. R(3)MeN(+).HCl(2)(-) for hydrochloric acid and R(3)MeN(+).LiCl(2)(-) for lithium chloride). PMID- 21666366 TI - Determination of trace aluminum by fluorescence quenching with m carboxyphenylfluorone as analytical reagent. AB - An improved method for the fluorophotometric determination of trace Al(III) has been developed. This method involves a fluorescence quenching reaction that results in the formation of an m-carboxyphenylfluorone-Al(III) complex in a poly(N-vinylpyrrolidone) micellar medium. The calibration curve was found to be linear in the range of 0.03-1.50 ug dm(-3). We successfully applied the proposed method to an assay of Al(III) in canned beverages, which required only sample dilution and no sample pretreatment. The proposed method is expected to determine Al(III) in a simple and rapid manner. PMID- 21666367 TI - Simultaneous determination of dextromethorphan and its metabolite dextrorphan in plasma samples using second-order calibration coupled with excitation-emission matrix fluorescence. AB - Dextromethorphan (DEX) is an antitussive agent used in many cough and cold medications, and dextrorphan (DOR) is its metabolite. Owing to their similar structures, optimization of the condition for the chromatography approach, which is in common use for determination, is both demanding and time-consuming. This paper describes a methodology that combines excitation-emission matrix fluorescence spectra with second-order calibration, and was applied to simultaneously and directly determine DEX and DOR contents in plasma samples. PMID- 21666368 TI - Diagnostic strategy in ischemic heart disease at the era of multimodality cardiac imaging. PMID- 21666369 TI - Non-invasive diagnostic workup of patients with suspected stable angina by combined computed tomography coronary angiography and magnetic resonance perfusion imaging. AB - BACKGROUND: To evaluate additional adenosine magnetic resonance perfusion (MRP) imaging in the diagnostic workup of patients with suspected stable angina with computed tomography coronary angiography (CTCA) as first-line diagnostic modality. METHODS AND RESULTS: Two hundred and thirty symptomatic patients (male, 52%; age, 56 year) with suspected stable angina underwent CTCA. In patients with a stenosis of >50% as visually assessed, MRP was performed and the quantitative myocardial perfusion reserve index (MPRI) was calculated. Coronary flow reserve (CFR) using invasive coronary flow measurements served as the standard of reference. CTCA showed non-significant CAD in 151/230 (66%) patients and significant CAD in 79/230 patients (34%), of whom 50 subsequently underwent MRP and CFR. MRP showed reduced perfusion in 32 patients (64%), which was confirmed by CFR in 27 (84%). All 18 cases of normal MRP (36%) were confirmed by CFR. The positive likelihood ratio of MRP for the presence of functional significant disease in patients with a lesion on CTCA was 4.49 (95% confidence interval [CI] 2.12-9.99). The negative likelihood ratio was 0.05 (95%CI 0.01-0.34). CONCLUSIONS: CTCA as first-line diagnostic modality excluded coronary artery disease in a high percentage of patients referred for diagnostic workup of suspected stable angina. MRP made a significant contribution to the detection of functional significant lesions in patients with a positive CTCA. PMID- 21666370 TI - Antithrombotic therapy in atrial fibrillation: evaluation and positioning of new oral anticoagulant agents. AB - Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for stroke. For more than 60 years, warfarin has been the only approved anticoagulant for prevention of stroke in patients with AF. Although highly effective, it has many limitations that make its use difficult. Therefore, several novel anticoagulants are under development to overcome the limitations of warfarin, and some of these have entered phase III clinical trials. Dabigatran is an oral, reversible direct thrombin inhibitor approved in Europe and in several other countries for the prevention of venous thromboembolism after elective knee and hip replacement surgery. It has also been approved in the United States and Japan for the prevention of stroke and systemic embolism in patients with nonvalvular AF. In this review, the mechanism of action and pharmacological properties of new anticoagulants are described in detail, and the correct use of dabigatran in clinical practice is discussed. PMID- 21666371 TI - [Dose evaluation in mammography for Japanese breast thickness]. AB - Accuracy control of mammography equipment involves more than just equipment management; the proportions of the mammary glands used to obtain appropriate images is also important, as is control of the glandular X-ray dose in accordance with thickness. Methods for evaluating glandular dose include the ACR, EUREF, and IAEA protocols. The aim of this study was to elucidate the differences between the various protocols and to suggest a dose evaluation method suited to Japanese breast thickness. An ionization chamber dosimeter was used for dose measurement, with a 156 phantom used as a breast phantom for the ACR and a PMMA phantom used for the EUREF and IAEA. There were no major differences in the protocols. The AGDs in the breast phantoms recommended HVLs for each protocol but were 25-30% higher in the EUREF and IAEA compared with the ACR, owing to the different breast thicknesses in each case. The IAEA should be regarded as the basic method for implementing optimum accuracy control in Japan, and a 35-mm PMMA should be used to correspond most closely to Japanese breast thickness. PMID- 21666372 TI - [T2 and T1rho values of the knee joint cartilage]. AB - Measurement of T(2) and T(1)rho relaxation time is a quantitative evaluation technique that uses magnetic resonance imaging. This study aimed to evaluate T(2) and T(1)rho relaxation time considering the load on the knee. 14 healthy volunteers were studied at 3 T. Four main compartments were defined for cartilage analysis in the knee joint: lateral femoral condyle (LFC), medial femoral condyle (MFC), and lateral and medial tibia (LT and MT). Femur cartilage was partitioned into anterior, middle, and posterior nonweight-bearing (a-NWB, m-NWB, p-NWB) portions and weight-bearing (WB) portions. T(2) and T(1)rho values between the medial side and lateral side indicated a nonsignificant difference. T(2) and T(1)rho values of NWB portions were higher than those of WB portions. The measured value rate of extension of NWB to WB was more remarkable in the T(1)rho value than in the T(2) value. Therefore, evaluating cartilaginous injuries and damages using the T(1)rho value seems to more effectively describe them. PMID- 21666373 TI - [Impact of multileaf collimator leaf positioning accuracy on intensity modulated radiation therapy]. AB - In multileaf collimator (MLC)-based intensity modulated radiation therapy (IMRT), the dose is influenced by the uncertainty of MLC driving control. In this study, we examined the influence of MLC driving control accuracy on dose evaluation (gamma analysis) by evaluating 60-day MLC driving control accuracy (stationary positioning accuracy and positioning reproducibility) once a week as well as measuring IMRT dose distribution. The MLC positioning accuracy accompanied variation over time and tended to expand by 0.1 to 0.15 mm in one week and about 1 mm in 60 days. In terms of reproducibility, errors were within 0.2 mm for more than 95%. For prostate IMRT, when MLC stationary positioning accuracy was around 1 mm, no significant difference was observed in the pass rate in gamma analysis. Therefore, the results suggest that regular maintenance by setting a permissible value determined by the MLC positioning accuracy test can be an effective indicator in the future for maintaining the safety of IMRT. PMID- 21666374 TI - [Development of software for estimating exposure dose and radiation exposure region in cardiac catheterization inspection]. AB - We developed software for estimating exposure doses and radiation exposure regions in cardiac catheterization inspection. In the software, the back of a thoracic phantom were divided into a total of 21 square blocks with a width of 30 degrees. Furthermore, we developed a system with which reference air kerma is distributed to each of the above blocks in accordance with the distribution ratio calculated from the data obtained by the system, and the calculation results are displayed. Coronary angiography was performed using thoracic phantoms, and actual measurements were obtained using a fluoroglass dosimeter. The calculated results obtained using the software were compared to the measured results. An almost identical tendency was seen, and the radiation regions of the top three estimated exposure doses were successfully estimated. Radiation region estimation using this software is affected by exposure time as one of its properties. This software enables estimating radiation exposure regions and exposure doses. PMID- 21666375 TI - [Study of collimator broad correction in myocardial perfusion imaging]. AB - The purpose of this study was to evaluate the effect of myocardial perfusion imaging that is reconstructed using the ordered subsets-expectation maximization (OS-EM) method with collimator broad correction. METHODS: A cardiac phantom and clinical data (with ten normal patients) were used. These projection data were reconstructed using OS-EM with collimator broad correction (OS-EM(+)), without collimator broad correction (OS-EM(-)), and with filtered back projection (FBP). We analyzed the reconstructed images using the following: FWHM of reoriented short-axis data, volume calculated using QGS software, and a polar map calculated using QPS software. RESULTS AND CONCLUSION: On the important point of spatial resolution, OS-EM(+) was excellent compared with FBP. However, a difference in % uptake was seen in one segment. Therefore, when a quantitative myocardial SPECT evaluation is done, the treatment of the numerical value needs to be noted. PMID- 21666376 TI - [Evaluation of shortened protocol of graph plot method with 123I-IMP]. AB - The (123)I-IMP Graph Plot is a convenient method of analyzing cerebral blood flow without blood sampling. Data acquisition requires 45 minutes after the infusion of (123)I-IMP because the method is matched to the protocol of autoradiography (conventional method). However, we think that those protocols do not have to be matched because those theories are different. Therefore, we contrived a protocol for shortening that time by beginning SPECT data acquisition earlier and shortening the acquisition time compared to the conventional method. We compared count ratios of the decreased area to an area of the healthy side, quantitative values, and results of statistical analysis of the shortened protocol and the conventional method for cases of cerebral infarction and of dementia with Lewy bodies (DLB). Some count ratios of the shortened protocol were inferior to those of the conventional method, but the degrees did not affect the clinical diagnosis. In the other areas and cases also, the differences did not affect the clinical diagnosis. In addition to the results of this study, some previous reports have described that early SPECT images after infusion show the true cerebral blood flow. Therefore, we judged that this shortened protocol can be used as a clinical protocol. PMID- 21666377 TI - [Evaluation of several commercial attenuation correction software programs installed by vendors for data processing: a simulation phantom study]. AB - PURPOSE: An attenuation correction is necessary to improve quantitative SPECT evaluation. The aim of this study was to evaluate the performance of several different types of commercial attenuation correction algorithms. METHODS: We investigated the performance of four attenuation correction algorithms using a simulation phantom with and without scatter. The attenuation correction was performed on clinical SPECT workstations: GMS5500/PI (Toshiba), GMS7700/A (Toshiba), e.soft (Siemens), and Xeleris (GE). Then, the effect of the attenuation correction was evaluated using the count profile curve and attenuation coefficient that maintained uniformity of the radioisotope distribution in the uniform region of the images. RESULTS: In the without-scatter condition, the count profile curve showed a similar shape on all workstations. The attenuation coefficients that maintained uniformity were 0.134, 0.133, 0.133, and 0.135 cm(-1) using GMS5500/PI, GMS7700/A, e.soft, and Xeleris, respectively. There was no significant difference among these workstations. With scatter, the attenuation coefficients differed by 0.109-0.121 cm(-1) with the types of attenuation correction algorithms. CONCLUSION: Without scatter, the effects of the attenuation corrections were equivalent. However, with scatter, a few differences were observed in the effects of correction with several types of algorithms. Therefore, our results suggest that careful evaluation should be considered when different types of clinical SPECT workstations are used. PMID- 21666379 TI - [Symposium 3: Knowledge and technology for performance of coronary CT angiography]. PMID- 21666378 TI - [Survey on medical information education for radiologic technologists working at hospitals]. AB - Recently, the importance of medical information for radiologic technologists has increased. The purpose of this questionnaire survey was to clarify the method of acquiring skill in medical information for radiologic technologists from the point of view of the managers of radiology departments. The questionnaire was sent to 260 hospitals that had introduced picture archiving and communication systems (PACSs) for the person responsible for medical information in the radiology department. The response rate was 35.4% (92 hospitals). The results of this survey clarified that few hospital have staff for medical information in the radiology department. Nevertheless, the excellent staff who have the skills to troubleshoot and develop systems are earnestly needed in radiology departments. To solve this problem, many technologists should understand the content, work load, and necessity of medical information. In addition, cooperation between radiologic technologist schools and hospitals is important in the field of medical information education. PMID- 21666380 TI - [Definition of medical safety method to attain the medical safety for everybody]. PMID- 21666381 TI - [MR engineering]. PMID- 21666382 TI - [The role of the CT-oriented radiological technologist in medicine and in patient care]. PMID- 21666383 TI - [Role of academic societies in standardization activities of waste management of induced radioactivity in therapeutic accelerators]. PMID- 21666385 TI - [8. Introduction to statistics for radiological technology studies]. PMID- 21666384 TI - [Usefulness of positron emission tomography in oncology]. PMID- 21666387 TI - [Who is writing the JSRT papers?]. PMID- 21666386 TI - [In pursuit of optimal scan protocol for 64-multidetector CT coronary angiography]. PMID- 21666388 TI - [Exhibiting JIRA booth in ECR 2011--reported by JIRA International Exhibition WG]. PMID- 21666389 TI - Community variability of bacteria in alpine snow (Mont Blanc) containing Saharan dust deposition and their snow colonisation potential. AB - Microorganisms uplifted during dust storms survive long-range transport in the atmosphere and could colonize high-altitude snow. Bacterial communities in alpine snow on a Mont Blanc glacier, associated with four depositions of Saharan dust during the period 2006-2009, were studied using 16S rRNA gene sequencing and flow cytometry. Also, sand from the Tunisian Sahara, Saharan dust collected in Grenoble and Mont Blanc snow containing no Saharan dust (one sample of each) were analyzed. The bacterial community composition varied significantly in snow containing four dust depositions over a 3-year period. Out of 61 phylotypes recovered from dusty snow, only three phylotypes were detected in more than one sample. Overall, 15 phylotypes were recognized as potential snow colonizers. For snow samples, these phylotypes belonged to Actinobacteria, Proteobacteria and Cyanobacteria, while for Saharan sand/dust samples they belonged to Actinobacteria, Bacteroidetes, Deinococcus-Thermus and Proteobacteria. Thus, regardless of the time-scale, Saharan dust events can bring different microbiota with no common species set to alpine glaciers. This seems to be defined more by event peculiarities and aeolian transport conditions than by the bacterial load from the original dust source. PMID- 21666390 TI - Effects of land uses on fecal indicator bacteria in the water and soil of a tropical watershed. AB - Effects of different land uses on densities of Escherichia coli, enterococci, and Clostridium perfringens in the water and soil of a tropical watershed were investigated. Densities of fecal indicator bacteria (FIBs) in the watershed exhibited a clear land-use dependency in the stream water. Significantly higher concentrations were detected in the urban portion of the stream (417, 420, and 44 CFU 100 mL(-1) for E. coli, enterococci, and C. perfringens, respectively) than in the forest portion (54, 32, and 5 CFU 100 mL(-1) for E. coli, enterococci, and C. perfringens, respectively). High concentrations of FIBs were also detected in the soil of the watershed with concentration ranges of 603-1,820,000, 69-17,000, and 0-525 CFU 100 g soil(-1) for E. coli, enterococci, and C. perfringens, respectively, which however were not affected by the different land uses. Prior cumulative rainfall significantly correlated with concentrations of E. coli and enterococci in the urban stream water (r=0.73-0.87, P<0.05), but not with the alternative FIB C. perfringens. Poor correlations were observed in the forest reach of the stream for all FIBs. Furthermore, the concentration of C. perfringens only correlated strongly and significantly with E. coli and enterococci in stream water (r=0.70-0.82, P<0.05), but not in tropical soil, indicating different survival and transport behaviors. PMID- 21666391 TI - Reporting catheter-associated urinary tract infections: denominator matters. AB - OBJECTIVE: To evaluate two different methods of measuring catheter-associated urinary tract infection (CAUTI) rates in the setting of a quality improvement initiative aimed at reducing device utilization. DESIGN, SETTING, AND PATIENTS: Comparison of CAUTI measurements in the context of a before-after trial of acute care adult admissions to a multicentered healthcare system. METHODS: CAUTIs were identified with an automated surveillance system, and device-days were measured through an electronic health record. Traditional surveillance measures of CAUTI rates per 1,000 device-days (R1) were compared with CAUTI rates per 10,000 patient-days (R2) before (T1) and after (T2) an intervention aimed at reducing catheter utilization. RESULTS: The device-utilization ratio declined from 0.36 to 0.28 between T1 and T2 (P = .001), while infection rates were significantly lower when measured by R2 (28.2 vs 23.2, P = .02). When measured by R1, however, infection rates trended upward by 6% (7.79 vs. 8.28, P = .47), and at the nursing unit level, reduction in device utilization was significantly associated with increases in infection rate. CONCLUSIONS: The widely accepted practice of using device-days as a method of risk adjustment to calculate device-associated infection rates may mask the impact of a successful quality improvement program and reward programs not actively engaged in reducing device usage. PMID- 21666392 TI - Denominators for device infections: who and how to count. PMID- 21666393 TI - Electronic memorandum decreases unnecessary antimicrobial use for asymptomatic bacteriuria and culture-negative pyuria. AB - OBJECTIVES: Asymptomatic bacteriuria/candidiuria (ASB) and culture-negative pyuria (CNP) are common and often result in inappropriate antibiotic use. We aimed to evaluate whether a standardized educational memorandum could reduce antimicrobial utilization for ASB/CNP. DESIGN, SETTING, AND PATIENTS: Quasi experimental study with a control group, from a convenience sample of inpatients with abnormal urinalysis or urine culture results in a Veterans Affairs hospital. INTERVENTION: An educational memorandum outlining guidelines for diagnosis and treatment of ASB was placed in the chart of patients with ASB/CNP who were receiving antimicrobials. METHODS: The records of patients meeting inclusion criteria were abstracted for demographics, comorbidities, antimicrobials, and symptoms suggestive of possible urinary tract infection (UTI). Patients were categorized as having ASB, CNP, or UTI. The number of antimicrobial-days attributed to ASB/CNP was compared between the control group and the intervention group. RESULTS: Charts of 301 patients with abnormal urine results were reviewed. Thirty of 117 (26%) patients in the control group received antimicrobials for ASB/CNP for an average of 6.3 days. In the intervention group, 24 of 92 (26%) patients received antimicrobials for ASB/CNP for an average of 2.2 days (t-test: P < .001). Adverse events from antimicrobials for ASB/CNP occurred in 3 of the 30 (10%) patients in the control group. There were no adverse events from untreated ASB/CNP in the intervention group. CONCLUSIONS: ASB and CNP resulted in antimicrobial exposure in more than one-quarter of our study patients. Placing a standardized memorandum in the electronic record was associated with a 65% relative reduction in antimicrobial-days for ASB and CNP. PMID- 21666394 TI - Using electronic health information to risk-stratify rates of Clostridium difficile infection in US hospitals. AB - BACKGROUND: Expanding hospitalized patients' risk stratification for Clostridium difficile infection (CDI) is important for improving patient safety. We applied definitions for hospital-onset (HO) and community-onset (CO) CDI to electronic data from 85 hospitals between January 2007 and June 2008 to identify factors associated with higher HO CDI rates. METHODS: Nonrecurrent CDI cases were identified among adult (>= 18-year-old) inpatients by a positive C. difficile toxin assay result more than 8 weeks after any previous positive result. Case categories included HO, CO-hospital associated (CO-HA), CO-indeterminate hospital association (CO-IN), and CO-non-hospital associated (CO-NHA). C. difficile testing intensity (CDTI) was defined as the total number of C. difficile tests performed, normalized to the number of patients with at least 1 C. difficile toxin test recorded. We calculated both the incidence density and the prevalence of CDI where appropriate. We fitted a multivariable Poisson model to identify factors associated with higher HO CDI rates. RESULTS: Among 1,351,156 unique patients with 2,022,213 admissions, 9,803 cases of CDI were identified; of these, 50.6% were HO, 17.4% were CO-HA, 9.0% were CO-IN, and 23.0% were CO-NHA. The incidence density of HO was 6.3 per 10,000 patient-days. The prevalence of CO CDI on admission was, per 10,000 admissions, 8.4 for CO-HA, 4.4 for CO-IN, and 11.1 for CO-NHA. Factors associated (P < .0001) with higher HO CDI rates included older age, higher CO-NHA prevalence on admission, and increased CDTI. CONCLUSION: Electronic health information can be leveraged to risk-stratify HO CDI rates by patient age and CO-NHA prevalence on admission. Hospitals should optimize diagnostic testing to improve patient care and measured CDI rates. PMID- 21666395 TI - Clostridium difficile infection in a long-term care facility: hospital-associated illness compared with long-term care-associated illness. AB - BACKGROUND: Controversy exists over whether Clostridium difficile infection (CDI) commonly occurs in long-term care facility residents who have not been recently transferred from an acute care hospital. OBJECTIVE: To assess the incidence and outcome of CDI in a long-term care facility. METHODS: Retrospective cohort study in a 262-bed long-term care Veterans Affairs facility in Pittsburgh, Pennsylvania, for the period January 2004 through June 2010. CDI was identified by positive stool C. difficile toxin assay and acute diarrhea. Patients were categorized as hospital-associated CDI (HACDI) or long-term care facility associated CDI (LACDI) and followed for 6 months. RESULTS: The annual rate of CDI varied between 0.11 and 0.23 per 1,000 resident-days for HACDI patients and between 0.04 and 0.28 per 1,000 resident-days for LACDI patients. We identified 162 patients, 96 patients (59.3%) with HACDI and 66 patients (40.7%) with LACDI. Median age was 74 and 77 years, respectively, for HACDI and LACDI (P = .055) patients. There were more patients with at least 1 relapse of CDI during 6 months of follow up in LACDI patients (32/66, 48.5%) than in HACDI patients (28/96, 29.2%; P = .005). Logistic regression showed that ages of at least 75 years (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.07-5.07; P = .005), more than 2 transfers to an acute care hospital (OR, 7.88; 95% CI, 1.88-32.95; P = .005), and LACDI (OR, 3.15; 95% CI, 1.41-7.05; P = .005) were associated with relapse of CDI. CONCLUSIONS: Forty percent of CDI cases were acquired within the long-term care facility, indicating a substantial degree of transmission. Optimal strategies to prevent CDI in the long-term care facility are needed. PMID- 21666396 TI - Glow gel hand washing in the waiting room: a novel approach to improving hand hygiene education. AB - OBJECTIVES: To characterize handwashing behaviors of children and assess the efficacy of a waiting room-based hand hygiene intervention at improving handwashing ability. DESIGN: Prospective randomized pilot study. SETTING: Emergency department waiting room at a freestanding urban pediatric hospital. PARTICIPANTS: Children (8-18 years) and their parent. INTERVENTION: Participants were randomized to glow gel hand washing without hand hygiene education or glow gel hand washing with hand hygiene education. After participants washed with glow gel, "dirty areas" were illuminated using a black light, and hands were scored. A questionnaire about handwashing behavior was administered. All subjects returned 2-4 weeks after intervention to repeat glow gel hand washing and the questionnaire. RESULTS: Sixty pediatric patients and 57 parents were recruited, with 77% of patients returning for follow up. Patients were 50% male, 58% Latino, 28% African American, and 8% Caucasian. At the initial visit, 91% of children reported hand washing after using the bathroom and 78% reported hand washing before dinner. On the basis of objective scoring, all children improved handwashing ability when compared with the initial visit (P = .02) and were more likely to use warm water at follow up (P = .01). Parents did not significantly improve in handwashing ability (P = .73). CONCLUSION: Glow gel hand washing is an effective method to improve children's handwashing ability. This short-term intervention was effective even in the absence of specific hand hygiene education. This intervention could serve as a valuable public health measure to teach hand washing in healthcare settings. PMID- 21666397 TI - Isolation of Acinetobacter baumannii complex and methicillin-resistant Staphylococcus aureus from hospital rooms following terminal cleaning and disinfection: can we do better? AB - OBJECTIVE: To study the frequency of isolation of Acinetobacter baumannii complex (ABC) and methicillin-resistant Staphylococcus aureus (MRSA) from surfaces of rooms newly vacated by patients with multidrug-resistant (MDR) ABC following various rounds of routine terminal cleaning and disinfection (C/D) with bleach or 1 round of C/D followed by hydrogen peroxide vapor (HPV) treatment. SETTING: A 900-bed tertiary care hospital. METHODS: ABC and MRSA cultures were obtained from hospital rooms including 312 rooms (mean, 18.3 sites/room) following 4 rounds of C/D, 37 rooms (mean, 20 sites/room) following 1 round of C/D before and after HPV treatment, and 134 rooms (mean, 20 sites/room) following 1 round of C/D and HPV treatment. RESULTS: Following 4 rounds of C/D, 83 (26.6%) rooms had 1 or more culture-positive sites; 102 (1.8%) sites in 51 (16.4%) rooms grew ABC, and 108 (1.9%) sites in 44 (14.1%) rooms grew MRSA. The addition of HPV treatment to 1 round of C/D resulted in a significant drop in ABC- and MRSA-positive room sites (odds ratio, 0 [95% confidence interval, 0-0.8]; P = .04 for both organisms). Following 1 round of C/D and HPV treatment, 6 (4.5%) rooms were culture-positive for ABC, MRSA, or both. CONCLUSIONS: Routine terminal C/D of hospital rooms vacated by MDRABC-positive patients may be associated with a significant number of ABC- or MRSA-positive room surfaces even when up to 4 rounds of C/D are performed. The addition of HPV treatment to 1 round of C/D appears effective in reducing the number of persistently contaminated room sites in this setting. PMID- 21666398 TI - Institutional control measures to curtail the epidemic spread of carbapenem resistant Klebsiella pneumoniae: a 4-year perspective. AB - OBJECTIVE: To describe the implementation of an institution-wide, multiple-step intervention to curtail the epidemic spread of carbapenem-resistant Klebsiella pneumoniae (CRKP). DESIGN: Consecutive intervention analyses. PATIENTS AND SETTING: All patients admitted to a 775-bed tertiary care medical center in Jerusalem, Israel, from 2006 through 2010. INTERVENTIONS: The effects of 4 interventions were assessed: (1) a policy of isolation for patients colonized or infected with CRKP in single rooms, which was started in March 2006; (2) cohorting of CRKP patients with dedicated nursing staff and screening of patients neighboring a patient newly identified as a carrier of CRKP, which was started in March 2007; (3) weekly active surveillance of intensive care unit patients, which was started during August 2008; and (4) selective surveillance of patients admitted to the emergency department, which was started in March 2009. Interrupted regression analysis and change-point analysis were used to assess the effect of each intervention on the CRKP epidemic. RESULTS: Patient isolation alone failed to control the spread of CRKP, with incidence increasing to a peak of 30 new cases per 1,000 hospital beds per month. Institution of patient cohorting led to a steep decline in the incidence of CRKP acquisition (P < .001). Introduction of active surveillance interventions was followed by a decrease in the incidence of CRKP-positive clinical cultures but an increase in the incidence of CRKP-positive screening cultures. The mean prevalence of CRKP positivity for the period after cohorting began showed a statistically significant change from the mean prevalence in the preceding period (P < .001). CONCLUSIONS: The cohorting of patients with dedicated staff, combined with implementation of focused active surveillance, effectively terminated the epidemic spread of CRKP. Cohorting reduced cross-infection within the hospital, and active surveillance allowed for earlier detection of carrier status. Both interventions should be considered in attempts to contain a hospital epidemic. PMID- 21666400 TI - The role played by contaminated surfaces in the transmission of nosocomial pathogens. AB - Studies in the 1970s and 1980s suggested that environmental surface contamination played a negligible role in the endemic transmission of healthcare-associated infections. However, recent studies have demonstrated that several major nosocomial pathogens are shed by patients and contaminate hospital surfaces at concentrations sufficient for transmission, survive for extended periods, persist despite attempts to disinfect or remove them, and can be transferred to the hands of healthcare workers. Evidence is accumulating that contaminated surfaces make an important contribution to the epidemic and endemic transmission of Clostridium difficile, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, Acinetobacter baumannii, Pseudomonas aeruginosa, and norovirus and that improved environmental decontamination contributes to the control of outbreaks. Efforts to improve environmental hygiene should include enhancing the efficacy of cleaning and disinfection and reducing the shedding of pathogens. Further high quality studies are needed to clarify the role played by surfaces in nosocomial transmission and to determine the effectiveness of different interventions in reducing associated infection rates. PMID- 21666399 TI - Coagulase-negative staphylococcal infections in the neonatal intensive care unit. AB - BACKGROUND: Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity, including neurodevelopmental impairment. OBJECTIVE: To describe the epidemiology of CoNS infections in the NICU. To determine mortality among infants with definite, probable, or possible CoNS infections. METHODS: We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from samples obtained from infants aged <121 postnatal days. SETTING: A total of 248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009. RESULTS: We identified 16,629 infants with 17,624 episodes of CoNS infection: 1,734 (10%) definite, 3,093 (17%) probable, and 12,797 (73%) possible infections. Infants with a lower gestational age and birth weight had a higher incidence of CoNS infection. When controlling for gestational age, birth weight, and 5-minute Apgar score, we found that infants with definite, probable, or possible CoNS infection had lower mortality (odds ratio [OR], 0.74 [95% confidence interval {CI}: 0.61, 0.89], 0.68 [95% CI, 0.59, 0.79], and 0.69 [95% CI, 0.63, 0.76], respectively) compared with infants who had negative culture results (P = .001). No significant difference in overall mortality was found in infants who had definite CoNS infection compared with those who had probable or possible CoNS infection (OR, 0.93 [95% CI, 0.75, 1.16] and 0.85 [95% CI, 0.70, 1.03], respectively). CONCLUSIONS: CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants with a diagnosis of definite, probable, or possible CoNS infection was observed. PMID- 21666401 TI - A practical method for surveillance of novel H1N1 influenza using automated hospital data. AB - We report a surveillance method for influenza that is based on automated hospital laboratory and pharmacy data. During the 2009 H1N1 influenza pandemic, this method was objective, easy to perform, and utilized readily available automated hospital data. This surveillance method produced results that correlated strongly with influenza-like illness surveillance data. PMID- 21666402 TI - An alternate approach to improving healthcare worker influenza vaccination rates. AB - Optimizing employee influenza vaccination rates has become a healthcare focus. We detail an approach involving a strong requirement for unvaccinated workers to wear a face mask and a superconvenient vaccination process. Our major teaching hospital achieved 95% compliance in 2009, and our health system reached 90% and 92% compliance for 2 years. PMID- 21666403 TI - Respiratory fluoroquinolone use and influenza. AB - We show that respiratory fluoroquinolone use is extremely seasonal and that fluoroquinolone use is strongly associated with influenza. In our time series model, instantaneous influenza activity was a significant predictor of use (P < .0001). Also, we estimated that reducing influenza activity by 20% would reduce prescriptions by 8%. PMID- 21666404 TI - Prevalence and predictors of antibiotic use in community-based elderly in Ontario, Canada. AB - Little is known about antibiotic use in the elderly receiving home care. We found that 6,873 (5.4%) of 126,339 home care patients in Ontario received antibiotic treatment; 26% of the antibiotics administered were fluoroquinolones. Antibiotic treatment was most frequent in patients less than 65 years of age and among those with a poorer health status. PMID- 21666405 TI - Faculty and resident physicians' attitudes, perceptions, and knowledge about antimicrobial use and resistance. AB - We surveyed faculty and residents to assess attitudes, perceptions, and knowledge about antimicrobial use and resistance. Most respondents were concerned about resistance when prescribing antibiotics and agreed that antibiotics are overused, that inappropriate use is professionally unethical, and that others, but not themselves, overprescribe antibiotics. Antimicrobial stewardship programs should capitalize on these perceptions. PMID- 21666406 TI - Risk factors for development of intestinal colonization with imipenem-resistant Pseudomonas aeruginosa in the intensive care unit setting. AB - Risk factors for development of intestinal colonization by imipenem-resistant Pseudomonas aeruginosa (IRPA) may differ between those who acquire the organism via patient-to-patient transmission versus by antibiotic selective pressure. The aim of this study was to quantify potential risk factors for the development of IRPA not due to patient-to-patient transmission. PMID- 21666408 TI - Device use ratio measured weekly can reliably estimate central line-days for central line-associated bloodstream infection rates. AB - Six hospitals joined to perform surveillance for central line-associated bloodstream infections outside of intensive care units (ICUs). To facilitate the counting of device-days, a weekly measure of the device use ratio was validated as an estimate of central line-days outside the ICU. PMID- 21666407 TI - Using oral vancomycin prescriptions as a proxy measure for Clostridium difficile infections: a spatial and time series analysis. AB - Sales for a drug may be correlated with the prevalence of a condition treated by the drug. We found that state data revealed a strong spatial association and national data a strong temporal association between Clostridium difficile and oral vancomycin prescription sales, suggesting a new "signal" for detecting disease activity. PMID- 21666409 TI - In vitro efficacy of antimicrobial-treated drainage catheters in preventing bacterial colonization in biological fluids. PMID- 21666410 TI - Survey of antimicrobial stewardship practices in Nebraska long-term care facilities. PMID- 21666412 TI - Pre-diabetes in Italian obese children and youngsters. AB - BACKGROUND AND AIM: Metabolic characteristics and rate of progression to overt Type 2 diabetes (T2D) in low-risk European obese children are not well documented. Aim of the study was to investigate differences in insulin sensitivity and secretion in Italian obese children and youngsters with pre diabetes. METHODS: Ninety-six obese children and youngsters with pre-diabetes, pair-matched with individuals with normal glucose tolerance (NGT) were included in the present study. Participants were screened by oral glucose tolerance. Pre diabetes was classified as impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and combined IFG-IGT. Homeostasis model assessment of insulin resistance (HOMA-IR), 2-h insulin, insulin sensitivity index (ISI) and disposition index (DI) were calculated to estimate fasting, peripheral and whole body insulin sensitivity and capacity of pancreatic islets to compensate for lower insulin sensitivity, respectively. One-way analysis of variance was used to compare groups. RESULTS: Eleven subjects had IFG (11.5%), 79 IGT (82.3%), 6 combined IFG-IGT (6.3%). Individuals with IFG showed the highest HOMA-IR (p=0.0007), those with IGT the highest 2-h insulin (p<0.0001), those with IFG-IGT the lowest ISI (p<0.0001), with severely reduced DI (p=0.0003). Compared with NGT, DI was 60% lower in those with IFG-IGT. CONCLUSION: IFG is linked primarily to fasting insulin resistance, IGT to peripheral insulin resistance. IFG-IGT is hallmarked by reduced whole body insulin sensitivity and an additional severe defect in DI. Further longitudinal studies are needed to understand whether the different categories of pre-diabetes in European obese adolescents represent real pre-diabetic alterations. PMID- 21666413 TI - Serum inhibin B levels before and after varicocelectomy in early adolescence. AB - BACKGROUND: Whereas no clear relationship has been observed between varicocelectomy and serum inhibin B levels in men, in adolescents comparison between inhibin B levels before and after varicocelectomy is lacking. AIM: To evaluate the effect of varicocele surgical treatment on inhibin B levels in adolescents at the beginning of puberty compared to a group of healthy adolescents. SUBJECTS AND METHODS: We studied 28 adolescents in Tanner 2 pubertal stage with a grade III left-sided varicocele (patients) compared to 13 age and pubertal stage-matched healthy adolescents (controls). All patients underwent blood tests to determine serum inhibin B levels before and 6 months after varicocelectomy by Palomo procedure. For comparison we investigated inhibin B levels in controls and repeated this test 6 months later. Testicular ultrasound was performed for patients only. RESULTS: Baseline inhibin B concentrations of patients and controls were 109.90 +/- 40.26 and 109.33 +/- 38.34 pg/ml, respectively. No significant changes were observed in patients' inhibin B concentrations after varicocelectomy (116.00 +/- 42.65 pg/ml), or in controls during the 6 months' follow-up (99.12 +/- 30.09 pg/ml). Doppler examination after treatment shows a complete resolution of varicocele in all the patients without alterations in testicular parenchyma. CONCLUSIONS: Varicocelectomy performed on adolescents at T2 pubertal stage might be useful to avoid alteration in inhibin B production and consequently in testicular function. Further studies are necessary to confirm the prognostic value of inhibin B levels and the benefit of early varicocelectomy in preserving the fertility of these adolescents. PMID- 21666414 TI - Glucagon-like peptide-1 secretion in women with gestational diabetes mellitus during and after pregnancy. AB - Gestational diabetes mellitus (GDM) predisposes women to future development of Type 2 diabetes mellitus (DM2) and the two conditions share similar metabolic alterations. Recent observations suggest that a defective glucose stimulated insulin secretion by glucagon-like peptide-1 (GLP- 1) plays a role in the pathogenesis of DM2. Whether such a defect is impaired in GDM remains to be ascertained. AIM: We have determined GLP-1 secretion in response to oral glucose tolerance test (OGTT) in GDM and normal glucose tolerance (NGT) during and after pregnancy. MATERIALS AND METHODS: 100-g-3h OGTT was performed in 12 GDM and 16 NGT women at 27.3 +/- 4.1 weeks of gestation, for determination of plasma GLP-1, glucose, insulin, and C-peptide. Insulin sensitivity (ISI) and insulin secretion (first and second phase); as well as ISI-secretion index (ISSI) were also derived. RESULTS: NGT and GDM women were comparable for age pre-pregnancy body mass index (BMI) and weight gain. GDM had higher glucose area under the curve (AUC): 27,575.5 +/- 3448 vs 20,685.88 +/- 2715 mg/dl min (p<0.01), but lower first-phase insulin secretion (993.12+/-367 vs 1376.61 +/- 423, p<0.05) and ISSI compared to controls (3873.23 +/- 1185 vs 6232.13 +/- 1734, p<0.001). When we examined GLP-1 mean levels in relation to mean glycemic values, GLP-1 secretion was inappropriately low with respect to mean glycemic values in GDM compared to NGT. At follow-up, AUCGLP-1 was significantly lower in post-partum GDM compared to post-partum NGT women (2542 +/- 273 vs 10,092 +/- 7367 pmol.l-1.min-1, p<0.05, respectively). CONCLUSIONS: Our study suggests that GLP-1 secretion in GDM women is inadequate for the prevailing glycemic levels both in pregnancy and post partum. Moreover, we cannot exclude that other important aspects of the incretin effect may be involved in GDM development. PMID- 21666415 TI - Is carcinogenesis a form of speciation? AB - Since cancers have individual clonal karyotypes, are immortal and evolve from normal cells treated by carcinogens only after exceedingly long latencies of many months to decades-we deduce that carcinogenesis may be a form of speciation. This theory proposes that carcinogens initiate carcinogenesis by causing aneuploidy, i.e., losses or gains of chromosomes. Aneuploidy destabilizes the karyotype, because it unbalances thousands of collaborating genes including those that synthesize, segregate and repair chromosomes. Driven by this inherent instability aneuploid cells evolve ever-more random karyotypes automatically. Most of these perish, but a very small minority acquires reproductive autonomy-the primary characteristic of cancer cells and species. Selection for autonomy stabilizes new cancer species against the inherent instability of aneuploidy within specific margins of variation. The speciation theory explains five common characteristics of cancers: (1) species-specific autonomy; (2) karyotypic and phenotypic individuality; (3) flexibility by karyotypic variations within stable margins of autonomy; (4) immortality by replacing defective karyotypes from constitutive pools of competent variants or subspecies generated by this flexibility; and (5) long neoplastic latencies by the low probability that random karyotypic alterations generate new autonomous species. Moreover, the theory explains phylogenetic relations between cancers of the same tissue, because carcinogenesis is restricted by tissue-specific transcriptomes. The theory also solves paradoxes of other cancer theories. For example, "aneuploidy" of cancers is now said to be a "paradox" or "cancer's fatal flaw," because aneuploidy impairs normal growth and development. But if the "aneuploidies" of cancers are in effect the karyotypes of new species, this paradox is solved. PMID- 21666418 TI - "Smart" coaching to promote physical activity, diet change, and cardiovascular health. PMID- 21666419 TI - American Heart Association: Council on Cardiovascular Nursing. PMID- 21666420 TI - Summaries of nursing care-related systematic reviews from the Cochrane library: statins for the primary prevention of cardiovascular disease. PMID- 21666421 TI - Prescription omega-3s: an overview for nurse practitioners. AB - Nurse practitioners (NPs) often take a multidisciplinary approach when treating and educating patients. Collaboration with a registered dietitian is not uncommon when treating patients with severe hypertriglyceridemia (triglycerides [TGs] >=500 mg/dL). Patients with severe hypertriglyceridemia should be treated and managed to normalize TG levels (TG level <150 mg/dL). Treatment for severe hypertriglyceridemia is often 3-fold, including lifestyle changes, diet modification, and pharmacotherapy. Therapeutic lifestyle changes are generally the first step in lowering TG levels. Registered dietitians promote a heart healthy diet rich in fruits and vegetables. Evidence has been mounting to support consumption of eicosapentaenoic acid and docosahexaenoic acid to decrease TGs. When lifestyle and diet changes do not effectively decrease TGs, NPs will recommend pharmacological therapy as a next step. A viable pharmacological option includes prescription omega-3 (P-OM3) fatty acid ethyl esters. Each 4-g/d dose of P-OM3 provides 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid. Clinical trials show that P-OM3 can safely and effectively decrease TGs by 45% in patients with severe hypertriglyceridemia. Nurse practitioners play an important role in the treatment of severe hypertriglyceridemia and in the education of patients about lifestyle and diet changes that can greatly impact patients' health. PMID- 21666422 TI - Postinfectious functional gastrointestinal disorders. AB - Functional gastrointestinal disorders are associated with low health-related quality of life and high resource utilization. Postinfectious irritable bowel syndrome (PI-IBS) is a functional gastrointestinal disorder defined as the acute onset of new IBS symptoms in an individual who has not previously met the Rome criteria for IBS, immediately after an acute illness characterized by 2 or more of the following: fever, vomiting, diarrhea, or a positive bacterial stool culture. Although the pathophysiological mechanisms involved in PI-IBS are currently unknown, it is believed that a transitory inflammation leads to subtle but permanent changes in the structure and function of the digestive system that induce symptoms. This review considers recent evidence surrounding the role of inflammatory mediators in the development of hypersensitivity, along with the mediators and mechanisms of abdominal pain and discomfort once the acute inflammation has cleared. Recent data suggest that anatomic changes to mast cells nerve fibers are necessary, but not sufficient to induce symptoms. It is now possible to estimate the risk of developing PI-FGID based on the presence and relative severity of different risk factors, including prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female sex, depression, hypochondriasis, and adverse life events in the preceding 3 months. PMID- 21666423 TI - Without doubt, functional digestive disorders constitute one of the main reasons for consultation in both gastroenterology and primary health care. Foreword. PMID- 21666424 TI - Making a positive diagnosis of irritable bowel syndrome. AB - The traditional diagnostic approach for irritable bowel syndrome (IBS) is to exclude other gastrointestinal conditions, which has led to patients being subjected to excessive testing. However, the development of consensus guidelines, such as Rome III, has enabled physicians to make a positive diagnosis of IBS based on the pattern and nature of symptoms. It is now possible to employ a more rational diagnostic strategy with a reduced need for laboratory testing based on symptom-based approaches aimed at standardizing IBS patient subgroups. Patient outcomes in IBS can be further improved by careful consideration of several diagnostic issues including differentiating between disorders (IBS is 1 of >20 functional gastrointestinal disorders), practical aspects of testing, the indications for colonoscopy, and the need to improve the physician-patient relationship and enhance the patient's adherence to treatment. PMID- 21666425 TI - Irritable bowel syndrome and other functional gastrointestinal disorders. AB - Irritable bowel syndrome is one of several highly prevalent functional gastrointestinal disorders (FGID) displaying symptoms of gastrointestinal dysmotility and visceral hypersensitivity. Substantial overlap of symptoms and comorbidities occur not only between irritable bowel syndrome and other FGID but also with gastrointestinal disorders that are not related to motility (eg, celiac disease and lactose intolerance) and to somatic conditions (eg, fibromyalgia and chronic fatigue syndrome). Pathogenic mechanisms common among FGIDs may include alternations in intestinal and colonic microflora. Evidence is also emerging of an interplay between gut immune cells/activity and alternations in motility, secretion, and sensation. The role of cytokine activity and inflammation is important in this regard. As recommended by Rome III, diagnostic testing should be guided by the patient's age, primary symptom characteristics, and other clinical and laboratory features. The high prevalence of coexisting conditions suggests the need to routinely assess patients for related disorders. Treatment should be based on an individualized evaluation, explanation, and reassurance. PMID- 21666426 TI - Understanding and treating abdominal pain and spasms in organic gastrointestinal diseases: inflammatory bowel disease and biliary diseases. AB - Abdominal pain and spasms are common symptoms in organic gastrointestinal diseases, yet are associated with significant unmet need in terms of recognition and treatment. The aim of this review was to help physicians to understand the pathophysiology and impact to patients of abdominal pain and spasms in inflammatory bowel disease (IBD) and biliary diseases. This may in turn help in the selection of the most appropriate treatment to improve patients' overall daily functioning and quality of life in addition to reducing health resource utilization. Relative to the healthy colon, the mechanisms of pain generation in IBD include peripheral sensitization, including visceral hypersensitivity, central processing and modulation, and associated features or modifiers. Calcitonin gene related peptide, substance P, transient receptor potential vanilloid type, and serotonin biosynthesis in the colon are implicated in these processes. For biliary pain, important factors include pressure change or high pressure in the gallbladder, gallbladder ejection fraction, and change in the shape of gallbladder. Pain management is multifactorial and may involve psychological and physical methods and drugs (nonsteroidal anti-inflammatory agents, opioids, antispasmodics, with regional and epidural analgesia reserved for severe cases) after appropriate risk-benefit assessment. Antispasmodic agents may be effective in selected patients with IBD, especially those who are in remission and have mild/moderate chronic pain. PMID- 21666427 TI - Chronic degenerative pain: an update on abdominal pain in comparison to rheumatic diseases. AB - Rheumatic diseases comprise a heterogeneous group of highly prevalent, usually chronic and progressively disabling disorders associated with poor patient quality of life and high healthcare resource utilization. The pain associated with these degenerative or inflammatory conditions represent some of the most important and complex problems of modern medicine, demanding an increasingly attentive, multidisciplinary, and continuous therapeutic approach. Extra articular syndromes, notably fibromyalgia, can be a lifelong rheumatic condition characterized by widespread musculoskeletal pain and functional impairment, without any known structural or inflammatory cause. Irritable bowel syndrome (IBS) occurs in around half of patients with fibromyalgia raising the possibility of a possible overlapping or underlying pathophysiology. The dysfunction of bidirectional neural pathways and viscerovisceral cross-interactions within the central nervous system has been proposed as a possible central hypersensitization disorder responsible for the extraintestinal manifestations of IBS. Common inflammatory and molecular pathways may also be present in which a dysregulation of the immune system leads to a chronic inflammatory response. Given that the treatment of degenerative chronic pain remains suboptimal, these findings may suggest new treatment strategies. PMID- 21666428 TI - Quality of life in patients with irritable bowel syndrome. AB - There has been an underestimation of the impact of irritable bowel syndrome (IBS) on an individual's functioning and quality of life (QoL). The general health status of both young and elderly individuals with IBS is generally found to be poorer than that of the general population. Patients with IBS seem to have worse health-related quality of life (HRQoL) than patients with certain other conditions such as gastroesophageal reflux disease, diabetes, and end-stage renal disease. Various disease-specific instruments are now available and are widely used in clinical trials to measure changes in QoL in patients with IBS after treatment intervention. Although few such data are presently available from clinical trials, it seems that patients who have a therapeutic response to therapy for IBS have a corresponding improvement in HRQoL. There seems to be no major differences in HRQoL based on IBS subtype (constipation-dominant or diarrhea-dominant). However, the severity of bowel symptoms in IBS is associated with a corresponding impact on HRQoL and patients with worse bowel symptoms have a greater diminished QoL compared with patients with milder symptoms. Evidence also indicates that HRQoL in patients with IBS is affected by sex and psychological conditions. Careful consideration of these factors may help to individualize a therapeutic strategy to optimize long-term outcomes. PMID- 21666429 TI - Central obesity in the elderly is related to late-onset Alzheimer disease. AB - The evidence relating obesity measured with body mass index (BMI) in the elderly to late-onset Alzheimer disease (LOAD) is conflicting. Central obesity in middle age is related to a higher risk of LOAD, but data in the elderly are lacking. We explored whether measures of central obesity, waist circumference, and waist to hip ratio (WHR) were better predictors of LOAD compared with BMI in the elderly. Participants were 1459 persons aged 65 years and older without dementia at baseline, with follow-up, and with anthropometric data from a longitudinal study of aging in New York City. Proportional hazards regression was used for multivariable analyses relating BMI, waist circumference, and WHR to LOAD. There were 145 cases of Alzheimer disease in 5734 person-years of follow-up. Only WHR was related to higher LOAD risk (hazard ratio of the fourth quartile compared with the first=2.5; 95% confidence interval=1.3, 4.7) after adjustment for age, sex, education, ethnic group, Apolipoprotein E-epsilon4, type 2 diabetes, hypertension, non-high-density lipoprotein-cholesterol, high-density lipoprotein cholesterol, and stroke. Our results support the notion that central obesity is related to a higher risk of LOAD. PMID- 21666430 TI - Suicide risk in frontotemporal lobe degeneration: to be considered, to be prevented. AB - Suicide is difficult to ascertain in elderly patients, and dementia might represent a risk factor, though predictors of suicide in dementia are still unknown. We report the case of a patient recently diagnosed as having a behavioral variant of frontotemporal lobar degeneration (FTLD), apathetic syndrome, who committed suicide by hanging. His personal and family history was negative for mental disorders; a depressive syndrome was diagnosed 1 year before FTLD diagnosis, and treated unsuccessfully. To the best of our knowledge, no data are available about self-harmful events in FTLD. This case report argues for the urgent need for developing specific tools for the assessment of suicidal ideation among at-risk population. PMID- 21666431 TI - Willingness to use computerized systems for the diagnosis of dementia: testing a theoretical model in an Israeli sample. AB - The aim of the study was to examine factors associated with the expressed willingness to use computerized systems (CSs) for dementia diagnosis. The conceptual model proposed that expressed willingness to use a CS would be directly associated with attitudes toward computerized programs, patient physician relationship, and satisfaction with current health care. In addition, it was hypothesized that technology anxiety and past behavior with CS for dementia diagnosis would affect the expressed willingness to use a CS. Interviews were conducted with a convenience sample of 420 Israeli adults (mean age, 64 y). Structural equation modeling was used to examine the hypothesized relationships. Expressed willingness to use a CS for dementia diagnosis was moderate, although significantly higher when performed by a professional than when performed alone. Overall, the expressed willingness to use a CS for dementia diagnosis was affected by attitudes toward computerized programs, toward patient-physician relationship, and by the level of technology anxiety. Participants with lower socioeconomic status and female participants reported lower levels of intention to use a CS for dementia diagnosis. Findings of the study encourage the development of educational interventions aimed at promoting the use of CS for dementia diagnosis. These programs should target potential users' attitudes, feelings of uneasiness, and anxiety regarding technology. PMID- 21666432 TI - Greater responsiveness to donepezil in Alzheimer patients with higher levels of acetylcholinesterase based on attention task scores and a donepezil PET study. AB - The aim of the study was to predict donepezil responders among patients with Alzheimer disease (AD) based on cognitive tests and positron emission tomography. The Mini-Mental State Examination, Digit Symbol subtest (DigSm) of Wechsler Adult Intelligence Scale Revised, and Trail-Making Test A were administered for 80 patients with AD to assess global function, attention, and executive function, respectively. The same tests and the Clinical Global Impression (CGI) scale were conducted after treatment with oral donepezil (5 mg/d) for 6 months (study 1). [C]-Donepezil positron emission tomography examinations were conducted before and after treatment for 30 randomly selected patients. The distribution volume (DV), which indicates the density of donepezil-binding sites, was calculated using Logan graphical analysis (study 2). In study 1, 35 patients were identified as responders based on the CGI and Mini-Mental State Examination changes. These patients had higher baseline DigSm scores compared with nonresponders. In study 2, 15 patients were responders. DigSm correlated with DV at baseline. DV at baseline and %DV change in responders were higher than in nonresponders, and these variables correlated with DeltaDigSm and CGI scores. Higher baseline attention may predict responsiveness to donepezil in patients with AD, and higher acetylcholinesterase levels result in a greater clinical effect. PMID- 21666433 TI - Isoflurane decreases self-renewal capacity of rat cultured neural stem cells. AB - BACKGROUND: In models, isoflurane produces neural and behavioral deficits in vitro and in vivo. This study tested the hypothesis that neural stem cells are adversely affected by isoflurane such that it inhibits proliferation and kills these cells. METHODS: Sprague-Dawley rat embryonic neural stem cells were plated onto 96-well plates and treated with isoflurane, 0.7, 1.4, or 2.8%, in 21% oxygen for 6 h and fixed either at the end of treatment or 6 or 24 h later. Control plates received 21% oxygen under identical conditions. Cell proliferation was assessed immunocytochemically using 5-ethynyl-2'-deoxyuridine incorporation and death by propidium iodide staining, lactate dehydrogenase release, and nuclear expression of cleaved caspase 3. Data were analyzed at each concentration using an ANOVA; P < 0.05 was considered significant. RESULTS: Isoflurane did not kill neural stem cells by any measure at any time. Isoflurane, 1.4 and 2.8%, reduced cell proliferation based upon 5-ethynyl-2'-deoxyuridine incorporation, whereas isoflurane, 0.7%, had no effect. At 24 h after treatment, the net effect was a 20 30% decrease in the number of cells in culture. CONCLUSIONS: Isoflurane does not kill neural stem cells in vitro. At concentrations at and above the minimum alveolar concentrations required for general anesthesia (1.4 and 2.8%), isoflurane inhibits proliferation of these cells but has no such effect at a subminimum alveolar concentration (0.7%). These data imply that dosages of isoflurane at and above minimum alveolar concentrations may reduce the pool of neural stem cells in vivo but that lower dosages may be devoid of such effects. PMID- 21666434 TI - Nerve stimulator-guided supplemental popliteal sciatic nerve block after a failed sciatic block does not increase the incidence of transient postoperative neurologic sequelae. AB - BACKGROUND: Supplemental peripheral nerve blocks are not commonly performed in adults because of concerns of cumulative exposure of the nerve to the local anesthetic as well as increased ischemia from epinephrine. The purpose of this study was to compare the incidence of postoperative neurologic symptoms after a failed subgluteal sciatic nerve block and a supplemental popliteal sciatic nerve block. METHODS: Five hundred twelve adult patients undergoing ambulatory surgery were prospectively studied (1 yr). Sciatic nerve blocks were performed using levobupivacaine 0.625% with epinephrine 1:200,000 (0.5 ml/kg). Patients who failed to achieve sensory and motor anesthesia at 30-60 min were given a popliteal sciatic nerve block (lidocaine 2% 10 ml + levobupivacaine 0.5% 10 ml). Subjects were contacted at 24 h to 48 h, 2 weeks, and 1 month. Symptomatic patients were contacted biweekly and reevaluated during follow-up surgeon visits until symptom resolution. RESULTS: Four hundred thirty-nine subjects were analyzed. Fifty-six received a popliteal sciatic nerve block. Four subjects (0.9%) had self-reported neurologic symptoms in the distribution of the sciatic nerve. Investigator-initiated follow-up revealed 33 subjects (8.7%) who received a single subgluteal sciatic block and 4 subjects (7.1%) after a supplemental sciatic nerve block with neurologic symptoms (P = 0.80). The median duration of symptoms was 4 weeks (95% CI 3-5) in the subgluteal and 4 weeks (95% CI 3-5) weeks in the popliteal group (P = 0.98). All symptoms resolved by 14 weeks postprocedure. CONCLUSION: Blocking the sciatic nerve at a more distal site after a failed subgluteal sciatic nerve block does not appear to influence the incidence or duration of neurologic sequelae. PMID- 21666436 TI - The mind body problem. PMID- 21666435 TI - Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. AB - BACKGROUND: The current study was designed to test the hypothesis that the increased duration of analgesia caused by adding dexmedetomidine to local anesthetic results from blockade of the hyperpolarization-activated cation (I(h)) current. METHODS: In this randomized, blinded, controlled study, the analgesic effects of peripheral nerve blocks using 0.5% ropivacaine alone or 0.5% ropivacaine plus dexmedetomidine (34 MUM or 6 MUg/kg) were assessed with or without the pretreatment of alpha(1)- and alpha(2)-adrenoceptor antagonists (prazosin and idazoxan, respectively) and antagonists and agonists of the I(h) current (ZD 7288 and forskolin, respectively). Sciatic nerve blocks were performed, and analgesia was measured by paw withdrawal latency to a thermal stimulus every 30 min for 300 min postblock. RESULTS: The analgesic effect of dexmedetomidine added to ropivacaine was not reversed by either prazosin or idazoxan. There were no additive or attenuated effects from the pretreatment with ZD 7288 (I(h) current blocker) compared with dexmedetomidine added to ropivacaine. When forskolin was administered as a pretreatment to ropivacaine plus dexmedetomidine, there were statistically significant reductions in duration of analgesia at time points 90-180 min (P < 0.0001 for each individual comparison). The duration of blockade for the forskolin (768 MUM) followed by ropivacaine plus dexmedetomidine group mirrored the pattern of the ropivacaine alone group, thereby implying a reversal effect. CONCLUSION: Dexmedetomidine added to ropivacaine caused approximately a 75% increase in the duration of analgesia, which was reversed by pretreatment with an I(h) current enhancer. The analgesic effect of dexmedetomidine was not reversed by an alpha(2)-adrenoceptor antagonist. PMID- 21666437 TI - Long-term follow-up of patients with metastatic breast cancer: results of a retrospective, single-center analysis from 2000 to 2005. AB - Recent epidemiological studies suggest that chemotherapy for metastatic breast cancer (MBC) has not contributed to a marked improvement in the patient outcome during the last decades. Randomized trials that investigated the efficacy of a first-line schedule for MBC, observed a median survival of 18-24 months. This study aimed to analyze patients with MBC who have been treated in a single university outpatient clinic for survival. Patients with MBC who had received their complete anticancer treatment in our outpatient clinic between 2000 and 2005 were analyzed for treatment schedules and survival. A total of 232 patients [median age, 53 years; range, 27-87 years; estrogen receptor and/or progesterone positive hormone receptor, n=174 (75%); human epidermal growth factor receptor 2 overexpression (human epidermal growth factor receptor 2 positive), n=79 (34%)] were included in this analysis, of which 43.7% of hormone receptor-positive patients received 1-2, 28.3% received 3-4, and 1.7% received more than four hormonal regimens. In addition, 53.4% of all patients received up to three chemotherapeutic agents in palliative intent, whereas four to six regimens were applied in 22.1, and 12.9% received more than six subsequent regimens. An increased number of regimens were associated with an improvement in survival. The median overall survival was 44 months (95% confidence interval: 39-49). HR positivity, bone only, or single-site metastases were associated with an improved survival. An improved survival was also shown in patients who underwent locoregional procedures for oligometastatic disease (n=31; median overall survival >50 months), whereas triple-negative breast cancer was related to worse outcome (16 months; 95% confidence interval: 7-25). These data collected from a selective patient population of a single center support the hypothesis that the sequential use of all treatment modalities for MBC to its full potential may result in an increased survival. Whether innovative medicine, a step-by-step escalation of all treatment modalities according to standard guidelines and individualized clinical requirements, and a multidisciplinary treatment approach contribute to these good outcomes is debatable. PMID- 21666438 TI - Triphendiol (NV-196), development of a novel therapy for pancreatic cancer. AB - Despite incremental progress in the treatment of pancreatic adenocarcinoma, the prognosis of patients remains poor. Here, we report the preclinical studies in pancreatic cancer cells that demonstrate the efficacy of triphendiol (NV-196, a synthetic isoflavene) both as a monotherapy and as a gemcitabine sensitizer. The in-vitro effects of triphendiol on the pancreatic cancer cell lines HPAC and MIAPaCa-2 were determined using cell proliferation, flow cytometry, and western blot analysis. The antiproliferative activity of triphendiol was also investigated in two xenograft models of pancreatic cancer (HPAC and MIAPaCa-2). As a monotherapy, triphendiol-inhibited cell proliferation-induced p53 independent G2/M cell cycle arrest and activation of the intrinsic (mitochondrial) apoptosis pathway. Triphendiol-induced apoptosis was caspase independent and death receptor independent, whereas cell necrosis was caspase mediated. Using combination index analysis, we have shown that pretreatment of pancreatic cancer cells with triphendiol enhanced the cytotoxic effect of gemcitabine, the standard of care used to treat advanced pancreatic cancer. In xenograft models of pancreatic cancer, the rate of tumor proliferation on mice coadministered with triphendiol and gemcitabine was significantly reduced when compared with the corresponding tumor proliferation rates from the respective monotherapy-control and vehicle-control groups. Triphendiol was recently granted Investigational New Drug status by the US Food and Drug Administration. These data justify the commencement of clinical studies investigating the utility of combining triphendiol and gemcitabine in patients with early-stage and late-stage pancreatic cancer. PMID- 21666440 TI - Cornelia de Lange syndrome associated with a de-novo novel NIPBL splice-site mutation and a coincidental inherited translocation t(3;5)(p13;q11). PMID- 21666441 TI - Relation of subclinical left and right ventricular dysfunctions measured by computed tomography angiography with the severity of coronary artery disease. AB - OBJECTIVE: Ventricular dysfunction in asymptomatic patients is directly linked to the eventual development of symptomatic congestive heart failure. This study investigates whether subclinical left ventricular (LV) and right ventricular (RV) dysfunctions measured by computed tomography angiography is associated with the severity of coronary artery disease (CAD). METHODS AND RESULTS: We studied 1608 consecutive patients with suspected CAD (age 62 +/- 10 years, 64% male), who underwent coronary artery calcium (CAC) scanning and computed tomography angiography. RV and LV volumes at end systole and end diastole were measured, and stroke volume and ejection fraction were calculated using the Simpson method and piecewise smooth subdivision surface (PSSS) method. Analysis by Simpson was performed on short axis and apical four-chamber views. Axial images were used to measure RV and LV volumes by the PSSS method. CAD was defined as normal, nonobstructive, and obstructive (0% stenosis, luminal stenosis 1-49 and 50%+, respectively). There was a strong agreement between PSSS and Simpson method RV ejection fraction (RVEF) and LV ejection fraction (LVEF) measurement. RVEF and LVEF decreased proportionally from CAC 0 to CAC 100+, also from normal-to diseased coronaries (P=0.001). After adjustment for cardiovascular risk factors, the mean LVEF and RVEF decreased 2.8 and 2.4%, respectively in CAC 100+ compared with CAC 0. Similarly, LVEF and RVEF decreased significantly in nonobstructive CAD (-3.5 and -3.1%, respectively) and obstructive CAD (-5.9 and -4.5%, respectively) compared with normal coronaries, respectively (P<0.05). The relative risk of each 5% decrease in LVEF and RVEF was 1.33 and 1.29 for nonobstructive CAD and 1.54 and 1.33 for obstructive CAD, respectively. CONCLUSION: The presence and severity of coronary atherosclerosis is significantly associated with subclinical RV and LV dysfunctions. PMID- 21666442 TI - Effect of pressure support on end-expiratory lung volume and lung diffusion for carbon monoxide. AB - OBJECTIVES: The level of pressure-support ventilation can affect mean airway pressure and potentially lung volume, but its increase is usually associated with a reduced respiratory rate, and the net effects on the gas exchange process and its components, including end-expiratory lung volume, have not been carefully studied. We measured pulmonary conductance for gas exchange based on lung diffusion for carbon monoxide in patients receiving pressure-support ventilation. DESIGN: Prospective, randomized, crossover study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Sixteen patients mechanically ventilated in pressure-support ventilation mode and free from chronic obstructive pulmonary disease. INTERVENTIONS: Two pressure-support ventilation levels (5 cm H2O difference) at the same level of positive end-expiratory pressure. MEASUREMENTS AND MAIN RESULTS: End-expiratory lung volume, lung diffusion for carbon monoxide, and SpO2/Fio2 were evaluated. Increasing pressure-support ventilation by 5 cm H2O significantly increased the mean tidal volume from 6.8 to 8.5 mL/kg of predicted body weight and decreased the mean respiratory rate by 6.6 breaths per minute. Although SpO2/Fio2 did not change significantly, there was a slight but significant decrease in lung diffusion for carbon monoxide (average decay rate of 4.5%) at high pressure-support ventilation. The pressure-support ventilation level did not significantly affect end-expiratory lung volume (1737+/-629 mL at 9.6+/-2.5 cm H2O pressure-support ventilation level vs. 1749+/-657 mL at 14.9+/ 2.1 cm H2O pressure-support ventilation level). CONCLUSIONS: A 5-cm H2O increase in pressure-support ventilation neither affected end-expiratory lung volume nor increased the pulmonary volume participating in gas exchange. A target tidal volume closer to 6 mL/kg of predicted body weight than to 8 mL/kg during pressure support ventilation was associated with better gas exchange. PMID- 21666443 TI - Simvastatin in traumatic brain injury: effect on brain edema mechanisms. AB - OBJECTIVES: Traumatic brain injury causes deleterious brain edema, leading to high mortality and morbidity. Brain edema exacerbates neurologic deficits and may be attributable to the breakdown of endothelial cell junction protein, leukocyte infiltration, and matrix metalloproteinase activation. These all contribute to loss of blood-brain barrier integrity. The pleiotropic effects of statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, may inhibit posttraumatic brain edema. We therefore investigated the effect of acute simvastatin on neurologic deficits, cerebral edema, and its origins. DESIGN: Randomized laboratory animal study. SETTINGS: University-affiliated research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats were subjected to lateral fluid percussion traumatic brain injury. Our preliminary dose-effect study indicated that 37.5 mg/kg simvastatin, administered orally 1 hr and 6 hrs after traumatic brain injury, has the greatest anti-edematous effect. This dose was used to study its effects on brain edema and on its mechanisms. MEASUREMENTS AND MAIN RESULTS: We first assessed the effects of simvastatin 24 hrs after traumatic brain injury on brain edema, brain claudin-5 expression, and the vascular endothelial-cadherin (pTyr731)/total vascular endothelial-cadherin ratio, matrix metalloproteinase-9 activity, intercellular adhesion molecule-1 expression, and polymorphonuclear neutrophil infiltration. We also evaluated blood-brain barrier permeability by measuring Evans blue and fluorescein sodium salt extravasation into the cerebral parenchyma. We then investigated whether simvastatin reduces neurologic deficits, edema, and blood-brain barrier permeability earlier than 24 hrs; these effects were evaluated 6 hrs after traumatic brain injury. The anti edematous effect of simvastatin 24 hrs after traumatic brain injury was associated with increased claudin-5 and decreased intercellular adhesion molecule 1, polymorphonuclear neutrophil infiltration, and blood-brain barrier permeability, with no effect on matrix metalloproteinase-9 activity or vascular endothelial-cadherin phosphorylation. Earlier, 6-hrs after traumatic brain injury, simvastatin reduced neurologic deficits, cerebral edema, and blood-brain barrier permeability. CONCLUSIONS: Simvastatin could be a new therapy for reducing posttraumatic edema by preventing damage to tight junctions and neutrophil infiltration into the parenchyma, thus preserving blood-brain barrier integrity. PMID- 21666444 TI - Reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle. AB - OBJECTIVES: Ventilator-associated pneumonia is the most common intensive care unit-acquired infection. Although there is widespread consensus that evidenced based interventions reduce the risk of ventilator-associated pneumonia, controversy has surrounded the importance of implementing them as a "bundle" of care. This study aimed to determine the effects of implementing such a bundle while controlling for potential confounding variables seen in similar studies. DESIGN: A before-and-after study conducted within the context of an existing, independent, infection surveillance program. SETTING: An 18-bed, mixed medical surgical teaching hospital intensive care unit. PATIENTS: All patients admitted to intensive care for 48 hrs or more during the periods before and after intervention. INTERVENTIONS: A four-element ventilator-associated pneumonia prevention bundle, consisting of head-of-bed elevation, oral chlorhexidine gel, sedation holds, and a weaning protocol implemented as part of the Scottish Patient Safety Program using Institute of Health Care Improvement methods. MEASUREMENTS AND MAIN RESULTS: Compliance with head-of-bed elevation and chlorhexidine gel were 95%-100%; documented compliance with "wake and wean" elements was 70%, giving overall bundle compliance rates of 70%. Compared to the preintervention period, there was a significant reduction in ventilator associated pneumonia in the postintervention period (32 cases per 1,000 ventilator days to 12 cases per 1,000 ventilator days; p<.001). Statistical process control charts showed the decrease was most marked after bundle implementation. Patient cohorts staying >=6 and >=14 days had greater reduction in ventilator-associated pneumonia acquisition and also had reduced antibiotic use (reduced by 1 and 3 days; p=.008/.007, respectively). Rates of methicillin resistant Staphylococcus aureus acquisition also decreased (10% to 3.6%; p<.001). CONCLUSIONS: Implementation of a ventilator-associated pneumonia prevention bundle was associated with a statistically significant reduction in ventilator associated pneumonia, which had not been achieved with earlier ad hoc ventilator associated pneumonia prevention guidelines in our unit. This occurred despite an inability to meet bundle compliance targets of 95% for all elements. Our data support the systematic approach to achieving high rates of process compliance and suggest systematic introduction can decrease both infection incidence and antibiotic use, especially for patients requiring longer duration of ventilation. PMID- 21666445 TI - Levosimendan reduces heart failure after cardiac surgery: a prospective, randomized, placebo-controlled trial. AB - OBJECTIVE: To investigate whether levosimendan diminishes the incidence of heart failure after cardiac surgery. DESIGN: Prospective, randomized, placebo controlled clinical study. SETTING: Cardiac surgery operating room and postanesthesia care unit in a university hospital. PATIENTS: Two hundred patients assigned to undergo heart valve or combined heart valve and coronary artery bypass grafting surgery. INTERVENTIONS: Patients were randomized to receive a 24 hr infusion of placebo or levosimendan administered as a 24 MUg/kg bolus over 30 mins and thereafter at a dose of 0.2 MUg/kg/min. MEASUREMENTS AND MAIN RESULTS: Heart failure was defined as cardiac index<2.0 L/min/m or failure to wean from cardiopulmonary bypass necessitating inotrope administration for at least 2 hrs postoperatively. Heart failure was less frequent in the levosimendan compared to the placebo group: 15 patients (15%) in the levosimendan and 59 patients (58%) in the placebo group experienced heart failure postoperatively (risk ratio 0.26; 95% confidence interval 0.16-0.43; p<.001). Accordingly, a rescue inotrope (adrenaline) was needed less frequently in the levosimendan compared to the placebo group (risk ratio 0.11; 95% confidence interval 0.01-0.89), p=.005. Intra aortic balloon pump was utilized in one patient (1%) in the levosimendan and in nine patients (9%) in the placebo group (risk ratio 0.11; 95% confidence interval 0.01-0.87), p=.018. The hospital and the 6-month mortality were comparable between groups. There were no significant differences in major organ failures postoperatively. Eighty-three patients were hypotensive and needed noradrenaline in the levosimendan compared to 52 patients in the placebo group, p<.001. The cardiac enzymes (creatine kinase MB isoenzyme mass) indicating myocardial damage were lower in the levosimendan group on the first postoperative day, p=.011. CONCLUSIONS: In the present study, levosimendan infusion reduced the incidence of heart failure in cardiac surgery patients but was associated with arterial hypotension and increased requirement of vasopressor agents postoperatively. Improved mortality or morbidity was not demonstrated. PMID- 21666447 TI - Comparisons of predictive performance of breathing pattern variability measured during T-piece, automatic tube compensation, and pressure support ventilation for weaning intensive care unit patients from mechanical ventilation. AB - OBJECTIVE: To investigate the influence of different ventilatory supports on the predictive performance of breathing pattern variability for extubation outcomes in intensive care unit patients. DESIGN AND SETTING: A prospective measurement of retrospectively analyzed breathing pattern variability in a medical center. PATIENTS: Sixty-eight consecutive and ready-for-weaning patients were divided into success (n=45) and failure (n=23) groups based on their extubation outcomes. MEASUREMENTS: Breath-to-breath analyses of peak inspiratory flow, total breath duration, tidal volume, and rapid shallow breathing index were performed for three 30-min periods while patients randomly received T-piece, 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure, and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure trials. Coefficient of variations and data dispersion (standard descriptor values SD1 and SD2 of the Poincare plot) were analyzed to serve as breathing pattern variability indices. MAIN RESULTS: Under all three trials, breathing pattern variability in extubation failure patients was smaller than in extubation success patients. Compared to the T-piece trial, 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure decreased the ability of certain breathing pattern variability indices to discriminate extubation success from extubation failure. The areas under the receiver operating characteristic curve of these breathing pattern variability indices were: T-piece (0.73-0.87)>100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure (0.60-0.79)>5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure (0.53-0.76). Analysis of the classification and regression tree indicated that during the T piece trial, a SD1 of peak inspiratory flow>3.36 L/min defined a group including all extubation success patients. Conversely, the combination of a SD1 of peak inspiratory flow <=3.36 L/min and a coefficient of variations of rapid shallow breathing index <=0.23 defined a group of all extubation failure patients. The decision strategies using SD1 of peak inspiratory flow and coefficient of variations of rapid shallow breathing index measured during 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure trials achieved a less clear separation of extubation failure from extubation success. CONCLUSIONS: Since 100% inspiratory automatic tube compensation with 5 cm H2O positive end-expiratory pressure and 5 cm H2O pressure support ventilation with 5 cm H2O positive end-expiratory pressure reduce the predictive performance of breathing pattern variability, breathing pattern variability measurement during the T-piece trial is the best choice for predicting extubation outcome in intensive care unit patients patients. PMID- 21666448 TI - Clinical practices, complications, and mortality in neurological patients with acute severe hypertension: the Studying the Treatment of Acute hyperTension registry. AB - OBJECTIVE: To determine the demographic and clinical features, hospital complications, and predictors of 90-day mortality in neurologic patients with acute severe hypertension. DESIGN: Studying the Treatment of Acute hyperTension (STAT) was a multicenter (n=25) observational registry of adult critical care patients with severe hypertension treated with intravenous therapy. SETTING: Emergency department or intensive care unit. PATIENTS: A qualifying blood pressure measurement>180 mm Hg systolic or >110 mm Hg diastolic (>140/90 mm Hg for subarachnoid hemorrhage) was required for inclusion in the STAT registry. Patients with a primary neurologic admission diagnosis were included in the present analysis. INTERVENTIONS: All patients were treated with at least one parenteral (bolus or continuous infusion) antihypertensive agent. MEASUREMENTS AND MAIN RESULTS: Of 1,566 patients included in the STAT registry, 432 (28%) had a primary neurologic diagnosis. The most common diagnoses were subarachnoid hemorrhage (38%), intracerebral hemorrhage (31%), and acute ischemic stroke (18%). The most common initial drug was labetalol (48%), followed by nicardipine (15%), hydralazine (15%), and sodium nitroprusside (13%). Mortality at 90 days was substantially higher in neurologic than in non-neurologic patients (24% vs. 6%, p<.0001). Median initial blood pressure was 183/95 mm Hg and did not differ between survivors and nonsurvivors. In a multivariable analysis, neurologic patients who died experienced lower minimal blood pressure values (median 103/45 vs. 118/55 mm Hg, p<.0001) and were less likely to experience recurrent hypertension requiring intravenous treatment (29% vs. 51%, p=.0001) than those who survived. Mortality was also associated with an increased frequency of neurologic deterioration (32% vs. 10%, p<.0001). CONCLUSION: Neurologic emergencies account for approximately 30% of hospitalized patients with severe acute hypertension, and the majority of those who die. Mortality in hypertensive neurologic patients is associated with lower minimum blood pressure values, less rebound hypertension, and a higher frequency of neurologic deterioration. Excessive blood pressure reduction may contribute to poor outcome after severe brain injury. PMID- 21666449 TI - Accuracy of a continuous noninvasive hemoglobin monitor in intensive care unit patients. AB - OBJECTIVE: To determine whether noninvasive hemoglobin measurement by Pulse CO Oximetry could provide clinically acceptable absolute and trend accuracy in critically ill patients, compared to other invasive methods of hemoglobin assessment available at bedside and the gold standard, the laboratory analyzer. DESIGN: Prospective study. SETTING: Surgical intensive care unit of a university teaching hospital. PATIENTS: Sixty-two patients continuously monitored with Pulse CO-Oximetry (Masimo Radical-7). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Four hundred seventy-one blood samples were analyzed by a point-of-care device (HemoCue 301), a satellite lab CO-Oximeter (Siemens RapidPoint 405), and a laboratory hematology analyzer (Sysmex XT-2000i), which was considered the reference device. Hemoglobin values reported from the invasive methods were compared to the values reported by the Pulse CO-Oximeter at the time of blood draw. When the case-to-case variation was assessed, the bias and limits of agreement were 0.0+/-1.0 g/dL for the Pulse CO-Oximeter, 0.3+/-1.3g/dL for the point-of-care device, and 0.9+/-0.6 g/dL for the satellite lab CO-Oximeter compared to the reference method. Pulse CO-Oximetry showed similar trend accuracy as satellite lab CO-Oximetry, whereas the point-of-care device did not appear to follow the trend of the laboratory analyzer as well as the other test devices. CONCLUSION: When compared to laboratory reference values, hemoglobin measurement with Pulse CO-Oximetry has absolute accuracy and trending accuracy similar to widely used, invasive methods of hemoglobin measurement at bedside. Hemoglobin measurement with pulse CO-Oximetry has the additional advantages of providing continuous measurements, noninvasively, which may facilitate hemoglobin monitoring in the intensive care unit. PMID- 21666446 TI - Noninvasive versus invasive ventilation for acute respiratory failure in patients with hematologic malignancies: a 5-year multicenter observational survey. AB - BACKGROUND: Mortality is high among patients with hematologic malignancies admitted to intensive care units for acute respiratory failure. Early noninvasive mechanical ventilation seems to improve outcomes. OBJECTIVE: To characterize noninvasive mechanical ventilation use in Italian intensive care units for acute respiratory failure patients with hematologic malignancies and its impact on outcomes vs. invasive mechanical ventilation. DESIGN, SETTING, PARTICIPANTS: Retrospective analysis of observational data prospectively collected in 2002-2006 on 1,302 patients with hematologic malignancies admitted with acute respiratory failure to 158 Italian intensive care units. MEASUREMENTS: Mortality (intensive care unit and hospital) was assessed in patients treated initially with noninvasive mechanical ventilation vs. invasive mechanical ventilation and in those treated with invasive mechanical ventilation ab initio vs. after noninvasive mechanical ventilation failure. Findings were adjusted for propensity scores reflecting the probability of initial treatment with noninvasive mechanical ventilation. RESULTS: Few patients (21%) initially received noninvasive mechanical ventilation; 46% of these later required invasive mechanical ventilation. Better outcomes were associated with successful noninvasive mechanical ventilation (vs. invasive mechanical ventilation ab initio and vs. invasive mechanical ventilation after noninvasive mechanical ventilation failure), particularly in patients with acute lung injury/adult respiratory distress syndrome (mortality: 42% vs. 69% and 77%, respectively). Delayed vs. immediate invasive mechanical ventilation was associated with slightly but not significantly higher hospital mortality (65% vs. 58%, p=.12). After propensity score adjustment, noninvasive mechanical ventilation was associated with significantly lower mortality than invasive mechanical ventilation. LIMITATIONS: The population could not be stratified according to specific hematologic diagnoses. Furthermore, the study was observational, and treatment groups may have included unaccounted for differences in covariates although the risk of this bias was minimized with propensity score regression adjustment. CONCLUSIONS: In patients with hematologic malignancies, acute respiratory failure should probably be managed initially with noninvasive mechanical ventilation. Further study is needed to determine whether immediate invasive mechanical ventilation might offer some benefits for those with acute lung injury/adult respiratory distress syndrome. PMID- 21666450 TI - Heart-lung interactions measured by electrical impedance tomography. AB - OBJECTIVE: The clinical value of stroke volume variations to assess intravascular fluid status in critically ill patients is well known. Electrical impedance tomography is a noninvasive monitoring technology that has been primarily used to assess ventilation. We investigated the potential of electrical impedance tomography to measure left ventricular stroke volume variation as an expression of heart-lung interactions. The objective of this study was thus to determine in a set of different hemodynamic conditions whether stroke volume variation measured by electrical impedance tomography correlates with those derived from an aortic ultrasonic flow probe and arterial pulse contour analysis. DESIGN: Prospective animal study. SETTING: University animal research laboratory. SUBJECTS: Domestic pigs, 29-50 kg. INTERVENTIONS: A wide range of hemodynamic conditions were induced by mechanical ventilation at different levels of positive end-expiratory pressure (0-15 cm H2O) and with tidal volumes of 8 and 16 mL/kg of body weight and by hypovolemia due to blood withdrawal with subsequent retransfusion followed by infusions of hydroxyethyl starch. MEASUREMENTS AND MAIN RESULTS: In eight pigs, aortic stroke volume variations measured by electrical impedance tomography were measured and compared to those derived from an aortic ultrasonic flow probe and from arterial pulse contour analysis. Data for four animals were used to develop and train a novel frequency-domain electrical impedance tomography analysis algorithm, while data for the remaining four were used to test the performance of the novel methodology. Correlation of stroke volume variation measured by electrical impedance tomography and that derived from an aortic ultrasonic flow probe was significant (r = 0.69; p < .001), as was the correlation between stroke volume variation measured by electrical impedance tomography and that derived from arterial pulse contour analysis (r = 0.73; p < .001). Correlation of stroke volume variation derived from an aortic ultrasonic flow probe and that derived from arterial pulse contour analysis was significant too (r = 0.82; p < .001). Bland-Altman analysis comparing stroke volume variation measured by electrical impedance tomography and that derived from an aortic ultrasonic flow probe revealed an overall bias of 1.87% and limits of agreement of +/- 7.02%; when comparing stroke volume variation measured by electrical impedance tomography and that derived from arterial pulse contour analysis, the overall bias was 0.49% and the limits of agreement were +/- 5.85%. CONCLUSION: Stroke volume variation measured by electrical impedance tomography correlated with both the gold standard of direct aortic blood flow measurements of stroke volume variation and pulse contour analysis, marking an important step toward a completely noninvasive monitoring of heart-lung interactions. PMID- 21666451 TI - Hypoglycemia at admission is associated with inhospital mortality in Ugandan patients with severe sepsis. AB - OBJECTIVE: Dysglycemia during sepsis is associated with poor outcomes in resource rich settings. In resource-limited settings, hypoglycemia is often diagnosed clinically without the benefit of laboratory support. We studied the utility of point-of-care glucose monitoring to predict mortality in severely septic patients in Uganda. DESIGN: Prospective observational study. SETTING: One national and two regional referral hospitals in Uganda. PATIENTS: We enrolled 532 patients with sepsis at three hospitals in Uganda. The analysis included 418 patients from the three sites with inhospital mortality data, a documented admission blood glucose concentration, and evidence of organ dysfunction at admission (systolic blood pressure<=100 mm Hg, lactate>4 mmol/L, platelet number<100,000/MUL, or altered mental status). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the association between admission point-of-care blood glucose concentration and inhospital mortality. We also assessed the accuracy of altered mental status as a predictor of hypoglycemia. Euglycemia occurred in 33.5% (140 of 418) of patients, whereas 16.3% (68 of 418) of patients were hypoglycemic and 50.2% (210 of 418) were hyperglycemic. Univariate Cox regression analyses comparing in-hospital mortality among hypoglycemic (35.3% [24 of 68], hazard ratio 2.0, 95% confidence interval 1.2-3.6, p=.013) and hyperglycemic (29.5% [62 of 210], hazard ratio 1.5, 95% confidence interval 0.96-2.4, p=.08) patients to euglycemic (19.3% [27 of 140]) patients showed statistically significantly higher rates of inhospital mortality for patients with hypoglycemia. Hypoglycemia (adjusted hazard ratio 1.9, 95% confidence interval 1.1-3.3, p=.03) remained significantly and independently associated with inhospital mortality in the multivariate model. The sensitivity and specificity of altered mental status for hypoglycemia were 25% and 86%, respectively. CONCLUSION: Hypoglycemia is an independent risk factor for inhospital mortality in patients with severe sepsis and cannot be adequately assessed by clinical examination. Correction of hypoglycemia may improve outcomes of critically ill patients in resource-limited settings. PMID- 21666452 TI - Pleural effusion complicates monitoring of respiratory mechanics. AB - OBJECTIVES: Although pleural effusion reduces respiratory system compliance by restricting the lungs, the effusion volume is partially accommodated by chest wall expansion. The implications for these opposing volume changes on airway pressure monitoring in ventilated patients with pleural effusion are unreported. We investigated the interactions among pleural effusion, positive end-expiratory pressure, and indices of respiratory mechanics in a swine model. DESIGN: Interventional animal model. SETTING: Hospital animal research facility. SUBJECTS: Nine deeply anesthetized swine. INTERVENTIONS: The preparation included tracheostomy, arterial/venous catheter placement, and chest tube insertion. Animals were ventilated throughout the study at 9 mL/kg, and frequency was adjusted to maintain normocapnia (inspiratory:expiratory=1:2, FIO2=0.5) and positive end-expiratory pressure of 1 cm H2O and 10 cm H2O. Fluid was instilled into the right pleural space to simulate effusions of 13 mL/kg (pleural effusion 1) and 26 mL/kg (pleural effusion 2). MEASUREMENTS AND MAIN RESULTS: Quantitative computerized tomography studies (in five animals) and functional residual capacity volumes (wash-in/wash-out technique) were obtained for each pleural effusion/positive end-expiratory pressure combination. Mean functional residual capacity compared to baseline at positive end-expiratory pressure of 1 cm H2O was decreased by pleural effusion 1 and pleural effusion 2 (-42%, -64%) and restored by positive end-expiratory pressure of 10 cm H2O (moderate) to +23% of baseline for pleural effusion 1 and +1% for pleural effusion 2. Plateau pressure increased and compliance decreased in response to pleural effusion 1 and pleural effusion 2. Moderate positive end-expiratory pressure applied during both pleural effusion quantities restored plateau pressure and tidal compliance to prepleural effusion values. Computed tomography studies revealed lung compression and tidal derecruitment cycles occurring with pleural effusion at positive end-expiratory pressure of 1 cm H2O, whereas a moderate positive end-expiratory pressure restored prepleural effusion functional residual capacity and prevented lung and intratidal derecruitment. CONCLUSIONS: When pleural effusion is present, respiratory mechanics must be interpreted cautiously and sufficient positive end expiratory pressure should be applied to prevent extensive collapse and intratidal cycles of recruitment/derecruitment. PMID- 21666454 TI - Murine models in critical care research. AB - INTRODUCTION: Access to genetically engineered mice has opened many new opportunities to address questions relevant to the pathophysiology and treatment of patients in critical conditions. However, the results of studies in mice cannot disregard the unique ability of small rodents to adjust their temperature and high metabolic rate and the corresponding respiratory and circulatory requirements in response to hypoxia. POINT OF VIEW: Studies performed in mice on questions related to metabolic, circulatory, and respiratory regulation should always be considered in light of the ability of mice to rapidly drop their nonshivering thermogenesis-related metabolism. As an example, it has been recently argued that a moderate level of inhaled hydrogen sulfide may have a potential benefit in patients in coma or shock or during an anoxic or ischemic insult, as this toxic gas dramatically reduces the metabolic rate in resting mice. However, acute hypometabolism has long been described in small mammals in response to hypoxia and is not specific to hydrogen sulfide. More importantly, mice have a specific metabolic rate that is 15-20 times higher than the specific metabolic level of a resting human. This difference can be accounted for by the large amount of heat produced by mice through nonshivering thermogenesis, related to the activity of uncoupling proteins. This mechanism, which is essential for maintaining homeothermia in small mammals, is virtually absent in larger animals, including in adult humans. Accordingly, no direct metabolic effect of hydrogen sulfide is observed in large mammals. We present the view that similar reasoning should be applied when the circulatory or respiratory response to hypoxic exposure is considered. This leads us to question whether a similar strategy could occur in mice in critical conditions other than hypoxia, such as in hypovolemic, septic, or cardiogenic shock. CONCLUSION: Mouse models developed to understand the mechanisms of protection against hypoxia or ischemia or to propose new therapeutic approaches applicable in critical care patients should be understood in light of the specificity of the metabolic, respiratory, and circulatory responses of mice to a hypoxic insult, since many of these adaptations have no clear equivalent in humans. PMID- 21666453 TI - Protective effect of milk fat globule-epidermal growth factor-factor VIII after renal ischemia-reperfusion injury in mice. AB - OBJECTIVES: Renal ischemia-reperfusion injury causes acute renal failure, and the hallmarks of renal ischemia-reperfusion injury are inflammation, apoptosis, necrosis, and capillary dysfunction. Milk fat globule-epidermal growth factor factor VIII (MFG-E8), a membrane-associated secretory glycoprotein, is produced by immune cells and reported to participate in multiple physiologic processes associated with tissue remodeling. We have recently shown that MFG-E8 treatment attenuates organ injury, inflammatory responses, and survival after sepsis through the enhancement of phagocytosis of apoptotic cells. The purpose of this study was to determine whether administration of MFG-E8 attenuates renal ischemia reperfusion injury. DESIGN: Prospective, controlled, and randomized animal study. SETTING: : A research institute laboratory. SUBJECTS: Male C57BL/6J mice (20-25 g). INTERVENTIONS: : Renal ischemia-reperfusion injury with bilateral renal pedicle clamping for 45 mins, followed by reperfusion. A recombinant murine MFG E8 (0.4 MUg/20 g) was given intraperitoneally at the beginning of reperfusion. MEASUREMENTS AND MAIN RESULTS: MFG-E8 levels, organ injury variables, inflammatory responses, histology, apoptosis, and capillary functions were assessed at 1.5 and 20 hrs after reperfusion. A 60-hr survival study was conducted in MFG-E8 and recombinant murine MFG-E8-treated wild-type mice. After renal ischemia-reperfusion injury, MFG-E8 mRNA and protein expressions were significantly decreased in the kidneys and spleen. Treatment with recombinant murine MFG-E8 recovered renal dysfunction, significantly suppressed inflammatory responses, apoptosis, necrosis, and improved capillary functions in the kidneys. In the survival study, MFG-E8 mice showed a significant deterioration and, in contrast, recombinant murine MFG-E8-treated wild-type mice showed a significant improvement of survival compared with vehicle-treated wild-type mice. CONCLUSIONS: MFG-E8 can be developed as novel treatment for renal ischemia reperfusion injury. This protective effect appears to be mediated through the enhancement of apoptotic cell clearance and improvement of capillary functions in the kidneys. PMID- 21666455 TI - Managing intravascular catheter-related infections in heart transplant patients: how far can we apply IDSA guidelines for immunocompromised patients? AB - PURPOSE OF REVIEW: This study discusses the applicability to heart transplant patients of recently issued guidelines on the diagnosis, management and prevention of catheter-related bloodstream infections (CR-BSIs). It also updates newly available information of possible interest to the care of heart transplant patients. RECENT FINDINGS: Catheters remain the leading cause of early bloodstream infections in heart transplant patients. The cause of CR-BSI is mainly attributable to Gram-positive microorganisms. Very frequently, the origin of a bloodstream infection in a heart transplant patient with multiple catheters is not clear, and a precise diagnosis is required. Management without catheter removal may be undertaken when indicated. Empiric therapy should cover Gram positive, multidrug resistant and Gram-negative bacteria along with Candida. Prolonged antibiotic treatment exceeding 14 days is recommended and should be continued up to 4-6 weeks in the case of Staphylococcus aureus. Prevention measures include education and training, maximal sterile barrier precautions during catheter insertion, a 2% chlorhexidine preparation for skin antisepsis, avoiding routine replacement of catheters and using antimicrobial/antiseptic impregnated short-term central vein catheters (CVCs) and chlorhexidine sponge dressings. SUMMARY: Until confirmatory data are obtained, present guidelines for diagnosing, managing and preventing CR-BSI can be applied to heart transplant patients. We would nevertheless highlight that the additional precautions should be taken of broader empiric antimicrobial therapy followed by longer duration treatment in these patients. PMID- 21666457 TI - Fungal pneumonia in patients with hematologic malignancies: current approach and management. AB - PURPOSE OF REVIEW: Fungal pneumonia is the most frequent presentation of invasive mold infections (IMIs) in patients with hematologic malignancies. In this review, we summarize recent advances in the epidemiology, diagnosis, and treatment of fungal pneumonia and improvement in the outcome of such patients. RECENT FINDINGS: The epidemiology of IMIs in hematopoietic stem cell transplant recipients has evolved in response to changes in conditioning regimens, increasing use of alternative sources of stem cells and antifungal prophylaxis, among other factors. PCR analysis and serologic tests, used in combination with imaging findings, have improved the timing and accuracy of diagnosis of these infections.Recent guidelines incorporated evidence-based treatment recommendations; however, application in real world situations is often difficult. A new treatment approach known as preemptive therapy, based on screening with biomarkers combined with early clinical and imaging findings, is being compared with the traditional empirical therapy in neutropenic patients with persistent or recurrent fever. The use of new triazoles and prompt diagnosis has contributed to improved outcomes in these patients. In addition, therapeutic drug monitoring may be useful when administering voriconazole. SUMMARY: Evidence based diagnosis and treatment of fungal pneumonia in patients with hematologic malignancies are becoming increasingly institution-specific and patient-specific, integrating host factors, new diagnostic methods, and epidemiologic and pharmacologic considerations. PMID- 21666456 TI - Immune responses against Aspergillus fumigatus: what have we learned? AB - PURPOSE OF REVIEW: Aspergillus fumigatus causes invasive and allergenic disease. Host defense relies on the ability of the respiratory immune system to restrict spore germination into invasive hyphae and to limit fungus-induced or inflammation-induced damage in infected tissues. This review covers the molecular and cellular events that mediate innate and CD4 T-cell responses to A. fumigatus and fungal attributes that counter hostile microenvironments and, in turn, affect host responses. RECENT FINDINGS: Host recognition of fungal cell wall components is critical for fungal uptake, killing, and the formation of protective innate and CD4 T-cell effector populations. Beyond the known role of neutrophils and macrophages, circulating monocytes, dendritic cells, and natural killer cells contribute to optimal defense against A. fumigatus. Genetic and pharmacologic manipulation of A. fumigatus reveals that hypoxia adaptation, cell wall assembly, and secondary metabolite production in mammalian tissues contribute to fungal pathogenesis and the outcome of infection. SUMMARY: Greater understanding of the immune mechanisms that underlie protective responses and fungal pathways that promote microbial adaptation and growth in mammalian tissue provide a conceptual framework for improving current antifungal therapies. PMID- 21666458 TI - Human herpesvirus 8-associated neoplasms: the roles of viral replication and antiviral treatment. AB - PURPOSE OF REVIEW: In this review, we highlight the importance of human herpesvirus 8 (HHV-8) lytic replication and the potential for antiviral therapies to prevent or treat HHV-8-related neoplasms. RECENT FINDINGS: Diseases caused by HHV-8 infection include Kaposi sarcoma, multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL), which occur primarily in patients with HIV infection. Kaposi sarcoma is the most common AIDS-associated malignancy worldwide. MCD and PEL occur less commonly but, like Kaposi sarcoma, are associated with poor treatment outcomes. Like all herpesviruses, HHV-8 is capable of either latent or lytic infection of cells. Although HHV-8 infection of tumor cells is predominately latent, accumulating data point to the importance of both lytic phase viral gene products and production of infectious virus. Antiviral agents that target herpesvirus DNA synthesis, such as ganciclovir, inhibit HHV-8 lytic replication and can prevent Kaposi sarcoma. Several HIV protease inhibitors may interfere with tumor growth and angiogenesis, and one protease inhibitor, nelfinavir, directly inhibits HHV-8 replication in vitro. SUMMARY: Controlled trials are indicated to determine the clinical utility of antiviral suppression of HHV-8 replication, and identify the optimal antiretroviral regimens, for the prevention and treatment of Kaposi sarcoma. PMID- 21666459 TI - Prevention of hospital-acquired legionellosis. AB - PURPOSE OF REVIEW: The incidence of hospital-acquired legionellosis appears to be increasing. Presence of Legionella in the hospital drinking water is the only risk factor known with certainty to be predictive of risk for contracting Legionnaires' disease. RECENT FINDINGS: Given the high frequency of infection by nonpneumophila and nonserogroup 1 species, both Legionella respiratory culture on selective media and urine antigen testing should be available in the hospital clinical microbiology laboratory. If the drinking water is contaminated by nonpneumophila or nonserogroup 1 species, Legionella culture on selective media must be available for patients with hospital-acquired pneumonia. The impact of PCR application for environmental water specimen remains to be elucidated. Its advantage is that it is a rapid test and its weakness is its low specificity. Copper-silver ionization disinfection and point-of-use (POU) filters have proved effective. Chlorine dioxide and monochloramine are under evaluation and their ultimate role remains to be elucidated. Routine Legionella cultures in concert with disinfectant levels are the best indicators for ensuring long-term efficacy. Percentage distal site positivity for Legionella in drinking water is accurate in predicting risk. Quantitative criteria (CFU/ml) have proven inaccurate and should be abandoned. SUMMARY: Infection control professionals, not healthcare facility personnel or engineers, should play the leadership role in selecting and evaluating the specific disinfection modality. Proactive measures of routine environmental cultures for hospital water and disinfection modalities allow for effective prevention of this high-profile hospital-acquired infection. PMID- 21666461 TI - Contraceptive considerations in overweight teens. AB - PURPOSE OF REVIEW: The purpose of this review is to explore the efficacy and safety of contraceptives in overweight adolescents. RECENT FINDINGS: There are few studies exploring hormonal contraceptive efficacy and safety in overweight and obese adults and almost none addressing these issues in adolescents. Luckily for teens, in terms of safety, many of the comorbidities associated with obesity are yet to transpire and their options for contraception remain relatively unrestricted. Studies of the combined oral contraceptive pill and patch in adults suggest that efficacy may be decreased in overweight adolescents. There is no evidence to suggest that the efficacy of the contraceptive implant or intrauterine device (IUD) is decreased in overweight adolescents. Indeed, these long-acting reversible methods will be the best choice for many adolescents because of their high efficacy. Although the literature is not definitive, there is probably a subset of adolescents who are susceptible to weight gain with use of depot medroxyprogesterone acetate. SUMMARY: Although there is little research regarding contraceptive efficacy in overweight adolescents, IUDs and implants will be the best methods for many adolescents because of their high efficacy, reversibility, and safety. PMID- 21666462 TI - Laparoscopic entry techniques. PMID- 21666460 TI - Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients. AB - PURPOSE OF REVIEW: New respiratory viruses have been discovered in recent years and new molecular diagnostic assays have been developed that improve our understanding of respiratory virus infections. This article will review the changing epidemiology of these viruses after hematopoietic stem cell and solid organ transplantation. RECENT FINDINGS: Respiratory viruses are frequently detected in transplant recipients. A number of viruses have been newly discovered or emerged in the last decade, including human metapneumovirus, human bocavirus, new human coronaviruses and rhinoviruses, human polyomaviruses, and a new 2009 pandemic strain of influenza A/H1N1. The potential for these viruses to cause lower respiratory tract infections after transplantation varies, and is greatest for human metapneumovirus and H1N1 influenza, but appears to be limited for the other new viruses. Acute and long-term complications in hematopoietic and solid organ transplant recipients are active areas of research. SUMMARY: Respiratory viral infections are frequently associated with significant morbidity following transplantation and are therefore of great clinical and epidemiologic interest. As new viruses are discovered, and more sensitive diagnostic methods are developed, defining the full impact of emerging respiratory viruses in transplant recipients must be elucidated by well designed clinical studies. PMID- 21666463 TI - Biochemistry, molecular biology and cell biology of gonadotropin-releasing hormone antagonists. AB - PURPOSE OF REVIEW: Gonadotropin-releasing hormone (GnRH) receptors are not only detected in the central nervous system but also in tissues such as ovary, endometrium, breast, gastrointestinal system, placenta and malignant tumors of ovary and breast. The direct role of GnRH-antagonists in ovarian function, implantation, cancer pathogenesis and treatment is under extensive investigation. This study reviews the biochemistry and molecular and cellular biology of GnRH antagonists as well as GnRH types and their receptors. RECENT FINDINGS: The best clinical evidence with GnRH-antagonists has accumulated in controlled ovarian hyperstimulation protocols for prevention of premature luteinizing hormone surge (cetrorelix, ganirelix) and in the treatment of advanced-stage prostate cancer (abarelix and degarelix). GnRH-GnRH receptor pathways may have a role in the embryo implantation. The controversy still exists whether GnRH antagonist protocols result in slightly decreased clinical pregnancy rates compared with the GnRH agonist protocols. GnRH-antagonists could be used in the near future to treat some cancer types that express GnRH receptors. SUMMARY: GnRH-antagonists have various clinical applications in gynecology, reproductive medicine, urology and oncology. The emergence of well tolerated, orally active GnRH-antagonists may provide an alternative to long-term injections and is likely to have a major impact on the utility of GnRH analogues in the treatment of human diseases. PMID- 21666464 TI - Endometriosis classification: an update. AB - PURPOSE OF REVIEW: Endometriosis remains an enigmatic disease for many reasons, not the least being a continued inability to stage its clinical presentation so that prognosis and treatment for both pain and infertility patients can be facilitated. This article reviews issues with current staging systems. RECENT FINDINGS: The revised American Fertility Society (rAFS) classification system has historically been the only classification system. Recently, the ENZIAN classification system, developed as an adjunct to the rAFS to describe more severe disease, has been introduced but is rarely used. More recently, the Endometriosis Fertility Index (EFI) that has been validated to predict pregnancy rates in infertility patients following surgical diagnosis and treatment of endometriosis was published. Currently, the AAGL is developing a categorization system that will be more focused on pain. Novel research in imaging, biomarkers, histology, and the human genome may provide useful information to develop future classification systems. SUMMARY: The only validated endometriosis classification system that predicts a clinical outcome is the EFI. It is to be hoped that renewed interest in the importance and utility of classification systems will result in novel classification systems that are clinically useful. PMID- 21666465 TI - The role of human papillomavirus on sperm function. AB - PURPOSE OF REVIEW: To review the role of human papillomavirus (HPV) on sperm parameters, fertility and implication of the use of infected sperm cells in assisted reproduction. RECENT FINDINGS: HPVs are agents of the most common sexually transmitted disease and can lead to warts and cancers both in men and women.A high incidence of HPV infection has been demonstrated in sperm from sexually active men with and without risk factors for HPV and from infertile patients. Semen infection is associated to an impairment of sperm parameters suggesting a possible role in male infertility. Interestingly, it has been demonstrated that when HPV is present in semen only a percentage of total cells are infected and the virus can be localized in sperm or in exfoliated cells with different impact on sperm motility. Moreover, infected sperm are able to penetrate the oocyte, to deliver HPV genome in the oocyte and HPV genes can be actively transcribed by the fertilized oocyte. Recently an increased risk of pregnancy loss has been demonstrated in couples undergoing in-vitro fertilization and particularly when HPV DNA was present in semen samples of male partners. SUMMARY: To date, no effective treatment, control strategy and prevention is provided for men despite the reported high incidence of HPV semen infection. Because this infection in men is also a problem for partners, and because growing evidence suggests that semen infection may cause infertility and early miscarriage, more attention should be paid to male HPV infection. This study reviews the more recent literature about the role of HPV infection on sperm function and human reproduction. PMID- 21666466 TI - Minimally invasive gynecologic procedures. AB - PURPOSE OF REVIEW: To evaluate different surgical options for the treatment of endometriomas. A heated debate is currently under way between advocates of excisional surgery and the ablative approach. With papers increasingly focusing on ovarian reserve after endometrioma surgery, a review was mandatory. RECENT FINDINGS: Excisional and ablative surgery are well known procedures. This paper describes a combined technique that allows preservation of ovarian volume and antral follicle count. The question of postoperative ovarian reserve is widely discussed and the risk of malignancy is addressed. SUMMARY: Some previously published reviews have probably too hastily concluded that excision is a better option than ablation. They failed to analyze the ovarian reserve, which is often significantly decreased after excisional surgery.This manuscript clearly explains the crucial importance of preserving the ovarian blood supply, as well as the ovarian cortex containing all primordial follicles, during surgery. PMID- 21666467 TI - Robotic versus laparoscopic hysterectomy: a review of recent comparative studies. AB - PURPOSE OF REVIEW: To illustrate the current stand on robotic versus conventional laparoscopic hysterectomy regarding operating times, clinical outcome and costs. RECENT FINDINGS: Only six studies were reviewed, as there are only few recent studies comparing robotic with laparoscopic hysterectomy and most are retrospective. Apart from one multicentre study with over 36 000 patients, 350 institutions and numerous surgeons, most studies were performed with few cases by one or two surgeons at one or two hospitals. Operating times for robotic hysterectomies generally were longer, ranging from 89.9 to 267 min. Surgery time for conventional laparoscopic hysterectomies was between 83 and 206 min. In all studies, clinical outcomes such as blood loss, complications or hospital stay of both the robotic and the conventional laparoscopic procedure were similar. Only two studies compared costs and both came up with very similar findings. Cost for a robot-assisted hysterectomy is approximately 2600 USD higher than that for conventional laparoscopic hysterectomy not including investment and amortization. SUMMARY: Robotic and conventional laparoscopic hysterectomy are essentially equivalent regarding surgical and clinical outcome. Operating times are slightly higher and costs are significantly higher for the robotic procedure. PMID- 21666468 TI - The treatment of rectal endometriosis and the role of laparoscopic surgery. AB - PURPOSE OF REVIEW: Rectal endometriosis is a very indolent disease whose treatment has been debated by a range of competing schools. Meanwhile, not all audiences in the scientific community are entirely familiar with the full aspects of the disease. Hence, the purpose of this review is to outline the basic as well as the recent literature pertaining to the disease, thus offering a broader view to the interested reader. RECENT FINDINGS: Laparoscopic shaving or disc excision for rectal endometriotic nodules may be simple, safe options of controlling the disease. On the contrary, laparoscopic rectal resections, originally reserved for more extensive disease, are now more skillfully mastered by surgeons and gynecologists. Meta-analyses, retrospective, and prospective studies are being published frequently supporting one form of therapy at a time and discrediting another at other times. SUMMARY: Laparoscopic shaving or disc excisions for rectal endometriotic foci or rectal resections are feasible and efficient methods for treating rectal endometriosis. More complex surgery to the bowel means more risk for complications. With the rising learning curve of the operators, laparoscopic rectal resections have become a safe option that should be offered to patients. The patient's preference to a particular treatment option should be central to the type of surgery to be elected. PMID- 21666469 TI - The role of laparoscopic myomectomy in the management of uterine fibroids. AB - PURPOSE OF REVIEW: Laparoscopic myomectomy has been described as comparable to open myomectomy in terms of fertility and obstetrical outcome with decreased intraoperative bleeding and postoperative disability. Despite this, laparoscopic myomectomy is not widely used reportedly due to lack of experience. This article presents our technique for laparoscopic myomectomy and assesses the current evidence-based literature for the use of this minimally invasive procedure in benign gynecological practice. RECENT FINDINGS: Literature continues to support the safety and feasibility of laparoscopic myomectomy for symptomatic women desiring to preserve their fertility. Alternatively, laparoscopically assisted myomectomy has been suggested when wider access is needed to perform the procedure. This variant of the technique allows palpating the uterus and does not require laparoscopic suturing skills. Robotic-assisted laparoscopic myomectomy currently has limited advantage over conventional laparoscopy due to longer operative time, loss of tactile sensation necessary to detect intramural myomas and high cost. Single-port surgery is a new promising approach, but still requires extensive investigation to determine whether it has significant benefits over conventional techniques. SUMMARY: Laparoscopic myomectomy cases are mostly doable, but may become difficult if bleeding problems occur. Extended operative times may be required for morcellation and extensive laparoscopic suturing. Gynecologists need to improve their laparoscopic skills, as minimally invasive surgery is becoming the sine qua non of a modern surgeon. PMID- 21666471 TI - Surgical methods in the treatment of congenital anomalies of the uterine cervix. AB - PURPOSE OF REVIEW: Cervical agenesis is an extremely rare congenital anomaly of the female reproductive tract. There are many anatomical forms that constitute this type of cervical abnormality and the literature is replete with attempts to surgically restore a patent outflow tract and preserve fertility in these patients. There are no carefully designed cohort or randomized trials to support a best surgical practice; past reports are descriptive only. RECENT FINDINGS: Of late, there has been renewed interest in the surgical treatment of cervical dysgenesis with techniques both through laparotomy with hysterotomy and more recently, minimally invasive approaches, which have attempted to restore a patent outflow tract without perineal dissection or graft harvesting in an attempt to avoid uterovaginal scarring if further surgery is necessary. To maintain consistency in the field of surgical reconstruction of the female reproductive tract, there has been a call for streamlined classifications of the anatomical abnormalities observed to better compare patient findings and the outcome of their surgical reconstruction in the literature. SUMMARY: The authors discuss the embryological development of this rare reproductive tract abnormality and have proposed a systematic surgical strategy for each anatomic finding. Ultimately, counseling patients on the best surgical approach requires a discussion on the potential postoperative complications, the degree of cervical abnormality, and the patient's desired treatment outcome. Whether the patient desires definitive treatment with a hysterectomy to avoid the risk of further surgery or, when anatomically appropriate, she wants to pursue a patent outflow tract and the possibility of future childbearing, evidence-based medicine must become the source for surgical strategies. PMID- 21666470 TI - Laboratory models for studying ectopic pregnancy. AB - PURPOSE OF REVIEW: Understanding the cause of tubal ectopic pregnancy (tEP) remains incomplete. We aim to summarize the latest advances in laboratory models of tEP that we believe will, ultimately, contribute to improving the diagnosis and management of the condition. RECENT FINDINGS: Progress in proteome prefractionation and multidimensional protein identification technology has proved particularly effective in identifying novel biomarkers of tEP. These, and related global proteomic and genomic approaches, have as yet to be fully exploited in this context but do have substantial potential to inform future hypothesis-driven studies. The majority of data generated since 2009 to explain the cause of tEP continues to derive from descriptive human ex-vivo studies. In vitro models of fallopian tube ciliary and smooth muscle function have improved to a limited degree, on the back of continuing advances in imaging and data acquisition. We believe that the recent development of a primary human fallopian tube epithelium culture system represents the most significant recent advance in laboratory models for studying ectopic pregnancy. There remain no good animal models of tEP. SUMMARY: The establishment of a viable animal model of tEP remains the key obstacle to a complete understanding of the cause of the condition. PMID- 21666472 TI - Some observations on prope tolerance. AB - PURPOSE OF REVIEW: To outline the rationale of powerful depleting induction therapy with alemtuzumab and minimal maintenance immunosuppression after organ transplantation. RECENT FINDINGS: The original observations in principle have been confirmed by many independent centres. SUMMARY: Follow-up of the 'prope tolerance' protocol has confirmed a low incidence of rejection, infection and post transplant lymphoproliferative disorder (PTLD). Especially, encouraging results were obtained in African-Americans. There were few side effects and the regimen was well tolerated by patients. Treg cells were observed in the circulation, which could be an important factor in the mechanisms of graft acceptance using a prope tolerance regimen. There was a considerable reduction in the costs of the transplantation procedure. It is suggested that this minimalisation of maintenance immunosuppression is the best therapy currently available that we can offer to our patients. PMID- 21666473 TI - Recent advances in immunosuppressive therapy for prevention of renal allograft rejection. AB - PURPOSE OF REVIEW: Current immunosuppressive therapies are highly successful at regulating acute allograft rejection and inducing long-term transplanted kidney survival; however, currently available medications are associated with generalized immune suppression and drug toxicities, including nephrotoxicity. In recent years, advances in immunosuppression that target specific pathways involved in immune activation have been developed. RECENT FINDINGS: In particular, promising medications are currently under evaluation that target ischemia-reperfusion injury as well as the cellular and humoral branches of the adaptive immune response. Targets of T-cell-mediated activation include antibodies and fusion proteins interfering with LFA-1/ICAM-1, CD2/LFA-3, CD40/CD154, and CD28/B7.1 and B7.2 interactions. Intracellular targets involved in T- and B-cell activation pathways are being evaluated, including protein kinase C inhibitors, Janus-associated kinase (JAK) inhibitors, and proteasome inhibitors. Several new medications demonstrate promise in inhibiting donor directed humoral immunity by targeting B-cell-activating factor (BAFF) and complement activation pathways. SUMMARY: The present review evaluates the recent clinical advances in immunosuppressive therapies for kidney transplantation. Publications regarding advances in immunosuppressive therapies over the past year were evaluated in the context of the specific immune pathways involved in allograft rejection. PMID- 21666475 TI - Quantifying HLA-specific antibodies in patients undergoing desensitization. AB - PURPOSE OF REVIEW: Two major desensitization protocols have been used to eliminate or reduce HLA antibodies to a level that allows transplantation with a low risk of antibody-mediated rejection (AMR). This review will focus on the antibody testing methods used to assess changes in the breadth and strength of antibody levels and the relative strength of donor HLA-specific antibodies (DHSAs). RECENT FINDINGS: Correlations of solid-phase immunoassay (SPI) class I and II levels with the donor-specific T and B cross-match results have shown the acceptable levels of DHSA that correlate with a low risk for AMR. The DSHA levels determined by SPI correlate with cross-match results and with clinical outcome. Therefore, the results of either assay can be used to determine the risk of AMR and when treatment has reduced DSHA to a level safe for transplantation. Monitoring DSHA is important for guiding the number of treatments as well as the timing of additional treatments needed to achieve these acceptable levels. SUMMARY: DSHA monitoring, in both protocols, uses the correlation of solid-phase antibody testing and the donor-specific cross-match to determine the efficacy of the protocol and when the acceptable level of DSHA is achieved permitting transplantation with minimal likelihood of AMR. PMID- 21666474 TI - Microchimerism in promoting graft acceptance in clinical transplantation. AB - PURPOSE OF REVIEW: Infusions of bone marrow-derived cells together with 'space making' continue to be tested in clinical organ transplant tolerance protocols. These trials are based on the hypothesis that this might produce initial multilineage chimerism. There is some evidence that this in turn induces regulatory cells that control alloimmunity. Although a wealth of knowledge is available from animal models, this review deals with what we know or can speculate about donor bone marrow cells and chimerism in human organ transplantation. RECENT FINDINGS: Calcineurin inhibitors are employed in most of these protocols to blunt the initial immune response. One protocol also has a stepwise regulatory cell generating treatment with sirolimus before total withdrawal. A number of donor chimeric lineages including stem cells, dendritic cells, myeloid precursors, and various lymphoid subpopulations have been described. Currently, it is recognized that the nature of cells that make up the chimerism could influence graft rejection versus acceptance. Tolerogenic donor chimeric cells may also generate regulatory subsets, thus controlling alloimmunity on two fronts. SUMMARY: It might be speculated that prolonged and sustained regulation or possible anergy induced by chimerism may eventually lead to clonal deletion, thereby bringing about classical immunologic tolerance. PMID- 21666476 TI - The calculated panel reactive antibody policy: an advancement improving organ allocation. AB - PURPOSE OF REVIEW: A major policy change affecting renal organ allocation to sensitized patients in the US was implemented in October, 2009. Extra allocation points are awarded to sensitized patients based on a calculated panel reactive antibody (CPRA). This review will discuss the reasons underlying this policy change and examine the evidence to date of its impact on renal allocation. RECENT FINDINGS: Comparison of both the proportion and transplant rates of sensitized renal transplant candidates during the 6 months prior to the policy implementation and 6 months after implementation showed a significant increase in transplantation of sensitized patients, with the greatest difference occurring among broadly sensitized patients with CPRA values of 80 or greater. Whereas there was a decrease in transplant rates among candidates with CPRA values from 1 to 20, both this decrease and the increased rates among the more highly sensitized recipients were proportional to the distributions of these groups on the wait list. Notably, following the policy change, there was a highly significant decrease in organ refusals due to positive cross-matches with an 83% reduction between the 6-month periods prior to and after the policy implementation. Additional analyses have recently shown the continuation of these trends 1 year after the policy implementation. SUMMARY: Implementation of the CPRA policy on national renal organ allocation in the US has increased efficiency in organ allocation and is helping to facilitate transplantation of broadly sensitized candidates. PMID- 21666477 TI - Current methodologies for detecting sensitization to HLA antigens. AB - PURPOSE OF REVIEW: Advances in solid-phase tests for antibodies directed against HLA antigens have opened new areas of sophistication in detecting and characterizing the antibodies and have improved access to transplantation for sensitized candidates. In considering desensitization as an option for sensitized patients, determining specificities and strengths of antibodies and the risk they pose before and after therapeutic interventions are critical. This review focuses on the tests that are used today to detect sensitization and their relevance to assessing risk for transplant candidates and recipients. RECENT FINDINGS: There are conflicting reports of the clinical relevance of antibodies that are detected in solid-phase assays, which provide exquisite levels of precision and sensitivity for antibody detection. There is growing evidence that low levels of donor-reactive antibody need not be always considered a contraindication to transplant. New tools for determining isotype and complement fixation in solid phase tests may also resolve some disparities. SUMMARY: Solid-phase tests for HLA antibodies now play a key role in transplantation laboratories and are widely utilized by transplant programs around the world. Although there are not rigid standards for their use and interpretation, transplant patients are benefiting from the use of these tests. PMID- 21666478 TI - Using donor exchange paradigms with desensitization to enhance transplant rates among highly sensitized patients. AB - PURPOSE OF REVIEW: Many sensitized patients have willing live donors but are unable to use them because of a human leukocyte antigen (HLA) incompatibility. The options for these patients include: remaining on the deceased-donor list, entering a kidney-paired donation scheme, or undergoing desensitization with high dose IVIg or plasmapheresis and low-dose IVIg. RECENT FINDINGS: Mathematical simulations verified by actual data from several national kidney-paired donation (KPD) programs has shed light on which donor/recipient phenotypes are likely to benefit from each transplant modality. Pairs that are easy to match are likely to receive compatible kidneys in a KPD. Those who are hard to match may be better served by desensitization. The phenotype which is both hard to match and hard to desensitize due to board and strong HLA reactivity are most likely to be transplanted by a hybrid modality utilizing desensitization after identifying a more immunologically favorable donor in a KPD. SUMMARY: Recent outcomes from desensitization in which starting donor-specific antibody strength is low have been very good. For broadly sensitized patients with a high-strength cross-match, searching for a better donor in a KPD pool can facilitate a safer, less expensive, and more successful desensitization treatment course. PMID- 21666479 TI - B-cell immunotherapeutics: emerging roles in solid organ transplantation. AB - PURPOSE OF REVIEW: The introduction of B-cell-directed therapies for autoimmune diseases illuminated the biologic relevance of B cells in mediation of autoimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation and the production of immune stimulating and immune modulatory cytokines. These advances clearly have implications for patients receiving solid organ transplants, especially those who are ABO incompatible, sensitized to human leukocyte antigen (HLA) pretransplant, or develop anti-HLA antibodies posttransplant. RECENT FINDINGS: Here, we will review the current and evolving agents developed for B-cell depletion or modulation and discuss their potential for modification of alloimmunity in transplant recipients. We will focus on data from humans and animal models in which B cells and antibodies are targeted to reduce inflammation in transplantation. This will include a review of the immunomodulatory drug intravenous immunoglobulin, anti-CD20 (rituximab) where more clinical experience has been reported. Finally, we will discuss emerging B cell-directed therapies which include those directed at the B-cell activating factor of the tumor necrosis family/A proliferation inducing ligand, anti-CD22, newer anti-CD20 monoclonals and antibodies to the interleukin 6 receptor (tocilizumab). SUMMARY: The primary objective of this review is to define the critical role of B cells in development of alloimmunity and how this can be modified by B-cell-directed therapies. PMID- 21666480 TI - Microchimerism: tolerance vs. sensitization. AB - PURPOSE OF REVIEW: The bidirectional exchange of cells, both mature and progenitor types, at the maternal-fetal interface is a common feature of mammalian reproduction. The presence of semiallogeneic cells in a host can have significant immunological effects on transplantation tolerance and rejection. Here, we review recent advances in this area. RECENT FINDINGS: Maternal microchimerism (MMc) in blood and various organs was found to be directly correlated with noninherited maternal antigen (NIMA)-specific CD4(+) regulatory T cells (Tregs), in F(1) backcross mice. In humans, MMc induced NIMA-specific FoxP3(+) CD4 Tregs in lymph nodes and spleen of fetuses. Tolerance to NIMA(+) allografts could be predicted in mice by measuring levels of the NIMA-specific Tregs in offspring before transplantation. On the contrary, fetal microchimerism (FMc) in multiparous female mice was largely confined to CD34(+) hematopoietic stem cells (HSCs) and was associated with sensitization rather than Treg induction. The recent discovery of a 'layered' T-cell development in humans whereby fetal HSCs are more likely to produce Tregs than adult HSCs, which may explain why MMc often induces tolerance, whereas FMc tends to induce sensitization. SUMMARY: Microchimerism may cause tolerance resulting in acceptance of an allograft bearing antigens shared by the microchimeric cells. However, microchimerism may also cause sensitization resulting in rejection. Distinguishing these effects prior to the transplant may revolutionize the field of living-related renal transplantation wherein MMc and FMc can exert a powerful influence on graft outcome. PMID- 21666481 TI - Pharmacological manipulation of dendritic cells in the pursuit of transplantation tolerance. AB - PURPOSE OF REVIEW: Although long-term immune suppression remains the intervention of choice for the treatment of allograft rejection, transplantation tolerance would achieve graft survival with fewer inherent risks. Although the use of dendritic cells for the induction of tolerance might confer antigen specificity, factors determining the balance between tolerogenicity and immunogenicity remain uncertain, as does the stability of the functional phenotype. Here, we review recent studies suggesting that pharmacological agents may profoundly influence this delicate balance and outline the insights they provide into parameters that contribute to the tolerogenic state. RECENT FINDINGS: Recent findings have revealed that the inhibition of dendritic cell maturation by pharmacological intervention is not a prerequisite for the acquisition of tolerogenicity, but that susceptibility to a tolerogenic phenotype may vary between dendritic cell subsets and depend on the nature of maturation stimuli to which the cells are exposed. Furthermore, such studies have highlighted the degree to which the maintenance of tolerogenicity is influenced by local environmental factors, such as the cytokine milieu. SUMMARY: Although the rational design of tolerogenic dendritic cells for modulating the outcome of organ transplantation remains ambitious, the use of pharmacological agents to influence their functional phenotype continues to illuminate the basic biology of this critical cell type. PMID- 21666482 TI - Preclinical and clinical studies on the induction of renal allograft tolerance through transient mixed chimerism. AB - PURPOSE OF REVIEW: The present review updates the current status of research for induction of tolerance through a mixed chimerism approach in nonhuman primates and humans. RECENT FINDINGS: Allograft tolerance has been successfully achieved with a nonmyeloablative conditioning regimen and donor bone marrow transplantation in human leukocyte antigen (HLA)-matched and mismatched kidney transplantation. In HLA-matched kidney transplantation, persistent mixed chimerism and renal allograft tolerance has been achieved in some patients. In HLA-mismatched combinations, induction of persistent mixed chimerism has not been achieved using a nonmyeloablative preparative regimen. Nevertheless, the transient mixed chimerism that has been achieved has resulted in long-term renal allograft tolerance in the majority of patients. Recent preclinical studies have demonstrated that the presence of heterologous memory T-cell responses observed in primates, but not in rodents, may be a major barrier for induction of durable chimerism and tolerance in primates. Strategies to overcome such memory T-cell responses may, therefore, be of great value in the development of reliable protocols for clinical tolerance induction. SUMMARY: Induction of tolerance in clinical kidney transplantation has been achieved via mixed chimerism approaches. Improvements in the consistency and safety of tolerance induction and extension of successful protocols to other organs and to organs from deceased donors will all be among the next steps in bringing tolerance to a wider range of clinical applications. PMID- 21666483 TI - The prognostic role of human papillomavirus in patients with vaginal cancer. AB - OBJECTIVE: The objective of the study was to evaluate the association between human papillomavirus (HPV) infection and clinical-pathological parameters in primary squamous cell carcinoma of the vagina and assess the value of HPV infection as a prognostic parameter. METHODS: In our retrospective study, we identified 37 consecutive patients with primary invasive squamous cell carcinoma of the vagina; 35 patients were eligible for further investigations. Human papillomavirus detection was assessed by in situ hybridization assays from paraffin-embedded tissue blocks. Human papillomavirus detection was correlated with clinical-pathological parameters by chi2 and Fisher exact tests. Univariate log-rank tests and multivariate Cox regression models were used to evaluate the association between HPV infection and patient survival. RESULTS: Human papillomavirus DNA was detected in 18 (51.4%) of 35 cases. Human papillomavirus status did no influence clinical-pathological parameters, such as clinical stage (P=0.9), grade (P=0.9), and tumor size (P=0.18). Prognosis did not significantly differ between HPV-positive and HPV-negative tumors in the entire cohort; however, patients with unfavorable tumor stage (International Federation of Gynecology and Obstetrics stage>=III) and HPV positivity had improved disease free (P=0.004) and overall survival (P=0.023). CONCLUSIONS: Human papillomavirus infection was frequently detected in squamous cell carcinoma of the vagina, and its presence may serve as a prognostic indicator in advanced stages. PMID- 21666484 TI - Comparison of survival outcomes between patients with malignant mixed mullerian tumors and high-grade endometrioid, clear cell, and papillary serous endometrial cancers. AB - INTRODUCTION: Malignant mixed mullerian tumors (MMMTs) are an aggressive subtype of endometrial cancer (EC). Previous studies compare survival between high-grade endometrioid (EM), clear cell (CC), and papillary serous (PS) ECs; yet few studies compare MMMTs to these aggressive subtypes. The goal of this study was to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) among EC subtypes. METHODS: We conducted a retrospective cohort study of EC cases treated at Magee-Women's Hospital between 1996 and 2008. Kaplan-Meier estimates of RFS, DSS, and OS as well as and log-rank tests were used to compare survival distributions between histologic subtypes. Cox regression was used to estimate hazard ratios for histologic subtypes, adjusted for other significant prognostic factors. Interactions between histologic subtype and prognostic factors were examined to assess effect modification. RESULTS: This cohort included 81 MMMT (15%), 254 high-grade EM (46%), 73 CC (13%), and 147 PS (26%) cases. Compared to high-grade EM (6%) and CC (7%) cases, relatively more MMMT (12%) and PS (12%) cases were nonwhite. Stage differed significantly among the subtypes, with 36%, 34%, 37%, and 51% of MMMT, high-grade EM, CC, and PS cases, respectively, diagnosed at advanced late stage (P<0.001). Kaplan-Meier curves and log-rank tests showed similar RFS, DSS, and OS between MMMT, high grade EM, CC, and PS cases stratified by stage. In adjusted Cox regression models, RFS and DSS were not significantly different between MMMT and other subtypes. High-grade EM cases had a significantly better OS compared to MMMT cases (HR, 0.63; 95% confidence interval [CI], 0.41-0.98). CONCLUSIONS: This is the first retrospective study to suggest that certain survival outcomes are similar among MMMT, high-grade EM, CC, and PS subtypes. Other large-scale studies are needed to confirm these findings. PMID- 21666485 TI - Venous thromboembolism in uterine cancer. AB - OBJECTIVES: To determine the incidence, time course, and risk factors associated with the development of venous thromboembolism (VTE) and the effect of VTE on survival in women with uterine cancer. METHODS: Using the California Cancer Registry, the date, stage, and histology of all incident uterine cancer cases during 1993-1999 were identified. These cases were linked with the state's hospital discharge database, allowing identification of incident VTE events, after excluding cases with a previous history of VTE. Proportional hazards modeling was used to analyze the association of baseline risk factors with the development of VTE (<1 year), using major surgery as a time-dependent covariate. In a similar model for death (<2 years), VTE was included as a time-dependent covariate. RESULTS: Among 18,440 cases with uterine cancer, the 2-year cumulative incidence of VTE was 2.7%. The cumulative incidence varied from 1.5% among women with local stage disease to 10.5% among women with advanced disease. Among cases diagnosed with local disease, risk factors for the development of VTE within 1 year in localized disease included major surgery (hazard ratio [HR]=2.1, P<0.01), presence of long-term comorbidities (HR=2.9 for >=3 comorbidities, P<0.0001), black race (HR=2.0, P<0.006), and sarcoma histology (HR=1.7, P<0.04). Among cases with regional disease, presence of comorbidities, black race, and sarcomas or nonendometrioid carcinomas were all associated with significantly higher risk of VTE. In advanced disease, the presence of any comorbidities and black race were the strongest predictors (HR=2.4 and 1.9, respectively). Women (aged<45 years) with advanced disease had a notably high 2-year incidence of 18%. Age did not predict VTE in localized and regional diseases. For all stages of cancer, development of VTE within 2 years was a significant predictor of decreased survival, and the magnitude of the risk was greatest among the cases diagnosed with localized disease (HR=6.1; confidence interval, 4.6-8.1). CONCLUSIONS: The incidence of VTE in women with uterine cancer was high, particularly in younger women with metastatic disease. The strong association between development of VTE and death suggests a close coupling between the biological aggressiveness of the cancer and the activation of thrombosis. PMID- 21666486 TI - A prospective evaluation of lymphatic dissemination in endometrial cancer: is it adequate to perform lymph node dissection up to the inferior mesenteric artery? AB - OBJECTIVE: This study aimed to assess para-aortic metastases relative to the inferior mesenteric artery (IMA). In addition, the clinicopathologic features of these patients are discussed. MATERIALS AND METHODS: Between 2007 and 2009, a total of 78 consecutive patients who had open systematic pelvic and para-aortic lymphadenectomy surgery for endometrial cancer extending to the renal vessels and who were treated at the gynecologic oncology department were included in this prospective study. The para-aortic lymph nodes (PALNs) removed from these patients were classified as supramesenteric (between the renal vein and the IMA) or inframesenteric (between the IMA and the presacral). Patients' clinical data, pathologic tumor characteristics, and operative and early postoperative data were recorded after surgery. Descriptive statistics were calculated using the SPSS 17.0 package program. RESULTS: Of these 78 patients, 18 (21.3%) had metastatic nodal involvement. From a total of 12 patients with PALN metastasis, 7 had only supramesenteric and 1 had only inframesenteric nodal involvement, whereas 4 had both supramesenteric and inframesenteric metastases. Of the 5 patients in the inframesenteric+/-supramesenteric group, none had a grade 1 tumor. On the other hand, of the 7 patients with only supramesenteric metastasis, 57.1% (n=4) had a grade 1 tumor and 42.8% (n=3) had less than half of myometrial invasion. CONCLUSIONS: In the case of well-defined risk factors in which a lymphadenectomy is indicated according to current guidelines from the International Federation of Gynecology and Obstetrics, a PALN dissection should be extended up to the renal vessels. We also conclude that tumor grade, histologic type, and myometrial invasion cannot be used as markers to decide on supramesenteric lymphadenectomy in endometrial cancer. PMID- 21666487 TI - Diagnostic usefulness of intraoperative ultrasonography in avoiding unnecessary para-aortic lymphadenectomy in women with endometrial carcinoma. AB - OBJECTIVE: To evaluate the usefulness of intraoperative ultrasonography (IU) in reducing the number of unnecessary para-aortic lymphadenectomy in women with endometrial carcinoma. METHODS: Computed tomography (CT) and IU were used to assess whether para-aortic lymph nodes were enlarged in 91 women with endometrial carcinoma. All women underwent hysterectomy and systematic pelvic and para-aortic lymphadenectomy. On the basis of the intrauterine pathological findings (IPF) of the removed uterus, the women were classified into low- and high-risk groups. It was assumed that para-aortic lymphadenectomy would be performed only when enlarged nodes were detected by CT or IU or only when women were classified into the high-risk group. The numbers of women who would have had missed metastases and who could have avoided para-aortic lymphadenectomy were calculated. RESULTS: Eighteen women had pathological para-aortic node metastases. Theoretically, the number of women who would have had missed metastases on the basis of CT, IU, and IPF were 11, 2, and 2, respectively; more metastases were missed with CT than with the other 2 methods. The number of women who could have avoided para-aortic lymphadenectomy on the basis of CT, IU, and IPF were 84, 59, and 29, respectively; compared to IPF, IU helped avoid para-aortic lymphadenectomy in more women. CONCLUSIONS: Intraoperative ultrasonography is the most efficient method for avoiding both unnecessary para-aortic lymphadenectomy and missed para aortic node metastases in women with endometrial carcinoma. PMID- 21666488 TI - Risk factors for developing multiple malignancies in patients with endometrial cancer. AB - OBJECTIVE: The purposes of this study were to investigate the clinical and pathologic characteristics of patients with endometrial cancer (EC) and associated breast, colorectal, or ovarian cancer, and to define the risk of developing an associated malignancy during follow-up after EC treatment. METHODS/MATERIALS: During a 13-year period, 1028 women had a hysterectomy for EC at our institution and available clinical information. An associated malignancy was defined as diagnosis of another malignant disease before or at the time of operation for EC or during follow-up. RESULTS: Of these 1028 patients, 208 (20%) had a history of another malignancy besides EC. Most frequent were carcinomas of the breast (10%), colon-rectum (3%), and ovary (4%). Patients with a family history of hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers and presence of EC in the lower uterine segment (LUS) had a higher risk of developing colorectal cancer within 5 years after hysterectomy (2% and 6%, respectively). After multivariate analysis, only LUS involvement remained significantly associated with this risk. Patients with EC and associated ovarian cancer were more likely to be younger and have superficially invasive EC, family history of HNPCC-related tumors, and family history of breast or ovarian cancer. After multivariate analysis, only age younger than 50 years (odds ratio [OR], 4.27; 95% confidence interval [CI], 1.49-12.21) and family history of breast or ovarian cancer (OR, 3.95; 95% CI, 1.60-9.72) were significantly related to risk of having ovarian cancer associated with EC. No significant risk factors were identified for development of an associated breast cancer after EC. CONCLUSIONS: Young age, family history of malignancy, and LUS involvement may indicate the need for more intensive preventive strategies for colorectal cancer and for evaluating the risk of synchronous ovarian cancer in patients with EC. PMID- 21666489 TI - KCC1 gene advances cell invasion ability by regulating ERK signaling pathway in endometrial cancer HEC-1B cell line. AB - INTRODUCTION: Human potassium chloride cotransporter-1 (KCC1) gene is expressed in endometrial cancer and related to metastasis of endometrial cancer. However, whether KCC1 contributes to invasion and metastasis of endometrial cancer has not been thoroughly investigated. The purpose of this study is to research the alternation effect of insulin-like growth factor I (IGF-I) on the expression of KCC1 in endometrial cancer HEC-1B cells and to explore the mechanism of how KCC1 regulates the invasion ability of HEC-1B cells through the extracellular signal regulated kinase (ERK) signaling pathway. METHODS: First, the inhibitive effect of RNA interference to KCC1 was detected by semiquantitative reverse transcriptase-polymerase chain reaction. Western blot was used to measure expression changes of KCC1 after exposure to IGF-I in the HEC-1B cells. The change in quantity of phosphorylated ERK1/2 (p-ERK1/2) and cell invasion ability also were measured. After RNA interference and treatment with U0126, the quantity of p-ERK1/2 and the cell invasion ability were measured again. RESULTS: After the application of IGF-I on the HEC-1B cells, the expression of KCC1 and p-ERK1/2 increased dramatically, and the cell invasion ability advanced. RNA interference could inhibit the expression of KCC1, and the quantity of p-ERK1/2 and the cell invasion ability decreased even under the effect of IGF-I. Furthermore, after treatment with U0126, the cell invasion ability no longer advanced even under the effect of IGF-I either. CONCLUSIONS: Insulin-like growth factors I can induce the upregulation of KCC1 gene, and KCC1 gene participates in the invasion ability of HEC-1B cells through the ERK signaling pathway. PMID- 21666490 TI - Wnt and hedgehog gene pathway expression in serous ovarian cancer. AB - OBJECTIVE: Ovarian cancer has very heterogeneous histological classification, and response to therapy of the same grade and type varies. We studied genes in the Wnt and hedgehog (Hh) pathways, which are essential for embryonic development and which play critical roles in proliferation in a variety of human cancers. Variations in these pathway genes causing proliferation could play a role in the variation in tumor progression and response to therapy. METHODS/MATERIALS: Using real-time polymerase chain reaction, we studied 16 primary grade 3 International Federation of Gynecology and Obstetrics stage III serous ovarian cancer samples for expression of the Wnt pathway gene AXIN2, fibroblast growth factor 9, and Hh pathway gene expressions of glioma-associated oncogene 1, glioma-associated oncogene 2, patched homolog 1, patched homolog 2, Indian Hedgehog (HH), sonic HH, and Smoothened, a G protein-coupled receptor protein. Normal ovary epithelial cell line was used as control. RESULTS: We found wide variation of up-regulation of pathway component and target genes in the primary tumor samples and apparent cross talk between the pathways. AXIN2, a Wnt target gene, showed increased expression in all serous ovarian cancer samples. Fibroblast growth factor 9 was also overexpressed in all tumors with greater than 1000-fold increase in gene expression in 4 tumors. Expression of Hh pathway genes varied greatly. More than half of the tumor samples showed involvement of Hh signaling or pathway activation either by expression of transcription factors and Hh ligands or by overexpression of Indian HH/sonic HH and the receptor-encoding patched homolog 1/patched homolog 2. CONCLUSION: We found a wide variation in fold expression of genes involved in the Wnt and Hh pathway between patient samples. PMID- 21666491 TI - Carotid to femoral pulse wave velocity: a comparison of real travelled aortic path lengths determined by MRI and superficial measurements. AB - OBJECTIVES: Carotid-femoral pulse wave velocity (PWV) is the gold standard method for determination of arterial stiffness. PWV is assessed by dividing travelled distance by travel time. Standardization and validation of the methodology for travelled distance measurement is of crucial importance. The aim of the current investigation was to standardize and validate the methodology for travelled distance measurement. METHODS: Real travelled carotid-femoral path lengths were measured with MRI in 98 healthy men/women (50% men, age 21-76 years) and are used as reference distance. This reference distance was compared with 11 estimates of aortic path length from body surface distances commonly used in PWV measurement, nine of them based on tape measures and two based on body height. Determinants of the difference between reference distance and the best body surface distance were determined. Additionally, the influence of body contours was identified. RESULTS: The tape measure distance from carotid to femoral artery (CA-FA), multiplied by 0.8, yielded the best agreement with the reference aortic path length [difference 0.26 cm (SD 3.8), not statistically significant]. Thirty percent of the variation in difference between the reference distance and tape measure distance (CA-FA * 0.8) was explained by age. Adding BMI increased this number to 34%. CONCLUSION: The tape measure distance from CA-FA, multiplied by 0.8, corresponds best with the real travelled aortic path length. This distance is moderately (yet statistically significantly) influenced by age and minimally by BMI. PMID- 21666492 TI - Comparison of the prognostic values of invasive and noninvasive assessments of baroreflex sensitivity in heart failure. AB - OBJECTIVES: No studies have compared the prognostic values of invasive (phenylephrine, Phe) and noninvasive (transfer function) assessments of baroreflex sensitivity (BRS). METHODS: Three hundred and one heart failure patients [age: 53 +/- 8 years, New York Heart Association class II-III: 88%, left ventricular ejection fraction (LVEF): 28 +/- 8%] underwent an 8 min ECG and arterial pressure recording, followed by Phe administration. RESULTS: Phe-BRS and transfer function BRS (TF-BRS) could be measured in 89 and 72% of cases, respectively. The correlation and the 5-95th percentiles of the difference between the two methods were 0.61 (P < 0.0001), and -7.6, +7.5 ms/mmHg, respectively. During a median of 36 months, 23% of the patients experienced a cardiac event. In the common dataset of 202 patients, both BRS measurements (<3 ms/mmHg) were significantly associated with the outcome (both P < 0.001), but Phe BRS had a better discriminatory power (area under the curve (AUC): 0.74 vs. 0.66, P = 0.03). Patients with a missing BRS (due to high grade ectopic activity) had a higher event rate (Phe-BRS: 38 vs. 24%, P = 0.23; TF-BRS: 37 vs. 19%, P = 0.002). Using this information, a prognostic index was derived for each BRS method, increasing measurability to 94 and 98%, respectively. Both indexes significantly predicted the outcome after adjustment for clinical covariates [hazard ratio (95% CI): 1.9 (1.1-3.3), P = 0.03 for Phe index and 2.0 (1.1-3.7), P = 0.02 for transfer function index]. CONCLUSION: Although the measurability of TF-BRS in heart failure patients is impaired, prognostic information can be extended to almost all patients, with a predictive power similar to that of Phe BRS. The two measurements, however, convey a certain amount of independent prognostic information. Hence, TF-BRS can be integrated with but not replace Phe BRS. PMID- 21666493 TI - Association of central hemodynamics with estimated 24-h urinary sodium in patients with hypertension. AB - OBJECTIVE: High salt intake is known to be the most pivotal environmental factor in the pathogenesis of hypertension. However, the association of high sodium intake with central hemodynamics in hypertensive individuals has not been well defined. Here, we determined the association of estimated 24-h urine sodium and potassium excretion estimated from a spot urine analysis with parameters of central pulse wave analysis in 515 hypertensive individuals. METHODS: Fasting spot urine samples were obtained in the early morning after the first void, and estimated 24-h urine sodium and potassium excretion were estimated from measurement of urine sodium, potassium and creatinine. Central hemodynamics and arterial stiffness parameters were assessed via pulse wave analysis of the radial artery. RESULTS: The estimated 24-h sodium and potassium excretion values were 150 +/- 40 and 49 +/- 10 mEq, respectively. There was a step-wise decrease in pulse pressure amplification with increasing estimated 24-h urine sodium excretion. Multiple linear regression analyses revealed that both estimated 24-h urine sodium excretion and sodium/potassium ratio were independently associated with increases in central pulse pressure, augmented aortic pressure and augmentation index and were inversely associated with pulse pressure amplification. CONCLUSION: The estimated 24-h urinary sodium excretion is independently associated with central hemodynamics. This may provide the basis for prospective interventional studies of epidemiologic scale to determine the potential beneficial effects of reduced salt consumption on central hemodynamics. PMID- 21666494 TI - Acute reductions in blood flow restricted to the dorsomedial medulla induce a pressor response in rats. AB - OBJECTIVES: The brainstem nucleus of the solitary tract (nucleus tractus solitarii, NTS) is a pivotal region for regulating the set-point of arterial pressure, the mechanisms of which are not fully understood. Based on evidence that the NTS exhibits O2-sensing mechanisms, we examined whether a localized disturbance of blood supply, resulting in hypoxia in the NTS, would lead to an acute increase in arterial pressure. METHODS: Male Wistar rats were used. Cardiovascular parameters were measured before and after specific branches of superficial dorsal medullary veins were occluded; we assumed these were drainage vessels from the NTS and would produce stagnant hypoxia. Hypoxyprobe-1, a marker for detecting cellular hypoxia in the post-mortem tissue, was used to reveal whether vessel occlusion induced hypoxia within the NTS. RESULTS: Following vessel occlusion, blood flow in the dorsal surface of the medulla oblongata including the NTS region showed an approximately 60% decrease and was associated with hypoxia in neurons located predominantly in the caudal part of the NTS as revealed using hypoxyprobe-1. Arterial pressure increased and this response was pronounced significantly in both magnitude and duration when baroreceptor reflex afferents were sectioned. CONCLUSION: These results suggest that localized hypoxia in the NTS increases arterial pressure. We suggest this represents a protective mechanism whereby the elevated systemic pressure is a compensatory mechanism to enhance cerebral perfusion. Whether this physiological mechanism has any relevance to neurogenic hypertension is discussed. PMID- 21666495 TI - Neuroprotective signaling mechanisms of telomerase are regulated by brain-derived neurotrophic factor in rat spinal cord motor neurons. AB - Telomerase can promote neuron survival and can be regulated by growth factors such as brain-derived neurotrophic factor (BDNF). Increases of BDNF expression and telomerase activity after brain injury suggest that telomerase may be involved in BDNF-mediated neuroprotection. We investigated BDNF regulation of telomerase in rat spinal cord motor neurons (SMNs). Our results indicate that BDNF increases telomerase expression and activity levels in SMNs and activates mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 and phosphatidylinositol-3-OH kinase/protein kinase B signals, and their downstream transcription factors nuclear factor-kappaB, c-Myc, and Sp1. Administration of the tyrosine kinase receptor B inhibitor K-252a, the mitogen activated protein kinase 1 inhibitor PD98059, and the phosphatidylinositol-3-OH kinase inhibitor LY294002 abolished BDNF-induced upregulation of these transcription factors and telomerase expression. The nuclear factor-kappaB inhibitor Bay11-7082 also attenuated c-Myc and Sp1 expression and increased telomerase promoter activity. Spinal cord motor neurons with higher telomerase levels induced by BDNF became more resistant to apoptosis; survival of SMNs that overexpressed the catalytic protein component of telomerase with reverse transcriptase activity was also enhanced against apoptosis. The neuronal survival promoting effect of telomerase was mediated through the regulation of Bcl-2, Bax, p53, and maintenance of mitochondrial membrane potential. Taken together, these data suggest that the neuroprotective effect of BDNF via telomerase is mediated by inhibition of apoptotic pathways. PMID- 21666497 TI - Moderate environmental enrichment mitigates tauopathy in a neurofibrillary tangle mouse model. AB - Epidemiological studies show that stimulating activities reduce the risk of dementia. In animal models of Alzheimer disease, there have been conflicting results of the effects of environmental enrichment (EE) on disease-related amyloid pathology. Here, we tested the direct effect of EE, independently of amyloid pathology, on brain neurofibrillary tangles (NFTs), which best correlate with dementia. We exposed transgenic mice (E257K/P301S-Tau-Tg driven by the natural tau promoter) to moderate nonstrained EE or regular environment. Concomitant with neurogenesis, we detected a decrease in NFT burden and a decrease in the activation of microglia in EE versus regular-environment mice. There was also a trend toward improvement in cognitive tasks in the EE mice. Increased immunoreactivity of brain-derived neurotrophic factor, which is involved in the regulation of tau phosphorylation, was detected in the EE mice, suggesting its possible involvement in the beneficial effects on NFTs and other parameters in the EE mice. These results suggest that NFTs may be directly responsive to environmental stimulating activities and that even nonstrained activities may mitigate tauopathies independent of the involvement of amyloid. PMID- 21666496 TI - Comparative characterization of the human and mouse third ventricle germinal zones. AB - Recent evidence indicates differences in neural stem cell biology in different brain regions. For example, we demonstrated that neurofibromatosis 1 (NF1) tumor suppressor gene inactivation leads to increased neural stem cell proliferation and gliogenesis in the optic chiasm and brainstem but not in the cerebral cortex. The differential effect of Nf1 inactivation in the optic nerve and brainstem (in which gliomas commonly form in children with NF1) versus the cortex (in which gliomas rarely develop) suggests the existence of distinct ventricular zones for gliomagenesis in children and in adults. Here, we characterized the third ventricle subventricular zone (tv-SVZ) in young and adult mouse and human brains. In children, but not adult humans, the tv-SVZ contains nestin-positive, glial fibrillary acidic protein-positive, brain fatty acid binding protein-positive, and sox2-positive cells with radial processes and prominent cilia. In contrast, the tv-SVZ in young mice contains sox2-positive progenitor cells and ciliated ependymal lining cells but lacks glial fibrillary acidic protein-positive, nestin positive radial glia. As in the lateral ventricle SVZ, proliferation in the human and murine tv-SVZ decreases with age. The tv-SVZ in adult mice lacks the hypocellular subventricular zone observed in adult human specimens. Collectively, these data indicate the existence of a subventricular zone relevant to our understanding of glioma formation in children and will assist interpretation of genetically engineered mouse glioma models. PMID- 21666498 TI - p16INK4A and p14ARF tumor suppressor pathways are deregulated in malignant rhabdoid tumors. AB - Malignant rhabdoid tumors (MRTs) are aggressive tumors associated with mutations in the SMARCB1 gene. In experimental systems, the loss of SMARCB1 is hypothesized to alter p16(INK4A) pathways resulting in the repression of tumor suppressors. To determine whether these pathways are deregulated in human MRT, we used immunohistochemistry on tissue microarrays to evaluate p16(INK4A)/E2F1/RB and p14(ARF)/MDM2/p53 pathways in 25 atypical teratoid/rhabdoid tumors (AT/RT) and 11 non-CNS MRT. p16(INK4A) was negative or showed focal weak expression. p16(INK4A) downstream targets CDK4/cyclin D1/ppRB were variably expressed at moderate to low levels; E2F1 was negative. Unexpectedly, p14(ARF) expression was seen in many cases, which correlated positively with p53 and inversely with MDM2 immunostaining in AT/RT. TP53 mutational analysis in 19 of 25 AT/RT and in 8 of 11 non-CNS MRT cases showed point mutations in only 3 AT/RT cases, suggesting that p53 expression was driven mainly by p14(ARF). Finally, nucleophosmin, a protein that stabilizes p53, was positive in most cases and colocalized with p53. Together, these data suggest that, in MRT, there is deregulation not only of p16(INK4A) but also of the p14(ARF) pathway. These results provide insights into cell cycle deregulation in the pathogenesis of human MRT and may aid in the design and evaluation of potential therapies for these tumors. PMID- 21666499 TI - Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model. AB - Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and although they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Using fluorescent in situ hybridization to detect Arc messenger RNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared with untreated transgenics, restoring enrichment induced Arc messenger RNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, although tangles do not preclude neurons from responding in a functional circuit. PMID- 21666500 TI - The cell cycle regulator phosphorylated retinoblastoma protein is associated with tau pathology in several tauopathies. AB - Retinoblastoma protein (pRb) is a ubiquitous 928-amino acid cell cycle regulatory molecule with diverse biologic activities. One critical function of pRb is the control of the G1-to-S phase checkpoint of the cell cycle. In the hypophosphorylated state, pRb suppresses the activity of E2F transcription factors thereby inhibiting transcription of cell cycle-promoting genes. On phosphorylation, primarily by cyclin-dependent kinases, phosphorylated pRb dissociates from E2F and permits cell cycle progression. We previously found phosphorylated pRb to be intimately associated with hyperphosphorylated tau containing neurofibrillary tangles of Alzheimer disease (AD), the pathogenesis of which is believed to involve dysregulation of the cell cycle and marked neuronal death. Here, we used immunohistochemistry to investigate the presence of phosphorylated pRb in other distinct neurodegenerative diseases that share the common characteristic of hyperphosphorylated tau pathology and neuronal loss with AD.We found colocalized labeling of tau pathology and phosphorylated pRb in Pick disease and progressive supranuclear palsy (3 cases each), neurodegeneration with brain iron accumulation type 1 (2 cases), and Parkinson-amyotrophic lateral sclerosis of Guam, subacute sclerosing panencephalitis, frontotemporal dementia and Parkinsonism linked to chromosome 17, and dementia pugilistica (1 case each). These observations further implicate aberrant neuronal cell cycle progression in neurodegenerative diseases, particularly tauopathies, and suggest a novel target for therapeutic intervention. PMID- 21666501 TI - Yes-associated protein 1 is widely expressed in human brain tumors and promotes glioblastoma growth. AB - The hippo pathway and its downstream mediator yes-associated protein 1 (YAP1) regulate mammalian organ size in part through modulating progenitor cell numbers. YAP1 has also been implicated as an oncogene in multiple human cancers. Currently, little is known about the expression of YAP1 either in normal human brain tissue or in central nervous system neoplasms. We used immunohistochemistry to evaluate nuclear YAP1 expression in the fetal and normal adult human brains and in 264 brain tumors. YAP1 was expressed in fetal and adult brain regions known to harbor neural progenitor cells, but there was little YAP1 immunoreactivity in the adult cerebral cortex. YAP1 protein was also readily detected in the nuclei of human brain tumors. In medulloblastoma, the expression varied between histologic subtypes and was most prominent in nodular/desmoplastic tumors. In gliomas, it was frequently expressed in infiltrating astrocytomas and oligodendrogliomas but rarely in pilocytic astrocytomas. Using a loss-of-function approach, we show that YAP1 promoted growth of glioblastoma cell lines in vitro. High levels of YAP1 messenger RNA expression were associated with aggressive molecular subsets of glioblastoma and with a nonsignificant trend toward reduced mean survival in human astrocytoma patients. These findings suggest that YAP1 may play an important role in normal human brain development and that it could represent a new target in human brain tumors. PMID- 21666502 TI - Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial reactivity. AB - Repetitive mild or "concussive" traumatic brain injury (TBI) can cause substantial neurologic impairment, but the pathological features of this type of injury are not fully understood. We report an experimental model of TBI in which the closed skulls of anesthetized male C57BL/6J mice are struck with an electromagnetically controlled rubber impactor twice with an interval of 24 hours between impacts. The mice had deficits in Morris water maze performance in the first week after injury that only partially resolved 7 weeks later. By routine histology, there was no apparent bleeding, neuronal cell loss, or tissue disruption, and amyloid precursor protein immunohistochemistry demonstrated very few immunoreactive axonal varicosities. In contrast, silver staining revealed extensive abnormalities in the corpus callosum and bilateral external capsule, the ipsilateral cortex and thalamus, and the contralateral hippocampal CA1 stratum radiatum and stratum oriens. Electron microscopy of white matter regions demonstrated axonal cytoskeletal disruption, intra-axonal organelle compaction, and irregularities in axon caliber. Reactive microglia were observed in the same areas as the injured axons by both electron microscopy and Iba1 immunohistochemistry. Quantitative analyses of silver staining and Iba1 immunohistochemistry at multiple time points demonstrated transient cortical and thalamic abnormalities but persistent white matter pathology as late as 7 weeks after injury.Thus, prominent and long-lasting abnormalities in this TBI model were underestimated using conventional approaches. The model may be useful for mechanistic investigations and preclinical assessment of candidate therapeutics. PMID- 21666505 TI - Comparison of intraoperative supine and postoperative standing radiographs after posterior instrumentation for adolescent idiopathic scoliosis. AB - The utility of intraoperative radiographs after posterior spinal segmental instrumentation for adolescent idiopathic scoliosis (AIS) is debatable. A retrospective review of 74 patients with moderately severe AIS revealed the main thoracic Cobb measurements of 57 degrees preoperatively, 17 degrees intraoperatively, 18 degrees on initial postoperative, and 20 degrees on final postoperative radiographs. On the basis of the extent and type of instrumentation (pedicle screws vs. hybrid construct), there was no clinically significant difference in curve magnitude between intraoperative and postoperative radiographs. After posterior segmental instrumentation for moderate AIS, frontal plane correction measured on intraoperative supine radiographs are comparable with similar measurements made on full-length postoperative standing radiographs. PMID- 21666503 TI - Nucleotide sequence of the Na+/H+ exchanger-8 in patients with congenital sodium diarrhea. AB - Sodium absorption by the intestine is mediated by brush border Na/H exchangers, which include the NHE3 and NHE8 isoforms. We demonstrated a maturational decrease in NHE8 and increase in NHE3 in mouse intestine mRNA abundance and brush border membrane protein abundance, indicating a developmental switch of isoforms. Congenital sodium diarrhea is a rare autosomal recessive disorder characterized by polyhydramnios, hyponatremia, metabolic acidosis, and diarrhea with a high sodium content. Previous studies using intestinal brush border membrane vesicles from patients with this disorder have demonstrated a decrease in Na/H exchanger activity. Because some patients with congenital sodium diarrhea improve with age and knowing the developmental switch from NHE8 to NHE3, NHE8 may be a candidate gene for this disorder. We sequenced NHE8 from 5 patients with this disorder and found no disease-causing homozygous mutations. Although brush border membrane Na/H exchange activity may be decreased, exonic mutations in NHE8 cannot account for this disorder in these subjects. PMID- 21666506 TI - Management of idiopathic clubfoot in toddlers by Ponseti's method. AB - The Ponseti method has been reported to have successful results in clubfoot patients less than 6 months of age but the literature on its efficacy in older clubfoot patients still remains sparse. In our study, we prospectively evaluated 55 clubfeet (37 patients) to determine clinically whether the Ponseti method is effective in the management of clubfoot in older children between the age of 12 and 36 months (mean: 24.8 months). All the patients belonged to moderate or severe grades of deformity as per the Pirani scoring. Painless, supple, plantigrade and cosmetically acceptable feet were achieved in 49 clubfeet. Seven patients (seven feet) developed recurrence of adduction, varus and equinus deformity whereas three patients (five feet) developed isolated recurrence of equinus deformity. These seven patients responded to repeat treatment and obtained satisfactory outcome. Four of these seven patients underwent tibialis anterior transfer to third cuneiform for dynamic supination. Three patients, those developed isolated recurrence of equinus deformity, underwent repeat tenotomy. One foot achieved satisfactory amount of dorsiflexion, three feet underwent tendoachilles lengthening whereas another foot underwent posterior release to obtain satisfactory dorsiflexion. Six to 12 numbers of casts (mean: 10) were required to obtain correction of clubfoot deformities. Mean period of immobilization in a cast was 13.9 weeks (10-15 weeks). We found that the Ponseti method is effective in children between the age of 12 and 36 months. PMID- 21666507 TI - Evaluation of calcium phosphate and calcium sulfate as injectable bone cements in sheep vertebrae. AB - STUDY DESIGN: An animal study. OBJECTIVE: To compare the biomechanical and biometabolic properties between calcium phosphate (CaP), calcium sulfate (CaS), and polymethylmethacrylate (PMMA) as bone void fillers in a sheep model of lumbar vertebral defect. SUMMARY OF BACKGROUND DATA: PMMA is commonly used as a bone void filler in vertebroplasty and kyphoplasty. However, it has certain intrinsic limitations. CaP and CaS are considered as potential PMMA substitutes, but further in vivo evaluations of their biomechanical and biometabolic properties are needed before they can be recommended for clinical use in routine vertebroplasty and kyphoplasty procedures. METHODS: Bone voids were experimentally created on lumbar vertebrae L2-L5 with L6 left intact as a normal control in 24 adult female sheep. The defect vertebrae L2-L5 in each of the animals were randomized to receive no filler augmentation (controls) or augmentation with CaP, CaS, or PMMA. Animals were killed after 2, 12, and 24 weeks of the bone filler augmentation, respectively. Vertebrae L2-L6 were collected and their biomechanical strength/stiffness, osseointegration activity, and biodegradability were evaluated. RESULTS: At all 3 time points tested, the PMMA-augmented lumbar vertebra had the highest biomechanical strength and stiffness, followed by the intact vertebra L6. CaP and CaS significantly improved the strength as compared with the sham augmentation, but did not yet restore it to the normal level. Osteogenesis occurred at low levels in the empty vertebrae, in the CaP-augmented defect vertebrae at 12 and 24 weeks, and in the CaS augmented vertebrae at 12 weeks, but at a substantially high level after 24 weeks of CaS augmentation. The filler biodegradation rate was low in the CaP-augmented vertebrae, but was substantially high in the CaS-augmented vertebrae. CONCLUSIONS: CaP and CaS are effective enough to strengthen the fractured lumbar vertebrae in a time-dependent manner, although not as good as PMMA. CaS has a much higher osseointegration capacity than CaP. PMID- 21666508 TI - A comparison of anterior and posterior instrumentation for restoring and retaining sagittal balance in patients with idiopathic adolescent scoliosis. AB - STUDY DESIGN: Retrospective, comparative study. OBJECTIVE: To compare the effects of anterior rod-screw instrumentation and posterior pedicle screw instrumentation on sagittal balance in patients with Lenke type 5 adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Lenke type 5 AIS is treated by anterior or posterior spinal fusion surgery. Most studies comparing anterior and posterior fusion surgery have focused on assessing improvement in coronal balance. Studies comparing the effects of anterior and posterior surgery on sagittal balance are lacking. METHODS: The records of 49 patients diagnosed with Lenke type 5 AIS were examined. A total of 21 patients underwent anterior surgery between 2000 and 2003, while 26 underwent posterior surgery between 2004 and 2006. Preoperative, postoperative, and follow-up thoracic kyphosis (T5-T12 and T2-T12), lumbar lordosis, thoracolumbar junction kyphosis, and spinal vertical axis measurements were made by examining radiographs. Quality of life was assessed using the Scoliosis Research Society-22 questionnaire. All patients were followed up for at least 2 years. RESULTS: There were no significant between group differences in coronal alignment, thoracic kyphosis, or T11-L2 alignment after surgery. Sagittal alignment improvement was significantly more pronounced in the anterior surgery group compared with the posterior surgery group. The fusion segment was also significantly shorter in the anterior surgery compared with the posterior surgery group. Quality of life scores were significantly higher in the anterior surgery group compared with the posterior surgery group. CONCLUSION: Anterior solid rod screw instrumentation results in shorter fusion segments, and better sagittal alignment and quality of life than posterior pedicle screw instrumentation in patients with Lenke type 5 AIS. PMID- 21666509 TI - Feasibility of C2 translaminar screw as an alternative or salvage of C2 pedicle screws in atlantoaxial instability. AB - STUDY DESIGN: A retrospective outcome study. OBJECTIVE: The purpose of this study was to analyze the clinical outcomes of our experience with the C2 translaminar screw technique and evaluate its feasibility as an alternative or salvage of the pedicle screw. SUMMARY OF BACKGROUND DATA: Pedicle screws are the most biomechanically stable screws for use in atlantoaxial fixation. However, in cases with elevated risk of neurovascular complications or failure of screw insertion attempts, a reliable alternative technique is required. METHODS: Fourteen patients with atlantoaxial instability underwent posterior fixation with C2 translaminar screws. Indications included traumatic instability, atlantoaxial subluxation, os odontoideum, and fusion failure after anterior fixation of a type II odontoid process fracture. A total of 26 screws were inserted and all patients were assessed both clinically and radiographically. RESULTS: No procedure-related complications or hardware failures were observed during the follow-up. Postoperative computed tomographic scans revealed laminar breach in 3 patients and none of these resulted in neurological symptoms. Radiographically demonstrated bony fusion was established in 11 patients (91.7%) at follow-up over 6 months, and 5 patients with initial neurological deficit demonstrated at least 1 grade improvement by Frankel grade. CONCLUSIONS: C2 translaminar screws provide surgeons with an expanded option for posterior fusion in high cervical lesions. This technique is safe and easy to adopt with a favorable rate of successful fusion. We believe that preoperative planning using computed tomographic scan is mandatory and use of an additional connector may reduce the stress and strain of the screws. PMID- 21666510 TI - Potential safety gaps in order entry and automated drug alerts: a nationwide survey of VA physician self-reported practices with computerized order entry. AB - OBJECTIVE: Understanding provider perceptions of and experiences with order entry and order checks (drug alerts) in an electronic prescribing system may help improve medication safety technology. DESIGN: Cross-sectional, national survey of Veterans Administration physicians practicing in various specialties. MEASUREMENT: Thirty-five question instrument was divided into 4 content domains. Response options included dichotomous, numeric, multiple choices, and Likert-like scales. Statistical methods included logistic regression. RESULTS: The adjusted response rate was 1543 of 3588 (43%). Almost all providers (90%) felt that the VA electronic prescribing system, including its order checks, improved prescribing safety to some degree. Most respondents (72%) reported that they always or almost always document outside medications in a clinic note, although only 44% always or almost always entered outside medications in the non-VA medication data field. Most physicians (88%) who encountered serious allergic or adverse drug reactions reported either notifying a pharmacist or entering the information in the allergies/adverse reactions field. Generalists and physicians with higher numbers of prescriptions were more likely to enter relevant data into the electronic medical record (or notify a pharmacist, in the case of adverse reactions). In addition, 48% of providers described critical drug-drug interaction alerts as very useful; medical specialists found these less useful, whereas surgical specialists found these more useful when compared with generalists. LIMITATIONS: Survey was conducted within a single healthcare system. CONCLUSION: Computerized provider order entry and related order checks are perceived to improve prescribing safety; however, provider entry of some relevant information into the appropriate electronic fields may not be optimal. PMID- 21666511 TI - Hospital nurse staffing: choice of measure matters. AB - BACKGROUND: Researchers frequently use nurse staffing measures to examine hospital quality of care. Measure choices include nurse-reported perception of staffing adequacy, nurse-reported patient workloads, and empirically derived hours per patient day (HPPD). OBJECTIVE: To examine the correlations across these measures and identify factors associated with these staffing measures. DESIGN, SETTINGS, AND SUBJECTS: A cross-sectional correlational study of 92 medical surgical, rehabilitation, and intermediate in 11 acute care hospitals was carried out. METHODS: We surveyed registered nurses on their perceived staffing adequacy, last shift patient workload, and unit-level structures and processes of care delivery. Individual responses to these measures were aggregated to the nursing unit level, and unit-level HPPD, unit-level case mix index were obtained from each hospital's administrative data. After examining the correlation matrix across variables, those associated with the 3 staffing measures were then examined using linear regression. RESULTS: HPPD and the nurse-reported patient workload on last shift were correlated (r=-0.276, P=0.008), and perceptions of the adequacy of staffing and nurse-reported patient workload on last shift were correlated (r=-0.384, P=0.000). In multivariable analyses, inadequate numbers of assistive personnel was significantly associated with both perceived staffing adequacy and nurse-reported patient loads. Unit-level case mix index was significantly associated with both HPPD and nurse-reported patient loads. These data suggest that the 3 measures of nurse staffing are not highly correlated, and may capture different elements of the unit context to explain nurse staffing. Researchers should consider the correlates of these measures when selecting nurse staffing measures for future investigations. PMID- 21666512 TI - Role of socioeconomic status measures in long-term mortality risk prediction after myocardial infarction. AB - BACKGROUND: The relationship of risk factors to outcomes has traditionally been assessed by measures of association such as odds ratio or hazard ratio and their statistical significance from an adjusted model. However, a strong, highly significant association does not guarantee a gain in stratification capacity. Using recently developed model performance indices, we evaluated the incremental discriminatory power of individual and neighborhood socioeconomic status (SES) measures after myocardial infarction (MI). METHODS: Consecutive patients aged <=65 years (N=1178) discharged from 8 hospitals in central Israel after incident MI in 1992 to 1993 were followed-up through 2005. A basic model (demographic variables, traditional cardiovascular risk factors, and disease severity indicators) was compared with an extended model including SES measures (education, income, employment, living with a steady partner, and neighborhood SES) in terms of Harrell c statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). RESULTS: During the 13-year follow-up, 326 (28%) patients died. Cox proportional hazards models showed that all SES measures were significantly and independently associated with mortality. Furthermore, compared with the basic model, the extended model yielded substantial gains (all P<0.001) in c statistic (0.723 to 0.757), NRI (15.2%), IDI (5.9%), and relative IDI (32%). Improvement was observed both for sensitivity (classification of events) and specificity (classification of nonevents). CONCLUSIONS: This study illustrates the additional insights that can be gained from considering the IDI and NRI measures of model performance and suggests that, among community patients with incident MI, incorporating SES measures into a clinical-based model substantially improves long-term mortality risk prediction. PMID- 21666513 TI - Survey nonresponders to a medication-beliefs survey have worse adherence and persistence to chronic medications compared with survey responders. AB - OBJECTIVE: The primary objective of this study was to investigate whether nonresponders to a medication-beliefs survey exhibited different adherence and persistence patterns than survey responders. METHODS: A medication-beliefs survey was mailed to 7795 adults aged from 40 to 88 years, who filled a qualifying index prescription (cardiovascular, dyslipidemia, oral-antihyperglycemic, oral bisphosphonate, and asthma-controller medications) in June 2008 at 1 national and 2 regional retail pharmacies. Adherence and persistence to the index drug class was measured using pharmacy-claims data over 12 months. A multivariate generalized linear model with a negative binomial distribution and log-link function was used to determine whether response status was a significant predictor of adherence. Kaplan-Meier estimates of survival curves were used to assess the time to discontinuation (persistence). Differences between nonresponders and responders were assessed using the log-rank test. RESULTS: The survey response rate was 24.25%. The final analytic sample size after exclusions was 6740 patients (5044 nonresponders and 1696 responders). On the basis of multivariate generalized linear model analysis, survey nonresponders had 11% lower medication adherence compared with responders (P < 0.01; goodness-of fit=1.09 as defined by deviance/df statistics). The proportion of nonresponders deemed nonpersistent at day 305 was 66.3% compared with 58.1% of responders (P < 0.001). The Kaplan-Meier persistence curves were significantly different for nonresponders and responders as assessed by the log-rank test (chi statistic=49.38; P < 0.001). CONCLUSIONS: Our study found that the responders and nonresponders to a medication-beliefs survey differed significantly in their subsequent adherence and persistence, suggesting that biased survey results are likely to accompany low response rates in surveys of medication use. The use of modest monetary incentives had a small effect on survey response; multiple survey levers are recommended to reduce nonresponse and the potential for biased results. PMID- 21666514 TI - Y-P30 confers neuroprotection after optic nerve crush in adult rats. AB - The survival-promoting peptide, Y-P30, has been shown to be neuroprotective and stimulates neurite outgrowth in vitro. In this study, we examined whether the peptide increases survival and induces axon outgrowth of retinal ganglion cells after an incomplete optic nerve crush. A single intraocular injection of the peptide directly after optic nerve crush increased the number of retinal ganglion cells that preserved an axonal connection with the superior colliculus in the adult rat by more than 50%. However, administration of Y-P30 into the vitreous or optic nerve had no effect on the number of axons growing into the crush site after optic nerve crush. These findings suggest that the peptide is a neuroprotective agent after optic nerve damage, but does not stimulate the axon outgrowth. PMID- 21666515 TI - Harmonic relationships influence auditory brainstem encoding of chords. AB - The cortical processing of musical sounds is influenced by listeners' sensitivity to the structural regularities of music, and particularly by sensitivity to harmonic relationships. As subcortical and cortical processing dynamically interact to shape auditory perception in an experience-dependent manner, we asked whether subcortical processing of musical sounds would be sensitive to harmonic relationships. We examined auditory brainstem responses to a chord that was preceded either by a harmonically related chord, by an unrelated chord, or was repeated. We observed higher spectral response magnitudes in the related than in the unrelated or repeated conditions, for both musician and nonmusician listeners. Our results suggest that listeners' implicit knowledge of musical regularities influences subcortical auditory processing. PMID- 21666516 TI - Glycine receptors influence radial migration in the embryonic mouse neocortex. AB - To investigate whether glycine receptors influence radial migration in the neocortex, we analyzed the effect of glycine and the glycinergic antagonist strychnine, on the distribution of 5-bromo-2'deoxyuridine-labeled neurons in organotypic slice cultures from embryonic mice cortices. Application of glycine impeded radial migration only in the presence of the glycine-transport blockers, ALX-5407 and ALX-1393. This effect was blocked by the specific glycine receptor antagonist strychnine, whereas application of strychnine in the absence of glycine was without effect. We conclude from these observations that an activation of glycine receptors can impede radial migration, but that the glycinergic system is not directly implicated in the regulation of radial migration in organotypic slice cultures. PMID- 21666517 TI - Columnar and layer-specific representation of spatial sensitivity in mouse primary auditory cortex. AB - The primary auditory cortex (AI) is implicated in coding sound location, as revealed by behavior-lesion experiments, but our knowledge about the functional organization and laminar specificity of neural spatial sensitivity is still very limited. Using single-unit recordings in mouse AI, we show that (i) an inverse relationship between onset latency and spike count is consistently observed when all the azimuthal points are taken; (ii) a substantial proportion of penetrations perpendicular to the AI surface showed columnar organization of best azimuths; (iii) the preferred azimuth range of AI neurons demonstrated layer-specific distribution pattern. Our findings suggest that similar to other response properties, the manner of sound space information processing in the auditory cortex is also layer dependent. PMID- 21666518 TI - GABAergic projections from the subplate to Cajal-Retzius cells in the neocortex. AB - Subplate neurons and Cajal-Retzius cells play an important role in the corticogenesis. Despite morphological evidence, the question whether subplate neurons innervate Cajal-Retzius cells has not been studied yet. We report that electrical stimulation in the subplate resulted in evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in Cajal-Retzius cells. The eIPSC latency showed minor variability and amounted to approximately 4 ms, suggesting the monosynaptic connection. During the first postnatal week: (i) eIPSC amplitude increased, (ii) eIPSC kinetics sped up, (iii) the size of readily releasable pool increased, and (iv) gamma-aminobutyric acid release probability decreased. We conclude that GABAergic subplate neurons innervate Cajal-Retzius cells. Surprisingly, despite the transient nature of both cell populations, these projections show developmental adjustments typical for many nontransient synaptic connections. PMID- 21666519 TI - Age-related changes in short-interval intracortical facilitation and dexterity. AB - Functional changes in the primary motor cortex might contribute to age-related decline in fine motor control. We measured short-interval intracortical facilitation (SICF) in an intrinsic hand muscle with paired-pulse transcranial magnetic stimulation at interstimulus intervals (ISIs) of 1.5, 2.5, and 4.5 ms in young and old participants and examined its association with dexterity. We found age-related effects in SICF, with greater facilitation in old than young participants at the 1.5-ms ISI and greater facilitation in young than old participants at the 2.5-ms ISI. SICF at the 2.5-ms ISI was positively correlated with performance on a task that required coordinated and dextrous use of both hands, suggesting that this measure indicates a capacity for executing demanding manual tasks. PMID- 21666520 TI - Involvement of CRF2 receptor in the brain regions in restraint-induced anorexia. AB - We have reported that corticotropin-releasing factor (CRF) receptor subtypes, CRF1 and CRF2, are involved in stress-induced anorexia. To clarify in which brain regions the CRF receptor is involved in mediating stress-induced anorexia, we examined the effect of microinjecting CRF1-selective or CRF2-selective antagonist into the lateral septum or the bed nucleus of the stria terminalis (BNST), which are implicated in regulating stress response. The results demonstrated that injecting antisauvagine-30 into the lateral septum or the BNST significantly attenuated restraint-induced anorexia, whereas injecting antalarmin into these regions did not affect anorexia. These results suggest that the CRF2 receptor in the lateral septum and the BNST is involved in the stress-induced inhibitory mechanism of feeding behavior. PMID- 21666521 TI - Pseudomonas keratitis 4 years after laser in situ keratomileusis. AB - PURPOSE: To report a patient who presented an infectious keratitis 4 years after laser in situ keratomileusis (LASIK) without any other predisposing risk factor than the LASIK procedure itself. CASE REPORT: We report a 32-year-old man operated by LASIK in January 2006 who presented with infectious keratitis in the OD in April 2010. Clinical examination showed a corneal abscess at 10-o'clock position in the interface and fibrin and Tyndall 4+ in the anterior chamber. Microbiological analysis identified Pseudomonas aeruginosa as the cause of infection. The patient was given ofloxacin, sulfate neomycin, polymyxin B, and prednisolone acetate to be used every 2 h. Treatment led to clinical improvement with resolution of corneal infiltrate. Keratitis with intact epithelium by Pseudomonas can occur up to 4 years after LASIK. CONCLUSIONS: LASIK treatment is a predisposing factor for bacterial keratitis even years after surgery. This report demonstrates the importance of continued postoperative vigilance by patient and his/her clinician. PMID- 21666522 TI - Corneal sublayer thickness measurements with the Nidek ConfoScan 4 (z Ring). AB - PURPOSE: To determine the repeatability of corneal sublayer thickness measurements using the Nidek ConfoScan 4 (CS4) with the z ring on a group of young adult subjects. METHODS: Thirty subjects aged 18 to 30 years were invited to have thickness measurements with the CS4 (z ring) on two different days, at similar time of the day to avoid diurnal variation. RESULTS: Only 22 subjects had valid measurements for analysis. The mean +/- SD of central corneal thickness (CCT) was 534 +/- 26 MUm, epithelial thickness was 42 +/- 8 MUm, Bowman's layer thickness was 19 +/- 7 MUm, and stromal thickness (ST) was 472 +/- 25 MUm. There was no significant difference in the between-visit thickness measurements of each layer with the CS4 (z ring) (paired t-tests, p > 0.05). The limits of agreement of between-visit measurements were -41 (8%) to 37 MUm (7%) for CCT, -21 (50%) to 19 MUm (45%) for epithelial thickness, -13 (68%) to 17 MUm (89%) for Bowman layer thickness, and -46 (10%) to 37 MUm (8%) for ST. CONCLUSIONS: Measurements of CCT and ST with the CS4 (z ring) showed reasonably good repeatability (7 to 10%). However, the repeatability of measurements of the thinner corneal layers, such as epithelium and Bowman's layer, was poor. PMID- 21666523 TI - Influence of age on peripheral ocular aberrations. AB - PURPOSE: To compare peripheral lower and higher order aberrations across the horizontal (+/-40 degrees ) and inferior (-20 degrees ) visual fields in healthy groups of young and old emmetropes. METHODS: We have measured off-axis aberrations in the groups of 30 younger (24 +/- 3 years) and 30 older (58 +/- 5 years) emmetropes. The aberrations of OD were measured using the COAS-HD VR Shack Hartmann aberrometer in 10 degrees steps to +/-40 degrees horizontally and -20 degrees inferiorly in the visual field. The aberrations were quantified with Zernike polynomials for a 4 mm pupil diameter. The second-order aberration coefficients were converted to their respective refraction components (M, J45, and J180). Mixed between-within subjects, analysis of variance were used to determine whether there were significant differences in the refraction and aberration components for the between-subjects variable age and the within subjects variable eccentricity. RESULTS: Peripheral refraction components were similar in both age groups. Among the higher order coefficients, horizontal coma (C3) and spherical aberration (C4) varied mostly between the groups. Coma increased linearly with eccentricity, at a more rapid rate in the older group than in the younger group. Spherical aberration was more positive in the older group compared with the younger group. Higher order root mean square increased more rapidly with eccentricity in the older group. CONCLUSIONS: Like the axial higher order aberrations, the peripheral higher order aberrations of emmetropes increase with age, particularly coma and spherical aberration. PMID- 21666524 TI - Latanoprost therapy after sunken eyes caused by travoprost or bimatoprost. AB - PURPOSE: To report clinical results of switching to latanoprost therapy in patients with deepening of the upper eyelid sulcus caused by travoprost and bimatoprost. METHODS: Prospective, clinical, observational case reports. Four patients presented with eyelid changes giving the eye a sunken eye appearance; two were being treated with travoprost and two with bimatoprost. Both patients on bimatoprost and one of the patients on travoprost therapy were switched to latanoprost while the eyelid sign was evident. The other patient discontinued the travoprost therapy for 4 months and switched to latanoprost therapy 1 month later, i.e., 5 months after discontinuing travaprost therapy. The physical changes in the eyelids were documented by photography and the intraocular pressure by Goldmann applanation tonometry. RESULTS: Three patients had a resolution of the sunken eye appearance 2 to 3 months after switching to latanoprost. The one patient who switched to latanoprost after recovery of the sunken eye had no recurrence during a 6 months follow-up period. There were no significant changes in the intraocular pressure in any of the subjects. CONCLUSIONS: A deepening of the upper eyelid sulcus is a complication of prostaglandin F2alpha analogs. However, this side effect may be less common with latanoprost and eyes with this side effect caused by travoprost or bimatoprost may tolerate latanoprost therapy. PMID- 21666525 TI - Repeatability of measurements obtained with a ray tracing aberrometer. AB - PURPOSE: To evaluate the repeatability of ocular aberrometry at distance and near vision conditions provided by the latest version of a ray tracing aberrometer. METHODS: A total of 22 healthy eyes of 22 patients with ages ranging from 21 to 65 years were included in this study. All eyes achieved a best spectacle corrected visual acuity of 20/20, and had not undergone previous ocular surgeries. Three consecutive aberrometric measurements were obtained with the iTrace system (Tracey Technologies) by an experienced examiner at distance (5 m) and near (40 cm). RESULTS: Low values of within-subject standard deviation (Sw) were found for sphere and cylinder at distance and near and for the power vector components of refraction. However, a more pronounced variability was observed for the coefficients associated with higher order aberrations, with the poorest repeatability for the vertical coma at near, Sw of 0.011 MUm for a mean value of 0.018 MUm. Additionally, Sw for vertical coma was significantly larger at near (p = 0.01). No significant differences between the distance and near values of Sw for the power vector components of refraction were found (p >= 0.08). The Sw values for the distance and near modulation transfer function parameters were low when compared with their corresponding mean values. CONCLUSIONS: The iTrace system provides repeatable measurements of the spherocylindrical refraction at near and distance, but consistency of aberrometric and optical quality measurements seems to be limited. PMID- 21666526 TI - Subconjunctival hemorrhages: presenting sign for hereditary hemochromatosis. AB - BACKGROUND: Hereditary hemochromatosis (HH) is a common hereditary disorder that primarily afflicts patients of Northern European descent. A single mutation of the HFE gene results in unregulated dietary iron uptake with the potential to deleteriously affect multiple organ systems including the eye. If HH is suspected, a screening test measuring transferrin saturation is initially obtained. Confirmation of this disorder is accomplished with genetic testing and liver biopsy. Treatment should commence immediately and undergo venesection (phlebotomy) treatments 2 to 4 times a year for the remainder of the patient's life. CASE REPORT: The following is a case of a 54-year-old male of Scottish German descent who was evaluated for a subconjunctival hemorrhage (SCH). A review of the patient's record disclosed that he had 12 previous episodes of SCH over a 10-year period. He was undergoing a comprehensive evaluation for HH due to the recent diagnosis of this condition in his older brother. Hematologic analysis showed that our patient had a serum ferritin level 4 to 5 times higher than normal (1340 MUg/L) and a homozygous recessive profile of the HFE gene. Once under maintenance venesection therapy, the frequency of the SCH diminished. CONCLUSIONS: HH must be considered a differential diagnosis in cases of recurrent SCH. Coupled with the recognition of characteristic physical signs and symptoms of HH, hematologic analysis and genetic testing may further aid in diagnosis. With early detection and treatment, the optometrist can make a significant impact on the life expectancy of the patient. PMID- 21666527 TI - Prospective longitudinal evaluation of lung function during the first year of life after repair of congenital diaphragmatic hernia. AB - OBJECTIVE: To evaluate lung function and respiratory morbidity prospectively during the first year of life in patients with congenital diaphragmatic hernia and to study the effect of extracorporeal membrane oxygenation therapy. DESIGN: Prospective longitudinal cohort study. SETTING: Outpatient clinic of a tertiary level pediatric hospital. PATIENTS: The cohort of 43 infants included 12 patients treated with extracorporeal membrane oxygenation. Evaluation was at 6 and 12 months; 33 infants were evaluated at both time points. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Maximal expiratory flow at functional residual capacity and functional residual capacity were measured with Masterscreen Babybody. Z-scores were calculated for maximal expiratory flow at functional residual capacity. Mean maximal expiratory flow at functional residual capacity values at 6 and 12 months were significantly below the expected values (mean z score -1.4 and -1.5, respectively) without a significant change between both time points. Values did not significantly differ between extracorporeal membrane oxygenation and nonextracorporeal membrane oxygenation-treated patients. Functional residual capacity values were generally high, 47% were above the suggested normal range, and did not change significantly over time. Mean functional residual capacity values in extracorporeal membrane oxygenation treated patients were significantly higher than in nonextracorporeal membrane oxygenation-treated patients (p = .006). The difference (5.1 mL/kg +/- 1.8 SE) did not change significantly between the two time points. Higher mean airway pressure and longer duration of ventilation were associated with higher functional residual capacity. None of the perinatal characteristics was associated with maximal expiratory flow at functional residual capacity. Mean weight z-scores were significantly below zero at both time points (p < .001). Mean weight z-score in extracorporeal membrane oxygenation-treated patients were lower than in nonextracorporeal membrane oxygenation-treated patients (p = .046). CONCLUSIONS: Infants with congenital diaphragmatic hernia have decreased expiratory flows and increased functional residual capacity within the first year of life. Extracorporeal membrane oxygenation-treated patients with congenital diaphragmatic hernia may have more respiratory morbidity and concomitant growth impairment. Close follow-up beyond the neonatal period is therefore required. PMID- 21666528 TI - Bedside ultrasound in pediatric critical care: a review. AB - OBJECTIVE: Bedside ultrasound, as performed by the intensivist, is gaining in popularity and has become a powerful tool to understand the physiological state of the critically ill patient and to decrease procedural risks. This review assesses clinical applications of bedside ultrasound in the pediatric intensive care unit. DESIGN: A literature review was conducted to identify English language studies in Pubmed as of June, 2010, using combinations of the following search terms: 'pediatric,' 'ultrasound,' 'critical care,' and 'intensive care.' Examination of reference lists of these studies yielded additional studies. Studies were reviewed by both authors. SETTING: Intensive care unit, emergency department, or operating rooms, as relevant to application of bedside ultrasound in the pediatric intensive care unit. PATIENTS/SUBJECTS: Pediatric patients (age 0-18 yrs) with adult patients (>18 yrs) in relevant studies utilizing bedside ultrasound by the treating clinician. INTERVENTIONS: Bedside ultrasound by treating clinician. MEASUREMENTS: Variable, per individual studies. MAIN RESULTS/CONCLUSIONS: Bedside ultrasound, as practiced by the pediatric intensivist, has the potential to improve pediatric critical care medicine, but data supporting its use is limited. Further studies are needed to explore applications, with specific emphasis on the training and experience of ultrasound operators. There is a need for a standardized educational curriculum, and questions remain as to the optimal mode of education and quality assurance of ultrasound operators. PMID- 21666529 TI - A spontaneous breathing trial with pressure support overestimates readiness for extubation in children. AB - OBJECTIVE: To evaluate the performance of an extubation readiness test based on a spontaneous breathing trial using pressure support. DESIGN: Retrospective chart review. SETTING: Pediatric intensive care unit. PATIENTS: All infants and children admitted to the pediatric intensive care unit requiring intubation from July 2007 to December 2008 were eligible for this study. INTERVENTIONS: Routine use of an extubation readiness test using pressure support set according to endotracheal tube size to determine completion of weaning and readiness for extubation. MEASUREMENTS AND MAIN RESULTS: A total of 755 extubation readiness tests were performed in 538 patients with a pass rate of 83%. Of 500 children who passed the extubation readiness test and were extubated without planned noninvasive ventilation use, the extubation failure rate was 11.2% (5.8% required reintubation). Extubation failure was defined as need for noninvasive ventilation or reintubation within 24 hrs of planned extubation. Logistic regression analysis revealed a significant association between duration of mechanical ventilation and extubation failure. Children ventilated for over 48 hrs had an 18.5% failure rate despite passing an extubation readiness test before extubation and the extubation readiness test was not a significant predictor of extubation success. Most extubation failures were the result of inadequate gas exchange attributable to lower respiratory tract dysfunction. CONCLUSIONS: A spontaneous breathing trial using pressure support set at higher levels for smaller endotracheal tubes overestimates readiness for extubation in children and contributes to a higher failed extubation rate. The objective data obtained during an extubation readiness test may help to identify patients who will benefit from extubation to noninvasive ventilation. PMID- 21666530 TI - The unique contribution of manual chest compression-vibrations to airflow during physiotherapy in sedated, fully ventilated children. AB - OBJECTIVE: This study aimed to quantify the specific effects of manual lung inflations with chest compression-vibrations, commonly used to assist airway clearance in ventilated patients. The hypothesis was that force applied during the compressions made a significant additional contribution to increases in peak expiratory flow and expiratory to inspiratory flow ratio over and above that resulting from accompanying increases in inflation volume. DESIGN: Prospective observational study. SETTING: Cardiac and general pediatric intensive care. PATIENTS: Sedated, fully ventilated children. INTERVENTIONS: Customized force sensing mats and a commercial respiratory monitor recorded force and respiration during physiotherapy. MEASUREMENTS: Percentage changes in peak expiratory flow, peak expiratory to inspiratory flow ratios, inflation volume, and peak inflation pressure between baseline and manual inflations with and without compression vibrations were calculated. Analysis of covariance determined the relative contribution of changes in pressure, volume, and force to influence changes in peak expiratory flow and peak expiratory to inspiratory flow ratio. MEASUREMENTS AND MAIN RESULTS: Data from 105 children were analyzed (median age, 1.3 yrs; range, 1 wk to 15.9 yrs). Force during compressions ranged from 15 to 179 N (median, 46 N). Peak expiratory flow increased on average by 76% during compressions compared with baseline ventilation. Increases in peak expiratory flow were significantly related to increases in inflation volume, peak inflation pressure, and force with peak expiratory flow increasing by, on average, 4% for every 10% increase in inflation volume (p < .001), 5% for every 10% increase in peak inflation pressure (p = .005), and 3% for each 10 N of applied force (p < .001). By contrast, increase in peak expiratory to inspiratory flow ratio was only related to applied force with a 4% increase for each 10 N of force (p < .001). CONCLUSION: These results provide evidence of the unique contribution of compression forces in increasing peak expiratory flow and peak expiratory to inspiratory flow ratio bias over and above that related to accompanying changes from manual hyperinflations. Force generated during compression-vibrations was the single significant factor in multivariable analysis to explain the increases in expiratory flow bias. Such increases in the expiratory bias provide theoretically optimal physiological conditions for cephalad mucus movement in fully ventilated children. PMID- 21666531 TI - A multicenter randomized controlled trial comparing effectiveness of two nasal continuous positive airway pressure devices in very-low-birth-weight infants. AB - OBJECTIVE: Many studies suggest nasal continuous positive airway pressure is an effective and relatively complication-free means of respiratory support in premature infants. However, only limited data exist regarding the practical aspects of nasal continuous positive airway pressure delivery, including the best way to provide the positive airway pressure. DESIGN: Our aim was to compare the results of treatment using two different nasal continuous positive airway pressure devices: variable flow Infant Flow and constant flow nasal continuous positive airway pressure in two different groups of very-low-birth-weight infants in a multicenter randomized controlled trial. The indication groups were elective to avoid intubation and weaning from mechanical ventilation. SETTING: Twelve leading tertiary care neonatal centers in Poland. PATIENTS: Among 276 infants (weighing between 750-1500g, with a gestational age <=32 wks) enrolled, 51% were randomized to receive Infant Flow and 49% to receive constant flow nasal continuous positive airway pressure. MEASUREMENTS AND MAIN RESULTS: Treatment success (i.e., no need for intubation/reintubation) occurred in 75% of our patients with a nonstatistically significant advantage seen with Infant Flow. The incidence of severe nasal complications and necrotizing enterocolitis were statistically significantly lower in the infants treated with Infant Flow. In our study, factors associated with elective nasal continuous positive airway pressure failure were birth weight <=1000 g, gestational age <=28 wks, clinical risk index for babies score >1, and PaO(2)/FIO(2) ratio of <150. Only birth weight <=1000 g was associated with weaning failure. CONCLUSIONS: We found fewer severe nasal complications but no statistically significant advantage in treatment success in infants assigned to Infant Flow nasal continuous positive airway pressure compared with those assigned to constant flow nasal continuous positive airway pressure treatment. Significant risk factors of treatment failure include small size, maturity, and severity of respiratory distress syndrome. PMID- 21666532 TI - Effect of race on the timing of the Glenn and Fontan procedures for single ventricle congenital heart disease. AB - OBJECTIVE: Disparities in health care have been documented between different racial groups in the United States. We hypothesize that there will be racial variance in the timing of the Glenn and Fontan procedures for children with single-ventricle physiology. DESIGN AND SETTING: We performed a retrospective review of a national pediatric intensive care unit database (Virtual PICU Performance System, LLC). PATIENTS: Children with hypoplastic left heart syndrome, tricuspid atresia, and common ventricle, admitted from January 2006 to July 2008, were included. Data included race, weight, age, medical length of stay, Paediatric Index of Mortality 2 score, and survival. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 423 patients from 29 hospitals. The study population was 7.6% black, 13.0% Hispanic, 59.8% white, 9.2% "other," and 11.6% had missing racial/ethnic information. Diagnoses included 255 patients with hypoplastic left heart syndrome, 91 with tricuspid atresia, and 77 with common ventricle. The median age for the Glenn procedure (n = 205) was 5.5 months (interquartile range, 4.6-7.0 months) and 39.7 months (interquartile range, 32.4 50.6 months) for the Fontan procedure (n = 218). There was no difference between the median age at the time of the Glenn or Fontan procedures between the different racial/ethnic groups (p = .65 and p = .16, respectively). The medical length of intensive care unit stay for patients receiving the Glenn and Fontan procedures was 3.7 days (interquartile range, 1.9-6.1 days) and 3.7 days (interquartile range, 1.9-6.8 days), respectively. There were no differences in medical length of intensive care unit stay for the Glenn procedure between the different racial/ethnic groups (p = .21). Hispanic patients had a longer medical length of intensive care unit stay (6.3 days; interquartile range, 3.1-9.9 days) than white patients (2.9 days; interquartile range, 1.8-5.3 days) for the Fontan procedure (p = .008). CONCLUSION: The timing of single-ventricle palliative procedures was not affected by race/ethnicity. PMID- 21666533 TI - Lipoxin A(4) and 8-isoprostane in the exhaled breath condensate of children hospitalized for status asthmaticus. AB - OBJECTIVE: To measure levels of 8-isoprostane and Lipoxin A4 in the exhaled breath condensate of children (7-17 yrs old) recovering from status asthmaticus in a pediatric intensive care unit and to compare their respective levels in the exhaled breath condensate collected from age-matched "healthy" children enrolled from an ambulatory pediatric clinic during well-child visits. DESIGN: Prospective case-controlled study. SETTING: Teaching hospitals and a research laboratory. PATIENTS: Children recovering from status asthmaticus and age-matched controls. INTERVENTIONS: Collection of exhaled breath condensate from patients recovering from status asthmaticus and controls for purpose of measurement of 8-isoprostane and Lipoxin A4. MEASUREMENTS AND MAIN RESULTS: There was no difference in age (11.9 +/- 3.0 vs. 12.0 +/- 3.3 yrs, p = .9) between patients and control subjects. All participants completed the exhaled breath condensate collection without complications. There was no difference in the pulmonary index (3.3 +/- 2.2 vs. 3.1 +/- 1.9, p = 1.0) after collection of exhaled breath condensate compared with baseline values in patients with status asthmaticus. The level of 8 isoprostane was significantly higher (63 +/- 9 vs. 41 +/- 13 pg/mL, p < .001), whereas the level of Lipoxin A4 was significantly lower (5.6 +/- 2.9 vs. 10.5 +/- 3.1 ng/mL, p < .001) in the exhaled breath condensate from children recovering from status asthmaticus compared with control subjects. CONCLUSIONS: 8 Isoprostane was elevated and Lipoxin A4 is decreased in the exhaled breath condensate of children recovering from status asthmaticus in a pediatric intensive care unit. These data may provide new insight into the pathophysiology of asthma in children in this clinical setting. PMID- 21666534 TI - Measured degree of dehydration in children and adolescents with type 1 diabetic ketoacidosis. AB - OBJECTIVE: Successful management of diabetic ketoacidosis depends on adequate rehydration while avoiding cerebral edema. Our objectives are to 1) measure the degree of dehydration in children with type 1 diabetes mellitus and diabetic ketoacidosis based on change in body weight; and 2) investigate the relationships between measured degree of dehydration and clinically assessed degree of dehydration, severity of diabetic ketoacidosis, and routine serum laboratory values. DESIGN: Prospective observational study. SETTING: University-affiliated tertiary care children's hospital. PATIENTS: Sixty-six patients <18 yrs of age with type 1 diabetic ketoacidosis. INTERVENTIONS: Patients were weighed using a portable scale at admission; 8, 16, and 24 hrs; and daily until discharge. Measured degree of dehydration was based on the difference between admission and plateau weights. Clinical degree of dehydration was assessed by physical examination and severity of diabetic ketoacidosis was assessed by blood gas values as defined by international guidelines. Laboratory values obtained on admission included serum glucose, urea nitrogen, sodium, and osmolality. MEASUREMENTS AND MAIN RESULTS: Median measured degree of dehydration was 5.2% (interquartile range, 3.1% to 7.8%). Fourteen (21%) patients were clinically assessed as mild dehydration, 49 (74%) as moderate, and three (5%) as severe. Patients clinically assessed as moderately dehydrated had a greater measured degree of dehydration (5.8%; interquartile range, 3.6% to 9.6%) than those assessed as mildly dehydrated (3.7%; interquartile range, 2.3% to 6.4%) or severely dehydrated (2.5%; interquartile range, 2.3% to 2.6%). Nine (14%) patients were assessed as mild diabetic ketoacidosis, 18 (27%) as moderate, and 39 (59%) as severe. Diabetic ketoacidosis severity groups did not differ in measured degree of dehydration. Variables independently associated with measured degree of dehydration included serum urea nitrogen and sodium concentration on admission. CONCLUSION: Hydration status in children with diabetic ketoacidosis cannot be accurately assessed by physical examination or blood gas values. Fluid therapy based on maintenance plus 6% deficit replacement is reasonable for most patients. PMID- 21666535 TI - Association between high cytokine levels with white matter injury in preterm infants with sepsis. AB - OBJECTIVE: To examine the association among interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1beta and white matter injury in very-low-birth-weight infants with clinical sepsis and to help predict infants at risk for development of white matter injury. DESIGN: A prospective cohort study was carried out. SETTING: Neonatal intensive care unit. PATIENTS: Very low birth weight infants with clinical early-onset sepsis. Exclusion criteria were death before 14 days, major malformations, and congenital infections. INTERVENTION: Ultrasound brain scans were carried out on the third day and weekly until the sixth week of life or discharge and confirmed by a magnetic resonance image performed in the first year. Plasma was assayed for interleukin-6, interleukin-8, tumor necrosis factor-alpha, interleukin-10, and interleukin-1beta in the same sample collected for sepsis work-up. Mann-Whitney, chi-square, t tests, multiple regression, and receiver operating characteristic analysis were applied. MEASUREMENTS AND MAIN RESULTS: From July 2005 to October 2007 we studied 84 very-low-birth-weight infants, 27 (32%) with white matter injury, and 57 (68%) control subjects (with no white matter injury). Proven early onset sepsis and necrotizing enterocolitis were high risk for white matter injury after adjustment for gestational age and birth weight (relative risk, 3.04; 1.93 4.80 and relative risk, 2.2; 1.31-3.74, respectively). Interleukin-6, interleukin 8, and tumor necrosis factor-alpha levels were higher in infants with white matter injury than in control subjects (p < .0001). Interleukin-1beta and interleukin-10 were similar. The areas under the curve for interleukin-6, interleukin-8, and tumor necrosis factor-alpha were 0.96 (0.92-0.99), 0.97 (0.94 1.0), and 0.93 (0.86-0.99), respectively. Interleukin-8 >=100 pg/mL was the best predictor of white matter injury; the sensitivity and specificity were 96% and 83%, respectively, and negative predictive value was 98%. CONCLUSIONS: Very-low birth-weight infants with proven early-onset sepsis, necrotizing enterocolitis, and high plasma levels of interleukin-6, interleukin-8, and tumor necrosis factor alpha are at high risk for white matter injury. PMID- 21666536 TI - Outcomes of neonates requiring extracorporeal membrane oxygenation for irreversible pulmonary dysplasia: the Extracorporeal Life Support Registry experience. AB - OBJECTIVE: Neonates with an irreversible pulmonary dysplasia such as alveolar capillary dysplasia, surfactant protein deficiency, and pulmonary lymphangiectasis may have a deteriorating clinical course requiring cardiopulmonary support with extracorporeal membrane oxygenation. These neonates are often difficult to distinguish from those with persistent pulmonary hypertension of the newborn. The objective of this study was to identify clinical variables that distinguish infants with irreversible pulmonary dysplasia from those with persistent pulmonary hypertension of the newborn before, and while receiving, extracorporeal membrane oxygenation support. DESIGN: A retrospective analysis of the Extracorporeal Life Support Registry from 2000 to 2010 was performed. SETTING: A total of 114 extracorporeal membrane oxygenation centers providing data to the Extracorporeal Life Support Registry. PATIENTS: All neonates day of life 0-31 reported to the Extracorporeal Life Support Registry with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn were identified. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient demographics, pre-extracorporeal membrane oxygenation variables, and survival were analyzed. Univariate analysis was performed using Student's t test or Fisher's exact test, and variables found to be significant underwent multivariate analysis by logistic regression. Neonates with irreversible pulmonary dysplasia were placed on extracorporeal membrane oxygenation later (day of life 5.3 vs. 3.0, p = .045) and for a longer duration (11.1 vs. 6.8 days, p < .001) than those with persistent pulmonary hypertension of the newborn. Initiation of extracorporeal membrane oxygenation at day of life >=5 (p = .026) and a duration of extracorporeal membrane oxygenation >=10 days (p = .003) were independent predictors of irreversible pulmonary dysplasia by multivariate analysis. No differences in demographics, blood gas values, or vascular access were observed. Survival to discharge was significantly lower for neonates with irreversible pulmonary dysplasia (3%) vs. persistent pulmonary hypertension of the newborn (81%, p < .001). CONCLUSION: Although neonates with irreversible pulmonary dysplasia and persistent pulmonary hypertension of the newborn have similar presentations, those with irreversible pulmonary dysplasia require extracorporeal membrane oxygenation support later in the perinatal period and for a longer duration. For neonates with a diagnosis of persistent pulmonary hypertension of the newborn, irreversible pulmonary dysplasia should be considered when extracorporeal membrane oxygenation is initiated on day of life >=5 and/or the duration of extracorporeal membrane oxygenation >=10 days. PMID- 21666537 TI - Diagnostic efficacy of activated partial thromboplastin time waveform and procalcitonin analysis in pediatric meningococcal sepsis. AB - OBJECTIVE: A biphasic activated partial thromboplastin time waveform predicts sepsis and disseminated intravascular coagulation in adults. This has not been previously investigated in children. Our aim is to ascertain whether there are changes in the activated partial thromboplastin time waveform in children with meningococcal disease and to compare its diagnostic use with procalcitonin. SETTING: Alder Hey Children's National Health Service Foundation Trust, Liverpool, UK. PATIENTS: Thirty-six children admitted to the hospital for the treatment of suspected meningococcal disease had activated partial thromboplastin time waveform and procalcitonin analysis performed at admission. The light transmittance level at 18 secs was used to quantitate the waveform. Severity of disease was assessed using the Glasgow Meningococcal Septicaemia Prognostic Score, Pediatric Risk of Mortality III score, and the Pediatric Logistic Organ Dysfunction score. MEASUREMENTS AND MAIN RESULTS: Twenty-four children had proven meningococcal disease, 12 had a presumed viral illness, and 20 control subjects were recruited. Transmittance level at 18 secs was lower in children with meningococcal disease and those with a viral illness (p < .0001) and control subjects (p < .0005). Sensitivity and specificity was 0.91 and 0.96 for transmittance level at 18 secs and 0.92 and 1 for procalcitonin in identifying meningococcal disease. There was a significant difference in procalcitonin between children with meningococcal disease and those with a viral illness and control subjects (p < .0005). A negative correlation was found between transmittance level at 18 secs and length of hospital stay (p < .0001), C reactive protein (p < .0001), procalcitonin (p < .0001), Glasgow Meningococcal Septicaemia Prognostic Score (p < .01), Pediatric Risk of Mortality III score (p < .0001), and Pediatric Logistic Organ Dysfunction score score (p < .0001). CONCLUSION: The activated partial thromboplastin time waveform is abnormal in children with meningococcal disease and may be a useful adjunct in the diagnosis and management of sepsis in children. PMID- 21666538 TI - Hospital-acquired viral infection increases mortality in children with severe viral respiratory infection. AB - OBJECTIVE: To investigate the association of method of acquisition (hospital acquired vs. community-acquired) and mortality in children with severe viral respiratory infection. DESIGN: Retrospective cohort study. SETTING: : Pediatric intensive care unit at an urban academic tertiary care children's hospital. PATIENTS: All patients aged <18 yrs admitted to our pediatric intensive care unit with laboratory-confirmed respiratory syncytial virus, influenza, parainfluenza, or adenovirus infection between October 2002 and September 2008. INTERVENTIONS: We stratified patients by method of viral acquisition and identified those patients with chronic medical conditions associated with an increased risk of complications from viral illness. MEASUREMENTS AND MAIN RESULTS: There were 289 patients admitted to the pediatric intensive care unit with laboratory-confirmed viral respiratory infection during the period of study. Fifty-three patients (18%) had hospital-acquired infection and 117 patients (40%) had chronic medical conditions associated with an increased risk of complications from viral illness. Hospital-acquired infection was associated with increased mortality and length of stay (all p < .001). Adjusting for age, chronic medical conditions, severity of illness index, and catheter-associated bloodstream infections, patients with hospital-acquired infection had a 5.8 (95% confidence interval 2.1-15.6) times greater odds (p = .001) of mortality. CONCLUSIONS: Our results suggest that in children with severe viral respiratory infection, hospital acquisition of infection is associated with increased mortality even after adjusting for chronic medical conditions that predispose to an increased risk of complications from viral illness. PMID- 21666539 TI - Which pressure to believe? A comparison of direct arterial with indirect blood pressure measurement techniques in the pediatric intensive care unit. AB - OBJECTIVE: To determine the accuracy of arterial blood pressure monitoring using 1) direct arterial; 2) automated oscillometric; and 3) sphygmomanometer/Doppler ultrasound measurements in pediatric intensive care patients comparing methods 1) and 2) with 3), the gold standard used to define normal blood pressure. DESIGN: Prospective observational study. SETTING: Pediatric intensive care unit of a tertiary care pediatric teaching hospital. PATIENTS: Forty children (birth to 17 yrs) admitted to the pediatric intensive care unit with various clinical conditions requiring a radial arterial catheter for continuous arterial blood pressure monitoring. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Each subject had measurements taken every 6 hrs over a 24-hr period. Each set of measurements were: direct arterial blood pressure, indirect blood pressure using the Phillips automated oscillometric device, and indirect blood pressure using the sphygmomanometer and Doppler ultrasound. Analysis used the Bland-Altman plot followed by paired t testing to compare the three different methods. One hundred sixty triads of measurements were analyzed. There were no significant differences between the methods of blood pressure measurement when groups were analyzed based on age. When analyzed by age-specific normo-, hypo-, and hypertensive criteria, arterial blood pressure measurements agree closely with Doppler ultrasound readings, whereas systolic arterial blood pressure measurements were lower than indirect blood pressure using the Phillips automated oscillometric device readings in the hypotensive group (p < .001). In the hypertensive group, the systolic arterial blood pressure values were higher and indirect blood pressure using the Phillips automated oscillometric device readings lower (p < .001) than Doppler ultrasound (p = .03). There was no clinically significant difference between methods in the normotensive group. Diastolic blood pressure measurements were higher by arterial blood pressure in normotensive and hypertensive groups but no different in the hypotensive group. CONCLUSION: Outside the normotensive range, the automated readings were higher during hypotension and lower during hypertension compared with the arterial and Doppler ultrasound methods. The arterial blood pressure was closer to the gold standard Doppler ultrasound blood pressure in all three blood pressure groups. PMID- 21666540 TI - Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of life. AB - BACKGROUND: There are no previous data describing nelfinavir and lamivudine pharmacokinetics in neonates treated with weight-band dosing regimens. DESIGN: Pharmacokinetic study of nelfinavir and lamivudine pharmacokinetics in infants during the first 2 weeks of life treated with weight-band dosing regimens. METHODS: Intensive 12-hour pharmacokinetic profiles were performed between either days 4-7 or days 10-14 of life in 26 Brazilian infants. RESULTS: Pharmacokinetic data were obtained from 26 infants who received median (range) per kg doses of 58.8 (48.4-79.0) mg/kg for nelfinavir and 2.0 (1.5-3.2) mg/kg for lamivudine. Median nelfinavir 12-hour AUC (AUC0-12) was 25.5 (1.7-183.5) MUg*h/mL and median 12-hour concentration (C12h) was 1.09 (<0.04-14.44) MUg/mL. AUC0-12 was less than 15 MUg*h/mL (the 10% for adults) in 12 infants (46%). Median lamivudine AUC0-12 was 7.8 (2.7-15.6) MUg*h/mL and median C12h was 0.23 (<0.04-0.74) MUg/mL. CONCLUSIONS: : Lamivudine pharmacokinetic parameters observed in this study were consistent with those seen in other studies of neonates. While median nelfinavir AUC and C12h in these neonates were above the exposure targets, interindividual variability in nelfinavir exposure was large and nelfinavir exposure failed to meet the exposure targets in 46% of infants. PMID- 21666541 TI - The impact of obesity on breast surgery complications. AB - BACKGROUND: The increasing prevalence of obesity may worsen surgical outcomes and confound standardized metrics of surgical quality. Despite anecdotal evidence, the increased risk of complications in obese patients is not accounted for in these metrics. To better understand the impact of obesity on surgical complications, the authors designed a study to measure complication rates in obese patients presenting for a set of elective breast procedures. METHODS: Using claims data from seven Blue Cross and Blue Shield plans, the authors identified a cohort of obese patients and a nonobese control group who underwent elective breast procedures covered by insurance between 2002 and 2006. The authors compared the proportion of patients in each group who experienced a surgical complication. Using multivariate logistic regression, the authors calculated the odds of developing a surgical complication when obesity was present. RESULTS: There were 2403 patients in the obese group (breast reduction, 80.7 percent; reconstruction, 10.3 percent; mastopexy with augmentation, 1.5 percent; mastopexy alone, 3.5 percent; and augmentation alone, 4.0 percent). The occurrence of complications was compared for each procedure to a nonobese control group of 5597 patients. Overall, 18.3 percent of obese patients had a claim for a complication, compared with only 2.2 percent in the control group (p<0.001). Obesity status increased the odds of experiencing a complication by 11.8-fold after adjusting for other variables. CONCLUSIONS: Obesity is associated with a nearly 12-fold increased odds of a postoperative complication after elective breast procedures. As quality measures are increasingly applied to surgical evaluation and reimbursement, appropriate risk adjustment to account for the effect of obesity on outcomes will be essential. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 21666542 TI - Meta-analysis of randomized trials on the association of prophylactic acyclovir and HIV-1 viral load in individuals coinfected with herpes simplex virus-2. AB - OBJECTIVE: To summarize the randomized evidence regarding the association between acyclovir use and HIV-1 replication as measured by plasma HIV-1 RNA viral load among individuals coinfected with herpes simplex virus (HSV)-2. DESIGN: Meta analysis of seven randomized trials conducted between 2000 and 2009. Inclusion criteria composed of acyclovir or valacyclovir use as prophylaxis among individuals coinfected with HIV-1 and HSV-2 who were ineligible for highly active antiretroviral therapy. HIV-1 viral load was the outcome. METHODS: Random-effects summarization was used to combine treatment effect estimates. Stratified and meta regression analyses were used to compare estimated treatment effects by characteristics of trials and participants. RESULTS: The summary treatment effect estimate was -0.33 (95% confidence interval: -0.56, -0.10, 95% population effects interval: -0.74, 0.08) log(10) copies, an approximate halving of plasma viral load. However, there was marked heterogeneity (P < 0.001). Older median age, valacyclovir, higher compliance, earlier publication, and shorter study length were associated with a larger decrease in viral load as compared with their counterparts. CONCLUSION: Current evidence suggests a range of favorable effects of acyclovir on plasma HIV-1 viral load among persons coinfected with HSV-2. PMID- 21666543 TI - Assessment of subjective workload in an anaesthesia simulator environment: reliability and validity. AB - BACKGROUND AND OBJECTIVE: For the subjective assessment of workload, Borg's Rating of Perceived Exertion (RPE) scale is a global measure of perceived workload during anaesthesia induction, maintenance and emergence in the real workplace. In the present study, validity and reliability of the RPE scale were analysed for a full-scale simulator environment using scenarios of induction of general anaesthesia with and without critical incidents. METHODS: Seventeen anaesthetists (professional experience 1-30 years) participated in this randomised cross-over trial. Each participant rated their workload using the RPE scale after three different simulator sessions. No critical incident was simulated in the 1st session. In a randomised order, workload was increased by simulation of a critical incident in the 2nd or 3rd session. For the analysis of validity and reliability, univariate and multivariate regression analysis and the concordance correlation coefficient were used. RESULTS: RPE scores were significantly increased after managing a simulated critical incident [13.0, 95% confidence interval (CI) 11.6-14.5] compared to normal anaesthesia induction (9.4, 95% CI 8.2-10.6; P < 0.001). Reliability was moderate (concordance correlation coefficient = 0.55; 95% CI 0.13-0.80) for uneventful sessions. CONCLUSION: RPE scores were significantly increased after critical incidents during simulated anaesthesia induction and indicate good construct validity. Reliability may be impaired by the fact that the first session was announced to be without a critical incident. The RPE scale is easy to administer and a valid tool for subjective workload assessment in simulator settings. Reliability is moderate. PMID- 21666544 TI - Propofol post-conditioning protects against cardiomyocyte apoptosis in hypoxia/reoxygenation injury by suppressing nuclear factor-kappa B translocation via extracellular signal-regulated kinase mitogen-activated protein kinase pathway. AB - BACKGROUND AND OBJECTIVE: Perioperative myocardial ischaemia leads to an exceedingly high mortality. Previous studies have indicated that propofol pre conditioning could mimic the cardioprotective effects of ischaemic pre conditioning. The purpose of this study was to determine whether propofol post conditioning is cardioprotective and to explore the possible molecular mechanism of propofol post-conditioning. METHODS: Primary cultured neonatal rat cardiomyocytes were exposed to 12 h of hypoxia followed by 4 h of reoxygenation (H/R) and post-conditioned by different concentrations of propofol at the onset of reperfusion with and without a specific inhibitor of extracellular signal regulated kinases (ERKs). Cell apoptosis and the generation of intracellular reactive oxygen species were measured using FACScalibur flow cytometric analysis. ERK1/2 phosphorylation and nuclear factor-kappa B (NF-kappaB) translocation were determined by western blot and immunofluorescence, respectively. RESULTS: Propofol post-conditioning enhanced cell viability (86.6 +/- 6.5 versus 64.1 +/- 3.4%) and reduced apoptosis (3.6 +/- 0.4 versus 12.5 +/- 2.1%) to protect cardiomyocytes against H/R injury. Meanwhile, propofol post-conditioning stimulated expression of phosphor-ERKs. H/R markedly induced p65 NF-kappaB nuclear translocation in cardiomyocytes, whereas propofol post-conditioning significantly suppressed H/R-primed NF-kappaB translocation. Moreover, addition of the mitogen-activated protein kinase kinase 1 inhibitor U0126 into cardiomyocytes 30 min before H/R eliminated the cardioprotection of propofol post conditioning. CONCLUSION: Propofol exerts cardioprotection when administered at the early phase of reperfusion. The effect is mediated through decrease in cardiomyocyte apoptosis and NF-kappaB nucleus translocation potentially via ERK signalling pathways. PMID- 21666545 TI - Learning from the past for the present: paravertebral blocks for thoracic surgery are not without risk. PMID- 21666546 TI - World Gastroenterology Organisation global guideline: Constipation--a global perspective. PMID- 21666547 TI - Liver failure after transarterial chemoembolization for patients with hepatocellular carcinoma and ascites: incidence, risk factors, and prognostic prediction. AB - BACKGROUND: Transarterial chemoembolization (TACE) is widely used in patients with hepatocellular carcinoma (HCC). Post-TACE liver failure may occur, especially in patients with poor hepatic reserve. Ascites is often present in patients with HCC with coexisting cirrhosis. This study investigated the incidence, risk factors, and prognostic predictors in patients with HCC and ascites receiving TACE. METHODS: A total of 614 patients with HCC were enrolled and analyzed. Liver failure was defined as an increase of serum bilirubin level (>=2.0 mg/dL), increasing or newly developed ascites, or hepatic encephalopathy within 2 weeks of TACE. RESULTS: Ascites that were present in 100 (16.2%) patients at study entry, independently predicted a poor prognosis in the Cox proportional hazard model [relative risk (RR)=1.75, P=0.004]. Post-TACE liver failure occurred in 17 (17.3%) of 98 patients with HCC who had ascites and long term follow-up. Child-Turcotte-Pugh class B (odds ratio=10.1, P=0.038) and post TACE gastrointestinal bleeding (odds ratio=10.86, P=0.006) were independent risk factors associated with liver failure in the multivariate analysis. Of the 17 patients with post-TACE liver failure, 16 (94%) died within the first year of treatment. Liver failure (RR: 2.13, P=0.029), serum alpha-fetoprotein level >51 ng/mL (RR=2.0, P=0.013) and poor performance status (RR: 2.17, P=0.003) independently predicted a poor prognosis in patients with ascites receiving TACE. CONCLUSIONS: Preexisting ascites increases the mortality in patients with HCC receiving TACE. In patients with HCC and ascites, Child-Turcotte-Pugh class B and gastrointestinal bleeding are associated with liver failure after TACE. Post-TACE liver failure is a common event and predicts a decreased survival in patients with HCC and ascites. PMID- 21666548 TI - Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene. AB - BACKGROUND: Orexin A and B are neuropeptides influencing, for example, arousal and respiration. Although panic disorder is characterized by both enhanced proneness for arousal and by respiratory abnormalities, the possible influence of orexin-related genes on the risk of developing this disorder has not been studied until now. METHODS: We have analyzed the Ile408Val polymorphism in the hypocretin receptor 1 (HCRTR1) gene and the Val308Iso (G1246A) polymorphism in the hypocretin receptor 2 (HCRTR2) gene in a sample of 215 panic disorder patients and 454 controls. RESULTS: Although the polymorphism in the HCRTR1 did not differ between groups, the Iso allele of the HCRTR2 polymorphism was significantly more frequent in patients than in controls. After the population was divided according to sex, the association between the Iso allele of the Val308Iso polymorphism and panic disorder was observed only in female patients. CONCLUSION: Our results suggest that the HCRTR2 polymorphism may be of importance for the pathophysiology of panic disorder. The results should be regarded as preliminary until replicated in an independent sample. This indicates that further research on the possible role of orexin in panic disorder may prove rewarding. PMID- 21666549 TI - Flavonoids from Praxelis clematidea R.M. King and Robinson modulate bacterial drug resistance. AB - Chemical studies of Praxelis clematidea R.M. King & Robinson resulted in the isolation of six flavones: Apigenine, genkwanine, 7,4'-dimethylapigenin, trimethylapigenin, cirsimaritin and tetramethylscutellarein, which were tested for their toxicity against Staphylococcus aureus SA-1199B, a strain possessing the NorA efflux pump. Efflux pumps are integral proteins of the bacterial membrane and are recognized as one of the main causes of bacterial drug resistance, since they expel antibiotics from the cell. The inhibition of this transporter is one form of modulating bacterial resistance to antimicrobial drugs. The flavones tested did not show any significant antibacterial activity against the Staphylococcus aureus strain used, but were able to modulate bacterial drug resistance. This property might be related to the degree of lipophilicity of the flavones conferred by the methoxyl groups, since 4',5,6,7 tetramethoxyflavone the most methoxylated compound, reduced the minimal inhibitory concentration of the drug 16-fold. PMID- 21666550 TI - The immuno-regulatory effects of Schisandra chinensis and its constituents on human monocytic leukemia cells. AB - Many diseases occur when the immune system is weakened. Intracellular signals activate immuno-responsive cells to produce cytokines that modulate the immune response. Schisandra chinensis has been used traditionally to treat general fatigue, neurasthenia, and spontaneous sweating. In the present study, the effect of constituents of S. chinensis on cytokine release by human monocytic leukemia cells (THP-1) was tested using microparticle-based flow cytometric analysis. Two major lignans, schizandrin (Sch) and gomisin A (Gom A), were identified and shown to induce interleukin (IL)-8, macrophage inflammatory protein-1beta (MIP-1beta), and granulocyte-macrophage-colony stimulating factor (GM-CSF) release by THP-1 cells. By reverse transcription polymerase chain reaction (RT-PCR) or quantitative real-time PCR, there was a dose-dependent increase of IL-8, MIP 1beta and GM-CSF mRNA levels. Thus, Sch and Gom A from S. chinensis enhance cytokine release by THP-1 cells and this effect occurs through mRNA upregulation. Upregulation of MIP-1beta and GM-CSF in particular may have clinical applications. Therefore, S. chinensis may be therapeutically beneficial by promoting humoral and cell-mediated immune responses. PMID- 21666551 TI - Synthetic studies on bioactive natural polyketides: intramolecular nitrile oxide olefin cycloaddition approach for construction of a macrolactone skeleton of macrosphelide B. AB - Studies on the synthesis of macrosphelide B via an intramolecular nitrile oxide olefin cycloaddition (INOC) is described. In particular, an asymmetric INOC approach using phase transfer catalysts seems to be a potentially efficient and versatile procedure for the construction of the macrolactone skeleton of macrosphelide B in terms of facial selectivity. Our preliminary and unprecedented stereoselective procedure is anticipated to be usefully applied through further studies for the synthesis of the macrosphelide family. PMID- 21666552 TI - Bilio-intestinal bypass for the treatment of obesity. AB - AIM: This study was a retrospective assessment of the results of bilio-intestinal bypass (a variation of the jejuno-ileal bypass, in which the intestinal blind loop is anastomosed to the gallbladder). METHODS: Seventy-five patients underwent the Eriksson bilio-intestinal bypass since 2003 to January 2009. Mean weight prior to surgery was 115.17 (SD+/-17.74 kg; range 82-177 kg). Mean preoperative BMI (Body Mass Index) was 41.75 kg/m2 (SD+/-4.42; range 35-60). Primary criteria taken into consideration have been: weight loss, blood tests, reversal rate and complications. RESULTS: One year after surgery BMI reported a mean decrease of 28.31% (SD+/-2.49%) from a mean of 41.75 to a mean 29.72. The mean follow-up is 26.81 months (SD+/-17.41 months; range 1-72 months). Blood glucose levels at one year follow-up were normalized, shifting from a mean of 138.5 (SD+/-23.8) to 86.2 (SD+/-2.6) mg/dL. Diabetic patients were all able to stop hypoglicemic drugs. Serum total cholesterol and triglycerides concentrations decreased of a mean of 31% and 44%. Morbidity was acceptable (two cases of enterorrhage, one biliary leak, one intra-abdominal abscess all treated conservatively). Reversal rate was 2.67%. No mortality was registered. CONCLUSION: Bilio-intestinal bypass is effective in inducing weight loss and metabolic improvement. This procedure is particularly indicated for the heavily obese who do not accept alimentary restrictions but are willing to submit to long-term monitoring. PMID- 21666553 TI - Lymph-nodal ratio in gastric cancer staging system. AB - AIM: Many studies have indicated that lymph node metastases and the depth of invasion of the primary tumor are the most reliable prognostic factors for patients with radically resected gastric cancer. Recently the ratio between metastatic and examined lymph nodes (n ratio) has been proposed as a new prognostic indicator. The aim of this study was to evaluate the prognostic value of n ratio in patients with gastric cancer. METHODS: We retrospectively reviewed the data of 399 patients who had undergone radical resection for gastric carcinoma. RESULTS: N ratio was significantly greater in patients with large and undifferentiated tumors. Moreover, it was significantly related to both the number and location of lymph node metastases. Survival curves showed that n ratio was strictly related to patients' survival. Multivariate analysis confirmed that it was an important independent prognostic indicator. CONCLUSION: N ratio is useful to better evaluate the status of lymph node metastases in patients with gastric cancer submitted to radical surgery. Moreover it is a very important independent prognostic factor for gastric cancer. PMID- 21666554 TI - [Enteric anastomosis and Tachosil(r)]. AB - AIM: Anastomotic leakage is a common complication of colorectal surgery. To date, no clinical study exists showing a significant effect in reducing its frequency by sealing the anastomosis with a fibrin glue-coated collagen patch; the aim of this study was to demonstrate the efficacy of Tachosil(r). METHODS: We considered patients undergoing open resective colorectal surgery. In selected cases, the Tachosil(r) patches were wrapped around the anastomotic line. The onset of anastomotic leakage was either defined clinically and investigated by contrast enema and CT scan. RESULTS: From January 2010 to February 2011, 63 patients underwent colorectal surgery at our Institute. Tachosil(r) was used in 24 cases. We recorded six major surgical complications; all complicated cases were in the no-Tachosil(r) group. A shorter mean postoperative stay of 7.2 days was observed for patients where Tachosil(r) was applied compared to 9.3 days for patients of no- Tachosil(r) group. These difference was mainly related to anastomotic insufficiencies recorded in the no-Tachosil(r), group. Fibrin-coated collagen glue is used in different fields of surgery to improve hemostasis and anastomotic healing. Our experience confirmed its safety with a low incidence of anastomotic leak. These experience is based on few, non-randomized cases and therefore cannot demonstrate a real efficacy of Tachosil(r) in anastomotic leak prevention. CONCLUSION: Anastomotic leakage is a relatively common and potentially catastrophic complication after gastrointestinal surgery. Our initial experience with Tachosil(r) has confirmed the safety of this patch and we can therefore suggest a possible positive effect on anastomotic healing. PMID- 21666556 TI - [A single effective way to reduce post-thyroidectomy discomfort: a clinical trial]. AB - AIM: Nausea, with or without vomiting (postoperative nausea and vomiting, PONV), occurs up to 60-76% after thyroidectomy and other head and neck surgeries. Due to the fact that patients typically have only mild-to-moderate pain after thyroid or parathyroid surgery, PONV might be the main source of discomfort, and it may be perceived as the most unpleasant aspect of postoperative recovery. This study aims to assess the effects of a preoperative single dose of 8 mg dexamethasone on the nausea, vomiting, pain, and subjective vocal function after thyroidectomy in patients undergoing surgery for benign disease. METHODS: Seventy patients operated on for thyroidectomy were randomized in two groups: Group A, 8 mg/2 mL of dexamethasone administered in 100 mL of physiologic saline given intravenously (i.v.) 20 minutes before the induction of anesthesia; group B, 2 mL NaCl 0.9% in 100 mL of physiologic saline. Postoperative therapy has been standardized. PONV have been evaluated with a scale of 4, degrees (0-3), pain by a Visual Analog Scale (0-100) and subjective vocal function by a Visual Analog Scale (0-100) at 8, 24, 32 and 48 hours after surgery. RESULTS: The severity of nausea was less in patients of group A (P=0.0001); Dexamethasone patients reported significantly less pain (P=0.008); no differences were noted about the subjective voice analysis (P=0.693). No steroid-related complications occurred. CONCLUSION: Dexamethasone 8 mg i.v. is a safe and effective method to reduce PONV and pain after thyroid resection and we advise its routine use. PMID- 21666555 TI - Comparison of total thyroidectomy, bilateral subtotal thyroidectomy and Dunhill operations in the treatment of benign thyroid disorders. AB - AIM: The surgical treatment of benign thyroid disease is still controversial. Many treatment modalities have been described for the surgical management of various thyroid diseases, including excision, bilateral subtotal thyroidectomy (BST), near-total thyroidectomy, and total thyroidectomy (TT). METHODS: Hospital records were reviewed for 2863 patients who underwent thyroid surgery for presumed multinodular goiter (MNG) between 1990 and 2009. However, due to the inefficiency of the hospital archive system, we were able to access detailed personal and surgical information for only 803 patients. RESULTS: Of the 803 patients, 227 (28.3%) underwent DP, 228 (28.4%) BST and 348 (43.3%) TT operations. While there were no complications in 683 (85.1%) of the 803 operations, complications developed with 120 (14.9%). A definite difference between TT and the other (BST and DP) types of operation in relation to complications. The duration of hospital stay was 2.2+/-0.4 days for the BST group, 2.2 +/- 0.4 days for the DP group and 2.3 +/- 0.7 days for the TT group. There was a significant difference among all three groups. Recurrence rates of the operations performed were 35 (15.3%), 20 (8.8%) and 4 (1.15%), respectively, for BST, DP and TT. There was significant difference between the recurrence rates of TT and BST, and between TT and DP. CONCLUSION: When the frequency of complications in recurrent operations and the malignity possibility of the thyroid tissue left behind are taken into consideration, we believe that TT will be more beneficial in the surgical treatment of benign thyroid disorders. PMID- 21666558 TI - Imaging and lung cancer. AB - Lung cancer remains the most common cause of cancer-related mortality in Scotland, accounting for 28.9% of all cancer deaths in 2007. Current guidelines recommend assessment of patient fitness and operability by a multidisciplinary team when selecting management options. Two of the most important prognostic markers are the stage of disease and ECOG performance status. In 1996, the International Association for the Study of Lung Cancer (IASLC) launched a worldwide TNM staging project to create international databases that would be used to continue the excellent efforts of Dr. Cliff Mountain, who pioneered this approach to lung cancer staging in 1973. Successive iterations of tumor, nodule, metastasis (TNM) staging for lung cancer have addressed shortcomings identified by the oncology community. Similarly, the IASLC recognized that it is important that further revisions continue to be made to ensure that the international staging system for lung cancer remains fit for its purpose. The last work of the International Staging Committee (ISC) was the conduct of the study that informed the seventh edition of the international staging system for lung cancer, in 2010. This review of image and staging in non small cell lung cancer (NSCLC), includes a summary of the different noninvasive tests currently available for staging non small cell lung cancer. PMID- 21666557 TI - Surgical treatment for IV-degree hemorrhoids: LigaSureTM hemorroidectomy vs. conventional diathermy. A prospective, randomized trial. AB - AIM: Milligan-Morgan operation is still considered the treatment of choice for IV degree haemorrhoids: it is frequently associated with significant postoperative pain and prolonged hospital stay. Many instruments were conceived to reduce these complications, such as the LigaSureTM (LS) system, a combination of radiofrequency and pressure that seems mainly effective where a large tissue demolition is required. This randomized study is METHODS: Fifty-two patients with IV-degree hemorrhoids were randomly assigned to two different surgical treatments (conventional diathermy vs. LigaSureTM hemorrhoidectomy). They were evaluated on the basis of the following main outcomes: mean operative time, postoperative pain, day of discharge early and late complications. The time of recovery of work was also assessed. All patients had a minimum follow-up of twelve months (range 12-24). All data were statistically evaluated. RESULTS: Twenty-seven patients were treated by conventional diathermy, 25 by LigaSureTM. The mean operative time was significantly shorter in LS, such as postoperative pain, mainly lower on the third and fourth postoperative day: moreover pain disappeared earlier in LS than CD. The time off-work was shorter in LS, while there was no difference in hospital stay and overall complications rate . CONCLUSION: This randomized prospective controlled trial confirms, according to other large trials in literature , the benefits of the LigaSureTM hemorrhoidectomy over conventional diathermy when a large tissue demolition is required, supporting the use of this device as treatment of choice in IV degree hemorrhoids, even if the procedure is more expensive than conventional operation. PMID- 21666559 TI - Lung nodule management: a new classification proposal. AB - Management of solitary pulmonary nodule (SPN) and micronodule (SPMN) is still debated. The use of 18F-FDG PET/CT or CT multislice screening for early lung cancer detection, have increased the frequency of displaying indeterminate single lung nodule with diameter between 0.1 cm and 2 cm. The first choice is to wait and do radiological follow-up, since the evaluation of temporal changes in a small mass may contribute to differentiate a malign from benign pathology. In case of unchanged images not capable of orientating the diagnostician or no possible preoperative diagnosis by bronchoscopy and percutaneous needle biopsy, surgical treatment is necessary allowing the histological characterization of lesion and a good prognosis of disease. Video-assisted thoracoscopic surgery and muscle-sparing minithoracotomy have become routine, each of these furnishing precise indications. The purpose of the study was to establish the main investigative method for indeterminate lung nodules, considering the continuous evolution of endoscopic and radiological techniques. PMID- 21666561 TI - Radiotherapy issues in non-small cell lung cancer: radiotherapy versus surgery in the treatment of early stage. AB - We discussed in this article about the role of surgery, in a broad sense, and radiotherapy for the treatment of early stage of non-small cell lung cancer (NSCLC), and we also examined if patients' outcomes after radiation therapy are comparable to the ones after surgery. Radiotherapy is at present a less attractive alternative to surgery in operable patients with early stage of NSCLC. Indeed, radiotherapy is frequently reserved for patients who are deemed unfit for surgery due to poor pulmonary function or other comorbidities. This introduces a large patient selection bias compared to surgery, rendering overall survival less suitable for comparison. When we compare patients who are deemed operable but refuse surgery, the 5-year overall survival rate observed, after a high effective dose, is equivalent to the outcome after surgery. On the other hand, it is difficult to enroll patients in randomized clinical trials for this purpose, propensity matched analysis allows to compares the effectiveness of radiotherapy and surgery using comparable series of patients, using this methodology two studies obtained similar results. This data support the need of continuous investigation for non-surgical alternatives in this disease, radiotherapy can be a good option. Until then, surgery remains the treatment of choice for early stage of NSCLC. PMID- 21666560 TI - Novel therapies in non-small cell lung cancer. AB - Over the last years, several new systemic cancer therapy strategies have been introduced to turn the growing insights of molecular aberrations involved in the development and progression of lung cancer into better treatment options fort the patients. This review presents some of the most important biological targets and biomarkers relevant in the treatment of non-small cell lung cancer. Especially EGFR mutations, anti-angiogenesis, multi kinase inhibition, vascular disrupting agents, vaccines, m-TOR inhibitors, TRAIL inhibition and several biomarkers are highlighted including current study results. PMID- 21666562 TI - K-ras role in lung cancer therapy. AB - The ras gene family provides a global effect on gene expression by encoding small GTP-binding proteins which act as molecular switches connecting extracellular signals with nuclear transcription factors. Mutations on the K-ras gene have been found in 20-30% of non-small-cell lung cancers are believed to play a key role in this malignancy. The ras-signaling pathway has attracted considerable attention as a target for anticancer therapy because of its important role in carcinogenesis. This review summarizes the structure and function of K-ras, with attention to the facets of K-ras biology that relate to tumorigenesis and focuses on those that have been targeted for lung cancer therapy. PMID- 21666563 TI - Adhesion between fiber post and root dentin: evaluation of post surface conditioning for bond strength improvement. AB - AIM: The aim of this paper was to evaluate two surface conditioning methods associated with the application of adhesive on the post surface for improving the bond to resin cement. METHODS: Sixty single-rooted bovine teeth were sectioned at 16 mm in length, prepared (9 mm depth), embedded in a PVC cylinder using acrylic resin, and allocated into 3 groups (N.=20) according to post surface treatment: cleaning with ethanol (control group); etching with hydrogen peroxide; etching with hydrofluoric acid. Ten posts for each group were silanized and other 10 posts were silanized and received an adhesive agent. The posts were cemented with self-adhesive resin cement (RelyX U100 resin cement). All teeth were sectioned perpendicularly to the long axis (2 mm thickness per slice), submitted to push out bond strength testing and the type of failure was recorded. The obtained data were submitted to two-way ANOVA and Turkey's test, with the level of significance set at 5%. RESULTS: Neither the hydrofluoric acid or hydrogen peroxide post surface treatment, nor the adhesive application, had an influence on bond strength values. The main type of failure was adhesive between cement and dentin. CONCLUSION: Etching and the application of an adhesive on the post surface did not presented a significant influence on the bond strength results for the fiber post resin cement-root dentin assembly. The cement appears to adhere very well to the fiber post surface rather than the dentin surface. PMID- 21666564 TI - Surgical endodontic therapy: retrofilling of apex with amalgam and SuperSeal. Retrospective study. AB - AIM: The aim of this study was to make a retrospective analysis on teeth with apicectomized roots, closed off by retrograde with amalgam and SuperSeal-Ogna(r) (cement oxide of zinc and eugenol modified by acidity ethoxy-benzoic acid), in order to achieve clinical evaluation and radiographic evidence of treated dental elements and surrounding tissue SuperSeal (Ogna(r)). METHODS: The study was conducted on 420 teeth, single and multi rooted, pertaining to 366 patients (189 women and 177 men) endodontically treated, in between 1998 and 2007. The teeth were treated with endodontic technique step-back and closed off with gutta percha. Following the roots were apicectomyzed and then was prepared a retrograde cavity using retrotip steel mounted on the ultrasonic device. After carrying out the retrograde cavity all the samples were divided into two groups . The retrograde filling in Group A was made in Superseal, group B with amalgama. Both groups were divided in those teeths who was treated with use of optical microscope and in groups of teeths preformed without microscope. RESULTS: Nevertheless amalgam against the SuperSeal offers almost the same quality of the seal and the same prognosis. However SuperSeal as a material of choice, proved excellent, for carrying out the retrograde fillings free of some side effects, such as dimensional instability, mercury poisoning and pigmentation of tissues (tattoos from amalgam). CONCLUSION: In any case, whatever the type of material is, the operative microscope significantly affects the occurrence of failure. This demonstrates the importance of the microscope in order to obtain greater visibility and accuracy of the apex seal, more than minor sacrifice of healthy tissue. PMID- 21666565 TI - In vitro study on micro-hardness of resin-modified glass ionomers at different depths. AB - AIM: It is very important to perform studies to evaluate micro-hardness and curation level at different depths to refine the clinical indications and orientations that the odontologist gives to the patients, helping to achieve more durable treatments when using resin-modified glass ionomers. This in vitro study evaluated knoop micro-hardness in 2 different brands of resin-modified glass ionomers: Ketac TM N100 (M1) and Fuji II LC (M2). METHODS: Tests were performed at three depths: surface (P1), 2 mm (P2) and 3 mm (P3). A total of 40 samples where made (20 of each type of resin), half of these measuring 5 x 2 mm and the other half with 5 x3 mm. To evaluate micro-hardness at different depths, 24 hours after the manufacture of samples, tests where made on both top and bottom surfaces. These tests were performed using an HMV-200 Micro Hardness Tester (Shimadzu brand). For statistical analysis data were collected and used first for ANOVA variance analysis (P<=0.01) followed then by Turkey's test. RESULTS: It also shows that the effect is not significant for the interaction between material and depth. Micro-hardness on P1 (34.7) is statistically greater than with P2 (29.2) and P3 (29.0) and these last two are statistically equal between them. M1 (27.8) presented less micro-hardness than M2 (34.2). CONCLUSION: Surface micro-hardness is greater than micro-hardness at other depths and M2 presented better results than M1. PMID- 21666566 TI - Surviving of bovine teeth adhesively restored with 3 types of fiber post after fatigue resistance. AB - AIM: Aim of this study was to evaluate the fatigue resistance of bovine roots adhesively restored with three fiber posts. METHODS: Twenty-four single-rooted bovine teeth were allocated into three groups (N.=8): Gr1- White Post DC; Gr2- DT Light Post; Gr3- FRC Postec Plus. Teeth were prepared using the preparation drill of the specific fiber post system for each group. After the specimen was embedded in a cylinder, using acrylic resin, up to 3 mm of the most coronal portion of the specimen, the posts were all cemented with same materials: Single Bond + Relyx CRA. After cementation, a standard core build-up was made with composite resin. The specimens were submitted to mechanical cycling (1.400.000, 50N, 8 Hz, 37 degrees C). After fatigue testing, a score was given to each specimen. The scores were submitted to Kruskal-Wallis (alpha=0.05) and the fractures were observed. RESULTS: The performance after mechanical fatigue cycling was similar for the three fiber posts systems (P=0.366). Just one failure was noted from each group, a failure at the composite core. CONCLUSION: The tested fiber posts had good performance, but attention should be taken regard of the adhesion of composite core to fiber past. PMID- 21666567 TI - Biaxial flexural strength of CAD/CAM ceramics. AB - AIM: Aim of the study was to evaluate the biaxial flexural strength of ceramics processed using the Cerec inLab system. The hypothesis was that the flexural strength would be influenced by the type of ceramic. METHODS: Ten samples (ISO 6872) of each ceramic (N.=50/n.=10) were made using Cerec inLab (software Cerec 3D) (O:15 mm, thickness: 1.2 mm). Three silica-based ceramics (Vita Mark II [VM], ProCad [PC] and e-max CAD ECAD]) and two yttria-stabilized tetragonal-zirconia polycrystalline ceramics (Y-TZP) (e-max ZirCad [ZrCAD] and Vita In-Ceram 2000 YZ Cubes [VYZ]) were tested. The samples were finished with wet silicone carbide papers up to 1 200-grit and polished in a polishing machine with diamond paste (3 um). The samples were then submitted to biaxial flexural strength testing in a universal testing machine (EMIC), 1 mm/min. The data (MPa) were analyzed using the Kruskal-Wallis and Dunn (5%) tests. Scanning electronic microscopy (SEM) was performed on a representative sample from each group. RESULTS: The values (median, mean+/-sd) obtained for the experimental groups were: VM (101.7, 102.1+/ 13.65 MPa), PC (165.2, 160+/-34.7 MPa), ECAD (437.2, 416.1+/-50.1 MPa), ZrCAD (804.2, 800.8+/-64.47 MPa) and VYZ (792.7, 807+/-100.7 MPa). The type of ceramic influenced the flexural strength values (P=0.0001). The ceramics ECADa, e-max ZrCADa and VYZa presented similar flexural strength values which were significantly higher than the other groups (PCb and VM IIb), which were similar statistically between them (Dunn's test). The hypothesis was accepted. CONCLUSION: The polycrystalline ceramics (Y-TZP) should be material chosen for make FPDs because of their higher flexural strength values. PMID- 21666568 TI - Videoendoscopic assisted curettage of central giant cell granuloma of the maxilla in pediatric age. AB - Giant cell granuloma is an uncommon bony benign lesion that generally involves the mandible and maxilla. It may be locally aggressive and result in extensive tissue destruction in advanced cases. Surgery is the traditional and still the most accepted treatment for giant cell granuloma. We report a pediatric case of central giant cell granuloma of the maxilla treated with videoendoscopic assisted surgical excision. PMID- 21666569 TI - Pigmented lichenoid drug eruption secondary to chloroquine therapy: an unusual presentation in lower lip. AB - Antimalarial drugs, like chloroquine, may produce hyperpigmentation of the oral mucosa, affecting most commonly the palate. Its pathogenesis is not clear; an increased production of melanin is currently believed to be the cause of this oral manifestation. The purpose of this study was to report a case of atypical oral mucosal hyperpigmentation secondary to antimalarial therapy. A 66-year-old, dark skinned woman was evaluated for oral pigmentation. The patient had a history of chloroquine therapy, and presented a diffuse blue-gray pigmentation in the hard palate and, mainly, in the lower lip. Diagnostic hypothesis were of physiologic pigmentation, drug-induced pigmentation, pigmentation associated with systemic diseases, smoker's melanosis and post-inflammatory pigmentation. Incisional biopsy was conducted and histopathological examination revealed lichenoid dermatitis and pigment incontinence. Fontana-Masson staining was positive for melanin, but Perl's iron staining was negative. The histopathological diagnosis was consistent with melanin incontinence related to drug-induced lichenoid reaction secondary to chloroquine therapy. Adequate correlation of clinical and microscopic aspects was essential for the definitive diagnosis, especially in atypical cases. This diagnosis is of great relevance for the patient, since the oral manifestation might be an early sign of ocular complications due to antimalarial therapy. Therefore, the identification of these oral manifestations indicates regular evaluations by an ophtalmologist, preventing greater complications of antimalarial therapy for the patient. PMID- 21666570 TI - Iatrogenic tracheobronchial ruptures: the debate continues. PMID- 21666572 TI - Use of synthetic colloids in sepsis: a critical review on efficacy, safety and patient benefits. AB - In this narrative review, the studies and analyses are discussed that pertain to benefits and detriments of synthetic colloids versus natural colloids or crystalloids used for fluid resuscitation in sepsis and septic shock. The relative amount of fluid infusions used to reach clinical or hemodynamic end points are reviewed, as well as potential toxicity of starch solutions on the kidney. Hence, it cannot be excluded that adverse effects partly offset beneficial hemodynamic effects that are similar to that of natural colloids, so that in most analyses a mortality benefit of synthetic colloid fluid resuscitation in sepsis and septic shock cannot be demonstrated. PMID- 21666574 TI - Group rehabilitation versus individual rehabilitation following knee and hip replacement: a pilot study with randomized, single-blind, cross-over design. AB - BACKGROUND: In recent years a vast literature has been dedicated to cost effectiveness analysis. In the rehabilitation field, the search for less costly forms of treatment is an area under intense discussion by the rehabilitation scientific community. Group rehabilitation programs for some pathological conditions could permit better allocation of economic resources, but few studies evaluated the efficacy of group physiotherapy as opposed to individual physiotherapy. AIM: The purpose of this study is to compare the effects of group rehabilitation (GrpR) with individual rehabilitation (IndR) for inpatients that have undergone knee and hip replacement. Design. This is a pilot study with randomized, single-blind, cross-over design. SETTING: Inpatients Physiotherapy Department of Don Gnocchi Foundation. METHODS: Clinical disability evaluation (JOASH, IKS, DI) and patient-oriented assessment (SF-36, WOMAC and VAS) were performed on 27 patients undergoing a physical therapy program after knee or hip replacement. Patients having partial weight-bearing postoperatively (about 50% of the total) and a range of motion >50% of the total in the joint replaced were included and then randomized (T0) in two intervention programs: GrpR/IndR - who performed GrpR for 15 days (T1), followed by the IndR for 15 days (T2); and IndR/GrpR - who performed the IndR for 15 days (T1), followed by GrpR for 15 days (T2). RESULTS: Comparing the changes from baseline T1-T0 and T2-T1 separately in the two groups most outcomes showed no significant difference. CONCLUSION: This pilot trial suggests that the group rehabilitation program is just as efficient as the individual rehabilitation for inpatients that have undergone knee and hip replacement and are able to weight-bear postoperatively. A potential benefit of group-based therapy is that it is less resource intensive. PMID- 21666575 TI - Assessing the benefits: outcome and future directions. AB - Pulmonary rehabilitation is a relatively recent practice in pulmonary medicine which is classically described as a multidisciplinary program of care for patients with chronic respiratory impairment. There is solid evidence of effectiveness for the pulmonary rehabilitation and, with lower level of evidence, for some of its specific components. There is evidence of benefit for exercise tolerance, symptoms, Health-Related Quality of Life, and health care need with indirect evidence of positive effects on survival. One quarter to one third of patients do not have benefits from pulmonary rehabilitation, studies failing to identify any important predictors of treatment success or failure. Outcomes assessment in pulmonary rehabilitation is of main importance to evaluate its evidence-based effectiveness. Although, several questions remain unresolved, pulmonary rehabilitation programs should be included in the comprehensive treatment of patients with respiratory diseases. PMID- 21666576 TI - Strategies for solutions in sarcoma management. PMID- 21666577 TI - A CD117 and CD34 immunoreactive sarcoma masquerading as a gastrointestinal stromal tumor: diagnostic pitfalls of ancillary studies in sarcoma. AB - BACKGROUND: The immunohistochemical hallmarks of gastrointestinal stromal tumors (GISTs) are positivity for CD117 (c-kit) and CD34; however, CD117 is not specific for GISTs, and the list of CD117+ tumors/tissues is increasing. Also, MDM2 is known to be amplified in several types of mesenchymal tumors, including liposarcoma. METHODS: We report a spindle cell sarcoma arising in the mediastinum that morphologically and immunohistochemically mimicked GIST to illustrate the potential diagnostic pitfalls of ancillary studies in sarcoma and their appropriate use in conjunction with clinical content. Clinical information was obtained from electronic medical databases. Cytological, histological, and ancillary studies were retrieved from the archives of the Department of Anatomic Pathology at Moffitt Cancer Center. Literature of the last 20 years was reviewed. The role of biomarkers and their molecular testing in the prognosis and prediction of GIST is also discussed. RESULTS: A 75-year-old woman with a history of well-differentiated liposarcoma of the trunk/inguinal canal 5 years earlier developed a 5.5-cm heterogeneously enhancing mediastinal mass by computed tomography. Fine-needle aspiration biopsy revealed spindle cells with moderate pleomorphism and immunohistochemically reactive to CD117 and CD34 suggestive of GIST, but the clinical picture was unusual for GIST. Mutational analyses for KIT and platelet-derived growth factor receptor alpha (PDGFRalpha) were negative; DOG1 was not immunoactive, and this was believed to rule out GIST. An additional study of MDM2 by fluorescent in situ hybridization was positive, suggesting that this tumor was a dedifferentiated liposarcoma vs a spindle cell sarcoma not otherwise specified. CONCLUSIONS: CD117+/CD34+ sarcoma is not diagnostic for GIST. KIT and PDGFRalpha mutational analyses are important in confirming a diagnosis of GIST and predicting its response to imatinib therapy. MDM2+ sarcoma is not diagnostic for liposarcoma. Although MDM2 is almost always positive in well-differentiated liposarcoma, which is useful in differentiating benign from atypical/well-differentiated lipomatous tumor, it should not be used in differentiating liposarcoma from other sarcomas. PMID- 21666578 TI - Advances in segmental endoprosthetic reconstruction for extremity tumors: a review of contemporary designs and techniques. AB - BACKGROUND: Improved understanding and advances in treatment regimens have led to increased longevity among patients diagnosed with extremity soft tissue sarcomas. Limb salvage techniques and implants have improved and continue to evolve to accommodate the increasing demands and survival of these patients. METHODS: The current report is a review of the literature for recent advancements in techniques, implant design, and outcomes in the field of limb salvage therapy using segmental megaprostheses for the treatment of extremity sarcomas. We report on our experience in this field utilizing a classification system of failure mechanisms to outline to discuss current controversies in management. RESULTS: Five mechanisms of failure have been identified: soft-tissue failure, aseptic loosening, structural failure, infection, and tumor progression. Infection was the most common mode of failure in our series, accounting for 34% of cases. Soft tissue failure occurred most commonly in the joints that depend heavily on periarticular muscles and ligaments for stability due to their high degree of functional range of motion. We observed a 28% soft-tissue failure rate about the shoulder and hip, aseptic loosening accounted for 19% of implant failures, and structural failure was seen in 17% of cases. Seventeen percent of cases failed due to tumor progression, an etiology that is defined by biological factors, surgical technique, and adjuvant therapies. CONCLUSIONS: Surgical techniques and megaprosthesis designs are constantly changing in order to meet the challenge of increasing functional demands and longevity in this unique patient population. A classification system defined by treatment failure etiologies provides the framework for discussion of current controversies in limb salvage therapy as well as a guide for advancement and potential solutions in this challenging arena. PMID- 21666579 TI - Computer-assisted navigation and musculoskeletal sarcoma surgery. AB - BACKGROUND: Despite advances in medical, surgical, and radiation oncology, deep seated bone sarcomas that require large osseous resections continue to present resection and reconstructive challenges to musculoskeletal surgeons. METHODS: We describe our experience with computer navigation techniques combined with complex pelvic resections and limb-preserving surgeries. RESULTS: Computer-assisted navigation has shown promise in aiding in optimal preoperative planning and in providing more accurate and precise feedback during surgery. CONCLUSIONS: Computer-assisted navigation offers precise instrumentation, technology-oriented imaging systems, and powerful information processing, all of which can assist in decision making, preoperative planning, and surgical accuracy. PMID- 21666580 TI - Current diagnosis and management of retroperitoneal sarcoma. AB - BACKGROUND: Retroperitoneal sarcomas are rare neoplasms that often present with multivisceral involvement. Treatment for these tumors requires careful decision making requiring a combination of surgery, chemotherapy, and radiation therapy. METHODS: We reviewed the scientific literature pertaining to the diagnosis and management of retroperitoneal sarcomas. We also identify recent developments in treatment and discuss future trends in the care of patients with this disease. RESULTS: Retroperitoneal tumors often present as large, locally advanced lesions. Evaluation of these tumors requires careful consideration of a multimodality approach. Retrospective data and historical prospective series have demonstrated the survival benefit of radical resection for these tumors with en bloc resection of involved structures. Compartmental resections in the retroperitoneum along with debulking of high-grade disease and regional therapy are controversial approaches with significant morbidity that can lead to long-term survival. The application of neoadjuvant and adjuvant therapies in select tumor histologies may improve local control and survival. CONCLUSIONS: The management of retroperitoneal sarcomas requires a multidisciplinary approach and is best accomplished at high-volume centers specializing in the care of patients with these complex malignancies. Current data suggest that radical resection remains the only chance for cure and that chemotherapy and radiation therapy may confer a survival benefit. PMID- 21666581 TI - Metastatic soft tissue sarcoma chemotherapy: an opportunity for personalized medicine. AB - BACKGROUND: Soft tissue sarcoma (STS) includes biologically and histologically diverse mesenchymal tumors that are relatively chemotherapy-resistant compared with other sarcoma subtypes. METHODS: The authors discuss the clinical challenges frequently encountered by medical oncologists and review the literature for predictive strategies to systematically approach chemotherapy decision making. RESULTS: There are no clinically validated predictive tests for chemotherapeutic response or resistance in STS. Clinical features including histology, stage, and patient age are currently used to guide therapy decisions in STS. CONCLUSIONS: A method to predict response or resistance to chemotherapy, utilizing both targeted and conventional agents, would be beneficial in reducing toxicity and improving response rates for patients with STS and also in designing clinical trials for this disease. PMID- 21666582 TI - Of mice and men: opportunities to use genetically engineered mouse models of synovial sarcoma for preclinical cancer therapeutic evaluation. AB - BACKGROUND: Synovial sarcoma is a soft tissue malignancy with a predilection for adolescents and young adults. Despite recent improvements in the understanding of its character and etiology, few therapeutic advances have been made. The mortality rate is high among the young population it affects. The low incidence of most subtypes of sarcoma, such as synovial sarcoma, makes disease-specific trials difficult to organize. The biological differences between sarcoma subtypes make inclusion of multiple types in general trials unsatisfactory as well. METHODS: A review of the literature regarding targetable pathways in synovial sarcoma was undertaken. A strategy has been devised to utilize available technologies in order to prioritize drug trial planning. RESULTS: Cell culture and xenograft research with synovial sarcoma cell lines have identified some critical pathways that may be targetable. Promising therapeutic strategies include newer cytotoxic chemotherapies, antiangiogenic agents, anti-IGF1R pathway agents, anti-Bcl-2/proapoptotic agents, and histone deacetylase complex inhibitors. CONCLUSIONS: We propose to prioritize potential therapeutic strategies via preclinical testing of agents in a genetic mouse model of synovial sarcoma. Preclinical optimization of treatment regimens can guide the development of more focused patient trials. PMID- 21666583 TI - [The new possibilities of postoperative complication's prophylaxis in abdominal surgery]. PMID- 21666585 TI - [Local treatment of the burnt wounds with silver-containing drugs. Sulfargin - a drug of choice]. PMID- 21666584 TI - [Antioxidant protection in surgical correction of inborn heart disease with the use of artificial circulation]. PMID- 21666586 TI - [Clinical signs of occipital cortex dysfunction in children]. AB - Cases with epileptiform EEG-changes, which are not associated with epileptic seizures and clinical signs of epileptic encephalopathy, are frequent in practical child neurology. We present the results of examination 52 children with abovementioned changes. The high frequency of migraine was found in families of these children as well as the association between EEG-changes and earlier traumatic brain injury and other diseases that impact brain maturation. PMID- 21666587 TI - [A role of sex in the development of manifesting schizophrenic psychoses in adolescents]. AB - To study an effect of sex on symptoms and course of schizophrenia, we have compared two groups (n=70) of adolescents of both sexes with manifesting schizophrenic psychoses. Between-group differences in the family history of schizophrenia, premorbid functioning, typology and duration of initial and manifesting stages of the attack, dynamics of psychosis, frequency of cognitive disorders have been revealed. These differences may predict a benign course of schizophrenic psychosis in girls as compared to boys. PMID- 21666589 TI - [Clinical and electroencephalographic effects of amantadine sulfate (PK-Merz) on consciousness disorders due to the severe traumatic brain injury]. AB - It was carried out a complex clinical-neurological and electroencephalographic study of 12 patients with consequences of severe traumatic brain injury with changes in consciousness, motor deficit, higher tonus of voluntary muscles and cognitive disorders. The study was conducted before, during and after treatment with amantadine sulfate. There were correlations between changes in mental and neurological status of patients and basic EEG. PMID- 21666588 TI - [Clinical-encephalographic evaluation of preterm children treated with cytoflavin during the first year of life]. AB - An aim of the study was the clinical and neurophysiological evaluation of the effect of cytoflavin and reanimation measures on the rate of nervous and mental development of preterm newborns with cerebral ischemia, II--III stage, during the first year of life. One hundred and twenty children with gestational age 28--36 weeks and body mass 1060-3150 g were studied. In the main group (n=61), the complex treatment included cytoflavin in dosage 2 ml/kg/day, intravenously during 5 days. The control group (n=59) received basic treatment without cytoflavin. The follow-up till the age of 1 year comprised the global assessment of state and neurological status using quantitative measurements of muscle postural tone on the INFANIB scale, psychomotor development (BSID-II) and assessment of CNS functional state by analyzing computed EEG signals during physiological sleep. The results obtained demonstrated the fast normalization of all studied measures of development of children treated with cytoflavin compared to those of the control group. PMID- 21666590 TI - [Levodopa medications in the treatment of Parkinson's disease]. AB - There are many medications presently available for management of Parkinson's disease. Levodopa is the most effective one. Pharmacotherapeutic efficacy of some forms of drug is not similar due to differences in composition (inactive ingredients, excipients, preservatives, colorants). Authors carried out an open labeled comparative study of pharmacotherapeutic efficacy of the original drug -- nakom and the generic one -- tidomed (both drugs include levodopa and carbidopa). The improvement as assessed by the UPDRS-3 was seen in patients receiving nakom de novo. The significant reduction of motor deficit and increase of daily activity and duration of action of a single dose were noted in patients with motor fluctuations treated with nakom. PMID- 21666591 TI - [Diagnosis of different stages of epileptogenesis by fractal EEG analysis]. AB - The diagnostic evaluation of brain activity disturbances using fractal EEG analysis was performed in 95 patients with different stages of epileptogenesis. The control group included 30 normals. Authors have shown the possibility to determine phases of the development of epileptic process according to the peculiarities of the dynamics of main EEG band power fluctuations with the spectrum in the form of 1/f(beta). The disturbances of alpha, theta, beta-1 and beta-2 band characteristics at the preclinical (initial) and clinical stages of epileptogenesis were revealed. There were topographical changes in indexes of fractal chaos linked with the growth of brain epileptization. The parameters of fractal fluctuations in alpha-band power proved to be the most informative for the objectification of the degree of intensity of epileptic disturbances. The method of fractal EEG analysis is concluded to be highly effective for diagnosis of all stages of epileptogenesis. PMID- 21666592 TI - [Genetic risk factors for multiple sclerosis in the population of Altay]. AB - The "case-control" research in Russian Altai territory population has proved that DR15 and DR3 as well as the combination of female sex and alleles A of TNFalpha of rs1800629 locus are associated with high risk of multiple sclerosis. The relationship between disease and CD40 polymorphism (rs6074022) was not found. PMID- 21666593 TI - [Architectonics of thalamic anterior dorsal and reticular nuclei of women's brain]. AB - Architectonics of anterior dorsal and reticular nuclei of the thalamus was studied. A study set consisted of 5 specimens from the brain collection of the Research Neurological Center of the Russian Academy of Medical Sciences. Specimens were female, aged 19--59 years, all right-handed, who died suddenly and had no neurological, severe somatic or mental diseases during life. The following parameters were measured: neuron density, satellite glia density, density of satellite-surrounded neurons. The individual variability in neuron density was found. It was more pronounced in the reticular nucleus compared to the anterior dorsal nucleus. The variability of satellite glia density was higher in anterior dorsal nucleus; no differences in density of satellite-surrounded neurons were seen between nuclei studied. Between-hemisphere asymmetry with greater values on the left hemisphere was seen for the neuron and satellite glia densities in the anterior dorsal nucleus compared to the reticular nucleus. The density of satellite-surrounded neurons was greater in the anterior dorsal nucleus of the left hemisphere and in the reticular nucleus of the right hemisphere. PMID- 21666594 TI - [Quantitative characteristics of the course of alcoholism: age aspect]. PMID- 21666595 TI - [The role of bacterialogical investigation in diagnostic of bacterial infections with a syndrome of purulent meningitis]. PMID- 21666596 TI - [Idebenone (noben) -- from theory to practice]. PMID- 21666597 TI - Atomic force microscopy captures MutS tetramers initiating DNA mismatch repair. AB - In spite of extensive research, the mechanism by which MutS initiates DNA mismatch repair (MMR) remains controversial. We use atomic force microscopy (AFM) to capture how MutS orchestrates the first step of E. coli MMR. AFM images captured two types of MutS/DNA complexes: single-site binding and loop binding. In most of the DNA loops imaged, two closely associated MutS dimers formed a tetrameric complex in which one of the MutS dimers was located at or near the mismatch. Surprisingly, in the presence of ATP, one MutS dimer remained at or near the mismatch site and the other, while maintaining contact with the first dimer, relocated on the DNA by reeling in DNA, thereby producing expanding DNA loops. Our results indicate that MutS tetramers composed of two non-equivalent MutS dimers drive E. coli MMR, and these new observations now reconcile the apparent contradictions of previous 'sliding' and 'bending/looping' models of interaction between mismatch and strand signal. PMID- 21666598 TI - Shugoshin is a Mad1/Cdc20-like interactor of Mad2. AB - Mammalian centromeric cohesin is protected from phosphorylation-dependent displacement in mitotic prophase by shugoshin-1 (Sgo1), while shugoshin-2 (Sgo2) protects cohesin from separase-dependent cleavage in meiosis I. In higher eukaryotes, progression and faithful execution of both mitosis and meiosis are controlled by the spindle assembly checkpoint, which delays anaphase onset until chromosomes have achieved proper attachment to microtubules. According to the so called template model, Mad1-Mad2 complexes at unattached kinetochores instruct conformational change of soluble Mad2, thus catalysing Mad2 binding to its target Cdc20. Here, we show that human Sgo2, but not Sgo1, specifically interacts with Mad2 in a manner that strongly resembles the interactions of Mad2 with Mad1 or Cdc20. Sgo2 contains a Mad1/Cdc20-like Mad2-interaction motif and competes with Mad1 and Cdc20 for binding to Mad2. NMR and biochemical analyses show that shugoshin binding induces similar conformational changes in Mad2 as do Mad1 or Cdc20. Mad2 binding regulates fine-tuning of Sgo2's sub-centromeric localization. Mad2 binding is conserved in the only known Xenopus laevis shugoshin homologue and, compatible with a putative meiotic function, the interaction occurs in oocytes. PMID- 21666599 TI - Modulation of Tcf3 repressor complex composition regulates cdx4 expression in zebrafish. AB - The caudal homeobox (cdx) gene family is critical for specification of caudal body formation and erythropoiesis. In zebrafish, cdx4 expression is controlled by the Wnt pathway, but the molecular mechanism of this regulation is not fully understood. Here, we provide evidence that Tcf3 suppresses cdx4 expression through direct binding to multiple sites in the cdx4 gene regulatory region. Tcf3 requires corepressor molecules such as Groucho (Gro)/TLE and HDAC1 for activity. Using zebrafish embryos and cultured mammalian cells, we show that the transcription factor E4f1 derepresses cdx4 by dissociating corepressor proteins from Tcf3 without inhibiting its binding to cis-regulatory sites in the DNA. Further, the E3 ubiquitin ligase Lnx2b, acting as a scaffold protein irrespective of its enzymatic activity, counteracts the effects of E4f1. We propose that the modulation of Tcf3 repressor function by E4f1 assures precise and robust regulation of cdx4 expression in the caudal domain of the embryo. PMID- 21666600 TI - Epigenetically coordinated GATA2 binding is necessary for endothelium-specific endomucin expression. AB - GATA2 is well recognized as a key transcription factor and regulator of cell-type specificity and differentiation. Here, we carried out comparative chromatin immunoprecipitation with comprehensive sequencing (ChIP-seq) to determine genome wide occupancy of GATA2 in endothelial cells and erythroids, and compared the occupancy to the respective gene expression profile in each cell type. Although GATA2 was commonly expressed in both cell types, different GATA2 bindings and distinct cell-specific gene expressions were observed. By using the ChIP-seq with epigenetic histone modifications and chromatin conformation capture assays; we elucidated the mechanistic regulation of endothelial-specific GATA2-mediated endomucin gene expression, that was regulated by the endothelial-specific chromatin loop with a GATA2-associated distal enhancer and core promoter. Knockdown of endomucin markedly attenuated endothelial cell growth, migration and tube formation. Moreover, abrogation of GATA2 in endothelium demonstrated not only a reduction of endothelial-specific markers, but also induction of mesenchymal transition promoting gene expression. Our findings provide new insights into the correlation of endothelial-expressed GATA2 binding, epigenetic modification, and the determination of endothelial cell specificity. PMID- 21666601 TI - A dual role of H4K16 acetylation in the establishment of yeast silent chromatin. AB - Discrete regions of the eukaryotic genome assume heritable chromatin structure that is refractory to transcription. In budding yeast, silent chromatin is characterized by the binding of the Silent Information Regulatory (Sir) proteins to unmodified nucleosomes. Using an in vitro reconstitution assay, which allows us to load Sir proteins onto arrays of regularly spaced nucleosomes, we have examined the impact of specific histone modifications on Sir protein binding and linker DNA accessibility. Two typical marks for active chromatin, H3K79(me) and H4K16(ac) decrease the affinity of Sir3 for chromatin, yet only H4K16(ac) affects chromatin structure, as measured by nuclease accessibility. Surprisingly, we found that the Sir2-4 subcomplex, unlike Sir3, has higher affinity for chromatin carrying H4K16(ac). NAD-dependent deacetylation of H4K16(ac) promotes binding of the SIR holocomplex but not of the Sir2-4 heterodimer. This function of H4K16(ac) cannot be substituted by H3K56(ac). We conclude that acetylated H4K16 has a dual role in silencing: it recruits Sir2-4 and repels Sir3. Moreover, the deacetylation of H4K16(ac) by Sir2 actively promotes the high-affinity binding of the SIR holocomplex. PMID- 21666665 TI - Structural basis of steroid hormone perception by the receptor kinase BRI1. AB - Polyhydroxylated steroids are regulators of body shape and size in higher organisms. In metazoans, intracellular receptors recognize these molecules. Plants, however, perceive steroids at membranes, using the membrane-integral receptor kinase BRASSINOSTEROID INSENSITIVE 1 (BRI1). Here we report the structure of the Arabidopsis thaliana BRI1 ligand-binding domain, determined by X ray diffraction at 2.5 A resolution. We find a superhelix of 25 twisted leucine rich repeats (LRRs), an architecture that is strikingly different from the assembly of LRRs in animal Toll-like receptors. A 70-amino-acid island domain between LRRs 21 and 22 folds back into the interior of the superhelix to create a surface pocket for binding the plant hormone brassinolide. Known loss- and gain of-function mutations map closely to the hormone-binding site. We propose that steroid binding to BRI1 generates a docking platform for a co-receptor that is required for receptor activation. Our findings provide insight into the activation mechanism of this highly expanded family of plant receptors that have essential roles in hormone, developmental and innate immunity signalling. PMID- 21666666 TI - Structural insight into brassinosteroid perception by BRI1. AB - Brassinosteroids are essential phytohormones that have crucial roles in plant growth and development. Perception of brassinosteroids requires an active complex of BRASSINOSTEROID-INSENSITIVE 1 (BRI1) and BRI1-ASSOCIATED KINASE 1 (BAK1). Recognized by the extracellular leucine-rich repeat (LRR) domain of BRI1, brassinosteroids induce a phosphorylation-mediated cascade to regulate gene expression. Here we present the crystal structures of BRI1(LRR) in free and brassinolide-bound forms. BRI1(LRR) exists as a monomer in crystals and solution independent of brassinolide. It comprises a helical solenoid structure that accommodates a separate insertion domain at its concave surface. Sandwiched between them, brassinolide binds to a hydrophobicity-dominating surface groove on BRI1(LRR). Brassinolide recognition by BRI1(LRR) is through an induced-fit mechanism involving stabilization of two interdomain loops that creates a pronounced non-polar surface groove for the hormone binding. Together, our results define the molecular mechanisms by which BRI1 recognizes brassinosteroids and provide insight into brassinosteroid-induced BRI1 activation. PMID- 21666667 TI - High-content behavioral analysis of Caenorhabditis elegans in precise spatiotemporal chemical environments. AB - To quantitatively understand chemosensory behaviors, it is desirable to present many animals with repeatable, well-defined chemical stimuli. To that end, we describe a microfluidic system to analyze Caenorhabditis elegans behavior in defined temporal and spatial stimulus patterns. A 2 cm * 2 cm structured arena allowed C. elegans to perform crawling locomotion in a controlled liquid environment. We characterized behavioral responses to attractive odors with three stimulus patterns: temporal pulses, spatial stripes and a linear concentration gradient, all delivered in the fluid phase to eliminate variability associated with air-fluid transitions. Different stimulus configurations preferentially revealed turning dynamics in a biased random walk, directed orientation into an odor stripe and speed regulation by odor. We identified both expected and unexpected responses in wild-type worms and sensory mutants by quantifying dozens of behavioral parameters. The devices are inexpensive, easy to fabricate, reusable and suitable for delivering any liquid-borne stimulus. PMID- 21666668 TI - CREST maps somatic structural variation in cancer genomes with base-pair resolution. AB - We developed 'clipping reveals structure' (CREST), an algorithm that uses next generation sequencing reads with partial alignments to a reference genome to directly map structural variations at the nucleotide level of resolution. Application of CREST to whole-genome sequencing data from five pediatric T lineage acute lymphoblastic leukemias (T-ALLs) and a human melanoma cell line, COLO-829, identified 160 somatic structural variations. Experimental validation exceeded 80%, demonstrating that CREST had a high predictive accuracy. PMID- 21666669 TI - Identification of clustering artifacts in photoactivated localization microscopy. PMID- 21666670 TI - Fluorogenic DNA sequencing in PDMS microreactors. AB - We developed a multiplex sequencing-by-synthesis method combining terminal phosphate-labeled fluorogenic nucleotides (TPLFNs) and resealable polydimethylsiloxane (PDMS) microreactors. In the presence of phosphatase, primer extension by DNA polymerase using nonfluorescent TPLFNs generates fluorophores, which are confined in the microreactors and detected. We immobilized primed DNA templates in the microreactors, then sequentially introduced one of the four identically labeled TPLFNs, sealed the microreactors and recorded a fluorescence image after template-directed primer extension. With cycle times of <10 min, we demonstrate 30 base reads with ~99% raw accuracy. Our 'fluorogenic pyrosequencing' offers benefits of pyrosequencing, such as rapid turnaround, one color detection and generation of native DNA, along with high detection sensitivity and simplicity of parallelization because simultaneous real-time monitoring of all microreactors is not required. PMID- 21666671 TI - TACE (ADAM17) inhibits Schwann cell myelination. AB - Tumor necrosis factor-alpha-converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS. PMID- 21666672 TI - KCNQ5 channels control resting properties and release probability of a synapse. AB - Little is known about which ion channels determine the resting electrical properties of presynaptic membranes. In recordings made from the rat calyx of Held, a giant mammalian terminal, we found resting potential to be controlled by KCNQ (Kv7) K(+) channels, most probably KCNQ5 (Kv7.5) homomers. Unlike most KCNQ channels, which are activated only by depolarizing stimuli, the presynaptic channels began to activate just below the resting potential. As a result, blockers and activators of KCNQ5 depolarized or hyperpolarized nerve terminals, respectively, markedly altering resting conductance. Moreover, the background conductance set by KCNQ5 channels, together with Na(+) and hyperpolarization activated and cyclic nucleotide-gated (HCN) channels, determined the size and time course of the response to subthreshold stimuli. Signaling pathways known to directly affect exocytic machinery also regulated KCNQ5 channels, and increase or decrease of KCNQ5 channel activity controlled release probability through alterations in resting potential. Thus, ion channel determinants of presynaptic resting potential also control synaptic strength. PMID- 21666673 TI - A readily retrievable pool of synaptic vesicles. AB - Although clathrin-mediated endocytosis is thought to be the predominant mechanism of synaptic vesicle recycling, it seems to be too slow for fast recycling. Therefore, it was suggested that a presorted and preassembled pool of synaptic vesicle proteins on the presynaptic membrane might support a first wave of fast clathrin-mediated endocytosis. In this study we monitored the temporal dynamics of such a 'readily retrievable pool' of synaptic vesicle proteins in rat hippocampal neurons using a new type of probe. By applying cypHer5E, a new cyanine dye-based pH-sensitive exogenous marker, coupled to antibodies to luminal domains of synaptic vesicle proteins, we could reliably monitor synaptic vesicle recycling and demonstrate the preferential recruitment of a surface pool of synaptic vesicle proteins upon stimulated endocytosis. By using fluorescence nanoscopy of surface-labeled synaptotagmin 1, we could resolve the spatial distribution of the surface pool at the periactive zone in hippocampal boutons, which represent putative sites of endocytosis. PMID- 21666674 TI - Synaptically driven state transitions in distal dendrites of striatal spiny neurons. AB - Striatal spiny neurons (SPNs) associate a diverse array of cortically processed information to regulate action selection. But how this is done by SPNs is poorly understood. A key step in this process is the transition of SPNs from a hyperpolarized 'down state' to a sustained, depolarized 'up state'. These transitions are thought to reflect a sustained synaptic barrage, involving the coordination of hundreds of pyramidal neurons. Indeed, in mice, simulation of cortical input by glutamate uncaging on proximal dendritic spines produced potential changes in SPNs that tracked input time course. However, brief glutamate uncaging at spines on distal dendrites evoked somatic up states lasting hundreds of milliseconds. These regenerative events depended upon both NMDA receptors and voltage-dependent Ca(2+) channels. Moreover, they were bidirectionally regulated by dopamine receptor signaling. This capacity not only changes our model of how up states are generated in SPNs, it also has fundamental implications for the associative process underlying action selection. PMID- 21666675 TI - Recognition of the F&H motif by the Lowe syndrome protein OCRL. AB - Lowe syndrome and type 2 Dent disease are caused by defects in the inositol 5 phosphatase OCRL. Most missense mutations in the OCRL ASH-RhoGAP domain that are found in affected individuals abolish interactions with the endocytic adaptors APPL1 and Ses (both Ses1 and Ses2), which bind OCRL through a short phenylalanine and histidine (F&H) motif. Using X-ray crystallography, we have identified the F&H motif binding site on the RhoGAP domain of OCRL. Missense mutations associated with disease affected F&H binding indirectly by destabilizing the RhoGAP fold. By contrast, a disease-associated mutation that does not perturb F&H binding and ASH-RhoGAP stability disrupted the interaction of OCRL with Rab5. The F&H binding site of OCRL is conserved even in species that do not have an identified homolog for APPL or Ses. Our study predicts the existence of other OCRL binding partners and shows that the perturbation of OCRL interactions has a crucial role in disease. PMID- 21666676 TI - Phospholipid-dependent regulation of the motor activity of myosin X. AB - Myosin X is involved in the reorganization of the actin cytoskeleton and protrusion of filopodia. Here we studied the molecular mechanism by which bovine myosin X is regulated. The globular tail domain inhibited the motor activity of myosin X in a Ca(2+)-independent manner. Structural analysis revealed that myosin X is monomeric and that the band 4.1-ezrin-radixin-moesin (FERM) and pleckstrin homology (PH) domains bind to the head intramolecularly, forming an inhibited conformation. Binding of phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P(3)) to the PH domain reversed the tail-induced inhibition and induced the formation of myosin X dimers. Consistently, disruption of the binding of PtdIns(3,4,5)P(3) attenuated the translocation of myosin X to filopodial tips in cells. We propose the following mechanism: first, the tail inhibits the motor activity of myosin X by intramolecular head-tail interactions to form the folded conformation; second, phospholipid binding reverses the inhibition and disrupts the folded conformation, which induces dimer formation, thereby activating the mechanical and cargo transporter activity of myosin X. PMID- 21666677 TI - Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin. AB - Accurate read-out of chromatin modifications is essential for eukaryotic life. Mutations in the gene encoding X-linked ATRX protein cause a mental-retardation syndrome, whereas wild-type ATRX protein targets pericentric and telomeric heterochromatin for deposition of the histone variant H3.3 by means of a largely unknown mechanism. Here we show that the ADD domain of ATRX, in which most syndrome-causing mutations occur, engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. In vivo experiments show this combinatorial readout is required for ATRX localization, with recruitment enhanced by a third interaction through heterochromatin protein-1 (HP1) that also recognizes trimethylated Lys9. The cooperation of ATRX ADD domain and HP1 in chromatin recruitment results in a tripartite interaction that may span neighboring nucleosomes and illustrates how the 'histone-code' is interpreted by a combination of multivalent effector-chromatin interactions. PMID- 21666678 TI - An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. AB - Mutations in TARDBP, encoding TAR DNA-binding protein-43 (TDP-43), are associated with TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We compared wild-type TDP-43 and an ALS associated mutant TDP-43 in vitro and in vivo. The A315T mutant enhances neurotoxicity and the formation of aberrant TDP-43 species, including protease resistant fragments. The C terminus of TDP-43 shows sequence similarity to prion proteins. Synthetic peptides flanking residue 315 form amyloid fibrils in vitro and cause neuronal death in primary cultures. These data provide evidence for biochemical similarities between TDP-43 and prion proteins, raising the possibility that TDP-43 derivatives may cause spreading of the disease phenotype among neighboring neurons. Our work also suggests that decreasing the abundance of neurotoxic TDP-43 species, enhancing degradation or clearance of such TDP-43 derivatives and blocking the spread of the disease phenotype may have therapeutic potential for TDP-43 proteinopathies. PMID- 21666679 TI - ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome. AB - ATR-X (alpha-thalassemia/mental retardation, X-linked) syndrome is a human congenital disorder that causes severe intellectual disabilities. Mutations in the ATRX gene, which encodes an ATP-dependent chromatin-remodeler, are responsible for the syndrome. Approximately 50% of the missense mutations in affected persons are clustered in a cysteine-rich domain termed ADD (ATRX-DNMT3 DNMT3L, ADD(ATRX)), whose function has remained elusive. Here we identify ADD(ATRX) as a previously unknown histone H3-binding module, whose binding is promoted by lysine 9 trimethylation (H3K9me3) but inhibited by lysine 4 trimethylation (H3K4me3). The cocrystal structure of ADD(ATRX) bound to H3(1 15)K9me3 peptide reveals an atypical composite H3K9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage. Notably, H3K9me3-pocket mutants and ATR-X syndrome mutants are defective in both H3K9me3 binding and localization at pericentromeric heterochromatin; thus, we have discovered a unique histone-recognition mechanism underlying the ATR-X etiology. PMID- 21666680 TI - Giant enhancement of spin accumulation and long-distance spin precession in metallic lateral spin valves. AB - The non-local spin injection in lateral spin valves is strongly expected to be an effective method to generate a pure spin current for potential spintronic application. However, the spin-valve voltage, which determines the magnitude of the spin current flowing into an additional ferromagnetic wire, is typically of the order of 1 MUV. Here we show that lateral spin valves with low-resistivity NiFe/MgO/Ag junctions enable efficient spin injection with high applied current density, which leads to the spin-valve voltage increasing 100-fold. Hanle effect measurements demonstrate a long-distance collective 2pi spin precession along a 6 MUm-long Ag wire. These results suggest a route to faster and manipulable spin transport for the development of pure spin-current-based memory, logic and sensing devices. PMID- 21666681 TI - Arrays of indefinitely long uniform nanowires and nanotubes. AB - Nanowires are arguably the most studied nanomaterial model to make functional devices and arrays. Although there is remarkable maturity in the chemical synthesis of complex nanowire structures, their integration and interfacing to macro systems with high yields and repeatability still require elaborate aligning, positioning and interfacing and post-synthesis techniques. Top-down fabrication methods for nanowire production, such as lithography and electrospinning, have not enjoyed comparable growth. Here we report a new thermal size-reduction process to produce well-ordered, globally oriented, indefinitely long nanowire and nanotube arrays with different materials. The new technique involves iterative co-drawing of hermetically sealed multimaterials in compatible polymer matrices similar to fibre drawing. Globally oriented, endlessly parallel, axially and radially uniform semiconducting and piezoelectric nanowire and nanotube arrays hundreds of metres long, with nanowire diameters less than 15 nm, are obtained. The resulting nanostructures are sealed inside a flexible substrate, facilitating the handling of and electrical contacting to the nanowires. Inexpensive, high-throughput, multimaterial nanowire arrays pave the way for applications including nanowire-based large-area flexible sensor platforms, phase-changememory, nanostructure-enhanced photovoltaics, semiconductor nanophotonics, dielectric metamaterials,linear and nonlinear photonics and nanowire-enabled high-performance composites. PMID- 21666682 TI - The PIAS homologue Siz2 regulates perinuclear telomere position and telomerase activity in budding yeast. AB - Budding yeast telomeres are reversibly bound at the nuclear envelope through two partially redundant pathways that involve the Sir2/3/4 silencing complex and the Yku70/80 heterodimer. To better understand how this is regulated, we studied the role of SUMOylation in telomere anchoring. We find that the PIAS-like SUMO E3 ligase Siz2 sumoylates both Yku70/80 and Sir4 in vivo and promotes telomere anchoring to the nuclear envelope. Remarkably, loss of Siz2 also provokes telomere extension in a telomerase-dependent manner that is epistatic with loss of the helicase Pif1. Consistent with our previously documented role for telomerase in anchorage, normal telomere anchoring in siz2 Delta is restored by PIF1 deletion. By live-cell imaging of a critically short telomere, we show that telomeres shift away from the nuclear envelope when elongating. We propose that SUMO-dependent association with the nuclear periphery restrains bound telomerase, whereas active elongation correlates with telomere release. PMID- 21666683 TI - A membrane trafficking pathway regulated by the plant-specific RAB GTPase ARA6. AB - Endosomal trafficking plays an integral role in various eukaryotic cell activities and serves as a basis for higher-order functions in multicellular organisms. An understanding of the importance of endosomal trafficking in plants is rapidly developing, but its molecular mechanism is mostly unknown. Several key regulators of endosomal trafficking, including RAB5, which regulates diverse endocytic events in animal cells, are highly conserved. However, the identification of lineage-specific regulators in eukaryotes indicates that endosomal trafficking is diversified according to distinct body plans and lifestyles. In addition to orthologues of metazoan RAB5, land plants possess a unique RAB5 molecule, which is one of the most prominent features of plant RAB GTPase organization. Plants have also evolved a unique repertoire of SNAREs, the most distinctive of which are diverse VAMP7-related longins, including plant unique VAMP72 derivatives. Here, we demonstrate that a plant-unique RAB5 protein, ARA6, acts in an endosomal trafficking pathway in Arabidopsis thaliana. ARA6 modulates the assembly of a distinct SNARE complex from conventional RAB5, and has a functional role in the salinity stress response. Our results indicate that plants possess a unique endosomal trafficking network and provide the first indication of a functional link between a specific RAB and a specific SNARE complex in plants. PMID- 21666684 TI - Myosin 1b promotes the formation of post-Golgi carriers by regulating actin assembly and membrane remodelling at the trans-Golgi network. AB - The function of organelles is intimately associated with rapid changes in membrane shape. By exerting force on membranes, the cytoskeleton and its associated motors have an important role in membrane remodelling. Actin and myosin 1 have been implicated in the invagination of the plasma membrane during endocytosis. However, whether myosin 1 and actin contribute to the membrane deformation that gives rise to the formation of post-Golgi carriers is unknown. Here we report that myosin 1b regulates the actin-dependent post-Golgi traffic of cargo, generates force that controls the assembly of F-actin foci and, together with the actin cytoskeleton, promotes the formation of tubules at the TGN. Our results provide evidence that actin and myosin 1 regulate organelle shape and uncover an important function for myosin 1b in the initiation of post-Golgi carrier formation by regulating actin assembly and remodelling TGN membranes. PMID- 21666685 TI - External forces control mitotic spindle positioning. AB - The response of cells to forces is essential for tissue morphogenesis and homeostasis. This response has been extensively investigated in interphase cells, but it remains unclear how forces affect dividing cells. We used a combination of micro-manipulation tools on human dividing cells to address the role of physical parameters of the micro-environment in controlling the cell division axis, a key element of tissue morphogenesis. We found that forces applied on the cell body direct spindle orientation during mitosis. We further show that external constraints induce a polarization of dynamic subcortical actin structures that correlate with spindle movements. We propose that cells divide according to cues provided by their mechanical micro-environment, aligning daughter cells with the external force field. PMID- 21666686 TI - FOXO1-FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma. AB - Rhabdomyosarcoma is the most common pediatric soft tissue malignancy. Two major subtypes, alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma, constitute 20 and 60% of all cases, respectively. Approximately 80% of alveolar rhabdomyosarcoma carry two signature chromosomal translocations, t(2;13)(q35;q14) resulting in PAX3-FOXO1 fusion, and t(1;13)(p36;q14) resulting in PAX7-FOXO1 fusion. Whether the remaining cases are truly negative for gene fusion has been questioned. We are reporting the case of a 9-month-old girl with a metastatic neck mass diagnosed histologically as solid variant alveolar rhabdomyosarcoma. Chromosome analysis showed a t(8;13;9)(p11.2;q14;9q32) three-way translocation as the sole clonal aberration. Fluorescent in situ hybridization (FISH) demonstrated a rearrangement at the FOXO1 locus and an amplification of its centromeric region. Single-nucleotide polymorphism-based microarray analysis illustrated a co amplification of the FOXO1 gene at 13q14 and the FGFR1 gene at 8p12p11.2, suggesting formation and amplification of a chimerical FOXO1-FGFR1 gene. This is the first report to identify a novel fusion partner FGFR1 for the known anchor gene FOXO1 in alveolar rhabdomyosarcoma. PMID- 21666687 TI - Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: a study of seven cases. AB - Histiocytic and interdigitating dendritic cell sarcomas are rare tumors originating from bone marrow-derived myeloid stem cells. Recent studies have shown evidence of cross-lineage transdifferentiation of B cells in follicular lymphoma to histiocytic and dendritic cell sarcomas. In this study, we report the morphologic, molecular and cytogenetic analysis of seven cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) associated with histiocytic and dendritic cell sarcomas. All seven patients were elderly males (median age 71 years). The B-cell neoplasms preceded the development of the histiocytic and dendritic cell sarcomas in six of seven patients, and one patient had both tumors diagnosed at the same time. The tumors included four interdigitating dendritic cell sarcomas: one Langerhans cell sarcoma, one histiocytic sarcoma and one immature neoplasm with evidence of histiocytic origin. Laser-capture microdissection and PCR analysis showed identical clonal immunoglobulin gene rearrangements in the two phenotypically distinct components in all cases. There was a preferential usage of IGHV4-39 by the V-D-J gene rearrangement. By fluorescence in situ hybridization (FISH) analysis, two cases showed deletion 17p in both components, whereas four cases had normal cytogenetic findings by FISH in the CLL/SLL cells, but acquired cytogenetic abnormalities in the corresponding histiocytic and dendritic tumors. Chromosome 17p abnormalities were the most common cytogenetic abnormality detected in the sarcomas, seen in five of six cases studied. Compared with the CLL/SLL cells, the histiocytic/dendritic cells were largely negative for PAX5, but showed strong expression of PU.1 and variable and weak expression of CEBPbeta. Our study provides evidence for transdifferentiation of CLL/SLL B cells to tumors of dendritic and less often histiocytic lineage, and suggests that secondary genetic events may play a role in this phenomenon. PMID- 21666688 TI - A biosensor generated via high-throughput screening quantifies cell edge Src dynamics. AB - Fluorescent biosensors for living cells currently require laborious optimization and a unique design for each target. They are limited by the availability of naturally occurring ligands with appropriate target specificity. Here we describe a biosensor based on an engineered fibronectin monobody scaffold that can be tailored to bind different targets via high-throughput screening. We made this Src-family kinase (SFK) biosensor by derivatizing a monobody specific for activated SFKs with a bright dye whose fluorescence increases upon target binding. We identified sites for dye attachment and changes to eliminate vesiculation in living cells, providing a generalizable scaffold for biosensor production. This approach minimizes cell perturbation because it senses endogenous, unmodified target, and because sensitivity is enhanced by direct dye excitation. Automated correlation of cell velocities and SFK activity revealed that SFKs are activated specifically during protrusion. Activity correlates with velocity, and peaks 1-2 MUm from the leading edge. PMID- 21666689 TI - The development of inducible bronchus-associated lymphoid tissue depends on IL 17. AB - Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4(+)CD3(-) lymphoid tissue-inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. Instead, we found that interleukin 17 (IL-17) produced by CD4(+) T cells was essential for the formation of iBALT. IL-17 acted by promoting lymphotoxin-alpha-independent expression of the chemokine CXCL13, which was important for follicle formation. Our results suggest that IL-17-producing T cells are critical for the development of ectopic lymphoid tissues. PMID- 21666690 TI - A semi-invariant Valpha10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen-recognition properties. AB - Type I natural killer T cells (NKT cells) are characterized by an invariant variable region 14-joining region 18 (V(alpha)14-J(alpha)18) T cell antigen receptor (TCR) alpha-chain and recognition of the glycolipid alpha galactosylceramide (alpha-GalCer) restricted to the antigen-presenting molecule CD1d. Here we describe a population of alpha-GalCer-reactive NKT cells that expressed a canonical V(alpha)10-J(alpha)50 TCR alpha-chain, which showed a preference for alpha-glucosylceramide (alpha-GlcCer) and bacterial alpha glucuronic acid-containing glycolipid antigens. Structurally, despite very limited TCRalpha sequence identity, the V(alpha)10 TCR-CD1d-alpha-GlcCer complex had a docking mode similar to that of type I TCR-CD1d-alpha-GalCer complexes, although differences at the antigen-binding interface accounted for the altered antigen specificity. Our findings provide new insight into the structural basis and evolution of glycolipid antigen recognition and have notable implications for the scope and immunological role of glycolipid-specific T cell responses. PMID- 21666691 TI - Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. AB - Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 * 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 * 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 * 10( 12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 * 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis. PMID- 21666692 TI - Genome-wide association study reveals three susceptibility loci for common migraine in the general population. AB - Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 * 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 * 10(-9); rs10166942, OR = 0.85, P = 5.5 * 10(-12); and rs11172113, OR = 0.90, P = 4.3 * 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology. PMID- 21666694 TI - The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. AB - Here we report that the transcription factor cyclic AMP-responsive element binding protein H (CREB-H, encoded by CREB3L3) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H-deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2, Apoa4 and Apoa5 (encoding apolipoproteins C2, A4 and A5, respectively) and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism. PMID- 21666698 TI - Highlights from the prostate cancer genome report. PMID- 21666695 TI - Identification of an innate T helper type 17 response to intestinal bacterial pathogens. AB - Interleukin 17 (IL-17) is a central cytokine implicated in inflammation and antimicrobial defense. After infection, both innate and adaptive IL-17 responses have been reported, but the type of cells involved in innate IL-17 induction, as well as their contribution to in vivo responses, are poorly understood. Here we found that Citrobacter and Salmonella infection triggered early IL-17 production, which was crucial for host defense and was mediated by CD4(+) T helper cells. Enteric innate T helper type 17 (iT(H)17) responses occurred principally in the cecum, were dependent on the Nod-like receptors Nod1 and Nod2, required IL-6 induction and were associated with a decrease in mucosal CD103(+) dendritic cells. Moreover, imprinting by the intestinal microbiota was fully required for the generation of iT(H)17 responses. Together, these results identify the Nod iT(H)17 axis as a central element in controlling enteric pathogens, which may implicate Nod-driven iT(H)17 responses in the development of inflammatory bowel diseases. PMID- 21666699 TI - Thai men's health and sexual attitude. AB - Men's health awareness, including the research and study of quality of life, sexual desires and risk factors, has increased worldwide. In Thailand, this advancement is made possible by cooperation, research and sponsorship from the local Thai community. This article aims to illustrate the sexual attitudes of Thai people, to determine the degree of erectile dysfunction (ED) and to investigate how to manage and cope with ED in a Thai community. We reviewed the relevant literature from Thai-based articles and surveys in regard to men's health, sexual attitudes, the prevalence of ED and common risk factors in the Thai community. The primary risk factor for ED in Thai men was age-related health decline and the presence of vascular disease. Most Thai men will seek consultation from their partner in regard to ED. The main presentation of metabolic disease in Thai patients was dyslipidemia. New selective serotonin reuptake inhibitors are not available for premature ejaculation in Thai communities. The debate in regard to malpractice compensation is an issue that should be closely monitored. There is currently a shortage of home care for the elderly in Thailand. The insights provided by the articles helped recruit the study patients and in turn, helped us gain knowledge that can be translated into improved men's health care in Thailand. PMID- 21666700 TI - Androgens exert sexually dimorphic effects on angiogenesis: novel insight into the relationship between androgens and cardiovascular disease. PMID- 21666701 TI - Inhibition of hypoxia-inducible carbonic anhydrase-IX enhances hexokinase II inhibitor-induced hepatocellular carcinoma cell apoptosis. AB - AIM: The hypoxic condition within large or infiltrative hypovascular tumors produces intracellular acidification, which could activate many signaling pathways and augment cancer cell growth and invasion. Carbonic anhydrase-IX (CA IX) is an enzyme lowering pH. This study is to examine whether hypoxia induces CA IX in hepatocellular carcinoma (HCC) cells, and to evaluate its clinical implication in HCC patients. METHODS: Human HCC cell lines (Huh-7 and HepG2 cells) were used, and cell growth was assessed using MTS assay. CA-IX expression and apoptotic/kinase signaling were evaluated using immunoblotting. The cells were transfected with CA-IX-specific siRNA, or treated with its inhibitor 4-(2 aminoethyl) benzenesulfonamide (CAI#1), and/or the hexokinase II inhibitor, 3 bromopyruvate (3-BP). A clinic pathological analysis of 69 patients who underwent an HCC resection was performed using a tissue array. RESULTS: Incubation of HCC cells under hypoxia (1% O2, 5% CO2, 94% N2) for 36 h significantly increased CA IX expression level. CAI#1 (400 MUmol/L) or CA-IX siRNA (100 MUmol/L) did not influence HCC cell growth and induce apoptosis. However, CAI#1 or CA-IX siRNA at these concentrations enhanced the apoptosis induced by 3-BP (100 MUmol/L). This enhancement was attributed to increased ER stress and JNK activation, as compared with 3-BP alone. Furthermore, a clinic pathological analysis of 69 HCC patients revealed that tumor CA-IX intensity was inversely related to E-cadherin intensity. CONCLUSION: Inhibition of hypoxia-induced CA-IX enhances hexokinase II inhibitor-induced HCC apoptosis. Furthermore, CA-IX expression profiles may have prognostic implications in HCC patients. Thus, the inhibition of CA-IX, in combination with a hexokinase II inhibitor, may be therapeutically useful in patients with HCCs that are aggressively growing in a hypoxic environment. PMID- 21666702 TI - Effects of ticlopidine on pharmacokinetics of losartan and its main metabolite EXP-3174 in rats. AB - AIM: Losartan and antiplatelet agent ticlopidine can be prescribed concomitantly for prevention or therapy of cardiovascular diseases. Hence, the effects of ticlopidine on the pharmacokinetics of losartan and its active metabolite EXP 3174 were evaluated in rats. METHODS: Ticlopidine (4 or 10 mg/kg po) was administered 30 min before administration of losartan (9 mg/kg po or 3 mg/kg iv). The activity of human CYP2C9 and 3A4 were measured using the CYP inhibition assay kit. The activity of P-gp was evaluated using rhodamine-123 retention assay in MCF-7/ADR cells. RESULTS: Ticlopidine (10 mg/kg) significantly increased the areas under the plasma concentration-time curves (AUCs) and peak plasma concentration (C(max)) of oral losartan (9 mg/kg), as well as the AUCs of the active metabolite EXP-3174. Ticlopidine (10 mg/kg) did not significantly change the pharmacokinetics of intravenous losartan (3 mg/kg). Ticlopidine inhibited CYP2C9 and 3A4 with IC50 values of 26.0 and 32.3 MUmol/L, respectively. The relative cellular uptake of rhodamine-123 was unchanged. CONCLUSION: The significant increase in the AUC of losartan (9 mg/kg) by ticlopidine (10 mg/kg) could be attributed to the inhibition of CYP2C9- and 3A4-mediated losartan metabolism in small intestine and/or in liver. The inhibition of P-gp in small intestine and reduction of renal elimination of losartan by ticlopidine are unlikely to be causal factors. PMID- 21666703 TI - Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo. AB - AIM: To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin. METHODS: Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits. RESULTS: The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%+/-0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%. CONCLUSION: Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water. PMID- 21666704 TI - Anti-cancer effects of p21WAF1/CIP1 transcriptional activation induced by dsRNAs in human hepatocellular carcinoma cell lines. AB - AIM: To investigate the anti-cancer effects of p21WAF1/CIP1 transcriptional activation induced by dsRNAs in hepatocellular carcinoma (HCC) cell lines. METHODS: HCC cell lines BEL7402, SMMC-7721, MHCC97L, MHCC97H, and MHCCLM3 were used. HCC cells were treated with dsP21-322 (50 nmol/L), dsControl (50 nmol/L), siP21 (50 nmol/L), or mock transfection. The expression of p21 was detected using quantitative PCR and Western blot. The effects of RNA activation on HCC cells were determined using cell viability assays, apoptosis analyses and clonogenic survival assays. Western blot was also conducted to detect the expression of Bcl xL, survivin, cleaved caspase-3, cleaved caspase-9 and cleaved PARP. RESULTS: At 72 to 120 h following the transfection, dsP21-322 markedly inhibited the viability of HCC cells and clone formation. At the same times, dsP21-322 caused a significant increase in HCC cell apoptosis, as demonstrated with cytometric analysis. The phenomena were correlated with decreased expression levels of the anti-apoptotic proteins Bcl-xL, surviving, and increased expression of cleaved caspase-3, cleaved caspase-9 and cleaved PARP. CONCLUSION: RNA-induced activation of p21 gene expression may have significant therapeutic potential for the treatment of hepatocellular carcinoma and other cancers. PMID- 21666693 TI - Variation in genome-wide mutation rates within and between human families. AB - J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families. PMID- 21666706 TI - Anti-gammadelta TCR antibody-expanded gammadelta T cells: a better choice for the adoptive immunotherapy of lymphoid malignancies. AB - Cell-based immunotherapy for lymphoid malignancies has gained increasing attention as patients develop resistance to conventional treatments. gammadelta T cells, which have major histocompatibility complex (MHC)-unrestricted lytic activity, have become a promising candidate population for adoptive cell transfer therapy. We previously established a stable condition for expanding gammadelta T cells by using anti-gammadelta T-cell receptor (TCR) antibody. In this study, we found that adoptive transfer of the expanded gammadelta T cells to Daudi lymphoma bearing nude mice significantly prolonged the survival time of the mice and improved their living status. We further investigated the characteristics of these antibody-expanded gammadelta T cells compared to the more commonly used phosphoantigen-expanded gammadelta T cells and evaluated the feasibility of employing them in the treatment of lymphoid malignancies. Slow but sustained proliferation of human peripheral blood gammadelta T cells was observed upon stimulation with anti-gammadelta TCR antibody. Compared to phosphoantigen stimulated gammadelta T cells, the antibody-expanded cells manifested similar functional phenotypes and cytotoxic activity towards lymphoma cell lines. It is noteworthy that the anti-gammadelta TCR antibody could expand both the Vdelta1 and Vdelta2 subsets of gammadelta T cells. The in vitro-expanded Vdelta1 T cells displayed comparable tumour cell-killing activity to Vdelta2 T cells. Importantly, owing to higher C-C chemokine receptor 4 (CCR4) and CCR8 expression, the Vdelta1 T cells were more prone to infiltrate CCL17- or CCL22-expressing lymphomas than the Vdelta2 T cells. Characterizing the peripheral blood gammadelta T cells from lymphoma patients further confirmed that the anti gammadelta TCR antibody-expanded gammadelta T cells could be a more efficacious choice for the treatment of lymphoid malignancies than phosphoantigen-expanded gammadelta T cells. PMID- 21666707 TI - Persistence of tumor-infiltrating CD8 T cells is tumor-dependent but antigen independent. AB - How tumor-infiltrating lymphocytes (TILs) that are tumor-specific but functionally tolerant persist in the antigen-expressing tumor tissue is largely unknown. We have previously developed a modified TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model where prostate cancer cells express the T-cell epitope SIYRYYGL (SIY) recognized by CD8 T cells expressing the 2C T-cell receptor (TCR) (referred to as TRP-SIY mice). In TRP-SIY mice, activated 2C T cells rapidly become tolerant following infiltration into the prostate tumor. In this study, we show that tolerant 2C T cells persist in the prostate tumor of TRP SIY mice by proliferating slowly in a tumor-dependent, but antigen-, interleukin (IL)-7- and IL-15-independent manner. We also show that disappearance of 2C T cells from the lymphoid organs of TRP-SIY mice are due to antigen-induced T-cell contraction rather than altered trafficking or generalized T-cell depletion in the mice. Finally, we show that clonal T cells unreactive to SIY are equally capable of persisting in the prostate tumor. These findings suggest that while functional tolerance of TILs is induced by antigen, persistence of tolerant TILs in the tumor tissue is mediated by a novel mechanism: slow proliferation independent of antigen and homeostatic cytokines. These results also allow CD8 T cell survival in the tumor environment to be compared with T-cell survival in chronic infection. PMID- 21666705 TI - Strategies of mucosal immunotherapy for allergic diseases. AB - Incidences of allergic disease have recently increased worldwide. Allergen specific immunotherapy (SIT) has long been a controversial treatment for allergic diseases. Although beneficial effects on clinically relevant outcomes have been demonstrated in clinical trials by subcutaneous immunotherapy (SCIT), there remains a risk of severe and sometimes fatal anaphylaxis. Mucosal immunotherapy is one advantageous choice because of its non-injection routes of administration and lower side-effect profile. This study reviews recent progress in mucosal immunotherapy for allergic diseases. Administration routes, antigen quality and quantity, and adjuvants used are major considerations in this field. Also, direct uses of unique probiotics, or specific cytokines, have been discussed. Furthermore, some researchers have reported new therapeutic ideas that combine two or more strategies. The most important strategy for development of mucosal therapies for allergic diseases is the improvement of antigen formulation, which includes continuous searching for efficient adjuvants, collecting more information about dominant T-cell epitopes of allergens, and having the proper combination of each. In clinics, when compared to other mucosal routes, sublingual immunotherapy (SLIT) is a preferred choice for therapeutic administration, although local and systemic side effects have been reported. Additionally, not every allergen has the same beneficial effect. Further studies are needed to determine the benefits of mucosal immunotherapy for different allergic diseases after comparison of the different administration routes in children and adults. Data collected from large, well-designed, double-blind, placebo-controlled, and randomized trials, with post-treatment follow-up, can provide robust substantiation of current evidence. PMID- 21666708 TI - Fever from the forest: prospects for the continued emergence of sylvatic dengue virus and its impact on public health. AB - The four dengue virus (DENV) serotypes that circulate among humans emerged independently from ancestral sylvatic progenitors that were present in non-human primates, following the establishment of human populations that were large and dense enough to support continuous inter-human transmission by mosquitoes. This ancestral sylvatic-DENV transmission cycle still exists and is maintained in non human primates and Aedes mosquitoes in the forests of Southeast Asia and West Africa. Here, we provide an overview of the ecology and molecular evolution of sylvatic DENV and its potential for adaptation to human transmission. We also emphasize how the study of sylvatic DENV will improve our ability to understand, predict and, ideally, avert further DENV emergence. PMID- 21666709 TI - Biased gene transfer in microbial evolution. AB - Horizontal gene transfer (HGT) is an important evolutionary process that allows the spread of innovations between distantly related organisms. We present evidence that prokaryotes (bacteria and archaea) are more likely to transfer genetic material with their close relatives than with distantly related lineages. This bias in transfer partners can create phylogenetic signals that are difficult to distinguish from the signal created through shared ancestry. Preferences for transfer partners can be revealed by studying the distribution patterns of divergent genes with identical functions. In many respects, these genes are similar to alleles in a population, except that they coexist only in higher taxonomic groupings and are acquired by a species through HGT. We also discuss the role of biased gene transfer in the formation of taxonomically recognizable natural groups in the tree or net of life. PMID- 21666710 TI - C/EBP-delta regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1alpha. AB - CCAAT/enhancer-binding protein-delta (C/EBP-delta), a transcription factor, is elevated in carcinoma compared with that in normal tissue. This study reports a novel function of C/EBP-delta in lymphangiogenesis and tumor metastasis. Genetic deletion of C/EBP-delta in mice resulted in a significant reduction of lymphangiogenesis and pulmonary metastases, with a dramatic reduction of vascular endothelial growth factor-C (VEGF-C) and its cognate receptor VEGF receptor-3 (VEGFR3) in lymphatic endothelial cells (LECs). By contrast, no difference of VEGF-C in tumor tissues and bone marrow was observed between null and wild-type mice. Consistently, forced expression of C/EBP-delta increased VEGF-C and VEGFR3 expression in cultured LECs. These findings suggest a specific and important role of C/EBP-delta in the regulation of VEGFR3 signaling in LECs. Furthermore, expression of C/EBP-delta in cultured LECs significantly increased cell motility, and knockdown of C/EBP-delta inhibited cell motility and lymphatic vascular network formation in vitro. Forced expression of VEGF-C, but not recombinant VEGF C, rescued the knockdown of C/EBP-delta-induced cell apoptosis, indicative of autonomous VEGF-C autocrine signaling essential for LEC survival. Moreover, hypoxia induces C/EBP-delta expression and C/EBP-delta regulates HIF-1alpha expression. Blocking HIF-1alpha activity totally blocked CEBP-delta-induced VEGF C and VEGFR3 expression in LECs. Together, these findings uncover a new function of CEBP-delta in lymphangiogenesis through regulation of VEGFR3 signaling in LECs. PMID- 21666712 TI - The autophagy conundrum in cancer: influence of tumorigenic metabolic reprogramming. AB - Tumorigenesis is often accompanied by metabolic changes that favor rapid energy production and increased biosynthetic capabilities. These metabolic adaptations promote the survival and proliferation of tumor cells, and in conjunction with the hypoxic and metabolically challenged tumor microenvironment, influence autophagic activity. Autophagy is a catabolic process that allows cellular macromolecules to be broken down and re-utilized as metabolic precursors. Stimulation of autophagy promotes the survival of tumor cells under stressful metabolic and environmental conditions, and counters the potentially deleterious effects of mitochondrial dysfunction and the ROS that these organelles generate. However, inhibition of autophagy has also been reported to fuel tumorigenesis. In spite of the advances in our understanding of the relationship between autophagy and tumorigenesis, it remains unclear whether the therapeutic approaches targeting autophagy should aim to increase or decrease autophagic flux in tumor tissues in human patients. Here, we review how metabolic reprogramming influences autophagic activity in tumors, and discuss how inhibition of autophagy might be exploited to target tumor cells that show altered metabolism. PMID- 21666711 TI - Upregulation of VEGF-A and CD24 gene expression by the tGLI1 transcription factor contributes to the aggressive behavior of breast cancer cells. AB - The Hedgehog signaling pathway is one of the most dysregulated pathways in human cancers. The glioma-associated oncogene homolog 1 (GLI1) transcription factor is the terminal effector of the Hedgehog pathway, frequently activated in human breast cancer and an emerging target of breast cancer therapy. While somatic mutations in the human GLI1 gene have never been reported in any cell or tumor type, we recently uncovered the existence of a novel alternatively spliced, truncated GLI1 (tGLI1) that has an in-frame deletion of 41 codons spanning the entire exon 3 and part of exon 4 of the GLI1 gene. Using glioblastoma models, we showed that tGLI1 has gained the ability to promote glioblastoma migration and invasion via its gain-of-function transcriptional activity. However, the pathological impact of tGLI1 on breast cancer remains undefined. Here, we report that tGLI1 is frequently expressed in human breast cancer cell lines and primary specimens we have examined to date, but is undetectable in normal breast tissues. We found for the first time that tGLI1, but not GLI1, binds to and enhances the human vascular endothelial growth factor-A (VEGF-A) gene promoter, leading to its upregulation. Consequently, tGLI1-expressing MDA-MB-231 breast cancer cells secret higher levels of VEGF-A and contain a higher propensity, than the isogenic cells with control vector and GLI1, to stimulate in vitro angiogenesis of human vascular endothelial cells. We further showed that tGLI1 has gained the ability to enhance the motility and invasiveness of breast cancer cells in a proliferation-independent manner and that this functional gain is associated with increased expression of migration/invasion-associated genes, CD24, MMP-2 and MMP 9. tGLI1 has also acquired the property to facilitate anchorage-independent growth of breast cancer cells. Collectively, our results define tGLI1 as a gain of-function GLI1 transcription factor and a novel mediator of the behavior of clinically more aggressive breast cancer. PMID- 21666713 TI - Tamoxifen downregulation of miR-451 increases 14-3-3zeta and promotes breast cancer cell survival and endocrine resistance. AB - Many estrogen receptor (ER)-positive breast cancers respond well initially to endocrine therapies, but often develop resistance during treatment with selective ER modulators (SERMs) such as tamoxifen. We have reported that the 14-3-3 family member and conserved protein, 14-3-3zeta, is upregulated by tamoxifen and that high expression correlated with an early time to disease recurrence. However, the mechanism by which tamoxifen upregulates 14-3-3zeta and may promote the development of endocrine resistance is not known. Our findings herein reveal that the tamoxifen upregulation of 14-3-3zeta results from its ability to rapidly downregulate microRNA (miR)-451 that specifically targets 14-3-3zeta. The levels of 14-3-3zeta and miR-451 were inversely correlated, with 14-3-3zeta being elevated and miR-451 being at a greatly reduced level in tamoxifen-resistant breast cancer cells. Of note, downregulation of miR-451 was selectively elicited by tamoxifen but not by other SERMs, such as raloxifene or ICI182,780 (Fulvestrant). Increasing the level of miR-451 by overexpression, which decreased 14-3-3zeta, suppressed cell proliferation and colony formation, markedly reduced activation of HER2, EGFR and MAPK signaling, increased apoptosis, and, importantly, restored the growth-inhibitory effectiveness of SERMs in endocrine resistant cells. Opposite effects were elicited by miR-451 knockdown. Thus, we identify tamoxifen downregulation of miR-451, and consequent elevation of the key survival factor 14-3-3zeta, as a mechanistic basis of tamoxifen-associated development of endocrine resistance. These findings suggest that therapeutic approaches to increase expression of this tumor suppressor-like miR should be considered to downregulate 14-3-3zeta and enhance the effectiveness of endocrine therapies. Furthermore, the selective ability of the SERM tamoxifen but not raloxifene to regulate miR-451 and 14-3-3zeta may assist in understanding differences in their activities, as seen in the STAR (Study of Tamoxifen and Raloxifene) breast cancer prevention trial and in other clinical trials. PMID- 21666715 TI - Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer. AB - Human breast tumors comprise a minor sub-population of tumor-initiating cells (TICs), commonly termed cancer stem cells. TICs are thought to sustain tumor growth and to confer resistance to current anticancer therapies. Hence, targeting TIC may be essential to achieving durable cancer cures. To identify molecular targets in breast TIC, we employed a transgenic mouse model of ERBB2 breast cancer; tumors arising in this model comprise a very high frequency of TIC, which is maintained in tumor cell populations propagated in vitro as non-adherent tumorspheres. The Notch pathway is dysregulated in human breast tumors and overexpression of constitutively active Notch proteins induces mammary tumors in mice. The Notch pathway has also been implicated in stem cell processes including those of mammary epithelial stem cells. Hence, we investigated the potential that the Notch pathway is required for TIC activity. We found that an antagonist of Notch signaling, a gamma (gamma)-secretase inhibitor termed MRK-003, inhibited the survival of tumorsphere-derived cells in vitro and eliminated TIC as assessed by cell transplantation into syngeneic mice. Whereas MRK-003 also inhibited the self-renewal and/or proliferation of mammosphere-resident cells, this effect of the inhibitor was reversible thus suggesting that it did not compromise the survival of these cells. MRK-003 administration to tumor-bearing mice eliminated tumor-resident TIC and resulted in rapid and durable tumor regression. MRK-003 inhibited the proliferation of tumor cells, and induced their apoptosis and differentiation. These findings suggest that MRK-003 targets breast TIC and illustrate that eradicating these cells in breast tumors ensures long-term, recurrence-free survival. PMID- 21666714 TI - EphA2 is a critical oncogene in melanoma. AB - EphA2 is a member of the Eph family of receptor tyrosine kinases and is highly expressed in many aggressive cancer types, including melanoma. We recently showed that EphA2 is also upregulated by ultraviolet radiation and is able to induce apoptosis. These findings suggest that EphA2 may have different, even paradoxical, effects on viability depending on the cellular context and that EphA2 mediates a delicate balance between life and death of the cell. To functionally clarify EphA2's role in melanoma, we analyzed a panel of melanoma cell lines and found that EphA2 levels are elevated in a significant fraction of the samples. Specific depletion of EphA2 in high-expressing melanoma cells using short hairpin RNA led to profound reductions in cellular viability, colony formation and migration in vitro and a dramatic loss of tumorigenic potential in vivo. Stable introduction of EphA2 into low-expressing cell lines enhanced proliferation, colony formation and migration, further supporting its pro malignant phenotype. Interestingly, transient expression of EphA2 and/or Braf(V600E) in non-transformed melanocytes led to significant and additive apoptosis. These results verify that EphA2 is an important oncogene and potentially a common source of 'addiction' for many melanoma cells. Moreover, acute induction of EphA2 may purge genetically susceptible cells, thereby uncovering a more aggressive population that is in fact dependent on the oncogene. PMID- 21666716 TI - Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells. AB - Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epithelial-like morphology; stabilized E cadherin and beta-catenin localization at cell-cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased E-cadherin and beta catenin localization at cell-cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIB-induced inhibitor of the Wnt/beta-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer. PMID- 21666718 TI - Overexpression of miR-370 and downregulation of its novel target TGFbeta-RII contribute to the progression of gastric carcinoma. AB - MicroRNAs (miRNAs) are endogenous non-coding RNAs that are known to be involved in the pathogenesis of tumors. Gastric carcinoma (GC) is a common malignancy worldwide. The aim of this study was the identification of the expression signature and functional roles of aberrant miRNAs in GC. Initial screening established a profile of aberrantly expressed miRNAs in tumors. miR-370 was confirmed to be overexpressed in GC tissues. Higher expression of miR-370 in GC tissues was associated with more advanced nodal metastasis and a higher clinical stage compared with controls. In addition, significantly higher level of miR-370 was noted in the plasma of GC patients compared with controls. Patients having more invasive or advanced tumors also exhibited a higher plasma level of miR-370. In vitro assays indicated that exogenous miR-370 expression enhanced the oncogenic potential of GC cells. The AGS-GFPM2 cells with exogenous miR-370 expression also exhibited enhanced abdominal metastatic dissemination in nude mice. Reporter assays confirmed that miR-370 targeted predicted sites in 3'UTR of transforming growth factor-beta receptor II (TGFbeta-RII) gene. The exogenous miR 370 expression decreased TGFbeta-RII expression and the phosphorylation of Smad3 elicited by TGFbeta1. The TGFbeta1-mediated repression in cell migration was reverted by exogenous miR-370 expression. A reverse correlation between miR-370 and TGFbeta-RII expression was noted in GC tissues. This study concludes that miR 370 is a miRNA that is associated with GC progression by downregulating TGFbeta RII. The miRNA expression profile described in this study should contribute to future studies on the role of miRNAs in GC. PMID- 21666717 TI - Kinome siRNA-phosphoproteomic screen identifies networks regulating AKT signaling. AB - To identify regulators of intracellular signaling, we targeted 541 kinases and kinase-related molecules with small interfering RNAs (siRNAs), and determined their effects on signaling with a functional proteomics reverse-phase protein array (RPPA) platform assessing 42 phospho and total proteins. The kinome-wide screen demonstrated a strong inverse correlation between phosphorylation of AKT and mitogen-activated protein kinase (MAPK) with 115 genes that, when targeted by siRNAs, demonstrated opposite effects on MAPK and AKT phosphorylation. Network based analysis identified the MAPK subnetwork of genes along with p70S6K and FRAP1 as the most prominent targets that increased phosphorylation of AKT, a key regulator of cell survival. The regulatory loops induced by the MAPK pathway are dependent on tuberous sclerosis complex 2 but demonstrate a lesser dependence on p70S6K than the previously identified FRAP1 feedback loop. The siRNA screen also revealed novel bi-directionality in the AKT and GSK3 (Glycogen synthase kinase 3) interaction, whereby genetic ablation of GSK3 significantly blocks AKT phosphorylation, an unexpected observation as GSK3 has only been predicted to be downstream of AKT. This method uncovered novel modulators of AKT phosphorylation and facilitated the mapping of regulatory loops. PMID- 21666719 TI - Willin/FRMD6 expression activates the Hippo signaling pathway kinases in mammals and antagonizes oncogenic YAP. AB - The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The Drosophila melanogaster protein Expanded acts in the Hippo signaling pathway to control organ size. Previously, willin/FRMD6 has been proposed as the human orthologue of Expanded. Willin lacks C-terminal sequences that are present in Expanded and, to date, little is known about the functional role of willin in mammalian cells. When willin is expressed in D. melanogaster epithelial tissues, it has the same subcellular localization as Expanded, but cannot rescue growth defects associated with expanded deficiency. However, we show that ectopic willin expression causes an increase in phosphorylation of the core Hippo signaling pathway components MST1/2, LATS1 and YAP, an effect that can be antagonized by ezrin. In MCF10A cells, loss of willin expression displays epithelial-to-mesenchymal transition features and willin overexpression antagonizes YAP activity via the N-terminal FERM domain of willin. Therefore, in mammalian cells willin influences Hippo signaling activity by activating the core Hippo pathway kinase cassette. PMID- 21666720 TI - Notch-induced mammary tumorigenesis does not involve the lobule-limited epithelial progenitor. AB - The mouse mammary epithelial cell hierarchy contains both multipotent stem cell as well as lineage-limited duct and lobular progenitor cell functions. The latter also termed parity-identified mammary epithelial cells (PI-MECs)-are marked by beta-galactosidase (beta Gal) expression following pregnancy and involution in whey acidic protein promoter (WAP)-Cre/Rosa26-flox-stop-flox-lacZ (WC/R26) mice, and are the targets of tumorigenic transformation in mouse mammary tumor virus erbB2 transgenic mice. In this study, we demonstrate that an epithelial population distinct from PI-MECs is transformed during WAP-Int3 tumorigenesis. As expected, WAP-Int3/WC/R26 triple-transgenic mice failed to undergo secretory alveolar development, failed to lactate and developed mammary tumors. Following pregnancy and involution, beta Gal+ mammary epithelial cells were found in the normal mammary tissue, but the resulting mammary tumors were all beta Gal-. WAP Int3/WC/R26 mammary glands contained ample estrogen receptor alpha (ERalpha)+ MECs, but only rare (<1%) progesterone receptor (PR)+ and RANKL+ cells. In addition, dissociated MECs from WAP-Int3/WC/R26 glands failed to regenerate a mammary tree upon transplantation into a cleared fat-pad of a nu/nu recipient mouse. However, when mixed with normal MECs, PI-MECs from WAP-Int3/WC/R26 mice contributed progeny to the resulting functional outgrowth. The WAP-Int3/WC/R26 derived PI-MECs displayed all of the properties of fully functional lobular progenitors including giving rise to ERalpha+, PR+, smooth muscle actin+ and RANKL+ epithelial progeny. These results demonstrate that WAP-Int3 has no oncogenic effect upon PI-MECs and that the expansion of functional lobular progenitors is required for secretory alveolar development and lactation. Furthermore, lobular progenitor function is ultimately controlled by signals within its microenvironment. PMID- 21666721 TI - Modulation of Wnt/beta-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer. AB - Using a screen for Wnt/beta-catenin inhibitors, a family of 8-hydroxyquinolone derivatives with in vivo anti-cancer properties was identified. Analysis of microarray data for the lead compound N-((8-hydroxy-7-quinolinyl) (4 methylphenyl)methyl)benzamide (HQBA) using the Connectivity Map database suggested that it is an iron chelator that mimics the hypoxic response. HQBA chelates Fe(2+) with a dissociation constant of ~10(-19) M, with much weaker binding to Fe(3+) and other transition metals. HQBA inhibited proliferation of multiple cell lines in culture, and blocked the progression of established spontaneous cancers in two distinct genetically engineered mouse models of mammary cancer, MMTV-Wnt1 and MMTV-PyMT mice, without overt toxicity. HQBA may inhibit an iron-dependent factor that regulates cell-type-specific beta-catenin driven transcription. It inhibits cancer cell proliferation independently of its effect on beta-catenin signaling, as it works equally well in MMTV-PyMT tumors and diverse beta-catenin-independent cell lines. HQBA is a promising specific intracellular Fe(2+) chelator with activity against spontaneous mouse mammary cancers. PMID- 21666722 TI - Inflammatory signaling compromises cell responses to interferon alpha. AB - Interferon alpha (IFNalpha) is widely used for treatment of melanoma and certain other malignancies. This cytokine as well as the related IFNbeta exerts potent anti-tumorigenic effects; however, their efficacy in patients is often suboptimal. Here, we report that inflammatory signaling impedes the effects of IFNalpha/beta. Melanoma cells can secrete pro-inflammatory cytokines that inhibit cellular responses to IFNalpha/beta via activating the ligand-independent pathway for the phosphorylation and subsequent ubiquitination and accelerated degradation of the IFNAR1 chain of type I IFN receptor. Catalytic activity of the p38 protein kinase was required for IFNAR1 downregulation and inhibition of IFNalpha/beta signaling induced by proinflammatory cytokines such as interleukin 1 (IL-1). Activation of p38 kinase inversely correlated with protein levels of IFNAR1 in clinical melanoma specimens. Inhibition of p38 kinase augmented the inhibitory effects of IFNalpha/beta on cell viability and growth in vitro and in vivo. The roles of inflammation and p38 protein kinase in regulating cellular responses to IFNalpha/beta in normal and tumor cells are discussed. PMID- 21666723 TI - Ezrin is key regulator of Src-induced malignant phenotype in three-dimensional environment. AB - The oncogenic tyrosine kinase Src has a role in cancer development, especially by promoting invasive and metastatic behavior. It is, however, unclear which of the Src-regulated signaling cascades induce malignant phenotype in three-dimensional environment. One of Src substrates is ezrin, a cytoskeletal organiser and regulator of signal transduction. Ezrin expression correlates with poor outcome of diverse cancers and is essential in experimental metastatic osteosarcoma. We reconstituted genetically ezrin-deficient cells with wild-type (WT) or phosphorylation-deficient Y477F ezrin together with constitutively active Src. In two-dimensional cultures, Src induced malignant features regardless of the presence or absence of ezrin. In contrast, only WT ezrin-expressing cells grew efficiently in soft agar or in suspension. In Matrigel, only WT ezrin significantly promoted growth and invasion, and was targeted to specific regions on the plasma membrane. WT and Y477F ezrin-expressing cells showed marked differences only when growing or scattering in three-dimensional matrix. Additional experiments showed that Y477-phosphorylated ezrin is also needed for the growth of Src-transformed epithelial cells in three-dimensional matrix. Cells lacking functional ezrin had reduced cyclin D levels and fewer cells in G2+S phase, possibly as a consequence of abnormal mTOR signaling, as ezrin Y477F cells showed lower expression of phosphorylated intermediates downstream of mTOR than WT cells. We conclude that the pathways activated by Src depend on the type of environment and that ezrin is a crucial element of Src-induced malignant features in cells growing inside three-dimensional environment. PMID- 21666726 TI - Hepatitis C. PMID- 21666724 TI - Identification and functional analysis of 9p24 amplified genes in human breast cancer. AB - Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16(INK4a), p21(Waf1/Cip1) and p27(Kip1). Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis. PMID- 21666725 TI - Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. AB - Expression of the breast cancer-associated gene 1 (BRCA1) in sporadic breast cancers is usually reduced, yet the underlying mechanisms remains elusive. To identify factors that are responsible for reduced BRCA1 expression, we screened 92 known transcription factors for their ability to regulate expression of BRCA1. Among several potential regulators, the Gli-Krueppel-related transcription factor Yin Yang 1 (YY1) showed the most dramatic transactivation of the BRCA1 promoter. YY1 binds to the promoter of BRCA1, and its overexpression resulted in increased expression of BRCA1 and a number of BRCA1 downstream genes. We further showed that overexpression of YY1 in cancer cells inhibited cell proliferation, foci formation and tumor growth in nude mice. To assess the clinical relevance between YY1 and BRCA1, we studied expression of YY1 and BRCA1 from human breast cancer samples and tissue arrays, and detected a significant positive correlation between the level of YY1 and BRCA1 expression in these cancers. Taken together, these findings suggest that YY1 is a key regulator of BRCA1 expression and may be causally linked to the molecular etiology of human breast cancer. PMID- 21666727 TI - Perspective: recognizing resistance. PMID- 21666728 TI - Global health: a uniquely Egyptian epidemic. PMID- 21666729 TI - Research technique: the murine candidate. PMID- 21666730 TI - Vaccines: a moving target. PMID- 21666731 TI - Introduction: a smouldering public-health crisis. PMID- 21666732 TI - Diagnostics: a testing journey. PMID- 21666733 TI - Therapeutics: new drugs hit the target. PMID- 21666734 TI - Perspective: miles to go before we sleep. PMID- 21666735 TI - Pharmacogenomics: playing the odds. PMID- 21666736 TI - Donors as research subjects: a challenge. PMID- 21666737 TI - Autoimmune-like hepatitis following unrelated BMT successfully treated with rituximab. PMID- 21666738 TI - Failure of haematopoietic recovery overcome by SCT despite invasive mucormycosis infection. PMID- 21666739 TI - Dermatomyositis developed in a recipient of allogeneic BMT; the differentiation of chronic GVHD and autoimmune disease. PMID- 21666740 TI - Death and best interests: a response to the legal challenge. AB - In an earlier paper I argued that we do not have an objective conception of best interests and that this is a particular problem because the courts describe that they use an '...objective approach or test. That test is the best interests of the patient' when choosing for children. I further argued that there was no obvious way in which we could hope to develop an objective notion of best interests. As well as this, I argued that a best-interest-based approach was a particular problem around the time of death of some children. A response from a legal perspective argued that, while there is not a clear conception of objective best interests, the courts have a well-described approach to finding a child's objective best interests. In this paper, I argue that without clear agreement on an objective conception of best interests, the courts are unable to locate an objective sense of best interests and that the solutions do not solve the problems that were identified in the initial paper 'Death and best interests'. PMID- 21666741 TI - Consenting futures: professional views on social, clinical and ethical aspects of information feedback to embryo donors in human embryonic stem cell research. AB - This paper reports from an ongoing multidisciplinary, ethnographic study that is exploring the views, values and practices (the ethical frameworks) drawn on by professional staff in assisted conception units and stem cell laboratories in relation to embryo donation for research purposes, particularly human embryonic stem cell (hESC) research, in the UK. We focus here on the connection between possible incidental findings and the circumstances in which embryos are donated for hESC research, and report some of the uncertainties and dilemmas of our staff participants. We explore the views of our study participants in relation to two themes: (1) rights to information and anticipating how donors might be informed about future research findings and (2) occupational work goals and trust. PMID- 21666742 TI - The meanings of consent to the donation of cord blood stem cells: perspectives from an interview-based study of a public cord blood bank in England. AB - This paper explores the perspectives of women who have agreed that their umbilical cord blood may be collected for a public 'cord blood bank', for use in transplant medicine or research. Drawing on interview data from 27 mothers who agreed to the collection and use of their umbilical cord blood, these choices and the informed consent process are explored. It is shown that the needs of sick children requiring transplants are prominent in narrative accounts of cord blood banking, together with high expectations for future applications of stem cells. Given this dynamic, a concern arises that the complex and multiple uses of tissues and related data might be oversimplified in the consent process. In conclusion, the positive finding of a commitment to mutuality in cord blood banking among these women is underlined, and its implications for the wider debate on cord blood banking are discussed. PMID- 21666743 TI - Psychological health of orphan bonobos and chimpanzees in African sanctuaries. AB - BACKGROUND: Facilities across Africa care for apes orphaned by the trade for "bushmeat." These facilities, called sanctuaries, provide housing for apes such as bonobos (Pan paniscus) and chimpanzees (Pan troglodytes) who have been illegally taken from the wild and sold as pets. Although these circumstances are undoubtedly stressful for the apes, most individuals arrive at the sanctuaries as infants and are subsequently provided with rich physical and social environments that can facilitate the expression of species-typical behaviors. METHODS AND FINDINGS: We tested whether bonobo and chimpanzee orphans living in sanctuaries show any behavioral, physiological, or cognitive abnormalities relative to other individuals in captivity as a result of the early-life stress they experience. Orphans showed lower levels of aberrant behaviors, similar levels of average cortisol, and highly similar performances on a broad battery of cognitive tests in comparisons with individuals of the same species who were either living at a zoo or were reared by their mothers at the sanctuaries. CONCLUSION: Taken together, these results support the rehabilitation strategy used by sanctuaries in the Pan-African Sanctuary Alliance (PASA) and suggest that the orphans we examined did not show long-term signs of stress as a result of their capture. Our findings also show that sanctuary apes are as psychologically healthy as apes in other captive settings and thus represent a valuable resource for non-invasive research. PMID- 21666745 TI - Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay. AB - The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES) cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCastTM chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (alpha,beta myosin heavy chain; MYH6/MYH7) and cytotoxicity (DRAQ5TM/Sapphire700TM) were measured by In-Cell WesternTM analysis. Half-maximal activity concentration (AC50) values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (~500) revealed significant associations for a subset of chemicals (26) that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A) were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation. PMID- 21666744 TI - Randomized trial of safety and effectiveness of chlorproguanil-dapsone and lumefantrine-artemether for uncomplicated malaria in children in the Gambia. AB - BACKGROUND: Chlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure. METHODS: 1238 children aged 6 months to 10 years with uncomplicated malaria were randomized to receive CD or artemether-lumefantrine (AL) and followed for 28 days. The first dose was supervised, subsequent doses given unsupervised at home. G6PD genotype was determined to assess the interaction between treatment and G6PD status in their effects on anaemia. The main endpoints were clinical treatment failure by day 28, incidence of severe anaemia (Hb<5 g/dL), and haemoglobin concentration on day 3. FINDINGS: One third of patients treated with AL, and 6% of patients treated with CD, did not complete their course of medication. 18% (109/595) of children treated with CD and 6.1% (36/587) with AL required rescue medication within 4 weeks, risk difference 12% (95%CI 8.9%-16%). 23 children developed severe anaemia (17 (2.9%) treated with CD and 6 (1.0%) with AL, risk difference 1.8%, 95%CI 0.3%-3.4%, P = 0.02). Haemoglobin concentration on day 3 was lower among children treated with CD than AL (difference 0.43 g/dL, 95% CI 0.24 to 0.62), and within the CD group was lower among those children who had higher parasite density at enrollment. Only 17 out of 1069 children who were typed were G6PD A- deficient, of these 2/9 treated with CD and 1/8 treated with AL developed severe anaemia. 5/9 treated with CD had a fall of 2 g/dL or more in haemoglobin concentration by day 3. INTERPRETATION: AL was well tolerated and highly effective and when given under operational conditions despite poor adherence to the six-dose regimen. There were more cases of severe malaria and anaemia after CD treatment although G6PD deficiency was uncommon. TRIAL REGISTRATION: Clinicaltrials.gov NCT00118794. PMID- 21666746 TI - Unraveling molecular signatures of immunostimulatory adjuvants in the female genital tract through systems biology. AB - Sexually transmitted infections (STIs) unequivocally represent a major public health concern in both industrialized and developing countries. Previous efforts to develop vaccines for systemic immunization against a large number of STIs in humans have been unsuccessful. There is currently a drive to develop mucosal vaccines and adjuvants for delivery through the genital tract to confer protective immunity against STIs. Identification of molecular signatures that can be used as biomarkers for adjuvant potency can inform rational development of potent mucosal adjuvants. Here, we used systems biology to study global gene expression and signature molecules and pathways in the mouse vagina after treatment with two classes of experimental adjuvants. The Toll-like receptor 9 agonist CpG ODN and the invariant natural killer T cell agonist alpha galactosylceramide, which we previously identified as equally potent vaginal adjuvants, were selected for this study. Our integrated analysis of genome-wide transcriptome data determined which signature pathways, processes and networks are shared by or otherwise exclusive to these 2 classes of experimental vaginal adjuvants in the mouse vagina. To our knowledge, this is the first integrated genome-wide transcriptome analysis of the effects of immunomodulatory adjuvants on the female genital tract of a mammal. These results could inform rational development of effective mucosal adjuvants for vaccination against STIs. PMID- 21666747 TI - Yielding and irreversible deformation below the microscale: surface effects and non-mean-field plastic avalanches. AB - Nanoindentation techniques recently developed to measure the mechanical response of crystals under external loading conditions reveal new phenomena upon decreasing sample size below the microscale. At small length scales, material resistance to irreversible deformation depends on sample morphology. Here we study the mechanisms of yield and plastic flow in inherently small crystals under uniaxial compression. Discrete structural rearrangements emerge as a series of abrupt discontinuities in stress-strain curves. We obtain the theoretical dependence of the yield stress on system size and geometry and elucidate the statistical properties of plastic deformation at such scales. Our results show that the absence of dislocation storage leads to crucial effects on the statistics of plastic events, ultimately affecting the universal scaling behavior observed at larger scales. PMID- 21666748 TI - Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade. AB - BACKGROUND: Antidepressant drugs (ADs) have been shown to activate BDNF (brain derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. METHODOLOGY: In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines. PRINCIPAL FINDINGS: Using a chemical-genetic TrkB(F616A) mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf-/- knock-out mice (132.4+/-8.5% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB. CONCLUSIONS: The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain. PMID- 21666751 TI - [Neighbourhood characteristic as risk-protective factor related to substance use by youth Review of the contemporary research.] AB - Przedmiotem artykulu jest przeglad prac badawczych dotyczacych zwiazku miedzy cechami srodowiska sasiedzkiego a uzywaniem przez mlodziez substancji psychoaktywnych. W pierwszej czesci pracy opisano sposoby definiowania obszaru srodowiska sasiedzkiego, w drugiej scharakteryzowano podstawy teoretyczne badan, w trzeciej - metody pomiaru cech srodowiska sasiedzkiego, a w czwartej przedstawiono wynik badan. Najczesciej przywolywanymi w badaniach teoriami, wyjasniajacymi zwiazek miedzy srodowiskiem sasiedzkim a zachowaniem mlodziezy byly teoria spolecznej dezorganizacji oraz teoria kapitalu spolecznego. Odwolywano sie ponadto do mechanizmow wplywu srodowiska sasiedzkiego na mlodziez, takich jak: mechanizm norm i kolektywnej skutecznosci, mechanizm zasobow instytucjonalnych, mechanizm relacji rodzinnych, mechanizm poczucia wspolnoty ze spolecznosci lokalna oraz model kolektywnego stylu zycia. Najpowszechniej wykorzystywanym zrodlem informacji o cechach srodowiska byly dane ze spisu powszechnego dotyczace spolecznej i demograficznej charakterystyki mieszkancow. Stosowano rowniez takie metody pomiaru, jak obserwacje w terenie, analiza dokumentacji oraz ankiety i wywiady z osobami badanymi, mlodzieza i rodzicami mlodych ludzi. Wyniki badan potwierdzily, ze cechy srodowiska sasiedzkiego maja bezposredni i posredni wplyw na sieganie przez mlodziez po papierosy, alkohol i narkotyki. Stwierdzono, ze znaczacym czynnikiem ryzyka jest charakterystyczna dla niekorzystnych srodowisk latwa dostepnosc substancji psychoaktywnych. Czynnikami chroniacymi sa bezpieczenstwo w sasiedztwie, kontrola spoleczna oraz dostepnosc zasobow instytucjonalnych. Zaproponowane przez badaczy modele teoretyczne, odnoszace sie do wplywu srodowiska sasiedzkiego na zachowanie mlodziezy, wyznaczaja obiecujace obszary badan. Zebrane dotychczas wyniki wskazuja, ze w dzialaniach profilaktycznych i interwencyjnych istotne znaczenie ma ksztaltowanie indywidualnych czynnikow chroniacych mlodziez przed negatywnym wplywem srodowiska sasiedzkiego, poprawa dostepnosci do zasobow materialnych oraz wzmacnianie kapitalu spolecznego mlodych ludzi. PMID- 21666749 TI - Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer. AB - BACKGROUND: Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes-WHSC1L1, LETM2, and FGFR1-is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition. CONCLUSIONS/SIGNIFICANCE: These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer. PMID- 21666750 TI - Omega-3 fatty acids from fish oil lower anxiety, improve cognitive functions and reduce spontaneous locomotor activity in a non-human primate. AB - Omega-3 (omega3) polyunsaturated fatty acids (PUFA) are major components of brain cells membranes. omega3 PUFA-deficient rodents exhibit severe cognitive impairments (learning, memory) that have been linked to alteration of brain glucose utilization or to changes in neurotransmission processes. omega3 PUFA supplementation has been shown to lower anxiety and to improve several cognitive parameters in rodents, while very few data are available in primates. In humans, little is known about the association between anxiety and omega3 fatty acids supplementation and data are divergent about their impact on cognitive functions. Therefore, the development of nutritional studies in non-human primates is needed to disclose whether a long-term supplementation with long-chain omega3 PUFA has an impact on behavioural and cognitive parameters, differently or not from rodents. We address the hypothesis that omega3 PUFA supplementation could lower anxiety and improve cognitive performances of the Grey Mouse Lemur (Microcebus murinus), a nocturnal Malagasy prosimian primate. Adult male mouse lemurs were fed for 5 months on a control diet or on a diet supplemented with long-chain omega3 PUFA (n = 6 per group). Behavioural, cognitive and motor performances were measured using an open field test to evaluate anxiety, a circular platform test to evaluate reference spatial memory, a spontaneous locomotor activity monitoring and a sensory-motor test. omega3-supplemented animals exhibited lower anxiety level compared to control animals, what was accompanied by better performances in a reference spatial memory task (80% of successful trials vs 35% in controls, p<0.05), while the spontaneous locomotor activity was reduced by 31% in omega3 supplemented animals (p<0.001), a parameter that can be linked with lowered anxiety. The long-term dietary omega3 PUFA supplementation positively impacts on anxiety and cognitive performances in the adult mouse lemur. The supplementation of human food with omega3 fatty acids may represent a valuable dietary strategy to improve behavioural and cognitive functions. PMID- 21666752 TI - Qualitative and Mixed Methods Research in Cross-cultural Psychology: Introduction to the Special Issue. PMID- 21666753 TI - Impact of Social and Structural Influence Interventions on Condom Use and Sexually Transmitted Infections Among Establishment-Based Female Bar Workers in the Philippines. AB - This quasi-experimental study evaluated the influence of structural intervention components (e.g., changing organizational and social influence factors) in reducing biological sexually transmitted infections (STIs) and reports of unprotected sex among female bar workers (FBWs) in the Philippines (N = 369 at baseline). Recruited from four large southern Philippines cities, FBWs were exposed to a standard care, a manager influence, a peer influence, or a combined manager/peer influence condition. After the two-year intervention period, FBWs in the combined peer and manager intervention condition showed greater reductions in STIs and unprotected sex relative to those in the standard care condition. FBWs in the combined and the manager only conditions also showed a decrease in STIs compared to those in the standard care condition. Managers in the standard care condition reported lower positive condom attitudes and lower attendance at HIV/AIDS related training sessions compared to those in the combined condition. The combined effect of managers and peers had a positive, synergistic effect on condom use behavior and STI reduction compared to the standard care. This research provides empirical evidence that structural changes such as rules, regulations, and increased accessibility of condoms must be in combination with normative changes (individuals' attitudes, beliefs and normative expectancies) in order to achieve the greatest benefit in condom use behavior and STI reduction/prevention. PMID- 21666754 TI - Un-"ESCRT"-ed budding. AB - In their recent publication, Rossman et al. describe how the inherent budding capability of its M2 protein allows influenza A virus to bypass recruitment of the cellular ESCRT machinery enlisted by several other enveloped RNA and DNA viruses, including HIV, Ebola, rabies, herpes simplex type 1 and hepatitis B. Studies from the same laboratory and other laboratories indicate that budding of plasmid-derived virus-like particles can be mediated by the influenza virus hemagglutinin and neuraminidase proteins in the absence of M2. These events are also independent of canonical ESCRT components. Understanding how intrinsic properties of these influenza virus proteins permit ESCRT-independent budding expands our understanding of the budding process itself. PMID- 21666755 TI - Left Ventricular Vortex Under Mitral Valve Edge-to-Edge Repair. AB - Mitral valve (MV) edge-to-edge repair (ETER) changes MV geometry by approximation of MV leaflets, and impacts left ventricle (LV) filling fluid mechanics. The purpose of this study was to investigate LV vortex with MV ETER during diastole. A computational MV-LV model was developed with MV ETER at the central free edges of the anterior and posterior leaflets. It was supposed that LV would elongate apically during diastole. The elongation deformation was controlled by the intraventricular flow rate. MV leaflets were modeled as a semi-prolate sphere with two symmetrical circular orifices and fixed at the maximum valve opening. MV chordae were neglected. FLUENT was used to simulate blood flow through the MV and in the LV. MV ETER generated two jets deflected laterally toward the LV wall in rapid LV filling. The jets impinged the LV wall obliquely and moved apically along the LV wall. Jet energy was primarily lost near the impingement. The jet from each MV orifice was surrounded by a vortex ring. The two vortex rings dissipated at the end of diastole. The total energy loss increased inversely with the MV orifice area. The atrio-ventricular pressure gradient was adverse near the end of diastole and possibly in diastasis. Reduction of the total orifice area led to more increment in the transmitral pressure drop than in the transmitral velocity. In conclusion, during diastole, two deflected jets from the MV under ETER impinged the LV wall. Major energy loss occurred around the jet impingement. Two vortex rings dissipated at the end of diastole with little storage of inflow energy for blood ejection in the following process of systole. MV ETER increased energy loss and lowered LV filling efficiency. The maintaining of a larger orifice area after ETER might not significantly increase energy loss in the LV during diastole and the transmitral pressure drop. The adverse pressure gradient from the atrium to the LV might be the mechanism of MV closure in the late diastole. PMID- 21666756 TI - Neurologic Manifestations of Leishmania spp. Infection. AB - When listing common clinical signs of the spectra of Leishmania-derived diseases, neurologic malfunctions are not commonly included. Despite this, there are multiple reported instances both in human and veterinary medicine where neurologic manifestations, whether central or peripheral, are described. In this review, we describe neurologic manifestations seen during infection with Leishmania spp. with some discussion of the implicit effect of inflammation on the blood brain barrier in both medical and veterinary cases. Taken together, the material discussed here suggests that in patients from Leishmania-endemic areas, when observing neurologic symptoms, causation secondary to infection with Leishmania spp. should be highly considered. PMID- 21666758 TI - Gold Nanopyramids Assembled into High-Order Stacks Exhibit Increased SERS Response. AB - This Letter describes how gold pyramidal nanoshells (nanopyramids) can be assembled into low- and high-order structures by varying the rate of solvent evaporation and surface wettability. Single-particle and individual-cluster dark field scattering spectra on isolated, dimers and trimers of nanopyramids were compared. We found that the short wavelength resonances blue-shifted as the particles assembled; the magnitude of this shift was greater for high-order structures. To test which assembled architecture supported a larger Raman-active volume, we compared their surface enhanced Raman scattering (SERS) response of the resonant Raman molecule methylene blue (lambda(ex) = 633 nm). We discovered that high-order structures exhibited more Raman scattering compared to low-order assemblies. Finite-difference time-domain modeling of nanopyramid assemblies revealed that the highest electromagnetic field intensities were localized between adjacent particle faces, a result that was consistent with the SERS observations. Thus, the local spatial arrangement of the same number of nanoparticles in assembled clusters is an important design parameter for optimizing nanoparticle-based SERS sensors. PMID- 21666759 TI - RACE, CODE OF THE STREET, AND VIOLENT DELINQUENCY: A MULTILEVEL INVESTIGATION OF NEIGHBORHOOD STREET CULTURE AND INDIVIDUAL NORMS OF VIOLENCE. AB - The study outlined in this article drew on Elijah Anderson's (1999) code of the street perspective to examine the impact of neighborhood street culture on violent delinquency. Using data from more than 700 African American adolescents, we examined 1) whether neighborhood street culture predicts adolescent violence above and beyond an adolescent's own street code values and 2) whether neighborhood street culture moderates individual-level street code values on adolescent violence. Consistent with Anderson's hypotheses, neighborhood street culture significantly predicts violent delinquency independent of individual level street code effects. Additionally, neighborhood street culture moderates individual-level street code values on violence in neighborhoods where the street culture is widespread. In particular, the effect of street code values on violence is enhanced in neighborhoods where the street culture is endorsed widely. PMID- 21666757 TI - Regulation of Ryanodine Receptor Ion Channels Through Posttranslational Modifications. PMID- 21666760 TI - Individual Differences in Effectiveness of Cochlear Implants in Children Who Are Prelingually Deaf: New Process Measures of Performance. AB - The efficacy of cochlear implants in children who are deaf has been firmly established in the literature. However, the effectiveness of cochlear implants varies widely and is influenced by demographic and experiential factors. Several key findings suggest new directions for research on central auditory factors that underlie the effectiveness of cochlear implants. First, enormous individual differences have been observed in both adults and children on a wide range of audiological outcome measures. Some patients show large increases in speech perception scores after implantation, whereas others display only modest gains on standardized tests. Second, age of implantation and length of deafness affect all outcome measures. Children implanted at younger ages do better than children implanted at older ages, and children who have been deaf for shorter periods do better than children who have been deaf for longer periods. Third, communication mode affects outcome measures. Children from "oral-only" environments do much better on standardized tests that assess phonological processing skills than children who use Total Communication. Fourth, at the present time there are no preimplant predictors of outcome performance in young children. The underlying perceptual, cognitive, and linguistic abilities and skills emerge after implantation and improve over time. Finally, there are no significant differences in audiological outcome measures among current implant devices or processing strategies. This finding suggests that the major source of variance in outcome measures lies in the neural and cognitive information processing operations that the user applies to the signal provided by the implant. Taken together, this overall pattern of results suggests that higher-level central processes such as perception, attention, learning, and memory may play important roles in explaining the large individual differences observed among users of cochlear implants. Investigations of the content and flow of information in the central nervous system and interactions between sensory input and stored knowledge may provide important new insights into the basis of individual differences. Knowledge about the underlying basis of individual differences may also help in developing new intervention strategies to improve the effectiveness of cochlear implants in children who show relatively poor development of oral/aural language skills. PMID- 21666761 TI - ADOLESCENTS' EXPOSURE TO COMMUNITY VIOLENCE: ARE NEIGHBORHOOD YOUTH ORGANIZATIONS PROTECTIVE? AB - Using data from the Project on Human Development in Chicago Neighborhoods (PHDCN), we identified a significant inverse association between the variety of youth organizations available at the neighborhood level and adolescents' exposure to community violence. We examined two non-competing explanations for this finding. First, at the individual level, we tested the hypothesis that access to a greater variety of neighborhood youth organizations predicts adolescents' participation in organized community-based activities, which, in turn, protects against community violence exposure. Second, at the neighborhood level, we tested the hypothesis that lower violent crime rates explain the inverse relation between neighborhood youth organization variety and community violence exposure. Our findings supported the latter of these two mechanisms. PMID- 21666762 TI - Inhaled Corticosteroids Adverse Events In Asthmatic Children: A Review. AB - BACKGROUND: Inhaled corticosteroids (ICS) have an important role in the treatment of chronic asthma in children. The prevalence of asthma symptoms in children varies from 0 to 30 percent in different populations with the highest prevalence occurring in Australia, New Zealand and England. METHODS: A review of the literature and studies about inhaled corticosteroids safety, action and adverse events in children and adults where applicable was done. CONCLUSION: Inhaled corticosteroids are the main stay therapy for persistent asthma in children. Their safety and efficacy is proven from the literature. Proper education of the parents about asthma and inhaled corticosteroids is very important and improve asthma control. Keeping in mind to taper the inhaled corticosteroids to the lowest dose needed to control asthma and using correct inhalation technique by the use of spacers with metered dose inhalers or dry powder inhalers (Turbuhaler and Diskus) will prevent the occurrence of adverse events. PMID- 21666763 TI - Non word Repetition and Reading Skills in Children Who Are Deaf and Have Cochlear Implants. AB - Reading skills in hearing children are closely related to their phonological processing skills, often measured using a nonword repetition task in which a child relies on abstract phonological representations in order to decompose, encode, rehearse in working memory and reproduce novel phonological patterns. In the present study of children who are deaf and have cochlear implants, we found that nonword repetition performance was significantly related to nonword reading, single word reading and sentence comprehension. Communication mode and nonverbal IQ were also found to be correlated with nonword repetition and reading skills. A measure of the children's lexical diversity, derived from an oral language sample, was found to be a mediating factor in the relationship between nonword repetition and reading skills. Taken together, the present findings suggest that the construction of robust phonological representations and phonological processing skills may be important contributors to the development of reading in children who are deaf and use cochlear implants. PMID- 21666764 TI - A Single-Center Review of Prescribing Trends and Outcomes of Corticosteroid Replacement Therapy in Critically Ill Children with Septic Shock. AB - Recently published consensus treatment guidelines for pediatric sepsis recommend initiating corticosteroid replacement therapy (CRT) for those critically ill children with adrenal insufficiency and refractory shock. The data to support this recommendation is limited, and multiple studies have demonstrated significant variation in both the diagnosis and treatment of adrenal insufficiency and refractory shock in children. In order to better define the variation in practice at our institution, we retrospectively reviewed the experience with CRT in critically ill children with refractory septic shock over a 1-year-period. In addition, as a secondary aim we compared outcomes in critically ill children treated with CRT for variable lengths of time. We found that the initiation of CRT at our center is relatively consistent. However, we noted significant variation in the duration of CRT and whether CRT was gradually tapered or stopped abruptly. The majority of the patients in our cohort received less than the currently recommended duration of 7 days of CRT. There were a higher number of treatment failures in those patients who received CRT for greater than 7 days, suggesting that CRT should be tapered gradually in these patients. There is significant variation in prescribing trends for CRT at our institution, which are likely to be compounded in any multi-center cohort study of CRT in critically ill children with septic shock. Practice variation in CRT should be standardized to address the impact of CRT in this population. PMID- 21666765 TI - Working Memory Spans as Predictors of Spoken Word Recognition and Receptive Vocabulary in Children with Cochlear Implants. AB - The present study investigated whether individual differences in working memory could account for a significant proportion of the variance in the open-set word recognition and receptive vocabulary skills of prelingually deafened, pediatric cochlear implant recipients, after the contribution of known predictors was taken into account. The contributions of four measures of working memory were examined separately for children using oral communication (OC) (n = 32) and Total Communication (TC) (n = 29). Wechsler Intelligence Scale for Children-Third Edition (WISC) digit-spans, requiring immediate recall of auditory-only lists in both forwards and backwards directions were, collected. Two versions of a novel "memory span game" were also administered: One required memory for sequences of colored lights; the other assessed memory for colored lights presented in conjunction with auditory color-names. A contribution from working memory was observed only for the span tasks that incorporated an auditory processing component. These results suggest a relationship between working memory and the examined outcome measures that is specific to the auditory modality, partially linked to communication mode, and not related to individual differences in a general-purpose component of working memory. PMID- 21666767 TI - Activation of Multiple Molecular Mechanisms for Increasing Apoptosis in Human Glioblastoma T98G Xenograft. AB - Glioblastoma is the most malignant brain tumor of astroglial origin. It renders poor response or resistance to existing therapeutics. We used all-trans retinoic acid (ATRA) and interferon gamma (IFN-gamma) alone and in combination for controlling human glioblastoma T98G xenografted in nude mice. Histopathological examination showed astrocytic differentiation in ATRA group, some apoptosis in IFN-gamma group, and occurrence of differentiation and enhancement of apoptosis in ATRA plus IFN-gamma group. ATRA plus IFN-gamma induced extrinsic pathway of apoptosis by activation of caspase-8 and cleavage of Bid to tBid and also down regulation of hTERT, c-IAP2, and survivin and upregulation of Smac/Diablo to promote apoptosis. Mitochondrial release of apoptosis-inducing factor (AIF) induced caspase-independent pathway and also upregulation of calpain and caspase dependent pathways ultimately activated caspase-3 for apoptosis. Increased activities of calpain and caspase-3 degraded 270 kD alpha-spectrin at the specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. In situ TUNEL and double immunofluorescent labelings detected apoptosis with increased expression of calpain, caspase-12, caspase-3, and AIF in tumors after treatment with IFN-gamma and most effectively with ATRA plus IFN gamma. Results indicated that ATRA plus IFN-gamma activated multiple molecular mechanisms for increasing apoptosis in human glioblastoma in vivo. PMID- 21666768 TI - Seeing Eye to Eye: Predicting Teacher-Student Agreement on Classroom Social Networks. AB - This study examines the association between classroom characteristics and teacher student agreement in perceptions of students' classroom peer networks. Social network, peer nomination, and observational data were collected from a sample of second through fourth grade teachers (N=33) and students (N=669) in 33 classrooms across five high poverty urban schools. Results demonstrate that variation in teacher-student agreement on the structure of students' peer networks can be explained, in part, by developmental factors and classroom characteristics. Developmental increases in network density partially mediated the positive relationship between grade level and teacher-student agreement. Larger class sizes and higher levels of normative aggressive behavior resulted in lower levels of teacher-student agreement. Teachers' levels of classroom organization had mixed influences, with behavior management negatively predicting agreement, and productivity positively predicting agreement. These results underscore the importance of the classroom context in shaping teacher and student perceptions of peer networks. PMID- 21666766 TI - The pathogenesis of Rift Valley fever. AB - Rift Valley fever (RVF) is an emerging zoonotic disease distributed in sub Saharan African countries and the Arabian Peninsula. The disease is caused by the Rift Valley fever virus (RVFV) of the family Bunyaviridae and the genus Phlebovirus. The virus is transmitted by mosquitoes, and virus replication in domestic ruminant results in high rates of mortality and abortion. RVFV infection in humans usually causes a self-limiting, acute and febrile illness; however, a small number of cases progress to neurological disorders, partial or complete blindness, hemorrhagic fever, or thrombosis. This review describes the pathology of RVF in human patients and several animal models, and summarizes the role of viral virulence factors and host factors that affect RVFV pathogenesis. PMID- 21666769 TI - Visible Light Photocatalysis of Radical Anion Hetero-Diels-Alder Cycloadditions. AB - We have discovered a photocatalytic intramolecular hetero-Diels-Alder reaction of tethered bis(enones). This transformation involves the intermediacy of an enone radical anion and constitutes the formal coupling of an electron-deficient heterodiene with an electronically mismatched enone dienophile. The diastereoselectivity and regioselectivity of the process are high, and the dihydropyran products are amenable to a variety of synthetically useful transformations. PMID- 21666770 TI - Trichomes + roots + ROS = artemisinin: regulating artemisinin biosynthesis in Artemisia annua L. AB - Artemisinin is a highly effective sesquiterpene lactone therapeutic produced in the plant, Artemisia annua. Despite its efficacy against malaria and many other infectious diseases and neoplasms, the drug is in short supply mainly because the plant produces low levels of the compound. This review updates the current understanding of artemisinin biosynthesis with a special focus on the emerging knowledge of how biosynthesis of the compound is regulated in planta. PMID- 21666771 TI - Is cooperation viable in mobile organisms? Simple Walk Away rule favors the evolution of cooperation in groups. AB - The evolution of cooperation through partner choice mechanisms is often thought to involve relatively complex cognitive abilities. Using agent-based simulations I model a simple partner choice rule, the 'Walk Away' rule, where individuals stay in groups that provide higher returns (by virtue of having more cooperators), and 'Walk Away' from groups providing low returns. Implementing this conditional movement rule in a public goods game leads to a number of interesting findings: 1) cooperators have a selective advantage when thresholds are high, corresponding to low tolerance for defectors, 2) high thresholds lead to high initial rates of movement and low final rates of movement (after selection), and 3) as cooperation is selected, the population undergoes a spatial transition from high migration (and a many small and ephemeral groups) to low migration (and large and stable groups). These results suggest that the very simple 'Walk Away' rule of leaving uncooperative groups can favor the evolution of cooperation, and that cooperation can evolve in populations in which individuals are able to move in response to local social conditions. A diverse array of organisms are able to leave degraded physical or social environments. The ubiquitous nature of conditional movement suggests that 'Walk Away' dynamics may play an important role in the evolution of social behavior in both cognitively complex and cognitively simple organisms. PMID- 21666772 TI - Design and Synthesis of a Fluorescently End-Labeled Poly(beta-amino ester): Application to the Characterization of Degradable Polyelectrolyte Multilayers. AB - We report the synthesis of a fluorescently end-labeled analog of a synthetic and degradable cationic poly(beta-amino ester) (PBAE; polymer 1) used in past studies for the delivery of DNA and the layer-by-layer assembly of erodible polyelectrolyte multilayers (PEMs). The synthesis of an analog of polymer 1 having acrylate functionalized end groups provided a platform for the introduction of fluorescent labels by post-polymerization conjugate addition of amine-functionalized fluorophores. This approach enabled the synthesis of fluorescently end-labeled polymer (polymer 1(FL)) with molecular weights and polydispersities (M(n) = 18,000; PDI ~1.8) similar to those used in past studies for the fabrication of PEMs using polymer 1. Layer-by-layer assembly of PEMs using polymer 1(FL) and poly(styrene sulfonate) enabled characterization of film erosion and, for the first time, direct observation of the release of cationic polymer from these assemblies using fluorescence microscopy and fluorometry. Our results shed new light on the behaviors of the cationic components of these PEMs and could prove useful for the design of thin films for a range of different controlled release applications. Our results also provide new fluorescent cationic polymer probes that could be useful for characterization of the behaviors of PBAEs in other fundamental or applied biotechnological contexts. PMID- 21666773 TI - Network Sampling and Classification:An Investigation of Network Model Representations. AB - Methods for generating a random sample of networks with desired properties are important tools for the analysis of social, biological, and information networks. Algorithm-based approaches to sampling networks have received a great deal of attention in recent literature. Most of these algorithms are based on simple intuitions that associate the full features of connectivity patterns with specific values of only one or two network metrics. Substantive conclusions are crucially dependent on this association holding true. However, the extent to which this simple intuition holds true is not yet known. In this paper, we examine the association between the connectivity patterns that a network sampling algorithm aims to generate and the connectivity patterns of the generated networks, measured by an existing set of popular network metrics. We find that different network sampling algorithms can yield networks with similar connectivity patterns. We also find that the alternative algorithms for the same connectivity pattern can yield networks with different connectivity patterns. We argue that conclusions based on simulated network studies must focus on the full features of the connectivity patterns of a network instead of on the limited set of network metrics for a specific network type. This fact has important implications for network data analysis: for instance, implications related to the way significance is currently assessed. PMID- 21666774 TI - MicroRNA control of ovarian function. AB - Post-transcriptional gene regulation, a regulatory mechanism classically involved in female and male germ cell function has recently been implicated in control of somatic cells of the ovary and testis. Recent advancements in this field may be attributed primarily to the discovery and study of microRNAs (miRNA), small RNA transcripts that can influence mRNA expression via post-transcriptional gene regulatory mechanisms. In the ovary, targeted deletion of Dicer 1, a key enzyme in miRNA biogenesis, provided the first empirical evidence that miRNA/siRNA were critically involved in multiple aspects of ovarian function (folliculogenesis, oocyte maturation, ovulation, and luteal function). Functional studies of miRNA in the ovary have mostly focused on granulosa cells during the critical period of the ovarian cycle surrounding the ovulatory surge of luteinizing hormone (LH). Specific miRNA have been implicated in ovarian responses, due to their transcriptional induction by the LH surge (i.e., miR-21, -132 and -212) or through bioinformatic approaches (miR-224, -17-5p and let-7b). Numerous other miRNA are highly abundant in ovarian somatic tissues, suggesting that we have much to discover with respect to the role of miRNA and regulation of ovarian function. This review will recap the key observations of these early studies and provide insight into future experiments that might further our understanding of ovarian function. PMID- 21666775 TI - 7.5% saline and 7.5% saline/6% dextran for hypovolemic shock. PMID- 21666776 TI - Half-sandwich ruthenium-arene complexes with thiosemicarbazones: synthesis and biological evaluation of [(eta6-p-cymene)Ru(piperonal thiosemicarbazones)Cl]Cl complexes. AB - The synthesis and characterization of a number of organometallic ruthenium(II) complexes containing a series of bidentate thiosemicarbazone ligands derived from piperonal is reported. The structure of compounds have been confirmed by spectroscopic analysis (IR and NMR) as well as X-ray crystallographic analysis of [(eta6-p-cymene)Ru(pPhTSC)Cl]Cl (4) (pPhTSC is piperonal-N(4) phenylthiosemicarbazone). The interaction of the complexes ([(eta6-p cymene)Ru(pEtTSC)Cl]Cl) (3) (pEtTSC is piperonal-N(4)-ethylthiosemicarbazone) and 4 with calf thymus DNA, human serum albumin (HSA) and pBR322 plasmid DNA were studied by spectroscopic, gel electrophoresis and hydrodynamic methods. The apparent binding constant for the interaction with DNA was determined to be 3.97*103 M-1 and 4.07*103 M-1 at 293 K for 3 and 4 respectively. The complexes bind strongly to HSA with binding constants of 2.94*104 M-1 and 12.2*104 M-1 at 296 K for 3 and 4 respectively. The in vitro anticancer activity of 3 and 4 has been evaluated against two human colon cancer cell line (HCT-116 and Caco-2) with IC50 values in the range of 26-150 MUM. Both 3 and 4 show good activity as a catalytic inhibitor of human topoisomerase II at concentrations as low as 20 MUM. The proficiency of 3 and 4 to act as antibacterial agents was also evaluated against six pathogenic bacterial strains with the best activity seen against Gram positive strains. PMID- 21666777 TI - Do cancer proteins really interact strongly in the human protein-protein interaction network? AB - Protein-protein interaction (PPI) network analysis has been widely applied in the investigation of the mechanisms of diseases, especially cancer. Recent studies revealed that cancer proteins tend to interact more strongly than other categories of proteins, even essential proteins, in the human interactome. However, it remains unclear whether this observation was introduced by the bias towards more cancer studies in humans. Here, we examined this important issue by uniquely comparing network characteristics of cancer proteins with three other sets of proteins in four organisms, three of which (fly, worm, and yeast) whose interactomes are essentially not biased towards cancer or other diseases. We confirmed that cancer proteins had stronger connectivity, shorter distance, and larger betweenness centrality than non-cancer disease proteins, essential proteins, and control proteins. Our statistical evaluation indicated that such observations were overall unlikely attributed to random events. Considering the large size and high quality of the PPI data in the four organisms, the conclusion that cancer proteins interact strongly in the PPI networks is reliable and robust. This conclusion suggests that perturbation of cancer proteins might cause major changes of cellular systems and result in abnormal cell function leading to cancer. PMID- 21666778 TI - Gene expression analysis of amniotic fluid: new biomarkers and novel antenatal treatments. PMID- 21666779 TI - Clinical Implications for Muscle Strength Differences in Women of Different Age and Racial Groups: The WIN Study. AB - BACKGROUND: Reduction in muscle strength is strongly associated with functional decline in women, and women with lower quadriceps strength adjusted for body weight are more likely to develop knee osteoarthritis. OBJECTIVE: To compare body weight--adjusted strength among women of different age/racial groups. STUDY DESIGN: Cross-sectional study of muscle strength in 918 women aged 20--83 (M +/- SD = 52 +/- 13). METHODS: An orthopedic examination was conducted including measurement of handgrip and lower extremity strength (hip abductors/external rotators, knee flexors/extensors). Data were grouped into young (20--39 years, n = 139), middle (40--54 years, n = 300), and older (55+ years, n = 424) ages for white (n = 699) and African American (AA) (n = 164) women. Means and standard deviations for strength adjusted for body weight were calculated for each age and racial group and compared using 2-way multivariate analysis of variance and post hoc tests. RESULTS: No significant age-by-race interaction (P = .092) but significant main effects for age and race (P < .001). Pairwise comparisons revealed significant differences in knee extensor and flexor strength between all age groups. For grip and hip external rotator strength, significant differences were found between the middle and older groups. Differences in hip abductor strength were found between the young and middle-aged groups. AA women had lower strength than white women in all muscle groups (P < .05) except hip external rotators. CONCLUSIONS: Strength decreased with age in all muscle groups but magnitude of decrease varied by muscle. Strengthening programs should target different muscles, depending on a woman's age and race. PMID- 21666780 TI - Sensitivity Comparison of Surface Plasmon Resonance and Plasmon-Waveguide Resonance Biosensors. AB - Plasmon-waveguide resonance (PWR) sensors are particularly useful for investigation of biomolecular interactions with or within lipid bilayer membranes. Many studies demonstrated their ability to provide unique qualitative information, but the evaluation of their sensitivity as compared to other surface plasmon resonance (SPR) sensors has not been broadly investigated. We report here a comprehensive sensitivity comparison of SPR and PWR biosensors for the p polarized light component. The sensitivity of five different biosensor designs to changes in refractive index, thickness and mass are determined and discussed. Although numerical simulations show an increase of the electric field intensity by 30-35 % and the penetration depth by four times in PWR, the waveguide-based method is 0.5 to 8 fold less sensitive than conventional SPR in all considered analytical parameters. The experimental results also suggest that the increase in the penetration depth in PWR is made at the expense of the surface sensitivity. The physical and structural reasons for PWR sensor limitations are discussed and a general viewpoint for designing more efficient SPR sensors based on dielectric slab waveguides is provided. PMID- 21666782 TI - Differences in Professional and Informal Help Seeking among Older African Americans, Black Caribbeans and Non-Hispanic Whites. AB - This study uses a national probability sample of older adults to examine racial and ethnic differences in the use of professional services and informal support for a stressful personal problem. Using data from the National Survey of American Life, this study focuses on African Americans, Black Caribbean immigrants, and Whites aged 55 years and older who experienced a personal problem that caused them significant distress (n=862). Multinomial logistic regression is used to estimate the association of race with the use of professional services only, informal support only, both professional services and informal support, or no help at all, while controlling for demographic and socioeconomic variables, characteristics of the informal support network, the type of problem experienced, and experiences of racial discrimination. Examining the use of professional services and informal support provides a more complete picture of racial and ethnic differences of help-seeking behaviors among older adults, and the factors associated with the sources from which these adults request help. Most respondents use informal support alone or in combination with professional services. Black Caribbeans are more likely than African Americans to rely on informal support only, whereas African Americans are more likely than Whites to not receive help. However, these findings are accounted for by differences in social support and experiences of discrimination. PMID- 21666783 TI - Tri-Axial MRI Compatible Fiber-optic Force Sensor. AB - Magnetic resonance imaging (MRI) has been gaining popularity over standard imaging modalities like ultrasound and CT because of its ability to provide excellent soft-tissue contrast. However, due to the working principle of MRI, a number of conventional force sensors are not compatible. One popular solution is to develop a fiber-optic force sensor. However, the measurements along the principal axes of a number of these force sensors are highly cross-coupled. One of the objectives of this paper is to minimize this coupling effect. In addition, this paper describes the design of elastic frame structures that are obtained systematically using topology optimization techniques for maximizing sensor resolution and sensor bandwidth. Through the topology optimization approach, we ensure that the frames are linked from the input to output. The elastic frame structures are then fabricated using polymers materials, such as ABS and Delrin((r)), as they are ideal materials for use in MRI environment. However, the hysteresis effect seen in the displacement-load graph of plastic materials is known to affect the accuracy. Hence, this paper also proposes modeling and addressing this hysteretic effect using Prandtl-Ishlinskii play operators. Finally, experiments are conducted to evaluate the sensor's performance, as well as its compatibility in MRI under continuous imaging. PMID- 21666784 TI - Migration and "low-skilled" workers in destination countries. PMID- 21666781 TI - Regulation of appetite to treat obesity. AB - Obesity has escalated into a pandemic over the past few decades. In turn, research efforts have sought to elucidate the molecular mechanisms underlying the regulation of energy balance. A host of endogenous mediators regulate appetite and metabolism, and thereby control both short- and long-term energy balance. These mediators, which include gut, pancreatic and adipose neuropeptides, have been targeted in the development of anti-obesity pharmacotherapy, with the goal of amplifying anorexigenic and lipolytic signaling or blocking orexigenic and lipogenic signaling. This article presents the efficacy and safety of these anti obesity drugs. PMID- 21666785 TI - Coma associated with microscopy-diagnosed Plasmodium vivax: a prospective study in Papua, Indonesia. AB - BACKGROUND: Coma complicates Plasmodium falciparum infection but is uncommonly associated with P. vivax. Most series of vivax coma have been retrospective and have not utilized molecular methods to exclude mixed infections with P. falciparum. METHODS: We prospectively enrolled patients hospitalized in Timika, Indonesia, with a Glasgow Coma Score (GCS) <=10 and P. vivax monoinfection on initial microscopy over a four year period. Hematological, biochemical, serological, radiological and cerebrospinal fluid (CSF) examinations were performed to identify other causes of coma. Repeat microscopy, antigen detection and polymerase chain reaction (PCR) were performed to exclude infections with other Plasmodium species. RESULTS: Of 24 patients fulfilling enrolment criteria, 5 had clear evidence for other non-malarial etiologies. PCR demonstrated 10 mixed infections and 3 P. falciparum monoinfections. 6 (25%) patients had vivax monoinfection and no apparent alternative cause, with a median GCS of 9 (range 8 10) and a median coma duration of 42 (range 36-48) hours. CSF leukocyte counts were <10/ul (n=3); 2 of the 3 patients without CSF examination recovered with antimalarial therapy alone. One patient had a tremor on discharge consistent with a post-malarial neurological syndrome. No patient had other organ dysfunction. The only death was associated with pure P. falciparum infection by PCR. Vivax monoinfection-associated risk of coma was estimated at 1 in 29,486 clinical vivax infections with no deaths. In comparison, the risk of falciparum-associated coma was estimated at 1 in 1,276 clinical infections with an 18.5% mortality rate. CONCLUSIONS: P. vivax-associated coma is rare, occurring 23 times less frequently than that seen with falciparum malaria, and is associated with a high proportion of non-malarial causes and mixed infections using PCR. The pathogenesis of coma associated with vivax malaria, particularly the role of comorbidities, is uncertain and requires further investigation. PMID- 21666786 TI - Predictors of visceral leishmaniasis relapse in HIV-infected patients: a systematic review. AB - BACKGROUND AND OBJECTIVES: Visceral leishmaniasis (VL) is a common complication in AIDS patients living in Leishmania-endemic areas. Although antiretroviral therapy has changed the clinical course of HIV infection and its associated illnesses, the prevention of VL relapses remains a challenge for the care of HIV and Leishmania co-infected patients. This work is a systematic review of previous studies that have described predictors of VL relapse in HIV-infected patients. REVIEW METHODS: We searched the electronic databases of MEDLINE, LILACS, and the Cochrane Central Register of Controlled Trials. Studies were selected if they included HIV-infected individuals with a VL diagnosis and patient follow-up after the leishmaniasis treatment with an analysis of the clearly defined outcome of prediction of relapse. RESULTS: Eighteen out 178 studies satisfied the specified inclusion criteria. Most patients were males between 30 and 40 years of age, and HIV transmission was primarily via intravenous drug use. Previous VL episodes were identified as risk factors for relapse in 3 studies. Two studies found that baseline CD4+ T cell count above 100 cells/mL was associated with a decreased relapse rate. The observation of an increase in CD4+ T cells at patient follow-up was associated with protection from relapse in 5 of 7 studies. Meta-analysis of all studies assessing secondary prophylaxis showed significant reduction of VL relapse rate following prophylaxis. None of the five observational studies evaluating the impact of highly active antiretroviral therapy use found a reduction in the risk of VL relapse upon patient follow-up. CONCLUSION: SOME PREDICTORS OF VL RELAPSE COULD BE IDENTIFIED: a) the absence of an increase in CD4+ cells at follow-up; b) lack of secondary prophylaxis; and c) previous history of VL relapse. CD4+ counts below 100 cells/mL at the time of primary VL diagnosis may also be a predictive factor for VL relapse. PMID- 21666788 TI - Effects of chronic ascariasis and trichuriasis on cytokine production and gene expression in human blood: a cross-sectional study. AB - BACKGROUND: Chronic soil-transmitted helminth (STH) infections are associated with effects on systemic immune responses that could be caused by alterations in immune homeostasis. To investigate this, we measured the impact in children of STH infections on cytokine responses and gene expression in unstimulated blood. METHODOLOGY/PRINCIPAL FINDINGS: Sixty children were classified as having chronic, light, or no STH infections. Peripheral blood mononuclear cells were cultured in medium for 5 days to measure cytokine accumulation. RNA was isolated from peripheral blood and gene expression analysed using microarrays. Different infection groups were compared for the purpose of analysis: STH infection (combined chronic and light vs. uninfected groups) and chronic STH infection (chronic vs. combined light and uninfected groups). The chronic STH infection effect was associated with elevated production of GM-CSF (P=0.007), IL-2 (P=0.03), IL-5 (P=0.01), and IL-10 (P=0.01). Data reduction suggested that chronic infections were primarily associated with an immune phenotype characterized by elevated IL-5 and IL-10, typical of a modified Th2-like response. Chronic STH infections were associated with the up-regulation of genes associated with immune homeostasis (IDO, P=0.03; CCL23, P=0.008, HRK, P=0.005), down-regulation of microRNA hsa-let-7d (P=0.01) and differential regulation of several genes associated with granulocyte-mediated inflammation (IL-8, down regulated, P=0.0002; RNASE2, up-regulated, P=0.009; RNASE3, up-regulated, p=0.03). CONCLUSIONS/SIGNIFICANCE: Chronic STH infections were associated with a cytokine response indicative of a modified Th2 response. There was evidence that STH infections were associated with a pattern of gene expression suggestive of the induction of homeostatic mechanisms, the differential expression of several inflammatory genes and the down-regulation of microRNA has-let-7d. Effects on immune homeostasis and the development of a modified Th2 immune response during chronic STH infections could explain the systemic immunologic effects that have been associated with these infections such as impaired immune responses to vaccines and the suppression of inflammatory diseases. PMID- 21666787 TI - Comparative microsatellite typing of new world leishmania infantum reveals low heterogeneity among populations and its recent old world origin. AB - Leishmania infantum (syn. L. chagasi) is the causative agent of visceral leishmaniasis (VL) in the New World (NW) with endemic regions extending from southern USA to northern Argentina. The two hypotheses about the origin of VL in the NW suggest (1) recent importation of L. infantum from the Old World (OW), or (2) an indigenous origin and a distinct taxonomic rank for the NW parasite. Multilocus microsatellite typing was applied in a survey of 98 L. infantum isolates from different NW foci. The microsatellite profiles obtained were compared to those of 308 L. infantum and 20 L. donovani strains from OW countries previously assigned to well-defined populations. Two main populations were identified for both NW and OW L. infantum. Most of the NW strains belonged to population 1, which corresponded to the OW MON-1 population. However, the NW population was much more homogeneous. A second, more heterogeneous, population comprised most Caribbean strains and corresponded to the OW non-MON-1 population. All Brazilian L. infantum strains belonged to population 1, although they represented 61% of the sample and originated from 9 states. Population analysis including the OW L. infantum populations indicated that the NW strains were more similar to MON-1 and non-MON-1 sub-populations of L. infantum from southwest Europe, than to any other OW sub-population. Moreover, similarity between NW and Southwest European L. infantum was higher than between OW L. infantum from distinct parts of the Mediterranean region, Middle East and Central Asia. No correlation was found between NW L. infantum genotypes and clinical picture or host background. This study represents the first continent-wide analysis of NW L. infantum population structure. It confirmed that the agent of VL in the NW is L. infantum and that the parasite has been recently imported multiple times to the NW from southwest Europe. PMID- 21666789 TI - Protection against diarrhea associated with Giardia intestinalis Is lost with multi-nutrient supplementation: a study in Tanzanian children. AB - BACKGROUND: Asymptomatic carriage of Giardia intestinalis is highly prevalent among children in developing countries, and evidence regarding its role as a diarrhea-causing agent in these settings is controversial. Impaired linear growth and cognition have been associated with giardiasis, presumably mediated by malabsorption of nutrients. In a prospective cohort study, we aim to compare diarrhea rates in pre-school children with and without Giardia infection. Because the study was conducted in the context of an intervention trial assessing the effects of multi-nutrients on morbidity, we also assessed how supplementation influenced the relationship between Giardia and diarrhoea rates, and to what extent Giardia modifies the intervention effect on nutritional status. METHODS AND FINDINGS: Data were collected in the context of a randomized placebo controlled efficacy trial with 2*2 factorial design assessing the effects of zinc and/or multi-micronutrients on morbidity (n=612; height-for-age z-score <-1.5 SD). Outcomes measures were episodes of diarrhea (any reported, or with >=3 stools in the last 24 h) and fever without localizing signs, as detected with health-facility based surveillance. Giardia was detected in stool by enzyme linked immunosorbent assay. Among children who did not receive multi-nutrients, asymptomatic Giardia infection at baseline was associated with a substantial reduction in the rate of diarrhea (HR 0.32; 0.15-0.66) and fever without localizing signs (HR 0.56; 0.36-0.87), whereas no such effect was observed among children who received multi-nutrients (p-values for interaction 0.03 for both outcomes). This interaction was independent of age, HAZ-scores and distance to the research dispensary. There was no evidence that Giardia modified the intervention effect on nutritional status. CONCLUSION: Although causality of the Giardia-associated reduction in morbidity cannot be established, multi-nutrient supplementation results in a loss of this protection and thus seems to influence the proliferation or virulence of Giardia or associated intestinal pathogens. PMID- 21666790 TI - Increased vascularity in cervicovaginal mucosa with Schistosoma haematobium infection. AB - BACKGROUND: Close to 800 million people in the world are at risk of schistosomiasis, 85 per cent of whom live in Africa. Recent studies have indicated that female genital schistosomiasis might increase the risk of human immunodeficiency virus (HIV) infection. The aim of this study is to quantify and analyse the characteristics of the vasculature surrounding Schistosoma haematobium ova in the female genital mucosa. METHODOLOGY/PRINCIPAL FINDINGS: Cervicovaginal biopsies with S. haematobium ova (n=20) and control biopsies (n=69) were stained with immunohistochemical blood vessel markers CD31 and von Willebrand Factor (vWF), which stain endothelial cells in capillary buds and established blood vessels respectively. Haematoxylin and eosin (HE) were applied for histopathological assessment. The tissue surrounding S. haematobium ova had a higher density of established blood vessels stained by vWF compared to healthy controls (p=0.017). Immunostain to CD31 identified significantly more granulation tissue surrounding viable compared to calcified ova (p=0.032), and a tendency to neovascularisation in the tissue surrounding viable ova compared to healthy cervical mucosa (p=0.052). CONCLUSIONS/SIGNIFICANCE: In this study female genital mucosa with S. haematobium ova was significantly more vascularised compared to healthy cervical tissue. Viable parasite ova were associated with granulation tissue rich in sprouting blood vessels. Although the findings of blood vessel proliferation in this study may be a step to better understand the implications of S. haematobium infection, further studies are needed to explore the biological, clinical and epidemiological features of female genital schistosomiasis and its possible influence on HIV susceptibility. PMID- 21666791 TI - Genetic control of resistance to Trypanosoma brucei brucei infection in mice. AB - BACKGROUND: Trypanosoma brucei brucei infects livestock, with severe effects in horses and dogs. Mouse strains differ greatly in susceptibility to this parasite. However, no genes controlling these differences were mapped. METHODS: We studied the genetic control of survival after T. b. brucei infection using recombinant congenic (RC) strains, which have a high mapping power. Each RC strain of BALB/c c-STS/A (CcS/Dem) series contains a different random subset of 12.5% genes from the parental "donor" strain STS/A and 87.5% genes from the "background" strain BALB/c. Although BALB/c and STS/A mice are similarly susceptible to T. b. brucei, the RC strain CcS-11 is more susceptible than either of them. We analyzed genetics of survival in T. b. brucei-infected F(2) hybrids between BALB/c and CcS 11. CcS-11 strain carries STS-derived segments on eight chromosomes. They were genotyped in the F(2) hybrid mice and their linkage with survival was tested by analysis of variance. RESULTS: We mapped four Tbbr (Trypanosoma brucei brucei response) loci that influence survival after T. b. brucei infection. Tbbr1 (chromosome 3) and Tbbr2 (chromosome 12) have effects on survival independent of inter-genic interactions (main effects). Tbbr3 (chromosome 7) influences survival in interaction with Tbbr4 (chromosome 19). Tbbr2 is located on a segment 2.15 Mb short that contains only 26 genes. CONCLUSION: This study presents the first identification of chromosomal loci controlling susceptibility to T. b. brucei infection. While mapping in F(2) hybrids of inbred strains usually has a precision of 40-80 Mb, in RC strains we mapped Tbbr2 to a 2.15 Mb segment containing only 26 genes, which will enable an effective search for the candidate gene. Definition of susceptibility genes will improve the understanding of pathways and genetic diversity underlying the disease and may result in new strategies to overcome the active subversion of the immune system by T. b. brucei. PMID- 21666792 TI - Serologic cross-reactivity of human IgM and IgG antibodies to five species of Ebola virus. AB - Five species of Ebola virus (EBOV) have been identified, with nucleotide differences of 30-45% between species. Four of these species have been shown to cause Ebola hemorrhagic fever (EHF) in humans and a fifth species (Reston ebolavirus) is capable of causing a similar disease in non-human primates. While examining potential serologic cross-reactivity between EBOV species is important for diagnostic assays as well as putative vaccines, the nature of cross-reactive antibodies following EBOV infection has not been thoroughly characterized. In order to examine cross-reactivity of human serologic responses to EBOV, we developed antigen preparations for all five EBOV species, and compared serologic responses by IgM capture and IgG enzyme-linked immunosorbent assay (ELISA) in groups of convalescent diagnostic sera from outbreaks in Kikwit, Democratic Republic of Congo (n=24), Gulu, Uganda (n=20), Bundibugyo, Uganda (n=33), and the Philippines (n=18), which represent outbreaks due to four different EBOV species. For groups of samples from Kikwit, Gulu, and Bundibugyo, some limited IgM cross reactivity was noted between heterologous sera-antigen pairs, however, IgM responses were largely stronger against autologous antigen. In some instances IgG responses were higher to autologous antigen than heterologous antigen, however, in contrast to IgM responses, we observed strong cross-reactive IgG antibody responses to heterologous antigens among all sets of samples. Finally, we examined autologous IgM and IgG antibody levels, relative to time following EHF onset, and observed early peaking and declining IgM antibody levels (by 80 days) and early development and persistence of IgG antibodies among all samples, implying a consistent pattern of antibody kinetics, regardless of EBOV species. Our findings demonstrate limited cross-reactivity of IgM antibodies to EBOV, however, the stronger tendency for cross-reactive IgG antibody responses can largely circumvent limitations in the utility of heterologous antigen for diagnostic assays and may assist in the development of antibody-mediated vaccines to EBOV. PMID- 21666793 TI - RNAi effector diversity in nematodes. AB - While RNA interference (RNAi) has been deployed to facilitate gene function studies in diverse helminths, parasitic nematodes appear variably susceptible. To test if this is due to inter-species differences in RNAi effector complements, we performed a primary sequence similarity survey for orthologs of 77 Caenorhabditis elegans RNAi pathway proteins in 13 nematode species for which genomic or transcriptomic datasets were available, with all outputs subjected to domain structure verification. Our dataset spanned transcriptomes of Ancylostoma caninum and Oesophagostomum dentatum, and genomes of Trichinella spiralis, Ascaris suum, Brugia malayi, Haemonchus contortus, Meloidogyne hapla, Meloidogyne incognita and Pristionchus pacificus, as well as the Caenorhabditis species C. brenneri, C. briggsae, C. japonica and C. remanei, and revealed that: (i) Most of the C. elegans proteins responsible for uptake and spread of exogenously applied double stranded (ds)RNA are absent from parasitic species, including RNAi-competent plant-nematodes; (ii) The Argonautes (AGOs) responsible for gene expression regulation in C. elegans are broadly conserved, unlike those recruited during the induction of RNAi by exogenous dsRNA; (iii) Secondary Argonautes (SAGOs) are poorly conserved, and the nuclear AGO NRDE-3 was not identified in any parasite; (iv) All five Caenorhabditis spp. possess an expanded RNAi effector repertoire relative to the parasitic nematodes, consistent with the propensity for gene loss in nematode parasites; (v) In spite of the quantitative differences in RNAi effector complements across nematode species, all displayed qualitatively similar coverage of functional protein groups. In summary, we could not identify RNAi effector deficiencies that associate with reduced susceptibility in parasitic nematodes. Indeed, similarities in the RNAi effector complements of RNAi refractory and competent nematode parasites support the broad applicability of this research genetic tool in nematodes. PMID- 21666794 TI - Differential expression of chemokine and matrix re-modelling genes is associated with contrasting schistosome-induced hepatopathology in murine models. AB - The pathological outcomes of schistosomiasis are largely dependent on the molecular and cellular mechanisms of the host immune response. In this study, we investigated the contribution of variations in host gene expression to the contrasting hepatic pathology observed between two inbred mouse strains following Schistosoma japonicum infection. Whole genome microarray analysis was employed in conjunction with histological and immunohistochemical analysis to define and compare the hepatic gene expression profiles and cellular composition associated with the hepatopathology observed in S. japonicum-infected BALB/c and CBA mice. We show that the transcriptional profiles differ significantly between the two mouse strains with high statistical confidence. We identified specific genes correlating with the more severe pathology associated with CBA mice, as well as genes which may confer the milder degree of pathology associated with BALB/c mice. In BALB/c mice, neutrophil genes exhibited striking increases in expression, which coincided with the significantly greater accumulation of neutrophils at granulomatous regions seen in histological sections of hepatic tissue. In contrast, up-regulated expression of the eosinophil chemokine CCL24 in CBA mice paralleled the cellular influx of eosinophils to the hepatic granulomas. Additionally, there was greater down-regulation of genes involved in metabolic processes in CBA mice, reflecting the more pronounced hepatic damage in these mice. Profibrotic genes showed similar levels of expression in both mouse strains, as did genes associated with Th1 and Th2 responses. However, imbalances in expression of matrix metalloproteinases (e.g. MMP12, MMP13) and tissue inhibitors of metalloproteinases (TIMP1) may contribute to the contrasting pathology observed in the two strains. Overall, these results provide a more complete picture of the molecular and cellular mechanisms which govern the pathological outcome of hepatic schistosomiasis. This improved understanding of the immunopathogenesis in the murine model schistosomiasis provides the basis for a better appreciation of the complexities associated with chronic human schistosomiasis. PMID- 21666795 TI - Burden of podoconiosis in poor rural communities in Gulliso woreda, West Ethiopia. AB - BACKGROUND: Podoconiosis is an environmental lymphoedema affecting people living and working barefoot on irritant red clay soil. Podoconiosis is relatively well described in southern Ethiopia, but remains neglected in other parts of the Ethiopian highlands. This study aimed to assess the burden of podoconiosis in rural communities in western Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: A cross sectional study was conducted in Gulliso woreda (district), west Ethiopia. A household survey in the 26 rural kebeles (villages) of this district was conducted to identify podoconiosis patients and to measure disease prevalence. A more detailed study was done in six randomly selected kebeles to describe clinical features of the disease, patients' experiences of foot hygiene, and shoe wearing practice. 1,935 cases of podoconiosis were registered, giving a prevalence of 2.8%. The prevalence was higher in those aged 15-64 years (5.2%) and in females than males (prevalence ratio 2.6?1). 90.3% of patients were in the 15-64 year age group. In the detailed study, 335 cases were interviewed and their feet assessed. The majority of patients were farmers, uneducated, and poor. Two third of patients developed the disease before the age of thirty. Almost all patients (97.0%) had experienced adenolymphangitis (ALA - red, hot legs, swollen and painful groin) at least once during the previous year. Patients experienced an average of 5.5 ALA episodes annually, each of average 4.4 days, thus 24 working days were lost annually. The incidence of ALA in podoconiosis patients was higher than that reported for filariasis in other countries. Shoe wearing was limited mainly due to financial problems. CONCLUSIONS: We have documented high podoconiosis prevalence, frequent adenolymphangitis and high disease-related morbidity in west Ethiopia. Interventions must be developed to prevent, treat and control podoconiosis, one of the core neglected tropical diseases in Ethiopia. PMID- 21666796 TI - A cross-sectional study of people with epilepsy and neurocysticercosis in Tanzania: clinical characteristics and diagnostic approaches. AB - Neurocysticercosis (NCC) is a major cause of epilepsy in regions where pigs are free-ranging and hygiene is poor. Pork production is expected to increase in the next decade in sub-Saharan Africa, hence NCC will likely become more prevalent. In this study, people with epilepsy (PWE, n=212) were followed up 28.6 months after diagnosis of epilepsy. CT scans were performed, and serum and cerebrospinal fluid (CSF) of selected PWE were analysed. We compared the demographic data, clinical characteristics, and associated risk factors of PWE with and without NCC. PWE with NCC (n=35) were more likely to be older at first seizure (24.3 vs. 16.3 years, p=0.097), consumed more pork (97.1% vs. 73.6%, p=0.001), and were more often a member of the Iraqw tribe (94.3% vs. 67.8%, p=0.005) than PWE without NCC (n=177). PWE and NCC who were compliant with anti-epileptic medications had a significantly higher reduction of seizures (98.6% vs. 89.2%, p=0.046). Other characteristics such as gender, seizure frequency, compliance, past medical history, close contact with pigs, use of latrines and family history of seizures did not differ significantly between the two groups. The number of NCC lesions and active NCC lesions were significantly associated with a positive antibody result. The electroimmunotransfer blot, developed by the Centers for Disease Control and Prevention, was more sensitive than a commercial western blot, especially in PWE and cerebral calcifications. This is the first study to systematically compare the clinical characteristics of PWE due to NCC or other causes and to explore the utility of two different antibody tests for diagnosis of NCC in sub-Saharan Africa. PMID- 21666797 TI - Polyandry is a common event in wild populations of the Tsetse fly Glossina fuscipes fuscipes and may impact population reduction measures. AB - BACKGROUND: Glossina fuscipes fuscipes is the main vector of human and animal trypanosomiasis in Africa, particularly in Uganda. Attempts to control/eradicate this species using biological methods require knowledge of its reproductive biology. An important aspect is the number of times a female mates in the wild as this influences the effective population size and may constitute a critical factor in determining the success of control methods. To date, polyandry in G.f. fuscipes has not been investigated in the laboratory or in the wild. Interest in assessing the presence of remating in Ugandan populations is driven by the fact that eradication of this species is at the planning stage in this country. METHODOLOGY/PRINCIPAL FINDINGS: Two well established populations, Kabukanga in the West and Buvuma Island in Lake Victoria, were sampled to assess the presence and frequency of female remating. Six informative microsatellite loci were used to estimate the number of matings per female by genotyping sperm preserved in the female spermathecae. The direct count of the minimum number of males that transferred sperm to the spermathecae was compared to Maximum Likelihood and Bayesian probability estimates. The three estimates provided evidence that remating is common in the populations but the frequency is substantially different: 57% in Kabukanga and 33% in Buvuma. CONCLUSIONS/SIGNIFICANCE: The presence of remating, with females maintaining sperm from different mates, may constitute a critical factor in cases of re-infestation of cleared areas and/or of residual populations. Remating may enhance the reproductive potential of re invading propagules in terms of their effective population size. We suggest that population age structure may influence remating frequency. Considering the seasonal demographic changes that this fly undergoes during the dry and wet seasons, control programmes based on SIT should release large numbers of sterile males, even in residual surviving target populations, in the dry season. PMID- 21666798 TI - Interferon-gamma and proliferation responses to Salmonella enterica Serotype Typhi proteins in patients with S. Typhi Bacteremia in Dhaka, Bangladesh. AB - BACKGROUND: Salmonella enterica serotype Typhi is a human-restricted intracellular pathogen and the cause of typhoid fever. Cellular immune responses are required to control and clear Salmonella infection. Despite this, there are limited data on cellular immune responses in humans infected with wild type S. Typhi. METHODOLOGY/PRINCIPAL FINDINGS: For this work, we used an automated approach to purify a subset of S. Typhi proteins identified in previous antibody based immuno-affinity screens and antigens known to be expressed in vivo, including StaF-putative fimbrial protein-STY0202, StbB-fimbrial chaperone STY0372, CsgF-involved in curli production-STY1177, CsgD- putative regulatory protein-STY1179, OppA-periplasmic oligopeptide binding protein precursor-STY1304, PagC-outer membrane invasion protein-STY1878, and conserved hypothetical protein STY2195; we also generated and analyzed a crude membrane preparation of S. Typhi (MP). In comparison to samples collected from uninfected Bangladeshi and North American participants, we detected significant interferon-gamma responses in PBMCs stimulated with MP, StaF, StbB, CsgF, CsgD, OppA, STY2195, and PagC in patients bacteremic with S. Typhi in Bangladesh. The majority of interferon-gamma expressing T cells were CD4 cells, although CD8 responses also occurred. We also assessed cellular proliferation responses in bacteremic patients, and confirmed increased responses in infected individuals to MP, StaF, STY2195, and PagC in convalescent compared to acute phase samples and compared to controls. StaF is a fimbrial protein homologous to E. coli YadK, and contains a Pfam motif thought to be involved in cellular adhesion. PagC is expressed in vivo under the control of the virulence-associated PhoP-regulon required for intra-macrophage survival of Salmonella. STY2195 is a conserved hypothetical protein of unknown function. CONCLUSION/SIGNIFICANCE: This is the first analysis of cellular immune responses to purified S. Typhi antigens in patients with typhoid fever. These results indicate that patients generate significant CD4 and CD8 interferon-gamma responses to specific S. Typhi antigens during typhoid fever, and that these responses are elevated at the time of clinical presentation. These observations suggest that an interferon-gamma based detection system could be used to diagnose individuals with typhoid fever during the acute stage of illness. PMID- 21666799 TI - Population genetics of Trypanosoma evansi from camel in the Sudan. AB - Genetic variation of microsatellite loci is a widely used method for the analysis of population genetic structure of microorganisms. We have investigated genetic variation at 15 microsatellite loci of T. evansi isolated from camels in Sudan and Kenya to evaluate the genetic information partitioned within and between individuals and between sites. We detected a strong signal of isolation by distance across the area sampled. The results also indicate that either, and as expected, T. evansi is purely clonal and structured in small units at very local scales and that there are numerous allelic dropouts in the data, or that this species often sexually recombines without the need of the "normal" definitive host, the tsetse fly or as the recurrent immigration from sexually recombined T. brucei brucei. Though the first hypothesis is the most likely, discriminating between these two incompatible hypotheses will require further studies at much localized scales. PMID- 21666800 TI - Mapping helminth co-infection and co-intensity: geostatistical prediction in ghana. AB - BACKGROUND: Morbidity due to Schistosoma haematobium and hookworm infections is marked in those with intense co-infections by these parasites. The development of a spatial predictive decision-support tool is crucial for targeting the delivery of integrated mass drug administration (MDA) to those most in need. We investigated the co-distribution of S. haematobium and hookworm infection, plus the spatial overlap of infection intensity of both parasites, in Ghana. The aim was to produce maps to assist the planning and evaluation of national parasitic disease control programs. METHODOLOGY/PRINCIPAL FINDINGS: A national cross sectional school-based parasitological survey was conducted in Ghana in 2008, using standardized sampling and parasitological methods. Bayesian geostatistical models were built, including a multinomial regression model for S. haematobium and hookworm mono- and co-infections and zero-inflated Poisson regression models for S. haematobium and hookworm infection intensity as measured by egg counts in urine and stool respectively. The resulting infection intensity maps were overlaid to determine the extent of geographical overlap of S. haematobium and hookworm infection intensity. In Ghana, prevalence of S. haematobium mono infection was 14.4%, hookworm mono-infection was 3.2%, and S. haematobium and hookworm co-infection was 0.7%. Distance to water bodies was negatively associated with S. haematobium and hookworm co-infections, hookworm mono infections and S. haematobium infection intensity. Land surface temperature was positively associated with hookworm mono-infections and S. haematobium infection intensity. While high-risk (prevalence >10-20%) of co-infection was predicted in an area around Lake Volta, co-intensity was predicted to be highest in foci within that area. CONCLUSIONS/SIGNIFICANCE: Our approach, based on the combination of co-infection and co-intensity maps allows the identification of communities at increased risk of severe morbidity and environmental contamination and provides a platform to evaluate progress of control efforts. PMID- 21666801 TI - Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans. AB - Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect. PMID- 21666803 TI - The mismeasure of science: Stephen Jay Gould versus Samuel George Morton on skulls and bias. PMID- 21666802 TI - Zyxin links fat signaling to the hippo pathway. AB - The Hippo signaling pathway has a conserved role in growth control and is of fundamental importance during both normal development and oncogenesis. Despite rapid progress in recent years, key steps in the pathway remain poorly understood, in part due to the incomplete identification of components. Through a genetic screen, we identified the Drosophila Zyxin family gene, Zyx102 (Zyx), as a component of the Hippo pathway. Zyx positively regulates the Hippo pathway transcriptional co-activator Yorkie, as its loss reduces Yorkie activity and organ growth. Through epistasis tests, we position the requirement for Zyx within the Fat branch of Hippo signaling, downstream of Fat and Dco, and upstream of the Yorkie kinase Warts, and we find that Zyx is required for the influence of Fat on Warts protein levels. Zyx localizes to the sub-apical membrane, with distinctive peaks of accumulation at intercellular vertices. This partially overlaps the membrane localization of the myosin Dachs, which has similar effects on Fat-Hippo signaling. Co-immunoprecipitation experiments show that Zyx can bind to Dachs and that Dachs stimulates binding of Zyx to Warts. We also extend characterization of the Ajuba LIM protein Jub and determine that although Jub and Zyx share C terminal LIM domains, they regulate Hippo signaling in distinct ways. Our results identify a role for Zyx in the Hippo pathway and suggest a mechanism for the role of Dachs: because Fat regulates the localization of Dachs to the membrane, where it can overlap with Zyx, we propose that the regulated localization of Dachs influences downstream signaling by modulating Zyx-Warts binding. Mammalian Zyxin proteins have been implicated in linking effects of mechanical strain to cell behavior. Our identification of Zyx as a regulator of Hippo signaling thus also raises the possibility that mechanical strain could be linked to the regulation of gene expression and growth through Hippo signaling. PMID- 21666804 TI - Histones are passed back to stay in place, more or less. PMID- 21666805 TI - Patterns and mechanisms of ancestral histone protein inheritance in budding yeast. AB - Replicating chromatin involves disruption of histone-DNA contacts and subsequent reassembly of maternal histones on the new daughter genomes. In bulk, maternal histones are randomly segregated to the two daughters, but little is known about the fine details of this process: do maternal histones re-assemble at preferred locations or close to their original loci? Here, we use a recently developed method for swapping epitope tags to measure the disposition of ancestral histone H3 across the yeast genome over six generations. We find that ancestral H3 is preferentially retained at the 5' ends of most genes, with strongest retention at long, poorly transcribed genes. We recapitulate these observations with a quantitative model in which the majority of maternal histones are reincorporated within 400 bp of their pre-replication locus during replication, with replication independent replacement and transcription-related retrograde nucleosome movement shaping the resulting distributions of ancestral histones. We find a key role for Topoisomerase I in retrograde histone movement during transcription, and we find that loss of Chromatin Assembly Factor-1 affects replication-independent turnover. Together, these results show that specific loci are enriched for histone proteins first synthesized several generations beforehand, and that maternal histones re-associate close to their original locations on daughter genomes after replication. Our findings further suggest that accumulation of ancestral histones could play a role in shaping histone modification patterns. PMID- 21666807 TI - How cells cope with obesity. PMID- 21666806 TI - phot1 inhibition of ABCB19 primes lateral auxin fluxes in the shoot apex required for phototropism. AB - It is well accepted that lateral redistribution of the phytohormone auxin underlies the bending of plant organs towards light. In monocots, photoreception occurs at the shoot tip above the region of differential growth. Despite more than a century of research, it is still unresolved how light regulates auxin distribution and where this occurs in dicots. Here, we establish a system in Arabidopsis thaliana to study hypocotyl phototropism in the absence of developmental events associated with seedling photomorphogenesis. We show that auxin redistribution to the epidermal sites of action occurs at and above the hypocotyl apex, not at the elongation zone. Within this region, we identify the auxin efflux transporter ATP-BINDING CASSETTE B19 (ABCB19) as a substrate target for the photoreceptor kinase PHOTOTROPIN 1 (phot1). Heterologous expression and physiological analyses indicate that phosphorylation of ABCB19 by phot1 inhibits its efflux activity, thereby increasing auxin levels in and above the hypocotyl apex to halt vertical growth and prime lateral fluxes that are subsequently channeled to the elongation zone by PIN-FORMED 3 (PIN3). Together, these results provide new insights into the roles of ABCB19 and PIN3 in establishing phototropic curvatures and demonstrate that the proximity of light perception and differential phototropic growth is conserved in angiosperms. PMID- 21666809 TI - Diverticulitis presenting as a tubo-ovarian abscess with subsequent colon perforation. AB - Described here is an unusual complication of a common condition; diverticulitis resulting in a tubo-ovarian abscess. The etiology of this abscess was clinically unapparent due to atypical presenting symptoms and signs. Furthermore, radiological diagnosis was misleading because of an inflammatory reaction of the colon which prevented visualization of diverticula. Failure to correctly identify the underlying pathology early in the patient's course of treatment led to a perforation of the colon. PMID- 21666808 TI - How to assess intestinal viability during surgery: A review of techniques. AB - Objective and quantitative intraoperative methods of bowel viability assessment are essential in gastrointestinal surgery. Exact determination of the borderline of the viable bowel with the help of an objective test could result in a decrease of postoperative ischemic complications. An accurate, reproducible and cost effective method is desirable in every operating theater dealing with abdominal operations. Numerous techniques assessing various parameters of intestinal viability are described by the studies. However, there is no consensus about their clinical use. To evaluate the available methods, a systematic search of the English literature was performed. Virtues and drawbacks of the techniques and possibilities of clinical application are reviewed. Valuable parameters related to postoperative intestinal anastomotic or stoma complications are analyzed. Important issues in the measurement and interpretation of bowel viability are discussed. To date, only a few methods are applicable in surgical practice. Further studies are needed to determine the limiting values of intestinal tissue oxygenation and flow indicative of ischemic complications and to standardize the methods. PMID- 21666810 TI - Physiological roles of mitogen-activated-protein-kinase-activated p38 regulated/activated protein kinase. AB - Mitogen-activated protein kinases (MAPKs) are a family of proteins that constitute signaling pathways involved in processes that control gene expression, cell division, cell survival, apoptosis, metabolism, differentiation and motility. The MAPK pathways can be divided into conventional and atypical MAPK pathways. The first group converts a signal into a cellular response through a relay of three consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinase, and MAPK. Atypical MAPK pathways are not organized into this three tiered cascade. MAPK that belongs to both conventional and atypical MAPK pathways can phosphorylate both non-protein kinase substrates and other protein kinases. The latter are referred to as MAPK-activated protein kinases. This review focuses on one such MAPK-activated protein kinase, MAPK-activated protein kinase 5 (MK5) or p38-regulated/activated protein kinase (PRAK). This protein is highly conserved throughout the animal kingdom and seems to be the target of both conventional and atypical MAPK pathways. Recent findings on the regulation of the activity and subcellular localization, bona fide interaction partners and physiological roles of MK5/PRAK are discussed. PMID- 21666811 TI - High tolerance to mutations in a Chlamydia trachomatis peptide deformylase loop. AB - AIM: To determine if and how a loop region in the peptide deformylase (PDF) of Chlamydia trachomatis regulates enzyme function. METHODS: Molecular dynamics simulation was used to study a structural model of the chlamydial PDF (cPDF) and predict the temperature factor per residue for the protein backbone atoms. Site directed mutagenesis was performed to construct cPDF variants. Catalytic properties of the resulting variants were determined by an enzyme assay using formyl-Met-Ala-Ser as a substrate. RESULTS: In silico analysis predicted a significant increase in atomic motion in the DGELV sequence (residues 68-72) of a loop region in a cPDF mutant, which is resistant to PDF inhibitors due to two amino acid substitutions near the active site, as compared to wild-type cPDF. The D68R and D68R/E70R cPDF variants demonstrated significantly increased catalytic efficiency. The E70R mutant showed only slightly decreased efficiency. Although deletion of residues 68-72 resulted in a nearly threefold loss in substrate binding, this deficiency was compensated for by increased catalytic efficiency. CONCLUSION: Movement of the DGELV loop region is involved in a rate-limiting conformational change of the enzyme during catalysis. However, there is no stringent sequence requirement for this region for cPDF enzyme activity. PMID- 21666812 TI - Targeting the inflammasome and adenosine type-3 receptors improves outcome of antibiotic therapy in murine anthrax. AB - AIM: To establish whether activation of adenosine type-3 receptors (A3Rs) and inhibition of interleukin-1beta-induced inflammation is beneficial in combination with antibiotic therapy to increase survival of mice challenged with anthrax spores. METHODS: DBA/2 mice were challenged with Bacillus anthracis spores of the toxigenic Sterne strain 43F2. Survival of animals was monitored for 15 d. Ciprofloxacin treatment (50 mg/kg, once daily, intraperitoneally) was initiated at day +1 simultaneously with the administration of inhibitors, and continued for 10 d. Two doses (2.5 mg/kg and 12.5 mg/kg) of acetyl-tyrosyl-valyl-alanyl aspartyl-chloromethylketone (YVAD) and three doses (0.05, 0.15 and 0.3 mg/kg) of 1-[2-Chloro-6-[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-beta D- ribofuranuronamide (Cl-IB-MECA) were tested. Animals received YVAD on days 1 4, and Cl-IB-MECA on days 1-10 once daily, subcutaneously. Human lung epithelial cells in culture were challenged with spores or edema toxin and the effects of IB MECA on phosphorylation of AKT and generation of cAMP were tested. RESULTS: We showed that the outcome of antibiotic treatment in a murine anthrax model could be substantially improved by co-administration of the caspase-1/4 inhibitor YVAD and the A3R agonist Cl-IB-MECA. Combination treatment with these substances and ciprofloxacin resulted in up to 90% synergistic protection. All untreated mice died, and antibiotic alone protected only 30% of animals. We conclude that both substances target the aberrant host signaling that underpins anthrax mortality. CONCLUSION: Our findings suggest new possibilities for combination therapy of anthrax with antibiotics, A3R agonists and caspase-1 inhibitors. PMID- 21666813 TI - Differential diagnosis of tachycardia with a typical left bundle branch block morphology. AB - The evaluation of wide QRS complex tachycardias (WCT) remains a common dilemma for clinicians. Numerous algorithms exist to aid in arriving at the correct diagnosis. Unfortunately, these algorithms are difficult to remember, and overreliance on them may prevent cardiologists from understanding the mechanisms underlying these arrhythmias. One distinct subcategory of WCTs are those that present with a "typical" or "classic" left bundle branch block pattern. These tachycardias may be supraventricular or ventricular in origin and arise from functional or fixed aberrancy, bystander or participating atriofascicular pre excitation, and bundle branch reentry. This review will describe these arrhythmias, illustrate their mechanisms, and discuss their clinical features and treatment strategies. PMID- 21666814 TI - Diagnosis and management of pericardial effusion. AB - Pericardial effusion is a common finding in everyday clinical practice. The first challenge to the clinician is to try to establish an etiologic diagnosis. Sometimes, the pericardial effusion can be easily related to a known underlying disease, such as acute myocardial infarction, cardiac surgery, end-stage renal disease or widespread metastatic neoplasm. When no obvious cause is apparent, some clinical findings can be useful to establish a diagnosis of probability. The presence of acute inflammatory signs (chest pain, fever, pericardial friction rub) is predictive for acute idiopathic pericarditis irrespective of the size of the effusion or the presence or absence of tamponade. Severe effusion with absence of inflammatory signs and absence of tamponade is predictive for chronic idiopathic pericardial effusion, and tamponade without inflammatory signs for neoplastic pericardial effusion. Epidemiologic considerations are very important, as in developed countries acute idiopathic pericarditis and idiopathic pericardial effusion are the most common etiologies, but in some underdeveloped geographic areas tuberculous pericarditis is the leading cause of pericardial effusion. The second point is the evaluation of the hemodynamic compromise caused by pericardial fluid. Cardiac tamponade is not an "all or none" phenomenon, but a syndrome with a continuum of severity ranging from an asymptomatic elevation of intrapericardial pressure detectable only through hemodynamic methods to a clinical tamponade recognized by the presence of dyspnea, tachycardia, jugular venous distension, pulsus paradoxus and in the more severe cases arterial hypotension and shock. In the middle, echocardiographic tamponade is recognized by the presence of cardiac chamber collapses and characteristic alterations in respiratory variations of mitral and tricuspid flow. Medical treatment of pericardial effusion is mainly dictated by the presence of inflammatory signs and by the underlying disease if present. Pericardial drainage is mandatory when clinical tamponade is present. In the absence of clinical tamponade, examination of the pericardial fluid is indicated when there is a clinical suspicion of purulent pericarditis and in patients with underlying neoplasia. Patients with chronic massive idiopathic pericardial effusion should also be submitted to pericardial drainage because of the risk of developing unexpected tamponade. The selection of the pericardial drainage procedure depends on the etiology of the effusion. Simple pericardiocentesis is usually sufficient in patients with acute idiopathic or viral pericarditis. Purulent pericarditis should be drained surgically, usually through subxiphoid pericardiotomy. Neoplastic pericardial effusion constitutes a more difficult challenge because reaccumulation of pericardial fluid is a concern. The therapeutic possibilities include extended indwelling pericardial catheter, percutaneous pericardiostomy and intrapericardial instillation of antineoplastic and sclerosing agents. Massive chronic idiopathic pericardial effusions do not respond to medical treatment and tend to recur after pericardiocentesis, so wide anterior pericardiectomy is finally necessary in many cases. PMID- 21666815 TI - PPARgamma activator, rosiglitazone: Is it beneficial or harmful to the cardiovascular system? AB - Rosiglitazone is a synthetic agonist of peroxisome proliferator-activated receptor gamma which is used to improve insulin resistance in patients with type II diabetes. Rosiglitazone exerts its glucose-lowering effects by improving insulin sensitivity. Data from various studies in the past decade suggest that the therapeutic effects of rosiglitazone reach far beyond its use as an insulin sensitizer since it also has other benefits on the cardiovascular system such as improvement of contractile dysfunction, inhibition of the inflammatory response by reducing neutrophil and macrophage accumulation, and the protection of myocardial injury during ischemic/reperfusion in different animal models. Previous clinical studies in type II diabetes patients demonstrated that rosiglitazone played an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and reducing chronic inflammation of the vascular system. Despite these benefits, inconsistent findings have been reported, and growing evidence has demonstrated adverse effects of rosiglitazone on the cardiovascular system, including increased risk of acute myocardial infarction, heart failure and chronic heart failure. As a result, rosiglitazone has been recently withdrawn from EU countries. Nevertheless, the effect of rosiglitazone on ischemic heart disease has not yet been firmly established. Future prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone would be the best way to resolve the uncertainties regarding the safety of rosiglitazone in patients with heart disease. PMID- 21666816 TI - Clinical evidence of interaction between clopidogrel and proton pump inhibitors. AB - Clopidogrel is approved for reduction of atherothrombotic events in patients with cardiovascular (CV) and cerebrovascular disease. Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after acute coronary syndrome or percutaneous coronary intervention, compared with aspirin alone. Due to concern about gastrointestinal bleeding in patients who are receiving clopidogrel and aspirin therapy, current guidelines recommend combined use of a proton pump inhibitor (PPI) to decrease the risk of bleeding. Data from previous pharmacological studies have shown that PPIs, which are extensively metabolized by the cytochrome system, may decrease the ADP-induced platelet aggregation of clopidogrel. Results from retrospective cohort studies have shown a higher incidence of major CV events in patients receiving both clopidogrel and PPIs than in those without PPIs. However, other retrospective analyses of randomized clinical trials have not shown that the concomitant PPI administration is associated with increased CV events among clopidogrel users. These controversial results suggest that large specific studies are needed. This article reviews the metabolism of clopidogrel and PPIs, existing clinical data regarding the interaction between clopidogrel and PPIs, and tries to provide recommendations for health care professionals. PMID- 21666817 TI - Percutaneous endovascular management of atherosclerotic axillary artery stenosis: Report of 2 cases and review of literature. AB - With recent advancement in percutaneous endovascular management, most atherosclerotic peripheral arterial diseases are amenable for intervention. However, there is limited published literature about atherosclerotic axillary artery involvement and its endovascular management. We report two cases of atherosclerotic axillary artery stenosis, which were successfully managed with stent angioplasty using self expanding nitinol stents. The associated coronary artery disease was treated by percutaneous angioplasty and stenting. The long term follow-up revealed patent axillary stents in both cases. PMID- 21666818 TI - Imaging appearance of bone tumors of the maxillofacial region. AB - This paper reviews the imaging appearance of benign and malignant bone tumors of the maxillofacial region. A benign bone tumor commonly appears as a well circumscribed lesion. The matrix of the tumor may be calcified or sclerotic. Malignancies often display aggressive characteristics such as cortical breakthrough, bone destruction, a permeative pattern and associated soft-tissue masses. Computed tomography scan is an excellent imaging modality for accurate localization of the lesion, characterization of the tumor matrix and detection of associated osseous changes such as bone remodeling, destruction or periosteal reaction. Magnetic resonance imaging is of limited value in the evaluation of maxillofacial bone tumors. PMID- 21666819 TI - Abdominal crush injury in the Sichuan earthquake evaluated by multidetector computed tomography. AB - AIM: To investigate the features of abdominal crush injuries resulting from an earthquake using multidetector computed tomography (MDCT). METHODS: Fifty-one survivors with abdominal crush injuries due to the 2008 Sichuan earthquake underwent emergency non-enhanced scans with 16-row MDCT. Data were reviewed focusing on anatomic regions including lumbar vertebrae, abdominal wall soft tissue, retroperitoneum and intraperitoneal space; and types of traumatic lesions. RESULTS: Fractures of lumbar vertebrae and abdominal wall soft tissue injuries were more common than retro- and intraperitoneal injuries (P < 0.05). With regard to the 49 lumbar vertebral fractures in 24 patients, these occurred predominantly in the transverse process (P < 0.05), and 66.67% of patients (16/24) had fractures of multiple vertebrae, predominantly two vertebrae in 62.5% of patients (10/16), mainly in L1-3 vertebrae in 81.63% of the vertebrae (40/49). Retroperitoneal injuries occurred more frequently than intraperitoneal injuries (P < 0.05), and renal and liver injuries were most often seen in the retroperitoneum and in the intraperitoneal space, respectively (all P < 0.05). CONCLUSION: Transverse process fractures in two vertebrae among L1-3 vertebrae, injury of abdominal wall soft tissue, and renal injury might be features of earthquake-related crush abdominal injury. PMID- 21666820 TI - Era of diagnostic and interventional ultrasound. AB - It is an era of diagnostic and interventional ultrasound (US). Various new techniques such as three-dimensional US (3D US), interventional US, and contrast enhanced US (CEUS) have been introduced into clinical practice. Dr. Xu and his colleagues have taken advantage of these techniques and carried out a series of relevant studies. Their use of 3D US in the liver, gallbladder, liver tumor volumetry, guidance for ablation, and 3D CEUS has widened the application of 3D US in the clinic. They found that prognosis in patients with hepatocellular carcinoma (HCC) after thermal ablation with curative intent was determined by treatment response to ablation, pretreatment serum AFP, and liver function reserve. Tumor response to treatment was the most predictive factor for long-term survival. They compared the use of percutaneous microwave ablation and radiofrequency ablation for the treatment of HCC and found that both are effective methods in treating HCCs. The local tumor control, complications related to treatment, and long-term survival were equivalent for the two modalities. They first compared the enhancement patterns of HCC and intrahepatic cholangiocarcinoma (ICC) and proposed the diagnostic clues for ICC, liver angiomyolipoma (AML), gallbladder cancer, renal carcinoma, and renal AML, which have greatly enhanced the role of CEUS in the clinic. They also evaluated the diagnostic performance of CEUS in characterizing complex cystic focal liver lesions and the agreement between two investigators with different experience levels; and found that CEUS is especially useful for the young investigator. They assessed the effect of anti-angiogenic gene therapy for HCC treated by microbubble-enhanced US exposure and concluded that gene therapy mediated by US exposure enhanced by a microbubble contrast agent may become a new treatment option for HCC. PMID- 21666821 TI - Preclinical transplantation and safety of HS/PCs expanded from human umbilical cord blood. AB - AIM: To expand hematopoietic/progenitor stem cells (HS/PCs) from umbilical cord blood (UCB) and prepare the HS/PC product, and analyze preclinical transplantation and safety of HS/PC product. METHODS: Human bone marrow-derived mesenchymal stem cells (MSCs) were used as feeder cells to expand HS/PCs from UCB in a serum-free culture system. The proliferation potential of HS/PCs was analyzed. The expanded HS/PCs were suspended in the L-15 medium to prepare the HS/PC product. The contamination of bacteria, fungi and mycoplasmas, the infection of exogenous virus, the concentration of bacterial endotoxin, and the SCF residual in HS/PC product were determined. Finally, cells from the HS/PC product with or without bone marrow-derived mesenchymal stem cells (BM-MSCs) were transplanted into the irradiated NOD/SCID mice to determine the in vivo engraftment potential. RESULTS: After co-culture for 10 d, the total nuclear cells (TNCs) increased 125-fold, and CD34(+) cells increased 43-fold. The granulocyte-macrophage colony- forming cells (GM-CFCs) and erythroid colony forming cells (E-CFCs) increased 3.3- and 4.7-fold respectively. The expanded cells were collected and prepared as the expanded product of HS/PCs by re suspending cells in L-15 medium. For preclinical safety, the HS/PC product was analysed for contamination by bacteria, fungi and mycoplasmas, the bacterial endotoxin concentration and the SCF content. The results showed that the HS/PC product contained no bacteria, fungi or mycoplasmas. The bacterial endotoxin concentration was less than the detection limit of 6 EU/mL, and residual SCF was 75 pg/mL. Based on clinical safety, the HS/PC product was qualified for clinical transplantation. Finally, the HS/PC product was transplanted the irradiated mice where it resulted in rapid engraftment of hematopoietic cells. CONCLUSION: HSPC product prepared from UCB in the serum-free culture system with hMSCs as feeder cells should be clinically safe and effective for clinical transplantation. PMID- 21666822 TI - Resolving the negative data publication dilemma in translational stroke research. PMID- 21666823 TI - Sampling of CSF via the Cisterna Magna and Blood Collection via the Heart Affects Brain Water Content in a Rat SAH Model. AB - The aim of this study was to evaluate whether sampling of cerebrospinal fluid (CSF) via the cisterna magna and of blood via the heart affects brain water content in a rat subarachnoid hemorrhage (SAH) model. Twenty-nine animals were divided into four groups: sham-operated group with sampling of CSF and blood (Sham S+), sham-operated group without sampling of CSF and blood (Sham S-), SAH group with sampling of CSF and blood (SAH S+), and SAH without sampling of CSF and blood (SAH S-). SAH was induced via endovascular perforation of the left internal carotid artery bifurcation. Cerebrospinal fluid via the cisterna magna and blood via cardiac puncture was collected in the Sham S+ and SAH S+ groups before killing the animals for brain water content measurements. Left hemisphere brain water content was significantly higher in the SAH S- group compared with the Sham S- group (p< 0.05) and in Sham S+ group compared with the Sham S- group (p<0.05). There was no significant difference in brain water content of the left hemisphere between the SAH S+ and Sham S+ groups (p=NS). There was no significant difference in brain water content in other parts of brains. Sampling of CSF and blood affected brain water content in Sham animals and therefore it is not accurate to use these values from Sham animals for comparison with SAH animals. PMID- 21666824 TI - PRODUCTION OF SOUND BY UNSTEADY THROTTLING OF FLOW INTO A RESONANT CAVITY, WITH APPLICATION TO VOICED SPEECH. AB - An analysis is made of the sound generated by the time-dependent throttling of a nominally steady stream of air through a small orifice into a flow-through resonant cavity. This is exemplified by the production of voiced speech, where air from the lungs enters the vocal tract through the glottis at a time variable volume flow rate Q(t) controlled by oscillations of the glottis cross-section. Voicing theory has hitherto determined Q from a heuristic, reduced complexity 'Fant' differential equation (G. Fant, Acoustic Theory of Speech Production, 1960). A new self-consistent, integro-differential form of this equation is derived in this paper using the theory of aerodynamic sound, with full account taken of the back-reaction of the resonant tract on the glottal flux Q. The theory involves an aeroacoustic Green's function (G) for flow-surface interactions in a time-dependent glottis, so making the problem non-self-adjoint. In complex problems of this type it is not usually possible to obtain G in an explicit analytic form. The principal objective of the paper is to show how the Fant equation can still be derived in such cases from a consideration of the equation of aerodynamic sound and from the adjoint of the equation governing G in the neighbourhood of the 'throttle'. The theory is illustrated by application to the canonical problem of throttled flow into a Helmholtz resonator. PMID- 21666825 TI - Catechol Redox Induced Formation of Metal Core-Polymer Shell Nanoparticles. AB - A novel strategy was developed to synthesize polymer-coated metal nanoparticles (NPs) through reduction of metal cations with 3,4-dihydroxyphenylalanine (DOPA) containing polyethylene glycol (PEG) polymers. Catechol redox chemistry was used to both synthesize metal NPs and simultaneously form a cross-linked shell of PEG polymers on their surfaces. DOPA reduced gold and silver cations into neutral metal atoms, producing reactive quinones that covalently cross-linked the PEG molecules around the surface of the NP. Importantly, these PEG-functionalized metal NPs were stable in physiological ionic strengths and under centrifugation, and hold broad appeal since they absorb and scatter light in aqueous solutions. PMID- 21666826 TI - Stable isotope resolved metabolomics of lung cancer in a SCID mouse model. AB - We have determined the time course of [U-(13)C]-glucose utilization and transformations in SCID mice via bolus injection of the tracer in the tail vein. Incorporation of (13)C into metabolites extracted from mouse blood plasma and several tissues (lung, heart, brain, liver, kidney, and skeletal muscle) were profiled by NMR and GC-MS, which helped ascertain optimal sampling times for different target tissues. We found that the time for overall optimal (13)C incorporation into tissue was 15-20 min but with substantial differences in (13)C labeling patterns of various organs that reflected their specific metabolism. Using this stable isotope resolved metabolomics (SIRM) approach, we have compared the (13)C metabolite profile of the lungs in the same mouse with or without an orthotopic lung tumor xenograft established from human PC14PE6 lung adenocarcinoma cells. The (13)C metabolite profile shows considerable differences in [U-(13)C]-glucose transformations between the two lung tissues, demonstrating the feasibility of applying SIRM to investigate metabolic networks of human cancer xenograft in the mouse model. PMID- 21666827 TI - 3-Alkoxy-1,2-Dioxolanes: Synthesis and Evaluation as Potential Antimalarial Agents. AB - A number of 3-alkoxy-1,2-dioxolanes exhibit promising levels of antimalarial activity against P. falciparum. A new route to the 1,2-dioxolane core is reported based on tandem peroxidation/cyclization of enones. PMID- 21666828 TI - Region of Birth and Disability Among Recent U.S. Immigrants: Evidence from the 2000 Census. AB - This study aimed to test the "healthy immigrant" hypothesis and assess health heterogeneity among newly arrived working-age immigrants (18-64 years) from various regions of origin. Using the 5% sample of the 2000 U.S. Census (PUMS), we found that, compared with their native-born counterparts, immigrants from all regions of the world were less likely to report mental disability and physical disability. Immigrants from selected regions of origin were, however, more likely to report work disability. Significant heterogeneity in disabilities exists among immigrants: Those from Eastern Europe and Southeast Asia reported the highest risk of mental and physical disability, and those from East Asia reported the lowest risk of physical disability. Furthermore, Mexican immigrants reported the lowest risk of mental disability, and Canadian immigrants reported the lowest risk of work disability. Socioeconomic status and English proficiency partially explained these differences. The health advantage of immigrants decreased with longer U.S. residence. PMID- 21666829 TI - Financial Strain, Religious Involvement, and Life Satisfaction Among Older Mexican Americans. AB - The purpose of this study is to see if financial strain affects the religious involvement and life satisfaction of older Mexican Americans. In the process, an effort was made to explore the factors that promote financial strain in this ethnic group, including immigration status and English language use. The data come from a nationwide survey of older Mexican Americans. Support was found for the following core relationships in the study model: (1) older adults who were born in Mexico will have less schooling; (2) less education will be associated with less frequent use of English; (3) less frequent use of English will be associated with greater financial strain; (4) greater financial strain leads to less formal involvement in the church; (5) older people who are less involved in the church will have a diminished sense of religious meaning; and (6) older adults with a lower sense of religious meaning will be less satisfied with life. PMID- 21666830 TI - Synthesis and Evaluation of Fluorinated Aporphines: Potential Positron Emission Tomography Ligands for D2 Receptors AB - The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11 monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands. PMID- 21666831 TI - An improved synthesis of 'octa-acid' deep-cavity cavitand. AB - An improved synthesis of a water-soluble deep-cavity cavitand (octa-acid, 1) is presented. Previously (Gibb, C. L. D. & Gibb, B. C., J. Am. Chem. Soc., 2004, 126, 11408-11409) we documented access to host 1 in eight (non-linear) steps starting from resorcinol; a synthesis that required four steps involving chromatographic purification. Here we reveal a modified synthesis of host 1. Consisting of seven (non-linear) steps, this new synthesis involves only one chromatographic step, and avoids a minor impurity observed in the original approach. This improved synthesis will therefore be useful for the laboratories that are investigating the properties of these types of host. PMID- 21666832 TI - Generation of quaternary centers by reductive cross-coupling: shifting of regioselectivity in a subset of allylic alcohol-based coupling reactions. AB - Regioselective titanium alkoxide-mediated reductive cross-coupling reactions of allylic alcohols with vinylsilanes and imines have previously been demonstrated to proceed with allylic transposition by formal metallo-[3,3]-rearrangement [thought to proceed by a sequence of: 1) directed carbometalation, and 2) syn elimination]. While many examples have been described that support this reaction path, a collection of substrates have recently been identified that react by way of an alternative pathway, delivering a concise convergent route to coupled products bearing a quaternary center. PMID- 21666833 TI - Neural Correlates of Individual Differences in Infant Visual Attention and Recognition Memory. AB - Past studies have identified individual differences in infant visual attention based upon peak look duration during initial exposure to a stimulus. Colombo and colleagues (e.g., Colombo & Mitchell, 1990) found that infants that demonstrate brief visual fixations (i.e., short lookers) during familiarization are more likely to demonstrate evidence of recognition memory during subsequent stimulus exposure than infants that demonstrate long visual fixations (i.e., long lookers). The current study utilized event-related potentials to examine possible neural mechanisms associated with individual differences in visual attention and recognition memory for 6- and 7.5-month-old infants. Short- and long-looking infants viewed images of familiar and novel objects during ERP testing. There was a stimulus type by looker type interaction at temporal and frontal electrodes on the late slow wave (LSW). Short lookers demonstrated a LSW that was significantly greater in amplitude in response to novel stimulus presentations. No significant differences in LSW amplitude were found based on stimulus type for long lookers. These results indicate deeper processing and recognition memory of the familiar stimulus for short lookers. PMID- 21666834 TI - Sequential Support Vector Regression with Embedded Entropy for SNP Selection and Disease Classification. AB - Comprehensive evaluation of common genetic variations through association of SNP structure with common diseases on the genome-wide scale is currently a hot area in human genome research. For less costly and faster diagnostics, advanced computational approaches are needed to select the minimum SNPs with the highest prediction accuracy for common complex diseases. In this paper, we present a sequential support vector regression model with embedded entropy algorithm to deal with the redundancy for the selection of the SNPs that have best prediction performance of diseases. We implemented our proposed method for both SNP selection and disease classification, and applied it to simulation data sets and two real disease data sets. Results show that on the average, our proposed method outperforms the well known methods of Support Vector Machine Recursive Feature Elimination, logistic regression, CART, and logic regression based SNP selections for disease classification. PMID- 21666835 TI - PERFORMANCE GUARANTEES FOR INDIVIDUALIZED TREATMENT RULES. AB - Because many illnesses show heterogeneous response to treatment, there is increasing interest in individualizing treatment to patients [11]. An individualized treatment rule is a decision rule that recommends treatment according to patient characteristics. We consider the use of clinical trial data in the construction of an individualized treatment rule leading to highest mean response. This is a difficult computational problem because the objective function is the expectation of a weighted indicator function that is non-concave in the parameters. Furthermore there are frequently many pretreatment variables that may or may not be useful in constructing an optimal individualized treatment rule yet cost and interpretability considerations imply that only a few variables should be used by the individualized treatment rule. To address these challenges we consider estimation based on l(1) penalized least squares. This approach is justified via a finite sample upper bound on the difference between the mean response due to the estimated individualized treatment rule and the mean response due to the optimal individualized treatment rule. PMID- 21666836 TI - Building complex reference objects from dual sets. AB - There has been considerable psycholinguistic investigation into the conditions that allow separately introduced individuals to be joined into a plural set and represented as a complex reference object (e.g., Eschenbach, et al., 1989; Garrod & Sanford, 1982; Koh & Clifton, 2002; Koh et al., 2008; Moxey et al., 2004; Sanford & Lockhart, 1990). The current paper reports three eye-tracking experiments that investigate the less-well understood question of what conditions allow pointers to be assigned to the individuals within a previously undifferentiated set, turning it into a complex reference object. The experiments made use of a methodology used in Patson and Ferreira (2009) to distinguish between complex reference objects and undifferentiated sets. Experiments 1 and 2 demonstrated that assigning different properties to the members of an undifferentiated dual set via a conjoined modifier or a comparative modifier transformed it into a complex reference object. Experiment 3 indicated that assigning a property to only one member of an undifferentiated dual set introduced pointers to both members. These results demonstrate that pointers can be established to referents within a plural set without picking them out via anaphors; they set boundaries on the kinds of implicit contrasts between referents that establish pointers; and they illustrate that extremely subtle properties of the semantic and referential context can affect early parsing decisions. PMID- 21666838 TI - JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-hydroxydopamine Model of Parkinson's Disease. AB - Parkinson's disease (PD) results from the loss of dopamine neurons located in the substantia nigra pars compacta (SNpc) that project to the striatum. A therapeutic has yet to be identified that halts this neurodegenerative process, and as such, development of a brain penetrant small molecule neuroprotective agent would represent a significant advancement in the treatment of the disease. To fill this void we developed an aminopyrimidine JNK inhibitor (SR-3306) that reduced the loss of dopaminergic cell bodies in the SNpc and their terminals in the striatum produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway. Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increased the number of tyrosine hydroxylase immunoreactive (TH(+)) neurons in the SNpc by six-fold and reduced the loss of the TH(+) terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that received only vehicle (p<0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreased d-amphetamine-induced circling by 87% compared to 6-OHDA-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 were 347 nM, which was approximately two-fold higher than the cell-based IC(50) for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) revealed that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produced a 2.3-fold reduction of the number of immunoreactive neurons in the SNpc relative to vehicle treated rats. Collectively, these data suggest that orally bioavailable JNK inhibitors may be useful neuroprotective agents for the treatment of Parkinson's disease. PMID- 21666837 TI - MAPKs in development: insights from Dictyostelium signaling pathways. AB - Mitogen activated protein kinases (MAPKs) play important roles in the development of eukaryotic organisms through the regulation of signal transduction pathways stimulated by external signals. MAPK signaling pathways have been associated with the regulation of cell growth, differentiation, and chemotaxis, indicating MAPKs contribute to a diverse set of developmental processes. In most eukaryotes, the diversity of external signals is likely to far exceed the diversity of MAPKs, suggesting that multiple signaling pathways might share MAPKs. Do different signaling pathways converge before MAPK function or can MAPKs maintain signaling specificity through interactions with specific proteins? The genetic and biochemical analysis of MAPK pathways in simple eukaryotes such as Dictyostelium offers opportunities to investigate functional specificity of MAPKs in G protein mediated signal transduction pathways. This review considers the regulation and specificity of MAPK function in pathways that control Dictyostelium growth and development. PMID- 21666839 TI - Small Molecule c-jun-N-terminal Kinase (JNK) Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson's Disease. AB - There are currently no drugs to treat neurodegeneration in Parkinson's disease (PD) and all existing medications only treat symptoms, lose efficacy over time, and produce untoward side effects. In the current work, we report the first highly selective, orally bioavailable, c-jun-N-terminal kinase (JNK) inhibitor for protection of dopaminergic neurons in vitro and in vivo. At 300 nM this compound showed statistically significant protection of primary dopaminergic neurons exposed to 1-methyl-4-phenylpyridinium (MPP(+)), had pharmacokinetic properties in rodents consistent with twice daily (b.i.d.) dosing, and was orally efficacious at 30 mg/kg in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Moreover, a dose-dependent target modulation of c-jun phosphorylation served as a biomarker for demonstrating on-target inhibition of JNK as the mechanism of action for this compound. Collectively these results suggest that this JNK inhibitor could be a promising therapeutic neuroprotective agent in the treatment of Parkinson's disease. PMID- 21666840 TI - Scaffolds and chaperones in myofibril assembly: putting the striations in striated muscle. AB - Sarcomere assembly in striated muscles has long been described as a series of steps leading to assembly of individual proteins into thick filaments, thin filaments and Z-lines. Decades of previous work focused on the order in which various structural proteins adopted the striated organization typical of mature myofibrils. These studies led to the view that actin and alpha-actinin assemble into premyofibril structures separately from myosin filaments, and that these structures are then assembled into myofibrils with centered myosin filaments and actin filaments anchored at the Z-lines. More recent studies have shown that particular scaffolding proteins and chaperone proteins are required for individual steps in assembly. Here, we review the evidence that N-RAP, a LIM domain and nebulin repeat protein, scaffolds assembly of actin and alpha-actinin into I-Z-I structures in the first steps of assembly; that the heat shock chaperone proteins Hsp90 & Hsc70 cooperate with UNC-45 to direct the folding of muscle myosin and its assembly into thick filaments; and that the kelch repeat protein Krp1 promotes lateral fusion of premyofibril structures to form mature striated myofibrils. The evidence shows that myofibril assembly is a complex process that requires the action of particular catalysts and scaffolds at individual steps. The scaffolds and chaperones required for assembly are potential regulators of myofibrillogenesis, and abnormal function of these proteins caused by mutation or pathological processes could in principle contribute to diseases of cardiac and skeletal muscles. PMID- 21666841 TI - Formal Estimation of Errors in Computed Absolute Interaction Energies of Protein ligand Complexes. AB - A largely unsolved problem in computational biochemistry is the accurate prediction of binding affinities of small ligands to protein receptors. We present a detailed analysis of the systematic and random errors present in computational methods through the use of error probability density functions, specifically for computed interaction energies between chemical fragments comprising a protein-ligand complex. An HIV-II protease crystal structure with a bound ligand (indinavir) was chosen as a model protein-ligand complex. The complex was decomposed into twenty-one (21) interacting fragment pairs, which were studied using a number of computational methods. The chemically accurate complete basis set coupled cluster theory (CCSD(T)/CBS) interaction energies were used as reference values to generate our error estimates. In our analysis we observed significant systematic and random errors in most methods, which was surprising especially for parameterized classical and semiempirical quantum mechanical calculations. After propagating these fragment-based error estimates over the entire protein-ligand complex, our total error estimates for many methods are large compared to the experimentally determined free energy of binding. Thus, we conclude that statistical error analysis is a necessary addition to any scoring function attempting to produce reliable binding affinity predictions. PMID- 21666842 TI - Inverse regression estimation for censored data. AB - An inverse regression methodology for assessing predictor performance in the censored data setup is developed along with inference procedures and a computational algorithm. The technique developed here allows for conditioning on the unobserved failure time along with a weighting mechanism that accounts for the censoring. The implementation is nonparametric and computationally fast. This provides an efficient methodological tool that can be used especially in cases where the usual modeling assumptions are not applicable to the data under consideration. It can also be a good diagnostic tool that can be used in the model selection process. We have provided theoretical justification of consistency and asymptotic normality of the methodology. Simulation studies and two data analyses are provided to illustrate the practical utility of the procedure. PMID- 21666843 TI - Luteinizing hormone receptor deficiency increases the susceptibility to alkylating agent-induced lymphomagenesis in mice. AB - Previous studies have revealed a close link between luteinizing hormone (LH)/human chorionic gonadotropin (hCG) signaling and oncogenesis in gonadal and nongonadal tissues. To investigate whether genetic ablation of LH receptor (Lhr) affects the animal's oncogenic susceptibility, adult female wild-type (wt), heterozygous, and homozygous Lhr knockout (LhrKO) mice were intraperitoneally injected with an alkylating agent, N-methyl-N-nitrosourea (MNU, 50 mg/kg of body weight). The mice were sacrificed when they were short of breath or 10 months after the injection. The results showed that MNU induced non-Hodgkin's thymic and lymphonodus lymphomas in 70.6% and 100% of heterozygous and homozygous animals, respectively, compared with 35.7% in wt siblings. The tumor development was rapid; they were more aggressive and metastasized to the spleen, liver, and kidney in Lhr-deficient mice compared to wt siblings. All tumors were immunostained-positive for a T-cell specific marker, CD3, but not for a B-cell marker, CD22, suggesting that all the lymphomas arose from T-cells, which are known to be LH/hCG receptor-positive. There was no rearrangement of the Lhr gene locus or differences in thymic cell proliferation among the genotypes. However, apoptosis was lower in the Lhr-deficient thymuses. The thymic Bcl-2 levels were elevated and caspase-3 activation was reduced in Lhr heterozygous and homozygous animals. In conclusion, MNU induced a higher incidence and an earlier onset of aggressive lymphomas in LhrKO animals, which may be associated with a reduction in apoptosis of thymocytes. PMID- 21666844 TI - A standard set of American-English voiced stop-consonant stimuli from morphed natural speech. AB - Linear predictive coding (LPC) analysis was used to create morphed natural tokens of English voiced stop consonants ranging from /b/ to /d/ and /d/ to /g/ in four vowel contexts (/i/, /ae/, /a/, /u/). Both vowel-consonant-vowel (VCV) and consonant-vowel (CV) stimuli were created. A total of 320 natural-sounding acoustic speech stimuli were created, comprising 16 stimulus series. A behavioral experiment demonstrated that the stimuli varied perceptually from /b/ to /d/ to /g/, and provided useful reference data for the ambiguity of each token. Acoustic analyses indicated that the stimuli compared favorably to standard characteristics of naturally-produced consonants, and that the LPC morphing procedure successfully modulated multiple acoustic parameters associated with place of articulation. The entire set of stimuli is freely available on the Internet (http://www.psy.cmu.edu/~lholt/php/StephensHoltStimuli.php) for use in research applications. PMID- 21666845 TI - Defining an ontology of cognitive control requires attention to component interactions. AB - Cognitive control is not only componential, but those components may interact in complicated ways in the service of cognitive control tasks. This complexity poses a challenge for developing an ontological description, because the mapping may not be direct between our task descriptions and true component differences reflected in indicators. To illustrate this point, I discuss two examples: (a) the relationship between adaptive gating and working memory and (b) the recent evidence for a control hierarchy. From these examples, I argue that an ontological program must simultaneously seek to identify component processes and their interactions within a broader processing architecture. PMID- 21666847 TI - Tridentate N(2)S ligand from 2,2'-dithiodibenzaldehyde and N,N dimethylethylenediamine: Synthesis, structure, and characterization of a Ni(II) complex with relevance to Ni Superoxide Dismutase. AB - Nickel Superoxide Dismutase (NiSOD) and the A-cluster of Carbon Monoxide Dehydrogenase/Acetyl Coenzyme A Synthase (CODH/ACS) both feature active sites with Ni coordinated by thiolate and amide donors. It is likely that the particular set of donors is important in tuning the redox potential of the Ni center(s). We report herein an expansion of our efforts involving the use of 2,2' dithiodibenzaldehyde (DTDB) as a synthon for metal-thiolate complexes to reactions with Ni complexes of N,N-dimethylethylenediamine (dmen). In the presence of coordinating counterions, these reactions result in monomeric square planar complexes of the tridentate N(2)S donor ligand derived from the Schiff base condensation of dmen and DTDB. In the absence of a coordinating counterion, we have isolated a Ni(II) complex with an asymmetric N(2)S(2) donor set involving one amine and one imine N donor in addition to two thiolate donors. This latter complex is discussed with respect to its relevance to the active site of NiSOD. PMID- 21666846 TI - Endoscopic sinus surgery reduces antibiotic utilization in rhinosinusitis. AB - BACKGROUND: Antibiotics are a mainstay of treatment for chronic rhinosinusitis (CRS) and recurrent acute rhinosinusitis(RARS). Although quality-of-life outcomes following endoscopic sinus surgery (ESS) have been studied, the change in antibiotic utilization following ESS is less wellknown. OBJECTIVE: We aimed to determine the effect of ESS on antibiotic utilization in CRS and RARS. METHODS: A multi-institutional, prospective cohort of patients with CRS and RARS was enrolled between January 2001 and January 2009. Patients completed the medication subscale of the Chronic Sinusitis Survey (CSS), and the Wilcoxon signed-rank test was used to compare differences in the overall reported time of antibiotic between preoperative and postoperative time points. RESULTS: A total of 503 patients were followed for an average 17.3 months. Overall, patients reported a 57.2% reduction in time on antibiotics following ESS. The majority of patients (60.4%) reported significantly less antibiotic utilization after ESS (p < 0.001) consisting of an 83.7% reduction in the time on antibiotics. Subgroup analysis also revealed a significant reduction in antibiotic utilization for patients with and without nasal polyposis (59.0% and 58.2%; both p < 0.001) as well as RARS (61.2%; p = 0.001). CONCLUSION: ESS significantly reduces antibiotic utilization for CRS and RARS. This finding demonstrates potential for lower health care expenditures related to antibiotics, as well as reduced risk of both antibiotic related morbidity and development of bacterial resistance. PMID- 21666848 TI - Cross Tolerance to Environmental Stressors: Effects of Hypoxic Acclimation on Cardiovascular Responses of Channel Catfish (Ictalurus punctatus) to a Thermal Challenge. AB - Hypoxia and temperature are two major, interactive environmental variables that affect cardiovascular function in fishes. The purpose of this study was to determine if acclimation to hypoxia increases thermal tolerance by measuring cardiovascular responses to increasing temperature in two groups of channel catfish. The hypoxic group was acclimatized to moderate hypoxia (50% air saturation, a P(O2) of approximately 75 torr) at a temperature of 22 degrees C for seven days. The normoxic (i.e. control) group was maintained the same, but under normoxic conditions (a P(O2) of approximately 150 torr). After acclimation, fish were decerebrated, fitted with dorsal aorta cannulae, and then exposed to increasing temperature while cardiovascular variables were recorded. The end point (critical thermal maximum, CTMax) was defined as a temperature at which heart rate and blood pressure sharply decreased indicating cardiovascular collapse. Fish acclimatized to moderate hypoxia had higher resting heart rate than controls. Hypoxic acclimatized fish had a significantly higher CTMax. Acclimation to hypoxia increases the cardiovascular ability of channel catfish to withstand an acute temperature increase. PMID- 21666849 TI - Synaptosomes as a platform for loading nanoparticles into synaptic vesicles. AB - Synaptosomes are intact, isolated nerve terminals that contain the necessary machinery to recycle synaptic vesicles via endocytosis and exocytosis upon stimulation. Here we use this property of synaptosomes to load quantum dots into synaptic vesicles. Vesicles are then isolated from the synaptosomes, providing a method to probe isolated, individual synaptic vesicles where each vesicle contains a single, encapsulated nanoparticle. This technique provided an encapsulation efficiency of ~16%, that is, ~16% of the vesicles contained a single quantum dot while the remaining vesicles were empty. The ability to load single nanoparticles into synaptic vesicles opens new opportunity for employing various nanoparticle-based sensors to study the dynamics of vesicular transporters. PMID- 21666850 TI - Superelectrophilic chemistry of amino-nitriles and related substrates. AB - The superacid-promoted Houben-Hoesch reactions of amino-nitriles and related compounds have been studied. The nitriles form dicationic electrophiles and react with benzene in fair to good yields (12-95%). The intermediate iminium ions may also be reduced to the benzylic amines by NaBH(4) or H(2). PMID- 21666851 TI - Intrahospital Transport to the Radiology Department: Risk for Adverse Events, Nursing Surveillance, Utilization of a MET and Practice Implications. AB - Nurses providing care in the Radiology Department (RD) are challenged by the broad scope of conditions and varied acuity of patients served by this unit. Nurses must facilitate the required diagnostic testing and simultaneously provide the surveillance necessary to detect physiologic changes signaling the need for rescue interventions. When instability occurs, one method of rescue involves activation of a Medical Emergency Team (MET) to bring an experienced cadre of critical care providers to the unstable patient. Despite recognition that the RD can be a high risk area, there is little in the literature specific to the surveillance of RD patients, risk for and prevention of adverse events, MET activation or the management of patient instability specific to the RD. The purpose of this paper is to examine what is known regarding risk for adverse events during intrahospital transport, utilization of a MET as a rescue intervention, and practice implications. PMID- 21666852 TI - Corticosteroids in brain cancer patients: benefits and pitfalls. AB - Glucocorticoids have been used for decades in the treatment of brain tumor patients and belong to the most powerful class of agents in reducing tumor associated edema and minimizing side effects and the risk of encephalopathy in patients undergoing radiation therapy. Unfortunately, corticosteroids are associated with numerous and well-characterized adverse effects, constituting a major challenge in patients requiring long-term application of corticosteroids. Novel antiangiogenic agents, such as bevacizumab (Avastin(r)), which have been increasingly used in cancer patients, are associated with significant steroid sparing effects, allowing neuro-oncologists to reduce the overall use of corticosteroids in patients with progressive malignant brain tumors. Recent experimental studies have revealed novel insights into the mechanisms and effects of corticosteroids in cancer patients, including modulation of tumor biology, angiogenesis and steroid-associated neurotoxicity. This article summarizes current concepts of using corticosteroids in brain cancer patients and highlights potential pitfalls in their effects on both tumor and neural progenitor cells. PMID- 21666854 TI - Spousal Social Control During a Weight Loss Attempt: A Daily Diary Study. AB - We investigated perceptions of spousal social control and the partners' behavior, affect, and relationship satisfaction at the start of a weight loss attempt. Gender and body mass index (BMI) were explored as moderators. In order to examine the short-term effects of social control, participants completed daily assessments reporting spouses' influence and their own behavior and well-being. Instrumental and reinforcing social control were associated with better health behavior, well-being, and relationship satisfaction, but showed no impact over time. Monitoring control was inconsistently associated with health behavior and well-being. BMI moderated some of the relations between social control strategies, health behavior, and well-being. Findings suggest spouses can contribute to partners' weight loss attempts with influence strategies, but considering weight status may determine which strategies are the most beneficial. PMID- 21666853 TI - Emerging Therapies: Pleiotropic Multi-target Drugs to Treat Stroke Victims. PMID- 21666855 TI - Cytotoxicity of Metal Ions Released from Nitinol Alloys on Endothelial Cells. AB - Most implantable medical devices are expected to function in the body over an extended period of time. Therefore, immersion tests under simulated conditions can be useful for assessing the amount of metal ions released in situ. In this investigation, dissolved ions from as-received binary and ternary Nitinol alloys in cell culture media were periodically measured under static and dynamic conditions. Endothelial cells were grown in aliquots of culture media obtained and the effect of dissolved ions on cell proliferation and viability of endothelial cells (HUVEC) was studied by cytotoxicity assays. The concentration of metal ions in the media was measured by inductively coupled plasma mass spectrometry. PMID- 21666856 TI - Population decline induced by gonorrhoea and tuberculosis transmission: Micronesia during the Japanese occupation, 1919-45. AB - The islands of Yap in Micronesia survived a period of severe depopulation during the Japanese occupation from 1919 to 1945. Using data from historical documents, supplemented by ethnographic evidence, we calibrate a simulation model that accounts for this phenomenon. Our model tracks the reproduction histories of a synthetic cohort of women in Yap, including effects of infertility due to gonorrhoea as well as tuberculosis mortality, and predicts the net reproduction rate (NRR). In this particular case and throughout history, human migrations and associated social and cultural interactions have frequently been accompanied by dramatic changes in patterns of disease transmission and substantial demographic consequences. Despite the broad emphasis on mortality as a measure of demographic consequences in the historical and contemporary literature, there are important instances where life expectancy at birth, fertility rates, and total population size are important demographic consequences. We find that gonorrhoea may have significantly contributed to depopulation during the Japanese occupation of Micronesia, due to repeated infections and high risk of sterility. Results of our model suggest that gonorrhoea alone could have reduced the net reproduction rate by 82%, whereas deaths from tuberculosis may have contributed to a 17% decline. PMID- 21666857 TI - Quantitative temporal profiles of penumbra and infarction during permanent middle cerebral artery occlusion in rats. AB - The basic premise of neuroprotection in acute stroke is the presence of salvageable tissue, but the spatiotemporal volume profiles of the penumbra and infarction remain poorly defined in preclinical animal models of acute stroke used to evaluate therapies for clinical application. Our aim was to define these profiles using magnetic resonance imaging (MRI) quantitative cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) for dual-parameter voxel analysis in the rat suture permanent middle cerebral artery occlusion (pMCAO) model. Eleven male Sprague Dawley rats were subjected to pMCAO with MRI measurements of quantitative CBF and ADC at baseline, over the first 4 h (n=9) and at 7, 14, and 21 days (n=4). Voxel analysis of CBF and ADC was used to characterize brain tissue ischemic transitions. Penumbra, core, and hyperemic infarction volumes were significantly elevated (P<0.05) and unchanged over the first 4 h of pMCAO while the total lesion volume progressively rose. At 7, 14, and 21 days, tissue compartment transitions reflected infarction, tissue cavitation, and selective ischemic neuronal necrosis. Anatomical distribution of penumbra and core revealed marked heterogeneity with penumbra scattered within core and penumbra persisting even after 4 h of permanent MCAO. PMID- 21666858 TI - Assessment of Corrosion Resistance and Metal Ion Leaching of Nitinol Alloys. AB - Nitinol usage for biomedical implant devices has received significant attention due to its high corrosion resistance and biocompatibility. However, surface treatments are known to affect surface charge, surface chemistry, morphology, wettability, and corrosion resistance. In this investigation, the corrosion resistance of a binary and various ternary Nitinol alloys was determined after being subjected to electropolishing, magnetoelectropolishing, and water boiling and passivation. Cyclic polarization in vitro corrosion tests were conducted in Phosphate Buffer Saline (PBS) in compliance with ASTM F 2129-08 before and after surface treatments. The concentrations of dissolved metal ions in the electrolyte were also determined by ICPMS. PMID- 21666859 TI - Effect of Manufacturing Process on the Biocompatibility and Mechanical Properties of Ti-30Ta Alloy. AB - Ti alloys have been widely used in the aerospace, chemical, and biomedical industries for their high strength/weight ratio and corrosion resistance. However, Nitinol's usage in the latter industry has been fraught with concerns of allergic and toxic effects of Ni released from implants. Recently, much attention has been placed on the development of Ni-free Ti-Ta alloys, which are considered prime candidates for applications such as metal-on-metal spinal disk replacements, orthopedic implants, cardiovascular stents, dental posts, and guide wires. In this research, the biocompatibility of Ti-30Ta alloys manufactured by powder metallurgy (PM) and arc melting (ARC) were investigated. The corrosion resistance of each alloy was determined in accordance with ASTM F 2129-08 in phosphate buffered saline (PBS) and PBS with amino acids at 37 degrees C. The concentration of metal ions released during corrosion was measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). Scanning Electron Microscopy (SEM) was used to assess the morphology of the alloys before and after corrosion. Vicker's hardness tests were performed to compare the hardness and tensile strength of the alloys. Human osteoblast cells were successfully grown on the surface of both alloys. PMID- 21666860 TI - Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. AB - Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological inactivation of FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for the treatment of inflammatory pain and other nervous system disorders. Herein, we report the discovery and characterization of a highly efficacious and selective FAAH inhibitor PF-04457845 (23). Compound 23 inhibits FAAH by a covalent, irreversible mechanism involving carbamylation of the active-site serine nucleophile of FAAH with high in vitro potency (k(inact)/K(i) and IC(50) values of 40300 M(-1) s(-1) and 7.2 nM, respectively, for human FAAH). Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling. Oral administration of 23 at 0.1 mg/kg results in efficacy comparable to that of naproxen at 10 mg/kg in a rat model of inflammatory pain. Compound 23 is being evaluated in human clinical trials. PMID- 21666861 TI - A Model for Stress Fiber Realignment Caused by Cytoskeletal Fluidization During Cyclic Stretching. AB - Uniaxial cyclic substrate stretching results in a concerted change of cytoskeletal organization such that stress fibers (SFs) realign away from the direction of stretching. Recent experiments revealed that brief transient stretch promptly ablates cellular contractile stress by means of cytoskeletal fluidization, followed by a slow stress recovery by means of resolidification. This, in turn, suggests that fluidization, resolidification and SF realignment may be linked together during stretching. We propose a mathematical model that simulates the effects of fluidization and resolidification on cytoskeletal contractile stress in order to investigate how these phenomena affect cytoskeletal realignment in response to pure uniaxial stretching of the substrate. The model comprises of individual elastic SFs anchored at the endpoints to an elastic substrate. Employing the global stability convention, the model predicts that in response to repeated stretch-unstretch cycles, SFs tend to realign in the direction perpendicular to stretching, consistent with data from the literature. The model is used to develop a computational scheme for predicting changes in cell orientation and polarity during stretching and how they relate to the underlying alterations in the cytoskeletal organization. We conclude that depletion of cytoskeletal contractile stress by means of fluidization and subsequent stress recovery by means of resolidification may play a key role in reorganization of cytoskeletal SFs in response to uniaxial stretching of the substrate. PMID- 21666862 TI - Controllable synthesis of NaYF(4) : Yb,Er upconversion nanophosphors and their application to in vivo imaging of Caenorhabditis elegans. AB - beta-NaYF(4) : Yb,Er upconversion nanoparticles (UCNPs) can emit bright green fluorescence under near-infrared (NIR) light excitation which is safe to the body and can penetrate deeply into tissues. The application of UCNPs in biolabeling and imaging has received great attention recently. In this work, beta-NaYF(4) : Yb,Er UCNPs with an average size of 35 nm, uniformly spherical shape, and surface modified with amino groups were synthesized by a one-step green solvothermal approach through the use of room-temperature ionic liquids as the reactant, co solvent and template. The as-prepared UCNPs were introduced into Caenorhabditis elegans (C. elegans) to achieve successful in vivo imaging. We found that longer incubation time, higher UCNP concentration and smaller UCNP size can make the in vivo fluorescence of C. elegans much brighter and more continuous along their body. The worms have no apparent selectivity on ingestion of the UCNPs capped with different capping ligands while having similar size and shape. The next generation of worms did not show fluorescence under excitation. In addition, low toxicity of the nanoparticles was demonstrated by investigating the survival rates of the worms in the presence of the UCNPs. Our work demonstrates the potential application of the UCNPs in studying the biological behavior of organisms, and lays the foundation for further development of the UCNPs in the detection and diagnosis of diseases. PMID- 21666863 TI - Operator Splitting Implicit Integration Factor Methods for Stiff Reaction Diffusion-Advection Systems. AB - For reaction-diffusion-advection equations, the stiffness from the reaction and diffusion terms often requires very restricted time step size, while the nonlinear advection term may lead to a sharp gradient in localized spatial regions. It is challenging to design numerical methods that can efficiently handle both difficulties. For reaction-diffusion systems with both stiff reaction and diffusion terms, implicit integration factor (IIF) method and its higher dimensional analog compact IIF (cIIF) serve as an efficient class of time stepping methods, and their second order version is linearly unconditionally stable. For nonlinear hyperbolic equations, weighted essentially non-oscillatory (WENO) methods are a class of schemes with a uniformly high-order of accuracy in smooth regions of the solution, which can also resolve the sharp gradient in an accurate and essentially non-oscillatory fashion. In this paper, we couple IIF/cIIF with WENO methods using the operator splitting approach to solve reaction-diffusion-advection equations. In particular, we apply the IIF/cIIF method to the stiff reaction and diffusion terms and the WENO method to the advection term in two different splitting sequences. Calculation of local truncation error and direct numerical simulations for both splitting approaches show the second order accuracy of the splitting method, and linear stability analysis and direct comparison with other approaches reveals excellent efficiency and stability properties. Applications of the splitting approach to two biological systems demonstrate that the overall method is accurate and efficient, and the splitting sequence consisting of two reaction-diffusion steps is more desirable than the one consisting of two advection steps, because CWC exhibits better accuracy and stability. PMID- 21666864 TI - "I'LL DIE WITH THE HAMMER IN MY HAND": JOHN HENRYISM AS A PREDICTOR OF HAPPINESS. AB - This paper examines the association between John Henryism - a behavioral predisposition to cope actively with psychosocial environmental stressors - and happiness. On the basis of previous research on aspiration and goal regulation, we predicted that John Henryism would be negatively associated with happiness when controlling for demographic factors and attainment in various domains of life. We tested the prediction in a sample of hypertensive participants (n=758) drawn from an inner-city, mainly African-American, safety-net hospital in Jefferson County, Alabama. Bivariate analysis revealed no association between John Henryism and attainment in six domains of life: marriage, children, education, employment, income, and health. However, a significant negative association between John Henryism and happiness was found both in bivariate analysis (Spearman's rho= -0.335; p<.001) and when controlling for demographic factors and attainment using ordinal logistic regression analysis. There was a significant interaction effect between John Henryism and gender: being male was positively associated with happiness among participants with low John Henryism, but negatively associated with happiness among participants with high John Henryism. While further study would be required in order to establish the extent to which these findings can be generalized as well as their causal underpinnings, the results indicate that John Henryism is negatively associated with happiness, especially among men, and underscore the limitations of using self-reported measures of happiness as proxies for well-being for purposes of public policy. PMID- 21666865 TI - The development of culturally-sensitive measures for research on ageing. AB - Attempts to import existing measures developed in other countries when constructing research instruments for use with older people can result in several problems including inappropriate wording, unsuitable response sets, and insufficient attention to cultural nuances. This paper addresses such problems by discussing a mixed methods approach to measurement development (i.e. both qualitative and quantitative) that incorporates input from the aging adults for whom the measure is intended. To test this approach, a step-by step process to the development of a culturally-grounded measure for older Thai people is described. Using focus groups and in-depth interviews, the process begins with an identification of the culturally meaningful domains of the construct under study. Next, input is gathered from other studies; a preliminary quantitative measure is developed; the measure is reviewed by a panel of experts; and then it is pilot tested. Cognitive interviews are utilized when pilot-testing of the items detects problems with measurement construction or interview methods. When these problems are remedied, the measure is incorporated into a large-scale survey and tested for its psychometric qualities. In addition to providing a template for culturally-sensitive measurement development in gerontology, this paper also highlights issues that researchers should consider when attempting to develop measures and provides suggestions for how to address such issues. PMID- 21666866 TI - Cytotoxicity of Ni from Surface-Treated Porous Nitinol (PNT) on Osteoblast Cells. AB - The leaching of nickel from the surface of porous Nitinol (PNT) is mainly dependent on its surface characteristics, which can be controlled by appropriate surface treatments. In this investigation, PNT was subjected to two surface treatments, namely, water-boiling and dry-heating passivations. Phosphate buffer saline (PBS) solutions obtained from cyclic potentiodynamic polarization tests on PNT were employed to assess the cytotoxicity of Ni contained therein on osteoblast cells by Sulforhodamine B (SRB) assay. In addition, similar concentrations of Ni were added exogenously to cell culture media to determine cytotoxic effects on osteoblast cells. The morphologies of the untreated and the surface-treated PNTs were examined using SEM and AFM. Furthermore, growth of human osteoblast cells was observed on the PNT surfaces. PMID- 21666867 TI - Age-Related Changes in Biomarkers: Longitudinal Data from a Population-Based Sample. AB - Identifying how biological parameters change with age can provide insights into the physiological determinants of disease, and ultimately, death. Most prior studies of age-related change in biomarkers are based on cross-sectional data, small or selective samples, or a limited number of biomarkers. We use data from a nationally-representative longitudinal sample of 639 Taiwanese aged 54 and older in 2000 to assess changes over a six-year period in a wide range of biomarkers. Markers that increased most with age were glycoslyated hemoglobin, interleukin-6, and norepinephrine. Markers that decreased most with age were diastolic blood pressure and creatinine clearance. For example, glycoslyated hemoglobin increased by 8-13%, on average, over this six-year period. Several standard clinical risk factors exhibited little evidence of age-related change. Further research is needed to determine whether the observed variation between individuals in biomarker changes represents differences in underlying physiological function that are predictive of future health and survival. PMID- 21666868 TI - In Vitro and In Vivo Osteogenic Activity of Largazole. AB - Due to their capability of modifying chromatin structure and thereby regulating gene transcription, histone deacetylases (HDACs) have been reported to play important roles in osteogenesis and considered a promising potential therapeutic target for bone diseases, including osteoporosis. We showed that the novel marine derived HDAC inhibitor largazole exhibits in vitro and in vivo osteogenic activity. Largazole significantly induced the expression of ALP and OPN. The osteogenic activity of largazole was mediated through the increased expression of Runx2 and BMPs. Importantly, largazole showed in vivo bone-forming efficacy in the mouse calvarial bone formation assay and the rabbit calvarial bone fracture healing model. The dual action of largazole to stimulate bone formation and inhibit bone resorption would be a useful feature in drug development for bone related disorders. PMID- 21666869 TI - NEW EFFICIENT ESTIMATION AND VARIABLE SELECTION METHODS FOR SEMIPARAMETRIC VARYING-COEFFICIENT PARTIALLY LINEAR MODELS. AB - The complexity of semiparametric models poses new challenges to statistical inference and model selection that frequently arise from real applications. In this work, we propose new estimation and variable selection procedures for the semiparametric varying-coefficient partially linear model. We first study quantile regression estimates for the nonparametric varying-coefficient functions and the parametric regression coefficients. To achieve nice efficiency properties, we further develop a semiparametric composite quantile regression procedure. We establish the asymptotic normality of proposed estimators for both the parametric and nonparametric parts and show that the estimators achieve the best convergence rate. Moreover, we show that the proposed method is much more efficient than the least-squares-based method for many non-normal errors and that it only loses a small amount of efficiency for normal errors. In addition, it is shown that the loss in efficiency is at most 11.1% for estimating varying coefficient functions and is no greater than 13.6% for estimating parametric components. To achieve sparsity with high-dimensional covariates, we propose adaptive penalization methods for variable selection in the semiparametric varying-coefficient partially linear model and prove that the methods possess the oracle property. Extensive Monte Carlo simulation studies are conducted to examine the finite-sample performance of the proposed procedures. Finally, we apply the new methods to analyze the plasma beta-carotene level data. PMID- 21666870 TI - MicroRNAs in mouse models of lymphoid malignancies. AB - The discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation that affects many normal and pathologic biological systems. Among the malignancies affected by the dysregulation of miRNAs there are cancers of lymphoid origin, in which miRNAs are thought to have tumor suppressive or tumor promoting activities, depending on the nature of their specific targets. In the last 4-5 years, the experimental field that provided the deepest insights into the in vivo biology of miRNAs is that of mouse modeling in which transgenic and knockout animals mimic, respectively, over-expression or down-regulation of specific miRNAs involved in human leukemia/lymphoma. This review discusses recent advances in our understanding of lymphoid malignancies based on the natural and engineered mouse models of three different miRNAs, miR-15a/16-1 cluster, miR-155, and miR-17-92 cluster. PMID- 21666871 TI - Legal Conceptions of Equality in the Genomic Age. PMID- 21666872 TI - Comparative Markedness and Induced Opacity. AB - Results are reported from a descriptive and experimental study that was intended to evaluate comparative markedness (McCarthy 2002, 2003) as an amendment to optimality theory. Two children (aged 4;3 and 4;11) with strikingly similar, delayed phonologies presented with two independent, interacting error patterns of special interest, i.e., Deaffrication ([tin] 'chin') and Consonant Harmony ([gog] 'dog') in a feeding interaction ([kik] 'cheek'). Both children were enrolled in a counterbalanced treatment study employing a multiple base-line single-subject experimental design, which was intended to induce a grandfather effect in one case ([dog] 'dog' and [kik] 'cheek') and a counterfeeding interaction in the other ([gog] 'dog' and [tik] 'cheek'). The results were largely supportive of comparative markedness, although some anomalies were observed. The clinical implications of these results are also explored. PMID- 21666873 TI - Parallel Materialization of Large ABoxes. AB - This paper is concerned with the efficient computation of materialization in a knowledge base with a large ABox. We present a framework for performing this task on a shared-nothing parallel machine. The framework partitions TBox and ABox axioms using a min-min strategy. It utilizes an existing system, like SwiftOWLIM, to perform local inference computations and coordinates exchange of relevant information between processors. Our approach is able to exploit parallelism in the axioms of the TBox to achieve speedup in a cluster. However, this approach is limited by the complexity of the TBox. We present an experimental evaluation of the framework using datasets from the Lehigh University Benchmark (LUBM). PMID- 21666874 TI - SOCR Analyses: Implementation and Demonstration of a New Graphical Statistics Educational Toolkit. AB - The web-based, Java-written SOCR (Statistical Online Computational Resource) tools have been utilized in many undergraduate and graduate level statistics courses for seven years now (Dinov 2006; Dinov et al. 2008b). It has been proven that these resources can successfully improve students' learning (Dinov et al. 2008b). Being first published online in 2005, SOCR Analyses is a somewhat new component and it concentrate on data modeling for both parametric and non parametric data analyses with graphical model diagnostics. One of the main purposes of SOCR Analyses is to facilitate statistical learning for high school and undergraduate students. As we have already implemented SOCR Distributions and Experiments, SOCR Analyses and Charts fulfill the rest of a standard statistics curricula. Currently, there are four core components of SOCR Analyses. Linear models included in SOCR Analyses are simple linear regression, multiple linear regression, one-way and two-way ANOVA. Tests for sample comparisons include t test in the parametric category. Some examples of SOCR Analyses' in the non parametric category are Wilcoxon rank sum test, Kruskal-Wallis test, Friedman's test, Kolmogorov-Smirnoff test and Fligner-Killeen test. Hypothesis testing models include contingency table, Friedman's test and Fisher's exact test. The last component of Analyses is a utility for computing sample sizes for normal distribution. In this article, we present the design framework, computational implementation and the utilization of SOCR Analyses. PMID- 21666875 TI - Poly(vinyl alcohol) Rehydratable Photonic Crystal Sensor Materials. AB - We developed a new photonic crystal hydrogel material based on the biocompatible polymer poly (vinyl alcohol) (PVA), which can be reversibly dehydrated and rehydrated, without the use of additional fillers, while retaining the diffraction and swelling properties of polymerized crystalline colloidal arrays (PCCA). This chemically modified PVA hydrogel photonic crystal efficiently diffracts light from the embedded crystalline colloidal array. This diffraction optically reports on volume changes occurring in the hydrogel by shifts in the wavelength of the diffracted light. We fabricated a pH sensor, which demonstrates a 350 nm wavelength shift between pH values of 3.3 and 8.5. We have also fabricated a Pb(+2) sensor, in which pendant crown ether groups bind lead ions. Immobilization of the ions within the hydrogel increases the osmotic pressure due to the formation of a Donnan potential, swelling the hydrogel and shifting the observed diffraction in proportion to the concentration of bound ions. The sensing responses of rehydrated PVA pH and Pb(+2) sensors were similar to that before drying. This reversibility of rehydration enables storage of these hydrogel photonic crystal sensors in the dry state, which makes them much more useful for commercial applications. PMID- 21666876 TI - A Review of Existing Relational Aggression Programs: Strengths, Limitations, and Future Directions. AB - Research suggests that involvement in relational aggression is associated with serious adjustment problems, including concurrent and future social maladjustment (e.g., problematic friendships; rejection), internalizing problems (e.g., depressive symptoms), and school avoidance. Despite the burgeoning literature focusing on the harmful and damaging nature of relationally aggressive behavior, this research has only recently begun to be used to inform school-based prevention and intervention programming. This article reviews the developmental research related to relational aggression and presents a systematic examination of nine published school-based prevention and intervention programs to prevent relational aggression. Programs reviewed target preschool through eighth-grade students. Strengths and limitations of each program are discussed. Recommendations are offered for future research to develop and validate school based programming for relational aggression, and implications for school psychologists are discussed. PMID- 21666877 TI - SYNTHESIS OF (S,S)-DIISOPROPYL TARTRATE (E)-CROTYLBORONATE AND ITS REACTION WITH ALDEHYDES: (2R,3R,4R)-1,2-DIDEOXY-2-ETHENYL-4,5-O-(1-METHYLETHYLIDENE)-XYLITOL. PMID- 21666878 TI - A Study of Solvent Effects in the Solvolysis of Propargyl Chloroformate. AB - The specific rates of solvolysis of propargyl chloroformate (1) are analyzed in 22 solvents of widely varying nucleophilicity and ionizing power values at 25.0 degrees C using the extended Grunwald-Winstein equation. Sensitivities to solvent nucleophilicity (l) of 1.37 and to solvent ionizing power (m) of 0.47 suggest a bimolecular process with the formation of a tetrahedral intermediate. A plot of the rates of solvolysis of 1 against those previously reported for phenyl chloroformate (2) results in a correlation coefficient (R) of 0.996, a slope of 0.86, and an F-test value of 2161. The unequivocal correlation between these two substrates attest that the stepwise association-dissociation (A(N) + D(N)) mechanism previously proposed for 2 is also operative in 1. PMID- 21666880 TI - Optimization of Applications with Non-blocking Neighborhood Collectives via Multisends on the Blue Gene/P Supercomputer. AB - We explore the multisend interface as a data mover interface to optimize applications with neighborhood collective communication operations. One of the limitations of the current MPI 2.1 standard is that the vector collective calls require counts and displacements (zero and nonzero bytes) to be specified for all the processors in the communicator. Further, all the collective calls in MPI 2.1 are blocking and do not permit overlap of communication with computation. We present the record replay persistent optimization to the multisend interface that minimizes the processor overhead of initiating the collective. We present four different case studies with the multisend API on Blue Gene/P (i) 3D-FFT, (ii) 4D nearest neighbor exchange as used in Quantum Chromodynamics, (iii) NAMD and (iv) neural network simulator NEURON. Performance results show 1.9* speedup with 32(3) 3D-FFTs, 1.9* speedup for 4D nearest neighbor exchange with the 2(4) problem, 1.6* speedup in NAMD and almost 3* speedup in NEURON with 256K cells and 1k connections/cell. PMID- 21666879 TI - An ERP study of conflict monitoring in 4-8-year old children: associations with temperament. AB - Although there is great interest in identifying the neural correlates of cognitive processes that create risk for psychopathology, there is a paucity of research in young children. One event-related potential (ERP), the N2, is thought to index conflict monitoring and has been linked cognitive and affective risk factors for anxiety. Most of this research, however, has been conducted with adults, adolescents, and older children, but not with younger children. To address this gap, the current study examined 26 4-8-year-olds, who completed a cued flanker task while EEG was continuously recorded. We assessed whether the N2 was detectable in this group of young children and examined associations between the N2 and factors reflecting affective risk (e.g., reduced executive attention, temperamental effortful control, and temperamental surgency). We documented an N2 effect (greater N2 amplitude to incongruent versus congruent flankers), but only in children older than 6 years of age. Increases in the N2 effect were associated with less efficient executive attention and lower temperamental effortful control. We discuss the implications of these findings and consider how they may inform future studies on biomarkers for cognitive and affective risk factors for anxiety. PMID- 21666881 TI - Flow modification in canine intracranial aneurysm model by an asymmetric stent: studies using digital subtraction angiography (DSA) and image-based computational fluid dynamics (CFD) analyses. AB - An asymmetric stent with low porosity patch across the intracranial aneurysm neck and high porosity elsewhere is designed to modify the flow to result in thrombogenesis and occlusion of the aneurysm and yet to reduce the possibility of also occluding adjacent perforator vessels. The purposes of this study are to evaluate the flow field induced by an asymmetric stent using both numerical and digital subtraction angiography (DSA) methods and to quantify the flow dynamics of an asymmetric stent in an in vivo aneurysm model. We created a vein-pouch aneurysm model on the canine carotid artery. An asymmetric stent was implanted at the aneurysm, with 25% porosity across the aneurysm neck and 80% porosity elsewhere. The aneurysm geometry, before and after stent implantation, was acquired using cone beam CT and reconstructed for computational fluid dynamics (CFD) analysis. Both steady-state and pulsatile flow conditions using the measured waveforms from the aneurysm model were studied. To reduce computational costs, we modeled the asymmetric stent effect by specifying a pressure drop over the layer across the aneurysm orifice where the low porosity patch was located. From the CFD results, we found the asymmetric stent reduced the inflow into the aneurysm by 51%, and appeared to create a stasis-like environment which favors thrombus formation. The DSA sequences also showed substantial flow reduction into the aneurysm. Asymmetric stents may be a viable image guided intervention for treating intracranial aneurysms with desired flow modification features. PMID- 21666882 TI - Active Guidance of a Handheld Micromanipulator using Visual Servoing. AB - In microsurgery, a surgeon often deals with anatomical structures of sizes that are close to the limit of the human hand accuracy. Robotic assistants can help to push beyond the current state of practice by integrating imaging and robot assisted tools. This paper demonstrates control of a handheld tremor reduction micromanipulator with visual servo techniques, aiding the operator by providing three behaviors: snap-to, motion-scaling, and standoff-regulation. A stereo camera setup viewing the workspace under high magnification tracks the tip of the micromanipulator and the desired target object being manipulated. Individual behaviors activate in task-specific situations when the micromanipulator tip is in the vicinity of the target. We show that the snap-to behavior can reach and maintain a position at a target with an accuracy of 17.5 +/- 0.4MUm Root Mean Squared Error (RMSE) distance between the tip and target. Scaling the operator's motions and preventing unwanted contact with non-target objects also provides a larger margin of safety. PMID- 21666884 TI - Approach-specific multi-grid anatomical modeling for neurosurgery simulation with public-domain and open-source software. AB - We present on-going work on multi-resolution sulcal-separable meshing for approach-specific neurosurgery simulation, in conjunction multi-grid and Total Lagrangian Explicit Dynamics finite elements. Conflicting requirements of interactive nonlinear finite elements and small structures lead to a multi-grid framework. Implications for meshing are explicit control over resolution, and prior knowledge of the intended neurosurgical approach and intended path. This information is used to define a subvolume of clinical interest, within some distance of the path and the target pathology. Restricted to this subvolume are a tetrahedralization of finer resolution, the representation of critical tissues, and sulcal separability constraint for all mesh levels. PMID- 21666883 TI - Statistical learning and language acquisition. AB - Human learners, including infants, are highly sensitive to structure in their environment. Statistical learning refers to the process of extracting this structure. A major question in language acquisition in the past few decades has been the extent to which infants use statistical learning mechanisms to acquire their native language. There have been many demonstrations showing infants' ability to extract structures in linguistic input, such as the transitional probability between adjacent elements. This paper reviews current research on how statistical learning contributes to language acquisition. Current research is extending the initial findings of infants' sensitivity to basic statistical information in many different directions, including investigating how infants represent regularities, learn about different levels of language, and integrate information across situations. These current directions emphasize studying statistical language learning in context: within language, within the infant learner, and within the environment as a whole. WIREs Cogn Sci 2010 1 906-914 This article is categorized under: Linguistics > Language Acquisition Psychology > Language. PMID- 21666885 TI - Correlates of Psychological Distress and Major Depressive Disorder Among African American Men. AB - This study examines the demographic correlates of depressive symptoms, serious psychological distress (SPD), and major depressive disorder (MDD; 12-month and lifetime prevalence) among a national sample of African American men. Analysis of the National Survey of American Life (NSAL) data set provides first-time substantiation of important demographic differences in depressive symptoms (measured by the Center for Epidemiological Studies Depression scale [CES-D]), SPD (measured by the K6), and 12-month and lifetime MDD among African American men. Findings illuminate the heterogeneity within the African American male population. Findings also demonstrate the need for additional research focusing on within-group differences and a comprehensive research and mental health promotion agenda that recognizes the importance of improving access to education and employment and promoting healthy coping behaviors, while acknowledging the larger social context in which African American men live. PMID- 21666886 TI - Shift Work and Child Behavioral Outcomes. AB - Using a large, contemporary U.S. dataset, the National Longitudinal Survey of Youth-Child Supplement, this paper explores the relationship between maternal shift work and the behavioral outcomes of children aged 4 to 10. Special attention was given to subgroups of children (e.g., based on family type, family income, and mother's occupation and working hours) and the patterns of parental work schedules and work hours. Regression results suggest that maternal shift work may contribute to more behavioral problems. Of all children whose mothers worked non-day shifts, the strongest associations were found for children who lived in single-mother or low-income families, whose mothers worked in cashier or service occupations, and whose mothers worked non-day shifts full-time. Implications for future research are discussed. PMID- 21666887 TI - Chitinolytic enzymes from bacterium inhabiting human gastrointestinal tract -- critical parameters of protein isolation from anaerobic culture. AB - The object of this study are chitinolytic enzymes produced by bacterium Clostridium paraputrificum J4 isolated from the gastrointestinal tract of a healthy human. In particular, we focus on the development of purification protocols, determination of properties of the enzymes and their activity profiles. The process of bacteria cultivation and isolation of chitinolytic complex of enzymes showing specific activities of endo-, exo-chitinase and N acetyl-beta-glucosaminidase was optimized. A range of various purification procedures were used such as ultrafiltration, precipitation, chromatographic separations (ion-exchange, size exclusion, chromatofocusing) in altered combinations. The optimal purification protocol comprises two or three steps. Individual samples were analyzed by SDS/PAGE electrophoresis and after renaturation their activity could be detected using zymograms. Mass spectroscopy peptide fragment analysis and MALDI analysis of the purest samples indicate presence of endochitinase B (molecular mass about 85 kDa) and of 60-kDa endo- and exochitinases. PMID- 21666888 TI - PDZ domain from Dishevelled -- a specificity study. AB - Intracellular signaling cascades induced by Wnt proteins play a key role in developmental processes and are implicated in cancerogenesis. It is still unclear how the cell determines which of the three possible Wnt response mechanisms should be activated, but the decision process is most likely dependent on Dishevelled proteins. Dishevelled family members interact with many diverse targets, however, molecular mechanisms underlying these binding events have not been comprehensively described so far. Here, we investigated the specificity of the PDZ domain from human Dishevelled-2 using C-terminal phage display, which led us to identification of a leucine-rich binding motif strongly resembling the consensus sequence of a nuclear export signal. PDZ interactions with several peptide and protein motifs (including the nuclear export signal sequence from Dishevelled-2 protein) were investigated in detail using fluorescence spectroscopy, mutational analysis and immunoenzymatic assays. The experiments showed that the PDZ domain can bind the nuclear export signal sequence of the Dishevelled-2 protein. Since the intracellular localization of Dishevelled is governed by nuclear localization and nuclear export signal sequences, it is possible that the intramolecular interaction between PDZ domain and the export signal could modulate the balance between nuclear and cytoplasmic pool of the Dishevelled protein. Such a regulatory mechanism would be of utmost importance for the differential activation of Wnt signaling cascades, leading to selective promotion of the nucleus-dependent Wnt beta-catenin pathway at the expense of non canonical Wnt signaling. PMID- 21666889 TI - A conjugate of pyridine-4-aldoxime and atropine as a potential antidote against organophosphorus compounds poisoning. AB - A conjugate of pyridine-4-aldoxime and atropine (ATR-4-OX) was synthesized and its antidotal efficiency was tested in vitro on tabun- or paraoxon-inhibited acetylcholinesterase (AChE) of human erythrocytes as well as in vivo using soman , tabun- or paraoxon-poisoned mice. Its genotoxic profile was assessed on human lymphocytes in vitro and was found acceptable for further research. ATR-4-OX showed very weak antidotal activity, inadequate for soman or tabun poisoning. Conversely, it was effective against paraoxon poisoning both in vitro and in vivo. All animals treated with 5 % or 25 % LD(50) doses of the new oxime survived after administration of 10.0 or 16.0 LD(50) doses of paraoxon, respectively. Based on the persistence of toxicity symptoms in mice, the atropine moiety had questionable effects in attenuating such symptoms. It appears that ATR-4-OX has a therapeutic effect related to the reactivation of phosphylated AChE, but not to receptor antagonization. PMID- 21666890 TI - Asynchronous magnetic bead rotation (AMBR) biosensor in microfluidic droplets for rapid bacterial growth and susceptibility measurements. AB - Inappropriate antibiotic use is a major factor contributing to the emergence and spread of antimicrobial resistance. The long turnaround time (over 24 hours) required for clinical antimicrobial susceptibility testing (AST) often results in patients being prescribed empiric therapies, which may be inadequate, inappropriate, or overly broad-spectrum. A reduction in the AST time may enable more appropriate therapies to be prescribed earlier. Here we report on a new diagnostic asynchronous magnetic bead rotation (AMBR) biosensor droplet microfluidic platform that enables single cell and small cell population growth measurements for applications aimed at rapid AST. We demonstrate the ability to rapidly measure bacterial growth, susceptibility, and the minimum inhibitory concentration (MIC) of a small uropathogenic Escherichia coli population that was confined in microfluidic droplets and exposed to concentrations above and below the MIC of gentamicin. Growth was observed below the MIC, and no growth was observed above the MIC. A 52% change in the sensor signal (i.e. rotational period) was observed within 15 minutes, thus allowing AST measurements to be performed potentially within minutes. PMID- 21666891 TI - Fine tuning of emission color of iridium(III) complexes from yellow to red via substituent effect on 2-phenylbenzothiazole ligands: synthesis, photophysical, electrochemical and DFT study. AB - Four novel iridium(III) complexes bearing biphenyl (7a-7c) or fluorenyl (7d) modified benzothiazole cyclometallate ligands are synthesized. In comparison with the yellow parent complex, bis(2-phenylbenzothiozolato-N,C(2')) iridium(III) (acetylacetonate) [(pbt)(2)Ir(acac)] (lambda(PLmax) = 557 nm, phi(PL) = 0.26), 7a 7d show 20-43 nm bathochromic shifted orange or red phosphorescence in solution, with maximum photoluminescence (PL) quantum yield of 0.62, and PL lifetime of 1.8 2.0 MUs. Meanwhile, the resulting complexes also exhibit intense orange or red phosphorescence of lambda(PLmax) = 588-611 nm in solid films. The complex 7c with two tert-butyl substituents possesses the highest phosphorescent efficiency both in dilute solution and thin solid films, therefore may be a prospective candidate for both doping and host emitting electrophosphorescent material. Furthermore, despite the observation of severe oxygen quenching for 7a-7d in solution, 7a and 7c even show efficient emission intensity quenching by oxygen in their solid state due to the existence of void channels in crystals; consequently, they are promising molecular oxygen sensor reagents. Electrochemical measurement and DFT calculation results suggest that all these chelates own declined LUMOs of 0.1 eV relative to that of (pbt)(2)Ir(acac) owing to the contribution of the phenyl substituents; whereas only 7d shows a more destabilized HOMO (~0.1 eV) compared with the parent chelate. PMID- 21666892 TI - Novel approaches to model-free analysis of lanthanide-induced shifts, targeted to the investigation of contact term behavior. AB - Three novel equations were proposed to perform graphical model-free analysis of lanthanide-induced shifts in NMR spectra of axially symmetrical complexes within Bleaney's T(-2) expansion. Application and efficiency of these newly developed approaches were demonstrated on the example of heteroleptic triple-decker crown phthalocyaninates (Pc)M[(15C5)(4)Pc]M(Pc), where (15C5)--15-crown-5, (Pc(2-))- phthalocyaninato-dianion, M = Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb and Y as diamagnetic reference. By construction of these equations, the proposed analytical techniques are more sensitive to variations of hyperfine coupling terms throughout lanthanide series, in comparison with previously developed approaches, becoming a valuable tool for the investigation of structural and electronic characteristics of lanthanide complexes. PMID- 21666893 TI - Technical advances to genetically engineering human embryonic stem cells. AB - Human embryonic stem cells (hESC) are important to basic scientific research as an in vitro model system for the study of human development and to clinical research as an invaluable cell source for regenerative medicine. The ability to genetically engineer hESC is a critical resource as it facilitates many fundamental studies to understand gene regulation and cell development. These techniques include (1) unidirectional or reversible; (2) non-, pseudo- or completely site-specific; and (3) endogenous and/or pre-engineered DNA sequences modification; where each has its own strengths and limitations. This article reviews the various methodologies to genetically engineer hESC to achieve a stable gene insertion or deletion. We discuss the existing challenges of the well established methodologies (lentivirus and Cre/loxP system), and further examine recent advances in this field, such as the latest genetic modifying tools (phiC31 integrase, PiggyBac transposase and zinc finger nucleases). We also propose new opportunities for future developments to aid genetic modifications of hESC, and new applications for future basic and therapeutic research in hESC. PMID- 21666894 TI - Connectivity of PS-b-PEO templated spherical pores in titanium oxide films. AB - Titania films having relatively uniform spherical pores were successfully fabricated using polystyrene-block-poly(ethylene oxide) (PS(n)-b-PEO(m)) diblock copolymers. Depending on the molecular weight of PS(n)-b-PEO(m), the spherical pores were varied from large mesopores (n = 40,000, m = 53,000; ~40 nm) to macropores (n = 58,600, m = 71,000; ~60 nm, n = 100,000, m = 150,000; ~100 nm) in diameter. It was confirmed that the porous structures were thermally stable with crystallization of the titania frameworks. Interconnectivity between the spherical pores was reliant on the micellar arrangement of hydrophobic PS cores, while the amount of isolated pores was increased in the films prepared using low molecular weight PS(n)-b-PEO(m). The presence of such isolated pores was confirmed on the basis of adsorption experiments by using a globular hemoprotein cytochrome c (ca. 3.1 nm). Highly interconnected spherical pores, which were preferentially fabricated using high molecular weight PS(n)-b-PEO(m), were quite helpful for smooth diffusion-adsorption of bulky proteins inside the porous films. PMID- 21666895 TI - New chemistry of 1,2-closo-P2B10H10 and 1,2-closo-As2B10H10; in silico and gas electron diffraction structures, and new metalladiphospha- and metalladiarsaboranes. AB - The molecular structures of 1,2-closo-P(2)B(10)H(10) (1) and 1,2-closo As(2)B(10)H(10) (2) have been determined by gas electron diffraction and the results obtained compared with those from computation at the MP2/6-31G** level of theory. The level of agreement is good for 2 (root-mean-square [rms] misfit for As and B atoms 0.0297 A) and very good for 1 (rms misfit for P and B atoms 0.0082 A). In comparing the structures of 1 and 2 with that of 1,2-closo-C(2)B(10)H(12) (I) it is evident that expansion of the polyhedron from I to 1 to 2 is restricted only to the heteroatom vertices and the B(6) face to which these are bound. Following deboronation (at B3) and subsequent metallation, compounds 1 and 2 have been converted into the new metalladiheteroboranes 3-(eta-C(9)H(7))-3,1,2-closo CoAs(2)B(9)H(9) (4), 3-(eta-C(10)H(14))-3,1,2-closo-RuAs(2)B(9)H(9) (5), 3-(eta C(5)H(5))-3,1,2-closo-CoP(2)B(9)H(9) (6), 3-(eta-C(9)H(7))-3,1,2-closo CoP(2)B(9)H(9) (7) and 3-(eta-C(10)H(14))-3,1,2-closo-RuP(2)B(9)H(9) (8), the last three constituting the first examples of metalladiphosphaboranes. Together with the known compound 3-(eta-C(5)H(5))-3,1,2-closo-CoAs(2)B(9)H(9) (3), compounds 4-8 have been analysed by NMR spectroscopy and (except for 8) single crystal X-ray diffraction. The (11)B NMR spectra of analogous pairs of metalladiphosphaborane and metalladiarsaborane (6 and 3, 7 and 4, 8 and 5) reveal a consistently narrower (9-10 ppm) chemical shift range for the metalladiarsaboranes, the combined result of a deshielding of the lowest frequency resonance (B6) and an increased shielding of the highest frequency resonance (B8) via an antipodal effect. In crystallographic studies, compounds 3 and 5B (one of two crystallographically-independent molecules) suffer As/B disorder, but in both cases it was possible to refine distinct, ordered, components of the disorder, the first time this has been reported for metalladiarsaboranes. Moreover, whilst the Cp compounds 6 and 3 are disordered, their indenyl analogues 7 and 4 are either ordered or significantly less disordered, a consequence of both the reduced symmetry of an indenyl ligand compared to a Cp ligand and the preference of the former for a distinct conformation relative to the cage heteroatoms. Unexpectedly, whilst this conformation in the cobaltadiphosphaborane 7 is cis-staggered (similar to that previously established for the analogous cobaltadicarborane), in the cobaltadiarsaborane 4 the conformation is close to cis-eclipsed. PMID- 21666896 TI - Stereospecificity in the Au-catalysed cyclisation of monoallylic diols. Synthesis of (+)-isoaltholactone. AB - We describe a concise synthesis of (+)-isoaltholactone via a Au-catalysed cyclisation of a monoallylic diol to form the tetrahydrofuranyl ring. Analogous cyclisations show that the stereochemical outcome is dictated by the stereochemistry of the diol substrate. PMID- 21666897 TI - Synthesis and antiviral activity of highly water-soluble polycarboxylic derivatives of [70]fullerene. AB - We report here a facile preparation of highly water-soluble derivatives C(70)[p C(6)H(4)(CH(2))(n)COOH](8) (n = 2, 3) starting from readily available chlorinated [70]fullerene precursors C(70)Cl(8) and C(70)Cl(10). The synthesized fullerene derivatives showed pronounced antiviral activity in vitro, particularly against human immunodeficiency virus (HIV) and influenza A virus (subtypes H1N1 and H3N2). PMID- 21666898 TI - Templating an organic array with Si(111)-7*7. AB - We demonstrate that nearest neighbor molecular adsorption can be sterically hindered on the Si(111)-7*7 surface reconstruction. This breaks the energetic equivalence of corner and edge di-sigma attachment geometries and allows a translationally ordered organic layer to be templated directly on the 7*7 reconstruction. PMID- 21666899 TI - Design and synthesis of novel mesostructured metal-organic frameworks templated by cationic surfactants via cooperative self-organization. AB - A novel design strategy to synthesize highly ordered hexagonally mesostructured metal-organic framework materials was successfully explored, which means the realization of directly cooperative self-assembly of metal ions, bridging ligands and surfactants in an aqueous system. PMID- 21666900 TI - Post-polymerization functionalization of linear polyglycidol with diethyl vinylphosphonate. AB - In this communication we report on the base catalyzed Michael addition of the hydroxy methyl side groups in polyglycidol to diethyl vinyl phosphonate. Hydrolysis of the diethyl phosphonato ethyl side groups with bromotrimethylsilane leads to a new class of polyglycidols with pendant phosphonic acid groups. PMID- 21666901 TI - Control of selectivity in the generation and reactions of oxonium ylides. AB - Dirhodium catalyzed reactions of aryl-substituted tetrahydropyranone diazoacetoacetates produce ylide intermediates that unexpectedly yield two oxabicyclo[4.2.1]-nonane diastereoisomers, but a single diastereoisomer is formed by increasing the steric bulk of the aryl substituent. PMID- 21666902 TI - Physicochemical properties and plastic crystal structures of phosphonium fluorohydrogenate salts. AB - Fluorohydrogenate salts of quaternary phosphonium cations with alkyl and methoxy groups (tetraethylphosphonium (P(2222)(+)), triethyl-n-pentylphosphonium (P(2225)(+)), triethyl-n-octylphosphonium (P(2228)(+)), and triethylmethoxymethylphosphonium (P(222(101))(+))) have been synthesized by the metatheses of anhydrous hydrogen fluoride and the corresponding phosphonium bromide or chloride precursors. The three salts with asymmetric cations, P(222m)(FH)(2.1)F (m = 5, 8, and 101), are room temperature ionic liquids (ILs) and are characterized by differential scanning calorimetry, density, viscosity, and conductivity measurements. Linear sweep voltammetry using a glassy carbon working electrode shows these phosphonium fluorohydrogenate ILs have wide electrochemical windows (>4.9 V) with the lowest viscosity and highest conductivity in the known phosphonium-based ILs. Thermogravimetry shows their thermal stabilities are also improved compared to previously reported alkylammonium cation-based fluorohydrogenate salts. Differential scanning calorimetry and X-ray diffraction revealed that tetraethylphosphonium fluorohydrogenate salt, P(2222)(FH)(2)F, exhibits two plastic crystal phases. The high temperature phase has a hexagonal lattice, which is the first example of a plastic crystal phase with an inverse nickel arsenide-type structure, and the low temperature phase has an orthorhombic lattice. The high-temperature plastic crystal phase exhibits a conductivity of 5 mS cm(-1) at 50 degrees C, which is the highest value for the neat plastic crystals. PMID- 21666903 TI - Towards mild metal-catalyzed C-H bond activation. AB - Functionalizing traditionally inert carbon-hydrogen bonds represents a powerful transformation in organic synthesis, providing new entries to valuable structural motifs and improving the overall synthetic efficiency. C-H bond activation, however, often necessitates harsh reaction conditions that result in functional group incompatibilities and limited substrate scope. An understanding of the reaction mechanism and rational design of experimental conditions have led to significant improvement in both selectivity and applicability. This critical review summarizes and discusses endeavours towards the development of mild C-H activation methods and wishes to trigger more research towards this goal. In addition, we examine select examples in complex natural product synthesis to demonstrate the synthetic utility of mild C-H functionalization (84 references). PMID- 21666904 TI - The valence electronic structure and conformational flexibility of epichlorohydrin. AB - The electronic structure of epichlorohydrin is investigated in the whole valence region by a combined experimental and theoretical study. The issue of controversial assignments of the molecular electronic structure is here addressed. Photoelectron spectra (PES) and Threshold Photoelectron spectra (TPES) of room temperature molecules in the gas phase are recorded. Geometries and energies of the stable conformers due to internal rotation of the C-C-C-Cl dihedral angle, gauche-II (g-II), gauche-I (g-I), and cis, are calculated, and the effect of the conformational flexibility on the photoionization energetics is studied by DFT and 2h-1p Configuration Interaction (CI) methods. Strong breakdown of the Koopmans Theorem (KT) is obtained for the four outermost ionizations, which are further investigated by higher level ab initio calculations. The full assignment of the spectrum is put on a firm basis by the combination of experimental and theoretical results. The orbital composition from correlated calculations is found closer to the DFT orbitals, which are then used to analyze the electronic structure of the molecule. The Highest Occupied Molecular Orbital (HOMO) and HOMO--2 are n(O)/n(Cl) mixed orbitals. The nature of each valence MO is generally preserved in all the conformers, although the magnitude of the n(O)/n(Cl) mixing in HOMO and HOMO--2 varies to some extent with the C-C-C-Cl dihedral angle. The low energy part of the HOMO PE band is predicted to be substantially affected by the conformational flexibility, as experimentally observed in the spectra. The rest of the spectrum is described in terms of the dominant conformer g-II, and a good agreement between experiment and theory is found. The inner-valence PE spectrum is characterized by satellite structures, due to electron correlation effects, which are interpreted by means of 2h-1p CI calculations. PMID- 21666905 TI - Selective gas sorption in a [2+3] 'propeller' cage crystal. AB - A [2+3] organic cage compound based on the condensation reaction of 1,3,5-tri(4 formylphenyl)benzene with 1,5-pentanediamine was synthesized. The resulting porous molecular crystal demonstrates selective adsorption of hydrogen and carbon dioxide over nitrogen. As for porous polymer membranes, a trade-off between sorption capacity and selectivity is observed for materials in this class. PMID- 21666906 TI - Encapsulated droplets with metered and removable oil shells by electrowetting and dielectrophoresis. AB - A water-core and oil-shell encapsulated droplet exhibits several advantages including enhanced fluidic manipulation, reduced biofouling, decreased evaporation, and simplified device packaging. However, obtaining the encapsulated droplet with an adjustable water-to-oil volume ratio and a further removable oil shell is not possible by reported techniques using manual pipetting or droplet splitting. We report a parallel-plate device capable of generation, encapsulation, rinsing, and emersion of water and/or oil droplets to achieve three major aims. The first aim of our experiments was to form encapsulated droplets by merging electrowetting-driven water droplets and dielectrophoresis actuated oil droplets whose volumes were precisely controlled. 25 nL water droplets and 2.5 nL non-volatile silicone oil droplets with various viscosities (10, 100, and 1000 cSt) were individually created from their reservoirs to form encapsulated droplets holding different water-to-oil volume ratios of 10:1 and 2:1. Secondly, the driving voltages, evaporation rates, and biofouling of the precise encapsulated droplets were measured. Compared with the bare and immersed droplets, we found the encapsulated droplets (oil shells with lower viscosities and larger volumes) were driven at a smaller voltage or for a wider velocity range. In the dynamic evaporation tests, at a temperature of 20 +/- 1 degrees C and relative humidity of 45 +/- 3%, 10 cSt 10:1 and 2:1 encapsulated droplets were moved at the velocity of 0.25 mm s(-1) for 22 and 35 min until losing 16.6 and 17.5% water, respectively, while bare droplets followed the driving signal for only 6 min when 11.4% water was lost. Evaporation was further diminished at the rate of 0.04% min(-1) for a carefully positioned stationary encapsulated droplet. Biofouling of 5 MUg ml(-1) FITC-BSA solution was found to be eliminated by the encapsulated droplet from the fluorescent images. The third aim of our research was to remove the oil shell by dissolving it in an on-chip rinsing reservoir containing hexane. After emersion from the rinsing reservoir, the bare droplet was restored as hexane rapidly evaporated. Removal of the oil shell would not only increase the evaporation of the core droplet when necessary, but also enhance the signal-to-noise ratio in the following detection steps. PMID- 21666907 TI - New strategy of photodynamic treatment of TiO2 nanofibers combined with celastrol for HepG2 proliferation in vitro. AB - As one of the best biocompatible semiconductor nanomaterials, TiO(2) nanofibers can act as a good photosensitizer material and show potential application in the field of drug carriers and photodynamic therapy to cure diseases. Celastrol, one of the active components extracted from T. wilfordii Hook F., was widely used in traditional Chinese medicine for many diseases. In this study, the cytotoxicity of celastrol for HepG2 cancer cells was firstly explored. The results showed that celastrol could inhibit cancer cell proliferation in a time-dependent and dose dependent manner, inducing apoptosis and cell cycle arrest at G2/M phase in HepG2 cells. After the TiO(2) nanofibers were introduced into the system of celastrol, the cooperation effect showed that the nanocomposites between TiO(2) nanofibers and celastrol could enhance the cytotoxicity of celastrol for HepG2 cells and cut down the drug consumption so as to reduce the side-effect of the related drug. Associated with the photodynamic effect, it is evident that TiO(2) nanofibers could readily facilitate the potential application of the active compounds from natural products like celastrol. Turning to the advantages of nanotechnology, the combination of nanomaterials with the related monomer active compounds of promising Chinese medicine could play an important role to explore the relevant mechanism of the drug cellular interaction and promote the potential application of TiO(2) nanofibers in the clinical treatment. PMID- 21666908 TI - Comment on "The electron density vs. NICS scan: a new approach to assess aromaticity in molecules with different ring sizes" by C. Foroutan-Nejad, S. Shahbazian and P. Rashidi-Ranjbar, Phys. Chem. Chem. Phys., 2010, 12, 12630: is there a connection between electron densities at the ring critical points and NICS? PMID- 21666910 TI - Effect of normal variations on disease classification of Raman spectra from cervical tissue. AB - In this paper, we examine how variations in normal tissue can influence disease classification of Raman spectra. Raman spectra from normal areas may be affected by previous disease or proximity to areas of dysplasia. Spectra were acquired in vivo from 172 patients and classified into five tissue categories: true normal (no history of disease), previous disease normal (history of disease, current normal diagnosis), adjacent normal (disease on cervix, spectra acquired from visually normal area), low grade, and high grade. Taking into account the various "normal" states of the tissue before statistical analysis led to a disease classification accuracy of 97%. These results indicate that abnormal changes significantly affect Raman spectra, even when areas are histopathologically normal. The sensitivity of Raman spectroscopy to subtle biochemical differences must be considered in order to successfully implement it in a clinical setting for diagnosing cervical dysplasia and cancer. PMID- 21666911 TI - Kinetics of thermo-induced micelle-to-vesicle transitions in a catanionic surfactant system investigated by stopped-flow temperature jump. AB - The kinetics of thermo-induced micelle-to-vesicle transitions in a catanionic surfactant system consisting of sodium dodecyl sulfate (SDS) and dodecyltriethylammonium bromide (DEAB) were investigated by the stopped-flow temperature jump technique, which can achieve T-jumps within ~2-3 ms. SDS/DEAB aqueous mixtures ([SDS]/[DEAB] = 2/1, 10 mM) undergo microstructural transitions from cylindrical micelles to vesicles when heated above 33 degrees C. Upon T jumps from 20 degrees C to final temperatures in the range of 25-31 degrees C, relaxation processes associated with negative amplitudes can be ascribed to the dilution-induced structural rearrangement of cylindrical micelles and to the dissolution of non-equilibrium mixed aggregates. In the final temperature range of 33-43 degrees C the obtained dynamic traces can be fitted by single exponential functions, revealing one relaxation time (tau) in the range of 82-440 s, which decreases with increasing temperature. This may be ascribed to the transformation of floppy bilayer structures into precursor vesicles followed by further growth into final equilibrium vesicles via the exchange and insertion/expulsion of surfactant monomers. In the final temperature range of 45 55 degrees C, vesicles are predominant. Here T-jump relaxations revealed a distinctly different kinetic behavior. All dynamic traces can only be fitted with double exponential functions, yielding two relaxation times (tau(1) and tau(2)), exhibiting a considerable decrease with increasing final temperatures. The fast process (tau(1)~ 5.2-28.5 s) should be assigned to the formation of non equilibrium precursor vesicles, and the slow process (tau(2)~ 188-694 s) should be ascribed to their further growth into final equilibrium vesicles via the fusion/fission of precursor vesicles. In contrast, the reverse vesicle-to-micelle transition process induced by a negative T-jump from elevated temperatures to 20 degrees C occurs quite fast and almost completes within the stopped-flow dead time (~2-3 ms). PMID- 21666912 TI - Multiplexed immunoassay for the rapid detection of anti-tumor-associated antigens antibodies. AB - TAAs (tumor-associated antigens) microarrays were designed to detect auto antibodies directly in patient sera. Twelve different probes were chosen according to their described occurrence in cancer pathologies (Cyclin B1, Cyclin D1, Complement factor H, c-myc, IMP1, p53, p62, survivin, Her2/neu, Koc, NY-ESO-1 and PSA). Microarrays of these 12 proteins were immobilized within the nitrocellulose/cellulose acetate membrane of a 96-well filtering microtiter plate bottom. The captured auto-antibodies were detected using a staining approach based on alkaline phosphatase labeling. Thus, the presence of specific auto antibodies in samples was visualized through the positive staining of the corresponding TAA spots. The TAA HiFi microarrays were shown to be able to capture specific purified anti-TAA antibodies. In real samples, 9 proteins from the 12 TAAs panel were shown to generate specific signal and 5 antigens (p53, NY ESO-1, IMP1, cyclin B1 and c-myc) were shown to have interaction with more than 10% of the positive sera from cancer patients. This protein subpanel was proven to be able to detect 72.2% of the cancer patients tested (within a 34 panel of 18 patients and 16 healthy donors). PMID- 21666913 TI - One-step assay for detecting influenza virus using dynamic light scattering and gold nanoparticles. AB - Herein we detail the development of a simple, rapid, and sensitive method for quantitative detection of influenza A virus using dynamic light scattering (DLS) and gold nanoparticle (AuNP) labels. Influenza-specific antibodies are conjugated to AuNPs, and aggregation of the AuNP probes is induced upon addition of the target virus. DLS is used to measure the extent of aggregation and the mean hydrodynamic diameter is correlated to virus concentration. The effects of nanoparticle concentration and size on the analytical performance of the assay were systematically investigated. It was determined that decreasing the AuNP probe concentration improves the detection limit while the effect of changing the AuNP size is minimal. Optimization of the assay provided a detection limit of <100 TCID(50)/mL which is 1-2 orders of magnitude improved over commercial diagnostic kits without increasing the assay time or complexity. Additionally, this assay was demonstrated to perform equivalently for influenza virus prepared in different biological matrices. PMID- 21666914 TI - The influence of hydrogen bonding on the physical properties of ionic liquids. AB - Potential applications of ionic liquids depend on the properties of this class of liquid material. To a large extent the structure and properties of these Coulomb systems are determined by the intermolecular interactions among anions and cations. In particular the subtle balance between Coulomb forces, hydrogen bonds and dispersion forces is of great importance for the understanding of ionic liquids. The purpose of the present paper is to answer three questions: Do hydrogen bonds exist in these Coulomb fluids? To what extent do hydrogen bonds contribute to the overall interaction between anions and cations? And finally, are hydrogen bonds important for the physical properties of ionic liquids? All these questions are addressed by using a suitable combination of experimental and theoretical methods including newly synthesized imidazolium-based ionic liquids, far infrared spectroscopy, terahertz spectroscopy, DFT calculations, differential scanning calorimetry (DSC), viscometry and quartz-crystal-microbalance measurements. The key statement is that although ionic liquids consist solely of anions and cations and Coulomb forces are the dominating interaction, local and directional interaction such as hydrogen bonding has significant influence on the structure and properties of ionic liquids. This is demonstrated for the case of melting points, viscosities and enthalpies of vaporization. As a consequence, a variety of important properties can be tuned towards a larger working temperature range, finally expanding the range of potential applications. PMID- 21666915 TI - Capacitance in carbon pores of 0.7 to 15 nm: a regular pattern. AB - The study of 28 porous carbons shows that the specific capacitance in the electrolyte (C(2)H(5))(4)NBF(4)/acetonitrile is relatively constant between 0.7 and 15 nm (0.094 +/- 0.011 F m(-2)). The increase in pores below 1 nm and the lower values between 1 and 2 nm reported earlier are not observed in the present work. PMID- 21666916 TI - Role of water in atomic resolution AFM in solutions. AB - We use computer modelling to investigate the mechanism of atomic-scale corrugation in frequency modulation atomic force microscopy imaging of inorganic surfaces in solution. Molecular dynamics simulations demonstrate that the forces acting on a model microscope tip result from the direct interaction between a tip and a surface, and forces entirely due to the water structure around both tip and surface. The observed force is a balance between largely repulsive potential energy changes as the tip approaches and the entropic gain when water is sterically prevented from occupying sites near the tip and surface. Only extremely sharp tips are likely to measure direct tip-surface interactions. An investigation into the dynamics of water confined between tip and surface shows that water diffusion can be slowed by at least two orders of magnitude compared to its rate in bulk solution. PMID- 21666917 TI - A terminal nickel(II) anilide complex featuring an unsymmetrically substituted amido pincer ligand: synthesis and reactivity. AB - This work describes preparation and reaction chemistry of a terminal nickel(II) anilide complex supported by an unsymmetrically substituted diarylamido diphosphine ligand, [N(o-C(6)H(4)PPh(2))(o-C(6)H(4)P(i)Pr(2))](-) ([Ph-PNP (i)Pr](-)). Treatment of NiCl(2)(DME) with H[Ph-PNP-(i)Pr] in THF at room temperature produced [Ph-PNP-(i)Pr]NiCl as green crystals in 82% yield. Salt metathesis of [Ph-PNP-(i)Pr]NiCl with LiNHPh(THF) in THF at -35 degrees C generated cleanly [Ph-PNP-(i)Pr]NiNHPh as a greenish blue solid. The anilide complex deprotonates protic (e.g., PhOH and PhSH) and aprotic (e.g., trimethylsilylacetylene, phenylacetylene, and acetonitrile) acids in benzene at room temperature to give quantitatively [Ph-PNP-(i)Pr]NiX (X = OPh, SPh, C=CSiMe(3), C=CPh, CH(2)CN). In addition, [Ph-PNP-(i)Pr]NiNHPh also behaves as a nucleophile to react with acetyl chloride to yield [Ph-PNP-(i)Pr]NiCl and N phenylacetamide quantitatively. Carbonylation of [Ph-PNP-(i)Pr]NiNHPh with carbon monoxide affords cleanly the carbamoyl derivative [Ph-PNP-(i)Pr]Ni[C(O)NHPh]. The relative bond strengths of Ni-E in [Ph-PNP-(i)Pr]NiEPh (E = NH, O, S, C=C) are assessed and discussed. PMID- 21666918 TI - Infrared spectrum of the CS2 trimer: observation of a structure with D3 symmetry. AB - Infrared spectra of a carbon disulfide trimer formed in a pulsed supersonic slit jet expansion are obtained via direct absorption of a tuneable diode laser in the region of the CS(2)nu(3) fundamental (~1535 cm(-1)). This is the first high resolution spectroscopic observation of (CS(2))(3). Two bands sharing the same lower state are assigned to ((12)C(32)S(2))(3). These correspond to the two infrared active trimer vibrations (a parallel and a perpendicular band) of the constituent CS(2) monomer asymmetric stretches. The weaker perpendicular band is centered at 1524.613 cm(-1), shifted by -10.74 cm(-1) with respect to the free CS(2) monomer. The parallel band is centered at 1545.669 cm(-1), a vibrational shift of +10.31 cm(-1). Transitions with K? 3n and those with K = 0, J = odd in the ground state are absent, establishing that this trimer has D(3) symmetry. The two parameters required to define this structure are determined to be 3.811 A for the C-C bond distance and 61.8 degrees for the angle between a monomer axis and the plane containing the C atoms. In addition, a parallel band arising from trimers with a single (34)S substitution is observed around 1544.46 cm(-1). Together with the recently observed cross-shaped CS(2) dimer, these results indicate a tendency for CS(2) to form highly symmetric clusters. PMID- 21666919 TI - Nucleic acid X-ray crystallography via direct selenium derivatization. AB - X-ray crystallography has proven to be an essential tool for structural studies of bio-macromolecules at the atomic level. There are two major bottle-neck problems in the macromolecular crystal structure determination: phasing and crystallization. Although the selenium derivatization is routinely used for solving novel protein structures through the MAD phasing technique, the phase problem is still a critical issue in nucleic acid crystallography. The background and current progress of using direct selenium-derivatization of nucleic acids (SeNA) to solve the phase problem and to facilitate nucleic acid crystallization for X-ray crystallography are summarized in this tutorial review. PMID- 21666920 TI - Stereochemistry of post-transition metal oxides: revision of the classical lone pair model. AB - The chemistry of post transition metals is dominated by the group oxidation state N and a lower N-2 oxidation state, which is associated with occupation of a metal s(2) lone pair, as found in compounds of Tl(I), Pb(II) and Bi(III). The preference of these cations for non-centrosymmetric coordination environments has previously been rationalised in terms of direct hybridisation of metal s and p valence orbitals, thus lowering the internal electronic energy of the N-2 ion. This explanation in terms of an on-site second-order Jahn-Teller effect remains the contemporary textbook explanation. In this tutorial review, we review recent progress in this area, based on quantum chemical calculations and X-ray spectroscopic measurements. This recent work has led to a revised model, which highlights the important role of covalent interaction with oxygen in mediating lone pair formation for metal oxides. The role of the anion p atomic orbital in chemical bonding is key to explaining why chalcogenides display a weaker preference for structural distortions in comparison to oxides and halides. The underlying chemical interactions are responsible for the unique physicochemical properties of oxides containing lone pairs and, in particular, to their application as photocatalysts (BiVO(4)), ferroelectrics (PbTiO(3)), multi ferroics (BiFeO(3)) and p-type semiconductors (SnO). The exploration of lone pair systems remains a viable a venue for the design of functional multi-component oxide compounds. PMID- 21666921 TI - Achieving C-N bond cleavage in dinuclear metal cyanide complexes. AB - Cleavage of cyanide is more difficult to achieve compared to dinitrogen and carbon monoxide, even though these species contain triple bonds of greater strength. In this work, we have used computational methods to investigate thermodynamic and mechanistic aspects of the C-N bond cleavage process in [L(3)M CN-M'L(3)] systems consisting of a central cyanide unit bound in an end-on fashion to two terminal metal tris-amide complexes. In these systems, [M] is a d(3) transition metal from the 3d, 4d, 5d, or 6d series and groups 4 through 7, and [L] is either [NH(2)], [NMe(2)], [N(i)PrPh], or [N(t)BuAr]. A comparison of various models for the experimentally relevant [L(3)Mo-CN-MoL(3)] system has shown that while the C-N cleavage step appears to be an energetically favourable process, a large barrier exists for the dissociation of [L(3)Mo-CN-MoL(3)]((-)) into [L(3)Mo-C]((-)) and [N-MoL(3)], which possibly explains why C-N bond scission is not observed experimentally. The general structural, bonding, and thermochemical trends across the transition metal series investigated, indicate that the systems exhibiting the greatest degree of C-N activation, and most favourable energetics for C-N cleavage, also possess the most favourable electronic properties, namely, a close match between the relevant pi-like orbitals on the metal-based and cyanide fragments. The negative charge on the cyanide fragment leads to significant destabilization of the pi* level which needs to be populated through back-donation from the metal centres in order for C N bond scission to be achieved. Therefore, metal-based systems with high-lying d(pi) orbitals are best suited to C-N cleavage. In terms of chemical periodicity, these systems can be identified as the heavier members within a group and the earlier members within a period. As a consequence, Mo complexes are not well suited to cleaving the C-N bond, whereas the Ta analogues are the most favourable systems and should, in principle, be capable of cleaving cyanide under relatively mild conditions. An important conclusion from this work is that a successful strategy for achieving cleavage of multiply-bonded, and relatively unreactive, molecular fragments, may simply lie in tuning the electronic structures and orbital interactions by judicious choice of metal sites and ligand groups. PMID- 21666922 TI - Monitoring of pharmaceutically active compounds on the Guadalquivir River basin (Spain): occurrence and risk assessment. AB - Guadalquivir River (South of Spain) is among the major freshwater sources of the European Atlantic basin. Until now scientific efforts have been focused on contamination by heavy metals and some priority pollutants in Guadalquivir River. However, the presence of "emerging contaminants", such as pharmaceutically active compounds, has not yet been studied. In this work the occurrence and risk assessment of sixteen pharmaceutically active compounds, belonging to different therapeutic groups, in Guadalquivir River during its course through Seville city are reported. Wastewater effluents from four wastewater treatment plants discharging into Guadalquivir River and river water samples were analyzed. All studied pharmaceutically active compounds, except sulfamethoxazole, trimethoprim, estrone and clofibric acid, were detected in effluent wastewaters at concentration levels up to 28.9 MUg L(-1). Among the pharmaceutically active compounds found in effluent wastewater, seven were present in Guadalquivir River samples at concentration levels up to 0.75 MUg L(-1), which indicated an important dilution from effluent discharge. Environmental risk assessment reveals that potential ecotoxicological risk cannot be expected on Guadalquivir River at measured concentration levels. Only, the lipid regulator gemfibrozil showed a medium risk for the environment. The risk for acute toxic effects in the environment with the current use of active pharmaceutical ingredients is unlikely. However, the results do not rule out the potential for chronic environmental effects. PMID- 21666923 TI - Integrin alpha3 blockade enhances microtopographical down-regulation of alpha smooth muscle actin: role of microtopography in ECM regulation. AB - Development of functional engineered matrices for regenerative therapies can benefit from an understanding of how physical cues at the microscale affect cell behavior. In this work, we use microfabricated systems to study how stiffness and microscale topographical cues in the form of "micropegs" affect extracellular matrix synthesis. Previous work from our lab has shown that microtopographical cues in 2D and 3D systems decrease cellular proliferation and regulate matrix synthesis. In this work, the combined role of stiffness and topography on ECM synthesis is investigated in a 2D micropeg system. These studies show that fibroblasts cultured on polydimethylsiloxane (PDMS) substrates with micropegs have reduced expression of collagen type I (Col I) and collagen type VI (Col VI) compared to fibroblasts cultured on flat substrates. In addition, cells on micropegged substrates exhibit down-regulation of other important regulators of ECM synthesis such as alpha-smooth muscle actin (alpha-SMA), and integrin alpha3 (Int alpha3). Interestingly, this effect is dependent on the contractility and adhesion of the cells. When cultured in the presence of RhoA kinase (ROCK) and myosin light chain kinase (MLCK) inhibitors, no significant differences in the expression of collagen, alpha-SMA, Int alpha3, and TGFB1 are observed. Additionally, disruptions in cell adhesion prevent microtopographical regulation of ECM synthesis. When using an antibody to block the extracellular domain of Int alpha3, no differences in the expression of collagen are observed and blocking Int alpha3 results in enhanced down-regulation of alpha-SMA on the stiffer micropegged substrates. These findings demonstrate that regulation of extracellular matrix production by cells on a synthetic substrate can be guided via physical cues at the microscale, and add to the body of knowledge on the role of integrin-mediated mechanotransduction. PMID- 21666924 TI - Synthesis of 3-(aminomethylene)-2-oxoindolines by palladium-catalyzed annulation of 3-chloro-2-iodo-N-arylacrylamides with amides or amines. AB - A new palladium-catalyzed C-H bond activation-annulation-amination tandem method was presented for selectively synthesizing 3-(aminomethylene)-2-oxoindolines. In the presence of Pd(dba)(2), xantphos (L8), AgOAc and Na(2)CO(3), a variety of 3 chloro-2-iodo-N-arylacrylamides underwent the reaction with amides or amines to afford the corresponding 3-(aminomethylene)-2-oxoindolines in moderate to good yields. PMID- 21666925 TI - On the weakly C-H...pi hydrogen bonded complexes of sevoflurane and benzene. AB - A vibrational assignment of the anaesthetic sevoflurane, (CF(3))(2)CHOCH(2)F, is proposed and its interaction with the aromatic model compound benzene is studied using vibrational spectroscopy of supersonic jet expansions and of cryosolutions in liquid xenon. Ab initio calculations, at the MP2/cc-pVDZ and MP2/aug-cc-pVDZ levels, predict two isomers for the 1 : 1 complex, one in which the near-cis, gauche conformer of sevoflurane is hydrogen bonded through its isopropyl-hydrogen atom, the other in which the same conformer is bonded through a bifurcated hydrogen bond with the fluoromethyl hydrogen atoms. From the experiments it is shown that the two isomers are formed, however with a strong population dominance of the isopropyl-bonded species, both in the jet and liquid phase spectra. The experimental complexation enthalpy in liquid xenon, DeltaH(o)(LXe), of this species equals -10.9(2) kJ mol(-1), as derived from the temperature dependent behaviour of the cryosolution spectra. Theoretical complexation enthalpies in liquid xenon were obtained by combining the complete basis set extrapolated complexation energies at the MP2/aug-cc-pVXZ (X = D,T) level with corrections derived from statistical thermodynamics and Monte Carlo Free Energy Perturbation calculations, resulting in a complexation enthalpy of -11.2(3) kJ mol(-1) for the isopropyl-bonded complex, in very good agreement with the experimental value, and of -11.4(4) kJ mol(-1), for the fluoromethyl-bonded complex. The Monte Carlo calculations show that the solvation entropy of the isopropyl-bonded species is considerably higher than that of the fluoromethyl-bonded complex, which assists in explaining its dominance in the liquid phase spectra. PMID- 21666926 TI - Phosphatase-like activity, DNA binding, DNA hydrolysis, anticancer and lactate dehydrogenase inhibition activity promoting by a new bis-phenanthroline dicopper(II) complex. AB - A new bis-phenanthroline dicopper(II) complex has been synthesized and characterized by elemental analysis and spectroscopic methods. The molecular structure of the dinuclear Cu(II) complex [Cu(2)(MU-CH(3)COO)(MU-H(2)O)(MU OH)(phen)(2)](2+) (phen = 1,10-phenanthroline) (1) was determined by single crystal X-ray diffraction technique. The coordination environment around each Cu(II) ion in complex 1 can be described as slightly distorted square pyramidal geometry. The distance between the CuCu centers in the complex is found to be 2.987 A. The electronic, redox, phosphate hydrolysis, DNA binding and DNA cleavage have been studied. The antiproliferative effect of complex 1 was confirmed by the lactate dehydrogenase (LDH) enzyme level in MCF-7 cancer cell lysate and content media. The dicopper(II) complex inhibited the LDH enzyme as well as the growth of the human breast cancer MCF7 cell line at an IC(50) value of 0.011 MUg ml(-1). The results strongly suggest that complex 1 is a good cancer therapeutic agent. Electrochemical studies of complex 1 showed an irreversible, followed by a quasi-reversible, one electron reduction processes between -0.20 to -0.8 V. Michaelis-Menten kinetic parameters for the hydrolysis of 4-nitrophenyl phosphate by complex 1 are k(cat) = 3.56 * 10(-2) s(-1) and K(M) = 4.3 * 10(-2) M. Complex 1 shows good binding propensity to calf thymus DNA, with a binding constant value of 1.3 (+/-0.13) * 10(5) M(-1) (s = 2.1). The size of the binding site and viscosity data suggest a DNA intercalative binding nature of the complex. Complex 1 shows efficient hydrolytic cleavage of supercoiled pBR322-DNA in the dark and in the absence of any external reagents, as demonstrated by the T4 ligase experiment. The pseudo-Michaelis-Menten kinetic parameters for DNA hydrolysis by complex 1 are k(cat) = 1.27 +/- 0.4 h(-1) and K(M) = 7.7 * 10(-2) M. PMID- 21666927 TI - Structure and pulsed EPR characterization of N,N'-bis(5-tert-butylsalicylidene) 1,2-cyclohexanediamino-vanadium(IV) oxide and its adducts with propylene oxide. AB - The role of steric hindrance in controlling the binding mode of propylene oxide to a novel vanadyl salen-type complex N,N'-bis(5-tert-butylsalicylidene)-1,2 cyclohexanediamino-vanadium(IV) oxide, [VO(3)], has been investigated using CW/pulse EPR, ENDOR and HYSCORE spectroscopy and compared to that of the parent complex N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino vanadium(IV) oxide, [VO(1)]. The single-crystal X-ray structure of [VO(3)].HCCl(3) has been determined by X-ray analysis and is complemented by DFT calculations and circular dichroism measurements. The structure of the complex in frozen solution, as revealed by the EPR methods, is in good agreement with the X ray and DFT analyses. Removal of the 'inner'tert-butyl groups from the salicylidene rings reduces the steric hindrance between the ligand and epoxide substrate. As a result the selectivity for binding single enantiomers of propylene oxide in these complexes is reversed in [VO(3)] relative to [VO(1)]. PMID- 21666928 TI - Metabolic engineering is key to a sustainable chemical industry. AB - The depletion of fossil fuel stocks will prohibit their use as the main feedstock of future industrial processes. Biocatalysis is being increasingly used to reduce fossil fuel reliance and to improve the sustainability, efficiency and cost of chemical production. Even with their current small market share, biocatalyzed processes already generate approximately US$50 billion and it has been estimated that they could be used to produce up to 20% of fine chemicals by 2020. Until the advent of molecular biological technologies, the compounds that were readily accessible from renewable biomass were restricted to naturally-occurring metabolites. However, metabolic engineering has considerably broadened the range of compounds now accessible, providing access to compounds that cannot be otherwise reliably sourced, as well as replacing established chemical processes. This review presents the case for continued efforts to promote the adoption of biocatalyzed processes, highlighting successful examples of industrial chemical production from biomass and/or via biocatalyzed processes. A selection of emerging technologies that may further extend the potential and sustainability of biocatalysis are also presented. As the field matures, metabolic engineering will be increasingly crucial in maintaining our quality of life into a future where our current resources and feedstocks cannot be relied upon. PMID- 21666929 TI - A programmable "build-couple" approach to the synthesis of heterofunctionalized polyvalent molecules. AB - A maximally divergent "build-couple" synthesis of heterofunctionalized polyvalent molecules is described. This strategic approach enables the synthesis of highly diverse polyvalent structures from a pre-programmed combinatorial set of modules. PMID- 21666930 TI - Temperature-controlled poly(propylene) glycol hydrophobicity on the formation of inclusion complexes with modified cyclodextrins. A DSC and ITC study. AB - The study highlighted the main forces driving the formation of hydroxypropyl cyclodextrins (HP-CDs) + poly(propylene) glycol 725 g mol(-1) inclusion complexes. The temperature parameter was chosen as the variable to modulate the hydrophobicity of the polymer, and consequently ITC experiments as functions of temperature as well as DSC measurements were done in a systematic way. The polymer is not included into HP-alpha-CD, it is strongly bound to HP-beta-CD and it is floating in HP-gamma-CD. The stability of the inclusion complexes is entropy controlled. The gain of the entropy is a unique result compared to the opposite literature findings for inclusion complexes based on polymers and CDs. This peculiarity is ascribable to the removal of water molecules from cages during complexation and this effect compensates the entropy loss due to constraints caused by the CD threading. In spite the host-guest van der Waals contacts are optimized, the enthalpies for the inclusion complex formation are positive and reveal the large heat required for dehydrating the propylene oxide units. All the macrocycles enhanced the polymer solubility in water. Increasing the affinity of the macrocycle to the macromolecule makes more expanded the one phase area of the binodal curve. A new thermodynamic approach was proposed to predict quantitatively the binodal curve as well as the dependence of the enthalpy of separation phase on the macrocycle composition. The agreement between the experimental data and the computed values was excellent. PMID- 21666931 TI - Locking of Turing patterns in the chlorine dioxide-iodine-malonic acid reaction with one-dimensional spatial periodic forcing. AB - We use the photosensitive chlorine dioxide-iodine-malonic acid reaction-diffusion system to study wavenumber locking of Turing patterns with spatial periodic forcing. Wavenumber-locked stripe patterns are the typical resonant structures that labyrinthine patterns exhibit in response to one-dimensional forcing by illumination when images of stripes are projected on a working medium. Our experimental results reveal that segmented oblique, hexagonal and rectangular patterns can also be obtained. However, these two-dimensional resonant structures only develop in a relatively narrow range of forcing parameters, where the unforced stripe pattern is in close proximity to the domain of hexagonal patterns. Numerical simulations based on a model that incorporates the forcing by illumination using an additive term reproduce well the experimental observations. These findings confirm that additive one-dimensional forcing can generate a two dimensional resonant response. However, such a response is considerably less robust than the effect of multiplicative forcing. PMID- 21666932 TI - A new Os,Rh bimetallic with O2 independent DNA cleavage and DNA photobinding with red therapeutic light excitation. AB - Many Ru and Os systems display photoactive (3)MLCT states. Systems activated by therapeutic window light in the absence of O(2) remain elusive. [(bpy)(2)Os(dpp)RhCl(2)(phen)](3+) photobinds and photocleaves DNA under red light in an oxygen independent manner, due to molecular design involving one Os chromophore coupled to a photoactive cis-Rh(III)Cl(2) moiety. PMID- 21666933 TI - Tip- or electron beam-induced surface polymerization. AB - Control on the formation of a two-dimensional polymer could be achieved in two different ways. Manipulation with the tip of a scanning tunneling microscope allowed for assigning the localization of the polymerization reaction. Additionally, electron irradiation could accelerate greatly the reaction kinetics. PMID- 21666934 TI - Nanoporous TiO2 spheres with narrow pore size distribution and improved visible light photocatalytic abilities. AB - Nanoporous TiO(2) nanospheres with excellent visible light photocatalytic abilities and narrow pore size (11 +/- 1 nm) distribution can be obtained via a rapid vapor assisted hydrolysis technique. PMID- 21666935 TI - Microscopy, culture, and sensitive management of uncomplicated urinary tract infections in adults in the primary care setting. AB - The high prevalence of urinary tract infections (UTIs) places a significant burden on healthcare systems. Clinicians may over-manage the issue, and there is great variability in practice, with economic- and resource- implications. Up to 40% of patients with a suspected UTI do not have an infection. Using PubMed (Medline) to shortlist relevant papers in English from the last 30 years, and further sub-selection to include only uncomplicated UTIs in adults in primary care, we reviewed the literature pertaining to uncomplicated UTIs, and how it should be managed efficiently in the primary care setting. In general practice, there is no advantage to routinely request microscopy and culture of urine samples in the presence of an appropriate history and urinalysis reagent-strip testing. If antibiotics are required, then a 3-day course shall suffice. Larger epidemiological studies focusing on more susceptible sub-populations may provide better guidance for discriminatory factors to produce an algorithm for treatment. PMID- 21666936 TI - Cardiac effects of bee venom in rats. AB - OBJECTIVE: To elucidate the possible effects of bee venom (BV) on cardiac electrophysiological properties in vivo, the inotropic and chronotropic properties of the isolated hearts in vitro, and the cardiac responsiveness to progressive adrenergic stimulation by isoproterenol. METHODS: This randomized control study was conducted in the Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt, from April to June 2010. This work was carried out on 22 female Wistar rats. Rats were allocated into 2 groups; BV treated group (rats were treated with BV in a dose of 20 microgram/kg body weight, administered subcutaneously for 4 days), and the control group. Prior to sacrifice, the studied animals underwent electrocardiographic (ECG) assessments under anesthesia. Thereafter, isolated hearts were studied in a Langendorff preparation for their intrinsic properties, and their responses to beta adrenergic stimulation. Following recovery, heart tissues were used for assessment of myocardial calcium content, and for histological examination. RESULTS: No abnormal ECG findings were observed in the BV-treated group. The BV treatment enhanced tension generation in the cardiac muscle in response to beta adrenergic stimulation, and improved the inotropic cardiac reserve. Calcium content of the myocardial tissue of BV-treated group was significantly increased. Histological examination of the cardiac tissue of BV-treated group demonstrated preserved myofilament and mitochondrial ultrastructural integrity. CONCLUSION: The BV enhanced the cardiac inotropic reserve to beta-receptor agonists. Meanwhile, BV protected the heart against calcium overload-induced injury. PMID- 21666937 TI - The impact of stepwise stent deployment on the angiographic and clinical outcome of coronary angioplasty in the setting of an acute myocardial infarction. AB - OBJECTIVE: To detect a reduction in the incidence of no-reflow, and a possible improvement in angiographic and clinical outcome after stepwise stenting in comparison with conventional method in the percutaneous coronary intervention (PCI) of patients with anterior ST elevation myocardial infarction. METHODS: Between March 2007 and December 2009, patients with anterior acute myocardial infarction (AMI) treated with streptokinase less than 6 hours from presentation who underwent early PCI were enrolled in this multicenter randomized clinical trial. The study was carried out in the Cardiology Departments of Valiasr Hospital of Zanjan, Imam Reza, and Shahid Madani Heart Hospitals, Tabriz, Iran. RESULTS: Four hundred and three patients were enrolled in this study. Patients were randomly divided into 2 groups: Group I (n=202) with stepwise stent deployment (SSD), and Group II (n=201) with routine conventional stent deployment (CSD). The patients' mean age was 57.7 +/- 10.7 years. After PCI, thrombolysis in myocardial infarction myocardial perfusion grade (TMPG) 0/1, suggestive of no reflow was significantly higher in CSD group (p=0.0001). In hospital based, death occurred in 15 patients (7.5%) from CSD group while 4 (2%) from the SSD group (p=0.01). The TMPG was also significantly higher in SSD group (average 2.32 +/- 0.18) compared with CSD group, (average 1.66 +/- 0.24) (p=0.0001). Conventional stenting technique was an independent predictor of no-reflow in multivariate logistic regression analysis (hazard ratio - 1.43; 95% confidence interval: 1.15 1.73; p=0.01). CONCLUSION: The SSD was associated with improved angiographic reperfusion indices and reduced mortality in early PCI for AMI. PMID- 21666938 TI - Effect of mode of delivery on postnatal decline in pulmonary artery pressure. AB - OBJECTIVE: To evaluate the effect of the mode of delivery on the course of pulmonary artery pressure (PAP) in neonates. METHODS: Eighty healthy and term neonates delivered in the maternity wards of Dunya Maternity Hospital, Camlica Maternity Center, and Sultan Maternity Hospital in Diyarbakir, Turkey from June to August 2009 were included in the study. Tricuspid regurgitation (TR) was determined using color Doppler echocardiography, and the measurements were carried out with continuous wave technique on the first, third, and the fifth days of birth. The babies who had no TR flow on the first, third, or the fifth day were excluded, and the study was completed with 42 cases. Twenty-two of them were delivered by cesarean section (CS), and 20 by vaginal delivery. The peak flow velocity of TR was used in the calculation of the right ventricular pressure, which reflects PAP. RESULTS: In both groups, PAP continued to decline on the third and fifth days. However, in the vaginal delivery group, the decrease between the third and fifth days was statistically insignificant, whereas a statistically significant decline (p=0.01) in the CS group lasted until the fifth day. CONCLUSION: Although the birth method does not create a clinical morbidity on the circulatory system as seen in the respiratory system, it can be stated that the circulatory adaptation of vaginally delivered babies is completed earlier. PMID- 21666939 TI - Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients. AB - OBJECTIVE: To examine the effects of alpha-lipoic acid (ALA) treatment over a period of 2 months on fasting blood glucose (FBG), insulin resistance (IR), and glutathione peroxidase (GH-Px) activity in type 2 diabetes (T2DM) patients. METHODS: This study took place in Motahari Clinic, Shiraz, Iran, which is affiliated to Shiraz University of Medical Sciences from May to October 2006. Type 2 DM patients (n=57) were divided into 2 groups to receive either ALA (300 mg daily) or placebo by systematic randomization, and were followed-up for 8 weeks. After an overnight fasting and 2 hours after breakfast, patients' blood samples were drawn and tested for FBG, 2 hours PPG, serum insulin level, and GH Px activity. RESULTS: The result of the study showed a significant decrease in FBG and PPG levels, IR-Homeostasis Model Assessment (IR-HOMA index) and GH-Px level in the ALA group. The comparison of differences between FBG and IR at the beginning and at the end of study in the ALA treated group and the placebo group were also significant. CONCLUSION: This study supports the use of ALA as an antioxidant in the care of diabetic patients. PMID- 21666940 TI - Vitamin D levels in Saudi children with type 1 diabetes. AB - OBJECTIVE: To assess the prevalence of vitamin D deficiency in type 1 diabetic (T1DM) children. METHODS: In this prospective cross-sectional study, we included 100 Saudi children with T1DM attending the Pediatric Endocrinology and Diabetes Clinics, and 100 healthy controls from the Department of Pediatrics, Security Forces Hospital, Riyadh, Kingdom of Saudi Arabia from June to September 2010. We measured serum 25-hydroxy vitamin D (25OHD), parathyroid hormone, calcium, phosphate, and alkaline phosphatase in these patients, and compared the results with age, gender, and ethnicity-matched control subjects. RESULTS: The mean levels of 25OHD were significantly lower in the T1DM children compared to the controls (36.7 +/- 14.3 nmol/l versus 44.8 +/- 14.1 nmol/l). In the T1DM children, 64% were mildly, 16% were moderately, and 4% were severely vitamin D deficient as compared with 52% (mildly), 6% (moderately), and 1% (severely) in the control group. Overall, 84% of the T1DM children, and 59% of the healthy children were vitamin D deficient. There was no correlation between glycemic control and 25OHD level. CONCLUSION: Prevalence of vitamin D deficiency in diabetic children is relatively high. Therefore, screening for vitamin D deficiency and supplementation of children with low vitamin D levels should be warranted. PMID- 21666941 TI - Comparison of the effects of sedation and general anesthesia in surgically assisted rapid palatal expansion. AB - OBJECTIVE: To compare the effects of sedation and general anesthesia for surgically assisted rapid palatal expansion (SARPE). METHODS: This randomized prospective study included 30 patients who were scheduled for SARPE, and was performed between January 2008 to February 2010 in the Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Marmara University, Istanbul, Turkey. Patients were allocated into Group S - midazolam + fentanyl sedation (n=15), and Group G - general anesthesia (n=15). Hemodynamic parameters, duration of anesthesia, surgery, recovery time, time to discharge, visual analogue scale (VAS) pain scores at 30 minutes (min), one hour (hr), 4 hours, 12 hours, and 24 hours, first consumption of analgesic time, total amount of consumption of analgesics, patient and surgeon satisfaction, nausea, and vomiting were recorded. RESULTS: Analgesic time was significantly longer in Group S (p=0.008), and total analgesic consumption was significantly lower in Group S than in Group G (p=0.031). Patient satisfaction was statistically higher in Group S (p=0.035). At 30 min, one hr, and 12 hrs, VAS satisfaction scores in Group S were statistically lower than those in Group G, and at 4 hrs and 24 hrs there was no statistical difference in VAS scores for both groups. CONCLUSION: The use of sedation for outpatient SARPE resulted in lower pain scores at discharge, lower analgesic consumption, and greater patient satisfaction. PMID- 21666942 TI - Incidence of influenza A H1N1 2009 infection in Eastern Saudi Arabian hospitals. AB - OBJECTIVE: To describe the clinical and epidemiologic features of pandemic influenza A (H1N1) cases. METHODS: This study was conducted in Saudi Aramco Medical Services Organization (SAMSO) facilities in the Eastern province of the Kingdom of Saudi Arabia (KSA). Electronic medical records for H1N1 infected patients who visited SAMSO between June and October 2009 were reviewed retrospectively. Nasopharyngeal and oropharyngeal swabs were collected from suspected patients, and sent to the Ministry of Health (MOH) Regional Laboratory in Dammam, KSA to confirm the diagnosis. RESULTS: A total of 587 cases were diagnosed with H1N1 given an incidence rate of 3.5 per 1000. Most of the infected cases were outpatients. The study showed that H1N1 was more common in the younger age group (median age; 22 years), and in female dependents at all ages, which differs from that reported by other researchers. CONCLUSION: Influenza A H1N1 was more common in the younger age group and in female dependents, and it was more severe among pregnant women. In addition, obesity did not affect the frequency of H1N1 infection. PMID- 21666943 TI - Narrowband ultraviolet B phototherapy improves the quality of life in patients with psoriasis. AB - OBJECTIVE: To examine whether narrowband ultraviolet B (NBUVB) phototherapy administration to plaque-type psoriatic patients leads to an improvement in patient's quality of life (QoL). METHODS: A total of 95 patients with plaque-type psoriasis were recruited in the Outpatient Dermatology Clinics of Qassim University affiliated hospitals, Buraydah, Kingdom of Saudi Arabia from January to October 2010. The NBUVB phototherapy was administrated 3 times a week for 6 months in a standardized fashion. Patients were asked to complete pre- and post phototherapy Dermatology Life Quality Index (DLQI) questionnaire. Seventy-two patients were included in the study, while the remaining 23 were excluded, as they had not completed the post-phototherapy DLQI questionnaire. The statistical differences in mean +/- standard deviation of QoL were measured using Origin 6.1 software package (one paired two tailed t-test with one way analysis of variance) based on pre- and post-phototherapy questionnaires. RESULTS: The administration of NBUVB phototherapy to plaque-type psoriasis patients significantly improved the QoL, and was well-correlated with the reduction in psoriasis area and severity index (PASI) score. Data showed that DLQI significantly improved in both male and female patients (p=0.00) after NBUVB phototherapy. The visual analogue scale (VAS) scores also significantly improved (p=0.00) with NBUVB. CONCLUSION: In this study, we found that NBUVB phototherapy improves the QoL of plaque-type psoriasis patients. PMID- 21666944 TI - Investigation of the availability of tongue movements in Mallampati classification. AB - OBJECTIVE: To investigate the relation of Mallampati classification with a new alternative method suggested for use in the estimation of tongue movements. METHODS: This study was conducted in the Department of Anesthesiology, Faculty of Medicine, Trakya University, Edirne, Turkey from April to October 2009. Two hundred and thirty patients were enrolled in this study. The modified Mallampati score (MMS) was devised by an anesthetist. To define tongue movements, horizontal and vertical lines were utilized. Horizontal lines passing through the mid points of the upper lip and mandible, and vertical lines passing through the right and left infraorbital points were constituted on each subject. Subjects were asked to elevate, depress, and abduct (right-left) the tip of the tongue. The scores corresponding with the movements of the tongue were determined. RESULTS: Depression of the tip of the tongue (DTT) and elevation of the tip of the tongue (ETT) levels were significantly different between MMS 1, MMS 2, and MMS 3, MMS 4 groups (p=0.001). The risk of being MMS 3 or MMS 4 for the groups that cannot reach the borderline for the DTT or ETT are 5.5 times and 5.4 times higher consequently than the groups that can reach the borderline. CONCLUSION: This new method can be combined with MMS classification, which requires clinical experience and knowledge in predicting difficult intubation. PMID- 21666945 TI - Domestic violence and its impact on married women's health in Eastern Saudi Arabia. AB - OBJECTIVE: To identify the prevalence of domestic violence (DV) in Al-Ahsa, and its impact on married women's health. METHODS: This study is a community-based cross-sectional survey conducted from January to June 2010 in Al-Ahsa oasis in the Eastern province of the Kingdom of Saudi Arabia. It included 2000 ever married women, 15-60 years old, and selected by a 2-stage proportionate cluster random sample. Data was gathered through structured interviews. Univariate and multivariate analysis was carried out using the Statistical Package for Social Sciences version 15. RESULTS: The prevalence of lifetime DV was 39.3%, 35.9% for mental, 17.9% for physical, and 6.9% for sexual violence. Lower rates of recent (within one month prior to the interview) violence were encountered, that is: overall (32.7%); mental (29.1%); physical (22.8%); and sexual (11.8%). Eleven percent of women were beaten, and 7% were kicked on the abdomen during pregnancy. Lifetime violence was significantly associated with perceived bad general health, disease, abortion, hemorrhage, and body mass index. Recent violence increased the number of doctor visits, and the odds of feeling dizzy (OR=1.93), vaginal bleeding (OR=1.83), movement and activity problems, pain, taking drugs (OR=1.95), and stress significantly during the last 4 weeks before the interview. A large proportion of women tolerated violence without seeking help (41.4%). Common reactions included complaining to own family, treating the perpetrator violently, and complaining to a friend. CONCLUSION: We found that DV is prevalent in Al Ahsa. We recommend awareness programs aiming at educating current and future couples, and proper training of health care providers in assisting the cases of DV. PMID- 21666946 TI - Unhealthy nutritional habits in university students are a risk factor for cardiovascular diseases. AB - OBJECTIVE: To evaluate the relationship between the nutritional habits of university students with health parameters related to cardiovascular risk. METHODS: Three hundred and twelve students (180 females and 132 males; mean age 21.1 +/- 2.8 years) attending King Saud University, Riyadh, KSA were randomly selected from the university register and invited to participate in the study during 2008-2009. Students who consented to participate completed a self-reported questionnaire including: nutritional screen, health habits, and lifestyle practice. Daily food consumption was recorded, and nutritional analysis was performed. Blood pressure (BP) was also measured. RESULTS: A quarter of students was found to be overweight (21%) or obese (6.5%). The percentage of overweight and obese male students was 23% and 7% compared with female students who were 19% overweight and 6% obese. There was a positive correlation between fat consumption and BMI as well as BP in both genders, between economical status and BMI (p=0.05), and between salty food and BP (p=0.05). There was a negative correlation between consumption of fiber, grains, vegetables, fruits, beans, and BMI as well as BP in both genders (p=0.05). CONCLUSION: Our findings suggest that lifestyle modification is important especially in young age groups. The preventive interventions should focus not only on obesity, but also on related diseases. There is a need for strategies and coordinated efforts to reduce the tendency of overweight and obesity among college students. PMID- 21666947 TI - Medical students' knowledge and attitude toward cancer pain management in Saudi Arabia. AB - OBJECTIVE: To assess the final year medical students' knowledge, beliefs, and attitude toward cancer pain, and the need for a formal pain curriculum in medical schools. METHODS: An epidemiological study was conducted from May 2008 to October 2009 at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia to assess the students' knowledge and attitude toward cancer pain management. A survey in the form of self-conducted questionnaire was distributed among them. RESULTS: Response rate was 55% (N=325). Fifty-four percent of the respondents believed that <40% of cancer patients suffered from pain. Forty-six percent of them considered cancer pain as untreatable, while 41.6% considered pain as a minor problem, and 58.6% considered the risk of addiction is high with legitimate opioids' prescription. There are 23.1% of students believed that patients are poor judges of their pain, 68% of them limited opioids prescription to patients with poor prognosis, and 77.1% believed that drug tolerance or psychological dependence, rather than advanced stages' cancer is the cause of increasing analgesic doses. The students' knowledge on the causes of cancer pain, pain clinic rule, and pain inclusion in the medical curriculum was poor. The correlation between personal life experience and respondents' attitude toward cancer pain management did not reveal any statistical significant. CONCLUSION: The study revealed poor knowledge and negative attitude of medical students' toward cancer pain. A structured teaching pain program is needed to improve the knowledge and attitude of future doctors toward pain. PMID- 21666948 TI - Parasitic leiomyoma. A rare cause of inguinal mass in females. AB - Leiomyoma of the uterus is a common tumor during the reproductive age of females. It is classified as intrauterine and extrauterine. Extrauterine leiomyomas may occur without a concurrent uterine pathology. Different growth patterns have been described, like retroperitoneal and parasitic growth. We report a case of a 28 year-old female who was found to have inguinal mass, and it was finally diagnosed as parasitic leiomyoma. The mass was coming through the posterior inguinal wall into the subcutaneous region, like a direct inguinal hernia. She underwent excision of the mass, and repair of posterior inguinal wall. Parasitic leiomyoma can be a rare cause of inguinal swelling. When diagnosed, surgical excision is the treatment of choice. PMID- 21666949 TI - Global health professions student survey in Saudi Arabia. PMID- 21666950 TI - Growth medium with low serum and transforming growth factor beta 3 promotes better chondrogenesis of bone marrow-derived stem cells in vitro and in vivo. PMID- 21666951 TI - Impact of ozone on healing after alveolectomy of impacted lower third molars. PMID- 21666952 TI - Osteogenesis imperfecta. PMID- 21666953 TI - Effects of Ramadan fasting on glucose levels and serum lipid profile among type 2 diabetic patients. PMID- 21666954 TI - Insulin resistance in China. PMID- 21666955 TI - Pregnancy outcome in women with inflammatory bowel disease. PMID- 21666956 TI - Monoclonal anti-HMGB1 (high mobility group box chromosomal protein 1) antibody protection in two experimental arthritis models. AB - High mobility group box chromosomal protein 1 (HMGB1) is a DNA-binding nuclear protein that can be released from dying cells and activated myeloid cells. Extracellularly, HMGB1 promotes inflammation. Experimental studies demonstrate HMGB1 to be a pathogenic factor in many inflammatory conditions including arthritis. HMGB1-blocking therapies in arthritis models alleviate disease and confer significant protection against cartilage and bone destruction. So far, the most successful HMGB1-targeted therapies have been demonstrated with HMGB1 specific polyclonal antibodies and with recombinant A box protein, a fragment of HMGB1. The present study is the first to evaluate the potential of a monoclonal anti-HMGB1 antibody (2G7, mouse IgG2b) to ameliorate arthritis. Effects of repeated injections of this antibody have now been studied in two conceptually different models of arthritis: collagen type II-induced arthritis (CIA) in DBA/1 mice and in a spontaneous arthritis disease in mice with combined deficiencies for genes encoding for the enzyme DNase type II and interferon type I receptors. These mice are unable to degrade phagocytozed DNA in macrophages and develop chronic, destructive polyarthritis. Therapeutic intervention in CIA and prophylactic administration of anti-HMGB1 monoclonal antibody (mAb) in the spontaneous arthritis model significantly ameliorated the clinical courses. Anti HMGB1 mAb therapy also partially prevented joint destruction, as demonstrated by histological examination. The beneficial antiarthritic effects by the anti-HMGB1 mAb in two diverse models of arthritis represent additional proof-of-concept, indicating that HMGB1 may be a valid target molecule to consider for development of future clinical therapy. PMID- 21666958 TI - [Investigation in nutrition: from the clinical grounds to the best scientific evidence]. PMID- 21666957 TI - Caspase-1 is hepatoprotective during trauma and hemorrhagic shock by reducing liver injury and inflammation. AB - Adaptive immune responses are induced in liver after major stresses such as hemorrhagic shock (HS) and trauma. There is emerging evidence that the inflammasome, the multiprotein platform that induces caspase-1 activation and promotes interleukin (IL)-1beta and IL-18 processing, is activated in response to cellular oxidative stress, such as after hypoxia, ischemia and HS. Additionally, damage-associated molecular patterns, such as those released after injury, have been shown to activate the inflammasome and caspase-1 through the NOD-like receptor (NLR) NLRP3. However, the role of the inflammasome in organ injury after HS and trauma is unknown. We therefore investigated inflammatory responses and end-organ injury in wild-type (WT) and caspase-1(-/-)mice in our model of HS with bilateral femur fracture (HS/BFF). We found that caspase-1(-/-) mice had higher levels of systemic inflammatory cytokines than WT mice. This result corresponded to higher levels of liver damage, cell death and neutrophil influx in caspase-1( /-) liver compared with WT, although there was no difference in lung damage between experimental groups. To determine if hepatoprotection also depended on NLRP3, we subjected NLRP3(-/-) mice to HS/BFF, but found inflammatory responses and liver damage in these mice was similar to WT. Hepatoprotection was also not due to caspase-1-dependent cytokines, IL-1beta and IL-18. Altogether, these data suggest that caspase-1 is hepatoprotective, in part through regulation of cell death pathways in the liver after major trauma, and that caspase-1 activation after HS/BFF does not depend on NLRP3. These findings may have implications for the treatment of trauma patients and may lead to progress in prevention or treatment of multiple organ failure (MOF). PMID- 21666959 TI - [The Spanish Society of Parenteral and Enteral Nutrition (SENPE) and its relation with healthcare authorities]. AB - It has been well documented in medical literature that hyponutrition is a common issue at all healthcare levels, from primary to specialized health care, as well as geriatric healthcare facilities. This problem is not limited to countries with scarce economic resources or limited social development; it is also a universal issue in Europe. Hyponutrition increases the rates of morbidity, mortality, hospital admissions, and hospital stay. These higher figures also represent a higher use of healthcare resources. In spite of this, hyponutrition may often go undetected and the patient may not receive the necessary treatment. This problem requires the cooperation of multiple agents such as the Governments, the healthcare professionals, and the citizens themselves. The VIII Discussion Forum concludes on the need to establish a clear-cut plant for action (similar to the European Alliance for Health Nutrition) and the creation of a platform (coalition) encompassing the voices of healthcare professionals associations, institutions, professional colleges, patients associations, the pharmaceutical companies, and insurance companies. The goals of this platform will be to inform about the extent of this issue, to identity and promote leaders that will convey the aims of this initiative to regional and national healthcare authorities, to present solutions and to collaborate in their implementation, and finally to assess/control the actions taken. PMID- 21666960 TI - [Hospital hyponutrition]. AB - Identifying hyponutrition is essential at the hospital setting to avoid or minimize the impact on the patients' clinical course and its association with more severe complications, longer hospital staying, and increased mortality, and all of this is associated with increased costs for the institution and the society. The aims of this study were to disbelieve the epidemiology of hospital hyponutrition, the types of hyponutrition, the body response to fasting, the clinical course of the patient with hyponutrition and the consequences of hyponutrition in the different live stages and, thus, we carried out a review on hospital hyponutrition. We found that hyponutrition prevalence is high in the hospital setting, hyponutrition influences genetic, metabolic, and hormonal factors of the human being and leads to harmful effects from the intrauterine fetal development until the adulthood. There are also different types of hyponutrition, the differentiation being important to decide the best therapy. We also found that hyponutrition is related to inflammation. When inflammation is chronic and mild to moderate (such as in organ failure, pancreatic cancer, obesity, rheumatoid or sarcopenic arthritis), the term "hyponutrition-related chronic disease", and when inflammation is acute and severe (severe infection, burns, trauma or head trauma), the preferred term is "hyponutrition-related acute disease or hyponutrition-related lesions". Finally, the patient with hyponutrition has worse clinical course than the patient with an appropriate nutritional status. PMID- 21666961 TI - [Intervention programs to promote physical activity in school children: systematic review]. AB - OBJECTIVE: The purpose of this systematic review was to assess physical activity promotion programs in school children from 6 to 12 years old. METHODS: Randomized and non-randomized controlled trials of physical activity studies with an intervention period equal to or more than 12 months, published in the databases of MEDLINE/PubMed, SciELO, EBSCO and SPORTDiscus through may 2010 were searched. RESULTS: Seven studies were analyzed. Overall, the study design, the follow-up periods, the ethnic characteristics of the population, and the instruments used to evaluate the interventions were heterogeneous. The outcomes showed moderate impact of intervention programs to increase the physical activity in children and adolescents. In two of the studies was observed an increase in the physical activity and in five of the studies no significant difference in the physical activity assessed with accelerometers and pedometers. CONCLUSION: In five out of seven studies it was not shown statistical differences in cpm, including the longest experimental study. These results suggest the need of designing studies including modifications in different environments. PMID- 21666962 TI - Peroxisome proliferator-activated receptor: effects on nutritional homeostasis, obesity and diabetes mellitus. AB - The obesity and the metabolic disorders associated characterize the metabolic syndrome, which has increased at an alarming rate around the world. It is known that environmental and genetic factors are involved in the genesis of obesity. Peroxisome Proliferator-Activated Receptors (PPARs) stand out among these factors. They compose the nuclear receptor superfamily and there are in three isoforms (PPARalpha,PPARbeta/delta and PPARgamma), which play an important role in the regulation of the metabolism of carbohydrates, lipids and proteins. The present review aims to understand the relationship between the diet, the PPARs and the control of the blood glucose and body weight, since the understanding about the mechanisms by which these receptors act may benefit the development of the strategies aiming at prevention and elaboration of therapeutics actions which are more effective for the treatment of obesity and diabetes. PMID- 21666963 TI - Retinol, beta-carotene, alpha-tocopherol and vitamin D status in European adolescents; regional differences an variability: a review. AB - Currently, blood levels to define vitamin deficiency or optimal status in adolescents are extrapolated from adults. This may be not adequate as vitamin requirements during adolescence depend on the process of sexual maturation, rapid increasing height and weight, among other factors. In order to establish the state of the art, Medline database (www.ncvi.nlm.nih.gov) was searched for studies published in Europe between 1981 and 2010 related to liposoluble vitamin status in adolescents. A comparison of the vitamin status published in the reviewed articles was difficult due to the lack of studies, lack of consensus on cut-off levels indicating deficiency and optimal vitamin levels and the different age-ranges used. In spite of that, deficiency prevalence varied for vitamin D (13 72%), vitamin A (3%), E (25%) and beta-carotene (14-19%). Additional factors were considered as possible determinants. We conclude that it is necessary to establish a consensus on acceptable ranges and cut-offs of these vitamins during adolescence. Representative data are still missing; therefore, there is a high need to get deeper into the investigation on liposoluble vitamins in this population group. PMID- 21666964 TI - [Beneficial effects of chocolate on cardiovascular health]. AB - Since ancient times, numerous health beneficial effects have been attributed to chocolate, closing up its consumption to a therapeutic use. The present study reviews some relevant studies about chocolate (and its bioactive compounds) on some cardiovascular risk factors and stresses the need of future studies. The consumption of cocoa/ chocolate (i) increases plasma antioxidant capacity, (ii) diminishes platelet function and inflammation, and (iii) decreases diastolic and systolic arterial pressures. Data currently available indicate that daily consumption of cocoa-rich chocolate (rich in polyphenols) may at least partially lower cardiovascular disease risk. Further studies are required in order to establish the bioavailability and mechanisms of action of bioactive compounds in chocolate. The study of the interaction of chocolate and its components with candidate genes will also supply necessary information regarding the individuals best suited to benefit from a potential cardiovascular disease treatment with chocolate. PMID- 21666965 TI - Analysis of plasma and erythrocyte zinc levels in premenopausal women with breast cancer. AB - INTRODUCTION: Zinc deficiency has been associated with damage and oxidative changes in DNA that may increase an individual's risk of cancer. Furthermore, zinc metabolism may be affected in cancer patients, leading to alterations in its distribution that would favor carcinogenesis. Plasma and erythrocyte zinc levels in women with breast cancer were evaluated in this cross-sectional, controlled study. MATERIAL AND METHODS: Fifty-five premenopausal women of 25 to 49 years of age with and without breast cancer were divided into two groups: Group A, composed of women without breast cancer (controls, n = 26) and Group B, composed of women with breast cancer (cases, n = 29). Plasma and erythrocyte zinc levels were measured by flame atomic absorption spectrophotometry at gamma = 213.9 nm. Diet was assessed using the 3-day diet recall method and analyzed using the NutWin software program, version 1.5. Student's t-test was used to compare means and significance was established at p = 0.05. RESULTS: Mean plasma zinc levels were 69.69 +/- 9.00 g/dL in the breast cancer patients and 65.93 +/- 12.44 g/dL in the controls (p = 0.201). Mean erythrocyte zinc level was 41.86 +/- 8.28 MUgZn/gHb in the cases and 47.93 +/- 7.00 MUgZn/gHb in the controls (p < 0.05). In both groups, dietary zinc levels were above the estimated average requirement. CONCLUSIONS: The present results suggest that zinc levels are lower in the erythrocyte compartment of pre-menopausal women with breast cancer. PMID- 21666966 TI - Association of uricemia with biochemical and dietary factors in human adults with metabolic syndrome genotyped to C677T polymorphism in the methylenetetrahydrofolate reductase gene. AB - It is suggested that hyperuricemia is a marker of cardiovascular risk in human adults with metabolic syndrome (MS). The C677T polymorphism in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR) is associated with hyperuricemia. Data on factors associated with uricemia in human adults with MS genotyped for this polymorphism are lacking. We aimed to investigate the factors associated with uricemia in human adults with MS genotyped for the C677T polymorphism in the MTHFR gene. Cross-sectional study was conducted with 63 human adults (24 men and 39 women) with MS. Body weight, body mass index, waist circumference, body fat, glycemia, lipid profile, uricemia, insulinemia, homocysteinemia, plasma folate, erythrocyte folate, blood pressure, smoking, diuretics use, usual dietary alcohol and protein intakes, MTHFR and the presence of the C677T polymorphism in the gene were assessed. Hyperuricemia was observed in 16 (25.4%) human adults (10 men and 6 women). In the group, 33% (n = 21) showed the C677T polymorphism, being 19 heterozygous and 2 mutant homozygous. A significant association between hyperuricemia and C677T polymorphism was not verified. Uricemia was positively associated with homocys-teinemia (r = 0.43, p < 0.05), triglyceridemia (r = 0.41, p<0.05), serum concentrations of very-low density lipoprotein (r = 0.27, p< 0.05) and the habitual alcohol intake (r = 0.37, p < 0.05). However, only homocysteinemia, triglyc-eridemia, and habitual alcohol intake remained in the final model of linear regression. In human adults with MS geno-typed for the C677T polymorphism in the MTHFR gene, uricemia was positively associated with homocysteinemia, triglyceridemia and the habitual alcohol intake. PMID- 21666967 TI - Association between dyslipidemia and anthropometric indicators in adolescents. AB - The dyslipidemia associated with excess weight is a risk profile global call for cardiovascular disease (CVD). The aim of this study was to investigate the association between dyslipidemias and other risk factors for cardiovascular diseases (CVD) in adolescents, considering sexual maturation. A cross-sectional study was carried out with 432 adolescents from public schools, aged 10-19 years. The correlations between the variables from the lipid profile and the Body Mass Index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), sexual maturation, familial history and maternal education were evaluated using Pearson's correlation coefficient. Low high-density lipoprotein cholesterol (HDL C) was the most prevalent dyslipidemia (50.5%), regardless of gender. There were significant correlations between triglycerides and BMI (r = 0.30, p<0.01), WC (r = 0.32, p < 0.01) and WHtR (r = 0.33, p < 0.01). The linear model, which took into consideration sexual maturation, age and BMI, explain about 1 to 10.4% of the lipid profile variation. The low HDL-c was the most prevalent dyslipidemia in all adolescents and hypertriglyceridemia was most prevalent in overweight adolescents. Associations between dyslipidemias and anthropometric indicators (BMI and RCA) detected in this study can generate the hypothesis of the risk factors for CVD in adolescents. PMID- 21666968 TI - Cell activation state influences the modulation of HLA-DR surface expression on human monocytes/macrophages by parenteral fish oil lipid emulsion. AB - Abnormal surface expression of HLA-DR by leukocytes is associated with a poor prognosis in critical care patients. Critical care patients often receive total parenteral nutrition with lipid emulsion (LE). In this study we evaluated the influence of fish oil LE (FO) on human monocyte/macrophage (Mphi) expression of surface HLA-DR under distinct activation states. Mononuclear leukocytes from the peripheral blood of healthy volunteers (n=18) were cultured for 24 hours without LE (control) or with 3 different concentrations (0.1, 0.25, and 0.5%) of the follow LE: a) pure FO b) FO in association (1:1-v/v) with LE composed of 50% medium-chain trygliceride and 50% soybean oil (MCTSO), and c) pure MCTSO. The leukocytes were also submitted to different cell activation states, as determinate by addition time: no INF-gamma addition, 18 hours before, or at the time of LE addition. HLA-DR expression on Mphi surface was evaluated by flow cytometry using specific monoclonal antibodies. In relation to controls (for 0.1%, 0.25%, and 0.5%: 100) FO decreased the expression of HLA-DR when added alone [in simultaneously-activated Mphi, for 0.1%: 70 (59 +/- 73); for 0.25%: 51 (48 +/- 56); and for 0.5%: 52.5 (50 +/- 58)] or in association with MCTSO [in simultaneously-activated Mphi, for 0.1%: 50.5 (47 +/- 61); for 25%: 49 (45 +/- 52); and for 0.5%: 51 (44 +/- 54) and in previously-activated Mf, for 1.0%: 63 (44 +/- 88); for 0.25%: 70 (41 +/- 88); and for 0.5%: 59.5 (39 +/- 79)] in culture medium (Friedman p < 0.05). In relation to controls (for 0.1%, 0.25%, and 0.5%: 100), FO did not influence the expression of these molecules on non activated Mphi [for 0.1%: 87.5 (75+/-93); for 0.25%: 111 (98 +/- 118); and for 0.5%: 101.5 (84 +/- 113)]. Results show that parenteral FO modulates the expression of HLA-DR on human Mphi surface accordingly to leukocyte activation state. Further clinical studies evaluating the ideal moment of fish oil LE infusion to modulate leukocyte functions may contribute to a better understanding of its immune modulatory properties. PMID- 21666969 TI - Roles of G1359A polymorphism of the cannabinoid receptor gene (CNR1) on weight loss and adipocytokines after a hypocaloric diet. AB - BACKGROUND: A intragenic biallelic polymorphism (1359 G/A) of the CB1 gene resulting in the substitution of the G to A at nucleotide position 1359 in codon 435 (Thr), was reported as a common polymorphism in Caucasian populations. Intervention studies with this polymorphism have not been realized. OBJECTIVE: We decided to investigate the role of the polymorphism (G1359A) of CB1 receptor gene on adipocytokines response and weight loss secondary to a lifestyle modification (Mediterranean hypocaloric diet and exercise) in obese patients. DESIGN: A population of 94 patients with obesity was analyzed. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for the combined G1359A and A1359A as a group and wild type G1359G as second group, with a dominant model. RESULTS: Forty seven patients (50%) had the genotype G1359G (wild type group) and 47 (50%) patients G1359A (41 patients, 43.6%) or A1359A (6 patients, 6.4%) (mutant type group) had the genotype. In wild and mutant type groups, weight, body mass index, fat mass, waist circumference and systolic blood pressure decreased. In mutant type group, resistin (4.15 +/- 1.7 ng/ml vs. 3.90 +/- 2.1 ng/ml: P < 0.05), leptin (78.4 +/- 69 ng/ml vs 66.2 +/ 32 ng/ml: P < 0.05) and IL-6 (1.40 +/- 1.9 pg/ml vs 0.81 +/- 1.5 pg/ml: P < 0.05) levels decreased after dietary treatment. CONCLUSION: The novel finding of this study is the association of the mutant allele (A1359) with a decrease of resistin, leptin and interleukin-6 secondary to weight loss. PMID- 21666970 TI - Importance of a balanced omega 6/omega 3 ratio for the maintenance of health: nutritional recommendations. AB - The modification of dietary patterns has led to a change in fatty acid consumption, with an increase in the consumption of omega-6 fatty acids and a marked reduction in the consumption of omega-3 fatty acids. This in turn has given rise to an imbalance in the omega-6/omega-3 ratio, which is now very different from the original 1:1 ratio of humans in the past. Given the involvement of omega-6 and omega-3 essential fatty acids in disease processes, the present article examines changes in dietary patterns that have led to the present reduction in the consumption of omega-3 essential fatty acids, and to study the importance of the omega-6/omega-3 balance in maintaining good health. In addition, an assessment is made of the established recommendations for preventing a poor intake of omega-3 essential fatty acids, and the possible options for compensating the lack of these fatty acids in the diet. PMID- 21666971 TI - [Spanish diet quality according to the healthy eating index]. AB - OBJECTIVE: To determine the quality of the Spanish diet by means of the Healthy Feeding Index (IASE) and its relationship with geographical and socioeconomic variables. METHODS: Cross-sectional descriptive study from the National Heath Questionnaire 2006 (ENS-2006). 29,478 people answering the Frequency of Consumption Questionnaire (CFC) were studied (women = 15,019; men =14,459). The IASE comprises 10 variables (grains and derivatives, vegetables, fruits, dairy products, meats, legumes, cold-processed meats, sweets, beverages, and diet variety) constructed from the CFC and the recommendations of the Feeding Guidelines (Spanish Society of Community Nutrition 2004). The IASE categories (maximum score: 100) were: healthy feeding > 80 points; Need-for-change > 5,080; Little healthy, 50. A descriptive analysis was performed with differences of the means (Kruskal-Wallis and Mann-Whitney tests), and the Chi-square test to study the independency of the variables such as age, gender, social class, and educational level with the IASE categories. RESULTS: 72% of the whole sample needs changes in their feeding patterns. The mean score for women was 73.7 +/- 10.5 and for men 69.9 +/- 11.3 (p < 0.001). Among the healthy category, the age group > 65 years and women obtain higher percentage (38.8% and 28.3%, respectively) in comparison to men (18.4%). Besides, the higher the social class the higher the healthy diet index will be (class-I: 24.4%, class-II: 25.0%, class III: 25.8%) (p < 0.001). The Autonomous Communities from Valencia (5.4%), Balearic Islands (4.6%) and Andalusia (4.3%) are the ones presenting the highest index of little healthy feeding. CONCLUSIONS: The IASE is a rapid and cheap method to estimate the quality of the diet in the population since it uses secondary data coming from the ENS and the feeding guidelines. It is useful to planning the nutritional policies in Spain. PMID- 21666972 TI - [Prevalence of food habits and nutritional status in adult population served in primary care]. AB - OBJECTIVE: To identify dietary patterns and nutritional status of the population between 18-44 years visited at a health center (HC) and explore the associated factors. METHODS: Cross-sectional study conducted in an urban HC in a random sample of 201 people. Were analyzed socio-demographic data, anthropometric measurements, 24 hours latest reminder intake, weekly food frequency questionnaire. RESULTS: The mean age of participants was 32.81 years (standard deviation 6.72). 63.68% (128) were women and 62.69% (126) immigrants. 45.27% (91) expressed no exercise. About 60% of participants related a deficit in consumption milk, fruits, meat and farinaceous and 80% vegetables, 58% related excessive fat. 44.4% (56) of immigrants was 20.3% with respect to obese (15) of native (P = 0.001). The proportion of people with "waist-risk" was higher among immigrants as compared to the native (19.0% vs 6.8%, P = 0.017) and among those who did not exercise with respect to each other (17.6% vs 8.1%, P = 0.049). Immigrants perform less physical activity related to the native (42.1% vs 62.7%, P = 0.013). Being an immigrant was the variable explaining of distribution acceptable daily macronutrient intake (Odds Ratio 4.7, Confidence Interval 95% 2.02-11.03). DISCUSSION: The participants related excessive consumption of fats and deficient in the rest of food groups. Obesity and the "risk waist" were more common among immigrants and sedentary population. Immigrants talked of a better distribution of nutrients in your daily diet. PMID- 21666973 TI - [Study of the nutritional status of elders in Cantabria]. AB - INTRODUCTION: Population ageing is a main concern under the biosanitary point of view. AIM: To assess the nutritional status of people 65 year-old and older in Cantabria (Spain) METHOD: A total of 1605 persons were studied by means of the MNA (Mini Nutritional Assessment); a) by primary care (59.9% in the unit, and 4.7% at home) and, b) in nursing homes (35.4%). RESULTS: Nutritional score (NS) was 23.4 +/- 4.1 for women and 24.4 +/- 4 in males (p < 0.001). We emphasize the fact that 22.3% of people studied in the nursing homes were malnourished or at risk of malnutrition, compared with 14.2% of those studied at the unit, and only 3.3% of the home visited elders. The correlation between the value of the NS and the subjective estimation of nutrition status showed a high value (0.65). We emphasize the negative correlation (-0.53) between BNI value and the incidence of skin lesions. CONCLUSION: Our results highlight the importance of identifying malnutrition or its risk in elders in order to prevent the negative consequences of this deficiency. PMID- 21666974 TI - [Overweight and obesity among Spanish adults]. AB - AIM: to assess the prevalence of overweight and obesity in Spanish adults and to know the current situation and its evolution in the last years. MATERIAL AND METHODS: The study involved 418 subjects (196 men and 222 women) from 18 to 60 years, who were selected to constitute a representative sample of the Spanish population as a whole. Sanitary, socioeconomic and anthropometric (weight, height, waist circumference and percentage body fat by bioimpedance) data was collected. Body Mass Index and waist-height were ratio calculated. RESULTS: The prevalence of overweight was 34.2%, 43.9% in men and 25.7% in women, and the prevalence of obesity was 13.6% (it was similar in men and women). 47.8% of the population had excess of body weight and 70.2% excess of body fat, these parameters were higher in men than in women and they increased with age. 22.2% of the population had central obesity (taking waist circumference as reference) and 54.7% central obesity and high cardiovascular risk (because waist/height was > 0.5), both parameters were higher in men than in women. CONCLUSION: Overweight and obesity prevalence among the Spanish population is very high and more than the half of the population is in risk of suffering from cardiovascular disease. Furthermore, the situation is worse than a few years ago, so it is necessary to continue working to decrease the prevalence of overweight and obesity among the Spanish population. PMID- 21666975 TI - [The reality of home-based parenteral nutrition in Spain]. AB - It is important to be acquainted with the magnitude and characteristics of Parental Home Nutrition NPD in Spain to fundamentally provide decision making in clinics as well as the steps to be taken based on knowledge. AIM: To be aware of the perception and characteristics of the NPD in Spain throughout the year 2008. MATERIAL AND METHODS: Description Time Research made in the 713 Spanish hospitals including those listed in the Health, Social, Social Political and Equanimity Ministry, which fulfilled the criterion inclusion during 2008. The Hospital Pharmacy Services were contacted through telephone survey. RESULTS: From the 713 hospital included, 62 (8,70%) carried out NPD, treating 228 patients, of which 201 (88,16%) were adults. The prevalence in Spain was of 4,91/10(6) inhabitants during 2008, being in adults 5,06/10(6) inhabitants and in children 4,01/10(6) inhabitants. The Autonomous Community of Madrid reached the highest prevalence 11,53/10(6) inhabitants. The Nutritional Units carried out the following up in 26 of the hospitals. CONCLUSIONS: With this work, a base for the future analysis and investigation about the situation of the NPD is established. It can also be a reference for different data bases. PMID- 21666976 TI - [Prevalence and factors associated to malnutrition in patients admitted to a medium-long stay hospital]. AB - OBJECTIVES: To determine the prevalence of hyponutrition at admission at a mid- to long-term stay hospital. To analyze the possible factors associated to hyponutrition; the possible relationship with mortality at one month, and the treatments for hyponutrition performed. MATERIALS AND METHOD: Descriptive study from the laboratory data obtained in 140 patients. For diagnosing hyponutrition, a tool based on albumin, total cholesterol, and lymphocytes levels was used. Demographical (age and gender) and clinical data (presence of pressure soars, nasogastric tube, dementia, neoplasm, previous admission to the ICU, and main diagnosis) were gathered at admission as well as the mortality at the first month. The treatments used for hyponutrition were reviewed. RESULTS: patients' age was 77.1 years and 63% were females. 17.1% of the patients presented normal nutritional status, 50.7% met the criteria for mild hyponutrition, 26.4% of moderate hyponutrition, and 5.7% of severe hyponutrition. We found no association between hyponutrition and gender, nasogastric tube, soars, dementia or neoplasm, but we did so with age (P = 0.033). We found a relationship between moderate severe hyponutrition and pressure soars (P = 0.036). We found an association between hyponutrition and mortality at one month (OR = 1.357, 95% CI 1.121 to 1.643; P = 0.02). 35.6% of the patients with moderate-severe hyponutrition received therapy for this condition (28.9% with protein supplements and 6.7% with enteral diet). CONCLUSIONS: hyponutrition affects most of the patients admitted to a mid to long-term stay hospitals and is associated with higher mortality. One third of hyponutrition patients receive nutritional therapy. PMID- 21666977 TI - [Maternal and fetal outcomes in pregnancy following bariatric surgery]. AB - BACKGROUND: Obesity is the most frequent metabolic disease in the World, and is associated with several comorbidities. Bariatric procedures arise as a promising treatment when classical approach is ineffective. Half of the operated patients are reproductive-aged women and there is evidence that obesity is related to worse maternal and fetal outcomes. Because nutritional status is affected by bariatric surgery and is a vital component during pregnancy, the aim of our study is to asses the impact of bariatric surgery on pregnancy in these patients. MATERIAL AND METHODS: We studied 10 women and 15 pregnancies following bariatric surgery between 2003 and 2009. The visits took place every three months by an obstetrician and an endocrinologist with experience in nutrition, recording clinical features and lab work. RESULTS: We found iron deficiency in 80% of the pregnancies, vitamin D in 46,7%, vitamin A in 20%, vitamin E in 13,3% and vitamin B12 in 26,7%. There were no complications during pregnancy, except one case of gravidic hiperemesis. There were nine deliveries without malformations, three of them were small for gestational age newborns and one suffered aspiration pneumonia. There were three stillbirths and one preterm delivery with fetal death. CONCLUSIONS: our results show fewer complications during pregnancy in these women than obese women and similar to general population. PMID- 21666978 TI - Selecting the best anthropometric variables to characterize a population of healthy elderly persons. AB - The objective is to select the best anthropometric measurements to characterize a healthy elderly population. For that, 1030 healthy elderly persons (508 men and 522 women) living independently or in an institution (in both public and private homes) were enrolled for this population-based, cross-sectional study conducted from February 2004 to May 2005. Anthropometric measurements were made by the same investigator according to standard techniques of the WHO. Across several age groups, men were significantly heavier and taller than women whereas skinfold thicknesses were significantly greater in women than men. Through statistical analysis we were able to identify the variables providing most information and that could also best discriminate between sex, age and independent versus institutionalized persons: height, weight, one of the skinfold thickness measurements and mid-upper arm circumference. The number of age groups in both the male and female populations could be limited to three. PMID- 21666979 TI - Dietary supplements for the lactating adolescent mother: influence on plasma micronutrients. AB - INTRODUCTION: The nutritional status of micronutrients in lactating adolescent women is crucial to guarantee an adequate secretion of these in breast milk and, consequently, an adequate nutritional status of children. Hence, more attention should be given to micronutrient status of adolescent mother who breastfeed. This study aimed to evaluate the influence of multimicronutrients supplementation upon nutritional status of iron, copper, zinc and calcium of lactating adolescent mother from low socioeconomic status in Rio de Janeiro/Brazil. METHODS: We conducted a randomized, placebo-controlled trial. During 60 days, 36 adolescents were allocated into two groups: supplemented group (SG) with 17 volunteers, receiving daily multimicronutrients supplement and the placebo group (PG) with 19 volunteers, receiving an inert compound. Plasma iron, copper, zinc and calcium and hemoglobin were determined at 7, 11 and 15 of the postpartum weeks (PPW). The effect of supplementation was analyzed by analysis of variance, comparing the differences between groups and within groups. RESULTS: The average age of volunteers was 17.1 +/- 0.8 for the supplemented group and 16.3 +/- 1.4 for the placebo group. We observed an increase in the mean concentration of zinc (p < 0.05) and hemoglobin (p < 0.05) in the SG during the study (60 days), while the PG showed reduction (p < 0.05) in the mean concentration of copper between the 7th and 11t h PPW. CONCLUSION: The results of this study show that supplementation with multimicronutrientes exerted positive effect on hemoglobin, copper and zinc. PMID- 21666980 TI - [Percutaneous endoscopic gastrostomy: a 7 years experience long-term tube feeding. Follow-up]. AB - Percutaneous endoscopic gastrostomy (PEG) is the first choice method for long term enteral feeding when the digestive tube is undamaged and the patients' survival is longer than 2 months. There are increasing series and indications reported and although it is a safe technique we should take into account an appropriate patient selection. The aim of this work was to analyze the follow-up of the patients undergoing percutaneous endoscopic gastrostomy (PEG) at a hospital with high assistance level and one of the referents for organ transplantation in our community, with the peculiarities that this may have on our series. We analyze a cohort of 73 patients submitted to PEG during the years 2000-2007 at the Reina Sofia Hospital of Cordoba. Neurological and ENT neoplasms and upper GI tract neoplasms are among the most frequent causes, with similar results to those reported in other series. We highlight the number of young patients with cystic fibrosis (CF) in our series with nutritional support through PEG complementing oral and nocturnal feeding, which has lead to improved nutritional parameters before lung transplant. In consequence, we therefore analyze patients' selection and their characteristics, the ethical and moral implications in some of these patients, such in neurological patients, their complications, mortality, and we mention as being of interest the transient and well tolerated indication in a subgroup of CF patients that deserves special mention. PMID- 21666981 TI - Substance abuse and health self-perception in Spanish children and adolescents. AB - OBJECTIVE: The aim of this study was to analyze substance abuse and health self perception in children and adolescents from the province of Cadiz (Spain). METHODOLOGY: Participants were 738 students, 50.9 boys and 49.1% girls, from elementary school to high school (1st to 12th grade, mean age 12.2. years), who responded a Spanish adaptation of the Health Behavior in School-aged Children Inventory. RESULTS: No difference was observed in percentage of boys and girls reporting to smoke or drink alcohol. Smoking and drinking habits increased with age, being higher in 11th and 12th grade students. Significant differences were observed among the percentage of smokers and non smokers recognizing to have parents, older brothers or friends who smoke. Rates of drug abuse were generally low, being cannabis the most frequently consumed illicit drug. Most respondents had a perception of excellent or good health, with no significant gender differences. About half of subjects considered that health exclusively depends on self behavior, but an important percentage also gave a relevant role to luck. Stomach-ache was the most frequent physical complaint, followed by headache. Psychological complaints mainly corresponded to nervousness and bad temper. Only a small percentage of subjects declared the use of medicines or tablets without prescription. No significant difference in the percentage of respondent who perceived an excellent or good health was observed among substance users and non users. CONCLUSIONS: Substance abuse and health self-perception in children and adolescents are the result of the interaction of a complex series of individual and social factors. Activities aimed to improve health focusing on partial aspects of adolescents' lifestyle most probably will have limited results, and global programs are required. PMID- 21666982 TI - Are calcium and fiber beneficial for poorly controlled diabetic patients? AB - No nutritional protocol for poorly controlled diabetic patients receiving well managed drug treatment is currently available. OBJECTIVE: Aims were to compare dietary consumption of calcium and fibers with lipid profile and glycosilated hemoglobin HbA1c. METHODOLOGY: This was a prospective observational study. Patients with poorly controlled diabetes were consecutively recruited. A food frequency questionnaire and tests for lipid profile, HbA1c, and C reactive protein were collected, along with clinical and anthropometric assessment. RESULTS: Patients (N = 114, age 65.7 +/- 6.5 years, 75.4% females, BMI 29.0 +/- 5.3 kg/m2) were often insulin-dependent (32.5%) and with systemic inflammation (C reactive protein 4.2 +/- 3.9 mg/L). Diet was energy restricted (1,365 +/- 565 kcal/day) and mostly adequate but with suboptimal fiber (15.4 +/- 8.6 g/day) and very low calcium (592.4 +/- 204.4 mg/day). Calcium and fiber in the diet correlated with serum lipids, whereas fiber alone displayed a protective association regarding diabetes (HBA1c, insulin use) and arterial hypertension. CONCLUSIONS: Calcium and fiber ingestion exhibited correlations with important markers of metabolic status and cardiovascular risk. Future studies should address enhancement of these ingredients by means of dietary changes and supplements. PMID- 21666983 TI - Flaxseed and its contribution to body growth and brain of Wistar rats during childhood and adolescence. AB - OBJECTIVES: To evaluate the effect of flaxseed upon body growth and brain of rats. METHODS: Experimental phase lasted 52 days, using 42 Wistar rats which were divided into four groups: Control (CG, n = 12), 10% casein diet; Flaxseed (GL, n = 12), 10% flaxseed diet plus casein; Modified Control (GCM, n = 12), 10% casein diet with changes in lipid and fiber comparable to GL; Non-protein (GA, n = 6), diet without protein. Considering food intake, protein intake and weight variation, the Protein Efficiency Ratio (PER) was calculated. Net Protein Retention (NPR) and the Food Efficiency Ratio (CEA) were also determined relative to brain weight at 30 days of life (M30) and at 52 days (M52). Analysis of Variance (ANOVA), Test of Sheffe and post-test of Bonferroni were used, p < 0.05. RESULTS: GL had lower food intake, protein and weight variation than GC, but had higher values than GCM. Concerning PER, GL was lower than GC and similar to the GCM, as well as CEA. As for NPR, GL had lower values than the CG and GCM. At M30, GL was superior to GC in relation to brain weight. Likewise, the same was observed at M52. CONCLUSION: Flaxseed promoted adequate growth and better brain development in animals, which might be explained by increased incorporation of omega-3 into these tissues. PMID- 21666984 TI - [Phrynoderma secondary to vitamin A deficiency in a patient with biliopancreatic diversion]. AB - Biliopancreatic diversion (BPD) is a malabsorptivebariatric procedure can lead to the development of several nutritional complications, including fat-soluble vitamins deficiencies. Routine supplementation with vitamins and trace elements and a close follow-up long-term can prevent these nutritional risks. Vitamin A participates in ocular metabolism, epithelial differentiation, growth, and embryogenesis. Have been described several cases of ophthalmological and fetal complications associated with vitamin A deficiency in patients who have undergone BPD. Few information exists in literature about dermatologic manifestations that may occur in these patients. Phrynoderma is a type of follicular hyperkeratosis located on the extensor surfaces of the extremities whose main cause is vitamin A deficiency. We report an exceptional case of severe cutaneous and ocular complications in a patient who had undergone BPD with poor adherence to treatment and postoperative follow-up. Our patient presented simultaneously the characteristic skin lesions of phrynoderma with nytalopia and xerophthalmia in a setting of low serum levels of vitamin A. Treatment with high doses vitamin A obtained the resolution of both processes. We review and discuss the relationship between phrynoderma, malnutrition and vitamin A deficiency. PMID- 21666985 TI - Candida bezoars with urinary tract obstruction in two women without immunocompromising conditions. AB - More than half of the cases of fungal infections of the urinary tract are caused by Candida sp., but occurrence of obstructive uropathy caused by mycetomas or fungus balls (urobezoars) is extremely rare. The latter are conglomerates of fungal hyphae. Diabetes mellitus, immunosuppression, chronic disease, and malignancies are known predisposing factors. Preoperative imaging is not pathognomonic; blood clots, radiolucent urinary calculi, air bubbles, and inflammatory debris can mimic urobezoars. We report on two otherwise healthy women presenting with urinary tract obstruction caused by candidal mycetomas of the renal pelvis that mimicked matrix lithiasis. PMID- 21666986 TI - Composite oncocytoma and papillary renal cell carcinoma of the kidney treated by partial nephrectomy: a case report. AB - We present the case of a 73-year-old woman who presented with lethargy and a nonproductive cough. Computerised tomography of her abdomen revealed a 38-mm mass in the lower pole of her left kidney. She underwent a partial nephrectomy, with final histopathological analysis confirming the presence of a concomitant oncocytoma and papillary cell carcinoma. To our knowledge, this is the only case report in the world literature describing a papillary renal cell carcinoma within an oncocytoma treated by partial nephrectomy. PMID- 21666987 TI - Comorbidity, use of common medications, and risk of early death in patients with localized or locally advanced prostate cancer. AB - In this paper, we analyze predictive factors for early death from comorbidity (defined as death within 3 years from diagnosis and unrelated to prostate cancer) in patients with localized or locally advanced prostate cancer. Such information may guide individually tailored treatment or observation strategies, and help to avoid overtreatment. We retrospectively analyzed baseline parameters including information on comorbidity and medication use among 177 patients (median age at diagnosis 70 years). Actuarial survival analyses were performed. During the first 3 years, two patients (1.1%) died from progressive prostate cancer after they had developed distant metastases. The risk of dying from other causes (3.4%) was numerically higher, although not to a statistically significant degree. Six patients who died from other causes had age-adjusted Charlson comorbidity index (CCI) scores >=5 (CCI is a sum score where each comorbid condition is assigned with a score depending on the risk of dying associated with this condition). The main comorbidity was cardiovascular disease. The two statistically significant predictive factors were medication use and age-adjusted CCI score >=5 (univariate analysis). However, medication use was not an independent factor as all patients with age-adjusted CCI score >=5 also used at least one class of medication. Median survival was 30 months in patients with age-adjusted CCI score >=5. Prediction of non-prostate cancer death may be important to prevent overtreatment in patients who are more threatened by comorbidity. Our data suggest that simple parameters such as use of medications vs. none, or presence of serious cardiac disease vs. none, are not sufficient, and that age-adjusted CCI scores outperform the other factors included in our analysis. PMID- 21666988 TI - Bladder cancer and cancer stem cells: basic science and implications for therapy. AB - Bladder cancer is the fifth most common cancer in Western society, with the global burden predicted to increase significantly in the foreseeable future. Over 90% of these bladder cancers are transitional cell carcinomas of urothelial origin (urothelial carcinomas or UCs) and at presentation, over 70% will be non muscle-invasive or stage Ta/T1 tumours, with the remainder being muscle-invasive or stages T2-4. Bladder UC is a highly heterogeneous disease: for the 50-55% of bladder cancer patients presenting with Ta tumours, recurrence is the main issue, but for the 20-25% of patients presenting with T1 tumours, progression is the main issue. Progression to, or presentation with, muscle-invasive disease represents the critical step for patients, necessitating more aggressive therapies and carrying significantly worse survival rates. We therefore urgently require detailed molecular insights into the pathogenesis of muscle-invasive bladder cancer so that the disease can be more adequately and appropriately treated at presentation, so that progression from stages Ta/T1 can be abrogated, and so that the risk of recurrence following treatment can be minimised. The recently identified bladder cancer stem cells are considered to be mediators of resistance to current therapies and therefore represent strong candidate biological targets. The aim of this review is to discuss the background and basic science of such cells, and the implications for current and future therapies. PMID- 21666989 TI - Investigation of the association between metabolic syndrome and disease activity in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis. Increased prevalence of metabolic syndrome (MetS) in RA may occur secondary to specific drug treatment and reduced physical activity associated with this condition. However, some recent studies suggest contradictory theories about the association of RA with MetS. This study was designed to evaluate the frequency of MetS in RA patients and the relationship between MetS with RA disease activity and body mass index (BMI). The study was conducted on 120 RA patients and 431 age and sex-matched apparently healthy controls. A considerable proportion of patients were being treated with prednisolone and/or methotrexate and/or hydroxychloroquine. Disease activity was measured by the 28 joint count of disease activity score-Cerythrocyte sedimentation rate (DAS28ESR). MetS was evaluated according to International Diabetic Federation (IDF) and Adult Treatment Panel III (ATP III) criteria. The prevalence of MetS was significantly higher in the control group (p = 0.005). We did not find any difference in the prevalence of MetS between the patients with DAS < 3.2 and DAS >= 3.2. There was no association between the DAS28 score and the presence of MetS components by either definition. Multiple logistic regression analysis showed that the odds of a DAS > 3.2 in patients with BMI between 25 and 30 kg/m2 (OR = 0.1, p = 0.01) and BMI > 30 kg/m2 (OR = 0.3, p = 0.1), in comparison to BMI < 25 kg/m2, was 1/5 and 1/3, respectively. RA was not found to increase the risk of MetS. In addition, disease activity in RA patients was not influenced by the presence of MetS. PMID- 21666990 TI - Changes in hemodynamics and tissue oxygenation saturation in the brain and skeletal muscle induced by speech therapy - a near-infrared spectroscopy study. AB - Arts speech therapy (AST) is a therapeutic method within complementary medicine and has been practiced for decades for various medical conditions. It comprises listening and the recitation of different forms of speech exercises under the guidance of a licensed speech therapist. The aim of our study was to noninvasively investigate whether different types of recitation influence hemodynamics and oxygenation in the brain and skeletal leg muscle using near infrared spectroscopy (NIRS). Seventeen healthy volunteers (eight men and nine women, mean age +/- standard deviation 35.6 +/- 12.7 years) were enrolled in the study. Each subject was measured three times on different days with the different types of recitation: hexameter, alliteration, and prose verse. Before, during, and after recitation, relative concentration changes of oxyhemoglobin (Delta[O2Hb]), deoxyhemoglobin (Delta[HHb]), total hemoglobin (Delta[tHb]), and tissue oxygenation saturation (StO2) were measured in the brain and skeletal leg muscle using a NIRS device. The study was performed with a randomized crossover design. Significant concentration changes were found during recitation of all verses, with mainly a decrease in Delta[O2Hb] and DeltaStO2 in the brain, and an increase in Delta[O2Hb] and Delta[tHb] in the leg muscle during recitation. After the recitations, significant changes were mainly increases of Delta[HHb] and Delta[tHb] in the calf muscle. The Mayer wave spectral power (MWP) was also significantly affected, i.e., mainly the MWP of the Delta[O2Hb] and Delta[tHb] increased in the brain during recitation of hexameter and prose verse. The changes in MWP were also significantly different between hexameter and alliteration, and hexameter and prose. Possible physiological explanations for these changes are discussed. A probable reason is a different effect of recitations on the sympathetic nervous system. In conclusion, these changes show that AST has relevant effects on the hemodynamics and oxygenation of the brain and muscle. PMID- 21666991 TI - Effects of changes in colored light on brain and calf muscle blood concentration and oxygenation. AB - Color light therapy is a therapeutic method in complementary medicine. In color therapy, light of two contrasting colors is often applied in a sequential order. The aim of this study was to investigate possible physiological effects, i.e., changes in the blood volume and oxygenation in the brain and calf muscle of healthy subjects who were exposed to red and blue light in sequential order. The hypothesis was that if a subject is first exposed to blue and then red light, the effect of the red light will be enhanced due to the contrastingly different characteristics of the two colors. The same was expected for blue light, if first exposing a subject to red and then to blue light. Twelve healthy volunteers (six male, six female) were measured twice on two different days by near-infrared spectroscopy during exposure to colored light. Two sequences of colored light were applied in a controlled, randomized, crossover design: first blue, then red, and vice versa. For the brain and muscle, the results showed no significant differences in blood volume and oxygenation between the two sequences, and a high interindividual physiological variability. Thus, the hypothesis had to be rejected. Comparing these data to results from a previous study, where subjects were exposed to blue and red light without sequential color changes, shows that the results of the current study appear to be similar to those of red light exposure. This may indicate that the exposure to red light was preponderant and thus effects of blue light were outweighed. PMID- 21666992 TI - Frontiers in vitamin research: new antibodies, new data. AB - Since 2004, the anatomical distribution of vitamins in the monkey brain, studied using immunohistochemical techniques and new tools (specific antisera that discriminate different vitamins reasonably well), has been an ongoing research field. The visualization of immunoreactive structures containing vitamins (folic acid, riboflavin, thiamine, pyridoxal, and vitamin C) has recently been reported in the monkey brain (Macaca fascicularis), all these vitamins showing a restricted or very restricted distribution. Folic acid, thiamine, and riboflavin have only been observed in immunoreactive fibers, vitamin C has only been found in cell bodies (located in the primary somatosensory cortex), and pyridoxal has been found in both fibers and cell bodies. Perikarya containing pyridoxal have been observed in the paraventricular hypothalamic nucleus, the periventricular hypothalamic region, and in the supraoptic nucleus. The fibers containing vitamins are thick, smooth (without varicosities), and are of medium length or long, whereas immunoreactive cell bodies containing vitamins are round or triangular. At present, there are insufficient data to elucidate the roles played by vitamins in the brain, but the anatomical distribution of these compounds in the monkey brain provides a general idea (although imprecise and requiring much more study) about the possible functional implications of these molecules. In this sense, here the possible functional roles played by vitamins are discussed. PMID- 21666993 TI - Ovarian epithelial cancer stem cells. AB - The last decade witnessed an explosion of interest in cancer stem cells (CSCs). The realization of epithelial ovarian cancer (EOC) as a CSC-related disease has the potential to change approaches in the treatment of this devastating disease dramatically. The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies. Compared to the CSCs of other cancer types, the identification and study of EOC stem cells (EOCSCs) is rather difficult due to several major obstacles: the heterogeneity of tumors comprising EOCs, unknown cells of origin, and lack of knowledge considering the normal ovarian stem cells. This poses a major challenge for urgent development in this research field. This review summarizes and evaluates the current evidence for the existence of candidate normal ovarian epithelial stem cells as well as EOCSCs, emphasizing the requirement for a more definitive laboratory approach for the isolation, identification, and enrichment of EOCSCs. The present review also revisits the ongoing debate regarding other cells and tissues of origin of EOCs, and discusses early events in the pathogenesis of this disease. Finally, this review discusses the signaling pathways that are important regulators of candidate EOCSC maintenance and function, their potential role in the distinct pathogenesis of different EOC subtypes, as well as potential mechanisms and clinical relevance of EOCSC involvement in drug resistance. PMID- 21666994 TI - From hydra regeneration to human brain structural plasticity: a long trip through narrowing roads. AB - Regeneration is a strategy to maintain form and function throughout life. Studies carried out on animal models throughout the phylogenetic tree have flourished in the last decades in search of mechanisms underlying the regenerative processes. The development of such studies is strictly linked with stem cell research and both are viewed as one of the most promising outcomes for regenerative medicine; yet, regeneration, stem cells, and tissue repair do not seem to follow a logical path through the different animal species and tissues. As a result, some mammalian organs, e.g., kidney and brain, have lost most of their regenerative capacity. The human nervous system, although harboring neural stem cells, is placed at the extreme of "perennial" tissues. In addition, it is affected by neurodegenerative diseases, whose heavy burden is heightened by enhanced life spans. This review, starting from the basic principles of tissue regeneration viewed in a comparative context, tries to answer this question: To which extent can regenerative medicine be figured out in a mammalian brain equipped with many anatomical/evolutionary constraints? PMID- 21666995 TI - Nanoparticles and inflammation. AB - The development of nanoscale molecular probes capable of diagnosis, characterization, and clinical treatment of disease is leading to a new generation of imaging technologies. Such probes are particularly relevant to inflammation, where the detection of subclinical, early disease states could facilitate speedier detection that could yield enhanced, tailored therapies. Nanoparticles offer robust platforms capable of sensitive detection, and early research has indicated their suitability for the detection of vascular activation and cellular recruitment at subclinical levels. This suggests that nanoparticle techniques may provide excellent biomarkers for the diagnosis and progression of inflammatory diseases with magnetic resonance imaging (MRI), fluorescent quantum dots (QDs), and surface enhanced Raman scattering (SERS) probes being just some of the new methodologies employed. Development of these techniques could lead to a range of sensitive probes capable of ultrasensitive, localized detection of inflammation. This article will discuss the merits of each approach, with a general overview to their applicability in inflammatory diseases. PMID- 21666996 TI - [Bacteraemia due to Escherichia coli producing extended-spectrum beta-lactamases (ESBL): clinical relevance and today's insights]. AB - Antibiotic resistance is an old problem with new face as the rate of infections due to multidrug resistant bacteria is higher everyday and the number of new antibiotics to overwhelm the problem is becoming smaller. E. coli is the most frequent agent causing nosocomial or community-acquired bacteraemia being in our country 10% of them extended-spectrum beta-lactamases (ESBL) producing E. coli isolates. Nowadays the number of community- acquired or health-related infections caused by these ESBL producing E. coli is increasing. CTX-M has also become the most frequent ESBL compared to other enzymes. The role of these enzymes as a virulence factor increasing mortality in patients with bacteraemia due to E. coli is not well defined. The relevance of ESBL-E. coli seems to be related with the higher frequency of inadequate treatment and therefore the importance of identifying factors or features that might predict that the patient's infection is due to one of these isolates. In terms of prevention and control of infection measures, the role of patient's isolation is not clear but a proper prescription of antibiotics and antibiotic control policies are probably important to reduce the problem. PMID- 21666997 TI - [Pharmacology]. AB - Two of the main characteristics of western societies in the last fifty years have been the medicalization of the human life and the environmental degradation. The first one has forced human being to consider medicines use related to what would be rational, reasonable and well-reasoned. The second one brought us to a new ecologist conscience. In relation to the "human social system", the effects of medication can be considered very positive as a whole, particularly those related to the amazing increase of expectative and quality of life. But, along with those unquestionable beneficial effects, medicines have also caused some negative effects for other biotic and abiotic systems, such as microbian alterations and their undesirable consequences which have involved the massive use of antibiotics in medicine and veterinary, the uncontrolled elimination of millions of doses of all kind of drugs, additives and excipients, etc., as well as atmospheric contamination and degradation of forests and deep oceans which can have been caused by investigation and production of determinated drugs. In this context Pharmacology appears as a scientific discipline that studies the research (R), development (D), production (P), and utilization (U) of drugs and medical substances in relation to the environment. From a farmaecologic perspective the drugs utilization has its development in three main contexts, all of them closely related: prescription quality, farmaceutical care, and patient's active participation in his own disease and treatment. PMID- 21666998 TI - Activity of vancomycin, ciprofloxacin, daptomycin, and linezolid against coagulase-negative staphylococci bacteremia. AB - OBJECTIVE: Multiresistant coagulase-negative staphylococci (CNS) infections are mainly increased in hospitalized patients. We have studied the activity of vancomycin, ciprofloxacin, daptomycin and linezolid in methicillin-resistant CNS strains, isolated from true blood cultures. METHODS: We collected 87 strains of different CNS species from positive blood cultures. Staphylococci were identified by MicroScan Walkaway (Dade Behring, Siemens) and with the Api ID 32 Staph (BioMerieux, France). The susceptibility to oxacillin, vancomycin and ciprofloxacin was performed by automatic microdilution plate as cited above. The susceptibility to daptomycin and linezolid was performed by Etest (AB BioMerieux, Solna, Sweden). Interpretative criteria were done following the CLSI guidelines. RESULTS: Eighty-seven CNS strains were studied: 55 (63%) were S. epidermidis, 15 (17%) S. haemolyticus, 10 (12%) S. hominis, and 7 (8%) other species. Fifty-three (61%) strains showed loss of susceptibility to vancomycin, MIC = 2 mg/L. Ciprofloxacin resistance, MIC > 2 mg/L, was observed in 56 (64%) strains. Daptomycin resistance was not observed, with a susceptibility range between 0.032 1 mg/L and modal value of 0.25 mg/L. Ten strains (11.5%) resistant to linezolid were observed. Nine patients were in ICU, where the average length of stay was 38 days (range 16-58 days) and one belonged to Hepato-Pancreatic Surgery, where he stayed for 64 days. CONCLUSIONS: Low susceptibility to vancomycin is frequent in the CNS strains studied in our hospital. Daptomycin shows a high efficacy against CNS, and it could be useful for the treatment of primary bacteremia or catheter associated bacteremia. The massive and continuous use of linezolid has led to the appearance of resistance. PMID- 21666999 TI - [Do general practitioners follow the therapeutical recommendations of cystitis in women? INURA study]. AB - OBJECTIVE: The management of lower urinary tract infections varies from physician to physician. The aim of this study was to assess whether general practitioners follow the evidence-based guidelines for the management of cystitis in women. METHODS: Cross-sectional study carried out from March to July 2009 in which physicians consecutively registered in a template during a 8-week period the first six episodes of cystitis by means attended at the medical consultation. Age, episode of infection, associated morbidity, antibiotic prescription, and type of antibiotic course (short or long regimen) were determined. RESULTS: Out of 176 physicians invited to participate, 110 included 658 women with lower urinary tract infections with antibiotic treatment being administered in 634 cases. Short courses were given to 385 women (60.7%) and 249 women were given long schedules (39.3%). A total of 343 out of all noncomplicated cystitis were treated with short courses (62.9%) and 75 out of complicated cystitis were treated with long courses (66.4%). First-choice antibiotics were administered as empiric treatment in only 111 women (17.5%). CONCLUSIONS: These results highlight a poor adherence of general practitioners to current recommendations of clinical practice guidelines in cystitis with a low utilization of first-choice antibiotics. PMID- 21667000 TI - Resistance of Streptococcus pneumoniae isolated from Lebanese patients between 2005 and 2009. AB - INTRODUCTION: Streptococcus pneumoniae is an important organism in view of its prevalence and ability to cause serious infections; its resistance to antimicrobial agents is increasing worldwide. The purpose of this study was to evaluate the patterns of resistance of S. pneumoniae to penicillin, macrolides and various other antibiotics in strains isolated from Lebanese patients. METHODS: 121 strains isolated between January 2005 and January 2009 from two university hospitals in Beirut were identified and tested for MIC determination using the E-test method. The presence of erm(B) and mef(A/E) genes was investigated using PCR. RESULTS: The majority of the strains (73.5%) were isolated from respiratory tract infections, 50.4% were isolated in winter, 15.7% were invasive strains, 61.9% came from male patients, and 68.5% from adults. Out of 121 isolates, 58 were susceptible to penicillin, 61 were intermediate, and 2 were fully resistant to this antibiotic. Amoxicillin-clavunanic acid and cefpodoxime showed 100% activity on all tested isolates. In general, the MICs90 appear to fluctuate within the same range over the four years. The erm(B) gene was detected in 85.3% of the isolates, mef(A/E) in 19.5% whereas erm(A) was not detected in any of the macrolide resistant strains. DISCUSSION: The results of this study have important impact on the empirical antibiotic prescriptions; the increasing prevalence of resistance jeopardises the treatment choices posing a serious threat. Further surveillance and epidemiological serotyping are needed to monitor the local and regional resistance patterns and to track the spread route of resistance. PMID- 21667001 TI - [Antimicrobial susceptibility of methicillin-resistant Staphylococcus aureus strains from outpatient individuals]. AB - BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA MRSA) has emerged worldwide as a cause of infections among patients without risk factors. This CA-MRSA is different from nosocomial strains in terms of epidemiology, microbiology and clinical manifestations. We report the epidemiologic characteristics and resistance to antimicrobial agents of CA-MRSA strains isolated in the last three years in the Microbiology Lab of Hospital General La Mancha-Centro (Alcazar de San Juan, Ciudad Real). METHODS: We performed a retrospective analysis of microbiological cultures in patients with S. aureus diagnosed from 2007 to 2009 in La Mancha-Centro Health-Care Area, within Castilla-La Mancha Community. RESULTS: The distribution of CA-MRSA in the studied period was 26 out of a total of 97 S. aureus isolates in 2007 (26.8%), 40/113 in 2008 (35.4%) and 57/157 in 2009 (36.3%). The percentage from purulent skin and soft tissue infections was 63.4%. All strains were susceptible to linezolid, quinupristin/dalfopristin, and glycopeptides. The resistance was high to fluoroquinolones (94.3%), erythromycin (87.0%), tobramycin (82.9%), and clindamycin (65.3%). CONCLUSIONS: CA-MRSA isolates percentage increased along the period of the study. The majority were obtained from skin and soft tissue specimens. The most commonly associated antimicrobial resistance was to fluoroquinolones, erythromycin, tobramycin and clindamycin. An understanding of the CAMRSA epidemiology is important to prevent these organisms from becoming endemic in the world. PMID- 21667002 TI - [Results of a counselling programme in antibiotic treatment in a secondary hospital]. AB - BACKGROUND: The inappropriate use of antimicrobial agents may contribute to the development of bacterial resistance to the principal antimicrobial drugs. There is no provision in the immediate future of marketing of new broad-spectrum antibiotics, especially with activity against Enterobacteriaceae, so programs should be implemented to optimize antimicrobial therapy. We describe the results of a year of a counselling program in antibiotic treatment in a secondary Andalusian hospital. METHODS: We describe 276 interventions of a multidisciplinary non-compulsory counselling program of antimicrobial management on the Costa del Sol Hospital in Marbella. We evaluated the adequacy of empirical treatment, possibility of antibiotic de-escalation, duration and dose used. We analyzed the evolution of the sensitivity profile of the main microorganisms as well as a cost-effective analysis. RESULTS: 90% of the recommendations were accepted. The main actions were assessment of empirical therapy and deescalation in relation with the result of cultures. The main drugs tested were imipenem, meropenem, cefepime, and linezolid. The sensitivity profile of imipenem and meropenem improved slightly over previous years. It was found a considerable savings in annual drug spending. CONCLUSIONS: The non-compulsory counselling programs are useful tools for optimization of antimicrobial therapy, can prevent an increase of antimicrobial resistance and reduce the cost of antibiotic treatment. PMID- 21667003 TI - [Consumption of antibiotics of the general population of Segovia area during the period between 1999 to 2007]. AB - INTRODUCTION: The antibiotics are the medicaments most used after the analgesics, being prescribed more than 85 % in Primary Care. The aim of the study is to analyze the evolution of the prescription of antibiotics of systemic use in the general population of the Area of Segovia, during the years 1999-2007 and to know his trends evolution. MATERIAL AND METHODS: Antibiotics prescribed to the general population on the part of the Family physicians were processed using the information system of drugstore "CONCYLIA" that supplies the information in the shape of defined daily dose (DDD), transformed later into the indicator DHD (DDD for 1.000 inhabitants per day) taking as a base the population information of sanitary card. RESULTS: The global prescription of antibiotics of systemic use was high, 18,06 DHD (IC:17,22-18,90), with a variable evolution along the study in the shape of basin of low concavity. The percentage of prescription of penicillins was 64.42 % of the total of prescriptions corresponding to the group J01. CONCLUSIONS: The prescription in the Area of Segovia has presented a contained consumption in relation to other studies, showing differences in the volume of prescription from each the subgroups. The centralization of the consumption emphasizes in the subgroup of penicillins that supposed almost two third parts of the prescribed DDD. A change in the habits of prescription is observed detailing a decrease of the amoxicillin use and an increase of amoxicillin-clavulanic acid. PMID- 21667004 TI - [Methicillin-resistant Staphylococcus aureus: changes in the susceptibility pattern to daptomycin during a 10-year period (2001-2010)]. AB - INTRODUCTION: The objective of this study was to evaluate the activity of daptomycin and other agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates collected from 2001 to 2010, in order to determine changes and to detect resistance trends. METHODS: The study included a total of 1,130 MRSA isolates collected as part of a multicenter surveillance program for antibiotic resistance, Estudio de Vigilancia de Resistencia a los Antimicrobianos (VIRA study), from 51 medical centers throughout Spain between 2001 and 2010. Broth microdilution test was performed according to the Clinical Laboratory Standards Institute guidelines. RESULTS: Daptomycin showed excellent activity and maintained its activity over time; only one MRSA isolate collected in 2001 was nonsusceptible to this agent (MIC=2 mg/L). Based on the MIC90, daptomycin was 2-4 dilutions more active than vancomycin, teicoplanin and linezolid. Daptomycin retained activity against MRSA isolates that were resistant to linezolid, to quinupristin-dalfopristin, or showed intermediate susceptibility to vancomycin. CONCLUSIONS: Our data and those of other studies, coupled with daptomycin's rapid bactericidal activity, suggest that this antimicrobial could be an alternative in the treatment of severe infections caused by multiresistant S. aureus. PMID- 21667005 TI - [Infections due to Listeria monocytogenes]. PMID- 21667006 TI - [Intraperitoneal abscess for Eikenella corrodens]. PMID- 21667007 TI - What promotes sustained return to work of employees on long-term sick leave? Perspectives of vocational rehabilitation professionals. AB - OBJECTIVES: The aim of this study was to (i) explore promoting factors for sustained return to work (RTW), according to vocational rehabilitation professionals (VRP) that are amenable to change for employees who have been on sick leave >18 months and (ii) gain insight into crucial aspects of interventions. METHODS: Semi-structured interviews were carried out with 23 VRP. All interviews were transcribed fully verbatim. An inductive analysis of the transcripts was performed, using a process of identifying, coding, and categorizing the primary patterns in the data. RESULTS: Key influenceable promoting factors for sustained RTW by long-term sick-listed employees include: employee-based vocational guidance; integral, effective communication between the sick-listed employee and all RTW stakeholders; personal factors; a supportive work environment; and a stimulating social environment. Crucial aspects of interventions include: gathering information and setting priorities; improving qualifications; influencing cognitions; monitoring the sick-listed employee through the rehabilitation process; offering tailor-made interventions at different stages within a personal time-bound action plan; and preparing the employee and the work environment for RTW. CONCLUSIONS: Sustained RTW for long term sick-listed employees can be achieved by focusing on the influenceable promoting factors for RTW. The use of combined interventions in a holistic approach involving the worker and his environment is considered the best way to address the multicausality of work disability and could help maximize RTW outcomes. PMID- 21667008 TI - Participation after acquired brain injury: clinical and psychometric considerations of the Sydney Psychosocial Reintegration Scale (SPRS). AB - OBJECTIVE: To examine the psychometric qualities and develop the clinical utility of the Sydney Psychosocial Reintegration Scale (SPRS) as a measure of participation in people with traumatic brain injury. DESIGN: Data generated from previous prospective studies. SUBJECTS/PATIENTS: Convenience samples of healthy community-based volunteers (n=105) and people with severe brain injury (n=510). METHODS: (i) The equivalence of a new 5-point version of the SPRS was determined vs the original 7-point version; (ii) construct validity was tested using Rasch analyses; (iii) normative and comparative data tables were produced, and data examined for floor/ceiling effects; (iv) a reliable change index score was generated. RESULTS: Patterns of psychometric properties for the 5- and 7-point versions were almost identical (e.g. total scores rs=0.98). Rasch analyses on Forms A and B found good fit to the model, for person (3.36 and 3.03, respectively) and item (7.78 and 7.25, respectively) separation; reliability coefficients were high (all >= 0.90). Mean infit statistics met standard criteria (between 0.7 and 1.3). No floor/ceiling effects were detected. The reliable change index value was calculated for the total score for Form A using logit scores, and a conversion table provided. CONCLUSION: The 5-point version of the SPRS demonstrates strong psychometric qualities as a measure of participation after traumatic brain injury. PMID- 21667009 TI - Outcomes of high- and low-intensity rehabilitation programme for persons in chronic phase after Guillain-Barre syndrome: a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of a high- vs low--intensity multidisciplinary ambulatory rehabilitation programme over 12 months for persons in the chronic phase after Guillain-Barre syndrome (pwGBS) in an Australian community cohort. METHOD: A total of 79 pwGBS, recruited from a tertiary hospital, were randomized to a treatment group (n = 40) for an individualized high-intensity programme, or a control group (n = 39) for a lower intensity programme. The primary outcome the Functional Independence Measure (FIM) motor subscale assessed "activity limitation"; while secondary measures for "participation" included: World Health Organization Quality of Life; Depression, Anxiety Stress Scale; and Perceived Impact Problem Profile (PIPP) scales. All outcome measures were assessed at baseline and at 12 months. RESULTS: Intention to treat analysis of data from 69 participants (treatment n = 35, control n = 34) showed reduced disability in the treatment group in post-treatment FIM domains (mobility, transfers, sphincter control and locomotion; all p < 0.005) and PIPP scores (relationships; p = 0.011), with moderate-to-small effect sizes (r = 0.36 0.23). The treatment group compared with control group showed significant improvement in function (FIM scores): 68% vs 32%. CONCLUSION: Higher intensity rehabilitation compared with less intense intervention reduces disability in pwGBS in later stages of recovery. Further information on rehabilitation modalities and impact on quality of life is needed. PMID- 21667010 TI - Intervention and societal costs of residential community reintegration for patients with acquired brain injury: a cost-analysis of the Brain Integration Programme. AB - OBJECTIVE: The objective of this study was to examine the intervention costs of a residential community reintegration programme for patients with acquired brain injury and to compare the societal costs before and after treatment. METHODS: A cost-analysis was performed identifying costs of healthcare, informal care, and productivity losses. The costs in the year before the Brain Integration Programme (BIP) were compared with the costs in the year after the BIP using the following cost categories: care consumption, caregiver support, productivity losses. Dutch guidelines were used for cost valuation. RESULTS: Thirty-three cases participated (72% response). Mean age was 29.8 years, 59% traumatic brain injury. The BIP costs were ?68,400. The informal care and productivity losses reduced significantly after BIP (p < 0.05), while healthcare consumption increased significantly (p < 0.05). The societal costs per patient were ?48,449. After BIP these costs were ?39,773; a significant reduction (p < 0.05). Assuming a stable situation the break-even point is after 8 years. CONCLUSION: The reduction in societal costs after the BIP advocates the allocation of resources and, from an economic perspective, favours reimbursement of the BIP costs by healthcare insurance companies. However, this cost-analysis is limited as it does not relate costs to clinical effectiveness. : PMID- 21667012 TI - Paronychia and pyogenic granuloma induced by new anticancer mTOR inhibitors. PMID- 21667013 TI - Novel monoclonal antibodies against pancreatic juice from pancreatic cancer patients and their possible application in differential diagnosis. AB - Pancreatic cancer (PC) has a poor clinical prognosis with a <10% 5-year survival rate. Because there are no specific biomarkers of PC, it is difficult to detect small PC tumors and most patients are diagnosed at an advanced stage. Specific biomarkers are useful tools for the early detection of cancer. However, PC related biomarkers, such as CA19-9 lack specificity and sensitivity. In this study, we took an immunological approach to establish novel monoclonal antibodies (mAbs) specific for the pancreatic juice from PC patients, which would be potentially useful in the diagnosis of PC. Mice were immunized by subtractive immunization using mixed pancreatic juices from chronic pancreatitis and PC patients as the tolerogen and the immunogen, respectively. After screening by Western blotting, four mAbs were obtained: 2P-1-2-1, 2P-1-17-1, 6P-3-2-4 and 7P-9 11-6. The mAb 2P-1-2-1 showed reactivity against the tolerogen at 115 and 120 kDa, but only the 120-kDa antigen was also reactive to the immunogen. The mAb 2P 1-17-1 showed an intense smear reactivity at ~150 kDa against the immunogen. Finally, the mAbs 6P-3-2-4 and 7P-9-11-6 showed PC-specific reactivity to the immunogen at >250 kDa and at ~70 kDa, respectively. We propose that investigation of pancreatic juice samples with these mAbs may enable us to perform reliable differential diagnosis of benign and malignant diseases. Furthermore, we demonstrated that subtractive immunization is a useful method for producing mAbs specific for the pancreatic juice from PC patients. PMID- 21667014 TI - Interleukin-33 suppresses Notch ligand expression and prevents goblet cell depletion in dextran sulfate sodium-induced colitis. AB - Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 plays an important role in Th2 immune responses, and induces goblet cell hyperplasia in the intestinal mucosa. In this study, to elucidate the molecular mechanisms underlying IL-33-induced goblet cell hyperplasia, we investigated how IL-33 modulates the Notch signaling pathway in dextran sulfate sodium (DSS)-induced experimental colitis. DSS colitis was induced in BALB/c mice with intraperitoneal administrations of IL-33 (1 ug/body) every 48 h. Tissue samples were evaluated by standard immunohistochemical procedures. The mucosal mRNA expression of the Notch ligands was analyzed by a real-time polymerase chain reaction. The mucosal mRNA expression of Notch ligands [Jagged1 (Jag1) and Delta-like (Dll) 1 and 4] was significantly increased in DSS-colitis mice. IL-33-induced goblet cell hyperplasia in the control mice. In the DSS-colitis mice, the goblet cells were depleted in the colon, but IL-33 completely prevented goblet cell depletion in the DSS-colitis mice. IL-33 induced a significant decrease in Jag1 and Dll4 mRNA expression in the mucosa of the control mice. Mucosal mRNA expression for Jag1, Dll1 and 4 was significantly elevated in the DSS-colitis mice, but this elevation was significantly blocked by the administration of IL-33. IL-33 dose-dependently decreased Jag1 mRNA expression in mouse colonic subepithelial myofibroblasts. In contrast to its preventive effects on goblet cell depletion, IL-33 aggravated DSS colitis. IL-33 prevented goblet cell depletion via its inhibitory actions against Notch ligand expression in DSS colitis, but exacerbated the disease activity. IL 33 plays two counter actions in mucosal inflammation; the first is a protective action via goblet cell induction, and the second is a pro-inflammatory action as a Th2 cytokine. PMID- 21667015 TI - Molecular mechanism of HIF-1-independent VEGF expression in a hepatocellular carcinoma cell line. AB - Hypoxia-inducible factor-1 (HIF-1) is a master transcription factor that plays a central role in the hypoxic expression of various genes. Vascular endothelial growth factor (VEGF), a known target gene of HIF-1alpha, has been shown to be induced by hypoxia through a HIF-1alpha-independent pathway. HIF-1alpha dominant negative lentiviral vectors were introduced to decrease the expression of HIF in Hep3B cells. Cells were incubated under normoxic or hypoxic conditions. We performed a VEGF enzyme-linked immunosorbent assay (ELISA) using cell culture supernatants, and Western blotting using cell lysates. To validate signaling via HIF-1-dependent or HIF-1-independent pathways, we treated cells with an extracellular signal-regulated kinase (ERK) kinase inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, and transfected cells with siSP1. HIF-1alpha protein expression was induced and the levels of VEGF increased under hypoxic conditions. Cells were transfected with siHIF-1alpha and incubated under normoxic or hypoxic conditions. We found that a significant amount of VEGF was produced by a HIF-1 independent pathway. PI3K inhibitor treatment and siSP1 transient transfection decreased VEGF expression in siHIF-1alpha-transfected cells. Therefore, VEGF regulation in Hep3B cells is primarily controlled by the Akt/PI3K and SP1 pathways and is independent of HIF-1 under hypoxic conditions. PMID- 21667017 TI - A combination of MSH2 DNA mismatch repair deficiency and expression of the SV40 large T antigen results in cisplatin resistance of mouse embryonic fibroblasts. AB - Mutations in the human mismatch repair (MMR) genes are associated with hereditary non-polyposis colorectal cancer as well as other sporadic cancers. MMR gene mutations have been implicated in the resistance of human tumours to cisplatin and several tumour-derived MMR-deficient cells show cisplatin resistance in vitro. In addition, hypoxia, a common feature of the tumour microenvironment, has been shown to influence tumour responses to conventional cancer treatments. We have examined the role of the mMSH2 MMR protein on repair of cisplatin-damaged DNA and cisplatin sensitivity in mMSH2-deficient murine fibroblasts and mMSH2 proficient controls under conditions of normoxia and hypoxia. Sensitivity to cisplatin was measured using the MTT assay and clonogenic survival. Repair of cisplatin-damaged DNA was measured using a host cell reactivation (HCR) assay employing a non-replicating recombinant virus expressing the beta-galactosidase reporter gene. Sensitivity to cisplatin was significantly less and HCR of the cisplatin-damaged reporter gene was significantly greater in SV40-transformed mMSH2-deficient cells (MS5-7) compared to mMSH2-proficient controls (BC1-6) under both normoxic and hypoxic conditions. In contrast, sensitivity to cisplatin was significantly greater and HCR was similar in primary mMSH2-deficient compared to mMSH2-proficient murine fibroblasts under both normoxic and hypoxic conditions. Sensitivity to cisplatin was also significantly greater and HCR was similar in primary mMSH2-deficient compared to mMSH2-proficient murine fibroblasts transfected with a control plasmid under both normoxic and hypoxic conditions. In contrast, sensitivity to cisplatin was less and HCR was similar in primary mMSH2 deficient compared to mMSH2-proficient murine fibroblasts transfected with a plasmid expressing SV40 large T antigen under both normoxic and hypoxic conditions. These results suggest that loss of MMR alone does not result in increased resistance to cisplatin in murine fibroblasts and that additional concomitant alterations in cells expressing the SV40 large T antigen are responsible for cisplatin resistance through a modulation of DNA repair capacity and/or apoptosis. PMID- 21667016 TI - Decellularized bovine reinforced vessels for small-diameter tissue-engineered vascular grafts. AB - The aim of the present study was to investigate the influence of a decellularization protocol on the structure and the mechanical behavior of small diameter (<6 mm) tibial calf arteries and veins. Calf vessels were decellularized by a detergent-enzymatic method (DEM), partially hydrolyzed with trypsin and subsequently cross-linked using poly(ethylene glycol) diglycidyl ether. Our results showed that i) the DEM can be considered a simple and valuable procedure for the preparation of complete acellular arteries and veins able to preserve a high degree of collagen and elastic fibers, and ii) poly(ethylene glycol) diglycidyl ether cross-linking treatment provides appropriate mechanical reinforcement of blood vessels. Histologically, the decellularized vessels were obtained employing the detergent-enzymatic procedure and their native extracellular matrix histoarchitecture and components remained well preserved. Moreover, the decellularization protocol can be considered an effective method to remove HLA class I antigen expression from small-diameter tibial calf arteries and veins. Cytocompatibility of decellularized cross-linked vessels was evaluated by endothelial and smooth muscle cell seeding on luminal and adventitial vessel surfaces, respectively. PMID- 21667018 TI - Rac1b recruits Dishevelled and beta-catenin to Wnt target gene promoters independent of Wnt3A stimulation. AB - We previously reported a functional interaction between aberrant Wnt signaling and Rac1/Rac1b GTPases in tumorigenesis. In this study, we further investigated the mechanistic role of nuclear Rac1b. Using chromatin immunoprecipitation (ChIP) studies, we show that Rac1b resides at the promoters of Wnt target genes, c-Myc and Cyclin D1, in HCT116 cells with aberrant Wnt pathway. In HEK293T cells with intact Wnt signaling, Rac1b is tethered to these same gene promoters independent of Wnt3A stimulation and is further observed to recruit Dishevelled and beta catenin in the absence of Wnt3A stimulation. Our studies suggest a novel transcriptional co-activator role of Rac1b in beta-catenin/TCF-mediated transcription. PMID- 21667019 TI - Anticancer mechanism of equol in 7,12-dimethylbenz(a)anthracene-treated animals. AB - This study investigated the anticancer effects of equol, the major metabolite of the antioxidant phytochemical daidzein, on 7,12-dimethylbenz(a)anthracene (DMBA) treated animals and explored its anticancer mechanism. The experiment consisted of two parts. In the first part, Sprague-Dawley rats were given equol daily at 5 and 25 mg/kg body weight (BW) for 8 weeks after a single dose of DMBA (100 mg/kg BW). As a control, rats were divided into vehicle alone and DMBA alone groups. Equol administration at a higher dose effectively suppressed tumor formation and PCNA over-expression. The activation of p53 by equol subsequently affected the cyclin-dependent kinase inhibitor p21Cip1. This was associated with equol-induced apoptosis in mammary gland tumors, as evidenced by the decreased Bcl-2 expression and increased Bax expression, together with the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). In the second part, oral pre-administration of equol to mice which received DMBA intragastrically twice a week for 2 weeks significantly decreased their levels of biomarkers (thiobarbituric acid-reactive substances, carbonyl content and serum 8-hydroxy-2-deoxyguanosine) of DMBA induced oxidative stress. Although several antioxidant enzymes were down regulated in mice treated with DMBA alone, pre-administration of equol blocked much of this effect, increasing catalase and superoxide dismutase activity in a dose-dependent manner. Although equol did not affect the ratio of oxidized to reduced glutathione, it activated the glutathione peroxidase and glutathione reductase enzymes, and this effect was significant at a dose of 25 mg equol/kg body weight. DMBA treatment induced apoptosis, as shown by a decrease in the Bcl 2 levels and an increase in the levels of Bax, cleaved caspase-3 and poly(ADP ribose) polymerase. These apoptotic effects were also reversed by equol at all doses tested. Based on these results, equol possesses anticancer activity that suppresses tumor formation via apoptosis induction in rats with DMBA-induced mammary gland tumors. In addition, equol showed a hepatic protective effect by acting as an antioxidant and by reducing apoptosis. PMID- 21667021 TI - Early in vitro passages of breast cancer cells are differentially susceptible to retinoids and differentially express RARbeta isoforms. AB - The effect of retinoids on breast cancer has been predominantly studied in vitro, on established cell lines, which in biology differ significantly from primary tumor cells. Little is known on whether early in vitro passages of breast cancer cells (EPBCCs) are differentially sensitive to retinoids and differentially express retinoid acid receptors (RARs) and retinoid X receptors (RXRs). We have previously identified a novel RARbeta isoform (RARbeta5) and hypothesized that it may serve as a potential target of retinoids in EPBCCs. Breast cancer cells isolated from primary tumors were cultured in vitro for 6-12 passages (EPBCCs) and their epithelial origin was confirmed by a cocktail of antibodies against cytokeratins. EPBCCs were treated for 4 days with 1.0 uM of all-trans retinoic acid (atRA), 9-cis retinoic acid (9cRA) or 4-hydroxy-phenylretinamide (4-HPR) and their viability determined by MTT assay. Among nine EPBCCs consistently grown in vitro, three were resistant to the above retinoids, five were susceptible to atRA, four to 4-HPR and two to 9cRA, suggesting that patients with breast carcinomas may differentially respond to various retinoids. All EPBBCs differentially expressed RARalpha, RARgamma, RXRalpha, RXRbeta proteins and RARbeta5 and RARbeta2 mRNAs. However, only one EPBCC (BCA-2) expressed RARbeta5 at mRNA and protein level and it was resistant to retinoids, both in vitro and in a xenograft tumor assay. RARbeta5 suppression by siRNA in BCA-2 cells increased their susceptibility to atRA. No correlation was found between sensitivity of EPBCCs to the above retinoids and RARbeta5 and RARbeta2 mRNA expression. atRA reduced RARbeta expression in most EPBCCs suggesting that this retinoid receptor is most probably the prime target of retinoids in breast cancer. These data may have clinical implication in selecting patients with breast cancer that would benefit the most from clinical trials with retinoids. PMID- 21667020 TI - Safety and effectiveness of a new enzyme-targeting radiosensitization treatment (KORTUC II) for intratumoral injection for low-LET radioresistant tumors. AB - Linear accelerator-based radiotherapy has little effect on tumors such as malignant melanoma, various types of sarcoma, and most locally-advanced neoplasms that have grown to several centimeters or more. These tumors contain many hypoxic cancer cells or large amounts of anti-oxidative enzymes, and are therefore resistant to low linear energy transfer radiation. Therefore, it was necessary to develop a new radiosensitizer to overcome these situations. We previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which uses 3% w/v hydrogen peroxide solution-soaked gauze. We developed a new radiosensitizer for intratumoral injection (KORTUC II), comprising a combination of hydrogen peroxide and sodium hyaluronate. After providing a fully informed written consent, 52 patients with unresectable or recurrent neoplasms (53 lesions) were enrolled in the KORTUC II trial. The present study of 52 patients with unresectable or recurrent neoplasms showed that KORTUC II is safe when injected intratumorally, well tolerated, and can efficiently exert a radiation sensitizing effect. Because this radiosensitizer is safe and less expensive than other methods, and can be applied for almost every type of low-LET radio resistant neoplasm, it has potential for worldwide and immediate use. PMID- 21667022 TI - The novel synthesized 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) compound exhibits anti-metastatic effects in human osteosarcoma U-2 OS cells through targeting insulin-like growth factor-I receptor. AB - Our previous study demonstrated that 6-fluoro-(3-fluorophenyl)-4-(3 methoxyanilino)quinazoline (LJJ-10) possesses potential anticancer activity and exhibits greater antitumor effect than the other quinazoline compounds in human osteogenic sarcoma U-2 OS cells via in vitro screening. In this study, we focused on investigating the anti-metastatic activity and the signaling pathways involved in LJJ-10 action in U-2 OS cells. The results from wound healing and Boyden chamber transwell assays indicated that LJJ-10 exhibited an inhibitory effect on the migration and invasion of U-2 OS cells. LJJ-10 also inhibited matrix metalloproteinase-2 (MMP-2) and MMP-9 enzyme activities and caused a concentration-dependent decrease in protein levels by gelatin zymography assay and Western blot analysis, respectively. Meanwhile, LJJ-10 suppressed MMP-2 and MMP-9 mRNA levels in a concentration-dependent fashion after 12-h exposure in U-2 OS cells. Computational modeling showed that LJJ-10 is bound into the IGF-1R via hydrophobic interactions with Leu975, Val983, Ala1001, Glu1050 and Met1052 with one hydrogen bond between 6-F and Met1052. LJJ-10 reduced the protein levels of p JNK, p-p38, p-ERK, p-AKT and p-IGFR by Western blotting and these influences are concentration-dependent. Based on these observations, this study suggests that molecular targeting of the insulin-like growth factor-I receptor (IGF-1R) signaling leads to the suppression of downstream MAPK/AKT signaling and downregulation of MMP-2 and -9 RNA levels and protein levels in LJJ-10-treated U 2 OS cells. Therefore, the inhibition of metastasis in human osteosarcoma cells by treatment with this novel agent, LJJ-10 may be a useful chemotherapeutic approach. PMID- 21667023 TI - Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells. AB - In this study, 2-aminophenoxazine-3-one (Phx-3) exhibited a potent cell growth inhibitory effect with apoptotic features in a dose-dependent manner in various cancer cell lines tested. Comparison of the expression profiles of endoplasmic reticulum (ER) stress-related genes in U266 multiple myeloma cells after treatment with Phx-3 and the ER stress inducers tunicamycin (TNM) and thapsigargin (TPG) indicated that although TNM and TPG potently induced pro apoptotic transcription factor CHOP (GADD153) within 8 h of treatment, Phx-3 induced almost no CHOP within 48 h of treatment in U266 cells. However, murine embryonic fibroblast (MEF) cells and other cancer cell lines (e.g. A549 lung cancer cells and HL-60 acute leukemia cells) exhibited up-regulation of CHOP after treatment with Phx-3. The potency of CHOP induction in response to Phx-3 appeared to be partially correlated with the cytotoxic sensitivity of Phx-3 among various cell lines tested. MEF cells derived from CHOP knockout mice were more resistant to Phx-3 than wild-type MEF cells. Since Phx-3 has been shown to induce activation of NF-kappaB, a transcription factor functioning as a repressor of CHOP, we further treated U266 cells with a combination of Phx-3 and NF-kappaB inhibitors (e.g. BAY11-7082 or parthenolide). This enhanced cytotoxicity along with up-modulation of CHOP in U266 cells. These data suggest that ER stress mediated CHOP induction by Phx-3 is involved in the cytotoxic effect. Regulation of CHOP expression appears to be a potent therapeutic target for cancer treatment. PMID- 21667024 TI - Mesenchymal stem cells and carcinoma-associated fibroblasts sensitize breast cancer cells in 3D cultures to kinase inhibitors. AB - Stromal cells, such as mesenchymal stem cells (MSCs) and carcinoma-associated fibroblasts (CAFs), play a role in cancer progression. To analyze their ability to modulate drug response, we generated spheroids of MCF-7 or MDA-MB-231 breast cancer cells in the absence or presence of human (h)MSCs or hCAFs and tested the susceptibility of the breast cancer cells to three different kinase inhibitors (TKI258, RAD001 and RAF265) used in cancer therapy. While stromal cells did not affect the response of either breast cancer cell line to the PDGFR/FGFR/VEGFR inhibitor TKI258, they sensitized breast cancer cells to the mTOR inhibitor RAD001. In MCF-7 cells, this was accompanied by increased apoptosis. hMSCs and to a lesser extent hCAFs also enhanced the cytotoxic effect of RAF inhibitor RAF265 on MDA-MB-231 cells. Searching for the mechanism that underlies the effect of stromal cells on RAF265 response we found that stromal cells inhibited RAF265 induced increase in ERK1/2 phosphorylation, supported RAF265-dependent downregulation of PKCalpha (protein kinase Calpha) and prevented RAF265-induced conversion of LC3B, a marker of autophagy. To mimic the changes in ERK1/2 phosphorylation and PKCalpha expression in response to the stromal cells, we treated cells with MEK1 inhibitor U0126 or PKCalpha inhibitor Go6976, respectively. U0126, but not Go6976, was as effective as hMSCs in sensitizing MDA MB-231 cells to RAF265. This suggests that hMSCs and hCAFs increased the cytotoxic effect of RAF265 on MDA-MB-231 cells by downregulating ERK1/2 phosphorylation. In summary, this study shows that hMSCs are able to render breast cancer cells more susceptible to kinase inhibitors and that, to the most part, hCAFs to which hMSCs can differentiate are able to mimic the drug sensitizing effects of hMSCs. PMID- 21667025 TI - Non-invasive monitoring of hypoxia-inducible factor activation by optical imaging during antiangiogenic treatment in a xenograft model of ovarian carcinoma. AB - Targeting the hypoxia response pathway and angiogenesis are two promising therapeutic strategies for cancer treatment. Their use as single strategies has important limitations. Thus, development of combined regimens has become an important step toward improving therapeutic efficacy. Also, non-invasive monitoring of the response to targeted biological therapies, as well as determination of the optimal schedule for combination regimens has become an active field of research over the last five years, with relevance for both preclinical and clinical settings. Here, we used an optical imaging method to non invasively monitor the functional changes in HIF activity in response to antiangiogenic treatment in a xenograft model of human ovarian carcinoma. A bioluminescent reporter construct containing nine copies of the hypoxia response element upstream of the luciferase gene (9xHRE-luciferase) was characterized in vitro in a panel of tumor cell lines and in vivo in a subcutaneous xenograft model of ovarian carcinoma by means of optical imaging. We showed that in OVCAR-3 subcutaneous xenografts, the most abrupt change in the HIF functional reporter occurs before the onset of massive tumor growth. However, this system failed to detect hypoxia induced upon antiangiogenic treatment due to the compensating effects of increased hypoxia and decreased tumor cell viability caused by imbalanced neovascularization vs. tumor expansion. Therefore, the readout based on HIF functional reporter could be conditioned by the dynamics of tumor growth and angiogenesis, which is highly variable depending on the tumor type, tumor model and stage of progression. PMID- 21667026 TI - Differential expression of Mart-1 in human uveal melanoma cells. AB - Uveal melanoma (UM) is one of the most common primary intraocular malignant tumors in adults. Melanoma antigen recognized by T cell-1 (Mart-1), one of the melanosome-specific proteins, has been widely studied as a marker recognized by cytotoxicity T lymphocytes. Mart-1 is considered to play a critical role in the immunotherapy for melanoma. Additionally, as a biomarker, Mart-1 is often used with other tumor-associated antigens for antidiastole in cutaneous melanoma (CM), uveal melanoma (UM) and nevus. In this study, the differential expression of Mart 1 was investigated in four human UM cells (SP6.5, VUP, OCM-1 and OM431) on three levels of analysis: messenger ribonucleic acid (mRNA), protein and, eventually, morphology. The results revealed that SP6.5 cells had high Mart-1 protein expression while VUP cells had almost none. OCM-1 and OM431 cells produced less Mart-1 than SP6.5 cells according to Western blot analysis, although OM431 cells had the highest expression of Mart-1 mRNA according to real-time PCR. The results indicate the potential use of Mart-1 in the development of therapy for UM. PMID- 21667027 TI - Autoimmunity against hNinein, a human centrosomal protein, in patients with rheumatoid arthritis and systemic lupus erythematosus. AB - Centrosomes are organelles involved in the organization of the mitotic spindle and may also be the targets of autoantibodies in autoimmune diseases. Human Ninein (hNinein) is a centrosomal autoantigen that is identified by autoimmune patient sera. However, none of the hNinein-specific fragments recognized by the autoantibodies in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) sera have been thoroughly characterized. We thus attempted to identify the fine specificity within the hNinein protein. In this study, four recombinant proteins in two isoforms of hNinein were used as autoantigens along with immunoassays as a molecular tool to investigate the prevalence of hNinein autoreactivity and its specificity in 22 RA and 32 SLE autoimmune disease sera. The data indicated a 50% higher prevalence of isoform 4 hNinein N-terminal autoantibodies in RA sera, whereas 22% of SLE patients were autoreactive to the N terminal of isoform 4 hNinein compared to only a small percentage of autoreactive normal sera (5%). These results showed that autoepitopes on autoantigen hNinein are restricted to the N-terminal region and that a more significant proportion of RA patients exhibited centrosome reactivity. PMID- 21667028 TI - Antioxidant activity of the giant jellyfish Nemopilema nomurai measured by the oxygen radical absorbance capacity and hydroxyl radical averting capacity methods. AB - The giant jellyfish Nemopilema nomurai (reaching sizes of up to 2 m diameter and 150 kg), which forms dense blooms, has caused extensive damage to fisheries by overloading trawl nets, while its toxic nematocysts cause dermatological symptoms. Giant jellyfish are currently discarded on the grounds of pest control. However, the giant jellyfish is considered to be edible and is part of Chinese cuisine. Therefore, we investigated whether any benefits for human health may be derived from consumption of the jellyfish in order to formulate medicated diets. Antioxidant activity of Nemopilema nomurai was measured using the oxygen radical absorbance capacity (ORAC) and hydroxyl radical averting capacity (HORAC) methods. Based on the results, the ORAC value of the giant jellyfish freeze-dried sample was 541 umol trolox equivalent (TE)/100 g and the HORAC value was 3,687 umol gallic acid equivalent (GAE)/100 g. On the other hand, the IC50 value of hydroxyl radical scavenging activity measured by using the electron spin resonance method was 3.3%. In conclusion, the results suggest that the freeze dried powder of the giant jellyfish Nemopilema nomurai is a potentially beneficial food for humans. PMID- 21667029 TI - Antitumor effects of PLGA nanoparticles encapsulating the human PNAS-4 gene combined with cisplatin in ovarian cancer. AB - Human PNAS-4 (hPNAS-4), as a pro-apoptotic gene, can inhibit tumor growth when overexpressed in some malignant cells. Poly (lactic-co-glycolic acid) (PLGA) was used as a gene transfer vector due to the advantage of sustained release, nontoxicity and biodegradability. In this study, we aimed to investigate the effect of PLGA nanoparticles encapsulating hPNAS-4 combined with cisplatin (DDP) on ovarian carcinoma. Expression of hPNAS-4 was determined by RT-PCR. Mice bearing intraperitoneal ovarian carcinomas were treated with PBS, pVAX-PLGA nanoparticles (P-P), pVAX-hPNAS-4-PLGA nanoparticles (PhP-P), DDP and PhP-P plus DDP, respectively. Intraperitoneal tumors were weighed to assess the antitumor efficacy. The percentage of proliferative cells and apoptotic cells was evaluated by Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. The anti-angiogenic effects were detected by CD31 staining and the alginate-encapsulate assay. Overexpression of hPNAS-4 was detected by RT-PCR in the PhP-P and PhP-P plus DDP groups. PhP-P exerted significant antitumor activity through induction of apoptosis, inhibition of cell proliferation and suppression of angiogenesis, compared with treatment with P-P or PBS alone. The combination of PhP-P with DDP showed enhanced antitumor activity compared with therapy of PhP P or DDP alone. PLGA encapsulating hPNAS-4 combined with DDP may have promising applications in the therapy of ovarian cancer. PMID- 21667030 TI - 18F-fluorothymidine PET/CT as an early predictor of tumor response to treatment with cetuximab in human lung cancer xenografts. AB - We investigated whether 18F-fluorothymidine-positron-emission tomography/computed tomography (18F-FLT-PET/CT) is useful for the evaluation of the very early response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab therapy in human lung cancer xenografts. A human tumor xenograft model was established with a human non-small cell lung cancer cell line. The mice were randomly assigned to four groups: tumor growth follow-up, ex vivo study, PET/CT imaging and non-treated control. Mice were administered saline as control or cetuximab on day 1. An immunohistochemical study with Ki-67 was performed. Tumor volume treated with cetuximab was kept significantly smaller than control after day 8, although there was no difference on day 3. On day 3, 18F-FLT distribution was higher in the tumor than in other tissues, and was significantly decreased by treatment with cetuximab. On PET/CT imaging, 18F-FLT distribution in the tumor was clearly visualized, and the maximum standardized uptake value (SUV) was significantly decreased after treatment with cetuximab (p<0.01). Ki-67 expression was also significantly decreased on day 3 (p=0.01). These results suggest that 18F-FLT-PET/CT can be a useful predictor to determine the response to molecular targeted drugs such as cetuximab at an earlier time point than the change of tumor size. PMID- 21667031 TI - BRCA1, BRCA2, AR and IGF-I expression in prostate cancer: correlation between RT qPCR and immunohistochemical detection. AB - Identification and characterization of biomarkers in prostate cancer are important for improving the diagnosis. The aim of this study was to determine differences in the expression of 4 genes according to the stage of malignancy in prostate cancer. We analyzed BRCA1, BRCA2, androgen receptor (AR) and IGF-I gene expression in a cohort of 98 prostate biopsies. We used TaqMan RT-qPCR for mRNA detection, and correlation with proteins was performed using immunohistochemistry. Among the 98 studied prostate biopsies, high heterogeneity in the expression of the 4 genes was detected among the different histological types. However, down-regulation of BRCA1 and BRCA2 mRNA was detected, particularly in the normal tissues. The expression of AR was dependent on the stage of the tumor. The IGF-I gene was specifically expressed in the tumor tissues. Upon comparison between protein and mRNA expression for BRCA1, BRCA2 and AR, we obtained a trend; however, this did not achieve statistical significance. Regarding IGF-I, a correlation between mRNA expression and staining intensity of the protein was found to be significant (p<0.012). The AR biomarker was found to be slightly correlated with the prostate cancer diagnosis (p=0.013). AR was found to be decreased in the tumors with a 43% sensitivity and 90% specificity. The relative risk of 2.05 (1.13-3.69) indicated a 2-fold higher chance of cancer occurrence when AR was <=0.206. PMID- 21667032 TI - Effective targeted chemotherapy using AEZS-108 (AN-152) for LHRH receptor positive pancreatic cancers. AB - Pancreatic cancer is the fourth commonest cause of cancer-related mortality across the world. Because of the poor response to conventional chemotherapy, small molecules, radiation therapy and surgery, development of new targeted therapies is necessary. In the present study, we have analyzed expression of the luteinizing hormone releasing hormone (LHRH) receptor in specimens of human pancreatic cancers. Furthermore, we have investigated in vitro and in vivo whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in human pancreatic cancer cells that express LHRH receptors. LHRH receptor expression in tumor specimens of human pancreatic cancers was assessed using immunohistochemistry. Cell proliferation was analyzed using the alamar blue proliferation assay. Induction of apoptosis was analyzed using the TUNEL assay and quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human pancreatic tumors. Thirteen of 40 human pancreatic adenocarcinomas (32.5%) expressed LHRH receptors. We were able to show that treatment of LHRH receptor positive MiaPaCa-2 and Panc-1 human pancreatic cancer cells with AEZS-108 (AN 152) resulted in apoptotic cell death in vitro. The antitumor effects could be confirmed in nude mice. AEZS-108 (AN-152) inhibited the growth of xenotransplants of human pancreatic cancers in nude mice significantly, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for treatment of LHRH receptor-positive human pancreatic cancers with little toxicity. PMID- 21667033 TI - A fully integrated, automated and rapid detection system for KRAS mutations. AB - KRAS mutations are detected in tumors of various organs, and they are also markers of resistance for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and monoclonal antibodies against the EGFR. Thus, the accurate and rapid detection of KRAS mutations is crucial, not only for screening, but also for the prediction of the efficacy of molecular-targeted therapy. The aim of the present study was to establish a novel automated detection system for KRAS mutations. One hundred and thirty-six lung adenocarcinoma patients were genotyped for KRAS mutations with both the conventional direct sequence (DS) method and with the newly developed quenching probe (QP) method that obtains data automatically within 60 min. The detection limit of the QP method using a control plasmid containing the KRAS mutation was 50 copies, and 10% mutant plasmid was detected in the mixture of wild-type and mutants. The results obtained by the QP and DS methods were identical in all but two of the 136 cases. The two differentially identified samples, which consisted of substantially fewer lung cancer cells, were positive according to the QP method but negative as determined by DS for KRAS mutations. These findings characterize the QP method as an accurate and rapid detection system for KRAS mutations. PMID- 21667034 TI - Preliminary evidence of the presence of lymphatic vessels immunoreactive for D2 40 and Prox-1 in human pterygium. AB - Human pterygium is a benign fibrovascular outgrowth of the corneo-conjunctival junction, characterized by tissue remodeling, cellular proliferation, angiogenesis and inflammation. No data are available concerning the presence of lymphatic vessels in this pathological condition. The aim of this study was to evaluate by immunohistochemistry, using antibodies against D2-40, Prox-1 and Ki 67, the presence and the proliferative activity of lymphatic vessels in human pterygium. An increased lymphatic microvessel density was observed in the human pterygium compared to the normal conjunctiva. Moreover, D2-40-positive lymphatic endothelial cells were also actively proliferating, as assessed by Ki-67 immunostaining, while in normal conjunctiva proliferating lymphatic endothelial cells were not detectable. Overall, these data clearly indicate the presence of active proliferating lymphatic vessels in human pterygium, suggesting that active lymphangiogenesis occurs in this pathological condition. PMID- 21667035 TI - Stage II/III cancer of the rectosigmoid junction: an independent tumor type? AB - The 5-year relapse-free survival rate (5Y-RFS) and 5-year overall survival rate (5Y-OS) were investigated in 766 patients with stage II/III colorectal cancer (CRC). The Stage II group included 283 patients with colon cancer (CC), 40 patients with rectosigmoid junction cancer (RSC), and 74 patients with rectal cancer (RC), while the Stage III group comprised 226 patients with CC, 52 patients with RSC, and 91 patients with RC. Stage III patients with RC were further divided into 68 patients with Ra cancer (Ra, rectum/above the peritoneal reflection) and 23 patients with Rb cancer (Rb, rectum/below the peritoneal reflection). Then the 5Y-RFS and 5Y-OS were calculated for each category or subcategory. The 5Y-RFS/5Y-OS was 80.3/80.6% for Stage II patients and 63.7% (p<0.001)/66.2% (p<0.001) for Stage III patients. In the Stage II group, the survival rates were 82.9/81.2% for CC, 77.6/74.8% for RSC, and 72.9/80.5% for RC, with no significant differences between each category. In the Stage III group, the survival rates were 69.3/72.8% for CC, 71.6/77.7% for RSC, and 46.5/46.2% for RC. There was no significant difference of survival for CC vs. RSC, but significant differences were noted for CC vs. RC (p<0.001/p<0.001) and RSC vs. RC (p=0.008/p=0.007). In the Stage III group, survival rates were 71.6/77.7% for RSC, 47.6/44.8% for Ra, and 45.7/51.3% for Rb, with significant differences for RSC vs. Ra (p=0.013/p=0.005) and RSC vs. Rb (p=0.026/p=0.180), but not for Ra vs. Rb. These results suggest that Stage II/III RS cancer should be classified as colon cancer and should not be considered an independent tumor type. PMID- 21667036 TI - Expression and clinical significance of cathepsin B and stefin A in laryngeal cancer. AB - The aim of this study was to investigate the roles of the cathepsin B cysteine protease and its endogenous inhibitor stefin A in laryngeal cancer. Immunohistochemistry was employed to detect the expression of cathepsin B and stefin A in 84 patients with laryngeal cancer, respectively. The protein expression of stefin A was negatively associated with lymphatic metastasis, recurrence of laryngeal cancer and the survival rate, which was not observed with cathepsin B protein expression. Both down-regulation of cathepsin B and up regulation of stefin A in vitro significantly inhibited the migration, invasion and proliferation of laryngeal cancer cells, respectively. Our results strongly suggest that stefin A may be a potential predictor of laryngeal cancer and may be used in the molecular diagnosis and gene therapy of laryngeal cancer. Cathepsin B may be used as a promising therapeutic target in the treatment of laryngeal cancer. PMID- 21667037 TI - Quantitative trait loci and underlying candidate genes controlling agronomical and fruit quality traits in octoploid strawberry (Fragaria * ananassa). AB - Breeding for fruit quality traits in strawberry (Fragaria * ananassa, 2n = 8x = 56) is complex due to the polygenic nature of these traits and the octoploid constitution of this species. In order to improve the efficiency of genotype selection, the identification of quantitative trait loci (QTL) and associated molecular markers will constitute a valuable tool for breeding programs. However, the implementation of these markers in breeding programs depends upon the complexity and stability of QTLs across different environments. In this work, the genetic control of 17 agronomical and fruit quality traits was investigated in strawberry using a F(1) population derived from an intraspecific cross between two contrasting selection lines, '232' and '1392'. QTL analyses were performed over three successive years based on the separate parental linkage maps and a pseudo-testcross strategy. The integrated strawberry genetic map consists of 338 molecular markers covering 37 linkage groups, thus exceeding the 28 chromosomes. 33 QTLs were identified for 14 of the 17 studied traits and approximately 37% of them were stable over time. For each trait, 1-5 QTLs were identified with individual effects ranging between 9.2 and 30.5% of the phenotypic variation, indicating that all analysed traits are complex and quantitatively inherited. Many QTLs controlling correlated traits were co-located in homoeology group V, indicating linkage or pleiotropic effects of loci. Candidate genes for several QTLs controlling yield, anthocyanins, firmness and L-ascorbic acid are proposed based on both their co-localization and predicted function. We also report conserved QTLs among strawberry and other Rosaceae based on their syntenic location. PMID- 21667038 TI - Analysis of genetic structure in a panel of elite wheat varieties and relevance for association mapping. AB - During the last decades, with the intensification of selection and breeding using crosses between varieties, a very complex genetic structure was shaped in the elite wheat germplasm. However, precise description of this structure with panels and collections is becoming more and more crucial with the development of resource management and new statistical tools for mapping genetic determinants (e.g. association studies). In this study, we investigated the genetic structure of 195 Western European elite wheat varieties using the recent development of high throughput screening methods for molecular markers. After observing that both microsatellites and Diversity Array Technology markers are efficient to estimate the structure of the panel, we used different complementary approaches (Genetic distances, principal component analysis) that showed that the varieties are separated by geographical origin (France, Germany and UK) and also by breeding history, confirming the impact of plant breeding on the wheat germplasm structure. Moreover, by analysing three phenotypic traits presenting significant average differences across groups (plant height, heading date and awnedness), and by using markers linked to major genes for these traits (Ppd-D1, Rht-B1, Rht-D1 and B1), we showed that for each trait, there is a specific optimal Q matrix to use as a covariate in association tests. PMID- 21667040 TI - Grasping and hitting moving objects. AB - Some experimental evidence suggests that grasping should be regarded as independent control of the thumb and the index finger (digit control hypothesis). To investigate this further, we compared how the tips of the thumb and the index finger moved in space when grasping spheres to how they moved when they were hitting the sphere using only one digit. In order to make the tasks comparable, we designed the experiment in such a way that subjects contacted the spheres in about the same way in the hitting task as when grasping it. According to the digit control hypothesis, the two tasks should yield similar digit trajectories in space. People hit and grasped stationary and moving spheres. We compared the similarity of the digits' trajectories across the two tasks by evaluating the time courses of the paths of the average of the thumb and the index finger. These paths were more similar across tasks than across sphere motion, supporting the notion that grasping is not controlled fundamentally differently than hitting. PMID- 21667039 TI - Visual information gain and task asymmetry interact in bimanual force coordination and control. AB - This study examined the question of whether and how the influence of visual information on force coordination patterns is dependent on the settings of a task asymmetry constraint. In a bimanual isometric force experiment, the task asymmetry was manipulated via imposing different coefficients on the index finger forces such that the weighted sum of the finger forces matched the target force. The environmental constraint was quantified by the visual performance error and was manipulated through the change of visual gain (number of pixels on the screen representing the unit of force). The constraint arising from the individual was quantified by the bilateral coupling effect (i.e., symmetric force production) between hands. The results revealed improved performance in terms of lower variability and performance error and more complex total force structure with higher visual gain. The influence of visual gain on the force coordination pattern, however, was found to be dependent on the task coefficients imposed on the finger forces. Namely, the force sharing between hands became more symmetric with high visual gain only when the right finger force had the higher coefficient, and an error-compensatory strategy was evident with high gain only when symmetric coefficients were imposed on the two fingers. The findings support the proposition that the motor coordination and control patterns are organized by the interactive influence of different categories of constraints where the functional influence of the information provided is dependent on the motor output. PMID- 21667041 TI - Defect in mevalonate pathway induces pyroptosis in Raw 264.7 murine monocytes. AB - The inhibition of mevalonate pathway by the aminobisphosphonate alendronate (ALD) has been previously associated with an augmented lipopolysaccharide-induced interleukin-1beta (IL-1beta) secretion in monocytes, as demonstrated in an auto inflammatory disease known as mevalonate kinase deficiency (MKD). In this study we investigated the effect of ALD + LPS on monocyte cell line (Raw 264.7) death. ALD strongly augmented LPS-induced programmed cell death (PCD) as well as IL 1beta secretion in Raw murine monocytes, whereas necrosis was rather unaffected. ALD + LPS induced caspase-3 activation. Inhibition of IL-1beta stimulation partially restored cell viability. These findings suggest that the inhibition of mevalonate pathway, together with a bacterial stimulus, induce a PCD partly sustained by the caspase-3-related apoptosis and partly by caspase-1-associated pyroptosis. The involvement of pyroptosis is a novel hit in our cell model and opens discussions about its role in inflammatory cells with chemical or genetic inhibition of mevalonate pathway. PMID- 21667042 TI - Low doses of the novel caspase-inhibitor GS-9450 leads to lower caspase-3 and -8 expression on peripheral CD4+ and CD8+ T-cells. AB - Chronic hepatitis C virus (HCV) infection is characterized by increased rates of apoptotic hepatocytes and activated caspases have been shown in HCV-infected patients. GS-9450, a novel caspase-inhibitor has demonstrated hepatoprotective activity in fibrosis/apoptosis animal models. This study evaluated the effects of GS-9450 on peripheral T-cell apoptosis in chronic HCV-infected patients. As sub study of the GS-US-227-0102, a double-blind, placebo-controlled phase 2a trial evaluating the safety and tolerability of GS-9450, apoptosis of peripheral CD4+ and CD8+ T-cells was measured using activated caspase-3, activated caspase-8 and CD95 (Fas). Blood samples were drawn at baseline, day 14 after therapy and at 5 weeks off-treatment follow-up in the first cohort of 10 mg. In contrast to the placebo-treated patients, GS-9450 caused a median of 46% decrease in ALT-values from baseline to day 14 in all treated patients (median of 118-64 U/l) rising again to a median of 140 U/l (19%) at 5 weeks off-treatment follow-up. In GS9450 treated patients, during treatment and follow-up, percentages of activated caspase-3+ and caspase-8 expression tended to decrease, in contrast to placebo treated patients. Interestingly, compared to healthy controls, higher percentages of caspase-3 and caspase-8 positive CD4+ and CD8+ T-cells were demonstrated in HCV-infected patients at baseline. Decreased ALT-values were observed in all HCV infected patients during treatment with low dose of the caspase-inhibitor GS-9450 accompanied by a lower expression of caspase-3 and -8 on peripheral T-cells. Furthermore, at baseline percentages of activated caspase-3, activated caspase-8 and CD95+ T-cells were higher in chronic HCV-infected patients compared to healthy controls. PMID- 21667043 TI - HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells. AB - Enzastaurin is an investigational PKCbeta inhibitor that has growth inhibitory and pro-apoptotic effects in both B and T-cell lymphomas. We investigated the cytotoxicity and mechanisms of cell death of the combination of enzastaurin and low concentrations of histone deacetylase (HDAC) inhibitors in B-cell and T-cell lymphoma cell lines and primary lymphoma/leukemia cells. Combined enzastaurin/suberoylanilide hydroxamic acid treatment synergistically induced apoptosis in diffuse large B-cell lymphoma and T-cell lymphoma cell lines, and primary lymphoma/leukemia samples. Similarly, combined treatment of B-cell-like lymphoma cells with enzastaurin and two different HDAC inhibitors, valproic acid and (2E,4E)-6-(4-chlorophenylsulfanyl)-2,4-hexadienoic acid hydroxyamide synergistically induced apoptosis, suggesting the synergy is generalizable to other HDAC inhibitors. Our data indicate that enzastaurin/HDAC inhibitors therapy can synergistically inhibit growth and induce apoptosis in lymphoid malignancies and may be an effective therapeutic strategy. Potential mechanisms including enzastaurin mediated inhibition of HDAC inhibitor-induced compensatory survival pathways are discussed. PMID- 21667044 TI - The microtubule depolymerizing agent naphthazarin induces both apoptosis and autophagy in A549 lung cancer cells. AB - Naphthazarin (DHNQ, 5,8-dihydroxy-l,4-naphthoquinone) is a naturally available 1,4-naphthoquinone derivatives. In this study, we focused on elucidating the cytotoxic mechanism of naphthazarin in A549 non-small cell lung carcinoma cells. Naphthazarin reduced the A549 cell viability considerably with an IC(50) of 16.4 +/- 1.6 MUM. Naphthazarin induced cell death in a dose- and time-dependent manner by activating apoptosis and autophagy pathways. Specifically, we found naphthazarin inhibited the PI3K/Akt cell survival signalling pathway, measured by p53 and caspase-3 activation, and PARP cleavage. It also resulted in an increase in the ratio of Bax/Bcl2 protein levels, indicating activation of the mitochondrial apoptotic pathway. Similarly naphthazarin triggered LC3II expression and induced autophagic flux in A549 cells. We demonstrated further that naphthazarin is a microtubule inhibitor in cell-free system and in A549 cells. Naphthazarin treatment depolymerized interphase microtubules and disorganised spindle microtubules and the majority of cells arrested at the G(2)/M transition. Together, these data suggest that naphthazarin, a microtubule depolymerizer which activates dual cell death machineries, could be a potential novel chemotherapeutic agent. PMID- 21667045 TI - Expansion and diversification of the signaling capabilities of the CD2/SLAM family in Xenopodinae amphibians. AB - We studied the evolution of the CD2 family in tetrapods by extracting and analyzing CD2-like genes from the genome of the amphibian species Silurana (Xenopus) tropicalis. An exhaustive analysis of the genomic and cDNA databases resulted in the identification of at least 70 CD2-like genes. The predicted receptors mostly maintain the typical VC2 ectodomains, but are highly diverse in their C-termini, which suggests a broad range of signaling capacities. Apart from the presumed monomeric receptors with ITSM and/or ITIM motifs, the Silurana family includes secreted proteins. Furthermore, a fraction of the receptors contain a conserved TM subtype with the NxxR motif that is known to promote an association with the FcRgamma subunit and that was previously found in the members of the FcR- and KIR-related receptors. The expression analysis of a sample of the genes showed broad tissue distribution and gene-specific expression patterns. Phylogenetic analysis predicted that the CD58, CD150/SLAM, and SLAMF8 genes were maintained as single-copy genes in both mammals and amphibians, while others expanded/contracted in a lineage-specific manner. PMID- 21667047 TI - Metastatic Crohn's disease of the penis: two cases. AB - Metastatic Crohn's disease is a rare inflammatory process that is non-contiguous from the bowel. It can affect the penis and is variable in presentation and onset in relation to bowel symptoms. It has been treated with oral, topical, systemic, and surgical therapies. We describe our experience with two cases of penile metastatic Crohn's disease and their management in comparison with other cases described in the literature. Both our patients were of the lymphoedematous type and had sexual and voiding dysfunction. They were treated with topical and intra lesional steroids and circumcision after unsuccessful systemic treatments. PMID- 21667046 TI - Analysis of the mouse 129-strain Nkrp1-Clr gene cluster reveals conservation of genomic organization and functional receptor-ligand interactions despite significant allelic polymorphism. AB - The Nkrp1 (Klrb) family of NK cell receptors and their genetically linked Clr (Clec2) ligands are conserved between rodents and humans. Nonetheless, certain mouse and rat Nkrp1 genes exhibit significant allelic polymorphism between inbred strains. We previously demonstrated that the Nkrp1-Clr recognition system is genetically and functionally conserved between the B6 and BALB/c strains, with focused sequence divergence evident in certain genes (e.g., Nkrp1b,c). Here, we extend this finding by mapping the 129-strain Nkrp1-Clr gene cluster, which is structurally conserved yet displays significant sequence divergence relative to the B6 haplotype. In addition, we show that 129-strain NK cells possess comparable Nkrp1 and Clr transcript expression, and characterize several NKR P1:Clr interactions that are functionally conserved between the B6 and 129 strains, including documented and novel receptor-ligand pairs. Thus, despite significant allelic polymorphism observed in the Nkrp1-Clr region, the overall genetic organization and functional repertoire appear to be conserved among mouse strains, in contrast to the striking variation observed in the corresponding Ly49 region. These data extend our knowledge of the complex genetically linked Nkrp1 Clr NK recognition system in mice. PMID- 21667048 TI - Cognitive behavioral symptom management intervention in patients with cancer: survival analysis. AB - PURPOSE: Associations between psychological factors and cancer survival have been under debate. We retrospectively explored the effect of the Cancer Care Intervention (CCI), an individually delivered cognitive behavioral symptom management intervention on survival in individuals with cancer. METHODS: Data were obtained from a randomized controlled trial (R01 CA79280; 1997-2003) that were originally designed to evaluate the CCI to reduce symptom severity in 237 individuals with solid tumors during their first course of chemotherapy. Participants were randomized into: (1) ten-contact, 20-week CCI plus usual care (n = 118) and (2) usual care only (n = 119). Survival data as of June 2009 were censored based upon Social Security Death Index. RESULTS: Participants were mostly female (73.4%), Caucasian (92.8%), and 59.6 +/- 10.5 years old. Breast (38.8%) and lung (35%) cancer were the most common cancer types. At enrollment, 66.7% of the participants had cancers at stage III or greater. Overall mortality was 53.2% (126 of 237). The CCI did not significantly affect survival (median survival, CCI = 88 months; usual care = 53.3 months; log rank = 0.30, p = 0.58). Age, stage of cancer, and surgical removal of the tumor were the only factors significantly associated with survival. Post hoc analysis stratified by cancer site and gender (women with breast cancer, women with lung cancer, men with lung cancer, and others) showed no survival effect from the CCI. CONCLUSION: In this analysis, the CCI was not associated with better survival. For future research, studies exploring survival outcomes need to consider specific characteristics of each intervention and cancer type. PMID- 21667049 TI - Measuring perceived benefit and disease-related burden in young cancer survivors: validation of the Benefit and Burden Scale for Children (BBSC) in The Netherlands. AB - PURPOSE: Perceiving favourable changes from one's illness may go hand in hand with experiencing harmful psychosocial effects. Each of these constructs should be considered when examining children's levels of psychological adjustment following stressful life events. A paediatric instrument that accounts for both positive and negative impact of stressful events has not been investigated in The Netherlands before. The aim of the study was to investigate psychometric properties of the Dutch version of the Benefit and Burden Scale for Children (BBSC), a 20-item questionnaire that intends to measure potential benefit and burden of illness in children. METHODS: Dutch paediatric survivors of childhood cancer aged 8-18 (N = 77) completed the BBSC and other psychological questionnaires: Pediatric Quality of Life Inventory (health-related quality of life), State-Trait Anxiety Inventory for Children (anxiety), Children's Revised Impact of Event Scale (posttraumatic stress) and Strengths and Difficulties Questionnaire (behavioural functioning). Reliability and validity were evaluated. RESULTS: Internal consistency (Cronbach's alpha, benefit 0.84, burden 0.72), test retest reliability (benefit r = 0.74, burden r = 0.78) and homogeneity (mean inter-item correlation, benefit r = 0.34, burden r = 0.22) were satisfactory. Burden was associated with HRQoL (-), anxiety (+), posttraumatic stress symptoms (+) and behavioural problems. Benefit did not correlate with the psychological outcomes. CONCLUSIONS: The Dutch version of the BBSC shows promising psychometric properties. Perceived benefit and disease-related burden are distinct constructs; both should be considered when examining children's psychological adjustment to potentially traumatic experiences. The BBSC may be useful as monitoring and screening instrument. PMID- 21667050 TI - Developmental venous anomalies with capillary stain: a subgroup of symptomatic DVAs? AB - INTRODUCTION: Intracranial developmental venous anomalies (DVAs) are considered benign vascular dispositions; they are asymptomatic in the vast majority of cases. They represent extreme variations of the venous drainage and may rarely be responsible for focal venous ischemia leading to neurological dysfunction. The aim of the study is to analyze a group of patients with symptomatic DVAs with capillary stain at angiography. METHODS: We retrospectively reviewed the clinical and radiological features of patients in which a DVA was considered the cause of a neurological event. In all the patients, the DVA was suspected by angio-CT or MRI and conventional angiography was performed to detail the angioarchitecture of the DVA. RESULTS: A total of 7 patients and 11 DVAs were identified; three patients had multiple DVAs. Three DVAs were frontal, two were parietal, two were thalamic, one was in the midbrain, and three were cerebellar. Patients presented with progressive neurological deficits, seizures, or cerebral hemorrhage. All these DVAs were associated with a peculiar capillary stain at angiography. CONCLUSION: Although being normal anatomical variations, DVAs may create, because of hemodynamic unbalance, venous ischemia that induces angiogenic phenomena. MRI shows the suffering of the brain and angiography witnesses this angiogenesis under the form of capillary stain. Conventional angiography can thus provide useful information to recognize "atypical" symptomatic DVAs. PMID- 21667051 TI - Plasma endoglin as a marker to predict cardiovascular events in patients with chronic coronary artery diseases. AB - Recent clinical studies have revealed that the expression of endoglin, an accessory protein for the TGF-beta receptor, is increased in patients with atherosclerotic diseases. The plasma endoglin level is thought to represent endothelial activation, inflammation, and senescence. To clarify the significance of plasma endoglin in chronic coronary artery disease. Human umbilical vein endothelial cells (HUVECs) were cultured to examine changes in soluble endoglin (s-endoglin) levels caused by atherogenic stimulation in vitro. We studied 318 patients with stable coronary artery disease who underwent a successful percutaneous coronary intervention (PCI). Patients with acute coronary syndrome were excluded. Major adverse cardiovascular events (MACE) were congestive heart failure, acute myocardial infarction, stroke, and sudden cardiac death. All patients were followed-up to examine MACE after the procedure. We confirmed that the levels of s-endoglin was increased in the culture medium of HUVECs by senescence, tumor necrosis factor-alpha and hydrogen peroxide. In a clinical study, mean follow-up period was 1055 +/- 612 days (49-2136 days) with 27 incidents of MACE (8.5%). We divided patients into three groups according to the plasma s-endoglin levels. Kaplan-Meier curves revealed that the highest endoglin group had a significantly higher MACE rate than the lowest endoglin group (log rank test, p = 0.009). A Cox proportional hazards model showed that chronic kidney disease, left ventricular ejection fraction and s-endoglin level were significant factors to predict MACE. Plasma endoglin could be a marker to predict cardiovascular events in patients with chronic coronary artery disease after PCI. PMID- 21667052 TI - Compliance with and effects of preoperative immunonutrition in patients undergoing pancreaticoduodenectomy. AB - BACKGROUND/PURPOSE: This study was conducted to ascertain the feasibility and effectiveness of preoperative enteral immunonutrition using an immune-enhanced formula (Impact) in patients undergoing pancreaticoduodenectomy. METHODS: Twenty five patients undergoing an elective pancreaticoduodenectomy were asked to ingest Impact for 5 days (750 mL/day) prior to surgery in addition to their normal diets. We retrospectively compared the early postoperative outcomes of the Impact group (n = 18), which consisted of patients who fully complied with the study protocol, and a control group (n = 13), which consisted of patients who had not ingested Impact prior to surgery. RESULTS: Overall, 82.6% of the patients complied with the preoperative oral ingestion of Impact; all but four patients tolerated a daily intake of 750 mL. While the clinical backgrounds of the Impact and control groups were not significantly different, the frequency of incisional wound infection was lower (0 vs. 30.8%, p = 0.012) and the change in systemic severity as evaluated using the acute physiology and chronic health evaluation (APACHE)-II scoring system was milder (p = 0.033) in the Impact group than in the control group. CONCLUSION: The preoperative oral ingestion of Impact was well tolerated and appeared to be effective for preventing incisional wound infection and reducing the response to surgical stress in patients undergoing a pancreaticoduodenectomy. PMID- 21667053 TI - D-dimer as a marker of severity in patients with severe acute pancreatitis. AB - BACKGROUND/PURPOSE: Coagulative disorder is known to occur in the early phase of severe acute pancreatitis (SAP) and D: -dimer is a commonly used clinical parameter of hemostasis. The aim of this study was to assess the value of the plasma D: -dimer level as a marker of severity in the first 3 days after admission in patients with SAP. METHODS: From January 2009 to February 2011, 45 patients admitted for SAP were included in this observational study. The D: dimer level was measured on a daily basis during days 1-3 after admission and the acute physiology and chronic health evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score, and other clinical parameters were recorded at the same time. The maximum and the mean D: -dimer values were used for analysis and compared with other prognostic factors of SAP. RESULTS: Both the maximum and mean levels of D: -dimer were significantly different between patients with and without clinical variables such as multiple-organ dysfunction syndrome (MODS), need for surgical intervention, and the presence of pancreatic infection. The D: -dimer level also showed great precision for the prediction of MODS and secondary infection. Additionally, the D: -dimer level correlated well with two usual markers of SAP severity-the APACHE II score and the C-reactive protein level. CONCLUSION: D: -dimer measurement is a useful, easy, and inexpensive early prognostic marker of the evolution and complications of SAP. PMID- 21667054 TI - Covered metallic stenting for malignant distal biliary obstruction: clinical results according to stent type. AB - BACKGROUND: In the endoscopic management of unresectable malignant biliary obstructions, covered metallic stents (CMSs) showed longer patency and lower incidence of stent occlusion than uncovered metallic stents (UMCs). However, there are very few reports on factors influencing the results of inserting CMSs. We evaluated differences in clinical results according to stent type. METHODS: We reviewed the results of four types of CMS (polyurethane-covered Diamond stent (PCD), silicone-covered WALLSTENT (SCW), ComVi stent, and VIABIL biliary stent) and an uncovered MS (UMS), based on our experience and the literature. CMSs were characterized according to the axial and radial forces, covering (partial, full), smoothness of the inner surface, and presence of an anti-migration system. RESULTS: CMSs were patent significantly longer than UMSs. There were differences in stent patency among the CMSs, including the cause of occlusion and other complications. The PCD had good patency and a low incidence of migration. The ComVi stent occluded early due to food impaction, but had the longest median stent patency and a low migration rate. The incidence of migration of SCW was relatively high and the SCW was occluded primarily by sludge. CONCLUSIONS: We should assess the differences between the various CMSs and select the best one for each patient. PMID- 21667055 TI - Preoperative biliary stents in pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is a common digestive cancer with high mortality, and surgical resection is the only potential curative treatment option. Pancreatic head cancer is usually accompanied by biliary obstruction, which potentially increases surgical complications following pancreaticoduodenectomy. Thus, preoperative biliary drainage has long been advocated. METHODS: A review of the literature using Medline, Embase and Cochrane databases was undertaken. RESULTS: Endoscopic or percutaneous biliary stent placement is technically successful in most patients. The use of routine preoperative biliary drainage in the setting of pancreatic cancer with biliary obstruction is controversial. Prospective studies have shown that complications related to preoperative biliary drainage using endoscopic placement of traditional plastic endoprostheses increase the overall morbidity compared to pancreaticoduodenectomy alone. Placement of self-expandable metal stents could reduce stent-related complication rates such as early occlusion because of prolonged patency, especially when surgery is delayed. CONCLUSION: Pancreatic cancer patients with deep jaundice and expected delay prior to curative intent surgery are potential candidates for temporary biliary drainage. Cholangitis remains a formal indication for early, urgent preoperative biliary decompression for patients with pancreatic cancer. PMID- 21667056 TI - Five-year prospective clinical study of posterior three-unit zirconia-based fixed dental prostheses. AB - This prospective clinical trial aimed at evaluating the clinical performance of three-unit posterior zirconia fixed dental prostheses (FDPs) after 5 years of clinical function. Thirty-seven patients received 48 three-unit zirconia-based FDPs. The restorations replaced either a premolar or a molar. Specific inclusion criteria were needed. Tooth preparation was standardized. Computer-aided design/computer-assisted manufacturing frameworks with a 9-mm(2) cross section of the connector and a 0.6-mm minimum thickness of the retainer were made. The restorations were luted with resin cement. The patients were recalled after 1, 6, 12, 24, 36, 48, and 60 months. The survival and success of the ceramics and zirconia were evaluated. The technical and aesthetic outcomes were examined using the United States Public Health Service criteria. The biologic outcomes were analyzed at abutment and contralateral teeth. Descriptive statistics were performed. All FDPs completed the study, resulting in 100% cumulative survival rate and 91.9% and 95.4% cumulative success rates for patients wearing one and two FDPs, respectively. No losses of retention were recorded. Forty-two restorations were rated alpha in all measured parameters. A minor chipping of the ceramics was detected in three restorations. No significant differences between the periodontal parameters of the test and control teeth were observed. Five-year clinical results proved that three-unit posterior zirconia-based FDPs were successful in the medium term for both function and aesthetic. Zirconia can be considered a promising substitute of metal frameworks for the fabrication of short-span posterior prostheses. PMID- 21667057 TI - Assessment of left ventricular volumes, ejection fraction and regional wall motion with retrospective electrocardiogram triggered 320-detector computed tomography: a comparison with 2D-echocardiography. AB - Left ventricular (LV) volumes, ejection fraction (LVEF) and regional wall motion (LVRWM) have important treatment and prognostic implications in patients with coronary artery disease. We sought to determine the accuracy of 320-row multidetector computed tomography (MDCT) for the assessment of LV volumes, LVEF and LVRWM, using 2D-echocardiography as the reference standard. We evaluated 50 consecutive patients (mean age 60 +/- 14 years, 66% male) who underwent 320 detector MDCT (dose-modulated retrospective electrocardiogram-triggering) and 2D echocardiography within 14 days for investigation of known or suspected coronary artery disease. Two blinded readers measured LV volumes on MDCT and visually assessed LVRWM with a 3-point scale using a 17-segment model. A separate experienced echocardiologist, blinded to MDCT findings, assessed LVRWM on 2D echocardiograms and determined LV volumes and LVEF using Simpson's biplane method. 2D-echocardiography served as the reference standard. Mean LVEF was 59 +/ 9% (range 26-75%) on 2D-echocardiography and 60 +/- 9% (range 27-76%) on MDCT. Using linear regression analysis, MDCT agreed very well with 2D-echocardiography for assessment of LVEDV (r(2) = 0.88; P < 0.001), LVESV (r(2) = 0.95; P < 0.001) and LVEF (r(2) = 0.90; P < 0.001). Mean differences (+/-standard deviation) of 14 +/- 13 ml, 5 +/- 7 ml and 1 +/- 3% were observed between MDCT and 2D echocardiography for LVEDV, LVESV and LVEF, respectively. On 2D-echocardiography, 81/850 (9.5%) segments had abnormal LVRWM. Agreement for assessment of LVRWM between 2D-echocardiography and MDCT was excellent (96%, k = 0.76). Accurate assessment of LV volumes, LVEF and LVRWM is feasible with 320-detector MDCT, with MDCT demonstrating slightly larger LV volumes than 2D-echocardiography. PMID- 21667058 TI - Urinary beta2-microglobulin in very preterm neonates with chorioamnionitis. AB - It is important to identify premature infants with prenatal inflammation as it contributes to short- and long-term complications. Our object was to study how prenatal inflammation affects the urinary beta(2)-microglobulin (beta(2)-MG) level. Preterm neonates were divided based on the presence of chorioamnionitis (CAM) into the CAM (n = 100) and non-CAM groups (n = 117). These were further subdivided into five groups each: 30 preterm neonates of 23-26; 42 neonates of 27 28; 54 neonates of 29-30; 51 neonates of 31-32; and 40 neonates of 33-34 weeks' gestation. The urinary beta(2)-MG level within 48 h of birth was significantly higher in the CAM group than in the non-CAM group among the neonates of 23-26 weeks' gestation (18.3 +/- 6.9 vs 10.0 +/- 5.6 * 10(4) MUg/gCr, p = 0.0018) and the neonates of 27-28 weeks' gestation (16.2 +/- 10.8 vs 8.8 +/- 3.3 * 10(4) MUg/gCr, p = 0.0101). However, there was no difference in urinary beta(2)-MG level between the CAM and the non-CAM group among the neonates >= 29 weeks 'gestation. Moreover, the elevated urinary beta(2)-MG level in the neonates <= 28 weeks ' gestation with CAM had disappeared by 1 week after birth. The reasons for the increase in urinary beta(2)-MG level within 48 h of birth in very preterm neonates (<= 28 weeks' gestation) with CAM are believed to be not only prematurity, but also prenatal inflammation. It is suggested that the urinary beta(2)-MG level during the early postnatal period can identify prenatal inflammation. PMID- 21667059 TI - Elemental ratio determinations and compound-independent calibration using microsecond pulsed glow discharge time-of-flight mass spectrometry. AB - A new prototype based on a microsecond pulsed glow discharge ion source coupled to a time-of-flight mass spectrometer was recently designed, constructed and analytically evaluated in our laboratory for simultaneous collection of elemental and molecular information, and as a gas-chromatographic detector of compounds of environmental concern. To investigate further the analytical capabilities of such a new setup, its capability for the determination of element ratios in volatile organic halogenated compounds has been explored. Moreover, compound-independent calibration has been carried out with the prototype as well. The results demonstrated that the intensity ratios (analyte to internal standard) were linear with the corresponding ratio of concentrations. Both for chlorine and bromine (measured in the prepeak) and for BrC (measured in the plateau) the slope was 1 and the intercept was 0. Moreover, detection limits were improved by more than 1 order of magnitude as compared with using external calibration. The applicability of the proposed approach has been demonstrated for the straightforward determination of chloroform in drinking and river waters. PMID- 21667060 TI - Using laser ablation/inductively coupled plasma mass spectrometry to bioimage multiple elements in mouse tumors after hyperthermia. AB - In this study, we employed laser ablation/inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the spatial distribution of Gd-doped iron oxide nanoparticles (IONPs) in one tumor slice that had been subjected to magnetic fluid hyperthermia (MFH). The mapping results revealed the high resolution of the elemental analysis, with the distribution of Gd atoms highly correlated with that of the Fe atoms. The spatial distributions of C, P, S, and Zn atoms revealed that the effect of MFH treatment was significantly dependent on the diffusion of the magnetic fluid in the tissue. An observed enrichment of Cu atoms after MFH treatment was probably due to inflammation in the tumor. The abnormal distribution of Ni atoms suggests a probable biochemical reaction in the tumor. Therefore, this LA-ICP-MS mapping technique can provide novel information regarding the spatial distribution of elements in tumors after cancer therapy. PMID- 21667061 TI - Determination of pyrethroid metabolites in human urine using liquid phase microextraction coupled in-syringe derivatization followed by gas chromatography/electron capture detection. AB - Metabolites of synthetic pyrethroids such as cis-3-(2,2-dibromovinyl)-2,2-di methylcyclo-propane-1-carboxylic acid, cis- and trans-3-(2,2-dichlorovinyl)-2,2 dimethylcyclopropane-1-carboxylic acid), 3-phenoxybenzoic acid (3-PBA), and 4 fluoro-3-PBA are biomarkers for exposure to phenothrin, tetramethrin, cyfluthrin, cypermethrin, deltamethrin, and permethrin. In this study, the pyrethroid metabolites in workers' urine samples were monitored for the first time with a novel sample pretreatment process combining hollow fiber liquid phase microextraction (HF-LPME) and in-syringe derivatization (ISD) followed by gas chromatography-electron capture detector (GC-ECD) analysis. A micro-syringe pre filled with derivatizing agents and syringe needle connected to an extracting solvent impregnated hollow fiber segment was used as the LPME probe. Pyrethroid metabolites were extracted and enriched simultaneously from urine samples by HF LPME sampling and acid hydrolysis at 70 degrees C for 10 min. After sampling, the ISD was performed by mixing the extracting solution and derivatizing agents through plunger movements, followed by GC-ECD analysis. Parameters influencing the HF-LPME efficiency and ISD were investigated and optimized. Under optimum conditions, the method provided enrichment factors of 69.8-154.6, repeatability from 5.0 to 12% (n = 5), and good linearity (R(2) = 0.9980-0.9998) for interested analytes spiked in urine samples. The method detection limits ranged from 1.6 to 17 ng/mL. A comparison was performed between the proposed method and conventional methods. The proposed method was applied to analyze pyrethroid metabolites in the urine samples collected from workers of pesticide formulation plants. The results suggested that the proposed HF-LPME coupled ISD method was a rapid, simple, efficient, and eco-friendly technique in the biomonitoring of metabolites of pyrethroids in workers' urine. PMID- 21667062 TI - A round robin exercise in archaeometry: analysis of a blind sample reproducing a seventeenth century pharmaceutical ointment. AB - Chemical analysis of ancient residues of pharmaceutical or cosmetic preparations such as balms or ointments is made problematic by the high complexity of these mixtures, composed of organic and inorganic materials. Consequently, a multi analytical approach and special caution in the interpretation of the results are necessary. In order to contribute to the improvement of analytical strategies for the characterization of complex residues and to reconstruct ancient medical practices, a replica of a pharmaceutical formulation of the seventeenth century was prepared in the laboratory according to a historically documented recipe. In a round robin exercise, a portion of the preparation was analysed as a blind sample by 11 laboratories using various analytical techniques. These included spectroscopic, chromatographic and mass spectrometric methods. None of the laboratories was able to completely reconstruct the complex formulation, but each of them gave partial positive results. The round robin exercise has demonstrated that the application of a multi-analytical approach can permit a complete and reliable reconstruction of the composition. Finally, on the basis of the results, an analytical protocol for the study of residues of ancient medical and pharmaceutical preparations has been outlined. PMID- 21667063 TI - The copper-transporting capacity of ATP7A mutants associated with Menkes disease is ameliorated by COMMD1 as a result of improved protein expression. AB - Menkes disease (MD) is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copper-dependent enzymes. Most MD patients die in early childhood, although mild forms of MD have also been described. A diversity of mutations in the gene encoding of the Golgi-resident copper-transporting P(1B)-type ATPase ATP7A underlies MD. To elucidate the molecular consequences of the ATP7A mutations, various mutations in ATP7A associated with distinct phenotypes of MD (L873R, C1000R, N1304S, and A1362D) were analyzed in detail. All mutants studied displayed changes in protein expression and intracellular localization parallel to a dramatic decline in their copper-transporting capacity compared to ATP7A the wild-type. We restored these observed defects in ATP7A mutant proteins by culturing the cells at 30 degrees C, which improves the quality of protein folding, similar to that which as has recently has been demonstrated for misfolded ATP7B, a copper transporter homologous to ATP7A. Further, the effect of the canine copper toxicosis protein COMMD1 on ATP7A function was examined as COMMD1 has been shown to regulate the proteolysis of ATP7B proteins. Interestingly, in addition to adjusted growth temperature, binding of COMMD1 partially restored the expression, subcellular localization, and copper-exporting activities of the ATP7A mutants. However, no effect of pharmacological chaperones was observed. Together, the presented data might provide a new direction for developing therapies to improve the residual exporting activity of unstable ATP7A mutant proteins, and suggests a potential role for COMMD1 in this process. PMID- 21667064 TI - Immune biology of Ag-specific gammadelta T cells in infections. AB - Accumulating evidence suggests that human gammadelta T cells act as non-classical T cells and contribute to both innate and adaptive immune responses in infections. Vgamma2 Vdelta2 T (also termed Vgamma9 Vdelta2 T) cells exist only in primates, and in humans represent a dominant circulating gammadelta T-cell subset. Primate Vgamma2 Vdelta2 T cells are the only gammadelta T cell subset capable of recognizing microbial phosphoantigen. Since nonhuman primate Vgamma2 Vdelta2 T cells resemble their human counterparts, in-depth studies have been undertaken in macaques to understand the biology and function of human Vgamma2 Vdelta2 T cells. This article reviews the recent progress for immune biology of Vgamma2 Vdelta2 T cells in infections. PMID- 21667066 TI - Opposite effect of capsaicin and capsazepine on behavioral thermoregulation in insects. AB - Transient receptor potential channels are implicated in thermosensation both in mammals and insects. The aim of our study was to assess the effect of mammalian vanilloid receptor subtype 1 (TRPV1) agonist (capsaicin) and antagonist (capsazepine) on insect behavioral thermoregulation. We tested behavioral thermoregulation of mealworms larvae intoxicated with capsaicin and capsazepine in two concentrations (10(-7) and 10(-4) M) in a thermal gradient system for 3 days. Our results revealed that in low concentration, capsaicin induces seeking lower temperatures than the ones selected by the insects that were not intoxicated. After application of capsazepine in the same concentration, the mealworms prefer higher temperatures than the control group. The observed opposite effect of TRPV1 agonist and antagonist on insect behavioral thermoregulation, which is similar to the effect of these substances on thermoregulation in mammals, indicates indirectly that capsaicin may act on receptors in insects that are functionally similar to TRPV1. PMID- 21667065 TI - Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson's disease in Sardinia. AB - Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson's disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51-79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD. PMID- 21667067 TI - Estimation of cancer cases and deaths attributable to infection in China. AB - BACKGROUND: The burden of cancer attributable to infection in China has not been systematically quantified in detail. METHODS: Using the findings of systematic review of prevalence of infectious agents and their relative risks (RRs) of specific cancers, a standard approach was applied to estimate the population proportions of cancers attributed to specific infectious agents in China (attributable fractions, AFs). Together with information from the latest national mortality survey and cancer registries in China, the overall and detailed numbers of cancer cases and deaths caused by infection were estimated. RESULTS: A total of 668,763 cancer cases and 526,567 cancer deaths were attributed to infections in China in 2005, which accounted for 25.9 and 29.4% of the overall cancer cases and deaths of the local population, respectively. More infection-related cancers in men (of ~30%) were found compared to that in women (of 25.3% cases and 21.8% deaths). CONCLUSIONS: Infectious agents contributed more than one-quarter of the overall cancer number among population in China; further persistently effective vaccination and screening interventions and other preventive efforts against relevant infections should be initiated and strengthened. PMID- 21667068 TI - Serum estrogen levels and prostate cancer risk in the prostate cancer prevention trial: a nested case-control study. AB - OBJECTIVE: Finasteride reduces prostate cancer risk by blocking the conversion of testosterone to dihydrotestosterone. However, whether finasteride affects estrogens levels or change in estrogens affects prostate cancer risk is unknown. METHODS: These questions were investigated in a case-control study nested within the prostate cancer prevention trial (PCPT) with 1,798 biopsy-proven prostate cancer cases and 1,798 matched controls. RESULTS: Among men on placebo, no relationship of serum estrogens with risk of prostate cancer was found. Among those on finasteride, those in the highest quartile of baseline estrogen levels had a moderately increased risk of Gleason score < 7 prostate cancer (for estrone, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.06-2.15; for estradiol, OR = 1.50, 95% CI = 1.03-2.18). Finasteride treatment increased serum estrogen concentrations; however, these changes were not associated with prostate cancer risk. CONCLUSION: Our findings confirm those from previous studies that there are no associations of serum estrogen with prostate cancer risk in untreated men. In addition, finasteride results in a modest increase in serum estrogen levels, which are not related to prostate cancer risk. Whether finasteride is less effective in men with high serum estrogens, or finasteride interacts with estrogen to increase cancer risk, is uncertain and warrants further investigation. PMID- 21667069 TI - Clinical efficacy of arbekacin for Gram-negative bacteria. AB - In an analysis of methicillin-resistant Staphylococcus aureus (MRSA) infected patients treated with arbekacin (ABK) only, Gram-negative bacteria (GNB) that were inhibited by low minimal inhibitory concentrations (MICs) of amikacin (AMK) or gentamycin (GM) were eradicated by the end of the ABK treatment. On the other hand, GNB that were only inhibited by high MICs of AMK or GM persisted until the end of treatment with ABK only. Thus, ABK can be expected to be effective even in cases of mixed infection with GNB and MRSA. PMID- 21667070 TI - Do cardiovascular disease risk prediction tools need to be updated in Europe? PMID- 21667071 TI - Peripheral artery disease and atrial fibrillation: a potentially dangerous combination. AB - Atrial fibrillation (AF) is commonly associated with a significant increase in stroke and thromboembolic risk. Many patients with AF have associated atherothrombosis given the many risk factors for atherosclerosis that also predispose to AF. Vascular disease, whether peripheral artery disease or myocardial infarction, contributes to the increased risk of stroke and thromboembolism, and has been included in stroke risk assessment schema. This review analyzes the interplay between AF and peripheral artery disease in relation to their associated pathophysiology, as well as epidemiological data linking both conditions and the associated thromboembolic complications conferred by the presence of both. PMID- 21667072 TI - Molecular docking and structural analysis of cofactor-protein interaction between NAD+ and 11beta-hydroxysteroid dehydrogenase type 2. AB - Molecular docking and structural analysis of the cofactor-protein interaction between NAD(+) and human (h) or mouse (m) 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) were performed with the molecular operating environment (MOE). 11betaHSD1 (PDB code: 3HFG) was selected as a template for the 3D structure modeling of 11betaHSD2. The MOE docking (MOE-dock) and the alpha sphere and excluded volume-based ligand-protein docking (ASE-dock) showed that both NAD(+)-h11betaHSD2 and NAD(+)-m11betaHSD2 models have a similar binding orientation to the template cofactor-protein model. Our present study also revealed that Asp91, Phe94, Tyr232 and Thr267 could be of importance in the interaction between NAD(+) and 11betaHSD2. NADP(+) was incapable of entering into the cofactor-binding site of the 11betaHSD2 models. The present study proposes the latest models for 11betaHSD2 and its cofactor NAD(+), and to the best of our knowledge, this is the first report of a m11betaHSD2 model with NAD(+). PMID- 21667073 TI - Determination of best-fit potential parameters for a reactive force field using a genetic algorithm. AB - The ReaxFF interatomic potential, used for organic materials, involves more than 600 adjustable parameters, the best-fit values of which must be determined for different materials. A new method of determining the set of best-fit parameters for specific molecules containing carbon, hydrogen, nitrogen and oxygen is presented, based on a parameter reduction technique followed by genetic algorithm (GA) minimization. This work has two novel features. The first is the use of a parameter reduction technique to determine which subset of parameters plays a significant role for the species of interest; this is necessary to reduce the optimization space to manageable levels. The second is the application of the GA technique to a complex potential (ReaxFF) with a very large number of adjustable parameters, which implies a large parameter space for optimization. In this work, GA has been used to optimize the parameter set to determine best-fit parameters that can reproduce molecular properties to within a given accuracy. As a test problem, the use of the algorithm has been demonstrated for nitromethane and its decomposition products. PMID- 21667074 TI - Cannabidiol potentiates Delta9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. AB - RATIONALE: The interactions between Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models. OBJECTIVES: The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses. METHODS: Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB(1) and 5-HT(1A) receptor binding were assessed. RESULTS: CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB(1) receptor binding and no drug effects on 5-HT(1A) receptor binding were observed. CONCLUSIONS: CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs. PMID- 21667075 TI - Seroepidemiological study of bovine respiratory viruses (BRSV, BoHV-1, PI-3V, BVDV, and BAV-3) in dairy cattle in central region of Iran (Esfahan province). AB - Respiratory diseases in calves are responsible for major economic losses in both beef and dairy production. Several viruses, such as bovine respiratory syncytial virus (BRSV), bovine herpes virus-1 (BoHV-1), bovine parainfluenza virus-3 (BPI 3V), bovine viral diarrhea virus (BVDV), and bovine adenoviruses (BAV), are detected in most clinical cases with respiratory signs. The aim of this study is to define seroprevalences of five major viral causes of bovine respiratory infections in cattle in central region of Iran (Esfahan province). The population targeted was 642 dairy cows (Holstein-Friesian) from 25 farms. Samples of blood serum from female cattle were examined. Sera were tested by commercial ELISA kits to detect antibody against BRSV, BoHV-1, BPI-3V, BVDV, and BAV-3. The results were analyzed by Chi-square test. In the present study, seroprevalences of BRSV, BoHV-1, PI3V, BVDV, and BAV-3 were 51.1%, 72%, 84.4%, 49.2%, and 55.6%, respectively. The present study shows that infections of bovine respiratory viruses are very common in cattle in Esfahan. PMID- 21667076 TI - Prevalence and pathology of dermatophilosis in camels (Camelus dromedaries) in Iran. AB - Gross and histopathologic lesions of the integumentary system were studied in 103 camels (Camelus dromedarius) slaughtered in Yazd Province of Iran. Dermatophilosis was diagnosed in 14 (13.6%) of the studied camels. Grossly, patchy thickening of the skin with dark brown scabs or crusts were observed on the rump, flanks, abdomen, shoulders, and neck. A heavy infestation with brown hard ticks was present on the lesions in almost all of the affected camels. On parasitology examination, all the ticks were identified as Hyalomma spp. Histopathologic examination of the affected skins revealed prominent superficial thickening of the epidermis as orthokeratotic and parakeratotic hyperkeratosis, degenerating neutrophils, serous fluid, and bacterial filaments. A lot of keratinaceous debris associated with an exudate rich in neutrophils were seen as remarkable features of the lesions on the superficial epidermis. Dermal inflammation was mild with infiltration of mononuclear inflammatory cells, particularly lymphocytes, around superficial vessels. A Gram-positive filamentous organism which was divided into parallel rows of cocci was observed in the crusts by Brown and Brenn Gram stain. This is the first report of the occurrence of dermatophilosis in the camels of Iran. With regard to infestation of the lesions by Hyalomma spp., it seems that this tick may have an important role in the pathogenesis of dermatophilosis in the camels of this region. PMID- 21667077 TI - Rural livestock asset portfolio in northern Ethiopia: a microeconomic analysis of choice and accumulation. AB - Livestock fulfill different functions. Depending on their livelihood strategies, households differ in their choice of what type of animal to keep and on accumulation of the chosen animal overtime. Using a panel data of 385 rural households in a mixed farming system in northern Ethiopia, this paper investigates the dynamic behavior of rural households' livestock holding to identify determinants of choice and accumulation of livestock overtime. Choice is analyzed for a principal animal, the animal that constituted the largest value of livestock assets a household possessed, using a multinomial logit model. Results indicate that rural households differ in their choice of what type of animal to keep. Agro-climatic conditions, sex and age of household head, presence of an adult male member in a household, and liquidity are the major factors that influence the type of principal animal households keep. Conditional on the principal animal selected, we analyzed the factors that determine the accumulation of the chosen animals by correcting for selection bias. Area of land cultivated is the most significant factor that explains the number of animals households keep. Other factors include sex of household head, diversification into nonfarm self-employment, and shocks. PMID- 21667078 TI - Seasonal distribution of systemic lupus erythematosus activity and its correlation with climate factors. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a variety of clinical manifestations. Although inter-individual variations exist with respect to susceptibility to develop SLE, no study has been carried out to determine the role of different climate conditions in predisposing the susceptible individuals to SLE. The objective of this study was to investigate the role of different seasons and climate factors on SLE activity. From 2000 to 2009, the seasonal distribution of 2,802 active SLE patients recruited from Anhui Provincial Hospital and the First Affiliated Hospital of Anhui Medical University was analyzed retrospectively. The climate data were provided by the Institute of Geographical Sciences and Resources, Chinese Academy of Sciences. The correlation between climate factors and SLE activity was also analyzed. The proportion of active SLE patients in winter, spring, summer, and autumn was 10.06, 10.31, 9.74, and 8.660/00, respectively. In autumn, the proportion was much lower than that in winter and spring (P < 0.05). The proportion among winter, spring, and summer had no statistical difference (P > 0.05). The number of active SLE patients had no correlation with air temperature (r = 0.483, P > 0.05), relative humidity (r = 0.294, P > 0.05), and sunshine percentage (r = 0.503, P > 0.05), but it had positive correlation with amount of precipitation (r = 0.601, P < 0.05), wind velocity (r = 0.713, P < 0.01), and sunshine duration (r = 0.769, P < 0.01) and negative correlation with barometric pressure (r = -0.664, P < 0.05). The disease activity of patients with SLE is affected by seasons and climate factors. PMID- 21667079 TI - Simulation and experimental studies on magnetic hyperthermia with use of superparamagnetic iron oxide nanoparticles. AB - Our purpose of this study was to present simulation and experimental studies on magnetic hyperthermia (MH) with use of an alternating magnetic field (AMF) and superparamagnetic iron oxide nanoparticles (Resovist(r)). In the simulation studies, the energy dissipation (P) and temperature rise rate (?T/?t) were computed under various conditions by use of the probability density function of the particle size distribution based on a log-normal distribution. P and ?T/?t and their dependence on the frequency of the AMF (f) largely depended on the particle size of Resovist(r). P and ?T/?t reached maximum at a diameter of ~24 nm, and were proportional to the amplitude of the AMF (H (0)) raised to a power of ~2.0. In the experimental studies, we made a device for generating an AMF, and measured the temperature rise under various concentrations of Resovist(r), H (0), and f. The temperature rise at 10 min after the start of heating was linearly proportional to the concentration of Resovist(r), and proportional to H (0) raised to a power of ~2.4, which was slightly greater than that expected from the simulation studies. There was a tendency for the temperature rise to saturate with increasing f. In conclusion, this study will be useful for investigating the feasibility of MH with Resovist(r) and optimizing the parameters for it. PMID- 21667080 TI - Chimpanzees' use of conspecific cues in matching-to-sample tasks: public information use in a fully automated testing environment. AB - Social animals have much to gain from observing and responding appropriately to the actions of their conspecific group members. This can in turn lead to the learning of novel behavior patterns (social learning) or to foraging, ranging, or social behavioral choices copied from fellow group members, which do not necessarily result in long-term learning, but at the time represent adaptive responses to environmental cues (public information use). In the current study, we developed a novel system for the study of public information use under fully automated conditions. We modified a classic single-subject laboratory paradigm- matching-to-sample (MTS)--and examined chimpanzees' ability to interpret and utilize cues provided by the behavior of a conspecific to solve the task. In Experiment 1, two subjects took turns on an identity MTS task, with one subject (the model) performing the first half of the trial and the other subject (the observer) completing the trial using the model's actions as discriminative cues. Both subjects performed above chance from the first session onwards. In Experiment 2, the subjects were tested on a symbolic version of the same MTS task, with one subject showing spontaneous transfer. Our study establishes a novel method for examining public information use within a highly controlled and automated setting. PMID- 21667082 TI - Global gene expression profiles for the growth phases of Trichophyton rubrum. AB - Trichophyton rubrum (T. rubrum) is a common superficial fungus. Molecular and genetic studies of T. rubrum are still limited. In this paper, we report the global analysis of gene expression profiles at different growth phases using cDNA microarray technology. A total of 2044 differentially expressed genes were obtained and clustered into three expression patterns. Our data confirmed previous results that many mRNAs were pre-stored in the conidia of T. rubrum. Transcriptional profiling and function analysis showed that some glycolytic enzymes share similar expression patterns and may be coregulated during the transition of growth phases. Some genes involved in small GTPase signaling pathways, and in cAMP-dependent and MAPK regulation pathways were induced in response to the growth dynamics of T. rubrum. Although the detailed biological roles of these T. rubrum genes are still unknown, our results suggest that these genes may be involved in regulation mechanisms in the life cycle of the fungus. PMID- 21667081 TI - Epistatic interactions of genes influence within-individual variation of physical activity traits in mice. AB - A number of quantitative trait loci (QTLs) recently have been discovered that affect various activity traits in mice, but their collective impact does not appear to explain the consistently moderate to high heritabilities for these traits. We previously suggested interactions of genes, or epistasis, might account for additional genetic variability of activity, and tested this for the average distance, duration and speed run by mice during a 3 week period. We found abundant evidence for epistasis affecting these traits, although, recognized that epistatic effects may well vary within individuals over time. We therefore conducted a full genome scan for epistatic interactions affecting these traits in each of seven three-day intervals. Our intent was to assess the extent and trends in epistasis affecting these traits in each of the intervals. We discovered a number of epistatic interactions of QTLs that influenced the activity traits in the mice, the majority of which were not previously found and appeared to affect the activity traits (especially distance and speed) primarily in the early or in the late age intervals. The overall impact of epistasis was considerable, its contribution to the total phenotypic variance varying from an average of 22-35% in the three traits across all age intervals. It was concluded that epistasis is more important than single-locus effects of genes on activity traits at specific ages and it is therefore an essential component of the genetic architecture of physical activity. PMID- 21667083 TI - Evaluation of lung epithelial permeability in the volatile substance abuse using Tc-99m DTPA aerosol scintigraphy. AB - AIM: Chronic inhalant use is associated with significant toxic effects, including neurological, renal, hepatic, and pulmonary damage. However, there is a paucity of reports regarding respiratory complications in inhalant abusers. The aim of this study was to evaluate pulmonary epithelial permeability in the volatile substance abuse (VSA) using Tc-99m DTPA aerosol scintigraphy. METHODS: This study included 18 patients with volatile substance abuse and 18 volunteer controls. All of patients and controls were smokers. Tc-99m DTPA aerosol scintigraphy was performed in all cases. Time-activity curves from each lung were generated and clearance half-time (T(1/2)) of Tc-99m DTPA were calculated. T(1/2) of whole lung was calculated as a mean of the T(1/2) of left and right lung. RESULTS: The T(1/2) values of Tc-99m DTPA clearance in the substance abusers were significantly decreased as compared to the control group with respective mean values of 28.86 +/- 8.44, and 62.14 +/- 26.12 min (p = 0.001). It was seen Tc-99m DTPA clearance from lung was faster as the duration of substance abuse was increased. CONCLUSIONS: Tc-99m DTPA pulmonary clearance is markedly accelerated in the volatile substance abuse. This suggests that inhalant abuse of substance may produce abnormalities in pulmonary alveolo-capillary membrane function. PMID- 21667084 TI - Regulatory and metabolic network of rhamnolipid biosynthesis: traditional and advanced engineering towards biotechnological production. AB - During the last decade, the demand for economical and sustainable bioprocesses replacing petrochemical-derived products has significantly increased. Rhamnolipids are interesting biosurfactants that might possess a broad industrial application range. However, despite of 60 years of research in the area of rhamnolipid production, the economic feasibility of these glycolipids is pending. Although the biosynthesis and regulatory network are in a big part known, the actual incidents on the cellular and process level during bioreactor cultivation are not mastered. Traditional engineering by random and targeted genetic alteration, process design, and recombinant strategies did not succeed by now. For enhanced process development, there is an urgent need of in-depth information about the rhamnolipid production regulation during bioreactor cultivation to design knowledge-based genetic and process engineering strategies. Rhamnolipids are structurally comparable, simple secondary metabolites and thus have the potential to become instrumental in future secondary metabolite engineering by systems biotechnology. This review summarizes current knowledge about the regulatory and metabolic network of rhamnolipid synthesis and discusses traditional and advanced engineering strategies performed for rhamnolipid production improvement focusing on Pseudomonas aeruginosa. Finally, the opportunities of applying the systems biotechnology toolbox on the whole-cell biocatalyst and bioprocess level for further rhamnolipid production optimization are discussed. PMID- 21667085 TI - Chemo-enzymatic synthesis of polyhydroxyalkanoate (PHA) incorporating 2 hydroxybutyrate by wild-type class I PHA synthase from Ralstonia eutropha. AB - A previously established improved two-phase reaction system has been applied to analyze the substrate specificities and polymerization activities of polyhydroxyalkanoate (PHA) synthases. We first analyzed the substrate specificity of propionate coenzyme A (CoA) transferase and found that 2-hydroxybutyrate (2HB) was converted into its CoA derivative. Then, the synthesis of PHA incorporating 2HB was achieved by a wild-type class I PHA synthase from Ralstonia eutropha. The PHA synthase stereoselectively polymerized (R)-2HB, and the maximal molar ratio of 2HB in the polymer was 9 mol%. The yields and the molecular weights of the products were decreased with the increase of the (R)-2HB concentration in the reaction mixture. The weight-average molecular weight of the polymer incorporating 9 mol% 2HB was 1.00 * 10(5), and a unimodal peak with polydispersity of 3.1 was observed in the GPC chart. Thermal properties of the polymer incorporating 9 mol% 2HB were analyzed by DSC and TG-DTA. T (g), T (m), and T (d) (10%) were observed at -1.1 degrees C, 158.8 degrees C, and 252.7 degrees C, respectively. In general, major components of PHAs are 3 hydroxyalkanoates, and only engineered class II PHA synthases have been reported as enzymes having the ability to polymerize HA with the hydroxyl group at C2 position. Thus, this is the first report to demonstrate that wild-type class I PHA synthase was able to polymerize 2HB. PMID- 21667086 TI - Diversity and enrichment of nitrite-dependent anaerobic methane oxidizing bacteria from wastewater sludge. AB - Recently discovered microorganisms affiliated to the bacterial phylum NC10, named "Candidatus Methylomirabilis oxyfera", perform nitrite-dependent anaerobic methane oxidation. These microorganisms could be important players in a novel way of anaerobic wastewater treatment where ammonium and residual dissolved methane might be removed at the expense of nitrate or nitrite. To find suitable inocula for reactor startup, ten selected wastewater treatment plants (WWTPs) located in The Netherlands were screened for the endogenous presence of M. oxyfera using molecular diagnostic methods. We could identify NC10 bacteria with 98% similarity to M. oxyfera in nine out of ten WWTPs tested. Sludge from one selected WWTP was used to start a new enrichment culture of NC10 bacteria. This enrichment was monitored using specific pmoA primers and M. oxyfera cells were visualized with fluorescence oligonucleotide probes. After 112 days, the enrichment consumed up to 0.4 mM NO(2)(-) per day. The results of this study show that appropriate sources of biomass, enrichment strategies, and diagnostic tools existed to start and monitor pilot scale tests for the implementation of nitrite-dependent methane oxidation in wastewater treatment at ambient temperature. PMID- 21667087 TI - Effect of culture operating conditions on succinate production in a multiphase fed-batch bioreactor using an engineered Escherichia coli strain. AB - A metabolically engineered Escherichia coli strain SBS550MG (pHL413) was used in this study to investigate the impact of various culture operating conditions for improving the specific succinate production rate for better final titer while maintaining the theoretical succinate yield on glucose in multiphase fed-batch cultures. Previously, we reported that changes in the level of aeration during the cell growth phase significantly modified gene expression profiles and metabolic fluxes in this system (Martinez et al. 2010). Based on these observations, the examination of culture conditions was mainly focused on the aerobic growth phase. It was found that 2-5 h of low dissolved oxygen culture during the aerobic phase improves cell productivity, but pH control during the aerobic phase was not favorable for the system. Cell viability has been identified as a major limiting factor for succinate production. Supplementing LB medium and betaine, an anti-osmotic stress reagent, did not improve cell activity. A higher succinate titer (537.8 mM) using the current metabolic engineering E. coli strain was achieved, which can potentially be improved further by increasing cell viability. PMID- 21667089 TI - Tibial rotation in single- and double-bundle ACL reconstruction: a kinematic 3-D in vivo analysis. AB - PURPOSE: The effect of double-bundle ACL reconstruction on knee kinematics has recently been studied by several authors under controlled laboratory conditions however little evidence has been derived from dynamic in vivo evaluations. This study hypothesized that tibial rotation during pivoting motor tasks would be better restored after double-bundle ACL reconstructions when compared with single bundle procedures. METHODS: Twenty patients with a chronic ACL rupture were randomly assigned to receive a single- or double-bundle ACL reconstruction. Both knees were evaluated pre-operatively by kinematic 3-D gait analysis while performing low- and high-demand motor tasks, including pivoting. At 6 months post operatively, measurements were repeated in 16 patients. Ten healthy, sex- and age matched subjects with no history of lower limb pathology formed the control group. The tibial rotational excursion was set as the dependent variable. RESULTS: The results indicate that at 6 months after surgery both "anatomic" single- and double-bundle ACL reconstruction are able to restore tibial rotational excursion when compared with the contralateral knees and with control knees from uninjured subjects. Chronic ACL-deficient patients show an increase in tibial rotation in both knees during high-demand pivoting tasks. CONCLUSIONS: Both "anatomic" single- and double-bundle ACL reconstruction adequately restore tibial rotational excursion in a human, "in vivo" kinematic model. As knee stability measurements by in vivo kinematic 3-D analysis more accurately represent actual knee loading during activities, the results of this study might better correlate with functional outcome after ACL reconstructions compared with static knee stability tests or ex vivo laboratory experiments. In such, the results of this dynamic study do not support the theoretical advantage of a double-bundle ACL reconstruction over an "anatomic" single-bundle ACL reconstruction. PMID- 21667088 TI - Effects of Rho-associated protein kinase inhibitors Y-27632 and Y-39983 on isolated rabbit ciliary arteries. AB - PURPOSE: In normotensive eyes, reduced ocular blood flow can lead to glaucoma pathogenesis. Drugs that reduce intraocular pressure (IOP) often cause vasodilation of the ciliary arteries and improve blood flow to the eye. A novel class of drugs called Rho-associated coiled coil-forming protein kinase (ROCK) inhibitors can lower IOP. Therefore, we tested the ability of two ROCK inhibitors, Y-27632 and Y39983, to relax rabbit ciliary arteries. METHODS: We measured in vitro ciliary artery smooth muscle contractions by isometric tension recordings and changes of intracellular free calcium concentration ([Ca(2+)](i)) by fluorescence photometry. RESULTS: Both Y-27632 and Y-39983 induced a concentration-dependent relaxation in rabbit ciliary arteries precontracted with a high-potassium (high-K) solution. The amplitude of relaxation induced by Y 27632 and Y-39983 was not affected by either 100 MUM N (G)-nitro-L: -arginine methyl ester (L: -NAME) or 10 MUM indomethacin. In Ca(2+)-free solution, Y-27632 and Y-39983 significantly inhibited the transient contraction of ciliary arteries induced by 10 MUM histamine. However, neither Y-27632 nor Y-39983 affected the elevation of [Ca(2+)](i) induced by high-K solution and histamine. CONCLUSIONS: We concluded that Y-27632 and Y-39983 relaxed isolated rabbit ciliary artery segments in vitro. The mechanism of relaxation was not dependent on endothelial derived factors such as nitric oxide (NO) or prostacyclin, nor was it dependent on changes in intracellular Ca(2+) concentration. PMID- 21667090 TI - Scheduling admissions and reducing variability in bed demand. AB - Variability in admissions and lengths of stay inherently leads to variability in bed occupancy. The aim of this paper is to analyse the impact of these sources of variability on the required amount of capacity and to determine admission quota for scheduled admissions to regulate the occupancy pattern. For the impact of variability on the required number of beds, we use a heavy-traffic limit theorem for the G/G/infinity queue yielding an intuitively appealing approximation in case the arrival process is not Poisson. Also, given a structural weekly admission pattern, we apply a time-dependent analysis to determine the mean offered load per day. This time-dependent analysis is combined with a Quadratic Programming model to determine the optimal number of elective admissions per day, such that an average desired daily occupancy is achieved. From the mathematical results, practical scenarios and guidelines are derived that can be used by hospital managers and support the method of quota scheduling. In practice, the results can be implemented by providing admission quota prescribing the target number of admissions for each patient group. PMID- 21667091 TI - Bacterial expression of mutant argininosuccinate lyase reveals imperfect correlation of in-vitro enzyme activity with clinical phenotype in argininosuccinic aciduria. AB - BACKGROUND: The urea cycle defect argininosuccinate lyase (ASL) deficiency has a large spectrum of presentations from highly severe to asymptomatic. Enzyme activity assays in red blood cells or fibroblasts, although diagnostic of the deficiency, fail to discriminate between severe, mild or asymptomatic cases. Mutation/phenotype correlation studies are needed to characterize the effects of individual mutations on the activity of the enzyme. METHODS: Bacterial in-vitro expression studies allowed the enzyme analysis of purified mutant ASL proteins p.I100T (c.299 T > C), p.V178M (c.532 G > A), p.E189G (c.566A > G), p.Q286R (c.857A > G), p.K315E (c.943A > G), p.R379C (c.1135 C > T) and p.R385C (c.1153 C > T) in comparison to the wildtype protein. RESULTS: In the bacterial in-vitro expression system, ASL wild-type protein was successfully expressed. The known classical p.Q286R, the novel classical p.K315E and the known mutations p.I100T, p.E189G and p.R385C, which all have been linked to a mild phenotype, showed no significant residual activity. There was some enzyme activity detected with the p.V178M (5 % of wild-type) and p.R379C (10 % of wild-type) mutations in which K(m) values for argininosuccinic acid differed significantly from the wild-type ASL protein. CONCLUSION: The bacterially expressed enzymes proved that the mutations found in patients and studied here indeed are detrimental. However, as in the case of red cell ASL activity assays, some mutations found in genetically homozygous patients with mild presentations resulted in virtual loss of enzyme activity in the bacterial system, suggesting a more protective environment for the mutant enzyme in the liver than in the heterologous expression system and/or in the highly dilute assays utilized here. PMID- 21667092 TI - Impaired regulation of calcium excretion in kidney transplant recipients. AB - Disorders of mineral metabolism and hypercalcemia are frequent in kidney transplant recipients. Calcium to creatinine (Ca/Cr) clearance ratio was used as a criterion to distinguish between different calcium metabolism disorders. The study comprised 91 (53 men, 38 women) kidney recipients aged 23-70 years, with creatinine clearance (CrCl) >60 ml/min. The following parameters related to mineral metabolism were measured in serum: iPTH, total alkaline phosphatase (tALP), telopeptide (bone degradation marker, CTX), 25(OH)D(3), total and ionized calcium, Ca(++), Pi, creatinine (Cr). Creatinine and Ca were also determined in urine, as well as Ca/Cr clearance ratio. According to the Ca/Cr clearance ratio, patients were divided into three groups as follows: <0.01 (found in disorders caused by reduced calcium-sensing receptor sensitivity, N = 30), 0.01-0.02 (normal value, N = 45), and >0.02 (found in hyperparathyroidism, N = 16). In the group of patients with Ca/Cr clearance ratio <0.01, seven patients had hypercalcemia, and four patients had hypercalcemia and elevated iPTH. It seems that impairment of renal calcium excretion may occur in kidney transplant recipients with good kidney function. Inappropriately low calciuria and impaired sensitivity of calcium-sensing receptor may be pathogenetic factors causing hypercalcemia in kidney transplant recipients. PMID- 21667093 TI - Characterization of Sulfolobus islandicus rod-shaped virus 2 gp19, a single strand specific endonuclease. AB - The hyperthermophilic Sulfolobus islandicus rod-shaped virus 2 (SIRV2) encodes a 25-kDa protein (SIRV2gp19) annotated as a hypothetical protein with sequence homology to the RecB nuclease superfamily. Even though SIRV2gp19 homologs are conserved throughout the rudivirus family and presumably play a role in the viral life cycle, SIRV2gp19 has not been functionally characterized. To define the minimal requirements for activity, SIRV2gp19 was purified and tested under varying conditions. SIRV2gp19 is a single-strand specific endonuclease that requires Mg(2+) for activity and is inactive on double-stranded DNA. A conserved aspartic acid in RecB nuclease superfamily Motif II (D89) is also essential for SIRV2gp19 activity and mutation to alanine (D89A) abolishes activity. Therefore, the SIRV2gp19 cleavage mechanism is similar to previously described RecB nucleases. Finally, SIRV2gp19 single-stranded DNA endonuclease activity could play a role in host chromosome degradation during SIRV2 lytic infection. PMID- 21667094 TI - Poly(3-hydroxybutyrate) influences biofilm formation and motility in the novel Antarctic species Pseudomonas extremaustralis under cold conditions. AB - Polyhydroxyalkanoates (PHAs) are highly reduced bacterial storage compounds that increase fitness in changing environments. It has previously shown that polyhydroxybutyrate (PHB) accumulation is essential during the growth under cold conditions. In this work, the relationship between PHB accumulation and biofilm development at low temperature was investigated. P. extremaustralis, an Antarctic strain able to accumulate PHB, and its phaC mutant, impaired in the synthesis of this polymer, were used to analyze microaerobic growth, biofilm development, EPS content and motility. PHB accumulation increased motility and survival of planktonic cells in the biofilms developed by P. extremaustralis under cold conditions. Microaerobic conditions rescued the cold growth defect of the mutant strain. The PHB accumulation capability could constitute an adaptative advantage for the colonization of new ecological niches in stressful environments. PMID- 21667096 TI - Electroanatomical mapping-assisted surgical treatment of incessant ventricular tachycardia associated with an intramyocardial giant lipoma. PMID- 21667095 TI - Resting-state brain networks: literature review and clinical applications. AB - This review focuses on resting-state functional connectivity, a functional MRI technique which allows the study of spontaneous brain activity generated under resting conditions. This approach is useful to explore the brain's functional organization and to examine if it is altered in neurological or psychiatric diseases. Resting-state functional connectivity has revealed a number of networks which are consistently found in healthy subjects and represent specific patterns of synchronous activity. In this review, we examine the behavioral, physiological and neurological evidences relevant to this coherent brain activity and, in particular, to each network. The investigation of functional connectivity appears promising from a clinical perspective, considering the amount of evidence regarding the importance of spontaneous activity and that resting-state paradigms are inherently simple to implement. We also discuss some examples of existing clinical applications, such as in Alzheimer's disease, and emerging possibilities such as in pre-operative mapping and disorders of consciousness. PMID- 21667097 TI - Characteristic changes of volume and three-dimensional structure of the left atrium in different forms of atrial fibrillation: predictive value after ablative treatment. AB - INTRODUCTION: Atrial fibrillation (AF) is associated with electroanatomical remodelling of the left atrium (LA), especially with LA dilatation. However, little is known about the changes of the three-dimensional structure of the LA, regarding the type of atrial fibrillation and their prognostic value after an ablative treatment. METHODS: One hundred fifteen patients (72 males, 59 +/- 11 years) with an indication for AF ablation were prospectively included. Preoperatively, all patients underwent cardiac computed tomography (CCT). A reconstruction of the LA and the pulmonary veins (PV) was made from CCT data using specialized software (EP PreNavigator, Philips, The Netherlands). Left atrial volume (LAV) after exclusion of the atrial appendage (LAA) and the PV was determined. The LA was then arbitrarily divided by a cutting plane, between the anterior segment of the PV ostia and the atrial appendage and parallel to the posterior wall, to anterior-(LA-Ant.) and posterior-LA (LA-Post.). The ratio LA Ant./LAV was defined as asymmetry index (ASI). The cardiac CT data, of 25 patients (11 women, 47 +/- 11 years) without organic heart disease, were similarly studied for the same parameters, as a control group. RESULTS: Patients with paroxysmal AF (n = 63) had significantly higher LAV (131 +/- 31 vs. 95 +/- 18 ml, p < 0.001) and higher ASI (61 +/- 6 % vs. 57 +/- 4, p = 0.002) than the control group. Patients with persistent AF (n = 34) in comparison with paroxysmal AF showed significantly larger volumes (154 +/- 44 vs. 131 +/- 31 ml, p = 0.007) but no difference in the ASI (60 +/- 8% vs. 61 +/- 6%, p = 0.63). Finally, patients with long-term persistent AF (n = 18) showed a bigger asymmetry index than the patients with persistent AF (64 +/- 5% vs. 60 +/- 8%, p = 0.06) but no significant difference in volumes (161 +/- 21 vs. 154 +/- 44 ml, p = 0.49). LAA and partial LA volumes had a dilatation pattern similar to LAV. During a follow up of over 25 +/- 7 months, AF recurred in 31 (27%) patients. Multivariate analysis showed that ASI and LAV were the only two significant predictors of AF recurrence after ablative treatment. Independent of LAV, an ASI over 60% predicted AF recurrence with 74% sensitivity and 73% specificity. CONCLUSION: Characteristic differences of both left atrial volume and geometry exist between the different forms of atrial fibrillation (paroxysmal, persistent and long-term persistent). The asymmetry index is a simple parameter derived by cardiac CT data that reflects these changes of LA geometry and predicts the outcome after the pulmonary vein isolation. PMID- 21667098 TI - Approaching a decade of cryo catheter ablation for type 1 atrial flutter-a meta analysis and systematic review. AB - PURPOSE: Despite increasingly widespread use of cryo catheter ablation (CCA) in clinical practice, current ACC/AHA/ESC guidelines for management of supraventricular arrhythmias cite only radiofrequency catheter ablation (RFCA) as first-line treatment for type 1 atrial flutter (AFL). We performed a meta analysis of efficacy and procedure outcomes from randomized controlled clinical trials comparing CCA with RFCA for type 1 AFL. A systematic review of non randomized, single-arm clinical studies of CCA for type 1 AFL was also done. METHODS: An English language search of Medline, Cochrane, Embase, and an extensive bibliography search from January 2000 to May 2010 was conducted. Inclusion/exclusion criteria were met by six randomized clinical trials for meta analysis (n = 341) and 13 non-randomized, single-arm clinical studies for systematic review (n = 763). Four primary outcomes were analyzed, namely, percent of patients with bidirectional conduction block (BCB) at procedure, proportion of patients who were asymptomatic during follow-up, procedure time, and fluoroscopy time. RESULTS: Random effect analyses for CCA versus RFCA favored the latter ablation modality for percent of patients with BCB at procedure (84.3% vs. 93.3%; OR = 0.51; p = 0.14). A similar proportion of patients were asymptomatic during follow-up (85.5% vs. 87.3%; OR = 0.68; p = 0.53). A significantly longer procedure time was determined for CCA (171.7 min vs. 134.5 min; Std diff means = 0.57; p < 0.001), but fluoroscopy time was similar for both (27.5 vs. 27.3 min; Std diff means = 0.12; p = 0.28). Sensitivity analyses revealed a shift in favor of CCA with large tip size catheters only versus RFCA for long-term effectiveness (OR = 1.5; p = 0.09). CONCLUSIONS: Results from this meta-analysis and systematic review do not generally favor one ablation modality over another for treatment of type 1 AFL. Indeed, there is higher percent BCB at procedure and shorter procedure time with RFCA. However, chronic success and fluoroscopy time were similar for both ablation modalities. Ultimately, investigator experience, catheter costs, and patient preference may sway device selection in clinical practice. PMID- 21667099 TI - Computerized disease profiling using GPS-linked multi-function sensor cartridges. AB - Disease identification in public health monitoring routinely employs analyte detection systems capable of discriminating mixtures of analytes, toxins, cells and/or bacteria in medical and/or environmental solutions. The development of smart sensors capable of discriminating such compounds has become increasingly important for clinical, environmental, and health applications. While some sensors have been fashioned for single analyte detection, methods and systems that facilitate rapid screening of multiple clinical components are needed, serving as triggers for potential epidemics or more specific confirmatory testing. In public health applications, there is like need for immediate collection of geocoded data tagged by disease identification characteristics, with corresponding alerting capabilities. In this technology review we propose one promising model for using a combination of emerging systems-based technologies in multi sensor cartridges, integrated with GPS-enabled, alert capable mobile phone devices. PMID- 21667100 TI - [Acute hepatic vascular complications]. AB - Acute hepatic vascular complications are rare. Acute portal vein thrombosis (PVT) and the Budd-Chiari syndrome (BSC) are the leading causes. Coagulopathy and local factors are present in up to 80% of cases. Diagnosis is established by colour coded Doppler sonography, contrast-enhanced computed tomography or magnetic resonance imaging. Patients with acute PVT present with abdominal pain and disturbed intestinal motility. In the absence of cirrhosis anticoagulation with heparin is established followed by oral anticoagulation. In severe cases, surgical thrombectomy or transjugular thrombolysis with stent shunt may be necessary. Acute or fulminant BCS may require emergency liver transplantation or a transjugular intrahepatic portosystemic stent shunt, if patients present with acute liver failure. Milder cases receive anticoagulation for thrombolysis of occluded hepatic veins. Sinusoidal obstruction syndrome (SOS) is diagnosed after total body irradiation or chemotherapy, the term SOS replacing the former veno occlusive disease. The treatment of congenital vascular malformations, complications in the setting of OLTX as well as patients with hepatic involvement of hereditary hemorrhagic telangiectasia requires significant expertise in a multidisciplinary approach. PMID- 21667101 TI - Preimplantation genetic diagnosis for alpha-and beta-double thalassemia. AB - PURPOSE: To evaluate the use of multiple displacement amplification (MDA) for preimplantation genetic diagnosis (PGD) of alpha- and beta-double thalassemia. METHOD: Whole genome of a single cell was directly amplified using MDA and its products were used as templates in fluorescent gap polymerase chain reaction (PCR) analysis of alpha-thalassemia and in PCR-reverse dot blot analysis, singleplex fluorescent PCR of beta-28 and CD17 mutation and HumTH01 for beta thalassemia. RESULTS: 1) MDA from single cell could produce enough DNA templates for the detection of both alpha and beta-thalassemia; 2) The established MDA-PGD protocol for alpha- and beta-double thalassemia was successfully applied in PGD of six embryos, among which, three were transferred, but no pregnancy ensued. CONCLUSIONS: The use of MDA as a universal step allows for the simultaneous diagnosis of two or more hereditary defects. PMID- 21667102 TI - Molecular characterization of the human ovulatory cascade-lesson from the IVF/IVM model. AB - AIMS: Ovarian follicular development and ovulation in mammals is a complex and highly regulated process. Most advances in the understanding of the ovulatory process have come from animal models. However, translational research in humans is of crucial importance for improving fertility treatment and control. METHODS: IVM/IVF procedures allow us to obtain follicular fluid and granulosa cells (GC) from follicles in different developmental stages with and without hCG priming. RESULTS: Using the cells and fluids obtained in IVM/IVF procedures allowed us to characterize human ovulatory gene expression during antral folliculogenesis and ovulation, examine gene expression in luteinized and non-luteinized GC in vivo and in vitro and to use cumulus GC genes as biomarkers for oocyte and embryo maturity and competence. CONCLUSION: Biological material obtained during IVM/IVF procedures is an important tool to study the human ovulatory cascade and can serve to improve IVM techniques and fertility treatment and control. PMID- 21667103 TI - Digital holographic microscopy in human sperm imaging. AB - PURPOSE: The aim of this study was to use digital holographic microscopy (DHM) in human sperm imaging and compare quantitative phase contrast of sperm heads in normozoospermia (NZ) and oligoasthenozoospermia (OAT). METHODS: DHM spermatozoa imaging and repeated quantitative phase shift evaluation were used. Five NZ and 5 OAT samples were examined. Semen samples were examined by semen analysis and processed for DHM. Main outcome measures were maximum phase shift value of the sperm heads. Differences of the phase shift and in NZ and OAT samples were statistically tested. RESULTS: In NZ samples median phase shifts were in the range 2.72-3.21 rad and 2.00-2.15 in OAT samples. Differences among individual samples were statistically significant (p < 0.001) in both groups. Median phase shift according to sperm count was 2.90 rad in NZ samples and 2.00 rad in OAT samples. This difference was statistically significant (p < 0.001). CONCLUSION: Quantitative evaluation of the phase shift by DHM could provide new information on the exact structure and composition of the sperm head. At present, this technique is not established for clinical utility. PMID- 21667104 TI - Polymorphisms of the bovine luteinizing hormone/choriogonadotropin receptor (LHCGR) gene and its association with superovulation traits. AB - The major limitation to the development of embryo transfer technique in cattle is the highly variable between individuals in ovulatory response to FSH-induced superovulation. The objective of this study was to identify a predictor to forecast superovulation response on the basis of associations between superovulation performance and gene polymorphism, variation in the bovine luteinizing hormone/choriogonadotropin receptor (LHCGR) gene was investigated using PCR-single-strand conformational (PCR-SSCP) and DNA sequencing. Four single nucleotide polymorphisms (SNPs) of G51656T, A51703G, A51726G and G51737A were identified at the intron 9 of the LHCGR gene in 171 Chinese Holstein cows treated for superovulation, and evaluated its associations with superovulatory response. Association analysis showed that these four SNPs had significant effects on the total number of ova (TNO) (P < 0.05). Moreover, the A51703G and A51726G polymorphisms significantly associated with the number of transferable embryos (NTE) (P < 0.05). In addition, significant additive effect on TNO was detected in polymorphisms of G51656T (P < 0.05) and A51703G (P < 0.01), and the A51703G polymorphism also had significant additive effects on NTE (P < 0.01). These results indicate that LHCGR gene is a potential marker for superovulation response and can be used to predict the most appropriate dose of FSH for superovulation in Chinese Holstein cows. PMID- 21667105 TI - Molecular characterization of Vigna radiata (L.) Wilczek genotypes based on nuclear ribosomal DNA and RAPD polymorphism. AB - Mungbean germplasm characterization, evaluation and improvement are fundamentally based on morpho-agronomic traits. The lack of break-through in mungbean production has been due to non-availability of genetic variability for high yield potential. Forty-four genotypes of mungbean [Vigna radiata (L.)Wilczek] were subjected to random amplified polymorphic DNA (RAPD) analysis to assess the genetic diversity and relationships among the genotypes. Multilocus genotyping by twelve RAPD primers generated 166 markers and detected an average of intraspecific variation amounting to 82% polymorphism in banding patterns. Dendrogram obtained from cluster analysis delineated all the 44 genotypes into six clusters. Higher values of Nei's gene diversity (h) and Shannon information index (i) and genetic distance analysis validate existence of wide genetic diversity among mungbean genotypes tested. Besides internal transcribed spacer (ITS) length variations, single nucleotide polymorphisms (SNPs) and insertions/deletions (INDELS) were detected at number of sites in nuclear rDNA region and the sequences of representatives of each sub-cluster and all distinct genotypes have been submitted to NCBI database and assigned Gen accession numbers HQ 148136-148147. Multiple sequence alignment revealed further lineages of distinct genotypes with main RAPD clusters. The measures of relative genetic distances among the genotypes of mungbean did not completely correlate the geographical places of their development. The homogeneous phenotypic markers proved insufficient in exhibiting genetic divergence among mungbean genotypes studied. RMG-62, RMG-976, and NDM-56 have been identified as potential source of parents for crop improvement. RAPD primers, OPA-9 and OPA-2 as polymorphic genetic markers and number of pods/plant and number of seeds/plant as dependable phenotypic markers have been identified for improving yield potentials. This genetic diversity will be of significance in developing intraspecific crosses in mungbean crop improvement programme. PMID- 21667106 TI - Molecular cloning and functional characterization of a putative sulfite oxidase (SO) ortholog from Nicotiana benthamiana. AB - Sulfite oxidase (SO) catalyzes the oxidation of sulfite to sulfate and thus has important roles in diverse metabolic processes. However, systematic molecular and functional investigations on the putative SO from tobacco (Nicotiana benthamiana) have hitherto not been reported. In this work, a full-length cDNA encoding putative sulfite oxidase from N. benthamiana (NbSO) was isolated. The deduced NbSO protein shares high homology and typical structural features with other species SOs. Phylogenetic analysis indicates that NbSO cDNA clone encodes a tobacco SO isoform. Southern blot analysis suggests that NbSO is a single-copy gene in the N. benthamiana genome. The NbSO transcript levels were higher in aerial tissues and were up-regulated in N. benthamiana during sulfite stress. Reducing the SO expression levels through virus-induced gene silencing caused a substantial accumulation in sulfite content and less sulfate accumulation in N. benthamiana leaves when exposed to sulfite stress, and thus resulted in decreased tolerance to sulfite stress. Taken together, this study improves our understanding on the molecular and functional properties of plant SO and provides genetic evidence on the involvement of SO in sulfite detoxification in a sulfite oxidizing manner in N. benthamiana plants. PMID- 21667107 TI - Diversification, phylogeny and evolution of auxin response factor (ARF) family: insights gained from analyzing maize ARF genes. AB - Auxin response factors (ARFs), member of the plant-specific B3 DNA binding superfamily, target specifically to auxin response elements (AuxREs) in promoters of primary auxin-responsive genes and heterodimerize with Aux/IAA proteins in auxin signaling transduction cascade. In previous research, we have isolated and characterized maize Aux/IAA genes in whole-genome scale. Here, we report the comprehensive analysis of ARF genes in maize. A total of 36 ARF genes were identified and validated from the B73 maize genome through an iterative strategy. Thirty-six maize ARF genes are distributed in all maize chromosomes except chromosome 7. Maize ARF genes expansion is mainly due to recent segmental duplications. Maize ARF proteins share one B3 DNA binding domain which consists of seven-stranded beta sheets and two short alpha helixes. Twelve maize ARFs with glutamine-rich middle regions could be as activators in modulating expression of auxin-responsive genes. Eleven maize ARF proteins are lack of homo- and heterodimerization domains. Putative cis-elements involved in phytohormones and light signaling responses, biotic and abiotic stress adaption locate in promoters of maize ARF genes. Expression patterns vary greatly between clades and sister pairs of maize ARF genes. The B3 DNA binding and auxin response factor domains of maize ARF proteins are primarily subjected to negative selection during selective sweep. The mixed selective forces drive the diversification and evolution of genomic regions outside of B3 and ARF domains. Additionally, the dicot-specific proliferation of ARF genes was detected. Comparative genomics analysis indicated that maize, sorghum and rice duplicate chromosomal blocks containing ARF homologs are highly syntenic. This study provides insights into the distribution, phylogeny and evolution of ARF gene family. PMID- 21667108 TI - Expression and stress tolerance of PR10 genes from Panax ginseng C. A. Meyer. AB - Pathogenesis-related 10 protein families (PgPR10 proteins) from ginseng are reported to have ribonuclease activity, conferring defense-related resistance against various stresses. Homology-based PCR using PgPR10-2 specific primers allowed for the isolation of two additional PgPR10 genes. PgPR10-1 is identical to the previously reported ribonuclease 1, while PgPR10-3 is a newly-discovered protein, suggesting that the PgPR10s are a multi-gene family. Differential organ specific transcripts of PgPR10-1 and PgPR10-2 in the flower bud and root, respectively, indicate that there are tissue-specific functional roles for this gene family. Overexpression of PgPR10-2 in Arabidopsis conferred longer root length and a tolerant growth phenotype on NaCl-supplemented media. Further changes in transcriptional levels against sets of abiotic stressors suggest similar functional roles of PgPR10-1 in the root and predominantly in the flower organ based on its higher expression levels. Overall, this suggests that the manipulation of PgPR10 genes in plants can be used as valuable tool to enhance its physiological status. PMID- 21667109 TI - Geographic patterns of histone H1 encoding genes allelic variation in Aegilops tauschii Coss. (Poaceae). AB - An electrophoretic analysis of histone H1 of Aegilops tauschii was carried out using the collection of 303 accessions (156 of ssp. tauschii and 147 of ssp. stangulata) representing all the species range. Three, four and six allelic variants were found for Hst1, Hst2 and Hst3 locus, respectively. The level of histone H1 allelic variability in ssp. strangulata was considerably higher than in ssp. tauschii. Expected heterozygosity (H(E)) for the loci Hst1, Hst2 and Hst3 made up 0.066, 0.484 and 0.224 respectively in ssp. strangulata vs. 0.024, 0.051 and 0.214 in ssp. tauschii. Besides the most common haplotype, Hst1 (1000), Hst2 (1000), Hst3 (1000), five other haplotypes with frequencies of occurrence higher than 0.02 were found in ssp. strangulata, and only one such haplotype--in ssp. tauschii. The most part of histone H1 variation in ssp. tauschii was in the western part of the area. In ssp. strangulata, the alleles Hst2 (988) and Hst2 (973) were found only in Caucasia, and the allele Hst1 (1043)--only in Precaspian Iran and south-eastern Azerbaijan. Histone H1 variation patterns in Ae. tauschii are very similar to those of non-coding sequences of chloroplast DNA. Therefore, histone H1 allelic variation in this species seems to be mostly neutral. Nevertheless, the evidences were pointed out, revealing that some part of variation at Hst2 locus in ssp. strangulata could be adaptive. It seems that Hst2 (1026) allele is disadvantageous in western Precaspian Iran, the region with the high annual rainfall, and being eliminated by natural selection. PMID- 21667110 TI - A potato pathogenesis-related protein gene, StPRp27, contributes to race nonspecific resistance against Phytophthora infestans. AB - Late blight caused by Phytophthora infestans is the most important disease of potato. Many efforts have been made to understand molecular mechanism of the durable resistance to address the challenge raised by rapid evolution of the pathogen. A pathogenesis related protein (PR) gene StPRp27 was previously isolated from the potato leaves challenged by P. infestans. The sequence analysis and expression pattern reveal that StPRp27 may be associated with resistance to P. infestans. In present research, transient expression of StPRp27 in Nicotiana benthamiana enhanced resistance to P. infestans isolates 99189 and PY23 indicating its potential contribution to the disease resistance. These findings were also confirmed by over-expression of StPRp27 in potato cv. E-potato 3, which significantly slowed down the development of the disease after inoculation with a mixture of P. infestans races. Further, silencing of StPRp27 homologous genes in N. benthamiana harboring dominant Phytophthora resistance gene Rpi-blb1 or Rpi blb2 showed no effects on the resistance triggered by these R genes. Our results suggest that StPRp27 contributes to a race-nonspecific resistance against P. infestans by inhibiting the disease development and has a potential use in selection and breeding for durable resistance to late blight. PMID- 21667111 TI - RCCS enhances EOE cell proliferation and their differentiation into ameloblasts. AB - In this article we report on the culturing of dental enamel organ epithelia (EOE) using a rotary cell culture system (RCCS) bioreactor associated with a cytodex-3 microcarrier. This culture system enhanced the proliferation and differentiation of the EOE into ameloblasts. Primary dental EOE trypsinized from 4-day old post natal rat pups were cultured in the RCCS associated with Cytodex-3. The results were analyzed in comparison to a conventional plate system (control). Cells grown in RCCS have shown higher viabilities (above 90%) and final cell densities in terms of cells/ml than in the control system. In the case of RCCS, 46+/-2 manifold increases were obtained, while significantly lower yields of 10.8+/-2.5 manifod were obtained for control plates. Throughout the experiments, glucose levels were maintained within the accepted physiological range. In this case, LDH levels are kept low (below 150 mmol/ml), which is in accordance with the low cell death observed in the RCCS. Scanning electron microscopy revealed cells that were spread and forming three dimensional aggregates on the surface of cytodex-3. Cells cultured in the RCCS exhibited a stronger positive immunofluorescence staining for ameloblastin than those in control plates. RT-PCR results revealed that cells cultured in RCCS have higher amelogenin mRNA levels compared to controls. We have done an exploratory study on biological characteristics and self-assembling of epithelium cellula intersitialis, which demonstrated that the special 3D environment enhanced the rat dental EOE cell proliferation and differentiation into ameloblasts. The study has revealed that RCCS could be used to study the reaction of the EOE cells, tooth enamel organ cells and mesenchymal cells under the spacial 3D culture system, which will also provide a novel hypothesis for dental regeneration. PMID- 21667112 TI - XPD Lys751Gln polymorphism and esophageal cancer susceptibility: a meta-analysis of case-control studies. AB - The published data on the association between xeroderma pigmentosum group D (XPD) Lys751Gln polymorphism and esophageal cancer (EC) remained controversial. The present meta-analysis of literatures was performed to derive a more precise estimation of the relationship. A comprehensive literature search was conducted to identify all case-control studies of Lys751Gln polymorphism and risk for two main types of EC: esophageal adenocarcinoma (EADC) and esophageal squamous cell carcinoma (ESCC). A total of 12 studies were identified to the meta-analysis, including 2,575 cases (1,294 ESCC and 1,281 EADC) and 4,951 controls (1,891 ESCC and 3,060 EADC). Random-effects or fix-effects model was used according to between-study heterogeneity. The odds ratio (OR) for the variant homozygous genotype Gln/Gln of the Lys751Gln polymorphism, compared with the wild type homozygote Lys/Lys, was 1.26, with 95% confidence interval (95% CI) 1.02-1.56, for EADC risk without between-study heterogeneity. When stratified by ethnicity, statistically significantly elevated risk was found among Chinese (Gln/Gln vs. Lys/Lys: OR 2.45, 95% CI = 1.10-5.44). However, no significant associations were found between XPD Lys751Gln polymorphism and EC risk when all studies pooled into the meta-analysis (Lys/Gln vs. Lys/Lys: OR 1.07, 95% CI = 0.88-1.28; Gln/Gln vs.us Lys/Lys: OR 1.25, 95% CI = 0.92-1.71; dominant model: OR 1.09, 95% CI = 0.90-1.33). In conclusion, this meta-analysis suggests that the Lys751Gln genetic polymorphism may be a potential biomarker of EC susceptibility in Chinese populations. And a study with the larger sample size is needed to further evaluate gene-environment interaction on XPD Lys751Gln polymorphism and EC risk. PMID- 21667113 TI - Harvest-inducibility of the promoter of alfalfa S-adenosyl-L-methionine: trans caffeoyl-CoA3-O-methyltransferase gene. AB - A major limitation on the expression of some foreign proteins in transgenic plants is the toxic effect of such proteins on the host plant resulting in inhibition of normal growth and development. A solution to this problem is to control the expression of genes for such proteins by means of inducible promoters, as is frequently done in microbial systems. A cDNA clone was obtained from subtractive hybridization of non-harvested and harvested alfalfa leaf tissue, named hi12. The hi12 cDNA was identified as part of the S-adenosyl-L methionine: trans-caffeoyl-CoA3-O-methyltransferase gene of alfalfa, a gene encoding an essential key enzyme in lignin synthesis. The hi12 gene was strongly induced by harvesting and wounding but not by heat shock. The promoter of the hi12 gene, isolated by genomic walking, contained several stress response cis elements. Transgenic plants of tobacco and Medicago truncatula containing the GUS gene driven by the promoter showed GUS expression following harvesting, demonstrating the activity of these regulatory regions in other plant species. PMID- 21667115 TI - [Pathology of the lower gastrointestinal tract]. PMID- 21667114 TI - [Tropheryma whipplei infection. Colonization, self-limiting infection and Whipple's disease]. AB - Whipple's disease is a multisystemic infection caused by the ubiquitous bacterium Tropheryma whipplei. Immunological host factors enable classical Whipple's disease; however, T. whipplei can be found in three other clinical conditions: healthy colonization, self-limiting infections, and isolated endocarditis. The genetic predisposition of the host rather than the genotype of the bacterium influences the infection. Modern diagnostic methods elucidate the many facets of Whipple's disease. In particular, isolated T. whipplei-induced infective endocarditis can only be diagnosed after valve resection. The sole treatment of Whipple's disease evaluated prospectively comprises intravenous induction therapy with ceftriaxone or meropenem, followed by continuation therapy with oral TMP SMX. In the case of Immune reconstitution inflammatory syndrome (IRIS) or inflammatory lesions of the CNS in the setting of Whipple's disease, additional treatment with corticosteroids should be considered to avoid severe tissue damage. PMID- 21667116 TI - Diagnosis and outcome of neutropenic enterocolitis: experience in a single tertiary pediatric surgical center in China. AB - BACKGROUND/PURPOSE: Neutropenic enterocolitis (NE) is clinically defined by the triad of neutropenia, abdominal pain and fever. This retrospective study is to review 24 cases of NE in a single Chinese tertiary center, to elucidate clinical feature, treatments and outcome for this dangerous gastrointestinal complication of neutropenia. PATIENTS AND METHODS: The medical records of pediatric patients who were diagnosed with neutropenic enterocolitis from 2000 to 2009 were reviewed. RESULTS: Of 24 cases, the ratio of male to female was 2:1, the mean age was 7.2 years. There were eight cases of acute lymphocytic leukemia, eight cases of acute non-lymphocytic leukemia, four cases of non-Hodgkin's lymphoma, one case of severe aplastic anemia, one case of neuroblastoma and two cases of simple neutropenia without underlying cause. The hematologic malignancy was significantly associated with the occurrence of NE (OR = 19.4). Seventeen cases developed NE during anticancer chemotherapy (chemo group), four cases presented with leukemia and one case presented with aplastic anemia before the initiation of chemotherapy and their presenting event leading to diagnosis. Two cases simply presented with NE without definitive reasons (no chemo group). All the patients had the typical clinical presentation, six cases had disseminated peritonitis, toxic shock, and assisted ventilations were necessary in three of these six cases. CT or ultrasound demonstrated bowel wall thickness, paucity of air in the cecum and/or right colon, pneumatosis or pneumoperitoneum. There was no difference in the nadir neutrophil count in patients, who received chemotherapy versus those who did not (P = 0.001), but the recovering time from NE in chemo group (9.3 +/- 1.9) was shorter than non-chemo group (10.7 +/- 5.3, P = 0.034). Sixteen (88.8%) cases have been successfully managed medically, using aggressive hemodynamic support, bowel rest, and broad-spectrum antibiotic therapy with surgical intervention reversed only for the more severe six cases (25%). Two cases died. CONCLUSION: NE is a life-threatening gastrointestinal complication of neutropenia. Physicians might remain vigilant and consider NE in any neutropenic patient rather than only in oncologic patients. It has typical clinical presentation and CT can provide clear delineation for diagnosis. Early recognition and progressed management have reduced mortality. Most children with NE may be treated without surgery with favorable outcome. PMID- 21667117 TI - MMP-2 expression in 102 patients with glottic laryngeal cancer. AB - In order to evaluate the potential of matrix metalloproteinase 2 (MMP-2) as a prognostic factor for glottic laryngeal cancer. One hundred and two surgical specimens from patients with glottic laryngeal cancer who underwent laryngectomy for their disease in the University Hospital of Patras, Greece from 1998 to 2005 were reviewed retrospectively regarding MMP-2 expression via immunohistochemistry. Immunostaining was performed using a streptavidin-biotin peroxidase complex technique (LSAB). Results revealed that 54 of 102 patients (52.9%) had positive cytoplasmic staining for MMP-2. Kaplan-Meier analysis demonstrated statistically significant difference (p = 0.037) for the 5-year overall survival rate between the groups with positive and negative MMP-2 expression, and marginal statistical significance for the disease free survival rate (p = 0.048). The capsule rupture of metastatic lymph nodes and MMP-2 expression in primary tumor site also seems to be related (p = 0.047). Statistical significance could not be established between MMP-2 expression and the clinicopathological features of the disease (T stage, N stage, clinical stage, differentiation). In conclusion, MMP-2 expression was related with worse overall and disease-free survival and could be considered as a potential marker of poor prognosis. PMID- 21667118 TI - Ascorbic acid increases the activity and synthesis of tyrosinase in B16F10 cells through activation of p38 mitogen-activated protein kinase. AB - Ascorbic acid, a potential antioxidant, is known to inhibit melanogenesis. However, there are conflicting findings that ascorbic acid has very low stability and acts as a pro-oxidant, eventually increasing proliferation and melanin content in melanoma cells. In the present study, we explored the effects of ascorbic acid on the activity and expression of tyrosinase and melanin pigmentation in the presence and absence of alpha-melanocyte-stimulating hormone (alpha-MSH) using B16F10 melanoma cells. The mechanism by which ascorbic acid stimulated the expression of tyrosinase was also investigated. No inhibitory effect on melanin content was observed in ascorbic acid-treated cells, regardless of the presence of alpha-MSH. Ascorbic acid stimulated the activity and expression of tyrosinase and increased the expression of melanogenic regulatory factors, such as tyrosinase-related protein-1 (TRP-1), dihydroxyphenylalaminechrome tautomerase (TRP-2), and microphthalmia-associated transcription factor (MITF). Ascorbic acid also induced phosphorylation of p38 mitogen-activated protein kinase (MAPK). The inhibition of p38 MAPK pathway by SB203580 led to the suppression of tyrosinase, TRP-1, and TRP-2 expression in cells treated with ascorbic acid. Combined treatment with N-acetyl-L: -cysteine and/or desferrioxamine mesylate attenuated the stimulating effect of ascorbic acid on tyrosinase activation in the cells. Collectively, ascorbic acid stimulates tyrosinase activity and expression in B16F10 cells via activation of p38 MAPK signaling and subsequent up-regulation of MITF, tyrosinase, and TRP expression. PMID- 21667119 TI - Clinical retrospective analysis of erlotinib in the treatment of elderly patients with advanced non-small cell lung cancer. AB - In order to evaluate the clinical efficacy and the safety profile of molecularly targeted therapies as a palliative approach in elderly populations affected by advanced thoracic neoplasms, we retrospectively studied, in terms of effectiveness and toxicities, a group of pretreated elderly metastatic non-small cell lung cancer (NSCLC) patients admitted to our institution and treated with erlotinib at standard daily/dose. Forty-three patients aged 70 years or older who had previously failed on chemotherapy or radiotherapy were treated with oral Eerlotinib (150 mg/d) until disease progression or unacceptable toxicity. Clinical data, pathological types, potential prognostic factors, efficacy and toxicity of erlotinib were included in this analysis. In our series we observed: objective responses in six patients (14%) and stable disease in 15 (35%). Skin rash was the most common side effect (67%). Grade 3-4 adverse events were observed in 16 cases (37%). The median overall survival and the median progression-free survival were 8.4 months (CI 95%: 0.7-43.6) and 3 months (CI 95%: 0.4-28.4), respectively. Patients with adenocarcinoma achieved the best disease control rate (p = 0.027), while not/former smokers showed a better response (p = 0.069). In our experience the use of erlotinib after chemotherapy failure in an unselected elderly population affected by NSCLC showed moderate efficacy and a moderate safety profile. However, erlotinib represents a valid option in this setting, but other factors such as biological information, comorbidities and concomitant medications need to be carefully take into consideration in this particular subset of cancer patients. PMID- 21667120 TI - A prognostic model for lymph node-negative breast cancer patients based on the integration of proliferation and immunity. AB - A model for a more precise prognosis of the risk of relapse is needed to avoid overtreatment of lymph node-negative breast cancer patients. A large derivation data set (n = 684) was generated by pooling three independent breast cancer expression microarray data sets. Two major prognostic factors, proliferation and immune response, were identified among genes showing significant differential expression levels between the good outcome and poor outcome groups. For each factor, four proliferation-related genes (p-genes) and four immunity-related genes (i-genes) were selected as prognostic genes, and a prognostic model for lymph node-negative breast cancer patients was developed using a parametric survival analysis based on the lognormal distribution. The p-genes showed a predominantly negative correlation (coefficient: -0.603) with survival time, while the i-genes showed a positive correlation (coefficient: 0.243), reflecting the beneficial effect of the immune response against deleterious proliferative activity. The prognostic model shows that approximately 54% of lymph node negative breast cancer patients were predicted to be distant metastasis-free for more than 5 years with at least 85% survival probability. The prognostic model showed a robust and high prognostic performance (HR 2.85-3.45) through three external validation data sets. Based on the integration of proliferation and immunity, the new prognostic model is expected to improve clinical decision making by providing easily interpretable survival probabilities at any time point and functional causality of the predicted prognosis with respect to proliferation and immune response. PMID- 21667121 TI - Risk factors by molecular subtypes of breast cancer across a population-based study of women 56 years or younger. AB - Differences in incidence, prognosis, and treatment response suggest gene expression patterns may discern breast cancer subtypes with unique risk factor profiles; however, previous results were based predominantly on older women. In this study, we examined similar relationships in women <= 56 years, classified by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 for 890 breast cancer cases and 3,432 frequency-matched population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) for tumor subtypes were calculated using multivariate polytomous regression models. A total of 455 (51.1%) tumors were considered luminal A, 72 (8.1%) luminal B, 117 (13.1%) non-luminal HER-2/neu+, and 246 (27.6%) triple negative. Triple negative tumors were associated with breast feeding duration (per 6 months: OR = 0.76, 95% CI 0.64-0.90). Among premenopausal women, increasing body size was more strongly associated with luminal B (OR = 1.73, 95% CI 1.07-2.77) and triple negative tumors (OR = 1.67, 95% CI 1.22-2.28). A history of benign breast disease was associated only with increased risk of luminal A tumors (OR = 1.89, 95% CI 1.43-2.50). A family history of breast cancer was a risk factor for luminal A tumors (OR = 1.93, 95% CI 1.38-2.70) regardless of age, and triple negative tumors with higher risks for women <45 (OR = 5.02, 95% CI 2.82-8.92; P for age interaction = 0.005). We found that little-to-no breastfeeding and high BMI were associated with increased risk of triple negative breast cancer. That some risk factors differ by molecular subtypes suggests etiologic heterogeneity in breast carcinogenesis among young women. PMID- 21667122 TI - Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups. AB - The tumor suppressor gene TP53 and its regulator MDM2 are both important players in the DNA-damage repair "TP53 response pathway". Common germline polymorphisms in these genes may affect outcome in patients with tumors characterized by additional somatic changes in the same or a related pathway. To evaluate this hypothesis, we determined the effect of the common germline TP53 R72P and MDM2 SNP309 polymorphisms on breast cancer survival in a consecutive cohort of breast cancer patients (age at diagnosis <53 years, n = 295) with gene expression data available. Patients were classified in subgroups according to their tumor TP53 mutation status and three gene expression profiles; a TP53 mutation status expression signature, a PTEN/PI3K pathway signature and the 70-gene prognosis profile. Survival analyses were performed using Cox regression models adjusting for clinico-pathological characteristics and treatment. An increase in breast cancer-specific mortality was observed for carriers of the germline MDM2 SNP309 rare GG-genotype (range hazard ratios: 2-3) or TP53 R72P heterozygous GC-genotype (range hazard ratios: 1-2) compared to those having the common genotypes within subgroups of tumors displaying a "more aggressive phenotype" gene expression profile. There was no evidence of such an effect on survival within the TP53 mutated tumor group for TP53 R72P carriers but a suggestion of an effect for MDM2 SNP309 carriers (GG vs. TT-genotype HR 2.99, P = 0.06). These results indicate that common polymorphisms in specific pathways may add to the worse prognosis of patients with tumors in which these pathways are affected by somatic alterations. PMID- 21667123 TI - ER, HER2, and TOP2A expression in primary tumor, synchronous axillary nodes, and asynchronous metastases in breast cancer. AB - At recurrence of breast cancer, the therapeutic target is the metastases. However, it is current practice to base the choice of systemic treatment on the biomarker profile of the primary tumor. In the present study, confirmatory biopsies were obtained from suspected metastatic lesions and compared with the primary tumors with respect to ER, HER2, and TOP2A. In the prospective tissue collection study, 81 patients had biopsy from a suspected relapse. Additional archived paired material was included, leaving a total of 119 patients with paired primary tumor, synchronous axillary nodes (available in 52 patients) and asyncronous metastases available for analysis. ER, HER2, and TOP2A expression of primary tumors, axillary nodes and metastases were re-analysed and determined centrally by immunohistochemistry, chromogenic in situ hybridization, and fluorescence in situ hybridization. Of the 81 patients with a biopsy from a suspected relapse, 65 (80%) were diagnosed with recurrent breast carcinoma, 3 (4%) were diagnosed with other malignancies, 6 (7%) had benign conditions, and in 7 (9%) patients the biopsy was non-representative. Discordance in ER, HER2, and TOP2A (aberration vs. normal) status between primary tumor and corresponding asynchronous metastasis was 12% (14/118), 9% (10/114), and 23% (17/75), respectively. There were no significant associations with biomarker discordance and prior adjuvant therapy, or location of biopsy. Expression of ER, HER2, and TOP2A displayed discordance with a sufficient frequency to emphasize the role of confirmatory biopsies from metastatic lesions in future management of recurrent breast cancer. PMID- 21667124 TI - Ectopic posterior pituitary and stalk abnormality predicts severity and coexisting hormone deficiencies in patients with congenital growth hormone deficiency. AB - Certain pituitary imaging abnormalities are a specific indicator of hypopituitarism. The objective of this study is to compare phenotypical features with radiological findings in patients with congenital growth hormone deficiency (GHD). Magnetic Resonance imaging (MRI) was performed in 103 patients [72 with Isolated GHD (IGHD) and 31 with Combined Pituitary Hormone Deficiency (CPHD)]. Images were assessed for the following abnormalities: (1) small/absent anterior pituitary, (2) thin or interrupted pituitary stalk (PSA), and (3) Ectopic posterior pituitary (EPP), and (4) others. Radiological findings were correlated with the clinical and biochemical parameters. MRI abnormalities were observed in 48.6% patients with IGHD, 93.5% with CPHD. Jaundice, hypoxia, hypoglycemia and breech deliveries were more common in EPP/PSA group. EPP/PSA was observed in 87.1% patients with severe GHD (peak GH < 3 MUg/L) as compared to 12.9% with mild to moderate GHD (peak GH: 3-10 MUg/L). Amongst CPHD, EPP/PSA was present in 80% of subjects with associated hypocortisolism +/- hypothyroidism as compared to 18.2% of subjects with hypogonadism. Over a mean follow up period of 4.5 years, 5.4% of subjects with IGHD and abnormal MRI progressed to CPHD while none of those with normal MRI progressed. This study emphasizes a significant clinico radiological correlation in Asian Indian GHD patients. MRI abnormalities in the hypothalamic pituitary area, especially EPP/PSA are more common in patients with CPHD and severe GHD. Among CPHD, EPP/PSA predicts association with hypothyroidism or hypocortisolism. IGHD with MRI abnormality may evolve into CPHD. PMID- 21667125 TI - Drug utilisation pattern and off-label use of medicines in Estonian neonatal units. AB - OBJECTIVES: To characterise neonatal hospital drug use and to compare the availability of drug information between Estonian Summaries of Product Characteristics (SPCs) and other sources. STUDY DESIGN: This was a prospective cohort study in which pharmacotherapy information on neonates admitted to Tartu University Clinics between 1 February and 1 August 2008 and to Tallinn Children's Hospital between 1 February and 1 August 2009 was collected. Drug labelling status was determined according to Estonian SPCs, and neonatal information was compared with the British National Formulary for Children (BNFC) and the Thomson Micromedex database. RESULTS: Of 490 hospitalised neonates, 71% received pharmacotherapy. Within the entire study period, there were 1981 prescriptions for 115 products, with a median of four (interquartile range 2-7) products per child. Antibacterial, cardiovascular and central nervous system drugs were the most commonly prescribed. All treated preterm neonates received at least one unlicensed or age-related off-label prescription. All prescriptions for alimentary, genitourinary, musculoskeletal and sensory system drugs were off label. There were large differences in the neonatal information provided by the different sources, with the largest differences found for term neonates, for whom the information was available for 67, 38 and 24% of prescriptions according to the BNFC, Micromedex and Estonian SPC, respectively. CONCLUSIONS: The high rate of age-related off-label prescribing for neonates calls for urgent action from medical professionals and others to reinforce effective and safe pharmacotherapy for this age group. The existing SPCs should be regularly updated and more closely harmonised to each other. PMID- 21667126 TI - Molecular characterization of Tobacco leaf curl Pusa virus, a new monopartite Begomovirus associated with tobacco leaf curl disease in India. AB - Leaf curl disease of tobacco (TbLCD) is endemic in India. A monopartite Begomovirus, a betasatellite and an alphasatellite were found associated with the disease in Pusa, Bihar. The DNA-A of the Begomovirus associated with TbLCD in Pusa, Bihar was found to comprise of 2707 nt with a typical Old World begomovirus like genome organization. The full-length sequence of DNA-A [HQ180391] showed that the Pusa isolate is a newly described member of the genus Begomovirus, as it had <89% sequence homology with DNA-A of all the known begomoviruses. The isolate is tentatively named as Tobacco leaf curl Pusa virus [India:Pusa:2010]. The betasatellite (HQ180395) associated with TbLCD in Pusa was identified as a variant of Tomato leaf curl Bangladesh betasatellite [IN:Raj:03], with which it shared 90.4% sequence identity. The alphasatellite (HQ180392) associated with the disease had highest 87% nucleotide sequence identity with Tomato leaf curl alphasatellite. The Begomovirus, betasatellite, and alphasatellite associated with TbLCD in Pusa, Bihar, India were found to be recombinants of extant begomoviruses, betasatellites and alphasatellites spreading in the Indian sub continent and South-East Asia. PMID- 21667127 TI - Vygotsky circle as a personal network of scholars: restoring connections between people and ideas. AB - The name of Lev Vygotsky (1896-1934) is well-known among contemporary psychologists and educators. The cult of Vygotsky, also known as "Vygotsky boom", is probably conducive to continuous reinterpretation and wide dissemination of his ideas, but hardly beneficial for their understanding as an integrative theory of human cultural and biosocial development. Two problems are particularly notable. These are, first, numerous gaps and age-old biases and misconceptions in the historiography of Soviet psychology, and, second, the tendency to overly focus on the figure of Vygotsky to the neglect of the scientific activities of a number of other protagonists of the history of cultural-historical psychology. This study addresses these two problems and reconstructs the history and group dynamics within the dense network of Vygotsky's collaborators and associates, and overviews their research, which is instrumental in understanding Vygotsky's integrative theory in its entirety as a complex of interdependent ideas, methods, and practices. PMID- 21667128 TI - Mouse models of diseases of megakaryocyte and platelet homeostasis. AB - Platelets are the small anuclear blood cells that are the product of megakaryocytopoiesis, the process of hematopoietic stem cell commitment to megakaryocyte production and the differentiation and maturation of these cells for platelet release. Deregulation or disruption of megakaryocytopoiesis can result in platelet deficiencies, the thrombocytopenias, with attendant risk of hemorrhage or thrombocytosis, a pathological excess of platelet numbers. Mouse models, particularly those engineered to carry genetic alterations modeling mutations associated with human disease, have provided important insights into megakaryocytopoiesis and deregulation of this process in disease. This review focuses on mouse models of diseases of altered megakaryocyte and platelet number, illustrating the profound contribution of these models in validating suspected roles of disease-associated genetic alterations, promoting discovery of new links between genetic mutations and specific diseases, and providing unique tools for better understanding of disease pathophysiology and progression, as well as resources to define drug action or develop new therapeutic strategies. PMID- 21667130 TI - Effectiveness of interspinous implant surgery in patients with intermittent neurogenic claudication: a systematic review and meta-analysis. AB - INTRODUCTION: Despite an increasing implantation rate of interspinous process distraction (IPD) devices in the treatment of intermittent neurogenic claudication (INC), definitive evidence on the clinical effectiveness of implants is lacking. The main objective of this review was to perform a meta-analysis of all systematic reviews, randomized clinical trials and prospective cohort series to quantify the effectiveness of IPDs and to evaluate the potential side-effects. METHODS: Data from all studies prospectively describing clinical results based on validated outcome scales and reporting complications of treatment of patients with INC with IPD placement. We searched MEDLINE, EMBASE, Web of Science, Cochrane (CENTRAL), CINAHL, Academic Search Premier, Science Direct up to July 2010. Studies describing patients with INC caused by lumbar stenosis, reporting complication rate and reporting based on validated outcome scores, were eligible. Studies with only instrumented IPD results were excluded. RESULTS: Eleven studies eligible studies were identified. Two independently RCTs and eight prospective cohorts were available. In total 563 patients were treated with IPDs. All studies showed improvement in validated outcome scores after 6 weeks and 1 year. Pooled data based on the Zurich Claudication Questionnaire of the RCTs were more in favor of IPD treatment compared with conservative treatment (pooled estimate 23.2, SD 18.5-27.8). Statistical heterogeneity after pooled data was low (I squared 0.0, p = 0.930). Overall complication rate was 7%. CONCLUSION: As the evidence is relatively low and the costs are high, more thorough (cost-) effectiveness studies should be performed before worldwide implementation is introduced. PMID- 21667131 TI - Rapid progression of spinal epidural lipomatosis. AB - Spinal epidural lipomatosis (SEL) is a rare but well-recognized condition. In general, the onset of its symptoms is insidious and the disease progresses slowly. We report two cases of rapid progression of SEL with no history of steroid intake in non-obese individuals after epidural steroid injection. These SEL patients developed neurologic symptoms after less than 5 months; these symptoms were confirmed to be due to SEL by serial MR images. After the debulking of the epidural fat, their symptoms improved. PMID- 21667129 TI - The mouse notches up another success: understanding the causes of human vertebral malformation. AB - The defining characteristic of all vertebrates is a spine composed of a regular sequence of vertebrae. In humans, congenital spinal defects occur with an incidence of 0.5-1 per 1,000 live births and arise when the formation of vertebral precursors in the embryo is disrupted. These precursors (somites) form in a process (somitogenesis) in which each somite is progressively separated from an unsegmented precursor tissue. In the past decade the underlying genetic mechanisms driving this complex process have been dissected using animal models, revealing that it requires the coordinated action of at least 300 genes. Deletion of many of these genes in the mouse produces phenotypes with similar vertebral defects to those observed in human congenital abnormalities. This review highlights the role that such mouse models have played in the identification of the genetic causes of the malsegmentation syndrome spondylocostal dysostosis. PMID- 21667132 TI - Single-port access laparoscopic abdominoperineal resection through the colostomy site: a case report. AB - Single-port access (SPA) laparoscopic surgery is emerging as an alternative to conventional laparoscopic and open surgery, although its benefits still have to be determined. We present the case of a 87-year-old woman who underwent abdominoperineal resection (APR) with SPA. The abdominal part of the operation was performed with a SILS port inserted through the marked colostomy site, and the specimen was removed through the perineum after intersphincteric dissection. Operating time was 317 min. Bleeding was negligible. The specimen measured 26 cm in length. Thirteen lymph nodes were found, 2 with metastasis. The patient recovered bowel function on the first postoperative day, was discharged on the 7th day and immediately resumed her to normal activities. Laparoscopic APR through SPA can be an alternative option for selected patients but requires advanced laparoscopic skills. PMID- 21667133 TI - Multicenter study of the long-term outcomes of endoscopic submucosal dissection for early gastric cancer in patients 80 years of age or older. AB - BACKGROUND: Little information is available on the long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in patients of advanced age (>=80 years). METHODS: A multicenter study was conducted at 10 Japanese institutions concerning their results for ESD. Data on 440 patients of advanced age (>=80 years) with EGC (470 lesions) were collected and reviewed. Early and long-term outcomes of ESD were assessed. We compared the overall survival rates between 3 patient groups, those with curative ESD, additional surgery after noncurative ESD, and nonsurgical follow-up after noncurative ESD. RESULTS: Bleeding and perforation rates were 3.2 and 2.8%, respectively. Curative ESD was achieved in 366 of the 470 lesions (77.9%). Of the 104 patients with noncurative ESD, 12 patients (11.5%) underwent additional surgery and 91 patients (87.5%) were followed without surgery. The 5-year survival rate in the patients with nonsurgical follow-up after noncurative ESD (66.7%) was significantly lower than that in the patients with curative ESD (80.3%, p = 0.0001). There was no significant difference in the 5-year survival rates between the patients with curative ESD and those with surgery after noncurative ESD (100%, p = 0.21), nor was there a difference in these rates between the patients with surgery after noncurative ESD and those with nonsurgical follow-up after noncurative ESD (p = 0.061). None of the patients developed cancer recurrence after curative ESD, and none developed cancer recurrence following the additional surgery after noncurative ESD. In the patients with curative ESD and in those with surgery after noncurative ESD, the cumulative observed survival was better than the expected survival for the general population of similar age and gender. CONCLUSIONS: ESD is safe for the treatment of EGC in patients 80 years of age or older. Both curative ESD and additional surgery after noncurative ESD may contribute to the extension of life expectancy. PMID- 21667134 TI - Phase II trial of combined treatment consisting of preoperative S-1 plus cisplatin followed by gastrectomy and postoperative S-1 for stage IV gastric cancer. AB - BACKGROUND: To improve the poor prognosis in patients with stage IV (StIV) gastric cancer (GC), we conducted a multicenter phase II study of preoperative S 1 plus cisplatin followed by gastrectomy and postoperative S-1 for StIV GC (the protocol is registered at the clinical trial site of the National Cancer Institute; KYUH-UHA-GC03-01, NCT00088816). METHODS: Eligibility criteria included histologically proven StIVGC. Patients received S-1 (80 mg/m(2)/day, days 1-21) plus cisplatin (60 mg/m(2) on day 8) for 2 courses. After preoperative chemotherapy (CTx), radical gastrectomy was performed. Postoperative S-1 (80 mg/m(2)/day, days 1-14) was administered every 3 weeks for 1 year. RESULTS: Fifty one patients were enrolled and all patients were followed for more than 2 years. The 2-year overall survival and progression-free survival rates were 43.1% (95% confidence interval [CI] 29.4-56.1%) and 33.3% (95% CI 20.9-46.2%), respectively. Preoperative chemotherapy was accomplished in 44 patients (86.3%). These 44 patients underwent surgery and R0 resection was achieved in 26. The rate of R0 resection for GC with a single StIV factor (n = 24) was 79.2% and that for GC with multiple StIV factors (n = 27) was 25.9%. All patients with cancer cells in peritoneal washings (cytology [Cy] 1) alone (n = 12) became Cy0 after preoperative chemotherapy. Postoperative chemotherapy was completed in 11 patients, including 8 with Cy1 alone. No treatment-related death was recorded. Recurrences were observed in 14 patients after R0 resection. The most frequent recurrence site was the peritoneum. Patients who underwent R0 resection and those with Cy1 alone had a better survival. CONCLUSIONS: This perioperative treatment was safe and feasible for StIVGC but failed to show a survival benefit. In patients with StIVGC with Cy1 alone this treatment resulted in a better prognosis. PMID- 21667135 TI - Frequent development of leptomeningeal carcinomatosis in patients with peritoneal dissemination of gastric cancer. AB - We detected 7 cases of leptomeningeal carcinomatosis in 126 patients with peritoneal dissemination of gastric cancer who received combined systemic and intraperitoneal chemotherapy. Leptomeningeal carcinomatosis was diagnosed 79-1540 days after the diagnosis of the primary gastric cancer. Patients presenting with various neurological symptoms were diagnosed by cerebrospinal fluid (CSF) cytology and radiological imaging. Irradiation to the whole brain and spine was performed in 4 patients, and provided palliation and increased survival for 1 patient. Intrathecal chemotherapy and drainage of CSF was performed in 1 patient each, but produced no significant clinical benefit in either of them. Survival after the diagnosis of leptomeningeal carcinomatosis was between 3 and 155 days. As patients with peritoneal dissemination of gastric cancer are living longer because of improved chemotherapy, clinicians must recognize the possibility of leptomeningeal carcinomatosis when patients complain of neurological symptoms. PMID- 21667136 TI - A systematic review of the accuracy and indications for diagnostic laparoscopy prior to curative-intent resection of gastric cancer. AB - BACKGROUND: Despite improved preoperative imaging techniques, patients with incurable or unresectable gastric cancer are still subjected to non-therapeutic laparotomy. Diagnostic laparoscopy (DL) has been advocated by some to be essential in decision-making in gastric cancer. We aimed to identify and synthesize findings on the value of DL for patients with gastric cancer, in this era of improved preoperative imaging. METHODS: Electronic literature searches were conducted using Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1, 1998 to December 31, 2009. We calculated the change in management and avoidance of laparotomy based on the addition of DL and laparoscopic ultrasound (LUS). The accuracy, agreement (kappa), sensitivity, and specificity of DL in assessing tumor extent, nodal involvement, and the presence of metastases with respect to the gold standard (pathology) were also calculated. RESULTS: Twenty-one articles were included. DL showed moderate to substantial agreement with final pathology for T stage, but only fair agreement for N stage. For M staging, DL had an overall accuracy, sensitivity, and specificity ranging from 85-98.9%, 64.3-94%, and 80-100%, respectively. The use of DL altered treatment in 8.5-59.6% of cases, avoiding laparotomy in 8.5-43.8% of cases. LUS provided additional benefit in 5.8-7.2% of cases. CONCLUSIONS: Despite evolving preoperative imaging techniques, diagnostic laparoscopy continues to be of substantial value in staging patients with gastric cancer and in avoiding unnecessary laparotomy. The current data support DL for all patients with advanced gastric cancer. PMID- 21667137 TI - Does ultra-pulse CO(2) laser reduce the risk of enamel damage during debonding of ceramic brackets? AB - This study seeks to evaluate the enamel surface characteristics of teeth after debonding of ceramic brackets with or without laser light. Eighty premolars were bonded with either of the chemically retained or the mechanically retained ceramic brackets and later debonded conventionally or through a CO(2) laser (188 W, 400 Hz). The laser was applied for 5 s with scanning movement. After debonding, the adhesive remnant index (ARI), the incidence of bracket and enamel fracture, and the lengths, frequency, and directions of enamel cracks were compared among the groups. The increase in intrapulpal temperature was measured in ten extra specimens. The data were analyzed with SPSS software. There was one case of enamel fracture in the chemical retention/conventional debonding group. When brackets were removed with pliers, incidences of bracket fracture were 45% for the chemical retention, and 15% for the mechanical retention brackets. No case of enamel or bracket fracture was seen in the laser-debonded teeth. A significant difference was observed in ARI scores among the groups. Laser debonding caused a significant decrease in the frequency of enamel cracks, compared to conventional debonding. The increase in intrapulpal temperatures was below the benchmark of 5.5 degrees C for all the specimens. Laser-assisted debonding of ceramic brackets could reduce the risk of enamel damage and bracket fracture, and produce the more desirable ARI scores without causing thermal damage to the pulp. However, some augmentations in the length and frequency of enamel cracks should be expected with all debonding methods. PMID- 21667138 TI - A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR-2, FAK and Akt. AB - Amino acids 50-77 (p28) of azurin, a 128 aa cupredoxin isolated from Pseudomonas aeruginosa, is essentially responsible for azurin's preferential penetration of cancer cells. We now report that p28 also preferentially penetrates human umbilical vein endothelial cells (HUVEC), co-localized with caveolin-1 and VEGFR 2, and inhibits VEGF- and bFGF-induced migration, capillary tube formation and neoangiogenesis in multiple xenograft models. The antiangiogenic effect of p28 in HUVEC is associated with a dose-related non-competitive inhibition of VEGFR-2 kinase activity. However, unlike other antiangiogenic agents that inhibit the VEGFR-2 kinase, p28 decreased the downstream phosphorylation of FAK and Akt that normally precedes cellular repositioning of the cytoskeletal (F-actin), focal adhesion (FAK and paxillin), and cell to cell junction protein PECAM-1, inhibiting HUVEC motility and migration. The decrease in pFAK and pAkt levels suggests that p28 induces a pFAK-mediated loss of HUVEC motility and migration and a parallel Akt-associated reduction in cell matrix attachment and survival. This novel, direct antiangiogenic effect of p28 on endothelial cells may enhance the cell cycle inhibitory and apoptotic properties of this prototype peptide on tumor cell proliferation as it enters a Phase II clinical trial. PMID- 21667139 TI - Optimal study design for pioglitazone in septic pediatric patients. AB - The objective was to demonstrate the methodology and process of optimal sparse sampling pharmacokinetics (PK). This utilized a single daily dose of pioglitazone for pediatric patients with severe sepsis and septic shock based upon adult and minimal adolescent data. Pioglitazone pharmacokinetics were modeled using non compartment analysis WinNonlin Pro (version 5.1) and population kinetics using NONMEM (version 7.1) with first order conditional estimation method (FOCE) with interaction. The initial model was generated from single- and multiple-dose pioglitazone PK data (15 mg, 30 mg, and 45 mg) in 36 adolescents with diabetes. PK models were simulated and overlaid upon original data to provide a comparison best described by a single compartment, first order model. The optimal design was based on the simulated oral administration of pioglitazone to three groups of pediatric patients, age 3.8 (2-6 years), weight 14.4 (7-28 kg); age 9.6 (6.1-11.9 years), weight 36.5 (28.1-48 kg) and age 15.5 (12-17 years,) weight 61.6 (48.1-80 kg). PFIM (version 3.2) was used to evaluate sample study size. Datasets were compiled using simulation for each dose (15, 30 and 45 mg) for the potential age/weight groups. A target dose of 15 mg daily in the youngest and middle groups was considered appropriate with area under the curve exposure levels (AUC) comparable to studies in adolescents. The final optimal design suggested time points of 0.5, 2, 6 and 21 h for 24 h dosing. This methodology provides a robust method of utilizing adult and limited adolescent data to simulate allometrically scaled, pediatric data sets that allow the optimal design of a pediatric trial. The pharmacokinetics of pioglitazone were described adequately and simulated data estimates were comparable to literature values. The optimal design provided clinically attainable sample times and windows. PMID- 21667140 TI - Diospyros blancoi attenuates asthmatic effects in a mouse model of airway inflammation. AB - Asthma is a complex disease linked to various pathophysiological events, including proteinase activity. In this study, we examined whether a Diospyros blancoi methanolic extract (DBE) exerts protective effects on allergic asthma in a murine asthma model. To investigate the specific role of DBE, we employed a murine model of allergic airway inflammation. BALB/c mice sensitized and challenged with ovalbumin (OVA) were orally administered 20 or 40 mg/kg DBE for 3 days during OVA challenge. DBE induced significant suppression of the number of OVA-induced total inflammatory cells, including eosinophils, macrophages, and lymphocytes, in bronchoalveolar lavage fluid (BALF). Moreover, treatment with DBE led to significant decreases in interleukin (IL)-4, IL-5, and eotaxin levels in BALF and OVA-specific immunoglobulin (Ig)E and IgG1 levels in serum. Histological examination of lung tissue revealed marked attenuation of allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. Additionally, DBE suppressed matrix metalloproteinase-9 activity and induced heme oxygenase-1 expression. The present findings collectively suggest that DBE exhibits anti-inflammatory activity in an airway inflammation mouse model, supporting its therapeutic potential for the treatment of allergic bronchial asthma. PMID- 21667141 TI - The influence of alcohol-specific communication on adolescent alcohol use and alcohol-related consequences. AB - Alcohol-specific communication, a direct conversation between an adult and an adolescent regarding alcohol use, contains messages about alcohol relayed from the adult to the child. The current study examined the construct of alcohol specific communication and the effect of messages on adolescent alcohol use and alcohol-related consequences. Parent-adolescent dyads were assessed biannually for 3 years (grades 9-11 at wave 6) to examine these relations in a large longitudinal study of adolescents initially in grades 6 through 8. An exploratory factor analysis identified two factors among alcohol-specific communication items, permissive messages and negative alcohol messages. Results showed previous level of adolescent alcohol use moderated the relation between permissive messages and alcohol use outcomes. Plotting of these interactions showed greater alcohol use and consequences with increasing permissive messages in adolescents with higher versus lower levels of previous alcohol use. Results suggest that parental messages regarding alcohol use may impact adolescent alcohol use beyond the effect of general parenting style and parental alcohol use. PMID- 21667142 TI - Effects of Communities That Care on the adoption and implementation fidelity of evidence-based prevention programs in communities: results from a randomized controlled trial. AB - This paper describes findings from the Community Youth Development Study (CYDS), a randomized controlled trial of the Communities That Care (CTC) prevention system, on the adoption and implementation fidelity of science-based prevention programming in 24 communities. Data were collected using the Community Resource Documentation (CRD), which entailed a multi-tiered sampling process and phone and web-based surveys with directors of community-based agencies and coalitions, school principals, service providers, and teachers. Four years after the initiation of the CTC prevention system, the results indicated increased use of tested, effective prevention programs in the 12 CTC intervention communities compared to the 12 control communities, and significant differences favoring the intervention communities in the numbers of children and families participating in these programs. Few significant differences were found regarding implementation quality; respondents from both intervention and control communities reported high rates of implementation fidelity across the services provided. PMID- 21667143 TI - Hyperbaric oxygen therapy for carbon monoxide poisoning. PMID- 21667144 TI - Antioxidant potential and health relevant functionality of traditionally processed Cassia hirsuta L. seeds: an Indian underutilized food legume. AB - The methanolic extract of Cassia hirsuta L. seed materials, an underutilized food legume collected from India, was analyzed for antioxidant activity and health relevant functionality. The methanolic extract of raw seeds contained a total free phenolic content of 15.82 +/- 1.69 g catechin equivalent/100 g extract DM. Encouraging levels of ferric reducing/antioxidant power (FRAP, 1,446 mmol Fe[II]/mg extract), inhibition of beta-carotene degradation (48.81%) and scavenging activity against DPPH (64.40%) and superoxide (43.78%) radicals were exhibited by the raw samples. Further, 83.11% of alpha-amylase and 62.79% of alpha-glucosidase enzyme inhibition characteristics under in vitro starch digestion bioassay were also recorded. Sprouting + oil-frying caused an apparent increase on the total free phenolic content and a significant improvement in the antioxidant and free radical scavenging capacity of methanolic extract of C. hirsuta seeds, while soaking + cooking as well as open-pan roasting treatments showed diminishing effects. The analysis of the phenolic profile revealed the presence of gallic acid, p-coumaric acid and (+)-catechin in the methanolic extract of these seeds. PMID- 21667145 TI - Changes in phenolic compounds in garlic (Allium sativum L.) owing to the cultivar and location of growth. AB - The contents of total phenolic compounds, flavonoids, and phenolic acids were determined in selected garlic cultivars grown at four locations. The total phenolic content varied from 3.4 mg gallic acid equivalents (GAE)/g of dry matter (dm) to 10.8 mg GAE/g of dm with a mean value of 6.5 mg GAE/g of dm. The myricetin, quercetin, kaempferol, and apigenin flavonoids were not detected in any of the samples. Caffeic acid and ferulic acid were the major phenolic acids found with mean values of 2.9 mg/kg of dm and 2.6 mg/kg of dm, respectively. The mean contents of vanillic, p-hydroxybenzoic, and p-coumaric acids were comparable (0.4-0.8 mg/kg of dm), and the level of sinapic acid was negligible (< 0.1 mg/kg of dm). There was a significant effect of location but an insignificant effect of genotype on contents of caffeic, vanillic, p-hydroxybenzoic, and p-coumaric acids. However, genotype but not location affected the contents of total phenolics and ferulic acid. On average, the white garlic cultivars and Chinese garlic cultivars contained higher contents of total phenolics and ferulic acid than the purple garlic cultivars. However, the differences in the total phenolic content between the purple and white garlic cultivars were not significant. PMID- 21667146 TI - Radiological Society of North America (RSNA) 2010 Annual Meeting. AB - A tailored review of peer-reviewed abstracts presented at the 2010 Radiological Society of North America (RSNA) Annual Meeting was performed following oral presentation. This review will highlight 15 formal and informal scientific paper presentations focusing on three main topics: (1) 3D isotropic MR imaging of joints, (2) diffusion tensor imaging of peripheral nerves, and (3) dual-energy CT in the diagnosis of Gout. PMID- 21667147 TI - The Delphi method: an efficient procedure to generate knowledge. PMID- 21667149 TI - Conservative management of spontaneous rupture of the urinary bladder: comment. PMID- 21667150 TI - Secondary metabolites released by the burying beetle Nicrophorus vespilloides: chemical analyses and possible ecological functions. AB - Burying beetles of the genus Nicrophorus localize small vertebrate carcasses by emitted volatiles. The carcass that serves as reproduction and breeding site is buried in the soil by the beetles. Biparental care for offspring includes both preservation of the carrion and its preparation as diet and nursery. Buried carcasses show no signs of microbial decay, and those experimentally treated with Nicrophorus secretions are known to grow fewer bacteria and fungi. In order to investigate the chemical composition of these secretions, we used GC-MS for analysis of methanolic extracts of anal and oral secretions released by adult N. vespilloides. Furthermore, we analyzed the headspace of adult N. vespilloides by SPME-GC-MS and searched for compounds with known antimicrobial activity. We identified 34 compounds in the headspace, and anal and oral secretions, 26 of which occurred consistently. We discuss the ecological relevance of these compounds with respect to both their antimicrobial activity and ecological relevance. PMID- 21667151 TI - Mucin phenotype and narrow-band imaging with magnifying endoscopy for differentiated-type mucosal gastric cancer. AB - BACKGROUND: Several studies have described the surface glandular structure in differentiated early gastric cancer observed by narrow-band imaging with magnifying endoscopy (NBI-ME) in two main patterns, i.e., a papillary or granular structure in an intralobular loop pattern (ILL) and a pit structure in a fine network pattern (FNP). However, it is uncertain why the NBI-ME findings of differentiated-type carcinomas are divided into two main patterns. We investigated the significance of the mucin phenotype in the morphogenetic difference between ILL and FNP. METHODS: We evaluated 120 intramucosal, well- or predominantly well-differentiated tubular adenocarcinomas. In each lesion, one area that showed the predominant pattern of microsurface structures and microvessels was selected and marked by electrocoagulation for a strict comparative study by NBI-ME and pathological investigation. NBI-ME findings were classified into three patterns: ILL, FNP, and intermediate. Mucin phenotypes were judged as gastric, intestinal, or gastrointestinal type by immunohistochemistry. RESULTS: The mucin phenotype was gastric or gastrointestinal type in 24 (92.3%) of 26 ILL lesions. Intestinal phenotype was observed in 22 (84.6%) of 26 FNP lesions. The gastrointestinal phenotype was observed in 50 (73.5%) of 68 intermediate pattern lesions. The mucin phenotype and NBI-ME results were significantly correlated (P < 0.001). CONCLUSIONS: The mucin phenotype of differentiated early gastric cancer might be involved in morphogenetic differences between the papillary and pit structures visualized by NBI-ME. PMID- 21667152 TI - Comment to the paper: palliative functional hemispherectomy for treatment of refractory status epilepticus associated with Alpers' disease. AB - INTRODUCTION: Performing epilepsy surgery in a child with a neurodegenerative illness is a relatively unexplored challenge. In this issue of CNS, Lupashko and coauthors report the use of epilepsy surgery to eliminate seizures without influencing the underlying progressive disorder. METHOD: Functional hemispherectomy was performed in a 4-year-old girl with seizures caused by Alpers' disease. RESULTS: Seizure freedom and an improved quality of life were achieved briefly despite deteriorating neurologic status. CONCLUSION: Further studies will be needed to confirm the positive benefits of palliative epilepsy surgery in children with progressive neurologic illnesses. PMID- 21667153 TI - Dependence of spontaneous neuronal firing and depolarisation block on astroglial membrane transport mechanisms. AB - Exposed to a sufficiently high extracellular potassium concentration ([K( + )]0), the neuron can fire spontaneous discharges or even become inactivated due to membrane depolarisation ('depolarisation block'). Since these phenomena likely are related to the maintenance and propagation of seizure discharges, it is of considerable importance to understand the conditions under which excess [K( + )]0 causes them. To address the putative effect of glial buffering on neuronal activity under elevated [K( + )](o) conditions, we combined a recently developed dynamical model of glial membrane ion and water transport with a Hodgkin-Huxley type neuron model. In this interconnected glia-neuron model we investigated the effects of natural heterogeneity or pathological changes in glial membrane transporter density by considering a large set of models with different, yet empirically plausible, sets of model parameters. We observed both the high [K( + )]0-induced duration of spontaneous neuronal firing and the prevalence of depolarisation block to increase when reducing the magnitudes of the glial transport mechanisms. Further, in some parameter regions an oscillatory bursting spiking pattern due to the dynamical coupling of neurons and glia was observed. Bifurcation analyses of the neuron model and of a simplified version of the neuron-glia model revealed further insights about the underlying mechanism behind these phenomena. The above insights emphasise the importance of combining neuron models with detailed astroglial models when addressing phenomena suspected to be influenced by the astroglia-neuron interaction. To facilitate the use of our neuron-glia model, a CellML version of it is made publicly available. PMID- 21667154 TI - A simple integrative electrophysiological model of bursting GnRH neurons. AB - In this paper a modular model of the GnRH neuron is presented. For the aim of simplicity, the currents corresponding to fast time scales and action potential generation are described by an impulsive system, while the slower currents and calcium dynamics are described by usual ordinary differential equations (ODEs). The model is able to reproduce the depolarizing afterpotentials, afterhyperpolarization, periodic bursting behavior and the corresponding calcium transients observed in the case of GnRH neurons. PMID- 21667155 TI - The Ising decoder: reading out the activity of large neural ensembles. AB - The Ising model has recently received much attention for the statistical description of neural spike train data. In this paper, we propose and demonstrate its use for building decoders capable of predicting, on a millisecond timescale, the stimulus represented by a pattern of neural activity. After fitting to a training dataset, the Ising decoder can be applied "online" for instantaneous decoding of test data. While such models can be fit exactly using Boltzmann learning, this approach rapidly becomes computationally intractable as neural ensemble size increases. We show that several approaches, including the Thouless Anderson-Palmer (TAP) mean field approach from statistical physics, and the recently developed Minimum Probability Flow Learning (MPFL) algorithm, can be used for rapid inference of model parameters in large-scale neural ensembles. Use of the Ising model for decoding, unlike other problems such as functional connectivity estimation, requires estimation of the partition function. As this involves summation over all possible responses, this step can be limiting. Mean field approaches avoid this problem by providing an analytical expression for the partition function. We demonstrate these decoding techniques by applying them to simulated neural ensemble responses from a mouse visual cortex model, finding an improvement in decoder performance for a model with heterogeneous as opposed to homogeneous neural tuning and response properties. Our results demonstrate the practicality of using the Ising model to read out, or decode, spatial patterns of activity comprised of many hundreds of neurons. PMID- 21667156 TI - Dipole characterization of single neurons from their extracellular action potentials. AB - The spatial variation of the extracellular action potentials (EAP) of a single neuron contains information about the size and location of the dominant current source of its action potential generator, which is typically in the vicinity of the soma. Using this dependence in reverse in a three-component realistic probe + brain + source model, we solved the inverse problem of characterizing the equivalent current source of an isolated neuron from the EAP data sampled by an extracellular probe at multiple independent recording locations. We used a dipole for the model source because there is extensive evidence it accurately captures the spatial roll-off of the EAP amplitude, and because, as we show, dipole localization, beyond a minimum cell-probe distance, is a more accurate alternative to approaches based on monopole source models. Dipole characterization is separable into a linear dipole moment optimization where the dipole location is fixed, and a second, nonlinear, global optimization of the source location. We solved the linear optimization on a discrete grid via the lead fields of the probe, which can be calculated for any realistic probe + brain model by the finite element method. The global source location was optimized by means of Tikhonov regularization that jointly minimizes model error and dipole size. The particular strategy chosen reflects the fact that the dipole model is used in the near field, in contrast to the typical prior applications of dipole models to EKG and EEG source analysis. We applied dipole localization to data collected with stepped tetrodes whose detailed geometry was measured via scanning electron microscopy. The optimal dipole could account for 96% of the power in the spatial variation of the EAP amplitude. Among various model error contributions to the residual, we address especially the error in probe geometry, and the extent to which it biases estimates of dipole parameters. This dipole characterization method can be applied to any recording technique that has the capabilities of taking multiple independent measurements of the same single units. PMID- 21667157 TI - Comparison of ICD-10 and DC: 0-3R diagnoses in infants, toddlers and preschoolers. AB - The purpose of this study was to analyze and compare diagnoses of patients from a special outpatient department for infants, toddlers and preschoolers. Specifically, overlap, age and gender differences according to the two classification systems DC: 0-3R and ICD-10 were examined. 299 consecutive children aged 0-5; 11 years received both ICD-10 and DC: 0-3R diagnoses. All ICD 10 diagnoses were given prospectively at the initial contact. The DC: 0-3R diagnoses were allotted in mutual consensus conferences. The most common ICD-10 disorders were Oppositional Defiant (ODD), Hyperkinetic (HKD) and Emotional Disorders. In DC: 0-3R, nearly half of the children could not be coded adequately ('Other Disorders'). Sleep Behavior Disorders were followed by Feeding Behavior and Regulation Disorders. Both classification systems are needed in infant, toddler and preschool psychiatry. There is a good concordance of the two systems for Feeding, Sleeping, Adjustment and Attachment Disorders, whereas the ICD-10 diagnoses HKD and ODD are not adequately represented in DC: 0-3R. PMID- 21667158 TI - Anticancer effects of 6-o-palmitoyl-ascorbate combined with a capacitive resistive electric transfer hyperthermic apparatus as compared with ascorbate in relation to ascorbyl radical generation. AB - The aim of the present study is to determine the anti-proliferative activity of 6 o-palmitoyl-L: -ascorbic acid (Asc6Palm) that is a lipophilic derivative of L: ascorbic acid (Asc), on human tongue squamous carcinoma HSC-4 cells by combined use of hyperthermia in comparison to Asc. Asc6Palm or Asc were administered to HSC-4 cells for 1 h, to which hyperthermia at 42 degrees C was applied for initial 15 min. After further 1-72 h incubation at 37 degrees C, cell proliferation was determined with Crystal Violet staining. Ascorbyl radical (AscR) in HSC-4 cell suspension was measured by electron spin resonance (ESR), and cell morphology was observed with scanning electron microscopy (SEM). At 37 degrees C, 4 mM Asc or 0.35 mM Asc6Palm were enough to suppress proliferation of HSC-4 cells. By combined use of hyperthermia at 42 degrees C, cell proliferation was decreased when compared to 37 degrees C. After Asc of 4 mM was incubated with HSC-4 cell suspensions at 37 degrees C or 42 degrees C for 0-180 min, the signal intensity of ascorbyl radical (AscR) by ESR was not different regardless of the presence or absence of cells at 37 degrees C, whereas AscR signal was enlarged in the presence of HSC-4 cells at 42 degrees C. It was suggested that oxidation of Asc occurred rapidly in HSC-4 cells by hyperthermia, and thereby enhanced the anti-proliferative activity. By SEM observation, the surface of HSC 4 cells treated with Asc6Palm revealed distinct morphological changes. Thus, the combined regimen of Asc6Palm and hyperthermia is expected to exert a marked antitumor activity. PMID- 21667159 TI - Cyclophilin A promotes human hepatocellular carcinoma cell metastasis via regulation of MMP3 and MMP9. AB - Cyclophilin A (CypA) is a member of peptidyl prolyl isomerases (PPIases), which catalyze the cis/trans isomerization of prolyl peptide bonds on the NH-terminal side of Pro residues in peptide chains. Altered expression of CypA has been reported in hepatocellular carcinoma (HCC), but the biological functions of CypA in HCC remain unknown. We found that the level of CypA expression correlated with the metastatic capability of two HCC cell lines, MHCC97-L and MHCC97-H. Stable expression of ectopic CypA in SK-Hep1 cells promotes cell adhesion, motility, chemotaxis, and in vivo lung metastasis, without affecting cell proliferation. We further analyzed microarray results to identify target genes controlled by CypA. Twenty-one genes related to metastasis were altered by CypA over-expression. A member of matrix metalloproteinase, MMP3, was identified by microarray analysis. The regulation of MMP3 and its homologue MMP9 by CypA were further confirmed by quantitative real-time RT-PCR and zymography assay. Taken together, our data suggest that CypA promotes HCC cell metastasis at least partially through up regulation of MMP3 and MMP9. PMID- 21667160 TI - Simulated colon fiber metabolome regulates genes involved in cell cycle, apoptosis, and energy metabolism in human colon cancer cells. AB - High level of dietary fiber has been epidemiologically linked to protection against the risk for developing colon cancer. The mechanisms of this protection are not clear. Fermentation of dietary fiber in the colon results in production of for example butyrate that has drawn attention as a chemopreventive agent. Polydextrose, a soluble fiber that is only partially fermented in colon, was fermented in an in vitro colon simulator, in which the conditions mimic the human proximal, ascending, transverse, and distal colon in sequence. The subsequent fermentation metabolomes were applied on colon cancer cells, and the gene expression changes studied. Polydextrose fermentation down-regulated gene ontology classes linked with cell cycle, and affected number of metabolically active cells. Furthermore, up-regulated effects on classes linked with apoptosis, with increased caspase 2 and 3 activity, implicate that polydextrose fermentation plays a role in induction of apoptosis in colon cancer cells. The up-regulated genes involved also key regulators of lipid metabolism, such as PPARalpha and PGC 1alpha. These results offer hypotheses for the mechanisms of two health benefits linked with consumption of dietary fiber, reducing risk of development of colon cancer, and dyslipidemia. PMID- 21667161 TI - [Immunoadsorption for steroid-unresponsive multiple sclerosis-relapses: clinical data of 14 patients]. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating immune-mediated disease of the central nervous system, often associated with relapses. Plasma exchange (PE) has become established as an escalation therapy for steroid-unresponsive relapses in national and international guidelines. PE is a non-selective apheresis method with elimination of the entire plasma with subsequent substitution. Selective extracorporeal elimination of autoantibodies and immune complexes with immunoadsorption (IA) is increasingly replacing PE for the treatment of autoimmune neurological diseases due to its equivalent efficacy and advantageous safety profile. The use of IA for MS still remains to become established. The aim of this retrospective investigation was to evaluate efficacy and safety of IA in patients with steroid-unresponsive relapses. PATIENTS AND METHODS: Fourteen patients with steroid-unresponsive MS relapses were retrospectively analysed. Patients received six IA treatments within 2 weeks using the single-use tryptophan adsorber. Peripheral venous access was used in 11 patients, and 3 patients needed a central line. The plasma volume treated was 2 l per IA. Efficacy criteria were improvement in symptoms of MS relapses which were measured with the Kurtzke scale (EDSS, FS) and visual acuity measurements for patients with optic neuritis. RESULTS: In 12 of 14 patients the major symptom of MS relapse improved to a clinically relevant extent after tryptophan IA; no patient got worse, corresponding to a response rate of 86%. Mean EDSS and FS in patients with spastic paresis (n=4) and dizziness (n=2) as well as mean visual acuity in patients with optic neuritis (n=8) significantly improved after IA. IA treatments were safe, with good tolerability, and no severe adverse events occurred. CONCLUSION: Immunoadsorption for the treatment of steroid-unresponsive MS relapses was safe and effective. The response rate was comparable to published results with PE. With IA, in contrast to unselective PE, administration of human plasma products is not necessary, avoiding associated risks. PMID- 21667162 TI - Survival benefit of abdominal adiposity: a 6-year follow-up study with Dual X-ray absorptiometry in 3,978 older adults. AB - In contrast to that in the middle-aged, higher body mass index (BMI) in older people is associated with higher survival rates. Yet, BMI makes no distinction between fat elsewhere and abdominal fat, the latter being metabolically more harmful. We hypothesized that overall adiposity might be protective in old age, but that central fat might offset that benefit and remained harmful as in the middle-aged. Three thousand nine hundred seventy-eight Chinese elderly >=65 years had demographics, medical conditions, physical activity, and body composition by DXA recorded at baseline. Overall adiposity was measured as whole body fat%, and abdominal adiposity as waist circumference, waist-hip ratio, and relative abdominal fat (RAF) (relative abdominal fat = abdominal fat according to anatomical landmarks/whole body fat). Deaths within 1 year from baseline were excluded from analysis. All-cause and cardiovascular mortality were analyzed using Cox regression, adjusted for covariates. The lowest quintile of adiposity measurements was used for comparison. After a mean follow-up of 72.3 months, 13.7% men and 4.5% women had died. In men, the highest two quintiles of whole body fat % and the upper four quintiles of RAF were associated with significantly lower all-cause mortality, and adjusted hazard ratio (95% CI) in ascending quintiles of RAF compared with the lowest quintile was 0.62 (0.43-0.89), 0.58 (0.4-0.85), 0.52 (0.36-0.77), and 0.67 (0.47-0.96). No relationship was found between abdominal adiposity and cardiovascular mortality in both genders. Higher whole body fat % as well as higher proportion of abdominal fat was associated with lower all-cause mortality in men. No such relation was found in women. PMID- 21667163 TI - Phospholipase C epsilon plays a suppressive role in incidence of colorectal cancer. AB - In our previous study, we have found that PLCE1 was down-regulated in sporadic colorectal cancer. But the role of PLCE1 in the incidence of colorectal cancer is still not definite. Therefore, in order to validate whether PLCE1 displays a suppressive role, in this study, we examined the expression of PLCE1 in sporadic colorectal cancer with a larger sample size and the effect of PLCE1 overexpression on cancer cell malignant degree. The expression level of PLCE1 in 50 colorectal cancers with their pair-matched normal tissues was measured by RT PCR, Western blot, and immunohistochemistry. The effect of PLCE1 overexpression on cancer cell malignant degree was measured by MTT assay, plate colony formation assay, soft agar colony formation assay, cell cycle and apoptosis analysis, and xenograft assay. We found that PLCE1 was down-regulated in 42% (21/50) of colorectal cancer tissues compared with pair-matched normal tissues, more frequent in the poor differentiation tumor in patients under 60. Overexpression of PLCE1 significantly inhibited the proliferation of colon cancer cells and degraded its malignant degree. These results suggest that PLCE1 may be involved in the development of sporadic colorectal cancer through its inhibitory effect on cell proliferation. PLCE1 exhibits a suppressive role in incidence of colorectal cancer. PMID- 21667164 TI - Do both areal BMD and injurious falls explain the higher incidence of fractures in women than in men? AB - The higher incidence of fractures in women than in men is generally attributed to the lower areal bone mineral density (areal BMD, g/cm(2)) of the former. The purpose of the present study was to investigate both areal BMD and injurious falls as risk factors for fractures. In a first cohort, areal BMD was measured in 5,131 men and women (age range 40-95 years). In a second cohort, consisting of 26,565 men and women (age range 40-69 years), a health survey was conducted including questions about lifestyle and medication. Main outcome measures included validated prospective injurious falls and fractures in both cohorts. The higher areal BMD and femoral neck BMD in men compared to women (P < 0.001) were explained by a higher diameter of the femoral neck. Importantly, the diameter of the femoral neck was not associated with fractures in either sex (hazard ratio [HR] 0.94-1.04, P > 0.05 for all), suggesting that a higher areal BMD and lower incidence of osteoporosis in men do not explain their lower incidence of fractures. In contrast, women were more prone to sustain injurious falls than men in both cohorts investigated (HR for women = 1.61 and 1.84, P < 0.001 for both), resulting in a higher incidence of fractures (HR for women = 2.24 and 2.36, P < 0.001 for both). The number of injurious falls and fractures occurring each month during the study period showed a very strong correlation in both women (r = 0.95, P < 0.00001) and men (r = 0.97, P < 0.00001). In summary, low areal BMD, and thus osteoporosis, may not explain the higher fracture incidence in women than in men. Instead, a higher incidence of injurious falls in women was strongly associated with the higher fracture risk. PMID- 21667165 TI - Teaching and training in laparoscopic surgery: experience of Catholic Laparoscopy Advanced Surgery School in the basic gynecological surgery. AB - PURPOSE: To evaluate the effectiveness of our training method for basic "hands on" laparoscopic courses. METHODS: A prospective observational study between September 2008 and December 2010 at Catholic Laparoscopy Advanced Surgery School of the Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Sacred Heart-Rome, was conducted. Each course lasted for 3 days, divided into theoretical and practical parts, ending with a live surgery. Gynecologists who attended our 'hands-on' laparoscopic courses had no or minimum experience with laparoscopic technique. The teachers were expert laparoscopists of our Division, and every single group of participants had the same tutor for the entire course. Trainees completed self-assessment anonymous questionnaire of laparoscopic knowledge, before and immediately after the course. RESULTS: During the study period, we performed 20 basic courses, enrolling 120 consecutive gynecologists. Among them, 114 (95%) decided to participate. Average age was 41 years (range 35-60 years) and 108 (94.7%) trainees were Italian. The subjective assessment showed an immediate improvement of motor skills. CONCLUSIONS: Laparoscopic training course can improve both theoretical knowledge and motor skills. Such courses result in a short-term subjective improvement. PMID- 21667166 TI - Growth phase-dependent UV-C resistance of Bacillus subtilis: data from a short term evolution experiment. AB - After 700 generations of a short-term evolution experiment with Bacillus subtilis 168, two strains were isolated, the UV-adapted strain MW01 and the UV-unexposed control strain DE69, and chosen for UV-C radiation resistance studies with respect to growth phase. The ancestral strain from the evolution experiment was used as reference for comparative purposes. Cells of the UV-adapted strain showed significant differences in their physiology (growth behavior, doubling time, cell density, and sporulation capacity) and were more resistant to UV in all monitored stages. These findings implicate the evolution to an increased UV radioresistance was not limited to a specific growth phase and led to reduced growth dynamics, compared with those obtained from the ancestral and the control strain. PMID- 21667167 TI - Regeneration of skeletal muscle. AB - Skeletal muscle has a robust capacity for regeneration following injury. However, few if any effective therapeutic options for volumetric muscle loss are available. Autologous muscle grafts or muscle transposition represent possible salvage procedures for the restoration of mass and function but these approaches have limited success and are plagued by associated donor site morbidity. Cell based therapies are in their infancy and, to date, have largely focused on hereditary disorders such as Duchenne muscular dystrophy. An unequivocal need exists for regenerative medicine strategies that can enhance or induce de novo formation of functional skeletal muscle as a treatment for congenital absence or traumatic loss of tissue. In this review, the three stages of skeletal muscle regeneration and the potential pitfalls in the development of regenerative medicine strategies for the restoration of functional skeletal muscle in situ are discussed. PMID- 21667168 TI - How serious a problem is bleeding in patients with acute coronary syndromes? AB - Recent studies have highlighted the critical importance of bleeding complications on prognosis in patients with acute coronary syndromes (ACS). In fact, the hazard for an adverse cardiovascular event associated with bleeding is similar to that of a myocardial infarction. Several bleeding risk scores are now available that reliably quantify the probability of an ACS patient experiencing a bleeding complication. Consistent and strong correlates of bleeding include older age, female sex, renal impairment, and an invasive management approach. Although patients who tend to bleed are usually more morbid compared with their non bleeding counterparts, several lines of experimental and clinical evidence suggest an independent and causal pathway for bleeding-associated cardiovascular risk. Given the frequency and adverse prognosis associated with bleeding, interventions that might reduce such complications are now a major emphasis in the current era of ACS treatment. Recent trials have shown that several novel antithrombotics, bivalirudin and fondaparinux, reduce bleeding risk while maintaining efficacy in reducing ischemic events during ACS. Other promising strategies that continue to be tested include the use of vascular closure devices and transradial arterial access during percutaneous coronary intervention. PMID- 21667169 TI - Upper and lower gastrointestinal endoscopy mortality: the medical examiner's perspective. AB - Fiberoptic endoscopy is utilized to diagnose and treat a wide variety of gastrointestinal tract diseases and is currently one of the most commonly performed invasive medical procedures. Though generally considered to be safe, the procedure may be associated with serious complications including death. Herein, we correlate the clinical history with the autopsy findings in gastrointestinal endoscopy (GIE) related fatalities that were reported to the New York City Medical Examiner Office over a 5 year period. The complication rate is higher in therapeutic procedures when compared to diagnostic procedures. Though fatalities following iatrogenic complications are four times more common, emphasis is placed on patients who died following a cardiorespiratory event during or immediately following the procedure. Of 41 upper and 36 lower GIE related fatalities, 10 and 9 respectively, fit this category. The comorbidities frequently associated with fatal cardiorespiratory events were: hypertension and obesity with associated cardiac hypertrophy, diabetes mellitus and coronary artery atherosclerosis. For colonoscopies, the approximate incidence of perforation was 0.00625% and the procedure-related fatality rate was 0.014%. The literature on anesthesia for GIE is also discussed. PMID- 21667170 TI - When is a peri-procedural death iatrogenic in nature? AB - In almost any instance of suspected iatrogenic fatality, the attending forensic pathologist faces the challenging and often daunting task in ascertaining the cause of death, determining if an iatrogenic injury had indeed occurred and if so, its contribution to the causation of death. The Forensic Medicine Division of the Health Sciences Authority in Singapore embarked on a 6 year study of such deaths to identify pertinent factors that may facilitate the assessment of iatrogenic injuries and their contribution to mortality. A total of 106 iatrogenic deaths, arising from 613 coroner's peri-procedural autopsies conducted during the period of 2005-2010 were reviewed with particular reference to the following parameters: (1) clinico-pathological correlation; (2) the length of survival; (3) the number of interventional procedures. A comprehensive analysis of these cases indicated that they could be classified into the following 3 categories, in relation to the role of clinico-pathological correlation in the ascertainment of the causes of death: (A) advantageous but not essential; (B) essential; (C) critical. A large proportion of the cases (76.5%) were assigned categories B and C. Only the minority of cases (23.6%) were assigned category A. Also, as the number of days of survival between injury and death, and the number of interventional procedures after injury increases, the greater the need for detailed clinical documentation to ascertain the cause of death. PMID- 21667171 TI - The usefulness of dental and cervical maturation stages in New Zealand children for Disaster Victim Identification. AB - Age estimation of young victims of natural and un-natural disasters remains a crucial and challenging task during the process of Disaster Victim Identification (DVI). The purpose of this study was to compare dental maturity using the Demirjian and Cameriere methods and to explore the relationship between dental age and cervical vertebral maturity (CVM) using the Hassel and Farman method for a group of New Zealand children. The study used lateral cephalometric and panoramic radiographs of 200 orthodontic patients aged 7-17 years. Dental age was calculated from mandibular tooth formation stages using the Demirjian and Cameriere methods by calculating the ratio of tooth length to apex width for these teeth. CVM was assessed using stages from Hassel and Farman. Reliability of maturity from reassessment of 20 radiographs showed good agreement for the three methods. Chronological and dental ages were compared using a mixed model. Descriptive statistics of dental ages by CVM stage were calculated. The results show that both dental methods were similar in assessing maturity. A disadvantage of using the Cameriere method was that all seven teeth reached maturity at 13.69 and 14.06 years in females and males respectively, compared to age 16 using the Dermijian method. Females reached CVM stages at earlier chronological and dental ages than males. Mean chronological age for CVM stages 2-5 is about 1 year earlier in females than males. The Demirjian and Cameriere methods of dental maturity and CVM are reliable and useful in assessing dental and skeletal maturity. Ideally in a DVI situation, both the methods of Demirjian and Cameriere, together with CVM, should be employed in the ageing of individuals suspected of being between 7 and 16 years. PMID- 21667172 TI - An analysis of indications for surgical excision and complications in 116 consecutive cases of osteochondroma. AB - The indications for surgery in 116 cases of osteochondroma included cosmetic problem in 38, pain (on hitting some object or continuous pain due to bursitis) in 50, pressure (on adjacent nerves) in 18, hindrances of joint movements in 8, fracture of the growth in 1 and malignant change in 1 patient. The complications of surgical excision included infection in 2 patients (which was controlled with antibiotics and dressings) and injury to posterior tibial artery in one case (which was repaired with the help of vascular surgeon immediately). In 94 patients, the tumour was excised before epiphyseal fusion (done carefully so as to prevent damage to the growth plate). It is not essential to wait until skeletal maturity as many patients want to get it excised as early as possible for cosmetic reasons. All the cases were relieved of their symptoms. There was no recurrence. PMID- 21667173 TI - Development of tinnitus in CBA/CaJ mice following sound exposure. AB - Tinnitus, the perception of a sound without an external acoustic source, is a complex perceptual phenomenon affecting the quality of life in 17% of the adult population. Despite its ubiquity and morbidity, the pathophysiology of tinnitus is a work in progress, and there is no generally accepted cure or treatment. Development of a reliable common animal model is crucial for tinnitus research and may advance this field. The goal of this study was to develop a tinnitus mouse model. Tinnitus was induced in an experimental group of mice by an exposure to a loud (116 dB sound pressure level (SPL)) narrow band noise (one octave, centered at 16 kHz) during 1 h under anesthesia. The tinnitus was then assessed behaviorally by measuring gap induced suppression of the acoustic startle reflex. We found that a vast majority of the sound-exposed mice (86%) developed behavioral signs of tinnitus. This was a complex, long lasting, and dynamic process. On the day following exposure, all mice demonstrated signs of acute tinnitus over the entire range of sound frequencies used for testing (10-31 kHz). However, 2-3 months later, a behavioral evidence of tinnitus was evident only at a narrow frequency range (20-31 kHz) representing a presumed chronic condition. Extracellular recordings confirmed a significantly higher rate of spontaneous activity in inferior colliculus neurons in sound-exposed compared to control mice. Surprisingly, unilateral sound exposure suppresses startle responses in mice and they remained suppressed even 3 months post-exposure, whereas auditory brainstem response thresholds were completely recovered during 2 months following exposure. In summary, behavioral evidence of tinnitus can be reliably developed in mice by sound exposure, and tinnitus induction can be assessed by quantifying prepulse inhibition of the acoustic startle reflex. PMID- 21667174 TI - Presence of a functional (TTAGG)(n) telomere-telomerase system in aphids. AB - The structure of the telomeres of four aphid species (Acyrthosiphon pisum, Megoura viciae, Myzus persicae and Rhopalosiphum padi) was evaluated by Southern blotting and fluorescent in situ hybridization, revealing that each chromosomal end consists of a (TTAGG)(n) repeat. The presence of a telomerase coding gene has been verified successively in the A. pisum genome, revealing that aphid telomerase shares sequence identity ranging from 12% to 18% with invertebrate and vertebrate homologues, and possesses the two main domains involved in telomerase activity. Interestingly, telomerase expression has been verified in different somatic tissues suggesting that, in aphids, telomerase activity is not as restricted as in human cells. The study of telomeres in a M. persicae strain with a variable chromosome number showed that aphid telomerase can initiate the de novo synthesis of telomere sequences at internal breakpoints, resulting in the stabilization of chromosomal fragments. PMID- 21667175 TI - The effects of alerting signals in action control: activation of S-R associations or inhibition of executive control processes? AB - Non-informative, task-irrelevant auditory alerting signals often lead to increased interference effects in selective attention paradigms (e.g., Simon, Eriksen flanker). Some authors conclude that the alerting attentional network, activated by the alerting signal, reveals an inhibitory influence upon the executive attentional network, resulting in attenuated executive control. Alternatively, in the present study we argue that increased interference effects might be explained by alerting signals facilitating response activation processes (i.e., the activation of established S-R links). In a modified Eriksen-flanker paradigm, we contrasted these assumptions. We used word flanker stimuli for which S-R associations were established and word flanker stimuli without S-R associations. The presence of an alerting signal increased flanker compatibility only for flanker stimuli for which S-R associations existed while flanker compatibility effects were the same for all flanker types in conditions without alerting signals. Therefore, we conclude that alerting signals enhance stimulus triggered visuo-motor response activation processes. PMID- 21667176 TI - An attentional approach to study mental representations of different parts of the hand. AB - The aim of this study is to investigate whether the fingers are represented separately from the palm. An exogenous spatial orientation paradigm was used where participants had to detect a tactile stimulus that could appear on the palm, the middle finger or the ring finger of the left hand. The tactile target was preceded by a non-predictive cue using different stimulus-onset asynchronies (SOA). We observed a Facilitation Effect in the palm and inhibition of return (IOR) for fingers using a short cue-target SOA, whereas the IOR was found in fingers and palm in long cue-target SOA. Also we observed a 'Cue above Target' effect (facilitation effect when the Cue had appeared distal to the target location in a vertical line) at the long SOA. Together, we suggest that the general pattern of results supports the proposed hypothesis about the different mental representation of fingers and palms, but with a considerable and hierarchical interrelation between them. PMID- 21667177 TI - Gender difference in subjective response to whole-body vibration under standing posture. AB - PURPOSE: The aim of this study was to examine whether there exist gender differences in subjective response to whole-body vibration (WBV) under standing posture. METHODS: Totally twenty-four participants (twelve males and twelve females) rated the discomfort of the test stimuli. The test stimuli included fore and-aft (x), lateral (y), and vertical (z) vibration of three intensity levels (0.2, 0.4, and 0.8 m/s(2) r.m.s., unweighted), each of which had a constant power spectrum density at frequencies ranging from 1.0 to 20 Hz. The order of the test stimuli was fully randomized, and each stimulus was repeated three times. Subjective scale for discomfort caused by whole-body vibration exposure was obtained for each direction by using the category judgment method. Also, the mean Stevens' power law exponent was obtained for females and males at each vibration direction. RESULTS: The power exponents for females were significantly higher than those for males under fore-and-aft and lateral WBV exposure. Subjective discomfort scales obtained under fore-and-aft and lateral vibration exposure exhibited significant gender differences: the upper limits of categories up to "4: uncomfortable" for females were observed to be higher than those for males while the upper limits of category "5: very uncomfortable" for females were lower than those for males. In contrast, no significant gender differences were observed in the subjective discomfort scale or in the power law exponent for vertical WBV exposure. CONCLUSIONS: Our results suggest that females are subjectively more sensitive than males for fore-and-aft and lateral WBV exposure, especially at higher vibration magnitude. Therefore, the differential effects in subjective responses to WBV in females and males should be taken into account in the ISO standard currently used in discomfort evaluation. PMID- 21667178 TI - Structural properties of a new fixation strategy in double bundle ACL reconstruction: the MiniShim. AB - INTRODUCTION: Double-bundle reconstruction of the ACL has become the focus of scientific and clinical interest in the last years. However, there is still a discussion about the most appropriate technique for graft fixation. Both, extracortical fixation systems like the Endobutton and aperture fixation by interference screws have advantages as well as disadvantages. Aim of this study was to analyze the biomechanical properties of a new small wedge shaped implant (MiniShim, Karl Storz, Germany) for the fixation of a soft tissue graft in double bundle ACL reconstruction and to compare it to an aperture fixation by interference screw and an extracortical fixation. METHODS: Porcine knees and flexor tendons were used for this study. 5 and 6 mm tunnels were drilled. The following fixation strategies were tested: 4 and 5 mm MiniShim (Karl Storz Germany), 6 mm interference screw (MegaFix, Karl Storz, Germany), hybridfixation by FlippTack (FlippTack, Karl Storz, Germany) and MiniShim and hybridfixation by FlippTack and 6 mm interference screw. All fixation strategies were tested with a 5 and 6 mm tendon graft. Maximum load, yield load and stiffness were recorded using a material testing machine. Load was applied in line with the bone tunnel. Grafts were cyclically preconditioned between 0 and 20 N for 10 cycles before the graft-bone-complex was loaded to failure. Statistical evaluation was performed using SPSS Version 11.0. RESULTS: Load to failure for the 5 mm graft was 81.1 and 118.0 N for the 4 and 5 mm MiniShims. Fixation by interference screw reached 237.4 N. The extracortical fixation resulted in a load to failure of 471.7 N. Load to failure for the 6 mm tendon grafts was 52.0 and 92.8 N for the 4 and 5 mm MiniShims. Fixation by interference screw resulted in a load to failure of 214.0 N. Extracortical fixation failed at 451.7 N. The difference between MiniShim and interference screw was statistically significant. Load to failure was significantly higher for extracortical fixation compared to fixation by MiniShim or interference screw. Hybrid fixation showed higher fixation strength compared to fixation by interference screw or MiniShim alone. This difference was statistically significant. Stiffness was significantly higher for fixation by interference screw compared to extracortical fixation and fixation by MiniShim. Four different modes of failure could be seen. All 4 mm MiniShims failed by slippage of the tendon past the MiniShim. In the 5 mm group the fixation failed by pullout of the MiniShim or the tendon past the MiniShim. Hybrid fixation failed by rupture of the linkage material. When the graft was fixed by an interference screw failure occurred by rupture of the tendon at the fixation side. CONCLUSION: Hybrid fixation using the MiniShim provides biomechanical properties strong enough to withstand the forces occurring during rehabilitation and comparable to the fixation strength provided by interference screw. While fixation by MiniShim alone does not provide sufficient fixation strength in double bundle ACL reconstruction, hybridfixation using a cortical fixation by FlippTack is an alternative to aperture fixation by interference screw concerning primary stability. PMID- 21667179 TI - Stakeholder analysis and social-biophysical interdependencies for common pool resource management: La Brava Wetland (Argentina) as a case study. AB - This article gives an account of the implementation of a stakeholder analysis framework at La Brava Wetland Basin, Argentina, in a common-pool resource (CPR) management context. Firstly, the context in which the stakeholder framework was implemented is described. Secondly, a four-step methodology is applied: (1) stakeholder identification, (2) stakeholder differentiation-categorization, (3) investigation of stakeholders' relationships, and (4) analysis of social biophysical interdependencies. This methodology classifies stakeholders according to their level of influence on the system and their potential in the conservation of natural resources. The main influential stakeholders are La Brava Village residents and tourism-related entrepreneurs who are empowered to make the more important decisions within the planning process of the ecosystem. While these key players are seen as facilitators of change, there are other groups (residents of the inner basin and fishermen) which are seen mainly as key blockers. The applied methodology for the Stakeholder Analysis and the evaluation of social-biophysical interdependencies carried out in this article can be seen as an encouraging example for other experts in natural sciences to learn and use these methods developed in social sciences. Major difficulties and some recommendations of applying this method in the practice by non-experts are discussed. PMID- 21667180 TI - Biographical sketch: Charles S. Neer, II, MD (1917-2011). PMID- 21667181 TI - Single- versus double-bundle ACL reconstruction: is there any difference in stability and function at 3-year followup? AB - BACKGROUND: Despite a number of studies comparing postoperative stability and function after anatomic double-bundle and single-bundle anterior cruciate ligament reconstruction (ACLR), it remains unclear whether double-bundle reconstruction improves stability or function. QUESTIONS/PURPOSES: We therefore asked whether patients having single- and double-bundle ACLR using semitendinosus (ST) alone differed with regard to (1) postoperative stability; (2) ROM; and (3) five functional scores. METHODS: We prospectively followed 60 patients with an isolated anterior cruciate ligament (ACL) injury. Thirty patients underwent single-bundle and 30 patients underwent double-bundle ACL reconstruction. Clinically we assessed stability and range of motion (ROM); anteroposterior stability was assessed by Rolimeter and rotational stability by a pivot shift test. Function was assessed by IKDC, Noyes, Lysholm, Marx, and Tegner activity scales. The minimum followup was 36 months (mean, 46.2 months; range, 36-60 months). RESULTS: Residual anteroposterior laxity at 3 years postoperatively was similar in both groups: 1.4 +/- 0.3 mm versus 1.4 +/- 0.2 mm, respectively. We observed no difference in the pivot shift test. ROM was similar in both groups, although double-bundle patients required more physical therapy sessions to gain full ROM. IKDC, Noyes, Lysholm, Marx, and Tegner scores were similar at final followup. CONCLUSION: Double-bundle reconstruction of the ACL did not improve function or stability compared with single-bundle reconstruction. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21667182 TI - Effect of daily fiber intake on luteinizing hormone levels in reproductive-aged women. AB - PURPOSE: To evaluate whether the association between fiber intake and LH levels is driven by the association between fiber and estradiol, or whether there is an independent association. METHODS: A prospective cohort of 259 premenopausal women were followed for up to 2 menstrual cycles. Estrogen and LH were measured <=8 times per cycle at visits scheduled using fertility monitors. Diet was assessed <=4 times per cycle by 24-h recall. Linear mixed models on the log scale of hormones were utilized to evaluate the total effects of fiber intake. Inverse probability weights were utilized to estimate the independent effect of fiber on LH levels. RESULTS: In unweighted analyses, we observed a significant, inverse association between fiber intake (in 5 g/day increments) and log LH levels (beta, -0.051, 95% confidence interval (CI), -0.100, -0.002). No association was observed in the weighted analyses, after estradiol levels were taken into account (beta, -0.016, 95% CI, -0.060, 0.027). CONCLUSIONS: The decreased levels of LH associated with high fiber intake were attenuated after taking estradiol levels into account, suggesting that the association between fiber and LH is most likely a consequence of fiber's impact on estradiol and not due to an independent mechanism. PMID- 21667183 TI - A case of left main pulmonary artery aneurysm associated with valvular pulmonary stenosis in a child. AB - Aneurysm of the main pulmonary artery is a rare clinical entity that can be congenital or acquired. Most cases occur in association with other congenital malformations, severe pulmonary hypertension, vasculitides, infectious agents, or collagen vascular disorders. We report here a pediatric case of left pulmonary artery aneurysm associated with valvular pulmonary stenosis and a hypoplastic right pulmonary artery, which we confirmed via multidetector computed tomography angiography. PMID- 21667184 TI - Significance of circulating hepatocyte growth factor in protein-losing enteropathy after Fontan operation. AB - The purpose of this study was to measure serum hepatocyte growth factor (HGF) and elucidate the relationship between HGF and protein-losing enteropathy (PLE) after Fontan operation (FO). Ten patients with PLE (mean age 15.7 +/- 8.7 years) who underwent FO were enrolled. Control group 1 comprised 20 patients without PLE after FO, and control group 2 comprised 10 patients with nephrotic syndrome (NS). Serum HGF, vascular endothelial growth factor, albumin, and random stool alpha-1 antitrypsin concentration were measured. Transthoracic echocardiography was completed. Serum HGF level was significantly greater in the PLE patients (0.61 +/ 0.27 ng/ml) after FO than in the two control groups (0.41 +/- 0.12 ng/ml [P = 0.024] for the Fontan group without PLE and 0.26 +/- 0.12 ng/ml [P = 0.002] for the patients with NS). Serum albumin of patients with PLE (2.82 +/- 0.96 g/dl) showed significantly lower levels compared with those of patients without PLE after FO (4.30 +/- 0.37 g/dl, P < 0.001) but significantly greater levels compared with patients with NS (1.91 +/- 0.33 g/dl, P = 0.019). Patients with greater serum HGF levels showed significant correlation with lower serum albumin level (P = 0.006, r = -0.495). Because serum HGF levels were significantly greater in patients with PLE after FO, HGF may play a role in the development of PLE after FO. PMID- 21667185 TI - Control of a vehicle with EEG signals in real-time and system evaluation. AB - To construct and evaluate a novel wheelchair system that can be freely controlled via electroencephalogram signals in order to allow people paralyzed from the neck down to interact with society more freely. A brain-machine interface (BMI) wheelchair control system was constructed by effective signal processing methods, and subjects were trained by a feedback method to decrease the training time and improve accuracy. The implemented system was evaluated through experiments on controlling bars and avoiding obstacles using three subjects. Furthermore, the effectiveness of the feedback training method was evaluated by comparison with an imaginary movement experiment without any visual feedback for two additional subjects. In the bar-controlling experiment, two subjects achieved a 95.00% success rate, and the third had a 91.66% success rate. In the obstacle avoidance experiment, all three achieved success rate over 90% success rate, and required almost the same amount of time to reach as that when driving with a joystick. In the experiment on imaginary movement without visual feedback, the two additional subjects adapted to the experiment far slower than they did with visual feedback. In this study, the feedback training method allowed subjects to easily and rapidly gain accurate control over the implemented wheelchair system. These results show the importance of the feedback training method using neuroplasticity in BMI systems. PMID- 21667187 TI - Particle size and shape effects in medical syringe needles: experiments and simulations for polymer microparticle injection. AB - Injection of polymeric microparticles is the final step in the drug delivery process. Experience has shown that blockage of the syringe mechanism can be a problem under certain conditions leading to poor control of the final product. Particle size and shape are postulated to be significant factors. In this article 2D Discrete element model (DEM) simulations of circles and semi-circles are used to demonstrate the effect of shape on blockage of the syringe mechanism. To corroborate the calculations, a range of experiments on glass spheres and polymers show good agreement with simulations of normally distributed particle sizes. A similar scenario is also briefly modelled in 3D DEM showing similar trends. PMID- 21667186 TI - Does insulin-like growth factor 1 genotype influence muscle power response to strength training in older men and women? AB - The CA-repeat polymorphism in the insulin-like growth factor 1 (IGF1) gene promoter region has been associated with strength and circulating IGF-I protein levels. The purpose of the study was to determine if the IGF1 CA-repeat polymorphism influences muscle power at baseline and in response to ST in older adults. Knee extensor peak power (PP) was measured at 50, 60, and 70% of 1-RM strength before and after 10 weeks of unilateral knee extensor ST in older adults, aged 50-85 years, to determine the changes in absolute and relative PP with ST. Subjects (N = 114) were genotyped for the IGF1 CA-repeat polymorphism and grouped as homozygous for the 192 allele, heterozygous, or non-carriers of the 192 allele. The 192 homozygotes had significantly lower baseline PP at 50, 60, and 70% of 1-RM strength than the non-carriers when age, sex, and baseline fat-free mass were covaried (all P < 0.05). This same relationship was observed when the highest PP within these ranges was compared (e.g., 317.6 +/- 13.5 for 192 homozygotes and 380.2 +/- 16.3 for non-carriers of the 192 allele, P < 0.05). Both absolute and relative PP increased significantly with ST in all genotype groups as expected, but there were no significant relationships among IGF1 genotypes and any of the PP changes. Despite a significant relationship between IGF1 genotype and knee extensor peak power at baseline, IGF1 genotype does not appear to influence changes in knee extensor peak power with ST. PMID- 21667188 TI - Integrated backscatter for the in vivo quantification of supraphysiological vitamin D(3)-induced cardiovascular calcifications in rats. AB - Cardiovascular calcifications are frequently found in the aging population and are independent predictors of future cardiovascular events. Integrated backscatter (IB) of ultrasound reflectivity can easily quantify calcifications. For this purpose, 30 male Wistar rats received 25,000 IU/kg/day of vitamin D(3) (group 1, n = 8), 18,800 IU/kg/day (group 2, n = 8), or injections with the vehicle only (group 3, n = 14), for 10 weeks. Echocardiographic calibrated IB (cIB) was measured and calculated at baseline and after 10 weeks, followed by ex vivo micro-CT and histopathology of the aortic valve, ascending aorta, and myocardium. After 10 weeks, the mean cIB value of the aortic valve was significantly higher for vitamin D(3)-dosed animals compared to controls. The mean cIB value of the ascending aorta and the myocardium was also significantly higher in group 1 compared to group 3. In vivo IB results were confirmed by ex vivo micro-CT and histopathology. In conclusion, IB is a non-ionizing, feasible, and reproducible tool to quantify cardiovascular calcifications in an in vivo rat model. The integration of IB in the standard echocardiographic examination for the quantification of cardiovascular calcifications could be useful for serial evaluation of treatment efficacy and for prognosis assessment. PMID- 21667189 TI - Oxidative damage induced by chromium (VI) in rat erythrocytes: protective effect of selenium. AB - Excess chromium (Cr) exposure is associated with various pathological conditions including hematological dysfunction. The generation of oxidative stress is one of the plausible mechanisms behind Cr-induced cellular deteriorations. The efficacy of selenium (Se) to combat Cr-induced oxidative damage in the erythrocytes of adult rats was investigated in the current study. Female Wistar rats were randomly divided into four groups of six each: group I served as controls which received standard diet, group II received in drinking water K(2)Cr(2)O(7) alone (700 ppm), group III received both K(2)Cr(2)O(7) and Se (0.5 Na(2)SeO(3) mg/kg of diet), and group IV received Se (0.5 mg/kg of diet) for 3 weeks. Rats exposed to K(2)Cr(2)O(7) showed an increase of malondialdehyde and protein carbonyl levels and a decrease of sulfhydryl content, glutathione, non-protein thiol, and vitamin C levels. A decrease of enzyme activities like catalase, glutathione peroxidase, and superoxide dismutase activities was also noted. Co-administration of Se with K(2)Cr(2)O(7) restored the parameters cited above to near-normal values. Therefore, our investigation revealed that Se was a useful element preventing K(2)Cr(2)O(7)-induced erythrocyte damages. PMID- 21667190 TI - Family size and perinatal circumstances, as mental health risk factors in a Scottish birth cohort. AB - PURPOSE: Higher maternal parity and younger maternal age have each been observed to be associated with subsequent offspring suicidal behaviour. This study aimed to establish if these, and other variables from the perinatal period, together with family size, are also associated with other psychiatric morbidity. METHODS: Linked datasets of the Scottish Morbidity Record and Scottish death records were used to follow up, into young adulthood, a birth cohort of 897,685. In addition to the index maternity records, mothers' subsequent pregnancy records were identified, allowing family size to be estimated. Three independent outcomes were studied: suicide, self-harm, and psychiatric hospital admission. Data were analysed using Cox regression. RESULTS: Younger maternal age and higher maternal parity were independently associated with increased risk in offspring of suicide, of self-harm and of psychiatric admission. Risk of psychiatric admission was higher amongst those from families of three or more, but, compared with only children, those with two or three siblings had a lower risk of self harm. CONCLUSION: Perinatal and family composition factors have a broad influence on mental health outcomes. These data suggest that the existence of younger, as well as elder siblings may be important. PMID- 21667192 TI - Investigation of the antigenic evolution of field isolates using the reverse genetics system of infectious bursal disease virus (IBDV). AB - The antigenic profiles of over 300 infectious bursal disease virus (IBDV) isolates were analyzed using a panel of monoclonal antibodies in a reverse genetics system. In addition, the sequences of a large portion of the neutralizing-antibody-inducing VP2 of IBDV were determined. Phylogenetic analysis of nucleotide and amino acid sequences in combination with the antigenic profiles obtained using the monoclonal antibody panel, revealed a lack of correlation between antigenicity and isolate's placement within the phylogenetic tree. In depth analysis of amino acid exchanges revealed that changes within a certain region of the VP2 molecule resulted in differences in the antigenicity of the virus. This comprehensive analysis of VP2 sequences indicated a high selective pressure in the field that was likely due to vaccination programs, which increase the rate of evolution of the virus. PMID- 21667191 TI - Effect of lisinopril on renal tissue damage in unilateral ureteral obstruction in rats. AB - In this study, it was aimed to investigate apoptosis in renal injury and the effect of lisinopril in rat model, which constitute unilateral ureteral obstruction. The retroperitoneal ureter was ligated with a 4.0 silk for the experimental model of ureteral obstruction in Wistar albino rats. Untreated group (n = 20) received no treatment. For the lisinopril-treated group (n = 20), 20 mg/kg/day of drug was given orally. Ultrastructural differences were analyzed using electron microscopic technique; apoptotic distribution was analyzed using the TUNEL method. After electron microscopic evaluation, on the 4th and 14th day in the untreated group, edema in the glomeruli, loss of microvillus and apoptotic cells in proximal tubule cells and sclerosis in the glomeruli were detected. On the 4th day in the lisinopril-treated group, the kidney was ultrastructurally normal and a less number of apoptotic cells were only observed on the 14th day. On light microscopic examination on the 4th and 14th day in the untreated group, while the glomeruli were normal in structure, the boundary of the proximal tubule was disrupted and some picnotic cells in both the proximal and collecting tubules were observed. In both 4th and 14th day of the lisinopril-treated group, kidney showed normal structure, although in some places picnotic cells in the collecting tubules were observed. In conclusion, lisinopril was effective and it may prevent early renal damage in the direct obstruction model. PMID- 21667194 TI - Lymphatic tumor emboli detected by D2-40 immunostaining can more accurately predict lymph-node metastasis. AB - BACKGROUND: Resected specimens of superficial squamous cell carcinoma of the esophagus (SSCCE) underwent D2-40 immunostaining to accurately assess lymphatic tumor emboli (LY) and to analyze correlations between LY and lymph node metastasis (N). This present study was designed to determine the accuracy of LY grade for predicting the risk of N. MATERIALS AND METHODS: We studied 75 patients with SSCCE who underwent surgical resection of their tumors. Resected specimens were sliced into continuous sections at 5 mm intervals. Intramucosal cancers are classified into three groups (m1, m2, m3), and submucosal cancers are also divided into three groups (sm1, sm2, sm3). The numbers of LY present in lymphatic ducts on D2-40 immunostaining, venous tumor emboli (V) on CD34 immunostaining, and lymphatic tumor emboli (ly) and V on hematoxylin-eosin staining (HE) and elastica van Gieson staining (EVG) were counted for each case. The presence of lymphatic tumor emboli was graded according to the total number of LY per case as follows: 0, LY0; 1 to 2, LY1; 3 to 9, LY2; and 10 or more, LY3. RESULTS: All m1 and m2 cases were LY- and N- Lymphatic tumor emboli were present in 54% of m3 cases, 70% of sm1 cases, 54% of sm2 cases, and 75% of sm3 cases. Determination of N was positive in 18% of m3 cases, 47% of sm1 cases, 36% of sm2 cases, and 62% of sm3 cases. The frequency of LY significantly correlated with the number of N (p < 0.0001). Multiple regression analysis showed that only LY and V significantly correlated with N. When the detection rate of N was compared between LY and ly, LY was superior to ly in terms of specificity, accuracy, positive predictive value, and false positive rate. As for LY grade, N was positive in 39.1% of LY1 cases, 81.8% of LY2 cases, and 100% of LY3 cases. Even in LY-, N was positive in one sm1 case and in two sm2 cases. In the sm1 case, the depth of invasion was 350 MUm from the lower margin of the muscularis mucosae. CONCLUSIONS: Evaluation of lymphatic invasion on the basis of LY is more accurate for the prediction of N than conventional techniques, and LY grade strongly correlates with N. In patients with SSCCE, mucosal cancers (m1, m2, and m3) and submucosal cancers with a depth of invasion of <= 200 MUm from the lower margin of the muscularis mucosae on endoscopic mucosal resection have a low risk of N if the number of LY is 0. Endoscopic mucosal resection alone can provide good treatment outcomes in such patients. PMID- 21667195 TI - Composition and stability of the microbial community inside the digestive tract of the aquatic crustacean Daphnia magna. AB - Small filter-feeding zooplankton organisms like the cladoceran Daphnia spp. are key members of freshwater food webs. Although several interactions between Daphnia and bacteria have been investigated, the importance of the microbial communities inside Daphnia guts has been studied only poorly so far. In the present study, we characterised the bacterial community composition inside the digestive tract of a laboratory-reared clonal culture of Daphnia magna using 16S rRNA gene libraries and terminal-restriction length polymorphism fingerprint analyses. In addition, the diversity and stability of the intestinal microbial community were investigated over time, with different food sources as well as under starvation stress and death, and were compared to the community in the cultivation water. The diversity of the Daphnia gut microbiota was low. The bacterial community consisted mainly of Betaproteobacteria (e.g. Limnohabitans sp.), few Gammaproteobacteria (e.g. Pseudomonas sp.) and Bacteroidetes that were related to facultatively anaerobic bacteria, but did not contain typical fermentative or obligately anaerobic gut bacteria. Rather, the microbiota was constantly dominated by Limnohabitans sp. which belongs to the Lhab-A1 tribe (previously called R-BT065 cluster) that is abundant in various freshwaters. Other bacterial groups varied distinctly even under constant cultivation conditions. Overall, the intestinal microbial community did not reflect the community in the surrounding cultivation water and clustered separately when analysed via the Additive Main Effects and Multiplicative Interaction model. In addition, the microbiota proved to be stable also when Daphnia were exposed to bacteria associated with a different food alga. After starvation, the community in the digestive tract was reduced to stable members. After death of the host animals, the community composition in the gut changed distinctly, and formerly undetected bacteria were activated. Our results suggest that the Daphnia microbiota consists mainly of an aerobic resident bacterial community which is indigenous to this habitat. PMID- 21667196 TI - Phylogenetic inference of colony isolates comprising seasonal Microcystis blooms in Lake Taihu, China. AB - Blooms of the toxin-producing cyanobacterium, Microcystis spp., are an increasingly prevalent water quality problem and health hazard worldwide. China's third largest lake, Lake Taihu, has been experiencing progressively more severe Microcystis blooms over the past three decades. In 2009 and 2010, individual Microcystis colonies, consisting of four different morphospecies, were isolated and genotyped using a whole-cell multiplex PCR assay. The 16S-23S rDNA-ITS sequences were aligned based on Bayesian inference and indicated that one morphospecies was genetically unique (Microcystis wesenbergii) and three were indistinguishable (Microcystis aeruginosa, Microcystis flos-aquae, and Microcystis ichthyoblabe). Microcystin (mcyB) genes were detected intermittently in two of the morphospecies while the other two morphospecies lacked the mcyB gene in all samples. Water temperature was found to influence bloom formation and morphotype prevalence, and chlorophyll a and temperature were positively and significantly correlated with microcystin concentration. Cooler water temperatures promoted toxigenic strains of Microcystis. Wind appeared to influence the distribution of morphotypes across the lake, with M. aeruginosa and M. ichthyoblabe being more susceptible to wind stress than M. wesenbergii and M. flos-aquae. The results of this study indicated that the blooms were composed of a variety of Microcystis morphospecies, with more genotypes observed than can be attributed to individual morphotypes. We conclude that morphology is not a reliable indicator of toxigenicity in Lake Taihu, and caution should be exercised when the M. aeruginosa morphotype is present because it is capable of producing MC-LR, the most toxic microcystin isoform. PMID- 21667197 TI - Scale-up of ethanol production from winter barley by the EDGE (enhanced dry grind enzymatic) process in fermentors up to 300 l. AB - A fermentation process, which was designated the enhanced dry grind enzymatic (EDGE) process, has recently been developed for barley ethanol production. In the EDGE process, in addition to the enzymes normally required for starch hydrolysis, commercial beta-glucanases were used to hydrolyze (1,3)(1,4)-beta-D: -glucans to smaller molecules, thus reducing the viscosity of the mash to levels sufficiently low to allow transport and mixing in commercial equipment. Another enzyme, a developmental beta-glucosidase, then was used to hydrolyze the resulting oligomers to glucose, which subsequently was fermented to produce additional ethanol. The EDGE process was developed with Thoroughbred, a winter hulled barley, using a shake flask model. To move toward commercialization, it is necessary to prove that the developed process would be applicable to other barley varieties and also to demonstrate its scalability. Experiments were performed in 7.5, 70, and 300-l fermentors using Thoroughbred and Eve, a winter hull-less barley. It was shown that the process was scalable for both barley varieties. Low levels of glucose throughout the course of the fermentations demonstrated the high efficiency of the simultaneous saccharification and fermentation process. Final ethanol concentrations of 14% (v/v) were achieved for initial total solids of 28.5-30% (w/w), which gave an ethanol yield of 83-87% of the theoretical values. The distillers dried grains with solubles co-products contained very low levels of beta-glucans and thus were suitable for use in feed formulations for all animal species. PMID- 21667199 TI - Comparison of behavioral intervention and sensory-integration therapy in the treatment of challenging behavior. PMID- 21667198 TI - Role of allergen sensitization in older adults. AB - There is a common perception among physicians and patients that allergic diseases are not relevant in older adults. There is also recognition that innate and adaptive immune functions decline with aging. It is the function of a variety of immune cells in the form of allergic inflammation that is a hallmark of allergic diseases. In fact, there is a fairly consistent observation that measures of allergic sensitization, such as skin prick testing, specific IgE, or total IgE, decline with age. Nonetheless, the association between allergic sensitization and allergic diseases, particularly asthma and allergic rhinitis, remains robust in the older adult population. Consequently, an appropriate evaluation of allergic sensitivities is warranted and indicated in older asthma and rhinitis patients to provide optimal care for the individual and minimize any resultant morbidity and mortality. PMID- 21667200 TI - Design and subject characteristics in the federally-funded citalopram trial in children with pervasive developmental disorders. AB - The Studies to Advance Autism Research and Treatment Network conducted a randomized trial with citalopram in children with Pervasive developmental disorders (PDDs). We present the rationale, design and sample characteristics of the citalopram trial. Subjects (128 boys, 21 girls) had a mean age of 9.3 (+/ 3.12) years; 132 (88.6%) were diagnosed with autistic disorder (4.7% with Asperger's Disorder; 6.7% with PDD-not otherwise specified). Less than half of the subjects were intellectually disabled; 117 (78.5%) were rated Moderate or Marked on the Clinical Global Impression for Severity. Study measures were similar to previous Research Units on Pediatric Psychopharmacology trials. Subjects in this trial were slightly older and more likely to have complaints of repetitive behavior than participants in RUPP trials. PMID- 21667201 TI - Unmet need and problems accessing core health care services for children with autism spectrum disorder. AB - To investigate the health care experiences of children with autism spectrum disorder, whether they have unmet needs, and if so, what types, and problems they encounter accessing needed care. We address these issues by identifying four core health care services and access problems related to provider and system characteristics. Using data from the 2005-2006 National Survey of Children with Special Health Care Needs (NS-CSHCN) we compared children with autism spectrum disorder with children with special health care needs with other emotional, developmental or behavioral problems (excluding autism spectrum disorder) and with other children with special health care needs. We used weighted logistic regression to examine differences in parent reports of unmet needs for the three different health condition groups. Overall unmet need for each service type among CSHCN ranged from 2.5% for routine preventive care to 15% for mental health services. After controlling for predisposing, enabling and need factors, some differences across health condition groups remained. Families of children with autism spectrum disorder were in fact significantly more at risk for having unmet specialty and therapy care needs. Additionally, families of children with autism spectrum disorder were more likely to report provider lack of skills to treat the child as a barrier in obtaining therapy and mental health services. Disparities in unmet needs for children with autism suggest that organizational features of managed care programs and provider characteristics pose barriers to accessing care. PMID- 21667202 TI - Cardiac catheterization: haemostatic changes in pediatric versus adult patients. AB - Thrombophilic or haemorrhagic complications are possible adverse events following cardiac catheterization particularly in pediatric patients. It was therefore the aim of our study to compare the cardiac catheterization-related haemostatic changes in children with that in adults. The total of 50 patients was subdivided into Gr I (1-6 years), Gr II (7-18 years), and Gr III (19-58 years). Parameters of coagulation activation, plasma levels of various clotting factors and heparinase-modified thrombelastometry parameters were determined prior and immediately after cardiac catheterization. The haemostatic system of pediatric patients was markedly more affected by the procedure than that of adults. Levels of thrombin/antithrombin complex and prothrombin fragment 1+2 in the post catheter plasma samples were significantly increased in Grs I and II, not in Gr III. The catheter-related decrease in fibrinogen and F II levels was higher in Gr I than in Grs II and III. F VII levels were significantly decreased in Grs I and II, not in Gr III. The catheter-related prolongation of Coagulation times was highest in Gr I, followed by Gr II and finally Gr III. A significant catheter related decrease of maximum clot firmness was observed solely in Gr I. Our results show that cardiac catheterisation perturbs the haemostatic system of adults, and, even more pronounced, that of pediatric patients. Thus, our results indicate that children might be at a higher risk for either thrombotic complications or post-operative bleeding events than adults. PMID- 21667203 TI - Performance measures for improving the prevention of venous thromboembolism: achievement in clinical practice. AB - Venous thromboembolism (VTE) is a common complication during and after hospitalization for acute medical illness or surgery. Despite the existence of evidence-based guidelines for VTE prevention, real-world prescribing practices are frequently suboptimal. Specific performance measures relating to VTE prevention and treatment have been developed by US health care organizations to increase adherence with best-practice recommendations and ultimately reduce the number of preventable VTE events. Two measures developed by the Surgical Care Improvement Project have been endorsed by the National Quality Forum (NQF) and focus on VTE prevention. In addition, six measures have been developed recently by The Joint Commission in collaboration with the NQF; three measures relate to VTE prevention and three focus on treatment. To attain widespread achievement of these performance goals, it is essential to raise awareness of their existence and specifications. It is also imperative that hospitals develop and implement effective VTE protocols. The use of multiple, active strategies, such as computer decision support systems with regular audit and feedback, may be particularly valuable approaches to improve current practices within an integrated quality improvement program. During practical implementation of VTE protocols at Norton Healthcare (Kentucky's largest healthcare system), strong leadership, physician engagement, and caregiver accountability were identified as key factors influencing the process. As such, more hospitals may be able to increase adherence with guidelines, improve achievement of quality goals, and help to reduce the substantial burden associated with avoidable VTE. PMID- 21667204 TI - Methyl-1-hydroxy-2-naphthoate, a novel naphthol derivative, inhibits lipopolysaccharide-induced inflammatory response in macrophages via suppression of NF-kappaB, JNK and p38 MAPK pathways. AB - OBJECTIVE AND DESIGN: The anti-inflammatory effect of methyl-1-hydroxy-2 naphthoate (MHNA), a novel naphthol derivative, was evaluated in the lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages. MATERIALS AND METHODS: The release of nitric oxide (NO), interleukin-1beta (IL 1beta) and interleukin-6 (IL-6) were detected by the Griess reagent and ELISA methods. The protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were examined by Western blotting. The mRNA expressions of IL-1beta, IL-6, iNOS and COX-2 were determined by real-time PCR. Activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappaB) pathways were detected by Western blotting, reporter gene assay and electrophoretic mobility shift assay. RESULTS: MHNA significantly inhibited the release of NO, IL-1beta and IL-6 as well as the protein expression of iNOS and COX-2 in LPS-stimulated macrophages. It also inhibited the mRNA expression of iNOS, COX-2, IL-1beta and IL-6. Further studies indicated that MHNA inhibited LPS induced increases in NF-kappaB DNA-binding activity and NF-kappaB transcriptional activity as well as IkappaB-alpha degradation and NF-kappaB translocation in a dose-dependent manner. Meanwhile, the activation of p38 MAPK and c-Jun N-terminal kinases (JNK) induced by LPS were decreased by MHNA. CONCLUSIONS: MHNA inhibits the LPS-induced inflammatory response in murine macrophages via suppression of NF kappaB and MAPKs signaling pathways activation. PMID- 21667205 TI - Painting the chromosomes of Brachypodium: current status and future prospects. AB - Chromosome painting is one of the most powerful and spectacular tools of modern molecular cytogenetics, enabling complex analyses of nuclear genome structure and evolution. For many years, this technique was restricted to the study of mammalian chromosomes, as it failed to work in plant genomes due mainly to the presence of large amounts of repetitive DNA common to all the chromosomes of the complement. The availability of ordered, chromosome-specific BAC clones of Arabidopsis thaliana containing relatively little repetitive genomic DNA enabled the first chromosome painting in dicotyledonous plants. Here, we show for the first time chromosome painting in three different cytotypes of a monocotyledonous plant-the model grass, Brachypodium distachyon. Possible directions of further detailed studies are proposed, such as the evolution of grass karyotypes, the behaviour of meiotic chromosomes, and the analysis of chromosome distribution at interphase. PMID- 21667206 TI - Efficacy of a single treatment of head lice with a neem seed extract: an in vivo and in vitro study on nits and motile stages. AB - An anti-louse shampoo (Licener(r)) based on a neem seed extract was tested in vivo and in vitro on its efficacy to eliminate head louse infestation by a single treatment. The hair of 12 children being selected from a larger group due to their intense infestation with head lice were incubated for 10 min with the neem seed extract-containing shampoo. It was found that after this short exposition period, none of the lice had survived, when being observed for 22 h. In all cases, more than 50-70 dead lice had been combed down from each head after the shampoo had been washed out with normal tap water. A second group of eight children had been treated for 20 min with identical results. Intense combing of the volunteers 7 days after the treatment did not result in the finding of any motile louse neither in the 10-min treated group nor in the group the hair of which had been treated for 20 min. Other living head lice were in vitro incubated within the undiluted product (being placed inside little baskets the floor of which consisted of a fine net of gauze). It was seen that a total submersion for only 3 min prior to washing 3* for 2 min with tap water was sufficient to kill all motile stages (larvae and adults). The incubation of nits at 30 degrees C into the undiluted product for 3, 10, and 20 min did not show differences. In all cases, there was no eyespot development or hatching larvae within 7-10 days of observation. This and the fact that the hair of treated children (even in the short-time treated group of only 10 min) did not reveal freshly hatched larval stages of lice indicate that there is an ovicidal activity of the product, too. PMID- 21667207 TI - Bowel obstruction after laparoscopic and open colon resection for cancer: results of 5 years of follow-up in a randomized trial. AB - BACKGROUND: Postoperative bowel obstruction caused by intra-abdominal adhesions occurs after all types of abdominal surgery. It has been suggested that the laparoscopic technique should reduce the risk for adhesion formation and thus for postoperative bowel obstruction. This study was designed to compare the incidence of bowel obstruction in a randomized trial where laparoscopic and open resection for colon cancer was compared. METHODS: A retrospective analysis was performed, collecting data of episodes of bowel obstruction with or without surgery. Only episodes treated in the hospital where the index surgery took place were included. Data for 786 patients were collected for the 5-year period after cancer surgery. RESULTS: Baseline characteristics for the evaluated laparoscopic (n = 383) and open (n = 403) groups were comparable. The cumulative obstruction percentages at 5 years for the open and laparoscopic groups were 6.5 and 5.1% respectively and did not significantly differ from each other. Tumor stage seemed to influence the risk for bowel obstruction: 2.8% in stage I, 6.6% in stage II, and 7% in stage III, but the differences were not significant. CONCLUSIONS: This analysis does not support the hypothesis that laparoscopy leads to fewer episodes of bowel obstruction compared with open surgery. PMID- 21667208 TI - Evolution of endoscopic thyroidectomy. PMID- 21667209 TI - Multimedia manuscript: laparoscopic resection of hepatocellular carcinoma at segment 7: the posterior approach to anatomic resection. AB - BACKGROUND: Open anatomical liver resections remain one of the most effective treatments of hepatocellular carcinoma (HCC) and results in better recurrence free and overall survival compared to nonanatomical resections [1]. On the other hand, laparoscopic hepatectomies for HCC have recently emerged with the benefits of reduced blood loss, shorter hospital stay, and less severe wound pain [2, 3]. Classically, liver lesions considered suitable for laparoscopic resection were those small tumors (<4 cm) located over the anterior and left lateral segments [3]. However, we would like to expand the current indications and here we present our techniques of laparoscopic anatomical resection for a HCC that was located at right posteriosuperior segment 7. METHODS: Our patient was a 60-year-old gentleman who had Child's A hepatitis B cirrhosis and was on entecavir. During a follow-up CT scan, a 2.6-cm segment 7 lesion with early arterial enhancement and contrast washout was noted and was subsequently confirmed with arteriogram. alpha Fetoprotein was 3 ng/ml (normal < 20 ng/ml). The video demonstrates a posterior approach to laparoscopic resection of segment 7. RESULTS: Operative time was 510 min. Blood loss was 800 ml and no perioperative transfusion was required. Postoperative recovery was uneventful and only simple oral analgesics were required for pain control. He was discharged on postoperative day 6. Histology showed a moderately differentiated hepatocellular carcinoma and all resection margins were clear. Subsequent follow-up CT scan 6 months after the operation showed no evidence of recurrence and alpha-fetoprotein level was normal. CONCLUSIONS: Laparoscopic hepatectomy for HCC over the right posterior segment of the liver is feasible in selected patients with favorable results in terms of wound size, postoperative recovery, and hospital stay. Maximal liver conservation was achieved in performing oncologic anatomical resection of segment 7 instead of a posterior sectionectomy. On the other hand, a posterior approach was recommended because it allowed early intrahepatic control of pedicles and identification of the right hepatic vein to guide parenchymal transection along the intersegmental plane. PMID- 21667210 TI - A comparative study of standard versus laparoendoscopic single-site surgery (LESS) totally extraperitoneal (TEP) inguinal hernia repair. AB - BACKGROUND: Laparoscopic inguinal hernia repair has been around since the 1990s. A novel surgical approach known as laparoendoscopic single-site surgery (LESS) has been developed to reduce the port-related morbidities and improve the cosmetic outcomes of laparoscopic surgery, including totally extraperitoneal (TEP) inguinal hernia repair. The aim of the present study was to evaluate the safety and feasibility of the LESS TEP technique for inguinal hernia repair and compare the outcomes with the standard TEP approach. METHODS: Between January and May 2009, 54 consecutive healthy patients (48 men and 6 women) underwent LESS TEP inguinal hernia repair at our institute. All procedures were performed using our homemade single port for simultaneous passage of the laparoscope and instruments. The perioperative data, including patient age, sex, body mass index (BMI), hernia characteristics, operative time, complications, length of hospital stay, return to normal activity, pain score, and cosmetic result, were prospectively collected. RESULTS: All LESS TEP procedures were completed successfully without conversion to standard laparoscopic or open surgery. A total of 98 LESS TEP hernia repairs were performed in 54 patients and compared with 152 standard TEP operations. The mean operative time was significantly shorter in the standard TEP series (61.8 +/- 26.0 vs. 70.9 +/- 23.8 min, p = 0.04). Other perioperative parameters, including the length of hospital stay, time until return to full activity, complication rate, pain score, and cosmetic result, were all comparable between the two techniques. CONCLUSION: Our short-term experience with LESS TEP inguinal hernia repair has shown that in experienced hands, inguinal hernia repair via the LESS TEP technique is as safe as the standard TEP technique. However, based on our evidence, we currently believe that the LESS TEP technique is not an efficacious surgical alternative to the standard TEP technique for inguinal hernias. PMID- 21667211 TI - Identification of motion from multi-channel EMG signals for control of prosthetic hand. AB - The authors in this paper propose an effective and efficient pattern recognition technique from four channel electromyogram (EMG) signals for control of multifunction prosthetic hand. Time domain features such as mean absolute value, number of zero crossings, number of slope sign changes and waveform length are considered for pattern recognition. The patterns are classified using simple logistic regression (SLR) technique and decision tree (DT) using J48 algorithm. In this study six specific hand and wrist motions are identified from the EMG signals obtained from ten different able-bodied. By considering relevant dominant features for pattern recognition, the processing time as well as memory space of the SLR and DT classifiers is found to be less in comparison with neural network (NN), k-nearest neighbour model 1 (kNN-Model-1), k-nearest neighbour model 2 (kNN Model-2) and linear discriminant analysis. The classification accuracy of SLR classifier is found to be 91 +/- 1.9%. PMID- 21667212 TI - Antidiabetic vanadium compound and membrane interfaces: interface-facilitated metal complex hydrolysis. AB - The interactions of metabolites of the antidiabetic vanadium-containing drug bis(maltolato)oxovanadium(IV) (BMOV) with lipid interface model systems were investigated and the results were used to describe a potentially novel mechanism by which these compounds initiate membrane-receptor-mediated signal transduction. Specifically, spectroscopic studies probed the BMOV oxidation and hydrolysis product interaction with interfaces created from cetyltrimethylammonium bromide (CTAB) which mimics the positively charged head group on phosphatidylcholine. (1)H and (51)V NMR spectroscopies were used to determine the location of the dioxobis(maltolato)oxovanadate(V) and the maltol ligand in micelles and reverse micelles by measuring changes in the chemical shift, signal linewidth, and species distribution. Both micelles and reverse micelles interacted similarly with the complex and the ligand, suggesting that interaction is strong as anticipated by Coulombic attraction between the positively charged lipid head group and the negatively charged complex and deprotonated ligand. The nature of the model system was confirmed using dynamic light scattering studies and conductivity measurements. Interactions of the complex/ligand above and below the critical micelle concentration of micelle formation were different, with much stronger interactions when CTAB was in the form of a micelle. Both the complex and the ligand penetrated the lipid interface and were located near the charged head group. These studies demonstrate that a lipid-like interface affects the stability of the complex and raise the possibility that ligand exchange at the interface may be important for the mode of action for these systems. Combined, these studies support recently reported in vivo observations of BMOV penetration into 3T3-L1 adipocyte membranes and increased translocation of a glucose transporter to the plasma membrane. PMID- 21667213 TI - Regulation of phosphatidic acid levels in Trypanosoma cruzi. AB - Lipid kinases and phosphatases play essential roles in signal transduction processes involved in cytoskeletal rearrangement, membrane trafficking, and cellular differentiation. Phosphatidic acid (PtdOH) is an important mediator lipid in eukaryotic cells, but little is known regarding its regulation in the parasite Trypanosoma cruzi, an agent of Chagas disease. In order to clarify the relationship between PtdOH metabolism and developmental stages of T. cruzi, epimastigotes in culture were subjected to hyperosmotic stress (~1,000 mOsm/L), mimicking the environment in the rectum of vector triatomine bugs. These experimental conditions resulted in differentiation to an intermediate form between epimastigotes and trypomastigotes. Morphological changes of epimastigotes were correlated with an increase in PtdOH mass accomplished by increased enzyme activity of diacylglycerol kinase (DAGK, E.C. 2.7.1.107) and concomitant decreased activity of phosphatidate phosphatases type 1 and type 2 (PAP1, PAP2, E.C. 3.1.3.4). Our results indicate progressive increases of PtdOH levels during the differentiation process, and suggest that the regulation of PtdOH metabolism is an important mechanism in the transition from T. cruzi epimastigote to intermediate form. PMID- 21667214 TI - Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet. AB - AIMS/HYPOTHESIS: Urocortins are the endogenous ligands for the corticotropin releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3. METHODS: Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (Ucn3(+)) under control conditions and following an obesogenic high-fat diet (HFD) challenge. RESULTS: Ucn3(+) mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in Crfr2 (also known as Crhr2)-null mice negated key aspects of the Ucn3(+) phenotype. Ucn3(+) mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in Ucn3(+) muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in Ucn3(+) muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed. CONCLUSIONS/INTERPRETATION: Urocortin 3 acting on CRFR2 in skeletal muscle of Ucn3(+) mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity. PMID- 21667215 TI - Histopathological effects of carbaryl on testes of snake-eyed lizard, Ophisops elegans. AB - BACKGROUND, AIM AND SCOPE: Due to their ecological niche and insectivore nature, lizards are of increased risk of exposure to pesticides in agricultural areas. In addition to their potential direct effects on non-target species, insecticides can also result in indirect impacts on lizard population by reducing their food source. Carbaryl is a common insecticide that is widely used in areas of Turkey that are home to a variety of reptiles. However, to date, little is known about the potential effects of the exposure of reptiles such as lizards or snakes to this pesticide. The aim of the study was to investigate toxic effects of carbaryl on the testes of snake-eyed lizard, Ophisops elegans that is common to regions in Turkey where Carbaryl is applied and that it can be easily cultured in the laboratory. MATERIAL AND METHODS: Adult male lizards were exposed to carbaryl once by oral gavage in concentrations of 2.5, 25 and 250 MUg/g. After 96 h, lizards were euthanized and dissected. Histopathological changes were detected by randomly counting 100 tubules in each lizard. Seminiferous tubules were categorized as normal, sloughing and disorganized tubules. Diameters of tubules were also measured. The differences in histopathological changes and tubule diameters were compared for statistical significance by one-way ANOVA, using SPSS 16.0. RESULTS AND DISCUSSION: Histopathological changes were more prominent in medium- (25 MUg/g) and high-dose (250 MUg/g) groups than in the low-dose (2.5 MUg/g) group. In the medium-dose group, the hexagonal appearance of most tubules disappeared, and they took on an oval shape. Sloughing was the characteristic tubule appearance of the medium group. In the high-dose group, significant increases in the number of disorganized tubules and prominence of haemorrhages was observed. CONCLUSION: Carbaryl caused histopathological defects on the testes of O. elegans, so it is clear that carbaryl affects male fertility in O. elegans. PMID- 21667216 TI - Adherence to CPAP therapy improves quality of life and reduces symptoms among obstructive sleep apnea syndrome patients. AB - PURPOSE: The aim of the study was to asses quality of life and symptoms of obstructive sleep apnea syndrome (OSAS) patients after adhering to 6 months of continuous positive airway pressure (CPAP) treatment. METHODS: A group of 50 patients (41 men and 9 women) were diagnosed by polysomnography and treated with CPAP therapy for 6 months. Their symptoms and health-related quality of life were assessed by administering a validated and translated version of the sleep apnea quality of life index (SAQLI). Sleepiness was measured using the Epworth Sleepiness Scale (ESS) and through electronic monitoring of CPAP usage per night of sleep. RESULTS: Mean CPAP usage was 4.5 +/- 0.5 h per night. Comparisons between quality of life indexes before and after CPAP treatment showed an improvement in the total SAQLI score (3.8 +/- 0.9 vs. 5.8 +/- 0.8 after CPAP, p < 0.01), in daily functioning (4.2 +/- 1.4 vs. 6.0 +/- 0.9, p < 0.01), social interactions (4.8 +/- 1.3 vs.6.3 +/- 0.7, p < 0.01), emotional functioning (4.4 +/- 1.4 vs. 5.7 +/- 1.0, p < 0.01), symptoms (1.6 +/- 0.8 vs. 5.8 +/- 1.2, p < 0.01), and in the ESS (13.7 +/- 6.5 vs. 3.9 +/- 3.8, p < 0.01). Regarding the patients' symptoms, improvement was noticed for "sleepiness while watching a spectacle" (96%), "reading" (95%), "carrying on a conversation" (95%), "driving" (92.9%), "restless sleep" (87.8%), and "urinating more than once per night" (84.8%). Smaller improvements were observed for the reported "dry mouth-throat upon awakening" (36.1%),"excessive fatigue" (54.5%), and "decreased energy" (55.3%). CONCLUSION: We conclude that OSAS patients who adhere to nighttime CPAP therapy show significant improvement of their quality of life, daytime sleepiness, and other symptoms after 6 months of treatment with CPAP. PMID- 21667217 TI - On the stock estimation for a harvested fish population. AB - We consider a stage-structured model of a harvested fish population and we are interested in the problem of estimating the unknown stock state for each class. The model used in this work to describe the dynamical evolution of the population is a discrete time system including a nonlinear recruitment relationship. To estimate the stock state, we build an observer for the considered fish model. This observer is an auxiliary dynamical system that uses the catch data over each time interval and gives a dynamical estimate of the stock state for each stage class. The observer works well even if the recruitment function in the considered model is not well known. The same problem for an age-structured model has been addressed in a previous work. PMID- 21667218 TI - A modified bite block for fibreoptic bronchoscopy in patients with face and neck scars. PMID- 21667219 TI - Paediatric pneumococcal disease in Central Europe. AB - Streptococcus pneumoniae causes considerable global paediatric morbidity and mortality, despite the availability of safe and effective pneumococcal conjugate vaccines (PCVs). To justify the introduction of PCVs, accurate information on the burden of disease is required. Here, we present an appraisal of the pneumococcal epidemiological situation in 11 Central European countries. The data are based on study findings presented at the 12th Central European Vaccine Advisory Group (CEVAG) meeting, held on 21-22 May 2010 in Sofia, Bulgaria, and a literature review of the PubMed database using the search terms 'pneumococcal' or 'Streptococcus pneumoniae', in combination with 'otitis media', 'pneumonia', 'meningitis' or 'bacteraemia/sepsis', and '[Central European country name]'. The incidence of pneumococcal disease appears to be lower in Central Europe than previously reported for Europe as a whole, with the highest risk in infants aged 0-2 years. The fatality rates in the under fives from invasive infections are up to 40%. A paucity of comprehensive country-specific data on pneumococcal disease burden arises from the lack of homogenous surveillance programmes. Standardised, active surveillance systems are required for the accurate evaluation of the pneumococcal disease burden in the region. Only then can the need for vaccination be addressed. PMID- 21667220 TI - Femoral shortening and cementless arthroplasty in Crowe type 4 congenital dislocation of the hip. AB - PURPOSE: In reconstruction of congenital hip dislocation by total hip arthroplasty (THA), positioning of the acetabular component in the true acetabulum is sometimes accompanied by shortening of the femur. Shortening of the femur is of importance for minimising risk of damaging neurovascular structures due to excessive limb lengthening. Furthermore, reduction of the femoral head into the true acetabulum remains challenging without shortening of the femur. METHODS: We performed a consecutive case series of cementless THA with femoral shortening and Crowe type 4 congenital dislocation. All acetabular cups were placed in their original anatomical location. In all cases a proximal diaphyseal step-cut shortening osteotomy was performed and stabilised with two to three titanium cerclage bands. RESULTS: At an average of 60 months follow-up (range 36 96), 12 patients (13 THA) were scored clinically by the Merle D'Aubigne and Harris hip scores. In ten cases good to excellent outcome scores were observed. During the follow-up period no cases of aseptic loosening, nerve palsy, nonunions or dislocations were found. CONCLUSIONS: This technique seems to be an excellent treatment option in the case of Crowe type 4 hips presenting with endstage osteoarthritis. PMID- 21667221 TI - The Consequence of a Founder Effect: CCR5-?32, CCR2-64I and SDF1-3'A Polymorphism in Vlach Gypsy Population in Hungary. AB - Frequencies of genetic polymorphisms of the three most frequent HIV-1 resistance conferring alleles playing an important role in HIV-1 pathogenesis were analysed in Vlach Gypsy populations living in Hungary, as the largest minority. Mutations in the encoding genes, such as CCR5-?32, CCR2-64I and SDF1-3'A are shown to result in protective effects against HIV-1 infection and disease progression. 560 samples collected from Vlach Gypsy individuals living in 6 North-East Hungarian settlements were genotyped by PCR-RFLP method. Overall allele frequencies of CCR5 ?32, CCR2-64I and SDF1-3'A were found as 0.122, 0.186 and 0.115 respectively. All the observed genotype frequencies were in accordance with Hardy-Weinberg equilibrium . In regions, however, Vlach Gypsies live in majority and in ethnically homogenous communities, a higher CCR5-?32 mutations were found, with allele frequencies of 0.148 and 0.140 respectively, which are remarkably higher than those in general Hungarian people, and ten times higher than in regions of North-Western India from where present day Hungarian Gypsies originated in the Middle Ages. In the background of this higher CCR5-?32 allele frequency in the population analysed in our study a genetic founder effect could be assumed. Allele frequency of CCR2-64I was found to be among the highest in Europe. SDF1 3'A allele frequency in Vlach Gypsies was significantly lower than in ethnic Hungarians. 63% of the total 560 individuals tested carried at least one of the mutations studied. These results could partially explain the low incidence of HIV/AIDS among Vlach Gypsies in Hungary. PMID- 21667222 TI - Requirements for generic antiepileptic medicines: a clinical perspective. AB - Many antiepileptic drugs (AEDs) are now available as a generic product. This can potentially save the healthcare providers massive costs. Hence, governmental authorities have introduced rules and incentives for clinicians to switch from the original branded AED to a generic product. Clinicians and patients with epilepsy are reluctant to switch. The licensing of generic AEDs is based on the equation that bioavailability means therapeutic equivalence. However, from a clinical standpoint one has to consider several other relevant issues: (1) Do generic AEDs have the same efficacy, safety and quality? (2) Can generic AEDs be used as substitutions for brand AEDs? (3) Can generic products of AEDs be used interchangeably? (4) Does the generic AED manufacturer guarantee the long-term consistency of availability on the market? (4) Do generic AEDs reduce the costs, and--if so--are these costs worth any additional risk to patient's safety? This article reviews the clinical issues related to current bioequivalence, prescribability, and switchability of AEDs. PMID- 21667223 TI - Can fast-component of nystagmus on caloric vestibulo-ocular responses predict emergence from vegetative state in ICU? AB - The aim of the study was to determine if bedside caloric vestibulo-ocular responses (VOR) are able to predict consciousness recovery from clinically determined vegetative state (VS) in the ICU. Twenty-six severely brain injured patients that were clinically in VS were included. Horizontal VOR were tested at bedside by cold-water irrigation of the external auditory canal. Visual inspection evaluated the presence of a slow drift toward the side of stimulation (slow-component of nystagmus or tonic deviation) as well as the presence of a rapid compensatory movement/jerk back to the midline (fast-component of nystagmus). Patients were then divided into two groups according to whether they eventually regained consciousness or not. Patients were 59 +/- 21 years old. Thirteen out of 26 patients ultimately recovered consciousness and 13 remained unconscious. Thirteen patients (100%) presented a slow-component of nystagmus during VOR testing in the group that recovered consciousness and 11 (85%) in the group that remained unconscious. All the patients that recovered consciousness (13, 100%) presented a fast-component of nystagmus during VOR testing compared to only one of 11 patients (8%) in the group that remained unconscious. Sensitivity of fast-component of nystagmus during VOR testing to predict recovering of consciousness was 1.00, specificity was 0.92, positive predictive value was 0.93 and negative predictive value was 1.00. Bedside VOR testing in clinically VS patients seems able to predict consciousness recovery from vegetative state and could help to preclude active medical treatment withdrawal and to indicate the need for further complementary explorations, i.e. event-related potentials, functional MRI or PET-scan. PMID- 21667224 TI - Computer-aided analysis of biochemical mechanisms that increase metabolite and proton stability in the heart during severe hypoxia and generate post-ischemic PCr overshoot. AB - During severe hypoxia in the heart, impaired supply of ATP by oxidative phosphorylation could lead to a great drop in ATP turnover and heart work. Anaerobic glycolysis enables unchanged ATP turnover to be maintained, but leads to huge changes in metabolite (PCr, ATP, ADP, P (i)) concentrations and to cytosol acidification. A computer model of heart energetics developed previously is used to analyze semi-quantitatively the effect of different processes/mechanisms that can partly counteract these effects. Down-regulation of ATP usage compromises cardiac output, but reduces changes in cytosolic pH and metabolite concentrations. AMP decomposition delays cytosol acidification but reduces metabolite homeostasis (concentration stability). An increase in the parallel activation of oxidative phosphorylation (OXPHOS) (a hypothetical mechanism involving direct activation of all OXPHOS complexes by a cytosolic factor, postulated to take place also during work increase) reduces cytosol acidification and elevates metabolite homeostasis. All these mechanisms can generate the post-ischemic PCr overshoot. PMID- 21667225 TI - The status of MGMT protein expression is a prognostic factor for meningeal hemangiopericytoma: a clinicopathologic and immunohistochemical study of 12 cases at a single institution. AB - Meningeal hemangiopericytoma (HPC) is a clinicopathologically well-characterized malignancy with a high tendency to recur locally and to metastasize outside the central nervous system (CNS). We render clinicopathologic features of 12 cases of this uncommon tumor to further elucidate the relationship between the status of the DNA-repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) and the prognosis. Twenty-five specimens of meningeal HPC belonging to 12 patients were obtained at a single institution from 1992 to 2001. Correlations of histologic parameters, immunohistochemical study and clinical features were assessed. This series included five men and seven women with a median age of 37.5 years at the first surgery. The median post-operative follow-up period was 7.6 years. Six patients (55%) had single or multiple local tumor recurrences. The mean time to recurrence was 6.7 years. Distant metastasis occurred in three patients (27%) at a mean time of 6.5 years after first operation. The most frequent metastatic sites were liver and lung. Histopathologically, eight primary tumors (67%) belonged to WHO grade II, while four primary tumors (33%) belonged to WHO grade III. Immunohistochemically, 18% primary tumors exhibited 3+ to 4+ nuclear staining for MGMT protein, 18% exhibited 2+ staining, and 64% exhibited 0 to 1+ staining. The overall survival rate was 67 and 33% for primary tumors with 0 to 1+ and 2+ to 4+ MGMT staining, respectively (P = 0.018). The study illustrates aggressive behavior of meningeal HPC and the prognostic value of the status of MGMT protein expression. PMID- 21667226 TI - Extract from Terminalia chebula seeds protect against experimental ischemic neuronal damage via maintaining SODs and BDNF levels. AB - The fruit of Terminalia chebula Retz has been used as a traditional medicine in Asia and contains tannic acid, chebulagic acid, chebulinic acid and corilagin. Extract from T. chebula seeds (TCE) has various biological functions. We observed the neuroprotective effects of TCE against ischemic damage in the hippocampal C1 region (CA1) of the gerbil that had received oral administrations of TCE (100 mg/kg) once a day for 7 days before the induction of transient cerebral ischemia. In the TCE-treated ischemia group, neuronal neuclei (a marker for neurons) positive neurons were distinctively abundant (62% of the sham group) in the CA1 4 days after ischemia-reperfusion (I-R) compared to those (12.2% of the sham group) in the vehicle-treated ischemia group. Four days after I-R TCE treatment markedly decreased the activation of astrocytes and microglia in the ischemic CA1 compared with the vehicle-treated ischemia group. In addition, immunoreactivities of Cu, Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2) and brain-derived neurotrophic factor (BDNF) in the CA1 of the TCE-treated ischemia group were much higher than those in the vehicle-ischemia group 4 days after I-R. Protein levels of SOD1, SOD2 and BDNF in the TCE-treated ischemia group were also much higher than those in the vehicle-ischemia group 4 days after I-R. These results indicate that the repeated supplement of TCE protected neurons from ischemic damage induced by transient cerebral ischemia by maintaining SODs and BDNF levels as well as decreasing glial activation. PMID- 21667227 TI - Anisotropic circular dichroism signatures of oriented thylakoid membranes and lamellar aggregates of LHCII. AB - In photosynthesis research, circular dichroism (CD) spectroscopy is an indispensable tool to probe molecular architecture at virtually all levels of structural complexity. At the molecular level, the chirality of the molecule results in intrinsic CD; pigment-pigment interactions in protein complexes and small aggregates can give rise to excitonic CD bands, while "psi-type" CD signals originate from large, densely packed chiral aggregates. It has been well established that anisotropic CD (ACD), measured on samples with defined non random orientation relative to the propagation of the measuring beam, carries specific information on the architecture of molecules or molecular macroassemblies. However, ACD is usually combined with linear dichroism and can be distorted by instrumental imperfections, which given the strong anisotropic nature of photosynthetic membranes and complexes, might be the reason why ACD is rarely studied in photosynthesis research. In this study, we present ACD spectra, corrected for linear dichroism, of isolated intact thylakoid membranes of granal chloroplasts, washed unstacked thylakoid membranes, photosystem II (PSII) membranes (BBY particles), grana patches, and tightly stacked lamellar macroaggregates of the main light-harvesting complex of PSII (LHCII). We show that the ACD spectra of face- and edge-aligned stacked thylakoid membranes and LHCII lamellae exhibit profound differences in their psi-type CD bands. Marked differences are also seen in the excitonic CD of BBY and washed thylakoid membranes. Magnetic CD (MCD) spectra on random and aligned samples, and the largely invariable nature of the MCD spectra, despite dramatic variations in the measured isotropic and anisotropic CD, testify that ACD can be measured without substantial distortions and thus employed to extract detailed information on the (supra)molecular organization of photosynthetic complexes. An example is provided showing the ability of CD data to indicate such an organization, leading to the discovery of a novel crystalline structure in macroaggregates of LHCII. PMID- 21667228 TI - The validity of subjective quality of life measures in psychotic patients with severe psychopathology and cognitive deficits: an item response model analysis. AB - PURPOSE: Subjective quality of life (SQOL) is an established patient-reported outcome in the evaluation of treatments for psychosis. The use of SQOL measures in the presence of psychiatric symptoms and cognitive deficits has been questioned. However, there is little evidence on whether items function differently as indicators of SQOL in psychotic patients with different levels of symptoms and deficits. Substantial differential item functioning (DIF) would, indeed, challenge the validity of established measures. We aimed to investigate the validity of a widely used measure of subjective quality of life (SQOL), i.e., the Lancashire Quality of Life Profile (LQOLP), in the presence of cognitive deficits and psychiatric symptoms in patients with severe and enduring psychosis. METHOD: We analysed SQOL ratings of 690 psychotic patients on the LQOLP using item response modelling to detect differential item functioning (DIF) attributable to psychiatric symptoms and cognitive deficits. RESULTS: Patients with more severe general psychopathology were less likely to rate their 'personal safety' positively (OR .96, 95% CI .93-.99). More severely depressed patients were less likely to endorse positive 'life as a whole' (OR .93, 95% CI .89-.98) and 'mental health' (OR .93, 95% CI .91-.97) ratings. There was no DIF attributable to cognitive deficits. CONCLUSIONS: The findings suggest that the validity of the LQOLP in psychotic patients may be impaired by DIF due to psychopathology, although the magnitude of effects is unlikely to be of clinical significance. The validity appears not to be compromised by cognitive deficits. PMID- 21667229 TI - Cleavage of endogenous gammaENaC and elevated abundance of alphaENaC are associated with increased Na+ transport in response to apical fluid volume expansion in human H441 airway epithelial cells. AB - Using human H441 airway epithelial cells cultured at air-liquid interface (ALI), we have uniquely correlated the functional response to apical fluid volume expansion with the abundance and cleavage of endogenous alpha- and gammaENaC proteins in the apical membrane. Monolayers cultured at ALI rapidly elevated I (sc) when inserted into fluid-filled Ussing chambers. The increase in I (sc) was not significantly augmented by the apical addition of trypsin, and elevation was abolished by the protease inhibitor aprotinin and an inhibitor of the proprotein convertase, furin. These treatments also increased the IC50 amiloride indicating that the effect was via inhibition of highly Na+-selective ENaC channels. Apical fluid, 5-500 MUl for 1 h in culture, increased the spontaneous starting I (sc) in a dose-dependent manner, whilst maximal fluid-induced I (sc) in the Ussing chamber was unchanged. Apical fluid expansion increased the abundance of 63-65 kDa alphaENaC proteins in the apical membrane. However, this could not be attributed to increased cleavage as protease inhibitors had no effect on the ratio of cleaved to non-cleaved (90 kDa) alphaENaC proteins. Instead, fluid expansion increased alphaENaC abundance in the membrane. In contrast, function correlated well with gammaENaC cleavage at known sites by furin and extracellular proteases. Interestingly, cleavage of gammaENaC was associated with increased retrieval from the membrane via the proteosomal pathway. Thus, the response to apical fluid volume expansion in H441 airway epithelial cells involves cleavage of gammaENaC, and changes in alpha- and gammaENaC protein abundance at the apical membrane. PMID- 21667230 TI - Is rate of skin wound healing associated with aging or longevity phenotype? AB - Wound healing (WH) is a fundamental biological process. Is it associated with a longevity or aging phenotype? In an attempt to answer this question, we compared the established mouse models with genetically modified life span and also an altered rate of WH in the skin. Our analysis showed that the rate of skin WH in advanced ages (but not in the young animals) may be used as a marker for biological age, i.e., to be indicative of the longevity or aging phenotype. The ability to preserve the rate of skin WH up to an old age appears to be associated with a longevity phenotype, whereas a decline in WH-with an aging phenotype. In the young, this relationship is more complex and might even be inversed. While the aging process is likely to cause wounds to heal slowly, an altered WH rate in younger animals could indicate a different cellular proliferation and/or migration capacity, which is likely to affect other major processes such as the onset and progression of cancer. As a point for future studies on WH and longevity, using only young animals might yield confusing or misleading results, and therefore including older animals in the analysis is encouraged. PMID- 21667231 TI - A psychosocial study of male-to-female transgendered and male hustler sex workers in Sao Paulo, Brazil. AB - This study examined sociodemographic variables, personality characteristics, and alcohol and drug misuse among male sex workers in the city of Santo Andre, Sao Paulo, Brazil. A total of 45 male-to-female transgender sex workers and 41 male hustlers were evaluated in face-to-face interviews at their place of work from 2008 to 2010. A "snowball" sampling procedure was used to access this hard-to reach population. Male-to-female transgender sex workers reported fewer conventional job opportunities, fewer school problems, and higher harm avoidance and depression levels than male hustlers. Also, transgender sex workers reported earning more money through sex work and more frequently living in hostels with peers than their counterparts. As biological male sex workers are a heterogeneous population, attempts to classify them into distinctive groups should be further carried out as a way to better understand and identify their behavior, design effective health interventions, and consequently minimize the likelihood of unintended adverse outcomes. Our study showed that gender performance can be an important variable to be considered by researchers and policy makers when working with sex workers and developing HIV/AIDS prevention and public health programs, given that transgender and male sex workers not only display distinctive behavior and physical appearance but also reveal differences on specific psychological measures, such as personality traits and depression levels. We recommend that counselors working with this population strike a balance between facilitating self-disclosure and establishing more evidence-based directive interventions. PMID- 21667232 TI - Avoiding experiences: sexual dysfunction in women with a history of sexual abuse in childhood and adolescence. AB - Women with a history of sexual abuse during childhood/adolescence experience a high rate of sexual dysfunction. Evidence also suggests that they often use avoidant coping strategies, such as substance abuse, dissociation, and emotional suppression, which are likely factors implicated with their psychopathology. There is a dearth of information on potential psychological mechanisms affecting the sexuality of these women. Therefore, it is relevant to investigate whether avoidance, an important cognitive mechanism associated with anxiety disorders, relates to sexual functioning in this population. In this study, participants with (N = 34) and without (N = 22) a history of sexual abuse prior to age 16 years completed questionnaires on severity of sexual abuse, sexual functioning, and a tendency to avoid experiences. A three-step hierarchical regression investigated the effects of childhood/adolescent sexual abuse and avoidance tendencies on different aspects of sexual functioning. A significant interaction between childhood/adolescent sexual abuse and avoidance tendencies was found for orgasm function, with the combination of sexual abuse and avoidance tendencies explaining lower orgasm function. These findings suggest that, for women with a history of early sexual abuse, the tendency to avoid interpersonal closeness and avoid emotional involvement predicts orgasm functioning. PMID- 21667233 TI - The effect of pre-existing affect on the sexual responses of women with and without a history of childhood sexual abuse. AB - Women with a history of childhood sexual abuse (CSA) are at greater risk for experiencing sexual problems in their adult lives. Yet, little is known about the possible role of cognitive and affective mechanisms in the development of sexual arousal difficulties in this population. This study investigated the role of pre existing affect (affect prior to exposure to sexual stimuli) on genital responses, subjective sexual arousal, and affect elicited during the presentation of erotic film excerpts in a community sample of 25 women with and 25 women without a history of CSA. The CSA group showed greater pre-existing negative affect and smaller genital responses to the erotic film stimuli compared to the NSA group. Findings support a moderating effect of CSA, in that pre-existing negative affect was associated with strength of genital responses in the NSA but not in the CSA group. The results did not support a mediation model of pre existing negative affect as an explanation for smaller physiological sexual responses in the CSA group. Taken together, the findings suggest that pre existing affect may be more relevant for women with no history of CSA and call for more research on factors implicated in impaired sexual responses in women with a history of CSA. PMID- 21667234 TI - Infidelity in heterosexual couples: demographic, interpersonal, and personality related predictors of extradyadic sex. AB - This study aimed to assess the relative importance of demographic, interpersonal, and personality factors in predicting sexual infidelity in heterosexual couples. A total of 506 men (M age = 32.86 years, SD = 10.60) and 412 women (M age = 27.66 years, SD = 8.93), who indicated they were in a monogamous sexual relationship, completed a series of questionnaires, including the Sexual Excitation/Inhibition (SES/SIS) scales and the Mood and Sexuality Questionnaire, and answered questions about, among others, religiosity, education, income, relationship and sexual satisfaction, and sexual compatibility. Almost one-quarter of men (23.2%) and 19.2% of women indicated that they had "cheated" during their current relationship (i.e., engaged in sexual interactions with someone other than their partner that could jeopardize, or hurt, their relationship). Among men, a logistic regression analysis, explaining 17% of the variance, revealed that a higher propensity of sexual excitation (SES) and sexual inhibition due to "the threat of performance concerns" (SIS1), a lower propensity for sexual inhibition due to "the threat of performance consequences" (SIS2), and an increased tendency to engage in regretful sexual behavior during negative affective states were all significant predictors of infidelity. In women, a similar regression analysis explained 21% of the variance in engaging in infidelity. In addition to SIS1 and SIS2, for which the same patterns were found as for men, low relationship happiness and low compatibility in terms of sexual attitudes and values were predictive of infidelity. The findings of this study suggest that, for both men and women, sexual personality characteristics and, for women, relationship factors are more relevant to the prediction of sexual infidelity than demographic variables such as marital status and religiosity. PMID- 21667235 TI - Level and fate of etoxazole in green bean (Phaseolus vulgaris). AB - The objective of this study was to estimate the total etoxazole residues balance (residue in pods, leaves and soil under the treated plant) in green bean and for identification of the degradative metabolites of etoxazole in soil under the treated plant. The results showed half life (t(1/2)) values of 3.13, 2.73 and 2.11 days for etoxazole in green bean pods, leaves and soil, respectively. According to the maximum residue limits (MRL) the pre harvest intervals (PHI) of etoxazole on green bean pods was 4-days after the treatment. The results of GC-Ms analysis of soil extracts under the treated plant showed that, at zero time unchanged etoxazole was found. The proportion of etoxazole in soil extracts detected decreased with the time. GC-Ms analysis of soil extracts show the presence of compound having the formula of C(14)H(23)NO(2) which was suggested to be 2-amino-2(4-tert-butyl-2-ethoxyphenyl) ethanol. The other founded compound has the formula C(13)H(18)O(3) and suggested to be 4-tert-butyl-2-ethoxybenzoic acid. PMID- 21667236 TI - Planktonic rotifer assemblages of the Danube River at Budapest after the red sludge pollution in Hungary. AB - In the autumn of 2010 an industrial red sludge spill occurred in Hungary. The toxic chemical waste with high alkalinity (pH 13.5) reached the Danube 2 days later, where no change was expected because of the high level of dilution. The planktonic rotifer assemblages of the Danube were investigated at Budapest during the contamination. The median of community density decreased from 500 ind. 100 L( 1) to zero, the species richness from 3.00 to 0.00, Shannon-Weaver diversity from 1.10 to 0.00 after the arrival of the contamination. The rotifer assemblages seemed to have recovered after 3 weeks, but the initial levels of diversity and density were not reached again. PMID- 21667237 TI - Life history response of Daphnia magna to a mixotrophic golden alga, Poterioochromonas sp., at different food levels. AB - The toxicity of Poterioochromonas to Daphnia magna was investigated at different food (Scenedesmus acutus) levels. Poterioochromonas alone of 0.4-20 mg C L(-1) was not acutely toxic to D. magna, but did not support D. magna growth, either. When fed mixed diets (2 mg C L(-1) in total), D. magna's survival and reproduction were significantly depressed when Poterioochromonas comprised above 50%, likely due to the inhibition of food ingestion. Large juveniles were less sensitive to poor quality food than neonates. Therefore, Poterioochromonas may affect D. magna living to various extents depending on its concentration, age structure of D. magna populations and availability of other food. PMID- 21667238 TI - Responsiveness of adjacent ductal carcinoma in situ and changes in HER2 status after neoadjuvant chemotherapy/trastuzumab treatment in early breast cancer- results from the GeparQuattro study (GBG 40). AB - Adjacent ductal carcinoma in situ (DCIS) is found in approximately 45% of invasive ductal carcinomas (IDC) of the breast. Pure DCIS overexpresses HER2 in approximately 45%. There is uncertainty whether adjacent DCIS impacts on the response to neoadjuvant chemotherapy and trastuzumab as well as whether HER2 expression in IDC component or adjacent DCIS changes throughout treatment. Core biopsies and surgical tissue from participants of the GeparQuattro study with HER2-positive IDC were centrally examined for the area of invasive ductal component and adjacent DCIS before and after receiving neoadjuvant anthracycline taxane-trastuzumab containing chemotherapy. HER2 overexpression in IDC and adjacent DCIS was quantified separately by immunohistochemistry using the Ventana automated staining system. Pathological complete response (pCR) was defined as no residual invasive or non-invasive tumor tissue. Fifty-nine (37.3%) of 158 IDCs presented with adjacent DCIS at diagnosis. These tumors showed lower regression grades than pure IDC (P = 0.033). The presence of adjacent DCIS was an independent negative predictor of pCR [odds ratio 0.42 (95% CI 0.2-0.9), P = 0.027]. Adjacent DCIS area decreased from pre-treatment to surgery (r = 0.205) with 30 (50.8%) IDCs with adjacent DCIS showing complete eradication of adjacent DCIS. HER2 status of adjacent DCIS was highly correlated with HER2 status of IDC component before (r = 0.892) and after treatment (r = 0.676). Degree of HER2 overexpression of the IDC component decreased in 16 (33.3%) out of 49 patients without a pCR. These 16 IDCs showed lower RGs compared to the 33 IDCs with unchanged HER2 expression (P = 0.055). HER2-positive IDCs with adjacent DCIS is less responsive to neoadjuvant chemotherapy and trastuzumab compared to pure IDC. However, complete eradication of adjacent DCIS is frequently observed. HER2 overexpression of the invasive ductal component decreases in a subset of tumors, which showed less tumor regression. PMID- 21667239 TI - Molecular cloning, promoter analysis, SNP detection of Clusterin gene and their associations with mastitis in Chinese Holstein cows. AB - To examine the effect of Clusterin (CLU) on mastitis, genetic association analysis was applied on mastitis and milk production traits of 1,137 Chinese Holstein cows. We detected two novel single nucleotide polymorphisms (SNPs), G+15781A in the seventh exon and C-994T before 5'-upstream region (UTR) of CLU gene, found five TATA box, one CpG island and more transcription factor binding sites in promoter region, respectively, Milk fat rate in genotype AA was significantly higher than in GG on fat rate (P < 0.01), milk fat and milk yield in combined haplotype H1H4 (AGCT) were significantly higher than in H3H4 (GGCT) (P < 0.05), H1H4 was decided advantage in nine milk production traits. Quadruplet cows in G+15781A were decided advantage in each milk production traits that 305 day milk yield, fat rate, protein rate and somatic cell scores (SCS) increased following with birth order. A allele and T allele had positive effect on SCS. In conclusion, this study showed that the haplotype AA may be a genetic marker on mastitis and other performance for Chinese Holstein cows. PMID- 21667240 TI - Effects of the polymorphisms of Mx1, BAT2 and CXCL12 genes on immunological traits in pigs. AB - It is necessary that genetic markers or biomarkers can be used to predict resistance towards a wide range of infectious diseases. In the present study, we estimated the potential markers and measured their relationship with heritabilities of a wide range of immune traits. Polymorphisms in exon 13 of Mx1, intron 25 of BAT2 and intron 3 of CXCL12 were identified by sequencing, and the genotypes were analyzed by PCR-RFLP in a resource population composed of 352 pure breed Landrace piglets at days 0, 17 and 32 after birth. Associations of single nucleotide polymorphisms (SNPs) in these genes with a variety of immunological traits and antibody levels for pig reproduction and porcine respiratory syndrome virus (PRRSV), pseudorabies virus (PRV) and classical swine fever virus (CSFV) were performed. The performance of GG genotype of BAT2 on hemoglobin concentration (HBG) and hematocrit (HCT) of piglets at day 0 was significantly higher than that of the AA and AG individuals. For Mx1, compared with CT genotype, the pigs with TT or CC generated more PRRS antibody at day 0. The piglets with CT genotype had highly significant difference of PRV antibody from those with CC and TT genotypes at day 0. And the piglets with CC genotype had higher level red blood cell count (RBC), hemoglobin concentration (HBG) and hematocrit (HCT) than those with CT and TT genotypes at day 17. For the C7462G SNP in the intron 3 of CXCL12, the PRV antibody level of piglets with the CG genotype were higher than that of piglets with CC and GG genotypes at day 17, and the mean corpuscular volume (MCV) of GG piglets were larger than that of CC and CG individuals at day 0. At the locus 7331 bp in the intron 3 of CXCL12, there were significantly differences of mean corpuscular hemoglobin concentrations (MCHC) at day 0 and white blood cell count (WBC) at day 32, which showed the trend GG or AG>AA, AA>AG or GG, respectively. The pigs with AA or GG genotype had more platelet distribution width (PDW), mean platelet volume (MPV) and platelet large cell ratio (PLR) at day 17 than those with AG. The results of this study indicated that polymorphisms in Mx1, BAT2 and CXCL12 genes were significantly associated with the immunological traits in Landrace piglets and had potential application value for marker-assisted selection of pig breeding with disease resistance. PMID- 21667241 TI - A novel CASR mutation in a Tunisian FHH/NSHPT family associated with a mental retardation. AB - The calcium-sensing receptor (CASR), a plasma membrane G-protein coupled receptor, is expressed in parathyroid gland and kidney, and controls systemic calcium homeostasis. Inactivating CASR mutations have previously been identified in patients with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT). The aim of the present study is to determine the underlying molecular defect of FHH/NSHPT disease in a consanguineous Tunisian family. Mutation screening was carried out using RFLP-PCR and direct sequencing. We found that the proband is homozygous for a novel 15 bp deletion in the exon 7 (c.1952_1966del) confirming the diagnosis of NSHPT. All the FHH members were found to be heterozygous for the novel detected mutation. The mutation, p.S651_L655del, leads to the deletion of 5 codons in the second trans-membrane domain of the CASR which is thought to be involved in the processes of ligand induced signaling. This alteration was associated with the evidence of mental retardation in the FHH carriers and appears to be a novel inactivating mutation in the CASR gene. Our findings provide additional support for the implication of CASR gene in the FHH/NSHPT pathogenesis. PMID- 21667242 TI - Molecular cloning and characterization of an F-box family gene CarF-box1 from chickpea (Cicer arietinum L.). AB - F-box protein family has been found to play important roles in plant development and abiotic stress responses via the ubiquitin pathway. In this study, an F-box gene CarF-box1 (for Cicer arietinum F-box gene 1, Genbank accession no. GU247510) was isolated based on a cDNA library constructed with chickpea seedling leaves treated by polyethylene glycol. CarF-box1 encoded a putative protein with 345 amino acids and contained no intron within genomic DNA sequence. CarF-box1 is a KFB-type F-box protein, having a conserved F-box domain in the N-terminus and a Kelch repeat domain in the C-terminus. CarF-box1 was localized in the nucleus. CarF-box1 exhibited organ-specific expression and showed different expression patterns during seed development and germination processes, especially strongly expressed in the blooming flowers. In the leaves, CarF-box1 could be significantly induced by drought stress and slightly induced by IAA treatment, while in the roots, CarF-box1 could be strongly induced by drought, salinity and methyl jasmonate stresses. Our results suggest that CarF-box1 encodes an F-box protein and may be involved in various plant developmental processes and abiotic stress responses. PMID- 21667243 TI - Computational identification of microRNAs in peach expressed sequence tags and validation of their precise sequences by miR-RACE. AB - Twenty-two potential miRNAs from seven miRNA families were first predicted from more than 80,857 EST sequences of peach (Prunus persica). Using two specific 5' and 3' miRNA RACE (miR-RACE) PCR reactions and sequence-directed cloning, we accurately determined the precise sequences, especially both ends, of eight candidate miRNAs. The sequencing results demonstrated that the ppe-miRNAs were conserved to those that were predicted computationally except ppe-miR171b. We validated the existence of two members (ppe-miR171a and miR171b) of the miR171 family in peach that belonged to different precursors. qRT-PCR was further employed in analyzing expression of the eight miRNAs in peach leaves, flowers, and fruits at different developing stages, where some of the miRNAs showed tissue specific expression. PMID- 21667244 TI - Induced bone marrow mesenchymal stem cells improve cardiac performance of infarcted rat hearts. AB - We investigated whether transplantation of bone marrow mesenchymal stem cells (BMSC) with induced BMSC (iBMSC) or uninduced BMSC (uBMSC) into the myocardium could improve the performance of post-infarcted rat hearts. BMSCs were specified by flowcytometry. IBMSCs were cocultured with rat cardiomyocyte before transplantation. Cells were injected into borders of cardiac scar tissue 1 week after experimental infarction. Cardiac performance was evaluated by echocardiography at 1, 2, and 4 weeks after cellular or PBS injection. Langendorff working-heart and histological studies were performed 4 weeks after treatment. Myogenesis was detected by quantitative PCR and immunofluorescence. Echocardiography showed a nearly normal ejection fraction (EF) in iBMSC-treated rats and all sham control rats but a lower EF in all PBS-treated animals. The iBMSC-treated heart, assessed by echocardiography, improved fractional shortening compared with PBS-treated hearts. The coronary flow (CF) was decreased obviously in PBS and uBMSC-treated groups, but recovered in iBMSC-treated heart at 4 weeks (P < 0.01). Immunofluorescent microscopy revealed co-localization of Superparamagnetic iron oxide (SPIO)-labeled transplanted cells with cardiac markers for cardiomyocytes, indicating regeneration of damaged myocardium. These data provide strong evidence that iBMSC implantation is of more potential to improve infarcted cardiac performance than uBMSC treatment. It will open new promising therapeutic opportunities for patients with post-infarction heart failure. PMID- 21667245 TI - Isolation and characterization of an AGAMOUS-like gene from Hosta plantaginea. AB - Based on genetic and molecular analyses, the ABC model was proposed to explain the genetic control of floral development. The C-class MADS box gene AGAMOUS (AG) plays crucial roles in Arabidopsis thaliana development through regulation of the organ identity of stamens and gynoecium. The present research reports for the first time the cloning of an AG homologue (HpAG) from Hosta plantaginea Aschers. Phylogenetic analysis shows HpAG is a homologue of AG that is closely related to C-lineage AG homologues from monocot species. Semi-quantitative PCR and real-time PCR analyses show that HpAG is stamen- and gynoecium-specific in expression and has spatial and temporal expression patterns in the reproductive organs of H. plantaginea. The transcriptional activation property of HpAG is also verified by a yeast one-hybrid. Functional analysis is carried out in Arabidopsis by overexpression of HpAG. The homeotic transformations of petals into staminoid organs are observed in 35S::HpAG transgenic plants. All these results show that HpAG1 plays a crucial role in stamen specification and gynoecium development. PMID- 21667246 TI - Large-scale sequencing of normalized full-length cDNA library of soybean seed at different developmental stages and analysis of the gene expression profiles based on ESTs. AB - Although GenBank has now covered over 1,400,000 expressed sequence tags (ESTs) from soybean, most ESTs available to the public have been derived from tissues or environmental conditions rather than developing seeds. It is absolutely necessary for annotating the molecular mechanisms of soybean seed development to analyze completely the gene expression profiles of its immature seed at various stages. Here we have constructed a full-length-enriched cDNA library comprised of a total of 45,408 cDNA clones which cover various stages of soybean seed development. Furthermore, we have sequenced from 5' ends of these clones, 36,656 ESTs were obtained in the present study. These EST sequences could be categorized into 27,982 unigenes, including 22,867 contigs and 5,115 singletons, among which 27,931 could be mapped onto soybean 20 chromosome sequences. Comparative genomic analysis with other plants has revealed that these unigenes include lots of candidate genes specific to dicot, legume and soybean. Approximately 1,789 of these unigenes currently show no homology to known soybean sequences, suggesting that many represent mRNAs specifically expressed in seeds. Novel abundant genes involved in the oil synthesis have been found in this study, may serve as a valuable resource for soybean seed improvement. PMID- 21667247 TI - Influence of acute cadmium exposure on the liver proteome of a teleost fish, ayu (Plecoglossus altivelis). AB - Cadmium (Cd) is a toxic heavy metal that causes the disruption of a variety of physiological processes. In this study, the effect of Cd on liver proteome of ayu, Plecoglossus altivelis, was investigated by two-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption ionization time-of flight tandem mass spectrometry (MALDI-TOF-MS/MS). Twenty-three altered protein spots were successfully identified. They were involved in oxidative stress response, metal metabolism, methylation, and so on. The mRNA expression of 60S acidic ribosomal protein P0, heat shock protein 70, apolipoprotein A-I, betaine homocysteine S-methyltransferase, parahox cluster neighbor, and transferrin was subsequently determined by real-time PCR. The mRNA expression of these genes was consistent with proteomic results. These findings enrich our knowledge on the influence of Cd toxicity to teleost fish, and may be worthy of further investigation to develop biomarkers. PMID- 21667248 TI - Molecular cloning, sequence characterization, polymorphism and association analysis of porcine ROPN1 gene. AB - The full-length cDNA sequence of one porcine gene, ROPN1, was isolated using the rapid amplification of cDNA ends (RACE) method based on one pig EST sequence which was highly homologous to the coding sequence of human ROPN1 gene. The porcine ROPN1 gene encodes a protein of 212 amino acids which shares high homology with the rhophilin associated protein 1 (ROPN1) of eight species: gray short-tailed opossum (96%), horse (95%), cattle (94%), mouse (93%), rat (92%), chimpanzee (85%), human (85%) and rhesus monkey (85%). Phylogenetic analysis revealed that the porcine ROPN1 gene has a closer genetic relationship with the ROPN1 gene of gray short-tailed opossum. Polymorphism analysis showed that there was a T/C mutation at the position of 536 bp of mRNA and this leaded to the amino acid alteration from the Arg residue to the Cys residue. PCR-Hae III-RFLP was established to detect this T/C mutation and eight pig breeds display obvious genotype and allele frequency differences at this mutation locus. Association of this SNP with litter size traits was assessed in Large White (n = 100) and Landrace (n = 100) pig populations, and results demonstrated that this polymorphic locus was significantly associated with the litter size of first parity (P < 0.01) and all parities (P < 0.05) in Large White sows, and also significantly associated with the litter size of all parities in Landrace sows (P < 0.01). Therefore, ROPN1 gene could be a useful candidate gene in selection for increasing litter size in pigs. These data serve as a foundation for further insight into this novel porcine gene. PMID- 21667249 TI - Molecular characterization, expression patterns and subcellular localization of Myotrophin (MTPN) gene in porcine skeletal muscle. AB - Myotrophin (MTPN) is an effective growth factor in promoting skeletal muscle growth in vitro and vivo and has been purified from porcine skeletal muscle. However, in pigs, the information on MTPN gene is very limited. In this study, we cloned cDNA sequences and analyzed the genomic structure of porcine MTPN gene. The deduced amino acid sequence of porcine MTPN contains two the ankyrin repeat domains. RT-PCR analysis revealed that porcine MTPN gene was widely expressed in many tissues, a high expression level was observed in the spleen, liver and uterus, and transient transfection indicated that porcine MTPN proteins was located in cytoplasms within Pig Kidney Epithelial cells (PK15). Quantitative real-time PCR (qRT-PCR) analyses showed that MTPN expression peaked at embryonic 65 day post conception (dpc). During postnatal muscle development, MTPN expression was down-regulated from the 3 day to the 180 day in Yorkshire pigs. This result suggests that the MTPN gene may be important gene for skeletal muscle growth and provides useful information for further studies on its roles in porcine skeletal muscle. PMID- 21667250 TI - Spontaneous uptake of exogenous DNA by goat spermatozoa and selection of donor bucks for sperm-mediated gene transfer. AB - Sperm-mediated gene transfer (SMGT) has been long heralded as a faster and cheaper alternative to more commonly used methods of producing transgenic animals. In this study, the capra semen ejaculates were pooled together and then incubated in vitro with DIG-labeled DNA. The binding and internalizing rates were observed by the in situ hybridization methods. We also compared the standard sperm parameters and the efficiencies of interaction with exogenous DNA of 60 individuals to select donor bucks for SMGT. It was showed that labeled exogenous DNA was detected in different localizations in spermatozoa but genuine DNA uptake, in contrast to mere binding, seems to be limited to the postacrosomal region. The removal of seminal plasma increased significantly (P < 0.01) the capability in picking up exogenous DNA. Use of frozen-thawed semen (without cryoprotectant agents) and Triton X-100 treatment also increased significantly (P < 0.01) the DNA-binding capacity, but reduced the sperm viability. The binding rates (the proportion of labeled-DNA positive spermatozoa to all the spermatozoa counted) of 60 buck individuals were in the range of 3.08-73.39%, and the internalizing rates (the proportion of DNaseI-treated labeled-DNA positive spermatozoa to all the spermatozoa counted) were 4.83-70.00%. About 8.34% (5/60) bucks showed high binding, but low internalizing ability. Chi-square test showed that there was significant difference among the breeds (x(2) = 26.515, P < 0.01). Eight individual bucks that demonstrated high DNA uptake were selected for SMGT. It was demonstrated that the goat spermatozoa was capable of spontaneous uptake of exogenous DNA. Seminal fluid inhibits DNA uptake and that membrane disruption increases DNA binding but greatly diminishes uptake. PMID- 21667251 TI - The CAG repeat polymorphism of androgen receptor gene and prostate cancer: a meta analysis. AB - The association between the polymorphic CAG repeat in androgen receptor gene (AR) and prostate cancer susceptibility has been studied extensively. However, the results are contradictory. The purpose of our meta-analysis was to investigate whether CAG repeat related to prostate cancer risk and had genetic heterogeneity across different geographic regions and study designs. Random-effects model was performed irrespective of between-study heterogeneity. Data and study quality were assessed in duplicate. Publication bias was assessed by the fail-safe number and Egger's test. There were 16 (patients/controls: 2972/3792), 19 (3835/4908) and 12 (3372/2631) study groups for comparisons of >= 20, 22 and 23 repeats of CAG sequence, respectively. Compared with CAG repeat <20, 22 or 23, carriers of >= 20, 22 or 23 repeats had 21% (95% CI: 0.61-1.02; P = 0.076), 5% (95% CI: 0.81 1.11; P = 0.508) and 5% (95% CI: 0.76-1.20; P = 0.681) decreased risk of prostate cancer. After classifying studies by geographic areas, carriers of >= 20 repeats had 11% decreased risk in populations from USA, 53% from Europe, and 20% from Asia (P > 0.05), whereas comparison of >= 23 repeats with others generated a significant prediction in European populations (OR = 1.17; P = 0.039). Stratification by study designs revealed no material changes in risk estimation. Meta-regression analysis found no significant sources of between-study heterogeneity for age, study design and geographic region for all comparisons. There was no identified publication bias. Taken together, our results demonstrated that AR CAG repeat polymorphism with >= 20 repeats might confer a protective effect among the prostate cancer patients with 45 years older but not all the prostate cancer patients. PMID- 21667252 TI - Inhibition of porcine reproductive and respiratory syndrome virus replication by RNA interference in MARC-145 cells. AB - With the ultimate aim of producing an RNA interference-mediated transgenic pig that is resistant to porcine reproductive and respiratory syndrome virus (PRRSV), we have investigated the effect of RNA interference (RNAi) on silencing the expression of viral genes in the MARC-145 cell line. Twenty small interfering RNAs (siRNAs) were designed and screened for their ability to suppress the expression of the genes ORF1b, 5, 6, and 7 from the highly virulent isolate, PRRSV-JXwn06. Of these siRNAs, the four most effective were selected and four short hairpin RNA (shRNA) expression vectors (pGenesil-1-1b-135, pGenesil-1-1b 372, pGenesil-1-6-135, and pGenesil-1-6-169) targeting ORF1b and ORF6 were constructed and delivered into MARC-145 cells. These cells were then infected with JXwn06. All four vectors inhibited the PRRSV-specific cytopathic effect (CPE). The virus titers in cells transfected with pGenesil-1-1b-135, pGenesil-1 1b-372, pGenesil-1-6-135, and pGenesil-1-6-169 were lower than that of control cells by approximately 150-, 600-, 2.3- and 1.7-fold, respectively. In addition, the expression levels of ORF1 and ORF6 were reduced compared with controls. The unglycosylated membrane protein M, encoded by ORF6, was not detectable in cells transfected with shRNA expression vectors. These results verified that RNAi can effectively inhibit PRRSV-JXwn06 replication in cultured cells in vitro. The four shRNA expression vectors are an initial step in the production of transgenic pigs with PRRSV resistance. PMID- 21667253 TI - siRNA targeting Notch-1 decreases glioma stem cell proliferation and tumor growth. AB - Glioblastoma multiforme (GBM), the most common brain tumor in adults, is neurologically destructive and has a dismal response to virtually all therapeutic modalities. One phenomenon that can contribute to this complexity is the presence of a relatively small subset of glioma stem cells (GSCs) within the tumor and the activation of pathways that control cellular differentiation. The Notch signaling pathway, which is responsible for maintaining a balance between cell proliferation and apoptosis, is believed to be deregulated in cancer stem cells (CSCs), leading to tumor growth through the generation or expansion of CSCs. In this study, Notch-1 small interfering RNA (siRNA) was used to silence Notch-1 gene expression in GSCs. An MTT assay demonstrated inhibitory effects on the proliferation of GSCs in vitro. Real-time PCR showed that Notch-1 expression levels were markedly decreased in GSCs transfected with Notch-1 siRNA in vitro. Notch-1 silenced GSCs engrafted on Balb/c nude mice showed a significantly greater reduction in oncogenicity than the control group (P < 0.05). Furthermore, direct intratumoral injections of Notch-1-siRNA/PEI significantly delayed the growth of pre-established tumors in nude mice (P < 0.05). These results suggest that siRNA-mediated silencing of the Notch-1 gene may represent a novel target for gene therapy of GBM. PMID- 21667256 TI - Chinese-Australian women's knowledge, facilitators and barriers related to cervical cancer screening: a qualitative study. AB - Understanding the different facilitators and barriers to screening within cultural and ethnic groups is important for developing appropriate education and outreach programs to underserved groups. Qualitative methods were employed to gain a rich understanding of participant views. In-depth interviews were conducted with 18 Chinese Australian women in their native languages and analysed using content analysis. Knowledge of cervical cancer was low, and few participants understood the benefits and purpose of screening. Having a doctor's recommendation was a strong motivator, and returning for screening was encouraged by having a female Chinese doctor perform the exam, receiving a reminder letter and the absence of cost for screening participation. However, participation was inhibited by logistical barriers, cultural beliefs and previous painful screening experiences. A range of multifaceted facilitators and barriers must be considered when developing interventions to increase the rates of cervical screening in this population. PMID- 21667254 TI - Current chemotherapeutic strategies against bladder cancer. AB - Urothelial cancer is a chemotherapy-sensitive malignancy, with the regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) until recently considered to be the first choice for chemotherapy. Poor survival and substantial toxicity associated with M-VAC have led to investigations into alternative chemotherapy strategies, and the combination of gemcitabine and cisplatin (GC) may be promising. In addition, combination chemotherapy of taxanes along with gemcitabine and/or platinum-based agents is also considered to provide clinical benefits as second-line chemotherapy following M-VAC or GC therapy. In the near future, results of trials using molecular target therapies may bring improved outcomes for patients with bladder cancer. PMID- 21667258 TI - The application of intraoperative ultrasound during partial hepatectomy for the accurate detection and removal of intrahepatic bile duct stones. AB - To evaluate the application of intraoperative ultrasound (IOUS) during partial hepatectomy to accurately detect and remove intrahepatic bile duct stones. Intrahepatic bile duct stones were precisely localized during surgery by using IOUS. Furthermore, guiding stone extraction, and determining the scope of liver resection and choice of surgical procedures were also evaluated using this technique. Of the 25 patients used in this study, 16 patients received a left lateral liver resection, 7 patients received a left liver resection, 1 patient had a liver resection of segments V and VI, 9 patients had common bile duct stones, and 6 patients had bile duct stones that underwent jejunal Roux-en-y anastomosis. In addition, IOUS exploration after liver resection and post operative T-tube cholangiography showed one case with residual stones. The use of IOUS showed high diagnostic accuracy, while also rectifying the misdiagnosis and missed diagnosis of bile stones in preoperative imaging. IOUS also assisted with positioning accuracy, which is very important in determining the extent of surgical resection and choice of surgical procedure. Thus, IOUS can dynamically monitor the surgical procedure, guide the operation, and inspect the outcome of operations, therefore, effectively improving the quality of operation. PMID- 21667259 TI - FE NO concentrations in World Trade Center responders and controls, 6 years post 9/11. AB - The aim of this study was to evaluate whether underlying respiratory disease may be revealed by offline fractional exhaled nitric oxide (FE(NO)) testing among a cohort of New York State (NYS) World Trade Center (WTC) responders in comparison with a control group of similar but unexposed NYS employees, 6 years post-9/11. Participants (92 exposed, 141 unexposed) provided two breath samples that were collected in Mylar bags and sent to a central laboratory for FE(NO) testing. Participants also completed a brief questionnaire. Ambient air pollution was characterized using particulate matter (PM(2.5)) and ozone concentration data from the NYS Department of Environmental Conservation air-monitoring sites closest to each testing site for each day of sample collection. WTC exposure did not appear to be associated with elevated FE(NO) concentrations. FE(NO) concentrations were higher on days with elevated levels of PM(2.5) (>= 35 MUg/m3) and ozone (>= 0.08 ppm). FE(NO) concentrations were higher in men and lower in smokers. Our results do not suggest an association between WTC exposure and elevated FE(NO) concentrations, 6 years post-9/11, in this moderately exposed cohort of responders. Results do suggest that FE(NO) concentrations were elevated in relation to higher levels of ambient air pollutants. Our results also offer useful reference values for future research involving FE(NO) testing. This study demonstrates that offline FE(NO) testing is a useful method for epidemiological studies requiring collection of samples in the field, potentially over a broad geographic area. PMID- 21667260 TI - Response to oyster mushroom (Pleurotus ostreatus) extract by sensitized and nonsensitized guinea pig trachea. AB - Occupational exposure to oyster mushroom (Pleurotus ostreatus) has been associated with obstructive lung disease. Previously, we studied an extract of oyster mushroom (OME) and determined that it causes dose-dependent contractions of nonsensitized guinea pig trachea (GPT). We extend these studies to the investigation of sensitized tissue. In the present study 24 animals were sensitized using ovalbumin (OA) and subsequently challenged with an aerosol of 2.5% OA. A control group of 12 nonsensitized GPs was also studied. Tracheas were removed and were divided into rings in which the epithelium was retained (EP+) or removed (EP-). Dose-related contractions of sensitized and nonsensitized GPTs were elicited with OME. In nonsensitized animals the EP+ GPTs demonstrated a significantly greater response to OME (100-1000 MUl) than did the EP- GPTs (p < 0.01). By contrast, in sensitized GPTs with and without epithelium there was no difference to challenge with OME. Finally, sensitized GPTs with and without epithelium and nonsensitized GPTs with epithelium responded similarly to challenge with OME. These findings suggest that in nonsensitized animals there is an enhancement of contractile response to OME which is in part mediated by the GPT epithelium. In sensitized animals with or without epithelium, the level of bronchoconstrictor response is similar to that of the nonsensitized animals with epithelium, suggesting an enhanced constrictor response independent of epithelium in the sensitized animals. PMID- 21667261 TI - Retroperitoneal hernia following radical cystectomy: case report. AB - Retroperitoneal hernias are rare. When they occur, they most often occur in naturally occurring fossas, such as with paraduodenal hernias. Due to the anatomy of the ureterovesicular system, patients with prior urological operations may be more likely to develop retroperitoneal hernias. We report the case of a 76-year old male who had undergone a radical cystectomy with ileal loop conduit for bladder cancer, who presented with recurrent episodes of nausea and vomiting. Upon exploratory laparotomy, he was found to have a retroperitoneal hernia. The patient underwent resection of the strangulated loop of small bowel, and recovered without complications. In our patient, ureteral dissection from his prior procedure had created a defect in the peritoneum posterior to the sigmoid mesocolon, which allowed for herniation and subsequent strangulation of a portion of small bowel. Retroperitoneal hernias may represent an under-diagnosed etiology of intestinal obstruction in post-operative urological patients. Knowledge of anatomy is crucial in patients with previous abdominal operations, and prior operative notes should be reviewed, including non general surgical operations such as urological and gynecological procedures. The surgeon must remain vigilant in such cases of small bowel obstruction, as delayed intervention may lead to bowel compromise. PMID- 21667262 TI - Use of vacuum-assisted closure in open incisional hernia repair: a novel approach to prevent seroma formation. AB - INTRODUCTION: Frequent complications in incisional hernia surgery are re herniation, wound infection and seroma formation. The use of subatmospheric pressure dressings such as the vacuum-assisted closure (VAC) device has been shown to be an effective way to accelerate healing of various wounds. Here, we describe the application of the VAC device as a postoperative dressing to prevent seroma formation after open incisional hernia repair. METHODS: Three consecutive patients (63, 65 and 60 years of age, respectively) underwent incisional hernia repair. Patient body mass index was 30.9, 26.6 and 29 kg/m(2), respectively. All hernias were complex with a defect size greater than 10 cm and were repaired using the onlay technique. After suture skin closure the incision was covered with a thin VAC sponge (KCI, San Antonio, TX) that was set at -125 mm Hg and left in place for 5 days before removal. RESULTS: An abdominal CT scan performed before discharge from the hospital did not show seroma formation. Physical examination 3 months after surgery was normal with no evidence of seroma (abdominal bulge and/or fluid wave). CONCLUSIONS: This successful preliminary experience in three patients encourages the use of the VAC system in incisional hernia repair, particularly in selected patients with risk factors for seroma formation (e.g., large defects, obesity, patient comorbidities, nutritional status, number of prior abdominal incisions, etc.). Therefore, prevention of seroma formation after incisional hernia repair may be added as a novel application of the VAC device. PMID- 21667263 TI - Morphometry of the synovial folds of the lateral atlanto-axial joints: the anatomical basis for understanding their potential role in neck pain. AB - PURPOSE: Intra-articular synovial folds of the cervical spine are considered to be a potential source of neck pain and disability. The purpose of the present study was to devise and validate a method to determine the normal morphometry of the synovial folds as a basis for understanding their functional and clinical significance. METHODS: Nine cadaver cervical spines were sectioned in the sagittal plane. The presence of the synovial folds at the lateral atlanto-axial joints was determined and their morphology described. Depth of projection, cross sectional area and volume of the ventral and dorsal synovial folds of the right and left lateral atlanto-axial joints were measured from sagittal sections and compared. The relationship between synovial fold dimensions and subject age and cartilage degeneration were determined. Repeat measurements were made for the calculation of method reliability, and the water displacement method was used to determine method validity. RESULTS: There was a trend for ventral synovial folds to be larger than dorsal synovial folds. There was no correlation between synovial fold dimensions and age and extent of cartilage degeneration. Measurement reliability ranged from intraclass correlation coefficient 0.95-1.00 (intra-observer), 0.95-1.00 (test-retest) and 0.61-1.00 (inter-observer). Limits of agreement for the sectional and water displacement methods for the measurement of synovial fold volume were -1.04 +/- 3.35 mm(3). CONCLUSIONS: A reliable method for quantifying synovial fold dimensions was devised. The results of this study provide a basis for the determination and diagnosis of pathologies affecting the synovial folds. PMID- 21667264 TI - Identification of c-myc-dependent proteins in the medulloblastoma cell line D425Med. AB - High c-myc levels are linked to poor prognosis in medulloblastoma (MB), and it was the aim of the current study to search for c-myc-dependent proteins in the MB cell line D425Med. For this purpose D425Med cells and cells with knocked-down c myc (by siRNA) were analysed by a gel-based differential proteomics study using mass spectrometry. Heterogeneous nuclear ribonucleoproteins C1/C2, heterogeneous nuclear ribonucleoprotein A/B, stathmin, endoplasmic reticulum protein ERp29 precursor and guanidinoacetate N-methyltransferase were c-myc dependently expressed. Signalling, the protein machinery, metabolism and endoplasmic reticulum function may be affected and these results enable studying tumour tissue for these proteins as potential dignity markers or pharmacological targets. PMID- 21667265 TI - Taurine-like GABA aminotransferase inhibitors prevent rabbit brain slices against oxygen-glucose deprivation-induced damage. AB - The activation of the GABAergic system has been shown to protect brain tissues against the damage that occurs after cerebral ischaemia. On the other hand, the taurine analogues (+/-)Piperidine-3-sulphonic- (PSA), 2-aminoethane phosphonic- (AEP), 2-(N-acetylamino) cyclohexane sulfonic-acids (ATAHS) and 2-aminobenzene sulfonate-acids (ANSA) have been reported to block GABA metabolism by inhibiting rabbit brain GABA aminotransferase and to increase GABA content in rabbit brain slices. The present investigation explored the neuroprotection provided by GABA, Vigabatrin (VIGA) and taurine analogues in the course of oxygen-glucose deprivation and reperfusion induced damage of rabbit brain slices. Tissue damage was assessed by measuring the release of glutamate and lactate dehydrogenase (LDH) during reperfusion and by determining final tissue water gain, measured as the index of cell swelling. GABA (30-300 MUM) and VIGA (30-300 MUM) significantly antagonised LDH and glutamate release, as well as tissue water gain caused by oxygen-glucose deprivation and reperfusion. Lower (1-10 MUM) or higher concentrations (up to 3,000 MUM) were ineffective. ANSA, PSA and ATAHS significantly reduced glutamate and LDH release and tissue water gain in a range of concentrations between 30 and 300 MUM. Lower (0-10 MUM) or higher (up to 3,000 MUM) concentrations were ineffective. Both mechanisms suggest hormetic ("U shaped") effects. These results indicate that the GABAergic system activation performed directly by GABA or indirectly through GABA aminotransferase inhibition is a promising approach for protecting the brain against ischemia and reperfusion induced damage. PMID- 21667266 TI - Elastic modulus of tree frog adhesive toe pads. AB - Previous work using an atomic force microscope in nanoindenter mode indicated that the outer, 10- to 15-MUm thick, keratinised layer of tree frog toe pads has a modulus of elasticity equivalent to silicone rubber (5-15 MPa) (Scholz et al. 2009), but gave no information on the physical properties of deeper structures. In this study, micro-indentation is used to measure the stiffness of whole toe pads of the tree frog, Litoria caerulea. We show here that tree frog toe pads are amongst the softest of biological structures (effective elastic modulus 4-25 kPa), and that they exhibit a gradient of stiffness, being stiffest on the outside. This stiffness gradient results from the presence of a dense network of capillaries lying beneath the pad epidermis, which probably has a shock absorbing function. Additionally, we compare the physical properties (elastic modulus, work of adhesion, pull-off force) of the toe pads of immature and adult frogs. PMID- 21667267 TI - The oscar, Astronotus ocellatus, detects and discriminates dipole stimuli with the lateral line system. AB - We studied the role of the lateral line system for detection and discrimination of dipole stimuli in the oscar, Astronotus ocellatus (Family Cichlidae), and determined detection thresholds in still water and frequency discrimination capabilities in still and turbulent water. Average detection threshold of six animals for a 100-Hz dipole stimulus was 0.0059 MUm peak-to-peak water displacement at the surface of the fish. After inactivation of the neuromast receptor organs of the lateral line system with the antibiotic streptomycin, dipole detection was reduced, but recovered within 2-4 weeks. This suggests that the oscar relied strongly on hydrodynamic information received by the lateral line system. Five oscars learned to discriminate a 100-Hz stimulus from 70 Hz and lower frequencies. When turbulence was introduced into the experimental tank, fish were still able to discriminate 100 Hz from frequencies 70 Hz and lower indicating that frequency discrimination mediated by the lateral line system was not reduced in turbulent water. PMID- 21667268 TI - Neutral metallated and meso-substituted porphyrins as antimicrobial agents against gram-positive pathogens. AB - Staphylococcus aureus is a bacterial pathogen that causes severe infections among humans. The increasing emergence of antibiotic resistance necessitates the development of new strategies to combat the spread of disease. One approach is photodynamic inactivation using porphyrin photosensitizers, which generate superoxide and other radicals in the presence of light, causing cell death via the oxidation of proteins and lipids. In this study, we analyzed a novel library of meso-substituted and metallated porphyrins for activity against multidrug resistant S. aureus. From a library of 251 compounds, 51 showed antimicrobial activity, in three discrete classes of activity: those that functioned only in light, those that had toxicity only in darkness, and those that displayed activity regardless of illumination. We further demonstrated the broad-spectrum activity of these compounds against a variety of pathogens, including Bacillus anthracis, Enterococcus faecalis, and Escherichia coli. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) analyses of lead compounds (XPZ-263 and XPZ-271) revealed strong activity and killing towards methicillin-resistant S. aureus (MRSA) strains. An analysis of mutation frequencies revealed low incidences of resistance to lead compounds by E. coli and MRSA. Finally, an exploration of the underlying mechanism of action suggests that these compounds do not depend solely upon light-induced radical generation for toxicity, highlighting their potential for clinical applications. PMID- 21667269 TI - Enterococcus avium bacteremia: a 12-year clinical experience with 53 patients. AB - Because Enterococcus avium is rarely isolated from blood cultures, little is known about the clinical features and outcomes of bacteremia caused by this organism, formerly called "group Q streptococcus". We retrospectively evaluated the clinical features and outcomes of patients with clinically significant bacteremia caused by E. avium presenting at a tertiary-care hospital in Korea between February 1997 and February 2009. We identified 53 patients over the 12 year period; of these, 27 (50.9%) had biliary and 13 (24.5%) had intra-abdominal E. avium infections. Thirty-six (67.9%) of the episodes were polymicrobial. Thirty-three (62.3%) episodes were nosocomial bloodstream infections and resistance to vancomycin was not observed. The crude mortality rate was 24.5% (13/53), and the E. avium bacteremia-related mortality rate was 11.3% (6/53). Multivariate analysis showed that underlying rapidly fatal or ultimately fatal disease (adjusted odds ratio [AOR], 6.92; 95% confidence interval [CI], 1.56 30.65; P = 0.011) and inadequate antimicrobial therapy (AOR, 7.29; CI, 1.27 41.93; P = 0.026) were independent risk factors for mortality. In summary, bacteremia due to E. avium was commonly of biliary or intraabdominal origin and was often associated with polymicrobial bacteremia. The crude mortality rate was considerable. Severe underlying conditions and inadequate antimicrobial therapy were significant and independent risk factors for crude patient mortality. PMID- 21667271 TI - Responses of maize (Zea mays L.) near isogenic lines carrying Wsm1, Wsm2, and Wsm3 to three viruses in the Potyviridae. AB - Genes on chromosomes six (Wsm1), three (Wsm2) and ten (Wsm3) in the maize (Zea mays L.) inbred line Pa405 control resistance to Wheat streak mosaic virus (WSMV), and the same or closely linked genes control resistance to Maize dwarf mosaic virus (MDMV) and Sugarcane mosaic virus (SCMV). Near isogenic lines (NIL) carrying one or two of the genes were developed by introgressing regions of the respective chromosomes into the susceptible line Oh28 and tested for their responses to WSMV, MDMV, and SCMV in the field and greenhouse. F(1) progeny from NIL * Oh28 were also tested. Wsm1, or closely linked genes, provided resistance to all three viruses, as determined by symptom incidence and severity. Wsm2 and Wsm3 provided resistance to WSMV. Wsm2 and/or Wsm3 provided no resistance to MDMV, but significantly increased resistance in plants with one Wsm1 allele. NIL carrying Wsm1, Wsm2, or Wsm3 had similar SCMV resistance in the field, but NIL with Wsm2 and Wsm3 were not resistant in the greenhouse. Addition of Wsm2 to Wsm1 increased SCMV resistance in the field. For all viruses, symptom incidence was higher in the greenhouse than in the field, and relative disease severity was higher in the greenhouse for WSMV and MDMV. An Italian MDMV isolate and the Ohio SCMV infected the Wsm1 NIL, while the Ohio MDMV and Seehausen SCMV isolates did not. Our results indicate that the three genes, or closely linked loci, provide virus resistance. Resistance conferred by the three genes is influenced by interactions among the genes, the virus species, the virus isolate, and the environment. PMID- 21667270 TI - Evaluation of GeneOhm VanR and Xpert vanA/vanB molecular assays for the rapid detection of vancomycin-resistant enterococci. AB - Rapid diagnosis is critical for treating and preventing infections due to vancomycin-resistant enterococci (VRE). We assessed the performance of GeneOhm VanR and Xpert vanA/vanB assays that detect vanA and vanB, the two most important genes encoding vancomycin resistance, utilizing 50 stool samples from renal dialysis patients, as well as well-characterized VRE strains. Stool samples were screened for the presence of VRE by culture followed by polymerase chain reaction (PCR) for the detection of van genes in isolates. Furthermore, the direct detection of vanA/vanB from aerobically and anaerobically pre-enriched stools was performed by in-house PCR sequencing. GeneOhm was less sensitive (43.5% vs. 73.9%) and more specific (100% vs. 92.6%) than Xpert in detecting vanA from stool samples. vanB detection by GeneOhm was more sensitive than Xpert (100% vs. 87.5%), but equally non-specific (20.6% vs. 14.7%). A further estimation on log serial dilutions of VRE strains showed that Xpert was more sensitive at detecting VRE at low concentrations (10-100 colony forming units [cfu]/ml). PMID- 21667272 TI - Special issue: amine oxidases: structures, mechanisms and therapeutic targets. PMID- 21667273 TI - Influence of coronary calcification on the diagnostic accuracy of 64-slice computed tomography coronary angiography: a systematic review and meta-analysis. AB - To determine via meta-analysis the diagnostic accuracy of 64-slice computed tomography coronary angiography (CTA) for assessment of significant obstructive coronary artery stenosis at different coronary artery calcium score (CACS) levels. Data of 12,053 versus 5,890 segments, 906 versus 758 arteries and 1,120 versus 514 patients in low versus high CACS subgroups from 19 eligible studies were compared. The per-patient prevalence of coronary artery disease was 48% versus 68%, respectively. Subgroups were stratified by different CACS thresholds ranging from 100 to 400. Meta-analyses of per-patient data comparing overall low versus high CACS subgroups resulted in a sensitivity of 97.5 (95.5-99)% versus 97 (94.5-98.5)%, specificity of 85 (82-88)% versus 66.5 (58-74.5)%, diagnostic odds ratio of 153 (81-290) versus 40 (20-83), positive predictive value of 85 (82-87)% versus 86 (84-88)%, negative predictive value of 97.5 (95-99)% versus 91 (88-94)% and overall accuracy of 91% versus 89% with 95% confidence interval, respectively. The drop in specificity was significant (P = 0.035), while the sensitivity and overall accuracy were insignificantly changed (P > 0.05). Meta analyses of independent subgroups at CACS levels <=10 and <=100 demonstrated high specificities of 90 (94-100)% and 88.5 (81-91.5)%, whereas at CACS levels >=400 the specificity declined significantly to 42 (28-56)% but with consistently retained high sensitivity of 97.5 (94-99)%. The specificity of CTA decreases with increasing CACS, while the sensitivity remains high independent of that. The suggested CACS thresholds are arbitrary and do not necessarily warrant cancelling angiography. Diagnostic studies are needed to explore whether a specific CACS threshold may serve as a pre-angiographic gatekeeper to prevent likely equivocal angiographies. PMID- 21667274 TI - Development and characterization of DehaloR^2, a novel anaerobic microbial consortium performing rapid dechlorination of TCE to ethene. AB - A novel anaerobic consortium, named DehaloR^2, that performs rapid and complete reductive dechlorination of trichloroethene (TCE) to ethene is described. DehaloR^2 was developed from estuarine sediment from the Back River of the Chesapeake Bay and has been stably maintained in the laboratory for over 2 years. Initial sediment microcosms showed incomplete reduction of TCE to DCE with a ratio of trans- to cis- isomers of 1.67. However, complete reduction to ethene was achieved within 10 days after transfer of the consortium to sediment-free media and was accompanied by a shift to cis-DCE as the prevailing intermediate metabolite. The microbial community shifted from dominance of the Proteobacterial phylum in the sediment to Firmicutes and Chloroflexi in DehaloR^2, containing the genera Acetobacterium, Clostridium, and the dechlorinators Dehalococcoides. Also present were Spirochaetes, possible acetogens, and Geobacter which encompass previously described dechlorinators. Rates of TCE to ethene reductive dechlorination reached 2.83 mM Cl- d(-1) in batch bottles with a Dehalococcoides sp. density of 1.54E+11 gene copies per liter, comparing favorably to other enrichment cultures described in the literature and identifying DehaloR^2 as a promising consortium for use in bioremediation of chlorinated ethene-impacted environments. PMID- 21667275 TI - B cells are required for tumor-targeting Salmonella in host. AB - Systemic administration of Salmonella to tumor-bearing mice leads to the preferential accumulation within tumor sites and retardation of the tumor growth. Host factors including innate and adaptive immune responses influence Salmonella induced antitumor activity. Antitumor activities of Salmonella are not only determined by the tumor regression but also by the host immune response. Herein, we demonstrated that B cells play an important role in the antitumor activity mediated by Salmonella. Body weight and survival of B cell-deficient mice were decreased compared with wild-type, CD8(+) cell-deficient, or CD4(+) cell deficient mice after Salmonella administration. Although Salmonella accumulated within the tumors in B cell-deficient mice, the bacterial loads of healthy organs were higher than those in wild-type mice. The inflammation cytokine and bacteremia were found in B cell-deficient mice after Salmonella treatment. When Salmonella accumulated within the tumor, B cells inhibited the dissemination of Salmonella to other healthy organs. The depletion of host B cells resulted in a noticeably higher total number of Salmonella in the tumor and inhibited tumor growth. Meanwhile, B cell-depletive and B cell-adoptive transfer of serum experiments demonstrated that the natural antibody produced by B cell takes part in the control of Salmonella dissemination in tumor-bearing mice. In this study, we want to address the mechanisms of incorporating host immunoresponse as a way to augment the antitumor activities of Salmonella. PMID- 21667276 TI - Use of primer selection and restriction enzymes to assess bacterial community diversity in an agricultural soil used for potato production via terminal restriction fragment length polymorphism. AB - Terminal restriction fragment length polymorphism (T-RFLP) can be used to assess how land use management changes the dominant members of bacterial communities. We compared T-RFLP profiles obtained via amplification with forward primers (27, 63F) each coupled with the fluorescently labeled reverse primer (1392R) and multiple restriction enzymes to determine the best combination for interrogating soil bacterial populations in an agricultural soil used for potato production. Both primer pairs provide nearly universal recognition of a 1,400-bp sequence of the bacterial domain in the V(1)-V(3) region of the 16S ribosomal RNA (rRNA) gene relative to known sequences. Labeling the reverse primer allowed for direct comparison of each forward primer and the terminal restriction fragments' relative migration units obtained with each primer pair and restriction enzyme. Redundancy analysis (RDA) and nested multivariate analysis of variance (MANOVA) were used to assess the effects of primer pair and choice of restriction enzyme on the measured relative migration units. Our research indicates that the 63F 1392R amplimer pair provides a more complete description with respect to the bacterial communities present in this potato (Solanum tuberosum L.)-barley (Hordeum vulgare L.) rotation over seeded to crimson clover (Trifolium praense L.). Domain-specific 16S rRNA gene primers are rigorously tested to determine their ability to amplify across a target region of the gene. Yet, variability within or between T-RFLP profiles can result from factors independent of the primer pair. Therefore, researchers should use RDA and MANOVA analyses to evaluate the effects that additional laboratory and environmental variables have on bacterial diversity. PMID- 21667277 TI - Forming a tough shell via an intracellular matrix and cellular junctions in the tail epidermis of Oikopleura dioica (Chordata: Tunicata: Appendicularia). AB - A postanal tail is a major synapomorphy of the phylum Chordata, which is composed of three subphyla: Vertebrata, Cephalochordata, and Tunicata (Urochordata). Among tunicates, appendicularians are the only group that retains the tail in the adult, and the adult tail functions in locomotion and feeding in combination with a cellulose-based house structure. Given the phylogenetic position of tunicates, the appendicularian adult tail may possess ancestral features of the chordate tail. We assess the ultrastructural development of the tail epidermis of the appendicularian Oikopleura dioica. The epidermis of the larval tail is enclosed by the larval envelope, which is a thin sheet similar to the outer tunic layer of ascidian larvae. The epidermis of the adult tail seems to bear no tunic-like cellulosic integuments, and the tail fin is a simple folding of the epidermis. Every epidermal cell, except for the triangular cells at the edge of the tail fin, has a conspicuous matrix layer of fibrous content in the apical cytoplasm without enclosing membranes. The epidermis of the larval tail does not have a fibrous matrix layer, suggesting the production of the layer during larval development and metamorphosis. Zonulae adhaerentes firmly bind the epidermal cells of the adult tail to one another, and the dense microfilaments lining the cell borders constitute a mechanical support for the cell membranes. The intracellular matrix, cell junctions, and cytoskeletons probably make the tail epidermis a tough, flexible shell supporting the active beating of the oikopleuran adult tail. PMID- 21667278 TI - Neuroprotection by ulinastatin in experimental autoimmune encephalomyelitis. AB - Ulinastatin has previously been used as a drug for patients with acute inflammatory disorders. The goal of the present study was to investigate the protective effects of ulinastatin on myelin sheaths and oligodendrocytes in experimental autoimmune encephalomyelitis (EAE), and to explore the possible underlying mechanism. Mice were divided into an ulinastatin treatment group, a normal saline treatment group, and a normal control group. EAE was induced in the mice with and without ulinastatin treatment. Demyelination was evaluated, as was the number of oligodendrocytes. The ulinastatin treatment group had a significantly lower clinical score, demyelinating score, and large numbers of oligodendrocytes compared with the group without ulinastatin treatment. Furthermore, ulinastatin treatment increased the expression of nerve growth factor and brain-derived neurotrophic factor, and protected against oligodendrocyte apoptosis. Thus, ulinastatin is shown to have a protective effect against EAE. PMID- 21667279 TI - MPP(+)-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress. AB - Accumulating evidence suggests that endogenous dopamine may act as a neurotoxin and thereby participate in the pathophysiology of Parkinson's disease (PD). Cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of PD due to its ability to generate reactive oxygen species (ROS). Inhibition of COX-2 leads to neuroprotection by preventing the formation of dopamine-quinone. In this study, we examined whether dopamine mediates 1-methyl-4-phenylpyridinium (MPP(+)) induced toxicity in primary ventral mesencephalic (VM) neurons, an in vitro model of PD, and if so, whether the protective effects of COX-2 inhibitors on dopamine mediated MPP(+)-induced VM neurotoxicity and VM dopaminergic cell apoptosis result from the reduction of ROS. Reserpine, a dopamine-depleting agent, significantly reduced VM neurotoxicity induced by MPP(+), whereas dopamine had an additive effect on MPP(+)-induced VM neurotoxicity and VM dopaminergic cell apoptosis. However, inhibition of COX-2 by a selective COX-2 inhibitor (DFU) or ibuprofen significantly attenuated MPP(+)-induced VM cell toxicity and VM dopaminergic cell apoptosis, which was accompanied by a decrease in ROS production in VM dopaminergic neurons. These results suggest that dopamine itself mediates MPP(+)-induced VM neurotoxicity and VM dopaminergic cell apoptosis in the presence of COX-2. PMID- 21667280 TI - Review on the validity of self-report to assess work-related diseases. AB - PURPOSE: Self-report is an efficient and accepted means of assessing population characteristics, risk factors, and diseases. Little is known on the validity of self-reported work-related illness as an indicator of the presence of a work related disease. This study reviews the evidence on (1) the validity of workers' self-reported illness and (2) on the validity of workers' self-assessed work relatedness of an illness. METHODS: A systematic literature search was conducted in four databases (Medline, Embase, PsycINFO and OSH-Update). Two reviewers independently performed the article selection and data extraction. The methodological quality of the studies was evaluated, levels of agreement and predictive values were rated against predefined criteria, and sources of heterogeneity were explored. RESULTS: In 32 studies, workers' self-reports of health conditions were compared with the "reference standard" of expert opinion. We found that agreement was mainly low to moderate. Self-assessed work relatedness of a health condition was examined in only four studies, showing low to-moderate agreement with expert assessment. The health condition, type of questionnaire, and the case definitions for both self-report and reference standards influence the results of validation studies. CONCLUSIONS: Workers' self reported illness may provide valuable information on the presence of disease, although the generalizability of the findings is limited primarily to musculoskeletal and skin disorders. For case finding in a population at risk, e.g., an active workers' health surveillance program, a sensitive symptom questionnaire with a follow-up by a medical examination may be the best choice. Evidence on the validity of self-assessed work relatedness of a health condition is scarce. Adding well-developed questions to a specific medical diagnosis exploring the relationship between symptoms and work may be a good strategy. PMID- 21667281 TI - Impact of Mindfulness-Based Stress Reduction (MBSR) on attention, rumination and resting blood pressure in women with cancer: a waitlist-controlled study. AB - The present study is a waitlist-controlled investigation of the impact of a Mindfulness-Based Stress Reduction (MBSR) program on mindful attentiveness, rumination and blood pressure (BP) in women with cancer. Female post-treatment cancer patients were recruited from the MBSR program waitlist. Participants completed self-report measures of mindfulness and rumination and measured casual BP at home before and after the 8-week MBSR program or waiting period. MBSR group participants demonstrated higher levels of mindful attentiveness and decreased ruminative thinking following the intervention but no difference in BP, when compared to controls. In the MBSR group, decreases in rumination correlated with decreases in SBP and increases in mindful attention. When participants were assigned to "Higher BP" and "Lower BP" conditions based on mean BP values at week 1, "Higher BP" participants in the MBSR group (n=19) had lower SBP at week 8 relative to the control group (n=16). A MBSR program may be efficacious in increasing mindful attention and decreasing rumination in women with cancer. Randomized controlled trials are needed to evaluate an impact on clinically elevated BP. PMID- 21667282 TI - Whole genome sequencing and characterization of a virulent Newcastle disease virus isolated from an outbreak in Sweden. AB - In this study, the complete genome sequence of a Newcastle disease virus (NDV) isolate collected from an outbreak in 1995 in chickens was fully characterized and compared with other NDV sequences. The genome was found to be 15,192 nucleotides long and to consist of six genes in the order 3'-NP-P-M-F-HN-L-5', similar to other avian paramyxoviruses type-I. However, a six-nucleotide insertion was observed in the 5' non-coding regions of the nucleoprotein (NP) gene, a feature that is unique to some NDV isolates. The isolate shows the amino acid sequence (112)RRQKRF(117) at the cleavage site of the F protein, which is identical to a known motif for virulent pathotypes of NDV. The phylogenetic analysis of the coding region of the F gene indicated that this isolate belongs to genotype VI, more specifically to genotype VId, along with isolates from the other European countries (Denmark, Switzerland and Austria). The same genotype caused outbreaks in the Middle East and Greece in the late 1960s, and in Hungary, in the early 1980s, suggesting a common source for these outbreaks. PMID- 21667283 TI - Candidate chemosensory cells in the porcine stomach. AB - A continuous chemosensory monitoring of the ingested food is of vital importance for adjusting digestive processes according to diet composition. Although any dysfunction of this surveillance system may be the cause of severe gastrointestinal disorders, information about the cellular and molecular basis of chemosensation in the gastrointestinal tract is limited. The porcine alimentary canal is considered as an appropriate model for the human gastrointestinal tract. Therefore, in this study we have investigated the gastric mucosa of swine for cells which express gustatory transduction elements such as TRPM5 or PLCbeta2, and thus may represent candidate "chemosensors". It was found that the porcine stomach indeed contains cells expressing gustatory marker molecules; however, the morphology and topographic distribution of putative chemosensory cells varied significantly from that in mice. Whereas in the murine stomach these cells were clustered at a distinct region near the gastric entrance, no such compact cell cluster was found in the pig stomach. These results indicate substantial differences regarding the phenotype of candidate chemosensory cells of mice and swine and underline the importance of choosing the most suitable model organisms. PMID- 21667285 TI - Anticipation in hereditary disease: the history of a biomedical concept. AB - In the mid-nineteenth century, it was commonly believed that hereditary disease struck at the same time in succeeding generations, except for those cases in which it appeared at an earlier age. This exception to the rule was the precursor for the concept of anticipation in hereditary disease, a pattern of inheritance where a hereditary illness strikes earlier and often more severely in succeeding generations. Anticipation underwent cycles of acceptance and rejection over the course of the twentieth century and the ways in which this concept was received reveal complex interactions between science, medicine, and society. PMID- 21667286 TI - Complete nucleotide sequences of two dsRNAs associated with a new partitivirus infecting Aspergillus fumigatus. PMID- 21667284 TI - X-inactivation and X-reactivation: epigenetic hallmarks of mammalian reproduction and pluripotent stem cells. AB - X-chromosome inactivation is an epigenetic hallmark of mammalian development. Chromosome-wide regulation of the X-chromosome is essential in embryonic and germ cell development. In the male germline, the X-chromosome goes through meiotic sex chromosome inactivation, and the chromosome-wide silencing is maintained from meiosis into spermatids before the transmission to female embryos. In early female mouse embryos, X-inactivation is imprinted to occur on the paternal X chromosome, representing the epigenetic programs acquired in both parental germlines. Recent advances revealed that the inactive X-chromosome in both females and males can be dissected into two elements: repeat elements versus unique coding genes. The inactive paternal X in female preimplantation embryos is reactivated in the inner cell mass of blastocysts in order to subsequently allow the random form of X-inactivation in the female embryo, by which both Xs have an equal chance of being inactivated. X-chromosome reactivation is regulated by pluripotency factors and also occurs in early female germ cells and in pluripotent stem cells, where X-reactivation is a stringent marker of naive ground state pluripotency. Here we summarize recent progress in the study of X inactivation and X-reactivation during mammalian reproduction and development as well as in pluripotent stem cells. PMID- 21667287 TI - Receptor-bound porcine epidemic diarrhea virus spike protein cleaved by trypsin induces membrane fusion. AB - Porcine epidemic diarrhea virus (PEDV) infection in Vero cells is facilitated by trypsin through an undefined mechanism. The present study describes the mode of action of trypsin in enhancing PEDV infection in Vero cells during different stage of the virus life cycle. During the viral entry stage, trypsin increased the penetration of Vero-cell-attached PEDV by approximately twofold. However, trypsin treatment of viruses before receptor binding did not enhance infectivity, indicating that receptor binding is essentially required for trypsin-mediated entry upon PEDV infection. Trypsin treatment during the budding stage of virus infection induces an obvious cytopathic effect in infected cells. Furthermore, we also show that the PEDV spike (S) glycoprotein is cleaved by trypsin in virions that are bound to the receptor, but not in free virions. These findings indicate that trypsin affects only cell-attached PEDV and increases infectivity and syncytium formation in PEDV-infected Vero cells by cleavage of the PEDV S protein. These findings strongly suggest that the PEDV S protein may undergo a conformational change after receptor binding and cleavage by exogenous trypsin, which induces membrane fusion. PMID- 21667288 TI - Virtual screening for potential inhibitors of bacterial MurC and MurD ligases. AB - Mur ligases are bacterial enzymes involved in the cytoplasmic steps of peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have performed virtual screening for potential ATP-competitive inhibitors targeting MurC and MurD ligases, using a protocol of consecutive hierarchical filters. Selected compounds were evaluated for inhibition of MurC and MurD ligases, and weak inhibitors possessing dual inhibitory activity have been identified. These compounds represent new scaffolds for further optimisation towards multiple Mur ligase inhibitors with improved inhibitory potency. PMID- 21667289 TI - New challenges in radiobiology research with microbeams. AB - There is a continuing interest in the use of microbeam systems designed to deliver ionizing radiation (both photons and particles) with a resolution of a few micrometers or less in biological targets. With more than 30 facilities currently in operation, several new research topics can be explored. In the 9th International Microbeam Workshop held in Darmstadt, Germany, in July 2010, several new ideas and results have been presented, indicating that microbeams will be increasingly important in radiobiology. Subnuclear targeting of single cells for DNA repair studies and microirradiation of 3D or small animal models are among the most promising new research perspectives. PMID- 21667290 TI - Effects of exercise intensity and duration on nocturnal heart rate variability and sleep quality. AB - Acute physical exercise may affect cardiac autonomic modulation hours or even days during the recovery phase. Although sleep is an essential recovery period, the information on nocturnal autonomic modulation indicated by heart rate variability (HRV) after different exercises is mostly lacking. Therefore, this study investigated the effects of exercise intensity and duration on nocturnal HR, HRV, HR, and HRV-based relaxation, as well as on actigraphic and subjective sleep quality. Fourteen healthy male subjects (age 36 +/- 4 years, maximal oxygen uptake 49 +/- 4 ml/kg/min) performed five different running exercises on separate occasions starting at 6 p.m. with HR guidance at home. The effect of intensity was studied with 30 min of exercises at intensities corresponding to HR level at 45% (easy), 60% (moderate) and 75% (vigorous) of their maximal oxygen uptake. The effect of duration was studied with 30, 60, and 90 min of moderate exercises. Increased exercise intensity elevated nocturnal HR compared to control day (p < 0.001), but it did not affect nocturnal HRV. Nocturnal HR was greater after the day with 90- than 30- or 60-min exercises (p < 0.01) or control day (p < 0.001). Nocturnal HRV was lower after the 90-min exercise day compared to control day (p < 0.01). Neither exercise intensity nor duration had any impact on actigraphic or subjective sleep quality. The results suggest that increased exercise intensity and/or duration cause delayed recovery of nocturnal cardiac autonomic modulation, although long exercise duration was needed to induce changes in nocturnal HRV. Increased exercise intensity or duration does not seem to disrupt sleep quality. PMID- 21667291 TI - Performance and physiological responses during a sprint interval training session: relationships with muscle oxygenation and pulmonary oxygen uptake kinetics. AB - The purpose of this study was to examine the cardiorespiratory and muscle oxygenation responses to a sprint interval training (SIT) session, and to assess their relationships with maximal pulmonary O(2) uptake [Formula: see text], on- and off- [Formula: see text] kinetics and muscle reoxygenation rate (Reoxy rate). Ten male cyclists performed two 6-min moderate-intensity exercises (~90-95% of lactate threshold power output, Mod), followed 10 min later by a SIT session consisting of 6 * 30-s all out cycling sprints interspersed with 2 min of passive recovery. [Formula: see text] kinetics at Mod onset ([Formula: see text]) and cessation ([Formula: see text]) were calculated. Cardiorespiratory variables, blood lactate ([La](b)) and muscle oxygenation level of the vastus lateralis (tissue oxygenation index, TOI) were recorded during SIT. Percentage of the decline in power output (%Dec), time spent above 90% of [Formula: see text] (t > 90% [Formula: see text]) and Reoxy rate after each sprint were also recorded. Despite a low mean [Formula: see text] (48.0 +/- 4.1% of [Formula: see text]), SIT performance was associated with high peak [Formula: see text] (90.4 +/- 2.8% of [Formula: see text]), muscle deoxygenation (sprint DeltaTOI = -27%) and [La](b) (15.3 +/- 0.7 mmol l(-1)) levels. Muscle deoxygenation and Reoxy rate increased throughout sprint repetitions (P < 0.001 for both). Except for t > 90% [Formula: see text] versus [Formula: see text] [r = 0.68 (90% CL, 0.20; 0.90); P = 0.03], there were no significant correlations between any index of aerobic function and either SIT performance or physiological responses [e.g., %Dec vs. [Formula: see text]: r = -0.41 (-0.78; 0.18); P = 0.24]. Present results show that SIT elicits a greater muscle O(2) extraction with successive sprint repetitions, despite the decrease in external power production (%Dec = 21%). Further, our findings obtained in a small and homogenous group indicate that performance and physiological responses to SIT are only slightly influenced by aerobic fitness level in this population. PMID- 21667293 TI - CCN2 expression and localization in melanoma cells. AB - The matricellular protein connective tissue growth factor (CTGF, CCN2) is overexpressed in several forms of cancer and may represent a novel target in anti cancer therapy. However, whether CCN2 is expressed in melanoma cells is unknown. The highly metastatic murine melanoma cell line B16(F10) was used for our studies. Real time polymerase chain reaction analysis was used to detect mRNA expression of CCN1, CCN2, CCN3 and CCN4 in Western blot and immunofluorescence analyses were used to detect CCN2 protein. Inhibitors of signal transduction cascades were used to probe the mechanism underlying CCN2 expression in B16(F10) cells. CCN2 was expressed in B16(F10) cells, and was reduced by the FAK/src inhibitor PP2 and the MEK/ERK inhibitor U0126 indicating that CCN2 acts downstream of these pathways in B16(F10) murine melanoma cells. Expression of CCN1, CCN3 and CCN4 was not reduced by PP2 or U0126; in fact, expression of CCN4 mRNA was elevated by PP2 or U0126 treatment. To our surprise, CCN2 protein was detected in the nuclei of B16(F10) cells, and was undetectable in the cytoplasm. CCN2 was expressed in B16(F10) melanoma cells, adding to the list of cancer cells in which CCN2 is expressed. Of the CCN family members tested, only CCN2 is downstream of the highly oncogenic MEK/ERK pathway. CCN2 should be further evaluated for a possible role in melanoma growth and progression. PMID- 21667294 TI - Early adolescent peer ecologies in rural communities: bullying in schools that do and do not have a transition during the middle grades. AB - The transition to middle school is considered to be a heightened period for involvement in bullying because the lack of a defined dominance hierarchy is thought to promote jockeying for social positions among students. Accordingly, this study examined bullying in peer ecologies at the beginning of the middle grade years in rural schools that did and did not have a transition to middle school. Thirty-six schools (20 with transitions, 16 without transitions) participated in this research with a sample of 1,800 participants (52% female) who were in sixth grade during the second year of data collection. Overall, 67% were White, 19% African American, 7% Latino, 2% Native American, and 5% other (multi-racial, Asian, unknown). Compared to schools without a transition, schools with a transition had fewer bullies following the move from fifth to sixth grade and the social dynamics in schools with a transition appeared to be less supportive of bullying. Further, students in schools with a transition reported being bullied less frequently in sixth grade and they perceived the sixth grade peer ecology as being more protective against bullying than did students in schools without a transition. In addition, proportionally more youth had controversial sociometric status in schools without a transition during sixth grade than in schools with a transition. Collectively, these findings suggest that risk for involvement in bullying may be elevated in schools that do not have a transition to middle school. They also bring into question the conventional view of the small K-8 or K-12 rural school as a peaceful and supportive peer community. PMID- 21667292 TI - Manipulation of a fragile object by elderly individuals. AB - We investigated strategies of healthy elderly participants (74-84 years old) during prehension and transport of an object with varying degrees of fragility. Fragility was specified as the maximal normal force that the object could withstand without collapsing. Specifically, kinetic and kinematic variables as well as and force covariation indices were quantified and compared to those shown by young healthy persons (19-28 years old). We tested three hypotheses related to age-related changes in two safety margins (slip safety margin and crush safety margin) and indices of force covariation. Compared to young controls, elderly individuals exhibited a decrease in object acceleration and an increase in movement time, an increase in grip force production, a decrease in the correlation between grip and load forces, an overall decrease in indices of multi digit synergies, and lower safety margin indices computed with respect to both dropping and crushing the object. Elderly participants preferred to be at a relatively lower risk of crushing the object even if this led to a higher risk of dropping it. Both groups showed an increase in the index of synergy stabilizing total normal force produced by the four fingers with increased fragility of the object. Age-related changes are viewed as a direct result of physiological changes due to aging, not adaptation to object fragility. Such changes in overall characteristics of prehension likely reflect diminished synergic control by the central nervous system of finger forces with aging. The findings corroborate an earlier hypothesis on an age-related shift from synergic to element-based control. PMID- 21667295 TI - General versus specific predictors of male arrest trajectories: a test of the Moffitt and Patterson theories. AB - Developmental taxonomies of crime disagree on whether distinctive offender trajectories are related to common or unique risks. This study examined childhood risks of differing arrest trajectories across childhood through early adulthood (from ages 10-11 to 26-27 years) that were identified in prior work for 203 at risk, predominantly Caucasian young men. Multivariate analyses revealed that when both distal (childhood risk factors) and proximal risk factors (deviant peer association as a time-varying covariate) were included in the model, relatively few childhood risk factors (assessed at age 9-10 years) discriminated the chronic offender groups from rare offenders (i.e., child antisocial behavior, child attention problems, parents' antisocial behavior). Rather, deviant peer association was significantly related to levels of offending within each trajectory group (i.e., chronic and rare offender groups). No predictor differentially predicted membership in the two chronic groups, supporting the linear gradation argument. Theoretical and prevention implications are discussed. PMID- 21667296 TI - A genetic basis for the manipulation of sink-source relationships by the galling aphid Pemphigus batae. AB - We examined how the galling aphid Pemphigus batae manipulates resource translocation patterns of resistant and susceptible narrowleaf cottonwood Populus angustifolia. Using carbon-14 ((14)C)-labeling experiments in common garden trials, five patterns emerged. First, although aphid galls on resistant and susceptible genotypes did not differ in their capacity to intercept assimilates exported from the leaf they occupied, aphids sequestered 5.8-fold more assimilates from surrounding leaves on susceptible tree genotypes compared to resistant genotypes. Second, gall sinks on the same side of a shoot as a labeled leaf were 3.4-fold stronger than gall sinks on the opposite side of a shoot, which agrees with patterns of vascular connections among leaves of the same shoot (orthostichy). Third, plant genetic-based traits accounted for 26% of the variation in sink strength of gall sinks and 41% of the variation in sink strength of a plant's own bud sinks. Fourth, tree susceptibility to aphid gall formation accounted for 63% of the variation in (14)C import, suggesting strong genetic control of sink-source relationships. Fifth, competition between two galls was observed on a susceptible but not a resistant tree. On the susceptible tree distal aphids intercepted 1.5-fold more (14)C from the occupied leaf than did basal aphids, but basal aphids compensated for the presence of a distal competitor by almost doubling import to the gall from surrounding leaves. These findings and others, aimed at identifying candidate genes for resistance, argue the importance of including plant genetics in future studies of the manipulation of translocation patterns by phytophageous insects. PMID- 21667297 TI - The effects of traumatic stressors and HIV-related trauma symptoms on health and health related quality of life. AB - The study identified relations among traumatic stressors, HIV-related trauma symptoms, comorbid medical conditions, and health related quality of life (HRQL) in individuals with HIV. Participants (N = 118) completed a structured clinical interview on HIV as a traumatic stressor and other severe traumatic stressors and completed the Impact of Event Scale to assess HIV-related trauma symptoms and the Medical Outcomes Study 36-item Short Form (SF-36) to assess HRQL. Medical chart reviews determined comorbid conditions. Path analysis findings indicated participants with prior severe traumatic stressors experienced their HIV diagnosis as traumatic and in turn were more likely to have current HIV-related trauma symptoms which were negatively related to HRQL. HIV as a traumatic stressor was related to coronary artery diseases and HRQL. Traumatic stressors and HIV-related trauma symptoms impact health in individuals with HIV and highlight the need for psychological interventions prior to diagnosis and throughout treatment. PMID- 21667298 TI - Backbone resonance assignment and order tensor estimation using residual dipolar couplings. AB - An NMR investigation of proteins with known X-ray structures is of interest in a number of endeavors. Performing these studies through nuclear magnetic resonance (NMR) requires the costly step of resonance assignment. The prevalent assignment strategy does not make use of existing structural information and requires uniform isotope labeling. Here we present a rapid and cost-effective method of assigning NMR data to an existing structure-either an X-ray or computationally modeled structure. The presented method, Exhaustively Permuted Assignment of RDCs (EPAR), utilizes unassigned residual dipolar coupling (RDC) data that can easily be obtained by NMR spectroscopy. The algorithm uses only the backbone N-H RDCs from multiple alignment media along with the amino acid type of the RDCs. It is inspired by previous work from Zweckstetter and provides several extensions. We present results on 13 synthetic and experimental datasets from 8 different structures, including two homodimers. Using just two alignment media, EPAR achieves an average assignment accuracy greater than 80%. With three media, the average accuracy is higher than 94%. The algorithm also outputs a prediction of the assignment accuracy, which has a correlation of 0.77 to the true accuracy. This prediction score can be used to establish the needed confidence in assignment accuracy. PMID- 21667299 TI - Mammalian production of an isotopically enriched outer domain of the HIV-1 gp120 glycoprotein for NMR spectroscopy. AB - NMR spectroscopic characterization of the structure or the dynamics of proteins generally requires the production of samples isotopically enriched in (15)N, (13)C, or (2)H. The bacterial expression systems currently in use to obtain isotopic enrichment, however, cannot produce a number of eukaryotic proteins, especially those that require post-translational modifications such as N-linked glycosylation for proper folding or activity. Here, we report the use of an adenovirus vector-based mammalian expression system to produce isotopically enriched (15)N or (15)N/(13)C samples of an outer domain variant of the HIV-1 gp120 envelope glycoprotein with 15 sites of N-linked glycosylation. Yields for the (15)N- and (15)N/(13)C-labeled gp120s after affinity chromatography were 45 and 44 mg/l, respectively, with an average of over 80% isotope incorporation. Recognition of the labeled gp120 by cognate antibodies that recognize complex epitopes showed affinities comparable to the unlabeled protein. NMR spectra, including (1)H-(15)N and (1)H-(13)C HSQCs, (15)N-edited NOESY-HSQC, and 3D HNCO, were of high quality, with signal-to-noise consistent with an efficient level of isotope incorporation, and with chemical shift dispersion indicative of a well folded protein. The exceptional protein yields, good isotope incorporation, and ability to obtain well-folded post-translationally modified proteins make this mammalian system attractive for the production of isotopically enriched eukaryotic proteins for NMR spectroscopy. PMID- 21667300 TI - Cognitive ability, neighborhood deprivation, and young children's emotional and behavioral problems. AB - PURPOSE: To examine if cognitive ability moderates the effect of area (neighborhood) deprivation on young children's problem behavior. METHODS: Data from the first two sweeps of the Millennium Cohort Study (MCS) in the UK were used. Children were clustered in small areas in nine strata in the UK and were aged 9 months at Sweep 1 and 3 years at Sweep 2. Neighborhood deprivation was measured with the Index of Multiple Deprivation at Sweep 1. Overall and specific problem behavior was measured with the Strengths and Difficulties Questionnaire at Sweep 2. To explore moderator specificity we used three indices of ability (verbal cognitive ability, non-verbal cognitive ability, and attainment of developmental milestones). Adjustment was made for child's age and sex, and for Sweep 1 family adversity (number of adverse life events), family structure, mother's social class and psychological distress, and family socio-economic disadvantage. RESULTS: We found both support for our main hypothesis, and evidence for specificity. Neighborhood deprivation was, even after adjustment for covariates, significantly associated with children's peer problems. However, verbal and non-verbal cognitive ability moderated this association. CONCLUSIONS: Neighborhood deprivation was related to peer problems even at preschool age. Although the effect of neighborhood deprivation on externalizing problems was mediated by family poverty and parental socio-economic position and although its effect on internalizing problems was mediated by parental mental health, its effect on difficulties with peers was independent of both parental and child characteristics. Cognitive ability moderated the effect of neighborhood deprivation on preschoolers' peer relationships difficulties. PMID- 21667301 TI - The effect of rural-to-urban migration on social capital and common mental disorders: PERU MIGRANT study. AB - OBJECTIVE: This study aims to investigate whether there are differences in the prevalence of common mental disorders and social capital between migrant and non migrant groups in Peru. METHODOLOGY: The PERU MIGRANT study is a cross-sectional study comprising three groups: an urban group from a shanty town in Lima; a rural group from a community in Ayacucho-Peru; and a migrant group originally from Ayacucho currently living in the same urban shanty town. Common mental disorders were assessed using the General Health Questionnaire (GHQ-12), and social capital was assessed using the Short Social Capital Assessment Tool (SASCAT). Poisson regression with robust standard errors was used to estimate prevalence ratios. RESULTS: The overall prevalence of common mental disorders was 39.4%; the highest prevalence was observed in the rural group. Similar patterns were observed for cognitive social capital and structural social capital. However after adjustment for sex, age, family income and education, all but one of the significant relationships was attenuated, suggesting that in this population migration per se does not impact on common mental health disorders or social capital. CONCLUSIONS: In the PERU MIGRANT study, we did not observe a difference in the prevalence of common mental disorders, cognitive and structural social capital between migrant and urban groups. This pattern of associations was also similar in rural and urban groups, except that a higher prevalence ratio of structural social capital was observed in the rural group. PMID- 21667302 TI - Dropout from outpatient mental health care: results from the Israel National Health Survey. AB - OBJECTIVES: To examine the dropout rates from outpatient mental health treatment in the general medical and mental health sectors and to identify the predictors of dropout. METHOD: The study population was extracted from the Israel National Health Survey. The analysis was related to 12-month service utilization for mental health reasons. RESULTS: The total dropout rate from mental health treatment was 24%, but differed between sectors. The dropout rate from general medical care was 32, and 22% from mental health care. In the general medical care sector, 30% ended treatment within two visits, while only 10% did so in the mental health-care sector. Chronic health condition, but not severity of psychiatric disorder, predicted dropout in the mental health sector. DISCUSSION: The higher rate of early dropout in general medical care may be related to the brevity of general medical visits and/or the inexperience of primary care physicians, which limits the opportunity to develop patient-physician rapport. Providers of services will have to promote education programs for GPs and allocate proper time to psychiatric patients. LIMITATION: The sample, although based on a national representative cohort, was small and limited the number of independent variables that could be examined. PMID- 21667304 TI - The ventral hippocampus is necessary for expressing a spatial memory. AB - Current views posit the dorsal hippocampus (DHipp) as contributing to spatial memory processes. Conversely, the ventral hippocampus (VHipp) modulates stress, emotions and affects. Arguments supporting this segregation include differences in (i) connectivity: the DHipp is connected with the entorhinal cortex which receives visuospatial neocortical inputs; the VHipp is connected with both the amygdala and hypothalamus, (ii) electrophysiological characteristics: there is a larger proportion of place cells in the DHipp than in the VHipp, and an increasing dorsoventral gradient in the size of place fields, suggesting less refined spatial coding in the VHipp, and (iii) consequences of lesions: spatial memory is altered after DHipp lesions, less dramatically, sometimes not, after VHipp lesions. Using reversible inactivation, we report in rats, that lidocaine infusions into the DHipp or VHipp right before a probe trial impair retrieval performance in a water-maze task. This impairment was found at two post acquisition delays compatible with recent memory (1 and 5 days). Pre-training blockade of the VHipp did not prevent task acquisition and drug-free retrieval, on the contrary to pre-training blockade of DHipp, which altered performance in a subsequent drug-free probe trial. Complementary experiments excluded possible locomotor, sensorimotor, motivational or anxiety-related biases from data interpretation. Our conclusion is that a spatial memory can be acquired with the DHipp, less efficiently with the VHipp, and that the retrieval of such a memory and/or the expression of its representation engages the dorsoventral axis of the hippocampus when the task has been learnt with an entirely functional hippocampus. PMID- 21667303 TI - Neuroanatomic changes and their association with cognitive decline in mild cognitive impairment: a meta-analysis. AB - Mild cognitive impairment (MCI) is an acquired syndrome characterised by cognitive decline not affecting activities of daily living. Using a quantitative meta-analytic approach, we aimed to identify consistent neuroanatomic correlates of MCI and how they are related to cognitive dysfunction. The meta-analysis enrols 22 studies, involving 917 MCI (848 amnestic MCI) patients and 809 healthy controls. Only studies investigating local changes in grey matter and reporting whole-brain results in stereotactic coordinates were included and analysed using the activation likelihood estimation approach. Probabilistic cytoarchitectonic maps were used to compare the localization of the obtained significant effects to histological areas. A correlation between the probability of grey matter changes and cognitive performance of MCI patients was performed. In MCI patients, the meta-analysis revealed three significant clusters of convergent grey matter atrophy, which were mainly situated in the bilateral amygdala and hippocampus, extending to the left medial temporal pole and thalamus, as well as in the bilateral precuneus. A sub-analysis in only amnestic MCI revealed a similar pattern. A voxel-wise analysis revealed a correlation between grey matter reduction and cognitive decline in the right hippocampus and amygdala as well as in the left thalamus. This study provides convergent evidence of a distinct neuroanatomical pattern in MCI. The correlation analysis with cognitive-mnestic decline further highlights the impact of limbic structures and the linkage with data from a functional neuroimaging database provides additional insight into underlying functions. Although different pathologies are underlying MCI, the observed neuroanatomical pattern of structural changes may reflect the common clinical denominator of cognitive impairment. PMID- 21667305 TI - Hepatoid adenocarcinoma of the colon: what should we target? AB - Hepatoid adenocarcinoma is a rare extra hepatic neoplasm that displays morphological and phenotypic features similar to those of hepatocellular carcinoma. We report a case of a 75-year-old woman, presenting with abdominal pain and complaints of weakness and lost of appetite, who was found to have a mass on her right colon. She underwent right hemicolectomy for a pT3N2M0, stage IIIC colon cancer. The tumor phenotype and immunophenotype, as documented by alpha-fetoprotein immunoreaction positivity, were consistent with adenocarcinoma of hepatoid origin. The patient received FOLFOX-4 regimen as adjuvant treatment, relapsed after six cycles, then was switched to FOLFIRI regimen plus Bevacizumab and progressed after only four cycles. She died 1 month later, eight months after the diagnosis. The lack of any clinical benefit despite an aggressive and multimodal therapeutic strategy, raises a question about what should be targeted when we face this rare disease associated with a very poor prognosis. PMID- 21667306 TI - Low frequency of PIK3CA gene mutations in hepatocellular carcinoma in Chinese population. AB - PI3K/AKT constitutes an important pathway regulating the signaling of multiple biological processes and plays a critical role in carcinogenesis. PIK3CA gene missense mutations have been reported in many human cancer types. The mutation of it in hepatocellular carcinoma cases varies with different races and regions. In this study, we investigated PIK3CA mutation in Chinese hepatocellular carcinoma patients. A total 90 Chinese patients of hepatocellular carcinoma were recruited in this study. Exons 9 and 20 hotspots mutations of PIK3CA gene were detected by PCR-based DNA sequencing. Two point mutations (E542K and D549H) in exon 9 were found in only one patient (1/90; 1.11%), no mutation was found in exon 20 in any cases. 57 patients are associated with HBV infection (57/90; 63.3%), and 8 patients with HCV infection (8/90; 8.9%). The frequency of the PIK3CA mutations in hepatocellular carcinoma seems to be lower in Chinese hepatocellular carcinoma patients. These findings suggest that PI3K mutations may not play a major role in hepatic carcinogenesis in Chinese. HBV infection has close relationship with HCC in Chinese. PMID- 21667307 TI - Protein profile of Bacillus subtilis spore. AB - Natural wild-type strains of Bacillus subtilis spore is regarded as a non pathogenic for both human and animal, and has been classified as a novel food which is currently being used as probiotics added in the consumption. To identify B. subtilis spore proteins, we have accomplished a preliminary proteomic analysis of B. subtilis spore, with a combination of two-dimensional electrophoretic separations and matrix-assisted laser desorption ionization tandem time of flight mass spectrometry (MALDI-TOF-MS). In this article, we presented a reference map of 158 B. subtilis spore proteins with an isoelectric point (pI) between 4 and 7. Followed by mass spectrometry (MS) analysis, we identified 71 B. subtilis spore proteins with high level of confidence. Database searches, combined with hydropathy analysis and GO analysis revealed that most of the B. subtilis spore proteins were hydrophilic proteins related to catalytic function. These results should accelerate efforts to understand the resistance of spore to harsh conditions. PMID- 21667308 TI - Identification of fruity aroma-producing compounds from Chryseobacterium sp. isolated from the Western Ghats, India. AB - A fruity aroma-producing strain WG4 was isolated from a water sample collected from the Western Ghats, India. The 16S rRNA gene sequence analysis of strain WG4 indicated that Chryseobacterium indologenes, a member of the family 'Flavobacteriaceae' is the closest related species with a pair-wise sequence similarity of 98.6%. Strain WG4 produces a fruity aroma when grown on nutrient or trypticase soy agar plates. The fruity aroma is more when the strain WG4 is grown on agar plates compared to their growth in broth. The aromatic compounds produced by the strain WG4 were identified as ester compounds and were confirmed as ethyl 2-methylbutyrate and ethyl-3-methylbutyrate based on Gas Chromatography-Mass Spectrometry (GC-MS) analysis and using standard reference compounds. Even after repeated subcultures strain WG4 produced the same aroma in high intensity. Thus, strain WG4 could serve as a source for the production of these flavour compounds. PMID- 21667309 TI - Cyclooxygenase expression and prostaglandin levels in central nervous system tissues during the course of chronic relapsing experimental autoimmune encephalomyelitis (EAE). AB - OBJECTIVE: Multiple sclerosis (MS) and its animal counterpart experimental autoimmune encephalomyelitis (EAE) have a major inflammatory component that drives and orchestrates both diseases. One particular group of mediators are the prostaglandins (PGs), which we have previously shown, through quantitation and pharmacological intervention, to be closely involved in the pathology of MS and EAE. The aim of the current study was to determine the expression of the PG generating cyclooxygenase (COX) enzymes and the profile of PGE(2) and PGD(2), in selected central nervous system (CNS) tissues, with the development of the chronic relapsing (CR) form of EAE. In particular, the work investigates the possible relationship between the expression of COX isoenzymes and PG levels during the neurological phases of CR EAE. METHODS: CR EAE was induced in Biozzi mice with inoculum containing lyophilised, syngeneic spinal cord emulsified in complete Freund's adjuvant. The cerebral cortex, cerebellum and spinal cord were dissected from mice during the acute, remission and relapse stages of disease with a minimum of five animals per treatment. The expression of COX-1, COX-1b variant and COX-2, in pooled samples, was determined by Western blotting. PGE(2) and PGD(2) levels in extracted samples were measured using commercial enzyme immunoassay kits. RESULTS: COX-2 expression in spinal cords during acute disease remained unaltered and was in contrast to an enhancement of the enzyme, together with COX-1 and COX-1b, in all other sampled areas. PGE(2) and PGD(2) levels remained unchanged during the acute phase and the subsequent remission of symptoms. COX-1 and COX-1b expression was elevated in tissues during the relapse stage of CR EAE and concentrations of the prostanoids were markedly increased. CONCLUSIONS: The study examines the implications of COX isoenzyme expression over the course of CR EAE and discusses the reported relationship between PGE(2) and PGD(2) in the instigation and resolution of CNS inflammation. Consideration is also given to the treatment of CR EAE and suggests that drugs designed to limit the inflammatory effects of the PGs should be administered prior to or during the relapse phase of the disease. PMID- 21667310 TI - Combination of extended X-ray absorption fine structure spectroscopy with lipidic cubic phases for the study of cation binding in bacteriorhodopsin. AB - We have performed a quantitative X-ray absorption fine structure analysis of bacteriorhodopsin in purple membrane patches and in lipidic cubic phases regenerated with Mn(2+). Lipidic cubic phases and purple membrane results have been compared, demonstrating that the lipidic cubic phase process does not introduce relevant distortions in the local geometry of the cation binding sites. For both samples, we have observed similarities for Mn(2+) coordination in terms of type, number, and average distances of surrounding atoms, indicating a first coordination shell composed by 6 O atoms, and 3/4 C atoms located in the second coordination shell. PMID- 21667312 TI - Degradation studies of fenazaquin in soil under field and laboratory conditions. AB - Degradation of fenazaquin in sandy loam soil was investigated under field and laboratory conditions. Fenazaquin (Magister 10EC) was applied @ 125 and 250 g a.i./ha in field and in pot under field capacity moisture in laboratory. Samples drawn periodically were analyzed on GC-NPD. The residues of fenazaquin in both the doses and conditions dissipated almost 90% in 90 days. Half-life period were 32.04 and 31.35 days at two doses, respectively at field conditions and 30.10 and 28.94 days at laboratory conditions. Dissipation was approximated to first order kinetics in both conditions having correlation coefficient ranging from -0.9848 to -0.9914. PMID- 21667311 TI - RhoA/ROCK signaling mediates plasticity of scirrhous gastric carcinoma motility. AB - The small guanosine triphosphatase (GTPase) Rho and its downstream effector Rho associated kinase (ROCK) is one of a key mediator involved in controlling focal adhesions and the dynamics of actin stress fibers. The molecular mechanisms for the function of Rho/ROCK pathway leading to the progression in scirrhous gastric carcinoma cells have not been defined. The activation of RhoA in several gastric carcinoma cells was examined. The role of RhoA/ROCK pathway in the metastatic processes of gastric carcinoma cells, using a human scirrhous gastric cancer cell line, OCUM-2MD3 was investigated by in vitro adhesion and invasion assay. The effect of ROCK inhibitor, Y-27632 on the mRNA expression of the integrin family and MMP in gastric carcinoma cells was subsequently examined by Reverse transcriptional (RT)-PCR analysis. Finally, Random OCUM-2MD3 cell motility was evaluated using Time-lapse microscopy. ROCK inhibitor significantly increased the adhesion of OCUM-2MD3 cells to the extracellular matrix (ECM) protein matrigel. Further examination using ECM components showed enhanced binding ability was obtained only in laminin and Integrin subunits alpha3-integrin was clearly up regulated by treatment with Y-27632 in OCUM-2MD3 cells. ROCK inhibitor also enhanced the invasion of OCUM-2MD3 cells through matrigel and the expression of membrane-type 1 matrix metalloproteinase (MT1-MMP). Time-lapse microscopy showed conversion of OCUM-2MD3 cells from round to more elongated morphology in the presence of Y-27632, suggesting that inhibition of RhoA/ROCK pathway undergo a so called 'amoeboid to mesenchymal' transition. The fact that Rac1 inhibitor decreased the facilitated invasion by ROCK inhibitor suggested the possibility that increased invasion ability of OCUM-2MD3 cells was related to Rac activity. These data may suggest that RhoA/ROCK regulate plasticity of metastatic gastric carcinoma via mesenchymal-amoeboid transition, leading to provide new insights for designing a new and effective treatment for this type of refractory carcinoma. PMID- 21667313 TI - Mind the gap: gender differences in child special health care needs. AB - The gendered nature of special health care needs in childhood is an important yet understudied area. Although gendered differences in the prevalence of special health care needs have been documented, there is less knowledge about the factors which contribute to those differences. Two research questions guide this inquiry. First, is the gender gap consistent across child special health care need indicators? Second, to what extent is the gender gap in special health care needs driven by behavioral conditions? We use multiple indicators from the U.S. National Survey of Children's Health to expand our understanding about the dynamic relationship between gender and childhood health. There are clear gender differences in the prevalence of special health care needs. Boys are more likely than girls to have special health care needs overall and on the five separate components examined (medication, more care than typical, limitations, special therapies, and educational or behavioral problem). This gender gap is dynamic and varies by indicator; while behavioral conditions play a role, it remains even after controlling for behavioral conditions. The reasons for the gender differences appear to be both biological and social but much remains unknown about this pattern. PMID- 21667314 TI - RAPD fingerprint to appraise the genetic fidelity of in vitro propagated Araucaria excelsa R. Br. var. glauca plantlets. AB - Randomly amplified polymorphic DNA (RAPD) was used as a tool to assess the genetic fidelity of in vitro propagated Araucaria excelsa R. Br. var. glauca with explants taken from orthotropic stem along with their related mother plants after treatment with kinetin, 2iP, BA (0.02-0.26 mg/l) and TDZ (0.001-1 mg/l) to produce axillary shoots. TDZ and kinetin induced more shoot and higher length per explant. Results showed a total of 1,676 fragments were generated with 12 RAPD primers in micropropagated plants and their donor mother plants. The number of loci ranged from 6 in OPB 12-18 in OPY 07 with a size ranging from 250 bp in OPH 19-3500 bp in OPH 11. Cluster analysis of RAPD data using UPGMA (unweighted pair group method with arithmetic average) revealed more than 92% genetic similarities between tissue cultured plants and their corresponding mother plant measured by the Jaccard's similarity coefficient. Similarity matrix and PCoA (two dimensional principal coordinate analysis) resulted in the same affinity. Primers had shown 36% polymorphism. However, careful monitoring of tissue culture derived plants might be needed to determine that rooted shoots are adventitious in origin. PMID- 21667315 TI - Crisis water management and ibis breeding at Narran Lakes in arid Australia. AB - Narran Lakes is a Ramsar site recognised for its importance for colonial waterbird breeding, which only occurs after large highly variable flooding events. In 2008, 74,095 pairs of ibis bred for the first time in seven years, establishing two contiguous colonies, a month apart. Most (97%) of the colony consisted of the straw-necked ibis (Threskiornis spinicollis) with the remainder consisting of glossy ibis (2%, Plegadis falcinellus) and Australian white ibis (1%, T. molucca). Following cessation of river flows, water levels fell rapidly in the colony site, resulting in a crisis management decision by governments to purchase and deliver water (10,423 Ml) to avert mass desertion of the colonies. There were significant differences in the reproductive success of each colony. In colony 1 60% of eggs hatched and 94% of chicks fledged, while in colony 2 40% of eggs hatched with only 17% of chicks fledging. Statistical analyses found that water depth was a significant variable in determining reproductive success. Rapid falls in water level during the chick stage in colony 2 resulted in decreased chick and overall offspring success. The results of this study identify the impact of upstream water resource development on colonial waterbird breeding and have implications for water management policies. PMID- 21667316 TI - Forest insect pest management and forest management in China: an overview. AB - According to the Seventh National Forest Inventory (2004-2008), China's forests cover an area of 195.45 million ha, or 20.36% of the total land area. China has the most rapidly increasing forest resources in the world. However, China is also a country with serious forest pest problems. There are more than 8,000 species of potential forest pests in China, including insects, plant diseases, rodents and lagomorphs, and hazardous plants. Among them, 300 species are considered as economically or ecologically important, and half of these are serious pests, including 86 species of insects. Forest management and utilization have a considerable influence on the stability and sustainability of forest ecosystems. At the national level, forestry policies always play a major role in forest resource management and forest health protection. In this paper, we present a comprehensive overview of both achievements and challenges in forest management and insect pest control in China. First, we summarize the current status of forest resources and their pests in China. Second, we address the theories, policies, practices and major national actions on forestry and forest insect pest management, including the Engineering Pest Management of China, the National Key Forestry Programs, the Classified Forest Management system, and the Collective Forest Tenure Reform. We analyze and discuss three representative plantations Eucalyptus, poplar and Masson pine plantations-with respect to their insect diversity, pest problems and pest management measures. PMID- 21667317 TI - Application of a multi-objective optimization method to provide least cost alternatives for NPS pollution control. AB - Nonpoint source (NPS) pollutants such as phosphorus, nitrogen, sediment, and pesticides are the foremost sources of water contamination in many of the water bodies in the Midwestern agricultural watersheds. This problem is expected to increase in the future with the increasing demand to provide corn as grain or stover for biofuel production. Best management practices (BMPs) have been proven to effectively reduce the NPS pollutant loads from agricultural areas. However, in a watershed with multiple farms and multiple BMPs feasible for implementation, it becomes a daunting task to choose a right combination of BMPs that provide maximum pollution reduction for least implementation costs. Multi-objective algorithms capable of searching from a large number of solutions are required to meet the given watershed management objectives. Genetic algorithms have been the most popular optimization algorithms for the BMP selection and placement. However, previous BMP optimization models did not study pesticide which is very commonly used in corn areas. Also, with corn stover being projected as a viable alternative for biofuel production there might be unintended consequences of the reduced residue in the corn fields on water quality. Therefore, there is a need to study the impact of different levels of residue management in combination with other BMPs at a watershed scale. In this research the following BMPs were selected for placement in the watershed: (a) residue management, (b) filter strips, (c) parallel terraces, (d) contour farming, and (e) tillage. We present a novel method of combing different NPS pollutants into a single objective function, which, along with the net costs, were used as the two objective functions during optimization. In this study we used BMP tool, a database that contains the pollution reduction and cost information of different BMPs under consideration which provides pollutant loads during optimization. The BMP optimization was performed using a NSGA-II based search method. The model was tested for the selection and placement of BMPs in Wildcat Creek Watershed, a corn dominated watershed located in northcentral Indiana, to reduce nitrogen, phosphorus, sediment, and pesticide losses from the watershed. The Pareto optimal fronts (plotted as spider plots) generated between the optimized objective functions can be used to make management decisions to achieve desired water quality goals with minimum BMP implementation and maintenance cost for the watershed. Also these solutions were geographically mapped to show the locations where various BMPs should be implemented. The solutions with larger pollution reduction consisted of buffer filter strips that lead to larger pollution reduction with greater costs compared to other alternatives. PMID- 21667318 TI - The effect of lignin photodegradation on decomposability of Calamagrostis epigeios grass litter. AB - The common grass Calamagrostis epigeions produces a large amount of dead biomass, which remain above the soil surface for many months. In this study, we determined how exposure of dead biomass above the soil affects its subsequent decomposition in soil. Collected dead standing biomass was divided in two parts, the first one (initial litter) was stored in a dark, dry place. The other part was placed in litterbags in the field. The litterbags were located in soil, on the soil surface, or hanging in the air without contact with soil but exposed to the sun and rain. After 1 year of field exposure, litter mass loss and C and N content were measured, and changes in litter chemistry were explored using NMR and thermochemolysis-GC-MS. The potential decomposability of the litter was quantified by burying the litter from the litterbags and the initial litter in soil microcosms and measuring soil respiration. Soil respiration was greater with litter that had been hanging in air than with all other kinds of litter. These finding could not be explained by changes in litter mass or C:N ratio. NMR indicated a decrease in polysaccharides relative to lignin in litter that was buried in soil but not in litter that was placed on soil surface or that was hanging in the air. Thermochemolysis indicated that the syringyl units of the litter lignin were decomposed when the litter was exposed to light. We postulate that photochemical decay of lignin increase decomposability of dead standing biomass. PMID- 21667319 TI - A rat model of neonatal candidiasis demonstrates the importance of lipases as virulence factors for Candida albicans and Candida parapsilosis. AB - The host factors that contribute to the increased susceptibility of preterm neonates to invasive candidiasis have not been fully identified. In addition, there has been a lack of suitable models to study this problem. We show that rat pups, similar to premature neonates, display increased susceptibility to experimental Candida albicans infection. Further, we find that both C. albicans and Candida parapsilosis lipase disruptant mutants exhibit decreased virulence in rat pups, demonstrating the utility of the model to evaluate the impact of specific genes in disease pathogenesis. Our findings highlight the contribution of lipases to the virulence of C. albicans and C. parapsilosis and provide a new system to study the increased susceptibility of neonates to Candida infections. PMID- 21667320 TI - Aberrant expression of the polarity complex atypical PKC and non-muscle myosin IIA in active and inactive inflammatory bowel disease. AB - Epithelial barrier function is contingent on appropriate polarization of key protein components. Work in intestinal epithelial cell cultures and animal models of bowel inflammation suggested that atypical PKC (aPKC), the kinase component of the Par3-Par6 polarity complex, is downregulated by pro-inflammatory signaling. Data from other laboratories showed the participation of myosin light chain kinase in intestinal inflammation, but there is paucity of evidence for assembly of its major target, non-muscle myosin II, in inflammatory bowel disease (IBD). In addition, we showed before that non-muscle myosin IIA (nmMyoIIA) is upregulated in intestinal inflammation in mice and TNFalpha-treated Caco-2 cells. Thus far, it is unknown if a similar phenomena occur in patients with IBD. Moreover, it is unclear whether aPKC downregulation is directly correlated with local mucosal inflammation or occurs in uninvolved areas. Frozen sections from colonoscopy material were stained for immunofluorescence with extensively validated specific antibodies against phosphorylated aPKC turn motif (active form) and nmMyoIIA. Inflammation was scored for the local area from where the material was obtained. We found a significant negative correlation between the expression of active aPKC and local inflammation, and a significant increase in the apical expression of nmMyoIIA in surface colon epithelia in inflamed areas, but not in non-inflamed mucosa even in the same patients. Changes in aPKC and nmMyoIIA expression are likely to participate in the pathogenesis of epithelial barrier function in response to local pro-inflammatory signals. These results provide a rationale for pursuing mechanistic studies on the regulation of these proteins. PMID- 21667321 TI - Multimarker strategies for detecting NASH and NASH-related fibrosis: promises and caveats. PMID- 21667322 TI - Fatal pneumonitis after treatment with pegylated liposomal doxorubicin in a patient with metastatic breast cancer in complete remission. PMID- 21667324 TI - Studies on BVD involving establishment of sentinel calves and assessment of herd immunity in a large dairy farm in Saudi Arabia. AB - Little information is published, so far, regarding bovine viral diarrhea (BVD) in Saudi Arabia and the Gulf region. This study is the first of its kind in the country. Its aim was to explore the BVD situation in a large dairy farm, which has been experiencing reproduction problems suggestive of BVD virus infection, albeit the practice of routine vaccination. The study took two pathways; the first involved establishment of a cohort of sentinel calves so as: (a) to note the BVD virus activity in the farm by following the time lapse and pattern for waning of the maternally derived antibodies and detection of any subsequent seroconversion and (b) to look for any clinical signs suggestive of BVD virus infection in these calves. The second pathway was to assess the level of herd immunity in the different age groups of lactating cows and maiden heifers. The obtained results were discussed, and control strategies were outlined. PMID- 21667323 TI - Problem-solving education to prevent depression among low-income mothers of preterm infants: a randomized controlled pilot trial. AB - We sought to assess the feasibility and document key study processes of a problem solving intervention to prevent depression among low-income mothers of preterm infants. A randomized controlled pilot trial (n = 50) of problem-solving education (PSE) was conducted. We assessed intervention provider training and fidelity; recruitment and retention of subjects; intervention acceptability; and investigators' ability to conduct monthly outcome assessments, from which we could obtain empirical estimates of depression symptoms, stress, and functioning over 6 months. Four of four bachelor-level providers were able to deliver PSE appropriately with standardized subjects within 4 weeks of training. Of 12 randomly audited PSE sessions with actual subjects, all met treatment fidelity criteria. Nineteen of 25 PSE subjects (76%) received full four-session courses; no subjects reported negative experiences with PSE. Eighty-eight percent of scheduled follow-up assessments were completed. Forty-four percent of control group mothers experienced an episode of moderately severe depression symptoms over the follow-up period, compared to 24% of PSE mothers. Control mothers experienced an average 1.19 symptomatic episodes over the 6 months of follow-up, compared to 0.52 among PSE mothers. PSE appears feasible and may be a promising strategy to prevent depression among mothers of preterm infants. PMID- 21667325 TI - Copper, zinc, and iron concentrations in blood serum and diet of dairy cattle on semi-industrial farms in central Iran. AB - The aim of this study was to evaluate the blood serum and diet concentrations of copper, zinc, and iron in Holstein dairy cattle kept under semi-industrial farming in Isfahan province, central Iran. Moreover, the effects of season, pregnancy, and daily milk yield on serum Cu, Zn, and Fe concentrations were also evaluated. The study was carried out on 12 semi-industrial Holstein dairy cattle farms. A total of 120 blood serum samples (60 in each season) and 24 diet samples (12 in each season) were collected in the summer and winter. The Cu, Fe, and Zn contents were assessed in samples using atomic absorption spectrophotometer. In the summer, the mean concentrations of Cu and Fe in serum samples were lower and higher than the critical level, respectively (P < 0.05). In total diet samples, the mean concentrations of Zn were significantly higher than critical level (P < 0.05). In summer, winter, and total diet samples, the mean concentrations of Fe were significantly higher than critical level (P < 0.05). The serum Cu and Zn concentrations were significantly higher in the winter than those determined in the summer (P < 0.05). The serum Cu concentrations were significantly higher in nonpregnant than those in pregnant dairy cattle (P < 0.05). No significant difference was observed in serum Cu, Zn, and Fe concentrations of dairy cattle in different daily milk yield groups. It can be concluded that Holstein dairy cattle reared under semi-industrial dairy farming were deficient in serum Cu concentrations, especially in summer. Further, high level of Fe in blood serum might be due to feeding of cattle with diet containing excess quantity of Fe. PMID- 21667326 TI - Melorheostosis of the sacrum causing acute-onset neurological symptoms. PMID- 21667327 TI - Perfusion and parenchymal changes related to vascular alterations of the liver. AB - Imaging plays a significant role in the diagnosis of vascular abnormalities of the liver and sometimes provides the only clue to the correct diagnosis. With advances of imaging techniques and multiphasic acquisition of liver imaging, various perfusion changes are frequently encountered. Correct imaging diagnosis of significant vascular diseases can prompt appropriate work-up and timely management. Accurate differentiation of clinically insignificant perfusion phenomena from clinically significant findings including neoplastic conditions and in the setting of post-transplantation is essential. This pictorial essay illustrates various perfusion and parenchymal changes associated with portal venous inflow, hepatic venous outflow, and non-portal venous third inflow and describes brief background pathophysiology and differential points. PMID- 21667328 TI - Who goes where? A prospective study of referral patterns within a newly established primary care team. AB - BACKGROUND: Since the introduction of primary care teams, referral patterns of General Practitioners (GPs) in Ireland have not been studied. AIMS: To study the referral patterns of GPs within a primary care team (PCT) to allied health care professionals in a PCT and to secondary care. To identify indirect referral pathways. To study variation in individual GP referral patterns. METHOD: Questionnaire based survey. Statistical analysis was carried out using Epi Info version 3.5.1. RESULTS: Of 3,166 consultations, 2,841 (89.7%) were dealt with by the GP and required no referral, 107 (3.4%) were referred within the PCT, and 218 (6.9%) were referred elsewhere. Therefore, 93.1% of consultations were managed in primary care alone. Ninety percent of GPs refer patients to the PCT. Indirect referrals constituted 17% of all outpatient referrals. Females have significantly higher referral rates than males. Referral rates of GPs in single-handed practices are higher than GPs in group practices. CONCLUSIONS: GPs alone can manage the vast majority of presentations in general practice. Greater GP access to diagnostic and therapeutic interventions may reduce outpatient referrals. GPs in group practices may collectively have greater experience and expertise and therefore can manage more patients in primary care. There is a significant variation in referral rates between both genders. PMID- 21667329 TI - A new thymidine phosphorylase mutation causing elongation of the protein underlies mitochondrial neurogastrointestinal encephalomyopathy. PMID- 21667330 TI - Robot-assisted spleen-preserving laparoscopic distal pancreatectomy. AB - BACKGROUND: Spleen-preserving laparoscopic distal pancreatectomy would be an ideal approach for benign and borderline malignant tumors in the distal pancreas.1 However, this procedure requires advanced surgical experience and technique because of the disadvantages of conventional laparoscopic surgery.2 METHODS: A 35-year-old female patient visited our institution because of a growing pancreatic mass during follow-up. A preoperative image study showed a cystic tumor of about 3.0 * 2.5 cm in size in the body of the pancreas. Under the impression of a growing serous cystic tumor of the pancreas, she was scheduled to undergo robot-assisted spleen-preserving laparoscopic distal pancreatectomy. RESULTS: Under general anesthesia, the patient was placed in the supine position with her head and left side elevated. A total of five ports were used. Among them, one 12-mm port was placed for the assistant surgeon's intervention during the procedure. Stable 3-dimensional operative image, endo-wrist function of the instruments, and no tremor were thought to be very helpful for fine dissection of the pancreas from splenic vessels. The total operation time was 300 min, and the estimated intraoperative blood loss was 380 ml. No transfusion was required. The patient's postoperative recovery was uneventful. She was able to go home on the 6th postoperative day without a drain. CONCLUSIONS: The unique characteristics of a robotic surgical system were thought to be very helpful during the spleen preserving laparoscopic distal pancreatectomy.2 (-) 6 However, cost is one of the main obstacles for the procedure's popular clinical practice.2. PMID- 21667331 TI - EphB2: a signature of colorectal cancer stem cells to predict relapse. PMID- 21667332 TI - Conserved arginine residue in the membrane-spanning domain of HIV-1 gp41 is required for efficient membrane fusion. AB - Despite the high mutation rate of HIV-1, the amino acid sequences of the membrane spanning domain (MSD) of HIV-1 gp41 are well conserved. Arginine residues are rarely found in single membrane-spanning domains, yet an arginine residue, R(696) (the numbering is based on that of HXB2), is highly conserved in HIV-1 gp41. To examine the role of R(696), it was mutated to K, A, I, L, D, E, N, and Q. Most of these substitutions did not affect the expression, processing or surface distribution of the envelope protein (Env). However, a syncytia formation assay showed that the substitution of R(696) with amino acid residues other than K, a naturally observed mutation in the gp41 MSD, decreased fusion activity. Substitution with hydrophobic amino acid residues (A, I, and L) resulted in a modest decrease, while substitution with D or E, potentially negatively-charged residues, almost abolished the syncytia formation. All the fusion-defective mutants showed slower kinetics with the cell-based dual split protein (DSP) assay that scores the degree of membrane fusion based on pore formation between fusing cells. Interestingly, the D and E substitutions did show some fusion activity in the DSP assays, suggesting that proteins containing D or E substitutions retained some fusion pore-forming capability. However, nascent pores failed to develop, due probably to impaired activity in the pore enlargement process. Our data show the importance of this conserved arginine residue for efficient membrane fusion. PMID- 21667334 TI - Horizontal segregation of mono-layer granules coordinated by vertical motion. AB - We experimentally investigate the segregation of a binary mixture of spherical beads confined between two horizontal vertically vibrating plates. The two kinds of beads are of equal diameter and mass but have different restitution coefficients. Segregation occurs in particular ranges of vibration amplitude and frequency. We find that the collisions between beads at an angle to the horizontal plane induce an effective horizontal repulsive force. When one or both bead types bounce up and down in synchronization, the effective repulsive force between the two types of beads is likely to be larger than that found within a single bead type, resulting in the mixture segregating. Non-horizontal collisions also play a role in stabilizing the segregation state by transferring the horizontal kinetic energy back into vertical motion. PMID- 21667333 TI - Spliceosomal genes in the D. discoideum genome: a comparison with those in H. sapiens, D. melanogaster, A. thaliana and S. cerevisiae. AB - Little is known about pre-mRNA splicing in Dictyostelium discoideum although its genome has been completely sequenced. Our analysis suggests that pre-mRNA splicing plays an important role in D. discoideum gene expression as two thirds of its genes contain at least one intron. Ongoing curation of the genome to date has revealed 40 genes in D. discoideum with clear evidence of alternative splicing, supporting the existence of alternative splicing in this unicellular organism. We identified 160 candidate U2-type spliceosomal proteins and related factors in D. discoideum based on 264 known human genes involved in splicing. Spliceosomal small ribonucleoproteins (snRNPs), PRP19 complex proteins and late acting proteins are highly conserved in D. discoideum and throughout the metazoa. In non-snRNP and hnRNP families, D. discoideum orthologs are closer to those in A. thaliana, D. melanogaster and H. sapiens than to their counterparts in S. cerevisiae. Several splicing regulators, including SR proteins and CUG-binding proteins, were found in D. discoideum, but not in yeast. Our comprehensive catalog of spliceosomal proteins provides useful information for future studies of splicing in D. discoideum where the efficient genetic and biochemical manipulation will also further our general understanding of pre-mRNA splicing. PMID- 21667335 TI - The role of HIV replicative fitness in perinatal transmission of HIV. AB - Perinatal transmission of Human immunodeficiency virus (HIV), also called mother to-child transmission (MTCT), accounts for 90% of infections in infants worldwide and occurs in 30%-45% of children born to untreated HIV-1 infected mothers. Among HIV-1 infected mothers, some viruses are transmitted from mothers to their infants while others are not. The relationship between virologic properties and the pathogenesis caused by HIV-1 remains unclear. Previous studies have demonstrated that one obvious source of selective pressure in the perinatal transmission of HIV-1 is maternal neutralizing antibodies. Recent studies have shown that viruses which are successfully transmitted to the child have growth advantages over those not transmitted, when those two viruses are grown together. Furthermore, the higher fitness is determined by the gp120 protein of the virus envelope. This suggests that the selective transmission of viruses with higher fitness occurred exclusively, regardless of transmission routes. There are many factors contributing to the selective transmission and HIV replicative fitness is an important one that should not be neglected. This review summarizes current knowledge of the role of HIV replicative fitness in HIV MTCT transmission and the determinants of viral fitness upon MTCT. PMID- 21667336 TI - Characterization of the receptor-binding domain of Ebola glycoprotein in viral entry. AB - Ebola virus infection causes severe hemorrhagic fever in human and non-human primates with high mortality. Viral entry/infection is initiated by binding of glycoprotein GP protein on Ebola virion to host cells, followed by fusion of virus-cell membrane also mediated by GP. Using an human immunodeficiency virus (HIV)-based pseudotyping system, the roles of 41 Ebola GP1 residues in the receptor-binding domain in viral entry were studied by alanine scanning substitutions. We identified that four residues appear to be involved in protein folding/structure and four residues are important for viral entry. An improved entry interference assay was developed and used to study the role of these residues that are important for viral entry. It was found that R64 and K95 are involved in receptor binding. In contrast, some residues such as I170 are important for viral entry, but do not play a major role in receptor binding as indicated by entry interference assay and/or protein binding data, suggesting that these residues are involved in post-binding steps of viral entry. Furthermore, our results also suggested that Ebola and Marburg viruses share a common cellular molecule for entry. PMID- 21667337 TI - Host cell protein C9orf69 promotes viral proliferation via interaction with HSV-1 UL25 protein. AB - In light of the scarcity of reports on the interaction between HSV-1 nucleocapsid protein UL25 and its host cell proteins, the purpose of this study is to use yeast two-hybrid screening to search for cellular proteins that can interact with the UL25 protein. C9orf69, a protein of unknown function was identified. The interaction between the two proteins under physiological conditions was also confirmed by biological experiments including co-localization by fluorescence and immunoprecipitation. A preliminary study of the function of C9orf69 showed that it promotes viral proliferation. Further studies showed that C9orf69 did not influence viral multiplication efficiency by transcriptional regulation of viral genes, but indirectly promoted proliferation via interaction with UL25. PMID- 21667338 TI - Total chemical synthesis, assembly of human torque teno virus genome. AB - Torque teno virus (TTV) is a nonenveloped virus containing a single-stranded, circular DNA genome of approximately 3.8kb. We completely synthesized the 3 808 nucleotides of the TTV (SANBAN isolate) genome, which contains a hairpin structure and a GC-rich region. More than 100 overlapping oligonucleotides were chemically synthesized and assembled by polymerase chain assembly reaction (PCA), and the synthesis was completed with splicing by overlap extension (SOEing). This study establishes the methodological basis of the chemical synthesis of a viral genome for use as a live attenuated vaccine or gene therapy vector. PMID- 21667339 TI - Immune potential of a novel multiple-epitope vaccine to FMDV type Asia 1 in guinea pigs and sheep. AB - To develop a safe and efficient recombinant subunit vaccine to foot-and-mouth disease virus (FMDV) type Asia 1 in sheep, a tandem repeated multiple-epitope gene consisting of residues 137-160 and 197-211 of the VP1 gene of FMDV was designed and artificially synthesized. The biologically functional molecule, the ovine IgG heavy constant region (oIgG) as a protein carrier was introduced for design of the multiple-epitope recombinant vaccine and recombinant expression plasmids pET-30a-RE and pET-30a-RE-oIgG were successfully constructed. The recombinant proteins, RE and RE-oIgG, were expressed as a formation of inclusion bodies in E. coli. The immune potential of this vaccine regime in guinea pigs and sheep was evaluated. The results showed that IgG could significantly enhance the immune potential of antigenic epitopes. The recombinant protein RE-oIgG could not only elicit the high levels of neutralizing antibodies and lymphocytes proliferation responses in the vaccinated guinea pigs, but confer complete protection in guinea pigs against virus challenge. Although the recombinant protein RE could not confer protection in the vaccinated animals, it could delay the appearance of the clinical signs and reduce the severity of disease. Inspiringly, the titers of anti-FMDV neutralizing antibodies elicited in sheep vaccinated with RE-oIgG was significantly higher than that for the RE vaccination. Therefore, we speculated that this vaccine formulation may be a promising strategy for designing a novel vaccine against FMDV in the future. PMID- 21667340 TI - Establishment, growth kinetics, and susceptibility to AcMNPV of heat tolerant lepidopteran cell lines. AB - Lepidopteran heat-tolerant (ht) cell lines have been obtained with sf-9, sf-21 and several Bombyx cells. They have a distinct karyotype, membrane lipid composition, morphology and growth kinetics from the parental cell lines. In this paper, we report the development of ht cell lines from other insect species and examination of their growth characteristics and virus susceptibility. Adaptation of cell lines sf-9, BTI-TN-5B1-4 (High5) and BTI-TN-MG1 (MG1) to 33 degrees C and 35 degrees C was carried out by shifting the culture temperature between 28 degrees C and higher temperatures by a gradual stepwise increase in temperature. The process of adaption to a higher culture temperature was accomplished over a period of 2 months. The cell lines with the temperature adaption were designated as sf9-ht33, sf9-ht35, High5-ht33, High5-ht35, MG1-ht33, MG1-ht35. These cell lines have been subcultured over 70 passages. Adaption to high temperatures was confirmed by a constant population doubling time with individual cell lines. The population doubling time of heat adapted cell lines were 1-4 h less than these of parental cell lines. Cell shapes did not show obvious change, however, the cell size of sf9-ht cells was enlarged and those of High5 and MG1 ht cells were reduced after heat adaption. When the cell lines were infected with Autographa californica nuclear polyhedrosis virus (AcMNPV) at 28 degrees C, 33 degrees C, 35 degrees C and 37 degrees C, production of budded virus and occlusion bodies in each cell line was optimum at its own adapted temperature. PMID- 21667341 TI - Transforming activity of a novel mutant of HPV16 E6E7 fusion gene. AB - An optimized recombinant HPV16 E6E7 fusion gene (HPV16 ofE6E7) was constructed according to codon usage for mammalian cell expression, and a mutant of HPV16 ofE6E7 fusion gene (HPV16 omfE6E7) was generated by site-directed mutagenesis at L57G, C113R for the E6 protein and C24G, E26G for the E7 protein for HPV16 ofE6E7 [patent pending (CN 101100672)]. The HPV16 omfE6E7 gene constructed in this work not only lost the transformation capability to NIH 3T3 cells and tumorigenicity in SCID mice, but also maintained very good stability and antigenicity. These results suggests that the HPV16 omfE6E7 gene should undergo further study for application as a safe antigen-specific therapeutic vaccine for HPV16-associated tumors. PMID- 21667342 TI - Development of a loop-mediated isothermal amplification assay for porcine circovirus type 2. AB - In this study, the loop-mediated isothermal amplification (LAMP) method was used to develop a rapid and simple detection system for porcine circovirus type 2 (PCV2). According to the PCV2 sequences published in GenBank, multiple LAMP primers were designed targeting conserved sequences of PCV2. Using the DNA extracted from PCV2 isolates HUN-09 and SD-09 as the template, LAMP reactions in a PCV2 LAMP system was performed, the amplification products were detected by adding SYBR Green I and could be observed directly by the naked eye. The results showed highly-efficient and specific amplification in 30 min at 63 degrees C with a LAMP real-time turbidimeter. Furthermore, PCV2 DNA templates, with a detection limit of 5.5*10(-5) ng of nucleic acid, indicated that this assay was highly sensitive. The results obtained with the naked eye after SYBR Green I staining were consistent with those detected by the real-time turbidimeter, showing the potential simplicity of interpretation of the assay results. The LAMP assay appeared to have greater accuracy than PCR and virus isolation for the analysis of 18 clinical samples. In addition it offers higher specificity and sensitivity, shorter reaction times and simpler procedures than the currently available methods of PCV2 detection. It is therefore a promising tool for the effective and efficient detection of PCV2. PMID- 21667343 TI - Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. AB - We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease. PMID- 21667344 TI - Community perceptions of safety in relation to perceived youth violence delinquency in a primarily native Hawaiian and Asian American community in Hawai'i. AB - Perception of safety is an important component to the well-being of community members in their own neighborhood. The present study was the first of its kind to model community perception of safety utilizing a primarily Native Hawaiian and Asian American community sample (N = 101) and with perceived youth violence and delinquency as prominent potential influences. The study found that the majority of participants felt that several types of youth violence and delinquency were problems in the community. The overall social-ecological model evidenced a strong fit and indicated that community perception of safety was adversely impacted by perceived youth violence and delinquency and increased through positive relations with neighbors. The implications included the need for a more comprehensive approach to positive youth development and community capacity-building, including incorporation of cultural components, and to determine whether the model is applicable to other minority communities. PMID- 21667345 TI - Occasional staining for p63 in malignant vascular tumors: a potential diagnostic pitfall. AB - Expression of p63, a putative marker for epithelial or myoepithelial differentiation, has been used to distinguish spindle cell carcinoma from sarcoma. The specificity of p63 for epithelial differentiation has not been thoroughly evaluated however, since p63 expression has been explored in only a handful of mesenchymal tumors. After observing unexpected immunohistochemical staining for p63 in an angiosarcoma of the breast, we evaluated a series of benign and malignant vascular tumors to determine the frequency of such a finding. Nuclear immunoreactivity to p63 was detected, at least focally, in 24% of malignant vascular tumors other than Kaposi sarcoma, which was uniformly negative. Benign vascular tumors were also negative for p63. Although p63 expression in tumors of vascular differentiation is unusual, it may be seen occasionally in some malignant vascular tumors. Thus, p63 is not entirely specific for epithelial differentiation. Since soft tissue angiosarcomas and hemangioendotheliomas sometimes express cytokeratins, the finding of nuclear p63 represents another potential pitfall in the differential diagnosis between poorly differentiated carcinomas and vascular neoplasms. PMID- 21667346 TI - Fc-gamma-receptor IIIa polymorphism and gene expression profile do not predict the prognosis in diffuse large B-cell lymphoma treated with R-CHOP protocol. AB - The addition of rituximab to conventional chemotherapy has significantly improved the treatment outcome in diffuse large B-cell lymphoma. However, differences in treatment response and survival data can be observed independently from the International Prognostic Index scores. The current study evaluated the impact of Fc-gamma-receptor IIIa polymorphism and gene expression profile on the response of DLBCL patients to R-CHOP therapy as well as on their survival results. Fifty one patients were involved, thirty-two females, nineteen males, their median age was 53.1 years. The FCGR3A polymorphism at the 158. amino acid position determined with PCR method showed the following results: VV: 12 cases (23.5%), VF: 29 cases (56.8%) and FF: 10 cases (19.6%), respectively. There was no significant difference between the treatment responses of the three groups. The event-free survival data were less favorable in the F-allele carriers than in V/V homozygous patients, but without any significancy, and the overall survival curves were almost the same. As for the gene expression profile, 20 patients' biopsy specimens showed germinal center and 31 showed non-germinal center characteristics. Treatment results did not differ from each other in the two groups. Both the event-free and the overall survival data were more favorable in the GC group, however the differences were not significant. Our results contest the predictive value of Fc-gamma-receptor IIIa polymorphism and gene expression profile in diffuse large B-cell lymphoma. PMID- 21667347 TI - Folate analysis in foods by UPLC-MS/MS: development and validation of a novel, high throughput quantitative assay; folate levels determined in Australian fortified breads. AB - An ultra-performance liquid chromatography-tandem mass spectrometry method was developed, optimised and validated for the quantification of synthetic folic acid (FA), also called pteroyl-L: -glutamic acid or vitamin B9 and naturally occurring 5-methyltetrahydrofolate (5-MTHF) found in folate-fortified breads. Optimised sample preparation prior to analysis involved addition of (13)C(5) labelled internal standards, treatments with alpha-amylase and rat serum, solid-phase extraction using aromatic-selective cartridges and ultra-filtration. Analytes were separated on a Waters ACQUITY HSS T3 column during a 6-min run and analysed by positive ion electrospray selected reaction monitoring MS/MS. Standard calibration curves for the two analytes were linear over the range of 0.018-14 MUg FA/g of fresh bread (r(2) = 0.997) and 9.3-900 ng 5-MTHF/g of fresh bread (r(2) = 0.999). The absolute recoveries were 90% and 76% for FA and 5-MTHF, respectively. Intra-day coefficients of variation were 3% for FA and 18% for 5 MTHF. The limit of detection was 9.0 ng/g for FA and 4.3 ng/g for 5-MTHF, determined using pre-extracted tapioca starch as the blank matrix. The assay is rugged, fast, accurate and sensitive, applicable to a variety of food matrices and is capable of the detection and quantification of the naturally occurring low levels of 5-MTHF in wheat breads. The findings of this study revealed that the FA range in Australian fortified breads was 79-110 MUg/100 g of fresh bread and suggest that the flour may not have the mandated FA fortification level (200-300 MUg/100 g of flour), though this cannot be determined conclusively from experimental bread data alone, as variable baking losses have been documented by other authors. PMID- 21667348 TI - Measurement of bisphenol A, bisphenol A beta-D-glucuronide, genistein, and genistein 4'-beta-D-glucuronide via SPE and HPLC-MS/MS. AB - Bisphenol A (BPA) is a synthetic industrial reactant used in the production of polycarbonate plastics, and genistein is a natural phytoestrogen abundant in the soybean. Current studies investigating the endocrine-disrupting effects of concomitant exposures to BPA and genistein have warranted the development of an analytical method for the simultaneous measurement of BPA and genistein, as well as their primary metabolites, bisphenol A beta-D-glucuronide (BPA gluc) and genistein 4'-beta-D-glucuronide (genistein gluc), respectively. All four analytes were extracted from rat plasma via solid phase extraction (SPE). Three SPE cartridges and four elution schemes were tested. Plasma extraction using Bond Elut Plexa cartridges with sequential addition of ethyl acetate, methanol, and acetonitrile yielded optimal average recoveries of 98.1 +/- 1.8% BPA, 94.9 +/- 8.0% genistein, 91.4 +/- 6.1% BPA gluc, and 103 +/- 6.1% genistein gluc. Identification and quantification of the four analytes were performed by a validated HPLC-MS/MS method using electrospray ionization and selective reaction monitoring. This novel analytical method should be applicable to the measurement of BPA, genistein, BPA gluc, and genistein gluc in urine, cultures, and tissue following in vivo exposures. While reports of the determination of BPA and genistein independently exist, the simultaneous optimized extraction and detection of BPA, genistein, BPA gluc, and genistein gluc have not previously been reported. PMID- 21667349 TI - Investigation of the partially coherent effects in a 2D Talbot interferometer. AB - The recent use of a one-dimensional (1D) X-ray Talbot interferometer has triggered great interest in X-ray differential phase contrast imaging. As an improved version of a 1D interferometer, the development of two-dimensional (2D) grating interferometry strongly stimulated applications of grating-based imaging. In the framework of Fresnel diffraction theory, we investigated the self-image of 2D-phase gratings under partially coherent illumination. The fringe visibility of the self-image has been analyzed as a function of the spatial coherence length. From the viewpoint of self-image visibility, it is possible to find the optimal 2D grid for 2D X-ray grating interferometer imaging. Numerical simulations have been also carried out for quantitative evaluation. Results, in good agreement with theoretical analysis, indicate the spatial coherence requirements of the radiation illuminating a 2D grating interferometer. Moreover, our results can be used to optimize performances of a 2D grating interferometer and for further theoretical and experimental research on grating-based imaging systems. PMID- 21667350 TI - A piezoelectric immunosensor for Leishmania chagasi antibodies in canine serum. AB - The American visceral leishmaniasis is an important cause of morbidity and mortality in Brazil for both humans and dogs. Attempts to make a diagnosis of this disease need to be improved, especially in endemic areas, and in the tracking and screening of asymptomatic dogs, which are their main host in urban areas. A quartz crystal microbalance immunosensor for the diagnosis of the canine visceral leishmaniasis using a recombinant antigen of Leishmania chagasi (rLci2B NH6) was developed. The rLci2B-NH6 was tightly immobilized on a quartz crystal gold electrode by self-assembled monolayer based on short-chain length thiol. The strategy was the use of the antigen-histidine tail covalently linked to glutaraldehyde performing a Schift base which permits a major exposure of epitopes and a reduced steric hindrance. The immunosensor showed good results regarding sensitivity and reproducibility, being able to distinguish positive and negative canine serum for L. chagasi. Furthermore, the immunosensor can be reused through exposure to sodium dodecyl sulfate solution, which promotes the dissociation of antigen-antibody binding, restoring the sensor surface with immobilized biologically active antigens for further analysis. PMID- 21667351 TI - A surgical strategy for vertex epidural haematoma. PMID- 21667352 TI - Factors influencing the clinical outcome of methicillin-resistant Staphylococcus aureus bacteraemia. AB - Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is associated with high mortality due to a combination of host, pathogen and therapy related factors. This was a retrospective exploratory study to evaluate host, pathogen and therapy related factors influencing the clinical outcome of MRSA bacteraemia in a UK teaching hospital setting. Of the 38 consecutive episodes of MRSA bacteraemia over a 1-year period, 16 of 38 (40%) patients died at 1 month and 21/38 (55%) died at 6 months. Univariate analysis revealed age (p < 0.006), mean serum vancomycin level (p < 0.035), agr group I (p < 0.036) and set4-var2_11 gene (p < 0.036) at 1 month; and age (p < 0.004) and set4-var2_11 gene (p < 0.002) at 6 months as significant factors. However, there was no association between first trough vancomycin concentration and outcome at 1 month. Multivariate survival analysis from time of admission showed, for each one year increase in age, a patient is 1.121 (95% CI 1.006-1.250, p < 0.007) times more likely to die at any particular point in time, and patients with a mean serum vancomycin level of <10 mg/L, the odds ratio of adverse outcome is 16.129 (95% CI 2.398-111.111) compared to patients with a mean serum level >10 mg/L. A variety of host, pathogen, and therapy related factors influence the clinical outcome of MRSA bacteraemia. PMID- 21667353 TI - Uptake of FITC labeled silica nanoparticles and quantum dots by rice seedlings: effects on seed germination and their potential as biolabels for plants. AB - The use of fluorescent nanomaterials with good photostability and biocompatibility in live imaging of cells has gained increased attention. Even though several imaging techniques have been reported for mammalian cells, very limited literatures are available for nanomaterial based live imaging in plant system. We studied the uptake ability of two different nanomaterials, the highly photostable CdSe quantum dots and highly biocompatible FITC-labeled silica nanoparticles by rice seedlings which could provide greater opportunities for developing novel in vivo imaging techniques in plants. The effects of these nanomaterials on rice seed germination have also been studied for analyzing their phytotoxic effects on plants. We observed good germination of seeds in the presence of FITC-labeled silica nanoparticles whereas germination was arrested with quantum dots. The uptake of both the nanomaterials has been observed with rice seedlings, which calls for more research for recommending their safe use as biolabels in plants. PMID- 21667354 TI - Radiotherapy quality assurance review for a multi-center randomized trial of locally advanced esophageal cancer: the Japan Clinical Oncology Group (JCOG) trial 0303. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the radiotherapy (RT) quality assurance (QA) for JCOG 0303. METHODS AND MATERIALS: JCOG 0303 was a multi-center phase II/III trial that compared two types of chemotherapy administered concomitantly with RT for locally advanced esophageal cancer. RT requirements included a total dose of 60 Gy in 30 fractions and CTV with a 2-cm margin cranio-caudally to the primary tumor. The QA assessment was given as per protocol (PP), deviation acceptable (DA), violation unacceptable (VU), and incomplete/not evaluable following predefined criteria for quality parameters. RESULTS: A total of 142 cases were accrued. After excluding 36 incomplete/not evaluable, 106 (75%) were fully evaluable for RT quality review. Of these 106, there were 4 VU (4%) and overall RT compliance (PP + DA) was 96%. Comparing the incidence of VU based on the numbers enrolled by institution, the highest quarter of enrollment (>=7 cases) had no VU, while all VU (4; 11%) were from institutions enrolling <7 patients. CONCLUSIONS: The results of the RTQA assessment for JCOG 0303 were sufficient to provide reliable results. Additional improvements will be needed for institutions with low accrual rates. PMID- 21667355 TI - Central nervous system involvement in diabetic neuropathy. AB - Diabetic neuropathy is a chronic and often disabling condition that affects a significant number of individuals with diabetes. Long considered a disease of the peripheral nervous system, there is now increasing evidence of central nervous system involvement. Recent advances in neuroimaging methods detailed in this review have led to a better understanding and refinement of how diabetic neuropathy affects the central nervous system. Recognition that diabetic neuropathy is, in part, a disease that affects the whole nervous system is resulting in a critical rethinking of this disorder, opening a new direction for further research. PMID- 21667356 TI - Osteoporosis onset differences between rural and metropolitan populations: correlation to fracture type, severity, and treatment efficacy. AB - Osteoporosis is the prevalent cause of fractures in an ever-aging population, with an established correlation between daily activities and way of life. We aimed to delineate differences in onset of osteoporosis, T-score progression, quality of life, and correlation to prevalence, types, and severity of fractures in age-comparable populations of rural and metropolitan habitats in this multicenter, retrospective double-blind study. We evaluated data derived from the medical files of two comparable groups of osteoporotic patients: group A (n = 530, rural area) and group B (n = 171, metropolitan area). Both groups received comparable treatment for osteoporosis. Comparison was performed on the basis of osteoporosis onset, T-score in a maximum of 8 years follow-up, fracture types [American Academy of Orthopaedic Surgeons (AO) categorization], and type of treatment followed. Quality of life was assessed by use of specialized questionnaires. From the minimum 4-year follow-up of all patients included in the research, there was a statistically significant difference in favor of the rural population in all research parameters. Rural populations presented with osteoporosis at a later age than their metropolitan counterparts, exhibiting favorable T-scores with comparable treatments and simpler fractures (AO categorization). Metropolitan habitats and life therein have a deleterious effect on osteoporosis onset and response to treatment. Rural populations are diagnosed with osteoporosis on a later age, with better compliance and improved treatment outcome. Fracture categorization shows increased severity in the metropolitan populace and a suggested correlation between a poor-quality way of life and decreased activity levels. PMID- 21667357 TI - The identification of novel mutations in COL1A1, COL1A2, and LEPRE1 genes in Chinese patients with osteogenesis imperfecta. AB - Dominant inheritance of osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2, the genes that encode type I collagen, and CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, and SP7 mutations were recently detected in a minority of patients with autosomal recessive OI. However, these findings have been mostly restricted to Western populations. The proportion of mutations and the correlations between genotype and phenotype in Chinese patients with OI are completely unknown. In this study, mutation analyses were performed for COL1A1, COL1A2, CRTAP, and LEPRE1 in a cohort of 58 unrelated Chinese patients with OI; the relationship between collagen type I mutations and clinical features was examined. A total of 56 heterozygous mutations were identified in COL1A1 and COL1A2, including 43 mutations in COL1A1 and 13 mutations in COL1A2. Among the 56 causative COL1A1 and COL1A2 mutations, 24 novel mutations were found, and 25 (44.6%) resulted in the substitution of a glycine within the Gly-X-Y triplet domain of the triple helix. Compared with COL1A1 haploinsufficiency (n = 23), patients with mutations affecting glycine residues had a severe skeletal phenotype. In patients 18 years of age or older, on average patients with COL1A1 haploinsufficiency were taller and had higher femoral neck bone mineral density than with patients with helical mutations. Interestingly, we found two novel compound heterozygous mutations in the LEPRE1 gene in two unrelated families with autosomal recessive OI. Although the genotype-phenotype correlation is still unclear, our findings are useful to understand the genetic basis of Chinese patients with OI. PMID- 21667359 TI - Mapping the development of response inhibition in young children using a modified day-night task. AB - Response inhibition was examined in 40 children 31/2 to 8 years of age using a modified day-night task. Performance in a neutral condition explained variance in congruent and incongruent conditions, indicating that age-related improvements in these latter conditions were partly mediated by working memory and processing speed. After controlling for neutral performance, age did not explain variance in congruent performance but explained variance in incongruent performance. These findings indicate that the associative strength between pictures and labels used in the task is age invariant and that older children are better than younger children at inhibiting responses to these associations. PMID- 21667358 TI - Vertebral fracture risk and alendronate effects on osteoporosis assessed by a computed tomography-based nonlinear finite element method. AB - Computed tomography-based nonlinear finite element method (CT/FEM) can accurately predict vertebral compressive strength ex vivo and this method is clinically available in vivo. This study aimed to assess vertebral fracture risk and alendronate effects on osteoporosis in vivo using CT/FEM. Vertebral strength in 123 postmenopausal women was analyzed and the discriminatory power for vertebral fracture was assessed cross-sectionally. Alendronate effects were also prospectively assessed in 33 patients with postmenopausal osteoporosis who were treated with alendronate at a dose of 5 mg/day for 18 months. CT/FEM had higher discriminatory power for vertebral fracture than areal bone mineral density (BMD) and volumetric BMD and detected alendronate effects at 3 months. Marked bone density increases were noted in juxtacortical areas compared to inner trabecular areas. CT/FEM was useful for assessing vertebral fracture risk and therapeutic effects on osteoporosis. PMID- 21667360 TI - Transfer-of-learning effect with the tactual performance test using familiar and unfamiliar shapes with American, Lao, and Senegalese children. AB - The Tactual Performance Test (TPT) and a version of the TPT with unfamiliar geometric designs were presented to American, Lao, and Senegalese children. The nonstandard TPT was designed to evaluate the importance of familiarity of forms in improved performance between successive TPT learning trials. The nonstandard board was more difficult for all the groups, with poorer time-per-block performance across learning trials and poorer TPT memory measures. Irrespective, the transfer-of-learning (ToL) effect for the standard and nonstandard boards was consistent for all the cultural groups. ToL effect is not dependent on familiarity of the TPT forms and is consistent across cultures. PMID- 21667361 TI - Comparing Attentional Networks in fetal alcohol spectrum disorder and the inattentive and combined subtypes of attention deficit hyperactivity disorder. AB - The Attention Network Test (ANT) was used to examine alerting, orienting, and executive control in fetal alcohol spectrum disorder (FASD) versus attention deficit hyperactivity disorder (ADHD). Participants were 113 children aged 7 to 10 years (31 ADHD-Combined, 16 ADHD-Primarily Inattentive, 28 FASD, 38 controls). Incongruent flanker trials triggered slower responses in both the ADHD-Combined and the FASD groups. Abnormal conflict scores in these same two groups provided additional evidence for the presence of executive function deficits. The ADHD Primarily Inattentive group was indistinguishable from the controls on all three ANT indices, which highlights the possibility that this group constitutes a pathologically distinct entity. PMID- 21667362 TI - Selective changes in executive functioning ten years after severe childhood traumatic brain injury. AB - Pediatric traumatic brain injury (TBI) impacts on children's executive functions, but little is known of how such deficits evolve in the long term. Forty adolescents with TBI were assessed ten years post-injury and compared to 19 typically developing participants on a range of executive measures (attentional control, cognitive flexibility, goal setting, information processing). Children with mild or moderate TBI performed within age expectations on all tests; however, those with severe injuries had poorer performance on goal setting and processing speed tasks. Childhood TBI may result in subtle lasting changes in complex executive skills, which could require ongoing support into adulthood. PMID- 21667364 TI - Subtypes of developmental coordination disorder: research on their nature and etiology. AB - Children with Developmental Coordination Disorder (DCD) are a group embracing clumsiness and developmental dyspraxia. Our study provides a better understanding of the nature of DCD and its etiology, and identifies subtypes of dyspraxia. Forty-three children with DCD (5-15 years) were enrolled on the Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV-TR]; American Psychiatric Association, 2000) criteria. Extensive standardized evaluations were conducted. We distinguished from two patterns of "pure" developmental dyspraxia: ideomotor and visual-spatial/visual-constructional, and mix dyspraxia with more co morbidities. Our study provides a better understanding of the nature of DCD, and sheds light on its etiology and brain dysfunction, so as to identify subtypes of developmental DCD/dyspraxia with specific clinical criteria. PMID- 21667365 TI - Old wine in new bottles? The positioning of participation in 17 NIH-funded CBPR projects. AB - Influenced by Cooke and Kothari's (2001) suggestion that participation "remains a way of talking about rather than doing things" (p. 32), we question to what extent this is true in the public health funding process. Thus, the aim of this article was to investigate the ways in which recent National Institutes of Health (NIH)-funded community-based participatory research (CBPR) projects discursively positioned CBPR in their grant applications. We collected 17 NIH-funded CBPR proposals, analyzed them using a grounded theory approach, and subjected the findings to critical analysis focusing on the definition of community, the type of community "participation" promoted, and the nature of the research proposed. We conclude that certain types of CBPR projects are privileged in the funding review process and discuss the implications of these findings for future CBPR praxis. PMID- 21667363 TI - Abnormal gamma and beta MEG activity during finger movements in early-onset psychosis. AB - Patients with psychosis often exhibit abnormalities in basic motor control, but little is known about the neural basis of these deficits. This study examines the neuro-dynamics of movement using magnetoencephalography (MEG) in adolescents with early-onset psychosis and typically developing controls. MEG data were imaged using beamforming then evaluated for task and group effects before, during, and after movement onsets. Primary findings included weaker activation in patients during movement execution in cerebellar cortices. Such aberrations likely contribute to the decreased motor control exhibited by patients with psychosis, and may reflect GABAergic-based inhibitory deficits comparable to those seen in cellular and system-level studies. PMID- 21667367 TI - Local resistance to the global eradication of polio: newspaper coverage of the 2003-2004 vaccination stoppage in northern Nigeria. AB - Successful global health initiatives are executed on the recognition that globalization involves simultaneous pulls between global unification and fragmentation. This article responds to the need for more understanding of the role of fragmentation in global health initiatives through analyses of 52 northern Nigerian newspaper reports of the 2003-2004 northern Nigerian stoppage of the Global Polio Eradication Initiative. By 2009 the stoppage had resulted in an epidemic in Nigeria and polio importations in 20 previously polio-free countries. Findings pointed to beliefs in contemporary forms of Western control and abuse through global organizations (nongovernmental organizations and for profits), understandings of the "philanthropy" of the West and global organizations as self-serving and malevolent, and doubts about the polio vaccine product. PMID- 21667366 TI - A novel recruitment message to increase enrollment into a smoking cessation treatment program: preliminary results from a randomized trial. AB - Most smokers do not utilize approved interventions for nicotine dependence, reducing the probability of cessation. Smoking cessation programs typically use recruitment messages emphasizing the health threats of smoking. Augmenting this threat message by describing the genetic aspects of nicotine addiction may enhance enrollment into a cessation program. During telephone recruitment, 125 treatment-seeking smokers were randomized to receive by phone either a standard threat message or a threat plus genetic prime message and were offered open-label varenicline and counseling. There was a greater rate of enrollment into the cessation program for the threat plus genetic prime participants (51.7%) versus the threat-only participants (37.7%; p = .03). Smokers who self-identified from racial/ethnic minority groups were less likely to enroll in the cessation program (p = .01) versus smokers who self-identified as Caucasian. These preliminary data suggest that a simple, affordable, and transportable communication approach enhances enrollment of smokers into a smoking cessation program. A larger clinical trial to evaluate a genetic prime message for improving recruitment into smoking cessation programs is warranted. PMID- 21667368 TI - Case study. Uranium oxide solubility in simulated lung fluids. PMID- 21667370 TI - Solvent substitution: an analysis of comprehensive hazard screening indices. AB - The air index (psi(i)(air)) of the PARIS II software (Environmental Protection Agency), the Indiana Relative Chemical Hazard Score (IRCHS), and the Final Hazard Score (FHS) used in the P2OASys system (Toxics Use Reduction Institute) are comprehensive hazard screening indices that can be used in solvent substitution. The objective of this study was to evaluate these indices using a list of 67 commonly used or recommended solvents. The indices psi(i)(air), IRCHS and FHS were calculated considering 9, 13, and 33 parameters, respectively, that summarized health and safety hazards, and environmental impacts. Correlation and sensitivity analyses were performed. The vapor hazard ratio (VHR) was used as a reference point. Two good correlations were found: (1) between VHR and psi(i)(air) (rho = 0.84), (2) and between IRCHS and FHS (rho = 0.81). Values of sensitivity ratios above 0.2 were found with psi(i)(air) (4 of 9 parameters) and IRCHS (3 of 13 parameters), but not with FHS. Overall, the three indices exhibited important differences in the way they integrate key substitution factors, such as volatility, occupational exposure limit, skin exposure, flammability, carcinogenicity, photochemical oxidation potential, atmospheric global effects, and environmental terrestrial and aquatic effects. These differences can result in different choices of alternatives between indices, including the VHR. IRCHS and FHS are the most comprehensive indices but are very tedious and complex to use and lack sensitivity to several solvent-specific parameters. The index psi(i)(air) is simpler to calculate but does not cover some parameters important to solvents. There is presently no suitably comprehensive tool available for the substitution of solvents. A two-tier approach for the selection of solvents is recommended to avoid errors that could be made using only a global index or the consideration of the simple VHR. As a first tier, one would eliminate solvent candidates having crucial impacts. As a second tier, other parameters would be considered, with emphasis on the VHR. PMID- 21667371 TI - Effects of occupational exposure on the health of workers in the cricket bat manufacturing industry in Kashmir, India. PMID- 21667373 TI - Characterizing inward leakage in a pressure-demand, self-contained breathing apparatus. AB - An analytical model of the flow across a resistive flow path such as an orifice or pipe was applied to predict the inward leakage in the facepiece of a self contained breathing apparatus (SCBA) during a steady below-ambient facepiece pressure. The model was used to estimate leakage rates with respect to the size of the leak and for below-ambient (negative) pressure conditions reflective of measured occurrences. Results of the model were also used to make quantitative estimates of the protection level of the respirator. Experiments were designed to induce a continuous below-ambient pressure inside the facepiece of a pressure demand SCBA mounted on a headform. Negative facepiece pressure measured in the presence of a leak correlated with the measured particle concentration ratio. Results show that the analytical model generated reasonable estimates of leakage rates during conditions of negative pressure inside the facepiece. Thus, the analytical model performed well for constant flow conditions, demonstrating the capability to predict a momentary compromise in respirator protection during momentary negative facepiece pressure conditions. PMID- 21667372 TI - Safety and chemical exposure evaluation at a small biodiesel production facility. PMID- 21667374 TI - Adults with dual eligibility for Medicaid and Medicare: access to substance abuse treatment. AB - Access to substance abuse treatment is a noted concern for people with disabilities. Although much is known about elders with dual eligibility for Medicaid and Medicare regarding any care utilization and expenditures, little is known about their younger counterparts and how substance abuse might contribute. Drawing on national Medicaid claims, treatment utilization was explored for adults with and without dual eligibility for Medicare. People with dual eligibility were less likely to both initiate and engage in treatment as compared to those without dual eligibility. Implications relate to how existing systems provide substance abuse treatment to people with disabilities. PMID- 21667375 TI - Intentions and realities in rehabilitation service in Denmark. AB - We used Danish register data on rehabilitation benefits paid from 1994 to 2005. The purpose was to compare actual payments of rehabilitation benefits with intentions in the law. Legally, rehabilitation benefits should be used for providing living expenses during a planned rehabilitation period facilitating the recipients' return to the labor market. We found that one third of recipients were paid for less than 3 months, and half of remaining recipients had time gaps in their payments. The findings indicated that rehabilitation benefits were not paid only for planned rehabilitation periods, and that not all recipients followed the legally required plan. PMID- 21667376 TI - The need to know caregiver perspectives toward using smart home technology. AB - This article reviews the literature on adults with serious mental illness, their caregivers, and smart home technology. The article provides compelling evidence for social workers to undertake research aimed at investigating caregivers' perceptions toward using smart home technology for care of adult family members or friends with a serious mental illness. Empirical support for using smart home technologies with adults with serious mental illness is provided, and recommendations for future social work research are offered. PMID- 21667377 TI - Stressors and life goals of caregivers of individuals with disabilities. AB - Caregivers of individuals with disabilities can experience stress as they manage caregiving responsibilities while they attempt to balance family, work, and the satisfaction of their personal goals. In this pilot study, 31 caregivers of individuals with a variety of disabilities completed a quantitative-qualitative survey. A statistically significant relationship was found between the age and severity of disability of the family member receiving care, the length of time care had been provided, the educational level and the relationship of the caregiver to the family member and reported feelings of optimism, humbleness, quality of family relationships, financial concerns, loss of control, and hope. When life goals were probed, the most common reported were achieving financial stability, having a strong, healthy family, and experiencing happiness. The implications for supporting caregivers and their families are discussed. PMID- 21667378 TI - Schizophrenia, trauma, dissociation, and scientific revolutions. PMID- 21667379 TI - Dissociation as a mediator of posttraumatic symptoms in a Puerto Rican university sample. AB - The present study examined the role of dissociation as a mediator in the relationship between self-reported childhood abusive experiences and adult posttraumatic symptomatology in a nonclinical, Spanish-speaking Latino sample. Participants were 208 (144 female, 64 male) students at the University of Puerto Rico. It was hypothesized that dissociation would mediate the relationship between childhood abusive experiences and adult posttraumatic symptomatology. Dissociation was measured using the Dissociative Experiences Scale, and posttraumatic distress was measured using 9 of the 10 clinical scales of the Trauma Symptom Inventory (TSI). Results indicated that dissociation fully mediated the relationship between childhood abusive experiences and the Anxious Arousal and Dysfunctional Sexual Behavior scales of the TSI. Dissociation also partially mediated the relationship between childhood exposure and the other TSI clinical scales used in the analyses. Implications for clinicians working with Puerto Rican survivors of childhood abuse are discussed. PMID- 21667380 TI - The contributions of interpersonal trauma exposure and world assumptions to predicting dissociation in undergraduates. AB - This study examines the relationship between world assumptions and trauma history in predicting symptoms of dissociation. It was proposed that cognitions related to the safety and benevolence of the world, as well as self-worth, would be related to the presence of dissociative symptoms, the latter of which were theorized to defend against threats to one's sense of safety, meaningfulness, and self-worth. Undergraduates from a midwestern university completed the Multiscale Dissociation Inventory, World Assumptions Scale, and Traumatic Life Events Questionnaire. Consistent with the hypotheses, world assumptions were related to the extent of trauma exposure and interpersonal trauma exposure in the sample but were not significantly related to non-interpersonal trauma exposure. World assumptions acted as a significant partial mediator of the relationship between trauma exposure and dissociation, and this relationship held when interpersonal trauma exposure specifically was considered. The factor structures of dissociation and world assumptions were also examined using principal component analysis, with the benevolence and self-worth factors of the World Assumptions Scale showing the strongest relationships with trauma exposure and dissociation. Clinical implications are discussed. PMID- 21667381 TI - Possession experiences in dissociative identity disorder: a preliminary study. AB - Dissociative trance disorder, which includes possession experiences, was introduced as a provisional diagnosis requiring further study in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Consideration is now being given to including possession experiences within dissociative identity disorder (DID) in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.), which is due to be published in 2013. In order to provide empirical data relevant to the relationship between DID and possession states, I analyzed data on the prevalence of trance, possession states, sleepwalking, and paranormal experiences in 3 large samples: patients with DID from North America; psychiatric outpatients from Shanghai, China; and a general population sample from Winnipeg, Canada. Trance, sleepwalking, paranormal, and possession experiences were much more common in the DID patients than in the 2 comparison samples. The study is preliminary and exploratory in nature because the samples were not matched in any way. PMID- 21667386 TI - Defining (structural) dissociation: a debate. PMID- 21667387 TI - Dissociation in trauma: a new definition and comparison with previous formulations. AB - Amid controversy regarding the psychobiological construct of dissociation, efforts to formulate a precise definition of dissociation are rare. Some understandings of dissociation are so broad that a host of common psychobiological phenomena would qualify as dissociative. Overly narrow conceptualizations of dissociation exclude phenomena that originally, and for good reasons, have been regarded as dissociative. A common lack of conceptual distinctions between dissociation as process, organization, deficit, psychological defense, and symptom adds to the current confusion. In previous publications, we criticized many of these perspectives and proposed a detailed psychobiological theory of dissociation in trauma. However, what has remained missing is a precise definition of dissociation in trauma. This article first presents such a definition and elucidates its various components. Next the new definition is compared with several other major definitions of the concept. The strengths of the new formulation are highlighted and discussed. PMID- 21667388 TI - Nijenhuis and Van der Hart: one view of the elephant. PMID- 21667389 TI - Commentary on "dissociation in trauma: a new definition and comparison with previous formulations" by Nijenhuis and Van der Hart. PMID- 21667390 TI - Must dissociation be unusual? PMID- 21667391 TI - One split too many .... PMID- 21667392 TI - An excellent definition of structural dissociation and a dogmatic rejection of all other models. PMID- 21667393 TI - Defining and delimiting trauma-related dissociation: a view from cultural psychiatry. PMID- 21667395 TI - Introduction: elucidating the neural basis of the self. PMID- 21667396 TI - Anosognosia in neurodegenerative disease. AB - Patients with neurological disorders are often partially or completely unaware of the deficits caused by their disease. This impairment is referred to as anosognosia, and it is very common in neurodegenerative disease, particularly in frontotemporal dementia. Anosognosia has significant impacts on function and quality of life for patients with neurodegenerative disease and their caregivers, but the phenomenon has received little formal study, especially in non Alzheimer's (non-AD) dementias. Furthermore, few studies have attempted to systematically verify the potential role of specific cognitive impairments in producing anosognosia. As a result, the mechanisms underlying this phenomenon are poorly understood. Episodic memory likely plays an important role. In addition, the frontal lobe systems are important for intact self-awareness, but the most relevant frontal functions have not been identified. Motivation required to engage in self-monitoring and emotional activation marking errors as significant are often-overlooked aspects of performance monitoring that may underlie anosognosia in some patients. The present review offers a working model that incorporates these functions and stipulates specific processes that may be important for awareness of changes in one's abilities. Specification of the specific processes whose potential failure results in anosognosia can establish a roadmap for future studies. PMID- 21667397 TI - Characterization of recovery and neuropsychological consequences of orbitofrontal lesion: A case study. AB - We present a case study of a patient with acquired prefrontal lesion involving mainly ventromedial and orbital structures (VM-PFD). The patient showed behavioral and emotional disturbances one year after the injury. In a follow-up examination seven years later, we evaluated her performance in tasks found theoretically to be sensitive to orbital and medial lesions. In contrast to our hypothesis, her performance was in the normal range. We suggest that a possible explanation for her magnificent recovery may include a high cognitive reserve and the specific characteristics of her injury. PMID- 21667398 TI - Green tea and black tea consumption and prostate cancer risk: an exploratory meta analysis of observational studies. AB - Observational studies on tea consumption and prostate cancer (PCa) risk are still inconsistent. The authors conducted a meta-analysis to investigate the association between green tea and black tea consumption with PCa risk. Thirteen studies providing data on green tea or black tea consumption were identified by searching PubMed and ISI Web of Science databases and secondary referencing qualified for inclusion. A random-effects model was used to calculate the summary odds ratios (OR) and their corresponding 95% confidence intervals (CIs). For green tea, the summary OR of PCa indicated a borderline significant association in Asian populations for highest green tea consumption vs. non/lowest (OR = 0.62; 95% CI: 0.38-1.01); and the pooled estimate reached statistically significant level for case-control studies (OR = 0.43; 95% CI: 0.25-0.73), but not for prospective cohort studies (OR = 1.00; 95% CI: 0.66-1.53). For black tea, no statistically significant association was observed for the highest vs. non/lowest black tea consumption (OR = 0.99; 95% CI: 0.82-1.20). In conclusion, this meta analysis supported that green tea but not black tea may have a protective effect on PCa, especially in Asian populations. Further research regarding green tea consumption across different regions apart from Asia is needed. PMID- 21667399 TI - Molecular basis for maize as a risk factor for esophageal cancer in a South African population via a prostaglandin E2 positive feedback mechanism. AB - The incidence of squamous cancer of the esophagus varies up to a hundredfold in different regions of the world. In Transkei, South Africa, a particularly high incidence of the disease is observed. We have previously proposed an association between a maize-rich diet and elevated levels of intragastric prostaglandin E2 production (PGE(2)). Here we investigate the molecular mechanisms by which a high maize diet could lead to increased incidence of squamous cancer of the esophagus. We confirm that levels of PGE(2) are high (606.8 pg/ml) in the gastric fluid of individuals from Transkei. We also show that treatment of esophageal cells with linoleic acid, which is found at high levels in maize and is a precursor to PGE(2), leads to increased cell proliferation. Similarly, treatment of cells with PGE(2) or with gastric fluid from Transkeians also leads to increased proliferation. Our data suggest that the high levels of PGE(2) associated with a maize-rich diet stimulate cell division and induce the enzyme COX 2, resulting in a positive feedback mechanism that predisposes the esophagus to carcinoma. PMID- 21667400 TI - Omega-3 fatty acid inhibition of prostate cancer progression to hormone independence is associated with suppression of mTOR signaling and androgen receptor expression. AB - Currently, progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. In order to improve overall survival, novel treatment strategies that are based upon specific molecular mechanisms that prolong the androgen-dependent state and that are useful for androgen-independent disease need to be identified. Both epidemiological as well as preclinical data suggest that omega-3 fatty acids are effective primary tumor prevention agents; however, their efficacy at preventing and treating refractory prostate cancer has not been as thoroughly investigated. We used an in vitro model of androgen ablation to determine the effect of treatment with omega-3 fatty acids on the progression to an androgen-independent state. The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were able to prevent progression of LNCaP cells while the omega-6 fatty acid arachidonic acid (AA) actually promoted cell growth under conditions of hormone depletion. These results correlated with a decrease in the expression of the androgen receptor as well as suppression of the Akt/mTOR signaling pathway. Connecting the mechanisms by which omega-3 fatty acids affect phenotypic outcome is important for effective exploitation of these nutrient agents as a therapeutic approach. Understanding these processes is critical for the development of effective dietary intervention strategies that improve overall survival. PMID- 21667401 TI - Higher micronutrient intake is associated with human papillomavirus-positive head and neck cancer: a case-only analysis. AB - No studies have investigated dietary differences between head and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV)-positive tumors and patients with HPV-negative tumors. This study was designed to investigate the relationship between diet and HPV status in HNSCC patients. Cases of HNSCC were recruited from 2 clinical centers participating in the University of Michigan Head and Neck Specialized Program of Research Excellence (SPORE). HPV tissue genotyping was performed, and epidemiological and dietary data collected. Multivariable logistic regression tested whether pretreatment consumption of 12 selected micronutrients was significantly associated with HPV-positive status in 143 patients newly diagnosed with cancer of the oral cavity or pharynx. After controlling for age, sex, body mass index, tumor site, cancer stage, problem drinking, smoking, and energy intake, significant and positive associations were observed between vitamin A, vitamin E, iron, beta-carotene, and folate intake and HPV-positive status (P(trend) < 0.05), suggesting that diet may be a factor in the improved prognosis documented in those with HPV-positive HNSCC. Dietary differences by HPV status should be considered in prognostic studies to better understand the influence of diet on HNSCC survival. PMID- 21667402 TI - Aldosterone perturbs adiponectin and PAI-1 expression and secretion in 3T3-L1 adipocytes. AB - Aldosterone is considered as a new cardiovascular risk factor that plays an important role in metabolic syndrome; however, the underlying mechanism of these effects is not clear. Hypoadiponectinemia and elevated circulating concentration of plasminogen activator inhibitor-1 (PAI-1) are causally associated with obesity related insulin resistance and cardiovascular disease. The aim of the present study is to investigate the effect of aldosterone on the production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Northern and Western blot analyses revealed that aldosterone treatment inhibited adiponectin mRNA expression and secretion and simultaneously enhanced PAI-1 mRNA expression and secretion in a time- and dose-dependent manner. Rosiglitazone did not prevent aldosterone's effect on adiponectin or PAI-1 expression. In contrast, tumor necrosis factor (TNF)-alpha produced dramatic synergistic effects on adiponectin and PAI-1 expression when added together with aldosterone. Furthermore, the effects of aldosterone on adiponectin and PAI-1 expression appear to be mediated through glucocorticoid receptor (GR) but not mineralocorticoid receptor (MR). These results suggest that the effects of aldosterone on adiponectin and PAI-1 production are one of the underlying mechanisms linking it to insulin resistance, metabolic syndrome and cardiovascular disease. PMID- 21667403 TI - Inhibitory effects of ghrelin on sexual behavior: role of the peptide in the receptivity reduction induced by food restriction in mice. AB - Ghrelin (Ghr) is a gut/hypothalamus peptide with inhibitory actions on reproductive physiology; however, there are no previous reports of its role on estrous behavior. Under the hypothesis that the increase of plasma Ghr during food restriction (FR) is responsible for receptivity reduction, we intended to evaluate the receptivity percentage of female mice subjected to: exp. 1) acute and chronic FR and Ghr administration (3 nmol/animal/day, s. c.) and exp. 2) the co-administration of a ghrelin antagonist [ant=(d-Lys3)-GHRP-6; 6 nmol/animal/day s. c.]. All females were ovariectomized, primed with steroids, trained, and randomly subjected every week to each one of several protocols, followed by a behavioral test. Experiment 1 (n=8): basal, no treatment; acute FR (aFR), 24-h fasting; chronic FR (cFR), 50% FR for 5 days; acute ghrelin (aGhr), Ghr 30 min before test and chronic ghrelin (cGhr), Ghr for 5 days. Except for cGhr, all treatments significantly decreased the percentage of receptivity (mean+/-SEM): basal 61.9+/-6.0, aFR 33.1+/-8.1, cFR 18.8+/-7.7, aGhr 45.6+/-10.6, p<0.05 vs. basal. In exp. 2 (n=11), except for cFR+ant (55.0+/-6.4) the co-administration of the antagonist reversed the deleterious effects detected in exp. 1: basal 70.9+/ 5.4; aFR+ant 72.3+/-7.6; aGhr+ant 73.6+/-4.7. As expected, the administration of vehicle or antagonist alone did not modify receptivity. Besides, we found a significant correlation between percentage of body weight loss and percentage of receptivity reduction (r=0.62, p=0.0004). This is the first study demonstrating that ghrelin is able to inhibit female mice sexual behavior and that is involved, at least in part, in receptivity reduction after food scarcity. PMID- 21667404 TI - Duplication of abdominal aorta: a very rare congenital anomaly but a common ultrasound artifact. PMID- 21667405 TI - Ultrasonography for venous thromboembolism. PMID- 21667406 TI - Diagnostic sonography of peripheral nerves: indications, examination techniques and pathological findings. PMID- 21667407 TI - [Image analysis in the differential diagnosis of renal parenchyma lesions]. AB - PURPOSE: Visual analysis of echo intensity is of importance for the differential diagnosis of focal renal lesions. Quantification of the echo intensity and of other parameters might help with differential diagnosis. MATERIALS AND METHODS: In 145 patients with focal renal lesions, digitized images were evaluated (40 angiomyolipomas [group A], 70 renal cell carcinomas [group B], 20 pseudo-tumors [group C] and 15 other focal lesions in group D). With Photoshop(r), the average grayscale values of the lesion (defined as echo intensity focal, EF) and its variance s2 (as expression of the inhomogeneity focal, IF) were measured. These measurements were compared to the renal cortex (echo intensity renal cortex=ER, inhomogeneity renal renal cortex=I R). Other calculated parameters: Echo intensity quotient, echo intensity index, inhomogeneity quotient and inhomogeneity index. RESULTS: Angiomyolipomas had a higher echo intensity quotient EQ and echo intensity index EI than renal cell carcinomas, pseudo-tumors and other lesions (p<0.001). Pseudo-tumors had a lower inhomogeneity quotient than angiomyolipomas (p<0.001), renal cell carcinomas (p<0.05). Echo intensity quotient EQ>=2.0 and echo intensity index EI>=0.5 were typical for angiomyolipomas with a sensitivity of 96.4 % and a specificity of 97.3 % for tumors<3 cm. CONCLUSION: Quantitative echo intensity measurements enhance the differential diagnosis of focal renal lesions. The differentiation of typical angiomyolipomas to other lesions could be improved. PMID- 21667408 TI - Cyclosporine-induced fibroadenomatosis. PMID- 21667409 TI - CEUS and HCC: are the 2008 EFSUMB guidelines still valid or has their wash-out already started? PMID- 21667410 TI - New technology--combined use of 3D contrast enhanced endoscopic ultrasound techniques. PMID- 21667423 TI - Qualitative JPEG 2000 compression in digital mammography - evaluation using 480 mammograms of the CDMAM phantom. AB - PURPOSE: The DICOM standard supports both quantitative and qualitative lossy compression of mammograms.The purpose of this study was to investigate qualitative JPEG 2000 lossy compression and how different factors such as object thickness, radiation dose, and lossy compression levels affect image quality. MATERIALS AND METHODS: The CDMAM phantom Artinis 3.4 was radiographed with 4 different object thicknesses and 5 different doses. The images were compressed at 10 different compression levels. The image quality was assessed by the software interpolated IQFinv value. RESULTS: Lossy 90 resulted in 89 % data reduction, lossy 70 in 95 % data reduction and lossy 60 in 96 % data reduction. At higher compression levels (lossy 30), the resulting image quality ranged from 80 - 36 %, and at low compression levels (lossy 90), it ranged from 89 - 93 %. The object thickness was found to significantly interact with the compression level with regard to the resulting image quality: a higher object thickness resulted in increasingly poor image quality at increasing compression levels (p < 0.05). CONCLUSION: Higher qualitative JPEG 2000 compression levels contribute only little additional data reduction, while the resulting image quality cannot be reliably predicted. Factors affecting image quality such as radiation dose and object thickness should be taken into account when performing image compression. Large object thicknesses should be compressed with caution because the loss of image quality is greater when intelligent data compression algorithms are used. PMID- 21667424 TI - [Extrapulmonary tuberculosis: radiological imaging of an almost forgotten transformation artist]. AB - Tuberculosis (TB) continues to be one of the infectious diseases with the world's highest rates of avoidable morbidity and mortality. A continuing downward trend has only been observed in highly industrialized countries, including Germany with 4,400 cases in the year 2009 representing an incidence of 5.5 per 100,000 persons. At the same time, the exposure to this patient group and the clinical experience are decreasing. Tuberculosis may affect any organ. The lung was the manifestation site in 80% of cases, and extrapulmonary manifestations were recorded in 20% of cases in Germany in the year 2008. Lymph node involvement is most common with a rate of approximately 50% of all extrapulmonary cases followed by the pleura in 18% of cases, genitourinary tract in 13% of cases, bones and joints in 6% of cases, gastrointestinal tract in 6% of cases, the central nervous system in 3% of cases and the spine in 3% of cases. Symptoms like fever, night sweats and weight loss are non-specific and may be absent. The aim of the review is to raise awareness of this disease, which is increasingly falling into oblivion, with its various radiological manifestations and to point out clinical epidemiological and demographic factors that raise suspicion of tuberculosis. PMID- 21667425 TI - [Magnetic resonance cholangiographic (MRCP) features of ischemic-type biliary lesions (ITBL): a case-control study]. AB - PURPOSE: To evaluate the spectrum of MR cholangiography (MRCP) features of ischemic-type biliary lesions (ITBL) after orthotopic liver transplantation (OLT). MATERIALS AND METHODS: 30 patients (16 m, 14 f) with an average age of 52 years (9 - 69 y) were examined in two 1.5 MR units using breath-hold 2D-SS-FSE sequences and 3D-MRCP sequences. 20 of the 30 patients had an established ITBL, and the remaining 10 patients were post-OLT controls. MRCPs were evaluated independently by two experienced radiologists that were blinded to the clinical history as well as the results of other imaging modalities. All images were analyzed for the presence of 16 different pathological features. Differences between ITBL patients and controls were analyzed using the Mann-Whitney-U Test. Inter-rater variability was tested using the Cohen's Kappa test. RESULTS: Abnormal findings of bile ducts were seen in all patients. The most common findings were (in percentage for reader 1 / 2) intrahepatic bile duct dilatation (95 % / 95 %) and extrahepatic bile duct stenoses (95 % / 85 %), followed by intrahepatic main duct stenoses (90 % / 95 %) and segmental duct stenoses (85 % / 85 %). Differences between ITBL patients and controls were significant for most of the analyzed features (Mann-Whitney-U test, p < 0.05). For 12 of 16 features, there was substantial or almost perfect agreement (kappa = 0.61 - 1.00), for 2 of 16 features moderate agreement (kappa = 0.41- 0.60) and for 2 of 16 features fair agreement (kappa < 0.40). CONCLUSION: In patients with ITBL, MR cholangiography reveals characteristic features that may allow differentiation from other biliary complications after liver transplantation. PMID- 21667426 TI - Growth hormone, ghrelin and peptide YY secretion after oral glucose administration in healthy and obese women. AB - The mechanism of the altered GH secretion in obesity is unclear. There is evidence that oral glucose (OG) administration initially decreases and subsequently stimulates GH secretion. Ghrelin is a peptide that displays strong growth hormone-releasing activity. Its physiological importance on GH regulation is unclear. Our aim was to study fasting GH concentrations and their response to OG administration in relation with ghrelin secretion in obese and healthy women, in order to elucidate the hypothetical participation of ghrelin on post-oral glucose GH secretion. 36 women were included in the study. After an overnight fast, 75 g of oral glucose was administered; glucose, insulin, ghrelin, and PYY (1-36) were obtained at baseline and during 300 min. The area under the curve between 0 and 300 min (AUC) of GH MU/l.min) was lower in obese patients than in controls; 262.5+/-57.5 vs. 534.9+/-95.6, p=0.01, for obese and controls respectively. GH peak (MUg/l) was lower in obese patients than in controls; 3.7+/ 0.7 vs. 7.1+/-1.0, p=0.012, for obese and controls, respectively. The AUC of total ghrelin (pg/ml.min) was lower in obese patients than in controls; 233,032+/ 12,641 vs. 333,697+/-29,877, p=0.004, for the obese patients and controls respectively. PYY (1-36) was similar in obese and healthy women after OG. There were significant correlations between the different indices of post-oral glucose GH and ghrelin secretion. These data suggest that ghrelin is a physiological regulator of GH in the post-oral glucose state, and the decreased ghrelin secretion could be one of the mechanisms responsible for the altered GH secretion in obesity. PMID- 21667427 TI - Salivary cortisol increases after bariatric surgery in women. AB - Cortisol increases have been associated with psychological and physiological stress; however, cortisol dynamics after weight loss (bariatric) surgery have not been defined. Obese participants not using exogenous glucocorticoids were eligible to participate. Female participants (n=24) provided salivary cortisol samples at bedtime, upon awakening the following morning, and 30 min after awakening before, and at 6 or 12 months after bariatric surgery. The Medical Outcomes Study Short Form-12 version 2 questionnaire regarding health-related quality of life was also completed. Preoperatively, mean body mass index was 45.1+/-8.1 kg/m2. Mean late night (1.8+/-1.1 nmol/l), awakening (10.7+/-7.4 nmol/l), and after-awakening (11.5+/-7.9 nmol/l) salivary cortisol values were within normal ranges. The cortisol awakening response (mean 21.1+/-79.7%, median 13.7%) was at the low end of normal. Preoperatively, participants had lower mental and physical health-related quality of life scores than US adult norms (p<0.001). Salivary cortisol was not correlated with measures of health-related quality of life. Mean BMI decreased over time (p<0.001) and participants experienced improved physical and mental health-related quality of life (p<=0.011). Postoperative late night salivary cortisol was not different from preoperative values. Awakening and after-awakening cortisol levels were higher than preoperative values (15.3+/-7.7 nmol/l, p=0.013; 17.5+/-10.2 nmol/l, p=0.005; respectively), but the cortisol awakening response was not changed (mean 26.7+/-66.2%; median 7.8%). Morning salivary cortisol increased at long-term follow-up after bariatric surgery. Although self-evaluated mental and physical health improved after surgery, the cortisol awakening response is at the low end of normal, which may indicate continued physiological stress. PMID- 21667428 TI - Restrictive management of neonatal polycythemia. AB - Partial exchange transfusion (PET) is traditionally suggested as treatment for neonates diagnosed with polycythemia. Nevertheless, justification of this treatment is controversial. We evaluated the risk for short-term complications associated with a restrictive treatment protocol for neonatal polycythemia. A retrospective cross-sectional analytical study was conducted. Three treatment groups were defined and managed according to their degree of polycythemia, defined by capillary tube filled with venous blood and manually centrifuged hematocrit: group 1, hematocrit 65 to 69% and no special treatment was recommended; group 2, hematocrit 70 to 75% and intravenous fluids were given and feedings were withheld until hematocrit decreased to < 70%; and group 3, hematocrit >= 76% or symptomatic neonates and PET was recommended. During the study period, 190 neonates were diagnosed with polycythemia. The overall rate of short-term complications was 15% (28 neonates). Seizures, proven necrotizing enterocolitis, or thrombosis did not occur in any participating neonates. PET was performed in 31 (16%) neonates. The groups did not differ in their rate of early neonatal morbidities or length of hospitalization. Restrictive treatment for neonatal asymptomatic polycythemia is not associated with an increased risk of short-term complications. PMID- 21667429 TI - Treatment of severe nausea and vomiting of pregnancy with subcutaneous medications. AB - We examined treatment outcomes in women with severe nausea and vomiting of pregnancy (NVP) receiving outpatient nursing support and either subcutaneous metoclopramide or subcutaneous ondansetron via a microinfusion pump. Among women receiving outpatient nursing services, we identified those diagnosed with severe NVP having a Pregnancy-Unique Quantification of Emesis (PUQE) score of greater than 12 at enrollment and prescribed either metoclopramide (N = 355) or ondansetron (N = 521) by their physician. Maternal characteristics, response to treatment, and start versus stop values were compared between the medication groups. Allocation to group was based on intention-to-treat protocol. Maternal characteristics were similar between the groups. Days to reduction in PUQE score levels were similar (median 2 days, metoclopramide; 3 days, ondansetron; P = 0.206). Alteration from metoclopramide to ondansetron (31.8%) was more frequent than alteration from ondansetron to metoclopramide (4.4%; P < 0.001). Improvement of NVP symptoms and reduced need for hospitalization was noted with both medications. Treatment with either metoclopramide or ondansetron resulted in significant improvement of NVP symptoms with half of women showing a reduction from severe symptoms to moderate or mild symptoms within 3 days of treatment initiation. Alteration in treatment was significantly greater in patients initially prescribed metoclopramide. PMID- 21667430 TI - Diagnostic value of palpation, mammography, and ultrasonography in the diagnosis of fibroadenoma: impact of breast density, patient age, ultrasonographic size, and palpability. AB - PURPOSE: This retrospective study aimed to assess the diagnostic value of mammography, breast ultrasonography, and palpation in diagnosing fibroadenomas, making consistent use of the BI-RADS classification. The impact of breast density, patient age, and the size and palpability of the mass will be evaluated. PATIENTS AND METHODS: Between January 2000 and December 2009, a total of 339 fibroadenomas suitable for inclusion in this study were diagnosed and histologically verified at our institution. Based on their BI-RADS or BI-RADS analog classification, all lesions were categorized as benign or malignant. These results were compared to the corresponding histopathological findings. Specificities were calculated for each of the abovementioned parameters. Chi square test results with p-values < 0.05 were considered significant. Congruence between mammography and ultrasonography was assessed based on Cohen's kappa. RESULTS: Palpation had a specificity of 100 %, mammography 83.9 %, and ultrasonography 88.2 %. Considering the parameters under investigation, ultrasonography is superior to mammography. The specificity of the ultrasonographic assessment "benign" vs. "malignant" varied with patient age and palpability of the lesion (p = 0.001 and p = 0.025). Mammography and ultrasonography were most congruent for lesions rated ACR 1 - 2 and for lesions > 1.9 cm (kappa = 0.464, kappa = 0.444). CONCLUSION: For diagnosing fibroadenomas, ultrasonography is more specific than mammography when all examined variables are taken into account. Ultrasonography should therefore be favored, especially in younger patients. One needs to be aware of the effects of palpability and patient age on the ultrasonographic differentiation "malignant" vs. "benign". In some cases, mammography should be considered as an adjunct. PMID- 21667431 TI - Dynamic changes in the common bile duct after laparoscopic cholecystectomy: a prospective longitudinal sonographic study. AB - PURPOSE: The aim of this prospective study was to assess the dynamics of potential common bile duct (CBD) dilatation and to find the best predictors in patients after laparoscopic cholecystectomy due to gallstones. MATERIALS AND METHODS: Fifty patients (36 women, 14 men) with gallstones scheduled for laparoscopic cholecystectomy underwent preoperative sonography one day prior to surgery and again within 24 hours of cholecystectomy. In all patients, the diameter of the CBD was measured again on the 7 (th), 90 (th) and 180 (th) day after cholecystectomy. The luminal diameter was measured just below the bifurcation of hepatic ducts, at the level of intersection with the hepatic artery and at the level of the pancreatic head. The control group consisted of 50 healthy individuals (35 women and 15 men) with normal biochemistry and sonography, and without a history of hepatobiliary disease, clinical symptoms or surgery. RESULTS: The mean preoperative CBD diameter at three locations was 2.27 +/- 0.18, 3.49 +/- 0.23 and 4.31 +/- 0.30, respectively. The mean diameter of the common bile duct measured within 24 hours of surgery and on the seventh postoperative day did not significantly change with respect to the preoperative measurement. Three months after cholecystectomy, the CBD was statistically wider at all three locations (p < 0.05). Six months after cholecystectomy, the CBD remained significantly wider at the proximal and distal part when compared to the preoperative measurements. CONCLUSION: The CBD showed an overall trend towards a slight, but significant, dilatation after cholecystectomy. The common bile duct dilates significantly 3 months after cholecystectomy. Familiarity with these patterns prevents ultrasound misdiagnosis when examining patients within 6 months of cholecystectomy. PMID- 21667432 TI - [Cross-validation of the first trimester screening algorithm of the FMF London on 38,700 pregnancies in Germany]. AB - PURPOSE: Validation of the performance of the new algorithm of the FMF London for screening for trisomy 21 using a combination of maternal age, fetal nuchal translucency (NT) and maternal serum free beta-hCG and PAPP-A. MATERIALS AND METHODS: Between 2002 and 2007, NT was measured prospectively in 39,004 pregnancies in the context of routinely performed first trimester screening in Germany. Individual trisomy 21 risks were calculated by a combination of NT, maternal age, free beta-hCG, and PAPP-A using the FMF algorithm in force at the time of investigation. In this study we recalculated the trisomy 21 risks applying the new algorithm of the FMF UK that includes the new mixture model for the NT measurement. RESULTS: 38,751 singleton pregnancies could be included in the study of which 109 (0.3 %) had a trisomy 21. Only 35 % of the NT measurements of euploids were above the median and 25 % of the NT measurements were below the 5th percentile of the FMF UK. For sonographers that were qualified according to level II or III of the German DEGUM system, the median NT of fetuses with trisomy 21 was 0.9 mm above the median of the FMF UK and only 0.5 mm above the median for all other sonographers. Despite the limited performance of the NT measurement, the overall detection rate for a trisomy 21 was 90.8 % when combining the NT with maternal age, PAPP-A and free beta-hCG. The overall false-positive rate for a trisomy 21 was 6.5 % at a cut-off value of 1:300. CONCLUSION: In this study we were able to show that the use of the new risk algorithm of the FMF UK leads to a trisomy 21 detection rate of about 90 % at a 5 % false-positive rate in a German collective despite a significant underestimation of the NT. PMID- 21667433 TI - Real-Time Elastography: Strain Ratio Measurements Are Influenced by the Position of the Reference Area. AB - PURPOSE: Real-time elastography (RTE) is an ultrasound-based method for the visualization of relative strain distribution in soft tissues. Strain ratio is a semi-quantitative measurement of strain differences between two user-defined areas in an elastogram. The aim of this study was to evaluate the impact of the size and location of a reference area when measuring the strain ratio of focal lesions in a tissue-mimicking phantom and in normal liver tissue. We also investigated whether the strain ratio was affected by changing the scanner parameter: elasticity dynamic range (E-dyn). MATERIALS AND METHODS: Two investigators individually collected data by scanning 4 spherical inclusions with different elasticity in a phantom in which the elastic modulus was known in both the lesions and the background. Subsequently, a liver scan was performed in-vivo using the same scanning protocol. Five different setups with changes in reference area position or size were tested. All eight levels of the scanner setting E-dyn were recorded for each setup and the strain ratio was measured in 3 different representative elastograms for each recording situation. RESULTS: The four inclusions had significantly different mean strain ratio levels (p < 0.01) when compared to the surrounding material. Changing the position of the reference area to a deeper position influenced the strain ratio measurements significantly for all phantom lesions and in the liver. Changing the size of the reference area, while keeping the center depth unchanged, did not influence the mean strain ratio levels significantly. The strain ratio was independent of the E-dyn parameter setting. The intra- and interobserver reliability was high when measuring the strain ratio with a free-hand technique. CONCLUSION: Strain ratio provides reproducible measurements of inclusions representing different elastic contrasts using a free-hand technique in vitro. Changes in the distance of the reference areas to the ultrasound probe, representing the stress source, seem to have a significant impact on strain ratio measurements. PMID- 21667434 TI - Differentiation between benign and malignant adrenal mass using contrast-enhanced ultrasound. AB - PURPOSE: Adrenal masses can be detected by ultrasound with high sensitivity and specificity. The aim of the present study was to evaluate CEUS in a large patient population using CEUS patterns identified in a previous pilot study. MATERIALS AND METHODS: 116 adrenal masses were evaluated by ultrasound, including CEUS with the contrast agent Sonovue(r). The dynamic of contrast enhancement (CE) was analyzed using time-intensity curves. The time of the first CE in the adrenal mass was used to define four CEUS patterns: pattern I = early arterial CE, pattern II = arterial CE, pattern III = late CE, pattern IV = no CE. In addition, all patients received CT/MRI and hormonal testing. In suspicious cases biopsy or adrenalectomy was performed. RESULTS: CEUS patterns I&II were seen in all patients with primary or secondary malignant lesions of the adrenal gland (n = 16). The sensitivity and specificity of CEUS for the diagnosis of malignant adrenal mass were 100 % (CI [75;100]) and 67 % (CI [56;75]), respectively. Overall histology was available as a reference method for 40 adrenal masses. In 68 % of histologically diagnosed adrenal masses, MRI/CT and CEUS were congruent concerning the characterization of malignant versus benign adrenal mass. CONCLUSION: Contrast-enhanced ultrasound may be a useful method in the diagnostic work-up of adrenal mass with excellent sensitivity for the diagnosis of malignancy. PMID- 21667435 TI - Insulin resistance in non-obese women with polycystic ovary syndrome: relation to byproducts of oxidative stress. AB - To get more insight into molecular mechanisms underlying oxidative stress and its link with insulin resistance, oxidative stress parameters, as well as, antioxidant enzyme activities were studied in young, non-obese women with polycystic ovary syndrome (PCOS). Study was performed in 34 PCOS women and 23 age and body mass index (BMI)-matched healthy controls. Plasma nitrotyrosine and malondialdehyde (MDA), representative byproducts of protein and lipid oxidative damage, were determined by enzyme immunoassay. Antioxidant enzyme activities, superoxide dismutase (SOD) and glutathione peroxidase (GPX) were studied spectrophotometrically. Insulin resistance was calculated using homeostasis assessment model (HOMA-IR). Plasma nitrotyrosine and MDA were increased, but only nitrotyrosine was significantly higher (p < 0.05) in PCOS women compared to controls. Uric acid (surrogate marker of * antine oxidase) was also significantly elevated in PCOS (p < 0.05). Both plasma SOD and GPX activity showed no statistically significant difference between PCOS and controls. Indices of insulin resistance (insulin and HOMAIR) were significantly higher in PCOS group and positively correlated with level of MDA (r = 0.397 and r = 0.523, respectively; p < 0.05) as well as GPX activity (r = 0.531 and r = 0.358, respectively; p < 0.05). Our results indicate that insulin resistance could be responsible for the existence of subtle form of oxidative stress in young, nonobese PCOS women. Hence, presence of insulin resistance, hyperinsulinemia and oxidative damage are likely to accelerate slow development of cardiovascular disease in PCOS. PMID- 21667436 TI - Cell apoptosis of taste buds in circumvallate papillae in diabetic rats. AB - Diabetes mellitus may result in taste disturbance. The present study has revealed that cell apoptosis of taste buds in circumvallate papillae may contribute to the taste disturbance in a rat model of type2 diabetes. Type2 diabetes was induced in Wistar rats by feeding them with a high-fat diet (30% fat), and a single intraperitoneal injection of streptozotocin (30 mg/kg). The increased cell apoptosis of taste buds in circumvallate papilla sections was detected by TUNEL staining in diabetic rats, and the ultrastructure was further examined by transmission electronic microscopy. Immunohistochemical and Western blot analyses revealed the downregulation of Bcl-2, upregulation of Bax, and increased activation of caspase-9 and -3, in diabetic rats, indicating that the apoptosis of taste bud cells may be mediated via the intrinsic mitochondrial pathway in diabetics. PMID- 21667437 TI - Increase in energy intake leads to a decrease in obestatin in restricting-type of anorexia nervosa. AB - Restricting-type of anorexia nervosa (AN-R) is a serious disorder affecting adolescents and young adults, and decreases quality of life over long period. Successful weight restoration is an important prognostic factor for disease outcome; however, the underlying mechanism of refeeding-resistance, a core psychopathology relevant to 'ambivalent' eating behaviors, remains unclear in this disorder. Obestatin plays an important role in the regulation of growth hormone release, appetite, and energy metabolism. However, the progress of these patients and changes in the levels of obestatin during treatment were not reported. The purpose of this study was to determine the changes in obestatin levels when energy intake increases in AN-R patients. As a result, obestatin was higher in AN-R patients than in control subjects as well as acyl ghrelin and des acyl ghrelin. An increase in the intake calorie has decreased obestatin as well as des-acyl ghrelin. These findings indicate that the obestatin is an important factor in the diagnosis and treatment of AN-R, similarly to acyl ghrelin and des acyl ghrelin. In the future, the research on the clinical application of the ghrelin peptide family and the receptor will be expected to progress. PMID- 21667438 TI - Maternal autoimmune thyroid disease and the fetal immune system. AB - OBJECTIVE: Several studies indicate that in utero exposure to maternal autoimmune diseases and transplacental passage of autoantibodies affect the risk of autoimmunity in the offspring, e. g., maternally derived GAD65 autoantibody correlates with decreased risk of type 1 diabetes, whereas thyroid peroxidase autoantibody (TPOAb) positivity at birth is associated with increased incidence of autoimmune thyroid disease later in life. The aim of this study was to identify immunological changes in children born to mothers with thyroid autoimmunity that may be related to in utero exposure to autoantibodies. DESIGN AND METHOD: Open label prospective analysis of cord blood lymphocytes and serum cytokines by Flow Cytometry in children born to mothers with autoimmune thyroiditis (AIT) (n=31) and to healthy mothers (n=76) and titers of thyroid autoantibodies were determined in cord blood and in maternal peripheral blood at delivery. RESULTS: We found an increase (almost 30%) in the frequency of cord blood natural killer (NK) cells (p=0.0016) and a minor increase in the subset of T cells expressing NK markers (p=0.028), in children born to AIT mothers. There were no detectable differences in the phenotype or frequency of cord blood memory/activated T cells, including CD4 (+)CD25 (+) T cells, between the 2 groups. The levels of pro-inflammatory cytokines TNF-alpha, IL-10, IL-12p70, IFN gamma and IL-1beta were significantly decreased in offspring of AIT mothers as compared to healthy controls. CONCLUSIONS: Maternal thyroid autoimmunity and transplacental passage of autoantibodies against thyroid antigens may affect the generation or expansion of cells with NK activity and the secretion of inflammatory cytokines. PMID- 21667439 TI - Comparisons of serum sclerostin levels among patients with postmenopausal osteoporosis, primary hyperparathyroidism and osteomalacia. AB - Wnt-beta-catenin signaling is important for bone formation. Sclerostin inhibits bone formation mainly by suppressing this signal, and several studies suggest that the suppression of sclerostin expression contributes to the bone anabolic action of parathyroid hormone (PTH). We therefore examined serum sclerostin levels using enzyme-linked immunosolvent assay in 18 patients with postmenopausal osteoporosis, 9 postmenopausal women with primary hyperparathyroidism (pHPT) and 7 patients with osteomalacia. Serum levels of sclerostin were significantly lower in the group with pHPT, compared with those with postmenopausal osteoporosis. Moreover, serum sclerostin levels were significantly lower in the group with tumor-induced osteomalacia, but not in the group with osteomalacia without tumor, compared with those with postmenopausal osteoporosis. In patients with pHPT, serum sclerostin levels were significantly and negatively correlated to serum calcium and PTH levels. In patients with postmenopausal osteoporosis, serum levels of sclerostin levels were significantly and positively related to serum calcium and creatinine levels. In conclusion, we showed that serum sclerostin levels are decreased presumably through endogenous PTH elevation in postmenopausal women with pHPT, compared with the patients with postmenopausal osteoporosis. PMID- 21667440 TI - Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine: a single-center experience. AB - OBJECTIVE: Experience with chemotherapy in patients with medullary thyroid carcinomas (MTC) is limited. This retrospective study evaluated the outcome of a combination of cyclophosphamide, vincristine, and dacarbazine ('CVD-regimen'), which has previously been suggested for treatment of malignant pheochromocytomas. METHODS: 9 patients (5 males; age 55.0 +/- 4.0 years) with MTC were enrolled. Prior to chemotherapy, progressive disease was established in all patients by use of WHO criteria. On day 1 of each cycle, patients started with cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2), and dacarbazine 600 mg/m(2); on day 2, patients received dacarbazine alone (600 mg/m(2)). Treatment cycles were repeated at 21-day intervals and 6 cycles were planned for each patient. The standard imaging procedure was computed tomography, and the primary end point was the objective tumor response rate. After chemotherapy, patients were followed up until progression. RESULTS: 9 patients underwent a total of 57 cycles (mean 6.3 +/- 0.3 cycles). Treatment responses were: 0% complete response, 11% partial response, 56% stable disease, and 33% progressive disease. The median progression free survival was 13.6 months (range 5.8-24.2 months). The median change (baseline vs. end of treatment) of calcitonin was -19% (range -70% to +174%). Reversible myelosuppression and moderate gastrointestinal symptoms were the most common adverse events. CONCLUSION: Although objective tumor response rates were low, the CVD regimen allowed disease stabilization for a substantial period of time and had acceptable toxicity. After initial surgery, chemotherapy may therefore be considered as a medical treatment option. PMID- 21667441 TI - Genotoxicity and fetal abnormality in streptozotocin-induced diabetic rats exposed to cigarette smoke prior to and during pregnancy. AB - BACKGROUND: Maternal hyperglycemia during early pregnancy is associated with increased risk of abnormalities in the offspring. Malformation rates among the offspring of diabetic mothers are 2-5-fold higher than that of the normal population, and congenital malformations are the major cause of mortality and morbidity in the offspring of diabetic mothers. Metabolic changes, such as hyperglycemia and the metabolites obtained from cigarettes both increase the production of reactive oxygen species (ROS) in the embryo or fetus, causing DNA damage. OBJECTIVE: To evaluate the maternal and fetal genotoxicity, and to assess the incidence of fetal anomaly in diabetic female rats exposed to cigarette smoke at different stages of pregnancy in rats. MATERIAL AND METHOD: Diabetes was induced by streptozotocin administration and cigarette smoke exposure was produced by a mechanical smoking device that generated mainstream smoke that was delivered into a chamber. Female Wistar rats were randomly assigned to: non diabetic (ND) and diabetic (D) groups exposed to filtered air; a diabetic group exposed to cigarette smoke prior to and during pregnancy (DS) and a diabetic group only exposed to cigarette smoke prior to pregnancy (DSPP). On pregnancy day 21, blood samples were obtained for DNA damage analysis and fetuses were collected for congenital anomaly assessment. Statistical significance was set at p<0.05 for all analysis. RESULTS AND CONCLUSION: Exposure of diabetic rats to tobacco smoke prior to pregnancy increased fetal DNA damage, but failed to induce teratogenicity. Thus, these results reinforce the importance for women to avoid exposure to cigarette smoke long before they become pregnant. PMID- 21667442 TI - Maternal-fetal outcome, lipid profile and oxidative stress of diabetic rats neonatally exposed to streptozotocin. AB - BACKGROUND: There is no evidence about the integrated issue on glycemia, lipid profile, oxidative stress, and anomaly frequency of pregnant diabetic rats neonatally exposed to streptozotocin. OBJECTIVE: Evaluating the impact of hyperglycemia in diabetic rats neonatally exposed to streptozotocin on maternal reproductive and fetal outcomes and the relationship with lipid profile and maternal oxidative stress. MATERIAL AND METHODS: Ten 90-day-old female Wistar rats were mated to obtain offspring. Some of these newborns received streptozotocin (70 mg/kg, i. p. - n5-STZ group) and the remainder given only citrate buffer (control group) on their day 5 of life. At adult life, these rats (n=13 animals/group) were mated and, at day 21 of pregnancy, they were killed to obtain a maternal blood samples for biochemical determinations. The gravid uterus was weighed with its contents and fetuses were analyzed. RESULTS: At day 0 of pregnancy, glycemic means of n5-STZ rats were significantly greater compared to those of control rats, but presented fetuses classified as small for pregnancy age. The n5-STZ rats showed increased total cholesterol, triglycerides, MDA concentrations, lower SOD activity and increased frequency fetal visceral anomalies as compared to the control group. CONCLUSION: This study showed that the experimental model used led to mild hyperglycemia during pregnancy, although it did not lead to increased macrosomic fetus rates. The hyperglycemic maternal environment caused metabolic alterations, including increased triglyceride and total cholesterol concentrations, and elevated oxidative stress, contributing to increase fetal visceral anomalies. PMID- 21667443 TI - Influence of glycemic status and physical fitness on oxidative stress and the peroxiredoxin system in the erythrocytes of non-insulin-dependent type 2 diabetic men. AB - Oxidative stress plays a leading role in the progression of diabetic secondary complications, e.g., of cardio-vascular illnesses. Physical activity has been shown to delay and even prevent the progression of type 2 diabetes by improving the antioxidative capacity and thereby decreasing systemic oxidative stress. Peroxiredoxins (PRDX) are important antioxidative components that are highly abundant in erythrocytes. The present study examines the influence of glycemic control and physical fitness on oxidative stress and the peroxiredoxin system in the erythrocytes of non-insulin-dependent type 2 diabetic men ( N=22, years=61 +/ 10) at rest. Oxidative stress was measured by immunohistochemical stainings for 8-iso-prostaglandin-F2alpha (8-Iso-PGF) and the overoxidized form of peroxiredoxins (PRDX-SO (2-3)). Peroxiredoxin isoforms PRDX1 and PRDX2 were also quantified immunohistochemically. Physical fitness was determined during the WHO step test. Regression analyses showed a positive relationship between 8-Iso-PGF plotted against HbA (1c) (hyperbolic curve (y=a+b/x), R (2)=0.346, P=0.013), a positive relationship between 8-Iso-PGF plotted against fasting glucose (hyperbolic curve (y=a+b/x), R (2)=0.440, P=0.003), as well as positive relationships between PRDX2 plotted against VO (2 peak) (S-curve (y=e(a+b/x)), R(2)=0.259, P=0.018) and between PRDX2 plotted against the workload corresponding to the 4 mmol/l blood lactate concentration (hyperbolic curve (y=a+b/x), R(2)=0.203, P=0.041). Further significant relationships were not found. CONCLUSIONS: Poor glycemic control may increase oxidative stress in the erythrocytes of type 2 diabetic men. Good physical fitness seems to be associated with increased peroxiredoxin contents. Therefore, it can be speculated that physical training can contribute to the improvement of the erythrocyte peroxiredoxin system to counteract free radicals in type 2 diabetic patients. PMID- 21667444 TI - [Infection control in the operating room: preventive measures and isolation precautions in cases of multidrug resistant pathogens]. AB - BACKGROUND: Providing surgical treatment for patients colonised or infected with multidrug resistant organisms (MDROs) is daily routine in German hospitals. However, there is uncertainty about the application of adequate infection control measures in the OR. One of the reasons is that specific guidelines are not available. MATERIAL AND METHODS: We evaluated current practice in surgical departments of selected German university medical centres using a questionnaire. In addition, centres were asked to provide in-house standard operating procedures (SOP), if available. RESULTS: Nineteen questionnaires from 19 departments within 4 centres and 5 in-house SOPs were ana-lysed. The results showed a broad spectrum of applied infection control measures. Wide variations existed both within centres and within departments of the same centre regardless of existing in-house standards. CONCLUSIONS: Guidelines addressing perioperative infection control measures for patients harbouring MDROs should be developed with a focus on practicability to reduce both transmission of MDROs and unreasonable measures. Implementation of existing SOPs can be a target for optimisation. PMID- 21667445 TI - [Abscess formation after puncture of a thyroid cyst--a case report]. PMID- 21667446 TI - Cardiac surgery in Germany during 2010: a report on behalf of the German Society for Thoracic and Cardiovascular Surgery. AB - All cardiac surgical procedures performed in 79 German cardiac surgical units throughout the year 2010 are presented in this report, based on a voluntary registry which is organized by the German Society for Thoracic and Cardiovascular Surgery. In 2010 a total of 95,734 cardiac surgical procedures (ICD and pacemaker procedures excluded) have been collected in this registry. More than 12.4% of the patients were older than 80 years compared to 11.8% in 2009. Hospital mortality in 42,804 isolated CABG procedures (14.2% off-pump procedures) was 2.8%. In 25,127 isolated valve procedures (including 3660 transcatheter-valve implantations) a mortality of 4.9% has been observed. This voluntary registry of the German Society for Thoracic and Cardiovascular Surgery will continue to be an important tool enabling quality control and illustrating the development of cardiac surgery in Germany. PMID- 21667447 TI - [23 years at this periodical]. PMID- 21667449 TI - [Childhood Experiences of Care and Abuse (CECA) - validation of the German version of the questionnaire and interview, and results of an investigation of correlations between adverse childhood experiences and suicidal behaviour]. AB - OBJECTIVES: Validation of the German translation of a questionnaire and the corresponding interview for the assessment of adverse childhood experiences within the family environment and investigation of an association of these experiences with suicidal behaviour. METHOD: The questionnaire was tested in a consecutively recruited sample of 125 psychiatric inpatients (aged 13 to 25 years) at the University Hospital Heidelberg. Retests and corresponding interviews were also performed. Suicidal behaviour was measured by the Paykel Suicide Scale. RESULTS: The questionnaire and interview showed very good internal consistency and retest reliability; the interrater reliability of the interview was good, and there was a significant correlation between the questionnaire and the interview. Suicidal behaviour was significantly associated to all adverse childhood experiences, but maternal neglect and antipathy proved to be the best predictors of suicidal behaviour. CONCLUSIONS: The CECA instruments are reliable and valid instruments for the assessment of adverse childhood experiences. They assess a broad spectrum of adverse childhood experiences including negative bonding experiences. The association of these experiences to higher levels of suicidal behaviour shows the importance of assessing such experiences in research and therapy. PMID- 21667448 TI - [Psychopathological and comorbid disorders of incarcerated adolescents in Austria]. AB - OBJECTIVE: Incarcerated adolescents show a high prevalence rate of psychopathology and comorbid psychiatric conditions. Child and adolescent psychiatrists working in the penal system are confronted with the need to provide care and to develop specific treatment plans. METHOD: The data gathered from incarcerated juveniles were analyzed with a special focus on gender-specific treatment aspects. The Mini-International Neuropsychiatric Interview for children and adolescents was used to assess psychopathology in detained juveniles in Austria. The final study sample consisted of 333 juveniles (58 girls and 275 boys). RESULTS: 90 % of the juveniles in our sample suffered from at least one psychiatric disorder, and more than 60 % were diagnosed with two or more simultaneous psychiatric disorders. Using factor analyses we found three clinically relevant disorder patterns according to psychopathological characteristics for males: ADHD/conduct disorder and drug abuse; anxiety and depression; separation anxiety disorder/PTSD and alcohol abuse. In females, we found four disorder patterns: separation anxiety disorder/social phobia/dysthymia; PTSD and drug abuse in combination with either ADHD or conduct disorder; depression and alcohol abuse. CONCLUSIONS: Considering that juvenile detainees are burdened by high rates of psychopathology and comorbidity, it is essential to develop a substantiated diagnostic procedure in order when making treatment decisions; different disorder patterns must be considered in conjunction with detained juveniles. The patterns of psychopathology observed might be related to different characteristics in the development of delinquent behavior, in treatment needs, and legal prognosis. PMID- 21667450 TI - [How effective are long-term psychoanalytic treatments in adolescents? A comparison between the evaluations of the patients, their parents and their therapists]. AB - OBJECTIVE: Studies analyzing psychotherapy efficacy from the perspective of the different persons involved in the therapeutic process are lacking in the evaluation of psychotherapy outcome with children and adolescents. METHODS: Treatment efficacy of 28 long-term treatments with adolescents were analyzed from the perspective of the afflicted adolescents, their parents, and their therapist. Assessments were made three times over a mean frequency of 113 h. RESULTS: Therapy group (n = 28) and waiting group (n = 32) did not differ in relevant features, including diagnosis. In the therapy group, the therapists reported a strong reduction in symptomatology (eta(2 )= .62) and communicative disturbances with parents, siblings and friends (eta(2 )= .57) over time. Adolescents and parents reported a significant reduction in symptomatology (eta(2 )= .26) over time, but did not differ in their evaluation of treatment effectiveness. The diagnosis (internalizing vs. externalizing disturbances) had no impact on the evaluation of treatment effectiveness of adolescents and parents. CONCLUSIONS: Psychotherapy should include the different perspectives of all persons involved. PMID- 21667451 TI - [Cognitive and emotional empathy in children with ADHD and conduct disorder]. AB - OBJECTIVES: This study assesses the cognitive and emotional empathic competence in groups of children and adolescents with psychiatric disorders compared to a nonclinical control group. Subjective and objective diagnostic measures were employed. METHODS: A total of 96 boys were tested: 20 with attention deficit/hyperactivity disorder (ADHD) predominantly inattentive subtype (ADHD-I); 20 with ADHD combined subtype (ADHD-C); 20 with conduct disorder (CD); 36 healthy boys (control group; CG). Mean age was 12.0 years (SD = 2.36). As aspects of cognitive and emotional empathy emotional reactivity, we tested emotion recognition and perspective taking with subjective questionnaires and objective tasks, using as subjective questionnaires the Interpersonal Reactivity Index (IRI; Davis, 1983) and the Index of Empathy for Children and Adolescents (IECA; Bryant, 1982). As objective tasks, we adopted the Empathy Response Task (ERT; Ricard & Kamberk-Kilicci, 1995) and a task measuring emotion recognition according to Buitelaar et al. (1999). RESULTS: The CG outperformed participants with ADHD-C and CD in objective tasks assessing perspective taking, particularly when complex tasks were applied as stimuli. Children with ADHD-I showed significantly more emotional empathy than boys with ADHD-C when presented with simple tasks. No group differences were found for emotion recognition and subjective questionnaires. DISCUSSION: Deficits in perspective taking and emotional empathy were found for children with ADHD-C and CD, largely in accordance with the literature. Similar to the processing of cognitive information, the processing of emotional information seems to differ in ADHD subtypes. Objective tasks and tasks with a high ecological validity seem suitable for the measurement of empathy. PMID- 21667452 TI - [The training of social skills in children with ADHD - results of a pilot study]. AB - OBJECTIVE: Insufficient social competence belongs to the most frequent concomitants of ADHD. This is the first therapeutic concept for the training of social skills adapted to the specific deficits of children with ADHD and developed in the German-speaking region. METHOD: In a two-group, pre-posttest design with untreated waiting control group, 40 children between 7 and 13 years with the diagnoses F90.0, F90.1, and F98.8 were examined; 15 % were female, 85 % male. In groups of three they took part in the newly developed 10-h training TEAM. The record sheet of social skills for parents (ESF-E) was used to measure social competence. In addition, we recorded attention performances (FBB ADHS) and concomitant psychic factors. RESULTS: Significant effects of the training were demonstrated for almost all social skills (MANOVA/GLM). The outcomes on the different components of attention and the psychosocial concomitant factors are without uniformity. The strongest effects appeared in the areas of conflict management, regulation of emotions, and the capacity for empathy. CONCLUSIONS: Training of social skills is a sensible and effective supplement in the therapy of ADHD. An examination of long-term effects still needs to be done. PMID- 21667455 TI - Identification of a novel target of thiazide diuretics. AB - Thiazide diuretics are the older but still one of the most effective therapies for human hypertension. They are believed to act exclusively by blocking renal sodium absorption by the NaCl cotransporter NCC. We recently identified, however, a novel NaCl transport system that is expressed in intercalated cells of the collecting duct. This novel mechanism of NaCl transport operates by the combined action of 2 chloride/bicarbonate exchangers, 1 sodium-independent and 1 sodium dependent. We propose that part of the action of thiazide occurs through blockade of this novel system. PMID- 21667456 TI - N-Acetylcysteine protects the peritoneum from the injury induced by hypertonic dialysis solution. AB - BACKGROUND: Oxidative stress has been implicated in the development of peritoneal damage. The aim of this study was to evaluate the effects of N-acetylcysteine (NAC) in a rat peritoneal infusion model. METHODS: Eighteen male Wistar rats were divided in 3 groups: (i) control group; (ii) HDS group, receiving peritoneal dialysis solution (PDS); and (iii) HDS+NAC group, receiving PDS and oral NAC. Six weeks later they were evaluated for dialysate to plasma urea ratio (D/P), ratio of glucose concentration in peritoneal fluid (G1/G0), thiobarbituric acid reactive substances in plasma and urine and histology of peritoneal membrane. RESULTS: The HDS+NAC group presented a lower increase in solute transport (D/P 0.51 +/- 0.1, and G1/GO 0.35 +/- 0.06) in comparison with the HDS group (D/P 0.67 +/- 0.1; p=0.03, and G1/G0 0.27 +/- 0.07; p=0.01). The HDS+NAC group showed lower thiobarbituric acid reactive substance concentrations compared with the HDS group. In the treated group, the peritoneal membrane presented lower thickness. CONCLUSIONS: Functional and histological peritoneal changes were significantly reduced by the treatment with NAC. PMID- 21667457 TI - Clinical study protocol for the ARCH project - computational modeling for improvement of outcome after vascular access creation. AB - Despite clinical guidelines and the possibility of diagnostic vascular imaging, creation and maintenance of a vascular access (VA) remains problematic: avoiding short- and long-term VA dysfunction is challenging. Although prognostic factors for VA dysfunction have been identified in previous studies, their potential interplay at a systemic level is disregarded. Consideration of multiple prognostic patient specific factors and their complex interaction using dedicated computational modeling tools might improve outcome after VA creation by enabling a better selection of VA configuration. These computational modeling tools are developed and validated in the ARCH project: a joint initiative of four medical centers and three industrial partners (FP7-ICT-224390). This paper reports the rationale behind computational modeling and presents the clinical study protocol designed for calibrating and validating these modeling tools. The clinical study is based on the pre-operative collection of structural and functional data at a vascular level, as well as a VA functional evaluation during the follow-up period. The strategy adopted to perform the study and for data collection is also described here. PMID- 21667458 TI - The electrocardiographic method for positioning the tip of central venous catheters. AB - Tip position of a central venous access is of paramount importance and should be verified before starting infusion. Intra-procedural methods for verifying the location of the tip are to be preferred, since they avoid the risks, delays and costs of repositioning the tip. Among the intra-procedural methods, the electrocardiography (EKG) method has many advantages since it is as accurate as fluoroscopy, but simpler, more readily available, less expensive, safer and more cost-effective. The only contraindication to utilizing the EKG method is the difficulty in identifying the standard P-wave on a surface EKG (this happens - usually because of severe arrhythmias, such as atrial fibrillation - in only approximately 7% of cases: although such patients are easily identified before the procedure, and are referred to other methods for tip positioning). When dealing with the insertion of peripherally inserted central catheters (PICC), the EKG method (using the column of saline technique) virtually has no risk of false positives. The EKG method removes the need for the post-procedural chest x-ray, as long as there is no expected risk of pleuropulmonary damage to be ruled out (example: ultrasound guided central venipuncture for central venous catheter insertion or any kind of PICC insertion). In conclusion, evidence is mounting that the EKG method may be a valid and cost-effective alternative to the standard radiological control of the location of the tip of any central venous access device (VAD), and that will rapidly become the preferential method for confirming the tip position during PICC insertion. PMID- 21667459 TI - Extending outflow brachial vein length for transposition arteriovenous fistulas. AB - PURPOSE: Transposition arteriovenous fistulas (T-AVF) play an important role in establishing autogenous vascular access for many hemodialysis patients. When the basilic vein is not available, one of the paired brachial veins offers a reliable T-AVF option, generally as a two-staged operation. Uncommonly, the brachial vein outflow conduit dissipates into multiple small branches communicating with the paired brachial vein or occasionally with a residual proximal segment of the basilic vein. We utilized parallel outflow vein component segments to create additional outflow vein length necessary for successful T-AVFs in these patients. MATERIALS AND METHODS: We identified four patients where a vein length extension technique utilizing parallel and overlapping vein segments with an end-to-end anastomosis gained adequate length for successful T-AVFs. All transpositions were based on a first stage AVF with access outflow established into a brachial vein. CASE REPORTS: Three of the operations utilized paired brachial vein segments and one gained needed access outflow length with a brachial vein anastomosis to a residual proximal basilic vein segment. All four patients had functional T-AVFs at 4, 5, 7, and 14 month follow-up. None of the patients developed arm swelling. CONCLUSIONS: Creating a longer transposition AVF venous outflow segment using parallel and overlapping vein segments with an end-to-end anastomosis gained the adequate length needed for successful T-AVFs in these four patients. PMID- 21667460 TI - Endovascular electrocardiography to guide placement of totally implantable central venous catheters in oncologic patients. AB - PURPOSE: Appropriate tip position of totally implantable central venous catheters is essential in order to prevent catheter-related complications, in particular thrombosis. Endovascular electrocardiography is an economic and safe method to guide placement of catheters into the central veins. Although widely utilized, there is still lack of conclusive evidence about its efficacy. The aim of the study was to assess the efficacy and safety of endovascular electrocardiographic guided placement compared to the anthropometric method. METHODS: Endovascular ECG was employed to guide electrocardiographic placement of a central venous catheter in a cohort of oncologic patients. The rate of correct placement and the incidence of catheter-related thrombosis were considered. Patients in which central venous catheters were inserted with the anthropometric technique were considered as control group. RESULTS: The rate of correct placement was 91% and 50% for ECG-guided and anthropometric catheters (p<0.0001) respectively. None of the patients suffered from early insertion-related complications. The rate of catheter-related vascular thrombosis was lower for ECG-guided catheters (3.6% vs. 9.6%, n.s.), in particular for left-inserted catheters (0% vs. 33.3%, p=0.02). CONCLUSION: Endovascular electrocardiography was more effective than the anthropometric technique in placement of implantable central venous catheters and was associated with a lower incidence of catheter-related thrombosis, in particular for those inserted from the left-side. PMID- 21667461 TI - Great saphenous vein transposition to the forearm for dialysis vascular access; an under used autologous option? AB - PURPOSE: The recommended site for the next autologous vascular access in patients without suitable cephalic vein for fistula formation is basilic vein transposition. This study aims to compare outcomes from great saphenous vein transpositions to the forearm with that of basilic vein transposition. Comparison is reported in terms of primary and secondary patency, intervention, and complication rates in our unit. METHOD: A retrospective search of a prospectively maintained vascular database identified 24 consecutive patients undergoing great saphenous vein transposition (GSVT) and 34 consecutive patients having basilic vein transposition (BVT) were included for comparison. Primary and secondary patency details were obtained from hospital case notes and dialysis unit review records. Patency was studied using a Kaplan Meier analysis and compared using log rank testing. RESULTS: No significant difference was identified in primary or secondary patency between the procedures (P=0.745). Primary patency at 6, 12 and 24 months: for GSVT this was 62%, 41%, and 20%; for BVT this was 44%, 32%, and 15% respectively. Secondary patency at 6, 12, and 24 months; for GSVT this was 75%, 50%, and 41%; for BVT this was 65% respectively. Requirements for intervention were similar between groups. Complications were more common in the BVT group. CONCLUSION: Acceptable patency rates can be achieved using GSVT, thus adding another autologous option for upper limb dialysis access. Our results would suggest GSVT could be performed prior to BVT as the basilic vein may benefit from prior partial arterialization and can subsequently be used if GSVT fails. PMID- 21667462 TI - New frontiers in tumor marker studies: from biobanking to collaboration in translational research. PMID- 21667463 TI - Prevention of hyperopic surprise after LASIK in patients with refractive multifocal intraocular lenses. AB - PURPOSE: Three cases of patients who developed a similar hyperopic defect in refraction following laser in situ keratomileusis (LASIK) after multifocal intraocular lens (IOL) implantation are described. METHODS: Ophthalmologic evaluation including refractive status, corrected and uncorrected visual acuity (both at far and near), and corneal topography in patients presenting similar hyperopic refractive surprise in one eye as a result of LASIK refinement of residual ametropia after refractive multifocal IOL implantation. RESULTS: Laser in situ keratomileusis enhancement for residual ametropia of -1.00 to -1.50 D in patients with a prior implantation of refractive multifocal IOL resulted in a refractive surprise of +2.25 to +2.50 D. After excluding other possible sources of error, an explanation for such a refractive surprise is suggested, and a simple method for avoiding this error is presented. CONCLUSIONS: Proper knowledge of the defocus curve and the use of a systematic method for determining subjective refraction in patients implanted with refractive multifocal IOLs will reduce the possibility of refractive surprise after LASIK enhancement in a bioptics procedure. PMID- 21667464 TI - [Definition of diabetic microangiopathy (classification, etiology)]. PMID- 21667465 TI - [Epidemiology of diabetic microangiopathy in Japan--comparison with Western countries]. PMID- 21667466 TI - [Early predictors of microvascular complications in diabetes]. PMID- 21667467 TI - [Oxidative stress and endoplasmic reticulum stress]. PMID- 21667468 TI - [Protein kinase C activation]. PMID- 21667469 TI - [Role of cytokines in diabetic microangiopathy]. PMID- 21667470 TI - [The outlines of JEDIS-2, the new version of Japan Early Diabetes Intervension Study (JEDIS)]. PMID- 21667471 TI - [Japan Diabetes Outcome Intervention Trial 3]. PMID- 21667472 TI - [Kumamoto Study]. PMID- 21667474 TI - [EDIC(1) study]. PMID- 21667475 TI - [The impact of strict glycemic control on diabetic microangiopathy]. PMID- 21667476 TI - [Aldose reductase inhibitor]. PMID- 21667477 TI - [Renin-angiotensin blockades]. PMID- 21667478 TI - [Present status of pancreas transplantation]. PMID- 21667479 TI - [Disorder concept and symptomatology of diabetic retinopathy]. PMID- 21667480 TI - [Epidemiology of diabetic retinopathy]. PMID- 21667481 TI - [Pathology of diabetic retinopathy]. PMID- 21667482 TI - [Retinal-blood barrier]. PMID- 21667483 TI - [Vascular endothelial growth factor (VEGF)]. PMID- 21667484 TI - [Renin-angiotensin system]. PMID- 21667485 TI - [Retinal function evaluated by electroretinogram in diabetic retinopathy]. PMID- 21667486 TI - [Roles of ROCK in diabetic microangiopathy]. PMID- 21667487 TI - [Surgical treatment for eyes with diabetic macular edema]. PMID- 21667488 TI - [Visual prosthesis for diabetic retinopathy]. PMID- 21667489 TI - [Diabetic retinopathy and cardiovascular events]. PMID- 21667490 TI - [Pathology of diabetic nephropathy]. PMID- 21667492 TI - [The role of pro-angiogenic factors and angiogenesis inhibitors in diabetic nephropathy]. PMID- 21667491 TI - [Hyperfiltration]. PMID- 21667493 TI - [Microalbuminuria]. PMID- 21667494 TI - [Urinary liver type fatty acid binding protein (L-FABP)]. PMID- 21667495 TI - [Transferrin]. PMID- 21667496 TI - [Type IV collagen: structure, function, and its clinical significance]. PMID- 21667497 TI - [Cystatin C]. PMID- 21667498 TI - [Pentosidine]. PMID- 21667499 TI - [INNOVATION study]. PMID- 21667500 TI - [Treatment strategies according to the stage of diabetic nephropathy]. PMID- 21667501 TI - [(Pro)renin receptor blockers]. PMID- 21667502 TI - [How to use the drugs for diabetes patients with renal insufficiency]. PMID- 21667503 TI - [Medical nutrition for diabetic nephropathy]. PMID- 21667504 TI - [Physical exercise for the patients with diabetic microangiopathy]. PMID- 21667505 TI - [Smoking cessation]. PMID- 21667506 TI - [Current status and future sights in the dialysis therapy]. PMID- 21667507 TI - [Kidney transplantation for diabetic nephropathy]. PMID- 21667508 TI - [Clinical concept and symptomatology of diabetic neuropathy]. PMID- 21667510 TI - [Susceptibility genes for diabetic neuropathy]. PMID- 21667509 TI - [Abbreviated diagnostic criteria for diabetic polyneuropathy]. PMID- 21667511 TI - [Metabolic factors in the pathogenesis of diabetic neuropathy]. PMID- 21667512 TI - [Cytokine role in diabetic neuropathy]. PMID- 21667514 TI - [Diabetic polyneuropathy]. PMID- 21667513 TI - [Vascular endothelial function]. PMID- 21667515 TI - [Sensory disturbance in diabetic neuropathies]. PMID- 21667516 TI - [Autonomic nervous disorder]. PMID- 21667517 TI - [Motor skills disorder]. PMID- 21667518 TI - [Nerve function studies]. PMID- 21667519 TI - [Sensory function test]. PMID- 21667521 TI - [Painful neuropathy of diabetes]. PMID- 21667520 TI - [Diagnostic tests of gastrointestinal tract in diabetics]. PMID- 21667522 TI - [Cell transplantation therapy for diabetic neuropathy]. PMID- 21667523 TI - [Schwann cell cultures for studying peripheral nerve disorders]. PMID- 21667525 TI - Revived interest in bacteriophages. PMID- 21667524 TI - [Impairment of digestive function in diabetes]. PMID- 21667526 TI - Nancy Knowlton. PMID- 21667527 TI - [Abstracts of French Language Days of Neurology 2011. April 26-28, 2011. Paris, France]. PMID- 21667529 TI - Vitiligo: a review of the published work. AB - Vitiligo is a common depigmenting skin disorder, characterized by acquired, idiopathic, progressive, circumscribed hypomelanosis of the skin and hair, with total absence of melanocytes microscopically. It occurs worldwide, with an incidence rate of between 0.1% and 2%. Vitiligo is an important skin disease having a major impact on the quality of life of the patient suffering from it. The causes of this condition are uncertain but seem to be dependent on the interaction of genetic, immunological and neurological factors. Vitiligo coexists with other autoimmune disorders, Sutton or halo nevus, and malignant melanoma. The substantial disfigurement associated with vitiligo can cause serious emotional stress for the patient, which necessitates treatment. Because its pathogenesis is still not understood, there is a plethora of different treatments. Among them, topical steroids and narrowband ultraviolet B monotherapy were the most common as current treatments for localized and generalized vitiligo, respectively. Cosmetic improvement can be achieved by camouflage products and self-tanning dyes. The course of vitiligo is unpredictable, but often progressive. Spontaneous repigmentation may occur in a few people (10-20%), mainly in children, but this tends to be only partial and on sun-exposed areas. In this article, we review vitiligo as a whole, including epidemiology, pathogenesis and etiology, histopathology, clinical manifestations, classification, clinical variants, diagnosis and differential diagnoses, specific investigation, treatment, prognosis, psychosocial view and its association with other disorders. PMID- 21667528 TI - Collagen triple helix repeat containing-1 inhibits transforming growth factor-b1 induced collagen type I expression in keloid. AB - BACKGROUND: Keloids are benign skin tumours occurring during wound healing in genetically predisposed patients. There is evidence that transforming growth factor (TGF)-b is involved in keloid formation. Collagen triple helix repeat containing- 1 (Cthrc1) was identified as a novel gene expressed in the adventitia and neointima on arterial injury. It is indicated to be a cell type-specific inhibitor of TGF-b, which functionally increases cell migration while reducing collagen type I and III deposition. However, to our knowledge expression and regulatory mechanisms of Cthrc1 and TGF-b1 in keloid and normal skin have not been studied before. OBJECTIVES: Cthrc1 gene regulation and potential role in keloid formation were determined, and its correlation with TGF-b1 involved in keloid pathogenesis was examined in human fibroblasts of keloids and normal skin. METHODS: The expression of Cthrc1 and TGF-b1 was investigated in fibroblasts of keloid and normal skin. Collagen type I expression and collagen synthesis in keloid fibroblasts induced by TGF-b1 were examined. Then, recombinant Cthrc1 was applied to assess its correlation with TGF-b1. RESULTS: Increased TGF-b1 and Cthrc1 expression was examined in keloid compared with normal skin. Cthrc1 expression increased in a concentration-dependent manner induced by TGF-b1 in keloid fibroblasts. TGF-b1 stimulated collagen type I expression and collagen synthesis in keloid fibroblasts, which can be reversed by recombinant Cthrc1. CONCLUSIONS: TGF-b1 was upregulated in keloid fibroblasts and recombinant Cthrc1 inhibited TGF-b1-stimulated collagen type I synthesis, which suggests that Cthrc1 may be a potential therapeutic option for keloids. PMID- 21667530 TI - Cystic acne successfully treated with diaminodiphenylsulfone. PMID- 21667531 TI - C-myc expression in the microvessels of medulloblastoma. AB - The increased expression of c-myc is related to neoplastic transformation and angiogenesis. Therefore, the assessment of expression of c-myc in endothelial cells and neovascularization could help to determine the biological behavior of the tumor. We analyzed neovascularization and c-myc expression in 36 medulloblastoma specimens. The results were shown by determining immunohistochemical staining index (ISI), the sum of staining intensity (SI) and the percentage of positive cells (PPC) in the blood vessels endothelium of the tumor. We also performed the microvessel count (MVC) in 10 high-power fields (400X) with the most prominent vascularization and expressed it as microvessel density per mm2 (MVD). C-myc immunostaining intensity index in blood vessel endothelium is grouped into four groups, 0--no reaction, I-weak reaction (ISI = 1 or 2), II--moderate reaction (ISI = 3 or 4), III--strong reaction (ISI = 5 or 6). Statistically significant differences (p = 0.0214) have been found between groups 0 and 1 compared to groups 2 and 3. A higher percentage of positive cells has been found in male patients than in female ones (p = 0.0483). C-myc PPC 0 or 1 has on the average smaller density of blood vessels per mm2 than c-myc PPC 2 or 3, but the difference is not statistically significant. C-myc ISI 0 or 1 has, on the average, smaller density of blood vessels per mm2 than c-myc ISI 2 or 3, but the difference is not statistically significant. We concluded that c-myc staining intensity was associated with higher microvessels density. PMID- 21667532 TI - Hypocone reduction and Carabelli's traits in contemporary Jordanians and the association between Carabelli's trait and the dimensions of the maxillary first permanent molar. AB - The objective of this study is to determine the prevalence of expression and bilateralism of two dental morphological traits in contemporary Jordanians: The hypocone reduction trait on the maxillary second permanent molar and Carabelli's trait on maxillary permanent first and second molars. Furthermore, inter-trait correlation and the relationship of Carabelli's traits with upper first molar dimensions were investigated. Three hundred subjects of school children at their 10th grade and of an average age of 15.5 +/- 0.4 years were involved. Alginate impressions for the maxillary arch were taken, dental casts were reproduced. The selected accurate casts were of 132 male- and 155 female-students. The frequencies of hypocone reduction trait on the maxillary second molar and Carabelli's trait on the maxillary molars were examined. Buccolingual and mesiodistal diameters of the maxillary first molar were measured and recorded. Paired Sample t test and Nonparametric Correlation analysis were used for data analysis. Hypocone reduction trait on the maxillary second molar was found in 29.8% of the examined students. Positive forms of Carabelli's trait on first and second molars were observed in 65.0% and 3.8%, respectively. Nonparametric correlation analysis revealed positive association between Carabelli's trait on first molar and hypocone reduction trait on the maxillary second molar. The presence of Carabelli's trait on first molar was strongly associated with the increase of buccolingual, but not the mesiodistal, diameter. Bilateralism was found highly significant in the tested traits and both genders (p < 0.001). This finding might be a sign of relatively low environmental stresses in the living Jordanian population and/or great ability of its individuals to buffer the adverse effects of such stresses. PMID- 21667533 TI - Lead concentrations in teeth from people living in Kosovo and Austria. AB - The objective of this study was to compare lead concentrations in 86 human permanent teeth extracted from residents of three different geographical regions. The study included 31 permanent teeth from residents of Mitrovica (Kosovo), 32 from Klina (Kosovo) and 23 from Graz (Austria). The concentrations of lead were measured using Agilent 7500c inductively coupled plasma mass spectrometer (ICP MS) (Agilent, Waldbronn, Germany). The comparisons between groups were based on the geographic area, age and gender. The highest lead level was found in teeth extracted from Mitrovica residents (22.3 mg/kg), followed by Klina (3.2 mg/kg), and Graz (1.7 mg/kg). Lead levels in teeth from Mitrovica residents are significantly higher (p < 0.0001) than in other two groups, possibly due to environmental contamination with lead. Overall results in this study support the concept that tooth lead level may present an important indicator in evaluating environmental exposure of human population to heavy metals. PMID- 21667534 TI - The etiological relation between serum iron level and infection incidence in hemodialysis uremic patients. AB - Through the treatment of anaemia in dialysis patients part of the iron ions remain free in the serum which is at the bacterias disposal for growth and the strengthening of their virulence. The linear relation of the increased serum iron level and tissue iron stores in the body and the infection incidence in dialysed patients has become more emphasised. The need of a clearly defined upper threshold of the serum iron concentration limit has been mentioned in scientific journals intensely, and consequently the demand for more precise professional instructions for anaemia treatment. For the purpose of participating in these professional and scientific discussions, we have observed the relation between the iron overload of the organism and complication incidence in 120 of our haemodialysis uremic patients, with special emphasis on infections. It has been established that the sepses incidence is much higher in patients with a serum ferritin concentration above 500 microg/L, than in those patients with a ferritin level lower than the mentioned value ( 2 = 7.857, p = 0.005). The incidence of vascular access infection is significantly higher in those patients with a serum ferritin level above 500 microg/L than in those patients with a ferritin level lower than the mentioned value (Chi2 = 23.186, p = 0.001). Furthermore, it has been determined that the incidence of total infection in patients is 3.8 episodes per 100 patients months, which is in accordance to the referral values of other authors. CONCLUSION--In the analysis of the achieved results, it has been determined that the infection incidence is significantly higher in dialysed patients with a serum iron level higher than 500 g/L, than in those patients with lower values. PMID- 21667535 TI - The physicians and surgeons of Koper from the 14th to the 17th century. AB - Koper stands out among Istrian towns of the nordeastern Adriatic coast for its highly advanced medicine. Communal service developed between the 13th and 15th century. Beside the hospital, almshouse and a quarantine, the city also boasted highly trained physicians, surgeons and barbers. Trade, crafts and navigation prospered and numerous town intellectuals established an academy whose most active members were medical doctors. The aim of this article is to give a chronological presentation of physicians related to Koper by their birth or work and of other scientists who contributed to the development of local medicine. These includes (about forty names) S. Santorio, Ser Benvenuto, P P. Vergerio, G. Nuzio, E Nuzio, P de Castaldi, I. de Albertis, L. Zarotti, B. Petronio, I. Bratti, Z. Zarotti, A.Valdera, G. Vergerio and C. Zarotti of whom some are well known. The author wishes to systematisize the bibliography, fill the gaps and show ways for further research in the archives and museums of Istria, Triest, Venice and Vienna. PMID- 21667536 TI - Predicted coronary heart disease risk in croatian HIV infected patients treated with combination antiretroviral therapy. AB - We assessed the coronary heart disease (CHD) risk in 130 HIV-infected patients with no major past cardiovascular event treated with combination antiretroviral therapy (CART) between May 2004 and June 2005. We also investigated the association of HIV disease parameters (CD4 + T-cell counts, HIV viral load, AIDS diagnosis, antiretroviral medications and lipodystrophy), demographics, anthropometrics, clinical features, smoking status, dyslipidemia, adherence to the Mediterranean diet, and the metabolic syndrome (MS) to the Framingham risk score. The median 10-year CHD risk was 6.4% (IQR 3.3-13.0) for males and 1.8% (IQR 1.0-6.7) for females. The CHD risk was > or = 10% in 31.1% (32 of 103) males and in 14.8% (4 of 27) females. MS was present in 27 (20.8%) individuals. Participants who met the definition of the MS had a 2.63 times greater chance of having a CHD risk 210% (95% CI, 1.09-6.39; p = 0.032). On multivariable analysis, we found that a CHD risk > or = 10% was associated with: a lowest ever CD4+ T cell counts of less than 50 per microliter and a past history of AIDS (OR, 6.26; 95% CI, 1.61-24.36; p = 0.008); alcohol consumption 210 g/day (OR, 3.87; 95% CI, 1.56-14.22; p = 0.041); and age 243 years (OR, 1.30; 95% CI, 1.17-1.45; p < 0.001). Interventions to reduce the modifiable cardiovascular risk are needed in Croatian patients treated with CART PMID- 21667537 TI - Body size changes in elite junior rowers: 1997 to 2007. AB - The aim of this study was to determine whether elite international junior rowers in 2007 were heavier and taller than those evaluated in 1997, and to compare this change among finalists and non-finalists, and sweep rowers and scullers. Body weight and height data obtained by a questionnaire from a total of 398 rowers (42% female, 58% male) at the Junior World Rowing Championships in Beijing, People's Republic of China, in 2007 (65.9% of all competitors), were compared with data from 603 rowers measured at the Junior World Rowing Championships in Hazewinkel, Belgium in 1997 (36.5% female, 63.5% male, representing 90% and 89% of all competitors, respectively, by gender). Male and female rowers in 2007 were significantly taller compared to those in 1997 (1.0 cm, p = 0.009 and 2.1 cm, p < 0.001, respectively; one-sample t-test). No statistically significant difference was found for body mass. The finalists and sweep rowers were taller and heavier compared to nonfinalists and scullers at both Championships respectively. The heights of elite level junior rowers increased significantly over the decade. The finalists at World Junior Rowing Championships were again taller and heavier compared to the nonfinalists. PMID- 21667538 TI - Pain relieve after impacted wisdom teeth extraction dependent on the drug therapy. AB - Purpose of this study was to compare the effects of combined therapy using nonsteroid anti-inflammatory analgetics and corticosteroids, and the effects of the mono-therapy with same drugs for post-operative pain after surgical removal of the impacted mandibular third molar. The study was completed at the Department of Oral Surgery and at the Department of Dental Medicine of the Public Institute Health Center Zenica in Zenica. The research included 60 patients divided into 3 groups using random selection, including both sexes. Age range was between 18 and 45 years. All participants came without any pain or other inflammatory symptoms at the time of oral surgical intervention. Two medicaments were prescribed after the impacted tooth removal: 15 mg of nonsteroid anti-inflammatory analgesic drug (Meloxicam, Bosnalijek, BiH) and 32 mg Methylprednisolone (corticosteroid, Bosnalijek, BiH). Both medicaments were applied per os, according to schedule determined by the research protocol. The level of post-surgical pain was evaluated by the 1-10 visual analog scale (VAS). One way ANOVA was made with Tuckey post-hoc tests. Statistically significant difference (p < 0.05) was found between the group treated with mono therapy and the group treated with combined therapy. Application of monotherapy using only corticosteroids or only nonsteroid anti-inflammatory pain-killers was less effective compared to the combined therapy with both medicaments after surgical removal of the impacted mandibular third molar. PMID- 21667539 TI - Biphasic and monophasic pattern of brain natriuretic peptide release in acute myocardial infarction. AB - This study evaluated brain natriuretic peptide (BNP) release in acute myocardial infarction (AMI), absolute values as well as pattern of its release. There are two different patterns of BNP release in AMI; monophasic pattern--concentration in the first measurement is higher than in the second one, and biphasic pattern- concentration in the first measurement is lower than in the second one. We observed significance of biphasic and monophasic pattern of BNP release related to diagnostic and prognostic value. We included in this prospective observational study total of 75 AMI patients, 52 males and 23 females, average age of 62.3 +/- 10.9 years with range of 42 to 79 years. BNP was measured and pattern of its release was evaluated. In AMI group BNP levels were significantly higher than in controls (462.88 pg/mL vs. 35.36 pg/mL, p < 0.001). We found statistically significant real negative correlation (p < 0.05) between BNP concentration and left ventricle ejection fraction (LVEF) with high correlation coefficient (r = 0.684). BNP concentrations were significantly higher among patients in Killip class II and III compared to Killip class I; Killip class I BNP = 226.18 pg/mL vs. Killip class II 622.51 pg/mL vs. Killip class III 1530.28 pg/mL, p < 0.001. BNP concentrations were significantly higher in patients with; (i) myocardial infarction vs. controls; (BNP 835.80 pg/mL vs. 243.03 pg/mL); (ii) in pts with positive major adverse cardiac events (MACE) vs. negative MACE (BNP 779.08 pg/mL vs. 242.28 pg/mL, p < 0.001); (iii) in pts with positive compared to negative left ventricle (LV) remodelling (BNP 840.77 pg/mL vs. 341.41 pg/mL, p < 0.001). Group with biphasic pattern of BNP release had significantly higher BNP concentration compared to monophasic pattern group. In biphasic pattern group we found significant presence of lower LVEF, Killip class II and III, LV remodelling and MACE. We found that BNP is strong marker of adverse cardiac events in patients presenting with a myocardial infarction. In our AMI group we found significant elevation of BNP and it is suspected that second peak secretion is not only due to systolic dysfunction and subsequent remodeling of LV but also due to impact of ischaemia. Patients with biphasic pattern probably have worse prognosis due to severe coronary heart disease. Besides its diagnostic role as a simple blood marker of systolic function, BNP is also important prognostic marker who helps making clinical decision about early invasive vs. conservative management. PMID- 21667540 TI - The "round block" surgical technique in the management of multicentric fibroadenomas. AB - The "round block" surgical technique in the treatment of a female patient with multiple, multicentric fibroadenomas in both breasts is presented. The advantages of this technique for patients with multicentric benign breast lesions are minimal postoperative scar and a favourable aesthetic result. Breast dimensions and the areolar diameter were measured in 203 subjects of Primorsko-Goranska county during examination in the Out-Patient Hospital for Breast Diseases, including the operated patient. Smaller breast dimensions and a larger areolar diameter provide an easier access to any part of the breast due to a smaller distance between the incision and a fibroadenoma and a larger circumference of circular periareolar incision, thus facilitating the surgery. The analysis of average, maximum and minimum values measured shows that the "round block" technique can be performed in all cases of multiple and multicentric fibroadenomas regardless of breast size, areolar diameter and the location of fibroadenoma in the breast. PMID- 21667541 TI - A century of antivenom. AB - Because it primarily affects the poor in undeveloped parts of the world where medical care is often inadequate and insufficient, envenomation is considered a neglected public health issue, despite the existence of antivenom therapy for more than a century. This article provides an overview of the epidemiological situation for important venomous animals, together with achievements in the production, control, technological progress and safety of antivenoms since their discovery. PMID- 21667542 TI - Body composition variations in ageing. AB - Age-related physiological variations of body composition concern both the fat free mass (FFM) and the fat mass (FM). These variations expose the elderly person to the risk of malnutrition and could lead to conditions of disability. This paper aims to review the current state of knowledge on body composition in the aged population. The pattern of qualitative variations in body composition in old age is fairly well defined. In adulthood, the physiological variation of body mass involves a first increasing phase followed by a decreasing trend. The reduction is due mainly to the loss of fat-free mass, especially muscle mass. Total body water and bone mass also decrease. Fat mass tends to decrease and the reduction seems to be due mainly to the loss of subcutaneous fat. The quantitative aspects of the age of onset, rate and intensity of the physiological variations are still not completely clear. This poor quantitative definition is due to the variable and multifactorial phenomenology of ageing, the heterogeneity of assessment techniques and sampling models, and the limited number of empirical observations in oldest-old individuals. PMID- 21667543 TI - Inequalities in dental services utilization among Brazilian low-income children: the role of individual determinants. AB - OBJECTIVES: To assess the role of the individual determinants on the inequalities of dental services utilization among low-income children living in the working area of Brazilian's federal Primary Health Care program, which is called Family Health Program (FHP), in a big city in Southern Brazil. METHODS: A cross sectional population-based study was performed. The sample included 350 children, ages 0 to 14 years, whose parents answered a questionnaire about their socioeconomic conditions, perceived needs, oral hygiene habits, and access to dental services. The data analysis was performed according to a conceptual framework based on Andersen's behavioral model of health services use. Multivariate models of logistic regression analysis instructed the hypothesis on covariates for never having had a dental visit. RESULTS: Thirty one percent of the surveyed children had never had a dental visit. In the bivariate analysis, higher proportion of children who had never had a dental visit was found among the very young, those with inadequate oral hygiene habits, those without perceived need of dental care, and those whose family homes were under absent ownership. The mechanisms of social support showed to be important enabling factors: children attending schools/kindergartens and being regularly monitored by the FHP teams had higher odds of having gone to the dentist, even after adjusting for socioeconomic, demographic, and need variables. CONCLUSIONS: The conceptual framework has confirmed the presence of social and psychosocial inequalities on the utilization pattern of dental services for low-income children. The individual determinants seem to be important predictors of access. PMID- 21667544 TI - Overview and quality assurance for the oral health component of the National Health and Nutrition Examination Survey (NHANES), 2005-08. AB - The oral health component for the National Health and Nutrition Examination Survey (NHANES) was changed in 2005 from an examination conducted by dentists to an oral health screening conducted by health technologists rather than dental professionals. The oral health screening included a person-based assessment for dental caries, restorations, and sealants. This report provides oral health content information and presents results of data quality analyses that include dental examiner reliability statistics for data collected during NHANES 2005-08. Oral health data are available on 15,342 persons aged 5 years and older representing the civilian, noninstitutionalized population of the United States who participated in NHANES 2005-08. Overall, interrater reliability findings indicate that health technologist performance was excellent with concordance between examination teams and the survey reference examiner being almost perfect for a number of assessments. Concordance for dental caries and sealants (kappa statistics) between health technologists and the survey reference examiner ranged from 0.82 to 0.90 for the combined 4-year period. These findings support the use of health technologists in the assessment of person-based estimators of dental caries and sealant prevalence as part of an oral health surveillance system. PMID- 21667545 TI - Much to be gained by volunteering. PMID- 21667547 TI - Parental leave. PMID- 21667546 TI - More support needed for clinical placements. PMID- 21667548 TI - Patient-centred care--not an optional extra! PMID- 21667549 TI - Proximal plantar fibroma as an etiology of recalcitrant plantar heel pain. AB - Prompted by repeated pathology reports of fibromas at the origin of the plantar fascia after fasciectomy for chronic plantar heel pain, this study examines the incidence of proximal plantar fibroma. A retrospective study of 101 pathology specimens from 97 patients with the preoperative diagnosis of recalcitrant plantar fasciitis was performed. Patients ranged in age from 36 to 82, and included 30 males and 67 females. The specimens consisted of medial and central bands of the fascia obtained from transverse plantar fasciectomies. The fasciectomies were performed between July 1994 and March 2008. One quarter of the cases studied had a histological appearance of plantar fibroma. This new finding has not been reported in any literature in connection with recalcitrant heel pain. Histologic findings of the specimens were placed into 3 groups: neoplastic involvement (25%, 21 female and 6 male), inflammation without neoplastic involvement (21%, 13 female and 6 male), and other, which consisted of having no inflammatory or neoplastic response (54%, 32 female and 19 male). All of the patients failed a 3- to 6-month conservative treatment regimen, which included anti-inflammatory medication, modification of activities, injection of corticosteroids, night splints, custom molded orthotics, and physical therapy. Only 4 patients underwent bilateral plantar fasciectomies. No patient required a revisional procedure. The authors conclude that 25% of recalcitrant heel pain is neoplastic in origin, and that patients presenting with these lesions require excision and not fasciotomy. PMID- 21667551 TI - [From reflux to irritable bowel syndrome: hot topics from gastroenterology]. PMID- 21667550 TI - [Patient never saw a doctor - what was hidden under the handkerchiefs]. PMID- 21667552 TI - [Early diagnosis and modern medications make it possible: good and long survival with HIV]. PMID- 21667553 TI - [Autopsy: BAK persists with minimum compensation: payment is an insult]. PMID- 21667554 TI - [Anticoagulation for patients with atrial fibrillation. Two out of three strokes can be prevented]. PMID- 21667555 TI - [Diagnosis of thromboembolic risk in patients with atrial fibrillation]. PMID- 21667556 TI - [Current and future therapies for prophylaxis of thromboembolism in atrial fibrillation]. PMID- 21667557 TI - [Sudden onset of cold leg]. PMID- 21667558 TI - [Phytotherapy for psychosomatic diseases]. PMID- 21667559 TI - [Treatment of migrants with diabetes]. PMID- 21667560 TI - [Diabetic complications: good metabolic control protects]. PMID- 21667561 TI - [Soft tissue grafts for the treatment of mucogingival deformities and conditions on edentulous ridges]. AB - Soft tissue grafts are commonly used to restore and/or improve mucogingival deformities and conditions around teeth or on edentulous ridges. This include vertical and/or horizontal ridge deficiency, lack of gingiva/keratinized tissue, decreased vestibular depth and abnormal color. The present article describes and illustrates different procedures using autologous soft tissue grafts including masticatory mucosal free graft, masticatory mucosal pedicle graft, subepithelial free connective tissue graft, and subepithelial dermal graft. The functional and esthetic advantages and limitations of each graft for each condition are discussed. PMID- 21667562 TI - [Clinical dilemmas concerning immediate implants in the esthetic zone]. AB - Teeth replacement in the esthetic zone is a considerable challenge. Dental implants are usually the preferred treatment alternative for tooth replacement. The present review discusses several clinical issues concerning implant placement in the esthetic area. It is still unclear whether raising a flap at the time of implant placement enhances alveolar crest remodeling. However, a flapless surgical procedure could avoid changes in the free gingival margin and maintain the the attached gingiva width. A submarginal approach not involving the free gingival margin can be applied to treat bone defects with the GBR technique. Implants should be placed as palatal as possible while maintaining optimal restoration emergence profile and the horizontal bone defect filled with a non resorbable material such as bovine bone mineral. Thick periodontal biotype and coronally positioned free gingival margin usually lead to better results. Immediate implant placement in presence of a periapical lesion may be performed, however, sites should be thoroughly debrided prior to implant placement. PMID- 21667563 TI - [From an immediate implant placement in the post-extraction phase towards immediate loading application: current status]. AB - The fresh extraction socket site in the immediate post-extraction phase possesses unique characteristic wound healing cascade. Marked horizontal and vertical resorption of the edentulous ridge occurred shortly following tooth extraction. In periodontally involved teeth, when partial/full socket wall destruction is evident, the ingrowth of connective tissue into the extraction site is unavoidable leading to a deficient ridge. The use of bone substitute materials aiming to preserve the alveolar ridge by stabilizing the blood clot, thus maintaining the volume of the site and at the same time serves as an osteoconductive scaffold which facilitates continual bone formation. immediate Implant placement, is also a reliable, predictable, and successful procedure. Comparative studies regarding immediate implant placement vs. delayed placement (healed sites) reported similar high survival rate for both procedures. The addition of nonfunctional immediate provisionalization (clearance of all contacts in centric occlusion and during eccentric movements to avoid full functional loading of the implant during healing) achieving an instant aesthetic solution, has been shown to have predictable results. However, a meticulous surgical protocol should be followed. In recent years, an immediate functional loading of cross-arch splinted implants proved to be a reliable and successful approach. Moreover evidence-based data comparing immediate, early and delayed loading failed to show significant difference between those treatment modalities. Apparently, primary stability of implants is an important factor in achieving predictable success. It seems that the addition of controlled loading did not impair those results. A systematic review of the current literature related to this procedure showed a survival rate of over 95% in 34 prospective/retrospective studies. Since clinical parameters were proved to be equal whether implants were placed immediate post-extraction or delayed in a healed alveolar ridge, it appears that cross-arch immediate loading of implants placed in extraction and/or healed edentulous ridges is a predictable procedure with long term stability of the results. PMID- 21667564 TI - [Split crest to enlarge horizontal dimension of alveolar ridge. an overview of techniques and case demonstration]. AB - Restoration of the edentulous alveolar ridge with dental implants often requires the ridge width to be augmented in order to allow its placement. Technique of splitting the alveolar ridge aimed to enlarge its horizontal dimension is achieved by using different osseous surgical tools to allow simultaneous or staged placement of dental implants. Treatment of the thin alveolar ridge can be carried out predictably using ridge expansion technique. Good esthetic and functional outcomes can be achieved predictably as long as the surgical principles and protocols are followed carefully. A short literature overview of split crest techniques and a case presentation is included in this article. PMID- 21667565 TI - [The use of subepithelial connective tissue as a biological barrier]. AB - Bone regeneration may be enhanced when invasion of soft tissue into osseous defect is mechanically impeded by barrier membrane. Several studies have reported successful clinical outcomes for regenerative treatment of intrabony and furcation defects following use of free subepithelial connective tissue graft (SCTG) as biological barrier membrane. The current study introduces the use of SCTG as a barrier in following clinical situations: (1) Guided bone regeneration (GBR) of peri-implant bone lost due to early spontaneous exposure of submerged implants (2) Socket preservation combined with ridge augmentation (3) Guided tissue regeneration (GTR) of periodontal circumferential intrabony defect. Each of the above indication is presented to the reader by description in details of clinical cases in which SCTG was applied. PMID- 21667566 TI - [Buccal bony exostoses induced by free gingival grafts]. AB - Buccal Bony Exostoses (BBE) is a local benign osseous overgrowth continuous with the facial aspect of the jaw. Post operative BBE may be the result of dermal grafts used to restore the buccal vestibulum, of connective tissue graft placement, and of Free Gingival Grafts (FGG) procedures. In 46 patients in whom 72 FGG procedures were performed by the senior author (HT) over the past 12 years, BBE was clinically and radiographically diagnosed. In one case the tumor was surgically removed. The etiology, pathogenesis and frequency of BBE following FGG procedures was reviewed and discussed. We suggest that the BBE may develop owing to periosteal surgical trauma during FGG procedures, and suggest that this phenomenon receives further attention. PMID- 21667567 TI - [Guidelines for the treatment of gastroesophageal reflux disease]. PMID- 21667568 TI - Value-based dentistry: will it provide the best care for our patients' needs? PMID- 21667569 TI - Rice, Beans, heath, education: Public Health Policy in Brazil. PMID- 21667570 TI - Retraction notice to "Quantitative role of p42/44 and p38 in the production and regulation of cytokines TNF-alpha, IL-1beta and IL-12 by murine peritoneal macrophages in vitro by Concanavalin A" [Cytokine 2007;37:62-70] PMID- 21667571 TI - [About the NMDA-system again]. PMID- 21667572 TI - A bad trip: lawmakers try to stay one step ahead of the chemists manufacturing dangerous synthetic drugs. PMID- 21667573 TI - Regulating the medical loss ratio: implications for the individual market. PMID- 21667574 TI - A review of the evidence on hospital cost-shifting. PMID- 21667575 TI - Can you get what you pay for? Pay-for-performance and the quality of healthcare providers. AB - Despite the popularity of pay-for-performance (P4P) among health policymakers and private insurers as a tool for improving quality of care, there is little empirical basis for its effectiveness. We use data from published performance reports of physician medical groups contracting with a large network HMO to compare clinical quality before and after the implementation of P4P, relative to a control group. We consider the effect of P4P on both rewarded and unrewarded dimensions of quality. In the end, we fail to find evidence that a large P4P initiative either resulted in major improvement in quality or notable disruption in care. PMID- 21667577 TI - The language of modern nursing. PMID- 21667576 TI - [A cell-based detection of ciguatoxin using sodium fluorescence probe]. AB - OBJECTIVE: To establish a cell-based detection method of ciguatoxin using fluorescence assay. METHODS: Mouse neuroblastoma N-2A cells were exposed to ouabain and veratridine and different concentrations of standard ciguatoxin samples (P-CTX-1) to establish the curvilinear relationship between the toxin dosage and fluorescence intensity using the sodium fluorescence probe CoroNaTM Green. The toxicity curvilinear relationship was also generated between the toxin dosage and cell survival using CCK-8 method. Based on these standard curves, the presence of ciguatoxin was detected in 33 samples of deep-sea coral fish. RESULTS: A correlation was found between the detection results of cell-based fluorescence assay and cytotoxicity assay, whose detection limit reached 103 g/ml and 1012 g/ml, respectively. The cell-based fluorescent assay sensitivity showed a higher sensitivity than cytotoxicity assay with a 2-4 h reduction of the detection time. CONCLUSIONS: The cell-based fluorescent assay can quickly and sensitively detect ciguatoxin and may serve as a good option for preliminary screening of the toxin. PMID- 21667578 TI - Neonatal care pathway helps structure an end of life plan. PMID- 21667579 TI - Variations in practice for allergies increase allure of the high street. PMID- 21667580 TI - Developing information leaflets for parents of children with cancer. AB - Information aids parents' understanding of and adjustment to their child's disease and treatment, and their ability to care for their child safely at home. This article describes the development of a leaflet on conditions, treatments, side effects, management advice and contacts for parents of children receiving treatment for cancer using an Ommaya reservoir. Health professionals should be aware of developments in health care, to ensure that current evidence-based information for families is provided. PMID- 21667581 TI - Improving statutory health assessments for looked after children. AB - The aim of the change project described in this article was to improve the service provision of statutory health assessments for looked after children in the children's services department of a local authority in London. These children and young people are some of the most vulnerable in the UK, with many associated health needs and poor outcomes. Statute dictates they undergo a series of health assessments, but how this service is provided differs from borough to borough. The change process was led by a change agent and was based on change theory. It resulted in an effective referral system, with an increase of 93 per cent in the number of referrals received. Ongoing evaluation allows for continued development and improvement of the service. The changes have gone some way towards ensuring the health needs of this group are being better addressed by those who are accountable. PMID- 21667582 TI - Legal definitions of responsibility, accountability and liability. AB - The purpose of this article is to legally define the terms responsibility, accountability and liability. The connection between these terms for registered children's nurses, students and healthcare support workers are discussed, along with the implications for professional practice. PMID- 21667583 TI - Clinical features, psychological issues and management of constipation in childhood. AB - This article provides a basic introduction to constipation and stool withholding. Anatomy and physiology, psychology and the various treatment options, including fluid, fibre and laxatives, are covered. PMID- 21667584 TI - Pitfalls in full mouth implant dentistry, part one. PMID- 21667585 TI - All in an extra day's work. PMID- 21667587 TI - Incidence of significant findings on CBCT scans of an orthodontic patient population. PMID- 21667588 TI - A sustainable future: the 2011 MDA president's interview. PMID- 21667590 TI - James R. Jensen, Sr.: a life well lived. PMID- 21667591 TI - The Minnesota Prescription Monitoring Program. AB - We must keep in mind that health care professionals practice in an environment of legal and regulatory influences, where some patients with pain also have an addictive disease. As dentists routinely manage acute oral and dental pain by pharmacological means, people who abuse prescription medications see dentists as easy targets to "score" prescription opioids and controlled substances. This potential for deception must be balanced with our professional responsibility to prescribe and dispense controlled substances appropriately, guarding against abuse while ensuring that patients have medication available when appropriate and necessary. However, dentists also have a personal responsibility to protect themselves and their practices from becoming easy targets for drug abuse and diversion. Becoming aware of the potential signs and symptoms of drug seeking behavior and recognizing the signs of controlled substance misuse will safeguard patients, practices, and practitioners. Utilizing the services of the Minnesota Prescription Monitoring Program may help to not only improve patient care, but to facilitate appropriate pain management and help identify patients having drug seeking behaviors PMID- 21667592 TI - Pitfalls in full mouth implant dentistry. Part two: Effectively communicating costs and outcomes as a patient advocate in prosthodontic treatment planning. PMID- 21667593 TI - What's a dentist to do? The hand in the cookie jar. PMID- 21667594 TI - Brain waves and the era of cosmetic neurology. PMID- 21667595 TI - A tale of two stricken cities. PMID- 21667596 TI - Giving thought to primary care. PMID- 21667597 TI - Asymptomatic carotid stenosis: screening and management. PMID- 21667599 TI - Osteoporosis: screening, evaluation, and monitoring. PMID- 21667598 TI - Gastroesophageal reflux disease: endoscopy, duration of treatment, and choice of PPI. PMID- 21667600 TI - Venous thromboembolism: duration, IVC filters, and hypercoagulable workup. PMID- 21667601 TI - Acute low back pain: imaging, treatment, and referral. PMID- 21667602 TI - Electroconvulsive therapy in older adults. PMID- 21667603 TI - Sexual behavior and contraceptive use among Rhode Island adolescents. PMID- 21667604 TI - Prostatic abscess. PMID- 21667605 TI - A medical menagerie. PMID- 21667606 TI - Litigation in paediatrics. PMID- 21667607 TI - Baby walkers in Europe--time to consider a ban. PMID- 21667608 TI - New developments in service delivery. Are GP led sexual health clinics acceptable and satisfactory for patients attending? AB - Worldwide, sexually transmitted infections (STls) are among the most common causes of disease. The aim of this study was to evaluate why people attend a community based sexual health clinic and the benefits and satisfaction levels of providing this service to them. Phase I of the study was a cross sectional survey. Phase II was a retrospective review. Phase 1: N ='80 (41 F, 39 M - mean age 24.8 (SD 6.49)), 45 (56.3%) requested a general sexual health screen. Phase 2: N = 273, (139 F, 134 M - mean age 23.7 (SD 5.87)) 47 (15.5%/) reported use of condoms, 126(41.6%) do not use condoms ever, while 73 (24.1%) reported using condoms sometimes. 47 individuals (17%) tested positive for chlamydia. Attendees to the clinic expressed a high level of satisfaction overall with the services provided. The low use of condoms amongst a subgroup of patients with several sexual partners and the high level of chlamydia are causes for concern. PMID- 21667609 TI - Relationship between parent held child records for immunisations, parental recall and health service. AB - Parent held child records (PHCR) were introduced in Ireland in 2008. This study investigated the relationship between the PHCR, parental recall and regional Health Service Executive (HSE) records for immunisation uptake. It used the Lifeways cohort study of 1070 singleton children to compare immunisation data from PHCR at one year, parental recall at five years and information from the HSE. When compared to HSE records, full recording of primary immunisations in the PHCR was reported for 695 of 749 (92.8%) children. Parental recall was correct for 520 of 538 (96.7%) children. Of the 307 completed PHCRs, 207 (75.9%) agreed with the HSE records. Agreement between the three sources for primary immunisations was 74-93% but was not statistically significant. Agreement was 91% (p < 0.001) for measles, mumps and rubella (MMR) vaccines between parental recall and HSE records. PHCRs underestimated and parental recall overestimated immunisation status when compared with HSE records. PMID- 21667610 TI - Frequency and outcome of neoplastic brachial plexopathy: single institution experience. AB - Symptomatic neoplastic brachial plexopathy (NBP) is estimated to occur in about 0.4% of all patients with cancer. The aim of this review was to determine the incidence of NBP occurring in patients referred for magnetic resonance imaging (MRI). A retrospective review over a 5 year period revealed that a total of sixty six MRls of brachial plexus were performed. Twenty-nine were performed for assessment of suspected traumatic injuries. Eighteen MRIs were performed in patients with a known cancer diagnosis, one was performed in a patient with a benign thymoma, one with a neurofibroma and the remaining seventeen MRIs were ordered for other conditions. In total, thirteen MRls were positive for brachial plexopathy (seven traumatic, five due to cancer, one neurofibroma). Of the twenty MRIs performed in patients with neoplasms, six (30%) confirmed a diagnosis of NBRP. Twenty seven point eight per cent (5/18) of patients with a diagnosis of cancer had NBP. PMID- 21667611 TI - Neonatal respiratory extracorporeal membrane oxygenation (ECMO) referrals. AB - Extracorporeal membrane oxygenation (ECMO) is a complex technique for providing life support in neonatal respiratory failure. T UK Collaborative ECMO trial demonstrated cost-effectiveness and substantial improvements in neurological morbidity and mortality. Currently, infants requiring ECMO in Ireland are referred to one of various centres in the UK and Scandinavia. We aimed to review the number of infants referred from Ireland for respiratory ECMO. All infants with a non-cardiac condition referred from Ireland for ECMO were reviewed for diagnosis and outcomes. Eleven infants required ECMO between June 2006 and January 2009 and were referred to the Scandinavian team for ECMO transport although one infant improved and did not require ECMO following the arrival of the team. Four infants died: one infant died prior to arrival of the ECMO team, 3 infants had fatal diagnoses and one infant with congenital diaphragmatic hernia received pre-op ECMO. The median (inter-quartile range) gestational age was 39.7 (38.3-40.7) weeks and birth weight of 3.7 (3.2-4.0) kg. The median age at the decision to transfer for ECMO was 13h (4-123) and the team arrived at 23 h (12 132). All infants had a normal cranial ultrasound and echo prior to ECMO and 2 infants had an abnormal MRI post-ECMO. The time on ECMO was 9 days (3-17) and total length of hospital stay was 32 d (23-36). There were no pre-ECMO clinical or biochemical PMID- 21667612 TI - 'Ready-access' CT imaging for an orthopaedic trauma clinic. AB - 'Ready-Access' to CT imaging facilities in Orthopaedic Trauma Clinics is not a standard facility. This facility has been available at the regional trauma unit, in Merlin Park Hospital, Galway for the past four years. We reviewed the use of this facility over a 2-year period when 100 patients had CT scans as part of their trauma clinic assessment. The rate of CT scan per clinic was 0.6. The mean waiting time for a CT scan was 30 minutes. 20 (20%) new fractures were confirmed, 33 (33%) fractures were out-ruled, 25 (25%) fractures demonstrated additional information and 8 (8%) had additional fractures. 20 (20%) patients were discharged and 12 (12%) patients were admitted as a result of the CT scan. It adds little time and cost to CT scanning lists. PMID- 21667613 TI - Regional variation in electroconvulsive therapy use. AB - Although electroconvulsive therapy (ECT) is the most powerful treatment for depression, substantial variability in use has been described in Ireland. The Mental Health Commission collects usage data from approved centres but does not include home addresses or independent sector patients. Therefore, estimates of regional variation cannot be accurate, e.g. 145 (35% of total) independent sector patients were omitted from their 2008 analysis. When public and independent sector patients are combined inter-regional variation for 2008 is more than halved (chi-squared decreased from 83 to 30), with Western region contributing most to variation (chi-squared = 43). Ratio of ECT programmes to depressed admissions correlated negatively with rate for depressed admissions (r = -0.53, p = 0.01), while depressed admission numbers correlated with acute beds per area (r = 0.68, p = 0.001). Regional variation in ECT is less than previously reported; service factors probably account for much of this with smaller centres admitting severely ill patients more likely to require ECT. PMID- 21667614 TI - Overweight and obesity among older adults on admission to hospital. AB - Poor nutritional status, which includesboth under- a nd over-nutrition, i s associated w it h poor health outcomes. T his cross-sectional study assessed the nutritional status of older patients admitted to an acute geriatric ward of a Dublin hospital. Anthropometric and clinical measurements were made. Thirty patients, mean (sd) age 79 (7) y and body mass index 26.6 (4.7) kg/m2, participated. More patients were overweight (n = 12) or obese (n = 9) than underweight (n= 1) or healthy weight (n = 8) which indicates that this age-group may be part of the Irish obesity epidemic. PMID- 21667615 TI - An unusual case of Legionellosis. AB - Legionella species is a common cause of community-acquired pneumonia. However disease due to L. pneumophila serogroup 13 is rare and has not previously been reported in Ireland. It may not be detected by routine Legionella antigen and antibody kits. Due to these limitations, early culture should be considered when legionellosis is suspected. The potential therapeutic benefit of quinolones in the management of this disease is also illustrated. PMID- 21667616 TI - Extra-corporeal membrane oxygenation in the management of 2009 influenza A (H1N1) refractory respiratory failure. AB - Rapidly progressive acute respiratory failure attributed to 2009 H1N1 influenza A infection has been reported worldwide-3. Refractory hypoxaemia despite conventional mechanical ventilation and lung protective strategies has resulted in the use a combination of rescue therapies, such as conservative fluid management, prone positioning, inhaled nitric oxide, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO)4. ECMO allows for pulmonary or cardiopulmonary support as an adjunct to respiratory and cardiac failure, minimising ventilator-associated lung injury (VALI). This permits treatment of the underlying disease process, while concurrently allowing for recovery of the acute lung injury. This case documents a previously healthy twenty-two year old Asian male patient with confirmed pandemic (H 1N1) 2009 influenza A who was successfully managed with ECMO in the setting of severe refractory hypoxaemia and progressive hypercapnia. PMID- 21667617 TI - Through the looking glass, another look at migraine. PMID- 21667618 TI - Radiation dose of PET/CT. PMID- 21667619 TI - FTC antitrust rules offer hope of limiting ACO market power. PMID- 21667620 TI - Insurers play key role in improving medication reconciliation efforts. PMID- 21667621 TI - Payers: expect to feel a double-team pinch. PMID- 21667622 TI - 'High quality saves money,' or so the story goes. PMID- 21667623 TI - Are we finally getting serious about medical errors? PMID- 21667624 TI - FDA approvals of old drugs put new pressure on payers. PMID- 21667625 TI - Emerging insights about measuring disease management outcomes. PMID- 21667626 TI - Adherence to biologics demands greater attention. PMID- 21667628 TI - Include pharmacogenomic data in P&T decisions. PMID- 21667627 TI - Economic benefits of improved insulin stability in insulin pumps. AB - PURPOSE: Insulin pump users discard unused medication and infusion sets according to labeling and manufacturer's instructions. The stability labeling for insulin aspart (rDNA origin] (Novolog) was increased from two days to six. The associated savings was modeled from the perspective of a hypothetical one-million member health plan and the total United States population. DESIGN: The discarded insulin volume and the number of infusion sets used under a two-day stability scenario versus six were modeled. METHODS: A mix of insulin pumps of various reservoir capacities with a range of daily insulin dosages was used. Average daily insulin dose was 65 units ranging from 10 to 150 units. Costs of discarded insulin aspart [rDNA origin] were calculated using WAC (Average Wholesale Price minus 16.67%). The cost of pump supplies was computed for the two-day scenario assuming a complete infusion set change, including reservoirs, every two days. Under the six day scenario complete infusion sets were discarded every six days while cannulas at the insertion site were changed midway between complete changes. AWP of least expensive supplies was used to compute their costs. PRINCIPAL FINDINGS: For the hypothetical health plan (1,182 pump users) the annual reduction in discarded insulin volume between scenarios was 19.8 million units. The corresponding cost reduction for the plan due to drug and supply savings was $3.4 million. From the U.S. population perspective, savings of over $1 billion were estimated. CONCLUSIONS: Using insulin that is stable for six days in pump reservoirs can yield substantial savings to health plans and other payers, including patients. PMID- 21667629 TI - Imaging agents that identify Alzheimer's disease on the way. PMID- 21667630 TI - 10 times as many prostate cancers in 2021? PMID- 21667631 TI - Prepare and test for transition to 5010 transaction set. PMID- 21667632 TI - Eligibility verification: do you have what it takes? PMID- 21667633 TI - MAC prepayment reviews: prepare, respond, and prevent. PMID- 21667634 TI - One of great union leaders. PMID- 21667635 TI - Nurses and midwives create history during Cyclone Yasi. PMID- 21667636 TI - What is health reform? PMID- 21667637 TI - A 'nuts and bolts' guide to effective patient documentation. PMID- 21667638 TI - QFG EB a huge success. PMID- 21667639 TI - Nurses and midwives constantly at risk of workplace fatigue. PMID- 21667640 TI - The crisis continues in Palestine. PMID- 21667641 TI - Time to act on Millennium Development Goals. PMID- 21667642 TI - Directors quit in wake of reforms. PMID- 21667643 TI - CNO post to be split into two. PMID- 21667644 TI - "The timing of the mental health strategy may hinder its success". PMID- 21667645 TI - "There's a reason why nurses don't drive 4x4s and it's not cost". PMID- 21667646 TI - "Anger as medical and nursing boundaries blur is no surprise". PMID- 21667648 TI - Duty of care. PMID- 21667647 TI - Surveillance of surgical sites in primary care. AB - A surgical site surveillance programme with post-discharge follow-up and dedicated staff can have many benefits. This article describes the development of a surveillance programme and offers advice on setting up such programmes. PMID- 21667649 TI - Ethical issues in patient restraint. AB - This article examines the ethical issues that arise in relation to restraint in mental health, dementia care and stroke care. The themes can, however, be applied to all areas of healthcare. The article also discusses how "four quadrants" of practice situations--medical indications, patient preferences, quality of life and contextual features--can be used to analyse three different restraint situations. PMID- 21667650 TI - Food allergy in young people and children. PMID- 21667652 TI - Treasure island. PMID- 21667651 TI - Should nurses restrain violent and aggressive patients? AB - Violent and aggressive behaviour towards nurses is common, especially in mental health settings. This article explores the value and safety of existing approaches to dealing with violence and aggression, including the use of physical restraint and medication. It highlights the need for greater preventive and participatory measures, and the use of less reactive strategies, such as advance directives. PMID- 21667653 TI - Smooth operator: how to set up a hospital ward. PMID- 21667654 TI - No excuse for 'never events'. PMID- 21667655 TI - "The best stroke services are built around the individual". PMID- 21667657 TI - Caring for older people needs specific skills and knowledge. PMID- 21667656 TI - "We must stop throwing staff into an abyss of emotional burnout". PMID- 21667658 TI - What can we learn from the ombudsman? PMID- 21667659 TI - How to teach inhaler technique. AB - If adherence with therapy is to be achieved, when selecting a suitable device it is important to take into account individuals' ability to use inhalers as well as their attitude towards their disease, therapy and the acceptability of the selected device. Adherence and inhaler technique should be assessed at every consultation. PMID- 21667660 TI - From compliance to concordance. PMID- 21667661 TI - A patient finds her compression bandages keep loosening, so her ulcers are not healing. What can I do? PMID- 21667662 TI - Complex medicines management. AB - Patients with long-term conditions (LTCs) often take many prescribed drugs. A specialist nurse and pharmacist at a Milton Keynes practice identified the need for a more coordinated medication service for patients with LTCs who take multiple medicines. Adopting a holistic approach, they set up a joint medication management project. This article describes how the one-year project improved quality and safety, reduced out-of-hours presentations and hospital admissions, and cut costs. PMID- 21667664 TI - Ideas in motion. PMID- 21667665 TI - Hatching plans: the key to project management. PMID- 21667663 TI - Is splitting tablets dangerous? PMID- 21667666 TI - Bovine parthenogenotes produced by inhibition of first or second polar bodies emission. AB - Parthenogenetic embryos are an ethically acceptable alternative for the derivation of human embryonic stem cells. In this work, we propose a new strategy to produce bovine parthenogenetic embryos inhibiting the emission of the first polar body during in vitro maturation, and allowing the extrusion of the second polar body during oocyte activation. Cytochalasin B, an inhibitor of actin microfilaments, was employed during in vitro maturation to inhibit first polar body emission or during parthenogenetic activation to block second polar body emission. Only one polar body was inhibited in each strategy in order to keep the diploid chromosome set. In experiment 1, the effect of cytochalasin B on in vitro maturation of bovine oocytes was evaluated. Most oocytes (77%) were arrested at a meiotic stage characterized by the presence of a large internal metaphase plate and absence of polar body. In experiment 2, development of embryos exposed to cytochalasin B during in vitro maturation (CytoB-IVM) or during activation (CytoB ACT) was compared. Developmental rates did not differ between diploidization strategies, even when three agents were employed to induce activation. Both groups, CytoB-IVM and CytoB-ACT, tended to maintain diploidy. CytoB-IVM parthenogenesis could help to obtain embryos with a higher degree of homology to the oocyte donor. PMID- 21667667 TI - Salinity induced anatomical and morphological changes in Chloris gayana Kunth roots. AB - Chloris gayana Kunth is a grass species valuable as forage which was introduced into Argentina to be used as pasture in saline soils of subtropical and warm temperate zones, given its good adaptability to drought, salinity and mild freezing. However, its tolerance varies according to the cultivar. In tetraploid cultivars, important reductions in yield have been observed. Here, a study of the variations produced on the root and stem system by salinity at different NaCl concentrations (0, 150 and 250 mM) was performed in the Boma cultivar, with the aim of determining the anatomical and morphological alterations produced by the salt excess. Plants cultivated with the highest level of salinity showed, in the whole, significant differences in the measured variables. A diminution in absolute values of the variables and a major reduction in vascular tissue dimensions were observed, which suggests that the lack of tolerance to salt stress could be related to a deficient adaptation to absorb and transport water and nutrients from the roots. PMID- 21667668 TI - Detection of single copy sequences using BAC-FISH and C-PRINS techniques in sunflower chromosomes. AB - Bacterial artificial chromosome-fluorescence in situ hybridization (BAC-FISH) and cycling-primed in situ labeling (C-PRINS) techniques were evaluated for integration of physical and genetic maps of sunflower (Helianthus annuus L.). Single-site SSR markers were selected from three linkage groups of a high-density sunflower genetic map. This selection was based on previously identified QTL associated to S. sclerotiorum. These markers were used to select BACs contaning single copy sequences for BAC-FISH aplication. Blocking of highly dispersed repetitive sunflower sequences reduced unspecific hybridization, and allowed the detection of specific signals for BACs containing SSR markers HA4222 and HA2600, anchored to LG 16 and LG 10, respectively. Single-site FISH signal detection was optimized by adjusting the relative quantity and quality of unlabelled repetitive sequences present in the blocking DNA. The SSR marker ORS1247 anchored to the LG 17 was detected by C-PRINS, which yielded fluorescence signals that were specific and intense. This progress in localizing single-copy sequences using BAC-FISH and indirect C-PRINS strategies in sunflower will facilitate the integration of genetic and physical maps, allowing the identification of chromosomes containing key genes and/or QTL associated to agronomic important traits in sunflower. PMID- 21667669 TI - Evaluation of potential embryo toxicity of albendazole sulphoxide in CF1 mice. AB - Benzimidazole compounds are used in both humans and animals for controlling helminth parasites. Albendazole has teratogenic effects attributed to its active metabolite albendazole sulphoxide. The aim of this work was to evaluate the effect of the latter compound when administered to pregnant CF1 mice during the preimplantation period. Females were superovulated by intraperitoneal injection of 10 IU of eCG and 10 IU of hCG (48h later) and were paired with males of proven fertility. Albendazole sulphoxide (200 mg/kg) was orally administered by gavages at day 1, 2 or 3 of pregnancy; the control group received only the vehicle (carboxymethylcellulose). Females were killed by cervical dislocation at day 4 of pregnancy and embryos were flushed from uteri with Ham F10 media supplemented with bovine serum albumin (0.4%). Number of collected embryos per female, percentage of morphologically normal embryos, differentiation rate and number of cells per embryos were recorded. The variables were analyzed on a per litter basis by Kruskal-Wallis test. There was no effect of albendazole sulphoxide on parameters evaluated (P>0.05). We conclude that the preimplantation mouse embryo development was not significantly affected by albendazole sulphoxide. PMID- 21667670 TI - A glass bead protocol for recovery of host cell free Ehrlichia canis and quantification by Sybr-green real-time PCR. AB - E. canis infection of the canine cell line DH82 is a routine in studies with this bacteria. A protocol for isolation of host cell free bacteria was developed based on the use of glass beads. Improvement of infection with E. canis isolated by this method was detected by real-time PCR. PMID- 21667671 TI - Costs and coverage in turbulent times. PMID- 21667672 TI - Violence against nurses and its impact on stress and productivity. AB - The purpose of this study was to examine how violence from patients and visitors is related to emergency department (ED) nurses' work productivity and symptoms of post-traumatic stress disorder (PTSD). Researchers have found ED nurses experience a high prevalence of physical assaults from patients and visitors. Yet, there is little research which examines the effect violent events have on nurses' productivity, particularly their ability to provide safe and compassionate patient care. A cross-sectional design was used to gather data from ED nurses who are members of the Emergency Nurses Association in the United States. Participants were asked to complete the Impact of Events Scale-Revised and Healthcare Productivity Survey in relation to a stressful violent event. Ninety-four percent of nurses experienced at least one posttraumatic stress disorder symptom after a violent event, with 17% having scores high enough to be considered probable for PTSD. In addition, there were significant indirect relationships between stress symptoms and work productivity. Workplace violence is a significant stressor for ED nurses. Results also indicate violence has an impact on the care ED nurses provide. Interventions are needed to prevent the violence and to provide care to the ED nurse after an event. PMID- 21667673 TI - Outcomes and cost analysis of the impact of unit-level nurse staffing on post discharg utilization. AB - Under a proposal from the Centers for Medicare and Medicaid Services, hospitals would no longer be reimbursed for 30-day re-admissions or emergency department (ED) visits. Increasing RN staffing to reduce post-discharge utilization is one possible solution, but one that is not financially attractive to hospitals. This study demonstrates the impact of fluctuating staffing levels on ED visits within 30 days of discharge. RN overtime and RN vacancies also affected subsequent ED visits. It is important for nurse managers, directors, and administrators to recognize the impact of RN staffing on patient outcomes. Reimbursement models will need to be realigned to benefit both hospitals and payers. PMID- 21667674 TI - PCA oversedation: application of Healthcare Failure Mode Effect (HFMEA) Analysis. AB - Hospital systems utilize many varied problem-solving processes to address system improvements and ensure patient safety. The Healthcare Failure Mode Effect Analysis (HFMEA) model is one of these tools and uses a multidisciplinary team to look at processes, diagramming the steps involved to identify potential failure points. The application of the HFMEA model allowed one large health care system to address a complex process by prioritizing proactive change improvements in order to prevent postoperative patient-controlled anesthesia oversedation events. The changes implemented identified 16 failure points with a hazard score of 16 or greater. One year later, the established system HFMEA goal was met: oversedation events were reduced by 50%. PMID- 21667676 TI - The art and neurobiology of connection: the leader's challenge. AB - When we feel connected and safe, the cerebral cortex of our brain responds by becoming involved, which leads to peak performance. When we work in a culture of constant fear, the deeper levels of our brain are activated to respond to the fear and our cerebral cortex is disabled. ultures that are negative and focus on people's weaknesses create "learned helplessness" lead to high rates of depression among the workforce, and cannot achieve the results of optimistic workplaces. The profession loses far too many excellent nurses every year because of the inability of managers and leaders to seriously connect with the front line. What we do as leaders creates a physiological reaction and a basis for effective or ineffective work units. PMID- 21667675 TI - Work unit transformation to welcome new graduate nurses: using nurses' wisdom. AB - While providers, consumers, and administrators recognize the need to attract and retain nurses, recruiting, transitioning, and retaining new graduate nurses (NGRNs) remains problematic. The first 3-12 months of NGRN employment is a perilous and stressful time, with experiences during the transition period profoundly influencing their careers. The purpose of this project was to develop a dedicated transition unit using a theory-driven approach. It addressed employee on-boarding and practice environment issues and it focused on attracting and retaining experienced and newly graduated RNs on an active inpatient unit. Implications are described for those interested in improving the work environment for hospital nurses. PMID- 21667677 TI - American Academy of Ambulatory Care Nursing position statement: the role of the registered nurse in ambulatory care. AB - Ambulatory care nurses are leaders in their practice settings and across the continuum of care. They are uniquely qualified to influence organizational standards related to patient safety and care delivery in the ambulatory care setting. The current ambulatory care setting is diverse and multifaceted, requiring nurses highly skilled in patient assessment and with the ability to implement a broad range of nursing interventions in a variety of settings. The future of the American health care system depends upon our ability to utilize RNs to the fullest extent of their expertise, licensure, and certification. PMID- 21667678 TI - How should we collect data on the nursing workforce? AB - R esearchers who study the nursing workforce use data about nurses and data about nursing jobs. Diifferent approaches - sample surveys and relicensure surveys - used to collect data on RNs, and the benefits and weaknesses of these approaches, are reviewed. Predicting the future supply of nurses is more complex than estimating the current supply, as factors that affect future supply must be considered. Simple forecasts can be created with relatively few variables, which could be collected through relicensure surveys. However, more detailed assessments of potential retirement patterns, changing family norms regarding childcare and household work, and movements into higher education require the rich data more often found in sample surveys. PMID- 21667679 TI - The quest for quality: turning data into information. PMID- 21667680 TI - Medicaid transformation draws united opposition. PMID- 21667682 TI - More guts than glory. MS editorial review board members work hard, keep journal at its best. PMID- 21667683 TI - Locations and outcomes of premature births in Arkansas. AB - Most (57.6%) of the extremely premature infants were born at a hospital without the availability of neonatal and MFM specialists, and 38.4% of the very premature were born at a hospital without a neonatologist. Increasing evidence indicates that delivery at a Level 3 facility results in better survival for these high risk infants. Health professionals, administrators and policy leaders could fashion new approaches to obstetrical care in Arkansas to improve neonatal outcomes. PMID- 21667684 TI - Fetal alcohol spectrum disorders: flying under the radar. AB - Alcohol exposure during pregnancy has been shown to result in a spectrum of birth defects known as Fetal Alcohol Spectrum Disorders (FASD) that can negatively impact a child's growth, development, cognition, behavior and physical appearance over his or her entire lifespan. FASD is not a diagnostic term, unlike Fetal Alcohol Syndrome (FAS), which is the most serious disorder within the spectrum. Despite warnings by the U.S. Surgeon General and others, childbearing age women continue to drink at high levels, even in pregnancy. As there is no cure for an FASD, preventive activities are currently the only successful approach to reduce the risk of an Alcohol-Exposed Pregnancy (AEP) through screening, education, or brief interventions of childbearing age women. The Midwest Region Fetal Alcohol Syndrome Training Center (MRFASTC) has established teams in 8 states in the Midwest, including Arkansas, with the goal of training health care professionals in FASD recognition, diagnosis, treatment, and prevention. PMID- 21667685 TI - Depression, social anxiety, and health-related quality of life in overweight Arkansas youth. AB - INTRODUCTION: Excess weight in youth can have a profound impact on emotional and social functioning. This study investigated depression, social anxiety, and health-related quality of life in overweight Arkansas youth. METHODS: Sixty-three middle school students participated. Children completed the Child Depression Inventory, the Social Anxiety Scale, and the Pediatric Quality of Life. Height and weight were obtained. RESULTS: Overweight youth were similar to normal weight youth on all measures with no statistically or clinically significant differences. CONCLUSIONS: Results suggest that in a community with a high rate of overweight persons (youth and adults), the impact of the youth's own weight status on their emotional state and quality of life is negligible. PMID- 21667687 TI - Home Care & Hospice 2011. Strategic Planning Congress: presenting an industry priority report. PMID- 21667686 TI - Private duty equals custom care. PMID- 21667688 TI - Activity based in-home care: A model for the future. PMID- 21667690 TI - Private duty as the answer: Implementing new dimensions in health care delivery. PMID- 21667689 TI - Responding to challenging behaviors in those with Alzheimer's: communication matters. PMID- 21667691 TI - Creating a 'safe space' free from judgment to allow our grief to heal. PMID- 21667692 TI - Psychiatry's shame. PMID- 21667693 TI - A nation is what it honors. PMID- 21667694 TI - Euthanasia contentious issue. PMID- 21667695 TI - Collaborative arrangements. Are expanded roles for nurses and midwives being stifled? PMID- 21667696 TI - Traumatised communities ... traumatised nurses? PMID- 21667697 TI - Peak oil and health care without plastic. PMID- 21667698 TI - Working life. PMID- 21667699 TI - Identification and management of dysphagia in children with neurological impairments. PMID- 21667700 TI - Target parents to prevent obesity. PMID- 21667701 TI - No more "fake it"--it's time to fashion stake it! PMID- 21667702 TI - Caring at each stage of the child's journey from admission to discharge. PMID- 21667703 TI - Vaccines need a shot in the arm. PMID- 21667704 TI - Refugee child health checks. PMID- 21667706 TI - Wales now points the way forward. PMID- 21667707 TI - Early implementer sites: support to meet potential. PMID- 21667705 TI - Project boosts chances of infant suvival in Vietnam. PMID- 21667708 TI - SHINE on the midlands. PMID- 21667709 TI - An alternative vision. PMID- 21667710 TI - CPTs' perceptions of their role satisfaction and levels of professional burnout. AB - This paper reports on a multi-method research project that explored perceived role satisfaction and professional burnout among community practice teachers (CPTs) while facilitating post-registration education and caseload management. A bespoke Satisfaction Questionnaire and the Maslach Burnout Inventory (Educators) were completed by 23 participants to elicit quantitative and qualitative data. Findings are presented in relation to three themes--aspects of the CPT role leading to satisfaction, aspects leading to dissatisfaction or burnout, and ways to enhance satisfaction and reduce burnout. The majority of CPTs were satisfied with their current role. A number of factors were elicited that affected participants' perceived satisfaction. Respondents scored low levels of burnout overall, with high levels of personal accomplishment and low levels of depersonalisation. The relationship between participants' satisfaction and their levels of burnout was not found to be statistically significant. However, mean scores on the emotional exhaustion subscale indicate moderate levels of emotional exhaustion. The paper concludes with recommendations to improve the support provided by employers and partner universities for CPTs. PMID- 21667711 TI - Development and validation of a child health workforce competence framework. AB - Providing high quality, effective services is fundamental to the delivery of key health outcomes for children and young people. This requires a competent workforce. This paper reports on the development of a validated competence framework tool for the children and young people's health workforce. The framework brings together policy, strategic agendas and existing workforce competences. The framework will contribute to the improvement of children's physical and mental wellbeing by identifying competences required to provide proactive services that respond to children and young people with acute, continuing and complex needs. It details five core competences for the workforce, the functions that underpin them and levels of competence required to deliver a particular service. The framework will be of value to commissioners to inform contracting, to providers to ensure services are delivered by a workforce with relevant competences to meet identified needs, and to the workforce to assess existing capabilities and identify gaps in competence. PMID- 21667712 TI - The complexities of children missing from education: a local project to address the health needs of school-aged children. AB - The issue of children missing from education has been of concern both nationally and locally for many years. Following a local audit of health visitor and school nurse caseloads, the existence of unallocated child records or children who could not be found came to light. These records were held and managed by the local child health department. Children who did not attend school were not offered a school nursing service, and were monitored solely by the educational welfare service. This paper reports on a project to identify and investigate the whereabouts of these children and to allocate the remaining records to school nursing teams. This would ensure that all children in the local area were visible and that any unmet health needs were assessed and addressed. The project was led by the safeguarding children team and involved forging and developing cross agency links. The involvement of the school health department, team managers and school nursing teams was integral to its success. The school nursing service was reconfigured taking into account identified need for an inclusive service to all local children. PMID- 21667713 TI - Preparing for parenthood: the role of antenatal education. AB - The transition to parenthood is a time of great change for mothers and fathers, and also lays the foundation for the long-term health and wellbeing of the child. This emphasises the importance of preparation for parenthood. A Department of Health-commissioned review found provision and uptake of antenatal education to be variable, and so brought a group of experts together to consider Preparation for Pregnancy, Birth and Beyond. This paper provides an overview of the learning from the expert group's work, offering a new framework that professionals may use to plan effective local programmes and services. PMID- 21667714 TI - Adjusting to motherhood. PMID- 21667715 TI - Steering through change. PMID- 21667716 TI - Not a pretty picture. PMID- 21667717 TI - The swan song. PMID- 21667718 TI - Heavy metals in bottled natural spring water. AB - New regulations regarding the presence of contaminants in bottled water went into effect in California in January 2009. These requirements include testing, reporting, and notification to regulate the presence of heavy metals in bottled natural spring water sold in California. In the study described in this article, six sources of bottled natural spring water were purchased and analyzed for silver, arsenic, barium, beryllium, cadmium, cobalt, chromium, copper, mercury, molybdenum, nickel, lead, antimony, selenium, thallium, vanadium, and zinc. All of these metals except beryllium, mercury, and thallium were detected in at least one of the bottled natural spring water sources. No concentrations were above either federal or California maximum contaminant levels but arsenic concentrations exceeded California public health goals in all six sources. Improving the California notification requirements for bottled water contaminants would result in a process more similar to the notification process for tap water and would result in better-informed consumers. PMID- 21667719 TI - Evaluation of surface lead migration in pre-1950 homes: an on-site hand-held X ray fluorescence spectroscopy study. AB - Lead-paint concentration on specific surfaces (walls, floors, windowsills, etc.) in pre-1950 homes was measured using a hand-held X-ray fluorescence (XRF) spectroscope. Surface lead was examined concomitantly using wipe sampling and XRF Lead was detected in all 147 samples via XRF; and of these, 29 ( 20%) revealed surface lead contamination via wipe sampling. Seventeen of the positive wipe samples were collected from surfaces with clear visible defects, while 12 samples were collected from surfaces with no visible defects. Curve fitting of surface to lead-paint concentrations generated empirical relationships that described the migration of lead from inner layers at locations with and without visible defects. Curve fitting indicated that lead migration was power-law dependent when surface defects were present and linear when no defects were visible. These correlations may assist surveyors in predicting lead migration to the surface from lead-paint concentration measured with a hand-held XRF instrument. PMID- 21667720 TI - Keep calm and carry on: the 2009 NEHA sabbatical exchange ambassador report. AB - Sabbatical goal as an environmental health specialist working with the California Department of Public Health as an emergency planner, I was interested in the NEHA sabbatical exchange program for the opportunity it affords its awardees to see how Canada and the United Kingdom utilize their environmental health workforce. Specifically, I wanted to examine the role environmental health has in the preparations being made for the 2012 Olympic Games to be held in London. I had a special interest in the emergency preparedness efforts related to the games as my work involves promoting the integration of environmental health into the emergency response structure. In California, environmental health services are delivered by several state agencies as well as 62 local jurisdictions. This multifaceted system tends to diminish the important role environmental health plays in disaster response and recovery operations due to the lack of a central focus, and as a result, environmental health is often an overlooked resource. This situation is not unique to California, as the emergency management system in the U.S. has traditionally focused primarily on "blue light" first responders: police, fire, and emergency medical services. After an article caught my eye on involving environmental health in emergency planning, posted on the Chartered Institute of Environmental Health (CIEH) (NEHA's counterpart in the UK) Web site, I became intrigued and used it to form the basis of my sabbatical mission. PMID- 21667721 TI - Environmental public health systems and services research. PMID- 21667722 TI - Bed bugs, public health, and social justice. PMID- 21667723 TI - Fibrodysplasia ossificans progressiva: diagnosis and surgical management. AB - Fibrodysplasia (or Myositis) Ossificans Progressiva (FOP) is a rare genetic disease with variable expression, characterized by the association of congenital anomalies of the toes and fingers and progressive appearance of ectopic bone within the skeletal muscles, often following a trauma or an infection. FOP initially affects the nape and thoracic paravertebral muscles. With age, there is a progression of ossifications to other muscular groups following a proximodistal and cranio-caudal extension. Patients develop a restrictive respiratory insufficiency with atelectasis. The diagnosis of FOP is clinical and does not require biopsy. Circumscribed post-traumatic ossifying myositis is the most important differential diagnosis. It is characterized by the appearance of painful ossifications, in young adults, following a trauma and is limited to one localisation. The conservative treatment of FOP remains unsatisfactory. Surgical removal of osteomas to restore joint mobility leads to the development of additional heterotopic ossifications. Each surgical attempt brings about a quasi inevitable recurrence. Anaesthesia of patients with FOP is difficult because of spinal rigidity and ankylosis of the jaw. Surgery is indicated only with a focused indication to correct an invalidating deformity. PMID- 21667724 TI - Infection or metal hypersensitivity? The diagnostic challenge of failure in metal on-metal bearings. AB - The use of second generation metal-on-metal hip articulations has gained favour in the past few years. A hypersensitivity reaction to the metal-on-metal bearing, although rare, is a reported complication and is a novel mode of failure of these implants. Differentiating failure secondary to infection from failure secondary to metal hypersensitivity represents a significant diagnostic challenge. A retrospective review of all cases of hip arthroplasty using metal-on-metal bearings over a 5-year period at a tertiary referral centre identified 3 cases of failure secondary to metal hypersensitivity. Clinical presentation, serological markers, radiological imaging and histological analysis of all cases identified were evaluated. Histological analysis of periprosthetic tissue in all 3 cases identified characteristic features such as perivascular lymphocytic aggregates and chronic inflammation consistent with aseptic lymphocytic vasculitis associated lesions (ALVAL). This study highlights that failure secondary to metal hypersensitivity must be considered in patients presenting with the reappearance of persistent pain, marked joint effusion, and the development of early osteolysis in the absence of infection. PMID- 21667725 TI - Techniques for cartilage repair in chondral and osteochondral defects of the knee. AB - Many techniques are currently used in an attempt to regenerate cartilage surfaces in the presence of a chondral or osteochondral defect. Clinical results have been mixed and no single treatment has emerged as being superior. This article reviews the techniques previously and currently being used and evidence to support their use. PMID- 21667726 TI - Arthroscopic fixation of isolated type II SLAP lesions using a two-portal technique. AB - The purpose of this study was to assess the outcomes of twenty isolated type II SLAP lesions which were repaired arthroscopically using a two-portal technique. Shoulder function was evaluated at a mean follow-up of 2 years using the modified Constant-Murley score. The average preoperative score was 65.2%; it improved postoperatively to 86.4% (p < 0.0001). Pain improved from 6 points to 13 points (p <0.01) and strength increased from 10 kg to 17 kg (p < 0.01). Seventeen of the 20 patients participated in athletic activity before the arthroscopic SLAP repair; they were subdivided into two groups with regard to their age (< 40 years, and > 40 years). There were statistically significant differences between the groups, with 70% returning to the same level of competitiveness in the younger group versus 29% in the older age group. (p <0.0001). Arthroscopic repair of an isolated type II SLAP lesion using a two-portal technique, without using a trans rotator cuff portal, appeared as a reliable and effective procedure with respect to shoulder function and anatomy. PMID- 21667727 TI - Validation of a CT-based determination of the glenohumeral index. AB - The amount of bony support by the glenoid can be determined using the glenohumeral index, i.e. the maximum anteroposterior (AP) diameter of the humeral head divided by the maximum AP dimension of the glenoid. This index has been described theoretically, but has never been validated in practice. In this study we used 20 cadaver shoulders to determine the glenohumeral index in two different ways. One method evaluated the glenohumeral index on a CT scan of the shoulders. The second method determined the anatomical glenohumeral index of the same shoulders by direct measurement of anatomical specimens using a digital caliper. All CT and caliper measurements were repeated by three different investigators. We used the Wilcoxon Signed Rank Test, to calculate the statistical significance of intra-observer and inter-observer differences in measurements on CT and with the caliper. Statistical analysis showed no significant differences between CT scan and caliper measurements for each investigator separately, but we found a statistically significant inter-observer variability concerning the caliper measurements obtained by two different investigators. This study demonstrates that a two-dimensional CT scan of the shoulder is a reliable and very accurate tool to calculate the glenohumeral index, as the values measured for the AP diameter of the humeral head and the AP dimension of the glenoid compare well with those measured in vitro on anatomical specimens. PMID- 21667728 TI - Custom endoprosthetic reconstruction for malignant bone disease in the humeral diaphysis. AB - The optimal reconstructive method following segmental resection of malignant tumours in the humeral diaphysis is unknown as there are no prospective long-term studies comparing biologic with endoprosthetic reconstruction. This is a retrospective review of 13 patients who, between 1995 and 2010, had undergone limb salvage at our institution using a custom-made humeral diaphyseal endoprosthetic replacement following excision of malignant bone disease. There were 9 males and 4 females with a mean age of 35 years at the time of surgery (range: 10 to 78). Mean follow-up was 56.8 months (range: 5 to 148). Cumulative patient survival was 75% at 10 years. Implant survival, with removal of the endoprosthesis or part of it for any reason as an end point, was 47% at 10 years. Seven patients required revision (54%). Complications included metastases in four, aseptic loosening in four, peri-prosthetic fracture in two and local recurrence in two. Mean MSTS and TESS scores were 23 (18 to 27) and 67% (52-80) respectively. Custom-made humeral diaphyseal replacement following resection of malignant bone tumours provided functional results superior to amputation, without an obvious compromise in patient survival. There was a relatively high revision rate for aseptic loosening and peri-prosthetic fracture and patients should be counselled about this preoperatively. PMID- 21667729 TI - Percutaneous K-wire fixation versus palmar plating with locking screws for Colles' fractures. AB - Different methods exist to treat distal radius fractures. A prospective randomized study was conducted to establish whether palmar plate fixation with locking screws gave better results than percutaneous K-wire fixation in patients over 50 years of age. Only fractures with dorsal displacement after a simple fall were included in the study. Twenty wrists were treated with K-wires and 20 with a plate. Radiological parameters were measured on preoperative radiographs and at five weeks postoperatively. Clinical results and DASH scores were determined at three months postoperatively and at more than one year. No significant difference in radial inclination, palmar tilt, clinical outcome and DASH score was found between plating and K-wires, but the mean difference in ulnar variance between pre- and postoperative radiographs was significantly better with plates. It can be concluded that plates were superior to K-wires in restoring ulnar variance, but functional outcome was similar with both techniques. PMID- 21667730 TI - Can we predict the natural course of femoroacetabular impingement? AB - We conducted a multivariate regression analysis (including both radiographic and activity related variables) in patients with osteoarthritis of the hip and structural changes related with femoroacetabular impingement. The purpose of this study was to investigate whether the age at which total hip arthroplasty may have to be performed, can be predicted in patients with femoroacetabular impingement (FAI). In 121 patients with FAI-related osteoarthritis, radiographic variables describing FAI-related parameters were obtained and the patients were questioned about their activity during early adulthood by means of the validated Baecke et al questionnaire. None of the variables significantly correlated with the final outcome parameter : age at surgery. As expected, based on the low correlation ratios of the different parameters investigated, a multiple-regression model was not accurate enough to allow any prediction on the natural course of FAI. We found that it is difficult to accurately predict the age at which a patient with FAI will develop early osteoarthritis. From our findings it appears that a hip with FAI is not always prone to early end-stage osteoarthritic degeneration, not even in patients with a high level of physical activity. Hence, considering the high prevalence of FAI-related radiographic findings, we conclude that not every radiographic abnormality requires treatment. PMID- 21667731 TI - Does the place of fall influence the time to specialist treatment in patients sustaining hip fractures? A study of 4917 patients falling in four different settings. AB - Delay to treatment is a multifactorial issue for patients sustaining hip fractures. The place of fall could possibly impact on the time to specialist care. We aimed to investigate the correlation between the place where a hip fracture occurs, and the time to initiation of specialist fracture-specific treatment. We retrospectively analysed data that had been collected on 4917 consecutive hip fracture admissions to our unit. The recorded places of fall were divided into four groups, including those falling 'outside home', 'at home', 'residential or nursing home', and 'hospital inpatients' respectively. A 24-hour scale was used to record times of fall and of initiation of treatment. The latter was the time of admission to Accident & Emergency for groups 1-3, and the time of referral to the Orthopaedic team for group 4.23.5% patients fell outside their own home (group 1), and presented at only 2 hours post-injury. Patients in both group 2 (47.7%) and group 3 (23.6%) presented after 3 hours. Group 4 (4.9%) patients had to wait a median of 8 hours being referred to the Orthopaedic team. We found an interesting correlation between the place of injury and the delay in receiving treatment, in that those patients already receiving maximal healthcare attention, had to wait the longest to be referred to specialist care. PMID- 21667732 TI - Comparison of unilateral and rapidly staged bilateral hip resurfacing arthroplasty. AB - The purpose of this study was to compare the clinical results and complication rates after unilateral vs. staged bilateral metal-on-metal hip resurfacing arthroplasty (HRA) when using a comprehensive blood management program, to determine if there was increased risk for staged HRAs. The study group included 25 consecutive bilateral patients with osteoarthritis (OA) (50 hips). The control group consisted of the first 100 consecutive patients with OA (100 hips) who had unilateral resurfacing during the same period of time by the same surgeon. All patients were enrolled in the same comprehensive blood management program. No transfusion was required in either group. No patients experienced symptomatic anaemia. There was no difference in blood loss per hip between the two groups. This study suggests that transfusion can virtually be eliminated in both unilateral and staged HRA's using an appropriate blood management strategy without collection of autologous blood preoperatively. PMID- 21667733 TI - Mini-open versus closed reduction in titanium elastic nailing of paediatric femoral shaft fractures: a comparative study. AB - The purpose of this study is to compare retrospectively intraoperative fluoroscopy time and clinical-radiological results in pediatric femoral shaft fractures treated with titanium elastic nailing (TEN), with a mini-open "blind hand" technique versus closed reduction. The study included 87 children (18 girls and 69 boys) who underwent surgical treatment with TEN for femoral shaft fractures. Patients were divided into two groups. Group 1 included 42 patients (mean age : 83 +/- 2.7 years) treated with a mini-open "blind-ha nd" technique (a 2-3 cm lateral incision at the level of the fracture ; reduction achieved with one or two fingers, without visualization of the fracture). Group 2 consisted of 45 patients (mean age: 8.8 +/- 2.6 years) treated with a closed reduction technique. Duration of surgery and intraoperative fluoroscopy time were recorded in both groups. Clinical and radiologic results were assessed using the TEN scoring system after mean follow-up periods of 213 +/- 5.8 months and 193 +/- 5.6 months in group 1 and group 2, respectively. Mean duration of surgery was 31.7 +/ 7.6 and 52.1 +/- 14.4 minutes, and mean fluoroscopy time 32.9 +/- 22.1 and 75.1 +/- 31.5 seconds in group 1 and group 2, respectively. Both surgical and fluoroscopy time were significantly longer in group 2 (p < 0.001). There was no significant difference between the two groups in terms of clinical and radiological results. All fractures healed with solid union, and there was no complication that was expected to cause permanent disability. Although successful clinical and radiological results were obtained with both techniques, duration of surgery and intraoperative fluoroscopy time were significantly higher in the closed reduction group 2. We suggest the "blind-hand" technique as an alternative to closed reduction to prevent extensive intraoperative radiation exposure and to decrease the length of the surgical procedure. PMID- 21667734 TI - Early results of one-level cervical discectomy and fusion with stand-alone cervical cage and bone marrow soaked tricalcium phosphate. AB - Cervical disc prolapse has been traditionally treated with anterior discectomy and fusion, with good results; however autogenous bone graft and instrumentation remain a limiting factor. To avoid this, a stand-alone cage with bone marrow soaked tricalcium phosphate was used for single level cervical disc disease. Fifteen consecutive patients with single level cervical disc disease operated with the above technique were prospectively followed at six weeks, six and twelve months post-surgery. Clinical improvement was assessed by VAS and Odom's criteria. CT and plain radiography were used to assess fusion. Mean duration of symptoms was 7.2 months (SD: 4.14, range: 1-18 months). Mean preoperative VAS was 7 (SD: 131, range: 5-10) which improved to 1.4 (SD: 0.63, range: 1-3) at 6 weeks post op, 0.93 (SD: 0.80, range: 0-3) at 6 months and 0.80 (SD : 0.77, range : 0 3) at final follow-up. Similarly Odom's criteria were excellent in ten, good in three and satisfactory in 2 patients at six weeks. Results were rated excellent in eleven patients, good and satisfactory in two patients each respectively at six months and final follow-up. All patients had radiological fusion with no sign of cage extrusion. Results with this technique in terms of fusion, pain relief and overall functional outcomes were found to be good in this small patient population and warrant a larger sample size randomized long-term study. PMID- 21667735 TI - Single level cervical arthroplasty with the Discocerv prosthesis: a preliminary report. AB - The authors conducted a prospective nonrandomised study about a new cervical disc prosthesis: the Discocerv Cervidisc Evolution. Fourteen patients (10 men and 4 women) were treated at a single mobile level, between July 2006 and November 2008. Their mean age was 40.8 years (range 31-56), and the mean clinical follow up period was 12.8 months (range 9-18). Diagnosis was disc herniation (n = 12) and stenosis (n = 2). The VAS for neck pain, the VAS for radiating pain and the Neck Disability Index decreased significantly at last followup (p <0.05). According to Odom's criteria 81.6% of the patients had a good or excellent outcome. The range of movement of the cervical spine as a whole and of the treated functional segmental unit were preserved at final follow-up, which suggests that the disc prosthesis might prevent osteoarthritis at adjacent levels. The neutral sagittal alignment of the cervical spine as a whole and of the functional spinal unit showed kyphosis shortly after surgery, but lordosis was practically restored at final follow-up. PMID- 21667736 TI - Fracture risk in unicameral bone cyst. Is magnetic resonance imaging a better predictor than plain radiography? AB - The classical indication for treating a simple bone cyst is usually the risk of fracture, which can be predicted based on three parameters: the bone cyst index, the bone cyst diameter, and the minimal cortical thickness. A retrospective review was carried out based on imaging of 35 simple bone cysts (30 humeral and 5 femoral). The three parameters were measured on standard radiographs, and on T1 weighted and T2-weighted MRI. The measurements were performed by two independent reviewers, and twice by the same reviewer. Kappa values and binary logistic regression were used to assess the ability of the parameters to predict the fracture risk. Inter- and intra-observer agreement was measured. T1-weighted MRI was found to have the best inter- and intraobserver repeatability. The bone cyst index was found to be the best predictor for the risk of fracture. PMID- 21667737 TI - The presentation of rickets to orthopaedic clinics: return of the English disease. AB - Rickets is a potentially treatable disease of the bone that is most commonly due to deficiency of vitamin D and is increasing in incidence in developed countries. Risk factors include dietary factors, the practice of covering up and darker skin pigmentation. This small retrospective case study set out to examine all cases of rickets presenting to the Paediatric Orthopaedic clinic over a 15-month period. Rickets presented in a bimodal fashion in the 6 cases identified: in males and females aged 3 or less and female adolescents aged 10 and above. This is in keeping with what is known regarding the rapid phases of growth during development. Five cases were from ethnic minority groups. Both female adolescents presented with genu valgum. Rickets can present primarily to Orthopaedic clinics with vague musculoskeletal symptoms. We recommend that biochemical screening be performed on patients from ethnic minorities who may be 'at risk'. PMID- 21667738 TI - Snakebites of fingers or toes by viperidae family members: an orthopaedic approach. AB - The purpose of this study was to review current principles of therapy for affected patients and determine whether an emergent surgical approach or expectant management should be selected in cases of snakebites of fingers or toes by Viperidae family members. Over the past five years (January 2004 to December 2009), 12 patients bitten by Vipera ammodytes were admitted in our department. We retrospectively reviewed their demographic and epidemiological characteristics as well as their symptoms, laboratory findings, and complications. All snake bites occurred at the extremities (fingers and toes). The main complications were oedema, disseminated intravascular coagulation, and decrease in haematocrit. None of the patients developed compartment syndrome or required surgical debridement. The majority of the patients with snakebites of fingers or toes by Vipera ammodytes can be treated conservatively. Surgery is indicated only in case of compartment syndrome, where fasciotomies should be performed without delay after diagnosis. PMID- 21667739 TI - Modified double-row technique for arthroscopic Bankart repair: surgical technique and preliminary results. AB - Fixation by a double-row technique is a new concept in arthroscopic capsulolabral reconstruction for anterior shoulder instability. We report here a modified double-row arthroscopic Bankart repair technique. The capsulolabral complex is stabilised by sutures placed in a V-shaped manner. The sutures are fixed to the glenoid by suture anchors, thereby eliminating the necessity to tie or relay sutures under the scope. Compared with the conventional single-row repair method, our method has an advantage in that the complex is attached to the glenoid over a larger area. This procedure was performed on 28 shoulders in 25 patients. The operation time was shortened by almost 30% from that with the conventional procedure, and no complications were encountered in these patients. No recurrence of dislocation or subluxation was noted in 19 joints followed for 24 months or longer. PMID- 21667740 TI - Another string.... but no bow. AB - Based on a positive personal experience, the authors advocate the use of a wound protector/retractor such as the Alexis system in total hip arthroplasty, to avoid intra-operative bacterial contamination from the skin, while avoiding damage to the skin and other soft tissues. PMID- 21667741 TI - Vertebral Langerhans cell histiocytosis in an adult patient: case report and review of the literature. AB - Vertebral Langerhans cell histiocytosis, formerly called Histiocytosis X, is rarely seen in adults: a systematic non-quantitative review of the literature yielded only 27 cases. Vertebra plana is often associated in children, but this is not a feature in the adult population. The authors report the case of a 29 year-old woman with a two-month history of lumbar pain. Osteolysis of the right pedicle of L2 was noted on CT and MRI. Transpedicular curettage and fusion L1L3 were performed. Histopathological examination revealed Langerhans cell histiocytosis. Although rare, Langerhans cell histiocytosis should be included in the differential diagnosis of the solitary lytic vertebral lesion in the adult. Good results have been reported, in the absence of systemic manifestations, with the most conservative approach possible. PMID- 21667742 TI - Unrecognized acute exertional compartment syndrome of the leg and treatment. AB - Acute-on-chronic exertional compartment syndrome is rare and may be easily missed without a high degree of awareness and clinical suspicion. We report a case of unrecognized acute-on-chronic exertional compartment syndrome in a recreational soccer player. The late sequela of this condition, foot drop, was successfully treated with transfer of the peroneus longus tendon. PMID- 21667743 TI - Giant extraosseous Ewing sarcoma of the lung in a young adolescent female--a case report. AB - Extraosseous Ewing sarcoma is a rare soft tissue tumour that is histologically indistinguishable from the bone Ewing sarcoma. The translocation involving chromosome 22 along with CD 99 expression is pathognomonic and is useful in differentiating from other small round cell tumours. Primary lung involvement by this malignant tumour is very uncommon and up to this date only ten cases have been reported. We report a further case in a 15 year-old-female who presented with a huge lung mass causing an opaque haemithorax. PMID- 21667744 TI - Myositis ossificans mimicking parosteal osteosarcoma: a case report and literature review. AB - Myossitis ossificans (MO) is an aberrant reparative process that causes benign heterotopic ossification in soft tissue. We report a case of MO presenting as a large mass located at the dorsal aspect of the distal thigh, with no history of trauma, with radiological and clinical features mimicking parosteal sarcoma. An incisional biopsy was performed and the mass was excised. The histological features identified the lesion as MO. In half of the cases, these ossifications may adhere to the periosteum. In these cases, the lesion is known as parosteal MO, which may be confused with a parosteal osteosarcoma. This parosteal MO seldom becomes malignant. We emphasize the importance of a differential diagnosis of MO, since these lesions may simulate tumours and lead to misdiagnosis. PMID- 21667745 TI - Sample size in psychological research over the past 30 years. AB - The American Psychological Association (APA) Task Force on Statistical Inference was formed in 1996 in response to a growing body of research demonstrating methodological issues that threatened the credibility of psychological research, and made recommendations to address them. One issue was the small, even dramatically inadequate, size of samples used in studies published by leading journals. The present study assessed the progress made since the Task Force's final report in 1999. Sample sizes reported in four leading APA journals in 1955, 1977, 1995, and 2006 were compared using nonparametric statistics, while data from the last two waves were fit to a hierarchical generalized linear growth model for more in-depth analysis. Overall, results indicate that the recommendations for increasing sample sizes have not been integrated in core psychological research, although results slightly vary by field. This and other implications are discussed in the context of current methodological critique and practice. PMID- 21667746 TI - Effect of first ball possession on partial and final scores in 2003, 2005, and 2007 Water Polo World Championships. AB - The purpose was to analyze the influence of winning the first ball possession on the partial and final score in male and female water polo. The 288 matches disputed by the teams participating in the 2003, 2005, and 2007 Water Polo World Championship were recorded. The results reflect statistically significant differences for the influence of gaining the first ball possession on the partial and final scoreboard of each period and for the influence between the total number of first possessions obtained and the final result. PMID- 21667747 TI - Psychometric properties of the German version of the Barratt Impulsiveness Scale, Version 11 (BIS-11) for adolescents. AB - Impulsiveness is increasingly gaining attention as a potential risk factor for various mental disorders. Until now, there have been German instruments that allowed for assessing adolescents' self-reported impulsiveness multi dimensionally. The present study examined the German version of the Barratt Impulsiveness Scale-11 (BIS-11) for adolescents. The instrument was completed by 659 adolescents ages 10 to 20 years; 98 were retested after 6 months. Items showed adequate psychometric properties. An exploratory factor analysis identified three factors that showed slightdifferences from the initial questionnaire proposed by Barratt. The factors showed low to moderate intercorrelations, satisfactory internal consistency (dependent on factor), and were stable over time. Convergent validity was ascertained, and the item pool showed sufficient power to discriminate adolescents with symptoms of attention deficit hyperactivity disorder and those with loss of eating control from healthy adolescents. Findings suggest that the German BIS-11 is appropriate for reliable investigation of impulsiveness in adolescents. Future research should examine sensitivity as a screening tool, as well as sensitivity to change. PMID- 21667748 TI - Useful visual field in patients with schizophrenia: a choice reaction time study. AB - This study examined the size of the useful visual field in patients (9 men, 6 women) with schizophrenia. A choice reaction task was conducted, and performances at 2.5, 5, 7, 10, and 25 degrees in both visual fields were measured. Three key findings were shown. First, patients had slower choice reaction times (choice RTs) than normal controls. Second, patients had slower choice RTs in the right visual field than in the left visual field. Third, patients and normal controls showed the same U-shaped choice RT pattern. The first and second findings were consistent with those of other studies. The third finding was a clear indication of the patients' performance in peripheral vision, and a comparison with normal controls suggested that there was no difference in the size of the useful visual field, at least within PMID- 21667749 TI - Five-minute speech sample measure of expressed emotion among parents of typically developing Italian children: a pilot study. AB - Although community samples have been used for comparison with at-risk and disturbed children, very few studies have examined parental Expressed Emotion in family members of typically developing children. This descriptive study reports Expressed Emotion for a community-based Italian sample of mothers and fathers of children without clinical mental health problems (N=101) ages 6 to 11 years (M = 8.2, SD = 1.4). Children were drawn from regular elementary schools in Italy. Expressed Emotion was measured using the Five-minute Speech Sample. Mothers', fathers', and families' Expressed Emotion frequencies and percents were calculated, as well as frequencies and percents of Expressed Emotion subcomponents of Criticism and Emotional Over-involvement. As expected, low rates were found. There were no significant differences between fathers' and mothers' Expressed Emotion categories. PMID- 21667750 TI - Changes in background impair fluency-triggered positive affect: a cross-cultural test using a mere-exposure paradigm. AB - This study examined whether repeated exposure would enhance positive evaluations when only a part of a stimulus (e.g., the central object) was identical to a previously presented stimulus. Japanese and American participants were exposed to photographs of animals with scenery, then asked their preferences for each of four types of photographs of animals (photographs of animals with the original scenery, photographs of animals without scenery, photographs of animals with novel scenery, and photographs of animals not depicted previously). Finally, their recognition of the animals presented in the exposure phase was tested. Members of both groups showed the mere-exposure effect for the first two types of stimuli, irrespective of stimulus recognition accuracy, whereas this effect was not observed for animals presented with novel scenery. This suggests that changes in background impair positive affect as a result of repeated exposure. PMID- 21667751 TI - Multiple goals, writing strategies, and written outcomes for college students learning English as a second language. AB - This study examined relations of achievement goals of writers who are speakers of English as a foreign language (EFL), the frequency of their writing strategy use, and the quality of their writing from a multiple goals perspective. The goal profiles of 57 EFL college students with similar writing proficiency were based on rating items of an unpublished scale; Group 1 had strong mastery and strong performance-approach goals, and two groups included students with only one strong mastery (Group 2) or performance (Group 3) goal. Think-aloud protocols indicated that the participants adopted 21 strategies in an argumentative writing task, classified into five categories. Group 1 was found to use writing strategies of monitoring or evaluating, revising, and compensating significantly more often than the other two groups, and produced better essays. Strong mastery and performance-approach goals might be beneficial for EFL college writers. PMID- 21667752 TI - Dyslexia and handedness: developmental phonological and surface dyslexias are associated with different biases for handedness. AB - Developmental disorders of reading and spelling have long been associated with increased left- and mixed-handedness but the evidence has been controversial. The right shift (RS) theory of handedness and cerebral dominance, developed by Annett from 1972 onward, offers resolutions to several puzzles about laterality in the so-called dyslexias. This review of findings in the light of the theory shows that "phonological" dyslexics are less likely to be right-handed, while "surface" or "dyseidetic" dyslexics are more likely to be right-handed than the general population. PMID- 21667753 TI - Daily activities and sleep quality in young adults. AB - Daily activity levels were investigated as related to sleep quality in young adult college students aged 18 to 30 years. 85 participants (20 men, 65 women) completed the Young Adult Daily Activity Scale (YADAS). This 37-item checklist has 34 items based on focus group discussion points of college students' typical daily activities and three blank items for students to include their daily activities if not in the listing. The tabulation of type and amount of waking daily activities represents a unique measurement of factors that may affect sleep quality. The participants also rated their typical sleep quality using a standard 5-point scale (low indicating poor sleep). Correlations of sleep ratings and activities were not significant. PMID- 21667754 TI - Recognizing dynamic scenes: influence of processing orientation. AB - From face recognition studies, it is known that instructions are able to change processing orientation of stimuli, leading to an impairment of recognition performance. The present study examined instructional influences on the visual recognition of dynamic scenes. A global processing orientation without any instruction was assumed to lead to highest recognition performance, whereas instructions focusing participants' attention on certain characteristics of the event should lead to a local processing orientation with an impairment of visual recognition performance as a direct consequence. Since the pattern of results provided evidence for this hypothesis, theoretical contributions were discussed. PMID- 21667755 TI - Handedness and footedness: relations to differences in sprinting speed and multiple sprints performance in prepubertal boys. AB - Physical performance and movement skills are differentiated by brain hemispheric dominance. Relations of handedness and footedness to differences in sprint speed and multiple sprints performances were investigated in 362 prepubertal, male, novice wrestlers. Participants with two months of irregular training experience were grouped by hand and foot preferences and matched on age and anthropometry. Mean running speed was associated with the number of sprints and handedness, but not with footedness. The decrease in sprint speed was less for right-handed subjects, who also had better sprinting speed and multiple sprint performance. Symmetrical arm and leg strength development for left-handers should be emphasized. PMID- 21667756 TI - Attentional effects of masked famous faces (but not names) and subjective evaluations of a target person. AB - Two experiments are reported using a 1986 version of the dot-probe paradigm of MacLeod, Mathews, and Tata, in which the masked subliminal faces of famous persons were differentially associated with attention depending on participants' attitudes toward the famous person. There was attentional avoidance of the faces of persons invoking high disgust (Exp. 1, n=20) or dislike (Exp. 2) but attentional orientation toward the faces of persons invoking low disgust or liking. In Exp. 2 (n=28), this effect was apparent for the faces but not the names of famous persons, despite evidence that the famous names were recognised without awareness. The aversion of attention from faces, but not the names of famous persons who are regarded in a negative light but who are not particularly threatening, may suggest an automatic tendency to avoid making eye contact with an undesirable person thereby avoiding unwanted social interaction. PMID- 21667757 TI - Virtual navigation performance: the relationship to field of view and prior video gaming experience. AB - Two experiments examined whether learning a virtual environment was influenced by field of view and how it related to prior video gaming experience. In the first experiment, participants (42 men, 39 women; M age = 19.5 yr., SD = 1.8) performed worse on a spatial orientation task displayed with a narrow field of view in comparison to medium and wide field-of-view displays. Counter to initial hypotheses, wide field-of-view displays did not improve performance over medium displays, and this was replicated in a second experiment (30 men, 30 women; M age = 20.4 yr., SD = 1.9) presenting a more complex learning environment. Self reported video gaming experience correlated with several spatial tasks: virtual environment pointing and tests of Judgment of Line Angle and Position, mental rotation, and Useful Field of View (with correlations between .31 and .45). When prior video gaming experience was included as a covariate, sex differences in spatial tasks disappeared. PMID- 21667758 TI - An additive model for relations between AQT single- and dual-dimension naming speed. AB - Color-form naming in A Quick Test of Cognitive Speed (AQT) is used to assess processing speed on three rapid automatic naming tasks, two of which measure single-dimension and the third of which measures dual-dimension naming speed. These tests have been used to identify changes in processing speed associated with normal aging. The present study evaluated whether a simple additive model could explain the normally expected relation between scores on measures of single and dual-dimension naming speed. The AQT color (C), form (F), and color-form (CF) naming tests were administered individually to 270 adults (ages 18 to 70 yr.). Paired-sample t tests mean comparisons of C+F and CF naming times for the total group and for three age cohorts (ages 18 to 34, 35 to 54, and 55 to 70), each with 90 adults, indicated significant mean differences between these processing-speed measures for the total group and for the 18- to 34- and 35- to 54-year age cohorts. Thus, a simple additive model does not explain the relationship between single- and dual-dimension naming speed across ages. To provide a better description, an additive model with "overhead" (a measure of processing efficiency) was proposed and norm-referenced for using the AQT tests to assess normal and atypical ranges for dual-dimension processing efficiency (overhead). ANOVA with post hoc analysis (Scheffe) compared AQT C + F, CF, and overhead means across age cohorts. The results indicated significant mean differences for the CF and overhead measures, but not for the C+F measure. Normative ranges for typical overhead sizes were established for each age cohort. In clinical practice, an overhead larger than typical or normal for a given age would suggest executive dysfunction, involving attention, visual working memory, and set shifting. PMID- 21667759 TI - Effects of interior colors on mood and preference: comparisons of two living rooms. AB - The purpose was to assess whether various colors across room interiors do, in fact, evoke different moods. Digital images of two imaginary living rooms were used as the experimental settings. For each of the experiments, the rooms' spatial characteristics were fixed, with only the colors changed: either warm, cool, or achromatic colors. As predicted, warm colors tended to produce stronger participant responses when rating the scene on "high arousal," "exciting," and "stimulating." Cool colors tended be associated with "not very arousing," but to be rated higher on "spacious" and "restful." It is generally assumed that cool and achromatic colors evoke calmer and more peaceful emotions. The study's results show that the spatial characteristics of the imaginary spaces themselves affected participants' responses only on measures of "happiness" and "vividness." Lastly, sex differences were also found, with women's ratings generally more positive than those of men. PMID- 21667760 TI - Visual processing of music notation: a study of event-related potentials. AB - In reading music, the acquisition of pitch information depends mostly on the spatial position of notes, hence more spatial processing, whereas the acquisition of temporal information depends mostly on the visual features of notes and object recognition. This study used both electrophysiological and behavioral methods to compare the processing of pitch and duration in reading single musical notes. It was observed that in the early stage of note reading, identification of pitch could elicit greater N1 and N2 amplitude than identification of duration at the parietal lobe electrodes. In the later stages of note reading, identifying pitch elicited a greater negative slow wave at parietal electrodes than did identifying note duration. The sustained contribution of parietal processes for pitch suggests that the dorsal pathway is essential for pitch processing. However, the duration task did not elicit greater amplitude of any early ERP components than the pitch task at temporal electrodes. Accordingly, a double dissociation, suggesting involvement of the dorsal visual stream, was not observed in spatial pitch processing and ventral visual stream in processing of note durations. PMID- 21667761 TI - An exploratory investigation of coffee and lemon scents and odor identification. AB - Fragrance sellers often provide coffee beans to their customers as a "nasal palate cleanser," to reduce the effects of olfactory adaptation and habituation. To test this idea, college students smelled three fragrances multiple times, rating odors each time. After completing nine trials, participants sniffed coffee beans, lemon slices, or plain air. Participants then indicated which of four presented fragrances had not been previously smelled; Coffee beans did not yield better performance than lemon slices or air. PMID- 21667763 TI - Competitive state anxiety and performance in young female rhythmic gymnasts. AB - The study was designed to examine the competitive state anxiety and self confidence of rhythmic gymnasts participating in the Greek national competition. 86 participants, ages 11 and 12 years, completed the Competitive State Anxiety Inventory-2, 1 hr. before competition. The athletes, classified by performance (high and low performance) and participation in the finals (finalists and nonfinalists), responded to the three subscales: Cognitive Anxiety, Somatic Anxiety, and Self-confidence. Analyses indicated differences in Self-confidence between high versus low performance groups and finalists versus nonfinalists. No significant differences were found on Cognitive and Somatic Anxiety. In a regression analysis, Self-confidence was the only significant predictor of performance for this sample. Implications refer to the development of strategies to enhance self-confidence in order to improve the gymnast's performance during competition. PMID- 21667762 TI - Response normalized omni rating of perceived exertion at the ventilatory breakpoint in division I football players. AB - This investigation identified an OMNI Scale rating of perceived exertion associated with the ventilatory breakpoint in Division I football players. This easily applied prescriptive reference may be used to self-regulate training intensity. The OMNI Scale format may facilitate estimation of exertional perceptions. 34 participants completed a maximal treadmill test. OMNI ratings of perceived exertion were estimated during the last 15 sec. of each workload. The rating corresponding to the ventilatory breakpoint was determined for each participant using linear regression analysis. The ventilatory breakpoint corresponded to 68.8% of VO2max (SD = 7.5% of VO2 max) and a heart rate of 158.9 beats min(-1) (SD = 11.9 beats min(-1)). The rating of perceived exertion associated with the ventilatory breakpoint was 5.1 (SD = 1.2). This perceptual reference point, not previously identified in Division I football players, could be used in field settings to self-select exercise intensity around the ventilatory threshold. PMID- 21667764 TI - Different gripping intervals in reproducibility of force-decreasing curve and muscle oxygenation kinetics during sustained maximal gripping. AB - The purpose was to examine the properties and reproducibility of the force decreasing curve and muscle-oxygenation kinetics measured by near infrared spectroscopy in sustained isometric grip and rhythmic repeated grip measurements using various contraction intervals (2 to 5 sec.). 10 healthy young adults performed both grip tests for 6 min., during which muscle-oxygenation kinetics were measured. The intraclass correlation coefficients of the time to reach the minimum value for oxygenated hemoglobin and myoglobin tended to become lower with longer relaxation time, especially over a 3-sec. interval. Although blood-flow obstruction closely influences the initial decreasing grip force during both grip tests with a 2-sec. interval, the decreasing grip force during rhythmic repeated gripping with over a 3-sec. interval is low. Hence, the physiological mechanism related to rhythmic repeated grip with over a 3-sec. interval may differ from that related to sustained isometric grip and rhythmic repeated grip with a 2-sec. interval. PMID- 21667765 TI - Physical and motor skill training for children with intellectual disabilities. AB - This study investigated the effectiveness of using special training machines for children with intellectual disabilities to strengthen their body's inner muscles and improve their ability to maintain standing posture and improve walking movement. The participants were 23 high school age boys with intellectual disabilities who had difficulties expressing greetings, and needed to be led by the hand when walking. Four special training machines were used for walking movements, for standing and walking balance, for leg-hip extension, and for ipsilateral movement in a sitting position. Each participant underwent 30 min. of training once a week over a 3-mo. period during school time. Body control ability required to perform each training exercise was improved over the training period. A significant improvement was observed in the 50-m dash, mean 10-m walk time, and 10-m obstacle course walk. The hip joint split angle showed a significant increase. Legal guardians all reported their child had "improved and/or progressed" for each of the targeted movements. PMID- 21667766 TI - Elite sport is not an additional source of distress for adolescents with high stress levels. AB - This study examined whether participation in elite sport interacts with stress in decreasing or increasing symptoms of depression and anxiety among adolescents, and further, whether the interplay between participation in high-performance sport and stress is related to the perceived quality of sleep. 434 adolescents (278 girls, 156 boys; age: M = 17.2 yr.) from 15 "Swiss Olympic Sport Classes" and 9 conventional classes answered a questionnaire and completed a 7-day sleep log. Analyses of covariance showed that heightened stress was related to more depressive symptoms and higher scores for trait-anxiety. Moreover, those classified as having poor sleep by a median split cutoff reported higher levels of depressive symptoms. No significant (multivariate) main effects were found for high-performance sport athletes. Similarly, no significant two- or three-way interaction effects were found. These results caution against exaggerated expectations concerning sport participation as a stress buffer. Nevertheless, participation in high-performance sport was not found to be an additional source of distress for adolescents who reported high stress levels despite prior research that has pointed toward such a relationship. PMID- 21667767 TI - Re-examining the home disadvantage in professional ice hockey. AB - Occurrence of the home disadvantage in professional ice hockey was examined by analyzing shootout data from 2005 through 2008. Results indicated that teams involved in shootouts playing at their home arenas did not lose significantly more games at home than on the road. Results did not support the hypotheses that emphasize the roles of physical contact and diffusion of responsibility in accounting for past failures to find the home disadvantage in professional ice hockey. PMID- 21667768 TI - Children's discrimination of fantastic vs. realistic visual displays after watching a film with magical content. AB - Six- and nine-yr.-old children (n=28 of each) were divided into equal experimental and control groups. The experimental groups were shown a film with a magical theme, and the control groups were shown a film with a nonmagical theme. All groups then were presented with a choice task requiring them to discriminate between ordinary and fantastic visual displays on a computer screen. Statistical analyses indicated that mean scores for correctly identifying the ordinary and fantastic displays were significantly different between experimental and control groups. The children in the experimental groups who watched the magical film had significantly higher scores on correct identifications than children in the control groups who watched the nonmagical film for both age groups. The results suggest that watching films with a magical theme might enhance children's sensitivity toward the fantasy/reality distinction. PMID- 21667769 TI - Efficacy of an explicit handwriting program. AB - The aim of this study was to investigate the effects of an explicit handwriting program introduced during the first grade of elementary school. Grade 1 children (N=23) with an age range of 6.1 to 7.4 yr. (15 girls, 8 boys) were administered an additional handwriting program of two weekly sessions of 45 min. over six weeks. Another group of 19 Grade 1 children (11 girls, 8 boys) received only the regular handwriting program of one weekly session. The Concise Assessment Scale for Children's Handwriting was administered to measure the changes in quality and speed of handwriting. The children given the explicit program showed better quality and speed of handwriting than did the control group. Their handwriting was more regular, with fewer ambiguous letters and fewer incorrect relative heights. PMID- 21667770 TI - Discrimination of amount of spinal flexion for movements made with and without vision after lumbar disc replacement. AB - Discrimination of differences between small lumbar flexion movements made when standing may differ depending on whether vision is available. Dependence on general vision during trunk movements may be increased following surgery, in which an intervertebral disc is replaced with a prosthetic disc. This study investigated whether the availability of vision changed discrimination of small differences in lumbar forward flexion movement when standing for patients with lumbar disc replacement and healthy peers. 20 volunteers without a history of back pain and 20 with disc replacement undertook a 100-trial sequence of forward flexion movements to a set of physical stops, making an absolute judgement as to the position after each movement. General (nontarget) vision during the movement was available or removed randomly trial by trial. Availability of vision did not affect discrimination of flexion movements of the lumbar spine either in normal healthy individuals or those with disc replacement. PMID- 21667771 TI - Differentiating clinical groups using the serial color-word test (S-CWT). AB - The present study attempted to differentiate 11 diagnostic groups by means of the Serial Color-Word Test (S-CWT), using multivariate discriminant analysis. Two alternative scoring systems of the S-CWT were outlined. Asample of 514 individuals who had clinical diagnoses of various types and 397 controls who had no diagnostic findings comprised the sample. The first discriminant analysis failed to differentiate the groups adequately. The groups were consequently reduced to four (schizophrenia, bipolar disorders, temporo-mandibular joint pain dysfunction syndrome, and eating disturbances), which gave better reclassification findings for a clinical application of the test. This classification gave over 55% correct assignments. The final four groups had a statistically significant discrimination on the test, which remained stable also in a bootstrap procedure. Implications for treatment indications and outcomes as well as strategies for further studies using the S-CWT are discussed. PMID- 21667772 TI - A review of time-motion analysis and combat development in mixed martial arts matches at regional level tournaments. AB - Mixed martial arts (MMA) have become a fast-growing worldwide expansion of martial arts competition, requiring high level of skill, physical conditioning, and strategy, and involving a synthesis of combat while standing or on the ground. This study quantified the effort-pause ratio (EP), and classified effort segments of stand-up or groundwork development to identify the number of actions performed per round in MMA matches. 52 MMA athletes participated in the study (M age = 24 yr., SD = 5; average experience in MMA = 5 yr., SD = 3). A one-way analysis of variance with repeated measurements was conducted to compare the type of action across the rounds. A chi-squared test was applied across the percentages to compare proportions of different events. Only one significant difference (p < .05) was observed among rounds: time in groundwork of low intensity was longer in the second compared to the third round. When the interval between rounds was not considered, the EP ratio (between high-intensity effort to low-intensity effort plus pauses) was 1:2 to 1:4. This ratio is between ratios typical for judo, wrestling, karate, and taekwondo and reflects the combination of ground and standup techniques. Most of the matches ended in the third round, involving high-intensity actions, predominantly executed during groundwork combat. PMID- 21667773 TI - Cognitive parameters and morning and evening types: two decades of research (1990 2009). AB - An important area of study has examined cognitive aspects of morningness eveningness orientation. Optimal times of efficiency in participants classified as Morning and Evening types are of great importance for understanding their cognitive abilities. The present review covers the last two decades (1990-2009), during which the important review by Tankova, Adan, and Buela-Casal appeared, and focuses particularly on attention, memory, and executive functions. PMID- 21667774 TI - Personal equations: reflections on the history of fieldwork, with special reference to sociocultural anthropology. AB - In the latter part of the nineteenth century, diverse sciences grounded in natural history made a virtue of field research that somehow tested scientists' endurance; disciplinary change derived from the premise that witnesses were made reliable by character-molding trials. The turn to the field was a function of structural transformations in various quarters, including (but hardly limited to) global politics, communications systems, and scientific institutions, and it conduced to biogeographical explanations, taxonomic schemes that admitted of heterogeneity, and affective research styles. Sociocultural anthropology, which took specialized shape at the beginning of the twentieth century, shared many properties with other field sciences, but its method--participant observation-was distinctive. Critical to the method's definition were the efforts of the British experimental psychologist-anthropologist W. H. R. Rivers, who relied on notions then widespread in Europe and the United States. The discipline's future mythic hero, Bronislaw Malinowski, embraced Rivers's model. For both men, proper fieldwork meant using the researcher's body as an instrument and entailed understanding both the anthropologist's body and the research subject's body as energy systems; this symmetry facilitated a relativist perspective. Participant observation remains central to sociocultural anthropology, but the discipline's pedagogic habits contributed to loss of memory of its energetic conceptualization. PMID- 21667775 TI - Public science for a global empire: The British quest for the South Magnetic Pole. AB - It is well known to historians of science that, early in the nineteenth century, terrestrial magnetism became both a popular science and a significant research enterprise in Europe. For Britain, as a maritime power, it offered benefits for navigation. Theoretical physicists claimed that, with enough observations of magnetic variation, intensity, and dip taken throughout the world over time, they could deduce regular mathematical laws to explain the phenomena. Because of the lack of data from the region, particular attention focused on field research in deep southern latitudes. Finding the precise location of the South Magnetic Pole became a prime goal for some enthusiasts. With burgeoning colonies in Africa and the Antipodes, Britain assumed a leading role in this effort. British scientists looked to their government for funding and called on the Admiralty to dispatch expeditions. It is less well known that both popular and scientific interest in terrestrial magnetism continued throughout the nineteenth century and into the early twentieth century. The H.M.S. Erebus and H.M.S. Terror (1839-1843), H.M.S. Challenger (1872-1876), and R.Y. Discovery (1901-1904) sailed to the Antarctic as part of Britain's extended "Magnetic Crusade," which culminated with Royal Society geologist T. W. Edgeworth David of the Nimrod expedition reaching the South Magnetic Pole in 1909. PMID- 21667776 TI - The experimenter's museum: GenBank, natural history, and the moral economies of biomedicine. AB - Today, the production of knowledge in the experimental life sciences relies crucially on the use of biological data collections, such as DNA sequence databases. These collections, in both their creation and their current use, are embedded in the experimentalist tradition. At the same time, however, they exemplify the natural historical tradition, based on collecting and comparing natural facts. This essay focuses on the issues attending the establishment in 1982 of GenBank, the largest and most frequently accessed collection of experimental knowledge in the world. The debates leading to its creation-about the collection and distribution of data, the attribution of credit and authorship, and the proprietary nature of knowledge-illuminate the different moral economies at work in the life sciences in the late twentieth century. They offer perspective on the recent rise of public access publishing and data sharing in science. More broadly, this essay challenges the big picture according to which the rise of experimentalism led to the decline of natural history in the twentieth century. It argues that both traditions have been articulated into a new way of producing knowledge that has become a key practice in science at the beginning of the twenty-first century. PMID- 21667777 TI - Focus: between and beyond "histories of science" and "histories of medicine". Introduction. AB - Historians tend to treat science and medicine as having developed in parallel, and we maintain separate societies and journals, often giving primacy to science, at least for intellectual history. Yet much of "science" before circa 1800 was dependent on the organizations of medicine, and much of science now is promoted for the improvement of medical diagnoses and therapies. This Focus section unpicks some of the historical and historiographical relationships, recognizing the present prominence of biomedicine and the diminishing utility of distinctions between science, medicine, and technology. PMID- 21667778 TI - The history of medicine and the scientific revolution. AB - The "new philosophy" of the seventeenth century has continued to be explained mainly on its own terms: as a major philosophical turn. Twentieth-century modernism gave pride of place to big ideas and reinforced the tendency to explain the rise of science in light of new ideas. Such orientations subordinated medicine (and technology) to sciences that appeared to be more theoretical. In attempts to persuade historians of science of the importance of medicine, then, many authors took an approach arguing that the major changes in the history of medicine during the so-called scientific revolution arose from philosophical commitments. Yet because medicine is also intimately connected to other aspects of life, its histories proved to be recalcitrant to such reductions and so continue to offer many possibilities for those who seek fresh means to address histories of body and mind united rather than divided. PMID- 21667779 TI - Practice and the science of medicine in the nineteenth century. AB - A generation ago the nineteenth century was at the heart of medical historical scholarship, as the era when modem medicine was born. Over the last decade or so things have changed: other centuries vie for center stage, and former key "turning points," like hospital medicine and laboratory medicine, are now seen in terms of continuities on longer timescales. But though chronologically reframed, the modes of medicine still appear chiefly at the level of programmatic intentions, including rhetorical uses of science. This essay argues that work in this vein needs to be complemented with equal attention to the performative aspects of practice--in the clinic, in the laboratory, and in the field--and that historians of medicine still have much to learn from the "practice turn" in the history of science. PMID- 21667780 TI - Historiography of biomedicine: "bio," "medicine," and in between. AB - History of biomedicine is a hybrid domain, intersecting with many other scholarly disciplines. From the 1970s, historians who investigated recent developments in medicine increasingly shared the approaches, presuppositions, and methods of inquiry of historians and sociologists of science and technology. One reason is that the increasing reliance of medicine on technologies, instruments, and drugs makes the demarcation between "medicine," "science," and "industry" more difficult. Another is the "practice turn" in the history of science, which gave greater attention to the ways scientists and physicians work. The impressive achievements of historians who applied these new approaches came, however, at a cost. The neglect of an earlier generation of historians of medicine may have limited more recent ambitions for understanding health and disease in society. Closer links with historians of science and technology and sociologists of science may have blurred the specificity of medicine as a domain grounded in the distinction between the normal and the pathological and lessened scholars' interest in "the clinic" as a unique site of the production of knowledge. PMID- 21667781 TI - Sketching together the modern histories of science, technology, and medicine. AB - This essay explores ways to "write together" the awkwardly jointed histories of "science" and "me dicine"--but it also includes other "arts" (in the old sense) and technologies. It draws especially on the historiography of medicine, but I try to use terms that are applicable across all of science, technology, and medicine (STM). I stress the variety of knowledges and practices in play at any time and the ways in which the ensembles change. I focus on the various relations of "science" and "medicine," as they were understood for a succession of periods- from mainly agricultural societies, through industrial societies, to our biomedical present--trying to sketch a history that encompasses daily practices and understandings as well as major conceptual and technical innovations. The model is meant to facilitate inquiry across topics and across times, including those to come. PMID- 21667782 TI - The engrained notion that Newton's genius can account for the advent of scientific modernity and the subsequent French Enlightenment. PMID- 21667783 TI - The real deal. PMID- 21667784 TI - Global service-learning and nursing education: Merging with the world through pedagogy. PMID- 21667785 TI - Going global: Enhancing nurse educators' participation in achieving the millennium development goals. PMID- 21667786 TI - Tamara McKinnon, MS, RN. PMID- 21667787 TI - Student achievement and NCLEX-RN success: Problems that persist. AB - While most nurse graduates are successful on the NCLEX-RN licensure examination, certain students continue to be at risk for failure. To understand the complexity of at-risk students and NCLEX-RN failure, systems theory was used to analyze the interdependency of the nursing education system and the nursing student learning system. From this perspective, these problems relate to flaws in perceived learning gaps and student outcome measures. Predicting NCLEX-RN success is further complicated because students leave the teaching system prior to taking the exam, making them vulnerable to other influencing variables. The student's approach to learning (SAL) theory was used to aid in identifying effective strategies. The literature supports this theoretical approach, which targets changing the teaching and learning environment. However, there is limited research on the nursing student's approach to learning, on the benefits of innovative student-centered learning environments, and the most effective use of NCLEX-RN assessment products. PMID- 21667788 TI - Getting started: Needs and preferences of Colorado faculty for graduate education in nursing. AB - The projected shortage of nurses is greatly influenced by the shortage of nursing faculty. This is of significant concern in Colorado due to increasing requirements for master's-prepared instructors at all levels. While there are many reasons for the faculty shortage, this study looked specifically at the needs and preferences of current nursing instructors related to obtaining graduate education in nursing. The survey results paint a picture of nurse faculty who need new approaches to managing graduate course work in addition to teaching and family responsibilities. Help with expenses through grants, scholarships, and loan forgiveness is vital. Potential graduate students rarely consider full-time or on-campus study, instead favoring online, one-per-semester, year-round courses. They are concerned about practicum hours, less concerned about graduate-level academic work, and not very concerned about online methods. There were no evident differences in needs and preferences for further education based on rural/urban location or community college/university setting. PMID- 21667789 TI - Are nursing students engaged in learning? A secondary analysis of data from the National Survey of Student Engagement. AB - Evidence in higher education supports the practice of active learning as a method of promoting student engagement among college students that has positive effects on problem solving, critical thinking, and persistence. No studies have been reported that evaluate the undergraduate nursing students' level of engagement in college compared with other majors. The purpose of this study was to determine if differences exist between levels of nursing students' engagement and those of education and other health professional students as measured by the National Survey of Student Engagement (NSSE). The NSSE is a self-reporting instrument consisting of 70 items measuring level of academic challenge; student interactions with faculty; supportiveness of the campus environment; participation in active and collaborative learning; and enriching educational experiences. Using a descriptive, correlation design, the study incorporated a secondary analysis of NSSE data collected from freshmen and seniors during 2003. Selected demographic data (freshman or senior status) and NSSE data measuring five benchmarks of engagement were analyzed using ANOVA and t-tests to determine relationships. Freshmen were found to be less engaged than seniors on four of five benchmarks. Nursing and other health profession majors perceived themselves to be significantly less engaged in active and collaborative learning than education majors. Nursing students perceived themselves as significantly more academically challenged than their peers in education and other health professions. Results indicate that although nursing students are engaged in rigorous curricula, they do not perceive themselves to be engaged in student centered and interactive pedagogies. Implications for further research exploring potential barriers surrounding active and collaborative learning strategies are discussed. PMID- 21667790 TI - Core principles for developing global service-learning programs in nursing. AB - Global service-learning enables nursing to develop its role in promoting global health and enabling vulnerable and marginalized global communities to develop their own capacity for growth and development. Global service-learning requires good planning that is based on sound best-practice principles. Drawing on the growing body of literature on service-learning, the authors outline and discuss seven key principles that can usefully guide global service-learning. These are: are compassion, curiosity, courage, collaboration, creativity, capacity building, and competence. These principles can form the basis for ethically sound program development, offer a means of standardizing program development, and provide common criteria with which to evaluate a program's success. PMID- 21667791 TI - Evaluating the effectiveness of intercultural teachers. AB - With globalization and major immigration flows, intercultural teaching encounters are likely to increase, along with the need to assure intercultural teaching effectiveness.Thus, the purpose of this article is to present a conceptual framework for nurse educators to consider when anticipating an intercultural teaching experience. Kirkpatrick's and Bushnell's models provide a basis for the conceptual framework. Major concepts of the model include input, process, output, and outcome.The model may possibly be used to guide future research to determine which variables are most influential in explaining intercultural teaching effectiveness. PMID- 21667792 TI - Validating graduate student programmatic outcomes. AB - One area of paramount importance for a school of nursing's accreditation process is the evaluation of competencies and/or outcomes for the program. Each course within a program is expected to bring the students to the point of comprehending the selected programmatic outcomes while determining an improvement in the mastery of the designated competencies. Schools of nursing have used capstone courses to provide an avenue for the documentation of the synthesis and acquisition of material addressed by programmatic outcomes.This article provides a discussion of one such capstone endeavor used within a university setting, where the school of nursing elected to conduct a non-thesis-requiring program. The capstone experience employed for this program allows for synthesis of concepts, self-reflection, personal assessment, and striving for completeness. PMID- 21667793 TI - Creating and measuring social presence in online graduate nursing courses. AB - The literature has shown that social presence is one of the most significant factors in building a sense of community in online education. This pilot study examines the outcomes of integrating social presence strategies into an online graduate nursing course and lays the groundwork for a larger study into dimensions of social presence and student satisfaction. Using a two-group comparison design, the results demonstrate that the purposeful incorporation of specific social presence techniques had a positive impact on student perceptions of social presence and group interaction as well as online learning expectations. PMID- 21667794 TI - Social presence, satisfaction, and perceived learning of RN-to-BSN students in Web-based nursing courses. AB - The purpose of this study was to assess social presence in online nursing courses and its relationship to student satisfaction and perceived learning. The Social Presence scale and the Satisfaction scale were administered via an Internet survey to students (n = 128) in an online RN-BSN program. Results indicated a strong relationship among satisfaction, social presence, and instructor performance. All subdomains of social presence correlated highly with the satisfaction subdomains, except the communication factor. A strong relationship was found between perceived learning and social presence and comfort with the online course. Overall social presence, instructor performance, and the subdomains of social presence predicted a significant amount of total variance in overall satisfaction and perceived learning. No significant relationships were found between the demographic factors and overall social presence or perceived learning. Results of this study can assist nurse educators in providing optimal online educational experiences for students. PMID- 21667796 TI - Nursing education 2.0: The need for social media policies for schools of nursing. PMID- 21667795 TI - Assessing continued competency through simulation: A call for stringent action. AB - This article proposes that simulation has potential as a method to validate critical and reflective thinking skills and continued competency of registered nurses. The authors recognize the challenges and benefits for using simulation in assessing competency. Furthermore, the authors stress that the potential use of simulation in competency testing cannot be achieved until educators and researchers acquire the specific knowledge and skills to make informed decisions and recommend policy. PMID- 21667797 TI - Basic life support: A call for reevaluation by nurse educators. PMID- 21667798 TI - Developing a portrait of a nursing education leader. PMID- 21667799 TI - Re: Myocardial infarction after TASER exposure. J La State Med Soc 2010; 162: 291 295. PMID- 21667800 TI - ECG of the month. ECG the day after aortic valve replacement. Isorhythmic dissociation of an accelerated junctional rhythm from sinus rhythm, left anterior fascicular block, left ventricular hypertrophy with repolarization change. PMID- 21667801 TI - Radiology case of the month. Foot pain and swelling. Lisfranc fracture dislocation with associated ligamentous tear. PMID- 21667802 TI - Serum markers for severe Clostridium difficile infection in immunosuppressed hospitalized patients. AB - Clostridium difficile infection (CDI) has emerged as the leading cause of nosocomial diarrhea in the developed world. The prompt recognition of severe CDI is essential in providing early aggressive therapy. Though previous studies have identified leukocytosis, azotemia, and hypoalbuminemia as markers to differentiate severe from non-severe CDI in the general patient population, there is little data in immunosuppressed patients. We conducted a retrospective chart review of immunosuppressed patients with CDI to identify serum markers associated with severe CDI. Twenty-nine immunosuppressed patients with CDI (nine with severe disease) were identified. Those with severe disease were older and had evidence of renal dysfunction. The white blood cell count, platelet, and albumin levels were the same in the severe and non-severe immunosuppressed CDI patients. Therefore, recognized serum markers of severe CDI are not universally useful in immunosuppressed patients. Moreover, the clinician must be aware that immunosuppressed patients can develop severe CDI while remaining leukopenic. PMID- 21667803 TI - Continuity of care and diabetes mellitus management in an internal medicine residency program. AB - The advantages of the continuity of care in residency training have yet to be established. We evaluated the association between continuity of care and diabetes quality of care in an internal medicine residency program with two clinics, a "primary care clinic (non-continuity clinic)" and a "medicine continuity clinic (continuity clinic)." Study subjects were those who: 1) had visited the non continuity clinic or continuity clinic between July 2005 and June 2006, 2) were aged 40 to 75, and 3) have diabetes (N=423). Although more subjects in continuity clinic had proteinuria testing and ophthalmologist visit than subjects in non continuity clinic, there was no significant difference in any process measures between the two clinics after multiple adjustments. Health outcomes did not differ between the continuity clinic and non-continuity clinic before and after multiple adjustments. The concept of continuity needs to be revisited with respect to the processes and outcomes of diabetes care. PMID- 21667804 TI - Who's your donor? Bringing about Louisiana's first domino paired exchange transplants. AB - Although living donation is the preferred method of kidney transplant, many donors are not a match with their intended recipient. One unique way of overcoming this is by performing a donor paired exchange. By swapping donors, transplant centers may be able to bring about multiple transplants that would not have otherwise been possible. This manuscript describes the first three way domino paired donor exchange transplant in Louisiana. Because of a single altruistic donor, we were able to facilitate three recipients getting transplanted. We discuss the formulation of this unique program, the choosing of potential donor/recipient pairs and outcomes. A review of the controversies of paired kidney donation is also presented. PMID- 21667805 TI - Surgical treatment of pancreatic cancer. PMID- 21667806 TI - Pancreatic adenocarcinoma presenting as acute pancreatitis during pregnancy: clinical and radiologic manifestations. AB - Only seven cases of pancreatic adenocarcinoma diagnosed during pregnancy have been reported. In this article, we describe a case of pancreatic adenocarcinoma presenting clinically as acute pancreatitis in a pregnant patient. Magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) revealed a pancreatic mass with an inflammatory component and multiple hyperintense metastatic lesions in the liver. The patient was initially treated for biliary pancreatitis, and pancreatic cancer was not suspected given her young age and absence of risk factors. A diagnosis of pancreatic cancer in a pregnant patient requires a high index of suspicion, and pancreatitis can be a mode of presentation. PMID- 21667807 TI - Be a responsible leader. PMID- 21667808 TI - Think tank moots alternative path to reform. PMID- 21667809 TI - Can-do attitudes get staff and patients onside. PMID- 21667810 TI - Openness is the way to learn. PMID- 21667811 TI - Room at the top for true leaders. PMID- 21667812 TI - Promoting patient involvement in safety initiatives. AB - Between 300,000 and 1.4 million adverse events occur each year in the NHS, and about half of those that occur in inpatient settings are preventable (Department of Health Expert Group on Learning from Adverse Events in the NHS 2000). Strategies to reduce these events have focused mainly on changing systems of care and professional behaviour, but there is growing interest in involving patients in safety initiatives. This stresses the development and use of interventions to promote and support patients' and their representatives' roles in securing their own safety in health care. This article reports the results of a series of linked studies that examined how patients might effectively promote their own safety, and to explore how this might vary by context, place or demography. PMID- 21667813 TI - Improving care on mental health wards with hourly nurse rounds. AB - Hourly rounds are becoming more popular on inpatient medical wards and are known to be beneficial to patients and nurses. However, there is little evidence about their impact in psychiatry and what hourly rounds would look like on inpatient mental health units. This article examines the introduction of hourly nurse rounds on inpatient mental health wards in an American hospital, and how they were adapted to the needs of psychiatric patients. The positive effects on patient care and staff are reported. PMID- 21667814 TI - The productive ward: encouraging teambuilding and innovation. AB - The aim of the NHS Institute for Innovation and Improvement's Productive Ward series is to remove wasteful activities from ward processes and reinvest the time saved in making care more interactive, stimulating, reliable and safe. This article describes how the introduction of Productive Ward on one unit in a mental health trust has delivered improvements in general ward organisation and a range of ward processes, and has motivated and empowered team members to make changes and innovate. The article also describes leadership and teamworking lessons that the ward matron and project facilitator have learnt. PMID- 21667815 TI - Staff support in continuing professional development. AB - This article reports on a training needs analysis (TNA) project, undertaken with three different hospital trusts in England, that uses a work-based and action learning approach. It relates to the format of the projects and the identification of training needs for healthcare practitioners. A second article will report on the implementation of TNA in one trust after completion of the project. The work is important for nurse managers and leaders responsible for continuing professional development budgets. The project was targeted at the delivery of trust priorities and offered potential for a different way of working designed to meet new and emerging NHS organisational requirements. In addition, given its multidisciplinary nature, it offered the facility to work with multidisciplinary clinical colleagues to explore different learning and development opportunities and issues. PMID- 21667816 TI - Everyone benefits. PMID- 21667817 TI - Determination of lymphatic vascular identity and developmental timecourse in zebrafish (Danio rerio). AB - Zebrafish lymphatics have been shown to share a number of characteristics with their human counterparts, making the fish a potentially useful model for studying lymphatic development and disease. The utility of the zebrafish lymphatic model would be substantially enhanced by an improved understanding of the spatiotemporal development of the primary lymphatic vasculature. The goal of this project is to identify and map the major zebrafish lymphatic structures throughout embryonic to early juvenile stages of development. Two transgenic lines, kdr-1:RASmCherryxfli1:GFP and stabilin1:YFP, were recently derived to assist in the study of developing lymphatic vasculature, but their specificity has not been rigorously tested. In the course of the present study, we experimentally validate the utility of these two marker lines as potential tools for establishing lymphatic vascular identity and visualizing developmental lymphangiogenesis. We introduced twenty nanometer red florescent microspheres into the blood vasculature of flil:GFP zebrafish and collected tiled optical z sections at time intervals spanning early development. Three-dimensional reconstructions of the vasculature were used to differentiate between blood and lymphatic vessels. Age-matched injected embryos were compared to the two transgenic lines to further assess their specificity. We created a spatiotemporal map of the major lymphatic vessels in the developing zebrafish including a previously unidentified lymphatic vessel in the gastrointestinal tract. We conclude that the kdr-1:RASmCherryxfli1:GFP line accurately identifies developing lymphatic vessels with the exception of those associated with the gastrointestinal tract. The stabilin1:YFP line, however, is less reliable, as it marks both venous vessels and lymphatic vessels. PMID- 21667818 TI - Impact of manual lymphatic drainage on hemodynamic parameters in patients with heart failure and lower limb edema. AB - Manual lymphatic drainage (MLD), intermittent sequential pneumatic therapy (ISPT), multilayered bandages (MLB), and compression garments are main techniques in conservative treatment of peripheral lymphedema. Since 1990, it has been thought that ISPT applied to both lower limbs simultaneously should not be used for patients with heart failure because right atrial, pulmonary arterial, and pulmonary wedge pressures may increase to a critical point. In 2005, these same results were observed in patients with heart failure wearing MLB. For these reasons, MLB and ISPT have been contraindicated during lymphedema treatment in cardiac patients. The aim of this study was to determine if we may continue the treatment of lower limb lymphedema using MLD in patients with heart failure. We evaluated hemodynamic parameters using echography during MLD in patients with cardiac disease and obtained circumferential measurements of the edematous limb before and after treatment. MLD treatment significantly decreased the limbs as expected. The heart rate also decreased following MLD in contrast with all other hemodynamic parameters which were not affected by MLD. The findings suggest that there is no contraindication to use MLD in patients with heart failure and lower limb edema. PMID- 21667819 TI - Somatostatin receptors SSTR2 and SSTR5 are expressed in the human thoracic duct. AB - Somatostatin and its analog octreotide have been used successfully to treat postoperative chylothorax, and it has been shown that octreotide binds with high affinity to somatostatin receptor (SSTR) subtypes 2 and 5. Therefore, we investigated expression of SSTR2 and SSTR5 in the human thoracic duct by immunohistochemistry. Normal rat pancreas was used as a positive control for antibodies against SSTR2 and SSTR5, and Factor VIII-related antigen, SMA, actin, elastin, or collagen type II, III, IV or V antibodies were used to identify cell types and structures within the human thoracic duct. The antibodies against SSTR2 and SSTR5 worked well and yielded positive staining in control rat islets. In the human thoracic duct, SSTR2 was present in smooth muscle cells and some scattered structures which were stained by antibodies against Factor VIII-related antigen, SMA, actin, elastin or collagen type II, III, IV or V. SSTR5 was also present in smooth muscle cells. The presence of SSTR2 and SSTR5 in the human thoracic duct sheds light on the mechanism of somatostatin and octreotide use in the successful treatment of chylothorax and offers new molecular pathways to explore for potential future therapies. PMID- 21667820 TI - B-type natriuretic peptide in lymphedema. AB - Lymphedema often responds to compression therapy which can also cause undesirable cardiac overload if heart failure coexists. We hypothesized that the biomarker B type natriuretic peptide (BNP) can be used to screen lymphedema patients for undetected cardiac dysfunction. We studied unselected consecutive patients with lymphedema to determine their BNP status and compared these data with those obtained from healthy subjects without known cardiovascular diseases. Out of a total of 305 subjects with lymphedema screened, 102 (33%) consented to take part in this study. The majority (87%) were female with a mean age of 60.5 +/- 13.2 (SD) years, and 47% had just lower limb swelling. The groups were equally divided between cancer and non-cancer related causes. There were 45 females and 4 males under 60 years old, and 44 female and 9 male patients over 60 years old. Median (IQR) BNP (ng/L) were as follows: <60 years females = 17.9 (15.2) (median [RR: 3 64] and males = 12.4 (14.7) [RR: 0.2 - 44], >60 years females = 35.8 (57.9) [RR: 2 -247)] and males = 47.2 (44.1) [RR: 2 - 238]. For this population, the BNP concentration 100 ng/L was adopted as the value to exclude heart failure. Using this definition, 7 lymphedema subjects had BNP concentrations of 120 (19.8) ng/L, and all were found to have cardiac abnormalities on echocardiography. This study demonstrated that 93% of unselected subjects with lymphedema had BNP concentrations that exclude a diagnosis of heart failure. Those subjects with elevated BNP were found on subsequent echocardiography to have cardiac abnormalities. The use of a BNP assay is of potential value in screening patients who are more likely to have cardiac failure. Indicative factors include bilateral leg swelling, over the age of 50 years, breathlessness, where there is no known cause for the swelling. A BNP assay using a BNP concentration threshold of 100 ng/L (29 pmol/L) will identify those patients who require more detailed investigations. PMID- 21667821 TI - FOXC2 transcription factor: a novel regulator of lymphangiogenesis. AB - Lymphangiogenesis is the critical process of forming new lymphatic vessels under physiological and pathological conditions and involves both molecular and morphological changes. Despite evidence that lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and Prox1, regulate lymphangiogenesis, the molecular mechanisms underlying gene regulation in lymphatic vessel remodeling and maturation are not fully understood. Importantly, recent studies demonstrate that Forkhead transcription factor FOXC2 controls later steps of lymphatic vascular development and is responsible for establishing a collecting lymphatic vessel identity by regulating expression of downstream genes involved in lymphangiogenesis, including PDGF-beta, Delta-like 4 (Dll4) and angiopoietin (Ang)-2. Thus, FOXC2 is now recognized as a novel regulator of lymphatic vascular formation and remodeling. This review summarizes current knowledge about the function of FOXC2 in lymphangiogenesis and discusses prospects for future research in FOXC2-mediated pathological lymphangiogenesis in lymphatic-related disease. PMID- 21667822 TI - The role of the lymphovascular system in cancer metastasis. PMID- 21667823 TI - Bond strength comparison of color change adhesives for orthodontic bonding. AB - This study investigated whether three different color change light-cured orthodontic bonding adhesives have comparable shear bond strengths to a conventional light-cured orthodontic bonding adhesive. The sample of 240 bovine incisors was divided into four groups of 60 each. Each group tested one of four orthodontic bonding adhesives: 3M Unitek Transbond PLUS, Ormco Grengloo, Ormco Blugloo, and 3M Unitek Transbond XT (control). The four groups were further divided into two subgroups of 30 with shear bond strength tested at two different times (15 minutes and 24 hours) post-bond. The shear bond strength was measured on a universal testing machine. The data were analyzed by two-way analysis of variance and post-hoc comparisons (Fisher's PLSD) at the 0.05 level of significance. The average shear bond strength was greater at 24 hours than at 15 minutes for Transbond PLUS, Blugloo, and Transbond XT. For Grengloo, the average shear bond strength was greater at 15 minutes than at 24 hours. Grengloo tested at 15 minutes had the highest average shear bond strength. Grengloo tested at 24 hours had the lowest average shear bond strength. All four orthodontic bonding adhesives demonstrated bond strengths considered to be clinically acceptable for orthodontic purposes. PMID- 21667824 TI - Summary of the new 2010 American Heart Association Guidelines for Basic Life Support (CPR). AB - Approximately every 5 years, American Heart Association (AHA) experts review emerging scientific evidence and recent clinical experiences and update the AHA guidelines for basic and advanced life support procedures for in-hospital and out of-hospital victims of life-threatening cardiac events. This article summarizes many of the 2010 changes in those guidelines as they apply to dental healthcare providers (HCP). More detailed information will be available in the near future as these guidelines are fully implemented and instructional materials are released by the AHA. Until they are trained in future AHA or American Red Cross (ARC) basic or advanced cardiac life support (BLS, ACLS) courses in 2011, dentists, dental assistants, dental hygienists, and office staff should continue to rely on the training and information they received in their most recent basic (and/or advanced cardiac) life support training course. PMID- 21667825 TI - Oral and maxillofacial pathology case of the month. Adenomatoid odontogenic tumor. PMID- 21667826 TI - Improved temporization with modern materials. PMID- 21667827 TI - Light curing may not be as simple as it seems! PMID- 21667828 TI - Defective dental restorations: to repair or not to repair? Part 2: All-ceramics and porcelain fused to metal systems. AB - With the increasing use of ceramics in restorative dentistry, and trends to extend restoration longevity through the use of minimal interventive techniques, dental practitioners should be familiar with the factors that may influence the decision either to repair or replace fractured metal-ceramic and all-ceramic restorations and, also, the materials and techniques available to repair these restorations. This second of two papers addresses the possible modes of failure of ceramic restorations and outlines indications and techniques in this developing aspect of restoration repair in clinical practice. CLINICAL RELEVANCE: The repair of metal-ceramic and all-ceramic restorations is a reliable low-cost, low-risk technique that may be of value for the management of loss or fracture of porcelain from a crown or bridge in clinical practice. PMID- 21667829 TI - Maxillary labial fraenectomy: indications and technique. AB - A labial fraenectomy is indicated in various clinical situations and is performed to facilitate orthodontic closure of a maxillary midline diastema. In these clinical situations, timing of surgery during the phase of orthodontic treatment is important. Labial fraenectomy can be performed before, during or after the orthodontic closure of the maxillary midline diastema, depending on the individual case. It is important to understand how to perform the procedure efficiently and effectively. Success relies as much on accurate diagnosis of the fleshy, prominent or persistent fraenum as it does on meticulous technique to ensure its complete elimination. This article presents the indications for labial fraenectomy. The appropriate timing of the labial fraenectomy procedure to facilitate orthodontic treatment is discussed. CLINICAL RELEVANCE: A surgical technique to perform maxillary labial fraenectomy procedure in an effective and efficient manner is a useful addition to the clinician's armamentarium. PMID- 21667830 TI - Toothwear and the older patient. AB - Toothwear is commonly observed in dentate older patients and may be physiological or pathological in nature. Toothwear can be caused by abrasion, attrition, erosion or a combination of aetiologies. Where treatment is required, a number of options exist, including the use of adhesive materials and fixed and removable prosthodontics. CLINICAL RELEVANCE: With patients retaining natural teeth into old age, physiological and pathological toothwear amongst dentate older patients is an increasingly common presentation. PMID- 21667831 TI - Gagging during impression making: techniques for reduction. AB - In everyday dental practice one encounters patients who either believe themselves, or subsequently prove themselves, to be gaggers. Gagging is most frequently experienced during impression making, but is also reported during the taking of radiographs, in the placement of restorations in posterior teeth and, in some individuals, the insertion of a finger for examination purposes. This paper describes some techniques that can easily be mastered by clinicians that may help both operator and patient avoid this unpleasant occurrence. Techniques such as acupressure, the adaptation of trays, or even the use of alternative impression materials and breathing techniques all have their place, and clinicians may have to try several of these, perhaps in conjunction, in order to assist their patients. CLINICAL RELEVANCE: A significant number of patients attend for dental treatment that require impressions, and for those with gagging problems it can be a horrendous experience. Being able to make the procedure less of an ordeal is better for all involved. PMID- 21667832 TI - Routine and emergency management guidelines for the dental patient with renal disease and kidney transplant. Part 1. AB - The number of kidney patients is increasing in all developed countries, mainly due to the increase in patients with type II diabetes. These patients may be asked by their renal physician to attend their general dental practitioner for an oral review prior to undergoing further renal treatment. Dental surgeons working in the primary care setting will be required to manage patients who are at various stages of renal support, whether pre-dialysis patients with chronic kidney disease (CKD), dialysis patients, and also those who have had a kidney or kidney and pancreas transplant. In addition, dental practitioners may be faced with having to deal with the emergency management of such patients attending their practices in acute pain. CLINICAL RELEVANCE: This paper aims to provide the general dental practitioner with the necessary knowledge to manage renal patients, and outlines the guidance regarding the criteria for referral, work up procedure and dental management of such patients. PMID- 21667833 TI - Chondrolipoma presenting as a lump on the lateral tongue. AB - The oral cavity is an uncommon site for a true lipoma. A distinct histological variant is chondrolipoma, which is a rare oral lesion. A case of chondrolipoma in a 71-year-old male is reported and histology and differential diagnosis are discussed. CLINICAL RELEVANCE: An oral lump is a common presenting complaint and requires further investigation. PMID- 21667834 TI - Importance of quality in referral letters sent for potentially malignant oral, head and neck lesions. AB - Early diagnosis of oral, head and neck cancer is very important. Delay in diagnosis and referral to a specialist unit can result in an enlarged tumour with an increased chance of metastatic spread which will result in upstaging of the tumour, thus worsening the five year survival rate. There is a great need for early identification and referral of potentially malignant lesions by general dental and medical practitioners. Referral letters are the standard and, typically, the sole method of communicating confidential information between two professionals. It is vital that the referral letters sent for potential malignant lesions are of good quality, clearly marked as urgent and contain adequate administrative and clinical data. An audit was undertaken at the Oral and Maxillofacial Department at Barnet and Chase Farm NHS Trust, to examine the quality of referral letters sent for potentially malignant oral, head and neck lesions. The outcome is discussed and a standard referral letter is also proposed if not referring using the standard local cancer network referral proforma. CLINICAL RELEVANCE: A good quality referral letter should minimize delay in diagnoses and management of a patient with an oral, head and neck lesion. PMID- 21667835 TI - Chronic periapical periodontitis containing mature human hair shaft: a case report. AB - A case is reported of a 44-year-old male who was referred with persistent pus discharge associated with his UL2 which had been root treated on two occasions. Radiographic examination revealed a radiolucency of approximately 8 mm diameter. An apicectomy was performed and histopathological examination revealed the presence of mature birefringent hair-shaft structures within a chronic periapical periodontitis. CLINICAL RELEVANCE: This article presents a rare occurrence, the presence of human hair in the periapical tissues. PMID- 21667836 TI - The 'secret' of success. Part 2. AB - Practice success is defined across the four 'dimensions' of oral health, patient satisfaction, job satisfaction and financial profit. It is suggested that the 'secret' of success in dental practice is to make patient (customer) satisfaction the primary focus. Not a very earth shattering or surprising 'secret' perhaps! This is hardly a new idea, and not a concept restricted to dental practice. This principle applies to all businesses. This series of articles reviews evidence from across a broad spectrum of publications: from populist business publications through to refereed scientific papers, this 'secret' seems to be confirmed. The evidence for which aspects of our service are most important in achieving patient satisfaction (and therefore success) is explored. CLINICAL RELEVANCE: Good oral health outcomes for patients are defined as the primary purpose of dental practice and, therefore, an essential dimension of success. The link between positive patient perceptions of general care and their own oral health to practice success is explored. PMID- 21667837 TI - Oral cancer: comprehending the condition, causes, controversies, control and consequences. 5. Clinical features and diagnosis of cancer. PMID- 21667839 TI - The importance of physicians and philanthropy. PMID- 21667838 TI - Medical conditions in dental practice. Case 83. Physical signs for the general dental practitioner. Fungal nail infection. PMID- 21667840 TI - Your advocacy has a measurable impact. PMID- 21667842 TI - Healthcare reform in 2011 and beyond. PMID- 21667841 TI - Challenges regarding FSAs and OTC medications ... and an update on HIPAA. PMID- 21667843 TI - Integrating the EHR into the patient relationship. PMID- 21667844 TI - Independent image problem. PMID- 21667845 TI - Trust denies pay rise to staff with more than ten days off sick. PMID- 21667847 TI - Trusts report varied compliance with new mixed sex ward rules. PMID- 21667846 TI - Staff transferred out of health service left feeling 'marooned'. PMID- 21667848 TI - Groundbreaking bereavement service proves to be a winner. PMID- 21667849 TI - Inspiring nurse's accolade helps fulfil the final wish of a grateful patient. PMID- 21667850 TI - Meet the pioneers. AB - Staff in a rehabilitation service have been carving out a role that takes on much of the work traditionally done by junior doctors. PMID- 21667851 TI - A better death. AB - The appalling care of patients at the end of life shown in a recent television documentary rightly shocked people. But, according to experts, this is no longer the norm in England. PMID- 21667852 TI - Straight to the point. AB - Speeding up patients referrals, increasing nurses' job satisfaction and saving money have been achieved by NHS Forth Valley. PMID- 21667853 TI - Testing the limits. AB - A steep rise in the number of HIV positive people has led to calls for routine screening in areas with a high incidence of the infection. PMID- 21667854 TI - Leadership and responsive care: principle of Nursing Practice H. AB - This is the final article in a nine-part series describing the Principles of Nursing Practice developed by the Royal College of Nursing (RCN) in collaboration with patient and service organisations, the Department of Health, the Nursing and Midwifery Council, nurses and other healthcare professionals. This article discusses Principle H, the need for leadership among staff and the provision of care that is responsive to individuals' needs. PMID- 21667855 TI - An evaluation of sharp safety hypodermic needle devices. AB - Sharps injury and exposure to blood-borne viruses is an occupational hazard for healthcare professionals. This article describes an evaluation of three sharp safety hypodermic needle devices in six hospitals in Wales. User acceptability and performance was assessed. PMID- 21667856 TI - An overview and update of psoriasis. AB - Psoriasis is a common, chronic skin condition and nurses can expect to encounter patients with psoriasis in both primary and secondary care settings. This article focuses on the physical and psychosocial effects of the condition and on appropriate management strategies, including the use of biologic therapies to treat moderate to severe psoriasis. Quality of life issues are also addressed. PMID- 21667857 TI - Peripheral cannulation. PMID- 21667858 TI - See the bigger picture. PMID- 21667859 TI - Training aimed at complex needs. PMID- 21667860 TI - Seeking bright ideas. PMID- 21667861 TI - Seeking the united state of HIEs. Connecting information exchange efforts is ONC's next challenge. AB - The federal government has been actively encouraging health information exchange through direct grants and leadership. However, its challenge now is keeping focused and getting the multiple efforts aligned. PMID- 21667862 TI - Opting for opt out. How one HIE manages patient consent. AB - Every health information exchange must determine how it will gain consent from patients to share their information. The Nebraska Health Information Initiative chose opt out and with good communication and management has maintained a high rate of patient participation. PMID- 21667863 TI - Direct results. An HIE tests simple information exchange using the direct project. AB - Some HIEs were surprised when the federal government announced a project to enable direct provider-to-provider information exchange. But CareSpark, an HIE piloting the lightweight exchange method, is seeing the benefits for users and a logical integration into the services it offers. PMID- 21667864 TI - Speeding decisions. Social security's information exchange program. AB - The Social Security Administration has plenty of reasons to streamline its records request process-more than 15 million reasons each year, in fact. That's why it has been pioneering information exchange projects with the private sector, including use of the Nationwide Health Information Network. PMID- 21667865 TI - Encryption basics. PMID- 21667866 TI - HIE patient consent model options. PMID- 21667867 TI - ONC's standards harmonization efforts: ONC's S&I framework seeks to harmonize standards for clinical data exchange. PMID- 21667868 TI - The patient's role in ensuring legal EHR data integrity. PMID- 21667869 TI - HIE management and operational considerations. PMID- 21667870 TI - The circulatory system and ICD-10-CM/PCS. PMID- 21667871 TI - Staying alert on sleep medicine coding. PMID- 21667872 TI - Privacy rights never die and sometimes complications linger on. PMID- 21667873 TI - Job embeddedness factors and retention of nurses with 1 to 3 years of experience. AB - An aging work force, predictions of job growth in health care, and an eventual economic recovery suggest that the current reprieve from the national nursing shortage is temporary. New graduate nurses are an important part of the work force and are needed to replace nurses who will retire in the next decade. Organizational leaders can address the forecasted work force demand by proactively investing in programs for workplace development and retention. Recent literature reports an increased focus on understanding the work experience and career support needed for new graduate nurses. Several studies report improvements in job satisfaction and retention after implementation of structured mentoring programs for new graduate nurses. However, despite successful transition programs, turnover for these same nurses after 1 to 3 years of organizational tenure remains high. Studying factors that contribute to retention and supporting careers beyond the first year of practice may have a significant effect on improving retention and will contribute new knowledge to the nursing literature. This study, undertaken at a Midwestern pediatric academic medical center, examined job factors and career development support that lead to retention of nurses with 1 to 3 years of experience. Understanding these issues may guide nursing leaders and staff development educators in investing in focused retention and career development plans during an economic recession. PMID- 21667874 TI - Filling the gaps: immersing student nurses in specialty nursing and professional associations. AB - The national nursing shortage demands innovative strategies to attract students to the nursing profession. This article provides a potential solution for recruiting and retaining nurses for specialty areas of nursing as well as professional nursing associations by pairing student nurses with professional nurses who belong to nursing associations. An immersion program such as the one described in this article provides a strategy that addresses the nursing work force shortage and professional association membership. The experiential knowledge gained through this type of program may advance the profession throughout the country. PMID- 21667876 TI - Religion and spirituality: can it adversely affect mental health treatment? PMID- 21667880 TI - Refractive lens exchange with toric intraocular lenses in keratoconus. AB - PURPOSE: To report the clinical characteristics and surgical outcomes of patients with nonprogressive keratoconus treated with in-the-bag toric intraocular lens (IOL) implantation. METHODS: A retrospective review was conducted of the medical records of patients diagnosed with keratoconus treated with refractive lens exchange (RLE) and in-the-bag toric IOL implantation (models T3 to T9, AcrySof SN60TT; Alcon Laboratories Inc). Age, pre- and postoperative uncorrected (UDVA) and corrected distance visual acuity (CDVA), objective and subjective refraction, spherical equivalent refraction, total keratometric power, total astigmatism, axis, and toric IOL model and power were analyzed. All cases had topographic and/or refractive stability for at least 1 year prior to undergoing IOL implantation. RESULTS: Nineteen eyes of 13 patients (mean age 48.15 +/- 6.6 years), including 12 patients with a topographic diagnosis of keratoconus and 1 with pellucid marginal degeneration, were evaluated. Mean follow-up after RLE was 7.89 +/- 6.61 months. Mean preoperative sphere was -5.25 +/- 6.40 diopters (D), and mean postoperative sphere was 0.22 +/- 1.01 D (P<.001). Mean preoperative cylinder was 3.95 +/- 1.30 D, which decreased to 1.36 +/- 1.17 D postoperatively (P<.001). Mean pre- and postoperative spherical equivalent refractions were -7.10 +/- 6.41 D and -0.46 +/- 1.12 D, respectively (P<.001). Preoperative mean UDVA was 1.35 +/- 0.36 D (20/447 Snellen) and postoperative mean UDVA was 0.29 +/- 0.23 D (20/39 Snellen) (P<.001). CONCLUSIONS: Toric IOL implantation may be an effective therapeutic option in the optical rehabilitation of patients with stable and nonprogressive keratoconus. PMID- 21667881 TI - Audio feedback for student writing in online nursing courses: exploring student and instructor reactions. AB - Because scientific writing is an essential skill for advanced practice nurses, it is an important component of graduate education. Faculty typically provide written feedback about student writing, but this may not be the most effective choice for the distance-learning environment. This exploratory pilot study's aim was to compare spoken, recorded feedback with written feedback in three areas: which approach do students perceive as providing more useful guidance; which approach helps students feel more connected to the course; and which approach do instructors prefer? Students enrolled in an evidence-based practice graduate level course received asynchronous audio feedback on their written assignments instead of the written feedback they received in other courses. Results from a survey completed by 30 students at completion of the course suggest a strong preference for audio feedback. This pilot study suggests that audio feedback may be preferable to written comments for distance learning courses. PMID- 21667882 TI - Course facilitators assisting accelerated nursing students: a literature review. AB - Nursing education is now well established within the tertiary sector. Globally, recent years have seen the implementation of numerous admission pathways to a nursing degree, enabling applicants from varying backgrounds to enter the nursing profession. A major catalyst for these pathways has been to address the perennial shortage in the nursing workforce. The accelerated pathway is one such admission avenue where students possessing a degree in a discipline other than nursing qualify for admission and complete the degree in a condensed time. Students commence these courses equipped with a skills base developed from life experiences and previous tertiary study. These are used as facilitators throughout accelerated education to enhance course negotiation and performance. Minimal research is available exploring these course facilitators. This literature review examines the existent research to deepen an understanding of these facilitators described as unique to accelerated students. Implications for nursing education and nursing research are discussed. PMID- 21667883 TI - The diversity pyramid: an organizational model to structure diversity recruitment and retention in nursing programs. AB - The literature on increasing the diversity of individuals who enter and practice the nursing profession comes with sound argument, yet we have seen only modest gains in diversification over the past 10 years. This article addresses how to develop a sustainable program to increase the recruitment and retention of underrepresented students. The diversity pyramid is suggested as a conceptual planning model for increasing diversity that is matched to an institution and its resources. The foundation of the pyramid is an organizational commitment to attracting and retaining diverse students. The middle level addresses financial support for underrepresented students. From the top of the pyramid, one chooses appropriate media and relational tactics necessary to attract the underrepresented students a program seeks. All three elements of the pyramid organizational commitment to diversity, significant financial support, and a targeted use of resources-play important and sequential roles in building a sustainable diversity initiative. PMID- 21667884 TI - Report of survey results for newly licensed registered nurses in Washington state. AB - Current projections for the need for nurses in Washington state are based on an increase in the need for health care, the aging of the population, and the inability of the nursing educational institutions to supply adequate numbers of graduates. Yet many new graduates are providing anecdotal evidence that they cannot find a job in nursing. This study gathered information regarding the employment of newly licensed registered nurses in Washington between May 2009 and August 2010. Questionnaires were administered to a randomly selected sample of 2,200 newly licensed nurses; 532 responses were returned. Nearly 81% reported current employment as a registered nurse and 69.5% reported that they were very or somewhat satisfied with their employment situation. The job search strategies, type of job sought, and factors contributing to their success are reported. Factors contributing to the success of their job search and to job dissatisfaction are explored. PMID- 21667885 TI - Drug therapies for tardive dyskinesia: part 2. AB - Tardive dyskinesia (TD) is a serious complication associated with the long-term use of dopamine receptor-blocking drugs. No drugs are approved by the U.S. Food and Drug Administration for treating TD. A number of drugs appear to have some benefit for its treatment, including branched-chain amino acids, piracetam (Nootropil((r)), Nootrop((r)), Nootropyl((r))), clonazepam (Klonopin((r))), levetiracetam (Keppra((r))), propranolol (Inderal((r))), and clonidine (Catapres((r))), and they would be clinically reasonable to try. Gabapentin (Neurontin((r)) and others) has a good safety profile and would be appropriate to consider, although no controlled trials confirm its efficacy. The efficacy of ginkgo biloba should be balanced against its safety concerns. Essential fatty acids have not been shown to be effective. Antioxidant therapies, including vitamin E, melatonin, and vitamin B6, could conceivably be used together with other drug therapies for the treatment of TD. PMID- 21667886 TI - Caring for older adults with bipolar disorder. AB - Bipolar disorder is a recurrent, chronic mental illness that has a profound impact on the lives of patients and their families and may require extensive use of mental health services. Although bipolar disorder is often considered an illness of young people, the disorder is being recognized as more common in older adults than previously thought. Much more research needs to be done to understand the impact of aging on the course and treatment of bipolar disorder. Evidence based interventions for treatment of this disorder in older adults must be developed. Mental health nurses can play a key role in enhancing medication adherence, implementing structured psychosocial interventions, and carrying out research to enhance diagnosis and treatment of older adults with bipolar disorder. PMID- 21667887 TI - The elder justice act. AB - The Elder Justice Act (a part of the Patient Protection and Affordable Care Act of 2010) focuses on the development of a comprehensive mechanism to "prevent, detect, treat, intervene in, and prosecute elder abuse, neglect, and exploitation." Elements of the Act that offer opportunities for nurses to demonstrate their advocacy role on behalf of older adults include (a) participating in the training of ombudsmen and/or becoming an ombudsman; (b) serving on the Elder Justice Act's Advisory Board on Elder Abuse, Neglect, and Exploitation; (c) working in either a stationary or mobile forensic center dedicated to addressing elder abuse; (d) having an active role in the curriculum design and implementation of degree and certificate programs to build competency in gerontology and gerontological nursing; and (e) providing consultation to long term care facilities in the areas of staff recruitment and quality of care. PMID- 21667888 TI - Washington State Death with Dignity Act: implications for long-term care. AB - The Washington Death with Dignity Act (DWDA) allows competent, terminally ill adults to request a lethal dose of medication from a physician. The purpose of this study was to explore knowledge of Directors of Nursing (DONs) in long-term care (LTC) and assisted living facilities regarding the DWDA. Findings of the survey provide insight into DONs' understanding of the law and whether they have provided staff education regarding how to respond to resident requests. This survey, although limited by sample size, may provide guidance for policy development in LTC settings regarding similar laws. PMID- 21667889 TI - The ring. PMID- 21667890 TI - Driving and dementia: what nurses need to know. AB - Driving is considered an instrumental activity of daily living and, for many older adults, is also associated with the ability to maintain independence. The diagnosis of dementia, distressing on its own, paired with the threat to driving independence, makes this a difficult issue for patients, families, and clinicians. The purpose of this article is to provide a brief overview of the current research regarding driving safety and dementia, guidelines that can be used to assess driving risk, and counseling tips for patients and families regarding driving safety. PMID- 21667891 TI - Osteoporosis treatment: an evidence-based approach. AB - Osteoporosis is a disease that results in decreased bone mass and quality of bone, which may lead to fracture. Clinicians need to counsel individuals on appropriate intake of calcium and vitamin D, increasing weight-bearing exercise, limiting alcohol and caffeine, and avoiding smoking. A variety of nonhormonal pharmacological options are available for prevention and treatment of osteoporosis, including bisphosphonates, calcitonin (Miacalcin(r)), raloxifene (Evista(r)), teriparatide (Forteo(r)), and denosumab (Prolia(r)). The National Osteoporosis Foundation and the American Association of Clinical Endocrinologists have recently published new guidelines, and it is important for clinicians to be familiar with the evidence behind each of these treatment modalities. It is paramount for nurses to make evidence-based, cost-effective decisions about pharmacological therapy based on individual patient-specific factors. PMID- 21667892 TI - Building on a national health information technology strategic plan for long-term and post-acute care: comments by the Long Term Post Acute Care Health Information Technology Collaborative. AB - The LTPAC (Long Term Post Acute Care) Health Information Technology (HIT) Collaborative consists of an alliance of long-term services and post-acute care stakeholders. Members of the collaborative are actively promoting HIT innovations in long-term care settings because IT adoption for health care institutions in the United States has become a high priority. One method used to actively promote HIT is providing expert comments on important documents addressing HIT adoption. Recently, the Office of the National Coordinator for HIT released a draft of the Federal Health Information Technology Strategic Plan 2011-2015 for public comment. The following brief is intended to inform about recommendations and comments made by the Collaborative on the strategic plan. PMID- 21667893 TI - Ocular biomechanics: measurement parameters and terminology. PMID- 21667894 TI - Real-time measurement of intraocular pressure during femtosecond laser enabled keratoplasty. PMID- 21667895 TI - Bilateral unstable slipped capital femoral epiphysis: a look at risk factors. AB - Unstable slipped capital femoral epiphysis can have disastrous complications including osteonecrosis and chondrolysis. It has been shown that 20% to 80% of patients may develop a contralateral slip <=18 months after diagnosis. The purpose of this article is to report and characterize patients who developed bilateral unstable slips. After Institutional Review Board approval, the patients included were only those with bilateral unstable slipped capital femoral epiphyses. A minimum 2-year follow-up was required. Seven patients, all female, were included in the study, with an average age of 11.4 years at the time of their first slips. The interval between slips averaged 127 days (range, 0-245 days). All but 1 patient presented with a severe slip. The second slip was also severe in 3 patients and less severe in 4 patients. The triradiate cartilage was open in 3 patients. Two patients required corrective osteotomies. Chondrolysis developed in 2 patients with no osteonecrosis reported. The incidence of bilateral unstable slips ranged from 4% to 20% of all unstable slipped capital femoral epiphyses based on our findings. Skeletal immaturity was not a risk factor. The surgeon must be vigilant for the possibility of bilateral slips. The family must be instructed on precautions patients must take while recuperating from unstable slipped capital femoral epiphyses. Contralateral fixation of the unaffected side may be warranted in patients with initial severe unstable slipped capital femoral epiphyses to prevent this condition. PMID- 21667896 TI - In vivo assessment of total hip femoral head separation from the acetabular cup during 4 common daily activities. AB - In vivo video fluoroscopies of well-functioning total hip arthroplasties (THA) have shown that femoral head separation from the medial articular bearing surface occurs during gait. Other activities may cause the same phenomenon. We examined this while patients performed the following 4 activities of daily living: pivoting to each side in stance, shoe tying, sitting down, and standing up. Ten healthy patients (5 men, 5 women, average age 66 years) all 1 year or more after cementless THA performed for degenerative arthritis, with Harris Hip Scores >=90, were studied. Each patient performed the activities of daily living while data was captured using video fluoroscopy. Based on previously reported criteria, femoral head separation (the femoral head sliding lateral to the acetabular liner) was determined to be reliably predicted if the distance between the femoral head and acetabular cup was >=0.5. Results showed that the greatest femoral head separation occurred during the pivoting activity (mean, 1.53 mm; range, 0.00-3.34 mm; SD, 1.05 mm). The separation values identified during pivoting occurred at the extremes of internal or external rotation for all patients. The other 3 activities showed lower separation distances. Separation during the pivoting activity exceeded the reported separations occurring during walking. This finding was seen in a small group of patients, and the data should be interpreted with caution. We conclude from this study that the evaluation of gait alone may not be sufficient to accurately assess femoral head separation occurring during activities of daily living for healthy, active patients. PMID- 21667897 TI - Preliminary clinical and radiographic results of large ceramic heads on highly cross-linked polyethylene. AB - Data are limited regarding large ceramic femoral heads with highly cross-linked polyethylene. We hypothesized that large ceramic head articulation with highly cross-linked polyethylene is safe with a low wear rate, comparable to metal-on highly cross-linked polyethylene.The study group comprised 63 patients (72 hips) who had undergone total hip replacement (THR) with ceramic-on-highly cross-linked polyethylene between April 2006 and March 2007 with a minimum 2-year follow-up. Postoperative Western Ontario and Mc-Master Universities Arthritis Index (WOMAC) and Hospital for Special Surgery (HSS) scores were used for clinical assessment. Six-week and 2-year radiographs were analyzed by 2 independent observers using Roman 1.70 software. Twenty-six patients (29 hips) had 32-mm and 37 patients (43 hips) had 36-mm Biolox delta ceramic femoral heads (Ceramtec, Plochingen, Germany). Mean patient age was 60.9 +/- 8.9 years, and mean follow-up was 2.9 +/- 0.5 years. Mean postoperative WOMAC and HSS hip scores were 30.4 and 36.6, respectively. Mean wear at 1 and 2 years postoperatively was 0.06 +/- 0.28 and 0.006 +/- 0.12 mm/yr for all hips, respectively. Mean wear at 1 and 2 years postoperatively for the 32-mm femoral head was 0.063 +/- 0.278 and 0.007 +/- 0.126 mm/yr, respectively, and for the 36-mm femoral head was 0.057 +/- 0.292 and 0.006 +/- 0.118 mm/yr, respectively. No patient had any clinical complications, such as reoperation, infection, fractures, or radiographic evidence of osteolysis or loosening. The early results of THR with large ceramic heads demonstrate high safety and efficacy. Our data with 2-year follow-up show low wear rates, similar to published data for metal-on-highly cross-linked polyethylene. PMID- 21667898 TI - Predicting ACL rupture in the population actively engaged in sports activities based on anatomical risk factors. AB - The purposes of this article were identification (ie, verification and gradation) of anatomical risk factors that lead to anterior cruciate ligament (ACL) injury and determination of the probability of ACL injury among the population actively engaged in sports activities. We evaluated 66 patients divided into 2 groups: 33 patients in the examined group diagnosed with ACL lesion, and 33 patients in the control group diagnosed with patellofemoral pain. Patients were matched by age, sex, type of lesion, and whether the lesion was left or right sided. Measurements were carried out by radiography and magnetic resonance imaging. The study examined 32 anatomical factors. After identifying factors that lead to ACL injury, the following were determined: the coefficient of significance for each individual factor via the discriminant analysis and the canonical discriminant (i.e., canonical correlation). Fifteen factors in men and 8 factors in women were differentiated as having influence on ACL injury. Based on these factors, it was determined whether the patients belonged to the examined or the control group with a success rate of 100% in men (100% sensitivity and specificity) and 91.7% in women (100% sensitivity and 83.3% specificity). The anatomy of the ACL prone to rupture and of the skeletal structures influencing it is significantly different from the anatomy of the ACL ligament resistant to injury. The probability of precise prognosis of ACL injury based on differentiated anatomical factors is 88.9% in men and 75.7% in women actively engaged in sports activities. PMID- 21667899 TI - Subvastus and medial parapatellar approaches in TKA: comparison of functional results. AB - The purpose of this study was to compare the clinical results of total knee arthroplasty (TKA) in the early and late postoperative period using subvastus and medial parapatellar approach. A prospective randomized controlled study was conducted in a group of 169 patients (180 TKAs) with 2-year follow-up. Patients were divided into a study group (97 TKAs) with a subvastus approach and a control group (83 TKAs) with a parapatellar approach. Assessment of the results of both operating approaches was based on functional, clinical Knee Society Score, and pain (visual analog scale). Patients in the subvastus group achieved full active extension, better range of motion, and better Knee Society Score results at 12 days, 6 weeks, and 12 weeks earlier than patients in the medial parapatellar group. They also had less pain at 12 days. No statistically significant differences existed between assessed end points in both groups at 24- and 52 weeks, and 24-months postoperatively. The subvastus approach has given patients better early clinical results; however, at longer follow-up, both groups had similar outcomes. The potential benefits of the subvastus approach are: protection of the extensor mechanism from damage, less risk of damaging the blood supply to the patella, earlier clinical recovery, and less pain in the early postoperative period. The subvastus approach is an alternative to the standard medial parapatellar approach in TKA. It can be used with equally good results, especially taking into consideration positive clinical aspects in the early postoperative period. PMID- 21667900 TI - Chemoprophylaxis without intra-articular wound drainage can replace autotransfusion in primary TKA. AB - We compared outcomes in 2 groups undergoing total knee arthroplasty (TKA) with different blood-saving strategies (ie, chemoprophylaxis vs reinfusion). We hypothesized that chemoprophylaxis would lead to reduced blood loss and fewer transfusions, with no increase in associated complications. Group A was a prospective series of 91 consecutive cemented TKAs undertaken with chemoprophylaxis to reduce bleeding and blood allogeneic exposure. Group B consisted of 44 historical TKAs undertaken with postoperative reinfusion. With the exception of mean patient age (group A, 74.3 years; group B, 70.9 years; P=.006), there were no statistically significant differences between the 2 study groups.Mean total blood loss throughout the 7-day perioperative period was 1490 mL in group A and 1828 mL in group B. The rate of blood transfusion in group A was almost zero. In group B, 41 of 44 patients were administered blood intravenously. Despite the absence of autotransfusion, postoperative hemoglobin levels were significantly higher in group A than in group B. No major bleeding complications emerged in the immediate postoperative period in either group.Chemoprophylaxis proved superior to reinfusion at decreasing blood transfusion requirements in the routine daily setting of unilateral cemented primary TKA. PMID- 21667901 TI - Posteromedial anatomical plate for the treatment of distal tibial fractures with anterior soft tissue injury. AB - The treatment of distal tibial fractures with anterior soft tissue injury is relatively difficult. The aim of this study was to explore the efficacy and safety of the posteromedial anatomical plate for such fractures. Between February 2006 and January 2009, twenty-six cases of distal tibial fracture with anterior soft tissue injury were treated with posteromedial anatomical plates designed by our traumatic orthopedic center. Of the 26 cases, 12 were open fractures (4 Gustilo-Anderson type I, 5 type II, 2 type IIIA, and 1 type IIIB), and 14 were closed fractures (3 Tscherne-Oestern type I, 9 type II, 2 type III). Operation time, intraoperative blood loss, fracture healing time, American Orthopaedic Foot and Ankle Society (AOFAS) ankle score, and complications were recorded to evaluate treatment effects.Mean operation time was 72.5 +/- 15.8 minutes (range, 45-105 minutes) with a mean intraoperative blood loss volume of 86.4 +/- 17.3 mL (range, 50-150 mL). All 26 patients had good postoperative fracture healing. Mean union time was 19.2 +/- 4.4 weeks (range, 13-30 weeks). Average AOFAS ankle score was 87.3 +/- 9.2 (range, 68-99). No malunion, nonunion, limb-shortening deformity, or neurovascular injury occurred. Our results suggest that the posteromedial anatomical plate for the treatment of distal tibial fractures with anterior soft tissue injury is effective and results in no severe complications. PMID- 21667902 TI - Arthroscopic management of stiff elbow. AB - Elbow stiffness is a common problem encountered by orthopedic surgeons. Various management options have been described in the literature, including conservative measures and open and arthroscopic surgery. Arthroscopic management of stiff elbow remains controversial. The purpose of this study was to evaluate the functional results of arthroscopic management of stiff elbow.Thirty patients with stiff elbow underwent arthroscopic release surgery and were followed up for an average of 27.3 months. Surgery included anterior and posterior capsular release, coronoid process debridement, bony spur excision, and loose body removal. Postoperative outcome was assessed using the Mayo Elbow Performance Score and range of motion at the elbow. Mayo Elbow Performance Score increased from a mean 64.5 preoperatively to a mean 83.17 postoperatively. Range of motion also improved, from a mean preoperative extension and flexion of 22.83 degrees and 96.83 degrees , respectively, vs a mean 10.83 degrees and 120.84 degrees , respectively, at final follow-up. No intra- or postoperative complication was seen in any case. Underlying etiology and timing of surgery influenced the end result, with better results seen in patients with traumatic etiology and those with a shorter duration of symptoms.Arthroscopic release allows good visualization and rectification of intra-articular pathology and is a safe and effective tool for the management of stiff elbow. PMID- 21667903 TI - Treatment of acute unstable distal clavicle fractures with single coracoclavicular suture fixation. AB - Distal clavicular fractures are less common than fractures involving the middle third of the clavicle. For Neer type IIb distal clavicular unstable fractures associated with disruption of the coracoclavicular ligament, surgical treatment is indicated because of the high risk of nonunion. Various surgical methods can be found in the literature, but no gold standard has been established. We treated 29 consecutive adult patients with unstable distal clavicular fracture with single coracoclavicular suture fixation by using single Mersilene tape (Ethicon, Somerville, New Jersey) and without repair of the torn coracoclavicular ligament or hardware implantation.Twenty-eight patients were followed for at least 46 months (mean, 57.3 months). All fractures healed without further treatment, with a mean time to union of 14.3 weeks. There was no major morbidity, but 2 minor complications occurred. One patient experienced a frozen shoulder on the treated side postoperatively. After adequate rehabilitation, the symptom resolved without any complications at final follow-up. Another patient reported uncomfortable skin tenting due to subcutaneous protrusion of the suture node of the Mersilene tape. After simple subcutaneous surgical removal of the node under local anesthesia, the discomfort resolved. Mean University of California Los Angeles shoulder rating score was 34 (range, 29-35). Twenty patients had excellent results and 8 had good results. All patients resumed their previous levels of activity. PMID- 21667904 TI - Palmar locking plates for corrective osteotomy of latent malunion of dorsally tilted distal radial fractures without structural bone grafting. AB - The purpose of this retrospective study was to investigate the clinical and radiological outcomes following corrective osteotomy for nascent malunion of distal radial fractures with dorsal tilt using palmar-locking plates without using autologous structural bone grafting for dorsal cortex support. The fractures were dorsally angulated distal radial fractures (AO types A2, A3, and C1) with neglected or delayed treatment for 5 to 8 weeks. Fractures were repaired using 2.4-mm palmar locking plates. Dorsal cortical defects at the osteotomy sites were filled with incipient healing callus. Radiographs were obtained before correction and at 2 and 6 weeks and 3, 4.5, 6, and 12 months postoperatively. Palmar tilt, radial inclination, and ulnar variance were measured. There were no cases of loss reduction, implant failure, or delayed fracture union without structural bone graft and casting. Clinical assessments included active range of motion of the wrist and function based on the Mayo Wrist Score. Even with wrist immobilization for >1 month preoperatively, all patients had excellent Mayo Wrist Scores at 4.5 months due to early postoperative rehabilitation. No further changes were apparent between 4.5- and 12-month follow-up.The palmar locking plates provided sufficient stability for corrective osteotomy within 8 weeks of injury without the need for structural bone grafting. Furthermore, casting immobilization was also unnecessary, and a good wrist range of motion was restored early after rehabilitation. PMID- 21667905 TI - The characteristics of patients with type 1: intraforaminal vertebral artery anomalies? AB - In a previous study, intraforaminal anomalies were found to occur at a rate of 7.6%. This increases the risk of injury to this vessel if the surgeon is unaware of such abnormalities preoperatively. The aim of our retrospective study was to identify patient factors that may predict anomalous intraforaminal vertebral arteries. Patient records were obtained from a previous study. In that study, the records of each consecutive patient who underwent cervical spine magnetic resonance imaging (MRI) for axial neck pain, radiculopathy, or myelopathy between January 2007 and January 2008 were reviewed. The social and medical histories of each patient were evaluated with respect to the presence or absence of an aberrant vertebral artery. We reviewed the medical records of the 250 patients whose MRIs were reviewed in the previous study. Seven patients were excluded for incomplete records. Chi-square and Fisher's exact tests were performed to compare the normal vertebral artery anatomy patients to the aberrant patients. The medical records of 19 patients with aberrant vertebral arteries and 224 patients with normal vertebral arteries were reviewed. The aberrant group was significantly older than the normal group (P=.00015). The only diagnostic condition that represented a statistically significant difference between the 2 groups was incidence of cancer. A relationship may exist between patient age, cancer, and medialization of the vertebral artery. The mechanism of this possible relationship is unclear. Although aberrant vertebral arteries are rare, a surgeon should have raised suspicion of this possibility in patients with a history of cancer. PMID- 21667907 TI - Fatigue load of current tibial intramedullary nail designs: a simulated study. AB - Comminuted tibial shaft fractures are traditionally treated with statically locked intramedullary nailing and protected weight bearing until fracture callous is evident. The purpose of this study was to demonstrate that a simulation of immediate full weight bearing following intramedullary nailing of these fractures does not result in implant failure.A comminuted fracture model was created using 2 pieces of polyvinyl chloride (PVC) pipe. Ten-millimeter-diameter tibial nails (Synthes, Paoli, Pennsylvania; Styker, Mahwah, New Jersey; Zimmer, Warsaw, Indiana; Smith & Nephew, Memphis, Tennessee) were inserted within the PVC pipe and secured proximally and distally with 2 or 3 locking bolts. The constructs were cycled in axial compression for 500,000 cycles or until implant failure. The tests were conducted using a modified staircase method (200 N per step), and the fatigue strength was identified for each of the tibial nail designs. When 2 interlocking bolts were placed proximally and distally, the fatigue strength was between 900 and 1100 N for the Stryker nail, 1100 and 1300 N for the Zimmer nail, 1200 and 1400 N for the Synthes nail, and 1400 and 1600 N for the Smith & Nephew nail. Adding a third interlocking bolt proximally and distally to the Smith & Nephew nail increased the fatigue strength by 13% to between 1700 and 1900 N. In all cases, implant failures occurred through the proximal or distal interlocking bolts.Biomechanical tests suggest that current tibial nail designs may permit immediate full weight bearing of comminuted tibial shaft fractures with minimal risk of implant failure. This may facilitate mobilization in the early postoperative period, especially in the multiply injured patient. PMID- 21667906 TI - Correlation between facial asymmetry, shoulder imbalance, and adolescent idiopathic scoliosis. AB - We conducted a prospective cross-sectional study to examine the correlation between facial asymmetry, shoulder imbalance, and adolescent idiopathic scoliosis. Sixty-nine adolescent idiopathic scoliosis patients and 29 healthy volunteers were enrolled in this study. All patients underwent whole-spine standing anteroposterior radiographs and frontal cephalograms. Patients were divided into mild, moderate, and severe groups depending on Cobb angle (10 degrees -25 degrees , 25 degrees -40 degrees , and >40 degrees , respectively). Facial measurements included maxilla height difference, ramus length difference, and anterior nasal spine-menton angle. Shoulder measurements included coracoid height difference, clavicular angle, clavicle-rib intersection difference, and radiographic shoulder height.The anterior nasal spine-menton angle in the severe group (>40 degrees ) was higher than in the other groups (P<.05), as was the clavicle-rib intersection difference (P<.05). In addition, the magnitude of the curve showed a possible correlation with the anterior nasal spine-menton angle and clavicle-rib intersection difference in scoliosis patients (r=0.433 and r=0.511, respectively). According to different curve patterns, the anterior nasal spine-menton angle and clavicle-rib intersection difference were significantly higher in the double thoracic group than in the other groups (P<.05). In the correlation analysis, the ramus length difference and anterior nasal spine-menton angle had a possible correlation with the coracoid height difference, clavicular angle, radiographic shoulder height, and clavicle-rib intersection difference (P<.05). PMID- 21667908 TI - Open repair and arthroscopic follow-up of severely delaminated femoral head cartilage associated with traumatic obturator fracture-dislocation of the hip. AB - This article describes an unusual case of a young adult with traumatic obturator fracture-dislocation of the hip, involving a large femoral head fragment and severe delamination of articular cartilage. The dislocation was irreducible by closed reduction because of interposing soft tissues, including the rectus femoris and iliopsoas muscles, and torn joint capsules, and therefore, open reduction was performed using an anterolateral approach in the lateral decubitus position. The large femoral head fragment was released from the ligamentum teres and fixed to the dislocated femoral head with headless screws. The severely delaminated femoral head cartilage was repaired with suture anchors and absorbable sutures. The patient was kept nonweight bearing for 6 weeks postoperatively, and was then allowed to resume full weight bearing gradually. He returned to normal activities of daily living at 14 weeks. At 9 months postoperatively, arthroscopic examination showed complete healing of the fracture and cartilage lesions, and at 12-month follow-up, there was no clinical or radiographic evidence of arthritis or osteonecrosis. The patient had no pain or limp, and achieved an excellent result according to Epstein's clinical evaluation criteria. To our knowledge, no previous report exists on the arthroscopic follow up of a repaired femoral head cartilage in patients with obturator fracture dislocation of the hip along with a large femoral head fragment and severe delamination of articular cartilage. PMID- 21667909 TI - Femoral stem dislodgement during bipolar hemiarthroplasty dislocation. AB - Bipolar hemiarthroplasty remains a treatment option for displaced femoral neck fractures in elderly patients without pre-existing hip disease. Implant-related complications associated with this procedure include acetabular erosion, dislocation, disassembly of the modular components, polyethylene debris-induced osteolysis, metallosis from outer cup impingement, and femoral component loosening. This article presents a case of a patient in whom the polished collarless tapered femoral stem dislodged out of the cement mantle during traumatic bipolar hemiarthroplasty dislocation, 28 days after the index procedure. This complication, associated with bipolar hemiarthroplasty dislocation, was adequately managed by driving the stem back to the original cement mantle, followed by reduction of bipolar component dislocation and placing bone cement over the shoulder of the femoral stem to prevent a new dislodgement episode. Although rare, dislodgement of cemented polished collarless tapered stems from the cement mantle has been recently reported either during dislocation or, more frequently, as a complication of reduction of a dislocated total hip arthroplasty. However, its occurrence in association with bipolar hemiarthroplasty dislocation was not found to have been reported in the literature. The occurrence of femoral stem dislodgement during bipolar hemiarthroplasty dislocation should be considered as a possible complication of such a procedure and may be prevented by routinely placing bone cement over the shoulder of the femoral implant. PMID- 21667910 TI - Endogenous heparinoids induced massive hemorrhage postoperatively following THA. AB - A 64-year-old woman presented with right hip pain of 6 years' duration, accompanied by limping of 1 years' duration. Preoperative pelvis radiograph showed narrowing of joint space, osteophyte formation, and cystis degeneration of the femoral head surrounded by bony sclerosis, without obvious collapse of the femoral head; the diagnosis was osteoarthrosis. The patient's blood pressure on admission was 128/76 mm Hg. The patient had no special previous history. Preoperative blood and coagulation tests were normal. Total hip arthroplasty was performed via a posterolateral approach, and intraoperative bleeding was 400 mL. In the first 10 hours postoperatively, the drainage volume decreased slowly, the initial dose of 0.3 mL Fraxiparine was administered, and the blood pressure was 84~92/45~56 mm Hg. The drainage volume increased gradually, and 10 hours after administration of Fraxiparine, the drainage volume increased sharply and maintained at a high level. Protamine was applied and the drainage volume decreased sharply, furthermore, a high concentration of endogenous heparinoids were detected in the blood. Although no direct evidence were detected, it was clear that the massive hemorrhage was associated with administration of low molecular-weight heparin (LMWH). The administration of LMWH combined with continuous low blood pressure caused by surgery and massive bleeding that resulted in low perfusion and inflammation in microcirculation, induced endogenous heparinoid synthesis in endothelial cells, and elevated concentration of endogenous heparinoids in blood led to more severe bleeding. Therefore, caution should be taken with administration of anticoagulant therapy in patients with massive hemorrhage, especially in patients with continuous low blood pressure. PMID- 21667911 TI - Negative pressure wound therapy for the treatment of infected wounds with exposed knee joint after patellar fracture. AB - Treatment of soft tissue defects with exposed bones and joints, resulting from trauma, infection, and surgical complications, represents a major challenge. The introduction of negative pressure wound therapy has changed many wound management practices. Negative pressure wound therapy has recently been used in the orthopedic field for management of traumatic or open wounds with exposed bone, nerve, tendon, and orthopedic implants. This article describes a case of a patient with a large soft tissue defect and exposed knee joint, in which negative pressure wound therapy markedly improved wound healing. A 50-year-old man presented with an ulceration of his left knee with exposed joint, caused by severe wound infections after open reduction and internal fixation of a patellar fracture. After 20 days of negative pressure wound therapy, a granulated wound bed covered the exposed bones and joint.To our knowledge, this is the first report of negative pressure wound therapy used in a patient with a large soft tissue defect with exposed knee joint. Despite the chronic wound secondary to infection, healing was achieved through the use of the negative pressure wound therapy, thus promoting granulation tissue formation and closing the joint. We suggest negative pressure wound therapy as an alternative option for patients with lower limb wounds containing exposed bones and joints when free flap transfer is contraindicated. Our result added to the growing evidence that negative pressure wound therapy is a useful adjunctive treatment for open wounds around the knee joint. PMID- 21667912 TI - Atypical tibial tuberosity fracture in an adolescent. AB - Avulsion fractures of the tibial tuberosity are typically sustained by adolescent males during sporting activities. Tibial tuberosity avulsions with simultaneous proximal tibial epiphyseal fractures are rare injuries. We present an unusual case of Ogden type IIIA avulsion fracture of tibial tuberosity with a Salter Harris type IV posterior fracture of proximal tibial epiphysis in a 13-year-old boy. We believe that the patient sustained the tibial tuberosity avulsion during the take-off phase of a jump while playing basketball due to sudden violent contraction of the quadriceps as the knee was extending. This was then followed by the posterior Salter Harris type IV fracture of proximal tibial physis as he landed on his leg with enormous forces passing through the knee. Although standard radiographs were helpful in diagnosing the complex fracture pattern, precise configuration was only established by computed tomography (CT) scan. The scan also excluded well-recognized concomitant injuries including ligament and meniscal injuries. Unlike other reported cases, our patient did not have compartment syndrome. Anatomic reduction and stabilization with a partially threaded transepiphyseal cannulated screw and a metaphyseal screw followed by early mobilization ensured an excellent recovery by the patient.Our case highlights the importance of vigilance and a high index of suspicion for coexisting fractures or soft tissue injuries when treating avulsion fractures of tibial tuberosity. A CT scan is justified in such patients to recognize complex fracture configurations, and surgical treatment should be directed appropriately to both the fractures followed by early rehabilitation. Patients with such injuries warrant close monitoring for compartment syndrome during the perioperative period. PMID- 21667913 TI - Chronic exertional compartment syndrome with medial tibial stress syndrome in twins. AB - Chronic exertional compartment syndrome and medial tibial stress syndrome are uncommon conditions that affect long-distance runners or players involved in team sports that require extensive running. We report 2 cases of bilateral chronic exertional compartment syndrome, with medial tibial stress syndrome in identical twins diagnosed with the use of a Kodiag monitor (B. Braun Medical, Sheffield, United Kingdom) fulfilling the modified diagnostic criteria for chronic exertional compartment syndrome as described by Pedowitz et al, which includes: (1) pre-exercise compartment pressure level >15 mm Hg; (2) 1 minute post-exercise pressure >30 mm Hg; and (3) 5 minutes post-exercise pressure >20 mm Hg in the presence of clinical features. Both patients were treated with bilateral anterior fasciotomies through minimal incision and deep posterior fasciotomies with tibial periosteal stripping performed through longer anteromedial incisions under direct vision followed by intensive physiotherapy resulting in complete symptomatic recovery. The etiology of chronic exertional compartment syndrome is not fully understood, but it is postulated abnormal increases in intramuscular pressure during exercise impair local perfusion, causing ischemic muscle pain. No familial predisposition has been reported to date. However, some authors have found that no significant difference exists in the relative perfusion, in patients, diagnosed with chronic exertional compartment syndrome. Magnetic resonance images of affected compartments have indicated that the pain is not due to ischemia, but rather from a disproportionate oxygen supply versus demand. We believe this is the first report of chronic exertional compartment syndrome with medial tibial stress syndrome in twins, raising the question of whether there is a genetic predisposition to the causation of these conditions. PMID- 21667914 TI - Proximal humerus shaft fracture after pectoralis major tendon rupture repair. AB - Surgical repair of a complete pectoralis major tendon rupture at the humeral insertion has superior results compared to nonoperative treatment. To our knowledge, a proximal humerus shaft fracture occurring at the site of the bone trough and cortical drill holes after a pectoralis major tendon rupture repair has not been reported in the literature.A 45-year-old man sustained an acute left pectoralis major tendon rupture at the humeral insertion while performing a bench press maneuver. He underwent acute surgical repair. Approximately 8 weeks postoperatively, the patient fell from a standing height and sustained a proximal humerus shaft fracture through the repair site at the bone trough. Three days after the fracture, the patient underwent open reduction and internal fixation of the proximal humerus shaft fracture and exploration of the pectoralis major tendon repair. The fracture was found to be at the level of the repair site, and the pectoralis major tendon was completely intact to the distal fragment. The fracture healed uneventfully, and the patient regained full motion and strength of his extremity with no limitations.Any type of surgical fixation that creates a hole in the humerus or decreases the cross-sectional area such as a bone trough creates a stress riser. Patients undergoing pectoralis tendon repair that involves violating the humerus with a bone trough or hole have a slight risk of postoperative humerus fracture, especially if sustaining an early traumatic event such as a fall. PMID- 21667915 TI - Repair of flexor carpi radialis tendon laceration at the wrist in a professional ice hockey player. AB - The flexor carpi radialis is a wrist flexor and radial deviator with half the relative strength of flexor carpi ulnaris. In the majority of patients, the flexor carpi radialis tendon is expendable and is routinely used for various reconstructive procedures about the hand and wrist. Isolated flexor carpi radialis lacerations at the wrist are rare. Flexor carpi radialis tendon ruptures, which have been reported in association with distal radius fractures, longstanding osteoarthritis, and percutaneous treatment of scaphoid fractures, are usually treated non-operatively. We report a case of a traumatic laceration of the flexor carpi radialis tendon at the wrist in a professional ice hockey player. Surgical repair and rehabilitation using established principles for intrasynovial flexor tendon repair allowed return to sport at the professional level in 2 months.Tension-free core suture repair was performed with a modified Kessler, 4-strand repair using a double-stranded 4-0 Supramid suture. A running epitendinous suture was then placed around the circumference of the tendon with 6 0 Prolene. Immobilization of the wrist in 20 degrees of flexion was maintained for 2 weeks. Full active and passive digital motion was allowed immediately postoperatively and continued throughout the rehabilitation. Therapy was initiated at 2 weeks postoperatively with full passive wrist flexion and passive wrist extension to a dorsal block of 20 degrees . At 4 weeks postoperatively, a dorsal splint was fabricated to keep the wrist in neutral. At this time, active extension to a dorsal block of zero and full passive flexion was allowed. Active wrist flexion without resistance was begun at 6 weeks, and full strengthening was allowed at 8 weeks postoperatively. The patient returned to sport at the professional level shortly thereafter. At latest follow-up, the patient has been able to fully participate in professional ice hockey without pain or functional limitation. PMID- 21667916 TI - Posterior spinal fusion for scoliosis in Ehlers-Danlos syndrome, kyphoscoliosis type. AB - The Ehlers-Danlos syndromes comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by articular hypermobility, skin extensibility, and tissue fragility. Surgical treatment of scoliosis associated with Ehlers-Danlos syndrome poses a challenge to spine surgeons because of the high risk of major complications. There is a paucity of evidence in the literature on surgical treatment for scoliosis in the Ehlers Danlos syndrome patient.This article describes 3 adolescent patients diagnosed with Ehlers-Danlos syndrome, kyphoscoliosis type, which was treated by posterior spinal fusion only. After unsuccessful conservative treatment for at least 1 year, the patients underwent posterior spinal surgery for the correction of spinal deformity. A satisfactory correction in the spinal curve was achieved, with no obvious loss of correction during follow-up. No intra- or postoperative major complications were observed.Our experience supports that a satisfactory correction of scoliosis can be achieved by posterior spinal fusion only in patients with Ehlers-Danlos syndrome, kyphoscoliosis type. PMID- 21667917 TI - Symptomatic spinal epidural lipomatosis with severe obesity at a young age. AB - Symptomatic spinal epidural lipomatosis is a rare disorder characterized by overgrowth of fat in the extradural space. Most patients have an underlying endocrine disorder, such as Cushing's syndrome, or have taken exogenous steroids chronically. Although less common, obesity alone is thought to be a cause of spinal epidural lipomatosis, representing <25% of reported cases. Patients rarely become symptomatic before middle age without chronic exogenous steroid use. The usual clinical manifestations are similar to degenerative lumbar stenosis with neurogenic claudication, resulting in decreased walking and standing endurance with variable neurological deficits.This article describes 2 unique cases of spinal epidural lipomatosis, both in young patients with underlying morbid obesity who presented with acute progressive leg weakness and urinary retention. The patients had no underlying endocrinopathy, nor any history of exogenous steroid use. They underwent emergency laminectomy and removal of epidural fat, and histopathological examination confirmed the diagnosis of epidural lipomatosis. Postoperatively, the patients demonstrated significant improvement.We conducted a review of the available English literature and compared the age distribution in each group. Based on our review, our 2 patients are considerably younger than those in past reports, especially in the patient group to which the steroid was not administered. In addition, few cases exist of spinal epidural lipomatosis with acute sphincter dysfunction and paraparesis. Our cases suggest that morbid obesity can lead to juvenile spinal epidural lipomatosis with acute neurological changes. PMID- 21667918 TI - Non-surface activity and micellization behavior of cationic amphiphilic block copolymer synthesized by reversible addition-fragmentation chain transfer process. AB - Cationic amphiphilic diblock copolymers of poly(n-butylacrylate)-b-poly(3 (methacryloylamino)propyl)trimethylammonium chloride) (PBA-b-PMAPTAC) with various hydrophobic and hydrophilic chain lengths were synthesized by a reversible addition-fragmentation chain transfer (RAFT) process. Their molecular characteristics such as surface activity/nonactivity were investigated by surface tension measurements and foam formation observation. Their micelle formation behavior and micelle structure were investigated by fluorescence probe technique, static and dynamic light scattering (SLS and DLS), etc., as a function of hydrophilic and hydrophobic chain lengths. The block copolymers were found to be non-surface active because the surface tension of the aqueous solutions did not change with increasing polymer concentration. Critical micelle concentration (cmc) of the polymers could be determined by fluorescence and SLS measurements, which means that these polymers form micelles in bulk solution, although they were non-surface active. Above the cmc, the large blue shift of the emission maximum of N-phenyl-1-naphthylamine (NPN) probe and the low micropolarity value of the pyrene probe in polymer solution indicate the core of the micelle is nonpolar in nature. Also, the high value of the relative intensity of the NPN probe and the fluorescence anisotropy of the 1,6-diphenyl-1,3,5-hexatriene (DPH) probe indicated that the core of the micelle is highly viscous in nature. DLS was used to measure the average hydrodynamic radii and size distribution of the copolymer micelles. The copolymer with the longest PBA block had the poorest water solubility and consequently formed micelles with larger size while having a lower cmc. The "non-surface activity" was confirmed for cationic amphiphilic diblock copolymers in addition to anionic ones studied previously, indicating the universality of non-surface activity nature. PMID- 21667919 TI - Behavior of the amphiphile CHAPS alone and in combination with the biopolymer inulin in water and isopropanol-water media. AB - Self-aggregation of the zwitterionic surfactant 3-[(3 cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) in water and isopropanol-water media, and interaction of the amphiphile with the biopolymer inulin in these media were investigated. The micellar properties of the zwitterionic surfactant and its associated interfacial and bulk properties along with the related energetic, and aggregation number were determined. The different stages of interaction of the CHAPS-inulin combines were identified and assessed. The complexes were formed and aggregated in solution at different stages of their molecular compositions. The aggregated sizes were determined by dynamic light scattering study and the morphology in the solvent removed states were examined using scanning electron microscope and transmission electron microscope techniques. The results witnessed formation of ensembles of varied and striking patterns. PMID- 21667920 TI - Confinement in carbon nanospace-induced production of KI nanocrystals of high pressure phase. AB - An outstanding compression function for materials preparation exhibited by nanospaces of single-walled carbon nanohorns (SWCNHs) was studied using the B1-to B2 solid phase transition of KI crystals at 1.9 GPa. High-resolution transmission electron microscopy and synchrotron X-ray diffraction examinations provided evidence that KI nanocrystals doped in the nanotube spaces of SWCNHs at pressures below 0.1 MPa had the super-high-pressure B2 phase structure, which is induced at pressures above 1.9 GPa in bulk KI crystals. This finding of the supercompression function of the carbon nanotubular spaces can lead to the development of a new compression-free route to precious materials whose syntheses require the application of high pressure. PMID- 21667921 TI - Nanopore translocation dynamics of a single DNA-bound protein. AB - We study the translocation dynamics of a single protein molecule attached to a double-stranded DNA that is threaded through a solid-state nanopore by optical tweezers and an electric field (nanopore force spectroscopy). We find distinct asymmetric and retarded force signals that depend on the protein charge, the DNA elasticity and its counterionic screening in the buffer. A theoretical model where an isolated charge on an elastic, polyelectrolyte strand is experiencing an anharmonic nanopore potential was developed. Its results compare very well with the measured force curves and explain the experimental findings that the force depends linearly on the applied electric field and exhibits a small hysteresis during back and forth translocation cycles. Moreover, the translocation dynamics reflects the stochastic nature of the thermally activated hopping between two adjacent states in the nanopore that can be adequately described by Kramers rate theory. PMID- 21667922 TI - NCN-chelated organoantimony(III) and organobismuth(III) phosphates: synthesis and solid-state and solution structures. AB - .Organoantimony(III) and organobismuth(III) phosphates (LM)(3)(PO(4))(2) [M = Sb (3) and Bi (4)], containing the NCN-chelating ligand L [L = 2,6 (CH(2)NMe(2))(2)C(6)H(3)], were prepared by the simple treatment of parent oxides 1 and 2 with H(3)PO(4). Both compounds were characterized by elemental analysis, electrospray ionization mass spectrometry, and IR and NMR spectroscopy and in the case of 3 by X-ray diffraction techniques. Compound 3 has an interesting behavior in solution, i.e., the formation of two possible conformational isomers, which was studied by (1)H, (13)C, and (31)P NMR spectroscopy. PMID- 21667923 TI - Solution-processed graphene/MnO2 nanostructured textiles for high-performance electrochemical capacitors. AB - Large scale energy storage system with low cost, high power, and long cycle life is crucial for addressing the energy problem when connected with renewable energy production. To realize grid-scale applications of the energy storage devices, there remain several key issues including the development of low-cost, high performance materials that are environmentally friendly and compatible with low temperature and large-scale processing. In this report, we demonstrate that solution-exfoliated graphene nanosheets (~5 nm thickness) can be conformably coated from solution on three-dimensional, porous textiles support structures for high loading of active electrode materials and to facilitate the access of electrolytes to those materials. With further controlled electrodeposition of pseudocapacitive MnO(2) nanomaterials, the hybrid graphene/MnO(2)-based textile yields high-capacitance performance with specific capacitance up to 315 F/g achieved. Moreover, we have successfully fabricated asymmetric electrochemical capacitors with graphene/MnO(2)-textile as the positive electrode and single walled carbon nanotubes (SWNTs)-textile as the negative electrode in an aqueous Na(2)SO(4) electrolyte solution. These devices exhibit promising characteristics with a maximum power density of 110 kW/kg, an energy density of 12.5 Wh/kg, and excellent cycling performance of ~95% capacitance retention over 5000 cycles. Such low-cost, high-performance energy textiles based on solution-processed graphene/MnO(2) hierarchical nanostructures offer great promise in large-scale energy storage device applications. PMID- 21667924 TI - Stochastic sensing of single molecules in a nanofluidic electrochemical device. AB - We report the electrochemical detection of individual redox-active molecules as they freely diffuse in solution. Our approach is based on microfabricated nanofluidic devices, wherein repeated reduction and oxidation at two closely spaced electrodes yields a giant sensitivity gain. Single molecules entering and leaving the cavity are revealed as anticorrelated steps in the faradaic current measured simultaneously through the two electrodes. Cross-correlation analysis provides unequivocal evidence of single molecule sensitivity. We further find agreement with numerical simulations of the stochastic signals and analytical results for the distribution of residence times. This new detection capability can serve as a powerful alternative when fluorescent labeling is invasive or impossible. It further enables new fundamental (bio)electrochemical experiments, for example, localized detection of neurotransmitter release, studies of enzymes with redox-active products, and single-cell electrochemical assays. Finally, our lithography-based approach renders the devices suitable for integration in highly parallelized, all-electrical analysis systems. PMID- 21667925 TI - Induced production of N-formyl alkaloids from Aspergillus fumigatus by co-culture with Streptomyces peucetius. AB - Co-culture of the fungus Aspergillus fumigatus with the bacteria Streptomyces peucetius led to the induction of production of formyl xanthocillin analogues. This mixed fermentation yielded two new metabolites, fumiformamide (1) and N,N' ((1Z,3Z)-1,4-bis(4-methoxyphenyl)buta-1,3-diene-2,3-diyl)diformamide (2), together with two known N-formyl derivatives and the xanthocillin analogue BU 4704. The structures were determined by spectroscopic methods and by comparison with literature. Cytotoxic activity of all the analogues was tested on the NCI-60 cell line screen, and compound 2 exhibited significant activity against several cell lines. The analogues did not show antimicrobial activity. PMID- 21667926 TI - Syntheses and reactivity of naphthalenyl-substituted arenediynes. AB - A series of naphthalenyl-substituted arenediynes were prepared to examine photochemical reactivity. For naphthalen-1-ylethynyl arenediyne, 350 nm photolysis resulted in a tandem [2 + 2] photocycloaddition to afford cyclobutene adducts. For naphthalen-2-ylethynyl derivatives, electron-donating methoxy substituents were found to facilitate C(1)-C(6) Bergman cyclization at 300 nm. Theoretical calculations provided further insight into thermal and photochemical reactivity. PMID- 21667927 TI - Synthesis of platinum single-twinned right bipyramid and {111}-bipyramid through targeted control over both nucleation and growth using specific peptides. AB - Shape-controlled synthesis requires rigorous kinetic control over both nucleation and growth. For platinum (Pt), to date it is still challenging to generate twinned seeds in nucleation in a controllable fashion. Here, we report that a specific Pt binding peptide BP7A is able to mediate and stabilize single-twinned seeds formation at the nucleation stage under mild conditions. Importantly, it targets the control over nucleation directly. Combining with control over growth, we further demonstrate the rational design and synthesis of single-twinned structures, right bipyramid and {111}-bipyramid, by incorporating targeted facet stabilization over {100} facet and {111} facet, respectively. To the best of our knowledge, this is the first report on the successful synthesis of single-twinned bipyramids for Pt nanocrystals (NCs) with high yields. The work here demonstrates the power of biomolecules in recognizing and mediating inorganic nanomaterials synthesis, guiding the formation of material structures that are otherwise unconventional, and hence presenting one step further toward predictable and programmable biomimetic synthesis. PMID- 21667928 TI - Asymmetric total syntheses of (-)-variabilin and (-)-glycinol. AB - Total syntheses of (-)-variabilin and (-)-glycinol have been accomplished, using the catalytic, asymmetric "interrupted" Feist-Benary reaction (IFB) as the key transformation to introduce both stereogenic centers. A monoquinidine pyrimidinyl ether catalyst affords the IFB products in over 90% ee in both cases. Other key steps include an intramolecular Buchwald-Hartwig coupling and a nickel-catalyzed aryl tosylate reduction. PMID- 21667929 TI - Investigation relevant to the conformation of the 17-membered Pt(d(GpG)) macrocyclic ring formed by Pt anticancer drugs with DNA: Pt complexes with a Goldilocks carrier ligand. AB - Platinum anticancer drug DNA intrastrand cross-link models, LPt(d(G*pG*)) (G* = N7-platinated G residue, L = R(4)dt = bis-3,3'-(5,6-dialkyl)-1,2,4-triazine), and R = Me or Et), undergo slow Pt-N7 bond rotation. NMR evidence indicated four conformers (HH1, HH2, DeltaHT1, and LambdaHT2); these have different combinations of guanine base orientation (head-to-head, HH, or head-to-tail, HT) and sugar phosphodiester backbone propagation relative to the 5'-G* (the same, 1, or opposite, 2, to the direction in B DNA). In previous work on LPt(d(G*pG*)) adducts, Pt-N7 rotation was too rapid to resolve conformers (small L with bulk similar to that in active drugs) or L was too bulky, allowing formation of only two or three conformers; LambdaHT2 was not observed under normal conditions. The (R(4)dt)Pt(d(G*pG*)) results support our initial hypothesis that R(4)dt ligands have Goldilocks bulk, sufficient to slow G* rotation but insufficient to prevent formation of the LambdaHT2 conformer. Unlike the (R(4)dt)Pt(5'-GMP)(2) adducts, ROESY spectra of (R(4)dt)Pt(d(G*pG*)) adducts showed no EXSY peaks, a result providing clear evidence that the sugar-phosphodiester backbone slows conformer interchange. Indeed, the LambdaHT2 conformer formed and converted to other conformers slowly. Bulkier L (Et(4)dt versus Me(4)dt) decreased the abundance of the LambdaHT2 conformer, supporting our initial hypothesis that steric crowding disfavors this conformer. The (R(4)dt)Pt(d(G*pG*)) adducts have a low abundance of the DeltaHT1 conformer, consistent with the proposal that the DeltaHT1 conformer has an energetically unfavorable phosphodiester backbone conformation; its high abundance when L is bulky is attributed to a small d(G*pG*) spatial footprint for the DeltaHT1 conformer. Despite the Goldilocks size of the R(4)dt ligands, the bases in the (R(4)dt)Pt(d(G*pG*)) adducts have a low degree of canting, suggesting that the ligand NH groups characteristic of active drugs may facilitate canting, an important aspect of DNA distortions induced by active drugs. PMID- 21667930 TI - Three-dimensional high-resolution imaging of gold nanorods uptake in sentinel lymph nodes. AB - In this paper, we demonstrate an application of a noninvasive imaging modality, photothermal optical coherence tomography (PT-OCT), for imaging gold nanorods (GNRs) uptake in sentinel lymph node (SLN) of mice in situ. This application enables us to obtain higher quality images of SLN structures due to the photothermal contrast properties of the GNRs. It is also demonstrated that GNRs accumulate differently within several SLN structures, and this uptake is time dependent. Finally, we determine the average concentration of GNRs within the whole SLN which is used to demonstrate uptake kinetics of the nanoparticles. PMID- 21667931 TI - Coordination of 1,10-phenanthroline and 2,2'-bipyridine to Li+ in different ionic liquids. How innocent are ionic liquids? AB - On the basis of (7)Li NMR measurements, we have made detailed studies on the influence of the ionic liquids [emim][NTf(2)], [emim][ClO(4)], and [emim][EtSO(4)] on the complexation of Li(+) by the bidentate N-donor ligands 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen). For each of the employed ionic liquids the NMR data implicate the formation of [Li(bipy)(2)](+) and [Li(phen)(2)](+), respectively. X-ray diffraction studies were performed to determine the coordination pattern in the solid state. In the case of [emim][ClO(4)] and [emim][EtSO(4)], crystal structures confirmed the NMR data, resulting in the complexes [Li(bipy)(2)ClO(4)] and [Li(phen)(2)EtSO(4)], respectively. On the contrary, the ionic liquid [emim][NTf(2)] generated the C(i) symmetric, dinuclear, supramolecular cluster [Li(bipy)(NTf(2))](2), where the individual Li(+) centers were found to be bridged by two [NTf(2)] anions. Density functional theory (DFT)-calculations lead to further information on the effect of stacking on the coordination geometry of the Li(+) centers. PMID- 21667932 TI - Macrobicyclic cage amine ligands for copper radiopharmaceuticals: a single bivalent cage amine containing two Lys3-bombesin targeting peptides. AB - The synthesis of new cage amine macrobicyclic ligands with pendent carboxylate functional groups designed for application in copper radiopharmaceuticals is described. Reaction of [Cu((NH(2))(2)sar)](2+) (sar = 3,6,10,13,16,19 hexaazabicyclo[6.6.6]icosane) with either succinic or glutaric anhydride results in selective acylation of the primary amine atoms of [Cu((NH(2))(2)sar)](2+) to give derivatives with either one or two aliphatic carboxylate functional groups separated from the cage amine framework by either a four- or five-atom linker. The Cu(II) serves to protect the secondary amine nitrogen atoms from acylation, and can be removed to give the free ligands. The newly appended carboxylate functional groups can be used as sites of attachment for cancer-targeting peptides such as Lys(3)-bombesin. The synthesis of the first dimeric sarcophagine peptide conjugate, possessing two Lys(3)-bombesin peptides tethered to a single cage amine, is presented. This species has been radiolabeled with copper-64 at ambient temperature and there is minimal dissociation of Cu(II) from the conjugate even after two days of incubation in human serum. PMID- 21667933 TI - Highly efficient all-optical control of surface-plasmon-polariton generation based on a compact asymmetric single slit. AB - By engaging a compact asymmetric single slit coated with a photorefractive polymer, surface-plasmon-polariton (SPP) generation was efficiently controlled by a pump beam. In the structure, the nonlinear light-matter interaction is enhanced because of the cavity effect, which increases the sensitivity of SPPs to the surrounding dielectric. By variation of the real part of the refractive index together with an interferometric configuration, high on/off switching ratios are achieved. Moreover, the SPP generation and modulation processes are integrated in the same asymmetric single slit, which makes the device ultracompact. Experimentally, a high on/off switching ratio of >20 dB and phase variation of >pi were observed with the device lateral dimension of only about 2 MUm. PMID- 21667934 TI - Taguchi design-based optimization of sandwich immunoassay microarrays for detecting breast cancer biomarkers. AB - Taguchi design, a statistics-based design of experiment method, is widely used for optimization of products and complex production processes in many different industries. However, its use for antibody microarray optimization has remained underappreciated. Here, we provide a brief explanation of Taguchi design and present its use for the optimization of antibody sandwich immunoassay microarray with five breast cancer biomarkers: CA15-3, CEA, HER2, MMP9, and uPA. Two successive optimization rounds with each 16 experimental trials were performed. We tested three factors (capture antibody, detection antibody, and analyte) at four different levels (concentrations) in the first round and seven factors (including buffer solution, streptavidin-Cy5 dye conjugate concentration, and incubation times for five assay steps) with two levels each in the second round; five two-factor interactions between selected pairs of factors were also tested. The optimal levels for each factor as measured by net assay signal increase were determined graphically, and the significance of each factor was analyzed statistically. The concentration of capture antibody, streptavidin-Cy5, and buffer composition were identified as the most significant factors for all assays; analyte incubation time and detection antibody concentration were significant only for MMP9 and CA15-3, respectively. Interactions between pairs of factors were identified, but were less influential compared with single factor effects. After Taguchi optimization, the assay sensitivity was improved between 7 and 68 times, depending on the analyte, reaching 640 fg/mL for uPA, and the maximal signal intensity increased between 1.8 and 3 times. These results suggest that Taguchi design is an efficient and useful approach for the rapid optimization of antibody microarrays. PMID- 21667935 TI - Oxidation and reduction of bis(imino)pyridine iron dicarbonyl complexes. AB - The oxidation and reduction of a redox-active aryl-substituted bis(imino)pyridine iron dicarbonyl has been explored to determine whether electron-transfer events are ligand- or metal-based or a combination of both. A series of bis(imino)pyridine iron dicarbonyl compounds, [((iPr)PDI)Fe(CO)(2)](-), ((iPr)PDI)Fe(CO)(2), and [((iPr)PDI)Fe(CO)(2)](+) [(iPr)PDI = 2,6-(2,6 (i)Pr(2)C(6)H(3)N?CMe)(2)C(5)H(3)N], which differ by three oxidation states, were prepared and the electronic structures evaluated using a combination of spectroscopic techniques and, in two cases, [((iPr)PDI)Fe(CO)(2)](+) and [((iPr)PDI)Fe(CO)(2)], metrical parameters from X-ray diffraction. The data establish that the cationic iron dicarbonyl complex is best described as a low spin iron(I) compound (S(Fe) = 1/2) with a neutral bis(imino)pyridine chelate. The anionic iron dicarbonyl, [((iPr)PDI)Fe(CO)(2)](-), is also best described as an iron(I) compound but with a two-electron-reduced bis(imino)pyridine. The covalency of the neutral compound, ((iPr)PDI)Fe(CO)(2), suggests that both the oxidative and reductive events are not ligand- or metal-localized but a result of the cooperativity of both entities. PMID- 21667936 TI - Bixbyite-type V2O3--a metastable polymorph of vanadium sesquioxide. AB - A metastable polymorph of vanadium sesquioxide was prepared by the reaction of vanadium trifluoride with a water-saturated gaseous mixture of 10 vol % hydrogen in argon. The new polymorph crystallizes in the bixbyite-type structure. At temperatures around 823 K a transformation to the well-known corundum-type phase is observed. Quantum-chemical calculations show that the bixbyite-type structure is about 9 kJ/mol less stable than the known corundum-based one. This result, in combination with the absence of imaginary modes in the phonon density of states, supports the classification of the bixbyite-type phase as a metastable V(2)O(3) polymorph. At ~50 K a paramagnetic to canted antiferromagnetic transition is detected. PMID- 21667937 TI - Synthesis and characterization of a stable bismuth(III) A3-corrole. AB - An efficient metalation procedure for bismuth complexes with meso-substituted corrole ligands is presented. Reaction of 5,10,15-tris-pentafluorophenylcorrole H(3)(TpFPC) with Bi{N(SiMe(3))(3)} converts the free ligand H(3)(TpFPC) to a neutral low-valent species Bi(TpFPC), which has been characterized by different spectroscopic techniques. (Spectro)electrochemical studies were performed in order to describe the redox potentials of the Bi(TpFPC) complex and to ascribe the sites of electron transfer. The first crystal structure of a bismuth corrole is presented and compared to the geometry-optimized molecular structure obtained with density functional theory (DFT) calculations. We show an example of a 4 coordinate metallocorrole with a very large out-of-plane displacement and significant doming. The electronic structure of the novel bismuth corrole system is discussed in detail. Time-dependent DFT results support the proposed assignment of electronic transitions observed for the Bi(TpFPC) derivative. To account for the reactivity we investigated the photocatalytic properties of the Bi(TpFPC) complex. PMID- 21667938 TI - Hydrothermal synthesis and crystal structures of two novel acentric mixed alkaline earth metal berylloborates Sr3Be2B5O12(OH) and Ba3Be2B5O12(OH). AB - The synthesis and structure of the isostructural acentric compounds Sr(3)Be(2)B(5)O(12)(OH) (1) and Ba(3)Be(2)B(5)O(12)(OH) (2) are reported for the first time. These compounds crystallize in the space group R3m, and the unit cell parameters are a = 10.277(15) A and c = 8.484(17) A for 1 and a = 10.5615(15) A and c = 8.8574(18) A for 2. The structures consist of a network of [Be(2)B(4)O(12)(OH)] units interwoven with a network consisting of MO(9) polyhedra (M = Sr, Ba) and BO(3) triangles and exemplify how acentric building blocks such as [BO(3)](3-), [BO(4)](5-), and [BeO(4)](6-) can be especially suitable to build noncentrosymmetric long-range structures. Both networks are centered on the 3-fold rotation axis and present themselves in alternating fashion along [001]. Acentricity is imparted by the alignment of the polarities of BO(3) and BeO(4) environments. Infrared spectroscopy has been used to confirm the local geometries of B and Be, as well as the presence of hydroxide in the crystal structure. Another interesting feature of these compounds is the presence of disorder involving Be and B at the tetrahedral Be site. The degree of the disorder has been confirmed by observing a noticeable shortening of average Be-O bond distances. PMID- 21667939 TI - Formation and NMR spectroscopy of omega-thiol protected alpha,omega-alkanedithiol coated gold nanoparticles and their usage in molecular charge transport junctions. AB - Gold nanoparticles (AuNPs) coated with stabilizing molecular monolayers are utilized in areas ranging from life sciences to nanoelectronics. Here we present a novel and facile one-pot single phase procedure for the preparation of stable AuNPs with good dispersity, which are coated with alpha,omega-alkanedithiols whose outer omega-thiol is protected by a triphenylmethyl group. Using dielectrophoresis we were able to trap these AuNPs, coated with omega-thiol protecting groups, in a 20 nm gold electrode nanogap. The omega-thiol group was then deprotected under acidic conditions in situ once the AuNPs were correctly positioned in the device. The subsequent deprotection resulted in an increase of conductance by up to 3 orders of magnitude, indicating that the isolated dithiol coated AuNPs were fused into a covalently bonded network with AuNP-molecule-AuNP as well as electrode-molecule-AuNP linkages. Furthermore, complete characterization of the AuNP surface-bonded alkanedithiols was achieved using a series of one- and two-dimensional NMR spectroscopy techniques. Our spectra of the molecule-coated AuNPs show well-resolved signals, only slightly broader than for free molecules in solution, which is in contrast to many earlier reported NMR spectral data of molecules attached to AuNPs. Complementary diffusion NMR spectroscopic experiments were performed to prove that the observed alkanedithiols are definitely surface-bonded species and do not exist in free and unattached form. PMID- 21667940 TI - [n]Imperilenes: stacked [n]trannulenes separated by planar cycloalkane rings. AB - Two trannulene moieties fused to each other by means of perfectly planar cycloalkane rings comprise an interesting class of molecules (above) named "imperilenes". Based on computed geometries and NICS(zz) values, only the [5], [7], and [9]imperilene singlet states as well as the 4+ charged [4], [6], and [8]imperilenes and their higher energy neutral quintet states are aromatic. The pi electron systems of the individual trannulene rings, rather than the overall electron count, determine the behavior. PMID- 21667941 TI - Anion receptors composed of hydrogen- and halogen-bond donor groups: modulating selectivity with combinations of distinct noncovalent interactions. AB - Studies of a series of urea-based anion receptors designed to probe the potential for anion recognition through combinations of hydrogen and halogen bonding are presented. Proton- and fluorine-NMR spectroscopy indicates that the two interactions act in concert to achieve binding of certain anions, a conclusion supported by computational studies. Replacement of the halogen-bond donating iodine substituent by fluorine (which does not participate in halogen bonding) enables estimation of the contribution of this interaction to the free energy of anion binding. Evidence for attractive contacts between anions and electron deficient arenes arising from the use of perfluoroarene-functionalized ureas as control receptors is also discussed. The magnitude of the free energy contribution of halogen bonding depends both on the geometric features of the group linking the hydrogen- and halogen-bond donor groups and on the identity of the bound anion. The results are interpreted in relation to fundamental features of the halogen-bonding interaction, including its directionality and unusual preference for halides over oxoanions. Cooperation between two distinct noncovalent interactions leads to unusual effects on receptor selectivity, a result of fundamental differences in the interactions of halogen- and hydrogen bond donor groups with anions. PMID- 21667942 TI - Phenylpyrrolocytosine as an unobtrusive base modification for monitoring activity and cellular trafficking of siRNA. AB - 6-Phenylpyrrolocytosine (PhpC) is a cytosine mimic with excellent base-pairing fidelity, thermal stability, and high fluorescence. In this work, PhpC-containing small interfering RNAs (siRNAs) are shown to possess thermal stability and gene silencing activity that is virtually identical to that of natural siRNA. The emissive properties of PhpC allow the cellular trafficking of PhpC-containing siRNAs to be monitored by fluorescence microscopy. Accumulation in the cytoplasm of HeLa cells was observed using real time imaging. These findings demonstrate that PhpC-modified siRNAs retain the properties of natural siRNAs while allowing for fluorescence-based detection and monitoring, providing an ideal system for probing siRNA uptake and trafficking. PMID- 21667944 TI - Rh(I)-catalyzed formal [6 + 2] cycloaddition of 4-allenals with alkynes or alkenes in a tether. AB - Rh(I)-catalyzed formal [6 + 2] cycloaddition of allenal 6 having an alkyne or alkene in a tether proceeded smoothly, giving 5-8- and 6-8-fused bicyclic ketone derivatives 7 in good to excellent yields. It was also found that cyclization of enantiomerically enriched (S)-6a (94% ee) gave cyclic ketone derivative (S)-7a in high yield with reasonable chirality transfer (86% ee). This result indicates that this cyclization proceeds through stereoselective formation of rhodacycle H' followed by insertion of a multiple bond. PMID- 21667943 TI - Concise total synthesis and stereochemical revision of all (-)-trigonoliimines. AB - The concise and enantioselective total syntheses of (-)-trigonoliimines A, B, and C are described. Our unified strategy to all three natural products is based on asymmetric oxidation and reorganization of a single bistryptamine, a sequence of transformations with possible biogenetic relevance. We revise the absolute stereochemistry of (-)-trigonoliimines A, B, and C. PMID- 21667945 TI - Organic contamination of settled house dust, a review for exposure assessment purposes. AB - People spend a considerable amount of time indoors. As a result, exposure to indoor contaminants is of great concern, notably via settled dust ingestion in particular for infants and toddlers. This paper proposes a critical review on the organic contamination of settled house dust and human exposure over the past 10 years and focused on sources, contaminations and measurement methods (sampling, pretreatment, storage and analysis). As many compounds were identified, arises the question of which ones to consider. Sensitive and selective analytical methods for simultaneous determination of targeted substances should be developed and evaluated. Various methods were described for sampling and sample preparation. Harmonization and standardization are needed to enable comparison of results from similar studies. Finally, an integrated multipollutant and multicompartment (settled dust, suspended particles and air) approach appears essential in order to determine the extent of the threat to public health posed by indoor contaminants. PMID- 21667946 TI - Destruction and detection of chemical warfare agents. PMID- 21667947 TI - Diastereoselectivity switch in cooperatively catalyzed three-component reactions of an aryldiazoacetate, an alcohol, and a beta,gamma-unsaturated alpha-keto ester. AB - A highly switchable,diastereoselectivity-controlled, three-component reaction of aryldiazoacetate, alcohol,and beta,gamma-unsaturated alpha-keto esters has been achieved through a dual-metal cooperative catalysis strategy. PMID- 21667948 TI - On the excited state dynamics of vibronic transitions. High-resolution electronic spectra of acenaphthene and its argon van der Waals complex in the gas phase. AB - Rotationally resolved fluorescence excitation spectroscopy has been used to study the dynamics, electronic distribution, and the relative orientation of the transition moment vector in several vibronic transitions of acenaphthene (ACN) and in its Ar van der Waals (vdW) complex. The 0(0)(0) band of the S(1) <- S(0) transition of ACN exhibits a transition moment orientation parallel to its a inertial axis. However, some of the vibronic bands exhibit a transition moment orientation parallel to the b-inertial axis, suggesting a Herzberg-Teller coupling with the S(2) state. Additionally, some other vibronic bands exhibit anomalous intensity patterns in several of their rotational transitions. A Fermi resonance involving two near degenerate vibrations has been proposed to explain this behavior. The high-resolution electronic spectrum of the ACN-Ar vdW complex has also been obtained and fully analyzed. The results indicate that the weakly attached argon atom is located on top of the plane of the bare molecule at ~3.48 A away from its center of mass in the S(0) electronic state. PMID- 21667949 TI - Cationic phenylene ethynylene polymers and oligomers exhibit efficient antiviral activity. AB - The antiviral activities of poly(phenylene ethynylene) (PPE)-based cationic conjugated polyelectrolytes (CPE) and oligo-phenylene ethynylenes (OPE) were investigated using two model viruses, the T4 and MS2 bacteriophages. Under UV/visible light irradiation, significant antiviral activity was observed for all of the CPEs and OPEs; without irradiation, most of these compounds exhibited high inactivation activity against the MS2 phage and moderate inactivation ability against the T4 phage. Transmission electron microscopy (TEM) and SDS polyacrylamide gel electrophoresis (SDS-PAGE) reveal that the CPEs and OPEs exert their antiviral activity by partial disassembly of the phage particle structure in the dark and photochemical damage of the phage capsid protein under UV/visible light irradiation. PMID- 21667950 TI - Carbon dioxide in the nitrosation of amine: catalyst or inhibitor? AB - Nitrosamines are a class of carcinogenic, mutagenic, and teratogenic compounds generally produced from the nitrosation of amine. This paper investigates the mechanism for the formation of nitrosodimethylamine (NDMA) from the nitrosation of dimethylamine (DMA) by four common nitrosating agents (NO(2)(-), ONOO(-), N(2)O(3), and ONCl) in the absence and presence of CO(2) using the DFT method. New insights are provided into the mechanism, emphasizing that the interactions of CO(2) with amine and nitrosating agents are both potentially important in influencing the role of CO(2) (catalyst or inhibitor). The role of CO(2) as catalyst or inhibitor mainly depends on the nitrosating agents involved. That is, CO(2) shows the catalytic effect when the weak nitrosating agent NO(2)(-) or ONOO(-) is involved, whereas it is an inhibitor in the nitrosation induced by the strong nitrosating agent N(2)O(3) or ONCl. To conclude, CO(2) serves as a "double edged sword" in the nitrosation of amine. The findings will be helpful to expand our understanding of the pathophysiological and environmental significance of CO(2) and to develop efficient methods to prevent the formation of carcinogenic nitrosamines. PMID- 21667951 TI - Understanding the HIV-1 protease reactivity with DFT: what do we gain from recent functionals? AB - The modeling of HIV-1 plays a crucial role in the understanding of its reactivity and its interactions with specific drugs. In this work, we propose a medium sized model to test the ability of a variety of quantum chemistry approaches to provide reasonable geometric parameters and energetics for this system. Although our model is large enough to include the main polarizing groups of the active site, it is small enough to be used within full quantum studies up to the second order Moller-Plesset (MP2) level with extrapolations to coupled cluster CCSD(T) level. These high level calculations are used as reference to assess the ability of electronic structure methods (semiempirical and DFT) to provide accurate geometries and energies for the HIV-1 protease reaction. All semiempirical methods fail to describe the geometry of the protease active site. Within DFT, pure generalized gradient approximation (GGA) functionals have difficulty in reproducing the reaction energy and underestimate the barrier. Hybrid and/or meta GGA approaches do not yield a consistent improvement. The best results are obtained with hybrid GGA B3LYP or X3LYP and with hybrid meta GGA functionals with a fraction of exact exchange around 30-40%, such as M06, B1B95, or BMK functionals. On the basis of these results, we propose an accurate and computationally efficient strategy, employing quantum chemistry methods. This is applied here to study the protonation state of the reaction intermediate and could be easily used in further QM/MM studies. PMID- 21667952 TI - Charge transport properties of stacking bisindenoanthrazolines: DFT studies. AB - Organic semiconductors to date having cofacial stacking motif are scarce compared to those having herringbone motif. Recently, Ahmed and co-workers have reported a series of novel n-type bisindenoanthrazolines (BIDAs) [Chem. Mater. 2010, 22, 5786], among which DADF and DADK adopt different slipped cofacial arrangements exhibiting distinct electron transport abilities. Here, we performed computational studies to understand the relationship between charge transport and molecular packing for these BIDAs molecules. This work focuses on the intrinsic molecular factors required for efficient and long-range charge transfer. Unlike the previous studies only focusing the charge injection barriers or the carrier mobilities, herein, we present the notion that lower electron injection barrier and higher intrinsic electron mobility should be both satisfied to achieve better n-type OFETs. We also note that the actual mobility can be significantly underestimated due to the limitation of the space-charge limited current method. Through computational modeling, we rationalized the superior electron conductivity of DADK and also shed light on the favorable or undesirable properties for efficient charge transport of BIDAs. Another key finding is that the intrinsic electron and hole mobilities are quite deviated from each other rather than comparable in current mobility calculations. PMID- 21667953 TI - Overcoming the genotoxicity of a pyrrolidine substituted arylindenopyrimidine as a potent dual adenosine A(2A)/A(1) antagonist by minimizing bioactivation to an iminium ion reactive intermediate. AB - 2-Amino-4-phenyl-8-pyrrolidin-1-ylmethyl-indeno[1,2-d]pyrimidin-5-one (1) is a novel and potent selective dual A(2A)/A(1) adenosine receptor antagonist from the arylindenopyrimidine series that was determined to be genotoxic in both the Ames and Mouse Lymphoma L5178Y assays only following metabolic activation. Compound 1 was identified as a frame-shift mutagen in Salmonella typhimurium tester strain TA1537 as indicated by a significant dose-dependent increase in revertant colonies as compared to the vehicle control. The metabolic activation-dependent irreversible covalent binding of radioactivity to DNA, recovery of 1 and its enamine metabolite from acid hydrolysis of covalently modified DNA, and protection of covalent binding to DNA by both cyanide ion and methoxylamine suggest that the frame-shift mutation in TA1537 strain involved covalent binding instead of simple intercalation to DNA. Compound 1 was bioactivated to endocyclic iminium ion, aldehyde, epoxide, and alpha,beta-unsaturated keto reactive intermediates from the detection of cyano, oxime, and glutathione conjugates by data-dependent high resolution accurate mass measurements. Collision-induced dissociation of these conjugates provided evidence for bioactivation of the pyrrolidine ring of 1. The epoxide and alpha,beta-unsaturated keto reactive intermediates were unlikely to cause the genotoxicity of 1 because the formation of their glutathione adducts did not ameliorate the binding of compound related material to DNA. Instead, the endocyclic iminium ions and amino aldehydes were likely candidates responsible for genotoxicity based on, first, the protection afforded by both cyanide ion and methoxylamine, which reduced the potential to form covalent adducts with DNA, and, second, analogues of 1 designed with low probability to form these reactive intermediates were not genotoxic. It was concluded that 1 also had the potential to be mutagenic in humans based on observing the endocyclic iminium ion following incubation with a human liver S9 preparation and the commensurate detection of DNA adducts. An understanding of this genotoxicity mechanism supported an evidence-based approach to selectively modify the structure of 1 which resulted in analogues being synthesized that were devoid of a genotoxic liability. In addition, potency and selectivity against both adenosine A(2A) and A(1) receptors were maintained. PMID- 21667954 TI - Photocontrollable J-aggregation of a diarylethene-phthalocyanine hybrid and its aggregation-stabilized photochromic behavior. AB - The photocontrollable J-aggregation of a diarylethene-phthalocyanine hybrid (T ZnPc) and its aggregation-stabilized photochromic behavior were investigated by various techniques. T-ZnPc initially exhibited slight J-aggregation tendency in solvents such as chloroform and toluene through conformational planarization effect, but formed much stronger J-aggregates upon the illumination of 254 nm UV light. In darkness, the UV-irradiated solutions gradually returned to their initial state. These phenomena can be explained by the pronounced change in molecular planarity accompanying the reversible isomerization of the diarylethene units of T-ZnPc. Besides, we have found that the thermal stability of the closed ring diarylethene isomers in molecularly dispersed T-ZnPc is much poorer than that in aggregates. As long as the aggregates were broken, they converted to corresponding open-ring form instantly. This study provided an example of fully photocontrollable aggregation of phthalocyanines and paved a new way for improving the stability of the photochromic systems. PMID- 21667955 TI - Robust hydrophobic surfaces displaying different surface roughness scales while maintaining the same wettability. AB - A range of surfaces coated with spherical silica particles, covering the size range from nanometer to micrometer, have been produced using Langmuir-Blodgett (LB) deposition. The particles were characterized both in suspension and in the Langmuir trough to optimize the surface preparation procedure. By limiting the particle aggregation and surface layer failures during the preparation steps, well-defined monolayers with a close-packed structure have been obtained for all particle sizes. Thus, this procedure led to structured surfaces with a characteristic variation in the amplitude and spatial roughness parameters. In order to obtain robust surfaces, a sintering protocol and an AFM-based wear test to determine the stability of the deposited surface layer were employed. Hydrophobization of the LB films followed by water contact angle measurements showed, for all tested particle sizes, the same increase in contact angle compared to the contact angle of a flat hydrophobic surface. This indicates nearly hexagonal packing and gives evidence for nearly complete surface wetting of the surface features. PMID- 21667956 TI - Investigation into the reactivity of unsupported and supported Ag7 and Ag8 clusters with toxic metal ions. AB - We report the chemical interactions of unsupported and alumina-supported Ag(7) and Ag(8) clusters protected with MSA (mercaptosuccinic acid) with heavy metal ions Hg(II), Cd(II), and Pb(II) in water at different concentrations. The investigation was carried out to determine the feasibility of this interesting new class of materials called quantum clusters for water purification. These systems were studied using various spectroscopic and microscopic techniques such as ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, X ray diffraction, dynamic light scattering, zeta potential measurements, scanning electron microscopy, transmission electron microscopy, Raman spectroscopy, and photoluminescence spectroscopy and in detail by X-ray photoelectron spectroscopy. We observed that the metal ions interact with both the silver atoms of the clusters and the functional groups of the capping agent (MSA). The mercuric ions were reduced to metallic mercury by both supported and unsupported clusters, due to the feasibility of the redox reaction, whereas no reduction was observed for Cd(II) and Pb(II). As a result of the interaction, the luminescence of the cluster is lost which can be used to sense Hg(II). At lower concentrations, the metal ions were chemically bonded to the carboxylate groups of MSA. Absence of reduction of Hg(II) at lower concentration is due to the chemical affinity of the ligands and the lower silver content per cluster compared to the number of carboxylate groups. PMID- 21667957 TI - Silver bioaccumulation dynamics in a freshwater invertebrate after aqueous and dietary exposures to nanosized and ionic Ag. AB - We compared silver (Ag) bioavailability and toxicity to a freshwater gastropod after exposure to ionic silver (Ag(+)) and to Ag nanoparticles (Ag NPs) capped with citrate or with humic acid. Silver form, exposure route, and capping agent influence Ag bioaccumulation dynamics in Lymnaea stagnalis. Snails efficiently accumulated Ag from all forms after either aqueous or dietary exposure. For both exposure routes, uptake rates were faster for Ag(+) than for Ag NPs. Snails efficiently assimilated Ag from Ag NPs mixed with diatoms (assimilation efficiency (AE) ranged from 49 to 58%) and from diatoms pre-exposed to Ag(+) (AE of 73%). In the diet, Ag NPs damaged digestion. Snails ate less and inefficiently processed the ingested food, which adversely impacted their growth. Loss rates of Ag were faster after waterborne exposure to Ag NPs than after exposure to dissolved Ag(+). Once Ag was taken up from diet, whether from Ag(+) or Ag NPs, Ag was lost extremely slowly. Large Ag body concentrations are thus expected in L. stagnalis after dietborne exposures, especially to citrate-capped Ag NPs. Ingestion of Ag associated with particulate materials appears as the most important vector of uptake. Nanosilver exposure from food might trigger important environmental risks. PMID- 21667958 TI - Experimental and theoretical investigation of topological and energetic characteristics of Sb complexes reversibly binding molecular oxygen. AB - The experimental distribution of electron density in Ph(3)(4,5-OMe-3,6-Bu(t) Cat)Sb.MeCN (1*) and Ph(3)(4,5-N(2)C(4)H(6)-3,6-Bu(t)-Cat)Sb.MeOH (2*) complexes was studied. According to atoms in molecules theory, the Sb-C(Ph), Sb O(catecholate), and Sb...N(O) bonds are intermediate, whereas the O-C and C-C bonds are covalent, respectively. The energy of the Sb...N(MeCN) and Sb...O(MeOH) bonds are 7.0 and 11.3 kcal/mol according to the Espinosa equation. Density functional theory and Hartree-Fock calculations were carried out for a series of catecholate and amidophenolate complexes of antimony(V). It was shown that such calculations reliably reproduce geometrical and topological parameters and therefore can be used for a criterion search of dioxygen reversible binding by the catecholate and amidophenolate complexes of antimony(V). It was found that the "critical" value of the HOMO energy vary in the range from -5.197 to -5.061 eV for reversible binding of dioxygen complexes. This can serve as a thermodynamic criterion to predict the possibility of the dioxygen reversible binding by the catecholate and amidophenolate complexes of Sb(V). The HOMO energies correlate with the conversion of the catecholate and amidophenolate complexes in corresponding spiroendoperoxide derivatives as well. The contribution of the atom orbitals of the carbon atoms in the five-membered metallocycle to HOMO in complexes with different substitutes in the 4- and 5 positions of the catecholate ligand allows predicting the place of dioxygen addition. PMID- 21667959 TI - Shape-persistent linear, kinked, and cyclic oligo(phenylene-ethynylene butadiynylene)s: self-assembled monolayers. AB - Shape-persistent rigid phenylene-ethynylene-butadiynylenes form lamellar self assembled monolayers (SAMs) at the HOPG/TCB interface, which were studied by scanning tunneling microscopy (STM) with submolecular resolution. Substitution of the terminating acetylene functions with polar cyanopropyldimethylsilyl groups leads to 2D phase separation and defined rod-rod interactions, which determine the packing distances between the rigid rods. The results stimulated the connection of rigid rods via septiarylene clamp units. They covalently link two rigid rod units and define the intramolecular rod-rod distance that matches the alkoxy substituent chain lengths. The systems can be described as half-ring structures of two rigid rods connected via a rotatable joint unit. These acetylene-terminated half-ring structures were also oligomerized under Cu and Pd catalysis to yield defined acyclic and cyclic oligomers. Detailed STM studies decoded the molecular origin of the surface patterning of such systems. The dodecyloxy side chains are adsorbed along the HOPG main axes and, together with the alkoxy backbone angle, determine the adsorption direction of the adlayers. PMID- 21667960 TI - Predicting equilibrium sorption of neutral organic chemicals into various polymeric sorbents with COSMO-RS. AB - There is an increasing use of polymers in analytical chemistry as sorbents for organic chemicals in sampling, cleanup, and chromatography. In order to find the optimal polymer for a given purpose, one needs to know the equilibrium partition constants of the chemicals of interest in a wide range of polymers. COSMOtherm, a quantum-chemically based software, is designed to predict such equilibrium partition constants based only on the molecular structure as input information. In this work, literature data for such equilibrium partition constants were collected for a wide range of different polymers and used to evaluate the performance of COSMOtherm. The results show good agreement between the predicted and experimental data from water and air for most of the tested polymers. The relative preference of analytes to sorb in a given polymer represented by the molecular structure of a monomer can be predicted without any calibration. If absolute values for the partition constants are required, then a few experimental values are needed to establish a log-linear regression between the model output and the experimental values. COSMOtherm appears to be a helpful tool for selecting the best sorbent polymer for a given task or for designing new polymers. The present evaluation is limited to chemicals with a rather simple structure. Further evaluation with complex chemicals that possess multiple functionalities is still warranted. PMID- 21667961 TI - Allosteric P?O-based receptors for dicarboxylic acids. AB - The synthesis of new P?O-disubstituted receptors with appended crown ethers and their properties as receptors for dicarboxylic acids have been studied. High affinities have been observed (oxalic and malonic acids with 4-, 5-, 6-, or 8 crown ethers). Binding of a cationic effector within the crown ether unit resulted in a positive "allosteric" effect, which has been determined to be K(rel) = 7 in the best case (binding of malonic acid with Li(+) @ rac-3b). PMID- 21667962 TI - Cu(II)-alkyl chlorocomplexes: stable compounds or transients? DFT prediction of their structure and EPR parameters. AB - DFT calculations were used for studying the structure and reactivity of organocuprates(II) usually considered as intermediates with very weak Cu-C bond. It was found that calculated principal g-tensor values of model compounds RCu(II)Cl(2(-)) are similar to the experimentally found values for organocopper product of photolysis of quaternary ammonium tetrachlorocuprates. The calculations confirm that the most of organocuprates(II) could be stable at ambient conditions, and short lifetimes of organocuprates(II) in solutions or soft matrices are caused by their high reactivity in various bimolecular processes; the rate of those may be close to the rate of diffusion controlled reactions. The charges, spin densities, and d-orbital populations of the Cu atom in them are typical for bivalent copper complexes. Natural bond orbital analysis of organochlorocuprates(II) confirms the formation of polar sigma-bond between copper and carbon atoms. PMID- 21667963 TI - Apportionment of motor vehicle emissions from fast changes in number concentration and chemical composition of ultrafine particles near a roadway intersection. AB - High frequency spikes in ultrafine number concentration near a roadway intersection arise from motor vehicles that accelerate after a red light turns green. The present work describes a method to determine the contribution of motor vehicles to the total ambient ultrafine particle mass by correlating these number concentration spikes with fast changes in ultrafine particle chemical composition measured with the nano aerosol mass spectrometer, NAMS. Measurements were performed at an urban air quality monitoring site in Wilmington, Delaware during the summer and winter of 2009. Motor vehicles were found to contribute 48% of the ultrafine particle mass in the winter measurement period, but only 16% of the ultrafine particle mass in the summer period. Chemical composition profiles and contributions to the ultrafine particle mass of spark vs diesel vehicles were estimated by correlating still camera images, chemical composition and spike contribution at each time interval.. The spark and diesel contributions were roughly equal, but the uncertainty in the split was large. The distribution of emissions from individual vehicles was determined by correlating camera images with the spike contribution to particle number concentration at each time interval. A small percentage of motor vehicles were found to emit a disproportionally large concentration of ultrafine particles, and these high emitters included both spark ignition and diesel vehicles. PMID- 21667964 TI - A model for in-vivo delivered dose estimation for inhaled bacillus anthracis spores in humans with interspecies extrapolation. AB - The quantitative yardstick for quantitative microbial risk assessment (QMRA) is the dose response assessment phase. In this phase of the QMRA paradigm a mathematical model is used to describe the relationship between host response (infection, disease, etc.) and pathogen dose. There are, however, key uncertainties which if addressed can expand our understanding of the dose response relationship and improve its accuracy. The dose response models most frequently used in this phase of QMRA are based on the average exposed dose (i.e., inhaled, ingested, etc.). However once inhaled, spores are considered infectious after being transported to a specific region of the lungs (alveoli), therefore, average exposed dose does not account for this required spore transport through the respiratory system. It is the aim of this manuscript to develop a model for the in vivo delivered dose to the alveolated region of the lungs that accounts for losses of spores through the respiratory system. A stochastic system is used to account for the physics in the respiratory system that account for the various sinks during respiration. This stochastic system is then integrated into the exponential and beta Poisson dose response models. The stochastic model is also then expanded to the respiratory systems of guinea pigs and rhesus macaques as these are common animal models. This work develops a framework for a new class of dose response models accounting for host physiology, making progress to understanding dose response heterogeneity among hosts. PMID- 21667965 TI - Two-step matrix application for the enhancement and imaging of latent fingermarks. AB - Matrix deposition is a crucial aspect for successful matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) analysis. The search for more efficient protocols over the years has resulted in the devising of "dry matrix methods" in which the matrix is solely or preliminarily deposited as powder and acts in most cases as a seeding agent. Although not fully embraced by the MALDI MSI community, these methods have proven to be more efficient in terms of ion intensity, ion abundance, and ion images in the experimental circumstances they were employed. Here we report a novel two-step matrix application method, that we have named the "dry-wet" method, where the matrix is dusted onto the sample followed by solvent spray using a robotic device. The new method has been successfully applied to the detection and mapping of several analyte classes within latent fingermarks. Dusting the matrix generated the added advantage of enhancing the latent fingermarks which are invisible. This allows not only for an optical image to be taken of the fingermark in situ but also bridges the gap in the application of MALDI MSI technology in this field; with the use of the methodology reported, fingermark enhancement, recovery, and analysis from different surfaces is now compatible with subsequent MALDI MSI analysis thus allowing visual and chemical information to be obtained simultaneously. PMID- 21667966 TI - Grain boundary segregation and interdiffusion effects in nickel-copper alloys: an effective means to improve the thermal stability of nanocrystalline nickel. AB - Nanocrystalline (nc) Ni films show pronounced grain growth and suffer from concomitant deterioration of their mechanical and magnetic properties after annealing at relatively low temperatures (T(ANN) >= 475 K). This constitutes a drawback for their applicability as coatings or in components of miniaturized devices. This work reveals that the thermal stability of nc Ni is significantly improved by controllably alloying Ni with Cu, by means of electrodeposition, to form a Ni(1-x)Cu(x) solid solution. To tune the composition of such nc alloys, Ni(1-x)Cu(x) films are deposited galvanostatically using an electrolytic bath containing Ni and Cu sulfate salts as electroactive species, saccharine as grain refining agent, and applying current densities ranging from -10 to -40 mA cm(-2). The enhanced thermal stability is ascribed to segregation of a Cu-rich phase at the Ni(1-x)Cu(x) grain boundaries, which acts as a shielding layer against grain growth. As a result, high values of hardness (in excess of 6 GPa) remain in nc Ni(1-x)Cu(x) for x >= 0.3, even after annealing at T(ANN) >= 575 K. From a magnetic point of view, Ni(1-x)Cu(x) films possess lower coercivity values than pure nc Ni films, both in the as-prepared and annealed states, thus offering potential advantages for certain soft magnetic applications. PMID- 21667967 TI - Selective interaction of 2,6-di-O-methyl-beta-cyclodextrin and Pluronic F127 micelles leading to micellar rupture: a nuclear magnetic resonance study. AB - The triblock-copolymer poly(ethylene oxide)-poly(propyleneoxide)-poly(ethylene oxide) (PEO-PPO-PEO), referred to as Pluronic, is widely studied for its unique aggregation properties and its applications in drug delivery and targeting. In previous studies [Dreiss, C. A.; et al. Soft Matter 2009, 5, 1888-1896], we showed that the interaction of heptakis (2,6-di-O-methyl)-beta cyclodextrin (DIMEB) with the triblock-copolymer Pluronic F127 in solutions above the CMC led to complete disruption of the polymeric micelles, while similar beta cyclodextrins (betaCD) derivatives, heptakis (2,3,6-tri-O-methyl)-betaCD (TRIMEB), hydroxypropyl-betaCD (HPBCD), and hydroxyethyl-betaCD (HEBCD), did not induce micellar break-up. In this work, nuclear magnetic resonance spectroscopy experiments were used to elucidate the nature of the interactions leading to break-up and highlight differences between the four betaCD derivatives studied, which could explain the very different outcome observed. Intermolecular nuclear Overhauser enhancements (NOEs) show that both DIMEB and TRIMEB interact selectively with the PPO methyl groups of F127 in a similar way. The interaction is mainly with the external methyl groups in the 6-position of the glucopyranose units of cyclodextrins. However, a weak but detectable interaction with the inner cyclodextrins protons is also observed. These interactions, both with the external surface and with the cavity of betaCD, suggest the formation of a loose complex, rather than the widely invoked pseudorotaxane type of inclusion. In addition, these interactions seem to be necessary but not sufficient to induce micellar break-up. Diffusion measurements show decreased diffusivity of DIMEB in the presence of F127 to a larger extent than the other CD derivatives, thus confirming the unique behavior of DIMEB toward F127 polymer. From the diffusion coefficients, an average of 1 DIMEB molecule per 4.2 PO groups of F127 is determined for the highest concentration of DIMEB considered (11 wt % DIMEB dissolved in 5 wt % F127). Micellar break-up is complete at a concentration as low as 1 DIMEB molecule per 8.2 PO units. PMID- 21667969 TI - Electrochemical enhancement of nitric oxide removal from simulated lean-burn engine exhaust via solid oxide fuel cells. AB - A solid oxide fuel cell (SOFC) unit is constructed with Ni-YSZ as the anode, YSZ as the electrolyte, and La(0.6)Sr(0.4)CoO(3)-Ce(0.9)Gd(0.1)O(1.95) as the cathode. The SOFC operation is performed at 600 degrees C with a cathode gas simulating the lean-burn engine exhaust and at various fixed voltage, at open circuit voltage, and with an inert gas flowing over the anode side, respectively. Electrochemical enhancement of NO decomposition occurs when an operating voltage is generated; higher O(2) concentration leads to higher enhancement. Smaller NO concentration results in larger NO conversion. Higher operating voltage and higher O(2) concentration can lead to both higher NO conversion and lower fuel consumption. The molar rate of the consumption of the anode fuel can be very much smaller than that of NO to N(2) conversion. This makes the anode fuel consumed in the SOFC-DeNO(x) process to be much less than the equivalent amount of ammonia consumed in the urea-based selective catalytic reduction process. Additionally, the NO conversion increases with the addition of propylene and SO(2) into the cathode gas. These are beneficial for the application of the SOFC-DeNO(x) technology on treating diesel and other lean-burn engine exhausts. PMID- 21667968 TI - Indoor formaldehyde removal by thermal catalyst: kinetic characteristics, key parameters, and temperature influence. AB - Thermal catalytic oxidation (TCO) technology can continuously degrade formaldehyde at room temperature without added energy. However, there is very little knowledge on the TCO kinetic reaction mechanism, which is necessary in developing such air cleaners and in comparison with other air cleaning techniques. This paper addresses the problem of a novel TCO catalyst, Pt/MnO(x) CeO(2). The experiments measuring the outlet concentrations of formaldehyde and other possible byproducts were conducted at temperatures of 25, 40, 60, 100, and 180 degrees C and at a series of inlet formaldehyde concentrations (280-3000 ppb). To measure the concentrations precisely and real timely, proton transfer reaction-mass spectrometry (PTR-MS) was used. We found the following from the experimental results: (1) no byproducts were detected; (2) the bimolecular L-H kinetic model best described the catalytic reaction rate; (3) the activation energy of the oxidation was about 25.8 kJ mol(-1); (4) TCO is most energy efficient at room temperature without auxiliary heating; (5) compared with photocatalytic oxidation (PCO) which needs ultraviolet light radiation, the reaction area of TCO can be much larger for a given volume so that TCO can perform much better not only in formaldehyde removal efficiency but also in energy saving. PMID- 21667970 TI - Novel inhibitors of trihydroxynaphthalene reductase with antifungal activity identified by ligand-based and structure-based virtual screening. AB - Curvularia lunata is a dark pigmented fungus that is the causative agent of several diseases in plants and in both immunodeficient and immunocompetent patients. 1,8-Dihydroxynaphthalene-melanin is found in the cell wall of C. lunata and is believed to be the important virulence factor of dematiaceous fungi. Trihydroxynaphthalene reductase is an enzyme of the 1,8-dihydroxynaphthalene melanin biosynthetic pathway, and it thus represents an emerging target for the development of novel fungicides and antimycotics. In the present study, we describe novel inhibitors of trihydroxynaphthalene reductase from C. lunata. These inhibitors were identified by ligand-based three-dimensional similarity searching and docking to a homology-built model and by subsequent biochemical and antifungal evaluation. Discovery of competitive inhibitors with K(i) values in low micromolar and even nanomolar concentration range proves the aplicability of homology-built model of 3HNR for hit finding by virtual screening methods. PMID- 21667971 TI - Profile-QSAR: a novel meta-QSAR method that combines activities across the kinase family to accurately predict affinity, selectivity, and cellular activity. AB - Profile-QSAR is a novel 2D predictive model building method for kinases. This "meta-QSAR" method models the activity of each compound against a new kinase target as a linear combination of its predicted activities against a large panel of 92 previously studied kinases comprised from 115 assays. Profile-QSAR starts with a sparse incomplete kinase by compound (KxC) activity matrix, used to generate Bayesian QSAR models for the 92 "basis-set" kinases. These Bayesian QSARs generate a complete "synthetic" KxC activity matrix of predictions. These synthetic activities are used as "chemical descriptors" to train partial-least squares (PLS) models, from modest amounts of medium-throughput screening data, for predicting activity against new kinases. The Profile-QSAR predictions for the 92 kinases (115 assays) gave a median external R2(ext) = 0.59 on 25% held-out test sets. The method has proven accurate enough to predict pairwise kinase selectivities with a median correlation of R2(ext) = 0.61 for 958 kinase pairs with at least 600 common compounds. It has been further expanded by adding a "C(k)XC" cellular activity matrix to the KxC matrix to predict cellular activity for 42 kinase driven cellular assays with median R2(ext) = 0.58 for 24 target modulation assays and R2(ext) = 0.41 for 18 cell proliferation assays. The 2D Profile-QSAR, along with the 3D Surrogate AutoShim, are the foundations of an internally developed iterative medium-throughput screening (IMTS) methodology for virtual screening (VS) of compound archives as an alternative to experimental high-throughput screening (HTS). The method has been applied to 20 actual prospective kinase projects. Biological results have so far been obtained in eight of them. Q2 values ranged from 0.3 to 0.7. Hit-rates at 10 uM for experimentally tested compounds varied from 25% to 80%, except in K5, which was a special case aimed specifically at finding "type II" binders, where none of the compounds were predicted to be active at 10 MUM. These overall results are particularly striking as chemical novelty was an important criterion in selecting compounds for testing. The method is completely automated. Predicted activities for nearly 4 million internal and commercial compounds across 115 kinase assays and 42 cellular assays are stored in the corporate database. Like computed physical properties, this predicted kinase activity profile can be computed and stored as each compound is registered. PMID- 21667972 TI - Benzyl derivatives with in vitro binding affinity for human opioid and cannabinoid receptors from the fungus Eurotium repens. AB - Bioassay-guided fractionation of the fungus Eurotium repens resulted in the isolation of two new benzyl derivatives, (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5 (3-methylbut-2-enyl)benzene-1,4-diol (1) and (E)-4-(hept-1-enyl)-7-(3-methylbut-2 enyl)-2,3-dihydrobenzofuran-2,5-diol (2), along with seven known compounds (3-9) including five benzaldehyde compounds, flavoglaucin (3), tetrahydroauroglaucin (4), dihydroauroglaucin (5), auroglaucin (6), and 2-(2',3-epoxy-1',3'- heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)benzaldehyde (7), one diketopiperazine alkaloid, echinulin (8), and 5,7-dihydroxy-4-methylphthalide (9). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data. Compounds 1-4 and 6 showed good binding affinity for human opioid or cannabinoid receptors. These findings have important implications for psychoactive studies with this class of compounds. PMID- 21667973 TI - Reversal of lysosomal storage in brain of adult MPS-I mice with intravenous Trojan horse-iduronidase fusion protein. AB - A mouse model of mucopolysaccharidosis (MPS) type I, which is null for the lysosomal enzyme, alpha-L-iduronidase (IDUA), is treated with intravenous, receptor-mediated enzyme replacement therapy of the brain. Murine IDUA, which does not cross the blood-brain barrier, is re-engineered for targeting to the brain as an IgG-enzyme fusion protein. The amino terminus of mature IDUA is fused to the carboxyl terminus of the heavy chain of a chimeric monoclonal antibody (mAb) against the murine transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-IDUA. The cTfRMAb part of the fusion protein acts as a molecular Trojan horse to ferry the fused IDUA across the BBB and neuronal cell membrane via transport on the TfR. The IDUA enzyme activity of the fusion protein, 776 +/- 79 units/MUg protein, is comparable to recombinant IDUA. MPSI null mice, 6-8 months of age, were treated iv twice a week for 8 weeks with either saline or 1 mg/kg cTfRMAb-IDUA. The glycosoaminoglycan levels in liver, spleen, heart, and kidney were reduced by >95%, 80%, 36%, and 20%, respectively. Lysosomal inclusion bodies in the brain were quantitated from semithin sections stained with o-toluidine blue and normalized per 100 nucleoli per brain section. Treatment of the MPSI mice with the cTfRMAb-IDUA reduced intracellular lysosomal inclusion bodies by 73% in brain, as compared to the MPSI mice treated with saline. In conclusion, the reversal of pre-existing neural pathology in the brain of MPSI mice is possible with receptor-mediated enzyme replacement therapy of the brain. PMID- 21667974 TI - Entrapment and kinetic resolution of stabilized axial and equatorial conformers of spiro-beta-lactams. AB - The facile synthesis of the stabilized axial and equatorial conformers of spiro beta-lactams was achieved via entrapment of cyclohexanone imines (Schiff bases) with acetoxyacetyl chloride in a [2 + 2]-cycloaddition reaction followed by their kinetic resolution. The immobilization of the racemic substrates on an inert solid support significantly reduced the reaction time and improved the enantioselectivity of conformers during kinetic resolution. The mechanism of the formation of the spiro-beta-lactams was explored using B3LYP/6-31+G* level quantum chemical calculations. PMID- 21667975 TI - Comment on "Theoretical study of polaron formation in poly(G)-poly(C) cations". PMID- 21667976 TI - Director configuration transitions of polyelectrolyte coated liquid-crystal droplets. AB - Liquid-crystal droplets are of great interest because of their large surface areas, rich phases, and tunable optical properties. The director configuration of liquid-crystal droplets provides a unique optical sign to detect the events occurring at the droplet surface. In this article, we report the alternating bipolar/radial configuration transitions of 4-n-pentyl-4'-cyanobiphenyl (5CB) droplets triggered by the layer-by-layer coating of negatively charged poly(styrenesulfonate sodium (PSS) and positively charged poly(diallyldimethylammonium chloride) (PDADMAC) on the droplet surface. The alternating configuration transitions are due to the interactions of the 5CB with polar versus nonpolar PDADMAC/PSS multilayer coatings. Furthermore, we find that the coating of PDADMAC/PSS multilayers makes the director configuration of the 5CB in the droplets sensitive to environmental salt concentrations. PMID- 21667978 TI - Actinide metals with multiple bonds to carbon: synthesis, characterization, and reactivity of U(IV) and Th(IV) bis(iminophosphorano)methandiide pincer carbene complexes. AB - Treatment of ThCl(4)(DME)(2) or UCl(4) with 1 equiv of dilithiumbis(iminophosphorano) methandiide, [Li(2)C(Ph(2)P?NSiMe(3))(2)] (1), afforded the chloro actinide carbene complexes [Cl(2)M(C(Ph(2)P?NSiMe(3))(2))] (2 (M = Th) and 3 (M = U)) in situ. Stable PCP metal-carbene complexes [Cp(2)Th(C(Ph(2)P?NSiMe(3))(2))] (4), [Cp(2)U(C(Ph(2)P?NSiMe(3))(2))] (5), [TpTh(C(Ph(2)P?NSiMe(3))(2))Cl] (6), and [TpU(C(Ph(2)P?NSiMe(3))(2))Cl] (7) were generated from 2 or 3 by further reaction with 2 equiv of thallium(I) cyclopentadienide (CpTl) in THF to yield 4 or 5 or with 1 equiv of potassium hydrotris(pyrazol-1-yl) borate (TpK) also in THF to give 6 or 7, respectively. The derivative complexes were isolated, and their crystal structures were determined by X-ray diffraction. All of these U (or Th)-carbene complexes (4-7) possess a very short M (Th or U)?carbene bond with evidence for multiple bond character. Gaussian 03 DFT calculations indicate that the M?C double bond is constructed by interaction of the 5f and 6d orbitals of the actinide metal with carbene 2p orbitals of both pi and sigma character. Complex 3 reacted with acetonitrile or benzonitrile to cyclo-add C=N to the U?carbon double bond, thereby forming a new C-C bond in a new chelated quadridentate ligand in the bridged dimetallic complexes (9 and 10). A single carbon-U bond is retained. The newly coordinated uranium complex dimerizes with one equivalent of unconverted 3 using two chlorides and the newly formed imine derived from the nitrile as three connecting bridges. In addition, a new crystal structure of [CpUCl(3)(THF)(2)] (8) was determined by X-ray diffraction. PMID- 21667977 TI - Voltammetric oxidation of 2-oxo-1,2,3,4-tetrahydropyrimidin-5-carboxamides: substituent effects. AB - Electrochemical oxidation of a series of 20 substituted 2-oxo-1,2,3,4 tetrahydropyrimidin-5-carboxamides (THPMs) in acetonitrile has been studied using voltammetric methods at a glassy carbon electrode to investigate the influence of the substituents on the 4- and 5-positions of the heterocyclic ring. Analysis of the results shows that the electronic nature and steric hindrance of the substituents, especially their orientations toward the heterocyclic ring, determine their effects on the oxidation potential. Analysis of the computational results obtained at the DFT-B3LYP/6-31++G** level of theory suggests a mechanism in which the first electron removal occurs from either the N(1) of the heterocyclic ring or N(17) of the amide substitution. This process is followed by a fast proton removal resulting in the formation of stable allylic and/or benzylic radicals which then undergo further oxidation to the 2-oxo-1,2 dihydropyrimidin-5-carboxamides (DHPMs). PMID- 21667980 TI - Hydrophilic pyrazine dyes as exogenous fluorescent tracer agents for real-time point-of-care measurement of glomerular filtration rate. AB - Various hydrophilic pyrazine-bis(carboxamides) derived from 3,5-diamino-pyrazine 2,5-dicarboxylic acid bearing neutral and anionic groups were prepared and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, the dianionic d-serine pyrazine derivatives 2d and 2j, and the neutral dihydroxypropyl 2h, exhibited favorable physicochemical and clearance properties. In vitro studies show that 2d, 2h, and 2j have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that these three compounds exhibit a plasma clearance equivalent to iothalamate (a commonly considered gold standard GFR agent). In addition, these compounds have a higher urine recovery compared to iothalamate. Finally, the plasma clearance of 2d, 2h, and 2j remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration only. Hence, 2d, 2h, and 2j are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR. PMID- 21667981 TI - A synthesis of pseudoconhydrine and its epimer via hydroformylation and dihydroxylation. AB - A synthesis of the alkaloid pseudoconhydrine and its epimer has been achieved using tandem hydroformylation-condensation to form the six-membered ring and stereoselective dihydroxylation to introduce oxygenation. The stereoselectivity of dihydroxylation can be explained by lipophilic and electrostatic effects, supported by DFT calculations. The alkaloids can be obtained either by regioselective dehydroxylation or by rearrangement, followed by reduction. PMID- 21667982 TI - Surface deposition and phase behavior of oppositely charged polyion-surfactant ion complexes. Delivery of silicone oil emulsions to hydrophobic and hydrophilic surfaces. AB - The adsorption from mixed polyelectrolyte-surfactant solutions at hydrophobized silica surfaces was investigated by in situ null-ellipsometry, and compared to similar measurements for hydrophilic silica surfaces. Three synthetic cationic copolymers of varying hydrophobicity and one cationic hydroxyethyl cellulose were compared in mixtures with the anionic surfactant sodium dodecylsulfate (SDS) in the absence or presence of a dilute silicone oil emulsion. The adsorption behavior was mapped while stepwise increasing the concentration of SDS to a polyelectrolyte solution of constant concentration. The effect on the deposition of dilution of the bulk solution in contact with the surface was also investigated by gradual replacement of the bulk solution with 1 mM aqueous NaCl. An adsorbed layer remained after complete exchange of the polyelectrolyte/surfactant solution for aqueous NaCl. In most cases, there was a codeposition of silicone oil droplets, if such droplets were present in the formulation before dilution. The overall features of the deposition were similar at hydrophobic and hydrophilic surfaces, but there were also notable differences. SDS molecules adsorbed selectively at the hydrophobized silica surface, but not at the hydrophilic silica, which influenced the coadsorption of the cationic polymers. The largest amount of deposited material after dilution was found for hydrophilic silica and for the least-hydrophobic cationic polymers. For the least hydrophobic polyions, no significant codeposition of silicone oil was detected at hydrophobized silica after dilution if the initial SDS concentration was high. PMID- 21667983 TI - Planar-to-planar chirality transfer in the excited state. Enantiodifferentiating photoisomerization of cyclooctenes sensitized by planar-chiral paracyclophane. AB - Photochemical planar-to-planar chirality transfer was effected by using (R) [10]paracyclophane-12-carboxylates as a planar-chiral sensitizer and (Z) cyclooctene and (Z,Z)-1,5-cyclooctadiene as prochiral substrates to give a planar chiral (E)- and (E,Z)-isomer in up to 44% and 87% enantiomeric excess, respectively, the latter of which being the highest ever reported for a sensitized photochirogenic reaction. PMID- 21667985 TI - Direct comparison of solution- and vacuum-processed small molecular organic light emitting devices with a mixed single layer. AB - It will be interesting and valuable information can be achieved if a direct comparison between organic light emitting devices (OLEDs) fabricated by vacuum evaporated method (vac) and solution-based manufacturing processes (sol) was realized. Small molecular OLEDs with a mixed organic layer structure (MOLOLEDs) make it possible for direct comparison between devices with the same materials but fabricated by the two processing methods. This article shows a direct comparison of the luminescence characteristics, charge conduction, and device physics between MOLOLEDs fabricated by vac- and sol-processing techniques. It gives an elementary explain how the organic/metal interfaces influence the charge conduction and device performance. PMID- 21667984 TI - Disassembly of a core-satellite nanoassembled substrate for colorimetric biomolecular detection. AB - The disassembly of a core-satellite nanostructured substrate is presented as a colorimetric biosensor observable under dark-field illumination. The fabrication method described herein utilizes thiol-mediated adsorption and streptavidin biotin binding to self-assemble core-satellite nanostructures with a sacrificial linking peptide. Biosensing functionality is demonstrated with the protease trypsin, and the optical properties of the nanoassemblies are characterized. A figure of merit is presented to determine the optimal core and satellite size for visual detection. Nanoassemblies with 50 nm cores and 30 or 50 nm satellites are superior as these structures achieve an orange to green color shift greater than 70 nm that is easily discernible by the naked eye. This colorimetric substrate may prove to be a favorable alternative to liquid-based colloidal sensors and a useful visual readout mechanism for point-of-care microfluidic diagnostic assays. PMID- 21667986 TI - Oxygen activation and intramolecular C-H bond activation by an amidate-bridged diiron(II) complex. AB - A diiron(II) complex containing two MU-1,3-(kappaN:kappaO)-amidate linkages has been synthesized using the 2,2',2''-tris(isobutyrylamido)triphenylamine (H(3)L(iPr)) ligand. The resulting diiron complex, 1, reacts with dioxygen (or iodosylbenzene) to effect intramolecular C-H bond activation at the methine position of the ligand isopropyl group. The ligand-activated product, 2, has been isolated and characterized by a variety of methods including X-ray crystallography. Electrospray ionization mass spectroscopy of 2 prepared from(18)O(2) was used to confirm that the oxygen atom incorporated into the ligand framework is derived from molecular oxygen. PMID- 21667987 TI - Stereospecific synthesis of syn-alpha-oximinoamides by a three-component reaction of isocyanides, syn-chlorooximes, and carboxylic acids. AB - A stereospecific multicomponent reaction among isocyanides, syn-chlorooximes, and carboxylic acids provides an efficient synthesis of biologically relevant syn alpha-oximinoamides. PMID- 21667988 TI - Cu-mediated chemoselective trifluoromethylation of benzyl bromides using shelf stable electrophilic trifluoromethylating reagents. AB - Copper-mediated chemoselective trifluoromethylation at the benzylic position by the use of shelf-stable electrophilic trifluoromethylating reagents 3 in good to high yields under mild conditions is described for the first time. The generality of this trifluoromethylation for a wide variety of benzyl bromides facilitates the rapid creation of structural diversity of medicinal candidates in drug discovery. PMID- 21667989 TI - Synthesis of a novel class of cyclodextrin-based nanotubes. AB - The synthesis and characterization of a novel class of structurally well-defined nanotubes from beta-cyclodextrin are described. These new hosts were formed using disulfide linkages that substitute all the primary hydroxyl groups of a beta cyclodextrin. A deep and rigid hydrophobic channel with a size of more than 1.5 nm is found in the molecules. Because of their unique geometry and the potential biodegradability of the disulfide bond, this class of molecules could find broad applications in biology and other areas of research. PMID- 21667990 TI - Cytotoxic 1,2-dialkynylimidazole-based aza-enediynes: aza-Bergman rearrangement rates do not predict cytotoxicity. AB - A new class of potential antitumor agents inspired by the enediyne antitumor antibiotics has been synthesized: the 1,2-dialkynylimidazoles. The aza-Bergman rearrangement of these 1,2-dialkynylimidazoles has been investigated theoretically at the B3LYP/6-31G(d,p) level and experimentally by measuring the kinetics of rearrangement in 1,4-cyclohexadiene. There is a good correlation between the theoretical and experimental results; subtle substituent effects on the initial aza-Bergman cyclization barrier predicted by theory are confirmed by experiment. Yet, despite the ability of these 1,2-dialkynylimidazoles to undergo Bergman rearrangement to diradical/carbene intermediates under relatively mild conditions, there is no correlation between the rate of Bergman cyclization and cytotoxicity to A459 cells. In addition, cytotoxic 1,2-dialkynylimidazoles do not cause nicking of supercoiled plasmid DNA or cleavage of bovine serum albumin. An alternative mechanism for cytotoxicity involving the unexpected selective thiol addition to the N-ethynyl group of certain 1,2-dialkynylimidazoles is proposed. PMID- 21667991 TI - Regioselective transformation of O-propargylic arylaldoximes to four-membered cyclic nitrones by copper-catalyzed skeletal rearrangement. AB - (E)-O-Propargylic arylaldoximes were regioselectively converted, in the presence of copper catalysts, into their corresponding four-membered cyclic nitrones in good to excellent yields. The reactions proceeded via a tandem [2,3] rearrangement and 4pi-electrocyclization of the N-allenylnitrone intermediate and involved cleavage of the carbon-oxygen bond. PMID- 21667992 TI - Cr(VI) induces DNA damage, cell cycle arrest and polyploidization: a flow cytometric and comet assay study in Pisum sativum. AB - Chromium(VI) is recognized as the most toxic valency of Cr, but its genotoxicity and cytostaticity in plants is still poorly studied. In order to analyze Cr(VI) cyto- and gentotoxicity, Pisum sativum L. plants were grown in soil and watered with solutions with different concentrations of Cr up to 2000 mg/L. After 28 days of exposure, leaves showed no significant variations in either cell cycle dynamics or ploidy level. As for DNA damage, flow cytometric (FCM) histograms showed significant differences in full peak coefficient of variation (FPCV) values, suggesting clastogenicity. This is paralleled by the Comet assay results, showing an increase in DNA damage for 1000 and 2000 mg/L. In roots, exposure to 2000 mg/L resulted in cell cycle arrest at the G(2)/M checkpoint. It was also verified that under the same conditions 40% of the individuals analyzed suffered polyploidization having both 2C and 4C levels. DNA damage analysis by the Comet assay and FCM revealed dose-dependent increases in DNA damage and FPCV. Through this, we have unequivocally demonstrated for the first time in plants that Cr exposure can result in DNA damage, cell cycle arrest, and polyploidization. Moreover, we critically compare the validity of the Comet assay and FCM in evaluating cytogenetic toxicity tests in plants and demonstrate that the data provided by both techniques complement each other and present high correlation levels. In conclusion, the data presented provides new insight on Cr effects in plants in general and supports the use of the parameters tested in this study as reliable endpoints for this metal toxicity in plants. PMID- 21667993 TI - IR and FTMW-IR spectroscopy and vibrational relaxation pathways in the CH stretch region of CH3OH and CH3OD. AB - Infrared spectra of jet-cooled CH(3)OD and CH(3)OH in the CH stretch region are observed by coherence-converted population transfer Fourier transform microwave infrared (CCPT-FTMW-IR) spectroscopy (E torsional species only) and by slit-jet single resonance spectroscopy (both A and E torsional species, CH(3)OH only). Twagirayezu et al. reported the analysis of nu(3) symmetric CH stretch region (2750-2900 cm(-1); Twagirayezu et al. J. Phys. Chem. A 2010, 114, 6818), and the present work addresses the more complicated higher frequency region (2900-3020 cm(-1)) containing the two asymmetric CH stretches (nu(2) and nu(9)). The additional complications include a higher density of coupled states, more extensive mixing, and evidence for Coriolis as well as anharmonic coupling. The overall observed spectra contain 17 interacting vibrational bands for CH(3)OD and 28 for CH(3)OH. The sign and magnitude of the torsional tunneling splittings are deduced for three CH stretch fundamentals (nu(3), nu(2), nu(9)) of both molecules and are compared to a model calculation and to ab initio theory. The number and distribution of observed vibrational bands indicate that the CH stretch bright states couple first to doorway states that are binary combinations of bending modes. In the parts of the spectrum where doorway states are present, the observed density of coupled states is comparable to the total density of vibrational states in the molecule, but where there are no doorway states, only the CH stretch fundamentals are observed. Above 2900 cm(-1), the available doorway states are CH bending states, but below, the doorway states also involve OH bending. A time-dependent interpretation of the present FTMW-IR spectra indicates a fast (~200 fs) initial decay of the bright state followed by a second, slower redistribution (about 1-3 ps). The qualitative agreement of the present data with the time-dependent experiments of Iwaki and Dlott provides further support for the similarity of the fastest vibrational relaxation processes in the liquid and gas phases. PMID- 21667994 TI - Ion mobility separation of isomeric phosphopeptides from a protein with variant modification of adjacent residues. AB - Ion mobility spectrometry (IMS), and particularly differential or field asymmetric waveform IMS (FAIMS), was recently shown capable of separating peptides with variant localization of post-translational modifications. However, that work was limited to a model peptide with Ser phosphorylation on fairly distant alternative sites. Here, we demonstrate that FAIMS (coupled to electrospray/mass spectrometry (ESI/MS)) can broadly baseline-resolve variant phosphopeptides from a biologically modified human protein, including those involving phosphorylation of different residues and adjacent sites that challenge existing tandem mass spectrometry (MS/MS) methods most. Singly and doubly phosphorylated variants can be resolved equally well and identified without dissociation, based on accurate separation properties. The spectra change little over a range of infusion solvent pH; hence, the present approach should be viable in conjunction with chromatographic separations using mobile phase gradients. PMID- 21667995 TI - Methylene green electrodeposited on SWNTs-based "bucky" papers for NADH and l malate oxidation. AB - This research introduces a cavity anode design based on new single-walled nanotube (SWNTs) papers, "bucky" papers, used for the oxidation (and regeneration) of nicotinamide adenine dinucleotide (NADH) and the oxidation of l malate. The materials designed are paper-like processed composites containing also additives: BP11 sample contains SWNTs and isopropanol (IPA); the BPMG sample contains SWNTs, IPA, and methylene green (MG). NADH/NAD(+) is the cofactor responsible for the oxidation of l-malate by malate dehydrogenase (MDH), in the Krebs' cycle. Because of the high overpotential of NADH oxidation, poly methylene green (PMG) was utilized as the electrocatalyst to produce NAD(+). The electrocatalyst was deposited on the surface of the "bucky" papers by electropolymerization by means of 10 voltammetric cycles in a range of -0.5 V and +1.3 V (vs Ag/AgCl reference electrode) at a scan rate of 5 mV/s. The catalytic performance of PMG was evaluated by chronoamperometric measurements of NADH oxidation at 0.3 V in phosphate buffer and l-malate oxidation at 0.1 V in the presence of MDH. For both "bucky" papers, the chronoamperometric curves of PMG, current vs NADH concentration, show a linear relationship demonstrating to have a first order Fick's law behavior for concentrations of NADH lower than 6 mM. The chronoamperometric curves in the presence of MDH, current against l-malate concentration, show a Michaelis-Menten behavior where no inhibition or competitive reaction are detected. Additionally, the anodic materials were characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS), the polymerization of MG is effectively observed in the form of particles nucleation. The anodes show an excellent electrocatalytic activity toward NADH oxidation. The electrode design is feasible, reproducible, and overall stable. PMID- 21667996 TI - A switch I mutant of Cdc42 exhibits less conformational freedom. AB - Cdc42 is a Ras-related small G-protein and functions as a molecular switch in signal transduction pathways linked with cell growth and differentiation. It is controlled by cycling between GTP-bound (active) and GDP-bound (inactive) forms. Nucleotide binding and hydrolysis are modulated by interactions with effectors and/or regulatory proteins. These interactions are centralized in two relatively flexible "Switch" regions as characterized by internal dynamics on multiple time scales [Loh, A. P., et al. (2001) Biochemistry 40, 4590-4600], and this flexibility may be essential for protein interactions. In the Switch I region, Thr(35) seems to be critical for function, as it is completely invariant in Ras related proteins. To investigate the importance of conformational flexibility in Switch I of Cdc42, we mutated threonine to alanine, determined the solution structure, and characterized the backbone dynamics of the single-point mutant protein, Cdc42(T35A). Backbone dynamics data suggest that the mutation changes the time scale of the internal motions of several residues, with several resonances not being discernible in wild-type Cdc42 [Adams, P. D., and Oswald, R. E. (2007) Biomol. NMR Assignments 1, 225-227]. The mutation does not appear to affect the thermal stability of Cdc42, and chymotrypsin digestion data further suggest that changes in the conformational flexibility of Switch I slow proteolytic cleavage relative to that of the wild type. In vitro binding assays show less binding of Cdc42(T35A), relative to that of wild type, to a GTPase binding protein that inhibits GTP hydrolysis in Cdc42. These results suggest that the mutation of T(35) leads to the loss of conformational freedom in Switch I that could affect effector-regulatory protein interactions. PMID- 21667997 TI - Hydrogen-bonding capability of a templating difluorotoluene nucleotide residue in an RB69 DNA polymerase ternary complex. AB - Results obtained using 2,4-difluorotoluene nucleobase (dF) as a nonpolar thymine isostere by Kool and colleagues challenged the Watson-Crick dogma that hydrogen bonds between complementary bases are an absolute requirement for accurate DNA replication. Here, we report crystal structure of an RB69 DNA polymerase L561A/S565G/Y567A triple mutant ternary complex with a templating dF opposite dTTP at 1.8 A-resolution. In this structure, direct hydrogen bonds were observed between: (i) dF and the incoming dTTP, (ii) dF and residue G568 of the polymerase, and (iii) dF and ordered water molecules surrounding the nascent base pair. Therefore, this structure provides evidence that a templating dF can form novel hydrogen bonds with the incoming dTTP and with the enzyme that differ from those formed with a templating dT. PMID- 21667998 TI - Inkjet metrology II: resolved effects of ejection frequency, fluidic pressure, and droplet number on reproducible drop-on-demand dispensing. AB - We report highly reproducible gravimetric and optical measurements of microdroplets that lend insights into the fundamentals of drop-on-demand (DOD) printing. Baseline fluidic pressure within the DOD dispenser was controlled to within 0.02 hPa, enabling long-term stability in dispensed droplet mass with observed variations near 1% (RSD) for isobutanol. The gravimetric measurements were sensitive enough to detect and avoid unwanted effects from air bubbles within the dispenser. The gravimetric and optical velocity measurements enabled consistent determination of droplet kinetic energy that governed baseline behavior across the operational variables. Mass and velocity were influenced in a nonlinear manner by the frequency of droplet ejection, the fluidic pressure within the dispensing device, and the number of droplets dispensed in a burst. Resolved effects were attributable to several possible mechanisms including acoustic resonances, energy partitioning from systematic orifice refill dynamics, pressure wavelets created within the dispenser cavity during "first-drop" formation, and residual ring-down after last-drop emergence. PMID- 21667999 TI - Asperaculin A, a sesquiterpenoid from a marine-derived fungus, Aspergillus aculeatus. AB - A novel sesquiterpenoid, asperaculin A, possessing a novel [5,5,5,6]fenestrane ring system, was isolated from the marine-derived fungus Aspergillus aculeatus CRI323-04. The structure of asperaculin A was established by analysis of spectroscopic data. The name aspergillane is proposed for the sesquiterpene skeleton in asperaculin A. PMID- 21668001 TI - Combined use of replica-exchange molecular dynamics and magic-angle-spinning solid-state NMR spectral simulations for determining the structure and orientation of membrane-bound peptide. AB - We report an approach to determining membrane peptides and membrane protein complex structures by magic-angle-spinning solid-state NMR and molecular dynamics simulation. First, an ensemble of low energy structures of mastoparan-X, a wasp venom peptide, in lipid bilayers was generated by replica exchange molecular dynamics (REMD) simulation with the implicit membrane/solvent model. Next, peptide structures compatible with experimental (13)C(alpha), C(beta), and C' chemical shifts were selected from the ensemble. The (13)C(alpha) chemical shifts alone were sufficient for the selection with backbone rmsd's of ~0.8 A from the experimentally determined structure. The dipolar couplings between the peptide protons and lipid (2)H/(31)P nuclei were obtained from the (13)C-observed (2)H/(31)P-selective (1)H-demagnetization experiments for selecting the backbone and side chain structures relative to the membrane. The simulated structure agreed with the experimental one in the depth and orientation. The REMD simulation can be used for supplementing the limited structural constraints obtainable from the solid-state NMR spectra. PMID- 21668000 TI - Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents. AB - Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity. PMID- 21668002 TI - Browning in ethanolic solutions of ascorbic acid and catechin. AB - Nonenzymatic browning occurs readily in alcoholic beverages and degrades their color quality. Ascorbic acid degradation in the presence of phenolic compounds is a major browning pathway in alcoholic beverages with fruit or fruit juice as the raw material or an ingredient. In the present study ethanolic solutions of ascorbic acid and catechin were prepared to simulate the alcoholic beverages. Ascorbic acid degradation and browning in these model solutions were investigated. Glycerol solutions with the same water activity (A(w)) values as those of the ethanolic model solutions were used as controls in the evaluation of browning rate. Results showed that the aerobic degradation of ascorbic acid dominates over the anaerobic one in ethanolic solutions, that the browning rate decreases as the ethanol concentration increases, that the compound 3-hydroxy-2 pyrone may not be a good indicator of browning in ethanolic ascorbic acid catechin solutions, and that A(w) is a major factor responsible for the difference in the browning rate among ascorbic acid-catechin solutions with different ethanol concentrations. PMID- 21668003 TI - RGD-modified angiogenesis inhibitor HM-3 dose: dual function during cancer treatment. AB - In the present study, we have undertaken pharmacodynamic studies of HM-3 in vitro and in vivo. A dual function of HM-3 with various doses was observed. HM-3 at low dose revealed obvious anticancer activity. In contrast, HM-3 at high dose had a tendency to promote tumorigenesis and tumor metastasis. Microarray analysis demonstrated that HM-3 at high dose could up-regulate the transcription of AKT1 and MEK1, which resulted in the promotion of tumorigenesis and metastasis. Therefore, the dose of angiogenesis inhibitors plays a critical role in cancer treatment. In order to achieve the ideal effect of angiogenesis inhibitor drugs on cancer treatment, a ful exploration of administration dose, frequency, and period for this kind of drugs is highly desired. PMID- 21668004 TI - Immobilization of nanostructured lipid particles in polysaccharide films. AB - Lipid-based equilibrium self-assemblies and their hierarchically ordered forms have been known since the last few decades. Related progress in colloids and interface science led the development of oil-in-water type internally self assembled lipid particles, known as Isasomes, which have aroused great interest in biotechnological applications. These submicrometer-sized lipid particles are internally nanostructured in a form of various liquid-crystalline or microemulsion phases, which facilitate their loading with hydrophilic, hydrophobic, and amphiphilic molecules. Their internal nanostructure can also be finely tuned. Recently, it has been shown that Isasomes can be entrapped in thermoreversible polysaccharide hydrogels. Herein, we report on the immobilization of Isasomes in solid polysaccharide films prepared by drying particle-loaded kappa-carrageenan and methyl cellulose-based hydrogels. These rather simple but elegant media facilitate the storage of these functional particles and their subsequent release by simple resolubilization in water and/or thermal transitions. Systematic rehydration studies of such Isasome-loaded films have shown that the Isasomes can be remobilized and/or recovered after resolubilization of loaded films, even after several months. PMID- 21668005 TI - Ionic liquid-promoted Wagner-Meerwein rearrangement of 16alpha,17alpha epoxyandrostanes and 16alpha,17alpha-epoxyestranes. AB - Ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim](+)[PF(6)]( )) and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim](+)[BF(4)](-)) were found to promote an unusual Wagner-Meerwein rearrangement of steroidal 16alpha,17alpha-epoxides leading to unnatural 13-epi-18-nor-16-one derivatives as the main products. These compounds were isolated in good to excellent yields. 16alpha-Hydroxy-Delta(13)-18-norsteroids, the results of the usual rearrangement, were obtained as minor components of the reaction mixtures. The ionic liquid [bmim](+)[PF(6)](-) was shown to induce C-ring aromatization of 16alpha,17alpha epoxyestranes due to the formation of HF, the hydrolysis product of [PF(6)](-). Increasing amounts of HF and [PO(2)F(2)](-) were detected by (19)F and (31)P NMR when the ionic liquid was reused. The structures of the steroidal products, 16 oxo-18-nor-13alpha-steroid derivatives, 16alpha-hydroxy-Delta(13)-18-norsteroids, and C-aromatic compounds were determined by two-dimensional NMR techniques and high-resolution mass spectrometry (HRMS). The ionic liquids were recirculated efficiently. PMID- 21668006 TI - Formation of singly bonded PhCH2C60-C60CH2Ph dimers from 1,2-(PhCH2)HC60 via electroreductive C60-H activation. AB - Singly bonded PhCH(2)C(60)-C(60)CH(2)Ph dimers are generated via controlled potential bulk electroreduction and electrooxidation of 1,2-(PhCH(2))HC(60). The reaction mixture was purified by HPLC, and the isolated fraction was characterized with single-crystal X-ray diffractions, (1)H and (13)NMR, MS, elemental analysis, and cyclic voltammetry. It was shown that the fraction consists of two HPLC-inseparable PhCH(2)C(60)-C(60)CH(2)Ph regioisomers, which are assigned as the meso and racemic regioisomers. The bulk electrolysis processes for the formation of the dimers were followed by in situ cyclic voltammetry and were further corroborated with an in situ voltammetric titration of 1,2-(PhCH(2))HC(60) with tetra-n-butylammonium hydroxide (TBAOH), on the basis of which a reaction mechanism is proposed. PMID- 21668007 TI - Structural rearrangement of beta-lactoglobulin at different oil-water interfaces and its effect on emulsion stability. AB - Understanding the factors that control protein structure and stability at the oil water interface continues to be a major focus to optimize the formulation of protein-stabilized emulsions. In this study, a combination of synchrotron radiation circular dichroism spectroscopy, front-face fluorescence spectroscopy, and dual polarization interferometry (DPI) was used to characterize the conformation and geometric structure of beta-lactoglobulin (beta-Lg) upon adsorption to two oil-water interfaces: a hexadecane-water interface and a tricaprylin-water interface. The results show that, upon adsorption to both oil water interfaces, beta-Lg went through a beta-sheet to alpha-helix transition with a corresponding loss of its globular tertiary structure. The degree of conformational change was also a function of the oil phase polarity. The hexadecane oil induced a much higher degree of non-native alpha-helix compared to the tricaprylin oil. In contrast to the beta-Lg conformation in solution, the non native alpha-helical-rich conformation of beta-Lg at the interface was resistant to further conformational change upon heating. DPI measurements suggest that beta Lg formed a thin dense layer at emulsion droplet surfaces. The effects of high temperature and the presence of salt on these beta-Lg emulsions were then investigated by monitoring changes in the zeta-potential and particle size. In the absence of salt, high electrostatic repulsion meant beta-Lg-stabilized emulsions were resistant to heating to 90 degrees C. Adding salt (120 mM NaCl) before or after heating led to emulsion flocculation due to the screening of the electrostatic repulsion between colloidal particles. This study has provided insight into the structural properties of proteins adsorbed at the oil-water interface and has implications in the formulation and production of emulsions stabilized by globular proteins. PMID- 21668008 TI - Covalent cell surface functionalization of human fetal osteoblasts for tissue engineering. AB - The chemical functionalization of cell-surface proteins of human primary fetal bone cells with hydrophilic bioorthogonal intermediates was investigated. Toward this goal, chemical pathways were developed for click reaction-mediated coupling of alkyne derivatives with cellular azido-expressing proteins. The incorporation via a tetraethylene glycol linker of a dipeptide and a reporter biotin allowed the proof of concept for the introduction of cell-specific peptide ligands and allowed us to follow the reaction in living cells. Tuning the conditions of the click reaction resulted in chemical functionalization of living human fetal osteoblasts with excellent cell survival. PMID- 21668009 TI - Metabolite profiles for Antrodia cinnamomea fruiting bodies harvested at different culture ages and from different wood substrates. AB - Antrodia cinnamomea is a precious edible fungus endemic to Taiwan that has long been used as a folk remedy for health promotion and for treating various diseases. In this study, an index of 13 representative metabolites from the ethanol extract of A. cinnamomea fruiting body was established for use in quality evaluation. Most of the index compounds selected, particularly the ergostane-type triterpenoids and polyacetylenes, possess good anti-inflammation activity. A comparison of the metabolite profiles of different ethanol extracts from A. cinnamomea strains showed silmilar metabolites when the strains were grown on the original host wood (Cinnamomum kanehirai) and harvested after the same culture time period (9 months). Furthermore, the amounts of typical ergostane-type triterpenoids in A. cinnamomea increased with culture age. Culture substrates also influenced metabolite synthesis; with the same culture age, A. cinnamomea grown on the original host wood produced a richer array of metabolites than A. cinnamomea cultured on other wood species. We conclude that analysis of a fixed group of compounds including triterpenoids, benzolics, and polyacetylenes constitutes a suitable, reliable system to evaluate the quality of ethanol extract from A. cinnamomea fruiting bodies. The evaluation system established in this study may provide a platform for analysis of the products of A. cinnamomea. PMID- 21668010 TI - Mimicking heme enzymes in the solid state: metal-organic materials with selectively encapsulated heme. AB - To carry out essential life processes, nature has had to evolve heme enzymes capable of synthesizing and manipulating complex molecules. These proteins perform a plethora of chemical reactions utilizing a single iron porphyrin active site embedded within an evolutionarily designed protein pocket. We herein report the first class of metal-organic materials (MOMs) that mimic heme enzymes in terms of both structure and reactivity. The MOMzyme-1 class is based upon a prototypal MOM, HKUST-1, into which catalytically active metalloporphyrins are selectively encapsulated in a "ship-in-a-bottle" fashion within one of the three nanoscale cages that exist in HKUST-1. MOMs offer unparalleled levels of permanent porosity and their modular nature affords enormous diversity of structures and properties. The MOMzyme-1 class could therefore represent a new paradigm for heme biomimetic catalysis since it combines the activity of a homogeneous catalyst with the stability and recyclability of heterogeneous catalytic systems within a single material. PMID- 21668011 TI - Enhanced enzymatic stability and antitumor activity of daunorubicin-GnRH-III bioconjugates modified in position 4. AB - Here, we report on the synthesis, enzymatic stability, and antitumor activity of novel bioconjugates containing the chemotherapeutic agent daunorubicin attached through an oxime bond to various gonadotropin-releasing hormone-III (GnRH-III) derivatives. In order to increase the enzymatic stability of the bioconjugates (in particular against chymotrypsin), (4)Ser was replaced by N-Me-Ser or Lys(Ac). A compound in which (4)Lys was not acetylated was also prepared, with the aim of investigating the influence of the free epsilon-amino group on the biochemical properties. The in vitro cytostatic effect of the bioconjugates was determined on MCF-7 human breast, HT-29 human colon, and LNCaP human prostate cancer cells by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Their stability/degradation (1) in human serum, (2) in the presence of rat liver lysosomal homogenate, and (3) in the presence of digestive enzymes (trypsin, chymotrypsin, and pepsin) was analyzed by liquid chromatography in combination with mass spectrometry. The results showed that (1) all synthesized bioconjugates had in vitro cytostatic effect, (2) they were stable in human serum at least for 24 h, and (3) they were hydrolyzed in the presence of lysosomal homogenate. All compounds were stable in the presence of (1) pepsin and (2) trypsin (except for the (4)Lys containing bioconjugate). In the presence of chymotrypsin, all bioconjugates were digested; the degradation rate strongly depending on their structure. The bioconjugates in which (4)Ser was replaced by N-Me-Ser or Lys(Ac) had the highest enzymatic stability, making them potential candidates for oral administration. In vivo tumor growth inhibitory effect of two selected bioconjugates was evaluated on orthotopically developed C26 murine colon carcinoma bearing mice. The results indicated that the compound containing Lys(Ac) in position 4 had significantly higher antitumor activity than the parent bioconjugate. PMID- 21668013 TI - Synchrotron-based XANES speciation of chromium in the oxy-fuel fly ash collected from lab-scale drop-tube furnace. AB - Speciation of chromium (Cr) in the fly ash collected from oxy-firing of Victorian brown coal has been reported for the first time to address the potential formation of toxic Cr(VI) and the variation of the quantities of Cr(III)-bearing species with flue gas composition. Synchrotron-based X-ray absorption near-edge structure (XANES) was employed for Cr speciation. Apart from a pure O(2)/CO(2) mixture (27/73, v/v) versus air, the O(2)/CO(2) mixtures doped with SO(2), HCl, and steam individually or together to simulate real flue gas have also been tested. Under all of the conditions tested here, the fractions of Cr(VI) in the fly ashes are insignificant, constituting no more than 5% of the total Cr. The test of Cr-doped brown coal in pyrolysis further confirmed that the Cr(VI) formation preferentially occurred through a local oxidation of Cr(III) at the oxygen-containing functions sites within coal matrix, rather than through an oxidation by external bulk O(2). This reaction is also highly temperature dependent and slower than the interaction between Cr(III) and other metals such as iron oxide. Increasing temperature to 1000 degrees C inhibited the oxidation of Cr(IIII) to Cr(VI). Shifting the combustion gas from air to O(2)/CO(2) exerted little effect on the Cr(VI) formation. Instead, the formation of iron chromite (FeCr(2)O(4)) was facilitated in O(2)/CO(2), probably due to a strong reducing microenvironment formed by the CO(2) gasification reaction within the char matrix. The accumulation of HCl in flue gas favored the vaporization of chromium as gaseous chloride/oxychloride, as expected. The coexistence of SO(2) inhibited this phenomenon by promoting the formation of sulfate. The presence of steam was even beneficial for the inhibition of water-soluble Cr sulfate through stabilizing the majority of Cr into alumino-silicate which is in the slagging phase. PMID- 21668014 TI - Antiosteoporotic effects of Lactobacillus -fermented soy skim milk on bone mineral density and the microstructure of femoral bone in ovariectomized mice. AB - Osteoporosis is a major skeletal disease associated with loss of estrogen in postmenopausal women. In this study, Lactobacillus paracasei subsp. paracasei NTU 101 (NTU 101F) and Lactobacillus plantarum NTU 102 (NTU 102F) were used as starters to ferment soy skim milk. This was then used as a nutritional supplement for 8 weeks to ovariectomized (OVX) mice. This study reveals that soy skim milk fermented with lactobacilli can increase the contents of aglycone isoflavones, soluble calcium, and vitamin D(3). The trabecular bone volumes and trabecular number of the distal femur in mice fed NTU 101F increased by a factor of 1.48 and 1.74 compared with the OVX group. The bone network density and thickness of the distal metaphyseal trabecular in mice fed NTU 101F and Fosamax was significantly greater than that of OVX mice. These results suggest that fermented soy skim milk can attenuate bone loss in OVX mice and lower the risk of osteoporosis. PMID- 21668015 TI - Sequence-specific binding to telomeric DNA is not a conserved property of the Cdc13 DNA binding domain. AB - In the budding yeast Saccharomyces cerevisiae, chromosome end protection is provided by a heterotrimeric complex composed of Cdc13 in association with the RPA-like proteins Stn1 and Ten1. We report here that the high affinity and specificity of the S. cerevisiae Cdc13 DNA binding domain for single-stranded telomeric DNA are not widely shared by other fungal Cdc13 proteins, suggesting that restriction of this complex to telomeres may be limited to the Saccharomyces clade. We propose that the evolutionarily conserved task of Stn1 and Ten1 (and their associated large subunit) is a genome-wide role in DNA replication rather than a telomere-dedicated activity. PMID- 21668016 TI - Application of 6,7-indole aryne cycloaddition and Pd(0)-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions for the preparation of annulated indole libraries. AB - The construction of an unprecedented class of an indole-based library, namely, a 6,7-annulated-4-substituted 93-member indole library, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions is described. This work represents the first example of library development that employs the indole aryne methodology. Annulated indoles, with the exception of only a few biologically active natural products (i.e., the trikentrins, herbindoles, teleocidins, and nodulisporic acids), have no representation in the PubChem or MLSMR databases. These structural entities are therefore predicted to have unique chemical property space characteristics and a high probability of exhibiting interesting biological activity. PMID- 21668017 TI - Incidence of fumonisin B(2) production by Aspergillus niger in Portuguese wine regions. AB - Fumonisin B(2) (FB(2)) was recently found to be produced by Aspergillus niger . When grape-derived products were subsequently analyzed, FB(2) contamination was found in raisins, must, and wine. This study evaluated 681 strains of black aspergilli species isolated from Portuguese wine grapes for FB(2) production when grown on Czapek yeast agar. FB(2) was not detected in Aspergillus carbonarius (n = 75) or Aspergillus ibericus (n = 9) strains, but it was detected in 176 (29%) of the strains belonging to A. niger aggregate (n = 597). The amount of FB(2) produced by these strains ranged from 0.003 to 6.0 mg/kg with a mean of 0.66 mg/kg. The Alentejo region had the lowest percentage (10%) of fumonisinogenic strains, whereas the Douro region had the highest percentage of fumonisinogenic strains (38%). Only 10 strains were found to produce FB(2) and ochratoxin A simultaneously. PMID- 21668018 TI - Water analysis: emerging contaminants and current issues. PMID- 21668020 TI - Steric blocking as a tool to control molecular film geometry at a metal surface. AB - The application of steric blocking in surface science is exemplified by the control of surface patterns through the selective methylation of pentacenetetrone. Pentacenetetrones interact (with one another) on Cu(111) via intermolecular hydrogen bonding involving the carbonyl oxygen and the adjacent hydrogen atoms. Steric blocking of the intermolecular interaction by the successive insertion of inert methyl groups at terminal locations transforms a dense molecular pattern first into isolated double rows and eventually into single rows in a highly predictable fashion. Density functional theory modeling reveals the underlying energetics. PMID- 21668021 TI - Naturally occurring sphalerite as a novel cost-effective photocatalyst for bacterial disinfection under visible light. AB - The photocatalytic disinfection capability of the natural semiconducting mineral sphalerite is studied here for the first time. Natural sphalerite can completely inactivate 1.5 * 10(7) cfu/mL E. coli K-12 within 6 h under visible light irradiation. The photocatalytic disinfection mechanism of natural sphalerite is investigated using multiple scavengers. The critical role that electrons play in bactericidal actions is experimentally demonstrated. The involvement of H(2)O(2) in photocatalytic disinfection is also confirmed using a partition system combined with different scavengers. Moreover, the photocatalytic destruction of bacterial cells is observed through transmission electron microscopic analysis. A catalase activity study reveals that antioxidative enzyme activity is high in the initial stage of photocatalytic disinfection but decreases with time due to damage to enzymatic functioning. Natural sphalerite is abundant and easy to obtain and possesses excellent visible-light photocatalytic activity. These superior properties make it a promising solar-driven photocatalyst for large scale cost-effective wastewater treatment. PMID- 21668023 TI - Nanoparticle adsorption at liquid-vapor surfaces: influence of nanoparticle thermodynamics, wettability, and line tension. AB - We developed a statistical mechanical theory that describes the adsorption of nanoparticles (NPs) at liquid-vapor surfaces. This theory accounts for the surface to bulk NP thermodynamic equilibrium, as well as the NP mechanical equilibrium, wettability, and line tension at liquid-vapor surfaces. The theory is tested by examining the adsorption of 5 nm diameter dodecanethiol-ligated gold NPs at the liquid-vapor surface of a homologous series of n-alkane solvents, from n-nonane to n-octadecane, where the NP wettability decreases with an increasing n alkane chain length. PMID- 21668024 TI - Synthesis of an attapulgite clay@carbon nanocomposite adsorbent by a hydrothermal carbonization process and their application in the removal of toxic metal ions from water. AB - A new kind of attapulgite clay@carbon (ATP@C) nanocomposite adsorbent has been synthesized by a one-pot hydrothermal carbonization process under mild conditions using two cheap, ecofriendly materials (i.e., attapulgite clay (ATP), which is a magnesium aluminum silicate that is abundant in nature, and glucose, which is a green chemical obtained from biomass). Compared to carbon-based materials, this new ATP@C nanocomposite exhibits a high adsorption ability for Cr(VI) and Pb(II) ions with maximum adsorption capacities of 177.74 and 263.83 mg.g(-1), respectively. The results demonstrate that this nanocomposite is an exceptionally promising candidate as a low-cost, sustainable, and effective adsorbent for the removal of toxic ions from water. PMID- 21668025 TI - Benzylamine-assisted noncovalent exfoliation of graphite-protecting Pt nanoparticles applied as catalyst for methanol oxidation. AB - A novel method has been developed to physically exfoliate graphite and uniformly disperse Pt nanoparticles on graphite nanoplates without damaging the graphene structures. A stable aqueous suspension of graphite nanoplates was achieved by benzylamine-assisted noncovalent fuctionalization to graphite and characterized by transmission electron microscopy, X-ray diffraction and Raman spectroscopy. A uniform dispersion of Pt nanoparticles was then prepared on the graphite nanoplates, where the benzylamine acts as a stabilizer. These Pt loaded graphite nanoplates were then prepared as an electrode, which significantly increased catalytic activity toward the methanol oxidation reaction, resulting in a 60% increment in mass activity compared to that of E-TEK. PMID- 21668026 TI - Distribution and trophic transfer of short-chain chlorinated paraffins in an aquatic ecosystem receiving effluents from a sewage treatment plant. AB - Short-chain chlorinated paraffins (SCCPs) are an extremely complex group of industrial chemicals and found to be potential persistent organic pollutants (POPs), and thus have attracted extensive concern worldwide. In this study, influent, effluent, and sludge were collected from a large sewage treatment plant (STP) in Beijing, China. Water, sediment, and aquatic species were also collected from a recipient lake that receives effluents discharged from the STP. These samples were then analyzed to investigate the effect of STP effluent on distribution and trophic transfer of SCCPs in the local aquatic ecosystem. Concentrations of total SCCPs (SigmaSCCPs) in lake water and surface sediments were found in the range 162-176 ng/L and 1.1-8.7 MUg/g (dry weight, dw), respectively. Vertical concentration profiles of sediment cores showed SigmaSCCPs decreased exponentially with increasing depth. Specific congener composition analysis in sediment layers indicated possible in situ biodegradation might be occurring. High bioaccumulation of SCCPs was observed in the sampled aquatic species. The bioaccumulation factor (BAF) generally increased with the number of chlorines in the SCCP congeners. A significantly positive correlation between lipid-normalized SigmaSCCPs concentration and trophic levels (R(2) = 0.65, p < 0.05) indicate that SCCPs can biomagnify through the food chain in the effluent receiving aquatic ecosystem. PMID- 21668027 TI - Plasma-modified biomaterials for self-antimicrobial applications. AB - The surface compatibility and antibacterial properties of biomaterials are crucial to tissue engineering and other medical applications, and plasma-assisted technologies have been employed to enhance these characteristics with good success. Herein, we describe and review the recent developments made by our interdisciplinary team on self-antimicrobial biomaterials with emphasis on plasma based surface modification. Our results indicate that a self-antibacterial surface can be produced on various types of materials including polymers, metals, and ceramics by plasma treatment. Surface characteristics such as roughness, microstructure, chemistry, electronegativity, free energy, hydrophilicity, and interfacial physiochemistry are important factors and can be tailored by using the appropriate plasma-assisted processing parameters. In particular, mechanistic studies reveal that the interfacial physiochemical processes, biocidal agents, and surface free energy are predominantly responsible for the antibacterial effects of plasma-modified biomaterials. PMID- 21668029 TI - Nanoelectronic programmable synapses based on phase change materials for brain inspired computing. AB - Brain-inspired computing is an emerging field, which aims to extend the capabilities of information technology beyond digital logic. A compact nanoscale device, emulating biological synapses, is needed as the building block for brain like computational systems. Here, we report a new nanoscale electronic synapse based on technologically mature phase change materials employed in optical data storage and nonvolatile memory applications. We utilize continuous resistance transitions in phase change materials to mimic the analog nature of biological synapses, enabling the implementation of a synaptic learning rule. We demonstrate different forms of spike-timing-dependent plasticity using the same nanoscale synapse with picojoule level energy consumption. PMID- 21668028 TI - Inhibition of glycosphingolipid biosynthesis induces cytokinesis failure. AB - Although cells undergo dramatic shape changes during cytokinesis, the role of the plasma membrane and lipids is poorly understood. We report that inactivation of glucosyl ceramide synthase (GCS), either by RNAi or with the small molecule PPMP, causes failure of cleavage furrow ingression. Using mass-spectrometry-based global lipid profiling, we identify individual lipids that are enhanced or depleted due to GCS inhibition. We show that GCS inhibition results in the mislocalization of actin and the ERM proteins, key cytoskeletal proteins that connect the plasma membrane to the actin cortex. Our data suggest that ceramides participate in mediating the interactions between the membrane and the cortex. PMID- 21668030 TI - Interconnected silicon hollow nanospheres for lithium-ion battery anodes with long cycle life. AB - Silicon is a promising candidate for the anode material in lithium-ion batteries due to its high theoretical specific capacity. However, volume changes during cycling cause pulverization and capacity fade, and improving cycle life is a major research challenge. Here, we report a novel interconnected Si hollow nanosphere electrode that is capable of accommodating large volume changes without pulverization during cycling. We achieved the high initial discharge capacity of 2725 mAh g(-1) with less than 8% capacity degradation every hundred cycles for 700 total cycles. Si hollow sphere electrodes also show a Coulombic efficiency of 99.5% in later cycles. Superior rate capability is demonstrated and attributed to fast lithium diffusion in the interconnected Si hollow structure. PMID- 21668031 TI - Longitudinal erythronychia: individual or multiple linear red bands of the nail plate: a review of clinical features and associated conditions. AB - Longitudinal erythronychia is a linear red band on the nail plate that originates at the proximal nail fold, traverses the lunula, and extends to the free edge of the nail plate. Longitudinal erythronychia is classified based upon the number of nails affected and the number of red streaks present on each nail as follows: type Ia (monodactylous - single band), type Ib (monodactylous - bifid bands), type IIa (polydactylous - single band), and type IIb (polydactylous - multiple bands). Associated morphologic findings that can be present at the distal tip of the nail with longitudinal erythronychia include fragility, onycholysis, splinter hemorrhage, splitting, subungual keratosis, thinning, and V-shaped nick. Some patients with longitudinal erythronychia seek medical evaluation because of pain in the associated distal digit; however, the linear red nail plate dyschromia is often asymptomatic and the individual is concerned about the cosmetic appearance or distal nail fragility. Longitudinal erythronychia can be a clinical manifestation of an underlying local or systemic condition. Benign tumors (glomus tumor, onychopapilloma, and warty dyskeratoma), malignant neoplasms (malignant melanoma and squamous cell carcinoma), and other conditions (hemiplegia and postsurgical scar) can be associated with monodactylous longitudinal erythronychia or it may be idiopathic or the initial stage of polydactylous longitudinal erythronychia-associated systemic conditions. Polydactylous longitudinal erythronychia is most commonly reported in patients with Darier disease (keratosis follicularis); other associated conditions include acantholytic dyskeratotic epidermal nevus, acantholytic epidermolysis bullosa, acrokeratosis verruciformis of Hopf, amyloidosis, graft-versus-host disease, lichen planus, and pseudobulbar syndrome. Polydactylous longitudinal erythronychia has also been observed as an idiopathic finding. Biopsy of the nail matrix and nail bed may be necessary to establish the diagnosis of a longitudinal erythronychia-associated condition. Indeed, a biopsy should be seriously considered in patients aged more than 50 years who present with a monodactylous longitudinal red band to exclude squamous cell carcinoma. Treatment of longitudinal erythronychia depends on the etiology. For patients with longitudinal erythronychia-associated discomfort or severe nail splitting, a surgical excision may provide not only the underlying diagnosis of the nail dyschromia, but also relief of related symptoms. PMID- 21668032 TI - Drug-induced acneiform eruption. AB - Drug-induced acne is a specific subset of acne that usually has some specific features, namely a monomorphic pattern, an unusual location of the lesions beyond the seborrheic areas, an unusual age of onset, a resistance to conventional acne therapy and, of course, the notion of a recent drug introduction. Many drugs can be responsible for such a clinical pattern. Corticosteroids, neuropsychotherapeutic drugs, antituberculosis drugs, and immunomodulating molecules are the more classical drugs associated with induced acne. Recently, new drugs, mainly targeted therapy in the field of oncology, such as epidermal growth factor receptor inhibitors, have been associated with an increased frequency of this adverse effect. Disruption of the culprit drug is rarely mandatory in cases of drug-induced acne. Close cooperation between the dermatologist and medical staff in charge of the patient is an important challenge to achieve optimal management of the initial disease. PMID- 21668034 TI - Childhood vitiligo in China: clinical profiles and immunological findings in 620 cases. AB - BACKGROUND: Childhood vitiligo is a common pediatric skin disorder. The pathogenesis of vitiligo is unclear, and immunological dysfunction may play an important role. OBJECTIVES: This prospective study aimed to profile childhood vitiligo and to discuss its correlation with immunological dysfunction. METHODS: All of the 620 enrolled patients were aged younger than 14 years, and were assessed with a standard questionnaire. The levels of immunoglobulins, complement, and T-lymphocyte subsets were measured in 270 of these 620 patients. RESULTS: Of the 620 children, 302 (48.71%) were boys and 318 (51.29%) were girls, with an average disease onset age of 7.57 years. The average duration was 13.45 months. 453 (73.06%) children had head and neck involvement and 160 (25.81%) children had segmental vitiligo. 84 (13.55%) children had a family history. There was a correlation between the disease and seasons. The onset or progression usually occurred in summer and spring. Halo nevus was seen in both segmental and non-segmental vitiligo. Precipitating factors such as stress appeared more commonly in segmental vitiligo. As to the immunological findings, in segmental vitiligo, the levels of C3 and C4 were lower in the active relative to the quiescent stage (p < 0.05); and in non-segmental vitiligo, the percentages of CD3+ and CD4+ lymphocytes and the CD4+/CD8+ ratio were lower in the active relative to the quiescent stage (p < 0.01). CONCLUSIONS: Childhood vitiligo has its own clinical features. The different types of vitiligo have different characteristics. There is immunological dysfunction in children with vitiligo. Dysfunction of humoral immunity may play a role in the progression of segmental vitiligo, while non-segmental vitiligo is more related to cellular immunity. PMID- 21668033 TI - Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. AB - Cutaneous mastocytosis in children is a generally benign disease that can present at birth and is often associated with mast cell mediator-related symptoms including pruritus, flushing, and abdominal pain with diarrhea. The most common form of presentation is urticaria pigmentosa, also referred to as maculopapular mastocytosis. Flares of lesions are induced by triggers such as physical stimuli, changes in temperature, anxiety, medications, and exercise. The skin lesions are typically present on the extremities. Symptoms respond to topical and systemic anti-mediator therapy including antihistamines and cromolyn sodium. Remission at puberty is seen in a majority of cases. Progression to systemic mastocytosis with involvement of extracutaneous organs is not common. The cause of cutaneous mastocytosis is unknown and familial cases are rare. Mutations of c-kit have been observed in the skin of those affected. The diagnosis is established on clinical grounds and the findings on skin biopsy. Bone marrow studies are recommended if there is suspicion of progression of disease to an adult form, if cytoreductive therapy is contemplated, or if skin lesions remain present and/or tryptase levels remain elevated after puberty. The use of chemotherapy, including kinase inhibitors, is strongly discouraged unless severe hematologic disease is present, since malignant evolution is extremely rare. PMID- 21668035 TI - Pemphigus vulgaris with plaque-type psoriasis successfully treated with cyclosporine monotherapy. PMID- 21668036 TI - Molecular targeted therapy in ovarian cancer: what is on the horizon? AB - Over the past two decades, empirical optimization of cytotoxic chemotherapy combinations and surgical debulking procedures have improved outcomes and survival in epithelial ovarian cancer. Yet, this disease remains the fifth leading cause of cancer-related deaths in the US, as cure rates seem to have reached a plateau at approximately 20% with conventional chemotherapy. Novel high throughput genomic and proteomic analyses have improved the molecular understanding of ovarian carcinogenesis, thereby providing a vast array of new potential drug targets with complex signalling interactions. In order to yield the most significant impact on disease outcome, it is necessary to carefully select, and subsequently target, the driving molecular pathway(s) within a tumour or tumour subtype, which are most likely to correspond to high-frequency mutations and genomic aberrations. The identification of biomarkers predictive of response to targeted therapy is essential to avoid poor responses to potentially useful drugs in unselected trial populations. With some promising, albeit early, phase III data on the angiogenesis inhibitor bevacizumab, exciting new opportunities lie ahead with the ultimate goal of personalizing therapies to individual tumour profiles. PMID- 21668037 TI - Efficacy and safety of long-acting reversible contraception. AB - Long-acting reversible contraception (LARC) includes intrauterine devices (IUDs) and the subdermal implant. These methods are the most effective reversible methods of contraception, and have the additional advantages of being long lasting, convenient, well liked by users and cost effective. Compared with other user-dependent methods that increase the risk of noncompliance-related method failure, LARC methods can bring 'typical use' failure rates more in line with 'perfect use' failure rates. LARC methods are 'forgettable'; they are not dependent on compliance with a pill-taking regimen, remembering to change a patch or ring, or coming back to the clinician for an injection. LARC method failure rates rival that of tubal sterilization at <1% for IUDs and the subdermal implant. For these reasons, we believe that IUDs and implants should be offered as first-line contraception for most women. This article provides a review of the LARC methods that are currently available in the US, including their effectiveness, advantages, disadvantages and contraindications. Additionally, we dispel myths and misconceptions regarding IUDs, and address the barriers to LARC use. PMID- 21668039 TI - End-organ protection in patients with hypertension: focus on the role of angiotensin receptor blockers on renal function. AB - The renin-angiotensin system (RAS) plays a key role in a number of pathophysiological mechanisms that are involved in the development and progression of cardiovascular and renal disease. For these reasons, pharmacological antagonism of this system, particularly the blockade of formation or the receptor antagonism of angiotensin II, has been demonstrated to be an effective and safe strategy to reduce the burden of cardiovascular disease. Among different drug classes, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have provided an excellent alternative to ACE inhibitors, representing a more selective and a better tolerated pharmacological approach to interfere with the RAS. Results derived from large, international, randomized clinical trials have consistently indicated that ARB-based therapeutic strategies may effectively provide cardiovascular and renal disease prevention and protection in different clinical conditions across the entire cardiovascular continuum. This article reviews the pathophysiological rationale of RAS involvement in the pathogenesis of renal diseases, focusing on the beneficial effects provided by ARBs in terms of renal protection. PMID- 21668038 TI - New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias. There are currently no effective pharmacological therapies approved for the treatment of IPF. Despite the focus on targeting fibrogenic pathways, recent clinical trials have been largely disappointing. Progress is being made in elucidating key cellular processes and molecular pathways critical to IPF pathogenesis, and this should facilitate the development of more effective therapeutics for this recalcitrant disease. Emerging pathobiological concepts include the role of aging and cellular senescence, oxidative stress, endoplasmic reticulum stress, cellular plasticity, microRNAs and mechanotransduction. Therapeutic approaches that target molecular pathways to modulate aberrant cellular phenotypes and promote tissue homeostasis in the lung must be developed. Heterogeneity in biological and clinical phenotypes of IPF warrants a personalized medicine approach to diagnosis and treatment of this lung disorder. PMID- 21668042 TI - Denosumab: in the prevention of skeletal-related events in patients with bone metastases from solid tumours. AB - Denosumab, a fully human monoclonal antibody, binds to the receptor activator of nuclear factor-kappaB ligand (RANKL) and thereby inhibits RANKL-mediated bone resorption. In various individual countries, subcutaneous denosumab is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumours (featured indication), and/or for the treatment of postmenopausal osteoporosis and/or of cancer treatment-induced bone loss in prostate or breast cancer patients. In three, pivotal, double-blind, multinational trials in adult patients with cancer-related bone metastases (total n > 5700), including trials in patients with advanced breast or prostate cancer, subcutaneous denosumab (120 mg every 4 weeks) was shown to be noninferior to intravenous zoledronic acid (4 mg every 4 weeks), as determined by the median time to first on-study skeletal-related event (primary endpoint) at the time of the primary analysis (~34 or 41 months). Denosumab treatment was superior to zoledronic acid in terms of the primary endpoint in two trials in patients with breast cancer or prostate cancer, based on secondary superiority analyses. In a third trial in patients with solid tumours excluding breast or prostate cancer, superiority of denosumab treatment versus zoledronic acid treatment was not demonstrated. The tolerability profile of denosumab was manageable in patients with bone metastases from solid tumours. Osteonecrosis of the jaw occurred in 1.8% and 1.3% of patients in the denosumab and zoledronic acid groups during the primary treatment phase; the incidence after approximately 4 additional months of denosumab treatment was 2.2%. PMID- 21668041 TI - Botulinum toxin A (Dysport(r)): in dystonias and focal spasticity. AB - Dysport(r), a formulation of botulinum toxin A, blocks acetylcholine release at neuromuscular junctions causing denervation and temporary muscle paralysis. It is used to treat several medical conditions, including dystonias and focal spasticity. Subcutaneous Dysport(r) was effective in improving functional disability in adults with blepharospasm in a placebo-controlled trial with 16 weeks' follow-up, and in adults with hemifacial spasm in case series. Similarly, intramuscular Dysport(r) was effective in improving symptoms of cervical dystonia in adults, focal spasticity in adults with post-stroke upper limb spasticity and dynamic equinus spasticity in paediatric patients with cerebral palsy in placebo controlled trials with up to 20 weeks' follow-up. However, in two 12-week, placebo-controlled trials in adults with focal lower limb spasticity (spastic equinovarus deformity after stroke and hip adductor spasticity associated with multiple sclerosis) intramuscular Dysport(r) had limited efficacy. Available longer-term data indicated that Dysport(r) treatment was effective over several treatment cycles in patients with cervical dystonia or upper limb spasticity. Dysport(r) was generally well tolerated in patients with dystonias or focal spasticity. Most adverse events were mild to moderate and transient. PMID- 21668040 TI - Pharmacotherapeutic management of locally advanced prostate cancer: current status. AB - Locally advanced prostate cancer (LAPC) is a heterogeneous entity usually embracing T3-4 and/or pelvic lymph-node-positive disease in the absence of established metastases. Outcomes for LAPC with single therapies have traditionally been poor, leading to the investigation of adjuvant therapies. Prostate cancer is a hormonally sensitive tumour, which usually responds to pharmacological manipulation of the androgen receptor or its testosterone-related ligands. As such, androgen deprivation therapy (ADT) has become an important adjuvant strategy for the treatment of LAPC, particularly for patients managed primarily with radiotherapy. Such results have generally not been replicated in surgical patients. With increased use of ADT has come improved awareness of the numerous toxicities associated with long-term use of these agents, as well as the development of strategies for minimizing ADT exposure and actively managing adverse effects. Several trials are exploring agents to enhance radiation cell sensitivity as well as the application of adjuvant docetaxel, an agent with proven efficacy in the metastatic, castrate-resistant setting. The recent work showing activity of cabazitaxel, sipuleucel-T and abiraterone for castrate resistant disease in the post-docetaxel setting will see these agents investigated in conjunction with definitive surgery and radiotherapy. PMID- 21668043 TI - Tesamorelin: a review of its use in the management of HIV-associated lipodystrophy. AB - Tesamorelin (EgriftaTM) is a synthetic analogue of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral oedema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV associated lipodystrophy, thereby potentially improving self image. PMID- 21668044 TI - Ipilimumab: first global approval. AB - Ipilimumab (Yervoy(r)) is an anti-cytotoxic T-lymphocyte antigen (CTLA)-4 monoclonal antibody that has been approved in the US for the first- or second line treatment of patients with malignant melanoma. In the EU, it is awaiting approval as second-line therapy for melanoma. Ipilimumab blocks the effects of the negative T-cell regulator CTLA-4, which may in turn augment T-cell responses to tumour cells. Preclinical studies have indicated that antibody blocking of CTLA-4 can lead to potent immune responses. Ipilimumab is also in development as first- and second-line therapy for prostate cancer where it has progressed to phase III clinical trials worldwide, and it is in phase II development for non small cell lung cancer. Ipilimumab was originated by the University of California, Berkeley, in the US and subsequently licensed to Medarex, which was later acquired by Bristol-Myers Squibb. This article summarizes the milestones in the development of intravenous ipilimumab leading to this first approval. This profile has been extracted from Wolters Kluwer's R&D Insight drug pipeline database. R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch. PMID- 21668045 TI - Tuberculosis control in India: time to get dangerously ambitious? PMID- 21668046 TI - Estimating the burden of cancer. PMID- 21668047 TI - Trends in cancer incidence in Chennai city (1982-2006) and statewide predictions of future burden in Tamil Nadu (2007-16). AB - BACKGROUND: This paper investigates cancer trends in Chennai and predicts the future cancer burden in Chennai and Tamil Nadu state, India, using data on 89 357 incident cancers from the Chennai registry during 1982-2006, published incidence rates from the Dindigul Ambilikkai Cancer Registry during 2003-06 and population statistics during 1982-2016. METHODS: Age-specific incidence rates were modelled as a function of age, period and birth cohort using the NORDPRED software to predict future cancer incidence rates and numbers of cancer cases for the period 2007-11 and 2012-16 in Chennai. Predictions for Tamil Nadu state were computed using a weighted average of the predicted incidence rates of the Chennai registry and current rates in Dindigul district. RESULTS; In Chennai, the total cancer burden is predicted to increase by 32% by 2012-16 compared with 2002-06, with 19% due to changes in cancer risk and a further 13% due to the impact of demographic changes. The incidence of cervical cancer is projected to drop by 46% in 2015 compared with current levels, while a 100% increase in future thyroid cancer incidence is predicted. Among men, a 21% decline in the incidence of oesophageal cancer by 2016 contrasts with the 42% predicted increase in prostate cancer. The annual cancer burden predicted for 2012-16 is 6100 for Chennai, translating to 55 000 new cases per year statewide (in Tamil Nadu). Breast cancer would dislodge cervical cancer as the top-ranking cancer in the state, while lung, stomach and large bowel cancers would surpass cervical cancer in ranking in Chennai by 2016. CONCLUSION: In order to tackle the predicted increases in cancer burden in Tamil Nadu, concerted efforts are required to assess and plan the infrastructure for cancer control and care, and ensure sufficient allocation of resources. PMID- 21668048 TI - Leptospirosis: experience at a tertiary care hospital in northern India. AB - BACKGROUND: Leptospirosis is primarily a disease of wild and domestic mammals. Man is infected either directly through contact with an infected animal or indirectly by water or soil contaminated with the urine of an infected animal. We studied the incidence of leptospirosis in patients presenting with an acute febrile illness of more than 7 days to a tertiary care hospital in northern India. METHODS: This study was done over a period of 1 year and included 647 patients who presented with an acute febrile illness for more than 7 days. These patients were screened for leptospirosis using the Dri-Dot test and ELISA. RESULTS: Using the Dri-Dot screening test, 244 of 647 patients (37.7%) were positive for leptospirosis. Of these 244 patients, 200 (82%) were positive by ELISA. CONCLUSION: Leptospirosis is common in northern India and should be considered as a possible differential diagnosis in patients with an acute febrile illness of more than 7 days' duration. PMID- 21668049 TI - Is the skin sensitivity test required for administering equine rabies immunoglobulin? AB - BACKGROUND: Rabies immunoglobulins are life-saving in patients with severe exposure to rabies. Despite the high degree of purification of equine rabies immunoglobulin (ERIG), the product inserts still recommend a skin sensitivity test before administration of this heterologous serum. A recent WHO recommendation states that there are no scientific grounds for performing a skin test before administering ERIG because testing does not predict reactions and it should be given irrespective of the result of the test. In this conflicting situation, we assessed the use of the skin sensitivity test in predicting adverse events to ERIG. METHODS: The data analysed were from the Antirabies Clinic of the Kempegowda Institute of Medical Sciences Hospital, Bengaluru, India. The period of study was 26 months (June 2008-July 2010). The skin sensitivity test was validated by evaluating its sensitivity, specificity, predictability, falsepositive and false-negative results. RESULTS: A total of 51 (2.6%) adverse events were reported in 31 (1.5%) subjects. Most of these were mild to moderate in nature and subsided without medication. There was no serious adverse event. The sensitivity and specificity of the skin sensitivity test to predict an adverse event was 41.9% and 73.9%, respectively. CONCLUSION: Our experience with the skin sensitivity test suggests that it may not be required before administering ERIGs, as recommended by WHO. PMID- 21668050 TI - Comparison of the health-promoting orientation of three tertiary care hospitals of India. AB - BACKGROUND: Hospitals have been considered as places for the provision of curative services. Nowadays, services related to health promotion are also sought to be provided through hospitals. We compared the health-promoting hospital (HPH) orientation of the Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh with two other tertiary care hospitals in India, which have been declared HPH by WHO. METHODS: The score obtained by PGIMER as an HPH as per the WHO standards tool was compared with that of two other tertiary care hospitals in India. A short survey was also conducted of patients visiting PGIMER for their treatment through a selfadministered, pretested questionnaire. A statistical test for difference in proportions was applied. A SWOT analysis was done to assess how PGIMER performed as an HPH. RESULTS: The HPH score of PGIMER was significantly lower (35/80) than that of the other two hospitals. There was no formal HPH policy in PGIMER. One-third of the patients interviewed were not satisfied with the overall preventive and health-promoting services of PGIMER. Apart from the parameters of the HPH standards, PGIMER seemed to satisfy the expectations from it being an apex medical institute. CONCLUSION: In view of its low score as an HPH, PGIMER should frame an appropriate HPH policy and devise strategies to provide leadership to other hospitals in India. PMID- 21668051 TI - An unusual cause of failure to thrive in a child. AB - Classic Bartter syndrome, depending on the severity, presents during childhood or adolescence as failure to thrive and may be incorrectly labelled as protein energy malnutrition, particularly in children from a low socioeconomic stratum. We encountered a 5-year-old boy who was asymptomatic till the age of 3 years. Despite adequate dietary intake, he was admitted and managed in various hospitals as a case of protein-energy malnutrition. On evaluation, he had unusual features in the form of persistent hypokalaemia and polyuria leading us to suspect a renal tubular disorder. Treatment of the condition resulted in good weight gain and normalization of serum electrolytes. PMID- 21668052 TI - Human papillomavirus and oropharyngeal cancer: shifting paradigms and exploring opportunities. PMID- 21668053 TI - Treatment of acute anterior cruciate ligament tears. PMID- 21668054 TI - Time to move to more frequent haemodialysis? PMID- 21668055 TI - Why mental health services in low- and middle-income countries are under resourced, underperforming: an indian perspective. AB - The inadequacies of mental health services in low- and middleincome countries are often attributed to inadequate allocation of resources. This may not be entirely true. The experience in India suggests that a top-down approach to planning, divorced from the ground realities, poor governance, managerial incompetence and unrealistic expectations from low-paid/poorly motivated primary healthcare personnel play an important role and may result in the failure of even adequately funded programmes. The ambitious National Mental Health Programme (NMHP), launched in 1983 and aimed at providing basic mental health services through the existing primary healthcare system, using the Bellary model, failed to achieve any of its targets over the subsequent decades. In early 2001, the NMHP was radically revamped. It was re-launched as part of the Tenth Five-Year Plan (2002 07) and the budgetary allocation was increased more than 7-fold. However, the programme faltered due to techno-managerial underperformance and the initial momentum was lost. The reasons for this failure are analysed and possible remedial strategies suggested. While the experience documented in the paper is country-specific and relates to India, it may hold useful lessons for other low- and middle-income countries. PMID- 21668056 TI - Mental health initiatives in India (1947-2010). PMID- 21668058 TI - Angelic doctors. PMID- 21668057 TI - A pragmatic approach to integrating mental health in undergraduate training: The AIIMS experience and work in progress. PMID- 21668059 TI - Carving nature at its joints: the challenges of classifying mental disorders. PMID- 21668067 TI - Revised hippocratic oath-a step forward in the right direction. PMID- 21668068 TI - A new hippocratic oath. PMID- 21668069 TI - On the revised hippocratic oath. PMID- 21668070 TI - Padma awards to doctors in India: a few more thoughts. PMID- 21668071 TI - Short-cut to a medical qualification? PMID- 21668072 TI - Use of albumin in patients with cirrhosis: misuse or misconception? PMID- 21668073 TI - Does medical school training desensitize young doctors? PMID- 21668077 TI - Do executive and reactive disinhibition mediate the effects of familial substance use disorders on adolescent externalizing outcomes? AB - The present study examined the potential mediating roles of executive and reactive disinhibition in predicting conduct problems, attention deficit/hyperactivity disorder (ADHD) symptoms, and substance use among adolescents with and without a family history of substance use disorders. Using data from 247 high-risk adolescents, parents, and grandparents, structural equation modeling indicated that reactive disinhibition, as measured by sensation seeking, mediated the effect of familial drug use disorders on all facets of the adolescent externalizing spectrum. Executive disinhibition, as measured by response disinhibition, spatial short term memory, and "trait" impulsivity, was associated with ADHD symptoms. Moreover, although executive functioning weakness were unrelated to familial substance use disorders, adolescents with familial alcohol use disorders were at risk for "trait" impulsivity marked by a lack of planning. These results illustrate the importance of "unpacking" the broad temperament style of disinhibition and of studying the processes that underlie the commonality among facets of the externalizing spectrum and processes that predict specific externalizing outcomes. PMID- 21668078 TI - Gene-environment interplay in the association between pubertal timing and delinquency in adolescent girls. AB - Early pubertal timing places girls at elevated risk for a breadth of negative outcomes, including involvement in delinquent behavior. While previous developmental research has emphasized the unique social challenges faced by early maturing girls, this relation is complicated by genetic influences for both delinquent behavior and pubertal timing, which are seldom controlled for in existing research. The current study uses genetically informed data on 924 female female twin and sibling pairs drawn from the National Longitudinal Study of Adolescent Health to (1) disentangle biological versus environmental mechanisms for the effects of early pubertal timing and (2) test for gene-environment interactions. Results indicate that early pubertal timing influences girls' delinquency through a complex interplay between biological risk and environmental experiences. Genes related to earlier age at menarche and higher perceived development significantly predict increased involvement in both nonviolent and violent delinquency. Moreover, after accounting for this genetic association between pubertal timing and delinquency, the impact of nonshared environmental influences on delinquency are significantly moderated by pubertal timing, such that the nonshared environment is most important among early maturing girls. This interaction effect is particularly evident for nonviolent delinquency. Overall, results suggest early maturing girls are vulnerable to an interaction between genetic and environmental risks for delinquent behavior. PMID- 21668079 TI - The structure of PTSD among two cohorts of returning soldiers: before, during, and following deployment to Iraq. AB - Evidence suggests either a four-factor emotional numbing or dysphoria model likely reflects the underlying structure of posttraumatic stress disorder (PTSD). Questions remain as to which of these structures best represents PTSD, how the structure changes with time, the applicability of models to returning veterans, and the validity of the symptom clusters. The present study addresses these questions among two longitudinal samples of National Guard soldiers assessed prior to, during, and following a combat deployment to Iraq. Findings support a four-factor intercorrelated dysphoria model of PTSD that remains stable across samples and time points. Differential associations were observed among PTSD symptom clusters over time and between symptom clusters and both depression and combat exposure, supporting important distinctions between symptom clusters. PMID- 21668081 TI - Consideration of the BDNF gene in relation to two phenotypes: hoarding and obesity. AB - The gene coding for the brain derived neurotrophic factor (BDNF) has emerged as an interesting candidate for multiple brain and brain disorder-related phenomena. The primary aim of the present investigation was to consider the relationship between the BDNF Val66Met variant and two phenotypes: compulsive hoarding as a symptom dimension of obsessive-compulsive disorder (OCD), and body mass index (BMI). We examined the BDNF gene in a large (N=301) clinical sample of probands with OCD. Participants were classified as hoarding or nonhoarding using a strict, multimeasure grouping approach. Results revealed that the Val/Val genotype was linked with hoarding classification and more severe hoarding behaviors, as well as greater BMI levels. Hoarding status was also associated with greater BMI scores, with individuals in the hoarding group being far more likely to be classified as obese compared with the nonhoarding group. Our findings may provide a distinct avenue through which hoarding and BMI could be linked. These findings are suggestive of a complex gene, body weight, and psychopathology relationship wherein a primitive, survival "thrifty gene" strategy may be conserved and represented in a subgroup of humans manifesting severe hoarding symptoms. PMID- 21668082 TI - Unique roles of antisocial personality disorder and psychopathic traits in distress tolerance. AB - Previous research indicates that individuals with antisocial personality disorder (ASPD) evidence low distress tolerance, which signifies impaired ability to persist in goal-directed behavior during an aversive situation, and is associated with a variety of poor interpersonal and drug use outcomes. Based on theory and research indicating that psychopathic traits are associated with hypo-reactivity in emotional responding, a unique hypothesis emerges where psychopathic traits should have the opposite effect of ASPD and be related to high levels of distress tolerance. In a sample of 107 substance-dependent patients in an inner-city substance use residential treatment facility, this hypothesis was supported. ASPD was related to lower distress tolerance, while psychopathic traits were related to higher distress tolerance, with each contributing unique variance. Findings are discussed in relation to different presentations of distress tolerance as a function of psychopathic traits among those with an ASPD diagnosis. PMID- 21668083 TI - Recollection is impaired by the modification of interpretation bias. AB - The interpretation paradigm of cognitive-bias modification (CBM-I) was modified with instructions used in process-dissociation procedures for the purpose of investigating processes contributing to performance on the transfer task. In Experiment 1, nonanxious students were trained to interpret ambiguous situations in either a negative or benign way (or they read nonambiguous scenarios). They were then asked to respond to new ambiguous situations, in the same way as contextually similar analogues during training, or to respond differently. Benign training proactively impaired memory for negative outcomes. This effect was replicated by anxious students in Experiment 2 and discussed with respect to the assumptions underlying process-dissociation procedures and directions for future research. PMID- 21668080 TI - Progression along the bipolar spectrum: a longitudinal study of predictors of conversion from bipolar spectrum conditions to bipolar I and II disorders. AB - Little longitudinal research has examined progression to more severe bipolar disorders in individuals with "soft" bipolar spectrum conditions. We examine rates and predictors of progression to bipolar I and II diagnoses in a nonpatient sample of college-age participants (n = 201) with high General Behavior Inventory scores and childhood or adolescent onset of "soft" bipolar spectrum disorders followed longitudinally for 4.5 years from the Longitudinal Investigation of Bipolar Spectrum (LIBS) project. Of 57 individuals with initial cyclothymia or bipolar disorder not otherwise specified (BiNOS) diagnoses, 42.1% progressed to a bipolar II diagnosis and 10.5% progressed to a bipolar I diagnosis. Of 144 individuals with initial bipolar II diagnoses, 17.4% progressed to a bipolar I diagnosis. Consistent with hypotheses derived from the clinical literature and the Behavioral Approach System (BAS) model of bipolar disorder, and controlling for relevant variables (length of follow-up, initial depressive and hypomanic symptoms, treatment-seeking, and family history), high BAS sensitivity (especially BAS Fun Seeking) predicted a greater likelihood of progression to bipolar II disorder, whereas early age of onset and high impulsivity predicted a greater likelihood of progression to bipolar I (high BAS sensitivity and Fun Seeking also predicted progression to bipolar I when family history was not controlled). The interaction of high BAS and high Behavioral Inhibition System (BIS) sensitivities also predicted greater likelihood of progression to bipolar I. We discuss implications of the findings for the bipolar spectrum concept, the BAS model of bipolar disorder, and early intervention efforts. PMID- 21668084 TI - Introduction to a special section on implementing evidence-based interventions for substance use disorders. AB - This article introduces a Special Section of the Psychology of Addictive Behaviors on "Implementing Evidence-based Interventions for Substance Use Disorders." It briefly describes the content of each of the seven manuscripts comprising the Special Section. The articles provide a overview of conceptual frameworks for, and summarize research on, the implementation of evidence-based treatments and practices for substance use disorders. Taken together, the articles make clear that successful implementation of a treatment innovation generally requires a multifaceted approach that considers: (a) features of the clinical intervention to be implemented, (b) characteristics of the individuals that are expected to adopt the clinical intervention, (c) features of the proximal and more distal environments in which the clinical intervention will be implemented, and (d) the implementation strategy to be applied. PMID- 21668085 TI - Implementing evidence-based psychosocial treatment in specialty substance use disorder care. AB - Implementing evidence-based psychosocial or behavioral treatments for clients with substance use disorders (SUDs) presents significant challenges. In this article, we first identify the treatments for which there is some consensus that sufficient empirical support exists to designate them as "evidence-based," and then briefly consider the nature of that evidence. Following that, we review data from a Substance Abuse and Mental Health Services Administration survey on the extent to which these evidence-based treatments (EBTs) are used in SUD treatment in the United States. The main focus of the article is a review of 21 studies attempting to implement EBTs from which we glean information on factors associated with more and less successful implementation. We conclude that more conceptually driven, organizationally focused (not just individual-provider focused) approaches to implementation are needed and that, at least with some providers in some organizational contexts, it may be more effective to implement evidence-based practices or processes (EBPs) rather than EBTs. PMID- 21668088 TI - Public skepticism of psychology: why many people perceive the study of human behavior as unscientific. AB - Data indicate that large percentages of the general public regard psychology's scientific status with considerable skepticism. I examine 6 criticisms commonly directed at the scientific basis of psychology (e.g., psychology is merely common sense, psychology does not use scientific methods, psychology is not useful to society) and offer 6 rebuttals. I then address 8 potential sources of public skepticism toward psychology and argue that although some of these sources reflect cognitive errors (e.g., hindsight bias) or misunderstandings of psychological science (e.g., failure to distinguish basic from applied research), others (e.g., psychology's failure to police itself, psychology's problematic public face) reflect the failure of professional psychology to get its own house in order. I offer several individual and institutional recommendations for enhancing psychology's image and contend that public skepticism toward psychology may, paradoxically, be one of our field's strongest allies. PMID- 21668086 TI - Developing the tools of implementation science in substance use disorders treatment: applications of the consolidated framework for implementation research. AB - The implementation of evidence-based treatments (EBTs) and practices (EBPs) depends on both top-down and bottom-up responsibilities. Many articles in this special section on Implementation Science in Substance Use Disorders address the interaction between these two approaches when implementing new substance use disorder (SUD) treatments. Generally the articles place this interaction within the Consolidated Framework for Implementation Research (CFIR), a relatively new and comprehensive synthesis of theories and conceptualizations of the components needed for successful implementation strategies. The range of SUD treatments covered includes well-established behavioral interventions, such as screening and brief interventions for alcohol, as well as new pharmacotherapies, such as buprenorphine for opiates. One contribution uses the CFIR to review continuing care interventions and self-help groups that can follow-up after more intensive clinical care. External and internal pressures for change drive implementation. The successful EBT/EBP implementations reviewed in these articles recognized these potential change drivers in designing their strategy for introducing the EBT/EBP, and they modified aspects of the EBT/EBP to satisfy many of these drivers. The CFIR model has limitations, as do the contributions to this special section. The implementation science field is new and developing rapidly, and many of the EBTs and EBPs were developed and tested through controlled studies evaluating the efficacy of interventions under controlled conditions, rather than examining their performance in the broader landscape of addiction treatment programs. These limitations may also be considered as boundary conditions to be explored in further research, implementation, and development of the next edition of the CFIR. PMID- 21668089 TI - Further evidence that similar principles govern recall from episodic and semantic memory: the Canadian prime ministerial serial position function. AB - The serial position function, with its characteristic primacy and recency effects, is one of the most ubiquitous findings in episodic memory tasks. In contrast, there are only two demonstrations of such functions in tasks thought to tap semantic memory. Here, we provide a third demonstration, showing that free recall of the prime ministers of Canada also results in a serial position function. Scale Independent Memory, Perception, and Learning (SIMPLE), a local distinctiveness model of memory that was designed to account for serial position effects in episodic memory, fit the data. According to SIMPLE, serial position functions observed in episodic and semantic memory all reflect the relative distinctiveness principle: items will be well remembered to the extent that they are more distinct than competing items at the time of retrieval. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21668090 TI - Repetition and the SNARC effect with one- and two-digit numbers. AB - The SNARC (Spatial Numerical Association of Response Codes) effect is the finding that small numbers elicit faster left than right responses and large numbers elicit faster right than left responses. This effect suggests that numbers activate left-right magnitude-laterality codes and that these codes interact with the selection of left-right responses. In the present research, subjects made parity decisions for one-digit numbers (in Experiment 1) and two-digit numbers (in Experiment 2), and we examined the effect of stimulus repetition on the SNARC effect. With single-digit stimuli, responses were faster and the SNARC effect was eliminated when stimuli were identical on successive trials. With two-digit stimuli, responses were faster when the ones digit was repeated, but the SNARC effect was found regardless of whether the digit was repeated or not. We argue that magnitude-laterality codes are activated in the process of accessing number information in memory and that this process can be short circuited if the visual stimulus matches that on the previous trial. Thus, no SNARC effect is found in Experiment 1 when identical stimuli are presented on successive trials. However, this result is not found in Experiment 2 because successive stimuli do not match even if the ones digit is repeated. PMID- 21668091 TI - Congruency proportion reveals asymmetric processing of irrelevant physical and numerical dimensions in the size congruity paradigm. AB - When the proportion of congruent trials in conflict tasks is manipulated (e.g., Stroop, Simon), the typical result is that the magnitude of the conflict effect increases as the proportion of congruent trials increases. The present experiment investigated the influence of Congruency Proportion in the context of the Size Congruity Paradigm. Congruency Proportion had a significant impact on the Numerical Judgement Task (judging which of two numbers is numerically larger), but not on the Physical Judgement Task (judging which of two numbers is printed in a larger font). These data support the inference that physical size information is processed before, and more fluently than, numerical size information. The implications of this asymmetry are discussed in terms of the relative role of semantic and physical size information in representations of magnitude, and the role they play in both of these tasks. PMID- 21668092 TI - When benefits outweigh costs: reconsidering "automatic" phonological recoding when reading aloud. AB - Skilled readers are slower to read aloud exception words (e.g., PINT) than regular words (e.g., MINT). In the case of exception words, sublexical knowledge competes with the correct pronunciation driven by lexical knowledge, whereas no such competition occurs for regular words. The dominant view is that the cost of this "regularity" effect is evidence that sublexical spelling-sound conversion is impossible to prevent (i.e., is "automatic"). This view has become so reified that the field rarely questions it. However, the results of simulations from the most successful computational models on the table suggest that the claim of "automatic" sublexical phonological recoding is premature given that there is also a benefit conferred by sublexical processing. Taken together with evidence from skilled readers that sublexical phonological recoding can be stopped, we suggest that the field is too narrowly focused when it asserts that sublexical phonological recoding is "automatic" and that a broader, more nuanced and contextually driven approach provides a more useful framework. PMID- 21668093 TI - Fourth graders' sensitivity to morphological context in spelling. AB - An important aspect of spelling development in English involves the child's ability to use morphological context to deal with one-to-many sound-spelling mappings for word endings. One case involves /z/ endings that follow long vowels, where an "s" spelling is required in the case of inflected noun and verb contexts, but an "se" or "ze" spelling is required in the case of noninflected nouns and verbs. The present study examined the ability of good and poor spellers in Grade 4 to capture these morphological distinctions in a pseudoword spelling task. Overall, the good spellers outperformed the poor spellers, and both groups were more sensitive to the inflected-noninflected noun distinction than the inflected-noninflected verb distinction. These findings underscore the importance of linguistic factors in spelling development as well as the necessity of providing due consideration to these factors in spelling instruction. PMID- 21668094 TI - The sound of round: evaluating the sound-symbolic role of consonants in the classic Takete-Maluma phenomenon. AB - Kohler (1929) famously reported a bias in people's matching of nonsense words to novel object shapes, pointing to possible naive expectations about language structure. The bias has been attributed to synesthesia-like coactivation of motor or somatosensory areas involved in vowel articulation and visual areas involved in perceiving object shape (Ramachandran & Hubbard, 2001). We report two experiments testing an alternative that emphasizes consonants and natural semantic distinctions flowing from the auditory perceptual quality of salient acoustic differences among them. Our experiments replicated previous studies using similar word and image materials but included additional conditions swapping the consonant and vowel contents of words; using novel, randomly generated words and images; and presenting words either visually or aurally. In both experiments, subjects' image-matching responses showed evidence of tracking the consonant content of words. We discuss the possibility that vowels and consonants both play a role and consider some methodological factors that might influence their relative effects. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21668095 TI - On the (un)conditionality of automatic attitude activation: the valence proportion effect. AB - Affective priming studies have shown that participants are faster to pronounce affectively polarized target words that are preceded by affectively congruent prime words than affectively polarized target words that are preceded by affectively incongruent prime words. We examined whether affective priming of naming responses depends on the valence proportion (i.e., the proportion of stimuli that are affectively polarized). In one group of participants, experimental trials were embedded in a context of filler trials that consisted of affectively polarized stimulus materials (i.e., high valence proportion condition). In a second group, the same set of experimental trials was embedded in a context of filler trials consisting of neutral stimuli (i.e., low valence proportion condition). Results showed that affective priming of naming responses was significantly stronger in the high valence proportion condition than in the low valence proportion condition. We conclude that (a) subtle aspects of the procedure can influence affective priming of naming responses, (b) finding affective priming of naming responses does not allow for the conclusion that affective stimulus processing is unconditional, and (c) affective stimulus processing depends on selective attention for affective stimulus information. PMID- 21668096 TI - Young adult identities and their pathways: a developmental and life course model. AB - Developmental and life course studies of young adult identities have focused on 2 dimensions: subjective age and psychosocial maturity. This study examines the developmental synchrony of these 2 processes. In a longitudinal sample of young adults from Add Health (ages 18-22), a person-centered analysis of indicators of these dimensions identified 4 identity profiles. Two depict early and late patterns of identity; the others represent contrasting types of discordance: pseudo-adult, with subjective age more advanced than maturation level, and anticipatory, with subjective age less advanced than maturational level. The profiles vary by gender, socioeconomic status, and race-ethnicity, as well as by adolescent (ages 12-16) pubertal maturation, psychosocial adjustment, and family context. These results provide support for a more holistic, interdisciplinary understanding of adult identity and show that young adult identities in the Add Health sample follow differentiated paths into the adult years, with largely unknown consequences for the subsequent life course. PMID- 21668097 TI - Individual differences in early adolescents' beliefs in the legitimacy of parental authority. AB - Adolescents differ in the extent to which they believe that parents have legitimate authority to impose rules restricting adolescents' behavior. The purpose of the current study was to test predictors of individual differences in legitimacy beliefs during the middle school years. Annually, during the summers following Grades 5, 6, and 7, early adolescents (n = 218; 51% female, 47% African American, 73% in 2-parent homes) reported their beliefs regarding the legitimacy of parents' rules that restrict and monitor adolescents' free time activities. Cross-lagged analyses revealed that legitimacy beliefs were bidirectionally associated with independent decision making, psychological control, antisocial peer involvement, and resistance to control. Legitimacy beliefs declined more rapidly during the middle school years for boys than for girls and for adolescents who were older relative to their classmates. More independent decision making in Grades 5 and 6 predicted larger than expected declines in legitimacy beliefs in Grades 6 and 7. In sum, legitimacy beliefs weaken developmentally, and weaker legitimacy beliefs relative to same-grade peers are anteceded by premature autonomous experiences, psychological control, and adolescent attributes. PMID- 21668098 TI - Infants learn about objects from statistics and people. AB - In laboratory experiments, infants are sensitive to patterns of visual features that co-occur (e.g., Fiser & Aslin, 2002). Once infants learn the statistical regularities, however, what do they do with that knowledge? Moreover, which patterns do infants learn in the cluttered world outside of the laboratory? Across 4 experiments, we show that 9-month-olds use this sensitivity to make inferences about object properties. In Experiment 1, 9-month-old infants expected co-occurring visual features to remain fused (i.e., infants looked longer when co occurring features split apart than when they stayed together). Forming such expectations can help identify integral object parts for object individuation, recognition, and categorization. In Experiment 2, we increased the task difficulty by presenting the test stimuli simultaneously with a different spatial layout from the familiarization trials to provide a more ecologically valid condition. Infants did not make similar inferences in this more distracting test condition. However, Experiment 3 showed that a social cue did allow inferences in this more difficult test condition, and Experiment 4 showed that social cues helped infants choose patterns among distractor patterns during learning as well as during test. These findings suggest that infants can use feature co-occurrence to learn about objects and that social cues shape such foundational learning in distraction-filled environments. PMID- 21668100 TI - Processes underlying congruent and incongruent facial reactions to emotional facial expressions. AB - The present electromyographic study is a first step toward shedding light on the involvement of affective processes in congruent and incongruent facial reactions to facial expressions. Further, empathy was investigated as a potential mediator underlying the modulation of facial reactions to emotional faces in a competitive, a cooperative, and a neutral setting. Results revealed less congruent reactions to happy expressions and even incongruent reactions to sad and angry expressions in the competition condition, whereas virtually no differences between the neutral and the cooperation condition occurred. Effects on congruent reactions were found to be mediated by cognitive empathy, indicating that the state of empathy plays an important role in the situational modulation of congruent reactions. Further, incongruent reactions to sad and angry faces in a competition setting were mediated by the emotional reaction of joy, supporting the assumption that incongruent facial reactions are mainly based on affective processes. Additionally, strategic processes (specifically, the goal to create and maintain a smooth, harmonious interaction) were found to influence facial reactions while being in a cooperative mindset. Now, further studies are needed to test for the generalizability of these effects. PMID- 21668099 TI - Developmental trajectories in toddlers' self-restraint predict individual differences in executive functions 14 years later: a behavioral genetic analysis. AB - We examined whether self-restraint in early childhood predicted individual differences in 3 executive functions (EFs; inhibiting prepotent responses, updating working memory, and shifting task sets) in late adolescence in a sample of approximately 950 twins. At ages 14, 20, 24, and 36 months, the children were shown an attractive toy and told not to touch it for 30 s. Latency to touch the toy increased with age, and latent class growth modeling distinguished 2 groups of children that differed in their latencies to touch the toy at all 4 time points. Using confirmatory factor analysis, we decomposed the 3 EFs (measured with latent variables at age 17 years) into a Common EF factor (isomorphic to response inhibition ability) and 2 factors specific to updating and shifting. Less-restrained children had significantly lower scores on the Common EF factor, equivalent scores on the Updating-Specific factor, and higher scores on the Shifting-Specific factor than did the more-restrained children. The less restrained group also had lower IQ scores, but this effect was entirely mediated by the EF components. Twin models indicated that the associations were primarily genetic in origin for the Common EF variable but split between genetics and nonshared environment for the Shifting-Specific variable. These results suggest a biological relation between individual differences in self-restraint and EFs, one that begins early in life and persists into late adolescence. PMID- 21668101 TI - Implicit influence of affective postures on the perception of others: you can't show me how I feel. AB - This study examined how one's own posture influences the perception of another's posture in a task with implicit affective information. In 2 experiments, participants assumed or viewed a body posture and then compared that posture with a viewed posture. They were not told that postures varied in affective valence: positive, negative, neutral-abstract, or neutral-meaningful. Posture affect influenced both accuracy and response time measures of posture discrimination. Participants were slower and less accurate for targets that matched an assumed posture, but only for affective postures. This pattern did not hold for matching affectively neutral postures (meaningful or not), nonmatching postures, or for purely visual comparisons. These results are consistent with both cognitive embodiment theories postulating that personal body posture influences the perception of other's postures and emotional embodiment theories postulating sensorimotor and emotional simulation processes that create correspondences between one's own and another's emotional postures. Nonetheless, these findings differ from studies finding facilitation for explicit emotional judgments of affective congruence. People use different information depending on task requirements. The assumption of an affective posture may activate simulations of personal emotional experiences that may, in turn, serve to differentiate personal posture perception from ostensibly the same posture in another person. PMID- 21668102 TI - Can people really "laugh at themselves?"--experimental and correlational evidence. AB - Laughing at oneself is considered a core component of the sense of humor in the theories of several authors. In McGhee's (1996) eight-step-training program of the sense of humor, laughing at oneself constitutes one of the most difficult levels. However, until now, only little empirical evidence on laughing at oneself exists. Using a multimethod approach, in the current study, 70 psychology students and a total of 126 peers filled in the Sense of Humor Scale (SHS, McGhee, 1996), containing as a subscale "Laughing at oneself". In addition, the participants answered the Trait and State forms of the State-Trait-Cheerfulness Inventory (STCI, Ruch, Kohler, & van Thriel, 1996; Ruch, Kohler, & van Thriel, 1997). They then were confronted with six distorted images of themselves. Facial responses of the participants were videotaped and analyzed using the Facial Action Coding System (FACS, Ekman, Friesen, & Hager, 2002). Four indicators of exhilaration were examined: (a) experienced funniness, (b) AU12 smiles, (c) Duchenne displays, and (d) laughter. Furthermore, fake and masking smiles were studied. Results demonstrated that self- and peer reports of "laughing at oneself" converged moderately. All four indicators of exhilaration were shown, but funniness and laughter seemed to be the most strongly related indicators. Trait cheerfulness and (low) seriousness, and a cheerful mood state formed further characteristics of persons who laugh at themselves. PMID- 21668103 TI - Taking your place or matching your face: two paths to empathic embarrassment. AB - Empathic responding may be elicited by different processes, depending on the available situational and affective cues. We investigated two such processes, perspective-taking and nonverbal mimicry. In Study 1, participants watched an embarrassed or unembarrassed confederate dancing to music while either remaining objective or engaging in perspective-taking. Both manipulations affected empathic embarrassment. Study 2 further examined the effects of targets' embarrassment displays and observers' prior experience with the situation upon spontaneous perspective-taking, expressive mimicry, and empathic embarrassment. Embarrassment displays increased mimicry, but also spontaneous perspective-taking and subsequent empathy. Prior experience moderated the effects of embarrassment displays on perspective-taking and empathy. Path analyses demonstrated that embarrassment displays exerted indirect effects on empathic embarrassment through both perspective-taking and mimicry. The results suggest that available affective and situational cues can activate different routes to empathy, and highlight the value of simultaneously investigating target- and observer-based sources of influence. PMID- 21668104 TI - Judging approachability on the face of it: the influence of face and body expressions on the perception of approachability. AB - The aim of the current study was to examine how emotional expressions displayed by the face and body influence the decision to approach or avoid another individual. In Experiment 1, we examined approachability judgments provided to faces and bodies presented in isolation that were displaying angry, happy, and neutral expressions. Results revealed that angry expressions were associated with the most negative approachability ratings, for both faces and bodies. The effect of happy expressions was shown to differ for faces and bodies, with happy faces judged more approachable than neutral faces, whereas neutral bodies were considered more approachable than happy bodies. In Experiment 2, we sought to examine how we integrate emotional expressions depicted in the face and body when judging the approachability of face-body composite images. Our results revealed that approachability judgments given to face-body composites were driven largely by the facial expression. In Experiment 3, we then aimed to determine how the categorization of body expression is affected by facial expressions. This experiment revealed that body expressions were less accurately recognized when the accompanying facial expression was incongruent than when neutral. These findings suggest that the meaning extracted from a body expression is critically dependent on the valence of the associated facial expression. PMID- 21668105 TI - Assessing the way people look to judge their intentions. AB - Faces of unknown persons are processed to infer the intentions of these persons not only when they depict full-blown emotions, but also at rest, or when these faces do not signal any strong feelings. We explored the brain processes involved in these inferences to test whether they are similar to those found when judging full-blown emotions. We recorded the event-related brain potentials (ERPs) elicited by faces of unknown persons who, when they were photographed, were not asked to adopt any particular expression. During the ERP recording, participants had to decide whether each face appeared to be that of a positively, negatively, ambiguously, or neutrally intentioned person. The early posterior negativity, the EPN, was found smaller for neutrally categorized faces than for the other faces, suggesting that the automatic processes it indexes are similar to those evoked by full-blown expressions and thus that these processes might be involved in the decoding of intentions. In contrast, in the same 200-400 ms time window, ERPs were not more negative at anterior sites for neutrally intentioned faces. Second, the peaks of the late positive potentials (LPPs) maximal at parietal sites around 700 ms postonset were not significantly smaller for neutrally intentioned faces. Third, the slow positive waves that followed the LPP were larger for faces that took more time to categorize, that is, for ambiguously intentioned faces. These three series of unexpected results may indicate processes similar to those triggered by full-blown emotions studies, but they question the characteristics of these processes. PMID- 21668106 TI - Emotion enhances the subjective feeling of remembering, despite lower accuracy for contextual details. AB - Emotion strengthens the subjective experience of recollection. However, these vivid and confidently remembered emotional memories may not necessarily be more accurate. We investigated whether the subjective sense of recollection for negative stimuli is coupled with enhanced memory accuracy for contextual details using the remember/know paradigm. Our results indicate a double-dissociation between the subjective feeling of remembering, and the objective memory accuracy for details of negative and neutral scenes. "Remember" judgments were boosted for negative relative to neutral scenes. In contrast, memory for contextual details and associative binding was worse for negative compared to neutral scenes given a "remember" response. These findings show that the enhanced subjective recollective experience for negative stimuli does not reliably indicate greater objective recollection, at least of the details tested, and thus may be driven by a different mechanism than the subjective recollective experience for neutral stimuli. PMID- 21668107 TI - The processing of invariant and variant face cues in the Garner Paradigm. AB - Faces provide a complex source of information via invariant (e.g., race, sex and age) and variant (e.g., emotional expressions) cues. At present, it is not clear whether these different cues are processed separately or whether they interact. Using the Garner Paradigm, Experiment 1 confirmed that race, sex, and age cues affected the categorization of faces according to emotional expression whereas emotional expression had no effect on the categorization of faces by sex, age, or race. Experiment 2 used inverted faces and replicated this pattern of asymmetrical interference for race and age cues, but not for sex cues for which no interference on emotional expression categorization was observed. Experiment 3 confirmed this finding with a more stringently matched set of facial stimuli. Overall, this study shows that invariant cues interfere with the processing of emotional expressions. It indicates that the processing of invariant cues, but not of emotional expressions, is obligatory and that it precedes that of emotional expressions. PMID- 21668108 TI - Visual threat detection during moderate- and high-intensity exercise. AB - The aim of the study was to assess performance on a visual threat-detection task during concurrently performed vigorous exercise on a cycle ergometer. Thirty (15 female) participants completed a baseline condition of seated rest and then moderate- and high-intensity exercise. Moderate- and high-intensity exercise conditions were completed on the 2nd day in a counterbalanced order. During each exercise condition, participants responded to 3 * 3 picture matrices (256 trials in each condition) that contained discrepant fear-relevant and discrepant fear irrelevant pictures (Ohman, Flykt, & Esteves, 2001). Response accuracy was significantly greater, and reaction time was significantly faster, during moderate- and high-intensity exercise compared with the rest condition (ps < .001). The discrepant fear-relevant matrix type was detected significantly more accurately than a discrepant fear-irrelevant matrix (p < .001). The discrepant fear-relevant matrix was detected significantly faster than all other matrix types (p < .001). These results suggest that exercise at a moderate and high intensity may enhance the efficiency of visual detection of both threatening and nonthreatening targets. PMID- 21668109 TI - Is there a mutual relationship between opposite attentional biases underlying anxiety? AB - Current models that account for attentional processes in anxiety have proposed that high-trait anxious individuals are characterized by a hypervigilant-avoidant pattern of attentional biases to threat. We adopted a laboratory conditioning procedure to induce concomitant hypervigilance and avoidance to threat, emphasizing a putative relationship between lower-level reactive and upper-level controlled attentional mechanisms as the core account of attentional processes involved in the development and maintenance of anxiety. Eighty high- and low trait anxious participants underwent Pavlovian conditioning to a human face. Eye tracking was used to monitor attentional changes to the conditioned stimulus (CS+) face and the neutral stimulus (CS-) face, presented at 200, 500, and 800 ms durations. The high-anxious participants developed the expected attentional bias toward the CS+ at 200 ms presentation time and attentional avoidance at 500 and 800 ms durations. Hypervigilance to aversive stimuli at 200 ms and later avoidance to the same stimuli at 500 and 800 ms were associated with higher levels of galvanic skin conductance to the CS+. The low-anxious individuals developed the opposite attentional pattern with an initial tendency to orient attention away from the aversive stimuli in the 200 ms condition and to orient attention toward aversive stimuli in the remaining time. The differential modulation between hypervigilance and avoidance elicited in the two groups by the conditioning procedure suggests that vulnerability to anxiety is characterized by a latent relationship between diverse attentional mechanisms. Within this relationship, hypervigilance and avoidance to threat operate at different stages of information processing suggesting fuzzy boundaries between early reactive and later-strategic processing of threat. PMID- 21668110 TI - Anxiety, movement kinematics, and visual attention in elite-level performers. AB - We tested the predictions of Attentional Control Theory (ACT) by examining the effect of anxiety on attention control and the subsequent influence on both performance effectiveness and performance efficiency within a perceptual-motor context. A sample (N = 16) of elite shotgun shooters was tested under counterbalanced low (practice) and high (competition) anxiety conditions. A head mounted, corneal reflection system allowed point of gaze to be calculated in relation to the scene, while motion of the gun was evaluated using markers placed on the barrel which were captured by two stationary cameras and analyzed using optical tracking software. The quiet eye (QE) duration and onset were analyzed along with gun barrel displacement and variability; performance outcome scores (successful vs. unsuccessful) were also recorded. QE (Vickers, 1996) is defined as the final fixation or tracking gaze that is located on a specific location/object in the visual display for a minimum of 100 ms. Longer QE durations have been linked to successful performance in previous research involving aiming tasks. Participants demonstrated shorter quiet eye durations, and less efficient gun motion, along with a decreased performance outcome (fewer successful trials) under high compared with low anxiety conditions. The data support the predictions of ACT with anxiety disrupting control processes such that goal-directed attention was compromised, leading to a significant impairment in performance effectiveness. PMID- 21668111 TI - Nonverbal channel use in communication of emotion: how may depend on why. AB - This study investigated the hypothesis that different emotions are most effectively conveyed through specific, nonverbal channels of communication: body, face, and touch. Experiment 1 assessed the production of emotion displays. Participants generated nonverbal displays of 11 emotions, with and without channel restrictions. For both actual production and stated preferences, participants favored the body for embarrassment, guilt, pride, and shame; the face for anger, disgust, fear, happiness, and sadness; and touch for love and sympathy. When restricted to a single channel, participants were most confident about their communication when production was limited to the emotion's preferred channel. Experiment 2 examined the reception or identification of emotion displays. Participants viewed videos of emotions communicated in unrestricted and restricted conditions and identified the communicated emotions. Emotion identification in restricted conditions was most accurate when participants viewed emotions displayed via the emotion's preferred channel. This study provides converging evidence that some emotions are communicated predominantly through different nonverbal channels. Further analysis of these channel-emotion correspondences suggests that the social function of an emotion predicts its primary channel: The body channel promotes social-status emotions, the face channel supports survival emotions, and touch supports intimate emotions. PMID- 21668112 TI - The effects of tempo and familiarity on children's affective interpretation of music. AB - When and how does one learn to associate emotion with music? This study attempted to address this issue by examining whether preschool children use tempo as a cue in determining whether a song is happy or sad. Instrumental versions of children's songs were played at different tempos to adults and children ages 3 to 5 years. Familiar and unfamiliar songs were used to examine whether familiarity affected children's identification of emotion in music. The results indicated that adults, 4 year olds and 5 year olds rated fast songs as significantly happier than slow songs. However, 3 year olds failed to rate fast songs differently than slow songs at above-chance levels. Familiarity did not significantly affect children's identification of happiness and sadness in music. PMID- 21668113 TI - Automatic emotion regulation after social exclusion: tuning to positivity. AB - Nine experiments tested competing hypotheses regarding nonconscious affective responses to acute social exclusion and how such responses may relate to positive mental health. The results strongly and consistently indicated that acute social exclusion increased nonconscious positive affect. Compared to nonexcluded participants, excluded participants recalled more positive memories from childhood than did accepted participants (Experiment 1), gave greater weight to positive emotion in their judgments of word similarity (Experiments 2 and 3), and completed more ambiguous word stems with happy words (Experiments 4a and 4b). This process was apparently automatic, as participants asked to imagine exclusion overestimated explicit distress and underestimated implicit positivity (Experiment 3). Four final experiments showed that this automatic emotion regulation process was found among participants low (but not high) in depressive symptoms (Experiments 5 and 6) and among participants high (but not low) in self esteem (Experiments 7 and 8). These findings suggest that acute exclusion sets in motion an automatic emotion regulation process in which positive emotions become highly accessible, which relates to positive mental health. PMID- 21668114 TI - A tale of two negatives: differential memory modulation by threat-related facial expressions. AB - Facial expressions serve as cues that encourage viewers to learn about their immediate environment. In studies assessing the influence of emotional cues on behavior, fearful and angry faces are often combined into one category, such as "threat-related," because they share similar emotional valence and arousal properties. However, these expressions convey different information to the viewer. Fearful faces indicate the increased probability of a threat, whereas angry expressions embody a certain and direct threat. This conceptualization predicts that a fearful face should facilitate processing of the environment to gather information to disambiguate the threat. Here, we tested whether fearful faces facilitated processing of neutral information presented in close temporal proximity to the faces. In Experiment 1, we demonstrated that, compared with neutral faces, fearful faces enhanced memory for neutral words presented in the experimental context, whereas angry faces did not. In Experiment 2, we directly compared the effects of fearful and angry faces on subsequent memory for emotional faces versus neutral words. We replicated the findings of Experiment 1 and extended them by showing that participants remembered more faces from the angry face condition relative to the fear condition, consistent with the notion that anger differs from fear in that it directs attention toward the angry individual. Because these effects cannot be attributed to differences in arousal or valence processing, we suggest they are best understood in terms of differences in the predictive information conveyed by fearful and angry facial expressions. PMID- 21668115 TI - When does mimicry affect evaluative judgment? AB - We investigated the effect of subliminally presented happy or angry faces on evaluative judgments when the facial muscles of participants were free to mimic or blocked. We hypothesized and showed that subliminally presented happy expressions lead to more positive judgments of cartoons compared to angry expressions only when facial muscles were not blocked. These results reveal the influence of socially driven embodied processes on affective judgments and have also potential implications for phenomena such as emotional contagion. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21668116 TI - Toddlers' context-varying emotions, maternal responses to emotions, and internalizing behaviors. AB - Relations of toddlers' observed negative affect in high- and low-threat contexts to maternal perceptions of their toddlers' internalizing problems and to mothers' responses to emotions (RTE) for fear and sadness were examined. Child-driven, parent-driven, and reciprocal transactional models across 1 year were directly compared. Two-year-old toddlers (N = 106) participated in lab-based activities to elicit distress, and their negative affect was coded. Mothers completed measures of their child's internalizing behaviors and their responses to their toddler's fear and sadness at ages 2 and 3. At age 2, only negative affect in low-threat contexts was associated with greater internalizing problems. Mothers' punishing and minimizing RTE at age 2 predicted an increase in internalizing problems across 1 year. Age 2 internalizing problems predicted an increase in mother's use of supportive RTE over time. Results highlight the importance of considering the context of toddlers' negative affective displays and supported a reciprocal conceptualization of toddlers' internalizing behaviors and mothers' RTE. PMID- 21668117 TI - Mother and child interpretations of threat in ambiguous situations: relations with child anxiety and autonomic responding. AB - This study examined maternal and child interpretive bias to threat (IBT) during dyadic conversation, child physiological reactivity and regulation during dyadic conversation, and maternal report of child anxiety in a community sample of 35 mothers and their 8- to 10-year-old children. Mothers and children discussed one neutral and six ambiguous scenarios, which were subsequently coded for frequency of maternal and child initiation, minimization, and expansion of threat-related themes. Child electrocardiogram data were collected during these conversations and maternal reports of child anxiety and internalizing problems were obtained. Across the sample, children initiated threat-related discussion more often than mothers. Maternal threat expansions were significantly positively correlated with child anxiety and internalizing behaviors. Maternal minimizations of threat were significantly associated with augmented child vagal tone throughout the IBT paradigm. Implications for prevention of child anxiety and directions for extending IBT research within the context of the mother-child dyad are discussed. PMID- 21668118 TI - Using qualitative methods to guide clinical trial design: parent recommendations for intervention modification in type 1 diabetes. AB - Parents of young children with Type 1 diabetes assume significant responsibility for a complex daily illness regimen, yet little research has evaluated supportive interventions for this population. This study presents mixed-methods program evaluation data from participants who completed a five-session intervention designed to promote parent mastery of diabetes-related tasks and increase social and emotional support. Twelve parents (75% female) of young children with Type 1 diabetes completed a satisfaction survey following intervention completion. Additionally, four parents were selected for completion of an in-depth interview designed to elicit specific recommendations for program improvement. Results suggested high levels of satisfaction with the intervention program. Thematic coding of interview data revealed two clear directions for future research, including offering the intervention program closer to the time of diagnosis and enhancing educational and supportive offerings for parents and other caregivers. Incorporation of in-depth interviews and subsequent qualitative data analyses in addition to a quantitative satisfaction survey provided richly detailed data related to program evaluation and improvement. Results highlighted critical components for intervention refinement and provided a unique window into the experiences of parents of young children with Type 1 diabetes and the need for additional support in the months following diagnosis, both for themselves and other caregivers. PMID- 21668119 TI - Relations between spouses' depressive symptoms and marital conflict: a longitudinal investigation of the role of conflict resolution styles. AB - This study investigated longitudinal relations between spouses' depressive symptoms and styles of conflict resolution displayed by husbands and wives in marital conflict, including angry, depressive, and constructive patterns of expression. Behavioral observations were made from a community sample of 276 couples during marital conflict resolution tasks once a year for 3 years. Couples were observed engaging in a major and minor conflict resolution task. Constructive, angry, and depressive conflict resolution styles were derived from the behavioral observation coding. Couples self-reported on depressive symptoms and marital dissatisfaction. Path analyses provided support for an extension of the marital discord model of depression (Beach, Sandeen, & O'Leary, 1990). Specifically, angry, depressive, and constructive styles of conflict each mediated the link between marital dissatisfaction and depressive symptoms. Significant cross-spouse effects were found. Implications for the treatment of depressed and/or relationally discordant couples are discussed. PMID- 21668121 TI - Decisional strategy determines whether frame influences treatment preferences for medical decisions. AB - Decision makers are influenced by the frame of information such that preferences vary depending on whether survival or mortality data are presented. Research is inconsistent as to whether and how age impacts framing effects. This paper presents two studies that used qualitative analyses of think-aloud protocols to understand how the type of information used in the decision making process varies by frame and age. In Study 1, 40 older adults, age 65 to 89, and 40 younger adults, age 18 to 24, responded to a hypothetical lung cancer scenario in a within-subject design. Participants received both a survival and mortality frame. Qualitative analyses revealed that two main decisional strategies were used by all participants: one strategy reflected a data-driven decisional process, whereas the other reflected an experience-driven process. Age predicted decisional strategy, with older adults less likely to use a data-driven strategy. Frame interacted with strategy to predict treatment choice; only those using a data-driven strategy demonstrated framing effects. In Study 2, 61 older adults, age 65 to 98, and 63 younger adults, age 18 to 30, responded to the same scenarios as in Study 1 in a between-subject design. The results of Study 1 were replicated, with age significantly predicting decisional strategy and frame interacting with strategy to predict treatment choice. Findings suggest that framing effects may be more related to decisional strategy than to age. PMID- 21668120 TI - Longitudinal effects of adaptability on behavior problems and maternal depression in families of adolescents with autism. AB - Research on families of individuals with autism has tended to focus on child driven effects utilizing models of stress and coping. The current study used a family systems perspective to examine whether family level adaptability promoted beneficial outcomes for mothers and their adolescents with autism over time. Participants were 149 families of children diagnosed with autism who were between the ages of 10 and 22 years during the 3-year period examined. Mothers reported on family adaptability, the mother-child relationship, their own depressive symptoms, and the behavior problems of their children at Wave 1, and these factors were used to predict maternal depression and child behavior problems 3 years later. Family level adaptability predicted change in both maternal depression and child behavior problems over the study period, above and beyond the contribution of the dyadic mother-child relationship. These associations did not appear to depend upon the intellectual disability status of the individual with autism. Implications for autism, parent mental health, family systems theory, and intervention with this population are discussed. PMID- 21668124 TI - An examination of the RCMAS-2 scores across gender, ethnic background, and age in a large Asian school sample. AB - The present study investigated the factor structure, reliability, convergent and discriminant validity, and U.S. norms of the Revised Children's Manifest Anxiety Scale, Second Edition (RCMAS-2; C. R. Reynolds & B. O. Richmond, 2008a) scores in a Singapore sample of 1,618 school-age children and adolescents. Although there were small statistically significant differences in the average RCMAS-2 T scores found across various demographic groupings, on the whole, the U.S. norms appear adequate for use in the Asian Singapore sample. Results from item bias analyses suggested that biased items detected had small effects and were counterbalanced across gender and ethnicity, and hence, their relative impact on test score variation appears to be minimal. Results of factor analyses on the RCMAS-2 scores supported the presence of a large general anxiety factor, the Total Anxiety factor, and the 5-factor structure found in U.S. samples was replicated. Both the large general anxiety factor and the 5-factor solution were invariant across gender and ethnic background. Internal consistency estimates ranged from adequate to good, and 2-week test-retest reliability estimates were comparable to previous studies. Evidence providing support for convergent and discriminant validity of the RCMAS-2 scores was also found. Taken together, findings provide additional cross-cultural evidence of the appropriateness and usefulness of the RCMAS-2 as a measure of anxiety in Asian Singaporean school-age children and adolescents. PMID- 21668123 TI - Influences of APOE epsilon4 and expertise on performance of older pilots. AB - Little is known about how APOE epsilon4-related differences in cognitive performance translate to real-life performance, where training and experience may help to sustain performance. We investigated the influences of APOE epsilon4 status, expertise (FAA pilot proficiency ratings), and their interaction on longitudinal flight simulator performance. Over a 2-year period, 139 pilots aged 42-69 years were tested annually. APOE epsilon4 carriers had lower memory performance than noncarriers (p = .019). APOE interacted with Expertise (p = .036), such that the beneficial influence of expertise (p = .013) on longitudinal flight simulator performance was more pronounced for epsilon4 carriers. Results suggest that relevant training and activity may help sustain middle-aged and older adults' real-world performance, especially among APOE epsilon4 carriers. PMID- 21668125 TI - The Novaco Anger Scale-Provocation Inventory (1994 version) in Dutch forensic psychiatric patients. AB - We examined the psychometric properties of the Novaco Anger Scale-Provocation Inventory (NAS-PI, 1994 version) in Dutch violent forensic psychiatric patients and secondary vocational students. A confirmatory factor analysis of the subscale structure of the NAS was carried out, reliability was investigated, and relations were calculated between NAS-PI scores and other measures of personality traits and problem behaviors. The 3-subscale structure of the original NAS could not be confirmed. However, the internal consistency of the NAS and the PI was excellent, and the test-retest reliability of the NAS was good. The validity of the NAS and the PI was supported by a meaningful pattern of correlations with alternative measures of anger and personality traits. Forensic psychiatric outpatients displayed higher NAS scores than secondary vocational students, but inpatients scored even lower than this nonclinical control group. Our preliminary conclusion is that the NAS-PI is a valuable instrument for the assessment of anger in Dutch violent forensic psychiatric patients. PMID- 21668126 TI - Toward a process-focused model of test score validity: improving psychological assessment in science and practice. AB - Although definitions of validity have evolved considerably since L. J. Cronbach and P. E. Meehl's classic (1955) review, contemporary validity research continues to emphasize correlational analyses assessing predictor-criterion relationships, with most outcome criteria being self-reports. The present article describes an alternative way of operationalizing validity--the process-focused (PF) model. The PF model conceptualizes validity as the degree to which respondents can be shown to engage in a predictable set of psychological processes during testing, with those processes dictated a priori by the nature of the instrument(s) used and the context in which testing takes place. In contrast to the traditional approach wherein correlational methods are used to quantify the relationship between test score and criterion, the PF model uses experimental methods to manipulate variables that moderate test score-criterion relationships, enabling researchers to draw more definitive conclusions regarding the impact of underlying psychological processes on test scores. By complementing outcome-based validity assessment with a process-driven approach, researchers will not only improve psychology's assessment procedures but also enhance their understanding of test bias and test score misuse by illuminating the intra- and interpersonal factors that lead to differential performance (and differential prediction) in different groups. PMID- 21668127 TI - Pursuing goals with others: group identification and motivation resulting from things done versus things left undone. AB - This article addresses what factors best motivate individuals to work toward shared goals. We propose that when individuals do not identify highly with a group, their contributions will mimic others': An emphasis on things done will increase their contributions toward achieving a goal, because such emphasis suggests the goal is worth pursuing. Conversely, we propose that when individuals identify highly with a group, their contributions will compensate for others': An emphasis on things left undone will increase their own contributions, because missing contributions suggest insufficient progress toward a goal they already consider worthwhile. Five studies lend support to these predictions by measuring contributions to goals centered on idea generation and helping victims of various global disasters (earthquake in Haiti, wildfires in Southern California, rioting in Kenya). PMID- 21668128 TI - Dynamic prototypicality effects in visual search. AB - In recent studies, researchers have discovered a larger neural activation for stimuli that are more extreme exemplars of their stimulus class, compared with stimuli that are more prototypical. This has been shown for faces as well as for familiar and novel shape classes. We used a visual search task to look for a behavioral correlate of these findings regarding both simple geometrical shapes and more complex, novel shape classes. The latter stimulus set enabled us to control for the physical properties of the shapes, establishing that the effects are solely due to the positions of the particular stimuli in a particular shape space (i.e., more extreme versus more central in shape space) and not to specific shape features. The results indicate that finding an atypical instance of a shape class among more prototypical ones is easier and faster than the other way around. The prototypical status of a shape in our experiment could change very quickly, that is, within minutes, depending on the subset of shapes that was shown to the participants. Manipulating the degree of familiarity toward the shapes by selectively increasing familiarity for the extreme shapes did not influence our results. In general, we show that the prototypical status of a stimulus in visual search is a highly dynamic property, depending on the distribution of stimuli within a shape space but not on familiarity with the prototype. PMID- 21668129 TI - Rocking to the beat: effects of music and partner's movements on spontaneous interpersonal coordination. AB - People move to music and coordinate their movements with others spontaneously. Does music enhance spontaneous coordination? We compared the influence of visual information (seeing or not seeing another person) and auditory information (hearing movement or music or hearing no sound) on spontaneous coordination. Pairs of participants were seated side by side in rocking chairs, told a cover story, and asked to rock at a comfortable rate. Both seeing and hearing the other person rock elicited spontaneous coordination, and effects of hearing amplified those of seeing. Coupling with the music was weaker than with the partner, and the music competed with the partner's influence, reducing coordination. Music did, however, function as a kind of social glue: participants who synchronized more with the music felt more connected. PMID- 21668130 TI - Choice by value encoding and value construction: processes of loss aversion. AB - Loss aversion and reference dependence are 2 keystones of behavioral theories of choice, but little is known about their underlying cognitive processes. We suggest an additional account for loss aversion that supplements the current account of the value encoding of attributes as gains or losses relative to a reference point, introducing a value construction account. Value construction suggests that loss aversion results from biased evaluations during information search and comparison processes. We develop hypotheses that identify the influence of both accounts and examine process-tracing data for evidence. Our data suggest that loss aversion is the result of the initial direct encoding of losses that leads to the subsequent process of directional comparisons distorting attribute valuations and the final choice. PMID- 21668131 TI - Proposal of a two-qutrit contextuality test free of the finite precision and compatibility loopholes. AB - It has been argued that any test of quantum contextuality is nullified by the fact that perfect orthogonality and perfect compatibility cannot be achieved in finite precision experiments. We introduce experimentally testable two-qutrit violations of inequalities for noncontextual theories in which compatibility is guaranteed by the fact that measurements are performed on separated qutrits. The inequalities are inspired by the basic building block of the Kochen-Specker proof of quantum contextuality for a qutrit, despite the fact that their proof is completely independent of it. PMID- 21668132 TI - Optimal control technique for many-body quantum dynamics. AB - We present an efficient strategy for controlling a vast range of nonintegrable quantum many-body one-dimensional systems that can be merged with state-of-the art tensor network simulation methods such as the density matrix renormalization group. To demonstrate its potential, we employ it to solve a major issue in current optical-lattice physics with ultracold atoms: we show how to reduce by about 2 orders of magnitude the time needed to bring a superfluid gas into a Mott insulator state, while suppressing defects by more than 1 order of magnitude as compared to current experiments [T. Stoferle et al., Phys. Rev. Lett. 92, 130403 (2004)]. Finally, we show that the optimal pulse is robust against atom number fluctuations. PMID- 21668133 TI - Taming multiparticle entanglement. AB - We present an approach to characterize genuine multiparticle entanglement by using appropriate approximations in the space of quantum states. This leads to a criterion for entanglement which can easily be calculated by using semidefinite programing and improves all existing approaches significantly. Experimentally, it can also be evaluated when only some observables are measured. Furthermore, it results in a computable entanglement monotone for genuine multiparticle entanglement. Based on this, we develop an analytical approach for the entanglement detection in cluster states, leading to an exponential improvement compared with existing schemes. PMID- 21668134 TI - Stochastic matching problem. AB - The matching problem plays a basic role in combinatorial optimization and in statistical mechanics. In its stochastic variants, optimization decisions have to be taken given only some probabilistic information about the instance. While the deterministic case can be solved in polynomial time, stochastic variants are worst-case intractable. We propose an efficient method to solve stochastic matching problems which combines some features of the survey propagation equations and of the cavity method. We test it on random bipartite graphs, for which we analyze the phase diagram and compare the results with exact bounds. Our approach is shown numerically to be effective on the full range of parameters, and to outperform state-of-the-art methods. Finally we discuss how the method can be generalized to other problems of optimization under uncertainty. PMID- 21668135 TI - Nanohertz gravitational wave searches with interferometric pulsar timing experiments. AB - We estimate the sensitivity to nano-Hertz gravitational waves of pulsar timing experiments in which two highly stable millisecond pulsars are tracked simultaneously with two neighboring radio telescopes that are referenced to the same timekeeping subsystem (i.e., "the clock"). By taking the difference of the two time-of-arrival residual data streams we can exactly cancel the clock noise in the combined data set, thereby enhancing the sensitivity to gravitational waves. We estimate that, in the band (10(-9)-10(-8)) Hz, this "interferometric" pulsar timing technique can potentially improve the sensitivity to gravitational radiation by almost 2 orders of magnitude over that of single-telescopes. Interferometric pulsar timing experiments could be performed with neighboring pairs of antennas of the NASA's Deep Space Network and the forthcoming large arraying projects. PMID- 21668136 TI - Cosmological classicalization: maintaining unitarity under relevant deformations of the Einstein-Hilbert action. AB - Generic relevant deformations of Einstein's gravity theory contain additional degrees of freedom that have a multifaceted stabilization dynamics on curved spacetimes. We show that these relevant degrees of freedom are self-protected against unitarity violations by the formation of classical field lumps that eventually merge to a new background geometry. The transition is heralded by the massive decay of the original vacuum and evolves through a strong coupling regime. This process fits in the recently proposed classicalization mechanism and extends it further to free field dynamics on curved backgrounds. PMID- 21668137 TI - Sausage and kink oscillations in astrophysical disk configurations. AB - The development of hydrodynamic oscillations in various rotating astrophysical disks ranging from planetary rings to galaxies is studied analytically. The dispersion relation of wave propagation is derived. Modes of oscillation are examined from this dispersion relation that are suitable for obtaining information not just on oscillations but also on some instability properties of the disk-shaped structure. It is shown that unstable oscillations of different types, sausage compression and kink bending, may be excited effectively due to the Jeans gravitational instability and the kink transverse instability, respectively. The obtained results for the sausage oscillations may be applicable for such phenomena as the appearance of the in-plane spiral and circular structures, while the case for the kink mode is more relevant for the systematic vertical corrugations of astrophysical disks. PMID- 21668138 TI - Magnetic helicity conservation and inverse energy cascade in electron magnetohydrodynamic wave packets. AB - Electron magnetohydrodynamics (EMHD) provides a fluidlike description of small scale magnetized plasmas. An EMHD wave propagates along magnetic field lines. The direction of propagation can be either parallel or antiparallel to the magnetic field lines. We numerically study propagation of three-dimensional (3D) EMHD wave packets moving in one direction. We obtain two major results. (1) Unlike its magnetohydrodynamic (MHD) counterpart, an EMHD wave packet is dispersive. Because of this, EMHD wave packets traveling in one direction create opposite-traveling wave packets via self-interaction and cascade energy to smaller scales. (2) EMHD wave packets traveling in one direction clearly exhibit inverse energy cascade. We find that the latter is due to conservation of magnetic helicity. We compare inverse energy cascade in 3D EMHD turbulence and two-dimensional (2D) hydrodynamic turbulence. PMID- 21668139 TI - Signature of local motion in the microwave sky. AB - For observers moving with respect to the cosmic rest frame, the microwave background temperature fluctuations will no longer be statistically isotropic. Aside from the familiar temperature dipole, an observer's velocity will also induce changes in the temperature angular correlation function and create nonzero off-diagonal correlations between multipole moments. We show that both of these effects should be detectable in future full-sky maps from the Planck satellite, and can constrain modifications of the standard cosmological model proposed to explain anomalous current observations. PMID- 21668140 TI - Identifying the inflaton with primordial gravitational waves. AB - We explore the ability of experimental physics to uncover the underlying structure of the gravitational Lagrangian describing inflation. While the observable degeneracy of the inflationary parameter space is large, future measurements of observables beyond the adiabatic and tensor two-point functions, such as non-gaussianity or isocurvature modes, might reduce this degeneracy. We show that, even in the absence of such observables, the range of possible inflaton potentials can be reduced with a precision measurement of the tensor spectral index, as might be possible with a direct detection of primordial gravitational waves. PMID- 21668141 TI - Thermalization of strongly coupled field theories. AB - Using the holographic mapping to a gravity dual, we calculate 2-point functions, Wilson loops, and entanglement entropy in strongly coupled field theories in d=2, 3, and 4 to probe the scale dependence of thermalization following a sudden injection of energy. For homogeneous initial conditions, the entanglement entropy thermalizes slowest and sets a time scale for equilibration that saturates a causality bound. The growth rate of entanglement entropy density is nearly volume independent for small volumes but slows for larger volumes. In this setting, the UV thermalizes first. PMID- 21668143 TI - Three extra mirror or sequential families: case for a heavy Higgs boson and inert doublet. AB - We study the possibility of the existence of extra fermion families and an extra Higgs doublet. We find that requiring the extra Higgs doublet to be inert leaves space for three extra families, allowing for mirror fermion families and a dark matter candidate at the same time. The emerging scenario is very predictive: It consists of a standard model Higgs boson, with a mass above 400 GeV, heavy new quarks between 340 and 500 GeV, light extra neutral leptons, and an inert scalar with a mass below M(Z). PMID- 21668144 TI - Production of the exotic 1(--) hadrons phi(2170), X(4260), and Y(b)(10890) at the LHC and Tevatron via the Drell-Yan mechanism. AB - We calculate the Drell-Yan production cross sections and differential distributions in the transverse momentum and rapidity of the J(PC) = 1(--) exotic hadrons phi(2170), X(4260), and Y(b)(10890) at the LHC and the Tevatron. These hadrons are tetraquark (four-quark) candidates, with a hidden ss, cc, and bb quark pair, respectively. In deriving the distributions, we include the order alpha(s) QCD corrections, resum the large logarithms in the small transverse momentum region in the impact-parameter formalism, and use the state of the art parton distribution functions. Production rates for the processes pp(p) -> phi(2170)* (-> phi(1020)pi+ pi- -> K+ K- pi+ pi-) +..., pp(p) -> X(4260)( >J/psipi+ pi- -> MU+ MU- pi+ pi-)+..., and pp(p) -> Y(b)(10890)(-> Upsilon(1S,2S,3S)pi+ pi- -> MU+ MU- pi+ pi-) +... are presented. Their measurements will help in understanding the dynamics of these exotic hadrons. PMID- 21668146 TI - Ab initio calculation of the Hoyle state. AB - The Hoyle state plays a crucial role in the helium burning of stars heavier than our Sun and in the production of carbon and other elements necessary for life. This excited state of the carbon-12 nucleus was postulated by Hoyle as a necessary ingredient for the fusion of three alpha particles to produce carbon at stellar temperatures. Although the Hoyle state was seen experimentally more than a half century ago nuclear theorists have not yet uncovered the nature of this state from first principles. In this Letter we report the first ab initio calculation of the low-lying states of carbon-12 using supercomputer lattice simulations and a theoretical framework known as effective field theory. In addition to the ground state and excited spin-2 state, we find a resonance at 85(3) MeV with all of the properties of the Hoyle state and in agreement with the experimentally observed energy. PMID- 21668145 TI - 200 A GeV Au + Au collisions serve a nearly perfect quark-gluon liquid. AB - A new robust method to extract the specific shear viscosity (eta/s)(QGP) of a quark-gluon plasma (QGP) at temperatures T(c) < T ? 2T(c) from the centrality dependence of the eccentricity-scaled elliptic flow v2/epsilon measured in ultrarelativistic heavy-ion collisions is presented. Coupling viscous fluid dynamics for the QGP with a microscopic transport model for hadronic freeze-out we find for 200 A GeV Au + Au collisions that v2/epsilon is a universal function of multiplicity density (1/S)(dN(ch)/dy) that depends only on the viscosity but not on the model used for computing the initial fireball eccentricity epsilon. Comparing with measurements we find 1<4pi(eta/s)(QGP) < 2.5 where the uncertainty range is dominated by model uncertainties for the values of epsilon used to normalize the measured v2. PMID- 21668147 TI - Microwave guiding of electrons on a chip. AB - We demonstrate the transverse confinement and guiding of a low energy electron beam of several electron volts in a miniaturized linear quadrupole guide. The guiding potential is generated by applying a microwave voltage to electrodes fabricated on a planar substrate, which allows the potential landscape to be precisely shaped on a microscopic scale. We realize transverse trapping frequencies of 100 MHz and guide electrons along a circular section of 37 mm length. A detailed characterization of the guiding properties in terms of potential depth and dynamic stability is given. This new technique of electron guiding promises various applications in guided matter-wave experiments such as electron interferometry. PMID- 21668148 TI - Partitioning of the linear photon momentum in multiphoton ionization. AB - The balance of the linear photon momentum in multiphoton ionization is studied experimentally. In the experiment argon and neon atoms are singly ionized by circularly polarized laser pulses with a wavelength of 800 and 1400 nm in the intensity range of 10(14)-10(15) W/cm2. The photoelectrons are measured using velocity map imaging. We find that the photoelectrons carry linear momentum corresponding to the photons absorbed above the field free ionization threshold. Our finding has implications for concurrent models of the generation of terahertz radiation in filaments. PMID- 21668149 TI - Magnetoelectric directional nonreciprocity in gas-phase molecular nitrogen. AB - We report the direct observation of the nonreciprocity of the velocity of light, induced by electric and magnetic fields. This bilinear magneto-electro-optical effect appears in crossed electric and magnetic fields perpendicular to the light wave vector, as a refractive index difference between two counterpropagating directions. Using a high finesse ring cavity, we have measured this magnetoelectric nonreciprocity in molecular nitrogen at ambient temperature and atmospheric pressure; for light polarized parallel to the magnetic field it is 2eta(?exp)(N2) = (4.7+/-1)*10(-23) m V(-1) T(-1) for lambda = 1064 nm, in agreement with the expected order of magnitude. Our measurement opens the way to a deeper insight into light-matter interaction beyond the electric dipole approximation. We were able to measure a nonreciprocity as small as Deltan =(5+/ 2)*10(-18), which makes its observation in quantum vacuum a conceivable challenge. PMID- 21668150 TI - Spectral tuning by selective enhancement of electric and magnetic dipole emission. AB - We demonstrate that magnetic dipole transitions provide an additional degree of freedom for engineering emission spectra. Without the need for a high-quality optical cavity, we show how a simple gold mirror can strongly tune the emission of trivalent europium. We exploit the differing field symmetries of electric and magnetic dipoles to selectively direct the majority of emission through each of three major transitions (centered at 590, 620, and 700 nm), and present a model that accurately predicts this tuning from the local electric and magnetic density of optical states. PMID- 21668151 TI - Collisional 3He and 129Xe frequency shifts in Rb-noble-gas mixtures. AB - The Fermi-contact interaction that characterizes collisional spin exchange of a noble gas with an alkali-metal vapor also gives rise to NMR and EPR frequency shifts of the noble-gas nucleus and the alkali-metal atom, respectively. We have measured the enhancement factor kappa0 that characterizes these shifts for Rb 129Xe to be 493+/-31, making use of the previously measured value of kappa0 for Rb-3He. This result allows accurate 129Xe polarimetry with no need to reference a thermal-equilibrium NMR signal. PMID- 21668152 TI - Low-light-level cross-phase modulation with double slow light pulses. AB - We report on the first experimental demonstration of low-light-level cross-phase modulation (XPM) with double slow light pulses based on the double electromagnetically induced transparency (EIT) in cold cesium atoms. The double EIT is implemented with two control fields and two weak fields that drive populations prepared in the two doubly spin-polarized states. Group velocity matching can be obtained by tuning the intensity of either of the control fields. The XPM is based on the asymmetric M-type five-level system formed by the two sets of EIT. Enhancement in the XPM by group velocity matching is observed. Our work advances studies of low-light-level nonlinear optics based on double slow light pulses. PMID- 21668153 TI - Nuclear structure corrections in muonic deuterium. AB - The muonic hydrogen experiment measuring the 2P-2S transition energy [R. Pohl et al., Nature (London) 466, 213 (2010)] is significantly discrepant with theoretical predictions based on quantum electrodynamics. A possible approach to resolve this conundrum is to compare experimental values with theoretical predictions in another system, muonic deuterium MUD. The only correction which might be questioned in MUD is that due to the deuteron polarizability. We investigate this effect in detail and observe cancellation with the elastic contribution. The total value obtained for the deuteron structure correction in the 2P-2S transition is 1.680(16) meV. PMID- 21668154 TI - Controlling the XUV transparency of helium using two-pathway quantum interference. AB - Atoms irradiated with combined femtosecond laser and extreme ultraviolet (XUV) fields ionize through multiphoton processes, even when the energy of the XUV photon is below the ionization potential. However, in the presence of two different XUV photons and an intense laser field, it is possible to induce full electromagnetic transparency. Taking helium as an example, the laser field modifies its electronic structure, while the presence of two different XUV photons and the laser field leads to two distinct ionization pathways that can interfere destructively. This work demonstrates a new approach for coherent control in a regime of highly excited states and strong optical fields. PMID- 21668156 TI - Large effects of electric fields on atom-molecule collisions at millikelvin temperatures. AB - Controlling interactions between cold molecules using external fields can elucidate the role of quantum mechanics in molecular collisions. We create a new experimental platform in which ultracold rubidium atoms and cold ammonia molecules are separately trapped by magnetic and electric fields and then combined to study collisions. We observe inelastic processes that are faster than expected from earlier field-free calculations. We use quantum scattering calculations to show that electric fields can have a major effect on collision outcomes, even in the absence of dipole-dipole interactions. PMID- 21668155 TI - Experimental observation of rotational Doppler broadening in a molecular system. AB - The first experimental evidence of rotational Doppler broadening in photoelectron spectra, reported here, show good agreement with recently described theoretical predictions. The dependence of the broadening on temperature and photoelectron kinetic energy is quantitatively predicted by the theory. The experiments verify that the rotational contributions to the linewidth are comparable to those from translational Doppler broadening and must be considered in the analysis of high resolution photoelectron spectra. A classical model accounting for this newly observed effect is presented. PMID- 21668157 TI - Strong optical confinement between nonperiodic flat dielectric gratings. AB - We present a novel design of optical microcavity where the optical energy resides primarily in free space and therefore is readily accessible to foreign objects such as atoms, molecules, mechanical resonators, etc. We describe the physics of these resonators and propose a design method based on stochastic optimization. Cavity designs with diffraction-limited mode volumes and quality factors in the range of 10(4)-10(6) are presented. With a purely planar geometry, the cavity can be easily integrated on-chip by using conventional micro- and nanofabrication processes. PMID- 21668158 TI - Time reversal in dynamically tuned zero-gap periodic systems. AB - We show that short pulses propagating in zero-gap periodic systems can be reversed with 100% efficiency by using weak nonadiabatic tuning of the wave velocity at time scales that can be much slower than the period. Unlike previous schemes, we demonstrate reversal of broadband (few cycle) pulses with simple structures. Our scheme may thus open the way to time reversal in a variety of systems for which it was not accessible before. PMID- 21668159 TI - Realization of reflectionless potentials in photonic lattices. AB - We realize experimentally a true reflectionless potential, which facilitates nonresonant unity transmission for all incident waves and at the same time supports localized modes. We utilize arrays of evanescently coupled optical waveguides, where a particular modulation of the transverse waveguide separations provides a physical realization of reflectionless Ablowitz-Ladik soliton potentials. PMID- 21668142 TI - Search for production of heavy particles decaying to top quarks and invisible particles in pp collisions at ?s = 1.96 TeV. AB - We present a search for a new particle T' decaying to top quark via T' -> t + X, where X is an invisible particle. In a data sample with 4.8 fb(-1) of integrated luminosity collected by the CDF II detector at Fermilab in pp collisions with ?s = 1.96 TeV, we search for pair production of T' in the lepton + jets channel, pp -> tt + X + X -> lnubqq'b + X + X. We interpret our results primarily in terms of a model where T' are exotic fourth generation quarks and X are dark matter particles. Current direct and indirect bounds on such exotic quarks restrict their masses to be between 300 and 600 GeV/c2, the dark matter particle mass being anywhere below m(T'). The data are consistent with standard model expectations, and we set 95% confidence level limits on the generic production of T'T' -> tt + X + X. For the dark matter model we exclude T' at 95% confidence level up to m(T') = 360 GeV/c2 for m(X) <= 100 GeV/c2. PMID- 21668160 TI - Amorphous photonic lattices: band gaps, effective mass, and suppressed transport. AB - We study, experimentally and numerically, amorphous photonic lattices and the existence of band gaps therein. Our amorphous system comprises 2D waveguides distributed randomly according to a liquidlike model responsible for the absence of Bragg peaks, as opposed to ordered lattices with disorder which always exhibit Bragg peaks. In amorphous lattices the bands comprise localized states, but we find that defect states residing in the gap are more localized than the localization length of states within the band. Finally, we show how the concept of effective mass carries over to amorphous photonic lattices. PMID- 21668161 TI - Scattering lens resolves sub-100 nm structures with visible light. AB - The smallest structures that conventional lenses are able to optically resolve are of the order of 200 nm. We introduce a new type of lens that exploits multiple scattering of light to generate a scanning nanosized optical focus. With an experimental realization of this lens in gallium phosphide we imaged gold nanoparticles at 97 nm optical resolution. Our work is the first lens that provides a resolution better than 100 nm at visible wavelengths. PMID- 21668162 TI - Robust convergence in pulse-coupled oscillators with delays. AB - We show that for pulse-coupled oscillators a class of phase response curves with both excitation and inhibition exhibit robust convergence to synchrony on arbitrary aperiodic connected graphs with delays. We describe the basins of convergence and give explicit bounds on the convergence times. These results provide new and more robust methods for synchronization of sensor nets and also have biological implications. PMID- 21668163 TI - Finite-distance singularities in the tearing of thin sheets. AB - We investigate the interaction between two cracks propagating quasistatically in a thin sheet. Two different experimental geometries allow us to tear sheets by imposing an out-of-plane shear loading. A single tear propagates in a straight line independently of its position in the sheet. In contrast, we find that two tears converge along self-similar paths and annihilate each other. These finite distance singularities display geometry-dependent similarity exponents, which we retrieve using scaling arguments based on a balance between the stretching and the bending of the sheet close to the tips of the cracks. PMID- 21668164 TI - Pinning and avalanches in hydrophobic microchannels. AB - Rare events appear in a wide variety of phenomena such as rainfall, floods, earthquakes, and risk. We demonstrate that the stochastic behavior induced by the natural roughening present in standard microchannels is so important that the dynamics for the advancement of a water front displacing air has plenty of rare events. We observe that for low pressure differences the hydrophobic interactions of the water front with the walls of the microchannel put the front close to the pinning point. This causes a burstlike dynamics, characterized by series of pinning and avalanches, that leads to an extreme-value Gumbel distribution for the velocity fluctuations and a nonclassical time exponent for the advancement of the mean front position as low as 0.38. PMID- 21668165 TI - Fluid mixing from viscous fingering. AB - Mixing efficiency at low Reynolds numbers can be enhanced by exploiting hydrodynamic instabilities that induce heterogeneity and disorder in the flow. The unstable displacement of fluids with different viscosities, or viscous fingering, provides a powerful mechanism to increase fluid-fluid interfacial area and enhance mixing. Here we describe the dissipative structure of miscible viscous fingering, and propose a two-equation model for the scalar variance and its dissipation rate. Our analysis predicts the optimum range of viscosity contrasts that, for a given Peclet number, maximizes interfacial area and minimizes mixing time. In the spirit of turbulence modeling, the proposed two equation model permits upscaling dissipation due to fingering at unresolved scales. PMID- 21668166 TI - Fundamental nonambipolarity of electron fluxes in 2D plasmas. AB - It is demonstrated that in two-dimensional plasmas there is in general a vortex component of the electron motion, which means that electron and ion fluxes do not satisfy the ambipolarity condition. PMID- 21668167 TI - Gyrokinetic Fokker-Planck collision operator. AB - The gyrokinetic linearized exact Fokker-Planck collision operator is obtained in a form suitable for plasma gyrokinetic equations, for arbitrary mass ratio. The linearized Fokker-Planck operator includes both the test-particle and field particle contributions, and automatically conserves particles, momentum, and energy, while ensuring non-negative entropy production. Finite gyroradius effects in both field-particle and test-particle terms are evaluated. When implemented in gyrokinetic simulations, these effects can be precomputed. The field-particle operator at each time step requires the evaluation of a single two-dimensional integral, and is not only more accurate, but appears to be less expensive to evaluate than conserving model operators. PMID- 21668168 TI - New measure of the dissipation region in collisionless magnetic reconnection. AB - A new measure to identify a small-scale dissipation region in collisionless magnetic reconnection is proposed. The energy transfer from the electromagnetic field to plasmas in the electron's rest frame is formulated as a Lorentz invariant scalar quantity. The measure is tested by two-dimensional particle-in cell simulations in typical configurations: symmetric and asymmetric reconnection, with and without the guide field. The innermost region surrounding the reconnection site is accurately located in all cases. We further discuss implications for nonideal MHD dissipation. PMID- 21668169 TI - Local and nonlocal parallel heat transport in general magnetic fields. AB - A novel approach for the study of parallel transport in magnetized plasmas is presented. The method avoids numerical pollution issues of grid-based formulations and applies to integrable and chaotic magnetic fields with local or nonlocal parallel closures. In weakly chaotic fields, the method gives the fractal structure of the devil's staircase radial temperature profile. In fully chaotic fields, the temperature exhibits self-similar spatiotemporal evolution with a stretched-exponential scaling function for local closures and an algebraically decaying one for nonlocal closures. It is shown that, for both closures, the effective radial heat transport is incompatible with the quasilinear diffusion model. PMID- 21668170 TI - Velocity and timing of multiple spherically converging shock waves in liquid deuterium. AB - The fuel entropy and required drive energy for an inertial confinement fusion implosion are set by a sequence of shocks that must be precisely timed to achieve ignition. This Letter reports measurements of multiple spherical shock waves in liquid deuterium that facilitate timing inertial confinement fusion shocks to the required precision. These experiments produced the highest shock velocity observed in liquid deuterium (U(s) = 135 km/s at ~2500 GPa) and also the first observation of convergence effects on the shock velocity. Simulations model the shock-timing results well when a nonlocal transport model is used in the coronal plasma. PMID- 21668171 TI - Spin gradient demagnetization cooling of ultracold atoms. AB - We demonstrate a new cooling method in which a time-varying magnetic field gradient is applied to an ultracold spin mixture. This enables preparation of isolated spin distributions at positive and negative effective spin temperatures of +/-50 pK. The spin system can also be used to cool other degrees of freedom, and we have used this coupling to cool an apparently equilibrated Mott insulator of rubidium atoms to 350 pK. These are the lowest temperatures ever measured in any system. The entropy of the spin mixture is in the regime where magnetic ordering is expected. PMID- 21668172 TI - Imbibition of solids in nanopillar arrays. AB - The imbibition of a solid island on a substrate with a square array of pillars is studied by means of kinetic Monte Carlo simulations. Imbibition is found to occur via an intermediate state where an island sits on the film. Two dynamical regimes are identified depending on the geometry of the substrate: a stochastic regime, where the dynamics are controlled by the nucleation-limited motion of the imbibition front across the array of pillars, and a deterministic regime limited by the diffusion of atoms on top of the imbibition film. PMID- 21668173 TI - Faceting and branching in 2D crystal growth. AB - Using atomic scale time-dependent density functional calculations we confirm that both diffusion-controlled and diffusionless crystallization modes exist in simple 2D systems. We provide theoretical evidence that a faceted to nonfaceted transition is coupled to these crystallization modes, and faceting is governed by the local supersaturation at the fluid-crystalline interface. We also show that competing modes of crystallization have a major influence on mesopattern formation. Irregularly branched and porous structures are emerging at the crossover of the crystallization modes. The proposed branching mechanism differs essentially from dendritic fingering driven by diffusive instability. PMID- 21668174 TI - Electrically detected electron-spin-echo envelope modulation: a highly sensitive technique for resolving complex interface structures. AB - We show that the electrical detection of electron-spin-echo envelope modulation (ESEEM) is a highly sensitive tool to study interfaces. Taking the Si/SiO2 interface defects in phosphorus-doped crystalline silicon as an example, we find that the main features of the observed echo modulation pattern allow us to develop a microscopic model for the dangling-bond-like P(b0) center by comparison with the results of ab initio calculations. The ESEEM spectrum is found to be far more sensitive to the defect characteristics than the spectrally resolved hyperfine splitting itself. PMID- 21668175 TI - Epitaxial Pb(Zr,Ti)O3 ultrathin films under open-circuit electrical boundary conditions. AB - The temperature-versus-misfit-strain phase diagram of Pb(Zr,Ti)O3 ultrathin films under open-circuit electrical boundary conditions is simulated via the use of an effective Hamiltonian. Two novel phases, both exhibiting dipolar nanodomains and oxygen octahedral tilting, are discovered. The interplay between dipolar, antiferrodistortive, alloying, and strain degrees of freedom induces several striking features in these two phases, such as the chemical pinning of domain walls, the enhancement of oxygen octahedral tilting near the domain walls, and the existence of dipolar waves and cylindrical dipolar chiral bubbles. PMID- 21668176 TI - Hydrophobic interaction and charge accumulation at the diamond-electrolyte interface. AB - The hydrophobic interaction of surfaces with water is a well-known phenomenon, but experimental evidence of its influence on biosensor devices has been lacking. In this work we investigate diamond field-effect devices, reporting on Hall effect experiments and complementary simulations of the interfacial potential at the hydrogen-terminated diamond/aqueous electrolyte interface. The interfacial capacitance, derived from the gate-dependent Hall carrier concentration, can be modeled only when considering the hydrophobic nature of this surface and its influence on the structure of interfacial water. Our work demonstrates how profoundly the performance of potentiometric biosensor devices can be affected by their surfaces' hydrophobicity. PMID- 21668177 TI - Nonequilibrium quantum dynamics of a charge carrier doped into a Mott insulator. AB - We study real-time dynamics of a charge carrier introduced into an undoped Mott insulator propagating under a constant electric field F on the t-J ladder and a square lattice. We calculate the quasistationary current. In both systems an adiabatic regime is observed followed by a positive differential resistivity (PDR) at moderate fields where the carrier mobility is determined. Quantitative differences between the ladder and two-dimensional (2D) systems emerge when at large fields both systems enter the negative differential resistivity (NDR) regime. In the ladder system Bloch-like oscillations prevail, while in two dimensions the current remains finite, proportional to 1/F. The crossover between the PDR and NDR in two dimensions is accompanied by a change of the spatial structure of the propagating spin polaron. PMID- 21668178 TI - Thermalization of nonequilibrium electrons in quantum wires. AB - We study the problem of energy relaxation in a one-dimensional electron system. The leading thermalization mechanism is due to three-particle collisions. We show that for the case of spinless electrons in a single channel quantum wire the corresponding collision integral can be transformed into an exactly solvable problem. The latter is known as the Schrodinger equation for a quantum particle moving in a Poschl-Teller potential. The spectrum for the resulting eigenvalue problem allows for bound-state solutions, which can be identified with the zero modes of the collision integral, and a continuum of propagating modes, which are separated by a gap from the bound states. The inverse gap gives the time scale at which counterpropagating electrons thermalize. PMID- 21668179 TI - Impact of valley polarization on the resistivity in two dimensions. AB - We examine the temperature dependence of resistivity in a two-dimensional electron system formed in a silicon-on-insulator quantum well. The device allows us to tune the valley splitting continuously in addition to the electron density. Our data provide a global picture of how the resistivity and its temperature dependence change with valley polarization. At the boundary between valley polarized and partially polarized regions, we demonstrate that there is an insulating contribution from spin-degenerate electrons occupying the upper valley subband edge. PMID- 21668180 TI - Metallic behavior of cyclotron relaxation time in two-dimensional systems. AB - Cyclotron resonance of two-dimensional electrons is studied at low temperatures down to 0.4 K for a high-mobility Si/SiGe quantum well which exhibits a metallic temperature dependence of dc resistivity rho. The relaxation time tau(CR) shows a negative temperature dependence, which is similar to that of the transport scattering time tau(t) obtained from rho. The ratio tau(CR)/tau(t) at 0.4 K increases as the electron density N(s) decreases, and exceeds unity when N(s) approaches the critical density for the metal-insulator transition. PMID- 21668181 TI - Reversible switching of ultrastrong light-molecule coupling. AB - We demonstrate that photochromic molecules enable switching from the weak- to ultrastrong-coupling regime reversibly, by using all-optical control. This switch is achieved by photochemically inducing conformational changes in the molecule. Remarkably, a Rabi splitting of 700 meV is measured at room temperature, corresponding to 32% of the molecular transition energy. A similar coupling strength is demonstrated in a plasmonic structure. Such systems present a unique combination of coupling strength and functional capacities. PMID- 21668182 TI - Charge-density wave and superconducting dome in TiSe2 from electron-phonon interaction. AB - At low temperature TiSe2 undergoes a charge-density wave instability. Superconductivity is stabilized either by pressure or by Cu intercalation. We show that the pressure phase diagram of TiSe2 is well described by first principles calculations. At pressures smaller than 4 GPa charge-density wave ordering occurs, in agreement with experiments. At larger pressures the disappearing of the charge-density wave is due to a stiffening of the short-range force constants and not to the variation of nesting with pressure. Finally, we show that the behavior of T(c) as a function of pressure is entirely determined by the electron-phonon interaction without need of invoking excitonic mechanisms. Our work demonstrates that phase diagrams with competing orders and a superconducting dome are also obtained in the framework of the electron-phonon interaction. PMID- 21668183 TI - Spin nematic state as a candidate of the hidden order phase of URu2Si2. AB - Motivated by the recent discovery of broken fourfold symmetry in the hidden order phase of URu2Si2 [R. Okazaki et al., Science 331, 439 (2011)], we examine a scenario of a spin nematic state as a possible candidate of the hidden order phase. We demonstrate that the scenario naturally explains most of experimental observations, and furthermore, reproduces successfully the temperature dependence of the spin anisotropy detected by the above-mentioned experiment in a semiquantitative way. This result provides strong evidence for the realization of the spin nematic order. PMID- 21668184 TI - Resonant tunneling through electronic trapping states in thin MgO magnetic junctions. AB - We report an inelastic electron tunneling spectroscopy study on MgO magnetic junctions with thin barriers (0.85-1.35 nm). Inelastic electron tunneling spectroscopy reveals resonant electronic trapping within the barrier for voltages V>0.15 V. These trapping features are associated with defects in the barrier crystalline structure, as confirmed by high-resolution transmission electron microscopy. Such defects are responsible for resonant tunneling due to energy levels that are formed in the barrier. A model was applied to determine the average location and energy level of the traps, indicating that they are mostly located in the middle of the MgO barrier, in accordance with the high-resolution transmission electron microscopy data and trap-assisted tunneling conductance theory. Evidence of the influence of trapping on the voltage dependence of tunnel magnetoresistance is shown. PMID- 21668185 TI - Bulk band gap and surface state conduction observed in voltage-tuned crystals of the topological insulator Bi2Se3. AB - We report a transport study of exfoliated few monolayer crystals of topological insulator Bi2Se3 in an electric field effect geometry. By doping the bulk crystals with Ca, we are able to fabricate devices with sufficiently low bulk carrier density to change the sign of the Hall density with the gate voltage V(g). We find that the temperature T and magnetic field dependent transport properties in the vicinity of this V(g) can be explained by a bulk channel with activation gap of approximately 50 meV and a relatively high-mobility metallic channel that dominates at low T. The conductance (approximately 2*7e2/h), weak antilocalization, and metallic resistance-temperature profile of the latter lead us to identify it with the protected surface state. The relative smallness of the observed gap implies limitations for electric field effect topological insulator devices at room temperature. PMID- 21668186 TI - Spin-spin interactions in organic magnetoresistance probed by angle-dependent measurements. AB - The dependence of organic magnetoresistance (OMAR) on the orientation of the magnetic field has been investigated. In contrast with previous claims, a finite and systematic change in magnitude is observed when the orientation of the field is changed with respect to the sample. It is demonstrated that, to explain these effects, spin-spin interactions have to be included in the models previously suggested for OMAR. Dipole coupling and exchange coupling are introduced in combination with either an anisotropy of the orientation of the spin pairs or an anisotropy in the hyperfine fields. PMID- 21668187 TI - Internal electron diffraction from atomically ordered subsurface nanostructures in metals. AB - We demonstrate that a part of interface at a subsurface nanocavity in Cu(110) can efficiently induce electron scattering back to the surface even if it is inclined with respect to the surface, if the condition for electron diffraction is fulfilled. This backscattering induces oscillations of electron local density of states at the surface versus electron energy. In agreement with our model calculations, the diffraction is assigned to a specific atomic structure at the interface, and is found to be significantly enhanced by focussing of electron waves for propagation along the [110] direction. PMID- 21668188 TI - Conductance and vibrational states of single-molecule junctions controlled by mechanical stretching and material variation. AB - The changes of molecular conformation, contact geometry, and metal-molecule bonding are revealed by inelastic-electron-tunneling spectroscopy measurements characterizing the molecular vibrational modes and the metal-phonon modes in alkanedithiol molecular junctions at low temperature. Combining inelastic electron-tunneling spectroscopy with mechanical control and electrode material variation (Au or Pt) enables separating the influence of contact geometry and of molecular conformation. The mechanical strain of different electrode materials can be imposed onto the molecule, opening a new route for controlling the charge transport through individual molecules. PMID- 21668189 TI - Rapid collapse of spin waves in nonuniform phases of the second Landau level. AB - The spin degree of freedom in quantum phases of the second Landau level is probed by resonant light scattering. The long wavelength spin wave, which monitors the degree of spin polarization, is at the Zeeman energy in the fully spin-polarized state at nu = 3. At lower filling factors, the intensity of the Zeeman mode collapses, indicating loss of polarization. A novel continuum of low-lying excitations emerges that dominates near nu = 8/3 and nu = 5/2. Resonant Rayleigh scattering reveals that quantum fluids for nu < 3 break up into robust domain structures. While the state at nu = 5/2 is considered to be fully polarized, these results reveal unprecedented roles for spin degrees of freedom. PMID- 21668190 TI - Electrostatic conveyer for excitons. AB - We report on the study of indirect excitons in moving lattices-conveyers created by a set of ac voltages applied to the electrodes on the sample surface. The wavelength of this moving lattice is set by the electrode periodicity, the amplitude is controlled by the applied voltage, and the velocity is controlled by the ac frequency. We found the dynamical localization-delocalization transition for excitons in the conveyers and determined its dependence on exciton density and conveyer amplitude and velocity. PMID- 21668191 TI - 77Se NMR study of the pairing symmetry and the spin dynamics in K(y)Fe(2-x)Se2. AB - We present a 77Se NMR study of the newly discovered iron selenide superconductor K(y)Fe(2-x)Se2, in which T(c) = 32 K. Below T(c), the Knight shift 77K drops sharply with temperature, providing strong evidence for singlet pairing. Above T(c), Korringa-type relaxation indicates Fermi-liquid behavior. Our experimental results set strict constraints on the nature of possible theories for the mechanism of high-T(c) superconductivity in this iron selenide system. PMID- 21668192 TI - Two-Fermi-surface superconducting state and a nodal d-wave energy gap of the electron-doped Sm1.85Ce0.15CuO(4-delta) cuprate superconductor. AB - We report on laser-excited angle-resolved photoemission spectroscopy in the electron-doped cuprate Sm1.85Ce0.15CuO(4-delta). The data show the existence of a nodal hole-pocket Fermi surface both in the normal and superconducting states. We prove that its origin is long-range antiferromagnetism by an analysis of the coherence factors in the main and folded bands. This coexistence of long-range antiferrmagnetism and superconductivity implies that electron-doped cuprates are two-Fermi-surface superconductors. The measured superconducting gap in the nodal hole pocket is compatible with a d-wave symmetry. PMID- 21668193 TI - Fermi-edge singularity in the vicinity of the resonant scattering condition. AB - Fermi-edge absorption theory predicting the spectrum A(omega) ? omega( 2delta(0)/pi+delta(0)92)/pi2) relies on the assumption that scattering phase delta(0) is frequency independent. The dependence of delta(0) on omega becomes crucial near the resonant condition, where the phase changes abruptly by pi. In this limit, because of the finite time spent by electron on a resonant level, the scattering is dynamic. We incorporate the finite time delay into the theory, solve the Dyson equation with a modified kernel, and find that, near the resonance, A(omega) behaves as omega(-3/4)|lnomega|. Scattering off the core hole becomes resonant in 1D and 2D in the presence of an empty subband above the Fermi level; then a deep hole splits off a level from the bottom of this subband. Fermi edge absorption in the regime when resonant level transforms into a Kondo peak is discussed. PMID- 21668194 TI - Unveiling the nature of three-dimensional orbital ordering transitions: the case of e(g) and t(2g) models on the cubic lattice. AB - We perform large scale finite-temperature Monte Carlo simulations of the classical e(g) and t(2g) orbital models on the simple cubic lattice in three dimensions. The e(g) model displays a continuous phase transition to an orbitally ordered phase. While the correlation length exponent nu ~ 0.66(1) is close to the 3D XY value, the exponent eta ~ 0.15(1) differs substantially from O(N) values. At T(c) a U(1) symmetry emerges, which persists for T < T(c) below a crossover length scaling as Lambda ~ xi(a), with an unusually small a ~ 1.3. Finally, for the t(2g) model we find a first order transition into a low-temperature lattice nematic phase without orbital order. PMID- 21668195 TI - Theoretical prediction of a rotating magnon wave packet in ferromagnets. AB - We theoretically show that the magnon wave packet has a rotational motion in two ways: a self-rotation and a motion along the boundary of the sample (edge current). They are similar to the cyclotron motion of electrons, but unlike electrons the magnons have no charge and the rotation is not due to the Lorentz force. These rotational motions are caused by the Berry phase in momentum space from the magnon band structure. Furthermore, the rotational motion of the magnon gives an additional correction term to the magnon Hall effect. We also discuss the Berry curvature effect in the classical limit of long-wavelength magnetostatic spin waves having macroscopic coherence length. PMID- 21668196 TI - Dynamics of coupled vortices in a pair of ferromagnetic disks. AB - We here experimentally demonstrate that gyration modes of coupled vortices can be resonantly excited primarily by the ac current in a pair of ferromagnetic disks with variable separation. The sole gyration mode clearly splits into higher and lower frequency modes via dipolar interaction, where the main mode splitting is due to a chirality sensitive phase difference in gyrations of the coupled vortices, whereas the magnitude of the splitting is determined by their polarity configuration. These experimental results show that the coupled pair of vortices behaves similar to a diatomic molecule with bonding and antibonding states, implying a possibility for designing the magnonic band structure in a chain or an array of magnetic vortex oscillators. PMID- 21668197 TI - Slow magnetic order-order transition in the spin chain antiferromagnet Ca3Co2O6. AB - Using powder neutron diffraction, we have discovered an unusual magnetic order order transition in the Ising spin chain compound Ca3Co2O6. On lowering the temperature, an antiferromagnetic phase with a propagation vector k=(0.5,-0.5,1) emerges from a higher temperature spin density wave structure with k=(0,0,1.01). This transition occurs over an unprecedented time scale of several hours and is never complete. PMID- 21668198 TI - Charge separation in semicrystalline polymeric semiconductors by photoexcitation: is the mechanism intrinsic or extrinsic? AB - We probe charge photogeneration and subsequent recombination dynamics in neat regioregular poly(3-hexylthiophene) films over six decades in time by means of time-resolved photoluminescence spectroscopy. Exciton dissociation at 10 K occurs extrinsically at interfaces between molecularly ordered and disordered domains. Polaron pairs thus produced recombine by tunneling with distributed rates governed by the distribution of electron-hole radii. Quantum-chemical calculations suggest that hot-exciton dissociation at such interfaces results from a high charge-transfer character. PMID- 21668199 TI - Magnetic-field dependence of the electroluminescence of organic light-emitting diodes: a competition between exciton formation and spin mixing. AB - We explore the magnetoelectroluminescence (MEL) of organic light-emitting diodes by evaluating the magnetic-field dependent fraction of singlet excitons formed. We use two- and multisite polaron-hopping models with spin mixing by hyperfine fields and different singlet and triplet exciton formation rates k(S) and k(T). A huge MEL is predicted when exciton formation is in competition with spin mixing and when k(T) is significantly larger than k(S). This competition also leads to a low-field structure in the MEL that is in agreement with recent experiments. PMID- 21668200 TI - Plasmon response of a quantum-confined electron gas probed by core-level photoemission. AB - We demonstrate the existence of quantized "bulk" plasmons in ultrathin magnesium films on Si(111) by analyzing plasmon-loss satellites in core-level photoemission spectra, recorded as a function of the film thickness d. Remarkably, the plasmon energy is shown to vary as 1/d2 all the way down to three atomic layers. The loss spectra are dominated by the n=1 and n=2 normal modes, consistent with the excitation of plasmons involving quantized electronic subbands. With decreasing film thickness, spectral weight is gradually transferred from the plasmon modes to the low-energy single-particle excitations. These results represent striking manifestations of the role of quantum confinement on plasmon resonances in precisely controlled nanostructures. PMID- 21668201 TI - Checkerboard self-patterning of an ionic liquid film on mercury. AB - A-resolution studies of room temperature ionic liquid (RTIL) interfaces are scarce, in spite of their long-recognized importance for the science and many applications of RTILs. We present an A-resolution x-ray study of a Langmuir film of an RTIL on mercury. At low (high) coverage [90 (50) A2/molecule] a mono (bi)layer of surface-parallel molecules is found. The molecules self-assemble in a lateral ionic checkerboard pattern, unlike the uniform-charge, alternate-ion layers of this RTIL at its bulk-solid interface. A 2D-smectic order is found, with molecules packed in parallel stripes, forming long-range order normal to, but none along, the stripes. PMID- 21668202 TI - Experimental evidence of a Rayleigh-plateau instability in free falling granular jets. AB - A granular jet falling out of a funnel shaped container, subjected to small vertical vibrations, develops an instability farther downstream as may happen for ordinary liquid jets. Our results show that this instability is reminiscent of the Rayleigh-Plateau capillary instability leading to breakup of the jet at large scales. The first stages of this instability are captured in detail allowing a determination of the dispersion relation. Surface tensions measured in this unstable regime (of the order of mN/m) are in agreement with previously reported measurements carried out at much smaller scales. This instability and the breakup of the jet can be inhibited when the effect of the surrounding medium (air) is reduced by enclosing the jet in an evacuated chamber, showing that the effective surface tension measured is the result of a strong interaction with the surrounding air. PMID- 21668203 TI - Noninvasive protein structural flexibility mapping by bimodal dynamic force microscopy. AB - Mapping of the protein structural flexibility with sub-2-nm spatial resolution in liquid is achieved by combining bimodal excitation and frequency modulation force microscopy. The excitation of two cantilever eigenmodes in dynamic force microscopy enables the separation between topography and flexibility mapping. We have measured variations of the elastic modulus in a single antibody pentamer from 8 to 18 MPa when the probe is moved from the end of the protein arm to the central protrusion. Bimodal dynamic force microscopy enables us to perform the measurements under very small repulsive loads (30-40 pN). PMID- 21668204 TI - Hidden randomness between fitness landscapes limits reverse evolution. AB - In biological evolution, adaptations to one environment can in some cases reverse adaptations to another environment. To study this "reverse evolution" on a genotypic level, we measured the fitness of E. coli strains with each possible combination of five mutations in an antibiotic-resistance gene in two distinct antibiotic environments. While adaptations to one environment generally lower fitness in the other, we find that reverse evolution is rarely possible and falls as the complexity of adaptations increases, suggesting a probabilistic, molecular form of Dollo's law. PMID- 21668205 TI - Tears of venom: hydrodynamics of reptilian envenomation. AB - In the majority of venomous snakes, and in many other reptiles, venom is conveyed from the animal's gland to the prey's tissue through an open groove on the surface of the teeth and not through a tubular fang. Here we focus on two key aspects of the grooved delivery system: the hydrodynamics of venom as it interacts with the groove geometry, and the efficiency of the tooth-groove-venom complex as the tooth penetrates the prey's tissue. We show that the surface tension of the venom is the driving force underlying the envenomation dynamics. In so doing, we explain not only the efficacy of the open groove, but also the prevalence of this mechanism among reptiles. PMID- 21668206 TI - Reduced transport of swimming particles in chaotic flow due to hydrodynamic trapping. AB - We computationally study the transport of active, self-propelled particles suspended in a two-dimensional chaotic flow. The pointlike, spherical particles have their own intrinsic swimming velocity, which modifies the dynamical system so that the particles can break the transport barriers present in the carrier flow. Surprisingly, we find that swimming does not necessarily lead to enhanced particle transport. Small but finite swimming speed can result in reduced transport, as swimmers get stuck for long times in traps that form near elliptic islands in the background flow. Our results have implications for models of transport and encounter rates for small marine organisms. PMID- 21668207 TI - H = xp model revisited and the Riemann zeros. AB - Berry and Keating conjectured that the classical Hamiltonian H = xp is related to the Riemann zeros. A regularization of this model yields semiclassical energies that behave, on average, as the nontrivial zeros of the Riemann zeta function. However, the classical trajectories are not closed, rendering the model incomplete. In this Letter, we show that the Hamiltonian H = x(p + l(p)2/p) contains closed periodic orbits, and that its spectrum coincides with the average Riemann zeros. This result is generalized to Dirichlet L functions using different self-adjoint extensions of H. We discuss the relation of our work to Polya's fake zeta function and suggest an experimental realization in terms of the Landau model. PMID- 21668208 TI - Detecting quantum states with a positive Wigner function beyond mixtures of Gaussian states. AB - We propose a criterion giving a sufficient condition for quantum states of a harmonic oscillator not to be expressible as a convex mixture of Gaussian states. This nontrivial property is inherent to, e.g., a single-photon state and the criterion thus allows one to reveal a signature of the state even in quantum states with a positive Wigner function. The criterion relies on directly measurable photon number probabilities and enables detection of this manifestation of a single-photon state in quantum states produced by solid-state single-photon sources in a weak coupling regime. PMID- 21668209 TI - Hardy's paradox and violation of a state-independent Bell inequality in time. AB - Tests such as Bell's inequality and Hardy's paradox show that joint probabilities and correlations between distant particles in quantum mechanics are inconsistent with local realistic theories. Here we experimentally demonstrate these concepts in the time domain, using a photonic entangling gate to perform nondestructive measurements on a single photon at different times. We show that Hardy's paradox is much stronger in time and demonstrate the violation of a temporal Bell inequality independent of the quantum state, including for fully mixed states. PMID- 21668210 TI - Reappraisal of the electric dipole moment enhancement factor for thallium. AB - The electric dipole moment (EDM) enhancement factor of atomic Tl is of considerable interest as it has been used in determining the most accurate limit on the electron EDM to date. However, its value varies from -179 to -1041 in different approximations. In view of the large uncertainties associated with many of these calculations, we perform an accurate calculation employing the relativistic coupled-cluster theory and obtain -466, which in combination with the most accurate measurement of Tl EDM [Phys. Rev. Lett. 88, 071805 (2002)] yields a new limit for the electron EDM: |d(e)| < 2.0 * 10-27e cm. PMID- 21668211 TI - Slow quench dynamics of a one-dimensional Bose gas confined to an optical lattice. AB - We analyze the effect of a linear time variation of the interaction strength on a trapped one-dimensional Bose gas confined to an optical lattice. The evolution of different observables such as the experimentally accessible on site particle distribution are studied as a function of the ramp time by using time-dependent numerical techniques. We find that the dynamics of a trapped system typically displays two regimes: For long ramp times, the dynamics is governed by density redistribution, while at short ramp times, local dynamics dominates as the evolution is identical to that of an homogeneous system. In the homogeneous limit, we also discuss the nontrivial scaling of the energy absorbed with the ramp time. PMID- 21668212 TI - Heat fluctuations in a nonequilibrium bath. AB - We measure the energy fluctuations of a Brownian particle confined by an optical trap in an aging gelatin after a very fast quench (less than 1 ms). The strong nonequilibrium fluctuations due to the assemblage of the gel are interpreted, within the framework of fluctuation theorem, as a heat flux from the particle towards the bath. We derive an analytical expression of the heat probability distribution, which fits the experimental data and satisfies a fluctuation relation similar to that of a system in contact with two baths at different temperatures. PMID- 21668213 TI - Core-halo distribution in the Hamiltonian mean-field model. AB - We study a paradigmatic system with long-range interactions: the Hamiltonian mean field (HMF) model. It is shown that in the thermodynamic limit this model does not relax to the usual equilibrium Maxwell-Boltzmann distribution. Instead, the final stationary state has a peculiar core-halo structure. In the thermodynamic limit, HMF is neither ergodic nor mixing. Nevertheless, we find that using dynamical properties of Hamiltonian systems it is possible to quantitatively predict both the spin distribution and the velocity distribution functions in the final stationary state, without any adjustable parameters. We also show that HMF undergoes a nonequilibrium first-order phase transition between paramagnetic and ferromagnetic states. PMID- 21668215 TI - Galilean-invariant scalar fields can strengthen gravitational lensing. AB - The mystery of dark energy suggests that there is new gravitational physics on long length scales. Yet light degrees of freedom in gravity are strictly limited by Solar System observations. We can resolve this apparent contradiction by adding a Galilean-invariant scalar field to gravity. Called Galileons, these scalars have strong self-interactions near overdensities, like the Solar System, that suppress their dynamical effect. These nonlinearities are weak on cosmological scales, permitting new physics to operate. In this Letter, we point out that a massive-gravity-inspired coupling of Galileons to stress energy can enhance gravitational lensing. Because the enhancement appears at a fixed scaled location for dark matter halos of a wide range of masses, stacked cluster analysis of weak lensing data should be able to detect or constrain this effect. PMID- 21668214 TI - Cosmic-ray electron flux measured by the PAMELA experiment between 1 and 625 GeV. AB - Precision measurements of the electron component in the cosmic radiation provide important information about the origin and propagation of cosmic rays in the Galaxy. Here we present new results regarding negatively charged electrons between 1 and 625 GeV performed by the satellite-borne experiment PAMELA. This is the first time that cosmic-ray e- have been identified above 50 GeV. The electron spectrum can be described with a single power-law energy dependence with spectral index -3.18 +/- 0.05 above the energy region influenced by the solar wind (> 30 GeV). No significant spectral features are observed and the data can be interpreted in terms of conventional diffusive propagation models. However, the data are also consistent with models including new cosmic-ray sources that could explain the rise in the positron fraction. PMID- 21668216 TI - Gravitational wave emission from the single-degenerate channel of Type Ia supernovae. AB - The thermonuclear explosion of a C/O white dwarf as a Type Ia supernova (SN Ia) generates a kinetic energy comparable to that released by a massive star during a SN II event. Current observations and theoretical models have established that SNe Ia are asymmetric, and therefore--like SNe II--potential sources of gravitational wave (GW) radiation. We perform the first detailed calculations of the GW emission for a SN Ia of any type within the single-degenerate channel. The gravitationally confined detonation (GCD) mechanism predicts a strongly polarized GW burst in the frequency band around 1 Hz. Third-generation spaceborne GW observatories currently in planning may be able to detect this predicted signal from SNe Ia at distances up to 1 Mpc. If observable, GWs may offer a direct probe into the first few seconds of the SNe Ia detonation. PMID- 21668217 TI - Long, cold, early r process? Neutrino-induced nucleosynthesis in He shells revisited. AB - We revisit a nu-driven r-process mechanism in the He shell of a core-collapse supernova, finding that it could succeed in early stars of metallicity Z ? 10-3 Z(?), at relatively low temperatures and neutron densities, producing A ~ 130 and 195 abundance peaks over ~10-20 s. The mechanism is sensitive to the nu emission model and to nu oscillations. We discuss the implications of an r process that could alter interpretations of abundance data from metal-poor stars, and point out the need for further calculations that include effects of the supernova shock. PMID- 21668218 TI - Entanglement of low-energy excitations in conformal field theory. AB - In a quantum critical chain, the scaling regime of the energy and momentum of the ground state and low-lying excitations are described by conformal field theory (CFT). The same holds true for the von Neumann and Renyi entropies of the ground state, which display a universal logarithmic behavior depending on the central charge. In this Letter we generalize this result to those excited states of the chain that correspond to primary fields in CFT. It is shown that the nth Renyi entropy is related to a 2n-point correlator of primary fields. We verify this statement for the critical XX and XXZ chains. This result uncovers a new link between quantum information theory and CFT. PMID- 21668219 TI - Top quark forward-backward asymmetry and same-sign top quark pairs. AB - The top quark forward-backward asymmetry measured at the Tevatron collider shows a large deviation from standard model expectations. Among possible interpretations, a nonuniversal Z' model is of particular interest as it naturally predicts a top quark in the forward region of large rapidity. To reproduce the size of the asymmetry, the couplings of the Z' to standard model quarks must be large, inevitably leading to copious production of same-sign top quark pairs at the energies of the Large Hadron Collider (LHC). We explore the discovery potential for tt and ttj production in early LHC experiments at 7-8 TeV and conclude that if no tt signal is observed with 1 fb-1 of integrated luminosity, then a nonuniversal Z' alone cannot explain the Tevatron forward backward asymmetry. PMID- 21668226 TI - Nuclear spin effect on recombination of H3+ ions with electrons at 77 K. AB - Utilizing different ratios of para to ortho H2 in normal and para enriched hydrogen, we varied the population of para-H3+ in an H3+ dominated plasma at 77 K. Absorption spectroscopy was used to measure the densities of the two lowest rotational states of H3+. Monitoring plasma decays at different populations of para-H3+ allowed us to determine the rate coefficients for binary recombination of para-H3+ and ortho-H3+ ions: (p)alpha(bin)(77 K) = (1.9 +/- 0.4) * 10-7 cm3 s 1 and (o)alpha(bin)(77 K) = (0.2 +/- 0.2) * 10-7 cm3 s-1. PMID- 21668224 TI - Origin of the anomalous long lifetime of 14C. AB - We report the microscopic origins of the anomalously suppressed beta decay of 14C to 14N using the ab initio no-core shell model with the Hamiltonian from the chiral effective field theory including three-nucleon force terms. The three nucleon force induces unexpectedly large cancellations within the p shell between contributions to beta decay, which reduce the traditionally large contributions from the nucleon-nucleon interactions by an order of magnitude, leading to the long lifetime of 14C. PMID- 21668225 TI - Classical dynamics of laser-driven D3+. AB - A classical model of the triatomic D3+ molecule subjected to an intense, few cycle laser pulse is introduced. The model is capable of describing the laser induced correlated motion of both electrons and nuclei in three dimensions, and allows us to follow the motion of the two electrons and three deuterons from the initial field-free state, during the pulse, and until the bond breaking into the final fragments. By averaging over many trajectories, we calculate the relative yields of the ionization and dissociation channels, as well as the kinetic energy release (KER) from the fragment ions. A comparison with recent experimental KER spectra shows good qualitative agreement. In addition, we find a pathway in which an emitted electron recombines into a high-lying Rydberg state, resulting in D + D+ + D+ fragments with the same KER as in the D+ + D+ + D+ channel. PMID- 21668223 TI - Structural evolution in the neutron-rich nuclei 106Zr and 108Zr. AB - The low-lying states in 106Zr and 108Zr have been investigated by means of beta gamma and isomer spectroscopy at the radioactive isotope beam factory (RIBF), respectively. A new isomer with a half-life of 620 +/- 150 ns has been identified in 108Zr. For the sequence of even-even Zr isotopes, the excitation energies of the first 2+ states reach a minimum at N = 64 and gradually increase as the neutron number increases up to N = 68, suggesting a deformed subshell closure at N = 64. The deformed ground state of 108Zr indicates that a spherical subshell gap predicted at N = 70 is not large enough to change the ground state of 108Zr to the spherical shape. The possibility of a tetrahedral shape isomer in 108Zr is also discussed. PMID- 21668227 TI - Cavity-controlled collective scattering at the recoil limit. AB - We study collective scattering with Bose-Einstein condensates interacting with a high-finesse ring cavity. The condensate scatters the light of a transverse pump beam superradiantly into modes which, in contrast to previous experiments, are not determined by the geometrical shape of the condensate, but specified by a resonant cavity mode. Moreover, since the recoil-shifted frequency of the scattered light depends on the initial momentum of the scattered fraction of the condensate, we show that it is possible to employ the good resolution of the cavity as a filter selecting particular quantized momentum states. PMID- 21668228 TI - Bright spatially coherent wavelength-tunable deep-UV laser source using an Ar filled photonic crystal fiber. AB - We report on the spectral broadening of ~1 MUJ 30 fs pulses propagating in an Ar filled hollow-core photonic crystal fiber. In contrast with supercontinuum generation in a solid-core photonic crystal fiber, the absence of Raman and unique pressure-controlled dispersion results in efficient emission of dispersive waves in the deep-UV region. The UV light emerges in the single-lobed fundamental mode and is tunable from 200 to 320 nm by varying the pulse energy and gas pressure. The setup is extremely simple, involving <1 m of a gas-filled photonic crystal fiber, and the UV signal is stable and bright, with experimental IR to deep-UV conversion efficiencies as high as 8%. The source is of immediate interest in applications demanding high spatial coherence, such as laser lithography or confocal microscopy. PMID- 21668229 TI - Optomechanical coupling in a two-dimensional photonic crystal defect cavity. AB - Periodically structured materials can sustain both optical and mechanical modes. Here we investigate and observe experimentally the optomechanical properties of a conventional two-dimensional suspended photonic crystal defect cavity with a mode volume of ~3(lambda/n)3. Two families of mechanical modes are observed: flexural modes, associated to the motion of the whole suspended membrane, and localized modes with frequencies in the GHz regime corresponding to localized phonons in the optical defect cavity of diffraction-limited size. We demonstrate direct measurements of the optomechanical vacuum coupling rate using a frequency calibration technique. The highest measured values exceed 80 kHz, demonstrating high coupling of optical and mechanical modes in such structures. PMID- 21668230 TI - Optical beam steering based on the symmetry of resonant modes of nanoparticles. AB - We report a phenomenon that an optical beam transmits in a negative direction when passing through a single array of high-refractive-index dielectric nanorods. The mechanism of the negative directional transmission is believed to be due to the symmetry of resonant modes in the dielectric nanoparticles. It is expected to find applications in designing compact optical components to achieve the on-chip beam steering in photonic circuits. PMID- 21668231 TI - Stiffness of contacts between rough surfaces. AB - The effect of self-affine roughness on solid contact is examined with molecular dynamics and continuum calculations. The contact area and normal stiffness rise linearly with the applied load, and the load rises exponentially with decreasing separation between surfaces. Results for a wide range of roughness, system size, and Poisson ratio can be collapsed using Persson's contact theory for continuous elastic media. The compliance due to atomic-scale motion at the interface between solids has little effect on the area and normal stiffness, but can reduce the total transverse stiffness by orders of magnitude. The scaling of this effect with system size is discussed. PMID- 21668232 TI - Scratching as a fracture process: from butter to steel. AB - We present results of a hybrid experimental and theoretical investigation of the fracture scaling in scratch tests and show that scratching is a fracture dominated process. Validated for paraffin wax, cement paste, Jurassic limestone and steel, we derive a model that provides a quantitative means to relate quantities measured in scratch tests to fracture properties of materials at multiple scales. The scalability of scratching for different probes and depths opens new venues towards miniaturization of our technique, to extract fracture properties of materials at even smaller length scales. PMID- 21668234 TI - Rogue wave observation in a water wave tank. AB - The conventional definition of rogue waves in the ocean is that their heights, from crest to trough, are more than about twice the significant wave height, which is the average wave height of the largest one-third of nearby waves. When modeling deep water waves using the nonlinear Schrodinger equation, the most likely candidate satisfying this criterion is the so-called Peregrine solution. It is localized in both space and time, thus describing a unique wave event. Until now, experiments specifically designed for observation of breather states in the evolution of deep water waves have never been made in this double limit. In the present work, we present the first experimental results with observations of the Peregrine soliton in a water wave tank. PMID- 21668233 TI - Diffusive transport by thermal velocity fluctuations. AB - We study the contribution of advection by thermal velocity fluctuations to the effective diffusion coefficient in a mixture of two identical fluids. We find good agreement between a simple fluctuating hydrodynamics theory and particle and finite-volume simulations. The enhancement of the diffusive transport depends on the system size L and grows as ln(L/L0) in quasi-two-dimensional systems, while in three dimensions it scales as L0-1 - L-1, where L0 is a reference length. Our results demonstrate that fluctuations play an important role in the hydrodynamics of small-scale systems. PMID- 21668235 TI - Conformal invariance in three-dimensional rotating turbulence. AB - We examine turbulent flows in the presence of solid-body rotation and helical forcing in the framework of stochastic Schramm-Lowner evolution (SLE) curves. The data stem from a run with 15363 grid points, with Reynolds and Rossby numbers of, respectively, 5100 and 0.06. We average the parallel component of the vorticity in the direction parallel to that of rotation and examine the resulting (z) field for scaling properties of its zero-value contours. We find for the first time for three-dimensional fluid turbulence evidence of nodal curves being conformal invariant, belonging to a SLE class with associated Brownian diffusivity kappa = 3.6 +/- 0.1. SLE behavior is related to the self similarity of the direct cascade of energy to small scales and to the partial bidimensionalization of the flow because of rotation. We recover the value of kappa with a heuristic argument and show that this is consistent with several nontrivial SLE predictions. PMID- 21668236 TI - Freezing and melting of 3D complex plasma structures under microgravity conditions driven by neutral gas pressure manipulation. AB - Freezing and melting of large three-dimensional complex plasmas under microgravity conditions is investigated. The neutral gas pressure is used as a control parameter to trigger the phase changes: Complex plasma freezes (melts) by decreasing (increasing) the pressure. The evolution of complex plasma structural properties upon pressure variation is studied. Theoretical estimates allow us to identify the main factors responsible for the observed behavior. PMID- 21668237 TI - Suppression of the ablation phase in wire array Z pinches using a tailored current prepulse. AB - A new wire array configuration has been used to create thin shell-like implosions in a cylindrical array. The setup introduces a ~5 kA, ~25 ns current prepulse followed by a ~140 ns current-free interval before the application of the main (~1 MA) current pulse. The prepulse volumetrically heats the wires which expand to ~1 mm diameter leaving no dense wire core and without development of instabilities. The main current pulse then ionizes all the array mass resulting in suppression of the ablation phase, an accelerating implosion, and no trailing mass. Rayleigh-Taylor instability growth in the imploding plasma is inferred to be seeded by MUm-scale perturbations on the surface of the wires. The absence of wire cores is found to be the critical factor in altering the implosion dynamics. PMID- 21668238 TI - Spectroscopy for cold atom gases in periodically phase-modulated optical lattices. AB - The response of cold atom gases to small periodic phase modulation of an optical lattice is discussed. For bosonic gases, the energy absorption rate is given, within linear response theory, by the imaginary part of the current autocorrelation function. For fermionic gases in a strong lattice potential, the same correlation function can be probed via the production rate of double occupancy. The phase modulation gives thus direct access to the conductivity of the system, as a function of the modulation frequency. We give an example of application in the case of bosonic systems at zero temperature and discuss the link between the phase and amplitude modulation. PMID- 21668239 TI - Momentum distribution and contact of the unitary Fermi gas. AB - We calculate the momentum distribution n(k) of the unitary Fermi gas by using quantum Monte Carlo calculations at finite temperature T/epsilon(F) as well as in the ground state. At large momenta k/k(F), we find that n(k) falls off as C/k4, in agreement with the Tan relations. From the asymptotics of n(k), we determine the contact C as a function of T/epsilon(F) and present a comparison with theory. At low T/epsilon(F), we find that C increases with temperature, and we tentatively identify a maximum around T/epsilon(F) ? 0.4. Our calculations are performed on lattices of spatial extent up to N(x) = 14 with a particle number per unit volume of ? 0.03-0.07. PMID- 21668240 TI - Detecting the amplitude mode of strongly interacting lattice bosons by Bragg scattering. AB - We report the first detection of the Higgs-type amplitude mode using Bragg spectroscopy in a strongly interacting condensate of ultracold atoms in an optical lattice. By the comparison of our experimental data with a spatially resolved, time-dependent bosonic Gutzwiller calculation, we obtain good quantitative agreement. This allows for a clear identification of the amplitude mode, showing that it can be detected with full momentum resolution by going beyond the linear response regime. A systematic shift of the sound and amplitude modes' resonance frequencies due to the finite Bragg beam intensity is observed. PMID- 21668241 TI - Quantum degenerate mixtures of alkali and alkaline-earth-like atoms. AB - We realize simultaneous quantum degeneracy in mixtures consisting of the alkali and alkaline-earth-like atoms Li and Yb. This is accomplished within an optical trap by sympathetic cooling of the fermionic isotope 6Li with evaporatively cooled bosonic 174Yb and, separately, fermionic 173Yb. Using cross-thermalization studies, we also measure the elastic s-wave scattering lengths of both Li-Yb combinations, |a(6Li-174Yb)| = 1.0 +/- 0.2 nm and |a(6Li-173Yb)| = 0.9 +/- 0.2 nm. The equality of these lengths is found to be consistent with mass-scaling analysis. The quantum degenerate mixtures of Li and Yb, as realized here, can be the basis for creation of ultracold molecules with electron spin degrees of freedom, studies of novel Efimov trimers, and impurity probes of superfluid systems. PMID- 21668242 TI - InN thin film lattice dynamics by grazing incidence inelastic x-ray scattering. AB - Achieving comprehensive information on thin film lattice dynamics so far has eluded well established spectroscopic techniques. We demonstrate here the novel application of grazing incidence inelastic x-ray scattering combined with ab initio calculations to determine the complete elastic stiffness tensor, the acoustic and low-energy optic phonon dispersion relations of thin wurtzite indium nitride films. Indium nitride is an especially relevant example, due to the technological interest for optoelectronic and solar cell applications in combination with other group III nitrides. PMID- 21668243 TI - Flow transition within an evaporating binary mixture sessile drop. AB - The flow field along the base of an evaporating ethanol-water droplet and its evolution time was measured by particle image velocimetry. Three stages are revealed, a first stage dominated by multiple vortices, a second transition stage characterized by a remarkable spike in outward flow not previously identified, and a third stage dominated by outward flow identical to that found for pure water. Stage I is thought to be driven by surface tension gradients arising from local concentration variation. The spike in outward flow is explained in terms of a transition corresponding to almost total depletion of ethanol. An exponential decay in vorticity during the transition stage is explained in terms of ethanol diffusion from the bulk to the interface. We speculate on the existence of a zero concentration wave propagating from the apex to the contact line corresponding to the final total depletion of ethanol. PMID- 21668244 TI - Atomically resolved images of I(h) ice single crystals in the solid phase. AB - The morphology and crystal structure of nanoparticles of ice were examined by high-resolution transmission electron microscopy. Two different crystal structures were found and unambiguously assigned to hexagonal (I(h)) and cubic (I(c)) ice crystals. Direct observation of oxygen columns clearly revealed the hexagonal packing of water molecules. Electron energy-loss spectroscopy was used to monitor the electronic excitation in ice, suggesting possible dissociation of water molecules. Dynamic process of phase transition between I(h) and I(c) phases of individual ice nanoparticles under electron beam irradiation was also monitored by in situ transmission electron diffractometry. PMID- 21668245 TI - Expansion dynamics in the one-dimensional Fermi-Hubbard model. AB - Expansion dynamics of interacting fermions in a lattice is simulated within the one-dimensional (1D) Hubbard model, using the essentially exact time-evolving block decimation (TEBD) method. In particular, the expansion of an initial band insulator state is considered. We analyze the simulation results based on the dynamics of a two-site two-particle system, the so-called Hubbard dimer. Our findings describe essential features of a recent experiment on the expansion of a Fermi gas in a two-dimensional lattice. We show that the Hubbard-dimer dynamics, combined with a two-fluid model for the paired and nonpaired components of the gas, gives an efficient description of the full dynamics. This should be useful for describing dynamical phenomena of strongly interacting Fermions in a lattice in general. PMID- 21668246 TI - First-principles investigation of low energy E' center precursors in amorphous silica. AB - We show that oxygen vacancies are not necessary for the formation of E' centers in amorphous SiO2 and that a single O deficiency can lead to two charge traps. Employing molecular dynamics with a reactive potential and density functional theory, we generate an ensemble of stoichiometric and oxygen-deficient amorphous SiO2 atomic structures and identify low-energy network defects. Three-coordinated Si atoms appear in several low-energy defects both in stoichiometric and O deficient samples where, in addition to the neutral oxygen vacancy, they appear as isolated defects. PMID- 21668247 TI - Finite temperature formalism for composite quantum particles. AB - This Letter provides the missing part of the newly constructed many-body formalism for composite quantum particles: the introduction of a finite temperature. The finite T formalism we propose deeply relies on the existence of a compact closure relation for the (overcomplete) set of N-composite-particle states. As a first application, we here calculate the energy mean value of the exciton gas outside the condensation regime. We show that carrier exchanges increase its temperature dependence compared to elementary bosons, a signature of the degree-of-freedom increase resulting from the particle composite nature. PMID- 21668248 TI - Optical traps for dark excitons. AB - We propose a mechanism for optical trapping of dark excitons by linearly polarized unabsorbed standing waves, with a potential depth of the order of a few meV. Since this trapping, based on carrier exchanges with virtual excitons coupled to unabsorbed photons, equally acts on bright and dark states, Bose Einstein condensation of excitons--which occurs in dark states--must appear as dark spots in a cloud of bright excitons, at the trap potential minima, when the temperature decreases. PMID- 21668249 TI - Nanodopant-induced band modulation in AgPb(m)SbTe(2+m)-type thermoelectrics. AB - The structure-property relation is a key outstanding problem in the study of nanocomposite materials. Here we elucidate the fundamental physics of nanodopants in thermoelectric nanocomposites XPb(m)YTe(2+m) (X = Ag, Na; Y = Sb, Bi). First principles calculations unveil a sizable band-gap widening driven by nanodopant induced lattice strain and a band split-off mainly caused by the spin-orbit interaction in nanodopant. Boltzmann transport calculations on PbTe with modified band mimicking nanodopant-induced modulations show significant but competing effects on high-temperature electron transport behavior. These results offer insights for understanding experimental findings and optimizing thermoelectric properties of narrow band-gap semiconductor nanocomposites. PMID- 21668250 TI - Spin-to-charge conversion of mesoscopic spin currents. AB - Recent theoretical investigations have shown that spin currents can be generated by passing electric currents through spin-orbit coupled mesoscopic systems. Measuring these spin currents has, however, not been achieved to date. We show how mesoscopic spin currents in lateral heterostructures can be measured with a single-channel voltage probe. In the presence of a spin current, the charge current I(qpc) through the quantum point contact connecting the probe is odd in an externally applied Zeeman field B, while it is even in the absence of spin current. Furthermore, the zero-field derivative ?(B)I(qpc) is proportional to the magnitude of the spin current, with a proportionality coefficient that can be determined in an independent measurement. We confirm these findings numerically. PMID- 21668251 TI - Transport spectroscopy of an impurity spin in a carbon nanotube double quantum dot. AB - We make use of spin selection rules to investigate the electron spin system of a carbon nanotube double quantum dot. Measurements of the electron transport as a function of the magnetic field and energy detuning between the quantum dots reveal an intricate pattern of the spin state evolution. We demonstrate that the complete set of measurements can be understood by taking into account the interplay between spin-orbit interaction and a single impurity spin coupled to the double dot. The detection and tunability of this coupling are important for quantum manipulation in carbon nanotubes. PMID- 21668252 TI - Helical quantum states in HgTe quantum dots with inverted band structures. AB - We investigate theoretically the electron states in HgTe quantum dots (QDs) with inverted band structures. In sharp contrast to conventional semiconductor quantum dots, the quantum states in the gap of the HgTe QD are fully spin-polarized and show ringlike density distributions near the boundary of the QD and spin-angular momentum locking. The persistent charge currents and magnetic moments, i.e., the Aharonov-Bohm effect, can be observed in such a QD structure. This feature offers us a practical way to detect these exotic ringlike edge states by using the SQUID technique. PMID- 21668253 TI - Resolving band-structure evolution and defect-induced states of single conjugated oligomers by scanning tunneling microscopy and tight-binding calculations. AB - We study single conjugated polyphenylene oligomers consisting of 3n (2 <= n <= 12) phenyl units by means of cryogenic scanning tunneling microscopy and spectroscopy. The spatially resolved local densities of states reveal a progressive development of a continuous conduction band out of discrete molecular orbitals as the length of the oligomers increases. The experimental results are satisfactorily described by tight-binding calculations which gave a conduction band bandwidth of 4.5 +/- 0.2 eV and a band gap of 3.1 +/- 0.2 eV for an infinitely long polymer. We observed two types of defects, known as conformational torsional angle misfit and metasite kink. Tight-binding as well as density-functional theory model calculations confirm that both types of defects effectively destroy the delocalization. PMID- 21668254 TI - Collective modes and the periodicity of quantum Hall stripes. AB - We investigate the quantum Hall stripe phase at filling factor 9/2 at the microscopic level by probing the dispersion of its collective modes with the help of surface acoustic waves with wavelengths down to 60 nm. The dispersion is strongly anisotropic. It is highly dispersive and exhibits a roton minimum for wave vectors aligned along the easy transport direction. In the perpendicular direction, however, the dispersion is featureless, although not flat as predicted by theory. Oscillatory behavior in the absorption intensity of the collective mode with a wave vector perpendicular to the stripes is attributed to a commensurability effect. It allows us to extract the periodicity of the quantum Hall stripes. PMID- 21668255 TI - Direct observation of broken time-reversal symmetry on the surface of a magnetically doped topological insulator. AB - We study interference patterns of a magnetically doped topological insulator Bi(2 x)Fe(x)Te(3+d) by using Fourier transform scanning tunneling spectroscopy and observe several new scattering channels. A comparison with angle-resolved photoemission spectroscopy allows us to unambiguously ascertain the momentum space origin of distinct dispersing channels along high-symmetry directions and identify those originating from time-reversal symmetry breaking. Our analysis also reveals that the surface state survives far above the energy where angle resolved photoemission spectroscopy finds the onset of continuum bulk bands. PMID- 21668256 TI - Impact of disorder on the 5/2 fractional quantum Hall state. AB - We compare the energy gap of the nu = 5/2 fractional quantum Hall effect state obtained in conventional high mobility modulation-doped quantum-well samples with those obtained in high quality GaAs transistors (heterojunction insulated gate field-effect transistors). We are able to identify the different roles that long range and short-range disorders play in the 5/2 state and observe that the long range potential fluctuations are more detrimental to the strength of the 5/2 state than short-range potential disorder. PMID- 21668257 TI - Determination of gap symmetry from angle-dependent H(c2) measurements on CeCu2Si2. AB - The tetragonal heavy-fermion compound CeCu2Si2 exhibits a superconducting ground state (S type, T(c) = 0.67 K) close to a magnetic instability. Here, we present angle-resolved resistivity measurements of the upper critical field H(c2). In plane rotation of S-type CeCu2Si2 single crystals reveals a fourfold oscillation of H(c2). An extended weak-coupling BCS model for a d-wave symmetry including strong Pauli-limiting effects confirms the aforementioned angular dependence and points towards d(xy) symmetry of the order parameter. PMID- 21668258 TI - Parity-broken chiral spin dynamics in Ba3NbFe3Si2O14. AB - The spin-wave excitations emerging from the chiral helically modulated 120 degrees magnetic order in a langasite Ba3NbFe3Si2O14 enantiopure crystal were investigated by unpolarized and polarized inelastic neutron scattering. A dynamical fingerprint of the chiral ground state is obtained, singularized by (i) spectral weight asymmetries answerable to the structural chirality and (ii) a full chirality of the spin correlations observed over the whole energy spectrum. The intrinsic chiral nature of the spin waves' elementary excitations is shown in the absence of macroscopic time-reversal symmetry breaking. PMID- 21668259 TI - Two-stage ordering of spins in dipolar spin ice on the kagome lattice. AB - Spin ice, a peculiar thermal state of a frustrated ferromagnet on the pyrochlore lattice, has a finite entropy density and excitations carrying magnetic charge. By combining analytical arguments and Monte Carlo simulations, we show that spin ice on the two-dimensional kagome lattice orders in two stages. The intermediate phase has ordered magnetic charges and is separated from the paramagnetic phase by an Ising transition. The transition to the low-temperature phase is of the three-state Potts or Kosterlitz-Thouless type, depending on the presence of defects in the charge order. PMID- 21668260 TI - Thermodynamics of a gas of deconfined bosonic spinons in two dimensions. AB - We consider the quantum phase transition between a Neel antiferromagnet and a valence-bond solid (VBS) in a two-dimensional system of S = 1/2 spins. Assuming that the excitations of the critical ground state are linearly dispersing deconfined spinons obeying Bose statistics, we derive expressions for the specific heat C and the magnetic susceptibility chi at low temperature T in terms of a correlation length xi(T). Comparing with quantum Monte Carlo results for the J-Q model, which is a candidate for a deconfined Neel-VBS transition, we obtain an almost perfect consistency between C, chi, and xi. The corresponding expressions for magnon (triplet) excitations are not internally consistent, however, lending strong support for spinon excitations in the J-Q model. PMID- 21668261 TI - Numerical study of carrier multiplication pathways in photoexcited nanocrystal and bulk forms of PbSe. AB - Employing the interband exciton scattering model, we perform a numerical study of the direct photogeneration and population relaxation processes contributing to carrier multiplication (CM) in nanocrystalline and bulk PbSe. We argue that in both cases the impact ionization is the main mechanism of CM. This explains the weak contribution of the direct photogeneration to the total quantum efficiency (QE). An investigation of the size scaling of QE in nanocrystals and a comparison to the bulk limit provide microscopic insight into the experimentally observed trends. PMID- 21668262 TI - Ultrafast hopping dynamics of 5f electrons in the Mott insulator UO2 studied by femtosecond pump-probe spectroscopy. AB - We describe a femtosecond pump-probe study of ultrafast hopping dynamics of 5f electrons in the Mott insulator UO2 following Mott-gap excitation at temperatures of 5-300 K. Hopping-induced response of the lattice and electrons is probed by transient reflectivity at mid- and above-gap photon energies, respectively. These measurements show an instantaneous hop, subsequent picosecond lattice deformation, followed by acoustic phonon emission and microsecond relaxation. Temperature-dependent studies indicate that the slow relaxation results from Hubbard excitons formed by U3+-U5+ pairs. PMID- 21668263 TI - Electrically detected magnetic resonance of neutral donors interacting with a two dimensional electron gas. AB - We have measured the electrically detected magnetic resonance of donor-doped silicon field-effect transistors in resonant X- (9.7 GHz) and W-band (94 GHz) microwave cavities. The two-dimensional electron gas resonance signal increases by 2 orders of magnitude from X to W band, while the donor resonance signals are enhanced by over 1 order of magnitude. Bolometric effects and spin-dependent scattering are inconsistent with the observations. We propose that polarization transfer from the donor to the two-dimensional electron gas is the main mechanism giving rise to the spin resonance signals. PMID- 21668264 TI - Undulatory swimming in viscoelastic fluids. AB - The effects of fluid elasticity on the swimming behavior of the nematode Caenorhabditis elegans are experimentally investigated by tracking the nematode's motion and measuring the corresponding velocity fields. We find that fluid elasticity hinders self-propulsion. Compared to Newtonian solutions, fluid elasticity leads to up to 35% slower propulsion. Furthermore, self-propulsion decreases as elastic stresses grow in magnitude in the fluid. This decrease in self-propulsion in viscoelastic fluids is related to the stretching of flexible molecules near hyperbolic points in the flow. PMID- 21668265 TI - Common input explains higher-order correlations and entropy in a simple model of neural population activity. AB - Simultaneously recorded neurons exhibit correlations whose underlying causes are not known. Here, we use a population of threshold neurons receiving correlated inputs to model neural population recordings. We show analytically that small changes in second-order correlations can lead to large changes in higher-order redundancies, and that the resulting interactions have a strong impact on the entropy, sparsity, and statistical heat capacity of the population. Our findings for this simple model may explain some surprising effects recently observed in neural population recordings. PMID- 21668266 TI - Langevin dynamics deciphers the motility pattern of swimming parasites. AB - The parasite African trypanosome swims in the bloodstream of mammals and causes the highly dangerous human sleeping sickness. Cell motility is essential for the parasite's survival within the mammalian host. We present an analysis of the random-walk pattern of a swimming trypanosome. From experimental time autocorrelation functions for the direction of motion we identify two relaxation times that differ by an order of magnitude. They originate from the rapid deformations of the cell body and a slower rotational diffusion of the average swimming direction. Velocity fluctuations are athermal and increase for faster cells whose trajectories are also straighter. We demonstrate that such a complex dynamics is captured by two decoupled Langevin equations that decipher the complex trajectory pattern by referring it to the microscopic details of cell behavior. PMID- 21668267 TI - Dynamics of the field-induced formation of hexagonal zipped-chain superstructures in magnetic colloids. AB - Combining nuclear magnetic resonance and molecular dynamics simulations, we unravel the long-time dynamics of a paradigmatic colloid with strong dipole dipole interactions. In a homogeneous magnetic field, ionic ferrofluids exhibit a stepwise association process from ensembles of monomers over stringlike chains to bundles of hexagonal zipped-chain patches. We demonstrate that attractive van der Waals interactions due to charge-density fluctuations in the magnetic particles play the key role for the dynamical stabilization of the hexagonal superstructures against thermal dissociation. Our results give insight into the dynamics of self-organization in systems dominated by dipolar interactions. PMID- 21668268 TI - Phase diagram and effective shape of semiflexible colloidal rods and biopolymers. AB - We study suspensions of semiflexible colloidal rods and biopolymers using an Onsager-type second-virial functional for a segmented-chain model. For mixtures of thin and thick fd virus particles, we calculate full phase diagrams, finding quantitative agreement with experimental observations. We show that flexibility, which renders the rods effectively shorter and thicker depending on the state point, is crucial to understanding the topologies of the phase diagrams. We also calculate the stretching of wormlike micelles in a host fd virus suspension, finding agreement with experiments. PMID- 21668269 TI - Comment on "Loophole-free Bell test for continuous variables via wave and particle correlations". PMID- 21668271 TI - Comment on "Cavity induced shift and narrowing of the positronium Lyman-alpha transition". PMID- 21668273 TI - Comment on "Irreversibility in response to forces acting on graphene sheets". PMID- 21668275 TI - Impact of oral problems on daily activities of HIV-infected children. AB - AIM: Oral manifestations are common in HIV+ children, but the impact of these diseases on their daily life is unknown. So the aim of this study was to assess the impact of oral problems on the daily activities of HIV+ children. METHODS: The Child-OIDP-B was used with 59 10-12 year-old HIV+ children, who were outpatients at two public hospitals for HIV treatment in Rio de Janeiro, Brazil. Caries, biofilm and gingival bleeding indexes were recorded. The Kruskall-Wallis and Mann-Whitney tests as well as the Spearman's correlation coefficient were used for analysis. Statistical evaluation: Replies were analysed using the Statgraphics (r) Plus Version 5.0 statistics software system, in order to obtain comparative diagrams and graphs using the ANOVA multifactorial system. RESULTS: The Child-OIDP-B scores ranged from 0 to 30, (mean=6.09) and 71.2% of the children were affected by oral problems. Association was found between oral impact and number of caries (p=0.009). Children receiving HAART therapy had a Child-OIDP-B score (4.87), much lower than those who were not (8.87) (p=0.038). The most reported oral impact of the disease was eating (55.6%), but oral wounds were the most prevalent type of lesions (76.3%). As regards the level of intensity of the impact, moderate severity was prevalent in all 59 children and 66.1% reported that oral impacts affected 1-4 daily activities, 50.8% of all children were not satisfied with their appearance and oral health; 23.7% perceived the impact of HIV-infection on general health. CONCLUSION: Most children suffered the impact of oral problems on their daily activities, mainly functional impacts. PMID- 21668276 TI - Impact of oral health on the quality of life of 3-6-years old HIV-infected children. Quality of life in HIV+ children. AB - AIM: The objective was to assess the impact of oral health on the quality of life of HIV-infected patients aged 3-6 years based on their caregivers' perceptions. METHODS: A questionnaire for measuring the perception and the instrument Early Childhood Oral Health Impact Scale (ECOHIS) were applied to 31 caregivers whose children were being treated in a public hospital. Results The mean age of the children was 4.52 years (SD 1.22). The total ECOHIS score ranged from 0 to 26, with a mean value of 4.13 (SD 6.66). Seventeen children (54.8%) were found to have at least one impact: toothache (64.7%), herpetic gingivostomatitis (23.5%) or both (11.8%). Statistically significant difference was found between the ECOHIS score and presence of restored teeth, prior dental treatment, AIDS, and viral load. With respect to the caregivers' perception, it resulted to be adequate, as those caregivers whose children had a greater number of decayed teeth and higher biofilm index also considered the oral health to be bad (P<0.001). However, the children's general health was found to be good despite the worse immunological classification (P<0.017).Conclusion The quality of life of the HIV- infected children has been negatively affected by the oral health. PMID- 21668277 TI - Prevalence of dental caries and its correlation with the immunologic profile in HIV-Infected children on antiretroviral therapy. AB - AIM: To describe the prevalence of dental caries in HIV-infected children on antiretroviral therapy. METHODS One hundred and four HIV positive children on antiretroviral therapy, two to fourteen year old children of both sexes were examined for dental caries. Children were divided into three groups based on the dentition: primary, mixed and permanent. They were also grouped depending on their absolute CD4 count and CD4 percentage into mild, advanced and severe stages. RESULTS: The primary dentition group had a mean deft of 5.07 +/- 5.29 and a caries prevalence of 58.62%; in the mixed dentition group the mean deft was 3.81 +/- 3.41 and the mean DMFT was 1.40 +/- 2.03 with caries prevalence of 86.20%. In the permanent dentition group the mean DMFT was 3.00 +/- 2.37 with a caries prevalence of 76.47%. CONCLUSION: Prevalence of dental caries was high in HIV-infected children in advanced CD4 count group. A decrease in the absolute lymphocyte count was associated with an increase in dental caries prevalence. PMID- 21668278 TI - Prevalence of astigmatism in a paediatric population with malocclusions. AB - AIM: The purpose of this study was to investigate the prevalence of astigmatism among a paediatric population. MATERIALS AND METHODS: A total of 322 consecutive patients of the department of Orthodontics and Gnathology, Dental Clinic, University of L'Aquila, were enlisted for the study and 176 were selected according to the exclusion criteria. Pre- treatment diagnostic data, which included radiographic cephalometric and dental cast evaluation, were recorded and presence of astigmatism was assessed through an ophthalmological examination. Differences in the prevalence of astigmatism by sex and malocclusion were analysed by using the chi-square (Pearson's chi-square test) and Fisher's exact tests. RESULTS: According to the sagittal malocclusion, patients were classified as Class I (N=122), Class II Division 1 (N=26), Class II Division 2 (N=9), or Class III (N=19); according to the transverse malocclusion patients were classified into cross-bite (N=39) and no cross-bite (N=137) groups; after ophthalmological examination astigmatism was detected in 32 patients (18.18%). Statistically significant correlations were found between astigmatism and cross bite (p < 0.0001), while no associations were found with other malocclusions. No gender influence was found for astigmatism or malocclusion. DISCUSSION: Few study investigated a possible relationship between the ocular and stomatognathic system, and no data are available in the scientific literature. A higher prevalence of astigmatism was found in patients with cross-bite: as expected no other significant association was found. The relationship between astigmatism and cross-bite could be either related to a specific skeletal pattern, which could induce visual alterations, or to the effect of abnormal visual input on the postural system, which could induce stomatognathic alterations. CONCLUSION: The findings of the present study suggest a possible association between astigmatism and cross-bite, but future studies are needed to confirm and explain this observation. PMID- 21668279 TI - Wear of dental sealing materials using the replication technique. AB - AIM: The aim of the present study was an in vivo evaluation of the wear of different sealing materials using the replication technique. MATERIALS AND METHODS: Four different sealing materials were randomly applied on 2 out of 4 caries-free permanent first molars of each patient. Impressions were taken at T0: before the sealing material was applied; T1: right after the application; T2: 6 months after the application, and T3: 1 year after the application. The impressions were then processed for scanning electron microscopy analysis of the wear of the examined materials. Statistical analysis was used to evaluate differences among and within the 4 groups. RESULTS: At T2, the average ratio of residual material in all the groups was 62.37% +/- 1.21%, while at T3 it was 49.63% +/- 1.11%. At both T2 and T3 there were no statistically significant differences among the 4 groups examined (p=0.76 and p=0.50 respectively). Comparison within the same group at T2 and T3 showed that statistically significant differences were only detected in group D (p=0.015). CONCLUSION: Sealing materials do not undergo a complete loss after 1 year of application, thus indicating that they are suitable for caries prevention. PMID- 21668280 TI - Dental trauma management awareness among primary school teachers in the Emirate of Ajman, United Arab Emirates. AB - AIM: To assess, by means of self-administered structured questionnaire, the level of knowledge of primary schools teachers in Ajman with regards to the immediate emergency management of dental trauma. MATERIALS AND METHODS: The questionnaire was sent to teachers in randomly selected primary schools in Ajman. A total of 161 teachers responded (response rate 84.4%). The questionnaire surveyed teachers' background, knowledge and management of tooth fracture, avulsion, and also investigated teachers' attitudes and self-assessed knowledge. RESULTS: Ninety-one percent of the teachers were females, 51.6% in their thirties and 61.5% had university qualification. Fifty teachers had received formal first aid training, and only thirteen of them recalled that they had received training on the management of dental trauma. Concerning the management of tooth fracture, 138 respondents (85.8%) gave the appropriate management for fractured tooth. One hundred twenty-one (75%) of the respondents indicated that is very urgent to seek professional assistance if a permanent tooth is avulsed, but they had little knowledge on the correct media for transporting the avulsed tooth. Most teaches were unsatisfied with their level of knowledge for dental trauma and the majority were interested in having further education on the topic. CONCLUSION: The findings revealed that the level of knowledge of management of dental trauma (especially tooth avulsion) among school teachers in Ajman is inadequate, and education campaigns are necessary to improve their emergency management of dental injuries. PMID- 21668281 TI - Evaluation of certain risk factors for early childhood caries in Samsun, Turkey. AB - AIM: Early childhood caries (ECC) is a relatively new term used to describe any stage of caries lesion in any primary tooth surface in a child under 6 years of age. The purpose of this study was to identify certain factors that influence the development of ECC among children in Samsun, Turkey. MATERIALS AND METHODS: Data were collected for 226 children (108 girls, 118 boys) aged 3-6 years. Questionnaires were administered to the mothers of participating children to obtain information on infant feeding habits and the mother's level of education and oral health knowledge. Clinical diagnoses of ECC were based on intraoral examinations conducted using a flashlight, disposable mirror and wooden tongue depressor. RESULTS: ECC was diagnosed in 46.9% of children. The mean dmf-t was 2.87. Significant associations were found between ECC prevalence and bottle feeding while sleeping and between ECC and the mother's level of education (p<0.05). The caries rate increased with the addition of sugar-containing substances to bottles; however, the increase was not statistically significant (p>0.05). There were no correlations observed between ECC and the mother's oral health knowledge or attitude (p>0.05). CONCLUSION: Within the limitation of this study, among the various factors investigated, infant feeding habits and the mother's level of education were found to have significant effects on the development of ECC. PMID- 21668282 TI - Prevalence of malocclusion in primary dentition in a population-based sample of Brazilian preschool children. AB - AIM: The purpose of the present study was to assess the prevalence of malocclusion in the primary dentition in a randomised representative sample of Brazilian preschool children. MATERIALS AND METHODS: A cross-sectional survey was carried out in Belo Horizonte, Brazil, involving 1069 male and female preschool children from 60 to 71 months of age, randomly selected from public and private preschools and daycare centers. A questionnaire addressing demographic data was sent to parents/guardians in order to characterise the sample. The oral examination of the children was performed by a single, previously calibrated dentist (kappa inter-examiner agreement value = 0.82). The criterion for the categorisation of malocclusion was at least one of the following conditions: posterior crossbite, overjet (> 2 mm), anterior crossbite, anterior open bite and deep overbite. Univariate analysis was performed using the SPSS software RESULTS: The prevalence of malocclusion was 46.2%. Deep overbite was the most prevalent alteration (19.7% of the sample). Posterior crossbite was diagnosed in 13.1% of the children; 10.5% had accentuated overjet; 7.9% had anterior open bite; and 6.7% had anterior crossbite. CONCLUSION: Malocclusion in primary dentition is becoming a significant problem. The prevalence in the present study was high, especially vertical and transversal malocclusions. PMID- 21668283 TI - Obesity and dental caries in paediatric patients. A cross-sectional study. AB - AIM: The aim of the present cross-sectional study was to evaluate the relationship between childhood obesity and dental caries, in paediatric subjects, through the use of two methods of diagnosis of overweight-obesity: Body Mass Index (BMI), and Dual energy X-ray Absorptiometry (DXA). METHODS: A total of 107 healthy patients, aged between 6 and 12 years (53.3% females, 46.7% males) were included in the study. Each patient underwent a nutritional examination and dental check-up. The nutritional examination was performed at the Department of Neuroscience, Human Nutrition Unit, University of Rome Tor Vergata and consisted of anthropometric measurements, BMI calculation, DXA exam, body fat mass (FM) assessment. Dental examinations were performed by a trained dentist of the Paediatric Dentistry Unit of PTV Hospital, University of Rome Tor Vergata. Dental caries was assessed using visual-tactile method and X-rays (bite-wing and panoramic radiography); the dmft/DMFT index was calculated. The subjects were classified as underweight, normal weight, pre-obese, obese, according to different criteria: a) age- and sex-specific BMI according to the Cacciari growth charts and cut-offs, b) body fat mass percentage (FM%) according to the WHO cut offs, c) body fat mass percentage (FM%) according to the McCarthy growth charts and cut-offs. STATISTICS: The statistical analysis was performed with the SPSS software (version 11.01; SPSS Inc., Chicago, IL, USA). The dmft/DMFT index was checked for normality using the Kolmogorov-Smirnov test. Independence of the dmft/DMFT distribution from sex and age was checked by using the Mann Whitney and Kruskal Wallis tests. Differences in the dmft/DMFT values between groups, according to BMI and FM% classifications, were tested using the Mann Whitney test. The minimal level of significance of the differences was fixed at p- value <= 0.05 for all procedures. RESULTS: The comparison between BMI and DXA data shows statistically significant differences between BMI-%FM (WHO cut-offs) classifications (p <= 0.001) and BMI-%FM (McCarthy cut-offs) classifications (p <= 0.001). According to the BMI classification, there was no significant association between increase of dmft-DMFT and pre-obesity/obesity, but according to the FM% (WHO cut-offs) classification, the pre-obese/obese children had higher caries indexes than normal weight subjects, both in deciduous teeth (p=0.003) and permanent teeth (p=0.000). Furthermore, according to the FM% (McCarthy cut-offs) classification, obese children had higher caries indexes than normal weight and pre-obese subjects, both in deciduous teeth (p=0.030, p=0.02) and permanent teeth (p=0.019, p=0.011), respectively, but they had a dmft-DMFT value comparable with underweight children. CONCLUSION: The BMI misclassified adiposity status of the paediatric population compared to DXA, which provides a reliable screening and a more specific assessment of body composition. The misclassification of childhood obesity, determined by the BMI, could be used to explain the conflicting data in the literature on the association between obesity and dental caries. Our results highlighted for the first time the relationship between dental caries prevalence and body fat percentage measured by DXA. PMID- 21668284 TI - Comparison of the efficacy of articaine and prilocaine local anaesthesia for pulpotomy of maxillary and mandibular primary molars. AB - AIM: The aim of this study was to compare the local anaesthetic efficacy of articaine HCl and prilocaine HCl during an operative procedure after their administration by either mandibular nerve block or maxillary infiltration. MATERIALS AND METHODS: STUDY DESIGN: The study was a double-blind clinical study which comprised 162 children (81 boys and 81 girls), who required a pulpotomy on their primary molars. Pain-related behaviours were used to assess the severity of pain during the injection of either prilocaine HCl or articaine HCl and the operative procedures following either a maxillary infiltration or mandibular nerve block of the two local anaesthetic agents. The frequencies of post procedural adverse events in the prilocaine and articaine anaesthetised groups were also determined. RESULTS: Significantly more discomfort (p<0.05) was observed following maxillary infiltration compared to mandibular nerve block. There were no significant differences in the pain-related behaviours scores between the two local anaesthetic agents administered during the dental operative procedures, except for the removal of the coronal pulp. For this latter procedure, the pain-related behaviour score was 1.5- times higher in the prilocain-anaesthetised children than in the articaine-anaesthetised children. The frequencies of post- procedural adverse events in the prilocaine-treated children were similar to those found in the articaine-treated children. CONCLUSION: We concluded that local anaesthesia following mandibular nerve block is more effective than that following maxillary infiltration in 6-8-year-old children. However, the intensity of pain that was experienced by the children during administration of either prilocaine or articaine and some of the dental procedures after their administration were similar. PMID- 21668285 TI - Prevalence and distribution of hypodontia in a Turkish orthodontic patient population: results from a large academic cohort. AB - AIM: Purpose of this study is to investigate the prevalence and distribution of congenitally missing permanent teeth (CMT) in a Turkish orthodontic patient population. MATERIALS AND METHODS: Panoramic radiographs, intraoral photographs and dental casts of 2761 patients (females 1677, males 1084) aged from 9 to 46 who underwent orthodontic treatment at Selcuk University Department of Orthodontics from 1990 to 2005 were retrospectively reviewed for CMT. A comprehensive chart review was conducted in all subjects. Patient and treatment related data were registered in a computer database for comparative analysis. RESULTS: When missing third molar data were included, prevalence of CMT in the overall population was 30.64% with no significant differences between male and female patients (p=0.546). On the other hand, prevalence of CMT excluding third molars was 6.77% with a significantly higher prevalence in females compared to male patients (7.63% vs. 5.44%, p=0.030). The most commonly congenitally missing tooth types in decreasing order were the third molars followed by maxillary lateral incisors and mandibular second premolars. The majority of missing third molars were located in the maxilla (55.7%) with no significant gender differences (p=0.334). 58.4% of CMT excluding third molars in females were located in the maxilla compared to only 40.8% in males (p=0.001). In both gender groups, majority of CMT excluding third molars were located in the anterior segment (55.6% and 58.4% in male and female patients respectively, p=0.713). CONCLUSION: The most commonly congenitally missing tooth type is third molars followed by maxillary lateral incisors and mandibular second premolars in our population. Although there were no gender differences in prevalence and anatomical distribution of missing third molars, CMT excluding third molars was significantly more prevalent in females with predominantly maxillary distribution in our population. PMID- 21668286 TI - Uprighting and distalisation of first permanent maxillary molars in patients with undermining resorption: a case report. AB - AIM: This case report describes a treatment method for distalisation and uprighting of first permanent maxillary molars with the aim of preventing complications in the presence of undermining resorption of the second deciduous molar. We present a fixed appliance, which is a compliance-independent and effective alternative to the methods used thus far such as removable plates with distal screws or separating ligatures. PMID- 21668287 TI - Juvenile Idiopathic Arthritis with temporomandibular joint involvement: functional treatment. AB - AIM: Juvenile Idiopathic Arthritis is a disease that can involve the temporomandibular joint unilaterally or bilaterally causing specific malocclusions. CASE REPORT: This paper reports a case of Juvenile Idiopathic Arthritis in an 8-year-old male with unilateral involvement of the temporomandibular joint, with remarkable asymmetry of the left mandible and reduced left facial height. The management of the temporomandibular damage consisted in the treatment with an activator in order to help mandibular ramus growth with a subsequent enhancement in occlusion, masticatory function and profile. This treatment has several advantages and permits to correct the typical malocclusion exhibited by these patients, to improve the clinical signs of the disease and to obtain stability over time. PMID- 21668288 TI - Alleviation of allergic rhinitis symptoms with Pyeongwee-San extract (KMP6). AB - CONTEXT: Allergy is characterized by the overreaction of the immune system. Pyeongwee-San is a traditional Korean medicine which has been used for the treatment of the allergic disorder but the mechanism of action is not clear. OBJECTIVE: To investigate the effect of Pyeongwee-San extract (KMP6) and its component, hesperidin (HES) in the allergic rhinitis (AR) animal model. METHOD: We sensitized mice on 1, 5, and 14 days by intraperitoneal injections of 100 MUg ovalbumin (OVA) emulsified in 20 mg of aluminum hydroxide and we challenged mice with 1.5 mg OVA. Mice received KMP6 and HES before the intranasal OVA challenge for 10 days. RESULTS: The number of nose rubs after the OVA challenge in the OVA sensitized mice was significantly higher than that in the OVA-unsensitized mice. The increased number of nose rub was inhibited by the oral administration of KMP6 or HES. The increased levels of IgE and histamine level in serum of the OVA sensitized mice were reduced by KMP6 or HES administration. The level of interferon-gamma was enhanced while the level of IL-4 was reduced on the spleen tissue of the KMP6 or HES-administered AR mice. Inflammatory proteins level was reduced by KMP6 or HES administration in the nasal mucosa tissue of the OVA sensitized mice. In the KMP6 or HES-administered mice, mast cells and eosinophils infiltration increased by OVA-sensitization was decreased. CONCLUSION: These results indicate that KMP6 and HES ameliorate the allergic inflammatory reactions such as AR. PMID- 21668289 TI - Combination therapy: the Holy Grail for the treatment of postmenopausal osteoporosis? AB - Agents for the treatment of osteoporosis are divided into broad categories according to whether the predominant effect is to inhibit bone resorption (antiresorptive drugs) or stimulate bone formation (osteo-anabolic drugs). However, due to the coupling of these two components of bone remodeling, drugs that inhibit bone resorption generally also reduce bone formation, and those that stimulate bone formation also increase bone resorption. Since these synchronous changes may limit the beneficial effects of treatment, researchers have undertaken a search for combinations of antiresorptive and osteo-anabolic drugs given concurrently, sequentially, intermittently, or cyclically that could partially or totally uncouple bone resorption and bone formation. This offers the potential for greater increases in bone mineral density (BMD), restoration of lost structural elements, and perhaps greater reduction in fracture risk than monotherapy with currently approved drugs. While some methods of combining drugs have been shown to enhance BMD response and perhaps extend the duration of osteo anabolic effects compared to monotherapy, none have been proven to provide greater reduction of fracture risk. Upon completion of a course of osteo-anabolic therapy with daily subcutaneous parathyroid hormone, antiresorptive therapy must be started in order to prevent subsequent loss of BMD. PMID- 21668290 TI - Healthcare costs of fast-acting insulin analogues versus short-acting human insulin for Danish patients with type 2 diabetes on a basal-bolus regimen. AB - AIMS: Fast-acting insulin analogues (FAIAs) reduce hypoglycaemia and improve administration flexibility compared with short-acting human insulin (SHI). This analysis examines whether these benefits translate into cost offsets when comparing the total treatment costs for FAIA versus SHI used as basal-bolus therapy for treating type 2 diabetes (T2D). METHODS: Registry data covering the Danish population including demographic variables, prescription, hospital and primary care data formed the basis for analysis. To capture patients on basal bolus therapy only, inclusion criteria were >=2 prescriptions of either long acting insulin analogues (LAIAs) or neutral protamine Hagedorn (NPH) insulin (basal component), and >=2 prescriptions for either an FAIA or SHI (bolus component) during the inclusion period (1 January-31 December 2005). Patients using LAIAs (n = 521) or NPH (n = 2695) were analysed separately. Within each basal cohort, patients using FAIAs or SHI were matched regarding observable variables using propensity scores. Healthcare costs were analysed for a follow-up period (maximum 2 years post-inclusion). RESULTS: Within each cohort, matching produced groups with similar observed covariates. Overall direct healthcare costs in the LAIA cohort were ?4183 and ?5289 for FAIA and SHI, respectively. In the NPH cohort, costs were ?4940 and ?4699 for FAIA and SHI, respectively. For both basal cohorts, cost differences between FAIA and SHI were not statistically significant. LIMITATIONS: As the propensity score model cannot account for unobserved variables, conclusions of causality cannot be made. Moreover, exclusion of indirect costs and application of hospital contact charges accrued in the discharge year only may result in an underestimation of overall healthcare costs. CONCLUSION: Using matched cohorts, treating patients with T2D using basal bolus regimens containing FAIAs was no more costly to the Danish healthcare system than regimens using SHI. FAIAs provide a flexible administration and optimal glucose control for a similar cost. PMID- 21668291 TI - Structural dynamics of the DeltaE22 (Osaka) familial Alzheimer's disease-linked amyloid beta-protein. AB - A familial form of Alzheimer disease recently was described in a kindred in Osaka, Japan. This kindred possesses an amyloid beta-protein (Abeta) precursor mutation within the Abeta coding region that results in the deletion of Glu22 (DeltaE22). We report here results of studies of [DeltaE22]Abeta40 and [DeltaE22]Abeta42 that sought to elucidate the conformational dynamics, oligomerization behavior, fibril formation kinetics, fibril morphology, and fibril stability of these mutant peptides. Both [DeltaE22]Abeta peptides had extraordinary beta-sheet formation propensities. The [DeltaE22]Abeta40 mutant formed beta-sheet secondary structure elements ~400-fold faster. Studies of beta sheet stability in the presence of fluorinated alcohol cosolvents or high pH revealed that the DeltaE22 mutation substantially increased stability, producing a rank order of [DeltaE22]Abeta42 >>Abeta42 > [DeltaE22]Abeta40 > Abeta40. The mutation facilitated formation of oligomers by [DeltaE22]Abeta42 (dodecamers and octadecamers) that were not observed with Abeta42. Both Abeta40 and Abeta42 peptides formed nebulous globular and small string-like structures immediately upon solvation from lyophilizates, whereas short protofibrillar and fibrillar structures were evident immediately in the DeltaE22 samples. Determination of the critical concentration for fibril formation for the [DeltaE22]Abeta peptides showed it to be ~1/2 that of the wild type homologues, demonstrating that the mutations causes a modest increase in fibril stability. The magnitude of this increase, when considered in the context of the extraordinary increase in beta sheet propensity for the DeltaE22 peptides, suggests that the primary biophysical effect of the mutation is to accelerate conformational changes in the peptide monomer that facilitate oligomerization and higher-order assembly. PMID- 21668220 TI - Search for pair production of first-generation scalar leptoquarks in pp collisions at ?s = 7 TeV. AB - A search for pair production of first-generation scalar leptoquarks is performed in the final state containing two electrons and two jets using proton-proton collision data at ?s = 7 TeV. The data sample used corresponds to an integrated luminosity of 33 pb-1 collected with the CMS detector at the CERN LHC. The number of observed events is in good agreement with the predictions for the standard model background processes, and an upper limit is set on the leptoquark pair production cross section times beta2 as a function of the leptoquark mass, where beta is the branching fraction of the leptoquark decay to an electron and a quark. A 95% confidence level lower limit is set on the mass of a first generation scalar leptoquark at 384 GeV for beta = 1, which is the most stringent direct limit to date. PMID- 21668292 TI - The role of semaphorins and their receptors in platelets: Lessons learned from neuronal and immune synapses. AB - During thrombus formation, activated platelets come into close and increasingly stable contact with each other. This produces a microenvironment in which soluble agonists can accumulate, and proteins on the surface of adjacent platelets can directly interact with each other, potentially modulating subsequent thrombus growth and stability. In some ways, this microenvironment resembles the synapses that support signal propagation between neurons and the exchange of information between T-cells, B-cells, and dendritic cells. Drawing on this analogy, this brief review discusses the role of semaphorins and their receptors in platelets, two protein families that have previously been defined by their role at cell:cell contacts, in both the developing nervous system and adaptive immunity. PMID- 21668293 TI - Fusion and visualization of intraoperative cortical images with preoperative models for epilepsy surgical planning and guidance. AB - OBJECTIVE: During epilepsy surgery it is important for the surgeon to correlate the preoperative cortical morphology (from preoperative images) with the intraoperative environment. Augmented Reality (AR) provides a solution for combining the real environment with virtual models. However, AR usually requires the use of specialized displays, and its effectiveness in the surgery still needs to be evaluated. The objective of this research was to develop an alternative approach to provide enhanced visualization by fusing a direct (photographic) view of the surgical field with the 3D patient model during image guided epilepsy surgery. MATERIALS AND METHODS: We correlated the preoperative plan with the intraoperative surgical scene, first by a manual landmark-based registration and then by an intensity-based perspective 3D-2D registration for camera pose estimation. The 2D photographic image was then texture-mapped onto the 3D preoperative model using the solved camera pose. In the proposed method, we employ direct volume rendering to obtain a perspective view of the brain image using GPU-accelerated ray-casting. The algorithm was validated by a phantom study and also in the clinical environment with a neuronavigation system. RESULTS: In the phantom experiment, the 3D Mean Registration Error (MRE) was 2.43 +/- 0.32 mm with a success rate of 100%. In the clinical experiment, the 3D MRE was 5.15 +/- 0.49 mm with 2D in-plane error of 3.30 +/- 1.41 mm. A clinical application of our fusion method for enhanced and augmented visualization for integrated image and functional guidance during neurosurgery is also presented. CONCLUSIONS: This paper presents an alternative approach to a sophisticated AR environment for assisting in epilepsy surgery, whereby a real intraoperative scene is mapped onto the surface model of the brain. In contrast to the AR approach, this method needs no specialized display equipment. Moreover, it requires minimal changes to existing systems and workflow, and is therefore well suited to the OR environment. In the phantom and in vivo clinical experiments, we demonstrate that the fusion method can achieve a level of accuracy sufficient for the requirements of epilepsy surgery. PMID- 21668294 TI - Obesity and metabolic syndrome: association with chronodisruption, sleep deprivation, and melatonin suppression. AB - Obesity has become an epidemic in industrialized and developing countries. In 30 years, unless serious changes are made, a majority of adults and many children will be classified as overweight or obese. Whereas fatness alone endangers physiological performance of even simple tasks, the associated co-morbidity of obesity including metabolic syndrome in all its manifestations is a far more critical problem. If the current trend continues as predicted, health care systems may be incapable of handling the myriad of obesity-related diseases. The financial costs, including those due to medical procedures, absenteeism from work, and reduced economic productivity, will jeopardize the financial well-being of industries. The current review summarizes the potential contributions of three processes that may be contributing to humans becoming progressively more overweight: circadian or chronodisruption, sleep deficiency, and melatonin suppression. Based on the information provided in this survey, life-style factors (independent of the availability of abundant calorie-rich foods) may aggravate weight gain. Both epidemiological and experimental data support associations between disrupted physiological rhythms, a reduction in adequate sleep, and light at-night-induced suppression of an essential endogenously produced molecule, melatonin. The implication is that if these problems were corrected with life style changes, body-weight could possibly be more easily controlled. PMID- 21668222 TI - Measurement of dijet angular distributions and search for quark compositeness in pp collisions at ?s = 7 TeV. AB - Dijet angular distributions are measured over a wide range of dijet invariant masses in pp collisions at ?s = 7 TeV, at the CERN LHC. The event sample, recorded with the CMS detector, corresponds to an integrated luminosity of 36 pb 1. The data are found to be in good agreement with the predictions of perturbative QCD, and yield no evidence of quark compositeness. With a modified frequentist approach, a lower limit on the contact interaction scale for left handed quarks of Lambda+ = 5.6 TeV (Lambda- = 6.7 TeV) for destructive (constructive) interference is obtained at the 95% confidence level. PMID- 21668295 TI - Management of differentiated thyroid cancer of the follicular epithelium. AB - The incidence of thyroid cancer has been increasing in many countries over the last 30 years (from 3.6/100,000 people in 1973 to 8.7/100,000 people in 2002) while mortality has been slowly decreasing ( 1 , 2 ). The increase is mainly represented by papillary thyroid cancer, while follicular and anaplastic histotypes remained stable. It is a general opinion that the increase is attributable to better detection of small papillary carcinomas as a result of improved diagnostic accuracy (neck ultrasound and fine-needle aspiration cytology). Consequently, it is common experience in thyroid cancer referral centers that nearly 60%-80% of thyroid carcinomas detected nowadays are micropapillary thyroid carcinomas (less than 1 cm in size) carrying an excellent long-term prognosis. In view of this change in the presentation of the disease, the objective of thyroid cancer management should be aimed at achieving complete cure using the less aggressive diagnostic and therapeutic procedures. PMID- 21668296 TI - Psychogenic polydipsia: hidden or underdiagnosed? PMID- 21668297 TI - Should the clozapine protocol be obeyed? PMID- 21668298 TI - Ziprasidone induced symptomatic bradycardia: a case report. PMID- 21668300 TI - Telemicroscopes and point-of-care diagnostics team up with smartphones. PMID- 21668299 TI - Reflections on Tampa and the Annual American Telemedicine Association meeting. PMID- 21668302 TI - Leukemia-associated antigens are immunogenic and have prognostic value in acute myeloid leukemia. PMID- 21668301 TI - Pulling the trigger on the tumor's bodyguards: what puts Tregs out of action? PMID- 21668303 TI - Use of mesenchymal stem cells as treatment for graft-versus-host disease: current knowledge and controversies. PMID- 21668305 TI - Immunomodulatory effects of cyclophosphamide on the differentiation of Th17 cells. PMID- 21668306 TI - TSLP1: a new piece in the puzzle of tumor-associated Th2-type inflammation. PMID- 21668307 TI - Conference Scene: T-cell subset phenotype and function. AB - Organized by Euroscicon, this meeting focused on the complex and fast-paced research field of T-cell subset phenotype and function. During the past 20 years, this field has moved on from the simple Th1-Th2 paradigm to the discovery of a range of T-cell subsets, including Tregs and Th17 cells. The meeting brought together a variety of researchers currently exploring this field, to give insight into what we know, what we need to know and the potential implications of this research in the medical setting. PMID- 21668308 TI - Broad-spectrum immunosuppression by classless monocytes in non-Hodgkin's lymphoma. AB - The mechanisms of systemic immunosuppression in B-cell non-Hodgkin's lymphoma (NHL) are poorly characterized. Lin and colleagues collected blood from 40 NHL patients prior to therapy. Monocytes from NHL patients suppressed T-cell proliferation, were unresponsive to Toll-like receptor stimulation by CpG and resistant to maturing into CD83(+) dendritic cells. This suppression was mediated in part through arginine metabolism, as exogenous arginine supplementation reversed this, and NHL patients had elevated arginase I in their plasma. These cells had decreased HLA-DR and TNF-alpha receptor II (CD120b) expression compared with controls. Patients with increased ratios of CD14(+)HLA-DR(low/-) monocytes had more advanced disease and suppressed immune functions, indicating that CD14(+)HLA-DR(low/-) monocytes are a pivotal and profoundly effective contributor to systemic immunosuppression in NHL. PMID- 21668221 TI - Search for pair production of second-generation scalar leptoquarks in pp collisions at ?s = 7 TeV. AB - A search for pair production of second-generation scalar leptoquarks in the final state with two muons and two jets is performed using proton-proton collision data at ?s = 7 TeV collected by the CMS detector at the LHC. The data sample used corresponds to an integrated luminosity of 34 pb-1. The number of observed events is in good agreement with the predictions from the standard model processes. An upper limit is set on the second-generation leptoquark cross section times beta2 as a function of the leptoquark mass, and leptoquarks with masses below 394 GeV are excluded at a 95% confidence level for beta = 1, where beta is the leptoquark branching fraction into a muon and a quark. These limits are the most stringent to date. PMID- 21668309 TI - Homeostatic proliferation of NK cells: friend or foe in cellular immunotherapy? AB - NK cells are an important tool in cellular immunotherapy owing to their role in infections and antitumor immunity. Until recently, these cells have been thought to be short-lived cytotoxic effectors that are cleared from the body soon after resolution of an immune response. In the commented study, Sun et al. confirmed that, similar to T cells, NK cells sensed the space in the immune system and underwent homeostatic proliferation in order to provide necessary protection to the body. Moreover, homeostatically driven NK cells persisted in the tissues for a long time without loss of activity. These findings have important consequences for immunotherapy, suggesting that the mechanisms of homeostatic expansion can be deployed in order to expand NK cells for therapeutic purposes in vivo. As homeostatically driven NK cells are long-lived effectors, such therapies can exert prolonged effects for the immunity of the patients. PMID- 21668310 TI - Epitope spreading contributes to effective immunotherapy in metastatic melanoma patients. AB - In recent years, there have been reports of immunotherapy inducing objective clinical responses in limited numbers of cancer patients. More frequently, however, clinical responses are not observed. Understanding the immunological mechanisms underlying successful immunotherapy are crucial if the field is to move forward. In the article under evaluation, Coulie et al. examine the T-cell receptor repertoire in a melanoma patient showing durable remission after MAGE specific immunotherapy. The paper provides convincing evidence that the phenomenon of epitope spreading is critical to the development of effective antitumor immunity. PMID- 21668312 TI - Subcutaneous versus sublingual immunotherapy for allergic rhinitis and/or asthma. AB - Subcutaneous allergen-specific immunotherapy has long been used in allergic rhinitis and/or asthma and has been recognized to be efficacious. However, owing to the inconvenience of injection and the risk of serious side effects, alternative concepts inspiring the search for effective noninjective routes, namely sublingual administration of allergens, have emerged. Sublingual immunotherapy (SLIT) appears to be associated with a lower incidence of systemic reactions. The clinical efficacy of subcutaneous immunotherapy (SCIT) is well established for both rhinitis and asthma. Meta-analyses relating to its efficacy on asthma and rhinitis are available. SLIT has also been validated in this respect. Comparative clinical studies of SLIT versus SCIT are scarce demonstrating both routes to be clinically efficient. Knowledge of the exact mechanism of action of SLIT has been increasing in the last decade. In addition, recent studies have proved similarities of the immunological changes with the treatment of both routes. Further comparative clinical and immunological studies of SLIT versus SCIT are needed to confirm the long-term efficacy and to complete the knowledge of immunological mechanisms of both routes. Moreover, better understanding of the interaction of allergen and oral mucosal dendritic cells during SLIT may allow improved targeting of SLIT vaccines. PMID- 21668311 TI - Dual antigen target-based immunotherapy for prostate cancer eliminates the growth of established tumors in mice. AB - AIMS: We have previously shown that immunization with an adenovirus vector carrying an individual antigen induces antigen-specific CD8 T cells actively engaged in the destruction of tumor cells expressing the cognate antigen. In order to expand the range of antitumor responses beyond an individual antigen, we designed a recombinant adenovirus type 5 (rAd5) carrying a fusion construct of two full-length antigens. We used this adenovirus vector to test the concept that multiantigenic effector T cells could be generated simultaneously following a single immunization. METHOD: To perform the rAd5 constructs, we selected a combination of prostate-specific antigen (PSA) and prostate stem cell antigen (PSCA) genes based on their restricted distribution within the prostate tissue and their association with the development and progression of prostate cancer. RESULTS: Immunization of mice with rAd5 vector carrying a fusion construct of PSA and PSCA (Ad5-PSA/PSCA) simultaneously induced the expansion of anti-PSA and anti PSCA CD8 T cells, as measured by intracellular cytokine staining for IFN-gamma. The antigen-specific T-cell responses that developed were efficient in eliminating the target cells expressing cognate antigens measured by an in vivo cytotoxic T-cell assay. The in vivo tumor growth study showed that immunization of mice with Ad5-PSA/PSCA vaccine induced strong antitumor immunity when challenged with mouse prostate tumor cell lines (RM11) expressing human PSA (RM11/PSA). To further analyze the impact on therapeutic efficacy of Ad5-PSA/PSCA vaccine against the tumor cells expressing PSA and PSCA (RM11-PSA/PSCA) antigens, we injected mice with Ad5-PSA/PSCA vaccine. The vaccine inhibited the growth of established tumors with 80% of the mice becoming tumor free. These data provide useful information that antigen-specific effector T cells can be generated simultaneously and that their additive antitumor effect has the potential to eliminate the growth of established tumors. Therefore, the immunotherapy approach of using the simultaneous targeting of dual antigens associated with prostate cancer may have important implications for human clinical trials. PMID- 21668314 TI - Natural and adoptive T-cell immunity against herpes family viruses after allogeneic hematopoietic stem cell transplantation. AB - Reactivated infections with herpes family-related cytomegalovirus, Epstein-Barr virus and varicella zoster virus are serious and sometimes life-threatening complications for patients undergoing allogeneic hematopoietic stem cell transplantation. The pathogenesis of these infections critically involves the slow and inefficient recovery of antiviral T-cell immunity after transplantation. Although efficient drugs to decrease viral load during this vulnerable period have been developed, long-term control of herpes viruses and protection from associated diseases require the sufficient reconstitution of virus-specific memory T cells. To heal the deficiency by immunotherapeutic means, numerous research groups have developed antiviral vaccines and strategies based on the adoptive transfer of virus-specific T cells. This article summarizes the substantial progress made in this field during the past two decades and gives future perspectives about challenges that need to be addressed before antigen specific immunotherapy against herpes family viruses can be implemented in general clinical practice. PMID- 21668313 TI - Immune recognition and rejection of allogeneic skin grafts. AB - The transplantation of allogeneic skin grafts is associated with a potent inflammatory immune response leading to the destruction of donor cells and the rejection of the graft. Shortly after transplantation, skin dendritic cells (DCs) migrate out of the graft through lymphatic vessels and infiltrate the recipient's draining lymph nodes where they present donor antigens via two mechanisms: the direct pathway, in which T cells recognize intact donor MHC antigens on donor DCs; and the indirect pathway, involving T-cell recognition of donor peptides bound to self-MHC molecules on recipient DCs. Some recent studies have suggested that T cells can become activated via recognition of donor MHC molecules transferred on recipient antigen-presenting cells (semidirect pathway). Activation of T cells via direct or indirect allorecognition is sufficient to trigger acute rejection of allogeneic skin grafts. In addition, allospecific antibodies contribute to the rejection process either by killing allogeneic targets in a complement-dependent fashion or by opsonizing donor cells and forming immune complexes. Finally, several studies demonstrate that NK cells, activated due to missing self-MHC class I molecules on allogeneic cells, are involved in allogeneic skin graft rejection via direct killing of donor cells and through the production of proinflammatory cytokines including IFN-gamma and TNF alpha. PMID- 21668318 TI - Leydig cell tumour of the ovary localised with positron emission tomography/computed tomography. AB - Androgen-producing ovarian tumours can lead to assessment difficulties because of their small size. We present a case of virilising steroid cell ovarian tumour in a 41-year-old woman localised with Fluorine-18-Deoxyglucose Positron Emission Tomography/Computed Tomography ((18)FDG-PET/CT). Although the biochemical evaluation pointed to an ovarian source of androgen, diagnostic attempts to localise the source of hyperandrogenism with transvaginal ultrasound (US), and magnetic resonance imaging (MRI) of pelvis failed. Additional evaluation with (18)FDG-PET/CT showed an increased uptake in the right ovary. A laparoscopic right oophorectomy was performed and histopathology examination revealed a 1.2-cm Leydig cell tumour. The patient showed regression of clinical signs. PMID- 21668319 TI - Factors associated with asthma control among adults in five New England states, 2006-2007. AB - BACKGROUND: Despite the National Asthma Education and Prevention Program (NAEPP) guidelines that specify the goals of asthma control and management strategies, the number of patients with uncontrolled asthma remains high, and factors associated with uncontrolled asthma are unknown. OBJECTIVE: The aim was to examine the relationship between asthma control and socio-demographic characteristics, health-care access and use, asthma education, and medication use among adults with active asthma residing in New England. METHODS: Data from the 2006-2007 Behavior Risk Factor Surveillance System Adult Asthma Call-Back Survey were analyzed using multinomial logistic regression. Asthma control was categorized as "well controlled," "not well controlled," or "very poorly controlled" according to the NAEPP guidelines. RESULTS: Of the respondents (n = 3079), 30% met the criteria for well-controlled asthma, 46% for not well controlled asthma, and 24% for very poorly controlled asthma. Being of Hispanic ethnicity (odds ratio [OR] = 4.0; 95% confidence interval [CI] = 1.2-13.7), unemployed or unable to work (OR = 17.9; 95% CI = 6.0-53.4), high school educated or less (OR = 2.8; 95% CI = 1.6-4.7), current smokers (OR = 2.5; 95% CI = 1.3 5.1), or being unable to see a doctor or specialist for asthma care or unable to buy medication for asthma because of cost (OR = 7.6; 95% CI = 3.4-17.1) were associated with very poorly controlled asthma. In addition, having Coronary Obstructive Pulmonary Disease (COPD) (OR = 2.6; 95% CI = 1.5-4.5), two or more routine checkups for asthma (OR = 4.5; 95% CI = 2.3-8.9), or an emergency department visit, urgent care facility visit, and hospitalization in the past year (OR = 3.9; 95% CI = 2.1-7.3) were also associated with having very poorly controlled asthma. Using controller medication in the past year (OR = 2.6; 95% CI = 1.6-4.2) and taking a course on how to manage asthma (OR = 3.0; 95% CI = 1.2 7.8) were significantly associated with poor asthma control. CONCLUSION: The high prevalence (70%) of not well-controlled asthma and poorly controlled asthma in this study emphasizes the need to identify factors associated with poor asthma control for development of targeted intervention. A health policy of increasing asthma education, health-care access, and smoking cessation may be effective and result in better asthma control and management. PMID- 21668315 TI - The CD8 T-cell road to immunotherapy of toxoplasmosis. AB - Toxoplasma gondii infection induces a robust CD8 T-cell immunity that is critical for keeping chronic infection under control. In studies using animal models, it has been demonstrated that the absence of this response can compromise the host ability to keep chronic infection under check. Therapeutic agents that facilitate the induction and maintenance of CD8 T-cell response against the pathogen need to be developed. In the last decade, major strides in understanding the development of effector and memory response, particularly in viral and tumor models, have been made. However, factors involved in the generation of effector or memory response against T. gondii infection have not been extensively investigated. This information will be invaluable in designing immunotherapeutic regimens needed for combating this intracellular pathogen that poses a severe risk for pregnant women and immunocompromised individuals. PMID- 21668320 TI - Validity and specificity of the Persian version of the Saint George Respiratory Questionnaire. AB - INTRODUCTION: The Saint George Respiratory Questionnaire (SGRQ) is a well-known questionnaire for evaluating the quality of life in asthmatic patients. It has been translated to Persian and its validity and specificity should be evaluated for chronic obstructive pulmonary disease patients. In this study, we attempted to improve the questionnaire's adaptability to Persian culture and also evaluate its validity, specificity, and applicability among asthmatics at our tertiary referral center. MATERIALS AND METHODS: Previously translated and psychometrically evaluated SGRQ for chronic obstructive pulmonary disease patients was made more adaptive to Persian. Upon acceptability of the questionnaire by a small group of patients, 301 asthmatics referred for spirometry and completed the form. Consistency was evaluated using Cronbach's alpha coefficient and validity was assessed by comparison of scores with other measures of asthma exacerbation. These measures included FEV1, patient's clinical presentation, visual analog scale (used to assess difficulty breathing), Katz activity index and section scores of the General Health Questionnaire, anxiety, depression, and social impact. RESULTS: The study group included 165 female and 139 male asthmatics with a mean age of 44.4 +/- 1.0 years. Measurement of consistency for the SGRQ revealed Cronbach's alpha to be 0.699 for symptoms, 0.805 for activity, 0.879 for impact, and 0.916 for the total questionnaire. By omitting question 8, time of wheezing during the day increased Cronbach's coefficient of the symptoms section to 0.719. Omitting "uselessness of respiratory drugs" from the impact section increased Cronbach's alpha to 0.881. However, scoring of the section then varied from the original questionnaire. A statistically significant correlation was found between the SGRQ sections and total score (using Katz index and General Health Questionnaire, p < .001). CONCLUSION: Our study showed good validity and reliability for the Persian version of SGRQ for a population of asthmatics referred to our tertiary pulmonary clinic. PMID- 21668321 TI - The effect of physiotherapy-based breathing retraining on asthma control. AB - BACKGROUND: The mechanism of the breathing retraining effect on asthma control is not adequately based on evidence. OBJECTIVE: The present study was designed to evaluate the effect of physiotherapy-based breathing retraining on asthma control and on asthma physiological indices across time. STUDY DESIGN: A 6-month controlled study was conducted. Adult patients with stable, mild to moderate asthma (n = 40), under the same specialist's care, were randomized either to be trained as one group receiving 12 individual breathing retraining sessions (n = 20), or to have usual asthma care (n = 20). The main outcome was the Asthma Control Test score, with secondary outcomes the end-tidal carbon dioxide, respiratory rate, spirometry, and the scores of Nijmegen Hyperventilation Questionnaire, Medical Research Council scale, and SF-36v2 quality-of-life questionnaire. RESULTS: The 2 * 4 ANOVA showed significant interaction between intervention and time in asthma control (F = 9.03, p < .001, eta(2) = 0.19), end tidal carbon dioxide (p < .001), respiratory rate (p < .001), symptoms of hypocapnia (p = .001), FEV1% predicted (p = .022), and breathlessness disability (p = .023). The 2 * 4 MANOVA showed significant interaction between intervention and time, with respect to the two components of the SF-36v2 (p < .001). CONCLUSION: Breathing retraining resulted in improvement not only in asthma control but in physiological indices across time as well. Further studies are needed to confirm the benefits of this training in order to help patients with stable asthma achieve the control of their disease. PMID- 21668322 TI - Microbial pathogens causative of neonatal sepsis in Arabic countries. AB - OBJECTIVE: Neonatal sepsis is a major cause of morbidity and mortality worldwide. We analyzed the spectrum of pathogens causing neonatal sepsis in various Arabic countries. METHODS: We analyzed hospital-based published studies on neonatal sepsis in eight Arabic countries documenting etiological pathogens and onset of sepsis published between 1990 and 2009. RESULTS: Twelve studies from eight Arabic countries including 2308 newborns with culture proven sepsis and clinical signs of sepsis reported that early onset sepsis ranged from 24 to 74%. Gram-negative organisms were the predominant pathogens in Libya, Egypt, Jordan, and Iraq (65 90% of all sepsis cases) with Klebsiella species (spp.), Serratia spp., Enterobacter spp., Escherichia coli, and Pseudomonas spp. being the most frequent bacteria. In Saudi Arabia, Bahrain and Kuwait, the Gram-positive microorganisms, coagulase negative Staphylocooci and Staphylococcus aureus were taking the lead (64-75%). Group B Streptococci were the predominant pathogen (24%) in the United Arab of Emirates (UAE). Candida species were emerging in Egypt, UAE, Bahrain, and Kuwait. CONCLUSION: The spectrum of microorganisms responsible for neonatal sepsis varies considerably in different Arabic countries. The predominance of Gram-negative bacteria as well as the emergence of Candida species in some areas asks for neonatal networks, benchmarking instruments, and surveillance programs of microorganisms. PMID- 21668324 TI - Acute fatty liver of pregnancy: diagnosis, treatment, and outcome based on 35 consecutive cases. AB - OBJECTIVE: We describe our experience with the clinical diagnosis, management and, course of patients with acute fatty liver of pregnancy (AFLP). METHODS: During the period between January 1996 and June 2010, medical records of patients with AFLP were reviewed for symptoms, laboratory findings, clinical course, and maternal and perinatal outcomes. Routine laboratory evaluation included serial measurement of liver function tests, complete blood cell counts, coagulation profile, and renal function tests. RESULTS: During the study period 35 women had AFLP as the discharge diagnosis. The mean gestational age at delivery was 36 weeks, 39% were nulliparous and 4 had multiple gestation. The most common presenting symptom was nausea/vomiting (88.5%), jaundice (71.4%), and abdominal pain (51.4%). Maternal morbidity included hypoglycemia (94.2%), renal failure (94.2%), coagulopathy (77.1%), ascites (48.5%), and encephalopathy (40%). There were four maternal deaths (11.4%) and five perinatal deaths (12.5%). CONCLUSION: We found a typical 'AFLP-Triad' in women with AFLP. First (symptoms): nausea/vomiting, jaundice, epigastric pain; second (laboratory): results indicated renal dysfunction, coagulopathy, liver function abnormalities, low glycemia, and third (complications): renal failure, coagulopathy, ascites, and encephalopathy. We recommended that patients with this triad received evaluation to rule out the diagnosis of AFLP. PMID- 21668325 TI - AMTAS((r)): automated method for testing auditory sensitivity: III. sensorineural hearing loss and air-bone gaps. AB - OBJECTIVE: The objectives were to measure the occlusion effect produced by three earphones-circumaural, supra-aural, and insert-and to compare air- and bone conduction thresholds obtained with manual and automated methods for subjects with sensorineural hearing loss. DESIGN: Acoustic and psychoacoustic occlusion effects were measured with each earphone. Manual and automated, air- and bone conduction thresholds were compared. STUDY SAMPLE: Occlusion effects were measured for six adult subjects with normal external and middle ears. Pure-tone thresholds were measured for nineteen ears of thirteen subjects with sensorineural hearing loss. RESULTS: The supra-aural earphone produced the largest occlusion effects, followed by the insert and circumaural earphones. Some systematic differences in air-conduction thresholds were found for the two procedures that may be attributable to earphone differences. A large air-bone gap at 4 kHz, reported in a previous study, was replicated. CONCLUSIONS: From 0.5 to 8.0 kHz, occlusion effects produced by the circumaural earphone are sufficiently small that covering the ear does not appreciably alter bone-conduction thresholds. Air-conduction threshold differences warrant further study to determine if reference equivalent threshold sound pressure levels for the two earphones produce equivalent thresholds. The large air-bone gap at 4 kHz suggests the possibility of an incorrect reference equivalent threshold force level at that frequency. PMID- 21668323 TI - Why women request cesarean section without medical indication? AB - OBJECTIVE: To understand the reasons of the cesarean delivery on maternal request (CDMR) without medical indication would help to reduce the rates of unnecessary cesarean-delivery (CD). The objective of this study is to determine the basal knowledge of women regarding normal delivery (ND) and CD and also to assess their attitudes about CDMR, and to find out the reasons influencing those attitudes. METHODS: The study included 400 women who completed a 45-item questionnaire that assessed their basal knowledge of ND, CD, and their attitudes and beliefs about the mode of delivery and CDMR. RESULTS: Mean age of the study population was 32 +/- 10.2 years (range 18-66). Majority of the women would choose the ND because of its 'being completely natural' (89%) and no anesthesia and operative risk related with ND (76%). Only 33% of the women indicated that ND might cause genital organ prolapse and/or stress urinary incontinence and just 26% and 24% of the women would choose CD to prevent pelvic organ prolapse and stress urinary incontinence, respectively. On the other hand, 50% and 54% of the women would indicate that they could choose CD in order to prevent labor pain and to minimize the risk of fetal distress during the labor. Furthermore, 47% of the women had an opinion that that CD could be performed by maternal request without medical indication. Educational level had no effect of CDMR although more educated women had more accurate knowledge about the some risk and benefits of ND and CD. Binary logistic regression analysis revealed that fear of labor pain (p = 0.02, OR: 15.0, CI: 0.494-0.966), maternal age (p = 0.01, OR: 6.3,CI: 1.00-1.05), and knowledge about the relation between the ND and pelvic organ prolapse/urinary incontinence (p < 0.001, OR: 4.8, CI: 0.549-0.966) were the independent prognostic variables for the CDMR. CONCLUSION: Although majority of the women had wrong idea or no idea about the risks and benefits of CD, nearly half of them indicated that women can always demand CDMR. This study shows that basal knowledge of the women should be improved by education. PMID- 21668326 TI - The effects of reverberation on a listener's ability to recognize target sentences in the presence of up to three synchronized masking sentences. AB - OBJECTIVE: To determine the effects of room reverberation on target sentence recognition in the presence of 0-to-3 synchronous masking sentences. DESIGN: Target and masker sentences were presented through four loudspeakers (+/- 90 degrees and +/- 45 degrees azimuth; 1m from the listener) in rooms having reverberation times (RT) of 0.2, 0.4, 0.6, and 1.1 s. STUDY SAMPLE: Four groups of 13 listeners each participated in the study (N = 52). RESULTS: In rooms with RTs of 0.2, 0.4, and 0.6 s, mean speech recognition scores (SRSs) were similar, with scores ranging from 96-100%, 90-95%, 75-80%, and 53-60%, when 0, 1, 2, and 3 competing sentences were present, respectively. However, in the room with a RT = 1.1 s, SRSs deteriorated significantly faster as the number of competing sentences increased; mean scores were 93%, 73%, 26%, and 10%, in the 0, 1, 2, 3, competing sentence condition, respectively. The majority of errors in SRSs (98%) resulted from listeners reporting words presented in masking sentences along with those in target sentences (mixing errors). CONCLUSIONS: Results indicate that reverberation has a similar influence on SRSs measured in multi-talker environments, when room reverberation is <= 0.6 s. However, SRSs are dramatically reduced in the room with a RT = 1.1 s, even when only one competing talker is present. PMID- 21668328 TI - Interventional stress in renal stone treatment. AB - PURPOSE: To compare current minimally invasive strategies in renal stone treatment-shockwave lithotripsy (SWL), retrograde intrarenal surgery (RIRS), and minimally invasive percutaneous nephrolitholapaxy-with regard to interventional stress, measured by changes in interleukin (IL)-6 and C-reactive protein (CRP) serum levels during treatment. PATIENTS AND METHODS: 143 patients underwent stone therapy for renal pelvic stone (SWL, n=40, mean age+/-standard error of the mean [SEM]: 48.3+/-3.1 years; RIRS, n=74, 54.5+/-1.8; and minimally invasive percutaneous nephrolitholapaxy (MIP), n=29, 54.6+/-2.7) between 2006 and 2007. Blood samples were prospectively collected 24 hours before and 24 hours after the procedure. Interventional stress was analyzed by changes of the acute phase proteins IL-6 and CRP. RESULTS: Mean IL-6 (ng/L) difference (+/-SEM; 95% confidence interval [CI]) before and after therapy was +8.7 (+/-10.5; -13.9 31.2), +7.3 (+/-3.2; 1.5-13.1), and +20.5 (+/-8.1; 4.0-36.0) in the SWL, RIRS, and MIP groups, respectively (P=0.20). Differences in mean CRP (mg/dL) levels (+/ SEM; 95% CI) ranged between +0.9 (+/-1.6; -2.3-4.1) in SWL, +1.6 (+/-0.5; 0.6 2.5) in RIRS, and +1.8 (+/-,0.3, 1.2-2.5) in MIP patients (P=0.79). Mean stone sizes (mean/median mm(2)+/-SEM) differed significantly between SWL (27/20+/-3), RIRS (70/16+/-36), and MIP groups (346/160+/-104, P<0.0005). CONCLUSION: Contrary to common opinion that SWL is the least invasive therapy, the reported stress parameters did not show significant differences between SWL, RIRS, and MIP, although significantly bigger stones were treated with MIP. PMID- 21668332 TI - How basal insulin analogs have changed diabetes care. PMID- 21668333 TI - Pharmacokinetics and pharmacodynamics of basal insulins. AB - The two basal insulin analogs, insulin glargine and insulin detemir, were developed to ameliorate the well-known limitations of NPH insulin. In contrast to rapid-acting analogs, which differ exclusively in terms of primary structure while sharing similar pharmacokinetics (PK) and pharmacodynamics (PD), the two long-acting insulin analogs are different chemical and structural entities, exhibiting distinct modes of protracting the insulin effect. So far, PK and PD studies of long-acting analogs have often shown conflicting results, pointing out different conclusions, thereby leading to animated controversies. The methods used in the evaluation of basal insulins might have been partially responsible as, although the euglycemic clamp technique has been broadly acknowledged to be the "gold standard" reference to assess the glucose-lowering effect of an insulin preparation, its execution and interpretation might have been substantially different across studies, in various methodological and analytical aspects, ultimately providing an explanation for some of these controversies. This review will present and describe the basic methods used in the evaluation of basal insulins and will critically summarize the points that might have been responsible for the different outcomes. The findings of glucose clamp studies demonstrate that the two long-acting insulin analogs are different, to some extent, in both their PK and PD profiles. These differences should be taken into consideration when the individual analogs are introduced to provide basal insulin supplementation to optimize blood glucose control in patients with type 1 and type 2 diabetes as well. PMID- 21668334 TI - Postprandial and basal glucose in type 2 diabetes: assessment and respective impacts. AB - The independent contribution of postprandial glucose (PPG) excursions to the overall glucose exposure and its role in the development of both micro- and macrovascular complications of diabetes remain subject to continuing debate in type 2 diabetes. Discussion continues on whether postprandial hyperglycemia is the main contributor to the overall hyperglycemia in fairly well-controlled individuals, whereas basal hyperglycemia becomes the preponderant contributor in poorly controlled patients. The concern about the role of PPG as a risk factor for diabetes complications is related to the controversial data obtained in individuals with impaired glucose tolerance. It remains, however, that the total glucose exposure as reflected by hemoglobin A1c (HbA1c) levels is an undoubted major vascular risk factor. Excluding the contribution of PPG is nonsensical. In support of this position is the fact that the absolute impact of PPG on HbA1c, expressed as percentage levels of HbA1c, remains constant at 1% across the HbA1c continuum in non-insulin-treated type 2 diabetes patients. This key feature clearly depicts the absolute contribution of PPG in contrast to its relative contribution and better explains why PPG contributes to the excess of glycation with the basal hyperglycemia. PMID- 21668336 TI - Optimizing the replacement of basal insulin in type 1 diabetes mellitus: no longer an elusive goal in the post-NPH era. AB - In physiology, insulin is released continuously by the pancreas at a nearly constant rate between meals and in the fasting state (basal insulin secretion). The pivotal role of basal insulin is to restrain release of glucose from the liver and free fatty acids from adipose tissue, thus preventing hyperglycemia and ketosis. In type 1 diabetes mellitus (T1DM) (absolute insulin deficiency), the replacement of basal insulin is challenging because the currently available pharmacological preparations of long-acting insulin do not exactly reproduce the fine physiology of flat action profile of basal insulin of subjects without diabetes. NPH and NPH-based insulin mixtures no longer have a place in the treatment of T1DM because of their early peak effects and relatively short duration of action, which result into risk of nocturnal hypoglycemia and fasting hyperglycemia, respectively, after the evening injection. Only continuous subcutaneous (s.c.) insulin infusion (CSII) or long-acting analogs such as glargine (>24 h in duration, once a day) and detemir (<24 h in duration, once or more often twice a day) should be used as basal insulin in T1DM in combination with mealtime rapid-acting analogs. CSII and the long-acting analogs are nearly peakless and therefore reduce the risk for hypoglycemia (especially at night), blood glucose (BG) variability, and lower A1C with similar or less hypoglycemia. CSII is the "gold standard" of replacement of basal insulin because of better reproducibility of subcutaneous absorption of soluble insulin. Although CSII is not superior to multiple daily insulin injections in the general T1DM population, CSII might be indicated in subsets of T1DM (long-term T1DM with insulin "supersensitivity" and needs for low-dose insulin, some individuals with variable subcutaneous absorption of long-acting analogs) to minimize BG variability, reduce hypoglycemia, and benefit A1C. PMID- 21668335 TI - Basal insulin treatment in type 2 diabetes. AB - Insulin glargine is the first 24-h recombinant DNA insulin analog introduced to the market. Substitution of glycine for asparagine and addition of two arginine residues raise the isoelectric point of insulin glargine and result in microprecipitates, delaying absorption from subcutaneous tissue. This delayed absorption result in fairly flat 24-h insulin concentration profiles with no discernible peak. Large, multicenter, randomized, controlled trials in patients with type 2 diabetes show that although NPH insulin and insulin glargine are equally effective in lowering glycosylated hemoglobin (A1c) and fasting blood glucose, there is a clear advantage of insulin glargine over NPH insulin in reducing nocturnal and overall hypoglycemia. Lower risk of hypoglycemia with glargine was also consistently demonstrated by trials comparing insulin glargine and premixed analog insulins. These studies also showed greater reduction in A1c with twice-daily premixed insulins compared with glargine, when insulin glargine was administered without mealtime insulin coverage. Insulin glargine was also compared with another insulin analog, insulin detemir. Trials showed that both insulin analogs are equally effective in lowering A1c and have comparable risk of hypoglycemia. Trials comparing insulin glargine with glucagon-like peptide-1 agonists showed comparable significant reductions in A1c with both regimens. Insulin glargine is well tolerated, has low immunogenicity, reduced risks for acute myocardial infarction, and a lower risk of hypoglycemia compared with NPH insulin in individuals with type 2 diabetes. PMID- 21668337 TI - Insulin preparations with prolonged effect. AB - The discovery of insulin and its clinical application early in the last century dramatically improved the prospects of people with diabetes. However, the limitations of those initial, unmodified insulin preparations were quickly recognized; most notably, their relatively "short action" meant that multiple daily subcutaneous injections were required. This stimulated a concerted effort to modify the properties of insulin in order to extend the duration of its blood glucose-lowering effect, minimize dosing frequency, and decrease the burden of treatment. The first successful attempts to prolong insulin's action were achieved by modifying its formulation with additives such as protamine and zinc, culminating in the production of "intermediate-acting" neutral protamine Hagedorn (NPH) insulin in the 1940s and the lente family of insulins in the 1950s. However, NPH and lente insulins were still associated with several limitations, including considerable variability of effect and a pronounced peak in their time action profile. In the 1980s, the focus of research moved toward the modification of insulin itself with the aim of producing a "long-acting" insulin that would better satisfy basal insulin requirements over the entire day. Once-daily insulin glargine was the first "long-acting" insulin analog in clinical practice, followed by once- or twice-daily insulin detemir and, more recently, insulin degludec, which is now being evaluated for administration at less frequent intervals. These analogs demonstrate several benefits over "intermediate-acting" insulins, including a lower risk of both overall hypoglycemia and nocturnal hypoglycemia and reduced day-to-day glucose variability, making it more feasible to achieve better fasting and overall glycemic control. Long-acting insulin analogs (insulin glargine and insulin detemir) are now firmly established as key tools in the battle against diabetes, and ongoing clinical research of insulin based therapy should focus on treatment strategies to maximize their benefits. To date, the clinical experience with insulin degludec is limited but demonstrates it has comparable efficacy to insulin glargine. PMID- 21668338 TI - Hypoglycemia rates with basal insulin analogs. AB - Hypoglycemia has for the most part been studied inadequately for both of the commonly used long-acting insulin analogs in type 1 and type 2 diabetes. Almost all existing trials have been designed to investigate changes in glycemic control and not differences in hypoglycemia events. In this review, we present an overview of the hypoglycemic data available from the randomized controlled trials comparing insulin glargine and insulin detemir with NPH or continuous subcutaneous insulin infusion in type 1 and type 2 diabetes. The limited head-to head glargine versus detemir data are also discussed with comments on early results relating to the newer insulin analog, degludec. Basal insulin analogs are associated with reduced nocturnal hypoglycemia in both type 1 and type 2 diabetes. Most studies have excluded participants with impaired awareness of hypoglycemia or previous severe events, however, and hypoglycemia reporting is variable and inconsistent. This limits interpretation for those with long duration type 1 diabetes, and particularly impaired awareness of hypoglycemia, or long-duration more insulin-deficient type 2 diabetes. New optimally designed studies are required to elucidate the true impact of basal analogs on hypoglycemia burden in those living with long-term insulin therapy. PMID- 21668339 TI - Overall mortality in diabetes mellitus: where do we stand today? AB - Life expectancy for a patient with type 2 diabetes remains substantially shorter than an equivalent individual without diabetes, largely because of a greater risk of cardiovascular disease. Diabetes is also associated with an increased incidence of many types of cancer, suggesting that malignancy may also contribute to higher rates of mortality. Hyperglycemia is one of the key risk factors for diabetes-associated macro- and microvascular disease, and as such, intensive glycemic control is associated with improved outcomes for patients, including a reduction in this risk of death from any cause, when initiated early in the disease course. Recent trials in patients with more advanced disease have failed to demonstrate a mortality benefit with intensive glycemic control, although this may reflect their short observation period. Intensive multifactorial therapy, including lifestyle intervention and control of hyperglycemia, hypertension, lipids, thrombosis, and microalbuminuria, is likely to be the best strategy against diabetes-associated macrovascular mortality. However, analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicates that there may be a subpopulation of patients who are unable to achieve glycemic targets with intensive therapy and that aggressive intensification of treatment in this group may increase mortality risk. It remains to be determined whether the relationship between diabetes and malignancy is causal or whether they share common risk factors. Current recommendations for a healthy lifestyle based on good diet, physical exercise, and weight management in order to control diabetes related complications are likely to apply in reducing the risk of many forms of cancer and should be advocated for all patients. PMID- 21668340 TI - Basal plus basal-bolus approach in type 2 diabetes. AB - Type 2 diabetes is characterized by insulin resistance and progressive beta-cell deterioration. As beta-cell function declines, most patients with type 2 diabetes treated with oral agents, in monotherapy or combination, will require insulin therapy. Addition of basal insulin (glargine, detemir, or NPH/neutral protamine lispro insulin) to previous treatment is accepted as the simplest way to start insulin therapy in those patients. But even when basal insulin is adequately titrated, some patients will also need prandial insulin to achieve or maintain individual glycemic targets over time. Starting with premixed insulin is an effective option, but it is frequently associated with increased hypoglycemia risk, fixed meal schedules, and weight gain. As an alternative, a novel approached known as "basal plus strategy" has been developed. This approach considers the addition of increasing injections of prandial insulin, beginning with the meal that has the major impact on postprandial glucose values. Finally, if this is not enough intensification to basal-bolus will be necessary. In reducing hyperglycemia, this modality still remains the most effective option, even in people with type 2 diabetes. This article will review the currently evidence on the basal plus strategy and also its progression to basal-bolus therapy. In addition, practical recommendations to start and adjust basal plus therapy will be provided. PMID- 21668341 TI - What options are available when considering starting insulin: premix or basal? AB - Several large studies in diabetes have shown that early initiation of intensive therapy is better for the prevention of long-term complications and suggest that patients with more advanced disease may be at increased risk of adverse cardiovascular events. Despite these findings, insulin initiation is often delayed in patients with type 2 diabetes, typically until A1C exceeds 8.5%. Barriers to the use of insulin are many, arising from both a patient and a physician perspective, and the decision to initiate insulin treatment can be influenced by cost, risk of hypoglycemia, convenience, and the potential for weight gain. Choosing when to initiate insulin and which insulin/treatment regimen to adopt in patients with type 2 diabetes is key, and the importance of tailoring treatment to the patient is widely acknowledged. However, there is currently no universal consensus on the optimal course of action. Once-daily basal insulin and twice-daily premix insulin are commonly used for insulin initiation. Relatively few studies have directly compared these starter treatment regimens, although general findings suggest that, although glycemic control appears to be similar with once-daily basal insulin and twice-daily premix, the lower hypoglycemia rates, lower weight gain, simplicity, and convenience associated with basal insulin support its first-line use as a starter insulin regimen in patients failing on oral antidiabetes agents. Variables such as age, body mass index, and bedtime or post-breakfast plasma glucose levels may alter the efficacy of the chosen treatment regimen, further supporting the need to tailor treatment to meet individual patient's requirements. PMID- 21668342 TI - Evolution of devices in diabetes management. AB - Recent technological advancements in insulin administration and glucose monitoring have allowed patients with diabetes to become increasingly involved in their own care. Devices replacing the traditional vial and syringe, such as insulin pens, are gaining popularity and offer simple and convenient insulin administration. Pen devices are associated with improved dose accuracy, reducing the risk of hypo- or hyperglycemia, and are continually being updated with new safety features in order to optimize their performance. In patients for whom glucose variability remains a problem, continuous subcutaneous insulin infusion via an implanted canula or continuous intraperitoneal insulin infusion via an implanted pump is safe and effective when used correctly, although cost can be a limitation. More accurate retrospective and real-time continuous monitoring devices, which can better detect blood glucose excursions, have become standard components of modern-day diabetes management. The most recent devices have sensor signaling capabilities with wireless data transmission, leading to reduced time delay and more accurate alerts. Ultimately, though, while self-management remains a critical factor in improving glycemic control at present, human error may undermine even the most accurate treatment interventions. A key long-term goal in diabetes management is, therefore, to develop an automated and accurate closed loop system for blood glucose monitoring and insulin delivery to better reflect the physiological mechanisms of glucose homeostasis and remove the "human" element. This "artificial pancreas" would offer the most innovative intervention for diabetes management and has the potential to considerably reduce the patient's burden of self-care. PMID- 21668343 TI - Long-term effect of diode laser irradiation compared to sodium fluoride varnish in the treatment of dentine hypersensitivity in periodontal maintenance patients: a randomized controlled clinical study. AB - OBJECTIVE: The aim of this clinical study was to evaluate and compare the desensitizing effects of a gallium?aluminum?arsenide (GaAlAs) laser and sodium fluoride (NaF) varnish on dentine hypersensitivity (DH) in periodontal maintenance patients. BACKGROUND DATA: The use of lasers opens a new dimension in the treatment of DH. METHODS: Forty-eight patients with 244 teeth affected by DH were included in the trial. To be included in the study, the subjects had to have 4 or more hypersensitive teeth at different quadrants. Selected teeth were randomly assigned to a GaAlAs laser group, placebo laser group, NaF varnish group, or a placebo NaF varnish group. Laser therapy was performed at 8.5?J/cm(2) energy density. In the placebo laser group, the same laser without laser emission was used. In the NaF varnish group, the varnish was painted at the cervical region of the teeth. In the placebo NaF varnish group, the same treatment procedures were performed with a saline solution. DH was assessed with a visual analog scale (VAS); immediately, at 1 week, and at 1, 3, and 6 months after treatments. Intra-group time-dependent data were analyzed by Friedman's test, and Wilcoxon's rank sum test was used to evaluate the differences within groups. RESULTS: GaAlAs laser and NaF varnish treatments resulted in a significant reduction in the VAS scores immediately after treatments that were maintained throughout the study when compared to the baseline and placebo treatments. In the NaF group, there was a significant increase in the VAS scores at 3 and 6 months compared to at 1 week and 1 month. The placebo treatments showed no significant changes in VAS scores throughout the study period. CONCLUSIONS: Within the limits of the study, GaAlAs laser irradiation was effective in the treatment of DH, and it is a more comfortable and faster procedure than traditional DH treatment. PMID- 21668344 TI - Semi-closed-loop insulin delivery systems: early experience with low-glucose insulin suspend pumps. PMID- 21668345 TI - Survey of parasites in threatened stocks of coho salmon (Oncorhynchus kisutch) in Oregon by examination of wet tissues and histology. AB - We are conducting studies on the impacts of parasites on Oregon coastal coho salmon (Oncorhynchus kistuch). An essential first step is documenting the geographic distribution of infections, which may be accomplished by using different methods for parasite detection. Thus, the objectives of the current study were to (1) identify parasite species infecting these stocks of coho salmon and document their prevalence, density, and geographic distribution; (2) assess the pathology of these infections; and (3) for the first time, determine the sensitivity and specificity of histology for detecting parasites compared with examining wet preparations for muscle and gill infections. We examined 576 fry, parr, and smolt coho salmon in total by histology. The muscle and gills of 219 of these fish also were examined by wet preparation. Fish were collected from 10 different locations in 2006-2007. We identified 21 different species of parasites in these fish. Some parasites, such as Nanophyetus salmincola and Myxobolus insidiosus, were common across all fish life stages from most basins. Other parasites, such as Apophallus sp., were more common in underyearling fish than smolts and had a more restricted geographic distribution. Additional parasites commonly observed were as follows: Sanguinicola sp., Trichodina truttae , Epistylis sp., Capriniana piscium, and unidentified metacercariae in gills; Myxobolus sp. in brain; Myxidium salvelini and Chloromyxum majori in kidney; Pseudocapillaria salvelini and adult digenean spp. in the intestine. Only a few parasites, such as the unidentified gill metacercariae, elicted overt pathologic changes. Histology had generally poor sensitivity for detecting parasites; however, it had relatively good specificity. We recommend using both methods for studies or monitoring programs requiring a comprehensive assessment of parasite identification, enumeration, and parasite-related pathology. PMID- 21668346 TI - The pervasiveness, connectedness, and intrusiveness of social network site use among young adolescents. AB - Young adolescents are quickly becoming avid users of social networking sites (SNSs); however, little is known regarding how they use these sites. The goal of the present study was to examine the extent to which young adolescents use SNSs, with whom they connect via these sites, and whether SNS use disrupts daily functioning. Among 268 middle-school students surveyed, 63% reported having their own profile page on an SNS. On average, adolescents reported having 196 SNS contacts (friends), most of whom were known peers. Young adolescents with an SNS spent most of their time viewing and responding to comments written on their profile page. Among the SNS users, 39% reported getting behind on schoolwork and 37% reported losing sleep at least once because they were visiting an SNS. As SNS use becomes embedded in young teens' daily lives, it is important to better understand how such use affects their daily adaptive functioning. PMID- 21668347 TI - In vivo imaging of chikungunya virus in mice and Aedes mosquitoes using a Renilla luciferase clone. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that in humans causes an acute febrile illness characterized by fever, arthralgia, and rash. It is currently associated with large outbreaks in Asia, Africa, and islands of the Indian Ocean and has been introduced from these tropical regions into Europe, where local transmission has been recorded on two occasions. The underlying basis of the pathogenesis of CHIKV and related alphaviruses that produce similar symptoms remains unclear. By applying new techniques, for example, in vivo imaging in live animals and arthropods, we may improve our understanding of viral pathogenesis in vertebrates and viral replication in mosquitoes. This technical report describes the evaluation of a CHIKV?luciferase clone to visualize infection and dissemination in both Aedes aegypti and Aedes albopictus mosquitoes and mice. In mosquitoes, luciferase activity was seen at 3 and 7 days post infection in both head and abdomens. In vivo imaging of CHIKV-luciferase was detected in mice for up to 5 days post-infection at the site of inoculation with limited dissemination to the skeletal muscle. PMID- 21668348 TI - Toxicity of high-dose intravitreal adalimumab (Humira) in the rabbit. AB - PURPOSE: To evaluate the ocular toxicity of escalating doses of intravitreous adalimumab (Humira(r)) in the rabbit eye. METHODS: Thirty New Zealand albino rabbits received intravitreous injections of 0.5 mg (6 eyes), 1.0 mg (6 eyes), 2.5 mg (6 eyes), 5 mg (6 eyes), and 10 mg (6 eyes) adalimumab. Slit lamp biomicroscopy and fundoscopy were carried out at baseline, day 7, and day 14 after intravitreous injection, whereas electroretinography (ERG) was carried out at baseline and day 14. Animals were euthanized on day 14, and histopathological examination of the eyes was performed. RESULTS: Slit lamp biomicroscopy and fundoscopy were normal in all eyes receiving doses up to 5 mg. In the 10 mg group, 3 of 6 eyes showed mild anterior chamber inflammatory reaction on day 7. Similarly, scotopic and photopic a- and b-wave ERG amplitudes at baseline and day 14 were similar in all groups up to 5 mg, but there was a significant decrease in the photopic-wave ERG response in the 10 mg group (P=0.046). Finally, histopathology demonstrated no differences among eyes receiving balanced salt solution, 0.5, 1.0, 2.5, 5.0, or 10 mg of adalimumab. CONCLUSIONS: Intravitreous adalimumab exhibited no associated ocular short-term toxicity in rabbit eyes up to the 5 mg dose. In the 10 mg group mild clinical findings and ERG amplitude reduction could reflect early toxicity. PMID- 21668349 TI - "It's the consultation, stupid!".... Isn't it? PMID- 21668350 TI - The statistics of skin impedance. PMID- 21668351 TI - Prameha in Ayurveda: correlation with obesity, metabolic syndrome, and diabetes mellitus. Part 2--management of Prameha. AB - BACKGROUND: Obesity, metabolic syndrome, and diabetes mellitus are increasing to epidemic proportions globally. Prameha is a syndrome described in the ancient Ayurvedic texts that includes clinical conditions involved in obesity, prediabetes, diabetes mellitus, and metabolic syndrome. MATERIALS AND METHODS: Various dietary, lifestyle, and psychologic factors are involved in the etiology of Prameha, particularly in relation to disturbances in fat and carbohydrate metabolism. RESULTS: The Ayurvedic management of Prameha emphasizes dietary and lifestyle recommendations and herbal preparations, in accordance with the psychophysiologic constitution of the patient. Ayurveda also addresses the management of psychologic factors that contribute to the development of Prameha. Ayurvedic treatment known as Apatarpana (balanced diet with restricted calories) and Santarpana (highly nutritious, high-calorie diet intended to increase weight) are recommended for patients with type 2 and type 1 diabetes, respectively. Various Ayurvedic herbs and herbomineral formulations are utilized, based on the stage and type of disease as well as the psychophysiologic constitution of the patient. A large body of research has been conducted on these Ayurvedic herbs. CONCLUSIONS: Integrating the theory and modalities of Ayurveda in the management of these disorders may prove to be beneficial. PMID- 21668352 TI - Minimally invasive subnasal elevation and antral membrane balloon elevation along with bone augmentation and implants placement. AB - Atrophic edentulous anterior maxilla is a challenging site for implant placement and has been successfully treated surgically by anterior maxillary osteoplasty. This procedure is associated with considerable discomfort, morbidity, and cost and consequently reduced patient acceptance. The efficacy and safety of minimally invasive bone augmentation of the posterior maxilla has not been extended thus far to the anterior subnasal maxilla. We present 2 representative cases in which minimally invasive subnasal floor elevation was performed along with minimally invasive antral membrane balloon elevation. Both segments underwent bone grafting and implant placement during the same sitting. Minimally invasive anterior maxilla bone augmentation appears to be feasible. Designated instruments for alveolar ridge splitting and nasal mucosa elevation are likely to further enhance this initial favorable experience. PMID- 21668354 TI - Fractal patterns applied to implant surface: definitions and perspectives. AB - Fractal patterns are frequently found in nature, but they are difficult to reproduce in artificial objects such as implantable materials. In this article, a definition of the concept of fractals for osseointegrated surfaces is suggested, based on the search for quasi-self-similarity on at least 3 scales of investigation: microscale, nanoscale, and atomic/crystal scale. Following this definition, the fractal dimension of some surfaces may be defined (illustrated here with the Intra-Lock Ossean surface). However the biological effects of this architecture are still unknown and should be examined carefully in the future. PMID- 21668353 TI - Associations between physical activity and postpartum depressive symptoms. AB - BACKGROUND: Postpartum women are at increased risk for developing depression, which can contribute to the ill health of the mother and her family. Previous research indicates that mothers who are physically active during leisure experience lower levels of postpartum depressive symptoms than do inactive mothers. The objective of this investigation was to examine the associations between total and domain-specific moderate to vigorous physical activity (MVPA) and depressive symptoms postpartum. METHODS: Data were obtained from 550 women who participated in the Pregnancy, Infection, and Nutrition (PIN) Postpartum Study, a prospective cohort of mothers who delivered liveborn infants from October 2002 to December 2005 in North Carolina. Three-month postpartum MVPA was investigated as a predictor of 12-month postpartum depressive symptoms. RESULTS: Those who participated in MVPA had two times the odds of developing elevated depressive symptoms at 12 months postpartum than those with no MVPA (odds ratio [OR] 2.00, 95% confidence interval [CI] 0.71-6.75). Different associations were suggested when examining domain-specific MVPA. Those participating in adult and child care and indoor household MVPA at 3 months postpartum had more than double the odds of developing elevated depressive symptoms at 12 months postpartum (OR 2.66, 95% CI 1.03, 8.11 and OR 2.72, 95% CI 0.96-10.18, respectively). Work MVPA conferred a doubling of the odds (OR 1.95, 95% CI 0.46-7.13), but recreational and outdoor household MVPA showed no associations with depressive symptoms. CONCLUSIONS: Associations between MVPA and depressive symptoms differed by domain among postpartum women. Future studies of postpartum depressive symptoms should explore reasons for differences in physical activity by domain. PMID- 21668355 TI - Prevalence, motivations, and adverse effects of vaginal practices in Africa and Asia: findings from a multicountry household survey. AB - BACKGROUND: Women worldwide use various vaginal practices to clean or modify their vulva and vagina. Additional population-level information is needed on prevalence and motivations for these practices, characteristics of users, and their adverse effects. METHODS: This was a household survey using multistage cluster sampling in Tete, Mozambique; KwaZulu-Natal, South Africa; Yogyakarta, Indonesia; and Chonburi, Thailand. In 2006-2007, vaginal practices and their motivations were examined using structured interviews with women 18-60 years of age (n=3610). RESULTS: Prevalence, frequency, and motivations varied markedly. Two thirds of women in Yogyakarta and Chonburi reported one or more practices. In Yogyakarta, nearly half ingest substances with vaginal effects, and in Chonburi, external washing and application predominate. In Tete, half reported three or four current practices, and a quarter reported five or more practices. Labial elongation was near universal, and 92% of those surveyed cleanse internally. Two third's in KwaZulu-Natal practiced internal cleansing. Insertion of traditional solid products was rare in Chonburi and Yogyakarta, but one tenth of women in KwaZulu-Natal and nearly two thirds of women in Tete do so. Multivariate analysis of the most common practice in each site showed these were more common among less educated women in Africa and young urban women in Asia. Explicit sexual motivations were frequent in KwaZulu-Natal and Tete, intended for pleasure and maintaining partner commitment. Practices in Chonburi and Yogyakarta were largely motivated by femininity and health. Genital irritation was common at African sites. CONCLUSIONS: Vaginal practices are not as rare, exotic, or benign as sometimes assumed. Limited evidence of their biomedical consequences remains a concern; further investigation of their safety and sexual health implications is warranted. PMID- 21668357 TI - Binding of 2-acetylaminofluorene to DNA. AB - 2-Acetylaminofluorene (2-AAF) is a carcinogenic and mutagenic derivative of fluorene. It is used as a biochemical tool in the study of carcinogenesis. Studies have shown that it induces tumors in a number of species in the liver, bladder, and kidney. It is thought that 2-AAF-DNA adduct formation leads to mutation, and eventually tumor formation. The aim of this study was to examine the interactions of AAF with calf-thymus DNA in aqueous solution at physiological conditions, using constant DNA concentration (12.5 mM) and various AAF/polynucleotide (phosphate) ratios of 1/120, 1/80, 1/40, 1/20, 1/10, 1/5, 1/2, and 1/1. Fourier transform infrared and UV-visible spectroscopic methods and molecular modeling were used to determine the ligand binding mode, the binding constant, and the stability of AAF-DNA complexes in aqueous solution. Spectroscopic evidence showed both intercalation and external binding of AAF to DNA with an overall binding constant of K(AAF-DNA) = 2.33 * 10(7) M(-1). 2-AAF induced a partial B to A-DNA transition and DNA aggregation was observed at high AAF content. PMID- 21668356 TI - Association of signal transducer and activator of transcription 3 gene polymorphisms with cervical cancer in Chinese women. AB - Signal transducer and activator of transcription (STAT) plays an important role in regulating cell proliferation, differentiation, and apoptosis. Previous studies revealed that abnormal expression/activation of STAT family members were present in a large group of human malignant tumors. In the present study, using polymerase chain reaction (PCR)-restriction fragment length polymorphism, DNA sequencing, and Taqman probe real-time PCR techniques, we analyzed two single nucleotide polymorphisms (SNPs) in the STAT5B and STAT3 genes (rs6503691 and rs4769793, respectively) in 275 Chinese cervical cancer patients and 340 controls. Our results indicated that the genotype and allele frequencies of SNP rs4769793 were significantly different between the cervical cancer patients and normal subjects (p < 0.05, odds ratio = 1.35, 95% confidence interval = 1. 07 1.70). In addition, stratified analyses revealed that the polymorphism of rs4769793 was also associated with poor tumor differentiation and positive parametrial invasion (p < 0. 05). In contrast, SNP rs6503691 did not show any difference between patients and controls or association with patient clinical characteristics. Collectively, these findings suggested that STAT3 gene polymorphism (rs4769793) was associated with the susceptibility as well as poor differentiation and parametrial invasion of cervical cancer in Chinese women. PMID- 21668358 TI - Inflammatory responses at epithelial cell surfaces. PMID- 21668359 TI - Induction of inflammatory cytokines and toll-like receptors in human normal respiratory epithelial cells infected with seasonal H1N1, 2009 pandemic H1N1, seasonal H3N2, and highly pathogenic H5N1 influenza virus. AB - Respiratory epithelial cells are one of main targets for infections caused by influenza viruses. Recently, the induction of proinflammatory cytokines and toll like receptors (TLRs) in normal human bronchial/tracheal epithelial cells infected with seasonal H1N1, 2009 pandemic H1N1, seasonal H3N2, or highly pathogenic H5N1 influenza virus were studied to understand the pathogenesis and early immune responses. The cells were productively infected with the viruses. Among the inflammatory cytokines tested, interleukin (IL)-8 was predominantly induced in virus-infected cells. Among the chemokines tested, interferon-gamma inducible protein-10 (IP-10) and growth-related oncogene-alpha (GRO-alpha) were predominantly induced in virus-infected cells. TLR-5 was predominantly induced in cells infected with seasonal H1N1, pandemic H1N1, or H5N1 influenza virus, and TLR-3 was predominantly induced in cells infected with seasonal H3N2 influenza virus. Taken together, the results suggest that IL-8, IP-10, and GRO-alpha are predominantly induced in respiratory epithelial cells infected with influenza A viruses, and that TLR-5 and TLR-3 are involved in the stimulation of virus infected respiratory epithelial cells. PMID- 21668360 TI - Relative contribution of HIV-specific functional lymphocyte subsets restricted by protective and non-protective HLA alleles. AB - Expression of major histocompatibility complex (MHC) class I alleles such as B*57 and B*27 are associated with slow HIV disease progression. HIV-specific immune responses in slow progressors (SP) are characterized by a poly-functional profile. We previously observed within infected subjects that HIV peptide specific responses could differ from each other in their functional composition. We investigate here whether responses restricted by MHC class I alleles associated with slow disease progression have a more poly-functional profile than responses restricted by other alleles. We stimulated peripheral blood mononuclear cells (PBMCs) isolated from 36 chronically HIV-infected individuals with a panel of optimal peptides restricted by the HLA alleles expressed by each subject, and assessed the contribution of single IL-2-, single IFN-gamma-, and IFN-gamma/IL-2 secreting lymphocytes to the total response measured using a dual color ELISPOT assay. The contribution of functional subsets to responses restricted by HLA B*57/B*27 was similar in SP and progressors. For responses restricted by other MHC class I alleles, dual IFN-gamma/IL-2-secreting lymphocytes contributed significantly more to the total response in SP than progressors. Within SP subjects, peptides restricted by both B*57/B*27 and other alleles stimulated responses with similar functional profiles. In progressors, peptides restricted by B*57/B*27 stimulated responses composed of a significantly greater proportion of IFN-gamma/IL-2-secreting cells than peptides restricted by other alleles. Within progressors, the contribution of IFN-gamma/IL-2-secreting lymphocytes was greater to epitopes restricted by protective HLA alleles compared with responses restricted by other alleles. HLA haplotypes influence the relative functional composition of HIV-specific responses. PMID- 21668361 TI - Plasmids enriched with CpG motifs activate human peripheral blood mononuclear cells in vitro and enhance th-1 immune responses to hepatitis B surface antigen in mice. AB - T helper-1 (Th-1)-type immune responses play an important role in viral clearance during infection with hepatitis B virus (HBV). Unmethylated CpG motifs present in bacterial DNA can activate toll-like receptor 9 (TLR9) signals and act as potent adjuvants to induce Th-1-type immune responses. Here, a mini-plasmid with 812 base pairs in length was constructed and used as a vector to prepare a series of plasmids containing 3-21 copies of D-type CpG motifs. In vitro, these CpG enriched plasmids strongly stimulated proliferation of human peripheral blood mononuclear cells (PBMCs) and enhanced secretion of interferon-gamma (IFN-gamma) and interleukin-12 (IL-12). The responses of the PBMCs from healthy individuals to the plasmids were stronger than those obtained from HBV-infected individuals. Contrary to the strong Th-2-biased response induced by surface antigen of hepatitis B virus (HBsAg) plus alum adjuvant, immunization of BALB/c mice with HBsAg plus these plasmids induced a strong Th-1-biased response. The plasmids increased the titers of HBsAg-specific total immunoglobulin G (IgG) and IgG(2a). HBsAg-specific IL-2 and IFN-gamma production and cytotoxic activity were also enhanced in the presence of the plasmids. The strength of the immune responses positively correlated with the number of CpG motifs in the plasmids. These results indicate that the use of CpG-enriched plasmids as an adjuvant to recombinant HBsAg could provide a promising and cost-effective approach for the development of efficacious therapeutic vaccines against HBV infection. PMID- 21668362 TI - Ex-vivo recognition of late-lytic CD8 epitopes specific for Kaposi's sarcoma associated herpesvirus (KSHV) by HIV/KSHV-coinfected individuals. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), the most common cancer in individuals with untreated HIV/AIDS. Host control of KSHV infection and KS oncogenesis by CD8 T cells remains underexplored. Although KSHV CD8 epitopes have been identified, the responses they elicit are weak and little is known about their relative importance. We sought to make a direct comparison of the recognition of a selection of the best-described known epitopes by a cohort of KSHV-seropositive, HIV-co-infected individuals, in order to assess the relative dominance of these epitopes. We further sought to identify novel epitopes from within a candidate immunogenic protein encoded by KSHV ORF28. MHC binding and denaturation assays identified putative novel A*0201-restricted epitopes from within the late-lytic glycoprotein ORF28. Recognition of these candidate epitopes was tested in a cohort of KSHV-seropositive, HIV-1-seropositive, A*0201-positive individuals by ex vivo ELISPOT, and compared with recognition of nine previously described epitopes. One novel late-lytic epitope from ORF28 was recognized by 7.1% of individuals, and was used for further investigation of KSHV-specific T cells using multimer technology. One known late-lytic epitope from the glycoprotein encoding K8.1 was recognized by 71.4% of individuals, and represented an immunodominant KSHV epitope, but was too hydrophobic for multimer synthesis. This study identifies two KSHV CD8 epitopes derived from late-lytic antigens that are recognized by KSHV-seropositive, HIV co-infected individuals, and will be useful in future immunological studies into the CD8 response against KSHV in similar patient cohorts. PMID- 21668363 TI - Estimation of seroprevalence of the pandemic H1N1 2009 influenza virus using a novel virus-free ELISA assay for the detection of specific antibodies. AB - The pandemic H1N1 2009 influenza A emerged in April 2009 and spread rapidly all over the world. In Greece, the first case of the pandemic H1N1 was reported on May 18, 2009, while a considerable increase in the number of cases was noticed at the beginning of July 2009. The need for surveillance of the immune status of the Greek population led us to develop a virus-free ELISA that specifically recognizes pandemic H1N1 2009 influenza virus antibodies in human sera. The method is based on the use of synthetic peptides (H1-pep and N1-pep) that are derived from the hemagglutinin and neuraminidase of the 2009 pandemic strain, respectively, and differentiate the swine-origin influenza A/California/14/2009 (H1N1) from the seasonal influenza A viruses. Serum samples were obtained from 271 healthy blood donors during May, November, and December 2009. Among sera collected during May, November, and December, IgG antibodies against the peptide H1-pep were detected in 7.4, 13.8, and 19.3% of the donors, respectively, while IgG antibodies against the peptide N1-pep were detected in 5.3, 9.6, and 16.9% of the donors, respectively. The application of the immunoassay indicated a time dependent increase of the prevalence of anti-H1-pep and anti-N1-pep IgG antibodies during the pandemic H1N1 outbreak in Greece. The method could be also indicative for the discrimination of immune persons from those susceptible to infection with the pandemic H1N1 strain, as well as for the establishment of effective vaccination programs. PMID- 21668364 TI - Identification and characterization of novel B-cell epitopes within EBV latent membrane protein 2 (LMP2). AB - The purpose of this study was to screen and identify the linear B-cell epitopes of Epstein-Barr virus (EBV) latent membrane protein 2 (LMP2). The secondary structure and surface properties of EBV LMP2A protein were analyzed. In combination with hydrophilicity, accessibility, flexibility, and antigenicity analysis, and average antigenicity index (AI) of epitope peptide investigation, three peptides were selected as potential candidates of linear B-cell epitopes. The peptides were 199-209 (RIEDPPFNSLL), 318-322 (TLNLT), and 381-391 (KSLSSTEFIPN). The fragments encoding potential B-cell epitopes were cloned and overexpressed in an E. coli system. The immune sera of these fusion proteins were collected from BALB/c mice by subcutaneously immunizing them three times. Western blotting results showed that these epitope recombinant proteins could be recognized by the serum antibodies against the whole LMP2 from nasopharyngeal carcinoma (NPC). Indirect ELISA measuring individual sera from 196 NPC patients, 44 infectious mononucleosis (IM) patients, 253 healthy adults, and 61 healthy children, indicated that NPC patients had significantly higher reactivity to these epitope-fused proteins compared with IM and healthy individuals (p < 0.05). In addition, all the immune sera of peptide-fused proteins responded to native LMP2A antigen obtained from the EBV prototype strain, B95-8 cells. IFA results confirmed that specific antibodies induced by epitope peptide-fused proteins recognized intracellular regions of LMP2A. These results demonstrated that these three predictive epitopes not only were immunodominant B-cell epitopes of LMP2A, but also may be potential targets for applications in the design of diagnostic tools. PMID- 21668365 TI - Lipopolysaccharide inhibits Sindbis virus-induced IP-10 release in human peripheral blood mononuclear cells. AB - Chemokines play a pivotal role in the innate response to both bacterial and viral infections, and in mixed infections. To determine chemokine responses to Sindbis virus (SIN) in a co-infection model, peripheral blood mononuclear cells (PBMCs) derived from healthy volunteers were exposed to SIN in the presence and absence of lipopolysaccharide (LPS). Culture supernatants recovered at 2, 24, and 72 h post-exposure were evaluated for virus replication and analyzed for chemokines by ELISA. None of the PBMC cultures showed new virus release, GFP reporter expression, or viral RNA synthesis. While SIN had little effect on the induction of IL-8 and RANTES, the chemokines MCP-1, MIP1-alpha (p < 0.001), and MIP1-beta (p < 0.0004) were drastically upregulated by SIN as well as LPS. Both live and UV inactivated SIN induced secretion of IP-10 and I-TAC. Although LPS did not induce release of IP-10, it sharply inhibited (p = 0.004) SIN-mediated IP-10 secretion. On the contrary, the release of SLC was blocked by SIN. The adjuvant activity of IP-10, its antiangiogenic function, and antagonism between SIN and LPS for the release of select chemokines may be useful in understanding the pathogenesis of mixed infections, cross-talk between cellular pathways, and may have applications in cancer and sepsis. PMID- 21668366 TI - Effects of HIV-1 Nef on virus co-receptor expression and cytokine release in human bladder, laryngeal, and intestinal epithelial cell lines. AB - HIV infections are mainly acquired by mucosal transmission, through oral, rectal, or genital mucosa. Epithelial cells (EC) are the first cells encountered by HIV during infection through sexual transmission and breastfeeding. EC express several receptors critical for both primary HIV infection and secondary transmission. The regulation of co-receptor expression correlates with changes in susceptibility to infection by HIV-1 strains with different tropism. Moreover, inflammatory responses at mucosal surfaces after HIV-1 transmission may influence disease outcome. In the present study, we analyzed the effect of the accessory HIV-1 Nef protein on mucosal EC, using unstimulated or IFN-gamma-stimulated HEp 2, T24, and Caco2 cell lines as models for homeostatic or inflamed mucosal tracts. We found that Nef significantly upregulated the expression of CXCR4 on the Caco-2 cell surface and the expression of galactosylceramide on the T24 cell surface. In addition, Nef significantly upregulated IL-6 production by T24 and Caco-2 cells, and TNF-alpha release by all three cell lines analyzed. Notably, Nef abrogated the IFN-gamma-induced modulation of co-receptor expression and cytokine secretion. Our findings suggest that Nef differently regulates co receptor expression and cytokine secretion at the epithelial level, depending on the anatomical derivation of the cells and the inflammatory status. PMID- 21668367 TI - Nasalance norms in Greek adults. AB - The purposes of this study were to derive nasalance norms for monolingual Greek speakers, to examine nasalance scores as a function of gender and to draw cross linguistic comparisons based on normative data. Participants read aloud a corpus of linguistic material, consisting of (1) a nasal text, an oral text and a balanced text; (2) a set of nasal sentences and four sets of oral sentences and (3) repetitions of each of 12 syllable types (8 oral and 4 nasal). The last two sets of material corpus were based on an adaptation of the Simplified Nasometric Assessment Procedures Test (SNAP test) test ( MacKay and Kummer, 1994 ) in Greek, called the G-SNAP test. Eighty monolingual healthy young adult speakers of Greek, 40 males (mean age = 21 years) and 40 females (mean age = 20.5 years), with normal hearing and speech characteristics and unremarkable history were included in the study. The Nasometer (model 6200-3) was used to derive nasalance scores. Mean normative nasalance for spoken Greek was 25.50%, based on the G-oronasal text (with 8.6% nasals). Nasalance scores did not differ significantly with respect to gender. Finally, spoken Greek consistently yielded lower nasalance scores than other languages examined in past work. The aforementioned normative data on nasalance of young adult speakers of Greek are valid across gender and have direct clinical utility as they provide valuable reference information for the diagnosis and management of Greek adults with resonance disorders caused by velar dysfunction. PMID- 21668368 TI - Massage therapy usage and reported health in older adults experiencing persistent pain. AB - BACKGROUND: Persistent pain is a frequent complaint among older adults and can greatly decrease quality of life while also contributing to other negative outcomes such as poor health, increased pharmaceutical medication usage, increased rates of depression, and cognitive decline. OBJECTIVE: The current study (N = 69) examines the potential impact of massage therapy (MT) in older adults (60+ years) with persistent pain, by comparing self-reported health outcome scores among those who have and have not utilized massage therapy in the past year. DESIGN: The current study was derived from a larger study that collected data as part of a one-time, self-report, mail-in survey. PARTICIPANTS: Lexington, Kentucky area adults, 60 and older who reported persistent pain were eligible to participate in the study. OUTCOME MEASURES: The RAND 36-Item Health Survey was used to determine participant health-related quality of life. RESULTS: The current study demonstrated that for older adults experiencing persistent pain, massage is associated with self-report of less limitation due to physical or emotional issues, better emotional health, more energy/less fatigue, better social functioning, and better overall health. Age, education, cumulative morbidities, number of areas in which participants reported experiencing persistent pain, and number of complementary and alternative medicine options in addition to MT utilized in the past year did not affect the association between receipt of massage and better self-reports in those domains. CONCLUSIONS: While many causes of pain for older adults elude cure, further study is warranted that examines MT as an intervention to improve coping in older adults with persistent pain. PMID- 21668369 TI - GLUT4 gene polymorphisms and their association with type 2 diabetes in south Indians. AB - BACKGROUND AND OBJECTIVES: The GLUT4 gene, which encodes glucose transporter 4, is a candidate gene for type 2 diabetes mellitus (T2DM). The aim of this study was to screen the GLUT4 gene for polymorphisms and to study association of such polymorphisms with T2DM in an Asian Indian population in southern India. METHODS: The GLUT4 gene was sequenced in 25 normal glucose tolerance (NGT) and 25 T2DM subjects, and the variants found were then genotyped by polymerase chain reaction restriction fragment length polymorphism in a pilot study population of 552 NGT and 643 T2DM subjects, randomly selected from the Chennai Urban Rural Epidemiology Study. Two of the variants (rs5435 and the novel variant), which showed significantly higher minor allele frequency in T2DM compared with NGT individuals in the pilot study population, were then retested with an additional 465 NGT and 363 T2DM subjects, giving a final sample size of 1,017 NGT and 1,006 T2DM subjects. RESULTS: Sequencing of the GLUT4 gene revealed three known polymorphisms (rs5418, rs5421, and rs5435) and one novel T->G variant in the 3' untranslated region (UTR) at nucleotide position 6787483. The rs5418 and rs5421 polymorphisms did not show any association with diabetes. The rs5435 [Asn130Asn(C >T)] polymorphism was found to be associated with diabetes, with the odds ratio for the CT+TT genotype being 1.26 (95% confidence interval, 1.00-1.57; P=0.043) when the CC genotype was taken as reference. The frequency of the TG genotype of the novel 3'UTR T->G variant was significantly higher in diabetes subjects (1%) compared with NGT subjects (0.2%) (P=0.021). There was a significant difference in the proportion of the ACGT haplotype of the rs5418(A->G), rs5435(C->T), rs5421(C->G), and the T->G 3'UTR variant between the NGT (7.5%) and diabetes (5%) groups (P=0.003). CONCLUSION: The rs5435 (C->T) polymorphism of the GLUT4 gene is associated with type 2 diabetes in this south Indian population. PMID- 21668370 TI - Is playing exergames really exercising? A meta-analysis of energy expenditure in active video games. AB - This article reports a meta-analysis of energy expenditure (EE) of playing active video games (AVGs). In particular, heart rate (HR), oxygen consumption (VO2), and EE were assessed and three moderators for the effects of AVGs--types of AVG, player age, and player weight status--were analyzed. The results show that playing AVGs significantly increased HR, VO2, and EE from resting. The effect sizes of playing AVGs on HR, VO2, and EE were similar to traditional physical activities. AVG type and player age were significant moderators for the effects of AVGs. The finding suggests that AVGs are effective technologies that may facilitate light- to moderate-intensity physical activity promotion. PMID- 21668371 TI - Fluoroquinolone resistance mechanisms in urinary tract pathogenic Escherichia coli isolated during rapidly increasing fluoroquinolone consumption in a low-use country. AB - Resistance to ciprofloxacin in Escherichia coli from urinary tract infections (UTI) in Denmark is increasing parallel to increased use of fluoroquinolones both in Denmark and in other European countries. The objective was to investigate the occurrence of ciprofloxacin resistance mechanisms, phenotypic coresistance, and if ciprofloxacin resistance was caused by clonal spread or to individual mutational events in a collection of consecutively obtained E. coli submitted to a clinical microbiology department at a Danish hospital. One hundred four UTI related E. coli resistant toward nalidixic acid by disc diffusion were typed by Pulsed Field Gel Electrophoresis (PFGE) with XbaI. One isolate representing each PFGE type and only one patient (n = 77) were investigated for point mutations in sequenced PCR amplicons of the four topoisomerase genes; qnr genes by use of PCR; aac(6')-Ib-cr by BtsCI restriction of PCR products; and efflux using efflux pump inhibitors in a broth dilution assay. Minimal inhibitory concentration (MIC) was determined for 21 antibacterial agents, including ciprofloxacin. Of the 77 isolates, the majority were resistant to ciprofloxacin (91%) and multiresistant (resistant to >= 3 antimicrobial classes, 83%). Ciprofloxacin-resistant isolates showed at least one target mutation. A significant, positive correlation was found regarding MIC of ciprofloxacin and the number of target mutations. Efflux was found as a resistance mechanism in 77% of isolates tested (n = 60). The aac(6')-Ib-cr gene was detected on plasmids from five isolates showing ciprofloxacin MICs >512 mg/L. No overall clonal relationship among isolates was found according to PFGE. Target modification is the dominating fluoroquinolone resistance mechanism often found in combination with efflux and sometimes aac(6') Ib-cr. In Denmark, increasing ciprofloxacin resistance in E. coli is mainly due to mutational events and not to spread of clones. PMID- 21668372 TI - The International Collaboration on Complementary Therapy Resources (ICCR): working together to improve online CAM information. AB - BACKGROUND: Use of the Internet to find health information is increasing dramatically but the quality of information, particularly on complementary and alternative medicine (CAM) is variable. The International Collaboration on Complementary Therapy Resources (ICCR) involves collaboration between the national CAM information centers in Australia, Denmark, Norway, the United Kingdom, and the United States, and a CAM information service in Germany. OBJECTIVES: The study objectives were to compare the services and areas of expertise offered by each of the national CAM information services, to explore common challenges encountered in practice, and to establish specific objectives for the collaboration. DESIGN: The workshop incorporated set templates for presentations, brainstorming, and analysis of notes to identify common themes. RESULTS: Differences and similarities between the various services were revealed. Common challenges were identified under the main themes of overall context, users and needs, content and processes. Based on these themes, it was possible to agree on a number of specific objectives. CONCLUSIONS: The member organizations of the ICCR serve a range of different audiences and have varied remits to fulfill. For the international collaboration to be effective, it was necessary to identify common challenges and to agree on specific objectives and potential ways of working together. Progress to date is also discussed together with plans for the future. PMID- 21668373 TI - Hydrophobic and electrostatic interaction chromatography for estimating changes in cell surface charge of Escherichia coli cells treated with pulsed electric fields. AB - Pulsed electric field (PEF) treatments, a nonthermal process, have been reported to injure and inactivate bacteria in liquid foods. However, the effect of this treatment on bacterial cell surface charge and hydrophobicity has not been investigated. Apple juice (pH 3.8) purchased from a wholesale distributor was inoculated with cocktail of Escherichia coli O157:H7 at 7.4 log CFU/mL, processed with a PEF at a field strength of 18.4 kV/cm and 32.2 kV/cm at 25 degrees C, 35 degrees C, and 45 degrees C with a treatment time of 160 MUs and a flow rate of 120 mL/min. Bacterial cell surface charge and hydrophobicity of untreated and PEF treated E. coli O157:H7 were determined immediately and after storage at 5 degrees C and 23 degrees C using hydrophobic and electrostatic interaction chromatography. Similarly, the populations surviving the PEF treatments including injured cells were determined by plating 0.1 mL of the sample on sorbitol MacConkey agar and tryptic soy agar (TSA) plates. The surviving populations of E. coli cells after PEF treatment varied depending on field strength and treatment temperature used. Percent injury in the surviving populations was high immediately after PEF treatment and varied among treatment temperatures. Cell surface charge of E. coli bacteria before PEF treatment averaged 32.10+/-8.12. PEF treatments at 25 degrees C, 35 degrees C, and 45 degrees C reduced the above surface charge to 26.34+/-1.24, 14.24+/-3.30, and 6.72+/-2.82, respectively. Similarly, the surface hydrophobicity of untreated E. coli cells at 0.194+/-0.034 was increased to an average of 0.268+/-0.022, 0.320+/-0.124, and 0.586+/-0.123 after PEF treatments at 25 degrees C, 35 degrees C, and 45 degrees C, respectively. The results of this study indicate that PEF treatment affects the outer cell envelope of E. coli bacteria as evidenced by the changes in surface hydrophobicity and cell surface charge leading to injury and subsequent inactivation of the cells. PMID- 21668374 TI - The effect of photosensitizer drugs and light stimulation on osteoblast growth. AB - OBJECTIVE: A promising new treatment in dentistry involves the photodynamic process, which utilizes a combination of two therapeutic agents, namely a photosensitizer drug and a low dose of visible light. We investigated the in vitro effect of low intensity laser irradiation (visible light irradiation at 670 nm) using doses ranging between 0.5 and 3 J/cm(2), combined with nanoemulsion (NE) of the photosensitizer drug aluminum phthalocyanine chloride (AlClPc), ranging from 0.5 to 5 MUmol/L, on the growth and differentiation of osteoblastic cells isolated from rat bone marrow. BACKGROUND DATA: Treatments using laser radiation of low intensity in dentistry are of great interest, especially in bucco-maxillofacial surgery and dental implantology, where this approach is currently employed to stimulate osteogenesis. In the presence of oxygen, the combination of these agents could induce cellular biostimulation, via an efficient noninvasive method. METHODS: We have done the colorimetric MTT assay, collagen content, total protein content, ALP activity and bone-like nodule formation. RESULTS: We observed that an increased number of viable cells was evident upon application of a laser dosage equal to 0.5 J/cm(2) when combined with 0.5 MUmol/L of AlClPc/NE, suggesting cellular biostimulation. CONCLUSIONS: It was possible to demonstrate that low intensity laser irradiation can play an important role in promoting biostimulation of osteoblast cell cultures. Therefore, whether biostimulation of osteoblastic cell cultures by photodynamic therapy or the cytotoxic effect of this therapy occurs only depends upon the light dose, and the results can be completely reversed. PMID- 21668375 TI - Different power settings of LLLT on the repair of the calcaneal tendon. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of an 830-nm GaAlAs diode laser operating at output powers of 40, 60, 80, and 100 mW and energy density of 30 J/cm(2) on the repair of partial calcaneal tendon ruptures in rats. METHODS: A partial tendon rupture was induced in all animals, which were treated with laser irradiation for 5 consecutive days. Six days after injury, the injured tendons were removed and examined by polarized light microscopy. Collagen fiber organization was evaluated by birefringence measurements, and collagen content was determined by Picrosirius Red staining. RESULTS: It was observed that the higher the output power (60-100 mW) the greater the amount of type III collagen (p<0.01). The amount of type I collagen was significantly greater (p=0.05) in the 80 mW group than in the control group (sham stimulation). A non statistically significant improvement in the realignment of collagen fibers was observed in the irradiated groups. CONCLUSIONS: Low-level laser therapy resulted in significantly greater amounts of type III collagen (output powers of 60 mW or more) and type I collagen (output power of 80 mW), however, no significant differences between groups were found in the realignment of collagen fibers. PMID- 21668376 TI - Endovenous laser ablation with 980-nm diode laser: early and midterm results. AB - OBJECTIVE: Endovenous laser ablation (EVLA) is an efficient method to treat incompetent great saphenous veins (GSV) with high occlusion rates. The aim of this prospective study is to demonstrate the treatment outcomes of EVLA of incompetent GSV with a 980-nm diode laser in an ambulatory setting. BACKGROUND DATA: EVLA of the incompetent GSV with a 980-nm diode laser appears to be an extremely safe technique. There are several treatment alternatives available. Among the emerging techniques, EVLA is one of the most promising. METHODS: Ninety eight patients (103 limbs) with symptomatic varicose veins secondary to GSV insufficiency treated with 980-nm EVLA were prospectively studied. In all patients, laser energy was administered with constant pullback of fiberoptic laser catheter under tumescent anesthesia. The patients were assessed and followed by clinical examination and venous duplex ultrasonography. Pain scores of the patients from discharge to their first follow-up visit (7 days) were recorded by using visual analog scale (VAS). Patient satisfaction was assessed and recorded at 6 month follow-up. RESULTS: All patients tolerated EVLA procedure well, and were discharged from hospital on the same day with ablation procedure. The overall success rate was 97.5% in 98 patients. Mean length of measured treated vein segment was 29.93+/-6.36 cm. Mean applied total energy was 2006.24+/ 480.16 J. Major complications such as deep vein thrombosis and skin burns were not seen. Most of the complications were minor and improved quickly. All patients returned to daily activities within 2 days. CONCLUSIONS: EVLA of the GSV insufficiency using 980-nm diode laser is an effective and safe technique with a high patient satisfaction rate. The advantages of the procedure are that it is performed as an outpatient procedure, provides early mobilization, causes minimal cessation of daily activities, and avoids classic surgical complications. PMID- 21668377 TI - Association of caspases with an increased prostate cancer risk in north Indian population. AB - Dysregulation of apoptosis plays a crucial role in carcinogenesis. Thus, genetic alterations within caspase genes would be expected to provoke a deficient apoptotic signaling thereby facilitating the development of prostate cancer (PCa). In the present study we investigated whether three different polymorphisms in the caspase-5 and -3 genes are differentially expressed in PCa. In a hospital based case control study in northern India, we genotyped 192 PCa patients and 225 unrelated healthy controls for caspase-5 (G>C) (T>C) and caspase-3 (G>A) polymorphisms using amplification refractory mutation system and polymerase chain restriction fragment length polymorphism methods. Data were statistically analyzed and variant genotype GG of caspase-3 demonstrated increased risk for PCa (odds ratio [OR]=2.72, p=0.005). Similarly variant allele carrier (AG+GG) (OR=1.53, p=0.034) and G allele (OR=1.54, p=0.005) were also statistically associated with PCa risk. High risk for PCa was also observed with respect to caspase-5 (CC) diplotypes (OR=21.67, p=0.012, Pc=0.048). We observed significantly enhanced risk for PCa due to interaction between caspase-3 and -5 gene polymorphisms. In association of genotypes with clinical characteristics, heterozygous TC genotype of caspase-5 (T>C) conferred risk with high Gleason grade tumor (OR=2.35, p=0.042). In case-only analysis, interaction of environmental risk factors and genotypes did not further modulate the risk for PCa. Our observations suggested positive association of caspase-3 and diplotype analysis of caspase-5 to be associated with PCa risk. Interaction of caspase-3 and -5 genotypes also modulated the PCa risk. PMID- 21668378 TI - Older women survivors of physical and sexual violence: a systematic review of the quantitative literature. AB - BACKGROUND: This systematic review synthesizes the quantitative empirical literature concerning older women survivors of physical and sexual assault. METHODS: A literature search was conducted using a range of scholarly databases. Information is presented here on the prevalence, correlates, and consequences of these types of interpersonal violence in older women. Additionally, age-related differences in prevalence, psychiatric distress, and characteristics of violence, including information on perpetrators, are reviewed. RESULTS: Overall, older women report lower lifetime and past year rates of physical and sexual assault and associated negative psychologic consequences compared to younger and middle aged women. Additionally, older women who experienced interpersonal violence report greater psychiatric distress, including posttraumatic stress disorder (PTSD), than older women who have not experienced such events. CONCLUSIONS: Some women who have been physically or sexually assaulted decades earlier in life continue to report significant levels of PTSD well into older adulthood. Gaps in the literature, including lack of information on ethnicity and culture, are presented, and future research directions are proposed. PMID- 21668379 TI - Prenatal stress, anxiety, and depressive symptoms as predictors of intention to breastfeed among Hispanic women. AB - BACKGROUND: Studies on the relationship between prenatal psychosocial risk factors and breastfeeding are sparse, particularly in Hispanic women. METHODS: We evaluated this association among 424 participants in Proyecto Buena Salud, an ongoing prospective cohort of pregnant Hispanic women in Western Massachusetts. The Perceived Stress Scale (PSS), the State-Trait Anxiety Inventory (STAI), and the Edinburgh Postnatal Depression Scale (EPDS) were administered by bilingual interviewers in early pregnancy (mean 13.6 weeks gestation) and midpregnancy (mean 25.7 weeks gestation). Information on sociodemographic, behavioral, and acculturation factors was also collected. Breastfeeding intention was abstracted from medical records. Poisson regression was used to calculate prevalence risk ratios (PRR) and 95% confidence intervals (CI). RESULTS: A total of 274 (64.6%) women reported a positive intention to breastfeed. In multivariate analyses, women in the highest quartile of perceived stress (PRR 0.76, 95% CI 0.62-0.94) in early pregnancy and highest quartile of anxiety in early pregnancy (PRR 0.66, 95% CI 0.54-0.81) and midpregnancy (PRR 0.80, 95% CI 0.64-1.00) were less likely to intend to breastfeed compared to women in the lowest quartile. Women who had at least probable minor depression (EPDS score >=13) (PRR 0.79, 95% CI 0.65-0.95) or probable major depression (EPDS score >=15) (PRR 0.77, 95% CI 0.62-0.96) during midpregnancy were less likely to intend to breastfeed compared to women without depressive symptoms. Similarly, women with persistent depressive symptoms over pregnancy were 24%-33% less likely to intend to breastfeed compared to women without depressive symptoms. CONCLUSIONS: Psychosocial risk factors during pregnancy are important predictors of breastfeeding intention among Hispanic women. PMID- 21668380 TI - Substance abuse, violence, and HIV in women: a literature review of the syndemic. AB - Women in the United States are increasingly affected by HIV/AIDS. The SAVA syndemic-synergistic epidemics of substance abuse, violence, and HIV/AIDS-is highly prevalent among impoverished urban women and potentially associated with poor HIV outcomes. A review of the existing literature found 45 articles that examine SAVA's impact on (1) HIV-associated risk-taking behaviors, (2) mental health, (3) healthcare utilization and medication adherence, and (4) the bidirectional relationship between violence and HIV status. Overall, results confirm the profound impact of violence and victimization and how it is intertwined with poor decision making, increased risk taking and negative health consequences, particularly in the context of substance abuse. Among current findings, there remain diverse and inconsistent definitions for substance abuse, violence, mental illness, adherence, and healthcare utilization that confound interpretation of data. Future studies require standardization and operationalization of definitions for these terms. Development and adaptation of evidence-based interventions that incorporate prevention of violence and management of victimization to target this vulnerable group of women and thereby promote better health outcomes are urgently needed. PMID- 21668381 TI - Racial disparities in awareness of the human papillomavirus. AB - BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States yet is one of the least recognized among the general public. HPV awareness may be relatively low among minority women. Because HPV awareness is associated with uptake of the HPV vaccine, it is critical to assess HPV awareness in the population and identify any racial/ethnic gaps. METHODS: This study used nationally representative data collected by the National Survey of Family Growth between July 2007 and December 2008. A multivariable logistic regression model was used to determine the independent effect of race/ethnicity on HPV awareness while controlling for sociodemographic and clinical confounders in a sample of 4088 women. Stratified multivariable analysis was also conducted to assess the relationship between race/ethnicity and HPV awareness among women in different age groups. RESULTS: After adjusting for confounders, Hispanic and black women overall were significantly less likely to have heard of HPV compared to white women (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.29-0.54 and OR 0.39, 95% CI 0.29-0.54, respectively). Black women aged 15-18 and Hispanic women aged 19-26 had particularly low rates of HPV awareness (OR 0.17, 95% CI 0.07-0.43 and OR 0.18, 95% CI 0.11-0.30, respectively) compared to white women of the same ages. CONCLUSIONS: Hispanic and black women have significantly lower levels of HPV awareness than white women. Targeted educational efforts will be important to improve HPV awareness and associated preventive health measures to avoid HPV-related morbidity and mortality. PMID- 21668382 TI - Diabetes and depression in pregnancy: is there an association? AB - BACKGROUND: Prior studies have reported inconsistent findings regarding the association of antenatal depression with pregnancy-related diabetes. This study examined the association of diabetes and antenatal depression. METHODS: We conducted a cross-sectional analysis of baseline data from a prospective cohort study of pregnant women receiving prenatal care at a single University of Washington Medical Center clinic between January 2004 and January 2009. The primary exposure was diabetes in pregnancy (no diabetes, preexisting diabetes, or gestational diabetes [GDM]). Antenatal depression was defined by the Patient Health Questionnaire-9 (PHQ-9) score or current use of antidepressants. Antenatal depression was coded as (1) any depression (probable major or minor depression by PHQ-9 or current antidepressant use) and (2) major depression (probable major depression by PHQ-9 or current antidepressant use). Logistic regression was used to quantify the association between diabetes in pregnancy and antenatal depression. RESULTS: The prevalences of preexisting diabetes, GDM, any antenatal depression, and major antenatal depression were 9%, 18%, 13.6%, and 9.8%, respectively. In the unadjusted analysis, women with preexisting diabetes had 54% higher odds of any antenatal depression compared to those without diabetes (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.08-2.21). After adjusting for important covariates the association was attenuated (OR 1.16, 95% CI 0.79-1.71). Results were similar for antenatal major depression. GDM was not associated with increased odds for any antenatal depression or antenatal major depression. CONCLUSIONS: Neither preexisting diabetes nor GDM was independently associated with increased risk of antenatal depression. PMID- 21668383 TI - WISEWOMAN: addressing the needs of women at high risk for cardiovascular disease. AB - In the United States, the cardiovascular health of women is affected by the disparate impact of cardiovascular diseases (CVDs) on many minority ethnic and racial groups. Women with low income also endure a disproportionate impact of the burden of CVD. The Centers for Disease Control and Prevention's (CDC's) Well Integrated Screening and Evaluation for Women Across the Nation (WISEWOMAN) Program was authorized by Congress in 1993 to extend the preventive health services offered to participants of the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). These are low-income, uninsured, and underinsured women. The intent was to expand services of an existing federal program to address cardiovascular health concerns in this vulnerable, high-risk population. CDC funds 19 state health departments and 2 tribal organizations (both in Alaska) to implement WISEWOMAN. In the first 2 years of the current 5-year funding cycle, which began in June 2008, the WISEWOMAN grantees succeeded in providing almost 78,000 screenings, of which 46% were to women of minority racial and ethnic groups. The individual successes are important, and the WISEWOMAN Program also has achieved success in the broader arenas of healthcare and the communities in which WISEWOMAN is implemented. WISEWOMAN impacts clinical systems of care, provider education, physician extenders, and the broader community and will continue to play an important role in connecting low-income, uninsured, and underinsured women with clinical systems of care and other community resources that will result in the prevention, treatment, and management of their CVD risk. PMID- 21668384 TI - Favorable neonatal outcomes among immigrants in Taiwan: evidence of healthy immigrant mother effect. AB - BACKGROUND: Although racial/ethnic disparities in neonatal and infant health are well known, positive associations between migration and perinatal health exist among immigrant mothers in western countries. There are unique marriage migration, East Asia culture, universal national health insurance system, and adequate social support in Taiwan that may differ from the situation in western countries. We aimed to assess the neonatal outcomes among live births to married immigrant mothers in recent years in Taiwan. METHODS: We conducted a population based analysis among all the live births in Taiwan during the period 1998-2003 to assess neonatal outcomes, including incidence of low birth weight and preterm birth and of early and late neonatal mortality, according to maternal nationality. Logistic regression was used to estimate the odds ratios (ORs) associated with low birth weight and preterm birth, and Cox proportional hazards were used to estimate the relative risks (RRs) associated with mortality in the neonatal period. RESULTS: There were a total of 1,405,931 single live births, including 6.6% born to immigrant mothers and 93.4% born to Taiwanese mothers. Disparities existed among the intercultural couples, including paternal age, parental educational level, and residential distribution. Fewer low birth weight and fewer preterm babies were born to immigrant mothers than to Taiwanese mothers. In addition, babies born to immigrant mothers had lower early neonatal and neonatal mortalities than those born to Taiwanese mothers. There were lower risks of having a low birth weight (adjusted OR [AOR] 0.73, 95% confidence interval [CI] 0.70-0.75) or preterm (AOR 0.72, 95% CI 0.69-0.74) baby and lower hazard ratios (HRs) of having an early neonatal death (adjusted HR [AHR] 0.68, 95% CI 0.56-0.82) or neonatal death (AHR 0.74, 95% CI 0.64-0.87) in babies born to immigrant mothers. There is a gradual increase in the risks of adverse neonatal outcomes associated with increases in length of residence. CONCLUSIONS: Evidence of a healthy immigrant mother effect on neonatal health is clear. Despite lower parental education, advancing paternal age, and spatial distribution disparity, babies born to married immigrant mothers in Taiwan had favorable neonatal outcomes. PMID- 21668385 TI - Waist circumference percentile curves for Malaysian children and adolescents aged 6.0-16.9 years. AB - BACKGROUND: The prevalence of obesity is increasing rapidly and abdominal obesity especially is known to be a risk factor for metabolic syndrome and other non communicable diseases. Waist circumference percentile curves are useful tools which can help to identify abdominal obesity among the childhood and adolescent populations. OBJECTIVE: To develop age- and sex-specific waist circumference (WC) percentile curves for multi-ethnic Malaysian children and adolescents aged 6.0 16.9 years. Subjects and methods. A total of 16,203 participants comprising 8,093 boys and 8,110 girls recruited from all regions of Malaysia were involved in this study. Height, weight, WC were measured and BMI calculated. Smoothed WC percentile curves and values for the 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th and 97th percentiles were constructed using the LMS Method. RESULTS: WC was found to increase with age in both sexes, but boys had higher WC values at every age and percentile. Z-scores generated using the UK reference data shows that Chinese children had the highest WC compared to Malays, Indians and other ethnicities. Comparisons with other studies indicate that at the 50th percentile, Malaysian curves did not differ from the UK, Hong Kong and Turkish curves, but at the 90th percentile, Malaysian curves were higher compared with other countries, starting at 10 years of age. The 90th percentile was adopted as the cut-off point to indicate abdominal obesity in Malaysian children and adolescents. CONCLUSION: These curves represent the first WC percentiles reported for Malaysian children, and they can serve as a reference for future studies. PMID- 21668386 TI - Stress in migraine: personality-dependent vulnerability, life events, and gender are of significance. AB - BACKGROUND AND AIM: The individual's experiences of stress as well as constitutional factors, including high neuroticism and female gender, are known determinants for migraine. The present aim was to further elucidate factors of personality and stress, including life events, in relation to gender in migraine. METHODS: A cross-sectional study was performed on 150 persons, 106 women and 44 men, suffering from at least two migraine attacks a month. All obtained a doctor defined migraine diagnosis based on a structured face-to-face interview concerning their health situation and current and prior stress. All of them also answered validated questionnaires regarding personality traits (SSP), life events, and perceived ongoing stress. RESULTS: The personality trait inventory showed high mean scores for stress susceptibility and low mean scores for aggressiveness and adventure seeking, both for women and for men, as well as high mean scores for psychic and somatic anxiety in women. Stress susceptibility, the overall most deviant trait, correlated strikingly with current level of stress in both sexes. In women, stress susceptibility also correlated strongly with experiences of negative life events. Tension-type headache, anxiety, and depression were approximately twice as prevalent in women compared to men. CONCLUSIONS: The present study confirms previous research, showing that stress is an important factor in migraine. Stress susceptibility, life events, and concomitant psychosomatic illnesses should be considered important when evaluating individuals with migraine, and gender aspects need to be taken into account. PMID- 21668387 TI - Periprosthetic bone loss after insertion of an uncemented, customized femoral stem and an uncemented anatomical stem. A randomized DXA study with 5-year follow up. AB - BACKGROUND AND PURPOSE: Customized femoral stems are designed to have a perfect fit and fill in the femur in order to achieve physiological load transfer and minimize stress shielding. Dual-energy X-ray absorptiometry (DXA) is regarded as an accurate method for detection of small alterations in bone mineral density (BMD) around hip prostheses. We present medium-term DXA results from a randomized study comparing a customized and an anatomical femoral stem. METHODS: 100 hips were randomized to receive either the anatomical ABG-I stem or the Unique customized femoral stem, both uncemented. DXA measurements were conducted postoperatively and after 3, 6, 12, 24, 36, and 60 months, and BMD was computed for each of the 7 Gruen zones in the proximal femur. RESULTS: Results from 87 patients were available for analysis. 78 completed the 5-year follow-up: 35 patients in the ABG group and 43 patients in the Unique group. In both groups, we found the greatest degree of bone loss in the proximal Gruen zones. In zone 1, there was 15% reduction in BMD in the ABG-I group and 14% reduction in the Unique group. In zone 7, the reduction was 28% in the ABG-I group and 27% in the Unique group. The only statistically significant difference between the groups was found in Gruen zone 4, which is distal to the tip of the stem, with 1.6% reduction in BMD in the ABG-I group and 9.7% reduction in the Unique group (p = 0.003). INTERPRETATION: 5-year DXA results showed that because of stress-shielding, proximal bone loss could not be avoided-either for the anatomical ABG-I stem or for the customized Unique stem. PMID- 21668388 TI - Prospects for a hepcidin mimic to treat beta-thalassemia and hemochromatosis. PMID- 21668389 TI - Pain in sickle cell disease: the future of acute treatment. PMID- 21668391 TI - Clinical development of panobinostat in classical Hodgkin's lymphoma. AB - Deacetylase (DAC) inhibitors are promising new anticancer drugs that have complex mechanisms of action, including induction of cell-cycle arrest and apoptosis, inhibition of angiogenesis and induction of a favorable anti-tumor immune response. Panobinostat, a potent inhibitor of DAC 1-11 enzymatic activity, has demonstrated a significant in vitro antiproliferative activity against classical Hodgkin's lymphoma (cHL) cell lines in addition to a promising clinical activity in early Phase I studies in patients with relapsed cHL. In a recently completed large Phase II study in patients with relapsed cHL, panobinostat reduced tumor measurements in 74% of patients, including 23% partial and 4% complete remissions. In this article, we review the status of panobinostat drug development and compare its activity to those of other DAC inhibitors in patients with relapsed cHL. Future investigations should focus on designing rational combination regimens and identifying predictive markers that will assist in selecting patients who are likely to benefit from this novel therapy. PMID- 21668392 TI - Dasatinib for the treatment of chronic myeloid leukemia. AB - Earlier use of more potent tyrosine kinase inhibitors such as dasatinib improves response rates for patients with chronic myeloid leukemia (CML). The SRC-ABL Tyrosine Kinase Inhibition Activity Research Trials series displayed dasatinib efficacy in patients with all phases of CML who are resistant or intolerant to imatinib. More recently, dasatinib has been shown to induce rapid and high rates of response and has gained approval for newly diagnosed patients with CML in chronic phase. The future of CML therapy may incorporate more potent tyrosine kinase inhibitors such as dasatinib into initial treatment for newly diagnosed patients. The ability of dasatinib to induce rapid and high rates of response with a low progression to advanced forms of CML may translate into improvements in survival. PMID- 21668394 TI - Optimizing the selection of kinase inhibitors for chronic myeloid leukemia patients. AB - Long-term follow-up of clinical studies has demonstrated the efficacy of imatinib therapy in newly diagnosed chronic phase-chronic myeloid leukemia patients (CML). However, recent updates of two separate randomized Phase III studies demonstrated higher complete cytogenetic and major molecular response rates with dasatinib and nilotinib compared with imatinib 400 mg/day. Hence, for newly diagnosed chronic phase-CML patients there are multiple treatment options, including standard-dose imatinib, high-dose imatinib, and combination therapy of imatinib and interferon, dasatinib and nilotinib. This article critically analyzes the current literature and provides guidelines for the management of newly diagnosed CML. Disease and therapy-related prognostic factors, which may aid in the selection of therapeutic strategies to enable optimal treatment outcomes, are discussed. In addition, we provide commentary on the therapeutic options for patients who fail imatinib therapy. PMID- 21668395 TI - Managing multiple myeloma in the elderly: are we making progress? AB - Treatment of multiple myeloma has evolved rapidly over the last decade due to novel therapeutic agents. Improved upfront and salvage options have resulted in enhanced survival; however, this has been less pronounced in elderly patients compared with their younger counterparts. Indeed, treatment-related toxicities in older patients may have subverted the survival benefit made by newer treatment modalities. However, owing to the immaturity of current published data, the true survival impact made by novel agents in the elderly patient subgroup is far from being fully appreciated. Improved responses, along with increased salvage options, imply that progress for elderly patients is being made. The current challenge to improve survival for elderly patients not only rests with continued research into tolerable novel treatment regimens, but also, scrupulous supportive care and the judicious use of current novel agents in appropriate dosing, combinations and sequence. Here, we review the outcomes of elderly patients with multiple myeloma over recent years and focus on the current treatment options available for this group. PMID- 21668393 TI - The bone marrow microenvironment and leukemia: biology and therapeutic targeting. AB - Multiple studies have demonstrated that interaction with the bone marrow stromal microenvironment contributes to the survival of leukemia cells. One explanation for this phenomenon is the interaction between the cell surface receptors CXCR4 and CXCL12. Through CXCL12/CXCR4-mediated chemotaxis, leukemia cells migrate to microscopic niches within the bone marrow, which leads to increased proliferation and survival. Several studies have suggested that increased CXCR4 expression may portend a poor prognosis in various types of leukemia, possibly due to increased protection of leukemia cells by bone marrow stroma. A potential therapeutic strategy to overcome this stromal-mediated survival advantage is to target CXCR4. Inhibition of CXCR4 may allow leukemia cells to be released from bone marrow niches that confer resistance to chemotherapy and negate the survival benefit imparted by bone marrow stroma. PMID- 21668396 TI - Pathophysiologic mechanisms and management of neutropenia associated with large granular lymphocytic leukemia. AB - Large granular lymphocyte (LGL) syndrome includes a spectrum of clonal T cell and natural killer cell chronic lymphoproliferative disorders. These conditions are thought to arise from chronic antigenic stimulation, while the long-term survival of the abnormal LGLs appears to be sustained by resistance to apoptosis and/or impaired survival signaling. T-cell LGL (T-LGL) leukemia is the most common LGL disorder in the Western world. Despite its indolent course, the disease is often associated with neutropenia, the pathogenesis of which is multifactorial, comprising both humoral and cytotoxic mechanisms. This article addresses the pathogenesis of T-LGL leukemia and natural killer cell chronic lymphoproliferative disorder, as well as that of T-LGL leukemia-associated neutropenia. Furthermore, as symptomatic neutropenia represents an indication for initiating treatment, available therapeutic options are also discussed. PMID- 21668398 TI - Stem-cell transplantation in children and adults with sickle cell disease: an update. AB - Sickle cell disease (SCD) is associated with significant morbidity, a decreased lifespan and a poor quality of life. While there is increasing evidence that hydroxyurea can improve the course of severe SCD, hematopoeitic stem-cell transplantation (HSCT) remains the only curative option for SCD. Multicenter trials have shown that HSCT after myeloablative conditioning has excellent outcomes in children with SCD, with an overall survival ranging from 93 to 97% and an event-free survival between 82 and 86%. With better understanding of the course of SCD in adulthood, there has been increasing interest in making HSCT a viable intervention in adults. Nonetheless, older patients with severe disease have not been considered suitable candidates because of the higher risks associated with myeloablative conditioning. Recently, reduced-intensity regimens have been used in adults with good results, albeit in a small number of patients. The main limitation of HSCT in both adults and children with SCD remains the lack of availability of fully matched HLA sibling donors for patients meeting transplant criteria. PMID- 21668399 TI - Complications of thalassemia major and their treatment. AB - The life of patients with thalassemia has improved both in duration and in quality in industrialized countries. Complications are still common and include heart disease (heart failure and arrhythmias), chronic liver hepatitis, which can evolve in cirrhosis and, rarely, in hepatocellular carcinoma, endocrine problems (hypogonadism, hypothyroidism, diabetes, hypoparathyroidism), stunted growth, osteoporosis, thrombophilia and pseudoxanthoma elasticum. The incidence of complications is decreasing in younger cohorts of patients who have been transfused with blood that has been screened for viruses and thanks to the introduction of new oral iron chelators and imaging methods. The accurate measurement of iron deposits allows better management of iron overload. In addition, therapy for several complications is available. Specialized competence in treating patients with thalassemia is of great importance. PMID- 21668397 TI - Biomarkers in chronic graft-versus-host disease. AB - Chronic graft-versus-host disease (cGVHD ) is a leading cause of allogeneic hematopoietic stem-cell transplantation-related mortality and morbidity. It is an immune-mediated disorder that can target almost any organ in the body, often with devastating consequences. The immune-suppressive medications currently used to treat it are equally toxic and are often not very effective. At this time, our understanding of its pathophysiology is limited. The discovery of potential biomarkers offers new possibilities in the clinical management of cGVHD. They could potentially be used for diagnosing cGVHD, for predicting or evaluating response to therapy and for unique insights into the pathophysiology underlying the clinical manifestations of cGVHD. Understanding the biological origins of these biomarkers can help us construct a more comprehensive and clinically relevant model for the pathogenesis of this disease. In this article, we review existing evidence for candidate biomarkers that have been identified in the framework of how they may contribute to the pathophysiology of cGVHD. Issues regarding the discovery and application of biomarkers are discussed. PMID- 21668401 TI - Retroperitoneal fibrosis showing immunoglobulin G4-positive monoclonal B lymphocytes. PMID- 21668402 TI - Medically minimising the impact of hypoglycaemia in type 2 diabetes: a review. AB - INTRODUCTION: Some therapies for type 2 diabetes (T2DM) are limited by hypoglycaemia, and this underestimated side effect carries an associated morbidity and financial burden. Large trials that have examined strict glycaemic control and cardiovascular outcomes in T2DM have highlighted the potential harm of exposure to hypoglycaemia in people with coronary heart disease. AREAS COVERED: The responses to, and the morbidity associated with, hypoglycaemia in T2DM are discussed with identification of people most at risk of severe hypoglycaemia. The evidence base for non-pharmacological strategies and the risks of hypoglycaemia associated with various treatment modalities are examined. This review provides the clinician with a rational approach to the selection of different anti-diabetes drugs to minimize the risk of hypoglycaemia. EXPERT OPINION: When managing T2DM, insulin and insulin secretagogues should be used judiciously and glycaemic targets individualized to avoid hypoglycaemia. Incretin mimetics present a lower risk of hypoglycaemia with similar efficacy as traditional agents in treating hyperglycaemia. The potential relationship between hypoglycaemia and precipitation of acute cardiovascular events is a highly topical area of research and may help determine what glycaemic targets are appropriate in people with T2DM. PMID- 21668403 TI - New delivery systems to improve the bioavailability of resveratrol. AB - INTRODUCTION: Resveratrol (RSV) has been one of the most extensively studied polyphenols in the last 10 years, owing to its numerous and potent therapeutic activities, namely its high antioxidant properties. However, RSV's bioavailability is compromised by its physicochemical properties, such as low stability, increased oxidation on heat and light exposure, low water solubility and also its high hepatic uptake. Moreover, results obtained in human pharmacokinetic studies have shown a low amount of intact RSV in the systemic circulation, which does not justify its therapeutic activities, raising doubts about RSV's potential. RSV is already available as a nutritional supplement, although its translation to the clinic is not straightforward, owing to the lack of clinical data. AREAS COVERED: In this review, formulations that are being used for delivery of RSV are discussed. New delivery systems are presented as valid alternatives to circumvent the limitations of the physicochemical characteristics and pharmacokinetics of RSV. In this way, they are compared with classical formulations with regard to improving RSV protection and bioavailability. EXPERT OPINION: Despite promising results in preclinical settings, the applicability of RSV to humans has met with only limited success, largely owing to its inefficient systemic delivery and consequently its low bioavailability. To achieve an optimal response of RSV, new strategies are still required to enhance its bioavailability and reduce its perceived toxicity. PMID- 21668404 TI - Superficial fungal infections of the male genitalia: a review. AB - Fungal infections of the genitals are probably more common than realized; however, relatively few reports concerning fungal genital infections exist in the literature. In this review, the fungal microbiota of the penis are highlighted, and the epidemiological characteristics of Candida balanitis, penile pityriasis versicolor, and tinea genitalis are addressed. In addition, the benefits of circumcision on male genital infections are included. However, systemic mycoses affecting the penis and/or scrotum will not be addressed in this review. To obtain a reliable diagnosis of genital fungal infections, medical history, clinical examination, and mycological and histological investigations of the lesions are critical. PMID- 21668406 TI - A study of metachronous cancer after endoscopic resection of early gastric cancer. AB - OBJECTIVE: Endoscopic resection is commonly used for early gastric cancer (EGC) in Korea and Japan. There are only a few reports of metachronous cancer after endoscopic resection. The aim of this study was to identify clinical factors associated with metachronous gastric cancer after endoscopic resection. METHODS: A total of 176 patients with EGC who had underwent endoscopic submucosal dissection (ESD) were periodically followed-up with endoscopic examinations from January 2004 to December 2007. The incidence and variable factors of metachronous gastric cancer were investigated in a retrospective study. RESULTS: The median interval between the diagnosis of primary cancer and the diagnosis of the first metachronous cancer was 30 months (range 18-42 months). Metachronous gastric cancer had developed in nine patients (5.1%) during follow-up period and seven patients (4.0%) had synchronous gastric cancer lesions within 1 year of the initial endoscopic treatment. Annual incidence rate of metachronous cancer was approximately 3.3%. Antrum atrophy and old age were significantly associated with the incidence of metachronous cancer. The status of Helicobacter pylori, size, location and gross finding of lesion had no significant relationship with metachronous occurrence. CONCLUSIONS: We should examine more carefully older patients who have atrophic gastritis because secondary cancer including metachronous cancer might occur in remnant stomach after initial successful endoscopic resection. And prospective study will be needed for the optimal endoscopic surveillance interval. PMID- 21668407 TI - Reproducibility of the histological diagnosis of celiac disease. AB - OBJECTIVE: A small intestinal biopsy is considered to be the gold standard for the diagnosis of celiac disease (CD). However, the assessment of small intestinal histology may vary between pathologists. Our aim was, therefore, to determine the interobserver variability in the histological diagnosis of CD. MATERIAL AND METHODS: Biopsy specimens of 297 pediatric patients suspected of having CD were revised by a single experienced pathologist and compared to the original reports. Mucosal changes were scored using the Marsh classification. In patients with a discrepancy in diagnosis, clinical and serological data were used to determine the most probable diagnosis. RESULTS: Although the interobserver variability for the Marsh classification was found to be moderate with a Kappa value of 0.486, the Kappa value for the diagnosis reached an almost perfect agreement (0.850). Nevertheless, in 22 patients a different diagnosis was made by the second observer. Interestingly, in this subgroup relatively more biopsies were classified to be of suboptimal quality. Based on clinical presentation, serology and follow-up, 19 of those patients truly had CD. In 14 of them the diagnosis was originally missed by the first observer while five cases were under-diagnosed by the second pathologist. CONCLUSIONS: CD can be missed histologically due to assessment variation between pathologists. A final diagnosis of CD should be based on histology, serology as well as response to the diet. PMID- 21668405 TI - Mitochondrial dynamics and Parkinson's disease: focus on parkin. AB - SIGNIFICANCE: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. To provide more effective medical therapy for PD, better understanding of the underlying causes of the disease is clearly necessary. RECENT ADVANCES: A broad range of studies conducted over the past few decades have collectively implicated aberrant mitochondrial homeostasis as a key contributor to the development of PD. Supporting this, mutations in several PD-linked genes are directly or indirectly linked to mitochondrial dysfunction. In particular, recent discoveries have identified parkin, whose mutations are causative of recessive parkinsonism, as a key regulator of mitochondrial homeostasis. CRITICAL ISSUES: Parkin appears to be involved in the entire spectrum of mitochondrial dynamics, including organelle biogenesis, fusion/fission, and clearance via mitophagy. How a single protein can regulate such diverse mitochondrial events is as intriguing as it is amazing; the mechanism underlying this is currently under intense research. Here, we provide an overview of mitochondrial dynamics and its relationship with neurodegenerative diseases and discuss current evidence and controversies surrounding the role of parkin in mitochondrial quality control and its relevance to PD pathogenesis. FUTURE DIRECTIONS: Although the emerging field of parkin-mediated mitochondrial quality control has proven to be exciting, it is important to recognize that PD pathogenesis is likely to involve an intricate network of interacting pathways. Elucidating the reciprocity of pathways, particularly how other PD-related pathways potentially influence mitochondrial homeostasis, may hold the key to therapeutic development. PMID- 21668408 TI - Patent review. AB - The section on patent review will be focused in the areas of interest to the readers of CCHTS. The search was conducted using the following key words: combinatorial chemistry, high throughput screening, drug repurposing, chemical library, high content screening, drug discovery and natural products. All patents highlighted here are identified by the patent number issued either by the World Intellectual Property Organization or by a regional patent office. PMID- 21668409 TI - A rapid, four-component synthesis of functionalized thiazoles. AB - An efficient synthesis of 2-(dialkylamino)-4-phenyl)-1,3-thiazol-5 yl)(phenyl)methanone using acid chlorides, secondary amines, 2-bromoacethophenone and ammonium thiocyanate is described. PMID- 21668410 TI - HIV-1 gp41 ectodomain enhances Cryptococcus neoformans binding to human brain microvascular endothelial cells via gp41 core-induced membrane activities. AB - Cryptococcus neoformans causes life-threatening meningoencephalitis, particularly prevalent in AIDS patients. The interrelationship between C. neoformans and HIV-1 is intriguing, as both pathogens elicit severe neuropathological complications. We have previously demonstrated that the HIV-1 gp41 ectodomain fragments gp41-I33 (amino acids 579-611) and gp41-I90 (amino acids 550-639) can enhance C. neoformans binding to HBMECs (human brain microvascular endothelial cells). Both peptides contain the loop region of gp41. In the present study, we used immunofluorescence microscopy and transmission and scanning electron microscopy to explore the underlying mechanisms. Our findings indicated that both C. neoformans and gp41-I90 up-regulated ICAM-1 (intercellular adhesion molecule 1) on the HBMECs and elicited membrane ruffling on the surface of HBMECs. The HIV-1 gp41 ectodomain could also induce CD44 and beta-actin redistribution to the membrane lipid rafts, but it could not enhance PKCalpha (protein kinase Calpha) phosphorylation like C. neoformans. Instead, gp41-I90 was able to induce syncytium formation on HBMECs. The results of the present study suggest HIV-1 gp41-enhanced C. neoformans binding to HBMECs via gp41 core domain-induced membrane activities, revealing a potential mechanism of invasion for this pathogenic fungus into the brain tissues of HIV-1-infected patients. PMID- 21668412 TI - Vesicle trafficking and membrane remodelling in cytokinesis. AB - All cells complete cell division by the process of cytokinesis. At the end of mitosis, eukaryotic cells accurately mark the site of division between the replicated genetic material and assemble a contractile ring comprised of myosin II, actin filaments and other proteins, which is attached to the plasma membrane. The myosin-actin interaction drives constriction of the contractile ring, forming a cleavage furrow (the so-called 'purse-string' model of cytokinesis). After furrowing is completed, the cells remain attached by a thin cytoplasmic bridge, filled with two anti-parallel arrays of microtubules with their plus-ends interdigitating in the midbody region. The cell then assembles the abscission machinery required for cleavage of the intercellular bridge, and so forms two genetically identical daughter cells. We now know much of the molecular detail of cytokinesis, including a list of potential genes/proteins involved, analysis of the function of some of these proteins, and the temporal order of their arrival at the cleavage site. Such studies reveal that membrane trafficking and/or remodelling appears to play crucial roles in both furrowing and abscission. In the present review, we assess studies of vesicular trafficking during cytokinesis, discuss the role of the lipid components of the plasma membrane and endosomes and their role in cytokinesis, and describe some novel molecules implicated in cytokinesis. The present review covers experiments performed mainly on tissue culture cells. We will end by considering how this mechanistic insight may be related to cytokinesis in other systems, and how other forms of cytokinesis may utilize similar aspects of the same machinery. PMID- 21668413 TI - Cyclodextrin, a novel therapeutic tool for suppressing amyloidogenic transthyretin misfolding in transthyretin-related amyloidosis. AB - TTR (transthyretin), a beta-sheet-rich protein, is the precursor protein of familial amyloidotic polyneuropathy and senile systemic amyloidosis. Although it has been widely accepted that protein misfolding of the monomeric form of TTR is a rate-limiting step for amyloid formation, no effective therapy targeting this misfolding step is available. In the present study, we focused on CyDs (cyclodextrins), cyclic oligosaccharides composed of glucose units, and reported the inhibitory effect of CyDs on TTR amyloid formation. Of various branched beta CyDs, GUG-beta-CyD [6-O-alpha-(4-O-alpha-D-glucuronyl)-D-glucosyl-beta-CyD] showed potent inhibition of TTR amyloid formation. Far-UV CD spectra analysis showed that GUG-beta-CyD reduced the conformational change of TTR in the process of amyloid formation. In addition, tryptophan fluorescence and 1H-NMR spectroscopy analyses indicated that GUG-beta-CyD stabilized the TTR conformation via interaction with the hydrophobic amino acids of TTR, especially tryptophan. Moreover, GUG-beta-CyD exerted its inhibitory effect by reducing TTR deposition in transgenic rats possessing a human variant TTR gene in vivo. Collectively, these results indicate that GUG-beta-CyD may inhibit TTR misfolding by stabilizing its conformation, which, in turn, suppresses TTR amyloid formation. PMID- 21668411 TI - Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment. AB - Wnt signalling pathways have been shown to play key roles in both normal development and tumorigenesis. Progression of many human cancers is associated with defined mutations in Wnt pathway components that result in dysregulated beta catenin-mediated gene transcription. Although Wnt pathway mutations are rare in epithelial ovarian cancer (with the exception of the endometrioid histotype), accumulating evidence supports a role for Wnt signalling in ovarian tumorigenesis in the absence of genetic mutations. The present review summarizes evidence in support of activated Wnt signalling in ovarian tumours and discusses alternative mechanisms for Wnt pathway activation in the ovarian tumour microenvironment. PMID- 21668415 TI - Comparison of carbamazepine rash in multiple sclerosis and epilepsy. AB - OBJECTIVES: Studies on the comorbidity of multiple sclerosis (MS) and allergic disorders have shown conflicting results. Carbamazepine (CBZ) is widely used in MS to control pain. We have compared the incidence of rash from CBZ use in MS and epilepsy. MATERIALS AND METHODS: Consecutive adult patients with MS and epilepsy were studied retrospectively. A detailed survey of medical records concerning CBZ treatment was performed. RESULTS: A total of 495 patients with epilepsy and 442 patients with MS were included. Sixty-five per cent of patients with epilepsy and 20% of patients with MS had used CBZ. In CBZ-exposed patients, rash occurred in 15/89 (17%) in MS and in 43/323 (13%) in epilepsy, a difference which was not significant. Women below 50 years experienced more skin reactions than older women and men. The unadjusted odds ratio (OR) for rash in the MS vs epilepsy group was 1.32 (CI 0.70-2.51, P = 0.40). Adjusting groups for gender and age reduced the OR to 1.11 (CI 0.56-2.19, P = 0.76). CONCLUSION: Compared with epilepsy, which is only rarely caused by immunological mechanisms, the autoimmune disorder MS was not associated with a different occurrence of CBZ skin reactions. The trend towards an increased occurrence of rashes in MS can partly be explained by a higher predisposition to CBZ rash in women of fertile age. PMID- 21668414 TI - A drug targeting only p110alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. AB - Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110alpha in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110alpha have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110alpha inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110alpha/p110beta/p110delta in all cell lines tested. However, inhibition of p110alpha alone was sufficient to block insulin signalling to Akt/PKB in certain cell lines. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110alpha and class-Ia PI3K activity. This may explain the increased sensitivity of these cells to p110alpha inhibitors. We assessed the activation of Akt/PKB and tumour growth in xenograft models and found that tumours derived from two of the responsive cell lines were also responsive to A66 in vivo. These results show that inhibition of p110alpha alone has the potential to block growth factor signalling and reduce growth in a subset of tumours. PMID- 21668416 TI - Women's premonitions prior to the death of their baby in utero and how they deal with the feeling that their baby may be unwell. AB - OBJECTIVE: To identify whether mothers of stillborn babies had had a premonition that their unborn child might not be well and how they dealt with that premonition. Design. A mixed method approach. SETTING: One thousand and thirty four women answered a web questionnaire. SAMPLE: Six hundred and fourteen women fulfilled the inclusion criteria of having a stillbirth after the 22nd gestational week and answered questions about premonition. METHODS: Qualitative content analysis was used for the open questions and descriptive statistics for questions with fixed alternatives. MAIN OUTCOME MEASURE: The premonition of an unwell unborn baby. RESULTS: In all, 392 of 614 (64%) of the women had had a premonition that their unborn baby might be unwell; 274 of 614 (70%) contacted their clinic and were invited to come in for a check-up, but by then it was too late because the baby was already dead. A further 88 of 614 (22%) decided to wait until their next routine check-up, believing that the symptoms were part of the normal cycle of pregnancy, and that the fetus would move less towards the end of pregnancy. Thirty women (8%) contacted their clinic, but were told that everything appeared normal without an examination of the baby. CONCLUSIONS: Women need to know that a decrease in fetal movements is an important indicator of their unborn baby's health. Healthcare professionals should not delay an examination if a mother-to-be is worried about her unborn baby's wellbeing. PMID- 21668417 TI - Ureteral endometriosis and loss of renal function: mechanisms and interpretations. AB - Ureteral endometriosis is associated with deep endometriosis and is relatively uncommon. In some patients, progressive obstruction of the lower part of the ureter may occur, with silent loss of renal function as a consequence. We report on three patients with loss of renal function, in whom different pathogenic mechanisms probably were the decisive cause. Failure to diagnose deep endometriosis with ureteral involvement, misinterpretation of hydroureter at magnetic resonance imaging and lack of typical symptoms may all be reasons for development of loss of renal function. With only one functional kidney, these patients should be followed closely with renal function tests and ultrasound, and in certain cases also by magnetic resonance imaging or renal scintigraphy. PMID- 21668418 TI - Psychiatry's contract with society: what is expected? PMID- 21668419 TI - Cerebrospinal fluid biomarkers in suicide attempters. PMID- 21668420 TI - The importance of screening for depression in general practice. PMID- 21668424 TI - Clinical recognition of dementia and cognitive impairment in primary care: a meta analysis of physician accuracy. AB - OBJECTIVE: We aimed to examine the ability of the general practitioners (GPs) to recognize a spectrum of cognitive impairment from mild cognitive impairment (MCI) to severe dementia in routine practice using their own clinical judgment. METHOD: Using PRISMA criteria, a meta-analysis of studies testing clinical judgment and clinical documentation was conducted against semi-structured interviews (for dementia) and cognitive tests (for cognitive impairment). We located 15 studies reporting on dementia, seven studies that examined recognition of broadly defined cognitive impairment, and eight regarding MCI. RESULTS: By clinical judgment, clinicians were able to identify 73.4% of people with dementia and 75.5% of those without dementia but they made correct annotations in medical records in only 37.9% of cases (and 90.5% of non-cases). For cognitive impairment, detection sensitivity was 62.8% by clinician judgment but 33.1% according to medical records. Specificity was 92.6% for those without cognitive impairment by clinical judgment. Regarding MCI, GPs recognized 44.7% of people with MCI, although this was recorded in medical notes only 10.9% of the time. Their ability to identify healthy individuals without MCI was between 87.3% and 95.5% (detection specificity). CONCLUSION: GPs have considerable difficulty identifying those with MCI and those with mild dementia and are generally poor at recording such diagnoses in medical records. PMID- 21668425 TI - Narrowband ultraviolet B phototherapy for patients with refractory uraemic pruritus: a randomized controlled trial. AB - BACKGROUND: Pruritus is very common in uraemic patients, but the treatment remains challenging. Studies regarding narrowband ultraviolet B (NB-UVB) phototherapy for uraemic pruritus are rare. OBJECTIVES: To investigate whether or not NB-UVB phototherapy is an effective treatment for uraemic pruritus. METHODS: We conducted a single-blind, randomized, controlled trial for patients with refractory uraemic pruritus. The treatment group received NB-UVB phototherapy three times per week for 6 weeks. The dose of NB-UVB started from 210 mJ cm(-2) and was increased by 10% each time. The control group received time-matched exposures to long-wave UVA radiation. A visual analogue scale (VAS) score was evaluated weekly for pruritus intensity for 12 weeks. The characteristics of pruritus were also assessed by a questionnaire at baseline and after 6 weeks of phototherapy. RESULTS: Both the NB-UVB and control groups had significant and comparable improvement in the pruritus intensity VAS scores during the period of phototherapy and follow-up. Compared with the control group, the NB-UVB group showed a significant improvement in the involved body surface area affected by pruritus (P = 0.006), but not in sleep quality. More detailed regression and estimating analysis revealed that the patients in the NB-UVB group had lower pruritus intensity scores at week 6, week 10 and week 12. This may indicate a beneficial difference at certain time points, but the effect seems marginal. CONCLUSIONS: NB-UVB phototherapy does not show a significant effect in reducing pruritus intensity compared with a control group for refractory uraemic pruritus. Further studies are warranted. PMID- 21668426 TI - A novel frameshift mutation in keratin 16 underlies pachyonychia congenita with focal palmoplantar keratoderma. PMID- 21668427 TI - Primary cutaneous small cell carcinoma of the vulva arising from squamous cell carcinoma. PMID- 21668428 TI - Plantar basal cell carcinoma in a patient with xeroderma pigmentosum: importance of dermoscopy for early diagnosis of nonpigmented skin cancer. PMID- 21668429 TI - Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. AB - BACKGROUND: Hepatoerythropoietic porphyria (HEP) is a rare form of porphyria that results from a deficiency of uroporphyrinogen decarboxylase (UROD). The disease is caused by homoallelism or heteroallelism for mutations in the UROD gene. OBJECTIVE: To study a 19-year-old woman from Equatorial Guinea, one of the few cases of HEP of African descent and to characterize a new mutation causing HEP. METHODS: Excretion of porphyrins and residual UROD activity in erythrocytes were measured and compared with those of other patients with HEP. The UROD gene of the proband was sequenced and a new mutation identified. The recombinant UROD protein was purified and assayed for enzymatic activity. The change of amino acid mapped to the UROD protein and the functional consequences were predicted. RESULTS: The patient presented a novel homozygous G170D missense mutation. Porphyrin excretion showed an atypical pattern in stool with a high pentaporphyrin III to isocoproporphyrin ratio. Erythrocyte UROD activity was 42% of normal and higher than the activity found in patients with HEP with a G281E mutation. The recombinant UROD protein showed a relative activity of 17% and 60% of wild-type to uroporphyrinogen I and III respectively. Molecular modelling showed that glycine 170 is located on the dimer interface of UROD, in a loop containing residues 167-172 that are critical for optimal enzymatic activity and that the carboxyl side chain from aspartic acid is predicted to cause negative interactions between the protein and the substrate. CONCLUSIONS: The results emphasize the complex relationship between the genetic defects and the biochemical phenotype in homozygous porphyria. PMID- 21668430 TI - Analysis of TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 in autosomal recessive congenital ichthyosis from Galicia (NW Spain): evidence of founder effects. AB - BACKGROUND: Mutations in six genes have been identified in autosomal recessive congenital ichthyosis (ARCI). To date, few studies have analysed the spectrum of these mutations in specific populations. OBJECTIVES: We have studied the characteristics of patients with ARCI in Galicia (NW Spain). Methods We recruited patients by contacting all dermatology departments of Galicia and the Spanish patient organization for ichthyosis. TGM1, ALOX12B, ALOXE3, NIPAL4 and CYP4F22 were analysed in the patients and their relatives. RESULTS: We identified 23 patients with ARCI and estimated a prevalence of 1 : 122 000. Twenty of the patients were studied. Seventeen of them were clinically categorized as having lamellar ichthyosis (LI) and three as having congenital ichthyosiform erythroderma (CIE). TGM1 and ALOXE3 mutations were identified in 12/16 (75%) probands whereas no ALOX12B, NIPAL4 and CYP4F22 mutations were found. TGM1 mutations were found in 11/13 (85%) of LI probands. ALOXE3 mutations were identified in a single patient with CIE. Remarkably, mutations p.Arg760X, p.Asp408ValfsX21 and c.984+1G>A of TGM1 were present in six, four and two families, accounting for 41%, 23% and 14% of all TGM1 mutant alleles, respectively. CONCLUSIONS: The high percentage of patients with the same TGM1 mutations, together with the high number of homozygous probands (64%), indicates the existence of a strong founder effect in our population. PMID- 21668431 TI - Cardiomyopathy with alopecia and palmoplantar keratoderma (CAPK) is caused by a JUP mutation. AB - Inherited desmosomal cardiocutaneous syndromes are characterized by the quartet of woolly hair, palmoplantar keratoderma (PPK), skin fragility and cardiac abnormalities, which are caused by mutations in genes coding for desmosomal proteins. We describe a previously unrecognized autosomal recessive syndrome in a family with arrhythmogenic right ventricular cardiomyopathy associated with alopecia and PPK (named CAPK). Genetic investigation of the family led us to find a homozygous disease-causing mutation, p.R265H, in JUP which encodes plakoglobin, a well-described member of the desmosome complex. This study expands the clinical spectrum of disorders associated with germline mutations affecting desmosomal proteins by describing a novel phenotype. PMID- 21668432 TI - Investigation of variants of the aromatase gene (CYP19A1) in female pattern hair loss. PMID- 21668433 TI - Homoeopathic remedies in dermatology: a systematic review of controlled clinical trials. AB - BACKGROUND: Homoeopathic therapies are routinely used for the management of skin diseases. However, there is a lack of evidence-based data on their effectiveness. OBJECTIVES: To assess the evidence for the efficacy of homoeopathic treatments in dermatology. METHODS: We designed a systematic review of the controlled clinical trials (January 1962-April 2011) investigating homoeopathic therapies for the treatment of cutaneous diseases. We collected data from MEDLINE, PubMed, Current Contents, HomInform (Glasgow), reference lists, specialist textbooks and contacts with homoeopathic manufacturers. There was no restriction on language. Subsets were defined according to treated skin disease/condition. For each subset, two reviewers extracted data for information on study quality, type of remedy, population and outcomes. RESULTS: After an extensive search, we isolated a very limited number of trials investigating homoeopathic treatments for cutaneous diseases. Overall, of the 12 trials with interpretable results, nine trials indicated no positive effects of homoeopathy. The three trials showing a positive effect were of low methodological quality. CONCLUSIONS: Reviewed trials of homoeopathic treatments for cutaneous diseases were highly variable in methods and quality. We did not find sufficient evidence from these studies that homoeopathy is clearly efficacious for any single dermatological condition. PMID- 21668434 TI - New horizons for cutaneous microbiology: the role of biofilms in dermatological disease. AB - Human skin is colonized by bacteria. The development of new genomic microbiological techniques has revealed that the bacterial ecology of human skin is far more complex than previously imagined and includes many fastidious or noncultivable bacterial species which are found on both normal and diseased skin. In nature, the predominant bacterial phenotype on epithelial surfaces is that of organisms organized within a biofilm. This contrasts with the widely held belief that bacteria are planktonic, i.e. free-floating single cells. Biofilms are sessile bacterial communities encased in an extracellular matrix that have a well developed communication system and can regulate bacterial growth and metabolism, confer resistance to antimicrobials and to host inflammatory cells, and alter host metabolism. Biofilms have been observed on healthy skin and in a number of dermatological conditions, including some that were previously thought not to have an infectious aetiology. Here we review the concept of biofilms and their role in cutaneous health and disease. PMID- 21668436 TI - Cortical excitability changes associated with fixation-off sensitivity: a case report. AB - "Fixation-off sensitivity" (FOS) is an ideal human model for studying the features of epileptic discharges. Physiologically, FOS is expected to correspond to enhanced excitability of widespread cortical structures. To test this hypothesis, we measured by transcranial magnetic stimulation (TMS), the excitability level of the primary motor area in a 22-year-old woman with eyelid myoclonias and absences, who presented with generalized FOS. We also explored her visual system by pattern-reversal and flash-visual evoked potentials (VEPs). Both outside and within FOS, the cortical silent period was dramatically short, indicating defective gamma-aminobutyric acid (GABA)(B) inhibition as a persistent background factor. The same was true for the short-interval intracortical inhibition, a TMS marker of cortical GABA(A) inhibition. The FOS state corresponded then to a pathologic enhancement of intracortical facilitation, a TMS marker of Glu/Asp transmission. During FOS, the flash VEP exhibited a hugely enhanced afterdischarge, expressing a pathologic overactivity of secondary visual areas. Within the limits of a single-case study, we thus provide electrophysiologic evidence supporting a grossly imbalanced cortical excitability, in both the frontal and posterior areas, as an important correlate of the present FOS subtype. PMID- 21668435 TI - Immune adaptive microenvironment profiles in intracerebral and intrasplenic lymphomas share common characteristics. AB - A large body of evidence indicates that the immune microenvironment controls tumour development. Primary central nervous system lymphomas (PCNSL) are aggressive tumours growing in the central nervous system (CNS). To evaluate the role and characteristics of this immune-privileged site in anti-tumour defences, we compared the cellular and molecular immune microenvironments of growing murine lymphoma B cells injected into the brain or the spleen. In the brain, immune cells, including dendritic cells and T lymphocytes with a large proportion of CD4(+) forkhead box P3 (FoxP3(+)) regulatory T cells, rapidly infiltrated the tumour microenvironment. These populations also increased in number in the spleen. The T cell cytokine profiles in tumour-bearing mice were similar in the two sites, with predominant T helper type 1 (Th1)/Th17 polarization after polyclonal stimulation, although some interleukin (IL)-4 could also be found. We demonstrated that these T cells have anti-tumour activity in the CNS, although less than in the spleen: nude mice that received lymphoma cells intracerebrally died significantly earlier than immunocompetent animals. These results demonstrate that the brain is able to recruit all the major actors to mount a specific anti-tumour immune response against lymphoma. PMID- 21668437 TI - Population-specific spectrum of the F11 mutations in Koreans: evidence for a founder effect. AB - The aim of this study was to investigate a mutation spectrum of F11 among Korean patients with factor XI (FXI) deficiency and to determine the haplotypes of mutations frequently found in Koreans. Thirteen unrelated patients from non consanguineous families with FXI deficiency were included in the study. In the mutation analysis, the most frequently found mutations were Q263X (four cases; 31%) and Q226X (three cases; 23%). The frequency of Q263X-bearing haplotype was significantly different between normal and patient groups (p = 0.001), which is consistent with a founder effect of Q263X mutation. Testing for the presence of these two mutations should be the first genetic screening in Korean patients with FXI deficiency. PMID- 21668438 TI - Subcontinuous epileptiform activity after failed hippocampal radiosurgery. AB - PURPOSE: Although gamma-knife radiosurgery (GKS) has proved efficacious in temporal lobe epilepsy (TLE), its antiepileptic mechanism of action remains elusive. Human and experimental data suggest that subnecrotic radiation-induced tissue changes might contribute to the antiepileptic effect of GKS. However, there are no data regarding the evolution of electroencephalography (EEG) activity within GKS-treated hippocampus, information that aid in better understanding both the mechanism of action and the reason for failure of GKS treatment. METHODS: Two patients with disabling seizures 4 and 6 years after mesial temporal GKS with a marginal dose of 24 Gy were investigated with stereotactic intracerebral EEG recordings. Both patients had right TLE with hippocampal atrophy, but with past history of Coxsackie virus meningoencephalitis and congenital toxoplasmosis, respectively. Ten to 12 electrodes were implanted, including seven to eight electrodes within the epileptic temporal lobe. KEY FINDINGS: In both patients, depths electrodes placed within the irradiated mesial temporal structures disclosed a remarkable pattern of subcontinuous spiking activity intermingled with asymptomatic rhythmic discharges up to 1 min in duration. This activity differed from the abnormalities usually captured in mesial TLE (mTLE) and suggested radiosurgery-induced brain changes. Both patients underwent anterior temporal lobectomy and achieved a class I outcome after a follow-up of 18 and 40 months, respectively. Pathologic examination of the surgical specimens showed variable degrees of radiation-effect changes. SIGNIFICANCE: Our study shows that mesial temporal structures previously treated with GKS can demonstrate a persistent high degree of epileptiform activity in patients who failed to respond to that treatment. Although this persistent EEG activity appears likely to reflect GKS-induced brain changes, its relation to GKS seizure outcome remains unclear. PMID- 21668439 TI - Ganglioglioma arising from dysplastic cortex. AB - We report the case of a child who presented at 3 months of age with complex partial seizures, a linear facial nevus, and magnetic resonance imaging (MRI) showing delayed myelination and thickened cortex in the left temporal, parietal, and occipital regions. A repeat 3Tesla MRI scan with and without contrast at 6 months again showed cortical dysplasia of the left hemisphere. No other abnormalities were seen. A third scan at 3 years 6 months showed a 2.5 cm, round, hyperintense lesion on both T(2) and T(1) sequences. The lesion and surrounding dysplastic cortex were resected. Palmini grade IIA dysplasia and a ganglioglioma were diagnosed. These findings suggest that cellular components of cortical dysplasias have oncogenic potential. PMID- 21668440 TI - Orthogonal wave propagation of epileptiform activity in the planar mouse hippocampus in vitro. AB - PURPOSE: In vitro brain preparations have been used extensively to study the generation and propagation of epileptiform activity. Transverse and longitudinal slices of the rodent hippocampus have revealed various patterns of propagation. Yet intact connections between the transverse and longitudinal pathways should generate orthogonal (both transverse and longitudinal) propagation of seizures involving the entire hippocampus. This study utilizes the planar unfolded mouse hippocampus preparation to reveal simultaneous orthogonal epileptiform propagation and to test a method of arresting propagation. METHODS: This study utilized an unfolded mouse hippocampus preparation. It was chosen due to its preservation of longitudinal neuronal processes, which are thought to play an important role in epileptiform hyperexcitability. 4-Aminopyridine (4-AP), microelectrodes, and voltage-sensitive dye imaging were employed to investigate tissue excitability. KEY FINDINGS: In 50-MUm 4-AP, stimulation of the stratum radiatum induced transverse activation of CA3 cells but also induced a longitudinal wave of activity propagating along the CA3 region at a speed of 0.09 m/s. Without stimulation, a wave originated at the temporal CA3 and propagated in a temporal-septal direction could be suppressed with glutamatergic receptor antagonists. Orthogonal propagation traveled longitudinally along the CA3 pathway, secondarily invading the CA1 region at a velocity of 0.22 +/- 0.024 m/s. Moreover, a local lesion restricted to the CA3 region could arrest wave propagation. SIGNIFICANCE: These results reveal a complex two-dimensional epileptiform wave propagation pattern in the hippocampus that is generated by a combination of synaptic transmission and axonal propagation in the CA3 recurrent network. Epileptiform propagation block via a transverse selective CA3 lesion suggests a potential surgical technique for the treatment of temporal lobe epilepsy. PMID- 21668441 TI - Does semiology tell us the origin of seizures consisting mainly of an alteration in consciousness? AB - PURPOSE: Studies on seizures only with an alteration of consciousness were limited mainly to generalized epilepsy. This seizure type has been described rarely in focal epilepsy. We aimed to analyze the semiologic features of this seizure type in focal and generalized epilepsies in a blinded design. METHODS: A total of 338 seizure videos in 100 patients were included exclusively by semiologic criteria. Two investigators evaluated the seizure semiology (aura, seizure duration, blinking, mild motor phenomena including automatisms, and so on) from the videos. Primarily the ictal electroencephalography (EEGs) studies and all laboratory findings were evaluated for the localization of the epileptogenic zone and delineating the syndromes, in the second step. KEY FINDINGS: Of the focal epilepsy patients (n = 57), the epileptogenic zone could be localized to the temporal (n = 20), frontal (n = 9), and parietooccipital (n = 3) regions. The most common etiology of the generalized epilepsy patients (n = 43) was presumably genetic (n = 33). The presence of aura (none in generalized epilepsy vs. 35% in focal epilepsy; p = 0.0008), lack of blinking (19.3% in focal vs 65.1% in generalized epilepsy; p = 0.01), and longer seizure duration (generalized 14.3 +/- 17.7 s vs focal 54.9 +/- 40.1 s; p < 0.0001) are significantly associated with focal epilepsy, whereas high seizure frequency (p = 0.002), family history of epilepsy (p = 0.016), and responsiveness to therapy (p = 0.004) point to generalized epilepsy with logistic regression analysis. SIGNIFICANCE: Seizures consisting mainly of an alteration in consciousness may originate from any brain lobe in focal epilepsies and also occur in generalized epilepsies. Several semiologic and clinical features that help to differentiate between focal and generalized epilepsy should be considered in the syndrome diagnosis. PMID- 21668442 TI - The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study. AB - PURPOSE: Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors. METHODS: Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression. KEY FINDINGS: Age of onset ranged (77 infants) from <1 to 10 months (mean 5.2, standard deviation 2.1). Lead time to treatment was 7 days or less in 11, 8-14 days in 16, 15 days to 1 month in 8, 1-2 months in 15, >2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64-5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3-0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p=0.004). SIGNIFICANCE: Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants. PMID- 21668443 TI - GABAergic depolarization during early cortical development and implications for anticonvulsive therapy in neonates. AB - Epileptic seizures rank among the most frequent neurologic symptoms during the neonatal period. Accumulating data from experimental animal studies and clinical trials in humans suggest that neonatal seizures could adversely affect normal brain development and result in long-term neurologic sequelae. Unfortunately, currently used anticonvulsive drugs are often ineffective in the neonatal period. One particularity of the immature neuronal network during neonatal development is that the neurotransmitter gamma-aminobutyric acid (GABA) is mainly depolarizing, rather than hyperpolarizing as commonly observed in adults. This might, in part, explain not only the higher seizure propensity of the immature neuronal network, but also the limited anticonvulsive efficacy of GABA-enhancing drugs during early postnatal life. Accordingly, pharmacologic attenuation of GABAergic depolarization has been proposed as a strategy for neonatal seizure control. However, the underlying conjecture of a depolarizing mode of GABA action has been seriously challenged recently. In the present review, we will summarize the state of knowledge regarding GABAergic depolarization in early life and discuss how these data might impact a currently tested anticonvulsive strategy. PMID- 21668444 TI - Comorbidities and predictors of health-related quality of life in Dravet syndrome. AB - PURPOSE: Health-related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual's physical, social, and mental well-being. There is a paucity of data focusing on HRQOL in specific epilepsy syndromes and their associated needs. In this study our aim was to describe the comorbidities and disease-related predictors for HRQOL in Dravet syndrome, an epileptic encephalopathy, with defined genetic etiology. We anticipate that this will help us to better recognize and understand the needs of children and families and aid treatment planning in this severe epilepsy syndrome. METHODS: One hundred sixty-three individuals with Dravet syndrome and their families participated in the study. Detailed clinical and demographic information was available for each case. HRQOL was evaluated with two epilepsy specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL); a generic HRQOL instrument; the Pediatric Quality of Life Inventory (PedsQL); and a behavioral screening tool, the Strength and Difficulties Questionnaire (SDQ). KEY FINDINGS: HRQOL was significantly lower for children with Dravet syndrome compared to normative data (p < 0.001). A cross-sectional evaluation of measures across different age groups revealed that PedsQL generic core and cognitive function scales decreased in older age categories, indicating worse HRQOL (p < 0.001). Assessment of epilepsy severity demonstrated that symptoms were rated very severe in 10 (6%) of 162 cases, somewhat severe in 78 (48%) of 162, moderate in 51 (32%) of 162, and mild in 23 (14%) of 162 cases. The epilepsy severity correlated significantly with the IPES total impact score (r = 0.466, p < 0.001, n = 162). The IPES total impact scores in the Dravet group (n = 162) were significantly higher than scores measured in the original validation sample of epileptic children with and without learning difficulties (+/- SD) (21.0 +/- 8.7 vs. 11.6 +/- 5.4, t = 8.95, p < 0.001, n = 46). On the SDQ, 35% of children scored in the abnormal range for "conduct problems," 66% for "hyperactivity/ inattention," and 76% for "peer relationships." Regression analysis revealed that young age at seizure onset (p = 0.019), presence of myoclonic seizures (p = 0.029), motor disorder (p = 0.048), learning difficulties (p = 0.002), epilepsy severity (p < 0.001), and behavioral difficulties (p < 0.001) each independently predicted poorer HRQOL. Behavioral problems such as hyperactivity/inattention were the strongest predictors of poorer HRQOL. SIGNIFICANCE: This is the first comprehensive study of HRQOL in an etiologically well-defined epilepsy syndrome. HRQOL in Dravet syndrome depends on a series of independent factors including seizure control, behavior, cognitive, and motor problems. Identification of specific comorbidities in Dravet syndrome will facilitate a distinct and multidisciplinary approach to management, addressing seizure control, behavior problems, cognitive difficulties, and motor impairment. PMID- 21668445 TI - Modulation of human monocyte CD36 by type 2 diabetes mellitus and other atherosclerotic risk factors. AB - BACKGROUND: The pathophysiological role of CD36 in atherosclerosis seems to be largely dependent on its pro-inflammatory function and ability to take up oxidized low-density lipoprotein. Controversy exists concerning the potential beneficial/harmful effects of vascular CD36 inhibition in atherosclerosis. However, as atherosclerosis in murine models does not result in clinical end points such as plaque rupture and thrombotic ischaemia, typical of human disease, clinical studies are required to understand the functional role of CD36 in human atherosclerosis. MATERIALS AND METHODS: Our aim was to investigate whether CD36 expression in monocytes is modulated by the presence of an increasing number of atherosclerotic risk factors, and specifically by hyperglycaemia because of diabetes mellitus. The study included 33 patients with advanced atherosclerosis and eight healthy blood donors, as controls. The patients were classified according to the presence of atherosclerotic risk factors. Diabetes mellitus was classified as either well-controlled or poorly controlled. Monocytes were exposed in vitro to low (5.5mM) or high glucose (26mM) concentrations for increasing times. RESULTS: Our results demonstrated that protein levels of glycated CD36 were significantly higher in patients with 3-4 atherosclerotic risk factors than in those with 0-2 atherosclerotic risk factors or in subjects with no atherosclerotic symptoms (P=0.04, in both cases). However, when we analysed just the poorly controlled diabetic patients, their glycated CD36 levels were lower. These data were corroborated by in vitro studies demonstrating that increasing glucose concentrations reduced glycated protein levels (P<0.05). CONCLUSIONS: Our results demonstrate that CD36 expression is altered by hyperglycaemia in atherosclerotic patients. PMID- 21668446 TI - Executive functioning in children with specific language impairment. AB - BACKGROUND: A limited range of evidence suggests that children with specific language impairment (SLI) have difficulties with higher order thinking and reasoning skills (executive functioning, EF). This study involved a comprehensive investigation of EF in this population taking into account the contributions of age, nonverbal IQ and verbal ability. METHODS: Ten separate measures of EF were assessed in 160 children: 41 had SLI; 31 had low language/cognitive functioning but did not fulfil the criteria for SLI (low language functioning or LLF); and 88 were typically developing with no language difficulties. Group differences in performance were assessed after controlling for age, nonverbal IQ and verbal ability in a series of regression analyses. RESULTS: Children with SLI and LLF had significantly lower performance than typical children on 6 of the 10 EF tasks once age and nonverbal IQ had been controlled (verbal and nonverbal executive loaded working memory, verbal and nonverbal fluency, nonverbal inhibition and nonverbal planning). Performance on these EF tasks remained lower for those in the SLI group even when verbal IQ was entered in the regressions. CONCLUSIONS: Children with language impairments showed marked difficulties on a range of EF tasks. These difficulties were present even when adjustments were made for their verbal abilities. PMID- 21668447 TI - Methamphetamine neurotoxicity decreases phasic, but not tonic, dopaminergic signaling in the rat striatum. AB - Neurotoxic doses of methamphetamine (METH) are known to cause depletions in striatal dopamine (DA) tissue content. However, the effects of METH-induced insults on dopaminergic neurotransmission are not fully understood. Here, we employed fast-scan cyclic voltammetry at a carbon-fiber microelectrode in the anesthetized rat striatum to assess the effects of a neurotoxic regimen of METH on phasic and tonic modes of dopaminergic signaling and underlying mechanisms of DA release and uptake. Extracellular DA was electrically evoked by stimulation of the medial forebrain bundle mimicking tonic and phasic firing patterns for dopaminergic cells and was monitored simultaneously in both the dorsomedial and dorsolateral striatum. Kinetic analysis of evoked recordings determined parameters describing DA release and uptake. Striatal DA tissue content was quantified by high performance liquid chromatography with electrochemical detection. METH-pretreatment (four doses of 7.5 or 10.0 mg/kg s.c.) induced DA depletions of ~ 40% on average, which are reported in both striatal subregions. METH pre-treatment significantly decreased the amplitude of signals evoked by phasic, but not tonic, stimulation. Parameters for DA release and uptake were also similarly reduced by ~ 40%, consistent with effects on evoked phasic-like responses and DA tissue content. Taken together, these results suggest that METH pretreatment selectively diminishes phasic, but not tonic, dopaminergic signaling in the dorsal striatum. PMID- 21668448 TI - Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. AB - Cyclin dependent kinase-5 (Cdk5) activity is deregulated in Alzheimer's disease (AD) and contributes to all three hallmarks: neurotoxic beta-amyloid formation, neurofibrillary tangles, and neuronal death. However, the mechanism leading to Cdk5 deregulation remains controversial. Cdk5 deregulation in AD is usually linked to the formation of p25, a proteolysis product of Cdk5 activator p35, which leads to Cdk5 mislocalization and hyperactivation. A few studies have indeed shown increased p25 levels in AD brains; however, others have refuted this observation. These contradictory findings suggest that additional factors contribute to Cdk5 deregulation. This study identified glutathione-S-transferase pi 1 (GSTP1) as a novel Cdk5 regulatory protein. We demonstrate that it is a critical determinant of Cdk5 activity in human AD brains and various cancer and neuronal cells. Increased GSTP1 levels were consistently associated with reduced Cdk5 activity. GSTP1 directly inhibits Cdk5 by dislodging p25/p35, and indirectly by eliminating oxidative stress. Cdk5 promotes and is activated by oxidative stress, thereby engaging a feedback loop which ultimately leads to cell death. Not surprisingly, GSTP1 transduction conferred a high degree of neuroprotection under neurotoxic conditions. Given the critical role of oxidative stress in AD pathogenesis, an increase in GSTP1 level may be an alternative way to modulate Cdk5 signaling, eliminate oxidative stress, and prevent neurodegeneration. PMID- 21668449 TI - SV31 is a Zn2+-binding synaptic vesicle protein. AB - We recently identified in a proteomic screen a novel synaptic vesicle membrane protein of 31 kDa (SV31) of unknown function. According to its membrane topology and its phylogenetic relation SV31 may function as a vesicular transporter. Based on its amino acid sequence similarity to a prokaryotic heavy metal ion transporter we analyzed its metal ion-binding properties and show that recombinant SV31 binds the divalent cations Zn(2+) and Ni(2+) and to a minor extent Cu(2+), but not Fe(2+), Co(2+), Mn(2+), or Ca(2+). Zn(2+)-binding of SV31 in viable cells was verified following heterologous transfection of pheochromocytoma cells 12 (PC12) with recombinant red fluorescent SV31 (SV31-RFP) and the fluorescent zinc indicator FluoZin-3. Sucrose density gradient fractionation of SV31-RFP-transfected PC12 cells revealed a partial overlap of SV31-RFP with synaptic-like vesicle markers and the early endosome marker rab5. Immunocytochemical analysis demonstrated a punctuate distribution in the cell soma and in neuritic processes and in addition in a compartment in vicinity to the plasma membrane that was immunopositive also for synaptosomal-associated protein 25 (SNAP-25) and syntaxin1A. Our data suggest that SV31 represents a novel Zn(2+) -binding protein that in PC12 cells is targeted to endosomes and subpopulations of synaptic-like microvesicles. PMID- 21668451 TI - Perceptual reversals during binocular rivalry: ERP components and their concomitant source differences. AB - We used an intermittent stimulus presentation to investigate event-related potential (ERP) components associated with perceptual reversals during binocular rivalry. The combination of spatiotemporal ERP analysis with source imaging and statistical parametric mapping of the concomitant source differences yielded differences in three time windows: reversals showed increased activity in early visual (~120 ms) and in inferior frontal and anterior temporal areas (~400-600 ms) and decreased activity in the ventral stream (~250-350 ms). The combination of source imaging and statistical parametric mapping suggests that these differences were due to differences in generator strength and not generator configuration, unlike the initiation of reversals in right inferior parietal areas. These results are discussed within the context of the extensive network of brain areas that has been implicated in the initiation, implementation, and appraisal of bistable perceptual reversals. PMID- 21668450 TI - R3F, a novel membrane-associated glycogen targeting subunit of protein phosphatase 1 regulates glycogen synthase in astrocytoma cells in response to glucose and extracellular signals. AB - Abnormal regulation of brain glycogen metabolism is believed to underlie insulin induced hypoglycaemia, which may be serious or fatal in diabetic patients on insulin therapy. A key regulator of glycogen levels is glycogen targeted protein phosphatase 1 (PP1), which dephosphorylates and activates glycogen synthase (GS) leading to an increase in glycogen synthesis. In this study, we show that the gene PPP1R3F expresses a glycogen-binding protein (R3F) of 82.8 kDa, present at the high levels in rodent brain. R3F binds to PP1 through a classical 'RVxF' binding motif and substitution of Phe39 for Ala in this motif abrogates PP1 binding. A hydrophobic domain at the carboxy-terminus of R3F has similarities to the putative membrane binding domain near the carboxy-terminus of striated muscle glycogen targeting subunit G(M)/R(GL), and R3F is shown to bind not only to glycogen but also to membranes. GS interacts with PP1-R3F and is hyperphosphorylated at glycogen synthase kinase-3 sites (Ser640 and Ser644) when bound to R3F(Phe39Ala). Deprivation of glucose or stimulation with adenosine or noradrenaline leads to an increased phosphorylation of PP1-R3F bound GS at Ser640 and Ser644 curtailing glycogen synthesis and facilitating glycogen degradation to provide glucose in astrocytoma cells. Adenosine stimulation also modulates phosphorylation of R3F at Ser14/Ser18. PMID- 21668452 TI - Abstracts of the XXX Congress of the European Academy of Allergy and Clinical Immunology. Istanbul, Turkey. June 11-15, 2011. PMID- 21668453 TI - TCam-2 seminoma cell line exhibits characteristic foetal germ cell responses to TGF-beta ligands and retinoic acid. AB - Germ cell testicular cancer is understood to arise during embryogenesis, based on the persistence of embryonic germ cell markers in carcinoma in situ and seminoma. In this study, we examine the potential of the seminoma-derived TCam-2 cell line to be used as representative in functional analyses of seminoma. We demonstrate expression of several early germ cell markers, including BLIMP1, OCT3/4, AP2gamma, NANOG and KIT. Many TGF-beta superfamily receptors and downstream transcription factors are also present in these cells including the normally foetal ACTRIIA receptor, indicating potential responsiveness to TGF-beta superfamily ligands. Treatment with BMP4 or RA induces a significant increase in ACTRIA, ACTRIIA and ACTRIIB transcripts, whereas activin A decreases ACTRIB. BMP4 and RA each support TCam-2 survival and/or proliferation. In addition, despite increased KIT mRNA levels induced by BMP4, RA and activin A, activin A does not improve survival or proliferation. The capacity for BMP4 and retinoic acid to enhance foetal germ cell survival and proliferation/self-renewal has been demonstrated in mice, but not previously tested in humans. This study is the first to demonstrate a functional response in seminoma cells, using a well characterized cell line, consistent with their foetal germ cell-like identity. PMID- 21668454 TI - Patients as team members: opportunities, challenges and paradoxes of including patients in multi-professional healthcare teams. AB - Current healthcare policy emphasises the need for more collaborative, team-based approaches to providing care, and for a greater voice for service users in the management and delivery of care. Increasingly, policy encourages 'partnerships' between users and professionals so that users, too, effectively become team members. In examining this phenomenon, this paper draws on insights from the organisational-sociological literature on team work, which highlights the challenges of bringing together diverse professional groups, but which has not, to date, been applied in contexts where users, too, are included in teams. Using data from a qualitative study of five pilot cancer-genetics projects, in which service users were included in teams responsible for managing and developing new services, it highlights the difficulties involved in making teams of such heterogeneous members-and the paradoxes that arise when this task is achieved. It reveals how the tension between integration and specialisation of team members, highlighted in the literature on teams in general, is especially acute for service users, the distinctiveness of whose contribution is more fragile, and open to blurring. PMID- 21668455 TI - Framing health inequalities for local intervention: comparative case studies. AB - This article explores how health inequalities are constructed as an object for policy intervention by considering four framings: politics, audit, evidence and treatment. A thematic analysis of 197 interviews conducted with local managers in England, Scotland and Wales is used to explore how these framings emerge from local narratives. The three different national policy regimes create contrasting contexts, especially regarding the different degrees of emphasis in these regimes on audit and performance management. We find that politics dominates how health inequalities are framed for intervention, affecting their prioritisation in practice and how audit, evidence and treatment are described as deployed in local strategies. PMID- 21668456 TI - Identity, emotion and the internal goods of practice: a study of learning disability professionals. AB - Contemporary transitions in the delivery of health and social care are a global phenomenon. They prompt a particular need to reconsider how quality in relation to professional practice should be understood and whether greater importance should be attached to values such as goodwill, altruism and commitment. Based on a qualitative study of a small voluntary sector organisation in the North of England, this paper addresses how changes in policy articulate with the identities of professionals who work in learning disability services. Drawing on MacIntyre's After Virtue, which is discussed in relation to some recent sociological debates on emotion, it is suggested that professionals have an emotionally based commitment to their work as well as to the people they work with. Professional commitment is embedded in a coherent sense of self that problematises traditional binaries between the private and the public, and the cognitive and affective. The participants in this study appeared to pursue what MacIntyre terms the 'internal goods' of practice; they valued being able to work innovatively and responsively with service users. It is suggested that this requires a particular type of relationship with oneself, with others, and with practice, which engenders a criticality towards dominant professional discourses. PMID- 21668457 TI - The swan effect in midwifery talk and practice: a tension between normality and the language of risk. AB - Midwifery activity in the labour room coalesces around routine surveillance practices. When engaging in such practice, midwives have to cope with attempting to instil a sense of confidence in the mother's embodied ability to give birth to her baby spontaneously while concurrently attending to an array of risk-focused tests and measurements. Midwives are vigilant about the potential harm that may come to mother and baby while at the same time they are responsible for facilitating a normal birth. This article sets out to explore the tension between these two tasks and shows how routine midwifery practice during labour can communicate certain understandings about birth. Using empirical evidence taken from an ethnographic study of midwifery talk and practice, attention is given to how midwives' activity during labour and birth implicitly introduces a sense of danger, an imagined risk that confines practice and operates to unsettle normality. PMID- 21668458 TI - Review article: cyclic vomiting syndrome in adults--rediscovering and redefining an old entity. AB - BACKGROUND: Cyclic vomiting syndrome is a disorder characterised by recurrent episodes of severe nausea and vomiting separated by symptom-free periods. AIMS: To review the history, epidemiology, clinical aspects, pathophysiology, diagnosis and treatments of adult cyclic vomiting syndrome as well as to identify areas for further clinical research and the unanswered questions in this field. METHODS: We conducted a PubMed search using such keywords as cyclic vomiting syndrome; nausea; vomiting; pathophysiology; diagnosis; treatment; trigger factors; gastric emptying test; autonomic nerve function test; gastrointestinal hormones; outcome and natural history and combined this information with the knowledge and extensive clinical research and publications from the authors. RESULTS: Available data show that in adult cyclic vomiting syndrome, severe epigastric and sometimes diffuse abdominal pain accompanies most cycles of nausea and vomiting interspersed with periods of symptomatic remission. Psychological disorders, specifically anxiety and depression are common, and gastric emptying is actually rapid in approximately 60% of patients and normal in the remainder. There is an impressive and sustained response to high-dose tricyclic antidepressants. In up to 15% who are regarded as poor responders to tricyclic antidepressants, a predictable profile can be identified related to co-existing psychological disorders, marijuana use, poorly controlled migraine headache or chronic narcotic use. CONCLUSIONS: Cyclic vomiting syndrome in adults is an entity that is being increasingly recognised, but the need to educate Internists, Gastroenterologists and Emergency Department staff remains an ongoing challenge. PMID- 21668459 TI - The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes. AB - BACKGROUND: Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment. AIM: To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes. METHODS: Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression. RESULTS: Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001). CONCLUSIONS: Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective. PMID- 21668460 TI - Precision of information, sensational information, and self-efficacy information as message-level variables affecting risk perceptions. AB - Studies that investigate how the mass media cover risk issues often assume that certain characteristics of content are related to specific risk perceptions and behavioral intentions. However, these relationships have seldom been empirically assessed. This study tests the influence of three message-level media variables- risk precision information, sensational information, and self-efficacy information--on perceptions of risk, individual worry, and behavioral intentions toward a pervasive health risk. Results suggest that more precise risk information leads to increased risk perceptions and that the effect of sensational information is moderated by risk precision information. Greater self efficacy information is associated with greater intention to change behavior, but none of the variables influence individual worry. The results provide a quantitative understanding of how specific characteristics of informational media content can influence individuals' responses to health threats of a global and uncertain nature. PMID- 21668461 TI - Haemoglobin A1c is associated with carotid intima-media thickness in a Chinese population. AB - BACKGROUND: The association between haemoglobin A1c (HbA1c) levels and subclinical atherosclerosis in carotid arteries in Chinese populations is unknown. AIM, DESIGN AND METHODS: The objective of this study was to investigate this relationship and evaluate the ability of HbA1c levels to predict carotid atherosclerosis in a Chinese population. This was a cross-sectional study, which included 541 subjects without known diabetes (Taiwan Lifestyle Study). About 67 (9.2%) subjects were newly diagnosed with diabetes during the study. Carotid intima-media thickness (IMT) and the presence of carotid plaques were determined using ultrasonography. RESULTS: The HbA1c level in all subjects was positively correlated with carotid IMT (beta = 0.018, P = 0.03) after being adjusted for age, gender, smoking, low-density lipoprotein cholesterol level, hypertension and body mass index. HbA1c level was higher in subjects with plaques in carotid arteries (P = 0.01). There was a positive and linear relationship between HbA1c levels and the probability of having plaques, thickened carotid IMT or both (P for all comparisons, <0.05). The ability of HbA1c levels to predict thickened carotid IMT or the presence of plaques was only modest {the optimal cutoff of HbA1c level [5.7%] was determined from the receiver operating characteristic (ROC) curve (sensitivity = 67%, specificity = 61%) and the area under the ROC curve [0.666]}. CONCLUSIONS: Thus, HbA1c level is associated with subclinical atherosclerosis in carotid arteries in a Chinese population. The relationship is linear without an inflection point. However, HbA1c criterion is not a useful marker for the identification of subclinical atherosclerosis. PMID- 21668462 TI - Exploring serological classification tree model of active pulmonary tuberculosis by magnetic beads pretreatment and MALDI-TOF MS analysis. AB - Pulmonary tuberculosis (TB) is an infectious disease disturbing status of public health, and accurate diagnosis of TB would effectively help control the disturbance. Our study tried to establish a classification tree model that distinguished active TB from non-TB individuals. We used matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) combined with weak cationic exchange (WCX) magnetic beads to analyse 178 serum samples containing 75 patients with active TB and 103 non-TB individuals (43 patients with common pulmonary diseases and 60 healthy controls). Samples were randomly divided into a training set and a test set. Statistical softwares were applied to construct this model. An amount of 48 differential expressed peaks (P < 0.05) were identified by the training set, and our model was set up by three of them, m/z 7626, 8561 and 8608. This model can discriminate patients with active TB from patients with non-TB with a sensitivity of 98.3% and a specificity of 84.4%. The test set was used to verify the performance, which demonstrated good sensitivity and specificity: 85.7% and 83.3%, respectively. Differential expressed peaks between smear-positive and smear-negative active TB also have been analysed. It came out that m/z 8561 and 8608 not only acted as vital factors in the pathogenesis of active TB but also played an important role in regulating different active TB status. In conclusion, MALDI-TOF MS combined with WCX magnetic beads was a powerful technology for constructing classification tree model, and the model we built could serve as a potential diagnostic tool for active TB. PMID- 21668463 TI - Paying for the wrong kind of performance? Financial incentives and behaviour changes in National Health Service dentistry 1992-2009. AB - BACKGROUND: There is a tension between financial incentives and professional codes and norms, both of which are believed to influence the behaviour of health care professionals. This study examined the impact of changes to financial incentive structures on the behaviour of dentists working in the English National Health Service (NHS) as a result of a new national contract. METHODS: Comparison of six reference treatments delivered by all NHS dentists in England for the period 1992-2009. RESULTS: Large and abrupt changes in the provision of the reference treatments coincided with the introduction of changes in the incentive structure in 2006. Treatments which can be provided in the least amount of time (and therefore costs to dentists) such as extractions increased and treatments which are time consuming or have significant additional materials costs such as bridgework, crowns, root fillings and radiographs reduced substantially. CONCLUSIONS: Changes to financial incentive structures can produce large and abrupt changes in professional behaviours. In the context of multiple and conflicting goals, greater thought needs to be given to policies to change incentive structures to mitigate their unintended consequences. PMID- 21668464 TI - 'Now I understand': consulting parents on chart design and parental information for the UK-WHO child growth charts. AB - BACKGROUND: Regular assessment of growth is an important part of child health surveillance in the UK and most parents are very interested in their child's growth. UK parents are given a personal child health record (PCHR), including growth charts, which are plotted during baby clinic visits. Parents were consulted as part of the process of designing new UK charts to incorporate the World Health Organization growth standard. This paper describes the main themes that emerged and how they influenced the final design. METHOD: Three sets of consultations with 47 parents were conducted to collect preliminary information, and to evaluate proposed chart designs, instructions and written information for parents. RESULTS: At every consultation, the impact of the depiction of the 50th centile line in bold was mentioned spontaneously by parents. They also found aspects of the charts unclear, including the implications of a recorded weight on any particular centile, the difficulty of understanding existing text about charts in the PCHR, their preference for using pounds and ounces rather than metric weights and confusion about how frequently babies should be weighed. This led to the production of parental information including explanation of these issues which were then tested in two further sets of focus groups. CONCLUSION: Involving parents in the process of designing growth charts and information influenced the finished design and the text in the PCHR. Ensuring information meets parents' needs is important to ensure successful growth monitoring. PMID- 21668465 TI - Evaluation of family-centred practices in the early intervention programmes for infants and young children in Singapore with Measure of Processes of Care for Service Providers and Measure of Beliefs about Participation in Family-Centred Service. AB - BACKGROUND: The primary purpose of this study was to report on an evaluation of the perceptions and beliefs of service providers towards family-centred practices in 11 early intervention programmes for infants and young children in Singapore. METHODS: The Measure of Processes of Care for Service Providers (MPOC-SP) and Measure of Beliefs about Participation in Family-Centred Service (MBP-FCS) were administered to 213 service providers made up of teachers, therapists, psychologists and social workers providing centre-based therapy to children with special needs who were below the age of 6 years. RESULTS: Exploratory factor analyses were performed with both scales. Nineteen of the 27 MPOC-SP items were retained and supported the original four-factor structure model. The exploratory factor analyses on MBP-FCS provided a less satisfactory outcome. Fourteen of the 28 items were retained and these loaded onto four factors. The two factors relating to Beliefs about benefits of FCS and Beliefs about the absence of negative outcomes from FCS failed to emerge as separate factors. Further multiple regressions indicated that more direct work with families and positive self efficacy in implementing FCS contributed significantly to explaining service providers' positive perception towards family-centred practice in service delivery. CONCLUSIONS: This is the first time MPOC-SP and MBP-FCS were administered to a population in an Asian context. While MBP-FCS would benefit from further development work on its construct, MPOC-SP offered important insights into service providers' perspectives about family-centred practices that would have useful implications for professional and service development. PMID- 21668466 TI - Sleep behaviour in children with developmental co-ordination disorder. AB - BACKGROUND: Children with developmental co-ordination disorder (DCD) experience significant difficulty in the performance of everyday movement skills in the absence of obvious neurological, sensory or intellectual impairment. They often underachieve academically and have higher rates of anxiety than their typically developing peers. Such factors are known to be associated with sleep problems in other clinical populations but the sleep patterns of children with DCD have not been examined. Information about the frequency and nature of sleep problems in DCD will aid our understanding of this developmental disorder. It may also be clinically helpful, alerting clinicians to potential difficulties so that these can be identified early and appropriate support offered. OBJECTIVE: To examine sleep behaviour of children with DCD compared with typically developing control children. METHODS: Two groups of 16 boys aged 8 to 12 years (M = 10.28, SD = 1.28) participated: (1) the DCD group had Movement ABC-2 Checklist scores below the 5th percentile; (2) an age-matched control group of typically developing children had Movement ABC-2 Checklist scores above the 15th percentile. Parents of children from both groups completed the Children's Sleep Habits Questionnaire. RESULTS & DISCUSSION: The total sleep disturbance score was significantly higher for children with DCD compared with the control group (U= 24, P < 0.001). Subscale scores indicated particular problems with bedtime resistance (U= 77.5, P < 0.05), parasomnias (U= 28.5, P < 0.001) and daytime sleepiness (U= 58.00, P < 0.01). There were no differences between the groups for sleep onset delay, sleep duration, night wakings and sleep-disordered breathing. These preliminary results suggest that sleep patterns of children with DCD may be of clinical relevance and are worthy of further investigation. PMID- 21668467 TI - Subcutaneous panniculitis-like T-cell lymphoma in association with sarcoidosis. PMID- 21668468 TI - Gastrointestinal stromal tumours--an update for histopathologists. AB - This review aims to summarize recent knowledge gained about gastrointestinal stromal tumour (GIST) of particular relevance to histopathologists. KIT and PDGFRA mutation analyses can be useful for confirming a diagnosis of GIST, but there are some diagnostic limitations to these analyses, and so immunohistochemical markers currently remain crucial to the diagnostic process. Of these markers, CD117 and Discovered on GIST 1 (DOG1) are currently the most sensitive and specific markers of GIST, and recent data appear to disprove the fear that antigen retrieval causes false-positive CD117 immunostaining. The accurate prognostication of GIST has been greatly helped by the National Institutes of Health (NIH) and Armed Forces Institute of Pathology (AFIP) classification systems, although both systems still have limitations, and the behaviours of certain GIST subgroups are less well predicted by both systems. KIT and PDGFRA mutation analyses can help to predict the response of GISTs to receptor tyrosine kinase inhibitors, and both GISTs that respond and those that show resistance to these inhibitors may show characteristic pathological changes. Some GIST subgroups (e.g. Carney syndrome and paediatric GISTs) have had recently described clinicopathological and/or molecular characteristics which may help with the diagnosis and/or treatment of these specific neoplasms. PMID- 21668469 TI - The fittest person in the morgue? AB - The cardiovascular benefits of regular physical activity are well established (J. Sci. Med. Sport,7, 2004, 6). James Fixx wrote the best-selling book on running entitled The Complete Book of Running (1977), which led to an increase in popularity. However, when Fixx collapsed and died suddenly while running in 1984, people began to consider the adverse effects of sport on cardiac conditions. Going back in time, in 490 bc Phidippides, a young Greek messenger, ran 26.2 miles from Marathon to Athens delivering the news of the Greek victory over the Persians, and immediately collapsed and died. This is probably the first recorded incident of sudden death of an athlete running a marathon. According to Noakes (Med. Sci. Sports Exerc.,19, 1987, 187), one of the earliest reports on the association between running and cardiac risk was published in 1909, which claimed that school cross-country races over one mile for boys below the age of 19 years were totally inappropriate, and that the associated stress will cause damage in the heart and other organs. Death in athletes is highly publicized and has a substantial emotional impact on the community at large, given that athletes are perceived as the healthiest segment of society. PMID- 21668470 TI - Inflammatory disease of the bile ducts-cholangiopathies: liver biopsy challenge and clinicopathological correlation. AB - Liver biopsy challenge and clinicopathological correlation Liver biopsy interpretation in inflammatory diseases of the bile ducts or chronic cholangiopathies may be challenging, especially for pathologists working outside referral centres, where there is a limited exposure to relatively uncommon conditions. In view of the importance of sampling errors resulting from the patchy distribution of pathognomonic bile duct injuries and the misleading absence of cholestasis in the early stages, there is a need to recognize surrogate markers and subtle changes, in particular the early periportal deposition of copper and mild biliary interface activity. Such findings may either constitute the first indication of a primarily biliary disorder or be supportive of a clinically suspected diagnosis. Histological changes common to chronic cholangiopathies are reviewed at the variable stages of development that patients may first present to clinicians. As awareness of the protean clinical manifestations is essential for histological interpretation, the major and distinctive anatomoclinical features of primary biliary cirrhosis and primary and acquired sclerosing cholangitis are revisited, together with so-called overlapping syndromes and less common variants and associations, including more recently documented conditions, such as IgG4-related disease and the rarer multidrug resistance 3 deficiency. The review stresses the importance of evaluating histological changes in conjunction with clinical information. PMID- 21668471 TI - Invasive mammary carcinoma with neuroendocrine differentiation: histological features and diagnostic challenges. AB - AIMS: The aim of this study was to review the histomorphological features of primary neuroendocrine carcinomas (NEC) of the breast, in order to identify features useful in recognition of this entity for appropriate classification. METHODS AND RESULTS: 2003 World Health Organization (WHO) classification of tumors of the breast and female genital organs defined NEC of the breast as a subtype of invasive mammary carcinoma in which >50% of the tumor cells express neuroendocrine markers. Seventy-four cases that fulfilled the WHO diagnostic criteria for NEC of the breast, excluding small cell carcinoma and low-grade solid papillary carcinoma with a predominant in-situ component, were identified between 1984 and 2008 from MD Anderson Cancer Center, and were included in the study. NECs of the breast had variable histomorphological features. The most common histologic patterns were papillary (80%) and nested (64%). Mixed growth patterns were common (59%), including admixed ductal component. The tumor cells could be polygonal, round, plasmacytoid, spindled, or with signet ring cell features. The cytoplasm could be granular, eosinophilic, clear, or finely vacuolated. These tumors frequently mimicked invasive or in situ ductal carcinoma, or invasive lobular carcinoma. CONCLUSIONS: NEC of the breast is underrecognized. Careful attention to cytologic and architectural features can help to identify cases that require further immunophenotypic confirmation for correct tumor classification. PMID- 21668472 TI - Analysis of sentinel node biopsy - a single-institution experience supporting the use of serial sectioning and immunohistochemistry for detection of micrometastases by comparing four different histopathological laboratory protocols. AB - AIMS: Detecting micrometastases (>0.2 and <=2 mm/>200 cells) and isolated tumour cells (ITCs; <=0.2 mm/<200 cells) is important for staging of breast cancer patients. The aim of this study was to systematically compare several laboratory protocols used to detect metastases after initial intraoperative frozen section examination. METHODS AND RESULTS: Four different protocols for the work-up of sentinel lymph nodes (SLNs) after frozen sectioning were applied in the routine diagnostic process from 2001 to 2009. In addition, team-work with a limited number of laboratory technicians and pathologists handling SLNs was introduced in 2008. The present study shows that there were, overall, significantly more node positive patients in the period when team-work and intensive step sections including immunohistochemistry (IHC) were used (P = 0.01). This resulted in 13% more patients being found to have ITCs and micrometastases than in a time period when only step sections were performed. No increase in the number of false negative frozen sections was seen. CONCLUSIONS: Future guidelines for pathological work-up of sentinel nodes in women with breast cancer might include team-work and IHC if frozen sections are used intraoperatively. PMID- 21668473 TI - Oestrogen receptor/progesterone receptor and human epidermal growth factor receptor 2 status in breast cancer: a 9-year study at Princess Noorah Oncology Center, Saudi Arabia. AB - OBJECTIVE: To determine the oestrogen receptor/progesterone receptor (ER/PR) and human epidermal growth factor receptor 2 (HER2) status in Saudi Arabian patients presenting with breast cancer to Princess Noorah Oncology Center (PNOC) and to explore the correlation of these markers to each other, to tumour type and to grade. METHODS AND RESULTS: Pathology material and records of symptomatic patients presenting to the centre during 2001-2009 were reviewed for patients' age, tumour size, type and grade and ER/PR and HER2 immunohistochemistry (IHC) status using the Dako HercepTest Kit as well as fluorescence in situ hybridization (FISH) for HER2 IHC 2+ score cases, as per the 2007 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. There were 852 cases, with a mean age of 49years and a mean tumour size of 3.0 cm with 75% node positivity. Of all cases, 772 (90.6%) were ductal carcinoma; 64% were ER/PR(+) and 23% were HER2(+); triple-negative cases accounted for 24%. CONCLUSIONS: ER/PR and HER2 status did not differ from that reported previously, showing a direct correlation to tumour type and grade of ductal carcinoma. However, a difference exists in the relatively lower ER positivity in patients aged >50 years and the higher percentage of triple negative cases. This study would serve as a baseline for other future national studies and for planning strategies to targeted therapy. PMID- 21668474 TI - Recurrent copy number gains of ACVR1 and corresponding transcript overexpression are associated with survival in head and neck squamous cell carcinomas. AB - AIMS: This study aimed to evaluate the copy number alteration on 2q24, its association with ACVR1 transcript expression and the prognostic value of these data in head and neck squamous cell carcinomas. METHODS AND RESULTS: Twenty-eight samples of squamous cell carcinoma were evaluated by fluorescence in situ hybridization (FISH) using the probes RP11-546J1 (2q24) and RP11-21P18 (internal control). Significant gains at 2q24 were detected in most cases at frequencies varying from 3 to 35%. ACVR1 gains and amplifications were associated with longer overall survival (P = 0.022). ACVR1 mRNA expression analysis in 78 cases revealed overexpression in 44% (34 of 78) of these tumours, suggesting that gene copy number alterations could be involved in gene overexpression. In laryngeal carcinomas, overexpression of ACVR1 mRNA levels was associated with longer overall survival (P = 0.013). Multivariate analysis revealed that ACVR1 is an independent prognostic marker in laryngeal carcinomas (P = 0.012, hazard ratio = 0.165, 95% confidence interval =0.041-0.668). CONCLUSIONS: These findings suggest that copy number alterations at 2q24 can be involved in ACVR1 overexpression, which is associated with longer overall survival in laryngeal carcinomas. To our knowledge, this is the first report indicating the relevance of ACVR1 expression in head and neck cancers. PMID- 21668475 TI - Immunohistochemical investigation of tumorigenic pathways in sinonasal intestinal type adenocarcinoma. A tissue microarray analysis of 62 cases. AB - AIMS: Sinonasal intestinal-type adenocarcinoma (ITAC) is an uncommon neoplasm morphologically similar to colorectal adenocarcinoma, with a well-recognized association with occupational exposure to wood or leather dusts. Here, we analyse several gene products with pivotal roles in tumorigenesis, including p53, p16, deleted in colon cancer (DCC), retinoblastoma, adenomatous polyposis coli, beta catenin, E-cadherin and CD10, and discuss their relation to clinical behaviour and to similar pathways in colorectal adenocarcinomas. METHODS AND RESULTS: Immunohistochemical analysis of 62 ITACs was conducted on a tissue microarray. Aberrant expression of p53 and p16 were the most commonly observed alterations (61.3% and 64.5% of cases, respectively). Analysis according to the histological subtype showed that p53 overexpression was less frequent in mucinous ITACs (35.3% versus 71.1%, P = 0.018), while loss of DCC and E-cadherin were observed more frequently in this subtype (76.5% versus 31.1%, P=0.002 and 82.4% versus 31.1%, P<0.001, respectively). No correlation was found between the aberrant expression of these and clinical behaviour while mucinous adenocarcinomas had a significantly worse prognosis, with shorter disease-free interval and overall survival (P=0.005 and P<0.001, respectively). CONCLUSIONS: Mucinous ITACs appear to follow a distinct molecular pathway(s) from the non-mucinous variants, and pursue an aggressive clinical behaviour. PMID- 21668476 TI - Impact of CRTC1/3-MAML2 fusions on histological classification and prognosis of mucoepidermoid carcinoma. AB - AIMS: The aim of study was to evaluate the impact of CRTC1-MAML2 and CRTC3-MAML2 fusions on the histological classification of mucoepidermoid carcinoma (MEC) of the salivary glands and on the prognosis of patients. METHODS AND RESULTS: MEC cases (n = 111) were screened for CRTC1-MAML2 and CRTC3-MAML2 fusions by reverse transcription polymerase chain reaction. We developed a system of 'molecular Armed Forces Institute of Pathology (AFIP) classification' that combined the AFIP histological classification proposed by Goode et al. and the presence of CRTC1 MAML2 or CRTC3-MAML2 fusions. MEC cases positive for CRTC1-MAML2 or CRTC3-MAML2 fusion formed a favourable tumour subset that was distinct from fusion-negative cases. When positive for the fusions, 'high-risk' patients, including those with a higher histological grade or an advanced clinical stage, showed an excellent prognosis. For overall survival, 'molecular AFIP classification' was selected as a powerful independent prognostic factor (P=0.0038), as was the clinical stage (P =0.0032). For disease-free survival, 'molecular AFIP classification' was also selected as an independent prognostic factor (P = 0.0006). CONCLUSIONS: Molecular AFIP classification may be useful in predicting the prognosis of patients with MEC. PMID- 21668477 TI - Desmoplastic tumour-associated stroma versus neural tissue in central nervous system metastasis: effects of different microenvironments on tumour growth. AB - AIMS: Interactions between tumour cells and extracellular matrix (ECM) are critical in the metastatic cascade. We compared effects of desmoplastic stroma versus neural tissue on central nervous system (CNS) metastasis. METHODS AND RESULTS: Using integrins (ECM receptors), ECM (fibronectin, laminin and collagen IV) and CD31 and vascular endothelial growth factor (VEGF) for angiogenesis, this study examined immunohistochemically 69 consecutive cases of CNS metastases. In contrast to low-level expression in tumour-embedded neural tissue, ECM [fibronectin (71%), laminin gamma-1 (79%) and collagen IV (92%)] and CD31 positive microvascular densities (33 versus 4 vessels/field) were significantly richer in desmoplastic tumour stroma, which was present in 90% (53 of 59) of carcinomas, 100% (five of five) of malignant melanomas and 100% (two of two) of sarcomas. Collagen IV expression in tumour stroma was correlated with the expression of fibronectin (P = 0.013) and laminin (P = 0.034) and with infiltrative tumour edges (P = 0.005); fibronectin-positive tumour stroma was correlated with a higher microvascular density (P = 0.015). In addition, tumour cells expressed integrins (~75%) and laminin (84%) more frequently than VEGF (23%), and tumour expression of laminin was correlated with the presence of desmoplastic stroma (P = 0.006). Interestingly, laminin-positive tumour stroma was a worse prognosticator (P = 0.072). CONCLUSIONS: ECM- and vascular-rich stroma is important in tumour growth, which underlies therapeutic strategies targeting tumour-associated stroma. PMID- 21668478 TI - Prognostic value of partial genetic instability in neuroblastoma with <=50% neuroblastic cell content. AB - AIMS: Better understanding of neuroblastoma genetics will improve with genome wide techniques. However, performing these analyses in samples with <60% neuroblast cells is not adequate. We evaluated the utility of fluorescence in situ hybridization (FISH) on tissue microarrays (TMA) in detecting partial genetic instability (PGI), focusing on samples with <=50% neuroblast cells. METHODS AND RESULTS: Alterations of 11q and 17q were detected by FISH on 369 neuroblastoma samples in TMA. Status of the MYCN gene and 1p36 region has been established previously by FISH diagnosis. Partial genetic instability (PGI) was defined as the ratio between segmental genetic alterations detected and number of genetic markers diagnosed in each tumour. Of primary tumours, 14.6% harboured 11q deletions, whereas 42.6% showed 17q gain. PGI was established in 260 primary tumours, 67 of which contained <=50% neuroblasts. Outcomes were statistically worse for patients whose tumours presented high PGI (P < 0.0001). Multivariate analysis revealed moderate and high PGI as prognostic factors. CONCLUSIONS: In the cohort examined in this study, univariate and multivariate analysis confirmed the effect of PGI in patient outcome. PGI established by FISH on TMA is a useful method to identify high-risk patients even if tumours have a cell content of <=50% neuroblast cells. PMID- 21668479 TI - Is anticipatory care fundamental to nursing? PMID- 21668480 TI - Family carer personal concerns in Huntington disease. AB - AIM: To examine and compare the personal concerns of family members providing care for people with Huntington disease in the United Kingdom and the United States. BACKGROUND: Family carers of people with Huntington disease may feel burdened by caregiving responsibilities and concerned about illness risk for relatives. METHOD: A mailed personal concerns survey was completed by 108 United Kingdom and 119 United States adult family carers of people with Huntington disease in 2006 and 2007. Survey responses included frequency and intensity of concerns, and narrative comments. Data were analysed using descriptive statistics of the products of frequency and intensity of reaction scores to identify a personal concerns index for items with the twelve highest combined scores. Factor analysis identified three factors, which were compared between respondents by factor and items within factors using t tests mean frequency by intensity scores. Narrative comments were thematically analysed. RESULTS: Three main factors were labelled impact of role change, sense of isolation and concerns for children. Within the role change factor, United States family caregivers had significantly higher concerns about family finances and United Kingdom carers expressed significantly greater personal sadness. Both groups expressed concern about isolation from family. Although family carers in both countries expressed concern about their children, those of United States caregivers were significantly higher. CONCLUSION: Further studies are required to identify benefits of support services that are specific to carer concerns and consistent with national healthcare systems. PMID- 21668481 TI - Qualitative study of enrolled nurses transition to registered nurses. AB - AIM: This paper is a report of a study which aimed to explore the transition experiences of graduate Registered Nurses (RN) who had previously practised as Enrolled Nurses. BACKGROUND: The literature suggests that graduate RN who have previously practised as Enrolled Nurses (EN) have specific support needs during their first year of clinical practice. METHODS: A qualitative descriptive study using focus group interviews was undertaken in the Australian Capital Territory, Australia in 2009. Eight graduate nurses (GN) were interviewed 1 week after the graduate nurses programme (GNP) had commenced and five GN at the middle and four GN at the end of the programme. Content analysis of the transcribed data was used to explicate themes. RESULTS: Three main categories were identified from the data: stepping out of their comfort zone, being taken advantage of and needing support like any other new RN. The GN pleaded that they need to be treated as any other new nurses undertaking the graduate nurse programme and for staff to forget that they used to be Enrolled Nurses. CONCLUSION: Registered Nurses who had previously practised as Enrolled Nurses preferred not to be identified as having previous nursing experience as they feared being treated by their nurse managers as already capable of practicing as RN when in fact they needed support similar to any new graduate. PMID- 21668482 TI - Power relations in patient's experiences of suffering during treatment for cancer. AB - AIM: This paper is a report of how patients who have cancer experience suffering in the context of power relations. BACKGROUND: Many studies in Sweden and in other countries have detected inequality in healthcare use and resources, including unseen influences that can be connected to gender and distribution of resources. Few studies have examined how multiple relations of power - such as gender, ethnicity, age and education - influence how people with cancer experience suffering during treatment. METHOD: A hermeneutic design was used. Qualitative interviews were conducted with 12 women and 14 men receiving treatment for a variety of cancer diagnoses. The data collection was done at two hospitals in Sweden during 2008-2009. The interpretation of data was based on two theoretical perspectives - suffering and intersectionality. RESULTS: The results highlight patients suffering where two or more positions of power relations interacted with each other. Three main themes were identified: the complexity of control, the vulnerable effects of body changes, and the internal battle of survival. CONCLUSION: A vulnerable social situation for people with cancer concretely increased their suffering. Social inequalities, seemingly linked to social hierarchy, increased the suffering of people with cancer. For example, women with cancer with a low education belonging to an ethnic minority suffered more than highly educated patients belonging to the ethnic majority. PMID- 21668483 TI - 3-Methoxy-2-methyl-carbazole-1,4-quinone, carbazomycins D and F from Streptomyces sp. CMU-JT005. AB - 3-Methoxy-2-methyl-carbazole-1,4-quinone (1) together with carbazomycins D (2) and F (3) were isolated from the crude extract of Streptomyces CMU-JT005, an actinomycete with nematicidal activity. 3-Methoxy-2-methyl-carbazole-1,4-quinone is reported here for the first time from nature. In this paper, we describe the isolation and structure elucidation of the compounds together with the characterization of the Streptomyces strain CMU-JT005. PMID- 21668484 TI - Uptake dynamics of scrapie agent in the intestinal villous epithelium of suckling and weanling Syrian hamsters. AB - In mice, the number of intestinal villous columnar epithelium cells that incorporate abnormal prion protein (PrP(Sc) ) decreases significantly after weaning. In this study, the dynamics of PrP(Sc) uptake during the growth of hamsters were investigated by inoculating scrapie 263K agent orally into suckling and weanling Syrian hamsters and estimating the number of PrP(Sc) -positive villous epithelium cells immunohistochemically. The number of PrP(Sc) -positive cells declined significantly as the hamsters aged. The present results suggest that a tendency toward decline of PrP(Sc) -positive cells with increasing age might be a common phenomenon among the superfamily Muridae. PMID- 21668485 TI - A prospective study of intrafamilial transmission and antimicrobial susceptibility of Moraxella catarrhalis. AB - Moraxella catarrhalis has been recognized as a particularly threatening respiratory tract pathogen in humans. A prospective study was performed to investigate which strains of M. catarrhalis can be transmitted within families; the study also addressed features of antimicrobial susceptibility. Seventy-five strains were isolated from six participants between July 2002 and February 2004, including 73 that were verified as beta-lactamase-producing strains. Antimicrobial susceptibility was tested for six types of antibiotics and no treatment issues were found. Pulsed-field gel electrophoresis (PFGE) was performed on all strains and 25 independent PFGE patterns were detected. The dominant pattern L (defined in the present study) was found in 21 (28%) of strains that were continuously recovered from children from the same family over an 8-month period. Strains with the patterns G, J, L, M, R, S, U, and W seemed to spread among the children, but there was no evidence of child-parent transmission. In the present study, the characteristics of M. catarrhalis within families have been documented, and PFGE profiles found to reveal alternating colonization and intrafamilial transmission. PMID- 21668486 TI - Current joint therapy usage in equine practice: a survey of veterinarians 2009. AB - REASONS FOR PERFORMING STUDY: Medications are frequently employed to treat intra articular (IA) problems in the performance horse. Actual usage of the different IA medications in horses is not available. OBJECTIVES: To determine the most common usage of these medications, members of the American Association of Equine Practitioners (AAEP) were surveyed. METHODS: An email link to an online survey was electronically sent to 6305 AAEP members and the responses tabulated and analysed with a logistic regression model. RESULTS: A total of 831 survey responses were submitted and tabulated. Eighty per cent of the respondents indicated that they see 100% equine cases in their practice. The majority of respondents (77%) use triamcinolone acetonide (TA) to treat high motion joints and 73% use methylprednisolone acetate (MPA) to treat low motion joints. Veterinarians treating the Western performance and Sport horse were significantly more likely to use TA in high motion joints compared to MPA (P = 0.0201 and P<0.0001, respectively). Triamcinolone acetonide use compared to MPA in high motion joints by racehorse veterinarians was significantly lower compared to other veterinarians (P<0.0001). Polysulphated glycosaminoglycan (Adequan) and hyaluronate sodium (Legend) were the most commonly used disease modifying products (63 and 57% of respondents, respectively). Sport horse practitioners were significantly more likely than race or show horse veterinarians to utilise IRAP products (P = 0.0035 and P = 0.04, respectively). Respondents who had been in practice for more than 10 years were significantly less likely to use antimicrobials in their joint injections compared to those in practice for less than 10 years (P<0.0001). CONCLUSIONS: Significant differences existed in usage of medications related to primary discipline treated and years practicing. POTENTIAL RELEVANCE: The results of this study aid in defining the current usage of different joint therapy medications within equine practice. This knowledge can guide further research as well as education. PMID- 21668487 TI - Osteoconduction of a stoichiometric and bovine hydroxyapatite bilayer-coated implant. AB - OBJECTIVE: To impart rapid and durable osteoconductivity to implants, a commercial titanium screw implant was coated with stoichiometric hydroxyapatite (HA; 50 nm thick), and then with bovine hydroxyapatite (B-HA; 300 nm thick) using the pulsed laser deposition technique. As control specimens, a commercial implant coated with HA (20 MUm thick) using the flame spraying method (sprayed implant) and a simple titanium implant (basic implant) was used. METHODS: The osteoconductivities of these three types of implant, after implantation for 4-24 weeks, were histologically evaluated. RESULTS: Peeling of HA from the sprayed implant was observed by scanning electron microscopic observation. In the fourth postoperative week, the bilayered implant was already closely adhered to bone. On the other hand, the basic implant was surrounded by a gap containing connective tissue. With the sprayed implant, the bone adhered to the thick HA coating. CONCLUSION: The bilayer deposition technique supplies quick and long-term fixation of implants to bone, because the B-HA film dissolves to aid osteoconduction right immediately after implantation and the HA thin film maintains osteoconduction without dissolution. Neither of the thin-film fractures easily compared with thick coatings. PMID- 21668488 TI - What's in a name? Inflammatory airway disease in racehorses in training. AB - The term 'inflammatory airway disease' (IAD) is often used to describe the syndrome of lower airway inflammation that frequently affects young racehorses in training around the world. In practice, this inflammation is generally diagnosed using a combination of endoscopic tracheal examination, including grading of amounts of mucus present and tracheal wash sampling. However, a recent consensus statement from the American College of Veterinary Internal Medicine concluded that bronchoalveolar lavage (BAL) sampling, rather than tracheal wash (TW) sampling, is required for cytological diagnosis of IAD and that tracheal mucus is not an essential criterion. However, as BAL is a relatively invasive procedure that is not commonly used on racing yards, this definition can only be applied routinely to a biased referral population. In contrast, many practitioners continue to diagnose IAD using endoscopic tracheal examination and sampling. We argue that, rather than restricting the use of the term IAD to phenotypes diagnosed by BAL, it is important to distinguish in the literature between airway inflammation diagnosed by BAL and that identified in the field using TW sampling. We suggest the use of the term brIAD for the former and trIAD for the latter. It is essential that we continue to endeavour to improve our understanding of the aetiology, pathogenesis and clinical relevance of airway inflammation identified in racehorses in training using tracheal examination and sampling. Future studies should focus on investigations of the component signs of airway inflammation. PMID- 21668489 TI - Comparative study of equine bone marrow and adipose tissue-derived mesenchymal stromal cells. AB - REASONS FOR PERFORMING STUDY: Mesenchymal stromal cells (MSCs) represent an attractive source for regenerative medicine. However, prior to their application, fundamental questions regarding molecular characterisation, growth and differentiation of MSCs must be resolved. OBJECTIVES: To compare and better understand the behaviour of equine MSCs obtained from bone marrow (BM) and adipose tissue (AT) in culture. METHODS: Five horses were included in this study. Proliferation rate was measured using MTT assay and cell viability; apoptosis, necrosis and late apoptosis and necrosis were evaluated by flow cytometry. The mRNA expression levels of 7 surface marker genes were quantified using RT-qPCR and CD90 was also analysed by flow cytometry. Differentiation was evaluated using specific staining, measurement of alkaline phosphatase activity and analysis of the mRNA expression. RESULTS: High interindividual differences were observed in proliferation in both cell types, particularly during the final days. Statistically significant differences in viability and early apoptosis of cultured AT- and BM-MSCs were found. The highest values of early apoptosis were observed during the first days of culture, while the highest percentage of necrosis and late apoptosis and lowest viability was observed in the last days. Surface marker expression pattern observed is in accordance to other studies in horse and other species. Osteogenic differentiation was evident after 7 days, with an increasing of ALP activity and mRNA expression of osteogenic markers. Adipogenic differentiation was achieved in BM-MSCs from 2 donors with one of the 16 media tested. Chondrogenic differentiation was also observed. CONCLUSIONS: Proliferation ability is different in AT-MSCs and BM-MSCs. Differences in viability and early apoptosis were observed between both sources and CD34 was only found in AT-MSCs. Differences in their osteogenic and adipogenic potential were detected by staining and quantification of specific tissue markers. POTENTIAL RELEVANCE: To provide data to better understand AT-MSCs and BM-MSCs behaviour in vitro. PMID- 21668490 TI - Effects of constant rate infusion of lidocaine and ketamine, with or without morphine, on isoflurane MAC in horses. AB - REASONS FOR PERFORMING STUDY: Lidocaine and ketamine are administered to horses as a constant rate infusion (CRI) during inhalation anaesthesia to reduce anaesthetic requirements. Morphine decreases the minimum alveolar concentration (MAC) in some domestic animals; when administered as a CRI in horses, morphine does not promote haemodynamic and ventilatory changes and exerts a positive effect on recovery. Isoflurane-sparing effect of lidocaine, ketamine and morphine coadministration has been evaluated in small animals but not in horses. OBJECTIVES: To determine the reduction in isoflurane MAC produced by a CRI of lidocaine and ketamine, with or without morphine. HYPOTHESIS: Addition of morphine to a lidocaine-ketamine infusion reduces isoflurane requirement and morphine does not impair the anaesthetic recovery of horses. METHODS: Six healthy adult horses were anaesthetised 3 times with xylazine (1.1 mg/kg bwt i.v.), ketamine (3 mg/kg bwt i.v.) and isoflurane and received a CRI of lidocaine ketamine (LK), morphine-lidocaine-ketamine (MLK) or saline (CTL). The loading doses of morphine and lidocaine were 0.15 mg/kg bwt i.v and 2 mg/kg bwt i.v. followed by a CRI at 0.1 mg/kg bwt/h and 3 mg/kg bwt/h, respectively. Ketamine was given as a CRI at 3 mg/kg bwt/h. Changes in MAC characterised the anaesthetic sparing effect of the drug infusions under study and quality of recovery was assessed using a scoring system. RESULTS: Mean isoflurane MAC (mean +/- s.d.) in the CTL, LK and MLK groups was 1.25 +/- 0.14%, 0.64 +/- 0.20% and 0.59 +/- 0.14%, respectively, with MAC reduction in the LK and MLK groups being 49 and 53% (P<0.001), respectively. No significant differences were observed between groups in recovery from anaesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of lidocaine and ketamine via CRI decreases isoflurane requirements. Coadministration of morphine does not provide further reduction in anaesthetic requirements and does not impair recovery. PMID- 21668491 TI - Bovine papillomavirus type 1 and Equus caballus papillomavirus 2 in equine squamous cell carcinoma of the head and neck in a Connemara mare. AB - In January 2010, 18 months after excision of an ocular squamous cell carcinoma (SCC), a Connemara mare presented with anorexia and periorbital/parotideal lesions. Post mortem examination revealed these lesions as forming one entity, with 2 additional growths in the retropharyngeal region and the left jugular groove, respectively. The lesions were confirmed histopathologically as SCCs. Using PCR, peripheral blood mononuclear cells (PBMCs) from 2008 and 2010, tumour tissue, intact skin and vulval mucosa were screened for Equus caballus papillomavirus type 2 (EcPV-2) and bovine papillomavirus types 1 and 2 (BPV-1/2) DNA. Whereas PBMCs from 2008 scored negative, EcPV-2 DNA was present in PBMCs and SCCs from 2010. Furthermore, reverse transcription PCR revealed EcPV-2 E6 transcripts in these samples. BPV-1/2 DNA, but not RNA, was demonstrated in the periorbital/parotideal mass, the SCC of the jugular groove, vulval mucosa and intact skin, but not in the pharyngeal SCC and PBMCs. Sequencing revealed a 99% similarity of EcPV-2 amplicons with the published EcPV-2 sequence. BPV-1/2 amplicons corresponded to BPV type 1. This report is the first to describe co presence of BPV-1 and EcPV-2 DNA in a pony affected by an uncommon form of nongenital SCC, and the detection of EcPV-2 transcripts in lesions and PBMCs. PMID- 21668492 TI - Use of gastric balloon manometry for estimation of intra-abdominal pressure in horses. AB - REASONS FOR PERFORMING STUDY: Standing laparoscopic procedures, facilitated by abdominal insufflation with carbon dioxide, are being employed to an increasingly greater extent in horses. However, a sustained increase in abdominal pressure may be life-threatening. A practical method for intra-abdominal pressure (IAP) assessment is imperative. Although indirect methods for estimating IAP have been extensively studied in man, little work has been performed in veterinary medicine. OBJECTIVES: To investigate the utility of gastric manometry for purposes of evaluating IAP in horses. METHODS: Gastric pressure (P(ga) ) was estimated by balloon manometry in 8 healthy, mature horses, before and during a 30 min passive pneumoperitoneum induced by right paralumbar puncture. The balloon manometer was positioned within the gastric lumen and inflated using 2 separate volumes of air: 10 and 50 ml. P(ga) Gastric pressure was determined at baseline (0) and 5, 15 and 30 min after induction of passive pneumoperitoneum. Intra abdominal pressure was measured directly by right paralumbar puncture using an 8 gauge needle at baseline and immediately following establishment of passive pneumoperitoneum. RESULTS: Baseline IAP values were negative and increased (P<=0.05) during development of passive pneumoperitoneum. However, recorded P(ga) measurements for both inflation volumes were positive before (baseline) and during the course of the passive pneumoperitoneum. Measured P(ga) values did not correlate with IAP at any time. CONCLUSIONS AND POTENTIAL RELEVANCE: Our results suggest that the indirect method used in human patients for estimating IAP by P(ga) is not applicable for horses. PMID- 21668493 TI - Synoviocoeles associated with the tarsal sheath: description of the lesion and treatment in 15 horses. AB - REASONS FOR PERFORMING STUDY: To describe the presentation, clinical, ultrasonographic and endoscopic features associated with a defect in the tarsal sheath wall, to define the cavity created and to describe a method of treatment. HYPOTHESIS: So called 'false thoroughpins' can be caused by defects in the tarsal sheath wall creating a one way valve effect, removal of which could be therapeutic. METHODS: Case records and diagnostic images of horses with synoviocoeles associated with the tarsal sheath were reviewed retrospectively and follow-up information obtained. RESULTS: Synoviocoeles were diagnosed in 15 horses. All were managed similarly and 10 horses had clinical resolution and returned to work. CONCLUSION: Terminology previously used to describe lesions involving the tarsal sheath does not define accurately the condition described and the term synoviocoele is recommended. Endoscopic enlargement of the sheath wall defect produced good clinical results in 10/15 horses. POTENTIAL RELEVANCE: Clinicians should include synoviocoele in the list of differential diagnoses of fluid filled cavities associated with the tarsal sheath and should consider endoscopic surgery as a treatment modality. PMID- 21668494 TI - Disease prevalence in geriatric horses in the United Kingdom: veterinary clinical assessment of 200 cases. AB - REASONS FOR PERFORMING STUDY: Geriatric horses (aged >= 15 years) represent a substantial proportion of the equine population, yet few studies have investigated the prevalence of diseases within this population in the UK. OBJECTIVES: To describe the findings of veterinary clinical examination of 200 geriatric horses and ponies in north west England and north Wales, and to assess the effect of animal age and type (horse or pony) on the presence or absence of clinical signs and veterinary diagnosed health problems. METHODS: From responses to a cross-sectional postal questionnaire survey of owners of geriatric horses (n = 918/1144), 200 horses were randomly selected to receive a veterinary clinical examination covering the major body systems. RESULTS: Twenty-six percent of animals were overweight (body condition score, BCS, >3/5) and 4.5% were underweight (BCS <2/5). Seventy-one percent had a dermatological abnormality and 22% displayed hirsutism or abnormal moulting. Ophthalmic lesions frequently identified included vitreous degeneration (66.0%), cataracts (58.5%) and senile retinopathy (33.7%). The prevalence of cardiac murmurs was 20%. Whilst only 7.5% of animals had a spontaneous cough during the examination, 18.5% had some form of nasal discharge and 22% had abnormalities on thoracic auscultation at rest. Following rebreathing, 13.6% developed marked abnormalities consistent with lower airway disease. When assessed at walk, 18.6% were lame on at least one limb, while 50.5% were lame in trot. The majority of animals (83.5%) had a reduction in range of motion in at least one joint. Eighty percent of animals had hoof abnormalities. Dental abnormalities were identified in 95.4% of animals, with cheek teeth diastemata, excessive wear/cupped out teeth and focal overgrowths the most frequently identified conditions. CONCLUSIONS AND POTENTIAL RELEVANCE: This study has identified many prevalent clinical signs of disease in geriatric horses. Description of the most prevalent health problems and further identification of risk factors for these conditions will aid in targeted improvements in veterinary care, owner education and welfare. PMID- 21668495 TI - Serum omentin-1 and chemerin levels are interrelated in patients with Type 2 diabetes mellitus with or without ischaemic heart disease. AB - AIMS: Omentin-1 and chemerin have been identified as interesting novel adipokines that may modulate insulin action. Also, they have been suggested to be linked to obesity-induced insulin resistance. The aim of this study was to analyse the relationship between these adipokines and interleukin-6, insulin resistance and anthropometric and metabolic variables in patients with Type 2 diabetes mellitus and in patients with Type 2 diabetes who have ischaemic heart disease. METHODS: Seventy-five individuals with Type 2 diabetes and 15 healthy control subjects were enrolled in this study. Insulin levels, interleukin-6, omentin-1 and chemerin were measured by ELISA. RESULTS: Serum omentin-1 levels were found to be significantly decreased in patients with Type 2 diabetes (19.7 +/- 1 ng/ml) and in patients with Type 2 diabetes with ischaemic heart disease (18.5 +/- 1.6 ng/ml) compared with healthy control subjects (27.4 +/- 2.6 ng/ml) at P < 0.01. Moreover, serum chemerin levels were found to be significantly increased in patients with Type 2 diabetes (347 +/- 14 ng/ml) and in patients with Type 2 diabetes with ischaemic heart disease (341 +/- 16.5 ng/ml) compared with healthy control subjects (281 +/- 13 ng/ml) at P < 0.01. Interestingly, omentin-1 and chemerin levels were found to be significantly correlated negatively with each other as well as being individually correlated with some selected anthropometric, biochemical and clinical variables. In conclusion, both omentin-1 and chemerin might play as a pivotal role in obesity and its associated disorders as Type 2 diabetes; however, their role in cardiovascular diseases needs to be fully elucidated. PMID- 21668496 TI - Consensus at last? The International Diabetes Federation statement on bariatric surgery in the treatment of obese Type 2 diabetes. PMID- 21668497 TI - Organ donation from children: time for legal, ethical and cultural change. AB - Successful transplantation has lead to increasing need for donated organs from children; however, contemporaneously decreased brain-death rates means optimization of donation processes is crucial. Although excellent palliative care and organ donation are compatible, discrepancies exist both between and within European countries in abilities to offer families donation opportunities. Change will require address of legal, ethical and cultural barriers, and this review aims to explore such changes pertinent to both dead and living organ donation. CONCLUSION: We argue that across Europe it is surely time for legal, ethical and cultural change to facilitate parents, families and of course children in having the choice of donation. PMID- 21668498 TI - Floaters and decreased vision as initial symptoms of acute lymphoblastic leukaemia. PMID- 21668499 TI - Bilateral multifocal central serous chorioretinopathy in endogenous hypercortisolism. PMID- 21668500 TI - Peripheral aberration measurements: elliptical pupil transformation and variations in horizontal coma across the visual field. AB - BACKGROUND: The aim was to determine the critical eccentricity at which two methods of elaborating peripheral wavefront measurements are significantly different and to characterise horizontal coma in healthy young adults. METHODS: Peripheral aberrations were determined for 20 observers for central and eight peripheral gaze positions up to 20 degrees using an IRX-3 aberrometer. In one subject, additional measurements up to 40 degrees were obtained. Two definitions of stretching coefficients were compared. The raw empirical data were compared with theoretical modelling. RESULTS: For both 3.5 mm and 6.0 mm pupils, no significant differences were observed between recalculated and non-recalculated elliptical pupils for both methods (p > 0.05) up to 20 degrees eccentricity. For eccentricities greater than 20 degrees and up to 40 degrees , significant differences between circular and elliptical pupils at some eccentricities were apparent, which corresponded to theoretical models. Wide individual variations in horizontal coma across the peripheral field were observed. CONCLUSIONS: The data suggest that for eyes with average levels of aberrations, the elliptical transformation is of no practical importance for eccentricities up to 20 degrees . In some cases the slope of horizontal coma was reversed compared with previous findings in normal eyes. PMID- 21668501 TI - Achieving treatment goals of reducing or maintaining body iron burden with deferasirox in patients with beta-thalassaemia: results from the ESCALATOR study. AB - This analysis evaluated the effects of deferasirox on liver iron concentration in moderate and heavily iron-overloaded patients with beta-thalassaemia from the ESCALATOR trial (n = 231). Mean liver iron concentrations (LIC) decreased significantly from 21.1 +/- 8.2 to 14.2 +/- 12.1 mg Fe/g dry weight (dw) at 2 yr (P < 0.001) in patients with LIC >= 7 mg Fe/g dw at baseline; patients with LIC < 7 mg Fe/g dw maintained these levels over the treatment period. The proportion of patients with LIC < 7 mg Fe/g dw increased from 9.4% at core baseline to 39.3% by the end of year 2. The results showed that deferasirox enabled therapeutic goals to be achieved, by maintaining LIC in patients with LIC < 7 mg Fe/g dw at a mean dose of 22.4 +/- 5.2 mg/kg/d and significantly reducing LIC in patients with LIC >= 7 mg Fe/g dw at a mean dose of 25.7 +/- 4.2 mg/kg/d, along with a manageable safety profile. PMID- 21668503 TI - Acquired von Willebrand syndrome and mitral valve prosthesis leakage. A pilot study. AB - BACKGROUND: Of patients with severe aortic stenosis, 15-25% present with bleeding episodes possibly attributable to acquired von Willebrand syndrome (AVWS). AVWS associated with mitral valve prosthesis leakage has not been reported. METHODS AND RESULTS: Five patients receiving appropriate oral anticoagulation showed mitral valve prosthesis leakage and bleeding episodes; all of them required hospitalization and two blood transfusions, and a von Willebrand factor (VWF) analysis was performed. Two patients with normal functioning metallic prosthesis valves were included as controls. Before surgery, after cessation of acenocumarol, the patients had prolonged activated partial thromboplastin time; four had prolonged closure time (CT) from the platelet function analyzer. Factor VIII procoagulant activity (FVIII:C), VWF ristocetin cofactor activity (VWF:RCo), and VWF collagen binding (VWF:CB) were considerably elevated, while VWF antigen (VWF:Ag) was most elevated. Disproportionate VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag ratios were seen with the loss of large VWF multimers. Following surgery, all parameters were markedly increased and the ratios, CT, and multimeric VWF profile became normal. CONCLUSIONS: Acquired VWF qualitative alterations in mitral valve prosthesis leakage may be associated with or contribute to bleeding diathesis. AVWS should be taken into consideration in patients with mitral valve prosthesis leakage with bleeding diathesis not explained by excessive oral anticoagulation. PMID- 21668502 TI - Importance of optimal dosing >= 30 mg/kg/d during deferasirox treatment: 2.7-yr follow-up from the ESCALATOR study in patients with beta-thalassaemia. AB - Following 1-yr deferasirox therapy in the ESCALATOR study, 57% of previously chelated patients with beta-thalassaemia achieved treatment success (maintenance of or reduction in liver iron concentration (LIC) vs. baseline LIC). Seventy eight per cent had dose increases at median of 26 wk, suggesting that 1-yr results may not have reflected full deferasirox efficacy. Extension data are presented here. Deferasirox starting dose was 20 mg/kg/d (increases to 30/40 mg/kg/d permitted in the core/extension, respectively). Efficacy was primarily assessed by absolute change in LIC and serum ferritin. Overall, 231 patients received deferasirox in the extension; 67.4% (P < 0.0001) achieved treatment success. By the end of the extension, 66.2% of patients were receiving doses >= 30 mg/kg/d. By the end of the 1-yr extension, mean LIC had decreased by 6.6 +/- 9.4 mg Fe/g dw (baseline 19.6 +/- 9.2; P < 0.001) and median serum ferritin by 929 ng/mL (baseline 3356; P < 0.0001). There was a concomitant improvement in liver function markers (P < 0.0001). Fewer drug-related adverse events were reported in extension than core study (23.8% vs. 44.3%). Doses >= 30 mg/kg/d were generally required because of high transfusional iron intake and high baseline serum ferritin levels, highlighting the importance of administering an adequate dose to achieve net negative iron balance. PMID- 21668504 TI - Responsiveness and minimal important score differences in quality-of-life questionnaires: a comparison of the EORTC QLQ-C30 cancer-specific questionnaire to the generic utility questionnaires EQ-5D and 15D in patients with multiple myeloma. AB - OBJECTIVES: The aims of this study were to (i) compare the responsiveness of the EORTC QLQ-C30 cancer-specific questionnaire and the generic questionnaires EQ-5D and 15D used for economic evaluation of healthcare interventions and (ii) determine the minimal important differences (MIDs) in these questionnaires. The MID is the smallest change in a quality-of-life score considered important to patients. METHODS: Between 2006 and 2008, 239 patients with multiple myeloma completed the questionnaires at inclusion (T1) and after 3 months (T2). At T2, patients were asked whether they had noticed any change in their quality of life. Responsiveness and MIDs were determined by mean score changes (T2-T1) for patients who, in the interview, stated they had improved, deteriorated, or were unchanged. Responsiveness was also assessed using standardized response means. Wilcoxon tests for pair differences were used to evaluate the statistical significance of the changes. RESULTS: Patients who improved had significantly (P < 0.01) higher scores at T2 in all three questionnaires. Patients who deteriorated reported lower scores at T2; however, for the 15D, the differences in score were not statistically significant. The MIDs for the QLQ-C30, EQ-5D, and 15D were 8, 0.08, and 0.03 in patients who improved and 12, 0.10 and 0.02 in patients who deteriorated, respectively. CONCLUSIONS: All three questionnaires showed an acceptable responsiveness in patients who improved. However, the 15D did not respond optimally in patients who deteriorate and cannot be recommended for use in patients with myeloma. PMID- 21668505 TI - Lack of influence of the Schneiderian membrane in forming new bone apical to implants simultaneously installed with sinus floor elevation: an experimental study in monkeys. AB - AIM: To describe the early healing processes around the implants installed after elevation of the sinus mucosa applying the lateral access technique without the use of grafting material. MATERIAL AND METHODS: Immediately after the elevation of the maxillary sinus Schneiderian membrane by the lateral approach in eight monkeys, implants were installed without the use of grafting material. The healing of the tissue around the implants was evaluated after 4, 10, 20 and 30 days. Ground sections were prepared and analyzed histologically. RESULTS: After 4 days of healing, the formation of coagulum and provisional matrix was documented within the elevated area. At 10-day interval, sprouts of woven bone were in continuity with the parent bone, and partly in contact with the implant surface at the base of the augmented area. While bone-to-implant contact increased after 20 and 30 days, the area underneath the Schneiderian membrane appeared reduced in volume and condensed toward the apex of the implants. The sinus mucosa was to some extent collapsed onto the implant surface and on the newly formed bone. CONCLUSIONS: The void initially occupied by the coagulum after sinus membrane elevation shrank substantially during the observation period. A lack of influence of the Schneiderian membrane in bone formation apical to implants was documented in the early phase of healing. PMID- 21668507 TI - Counter-clockwise shift-work and prostate cancer: putting pieces in the puzzle. PMID- 21668508 TI - Mercaptoacetyltriglycine-3 renogram is not superior to estimated glomerular filtration rate measurement for the prediction of long-term renal function after nephrectomy. AB - OBJECTIVE: To evaluate the clinical usefulness of effective renal plasma flow (ERPF) measured using preoperative mercaptoacetyltriglycine-3 (MAG3) renogram for the prediction of chronic renal insufficiency after nephrectomy. METHODS: A total of 47 patients underwent preoperative MAG3 renal scintigraphy and subsequent unilateral nephrectomy. Correlations between the 5-year postoperative estimated glomerular filtration rate (eGFR) and the preoperative ERPF of the contralateral kidney (cERPF), ERPF of the diseased kidney (dERPF), total ERPF (tERPF), cERPF to dERPF ratio, serum creatinine (sCr) level, eGFR, as well as the influence of preoperative comorbidities (diabetes, hypertension) on the postoperative eGFR, were evaluated with both univariate and multivariate analyses. RESULTS: Multiple linear regression analysis showed that preoperative cERPF significantly correlated with postoperative eGFR. However, a much stronger correlation was observed between the preoperative and postoperative eGFR. Multiple logistic regression analysis showed that only preoperative eGFR was a significant predicator of the development of advanced-stage chronic kidney disease (CKD). CONCLUSIONS: Preoperative MAG3 renogram is not superior to eGFR measurement as a prognostic indicator of long-term renal function after unilateral nephrectomy. PMID- 21668509 TI - Laparoscopic resection of primary retroperitoneal mucinous cystadenoma by retroperitoneal approach. PMID- 21668510 TI - Axillary basal cell carcinoma: additional 25 patients and considerations. AB - BACKGROUND: Axillary basal cell carcinoma represents a rarely described occurrence in world literature. OBJECTIVE: To report our 14 years' experience of axillary basal cell carcinomas. METHODS: A review of Pathology department database is given. RESULTS: Twenty-five further patients with axillary basal cell carcinomas of 7367 basal cell carcinomas diagnosed are reported. These represent a percentage of 0.33%.The average age of patients was 64.96 years, not significantly different from the average age of patients with overall basal cell carcinomas. No patient had had previous radiant or immunosuppressive treatment or axillary sunburn. No patient had basal cell naevus syndrome. The subtypes involved were superficial and nodular. No patient of 17 patients followed up had recurrences or metastasis after 5 years of follow-up. CONCLUSION: Axillary Basal cell carcinomas are rare. No particular predisposing or risk factor is recorded. They do not seem to be significantly more aggressive than other basal cell carcinomas. PMID- 21668511 TI - Topical methyl aminolevulinate photodynamic therapy for management of basal cell carcinomas in patients with basal cell nevus syndrome improves patient's satisfaction and reduces the need for surgical procedures. AB - BACKGROUND: In basal cell nevus syndrome, basal cell carcinomas occur in early life. The treatment of basal cell carcinomas requires surgical excisions and may lead to unaesthetic scars. Photodynamic therapy (PDT) is a validated treatment of skin cancers, with good cosmetic outcomes. OBJECTIVES: The aim of the study was to evaluate patient's satisfaction, cosmetic outcome and number of surgical excisions before and after PDT, in patients with basal cell nevus syndrome treated with PDT. METHODS: A cross-sectional evaluation of all patients with basal cell nevus syndrome, treated with PDT for basal cell carcinomas. A questionnaire evaluated satisfaction, cosmetic outcomes for surgery and PDT. The number of surgeries before and after PDT was noted and efficacy was evaluated. RESULTS: Seven patients were evaluated; 85% of patients were satisfied with PDT vs. 55% for surgery. The average visual analogue score for the cosmetic result was 8.42/10 for PDT vs. 6.3/10 for surgery. The mean number of surgical excisions was 4.4 during the 6 months before the first session of PDT and 0.57 after. CONCLUSION: Methylaminolevulinate-photodynamic therapy seems an interesting option for the treatment of basal cell carcinomas in patients with basal cell nevus syndrome. PMID- 21668512 TI - Food allergy in patients with eczema: immediate symptoms are usual, with nuts and tomatoes the major allergens. AB - BACKGROUND: Food intolerance is a popular notion in the general population but limited data are available on the presence of food allergy in adult patients with eczema. OBJECTIVE: We wanted to characterize food hypersensitivity in this group of patients. METHOD: A retrospective study was carried out on all patients with food related symptoms attending a cutaneous allergy clinic. RESULTS AND CONCLUSION: Our study showed that while the reported prevalence of food allergy in adult patients with eczema is low (10%), more than half of these will show immunological evidence of a food allergy which support the clinical history. Immediate symptoms are usual, with nuts and tomatoes the major allergens. Demographic factors such as age, gender and duration of eczema did not significantly correlate with number of foods or an allergen-specific IgE of >=grade 2. Food-related symptoms were associated with significant anxiety in all our patients leading to a profound effect on their behaviour. PMID- 21668513 TI - Transcriptional analysis of antibiotic resistance and virulence genes in multiresistant hospital-acquired MRSA. AB - The staphylococcal chromosome cassette mec cannot solely explain the multiresistance phenotype or the relatively mild virulence profile of hospital acquired methicillin-resistant Staphylococcus aureus (HA-MRSA). This study reports that several multiresistant HA-MRSA strains differently expressed genes that may support antibiotic resistance, modify the bacterial surface and influence the pathogenic process. Genes encoding efflux pumps (norA, arsB, emrB) and the macrolide resistance gene ermA were found to be commonly expressed by HA MRSA strains, but not in the archetypal MRSA strain COL. At equivalent cell density, the agr system was considerably less activated in all MRSA strains (including COL) in comparison with a prototypic antibiotic-susceptible strain. These results are in contrast to those observed in recent community-acquired MRSA isolates and may partly explain how multiresistant HA-MRSA persist in the hospital setting. PMID- 21668514 TI - Efflux as a mechanism for drug resistance in Mycobacterium tuberculosis. AB - Tuberculosis remains an important global public health problem, with an estimated prevalence of 14 million individuals with tuberculosis worldwide in 2007. Because antibiotic treatment is one of the main tools for tuberculosis control, knowledge of Mycobacterium tuberculosis drug resistance is an important component for the disease control strategy. Although several gene mutations in specific loci of the M. tuberculosis genome have been reported as the basis for drug resistance, additional resistance mechanisms are now believed to exist. Efflux is a ubiquitous mechanism responsible for intrinsic and acquired drug resistance in prokaryotic and eukaryotic cells. Mycobacterium tuberculosis presents one of the largest numbers of putative drug efflux pumps compared with its genome size. Bioinformatics as well as direct and indirect evidence have established relationships among drug efflux with intrinsic or acquired resistance in M. tuberculosis. This minireview describes the current knowledge on drug efflux in M. tuberculosis. PMID- 21668515 TI - Effects of bovine cytochrome P450 single-nucleotide polymorphism, forage type and body condition on production traits in cattle. AB - Relating single-nucleotide polymorphisms (SNP) to cows with acceptable productivity could benefit cattle breeders in areas where tall fescue is the predominant forage. This study aimed to (i) identify SNPs in bovine cytochrome P450 3A28 (CYP3A28) and (ii) determine the associations between SNP genotype, forage and cow body condition (BC). Genotype (CC, CG or GG) and forage [Kentucky 31 wild-type endophyte-infected tall fescue (KY+) vs. bermudagrass] effects on milk volume and quality were determined in Herd 1 cows (123 cows); in Herd 2 (99 cows), genotype and BC (low vs. moderate) effects on ovarian follicle size, calving date and calving per cent were determined; and in Herd 3 (114 cows), effects of genotype and fescue cultivar [KY+ vs. non-toxic endophyte-infected tall fescue (HiMag4)] were related to calving per cent, calving date and weaning weights of both cow and her calf. A cytosine (C) to guanine (G) transversion at base 994 (C994G) in CYP3A28 was identified. There was a genotype * forage type interaction (p < 0.05) on milk protein in Herd 1 cows; CC cows grazing bermudagrass had greater milk protein percentage in relation to other cows in the herd. In Herd 2, BC and genotype * BC tended (p < 0.10) to influence follicle size and Julian calving date respectively. Diameter of the largest follicle tended to be larger in moderate BC than in low-BC cows; whereas, CC and CG cows in moderate BC and homozygous (CC and GG) cows in low BC tended to calve 14 days earlier in relation to CG cows in low BC. In Herd 3, there was a genotype * forage type interaction (p < 0.05) on calving per cent, Julian calving date and calf weaning weight. In this study, genetic alterations (G allele at C994G) coupled with nutritional factors (low BC and toxic tall fescue) resulted in overall lower productivity in cows. PMID- 21668516 TI - Detection of characteristic metabolites of Aspergillus fumigatus and Candida species using ion mobility spectrometry-metabolic profiling by volatile organic compounds. AB - Volatile metabolites of Aspergillus fumigatus and Candida species can be detected by gas chromatography/mass spectrometry (GC/MS). A multi-capillary column - ion mobility spectrometer (MCC-IMS) was used in this study to assess volatile organic compounds (VOCs) in the headspace above A. fumigatus and the four Candida species Candida albicans, Candida parapsilosis, Candida glabrata and Candida tropicalis in an innovative approach, validated for A. fumigatus and C. albicans by GC/MS analyses. For the detection of VOCs, a special stainless steel measurement chamber for the microbial cultures was used. The gas outlet was either attached to MCC-IMS or to adsorption tubes (Tenax GR) for GC/MS measurements. Isoamyl alcohol, cyclohexanone, 3-octanone and phenethylalcohol can be described as discriminating substances by means of GC/MS. With MCC-IMS, the results for 3 octanone and phenethylalcohol are concordant and additionally to GC/MS, ethanol and two further compounds (p_0642_1/p_683_1 and p_705_3) can be described. Isoamyl alcohol and cyclohexanone were not properly detectable with MCC-IMS. The major advantage of the MCC-IMS system is the feasibility of rapid analysis of complex gas mixtures without pre-concentration or preparation of samples and regardless of water vapour content in an online setup. Discrimination of fungi on genus level of the investigated germs by volatile metabolic profile and therefore detection of VOC is feasible. However, a further discrimination on species level for Candida species was not possible. PMID- 21668517 TI - Recent updates in oral terbinafine: its use in onychomycosis and tinea capitis in the US. AB - Onychomycosis and tinea capitis are prevalent fungal diseases that are difficult to cure and usually require systemic treatment. Onychomycosis has high recurrence rates and can significantly affect a patient's quality of life. Oral terbinafine has been approved for onychomycosis for 20 years in Europe and 15 years in the United States. Over these past 20 years, numerous studies show that oral terbinafine is a safe and efficacious treatment for onychomycosis. More recently, oral terbinafine also has been approved for tinea capitis. Once difficult to treat, terbinafine has revolutionised treatment of these fungal diseases. It has minimal side effects and its limited drug interactions make it an excellent treatment option for patients with co-morbidities. This review discusses oral terbinafine and new insights into the treatment of onychomycosis and tinea capitis. Recent publications have enhanced our knowledge of the mechanisms of oral terbinafine and its efficacy in treating onychomycosis. Oral terbinafine vs. other antifungal therapeutic options are reviewed. Overall, terbinafine remains a superior treatment for dermatophyte infections because of its safety, fungicidal profile, once daily dosing, and its ability to penetrate the stratum corneum. PMID- 21668518 TI - Caspofungin: when and how? The microbiologist's view. AB - The echinocandins are antifungal agents, which act by inhibiting the synthesis of beta-(1,3)-D-glucan, an integral component of fungal cell walls. Caspofungin, the first approved echinocandin, demonstrates good in vitro and in vivo activity against a range of Candida species and is an alternative therapy for Aspergillus infections. Caspofungin provides an excellent safety profile and is therefore favoured in patients with moderately severe to severe illness, recent azole exposure and in those who are at high risk of infections due to Candida glabrata or Candida krusei. In vivo/in vitro resistance to caspofungin and breakthrough infections in patients receiving this agent have been reported for Candida and Aspergillus species. The types of pathogens and the frequency causing breakthrough mycoses are not well delineated. Caspofungin resistance resulting in clinical failure has been linked to mutations in the Fksp subunit of glucan synthase complex. European Committee for Antimicrobial Susceptibility Testing and Clinical and Laboratory Standards Institute need to improve the in vitro susceptibility testing methods to detect fks hot spot mutants. Caspofungin represents a significant advance in the care of patients with serious fungal infections. PMID- 21668519 TI - Persistent fingernail onychomycosis caused by Fusarium proliferatum in a healthy woman. PMID- 21668520 TI - The effects of rose bengal- and erythrosine-mediated photodynamic therapy on Candida albicans. AB - The aim of this study was to evaluate the effects of photodynamic therapy (PDT) using rose bengal or erythrosine with light emitting diode (LED) on Candida albicans planktonic cultures and biofilms. Seven C. albicans clinical strains and one standard strain (ATCC 18804) were used. Planktonic cultures and biofilms of each C. albicans strain were submitted to the following experimental conditions: (a) treatment with rose bengal and LED (RB+L+); (b) treatment with erythrosine and LED (E+L+); and (c) control group, without LED irradiation or photosensitiser treatment (P-L-). After irradiation of the planktonic cultures and biofilms, the cultures were seeded onto Sabouraud dextrose agar (37 degrees C at 48 h) for counting of colony-forming units (CFU ml(-1) ) followed by posterior anova and Tukey's test analyses (P < 0.05). The biofilms were analysed using scanning electron microscopy (SEM). The results revealed a significant reduction of planktonic cultures (3.45 log(10) and 1.97 log(10) ) and of biofilms (<1 log(10) ) for cultures that were subjected to PDT mediated using either erythrosine or rose bengal, respectively. The SEM data revealed that the PDT was effective in reducing and destroying of C. albicans blastoconidia and hyphae. The results show that erythrosine- and rose bengal-mediated PDT with LED irradiation is effective in treating C. albicans. PMID- 21668522 TI - Efficacy and safety of micafungin for treatment of serious Candida infections in patients with or without malignant disease. AB - The aim of this study was to evaluate micafungin efficacy for treatment of invasive candidiasis/candidaemia in patients with cancer. Modified intent-to treat populations were analysed from two trials: one, in adults and children with confirmed Candida infection, compared micafungin (adults 100 mg day(-1); children 2 mg kg(-1) day(-1)) with liposomal amphotericin B (L-AmB 3 mg kg(-1) day(-1)); and the other, in adults only, compared micafungin (100 or 150 mg day(-1)) with caspofungin (50 mg day(-1); 70 mg loading dose). Primary efficacy endpoint in both trials was treatment success, defined as both clinical and mycological response at end of therapy. In the micafungin/L-AmB trial, 183/489 patients had malignancy (37% neutropenic). In the micafungin/caspofungin trial, 176/572 patients had malignancy (26% neutropenic). Micafungin treatment success rates were generally similar in patients with/without malignancy and to rates observed with L-AmB and caspofungin. Most patients with malignancy and neutropenia were successfully treated by all three drugs. For all drugs, incidence of discontinuations because of treatment-related adverse events was similar for patients with malignancy (<=7.7%) vs. no malignancy (<=8.0%). These results suggest that compared with L-AmB and caspofungin, micafungin was effective and well tolerated in patients with candidiasis/candidaemia with/without malignancy. Further prospective trials are recommended to evaluate comparative outcomes with a primary focus on patients with malignancies and invasive candidiasis. PMID- 21668521 TI - Invasive fungal infections in the intensive care unit: a multicentre, prospective, observational study in Italy (2006-2008). AB - Critically ill patients admitted to intensive care units (ICU) are highly susceptible to healthcare-associated infections caused by fungi. A prospective sequential survey of invasive fungal infections was conducted from May 2006 to April 2008 in 38 ICUs of 27 Italian hospitals. A total of 384 fungal infections (318 invasive Candida infections, three cryptococcosis and 63 mould infections) were notified. The median rate of candidaemia was 10.08 per 1000 admissions. In 15% of cases, the infection was already present at the time of admission to ICU. Seventy-seven percent of Candida infections were diagnosed in surgical patients. Candida albicans was isolated in 60% of cases, Candida glabrata and Candida parapsilosis in 13%, each. Candida glabrata had the highest crude mortality rate (60%). Aspergillus infection was diagnosed in 32 medical and 25 surgical patients. The median rate was 6.31 per 1000 admissions. Corticosteroid treatment was the major host factor. Aspergillosis was demonstrated to be more severe than candidiasis as the crude mortality rate was significantly higher (63% vs. 46%), given an equal index of severity, Simplified Acute Physiology Score (SAPS-II). The present large nationwide survey points out the considerable morbidity and mortality of invasive fungal infections in surgical as well as medical patients in ICU. PMID- 21668523 TI - Reactivation of a Cryptococcus gattii infection in a cheetah (Acinonyx jubatus) held in the National Zoo, Havana, Cuba. PMID- 21668524 TI - Addition of DNase improves the in vitro activity of antifungal drugs against Candida albicans biofilms. AB - Cells within Candida albicans biofilms display decreased susceptibility to most clinically used antifungal agents. We recently demonstrated that extracellular DNA (eDNA) plays an important role in biofilm integrity, as a component of the biofilm matrix. This study aimed at gaining insights into the contributions of eDNA to C. albicans biofilms antifungal susceptibility by the investigation of the impact of the combined use of deoxyribonuclease I (DNase) and antifungals to treat biofilms. Candida albicans biofilms were formed using a simple and reproducible 96-well plate-based method. The activity of the combined use of 0.13 mg l(-1) DNase and antifungals was estimated using the 2,3-bis(2-methoxy-4-nitro 5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay and total viable counts. Herein, we report the improved efficacy of amphotericin B when in combination with DNase against C. albicans biofilms, as assessed using XTT readings and viable counts. Furthermore, although DNase increased the efficacy of caspofungin in the reduction of mitochondrial activity, no changes were observed in terms of culturable cells. Deoxyribonuclease I did not affect biofilm cells susceptibility to fluconazole. This work suggests that agents that target processes affecting the biofilm structural integrity may have potential use as adjuvants of a catheter-lock therapy. PMID- 21668525 TI - Influence of serum on in vitro susceptibility testing of echinocandins for Candida parapsilosis and Candida guilliermondii. AB - Echinocandins are antifungal drugs used for the treatment of invasive candidiasis and aspergillosis. They bind to serum proteins within a rate of 96 to >99%. The effect of serum on in vitro echinocandin susceptibility tests of certain Candida and Aspergillus species was reported. This study was performed to determine the effect of human serum on in vitro susceptibility testing of echinocandins for clinical isolates of Candida parapsilosis and Candida guilliermondii, the species which generally have higher minimum inhibitor concentrations compared with other Candida species. One hundred C. parapsilosis and 20 C. guilliermondii isolates were included in the study. The susceptibility tests of caspofungin, micafungin and anidulafungin were performed using microdilution method, either in the presence or absence of 50% human serum, according to the Clinical and Laboratory Standards Institute (CLSI) M27-A3 guidelines. It was demonstrated that human serum significantly affects the in vitro susceptibility results of echinocandins for C. parapsilosis and C. guilliermondii isolates, mostly yielding an increase in MICs. The most prominent fold changes were for micafungin and anidulafungin in C. parapsilosis, and for anidulafungin in C. guilliermondii isolates. Serum influences the in vitro echinocandin susceptibility in C. parapsilosis and C. guilliermondii. The mechanism and clinical significance of this in vitro change need to be clarified. PMID- 21668526 TI - Anidulafungin: when and how? The clinician's view. AB - Anidulafungin is the newest addition to the antifungal arsenal. It possesses fungicidal activity against Candida spp., including isolates that are azole and polyene resistant. In addition, it is fungistatic against Aspergillus spp. Anidulafungin is unique in that it possesses no clinically relevant drug interactions and does not require dosage adjustment in renal or hepatic impairment. Anidulafungin was well tolerated in clinical trials and its clinical efficacy has been demonstrated in the treatment of candidemia and other forms of candidiasis. PMID- 21668527 TI - The question of induction? Maybe not all antibodies are equal ...*. PMID- 21668528 TI - DTG procurement guidelines in heart beating donors. PMID- 21668529 TI - IL-6 and IL-10 in post-transplant lymphoproliferative disorders development and maintenance: a longitudinal study of cytokine plasma levels and T-cell subsets in 38 patients undergoing treatment. AB - IL-6 and IL-10 have previously been implicated in the pathogenesis of post transplant lymphoproliferative disorders (PTLD) and, like peripheral lymphocyte populations, are markers of immune status that are amenable to study in vivo. Thus, we analyzed cytokine plasma levels as well as lymphocyte subsets in a longitudinal analysis of 38 adult transplant recipients undergoing treatment for PTLD. Pretherapeutically, we found significantly elevated IL-6 (13.8 pg/ml) and IL-10 plasma levels (54.7 pg/ml) - in the case of IL-10, even higher in treatment nonresponders than in responders (116 vs. 14 pg/ml). Over time, however, IL-10 levels did not correlate with the course of disease, whereas those of IL-6 did, falling in responders and rising in nonresponders. These findings were independent of histological EBV-status, treatment type, and total peripheral T cell counts, which were significantly reduced in patients with PTLD. Our observations support the idea that although IL-10 is important for creating a permissive environment for post-transplant lymphoma development, IL-6 is associated with PTLD proliferation. The analysis of lymphocyte subsets further identified HLA-DR+ CD8+ lymphocyte numbers as significantly different in non-PTLD controls (33%), treatment responders (44%) and nonresponders (70%). Although the specificity of these cells is unclear, their increase might correlate with the impaired tumor-specific cytotoxic-T-lymphocyte (CTL)-response in PTLD. PMID- 21668530 TI - Living donor liver transplantation in adults in the MELD era in Germany--a multi center retrospective analysis. AB - The aim of this analysis was to provide an update on the current trend in living donor liver transplantation (LDLT) for adult recipients in the model of end stage liver disease (MELD) era in Germany and to encourage a wider implementation of LDLT. We descriptively analysed the data of LDLTs in Germany from 15 December 2006 to 31 December 2009 using a multi-center retrospective analysis via a questionnaire and data provided by Eurotransplant. Ten German centers performed LDLTs in adults. Eighty four transplantations in 50 male recipients and 34 female recipients were performed during the review period, ranging from 1 to 16 LDLTs per center. Hepatocellular carcinoma in cirrhosis (15/84) was the most common transplantation indication. The recipient mean lab-MELD score was 15 (+/-8). Six re-transplantations were necessary after initial LDLTs. The 1-year patient survival was 81%. We obtained data of 79/84 donors. The incidence of complications was 30.4% (n = 24). There were no grade 5 complications according to the Clavien classification. LDLT is an established treatment option that may reduce the waiting time, provides high quality split liver grafts and should be advocated in the MELD era to reduce organ shortage and 'death on the waiting list'. PMID- 21668531 TI - Effectiveness of using a behavioural intervention to improve dietary fibre intakes in children with constipation. AB - BACKGROUND: Functional constipation is common in childhood; diets in affluent industrialised countries may be a significant contributory factor as a result of inadequate fibre content. Only a few intervention studies have been reported where childhood constipation has been treated by increasing dietary fibre. The present study aimed to demonstrate that dietary fibre intakes of children with constipation can be increased using a specifically-designed behaviour modification technique with a self-monitoring and reward system. METHODS: Forty three children, aged 2-14years, with functional constipation (defined as less than three bowel movements per week with hard stools and difficulty or delay in defecation) were randomised to one of two treatment groups: Control (n=20), receiving general advice on increasing dietary fibre intake, or Intervention (n=23), using the intervention tool. Fibre intake, laxative use and stool frequency were assessed at baseline, and at 3, 6 and 12months, using parent filled diaries. RESULTS: A behavioural intervention method significantly increases the fibre intakes of children with constipation at 3 months compared to standard dietary treatment (P=0.005), remaining so after adjusting for baseline fibre intake (P=0.007). Follow-up at 6 and 12months showed no further increase. No significant benefit in terms of a reduction in laxative use or increased stool frequency associated with additional fibre intake was demonstrated. CONCLUSIONS: The findings confirm the difficulties encountered in beginning and maintaining high-fibre diets in children. PMID- 21668532 TI - Mesenteric infusion of a volatile fatty acid prevents body weight loss and transiently restores luteinising hormone pulse frequency in ovariectomised, food restricted ewes. AB - Pulsatile luteinising hormone (LH) secretion is suppressed by food restriction and rapidly restored by return to ad lib. feeding concomitant with an increase in the oxidation of free fatty acids, although there is no increase in plasma leptin concentrations or body fat content in ovariectomised ewes. The ingestion of food may stimulate LH secretion by increasing availability of oxidisable metabolic substrates. Ruminal digestion is characterised by the production of volatile fatty acids and, of these, propionate is the major gluconeogenic substrate, and both glucose and propionate are oxidisable in a variety of tissues. To examine whether increases in mesenteric propionate concentrations are sufficient for restoration of pulsatile LH secretion during a period of food restriction, adult, food-restricted, hypogonadotrophic, ovariectomised ewes received mesenteric vein infusions of 5 MUmol/min/kg body weight (BW) propionate or saline, whereas normal weight, ad lib.-fed ewes received mesenteric infusions of saline for 10 days. Blood samples were taken every 10 min for 5 h before the start of the 10-day infusion period, and continued throughout the first 5 h of infusion on the afternoon of day 1, and in the morning on days 2, 7 and 10. Propionate-infused, food-restricted and ad lib.-fed, saline-infused ewes showed a significantly higher LH pulse frequency compared to that of food-restricted-saline-infused ewes on postinfusion days 1 and 2 but not on days 7 and 10, and only the saline infused, food-restricted group lost a significant amount of body weight. These results indicate that the reproductive system can respond acutely to infusion of metabolic fuels such as propionate, although a sustained recovery of pulsatile LH secretion requires more than an increase in this single metabolic substrate. PMID- 21668533 TI - Steroidogenic factor 1 and the central nervous system. AB - Steroidogenic factor 1 (SF-1; officially designated NR5a1) is a member of a nuclear receptor superfamily with important roles in the development of endocrine systems. Studies with global and tissue-specific (i.e. central nervous system) knockout mice have revealed several roles of SF-1 in brain. These include morphological effects on the development of the ventromedial nucleus of the hypothalamus and functional effects on body weight regulation through modulation of physical activity, anxiety-like behaviours and female sexual behaviours. Although such defects are almost certainly a result of the absence of SF-1 acting as a transcription factor in the hypothalamus, global SF-1 knockout mice also represent a model for studying the sex differences in the brain that develop in the absence of exposure to foetal sex steroid hormones as a result of the absence of gonads. In the present review, current knowledge of the roles of SF-1 protein in the central nervous system is discussed. PMID- 21668534 TI - NF-kappaB is activated in oesophageal fibroblasts in response to a paracrine signal generated by acid-exposed primary oesophageal squamous cells. AB - Oesophageal exposure to duodenogastro-oesophageal refluxate leads to reflux oesophagitis and is implicated in the development of Barrett's metaplasia (BM). NF-kappaB signalling in epithelial cells is associated with the activation of transcription factors believed to be central to BM development, whilst NF-kappaB activation in fibroblasts plays a critical role in matrix remodelling. Our aim was to study the effects of acid exposure on NF-kappaB activation in primary human oesophageal fibroblasts (HOFs) and primary and immortalized oesophageal squames and to investigate any epithelial/stromal interactions in the response of these cells to acid. Primary HOFs and primary and immortalized oesophageal epithelial cells were exposed to acid (pH 7 - pH 4 <= 120 min) in single or pulsed treatments. Conditioned medium from epithelial cells following acid exposure was also applied to fibroblasts. Cell viability was determined by MTT ESTA. NF-kappaB activation was determined by cellular localization of NF kappaB/p65 visualized by immunofluorescence. Conditioned medium from oesophageal epithelial cells, subjected to pH 5 pulsatile exposure, activated NF-kappaB in fibroblasts, with some inter-patient variability, but these conditions did not directly activate NF-kappaB in the epithelial cells themselves. Significant NF kappaB activation was seen in the epithelial cells but only with greater acidity and exposure times (pH 4, 60-120 min). Our findings show that acid exposure can cause indirect activation of stromal cells by epithelial-stromal interactions. This may contribute to the pathogenesis of oesophageal diseases, and the inter patient variability may go some way to explain why some patients with reflux oesophagitis develop BM and others do not. PMID- 21668535 TI - Interplay between calcium signalling and early signalling elements during defence responses to microbe- or damage-associated molecular patterns. AB - While diverse microbe- or damage-associated molecular patterns (MAMPs/DAMPs) typically trigger a common set of intracellular signalling events, comparative analysis between the MAMPs flg22 and elf18 revealed MAMP-specific differences in Ca(2+) signalling, defence gene expression and MAMP-mediated growth arrest in Arabidopsis thaliana. Such MAMP-specific differences are, in part, controlled by BAK1, a kinase associated with several receptors. Whereas defence gene expression and growth inhibition mediated by flg22 were reduced in bak1 mutants, BAK1 had no or minor effects on the same responses elicited by elf18. As the residual Ca(2+) elevations induced by diverse MAMPs/DAMPs (flg22, elf18 and Pep1) were virtually identical in bak1 mutants, a differential BAK1-mediated signal amplification to attain MAMP/DAMP-specific Ca(2+) amplitudes in wild-type plants may be hypothesized. Furthermore, abrogation of reactive oxygen species (ROS) accumulation, either in the rbohD mutant or through inhibitor application, led to loss of a second Ca(2+) peak, demonstrating a feedback effect of ROS on Ca(2+) signalling. Conversely, mpk3 mutants showed a prolonged accumulation of ROS but this did not significantly impinge on the overall Ca(2+) response. Thus, fine tuning of MAMP/DAMP responses involves interplay between diverse signalling elements functioning both up- or downstream of Ca(2+) signalling. PMID- 21668536 TI - Proton-driven sucrose symport and antiport are provided by the vacuolar transporters SUC4 and TMT1/2. AB - The vacuolar membrane is involved in solute uptake into and release from the vacuole, which is the largest plant organelle. In addition to inorganic ions and metabolites, large quantities of protons and sugars are shuttled across this membrane. Current models suggest that the proton gradient across the membrane drives the accumulation and/or release of sugars. Recent studies have associated AtSUC4 with the vacuolar membrane. Some members of the SUC family are plasma membrane proton/sucrose symporters. In addition, the sugar transporters TMT1 and TMT2, which are localized to the vacuolar membrane, have been suggested to function in proton-driven glucose antiport. Here we used the patch-clamp technique to monitor carrier-mediated sucrose transport by AtSUC4 and AtTMTs in intact Arabidopsis thaliana mesophyll vacuoles. In the whole-vacuole configuration with wild-type material, cytosolic sucrose-induced proton currents were associated with a proton/sucrose antiport mechanism. To identify the related transporter on one hand, and to enable the recording of symporter-mediated currents on the other hand, we electrophysiologically characterized vacuolar proteins recognized by Arabidopsis mutants of partially impaired sugar compartmentation. To our surprise, the intrinsic sucrose/proton antiporter activity was greatly reduced when vacuoles were isolated from plants lacking the monosaccharide transporter AtTMT1/TMT2. Transient expression of AtSUC4 in this mutant background resulted in proton/sucrose symport activity. From these studies, we conclude that, in the natural environment within the Arabidopsis cell, AtSUC4 most likely catalyses proton-coupled sucrose export from the vacuole. However, TMT1/2 probably represents a proton-coupled antiporter capable of high-capacity loading of glucose and sucrose into the vacuole. PMID- 21668537 TI - Identification of 14-3-3 proteins as a target of ATL31 ubiquitin ligase, a regulator of the C/N response in Arabidopsis. AB - The balance between carbon (C) and nitrogen (N) availability is an important determinant for various phases of plant growth; however, the detailed mechanisms regulating the C/N response are not well understood. We previously described two related ubiquitin ligases, ATL31 and ATL6, that function in the C/N response in Arabidopsis thaliana. Here, we used FLAG tag affinity purification and MS analysis to identify proteins targeted by ATL31, and thus likely to be involved in regulating the phase transition checkpoint based on C/N status. This analysis revealed that 14-3-3 proteins were associated with ATL31, and one of these, 14-3 3chi, was selected for detailed characterization. The interaction between ATL31 and 14-3-3chi was confirmed by yeast two-hybrid and co-immunoprecipitation analyses. In vitro assays showed that ubiquitination of 14-3-3chi is catalyzed by ATL31. Degradation of 14-3-3chiin vivo was shown to be correlated with ATL31 activity, and to occur in a proteasome-dependent manner. Furthermore, 14-3-3 protein accumulation was induced by a shift to high-C/N stress conditions in Arabidopsis seedlings, and this regulated response required both ATL31 and ATL6. It was also shown that over-expression of 14-3-3chi leads to hypersensitivity of Arabidopsis seedlings to C/N stress conditions. These results indicate that ATL31 targets and ubiquitinates 14-3-3 proteins for degradation via the ubiquitin proteasome system during the response to cellular C/N status. PMID- 21668539 TI - Editorial: the future of clinical nursing: meeting the needs of patients for compassionate and skilled nurses? PMID- 21668538 TI - TCP14 and TCP15 affect internode length and leaf shape in Arabidopsis. AB - TCP transcription factors constitute a small family of plant-specific bHLH containing, DNA-binding proteins that have been implicated in the control of cell proliferation in plants. Despite the significant role that is likely to be played by genes that control cell division in the elaboration of plant architecture, functional analysis of this family by forward and reverse genetics has been hampered by genetic redundancy. Here we show that mutants in two related class I TCP genes display a range of growth-related phenotypes, consistent with their dynamic expression patterns; these phenotypes are enhanced in the double mutant. Together, the two genes influence plant stature by promoting cell division in young internodes. Reporter gene analysis and use of SRDX fusions suggested that TCP14 and TCP15 modulate cell proliferation in the developing leaf blade and specific floral tissues; a role that was not apparent in our phenotypic analysis of single or double mutants. However, when the relevant mutants were subjected to computer-aided morphological analysis of the leaves, the consequences of loss of either or both genes became obvious. The effects on cell proliferation of perturbing the function of TCP14 and TCP15 vary with tissue, as has been suggested for other TCP factors. These findings indicate that the precise elaboration of plant form is dependent on the cumulative influence of many TCP factors acting in a context-dependent fashion. The study highlights the need for advanced methods of phenotypic analysis in order to characterize phenotypes and to construct a dynamic model for TCP gene function. PMID- 21668540 TI - Acceptability of Pain Behaviour Observational Methods (PBOMs) for use by nursing home staff. PMID- 21668541 TI - Not-for-profit volunteer clinics: rich source of nursing research data. PMID- 21668542 TI - The Stressors in Students (SIS) scale: development, reliability, and validity. PMID- 21668543 TI - Commentary on Hasselberg D, Ivarsson B, Andersson R & Tingstedt B (2010) The handling of peripheral venous catheters - from non-compliance to evidence-based needs. Journal of Clinical Nursing 19, 3358-3363. PMID- 21668544 TI - On our way with alternatives-to-discipline for nurses with addictions? Commentary on Monroe T & Kenaga H (2011) Don't ask don't tell: substance abuse and addiction among nurses. Journal of Clinical Nursing 20, 504-509. PMID- 21668545 TI - Commentary on Cheung DSK, Chein WT & Lai CKY (2011) Conceptual framework for cognitive function enhancement in people with dementia. Journal of Clinical Nursing 20, 1533-1541. PMID- 21668546 TI - Response to Underwood S & Ryan T (2010) Commentary on Sarna L, Bialous SA, Wells M, Kotlerman J, Wewers ME & Froelicher ES (2009) Frequency of nurses' smoking cessation interventions: report from a national survey. Journal of Clinical Nursing19, 294-296. PMID- 21668547 TI - Response to Gardiner C, and Ingelton C (2010) Commentary on Cronfalk BS, Ternestedt BM & Strang P (2010) Soft tissue massage: early intervention for relatives whose family members died in palliative cancer care. Journal of Clinical Nursing 19, 1040-1048. PMID- 21668548 TI - Research utilisation, organisational research culture and Corchon hypothesis: Response to Corchon S (2010) Commentary on Kocaman G, Seren S, Lash AA, Kurt S, Bengu N & Yurumezoglu HA (2010) Barriers to research usage by staff nurses in a university hospital. Journal of Clinical Nursing 19, 2076-2078. PMID- 21668549 TI - The effects of giving pacifiers to premature infants and making them listen to lullabies on their transition period for total oral feeding and sucking success. AB - AIM AND OBJECTIVE: This research aimed to assess the effect of giving pacifiers to premature infants and making them listen to lullabies on the transition period to total oral feeding, their sucking success and their vital signs (peak heart rate, respiration rate and oxygen saturation). BACKGROUND: It is very important that preterm infants start oral feeding as soon as possible to survive and get healthy quickly. Previous studies have shown that by using some external stimuli, premature babies can move to oral feeding at an earlier period than 34th gestational week, have increased daily weight gain and be discharged from hospital earlier. DESIGN: In this quasi-experimental and prospective study, 90 premature infants were studied with 30 premature infants allocated to each of pacifier, lullaby and control groups. METHOD: The research was conducted at a neonatal intensive care clinic and premature unit of a university hospital in the east of Turkey between December 2007-January 2009. The data were collected through demographic information form for premature infants, the LATCH Breastfeeding Charting System and patient monitoring. RESULTS: We found that the group who proceeded to the oral feeding in the shortest period was the pacifier group (p < 0.05), followed by the lullaby group and the control group, respectively (p > 0.05). We also found that the highest sucking success was achieved by infants in the pacifier group (p < 0.05) followed by the lullaby group (p > 0.05). CONCLUSION: These results demonstrate that giving pacifiers to premature infants and making them listen to lullabies has a positive effect on their transition period to oral feeding, their sucking success and vital signs (peak heart rate and oxygen saturation). RELEVANCE TO CLINICAL PRACTICE: Neonatal intensive care nurses can accelerate premature infants' transition to oral feeding and develop their sucking success by using the methods of giving them pacifiers and making them listen to lullabies during gavage feeding. PMID- 21668550 TI - Compatible interaction with its rice host leads to enhanced expression of the gamma subunit of oligosaccharyl transferase in the Asian rice gall midge, Orseolia oryzae. AB - The Asian rice gall midge, Orseolia oryzae, is a fast evolving, damaging pest of rice. Understanding the underlying molecular mechanism of interaction between the gall midge and rice will help in devising strategies to control and manage the pest. The present study aims to identify rice-responsive genes in the gall midge that aid pest survival. The abundance of transcripts coding for enzymes related to glycosylation, in a cDNA library prepared from maggots of the rice gall midge feeding on susceptible hosts, indicated their probable involvement in the gall midge-rice interaction. Hence, a full-length transcript for a gamma subunit of the oligosaccharyl transferase gene (OoOST) from the gall midge was cloned and characterized. It has 72% similarity to its orthologue cloned from Aedes aegypti. Tissue-specific analysis of the expression of OoOST revealed an increase (> sevenfold) in the transcripts of the gene in the salivary glands of maggots in susceptible plants when compared with the transcript level in the salivary glands of maggots feeding on resistant hosts. Using quantitative PCR, performed on different developmental stages of the maggots in two susceptible and two resistant hosts, we observed similar expression patterns (i.e. overexpression in the compatible interaction). These results indicate the involvement of OoOST in maggot survival and establishment in the susceptible host. In order to identify polymorphism in the gene, OoOST was cloned from three gall midge biotypes GMB1, GMB4 and GMB4M. PMID- 21668551 TI - Measures of linkage disequilibrium among neighbouring SNPs indicate asymmetries across the house mouse hybrid zone. AB - Theory predicts that naturally occurring hybrid zones between genetically distinct taxa can move over space and time as a result of selection and/or demographic processes, with certain types of hybrid zones being more or less likely to move. Determining whether a hybrid zone is stationary or moving has important implications for understanding evolutionary processes affecting interactions in hybrid populations. However, direct observations of hybrid zone movement are difficult to make unless the zone is moving rapidly. Here, evidence for movement in the house mouse Mus musculus domesticus * Mus musculus musculus hybrid zone is provided using measures of LD and haplotype structure among neighbouring SNP markers from across the genome. Local populations of mice across two transects in Germany and the Czech Republic were sampled, and a total of 1301 mice were genotyped at 1401 markers from the nuclear genome. Empirical measures of LD provide evidence for extinction and (re)colonization in single populations and, together with simulations, suggest hybrid zone movement because of either geography-dependent asymmetrical dispersal or selection favouring one subspecies over the other. PMID- 21668553 TI - Formula for success =3A + 4C + F. PMID- 21668554 TI - An 88-year old woman with long-lasting parkinsonism. PMID- 21668552 TI - Developmental changes in the sleep electroencephalogram of adolescent boys and girls. AB - The sleep electroencephalogram (EEG) changes across adolescence; however, there are conflicting data as to whether EEG changes are regionally specific, are evident in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, and whether there are sex differences. The present study seeks to resolve some of these issues in a combined cross-sectional and longitudinal analysis of sleep EEG in adolescents. Thirty-three healthy adolescents (18 boys, 15 girls; 11-14 years) were studied on two occasions 6-8 months apart. Cross-sectional analysis of data from the initial visit revealed significantly less slow-wave sleep, delta (0.3 to <4 Hz) and theta (4 to <8 Hz) power in both NREM and REM sleep with advancing age. The age-delta power relationship was significant at the occipital site, with age accounting for 26% of the variance. Longitudinal analysis revealed that NREM delta power declined significantly from the initial to follow-up visit, in association with declining delta amplitude and incidence (P < 0.01), with the effect being greatest at the occipital site. REM delta power also declined over time in association with reduced amplitude (P < 0.01). There were longitudinal reductions in theta, alpha and sigma power in NREM and REM sleep evident at the occipital site at follow-up (P < 0.01). No sex differences were apparent in the pattern of change with age for NREM or REM sleep. Declines in sleep EEG spectral power occur across adolescence in both boys and girls, particularly in the occipital derivation, and are not state-specific, occurring in both NREM and REM sleep. PMID- 21668555 TI - A 2 year-old boy with a posterior fossa tumor. PMID- 21668557 TI - What is the tachycardia? PMID- 21668558 TI - New anticoagulants for prevention of stroke in patients with atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac rhythm disorder and a major risk factor for ischemic stroke. Antithrombotic therapy using vitamin K antagonists (VKA) is currently prescribed for prevention of ischemic stroke in patients with AF. A narrow therapeutic range and frequent food and drug interactions underly the need for regular monitoring of anticoagulation intensity and impairs the utility and safety of VKA, stimulating a quest for alternative anticoagulant agents. Recently developed anticoagulants include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors rivaroxaban, apixaban, edoxaban, to name those in the most advanced stages of clinical development. This review focuses on advances in the development of novel antithrombotic agents to provide practical information to clinicians on the use of these new drugs in patients with AF. PMID- 21668559 TI - Benefit of increased irrigation channels? PMID- 21668560 TI - What is the mechanism of the atrial arrhythmia in a patient after orthotopic heart transplantation? AB - Atrial arrhythmias are quite common in patients after heart transplantation; they can occur via focal or reentrant mechanisms and are amenable to curative therapy with catheter ablation. Integration of the individual patient's surgical anatomy with the arrhythmia pattern on 12-lead electrocardiogram can help both to narrow the potential arrhythmia diagnoses and to facilitate therapeutic decision making. This case highlights the differential diagnosis and management of such a patient. PMID- 21668561 TI - Instantaneous electrophysiological changes characterizing achievement of mitral isthmus linear block. AB - BACKGROUND: Achievement of complete conduction block across left mitral isthmus (MI) is a challenging endpoint of linear lesion, and recognizing the precise moment of block is important during ongoing ablation. The objective of this study is to evaluate the changes in P wave morphology and local MI potential at the moment of block during ongoing radiofrequency (RF) application. METHODS AND RESULTS: We evaluated 69 patients (procedures) in whom successful MI linear conduction block was achieved during coronary sinus (CS) pacing. P wave morphology and/or local MI potential could be evaluated in 64 (93%) and 69 (100%) procedures, respectively. The achievement of MI block was associated with substantial instantaneous changes in 57/69 (82.6%) procedures. P wave morphology changed in 44 (64%) procedures with the change restricted to lateral leads in 39 (57%). Abrupt prolongation of local conduction delay from 106 +/- 24 ms to 167 +/ 39 ms (P < 0.0001) was observed on proximal bipole of ablation catheter in 34/69 (49.3%) procedures during ongoing RF application. In addition, prolongation of conduction delay was associated with significant change in the electrogram amplitude and polarity in 11 and 19 procedures, respectively. The substantial change in P wave morphology was not observed in any patients without achievement of complete block. CONCLUSIONS: The achievement of conduction block across MI line is associated with recognizable changes in the local MI electrograms and the P wave morphology especially in the lateral leads. These instantaneous critical changes may assist catheter ablation and indicate the requirement for prolonged RF application, if necessary. PMID- 21668562 TI - Clinical predictors of arrhythmia recurrences following pulmonary vein antrum isolation for atrial fibrillation: predicting arrhythmia recurrence post-PVAI. AB - INTRODUCTION: Pulmonary vein antrum isolation (PVAI) is an accepted treatment for atrial fibrillation (AF) refractory to medical therapy. The purpose of this study was to identify the patient, procedural, and follow-up factors associated with arrhythmia recurrences following PVAI. METHODS AND RESULTS: Clinical data were prospectively collected on all 385 consecutive patients who had 530 PVAI (age 58 +/- 11 years, 63% paroxysmal AF-PAF, follow-up 2.8 +/- 1.2 years) between February 2004 and March 2009. ECGs were recorded at each follow-up visit with Holter monitoring 1, 3, 6, and 12 months following PVAI and every 6 months thereafter. Recurrences < 3 months post-PVAI were defined as early, 3 months-1 year post-PVAI as late, and > 1 year post-PVAI as very late. Relationship between predictor variables and outcomes was modeled using Cox proportional hazards analysis. Late recurrences occurred in 42% with a lower rate among PAF versus non PAF patients (39% vs 56%, P = 0.001). Of the 256 patients with >= 1-year follow up, 121 (47%) had no arrhythmia off antiarrhythmic drugs (AADs) 1 year post-PVAI; 36 (30%) of these had a very late recurrence. In multivariate analysis, non-PAF, hypertension, and prior AAD failure predicted recurrence. When entered into the model, early recurrences remained the only predictor of late recurrences. CONCLUSION: Patients with non-PAF, hypertension, and prior failure of multiple AAD were more likely to experience arrhythmia recurrence post-PVAI. Early recurrences were the strongest predictor of late recurrences. Late and very late recurrences following PVAI were common and should be considered when planning long-term AF patient management. PMID- 21668563 TI - When differential pacing is not enough to assess mitral isthmus block: importance of the pacing threshold. PMID- 21668564 TI - Irregular ventricular activation results in QT prolongation and increased QT dispersion: a new insight into the mechanism of AF-induced ventricular arrhythmogenesis. AB - INTRODUCTION: Atrial fibrillation (AF) has been shown to be associated with increased risk of ventricular arrhythmias. We have previously shown reverse electrical remodeling of the ventricles following successful restoration of sinus rhythm in patients with persistent AF. The purpose of this study was to assess the relative role of irregular ventricular activation in mediating the previously observed changes. METHODS AND RESULTS: Twenty-two patients referred for an invasive electrophysiologic study were randomized to 30 minutes of regular or irregular atrioventricular (AV) sequential pacing at 100 beats per minute (bpm) with a programmed AV interval of 100 ms. Irregular pacing was triggered from prerecorded digital signal with a mean rate of 100 bpm, and a standard deviation of 150 ms (25% of the mean rate). In the regular pacing group, QT and QTc decreased from 448 +/- 102 ms and 453 +/- 105 ms to 428 +/- 109 ms and 442 +/- 104 ms, respectively (P < 0.001 for QT interval and P < 0.001 for QTc interval). There was no significant change in QT dispersion. In the irregular pacing group, QT and QTc increased from 477 +/- 104 ms and 486 +/- 78 ms to 489 +/- 106 ms and 500 +/- 106 ms (P < 0.01 for QT interval and P = 0.03 for QTc interval). In addition, there was a significant increase in QT dispersion from 50 +/- 22 ms to 66 +/- 22 ms (P = 0.001). Since the rate and pacing sites were similar between the groups, we attribute the repolarization changes in the irregular pacing group to the irregular activation of the ventricles. CONCLUSION: The detrimental effects of irregular pacing go beyond the hemodynamic changes and include electrical remodeling that favors an arrhythmogenic substrate. PMID- 21668565 TI - Elimination of right superior pulmonary vein firing during radiofrequency ablation around the left pulmonary veins: what is the mechanism? PMID- 21668566 TI - Arrhythmias in a patient with sarcoidosis. AB - Arrhythmias in a Patient With Sarcoidosis. Sarcoidosis is a multisystemic granulomatous disease of unknown etiology; up to 27% of cases entail cardiac involvement. Conduction abnormalities and ventricular tachycardia are the most common arrhythmias and can cause sudden death. We describe a patient who developed cardiac sarcoidosis 9 years after undergoing surgery for neurosarcoidosis. He presented with 2:1 second-degree atrioventricular block. Ventricular tachycardia with 3 morphologies was induced by exercise stress test. A DDD pacer/implantable cardioverter defibrillator (ICD) was implanted, which prevented exercise-induced ventricular tachycardia in a follow-up stress test. Treatment with steroids was initiated. The AVB disappeared, and no further arrhythmias were documented at the 1-year follow-up. PMID- 21668567 TI - Atrial electromechanical interval can identify patients with paroxysmal atrial fibrillation and is associated with CHADS2 score and peak velocity of left atrial appendage. AB - INTRODUCTION: It is difficult to discriminate patients with and without paroxysmal atrial fibrillation (PAF). The atrial electromechanical interval determined by the transthoracic echocardiogram is demonstrated to be a predictor of new onset AF. The aim of our study was to investigate whether the electromechanical interval is a useful parameter to identify patients with PAF. METHODS AND RESULTS: A total of 297 patients (PAF group = 103; control group = 194) with mean age of 59.4 +/- 12.4 years were enrolled. The electromechanical interval (PA-PDI) defined as the time interval from the initiation of the P-wave deflection to the peak of the mitral inflow A wave on the pulse-wave Doppler imaging was measured for every patient. Patients with PAF had significantly longer PA-PDI intervals compared with that of patients without it (152.7 +/- 13.8 ms vs 133.4 +/- 16.8 ms). The area under ROC curve based on the PA-PDI interval to diagnose PAF was 0.803 (95% confidence interval = 0.755-0.851, P < 0.001). At the cut-off value of 142 ms, the sensitivity and specificity in identifying PAF were 77.7% and 80.1%, respectively. In the PAF group, the PA-PDI interval was closely associated with the CHADS(2) score and inversely related with the peak velocity of left atrial appendage. CONCLUSIONS: The PA-PDI interval may be a useful parameter to identify patients with PAF. Further studies are necessary to evaluate the usefulness of PA-PDI intervals in diagnosing PAF in addition to the current methods and tools. PMID- 21668568 TI - A unique basaloid proliferation encountered during Mohs surgery: potential pitfall for overdiagnosis of basal cell carcinoma. PMID- 21668569 TI - Esophageal capsule endoscopy for evaluation of patients with chronic gastroesophageal reflux symptoms: findings and its image quality. AB - Esophageal capsule endoscopy (ECE) may offer an alternative approach to visualize esophageal lesions associated with gastroesophageal reflux (GER) disease. The objective of this study was to report the ECE findings in patients with GER symptoms and validate a new scoring system to assess ECE video quality. Five hundred two ECE were performed in patients with GER symptoms. We devised a new grading scale called ECE Utility score to assess the quality of images using five different parameters: anatomic landmarks visualized, esophageal transit time, image quality, illumination, and artifacts. The ECE cases were independently scored by two interpreters in a randomized, blinded fashion. Reflux esophagitis was diagnosed via ECE in 254 patients (50.5%). We identified 12 cases (2.4%) with suspected Barrett's esophagus and all of them had endoscopic evidence of Barrett's esophagus on esophagogastroduodenoscopy. Histologic confirmation Barrett's esophagus was found in six patients and dysplasia was found in one patient. From the 502 cases, mean +/- standard deviation total ECE Utility score was 8.89 +/- 0.96 for interpreter 1 and 8.96 +/- 0.93 for interpreter 2. The concordance rate between the two interpreters for the ECE Utility score ranged from 75.9-96.8% across the parameters and the Pearson correlation rate of the total score was 0.81. ECE is shown to be a simple noninvasive valuable technique for evaluating esophageal mucosa and producing high quality images in patients with GER symptoms. ECE can help as an alternative screening tool for diagnosing Barrett's esophagus. PMID- 21668570 TI - Comparison of bolus transit patterns identified by esophageal impedance to barium esophagram in patients with dysphagia. AB - Bolus transit through the esophagus has not been validated by videoesophagram in patients with dysphagia and changes in impedance with abnormal barium transit have not been described in those patients. The aim of this study was to compare esophageal impedance findings with barium esophagram measurements in patients with dysphagia. The consecutive patients with dysphagia underwent conventional multichannel esophageal impedance manometry, after which a barium videoesophagram was performed simultaneously with multichannel esophageal impedance manometry using a mean of three swallows of barium. Esophageal emptying patterns shown in the esophagogram were classified by the degree of intraesophageal stasis and presence of intraesophageal reflux. Bolus transit patterns in impedance were classified as complete and incomplete transit. Sixteen patients (M : F = 8 : 8, mean age, 47 years) were enrolled. Their manometric diagnosis were normal (n= 6), ineffective esophageal motility (n= 1), diffuse esophageal spasm (DES; n= 2), and achalasia (n= 7). Sixty-three swallows were analyzed. According to impedance analysis, 21/22 swallows with normal barium emptying showed complete transit (96%) and 31/32 swallows with severe stasis showed incomplete transit (97%). Nine swallows with mild stasis showed either complete or incomplete transit patterns in impedance. Swallows with mild barium stasis and complete transit in impedance were observed in patients who had received treatment (two patients with achalasia with history of esophageal balloonplasty and a patient with DES after nifedipine administration). Impedance reflected severe stasis with retrograde barium movement and described typical bolus transit patterns in patients with achalasia and DES. In conclusion, impedance-barium esophagram concordance is high for swallows with normal esophageal emptying and for severe barium stasis in patients with dysphagia. PMID- 21668571 TI - Immunohistochemical evaluation of p53, FHIT, and IGF2 gene expression in esophageal cancer. AB - The aim of the study was to evaluate the expression of tumor suppressor genes p53, fragile histidine triad gene (FHIT), and an oncogene insulin-like growth factor 2 (IGF2) as prognostic markers in the etiology of esophageal cancer. Immunohistochemistry (IHC) was performed in 39 archival tissue samples of different esophageal pathologies for the three genes. Abnormal p53 expression was maximum in all the cases of squamous cell carcinoma, while IGF2 expression was enhanced in squamous cell carcinoma (81%), adenocarcinoma (100%), and dysplasia of squamous epithelium (75%) samples when compared with normals (50%). To our surprise, 75% of normal tissues did not show FHIT expression, which was also not seen in 40% of dysplasias of squamous epithelium, 33.3% of adenocarcinoma, and 41% of squamous cell carcinoma. To the best of our knowledge, this is the first study evaluating IGF2 by IHC, as well as, correlating it with the expression of the two tumor suppressor genes, p53 and FHIT, in esophageal tissue. p53 expression was threefold higher than normal in dysplasias of squamous epithelium and adenocarcinoma, while it was eightfold higher in squamous cell carcinoma. IGF2 expression was low in normal and dysplasia tissue but was increased 1.97 fold in both types of malignancy. FHIT and p53 expression were well correlated in squamous cell carcinoma, supporting the observation that FHIT regulates and stabilizes p53. Altered/lowered FHIT levels may be a result of exposure to various exogenous agents; however, this could not be assessed in the present study as it was carried out on archival samples. A larger prospective study is warranted to establish the role of exogenous factors in FHIT expression. PMID- 21668572 TI - Endoscopic ablative therapy for Barrett's esophagus: a potential cause of eosinophilic esophagitis. AB - Markedly increased esophageal eosinophils are associated with allergy- or reflux based eosinophilic esophagitis. Other known disorders that cause this entity are unusual. To characterize the clinical, endoscopic, and histological findings of patients who develop marked esophageal eosinophilic infiltration after ablative therapy for Barrett's dysplasia. All patients who underwent endoscopic ablation of Barrett's esophagus between 1991 and 2009 with photodynamic therapy or radio frequency were screened for a pathologic descriptor of 'eosinophils' on biopsy. Patients whose biopsies demonstrated >15 eosinophils per high power (HPF) field in squamous epithelium after ablation were reviewed and included in the study group. Thirteen of 385 (3.4%) patients underwent ablation for Barrett's esophagus and subsequently had large numbers of intraepithelial eosinophils. All patients had long segment Barrett's (mean 8.0 cm) with low- or high-grade dysplasia or adenocarcinoma. All had undergone photodynamic therapy as their form of ablation. No patients had typical symptoms or endoscopic findings of eosinophilic esophagitis. Eleven patients were on proton pump inhibitors. The time between ablation and onset of esophageal eosinophilia ranged from 83 to 692 days. Intraepithelial eosinophil counts ranged from 30 to 150/HPF (mean 90). The majority of cases showed eosinophilic degranulation, spongiosis, increased papillary height, and basal zone thickening. The natural history of esophageal eosinophilia was variable after ablation, persisting consistently or sporadically on biopsy for up to 6 years. Ablation for Barrett's dysplasia can be followed rarely by eosinophil infiltrates with a histological resemblance to allergy-based eosinophilic esophagitis, but lacking dysphagia. The pathophysiology is unknown. PMID- 21668573 TI - Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007). AB - A prospective (2005-2007) hospital-based multicentre surveillance of EORTC/MSG proven or probable invasive aspergillosis (IA) cases whatever the underlying diseases was implemented in 12 French academic hospitals. Admissions per hospital and transplantation procedures were obtained. Cox regression models were used to determine risk factors associated with the 12-week overall mortality. With 424 case-patients included, the median incidence/hospital was 0.271/10(3) admissions (range 0.072-0.910) without significant alteration of incidence and seasonality over time. Among the 393 adults (62% men, 56 years (16-84 years)), 15% had proven IA, 78% haematological conditions, and 92.9% had lung involvement. Acute leukaemia (34.6%) and allogeneic stem cell transplantation (21.4%) were major host factors, together with chronic lymphoproliferative disorders (21.6%), which emerged as a new high-risk group. The other risk host factors consisted of solid organ transplantation (8.7%), solid tumours (4.3%), systemic inflammatory diseases (4.6%) and chronic respiratory diseases (2.3%). Serum galactomannan tests were more often positive (>=69%) for acute leukaemia and allogeneic stem cell transplantation than for the others (<42%; p <10(-3)). When positive (n = 245), cultures mainly yielded Aspergillus fumigatus (79.7%). First-line antifungal therapy consisted of voriconazole, caspofungin, lipid formulations of amphotericin, or any combination therapy (52%, 14%, 8% and 19.9%, respectively). Twelve-week overall mortality was 44.8% (95% CI, 39.8-50.0); it was 41% when first-line therapy included voriconazole and 60% otherwise (p <0.001). Independent factors for 12-week mortality were older age, positivity for both culture and galactomannan and central nervous system or pleural involvement, while any strategy containing voriconazole was protective. PMID- 21668574 TI - Evaluation of a commercial microarray as a confirmation test for the presence of extended-spectrum beta-lactamases in isolates from the routine clinical setting. AB - Since the diagnostic characteristics of the Check-KPC ESBL microarray as a confirmation test on isolates obtained in a routine clinical setting have not been determined, we evaluated the microarray in a random selection of 346 clinical isolates with a positive ESBL screen test (MIC >1 mg/L for cefotaxime or ceftazidime or an ESBL alarm from the Phoenix or Vitek-2 expert system) collected from 31 clinical microbiology laboratories in the Netherlands in 2009. Using sequencing as the reference method the sensitivity of the microarray was 97% (237/245), the specificity 98% (97/99), the positive predictive value 99% (237/239) and the negative predictive value 92% (97/105). PMID- 21668575 TI - Histopathological diagnosis of Japanese spotted fever using formalin-fixed, paraffin-embedded skin biopsy specimens: usefulness of immunohistochemistry and real-time PCR analysis. AB - Japanese spotted fever (JSF) is caused by Rickettsia japonica, and lethal cases are reported yearly in southwest Japan. We thus established the method of diagnosing JSF by immunohistochemistry (IHC) and real-time PCR (RT-PCR) using formalin-fixed, paraffin-embedded skin biopsy specimens. Two monoclonal antibodies were used for IHC, and the 17k genus common antigen gene served as the target of RT-PCR. We collected skin biopsy (n = 61) and autopsy (n = 1) specimens from 50 patients clinically suspected of JSF. Immunohistochemically, the rickettsial antigens were localized as coarse dots in the cytoplasm of endothelial cells and macrophages. Thirty-one seropositive cases plus one autopsy case (group A) and nine seronegative cases but with positive IHC and/or RT-PCR (group B) were judged as JSF. Nine cases were regarded as non-JSF disorders based on negative serology, IHC and RT-PCR (group C). Of 50 biopsies (eschar 34, eruptions 10, and scabs 6) from groups A and B, IHC and RT-PCR positivities were 94% (32/34) and 62% (21/34) for eschar, 80% (8/10) and 30% (3/10) for eruptions, and 33% (2/6) and 50% (3/6) for scabs. For IHC, eschar was most suitable, and scabs were insufficient. Unexpectedly, 18 biopsies happened to be fixed in 100% formalin, and this lowered the detection rate by RT-PCR, but IHC was tolerant. Sequence analysis using five skin biopsy specimens confirmed a 114 bp DNA stretch homologous to that reported for the target gene of R. japonica. In 26 (84%) of the 31 seropositive patients, the diagnosis was made by IHC and/or RT-PCR earlier than serology. PMID- 21668576 TI - The economic burden of Clostridium difficile. AB - Although Clostridium difficile (C. difficile) is the leading cause of infectious diarrhoea in hospitalized patients, the economic burden of this major nosocomial pathogen for hospitals, third-party payers and society remains unclear. We developed an economic computer simulation model to determine the costs attributable to healthcare-acquired C. difficile infection (CDI) from the hospital, third-party payer and societal perspectives. Sensitivity analyses explored the effects of varying the cost of hospitalization, C. difficile attributable length of stay, and the probability of initial and secondary recurrences. The median cost of a case ranged from $9179 to $11 456 from the hospital perspective, $8932 to $11 679 from the third-party payor perspective, and $13 310 to $16 464 from the societal perspective. Most of the costs incurred were accrued during a patient's primary CDI episode. Hospitals with an incidence of 4.1 CDI cases per 100 000 discharges would incur costs >=$3.2 million (hospital perspective); an incidence of 10.5 would lead to costs >=$30.6 million. Our model suggests that the annual US economic burden of CDI would be >=$496 million (hospital perspective), >=$547 million (third-party payer perspective) and >=$796 million (societal perspective). Our results show that C. difficile infection is indeed costly, not only to third-party payers and the hospital, but to society as well. These results are consistent with current literature citing C. difficile as a costly disease. PMID- 21668577 TI - Outbreak of KPC-3-producing, and colistin-resistant, Klebsiella pneumoniae infections in two Sicilian hospitals. AB - We report the first outbreak caused by colistin-resistant Klebsiella pneumoniae producing KPC-3 carbapenamase in two Italian hospitals. This spread occurred in 1 month, and was caused by eight colistin-resistant and carbapenem-resistant Klebsiella pneumoniae isolates from eight patients. A further three isolates were obtained from the intestinal tract and pharyngeal colonization. All isolates were multidrug-resistant (MDR), including being resistant to colistin, but they were susceptible to gentamicin and tigecycline. PCR detection showed that all isolates harboured the bla(KPC-3) gene associated with bla(SHV-11) , bla(TEM-1) and bla(OXA-9) . All K. pneumoniae isolates, genotyped by pulsed-field gel electrophoresis and multilocus sequence typing, belonged to the same sequence type (ST)258 clone. From our data and a review of the international literature, K. pneumoniae ST258 seems to be the most widespread genetic background for KPC dissemination in Europe. PMID- 21668578 TI - Trichinellosis in hospitalized patients from a Romanian endemic area, 2007-2009. AB - Trichinellosis continues to represent a major concern in Romania, a country that, over the years, has had favourable conditions for the transmission and maintenance of this disease. During the years 2007-2009, Romania has reported to the WHO's Regional Office for Europe the highest incidence of trichinellosis in humans. This study was aimed at analysing the epidemiological, clinical, laboratory and therapeutic aspects of trichinellosis in a well-known Romanian endemic area, and at determining the particular aspects of this disease in children and the adult population. We retrospectively investigated the medical records of patients from two western Romanian counties, diagnosed with trichinellosis and hospitalized between 2007 and 2009. During this period, a total of 91 persons presented with this disease, and the corresponding yearly average incidence was 2.7 cases per 100,000 inhabitants. Patients were aged 3-80 years (mean age 33.3 +/- 17.9 years), and most of them were adults (78%). Males accounted for 51.6% of cases. Unemployed adults belonging to the gypsy minority predominated within the study group (46.5%). Myalgia, fever and oedema were the most common symptoms. The mean eosinophil count was 25.1% +/- 17.1% (range 1 75.8%), and was significantly higher in adults than in children. All patients were treated with albendazole, and 52.7% had associated corticotherapy. Trichinellosis is still probably the most important parasitic disease in Romania. Recent reports have revealed inadequate application of prophylactic and control measures against this disease. Consequently, public health strategies should be reconsidered, and more efficient and rigorous education of the population is required. PMID- 21668579 TI - Acute fascioliasis--clinical and epidemiological features of four patients in Chile. AB - Because of its infrequent and protean presentation and the lack of clinical data, the management of acute infections with the foodborne trematode Fasciola hepatica is challenging. We report four serologically confirmed cases that illustrate our experience with this parasitic infection in Chile. All patients were adults presenting with upper abdominal pain. Other symptoms included fever, nausea/vomiting, and cutaneous manifestations. In all cases, marked eosinophilia was present. All patients lived in an urban environment, and three reported the consumption of raw watercress. Computed tomography (CT) scans showed hypodense hepatic lesions, whereas ultrasonography findings were unremarkable. One patient suffered portal vein thrombosis, which might be a rare complication of acute fascioliasis. All patients were successfully treated with triclabendazole. Our case series demonstrates that patients with acute fascioliasis typically present with a combination of upper abdominal pain, marked eosinophilia, and hypodense hepatic lesions on CT imaging. Diagnosis should be confirmed by serological investigation. A history of recent consumption of raw watercress is an important finding, but in some patients the source of infection remains obscure. PMID- 21668580 TI - Thymosin beta4 knockdown disrupts mitochondrial functions of SW480 human colon cancer cells. AB - Thymosin beta(4) (Tbeta(4)), overexpressed in various tumors, has been shown to be involved in cellular anti-oxidation. Reactive oxygen species (ROS) function as signaling molecules and play certain roles in tumor progression. To assess the anti-oxidative role of endogenous Tbeta(4) in tumor cells, its expression in SW480 cells was knocked down by a shRNA, which induced significant increases of ROS. Interestingly, some cristae-lost and several electron-dense mitochondria appeared in cells with Tbeta(4) knockdown that was accompanied by a marked decline of the membrane potential of these organelles. Strikingly, while the ATP and lactate levels in SW480 cells were notably elevated by Tbeta(4) downregulation, this treatment significantly diminished the mitochondrial DNA copy number and protein levels of several subunits of the electron transport complexes. Finally, immunofluorescent staining results suggested the presence of Tbeta(4) in mitochondria. To the best of our knowledge, this is the first report to demonstrate that Tbeta(4) knockdown can disrupt the morphology and some crucial functions of mitochondria in human colorectal carcinoma (CRC) cells. PMID- 21668581 TI - Glypican-3 could be an effective target for immunotherapy combined with chemotherapy against ovarian clear cell carcinoma. AB - Glypican-3 (GPC3) is useful not only as a novel tumor marker, but also as an oncofetal antigen for immunotherapy. We recently established HLA-A2-restricted GPC3(144-152) peptide-specific CTL clones from hepatocellular carcinoma patients after GPC3(144-152) peptide vaccination. The present study was designed to evaluate the tumor reactivity of a HLA-A2-restricted GPC3(144-152) peptide specific CTL clone against ovarian clear cell carcinoma (CCC) cell lines. The GPC3(144-152) peptide-specific CTL clone could recognize HLA-A2-positive and GPC3 positive ovarian CCC cell lines on interferon (IFN)-gamma enzyme-linked immunospot assay and showed cytotoxicity against KOC-7c cells. The CTL clone recognized naturally processed GPC3-derived peptide on ovarian CCC cells in a HLA class I-restricted manner. Moreover, we confirmed that the level of GPC3 expression was responsible for CTL recognition and that subtoxic-dose chemotherapy made tumor cells more susceptible to the cytotoxic effect of CTL. Thus, it might be possible to treat ovarian CCC patients by combining chemotherapy with immunotherapy. Our data suggest that GPC3 could be an effective target for immunotherapy against ovarian CCC. PMID- 21668582 TI - Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination. AB - Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. siRNA for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair. PMID- 21668583 TI - Downregulation of Cockayne syndrome B protein reduces human 8-oxoguanine DNA glycosylase-1 expression and repair of UV radiation-induced 8-oxo-7,8-dihydro-2' deoxyguanine. AB - Human 8-oxoguanine DNA glycosylase-1 (hOGG1) is the key DNA repair enzyme responsible for initiating repair of UV radiation-induced 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxo-dG). Previously we have shown that basal cells in human epidermis are particularly sensitive to UVA-mediated DNA damage probably due to low expression of hOGG1. Here we investigate some aspects of the regulatory role of Cockayne syndrome B (CSB) on hOGG1 expression and function. Cockayne syndrome B and hOGG1 genes were knocked down by miRNA technology in the HaCaT human keratinocyte cell line. Loss of the CSB gene decreased hOGG1 mRNA, and loss of hOGG1 increased CSB, indicating that they influence each other's expression. Protein levels were assessed in cells grown into engineered human skin using immunohistochemistry. This confirmed that CSB knockdown with miRNA reduced hOGG1 protein levels, but hOGG1 knockdown did not influence expression of CSB protein. Using comet assay we found that both hOGG1 and CSB knockdown reduced repair of both UVA- and UVB-induced 8-oxo-dG, consistent with CSB downregulation of hOGG1 mRNA and protein. In contrast, CSB but not hOGG1 knockdown reduced repair of UVB- and UVA-induced cyclobutane pyrimidine dimer photolesions. In engineered human skin, repair of UVA-induced 8-oxo-dG was inhibited by both hOGG1 and CSB knockdown, confirming the functional role of both proteins in cells with 3-D cellular contacts. These findings directly indicate that hOGG1 and CSB influence each other's expression. CSB is required for maintaining hOGG1 enzyme levels and function. Cockayne syndrome B could therefore be required for 8-oxo-dG repair due to its regulatory effect on hOGG1 expression. Cockayne syndrome B but not hOGG1 is also required for efficient repair of cyclobutane pyrimidine dimers. Cockayne syndrome B regulation of DNA repair could contribute to the effect of UVA in causing mutations that lead to skin cancer in humans. PMID- 21668584 TI - Genetic ablation of a candidate tumor suppressor gene, Rest, does not promote mouse colon carcinogenesis. AB - Colon carcinogenesis is a multistage process involving genetic alterations of various tumor suppressor genes and oncogenes. Repressor element 1 silencing factor (REST ), which was originally discovered as a transcriptional repressor of neuronal genes, plays an important role in neuronal differentiation. In a previous genetic screening for tumor suppressor genes in human cancers, REST was identified as a candidate tumor suppressor gene in colorectal carcinogenesis. However, the role of Rest in colon carcinogenesis in vivo remains unclear because of the embryonic lethal phenotype of the conventional Rest knockout mouse. In the present study, we conditionally deleted the Rest gene in the intestinal epithelium and investigated the effect of Rest ablation in mouse colon tumorigenesis. A conditional ablation of Rest in the colonic crypts led to a rapid upregulation of Rest-targeted genes, such as Syt4, Bdnf, and Tubb3, suggesting that Rest actually suppresses the expression of its target genes in the colon. However, Rest ablation did not lead to any significant effect on the development of colon tumors in two independent mouse models of colon carcinogenesis. In addition, despite the upregulation of neuronal genes in the colonic crypts, no neuronal differentiation was observed in the colonic crypts and tumors after the Rest ablation. These results indicate that the loss of Rest expression by itself does not promote the development of colon tumors in mice, and suggest that REST may exert a tumor suppressing activity in conjunction with the additional genetic/epigenetic abnormalities that occur during colon carcinogenesis. PMID- 21668585 TI - Systematic exploration of cancer-associated microRNA through functional screening assays. AB - MicroRNA (miRNA), non-coding RNA of approximately 22 nucleotides, post transcriptionally represses expression of its target genes. miRNA regulates a variety of biological processes such as cell proliferation, cell death, development, stemness and genomic stability, not only in physiological conditions but also in various pathological conditions such as cancers. More than 1000 mature miRNA have been experimentally identified in humans and mice, yet the functions of a vast majority of miRNA remain to be elucidated. Identification of novel cancer-associated miRNA seems promising considering their possible application in the development of novel cancer therapies and biomarkers. Currently, there are two major approaches to identify miRNA that are associated with cancer: expression profiling study and functional screening assay. The former approach is widely used, and a large number of studies have shown aberrant miRNA expression profiles in cancer tissues compared with their non-cancer counterparts. Although aberrantly expressed miRNA are potentially good biomarkers, in most cases a majority of them do not play causal roles in cancers when functional assays are performed. In contrast, the latter approach allows screening of 'driver' miRNA with cancer-associated phenotypes, such as cell proliferation and cell invasion. Thus, this approach might be suitable in finding crucial targets of novel cancer therapy. The combination of both types of approaches will contribute to further elucidation of the cancer pathophysiology and to the development of a novel class of cancer therapies and biomarkers. PMID- 21668586 TI - Changes in cognitive-emotional and physiological symptoms of depression following STN-DBS for the treatment of Parkinson's disease. AB - BACKGROUND AND PURPOSE: Subthalamic nucleus deep brain stimulation (STN-DBS) has been shown to have beneficial effects on the motor features of Parkinson's disease (PD), but its impact on non-motor symptoms, most notably mood, has not been fully explored. METHODS: In the first study to independently compare the emotional-cognitive and somatic/physiological symptoms of depression, we examined mood differences in 17 bilateral STN-DBS and 22 matched non-surgical PD patients at baseline and 6 months. RESULTS: The STN-DBS group reported higher levels of depression at baseline with significant endorsement of physical symptomatology. Postoperatively, no significant between-group differences in physical symptoms of depression were found. In contrast, a significant group by time interaction for cognitive-emotional symptoms of depression was found, with the STN-DBS group reporting an increase in psychological symptoms of distress. The STN-DBS group also reported an increase in anxiety following surgery. The suicide rate of 5% found in our study is consistent with other postoperative studies in PD. The impact of changes in levodopa and psychotropic medication are also explored. CONCLUSIONS: Preliminary results suggest that the motor improvement often observed in patients with PD following bilateral STN-DBS may be partially offset by an increase in affective-cognitive symptoms of depression. PMID- 21668587 TI - TdIF2 is a nucleolar protein that promotes rRNA gene promoter activity. AB - Terminal deoxynucleotidyltransferase (TdT) interacting factor 2 (TdIF2) is an acidic protein that binds to TdT. TdIF2 binds to DNA and core histones and contains an acidic-amino acid-rich region in its C-terminus. It has therefore been suggested to function as a histone chaperone within the nucleus. TdIF2 localized within the nucleolus in HEK 293T cells, and its N-terminal (residues 1 234) and C-terminal (residues 606-756) regions were crucial for the nucleolar localization. A chromatin immunoprecipitation (ChIP) assay showed that TdIF2 associated with the promoter of human ribosomal RNA genes (hrDNAP), and an in vitro luciferase assay system showed that it promoted hrDNAP activity. Using the yeast two-hybrid system with TdIF2 as the bait, we isolated the cDNA encoding HIV Tat interactive protein 60 (Tip60), which has histone acetyltransferase (HAT) activity, as a TdIF2-binding protein. TdIF2 bound to Tip60 in vitro and in vivo, inhibited the Tip60 HAT activity in vitro and co-localized with Tip60 within the nucleolus. In addition, TdIF2 promotes upstream binding factor (UBF) acetylation in vivo. Thus, TdIF2 might promote hrDNAP activity by suppressing Tip60's HAT activity and promoting UBF acetylation. PMID- 21668588 TI - Distinctive effects of arachidonic acid and docosahexaenoic acid on neural stem /progenitor cells. AB - Arachidonic acid (ARA) and docosahexaenoic acid (DHA), which are the dominant polyunsaturated fatty acids in the brain, have crucial roles in brain development and function. Recent studies have shown that ARA and DHA promote postnatal neurogenesis. However, the direct effects of ARA on neural stem/progenitor cells (NSPCs) and the effects of ARA and DHA on NSPCs at the neurogenic and subsequent gliogenic stages are still unknown. Here, we analyzed the effects of ARA and DHA on neurogenesis, specifically maintenance and differentiation, using neurosphere assays. We confirmed that primary neurospheres are neurogenic NSPCs and that tertiary neurospheres are gliogenic NSPCs. Regarding the effects of ARA and DHA on neurogenic NSPCs, ARA and DHA increased the number of neurospheres, whereas neither ARA nor DHA had a detectable effect on NSPCs in the differentiation condition. In gliogenic NSPCs, DHA increased the number of neurospheres, whereas ARA had no such effect. In contrast, ARA increased the number of astrocytes, whereas DHA increased the number of neurons in the differentiation condition. These results suggest that ARA promotes the maintenance of neurogenic NSPCs and might induce the glial differentiation of gliogenic NSPCs and that DHA promotes the maintenance of both neurogenic and gliogenic NSPCs and might lead to the neuronal differentiation of gliogenic NSPCs. PMID- 21668589 TI - miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1. AB - The protein known as Spred1 (Sprouty-related Ena/VASP homology-1 domain containing protein) has been identified as a negative regulator of growth factor induced ERK/mitogen-activated protein kinase activation. Spred1 has also been implicated as the target of microRNA-126 (miR126), a miRNA located within the Egfl7 gene, and is involved in the regulation of vessel development through its role in regulating VEGF signaling. In this study, we examined the role of miR126 and Spred1 in the hematopoietic system, as miR126 has been shown to be overexpressed in leukemic cells. miR126 levels were down-regulated during mast cell differentiation from bone marrow cells, whereas Spred1 expression was inversely up-regulated. Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated FcepsilonRI-mediated cytokine production. To confirm the effect of Spred1 reduction in vivo, we generated hematopoietic cell-specific Spred1-conditional knockout mice. These mice showed increased numbers of mast cells, and Spred1-deficient bone marrow-derived mast cells were highly activated by cross-linking of Fcepsilon-R stimulation as well as by IL-3 and SCF stimulation. These results suggest that Spred1 negatively regulates mast cell activation, which is modulated by miR126. PMID- 21668590 TI - First dengue virus detection in Aedes albopictus from Delhi, India: its breeding ecology and role in dengue transmission. AB - OBJECTIVE: To report dengue virus and its disease transmission in Aedes albopictus in the National Capital Territory of Delhi, India. METHODS: Monthly Aedes surveys were carried out in 126 urban localities of Delhi in 2008 and 2009. Pools of all three species of Aedes mosquitoes were tested for Dengue virus (DENV) using an antigen-capture enzyme-linked immunosorbent assay. RESULTS: Aedes aegypti was the most prevalent species, breeding throughout the year. Aedes albopictus was found in 9.52% of surveyed localities including the central urban part of Delhi, in March and from August to October. Aedes albopictus and Aedes vittatus are adapting to breed in manmade containers in the urban areas of Delhi in addition to their natural habitats of bamboo bushes and rock pits. Of the 229 pools of Ae. aegypti and 34 pools of Ae. albopictus tested, 10.5% and 11.76% were positive for dengue virus, respectively. No dengue virus infection was recorded in Ae. vittatus. CONCLUSION: This is the first report of dengue virus in Ae. albopictus from north India. Because DENV was detected in Ae. albopictus, which adapted to manmade containers, both its spread and transmission dynamics should be checked. PMID- 21668591 TI - Socioeconomic differences in diabetes prevalence, awareness, and treatment in rural southwest China. AB - OBJECTIVE: To examine how socioeconomic differences are related to the prevalence, awareness and treatment of diabetes in rural Yunnan province, a relatively undeveloped province in southwest China. METHODS: A cross-sectional survey was conducted from 2008 to 2010; 10,007 consenting individuals aged >= 18 years were selected to participate in the study using a stratified, multistage sampling technique. Information about participants' demographic characteristics, smoking habits, drinking habits, awareness and treatment of diabetes, and family history of diabetes were obtained using a standard questionnaire. Height, weight, waist circumference, hip circumference, fasting blood sugar level and blood pressure were also measured for each individual. Data were analysed using multivariate logistic regression. RESULTS: The age-standardised presence of diabetes was 6.8% in the study population. In diabetic subjects, 28.7% were aware that they had diabetes, and 22.6% had received treatment. After controlling for age, sex, smoking behaviour, drinking behaviour, hypertension, being overweight, central obesity and family history of diabetes, individual educational level was negatively associated with the prevalence of diabetes and positively associated with the awareness and treatment of diabetes. The awareness and treatment of diabetes showed a negative relationship with ethnic minority status and a positive relationship with individual household income. CONCLUSIONS: There are low levels of awareness and treatment among individuals living with diabetes in rural southwest China. Strategies that can enhance public awareness of diabetes and increase access to affordable medications are urgently needed, especially for poor, less educated individuals who belong to ethnic minorities. PMID- 21668592 TI - HIV prevention in southern Africa: why we must reassess our strategies? AB - Southern Africa continues to shoulder a disproportionate burden of the HIV epidemic with the number of new infections outstripping treatment initiation two- to threefold. Current prevention strategies have had a limited impact on the trajectory of the epidemic so far. The history of HIV prevention research is dominated by failed approaches, but recent developments have provided reason for hope. These include the successful male circumcision outcomes in trials in South Africa, Kenya and Uganda, the recent protective outcome of a tenofovir vaginal gel trial in South Africa and the proof that pre-exposure prophylaxis with oral combination tenofovir/emtricitabine can work in men. The latter positive outcome has however been shattered by the early closure of FEM-PrEP for futility. The challenge now is on how to best integrate emerging prevention methods with established strategies, recognising that some of the older methods have never been scaled up to saturation level. PMID- 21668593 TI - Simultaneous hydrocarbon biodegradation and biosurfactant production by oilfield selected bacteria. AB - AIMS: To study the bacterial diversity associated with hydrocarbon biodegradation potentiality and biosurfactant production of Tunisian oilfields bacteria. METHODS AND RESULTS: Eight Tunisian hydrocarbonoclastic oilfields bacteria have been isolated and selected for further characterization studies. Phylogenetic analysis revealed that three thermophilic strains belonged to the genera Geobacillus, Bacillus and Brevibacillus, and that five mesophilic strains belonged to the genera Pseudomonas, Lysinibacillus, Achromobacter and Halomonas. The bacterial strains were cultivated on crude oil as sole carbon and energy sources, in the presence of different NaCl concentrations (1, 5 and 10%, w/v), and at 37 or 55 degrees C. The hydrocarbon biodegradation potential of each strain was quantified by GC-MS. Strain C450R, phylogenetically related to the species Pseudomonas aeruginosa, showed the maximum crude oil degradation potentiality. During the growth of strain C450R on crude oil (2%, v/v), the emulsifying activity (E24) and glycoside content increased and reached values of 77 and 1.33 g l(-1), respectively. In addition, the surface tension (ST) decreased from 68 to 35.1 mN m(-1), suggesting the production of a rhamnolipid biosurfactant. Crude biosurfactant had been partially purified and characterized. It showed interest stability against temperature and salinity increasing and important emulsifying activity against oils and hydrocarbons. CONCLUSIONS: The results of this study showed the presence of diverse aerobic bacteria in Tunisian oilfields including mesophilic, thermophilic and halotolerant strains with interesting aliphatic hydrocarbon degradation potentiality, mainly for the most biosurfactant produced strains. SIGNIFICANCE AND IMPACT OF THE STUDY: It may be suggested that the bacterial isolates are suitable candidates for practical field application for effective in situ bioremediation of hydrocarbon-contaminated sites. PMID- 21668594 TI - Bidirectional insulin granule turnover in the submembrane space during K(+) depolarization-induced secretion. AB - Like primary mouse islets, MIN6 pseudoislets responded to the depolarization by 40 mm KCl and the resulting increase in the free cytosolic Ca(2+) concentration ([Ca(2+) ](i) ) with a massive increase in insulin secretion, whereas 15 mm KCl had little effect in spite of a clear increase in [Ca(2+) ](i) . Analysis of insulin-enhanced green fluorescent protein (EGFP)-labeled granules in MIN6 cells by total internal reflection fluorescence (TIRF) microscopy showed that 40 mm KCl increased the number of short-term resident granules (<1 second presence in the submembrane space), while the total granule number and the number of long-term resident granules decreased. The rates of granule arrival at and departure from the submembrane space changed in parallel and were two orders of magnitude higher than the release rates, suggesting a back-and-forth movement of the granules as the primary determinant of the submembrane granule number. The effect of 15 mm KCl resembled that of 40 mm but did not achieve significance. Both 15 and 40 mm KCl evoked a [Ca(2+) ](i) increase, which was antagonized by 10 um nifedipine. Nifedipine also antagonized the effect on secretion and on granule number and mobility. In conclusion, during KCl depolarization L-type Ca(2+) channels seem to regulate two processes, insulin granule turnover in the submembrane space and granule exocytosis. PMID- 21668596 TI - Plant cation/H+ exchangers (CAXs): biological functions and genetic manipulations. AB - Inorganic cations play decisive roles in many cellular and physiological processes and are essential components of plant nutrition. Therefore, the uptake of cations and their redistribution must be precisely controlled. Vacuolar antiporters are important elements in mediating the intracellular sequestration of these cations. These antiporters are energized by the proton gradient across the vacuolar membrane and allow the rapid transport of cations into the vacuole. CAXs (for CAtion eXchanger) are members of a multigene family and appear to predominately reside on vacuoles. Defining CAX regulation and substrate specificity have been aided by utilising yeast as an experimental tool. Studies in plants suggest CAXs regulate apoplastic Ca(2+) levels in order to optimise cell wall expansion, photosynthesis, transpiration and plant productivity. CAX studies provide the basis for making designer transporters that have been used to develop nutrient enhanced crops and plants for remediating toxic soils. PMID- 21668595 TI - Plasmodium falciparum apicoplast transit peptides are unstructured in vitro and during apicoplast import. AB - Trafficking of soluble proteins to the apicoplast in Plasmodium falciparum is determined by an N-terminal transit peptide (TP) which is necessary and sufficient for apicoplast import. Apicoplast precursor proteins are synthesized at the rough endoplasmic reticulum, but are then specifically sorted from other proteins in the secretory pathway. The mechanism of TP recognition is presently unknown. Apicoplast TPs do not contain a conserved sequence motif; therefore, we asked whether they contain an essential structural motif. Using nuclear magnetic resonance to study a model TP from acyl carrier protein, we found a short, low occupancy helix, but the TP was otherwise disordered. Using an in vivo localization assay, we blocked TP secondary structure by proline mutagenesis, but found robust apicoplast localization. Alternatively, we increased the helical content of the TP through mutation while maintaining established TP characteristics. Apicoplast import was disrupted in a helical mutant TP, but import was then restored by the further addition of a single proline. We conclude that structure in the TP interferes with apicoplast import, and therefore TPs are functionally disordered. These results provide an explanation for the amino acid bias observed in apicoplast TPs. PMID- 21668597 TI - Does facilitating pollinator learning impede deceptive orchid attractiveness? A multi-approach test of avoidance learning. AB - It has often been proposed that nectarless deceptive orchid species exploit naive pollinators in search of food before they learn to avoid their flowers, and that intraspecific floral trait polymorphism, often noted in this plant group, could prolong the time needed for learning, thus increasing orchid reproductive success. We tested the importance of avoidance learning in a European deceptive orchid, Anacamptis morio, which has been reported to have a highly variable fragrance bouquet among individuals. We used an indirect approach, i.e. we facilitated pollinators' ability to learn to avoid A. morio by adding anisaldehyde to selected inflorescences, a scent compound that is easily perceived by the natural pollinators and produced in large quantities by the closely related, nectar producing Anacamptis coriophora, a species that shares pollinator species with A. morio. In a series of three experiments (in artificial arrays, in natural populations and in bumblebee behavioural observations), we consistently found no difference either of reproductive success of or visitation rates to scent-added versus control inflorescences. We also found that the decrease of reproductive success over time in artificial populations of this deceptive species was not as important as expected. Together, these data suggest that pollinators do not fully learn to avoid deceptive inflorescences, and that pollinator avoidance behaviour alone may explain the lower reproductive success usually found in deceptive orchids. We discuss the possible explanations for this pattern in deceptive orchids, particularly in relation to pollinator cognition and learning abilities. Lastly, in light of our results, the potential for higher average reproductive success in deceptive orchids with high phenotypic variability driven by avoidance learning thus appears to be challenged. PMID- 21668598 TI - Reproductive biology of Trichocentrum pumilum: an orchid pollinated by oil collecting bees. AB - The reproductive biology, reward production and pollination mechanism of Trichocentrum pumilum were studied in a gallery forest in the interior of the State of Sao Paulo, southeast Brazil. The floral visitors and pollination mechanism were recorded, and experimental pollinations were carried out in order to determine the breeding system of this species. Trichocentrum pumilum blooms in spring. Each paniculate inflorescence bears an average of 85 flowers that present a central yellow callus and finger-like trichomes on the lateral lobes of the lip. A lipoidal substance is produced and stored among these trichomes. In the studied population, T. pumilum is exclusively visited and pollinated by two bee species (Tetrapedia diversipes and Lophopedia nigrispinis). Pollinaria are deposited on mouthparts of bees during collection of the lipoidal substance from the lateral lobes of the labellum. Trichocentrum pumilum is self-incompatible and pollinator-limited. Natural fruit set was low (9%, compared to 45% in experimentally cross-pollinated flowers). Potentially viable seed exceed 97% in fruits obtained through cross-pollination and in natural conditions (open pollination). PMID- 21668599 TI - Reproductive biology of two Himalayan alpine gingers (Roscoea spp., Zingiberaceae) in China: pollination syndrome and compensatory floral mechanisms. AB - According to the concept of pollination syndromes, floral traits reflect specialisation to a particular pollinator or set of pollinators. However, the reproductive biology of endemic, and often specialised, plants may require increased attention as climate change accelerates worldwide. Species of Roscoea endemic to the Himalayan region have striking orchid-like flowers with long corolla tubes, suggesting pollination by long-tongued insects. Until now, the reproductive biology of species of Roscoea has been poorly documented. We investigated the floral biology, breeding system and pollination ecology of R. cautleoides and R. humeana, from Hengduan Mountains, a global biodiversity hotspot in southwest China. We also tested whether floral longevity increases pollination success. Pollination experiments showed that the two species were self-compatible and depended on insects for fruit production. Over several flowering seasons we did not observe any potential pollinators with long tongues that matched the corolla tube visiting flowers in centres of distribution. The principal pollinators observed were pollen-collecting generalist bees, with low visitation frequencies. In general, members of the ginger family are characterised by short-lived (usually 1 day) flowers, but flowers of R. cautleoides and R. humeana last 8 and 6 days, respectively. Removing stigmas decreased fruit set in both study populations. Our results suggest that the original pollinators may have been long-tongued insects that are now absent from the Chinese Himalayas because habitats have responded to climate change. However, long-lived and self-compatible flowers, coupled with the presence of generalist pollinators, are traits that have allowed these gingers to reproduce and continue to persist in the alpine habitats. PMID- 21668601 TI - Pollen and stigma morphology of some Phaseoleae species (Leguminosae) with different pollinators. AB - Pollen transport to a receptive stigma can be facilitated through different pollinators, which submits the pollen to different selection pressures. This study aimed to associate pollen and stigma morphology with zoophily in species of the tribe Phaseoleae. Species of the genera Erythrina, Macroptilium and Mucuna with different pollinators were chosen. Pollen grains and stigmas were examined under light microscopy (anatomy), scanning electronic microscopy (surface analyses) and transmission electronic microscopy (ultrastructure). The three genera differ in terms of pollen wall ornamentation, pollen size, pollen aperture, thickness of the pollen wall, amount of pollenkitt, pollen hydration status and dominant reserves within the pollen grain, while species within each genus are very similar in most studied characteristics. Most of these features lack relationships to pollinator type, especially in Erythrina and Mucuna. Pollen reserves are discussed on a broad scale, according to the occurrence of protein in the pollen of invertebrate- or vertebrate-pollinated species. Some pollen characteristics are more associated to semi-dry stigma requirements. This apical, compact, cuticularised and secretory stigma occurs in all species investigated. We conclude that data on pollen and stigma structure should be included together with those on floral morphology and pollinator behaviour for the establishment of functional pollination classes. PMID- 21668600 TI - Actin-dependent deposition of putative endosomes and endoplasmic reticulum during early stages of wound healing in characean internodal cells. AB - We investigated the behaviour of organelles stained with FM1-43 (putative endosomes) and/or LysoTracker Red (LTred; acidic compartments) and of the endoplasmic reticulum (ER) during healing of puncture and UV-induced wounds in internodal cells of Nitella flexilis and Chara corallina. Immediately after puncture, wounds were passively sealed with a plug of solid vacuolar inclusions, onto which a bipartite wound wall was actively deposited. The outer, callose containing amorphous layer consisted of remnants of FM1-43- and LTred-labelled organelles, ER cisternae and polysaccharide-containing secretory vesicles, which became deposited in the absence of membrane retrieval (compound exocytosis). During formation of the inner cellulosic layer, exocytosis of secretory vesicles with the newly formed plasma membrane is coupled to endocytosis via coated vesicles. Migration of FM1-43- and LTred-stained organelles, ER and secretory vesicles towards the cell cortex and deposition of a bipartite wound wall could also be induced by spot-like irradiation with ultraviolet light. Cytochalasin D reversibly inhibited the accumulation and deposition of organelles. Our study indicates that active actin-dependent deposition of putative recycling endosomes is required for wound healing (plasma membrane repair) and supports the hypothesis that deposition of ER cisternae helps to restore wounding-disturbed Ca(2+) metabolism. PMID- 21668602 TI - Regulatory interplay of the Sub1A and CIPK15 pathways in the regulation of alpha amylase production in flooded rice plants. AB - Rice (Oryza sativa L.) can successfully germinate and grow even when flooded. Rice varieties possessing the submergence 1A (Sub1A) gene display a distinct flooding-tolerant phenotype, associated with lower carbohydrate consumption and restriction of the fast-elongation phenotype typical of flooding-intolerant rice varieties. Calcineurin B-like interacting protein kinase 15 (CIPK15) was recently indicated as a key regulator of alpha-amylases under oxygen deprivation, linked to both rice germination and flooding tolerance in adult plants. It is still unknown whether the Sub1A- and CIPK15-mediated pathways act as complementary processes for rice survival under O(2) deprivation. In adult plants Sub1A and CIPK15 may perhaps play an antagonistic role in terms of carbohydrate consumption, with Sub1A acting as a starch degradation repressor and CIPK15 as an activator. In this study, we analysed sugar metabolism in the stem of rice plants under water submergence by selecting cultivars with different traits associated with flooding survival. The relation between the Sub1A and the CIPK15 pathways was investigated. The results show that under O(2) deprivation, the CIPK15 pathway is repressed in the tolerant, Sub1A-containing, FR13A variety. CIPK15 is likely to play a role in the up-regulation of Ramy3D in flooding-intolerant rice varieties that display fast elongation under flooding and that do not possess Sub1A. PMID- 21668603 TI - An insight into functional genomics of transgenic lines of tomato cv Rio Grande harbouring yeast halotolerance genes. AB - Tomato cv Rio Grande plants were transformed with yeast halotolerance genes (HAL I or HAL II) using pPM7HAL I or pJRM16HAL II, with p35GUSINT as control. Transformation efficiency varied in the three constructs, with highest transformation found with p35GUSINT. Final selection of the transgenic plants was made on the basis of PCR. Transgene integration and copy number were assessed by Southern hybridisation. The primary transformants were allowed to self-pollinate and the expected Mendelian ratios were studied in second-generation progeny. Five independent homozygous lines each of HAL I and HAL II, as well as the control, were characterised to study inter-transformant expression variability. The transformants showed considerable variability in expression of the respective genes, as shown by salt tolerance assays, chlorophyll content and peroxidase activity. The transgene expression in transgenic lines was analysed by semi quantitative RT-PCR. In response to different salt concentrations, transgenic plants over-expressing HAL I and HAL II had significantly (alpha=0.05) better performance than the control This study presents the comparative responses of the three constructs under the same transformation conditions and suggests possible mechanisms governed by yeast HAL I and HAL II genes, which seem to work in a coordinated manner by relatively decreasing osmotic and oxidative shock at different rates. Our results suggest that the yeast HAL I increases K(+) /Na(+) selectivity and has a more functional role than HAL II in improving salt tolerance of the tomato cv Rio Grande grown in Pakistan. PMID- 21668604 TI - Physiology and proteomics of drought stress acclimation in sunflower (Helianthus annuus L.). AB - An easy and manageable in vitro screening system for drought tolerance of sunflower seedlings based on MS media supplemented with polyethylene glycol 6000 was evaluated. Morphological and physiological parameters were compared between control (-0.05 MPa) and drought-stressed (-0.6 MPa) seedlings of Helianthus annuus L. cv. Peredovick. There was a significant growth deficit in drought stressed plants compared to control plants in terms of hypocotyl length, and shoot and root fresh mass. Shoot growth was more restricted than root growth, resulting in an increased root/shoot ratio of drought-stressed plants. Accumulation of osmolytes such as inositol (65-fold), glucose (58-fold), proline (55-fold), fructose (11-fold) and sucrose (eightfold), in leaves of drought stressed plants could be demonstrated by gas-liquid chromatography. Soluble protein patterns of leaves were analysed with two-dimensional gel electrophoresis (2D-PAGE) and MALDI-TOF mass spectrometry. A set of 46 protein spots allowed identification of 19 marker proteins. Quantitative changes in protein expression of drought-stressed versus control plants were detected. In leaves of drought stressed sunflower seedlings six proteins were significantly up-regulated more than twofold: a putative caffeoyl-CoA 3-O-methyltransferase (4.5-fold), a fructokinase 3 (3.3-fold), a vegetative storage protein (2.5-fold), a glycine rich RNA binding protein (2.2-fold), a CuZn-superoxide dismutase (2.1-fold) and an unknown low molecular weight protein (2.3-fold). These proteins represent general stress proteins induced under drought conditions or proteins contributing to basic carbon metabolism. The up-regulated proteins are interesting candidates for further physiological and molecular investigations regarding drought tolerance in sunflower. PMID- 21668605 TI - Influence of physico-chemical parameters of the aquatic medium on germination of Eichhornia crassipes seeds. AB - The germination of seeds of Eichhornia crassipes in locations distant from the foci of infestation may be a means of dispersal of this invasive plant. Nonetheless, no modern studies have examined the influence of single components on germination, although the influence of temperature, oxygen and redox potential was examined in earlier studies. The effects of pH, conductivity, nitrate, phosphate, potassium, calcium, iron and boron on germination of E. crassipes were determined in seed germination tests. The results showed that external input of nutrients influences germination, since neither pH nor conductivity alone had any effect, but there was a significant increase in germination in growth media containing phosphorus at 3.95 mg.l(-1) (P/L; 95.5%) and boron at 10 mg.l(-1) (B/L; 97.5%); at higher concentrations, the latter was toxic. These findings contribute to knowledge of factors controlling the germination of E. crassipes seeds. Consequently, E. crassipes seeds would find very good conditions for germination in water classified as hypereutrophic, which may play a decisive role in expansion of this plant. PMID- 21668607 TI - Geographic variation in the flood-induced fluctuating temperature requirement for germination in Setaria parviflora seeds. AB - Our aim was to search for specific seed germinative strategies related to flooding escape in Setaria parviflora, a common species across the Americas. For this purpose, we investigated induction after floods, in relation to fluctuating temperature requirements for germination in seeds from mountain, floodplain and successional grasslands. A laboratory experiment was conducted in which seeds were imbibed or immersed in water at 5 degrees C. Seeds were also buried in flood prone and upland grasslands and exhumed during the flooding season. Additionally, seeds were buried in flooded or drained grassland mesocosms. Germination of exhumed seeds was assayed at 25 degrees C or at 20 degrees C/30 degrees C in the dark or in the presence of red light pulses. After submergence or soil flooding, a high fraction (>32%) of seeds from the floodplain required fluctuating temperatures to germinate. In contrast, seeds from the mountains showed maximum differences in germination between fluctuating and constant temperature treatment only after imbibition (35%) or in non-flooded soil conditions (40%). The fluctuating temperature requirement was not clearly related to the foregoing conditions in the successional grassland seeds. Maximum germination could also be attained with red light pulses to seeds from mountain and successional grasslands. Results show that the fluctuating temperature requirement might help floodplain seeds to germinate after floods, indicating a unique feature of the dormancy of S. parviflora seeds from floodplains, which suggests an adaptive advantage aimed at postponing emergence during inundation periods. In contrast, the fluctuating temperature required for germination among seeds from mountain and successional grasslands show its importance for gap detection. PMID- 21668606 TI - Over-expression of gsh1 in the cytosol affects the photosynthetic apparatus and improves the performance of transgenic poplars on heavy metal-contaminated soil. AB - Recent studies of transgenic poplars over-expressing the genes gsh1 and gsh2 encoding gamma-glutamylcysteine synthetase (gamma-ECS) and glutathione synthetase, respectively, provided detailed information on regulation of GSH synthesis, enzymes activities and mRNA expression. In this experiment, we studied quantitative parameters of leaves, assimilating tissues, cells and chloroplasts, mesophyll resistance for CO(2) diffusion, chlorophyll and carbohydrate content in wild-type poplar and transgenic plants over-expressing gsh1 in the cytosol after 3 years of growth in relatively clean (control) or heavy metal-contaminated soil in the field. Over-expression of gsh1 in the cytosol led to a twofold increase of intrafoliar GSH concentration and influenced the photosynthetic apparatus at different levels of organisation, i.e., leaves, photosynthetic cells and chloroplasts. At the control site, transgenic poplars had a twofold smaller total leaf area per plant and a 1.6-fold leaf area per leaf compared to wild-type controls. Annual aboveground biomass gain was reduced by 50% in the transgenic plants. The reduction of leaf area of the transformants was accompanied by a significant decline in total cell number per leaf, indicating suppression of cell division. Over-expression of gamma-ECS in the cytosol also caused changes in mesophyll structure, i.e., a 20% decrease in cell and chloroplast number per leaf area, but also an enhanced volume share of chloroplasts and intercellular airspaces in the leaves. Transgenic and wild poplars did not exhibit differences in chlorophyll and carotenoid content of leaves, but transformants had 1.3-fold fewer soluble carbohydrates. Cultivation on contaminated soil caused a reduction of palisade cell volume and chloroplast number, both per cell and leaf area, in wild-type plants but not in transformants. Biomass accumulation of wild-type poplars decreased in contaminated soil by more than 30-fold, whereas transformants showed a twofold decrease compared to the control site. Thus, poplars over-expressing gamma-ECS in the cytosol were more tolerant to heavy metal stress under field conditions than wild-type plants according to the parameters analysed. Correlation analysis revealed strong dependence of cell number per leaf area unit, chloroplast parameters and mesophyll resistance with the GSH level in poplar leaves. PMID- 21668608 TI - Genetic population structure, fitness variation and the importance of population history in remnant populations of the endangered plant Silene chlorantha (Willd.) Ehrh. (Caryophyllaceae). AB - Habitat fragmentation can lead to a decline of genetic diversity, a potential risk for the survival of natural populations. Fragmented populations can become highly differentiated due to reduced gene flow and genetic drift. A decline in number of individuals can result in lower reproductive fitness due to inbreeding effects. We investigated genetic variation within and between 11 populations of the rare and endangered plant Silene chlorantha in northeastern Germany to support conservation strategies. Genetic diversity was evaluated using AFLP techniques and the results were correlated to fitness traits. Fitness evaluation in nature and in a common garden approach was conducted. Our analysis revealed population differentiation was high and within population genetic diversity was intermediate. A clear population structure was supported by a Bayesian approach, AMOVA and neighbour-joining analysis. No correlation between genetic and geographic distance was found. Our results indicate that patterns of population differentiation were mainly caused by temporal and/or spatial isolation and genetic drift. The fitness evaluation revealed that pollinator limitation and habitat quality seem, at present, to be more important to reproductive fitness than genetic diversity by itself. Populations of S. chlorantha with low genetic diversity have the potential to increase in individual number if habitat conditions improve. This was detected in a single large population in the investigation area, which was formerly affected by bottleneck effects. PMID- 21668609 TI - Genetic variation in Mediterranean Helichrysum italicum (Asteraceae; Gnaphalieae): do disjunct populations of subsp. microphyllum have a common origin? AB - The yellow-flowered everlasting daisy Helichrysum italicum (Asteraceae, Gnaphalieae) is widely distributed in the Mediterranean basin, where it grows in continuous and widespread populations in diverse open habitats. Helichrysum italicum subsp. microphyllum has a disjunct distribution in the Balearic Islands (Majorca and Dragonera), Corsica, Sardinia, Crete and Cyprus. Numerous morphological intermediates between subsp. italicum and subsp. microphyllum are known from Corsica, where the two subspecies co-occur. The aims of the study were to investigate if subsp. microphyllum has a common origin, constituting an independent gene pool from subsp. italicum, or if the morphological differences between subsp. microphyllum and subsp. italicum have arisen independently in different locations from a common wider gene pool. Our analyses of AFLP, cpDNA sequences and morphological characters show that there is geographic structure to the genetic variation within H. italicum, with eastern and western Mediterranean groups, which do not correspond with the division into subsp. microphyllum and subsp. italicum as currently circumscribed. Local selection on quantitative trait loci provides sufficient explanation for the morphological divergence observed and is consistent with genetic data. Within the western Mediterranean group of the species we found considerable polymorphism in chloroplast DNA sequences among and within some populations. Comparison with chloroplast DNA sequences from other Helichrysum species showed that some chloroplast haplotypes are shared across species. PMID- 21668610 TI - The protective shell: sclereids and their mechanical function in corollas of some species of Camellia (Theaceae). AB - Studies of rain-wash effects on pollen have shown that flower structures can protect susceptible pollen from rain. It remains unclear, however, how a thin corolla can withstand external force and perform its protective function. The sclereids in petals of several species of Camellia (Theaceae) were anatomically investigated to determine their mechanical properties. To examine the effects of changing physical environment on the occurrence of sclereids in petals, sclereid density in petals of six species, including wild samples from different rainfall zones and samples from a greenhouse under mild conditions without wind and rain, were examined and statistically analysed. The results showed that the occurrence of sclereids in petals varied with physical environment. The number of sclereids in the same species increased with the increasing rainfall. There were abundant sclereids in petals of the wild species, but few or no sclereids in species cultivated in the greenhouse. Moreover, the anatomical features of sclereids, especially the unique distribution pattern that has not hitherto been described, were correlated with external environmental pressures. Our observations reveal a novel mechanical system in the corolla and provide further evidence for the hypothesis that flower structures may protect rain-susceptible pollen. PMID- 21668611 TI - Development of glutathione-deficient embryos in Arabidopsis is influenced by the maternal level of glutathione. AB - Glutathione (GSH) biosynthesis-deficient gsh1 and gsh2 null mutants of Arabidopsis thaliana have late embryonic-lethal and early seedling-lethal phenotypes, respectively, when segregating from a phenotypically wild-type parent plant, indicating that GSH is required for seed maturation and during germination. In this study, we show that gsh2 embryos generated in a partially GSH-deficient parent plant, homozygous for either the cad2 mutation in the GSH1 gene or homozygous for mutations in CLT1, CLT2 and CLT3 encoding plastid thiol transporters, abort early in embryogenesis. In contrast, individuals homozygous for the same combinations of mutations but segregating from heterozygous, phenotypically wild-type parents exhibit the parental gsh2 seedling-lethal phenotype. Similarly, homozygous gsh1 embryos generated in a gsh1/cad2 partially GSH-deficient parent plant abort early in development. These observations indicate that the development of gsh1 and gsh2 embryos to a late stage is dependent on the level of GSH in the maternal plant. PMID- 21668612 TI - Technical comment on Kroeker et al. (2010) Meta-analysis reveals negative yet variable effects of ocean acidification on marine organisms. Ecology Letters, 13, 1419-1434. AB - Meta-analysis of experimental results has been interpreted to imply that the calcification response of organisms depositing high Mg-calcite is more resilient to ocean acidification than organisms depositing aragonite/calcite. This conclusion might be biased by inadequate recognition and categorisation of high Mg-calcite according to mineral solubility. PMID- 21668613 TI - Nursing and the political. PMID- 21668615 TI - The incommensurability of nursing as a practice and the customer service model: an evolutionary threat to the discipline. AB - Corporate and commercial values are inducing some healthcare organizations to prescribe a customer service model that reframes the provision of nursing care. In this paper it is argued that such a model is incommensurable with nursing conceived as a moral practice and ultimately places nurses at risk. Based upon understanding from ongoing research on compassion fatigue, it is proposed that compassion fatigue as currently experienced by nurses may not arise predominantly from too great a demand for compassion, but rather from barriers to enacting compassionate care. These barriers are often systemic. The paradigm shift in which healthcare environments are viewed as marketplaces rather than moral communities has the potential to radically affect the evolution of nursing as a discipline. PMID- 21668616 TI - The 'well-run' system and its antimonies. AB - An aim of all of the management of healthcare systems is the smooth provision of services. A great deal of effort is put into ensuring processes will obtain this ideal--the well-run system. The central argument in this paper is that these processes result in a system that perpetrates violence and coercion on its clients and workers. This violence is structural and personalizing in its effects. Moreover, time and effort is taken away from the actual work of the system for its management. Under such managerialist control, the idea of chaos and the need to ensure order are used to fuel an apparatus that takes the focus from other aspects of the system such as the power relations that keep the system as it is. In such an ordering, the clinical audit is promoted as a method to ensure order by keeping ahead of, or removing the potential for chaos. In using Zizek's ideas about violence it is possible to identify how efforts and attempts to correct the system are doomed to fail just as they hide how nurses' enrolment in the service of the system leads to alienation and subjectification. A central aim of this paper is to rethink how power and implicit violence are practised in such processes. To overcome the inherent violence of the audit culture, this paper suggests an interruption of audit cultures with a promotion of more radical positions for nursing practice and clinically based research. The hope is to recalculate and interrupt how nurses are to operate in the management structures that organize healthcare. PMID- 21668617 TI - Stance and strategy: post-structural perspective and post-colonial engagement to develop nursing knowledge. AB - How should nursing knowledge advance? This exploration contextualizes its evolution past and present. In addressing how it evolved in the past, a probable historical evolution of its development draws on the perspectives of Frank & Gills's World System Theory, Kuhn's treatise on Scientific Revolutions, and Foucault's notions of Discontinuities in scientific knowledge development. By describing plausible scenarios of how nursing knowledge evolved, I create a case for why nursing knowledge developers should adopt a post-structural stance in prioritizing their research agenda(s). Further, by adopting a post-structural stance, I create a case on how nurses can advance their disciplinary knowledge using an engaging post-colonial strategy. Given an interrupted history caused by influence(s) constraining nursing's knowledge development by power structures external, and internal, to nursing, knowledge development can evolve in the future by drawing on post-structural interpretation, and post-colonial strategy. The post-structural writings of Deleuze & Guattari's understanding of 'Nomadology' as a subtle means to resist being constrained by existing knowledge development structures, might be a useful stance to understanding the urgency of why nursing knowledge should advance addressing the structural influences on its development. Furthermore, Bhabha's post-colonial elucidation of 'Hybridity' as an equally discreet means to change the culture of those constraining structures is an appropriate strategy to enact how nursing knowledge developers can engage with existing power structures, and simultaneously influence that engagement. Taken together, 'post-structural stance' and 'post-colonial strategy' can refocus nursing scholarship to learn from its past, in order to develop relevant disciplinary knowledge in its future. PMID- 21668618 TI - Serving two (or more) masters: accomplishing autonomous nursing practice in chronic disease management. AB - The concept of professional autonomy has figured prominently in literature that addresses nursing's project of professionalization. Nursing's capacity to determine the nature and scope of its practice is related in important ways to the location of practice. Within highly structured environments such as acute care hospitals, nurses' professional autonomy has frequently been contested yet is often implicated by nursing's elite as a necessary condition in the construction of quality work environments. Professional concerns and management practices related to retaining experienced nurses to support sustainability in healthcare delivery systems' impact on the ability of nurses to practice autonomously. Our paper focuses on the emerging field of practice of chronic disease management. We describe the complex relationships negotiated by a nurse in a theoretically autonomous practice setting as she seeks to fulfil both the requirements of a research protocol designed by physician experts representing the specialty of renal medicine, and her professional obligations to respond to the expressed needs of patients with early-stage renal disease. We utilize a case study approach to explore particular contemporary concerns that nurses in practice confront as they attempt to accomplish professional relationships with patients central to achieving prescribed medical outcomes where nursing practice, as an element of the achievement of those outcomes, is constituted as absent or unacknowledged by the medical researchers leading the project. Implications for nursing's discourses on the professional project of autonomy will be discussed. PMID- 21668619 TI - Maths for medications: an analytical exemplar of the social organization of nurses' knowledge. AB - Within the literature that circulates in the discourses organizing nursing education, there are embedded assumptions that link student performance on maths examinations to safe medication practices. These assumptions are rooted historically. They fundamentally shape educational approaches assumed to support safe practice and protect patients from nursing error. Here, we apply an institutional ethnographic lens to the body of literature that both supports and critiques the emphasis on numeracy skills and medication safety. We use this form of inquiry to open an alternate interrogation of these practices. Our main argument posits that numeracy skills serve as powerful distraction for both students and teachers. We suggest that they operate under specious claims of safety and objectivity. As nurse educators, we are captured by taken-for-granted understandings of practices intended to produce safety. We contend that some of these practices are not congruent with how competency actually unfolds in the everyday world of nursing practice. Ontologically grounded in the materiality of work processes, we suggest there is a serious disjuncture between educators' assessment and evaluation work where it links into broad nursing assumptions about medication work. These underlying assumptions and work processes produce contradictory tensions for students, teachers and nurses in direct practice. PMID- 21668620 TI - Pharmaceutical industry discursives and the marketization of nursing work: a case example. AB - Increasing pharmaceutical industry presence in health care research and practice has evoked critical social, political, economic, and ethical questions and concern among health care providers, ethicists, economists, and the general citizenry. The case example presented of the 'marketization' of nursing practice not only reveals the magnitude of the purview of the pharmaceutical industry, it demonstrates how that industry imparts effect upon the organization of nursing work, an area of health care professional practice where the ethical polemic of pharmaceutical industry involvement and influence has been largely ignored, and the profession of nursing conspicuously silent. Drawing on a Foucauldian dispositive analysis that troubled the complex apparatus responsible for the production of knowledge and action in the neurology subspecialty of multiple sclerosis (MS), the case discloses how the pharmaceutical industry has created compliance and adherence as clinical imperatives in the practice of MS nursing. The case makes explicit the conscious transformative self-action undertaken by MS nurses as a result of their subjectivation (marketization) and demonstrates how MS nurses have become pawns in pharmaceutical industry strategic games of power, truth, identity, and wealth creation by turning their clinical practice settings into heterodiscursive spaces of surveillance and persuasion. MS nurses have become instruments of the pharmaceutical industry, and their clinical practices ordered, organized, limited, constrained, and marketized as a result. PMID- 21668621 TI - Places inarticulately close. PMID- 21668622 TI - Engineering virus resistance using a modified potato gene. AB - Natural mutations in translation initiation factor eIF4E confer resistance to potyviruses in many plant species. Potato is a staple food crop plagued by several potyviruses, yet to date no known eIF4E-mediated resistance genes have been identified. In this study, we demonstrate that transgenic expression of the pvr1(2) gene from pepper confers resistance to Potato virus Y (PVY) in potato. We then use this information to convert the susceptible potato ortholog of this allele into a de novo allele for resistance to PVY using site-directed mutagenesis. Potato plants overexpressing the mutated potato allele are resistant to virus infection. Resistant lines expressed high levels of eIF4E mRNA and protein. The resistant plants showed growth similar to untransformed controls and produced phenotypically similar tubers. This technique disrupts a key step in the viral infection process and may potentially be used to engineer virus resistance in a number of economically important plant-viral pathosystems. Furthermore, the general public may be more amenable to the 'intragenic' nature of this approach because the transferred coding region is modified from a gene in the target crop rather than from a distant species. PMID- 21668624 TI - Vascularized bone marrow-based immunosuppression inhibits rejection of vascularized composite allografts in nonhuman primates. AB - Vascularized composite allograft (VCA) transplantation (also referred to as composite tissue allotransplantation) has demonstrated clinical success in cases of hand, arm and face transplantation despite prior belief that skin provides an insurmountable barrier to allograft rejection. These overall good outcomes are facilitated by substantial immunosuppressive requirements in otherwise healthy patients, yet still demonstrate frequent rejection episodes. We developed a nonhuman primate model of facial segment allotransplantation to elucidate the unique pathophysiology and immunosuppressive requirements of VCA with addition of concomitant vascularized bone marrow (VBM). Heterotopically transplanted facial segment VCA with VBM treated only with tacrolimus and mycophenolate mofetil (MMF) demonstrated prolonged rejection-free survival, compared to VCA without VBM that demonstrated early rejection episodes and graft loss. While VCA with VBM demonstrated sporadic macrochimerism, acute and chronic rejection and graft loss occurred after discontinuation of immunosuppression. These data support an immunomodulatory role of VBM in VCA that reduces immunosuppressive requirements while providing improved outcomes. PMID- 21668623 TI - Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. AB - Aging is a major risk factor for chronic disease in the human population, but there are little human data on gene expression alterations that accompany the process. We examined human peripheral blood leukocyte in-vivo RNA in a large scale transcriptomic microarray study (subjects aged 30-104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n= 58), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. Of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age associated, in gene set enrichment analysis, notably including the processing of messenger RNAs (mRNAs); [P<0.002, false discovery rate (FDR) q<0.05]. This is supported by our observation of age-associated disruption to the balance of alternatively expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging. PMID- 21668626 TI - Mastering the risk of HLA antibodies in kidney transplantation: an algorithm based on pretransplant single-antigen flow bead techniques. AB - The utilization of sensitive techniques of detection of HLA antibodies to define and measure sensitization has greatly evolved in recent years. We present here an approach to minimize the risk of HLA antibodies in kidney transplantation based on the evaluation of graft accessibility of sensitized patients by calculated PRA (cPRA) and estimation of potential matched donors (PMD) using a national simulation software program. This study included all registered patients on our waiting list (WL) for deceased donor (DD) kidney transplants. All patients were screened by single-antigen flow bead (SAFB) techniques. Of the 502 registered patients, 174 (34.7%) were sensitized. Among these, 48.3% (84 pts) had a cPRA>85%. For 75.3% of sensitized patients (90 pts with cPRA<=85% and 41 pts with cPRA>85%), the flow of PMD was considered sufficient to allow a transplant avoiding all unacceptable antigens. The 41 patients with a cPRA>85% (48.8%) had a satisfactory donor flow in the framework of the national prioritization program for highly sensitized patients. Finally, 43 sensitized patients (24.7%) were deemed eligible for a strategy of higher immunological risk through desensitization protocols or transplantation against HLA-DSAs. This approach provides a logical and systematic strategy to rationalize the access of sensitized patients to kidney transplantation minimizing the risk of HLA antibodies. PMID- 21668625 TI - Targeting B cells and antibody in transplantation. AB - There has been increasing interest in the role played by B cells, plasma cells and their associated antibody in the immune response to an allograft, driven by the need to undertake antibody-incompatible transplantation and evidence suggesting that B cells play a role in acute cellular rejection and in acute and chronic antibody-mediated rejection. A number of immunosuppressive agents have emerged which target B cells, plasma cells and/or antibody, for example, the B cell-depleting CD20 antibody rituximab. This review describes recent developments in the use of such agents, our understanding of the role of B cells in alloimmunity and the application of this knowledge toward novel therapies in transplantation. It also considers the evidence to date suggesting that B cells may act as regulators of an alloimmune response. Thus, future attempts to target B cells will need to address the problem of how to inhibit effector B cells, while enhancing those with regulatory capacity. PMID- 21668627 TI - Anti-complement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice. AB - While activation of serum complement mediates antibody-initiated vascular allograft injury, increasing evidence indicates that complement also functions as a modulator of alloreactive T cells. We tested whether blockade of complement activation at the C5 convertase step affects T cell-mediated cardiac allograft rejection in mice. The anti-C5 mAb BB5.1, which prevents the formation of C5a and C5b, synergized with subtherapeutic doses of CTLA4Ig to significantly prolong the survival of C57BL/6 heart grafts that were transplanted into naive BALB/c recipients. Anti-C5 mAb treatment limited the induction of donor-specific IFNgamma-producing T cell alloimmunity without inducing Th2 or Th17 immunity in vivo and inhibited primed T cells from responding to donor antigens in secondary mixed lymphocyte responses. Additional administration of anti-C5 mAb to the donor prior to graft recovery further prolonged graft survival and concomitantly reduced both the in vivo trafficking of primed T cells into the transplanted allograft and decreased expression of T cell chemoattractant chemokines within the graft. Together these results support the novel concept that C5 blockade can inhibit T cell-mediated allograft rejection through multiple mechanisms, and suggest that C5 blockade may constitute a viable strategy to prevent and/or treat T cell-mediated allograft rejection in humans. PMID- 21668628 TI - Kidney transplantation from donors after cardiac death: uncontrolled versus controlled donation. AB - Kidney donation after cardiac death has been popularized over the last decade. The majority of these kidneys are from controlled donors. The number of organs for transplantation can be further increased by uncontrolled donors after cardiac death. The outcome of uncontrolled compared to controlled donor kidney transplantation is relatively unknown. We compared the long-term outcome of kidney transplantation from uncontrolled (n = 128) and controlled (n = 208) donor kidneys procured in the Maastricht region from January 1, 1981 until January 1, 2008, and transplanted in the Eurotransplant region. The incidence of primary nonfunction and delayed graft function in both uncontrolled and controlled donor kidneys is relatively high (22% vs. 21%, and 61% vs. 56%, p = 0.43, respectively). Ten-year graft and recipient survival are similar in both groups (50% vs. 46%, p = 0.74 and 61% vs. 60%, p = 0.76, respectively). Estimated glomerular filtration rates 1 year after transplantation are 40 +/- 16 versus 42 +/- 19 mL/min/1.73 m(2) , p = 0.55, with a yearly decline thereafter of 0.67 +/- 3 versus 0.70 +/- 7 mL/min/1.73 m(2) /year, p = 0.97. The outcome of kidney transplantation from uncontrolled and controlled donors after cardiac death is equivalent. This justifies the expansion of the donor pool with uncontrolled donors to reduce the still growing waiting list for renal transplantation, and may stimulate the implementation of uncontrolled kidney donation programs. PMID- 21668629 TI - Very late heart transplant rejection is associated with microvascular injury, complement deposition and progression to cardiac allograft vasculopathy. AB - In heart transplants, the significance of very late rejection (after 7 years post transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical >=3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSA(max) -MFI = 1751 +/- 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow up postreference EMB of 6.4 +/- 1 years, the mean of CAV grade was 0.76 +/- 0.18 in the control group compared to 2.06 +/- 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up. PMID- 21668630 TI - The emerging role of Brazil in clinical trial conduct for transplantation. AB - Brazil is a country with over 190 000 000 inhabitants and a health system composed of a large public, government managed system. Between 1999 and 2010 the number of deceased donors increased by 161%, from 3.8 to 9.9 pmp, and the number of solid organ transplants increased by 121%, from 2891 to 6402. This growth was a consequence of the creation of a well-organized national transplant program. Government funding, decentralization and educational investment in transplant coordinators and related professional were decisive. In 2009 Brazil was the second largest country in the absolute number of kidney transplants (n = 4259). There are significant region disparities in performance which are mainly due to the development status. Improvements in transplant and research regulations resulted in an increasing participation of Brazilian transplant centers in multicenter trials, reaching over 44 studies during the last 11 years. Brazilian centers have been involved in clinical trials using everolimus, sirolimus, fingolimod, mycophenolate mofetyl, mycophenolate sodium, tacrolimus modified release, sotrastaurin, belatacept, JAK3 inhibitor CP690,550 and valganciclovir. The still increasing number of transplants performed every year along with more efficient regulatory and sanitary analysis, organized clinical research programs and reduction in region performance disparities will eventually increase even more the participation of Brazil in trials worldwide. PMID- 21668631 TI - Treprostinil, a prostacyclin analog, ameliorates ischemia-reperfusion injury in rat orthotopic liver transplantation. AB - Prostaglandins have been evaluated for their ability to reduce IRI after liver transplantation; however, poor stability, side effects and the inability to show a significant difference in primary endpoint have limited their clinical application. Treprostinil, a prostacyclin (PGI(2) ) analog, has a higher potency and longer elimination half-life than other commercially available PGI(2) analogs. We examined the efficacy of treprostinil to prevent IRI during OLT. OLT was performed in syngeneic Lewis rats after 18 h of cold preservation (4 degrees C) in the UW solution. IRI significantly increased serum ALT and AST levels, neutrophil infiltration, hepatic necrosis and mRNA levels of proinflammatory cytokines post-OLT, while treatment with treprostinil decreased all the parameters. Cold storage of liver grafts significantly reduced ATP levels and treprostinil restored energy levels in liver grafts early postreperfusion. In addition, treprostinil preserved the sinusoidal endothelial cell lining and reduced platelet deposition early post-transplantation compared to placebo. Hepatic tissue blood flow was significantly compromised in the placebo group, whereas treprostinil maintained blood-flow similar to normal levels. Treprostinil protected the liver graft against IRI during OLT. Treprostinil has the potential to serve as a therapeutic option to protect the liver graft against I/R injury in patients undergoing OLT. PMID- 21668632 TI - Can the dropout risk of candidates with hepatocellular carcinoma predict survival after liver transplantation? AB - In the last US national conference on liver transplantation for hepatocellular carcinoma (HCC), a continuous priority score, that incorporates model for end stage liver disease (MELD), alpha-fetoprotein and tumor size, was recommended to ensure a more equitable liver allocation. However, prioritizing highest alpha fetoprotein levels or largest tumors may select lesions at a higher risk for recurrence; similarly, patients with higher degree of liver failure could have lower postoperative survival. Data from 300 adult HCC recipients were reviewed and the proposed HCC-MELD equation was applied to verify if it can predict post transplantation survival. The 5-year survival and recurrence rates after transplantation were 72.8 and 13.5%, respectively. Cox regression analysis confirmed HCC-MELD as predictive of both postoperative survival and recurrence (p < 0.001). The 5-year predicted survival and recurrence rates were plotted against the HCC-MELD-based dropout probability: the higher the dropout probability while on waiting list, the lower the predicted survival after transplantation, that is worsened by hepatitis C positivity; similarly, the higher the predicted HCC recurrence rate after transplantation. The HCC priority score could predict the postoperative survival of HCC recipients and could be useful in selecting patients with greater possibilities of survival, resulting in higher post transplantation survival rates of HCC populations. PMID- 21668633 TI - Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients. AB - Prolonged-release tacrolimus was developed to provide a more convenient once daily dosing that could improve patient adherence. We conducted a multicenter, prospective, observational, 12-month study to describe the efficacy, safety and patient preference of conversion from tacrolimus twice-daily to once-daily formulation in stable kidney transplant recipients in routine clinical practice. Conversion was made on a 1 mg: 1 mg basis (1 mg: 1.1 mg in patients with trough levels <6 ng/mL). The study included 1832 patients (mean age (+/- SD): 50.0 +/- 13.4 years; 62.7% male). After conversion, a modest reduction in tacrolimus trough levels, necessitating an increase in daily dose, was observed (mean changes at 12 months of -9.1% and +1.24%, respectively; p < 0.0001). Mean glomerular filtration rate did not change significantly (56.5 +/- 19.7 mL/min at conversion vs. 55.7 +/- 20.6 mL/min at 12 months). Proteinuria, blood pressure, lipid, hepatic and glucose parameters remained stable. Eight patients (0.4%) had acute rejection and 34 patients (1.85%) discontinued treatment. Almost all patients (99.4%) preferred the once-daily formulation, because of less frequent dosing (66%) and improved adherence (34%). In conclusion, at similar doses to twice-daily tacrolimus, once-daily formulation provided stable renal function, a low acute rejection rate, and good tolerability in stable kidney transplant recipients in the routine clinical practice setting. PMID- 21668634 TI - Acute renal endothelial injury during marrow recovery in a cohort of combined kidney and bone marrow allografts. AB - An idiopathic capillary leak syndrome ('engraftment syndrome') often occurs in recipients of hematopoietic cells, manifested clinically by transient azotemia and sometimes fever and fluid retention. Here, we report the renal pathology in 10 recipients of combined bone marrow and kidney allografts. Nine developed graft dysfunction on day 10-16 and renal biopsies showed marked acute tubular injury, with interstitial edema, hemorrhage and capillary congestion, with little or no interstitial infiltrate (<=10%) and marked glomerular and peritubular capillary (PTC) endothelial injury and loss by electron microscopy. Two had transient arterial endothelial inflammation; and 2 had C4d deposition. The cells in capillaries were primarily CD68(+) MPO(+) mononuclear cells and CD3(+) CD8(+) T cells, the latter with a high proliferative index (Ki67(+) ). B cells (CD20(+) ) and CD4(+) T cells were not detectable, and NK cells were rare. XY FISH showed that CD45(+) cells in PTCs were of recipient origin. Optimal treatment remains to be defined; two recovered without additional therapy, six were treated with anti rejection regimens. Except for one patient, who later developed thrombotic microangiopathy and one with acute humoral rejection, all fully recovered within 2-4 weeks. Graft endothelium is the primary target of this process, attributable to as yet obscure mechanisms, arising during leukocyte recovery. PMID- 21668635 TI - The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients. AB - Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients. PMID- 21668636 TI - How to use mTOR inhibitors? The search goes on. PMID- 21668637 TI - Blood group A isoagglutinins in A(2) -> O simultaneous liver/kidney transplantation may not influence kidney function. AB - We simultaneously transplanted a liver and kidney (SLK) into a 55-year-old woman with end-stage liver disease secondary to recurrent primary biliary cirrhosis. The patient was blood group O, the donor was A(2) (A, non-A1) and the patient's A isoagglutinin titer was 512. Good renal function was evident by normalization of her creatinine values following transplantation. Recovery was unremarkable and she was discharged on post op day 9. The patient has not experienced an episode of rejection in either organ during the 6 months of follow-up. This case is important because high A IgG isoagglutinin levels (8 or higher) in kidney alone A(2) -> O transplantation are detrimental to outcome but do not affect outcome in liver alone A(2) -> O transplants; however, no such anti-A titer data have been published for A(2) -> O (or B) SLK transplantation. PMID- 21668638 TI - Passive transient transfer of peanut allergy by liver transplantation. AB - We report a case of transient symptomatic transferred IgE-mediated peanut allergy after elective blood-group compatible liver transplantation. We show that the allergy was transient and therefore passive, authorizing further uneventful peanut consumption. Skin tests with commercial peanut extract and native peanut were performed in the recipient. Circulating specific IgE against peanut and recombinant peanut allergens (rArah1, rArah2, rArah3) was measured in stored serum samples collected from the recipient between 6 months before and 8 months after liver transplantation. Specific IgE levels in the donor were measured at the time of multiorgan donation. In the recipient, diagnosis of IgE-mediated peanut anaphylaxis was based on the clinical history and detection of specific IgE against peanut and recombinant major peanut allergens (rArah1, rArah2 and rArah3). Skin tests were negative and specific IgE undetectable 6 months after the clinical reaction. Oral peanut challenge was negative excluding persistent peanut allergy. This case confirms that IgE-mediated peanut allergy can be transferred by liver transplantation and shows that it may be transient and therefore passively acquired. PMID- 21668639 TI - Left renal vein ligation: a technique to mitigate low portal flow from splenic vein siphon during liver transplantation. AB - Low portal vein flows in liver transplant have been associated with poor allograft survival. Identifying and ameliorating causes of inadequate portal flow is paramount. We describe successful reversal of significant splenic vein siphon from a spontaneous splenorenal shunt during liver transplant. The patient is a 43 year-old male with cirrhosis from hepatitis C and Budd-Chiari syndrome, who had a variceal hemorrhage necessitating an emergent splenorenal shunt with 8 mm PTFE graft. Imaging in 2006 revealed thrombosis of the splenorenal shunt and evidence of a new spontaneous splenorenal shunt. The patient developed hepatocellular carcinoma and underwent transplant in 2009. After reperfusion, portal flows were low (150-200 mL/min). A mesenteric varix was ligated without improvement. Due to adhesions, direct collateral ligation was not attempted. In order to redirect the splenic siphon, the left renal vein was stapled at its confluence with the inferior vena cava. Portal flows subsequently increased to 1.28 L/min. Postoperatively, the patient had stable renal and liver function. We conclude that spontaneous splenorenal shunts can cause low portal flows. A diligent search for shunts with understanding of flow patterns is critical; ligation or rerouting of splanchnic flow may be necessary to improve portal flows and allograft outcomes. PMID- 21668641 TI - Uncontrolled donation after circulatory determination of death (UDCDD) and the definition of death. PMID- 21668640 TI - Liver ischemia and reperfusion injury: new insights into mechanisms of innate adaptive immune-mediated tissue inflammation. AB - Ischemia and reperfusion injury (IRI) is a dynamic process that involves two distinctive yet interrelated phases of ischemic organ damage and inflammation mediated reperfusion injury. Although multiple cellular and molecular pathways contribute and regulate tissue/organ damage, integration of different players into a unified mechanism is warranted. The crosstalk between innate and adaptive immune systems plays a significant role in the pathogenesis of liver IRI. In this review, we focus on recent progress in the mechanism of liver innate immune activation by IR. Kupffer cells (KC), DCs, NK, as well as T cells initiate local inflammation response, the hallmark of IRI, by utilizing distinctive immune receptors to recognize and/or trigger various molecules, both endogenous and exogenous. The interlocked molecular signaling pathways in the context of multiple liver cell types, the IRI kinetics and positive versus negative regulatory loops in the innate immune activation process are discussed. Better appreciation of molecular interactions that mediate these intricate cascades, should allow for the development of novel therapeutic approached against IRI in liver transplant recipients. PMID- 21668642 TI - Anti-Cw donor-specific alloantibodies can lead to positive flow cytometry crossmatch and irreversible acute antibody-mediated rejection. PMID- 21668643 TI - BRICHOS domain associated with lung fibrosis, dementia and cancer--a chaperone that prevents amyloid fibril formation? AB - The BRICHOS domain was initially defined from sequence alignments of the Bri protein associated with familial dementia, chondromodulin associated with chondrosarcoma and surfactant protein C precursor (proSP-C) associated with respiratory distress syndrome and interstitial lung disease (ILD). Today BRICHOS has been found in 12 protein families. Mutations in the Bri2 and proSP-C genes result in familial dementia and ILD, respectively, and both these conditions are associated with amyloid formation. Amyloid is of great medical relevance as it is found in several major incurable diseases, like Alzheimer's and Parkinson's disease and diabetes mellitus. Work on recombinant BRICHOS domains and transfected cells indicate that BRICHOS is a chaperone domain that, during biosynthesis, binds to precursor protein regions with high beta-sheet propensities, thereby preventing them from amyloid formation. Regions prone to form beta-sheets are present in all BRICHOS-containing precursor proteins and are probably eventually released by proteolytic cleavage, generating different peptides with largely unknown bioactivities. Recombinant BRICHOS domains from Bri2 and proSP-C have been found to efficiently prevent SP-C, the amyloid beta peptide associated with Alzheimer's disease, and medin, found in aortic amyloid, from forming amyloid fibrils. The data collected so far on BRICHOS raise several interesting topics for further research: (a) amyloid formation is a potential threat for many more proteins than the ones recognized so far in amyloid diseases; (b) amyloid formation of widely different peptides involves intermediate(s) that are recognized by the BRICHOS domain, suggesting that they have distinct structural similarities; and (c) the BRICHOS domain might be harnessed in therapeutic strategies against amyloid diseases. PMID- 21668644 TI - Crystal structures of open and closed forms of d-serine deaminase from Salmonella typhimurium - implications on substrate specificity and catalysis. AB - Metabolism of D-amino acids is of considerable interest due to their key importance in cell structure and function. Salmonella typhimuriumd-serine deaminase (StDSD) is a pyridoxal 5' phosphate (PLP) dependent enzyme that catalyses degradation of D-Ser to pyruvate and ammonia. The first crystal structure of d-serine deaminase described here reveals a typical Foldtype II or tryptophan synthase beta subunit fold of PLP-dependent enzymes. Although holoenzyme was used for crystallization of both wild-type StDSD (WtDSD) and selenomethionine labelled StDSD (SeMetDSD), significant electron density was not observed for the cofactor, indicating that the enzyme has a low affinity for the cofactor under crystallization conditions. Interestingly, unexpected conformational differences were observed between the two structures. The WtDSD was in an open conformation while SeMetDSD, crystallized in the presence of isoserine, was in a closed conformation suggesting that the enzyme is likely to undergo conformational changes upon binding of substrate as observed in other Foldtype II PLP-dependent enzymes. Electron density corresponding to a plausible sodium ion was found near the active site of the closed but not in the open state of the enzyme. Examination of the active site and substrate modelling suggests that Thr166 may be involved in abstraction of proton from the Calpha atom of the substrate. Apart from the physiological reaction, StDSD catalyses alpha, beta elimination of D-Thr, D-Allothr and L-Ser to the corresponding alpha-keto acids and ammonia. The structure of StDSD provides a molecular framework necessary for understanding differences in the rate of reaction with these substrates. PMID- 21668645 TI - A short-chain dehydrogenase involved in terpene metabolism from Zingiber zerumbet. AB - The rhizome oil of Zingiber zerumbet Smith contains an exceptionally high content of sesquiterpenoids with zerumbone, a predominating potential multi-anticancer agent. Biosynthetic pathways of zerumbone have been proposed, and two genes ZSS1 and CYP71BA1 that encode the enzymes catalyzing the first two steps have been cloned. In this paper, we isolated a cDNA clone (ZSD1) that encodes an alcohol dehydrogenase capable of catalyzing the final step of zerumbone biosynthesis. ZSD1 has an open reading frame of 804 bp that encodes a 267-residue enzyme with a calculated molecular mass of 28.7 kDa. After expression in Escherichia coli, the recombinant enzyme was found to catalyze 8-hydroxy-alpha-humulene into zerumbone. ZSD1 is a member of the short-chain dehydrogenase/reductase superfamily (SDR) and shares high identities with other plant SDRs involved in secondary metabolism, stress responses and phytosteroid biosynthesis. In contrast to the transcripts of ZSS1 and CYP71BA1, which are almost exclusively expressed in rhizomes, ZSD1 transcripts are detected in leaves, stems and rhizomes, suggesting that ZSD1 may also be involved in other biological processes. Consistent with its proposed flexible substrate-binding pocket, ZSD1 also converts borneol to camphor with K(m) and k(cat) values of 22.8 MUm and 4.1 s(-1) , displaying its bisubstrate feature. PMID- 21668646 TI - Novel suppression mechanism operating in early phase of adipogenesis by positive feedback loop for enhancement of cyclooxygenase-2 expression through prostaglandin F2alpha receptor mediated activation of MEK/ERK-CREB cascade. AB - Prostaglandin (PG) F(2alpha) suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferator-activated receptor gamma. In this study, we identified a novel suppression mechanism, operating in the early phase of adipogenesis, that increased the production of anti-adipogenic PGF(2alpha) and PGE(2) by enhancing cyclooxygenase (COX) 2 expression through the PGF(2alpha) activated FP receptor/extracellular-signal-regulated kinase (ERK)/cyclic AMP response element binding protein (CREB) cascade. COX-2 expression was enhanced with a peak at 1 h for the mRNA level and at 3 h for the protein level after the addition of Fluprostenol, an FP receptor agonist. The Fluprostenol-derived elevation of COX-2 expression was suppressed by the co-treatment with an FP receptor antagonist, AL8810, with a mitogen-activated protein kinase (MEK; ERK kinase) inhibitor, PD98059. ERK was phosphorylated within 10 min after the addition of Fluprostenol, and its phosphorylation was inhibited by the co treatment with AL8810 or PD98059. Moreover, FP receptor mediated activation of the MEK/ERK cascade and COX-2 expression increased the production of PGF(2alpha) and PGE(2) . An FP receptor antagonist and each inhibitor for MEK and COX-2 suppressed the PGF(2alpha) -derived induction of synthesis of these PGs. Furthermore, promoter-luciferase and chromatin immunoprecipitation assays demonstrated that PGF(2alpha) -derived COX-2 expression was activated through binding of CREB to the promoter region of the COX-2 gene in 3T3-L1 cells. These results indicate that PGF(2alpha) suppresses the progression of the early phase of adipogenesis by enhancing the binding of CREB to the COX-2 promoter via FP receptor activated MEK/ERK cascade. Thus, PGF(2alpha) forms a positive feedback loop that coordinately suppresses the early phase of adipogenesis through the increased production of anti-adipogenic PGF(2alpha) and PGE(2) . PMID- 21668648 TI - New developments in protein structure-function analysis by MS and use of hydrogen deuterium exchange microfluidics. AB - The study of protein structure and function has evolved to become a leading discipline in the biophysical sciences. Although it is not yet possible to determine 3D protein structures from MS data alone, multiple MS-based techniques can be combined to obtain structural and functional data that are complementary to classical protein structure information obtained from NMR or X-ray crystallography. Monitoring gas-phase interactions of noncovalent complexes yields information on binding constants, complex stability, and the nature of interactions. Ion mobility MS and chemical crosslinking strategies can be applied to probe the architecture of macromolecular assemblies and protein-ligand complexes. MS analysis of hydrogen-deuterium exchange can be used to determine the localization of secondary structure elements, binding sites and conformational dynamics of proteins in solution. This minireview focuses first on new strategies that combine these techniques to gain insights into protein structure and function. Using one such strategy, we then demonstrate how a novel hydrogen-deuterium exchange microfluidics tool can be used online with an ESI mass spectrometer to monitor regional accessibility in a peptide, as exemplified with amyloid-beta peptide 1-40. PMID- 21668647 TI - Molecular basis of glyphosate resistance-different approaches through protein engineering. AB - Glyphosate (N-phosphonomethyl-glycine) is the most widely used herbicide in the world: glyphosate-based formulations exhibit broad-spectrum herbicidal activity with minimal human and environmental toxicity. The extraordinary success of this simple, small molecule is mainly attributable to the high specificity of glyphosate for the plant enzyme enolpyruvyl shikimate-3-phosphate synthase in the shikimate pathway, leading to the biosynthesis of aromatic amino acids. Starting in 1996, transgenic glyphosate-resistant plants were introduced, thus allowing application of the herbicide to the crop (post-emergence) to remove emerged weeds without crop damage. This review focuses on mechanisms of resistance to glyphosate as obtained through natural diversity, the gene-shuffling approach to molecular evolution, and a rational, structure-based approach to protein engineering. In addition, we offer a rationale for the means by which the modifications made have had their intended effect. PMID- 21668649 TI - Protective effect of magnesium-25 carrying porphyrin-fullerene nanoparticles on degeneration of dorsal root ganglion neurons and motor function in experimental diabetic neuropathy. AB - Diabetic neuropathy (DN) is the most common peripheral neuropathy and long-term complication of diabetes. In view of the pathological basis for the treatment of DN, it is important to prevent nerve degeneration. Most of the current treatment strategies are symptomatic therapies. In this study, we evaluated the effectiveness of magnesium-25, carrying porphyrin-fullerene nanoparticles, on diabetes-induced neuropathy. Previous studies have suggested that dorsal root ganglion (DRG) neurons comprise a specific target and may be responsible for the known complications of DN. Experimental DN was induced by intraperitoneal injection of streptozotocin (STZ) (45 mg/kg). Different forms of magnesium including (25)Mg-PMC16, (24)Mg-PMC16 and MgCl(2) were administered intravenously in equal dose (0.5 LD(50)) at 48-hr intervals before STZ injection. Peripheral nerves were studied after 2 months of diabetes in groups using qualitative approaches, morphometric analysis of DRG neurons and motor function tests. We showed that STZ-induced DN caused morphological abnormalities in DRG neurons comprising changes in area, diameter and number of A and B cells as well as motor dysfunction in DN. Moreover, our findings indicated that administration of (25)Mg PMC16 as a magnetic form of Mg improved morphological abnormalities and motor dysfunctions significantly, whereas other forms of Mg were ineffective. PMID- 21668650 TI - Synthesis and evaluation of antimalarial activity of oxygenated 3-alkylpyridine marine alkaloid analogues. AB - A series of new oxygenated analogues of marine 3-alkylpyridine alkaloids were prepared from 3-pyridinepropanol in few steps and in good yields. The key step for the synthesis of these compounds was a Williamson etherification under phase transfer conditions. All new compounds were evaluated for their antiplasmodial activity and cytotoxicity. A significant reduction in parasitaemia was observed for some of the prepared compounds, and the majority of them exhibited a selectivity index (SI) ranging from 2.78 to 15.58, which suggests that these compounds may be a promising class of substances with antimalarial activity. PMID- 21668651 TI - Study of human dopamine sulfotransferases based on gene expression programming. AB - A quantitative model is developed to predict the Km of 47 human dopamine sulfotransferases by gene expression programming. Each kind of compound is represented by several calculated structural descriptors of moment of inertia A, average electrophilic reactivity index for a C atom, relative number of triple bonds, RNCG relative negative charge, HA-dependent HDSA-1, and HBCA H-bonding charged surface area. Eight fitness functions of the gene expression programming method are used to find the best nonlinear model. The best quantitative model with squared standard error and square of correlation coefficient are 0.096 and 0.91 for training data set, and 0.102 and 0.88 for test set, respectively. It is shown that the gene expression programming-predicted results with fitness function are in good agreement with experimental ones. PMID- 21668653 TI - Drug-like leads for steric discrimination between substrate and inhibitors of human acetylcholinesterase. AB - Protection of the enzyme acetylcholinesterase (AChE) from the toxic effects of organophosphate insecticides and chemical warfare agents (OPs) may be provided by inhibitors that bind at the peripheral binding site (P-site) near the mouth of the active-site gorge. Compounds that bind to this site may selectively block access to the acylation site (A-site) catalytic serine for OPs, but not acetylcholine itself. To identify such compounds, we employed a virtual screening approach using AutoDock 4.2 and AutoDock Vina, confirmed using compounds experimentally known to bind specifically to either the A-site or P-site. Both programs demonstrated the ability to correctly predict the binding site. Virtual screening of the NCI Diversity Set II was conducted using the apo form of the enzyme, and with acetylcholine bound at the crystallographic locations in the A site only and in both and A- and P-sites. The docking identified 32 compounds that were obtained for testing, and one was demonstrated to bind specifically to the P-site in an inhibitor competition assay. PMID- 21668652 TI - High-throughput analysis of an RNAi library identifies novel kinase targets in Trypanosoma brucei. AB - New drugs are needed to treat human African trypanosomiasis because the currently approved treatments are toxic or limited in efficacy. One strategy for developing new drugs involves discovering novel genes whose products can be targeted for modulation by small-molecule chemotherapeutic agents. The Trypanosoma brucei genome contains many genes with the potential to become such targets. Kinases represent one group of genes that regulate many important cell functions and can be modulated by small molecules, thus representing a promising group of enzymes to screen for potential therapeutic targets. RNAi screens could help identify the most promising kinase targets, but the lack of suitable assays represents a barrier for optimizing the use of this technology in T. brucei. Here, we describe an RNAi screen of a small RNAi library targeting 30 members of the T. brucei kinome utilizing a luciferase-based assay. This screen both validated the luciferase-based assay as a suitable method for conducting RNAi screens in T. brucei and also identified two kinases (CRK12 and ERK8) that are essential for normal proliferation by the parasite. PMID- 21668654 TI - Homage to August Krogh celebrating the 90th anniversary of his Nobel prize in Physiology or Medicine. PMID- 21668655 TI - Automated vs. manual cerebrospinal fluid cell counts: a work and cost analysis comparing the Sysmex XE-5000 and the Fuchs-Rosenthal manual counting chamber. AB - INTRODUCTION: Cerebrospinal fluid (CSF) cell counts are traditionally performed by manual microscopy using the Fuchs-Rosenthal counting chamber. This procedure is time-, labour- and cost-intensive and requires experienced laboratory staff. METHODS: The Sysmex XE-5000 haematology analyzer offers a channel to quantify the total cell count of body fluids. We compared technical sensitivity and specificity, intra-assay variability, turn-around time (TAT) and costs for the determination of CSF cell counts between both methods. RESULTS: The mean coefficients of variation (CV) for total cell counts in CSF of the Fuchs Rosenthal chamber and the XE-5000 were 15.2% (range: 2.8-47.5%) and 12.5% (range: 1.9-50.6%). Setting the Fuchs-Rosenthal chamber as 'gold standard', our results revealed a sensitivity of 100% and a specificity of 75% for the XE-5000 to detect a pathological cell count (>= 6 cells/MUL), whereas the sensitivity and specificity to detect a severely pathological cell count (>= 20 cells/MUL) were 100% for both. Bland and Altman analysis revealed slightly higher cell counts with the XE-5000. The approximate duration of a single CSF cell count analysis was 635 s for the manual vs. 85 s for the automated method. Total analytical performance costs for the counting chamber were 6.74 EUR per mean analysis and 1.22 EUR for the XE-5000. CONCLUSION: Our study revealed a lower mean CV for the total cell count for the XE-5000 method. The fully automated CSF cell count results in a 7.5-fold reduction in TAT and leads to a significant decrease in total analytical performance costs. PMID- 21668656 TI - Assessment for antithrombin deficiency in the real world. PMID- 21668657 TI - Genotyping of human platelet antigen-15 by single closed-tube Tm-shift method. AB - INTRODUCTION: Genotyping of human platelet antigens (HPA) is useful for the diagnosis and prevention of platelet alloimmune syndromes. HPA-15 might play an important role in the development of platelet alloimmune syndromes. There are several disadvantages in the conventional methods for HPA-15 genotyping. The aim of this study was to develop a new method for HPA-15 genotyping by using single closed-tube melting temperature (T(m))-shift genotyping. METHODS: Two GC-rich tails of different lengths were attached to 5'-end of HPA-15 allele-specific PCR primers, such that HPA-15 alleles can be discriminated by the T(m)s of the PCR products. One hundred blood samples were genotyped for HPA-15 by the T(m)-shift and conventional polymerase chain reaction with sequence-specific primers (PCR SSP). RESULTS: The comparison of the PCR-SSP and the T(m)-shift method showed four discordant results in one hundred samples tested. Confirmatory results demonstrated that the PCR-SSP produced several errors, whereas HPA-15 genotyping by T(m)-shift is correct. The retesting results of T(m)-shift method were consistent with those of the initial testing. CONCLUSION: The single closed-tube T(m)-shift method for HPA-15 genotyping is high-throughput, rapid, reliable, reproducible and cost-effective and it is superior to conventional PCR-SSP used in routine genotyping of HPA-15. PMID- 21668658 TI - Do we need a fasting lipid profile to assess cardiovascular risk? PMID- 21668659 TI - Isolation of novel triple-reassortant swine H3N2 influenza viruses possessing the hemagglutinin and neuraminidase genes of a seasonal influenza virus in Vietnam in 2010. AB - Surveillance of swine influenza viruses (SIVs) in 31 pig farms in northern and southern parts of Vietnam was conducted. Six H3N2 influenza A viruses were isolated from a pig farm in southern Vietnam. They were novel genetic reassortants between a triple-reassortant SIV and a human seasonal H3N2 virus. Their hemagglutinin and neuraminidase genes were derived from a human virus circulating around 2004-2006 and the remaining genes from a triple-reassortant SIV that originated in North America. This is the first report describing the isolation of a novel triple-reassortant SIV in Vietnam. PMID- 21668660 TI - Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children. AB - BACKGROUND: Molecular testing for viral pathogens has resulted in increasing detection of multiple viruses in respiratory secretions of ill children. The clinical impact of multiple virus infections on clinical presentation and outcome is unclear. OBJECTIVES: To compare clinical characteristics and viral load between children with multiple virus versus single virus illnesses. PATIENTS/METHODS: Eight hundred and ninety-three residual nasal wash samples from children treated for respiratory illness at Children's Hospital, Seattle, from September 2003 to September 2004 were evaluated by quantitative PCR for respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (Flu), parainfluenza, adenoviruses, and coronaviruses (CoV). Illness severity and patient characteristics were abstracted from medical charts. RESULTS: Coinfections were identified in 103 (18%) of 566 virus-positive samples. Adenovirus was most commonly detected in coinfections (52%), followed by CoV (50%). Illnesses with a single virus had increased risk of oxygen requirement (P = 0.02), extended hospital stays (P = 0.002), and admissions to the inpatient (P = 0.02) or intensive care units (P = 0.04). For Adv and PIV-1, multiple virus illnesses had a significantly lower viral load (log(10) copies/ml) than single virus illnesses (4.2 versus 5.6, P = 0.007 and 4.2 versus 6.9, P < 0.001, respectively). RSV, Flu-A, PIV-3, and hMPV viral loads were consistently high whether or not another virus was detected. CONCLUSIONS: Illnesses with multiple virus detections were correlated with less severe disease. The relationship between viral load and multiple virus infections was virus specific, and this may serve as a way to differentiate viruses in multiple virus infections. PMID- 21668661 TI - Quantitative review of antibody response to inactivated seasonal influenza vaccines. AB - BACKGROUND: Seasonal influenza epidemics are associated with significant morbidity and mortality each year, particularly amongst young children and the elderly. Seasonal influenza vaccines have been available for decades, yet influenza remains a major public health threat in the US, sparking interest in studies evaluating the effectiveness of vaccination. OBJECTIVES: We sought to identify determinants of serological responses to inactivated seasonal influenza vaccines including number of doses, adjuvant, and subject characteristics. METHODS: We reviewed 60 articles published between 1987 and 2006. We used weighted multiple logistic regression and random-effects models to evaluate how seroconversion and seroprotection rates varied with host and vaccine factors. RESULTS: Both children and seniors tended to have poorer immune responses compared to adults whereas use of adjuvant and a second vaccine dose tended to improve immune response. Pre-vaccination serological status had a large impact on the immune response to vaccination. We found substantial heterogeneity among studies, even with similar population settings and vaccination regimen. CONCLUSIONS: Future studies should stratify their results by pre-vaccination serological status in an effort to produce more precise summary estimates of vaccine response. PMID- 21668662 TI - Epidemiological and clinical features of respiratory viral infections in hospitalized children during the circulation of influenza virus A(H1N1) 2009. AB - BACKGROUND: Seasonal influenza viruses and respiratory syncytial virus (RSV) are primary causes of acute respiratory tract infections (ARTIs) in children. New respiratory viruses including human metapneumovirus (hMPV), human bocavirus (hBoV), and influenza 2009 A(H1N1) virus have a strong impact on the pediatric population. OBJECTIVES: To evaluate epidemiological and clinical features of ARTIs in hospitalized children. METHODS: From December 1, 2008, to December 31, 2009, all children under age fifteen (n = 575) hospitalized for ARTIs were investigated for influenza A (subtype H1N1, H3N2, and 2009 H1N1) and B, RSV A and B, hMPV, and hBoV by PCR. RESULTS: Fifty-one percent of samples were positive for these respiratory viruses. The frequencies of virus detection were RSV 34.1%, hBoV 6.8%, hMPV 5%, seasonal influenza A 5%, and seasonal influenza B 0%. From April 2009, 11.6% of collected samples were influenza 2009 A(H1N1) positive. Respiratory syncytial virus activity peaked in January, hBoV in February, and hMPV in April. Seasonal influenza A was detected only between January and April 2009, while influenza 2009 A(H1N1) peaked in November. Respiratory syncytial virus and hMPV were mainly associated with lower respiratory tract infections (LRTIs) and with necessity of O(2) administration. The 2009 pandemic influenza was more frequently detected in elder children (P < 0.001) and was associated with higher, longer-lasting fevers compared with other viral infections (P < 0.05). CONCLUSIONS: All considered viruses were involved in LRTIs. The primary clinical relevance of RSV and a similar involvement of both seasonal influenza and emerging viruses investigated were observed on the pediatric population. PMID- 21668663 TI - Comparison of clinical features and outcomes of medically attended influenza A and influenza B in a defined population over four seasons: 2004-2005 through 2007 2008. AB - BACKGROUND: There are few prospectively collected data comparing illnesses caused by different subtypes of influenza. We compared the clinical presentation and outcomes of subjects with primarily outpatient-attended influenza A and B infections during four consecutive influenza seasons (2004-2005 through 2007 2008). METHODS: Patients were prospectively enrolled and tested for influenza following an encounter for acute respiratory illness. Influenza infections were confirmed by culture or reverse transcription polymerase chain reaction; subtype was determined for a sample of influenza A isolates each season. Clinical characteristics of influenza A and B infections were compared across and within individual seasons. RESULTS: We identified 901 cases of influenza A and 284 cases of influenza B; 98% of cases were identified through an outpatient medical encounter. Thirty-six percent of patients with each strain had received seasonal influenza vaccine prior to illness onset. There were no consistent differences in symptoms associated with influenza A and B. Influenza A infection was associated with earlier care seeking compared with influenza B during the 2005-2006 and 2007 2008 seasons, when H3N2 was the dominant type A virus, and in a combined analysis that included all seasons. Twenty-six (2.2%) of 1185 cases were diagnosed with radiographically confirmed pneumonia, and 59 (5%) of 1185 patients were hospitalized within 30 days of illness onset. CONCLUSIONS: Over four influenza seasons, aside from shorter intervals from illness onset to clinical encounter for infections with the A(H3N2) subtype, clinical symptoms and outcomes were similar for patients with predominantly outpatient-attended influenza A and B infections. PMID- 21668664 TI - Body mass index and the incidence of influenza-associated pneumonia in a UK primary care cohort. AB - BACKGROUND: Accumulating data suggest an association between increased BMI/obesity and morbidity in patients with pandemic (H1N1) 2009 influenza. Information on metabolic status and prognosis in seasonal influenza is lacking, however. METHODS: A retrospective cohort study was carried out using the UK General Practice Research Database. Patients aged >=18 with >=1 recorded BMI in the 12-58 kg/m(2) range between January 1, 2000, and December 31, 2007, were observed for an influenza-associated pneumonia diagnosis after the date of baseline BMI, including 'influenza with pneumonia' or a diagnosis of 'pneumonia' up to 30 days after a diagnosis of 'influenza'. RESULTS: A total of 1,074,315 patients were included, of whom 73.2% were within the reference BMI range or overweight and 2.2% were underweight (<18.5 kg/m(2)). Pneumonia rates were 32.33 37.48/100,000 in all BMI categories except the underweight (98.29/100,000). Relative to patients with acceptable weight, those who were underweight had an increased pneumonia rate [adjusted IRR = 2.32 (95% CI 1.80-2.94)], while being overweight (BMI = 25.0-29.9 kg/m(2)) or obese (BMI >= 30.0 kg/m(2)) was associated with a decreased pneumonia rate [adjusted IRR = 0.77 (95% CI 0.68 0.86) and 0.85 (95% CI 0.73-1.00), respectively]. On the other hand, women and obese women with type 2 diabetes had increased pneumonia rates [adjusted IRR = 1.37 (95% CI 1.08-1.72) and 1.47 (95%CI 1.01-2.06), respectively]. CONCLUSIONS: In contrast to initial data from pandemic influenza, influenza pneumonia, and pneumonia following influenza were the most common in underweight persons, and an apparent decreased rate of pneumonia was noted with increasing BMI categories. Women with type 2 diabetes had increased rates of pneumonia. PMID- 21668665 TI - Pandemic and seasonal influenza viruses among patients with acute respiratory illness in Kashmir (India). AB - BACKGROUND: With the emergence of pandemic influenza A (2009A/H1N1) virus in India, we sought to determine the prevalence and clinical presentations of seasonal and pandemic influenza viruses among acute respiratory illness (ARI) patients from Srinagar, a temperate climate area in northern India, during the peak winter season. METHODS: Combined throat and nasal swabs, obtained from 194 (108 male) presenting with ARI from January to March 2010 (Week 53-week 10), were tested by RT-PCR for influenza A and B, including 2009A/H1N1 viruses. HA1 gene of selected 2009A/H1N1-positive samples was sequenced, and phylogenetic analysis was carried out. RESULTS: Twenty-one (10.8%, age 15-80 years, median age 40 years) patients tested positive for influenza viruses: 13 (62%) for 2009A/H1N1 virus, 6 (28.5%) for seasonal influenza A (H3N2), and 2 (9.5%) for influenza B. Twelve of the 13 patients with 2009A/H1N1 presented with febrile ARI, and eight had associated comorbidities. All of the patients recovered. Phylogenetic analysis of HA gene (n = 8) revealed that all strains from Srinagar clustered in 2009A/H1N1 clade seven along with the other 2009A/H1N1 strains from India. Amino acid substitutions in the HA protein defining clade seven (P83S, S203T, and I321V) were found in almost all isolates from Srinagar. CONCLUSIONS: Both seasonal and 2009A/H1N1 viruses appear to be associated with ARI in Srinagar. The 2009A/H1N1 in Srinagar is genetically similar to globally circulating clade 7 strains, with unique signature sequences in the HA gene. Further investigations into ascertain the role of these mutations in possible alteration of the virulence and transmissibility of the virus are needed. PMID- 21668666 TI - The relative clinical impact of 2009 pandemic influenza A (H1N1) in the community compared to seasonal influenza in the Netherlands was most marked among 5-14 year olds. AB - BACKGROUND: So far, most pandemic influenza reports were based on case studies focusing on severe disease. For public health policy, it is essential to consider the overall impact of the pandemic, including mild diseases. OBJECTIVES: The aim of our study is to gain insight into the epidemiology of 2009 pandemic influenza in the community and to estimate the relative impact of pandemic compared to seasonal influenza. METHODS: The relative impact of pandemic influenza in the general population was assessed as the influenza-like illness (ILI) incidence during the pandemic season compared with that during regular seasons. Influenza like illness incidences and virus diagnostics were derived from continuous sentinel surveillance systems. The incidence of hospital admissions, based on the mandatory notification of pandemic influenza, was used to relate the impact of severe disease to that in the community. RESULTS: The overall incidence of general practitioners-attended ILI was 96 consultations per 10,000 persons. Highest incidences were reported in children and lowest in persons aged >=65 years. For 5-14 year olds, the incidence during the pandemic was higher than during all preceding seasons. Samples originating from 5 to 19 year olds were statistically significant more often positive for pandemic influenza A (H1N1) 2009 virus as compared with samples from 0 to 4 year olds. Moreover, the incidence of hospital admission owing to pandemic influenza was highest in the youngest children. CONCLUSIONS: Our study showed that while the absolute incidences of 2009 pandemic influenza were highest in children aged 0-4 years, the relative clinical impact in the community compared to seasonal influenza in previous years was most noticeable in healthy children 5-14 years of age. PMID- 21668667 TI - Has estimation of numbers of cases of pandemic influenza H1N1 in England in 2009 provided a useful measure of the occurrence of disease? AB - BACKGROUND: Surveillance indicators of influenza activity have generally provided robust comparative trend data for England. These indicators became less reliable, however, for monitoring trends in activity, or comparisons with previous years, during the influenza pandemic in 2009 because of changes in the perception of risk and changes in the systems of healthcare delivery. An approach was developed to estimate the number of cases of influenza-like illness (ILI) occurring because of infection with pandemic influenza virus. METHODS AND FINDINGS: The number of cases was estimated each week in England on the basis of total number of patients consulting healthcare services with ILI; estimates of the proportion of individuals in the community experiencing an ILI-seeking health care; and the proportion of these positive on laboratory testing. Almost 800,000 cases (range 375,000-1.6 million) of symptomatic ILI cases were estimated to have occurred over the course of the two waves of pandemic activity in England. More cases were estimated to have occurred in the second wave than in the first. CONCLUSIONS: These results underestimate the total number of infections as they do not include asymptomatic infections nor those with mild illness not meeting the definition of a case of ILI. Nevertheless, the case number estimates provide a useful indicator of the trend in influenza activity and weekly data were extensively used in media reports. Although surveillance methods differ between countries, the approach of synthesising available data sources to produce an overall estimate of case numbers could be applied more widely to provide comparative data. PMID- 21668668 TI - Comparison of pandemic and seasonal influenza A infections in pediatric patients: were they different? AB - This retrospective cohort study revealed that the presence of pandemic H1N1 influenza resulted in a 77.7% increase of patient visits in the emergency department for influenza like illnesses and a 67.2% increase of hospital days in our hospital by comparing to a regular influenza season (2008-2009 season). However, median length of hospital stay was no different in either period (pandemic: 3 days versus seasonal: 4 days, P = 0.06). Except for the patients hospitalized for pandemic H1N1 influenza (n = 111) were older (median age: 4.7 years versus 1.6 years, P = 0.04) and tended to have pre-existing asthma (21.6% versus 9.0%, P = 0.07) than those hospitalized for seasonal influenza A infections (n = 44), this study found no significant difference between the two comparison groups with regards of other clinical and epidemiological features. PMID- 21668669 TI - Pandemic influenza in Africa, lessons learned from 1968: a systematic review of the literature. AB - BACKGROUND: To help understand the potential impact of the 2009 H1N1 pandemic in Africa, we reviewed published data from Africa of the two previous influenza pandemics. METHODS: We conducted a systematic search of three biomedical databases for articles in any language on 1957 H2N2 or 1968 H3N2 pandemic influenza virus infection in Africa published from January 1950 through August 2008. RESULTS: We identified 1327 potentially relevant articles, and 298 warranted further review. Fourteen studies on 1968 H3N2 influenza met inclusion criteria, while two studies identified describing 1957 H2N2 were excluded for data limitations. Among these 14 studies, community attack rates for symptomatic infection during all 1968 pandemic waves were around 20%. However, the proportion infected in communities ranged from 6% in isolated communities to 100% in enclosed populations. A total of 22-64% of sampled clinic patients and 8-72% of hospitalized patients had evidence of 1968 H3N2 virus infection. After the second pandemic wave, up to 41-75% of persons tested had serological evidence of 1968 H3N2 virus infection. CONCLUSION: The 1968 H3N2 influenza pandemic, generally regarded as mild worldwide, appears to have had a substantial impact upon public health in Africa. Without more epidemiologic data the impact of the 2009 H1N1 pandemic in Africa cannot be assumed to have been mild. Assessment of the burden of 2009 H1N1 virus and future influenza pandemics in Africa should attempt to assess disease impact by a variety of methods, including substudies among specific populations. PMID- 21668670 TI - Matrix-M adjuvanted virosomal H5N1 vaccine confers protection against lethal viral challenge in a murine model. AB - BACKGROUND: A candidate pandemic influenza H5N1 vaccine should provide rapid and long-lasting immunity against antigenically drifted viruses. As H5N1 viruses are poorly immunogenic, this may require a combination of immune potentiating strategies. An attractive approach is combining the intrinsic immunogenicity of virosomes with another promising adjuvant to further boost the immune response. As regulatory authorities have not yet approved a surrogate correlate of protection for H5N1 vaccines, it is important to test the protective efficacy of candidate H5N1 vaccines in a viral challenge study. OBJECTIVES: This study investigated in a murine model the protective efficacy of Matrix-M adjuvanted virosomal influenza H5N1 vaccine against highly pathogenic lethal viral challenge. METHODS: Mice were vaccinated intranasally (IN) or intramuscularly (IM) with 7.5 MUg and 30 MUg HA of inactivated A/Vietnam/1194/2004 (H5N1) (NIBRG 14) virosomal adjuvanted vaccine formulated with or without 10 MUg of Matrix-M adjuvant and challenged IN with the highly pathogenic A/Vietnam/1194/2004 (H5N1) virus. RESULTS AND CONCLUSIONS: IM vaccination provided protection irrespective of dose and the presence of Matrix-M adjuvant, whilst the IN vaccine required adjuvant to protect against the challenge. The Matrix-M adjuvanted vaccine induced a strong and cross-reactive serum antibody response indicative of seroprotection after both IM and IN administration. In addition, the IM vaccine induced the highest frequencies of influenza specific CD4+ and CD8+ T-cells. The results confirm a high potential of Matrix-M adjuvanted virosomal vaccines and support the progress of this vaccine into a phase 1 clinical trial. PMID- 21668672 TI - Obese mice have increased morbidity and mortality compared to non-obese mice during infection with the 2009 pandemic H1N1 influenza virus. AB - BACKGROUND: Obesity has been identified as an independent risk factor for severe or fatal infection with 2009 pandemic H1N1 influenza (2009 pH1N1), but was not previously recognized for previous pandemic or seasonal influenza infections. OBJECTIVES: Our aim was to evaluate the role of obesity as an independent risk factor for severity of infection with 2009 pH1N1, seasonal H1N1, or a pathogenic H1N1 influenza virus. METHODS: Diet-induced obese (DIO) and their non-obese, age matched control counterparts were inoculated with a 2009 pH1N1, A/California/04/2009 (CA/09), current seasonal H1N1, A/NY/312/2001 (NY312), or highly pathogenic 1918-like H1N1, A/Iowa/Swine/1931 (Sw31), virus. RESULTS: Following inoculation with CA/09, DIO mice had higher mortality (80%) than control mice (0%) and lost more weight during infection. No effect of obesity on morbidity and mortality was observed during NY312 or Sw31 infection. Influenza antigen distribution in the alveolar regions of the lungs was more pronounced in DIO than control mice during CA/09 infection at 3 days post-inoculation (dpi), despite similar virus titers. During CA/09 infection, localized interferon-beta and proinflammatory cytokine protein responses in the lungs were significantly lower in DIO than control mice. Conversely, serum cytokine concentrations were elevated in DIO, but not control mice following infection with CA/09. The effect of obesity on differential immune responses was abrogated during NY312 or Sw31 infection. CONCLUSIONS: Together, these data support epidemiologic reports that obesity may be a risk factor for severe 2009 pandemic H1N1 influenza infection, but the role of obesity in seasonal or highly virulent pandemic influenza infection remains unclear. PMID- 21668671 TI - XIth International Symposium on Respiratory Viral Infections. PMID- 21668674 TI - RSV and HMPV seroprevalence in Tuscany (Italy) and North-Rhine Westfalia (Germany) in the winter season 2009/2010. PMID- 21668673 TI - Use of dried clinical samples for storing and detecting influenza RNA. AB - BACKGROUND: Most clinical samples collected for diagnostic influenza testing and monitoring require refrigerated or frozen storage or shipment, which imparts logistic and cost burdens. The ability to store and ship dried clinical specimens under ambient conditions for influenza testing would significantly reduce costs and protect samples from improper storage or equipment failure, especially in remote or resource-limited areas. OBJECTIVES: To evaluate the collection and storage of dried clinical samples on a transport matrix (ViveSTTM, ST) for influenza RNA testing by real-time reverse-transcription PCR (RT-PCR). METHODS: Viral transport medium from swab or sputum samples was applied to ST, dried, and stored under ambient conditions from 2 days to 6 months. Additional aliquots of samples were frozen. Testing of frozen and ST-stored samples was performed using the WHO/CDC real-time influenza A (H1N1) RT-PCR protocol and compared to the Luminex xTAG RVP assay. RESULTS: ST-stored samples yielded slightly higher threshold cycle values (median 2.54 cycles) compared to frozen samples tested in parallel. This difference was consistent regardless of viral input. There was no significant difference in signal recovery between samples stored for 1 week versus samples stored for 3 weeks, or from three samples stored for 6 months. Qualitatively, clinical specimens stored on ST were 100% concordant (36/36) with frozen samples for detecting the presence of influenza A RNA. CONCLUSION: ST processed dried specimens produced similar rates of seasonal or novel 2009 HIN1 influenza RNA detection compared to conventional sample processing and thus presents a viable alternative to refrigerated or frozen samples. PMID- 21668675 TI - Lack of evidence for pre-symptomatic transmission of pandemic influenza virus A(H1N1) 2009 in an outbreak among teenagers; Germany, 2009. AB - BACKGROUND: Observations on the role of pre-symptomatic transmission in the spread of influenza virus are scanty. In June 2009, an outbreak of pandemic A(H1N1) 2009 infection occurred at a teenager's party in Germany. The objective of this study was to identify risk factors for pandemic A(H1N1) 2009 infection. METHODS: We performed a retrospective cohort study among party guests. A case was defined as pandemic A(H1N1) 2009 infection confirmed by rRT-PCR who developed influenza-like illness between 1 and 5 June 2009. Contact patterns among party guests were evaluated. RESULTS: In eight (36%) of 27 party guests, the outcome was ascertained. A travel returnee from a country with endemic pandemic A(H1N1) 2009 who fell ill toward the end of the party was identified as the source case. Party guests with pandemic A(H1N1) 2009 infection had talked significantly longer to the source case than non-infected persons (P-value: 0.001). Importantly, none (0/9) of those who had left the party prior to the source case's symptom onset became infected compared to 7 (41%) of 17 who stayed overnight (P = 0.06), and these persons all had transmission-prone contacts to the source case. CONCLUSIONS: In this outbreak with one index case, there was no evidence to support pre-symptomatic transmission of pandemic A(H1N1) 2009. Further evidence is required, ideally from larger studies with multiple index cases, to more accurately characterize the potential for pre-symptomatic transmission of influenza virus. PMID- 21668676 TI - Confronting the next pandemic--workshop on lessons learned from potency testing of pandemic (H1N1) 2009 influenza vaccines and considerations for future potency tests, Ottawa, Canada, July 27-29, 2010. PMID- 21668677 TI - Epidemiologic and virologic assessment of the 2009 influenza A (H1N1) pandemic on selected temperate countries in the Southern Hemisphere: Argentina, Australia, Chile, New Zealand and South Africa. AB - INTRODUCTION AND SETTING: Our analysis compares the most comprehensive epidemiologic and virologic surveillance data compiled to date for laboratory confirmed H1N1pdm patients between 1 April 2009 - 31 January 2010 from five temperate countries in the Southern Hemisphere-Argentina, Australia, Chile, New Zealand, and South Africa. OBJECTIVE: We evaluate transmission dynamics, indicators of severity, and describe the co-circulation of H1N1pdm with seasonal influenza viruses. RESULTS: In the five countries, H1N1pdm became the predominant influenza strain within weeks of initial detection. South Africa was unique, first experiencing a seasonal H3N2 wave, followed by a distinct H1N1pdm wave. Compared with the 2007 and 2008 influenza seasons, the peak of influenza-like illness (ILI) activity in four of the five countries was 3-6 times higher with peak ILI consultation rates ranging from 35/1,000 consultations/week in Australia to 275/100,000 population/week in New Zealand. Transmission was similar in all countries with the reproductive rate ranging from 1.2-1.6. The median age of patients in all countries increased with increasing severity of disease, 4-14% of all hospitalized cases required critical care, and 26-68% of fatal patients were reported to have >=1 chronic medical condition. Compared with seasonal influenza, there was a notable downward shift in age among severe cases with the highest population-based hospitalization rates among children <5 years old. National population-based mortality rates ranged from 0.8-1.5/100,000. CONCLUSIONS: The difficulty experienced in tracking the progress of the pandemic globally, estimating its severity early on, and comparing information across countries argues for improved routine surveillance and standardization of investigative approaches and data reporting methods. PMID- 21668678 TI - Attempted early detection of influenza A (H1N1) pandemic with surveillance data of influenza-like illness and unexplained pneumonia. AB - BACKGROUND: To collect disease information and provide data for early detection of epidemics, two surveillance systems were established for influenza-like illness (ILI) and unexplained pneumonia (UP) in Wuxi, People's Republic of China. OBJECTIVES: The current study aims to describe the performance of these surveillance systems during 2004-2009 and to evaluate the value of surveillance data in detection of influenza epidemics. METHODS: Two national ILI sentinel hospitals and three UP sentinel hospitals provided data to the surveillance systems. The surveillance data from hospital-based outpatient clinics and emergency rooms were compared by year. The ILI data of 2009 were further modeled based on previous data using both a control chart method and a moving average regression method. Alarms of potential epidemics would be raised when the input surveillance data surpassed a threshold. RESULTS: In 2009, the proportions of ILI and respiratory illness with fever (one surveillance syndrome of the UP system) to total patient visits (3.40% and 11.76%, respectively) were higher than the previous years. The surveillance data of both systems also showed developing trends similar to the influenza A (H1N1) pandemic in 2009. When the surveillance data of 2009 were fitted in the two detection models, alarms were produced on the occurrence of the first local case of influenza A (H1N1), outbreaks in schools and in general populations. CONCLUSIONS: The results indicated the potential for using ILI and UP surveillance data as syndromic indicators to detect and provide an early warning for influenza epidemics. PMID- 21668679 TI - Pediatric non-influenza respiratory viruses during pandemic influenza. PMID- 21668680 TI - Evidence of reassortment of pandemic H1N1 influenza virus in swine in Argentina: are we facing the expansion of potential epicenters of influenza emergence? AB - In this report, we describe the occurrence of two novel swine influenza viruses (SIVs) in pigs in Argentina. These viruses are the result of two independent reassortment events between the H1N1 pandemic influenza virus (H1N1pdm) and human like SIVs, showing the constant evolution of influenza viruses at the human-swine interface and the potential health risk of H1N1pdm as it appears to be maintained in the swine population. It must be noted that because of the lack of information regarding the circulation of SIVs in South America, we cannot discard the possibility that ancestors of the H1N1pdm or other SIVs have been present in this part of the world. More importantly, these findings suggest an ever-expanding geographic range of potential epicenters of influenza emergence with public health risks. PMID- 21668681 TI - Respiratory illnesses in Canadian health care workers: a pilot study of influenza vaccine and oseltamivir prophylaxis during the 2007/2008 influenza season. AB - BACKGROUND: Data regarding both rates of acute respiratory illness in health care workers and experience with long-term antiviral prophylaxis are sparse. OBJECTIVE: To determine the efficacy and tolerability of oseltamivir prophylaxis versus seasonal influenza vaccine for the prevention of influenza among health care workers. METHODS: We conducted a pilot, randomized control study during the 2007/2008 influenza season in a tertiary care setting. Adult health care workers 18-69 years of age were recruited and randomly assigned in a 4:1 ratio to receive either oseltamivir (Tamiflu((r)); Roche) 75 mg once daily prophylaxis or seasonal influenza (Fluviral((r))) vaccine. RESULTS: Of 56 adults enrolled, 12 received vaccine and 44 received prophylaxis. Incidence of symptomatic laboratory confirmed influenza was similar for participants in the vaccine and prophylaxis arms (17% and 24%, respectively; P = 0.71). Participants who developed an acute respiratory illness during the study period reported working 85% of scheduled work days, and 29% stated that they worked despite feeling miserable because they were too busy to stay home. Of 42 participants who initiated oseltamivir prophylaxis, four discontinued it owing to side effects. Median duration of oseltamivir prophylaxis was 121 days, with 34 (81%) continuing >=12 weeks. CONCLUSIONS: During an extended season of suboptimal vaccine match, 22% of health care workers receiving antiviral prophylaxis or seasonal influenza vaccine developed symptomatic laboratory-confirmed influenza. Long-term antiviral prophylaxis against influenza was generally well tolerated with good compliance. PMID- 21668682 TI - Role of procalcitonin and C-reactive protein in differentiation of mixed bacterial infection from 2009 H1N1 viral pneumonia. AB - BACKGROUND: Mixed bacterial infection is an important contributor to morbidity and mortality during influenza pandemics. We evaluated procalcitonin (PCT) and C reactive protein (CRP) in differentiating pneumonia caused by mixed bacterial and 2009 H1N1 influenza infection from 2009 H1N1 influenza infection alone. METHODS: Data were collected retrospectively over a 7-month period during the 2009 H1N1 influenza pandemic. Patients visiting emergency department and diagnosed as community-acquired pneumonia caused by 2009 H1N1 infection were included (n = 60). RESULTS: Mixed bacterial and viral infection pneumonia (n = 16) had significantly higher PCT and CRP levels than pneumonia caused by 2009 H1N1 influenza alone (n = 44, P = 0.019, 0.022 respectively). The sensitivity and specificity for detection of mixed bacterial infection pneumonia was 56% and 84% for PCT > 1.5 ng/ml, and 69% and 63% for CRP > 10 mg/dl. Using PCT and CRP in combination, the sensitivity and specificity were 50% and 93%, respectively. CONCLUSION: Procalcitonin and CRP alone and their combination had a moderate ability to detect pneumonia of mixed bacterial infection during the 2009 H1N1 pandemic. Considering high specificity, combination of low CRP and PCT result may suggest that pneumonia is unlikely to be caused by mixed bacterial infection. PMID- 21668683 TI - An integrated, multistudy analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2-17 years. AB - BACKGROUND: Trivalent, Ann Arbor strain, live attenuated influenza vaccine (LAIV) is approved in several countries for use in eligible children aged >=2 years. OBJECTIVE: To describe the safety of Ann Arbor strain LAIV in children aged 2-17 years. METHODS: An integrated analysis of randomized, controlled trials of LAIV. RESULTS: A total of 4245 and 10,693 children received >=1 dose of LAIV in year 1 of 6 trivalent inactivated influenza vaccine (TIV)-controlled and 14 placebo controlled studies, respectively; 3212 children were revaccinated in year 2 of 4 placebo-controlled studies. Compared with placebo for days 0-10 post-vaccination, LAIV recipients exhibited increased runny/stuffy nose (+7%), headache (+7%), and tiredness/decreased activity (+2%) after dose 1; and a higher rate of decreased appetite (+4%) after year 2 revaccination. Compared with TIV, only runny/stuffy nose was increased (dose 1, +12%; dose 2, +4%). Compared with initial vaccination, LAIV reactogenicity was lower after dose 2 in year 1 and revaccination in year 2. Unsolicited adverse events (AEs) increased with LAIV in some comparisons were headache, nasal congestion/rhinorrhea, rhinitis, and pyrexia; ear pain and lower respiratory illness were decreased. There was no evidence of an increase in any potential vaccine-related serious AE in LAIV recipients. Among children aged 2-17 years and specifically aged 24-35 months, there was no evidence that lower respiratory illness or wheezing illness occurred at a higher rate in LAIV recipients. CONCLUSION: This analysis supports the safety of Ann Arbor strain LAIV in children aged 2-17 years and provides a consensus assessment of events expected after vaccination. PMID- 21668684 TI - 2009 versus 2010 comparison of influenza activity in southern hemisphere temperate countries. PMID- 21668686 TI - Online monitoring of flu in Belgium. AB - BACKGROUND: The diagnosis and treatment of patients with the A(H1N1) pandemic flu caused some serious burden for general practitioners (GPs) in the summer and autumn of 2009. OBJECTIVE: The aim of this study was to track the incidence of influenza and influenza-like illness (ILI) in Belgium and to describe the characteristics of the affected patients. METHODS: In July 2009, the Belgian online influenza surveillance system (BOISS) was set up to monitor the spread of influenza and ILI. Registrations were made by 93 GPs from all 10 Belgian provinces who participated at least 1 week during the first 12 months of the registration. Only patients who met the WHO criteria for flu were recorded. RESULTS: In total, 1254 patients (53% men) with influenza or ILI were included. Mainly younger persons were affected: 43% was under the age of 20 years. A risk factor for influenza-related complications was determined in 19% of cases, mainly patients with chronic respiratory problems. A treatment with oseltamivir or zanamivir was prescribed in 13%, and 3% of the patients was admitted to a hospital. The time of the peak incidence (44th week) and the magnitude (623 cases per week per 100,000 inhabitants) corresponded with the figures of the existing paper-based registration network. The small sample size and possible reporting biases may have influenced the findings of the study. CONCLUSIONS: The BOISS provides a good alternative to conduct surveillance activities for influenza and ILI in Belgium. It provides complementary information regarding ILI compared to the existing data capturing. PMID- 21668685 TI - Vaccination of health-care workers against influenza: our obligation to protect patients. AB - Nosocomial influenza poses a threat for specific groups of patients and is associated not only with the disruption of health-care services but also excess costs. Although vaccination of health-care workers (HCWs) has been recommended for almost three decades and constitutes the most convenient and effective means to prevent nosocomial transmission, vaccine uptake within this group remains unacceptably low worldwide. In regard to the pandemic influenza A H1N1, HCWs constitute a priority group for immunization. Nevertheless, low vaccination rates have been documented regarding the influenza pandemic and associated with the onset of nosocomial cases and outbreaks. HCWs, health-care institutions, and public health bodies have the moral obligation to protect vulnerable patients and therefore weigh the benefits of mandatory vaccination. Key effective interventions, such as the education of HCWs concerning the benefits and safety of influenza vaccination, the reinforcement of on-site, free of charge vaccinations, and the use of mobile vaccination teams in conjunction with incentives, should be widely implemented. PMID- 21668687 TI - Experimental challenge and pathology of highly pathogenic avian influenza virus H5N1 in dunlin (Calidris alpina), an intercontinental migrant shorebird species. AB - BACKGROUND: Shorebirds (Charadriiformes) are considered one of the primary reservoirs of avian influenza. Because these species are highly migratory, there is concern that infected shorebirds may be a mechanism by which highly pathogenic avian influenza virus (HPAIV) H5N1 could be introduced into North America from Asia. Large numbers of dunlin (Calidris alpina) migrate from wintering areas in central and eastern Asia, where HPAIV H5N1 is endemic, across the Bering Sea to breeding areas in Alaska. Low pathogenic avian influenza virus has been previously detected in dunlin, and thus, dunlin represent a potential risk to transport HPAIV to North America. To date no experimental challenge studies have been performed in shorebirds. METHODS: Wild dunlin were inoculated intranasally and intrachoanally various doses of HPAIV H5N1. The birds were monitored daily for virus excretion, disease signs, morbidity, and mortality. RESULTS: The infectious dose of HPAIV H5N1 in dunlin was determined to be 10(1.7) EID(50)/100 MUl and that the lethal dose was 10(1.83) EID(50)/100 MUl. Clinical signs were consistent with neurotropic disease, and histochemical analyses revealed that infection was systemic with viral antigen and RNA most consistently found in brain tissues. Infected birds excreted relatively large amounts of virus orally (10(4) EID(50)) and smaller amounts cloacally. CONCLUSIONS: Dunlin are highly susceptible to infection with HPAIV H5N1. They become infected after exposure to relatively small doses of the virus and if they become infected, they are most likely to suffer mortality within 3-5 days. These results have important implications regarding the risks of transport and transmission of HPAIV H5N1 to North America by this species and raises questions for further investigation. PMID- 21668688 TI - Sexual dimorphism in lung function responses to acute influenza A infection. AB - BACKGROUND: Males are generally more susceptible to respiratory infections; however, there are few data on the physiological responses to such infections in males and females. OBJECTIVES: To determine whether sexual dimorphism exists in the physiological/inflammatory responses of weanling and adult BALB/c mice to influenza. METHODS: Weanling and adult mice of both sexes were inoculated with influenza A or appropriate control solution. Respiratory mechanics, responsiveness to methacholine (MCh), viral titre and bronchoalveolar lavage (BAL) cellular inflammation/cytokines were measured 4 (acute) and 21 (resolution) days post-inoculation. RESULTS: Acute infection impaired lung function and induced hyperresponsiveness and cellular inflammation in both sexes at both ages. Males and females responded differently with female mice developing greater abnormalities in tissue damping and elastance and greater MCh responsiveness at both ages. BAL inflammation, cytokines and lung viral titres were similar between the sexes. At resolution, all parameters had returned to baseline levels in adults and weanling males; however, female weanlings had persisting hyperresponsiveness. CONCLUSIONS: We identified significant differences in the physiological responses of male and female mice to infection with influenza A, which occurred in the absence of variation in viral titre and cellular inflammation. PMID- 21668689 TI - Oseltamivir treatment of mice before or after mild influenza infection reduced cellular and cytokine inflammation in the lung. AB - BACKGROUND: Lung inflammation is a critical determinant of influenza infection outcomes but is seldom evaluated in animal studies of oseltamivir (OS), which have focused on viral titre and survival. OBJECTIVES: To study the effects of pre and post-infection dosing with OS on viral replication and inflammation in a mouse model of non-lethal influenza infection. METHODS: BALB/c mice were infected with a laboratory-adapted H3N1 strain of influenza. In pre-dosing studies, OS was gavaged twice daily (1 and 10 mg/kg/day) from 4 hours prior to infection and continuing for 5 days (d) post-infection (p.i). In the second post-infection dosing study, dosing at 10 mg/kg/day began at 24-48 hours p.i. Mice were dissected at d3, d5 and d7 p.i. (pre-dosing study) and d5 p.i. (post-dosing study). Lung viral titres were determined by plaque assay. Bronchoalveolar lavage fluid (BALF) was collected and used for the quantitation of inflammatory cells and mediators. RESULTS: Pre-infection dosing of OS reduced total cells, neutrophils and macrophages in BALF. With pre- or post-infection dosing, the pro inflammatory mediators TNF-alpha, IL-1beta, IL-6 and granulocyte-macrophage colony-stimulating factor, the neutrophil chemokines keratinocyte-derived chemokine and MIP-1alpha and the macrophage chemokine MCP-1 were reduced in BALF. Pre-dosing with 1 mg/kg OS did not reduce viral titres, while 10 mg/kg slightly reduced viral titres at d3 and d5 p.i. CONCLUSIONS: Oseltamivir reduced the inflammatory response to influenza when given pre- or post-infection. This anti inflammatory effect may contribute to the clinical benefit of OS. PMID- 21668690 TI - Transmission parameters of the A/H1N1 (2009) influenza virus pandemic: a review. AB - BACKGROUND: The new influenza virus A/H1N1 (2009), identified in mid-2009, rapidly spread over the world. Estimating the transmissibility of this new virus was a public health priority. METHODS: We reviewed all studies presenting estimates of the serial interval or generation time and the reproduction number of the A/H1N1 (2009) virus infection. RESULTS: Thirteen studies documented the serial interval from household or close-contact studies, with overall mean 3 days (95% CI: 2.4, 3.6); taking into account tertiary transmission reduced this estimate to 2.6 days. Model-based estimates were more variable, from 1.9 to 6 days. Twenty-four studies reported reproduction numbers for community-based epidemics at the town or country level. The range was 1.2-3.1, with larger estimates reported at the beginning of the pandemic. Accounting for under reporting in the early period of the pandemic and limiting variation because of the choice of the generation time interval, the reproduction number was between 1.2 and 2.3 with median 1.5. DISCUSSION: The serial interval of A/H1N1 (2009) flu was typically short, with mean value similar to the seasonal flu. The estimates of the reproduction number were more variable. Compared with past influenza pandemics, the median reproduction number was similar (1968) or slightly smaller (1889, 1918, 1957). PMID- 21668691 TI - Experimental transmission of avian-like swine H1N1 influenza virus between immunologically naive and vaccinated pigs. AB - BACKGROUND: Infection of pigs with swine influenza has been studied experimentally and in the field; however, little information is available on the natural transmission of this virus in pigs. Two studies in an experimental transmission model are presented here, one in immunologically naive and one in a combination of vaccinated and naive pigs. OBJECTIVES: To investigate the transmission of a recent 'avian-like' swine H1N1 influenza virus in naive piglets, to assess the antibody response to a commercially available vaccine and to determine the efficiency of transmission in pigs after vaccination. METHODS: Transmission chains were initiated by intranasal challenge of two immunologically naive pigs. Animals were monitored daily for clinical signs and virus shedding. Pairs of pigs were sequentially co-housed, and once virus was detected in recipients, prior donors were removed. In the vaccination study, piglets were vaccinated and circulating antibody levels were monitored by haemagglutination inhibition assay. To study transmission in vaccinates, a pair of infected immunologically naive animals was co-housed with vaccinated recipient pigs and further pairs of vaccinates were added sequentially as above. The chain was completed by the addition of naive pigs. RESULTS AND CONCLUSIONS: Transmission of the H1N1 virus was achieved through a chain of six pairs of naive piglets and through four pairs of vaccinated animals. Transmission occurred with minimal clinical signs and, in vaccinates, at antibody levels higher than previously reported to protect against infection. PMID- 21668692 TI - Parkinson's disease or Parkinson symptoms following seasonal influenza. AB - BACKGROUND: Influenza may cause neurological sequelae and has been associated with encephalitis lethargica, an entity displaying Parkinson's disease (PD) signs and symptoms that followed the 1918 influenza pandemic. We studied the association between diagnosed influenza and idiopathic PD or Parkinson symptoms (PS) not followed by a firm PD diagnosis. METHODS: We used the UK-based General Practice Research Database to perform a case-control analysis. We identified cases who developed an incident diagnosis of PD or PS between 1994 and March 2007, and we matched four controls on age, gender, general practice, calendar time, and history in the database to each case. We calculated odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression to assess the relative risk of developing PD or PS in association with previous influenza diagnoses. RESULTS: We identified 3976 PD cases and 18 336 PS cases. The risk of developing PD was not associated with previous influenza infections. However, PS was associated with recent influenza (last infection 0-29 days: OR 3.03, 95% CI 1.94-4.74; 30-364 days: OR 1.36, 95% CI 1.14-1.63), number of influenza episodes (1 attack: OR 1.20, 95% CI 1.12-1.28; 2 attacks: OR 1.52, 95% CI 1.28-1.81; >=3 attacks: OR 2.00, 95% CI 1.45-2.75), and severity of preceding influenza infections (>=1 severe attack: OR 1.45, 95% CI 1.25-1.68). CONCLUSIONS: Influenza is associated with PD-like symptoms such as tremor, particularly in the month after an infection, but not with an increased risk of developing idiopathic PD. PMID- 21668693 TI - Preliminary results of 2009 pandemic influenza surveillance in the United States using the Aggregate Hospitalization and Death Reporting Activity. AB - BACKGROUND: To augment established influenza surveillance systems in the United States, the Centers for Disease Control and Prevention and the Council of State and Territorial Epidemiologists implemented the Aggregate Hospitalization and Death Reporting Activity (AHDRA) in August 2009. The AHDRA was designed to meet increased demands for timely and detailed information describing illness severity during the 2009 H1N1 influenza A (pH1N1) pandemic response. OBJECTIVES: We describe the implementation of AHDRA and provide preliminary results from this new surveillance activity. METHODS: All 50 US states were asked to report influenza-associated hospitalizations and deaths to AHDRA each week using either a laboratory-confirmed or syndromic surveillance definition. Aggregate counts were used to calculate age-specific weekly and cumulative rates per 100,000, and laboratory-confirmed reports were used to estimate the age distribution of pH1N1 influenza-associated hospitalizations and deaths. RESULTS: From August 30, 2009, through April 6, 2010, AHDRA identified 41,689 laboratory-confirmed influenza associated hospitalizations and 2096 laboratory-confirmed influenza-associated deaths. Aggregate Hospitalization and Death Reporting Activity rates peaked earlier than hospitalization and death rates seen in previous influenza seasons with other surveillance systems, and the age distribution of cases revealed a tendency for hospitalizations and deaths to occur in persons <65 years for age. CONCLUSIONS: Aggregate Hospitalization and Death Reporting Activity laboratory confirmed reports provided important information during the 2009 pandemic response. Aggregate Hospitalization and Death Reporting Activity syndromic reports were marked by low representativeness and specificity and were therefore less useful. The AHDRA was implemented quickly and may be a useful surveillance system to monitor severe illness during future influenza pandemics. PMID- 21668694 TI - Immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccine: systematic review and meta-analysis. AB - The emergence of the 2009 H1N1 pandemic has highlighted the need to have immunogenicity and safety data on the new pandemic vaccines. There is already considerable heterogeneity in the types of vaccine available and of study performed around the world. A systematic review and meta-analysis is needed to assess the immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccines. We searched Medline, EMBASE, the Cochrane Library and other online databases up to 1st October 2010 for studies in any language comparing different pandemic H1N1 vaccines, with or without placebo, in healthy populations aged at least 6 months. The primary outcome was seroprotection according to haemagglutination inhibition (HI). Safety outcomes were adverse events. Meta analysis was performed for the primary outcome. We identified 18 articles, 1 only on safety and 17 on immunogenicity, although 1 was a duplicate. We included 16 articles in the meta-analysis, covering 17,921 subjects. Adequate seroprotection (>=70%) was almost invariably achieved in all age groups, and even after one dose and at low antigen content (except in children under 3 years receiving one dose of non-adjuvanted vaccine). Non-adjuvanted vaccine from international companies and adjuvanted vaccines containing oil in water emulsion (e.g. AS03, MF59), rather than aluminium, performed better. Two serious vaccination-associated adverse events were reported, both of which resolved fully. No death or case of Guillain-Barre syndrome was reported. The pandemic influenza (H1N1) 2009 vaccine, with or without adjuvant, appears generally to be seroprotective after just one dose and safe among healthy populations aged >=36 months; very young children (6 35 months) may need to receive two doses of non-adjuvanted vaccine or one dose of AS03(A/B)-adjuvanted product to achieve seroprotection. PMID- 21668697 TI - What is new in the Australasian Adult Resuscitation Guidelines for 2010? PMID- 21668695 TI - Respiratory hygiene practices by the public during the 2009 influenza pandemic: an observational study. AB - AIMS: To describe the public use of respiratory hygiene behaviours during the 2009 influenza pandemic and to test the feasibility of an observational method. METHODS: Respiratory behaviour was systematically observed at three public settings during August 2009 in the capital city of New Zealand (Wellington). Data on each coughing or sneezing event were collected. RESULTS: A total of 384 respiratory events were observed, at a rate of 0.8 cough/sneeze per observed person-hour. Around a quarter of respiratory events (27.3%) were uncovered, and there was infrequent use of the responses recommended by health authorities (i.e., covering with a tissue or handkerchief at 3.4% and covering with elbow or arm at 1.3%). Respiratory event rates were higher in all settings that were 'high flow' (for people movement) compared to 'low flow' settings. Uncovered events were more common among people at the hospital entrance versus the hospital cafe [risk ratio (RR) = 7.8, 95% confidence interval (CI): 1.1-52.6] and when a person was located within 1 m of others (RR = 1.5, 95% CI: 1.1-1.9). Observing respiratory hygiene was found to be feasible in all of the selected public locations. There was good agreement between observing pairs about whether or not respiratory events occurred (inter-observer correlation = 0.81) and for uncovered versus covered events (total Cohen's kappa score = 0.70). CONCLUSIONS: It was feasible to document respiratory hygiene behaviour in public urban settings during a influenza pandemic. Respiratory hygiene advice was not being adequately followed by this population towards the end of the first wave of the pandemic. PMID- 21668698 TI - Managing acute coronary syndromes in the prehospital and emergency setting: new guidelines from the Australian Resuscitation Council and New Zealand Resuscitation Council. PMID- 21668699 TI - Basic life support: managing an emergency. ARC and NZRC Guideline 2010. PMID- 21668700 TI - Basic life support: unconsciousness. ARC and NZRC Guideline 2010. PMID- 21668701 TI - Basic life support: airway. ARC and NZRC Guideline 2010. PMID- 21668702 TI - Basic life support: breathing. ARC and NZRC Guideline 2010. PMID- 21668703 TI - Basic life support: compressions. ARC and NZRC Guideline 2010. PMID- 21668704 TI - Basic life support: automated external defibrillation (AED). ARC and NZRC Guideline 2010. PMID- 21668705 TI - Basic life support: cardiopulmonary resuscitation. ARC and NZRC Guideline 2010. PMID- 21668706 TI - Introduction to advanced life support. ARC and NZRC Guideline 2010. PMID- 21668707 TI - Cardiopulmonary resuscitation for advanced life support providers. ARC and NZRC Guideline 2010. PMID- 21668708 TI - Protocols for adult advanced life support. ARC and NZRC Guideline 2010. PMID- 21668709 TI - Precordial thump and fist pacing. ARC and NZRC Guideline 2010. PMID- 21668710 TI - Electrical therapy for adult advanced life support. ARC and NZRC Guideline 2010. PMID- 21668711 TI - Medications in adult cardiac arrest. ARC and NZRC Guideline 2010. PMID- 21668713 TI - Post-resuscitation therapy in adult advanced life support. ARC and NZRC Guideline 2010. PMID- 21668712 TI - Equipment and techniques in adult advanced life support. ARC and NZRC Guideline 2010. PMID- 21668714 TI - Therapeutic hypothermia after cardiac arrest. ARC and NZRC Guideline 2010. PMID- 21668715 TI - Acute coronary syndromes: introduction to acute coronary syndromes. ARC and NZRC Guideline 2011. PMID- 21668716 TI - Acute coronary syndromes: presentation with ACS. ARC and NZRC Guideline 2011. PMID- 21668717 TI - Acute coronary syndromes: initial medical therapy. ARC and NZRC Guideline 2011. PMID- 21668718 TI - Acute coronary syndromes: reperfusion strategy. ARC and NZRC Guideline 2011. PMID- 21668719 TI - How useful are laboratory investigations in the emergency department evaluation of possible osteomyelitis? AB - We conducted a literature review to determine which laboratory investigations are useful for the ED evaluation of osteomyelitis. Thirty-six relevant papers were identified. We concluded that in adult and paediatric patients with a clinically low level of suspicion of osteomyelitis, an age-adjusted normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) <5 mg/L should reassure the clinician that no further urgent investigation is required. For patients with risk factors for osteomyelitis or a clinically high level of suspicion, a normal ESR or CRP <5 mg/L should not rule out the diagnosis of osteomyelitis, especially in patients with puncture wounds or foot ulcers/infections. In patients with any suspicion of osteomyelitis and otherwise unexplained ESR >30 mm/h and/or CRP >10 30 mg/L further definitive investigation is required. The white blood count is not helpful in the evaluation of osteomyelitis. PMID- 21668720 TI - Resources for the management of ocular emergencies in Australia. AB - The aim of the present paper is to assess the practical utility of the most common print resources used by practitioners in the management of ocular emergencies. Ten print resources were identified for review (three specialty eye texts, six general emergency medicine texts and one general practice text). The main outcome measures used were the extent a text matched crucial skills criteria in clinical assessment and treatment, and usability. No single print resource addressed all criteria. Red flag systems for clinical assessment and ease of navigation were the best match areas. Only one text inadequately stressed red flag conditions and one text was not ranked as easy to navigate. All texts made assumptions regarding the knowledge/skill level of practitioners, particularly in relation to eye examination procedures and treatment. Photographs ranged in number from 8 to 1500; 3/10 texts provided no photographs. Five texts included detailed instructions on the indications and urgency of referral and follow up for all conditions covered. The remainder lacked details. Only one text used the Australasian Triage Scale. Three texts included photographs/diagrams and instructions for the slit lamp and ophthalmoscope. None covered all procedures specified in the criteria. Only two reflected drug current practice in Australia and provided adequate details on usage. A single comprehensive reference (print and/or web-based) for dealing with ocular emergencies in Australia is clearly needed. Additionally, training and confidence levels of eye care providers must be addressed so that the risk of misdiagnosis and mismanagement of eye emergencies is reduced. PMID- 21668721 TI - Chest pain in rural communities; balancing decisions and distance. AB - OBJECTIVE: This pilot study examines the prevalence of cardiac risk factors in a cohort of agricultural workers, assesses their knowledge of local emergency health services and investigates their decision-making abilities with regard to when and how they would seek help when experiencing chest pain. METHODS: Farm men and women were recruited from 20 rural Victorian sites and underwent health assessments for total cholesterol, blood glucose, weight, height and blood pressure. Participants completed a survey to determine their knowledge of chest pain treatment, local emergency services and likely response to chest pain. RESULTS: Cardiac risk factors within this cohort of 186 adult farming men and women were common, with 61% of men (58/95, 95% confidence interval [CI] 51-70) and 74% of women (68/91, 95% CI 65-83) either overweight or obese. When asked to name their nearest ED, 10% of participants (19/184, 95% CI 7-16) nominated health services or towns where no ED exists. Furthermore, 67% of respondents (123/185, 95% CI 59-73) believed it was safe to travel to hospital by car while potentially having a myocardial infarction. CONCLUSIONS: This cohort of agricultural workers were at considerable risk of experiencing acute coronary events, but many would make decisions about when and how to seek medical help for chest pain that are at odds with published community guidelines. These results highlight the need for education to improve knowledge of local emergency services and address behavioural barriers to accessing care. PMID- 21668722 TI - Analgesic usage and reasons for emergency department attendance in ambulatory care patients with minor injury. AB - OBJECTIVE: The aim of the present study was to determine the reasons for which patients with minor injury attend the ED, comparing those who have and have not self-administered analgesia. Secondary outcomes were to quantify the proportion of patients who present without having taken analgesia, to describe the reasons why analgesia was not taken, and to compare pain scores between the two groups. METHODS: Prospective observational study of adult patients with minor injury presenting to the Emergency Department of Palmerston North Hospital, Palmerston North, New Zealand. Participants answered a questionnaire about their analgesic usage and reasons for ED attendance. RESULTS: Four hundred and seventy-three patients were enrolled, of which 63.9% had not self-administered analgesia. The most common primary reasons for ED attendance were for diagnosis (49.6%), and for treatment (31.3%). Patients who had not self-administered analgesia were significantly less likely to be seeking analgesia than those who had (22.8% vs 39.2% [P < 0.001]). They were also less likely to want an X-ray (31.8% vs 46.8% [P= 0.001]) and had a significantly lower pain score than those who had taken analgesia (47.2 vs 59.8, [P < 0.001]). They were significantly more likely to have come primarily for treatment (35.8% vs 23.1% [P= 0.017]). The most commonly cited reasons for not taking analgesia were 'didn't have any handy' (31.0%), or 'didn't have time' (27.4%). CONCLUSION: The majority of patients who attend ED with minor injury have not taken analgesia. They come primarily for diagnosis and treatment, and often believe that their condition is too urgent to stay at home and take analgesia. Pain is usually not their main concern. PMID- 21668723 TI - Prediction of hospital mortality from admission laboratory data and patient age: a simple model. AB - OBJECTIVE: To devise a simple clinical scoring system, using age of patients and laboratory data available on admission, to predict in-hospital mortality of unselected medical and surgical patients. METHODS: All patients admitted as emergencies to a large teaching hospital in Liverpool in the 5 months July November 2004 were reviewed retrospectively, identifying all who died in hospital and controls who survived. Laboratory data available on admission were extracted to form a derivation dataset. Factors that predicted mortality were determined using logistic regression analysis and then used to construct models tested using receiver operating characteristic curves. Models were simplified to include only seven data items, with minimal loss of predictive efficiency. The simplified model was tested in a second validation dataset of all patients admitted to the same hospital in October and November 2004. RESULTS: The derivation dataset included 550 patients who died and 1100 controls. After logistic regression comparisons, 22 dummy variables were given weightings in discriminant analysis and used to create a receiver operating characteristic curve with area under the curve (AUC) of 0.884. The model was simplified to include the seven most discriminant variables, which can each be assigned scores of 2, 3 or 4 to form an index predicting outcome; a validation dataset contained 4828 patients (overall mortality 4.7%), showed this simplified scoring system accurately predicted mortality with AUC 0.848, compared with an AUC of 0.861 in a model containing all 23 original variables. CONCLUSION: A simple scoring system accurately predicts in hospital mortality of unselected hospital patients, using age of patient and a small number of laboratory parameters available very soon after admission. PMID- 21668724 TI - Medical student/student doctor access to patients in an emergency department. AB - OBJECTIVES: To determine the proportion of patients in a teaching hospital ED who are available to medical students; identify barriers to student access to patients; and determine whether patients are more likely to be accessible if the term student doctor is used rather than medical student. METHODS: Repeated cross sectional study of the ED of a tertiary teaching hospital. Interviews were attempted with all patients in the ED during six 4 h periods. Outcome measures included: number of patients present and accessible to students; present but inaccessible, absent or unfit to be seen for clinical reasons; number of patients consenting to history, physical examination and certain procedures; and difference in patient consent between the terms 'medical student' and 'student doctor'. RESULTS: Overall, 180 of 450 (40.0%) patients completed the interview, 72 (16.0%) were able to be observed only, and 198 (44.0%) were not suitable for interview or observation. The common reasons for patient unsuitability were: physically not available (60%), being assessed by a health professional or undergoing a procedure (13.0%) altered mental status (7.4%), unstable or terminally ill (5.2%); refusal to participate in the study (4.8%), or dangerous or under arrest (4.1%). No significant differences were found in patient willingness to undergo clinical skills from 'student doctors' compared with 'medical students'. CONCLUSION: A minimum 40% of patients in a tertiary ED are accessible for student learning, with high proportions of patients accepting of students practising supervised history-taking, physical examination, and most less-invasive procedural skills. PMID- 21668725 TI - Massive pericardial effusion with diastolic right ventricular compression secondary to hypothyroidism in a 73-year-old woman. AB - Pericardial effusion is commonly seen in patients with hypothyroidism, but a massive pericardial effusion with obvious diastolic right ventricular compression is uncommon. We herein report a case of 73-year-old woman seen in the ED with generalized weakness and hypotension. Echocardiography revealed a massive pericardial effusion with diastolic right ventricular compression, and thyroid function testing revealed marked hypothyroidism. The pericardial effusion resolved after the administration of thyroid replacement therapy. This case reveals the importance of including hypothyroidism in the differential diagnosis of pericardia effusion. PMID- 21668726 TI - Lofgren's syndrome misdiagnosed as cellulitis. AB - Lofgren's syndrome is an acute-onset presentation of sarcoidosis that can be easily missed in an ED setting. A case is reported of Lofgren's syndrome presenting as erythema nodosum with bilateral ankle oedema. Although rare, this diagnosis should be considered when examining a patient with erythema nodosum and articular symptoms. PMID- 21668727 TI - Don't fade away. PMID- 21668728 TI - A stand against drug company advertising. PMID- 21668729 TI - Pervasive influence of commercial interests. PMID- 21668730 TI - Ultrasound credentialling: reply. PMID- 21668731 TI - Traumatic pericardial tamponade treated by pericardiocentesis. PMID- 21668735 TI - An exploration of the roles of nurse managers in evidence-based practice implementation. AB - BACKGROUND: Internationally, nurses face ongoing difficulties in making a reality of evidence-based practice. Existing studies suggest that nurse managers (NMs) should play a key role in leading and facilitating evidence-based practice, but the nature of this role has not yet been fully explored or articulated. This is one of the first studies to investigate the roles of NMs in evidence-based practice implementation. METHODOLOGY AND METHODS: Using a case study approach the study explores five propositions in relation to the NMs' potential evidence-based practice role and the extent to which their attitudes, knowledge, and skills support such a role. In doing so, it draws on interviews (n= 51), documentary analysis and observational data. FINDINGS: Data analysis reveals that the role of NMs in facilitating evidence-based practice is under-articulated, largely passive and currently limited by competing demands. Progress in implementing evidence based practice in the case study sites is largely explained by factors other than the role played by NMs. As such, the findings expose significant discrepancies between NMs' actual roles and those espoused in the literature as being necessary. Contextual factors are important and it is clear that the role of the contemporary NM places considerable emphasis on management and administration to the detriment of clinical practice concerns. CONCLUSIONS: The study reveals that NMs are only involved in evidence-based practice implementation in a passive role, not the full engagement described in the literature as being necessary. This study adds previously lacking detail of the roles of NMs. It elucidates why exhortations to NMs to become more involved in evidence-based practice implementation are ineffective without action to address the problems identified. PMID- 21668734 TI - Postweaning, forebrain-specific perturbation of the oxytocin system impairs fear conditioning. AB - Oxytocin (Oxt) and vasopressin (Avp) are important for a wide variety of behaviors and the use of transgenic mice lacking the peptides or their receptors, particularly when their loss is spatially and temporally manipulated, offers an opportunity to closely examine their role in a particular behavior. We used a cued fear conditioning paradigm to examine associative learning in three lines of transgenic mice: mice that constitutively lack vasopressin 1a (Avpr1a(-/-)) or Oxt receptors (Oxtr(-/-)) and mice that have Oxt receptor loss restricted to the forebrain that begins postweaning (Oxtr(FB/FB)). Oxtr(-/-) and Avpr1a(-/-) mice have normal conditioned freezing. Oxtr(FB/FB) mice have a reduction in freezing behavior during acquisition, as well as during context and cue retention. In addition to reduction of Oxtr in the central nucleus of the amygdala, in vitro receptor autoradiography showed that the Oxtr(FB/FB) mice have significantly reduced levels of Avpr1a only in that structure. Our results show that postweaning alteration of the distribution of Oxtr receptors is critically important for fear behavior, an effect mirrored in the neural structures that mediate it. While constitutive knockouts of Oxtr and Avpr1a are useful for identifying the neural underpinnings of some behaviors, compensatory mechanisms within some circuits may obscure other behavioral roles. PMID- 21668736 TI - A call to improve practice concerning cultural sensitivity in advance directives: a review of the literature. AB - BACKGROUND: The Patient Self Determination Act of 1990 mandates healthcare providers (HCP) to speak with patients about end-of-life preferences and advance directives (AD). HCP work with patients of varying cultures, and standard ADs do not address cultural differences. In order to understand various cultural beliefs, cultural sensitivity is important especially when discussing advance care planning (ACP). AIMS: Individuals from differing ethnic backgrounds are likely to turn to their traditional norms of practice when ill or treatment choices must be made. An AD that addresses varying cultural values and beliefs was sought. METHODS: A comprehensive review of the literature was conducted. Articles selected for review included qualitative and quantitative studies. The evidence was evaluated and synthesized for information related to cultural sensitivity and ADs. FINDINGS: Three common themes emerged related to ACP discussions and culture. Healthcare provider awareness, communication, and education concerning cultural differences and ACP assisted in meeting the needs for end-of-life planning in the current era of increased globalization. Education for HCP on cultural differences and how to lead discussions promoted ACP. IMPLICATION FOR PRACTICE: ADs are an essential part of health care and promote patient-centered care. (HCP) should be able to recognize differing cultural values and beliefs in order to initiate conversations about end of life. Initiating conversations about ACP can be facilitated by using open-ended questions that respect the values and beliefs of various cultures. PMID- 21668737 TI - Obstetric hemorrhage. AB - An obstetric hemorrhage may occur before or after delivery, but more than 80% of cases occur postpartum. Worldwide, a massive obstetric hemorrhage, resulting from the failure of normal obstetrical, surgical and/or systemic hemostasis, is responsible for 25% of the estimated 358,000 maternal deaths each year. Most women will not have identifiable risk factors. Nonetheless, primary prevention of a postpartum hemorrhage (PPH) begins with an assessment of identifiable risk factors. Women identified as being at high risk of a PPH should be delivered in a center with access to adequately trained staff and an onsite blood bank. A critical feature of a massive hemorrhage in obstetrics is the development of disseminated intravascular coagulation (DIC), which, in contrast to DIC that develops with hemorrhage from surgery or trauma, is frequently an early feature. Data from clinical trials to guide management of transfusion in PPH are lacking. There are likely to be similarities in the management of transfusion in severe PPH to that of major bleeding in other clinical situations, but the pathophysiological processes that contribute to a massive PPH may necessitate different transfusion strategies such as the ratio of red blood cells to plasma components, in particular fibrinogen. Caution should be exercised when considering the appropriate place for recombinant activated factor VII (rFVIIa) in the management of a major PPH. An early hysterectomy is recommended for severe bleeding as a result of placenta accreta or uterine rupture. However, in women with uterine atony who have ongoing bleeding in spite of an adequate transfusion, it may be reasonable to consider a trial of rFVIIa before a hysterectomy. PMID- 21668739 TI - c-Myb and GATA-1 alternate dominant roles during megakaryocyte differentiation. AB - BACKGROUND: Transcription factors are essential for blood cell formation. Mice expressing low levels of c-Myb (c-Myb(low)) have an increased number of bone marrow megakaryocytes (MKs) and corresponding thrombocytosis. In contrast, mice engineered to express low levels of GATA-1 (GATA-1(low)) in the megakaryocytic lineage exhibit aberrant megakaryocytopoiesis with hyperproliferation of progenitors and defective terminal differentiation leading to thrombocytopenia. These seemingly opposite roles may affect platelet turnover and thus be of clinical relevance. OBJECTIVE: To determine how these two transcription factors act together to control megakaryocytopoiesis and platelet formation. METHODS: We used a combination of cellular and molecular in vitro assays to examine the ability of bone marrow cells from mice expressing low levels of both c-Myb and GATA-1 (referred to as double(low)) to produce MKs and platelets. RESULTS: Double(low) cells, or those with low GATA-1 levels in which c-Myb is conditionally deleted, lack the hyperproliferative capacity of GATA-1(low) cells, allowing the cells to proceed towards more committed MKs that are, however, impaired in their capacity to produce fully differentiated cells, as confirmed by the abundance of morphologically aberrant cells that lack the ability to form proplatelets. CONCLUSION: c-Myb and GATA-1 act in concert to achieve correct megakaryocytic differentiation. GATA-1 regulates both the proliferation of megakaryocytic progenitors and their terminal maturation. c-Myb also acts at the level of the progenitor by influencing its commitment to differentiation, but in contrast to GATA-1 it does not have any effect on the process of terminal differentiation. PMID- 21668738 TI - Use of affinity-directed liquid chromatography-mass spectrometry to map the epitopes of a factor VIII inhibitor antibody fraction. AB - BACKGROUND: Neutralizing factor (F) VIII antibodies develop in approximately 30% of individuals with hemophilia A and show specificity to multiple sites in the FVIII protein. METHODS: Reactive epitopes to an immobilized IgG fraction prepared from a high-titer, FVIII inhibitor plasma were determined after immuno precipitation (IP) of tryptic and chymotryptic peptides derived from digests of the A1 and A2 subunits of FVIIIa and FVIII light chain. Peptides were detected and identified using highly sensitive liquid chromatography-mass spectrometry (LC MS). RESULTS: Coverage maps of the A1 subunit, A2 subunit and light chain represented 79%, 69% and 90%, respectively, of the protein sequences. Dot blots indicated that the inhibitor IgG reacted with epitopes contained within each subunit of FVIIIa. IP coupled with LC-MS identified 19 peptides representing epitopes from all FVIII A and C domains. The majority of peptides (10) were derived from the A2 domain. Three peptides mapped to the C2 domain, while two mapped to the A1 and A3 domains, and single peptides mapped to the a1 segment and C1 domain. Epitopes were typically defined by peptide sequences of < 12 residues. CONCLUSIONS: IP coupled with LC-MS identified extensive antibody reactivity at high resolution over the entire functional FVIII molecule and yielded sequence lengths of < 15 residues. A number of the peptides identified mapped to known sequences involved in functionally important protein-protein and protein-membrane interactions. PMID- 21668740 TI - Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time. PMID- 21668741 TI - Individual differences in morphine and butorphanol analgesia: a laboratory pain study. AB - OBJECTIVE: Responses to opioid analgesics are highly variable, and the understanding of contributing factors is limited. This laboratory study was designed to examine the contributions of sex and race to inter-individual variability in response to opioids. DESIGN: A randomized, double-blind, mixed design was implemented in the evaluation of analgesic response to a u-opioid agonist and mixed agonist-antagonist, using three well-validated experimental pain assays (thermal, pressure, and ischemic). SUBJECTS: Participants included a total of 142 healthy subjects (76 men/66 women), 119 non-Hispanic whites and 23 African Americans. INTERVENTION: Three sessions of pain testing were completed prior to and following an intravenous administration of morphine (0.08 mg/kg), butorphanol (0.016 mg/kg), and placebo (saline) in counterbalanced order. OUTCOME MEASURES: A change score was calculated from the difference between the pre-drug and postdrug values. Three separate change scores (morphine, saline, and butorphanol) were computed for each experimental pain variable. Mixed-model analyses of covariance were performed on analgesic change scores. RESULTS: Significant sex differences emerged for predrug pain measures with minimal differences for race. Sex differences in opioid analgesia were not demonstrated. However, significant race differences and race X drug interactions emerged for thermal, pressure, and ischemic pain measures. The pattern of results generally indicated that for pressure and ischemic pain, African American subjects showed greater analgesic responses to both medications compared with non-Hispanic whites. For thermal pain threshold, butorphanol but not morphine analgesia was greater for African American vs non-Hispanic whites. CONCLUSIONS: Findings are among the first to demonstrate race differences in a laboratory study of opioid analgesia. PMID- 21668742 TI - Painful medical conditions and alcohol use: a prospective study among older adults. AB - OBJECTIVE: To determine associations between older adults' baseline painful medical conditions and their 10-year drinking behavior, and whether personal and life context characteristics moderate these associations. METHODS: At baseline, then, 1, 4, and 10 years later, late-middle-aged community residents (M = 61 years; N = 1,291) were surveyed regarding their painful medical conditions, use of alcohol, and personal and life context characteristics. Latent growth modeling was used to determine concurrent and prospective relationships between painful medical conditions and 10-year drinking behavior, and moderating effects of personal and life context characteristics on these relationships. RESULTS: At baseline, individuals reporting more numerous painful medical conditions consumed alcohol less frequently, but had more frequent drinking problems, than did individuals with fewer such conditions. Being female and having more interpersonal social resources strengthened the association between painful medical conditions and less ethanol consumed. For men more so than women, more numerous painful medical conditions were associated with more frequent drinking problems. Baseline painful medical conditions alone had no prospective effect on 10-year change in drinking behavior, but being older and having more interpersonal social resources made it more likely that baseline painful medical conditions would predict decline over time in frequency of alcohol consumption and drinking problems. CONCLUSIONS: Late-middle-aged individuals who have more numerous painful medical conditions reduce alcohol consumption but nonetheless remain at risk for more frequent drinking problems. Gender, age, and interpersonal social resources moderate the influence of painful medical conditions on late-life alcohol use. These results imply that older individuals with pain are at little immediate or long-term risk for increased alcohol consumption, but clinicians should remain alert to drinking problems among their older pain patients, especially men. PMID- 21668744 TI - A tradition of traditional medicine. PMID- 21668743 TI - Catastrophizing, state anxiety, anger, and depressive symptoms do not correlate with disability when variations of trait anxiety are taken into account. a study of chronic low back pain patients treated in Spanish pain units [NCT00360802]. AB - OBJECTIVES: To assess the influence of pain severity, catastrophizing, anger, anxiety, and depression on nonspecific low back pain (LBP)-related disability in Spanish patients with chronic LBP. Study Design. Cross-sectional correlation between psychological variables and disability. Methods. One hundred twenty three patients treated for chronic LBP in pain units within nine Spanish National Health Service Hospitals, in eight cities, were included in this study. Intensity of LBP and pain referred to the leg, disability, catastrophizing, anger, state anxiety, trait anxiety, and depression were assessed through previously validated questionnaires. The association of disability with these variables, as well as gender, age, academic level, work status, and use of antidepressants, was analyzed through linear regression models. RESULTS: Correlations between LBP, referred pain, disability, catastrophizing, anger, state anxiety, trait anxiety, and depression were significant, except for the ones between anger and LBP and between anger and referred pain. The multivariate regression model showed that when variations of trait anxiety were taken into account, the association of the other psychological variables with disability was no longer significant. The final model explained 49% of the variability of disability. Standardized coefficients were 0.452 for trait anxiety, 0.362 for intensity of LBP, 0.253 for failed back surgery, and -0.140 for higher academic level. CONCLUSION: Among Spanish chronic LBP patients treated at pain units, the correlation of catastrophizing, state anxiety, anger, and depression with disability ceases to be significant when variations of trait anxiety are taken into account. Further studies with LBP patients should determine whether anxiety trait mediates the effects of the other variables, explore its prognostic value, and assess the therapeutic effect of reducing it. PMID- 21668745 TI - Role of dopaminergic gene polymorphisms (DBH 19 bp indel and DRD2 Nco I) in genetic susceptibility to migraine in North Indian population. AB - OBJECTIVE: The dopaminergic system plays a major role in migraine. We aimed to look for association of polymorphisms in dopaminergic genes in genetic susceptibility to migraine in North Indian population. In the present study, two polymorphisms, DBH 19 bp indel (rs no. 72393728) and DRD2 Nco I (rs no. 6275), were selected. DESIGN: Using case-control design, 301 migraine patients (202 migraine without aura and 99 migraine with aura) and 202 healthy controls were recruited in the study. Genotyping was done using polymerase chain reaction (PCR) (DBH 19 bp indel) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) (DRD2 Nco I). Logistic regression analysis was used to find the contribution of these polymorphisms in migraine. Bonferroni's correction was applied for multiple comparisons. RESULTS: In DBH 19 bp indel polymorphism, a significant association was observed at allelic level (P = 0.027) especially in females (P = 0.016) on comparing migraine patients with healthy controls. In DRD2 Nco I polymorphism, no significant association was observed in migraine patients or any subgroups. CONCLUSION: Our study suggests a potentially significant role of DBH 19 bp indel polymorphism in migraine susceptibility. PMID- 21668747 TI - What can we learn from first-year medical students' perceptions of pain in the primary care setting? AB - OBJECTIVE: Pain concerns are one of the leading causes of visits to primary care. However, practicing physicians find managing pain frustrating and complex. There is little information about how undergraduate medical students approach pain and its management. This study aimed to explore first-year medical students' perceptions of pain-related patient encounters in the primary care setting. DESIGN: Qualitative analysis was used to explore first-year students' reflective journals written during an early clinical experience in primary care. Using iterative process for text analysis, entries referencing pain-related encounters were coded by two independent researchers with 94% inter-rater reliability. Themes and categories were sought by immersion crystallization. RESULTS: Three themes emerged from the students' journals: positive, negative, and neutral perceptions of pain-related encounters. With further analysis of the journals, acute, chronic, end-of-life, iatrogenic, and emotional pain categories also emerged. Most journal entries were negative, and chronic pain generated the most negativity. CONCLUSIONS: First-year medical students identified pain as a major concern in their early clinical experience. Students' perceptions of pain-related encounters can inform curriculum design and may ultimately benefit both physicians and the patients. PMID- 21668746 TI - Presence of mental imagery associated with chronic pelvic pain: a pilot study. AB - OBJECTIVE: To ascertain whether a small sample of patients with chronic pelvic pain experienced any pain-related cognitions in the form of mental images. PATIENTS: Ten women with chronic pelvic pain consecutively referred from a tertiary referral center by the physicians in charge of their treatment. OUTCOME MEASURES: An interview was used to determine the presence, emotional valence, content, and impact of cognitions about pain in the form of mental images and verbal thoughts. The Brief Pain Inventory (BPI), Pain Catastrophizing Scale (PCS), Spontaneous Use of Imagery Scale (SUIS), and Hospital Anxiety and Depression Scale (HADS) were completed. RESULTS: In a population of patients with a prolonged duration of pain and high distress, all patients reported experiencing cognitions about pain in the form of mental images. For each patient, the most significant image was both negative in valence and intrusive. The associated emotional-behavioral pattern could be described within a cognitive behavioral therapy framework. Eight patients also reported coping imagery. CONCLUSION: Negative pain-related cognitions in the form of intrusive mental imagery were reported by women with chronic pelvic pain. Targeting such imagery has led to interesting treatment innovation in the emotional disorders. Thus, imagery, hitherto neglected in pain phenomenology, could provide a novel target for cognitive behavioral therapy in chronic pain. These exciting yet preliminary results require replication and extension in a broader population of patients with chronic pain. PMID- 21668748 TI - Botox A injection for pain after laparoscopic ventral hernia: a case report. AB - INTRODUCTION: Laparoscopic ventral hernia repair has many advantages over open techniques: adequate visualization of the entire abdominal wall, ease of placement of preperitoneal mesh with adequate overlap, and cosmesis. Intense and activity limiting pain is often one inferior aspect of this repair. We report the case of a patient who was intolerant of narcotic pain medicine with activity limiting pain. A novel technique for postoperative pain control was instituted utilizing Botox A (Allergan Inc., Irvine, CA, USA). METHODS: Botox A was diluted to 2 units per mL and three injection sites were chosen on each side of the abdominal wall. All three muscle bellies (external oblique, internal oblique, and transversus) were identified by ultrasound and 8 mL was injected in each. This resulted in three muscle layers at six sites for a total of 18 injections. A total of 300 units of Botox A were utilized. RESULTS: Pain scores improved from 10/10 to 2/10 and were durable at 3-month follow up. CONCLUSION: Botox A provided significant pain control for this patient after laparoscopic ventral hernia repair. Continued prospective study to define long-term outcomes, cost savings, and appropriate timing of injections is underway. PMID- 21668749 TI - Priapism following a lumbar sympathetic nerve block. AB - OBJECTIVE: To understand an unusual complication of a common procedure. DESIGN: This article chronicles the side effect of a lumbar sympathetic nerve block (LSNB). SETTING: Loyola University Medical Center Outpatient Chronic Pain Clinic. PATIENTS: One. RESULTS: Our patient had several hours of priapism following a LSNB. CONCLUSIONS: A bilateral lumbar sympathetic nerve block can lead to unopposed parasympathetic penile stimulation and cause priapism. PMID- 21668750 TI - A randomized, placebo-controlled trial of repetitive spinal magnetic stimulation in lumbosacral spondylotic pain. AB - OBJECTIVE: Lumbar spondylosis is a degenerative disorder of the spine, whereby pain is a prominent feature that poses therapeutic challenges even after surgical intervention. There are no randomized, placebo-controlled studies utilizing repetitive spinal magnetic stimulation (SMS) in pain associated with lumbar spondylosis. In this study, we utilize SMS technique for patients with this condition in a pilot clinical trial. METHODS: We randomized 20 patients into SMS treatment or placebo arms. All patients must have clinical and radiological evidence of lumbar spondylosis. Patients should present with pain in the lumbar region, localized or radiating down the lower limbs in a radicular distribution. SMS was delivered with a Medtronic R30 repetitive magnetic stimulator (Medtronic Corporation, Skovlunde, Denmark) connected to a C-B60 figure of eight coil capable of delivering a maximum output of 2 Tesla per pulse. The coil measured 90 mm in each wing and was centered over the surface landmark corresponding to the cauda equina region. The coil was placed flat over the back with the handle pointing cranially. Each patient on active treatment received 200 trains of five pulses delivered at 10 Hz, at an interval of 5 seconds between each train. "Sham" SMS was delivered with the coil angled vertically and one of the wing edges in contact with the stimulation point. RESULTS: All patients tolerated the procedure well and no side effects of SMS were reported. In the treatment arm, SMS had resulted in significant pain reduction immediately and at Day 4 after treatment (P < 0.05). In the placebo arm, however, no significant pain reduction was seen immediately and at Day 4 after SMS. SMS in the treatment arm had resulted in mean pain reduction of 62.3% postprocedure and 17.4% at Day 4. The placebo arm only achieved pain reduction of 6.1% postprocedure and 4.5% at Day 4. DISCUSSION: This is the first study to show that a single session of SMS resulted in significant improvement of pain associated with lumbar spondylosis in a randomized, double blind, placebo-controlled setting. The novel findings support the potential of this technique for future studies pertaining to neuropathic pain. PMID- 21668751 TI - Intra- and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake. AB - OBJECTIVE: This study aims to demonstrate the analgesic efficacy and opioid sparing effect of low dose ketamine in patients with preoperative narcotic intake undergoing major spine surgery. DESIGN: The study used a prospective, randomized, double-blinded, and placebo-controlled clinical trial. SETTINGS AND PATIENTS: We evaluated the analgesic efficacy and safety of low dose IV ketamine infusion after major spine surgery in patients with preoperative narcotic analgesic intake. Ketamine group received IV ketamine infusion (2 ug/kg/min) and saline group received saline intraoperatively and the first 24 hours postoperatively. In addition, all patients received IV patient-controlled hydromorphone and epidural bupivacaine. OUTCOME MEASURES: Pain scores, narcotic requirement, and side effects were compared between the groups for 48 hours postoperatively. RESULTS: Thirty patients completed the study (N = 15 in each group). No difference in pain scores at rest and movement was noted between the groups (P > 0.05). Patients in ketamine group received 40.42 +/- 32.86 mg IV hydromorphone at 48 hours compared with 38.24 +/- 26.19 mg in saline group (P = 0.84). Central nervous system side effects were observed in five (33%) ketamine group patients compared with nine (60%) in saline group (P = 0.29). CONCLUSION: The addition of IV very low dose ketamine infusion regimen did not improve postoperative analgesia. Side effects were not increased with low dose ketamine. PMID- 21668752 TI - Ending unnecessary opioid-related deaths: a national priority. PMID- 21668753 TI - Studying adverse events related to prescription opioids: the Utah experience. AB - BACKGROUND: Epidemiologists at the Utah Department of Health (UDOH) began to study prescription drug-related harm in 2004. We have analyzed several types of data including vital statistics, medical examiner records, emergency department diagnoses, and the state prescription registry to estimate the scope and correlates of prescription drug-related harm. OBJECTIVES: To describe data sets analyzed in Utah related to the problem of prescription drug-related harm with the goal of designing interventions to reduce the burden of adverse events and death. RESULTS: Prescription drug-related harm in Utah primarily involved opioids and can be examined with secondary analysis of administrative databases, although each database has limitations. CONCLUSIONS: More analyses, likely from cohort studies, are needed to identify risky prescribing patterns and individual-level risk factors for opioid-related harm. Combining data sets via linkage procedures can generate individual-level drug exposure and outcome histories, which may be useful to simulate a prospective cohort. PMID- 21668754 TI - An analysis of the root causes for opioid-related overdose deaths in the United States. AB - OBJECTIVE: A panel of experts in pain medicine and public policy convened to examine root causes and risk factors for opioid-related poisoning deaths and to propose recommendations to reduce death rates. METHODS: Panelists reviewed results from a search of PubMed and state and federal government sources to assess frequency, demographics, and risk factors for opioid-related overdose deaths over the past decade. They also reviewed results from a Utah Department of Health study and a summary of malpractice lawsuits involving opioid-related deaths. RESULTS: National data demonstrate a pattern of increasing opioid-related overdose deaths beginning in the early 2000s. A high proportion of methadone related deaths was noted. Although methadone represented less than 5% of opioid prescriptions dispensed, one third of opioid-related deaths nationwide implicated methadone. Root causes identified by the panel were physician error due to knowledge deficits, patient non-adherence to the prescribed medication regimen, unanticipated medical and mental health comorbidities, including substance use disorders, and payer policies that mandate methadone as first-line therapy. Other likely contributors to all opioid-related deaths were the presence of additional central nervous system-depressant drugs (e.g., alcohol, benzodiazepines, and antidepressants) and sleep-disordered breathing. CONCLUSIONS: Causes of opioid related deaths are multifactorial, so solutions must address prescriber behaviors, patient contributory factors, nonmedical use patterns, and systemic failures. Clinical strategies to reduce opioid-related mortality should be empirically tested, should not reduce access to needed therapies, should address risk from methadone as well as other opioids, and should be incorporated into any risk evaluation and mitigation strategies enacted by regulators. PMID- 21668756 TI - Depression, chronic pain, and suicide by overdose: on the edge. AB - Comorbid conditions that pose risks for suicide, especially depression, are prevalent in people living with chronic pain. The true numbers of failed attempts and successful suicides are unknown and may never be determined. Yet, risk factors for suicidal ideation are so high in this population that it must be assumed that some proportion of those who die of drug overdoses might have intended to end their lives, not just temporarily relieve their pain. The purpose of this manuscript is to highlight to clinicians the important association between chronic pain and intentional self-harm. Contemporary understanding of the epidemiology of depression and suicide and the relationship to chronic pain will be reviewed. Recommendations for the use of validated and practical screening tools as part of a comprehensive clinical assessment and for approaches to suicide prevention and interventions as crucial components of chronic pain management are outlined. PMID- 21668755 TI - Psychological variables potentially implicated in opioid-related mortality as observed in clinical practice. AB - Opioid-related deaths in the United States have become a public health problem, with accidental and unintended overdoses being especially troubling. Screening for psychological risk factors is an important first step in safeguarding against nonadherence practices and identifying patients who may be vulnerable to the risks associated with opioid therapy. Validated screening instruments can aid in this attempt as a complementary tool to clinicians' assessments. A structured screening is imperative as part of an assessment, as clinician judgment is not the most reliable method of identifying nonadherence. As a complement to formal screening, we present for discussion and possible future study certain psychological variables observed during years of clinical practice that may be linked to medication nonadherence and accidental overdose. These variables include catastrophizing, fear, impulsivity, attention deficit disorders, existential distress, and certain personality disorders. In our experience, chronic pain patients with dual diagnoses may become "chemical copers" as a way of coping with their negative emotion. For these patients, times of stress could lead to accidental overdose. Behavioral, cognitive-behavioral (acceptance and commitment, dialectical behavior), existential (meaning-centered, dignity), and psychotropic therapies have been effective in treating these high-risk comorbidities, while managing expectations of pain relief appears key to preventing accidental overdose. PMID- 21668757 TI - System dynamics modeling as a potentially useful tool in analyzing mitigation strategies to reduce overdose deaths associated with pharmaceutical opioid treatment of chronic pain. AB - OBJECTIVE: To illustrate a system-level, simulation-based approach for evaluating mitigation strategies to address the dramatic rise in abuse, addiction, and overdose deaths associated with the use of pharmaceutical opioid analgesics to treat chronic pain. SIMULATED INTERVENTIONS: Making available drug formulations with increased tamper-resistance, prescriber education programs, and programs that reduce rates of medical user-related abuse and addiction. SIMULATED OUTCOME MEASURE: Number of overdose deaths of medical users of pharmaceutical opioid analgesics, including those who abuse or have become addicted. METHODS: A demonstration system dynamics model is developed, tested, and used to evaluate the impact of candidate mitigation strategies on the outcome measures. RESULTS: Tamper-resistant drug products will likely reduce overdose death rates but may not reduce overall deaths if there is increased prescribing. Prescriber education would likely reduce deaths through a reduction in patient access to pharmaceutical opioid analgesics. CONCLUSIONS: The system dynamics approach may have potential for opioid-related policy evaluation. However, metrics must be carefully selected, and trade-offs may be involved. For example, it may be difficult to limit negative outcomes associated with pharmaceutical opioids without adversely affecting chronic pain patients' access to pharmaceutical treatment. Ultimately, a combination of metrics and value judgments will be needed to properly evaluate mitigation strategies. PMID- 21668758 TI - A review of forensic implications of opioid prescribing with examples from malpractice cases involving opioid-related overdose. AB - OBJECTIVE: To provide a forensic overview and trace common threads among malpractice lawsuits involving patients who overdosed while consuming therapeutic opioids. METHODS: One of us (LRW) reviewed 35 medical records of patients with chronic pain who overdosed, 20 of them fatally, while consuming therapeutic opioids, leading to lawsuits against physicians for malpractice. The reviews were requested by plaintiff and defense attorneys from across the United States from 2005 to 2009 to ascertain which drug(s) were primarily responsible for each death and whether the death was due to physician error, patient nonadherence, or some other reason. Complaints against pharmaceutical companies were excluded. Cases were examined for common trends, and comment is offered. RESULTS: Methadone was responsible for the most deaths at 10 (50%), and hydrocodone was second at four deaths (20%) The most common risk factors found in the medical records of decedents included prescriber error in initiating, converting or titrating doses, patient nonadherence to medical instruction, presence of comorbid mental disorders, toxicological presence of benzodiazepines, middle age, and unrelieved pain. This article focuses on examples of physician errors and how they can be prevented. CONCLUSIONS: Common trends emerge from medical records of opioid decedents. Patient actions con-tribute, but physician error, particularly regarding prescribing methadone for pain, is apparent as well. A focused effort to determine the types and causes of common physician errors and how they might be avoided may lead to safer, more effective clinical interventions in the management of pain. PMID- 21668759 TI - State-level strategies for reducing prescription drug overdose deaths: Utah's prescription safety program. AB - INTRODUCTION: The Utah Department of Health created a program to decrease deaths and other harm from prescription pain medication. Program goals included educating the public, providers, and patients on prescription safety and creating guidelines for providers on prescribing opioids. PROGRAM INTERVENTIONS: The department's Prescription Pain Medication Program was organized in collaboration with many state agencies as well as public and private organizations. The program developed a statewide media campaign, running messages using the slogan "Use Only As Directed" from May 2008 to May 2009. The program facilitated the publication and distribution of opioid prescribing guidelines. PROGRAM OUTCOMES: Collaboration among stakeholders to develop educational materials furthered use of the materials. The program distributed more than 2,800 copies of the prescribing guidelines and more than 120,000 copies of print materials, including bookmarks, patient information cards, and posters. STATEWIDE DATA: In 2008, unintentional overdose deaths from prescription opioids dropped 14.0% compared with the number of deaths in 2007. In 2009, the number of deaths remained stable from 2008. The campaign funding ended in May 2009. State agencies have continued collaborating and have pooled money to renew the media campaign in 2011. Evaluation of the impact of the prescribing guidelines is ongoing. CONCLUSIONS: The state-funded educational campaign may have contributed to a reduction in overdose deaths. Collaboration among state agencies and a sustained educational effort are important aspects of a successful prevention campaign. PMID- 21668760 TI - Provider detailing: an intervention to decrease prescription opioid deaths in Utah. AB - BACKGROUND: Utah undertook a multipronged effort to reverse an epidemic of deaths among patients taking prescription opioids. This article describes the provider detailing portion of the effort. METHODS: Presentations highlighting six recommended prescribing practices were developed and presented to health care workers. Participants were encouraged to utilize the state prescription database and to complete a series of surveys assessing confidence and behavior changes at 0, 1, and 6 months post-presentation. Continuing medical education credits incentivized participation. RESULTS: Utah's medication-related overdose deaths dropped 14.0% in 2008 compared with 2007 following program implementation. A total of 581 physicians and numerous nonphysician health care workers were reached during 46 presentations. Follow-up surveys regarding the degree of adoption of practice changes were completed by 366 participants at 0 months, 82 participants at 1 month, and 29 participants at 6 months. Combined results for all three evaluations showed that 60-80% of responding providers reported no longer prescribing long-acting opioids for acute pain or with sedatives; 50% noted using Utah's controlled substances database during patient care and utilizing lower starting doses and slower escalations; and 30-50% reported obtaining EKGs and sleep studies on appropriate patients, using patient education tools, and implementing Utah's prescribing guidelines. CONCLUSIONS: Provider detailing was associated with a decrease in Utah's prescription opioid death rate and improvements in provider self-reported prescribing behaviors. Other simultaneous interventions may have contributed to the decline in death rates. This intervention's effect was limited by short-term funding. PMID- 21668761 TI - Project Lazarus: community-based overdose prevention in rural North Carolina. AB - BACKGROUND: In response to some of the highest drug overdose death rates in the country, Project Lazarus developed a community-based overdose prevention program in Western North Carolina. The Wilkes County unintentional poisoning mortality rate was quadruple that of the state's in 2009 and due almost exclusively to prescription opioid pain relievers, including fentanyl, hydrocodone, methadone, and oxycodone. The program is ongoing. METHODS: The overdose prevention program involves five components: community activation and coalition building; monitoring and surveillance data; prevention of overdoses; use of rescue medication for reversing overdoses by community members; and evaluating project components. Principal efforts include education of primary care providers in managing chronic pain and safe opioid prescribing, largely through the creation of a tool kit and face-to-face meetings. RESULTS: Preliminary unadjusted data for Wilkes County revealed that the overdose death rate dropped from 46.6 per 100,000 in 2009 to 29.0 per 100,000 in 2010. There was a decrease in the number of victims who received prescriptions for the substance implicated in their fatal overdose from a Wilkes County physician; in 2008, 82% of overdose decedents received a prescription for an opioid analgesic from a Wilkes prescriber compared with 10% in 2010. CONCLUSIONS: While the results from this community-based program are preliminary, the number and nature of prescription opioid overdose deaths in Wilkes County changed during the intervention. Further evaluation is required to understand the localized effect of the intervention and its potential for replication in other areas. PMID- 21668762 TI - Obtaining adequate data to determine causes of opioid-related overdose deaths. AB - Current data collected by medical examiners and coroners are incomplete and inadequate to evaluate the factors that lead to fatalities involving prescription opioids. Determining cause of death is critically important. Two methods are proposed to improve consistency and accuracy in the collection and analysis of decedent data in opioid-related poisoning deaths. First, an improved death certificate is needed to collect evaluative data, including: extent to which opioids were judged to 1) cause, 2) contribute to, or 3) be present in investigated deaths; extent to which opioids as a cause of death were found 1) alone, 2) combined with other prescription drugs, 3) combined with alcohol, or 4) combined with illicit drugs; the time of death; the presence or absence of a valid prescription; and the estimated quantity of opioids taken proximal to death. Patient characteristics for analysis include age, gender, race/ethnicity, geographic area (particularly whether urban or rural), body mass index, duration of opioid usage and daily average dose during the last 2 weeks of life, and histories of chronic pain/medical conditions, substance abuse, and mental illness/psychiatric diagnoses. Second, expanding the scope of opioid toxicology categories used to classify and code cause-of-death data reported by death investigators would improve identification of individual drugs and classes most often associated with overdose deaths. Formulation-specific codes should be added to facilitate consistent recording of findings by death investigators and entry into national vital statistics databases. PMID- 21668764 TI - Exploring age differences in reasons for nonattendance for cervical screening: a qualitative study. AB - OBJECTIVES: To explore differences in barriers to attendance at cervical screening across age groups because coverage of the cervical screening programme in England has been falling, particularly among women in the youngest age group (25-29 years). DESIGN: A qualitative study. SETTING: A university in London. SAMPLE: Professionals working in the screening field (n=12) and women of varying ages who had either never attended for cervical screening or did not attend regularly (n=46). METHODS: In Study 1 we interviewed professionals to elicit their views on the reasons for lower screening attendance in young women. In Study 2, we carried out four focus groups (n=27) and 19 individual interviews with under-screened women to explore their barriers to attendance. Verbatim transcripts were analysed using Framework Analysis. RESULTS: Reasons for nonattendance were many and varied. Health professionals identified population level factors, service provision issues, time pressures, risk perceptions, lack of knowledge and psychological barriers. The nonattenders fell into two groups: those who had made an active decision not to take part (who tended to be older), and those who intended to be screened but did not attend (predominantly younger women). Practical barriers were raised more often by younger women whereas older women had more negative attitudes to screening. CONCLUSION: This study provides rich data on the complex reasons why women do not attend for cervical screening. It points to age differences in barriers to screening, and suggests that addressing practical issues such as appointment systems and clinic times may have a positive impact on attendance in young women. PMID- 21668763 TI - Alternative splicing factor or splicing factor-2 plays a key role in intron retention of the endoglin gene during endothelial senescence. AB - Alternative splicing involving intron retention plays a key role in the regulation of gene expression. We previously reported that the alternatively spliced short isoform of endoglin (S-endoglin) is induced during the aging or senescence of endothelial cells by a mechanism of intron retention. In this work, we demonstrate that the alternative splicing factor or splicing factor-2 (ASF/SF2) is involved in the synthesis of endoglin. Overexpression of ASF/SF2 in endothelial cells switched the balance between the two endoglin isoforms, favoring the synthesis of S-endoglin. Using a minigene reporter vector and RNA immunoprecipitation experiments, it was shown that ASF/SF2 interacts with the nucleotide sequence of the endoglin minigene, suggesting the direct involvement of ASF/SF2. Accordingly, the sequence recognized by ASF/SF2 in the endoglin gene was identified inside the retained intron near the consensus branch point. Finally, the ASF/SF2 subcellular localization during endothelial senescence showed a preferential scattered distribution throughout the cytoplasm, where it interferes with the activity of the minor spliceosome, leading to an increased expression of S-endoglin mRNA. In summary, we report for the first time the molecular mechanisms by which ASF/SF2 regulates the alternative splicing of endoglin in senescent endothelial cells, as well as the involvement of ASF/SF2 in the minor spliceosome. PMID- 21668765 TI - First-trimester ductus venosus screening for cardiac defects: a meta-analysis. AB - BACKGROUND: Heart defects are the most common congenital abnormalities. OBJECTIVE: We aimed to evaluate in a meta-analysis the screening performance of abnormal ductus venosus (DV) Doppler waveform for detection of congenital heart disease (CHD) in chromosomally normal fetuses. SEARCH STRATEGY: Studies were retrieved from a search of MEDLINE, ISI, SCOPUS and EMBASE (from 1999 to March 2011) using the keywords 'ductus venosus', 'DV', 'chromosomal abnormalities', 'congenital heart disease' and 'nuchal translucency'. SELECTION CRITERIA: We considered all studies that examined the diagnostic performance of DV in the first trimester for CHD in chromosomally normal fetuses. We included studies that were limited to fetuses with increased nuchal translucency (NT), normal NT, and studies that examined fetuses regardless of NT status. DATA COLLECTION AND ANALYSIS: Seven studies (n = 50,354) regardless of the NT status, nine studies (n = 2908) with increased NT and seven studies (n = 47,610) with normal NT were included in the meta-analysis. We drew hierarchical summary receiver operating characteristic (HSROC) curves using the parameters of the fitted models. MAIN RESULTS: In populations including participants regardless of NT status, the summary sensitivity and specificity of DV for detecting CHD were 50 and 93%, respectively. In participants with increased NT, the summary sensitivity and specificity were 83 and 80%, and in those with normal NT, they were 19 and 96%, respectively. AUTHORS' CONCLUSIONS: The estimated performance of DV assessment for detection of CHD in chromosomally normal fetuses can be considered in evaluating the potential use and limitations of this screening test. PMID- 21668766 TI - Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: evaluation of a 7-year clinical experience. AB - OBJECTIVE: To evaluate the diagnostic performance of noninvasive fetal blood group genotyping. DESIGN: Descriptive analysis. SETTING: Dutch national reference laboratory for pregnancies complicated by alloimmunisation. POPULATION: All consecutive alloimmunised pregnant women for whom fetal blood group genotyping of rhesus D, c, E or of K in maternal plasma was performed from 2003 up to 2010. METHODS: The test results of each individual assay were collected. Real-time polymerase chain reaction was performed for RHD exon 5 and RHD exon 7, or the specific allele of the RHCE or KEL gene. A stringent diagnostic algorithm was applied. In the case of a negative result, the presence of fetal DNA was ascertained by the analysis of the Y chromosome-specific SRY gene or other paternal genetic markers. Results were compared with available serology after birth or genotyping results of amniotic fluid cells. MAIN OUTCOME MEASURES: Percentage of conclusive test results and diagnostic accuracy. RESULTS: A total of 362 tests was performed (D: n = 168; c: n = 49; E: n = 85; K: n = 60). The median gestational age was 17 weeks (range 7-38 weeks). In 351 women (97%), a test result was issued: in seven samples, the presence of fetal DNA could not be confirmed; in two samples, non-specific amplification in the K assay led to an inconclusive result; in two samples, a maternal silent RHD gene prevented fetal RHD genotyping. No false-positive or false-negative results were found among those women for whom cord blood serology or genotyping results of amniotic fluid cells were available (n = 212). CONCLUSIONS: Noninvasive fetal blood group genotyping is accurate and applicable in a clinical diagnostic setting. PMID- 21668767 TI - Fetal blood sampling in addition to intrapartum ST-analysis of the fetal electrocardiogram: evaluation of the recommendations in the Dutch STAN(r) trial. AB - OBJECTIVES: To evaluate the recommendations for additional fetal blood sampling (FBS) when using ST-analysis of the fetal electrocardiogram. DESIGN: Prospective cohort study. SETTING: Three academic and six non-academic teaching hospitals in the Netherlands. POPULATION: Labouring women with a high-risk singleton pregnancy in cephalic position beyond 36 weeks of gestation. METHODS: In labouring women allocated to the STAN(r) arm of a previously published randomised controlled trial who underwent one or more FBS during delivery, we assessed whether FBS was performed according to the trial protocol and how fetal acidosis, defined as an FBS pH < 7.20, was related to ST-waveform analysis. MAIN OUTCOME MEASURES: The number of FBS showing fetal acidosis, related to the different STAN(r) criteria where additional FBS is recommended. RESULTS: Among 2827 women monitored with STAN(r), 297 underwent FBS, of whom 171 (57.6%) were performed according to the predefined criteria and 126 were performed in absence of these criteria. In the first group, rates of fetal acidosis (pH < 7.20) were two of 18, none of nine, 12 of 111 and three of 33 when FBS was taken for abnormal cardiotocogram (CTG) at the start, intermediary CTG at the start, abnormal CTG >60 minutes, and poor electrocardiogram quality, respectively. When the predefined criteria were not met and ST-analysis showed no ST-events, only two incidents of fetal acidosis were seen. CONCLUSIONS: The performance of FBS is valuable in the advised STAN(r) criteria. When these criteria are not met, performance of FBS does not seem helpful in the detection of fetal acidosis. PMID- 21668769 TI - Aerobic vaginitis in pregnancy. AB - Aerobic vaginitis (AV) is an alteration in vaginal bacterial flora that differs from bacterial vaginosis (BV). AV is characterised by an abnormal vaginal microflora accompanied by an increased localised inflammatory reaction and immune response, as opposed to the suppressed immune response that is characteristic of BV. Given the increased local production of interleukin (IL)-1, IL-6 and IL-8 associated with AV during pregnancy, not surprisingly AV is associated with an increased risk of preterm delivery, chorioamnionitis and funisitis of the fetus. There is no consensus on the optimal treatment for AV in pregnant or non-pregnant women, but a broader spectrum drug such as clindamycin is preferred above metronidazole to prevent infection-related preterm birth. The exact role of AV in pregnancy, the potential benefit of screening, and the use of newer local antibiotics, disinfectants, probiotics and immune modulators need further study. PMID- 21668768 TI - Haemodynamic effects of carbetocin and oxytocin given as intravenous bolus on women undergoing caesarean delivery: a randomised trial. AB - OBJECTIVE: This study compares the maternal heart rate effects of carbetocin and oxytocin during elective caesarean delivery. DESIGN: Double blind randomised single centre study (1:1). SETTING: University hospital providing intrapartum care. POPULATION: Fifty-six women undergoing elective caesarean section after spinal anaesthesia. METHODS: Haemodynamic parameters were measured non-invasively using the Task Force((r)) Monitor 3040i system. Measurements were taken for 500 seconds upon administration of a slow intravenous bolus of the clinically recommended doses of 100 MUg of carbetocin or 5 IU of oxytocin to prevent postpartum haemorrhage (PPH). MAIN OUTCOME MEASURE: Effect on maternal heart rate (HR). RESULTS: Statistically indistinguishable haemodynamic effects were seen for both drugs, with a maximal effect at about 30-40 seconds: HR increased 17.98 +/- 2.53 bpm for oxytocin and 14.20 +/- 2.45 bpm for carbetocin. Systolic blood pressure (sBP) decreased (-26.80 +/- 2.82 mmHg for oxytocin versus -22.98 +/- 2.75 mmHg for carbetocin). Following the maximal effect, women treated with carbetocin recovered slowly to baseline values asymptotically (HR and BP), whereas women treated with oxytocin displayed a slight rebound bradycardia at 200 seconds (-6.8 +/- 1.92 bpm). Patients under both treatments showed a similar profile of side effects without any indication of unexpected adverse effects. CONCLUSION: Both oxytocins have comparable haemodynamic effects and are uterotonic drugs with an acceptable safety profile for prophylactic use. Minimal differences in the recovery phase beyond 70 seconds are in keeping with the fact that carbetocin has an extended half-life compared with oxytocin. PMID- 21668771 TI - Trends in preterm birth: singleton and multiple pregnancies in the Netherlands, 2000-2007. AB - OBJECTIVE: Several studies have reported increasing trends in preterm birth in developed countries, mainly attributable to an increase in medically indicated preterm births. Our aim was to describe trends in preterm birth among singleton and multiple pregnancies in the Netherlands. DESIGN: Prospective cohort study. SETTING: Nationwide study. POPULATION: We studied 1,451,246 pregnant women from 2000 to 2007. METHODS: We assessed trends in preterm birth. We subdivided preterm birth into spontaneous preterm birth after premature prelabour rupture of membranes (pPROM), medically indicated preterm birth and spontaneous preterm birth without pPROM. We performed analyses separately for singletons and multiples. MAIN OUTCOME MEASURES: The primary outcome was preterm birth, defined as birth before 37 weeks of gestation, with very preterm birth (<32 weeks of gestation) being a secondary outcome. RESULTS: The risk of preterm birth was 7.7% and the risk of very preterm birth was 1.3%. In singleton pregnancies, the preterm birth risk decreased significantly from 6.4% to 6.0% (P < 0.0001), mainly as a result of the decrease in spontaneous preterm birth without pPROM (3.6-3.1%, P < 0.0001). In multiple pregnancies, the preterm birth risk increased significantly (47.3-47.7%, P = 0.047), mainly as a result of medically indicated preterm birth, which increased from 15.0% to 17.9% (P < 0.0001). CONCLUSION: In the Netherlands, the preterm birth risk in singleton pregnancies decreased significantly over the years. The trend of increasing preterm birth risk reported in other countries was only observed in (medically indicated) preterm birth in multiple pregnancies. PMID- 21668770 TI - Persistence of polypropylene mesh anisotropy after implantation: an experimental study. AB - OBJECTIVE: To determine whether anisotropy persisted after incorporation into the host, using a standardised rabbit model for abdominal wall reconstruction. DESIGN: Investigator-initiated prospective-controlled experimental study. SETTING: Centre for Surgical Technologies, Medical Faculty KU-Leuven. SAMPLE: Fifteen New Zealand White rabbits. METHODS: In each rabbit, four full thickness primarily repaired abdominal wall defects were covered by a 4 * 5-cm Prolift+M implant (Johnson & Johnson, Norderstedt, Germany), either with the stiffest (n = 6 rabbits) or most elastic (n = 6) direction parallel to the body axis. Prolift+M contains 32 g/m2 polypropylene, reinforced with polyglecaprone fibres. Harvesting was performed after 30, 60 and 120 days (n = 2 each time-point). The abdominal wall of three unoperated rabbits was used as negative control. MAIN OUTCOME MEASURES: Contraction, compliance and maximal strain and stress determined by uniaxial tensiometry. RESULTS: Anisotropy properties persist at lower, more physiological displacements, but not at higher displacements. The stiffness of a mesh-augmented repair in the lower strain range remains above that of native tissue. Eventual mesh contraction was limited to 4.3%. CONCLUSIONS: Anisotropic properties of Prolift+M persist in vivo and shrinkage is minimal. Compliance of mesh-augmented repair remains less than that of native tissue. The functional consequences of this remain to be studied. PMID- 21668772 TI - Impaired vascular permeability regulation caused by the VEGF165b splice variant in pre-eclampsia. AB - OBJECTIVE: Pre-eclampsia is diagnosed by hypertension and proteinuria, probably caused by endothelial dysfunction, resulting in symptoms including oedema, inflammation and altered metabolism. Vascular endothelial growth factor A (VEGF A) is detected at higher concentrations in plasma from patients with pre eclampsia than in plasma from normotensive pregnant patients when determined by radioimmunoassay. This study tested the hypothesis that circulating VEGF-A in pre eclamptic plasma is biologically active in vivo, and aimed to identify specific isoforms responsible for this activity. DESIGN: Plasma from pre-eclamptic (n = 17) and normotensive (n = 10) pregnant women was perfused into Rana mesenteric microvessels, and the subsequent change in microvascular permeability was measured using a single-vessel perfusion micro-occlusion technique. RESULTS: Pre eclamptic but not normotensive plasma resulted in a 5.25 +/- 0.8-fold acute increase in vascular permeability (P = 0.0003). This increase could be blocked by the incubation of plasma with bevacizumab, an antibody to VEGF-A (n = 7; P = 0012), and by VEGF-A receptor inhibition by SU5416 at doses specific to VEGF-A receptor-1 (VEGFR1), but not by the VEGF-A receptor-2 inhibitor, ZM323881. Although VEGF(165) b levels were not significantly altered in the PET samples, the increase in permeability was also inhibited by incubation of pre-eclamptic plasma with an inhibitory monoclonal antibody specific for VEGF165b (n=6; P<0.01), or by the addition of placental growth factor 1 (PlGF-1; n = 3; P < 0.001). PlGF-1 was detected at lower concentrations in pre-eclamptic plasma than in normotensive plasma. CONCLUSIONS: These findings suggest that circulating VEGF A levels in pre-eclampsia are biologically active because of a loss of repression of VEGFR1 signalling by PlGF-1, and VEGF165b may be involved in the increased vascular permeability of pre-eclampsia. PMID- 21668773 TI - Highs and lows of peripheral anterior synechiae. PMID- 21668774 TI - Missing X and Y: a review of participant ages in population-based eye studies. AB - Ophthalmic population-based studies have been used to establish the frequency of eye disease and the associated environmental and genetic factors that cause vision impairment and blindness. Most of these studies have concentrated on the diseases of ageing: cataract, age-related macular degeneration, glaucoma and diabetic retinopathy. Other studies have identified eye diseases in children but few studies of young adult eye disease exist. We conducted a systematic review of the ophthalmic literature to identify potential population-based eye studies and then note the age of participants in the studies. We then summarized the disease specific to young adults to show there is a need for further research to identify eye disease in this important and often-neglected group in the community. Eighty four large population-based studies have been conducted worldwide: 9 in North America, 2 in South America, 17 in Africa, 35 in Asia, 11 in Australia and the Pacific, 6 in Europe, 4 in the Middle East and 1 that covered 3 continents. No studies specifically examined young adults. Twenty-six per cent of studies included young adults as part of all ages examined but none of these examined a large number of young adults. PMID- 21668775 TI - Association between arterial blood pressure, cerebrospinal fluid pressure and intraocular pressure in the pathophysiology of optic nerve head diseases. PMID- 21668776 TI - Dynamic Disc Dimensioning: improved measurement of optic nerve height using red free light. PMID- 21668777 TI - Should macular optical coherence tomography be part of routine preoperative cataract assessment? PMID- 21668779 TI - Outcomes of cataract surgery in Timor-Leste 2010. PMID- 21668778 TI - Late-onset persistent epithelial ingrowth following uncomplicated clear corneal incision cataract surgery. PMID- 21668781 TI - Comparison of retinal nerve fibre layer thickness with visual evoked potential and visual field in patients with multiple sclerosis. AB - BACKGROUND: To evaluate retinal nerve fibre layer thickness and to compare results with visual evoked potentials and visual field in patients with multiple sclerosis. DESIGN: A prospective, case-control study, university hospital setting. PARTICIPANTS: Seventy-three eyes of 37 multiple sclerosis patients and 74 eyes of 37 healthy subjects. METHODS: All patients underwent a complete neurological and ophthalmological examination and peri-papillary retinal nerve fibre layer thickness was evaluated using scanning laser polarimetry (GDx). Furthermore, visual evoked potential and visual field testing were performed. MAIN OUTCOME MEASURES: The chi(2) test, Student's t-test, Mann-Whitney U-test and Pearson's correlation coefficient analysis of the GDx, visual evoked potential and visual field testing parameters. RESULTS: GDx measurements showed significantly more retinal nerve fibre layer damage in the patients than in the control groups. Comparison of the GDx parameters between patients with optic neuritis and non-optic neuritis demonstrated a statistically significant difference in symmetry (P = 0.046) and superior/nasal parameters (P = 0.009). A correlation was found between the number, superior and inferior ratio parameters, and P100 amplitude obtained with visual evoked potential in patients with non optic neuritis. Additionally, there was a correlation between the number, inferior ratio and superior/nasal parameters, and the mean deviation of visual field in the non-optic neuritis group. CONCLUSIONS: For retinal nerve fibre layer thickness measurements in multiple sclerosis patients, the GDx, along with other techniques, such as visual evoked potential, can be used as a diagnostic and follow-up criterion, particularly in patients without optic neuritis. PMID- 21668780 TI - Filtering blue light reduces light-induced oxidative stress, senescence and accumulation of extracellular matrix proteins in human retinal pigment epithelium cells. AB - BACKGROUND: Cumulative light exposure is significantly associated with ageing and the progression of age-related macular degeneration. To prevent the retina from blue-light damage in pseudophakia, blue light-absorbing intraocular lenses have been developed. This study compares the possible protective effects of a blue light-absorbing intraocular lens to an untinted ultraviolet-absorbing intraocular lens with regard to light-induced oxidative stress and senescence of human retinal pigment epithelium. METHODS: As primary human retinal pigment epithelium cells were exposed to white light, either an ultraviolet- and blue light absorbing intraocular lens or ultraviolet-absorbing intraocular lens was placed in the light beam. After 60 min of irradiation, cells were investigated by electron microscopy for viability, induction of intracellular reactive oxygen species, and senescence-associated beta-galactosidase activity. Expression and secretion of matrix metalloproteinases 1 and 3 and their mRNA were determined by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. RESULTS: Light exposure induced structural damage, decreased retinal pigment epithelium cell viability, and increased reactive oxygen species, senescence associated beta-galactosidase activity and matrix metalloproteinases 1 and 3 expression and secretion. Although both types of intraocular lens significantly reduced these effects, the protective effects of the ultraviolet- and blue light absorbing intraocular lens were significantly stronger than those of the ultraviolet-absorbing intraocular lens. CONCLUSIONS: The ultraviolet- and blue light-absorbing intraocular lens demonstrated significantly better protection against light-induced oxidative stress, senescence and structural damage than the ultraviolet-absorbing intraocular lens. These in vitro findings support the hypothesis that the ultraviolet- and blue light-absorbing intraocular lens may prevent retinal damage in clinical use. PMID- 21668782 TI - Regulation of cell-mediated collagen gel contraction in human retinal pigment epithelium cells by vascular endothelial growth factor compared with transforming growth factor-beta2. AB - BACKGROUND: To explore the potential role of vascular endothelial growth factor compared with transforming growth factor-beta2 in the regulation of human retinal pigment epithelium cell-mediated collagen gel contraction. METHODS: The retinal pigment epithelium cell mediated type I collagen gel contraction assay was performed to evaluate and compare the effect of vascular endothelial growth factor and transforming growth factor-beta2. The number of viable retinal pigment epithelium cells in the gel and the expression of alpha-smooth muscle actin were analysed. RESULTS: Both vascular endothelial growth factor and transforming growth factor-beta2 caused a time dependent gel contraction, associated with over expression of alpha-smooth muscle actin in retinal pigment epithelium cells undergoing a fibroblast like transformation. The decrease in volume of the collagen gel and increase in alpha-smooth muscle actin expression were more significant in the transforming growth factor-beta2-treated group than in vascular endothelial growth factor-treated group beginning at day 2, and the growth of retinal pigment epithelium cells was significantly more inhibited in the transforming growth factor-beta2-treated group compared with the vascular endothelial growth factor-treated group after day 1 (P < 0.05). Transforming growth factor-beta2 stimulation increased both vascular endothelial growth factor mRNA expression and secretion. The alpha-smooth muscle actin expression and the change in volume of collagen gel were significantly positively correlated in both experimental groups. CONCLUSIONS: Both vascular endothelial growth factor and transforming growth factor-beta2 can cause induction of retinal pigment epithelium cell-mediated collagen gel contraction in vitro via partial upregulation of alpha-smooth muscle actin expression. PMID- 21668783 TI - There is insufficient evidence to recommend lens extraction as a treatment for primary open-angle glaucoma: an evidence-based perspective. AB - Cataract extraction in primary open-angle glaucoma has not been thought to provide a clinically useful or predictable decrease in IOP. This concept has now been challenged, with the opposite belief being promulgated: namely, that lens exchange should be considered as treatment for glaucoma. This revelation could bring a significant change in the glaucoma treatment paradigm. There are no randomised controlled trials to guide the role of lens extraction in primary open angle glaucoma. The available evidence suggests at most a modest reduction in IOP from cataract extraction - greater in the presence of pseudoexfoliation - which is likely to be of marginal benefit, and only in milder forms of open-angle glaucoma. There is currently no evidence of any quality to suggest that lens extraction routinely represents a clinically useful treatment for primary open angle glaucoma. PMID- 21668784 TI - Devastating bilateral optic nerve leukaemic infiltration. PMID- 21668785 TI - Is a mobile surgical bus a safe setting for cataract surgery? A four-year retrospective study of intraoperative complications. PMID- 21668786 TI - Comparison of the effects of cylindrical correction with and without iris recognition technology in wavefront laser-assisted in situ keratomileusis. AB - BACKGROUND: To analyse the magnitude of cylindrical corrections over which cyclotorsion compensation with iris recognition (IR) technology is beneficial during wavefront laser-assisted in situ keratomileusis. DESIGN: A retrospectively comparative case series. PARTICIPANTS OR SAMPLES: Fifty-four eyes that underwent wavefront laser-assisted in situ keratomileusis without IR (non-IR group) and 53 eyes that underwent wavefront laser-assisted in situ keratomileusis with IR (IR group) were recruited. METHODS: Subgroup analysis based on baseline astigmatism were: a low degree of astigmatism (>=1.00 D to <2.00 D), a moderate degree of astigmatism (>=2.00 D to <3.00 D) and a high degree of astigmatism (>=3.00 D). MAIN OUTCOME MEASURES: Vector and non-vector analyses were used for comparison. RESULTS: The mean cylinder was -1.89 +/- 0.76 D in the non-IR group and -2.00 +/- 0.77 D in the IR group. Postoperatively, 38 eyes (74.50%) in the IR group and 31 eyes (57.50%) in the non-IR group were within +/- 0.50 D of the target induced astigmatism vector (P = 0.063). The difference vector was 0.49 +/- 0.28 in the IR group and 0.63 +/- 0.40 in the non IR group (P = 0.031). In the analysis of subgroups, the magnitude of error was significantly lower in the moderate IR subgroup than that of the moderate non-IR subgroup (P = 0.034). Furthermore, the moderate IR subgroup had a lower mean difference vector (P = 0.0078) and a greater surgically induced astigmatism (P = 0.036) than those of the moderate non-IR group. CONCLUSIONS: Wavefront laser assisted in situ keratomileusis for the treatment of astigmatism using IR technology was effective and accurate for the treatment of myopic astigmatism. PMID- 21668787 TI - Retinal venular calibre dilatation after intravitreal ranibizumab treatment for neovascular age-related macular degeneration. AB - BACKGROUND: To describe the changes in retinal vascular calibre in response to intravitreal ranibizumab injections in patients with neovascular age-related macular degeneration. DESIGN: Prospective interventional case series. PARTICIPANTS: Treatment naive patients with neovascular age-related macular degeneration were recruited over a 1-year period. METHODS: Each patient received three monthly intravitreal injections according to a 'loading dose'. Retinal arteriolar and venular calibre was measured from digital fundus photographs and summarized as central retinal artery equivalent and central retinal vein equivalent at baseline and 3 months. MAIN OUTCOME MEASURE: Central retinal artery equivalent and central retinal vein equivalent changes from baseline to 3 months. RESULTS: Seventy-four eyes of 71 patients had good quality images for grading vessel calibre at baseline and at 3 months in treated (study) eyes and 51 eyes of 51 patients had good quality images in fellow (control) eyes. Over 3 months, in study eyes treated with ranibizumab, there was a significant increase in central retinal vein equivalent over baseline (+6.20 um, P = 0.005), but no significant change in central retinal artery equivalent (+0.86 um, P = 0.55). In control eyes, there was no change in central retinal vein equivalent (-0.82 um, P = 0.70) or central retinal artery equivalent (0.34 um, P = 0.75). CONCLUSION: Intravitreal ranibizumab has a significant vasodilational effect on retinal venular calibre in eyes treated for neovascular age-related macular degeneration. The reason for this change is unclear, but may relate to changes in blood flow or inflammatory changes within the retina. PMID- 21668788 TI - Comparison of clinical outcomes between iris-fixated anterior chamber intraocular lenses and scleral-fixated posterior chamber intraocular lenses in Marfan syndrome with lens subluxation. AB - BACKGROUND: To compare the clinical outcomes in Marfan's with subluxated lens having phaco-emulsification with simultaneous scleral-fixated posterior chamber intraocular lens or iris-fixated anterior chamber intraocular lens implantation. DESIGN: Randomized case series in the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. PARTICIPANTS: Seventy-one eyes of 49 patients with Marfan syndrome with subluxated lens. METHODS: This is a randomized case series of patients with Marfan syndrome and subluxated lenses who underwent phaco-emulsification combined with scleral-fixated posterior chamber intraocular lens or iris-fixated anterior chamber intraocular lens implantation. MAIN OUTCOME MEASURES: The evaluation indexes included the surgery time, best corrected visual acuity, intraocular pressure, aqueous flare and cells counts, corneal endothelium counts and complications. RESULTS: Increase in best corrected visual acuity in both groups was not significant. The aqueous flare and cells rose in both groups postoperatively. Significant difference between the two groups at 1 week postoperatively was found, whereas no statistically significant difference was found later. The loss rate of corneal endothelium cells in the scleral-fixated posterior chamber intraocular lens group was 13.2% and 19.5% at 3 months and 1 year postoperatively, which in the iris-fixated anterior chamber intraocular lens group was 13.3% and 19.3% (P > 0.05). Prolapse of vitreous was found in 21 cases intraoperatively. The posterior capsule opacification rate was 32% and 15%, respectively. The decentration of the intraocular lens was found in 19 eyes (48.7%) in the scleral-fixated posterior chamber intraocular lens group 1 year postoperatively, whereas none was found in the iris-fixated anterior chamber intraocular lens group. CONCLUSIONS: Iris-fixated anterior chamber intraocular lens after phaco-emulsification presented a safe, simple and efficient approach for managing subluxated lens in Marfan syndrome. PMID- 21668789 TI - Deep sclerectomy augmented with combination of absorbable biosynthetic sodium hyaluronate scleral implant and mitomycin C or with mitomycin C versus trabeculectomy: long-term results. AB - BACKGROUND: To evaluate the long-term results following deep sclerectomy with mitomycin C-SKgel implant (DSMMC-SKgel), mitomycin C (DSMMC) and trabeculectomy. DESIGN: Comparative case series, Goztepe Training and Educational Hospital. PARTICIPANTS: Ninety-one open-angle glaucoma patients. METHODS: DSMMC-SKgel, DSMMC and trabeculectomy operations were performed in 28, 30 and 33 eyes, respectively. MAIN OUTCOME MEASURES: Intraocular pressures (IOP) and distance corrected visual acuities (DCVA) were measured preoperatively and postoperatively at days 1, 7 and months 1, 3, 6, 12, 18, 24, 30, 36, 48. RESULTS: At month 48, deep sclerectomy groups had better DCVAs, and in all groups mean IOPs and number of medications were significantly lower and DCVAs were worse than preoperative values. Mean IOPs in trabeculectomy group at week 1, months 1 and 3 were significantly lower than those in DSMMC group. Mean IOPs in DSMMC-SKgel group at week 1 and month 1 were significantly lower than those in DSMMC group. Mean preoperative IOPs, postoperative IOPs following 3rd month, complete (IOP <= 21 mmHg and <= 18 mmHg without medication) and qualified (IOP <= 21 mmHg and <= 18 mmHg with or without medication) success rates of all groups were not statistically different. Rate of complications such as hyphema, hypotony, shallow anterior chamber, bleb leak, bleb fibrosis, cataract, choroidal detachment and macular oedema were found to be significantly higher in trabeculectomy group (P < 0.05). No significant difference in the mean post-laser goniopuncture IOPs was found between the two deep sclerectomy groups during the follow up. CONCLUSIONS: DSMMC, DSMMC-SKgel and trabeculectomy operations were almost equally effective in lowering IOP at long-term follow up, but complication rates were higher after trabeculectomy operations. PMID- 21668790 TI - Pseudophakic rhegmatogenous retinal detachment in a large Asian tertiary eye centre: a cohort study. AB - BACKGROUND: To determine the incidence and identify risk factors for the development of rhegmatogenous retinal detachment in patients who had cataract surgery at the Singapore National Eye Centre between 2001 and 2003. DESIGN: Retrospective case-control study. PARTICIPANTS: All patients who had cataract surgery between 2001 and 2003 and subsequently retinal detachment surgery in the same eye, between 2001 and June 2008, at Singapore National Eye Centre. METHODS: Review of case records. MAIN OUTCOME MEASURES: Incidence of posterior capsular rupture and retinal detachment. RESULTS: Thirty-nine eyes, out of 24 846 cataract operations performed between 2001 and 2003, developed rhegmatogenous retinal detachment in the follow-up period from 2001 to 2008 (cumulative incidence 0.16%, 95% confidence interval 0.11-0.21%). Of the 508 eyes with posterior capsular rupture during cataract surgery, nine developed retinal detachment (cumulative incidence 1.77%, 95% confidence interval 0.87-3.23%). Men were more likely to develop retinal detachment (P < 0.001). On Kaplan-Meier survival analysis, younger patients had a higher probability of retinal detachment in comparison with older subjects (P < 0.001). Similarly, eyes with posterior capsular rupture during surgery had shorter interval duration to retinal detachment, compared with eyes that did not (P = 0.002). When compared with patients more than 70 years of age, younger patients had significantly higher hazard ratios of retinal detachment (hazard ratio 19.7, 95% confidence interval 3.6-107.3, P < 0.05). CONCLUSION: The incidence of pseudophakic retinal detachment in our institution is low. Posterior capsular rupture during surgery, men and younger age at time of surgery increases the risk of developing retinal detachment, and careful observation for the occurrence of retinal detachment may be warranted in these groups of patients. PMID- 21668791 TI - Long-term effectiveness of autologous cultured limbal stem cell grafts in patients with limbal stem cell deficiency due to chemical burns. AB - BACKGROUND: Chemical burns cause depletion of limbal stem cells and eventually lead to corneal opacity and visual loss. We investigated the long-term effectiveness of autologous cultured limbal stem cell grafts in patients with limbal stem cell deficiency. DESIGN: Prospective, non-comparative interventional case series. PARTICIPANTS: Sixteen eyes from 16 patients with severe, unilateral limbal stem cell deficiency caused by chemical burns. METHODS: Autologous ex vivo cultured limbal stem cells were grafted onto the recipient eye after superficial keratectomy. MAIN OUTCOME MEASURES: Clinical parameters of limbal stem cell deficiency (stability/transparency of the corneal epithelium, superficial corneal vascularization and pain/photophobia), visual acuity, cytokeratin expression on impression cytology specimens and histology on excised corneal buttons. RESULTS: At 12 months post-surgery, evaluation of the 16 patients showed that 10 (62.6%) experienced complete restoration of a stable and clear epithelium and 3 (18.7%) had partially successful outcomes (re-appearance of conjunctiva in some sectors of the cornea and instable corneal surface). Graft failure (no change in corneal surface conditions) was seen in three (18.7%) patients. Penetrating keratoplasty was performed in seven patients, with visual acuity improving up to 0.8 (best result). For two patients, regeneration of the corneal epithelium was confirmed by molecular marker (p63, cytokeratin 3, 12 and 19, mucin 1) analysis. Follow-up times ranged from 12 to 50 months. CONCLUSIONS: Grafts of autologous limbal stem cells cultured onto fibrin glue discs can successfully regenerate the corneal epithelium in patients with limbal stem cell deficiency, allowing to perform successful cornea transplantation and restore vision. PMID- 21668792 TI - Comparison of the use of 5-fluorouracil and bevacizumab in primary trabeculectomy: results at 1 year. AB - BACKGROUND: The present study compared the effects of adjuvant bevacizumab and 5 fluorouracil on the efficacy and safety of trabeculectomy. DESIGN: A nonrandomized, prospective, interventional case study. PARTICIPANTS: A total of 62 patients in two groups undergoing primary trabeculectomy. METHODS: In Group 1 (21 primary open-angle glaucoma, nine pseudoexfoliative glaucoma), trabeculectomy was performed with an adjuvant 5% solution of 5-fluorouracil administered for 4 min, intraoperatively. In Group 2 (21 primary open-angle glaucoma, 11 pseudoexfoliative glaucoma), trabeculectomy was enhanced with 1.25 mg of bevacizumab applied subconjunctivally immediately before and after surgery and again 1 and 7 days after surgery. MAIN OUTCOME MEASURES: Intraocular pressure, best corrected visual acuity, visual field index, bleb morphology, cornel endothelial cell count. RESULTS: Mean intraocular pressure was 28.0 +/- 8.0 mmHg before 5-fluorouracil-augmented trabeculectomy and 27.8 +/- 9.5 mmHg before bevacizumab-augmented trabeculectomy. After 12 months, mean intraocular pressure was 13.6 +/- 4.4 mmHg in the 5-fluorouracil group and 14.7 +/- 4.7 mmHg in the bevacizumab group. A 30% reduction of initial intraocular pressure was attained in 86.7% of patients in the 5-fluorouracil group and 78.1% of patients in the bevacizumab group at the end of follow up. No significant differences were noted between the two studied groups with respect to corneal endothelial density, visual field indices and postoperative complications. CONCLUSIONS: The 12-month intraocular pressure results showed no significant differences between the two groups of patients after bevacizumab or 5-fluorouracil to augment trabeculectomy. However, to obtain successful intraocular pressure control more patients in bevacizumab group needed medical therapy. PMID- 21668793 TI - Killing two birds with one stone: the potential effect of cataract surgery on the incidence of primary angle-closure glaucoma in a high-risk population. AB - BACKGROUND: To estimate the proportion of cataract surgery performed at various visual acuity and lens opacity thresholds that would coincidentally treat early angle-closure disease, and to estimate the effect of this surgery on the incidence of primary angle-closure glaucoma. DESIGN: Cross-sectional, population based survey in Meiktila, Myanmar. PARTICIPANTS: Total of 2076 inhabitants, 40 years of age and over were included. METHODS: Eyes with cataract-induced visual impairment, and primary angle-closure disease were identified. Analyses were stratified by various pinhole-corrected visual acuity and Lens Opacity Classification System III scores thresholds. MAIN OUTCOME MEASURES: The dual role of cataract surgery in primary cataract treatment and primary angle-closure glaucoma prevention was estimated. RESULTS: Of 4153 eyes available for analysis, 261 eyes were either primary angle-closure suspect or primary angle closure; 975 eyes had a visual acuity of <6/18 and Lens Opacity Classification System III score >= 3 on the nuclear or cortical scales. Of these, 86 eyes had either primary angle-closure suspect or primary angle closure. If cataract surgery were performed on all 975 eyes, this would potentially prevent up to 86 cases of primary angle-closure glaucoma in this population; 8.82% (95% confidence interval 7.12-10.78%) of the cataract surgery would address the cataract and prevent primary angle-closure glaucoma. This would achieve a 38.46% (95% confidence interval 20.23-59.43%) relative reduction in the incidence of primary angle closure glaucoma in the adult population. CONCLUSION: In populations with a high prevalence of both visually significant cataract and angle-closure disease, quality cataract extraction can serve a dual role of visual restoration and reducing the incidence of angle-closure disease in the population: killing two birds with one stone. PMID- 21668794 TI - Providers' HIV-related avoidance attitude and patient satisfaction. AB - OBJECTIVES: This article explores the associations between medical care providers' attitudes towards patients living with HIV (PLH) and the service satisfaction reported from general patients. METHODS: Data were collected from 40 county-level hospitals in China, including 1760 service providers and 1000 patients receiving medical services from the hospitals. Provider and patient assessments were conducted by self-administered questionnaires and face-to-face interviews, respectively. Random-effect regression models were used to examine relationships between the providers' avoidance attitudes and patient satisfaction at the hospital level while taking into account variations in demographics and professional experience within each hospital. RESULTS AND CONCLUSIONS: Service providers' avoidance attitudes towards PLH were negatively associated with general patients' satisfaction with service providers at the hospital level. The relationship was strong and significant whether or not adjustments were made for background characteristics. Medical care providers' stigmatizing attitudes towards PLH could be a reflection of the providers' general outlook with all patients. This study underscores a broader focus for HIV-related stigma reduction interventions in medical settings at both individual and institutional levels, targeting attitudes towards both patients with HIV/AIDS and the general patient population. PMID- 21668795 TI - A test of concordance between patient and psychiatrist valuations of multiple treatment goals for schizophrenia. AB - BACKGROUND: While much discussion has been placed on the problem of poor compliance in the treatment of schizophrenia, there has been little discussion on the concordance between patients and psychiatrists, an important contributing factor to patient-centred care. OBJECTIVE: To estimate the concordance between patients' and psychiatrists' (ordinal and cardinal) valuations of multiple goals for schizophrenia treatment and to illustrate the utility of the self-explicated method in valuing a large number of treatment goals. DESIGN: Twenty treatment goals were identified during focus groups and literature review and were presented to patients and psychiatrists during structured interviews. Respondents were asked to rank the multiple treatment goals and rate them on a 5-point Likert scale. Three scores were calculated based on the ranking (1-20), rating (Likert scale) (1-5) and a self-explicated method estimated as the product of rating and ranking score (1-100). Concordance was tested using Spearman's rho for overall ordinal rankings and via anova and F-test for the cardinal values assigned to a specific treatment goal. PARTICIPANTS: A total of 105 outpatients diagnosed with schizophrenia and 160 psychiatrists in Germany. RESULTS: Patient and psychiatrist values were concordant when the ordinal properties of their valuations were assessed by rating (rho = 0.63; P = 0.002), ranking (rho = 0.51; P = 0.02) and self-explicated methods (rho = 0.54; P = 0.01). Significant discordances were found when comparing the cardinal value placed on any given treatment goal using all three approaches, but the self-explicated method produced a more discerning statistic. Relative to patients, psychiatrists significantly (P < 0.05) overvalued reduced lack of emotion, improved sexual pleasure and improved communication while undervaluing reuptake of activities of daily living, improved satisfaction and recovered capacity for work. CONCLUSIONS: While there is an overall concordance between patients' and psychiatrists' valuation, significantly different valuations on specific goals can be identified. Here, psychiatrists tend to focus on 'textbook' outcomes, while patients are more concerned with functioning and living a normal life. This study also demonstrates the importance of comparing the concordance in treatment goals and the importance of preference based methods, such as the self-explicated method, in the study of concordance. PMID- 21668796 TI - Automated classification of psychotherapy note text: implications for quality assessment in PTSD care. PMID- 21668798 TI - Exsanguination by intent: controlled phlebotomy during resection of a giant vascular malformation in a 22-month-old child. AB - Resection of large vascular malformations may require transection across the lesion, resulting in uncontrollable bleeding with the risk of exsanguination or massive transfusion-related complications such as hyperkalemic cardiac arrest. We present the anesthetic management of a 22-month-old child with a giant vascular malformation who required surgical intervention because of increasing pain and bleeding from the lesion. As a standard resection carried a high risk of mortality for the patient, a novel surgical approach was performed, consisting of gradual compression of the lesion, reducing its base to allow transection across the smallest possible area. This compression resulted in acute massive autotransfusion managed by therapeutic phlebotomy of more than twice the circulating blood volume of the patient, guided by CVP and blood pressure. Although subsequent resection was still associated with large blood loss, the hemodynamic course of the patient was stable, and both bleeding and massive transfusion occurred in a controlled fashion allowing safe and successful resection of the malformation. PMID- 21668797 TI - A genome-wide association study of DSM-IV cannabis dependence. AB - Despite twin studies showing that 50-70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genome-wide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis-dependent cases with 2346 cannabis-exposed non-dependent controls was conducted using logistic regression in PLINK. None of the 948 142 single nucleotide polymorphisms met genome-wide significance (P at E-8). The lowest P values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, P values at E-7) in the ANKFN1 gene. While replication is required, this study represents an important first step toward clarifying the biological underpinnings of cannabis dependence. PMID- 21668799 TI - The effect of timing and temperature of oral fluids ingested after minor surgery in preschool children on vomiting: a prospective, randomized, clinical study. AB - BACKGROUND: The time at which children should resume oral intake after surgery is controversial. No information has been published about the relationship between postoperative vomiting and the temperature of the fluid ingested. This study was designed to analyze the effect on postoperative vomiting of the timing and temperature of the fluids ingested in the first oral intake. METHODS: Two hundred and thirty-seven male children aged 2-7 years, scheduled for correction of inguinal hernia or undescended testis under general anesthesia and were allocated into four groups. The patients in groups C1 and C2 received clear fluids at room temperature or at body temperature, respectively, 2 h after emergence. The patients in groups E1 and E2 received clear fluids at room temperature or at body temperature, respectively, 1 h after emergence. Vomiting was assessed at intervals of 30 min for 6 h postoperatively, starting from 10 min after emergence. RESULTS: The incidence of vomiting was higher in groups C1 (25%) (P = 0.016) and E1 (26.7%) (P = 0.011) than in groups C2 (6.9%) and E2 (10.2%). The incidence was found to be increased significantly 40 min after oral intake in groups C1 (P = 0.012) and E1 (P = 0.010) compared with earlier measurements in the same groups. CONCLUSION: A first oral intake in children 1 h after anesthesia for minor surgery seems not to increase the incidence of vomiting as long as the ingested fluid is at body temperature. PMID- 21668800 TI - Family quality of life: adult school children with intellectual disabilities in Bosnia and Herzegovina. AB - AIMS: This study endeavours to provide initial data on quality of life for families with adult children who have intellectual disabilities (ID) in the Canton of Sarajevo. METHODS: The principal measure used was the Family Quality of life Survey 2006 - main caregivers of people with intellectual or developmental disabilities. The sample consisted of the main caregivers of 35 families with adult school children with ID who attended classes in a specially adapted programme in the Center of Vladimir Nazor and in the Vocational Secondary School in Sarajevo. Of the 35 participants, 21 were male and 14 female. Students with disabilities ranged from 19 to 32 years old (mean 21.45). RESULTS: Consistent with previous research, the nine domains measured by the scale were all rated high for Importance. Opportunities were considered to be particularly low for Financial Well-Being and Support from Others. These domains were also rated lowest for Attainment and Satisfaction. Initiative was relatively high across all domains, and Stability (the degree to which things were seen as likely to improve or decline) varied slightly across domains but the means indicated that things are expected to stay almost the same or improve slightly. CONCLUSIONS: This research provides initial data for family quality of life in Bosnia and Herzegovina. It also provides suggestions for improving quality of life for families that have one or more members with ID. The results should also contribute to rejecting stereotypes and promoting inclusion of children with ID as well as the rights of their families. PMID- 21668801 TI - Family quality of life in 25 Belgian families: quantitative and qualitative exploration of social and professional support domains. AB - BACKGROUND: This article reports on the results of a study conducted in Belgium on family quality of life situated within a larger project focusing on the development of support strategies for young and adolescent siblings of persons with intellectual disabilities. The objectives of this article are twofold: (1) to present the results of the measures contained in the nine domains of the Family Quality of Life Survey-2006 (FQOLS-2006) from the perspective of parents (quantitative analysis); and (2) to come to a more in-depth understanding of two important domains of the FQOLS-2006 by exploring and comparing the quantitative and qualitative data from open-ended interviews with parents. METHOD: The FQOLS 2006 was completed by the main caregivers of 25 families living in one typical Belgian province. Subsequently, semi-structured interviews with one or both parents were conducted within the same families. Content analysis was carried out on the transcribed interviews using the qualitative software package MaxQDA. RESULTS: A detailed analysis of the quantitative data together with data from the content analysis of the interviews revealed important issues with regard to two family quality of life domains, support from others and support from services. In general, parents were satisfied with the professional support they received, whereas they were more critical of support from others. CONCLUSIONS: The quantitative data from the FQOLS-2006 were supported and further explained by the qualitative data. These findings highlight the importance of adequate professional support, which is a flexible and capable answer to each family's individual needs. The authors warn of the dangers of 'handicapism' and plea for a family-centred support approach that takes the whole family into account. Finally, they indicate the benefits of increased practical-pedagogical support. PMID- 21668802 TI - Needs and challenges of daily life for people with Down syndrome residing in the city of Rome, Italy. AB - BACKGROUND: Population-based surveys on the quality of life of people with Down syndrome (DS) are difficult to perform because of ethical and legal policies regarding privacy and confidential information, but they are essential for service planning. Little is known about the sample size and variability of quality of life of people with DS living in the city of Rome, which has a population of 2.7 million inhabitants. The aim of the present study is to explore the needs and challenges in health, social integration and daily life, of people with DS living in Rome. METHODOLOGY: A cross-sectional, census-based survey was conducted in 2006. All family doctors (3016 in total) of the National Health Service were involved by the Statistical Bureau of the Municipality of Rome. As per the census, every resident citizen is registered with a family doctor and every person with disabilities is coded. Associations for Down Syndrome encouraged their members to participate in the research. Questionnaires were completed by families of people with DS, in accordance with privacy laws. FINDINGS: An initial survey, conducted via a letter and a telephone contact with family doctors, identified 884 people with DS residing in the city of Rome. Data on the medical and social conditions of 518 people with DS, ranging in age from 0 to 64 years, were collected. Some 88% of these were living with their original family; 82.1% had one or more siblings, and 19.5% had lost one or both parents. A full 100% of children with DS were enrolled in the public school system. This ensures that they are fully occupied and entirely integrated in society. After secondary school there is a lack of opportunities. Thus, only 10% of adults were working with a regular contract. A mere 42.2% of people with DS aged 25-30 were involved in some form of regular activity (although not always on a daily basis). After the age of 30, the percentage of people demonstrating decline in function increased sharply, while disability-related support decreased. In other words, as people with DS age, daily life evolves increasingly around the home, with only occasional outdoor activities. CONCLUSION: The health, employment and social needs of the majority of people with DS in the city of Rome are not being met. The findings of this study underscore the urgent need for more comprehensive inclusion in society of adults with DS and for the provision of support services to create an enabling environment for inclusion. Because of the variability of performance among individuals with DS, there is a need to create more case specific options in terms of work, living arrangements, social networking and medical services. Schooling and social inclusion in childhood alone do not guarantee a satisfactory quality of life in adulthood. It is argued herewith that policy of inclusion and support should extend over the entire lifetime of people with DS. PMID- 21668803 TI - The maintenance effect of cognitive-behavioural treatment groups for the Chinese parents of children with intellectual disabilities in Melbourne, Australia: a 6 month follow-up study. AB - BACKGROUND: Caring for a child with intellectual disability can be stressful. No data on the longer-term effects of cognitive-behavioural treatment (CBT) on parents from a Chinese-speaking background who have children with intellectual disabilities are available in the literature. This study attempted to fill this research gap by examining the maintenance effect of CBT among the Chinese parents of such children in Melbourne, Australia. METHOD: Thirty-nine participants took part in our CBT groups and attended follow-up meetings. A questionnaire comprising four instruments, the Parenting Stress Index (PS) - Parent Domain, General Health Questionnaire-12 (GHQ-12), Abbreviated Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-18) and Dysfunctional Attitude Scale (DAS), was administered to the participants at the pre- and post-test stage and at the 6-month follow-up. RESULTS: One-way repeated-measures analyses of variance revealed significant time and group effects in the PS (F(2,27) = 16.93, P < 0.001), Q-LES-Q-18 (F(2,27) = 15.98, P < 0.001), GHQ-12 (F(2,27) = 81.93, P < 0.001) and DAS (F(2,27) = 15.50, P < 0.001) scores at the three measurement times. The participants continued to maintain significant improvements in mental health and quality of life and declines in the severity of parenting stress and dysfunctional attitudes at the 6-month follow-up. Effect size analyses revealed mostly large differences in the foregoing measurements (Cohen's d = 0.76-2.18) between the pre-test and 6-month follow-up. Employing a cut-off score of 3/4 in the GHQ-12 to identify at-risk and not-at-risk cases, approximately 90.5% of the participants could be classified as not-at-risk at the follow-up. Lastly, regression analyses showed that changes in DAS scores significantly predicted changes in the GHQ-12 and Q-LES-Q-18 scores at the follow-up. CONCLUSIONS: This study provides preliminary evidence of the 6-month maintenance effect of CBT groups for the Melbourne-resident Chinese parents of children with intellectual disabilities. PMID- 21668804 TI - Mediating haptic exploratory strategies in children who have visual impairment and intellectual disabilities. AB - This article provides a synthesis of literature pertaining to the development of haptic exploratory strategies in children who have visual impairment and intellectual disabilities. The information received through such strategies assumes particular significance for these children, given the restricted information available through their visual modality, often in combination with additional sensory and/or physical impairments. The literature reviewed from early child development highlights the importance of independent activity in the development of exploratory strategies, as well as the pivotal role of vision in 'mediating' information received through the haptic modality. In translating these findings to children who have visual impairment and intellectual disabilities, the role of the child's learning partner assumes greater significance in ensuring that haptic information is appropriately 'mediated' to meet the child's individual needs. The implications for developing appropriate developmentally paced intervention approaches are considered. A framework is outlined that seeks to account for the role of the child's adult partner in mediating haptic learning experiences to ensure they are appropriately structured and progressive. PMID- 21668805 TI - Inter-rater reliability of the Developmental Behaviour Checklist for Adults in community accommodation settings. AB - BACKGROUND: With the publication of the Developmental Behaviour Checklist for Adults (DBC-A), people of all ages with intellectual disability (ID) can now be assessed using a carer-completed screening checklist of emotional and behavioural disturbance. This provides a broad assessment framework across the life span, assists the process of clinical assessment, diagnosis and management, and, through efficient screening, helps ensure that people with ID and high levels of disturbed behaviour are more likely to receive the often scarce and costly behavioural and mental health services that are available. Earlier studies have reported acceptable results of test-retest reliability studies with family members and paid carers in community settings and the results of an inter-rater reliability study completed with family members. This study reports on another aspect of DBC-A reliability, inter-rater reliability with paid carers, in two small community-based accommodation settings. METHOD: Participants were 38 pairs of paid carers employed by two non-government agencies providing residential services in small group homes to 38 adults with ID in the community. RESULTS: An intraclass correlation coefficient (ICC) of 0.69 (n = 38, 95% CI 0.54-0.86) was found between pairs of paid carers employed in small group homes. DISCUSSION: Pairs of paid carers working with adults with ID in small group homes reliably completed DBC-A checklists. An ICC result of 0.69 compares favourably with the results of an earlier inter-rater study completed with the family members of people with ID living in the community. Inter-rater reliability on the six DBC-A sub-scales was also computed and the results were satisfactory. CONCLUSIONS: The carer-completed DBC-A provides a broad and comprehensive survey of the emotional and behavioural problems of adults with ID. It has satisfactory psychometric properties, which have been further extended. The DBC-A can be used in clinical, research and service settings to assess psychopathology across the adult life span in people with ID. PMID- 21668806 TI - Phenotyping interindividual variability in obstructive sleep apnoea response to temazepam using ventilatory chemoreflexes during wakefulness. AB - Centrally active agents have a variable impact in patients with obstructive sleep apnoea (OSA) that is unexplained. How to phenotype the individual OSA response is clinically important, as it may help to identify who will be at risk of respiratory depression and who will benefit from a centrally active agent. Based on loop gain theory, we hypothesized that OSA patients with higher central chemosensitivity have higher breathing instability following the use of a hypnosedative, temazepam. In 20 men with OSA in a double-blind, placebo controlled cross-over trial we tested the polysomnographically (PSG) measured effects of temazepam 10 mg versus placebo on sleep apnoea. Treatment nights were at least 1 week apart. Ventilatory chemoreflexes were also measured during wakefulness in each subject. The patients (mean +/- standard deviation; 44 +/- 12 years) had predominantly mild-to-moderate OSA [baseline apnoea-hypopnoea index (AHI) = 16.8 +/- 14.1]. Patients' baseline awake central chemosensitivity correlated significantly with both the change of SpO2 nadir between temazepam and placebo (r = -0.468, P = 0.038) and oxygen desaturation index (ODI; r = 0.485, P = 0.03), but not with the change of AHI (r = 0.18, P = 0.44). Peripheral chemosensitivity and ventilatory recruitment threshold were not correlated with the change of SpO2 nadir, ODI or AHI (all P > 0.05). Mild-moderate OSA patients with higher awake central chemosensitivity had greater respiratory impairment during sleep with temazepam. Relatively simple daytime tests of respiratory control may provide a method of determining the effect of sedative-hypnotic medication on breathing during sleep in OSA patients. PMID- 21668807 TI - Clonal genetic variation in a Wolbachia-infected asexual wasp: horizontal transmission or historical sex? AB - Wolbachia are endocellular bacteria known for manipulating the reproductive systems of many of their invertebrate hosts. Wolbachia are transmitted vertically from mother to offspring. In addition, new infections result from horizontal transmission between different host species. However, to what extent horizontal transmission plays a role in the spread of a new infection through the host population is unknown. Here, we investigate whether horizontal transmission of Wolbachia can explain clonal genetic variation in natural populations of Leptopilina clavipes, a parasitoid wasp infected with a parthenogenesis-inducing Wolbachia. We assessed variance of markers on the nuclear, mitochondrial and Wolbachia genomes. The nuclear and mitochondrial markers displayed significant and congruent variation among thelytokous wasp lineages, showing that multiple lineages have become infected with Wolbachia. The alternative hypothesis in which a single female became infected, the daughters of which mated with males (thus introducing nuclear genetic variance) cannot account for the presence of concordant variance in mtDNA. All Wolbachia markers, including the hypervariable wsp gene, were invariant, suggesting that only a single strain of Wolbachia is involved. These results show that Wolbachia has transferred horizontally to infect multiple female lineages during the early spread through L. clavipes. Remarkably, multiple thelytokous lineages have persisted side by side in the field for tens of thousands of generations. PMID- 21668809 TI - Association of maternal risk factors with early childhood caries in schoolchildren of Moradabad, India. AB - BACKGROUND: Children who have caries in their primary teeth in infancy or toddlerhood tend to develop dental caries in their permanent dentition. Although risk indicators are helpful in identifying groups at risk, they give little information about the causes of difference in caries experience. AIM: To identify the association between maternal risk factors and early childhood caries among 3- to 5-year-old schoolchildren of Moradabad City, Uttar Pradesh, India. DESIGN: A total of 150 child-mother pairs participated in the study. The maternal risk factors were assessed by a pretested questionnaire. After obtaining the consent, the mothers and their children were clinically examined for dental caries using Radike criteria (1968). Saliva was collected from all the participating mothers for assessing the Streptococcus mutans level. RESULTS: Significant differences were found in mothers' caries activity, high level of S. mutans, educational level, socioeconomic status, frequency of maternal sugar consumption, and their child's caries experience (P < 0.001). CONCLUSIONS: Differences between children's situations in these underlying factors play out as consequential disparities in both their health and the health care they receive. PMID- 21668810 TI - Masitinib decreases signs of canine atopic dermatitis: a multicentre, randomized, double-blind, placebo-controlled phase 3 trial. AB - This study investigated the efficacy and safety of masitinib, a selective tyrosine kinase inhibitor capable of downregulating mast cell functions, for treatment of canine atopic dermatitis (CAD). Dogs with confirmed CAD received masitinib at 12.5 mg/kg/day (n = 202) or control (n = 104) for 12 weeks. A reduction in CAD Extent and Severity Index (CADESI-02) score of >= 50% at week 12 was observed in 61% of masitinib-treated dogs versus 35% of control dogs (P < 0.001), according to the modified intent-to-treat population. For dogs resistant to ciclosporin and/or corticosteroids (60% of the study population), CADESI-02 response rates were 60 versus 31%, respectively (P = 0.004). The mean reduction in pruritus score of severely pruritic dogs was 46 versus 29%, respectively (P = 0.045). Furthermore, 65% of owners with severely pruritic dogs assessed masitinib efficacy as good/excellent versus 35% control (P = 0.05). Overall, 63% of investigators assessed masitinib efficacy as good/excellent versus 35% control (P < 0.001). Premature discontinuations from the modified intent-to-treat population (28.2% masitinib versus 26.0% control) were mainly due to adverse events (13.4 versus 4.8%, respectively) or lack of efficacy (12.4 versus 18.3%, respectively). In total, 13.2% dogs presented with severe adverse events (16.0% masitinib versus 7.7% control). Masitinib showed a risk of reversible protein loss, although regular surveillance of blood albumin and proteinuria allowed for discontinuation of treatment while the dog was still clinically asymptomatic. Masitinib proved to be an effective and mostly well-tolerated treatment of CAD, including severe and refractory cases, with medically manageable adverse effects. PMID- 21668808 TI - Molecular biodiversity of arbuscular mycorrhizal fungi in trace metal-polluted soils. AB - We assessed the indigenous arbuscular mycorrhizal fungi (AMF) community structure from the roots and associated soil of Plantago major (plantain) plants growing on sites polluted with trace metals (TM) and on unpolluted sites. Uncontaminated and TM-contaminated sites containing As, Cd, Cu, Pb, Sn and Zn were selected based on a survey of the TM concentration in soils of community gardens in the City of Montreal. Total genomic DNA was extracted directly from these samples. PCR followed by denaturing gradient gel electrophoresis (PCR-DGGE), augmented by cloning and sequencing, as well as direct sequencing techniques, was all used to investigate AMF community structure. We found a decreased diversity of native AMF (assessed by the number of AMF ribotypes) in soils and plant roots harvested from TM-polluted soils compared with unpolluted soils. We also found that community structure was modified by TM contamination. Various species of Glomus, Scutellospora aurigloba and S. calospora were the most abundant ribotypes detected in unpolluted soil; ribotypes of G. etunicatum, G. irregulare/G. intraradices and G. viscosum were found in both polluted and unpolluted soils, while ribotypes of G. mosseae and Glomus spp. (B9 and B13) were dominant in TM polluted soils. The predominance of G. mosseae in metal-polluted sites suggests the tolerance of this species to TM stress, as well as its potential use for phytoremediation. These data are relevant for our understanding of how AMF microbial communities respond to natural environments that contain a broad variety of toxic inorganic compounds and will substantially expand our knowledge of AMF ecology and biodiversity. PMID- 21668811 TI - First description of demodicosis in 12 galagos (Galago senegalensis). AB - Twelve Galago senegalensis from the Moscow Zoo were presented with papular to nodular (2-11 mm) lesions on the pinnae, containing a white, waxy material. Microscopic examination revealed large numbers of mites consistent with the morphology of Demodex spp. mites. Nine animals were treated with ivermectin, 600 MUg/kg/day topically, orally or subcutaneously for 3-10 months, while one remained untreated. All the treated animals achieved clinical remission. The control animal was still affected and died 11 months later due to pneumonia and possible eosinophilic leukaemia. No adverse effects were noted in any animals during the treatment. No animal relapsed in the 13-19 months follow-up period. To the authors' knowledge, this is the first report of demodicosis in G. senegalensis. The use of ivermectin in G. senegalensis was safe, although its effectiveness in the treatment of demodicosis needs further investigation. PMID- 21668812 TI - Qualitative research in transfusion medicine. AB - Transfusion medicine research has traditionally employed quantitative methods to answer clinical research questions. Increasingly, qualitative research methods are being used in the field to address a wide variety of research questions in areas such as blood donation, transfusion practices and policy development. This article describes the key characteristics, methodologies and methods of qualitative research and draws on examples to show how qualitative research approaches have been applied in the field of transfusion medicine. It is hoped that this overview will inform and encourage the application of qualitative research in the field of transfusion medicine. PMID- 21668814 TI - Peanuts for preschoolers: less preposterous than previously perceived? PMID- 21668815 TI - The long-term protective effects of domestic animals in the home. PMID- 21668816 TI - Anaphylaxis: mechanisms and management. AB - Anaphylaxis is a serious allergic reaction that can be rapid in onset and occasionally fatal. This is a review of the literature on the epidemiology of anaphylaxis, diagnostic criteria, mechanisms, and management. This current review of the literature is intended for clinicians, trainees, and researchers as a comprehensive review of anaphylaxis with a focus on incorporating the latest advances in the field. PMID- 21668817 TI - Cat allergen-induced blood basophil reactivity in vitro predicts acute human nasal allergen challenge responses in vivo. AB - BACKGROUND: Basophil histamine release (BHR) to allergen has been used as a confirmatory test to support the clinical diagnosis of allergic disease. OBJECTIVE: Among subjects reporting respiratory cat allergy, we hypothesized that cat-induced BHR in vitro would predict nasal allergen challenge (NAC) response in that same individual. We therefore compared the magnitude of cat allergen-induced BHR to NAC outcome and serological measures of cat-specific IgE and the ratio of cat-specific IgE to total IgE. METHODS: Forty-two subjects with a history of cat allergy, positive cat puncture skin test (PST) and detectable cat-specific IgE (> 0.1 kAU/L, ImmunoCap) participated with consent. Subjects were grouped as positive or negative cat allergen-induced BHR, with a positive result defined as the release of >= 20% of the total cellular histamine content. The majority of subjects also underwent a NAC with a positive result defined as >= 5 total sneezes. RESULTS: Subjects with a positive compared with a negative cat allergen BHR had higher cat-specific IgE levels at 5.40 +/- 1.24 kAU/L (n=25) vs. 1.55 +/- 0.73 kAU/L (n=17, P=0.01) as well as a higher cat-specific IgE/total IgE ratio [6.1 +/- 1.4% (n=25) vs. 1.6 +/- 0.9% (n=17, P=0.01)]. Of the 31 subjects who underwent a NAC, a positive NAC was observed in 78% (18/23) with a positive cat allergen BHR compared with 37% (3/8) with a negative cat allergen BHR, giving a positive predictive value of 78% and a negative predictive value of 63%. The diagnostic sensitivity and specificity of a positive BHR to predict a positive NAC was 86% and 50%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: A positive cat allergen-induced BHR is associated with higher cat-specific IgE levels, a higher cat-specific to total IgE ratio and is predictive of a positive cat induced NAC [ClinicalTrials.gov NCT00604786]. PMID- 21668818 TI - Lifetime dog and cat exposure and dog- and cat-specific sensitization at age 18 years. AB - BACKGROUND: Prior research about whether keeping a dog or cat at home causes allergies to that pet has been limited to outcomes in early childhood. OBJECTIVE: Evaluate the association between lifetime dog and cat exposure and allergic sensitization to the specific animal at 18 years of age. METHODS: Participants enrolled in the Detroit Childhood Allergy Study birth cohort during 1987-1989 were contacted at the age 18 years. Sensitization to dog or cat was defined as animal-specific IgE >= 0.35 kU/L. Annual interview data from childhood and follow up interviews at age 18 years were used to determine lifetime indoor dog and cat exposure (indoor was defined when the animal spent >50% of their time inside the house). Exposure was considered in various ways: first year, age groups and cumulative lifetime. Analyses were conducted separately for dogs and cats. RESULTS: Among males, those with an indoor dog during the first year of life had half the risk [relative risk (RR)=0.50, 95% confidence interval (CI) 0.27, 0.92] of being sensitized to dogs at age 18 compared with those who did not have an indoor dog in the first year. This was also true for males and females born via c section (RR=0.33, 95% CI 0.07, 0.97). Overall, teens with an indoor cat in the first year of life had a decreased risk (RR=0.52, 95% CI 0.31, 0.90) of being sensitized to cats. Neither cumulative exposure nor exposure at any other particular age was associated with either outcome. CONCLUSIONS AND CLINICAL RELEVANCE: The first year of life is the critical period during childhood when indoor exposure to dogs or cats influences sensitization to these animals. PMID- 21668820 TI - Editorial Comment on type 1 diabetes and antigen-specific immunotherapy. PMID- 21668821 TI - High levels of IgM against methylglyoxal-modified apolipoprotein B100 are associated with less coronary artery calcification in patients with type 2 diabetes. AB - OBJECTIVE: Advanced glycation end products (AGE) have been implicated in diabetic vascular complications through activation of pro-inflammatory genes. AGE modified proteins are also targeted by the immune system resulting in the generation of AGE-specific autoantibodies, but the association of these immune responses with diabetic vasculopathy remains to be fully elucidated. The aim of this study was to determine whether antibodies against apolipoprotein B100 modified by methylglyoxal (MGO-apoB100) are associated with coronary atherosclerosis in patients with type 2 diabetes. METHODS: We measured antibodies against MGO-apoB100 in plasma from 497 type 2 diabetic patients without clinical signs of cardiovascular disease. Severity of coronary disease was assessed as coronary artery calcium (CAC) imaging. Immunoglobulin (Ig)M and IgG levels recognizing MGO-apoB100 were determined by enzyme-linked immunosorbent assay. RESULTS: Anti-MGO-apoB100 IgM antibody levels were higher in subjects with a low to moderate CAC score (<=400 Agatston units) than in subjects with a high score (>400 Agatston units; 136.8+/-4.4 vs. 101.6+/- 7.4 arbitrary units (AU), P<0.0001) and in subjects demonstrating no progression of CAC during 30 months of follow-up (136.4+/-5.7 vs. 113.9 +/- 6.2 AU in subjects with progression, P<0.0001). Subjects with a family history of premature myocardial infarction had lower levels of anti-MGO-apoB100 IgM. Female subjects had higher levels of anti-MGO-apoB100 antibodies and lower CAC than men. Accordingly, high levels of IgM against MGO-apoB100 are associated with less severe and a lower risk of progression of coronary disease in subjects with type 2 diabetes. CONCLUSIONS: Although conclusions regarding causal relationships based on epidemiological observations need to be made with caution, our findings suggest the possibility that anti-MGO-apoB100 IgM may be protective in diabetic vasculopathy. PMID- 21668823 TI - Rotavirus vaccines: safety, efficacy and public health impact. AB - Rotaviruses are the cause of acute gastroenteritis, and disease is widespread amongst infants and young children throughout the world. Also, rotavirus is associated with significant mortality in developing countries with more than 500 000 children dying each year as a result of the severe dehydration associated with rotavirus disease. Efforts have been ongoing for more than 30 years to develop a safe and effective rotavirus vaccine. Currently, two vaccines, RotaRix and RotaTeq, have been licensed for use in many countries throughout the world following comprehensive safety and efficiency trials. Monitoring their effectiveness after licensure has confirmed that their incorporation into early childhood vaccination schedules can significantly prevent severe rotavirus diarrhoea, which would have resulted in hospitalizations, emergency room visits or increased diarrhoea-related mortality. Although the efficacy of both vaccines is lower at approximately 40-59% in developing countries, their use could significantly reduce the mortality associated with rotavirus disease that is concentrated in these countries. PMID- 21668822 TI - Chemotherapy only for localized Hodgkin lymphoma. AB - Radiation therapy (RT) alone and more recently in combination with chemotherapy (combined modality therapy; CMT) has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma (HL) for over 40 years. Because of increasing awareness of the late morbidity and mortality associated with RT, recent treatment regimens have attempted to limit its use. Chemotherapy only has been demonstrated to be a treatment option for most patients with localized HL. Current clinical trials have targeted subgroups of such patients who may be at an increased risk of recurrence for the addition of limited RT to chemotherapy. PMID- 21668824 TI - Dectin-1 mediates in vitro phagocytosis of Candida albicans yeast cells by retinal microglia. AB - We have investigated the expression of TLR2 and Dectin-1 in retinal microglia and their involvement in Candida albicans phagocytosis using a cytometric approach. The expression of both receptors has been demonstrated in CD11b(+) retinal cells. Phagocytosis of pHrodo-labelled C. albicans yeasts by microglial CD11b(+) cells of C57BL/6 mice was inhibited both by the Dectin-1 antagonist laminarin and anti Dectin-1 antibodies, whereas phagocytosis of yeasts by retinal microglia of TLR2 KO mice was unaffected. These data indicate that phagocytosis of C. albicans yeasts by retinal microglia is mediated by Dectin-1, whereas TLR2 does not play a significant role in this process. PMID- 21668825 TI - Toxic epidermal necrolysis and Stevens-Johnson syndrome at the Prague Burn Centre 1998-2008. AB - BACKGROUND: Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are skin disorders characterized by extensive necrosis of the mucous membranes and the epidermis caused by an autoimmune response. OBJECTIVES: To present experience of treating TEN and SJS at the Prague Burn Centre (PBC) 1998-2008. METHODS: 22 patients with the diagnosis TEN or SJS were enrolled. We collected data including the extent of the skin involvement, the ratio of men:women, the average age, the mortality rate, presence of comorbidities, the length of hospital stay, the period from the first symptoms to the admission to the PBC, corticosteroids administration prior to admission. RESULTS: 82% patients had injuries larger than 30% of body surface area. The ratio of men:women was 1 : 1.5; the average age was 48.4 years; the mortality was 32%. Significant comorbidities were present in 41% of the cases. The average length of hospital stay was 12.9 days. The period from the first symptoms to the admission to the PBC was 9.6 days; corticosteroids were administered to 68% of the cases. CONCLUSION: Treatment strategies at the PBC are based upon a multidisciplinary approach and focus on the general principles of treating patients with extensive skin loss. Corticosteroids must be avoided, antibiotics are not indicated and intravenous immunoglobulins are not justified in the standard therapy. Early diagnosis, prompt transport to a burn center are essential for patients outcomes. The medical community should be informed about these rare but potentially life threatening diseases. PMID- 21668826 TI - Speech and gesture in spatial language and cognition among the Yucatec Mayas. AB - In previous analyses of the influence of language on cognition, speech has been the main channel examined. In studies conducted among Yucatec Mayas, efforts to determine the preferred frame of reference in use in this community have failed to reach an agreement (Bohnemeyer & Stolz, 2006; Levinson, 2003 vs. Le Guen, 2006, 2009). This paper argues for a multimodal analysis of language that encompasses gesture as well as speech, and shows that the preferred frame of reference in Yucatec Maya is only detectable through the analysis of co-speech gesture and not through speech alone. A series of experiments compares knowledge of the semantics of spatial terms, performance on nonlinguistic tasks and gestures produced by men and women. The results show a striking gender difference in the knowledge of the semantics of spatial terms, but an equal preference for a geocentric frame of reference in nonverbal tasks. In a localization task, participants used a variety of strategies in their speech, but they all exhibited a systematic preference for a geocentric frame of reference in their gestures. PMID- 21668827 TI - Glaucoma and optometry: recognition, challenges and opportunities. PMID- 21668828 TI - The hypo/hypertension quandary. PMID- 21668829 TI - Modularity in developmental biology and artificial organs: a missing concept in tissue engineering. AB - Tissue engineering is reviving itself, adopting the concept of biomimetics of in vivo tissue development. A basic concept of developmental biology is the modularity of the tissue architecture according to which intermediates in tissue development constitute semiautonomous entities. Both engineering and nature have chosen the modular architecture to optimize the product or organism development and evolution. Bioartificial tissues do not have a modular architecture. On the contrary, artificial organs of modular architecture have been already developed in the field of artificial organs. Therefore the conceptual support of tissue engineering by the field of artificial organs becomes critical in its new endeavor of recapitulating in vitro the in vivo tissue development. PMID- 21668830 TI - Novel approach for designing a low weight hip implant used in total hip arthroplasty adopting skeletal design techniques. AB - Aseptic loosening is the major cause of failure of hip implants after total hip arthroplasty. Stress shielding of the femur is known to be the principal factor involved in the aseptic loosening of hip implants. Solid stems are found to have a greater rigidity; therefore, they transfer less load proximally, which results in greater stress shielding of the proximal femur. A stem of low stiffness alone would not suffice in achieving a reduced or optimal stress shielding. The femoral stem of the light weight hip implant has a skeletal design with a hexagonal base and neck cross-section. This novel design would ameliorate the implant fixation, aid in optimal rigidity, enhance the medullary revascularization, and offer better mobility to the patient. PMID- 21668831 TI - Influence of albumin dialysis on pharmacokinetics of amphotericin B colloidal dispersion and amphotericin B lipid complex. AB - Albumin dialysis (AD) is a therapeutic option in severe cholestatic liver failure. However, it can significantly enhance drug elimination. Pharmacokinetic data on antimicrobial agents--in particular on antimycotics--administered under this clinical condition are very sparse. Therefore, amphotericin B (AMB) plasma concentrations were measured in two critically ill patients who were treated with AD because of severe cholestatic liver failure and were prescribed lipid formulated AMB--either AMB colloidal dispersion (ABCD) or AMB lipid complex (ABLC)--for suspected invasive fungal infection. AD was performed with the molecular adsorbent recirculating system (MARS). Lipid-associated and liberated AMB were separately quantified on and off AD. The clearance of the liberated AMB fraction was not essentially affected (ABLC) or moderately enhanced during AD by a factor of 2.5 (ABCD). The clearance of the lipid-formulated fraction was increased by a factor of 4 during AD (ABCD) or was similar (ABLC) on and off AD. Despite the fact that there was a four-fold higher clearance of the lipid formulated fraction of ABCD, the clinically relevant area under the concentration time curve of the liberated AMB fraction was only moderately changed (by 37% in ABCD, 70% in ABLC) during AD. Thus, the effect of AD on lipid formulated AMB appears to be moderate. A daily dose of 5 mg/kg will probably lead to adequate plasma levels in patients on AD. PMID- 21668833 TI - Real-life use of underwear treated with fabric softeners improves skin dryness by decreasing the friction of fabrics against the skin. AB - Scientific evaluation of fabric softener use on the friction of fabrics and on dry skin in real life is very limited. The coefficient of friction of fabrics was measured with a surface tester using model skin and cotton fabrics. The effects and safety of fabric softener-treated T-shirts on subjects with dry skin were evaluated in real-life conditions in the cold and arid environment. Twenty male volunteers with dry skin used T-shirts without softener for 1 week before day 0 and then wore softener-treated T-shirts for 14 days. Effects were evaluated by clinical grading, subjective symptoms, stratum corneum water content (SCWC) and transepidermal water loss (TEWL). A significant decrease in the coefficient of friction of fabrics was detected. A significant improvement in SCWC was observed on the torso, waist and shoulder, but no improvement was found on the inner forearm. There was a slight change in TEWL. The visual grading of dryness improved significantly at all sites, but no significant change was found in subjective symptoms. Our results suggest that fabric softener provides benefits to individuals with dry skin because of the decreased friction of the garments against the skin. It is possible that the softener treatment of fabrics contributes to the state of moisturization of the skin and may work in collaboration with the application of moisturizers. PMID- 21668834 TI - Photochemical behaviour of hydrolysed keratin. AB - An investigation into the influence of UV irradiation on keratin hydrolysates was carried out using UV-Vis spectroscopy, Fourier transform infrared spectroscopy (FTIR) and fluorescence spectroscopy. It was found that the absorption of keratin hydrolysates in solution increased during irradiation of the sample, most notably between 250-280 and 320-410 nm. The increase in absorbance in the region 320-410 was because of the new photoproducts formed during UV irradiation of keratin hydrolysates. The fluorescence of keratin hydrolysates was observed at 328 nm after excitation at 270 nm. UV irradiation caused fluorescence fading at 328 nm, and after 60 min of irradiation, a new broad weak band of fluorescence, attributable to new photoproducts, emerged in the UV wavelength region with emission maximum between 400 and 500 nm. FTIR spectroscopy results showed degradation of keratin under UV irradiation. A slight increase in oxidized sulphur species was also observed. The results obtained suggest that UV irradiation can be used as modifying agent for preparation of keratin hydrolysates for cosmetic applications. PMID- 21668835 TI - Topical clindamycin 1% vs. linoleic acid-rich phosphatidylcholine and nicotinamide 4% in the treatment of acne: a multicentre-randomized trial. AB - It has been shown that topical linoleic acid rich-phosphatidylcholine seems to be effective in normalization of follicular hyperkeratinization, whereas nicotinamide has an interesting anti-inflammatory effect. However, little is known about their combined effect on acne. A multicentre, double-blind, 12-week randomized vehicle and parallel-active control study was conducted by clinical and biophysical non-invasive measurements to evaluate the efficacy, tolerability and safety of a 4% nicotinamide-phospholipidic (N-PHCL) emulsion vs. 1% topical clindamycin phosphate applied once daily. Four percentage N-PHCL cosmetic treatment resulted slightly superior to topical clindamycin with all the parameters studied for its better compliance and the global clinical improvement. PMID- 21668836 TI - Comparison of the antipyretic efficacy of ketoprofen, acetylsalicylic acid, and paracetamol, orally administered to swine. PMID- 21668837 TI - The use of phenylbutazone in the horse. AB - This review presents a brief historical prospective of the genesis of regulated medication in the US racing industry of which the nonsteroidal anti-inflammatory drug (NSAID) phenylbutazone (PBZ) is the focus. It presents some historical guideposts in the development of the current rules on the use of PBZ by racing jurisdictions in the US. Based on its prevalent use, PBZ remains a focus of attention. The review examines the information presented in a number of different models used to determine the effects and duration of PBZ in the horse. They include naturally occurring lameness and reversible-induced lameness models that directly examine the effects and duration of the administration of various doses of PBZ. The review also examines indirect plasma and tissue models studying the suppression of the release of arachidonic acid-derived mediators of inflammation. The majority of studies suggest an effect of PBZ at 24 h at 4.4 mg/kg. This reflects and substantiates the opinion of many clinical veterinarians, many of whom will not perform a prepurchase lameness examination unless the horse is free of NSAID. This remains the opinion of many regulatory veterinarians responsible for the prerace examination of race horses that they wish to examine a horse without the possibility of an NSAID interfering with the examination and masking possible musculoskeletal conditions. Based on scientific studies, residual effects of PBZ remain at 24 h. The impact of sustained effect on the health and welfare of the horse and its contribution to injuries during competition remains problematic. PMID- 21668839 TI - The increase in allergy and extended challenges. AB - The prevalence of allergic diseases shows a well-documented increase in developed countries over several decades. Currently, 20-25% of European adults are affected. Westernisation, urbanisation, and affluence contribute to allergy development, so allergy is expected to increase in developing countries in the future. Identifying primary causes, developing new therapies, and increasing treatment access may interrupt the allergic epidemic. PMID- 21668838 TI - Organochlorine compounds and testicular dysgenesis syndrome: human data. AB - Cryptorchidism, hypospadias, subfertility and testicular germ-cell tumour have been suggested to comprise a testicular dysgenesis syndrome (TDS) based on the premise that each may derive from perturbations of embryonal programming and gonadal development during foetal life. Endocrine-disrupting chemicals have been hypothesized to be associated with these disorders, given the importance of sex steroid hormones in urogenital development and homeostasis. Organochlorines are one such set of compounds which are defined as containing between one and ten covalently bonded chlorine atoms. These compounds are persistent pollutants with long half-lives, accumulate in adipose tissue when ingested, bioaccumulate and biomagnify, and have complex and variable toxicological profiles. Examples of organochlorines include dichloro-diphenyl-trichloroethane and its metabolites, polychlorinated biphenyls, and chlordane. In this comprehensive review of human epidemiologic studies which have tested for associations between organochlorines and facets of TDS, we find evidence for associations between the exposures p,p' DDE, cis-nonachlor and trans-nonachlor with testicular germ-cell tumour. The sum of the evidence from human epidemiological studies does not indicate any association between specific organochlorines studied and cryptorchidism, hypospadias or fertility. Many other endocrine-disrupting chemicals, including additional organochlorines, have yet to be assessed in relation to disorders associated with TDS, yet study of such chemicals has strong scientific merit given the relevance of such hypotheses to urogenital development. PMID- 21668840 TI - The influence of early environmental exposures on immune development and subsequent risk of allergic disease. AB - Environmental exposures in pregnancy and the early postnatal period affect early immune development. Early immune function and future allergy susceptibility appear to result from a combination of maternal phenotype, infant genotype, and environmental exposures in utero that affect early gene expression. Furthermore, epigenetic changes in gene expression in one generation can also be inherited across subsequent generations, potentially amplifying heritable allergy risk. PMID- 21668841 TI - The significance of environmental exposure on the progression of allergic diseases. AB - In addition to strong genetic influences on atopic sensitization and disease development in infancy and childhood, a number of environmental factors modulate clinical and immunological phenotypes early in life and even prenatally. These factors include gastrointestinal or skin exposure to food allergens; respiratory exposure to indoor and outdoor allergens; presence of environmental pollutants such as tobacco smoke; and exposure to microbial compounds. PMID- 21668843 TI - Infection and the development of allergic disease. AB - Persistent allergic diseases exemplified by atopic asthma frequently begin during very early life. Epidemiological findings indicate that progression from allergic sensitization to atopic asthma occurs most frequently when atopy is accompanied by early respiratory viral infections. The underlying mechanism appears to involve recruitment of atopy-associated effector mechanisms into the host response to the virus. This has the dual effect of antagonising anti-viral immunity and amplifying inflammation in the infected airway mucosa, driving asthma pathogenesis. Immune responses underlying the allergic state are uniquely plastic during childhood. Alleviating specific allergy during this period may reduce risk of subsequent asthma development. PMID- 21668842 TI - Allergic diseases, gene-environment interactions. AB - Allergic asthma develops in part from dysregulation of the innate and adaptive immune functions, particularly an imbalance in the Th2-driven adaptive immune response. This dysregulation is the result of complex interactions between genes and environment. These interactions occur both pre- and postnatally, providing opportunities for early interventions in immunological programming. PMID- 21668844 TI - Effect of parasite infection on allergic disease. AB - Vertebrates and helminths have co-evolved for 500 million years, developing mutual adaptation mechanisms between parasites and hosts. Today, however, helminth diseases are among the most neglected communicable diseases. Epidemiological evidence shows that exposure to helminth parasites is inversely correlated with allergy incidence, and helminths induce immune hyporeactivity in both the innate and adaptive systems. The mechanisms include parasite-derived regulatory molecules, the study of which opens new avenues for the control of allergic and autoimmune diseases. PMID- 21668845 TI - Allergen structures and epitopes. AB - Human type 1 hypersensitivity diseases such as allergic rhinoconjunctivitis are characterized by allergen-specific IgE antibodies produced in allergic individuals after allergen exposure. IgE antibodies bound to receptors on the surface of effector cells trigger an allergic response by interacting with three dimensional (conformational) epitopes on the allergen surface. Crystal structures are available for complexes of antibody specifically bound to five allergens, from birch pollen, bee venom, cockroach, cow's milk and timothy grass pollen. The details of the antibody-allergen interaction extending all the way to atomic resolution are available from such complexes. In vitro investigations using recombinant monoclonal antibodies and human basophils show that binding affinity is a key to triggering the allergic response. Continued molecular characterization of antibody-allergen interactions is paving the way for the use of recombinant allergens in allergen-specific diagnosis and immunotherapy. PMID- 21668846 TI - Mucosal dendritic cells in allergy and immunotherapy. AB - The oral epithelium contains oral mucosal Langerhans cells (oLCs) that constitutively express the high-affinity IgE-receptor FcepsilonRI, the lipopolysaccharide receptor CD14 and toll-like receptor (TLR)4. The distribution of oLCs profoundly differs at distinct oral mucosal sites, with higher numbers of oLCs detectable in the vestibulum compared with the sublingual region. The oLC response to activation of TLR4 and FcepsilonRI and to binding of allergen suggests that these cells are involved in the maintenance of tolerance towards bacterial components and allergens. Thus, oLCs are important targets for allergens and adjuvants during sublingual immunotherapy, and characterizing them is crucial for improving allergen-specific immunotherapy. PMID- 21668847 TI - Mechanisms of immunotherapy and surrogate markers. AB - Understanding mechanisms of inducible antigen-specific tolerance will improve immunotherapy and reveal the most relevant biomarkers for objectively measuring response to immunotherapy in clinical trials and routine practice. Various physiological and laboratory parameters are proposed as biomarkers of an immunological response to vaccines, although their surrogacy for clinical end points is unproven. Examples of physiological biomarkers include suppression of allergen-induced early- and late-phase responses. Laboratory biomarkers include increases in bioactive allergen-specific IgG and IgA levels and T-cell interleukin (IL)-10 production. There is a continuing unmet need for biomarkers that will allow prediction of treatment efficacy and assist in monitoring the response after starting therapy or postwithdrawal. PMID- 21668848 TI - The role of IgG antibodies in allergy and immunotherapy. AB - In specific immunotherapy (SIT), a beneficial response is associated with an increase in allergen-specific IgG(4) . This does not indicate that IgE-producing B cells have switched to IgG(4) production, because in human DNA, IgE is downstream from IgG(4) . Thus, by conventional switching, B cells should produce IgG(4) before IgE. This presentation discusses three possible hypotheses explaining the favourable association between IgG(4) and SIT, including that SIT causes B cells to become regulatory. Regulatory B cells may produce cytokines like IL-10 that promote IgG(4) production. IgG(4) can undergo in vitro switching to create bispecific antibodies that recognize more than one antigen, which has important consequences for reducing IgE-allergen complexes in immunotherapy. PMID- 21668849 TI - Anaphylaxis pathogenesis and treatment. AB - Anaphylaxis is a serious allergic reaction that is rapid in onset and sometimes leads to death. Understanding mechanisms, triggers, and patient-specific risk factors for severe or fatal anaphylaxis is critically important. Diagnosis of anaphylaxis is currently based on established clinical criteria. Epinephrine (adrenaline) is the first-line medication for anaphylaxis treatment and delay in injecting it contributes to biphasic reactions, hypoxic-ischemic encephalopathy, and fatality. Here, we focus on four important areas of translational research in anaphylaxis: studies of potential new biomarkers to support the clinical diagnosis of anaphylaxis, laboratory tests to distinguish allergen sensitization from clinical risk of anaphylaxis, the primary role of epinephrine (adrenaline) in anaphylaxis treatment, and strengthening the overall evidence base for anaphylaxis treatment. PMID- 21668850 TI - Anaphylaxis caused by Hymenoptera stings: from epidemiology to treatment. AB - Hymenoptera venom allergy occasionally causes fatal reactions. The prevalence of systemic reactions (SRs) is 0.3-8.9%, with anaphylaxis in 0.3-42.8% of cases. Factors contributing to reaction severity include older age, insect type, a previous less severe SR, preexisting diseases, concomitant treatments, mast cell diseases and elevated baseline tryptase serum concentration. Venom immunotherapy (VIT) is highly effective, as shown by sting challenge and spontaneous field stings. Indications for VIT are based on history of an SR, positive diagnostic tests, natural history and established risk factors for a severe outcome. Current strategies for reducing adverse reactions include anti-IgE monoclonal antibody pretreatment, and purified aqueous and purified aluminium hydroxide adsorbed preparations. New strategies for VIT, mostly using recombinant allergen, are in development. Further improvements will increase the safety and efficacy of VIT. PMID- 21668851 TI - Dosing and efficacy in specific immunotherapy. AB - Allergen-specific immunotherapy is used to treat allergic rhinoconjuctivitis and asthma worldwide. The clinical efficacy of the most common routes, subcutaneous (SCIT) and sublingual (SLIT) immunotherapy, is documented for respiratory allergy by double-blind, placebo-controlled, randomised clinical trials (DB PC RCT). However, dose-effect relationships are not available for all extracts. The 1998 WHO Consensus Report on Allergen Immunotherapy found SCIT ineffective at low doses, with high doses more likely to result in an unacceptably high level of systemic reactions. Recent large well-designed DB PC RCTs using SLIT grass pollen tablets have undergone phase II-III studies in adults with allergic rhinitis, yielding proper dose-response studies. These were analysed by the European Academy of Allergy and Clinical Immunology Immunotherapy Interest Group task force on dose effect. In general, low doses (5-7 MUg of allergen Phl p 5 per day) are ineffective. Daily doses of 15-25 MUg of the major allergen protein are required for significant clinical improvement measured by symptom scores. A higher dose (33-40 MUg of Phl p 5 per day) was not more effective than 15-25 MUg. Optimization of the allergen/adjuvant ratio may allow for lower allergen doses, increase the safety/efficacy profile and allow for shorter updosing. However, our analysis of the available studies concluded that every product requires its own dose-response relationship study. PMID- 21668852 TI - Safety and tolerability of immunotherapy using various updosing schedules of a new SCIT product with an optimised allergen/aluminium hydroxide ratio. AB - Allergen extracts for subcutaneous specific immunotherapy (SCIT) may be adsorbed to aluminium hydroxide for adjuvant effect and to delay allergen discharge. A product with an optimised allergen-to-aluminium hydroxide ratio enables a lower allergen dose and shorter introduction phase. The new therapeutic product Avanz (ALK, Denmark) has an optimised allergen-to-aluminium hydroxide ratio. A multicentre, randomised, phase II clinical trial evaluated the immunological effects and tolerability of two different five-step updosing schedules for Avanz in 400 patients with grass pollen-induced rhinoconjunctivitis with or without asthma, randomised into two groups. Group 1 were administered weekly, and group 2 were administered every 3 to 4 days. After updosing, patients received two maintenance injections after 2 and 4 weeks. In the updosing phase, local and systemic reactions were significantly more frequent in group 2 than group 1. In the maintenance phase, adverse reactions were less common in both groups. No generalised reactions with hypotension or fatal reactions occurred. An increase in allergen-specific immunoglobulin G(4) (IgG(4) ) and IgE antibodies was established one week after the last injection. Avanz is a SCIT product with an optimised allergen-to-aluminium hydroxide ratio that enables a shorter updosing phase. We established an improved safety profile with weekly updosing compared with 3-4-day intervals. Clinical trials are needed to confirm clinical efficacy. PMID- 21668853 TI - Immunological measures as potential markers of dose. AB - Specific immunotherapy (SIT) induces immunological changes leading to a decrease in allergen-driven symptoms and medication use. However, the use of arbitrary and variable assay formats and units hampers comparisons between SIT studies. The magnitude of IgG response induced by SIT is not directly linked to clinical improvement, so an increase in allergen-specific IgG(4) should be considered a necessary but not sufficient marker of clinical efficacy. Dose-dependent IgG(4) immune responses should be demonstrated by the manufacturer, not by doctors. Symptom and medication scores are essential end-points for immunotherapy studies, but are subjective, so close association with objective assay measurements will be difficult. Nonetheless, blocking antibody assays combining serology and cellular function may provide a solution for relating immunological assay measurements to clinical outcomes. PMID- 21668854 TI - Provocation tests as measure of efficacy and dosage. AB - Provocation and challenge tests have been used to understand the pathobiology of asthma, to facilitate diagnosis and to assess therapeutic efficacy and dosage. Current challenge tests expose the patient to 'natural conditions', for example, in an allergen chamber. For determining drug efficacy in asthma, allergen challenge has a moderate positive predictive value and an excellent negative predictive value. The best challenge tests are standardized, and the best bronchial challenge tests use a large allergen particle size. Allergen provocation tests are safe when performed by experienced investigators. PMID- 21668855 TI - Sustained effects of grass pollen AIT. AB - We report the sustained efficacy of the SQ-standardized grass allergy immunotherapy tablet Grazax(r) (Phleum pratense 75000 SQ-T/2,800 BAU, ALK, Denmark) from a 5-year randomized, double-blind, placebo-controlled phase III trial. Adults with moderate-to-severe grass pollen allergy inadequately controlled by symptomatic medications were followed for 2 years after the completion of 3 years of treatment. The active group demonstrated a 31% reduction in median rhinoconjunctivitis symptom score over the season compared with placebo. Individual symptom scores favoured active treatment. Combined symptom and medication scores demonstrated a 33% reduction in medians with active treatment. Persistent clinical efficacy was accompanied by prolonged increases in allergen-specific IgG(4) antibodies and IgE-blocking factor, confirming clinical and immunological tolerance for at least 2 years after the treatment completion. No safety issues were identified during follow-up. PMID- 21668856 TI - Effect of AIT in children including potential to prevent the development of asthma. AB - Allergy specific immunotherapy may alter the natural course of allergic disease. Thus, it is of significant importance, particularly in paediatric populations. Four studies using the grass allergy immunotherapy tablet (AIT) for allergic rhinoconjunctivitis in children showed good clinical outcomes and good safety profiles. Allergic rhinoconjunctivitis often precedes asthma, and treatment with specific immunotherapy has the potential to reduce the development of asthma in children suffering from rhinoconjunctivitis. Since Grazax(r) AIT has been shown to induce disease modification the prevention of asthma might be hypothesised. The GAP (Grazax(r) Asthma Prevention) trial is investigating the asthma preventive effect of standardised grass AIT in grass allergic children with rhinoconjunctivitis without asthma. The trial is a 5-year, multicentre, multinational, randomised, double-blind, placebo-controlled, prospective trial for children aged 5-12 years. In a few years, the results will show if grass AIT with Grazax(r) can prevent the development of asthma in children suffering from allergic rhinoconjunctivitis. PMID- 21668857 TI - Tolerability and efficacy of house dust mite AIT. AB - Sublingual immunotherapy based on grass pollen allergy immunotherapy tablets is an efficacious and well-tolerated treatment for rhinoconjunctivitis, and subcutaneous house dust mite (HDM) immunotherapy is effective against allergic asthma. Three studies have investigated a new ALK tablet for HDM allergy: two studies on tolerability in adults and children, and one on efficacy and safety in adults and adolescents with asthma. Treatment was well tolerated, mainly with mild-to-moderate local reactions pertaining to the administration site, such as temporary oral pruritus. The primary efficacy endpoint was a significant reduction in inhaled corticosteroid dose compared to baseline after 1 year of daily treatment. A positive therapeutic effect on asthma was demonstrated by a reduction of more than 80 MUg/day inhaled budesonide for a group receiving six developmental units daily compared to the placebo group. PMID- 21668858 TI - Treatment of respiratory allergy with allergy immunotherapy tablets. AB - Allergy immunotherapy tablets (AIT) have expanded the treatment options for patients suffering from respiratory allergies. Efficacy is established in adults and children for two different commercially available grass AITs. The ALK grass AIT has an efficacy comparable to subcutaneous immunotherapy (SCIT), with a proven disease-modifying effect after treatment completion. Safety profiles favour AIT over SCIT. Studies suggest that tablets in all aspects are superior to sublingual drops. AITs for other allergies including house dust mite and birch and ragweed pollen are in development. PMID- 21668859 TI - Immunotherapy concepts under investigation. AB - Allergen-specific immunotherapy (SIT) is effective, but used by only 5% of allergy patients, partly because it requires several years. Intralymphatic immunotherapy (ILIT) administers allergen directly into a subcutaneous lymph node and requires only three injections and a lower allergen dose than subcutaneous administration. ILIT was further improved using a recombinant allergen with enhanced uptake and decreased degradation by antigen-presenting cells. Another interesting route is transcutaneous/epicutaneous immunotherapy (TCIT, EPIT), which administers allergen by a skin patch. Clinical trials show that TCIT, EPIT is safe and comparably effective to conventional immunotherapy. Implementation of these new methods would increase the spectrum of SIT options, allowing greater individual choice of SIT. PMID- 21668860 TI - The future of specific immunotherapy: strategies and challenges for the next generation of allergy vaccines. AB - : The use of specific immunotherapy (SIT) for allergic disorders has recently been extended by introduction of a convenient, tablet-based, disease-modifying vaccine against grass pollen allergy. Allergy immunotherapy tablet (AIT) programmes targeting house dust mite and other allergies are currently in late phase development. Next-generation allergy vaccines can have optimised potency and onset of action without compromising safety or convenience. Key to achieving these objectives is a combination of evidence-based mode-of-action studies and biomarker-centric translational research approaches. This will rely on using biobank and bioinformatics resources for multi-omic characterisations of the 'immunome' of allergic disease. Other important areas are ongoing paediatric trials and long-term studies in adults for further defining the potential role of SIT in allergic disease and primary prevention of asthma. Finally, combining cellular- and serological-based assays, and developments in targeted delivery platforms and component-resolved diagnostics will lead to increased ability to stratify patients, with more personalised diagnosis and treatment. PMID- 21668861 TI - Historical perspective on the use of visual grading scales in evaluating skin irritation and sensitization. AB - Visual assessment of skin reactions has long been used to evaluate the safety of chemicals and preparations that contact the skin, and to meet regulatory requirements. This article reviews the history of visual grading scales, and the results of investigations into the reliability of the method. Some examples are provided to illustrate the diverse array of protocols that use visual scoring to evaluate skin irritation. Furthermore, as bioengineering methods are developed that can quantitate certain aspects of skin irritant and sensitization reactions, it is important to consider whether such measures should supplement or replace visual assessment. Examples of investigations comparing the outcomes of studies that use visual scoring and those that use bioengineering methods are discussed. These examples provide little evidence that bioengineering measures provide an improvement in overall quality in comparison with current testing methods that rely on visual assessment. In addition, such measuring techniques can add considerably to the complexity of testing protocols. When benefits and cost are weighed in the balance, the visual assessment scales popularized by Draize and others remain an effective, practical method of evaluation. PMID- 21668862 TI - Methods for testing platelet function for transfusion medicine. AB - BACKGROUND: Currently only indirect measures are required for monitoring the function of platelets in platelet concentrates (PC). METHODS: This is an overview on currently available commercialized methods that have been used to determine platelet function in donors, concentrates and after transfusion. We show examples for the application of the no/low shear methods light-transmission aggregometry, flow cytometry, multiple electrode aggregometry, thrombelastography and dynamic light scattering, and those applying high shear, the platelet function analyzer 100, and the cone and plate analyzer. Advantages and disadvantages of the various methods to screen donors, evaluate the haemostatic properties maintained in the PC and after transfusion are discussed, based on considerations of platelet physiology, and the feasibility of the various procedures. This survey focuses on reports from the last 10 years, as the technology for the production of PCs has advanced significantly during the last few years. CONCLUSION: Specific aspects of platelet function can be assessed by the no/low shear methods, while the high shear methods provide more general analysis of platelet haemostatic competence. Yet, there is no strong evidence that the in vitro data correspond with the clinical outcome. PMID- 21668863 TI - An international collaborative study to establish the WHO 1st international standard for alpha-1-antitrypsin. AB - BACKGROUND AND OBJECTIVES: The aim was to establish the 1st International Standard (IS) for alpha-1-antitrypsin (AAT) to standardise potency assignment of therapeutic products, calibrated in moles and mg active AAT in line with product labelling practice. Assigning total protein and antigen values to the IS was also investigated. MATERIALS AND METHODS: The active concentration of four candidate AAT preparations was determined in an international collaborative study by inhibition of trypsin (calibrated by active-site titration). Total protein and antigen content were determined for each candidate using local methods and in house standards, and a common AAT preparation. The total protein content of the IS was also determined by amino acid analysis. Potency determination of recombinant and transgenic materials against the IS was investigated in a follow up study. RESULTS: Data analysis for potency determination indicated no statistical difference between any of the candidates, or between the results for recombinant and plasma-derived products. Total protein content of the IS determined by amino acid analysis was consistent with the potency value. The variability in the total protein and antigen results for the other candidates was reduced when the data were recalculated relative to the IS. CONCLUSIONS: Candidate C (05/162) was established by the WHO Expert Committee on Biological Standardization (ECBS) in 2006 as the WHO 1st IS for AAT with a potency of 243 nmoles (12.4 mg) active inhibitor per ampoule. In 2008, ECBS approved the IS for potency determination of recombinant material and assigned a total protein and antigen value of 12.4 mg. PMID- 21668864 TI - Retraction: Boldt J, Mengistu A, Seyfert UT, Vogt A, Hellstern P: The impact of a medium molecular weight, low molar substitution hydroxyethyl starch dissolved in a physiologically balanced electrolyte solution on blood coagulation and platelet function in vitro. Vox Sang 2007; 93: 139-144. PMID- 21668865 TI - Transcriptional responses to cantharidin, a protein phosphatase inhibitor, in Arabidopsis thaliana reveal the involvement of multiple signal transduction pathways. AB - Cantharidin is a natural compound isolated from the blister beetle (Epicauta spp.). It is a potent inhibitor of protein serine/threonine phosphatases (PPPs), especially PP2A and PP4. Protein phosphatases and kinases maintain a sensitive balance between dephosphorylated and phosphorylated forms of appropriate proteins, thereby playing important roles in signal transduction pathways and regulation of gene expression, cellular proliferation, cell differentiation, apoptosis and other processes. The foliage of 12-day-old Arabidopsis thaliana seedlings was treated with 200 uM (IC(30) ) of the PPP inhibitor cantharidin, and the entire transcriptome profile was determined by microarray analysis at 2, 10 and 24 h after treatment. The transcription of approximately 10% (2577) of the 24 000 genes of Arabidopsis changed significantly (P<= 0.05 and signal log ratios: >=1 or <=-1) after treatment. Inhibition of PPPs significantly reduced transcription of genes associated with auxin and light signaling and induced expression of genes involved in the hypersensitive response and in flagellin and abscisic acid signaling. The great variety of up- and downregulated genes in this microarray experiment implied that cantharidin interfered with the activities of PPPs that interact directly or indirectly with receptors or are located near the beginning of signal transduction pathways. In many cases, PPPs interact with protein complexes of various receptors such as ethylene or light sensors localized in different cell compartments. They function as negative regulators modifying receptor functions, thus altering signaling that influences transcriptional responses. PMID- 21668867 TI - Sol-gel low-temperature synthesis of stable anatase-type TiO2 nanoparticles under different conditions and its photocatalytic activity. AB - In this work, TiO(2) nanoparticles in anatase phase was prepared by sol-gel low temperature method from titanium tetra-isopropoxide (TTIP) as titanium precursor in the presence of acetic acid (AcOH). The effects of synthesis parameters such as AcOH and water ratios, sol formation time, synthesis and calcination temperature on the photocatalytic activity of TiO(2) nanoparticles were evaluated. The resulting nanoparticles were characterized by X-ray diffraction, UV-Vis reflectance spectroscopy, transmission electron microscopy and Brunauer Emmett-Teller techniques. Photocatalytic activity of anatase TiO(2) nanoparticles determined in the removal of C. I. Acid Red 27 (AR27) under UV light irradiation. Results indicate that with increasing AcOH/TTIP molar ratio from 1 to 10, sol formation time from 1 to 3 h and synthesis temperature from 0 to 25 degrees C, increases crystallite size of synthesized nanoparticles. It was found that optimal conditions for low temperature preparation of anatase-type TiO(2) nanoparticles with high photocatalytic activity were as follows: TTIP:AcOH:water molar ratio 1:1:200, sol formation time 1 h, synthesis temperature 0 degrees C and calcination temperature 450 degrees C. PMID- 21668866 TI - Production of ROS by photosensitized anthracene under sunlight and UV-R at ambient environmental intensities. AB - The aim of this study was to analyze the photostability and phototoxicity mechanism of anthracene (ANT) in a human skin epidermal cell line (HaCaT) at ambient environmental intensities of sunlight/UV-R (UV-A and UV-B). Photomodification of ANT under sunlight/UV-R exposure produced two photoproducts, anthrone and 9,10 anthracenedione. Generation of (1)O(2), O(2)(*-) and (*)OH was measured under UV-R/sunlight exposure. Involvement of reactive oxygen species (ROS) was further substantiated by their quenching with free radical quenchers. Photodegradation of 2-deoxyguanosine and linoleic acid peroxidation showed that ROS were mainly responsible for ANT phototoxicity. ANT generates significant amount of intracellular ROS in cell line. Maximum cell viability (85%) was reduced under sunlight exposure (30 min). Results of MTT assay accord NRU assay. ANT (0.01 MUg mL(-1)) induced cell-cycle arrest at G1 phase. RT-PCR demonstrated constitutive inducible mRNA expression of CYP 1A1 and 1B1 genes. Photosensitive ANT upregulates CYP 1A1 (2.2-folds) and 1B1 (4.1-folds) genes. Thus, the study suggests that ROS and DNA damage were mainly responsible for ANT phototoxicity. ANT exposure may be deleterious to human health at ambient environmental intensities reaching the earth's surface through sunlight. PMID- 21668868 TI - A screening technique useful for testing the effectiveness of novel "self cleaning" photocatalytic surfaces. AB - We describe a screening methodology that can be used to quickly determine the effectiveness of newly synthesized photocatalysts. We were particularly interested in measuring the destruction of organic molecules painted onto a photocatalytic surface by spraying, with destruction proceeding in ambient air (as a model for airborne toxin destruction). Our method can utilize photocatalysts that are synthesized as powders (such as doped and undoped titanium oxide) and which are then calcined onto a glass substrate disk at 600 degrees C. Herein, we used UV illumination of Aeroxide P-25 TiO(2), but the method is general and can accommodate any region of the light spectrum. PMID- 21668869 TI - Sun protecting and sun exposing behaviors: testing their relationship simultaneously with indicators of ultraviolet exposure among adolescents. AB - The aim of this study was to build on existing understanding of adolescent sun related behavior by combining sun protecting and sun exposing behaviors and testing their relationship simultaneously with indicators of ultraviolet (UV) exposure. Data were collected for 692 adolescents aged between 12 and 18 years. General linear modeling was undertaken to test the relationship of sun-related behaviors with indicators of UV exposure. Overall, the combined sun protection and sun exposing behaviors accounted for 13.8% of the variance in the number of sunburns, 28.1% of the variance in current tan and 57.5% of the variance in desired tan, respectively. Results indicated that having a strong desire for a tan was significantly associated with spending time tanning, delaying the use of sun protection, wearing brief clothing and using no sun protection; whereas the number of sunburns was significantly associated with sunscreen use, avoiding peak hours and delaying sun protection. Current tan was significantly associated with wearing sunglasses, shade use and time spent tanning. In examining sun-related behaviors among adolescents, consideration needs to be given to both sun exposing and sun protecting behaviors. This research has important implications for conceptualizing outcomes in programs designed to reduce UV exposure. PMID- 21668870 TI - Roles of porphyrin and iron metabolisms in the delta-aminolevulinic acid (ALA) induced accumulation of protoporphyrin and photodamage of tumor cells. AB - delta-Aminolevulinic acid (ALA)-induced porphyrin accumulation is widely used in the treatment of cancer, as photodynamic therapy. To clarify the mechanisms of the tumor-preferential accumulation of protoporphyrin, we examined the effect of the expression of heme-biosynthetic and -degradative enzymes on the ALA-induced accumulation of protoporphyrin as well as photodamage. The transient expression of heme-biosynthetic enzymes in HeLa cells caused variations of the ALA-induced accumulation of protoporphyrin. When ALA-treated cells were exposed to white light, the extent of photodamage of the cells was dependent on the accumulation of protoporphyrin. The decrease of the accumulation of protoporphyrin was observed in the cells treated with inducers of heme oxygenase (HO)-1. The ALA dependent accumulation of protoporphyrin was decreased in HeLa cells by transfection with HO-1 and HO-2 cDNA. Conversely, knockdown of HO-1/-2 with siRNAs enhanced the ALA-induced protoporphyrin accumulation and photodamage. The ALA effect was decreased with HeLa cells expressing mitoferrin-2, a mitochondrial iron transporter, whereas it was enhanced by the mitoferrin-2 siRNA transfection. These results indicated that not only the production of porphyrin intermediates but also the reuse of iron from heme and mitochondrial iron utilization control the ALA-induced accumulation of protoporphyrin in cancerous cells. PMID- 21668871 TI - Single cell responses to spatially controlled photosensitized production of extracellular singlet oxygen. AB - The response of individual HeLa cells to extracellularly produced singlet oxygen was examined. The spatial domain of singlet oxygen production was controlled using the combination of a membrane-impermeable Pd porphyrin-dendrimer, which served as a photosensitizer, and a focused laser, which served to localize the sensitized production of singlet oxygen. Cells in close proximity to the domain of singlet oxygen production showed morphological changes commonly associated with necrotic cell death. The elapsed postirradiation "waiting period" before necrosis became apparent depended on: (1) the distance between the cell membrane and the domain irradiated, (2) the incident laser fluence and, as such, the initial concentration of singlet oxygen produced and (3) the lifetime of singlet oxygen. The data imply that singlet oxygen plays a key role in this process of light-induced cell death. The approach of using extracellularly generated singlet oxygen to induce cell death can provide a solution to a problem that often limits mechanistic studies of intracellularly photosensitized cell death: it can be difficult to quantify the effective light dose, and hence singlet oxygen concentration, when using an intracellular photosensitizer. PMID- 21668872 TI - Use of engineered unique cysteine residues to facilitate oriented coupling of proteins directly to a gold substrate. AB - A prerequisite for any "lab on a chip" device that utilizes an electrical signal from the sensor protein is the ability to attach the protein in a specific orientation onto a conducting substrate. Here, we demonstrate the covalent attachment to a gold surface of light-harvesting membrane proteins, from Rhodobacter sphaeroides, via cysteine (Cys) residues engineered on either the cytoplasmic or periplasmic face. This simple directed attachment is superior in its ability to retain light-harvesting complex (LHC) function, when compared to a similar attachment procedure utilizing a self-assembled monolayer on gold. LH 1 has previously been observed to have superior photostability over LH 2 (Magis et al. [2010] Biochim. Biophys. Acta, 1798, 637-645); this characteristic is maintained even with the introduction of Cys residues. PMID- 21668873 TI - Enhanced melanin fluorescence by stepwise three-photon excitation. AB - The fluorescence of eumelanin (from Sepia officinalis and black human hair) was activated and enhanced by almost three orders of magnitude by exposure to near infrared radiation. No activation or enhanced emission was observed when the samples were heated up to 100 degrees C. The near-infrared irradiation caused obvious changes to the eumelanin and could be seen by fluorescence and bright field imaging. The area of enhanced emission appeared to originate from a region with changes in the morphology of the eumelanin's granule and increased with exposure time. At least two different components with enhanced fluorescence were activated and could be distinguished by their excitation properties. One component could be excited efficiently with wavelengths in the visible region and exhibited linear absorption dependence with respect to the laser power level. The second component could be excited efficiently using near-infrared wavelengths by a nonlinear process and exhibited a third-order dependence on the excitation. The third-order dependence is explained by a step-wise excited-state absorption process since the same third-order dependence was present when either continuous wave or femtosecond pulsed laser, with similar average-power levels, was used. PMID- 21668874 TI - Analysis of network architecture reveals phylogenetic constraints on mycorrhizal specificity in the genus Orchis (Orchidaceae). AB - The specificity of orchids for their fungi can vary substantially, from highly specialist interactions to more generalist interactions, but little is known about the evolutionary history of the mycorrhizal specificity of orchids. Here, we used a network analysis approach to investigate orchid mycorrhizal associations in 16 species of the genus Orchis sampled across 11 different regions in Europe. We first examined in detail the structure of the network of associations and then tested for a phylogenetic signal in mycorrhizal specificity and identified the fungi with which the orchids associated. We found 20 different fungal lineages that associated with species of the genus Orchis, most of them being related to members of the Tulasnellaceae (84.33% of all identified associations) and a smaller proportion being related to members of the Ceratobasidiaceae (9.97%). Species associations formed a nested network that is built on asymmetric links among species. Evolution of mycorrhizal specificity in Orchis closely resembles a Brownian motion process, and the interaction between Orchis and Tulasnellaceae fungi is significantly influenced by the phylogenetic relationships between the Orchis species. Our results provide evidence of the presence of phylogenetic conservatism in mycorrhizal specificity in orchids and demonstrate that evolutionary processes may be an important factor in generating patterns of mycorrhizal associations. PMID- 21668875 TI - Physiological and molecular analysis of polyethylene glycol-induced reduction of aluminium accumulation in the root tips of common bean (Phaseolus vulgaris). AB - * Aluminium (Al) toxicity and drought are two major stress factors limiting common bean (Phaseolus vulgaris) production on tropical acid soils. Polyethylene glycol (PEG) treatment reduces Al uptake and Al toxicity. * The effect of PEG 6000-induced osmotic stress on the expression of genes was studied using SuperSAGE combined with next-generation sequencing and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for selected genes. * Less Al stress in PEG-treated roots was confirmed by decreased Al-induced up-regulation of MATE and ACCO genes. The withdrawal of PEG from the Al treatment solution restored the Al accumulation and reversed the expression of MATE and ACCO genes to the level of the treatment with Al alone. Using SuperSAGE, we identified 611 up- and 728 down-regulated genes in PEG-treated root tips, and the results were confirmed by qRT-PCR using 46 differentially expressed genes. Among the 12 genes studied in more detail, XTHa and BEG (down-regulated by PEG) and HRGP, bZIP, MYB and P5CS (up-regulated by PEG) recovered completely within 2 h after removal of PEG stress. * The results suggest that genes related to cell wall assembly and modification, such as XTHs, BEG and HRGP, play important roles in the PEG-induced decrease in cell wall porosity, leading to reduced Al accumulation in root tips. PMID- 21668876 TI - Computer availability and principals' perceptions of online surveys(*). AB - BACKGROUND: School-based risk behavior surveys traditionally have been administered via paper-and-pencil. This study assessed the feasibility of conducting in-class online surveys in US high schools. METHODS: A paper-and pencil questionnaire assessing computer availability and perceptions of online surveys was mailed to a nationally representative sample of public and private high school principals in fall 2008. Completed surveys were returned by principals from 580 of 704 selected schools. Prevalence and 95% confidence intervals were computed. RESULTS: Most high schools have at least 1 computer lab, most computers in computer labs are connected to the Internet, and just under half of schools with a stationary computer lab had a sufficient number of computers to accommodate an in-class online survey administration. The 2 most common problems associated with online surveys were logistics of providing enough computers for an entire class and rotating classes into computer labs. Nearly two thirds of principals preferred online to paper-and-pencil surveys when administered to 4 randomly selected classes that met at different times during the school day, but less than half reported this preference when administered to 4 randomly selected classes that met at the same time during the school day. CONCLUSION: Many schools do not have sufficient computer capacity to participate in a voluntary in-class online survey. An online survey could impose significant perceived and actual burden on schools and therefore could result in unacceptably low school participation rates. Online administration for in-class surveys of students in US high schools are not recommended. PMID- 21668877 TI - Correlates of gambling among eighth-grade boys and girls. AB - BACKGROUND: This study examined the correlates of gambling behavior among eighth grade students. METHODS: Children (n = 15,865) enrolled in publicly funded schools in Oregon completed the 2008 Oregon Healthy Teens survey. Multivariate logistic regression analyses assessed the combined and independent associations between risk and protective factors with active gambling among male and female youth separately. RESULTS: Approximately 17% of eighth-grade girls and 33% of eighth-grade boys had gambled during the past 3 months. Most health risk behaviors were positively associated with gambling. However, gambling was also positively associated with frequent physical activity participation and, among boys, eating 5 daily servings of fruits and vegetables. Logistic regression analyses identified significant differences among risk and protective factors between active gamblers and non-gamblers. Regardless of gender, relative to active gamblers, non-gamblers were more likely to hold strong personal health beliefs, be uninvolved in antisocial behavior, exhibit good safety behaviors, and not have experienced a mouth injury while playing sports during the past year. Female gamblers were more likely to be active tobacco users, to speak a language other than English at home, and engage in more than 2 hours a day of screen time than non-gamblers. Male gamblers were more likely to be physically active, Hispanic, use alcohol, and perceive lower levels of social control in their neighborhoods than non-gamblers. CONCLUSIONS: Gambling may be a topic that is appropriate for inclusion in school programs targeting health risk reduction among eighth-grade students. PMID- 21668878 TI - Peer victimization and academic adjustment among early adolescents: moderation by gender and mediation by perceived classmate support. AB - BACKGROUND: This study examined the moderating role of gender and the mediating role of perceived peer support in the association between peer victimization and academic adjustment. METHODS: Data were obtained from adolescents in grades 7 and 8 in the US 2005/2006 Health Behavior in School-aged Children study (N = 3436; mean age = 13.6 years). RESULTS: The magnitude of correlation between victimization and academic adjustment was -.155 for males and -.337 for females. After controlling for the socio-demographic variables, victimization had a significantly stronger influence on academic adjustment in females than in males. For both genders, perceived classmate support was negatively associated with peer victimization and positively associated with academic adjustment. Classmate support mediated the association between victimization and academic adjustment in males and was a partial mediator for females. CONCLUSION: These results provide support for efforts reducing victimization of female adolescents and fostering peer support in the school setting. PMID- 21668879 TI - Different forms of bullying and their association to smoking and drinking behavior in Italian adolescents. AB - BACKGROUND: Using data from the 2006 Health Behavior in School-aged Children (HBSC) survey, the prevalence of 6 forms of bullying (physical, verbal, relational, sexual, cyber, and racist), and the role of smoking and drinking in bullying was examined among Italian adolescents for this study. METHODS: The sample was composed of 2667 Italian middle and secondary school students (49.9% girls) randomly selected. The revised Olweus Bully/Victim Questionnaire was used to measure physical, verbal, relational, sexual, cyber, and racist forms of bullying. For each form, 3 categories were created and compared with students "not involved in bullying": bully, victim, and bully-victim. Logistic regressions were applied to test the connections among the 3 forms of involvement in different types of bullying and smoking and drinking. RESULTS: Prevalence of having been bullied or having bullied others at school at least once in the last 2 months was 11.6% for physical, 52% for verbal, 47.9% for relational, 18.5% for sexual, 19.4% for cyber, and 9.4% for racist bullying. Compared to girls, boys were more likely to be involved in physical bullying; moreover, boys were more involved as bullies in verbal, sexual, cyber, and racist bullying. In contrast, girls were more likely to be victims of verbal, relational, sexual, and cyber bullying than were boys. Logistic regressions showed the connection between the different forms of involvement in bullying and smoking and drinking. CONCLUSIONS: Our results indicate that all forms of bullying behavior are associated with legal substance use. Implication for prevention program was discussed. PMID- 21668880 TI - A longitudinal examination of the link between youth physical fitness and academic achievement. AB - BACKGROUND: Childhood obesity has been linked with other persistent health problems, but research is just beginning to examine its relationship with academic performance. This article tracks students longitudinally to examine the ways student physical fitness and changes in fitness align with school performance. METHODS: Using matched administrative data and individual growth modeling, we examine the relationship between academic achievement and overall physical fitness longitudinally from fourth to seventh and sixth to ninth grades for students in a California community. RESULTS: Comparing those who are persistently fit to those who are persistently unfit, we find disparities in both math and English language arts test scores. These academic disparities begin even before students begin fitness testing in fifth grade and are larger for girls and Latinos. Overall physical fitness is a better predictor of academic achievement than obesity as measured by body mass index. Socioeconomic status acts as a buffer for those who have poor physical fitness but strong academic performance. CONCLUSION: The findings indicate the presence of a physical fitness achievement gap that has consequences for potential students' future educational and health outcomes. This gap begins as early as fourth grade, which is before physical fitness testing begins in California. PMID- 21668881 TI - The influence of body mass index on long-term fitness from physical education in adolescent girls. AB - BACKGROUND: Physical education (PE) can improve physical fitness; however, little research has evaluated PE's long-term influence. The purpose is to determine PE's longitudinal effects on fitness in a group of adolescent girls and to determine whether body mass index (BMI) status influenced any potential effects. METHODS: Participants were enrolled in daily PE throughout their ninth grade. Data were collected at baseline and at the end of 9th, 10th, and 11th grades. BMI (kg/m(2) ) was classified into Centers for Disease Control and Prevention percentiles. Fitness was estimated from a 3-stage step test (change in exercise heart rate (HR) indicated improved fitness) and analyzed using repeated measures general linear modeling with adjustments for baseline BMI, baseline age, ethnicity, intervention status, and moderate-to-vigorous physical activity outside PE. RESULTS: Complete data were available for 131 girls (61% of sample) who were predominantly African American, 13.8 +/- 0.4 years, mean BMI 24.7 +/- 6.1 kg/m(2) at the ninth-grade baseline. Overall, stage 1 HR (bpm) decreased from baseline to 9th grade (-5.5 +/- 1.3, p < 0.0001), baseline to 10th grade (-7.2 +/- 1.4, p < 0.0001), and baseline to 11th grade (-7.0 +/- 1.5, p < 0.0001). Change differed by BMI status; fitness improvement was significant for normal and overweight, but not obese girls. After 2 years, change in stage 1 HR (bpm) was significantly different between BMI categories: normal-weight girls versus obese girls (-10.0 +/- 3.2, p = 0.002) and overweight girls versus obese girls (-9.3 +/- 3.9, p = 0.02). CONCLUSION: Fitness differences by BMI exist after a PE program in adolescent girls: fitness improved and was maintained in normal-weight and overweight girls, whereby obese girls had no improvement in fitness. PMID- 21668882 TI - The relationship of school absenteeism with body mass index, academic achievement, and socioeconomic status among fourth-grade children. AB - BACKGROUND: Data from a school-based study concerning fourth-grade children's dietary recall accuracy were linked with data from the South Carolina Department of Education (SCDE) through the South Carolina Budget and Control Board Office of Research and Statistics (ORS) to investigate the relationships of children's school absenteeism with body mass index (BMI), academic achievement, and socioeconomic status (SES). METHODS: Data for all variables were available for 920 fourth-grade children during 2 school years (2005-2006, 2006-2007). Number of school days absent for each child and eligibility for free/reduced-price school meals (SES measure) were provided to ORS by SCDE. Children's weight and height were measured by research staff; age/sex-specific BMI percentile was calculated and grouped into categories. For academic achievement, Palmetto Achievement Challenge Tests scores were provided by the school district. The associations of absenteeism with BMI, academic achievement, SES, and school year were investigated with logistic binomial models using the modified sandwich variance estimator to adjust for multiple outcomes within schools. RESULTS: The relationships between absenteeism and each of BMI percentile category and SES were not significant (all coefficient p values > .118). The relationship between absenteeism and academic achievement was inversely significant (p value < .0001; coefficient = -.087). CONCLUSIONS: These results support the inverse relationship between absenteeism and academic achievement that was expected and has been found by other researchers. The lack of significant results concerning the relationships between absenteeism and both BMI and SES differs from earlier, limited research. More research to investigate these relationships is needed. PMID- 21668883 TI - Children's eating behavior: the importance of nutrition standards for foods in schools. AB - BACKGROUND: To enhance the impact of school nutrition programs on children's health, more information is needed on the associations between healthy and unhealthy food offerings during school lunch periods and children's eating behavior. The purpose of this study is to evaluate the contributions of food offerings and participation in school lunch programs on children's overall (both in- and out-of-school) eating behavior. METHODS: A cross-sectional observational study was conducted in which 2039 students in 12 elementary and 10 middle schools reported their eating behavior and the frequencies with which they purchased meals and a la carte items in the school cafeteria. Food service managers from each school provided information on the availability of foods and beverages during school lunch periods. Multilevel regression analyses were conducted to identify school- and student-level predictors of children's eating behavior. RESULTS: The availability of nutritious foods during school lunch periods was associated with healthier eating behavior among students. However, this effect was observed only among children who infrequently purchased a la carte food items, and not among those who were frequent purchasers. CONCLUSION: Increased availability of fruits, vegetables, whole grains, and low-fat dairy products as components of school meals may be an effective strategy to promote healthy eating behaviors among children. Improving the nutrition standards for foods offered in competition with federally reimbursable school meals may enhance the positive effects of school meal programs on student eating behavior. PMID- 21668884 TI - The thylakoid protease Deg2 is involved in stress-related degradation of the photosystem II light-harvesting protein Lhcb6 in Arabidopsis thaliana. AB - * The thylakoid protease Deg2 is a serine-type protease peripherally attached to the stromal side of the thylakoid membrane. Given the lack of knowledge concerning its function, two T-DNA insertion lines devoid of Deg2 were prepared to study the functional importance of this protease in Arabidopsis thaliana. * The phenotypic appearance of deg2 mutants was studied using a combination of stereo and transmission electron microscopy, and short-stress-mediated degradation of apoproteins of minor light-harvesting antennae of photosystem II (PSII) was analysed by immunoblotting in the mutants in comparison with wild-type plants. * Deg2 repression produced a phenotype in which reduced leaf area and modified chloroplast ultrastructure of older leaves were the most prominent features. In contrast to the wild type, the chloroplasts of second-whorl leaves of 4-wk-old deg2 mutants did not display features typical of the early senescence phase, such as undulation of the chloroplast envelope and thylakoids. The ability to degrade the photosystem II light-harvesting protein Lhcb6 apoprotein in response to brief high-salt, wounding, high-temperature and high-irradiance stress was demonstrated to be impaired in deg2 mutants. * Our results suggest that Deg2 is required for normal plant development, including the chloroplast life cycle, and has an important function in the degradation of Lhcb6 in response to short-duration stresses. PMID- 21668885 TI - Calcium-regulated anion channels in the plasma membrane of Lilium longiflorum pollen protoplasts. AB - * Currents through anion channels in the plasma membrane of Lilium longiflorum pollen grain protoplasts were studied under conditions of symmetrical anionic concentrations by means of patch-clamp whole-cell configuration. * With Cl(-) based intra- and extracellular solutions, three outward-rectifying anion conductances, I(Cl1) , I(Cl2) and I(Cl3) , were identified. These three activities were discriminated by differential rundown behaviour and sensitivity to 5-nitro-2-(phenylpropylamino)-benzoate (NPPB), which could not be attributed to one or more channel types. All shared strong outward rectification, activated instantaneously and displayed a slow time-dependent activation for positive potentials. All showed modulation by intracellular calcium ([Ca(2+) ](in) ), increasing intensity from 6.04 nM up to 0.5 mM (I(Cl1) ), or reaching a maximum value with 8.50 MUM (I(Cl2) and I(Cl3) ). * After rundown, the anionic currents measured using NO(3) (-) -based solutions were indistinguishable, indicating that the permeabilities of the channels for Cl(-) and NO(3) (-) are similar. Additionally, unitary anionic currents were measured from outside-out excised patches, confirming the presence of individual anionic channels. * This study shows for the first time the presence of a large anionic conductance across the membrane of pollen protoplasts, resulting from the presence of Ca(2+) -regulated channels. A similar conductance was also found in germinated pollen. We hypothesize that these putative channels may be responsible for the large anionic fluxes previously detected by means of self-referencing vibrating probes. PMID- 21668886 TI - Evaluation of immunosuppressive regimens for immune-mediated haemolytic anaemia: a retrospective study of 42 dogs. AB - OBJECTIVES: Immune-mediated haemolytic anaemia (IMHA) is a severe disease for which evidence is lacking to make informed choices regarding immunosuppressive regimen. The aims of the current study were to determine the effect of different treatment regimens on outcome in affected animals and to identify parameters that may be used as prognostic factors for the disease. METHODS: The records of dogs presenting to a veterinary hospital in the period 2002 to 2010 for treatment of IMHA were examined and follow-up data were obtained. Statistical tests were performed to establish whether treatment regimen affected outcome and to identify prognostic factors for outcome. RESULTS: Treatment regimen had a significant effect on the outcome (measured as survival of hospitalisation) but there were insufficient subjects to determine the cause of the difference. Serum bilirubin and urea concentrations were found to be significant negative prognostic factors for the outcome of IMHA cases and the concentrations of these parameters were significantly different between animals that survived or died while hospitalised. CLINICAL SIGNIFICANCE: This study presents the first report of a significant difference in outcome comparing animals treated with immunosuppressive drugs which are in widespread clinical usage. Although possible confounding factors should be considered, these findings could have major consequences for the treatment of IMHA. PMID- 21668887 TI - Analysis of the salivary proteome in gingivitis patients. AB - BACKGROUND AND OBJECTIVE: Gingivitis is a disease that is characterized by inflammation of the gingival tissue, which can progress to periodontitis and tooth loss. Although many studies have attempted to identify salivary proteins that are associated with the disease, this is the first study to use a proteomic approach to analyze and compare the proteomic profile of whole saliva from gingivitis patients and healthy controls. MATERIAL AND METHOD: To analyze the saliva proteome, two-dimensional gel electrophoresis and liquid chromatography were used, followed by mass spectrometry. RESULTS: The analyses showed that gingival inflammation was associated with increased amounts of blood proteins (serum albumin and hemoglobin), immunoglobulin peptides and keratins. In the control group, salivary cystatins, which were detected using capillary Liquid Chromatography on line to electrospray ionization Quadrupole Time-of-flight mass spectrometry, appeared to be more abundant. CONCLUSION: This approach provides novel insight into profiles of the salivary proteome during gingival inflammation, which may contribute to improvements in diagnosis. PMID- 21668889 TI - Characterization of 1-(2-[18F] fluoro-3-pyridyl)-4-(2-isopropyl-1-oxo- isoindoline-5-yl)-5-methyl-1H-1,2,3-triazole, a PET ligand for imaging the metabotropic glutamate receptor type 1 in rat and monkey brains. AB - We developed 1-(2-[(18) F]fluoro-3-pyridyl)-4-(2-isopropyl-1-oxo-isoindoline-5 yl)-5-methyl-1H-1,2,3-triazole ([(18) F]FPIT) as a promising positron emission tomography (PET) ligand for in vitro and in vivo imaging of metabotropic glutamate receptor type 1 (mGluR1) in rat and monkey brains. In vitro autoradiography with [(18) F]FPIT was used to determine the distribution of radioactivity in rat and monkey brains. In vivo experiments were performed using dissection and small-animal PET on rats, and PET on monkey. Metabolite analysis was performed on rat plasma and brain, and monkey plasma. Autoradiography of rat and monkey brains showed that [(18) F]FPIT binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study on rat and monkey showed high brain uptake and distribution patterns consistent with those seen in the autoradiographic studies. The radioactivity in the brain was significantly decreased by pre-treatment with unlabeled FPIT, indicative of a specific signal for mGluR1 that was inhibited by mGluR1-selective ligand JNJ-16259865 in the brain. Metabolite analysis showed that the percentage of unchanged [(18) F]FPIT was 89% in the brain homogenate of rat at 90 min after injection. In the monkey plasma, the percentage of unchanged form was 50% at 90 min. [(18) F]FPIT produced in vitro and in vivo signals to visualize mGluR1 expression in rat and monkey brains, suggesting the usefulness of [(18) F]FPIT for imaging mGluR1 in human brain. PMID- 21668888 TI - Transcriptomic profiles of Wnt3a and insulin in primary cultured rat cortical neurones. AB - Glycogen synthase kinase 3 (GSK3) is a widely expressed, constitutively active, serine/threonine kinase that is negatively regulated by both Wnt and insulin via two independent signalling pathways. GSK3 is an important mediator in many physiological processes including glycogen metabolism, apoptosis and gene transcription. In addition, GSK3 is implicated in diseases such as Alzheimer's, schizophrenia and cancer, where it exhibits deregulated activity. In this study, we sought to determine the neuronal genes regulated by both Wnt and insulin in an in vitro cell culture model to further elucidate the signalling roles GSK3 plays in the CNS. Affymetrix Rat Genome 230 2.0 whole genome microarrays were used to explore the expression profiles of rat primary cortical neurones treated with recombinant Wnt3a (10 nM) or insulin (50 nM) for 2 h. Following a conservative correction (Bonferroni) for multiple testing, seven genes were identified to be differentially expressed from controls; four of these genes were regulated by insulin and three genes were regulated by both insulin and Wnt3a. The data were also analysed using a false discovery rate cut off, which is a less stringent correction for multiple testing. This approach yielded 105 genes that were differentially regulated from controls; 72 of the gene changes were attributable to insulin treatment, 11 were because of Wnt3a treatment and 22 genes were altered by both insulin and Wnt3a. These data demonstrate that the Wnt and insulin pathways exhibit both divergent and overlapping signalling activities in neuronal cells. The overlapping transcriptional response was not attributable to Wnt3a activating Akt. These findings have ramifications for neurodevelopment and neurological diseases, in which the Wnt and insulin signalling pathways are implicated. PMID- 21668891 TI - Social structure emerges via the interaction between local ecology and individual behaviour. AB - 1. The formation of groups is a fundamental aspect of social organization, but there are still many questions regarding how social structure emerges from individuals making non-random associations. 2. Although food distribution and individual phenotypic traits are known to separately influence social organization, this is the first study, to our knowledge, experimentally linking them to demonstrate the importance of their interaction in the emergence of social structure. 3. Using an experimental design in which food distribution was either clumped or dispersed, in combination with individuals that varied in exploratory behaviour, our results show that social structure can be induced in the otherwise non-social European shore crab (Carcinus maenas). 4. Regardless of food distribution, individuals with relatively high exploratory behaviour played an important role in connecting otherwise poorly connected individuals. In comparison, low exploratory individuals aggregated into cohesive, stable subgroups (moving together even when not foraging), but only in tanks where resources were clumped. No such non-foraging subgroups formed in environments where food was evenly dispersed. 5. Body size did not accurately explain an individual's role within the network for either type of food distribution. 6. Because of their synchronized movements and potential to gain social information, groups of low exploratory crabs were more effective than singletons at finding food. 7. Because social structure affects selection, and social structure is shown to be sensitive to the interaction between ecological and behavioural differences among individuals, local selective pressures are likely to reflect this interaction. PMID- 21668890 TI - Characterization of Dp71Delta(78-79), a novel dystrophin mutant that stimulates PC12 cell differentiation. AB - Dp71 has an important role in the central nervous system. To better understand the function of Dp71 domains in neuronal differentiation, PC12 cells were stably transfected with a dystrophin mutant, Dp71Delta(78-79) , which lacks exons 78 and 79. Based on the percentage of cells bearing neurites and neurite length analyses, we found that cells stably expressing Dp71Delta(78-79) (PC12-C11) differentiate more efficiently than non-transfected cells. While wild-type cells reach their maximum differentiation 9-12 days after initiating the differentiation process, the PC12-C11 cells reach differentiation in 4-6 days. Protein expression analysis showed a down-regulation of Dp71a and an up regulation of Dp71ab and/or Up71, beta-dystroglycan and neuron-specific enolase in undifferentiated and in neural growth factor differentiated PC12-C11 cells. No change was observed in the expression of Grb2 and Up400. The subcellular localization of Dp71Delta(78-79) was in the cell periphery, and there was no change in localization during the differentiation process, which was also observed throughout the neurite extensions. PMID- 21668892 TI - Patterns and causes of demographic variation in a harvested moose population: evidence for the effects of climate and density-dependent drivers. AB - 1. Better understanding of the mechanisms affecting demographic variation in ungulate populations is needed to support sustainable management of harvested populations. While studies of moose Alces alces L. populations have previously explored temporal variation in demographic processes, managers responsible for populations that span large heterogeneous landscapes would benefit from an understanding of how demography varies across biogeographical gradients in climate and other population drivers. Evidence of thresholds in population response to manageable and un-manageable drivers could aid resource managers in identifying limits to the magnitude of sustainable change. 2. Generalized additive models (GAMs) were used to evaluate the relative importance of population density, habitat abundance, summer and winter climatic conditions, primary production, and harvest intensity in explaining spatial variation in moose vital rates in Ontario, Canada. Tree regression was used to test for thresholds in the magnitudes of environmental predictor variables that significantly affected population vital rates. 3. Moose population growth rate was negatively related to moose density and positively related to the abundance of mixed deciduous habitat abundant in forage. Calf recruitment was negatively related to a later start of the growing season and calf harvest. The ratio of bulls to cows was related to male harvest and hunter access, and thresholds were evident in predictor variables for all vital rate models. 4. Findings indicate that the contributions of density-dependent and independent factors can vary depending on the scale of population process. The importance of density dependence and habitat supply to low-density ungulate populations was evident, and management strategies for ungulates may be improved by explicitly linking forest management and harvest. Findings emphasize the importance of considering summer climatic influences to ungulate populations, as recruitment in moose was more sensitive to the timing of vegetation green-up than winter severity. The efficacy of management decisions for harvested ungulates may require regional shifts in targets where populations span bioclimatic gradients. The use of GAMs in combination with recursive partitioning was demonstrated to be an informative analytical framework that captured nonlinear relationships common in natural processes and thresholds that are relevant to population management in diverse systems. PMID- 21668893 TI - Predation risk suppresses the positive feedback between size structure and cannibalism. AB - 1. Cannibalism can play a prominent role in the structuring and dynamics of ecological communities. Previous studies have emphasized the importance of size structure and density of cannibalistic species in shaping short- and long-term cannibalism dynamics, but our understanding of how predators influence cannibalism dynamics is limited. This is despite widespread evidence that many prey species exhibit behavioural and morphological adaptations in response to predation risk. 2. This study examined how the presence and absence of predation risk from larval dragonflies Aeshna nigroflava affected cannibalism dynamics in its prey larval salamanders Hynobius retardatus. 3. We found that feedback dynamics between size structure and cannibalism depended on whether dragonfly predation risk was present. In the absence of dragonfly risk cues, a positive feedback between salamander size structure and cannibalism through time occurred because most of the replicates in this treatment contained at least one salamander larvae having an enlarged gape (i.e. cannibal). In contrast, this feedback and the emergence of cannibalism were rarely observed in the presence of the dragonfly risk cues. Once salamander size divergence occurred, experimental reversals of the presence or absence of dragonfly risk cues did not alter existing cannibalism dynamics as the experiment progressed. Thus, the effects of risk on the mechanisms driving cannibalism dynamics likely operated during the early developmental period of the salamander larvae. 4. The effects of dragonfly predation risk on behavioural aspects of cannibalistic interactions among hatchlings may prohibit the initiation of dynamics between size structure and cannibalism. Our predation trials clearly showed that encounter rates among hatchlings and biting and ingestion rates of prospective prey by prospective cannibals were significantly lower in the presence vs. absence of dragonfly predation risk even though the size asymmetry between cannibals and victims was similar in both risk treatments. These results suggest that dragonfly risk cues first suppress cannibalism among hatchlings and then prevent size variation from increasing through time. 5. We suggest that the positive feedback dynamics between size structure and cannibalism and their modification by predation risk may also operate in other systems to shape the population dynamics of cannibalistic prey species as well as overall community dynamics. PMID- 21668894 TI - Demographic consequences of increased winter births in a large aseasonally breeding mammal (Bos taurus) in response to climate change. AB - 1. Studies examining changes in the scheduling of breeding in response to climate change have focused on species with well-defined breeding seasons. Species exhibiting year-round breeding have received little attention and the magnitudes of any responses are unknown. 2. We investigated phenological data for an enclosed feral population of cattle (Bos taurus L.) in northern England exhibiting year-round breeding. This population is relatively free of human interference. 3. We assessed whether the timing of births had changed over the last 60 years, in response to increasing winter and spring temperatures, changes in herd density, and a regime of lime fertilisation. 4. Median birth date became earlier by 1.0 days per year. Analyses of the seasonal distribution of calving dates showed that significantly fewer calves were born in summer (decline from 44% of total births to 20%) and significantly more in winter (increase from 12% to 30%) over the study period. The most pronounced changes occurred in winter, with significant increases in both the proportion and number of births. Winter births arise from conceptions in the previous spring, and we considered models that investigated climate and weather variables associated with the winter preceding and the spring of conceptions. 5. The proportion of winter births was higher when the onset of the plant growing season was earlier during the spring of conceptions. This relationship was much weaker during years when the site had been fertilised with lime, suggesting that increased forage biomass was over riding the impacts of changing plant phenology. When the onset of the growing season was late, winter births increased with female density. 6. Recruitment estimates from a stage-structured state-space population model were significantly negatively correlated with the proportion of births in the preceding winter, suggesting that calves born in winter are less likely to survive than those born in other seasons. 7. This is one of the first studies to document changes in the phenology of a year-round breeder, suggesting that the impact of climate on the scheduling of biological events may be more extensive than previously thought and that impacts may be negative, even for species with relatively flexible breeding strategies. PMID- 21668895 TI - Comparative axial morphology in pinnipeds and its correlation with aquatic locomotory behaviour. AB - Regional variation in the axial skeleton of pinnipeds (seals and walruses) and its correlation with aquatic locomotory behaviour is examined using vertebral functional profiles. The results demonstrate clear morpho-functional differences in the thoracolumbar region of modern pinnipeds (Phocidae, Otariidae, Odobenus) that can be strongly linked to swimming style. Phocid seals have a rigid thoracic region attached to a highly flexible lumbar region with long muscular lever arms providing the necessary mobility and leverage to perform pelvic oscillations. Conversely, otariid seals have extremely flexible inter-vertebral joints along the length of the column which should enhance manoeuvrability and turning performance. They also have greater muscular leverage in the anterior thoracic region to support pectoral oscillations. Odobenus (walrus) shows vertebral characteristics most similar to phocids, but with some otariid qualities, consistent with an intermediate or mixed form of aquatic locomotion, with pelvic oscillation dominating over pectoral oscillation. Comparison of the vertebral functional profiles in the fossil taxon Allodesmus kernensis with those of modern pinniped clades reveals that this extinct pinniped may also have used a combination of pectoral and pelvic oscillatory movements during swimming, but in a manner opposite to that of Odobenus, with pectoral oscillatory movements dominating. This study raises questions about the evolution and diversification of pinniped locomotory behaviours, but also provides the necessary framework to begin to examine axial mechanics and locomotory stages in other fossil pinnipedimorphs and their relatives in more detail. PMID- 21668896 TI - Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations. AB - Fibrochondrogenesis is documented to be a neonatally lethal rare recessively inherited disorder characterized by short-limbed skeletal dysplasia. Here we report two patients from two unrelated consanguineous Emirati families who have unexpectedly survived till the ages of 3 and 6 years. These patients show additional symptoms which include developmental delay, profound sensory-neural deafness, severe myopia and progressive severe skeletal abnormalities. Linkage of fibrochondrogenesis in the Emirati families to chromosome 1 has been established using homozygosity mapping confirming recent findings by Tompson et al. in 2010. Screening of the COL11A1 gene revealed two null homozygous mutations [c.4084C>T (p.R1362X) and c.3708+437T>G] in the aforementioned two families. The c.4084C>T mutation is predicted to introduce a stop codon at position Arg1362, whereas the c.3708+437T>G mutation causes the activation of an intronic pseudoexon between exons 48 and 49. This resulted in the insertion of 50 nucleotides into the mRNA. The carriers of these mutations display ocular defects with normal hearing. In conclusion, our data shall improve the overall understanding of fibrochondrogenesis especially in surviving homozygous patients and, at least partly, explain the phenotypic variability associated with COL11A1 gene mutations. PMID- 21668897 TI - Impaired hapten sensitization in patients with autoimmune disease. AB - An inverse relation between contact allergy and autoimmune diseases is suggested from epidemiological studies. The aim of this study was to investigate susceptibility and reactivity in patients with psoriasis, patients with diabetes and healthy controls in an experimental sensitization study. We sensitized 68 adult individuals (23 patients with psoriasis, 22 patients with diabetes and 23 healthy controls) with diphenylcyclopropenone (DPCP) and assessed challenge responses with visual scoring and ultrasound. Skin biopsies from challenged skin were investigated for differences in down-regulatory mechanisms with immunohistochemistry and gene-expression profiles using microarray technology. The sensitization ratios were 26%, 36% and 65% for the psoriatic, diabetic and healthy groups, respectively. Logistic regression analysis gave an odds ratio (OR) for a patient with psoriasis or diabetes type I of being sensitized to 0.18 [95% confidence interval (CI): 0.039-0.85], P = 0.031 and 0.74 (95% CI: 0.548 1.008), P = 0.056, respectively. A high degree of forkhead box P3-positive (FoxP3(+) ) cells were found in biopsies of positively challenged reactions, but only limited numbers in negatively challenged reactions, with no difference among the groups. No specific mRNA expression was found in the challenged skin of negative elicitation reactions, also indicating no sign of active down regulation. The study contibutes strongly to the evidence of a decreased susceptibility to develop contact allergy in individuals with autoimmune diseases such as psoriasis. PMID- 21668900 TI - Discussion by O'Quigley and Flandre. PMID- 21668898 TI - Colitogenic role of tumour necrosis factor (TNF) receptors in trinitrobenzene sulphonic acid colitis: TNF-R1 ablation does not affect systemic inflammatory response. AB - Tumour necrosis factor (TNF)-alpha plays a critical role in the pathogenesis of T helper type 1-mediated colitis such as Crohn's disease. However, the roles of its two receptors in mediating pathology remain largely unknown. In this study, trinitrobenzene sulphonic acid (TNBS) was used to induce colitis in TNF-receptor single or double knock-out (DKO) BALB/c mice and in wild-type counterparts. TNF R1(-/-) mice had significantly less weight loss, reduced mortality, colon shortening and oedema, colon histological damage and lower levels of colon myeloperoxidase compared with wild-type (WT) BALB/c mice. A similar manifestation was also observed in TNF-R2(-/-) and TNF-R1(-/-) TNF-R2(-/-) (TNF-R DKO) mice. Strikingly, systemic inflammatory response (including splenomegaly and monocyte expansion) was found in WT and TNF-R1(-/-) mice after TNBS, instead of TNF-R2(-/ ) and TNF-R DKO mice. Attenuated pathology of colitis in TNF-R1(-/-) or TNF-R2(-/ ) mice correlated with lower amounts of interleukin (IL)-6, IL-1beta, monocyte chemotactic protein (MCP)-1, IL-12p70 and interferon (IFN)-gamma production in the colons. Importantly, ablation of TNF-R1 or TNF-R2 reduced the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling (TUNEL)-positive apoptotic epithelial cells in the affected colons compared with WT TNBS-instilled controls, which might be due to the heightened ratio of Bcl-2/Bax and reduced activity of nuclear factor (NF)-kappaB. These findings suggest that either TNF-R1 or TNF-R2 plays a pathogenic role in the pathology of colitis and TNF signalling via TNF-R1 or TNF-R2 alone is not sufficient for inducing mucosal damage. PMID- 21668901 TI - Discussion of the paper of Ghosh, Taylor, and Sargent. PMID- 21668902 TI - Discussion contribution to 091037PR4 (Ghosh, Taylor, and Sargent). PMID- 21668903 TI - Meta-analysis for surrogacy: accelerated failure time models and semicompeting risks modeling. AB - There has been great recent interest in the medical and statistical literature in the assessment and validation of surrogate endpoints as proxies for clinical endpoints in medical studies. More recently, authors have focused on using metaanalytical methods for quantification of surrogacy. In this article, we extend existing procedures for analysis based on the accelerated failure time model to this setting. An advantage of this approach relative to proportional hazards model is that it allows for analysis in the semicompeting risks setting, where we model the region where the surrogate endpoint occurs before the true endpoint. Several estimation methods and attendant inferential procedures are presented. In addition, between- and within-trial methods for evaluating surrogacy are developed; a novel principal components procedure is developed for quantifying trial-level surrogacy. The methods are illustrated by application to data from several studies in colorectal cancer. PMID- 21668904 TI - Augmented cross-sectional studies with abbreviated follow-up for estimating HIV incidence. AB - Cross-sectional HIV incidence estimation based on a sensitive and less-sensitive test offers great advantages over the traditional cohort study. However, its use has been limited due to concerns about the false negative rate of the less sensitive test, reflecting the phenomenon that some subjects may remain negative permanently on the less-sensitive test. Wang and Lagakos (2010, Biometrics 66, 864-874) propose an augmented cross-sectional design that provides one way to estimate the size of the infected population who remain negative permanently and subsequently incorporate this information in the cross-sectional incidence estimator. In an augmented cross-sectional study, subjects who test negative on the less-sensitive test in the cross-sectional survey are followed forward for transition into the nonrecent state, at which time they would test positive on the less-sensitive test. However, considerable uncertainty exists regarding the appropriate length of follow-up and the size of the infected population who remain nonreactive permanently to the less-sensitive test. In this article, we assess the impact of varying follow-up time on the resulting incidence estimators from an augmented cross-sectional study, evaluate the robustness of cross sectional estimators to assumptions about the existence and the size of the subpopulation who will remain negative permanently, and propose a new estimator based on abbreviated follow-up time (AF). Compared to the original estimator from an augmented cross-sectional study, the AF estimator allows shorter follow-up time and does not require estimation of the mean window period, defined as the average time between detectability of HIV infection with the sensitive and less sensitive tests. It is shown to perform well in a wide range of settings. We discuss when the AF estimator would be expected to perform well and offer design considerations for an augmented cross-sectional study with abbreviated follow-up. PMID- 21668905 TI - A Bayesian model for estimating population means using a link-tracing sampling design. AB - Link-tracing sampling designs can be used to study human populations that contain "hidden" groups who tend to be linked together by a common social trait. These links can be used to increase the sampling intensity of a hidden domain by tracing links from individuals selected in an initial wave of sampling to additional domain members. Chow and Thompson (2003, Survey Methodology 29, 197 205) derived a Bayesian model to estimate the size or proportion of individuals in the hidden population for certain link-tracing designs. We propose an addition to their model that will allow for the modeling of a quantitative response. We assess properties of our model using a constructed population and a real population of at-risk individuals, both of which contain two domains of hidden and nonhidden individuals. Our results show that our model can produce good point and interval estimates of the population mean and domain means when our population assumptions are satisfied. PMID- 21668906 TI - Robust estimation of mean and dispersion functions in extended generalized additive models. AB - Generalized linear models are a widely used method to obtain parametric estimates for the mean function. They have been further extended to allow the relationship between the mean function and the covariates to be more flexible via generalized additive models. However, the fixed variance structure can in many cases be too restrictive. The extended quasilikelihood (EQL) framework allows for estimation of both the mean and the dispersion/variance as functions of covariates. As for other maximum likelihood methods though, EQL estimates are not resistant to outliers: we need methods to obtain robust estimates for both the mean and the dispersion function. In this article, we obtain functional estimates for the mean and the dispersion that are both robust and smooth. The performance of the proposed method is illustrated via a simulation study and some real data examples. PMID- 21668907 TI - Ancestral heterogeneity in a biethnic stroke population. AB - To test for and characterize heterogeneity in ancestral contributions to individuals among a population of Mexican American (MA) and non-Hispanic white (NHW) stroke/transient ischemic attack (TIA) cases, data from a community-based stroke surveillance study in south Texas were used. Strokes/TIA cases were identified (2004-2006) with a random sample asked to provide blood. Race ethnicity was self-reported. Thirty-three ancestry informative markers were genotyped and individual genetic admixture estimated using maximum likelihood methods. Three hypotheses were tested for each MA using likelihood ratio tests: (1) H(0) : MUi = 0 (100% Native American), (2) H(0) : MUi = 1.00 (100% European), (3) H(0) : MUi = 0.59 (average European). Among 154 self-identified MAs, estimated European ancestry varied from 0.26 to 0.98, with an average of 0.59 (SE = 0.014). We rejected hypothesis 1 for every MA and rejected hypothesis 2 for all but two MAs. We rejected hypothesis 3 for 40 MAs (20 < 59%, 20 > 59%). Among 84 self-identified NHWs, the estimated fraction of European ancestry ranged from 0.83 to 1.0, with an average of 0.97 (SE = 0.014). Self-identified MAs, and to a lesser extent NHWs, from an established bi-ethnic community were heterogeneous with respect to genetic admixture. Researchers should not use simple race-ethnic categories as proxies for homogeneous genetic populations when conducting gene mapping and disease association studies in multi-ethnic populations. PMID- 21668910 TI - A report of the first biennial meeting on Capita Selecta in Complex Disease Analysis (CSCDA2010), Leuven, Belgium, August 25-27, 2010. AB - There is a need for interdisciplinary assessments and interpretations of -omics underpinnings of human complex diseases. However, often investigators from different, yet overlapping, disciplines experience difficulties in understanding the other discipline's language and there is a clear need for establishing a platform that nourishes interdisciplinary team processes and allows tearing down the professional's tower of Babel. To accommodate these needs, the biennial mini conference Capita Selecta in Complex Disease Analysis was instigated. Abstracts are freely available online [http://www.aimontefiore.org/cscda2010/]. PMID- 21668909 TI - Selecting SNPs to identify ancestry. AB - An individual's genotypes at a group of single-nucleotide polymorphisms (SNPs) can be used to predict that individual's ethnicity or ancestry. In medical studies, knowledge of a subject's ancestry can minimize possible confounding, and in forensic applications, such knowledge can help direct investigations. Our goal is to select a small subset of SNPs, from the millions already identified in the human genome, that can predict ancestry with a minimal error rate. The general form for this variable selection procedure is to estimate the expected error rates for sets of SNPs using a training dataset and consider those sets with the lowest error rates given their size. The quality of the estimate for the error rate determines the quality of the resulting SNPs. As the apparent error rate performs poorly when either the number of SNPs or the number of populations is large; we propose a new estimate, the Improved Bayesian Estimate. We demonstrate that selection procedures based on this estimate produce small sets of SNPs that can accurately predict ancestry. We also provide a list of the 100 optimal SNPs for identifying ancestry. PMID- 21668908 TI - Successful aging shows linkage to chromosomes 6, 7, and 14 in the Amish. AB - Successful aging (SA) is a multidimensional phenotype involving preservation of cognitive ability, physical function, and social engagement throughout life. Multiple components of SA are heritable, supporting a genetic component. The Amish are genetically and socially isolated with homogeneous lifestyles, making them a suitable population for studying the genetics of SA. DNA and measures of SA were collected on 214 cognitively intact Amish individuals over age 80. Individuals were grouped into a 13-generation pedigree using the Anabaptist Genealogy Database. A linkage screen of 5944 single nucleotide polymorphisms (SNPs) was performed using 12 informative subpedigrees with an affected-only 2 point and multipoint linkage analysis. Eleven SNPs produced 2-point LOD scores >2, suggestive of linkage. Multipoint linkage analyses, allowing for heterogeneity, detected significant LOD scores on chromosomes 6 (HLOD = 4.50), 7 (LOD*= 3.11), and 14 (HLOD = 4.17), suggesting multiple new loci underlying SA. PMID- 21668911 TI - What is the optimal type of fluid to be used for peri-operative fluid optimisation directed by oesophageal Doppler monitoring? AB - The objective of this review was to determine the optimal type or class of intravenous fluid to be used during peri-operative patient optimisation guided by oesophageal Doppler monitoring and to identify future directions for research. We undertook a literature review of patients undergoing major (general, colorectal, orthopaedic and urological) surgery, whose fluid therapy was managed using peri operative oesophageal Doppler monitoring. We identified 10 studies that included 891 randomised patients. A variety of regimens and types of fluid were used in association with oesophageal Doppler monitoring, including crystalloid, gelatin and hydroxyethyl starch. A wide variety of hydroxyethyl starch preparations were used, including high molecular weight and highly substituted hetastarches, and lower molecular weight tetrastarches. Most studies were of high quality, associated with reduced hospital stay, but underpowered to evaluate other outcomes. In units with established enhanced recovery facilities, the benefits of colloid based on oesophageal Doppler monitoring were not reproduced. There is little evidence to support preferential use of any particular type of fluid during oesophageal Doppler guided optimisation; however, routine use of colloids is associated with significantly higher costs and may increase hospital stay. Furthermore, many of these fluids have not been evaluated in patient populations in whom optimisation is being applied or proposed, and the potential for harm cannot be excluded. Recommendations for future studies are provided, including adequate power for primary end points beyond hospital stay and adequate follow up, and inclusion of a crystalloid comparison group. PMID- 21668912 TI - Comparison of the Mapleson C system and adult and paediatric self-inflating bags for delivering guideline-consistent ventilation during simulated adult cardiopulmonary resuscitation. AB - There is a discrepancy between resuscitation teaching and witnessed clinical practice. Furthermore, deleterious outcomes are associated with hyperventilation. We therefore conducted a manikin-based study of a simulated cardiac arrest to evaluate the ability of three ventilating devices to provide guideline-consistent ventilation. Mean (SD) minute ventilation was reduced with the paediatric self inflating bag (7.0 (3.2) l.min-1) compared with the Mapleson C system (9.8 (3.5) l.min-1) and adult self-inflating bag (9.7 (4.2) l.min-1 ; p = 0.003). Tidal volume was also lower with the paediatric self-inflating bag (391 (52) ml) compared with the others (582 (87) ml and 625 (103) ml, respectively; p < 0.001), as was peak airway pressure (14.5 (5.2) cmH2O vs 20.7 (9.0) cmH2O and 30.3 (11.4) cmH2O, respectively; p < 0.001). Participants hyperventilated patients' lungs in simulated cardiac arrest with all three devices. The paediatric self-inflating bag delivered the most guideline-consistent ventilation. Its use in adult cardiopulmonary resuscitation may ensure delivery of more guideline-consistent ventilation in patients with tracheal intubation. PMID- 21668913 TI - Cholinesterase inhibitor and memantine use in newly admitted nursing home residents with dementia. AB - OBJECTIVES: To quantify the use of cholinesterase inhibitors (ChEIs) and memantine in nursing home (NH) residents with dementia upon NH admission and 3 months later and to examine factors associated with reduction in therapy. DESIGN: Retrospective cohort study. SETTING: Nationwide sample of U.S. NHs. PARTICIPANTS: Three thousand five hundred six NH residents with dementia newly admitted in 2006. MEASUREMENTS: Data from pharmacy dispensing records were used to determine ChEI and memantine medication use upon NH admission and at 3-month follow-up. The Minimum Data Set was used to determine resident- and facility-level characteristics. Severity of dementia was defined using the Cognitive Performance Scale (CPS). RESULTS: Overall, 40.1% (n=1,407) of newly admitted NH residents with dementia received ChEIs and memantine on NH admission. Use of ChEIs and memantine on admission was significantly greater in residents with mild to moderately severe dementia (41.2%) than in those with advanced dementia (33.3%, P=.001). After 3 months, ChEI and memantine use decreased by about half in both groups (48.6% with mild to moderately severe dementia vs 57.0% with advanced dementia, P<.05). NH residents with advanced dementia were significantly more likely reduce their use of ChEIs and memantine than those with mild to moderately severe dementia (odds ratio=1.44, 95% confidence interval=1.03-2.01, P=.04). CONCLUSION: Many NH residents with advanced dementia receive ChEIs and memantine upon NH admission, and approximately half of these decrease their medication use over the ensuing months. Further study is required to optimize use of ChEIs and memantine in NH populations and to determine the effects of withdrawing therapy on resident outcomes. PMID- 21668914 TI - Chronic kidney disease: a risk factor for dementia onset: a population-based study. The Osaki-Tajiri Project. AB - OBJECTIVES: To examine the relationship between the incidence of dementia and chronic kidney disease (CKD). DESIGN: Longitudinal data analyses. SETTING: Baseline data and follow-up data from the Osaki-Tajiri Project. PARTICIPANTS: The Tajiri Project dementia prevalence study in 1998 involved 497 community-dwelling, older men and women (346 with Clinical Dementia Rating score (CDR) of 0 (healthy), 119 with a CDR of 0.5 (questionable dementia), and 32 with a CDR of 1 or greater (dementia)). Two hundred fifty-four participants with CDR of 0 and 0.5 who were reclassified as converters (n=28) or nonconverters (n=230) to dementia in the incidence study in 2003 were followed. MEASUREMENTS: The prevalence of CKD and the onset of dementia were retrospectively analyzed, and the effects of other vascular risk factors on converters and CKD were analyzed. RESULTS: Weighted logistic regression showed CKD to be significantly associated with incident dementia after adjustment for age, sex, education, hypertension, diabetes mellitus, dyslipidemia, ischemic heart disease, and anemia. The odds ratio for conversion to dementia for those with CKD compared to those without was 5.3 (95% confidence interval=1.7, 16.2). Apart from dyslipidemia, there were no associations between dementia and the other vascular risk factors. CONCLUSION: CKD was strongly associated with the incidence of dementia independent of age, sex, education, and other vascular risk factors. PMID- 21668915 TI - Correlates and prevalence of insufficient 25-hydroxyvitamin D status in black and white older adults: the health, aging and body composition study. AB - OBJECTIVES: To determine the prevalence and correlates of vitamin D insufficiency in black and white older adults. DESIGN: Cross-sectional. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Nine hundred seventy-seven black and 1,604 white adults aged 70 to 81. MEASUREMENTS: Logistic regression and classification and regression tree analysis were used to identify correlates of vitamin D insufficiency (25-hydroxyvitamin D (25(OH)D) <30 ng/mL) separately in blacks and whites. RESULTS: The prevalence of 25(OH)D insufficiency was 84% in blacks and 57% in whites. Seventy-six percent of blacks and 56% of whites did not take a multivitamin; those who did not take a multivitamin were more likely to be vitamin D insufficient (odds ratio (OR)=5.17 (95% confidence interval (CI)=3.47 7.70) for blacks; OR=2.56, 95% CI=2.05-3.19 for white). Additional risk factors for vitamin D insufficiency were vitamin D-containing supplement use, female sex, and obesity in blacks; and winter season, low dietary vitamin D intake, obesity, type 2 diabetes mellitus, and female sex in whites. CONCLUSION: Vitamin D insufficiency was more prevalent in blacks than whites. Not consuming a multivitamin increased the odds of vitamin D insufficiency in blacks and whites. Knowledge of additional risk factors such as dietary intake and comorbid conditions may help identify older adults who are likely to be vitamin D insufficient. PMID- 21668916 TI - Depression and functional recovery after a disabling hospitalization in older persons. AB - OBJECTIVES: To determine the association between depression and functional recovery in community-living older persons who had a decline in function after an acute hospital admission. DESIGN: Prospective cohort study. SETTING: General community in greater New Haven, Connecticut, from March 1998 to December 2008. PARTICIPANTS: Seven hundred fifty-four persons aged 70 and older. MEASUREMENTS: Hospitalization and disability in essential activities of daily living (ADLs) and mobility were assessed each month for up to 129 months, and depressive symptoms were assessed every 18 months using the Center for Epidemiologic Studies Depression Scale (CES-D). Functional recovery was defined as returning to the community within 6 months at or above the prehospital level of ADL function and mobility. RESULTS: A decline in ADL function and mobility was observed after 42% and 41% of the hospitalizations, respectively. After controlling for several potential confounders, clinically significant depressive symptoms (CES-D score >=20) was associated with a lower likelihood of recovering mobility function (hazard ratio (HR)=0.79, 95% confidence interval (CI)=0.63-0.98) but not ADL function (HR=0.91, 95% CI=0.75-1.10) within 6 months of hospitalization. CONCLUSION: After a disabling hospitalization, community-living older persons with preexisting depression may be less likely to recover their prehospitalization level of mobility function but not ADL function, although the reasons remain to be elucidated. PMID- 21668917 TI - "Reversible" Alzheimer's disease? PMID- 21668918 TI - Neuromyelitis optica with very late onset. PMID- 21668919 TI - Early cervical cancer complicated by pyometra presenting as a pelvic cystic mass and vaginitis in a 102-year-old patient. PMID- 21668920 TI - A 91-year-old woman who suddenly talked more and slept less. PMID- 21668921 TI - Cognitive improvement with intrathecal administration of infliximab in a woman with Alzheimer's disease. PMID- 21668923 TI - Risks and characteristics of injuries in older adults in Korea. PMID- 21668922 TI - When hospital patients fall: preliminary data from Ferrara, Italy. PMID- 21668924 TI - Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin in older adults with type 2 diabetes mellitus. PMID- 21668925 TI - Advanced age is an independent predicting factor for recurrence in patients with N0 colonic cancer. PMID- 21668926 TI - Cerebrospinal fluid interleukin-8 levels are higher in people with hip fracture with perioperative delirium than in controls. PMID- 21668927 TI - Effect of bedroom size on falls in hospital: does one size fit all? PMID- 21668928 TI - Development and validation of a composite score as an easy-to-use instrument for clinical monitoring of dementia progression: the Composite Cognitive and Activities of Daily Living Functioning Score. PMID- 21668929 TI - Age and acute-severity illness portend daily activity dysfunction 6 months after hospital discharge. PMID- 21668930 TI - Heparin-induced thrombocytopenia: an increasingly common cause of bilateral adrenal hemorrhage. PMID- 21668932 TI - Caregiver support for older people with chronic obstructive pulmonary disease. PMID- 21668934 TI - Pyogenic liver abscess in older adults: comparison with younger individuals. PMID- 21668936 TI - Tools for the assessment of practical skills and performance. PMID- 21668937 TI - Transversus abdominis plane blocks for rescue analgesia after major abdominal surgery. PMID- 21668938 TI - Spread of local anesthetic during an ultrasound-guided interscalene block: does the injection site influence diffusion? AB - BACKGROUND: During interscalene block (ISB) placement, ultrasound guidance (USG) enables the practitioner to measure the spread of local anesthetic around the nerve trunks or roots, and to adjust the needle position in order to optimize diffusion. Moreover, USG helps determine the best injection level, i.e. the point from which diffusion gives the most complete brachial plexus block. The aim of this study was to compare C5 and C6 level injections and to determine which level allows the best diffusion. METHODS: Sixty randomized patients scheduled for shoulder surgery were divided into two groups. In group C5, injection was directed toward C5 while in group C6, the C6 nerve root was targeted. Block performance time was recorded. The onset of motor and sensory block of each nerve distribution was evaluated every 10 min over a 30-min period. RESULTS: The average time taken to perform a nerve block was 6.2+2.6 min in Group C6 and 6.0+2.1 min in Group C5 (NS). At 30 min, the number of patients with a satisfactory musculocutaneous and axillary nerve block was not notably greater in either group. By contrast, a significantly higher success rate was observed for other nerves in the C6 group as compared to the C5 group: ulnar nerve block: 93% vs. 19%, radial nerve block: 96% vs. 28%, median nerve block: 96%, vs. 69%. CONCLUSIONS: During USG ISB placement, injection below the C6 level provided the same efficiency in analgesia after shoulder surgery as an injection cranial to the C5 nerve root but a greater success rate of anesthesia in all distal nerve areas. This technique could be very interesting for trauma cases as an alternative to a supraclavicular block and offers a high success rate and is simple to perform, potentially promoting wide use and quicker learning for beginners. PMID- 21668940 TI - Single nucleotide polymorphism discovery from expressed sequence tags in the waterflea Daphnia magna. AB - BACKGROUND: Daphnia (Crustacea: Cladocera) plays a central role in standing aquatic ecosystems, has a well known ecology and is widely used in population studies and environmental risk assessments. Daphnia magna is, especially in Europe, intensively used to study stress responses of natural populations to pollutants, climate change, and antagonistic interactions with predators and parasites, which have all been demonstrated to induce micro-evolutionary and adaptive responses. Although its ecology and evolutionary biology is intensively studied, little is known on the functional genomics underpinning of phenotypic responses to environmental stressors. The aim of the present study was to find genes expressed in presence of environmental stressors, and target such genes for single nucleotide polymorphic (SNP) marker development. RESULTS: We developed three expressed sequence tag (EST) libraries using clonal lineages of D. magna exposed to ecological stressors, namely fish predation, parasite infection and pesticide exposure. We used these newly developed ESTs and other Daphnia ESTs retrieved from NCBI GeneBank to mine for SNP markers targeting synonymous as well as non synonymous genetic variation. We validate the developed SNPs in six natural populations of D. magna distributed at regional scale. CONCLUSIONS: A large proportion (47%) of the produced ESTs are Daphnia lineage specific genes, which are potentially involved in responses to environmental stress rather than to general cellular functions and metabolic activities, or reflect the arthropod's aquatic lifestyle. The characterization of genes expressed under stress and the validation of their SNPs for population genetic study is important for identifying ecologically responsive genes in D. magna. PMID- 21668941 TI - Mapping of QTL affecting incidence of blood and meat inclusions in egg layers. AB - BACKGROUND: Occurrence of blood and meat inclusions is an internal egg quality defect. Mass candling reveals most of the spots, but because brown eggshell hampers selection in brown chicken lines it has not been possible to eliminate the defect by selection. Estimated frequency of blood and meat inclusions in brown layers is about 18% whereas it is 0.5% in white egg layers. Several factors are known to increase the incidence of this fault: genetic background, low level of vitamin A and/or D, stress or infections, for instance. To study the genetic background of the defect, a mapping population of 1599 F2 hens from a cross of White Rock and Rhode Island Red lines was set up. RESULTS: Our histopathological analyses show that blood spots consist of mainly erythrocytes and that meat spots are accumulations of necrotic material. Linkage analysis of 27 chromosomes with 162 microsatellite markers revealed one significant quantitative trait locus (QTL) affecting blood spot and meat spot frequency. We sequenced a fragment of a candidate gene within the region, ZO-2, coding for a tight junction protein. Nine polymorphisms were detected and two of them were included in fine-mapping and association analysis. Fine-mapping defined the QTL result. To further verify the QTL, association analyses were carried out in two independent commercial breeding lines with the marker MCW241 and surrounding SNPs. Association was found mainly in a 0.8 Mb-wide chromosomal area on GGAZ. CONCLUSIONS: There was good agreement between the location of the QTL region on chromosome Z and the association results in the commercial breeds analyzed. Variations found in tight junction protein ZO-2 and microRNA gga-mir-1556 may predispose egg layers to blood and meat spot defects. This paper describes the first results of detailed QTL analyses of the blood and meat spots trait(s) in chickens. PMID- 21668942 TI - COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status. AB - BACKGROUND: Increased cyclooxygenase activity promotes progression of colorectal cancer, but the mechanisms behind COX-2 induction remain elusive. This study was therefore aimed to define external cell signaling and transcription factors relating to high COX-2 expression in colon cancer tissue. METHOD: Tumor and normal colon tissue were collected at primary curative operation in 48 unselected patients. COX-2 expression in tumor and normal colon tissue was quantified including microarray analyses on tumor mRNA accounting for high and low tumor COX 2 expression. Cross hybridization was performed between tumor and normal colon tissue. Methylation status of up-stream COX-2 promoter region was evaluated. RESULTS: Tumors with high COX-2 expression displayed large differences in gene expression compared to normal colon. Numerous genes with altered expression appeared in tumors of high COX-2 expression compared to tumors of low COX-2. COX 2 expression in normal colon was increased in patients with tumors of high COX-2 compared to normal colon from patients with tumors of low COX-2. IL1beta, IL6 and iNOS transcripts were up-regulated among external cell signaling factors; nine transcription factors (ATF3, C/EBP, c-Fos, Fos-B, JDP2, JunB, c-Maf, NF-kappaB, TCF4) showed increased expression and 5 (AP-2, CBP, Elk-1, p53, PEA3) were decreased in tumors with high COX-2. The promoter region of COX-2 gene did not show consistent methylation in tumor or normal colon tissue. CONCLUSIONS: Transcription and external cell signaling factors are altered as covariates to COX-2 expression in colon cancer tissue, but DNA methylation of the COX-2 promoter region was not a significant factor behind COX-2 expression in tumor and normal colon tissue. PMID- 21668943 TI - MeRy-B: a web knowledgebase for the storage, visualization, analysis and annotation of plant NMR metabolomic profiles. AB - BACKGROUND: Improvements in the techniques for metabolomics analyses and growing interest in metabolomic approaches are resulting in the generation of increasing numbers of metabolomic profiles. Platforms are required for profile management, as a function of experimental design, and for metabolite identification, to facilitate the mining of the corresponding data. Various databases have been created, including organism-specific knowledgebases and analytical technique specific spectral databases. However, there is currently no platform meeting the requirements for both profile management and metabolite identification for nuclear magnetic resonance (NMR) experiments. DESCRIPTION: MeRy-B, the first platform for plant (1)H-NMR metabolomic profiles, is designed (i) to provide a knowledgebase of curated plant profiles and metabolites obtained by NMR, together with the corresponding experimental and analytical metadata, (ii) for queries and visualization of the data, (iii) to discriminate between profiles with spectrum visualization tools and statistical analysis, (iv) to facilitate compound identification. It contains lists of plant metabolites and unknown compounds, with information about experimental conditions, the factors studied and metabolite concentrations for several plant species, compiled from more than one thousand annotated NMR profiles for various organs or tissues. CONCLUSION: MeRy-B manages all the data generated by NMR-based plant metabolomics experiments, from description of the biological source to identification of the metabolites and determinations of their concentrations. It is the first database allowing the display and overlay of NMR metabolomic profiles selected through queries on data or metadata. MeRy-B is available from http://www.cbib.u bordeaux2.fr/MERYB/index.php. PMID- 21668944 TI - Airway management in simulated restricted access to a patient--can manikin-based studies provide relevant data? AB - BACKGROUND: Alternatives to endotracheal intubation (ETI) are required when access to the cranial end of the patient is restricted. In this study, the success rate and time duration of standard intubation techniques were compared with two different supraglottic devices. Two different manikins were used for the study, and the training effect was studied when the same manikin was repeatedly used. METHODS: Twenty anaesthesiologists from the Air Ambulance Department used iGELTM, laryngeal tube LTSIITM and Macintosh laryngoscopes in two scenarios with either unrestricted (scenario A) or restricted (scenario B) access to the cranial end of the manikin. Different manikins were used for ETI and placement of the supraglottic devices. The technique selected by the physicians, the success rates and the times to completion were the primary outcomes measured. A secondary outcome of the study was an evaluation of the learning effect of using the same manikin or device several times. RESULTS: In scenario A, all anaesthesiologists secured an airway using each device within the maximum time limit of 60 seconds. In scenario B, all physicians secured the airway on the first attempt with the supraglottic devices and 16 (80%) successfully performed an ETI with either the Macintosh laryngoscope (n = 13, 65%) or with digital technique (n = 3, 15%). It took significantly longer to perform ETI (mean time 28.0 sec +/- 13.0) than to secure an airway with the supraglottic devices (iGelTM: mean 12.3 sec +/- 3.6, LTSIITM: mean 10.6 sec +/- 3.2). When comparing the mean time required for the two scenarios for each supraglottic device, there was a reduction in time for scenario B (significant for LTSIITM: 12.1 versus 10.6 seconds, p = 0.014). This may be due to a training effect using same manikin and device several times. CONCLUSIONS: The amount of time used to secure an airway with supraglottic devices was low for both scenarios, while classic ETI was time consuming and had a low success rate in the simulated restricted access condition. This study also demonstrates that there is a substantial training effect when simulating airway management with airway manikins. This effect must be considered when performing future studies. PMID- 21668945 TI - Constipation in children. AB - Constipation remains a frequent presentation to paediatricians, with significant health resource implications. We present a practical guide to the management of paediatric constipation and evaluate the current evidence for treatment regimens, to help the clinician in treating a condition that can be distressing and has a significant impact on affected families. PMID- 21668947 TI - Screening for cervical cancer: when theory meets reality. AB - Cervical cancer screening reduces morbidity and mortality due to cervical cancer. However, there are many factors that determine the success of any cervical cancer prevention effort: the prevalence of human papillomavirus infection in general population, the existence of an organized screening program and the corresponding coverage, the existence and quality of the field and laboratory facilities for screening and diagnostic follow-up, and the facilities available for treating diagnosed lesions. Monitoring the patient path or "chain of action" for each patient with an abnormal screening result is of crucial importance. Cost effectiveness models are widely used by decision-makers to determine which cervical cancer screening program would maximize health benefits within a given, usually limited, set of resources. Regardless of their level of sophistication, however, these models cannot replace empirical evaluations of the effectiveness of screening programs.Cervical cancer prevention activities need to be monitored and evaluated in each country where they are introduced to see that they meet performance standards. Policy-makers responsible for allocating resources for cervical cancer prevention have a duty to allocate resources not only for cervical cancer screening, but also for screening program surveillance. PMID- 21668946 TI - Evaluation of primary HPV-DNA testing in relation to visual inspection methods for cervical cancer screening in rural China: an epidemiologic and cost effectiveness modelling study. AB - BACKGROUND: A new lower-cost rapid-throughput human papillomavirus (HPV) test (careHPV, Qiagen, Gaithersburg, USA) has been shown to have high sensitivity for the detection of high grade cervical intraepithelial neoplasia. METHODS: We assessed the outcomes and cost-effectiveness of careHPV screening in rural China, compared to visual inspection with acetic acid, when used alone (VIA) or in combination with Lugol's iodine (VIA/VILI). Using data on sexual behaviour, test accuracy, diagnostic practices and costs from studies performed in rural China, we estimated the cost-effectiveness ratio (CER) and associated lifetime outcomes for once-lifetime and twice-lifetime screening strategies, and for routine screening at 5-yearly, 10-yearly and IARC-recommended intervals. The optimal age range for once-lifetime screening was also assessed. RESULTS: For all strategies, the relative ordering of test technologies in reducing cervical cancer incidence and mortality was VIA (least effective); VIA/VILI; careHPV@1.0 pg/ml and careHPV@0.5 pg/ml (most effective). For once-lifetime strategies, maximum effectiveness was achieved if screening occurred between 35-50 years. Assuming a participation rate of ~70%, once-lifetime screening at age 35 years would reduce cancer mortality by 8% (for VIA) to 12% (for careHPV@0.5) over the long term, with a CER of US$557 (for VIA) to $959 (for careHPV@1.0) per life year saved (LYS) compared to no intervention; referenced to a 2008 GDP per capita in Shanxi Province of $2,975. Correspondingly, regular screening with an age-standardised participation rate of 62% (which has been shown to be achievable in this setting) would reduce cervical cancer mortality by 19-28% (for 10-yearly screening) to 43 54% (using IARC-recommended intervals), with corresponding CERs ranging from $665 (for 10-yearly VIA) to $2,269 (for IARC-recommended intervals using careHPV@1.0) per LYS. CONCLUSIONS: This modelled analysis suggests that primary careHPV screening compares favourably to visual inspection screening methodologies in rural China, particularly if used as part of a regular screening program. PMID- 21668949 TI - Emphysematous cystitis with clinical subcutaneous emphysema. AB - Emphysematous cystitis (EC) is the presence of intramural gas, with or without luminal gas, within the bladder as a result of a primary infection of the lower urinary tract with a gas-producing organism. It is a well-recognised complication of urinary tract infections involving Escherichia coli in diabetic patients. Clinical subcutaneous emphysema is a rare complication of EC that appears to have poor prognosis. Only careful clinical judgement, and a high degree of suspicion, will lead to its early diagnosis and treatment. Here, we report a case of subcutaneous emphysema due to EC based on a clinical diagnosis confirmed using computed tomography (CT). PMID- 21668948 TI - Knowledge attitudes and practices of grade three primary schoolchildren in relation to schistosomiasis, soil transmitted helminthiasis and malaria in Zimbabwe. AB - BACKGROUND: Helminth infection rates in grade three children are used as proxy indicators of community infection status and to guide treatment strategies in endemic areas. However knowledge, attitudes and practices (KAP) of this target age group (8-10 years) in relation to schistosomiasis, soil transmitted helminthiasis (STHs) and malaria is not known at a time when integrated plasmodium - helminth control strategies are being advocated. This study sought to assess KAP of grade 3 children in relation to schistosomiasis, STHs and malaria in order to establish an effective school based health education for disease transmission control. METHODS: Grade 3 children (n = 172) attending four randomly selected primary schools (one in rural and 3 in the commercial farming areas) in Zimbabwe were interviewed using a pre-tested interviewer administered questionnaire. The urine filtration technique was used to determine S. haematobium infection status. Infection with S. mansoni and STHs was determined using a combination of results from the Kato Katz and formol ether concentration techniques. P. falciparum was diagnosed by examination of Giemsa stained thick blood smears. RESULTS: It was observed that 32.0%, 19.2% and 4.1% of the respondents had correct knowledge about the causes of schistosomiasis, malaria and STHs, respectively, whilst 22.1%, 19.2% and 5.8% knew correct measures to control schistosomiasis, malaria and STHs. Sixty-two percent and 44.8% did not use soap to wash hands after toilet and before eating food respectively, whilst 33.1% never wore shoes. There were no functional water points and soap for hand washing after toilet at all schools. There was a high prevalence distribution of all parasites investigated in this study at Msapa primary school - S. haematobium (77.8%), S. mansoni (33.3%) hookworms (29.6%) and P. falciparum (48.1%). Reports that participant had suffered from schistosomiasis and malaria before were significant predictors of these diseases (p = 0.001 and p = 0.042, respectively). Report that participant had blood in urine on the day of examination was a significant predictor of schistosomiasis (p = 0.045). CONCLUSION: There is a critical need for targeting health messages through schools in order to reach the most susceptible schoolchildren. This will empower the schoolchildren with the basic knowledge and skills ultimately protecting them from acquiring schistosomiasis, STHs and malaria. PMID- 21668951 TI - The experience of international nursing students studying for a PhD in the U.K: A qualitative study. AB - BACKGROUND: Educating nurses to doctoral level is an important means of developing nursing capacity globally. There is an international shortage of doctoral nursing programmes, hence many nurses seek their doctorates overseas. The UK is a key provider of doctoral education for international nursing students, however, very little is known about international doctoral nursing students' learning experiences during their doctoral study. This paper reports on a national study that sought to investigate the learning expectations and experiences of overseas doctoral nursing students in the UK. METHODS: Semi structured qualitative interviews were conducted in 2008/09 with 17 international doctoral nursing students representing 9 different countries from 6 different UK universities. Data were analysed thematically. All 17 interviewees were enrolled on 'traditional' 3 year PhD programmes and the majority (15/17) planned to work in higher education institutions back in their home country upon graduation. RESULTS: Studying for a UK PhD involved a number of significant transitions, including adjusting to a new country/culture, to new pedagogical approaches and, in some cases, to learning in a second language. Many students had expected a more structured programme of study, with a stronger emphasis on professional nursing issues as well as research - akin to the professional doctorate. Students did not always feel well integrated into their department's wider research environment, and wanted more opportunities to network with their UK peers. A good supervision relationship was perceived as the most critical element of support in a doctoral programme, but good relationships were sometimes difficult to attain due to differences in student/supervisor expectations and in approaches to supervision. The PhD was perceived as a difficult and stressful journey, but those nearing the end reflected positively on it as a life changing experience in which they had developed key professional and personal skills. CONCLUSIONS: Doctoral programmes need to ensure that structures are in place to support international students at different stages of their doctoral journey, and to support greater local-international student networking. Further research is needed to investigate good supervision practice and the suitability of the PhD vis a vis other doctoral models (e.g. the professional doctorate) for international nursing students. PMID- 21668950 TI - A computational approach to candidate gene prioritization for X-linked mental retardation using annotation-based binary filtering and motif-based linear discriminatory analysis. AB - BACKGROUND: Several computational candidate gene selection and prioritization methods have recently been developed. These in silico selection and prioritization techniques are usually based on two central approaches--the examination of similarities to known disease genes and/or the evaluation of functional annotation of genes. Each of these approaches has its own caveats. Here we employ a previously described method of candidate gene prioritization based mainly on gene annotation, in accompaniment with a technique based on the evaluation of pertinent sequence motifs or signatures, in an attempt to refine the gene prioritization approach. We apply this approach to X-linked mental retardation (XLMR), a group of heterogeneous disorders for which some of the underlying genetics is known. RESULTS: The gene annotation-based binary filtering method yielded a ranked list of putative XLMR candidate genes with good plausibility of being associated with the development of mental retardation. In parallel, a motif finding approach based on linear discriminatory analysis (LDA) was employed to identify short sequence patterns that may discriminate XLMR from non-XLMR genes. High rates (>80%) of correct classification was achieved, suggesting that the identification of these motifs effectively captures genomic signals associated with XLMR vs. non-XLMR genes. The computational tools developed for the motif-based LDA is integrated into the freely available genomic analysis portal Galaxy (http://main.g2.bx.psu.edu/). Nine genes (APLN, ZC4H2, MAGED4, MAGED4B, RAP2C, FAM156A, FAM156B, TBL1X, and UXT) were highlighted as highly-ranked XLMR methods. CONCLUSIONS: The combination of gene annotation information and sequence motif-orientated computational candidate gene prediction methods highlight an added benefit in generating a list of plausible candidate genes, as has been demonstrated for XLMR. PMID- 21668952 TI - Characterization the regulation of herpesvirus miRNAs from the view of human protein interaction network. AB - BACKGROUND: miRNAs are a class of non-coding RNA molecules that play crucial roles in the regulation of virus-host interactions. The ever-increasing data of known viral miRNAs and human protein interaction network (PIN) has made it possible to study the targeting characteristics of viral miRNAs in the context of these networks. RESULTS: We performed topological analysis to explore the targeting propensities of herpesvirus miRNAs from the view of human PIN and found that (1) herpesvirus miRNAs significantly target more hubs, moreover, compared with non-hubs (non-bottlenecks), hubs (bottlenecks) are targeted by much more virus miRNAs and virus types. (2) There are significant differences in the degree and betweenness centrality between common and specific targets, specifically we observed a significant positive correlation between virus types targeting these nodes and the proportion of hubs, and (3) K-core and ER analysis determined that common targets are closer to the global PIN center. Compared with random conditions, the giant connected component (GCC) and the density of the sub network formed by common targets have significantly higher values, indicating the module characteristic of these targets. CONCLUSIONS: Herpesvirus miRNAs preferentially target hubs and bottlenecks. There are significant differences between common and specific targets. Moreover, common targets are more intensely connected and occupy the central part of the network. These results will help unravel the complex mechanism of herpesvirus-host interactions and may provide insight into the development of novel anti-herpesvirus drugs. PMID- 21668953 TI - A short-term in vivo model for giant cell tumor of bone. AB - BACKGROUND: Because of the lack of suitable in vivo models of giant cell tumor of bone (GCT), little is known about its underlying fundamental pro-tumoral events, such as tumor growth, invasion, angiogenesis and metastasis. There is no existing cell line that contains all the cell and tissue tumor components of GCT and thus in vitro testing of anti-tumor agents on GCT is not possible. In this study we have characterized a new method of growing a GCT tumor on a chick chorio allantoic membrane (CAM) for this purpose. METHODS: Fresh tumor tissue was obtained from 10 patients and homogenized. The suspension was grafted onto the CAM at day 10 of development. The growth process was monitored by daily observation and photo documentation using in vivo biomicroscopy. After 6 days, samples were fixed and further analyzed using standard histology (hematoxylin and eosin stains), Ki67 staining and fluorescence in situ hybridization (FISH). RESULTS: The suspension of all 10 patients formed solid tumors when grafted on the CAM. In vivo microscopy and standard histology revealed a rich vascularization of the tumors. The tumors were composed of the typical components of GCT, including (CD51+/CD68+) multinucleated giant cells which were generally less numerous and contained fewer nuclei than in the original tumors. Ki67 staining revealed a very low proliferation rate. The FISH demonstrated that the tumors were composed of human cells interspersed with chick-derived capillaries. CONCLUSIONS: A reliable protocol for grafting of human GCT onto the chick chorio allantoic membrane is established. This is the first in vivo model for giant cell tumors of bone which opens new perspectives to study this disease and to test new therapeutical agents. PMID- 21668954 TI - Magnetic resonance imaging for lung cancer detection: experience in a population of more than 10,000 healthy individuals. AB - BACKGROUND: Recent refinements of lung MRI techniques have reduced the examination time and improved diagnostic sensitivity and specificity. We conducted a study to assess the feasibility of MRI for the detection of primary lung cancer in asymptomatic individuals. METHODS: A retrospective chart review was performed on images of lung parenchyma, which were extracted from whole-body MRI examinations between October 2000 and December 2007. 11,766 consecutive healthy individuals (mean age, 50.4 years; 56.8% male) were scanned using one of two 1.5-T scanners (Sonata and Sonata Maestro, Siemens Medical Solutions, Erlangen, Germany). The standard protocol included a quick whole-lung survey with T2-weighted 2-dimensional half Fourier acquisition single shot turbo spin echo (HASTE) and 3-dimensional volumetric interpolated breath-hold examination (VIBE). Total examination time was less than 10 minutes, and scanning time was only 5 minutes. Prompt referrals and follow-ups were arranged in cases of suspicious lung nodules. RESULTS: A total of 559 individuals (4.8%) had suspicious lung nodules. A total of 49 primary lung cancers were diagnosed in 46 individuals: 41 prevalence cancers and 8 incidence cancers. The overall detection rate of primary lung cancers was 0.4%. For smokers aged 51 to 70 years, the detection rate was 1.4%. TNM stage I disease accounted for 37 (75.5%). The mean size of detected lung cancers was 1.98 cm (median, 1.5 cm; range, 0.5-8.2 cm). The most histological types were adenocarcinoma in 38 (77.6%). CONCLUSION: Rapid zero-dose MRI can be used for lung cancer detection in a healthy population. PMID- 21668955 TI - Limited importance of the dominant-negative effect of TP53 missense mutations. AB - BACKGROUND: Heterozygosity of TP53 missense mutations is related to the phenomenon of the dominant-negative effect (DNE). To estimate the importance of the DNE of TP53 mutations, we analysed the percentage of cancer cases showing a single heterozygous mutation of TP53 and searched for a cell line with a single heterozygous mutation of this gene. This approach was based on the knowledge that genes with evident DNE, such as EGFR and IDH1, represent nearly 100% of single heterozygous mutations in tumour specimens and cell lines. METHODS: Genetic analyses (LOH and sequencing) performed for early and late passages of several cell lines originally described as showing single heterozygous TP53 mutations (H 318, G-16, PF-382, MOLT-13, ST-486 and LS-123). Statistical analysis of IARC TP53 and SANGER databases. Genetic analyses of N-RAS, FBXW7, PTEN and STR markers to test cross-contamination and cell line identity. Cell cloning, fluorescence activated cell sorting and SSCP performed for the PF-382 cell line. RESULTS: A database study revealed TP53 single heterozygous mutations in 35% of in vivo (surgical and biopsy) samples and only 10% of cultured cells (in vitro), although those numbers appeared to be overestimated. We deem that published in vivo TP53 mutation analyses are not as rigorous as studies in vitro, and we did not find any cell line showing a stable, single heterozygous mutation. G16, PF-382 and MOLT-13 cells harboured single heterozygous mutations temporarily. ST-486, H-318 and LS-123 cell lines were misclassified. Specific mutations, such as R175H, R273H, R273L or R273P, which are reported in the literature to exert a DNE, showed the lowest percentage of single heterozygous mutations in vitro (about 5%). CONCLUSION: We suggest that the currently reported percentage of TP53 single heterozygous mutations in tumour samples and cancer cell lines is overestimated. Thus, the magnitude of the DNE of TP53 mutations is questionable. This scepticism is supported by database investigations showing that retention of the wild-type allele occurs with the same frequency as either nonsense or missense TP53 mutations. PMID- 21668956 TI - Prevalence of asymptomatic celiac disease in children with fibromyalgia: a pilot study. AB - BACKGROUND: The objective of this study was to prospectively determine the prevalence of asymptomatic celiac disease among children presenting with fibromyalgia. The secondary objective was to investigate if their symptoms resolved on a gluten free diet. FINDINGS: All children seen in the Amplified Musculoskeletal Pain clinic between the ages of 12 and 17 years of age who fulfilled the 1990 American College of Rheumatology diagnostic criteria for fibromyalgia were invited to participate. A total immunoglobulin A (IgA) level, IgA antiendomysial (EMA) and IgA anti-TTG antibodies was obtained on all study subjects. A visual analog scale for pain and a functional disability inventory were obtained on all patients. If a patient had elevated EMA or TTG a small bowel biopsy was done. Patients with celiac disease were placed on a gluten-free diet and observed to see if their symptoms resolved.50 patients, 45 females, completed the study. Only one patient was found to have celiac disease. On a gluten-free diet her tissue transglutaminase antibody level returned to normal but her visual analog scale scores increased and her functional disability inventory was 40 initially and 21 at follow up. CONCLUSIONS: In this pilot, single center study at a tertiary children's hospital patients with fibromyalgia do not seem to have occult celiac disease at an increased rate over the population as a whole. PMID- 21668958 TI - Gebiss: an ImageJ plugin for the specification of ground truth and the performance evaluation of 3D segmentation algorithms. AB - BACKGROUND: Image segmentation is a crucial step in quantitative microscopy that helps to define regions of tissues, cells or subcellular compartments. Depending on the degree of user interactions, segmentation methods can be divided into manual, automated or semi-automated approaches. 3D image stacks usually require automated methods due to their large number of optical sections. However, certain applications benefit from manual or semi-automated approaches. Scenarios include the quantification of 3D images with poor signal-to-noise ratios or the generation of so-called ground truth segmentations that are used to evaluate the accuracy of automated segmentation methods. RESULTS: We have developed Gebiss; an ImageJ plugin for the interactive segmentation, visualisation and quantification of 3D microscopic image stacks. We integrated a variety of existing plugins for threshold-based segmentation and volume visualisation. CONCLUSIONS: We demonstrate the application of Gebiss to the segmentation of nuclei in live Drosophila embryos and the quantification of neurodegeneration in Drosophila larval brains. Gebiss was developed as a cross-platform ImageJ plugin and is freely available on the web at http://imaging.bii.a-star.edu.sg/projects/gebiss/. PMID- 21668957 TI - Autosomal Recessive Primary Microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum. AB - Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci (MCPH1-7) for this condition have been mapped with seven corresponding genes (MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, and STIL) identified from different world populations. Contribution of ASPM and WDR62 gene mutations in MCPH World wide is more than 50%. By and large, primary microcephaly patients are phenotypically indistinguishable, however, recent studies in patients with mutations in MCPH1, WDR62 and ASPM genes showed a broader clinical and/or cellular phenotype. It has been proposed that mutations in MCPH genes can cause the disease phenotype by disturbing: 1) orientation of mitotic spindles, 2) chromosome condensation mechanism during embryonic neurogenesis, 3) DNA damage-response signaling, 4) transcriptional regulations and microtubule dynamics, 5) certain unknown centrosomal mechanisms that control the number of neurons generated by neural precursor cells. Recent discoveries of mammalian models for MCPH have open up horizons for researchers to add more knowledge regarding the etiology and pathophysiology of MCPH. High incidence of MCPH in Pakistani population reflects the most probable involvement of consanguinity. Genetic counseling and clinical management through carrier detection/prenatal diagnosis in MCPH families can help reducing the incidence of this autosomal recessive disorder. PMID- 21668959 TI - Psychometric properties of the Brazilian version of the Early Childhood Oral Health Impact Scale (B-ECOHIS). AB - BACKGROUND: Oral disorders can have a negative impact on the functional, social and psychological wellbeing of young children and their families and cause pain/discomfort for the child. Oral health-related quality of life (OHRQoL) has emerged as an important health outcome in clinical trials and healthcare research. The Early Childhood Oral Health Impact Scale (ECOHIS) is a proxy measure of children's OHRQoL designed to assess the negative impact of oral disorders on the quality of life of preschool children. The objective of this study was to evaluate the psychometric properties of the Brazilian version of the ECOHIS (B-ECOHIS). METHODS: This investigation was carried out in preliminary and field studies. The preliminary study comprised a cross-sectional study carried out in the city of Petropolis, Brazil. A sample of 150 children from two to five years of age was recruited at a public hospital. In the field study, an epidemiological survey was carried out in public and private preschools of Belo Horizonte, Brazil. The B-ECOHIS was answered by 1643 parents/caregivers of five year-old male and female preschool children. In both phases, oral examinations were performed by a single previously calibrated dentist. Reliability was determined through test-retest reliability and internal consistency. Validity was determined through convergent and discriminant validities. The correlation between the scores obtained on the child and family impact sections was assessed. RESULTS: In the preliminary (P) and field (F) study, test-retest reliability correlation values were 0.98 and 0.99 for the child impact section and 0.97 and 0.99 for the family impact section, respectively. The B-ECOHIS demonstrated internal consistency: child impact section (P: alpha = 0.74; F: alpha = 0.80) and family impact section (P: alpha = 0.59; F: alpha = 0.76). The correlation between the scores obtained on the child and family impact sections was statistically significant (P: rs = 0.54; F: rs = 0.62; p <= 0.001). In both phases of the study, B-ECOHIS scores were significantly associated with the decayed, missing and filled teeth index, decayed teeth and discolored upper anterior teeth (p < 0.05). CONCLUSION: The B-ECOHIS proved reliable and valid for assessing the negative impact of oral disorders on the quality of life of preschool children. PMID- 21668961 TI - Predictors of web-based follow-up response in the Prevention Of Low Back Pain In The Military Trial (POLM). AB - BACKGROUND: Achieving adequate follow-up in clinical trials is essential to establish the validity of the findings. Achieving adequate response rates reduces bias and increases probability that the findings can be generalized to the population of interest. Therefore, the purpose of this study was to determine the influence of attention, demographic, psychological, and health status factors on web-based response rates in the ongoing Prevention of Low Back Pain in the Military (POLM) trial. METHODS: Twenty companies of Soldiers (n = 4,325) were cluster randomized to complete a traditional exercise program including sit-ups (TEP) with or without a psychosocial educational program (PSEP) or a core stabilization exercise program (CSEP) with or without PSEP. A subgroup of Soldiers (n = 371) was randomized to receive an additional physical and ultrasound imaging (USI) examination of key trunk musculature. As part of the surveillance program, all Soldiers were encouraged to complete monthly surveys via email during the first year. Descriptive statistics of the predictor variables were obtained and compared between responders and non-responders using two sample t-tests or chi-square test, as appropriate. Generalized linear mixed models were subsequently fitted for the dichotomous outcomes to estimate the effects of the predictor variables. The significance level was set at .05 a priori. RESULTS: The overall response rate was 18.9% (811 subjects) for the first year. Responders were more likely to be older, Caucasian, have higher levels of education and income, reservist military status, non smoker, lower BMI, and have received individualized attention via the physical/USI examination (p < .05). Age, race/ethnicity, education, military status, smoking history, BMI, and whether a Soldier received the physical/USI examination remained statistically significant (p < .05) when considered in a full multivariate model. CONCLUSION: The overall web based response rate during the first year of the POLM trial was consistent with studies that used similar methodology, but lower when compared to rates expected for standard clinical trials. One year response rate was significantly associated with demographic characteristics, health status, and individualized attention via additional testing. These data may assist for planning of future trials that use web based response systems. TRIAL REGISTRATION: This study has been registered at reports at http://clinicaltrials.gov (NCT00373009). PMID- 21668960 TI - Epidemics of enterovirus infection in Chungnam Korea, 2008 and 2009. AB - Previously, we explored the epidemic pattern and molecular characterization of enteroviruses isolated in Chungnam, Korea from 2005 to 2006. The present study extended these observations to 2008 and 2009. In this study, enteroviruses showed similar seasonal prevalent pattern from summer to fall and age distribution to previous investigation. The most prevalent month was July: 42.9% in 2008 and 31.9% in 2009. The highest rate of enterovirus-positive samples occurred in children < 1-year-old-age. Enterovirus-positive samples were subjected to sequence determination of the VP1 region, which resolved the isolated enteroviruses into 10 types in 2008 (coxsackievirus A4, A16, B1, B3, echovirus 6, 7, 9, 11, 16, and 30) and 8 types in 2009 (coxsackievirus A2, A4, A5, A16, B1, B5, echovirus 11, and enterovirus 71). The most prevalent enterovirus serotype in 2008 and 2009 was echovirus 30 and coxsackievirus B1, respectively, whereas echovirus 18 and echovirus 5 were the most prevalent types in 2005 and 2006, respectively. Comparison of coxsackievirus B1 and B5 of prevalent enterovirus type in Korea in 2009 with reference strains of each same serotype were conducted to genetic analysis by a phylogenetic tree. The sequences of coxsackievirus B1 strains segregated into four distinct clusters (A, B, C, and D) with some temporal and regional sub-clustering. Most of Korean coxsackievirus B1 strains in 2008 and 2009 were in cluster D, while only "Kor08-CVB1-001CN" was cluster C. The coxsackievirus B5 strains segregated in five distinct genetic groups (clusters A E) were supported by high bootstrap values. The Korean strains isolated in 2001 belonged to cluster D, whereas Korean strains isolated in 2005 and 2009 belonged to cluster E. Comparison of the VP1 amino acid sequences of the Korean coxsackievirus B5 isolates with reference strains revealed amino acid sequence substitutions at nine amino acid sequences (532, 562, 570, 571, 576-578, 582, 583, and 585). PMID- 21668962 TI - Is it feasible and effective to provide osteopathy and acupuncture for patients with musculoskeletal problems in a GP setting? A service evaluation. AB - BACKGROUND: Spinal manipulation and acupuncture can be helpful in reducing the symptoms of musculoskeletal (MSK) pain. Both approaches are currently recommended by NICE as treatment options for patients with persistent low back pain. However, there has been no previous evaluation of a GP service using them together for MSK pain. The purpose of this study was to evaluate acceptability and outcomes for an osteopathy and acupuncture service (delivered by complementary therapy practitioners) for patients with MSK problems provided within a General Practice. METHODS: Patients were asked to complete a questionnaire before and after their course of treatment. Outcome measures included the Bournemouth Questionnaire (measuring MSK problems), EuroQoL-5D (measuring quality of life), medication use, physical activity and general well-being. Non-parametric tests were used to compare pre- and post- treatment variables. Qualitative data, regarding participants' views on the service, were collected from patients via a service survey and healthcare professionals via interviews. Qualitative data were analysed using thematic analysis. RESULTS: 123 adults with MSK problems were referred into the service (79 female and 44 male, mean age 49 years). Complete patient questionnaire data sets (pre- and post- treatment) were available for 102 participants; 91 completed a service survey. All healthcare professionals involved in the service participated in interviews including all seven GPs and the administration manager at the practice, as well as the three acupuncture/osteopathy practitioners. Patient outcomes: comparisons between pre and post-treatment revealed a statistically significant improvement in MSK pain (p < 0.0001) and quality of life (p < 0.0001), and a statistically significant reduction in medication use (p < 0.0001). Qualitative analysis found that patients reported improvements in their MSK pain, mobility, other physical health conditions, well-being and self-management of their MSK problem.Acceptability of the service: overall patients and healthcare professionals were satisfied with the service and its provision within the Practice. Patients reported wanting increased appointment availability and flexibility, and more sessions. Complementary therapy practitioners reported finding the high number of referrals of chronic patients challenging, and wanting increased communication with GPs. CONCLUSIONS: Provision of acupuncture and osteopathy for MSK pain is achievable in General Practice. A GP surgery can quickly adapt to incorporate complementary therapy provided key principles are followed. PMID- 21668963 TI - Improvement in multiple dimensions of fatigue in patients with fibromyalgia treated with duloxetine: secondary analysis of a randomized, placebo-controlled trial. AB - INTRODUCTION: Fatigue is one of the most disabling symptoms associated with fibromyalgia that greatly impacts quality of life. Fatigue was assessed as a secondary objective in a 2-phase, 24-week study in outpatients with American College of Rheumatology-defined fibromyalgia. METHODS: Patients were randomized to duloxetine 60-120 mg/d (N = 263) or placebo (N = 267) for the 12-week acute phase. At Week 12, all placebo-treated patients were switched to double-blind treatment with duloxetine for the extension phase. Fatigue was assessed at baseline and every 4 weeks with the Multidimensional Fatigue Inventory (MFI) scales: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Activity, and Reduced Motivation. Other assessments that may be associated with fatigue included Brief Pain Inventory (BPI) average pain, numerical scales to rate anxiety, depressed mood, bothered by sleep difficulties, and musculoskeletal stiffness. Treatment-emergent fatigue-related events were also assessed. Changes from baseline to Week 12, and from Week 12 to Week 24, were analyzed by mixed effects model repeated measures analysis. RESULTS: At Week 12, duloxetine versus placebo significantly (all p < .05) reduced ratings on each MFI scale, BPI pain, anxiety, depressed mood, and stiffness. Improvement in ratings of being bothered by sleep difficulties was significant only at Weeks 4 and 8. At Week 24, mean changes in all measures indicated improvement was maintained for patients who received duloxetine for all 24 weeks (n = 176). Placebo-treated patients switched to duloxetine (n = 187) had significant within-group improvement in Physical Fatigue (Weeks 16, 20, and 24); General Fatigue (Weeks 20 and 24); Mental Fatigue (Week 20); and Reduced Activity (Weeks 20 and 24). These patients also experienced significant within-group improvement in BPI pain, anxiety, depressed mood, bothered by sleep difficulties, and stiffness. Overall, the most common (> 5% incidence) fatigue-related treatment-emergent adverse events were fatigue, somnolence, and insomnia. CONCLUSIONS: Treatment with duloxetine significantly improved multiple dimensions of fatigue in patients with fibromyalgia, and improvement was maintained for up to 24 weeks. TRIAL REGISTRATION: ClinicalTrials.gov registry NCT00673452. PMID- 21668964 TI - Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance. AB - BACKGROUND: Myocardial scarring at the LV pacing site leads to incomplete resynchronization and a suboptimal symptomatic response to CRT. We sought to determine whether the use of late gadolinium cardiovascular magnetic resonance (LGE-CMR) to guide left ventricular (LV) lead deployment influences the long-term outcome of cardiac resynchronization therapy (CRT). METHODS: 559 patients with heart failure (age 70.4 +/- 10.7 yrs [mean +/- SD]) due to ischemic or non ischemic cardiomyopathy underwent CRT. Implantations were either guided (+CMR) or not guided (-CMR) by LGE-CMR prior to implantation. Fluoroscopy and LGE-CMR were used to localize the LV lead tip and and myocardial scarring retrospectively. Clinical events were assessed in three groups: +CMR and pacing scar (+CMR+S); CMR and not pacing scar (+CMR-S), and; LV pacing not guided by CMR (-CMR). RESULTS: Over a maximum follow-up of 9.1 yrs, +CMR+S had the highest risk of cardiovascular death (HR: 6.34), cardiovascular death or hospitalizations for heart failure (HR: 5.57) and death from any cause or hospitalizations for major adverse cardiovascular events (HR: 4.74) (all P < 0.0001), compared with +CMR-S. An intermediate risk of meeting these endpoints was observed for -CMR, with HRs of 1.51 (P = 0.0726), 1.61 (P = 0.0169) and 1.87 (p = 0.0005), respectively. The +CMR+S group had the highest risk of death from pump failure (HR: 5.40, p < 0.0001) and sudden cardiac death (HR: 4.40, p = 0.0218), in relation to the +CMR S group. CONCLUSIONS: Compared with a conventional implantation approach, the use of LGE-CMR to guide LV lead deployment away from scarred myocardium results in a better clinical outcome after CRT. Pacing scarred myocardium was associated with the worst outcome, in terms of both pump failure and sudden cardiac death. PMID- 21668965 TI - Long-term oral nitrate therapy is associated with adverse outcome in diabetic patients following elective percutaneous coronary intervention. AB - BACKGROUND: To assess the impact of long-term oral nitrate therapy on clinical outcome following percutaneous coronary intervention (PCI) in patients with type II diabetes. METHODS: The incidence of major adverse cardiovascular events (MACEs) following elective PCI for stable coronary artery disease was evaluated in 108 patients with type II diabetes (age 64.6+/-10.5 years, 67.7% men). Major adverse cardiovascular events were defined as the need for revascularization, non fatal myocardial infarction or cardiovascular death. Multivariate Cox regression analysis was used to evaluate the predictive value of MACEs by clinical characteristics and the prescription of long-term nitrate therapy. RESULTS: Isosorbide mononitrate (ISMN) was prescribed to 46 patients with an average dose of 44.3+/-15.2 mg/day. After a mean follow up of 25.3+/-25 months, 16 patients developed MACEs. Patients who received ISMN were more likely to suffer from MACEs (26.1% vs. 6.5%, P=0.01), mainly driven by a higher rate of acute coronary syndrome (13.0 vs 0%, P=0.01). Average daily dose of nitrate and other cardiovascular medication was not associated with MACEs. Multivariate Cox regression analysis revealed that prescription of only ISMN (Hazard Ratio 3.09, 95% CI 1.10-10.21, P=0.04) was an independent predictor for the development of MACEs. CONCLUSION: Long-term oral nitrate therapy was associated with MACEs following elective coronary artery revascularization by PCI in patients with type II diabetes. PMID- 21668966 TI - Acute exhaustive exercise regulates IL-2, IL-4 and MyoD in skeletal muscle but not adipose tissue in rats. AB - BACKGROUND: The purpose of this study was to evaluate the effect of exhaustive exercise on proteins associated with muscle damage and regeneration, including IL 2, IL-4 and MyoD, in extensor digitorum longus (EDL) and soleus muscles and mesenteric (MEAT) and retroperitoneal adipose tissues (RPAT). METHODS: Rats were killed by decapitation immediately (E0 group, n = 6), 2 (E2 group, n = 6) or 6 (E6 group, n = 6) hours after the exhaustion protocol, which consisted of running on a treadmill at approximately 70% of VO(2max) for fifty minutes and then at an elevated rate that increased at one m/min every minute, until exhaustion. RESULTS: The control group (C group, n = 6) was not subjected to exercise. IL-2 protein expression increased at E0 in the soleus and EDL; at E2, this cytokine returned to control levels in both tissues. In the soleus, IL-2 protein expression was lower than that in the control at E6. IL-4 protein levels increased in EDL at E6, but the opposite result was observed in the soleus. MyoD expression increased at E6 in EDL. CONCLUSION: Exhaustive exercise was unable to modify IL-2 and IL-4 levels in MEAT and RPAT. The results show that exhaustive exercise has different effects depending on which muscle is analysed. PMID- 21668967 TI - The distinct binding properties between avian/human influenza A virus NS1 and Postsynaptic density protein-95 (PSD-95), and inhibition of nitric oxide production. AB - BACKGROUND: The NS1 protein of influenza A virus is able to bind with many proteins that affect cellular signal transduction and protein synthesis in infected cells. The NS1 protein consists of approximately 230 amino acids and the last 4 amino acids of the NS1 C-terminal form a PDZ binding motif. Postsynaptic Density Protein-95 (PSD-95), which is mainly expressed in neurons, has 3 PDZ domains. We hypothesise that NS1 binds to PSD-95, and this binding is able to affect neuronal function. RESULT: We conducted a yeast two-hybrid analysis, GST pull down assays and co-immunoprecipitations to detect the interaction between NS1 and PSD-95. The results showed that NS1 of avian influenza virus H5N1 (A/chicken/Guangdong/1/2005) is able to bind to PSD-95, whereas NS1 of human influenza virus H1N1 (A/Shantou/169/2006) is unable to do so. The results also revealed that NS1 of H5N1 significantly reduces the production of nitric oxide (NO) in rat hippocampal neurons. CONCLUSION: In summary, our study indicates that NS1 of influenza A virus can bind with neuronal PSD-95, and the avian H5N1 and human H1N1 influenza A viruses possess distinct binding properties. PMID- 21668968 TI - Oral Health-Related Quality of Life among a large national cohort of 87,134 Thai adults. AB - BACKGROUND: Oral health has been of interest in many low and middle income countries due to its impact on general health and quality of life. But there are very few population-based reports of adult Oral Health Related Quality of Life (OHRQoL) in developing countries. To address this knowledge gap for Thailand, we report oral health findings from a national cohort of 87,134 Thai adults aged between 15 and 87 years and residing all over the country. METHODS: In 2005, a comprehensive health questionnaire was returned by distance learning cohort members recruited through Sukhothai Thammathirat Open University. OHRQoL dimensions included were discomfort speaking, swallowing, chewing, social interaction and pain. We calculated multivariate (adjusted) associations between OHRQoL outcomes, and sociodemographic, health behaviour and dental status. RESULTS: Overall, discomfort chewing (15.8%), social interaction (12.5%), and pain (10.6%) were the most commonly reported problems. Females were worse off for chewing, social interaction and pain. Smokers had worse OHRQoL in all dimensions with Odds Ratios (OR) ranging from 1.32 to 1.51. Having less than 20 teeth was strongly associated with difficulty speaking (OR = 6.43), difficulty swallowing (OR = 6.27), and difficulty chewing (OR = 3.26). CONCLUSIONS: Self-reported adverse oral health correlates with individual function and quality of life. Outcomes are generally worse among females, the poor, smokers, drinkers and those who have less than 20 teeth. Further longitudinal study of the cohort analysed here will permit assessment of causal determinants of poor oral health and the efficacy of preventive programs in Thailand. PMID- 21668969 TI - New V. cholerae atypical El Tor variant emerged during the 2006 epidemic outbreak in Angola. AB - BACKGROUND: V. cholerae is the etiological agent of cholera, a major public health concern in most developing countries. Virulence of V. cholerae relies on the powerful cholera toxin, encoded by the CTX prophage. The emergence of new pathogenic variants in the recent years has been mostly associated with new CTX prophage rearrangements. RESULTS: In this retrospective study, we show that the epidemic V. cholerae O1 El Tor strain responsible for the 2006 outbreak in Angola is clonally and genetically different from El Tor strains circulating in the 1990s in the same area. Strains from 2006 carry ICEVchAng3 of the SXT/R391 family. This ICE is associated with a narrower multidrug resistance profile compared to the one conferred by plasmid p3iANG to strains of the 1990s. The CTX prophage carried by 2006 El Tor strains is characterized by rstR(ET) and ctxB(Cla) alleles organized in a RS1-RS2-Core array on chromosome I. Interestingly, the newly emerging atypical strain belongs to a clade previously known to comprise only clinical isolates from the Indian subcontinent that also contain the same ICE of the SXT/R391 family. CONCLUSIONS: Our findings remark the appearance of a novel V. cholerae epidemic variant in Africa with a new CTXPhi arrangement previously described only in the Indian Subcontinent. PMID- 21668970 TI - Serum PCB levels and congener profiles among teachers in PCB-containing schools: a pilot study. AB - BACKGROUND: PCB contamination in the built environment may result from the release of PCBs from building materials. The significance of this contamination as a pathway of human exposure is not well-characterized, however. This research compared the serum PCB concentrations, and congener profiles between 18 teachers in PCB-containing schools and referent populations. METHODS: Blood samples from 18 teachers in PCB-containing schools were analyzed for 57 PCB congeners. Serum PCB concentrations and congener patterns were compared between the teachers, to the 2003-4 NHANES (National Health and Nutrition Examination Survey) data, and to data from 358 Greater Boston area men. RESULTS: Teachers at one school had higher levels of lighter (PCB 6-74) congeners compared to teachers from other schools. PCB congener 47 contributed substantially to these elevated levels. Older teachers (ages 50-64) from all schools had higher total (sum of 33 congeners) serum PCB concentrations than age-comparable NHANES reference values. Comparing the teachers to the referent population of men from the Greater Boston area (all under age 51), no difference in total serum PCB levels was observed between the referents and teachers up to 50 years age. However, the teachers had significantly elevated serum concentrations of lighter congeners (PCB 6-74). This difference was confirmed by comparing the congener-specific ratios between groups, and principal component analysis showed that the relative contribution of lighter congeners differed between the teachers and the referents. CONCLUSIONS: These findings suggest that the teachers in the PCB-containing buildings had higher serum levels of lighter PCB congeners (PCB 6-74) than the referent populations. Examination of the patterns, as well as concentrations of individual PCB congeners in serum is essential to investigating the contributions from potential environmental sources of PCB exposure. PMID- 21668971 TI - Breast cancer treatment and sexual dysfunction: Moroccan women's perception. AB - BACKGROUND: This exploratory prospective study evaluated women's responses to questions that asked them to describe how their body image and sexual functioning had changed since their breast cancer diagnosis to treatment. METHODS: A questionnaire concerning body image scale and various sexual problems experienced after diagnosis and treatment was anonymously completed by 120 women in the outpatient clinic of our hospital's Division of medical Oncology. To be eligible, subjects had to be sexually active and had histology proven breast cancer. They also had to have received treatment for breast cancer. RESULTS: 100% of participants have never spoken with their doctor about this subject. 84% of the participants continued sexual activity after treatment, but there was an increase in the incidence of sexual functioning problems which resulted in a slight reduction in the quality of their sex lives. 65% of the women experienced dyspareunia followed by lubrication difficulties (54%) and the absence or reduction of sexual desire (48% and 64%, respectively) while, 37% had lack of satisfaction (37%). Female orgasmic disorder and brief intercourse and arousal were reported respectively by 40% and 38% of the subjects. The sexual dysfunctions were absent before diagnosis and management of breast cancer in 91.5% subjects and of these 100% subjects complained of a deterioration of the symptomatology after the various treatments. 90% of the dysfunctions were observed after chemotherapy, 9% after surgery and 3% after radiotherapy; none of the subjects indicated the onset of dysfunctions to have been associated with hormonotherapy. 100% expressed not having received sufficient information about how the disease and treatment (including surgery) might affect their sexual life. CONCLUSION: Breast cancer and its treatment may result in significant difficulties with sexual functioning and sexual life. Addressing these problems is essential to improve the quality of life of Moroccan women with breast cancer. PMID- 21668972 TI - Global analysis of gene expression in mineralizing fish vertebra-derived cell lines: new insights into anti-mineralogenic effect of vanadate. AB - BACKGROUND: Fish has been deemed suitable to study the complex mechanisms of vertebrate skeletogenesis and gilthead seabream (Sparus aurata), a marine teleost with acellular bone, has been successfully used in recent years to study the function and regulation of bone and cartilage related genes during development and in adult animals. Tools recently developed for gilthead seabream, e.g. mineralogenic cell lines and a 4 * 44K Agilent oligo-array, were used to identify molecular determinants of in vitro mineralization and genes involved in anti mineralogenic action of vanadate. RESULTS: Global analysis of gene expression identified 4,223 and 4,147 genes differentially expressed (fold change - FC > 1.5) during in vitro mineralization of VSa13 (pre-chondrocyte) and VSa16 (pre osteoblast) cells, respectively. Comparative analysis indicated that nearly 45% of these genes are common to both cell lines and gene ontology (GO) classification is also similar for both cell types. Up-regulated genes (FC > 10) were mainly associated with transport, matrix/membrane, metabolism and signaling, while down-regulated genes were mainly associated with metabolism, calcium binding, transport and signaling. Analysis of gene expression in proliferative and mineralizing cells exposed to vanadate revealed 1,779 and 1,136 differentially expressed genes, respectively. Of these genes, 67 exhibited reverse patterns of expression upon vanadate treatment during proliferation or mineralization. CONCLUSIONS: Comparative analysis of expression data from fish and data available in the literature for mammalian cell systems (bone-derived cells undergoing differentiation) indicate that the same type of genes, and in some cases the same orthologs, are involved in mechanisms of in vitro mineralization, suggesting their conservation throughout vertebrate evolution and across cell types. Array technology also allowed identification of genes differentially expressed upon exposure of fish cell lines to vanadate and likely involved in its anti-mineralogenic activity. Many were found to be unknown or they were never associated to bone homeostasis previously, thus providing a set of potential candidates whose study will likely bring insights into the complex mechanisms of tissue mineralization and bone formation. PMID- 21668973 TI - Synchronization of cytoplasmic and transferred mitochondrial ribosomal protein gene expression in land plants is linked to Telo-box motif enrichment. AB - BACKGROUND: Chloroplasts and mitochondria evolved from the endosymbionts of once free-living eubacteria, and they transferred most of their genes to the host nuclear genome during evolution. The mechanisms used by plants to coordinate the expression of such transferred genes, as well as other genes in the host nuclear genome, are still poorly understood. RESULTS: In this paper, we use nuclear encoded chloroplast (cpRPGs), as well as mitochondrial (mtRPGs) and cytoplasmic (euRPGs) ribosomal protein genes to study the coordination of gene expression between organelles and the host. Results show that the mtRPGs, but not the cpRPGs, exhibit strongly synchronized expression with euRPGs in all investigated land plants and that this phenomenon is linked to the presence of a telo-box DNA motif in the promoter regions of mtRPGs and euRPGs. This motif is also enriched in the promoter regions of genes involved in DNA replication. Sequence analysis further indicates that mtRPGs, in contrast to cpRPGs, acquired telo-box from the host nuclear genome. CONCLUSIONS: Based on our results, we propose a model of plant nuclear genome evolution where coordination of activities in mitochondria and chloroplast and other cellular functions, including cell cycle, might have served as a strong selection pressure for the differential acquisition of telo box between mtRPGs and cpRPGs. This research also highlights the significance of physiological needs in shaping transcriptional regulatory evolution. PMID- 21668974 TI - Ejecting chick cheats: a changing paradigm? AB - Evolutionary arms-races between avian brood parasites and their hosts have typically resulted in some spectacular adaptations, namely remarkable host ability to recognize and reject alien eggs and, in turn, sophisticated parasite egg mimicry. In a striking contrast to hosts sometimes rejecting even highly mimetic eggs, the same species typically fail to discriminate against highly dissimilar parasite chicks. Understanding of this enigma is still hampered by the rarity of empirical tests - and consequently evidence - for chick discrimination. Recent work on Australian host-parasite systems (Gerygone hosts vs. Chalcites parasites), increased not only the diversity of hosts showing chick discrimination, but also discovered an entirely novel host behavioural adaptation. The hosts do not desert parasite chicks (as in all previously reported empirical work) but physically remove living parasites from their nests. Here, I briefly discuss these exciting findings and put them in the context of recent empirical and theoretical work on parasite chick discrimination. Finally, I review factors responsible for a relatively slow progress in this research area and suggest most promising avenues for future research. PMID- 21668975 TI - Effects of preoperative feeding with a whey protein plus carbohydrate drink on the acute phase response and insulin resistance. A randomized trial. AB - BACKGROUND: Prolonged preoperative fasting increases insulin resistance and current evidence recommends carbohydrate (CHO) drinks 2 hours before surgery. Our hypothesis is that the addition of whey protein to a CHO-based drink not only reduces the inflammatory response but also diminish insulin resistance. METHODS: Seventeen patients scheduled to cholecystectomy or inguinal herniorraphy were randomized and given 474 ml and 237 ml of water (CO group) or a drink containing CHO and milk whey protein (CHO-P group) respectively, 6 and 3 hours before operation. Blood samples were collected before surgery and 24 hours afterwards for biochemical assays. The endpoints of the study were the insulin resistance (IR), the prognostic inflammatory and nutritional index (PINI) and the C-reactive protein (CRP)/albumin ratio. A 5% level for significance was established. RESULTS: There were no anesthetic or postoperative complications. The post operative IR was lower in the CHO-P group when compared with the CO group (2.75 +/- 0.72 vs 5.74 +/- 1.16; p = 0.03). There was no difference between the two groups in relation to the PINI. The CHO-P group showed a decrease in the both CRP elevation and CRP/albumin ratio (p < 0.05). The proportion of patients who showed CRP/albumin ratio considered normal was significantly greater (p < 0.05) in the CHO-P group (87.5%) than in the CO group (33.3%). CONCLUSIONS: Shortening the pre operative fasting using CHO and whey protein is safe and reduces insulin resistance and postoperative acute phase response in elective moderate operations. TRIAL REGISTRATION: ClinicalTrial.gov NCT01354249. PMID- 21668976 TI - The Sphingosine-1-phospate receptor 1 mediates S1P action during cardiac development. AB - BACKGROUND: Sphingosine-1-phosophate (S1P) is a biologically active sphingolipid metabolite that influences cellular events including differentiation, proliferation, and migration. S1P acts through five distinct cell surface receptors designated S1P1-5R, with S1P1R having the highest expression level in the developing heart. S1P1R is critical for vascular maturation, with its loss leading to embryonic death by E14.5; however, its function during early cardiac development is not well known. Our previous studies demonstrated that altered S1P levels adversely affects atrioventricular (AV) canal development in vitro, with reduced levels leading to cell death and elevated levels inhibiting cell migration and endothelial to mesenchymal cell transformation (EMT). RESULTS: We determined, by real-time PCR analysis, that S1P1R was expressed at least 10-fold higher than other S1P receptors in the developing heart. Immunohistochemical analysis revealed S1P1R protein expression in both endothelial and myocardial cells in the developing atrium and ventricle. Using AV canal cultures, we observed that treatment with either FTY720 (an S1P1,3,4,5R agonist) or KRP203 (an S1P1R-specific agonist) caused similar effects on AV canal cultures as S1P treatment, including induction of cell rounding, inhibition of cell migration, and inhibition of EMT. In vivo, morphological analysis of embryonic hearts at E10.5 revealed that S1P1R-/- hearts were malformed with reduced myocardial tissue. In addition to reduced myocardial tissue, E12.5 S1P1R-/- hearts had disrupted morphology of the heart wall and trabeculae, with thickened and disorganized outer compact layer and reduced fibronectin (FN) deposition compared to S1P1R+/+ littermates. The reduced myocardium was accompanied by a decrease in cell proliferation but not an increase in apoptosis. CONCLUSIONS: These data indicate that S1P1R is the primary mediator of S1P action in AV canal cultures and that loss of S1P1R expression in vivo leads to malformed embryonic hearts, in part due to reduced fibronectin expression and reduced cell proliferation. PMID- 21668977 TI - Mining beyond the exome. PMID- 21668978 TI - Characterization of single-nucleotide variation in Indian-origin rhesus macaques (Macaca mulatta). AB - BACKGROUND: Rhesus macaques are the most widely utilized nonhuman primate model in biomedical research. Previous efforts have validated fewer than 900 single nucleotide polymorphisms (SNPs) in this species, which limits opportunities for genetic studies related to health and disease. Extensive information about SNPs and other genetic variation in rhesus macaques would facilitate valuable genetic analyses, as well as provide markers for genome-wide linkage analysis and the genetic management of captive breeding colonies. RESULTS: We used the available rhesus macaque draft genome sequence, new sequence data from unrelated individuals and existing published sequence data to create a genome-wide SNP resource for Indian-origin rhesus monkeys. The original reference animal and two additional Indian-origin individuals were resequenced to low coverage using SOLiDTM sequencing. We then used three strategies to validate SNPs: comparison of potential SNPs found in the same individual using two different sequencing chemistries, and comparison of potential SNPs in different individuals identified with either the same or different sequencing chemistries. Our approach validated approximately 3 million SNPs distributed across the genome. Preliminary analysis of SNP annotations suggests that a substantial number of these macaque SNPs may have functional effects. More than 700 non-synonymous SNPs were scored by Polyphen-2 as either possibly or probably damaging to protein function and these variants now constitute potential models for studying functional genetic variation relevant to human physiology and disease. CONCLUSIONS: Resequencing of a small number of animals identified greater than 3 million SNPs. This provides a significant new information resource for rhesus macaques, an important research animal. The data also suggests that overall genetic variation is high in this species. We identified many potentially damaging non-synonymous coding SNPs, providing new opportunities to identify rhesus models for human disease. PMID- 21668979 TI - Family and community concerns about post-mortem needle biopsies in a Muslim society. AB - BACKGROUND: Post-mortem needle biopsies have been used in resource-poor settings to determine cause of death and there is interest in using them in Bangladesh. However, we did not know how families and communities would perceive this procedure or how they would decide whether or not to consent to a post-mortem needle biopsy. The goal of this study was to better understand family and community concerns and decision-making about post-mortem needle biopsies in this low-income, predominantly Muslim country in order to design an informed consent process. METHODS: We conducted 16 group discussions with family members of persons who died during an outbreak of Nipah virus illness during 2004-2008 and 11 key informant interviews with their community and religious leaders. Qualitative researchers first described the post-mortem needle biopsy procedure and asked participants whether they would have agreed to this procedure during the outbreak. Researchers probed participants about the circumstances under which the procedure would be acceptable, if any, their concerns about the procedure, and how they would decide whether or not to consent to the procedure. RESULTS: Overall, most participants agreed that post-mortem needle biopsies would be acceptable in some situations, particularly if they benefitted society. This procedure was deemed more acceptable than full autopsy because it would not require major delays in burial or remove organs, and did not require cutting or stitching of the body. It could be performed before the ritual bathing of the body in either the community or hospital setting. However, before consent would be granted for such a procedure, the research team must gain the trust of the family and community which could be difficult. Although consent may only be provided by the guardians of the body, decisions about consent for the procedure would involve extended family and community and religious leaders. CONCLUSIONS: The possible acceptability of this procedure during outbreaks represents an important opportunity to better characterize cause of death in Bangladesh which could lead to improved public health interventions to prevent these deaths. Obstacles for research teams will include engaging all major stakeholders in decision-making and quickly building a trusting relationship with the family and community, which will be difficult given the short window of time prior to the ritual bathing of the body. PMID- 21668980 TI - A multicenter, retrospective chart review study comparing index therapy change rates in open-angle glaucoma or ocular hypertension patients newly treated with latanoprost or travoprost-Z monotherapy. AB - BACKGROUND: Because latanoprost and the original formulation of travoprost that included benzalkonium chloride (BAK) have been shown to be similar with regard to tolerability, we compared initial topical intraocular pressure (IOP)-lowering medication change rates in patients newly treated with latanoprost or travoprost Z monotherapy. METHODS: At 14 clinical practice sites, medical records were abstracted for patients with a diagnosis of open-angle glaucoma or ocular hypertension and who were >=40 years of age, had a baseline and at least one follow-up visit, and had no prior history of ocular prostaglandin use. Data regarding demographics, ocular/systemic medical histories, clinical variables, therapy initiations and reasons for changes, adverse events, and resource utilization were recorded from randomly chosen eligible charts. Primary outcomes were rates of and reasons for changing from the initial therapy within six months and across the full study period (1000 days). RESULTS: Data from 900 medical charts (latanoprost, 632; travoprost-Z, 268) were included. For both cohorts, average follow-up was >1 year. Cohorts were similar with regard to age (median ~67 years), gender distribution (>50% female), and diagnosis (~80% with open angle glaucoma). Within six months, rates of index therapy change for latanoprost versus travoprost-Z were 21.2% (134/632) and 28.7% (77/268), respectively (p = 0.0148); across the full study period, rates were 34.5% (218/632) and 45.2% (121/268), respectively (p = 0.0026). Among those who changed their index therapy, insufficient IOP control was the most commonly reported reason followed by adverse events; hyperemia was the most commonly reported adverse event at index therapy change. CONCLUSIONS: In this "real world" study of changes in therapy in patients prescribed initial monotherapy with latanoprost with BAK or travoprost-Z with SofZia, medication changes were common in both treatment groups but statistically significantly more frequent with travoprost-Z. PMID- 21668981 TI - Transcriptional regulatory programs underlying barley germination and regulatory functions of Gibberellin and abscisic acid. AB - BACKGROUND: Seed germination is a complex multi-stage developmental process, and mainly accomplished through concerted activities of many gene products and biological pathways that are often subjected to strict developmental regulation. Gibberellins (GA) and abscisic acid (ABA) are two key phytohormones regulating seed germination and seedling growth. However, transcriptional regulatory networks underlying seed germination and its associated biological pathways are largely unknown. RESULTS: The studies examined transcriptomes of barley representing six distinct and well characterized germination stages and revealed that the transcriptional regulatory program underlying barley germination was composed of early, late, and post-germination phases. Each phase was accompanied with transcriptional up-regulation of distinct biological pathways. Cell wall synthesis and regulatory components including transcription factors, signaling and post-translational modification components were specifically and transiently up-regulated in early germination phase while histone families and many metabolic pathways were up-regulated in late germination phase. Photosynthesis and seed reserve mobilization pathways were up-regulated in post-germination phase. However, stress related pathways and seed storage proteins were suppressed through the entire course of germination. A set of genes were transiently up regulated within three hours of imbibition, and might play roles in initiating biological pathways involved in seed germination. However, highly abundant transcripts in dry barley and Arabidopsis seeds were significantly conserved. Comparison with transcriptomes of barley aleurone in response to GA and ABA identified three sets of germination responsive genes that were regulated coordinately by GA, antagonistically by ABA, and coordinately by GA but antagonistically by ABA. Major CHO metabolism, cell wall degradation and protein degradation pathways were up-regulated by both GA and seed germination. Those genes and metabolic pathways are likely to be important parts of transcriptional regulatory networks underlying GA and ABA regulation of seed germination and seedling growth. CONCLUSIONS: The studies developed a model depicting transcriptional regulatory programs underlying barley germination and GA and ABA regulation of germination at gene, pathway and systems levels, and established a standard transcriptome reference for further integration with various -omics and biological data to illustrate biological networks underlying seed germination. The studies also generated a great amount of systems biological evidence for previously proposed hypotheses, and developed a number of new hypotheses on transcriptional regulation of seed germination for further experimental validation. PMID- 21668982 TI - Healthcare workers' and parents' perceptions of measures for improving adherence to hand-hygiene. AB - BACKGROUND: This study was conducted to evaluate perceptions of healthcare workers (HCW) and parents regarding hand-hygiene and effectiveness of measures for increasing hand-hygiene adherence, in a children's hospital in Italy. METHODS: A cross-sectional study was performed from 5 to 13 July 2010, using two self-administered anonymous questionnaires (one for HCWs and one for parents/caregivers). The questionnaires included information regarding individual perceptions associated with hand hygiene. RESULTS: We collected 139 questionnaires from HCWs and 236 questionnaires from parents. Alcohol-based handrub was reported to be available at the point of care by 95.0% of the HCWs and in the child's room by 97.0% of the parents. For both HCWs and parents, availability of alcohol-based handrub was perceived as the most useful action for improving adherence to hand hygiene (scores >= 6 on a 7-point Likert-type scale: 84.8% [CI95%78.0-90.1] for HCWs and 87.9% [CI95% 83.3-91.7] for parents). Parents' reminding HCWs to perform hand hygiene was perceived as the least useful action (scores >= 6: 48.9% [CI95% 40.5-57.3] for HCWs and 55.7% [CI95% 49.2-62.1] for parents). Factors that affected HCWs' perceptions of the effectiveness of actions for improving adherence to hand hygiene included years of practice, type of ward and previous formal training on hand hygiene. For parents, factors affecting perceptions included previous information on hand hygiene and previous hospitalizations for their child. CONCLUSIONS: Investigating HCWs' and parents' perceptions of measures for improving adherence can provide useful information for implementing actions for hand-hygiene promotion in children's hospitals. In this study, HCWs' and parents' perceptions were similar; alcohol-based hand-rub availability was perceived as the most useful tool, confirming its crucial role in multimodal interventions. Poor perception of inviting parents to remind HCWs to perform hand-hygiene has been previously observed, and deserves further investigation. Information and education activities were associated with more positive perceptions regarding various improvement measures. Though the relationship between perceptions and behaviours remains to be fully determined, HCWs should participate in formal training and families should be properly informed, not only to increase knowledge but also to improve perceptions on effectiveness of actions to be implemented. PMID- 21668983 TI - Mechanism of the mitogenic influence of hyperinsulinemia. AB - Either endogenous or exogenous hyperinsulinemia in the setting of insulin resistance promotes phosphorylation and activation of farnesyltransferase, a ubiquitous enzyme that farnesylates Ras protein. Increased availability of farnesylated Ras at the plasma membrane enhances mitogenic responsiveness of cells to various growth factors, thus contributing to progression of cancer and atherosclerosis. This effect is specific to insulin, but is not related to the type of insulin used. Stimulatory effect of hyperinsulinemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin. PMID- 21668984 TI - Is gynaecological surgical training a cause for concern?: a questionnaire survey of trainees and trainers. AB - BACKGROUND: Concerns have been raised as to whether the current postgraduate training programme for gynaecological surgery is being detrimentally affected by changes in working practices, in particular the European Working Time Directive (EWTD). The purpose of this study was to investigate the surgical activity of obstetrics and gynaecology trainees and to explore trainees' and trainers' opinions on the current barriers and potential solutions to surgical training. METHODS: Two questionnaire surveys were conducted, one to obstetrics and gynaecology trainees working within the West Midlands Deanery and a second to consultant gynaecologists in the West Midlands region. RESULTS: One hundred and four trainees (64.3%) and 66 consultant gynaecologists (55.0%) responded. Sixty six trainees (66.7%) reported attending up to one operating list per week. However, 28.1% reported attending up to one list every two weeks or less and 5 trainees stated that they had not attended a list at all over the preceding 8 weeks. Trainees working in a unit with less than 3999 deliveries attended significantly more theatre sessions compared to trainees in units with over 4000 deliveries (p = 0.007), as did senior trainees (p = 0.032) and trainees attached to consultants performing major gynaecological surgery (p = 0.022). In the previous 8 weeks, only 6 trainees reported performing a total abdominal hysterectomy independently, all were senior trainees (ST6 and above). In the trainers' survey, only two respondents (3.0%) agreed that the current program produces doctors competent in general gynaecological surgery by the end of training, compared to 48 (73.8%) respondents who disagreed. CONCLUSIONS: Trainees' concerns over a lack of surgical training appear to be justified. The main barriers to training are perceived to be a lack of team structure and a lack of theatre time. PMID- 21668985 TI - Renal cell carcinoma primary cultures maintain genomic and phenotypic profile of parental tumor tissues. AB - BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is characterized by recurrent copy number alterations (CNAs) and loss of heterozygosity (LOH), which may have potential diagnostic and prognostic applications. Here, we explored whether ccRCC primary cultures, established from surgical tumor specimens, maintain the DNA profile of parental tumor tissues allowing a more confident CNAs and LOH discrimination with respect to the original tissues. METHODS: We established a collection of 9 phenotypically well-characterized ccRCC primary cell cultures. Using the Affymetrix SNP array technology, we performed the genome-wide copy number (CN) profiling of both cultures and corresponding tumor tissues. Global concordance for each culture/tissue pair was assayed evaluating the correlations between whole-genome CN profiles and SNP allelic calls. CN analysis was performed using the two CNAG v3.0 and Partek software, and comparing results returned by two different algorithms (Hidden Markov Model and Genomic Segmentation). RESULTS: A very good overlap between the CNAs of each culture and corresponding tissue was observed. The finding, reinforced by high whole-genome CN correlations and SNP call concordances, provided evidence that each culture was derived from its corresponding tissue and maintained the genomic alterations of parental tumor. In addition, primary culture DNA profile remained stable for at least 3 weeks, till to third passage. These cultures showed a greater cell homogeneity and enrichment in tumor component than original tissues, thus enabling a better discrimination of CNAs and LOH. Especially for hemizygous deletions, primary cultures presented more evident CN losses, typically accompanied by LOH; differently, in original tissues the intensity of these deletions was weaken by normal cell contamination and LOH calls were missed. CONCLUSIONS: ccRCC primary cultures are a reliable in vitro model, well-reproducing original tumor genetics and phenotype, potentially useful for future functional approaches aimed to study genes or pathways involved in ccRCC etiopathogenesis and to identify novel clinical markers or therapeutic targets. Moreover, SNP array technology proved to be a powerful tool to better define the cell composition and homogeneity of RCC primary cultures. PMID- 21668986 TI - Identification of CRISPR and riboswitch related RNAs among novel noncoding RNAs of the euryarchaeon Pyrococcus abyssi. AB - BACKGROUND: Noncoding RNA (ncRNA) has been recognized as an important regulator of gene expression networks in Bacteria and Eucaryota. Little is known about ncRNA in thermococcal archaea except for the eukaryotic-like C/D and H/ACA modification guide RNAs. RESULTS: Using a combination of in silico and experimental approaches, we identified and characterized novel P. abyssi ncRNAs transcribed from 12 intergenic regions, ten of which are conserved throughout the Thermococcales. Several of them accumulate in the late-exponential phase of growth. Analysis of the genomic context and sequence conservation amongst related thermococcal species revealed two novel P. abyssi ncRNA families. The CRISPR family is comprised of crRNAs expressed from two of the four P. abyssi CRISPR cassettes. The 5'UTR derived family includes four conserved ncRNAs, two of which have features similar to known bacterial riboswitches. Several of the novel ncRNAs have sequence similarities to orphan OrfB transposase elements. Based on RNA secondary structure predictions and experimental results, we show that three of the twelve ncRNAs include Kink-turn RNA motifs, arguing for a biological role of these ncRNAs in the cell. Furthermore, our results show that several of the ncRNAs are subjected to processing events by enzymes that remain to be identified and characterized. CONCLUSIONS: This work proposes a revised annotation of CRISPR loci in P. abyssi and expands our knowledge of ncRNAs in the Thermococcales, thus providing a starting point for studies needed to elucidate their biological function. PMID- 21668987 TI - Patient throughput times and inflow patterns in Swedish emergency departments. A basis for ANSWER, A National SWedish Emergency Registry. AB - OBJECTIVE: Quality improvement initiatives in emergency medicine (EM) often suffer from a lack of benchmarking data on the quality of care. The objectives of this study were twofold: 1. To assess the feasibility of collecting benchmarking data from different Swedish emergency departments (EDs) and 2. To evaluate patient throughput times and inflow patterns. METHOD: We compared patient inflow patterns, total lengths of patient stay (LOS) and times to first physician at six Swedish university hospital EDs in 2009. Study data were retrieved from the hospitals' computerized information systems during single on-site visits to each participating hospital. RESULTS: All EDs provided throughput times and patient presentation data without significant problems. In all EDs, Monday was the busiest day and the fewest patients presented on Saturday. All EDs had a large increase in patient inflow before noon with a slow decline over the rest of the 24 h, and this peak and decline was especially pronounced in elderly patients. The average LOS was 4 h of which 2 h was spent waiting for the first physician. These throughput times showed a considerable diurnal variation in all EDs, with the longest times occurring 6-7 am and in the late afternoon. CONCLUSION: These results demonstrate the feasibility of collecting benchmarking data on quality of care targets within Swedish EM, and form the basis for ANSWER, A National SWedish Emergency Registry. PMID- 21668988 TI - Intervention for depression among palliative care patients and their families: A study protocol for evaluation of a training program for professional care staff. AB - BACKGROUND: Clinical depression is highly prevalent yet under-detected and under treated in palliative care settings and is associated with a number of adverse medical and psychological outcomes for patients and their family members. This article presents a study protocol to evaluate a training intervention for non physician palliative care staff to improve the recognition of depression and provide support for depressed patients and their family members. Details of the hypotheses and expected outcomes, study design, training program development and evaluation measures are described. METHODS AND DESIGN: A randomised controlled trial will be implemented across two palliative care services to evaluate the "Training program for professional carers to recognise and manage depression in palliative care settings". Pre-, post- and three-month follow-up data will be collected to assess: the impact of the training on the knowledge, attitudes, self efficacy and perceived barriers of palliative care staff when working with depression; referral rates for depression; and changes to staff practices. Quantitative and qualitative methods, in the form of self-report questionnaires and interviews with staff and family members, will be used to evaluate the effectiveness of the intervention. DISCUSSION: This study will determine the effectiveness of an intervention that aims to respond to the urgent need for innovative programs to target depression in the palliative care setting. The expected outcome of this study is the validation of an evidence-based training program to improve staff recognition and appropriate referrals for depression, as well as improve psychosocial support for depressed patients and their family members. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000183088. PMID- 21668990 TI - Estimating equations for biomarker based exposure estimation under non-steady state conditions. AB - Unrealistic steady-state assumptions are often used to estimate toxicant exposure rates from biomarkers. A biomarker may instead be modeled as a weighted sum of historical time-varying exposures. Estimating equations are derived for a zero inflated gamma distribution for daily exposures with a known exposure frequency. Simulation studies suggest that the estimating equations can provide accurate estimates of exposure magnitude at any reasonable sample size, and reasonable estimates of the exposure variance at larger sample sizes. PMID- 21668989 TI - Selective anticancer activity of a hexapeptide with sequence homology to a non kinase domain of Cyclin Dependent Kinase 4. AB - BACKGROUND: Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, CDK4 gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of CDK2 and CDK6; and overexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor. RESULTS: A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy. CONCLUSION: These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4. PMID- 21668991 TI - Biological monitoring of blood naphthalene levels as a marker of occupational exposure to PAHs among auto-mechanics and spray painters in Rawalpindi. AB - BACKGROUND: Routine exposure to chemical contaminants in workplace is a cause for concern over potential health risks to workers. In Pakistan, reports on occupational exposure and related health risks are almost non-existent, which reflects the scarce availability of survey data and criteria for determining whether an unsafe exposure has occurred. The current study was designed to evaluate blood naphthalene (NAPH) levels as an indicator of exposure to polycyclic aromatic hydrocarbons (PAHs) among automobile workshop mechanics (MCs) and car-spray painters (PNs). We further determined the relationship between blood NAPH levels and personal behavioural, job related parameters and various environmental factors that may further be associated with elevated risks of occupational exposures to PAHs. METHODS: Sixty blood samples (n = 20 for each group i.e. MC, PN and control group) were collected to compare their blood NAPH levels among exposed (MCs and PNs) and un-exposed (control) groups. Samples were analyzed using high pressure liquid chromatography (HPLC). Data regarding demographic aspects of the subjects and their socioeconomic features were collected using a questionnaire. Subjects were also asked to report environmental hygiene conditions of their occupational environment. RESULTS: We identified automobile work areas as potential sites for PAHs exposure, which was reflected by higher blood NAPH levels among MCs. Blood NAPH levels ranged from 53.7 to 1980.6 MUgL(-1) and 54.1 to 892.9 MUgL(-1) among MCs and PNs respectively. Comparison within each group showed that smoking enhanced exposure risks several fold and both active and passive smoking were among personal parameters that were significantly correlated with log-transformed blood NAPH levels. For exposed groups, work hours and work experience were job related parameters that showed strong associations with the increase in blood NAPH levels. Poor workplace hygiene and ventilation were recognized as most significant predictors related to differences among workplaces that may enhance the extent of exposure to chemical contaminants. CONCLUSIONS: It appeared that chemical exposure at the workplace may be influenced by multiple environmental factors, but poor workplace hygiene and duration of exposure (long work hours) were the most important factors. Smoking and negligence of workers regarding self protection were among some of the important personal behaviours than can be addressed with better training. There is also a need to improve workplaces hygiene and to rationalize work hours to minimize health risks. Since smoking was an important confounding factor that supplemented most of the actual occupational exposure, a study based on non smoker subjects is needed to separate out the effects of smoking and other confounding factors that may obscure measurements of actual extent of occupational exposure. PMID- 21668992 TI - FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. AB - BACKGROUND: Alterations towards a permissive stromal microenvironment provide important cues for tumor growth, invasion, and metastasis. In this study, Fibroblast activation protein (FAP), a serine protease selectively produced by tumor-associated fibroblasts in over 90% of epithelial tumors, was used as a platform for studying tumor-stromal interactions. We tested the hypothesis that FAP enzymatic activity locally modifies stromal ECM (extracellular matrix) components thus facilitating the formation of a permissive microenvironment promoting tumor invasion in human pancreatic cancer. METHODS: We generated a tetracycline-inducible FAP overexpressing fibroblastic cell line to synthesize an in vivo-like 3-dimensional (3D) matrix system which was utilized as a stromal landscape for studying matrix-induced cancer cell behaviors. A FAP-dependent topographical and compositional alteration of the ECM was characterized by measuring the relative orientation angles of fibronectin fibers and by Western blot analyses. The role of FAP in the matrix-induced permissive tumor behavior was assessed in Panc-1 cells in assorted matrices by time-lapse acquisition assays. Also, FAP+ matrix-induced regulatory molecules in cancer cells were determined by Western blot analyses. RESULTS: We observed that FAP remodels the ECM through modulating protein levels, as well as through increasing levels of fibronectin and collagen fiber organization. FAP-dependent architectural/compositional alterations of the ECM promote tumor invasion along characteristic parallel fiber orientations, as demonstrated by enhanced directionality and velocity of pancreatic cancer cells on FAP+ matrices. This phenotype can be reversed by inhibition of FAP enzymatic activity during matrix production resulting in the disorganization of the ECM and impeded tumor invasion. We also report that the FAP+ matrix-induced tumor invasion phenotype is beta1-integrin/FAK mediated. CONCLUSION: Cancer cell invasiveness can be affected by alterations in the tumor microenvironment. Disruption of FAP activity and beta1-integrins may abrogate the invasive capabilities of pancreatic and other tumors by disrupting the FAP-directed organization of stromal ECM and blocking beta1-integrin dependent cell-matrix interactions. This provides a novel preclinical rationale for therapeutics aimed at interfering with the architectural organization of tumor-associated ECM. Better understanding of the stromal influences that fuel progressive tumorigenic behaviors may allow the effective future use of targeted therapeutics aimed at disrupting specific tumor stromal interactions. PMID- 21668993 TI - An effective virus-based gene silencing method for functional genomics studies in common bean. AB - BACKGROUND: Common bean (Phaseolus vulgaris L.) is a crop of economic and nutritious importance in many parts of the world. The lack of genomic resources have impeded the advancement of common bean genomics and thereby crop improvement. Although concerted efforts from the "Phaseomics" consortium have resulted in the development of several genomic resources, functional studies have continued to lag due to the recalcitrance of this crop for genetic transformation. RESULTS: Here we describe the use of a bean pod mottle virus (BPMV)-based vector for silencing of endogenous genes in common bean as well as for protein expression. This BPMV-based vector was originally developed for use in soybean. It has been successfully employed for both protein expression and gene silencing in this species. We tested this vector for applications in common bean by targeting common bean genes encoding nodulin 22 and stearoyl-acyl carrier protein desaturase for silencing. Our results indicate that the BPMV vector can indeed be employed for reverse genetics studies of diverse biological processes in common bean. We also used the BPMV-based vector for expressing the green fluorescent protein (GFP) in common bean and demonstrate stable GFP expression in all common bean tissues where BPMV was detected. CONCLUSIONS: The availability of this vector is an important advance for the common bean research community not only because it provides a rapid means for functional studies in common bean, but also because it does so without generating genetically modified plants. Here we describe the detailed methodology and provide essential guidelines for the use of this vector for both gene silencing and protein expression in common bean. The entire VIGS procedure can be completed in 4-5 weeks. PMID- 21668994 TI - Endoscopic papillary large balloon dilation alone without sphincterotomy for the treatment of large common bile duct stones. AB - BACKGROUND: Lethal pancreatitis has been reported after treatment for common bile duct stones using small endoscopic papillary balloon dilation. METHODS: We retrospectively evaluated the safety and efficacy of using large balloon dilation alone without the use of sphincterotomy for the treatment of large common bile duct stones in Kaohsiung Veterans General Hospital. Success rate of stone clearance, procedure-related adverse events and incidents, frequency of mechanical lithotripsy use, and recurrent stones were recorded. RESULTS: A total of 247 patients were reviewed in the current study. The mean age of the patients was 71.2 years. Most of them had comorbidities. Mean stone size was 16.4 mm. Among the patients, 132 (53.4%) had an intact gallbladder and 121 (49%) had a juxtapapillary diverticulum. The mean size of dilating balloon used was 13.2 mm. The mean duration of the dilating procedure was 4.7 min. There were 39 (15.8%) patients required the help of mechanical lithotripsy while retrieving the stones. The final success rate of complete retrieval of stones was 92.7%. The rate of pancreatic duct enhancement was 26.7% (66/247). There were 3 (1.2%) adverse events and 6 (2.4%) intra-procedure bleeding incidents. All patients recovered completely after conservative and endoscopic treatment respectively, and no procedure-related mortality was noted. 172 patients had a follow-up duration of more than 6 months and among these, 25 patients had recurrent common bile duct stones. It was significantly correlated to the common bile duct size (p = 0.036) CONCLUSIONS: Endoscopic papillary large balloon dilation alone is simple, safe, and effective in dealing with large common bile duct stones in relatively aged and debilitated patients. PMID- 21668995 TI - Spontaneous expulsion from rectum: a rare presentation of intestinal lipomas. AB - Lipomas are rare, subserosal, usually solitary, pedunculated small lesions appearing mainly in the large intestine with a minimal malignancy potential. They usually run asymptomatic and become symptomatic when they become enlarged or complicated causing intestinal obstruction, perforation, intusucception or massive bleeding. In rare cases they can be self-detached and expulsed via the rectum as fleshy masses. This event mainly occurs in large, pendunculated lipomas which detach from their pedicle. The reason for this event remains in most of cases unclear although in some cases a predisposing factor does exist. Abdominal pain and obstructive ileus may be observed while in many cases bleeding occurs. The expulsed mass sets the diagnosis and in most of the cases all symptoms subside. Diagnosis is rarely established before surgery with the use of barium enema, computed tomography and colonoscopy which additionally provides measures of treatment and diagnosis. In atypical cases though, in cases where the malignancy can not be excluded or in complicated cases, surgery is recommended. Usually the resection of the affected intestinal part is adequate. If during surgery a lipoma is encountered simple lipomatectomy seems also to be adequate. PMID- 21668996 TI - c-Myc activates BRCA1 gene expression through distal promoter elements in breast cancer cells. AB - BACKGROUND: The BRCA1 gene plays an important role in the maintenance of genomic stability. BRCA1 inactivation contributes to breast cancer tumorigenesis. An increasing number of transcription factors have been shown to regulate BRCA1 expression. c-Myc can act as a transcriptional activator, regulating up to 15% of all genes in the human genome and results from a high throughput screen suggest that BRCA1 is one of its targets. In this report, we used cultured breast cancer cells to examine the mechanisms of transcriptional activation of BRCA1 by c-Myc. METHODS: c-Myc was depleted using c-Myc-specific siRNAs in cultured breast cancer cells. BRCA1 mRNA expression and BRCA1 protein expression were determined by quantitative RT-PCR and western blot, respectively and BRCA1 promoter activities were examined under these conditions. DNA sequence analysis was conducted to search for high similarity to E boxes in the BRCA1 promoter region. The association of c-Myc with the BRCA1 promoter in vivo was tested by a chromatin immunoprecipitation assay. We investigated the function of the c-Myc binding site in the BRCA1 promoter region by a promoter assay with nucleotide substitutions in the putative E boxes. BRCA1-dependent DNA repair activities were measured by a GFP-reporter assay. RESULTS: Depletion of c-Myc was found to be correlated with reduced expression levels of BRCA1 mRNA and BRCA1 protein. Depletion of c-Myc decreased BRCA1 promoter activity, while ectopically expressed c-Myc increased BRCA1 promoter activity. In the distal BRCA1 promoter, DNA sequence analysis revealed two tandem clusters with high similarity, and each cluster contained a possible c-Myc binding site. c-Myc bound to these regions in vivo. Nucleotide substitutions in the c-Myc binding sites in these regions abrogated c-Myc dependent promoter activation. Furthermore, breast cancer cells with reduced BRCA1 expression due to depletion of c-Myc exhibited impaired DNA repair activity. CONCLUSIONS: The distal BRCA1 promoter region is associated with c-Myc and contributes to BRCA1 gene activation. PMID- 21668997 TI - Reconstructing genome-wide regulatory network of E. coli using transcriptome data and predicted transcription factor activities. AB - BACKGROUND: Gene regulatory networks play essential roles in living organisms to control growth, keep internal metabolism running and respond to external environmental changes. Understanding the connections and the activity levels of regulators is important for the research of gene regulatory networks. While relevance score based algorithms that reconstruct gene regulatory networks from transcriptome data can infer genome-wide gene regulatory networks, they are unfortunately prone to false positive results. Transcription factor activities (TFAs) quantitatively reflect the ability of the transcription factor to regulate target genes. However, classic relevance score based gene regulatory network reconstruction algorithms use models do not include the TFA layer, thus missing a key regulatory element. RESULTS: This work integrates TFA prediction algorithms with relevance score based network reconstruction algorithms to reconstruct gene regulatory networks with improved accuracy over classic relevance score based algorithms. This method is called Gene expression and Transcription factor activity based Relevance Network (GTRNetwork). Different combinations of TFA prediction algorithms and relevance score functions have been applied to find the most efficient combination. When the integrated GTRNetwork method was applied to E. coli data, the reconstructed genome-wide gene regulatory network predicted 381 new regulatory links. This reconstructed gene regulatory network including the predicted new regulatory links show promising biological significances. Many of the new links are verified by known TF binding site information, and many other links can be verified from the literature and databases such as EcoCyc. The reconstructed gene regulatory network is applied to a recent transcriptome analysis of E. coli during isobutanol stress. In addition to the 16 significantly changed TFAs detected in the original paper, another 7 significantly changed TFAs have been detected by using our reconstructed network. CONCLUSIONS: The GTRNetwork algorithm introduces the hidden layer TFA into classic relevance score based gene regulatory network reconstruction processes. Integrating the TFA biological information with regulatory network reconstruction algorithms significantly improves both detection of new links and reduces that rate of false positives. The application of GTRNetwork on E. coli gene transcriptome data gives a set of potential regulatory links with promising biological significance for isobutanol stress and other conditions. PMID- 21668999 TI - Residual-QSAR. Implications for genotoxic carcinogenesis. AB - INTRODUCTION: Both main types of carcinogenesis, genotoxic and epigenetic, were examined in the context of non-congenericity and similarity, respectively, for the structure of ligand molecules, emphasizing the role of quantitative structure activity relationship ((Q)SAR) studies in accordance with OECD (Organization for Economic and Cooperation Development) regulations. The main purpose of this report involves electrophilic theory and the need for meaningful physicochemical parameters to describe genotoxicity by a general mechanism. RESIDUAL-QSAR METHOD: The double or looping multiple linear correlation was examined by comparing the direct and residual structural information against the observed activity. A self consistent equation of observed-computed activity was assumed to give maximum correlation efficiency for those situations in which the direct correlations gave non-significant statistical information. Alternatively, it was also suited to describe slow and apparently non-noticeable cancer phenomenology, with special application to non-congeneric molecules involved in genotoxic carcinogenesis. APPLICATION AND DISCUSSIONS: The QSAR principles were systematically applied to a given pool of molecules with genotoxic activity in rats to elucidate their carcinogenic mechanisms. Once defined, the endpoint associated with ligand-DNA interaction was used to select variables that retained the main Hansch physicochemical parameters of hydrophobicity, polarizability and stericity, computed by the custom PM3 semiempirical quantum method. The trial and test sets of working molecules were established by implementing the normal Gaussian principle of activities that applies when the applicability domain is not restrained to the congeneric compounds, as in the present study. The application of the residual, self-consistent QSAR method and the factor (or average) method yielded results characterized by extremely high and low correlations, respectively, with the latter resembling the direct activity to parameter QSARs. Nevertheless, such contrasted correlations were further incorporated into the advanced statistical minimum paths principle, which selects the minimum hierarchy from Euclidean distances between all considered QSAR models for all combinations and considered molecular sets (i.e., school and validation). This ultimately led to a mechanistic picture based on the identified alpha, beta and gamma paths connecting structural indicators (i.e., the causes) to the global endpoint, with all included causes. The molecular mechanism preserved the self-consistent feature of the residual QSAR, with each descriptor appearing twice in the course of one cycle of ligand-DNA interaction through inter-and intra-cellular stages. CONCLUSIONS: Both basal features of the residual-QSAR principle of self consistency and suitability for non-congeneric molecules make it appropriate for conceptually assessing the mechanistic description of genotoxic carcinogenesis. Additionally, it could be extended to enriched physicochemical structural indices by considering the molecular fragments or structural alerts (or other molecular residues), providing more detailed maps of chemical-biological interactions and pathways. PMID- 21668998 TI - Effect of a structurally modified human granulocyte colony stimulating factor, G CSFa, on leukopenia in mice and monkeys. AB - BACKGROUND: Granulocyte colony stimulating factor (G-CSF) regulates survival, proliferation, and differentiation of neutrophilic granulocyte precursors, Recombinant G-CSF has been used for the treatment of congenital and therapy induced neutropenia and stem cell mobilization. Due to its intrinsic instability, recombinant G-CSF needs to be excessively and/or frequently administered to patients in order to maintain a plasma concentration high enough to achieve therapeutic effects. Therefore, there is a need for the development of G-CSF derivatives that are more stable and active in vivo. METHODS: Using site-direct mutagenesis and recombinant DNA technology, a structurally modified derivative of human G-CSF termed G-CSFa was obtained. G-CSFa contains alanine 17 (instead of cysteine 17 as in wild-type G-CSF) as well as four additional amino acids including methionine, arginine, glycine, and serine at the amino-terminus. Purified recombinant G-CSFa was tested for its in vitro activity using cell-based assays and in vivo activity using both murine and primate animal models. RESULTS: In vitro studies demonstrated that G-CSFa, expressed in and purified from E. coli, induced a much higher proliferation rate than that of wild-type G-CSF at the same concentrations. In vivo studies showed that G-CSFa significantly increased the number of peripheral blood leukocytes in cesium-137 irradiated mice or monkeys with neutropenia after administration of cyclophosphamide. In addition, G-CSFa increased neutrophil counts to a higher level in monkeys with a concomitant slower declining rate than that of G-CSF, indicating a longer half life of G-CSFa. Bone marrow smear analysis also confirmed that G-CSFa was more potent than G-CSF in the induction of granulopoiesis in bone marrows of myelo suppressed monkeys. CONCLUSION: G-CSFa, a structurally modified form of G-CSF, is more potent in stimulating proliferation and differentiation of myeloid cells of the granulocytic lineage than the wild-type counterpart both in vitro and in vivo. G-CSFa can be explored for the development of a new generation of recombinant therapeutic drug for leukopenia. PMID- 21669000 TI - Differential effects of dietary canola and soybean oil intake on oxidative stress in stroke-prone spontaneously hypertensive rats. AB - BACKGROUND: Canola oil shortens the life span of stroke-prone spontaneously hypertensive (SHRSP) rats compared with rats fed soybean oil when given as the sole dietary lipid source. One possible mechanism leading to the damage and deterioration of organs due to canola oil ingestion is oxidative stress. This study investigated the effect of canola oil intake on oxidative stress in this animal model. METHOD: Male SHRSP rats, were fed a defatted control diet containing 10% wt/wt soybean oil or a defatted treatment diet containing 10% wt/wt canola oil, and given water containing 1% NaCl. Blood pressure was measured weekly. Blood was collected prior to beginning the diets and at the end of completion of the study for analysis of red blood cell (RBC) antioxidant enzymes, RBC and plasma malondialdehyde (MDA), plasma 8-isoprostane and plasma lipids. RESULTS: Canola oil ingestion significantly decreased the life span of SHRSP rats compared with soybean oil, 85.8 +/- 1.1 and 98.3 +/- 3.4 days, respectively. Systolic blood pressure increased over time with a significant difference between the diets at the 6th week of feeding. Canola oil ingestion significantly reduced RBC superoxide dismutase, glutathione peroxidase and catalase activities, total cholesterol and low-density lipoprotein cholesterol compared with soybean oil. There were no significant differences in RBC MDA concentration between canola oil fed and soybean oil fed rats. In contrast, plasma MDA and 8-isoprostane concentration was significantly lower in the canola oil group compared to the soybean oil group. CONCLUSION: In conclusion, canola oil ingestion shortens the life span of SHRSP rats and leads to changes in oxidative status, despite an improvement in the plasma lipids. PMID- 21669001 TI - Proteomic analysis of the carotenogenic yeast Xanthophyllomyces dendrorhous. AB - BACKGROUND: The yeast Xanthophyllomyces dendrorhous is used for the microbiological production of the antioxidant carotenoid astaxanthin. In this study, we established an optimal protocol for protein extraction and performed the first proteomic analysis of the strain ATCC 24230. Protein profiles before and during the induction of carotenogenesis were determined by two-dimensional polyacrylamide gel electrophoresis and proteins were identified by mass spectrometry. RESULTS: Among the approximately 600 observed protein spots, 131 non-redundant proteins were identified. Proteomic analyses allowed us to identify 50 differentially expressed proteins that fall into several classes with distinct expression patterns. These analyses demonstrated that enzymes related to acetyl CoA synthesis were more abundant prior to carotenogenesis. Later, redox- and stress-related proteins were up-regulated during the induction of carotenogenesis. For the carotenoid biosynthetic enzymes mevalonate kinase and phytoene/squalene synthase, we observed higher abundance during induction and/or accumulation of carotenoids. In addition, classical antioxidant enzymes, such as catalase, glutathione peroxidase and the cytosolic superoxide dismutases, were not identified. CONCLUSIONS: Our results provide an overview of potentially important carotenogenesis-related proteins, among which are proteins involved in carbohydrate and lipid biosynthetic pathways as well as several redox- and stress related proteins. In addition, these results might indicate that X. dendrorhous accumulates astaxanthin under aerobic conditions to scavenge the reactive oxygen species (ROS) generated during metabolism. PMID- 21669002 TI - Chromosome-wide mapping of DNA methylation patterns in normal and malignant prostate cells reveals pervasive methylation of gene-associated and conserved intergenic sequences. AB - BACKGROUND: DNA methylation has been linked to genome regulation and dysregulation in health and disease respectively, and methods for characterizing genomic DNA methylation patterns are rapidly emerging. We have developed/refined methods for enrichment of methylated genomic fragments using the methyl-binding domain of the human MBD2 protein (MBD2-MBD) followed by analysis with high density tiling microarrays. This MBD-chip approach was used to characterize DNA methylation patterns across all non-repetitive sequences of human chromosomes 21 and 22 at high-resolution in normal and malignant prostate cells. RESULTS: Examining this data using computational methods that were designed specifically for DNA methylation tiling array data revealed widespread methylation of both gene promoter and non-promoter regions in cancer and normal cells. In addition to identifying several novel cancer hypermethylated 5' gene upstream regions that mediated epigenetic gene silencing, we also found several hypermethylated 3' gene downstream, intragenic and intergenic regions. The hypermethylated intragenic regions were highly enriched for overlap with intron-exon boundaries, suggesting a possible role in regulation of alternative transcriptional start sites, exon usage and/or splicing. The hypermethylated intergenic regions showed significant enrichment for conservation across vertebrate species. A sampling of these newly identified promoter (ADAMTS1 and SCARF2 genes) and non-promoter (downstream or within DSCR9, C21orf57 and HLCS genes) hypermethylated regions were effective in distinguishing malignant from normal prostate tissues and/or cell lines. CONCLUSIONS: Comparison of chromosome-wide DNA methylation patterns in normal and malignant prostate cells revealed significant methylation of gene-proximal and conserved intergenic sequences. Such analyses can be easily extended for genome wide methylation analysis in health and disease. PMID- 21669003 TI - Discrimination of individuals in a general population at high-risk for alcoholic and non-alcoholic fatty liver disease based on liver stiffness: a cross section study. AB - BACKGROUND: Factors associated with liver stiffness (LS) are unknown and normal reference values for LS have not been established. Individuals at high risk for alcoholic (ALD) and non-alcoholic fatty (NAFLD) liver disease need to be non invasively discriminated during routine health checks. Factors related to LS measured using a FibroScan and normal reference values for LS are presented in this report. METHODS: We measured LS using a FibroScan in 416 consecutive individuals who presented for routine medical checks. We also investigated the relationship between LS and age, body mass index (BMI), liver function (LF), alcohol consumption, and fatty liver determined by ultrasonography. We identified individuals at high-risk for ALD and NAFLD as having a higher LS value than the normal upper limit detected in 171 healthy controls. RESULTS: The LS value for all individuals was 4.7 +/- 1.5 kPa (mean +/- SD) and LS significantly and positively correlated with BMI and LF test results. The LS was significantly higher among individuals with, than without fatty liver. Liver stiffness in the 171 healthy controls was 4.3 +/- 0.81 kPa and the upper limit of LS in the normal controls was 5.9 kPa. We found that 60 (14.3%) of 416 study participants had abnormal LS. The proportion of individuals whose LS values exceeded the normal upper limit was over five-fold higher among those with, than without fatty liver accompanied by abnormal LF test results. CONCLUSIONS: Liver stiffness could be used to non-invasively monitor the progression of chronic liver diseases and to discriminate individuals at high risk for ALD and NAFLD during routine health assessments. PMID- 21669004 TI - Community-based intervention to promote breast cancer awareness and screening: the Korean experience. AB - BACKGROUND: There are many differences in culture, community identity, community participation, and ownership between communities in Western and Asian countries; thus, it is difficult to adopt the results of community intervention studies from Western countries. In this study, we conducted a multicity, multicomponent community intervention trial to correct breast cancer myths and promote screening mammography for women living in an urban community in Korea. METHODS: A 6-month, 2-city community intervention trial was conducted. In the intervention city, 480 women were surveyed at baseline and 7 months later to evaluate the effects of the intervention program. Strategies implemented in the intervention city included community outreach and clinic and pharmacy-based in-reach strategies. RESULTS: This study showed a 20.4-percentage-point decrease in myths about the link between cancer and breast size, a 19.2-percentage-point decrease in myths concerning mammography costs, and a 14.1-percentage-point increase in intention to undergo screening mammography. We also saw a 23.4-percentage-point increase in the proportion of women at the action stage of the transtheoretical model in the intervention city. In the comparison city, smaller decreases and increases were observed. CONCLUSIONS: Our study showed the value of an intervention study aimed at reducing belief in breast cancer myths in an urban community in Korea. The invention also made women more likely to undergo mammography in future. PMID- 21669005 TI - Characterization of the transcripts of human cytomegalovirus UL144. AB - BACKGROUND: The genome of human cytomegalovirus (HCMV) has been studied extensively, particularly in the UL/b' region. In this study, transcripts of one of the UL/b' genes, UL144, were identified in 3 HCMV isolates obtained from urine samples of congenitally infected infants. METHODS: Northern blot hybridization, cDNA library screening, and RACE-PCR were used. RESULTS: We identified at least 4 differentially regulated 3'-coterminal transcripts of UL144 in infected cells of 1,300, 1,600, 1,700, and 3,500 nucleotides (nt). The 1600 nt transcript was the major form of UL144 mRNA. The largest transcript initiated from the region within the UL141 open reading frame (ORF) and included UL141, UL142, UL143, UL144, and UL145 ORFs. CONCLUSIONS: These findings reveal the complex nature of the transcription of the UL144 gene in clinical isolates. PMID- 21669006 TI - Estimation of type- and subtype-specific influenza vaccine effectiveness in Victoria, Australia using a test negative case control method, 2007-2008. AB - BACKGROUND: Antigenic variation of influenza virus necessitates annual reformulation of seasonal influenza vaccines, which contain two type A strains (H1N1 and H3N2) and one type B strain. We used a test negative case control design to estimate influenza vaccine effectiveness (VE) against influenza by type and subtype over two consecutive seasons in Victoria, Australia. METHODS: Patients presenting with influenza-like illness to general practitioners (GPs) in a sentinel surveillance network during 2007 and 2008 were tested for influenza. Cases tested positive for influenza by polymerase chain reaction and controls tested negative for influenza. Vaccination status was recorded by sentinel GPs. Vaccine effectiveness was calculated as [(1--adjusted odds ratio) * 100%]. RESULTS: There were 386 eligible study participants in 2007 of whom 50% were influenza positive and 19% were vaccinated. In 2008 there were 330 eligible study participants of whom 32% were influenza positive and 17% were vaccinated. Adjusted VE against A/H3N2 influenza in 2007 was 68% (95% CI, 32 to 85%) but VE against A/H1N1 (27%; 95% CI, -92 to 72%) and B (84%; 95% CI, -2 to 98%) were not statistically significant. In 2008, the adjusted VE estimate was positive against type B influenza (49%) but negative for A/H1N1 (-88%) and A/H3N2 (-66%); none was statistically significant. CONCLUSIONS: Type- and subtype-specific assessment of influenza VE is needed to identify variations that cannot be differentiated from a measure of VE against all influenza. Type- and subtype-specific influenza VE estimates in Victoria in 2007 and 2008 were generally consistent with strain circulation data. PMID- 21669007 TI - Patient safety education for undergraduate medical students: a systematic review. AB - BACKGROUND: To reduce harm caused by health care is a global priority. Medical students should be able to recognize unsafe conditions, systematically report errors and near misses, investigate and improve such systems with a thorough understanding of human fallibility, and disclose errors to patients. Incorporating the knowledge of how to do this into the medical student curriculum is an urgent necessity. This paper aims to systematically review the literature about patient safety education for undergraduate medical students in terms of its content, teaching strategies, faculty availability and resources provided so as to identify evidence on how to promote patient safety in the curriculum for medical schools. This paper includes a perspective from the faculty of a medical school, a major hospital and an Evidence Based Medicine Centre in Sichuan Province, China. METHODS: We searched MEDLINE, ERIC, Academic Source Premier(ASP), EMBASE and three Chinese Databases (Chinese Biomedical Literature Database, CBM; China National Knowledge Infrastructure, CNKI; Wangfang Data) from 1980 to Dec. 2009. The pre-specified form of inclusion and exclusion criteria were developed for literature screening. The quality of included studies was assessed using Darcy Reed and Gemma Flores-Mateo criteria. Two reviewers selected the studies, undertook quality assessment, and data extraction independently. Differing opinions were resolved by consensus or with help from the third person. RESULTS: This was a descriptive study of a total of seven studies that met the selection criteria. There were no relevant Chinese studies to be included. Only one study included patient safety education in the medical curriculum and the remaining studies integrated patient safety into clinical rotations or medical clerkships. Seven studies were of a pre and post study design, of which there was only one controlled study. There was considerable variation in relation to contents, teaching strategies, faculty knowledge and background in patient safety, other resources and outcome evaluation in these reports. The outcomes from including patient safety in the curriculum as measured by medical students' knowledge, skills, and attitudes varied between the studies. CONCLUSIONS: There are only a few relevant published studies on the inclusion of patient safety education into the undergraduate curriculum in medical schools either as a selective course, a lecture program, or by being integrated into the existing curriculum even in developed countries with advanced health and education systems. The integration of patient safety education into the existing curriculum in medical schools internationally, provides significant challenges. PMID- 21669008 TI - Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines. AB - BACKGROUND: Cancer stem cells (CSCs) are regarded as the cause of tumor formation and recurrence. The isolation and identification of CSCs could help to develop novel therapeutic strategies specifically targeting CSCs. METHODS: Human hepatoma cell lines were plated in stem cell conditioned culture system allowed for sphere forming. To evaluate the stemness characteristics of spheres, the self-renewal, proliferation, chemoresistance, tumorigenicity of the PLC/PRF/5 sphere-forming cells, and the expression levels of stem cell related proteins in the PLC/PRF/5 sphere-forming cells were assessed, comparing with the parental cells. The stem cell RT-PCR array was performed to further explore the biological properties of liver CSCs. RESULTS: The PLC/PRF/5, MHCC97H and HepG2 cells could form clonal nonadherent 3-D spheres and be serially passaged. The PLC/PRF/5 sphere-forming cells possessed a key criteria that define CSCs: persistent self-renewal, extensive proliferation, drug resistance, overexpression of liver CSCs related proteins (Oct3/4, OV6, EpCAM, CD133 and CD44). Even 500 sphere-forming cells were able to form tumors in NOD/SCID mice, and the tumor initiating capability was not decreased when spheres were passaged. Besides, downstream proteins DTX1 and Ep300 of the CSL (CBF1 in humans, Suppressor of hairless in Drosophila and LAG1 in C. elegans) -independent Notch signaling pathway were highly expressed in the spheres, and a gamma-secretase inhibitor MRK003 could significantly inhibit the sphere formation ability. CONCLUSIONS: Nonadherent tumor spheres from hepatoma cell lines cultured in stem cell conditioned medium possess liver CSC properties, and the CSL-independent Notch signaling pathway may play a role in liver CSCs. PMID- 21669009 TI - Ultrastructural changes of the intracellular surfactant pool in a rat model of lung transplantation-related events. AB - BACKGROUND: Ischemia/reperfusion (I/R) injury, involved in primary graft dysfunction following lung transplantation, leads to inactivation of intra alveolar surfactant which facilitates injury of the blood-air barrier. The alveolar epithelial type II cells (AE2 cells) synthesize, store and secrete surfactant; thus, an intracellular surfactant pool stored in lamellar bodies (Lb) can be distinguished from the intra-alveolar surfactant pool. The aim of this study was to investigate ultrastructural alterations of the intracellular surfactant pool in a model, mimicking transplantation-related procedures including flush perfusion, cold ischemia and reperfusion combined with mechanical ventilation. METHODS: Using design-based stereology at the light and electron microscopic level, number, surface area and mean volume of AE2 cells as well as number, size and total volume of Lb were determined in a group subjected to transplantation-related procedures including both I/R injury and mechanical ventilation (I/R group) and a control group. RESULTS: After I/R injury, the mean number of Lb per AE2 cell was significantly reduced compared to the control group, accompanied by a significant increase in the luminal surface area per AE2 cell in the I/R group. This increase in the luminal surface area correlated with the decrease in surface area of Lb per AE2. The number-weighted mean volume of Lb in the I/R group showed a tendency to increase. CONCLUSION: We suggest that in this animal model the reduction of the number of Lb per AE2 cell is most likely due to stimulated exocytosis of Lb into the alveolar space. The loss of Lb is partly compensated by an increased size of Lb thus maintaining total volume of Lb per AE2 cell and lung. This mechanism counteracts at least in part the inactivation of the intra-alveolar surfactant. PMID- 21669010 TI - High body mass index is not associated with atopy in schoolchildren living in rural and urban areas of Ghana. AB - BACKGROUND: Factors which determine the development of atopy and the observed rural-urban gradient in its prevalence are not fully understood. High body mass index (BMI) has been associated with asthma and potentially atopy in industrialized countries. In developing countries, the transition from rural to urban areas has been associated with lifestyle changes and an increased prevalence of high BMI; however, the effect of high BMI on atopy remains unknown in this population. We therefore investigated the association between high BMI and atopy among schoolchildren living in rural and urban areas of Ghana. METHODS: Data on skin prick testing, anthropometric, parasitological, demographic and lifestyle information for 1,482 schoolchildren aged 6-15 years was collected. Atopy was defined as sensitization to at least one tested allergen whilst the Centres for Disease Control and Prevention (CDC, Atlanta) growth reference charts were used in defining high BMI as BMI >= the 85th percentile. Logistic regression was performed to investigate the association between high BMI and atopy whilst adjusting for potential confounding factors. RESULTS: The following prevalences were observed for high BMI [Rural: 16%, Urban: 10.8%, p < 0.001] and atopy [Rural: 25.1%, Urban: 17.8%, p < 0.001]. High BMI was not associated with atopy; but an inverse association was observed between underweight and atopy [OR: 0.57, 95% CI: 0.33-0.99]. Significant associations were also observed with male sex [Rural: OR: 1.49, 95% CI: 1.06-2.08; Urban: OR: 1.90, 95% CI: 1.30-2.79], and in the urban site with older age [OR: 1.76, 95% CI: 1.00-3.07], family history of asthma [OR: 1.58, 95% CI: 1.01-2.47] and occupational status of parent [OR: 0.33, 95% CI: 0.12-0.93]; whilst co-infection with intestinal parasites [OR: 2.47, 95% CI: 1.01-6.04] was associated with atopy in the rural site. After multivariate adjustment, male sex, older age and family history of asthma remained significant. CONCLUSIONS: In Ghanaian schoolchildren, high BMI was not associated with atopy. Further studies are warranted to clarify the relationship between body weight and atopy in children subjected to rapid life-style changes associated with urbanization of their environments. PMID- 21669011 TI - Polymorphism of Plasmodium falciparum Na(+)/H(+) exchanger is indicative of a low in vitro quinine susceptibility in isolates from Viet Nam. AB - BACKGROUND: The Plasmodium falciparum NA+/H+ exchanger (pfnhe1, gene PF13_0019) has recently been proposed to influence quinine (QN) susceptibility. However, its contribution to QN resistance seems to vary geographically depending on the genetic background of the parasites. Here, the role of this gene was investigated in in vitro QN susceptibility of isolates from Viet Nam. METHOD: Ninety-eight isolates were obtained from three different regions of the Binh Phuoc and Dak Nong bordering Cambodia provinces during 2006-2008. Among these, 79 were identified as monoclonal infection and were genotyped at the microsatellite pfnhe1 ms4760 locus and in vitro QN sensitivity data were obtained for 51 isolates. Parasite growth was assessed in the field using the HRP2 immunodetection assay. RESULTS: Significant associations were found between polymorphisms at pfnhe1 microsatellite ms4760 and susceptibility to QN. Isolates with two or more DNNND exhibited much lower susceptibility to QN than those harbouring zero or one DNNND repeats (median IC(50) of 682 nM versus median IC(50) of 300 nM; p = 0.0146) while isolates with one NHNDNHNNDDD repeat presented significantly reduced QN susceptibility than those who had two (median IC(50) of 704 nM versus median IC(50) of 375 nM; p < 0.01). These QNR associated genotype features were mainly due to the over representation of profile 7 among isolates (76.5%). The majority of parasites had pfcrt76T and wild-type pfmdr1 (> 95%) thus preventing analysis of associations with these mutations. Interestingly, area with the highest median QN IC(50) showed also the highest percentage of isolates carrying the pfnhe1 haplotype 7. CONCLUSIONS: The haplotype 7 which is the typical Asian profile is likely well-adapted to high drug pressure in this area and may constitute a good genetic marker to evaluate the dissemination of QNR in this part of the world. PMID- 21669013 TI - Individual differences in pronoun reversal: evidence from two longitudinal case studies. AB - Pronoun reversal, the use of you for self-reference and I for an addressee, has often been associated with Autism Spectrum Disorder (ASD) and impaired language. However, recent case studies have shown the phenomenon also to occur in typically developing and even precocious talkers. This study examines longitudinal corpus data from two children, a typically developing girl, and a boy with Asperger's syndrome. Both were precocious talkers who reversed the majority of their personal pronouns for several months. A comparison of the children's behaviors revealed quantitative and qualitative differences in pronoun use: the girl showed 'semantic confusion', using second person pronouns for self-reference, whereas the boy showed a discourse-pragmatic deficit related to perspective-taking. The results suggest that there are multiple mechanisms underlying pronoun reversal and provide qualified support for both the Name/Person Hypothesis (Clark, 1978; Charney, 1980b) and the Plurifunctional Pronoun Hypothesis (Chiat, 1982). PMID- 21669014 TI - Genetic and environmental risk factors for sexual distress and its association with female sexual dysfunction. AB - BACKGROUND: The DSM-V Working Group is currently re-evaluating distress as a primary diagnostic criterion for female sexual dysfunction (FSD). Here, for the first time, we explored the epidemiology of sexual distress and its putative aetiological relationship to FSD by estimating the influence of genetic and environmental risk factors. METHOD: Questionnaire data on a representative sample of 930 British female twins using validated scales of FSD and sexual distress were subject to variance components analyses to quantify latent genetic and environmental factors influencing phenotypic variation and covariation. Multiple regression analyses were used to identify other potential risk factors of sexual distress. RESULTS: Of 319 women with any sexual problems, only 36.5% reported distress. Of women classified as functional, 16.5% felt sexual distress. Sexual distress had a heritability of 44% [95% confidence interval (CI) 0.33-0.54]. Bivariate analysis suggested that the majority (91% CI 86-99%) of the covariance between sexual distress and FSD was due to unique environmental effects common to both traits. Associations were found between sexual distress and other risk variables, including relationship dissatisfaction [odds ratio (OR) 1.6, p<0.001], anxiety sensitivity and obsessive-compulsive symptomatology (OR 1.2, p<0.01, for both). CONCLUSIONS: There seems to be a weak phenotypic and genetic basis for including sexual distress as a diagnostic indicator of FSD. Instead, the data indicate that unrelated psychological factors play an important role in sexual distress and tentatively suggest that sexual distress is less a consequence of FSD and more related to general anxiety among women. PMID- 21669012 TI - Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer. AB - BACKGROUND: Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific VEGF polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab. METHODS: Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. VEGF -2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of VEGF polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of VEGF -1498 C/T polymorphism between bevacizumab-and control group. RESULTS: In the bevacizumab-group median PFS and OS of patients carrying VEGF -1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). VEGF -1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of VEGF -1498 C/T allelic variants and PFS or OS was found. Interaction between VEGF -1498 C/T variants and treatment effect suggested that the relation of VEGF -1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome. CONCLUSIONS: These data suggest a possible role for VEGF -1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing. PMID- 21669015 TI - Psychological well-being (PWB): a natural life outlook? An Italian twin study on heritability of PWB in young adults. AB - BACKGROUND: To date, the genetic and environmental architecture of the dimensions of psychological well-being (PWB) remains unexplored. METHOD: PWB of 742 twins aged 23-24 years and enrolled in the Italian Twin Registry was assessed with the three-item version of Ryff's Scales of Psychological Well-Being (SPWB). These scales include items for evaluating the PWB dimensions of self-acceptance, positive relations with others, autonomy, environmental mastery, purpose in life, and personal growth. A twin design was used to obtain correlations in the PWB dimensions for monozygotic (MZ) and dizygotic (DZ) twins and to estimate the contribution of genetic and environmental factors to variation and covariation in the dimensions. RESULTS: Genetic factors explained moderate to substantial proportions of variance in the six SPWB dimensions, with heritability estimates between 37% and 64%. The estimates of genetic correlations were very high (range 0.77-0.99), indicating that genetic factors that influence the expression of the different dimensions of PWB may be shared to a large extent. Non-shared environmental correlations ranged from substantial to high, with the exception of the correlation between autonomy and the dimensions of purpose in life, self acceptance and personal growth. CONCLUSIONS: This study presents a twin analysis of PWB measured by the SPWB dimensions; it was found that both genes and non shared environment play a role in individual differences. The genetic and non shared environmental correlations between SPWB dimensions suggest that common underlying genetic and non-shared environmental factors influence the expression of the different facets of PWB. PMID- 21669016 TI - Effect of antioxidants on the clinical outcome of patients with nasal polyposis. AB - AIM: To investigate the therapeutic effects of antioxidants on the clinical and biochemical outcome of patients with nasal polyposis. METHODS: Thirty-four patients with nasal polyposis were divided into two groups receiving either intranasal steroid or intranasal steroid plus per-oral vitamins A, C and E and selenium. Paranasal sinus computed tomography, endoscopy, and polyp tissue and serum sampling were conducted pre- and post-therapy. Serum levels of malondialdehyde, superoxide dismutase, nitrite and myeloperoxidase and tissue levels of malondialdehyde and superoxide dismutase were measured. Group results were compared using the Mann-Whitney U test and Wilcoxon signed-rank test. RESULTS: Both groups had significantly lower tissue parameters, computed tomography scores and serum malondialdehyde levels, comparing pre- versus post treatment results. Post-treatment, the steroid plus antioxidant group had significantly lower tissue malondialdehyde levels and a greater fall in tissue and serum malondialdehyde, compared with the steroid group. CONCLUSION: Serum and tissue levels of malondialdehyde (an oxidative marker) were significantly decreased by adding antioxidants to standard therapy. This is the first report of the positive effects of adding antioxidants to steroid therapy for nasal polyposis. PMID- 21669017 TI - Pro12Ala polymorphism in human peroxisome proliferator activated receptor gamma is associated with hyperlipidaemia in obstructive sleep apnoea hypopnoea syndrome. AB - OBJECTIVE: Peroxisome proliferator activated receptor gamma is a ligand-dependent transcription factor with an important role in insulin resistance and obesity. We investigated the associations between the Pro12Ala polymorphism of this receptor, obstructive sleep apnoea hypopnoea syndrome and hyperlipidaemia risk factors, in a Chinese cohort. SUBJECTS AND METHODS: We recruited 420 obstructive sleep apnoea hypopnoea syndrome patients and 190 healthy controls. Genetic analysis was conducted by restriction fragment length polymorphism. The hyperlipidaemia risk in both the study and control groups was analysed. RESULTS: Comparison of genotype and allele frequencies revealed no significant differences between patients and controls (p > 0.05). In patients, there was no correlation between genotype and clinical parameters (p > 0.05), apart from a significant association between the Ala12 allele and hyperlipidaemia (odds ratio = 2.181; p = 0.017; 95 per cent confidence interval = 1.133-4.198). CONCLUSION: In this Chinese cohort, the Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma was not associated with obstructive sleep apnoea hypopnoea syndrome, but was associated with increased hyperlipidaemia risk. PMID- 21669018 TI - Surgical anatomy of the anterior supralabyrinthine air cell tract. AB - INTRODUCTION: In order to safely explore the medial wall of the attic, a working knowledge of the anatomy of the anterior supralabyrinthine air cell tract is required. AIM: To clarify the surgically relevant anatomical relationships that comprise the anterior supralabyrinthine air cell tract. MATERIALS AND METHODS: Surgical dissection of 10 fresh cadaveric temporal bones was undertaken, including measurement of distances between the key anterior supralabyrinthine anatomical landmarks. RESULTS: The following mean distances were calculated: the labyrinthine segment between the geniculate ganglion and the ampullated end of the superior semicircular canal, 2.33 mm (range 1.75-2.75); the tympanic segment between the anterior margin of the oval window niche and the geniculate ganglion, 3.58 mm (range 3.25-4); and from the tympanic segment adjacent to the anterior margin of the oval window niche to the labyrinthine segment adjacent to the superior semicircular canal, 3.48 mm (range 3-4.25). CONCLUSION: The key anatomical landmarks of the anterior supralabyrinthine air cell tract define a distinct triangular segment of bone, knowledge of which is helpful in surgical dissection. PMID- 21669019 TI - Coblation resection of paediatric laryngeal papilloma. AB - OBJECTIVE: To demonstrate the successful treatment of laryngeal papillomatosis in a 32-month-old girl, using coblation (radio-frequency ablation) resection. CASE REPORT: A 32-month-old girl was referred to the ENT out-patients clinic due to a hoarse cry and a very croaky voice since birth. Under general anaesthesia, fibre optic airway endoscopy revealed a large papillomatous lesion involving the anterior glottis, which was reported as a laryngeal papilloma on histological analysis. This was later excised using an Evac 70Xtra wand. The patient made an uneventful post-operative recovery, and there were no signs of recurrence on repeated airway endoscopies at three and 18 months. CONCLUSION: Coblation (radio frequency ablation) is a promising surgical technique for the treatment of paediatric laryngeal papillomatosis. The main advantages of this technique include limited damage to underlying tissues and a bloodless field. PMID- 21669020 TI - Congenital vallecular cyst in an infant: case report and review of 52 recent cases. AB - OBJECTIVES: Vallecular cyst is uncommon in infants. We treated a female infant with vallecular cyst, and curious magnetic resonance imaging findings. We also review 51 other cases of vallecular cyst in infants reported over the past 23 years. CASE REPORT: A three-month-old female infant presented with congenital inspiratory stridor and failure to thrive. Flexible laryngoscopy and ultrasonography revealed a cystic mass in the vallecula. Magnetic resonance imaging findings were initially curious because of artefacts from breathing and swallowing. Marsupialisation of the cyst was performed. Post-operatively, the patient was immediately free of symptoms. CONCLUSION: Magnetic resonance imaging presents various difficulties in infants, but has the best diagnostic effectiveness. We recommend the use of magnetic resonance imaging, flexible fibroscopy and ultrasonography to enable extensive examination of suspected vallecular cysts in infants. Marsupialisation has a recurrence rate of only one in 39 cases, and its safety and effectiveness are well balanced. Thus, prompt marsupialisation of vallecular cyst is the recommended surgical procedure. PMID- 21669021 TI - The ideals of group living homes for people with dementia: do they practice what they preach? PMID- 21669022 TI - Risk factors for PTSD after Typhoon Morakot among elderly people in Taiwanese aboriginal communities. AB - BACKGROUND: This study aimed to investigate the risk factors associated with post traumatic stress disorder (PTSD) symptoms in a mid- and old-age population who experienced Typhoon Morakot in Taiwan. METHODS: One hundred and twenty people, who were mostly Taiwanese aboriginal people aged 55 years and above, were invited to participate in this study. PTSD symptoms were assessed using the PTSD Symptom Scale (PSS-I). Information regarding demographic characteristics, relocation, personal injury, family death, property damage, and self-perceived health was collected. RESULTS: 29.2% of study participants presented significant PTSD symptomatology during the previous month. Development of PTSD symptomatology after the disaster was significantly associated with being female (OR 3.63, 95% CI = 1.11-11.88), experiencing relocation (OR 5.64, 95% CI = 1.60-19.88), and having poorer self-perceived health (OR 4.24, 95% CI = 1.53-11.78) after controlling for age, education, personal injury, family death, and property damage. Further, by adding depression into the analysis, we found the risk factors were being female (OR 4.66, 95% CI = 1.16-18.80), experiencing relocation (OR 27.91, 95% CI = 3.74-229.80), family death (OR 67.62, 95% CI = 2.85-1063.68), and poorer self-perceived health (OR 28.69, 95% CI = 4.52-182.06). CONCLUSION: Nearly 30% of the elderly people studied who experienced Typhoon Morakot developed significant PTSD symptomatology. The risk factors for PTSD symptoms were female gender, poorer self-perceived health, relocation, family death, and depression. The elderly people who were relocated by governmental programs were more likely to develop PTSD symptomatology after experiencing trauma. Resettlement and rehabilitation programs after a disaster need to be more concerned with their psychological effects on victims. PMID- 21669023 TI - Multilocus sequence types of invasive Corynebacterium diphtheriae isolated in the Rio de Janeiro urban area, Brazil. AB - Invasive infections caused by Corynebacterium diphtheriae in vaccinated and non vaccinated individuals have been reported increasingly. In this study we used multilocus sequence typing (MLST) to study genetic relationships between six invasive strains of this bacterium isolated solely in the urban area of Rio de Janeiro, Brazil, during a 10-year period. Of note, all the strains rendered negative results in PCR reactions for the tox gene, and four strains presented an atypical sucrose-fermenting ability. Five strains represented new sequence types. MLST results did not support the hypothesis that invasive (sucrose-positive) strains of C. diphtheriae are part of a single clonal complex. Instead, one of the main findings of the study was that such strains can be normally found in clonal complexes with strains related to non-invasive disease. Comparative analyses with C. diphtheriae isolated in different countries provided further information on the geographical circulation of some sequence types. PMID- 21669024 TI - Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: down-regulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment. AB - Munc18-1 and syntaxin-1 are crucial interacting molecules for synaptic membrane fusion and neurotransmitter release. Contrasting abnormalities of several proteins of the exocytotic machinery, including the formation of SNARE (synaptobrevin, SNAP-25 and syntaxin-1) complexes, have been reported in schizophrenia. This study quantified in the dorsolateral prefrontal cortex (PFC, Brodmann area 9) the immunocontent of munc18-1a/b isoforms, syntaxin-1A, other presynaptic proteins (synaptotagmin, synaptophysin), and SNARE complexes, as well as the effects of psychoactive drug exposure, in schizophrenia (SZ, n=24), non schizophrenia suicide (SD, n=13) and major depression (MD, n=15) subjects compared to matched controls (n=39). SZ was associated with normal expression of munc18-1a/b and increased syntaxin-1A (+44%). The presence of antipsychotic drugs reduced the basal content of munc18-1a isoform (-23%) and synaptobrevin (-32%), and modestly reduced that of up-regulated syntaxin-1A (-16%). Munc18-1a and syntaxin-1A protein expression correlated positively in controls but showed a markedly opposite pattern in SZ, regardless of antipsychotic treatment. Thus, the ratio of syntaxin-1A to munc18-1a showed a net increase in SZ (+53/114%). The SNARE complex (75 kDa) was found unaltered in antipsychotic-free and reduced ( 28%) in antipsychotic-treated SZ subjects. None of these abnormalities were observed in SD and MD subjects, unexposed or exposed to psychoactive drugs. The results reveal some exocytotic dysfunctions in SZ that are probably related to an imbalance of the interaction between munc18-1a and SNARE (mainly syntaxin-1A) complex. Moreover, antipsychotic drug treatment is associated with lower content of key proteins of the exocytotic machinery, which could result in a destabilization/impairment of neurosecretion. PMID- 21669026 TI - Approaches to intestinal failure in Crohn's disease. AB - Crohn's disease is one of the leading causes of intestinal failure. The term 'type 2' intestinal failure is used to describe the relatively rare type of intestinal failure that occurs in association with septic, metabolic and complex nutritional complications, typically following surgical resection and/or laparostomy for intra-abdominal sepsis. A multidisciplinary approach to the management of patients with type 2 intestinal failure is crucial, and it is helpful to approach patient care in a structured manner using the 'sepsis nutrition-anatomy-plan' algorithm: resolution of sepsis is required before adequate nutritional repletion can be achieved, and it is crucial to optimise nutritional status, and define intestinal anatomy before delineating a definitive medical or surgical plan. A structured approach to the management of patients with inflammatory bowel disease, who have developed type 2 intestinal failure, should reduce the likelihood of these patients developing 'type 3' intestinal failure, which is characterised by the need for long-term parenteral nutrition. However, Crohn's disease is still the commonest indication for home parenteral nutrition in the UK. PMID- 21669025 TI - Dopamine in the hippocampus is cleared by the norepinephrine transporter. AB - Abnormal dopaminergic neurotransmission in the hippocampus may be involved in certain aspects of cognitive dysfunction. In the hippocampus, there is little, if any, expression of dopamine transporters (DAT), indicating that the mechanism for dopamine clearance differs from that in the striatum. Here, by means of in-vivo microdialysis in freely moving rats, we tested the hypothesis that the norepinephrine transporter (NET) is involved in dopamine clearance in the hippocampus. We found that systemic administration of the selective NET inhibitor reboxetine (3 mg/kg) and the psychostimulants amphetamine (0.5 mg/kg) and cocaine (10 mg/kg) increased hippocampal dopamine efflux. Local administration of reboxetine (300 MUM) produced a large increase in hippocampal dopamine levels that could not be further enhanced by the addition of the NET/DAT inhibitor nomifensine (100 MUM). Administration of the specific DAT inhibitor GBR12909 at a concentration (1 mM) that robustly increased dopamine in the nucleus accumbens had a comparably smaller effect in the hippocampus. In line with a minor role of DAT in the hippocampus, we detected very little DAT in this area using ligand binding with radiolabelled RTI-55. Moreover, in contrast to raclopride (100 MUM), a dopamine D2-autoreceptor antagonist, local administration of the alpha2 adrenoceptor antagonist idazoxan (100 MUM) increased hippocampal dopamine. Taken together, our data demonstrate an interaction between dopamine and norepinephrine systems in the hippocampus. It is proposed that this interaction originates from a shared uptake mechanism at the NET level. PMID- 21669027 TI - Knowledge, attitudes and practices of private sector providers of tuberculosis care: a scoping review. AB - SETTING: The past decade has seen a significant increase in private sector provision of tuberculosis (TB)care. While patients often seek and select treatment from private providers at significant out-of-pocket expense,treatment outcomes remain largely unknown. OBJECTIVE: To investigate the knowledge, attitudes and practices of private sector TB care providers in high burden countries. METHODS: Medline, PubMed, Embase, International Pharmaceutical Abstracts and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched using Medical Subject Headings terms,Emtree terms and key words. Searches were limited to the English language and published between 1998 and week 2 of November 2009. Studies were included if they reported the knowledge, attitudes or practice behaviours of private health care providers working in one of 22 high-TB-burden countries. Each included study was critically assessed using a structured data extraction tool. Data extracted included the study setting, objective, design, sample, response rate, outcomes and limitations. RESULTS: The 34 studies that met review inclusion criteriaen compassed diverse study methods and designs.All categories of TB care providers lacked comprehensive knowledge of national treatment guidelines. Procedures for referral, treatment monitoring, record keeping and case holding were not systematically implemented.However, there was a high degree of willingness to collaborate with national TB programmes. CONCLUSION: Research using standardised data collection methods may assist in identifying gaps in knowledge and practice among all providers of TB care. Further studies in developing and evaluating needs-based interventions should be undertaken; systematic reviews of such studies may then assist in strategic decision making in public-private mix DOTS expansion. PMID- 21669028 TI - Attributable mortality of ventilator-associated pneumonia: a meta-analysis. AB - OBJECTIVE: To investigate whether ventilator-associated pneumonia (VAP) is a true cause of mortality in the intensive care unit setting. METHODS: We performed a meta-analysis of available data without time restrictions. A conservative random effects model was employed to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of 968 retrieved reports, 44 studies fulfilled our inclusion criteria. Presence, as opposed to absence, of VAP was associated with higher mortality in the ICU setting (OR 1.96, 95%CI 1.26-3.04). This result persisted when matched case-control studies (OR 1.73, 95%CI 1.23 2.45) or studies in which VAP was microbiologically confirmed in all patients (OR 2.20, 95%CI 1.01-4.81) were evaluated separately. VAP continued to be associated with higher mortality when the impact of immune suppression was controlled. VAP was not associated with higher mortality in the subgroup analysis of studies including patients who received appropriate initial antimicrobial treatment (OR 1.64, 95%CI 0.68-3.96). CONCLUSION: Presence, compared to absence, of VAP seems to be associated with higher mortality in critically ill patients. Appropriateness of initial antimicrobial treatment in such patients may moderate this association. PMID- 21669029 TI - Programmatic management of multidrug-resistant tuberculosis: models from three countries. AB - BACKGROUND: Although multidrug-resistant tuberculosis (MDR-TB) is a major global health problem, there is a gap in programmatic treatment implementation. METHODS: This study describes MDR-TB treatment models in three countries--Peru, Russia and Lesotho-- using qualitative data collected over a 13-year period. RESULTS: A program analysis is presented for each country focusing on baseline medical care, initial implementation and program evolution. A pattern analysis revealed six overarching themes common to all three programs: 1) importance of baseline assessments, 2) early identification of key collaborators, 3) identification of initial locus of care, 4) minimization of patient-incurred costs, 5) targeted interventions for vulnerable populations and 6) importance of technical assistance and funding. Site commonalities and differences in each of these areas were analyzed. CONCLUSIONS: It is recommended that all programs providing MDR-TB treatment address these six areas during program development and implementation. PMID- 21669030 TI - Interferon-gamma release assays and childhood tuberculosis: systematic review and meta-analysis. AB - BACKGROUND: Children infected with Mycobacterium tuberculosis have significant risk of developing tuberculosis(TB) and can therefore benefit from preventive therapy. OBJECTIVE: To assess the value of interferon-gamma release assays (IGRAs) and the tuberculin skin test (TST)in the diagnosis of TB infection and disease in children. METHODS: Thirty-three studies were included, assessing commercial IGRAs (QuantiFERON(r)-TB [QFT] andT-SPOT.(r)TB) and TST. Reference standards for infection were incident TB or TB exposure. Test performance for disease diagnosis was evaluated in studies assessing children with confirmed and/or clinically diagnosed TB,compared to children where TB was excluded. RESULTS: Two small studies measured incident TB in children tested with QFT and found weak positive predictive value. Association of test response with exposure categorized dichotomously or as a gradient-was similar for all tests. The sensitivity and specificity of all tests were similar in diagnosing the disease. Stratified analysis suggested lower sensitivity for all tests in young or human immuno deficiency virus infected children. CONCLUSIONS: Available data suggest that TST and IGRAs have similar accuracy for the detection of TB infection or the diagnosis of disease in children. Heterogeneous methodology limited the comparability of studies and the interpretation of results. A rigorous, standardized approach to evaluate TB diagnostic tests in children is needed. PMID- 21669031 TI - In situ cardiomyogenic differentiation of implanted bone marrow mononuclear cells by local delivery of transforming growth factor-beta1. AB - Bone marrow mononuclear cells (BMMNCs) can be used to treat patients with myocardial infarction, since BMMNCs can differentiate in vitro toward cardiomyogenic lineages when treated with transforming growth factor-beta1 (TGF beta1). However, the in vitro cardiomyogenic differentiation culture process is costly and laborious, and the patients should wait during the culture period. In this study, we hypothesize that BMMNCs implanted in cardiomyogenically undifferentiated state to myocardial infarction site would differentiate cardiomyogenically in situ when exogenous TGF-beta1 is delivered to the cell implantation site. Heparin-conjugated poly(lactic-co-glycolic acid) nanospheres (HCPNs) suspended in fibrin gel were used as a TGF-beta1 delivery system. BMMNCs were labeled with a green fluorescent dye (PKH67) and implanted into the infarction border zone of rat myocardium using fibrin gel containing HCPNs and TGF-beta1. BMMNC implantation using fibrin gel and HCPNs without TGF-beta1 served as a control. Four weeks after implantation, the expression of cardiomyogenic marker proteins by the implanted BMMNCs was dramatically greater in the TGF beta1 delivery group than in the control group. This method can significantly improve the stem cell therapy technology for myocardial regeneration, since it can remove in vitro cell culture step for cardiomyogenic differentiation prior to cell implantation. PMID- 21669032 TI - Improvement of the cold storage of isolated human hepatocytes. AB - Increasing amounts of human hepatocytes are needed for clinical applications and different fields of research, such as cell transplantation, bioartificial liver support, and pharmacological testing. This demand calls for adequate storage options for isolated human liver cells. As cryopreservation results in severe cryoinjury, short-term storage is currently performed at 2-8 degrees C in preservation solutions developed for the storage of solid organs. However, besides slowing down cell metabolism, cold also induces cell injury, which is, in many cell types, iron dependent and not counteracted by current storage solutions. In this study, we aimed to characterize storage injury to human hepatocytes and develop a customized solution for cold storage of these cells. Human hepatocytes were isolated from material obtained from partial liver resections, seeded in monolayer cultures, and, after a preculture period, stored in the cold in classical and new solutions followed by rewarming in cell culture medium. Human hepatocytes displayed cold-induced injury, resulting in >80% cell death (LDH release) after 1 week of cold storage in University of Wisconsin solution or cell culture medium and 3 h of rewarming. Cold-induced injury could be significantly reduced by the addition of the iron chelators deferoxamine and LK 614. Experiments with modified solutions based on the new organ preservation solution Custodiol-N showed that ion-rich variants were better than ion-poor variants, chloride-rich solutions better than chloride-poor solutions, potassium as main cation superior to sodium, and pH 7.0 superior to pH 7.4. LDH release after 2 weeks of cold storage in the thus optimized solution was below 20%, greatly improving cold storage of human hepatocytes. The results were confirmed by the assessment of hepatocellular mitochondrial membrane potential and functional parameters (resazurin reduction, glucagon-stimulated glucose liberation) and thus suggest the use of a customized hepatocyte storage solution for the cold storage of these cells. PMID- 21669033 TI - Establishment, characterization, and successful adaptive therapy against human tumors of NKG cell, a new human NK cell line. AB - Natural killer (NK) cells play important roles in adoptive cellular immunotherapy against certain human cancers. This study aims to establish a new human NK cell line and to study its role for adoptive cancer immunotherapy. Peripheral blood samples were collected from 54 patients to establish the NK cell line. A new human NK cell line, termed as NKG, was established from a Chinese male patient with rapidly progressive non-Hodgkin's lymphoma. NKG cells showed LGL morphology and were phenotypically identified as CD56(bright) NK cell with CD16(-), CD27( ), CD3(-), alphabetaTCR(-), gammadeltaTCR(-), CD4(-), CD8(-), CD19(-), CD161(-), CD45(+), CXCR4(+), CCR7(+), CXCR1(-), and CX3CR1(-). NKG cells showed high expression of adhesive molecules (CD2, CD58, CD11a, CD54, CD11b, CD11c), an array of activating receptors (NKp30, NKp44, NKp46, NKG2D, NKG2C), and cytolysis related receptors and molecules (TRAIL, FasL, granzyme B, perforin, IFN-gamma). The cytotoxicity of NKG cells against tumor cells was higher than that of the established NK cell lines NK-92, NKL, and YT. NKG cell cytotoxicity depended on the presence of NKG2D and NKp30. When irradiated with 8 Gy, NKG cells were still with high cytotoxicity and activity in vitro and with safety in vivo, but without proliferation. Further, the irradiated NKG cells exhibited strong cytotoxicity against human primary ovarian cancer cells in vitro, and against human ovarian cancer in a mouse xenograft model. The adoptive transfer of NKG cells significantly inhibited the ovarian tumor growth, decreased the mortality rate and prolonged the survival, even in cases of advanced diseases. A number of NKG cells were detected in the ovarian tumor tissues during cell therapy. In use of the new human NK cell line, NKG would a promising cellular candidate for adoptive immunotherapy of human cancer. PMID- 21669034 TI - Stem cells decreased neuronal cell death after hypoxic stress in primary fetal rat neurons in vitro. AB - To explore stem cell-mediated neuronal protection through extracellular signaling pathways by transplanted stem cells, we sought to identify potential candidate molecules responsible for neuronal protection using an in vitro coculture system. Primary fetal rat hippocampal neurons underwent hypoxia (<=1% oxygen) for 96 h nad then were returned to a normoxic condition. The study group then received rat umbilical cord matrix-derived stem cells, while the control group received fresh media only. The experimental group showed decreased neuronal apoptosis compared to the control group [44.5 +/- 1.6% vs. 71.0 +/- 4.2% (mean +/- SD, p = 0.0005) on day 5] and higher neuronal survival (4.9 +/- 1.2 cells/100* field vs. 2.2 +/- 0.3, p = 0.02 on day 5). Among 90 proteins evaluated using a protein array, stem cell coculture media showed increased protein secretion of TIMP-1 (5.61-fold), TIMP-2 (4.88), CNTF-Ralpha (3.42), activin A (2.20), fractalkine (2.04), CCR4 (2.02), and decreased secretion in MIP-2 (0.30-fold), AMPK alpha1 (0.43), TROY (0.48), and TIMP-3 (0.50). This study demonstrated that coculturing stem cells with primary neurons in vitro decreased neuronal cell death after hypoxia with significantly altered protein secretion. The results suggest that stem cells may offer neuronal protection through extracellular signaling. PMID- 21669035 TI - Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: engraftment is dependent on cell type and adhesion molecule expression. AB - Stem cell transplantation procedures using intraparenchymal injections cause tissue injury in addition to associated surgical risks. Intravenous cell administration give engraftment in parenchymal lesions although the method has low efficacy and specificity. In pathological conditions with inflammation, such as traumatic brain injury, there is a transient up-regulation of ICAM-1 and VCAM 1 which might provide environmental cues for migration of stem cells from blood to parenchyma. The aim of this study was to i) analyze the effect of intra arterial administration on cellular engraftment, ii) compare engraftment and side effects between three different stem cell systems, and iii) analyze gene expression in these three systems. We performed specific intra-arterial transplantations with human mesenchymal stem cells (hMSCs), human neural progenitor cells (hNPCs), and rat neural progenitor cells (rNPCs) in a rat model of traumatic brain injury. These results were compared to the intravenous route for each cell type, respectively. Analysis of engraftment and recipient characterization was performed by immunohistochemistry. We further characterized the different types of cells by microarray and RT-qPCR analysis. Specific intra arterial transplantations produced significantly higher engraftment compared to intravenous transplantation with hMSCs and rNPCs. No engraftment was detected after intra-arterial or intravenous administration of hNPCs. Characterization of integrin expression indicated that CD49dVCAM-1 and possibly ICAM-1 interactions through CD18 and CD11a, respectively, are important for engraftment after intravascular cell administration. No side effects, such as thromboembolic complications, were detected. When translating stem cell therapies to clinical practice, the route of transplantation and the properties of the cell lines (homing, diapedesis, and migration) become important. This study supports the use of selective intra-arterial transplantation for improving engraftment after traumatic brain injury. In addition, we conclude that careful analysis of cells intended for local, intra-arterial transplantation with respect to integrin expression is important. PMID- 21669036 TI - Myogenic properties of human mesenchymal stem cells derived from three different sources. AB - Mesenchymal stem cells (MSCs) of mammals have been isolated from many tissues and are characterized by their aptitude to differentiate into bone, cartilage, and fat. Differentiation into cells of other lineages like skeletal muscle, tendon/ligament, nervous tissue, and epithelium has been attained with MSCs derived from some tissues. Whether such abilities are shared by MSCs of all tissues is unknown. We therefore compared for three human donors the myogenic properties of MSCs from adipose tissue (AT), bone marrow (BM), and synovial membrane (SM). Our data show that human MSCs derived from the three tissues differ in phenotype, proliferation capacity, and differentiation potential. The division rate of AT-derived MSCs (AT-MSCs) was distinctly higher than that of MSCs from the other two tissue sources. In addition, clear donor-specific differences in the long-term maintenance of MSC proliferation ability were observed. Although similar in their in vitro fusogenic capacity with murine myoblasts, MSCs of the three sources contributed to a different extent to skeletal muscle regeneration in vivo. Transplanting human AT-, BM-, or SM-MSCs previously transduced with a lentiviral vector encoding beta-galactosidase into cardiotoxin-damaged tibialis anterior muscles (TAMs) of immunodeficient mice revealed that at 30 days after treatment the frequency of hybrid myofibers was highest in the TAMs treated with AT-MSCs. Our finding of human-specific beta spectrin and dystrophin in hybrid myofibers containing human nuclei argues for myogenic programming of MSCs in regenerating murine skeletal muscle. For the further development of MSC-based treatments of myopathies, AT-MSCs appear to be the best choice in view of their efficient contribution to myoregeneration, their high ex vivo expansion potential, and because their harvesting is less demanding than that of BM- or SM-MSCs. PMID- 21669037 TI - Tissue factor knockdown in porcine islets: an effective approach to suppressing the instant blood-mediated inflammatory reaction. AB - Tissue factor (TF) expression on islets has been shown to trigger instant blood mediated inflammatory reaction (IBMIR), leading to rapid islet loss in portal vein islet transplantation. This study investigated whether antisense RNA mediated TF gene knockdown in islets could suppress IBMIR as a strategy to overcome IBMIR. Neonatal porcine islet cell clusters (NICCs) were transfected with or without TF-specific antisense RNA or a nonspecific RNA by a lipid-based method. Expression of both TF gene and protein in NICCs was analyzed after transfection by real-time PCR, Western blot, and FACS, respectively. The impact of antisense RNA transfection on NICC viability and in vitro function was examined by FACS and insulin release test, respectively. The effect of TF knockdown in NICCs on IBMIR was assessed with an in vitro tubing loop assay using human blood. A significant reduction in TF gene and protein expression was achieved in TF antisense RNA but not control RNA transfected NICCs, which did not affect NICCs' viability or their insulin secreting capacity. Incubation of TF antisense RNA transfected with human blood resulted in a considerable reduction in blood clot formation, platelet consumption, and complement and coagulation activation compared to that observed in the loops containing human blood and untreated or control RNA transfected NICCs. Consistent with these findings, infiltrating neutrophils in the blood clots with entrapped TF antisense RNA transfected NICCs was also reduced substantially compared to that seen in the clots containing untreated or control RNA transfected NICCs. This study presents a nontoxic TF antisense RNA-mediated TF knockdown in porcine islets that leads to an effective suppression of IBMIR, suggesting a potentially new strategy to improve islet transplantation outcomes. PMID- 21669038 TI - Transcriptional profiling of the hematopoietic support of interleukin-stimulated human umbilical vein endothelial cells (HUVECs). AB - Endothelial cells can be successfully used to maintain or increase the number of hematopoietic stem cells in vitro. Previously we identified hematopoietic progenitor cell (HPC) expansion or survival benefit induced by IL-1beta-, IL-3-, and IL-6-stimulated human umbilical vein endothelial cell (HUVEC) supernatants. In order to identify molecular mechanisms that support hematopoiesis, we examined the time-dependent expression profiles of IL-1beta-, IL-3-, and IL-6-stimulated HUVECs via microarray. Here, we present 24 common upregulated elements and three common downregulated elements of IL-1beta- and IL-3-stimulated HUVECs, with these factors exhibiting great potential for the observed HPC expansion. Furthermore, metabolic pathway analysis resulted in the identification of nonproteinogenic factors such as prostaglandin E(2) (PGE(2)) and nitric oxide (NO) and determined their HPC expansion potential via delta, methylcellulose, and cobblestone assays. We confirmed PGE(2) and spermine as hematopoietic expansion factors. Furthermore, we identified several factors such as SSAT, extracellular matrix components, microRNA21, and a microvesicle-mediated cross-talk between the endothelium and HPCs that may play a crucial role in determining stem cell fate. Our results suggest that microarray in combination with functional annotations is a convenient method to identify novel factors with great impact on HPC proliferation and differentiation. PMID- 21669039 TI - Human adipose tissue as a source of cells with angiogenic potential. AB - Endothelial cells (ECs) are involved in the process of angiogenesis, the outgrowth of new vessels from preexisting blood vessels. If available in sufficiently large numbers, ECs could be used therapeutically to establish blood flow through in vitro engineered tissues and tissues suffering from severe ischemia. Adipose tissue (AT) is an easily available source of large number of autologous ECs. Here we describe the isolation, in vitro expansion, and characterization of human AT derived ECs (AT-ECs). AT-ECs proliferated rapidly through 15-20 population doublings. The cultured cells showed cobblestone morphology and expressed EC markers including CD31, CD144, eNOS, CD309, CD105, von Willebrand factor, CD146, CD54, and CD102. They bound Ulex europaeus agglutinin I lectin and took up DiI-Ac-LDL. The AT-ECs formed capillary-like tubes in Matrigel in vitro and formed functional blood vessels in Matrigel following subcutaneous injection into immunodeficient mice. In conclusion, AT-ECs reach clinically significant cell numbers after few population doublings and are easily accessible from autologous AT, which also contains mesenchymal stem cells/pericytes. Thus, AT yields two cell populations that may be used together in the treatment of tissue ischemia and in clinical applications of tissue engineering. PMID- 21669040 TI - Anti-inflammatory properties of exenatide in human pancreatic islets. AB - Exenatide is an analog of the incretin hormone glucagon-like peptide (GLP-1) that is used for the treatment of T2D for their metabolic effects. In addition to its insulinotropic effects, exenatide increases functional islet mass and improves their survival. Improved outcomes have been reported in recent clinical islet transplantation trials for the treatment of type 1 diabetes. The purpose of this study was to investigate whether exenatide has anti-inflammatory properties in human islets. Exenatide treatment improved islet function, significantly reduced content of inflammation-related molecules (tissue factor, IFN-gamma, IL-17, IL 1beta, and IL-2) and caspase 3 activation, whereas increased phosphorylation of ERK1/2, STAT3, and Akt in vitro. Immunostaining showed expression of GLP-1R in beta-cells but not in alpha-cells. IL-1beta colocalized with GLP-1R in beta cells. Induction of serine proteinase inhibitor 9 (PI-9) was detected after exposure of human islets to exenatide in vitro and after transplantation into immunodeficient mice. GLP-1 induced PI-9 expression in vitro but to a lower extent than exenatide. This effect was partially blocked by the antagonist exendin-9 in vitro. As assessed by immunostaining PI-9 is mostly expressed in beta-cells but not in alpha-cells. In conclusion, we describe anti-inflammatory and cytoprotective properties of exenatide in human islets. Exenatide-mediated PI 9 expression, the only known granzyme B inhibitor, unveils potential immunoregulatory properties. PMID- 21669041 TI - Docosahexaenoic acid promotes dopaminergic differentiation in induced pluripotent stem cells and inhibits teratoma formation in rats with Parkinson-like pathology. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic (DA) neurons in the midbrain. Induced pluripotent stem (iPS) cells have shown potential for differentiation and may become a resource of functional neurons for the treatment of PD. However, teratoma formation is a major concern for transplantation-based therapies. This study examined whether functional neurons could be efficiently generated from iPS cells using a five-step induction procedure combined with docosahexaenoic acid (DHA) treatment. We demonstrated that DHA, a ligand for the RXR/Nurr1 heterodimer, significantly activated expression of the Nurr1 gene and the Nurr1-related pathway in iPS cells. DHA treatment facilitated iPS differentiation into tyrosine hydroxylase (TH)-positive neurons in vitro and in vivo and functionally increased dopamine release in transplanted grafts in PD-like animals. Furthermore, DHA dramatically upregulated the endogenous expression levels of neuroprotective genes (Bcl-2, Bcl-xl, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor) and protected against 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced apoptosis in iPS-derived neuronal precursor cells. DHA-treated iPS cells significantly improved the behavior of 6 hydroxydopamine (6-OHDA)-treated PD-like rats compared to control or eicosapentaenoic acid-treated group. Importantly, the in vivo experiment suggests that DHA induces the differentiation of functional dopaminergic precursors and improves the abnormal behavior of 6-OHDA-treated PD-like rats by 4 months after transplantation. Furthermore, we found that DHA treatment in iPS cell-grafted rats significantly downregulated the mRNA expression of embryonic stem cell-specific genes (Oct-4 and c-Myc) in the graft and effectively blocked teratoma formation. Importantly, 3 Tesla-magnetic resonance imaging and ex vivo green fluorescence protein imaging revealed that no teratomas were present in transplanted grafts of DHA-treated iPS-derived DA neurons 4 months after implantation. Therefore, our data suggest that DHA plays a crucial role in iPS differentiation into functional DA neurons and that this approach could provide a novel therapeutic approach for PD treatment. PMID- 21669042 TI - Surface expression of HLA-G is involved in mediating immunomodulatory effects of placenta-derived multipotent cells (PDMCs) towards natural killer lymphocytes. AB - Interactions between maternal natural killer lymphocytes (NKs) and fetal tissues are important in mediating maternal-fetal tolerance. We therefore investigated the interactions of NKs to placenta-derived multipotent cells (PDMCs) isolated from the term human placenta. PDMCs have similar cell surface marker expression as bone marrow mesenchymal stem cells (BMMSCs) and additionally express human embryonic stem cell markers SSEA-4 and CD-9. Differentiation into the tri mesodermal lineages of osteoblastic, adipocytic, and chondrogenic phenotypes can be readily achieved under the appropriate conditions. We found that PDMCs are more resistant to NK-mediated lysis than the major histocompatibility complex (MHC) class-I null target cell K562, and can suppress NK secretion of interferon gamma (IFN-gamma). Moreover, as third-party cells, PDMCs suppressed the cytotoxic effects of cytokine-stimulated NKs on K562. Pretreatment of PDMCs with IFN-gamma, a proinflammatory cytokine, surprisingly enhanced such immunosuppressive effects. Cell-cell contact between NKs and PDMCs is required for suppressive effects, which are partially mediated by slight upregulation of the NK inhibitory receptor killer inhibitory receptor and downregulation of the activating receptor NKp30. Moreover, enhancement of PDMC suppressive effects is also mediated by IFN-gamma induced surface expression of HLA-G--an immunomodulatory nonclassical MHC class I molecule--on PDMCs, as seen by partial reversibility with HLA-G neutralizing antibodies. With its broad immunosuppressive properties, PDMCs may represent a potential cell source for therapeutic use. PMID- 21669043 TI - Secretory unit of islet transplant objects (SUITO) index can predict severity of hypoglycemic episodes in clinical islet cell transplantation. AB - One endpoint of clinical islet cell transplantation for type 1 diabetic patients is the elimination or reduction of hypoglycemia. We previously developed a simple tool to evaluate islet graft function: the secretory unit of islet transplant objects (SUITO) index. The aim of this study is to clarify the association between the SUITO index and hypoglycemic episodes. Data from 310 clinical evaluations of 11 islet recipients were included in this study. Fasting plasma C peptide and glucose levels were measured at every evaluation. The SUITO index was calculated according to the following formula: 1500 * C-peptide level (ng/ml)/[blood glucose level (mg/dl) - 63]. The number of hypoglycemic events (<3.8 mmol/L) and severe hypoglycemic events (<2.2 mmol/L or hypoglycemic unawareness) was assessed on the basis of interviews and self-monitoring of blood glucose (SMBG). Receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of the SUITO index for hypoglycemic events. Based on the ROC study, follow-up data after transplantations were divided into the following three groups: low-SUITO (SUITO index <10, n = 91), middle-SUITO (10 <=SUITO index <26, n = 83), high-SUITO (SUITO index <=26, n = 125). The frequency of total hypoglycemia in the high-SUITO group was significantly decreased when compared to the other groups (value with Kruskal Wallis test p < 0.001). The frequency of total severe hypoglycemia was significantly decreased in the low-SUITO group compared to pretransplant status and further decreased in the middle- and high-SUITO group. Spearman correlation coefficients were -0.663 (p < 0.001) between the number of total hypoglycemic events per one month and the SUITO index and -0.521 (p < 0.001) between that of severe events and the SUITO index. The SUITO index could predict the severity of hypoglycemic episodes in type 1 diabetic patients who received islet cell transplantations. PMID- 21669044 TI - Derivation of high-purity definitive endoderm from human parthenogenetic stem cells using an in vitro analog of the primitive streak. AB - Human parthenogenetic stem cells (hpSCs) are pluripotent stem cells with enormous potential as cell sources for cell-based therapies: hpSCs may have histocompatibilty advantages over human embryonic stem cells (hESCs) and derivation of hpSCs does not require viable blastocyst destruction. For translation of all pluripotent stem cell-based therapies, derivation of differentiated cell products that are not contaminated with undifferentiated cells is a major technical roadblock. We report here a novel method to derive high-purity definitive endoderm (DE) from hpSCs, based on reproducing features of the normal human embryonic microenvironment. The method mimics the developmental process of transition through a primitive streak, using a differentiation device that incorporates a three-dimensional extracellular matrix (ECM) combined with a porous membrane. Treatment of undifferentiated hpSCs above the membrane results an epithelial-to-mesenchymal transition (EMT); thus, responsive cells acquire the ability to migrate through the membrane into the ECM, where they differentiate into DE. Importantly, the resultant DE is highly purified, and is not contaminated by undifferentiated cells, as assessed by OCT4 expression using immunocytochemistry and flow cytometry. The functional properties of the DE are also preserved by the process: DE differentiated in the device can generate a highly enriched population of hepatocyte-like cells (HLCs) characterized by expression of hepatic lineage markers, indocyanine green clearance, glycogen storage, cytochrome P450 activity, and engraftment in the liver after transplantation into immunodeficient mice. The method is broadly applicable and we obtained purified DE using hESCs, as well as several hpSC lines. The novel method described here represents a significant step toward the efficient generation of high-purity cells derived from DE, including hepatocytes and pancreatic endocrine cells, for use in regenerative medicine and drug discovery, as well as a platform for studying cell fate specification and behavior during development. PMID- 21669045 TI - In vitro generation of pancreatic endocrine cells from human adult fibroblast like limbal stem cells. AB - Stem cells might provide unlimited supply of transplantable cells for beta-cell replacement therapy in diabetes. The human limbus is a highly specialized region hosting a well-recognized population of epithelial stem cells, which sustain the continuous renewal of the cornea, and the recently identified stromal fibroblast like stem cells (f-LSCs), with apparent broader plasticity. However, the lack of specific molecular markers for the identification of the multipotent limbal subpopulation has so far limited the investigation of their differentiation potential. In this study we show that the human limbus contains uncommitted cells that could be potentially harnessed for the treatment of diabetes. Fourteen limbal biopsies were obtained from patients undergoing surgery for ocular diseases not involving the conjunctiva or corneal surface. We identified a subpopulation of f-LSCs characterized by robust proliferative capacity, expressing several pluripotent stem cell markers and exhibiting self-renewal ability. We then demonstrated the potential of f-LSCs to differentiate in vitro into functional insulin-secreting cells by developing a four-step differentiation protocol that efficiently directed f-LSCs towards the pancreatic endocrine cell fate. The expression of specific endodermal, pancreatic, islet, and beta-cell markers, as well as functional properties of f-LSC-derived insulin-producing cells, were evaluated during differentiation. With our stage-specific approach, up to 77% of f-LSCs eventually differentiated into cells expressing insulin (also assessed as C-peptide) and exhibited phenotypic features of mature beta-cells, such as expression of critical transcription factors and presence of secretory granules. Although insulin content was about 160-fold lower than what observed in adult islets, differentiated cells processed ~98% of their proinsulin content, similar to mature beta-cells. Moreover, they responded in vitro in a regulated manner to multiple secretory stimuli, including glucose. In conclusion, f-LSCs represent a possible relevant source of autologous, transplantable, insulin producing cells that could be tested for the reversal of diabetes. PMID- 21669047 TI - Optimization of immunosuppressive therapy for spinal grafting of human spinal stem cells in a rat model of ALS. AB - Previous rodent studies employing monotherapy or combined immunosuppressive regimens have demonstrated a variable degree of spinal xenograft survival in several spinal neurodegenerative models including spinal ischemia, trauma, or amyotrophic lateral sclerosis (ALS). Accordingly, the characterization of optimal immunosuppressive protocols for the specific neurodegenerative model is critical to ensure reliable assessment of potential long-term therapeutic effects associated with cell replacement. In the present study we characterized the survival of human spinal stem cells when grafted into the lumbar spinal cords of a rodent model of ALS, SOD1 (G93A) male and female rats (60-67 days old). Four different immunosuppressive protocols were studied: i) FK506 (q12h); ii) FK506 (qd) + mycophenolate (PO; q12h, up to 7 days postop); iii) FK506 (qd) + mycophenolate (IP; q12h, up to 7 days postop); and iv) FK506 (qd) + mycophenolate (IP; qd, up to 7 days postop). Three weeks after cell grafting the number of surviving human cells was then systematically assessed. The highest density of grafted cells was seen in animals treated with FK506 (qd) and mycophenolate (IP; qd; an average 915 +/- 95 grafted cells per spinal cord section). The majority of hNUMA-positive cells colocalized with doublecortin (DCX) immunoreactivity. DCX-positive neurons showed extensive axodendritic sprouting toward surrounding host neurons. In addition, migrating grafted cells were identified up to 500 MUm from the graft. In animals treated with FK506 (q12h), FK506 (qd) + mycophenolate (PO; q12h) or FK506 (qd) + mycophenolate (IP; q12h), 11.8 +/- 3.4%, 61.2 +/- 7.8%, and 99.4 +/- 8.9% [expressed as percent of the FK506 (qd) and mycophenolate (IP; qd)] cell survival was seen, respectively. In contrast to animals treated with a combination of FK506 + mycophenolate, robust CD4/8 immunoreactivity was identified in the vicinity of the injection tract in animals treated with FK506 only. These data suggest that a combined, systemically delivered immunosuppression regimen including FK506 and mycophenolate can significantly improve survival of human spinal stem cells after intraspinal transplantation in SOD1 (G93A) rats. PMID- 21669046 TI - Growth ability and repopulation efficiency of transplanted hepatic stem cells, progenitor cells, and mature hepatocytes in retrorsine-treated rat livers. AB - Cell-based therapies as an alternative to liver transplantation have been anticipated for the treatment of potentially fatal liver diseases. Not only mature hepatocytes (MHs) but also hepatic stem/progenitor cells are considered as candidate cell sources. However, whether the stem/progenitor cells have an advantage to engraft and repopulate the recipient liver compared with MHs has not been comprehensively assessed. Therefore, we used Thy1(+) (oval) and CD44(+) (small hepatocytes) cells isolated from GalN-treated rat livers as hepatic stem and progenitor cells, respectively. Cells from dipeptidylpeptidase IV (DPPIV)(+) rat livers were transplanted into DPPIV(-) livers treated with retrorsine following partial hepatectomy. Both stem and progenitor cells could differentiate into hepatocytes in host livers. In addition, the growth of the progenitor cells was faster than that of MHs until days 14. However, their repopulation efficiency in the long term was very low, since the survival period of the progenitor cells was much shorter than that of MHs. Most foci derived from Thy1(+) cells disappeared within 2 months. Many cells expressed senescence-associated beta galactosidase in 33% of CD44-derived foci at day 60, whereas the expression was observed in 13% of MH-derived ones. The short life of the cells may be due to their cellular senescence. On the other hand, the incorporation of sinusoidal endothelial cells into foci and sinusoid formation, which might be correlated to hepatic maturation, was completed faster in MH-derived foci than in CD44-derived ones. The survival of donor cells may have a close relation to not only early integration into hepatic plates but also the differentiated state of the cells at the time of transplantation. PMID- 21669048 TI - Seeding of endothelial cells on the luminal surface of a sheet model of cold stored (at 4 degrees C) sheep carotid arteries. AB - Cold-stored arteries are biomaterials that potentially represent an abundant "off the-shelf" source of vascular grafts for use in vascular surgery. One of the keys to reestablishing the antithrombogenic endothelial cell (EC) lining of cold stored arterial grafts is to maximize the number of ECs that attach following seeding. In this study, the cold-stored sheep carotid artery is used as a substrate to determine the conditions that maximize EC adherence following seeding. The effect of serum concentration, duration of seeding incubation, seeding density, and period of cold storage on attachment of ECs following seeding of 4-week cold-stored sheep carotid arteries (n = 5 arteries), 8-week cold-stored sheep carotid arteries (n = 5 arteries), and 12-week cold-stored sheep carotid arteries (n = 5 arteries) was examined. Three experiments (serum concentration, time of incubation, and seeding density) were conducted to determine the conditions that maximized the number of cultured sheep carotid artery ECs that attached to cold-stored sheep carotid artery following seeding. A flat sheet model was used. Serum concentration (0%, 10%, 20%, and 30%) in the seeding suspension did not have a significant effect on overall EC adherence on 4 , 8-, and 12-week cold-stored arteries. Time of seeding incubation (30, 60, and 90 min) did not have a significant effect on overall EC adherence on 4-, 8-, and 12-week cold-stored arteries. Seeding density (500,000 cells/ml, 1,000,000 cells/ml, and 2,000,000 cells/ml) had a significant effect (p = 0.036) on overall EC adherence on 4-, 8-, and 12-week cold-stored arteries. The period of cold storage (4, 8, and 12 weeks) of the artery had a significant effect (p = 0.002, p < 0.0001, p < 0.0001 in serum, time, and seeding density experiments, respectively) on overall EC adherence following seeding. Pairwise comparisons of EC adherence revealed the following. In the serum experiment, EC adherence on 4 week cold-stored arteries was significantly greater than on 8-week cold-stored arteries (p = 0.003) and 12-week cold-stored arteries (p = 0.002). This effect was due largely to the significant difference between EC adherence on 4-week and 8-week cold-stored arteries (p = 0.0002) and between EC adherence on 4-week and 12-week cold-stored arteries (p = 0.0091) at 20% serum. In the time experiment, EC adherence on 4-week cold-stored arteries was significantly greater than on 12 week cold-stored arteries (p < 0.0001). In the seeding density experiment, EC adherence on 4-week cold-stored arteries was significantly greater than on 8 week cold-stored arteries (p < 0.0001) and 12-week cold-stored arteries (p < 0.0001). In the same experiment, EC adherence following seeding at a density of 1,000,000 cells/ml and 2,000,000 cells/ml was significantly greater (p = 0.03 and p = 0.02, respectively) than EC adherence following seeding at a density of 500,000 cells/ml. Thus, it was determined that 4-week cold-stored arteries were superior to 8- and 12-week cold-stored arteries in terms of the number of ECs that adhered. It was also determined that a seeding density of 1,000,000 or 2,000,000 cells/ml was superior to a seeding density of 500,000 cells/ml in terms of producing maximal EC attachment. The ideal conditions, from those examined, for maximizing EC attachment to cold-stored arteries were 4 weeks of cold storage, a serum concentration of 20%, a seeding density of 2,000,000 cells/ml, and a duration of incubation of 30-90 min. PMID- 21669049 TI - Transplantation of rat synapsin-EGFP-labeled embryonic neurons into the intact and ischemic CA1 hippocampal region: distribution, phenotype, and axodendritic sprouting. AB - A major limitation of neural transplantation studies is assessing the degree of host-graft interaction. In the present study, rat hippocampal/cortical embryonic neurons (E18) were infected with a lentivirus encoding enhanced green fluorescent protein (GFP) under control of the neuron-specific synapsin promoter, thus permitting robust identification of labeled neurons after in vivo grafting. Two weeks after transient forebrain ischemia or sham-surgery, GFP-expressing neurons were transplanted into CA1 hippocampal regions in immunosuppressed adult Wistar rats. The survival, distribution, phenotype, and axonal projections of GFP immunoreactive (IR) positive transplanted neurons were evaluated in the sham operated and ischemia- damaged CA1 hippocampal regions 4, 8, and 12 weeks after transplantation. In both experimental groups, we observed that the main phenotype of host-derived afferents projecting towards grafted GFP-IR neurons as well as transplant-derived GFP-IR efferents were glutamatergic in both animal groups. GFP axonal projections were seen in the nucleus accumbens, septal nuclei, and subiculum-known target areas of CA1 pyramidal neurons. Compared to sham operated animals, GFP-IR neurons grafted into the ischemia-damaged CA1 migrated more extensively throughout a larger volume of host tissue, particularly in the stratum radiatum. Moreover, enhanced axonal sprouting and neuronal plasticity of grafted cells were evident in the hippocampus, subiculum, septal nuclei, and nucleus accumbens of the ischemia-damaged rats. Our study suggests that the adult rat brain retains some capacity to direct newly sprouting axons of transplanted embryonic neurons to the correct targets and that this capacity is enhanced in previously ischemia-injured forebrain. PMID- 21669050 TI - Therapeutic effect of carboxymethylated and quanternized chitosan on insulin resistance in high-fat-diet-induced rats and 3T3-L1 adipocytes. AB - Owing to their distinct biochemical properties, chitosan and its derivatives have a great potential in a range of bioapplications. One such application is as a dietary antilipidemic supplement to be used in reducing obesity and to improve insulin resistance. The lipid-binding efficiency of chitosan and its derivatives, however, remains debatable. Accordingly, in this study we investigated the interaction of chitosan and its two derivatives, O-carboxymethyl chitosan (O CMCs) and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl]chitosan chloride (N-CQCs), with plasma leptin, glucose, insulin and total cholesterol in a diet induced insulin-resistant rat model, and further interaction with mRNA expression of adipocytokines and its related molecule PPAR-gamma. The experiments were performed using the RT-PCR technique in cultured 3T3-L1 adipocytes, in which the mRNA expression of leptin, adiponectin, resistin and PPAR-gamma was recorded in the absence and presence of chitosan, O-CMCs and N-CQCs. The experimental results proved that chitosan, O-CMCs and N-CQCs not only lowered the level of plasma leptin, glucose, insulin and total cholesterol in vivo, but down-regulated mRNA expression of leptin and resistin, and up-regulated mRNA expression of adiponectin and PPAR-gamma in vitro, to achieve the desired insulin resistance therapy. PMID- 21669051 TI - Cytogenetic abnormalities in myelodysplastic syndrome: an overview. AB - The myelodysplastic syndromes (MDS) are clonal disorders of haematopoietic stem cells characterized by ineffective haematopoiesis leading to blood cytopenias and by high incidence of progression to acute myeloid leukaemia (AML). These disorders generally arise de novo, but may also occur years after exposure to mutagenic chemotherapy. Clonal cytogenetic abnormalities are detected in about 30 50% de novo cases, whereas more than 80% of therapy-related forms harbour such markers. Although in the Western countries, MDS cases are mainly reported in the elderly population and rarely in the paediatric age group; this disease is increasingly seen in young adults in India. Cytogenetic study plays an important role in the diagnosis and is useful for prediction of individual prognosis using the international prognostic scoring system. Specific chromosomal abnormalities, such as -5/5q-, -7/7q-, and complex abnormalities, play an important role in the development of new therapeutic options and clinical management of MDS. In this review, we summarize the cytogenetic abnormalities in MDS from various parts of the world. PMID- 21669052 TI - Non-random chromosomal deletion clustering at 20q in Waldenstrom macroglobulinemia. AB - Chromosome change at 20q11-q12, including del(20q), is sometimes reported in plasma cell dyscrasia, but most cases are found during or after chemotherapy. It is therefore still uncertain whether del(20q) is a primary change or therapy related. We performed cytogenetic studies and fluorescent in situ hybridization (FISH) analysis using 20q12 and 20qter probes to ascertain the possible involvement of 20q in nine patients with Waldenstrom macroglobulinemia (WM). The FISH study demonstrated deletions of 20q12 and/or 20qter in four of nine patients (44%) with WM at diagnosis, and one of them had the del(20q) chromosome. Moreover, one patient had de novo appearance of the del(20q) chromosome with 20q12 deletion after chemotherapy, although this patient had neither the del(20q) chromosome nor 20q12 deletion at WM diagnosis. Based on the results of this study, we conclude that chromosomal breakage at 20q13 is a non-random genetic change which plays a role in the neoplastic process of WM. PMID- 21669053 TI - Change in expression pattern of TCR-CD3 complex in patients with multiple myeloma. AB - In haematological malignancy, cell-mediated immunity has been shown to be suppressed in advanced disease. This immune dysfunction may be due, in part, to altered expression of the T cell receptor (TCR)-CD3 complex. The distribution and clonality of the TCR Vbeta repertoire and the expression levels of CD3gamma, CD3delta, CD3epsilon, and CD3zeta genes in T cells from patients with multiple myeloma (MM) were investigated. Specific Vbeta subfamily primers, reverse transcription polymerase chain reaction, and the GeneScan(r) technique were used to analyse the expression of the TCR Vbeta subfamily and the clonality of Vbeta T cells in 11 patients with MM. Real-time reverse transcription polymerase chain reaction was used to detect the expression levels of CD3gamma, CD3delta, CD3epsilon, and CD3zeta genes in peripheral blood mononuclear cells from 19 patients with MM. The beta2-microglobulin gene was used as an endogenous reference. A total of 5-22 Vbeta subfamily T cells were detected in different patients (mean value of expressed Vbeta subfamilies was 12.55+/-6.11), whereas all 24 Vbeta genes were identified in all control samples. The most frequently expressed Vbeta subfamilies were Vbeta1 (100%), Vbeta2, Vbeta3, Vbeta9, Vbeta13, and Vbeta16 (81.8%), while the expression of Vbeta20 was undetectable in all MM samples. Oligoclonal expansion of one or more Vbeta subfamily of T cells was detected in all patients. Such expansions involved different MM stages, and the numbers of expanded clonal Vbeta subfamilies seemed higher in stage I/II groups than in stage III; however, there was no significant difference. Among MM samples, of the Vbeta subfamily members, Vbeta13, Vbeta1, and Vbeta21, were expanded most frequently. A significant decrease in the expression level of the CD3gamma gene was observed in MM samples; in contrast, a higher expression of CD3epsilon was found in the MM group than in the healthy group. The expression pattern of the four CD3 chains was epsilon>zeta>delta>gamma in peripheral blood mononuclear cells from MM, while a gamma>epsilon>zeta>delta expression pattern was found in healthy controls. In conclusions, the present study presents precise data on changes in the variability of Vbeta patterns and expression of TCR signal transduction molecules in MM patients compared to controls, which may be associated with immune dysfunction. This study contributes to a better understanding of the cellular immune features in MM patients. PMID- 21669054 TI - A retrospective study of leukemia epidemiology in Northern Tunisia. AB - A hospital-based epidemiological study of leukemia was carried out in the northern part of Tunisia during a 5-year period, from 1999 to 2003. Of 402 Tunisians diagnosed with leukemia, 344 (85.6%) had acute leukemia and 58 (14.4%) had chronic leukemia. Age-specific incidence rates for acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL) and chronic myeloid leukemia (CML) are described. The distribution of leukemia in the governorate of Nabeul was established. These results are useful for the organization and follow-up of medical care. PMID- 21669056 TI - Risk factors of septic shock in patients with hematologic malignancies and Pseudomonas infections. AB - Pseudomonas is a clinically significant and opportunist pathogen, usually associated in causing high mortality nosocomial infections. The aim of this study was to determine the risk factors associated with septic shock in patients diagnosed with hematologic malignancies and Pseudomonas infections. A total of 80 Pseudomonas isolates (77 Pseudomonas aeruginosa) were collected from 66 patients aged 2-64 years: 52 with acute leukemia (79%), 7 with lymphoma (10.5%), and 7 with other hematologic disorders (10.5%), between 2001 and 2009. The median age of the patients was 30 years. Isolates were collected mostly from bloodstreams (45%) and skin lesions (31.5%). The median time for microbiologic documentation was 8 days (range 0-35 days) from onset of neutropenia. At least 11 patients (16.6%) had recurrent (>=2) infections. The clinical symptoms observed were skin lesions (34%), diarrhea (20%), isolated fever (18%), and respiratory symptoms (14%). The isolates tested were found resistant to piperacillin/tazobactam (43%), ceftazidime (31%), imipenem-cilastatin (26%), ciprofloxacin (25%), and amikacin (26%). Septic shock occurred in 16.2% of episodes (13/80). Crude mortality due to septic shock occurred in 19.6% of patients (13/66). The median time for response to antibiotic therapy in the remaining 80.4% of patients (53/66) was 2.5 days. Univariate analysis revealed that factors associated with septic shock were: fever for >=3 days in patients on antibiotic therapy (P = 0.019), serum lactate >5 mmol (P = 0.05), hemoglobin level <50 g/l (P = 0.042), hypoproteinemia <50 g/l (P = 0.01), procalcitonin >10 ng/ml (P = 0.031), and hypophosphatemia (P = 0.001). Multivariate analysis revealed that hypophosphatemia (P = 0.018), hypoproteinemia (P = 0.028), and high serum lactate (P = 0.012) are significant factors, independently associated with increased risk of septic shock in patients with hematologic malignancies and Pseudomonas infections. PMID- 21669055 TI - Long-term results of placental blood allografting using reduced-intensity conditioning: multicenter experience in a developing country. AB - BACKGROUND: Placental blood (PLB) hematopoietic stem cell transplantation has recently been explored in an increasing number of patients; the best conditioning regimen has not been established. MATERIAL AND METHODS: In an eight-year period, 66 consecutive patients, both children and adults (40 males and 26 females), were grafted with allogeneic placental blood cells using a reduced-intensity conditioning regimen: 23 patients were grafted because of a non-malignant condition and 43 patients for a malignant disease. The median age was 7 years (range 5 months to 72 years). RESULTS: Median time to recover >0.5*10(9)/l granulocytes was 19 days, whereas median time to recover >20*10(9)/l platelets was 23 days. Thirty-eight individuals failed to engraft and they either recovered endogenous hematopoiesis or died. Patients have been followed for periods ranging from 0.5 to 66 months, median 9 months. The median overall post-transplant survival (OS) was 22 months and the 36-month OS was 32%; it was significantly better for individuals grafted with 6/6 matched cords (45%). The cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) and grade III-IV acute GVHD for the patients who engrafted were 33 and 10%, respectively. DISCUSSION: The low engraftment rate should be improved by selecting better cord blood units; additional studies are needed to define if non-myeloablative conditioning is preferable over conventional conditioning. PMID- 21669057 TI - Molecular diagnosis and prognosis with DNA microarrays. AB - Microarray analysis makes it possible to determine thousands of gene expression values simultaneously. Changes in gene expression, as a response to diseases, can be detected allowing a better understanding and differentiation of diseases at a molecular level. By comparing different kinds of tissue, for example healthy tissue and cancer tissue, the microarray analysis indicates induced gene activity, repressed gene activity or when there is no change in the gene activity level. Fundamental patterns in gene expression are extracted by several clustering and machine learning algorithms. Certain kinds of cancer can be divided into subtypes, with different clinical outcomes, by their specific gene expression patterns. This enables a better diagnosis and tailoring of individual patient treatments. PMID- 21669059 TI - The expression pattern of CD3 chain genes in fetal/maternal interface. AB - In order to investigate the features of T-cell immune status in human placenta, the expression levels of CD3-gamma, -delta, -epsilon and -zeta chain genes in placenta were analyzed by real-time PCR. Umbilical cord blood obtained at delivery from the full-term healthy babies was used as a control. The beta2 microglobulin gene was employed as an endogenous reference, and the evaluations of mRNA expression level of each CD3 gene were used by the 2(-DeltaC(t))*100% method. The expression level of CD3-gamma, -epsilon and -zeta genes (mean rank is 0.13, 0.34, and 0.49 respectively) from placenta were significantly lower than those from CB (P<0.0001). CD3-delta genes (mean rank is 5.71) expressed stronger from placenta than from CB (P = 0.0.895). Thus, the expression pattern of the four CD3 genes was presented as delta>zeta>epsilon> gamma from placenta and epsilon>gamma>zeta>delta from CB on the contrary. In conclusion, the present study characterized the expression pattern of CD3-gamma, -delta, -epsilon and zeta chain genes from placenta, which contributes to further understanding of the features of T-cell immune status in placenta. PMID- 21669058 TI - Role of hERG1 K(+) channels in leukemia cells as a positive regulator in SDF-1a induced proliferation. AB - Previous work from our laboratory has confirmed that human ether-a-go-go-related gene 1 (hERG1) K(+) channels are constitutively expressed in leukemia cells and enhanced cell proliferation. More importantly, it has shown that stromal cell derived factor-1a (SDF-1a) significantly increases hERG1 K(+) tail current and a specific hERG1 K(+) channels inhibitor significantly blocks SDF-1a-induced migration of leukemic cells. In this study, we investigated a possible regulatory effect of hERG1 K(+) channels upon SDF-1a-mediated cell proliferation as a mean to uncover new molecular events involved in bone marrow microenvironment and leukemogenesis. RT-PCR showed that SDF-1a enhanced hERG1 expression in a dose dependent manner. Cell proliferation assay illustrated that SDF-1a promoted cell proliferation in a dose-dependent manner, whereas this effect was impaired by E 4031. In addition, E-4031 inhibited SDF-1a-stimulated leukemic cell proliferation by inducing G(0)/G(1) arrest. Interestingly, E-4031 promoted SDF-1a-induced apoptosis in HL-60 and leukemic blasts, which markedly impaired the protection effect of SDF-1a in AML. Moreover, SDF-1a increased the expression of Wnt/beta catenin target genes, including beta-catenin, cyclin-D1, and c-myc; however, this manner was abolished by blockage with the hERG1 K(+) channels. Taken together, our results provide evidence of a novel mechanism involved in the proliferative effects of SDF-1a and highlight hERG1 K(+) channels as a therapeutic target for leukemia treatment and prevention. PMID- 21669060 TI - Incidence of anemia and effect of nutritional supplementation on women in rural and tribal populations of eastern and northeastern India. AB - Screening of women of child bearing age among the tribal and rural population of different north eastern and eastern states of India was performed. More than 50% of women in some areas were found to have anemia. As part of the study nutritional supplementation was given to a proportion of the anemic population, comparing the effects of Spirulina, a compound containing vitamins and micronutrients and an iron-folic acid-B12 supplement. Follow-up of the cases was done over a period of one year and the impact of supplementation and a comparison of the two compounds made. PMID- 21669061 TI - Incorporation of an internal control into the PCR assay published in "Development of an improved protocol for the isolation and detection of Enterobacter sakazakii (Cronobacter) from powdered infant formula," J. Food Prot. 73(6):1016-1022 (2010). PMID- 21669062 TI - Frequency and behavior of Salmonella and Escherichia coli on whole and sliced jalapeno and serrano peppers. AB - The frequencies of coliform bacteria (CB), thermotolerant coliforms (TC), Escherichia coli, and Salmonella were determined for jalapeno and serrano peppers. In addition, the behavior of four serotypes of Salmonella and three E. coli strains on whole and sliced jalapeno and serrano peppers as well as in blended sauce at 25 +/- 2 degrees C and 3 to 5 degrees C was investigated. Chili peppers were collected from markets in the city of Pachuca, Hidalgo, Mexico. CB, TC, E. coli, and Salmonella were detected on serrano peppers in 100, 90, 50, and 10 % of the samples, and on jalapeno peppers in 100, 86, 32, and 12 % of the samples. Concentrations of CB ranged from 3.8 to 7.9 log CFU per serrano sample and from 5.3 to 8.2 log CFU per jalapeno sample, whereas concentrations of TC and E. coli were between < 3 and 1,100 most probable number per serrano and jalapeno samples. On whole serrano and jalapeno peppers stored at 25 +/- 2 degrees C or 3 to 5 degrees C, no growth was observed for rifampin-resistant strains of Salmonella and E. coli. After 6 days at 25 +/- 2 degrees C, the tested Salmonella serotypes and E. coli strains had decreased from an initial inoculum level of 5 log CFU to 1 and 2.5 log on serrano and jalapeno peppers, respectively, and at 3 to 5 degrees C they decreased to approximately 1.8 and 1.2 log, respectively, on serrano and jalapeno. Both the Salmonella serotypes and E. coli grew on sliced chili peppers and in blended sauce; after 24 h at 25 +/- 2 degrees C, both bacteria types had grown to approximately 4 and 5 log CFU on pepper slices and in sauce, respectively. At 3 to 5 degrees C the bacterial growth was inhibited. PMID- 21669063 TI - Modeling the thermal inactivation kinetics of heat-resistant Salmonella Enteritidis and Oranienburg in 10 percent salted liquid egg yolk. AB - There is no suitable model for predicting thermal inactivation kinetics of Salmonella spp. for many types of liquid egg products, including salted liquid egg yolk, for use in updating U.S. Department of Agriculture (USDA) pasteurization guidelines. This is because, in part, of the variations in Salmonella strains and the changes in the processing of liquid egg products over the past 40 years. The objectives of the present study were to determine the thermal inactivation kinetics and to create a general thermal inactivation kinetics model that can be used for estimating log reductions of salmonellae in 10% salted liquid egg yolk for temperatures between 62.2 and 69 degrees C. This model can be used by processors to help ensure adequate pasteurization. This was accomplished by studying the inactivation kinetics of a three-strain composite of heat-resistant Salmonella serovars Enteritidis and Oranienburg, inoculated into commercially processed 10% salted liquid egg yolk. The survival curves were convex, with asymptotic D-values. From these curves, a general model was developed to predict log reductions for given times at specified temperatures. For example, at a temperature of 67.3 degrees C (153.1 degrees F) for 3.5 min, our model predicts a 5-log reduction would be obtained, whereas with the current USDA minimum required pasteurization regimen (63.33 degrees C [146 degrees F] for 3.5 min), our model predicts that a reduction of only 2.7 log would be obtained. The results of this study provide information that can be used by processors to aid in producing safe, pasteurized egg yolk products, and for satisfying USDA pasteurization performance standards and developing industry guidance. PMID- 21669064 TI - Antimicrobial effects of weak acids on the survival of Escherichia coli O157:H7 under anaerobic conditions. AB - Outbreaks of disease due to vegetative bacterial pathogens associated with acid foods (such as apple cider) have raised concerns about acidified vegetables and related products that have a similar pH (3.2 to 4.0). Escherichia coli O157:H7 and related strains of enterohemorrhagic E. coli (EHEC) have been identified as the most acid resistant vegetative pathogens in these products. Previous research has shown that the lack of dissolved oxygen in many hermetically sealed acid or acidified food products can enhance survival of EHEC compared with their survival under aerobic conditions. We compared the antimicrobial effects of several food acids (acetic, malic, lactic, fumaric, benzoic, and sorbic acids and sulfite) on a cocktail of EHEC strains under conditions representative of non-heat-processed acidified vegetables in hermetically sealed jars, holding the pH (3.2) and ionic strength (0.342) constant under anaerobic conditions. The overall antimicrobial effectiveness of weak acids used in this study was ranked, from most effective to least effective: sulfite > benzoic acid > sorbic acid > fumaric acid > L- and D lactic acid > acetic acid > malic acid. These rankings were based on the estimated protonated concentrations required to achieve a 5-log reduction in EHEC after 24 h of incubation at 30 degrees C. This study provides information that can be used to formulate safer acid and acidified food products and provides insights about the mode of action of weak acids against EHEC. PMID- 21669065 TI - Inactivation of Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes in orange and tomato juice using ohmic heating. AB - The effects of ohmic heating on reduction of Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes in orange and tomato juice were investigated. Orange and tomato juice inoculated with E. coli O157:H7, Salmonella Typhimurium, and L. monocytogenes were subjected to ohmic heating with selected parameters including electric field strength from 10 to 20 V/cm and treatment times from 0 to 540 s. The number of pathogens was reduced by increasing the electric field strength from 10 to 20 V/cm as well as increasing treatment time. The population of E. coli O157:H7 was reduced more than 5 log after 120, 210, and 540 s of treatment in orange juice with 20, 15, and 10 V/cm electric field strengths, respectively. In tomato juice, levels of E. coli O157:H7 were reduced more than 5 log after 90, 180, and 480 s with the same electric field strengths. Similar phenomena were observed for Salmonella Typhimurium and L. monocytogenes, but E. coli O157:H7 was the most resistant to ohmic heating treatment. These results show that ohmic heating is potentially useful for inactivation of E. coli O157:H7, Salmonella Typhimurium, and L. monocytogenes and that the effect of inactivation depends on applied electric field strength, treatment time, pathogen species, and type of juice. PMID- 21669066 TI - Molecular epidemiology and antimicrobial susceptibility of Campylobacter jejuni and Campylobacter coli isolates of poultry, swine, and cattle origin collected from slaughterhouses in Hungary. AB - Campylobacter spp. are the most common cause of bacterial enteritis in Hungary, and the aim of this study was to identify the distribution, genotypes, and antimicrobial susceptibility of Campylobacter species in the most important food producing animals at the time of slaughter during 2008 and 2009. Of 1,110 samples, 266 were identified as Campylobacter coli (23.9%) and 143 as C. jejuni (12.9%) by real-time PCR. Resistance to enrofloxacin-ciprofloxacin and nalidixic acid was significant, especially in C. jejuni (73.3%) and C. coli (77.2%) from broilers. Higher erythromycin (P = 0.043) and tetracycline (P = 1.865e-14) resistance rates were found among C. coli isolates (9.7 and 74.1%, respectively) than among C. jejuni isolates (3.1 and 36.6%, respectively). A total of 47 fla short variable region sequences were identified among 73 selected C. coli and C. jejuni isolates, with 35 fla types detected only once. At the nucleotide level, fla types A66 and A21 were the most common. Using the pulsed-field gel electrophoresis method, 66% of strains exhibited unique profiles after Sma I digestion. Forty-two isolates assigned to 18 Sma I clusters were further typed by Kpn I, and of these, 24 were assigned to 10 Kpn I clusters. For isolates in five Kpn I clusters, epidemiological links were observed. Stable C. jejuni and C. coli clones were detected, indicating that further studies involving broiler and human isolates need to be conducted to elucidate the importance of these stable clones in human infections. PMID- 21669067 TI - Naturally colonized beef cattle populations fed combinations of yeast culture and an ionophore in finishing diets containing dried distiller's grains with solubles had similar fecal shedding of Escherichia coli O157:H7. AB - Beef steers (n = 252) were used to evaluate the effects of dietary supplement on fecal shedding of Escherichia coli O157:H7. Seven pens of 9 steers (63 steers per treatment) were fed diets supplemented with or without yeast culture (YC) or monensin (MON) and their combination (YC * MON). YC and MON were offered at 2.8 g/kg and 33 mg/kg of dry matter intake, respectively. Environmental sponge samples (from each pen floor, feed bunk, and water trough) were collected on day 0. Rectal fecal grab samples were collected on days 0, 28, 56, 84, 110, and 125. Samples were collected and pooled by pen and analyzed for presumptive E. coli O157:H7 colonies, which were confirmed by a multiplex PCR assay and characterized by pulsed-field gel electrophoresis (PFGE) typing. On day 0, E. coli O157:H7 was detected in 7.0% of feed bunk samples and 14.3% of pen floor samples but in none of the water trough samples. The 71.4% prevalence of E. coli O157:H7 in fecal samples on day 0 decreased significantly (P < 0.05) over time. E. coli O157:H7 fecal shedding was not associated with dietary treatment (P > 0.05); however, in cattle fed YC and YC * MON fecal shedding was 0% by day 28. Eight Xba I PFGE subtypes were identified, and a predominant subtype and three closely related subtypes (differing by three or fewer bands) accounted for 78.7% of environmental and fecal isolates characterized. Results from this study indicate that feeding YC to cattle may numerically decrease but not eliminate fecal shedding of E. coli O157:H7 at the onset of treatment and that certain E. coli O157 subtypes found in the feedlot environment may persist in feedlot cattle. PMID- 21669068 TI - Important vectors for Listeria monocytogenes transmission at farm dairies manufacturing fresh sheep and goat cheese from raw milk. AB - The aim of this study was to determine the transmission routs of Listeria spp. in dairy farms manufacturing fresh cheese made from ovine and caprine raw milk and to evaluate the impact of Listeria monocytogenes mastitis on raw milk contamination. Overall, 5,799 samples, including 835 environmental samples, 230 milk and milk product samples, and 4,734 aseptic half-udder foremilk samples were collected from 53 dairy farms in the dairy intensive area of Lower Austria. Farms were selected for the study because raw milk was processed to cheese that was sold directly to consumers. A total of 153 samples were positive for Listeria spp., yielding an overall prevalence of 2.6%; L. monocytogenes was found in 0.9% of the samples. Bulk tank milk, cheese, and half-udder samples were negative for Listeria spp. Because none of the sheep and goats tested positive from udder samples, L. monocytogenes mastitis was excluded as a significant source of raw milk contamination. L. monocytogenes was detected at 30.2% of all inspected farms. Swab samples from working boots and fecal samples had a significantly higher overall prevalence (P < 0.001) of L. monocytogenes (15.7 and 13.0%, respectively) than did swab samples from the milk processing environment (7.9%). A significant correlation was found between the prevalence of L. monocytogenes in the animal and in the milk processing environment and the silage feeding practices. Isolation of L. monocytogenes was three to seven times more likely from farms where silage was fed to animals throughout the year than from farms where silage was not fed to the animals. PMID- 21669069 TI - Hygienic food handling behaviors: attempting to bridge the intention-behavior gap using aspects from temporal self-regulation theory. AB - An estimated 25% of the populations of both the United States and Australia suffer from foodborne illness every year, generally as a result of incorrect food handling practices. The aim of the current study was to determine through the application of the theory of planned behavior what motivates these behaviors and to supplement the model with two aspects of temporal self-regulation theory- behavioral prepotency and executive function--in an attempt to bridge the "intention-behavior gap." A prospective 1-week design was utilized to investigate the prediction of food hygiene using the theory of planned behavior with the additional variables of behavioral prepotency and executive function. One hundred forty-nine undergraduate psychology students completed two neurocognitive executive function tasks and a self-report questionnaire assessing theory of planned behavior variables, behavioral prepotency, and intentions to perform hygienic food handling behaviors. A week later, behavior was assessed via a follow-up self-report questionnaire. It was found that subjective norm and perceived behavioral control predicted intentions and intentions predicted behavior. However, behavioral prepotency was found to be the strongest predictor of behavior, over and above intentions, suggesting that food hygiene behavior is habitual. Neither executive function measure of self-regulation predicted any additional variance. These results provide support for the utility of the theory of planned behavior in this health domain, but the augmentation of the theory with two aspects of temporal self-regulation theory was only partially successful. PMID- 21669070 TI - Detection of Alicyclobacillus species in fruit juice using a random genomic DNA microarray chip. AB - This study describes a method using a DNA microarray chip to rapidly and simultaneously detect Alicyclobacillus species in orange juice based on the hybridization of genomic DNA with random probes. Three food spoilage bacteria were used in this study: Alicyclobacillus acidocaldarius, Alicyclobacillus acidoterrestris, and Alicyclobacillus cycloheptanicus. The three Alicyclobacillus species were adjusted to 2 * 10(3) CFU/ml and inoculated into pasteurized 100% pure orange juice. Cy5-dCTP labeling was used for reference signals, and Cy3-dCTP was labeled for target genomic DNA. The molar ratio of 1:1 of Cy3-dCTP and Cy5 dCTP was used. DNA microarray chips were fabricated using randomly fragmented DNA of Alicyclobacillus spp. and were hybridized with genomic DNA extracted from Bacillus spp. Genomic DNA extracted from Alicyclobacillus spp. showed a significantly higher hybridization rate compared with DNA of Bacillus spp., thereby distinguishing Alicyclobacillus spp. from Bacillus spp. The results showed that the microarray DNA chip containing randomly fragmented genomic DNA was specific and clearly identified specific food spoilage bacteria. This microarray system is a good tool for rapid and specific detection of thermophilic spoilage bacteria, mainly Alicyclobacillus spp., and is useful and applicable to the fruit juice industry. PMID- 21669071 TI - Design and validation of a novel multiplex real-time PCR assay for Vibrio pathogen detection. AB - Three species--Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus- account for the majority of vibrio infections in humans. Rapid and accurate identification of Vibrio species has been problematic because phenotypic characteristics are variable within species. Additionally, biochemical identification and confirmation require 2 or more days to complete. Rapid and sensitive molecular techniques for the detection of vibrio pathogens would be useful for the surveillance and management of outbreaks. To facilitate the identification of human-pathogenic species, we designed and validated a highly sensitive, specific, and robust multiplex real-time PCR assay to identify V. cholerae, V. parahaemolyticus, and V. vulnificus using a four-dye configuration in a convenient lyophilized format. Multiple Vibrio strains were sequenced to verify candidate target TaqMan sites. Several individual assays within the multiplex contain multiple primers or probes to ensure detection of polymorphic variants. V. cholerae, V. parahaemolyticus, and V. vulnificus were detected either individually or in mixtures at <=30 genomic copies. V. cholerae was specifically detected in the presence or absence of Vibrio mimicus. The Vibrio multiplex assay showed 100% specificity to all targets analyzed and no detection of nearest neighbor strains. Each assay exhibited 100% +/- 10% efficiency. Multiplex real-time PCR can simplify pathogen detection and reduce costs per test since three species can be analyzed in a single reaction tube. Rapid and accurate detection of pathogenic vibrios in shellfish or seawater samples will improve the microbiological safety of seafood for consumers. PMID- 21669072 TI - Multistate outbreak of Listeria monocytogenes associated with Mexican-style cheese made from pasteurized milk among pregnant, Hispanic women. AB - Listeriosis is a severe infection caused by Listeria monocytogenes. Since 2004, the Centers for Disease Control and Prevention has requested that listeriosis patients be interviewed using a standardized Listeria Initiative (LI) questionnaire. In January 2009, states and the Centers for Disease Control and Prevention began investigating a multistate outbreak of listeriosis among pregnant, Hispanic women. We defined a case as an illness occurring between October 2008 and March 2009 with an L. monocytogenes isolate indistinguishable from the outbreak strain by pulsed-field gel electrophoresis. We conducted a multistate case-control study using controls that were selected from L. monocytogenes illnesses in non-outbreak-related pregnant, Hispanic women that were reported to the LI during 2004 to 2008. Eight cases in five states were identified. Seven of these were pregnant, Hispanic females aged 21 to 43 years, and one was a 3-year-old Hispanic girl, who was excluded from the study. Seven (100%) cases but only 26 (60%) of 43 controls had consumed Mexican-style cheese in the month before illness (odds ratio, 5.89; 95% confidence interval, 1.07 to infinity; P = 0.04). Cultures of asadero cheese made from pasteurized milk collected at a manufacturing facility during routine sampling by the Michigan Department of Agriculture on 23 February 2009 yielded the outbreak strain, leading to a recall of cheeses produced in the plant. Recalled product was traced to stores where at least three of the women had purchased cheese. This investigation highlights the usefulness of routine product sampling for identifying contaminated foods, of pulsed-field gel electrophoresis analysis to detect multistate outbreaks, and of the LI for providing timely exposure information for case-control analyses. Recalls of contaminated cheeses likely prevented additional illnesses. PMID- 21669073 TI - Zearalenone removal in synthetic media and aqueous part of canned corn by montmorillonite K10 and pillared montmorillonite K10. AB - The capacities of montmorillonite K10 (K10), aluminum pillared K10 (Al-K10), and iron pillared K10 (Fe-K10) to eliminate zearalenone (ZEN) from synthetic media and the aqueous part of canned corn were studied. Original clay and pillared clays were characterized in terms of X-ray powder diffraction analysis and N(2) adsorption-desorption isotherms. The maximum amounts of adsorption of ZEN by K10, Al-K10, and Fe-K10 at 25 degrees C and pH 7 were 0.202, 1.305, and 1.028 mg/g and 0.264, 0.096, and 0.255 mg/g, calculated from Langmuir and Freundlich isotherms, respectively. The adsorption of ZEN was also studied as a function of adsorbent amount (1 to 30 mg), ZEN concentration (2 to 20 mg/liter), pH of solution (pH 4 to 10), and contact time. Pillared clays could be an excellent alternative for removing ZEN in contaminated food samples and are potentially low-cost adsorbents with a promising future as an alternative to more costly materials. PMID- 21669074 TI - Rapid recognition of irradiated dry-cured ham by on-line coupling of reversed phase liquid chromatography with gas chromatography and mass spectrometry. AB - The use of on-line coupling of reversed-phase liquid chromatography and gas chromatography (RPLC-GC) with the through oven transfer adsorption desorption (TOTAD) interface and mass spectrometry (MS) was proposed for testing different types of commercial Spanish dry-cured ham for irradiation treatment at various doses (0, 1.5, 2, and 4 kGy). The qualitative analysis of radiation-specific compounds (e.g., n-pentadecane, 1-hexadecene, 1,7-hexadecadiene, n-heptadecane, 8 heptadecene, and 2-dodecylcyclobutanone) can be simultaneously established in a single run with samples that have or have not been irradiated. The overall analysis, which takes less than 100 min, includes a rapid extraction step using a small amount of dichloromethane-methanol (1:1, vol/vol) and anhydrous sodium sulfate, the subsequent fractionation of the sample in the first dimension of the system (RPLC), the transfer of the target fraction to the second dimension, the GC separation, and the MS detection. The calculated limits of detection in ham were lower than 22 ng/g. Repeatability studies provided relative standard deviation values of 0.8 to 13.5%. PMID- 21669075 TI - Financial impact of a dioxin incident in the Dutch dairy chain. AB - The aim of this study was to quantify the financial consequences of a milk-dioxin crisis on the stages of the dairy chain involved. The milk dioxin contamination impact model was designed for this purpose and also was used to estimate the net costs of control measures limiting the impact. Results obtained based on the assumption of the worst-case scenario in which the entire daily production of each business unit from feed supplier to milk processor is contaminated suggested that the financial impact of one dioxin incident would be ?141.2 million. Another assumption was that the dioxin contamination started at one feed processing plant and was detected 2 weeks after initial contamination (the high-risk period), which would result in the involvement of 714 dairy farms, 26 milk processors, and 2,664 retailers. The stages of the chain that contributed most to the total net costs were the milk processor (76.9%) and the dairy farm (20.5%). If the high risk period were shorter, i.e., 3 days, the estimated total financial impact decreases to ?10.9 million. Thus, early detection of the contamination is crucial for decreasing the number of food businesses involved and lowering the total financial impact. The most influential inputs of the model were the sale price of milk at the processing stage, the daily amount of milk processed per processing plant, the farm-blocking period, and the daily amount of milk produced per farm. However, the effect of these inputs on the total financial impact was less than 10.0%. These results can be used to establish priorities in the application of control measures to limit the financial and public health impacts of a possible food safety incident. PMID- 21669076 TI - A survey of total hydrocyanic acid content in ready-to-eat cassava-based chips obtained in the Australian market in 2008. AB - Cassava (Manihot esculenta Crantz) is a widely consumed food in the tropics that naturally contains cyanogenic glycosides (cyanogens, mainly composed of linamarin, acetone cyanohydrin, and hydrocyanic acid). If cassava is not adequately processed to reduce the level of cyanogens prior to consumption, these compounds can lead to the formation of hydrocyanic acid in the gut. Exposure to hydrocyanic acid can cause symptoms ranging from vomiting and abdominal pain to coma and death. In 2008, a survey of ready-to-eat (RTE) cassava-based snack foods was undertaken to determine levels of cyanogens measured as total hydrocyanic acid. This survey was undertaken in response to the New South Wales Food Authority being alerted to the detection of elevated levels of cyanogens in an RTE cassava-based snack food. This survey took 374 samples of RTE cassava chips available in the Australian marketplace. Significant variation in the levels of total hydrocyanic acid were observed in the 317 samples testing positive for cyanogens, with levels ranging from 13 to 165 mg of HCN equivalents per kg (mean value, 64.2 mg of HCN eq/kg for positive samples). The results from this survey serve as a timely warning for manufacturers of RTE cassava chips and other cassava-based snack foods to ensure there is tight control over the levels of cyanogens in the cassava ingredient. Evidence from this survey contributed to an amendment to the Australia New Zealand Food Standards Code, which now prescribes a maximum level for hydrocyanic acid in RTE cassava chips of 10 mg of HCN eq/kg, which aligns with the Codex Alimentarius Commission international standard for edible cassava flour. PMID- 21669077 TI - Occurrence of Campylobacter spp. in poultry and poultry products for sale on the Polish retail market. AB - In 2007 and 2008, a monitoring study was carried out in Poland to examine the occurrence of thermotolerant Campylobacter spp. in raw and cooked chicken products available on the retail market. A total of 912 samples were tested: 443 samples of raw chicken meat, 146 samples of giblets, and 323 ready-to-eat poultry products (150 samples of spit-roasted chicken, 56 samples of smoked chicken, and 117 samples of pate and cold meats). A high level of contamination of raw chicken meat (51.7% of samples) and chicken giblets (47.3% of samples) was detected. However, thermotolerant Campylobacter spp. were found in only 1.2% of the ready to-eat poultry products. PMID- 21669078 TI - Influence of refrigerated storage time on efficacy of irradiation to reduce Salmonella on sliced Roma tomatoes. AB - Contamination of tomatoes with Salmonella is a recurring food safety concern. Irradiation is a nonthermal intervention that can inactivate pathogens on fresh and minimally processed produce. However, the influence of tomato processing protocols, including time in refrigerated storage and time between slicing and irradiation, has not been determined. Roma tomatoes were sliced and inoculated with a cocktail of Salmonella outbreak strains. The inoculated tomatoes were held in refrigerated storage for various times after inoculation to simulate the potential time delay between packaging and irradiation. Tomatoes were irradiated immediately (0 h) or after 24, 48, or 72 h in storage. The surviving populations were recovered and enumerated. Irradiation effectively reduced Salmonella at all times. The D(10)-values (the dose necessary for a 1-log reduction of the pathogen) were not significantly different at each storage time and ranged from 0.382 to 0.473 kGy. These results suggest that the time required for holding of processed Roma tomatoes or shipment to an off-site irradiation service provider will not alter the efficacy of irradiation in a commercial environment. PMID- 21669079 TI - Use of commercially available antimicrobial compounds for prevention of Listeria monocytogenes growth in ready-to-eat minced tuna and salmon roe during shelf life. AB - Listeria monocytogenes found in minced tuna and fish roe can cause listeriosis. These products are classified in category B according to the Codex Alimentarius Commission, i.e., ready-to-eat foods in which L. monocytogenes growth can occur. We investigated the effectiveness of nisin and other commercially available antimicrobial compounds (lysozyme, epsilon-polylysine, and chitosan) for prevention of L. monocytogenes growth during the expected shelf life of raw minced tuna and salmon roe products. Food samples inoculated with L. monocytogenes were incubated with each antimicrobial at 10 degrees C for 7 days or at 25 degrees C for 12 h. Nisaplin (an antimicrobial containing nisin) effectively inhibited L. monocytogenes growth in minced tuna at 500 ppm and in salmon roe at 250 ppm within their standard shelf lives. The effective concentration of each antimicrobial was determined: 2,000 ppm for ART FRESH 50/50 (containing lysozyme) and SAN KEEPER No. 381 (containing epsilon-polylysine) and 10,000 ppm for SAN KEEPER K-3 (containing chitosan). PMID- 21669080 TI - Application of heat in postcook meat chillers reduces Listeria. AB - Electrical air-blowing heaters were used to heat and dry out holding chillers used for postcook commercial processed meats in an attempt to control the presence of Listeria. A baseline study of the prevalence of Listeria in holding chillers in seven facilities was undertaken. Listeria was detected in four of the seven chillers, and swab samples showed Listeria prevalence ranging from 7 (7.8%) of 90 to 6 (20%) of 30, depending on the facility. Two of the facilities with established Listeria contamination (A and E) were chosen for further studies. The heating trials consisted of three individual heating interventions at each of the two facilities, with 2 weeks of postintervention sampling after each treatment. The initial Listeria prevalence in chiller A was 19 (10.6%) of 180, and treatment at 37 degrees C for 36 h reduced prevalence to 3 (1.7%) of 180. The initial Listeria prevalence in chiller E was 7 (7.8%) of 90, and treatment at 50 degrees C for 2 h reduced prevalence to 0 of 90. Both reductions were statistically significant at P < 0.01. The incorporation of these two simple chiller heating protocols into these facilities' good manufacturing practices has effectively reduced prevalence of Listeria in chillers. PMID- 21669081 TI - Reduction of aflatoxin B1 in stored peanuts (Arachis hypogaea L.) using Saccharomyces cerevisiae. AB - Aflatoxin B(1) is a toxigenic and carcinogenic compound produced by Aspergillus flavus and Aspergillus parasiticus. To inhibit aflatoxin contamination of peanuts, seeds of two peanut breeds, IAC Caiapo and IAC Runner 886, were inoculated with A. parasiticus (1.0 * 10(6) spores per ml) and the yeast Saccharomyces cerevisiae (3.2 * 10(7) cells per ml) and incubated at 25 degrees C for 7 and 15 days. Two experiments were conducted for each incubation period separately. The treatments were completely randomized, with three replications per treatment. Treatments included the two cultivars and three types of inoculation (pathogen alone, yeast and pathogen, and yeast 3 h before pathogen). Aflatoxin B(1) was quantified with a densitometer at 366 nm after thin layer chromatography. Aflatoxin B(1) contamination in peanuts was reduced after the addition of S. cerevisiae. The concentration of aflatoxin B(1) decreased by 74.4 and 55.9% after 7 and 15 days, respectively. The greatest aflatoxin reduction was observed when S. cerevisiae was inoculated 3 h before the pathogen in IAC Caiapo seeds and incubated for 7 days at 25 degrees C. The use of S. cerevisiae is a promising strategy for biological control of aflatoxin contamination in peanuts. PMID- 21669082 TI - Aqueous extracts of Tulbaghia violacea inhibit germination of Aspergillus flavus and Aspergillus parasiticus conidia. AB - Aspergillus flavus and Aspergillus parasiticus are important plant pathogens and causal agents of pre- and postharvest rots of corn, peanuts, and tree nuts. These fungal pathogens cause significant crop losses and produce aflatoxins, which contaminate many food products and contribute to liver cancer worldwide. Aqueous preparations of Tulbaghia violacea (wild garlic) were antifungal and at 10 mg/ml resulted in sustained growth inhibition of greater than 50% for both A. flavus and A. parasiticus. Light microscopy revealed that the plant extract inhibited conidial germination in a dose-dependent manner. When exposed to T. violacea extract concentrations of 10 mg/ml and above, A. parasiticus conidia began germinating earlier and germination was completed before that of A. flavus, indicating that A. parasiticus conidia were more resistant to the antifungal effects of T. violacea than were A. flavus conidia. At a subinhibitory extract dose of 15 mg/ml, hyphae of both fungal species exhibited increased granulation and vesicle formation, possibly due to increased reactivity between hyphal cellular components and T. violacea extract. These hyphal changes were not seen when hyphae were formed in the absence of the extract. Transmission electron microscopy revealed thickening of conidial cell walls in both fungal species when grown in the presence of the plant extract. Cell walls of A. flavus also became considerably thicker than those of A. parasiticus, indicating differential response to the extract. Aqueous preparations of T. violacea can be used as antifungal treatments for the control of A. flavus and A. parasiticus. Because the extract exhibited a more pronounced effect on A. flavus than on A. parasiticus, higher doses may be needed for control of A. parasiticus infections. PMID- 21669083 TI - Transmission of Salmonella between swine farms by the housefly (Musca domestica). AB - The domestic pig is an important source of human salmonellosis, and houseflies are potential mechanical vectors of foodborne Salmonella pathogens. In 2005, we recovered 144 Salmonella isolates from flies and swine stool samples from 11 farms in Taoyuan County and Hsin Chu County (northwestern Taiwan). A total of 71.5% of the isolates were resistant to at least three antibiotics. There were a total of 14 serotypes, and 8 of these serotypes were present in both flies and swine stool samples. Some multidrug-resistant Salmonella strains coming from different swine farms were found to have identical pulsed-field gel electrophoresis (PFGE). Among four common serotypes, we identified 18 PFGE patterns, 8 of which were present in flies and swine stools. The similarity in PFGE profiles between isolates from swine and flies in different farms indicate the potential of flies to serve as a vector for transmission. PMID- 21669084 TI - Prevalence and antimicrobial resistance of Listeria monocytogenes isolated in chicken slaughterhouses in Northern Greece. AB - This study was conducted to determine the prevalence and antimicrobial resistance of Listeria monocytogenes recovered from chicken carcasses in slaughterhouses in Northern Greece. A total of 100 poultry samples (300 carcasses) were examined for Listeria spp. The samples were neck skin taken from four different slaughterhouses in Northern Greece. Forty samples were also taken from the environment of the slaughterhouses. Identification of L. monocytogenes was carried out by PCR and fingerprinting of the isolates by random amplified polymorphic DNA. L. monocytogenes strains isolated from chicken carcasses and from the environment of the slaughterhouses were also examined for antibiotic resistance. Fifty-five isolates of L. monocytogenes were tested for susceptibility to 20 antibiotics using the disk diffusion method. Listeria spp. were present in 99 of the poultry samples tested (99%), and 38 yielded L monocytogenes (38%). L. monocytogenes was also isolated in 80% of samples from the environment of a certain slaughterhouse, while the other slaughterhouses were found to be contaminated only with Listeria spp. All isolates were resistant to nalidixic acid and oxolinic acid, the majority of them to clindamycin, and only a few to tetracycline and oxytetracycline, whereas they were found to be susceptible to all other antimicrobials. The results of this study demonstrate a high prevalence of L. monocytogenes contamination in chicken carcasses, and all isolates were found to be sensitive to the antimicrobials most commonly used to treat human listeriosis. PMID- 21669085 TI - Recordkeeping practices of beef grinding activities at retail establishments. AB - Ground beef has been implicated as a transmission vehicle in foodborne outbreaks of infection with pathogens such as Escherichia coli O157:H7 and Salmonella. During outbreak investigations, traceback of contaminated beef to the producing facility is often unsuccessful because of inadequate recordkeeping at retail establishments that grind beef products. We conducted a survey in three states participating in the Environmental Health Specialists Network to describe beef grinding and recordkeeping practices at retail establishments. In each establishment that maintained grinding logs, three randomly selected records were reviewed to determine whether important data elements for traceback investigations were recorded. One hundred twenty-five stores were surveyed, of which 60 (49%) kept grinding logs, including 54 (74%) of 73 chain stores and 6 (12%) of 51 independent stores. One hundred seventy-six grinding records from 61 stores were reviewed. Seventy-three percent of the records included the establishment code of the source beef, 72% included the grind date and time, and 59% included the lot number of the source beef. Seventy-five percent of records noted whether trimmings were included in grinds, and 57% documented cleanup activities. Only 39 (22%) records had all of these variables completed. Of stores that did not keep grinding logs, 40% were unaware of their purpose. To facilitate effective and efficient traceback investigations by regulatory agencies, retail establishments should maintain records more detailed and complete of all grinding activities. PMID- 21669086 TI - Prevalence and characterization of Salmonella serovars isolated from oysters served raw in restaurants. AB - To determine if Salmonella-contaminated oysters are reaching consumer tables, a survey of raw oysters served in eight Tucson restaurants was performed from October 2007 to September 2008. Salmonella spp. were isolated during 7 of the 8 months surveyed and were present in 1.2% of 2,281 oysters tested. This observed prevalence is lower than that seen in a previous study in which U.S. market oysters were purchased from producers at bays where oysters are harvested. To test whether the process of refrigerating oysters in restaurants for several days reduces Salmonella levels, oysters were artificially infected with Salmonella and kept at 4 degrees C for up to 13 days. Direct plate counts of oyster homogenate showed that Salmonella levels within oysters did not decrease during refrigeration. Six different serovars of Salmonella enterica were found in the restaurant oysters, indicating multiple incidences of Salmonella contamination of U.S. oyster stocks. Of the 28 contaminated oysters, 12 (43%) contained a strain of S. enterica serovar Newport that matched by pulsed-field gel electrophoresis a serovar Newport strain seen predominantly in the study of bay oysters performed in 2002. The repeated occurrence of this strain in oyster surveys is concerning, since the strain was resistant to seven antimicrobials tested and thus presents a possible health risk to consumers of raw oysters. PMID- 21669087 TI - Microarray analysis reveals the actual specificity of enrichment media used for food safety assessment. AB - Microbial diagnostic microarrays are tools for simultaneous detection and identification of microorganisms in food, clinical, and environmental samples. In comparison to classic methods, microarray-based systems have the potential for high throughput, parallelism, and miniaturization. High specificity and high sensitivity of detection have been demonstrated. A microbial diagnostic microarray for the detection of the most relevant bacterial food- and waterborne pathogens and indicator organisms was developed and thoroughly validated. The microarray platform based on sequence-specific end labeling of oligonucleotides and the phylogenetically robust gyrB marker gene allowed a highly specific (resolution on genus and/or species level) and sensitive (0.1% relative and 10(4) CFU absolute sensitivity) detection of the target pathogens. In initial challenge studies of the applicability of microarray-based food analysis, we obtained results demonstrating the questionable specificity of standardized culture dependent microbiological detection methods. Taking into consideration the importance of reliable food safety assessment methods, comprehensive performance assessment is essential. Results demonstrate the potential of this new pathogen diagnostic microarray to evaluate culture-based standard methods in microbiological food analysis. PMID- 21669088 TI - Iceberg lettuce as suggested source of a nationwide outbreak caused by two Salmonella serotypes, Newport and Reading, in Finland in 2008. AB - A nationwide outbreak of Salmonella enterica serotypes Newport and Reading occurred between 17 October and 28 November 2008 in Finland. A total of 77 culture-confirmed Salmonella Newport and 30 Salmonella Reading cases, including one case with a double infection, were reported. All strains isolated from the patients were subtyped using serotyping, microbial resistance profiling, and pulsed-field gel electrophoresis (PFGE). Here, the PFGE patterns of the studied Salmonella Newport strains were identical, whereas four different PFGE profiles were found among the Salmonella Reading strains. Two elderly patients died within 2 weeks of the onset of symptoms. Three geographical clusters of cases with an epidemiological link were identified. The traceback investigation suggested that the factor connecting the cases was ready-chopped iceberg lettuce available for mass catering use. However, none of the tested food, environmental samples, or the samples taken from the staff of the processing plant contained Salmonella bacteria. Tracing back to outbreak sources with a short shelf life can be complex. PMID- 21669090 TI - Increased QT interval variability in 3 recently concussed athletes: an exploratory observation. AB - CONTEXT: The QT interval variability index (QTVI) is a noninvasive measure of beat-to-beat fluctuations of the QT interval as seen from a single electrocardiographic lead. It represents the relationship between the respective variabilities of the QT and R-R intervals. Recently, the QTVI was demonstrated to be an index of vagal cardiac autonomic modulation in resting conditions. OBJECTIVE: To determine whether QTVI varied in athletes at 48 hours, 1 week, and 2 weeks after a concussive head injury. DESIGN: Case series. SETTING: Testing facility. PATIENTS OR OTHER PARTICIPANTS: Three athletes with recent concussions and 3 uninjured athletes with similar demographic factors. MAIN OUTCOME MEASURE(S): Continuous 3-lead electrocardiograms were obtained in a seated, resting position over 2 successive weeks. Separate, unpaired t tests were performed to determine whether group-visit differences were present in the QTVI at 48 hours, 1 week, or 2 weeks. RESULTS: No demographic differences were present between groups. At 48 hours, the QTVI was greater in the concussion group than in the matched controls. At weeks 1 and 2, the QTVI in the concussion group was lower than at 48 hours and not different from that of the control group. CONCLUSIONS: Vagal cardiac autonomic modulation, as quantified by the QTVI, appeared to be negatively affected in concussed athletes within 48 hours of injury, resolved within 1 week, and remained at control group levels 2 weeks later. Serial assessments of QTVI may be of clinical utility in identifying suspected cases of acute concussion and may provide helpful information for determining when an athlete can return to play safely. PMID- 21669091 TI - Persistent motor system abnormalities in formerly concussed athletes. AB - CONTEXT: The known detrimental effects of sport concussions on motor system function include balance problems, slowed motor execution, and abnormal motor cortex excitability. OBJECTIVE: To assess whether these concussion-related alterations of motor system function are still evident in collegiate football players who sustained concussions but returned to competition more than 9 months before testing. DESIGN: Case-control study. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: A group of 21 active, university-level football players who had experienced concussions was compared with 15 university football players who had not sustained concussions. INTERVENTION(S): A force platform was used to assess center-of-pressure (COP) displacement and COP oscillation regularity (approximate entropy) as measures of postural stability in the upright position. A rapid alternating-movement task was also used to assess motor execution speed. Transcranial magnetic stimulation over the motor cortex was used to measure long-interval intracortical inhibition and the cortical silent period, presumably reflecting y-aminobutyric acid subtype B receptor-mediated intracortical inhibition. MAIN OUTCOME MEASURE(S): COP displacement and oscillation regularity, motor execution speed, long-interval intracortical inhibition, cortical silent period. RESULTS: Relative to controls, previously concussed athletes showed persistently lower COP oscillation randomness, normal performance on a rapid alternating-movement task, and more M1 intracortical inhibition that was related to the number of previous concussions. CONCLUSIONS: Sport concussions were associated with pervasive changes in postural control and more M1 intracortical inhibition, providing neurophysiologic and behavioral evidence of lasting, subclinical changes in motor system integrity in concussed athletes. PMID- 21669092 TI - Intrarater reliability of the adductor squeeze test in gaelic games athletes. AB - CONTEXT: Groin pain is commonly experienced by athletes involved in field-based sports and is particularly prevalent in Gaelic Games athletes. The adductor squeeze test is commonly used in the assessment of groin pain and injuries. To date, no evidence in the literature provides the reliability of the adductor squeeze test using a sphygmomanometer in assessing the adductor muscle integrity of Gaelic Games athletes. Given the high proportion of groin pain encountered in Gaelic Games athletes, establishing the reliability of the adductor squeeze test will allow clinicians to monitor injury responses and to assess return-to-play criteria. OBJECTIVE: To evaluate the intrarater reliability of a commercially available sphygmomanometer for measuring adductor squeeze values in Gaelic Games athletes and to determine if different squeeze values are associated with the 3 commonly used test positions. DESIGN: Descriptive laboratory study. SETTING: University clinical skills laboratory. PATIENTS OR OTHER PARTICIPANTS: Eighteen male Gaelic Games athletes without any previous or current history of groin or pelvic pain. INTERVENTION(S): Each participant performed the adductor squeeze test in 3 positions of hip joint flexion (0 degrees , 45 degrees , and 90 degrees ) on 2 test days separated by at least 1 week. MAIN OUTCOME MEASURE(S): Adductor squeeze test values (mm Hg) quantified by a commercially available sphygmomanometer. RESULTS: Intrarater reliability intraclass correlation values ranged from 0.89 to 0.92 (intraclass correlation coefficients were 0 degrees , 0.89; 45 degrees , 0.92; and 90 degrees , 0.90). The highest squeeze values were recorded in the 45 degrees of hip flexion test position, and these values differed from those demonstrated in the 0 degrees and 90 degrees hip flexion test positions (P < .05). CONCLUSIONS: A commercially available sphygmomanometer is a reliable device for measuring adductor squeeze test values. PMID- 21669093 TI - A preliminary multifactorial approach describing the relationships among lower extremity alignment, hip muscle activation, and lower extremity joint excursion. AB - CONTEXT: Multiple factors have been suggested to increase the risk of faulty dynamic alignments that predict noncontact anterior cruciate ligament injury. Few researchers have examined this relationship using an integrated, multifactorial approach. OBJECTIVE: To describe the relationship among static lower extremity alignment (LEA), hip muscle activation, and hip and knee motion during a single leg squat. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty men (age= 23.9+/- 3.6 years, height =178.5+/- 9.9 cm, mass= 82.0+/- 14.1 kg) and 30 women (age= 22.2+/- 2.6 years, height= 162.4+/- 6.3 cm, mass= 60.3+/- 8.1 kg). MAIN OUTCOME MEASURE(S): Pelvic angle, femoral anteversion, quadriceps angle, tibiofemoral angle, and genu recurvatum were measured to the nearest degree; navicular drop was measured to the nearest millimeter. The average root mean square amplitude of the gluteus medius and maximus muscles was assessed during the single-leg squat and normalized to the peak root mean square value during maximal contractions for each muscle. Kinematic data of hip and knee were also assessed during the single leg squat. Structural equation modeling was used to describe the relationships among static LEA, hip muscle activation, and joint kinematics, while also accounting for an individual's sex and hip strength. RESULTS: Smaller pelvic angle and greater femoral anteversion, tibiofemoral angle, and navicular drop predicted greater hip internal-rotation excursion and knee external-rotation excursion. Decreased gluteus maximus activation predicted greater hip internal rotation excursion but decreased knee valgus excursion. No LEA characteristic predicted gluteus medius or gluteus maximus muscle activation during the single leg squat. CONCLUSIONS: Static LEA, characterized by a more internally rotated hip and valgus knee alignment and less gluteus maximus activation, was related to commonly observed components of functional valgus collapse during the single-leg squat. This exploratory analysis suggests that LEA does not influence hip muscle activation in controlling joint motion during a single-leg squat. PMID- 21669094 TI - Differential ability of selected postural-control measures in the prediction of chronic ankle instability status. AB - CONTEXT: Chronic ankle instability (CAl) is a term used to identify a condition associated with recurrent ankle sprains and persistent symptoms. Balance deficits, evaluated using center-of-pressure (COP) force-plate measurements, have been shown to occur in people with CAl. OBJECTIVE: To determine the differential abilities of selected force-plate postural-control measures to assess CAl. DESIGN: Case-control study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 63 individuals with CAl (30 men, 33 women: age= 22.3+/- 3.7 years, height= 169.8 +/-9.6 cm, mass= 70.7+/- 14.3 kg) and 46 healthy controls (22 men, 24 women: age= 21.2+/- 4.1 years, height= 173.3+/- 9.2 cm, mass =69.2+/- 13.2 kg) volunteered. INTERVENTION(S): Participants performed 3 10-second trials of quiet, single-limb stance on a force plate under 2 conditions: eyes open and eyes closed. MAIN OUTCOME MEASURE(S): Measures of COP area, COP velocity, COP SO, COP range of excursion, percentage of COP range used, time-to-boundary absolute minimum, time-to-boundary mean of the minima, and time-to-boundary SO of the minima were calculated. All measures with the exception of COP area were calculated in both the mediolateral (ML) and anteroposterior directions. For each measure, a receiver operator curve analysis was created, and the corresponding area under the curve was tested. The optimal diagnostic threshold value for each measure was determined, and the corresponding positive and negative likelihood ratios were calculated. RESULTS: Three eyes-closed, single-limb force-plate measures (COP ML SO, ML percentage of COP range used, and time-to-boundary absolute minimum) predicted CAl status. However, all 3 measures had positive likelihood ratios associated with only small shifts in the probability of a patient with a positive test having CAl and negative likelihood ratios associated with very small shifts in the probability of a patient with a negative test not having CAl. CONCLUSIONS: No single force-plate measure was very effective in predicting if an individual had CAl or not. PMID- 21669095 TI - Motor-neuron pool excitability of the lower leg muscles after acute lateral ankle sprain. AB - CONTEXT: Neuromuscular deficits in leg muscles that are associated with arthrogenic muscle inhibition have been reported in people with chronic ankle instability, yet whether these neuromuscular alterations are present in individuals with acute sprains is unknown. OBJECTIVE: To compare the effect of acute lateral ankle sprain on the motor-neuron pool excitability (MNPE) of injured leg muscles with that of uninjured contralateral leg muscles and the leg muscles of healthy controls. DESIGN: Case-control study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Ten individuals with acute ankle sprains (6 females, 4 males; age= 19.2 +/- 3.8 years, height= 169.4 +/- 8.5 cm, mass= 66.3 +/- 11.6 kg) and 10 healthy individuals(6 females,4 males; age= 20.6 +/- 4.0 years, height = 169.9 +/- 10.6 cm, mass= 66.3 +/- 10.2 kg) participated. INTERVENTION(S): The independent variables were group (acute ankle sprain, healthy) and limb (injured, uninjured). Separate dependent t tests were used to determine differences in MNPE between legs. MAIN OUTCOME MEASURE(S): The MNPE of the soleus, fibularis longus, and tibialis anterior was measured by the maximal Hoffmann reflex (H(max)) and maximal muscle response (M(max)) and was then normalized using the H(max):M(max) ratio. RESULTS: The soleus MNPE in the ankle sprain group was higher in the injured limb (H(max):M(max) = 0.63; 95% confidence interval [Cl],0.46, 0.80) than the uninjured limb (H(max):M(max) = 0.47; 95%Cl, 0.08, 0.93)(t(6) = 3.62,P =.01).In the acute ankle-sprain group, tibialis anterior MNPE tended to be lower in the injured ankle (H(max):M(max) =0.06; 95% Cl, 0.01, 0.10) than in the uninjured ankle (H(max):M(max) =0.22; 95%Cl, 0.09, 0.35),but this finding was not different (t(9) =-2.01, P =.07). No differences were detected between injured (0.22; 95% Cl, 0.14, 0.29) and uninjured (0.25; 95%Cl, 0.12, 0.38) ankles for the fibularis longus in the ankle-sprain group (t(9) =-0.739, P =.48). We found no side-to-side differences in any muscle among the healthy group. CONCLUSIONS: Facilitated MNPE was present in the involved soleus muscle of patients with acute ankle sprains, but no differences were found in the fibularis longus or tibialis anterior muscles. PMID- 21669096 TI - Microdialysis and delivery of iontophoresis-driven lidocaine into the human gastrocnemius muscle. AB - CONTEXT: Iontophoresis is used frequently in physical medicine and rehabilitation, but many research techniques do not adequately measure it for depth of medicine delivery. OBJECTIVE: To determine if iontophoresis delivers lidocaine 5 mm under the surface of human skin. DESIGN: Descriptive laboratory study. SETTING: Therapeutic modalities research laboratory. PATIENTS OR OTHER PARTICIPANTS: Eight men and 5 women volunteers (age range = 21+/- 2.3 years) who had less than 5 mm of adipose tissue in the area we measured participated in the study. INTERVENTION(S): We inserted a microdialysis probe 5 mm under the skin of both legs and into the triceps surae muscle groups of 10 participants. Microdialysis was performed for 60 minutes to allow a recovery period for local skin blood flow to return to baseline. We then delivered 2 mL of 1% lidocaine to the treatment leg via iontophoresis at 40 mA/min. Next, microdialysis was performed continuously in both legs during the treatment and for 30 minutes posttreatment to collect the lidocaine samples. After we had gathered the samples, several saline solutions with various amounts of lidocaine (0.005%, 0.025%, 0.05%, and 0.1 %) were prepared in vitro and analyzed. Although we did not intend to do so as a part of the original study, we also performed an identical follow-up study at 3 mm in 3 participants. MAIN OUTCOME MEASURE(S): Both in vitro and in vivo samples were analyzed via reverse-phase high performance liquid chromatography (RP-HPLC). A protocol for detection and quantification of lidocaine using RP-HPLC was followed. RESULTS: We did not detect any measurable levels or concentrations of lidocaine in the 10 control samples. According to the RP-HPLC analysis, the 10 treatment samples also were negative for the presence of lidocaine. However, when we performed the study at 3 mm, microdialysis detected lidocaine in the 3 participants at this depth in the treatment leg only. CONCLUSIONS: Measurable levels of lidocaine were not detected at 5 mm but were found at 3 mm. More studies are needed to determine the efficacy of microdialysis in measuring iontophoresis-delivered compounds. PMID- 21669097 TI - Absorption of iontophoresis-driven 2% lidocaine with epinephrine in the tissues at 5 mm below the surface of the skin. AB - CONTEXT: In a recent study, we were unable to measure lidocaine in the human calf at a 5-mm depth via iontophoresis. We surmised that this might be due to a lack of epinephrine in the compound. Because epinephrine is a vasoconstrictor, it might allow the drug to pass beyond the capillaries and be delivered to the deeper tissues. OBJECTIVE: To determine if iontophoresis could deliver lidocaine with epinephrine 5 mm under the surface of human skin, as measured by microdialysis. DESIGN: Descriptive laboratory study. SETTING: Therapeutic modalities research laboratory. PATIENTS OR OTHER PARTICIPANTS: Ten volunteers (5 males, 5 females; age, 15-28 years) with less than 5 mm of adipose tissue in the area we measured and with no allergies to lidocaine participated. The measurement area had been free of any injury, swelling, or infection for at least 3 months before the study. INTERVENTION(S): We inserted a microdialysis probe 0.5 cm under the skin of the right lower leg. Next, microdialysis was performed through this area for 60 minutes, which allowed local skin blood flow to return to baseline. We then performed iontophoresis at 40 mA/min using 2 mL of 2% lidocaine. Iontophoresis was performed over this area for 10.5 minutes to collect the lidocaine samples. After this stage, the electrode was left in place for another 50 minutes for a total of 60 minutes. MAIN OUTCOME MEASURE(S): The samples of the drug were analyzed via reverse-phase high-performance liquid chromatography (RP HPLC) in the chemistry department. RESULTS: The RP-HPLC analysis confirmed the presence of lidocaine in all 10 participants. The mean concentration of lidocaine detected at the 5-mm depth was calculated as 3.63 mg/ mL (greater than 18% of delivered concentration). CONCLUSIONS: We found that 2% lidocaine can be delivered up to 5 mm below the surface of the skin when the drug compound contains epinephrine and when passive delivery occurs for at least 50 minutes after the active delivery has terminated. PMID- 21669098 TI - A profile of glenohumeral internal and external rotation motion in the uninjured high school baseball pitcher, part I: motion. AB - CONTEXT: The magnitude of motion that is normal for the throwing shoulder in uninjured baseball pitchers has not been established. Chronologic factors contributing to adaptations in motion present in the thrower's shoulder also have not been established. OBJECTIVES: To develop a normative profile of glenohumeral rotation motion in uninjured high school baseball pitchers and to evaluate the effect of chronologic characteristics on the development of adaptations in shoulder rotation motion. DESIGN: Cohort study. SETTING: Baseball playing field. PATIENTS OR OTHER PARTICIPANTS: A total of 210 uninjured male high school baseball pitchers (age = 16 +/- 1.1 years, height=1.8+/-0.1 m, mass=77.5+/-11.2 kg, pitching experience=6+/-2.3 years). INTERVENTION(S): Using standard goniometric techniques, we measured passive rotational glenohumeral range of motion bilaterally with participants in the supine position. MAIN OUTCOME MEASURE(S): Paired t tests were performed to identify differences in motion between limbs for the group. Analysis of variance and post hoc Tukey tests were conducted to identify differences in motion by age. Linear regressions were performed to determine the influence of chronologic factors on limb motion. RESULTS: Rotation motion characteristics for the population were established. We found no difference between sides for external rotation (ER) at 0 degrees of abduction (t(209) = 0.658, P = .51), but we found side-to-side differences in ER (t(209) =-13.012,P < .001) and internal rotation (t(209) =15.304, P < .001) at 90 degrees of abduction. Age at the time of testing was a significant negative predictor of ER motion for the dominant shoulder (R(2) = 0.019, P = .049) because less ER motion occurred at the dominant shoulder with advancing age. We found no differences in rotation motion in the dominant shoulder across ages (F(4,205) range, 0.451-1.730,P > .05). CONCLUSIONS: This range-of-motion profile might be used to assist with the interpretation of normal and atypical shoulder rotation motion in this population. Chronologic characteristics of athletes had no influence on range-of-motion adaptations in the thrower's shoulder. PMID- 21669099 TI - A profile of glenohumeral internal and external rotation motion in the uninjured high school baseball pitcher, part II: strength. AB - CONTEXT: A database describing the range of normal rotator cuff strength values in uninjured high school pitchers has not been established. Chronologic factors that contribute to adaptations in strength also have not been established. OBJECTIVES: To establish a normative profile of rotator cuff strength in uninjured high school baseball pitchers and to determine whether bilateral differences in rotator cuff strength are normal findings in this age group. DESIGN: Cohort study. SETTING: Baseball playing field. PATIENTS OR OTHER PARTICIPANTS: A total of 165 uninjured male high school baseball pitchers (age = 16 +/- 1 years, height=1.8+/-0.1 m, mass=76.8+/-10.1 kg, pitching experience =7+/ 2 years). MAIN OUTCOME MEASURE(S): Isometric rotator cuff strength was measured bilaterally with a handheld dynamometer. We calculated side-to-side differences in strength (external rotation [ER], internal rotation [IR], and the ratio of ER:IR at 90 degrees of abduction), differences in strength by age, and the influence of chronologic factors (participant age, years of pitching experience) on limb strength. RESULTS: Side-to-side differences in strength were found for ER, IR, and ER:IR ratio at 90 degrees of abduction. Age at the time of testing was a significant but weak predictor of both ER strength (R(2)=0.032, P = .02) and the ER:IR ratio (R(2)=0.051 , P = .004) at 90 degrees of abduction. CONCLUSIONS: We established a normative profile of rotator cuff strength for the uninjured high school baseball pitcher that might be used to assist clinicians and researchers in the interpretation of muscle strength performance in this population. These data further suggested that dominant-limb adaptations in rotator cuff strength are a normal finding in this age group and did not demonstrate that these adaptations were a consequence of the age at the time of testing or the number of years of pitching experience. PMID- 21669100 TI - Performance after rotator cuff tear and operative treatment: a case-control study of major league baseball pitchers. AB - CONTEXT: Little is known about pitching performance or lack of it among Major League Baseball (MLB) pitchers who undergo operative treatment of rotator cuff tears. OBJECTIVE: To assess pitching performance outcomes in MLB players who needed operative treatment of rotator cuff tears and to compare performance in these athletes with that in a control group of MLB players. DESIGN: Case-control study. SETTING: Publicly available player profiles, press releases, and team injury reports. PATIENTS OR OTHER PARTICIPANTS: Thirty-three MLB pitchers with documented surgery to treat rotator cuff tears and 117 control pitchers who did not have documented rotator cuff tears were identified. MAIN OUTCOME MEASURE(S): Major League Baseball pitching attrition and performance variables. RESULTS: Players who underwent rotator cuff surgery were no more likely not to play than control players. Performance variables of players who underwent surgery improved after surgery but never returned to baseline preoperative status. Players who needed rotator cuff surgery typically were more experienced and had better earned run averages than control players. CONCLUSIONS: Pitchers who had symptomatic rotator cuff tears that necessitated operative treatment tended to decline gradually in performance leading up to their operations and to improve gradually over the next 3 seasons. In contrast to what we expected, they did not have a greater attrition rate than their control counterparts; however, their performances did not return to preoperative levels over the course of the study. PMID- 21669101 TI - Perceptions of clinical athletic trainers on the spiritual care of injured athletes. AB - CONTEXT: Treating both the body and the mind of an injured or ill patient is accepted as necessary for full healing to occur. However, treating the spiritual needs of the patient has less consensus. OBJECTIVE: To determine the perceptions and practices of certified athletic trainers (ATs) working in the college/university setting pertaining to spiritual care of the injured athlete. DESIGN: Cross-sectional study. SETTING: A survey instrument was e-mailed to a stratified random sample of 2000 ATs at 4-year colleges and universities. PATIENTS OR OTHER PARTICIPANTS: Five hundred sixty-four. MAIN OUTCOME MEASURE(S): We measured the ATs' perceptions and practices related to spiritual care for athletes. RESULTS: We found that 82.4% of respondents agreed that addressing spiritual concerns could result in more positive therapeutic outcomes for athletes; however, 64.3% disagreed that ATs are responsible for providing the spiritual care. Positive correlations were found between personal spirituality and items favoring implementing spiritual care. CONCLUSIONS: Athletic trainers have a conceptual appreciation of the importance of spiritual care for athletes, but the practicalities of how to define, acquire skills in, and practice spiritual care are unresolved. PMID- 21669102 TI - National collegiate athletic association division and primary job title of athletic trainers and their job satisfaction or intention to leave athletic training. AB - CONTEXT: Membership in the National Athletic Trainers' Association (NATA) has declined in recent years, generating much debate about professional commitment. OBJECTIVE: To compare the contributing factors of job satisfaction and intention to leave athletic training of certified athletic trainers (ATs) employed in National Collegiate Athletic Association (NCAA) institutions. DESIGN: Cross sectional study. SETTING: A link to a Web-based questionnaire containing the Spector Job Satisfaction Survey (JSS) and an original Intention to Leave Survey (ITLS) was distributed by e-mail to 1003 certified members of the National Athletic Trainers' Association. PATIENTS OR OTHER PARTICIPANTS: A total of 191 certified members of the NATA employed in a college or university setting in a primarily clinical capacity; representing all NCAA divisions; and having the job title of head athletic trainer, associate/assistant athletic trainer, or graduate assistant/intern athletic trainer. MAIN OUTCOME MEASURE(S): We used separate 3 x 3 factorial analyses of variance to compare the mean scores of each JSS subscale and of the ITLS with NCAA division and job title. A stepwise multiple regression was used to determine the strength of the relationships between the JSS subscales and the ITLS. RESULTS: We found differences for job title in the subscales of Fringe Benefits (F(2182) = 7.82, P = .001 ) and Operating Conditions (F(2,182) = 12.01, P < .001). The JSS subscale Nature of Work was the'greatest indicator of intention to leave (beta = -0.45). CONCLUSIONS: We found a strong negative correlation between various facets of job satisfaction and intention to leave athletic training. The NCAA division seemed to have no effect on an individual's job satisfaction or intention to leave the profession. In addition, only Fringe Benefits and Operating Conditions seemed to be affected by job title. The ATs had similar levels of job satisfaction regardless of NCAA division, and their job titles were not a major factor in job satisfaction. PMID- 21669103 TI - Transient global amnesia in a collegiate baseball player with type I diabetes mellitus: a case report. AB - OBJECTIVE: To present the case of a collegiate pitcher with type I diabetes mellitus who developed transient global amnesia and to characterize the acute onset of symptoms and clinical diagnosis of this rarely reported neurologic condition in the student-athlete population. BACKGROUND: A 21-year-old collegiate pitcher with type I diabetes mellitus was found by his roommate to have acute onset memory loss. The athletic trainer identified normal blood glucose levels and normal vital signs but profound amnesia. The patient was evaluated by his team physician and referred to the local emergency department for acute-onset memory disturbance. DIFFERENTIAL DIAGNOSIS: Hypoglycemia, ketoacidosis, adverse drug reaction, infectious disease, transient epileptic amnesia, transient ischemic attack, acute confusional state, complex partial seizure, psychogenic amnesia, migraine, intracerebral hemorrhage, traumatic brain injury, tumor, and transient global amnesia. TREATMENT: Diagnostic studies included computed tomography of the head, urine and serum toxicology, urinalysis, blood glucose level, electrolytes, blood urea nitrogen level, creatinine level, complete blood count, and electroencephalography. The patient was admitted overnight to the neurology service. The next morning, electroencephalography was repeated, and magnetic resonance imaging of the head with contrast was performed. The patient was discharged with the diagnosis of transient global amnesia. UNIQUENESS: Transient global amnesia is considered a benign condition characterized by an acute episode of memory disturbance involving the inability to form new memories and recall recent events. It is rare in young people, with only 3 case reports involving young athletes published in the literature. CONCLUSIONS: Transient global amnesia is a rarely diagnosed neurologic disturbance that may present acutely in student-athletes, although most reported cases affect older adults. Unfamiliarity with the symptoms may cause anxiety for the athlete and bystanders. Transient global amnesia does not result in long-term neurologic deficit, and neurologic function will return to baseline. PMID- 21669105 TI - Respiratory care year in review 2010: part 2. Invasive mechanical ventilation, noninvasive ventilation, pediatric mechanical ventilation, aerosol therapy. AB - The purpose of this paper is to review the recent literature related to invasive mechanical ventilation, NIV, pediatric mechanical ventilation, and aerosol therapy. Topics covered related to invasive mechanical ventilation topics include the role of PEEP in providing lung protection during mechanical ventilation, unconventional modes for severe hypoxemia, and strategies to improve patient ventilator interactions. Topics covered related to NIV include real-life NIV use, NIV and extubation failure, and NIV and pandemics. For pediatric mechanical ventilation, the topics addressed are NIV, invasive respiratory support, and inhaled nitric oxide. Topics covered related to aerosol therapy include short acting beta-adrenergic agents, long-acting beta-adrenergic agents, long-acting antimuscarinic agents, inhaled corticosteroid therapy, phosphodiesterase type 4 (PDE4) inhibitors, long-acting beta-adrenergic plus inhaled corticosteroid, long acting antimuscarinic plus inhaled corticosteroid, nebulized hypertonic saline, inhaled mannitol, and inhaled antibiotic therapy. These topics were chosen and reviewed in a manner that is most likely to have interest to the readers of Respiratory Care. PMID- 21669106 TI - How much PEEP? Do we need another meta-analysis? PMID- 21669104 TI - National Athletic Trainers' Association position statement: safe weight loss and maintenance practices in sport and exercise. AB - OBJECTIVE: To present athletic trainers with recommendations for safe weight loss and weight maintenance practices for athletes and active clients and to provide athletes, clients, coaches, and parents with safe guidelines that will allow athletes and clients to achieve and maintain weight and body composition goals. BACKGROUND: Unsafe weight management practices can compromise athletic performance and negatively affect health. Athletes and clients often attempt to lose weight by not eating, limiting caloric or specific nutrients from the diet, engaging in pathogenic weight control behaviors, and restricting fluids. These people often respond to pressures of the sport or activity, coaches, peers, or parents by adopting negative body images and unsafe practices to maintain an ideal body composition for the activity. We provide athletic trainers with recommendations for safe weight loss and weight maintenance in sport and exercise. Although safe weight gain is also a concern for athletic trainers and their athletes and clients, that topic is outside the scope of this position statement. RECOMMENDATIONS: Athletic trainers are often the source of nutrition information for athletes and clients; therefore, they must have knowledge of proper nutrition, weight management practices, and methods to change body composition. Body composition assessments should be done in the most scientifically appropriate manner possible. Reasonable and individualized weight and body composition goals should be identified by appropriately trained health care personnel (eg, athletic trainers, registered dietitians, physicians). In keeping with the American Dietetics Association (ADA) preferred nomenclature, this document uses the terms registered dietitian or dietician when referring to a food and nutrition expert who has met the academic and professional requirements specified by the ADA's Commission on Accreditation for Dietetics Education. In some cases, a registered nutritionist may have equivalent credentials and be the commonly used term. All weight management and exercise protocols used to achieve these goals should be safe and based on the most current evidence. Athletes, clients, parents, and coaches should be educated on how to determine safe weight and body composition so that athletes and clients more safely achieve competitive weights that will meet sport and activity requirements while also allowing them to meet their energy and nutritional needs for optimal health and performance. PMID- 21669107 TI - Acute lung injury: time to find a way that works. PMID- 21669108 TI - Simple, difficult, or prolonged weaning: the most important factor is the success or failure of the first weaning trial. PMID- 21669109 TI - Bell, whistles, and leak profiles. PMID- 21669110 TI - Building a bridge to the future: some points to ponder. PMID- 21669111 TI - Principles of stroke management and prevention. PMID- 21669112 TI - Metabolic syndrome and its components as predictors of stroke in middle-aged and elderly Chinese people. AB - BACKGROUND AND PURPOSE: Little information is available on the role of metabolic syndrome (MetS) to predict first-ever stroke in the Chinese mainland. In this study, we investigated whether the metabolic syndrome and its single components, defined by original National Cholesterol Education Program (NCEP), International Diabetes Federation (IDF) and updated NCEP, could predict stroke in the middle aged and elderly (40-85 years) Chinese population. METHODS: In this prospective study, three metabolic syndrome definitions were applied to 19,369 subjects aged 40-85 years who were free of stroke and/or myocardial infarction at baseline and were followed up to 3 years. Multivariable Cox regression analysis was used to calculate the adjusted hazard ratios (HRs) and 95% confidence interval of metabolic syndrome and its single components with the first-ever stroke. RESULTS: The metabolic syndrome defined by the original NCEP, IDF and updated NCEP were all significantly associated with stroke even after adjustment for confounding variables (HRs: 1.51 to 2.14). For the single components of metabolic syndrome, the following components predicted stroke incidence in both genders: insulin resistance or previous diagnosis with diabetes (HRs: 1.48-1.54 for men and 1.66 1.92 for women); blood pressure >= 130/85 mmHg or using medication (HRs: 2.54 for men and 2.31 for women). For men, central obesity defined by the IDF or updated NCEP criteria (waist circumference >= 90 cm) had association with stroke (HR: 1.47). However, none of criteria of central obesity was associated with stroke in female. CONCLUSIONS: The metabolic syndrome is associated with first-ever stroke in this middle-aged and elderly Chinese population. Furthermore, blood pressure alone plays a more important role than metabolic syndrome in stroke risk in middle-aged and elderly Chinese population. PMID- 21669114 TI - Chronic Helicobacter pylori infection and ischemic stroke subtypes. AB - OBJECTIVE: Chronic infection by Helicobacter pylori is regarded as an etiological factor for vascular diseases. However, there are conflicting results on the relevance of chronic infection by Helicobacter pylori as a risk factor for ischemic stroke. The aim of our study was to investigate the association between Helicobacter pylori infection and ischemic stroke subtypes in Chinese. METHOD: A total of 150 patients with ischemic stroke were enrolled in the patient group. Analyses were stratified for etiologic stroke subtypes according to 2007 modified Trial of Org 10172 in Acute Stroke Treatment criteria: 119 patients with atherothrombosis, 15 patients with cardioembolism, and 12 patients with small artery disease. One hundred and thirty-one control subjects without clinical and instrumental evidence of atherosclerotic diseases were randomly selected from health check-up center. The potential risk factors for Helicobacter pylori infection and traditional risk factors for ischemic stroke of all subjects were analyzed. The serum specific antibody IgG of Helicobacter pylori was detected by enzyme-linked immunosorbent assay. Conditional logistic regression was used to analyze the data. RESULTS: The Helicobacter pylori/IgG-positive rate in the patient group was higher than that in the healthy control group, but the difference was not statistically significant [67.3% versus 61.8%; odds ratio (OR) = 1.272; P = 0.336]. This result remained non-significant after adjustment for other established risk factors [OR = 1.222; 95% confidence interval (CI): 0.688 2.171; P = 0.494]. Subgroup analysis using univariate and multivariate analyses yielded similar results in all etiologic stroke subtypes (univariate analysis, atherothrombosis: OR = 1.368, 95%CI: 0.810-2.311, P = 0.241; cardioembolism: OR = 0.926, 95%CI:0.311-2.758, P = 0.890; small artery disease: OR = 1.852, 95%CI: 0.478-7.167, P = 0.366; multivariate analysis, atherothrombosis: OR = 1.385, 95%CI: 0.726-2.639, P = 0.323; cardioembolism: OR = 0.832, 95%CI: 0.236-2.932, P = 0.775; small artery disease: OR = 1.836, 95%CI: 0.396-8.503, P = 0.437). CONCLUSIONS: This case-control study does not reveal any strong association between chronic Helicobacter pylori infection and ischemic stroke. Large case control prospective studies are required for further investigation of the potential association between Helicobacter pylori infection and ischemic stroke risk, particularly in certain subgroups. PMID- 21669113 TI - Relations between plasma ox-LDL and carotid plaque among Chinese Han ethnic group. AB - OBJECTIVES: To study the relationship between plasma oxidized low-density lipoprotein (ox-LDL) and carotid plaque, including plaque stability, of patients with acute ischemic stroke among Chinese Han ethnic group. METHODS: A total of 181 patients with acute ischemic stroke were recruited and enrolled. The subjects were divided into a carotid plaque group and a no-plaque group by carotid ultrasound. The stability of carotid atheromas was assessed by ultrasound echo density, and the carotid plaque group was further divided into a vulnerable plaque group and a stable plaque group based on the echo results. RESULTS: The study showed that the correlation between age [odds ratio (OR): 1.047; 95% confidence interval (CI): 1.014-1.082; P<0.01] and carotid plaque was significant. Plasma ox-LDL (OR: 1.020; 95%CI: 1.010-1.030; P<0.001) was also found to be significantly correlated with carotid plaque. Age was irrelevant to plaque stability (P = 0.0685). The ox-LDL of the vulnerable plaque group was found to be significantly higher than that of the stable plaque group (P = 0.015). By measuring the plasma ox-LDL in patients with ischemic stroke, the proportion under the receiver operating characteristic curve of vulnerable carotid plaques was 0.690 with a 95%CI of 0.613-0.767 (P<0.001). The point of cut off was 94.5943, the sensitivity was 0.805, and the specificity was 0.505. CONCLUSION: The plasma ox-LDL level and age are possible risk factors for carotid plaque among patients with ischemic stroke of the Chinese Han ethnic group. This study suggests that ox-LDL could be used as a biomarker in screening for vulnerable carotid plaque in clinical practice. PMID- 21669115 TI - Human cytomegalovirus-IgM seropositivity is not associated with atherogenic alterations of lipid profiles and inflammatory status in ischemic stroke patients: a preliminary study. AB - BACKGROUND: Past exposure to human cytomegalovirus has been suggested to participate in the pathogenetic events associated with atherosclerotic lesion establishment and progression. However, whether ongoing human cytomegalovirus infection is related to plaque instability, and subsequent acute cerebral ischemia, is relatively unknown. The purpose of this study was to evaluate the potential relationships between active human cytomegalovirus infection and ischemic stroke, especially in regard to metabolism and inflammation. METHODS: Ninety-nine acute ischemic stroke patients, associated with large artery atherosclerosis, were divided into two groups based on the presence or absence of human cytomegalovirus immunoglobulin M (IgM) (human cytomegalovirus-IgM positive/human cytomegalovirus-IgM-negative = 33:66). Baseline clinical characteristics, inflammatory factors, and biochemical assessments were compared in both groups. Then, all patients and human cytomegalovirus-IgM-positive patients were divided into quartiles according to their high-sensitivity C reactive protein levels, respectively, and risk factors were compared. Finally, correlations between inflammatory factors (high-sensitivity C-reactive protein and white blood cell count) and other atherosclerosis risk factors in both human cytomegalovirus-IgM-positive and -negative subjects were evaluated. RESULTS: An association between human cytomegalovirus-IgM seropositivity and atherogenic modification of metabolism and inflammatory status were not found in this study. Both age and white blood cell count increased across quartiles of high sensitivity C-reactive protein in all subjects (P = 0.001), while age and low density lipoprotein cholesterol increased across quartiles of high-sensitivity C reactive protein in the human cytomegalovirus-IgM-positive group (P = 0.02 and 0.007, respectively). Multivariate linear regression analysis showed that high sensitivity C-reactive protein was associated with age in human cytomegalovirus IgM-positive group (P = 0.002), while no other factor was associated with white blood cell count in these subjects. CONCLUSION: Our study provided no evidence for the direct implication of active systemic human cytomegalovirus infection, represented by human cytomegalovirus-IgM positivity, in the pathogenesis of acute ischemic strokes, particularly those involving plaque instability and metabolic disorders. PMID- 21669116 TI - Validation of the ABCD2-I score to predict stroke risk after transient ischemic attack. AB - OBJECTIVES: The primary aim of this study was to prospectively validate the predictive value of the ABCD2-I score and to then compare the predictive accuracy of the ABCD2 score and ABCD2-I score for 1-year risk of stroke in admitted patients with transient ischemic attack (TIA) as defined by the World Health Organization (WHO) time-based criteria. METHODS: Data were collected from patients with transient ischemic attack within 7 days of symptom onset, and all patients underwent diffusion-weighted imaging (DWI). The predictive values of stratified 1-year rates of recurrent stroke were compared using the age, blood pressure, clinical signs, symptom duration, and ABCD2 score with defined cutoff values (0-3, low-risk, 4-5, medium-risk, 6-7, high-risk) and ABCD2-I score cutoff values (0-3, low-risk, 4-6, medium-risk, 7-10, high-risk). In addition, to evaluate the performance of the two scores, we calculated the area under the curve by receiver-operating characteristic. RESULTS: Four hundred and ten patients with completed DWI and 12-month follow-up with initial TIA were enrolled in this study. Of these, 111 (27.07%) patients had annual stroke risk. The risk of stroke increased with increasing ABCD2 score and ABCD2-I score. The ABCD2-I score had the higher predictive value with areas under the curve of 0.77 than the ABCD2 score with areas under the curve of 0.59. CONCLUSION: The ABCD2-I score is a useful tool for stratifying the 1-year risk of stroke in TIA patients, and it improves the discriminatory power of the ABCD2 score for the prediction of stroke risk. PMID- 21669117 TI - Relationship between transcranial Doppler variables in acute stage and outcome of intracerebral hemorrhage. AB - OBJECTIVE: To investigate the characteristics of transcranial Doppler variables in the acute stage of intracerebral hemorrhage (ICH) and its relationship with 14 day death and outcomes at 90 day after onset. METHODS: Ninety first-time supratentorial nontraumatic ICH patients were prospectively included. Computed tomography and transcranial Doppler examinations were performed on the first, third, seventh, and fourteenth day after onset. Transcranial Doppler variables were obtained from bilateral middle cerebral arteries. The relationship between ICH outcome and the following variables were analyzed: systolic (V(s)), diastolic (V(d)), mean (V(m)) velocities, and pulsatiliy index (PI) from affected and unaffected hemispheres. RESULTS: Fourteen (15.6%) patients died within 14 days after onset of ICH. The stepwise logistic regression analyses proved presence of intraventricular hemorrhage (OR: 11.91; 95%CI: 1.62-87.42) and PI from unaffected hemisphere (OR: 1.64; 95%CI: 1.19-2.25) to be independent predictors of 14-day death. Forty-eight of the 90 ICH patients performed the transcranial Doppler monitoring at all four time points. V(m) from both hemispheres decreased gradually within 14 days after onset. Among the 48 patients, 22 patients were dependent (modified Rankin Scale >= 3) at 90 days after onset. Compared with patients who were independent at 90 days, V(d) (F = 4.98, P = 0.03) and V(m) (F = 7.30, P<0.01) from unaffected hemisphere were significantly lower, while the PI was significantly higher in patients who were dependent (F = 9.84, P<0.01). CONCLUSIONS: Presence of intraventricular hemorrhage and PI from unaffected hemisphere proved to be independent predictors of 14-day death. Sustained persistent decreases in V(d) and V(m) and increases in PI from the unaffected hemisphere during the acute stage may be related with dependency at 90 days. PMID- 21669118 TI - Effect of baseline magnetic resonance imaging (MRI) apparent diffusion coefficient lesion volume on functional outcome in ischemic stroke. AB - OBJECTIVE: We explored the relationship between predicted infarct core, predicted ischemic penumbras and predicted final infarct volumes obtained though apparent diffusion coefficient (ADC)-based method, as well as other clinical variables, and functional outcome. METHODS: Patients with acute cerebral ischemic stroke were retrospectively recruited. The National Institutes of Health Stroke Scale score was evaluated at baseline and the modified Rankin Scale (mRS) at day 90. Favorable outcome was defined as an mRS score of 0 to 2, and unfavorable outcome as 3 to 6. Multimodal stroke magnetic resonance imaging was carried out at presentation. The volumes of diffusion-weighted imaging (DWI) and perfusion weighted imaging (PWI) were measured using the regions of interest (ROI) method. The volumes of predicted infarct core, predicted ischemic penumbra and predicted final infarct were obtained by an automated image analysis system based on baseline ADC maps. The association between baseline magnetic resonance imaging volumes, baseline clinical variables, and functional outcome was statistically analyzed. RESULTS: The study included 30 males and 20 females (mean+/-SD age, 56+/-10 years). Baseline DWI, PWI and PWI-DWI mismatch volumes were not correlated with day-90 mRS (P>0.05). Predicted infarct core, predicted ischemic penumbra and predicted final infarct through ADC-based method were all correlated with day-90 mRS (P<0.05). A better outcome was associated with a smaller predicted volume. Low baseline National Institutes of Health Stroke Scale and recanalization also demonstrated a trend toward a favorable outcome. Receiver operating characteristic analysis showed that the area under the curve of predicted final infarct volume and recanalization were higher with statistical significance (P<0.001). DISCUSSION: Predicted volumes obtained from ADC-based methods, especially predicted final infarct volume, as well as baseline National Institutes of Health Stroke Scale and recanalization may have effect on functional outcome in acute ischemic stroke. PMID- 21669119 TI - Dynamics of nutritional status in dying patients with acute cerebral infarction in central China: a preliminary study. AB - BACKGROUND AND AIMS: Stroke is the number one cause of death in China. Although the effective management has reduced the mortality and lengthened survival, little attention has been paid to nutritional issues in patients with stroke in China. This study aimed to assess the premorbid nutrition status in dying patients with acute cerebral infarction. METHODS: In this study, a total of 185 acute ischemic stroke patients dying within 30 days were recruited from medical records. Characteristics of dying patients were assessed on admission, and serum biochemical parameters including serum total protein, serum albumin, and serum prealbumin were measured within 24 hours after stroke onset and every week routinely. RESULTS: Among 185 ischemic stroke patients, 86 dying patients experienced their first-ever acute cerebral infarction, while 99 dying patients were experiencing a recurrent cerebral infarction. The prevalence of dysphagia, post-stroke pneumonia, and gastrointestinal hemorrhage in recurrent stroke groups were higher than those in the first-ever stroke group (P<0.01). There were gradually declines in serum total protein, serum albumin, and serum prealbumin in dying patients from admission to death, especially in the recurrent ischemic stroke group, as compared to their normal range. The sensitive sequence of serum nutritional index for dying patients with ischemic infarction was: serum prealbumin>serum albumin>serum total protein. CONCLUSIONS: This study showed that hypoproteinemia and undernutrition were serious in dying patients with acute ischemic stroke, especially in patients with recurrent ischemic stroke. This study also confirmed that serum prealbumin is more sensitive than serum albumin to assess nutritional status. The strategies to improve malnutrition in stroke patients are urgently needed in China. PMID- 21669120 TI - Risk factors of stroke-associated pneumonia in Chinese patients. AB - OBJECTIVE: To explore the risk factors for stroke-associated pneumonia (SAP). METHODS: A retrospective research study was carried out to investigate the clinical data of 1435 patients admitted to the neurological intensive care unit at our university hospital between 1 January 2000 and 31 December 2009. RESULTS: A multi-factorial analysis produced the following results: (1) SAP is 1.113 times more likely to occur for each 1-year increase in age; (2) diabetic patients are 1.612 times more likely to develop SAP than non-diabetic patients; (3) the incidence of SAP decreases by a factor of 0.890 with a one-point increase in the Glasgow coma scale score; (4) nasal feeding patients are 4.981 times more likely to develop SAP than non-nasal feeding patients; (5) patients who use H2-receptor blocking agents are 2.837 times more likely to develop SAP than those who do not; (6) patients who preventively use antibiotics are 2.675 times more likely to develop SAP than those who do not; (7) patients whose hospitalization periods are >20 days are 0.500 times more likely to develop SAP than those who do not; (8) patients who suffer from tracheal intubation are 2.980 times more likely to develop SAP than those who do not; and (9) patients who suffer from tracheal incision are 2.190 times more likely to develop SAP than those who do not. CONCLUSIONS: SAP was more closely related with diabetes, age, consciousness, days of hospitalization, tracheal intubation, tracheal incision, nasal feeding treatment, and the application of H2-receptor blocking agents and antimicrobials. PMID- 21669121 TI - Remote ischemic post-conditioning reduced brain damage in experimental ischemia/reperfusion injury. AB - OBJECTIVES: To determine the protective effects of remote post-conditioning on ischemic brain lesions caused by middle cerebral artery (MCA) occlusion in rats. METHODS: A total of 54 animals were used in this present study. An ischemic stroke model was generated by 90-minute occlusion of right MCA (n = 42). Twelve rats were used as control for studying edema and blood-brain barrier (BBB) integrity. Remote post-conditioning was conducted immediately after MCA occlusion in the bilateral lower limb by occluding and releasing the femoral artery for three cycles; each occlusion and release lasted for 10 minutes. After 24 hours of reperfusion, the cerebral infarct volumes were quantified by 2,3,4 triphenytetrazolium-chloride, brain water content was determined by dry/wet weight method, and damage to the BBB was determined by Evans blue extravasation. RESULTS: Remote post-conditioning significantly reduced brain infarct damage (P<0.0001). Brain edema was significantly (P<0.01) reduced after stroke in the remote post-conditioning group. BBB leakage was significantly reduced in the remote post-conditioning group when compared to the control ischemic groups (P<0.05). CONCLUSION: These results provide evidence that remote post conditioning, which was initiated after ischemia and before reperfusion, protects against brain injury in experimental ischemic stroke. PMID- 21669122 TI - Neuroprotection by local intra-arterial infusion of erythropoietin after focal cerebral ischemia in rats. AB - OBJECTIVES: The neuroprotective effect of erythropoietin has been demonstrated by ischemia and reperfusion models in adult and neonatal rodents. However, administration of high-dose erythropoietin has potential complications. The goal of this study was to determine whether local infusion of low dose erythropoietin offers neuroprotective effects after ischemia and reperfusion injury. METHODS: Adult male Sprague-Dawley rats subject to middle cerebral artery occlusion were randomly divided into three groups: (1) sham group: the rats received the same procedure as the other two groups except that no suture was inserted; (2) vehicle group: intra-artery local infusion of saline was administered via middle cerebral artery after reperfusion; and (3) treatment group: 50 U/kg intra-artery local infusion of erythropoietin was administered via middle cerebral artery after reperfusion. Neurological deficit scores and infarct volume (determined by hematoxylin-eosin staining) were evaluated 48 hours after reperfusion. Apoptosis was measured through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expression of vascular endothelial growth factor and phosphorylated extracellular signal-regulated kinase were investigated by immunohistochemistry method. RESULTS: The results show that intra-artery local infusion of erythropoietin, via the middle cerebral artery, significantly reduced neurological deficit scores, foot fault number, and the infarct volume at 48 hours after reperfusion. Significant reductions were also found in the number of positive cells stained by TUNEL assay within the ischemic core and penumbra. Furthermore, local infusion of erythropoietin increased the expression of phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor. DISCUSSION: Local infusion of low-dose erythropoietin via the middle cerebral artery is shown to be neuroprotective against cerebral ischemia and reperfusion injury. The mechanism of neuroprotection may be associated with the increased expression of phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor. PMID- 21669123 TI - Diffusion tensor imaging and diffusion tensor imaging-fibre tractograph depict the mechanisms of Broca-like and Wernicke-like conduction aphasia. AB - OBJECTIVES: Conduction aphasia is usually considered a result of damage of the arcuate fasciculus, which is subjacent to the parietal portion of the supra marginal gyrus and the upper part of the insula. It is important to stress that many features of conduction aphasia relate to a cortical deficit, more than a pure disconnection mechanism. In this study, we explore the mechanism of Broca like and Wernicke-like conduction aphasia by using diffusion tensor imaging (DTI) and diffusion tensor imaging-fibre tractograph (DT-FT). METHODS: We enrolled five Broca-like conduction aphasia cases, five Wernicke-like aphasia conduction cases and 10 healthy volunteers residing in Beijing and speaking Mandarin. All are right handed. We analyzed the arcuate fasciculus, Broca's areas and Wernicke's areas by DTI and measured fractional anisotrogy (FA). The results of left and right hemispheres were compared in both conduction aphasia cases and volunteers. Then the results of the conduction aphasia cases were compared with those of volunteers. The fibre construction of Broca's and Wernicke's areas was also compared by DTI-FT. RESULTS: The FA occupied by the identified connective pathways (Broca's area, Wernicke's area and the arcuate fasciculus) in the left hemisphere was larger than that in the right hemisphere in the control group (P<0.05). Among Broca-like conduction aphasia cases, the FA of the left Broca's area was smaller than that of the right mirror side (P<0.05), and the FA of the left anterior segment of the arcuate fasciculus was smaller than that of right mirror side (P<0.05). On the other hand, among Wernicke-like conduction aphasia patients, the FA of the left Wernicke's area was smaller than that of right mirror side (P<0.05), and the FA of left posterior segment of arcuate fasciculus was smaller than that of right mirror side (P<0.05). CONCLUSIONS: Conduction aphasia results from not only arcuate fasciculus destruction, but also from disruption of the associated cortical areas. Along different segments of the arcuate fasciculus, the characteristics of language disorders of conduction aphasia were different. A lesion involving Broca's area and the anterior segments of the arcuate fasciculus would lead to Broca-like conduction aphasia, whereas a lesion involved Wernicke's area and posterior segments of the arcuate fasciculus would lead to Wernicke-like conduction aphasia. PMID- 21669124 TI - Public knowledge of stroke in Chinese urban residents: a community questionnaire study. AB - BACKGROUND AND PURPOSE: Intensive control of the risk factors of stroke and the pre-hospital delay after stroke onset both depend on the level of knowledge of stroke in the general population. Our primary objective was to assess the public knowledge about stroke among urban residents in four cities in China. METHODS: A semi-structured interview and questionnaire was delivered in a survey. Standardized risk factor and symptom statements were used to measure knowledge. The setting of two communities from four different cities of China was used to target a mix of social class and geography. Using systematic sampling and the household as a unit, at least 300 households were chosen in one community. Each household selected one person to fill in the self-designed questionnaire. Uniform training of community physicians was conducted before the survey, and the community physicians completed the survey by face to face indoor-investigation. RESULTS: Total integral questionnaires numbered 2519. The investigation showed that (1) hypertension was identified as a risk factor by nearly 90% of residents. Dyslipidemia, smoking, diabetes, and non-modifiable risk factors were identified by less than 65%; (2) medical therapy of hypertension and diabetes was known by nearly 80% of residents, and the awareness of lifestyle modification was less; (3) weakness or numbness were the most common symptoms identified by community residents (80.2%), and the awareness of other symptoms of stroke ranged from 58.2 to 71.2%; (4) the stroke knowledge score and education level were positively correlated (r(s) = 0.088, P<0.001), and age was negatively correlated (r(s) = 0.142, P<0.001); (5) 53.0% of residents would call an emergency medical system once stroke symptoms began; (6) the main sources of information about stroke were television (74.4%), doctors (63.2%) and newspapers (61.8%). CONCLUSION: At present, the urban community residents in China are lacking in knowledge about stroke. Going forward, we should strengthen health education through television, medical staff, newspapers, magazines. Targeted educational populations should be directed at those who are elderly, lower education, male and high risk. PMID- 21669125 TI - Nitric oxide (NO) and asymmetric dimethylarginine (ADMA): their pathophysiological role and involvement in intracerebral hemorrhage. AB - OBJECTIVE: Nitric oxide (NO) has a variety of functions in physiological systems, particularly in the vasculature and the central nervous system. Currently, the imbalance of the pathway involving nitric oxide, nitric oxide synthase, and asymmetric dimethylarginine (NO-NOS-ADMA) is increasingly discussed in connection with endothelial dysfunction. Knowledge about the role of this pathway in intracerebral hemorrhage (ICH), which represents the most devastating stroke subtype, is increasing but still sparse. This article aims to review the current knowledge about the role and metabolism of NO and ADMA. It will also address the role of the NO-NOS-ADMA pathway in ICH and delineate some questions that should be addressed by future studies. METHODS: A literature search regarding the data about NO, NOS, and ADMA and its role in ICH was conducted in PubMed. RESULTS: Experimental data from cell culture and animal models indicate that, after the occurrence of ICH, neuronal and inducible nitric oxide synthases (nNOS and iNOS) are both overexpressed and uncoupled through the induction of blood compound metabolites, including thrombin and inflammatory mediators. ADMA, the most potent endogenous inhibitor of NOS, is also overproduced following dysregulation of its metabolizing enzymes. Dysfunction of the NO-NOS-ADMA pathway results in cell death, blood-brain barrier (BBB) disruption, and brain edema via different pathological mechanisms. However, the available data from clinical studies are still rare and partially contradictory. CONCLUSION: Experimental data suggest an important role for the NO-NOS-ADMA pathway for secondary injury after ICH. Since the literature shows contradictory results, further studies are needed to address current confusion. PMID- 21669126 TI - Functional system scores provide a window into disease activity occurring during a multiple sclerosis treatment trial. AB - BACKGROUND: Average expanded disability status scale (EDSS) score on entry into pivotal trials of multiple sclerosis (MS) therapies lies between 2 and 3. These lower EDSS levels are determined by functional system score (FSS). OBJECTIVE: We examined contributions of each FSS to characterization of MS patients at entry to and exit from the pivotal trial of intramuscular interferon beta-1a (IM IFN-beta 1a), as well as contribution of changes in FSS to changes in EDSS. METHODS: We reviewed FSS and EDSS data collected at 6-month examinations during the IM IFN beta-1a pivotal trial (n = 286). To describe which functional systems were most affected by disease, we used an FSS cutoff of >= 2 (mild to moderate impairment) and defined sustained progression as a >= 1 point change in EDSS score or FSS being maintained for 6 months. RESULTS: The most frequently involved functional systems at baseline (FSS level of >= 2) were cerebellar (38%), pyramidal (37%), and sensory (34%). While all functional systems were affected to some extent by progressing MS, these FSSs were also most often affected at study end, with pyramidal and cerebellar FSSs being the greatest contributors to sustained EDSS progression. Treatment effect with IM IFN-beta-1a was most strongly seen in the pyramidal system. CONCLUSION: In this trial, some FSSs contributed more to detection of progression than others. While changes in lower EDSS were heavily weighted by the pyramidal FSS, all of the FSSs appeared to be important in understanding the overall impact of MS progression, demonstrating the responsive nature of the widely utilized EDSS. PMID- 21669127 TI - Endovascular treatment for cerebral perforating artery aneurysms. AB - OBJECTIVE: Cerebral perforating artery (CPA) aneurysms are rarely reported in the literature, making management decisions challenging. This study is to report neurological outcomes in a single institution experience of perforating artery aneurysms treated endovascularly. METHODS: All cases involving patients with CPA aneurysms who presented to Beijing Tiantan Hospital between September 2006 and September 2009 were reviewed retrospectively. RESULTS: Over 3 years, four patients with four CPA aneurysms were treated. The Hunt and Hess grade on admission ranged from 0 to IV, with intracranial hemorrhage in three of the four patients. Conventional angiography confirmed the presence of the aneurysms, and all patients underwent endovascular embolization using liquid embolic materials with parent artery sacrifice. Associated risk factor in our series of patients was brain arteriovenous malformation. The locations of aneurysm were lenticulostriate artery, anterior choroidal artery and medial posterior choroidal artery. The mean size of the aneurysms was 2.5 mm. The mean modified Rankin scale score at follow-up was 1.25. Three patients in whom the perforating artery was sacrificed had good outcomes, suggesting that loss of the artery is clinically well tolerated. CONCLUSIONS: This case series reveals that endovascular treatment of CPA aneurysms may be an appropriate, effective, and safe therapy. PMID- 21669128 TI - Does routine MR contrast enhancement correlate with internal thrombosis in cerebral cavernous malformations? A radiological-histopathological correlation in a case series. AB - OBJECTIVES: It is well known that cerebral cavernous malformations (CCMs) present with variable degrees of contrast enhancement on routine magnetic resonance imaging (MRI) studies. This is attributed to the presence of a low flow vascular architecture in these lesions. The aim of this preliminary study was to determine whether an additional reason for the different degree of contrast enhancement could be the degree of internal thrombosis. MATERIAL AND METHODS: Fourteen consecutive patients with surgically removed CCMs were included. In all patients, standard preoperative MRI (1.5 Tesla, T1 weighted images without and with contrast agent, slice thickness 5 mm, 0.1 mmol gadolinium/kg body weight, and delay ~5 minutes) and a histological specimen were available. The degree of contrast enhancement (none, little, moderate, and marked) was rated by two independent neuroradiologists blinded to the results of histopathology. The degree of internal thrombosis (none, little, moderate, and marked) was rated by a neuropathologist blinded to the results of MRI. RESULTS: Contrast enhancement was visible in six (43%) CCMs (Cohen's kappa = 0.76 or substantial). The degree of contrast enhancement was not dependent on the degree of internal thrombosis (P = 0.1, Fisher's exact test) and did not correlate with it (r = 0.06, P = 0.83, Pearson's correlation coefficient). CONCLUSION: The flow characteristics of CCMs seem to be the main factor contributing to the degree of contrast enhancement while the degree of internal thrombosis does not influence their contrast affinity. PMID- 21669129 TI - Effects of electromagnetic stimulation on osteogenic differentiation of human mesenchymal stromal cells seeded onto gelatin cryogel. AB - Bone tissue engineering typically uses biomaterial scaffolds, osteoblasts or cells that can become osteoblasts, and biophysical stimulations to promote cell attachment and differentiation. In this study, we investigated the effects of an electromagnetic wave on mesenchymal stromal cells isolated from the bone marrow and seeded upon gelatin cryogel disks. In comparison with control conditions without electromagnetic stimulus, the electromagnetic treatment (magnetic field, 2 mT; frequency, 75 Hz) increased the cell proliferation and differentiation and enhanced the biomaterial surface coating with bone extracellular matrix proteins. Using this tissue-engineering approach, the gelatin biomaterial, coated with differentiated cells and their extracellular matrix proteins, may be used in clinical applications as an implant for bone defect repair. PMID- 21669130 TI - A comparison of antibiotic release between a cement scaffold, a perforated cement scaffold and a cement scaffold mixed to calcium sulphate: in vitro study. AB - One of the most dangerous possible complications in joint replacement is infection due to bacteria adhere to prosthesis surface making biofilm difficult to erase. The gold standard treatment consists in prosthesis removal, placement of antibiotic-impregnated cement spacer and systemic antibiotics therapy. When the infection heals a new prosthesis is implanted. The antibiotic-impregnated spacer is important to maintain the prosthesis space and to guarantee a local high concentration of antibiotics. The release of the antibiotic by the cement happens at its surface so that, increasing this, the concentration of antibiotic should be increased as well. The aim of the present study is to verify the different release of antibiotic in plasma by different groups of scaffolds to identify the best solution to make the antibiotic spacer in septic prosthesis revision. Six groups of three antibiotic impregnated cement cube-shaped have been done. The first, made by only antibiotic and cement, the second by a double concentration of the antibiotic and cement, the third made by the antibiotic cement and perforated in every surface with a needle before hardening, the fourth similar to the previous but with a double concentration of antibiotic, the fifth by antibiotic-impregnated cement mixed with calcium sulphate pellets, the sixth similar to the previous with a double concentration of antibiotic. The cubes were immersed in plasma and the concentration of antibiotic released valued at specific times. The perforated cement scaffold demonstrated the best result during the first four weeks. PMID- 21669131 TI - Scaffolds combined with stem cells and growth factors in healing of pseudotumoral lesions of bone. AB - Reconstructions of large lesions or defects often require a bone graft or a bone substitute to promote healing. In common practice the reconstruction of a bone defect is dependent on the site and size of the lesion: in long bones intercalary defects may be managed with Ilizarov technique of bone transport and distraction osteogenesis or the use of a free or pedicled vascularized bone graft, or with Masquelet technique. For cavitary defects the available surgical options include autograft, allograft or xenograft or the use of synthetic scaffolds to promote bone regeneration. In order to promote a faster bone healing tissue engineering proposed the application of enriched graft to fill bone defects. The employment of enriched bone graft has been our choice in the last years to fill contained defects following curettage of a pseudotumoral lesion of bone. We report our clinical experience in terms of safety and success of these procedures at a long term follow up. PMID- 21669132 TI - Stimulation of bone formation and fracture healing with pulsed electromagnetic fields: biologic responses and clinical implications. AB - Pulsed electromagnetic fields (PEMF) have been used for several years to supplement bone healing. However, the mode of action of this non-invasive method is still debated and quantification of its effect on fracture healing is widely varied. At cellular and molecular level, PEMF has been advocated to promote the synthesis of extracellular matrix proteins and exert a direct effect on the production of proteins that regulate gene transcription. Electromagnetic fields may also affect several membrane receptors and stimulate osteoblasts to secrete several growth factors such as bone morphogenic proteins 2 and 4 and TGF-beta. They could also accelerate intramedullary angiogenesis and improve the load to failure and stiffness of the bone. Although healing rates have been reported in up to 87 % of delayed unions and non-unions, the efficacy of the method is significantly varied while patient or fracture related variables could not be clearly associated with a successful outcome. PMID- 21669133 TI - Regional anesthesia in a child with sotos syndrome. PMID- 21669134 TI - Osgood Schlatter lesion: histologic features of slipped anterior tibial tubercle. AB - No study reports the histological features of the various zone of the anterior tubercle of the tibia in the different stages of the Osgood-Schlatter (O-S) lesion. For this reason we carried on an histological study. Specimens were taken from 13 patients with O-S lesion prior to surgery. In 4 cases in the apophyseal stage lesions were present in an altered fibrocartilage anterior to the ossification centre. In 9 cases in the epiphyseal stage varying degrees of reparative tissues were observed in the bed of the fragment of the secondary ossification centre. In 3 of them a zone of lesion was observed within the fibrocartilage anterior to the ossification centre. These results suggest that the slippage of the patellar tendon insertion may be progressive and caused by pathological fibrocartilage. PMID- 21669135 TI - Side effects of radiation in musculoskeletal oncology: clinical evaluation of radiation-induced fractures. AB - Radiation therapy and chemotherapy, while they remain an essential part of the multidisciplinary treatment of cancers, they have led to unwanted complications. Radiation-induced complications include wound and bone, growth, nervous system, tumorigenic, lung, gastrointestinal, hepatic and other complications. In this article we review the side effects of radiation therapy in musculoskeletal oncology emphasizing on bone, present our long experience, and discuss the current literature regarding radiation-induced bone complications and their management and outcome. PMID- 21669136 TI - The clinical diagnosis of meniscal tear is not easy. Reliability of two clinical meniscal tests and magnetic resonance imaging. AB - AIM: to clarify the reliability of two clinical meniscal tests, McMurray's and Apley's and the MRI imaging, in order to establish how to reduce unjustified arthroscopies. METHODS: 102 patients were selected out of 160. All patients were submitted to a triple clinical examination (by a young surgeon and two skilled surgeons), MRI and an arthroscopic procedure. The investigated clinical tests were McMurray's and Apley's test. The positivity or negativity of the tests and MRI were compared to arthroscopic findings. Arthroscopy is considered the gold standard for the diagnosis of meniscal lesions. We measured the length of the meniscal lesions in order to correlate it to the clinical findings. RESULTS: From the clinical examination, we got the following data: McMurray's test: sensitivity 79.7%, specificity 78.5%, accuracy 79.4%, positive likelihood ratio 3.7, negative likelihood ratio 0.2. Apley's test: sensitivity 83.7%, specificity 71.4%, accuracy 80.3%, positive likelihood ratio 2.9, negative likelihood ratio 0.2. The composite assessment is strictly dependent on how the discordance of the two tests is evaluated. The assessment of the clinical tests was done even in relation to medial or lateral meniscal lesion. No statistical difference was found about the length of the meniscal tear. MRI gave the following results: sensitivity 78.3%, specificity 85.7%, accuracy 80.3%. CONCLUSIONS: If we use, as diagnostic means, McMurray's and Apley's clinical tests and MRI as imaging procedure, we have an accuracy of about 80%. It is important to keep in mind that it is not possible to have the absolute certainty of make a correct diagnosis in case of meniscal lesions. Patients, too, have to be informed about the risk of a negative arthroscopy. PMID- 21669137 TI - Tendinopathy and inflammation: some truths. AB - Overuse tendinopathies are a common cause of pain and disability in athletes. According to histological findings, it is a failed healing response to overuse tendon injury. In obesity, macrophages and mast cells migrate to adipose tissue, and the resulting decreased availability of immune circulating cells should be responsible for less effective immune responses to acute tendon injury. In diabetic patients, free glucose molecules attach to collagen, alter collagen solubility, increase resistance to enzymatic degradation, and impair cross linking, contributing to the subsequent development of chronic tendinopathy secondary to a failed healing response to a tendon insult. Prolonged systemic, low-grade inflammation and impaired insulin sensitivity act as a risk factor for a failed healing response after an acute tendon insult, and predispose to the development of chronic overuse tendinopathies. Further studies may reveal novel therapeutic treatment approaches. PMID- 21669138 TI - Bone grafts and bone graft substitutes in prosthetic hip surgery replacement. AB - The need for bone grafting procedures to replace skeletal defects has become more considerable because of increased opportunities to save major bone loss. We report our experience and a critical analysis about the role of bone grafts and bone graft substitutes in prosthetic hip surgery replacement. PMID- 21669139 TI - Regulatory functions of insulin-like growth factor binding proteins in osteoarthritis. AB - Insulin-like growth factor binding proteins (IGFBPs) are a group of secreted proteins, which bind to IGF-I (and IGF-II) with high affinity and modulate the biological actions of IGFs. Abundant evidence points the importance of the IGF I/IGFBP system on both cell growth and differentiation. A role for the IGF I/IGFBP system in the regulation of normal human cartilage has been previously reported. In this context, recent studies suggest an emerging role for IGFBPs in the failure of cartilage during osteoarthritis (OA). Indeed, increased IGFBP levels have been reported in both the articular cartilage and synovial fluid from patients with OA. Overexpression of IGFBPs, by altering the bioavailability and function of IGFs, is likely to deliver IGFs-independent signals for chondrocyte survival. This, at least in part, might explain the degenerative changes of the cartilage in OA. Further studies are necessary to clarify the mechanisms that cause the overexpression of IGFBPs in patients with OA. Advances in our understanding of the relationship between osteoarthritis and the IGF-I/IGFBP system may lead to new treatment strategies for this degenerative disease. PMID- 21669141 TI - Use of collagen scaffold and autologous bone marrow concentrate as a one-step cartilage repair in the knee: histological results of second-look biopsies at 1 year follow-up. AB - Chondral articular defects are a key concern in orthopaedic surgery. To overcome the disadvantages of autologous chondrocyte implantation (ACI) and to improve the outcomes of autologous matrix-induced chondrogenesis (AMIC), the latter technique is currently augmented with bone marrow concentrate injected under or seeded onto the scaffold. However, to date, only a little is known about histological outcomes of either the AMIC technique or AMIC associated with bone marrow concentrate. This study aimed to evaluate the quality of the repair tissue obtained from biopsies harvested during second-look arthroscopy after arthroscopic AMIC augmented with bone marrow concentrate. We analysed five second look core biopsies harvested at 12 months follow-up. At the time of biopsy the surgeon reported the quality of the repair tissue using the standard ICRS Cartilage Repair Assessment (CRA). Every biopsy together with patient data was sent to our centre to undergo blind histological evaluation (ICRS II Visual Histological Assessment Scale) and data analysis. Five asymptomatic patients (mean age 43.4 years) had isolated lesions (mean size was 3.7 cm2) at the medial femoral condyle. All the implants appeared nearly normal (ICRS CRA) at arthroscopic evaluation and had a mean overall histological (ICRS II) of 59.8+/ 14,5. Hyaline-like matrix was found in only one case, a mixture of hyaline/fibrocartilage was found in one case and fibrocartilage was found three cases. Our clinical and histological data suggest that this procedure achieved a nearly normal arthroscopic appearance and a satisfactory repair tissue, which was possibly still maturing at 12 months follow-up. Further studies are needed to understand the true potential of one-step procedures in the repair of focal chondral lesions in the knee. PMID- 21669140 TI - Ultra high molecular weight polyethylene is cytotoxic and causes oxidative stress, even when modified. PMID- 21669142 TI - Fabrication, characterization and cell cultures on a novel composite chitosan nano-hydroxyapatite scaffold. AB - This paper deals with the characterizations made during the development of a nano HAp loaded chitosan scaffold, obtained by the freeze-drying technique combined with a novel in situ crystal growth method. The nano-composites were characterized by a highly porous and interconnected structure. The XRD patterns and calculated domain sizes of the HAp nano-crystals nucleated on the chitosan scaffolds are very similar to the ones recorded for deproteinated bone apatite. Both osteoblasts (MG63) and mesenchimal cells (hMSC) were showing good proliferation and adhesion onto the scaffolds. The presence of extensive filopodia and excellent spreading in and around the interconnected porous structure, indicated a strong cellular adhesion and growth. Moreover a good hMSC osteogenic differentiation has been verified. The observations related to well developed structure morphology, physicochemical properties and high cytocompatibility suggest that the obtained chitosan-nHA porous scaffolds are potential candidate materials for bone regeneration. PMID- 21669143 TI - Platelet rich plasma and tendinopathy: state of the art. AB - Platelet-rich plasma (PRP) is increasingly used in the management of tendon injury in sports, supposedly accelerating the process of healing, tissue regeneration, and return to play. However, the scientific clinical evidence to support its use is scanty, and more level I studies need to be performed to justify its widespread use. PMID- 21669144 TI - Polytherapy in bone regeneration: clinical applications and preliminary considerations. AB - Polytherapy, namely the simultaneous application of three fundamental elements necessary for bone regeneration (growth factors, osteogenic cells and osteoconductive scaffolds) seems to lead to a very high success rate in the treatment of complex non-union (NU) cases and critical bone defects. NU are reported in 5-10% of long bone fractures. The use of autologous bone grafts has been long-considered the gold standard for the treatment of these cases. However the harvesting procedure from the iliac crest increases surgery time and presents some donor site complications which may be elevated. In recent years, surgeons have some alternatives to autologous grafting such as: application of organic or synthetic bone substitute, application of mesenchymal stromal cells (MSC) or growth factors (GF). In the literature there are many studies available about their application in monotherapy, but unfortunately the healing rate doesn't exceed 90%. Polytherapy seems to be a logical option to improve the healing rate, nevertheless, there are not still extensive studies that validate this strategy and moreover, some questions are not resolved. PMID- 21669145 TI - Histological and ultrastructural reaction to different materials for orthopaedic application. AB - Prosthetic joints loosening in absence of infection is the most common reason for revision surgery and is known as aseptic loosening. A significant role in the pathogenesis of implant failure undoubtedly played by the generation of wear debris, mainly from the load bearing joint surfaces, and the cellular reaction through the formation of tissue membrane around implants. This article analyzes histologic, immunohistochemical ad ultrastructural aspects of periprosthetic tissue membrane collected at time of surgical revision, paying attention on cell host response to different materials: metals, polyethylene and ceramics. Dimension of particles seems to be crucial in the activation of different cell population to wear debris. PMID- 21669146 TI - Pridie's marrow stimulation technique combined with collagen matrix for cartilage repair. a study in a still growing sheep model. AB - The study assessed the spontaneous repair of large critical full-thickness defects (FTD) in not mature and still growing sheep model and compared repaired tissue after Pridie's technique to the same technique combined with type I collagen matrix. Thirty-six FTD were divided into group 1 (untreated), group 2 (treated according to Pridie's technique with 10.2 as value ratio of marrow stimulation), and group 3 (treated using Pridie's marrow stimulation technique, and covered by a type I collagen matrix) . The histological exam at 12 months showed fibrous repair of the untreated defects. In group 2 the reparative tissue showed a prevalence of fibrocartilaginous tissue. The mean ICRS visual assessment scale score was 8.9. In group 3 the reparative tissue was similar to the normal surrounding cartilage. The mean ICRS visual assessment scale score was 14.7. Subchondral drilling with defined ratio between the stimulated marrow area and the lesion area could improve the quality of FTD repair in articular cartilage in not mature and still growing stifle sheep model if combined with type I collagen matrix. PMID- 21669147 TI - An original method for the evaluation of in vivo controlled release of the ceramic materials. AB - In recent years, the use of ceramic materials in orthopaedics and dentistry is becoming increasingly popular. However, it is important to know their biological and mechanical properties to optimize their use. The aim of this study is to describe a specific method to assess in vivo the effects of chronic release of ceramic materials implanted, in relation also to the type of material, pellets or powders. This was achieved by implanting ceramic powders and pellets, formed by low cohesion grains, in the patellar tendon of 48 New Zealand adult rabbits (24 with powders and 24 with pellets). The motion of the joint allowed easily and progressively the release of grains, detached from surface of the pellets and released to the joint space. Animals were sacrificed at different intervals (1, 3, 6, 12 months). Retrieved knee joints underwent X-Ray, histological and ultrastructural analysis. PMID- 21669148 TI - Bone integration of new stemless hip implants (proxima vs. nanos). A DXA study: preliminary results. AB - The development of short femoral prostheses has the advantage to preserve bone and soft tissues, restore hip geometry, permit mini-invasive techniques and allow quickly return to an active life, but very few studies described bone reaction to these new designed prostheses. The aim of the present study was to evaluate the osseointegration of two different partial neck retained stemless hip prosthesis at one year after surgery, measured by the changes of periprosthetic bone mineral density (BMD) in 5 regions of interest (ROIs) using a dual-energy X ray absorptiometry (DXA) device. The signs of stress-shielding were evaluated by standard radiographs. Thirty-two uncemented primary total hip arthroplasty (THA) patients allocated into 2 groups were evaluated. In the first group (n=19) a Proxima (De-Puy-J&J) hip stem was implanted. In the second group (n=12) a Nanos (Smith & Nephew) hip stem was used. We found that both the implants preserve metaphyseal bone stock and increase periprosthetic BMD. In Nanos prostheses a significant higher BMD values were observed in region of interest (ROI) 3 and 4 (p<0.05). No differences were found in ROIs 1, 2, and 5. Proxima stem seem to produce a physiological strain distribution in the femur. No signs of stress shielding were present in both the implants. In conclusion, this preliminary DXA analysis showed a physiological integration of both the stems that reproduces the biomechanical stress of proximal femur. New designed short stem implants showed optimal osseointegration after one year, and therefore appears an excellent alternative to traditional long stem hip prostheses. PMID- 21669149 TI - The effect of autologous conditioned plasma on the treatment of focal chondral defects of the knee. An experimental study. AB - The purpose of the present study was to evaluate the effect of local application of Autologous Conditioned Plasma (ACP) on the treatment of full-thickness cartilage injuries of the knee. The hypothesis of the study was that ACP can enhance healing response of injured cartilage. A full-thickness chondral lesion on the weight-bearing area of the medial femoral condyle was performed in 30 sheep. Animals were divided into 2 groups, according to postoperative treatment: in group 1, weekly injections of ACP for five times were performed; in group 2, lesions were left untreated. Animals were sacrificed at 3, 6 and 12 months after treatment. A histological evaluation was performed according to a modified O'Driscoll histological score. Comparison between groups for each time interval was performed with the Student's t-test. Significance was set at P<0.05. A post hoc power analysis was performed according to the hypothesis of the study. Histological evaluation at 3 and 6 months showed that group 1 had significantly greater total score than group 2. At 12 months, no significant difference was observed between groups. In conclusion, local injections of ACP for treatment of full-thickness cartilage injuries did not produce hyaline cartilage. However, it promoted reparative response of the cartilage defect until 6 months after treatment. PMID- 21669150 TI - Antibiotic-coated nails in orthopedic and trauma surgery: state of the art. AB - Optimal management of deep infections in orthopedic and trauma surgery is often challenging. Traditional prophylactic and treatment approaches are based on the systemic administration of relatively high doses of antibiotics, which may result in a number of side effects. Furthermore, systemically administered antimicrobials may not reach adequate concentration at the desired site. Finally, traditional approaches are based on two-step protocols, thus delaying definite fixation. In recent years, antibiotic-coated intramedullary nails (ACINs) have been introduced, which offer the advantage of delivering antibiotics locally, thus increasing their local concentrations and length of action. In addition, ACINs offer the great advantage of combining antimicrobial prophylaxis/treatment and stabilization in a single step. Preliminary evidence by small clinical studies appears to support the effectiveness of ACINs in the management of chronic osteomyelitis and infected non-unions, with high rates of infection eradication and bone union. However, randomized clinical trials are needed to definitely establish ACINs ' effectiveness and safety. PMID- 21669151 TI - Local adjuvants in surgical management of bone metastases. AB - Curettage is one of the most common method for surgical treatment of bone metastasis. Local adjuvant improve most commonly used for improving the effect of curettage in local cancer surgery may exerted their effects either chemically either physically; in Orthopedic Oncology the most common are phenol, liquid nitrogen, laser, and cement. This article reviewed the main characteristics of the most common chemical and physical agents used in bone oncology, emphasizing the toxic effects of some of them, especially phenol and liquid nitrogen. PMID- 21669152 TI - Trabecular metal cup without augments for acetabular revision in case of extensive bone loss and low bone-prosthesis contact. AB - Current evidences in revision hip arthroplasty suggest to treat severe acetabular bone loss with dedicated implants, such as anti-protrusio cages, stemmed cups, modular systems supplied with iliac flanges and obturatory hook. However recent literature is reporting satisfactory outcomes with simple elliptical Trabecular Metal cups. Purpose of the study was to evaluate mid-term results of such a surgical procedure. All hip revisions performed from 2008 to 2009 with implantation of a TMT multi-hole acetabular cup without augmentations were retrospectively reviewed. The cases with low-degree acetabular bone loss (stage I and II according to GIR classification), with surgical report poorly describing the bone defect, with inadequate pre- and post-operative x-rays were ruled out. Twenty-five cases were identified, but four were lost to follow-up. The twenty one patients were 71 year-old on average (from 60 to 82), with stage IV bone loss in 6 cases and stage III bone loss in 15 cases. Mean interval from surgery to evaluation was 20.9 months (from 13 to 30). The evaluation included bone prosthesis contact estimation, component position, survivorship, complications, final Harris Hip Score, presence of periprosthetic radiolucencies. Host bone prosthesis contact was estimated to be about 35%. Only three implant were subsequently reoperated (for infection, early migration, recurrent dislocation). The HHS among non-reoperated 18 patients was 81.96 on average (from 63.44 to 95.82). Six cases showed thin radiolucencies in one of the three Charnley zones, while three cases showed radiolucencies in two. None of these images was evolutive, thus they were not considered signs of loosening. The mid-term results of this series confirm the hypothesis that a porous tantalum acetabular cup is an effective option to deal with difficult acetabular revisions. Although no extra acetabular fixation device is available, the very high surface friction guaranteed by the material and the supplemental stability provided by trans acetabular screws seem to be sufficient to allow satisfactory reimplantation even in severely damaged pelves. PMID- 21669153 TI - Bioplasty for vertebral fractures: preliminary results of a pre-clinical study on goats using autologous modified skin fibroblasts. AB - The debate is still ongoing about the long term effects of the mininvasive vertebral augmentation techniques and their usefulness in treating more complex cases where a bone inducing effect more than a merely bone substitution would be suitable, such as the vertebral fractures in young patients. We previously developed a clinically relevant gene therapy approach using modified dermal fibroblasts for inducing bone healing and bone formation in different animal models. The aim of this study is to show the feasibility of a minimally invasive percutaneous intrasomatic ex vivo gene therapy approach to treat thoracolumbar vertebral fractures and anterior column bone defects in a goat model. PMID- 21669154 TI - Angiogenesis in hand chondroma: an immunohistochemical study. AB - Hand chondroma is a particular cartilagineous tumour, being clinically benign, but morphologically malignant. This study investigates the expression of VEGF together with other growth factors and proliferation markers such as TGFbeta2, Ki 67, TNF, FGF1, P53 in 8 cases of hand chondroma treated with courettage, in order to define the ethiopathogenesis of this tumour and the clinical significance of the resulting immunohistochemical profile, with particular respect to angiogenesis. VEGF was expressed in all cases; 5 cases were positive for TFGbeta2 and 3 for PDGF. None of the other factors was expressed. On the basis of histologic results a specific model of tumour progression based on the indicators of angiogenesis could be related to hand tumours, in which VEGF expression should be the first stadium of the tumour aggressiveness, and the following PDGF, TGF 2 expression should be accompanied with a morphological outline worsening. Nevertheless the non constant expression of these indicators and the absent expression of proliferated indicators can explain the scant tendency to the relapse in presence of accurate curettage. It is important to remember that the cellular polymorphism typical of the cartilaginous tumours does not allow the application of an only oncogenesis model. PMID- 21669155 TI - The manangement of knee cartilage defects with modified amic technique: preliminary results. AB - Cartilage defects represent a common problem in orthopaedic practice. The knee is frequently involved and the medial femoral condyle is the most common localization. Predisposing factors are: traumas, inflammatory conditions and biomechanics alterations. Several surgical options are available once correct diagnosis is given and accurate patient evaluation has been performed. The aim of our study was to prospectively evaluate functional results of modified autologous matrix induced chondrogenesis (AMIC) technique in a population of patients affected by focal cartilage defects A population of 17 patients was enrolled in this study. 10 patients were male, mean age at the time of surgery was 39 years, right side was involved in 11 cases. All patients were evaluated with accurate physical exam and complete imaging study. At an average FU of 36 months, mean IKDC score and Lysholm score improved from 32 to 82 and from 38 to 74. 13 patients out of 17 (76.5%) were satisfied or extremely satisfied with their functional result. MRI control showed reduction of the defect area and subchondral oedema in 10 cases (58.8%). AMIC technique is a relatively new option in the treatment of full thickness cartilage lesions. It enhances the advantages of microfractures since the Chondrogide membrane protects and stabilizes the blood plug acting as a matrix for new cartilage formation. First reports on AMIC technique, show comparable results to autologous chondrocyte implantation (ACI) with the advantage of a single stage technique and no donor site morbidity. AMIC technique represents a new option in the treatment of full thickness cartilage defect. It is safe and reliable. Our data are in accordance with previously reported series in literature and confirm the good objective and subjective results of this procedure. PMID- 21669157 TI - Orthopaedic research in italy: state of the art. AB - The most significant results in experimental and clinical orthopaedic research in Italy within the last three years have been primarily in major congenital diseases, bone tumors, regenerative medicine, joint replacements, spine, tendons and ligaments. The data presented in the following discussion is comparable with leading international results, highlighting Italian orthopaedic research excellemce as well as its shortcomings. PMID- 21669156 TI - Zirconia toughened alumina (ZTA) powders: ultrastructural and histological analysis. AB - Ceramic materials, as Alumina and Zirconia, has made an improvement in the choice of new biomaterials for the load bearing application in dental and orthopaedic implants. These materials has shown mechanical resistance to high stress related to weight bearing and low debris in time. For this reason they are indicated on young patients implant, with high demanding activities and long life expectance. In literature however the risk of chronic inflammation due to chronic wear debris release and the possibility of carcinogenesis, is still to be definitively investigated. Another point to investigate is the acute reaction of the tissue in case of acute release of powders of these materials. The aim of this study was to investigate the possible local and systemic acute effects of ceramic precursors in form of powders of different size when released into articular joint. Powders of ZTA were implanted in the knee joint of twenty-four New Zealand white adult rabbits, that were sacrificed at 1,3,6, and 12 months. Radiographic, histological and immunoistochemestry analysis were conducted on periprosthetic tissue and peripheral organs, to verifying local host response and systemic toxic effects. PMID- 21669158 TI - Spinal infection multidisciplinary management project (SIMP): from diagnosis to treatment guideline. AB - Spine infections require a multidisciplinary approach to be treated and solved. A guide line to drive physicians in the deep complexity of such a disease is extremely helpful. SIMP suggests a flow-chart built up on clear concepts such as right and well managed antibiotic therapy, sound stability of the spine, correct and smart use of the standard and functional imaging techniques, such as f18 FDG PET/CT. In 16 months a total of 41 patients have been treated for spondylodiscitis, discitis and vertebral osteomyelitis by our team of physicians and 25 patients have been enrolled in a prospective study whose target is the assessment of the SIMP flow-chart and of every single aspect that characterize it. PMID- 21669159 TI - [The phlegm theory of gastric cancer]. AB - Based on years of ancient literature research and clinical experience, Professor Pin-kang Wei developed the phlegm theory of gastric cancer. In light of the properties of gastric cancer and the method of differentiating syndromes within the traditional Chinese medicine (TCM) paradigm, it is believed that gastric cancer is closely related with phlegm. Much ancient literature regarding the relationship between phlegm and gastric cancer was reviewed to explain the rationale and academic inheritance of the phlegm theory. In this theory, gastric cancer is regarded as a form of phlegm stagnation and consists of phlegm core, phlegm collateral and phlegm contamination. In order to explain the mechanism of development, recurrence and metastasis of gastric cancer, phlegm contamination is regarded as the most fundamental cause and pathogenesis of gastric cancer. The therapy of resolving phlegm and dispersing nodules is suggested for the fundamental treatment of gastric cancer. PMID- 21669160 TI - [Concept and significance of a subjective and multiple index system of clinical evaluation for traditional Chinese medicine]. AB - Traditional Chinese medicine (TCM) has its own system of diagnosis and treatment theory, and its methods for evaluating clinical efficacy are different from those of Western medicine. Applying evaluation techniques and methods that are used in Western medicine mechanically to TCM will not work. So building evaluation techniques, which adhere to regulations and characteristics of TCM, is necessary and imperative. As the quality of life and patient-reported outcome instruments were brought into practice and developed, clinical evaluation ideas and methods for TCM are provided with an opportunity for development. This article puts forward the concept of subjective complex outcomes (SCOs), which constitutes subjective feelings gained from the patient, doctor and caregiver, different from laboratory parameters. SCOs provide a multidimensional and complex health-related quality of life (HRQL) assessment and focus on the source of assessment information of diseases. This article also introduces a case study building SCO methods of TCM treatment for chronic obstructive pulmonary diseases, in order to promote discussion and provide a platform for future research. PMID- 21669161 TI - The principle of randomization in scientific research. AB - Scientific research design includes specialty design and statistics design which can be subdivided into experimental design, clinical trial design and survey design. Usually, statistics textbooks introduce the core aspects of experimental design as the three key elements, the four principles and the design types, which run through the whole scientific research design and determine the overall success of the research. This article discusses the principle of randomization, which is one of the four principles, and focuses on the following two issues--the definition and function of randomization and the real life examples which go against the randomization principle, thereby demonstrating that strict adherence to the randomization principle leads to meaningful and valuable scientific research. PMID- 21669162 TI - An initial report on the efficacy of a millesimal potency Arsenicum Album LM 0/3 in ameliorating arsenic toxicity in humans living in a high-risk arsenic village. AB - BACKGROUND: Millions of people are at risk of groundwater arsenic contamination, and there is no known remedy that can effectively remove the symptoms of prolonged arsenic poisoning. A potentized homeopathic drug, Arsenicum Album LM 0/3 (Ars Alb LM 0/3), is claimed in homeopathic literature to have the ability to treat symptoms similar to that of arsenic poisoning. OBJECTIVE: This study examines whether Ars Alb LM 0/3 could provide some degree of amelioration for the victims living in an arsenic-affected village where no arsenic-free drinking water is available. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This study was carried out on volunteers living in an arsenic-affected village where no arsenic-free drinking water is available. Twenty-eight volunteers from the village of Dasdiya, in Haringhata block under Nadia District, West Bengal, India, an arsenic-contaminated village where wells contain 55 to 95 MUg/L arsenic, were selected to undertake a double-blind and placebo-controlled trial. The subjects provided samples of blood and urine before and after 2 months of taking either "verum" or "placebo". Another 18 subjects living in an arsenic-free village, served as the negative controls. MAIN OUTCOME MEASURES: Samples of blood and urine from the subjects were assayed for arsenic content, according to various toxicity biomarkers and pathophysiological parameters. RESULTS: Out of the original 28 subjects, only 14 subjects provided samples while the other 14 dropped out. There were elevated levels of arsenic in the blood and urine, alkaline and acid phosphatases, lipid peroxidation, and glutathione activities and increased blood glucose, triacylglycerol, cholesterol, and low-density lipoprotein cholesterol contents, whereas there were decreased levels of aspartate and alanine aminotransferases, gamma glutamyl transferase, glucose-6 phosphate dehydrogenase contents, high-density lipoprotein cholesterol and packed cell volume in the subjects. After 2 months of homeopathic remedy administration, the verum-fed subjects showed positive modulations within these parameters with slight lowering of matrix metalloproteinase activity as compared with the placebo group. CONCLUSION: Ars Alb LM 0/3 shows potential for use in high-risk arsenic villages as an interim treatment for amelioration of arsenic toxicity until more extensive medical treatment and facilities can be provided to the numerous victims of arsenic poisoning. PMID- 21669163 TI - [Relieving pre-exam anxiety syndrome with wrist-ankle acupuncture: a randomized controlled trial]. AB - BACKGROUND: Pre-exam anxiety syndrome is a common condition occurring in pre-exam students and directly affects their examination performance and physical state. Wrist-ankle acupuncture has significant therapeutic effects in treating mental disorders and may also relieve the symptoms of pre-exam anxiety syndrome. OBJECTIVE: To assess the therapeutic effect of wrist-ankle acupuncture on pre exam anxiety syndrome. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 60 students who met the inclusion criteria of pre-exam anxiety syndrome were enrolled from a university in Shanghai and they were randomly divided into treatment group and control group. There were 30 cases in each group, and no case failed to follow-up. In the treatment group, wrist-ankle acupuncture was adopted to point upper 1 bilaterally (impression between flexor carpi ulnaris tendon and ulnar margin), and there was no requirement for Deqi (arrival of qi). In the control group, sham acupuncture was adopted. The treatment was applied 3 times totally in both groups one week before the exam, once every other day, each time with the needles retained for 30 min. MAIN OUTCOME MEASURES: The therapeutic effects were compared between two groups. Before and after 3 treatments, Sarason Test Anxiety Scale (TAS) and Expectation and Treatment Credibility Scale (ETCS) were measured and evaluated. RESULTS: The therapeutic effect experienced by the treatment group was better than that of the control group (P<0.05). There were no statistically significant differences in TAS and ETCS before treatment between the two groups. The scores of TAS after treatment in two groups were higher than those before treatment (P<0.05, P<0.01). There were statistical differences in TAS absolute difference and TAS relative difference between the two groups and the treatment group had better results (P<0.05, P<0.01). After treatment, patients in the treatment group had higher scores in ETCS than those in the control group (P<0.05, P<0.01). No adverse reaction was reported. CONCLUSION: Wrist-ankle acupuncture can relieve the symptoms of pre-exam anxiety syndrome significantly, and this therapy is highly safe. PMID- 21669164 TI - Effects of soy extract on pentylenetetrazol-induced seizures in ovariectomized rats. AB - OBJECTIVE: To investigate the effects of soy extract on pentylenetetrazol (PTZ) induced seizures in ovariectomized (OVX) rats. METHODS: Female Wistar rats were randomly divided into 4 groups (n=15 in each group) as follows: sham-operated, OVX, low-dose soy (LDS) and high-dose soy (HDS). The rats in each group were divided into two subgroups and received daily injection of a low dose of PTZ (40 mg/kg body weight, intraperitoneally, n=7 in each subgroup) for 14 d or a single injection of a high dose of PTZ (90 mg/kg body weight, intraperitoneally, n=8 in each subgroup). The rats of LDS and HDS groups were injected with 20 and 60 mg/kg body weight of soy extract intraperitoneally, respectively, just 30 min before each PTZ injection. The rats of the sham-operated and the OVX groups received saline instead of soy extract. After treatment, the rats were placed in a plexiglas cage and their behaviors were observed for 60 min. RESULTS: The results of repeated injection of low dose of PTZ during 14 d showed that the seizure score of the rats of OVX group on days 3, 5, 8, 10, 11, 12, and 13 was lower than that of the sham-operated group (P<0.05 or P<0.01). However, the rats of both LDS and HDS groups had higher score compared with the OVX group on the mentioned days (P<0.05 or P<0.01). The results of a single injection of a high dose of PTZ showed a significant increase (P<0.01) in the generalized tonic-clonic seizure (GTCS), but not the minimal clonic seizure (MCS) in the OVX rats compared with the sham-operated rats. Treatment with both low and high doses of soy extract significantly decreased the GTCS and MCS latencies compared with the OVX group (P<0.01). CONCLUSION: Female hormones affect seizure severity induced by PTZ, and phytoestrogens of soy mimic this effects. However, more investigations need to be done in the future. PMID- 21669165 TI - Identification of antiplatelet and acetylcholinesterase inhibitory constituents in betel nut. AB - OBJECTIVE: To investigate the possible mechanism and the compound(s) responsible for the antiplatelet and acetylcholinesterase (AChE) inhibitory effects of Areca catechu crude extract (Ac.Cr). METHODS: Aqueous-methanol (70%) was used for extraction of plant material (betel nut). Antiplatelet activity was measured in human platelet-rich plasma by using a Lumi-aggregometer while anti-AChE activity was measured spectrophotometrically in vitro. In an attempt to find the responsible compound(s) in betel nut for antiplatelet and anti-AChE activities, different commercially available betel nut compounds were tested. RESULTS: Ac.Cr inhibited platelet aggregation induced by arachidonic acid (AA), adenosine diphosphate (ADP), platelet-activating factor (PAF), epinephrine and Ca(2+) ionophore. Ac.Cr was the most potent in inhibiting ADP- and Ca(2+)-ionophore induced aggregation. In the AChE assay, Ac.Cr showed significant AChE inhibitory activity with almost complete inhibition of the enzyme. Out of the tested compounds, none of the compounds in betel nut showed any antiplatelet effect except for catechin that was the most potent against epinephrine-induced aggregation. Catechin was significantly less potent than Ac.Cr, indicating a presence of additional compound(s) with antiplatelet activity. For the AChE inhibitory effect, only tannic acid, gallic acid, diosgenin and isoguvacine were found to be active, whereby tannic acid was more potent than Ac.Cr. CONCLUSION: This study shows the possible antiplatelet and AChE inhibitory potential of betel nut while further studies are needed to confirm and identify more compounds in betel nut for these actions. PMID- 21669166 TI - Antinociceptive, anti-inflammatory and antidiarrheal activities of ethanolic calyx extract of Hibiscus sabdariffa Linn. (Malvaceae) in mice. AB - OBJECTIVE: To evaluate the antinociceptive, anti-inflammatory and antidiarrheal activities of the ethanolic calyx extract of Hibiscus sabdariffa Linn. in mice. METHODS: In the present study, the dried calyxes of H. sabdariffa were subjected to extraction with 95% ethanol and the extract was used to investigate the possible activities. Antinociceptive activity of the extract was evaluated by using the acetic acid-induced writhing test. The anti-inflammatory effect of the extract was tested by using the xylene-induced ear edema model mice. Castor oil induced diarrheal model mice were used to evaluate the antidiarrheal activity of the extract. RESULTS: In acetic acid-induced writhing test, the extract produced inhibited writhing in mice significantly compared with the blank control (P<0.01). The extract showed significant inhibition of ear edema formation in xylene-induced ear edema model mice in a dose-related manner compared with the blank control (P<0.01). The extract demonstrated a significant antidiarrheal activity against castor oil-induced diarrheal in mice in which it decreased the frequency of defecation and increased the mean latent period at the doses of 250 and 500 mg/kg body weight (P<0.01). CONCLUSION: The above mentioned findings indicate that the calyx extract of H. sabdariffa possesses significant antinociceptive, anti-inflammatory and antidiarrheal activities that support its uses in traditional medicine. PMID- 21669167 TI - [Andrographolide inhibits extracellular signal-regulated kinase 1/2 signaling pathway in activated macrophages]. AB - OBJECTIVE: To investigate the effects of andrographolide on extracellular signal regulated kinase 1/2 (ERK1/2) signaling pathway and tumor necrosis factor-alpha (TNF-alpha) expression in lipopolysaccharide (LPS)-activated macrophages. METHODS: LPS-activated mouse peritoneal macrophages were cultured in media with different concentrations of andrographolide. Cytotoxicity of andrographolide was detected by cell counting kit-8. The macrophages were lysed, and then expressions of phosphorylated ERK1/2, JNK and p38 and nuclear factor-kappaB inhibitor (IkappaBalpha) protein were detected by Western blotting and TNF-alpha mRNA expression was detected by reverse transcription-polymerase chain reaction. Supernatants of the macrophages were used to detect content of TNF-alpha protein by enzyme-linked immunosorbent assay. RESULTS: Andrographolide at 1-100 MUg/mL showed no cytotoxicity on LPS-activated mouse peritoneal macrophages. Andrographolide inhibited ERK1/2 phosphorylation in LPS-activated murine peritoneal macrophages, which was concentration-dependent (P<0.01). Andrographolide at 1-25 MUg/mL had no effects on phosphorylation levels of JNK and p38 and IkappaBalpha degradation in LPS-stimulated mouse peritoneal macrophages. In activated macrophages, TNF-alpha expression was inhibited by 12 MUg/mL andrographolide and 20 MUmol/L PD98059 (inhibitor of ERK1/2 signaling pathway) at both mRNA expression and protein secretion levels. CONCLUSION: In LPS activated macrophages, andrographolide may inhibit the expression of TNF-alpha by inhibiting ERK1/2 signaling pathway. PMID- 21669168 TI - [Effects of taraxerol and taraxerol acetate on cell cycle and apoptosis of human gastric epithelial cell line AGS]. AB - OBJECTIVE: To investigate the effects of taraxerol and taraxerol acetate on cell cycle and apoptosis of human gastric epithelial cell line AGS cells. METHODS: The inhibitory effects of taraxerol and taraxerol acetate at different concentrations on AGS cell growth were measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) method and the concentrations of taraxerol and taraxerol acetate to be used in following experiments were decided. Then, cell cycle analysis was performed by FACScan flow cytometry after culture with taraxerol or taraxerol acetate. Annexin V-fluorescein isothiocyanate/propidium iodide staining was used to measure cell apoptosis. RESULTS: Taraxerol significantly inhibited AGS cell proliferation in a dose- and time-dependent manner. Taraxerol arrested the AGS cells at G(2)/M stage. 110 MUmol/L taraxerol elevated the population of AGS cells arrested in G(2)/M phase compared with solvent (P<0.05). Taraxerol also promoted early cell apoptosis in AGS cells. 110 MUmol/L taraxerol increased the early cell apoptosis rate from 4.45% to 10.29%, which was 1.31 times higher than that of the untreated cells. However, taraxerol acetate had a lower inhibitory effect than taraxerol, and it showed a tendency of G(2)/M arrest and apoptosis promotion but with no statistical significance (P>0.05). CONCLUSION: Taraxerol has inhibitory effects on AGS cell growth through inducing G(2)/M arrest and promotion of cell apoptosis. Taraxerol acetate has less effect on cell cycle arrest and apoptosis of AGS cells than taraxerol. PMID- 21669169 TI - [Changes of protein expression profile in vascular tissues of spontaneously hypertensive rats treated by a compound Chinese herbal medicine]. AB - OBJECTIVE: To investigate the effects of a Chinese herbal formula for calming liver and suppressing yang on the protein expressions of vascular tissues in spontaneously hypertensive rats (SHRs), and to explore the mechanism of efficacy. METHODS: Twenty SHRs were randomly divided into model group and treatment group. Another 10 Wistar-Kyoto rats were selected as a normal control. SHRs in the treatment group were administered with the formula for calming liver and suppressing Yang for 4 weeks. During the course of treatment, blood pressure and heart rates were monitored every week and the ethology of rats, including irritability and rotation endurance was also evaluated. After treatment, thoracic aorta was obtained and its proteins were separated by 2-dimensional gel electrophoresis (2-DE). The differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and database query. RESULTS: The formula for calming liver and suppressing yang not only decreased the systolic blood pressure and heart rate, but also improved irritability degree and rotation endurance time of SHRs. This experiment had established the 2-DE graph of protein expressions of vascular tissues in SHRs. Compared with the normal group, the expressions of 15 proteins were down-regulated, and 12 proteins were up-regulated in vascular tissues of the model group. The formula for calming liver and suppressing yang treatment up regulated expressions of 10 proteins in the 15 down-regulated proteins, and down regulated 8 proteins in the 12 up-regulated proteins in vascular tissues of SHRs. After analysis, 16 obviously differentially expressed proteins were found, and 13 of them were identified. CONCLUSION: The formula for calming liver and suppressing yang can improve the ethology of SHRs. The mechanism is probably concerned with regulating the protein expressions of vascular tissues. PMID- 21669170 TI - [Effects of Chinese herbal medicine Yiguanjian Decoction on collagen metabolism of hepatic tissues in rats with CCl4-induced liver fibrosis]. AB - OBJECTIVE: To investigate the effects of Yiguanjian Decoction, a compound traditional Chinese herbal medicine, on collagen metabolism of hepatic tissues in rats with carbon tetrachloride (CCl(4))-induced liver fibrosis. METHODS: Liver fibrosis was induced in rats by intraperitoneal injection of 50% CCl(4)-olive oil solution at a dose of 1 mL/kg body weight, twice per week for 9 consecutive weeks. Six rats were sacrificed for dynamic observation at the end of the 3rd and 6th week respectively, and the other rats were divided into 9-week untreated group and Yiguanjian Decoction group which was given Yiguanjian Decoction intragastrically in the subsequent 3-week modeling period. Another 6 rats were used as normal group. Rats in the normal group and 9-week untreated group were treated with distilled water. At the end of the 9th week, all rats were sacrificed, and their blood serum and liver tissue were collected for measuring hepatic histology and expressions of alpha-smooth muscle actin (alpha-SMA), tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, matrix metalloproteinase (MMP)-13, MMP-14, collagen type I (Col I), and activities of MMP-2 and -9. RESULTS: Compared with the normal group, collagen fiber deposition, expressions of alpha-SMA, Col I, TIMP-1, TIMP-2, MMP-13 and MMP-14 and activities of MMP-2 and -9 in the liver tissues gradually increased in the untreated group (P<0.05, P<0.01). These changes were significantly suppressed by Yiguanjian Decoction. CONCLUSION: Yiguanjian Decoction exerts inhibition on formation of CCl(4)-induced cirrhosis in rats. The therapeutic mechanism may be related to inhibiting hepatic stellate cell activation, collagen secretion, and promoting collagen fiber degradation. PMID- 21669171 TI - [Effects of electroacupuncture at Tianshu (ST25) on pro- and anti-inflammatory cytokines in rats with severe acute pancreatitis]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) at Tianshu (ST25) on pro- and anti-inflammatory cytokines in sodium taurocholate-induced severe acute pancreatitis (SAP) in rats. METHODS: Sixty-six male Sprague-Dawley rats were randomly divided into three groups: sham-operation group, SAP group and EA group. An SAP model was established by injecting 3.5% sodium taurocholate at a dose of 1 mL/kg through puncturing the pancreatic duct. In the EA group, EA at ST25 was performed with sparse-dense wave (2/100 Hz, 2 mA for 30 min) immediately after sodium taurocholate injection and 30 min before sacrifice. Rats were sacrificed at 3 (n=7), 6 (n=7) and 12 h (n=8) after operation. Levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-10 in serum were estimated by enzyme-linked immunosorbent assay. Pathological changes of pancreatic tissues were examined by hematoxylin and eosin staining and observed under a microscope and also scored. RESULTS: The levels of serum TNF-alpha and IL-6 of SAP rats were significantly higher than those of sham-operation rats at 3, 6 and 12 h. The level of IL-10 in serum of SAP rats was significantly higher than that of sham operation rats at 3 and 6 h (P<0.05). EA at ST25 down-regulated the levels of TNF alpha and IL-6 in serum and up-regulated the level of IL-10 and the ratio of IL 10/TNF-alpha, also attenuated the morphological damages at 6 and 12 h (P<0.05) in rats with SAP. The pathological scores of pancreatic tissues in the EA group were significantly less than those in the SAP group at 6 and 12 h (P<0.05). CONCLUSION: EA at ST25 may have a therapeutic effect on rats with SAP by down regulating the levels of TNF-alpha and IL-6 and up-regulating the level of IL-10 to re-establish the balance of pro- and anti-inflammatory cytokines, and to ameliorate the inflammatory response of SAP. PMID- 21669172 TI - [Classification of 365 Chinese medicines in Shennong's Materia Medica Classic based on a semi-supervised incremental clustering method]. AB - Evidence of the pharmacological activity of traditional Chinese medicine (TCM) provides the basis for clinical prescription. Study of the classification of Chinese medicines according to these activities is key to understanding the general active tendencies of medicinal prescriptions, exploring their material basis, investigating their properties and searching for their alternatives. Taking the herbal classic Shennong's Materia Medica Classic (Shennong Bencao Jing) for the data source, this paper studied the classification of Chinese medicines based on semi-supervised incremental clustering algorithm using "micro cluster" concept in order to investigate the complex similarity among Chinese medicines. The results showed that 253 Chinese medicines were reasonably classified into 14 types, such as invigoration, clearing heat, diuresis, dredging blockages in the channels, treating gynecological conditions and treating strange diseases caused by ghosts. The results also showed that the other 112 Chinese medicines were classified into 112 individual types and the same high similarity to different known types was the main reason for this. The semi-supervised incremental clustering algorithm employed in the study had a high quality and a good development for clustering which is suitable for classification of Chinese medicines. This study illustrated the diversity of Chinese medicines and their complex similarities, thus aiming to provide innovative ideas and methods for related research. PMID- 21669173 TI - [Changes in public health awareness of traditional Chinese medicine in Shanghai in the late Qing Dynasty]. AB - Public health awareness existed in the practice of traditional Chinese medicine (TCM) long ago. In the process of Shanghai's modernization and in competition with Western medicine, TCM in Shanghai has gradually accepted the modern public health awareness, fostering its strengths, circumventing its weaknesses and playing an important role in the local public health service. To study the vicissitude of TCM public health awareness at this time will be helpful to further understand the modern history of TCM and also provide useful reference for further participation of TCM in modern public health enterprise. In this paper, the authors used literature analysis and historical research to analyze the medical practice and writings of representative TCM practitioners, medical groups and journals. The results showed that the public health awareness of TCM in Shanghai has evolved from its traditional pattern to the modern pattern seen today; the traditional pattern was characterized by individual health care and some degree of medical collaboration, whereas the modern pattern is characterized by public health education. This process was propelled forward throughout by intense national spirit. TCM has made significant contributions to the local public health service in Shanghai in the late Qing Dynasty, which promoted the modernization of public health awareness of TCM in the People's Republic of China. The authors also found that one of the ways of modernizing TCM is to diversify the ways of publicizing TCM and make it easily understood, which can shed a new light on promoting the development of TCM. PMID- 21669174 TI - [Experience of diagnosis and treatment of exogenous high-grade fever]. AB - There is a regular pattern in the diagnosis and treatment of exogenous high-grade fever, of which the key point is formula syndrome identification. Syndrome differentiation of the six channels is appropriate for not only exogenous cold but also various other conditions. The diagnosis and treatment of high-grade fever can also follow the law of syndrome differentiation of the six channels. The theory of epidemic febrile diseases stems from and elaborates on an understanding of exogenous febrile conditions, so many effective formulas used to treat epidemic febrile diseases also have great value in the treatment of high grade fever. Deteriorated syndrome, which is central to this condition, is very commonly seen in cases of high-grade fever, the key therapeutic principle of which is established according to syndromes. Allowing analysis that does not rigidly adhere to either established modern diagnosis or traditional Chinese syndromes, prominent achievements could be made in treating high-grade fever by summarizing the regular presenting patterns in terms of the constitution and symptoms. PMID- 21669175 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: syndrome differentiation of liver and gallbladder diseases. PMID- 21669176 TI - Fluorescent vesicles for signal amplification in reverse phase protein microarray assays. AB - Developments in microarray technology promise to lead to great advancements in the biomedical and biological field. However, implementation of these analytical tools often relies on signal amplification strategies that are essential to reach the sensitivity levels required for a variety of biological applications. This is true especially for reverse phase arrays where a complex biological sample is directly immobilized on the chip. We present a simple and generic method for signal amplification based on the use of antibody-tagged fluorescent vesicles as labels for signal generation. To assess the gain in assay sensitivity, we performed a model assay for the detection of rabbit immunoglobulin G (IgG) and compared the limit of detection (LOD) of the vesicle assay with the LOD of a conventional assay performed with fluorescent reporter molecules. We evaluated the improvements for two fluorescence-based transduction setups: a high sensitivity microarray reader (ZeptoREADER) and a conventional confocal scanner. In all cases, our strategy led to an increase in sensitivity. However, gain in sensitivity widely depended on the type of illumination; whereas an approximately 2-fold increase in sensitivity was observed for readout based on evanescent field illumination, the contribution was as high as more than 200-fold for confocal scanning. PMID- 21669177 TI - Determination of the molar extinction coefficient for the ferric reducing/antioxidant power assay. AB - The FRAP reagent contains 2,4,6-tris(2-pyridyl)-s-triazine, which forms a blue violet complex ion in the presence of ferrous ions. Although the FRAP (ferric reducing/antioxidant power) assay is popular and has been in use for many years, the correct molar extinction coefficient of this complex ion under FRAP assay conditions has never been published, casting doubt on the validity of previous calibrations. A previously reported value of 19,800 is an underestimate. We determined that the molar extinction coefficient was 21,140. The value of the molar extinction coefficient was also shown to depend on the type of assay and was found to be 22,230 under iron assay conditions, in good agreement with published data. Redox titration indicated that the ferrous sulfate heptahydrate calibrator recommended by Benzie and Strain, the FRAP assay inventors, is prone to efflorescence and, therefore, is unreliable. Ferrous ammonium sulfate hexahydrate in dilute sulfuric acid was a more stable alternative. Few authors publish their calibration data, and this makes comparative analyses impossible. A critical examination of the limited number of examples of calibration data in the published literature reveals only that Benzie and Strain obtained a satisfactory calibration using their method. PMID- 21669178 TI - An affinity-based genome walking method to find transgene integration loci in transgenic genome. AB - Identifying a good transgenic event from the pool of putative transgenics is crucial for further characterization. In transgenic plants, the transgene can integrate in either single or multiple locations by disrupting the endogenes and/or in heterochromatin regions causing the positional effect. Apart from this, to protect the unauthorized use of transgenic plants, the signature of transgene integration for every commercial transgenic event needs to be characterized. Here we show an affinity-based genome walking method, named locus-finding (LF) PCR (polymerase chain reaction), to determine the transgene flanking sequences of rice plants transformed by Agrobacterium tumefaciens. LF PCR includes a primary PCR by a degenerated primer and transfer DNA (T-DNA)-specific primer, a nested PCR, and a method of enriching the desired amplicons by using a biotin-tagged primer that is complementary to the T-DNA. This enrichment technique separates the single strands of desired amplicons from the off-target amplicons, reducing the template complexity by several orders of magnitude. We analyzed eight transgenic rice plants and found the transgene integration loci in three different chromosomes. The characteristic illegitimate recombination of the Agrobacterium sp. was also observed from the sequenced integration loci. We believe that the LF PCR should be an indispensable technique in transgenic analysis. PMID- 21669179 TI - A simple assay for 3-deoxy-d-manno-octulosonate cytidylyltransferase and its use as a pathway screen. AB - This article describes the adaptation of a simple colorimetric assay for inorganic pyrophosphate to the enzyme 3-deoxy-d-manno-octulosonate cytidylyltransferase (CMP-KDO synthetase, KdsB, EC 2.7.7.38), a key enzyme in the biosynthesis of lipopolysaccharide (LPS) in Gram-negative organisms. This assay is particularly useful because it can be combined with the malachite green (MG) assay for inorganic phosphate to form an assay system capable of determining inorganic phosphate and inorganic pyrophosphate in the same solution (the MG/EK (eikonogen reagent) assay). This assay system has the potential for simultaneous screening of the 3-deoxy-d-manno-octulosonate (KDO) biosynthesis pathway. We tested this potential using two enzymes, KdsB and KdsC, involved in the biosynthesis and use of the key bacterial 8-carbon sugar, KDO. PMID- 21669180 TI - A polymerase chain reaction-based method for constructing a linear vector with site-specific DNA methylation. AB - DNA methylation is an important epigenetic modification that leads to a wide variety of biological functions, including transcription, growth and development, and diseases associated with altered gene expression such as cancers. However, tools to insert site-specific methylation into DNA for analyzing epigenetic functions are limited. Here we describe a novel polymerase chain reaction (PCR) based approach to provide site-specific DNA methylation at any site, including CpG or CpNpG islands. This method is simple and versatile, and it consists of four steps to construct the DNA methylation vector: (I) design and synthesis of methylated primers, (II) PCR amplification, (III) isolation of single-stranded DNA, and (IV) annealing and ligation of isolated single-stranded DNAs. First we produced and validated a linear green fluorescence protein (GFP) vector by this method. Next we applied this method to introduce methyl groups into the promoter of the cyclooxygenase-2 (COX-2) gene and found that site-specific DNA methylation at the CRE element significantly altered COX-2 gene expression. These results demonstrate that this PCR-based approach is useful for the analysis of biological functions that depend on DNA methylation. PMID- 21669181 TI - Impact of enzyme concentration and residence time on apparent activity recovery in jump dilution analysis. AB - Jump dilution analysis is commonly used to evaluate the reversibility of inhibition and to quantify the residence time of the inhibitor-enzyme complex. During hit and lead characterization, one sometimes observes apparently linear progress curves after jump dilution that display activity recoveries that are intermediate between those expected for fully reversible and irreversible inhibition. Computer simulations of progress curves after jump dilution indicate that seemingly linear progress curves can result when dealing with tight-binding inhibitors if substoichiometric concentrations of inhibitor are preincubated with enzyme. In this situation, the activity recovered is comparable to that expected for instantaneously reversible inhibitors. In addition, simulations demonstrate that intermediate values of activity recovery may be observed for compounds with modestly slow dissociation rates (i.e., residence times >0min but <=20min) when the attending curvature of the data is not accounted for. The observation of intermediate values of recovery can, thus, serve as an indication of either modest residence time or a contaminating inactivator within an inhibitor sample, in either case prompting greater scrutiny of the test compound. PMID- 21669182 TI - Evidence for a fluorescence yield change driven by a light-induced conformational change within photosystem II during the fast chlorophyll a fluorescence rise. AB - Experiments were carried out to identify a process co-determining with Q(A) the fluorescence rise between F(0) and F(M). With 3-(3',4'-dichlorophenyl)-1,1 dimethylurea (DCMU), the fluorescence rise is sigmoidal, in its absence it is not. Lowering the temperature to -10 degrees C the sigmoidicity is lost. It is shown that the sigmoidicity is due to the kinetic overlap between the reduction kinetics of Q(A) and a second process; an overlap that disappears at low temperature because the temperature dependences of the two processes differ. This second process can still relax at -60 degrees C where recombination between Q(A)( ) and the donor side of photosystem (PS) II is blocked. This suggests that it is not a redox reaction but a conformational change can explain the data. Without DCMU, a reduced photosynthetic electron transport chain (ETC) is a pre-condition for reaching the F(M). About 40% of the variable fluorescence relaxes in 100ms. Re-induction while the ETC is still reduced takes a few ms and this is a photochemical process. The fact that the process can relax and be re-induced in the absence of changes in the redox state of the plastoquinone (PQ) pool implies that it is unrelated to the Q(B)-occupancy state and PQ-pool quenching. In both +/-DCMU the process studied represents ~30% of the fluorescence rise. The presented observations are best described within a conformational protein relaxation concept. In untreated leaves we assume that conformational changes are only induced when Q(A) is reduced and relax rapidly on re-oxidation. This would explain the relationship between the fluorescence rise and the ETC-reduction. PMID- 21669183 TI - Plant actin controls membrane permeability. AB - The biological effects of electric pulses with low rise time, high field strength, and durations in the nanosecond range (nsPEFs) have attracted considerable biotechnological and medical interest. However, the cellular mechanisms causing membrane permeabilization by nanosecond pulsed electric fields are still far from being understood. We investigated the role of actin filaments for membrane permeability in plant cells using cell lines where different degrees of actin bundling had been introduced by genetic engineering. We demonstrate that stabilization of actin increases the stability of the plasma membrane against electric permeabilization recorded by penetration of Trypan Blue into the cytoplasm. By use of a cell line expressing the actin bundling WLIM domain under control of an inducible promotor we can activate membrane stabilization by the glucocorticoid analog dexamethasone. By total internal reflection fluorescence microscopy we can visualize a subset of the cytoskeleton that is directly adjacent to the plasma membrane. We conclude that this submembrane cytoskeleton stabilizes the plasma membrane against permeabilization through electric pulses. PMID- 21669184 TI - Binding of subunit E into the A-B interface of the A(1)A(O) ATP synthase. AB - Two of the distinct diversities of the engines A(1)A(O) ATP synthase and F(1)F(O) ATP synthase are the existence of two peripheral stalks and the 24kDa stalk subunit E inside the A(1)A(O) ATP synthase. Crystallographic structures of subunit E have been determined recently, but the epitope(s) and the strength to which this subunit does bind in the enzyme complex are still a puzzle. Using the recombinant A(3)B(3)D complex and the major subunits A and B of the methanogenic A(1)A(O) ATP synthase in combination with fluorescence correlation spectroscopy (FCS) we demonstrate, that the stalk subunit E does bind to the catalytic headpiece formed by the A(3)B(3) hexamer with an affinity (K(d)) of 6.1+/-0.2MUM. FCS experiments with single A and B, respectively, demonstrated unequivocally that subunit E binds stronger to subunit B (K(d)=18.9+/-3.7MUM) than to the catalytic A subunit (K(d)=53.1+/-4.4). Based on the crystallographic structures of the three subunits A, B and E available, the arrangement of the peripheral stalk subunit E in the A-B interface has been modeled, shining light into the A-B E assembly of this enzyme. PMID- 21669185 TI - Photoperiodic response requires mammalian-type cryptochrome in the bean bug Riptortus pedestris. AB - The hypothesis that a circadian clock comprised of circadian clock genes is causally involved in insect photoperiodism has been supported by several studies. However, there remains a possibility that the effects of the circadian clock genes on photoperiodism are exerted through pleiotropic (non-circadian) functions provided by each gene independently from its role in the circadian clock. In the present study, we investigated the involvement of the circadian clock gene mammalian-type cryptochrome (cry-m) in photoperiodic regulation of ovarian development in the bean bug Riptortus pedestris by using RNA interference (RNAi). Injection of cry-m double-stranded RNA (dsRNA) induced expression of period (per), whereas did not affect expression of cycle (cyc), showing that CRY-m functions as a negative element on CYC-mediated transcription in the circadian clock. If the circadian clock is indeed involved in photoperiodism, a phenotype produced by RNAi of cry-m will be the same as that produced by RNAi of per, another negative element. The intact insects and insects injected with control dsRNA were found to enter diapause when kept under short-day conditions after adult emergence, while they developed ovaries when kept under long-day conditions after adult emergence. However, cry-m RNAi significantly increased the incidence of reproductive individuals under diapause-inducing short-day conditions, as per RNAi did, in accordance with our expectation. PMID- 21669186 TI - Role of CD137 signaling in dengue virus-mediated apoptosis. AB - Hepatic dysfunction is a well recognized feature of dengue virus (DENV) infection. However, molecular mechanisms of hepatic injury are still poorly understood. A complex interaction between DENV and the host immune response contributes to DENV-mediated tissue injury. DENV capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx. A double substitution mutation in DENV C (R85A/K86A) abrogates Daxx interaction, nuclear localization and apoptosis. Therefore we compared the expression of cell death genes between HepG2 cells expressing DENV C and DENV C (R85A/K86A) using a real-time PCR array. Expression of CD137, which is a member of the tumor necrosis factor receptor family, increased significantly in HepG2 cells expressing DENV C compared to HepG2 cells expressing DENV C (R85A/K86A). In addition, CD137 mediated apoptotic activity in HepG2 cells expressing DENV C was significantly increased by anti-CD137 antibody compared to that of HepG2 cells expressing DENV C (R85A/K86A). In DENV-infected HepG2 cells, CD137 mRNA and CD137 positive cells significantly increased and CD137-mediated apoptotic activity was increased by anti-CD137 antibody. This work is the first to demonstrate the contribution of CD137 signaling to DENV-mediated apoptosis. PMID- 21669188 TI - Glutathione selectively inhibits Doxorubicin induced phosphorylation of p53Ser15, caspase dependent ceramide production and apoptosis in human leukemic cells. AB - Glutathione (GSH) is the most abundant non-protein antioxidant in mammalian cells. It has been implicated in playing an important role in different signal transduction pathways, and its depletion is an early hallmark in the progression of apoptosis in response to a number of proapoptotic stimuli. We have selectively investigated the role of GSH in cytotoxic response of Jurkat and Molt-4 human leukemic cells to the anti-cancer drug Doxorubicin. In this study, we have shown that extracellular supplementation of GSH to human leukemic cells renders them a resistant phenotype to Doxorubicin treatment. Glutathione pre-treatment inhibits Doxorubicin-induced p53Ser(15) phosphorylation, caspase dependent ceramide (Cer) generation, Poly (ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. Taken together, these results indicate that the major cellular antioxidant GSH influences the chemotherapeutic efficacy of Doxorubicin towards human leukemic cells. PMID- 21669187 TI - The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells. AB - Canertinib is a novel ErbB-receptor inhibitor currently in clinical development for the treatment of solid tumors overexpressing ErbB-receptors. We have recently demonstrated that canertinib displays anti-proliferative and pro-apoptotic effects in human myeloid leukemia cells devoid of ErbB-receptors. The mechanism mediating these effects are however unknown. In this study, we show that canertinib is able to act as a multi-kinase inhibitor by inhibition of several intracellular kinases involved in T-cell signaling such as Akt, Erk1/2 and Zap 70, and reduced Lck protein expression in the human T-cell leukemia cell line Jurkat. Treatment with canertinib at a concentration of 2 MUM caused accumulation of Jurkat cells in the G(1) cell cycle phase and increased doses induced apoptosis in a time-dependent manner. Apoptotic signs of treated cells were detected by Annexin V staining and cleavage of PARP, caspase-3, -8, -9, -10 and Bid. A subset of the pro-apoptotic signals mediated by canertinib could be significantly reduced by specific caspase inhibitors. Taken together, these results demonstrate the dual ability of canertinib to downregulate important signaling pathways and to activate caspase-mediated intrinsic apoptosis pathway in human T-cell leukemia cells. PMID- 21669189 TI - Development of recombinant hepatitis C virus with NS5A from strains of genotypes 1 and 2. AB - Nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) plays multiple and diverse roles in the viral lifecycle, and is currently recognized as a novel target for anti-viral therapy. To establish an HCV cell culture system with NS5A of various strains, recombinant viruses were generated by replacing NS5A of strain JFH-1 with those of strains of genotypes 1 (H77; 1a and Con1; 1b) and 2 (J6CF; 2a and MA; 2b). All these recombinant viruses were capable of replication and infectious virus production. The replacement of JFH-1 NS5A with those of genotype 1 strains resulted in similar or slightly reduced virus production, whereas replacement with those of genotype 2 strains enhanced virus production as compared with JFH-1 wild-type. A single cycle virus production assay with a CD81 negative cell line revealed that the efficient virus production elicited by replacement with genotype 2 strains depended on enhanced viral assembly, and that substitutions in the C-terminus of NS5A were responsible for this phenotype. Pulse-chase assays revealed that these substitutions in the C-terminus of NS5A were possibly associated with accelerated cleavage kinetics at the NS5A-NS5B site. Using this cell culture system with NS5A-substituted recombinant viruses, the anti-viral effects of an NS5A inhibitor were then examined. A 300- to 1000 fold difference in susceptibility to the inhibitor was found between strains of genotypes 1 and 2. This system will facilitate not only a better understanding of strain-specific roles of NS5A in the HCV lifecycle, but also enable the evaluation of genotype and strain dependency of NS5A inhibitors. PMID- 21669190 TI - Helenalin bypasses Bcl-2-mediated cell death resistance by inhibiting NF-kappaB and promoting reactive oxygen species generation. AB - Evasion of cell death by overexpression of anti-apoptotic proteins, such as Bcl 2, is commonly observed in cancer cells leading to a lack of response to chemotherapy. Hence, there is a need to find new chemotherapeutic agents that are able to overcome chemoresistance mediated by Bcl-2 and to understand their mechanisms of action. Helenalin, a sesquiterpene lactone (STL), induces cell death and abrogates clonal survival in a highly apoptosis-resistant Bcl-2 overexpressing Jurkat cell line as well as in two other Bcl-2 overexpressing solid tumor cell lines (mammary MCF-7; pancreatic L6.3pl). This effect is not achieved by directly affecting the mitochondria-protective function of Bcl-2 in the intrinsic pathway of apoptosis since Bcl-2 overexpressing Jurkat cells do not show cytochrome c release and dissipation of mitochondrial membrane potential upon helenalin treatment. Moreover, helenalin induces an atypical form of cell death with necrotic features in Bcl-2 overexpressing cells, neither activating classical mediators of apoptosis (caspases, AIF, Omi/HtrA2, Apaf/apoptosome) nor ER-stress mediators (BiP/GRP78 and CHOP/GADD153), nor autophagy pathways (LC3 conversion). In contrast, helenalin was found to inhibit NF-kappaB activation that was considerably increased in Bcl-2 overexpressing Jurkat cells and promotes cell survival. Moreover, we identified reactive oxygen species (ROS) and free intracellular iron as mediators of helenalin-induced cell death whereas activation of JNK and abrogation of Akt activity did not contribute to helenalin elicited cell death. Our results highlight the NF-kappaB inhibitor helenalin as a promising chemotherapeutic agent to overcome Bcl-2-induced cell death resistance. PMID- 21669191 TI - Benzylidenemalononitrile compounds as activators of cell resistance to oxidative stress and modulators of multiple signaling pathways. A structure-activity relationship study. AB - Benzylidenemalononitrile (BMN) tyrphostins are well known as potent tyrosine kinase inhibitors. Moreover, in recent years it has been recognized that members of the tyrphostin family possess additional biological activities independent of their ability to inhibit protein tyrosine kinases. In this study, we examined the relationship between the structure of 49 BMNs and related compounds, and their capacity to induce heme oxygenase 1 (HO-1) gene expression in U937 human monocytic cells, to activate upstream signaling pathways and to protect cells against menadione-induced oxidative stress. It was found that the electron withdrawing (NO(2), CN, halogen) groups in BMN molecules and double meta-MeO substituents increased the HO-1 gene induction, while the electron-donating groups in ortho/para position (OH, MeO and N-morpholino) significantly decreased it. The magnitude of activation of c-Jun, Nrf2, p38 MAPK, and p70S6K correlated with specific substitution patterns in the BMN structure. BMN-dependent maximal up-regulation of HO-1 required parallel increase in Nrf2 and phospho-c-Jun cellular levels. Liquid chromatography mass spectrometry (LC-MS) analysis revealed that BMNs can generate conjugates with one or two glutathione equivalent(s). This study supports the hypothesis that BMNs induce the expression of protective genes by alkylating sensitive cysteine residues of regulatory factors. PMID- 21669192 TI - Psoralidin, a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation. AB - Radiotherapy is the most significant non-surgical cure for the elimination of tumor, however it is restricted by two major problems: radioresistance and normal tissue damage. Efficiency improvement on radiotherapy is demanded to achieve cancer treatment. We focused on radiation-induced normal cell damage, and are concerned about inflammation reported to act as a main limiting factor in the radiotherapy. Psoralidin, a coumestan derivative isolated from the seed of Psoralea corylifolia, has been studied for anti-cancer and anti-bacterial properties. However, little is known regarding its effects on IR-induced pulmonary inflammation. The aim of this study is to investigate mechanisms of IR induced inflammation and to examine therapeutic mechanisms of psoralidin in human normal lung fibroblasts and mice. Here, we demonstrated that IR-induced ROS activated cyclooxygenases-2 (COX-2) and 5-lipoxygenase (5-LOX) pathway in HFL-1 and MRC-5 cells. Psoralidin inhibited the IR-induced COX-2 expression and PGE(2) production through regulation of PI3K/Akt and NF-kappaB pathway. Also, psoralidin blocked IR-induced LTB(4) production, and it was due to direct interaction of psoralidin and 5-lipoxygenase activating protein (FLAP) in 5-LOX pathway. IR induced fibroblast migration was notably attenuated in the presence of psoralidin. Moreover, in vivo results from mouse lung indicate that psoralidin suppresses IR-induced expression of pro-inflammatory cytokines (TNF-alpha, TGF beta, IL-6 and IL-1 alpha/beta) and ICAM-1. Taken together, our findings reveal a regulatory mechanism of IR-induced pulmonary inflammation in human normal lung fibroblast and mice, and suggest that psoralidin may be useful as a potential lead compound for development of a better radiopreventive agent against radiation induced normal tissue injury. PMID- 21669193 TI - GSTP1 mRNA expression in human circulating blood leukocytes is associated with GSTP1 genetic polymorphism. AB - OBJECTIVES: We explored association between GSTP1 Ile(105)Val (rs1695) polymorphism and GSTP1 mRNA expression in circulating blood leukocytes. DESIGN AND METHODS: GSTP1 transcripts level and polymorphism were determined by Real Time PCR in 51 bladder cancer and 90 healthy men. RESULTS: Individuals with at least one GSTP1 Val(105) variant allele possessed higher GSTP1 mRNA level in blood leukocytes compared to GSTP1 Ile(105)Ile carriers. CONCLUSIONS: GSTP1 Ile(105)Val gene polymorphism influences its expression in blood, regardless of cancer disease. PMID- 21669194 TI - Oxidative stress and pyrogenic fever pathogenesis. AB - The causative/regulatory connections between changes in tissue redox state and fever induction were investigated herein. Wherefore, LPS, the primary element of bacterial cell wall, in addition to inducing pro-inflammatory cytokines, activated macrophages and other leukocytes to secrete hydroxyl radical (OH), nitric oxide metabolites (NO(x)(-)), superoxide (O(2)) and other reactive oxygen/nitrogen species. Furthermore, inflammation response-associated hypoxia stimulated glutamate release, which caused excitotoxicity of cells by increasing extracellular Ca(2+). Cytokines and glutamate in turn also triggered the release of large amounts of NO(x)(-), OH, O(2), and other radicals. Those reactive nitrogen species in turn caused cellular injury via the peroxidation of membrane lipids and oxidative damage of proteins and DNA. Glutamate, NO(x)(-), OH and antioxidants participated in the pathogenesis and regulation of LPS- or cytokines induced fever. In particular, to highlight the role of glutamate, prostaglandin E(2), NO(x)(-) and OH generated in the hypothalamus during pyrogenic fever was attempted hereby. To find the link among the signaling with the glutamate, NO(x)( ) and OH/prostaglandin E(2) in the hypothalamus during pyrogenic fever will be challenging and could now clinically suppress pyrogenic fever. PMID- 21669195 TI - Targeting of a common receptor shared by CXCL8 and N-Ac-PGP as a therapeutic strategy to alleviate chronic neutrophilic lung diseases. AB - Persistent neutrophilia is implicated in the pathology of several chronic lung diseases and consequently targeting the signals that drive the recruitment of these cells offers a plausible therapeutic strategy. The tripeptide Pro-Gly-Pro (PGP) is a neutrophil chemoattractant derived from extracellular matrix collagen and implicated in diseases such as COPD and cystic fibrosis. It was anticipated that PGP exerts its chemoatactic activity by mimicking key sequences found within classical neutrophil chemokines, such as CXCL8, and binding their receptors, CXCR1/2. Recently, however, the role of CXCR1/2 as the receptors for PGP has been questioned. In this issue of European Journal of Pharmacology, three studies address this controversy and demonstrate CXCR1/2 to be a common receptor for CXCL8 and PGP. Accordingly, these studies demonstrate the therapeutic potential of targeting this shared receptor to simultaneously alleviate neutrophilic inflammation driven by multiple neutrophil chemoattractants. PMID- 21669196 TI - Inflammatory myofibroblastic tumor of the lung with unique histological pattern and association with Sjogren's disease and systemic lupus erythematosus. AB - Inflammatory myofibroblastic tumor (IMT) of the lung is a rare condition. Radiological properties and clinical presentation of this disease can mimic malignant process. We present a case of IMT of the lung in a 58 year old female patient with a single lung nodule. Tumor was unencapsulated, firm, and well circumscribed. Microscopically tumor had multinodular structure with single or multiple small blood vessels in the center of each nodule surrounded in circular pattern by connective tissue containing spindle cells embedded into the thick layers of extracellular matrix. Extracellular matrix was identified as type I and type III collagen fibrils embedded into type IV collagen and laminin. The tumor was surrounded by T-, B-lymphocytes and polyclonal plasma cells. Histological organization of this lesion's stromal component was unique, but cell composition was similar to inflammatory pseudotumor of the lung. In addition, tumor tissue sections exhibited strong positivity for IgG, weak positivity for IgA, 1Cq, but were negative for IgM, and C3. Mutational analysis of the EGFR, KRAS genes and ALK locus rearrangement were performed and did not reveal any mutations. This is the first report of an IMT associated with Sjogren's disease, systemic lupus erythematosus and Non-Hodgkin lymphoma developing in the lungs. Patient was clinically followed up for 18 months and no recurrence of the tumor observed. PMID- 21669197 TI - NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP. AB - Na+/H+ exchanger 1 (NHE1), an important regulator of intracellular pH (pH(i)) and extracellular pH (pH(e)), has been shown to play a key role in breast cancer metastasis. However, the exact mechanism by which NHE1 mediates breast cancer metastasis is not yet well known. We showed here that inhibition of NHE1 activity, with specific inhibitor Cariporide, could suppress MDA-MB-231 cells invasion as well as the activity and expression of MT1-MMP. Overexpression of MT1 MMP resulted in a distinguished increase in MDA-MB-231 cells invasiveness, but treatment with Cariporide reversed the MT1-MMP-mediated enhanced invasiveness. To explore the role of MAPK signaling pathways in NHE1-mediated breast cancer metastasis, we compared the difference of constitutively phosphorylated ERK1/2, p38 MAPK and JNK in non-invasive MCF-7 cells and invasive MDA-MB-231 cells. Interestingly, we found that the phosphorylation levels of ERK1/2 and p38 MAPK in MDA-MB-231 cells were higher than in MCF-7 cells, but both MCF-7 cells and MDA-MB 231 cells expressed similar constitutively phosphorylated JNK. Treating MDA-MB 231 cells with Cariporide led to decreased phosphorylation level of both p38 MAPK and ERK1/2 in a time-dependent manner, but JNK activity was not influenced. Supplementation with MAPK inhibitor (MEK inhibitor PD98059, p38 MAPK inhibitor SB203580 and JNK inhibitor SP600125) or Cariporide all exhibited significant depression of MDA-MB-231 cells invasion and MT1-MMP expression. Furthermore, we co-treated MDA-MB-231 cells with MAPK inhibitor and Cariporide. The result showed that Cariporide synergistically suppressed invasion and MT1-MMP expression with MEK inhibitor and p38 MAPK inhibitor, but not be synergistic with the JNK inhibitor. These findings suggest that NHE1 mediates MDA-MB-231 cells invasion partly through regulating MT1-MMP in ERK1/2 and p38 MAPK signaling pathways dependent manner. PMID- 21669198 TI - OSBP-related protein 7 interacts with GATE-16 and negatively regulates GS28 protein stability. AB - ORP7 is a member of oxysterol-binding protein (OSBP) family, the function of which has remained obscure. In this study, we identified by yeast two-hybrid screening an interaction partner of ORP7, GATE-16, which (i) regulates Golgi SNARE of 28kDa (GS28) function and stability, and (ii) plays a role in autophagosome biogenesis. The interaction was confirmed by bimolecular fluorescence complementation (BiFC) assay in living cells. The interacting regions were delineated within aa 1-142 of ORP7 and aa 30-117 of GATE-16. ORP7 knock-down in 293A cells resulted in a 40% increase of GS28 protein while ORP7 overexpression had the opposite effect (25% decrease of GS28). We show evidence that the regulation of GS28 by ORP7 does not occur at the level of transcription, but involves degradation of GS28 on proteasomes. Truncated ORP7 that lacks the GATE-16 binding region failed to affect GS28 stability, evidencing for specificity of the observed effect. Similar to ORP7 overexpression, treatment of cells with 25-hydroxycholesterol (25-OH) resulted in GS28 destabilization, which was potentiated by excess ORP7 and inhibited by ORP7 silencing. Overexpression of ORP7 led in most cells to formation of vacuolar structures positive for RFP-LC3, thus representing autophagic elements. Also GATE-16 was found in the vacuolar ORP7-positive elements, suggesting that excess ORP7 increases entrapment of GATE 16 in autophagosomes. Taken together, our results suggest that ORP7 negatively regulates GS28 protein stability via sequestration of GATE-16, and may mediate the effect of 25-OH on GS28 and Golgi function. PMID- 21669199 TI - Manganese porphyrin reduces retinal injury induced by ocular hypertension in rats. AB - This study aimed to clarify the possible therapeutic benefit of preferential nitric oxide synthase (NOS) inhibition and catalytic antioxidant Mn (III) meso tetrakis (N-n-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP(5+)) treatment in a rat model of elevated intraocular pressure (EIOP). Rats were randomly divided into different experimental groups which received either intraperitoneal MnTnHex 2-PyP(5+) (0.1 mg/kg/day), intragastric NOS inhibitor (S-methylthiourea: SMT; 5 mg/kg/day) or both agents for a period of 6 weeks. Ocular hypertension was induced by unilaterally cauterizing three episcleral vessels and the unoperated eye served as control. Neuroprotective effects of given treatments were determined via electrophysiological measurements of visual evoked potentials (VEP) while retina and vitreous levels of MnTnHex-2-PyP(5+) were measured via LC MS/MS. Latencies of all VEP components (P(1), N(1), P(2), N(2), P(3)) were significantly prolonged (p < 0.05) in EIOP and returned to control levels following all three treatment protocols. Ocular hypertension significantly increased retinal protein nitration (p < 0.001) which returned to baseline levels in all treated groups. NOS-2 expression and nitrate/nitrite levels were significantly greater in non-treated rats with EIOP. Retinal TUNEL staining showed apoptosis in all ocular hypertensive rats. The presented data confirm the role of oxidative injury in EIOP and highlight the protective effect of MnTnHex-2 PyP(5+) treatment and NOS inhibition in ocular hypertension. PMID- 21669200 TI - Similar hydrodynamic and morphological changes in the aqueous humor outflow pathway after washout and Y27632 treatment in monkey eyes. AB - Our previous studies in bovine eyes demonstrated that the structural correlate to the increase in outflow facility after either Rho-kinase inhibitor Y-27632 (Y27) treatment or washout appeared to be separation between the juxtacanalicular tissue (JCT) and inner wall (IW) of the aqueous plexus, the bovine equivalent of Schlemm's canal (SC). While these findings suggest that Y27 and washout may increase outflow facility through a similar mechanism, the anatomy of bovine outflow pathway differs considerably from both the human and monkey outflow pathway; however, only the human eye does not exhibit washout. In light of this, we compared the effects of Y27 and washout on outflow facility, hydrodynamic patterns of outflow, and the morphology of the IW and JCT in monkey eyes, given that their anatomy is closer to human eyes. Twelve freshly enucleated monkey eyes were used in this study. Eyes were perfused with Dulbecco's PBS containing 5.5 mM glucose (GPBS) to establish a baseline facility at 15 mmHg. Four eyes were perfused for a short-duration (30 min) as a control, 4 eyes for a long-duration (180 min) to induce washout, and 4 eyes with GPBS+50 MUM Y27 for 30 min. All eyes were then perfused with fluorescent microspheres (0.5 MUm; 0.002%) to label the hydrodynamic patterns of outflow and then perfusion-fixed. Confocal images of frontal sections were taken along the IW of SC. The total length (TL) and the tracer-decorated length (FL) of the IW were measured to calculate the average percent effective filtration length (PEFL = FL/TL). Sections with SC were examined by light and electron microscopy. The TL of the IW and the length exhibiting separation (SL) in the JCT were measured to calculate the average percent separation length (PSL = SL/TL). Outflow facility increased 149.2% (p < 0.01) from baseline after washout during long-duration perfusion, and 114.9% (p = 0.004) after Y27 treatment, but did not change significantly after short-duration perfusion in control eyes (p = 0.46). Distribution of the tracer labeling appeared punctate along the IW of control eyes, while a more uniform pattern was observed after washout and Y27 treatment. PEFL in washout (83.4 +/- 2.1%) and Y27 treated eyes (82.5 +/- 1.6%) was 3.4-fold larger compared to controls (24.2 +/- 4.2%, P < 0.001). The JCT appeared distended with loss of connections between JCT cells and between JCT cells and their extracelluar matrix in eyes with washout or after Y-27 treatment. PSL in the JCT was 2.3-fold larger in washout eyes (77.4 +/ 3.3%) and 2.2-fold larger in Y27 treated eyes (75.2 +/- 5.3%) versus controls (33.5 +/- 5.3%, p = 0.001). Significant positive correlations were found between outflow facility and PEFL, facility and PSL and between PEFL and PSL. Our data demonstrated that similar hydrodynamic and morphological changes occurred in the aqueous humor outflow pathway of monkey eyes after induction of washout and Y27 treatment. Both Y27 and washout increase outflow facility by redistributing aqueous outflow through a larger area in the JCT. These hydrodynamic changes are likely driven by morphologic changes associated with a decrease in cell-cell and cell-matrix connections in the JCT. PMID- 21669202 TI - Forster resonance energy transfer demonstrates a flavonoid metabolon in living plant cells that displays competitive interactions between enzymes. AB - We have used Forster resonance energy transfer detected by fluorescence lifetime imaging microscopy (FLIM-FRET) to provide the first evidence from living plants cells for the existence of a flavonoid metabolon. The distribution of flux within this system may be regulated by the direct competition of enzymes that catalyze key branch-point reactions, flavonol synthase 1 and dihydroflavonol 4-reductase, for association with the entry-point enzyme, chalcone synthase. Because the flavonoid enzymes were likely recruited from pathways of primary metabolism, our findings suggest a new general working model for the regulation of dynamic pathways in their native cellular context. PMID- 21669201 TI - Insights into the structure of the CCR4-NOT complex by electron microscopy. AB - The CCR4-NOT complex is a deadenylation complex, which plays a major role for mRNA stability. The complex is conserved from yeast to human and consists of nine proteins NOT1-NOT5, CCR4, CAF1, CAF40 and CAF130. We have successfully isolated the complex using a Protein A tag on NOT1, followed by cross-linking on a glycerol gradient. All components of the complex were identified by mass spectrometry. Electron microscopy of negatively stained particles followed by image reconstruction revealed an L-shaped complex with two arms of similar length. The arms form an accessible cavity, which we think could provide an extensive interface for RNA-deadenylation. PMID- 21669203 TI - Expression level of Hand2 affects specification of enteric neurons and gastrointestinal function in mice. AB - BACKGROUND & AIMS: Hand2 is a basic helix-loop-helix transcription factor required for terminal differentiation of enteric neurons. We studied Hand2 haploinsufficient mice, to determine whether reduced expression of Hand2 allows sufficient enteric neurogenesis for survival, but not for development of a normal enteric nervous system (ENS). METHODS: Enteric transcripts that encode Hand2 and the neuron-specific embryonic lethal abnormal vision proteins HuB, HuC, and HuD were quantified. Immunocytochemistry was used to identify and quantify neurons. Apoptosis was analyzed with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling procedure. Intracellular microelectrodes were used to record inhibitory junction potentials. Gastrointestinal transit and colonic motility were measured in vivo. RESULTS: Levels of of enteric Hand2 transcripts were associated with genotypes of mice, in the following order: Hand2(+/+) > Hand2(LoxP/+) > Hand2(+/-) > Hand2(LoxP/-). Parallel reductions were found in expression of HuD and in regional and phenotypic manners. Numbers of neurons, numbers of neuronal nitric oxide synthase(+) and calretinin(+), but not substance P(+) or vasoactive intestinal peptide(+) neurons, decreased. No effects were observed in stomach or cecum. Apoptosis was not detected, consistent with the concept that Hand2 inhibits neuronal differentiation, rather than regulates survival. The amplitude of inhibitory junction potentials in colonic circular muscle was similar in Hand2 wild-type and haploinsufficient mice, although in haploinsufficient mice, the purinergic component was reduced and a nitrergic component appeared. The abnormal ENS of haploinsufficient mice slowed gastrointestinal motility but protected mice against colitis. CONCLUSIONS: Reduced expression of factors required for development of the ENS can cause defects in the ENS that are subtle enough to escape detection yet cause significant abnormalities in bowel function. PMID- 21669204 TI - The epithelia-specific membrane trafficking factor AP-1B controls gut immune homeostasis in mice. AB - BACKGROUND & AIMS: Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B mediated protein sorting in the maintenance of gastrointestinal immune homeostasis. METHODS: The role of AP-1B in intestinal immunity was examined in AP 1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice. RESULTS: Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease. CONCLUSIONS: AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation. PMID- 21669205 TI - Measuring human T cell responses in blood and gut samples using qualified methods suitable for evaluation of HIV vaccine candidates in clinical trials. AB - The next generation of candidate HIV vaccines include replicating vectors selected for tropism to mucosal sites, where an efficacious T cell response will be required to limit T cell replication and HIV associated CD4 T cell loss. To fully assess immunogenicity of such candidates, there is a need to develop robust quality controlled analysis of gut derived HIV specific CD8+ T-cell responses. Despite obvious challenges in obtaining sufficient amounts of tissue, the highly compartmentalised nature of the mucosal immune responses, requires the assessment of CD8 T cells isolated directly from local tissue before any conclusions regarding the induction of mucosal responses are made. Here we describe the optimisation and subsequent qualification of a qualitative and quantitative polychromatic flow cytometry assay to assess antigen specific CD8+ T cells isolated from the gut, using samples from HIV positive and negative volunteers. Internal quality controls monitored over time, combined with the use of quality gating and standard operating procedures were used to demonstrate the generation of robust and reliable data. PMID- 21669207 TI - Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility. AB - A key regulatory step for serine proteases of the trypsin clan is activation of the initially secreted zymogens, leading to an increase in activity by orders of magnitude. Zymogen activation occurs by cleavage of a single peptide bond near the N-terminus of the catalytic domain. Besides the catalytic domain, most serine proteases have N-terminal A-chains with independently folded domains. Little is known about how zymogen activation affects the interplay between domains. This question is investigated with urokinase-type plasminogen activator (uPA), which has an epidermal growth factor domain and a kringle domain, connected to the catalytic domain by a 15-residue linker. uPA has been implicated under several pathological conditions, and one possibility for pharmacological control is targeting the conversion of the zymogen pro-uPA to active uPA. Therefore, a small angle X-ray scattering study of the conformations of pro-uPA and uPA in solution was performed. Structural models for the proteins were derived using available atomic-resolution structures for the various domains. Active uPA was found to be flexible with a random conformation of the amino-terminal fragment domain with respect to the serine protease domain. In contrast, pro-uPA was observed to be rigid, with the amino-terminal fragment domain in a fixed position with respect to the serine protease domain. Analytical ultracentrifugation analysis supported the observed difference between pro-uPA and uPA in overall shape and size seen with small-angle X-ray scattering. Upon association of either of two monoclonal Fab (fragment antigen-binding) fragments that are directed against the catalytic domain of, respectively, pro-uPA and uPA, rigid structures were formed. PMID- 21669206 TI - Dynamics of nucleosome invasion by DNA binding proteins. AB - Nucleosomes sterically occlude their wrapped DNA from interacting with many large protein complexes. How proteins gain access to nucleosomal DNA target sites in vivo is not known. Outer stretches of nucleosomal DNA spontaneously unwrap and rewrap with high frequency, providing rapid and efficient access to regulatory DNA target sites located there; however, rates for access to the nucleosome interior have not been measured. Here we show that for a selected high-affinity nucleosome positioning sequence, the spontaneous DNA unwrapping rate decreases dramatically with distance inside the nucleosome. The rewrapping rate also decreases, but only slightly. Our results explain the previously known strong position dependence on the equilibrium accessibility of nucleosomal DNA, which is characteristic of both selected and natural sequences. Our results point to slow nucleosome conformational fluctuations as a potential source of cell-cell variability in gene activation dynamics, and they reveal the dominant kinetic path by which multiple DNA binding proteins cooperatively invade a nucleosome. PMID- 21669208 TI - Reynolds number limits for jet propulsion: a numerical study of simplified jellyfish. AB - The Scallop theorem states that reciprocal methods of locomotion, such as jet propulsion or paddling, will not work in Stokes flow (Reynolds number=0). In nature the effective limit of jet propulsion is still in the range where inertial forces are significant. It appears that almost all animals that use jet propulsion swim at Reynolds numbers (Re) of about 5 or more. Juvenile squid and octopods hatch from the egg already swimming in this inertial regime. Juvenile jellyfish, or ephyrae, break off from polyps swimming at Re greater than 5. Many other organisms, such as scallops, rarely swim at Re less than 100. The limitations of jet propulsion at intermediate Re is explored here using the immersed boundary method to solve the 2D Navier-Stokes equations coupled to the motion of a simplified jellyfish. The contraction and expansion kinematics are prescribed, but the forward and backward swimming motions of the idealized jellyfish are emergent properties determined by the resulting fluid dynamics. Simulations are performed for both an oblate bell shape using a paddling mode of swimming and a prolate bell shape using jet propulsion. Average forward velocities and work put into the system are calculated for Re between 1 and 320. The results show that forward velocities rapidly decay with decreasing Re for all bell shapes when Re<10. Similarly, the work required to generate the pulsing motion increases significantly for Re<10. When compared to actual organisms, the swimming velocities and vortex separation patterns for the model prolate agree with those observed in Nemopsis bachei. The forward swimming velocities of the model oblate jellyfish after two pulse cycles are comparable to those reported for Aurelia aurita, but discrepancies are observed in the vortex dynamics between when the 2D model oblate jellyfish and the organism. This discrepancy is likely due to a combination of the differences between the 3D reality of the jellyfish and the 2D simplification, as well as the rigidity of the time varying geometry imposed by the idealized model. PMID- 21669210 TI - Model parameter uncertainties in a dual-species biofilm competition model affect ecological output parameters much stronger than morphological ones. AB - Bacterial biofilms are complex microbial depositions on immersed interfaces that form wherever the environmental conditions sustain microbial growth. Despite their name, biofilms can develop in highly irregular structures. Recently several mathematical concepts have been introduced to model these spatially structured microbial populations. Regardless of the type of model, they all have, even for microbially relatively simple systems, many parameters which generally are known at most approximately. We investigate the effect of uncertainties in model parameters on four morphological and four ecological output parameters using a nonlinear diffusion model for a biofilm in which two species compete for a shared nutrient. To this end we conduct an extensive computer simulation experiment for two different levels of data uncertainty, three different hydrodynamic conditions, and two different scenarios of bulk substrate availability. Our results indicate that input model parameter uncertainties have a much larger effect on ecological than on morphological output parameters. PMID- 21669209 TI - Coupling biochemistry and hydrodynamics captures hyperactivated sperm motility in a simple flagellar model. AB - Hyperactivation in mammalian sperm is characterized by highly asymmetrical waveforms and an increase in the amplitude of flagellar bends. It is important for the sperm to be able to achieve hyperactivated motility in order to reach and fertilize the egg. Calcium (Ca(2+)) dynamics are known to play a large role in the initiation and maintenance of hyperactivated motility. Here we present an integrative model that couples the CatSper channel mediated Ca(2+) dynamics of hyperactivation to a mechanical model of an idealized sperm flagellum in a 3-d viscous, incompressible fluid. The mechanical forces are due to passive stiffness properties and active bending moments that are a function of the local Ca(2+) concentration along the length of the flagellum. By including an asymmetry in bending moments to reflect an asymmetry in the axoneme's response to Ca(2+), we capture the transition from activated motility to hyperactivated motility. We examine the effects of elastic properties of the flagellum and the Ca(2+) dynamics on the overall swimming patterns. The swimming velocities of the model flagellum compare well with data for hyperactivated mouse sperm. PMID- 21669211 TI - Aging and photo-aging DNA repair phenotype of skin cells-evidence toward an effect of chronic sun-exposure. AB - Several studies have demonstrated the deleterious effect of aging on the capacity of cells to repair their DNA. However, current existing assays aimed at measuring DNA repair address only a specific repair step dedicated to the correction of a specific DNA lesion type. Consequently they provide no information regarding the repair pathways that handle other types of lesions. In addition to aging, consequences of photo-exposure on these repair processes remain elusive. In this study we evaluated the consequence of aging and of chronic and/or acute photo exposure on DNA repair in human skin fibroblasts using a multiplexed approach, which provided detailed information on several repair pathways at the same time. The resulting data were analyzed with adapted statistics/bioinformatics tools. We showed that, irrespective of the repair pathway considered, excision/synthesis was less efficient in non-exposed cells from elderly compared to cells from young adults and that photo-exposure disrupted this very clear pattern. Moreover, it was evidenced that chronic sun-exposure induced changes in DNA repair properties. Finally, the identification of a specific signature at the level of the NER pathway in cells repeatedly exposed to sun revealed a cumulative effect of UVB exposure and chronic sun irradiation. The uses of bioinformatics tools in this study was essential to fully take advantage of the large sum of data obtained with our multiplexed DNA repair assay and unravel the effects of environmental exposure on DNA repair pathways. PMID- 21669212 TI - Tetrabenazine inhibition of monoamine uptake and methamphetamine behavioral effects: locomotor activity, drug discrimination and self-administration. AB - Tetrabenazine (TBZ), a benzoquinolizine derivative, binds with high affinity to the vesicular monoamine transporter-2 (VMAT2), inhibiting uptake of cytosolic monoamines. The current study aimed to provide preclinical evidence supporting the potential use of TBZ as a treatment for methamphetamine abuse. Effects of TBZ on function of the dopamine transporter (DAT) and serotonin transporter (SERT) in striatal and hippocampal synaptosomes, respectively, and on VMAT2 function in isolated striatal synaptic vesicles were determined. Effect of TBZ (acute, 0.1 3.0 mg/kg, s.c.; repeated, 1.0 mg/kg for 7 days) on locomotor activity in methamphetamine-sensitized rats was assessed. Ability of TBZ (0.1-3.0 mg/kg; s.c.) or vehicle to decrease the discriminative effect of methamphetamine also was determined. Ability of TBZ (acute, 0.1-1.0 mg/kg, s.c.; repeated, 0.1 or 1.0 mg/kg for 7 days) to specifically decrease methamphetamine self-administration was determined; for comparison, a separate group of rats was assessed for effects of TBZ on food-maintained responding. Results show that TBZ was 11-fold more potent inhibiting DAT than SERT, and 2.5-fold more potent inhibiting VMAT2 than DAT. Results from behavioral studies showed that the lowest dose of TBZ transiently increased methamphetamine self-administration, whereas higher TBZ doses decreased methamphetamine self-administration. Also, TBZ at high doses decreased methamphetamine locomotor sensitization and discriminative stimulus effects, as well as food-maintained responding. Thus, despite acting as a potent VMAT2 inhibitor, these preclinical results indicate that TBZ lacks behavioral specificity as an inhibitor of methamphetamine-induced reinforcement, diminishing its viability as a suitable treatment for methamphetamine abuse. PMID- 21669213 TI - Up-regulation of dopamine D1 receptor in the hippocampus after establishment of conditioned place preference by cocaine. AB - The hippocampus plays an important role in the formation of contextual memory between the environment and the rewarding effect of abused drugs. The dopaminergic neural transmission in the hippocampus seems to be critical for such memory. Using conditioned place preference in rats, we found that the protein level of the dopamine D(1) receptor and its prerequisite mRNA in the hippocampus increased in animals that showed a clear preference for the environment paired with cocaine. The increase was not a simple reflection of the repeated administration of cocaine. Instead, it is attributable to conditioning, because systematic contingency between drug administration and exposure to a particular environment was necessary for the increase. Furthermore, we found that the mRNA of the dopamine D(1) receptors increased in the granule cell layer of the dentate gyrus. These results suggest that the alteration of dopamine D(1) receptor in the hippocampus, especially in the dentate gyrus, is related to the induction of drug induced contextual memory. The finding implicates the relevance of the dopaminergic signal transduction in the hippocampus to drug dependence. PMID- 21669215 TI - Optokinetic stimulation affects word omissions but not stimulus-centered reading errors in paragraph reading in neglect dyslexia. AB - Patients with right hemisphere lesions often omit or misread words on the left side of a text or the initial letters of single words, a phenomenon termed neglect dyslexia (ND). Omissions of words on the contralesional side of the page are considered as egocentric or space-based errors, whereas misread words can be viewed as a type of stimulus-centered error where the left part of a single perceptual entity (the word) is neglected. Previous patient studies have shown that optokinetic stimulation (OKS) significantly modulates many facets of the neglect syndrome, including the subjective body midline, line bisection and size distortions. An open question is whether OKS can also influence omissions and stimulus-centered errors in paragraph reading in ND. The current study compared the influence of OKS on both types of reading errors using controlled indented paragraph reading tests in a group of 9 right-hemisphere lesioned patients with ND, 7 patients without ND and 9 matched healthy controls. Leftward OKS significantly reduced omissions on the left side of the text in ND. In contrast, the pattern of stimulus-centered reading errors remained unchanged. In conclusion egocentric manipulations like OKS only appear to influence space-based attentional processes evident as omissions in paragraph reading but have no impact on stimulus-centered attentional processes evident as word-based errors during paragraph reading in ND. PMID- 21669217 TI - Ring A structural modified derivatives of withaferin A and the evaluation of their cytotoxic potential. AB - Regio-/stereoselective Michael addition to ring A of withaferin-A was performed using an optimized reaction procedure to synthesise a library of 2,3-dihydro,3 beta-substituted withaferin-A derivatives. The analogues thus obtained were evaluated for in vitro cytotoxicity against various human cancer cell lines. 3 Azido analogue exhibited 35-fold increase (IC(50)=0.02-1.9 MUM) in cytotoxicity against almost the entire cell lines tested when compared to the parent molecule. However, further modifications of 3-azido analogue with various alkynes under Husigen's cycloaddition conditions generated a variety of triazole derivatives with reduced cytotoxicity. PMID- 21669216 TI - Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin. AB - The blood-brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of obesity and anorexia. Strategic drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated. Here, we illustrate principles of SDDB with two different approaches to developing drugs based on leptin. In normal body weight humans and in non-obese rodents, leptin is readily transported across the BBB and into the CNS where it inhibits feeding and enhances thermogenesis. However, in obesity, the transport of leptin across the BBB is impaired, resulting in a resistance to leptin. As a result, it is difficult to treat obesity with leptin or its analogs that depend on the leptin transporter for access to the CNS. To treat obesity, we developed a leptin agonist modified by the addition of pluronic block copolymers (P85 leptin). P85-leptin retains biological activity and is capable of crossing the BBB by a mechanism that is not dependent on the leptin transporter. As such, P85 leptin is able to cross the BBB of obese mice at a rate similar to that of native leptin in lean mice. To treat anorexia, we developed a leptin antagonist modified by pegylation (PEG-MLA) that acts primarily by blocking the BBB transporter for endogenous, circulating leptin. This prevents blood-borne, endogenous leptin from entering the CNS, essentially mimicking the leptin resistance seen in obesity, and resulting in a significant increase in adiposity. These examples illustrate two strategies in which an understanding of the interactions among the BBB, CNS targets, and candidate therapeutics under physiologic and diseased conditions can be used to develop drugs effective for the treatment of brain disease. PMID- 21669218 TI - Testosterone response of hepatic gene expression in female mice having acquired testosterone-unresponsive immunity to Plasmodium chabaudi malaria. AB - Blood-stage malaria of Plasmodium chabaudi is characterized by its responsiveness to testosterone (T): T suppresses development of protective immunity, whereas once acquired immunity is T-unresponsive. Here, we have analyzed the liver, a T target and lymphoid organ with anti-malaria activity, for its T-responsiveness of gene expression in immune mice. Using Affymetrix microarray technology, in combination with quantitative RT-PCR, we have identified (i) T-unresponsive expression of newly acquired mRNAs encoding diverse sequences of IgG- and IgM antibodies, (ii) 24 genes whose expression has become T-unresponsive including those encoding the T(H)2 response promoting EHMT2 and the erythrocyte membrane protein band 7.2 STOM, (iii) T-unresponsive expression of mRNAs for the cytokines IL-1beta, IL-6, TNFalpha, and IFNgamma, as well as iNOS, which are even not inducible by infection, and (iv) 35 genes retaining their T-responsiveness, which include those encoding the infection-inducible acute phase proteins SAA1, SAA2, and ORM2 as well as those of liver metabolism which encode the T-downregulated female-prevalent enzymes CYP2B9, CYP2B13, CYP3A41, CYP7A1, and SULT2A2 and the T upregulated male-prevalent enzymes CYP2D9, CYP7B1, UGT2B1, HSD3B2, HSD3B5, respectively. The mRNA of the latter T-metabolizing enzyme is even 5-fold increased by T, suggesting a decrease in the effective T concentrations in the liver of immune mice. Collectively, our data suggest that the liver, which has acquired a selective T-unresponsiveness of gene expression, contributes to the acquired T-unresponsive, antibody-mediated protective immunity to blood-stage malaria of P. chabaudi. PMID- 21669219 TI - Effects of acute and chronic methylphenidate on delay discounting. AB - Methylphenidate (MPH) is one of the most common therapeutics used for the treatment of attention-deficit/hyperactivity disorder (ADHD), which consists of symptoms of inattention, and/or impulsivity and hyperactivity. Acute administration of MPH has been found to decrease impulsive choice in both humans and nonhuman animals, however, little is known about potential long-term changes in impulsive choice due to chronic administration of MPH. In the present experiment, effects of acute and chronic MPH (1.0-10.0mg/kg) were assessed on impulsive choice in the adult male Spontaneously Hypertensive Rat (SHR) to determine the extent of behavioral changes after chronic MPH exposure. Subjects chose between an immediate single food pellet and three food pellets delivered after a delay that increased within session (0 to 16s). At relatively higher doses during acute and chronic administration, choice maintained by the larger reinforcer was disrupted when there was no delay to either outcome, suggesting that MPH may be affecting stimulus control under the current delay-discounting task. When this disruption was not observed, however, MPH effects were selective in that only one intermediate dose (3.0mg/kg) decreased mean impulsive choice at one delay (8s) following acute administration. The same effect was observed following chronic MPH administration except that the dose was higher (5.6 mg/kg) and the delay was shorter (4s). Chronic administration of MPH did not show any negative indicators (e.g., an increase in impulsive choice) when administration was discontinued. PMID- 21669221 TI - The neurological safety of epidural parecoxib in rats. AB - Epidural injection of cyclooxygenase-2 inhibitors has been suggested as a useful therapeutic modality in pain management in animal studies and clinical settings. Direct epidural administration of parecoxib, a highly selective cyclooxygenase-2 inhibitor, may have advantages over its parenteral administration regarding required dose, side effects, and efficacy. However, no animal studies have been performed to investigate the possible neurotoxicity of epidurally injected parecoxib. Therefore, the present study was performed to assess the neurotoxicity of epidurally injected parecoxib in rats. Rats (n=45) were randomly divided into three groups: normal saline group (group N, n=15), ethanol group (group E, n=15), and parecoxib group (group P, n=15). 0.3 mL of epidural parecoxib (6 mg) and the same volume of epidural ethanol or normal saline were injected into the epidural space. Neurologic assessment was performed 3, 7 and 21 days after the injection by pinch toe testing. Histologic changes were evaluated for vacuolation of the dorsal funiculus, chromatolytic changes of the motor neurons, neuritis, and meningeal inflammation. All rats in groups N and P showed normal response to pinch-toe testing and had a normal gait at each observation point. Histological examination showed no evidence suggestive of neuronal body or axonal lesions, gliosis, or myelin sheet damage in group N or P at any time. However, all rats in group E showed sensory-motor dysfunction, behavioral change, or histopathological abnormalities. No neurotoxicity on the spinal cord or abnormalities in sensorimotor function or behavior was noted in rats that received epidural parecoxib. PMID- 21669214 TI - Endocannabinoid-mediated synaptic plasticity and addiction-related behavior. AB - Endogenous cannabinoids (eCBs) are retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CB1 receptors. Substantial evidence indicates that eCBs mediate various forms of short- and long-term plasticity in brain regions involved in the etiology of addiction. The present review provides an overview of the mechanisms through which eCBs mediate various forms of synaptic plasticity and discusses evidence that eCB-mediated plasticity is disrupted following exposure to a variety of abused substances that differ substantially in pharmacodynamic mechanism including alcohol, psychostimulants and cannabinoids. The possible involvement of dysregulated eCB signaling in maladaptive behaviors that evolve over long-term drug exposure is also discussed, with a particular focus on altered behavioral responses to drug exposure, deficient extinction of drug-related memories, increased drug craving and relapse, heightened stress sensitivity and persistent affective disruption (anxiety and depression). PMID- 21669222 TI - Cognitive and histological disturbances after chlorpyrifos exposure and chronic Abeta(1-42) infusions in Wistar rats. AB - Exposure to pesticides has been linked to an increased vulnerability to neurodegenerative diseases. In order to study whether the exposure to the organophosphate chlorpyrifos renders the brain prone to amyloid-beta peptide deposition and accelerates its neuropathological and behavioural effects, Wistar rats were injected a single subcutaneous dose of chlorpyrifos (250 mg/kg) and subsequently infused with Abeta(1-42) peptide (i.c.v.) for 15 days. No effects of either treatment were noted in the classic water maze test. The animals infused with Abeta peptide showed worse performance when the platform was both hidden and moved from trial to trial. Both groups showed worse performance when the platform was visible and moved from trial to trial. No amyloid deposition was observed in hippocampus or cerebral cortex after the infusion period, although microtubule associated protein 1A (MAP1A) immunoreactivity was significantly reduced in hippocampus and prefrontal cortex, whereas chlorpyrifos exposure produced a significant reduction of microtubule-associated protein 2 (MAP2) in the prefrontal cortex. Therefore, behavioural deficits could be related to a loss of dendrite and spine processes in these brain regions. PMID- 21669223 TI - Consensus review of the epidemiology and appropriate antimicrobial therapy of complicated urinary tract infections in Asia-Pacific region. AB - Urinary tract infections (UTIs) are among the most prevalent infectious diseases in the general population. They cause a substantial financial burden in the community and are associated with significant morbidity and mortality, particularly in hospitals. With increased rates of antimicrobial resistance, especially in the Asia-Pacific region, treatment of complicated UTIs (cUTIs) can be challenging for clinicians. Consideration of an optimal antimicrobial agent should be based on local resistance patterns, patient-specific factors, pharmacokinetic and pharmacodynamic principles, and cost. In the Asia-Pacific region, nearly half of Escherichia coli urinary isolates were resistant (including intermediate and resistant) to levofloxacin or ciprofloxacin and >=30% were resistant to third-generation cephalosporins (cefotaxime, ceftriaxone, and ceftazidime) and cefepime. Overall, 33% of urinary E. coli isolates exhibited extended-spectrum beta-lactamase (ESBL)-producing phenotypes. Prevalence of ESBL producing urinary E. coli was highest in India (60%), followed by Hong Kong (48%) and Singapore (33%). All urinary isolates of E. coli were susceptible to both ertapenem and imipenem. All urinary isolates of Klebsiella pneumoniae were susceptible to imipenem and 4% of them were resistant to ertapenem. Care should be exercised when using trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolones, and cephalosporins for the empirical treatment of UTIs, particularly cUTI among moderately to severely ill patients. Empiric antimicrobial treatment for serious cUTIs in which risk factors for resistant organisms exist should include broad-spectrum antibiotics such as carbapenems (ertapenem, imipenem, meropenem, and doripenem) and piperacillin-tazobactam. Aminoglycosides, tigecycline, and polymyxins (colistin or polymyxin B) can be used for the treatment of multidrug-resistant organisms or serious cUTIs when first-line options are deemed inappropriate or patients fail therapy. Because of considerable variability in different countries, local epidemiological data is critical in the effective management of UTIs in the Asia-Pacific region. PMID- 21669220 TI - Progesterone attenuates depressive behavior of younger and older adult C57/BL6, wildtype, and progesterone receptor knockout mice. AB - Progesterone may have actions independent of intracellular progestin receptors (PRs) to influence depressive behavior. To investigate this, we examined effects of progesterone (P; 10mg/kg, SC) on the depressive behavior of mice in the forced swim test (FST). In Experiment 1, subjects were 4 to 6 months old, intact or ovariectomized (OVX) female and intact or gonadectomized (GDX) male, C57/BL6 mice. Progesterone reduced depressive behavior of young diestrous and OVX mice but male mice were impervious to effects of P. In Experiment 2, subjects were intact aged (20-28 months old) C57/BL6 female and male mice. Progesterone reduced depressive behavior of aged female and male C57/BL6 mice, albeit effects were greater among males. In Experiment 3, effects of P were examined in 4 to 6 months old, gonadally-intact, female and male mice that were wildtype or PR knockouts (PRKOs). Progesterone decreased depressive behavior of young adult, wildtype and PRKO mice, which showed greater immobility than did their wildtype counterparts. In Experiment 4, subjects were 18-24 months old wildtype or PRKO mice (Exp 4). Progesterone decreased immobility among wildtype and PRKO mice (which were not different in terms of their baseline depressive behavior). Together these data demonstrate that P decreases depressive behavior of young and older adult C57/BL6, wildtype and PRKO mice, which suggest that acute anti-depressant effects of P may occur independent of actions at "classic" PRs. PMID- 21669224 TI - Orthopaedic device associated Candidal infection - a retrospective review of patient characteristics and outcome. PMID- 21669225 TI - Modelling ischaemia in vitro: effects of temperature and glucose concentration on dopamine release evoked by oxygen and glucose depletion in a mouse brain slice. AB - Current pharmacological interventions for acute stroke are largely ineffective or confounded by adverse effects, emphasising the need to develop new pharmacological treatments for neuroprotection. We have developed a robust in vitro model previously used in rats to assess dopamine release in mouse caudate nucleus brain slices, measured by fast cyclic voltammetry, during oxygen and glucose deprivation (OGD) as a model for cerebral ischaemia: this model will allow the study of transgenic mouse strains. During the pre-OGD equilibration period we found that a temperature of 33 degrees C, with solution containing 10 mM glucose provided the optimum baseline conditions from which reliable OGD induced changes in dopamine efflux could be measured, without being susceptible to spontaneous release events. During OGD we found no significant difference in any of the parameters measured between perfusion with glucose-free solution, and perfusion with solution containing 2 mM glucose. We therefore suggest, in agreement with previous work, that using 2 mM glucose during OGD is appropriate, and using these conditions we were able to reliably produce OGD-evoked dopamine release. PMID- 21669226 TI - Impairment of lung function might be related to IL-10 and IFN-gamma defective production in allergic children. AB - A functional defect of T regulatory cells (Tregs) has been proposed as pathogenic mechanism of allergic reaction. Impairment of lung function frequently occurs in children with respiratory allergy. This study aimed at investigating the possible role of IL-10 and IFN-gamma on lung function deterioration in allergic children. Forty children with mild asthma, monosensitized to house dust mites, were evaluated and followed-up for 2 years. Spirometry was performed in all children. IL-10 and IFN-gamma were evaluated in in vitro experiments. FEV(1), FVC, and FEF(25-75), evaluated as percent of predicted, significantly diminished over time (p<0.0001, p=0.03, and p<0.0001 respectively). There was a strong relationship between changes in spirometric parameters and IL-10 production and between changes in FEV(1) values and IFN-gamma production over time. This preliminary study provided evidence that IL-10 and IFN-gamma production could be defective in allergic children prone to develop functional impairment. PMID- 21669227 TI - Expression of herpes simplex virus type 1 recombinant thymidine kinase and its application to a rapid antiviral sensitivity assay. AB - Antiviral-resistant herpesvirus infection has become a great concern for immunocompromised patients. Herpes simplex virus type 1 (HSV-1) infections are treated with viral thymidine kinase (vTK)-associated drugs such as acyclovir (ACV), and most ACV-resistance (ACV(r)) is due to mutations in the vTK. The standard drug sensitivity test is usually carried out by the plaque reduction assay-based method, which requires over 10 days. To shorten the time required, a novel system was developed by the concept, in which 293T cells transiently expressing recombinant vTK derived from the test sample by transfection of the cells with an expression vector were infected with vTK-deficient and ACV(r) HSV-1 (TAR), and then cultured in a maintenance medium with or without designated concentrations of ACV, ganciclovir (GCV) and brivudine (BVdU). The replication of TAR was strongly inhibited by ACV, GCV and BVdU in 293T cells expressing recombinant vTK of the ACV-sensitive HSV-1, whereas replication was not or slightly inhibited in cells expressing the recombinant vTK of highly resistant or intermediately resistant HSV-1, respectively. An inverse correlation was demonstrated in the 50% effective concentrations (EC(50)s) and inhibitory effects of these compounds on the replication of TAR among ACV(s) and ACV(r) HSV-1 clones. These results indicate that the EC(50)s of the vTK-associated drugs including ACV can be assumed by measuring the inhibitory effect of drugs in 293T cells expressing recombinant vTK of the target virus. The newly developed antiviral sensitivity assay system for HSV-1 makes it possible to estimate EC(50) for vTK-associated drugs, when whole vTK gene is available for use by gene amplification directly from lesion's samples or from virus isolates. PMID- 21669228 TI - Resistance to raltegravir highlights integrase mutations at codon 148 in conferring cross-resistance to a second-generation HIV-1 integrase inhibitor. AB - Raltegravir is the first integrase strand-transfer inhibitor (INSTI) approved for use in highly active antiretroviral therapy (HAART) for the management of HIV infection. Resistance to antiretrovirals can compromise the efficacy of HAART regimens. Therefore it is important to understand the emergence of resistance to RAL and cross-resistance to other INSTIs including potential second-generation INSTIs such as MK-2048. We have now studied the question of whether in vitro resistance selection (IVRS) with RAL initiated with viruses derived from clinical isolates would result in selection of resistance mutations consistent with those arising during treatment regimens with HAART containing RAL. Some correlation was observed between the primary mutations selected in vitro and during therapy, initiated with viruses with identical IN sequences. Additionally, phenotypic cross-resistance conferred by specific mutations to RAL and MK-2048 was quantified. N155H, a RAL-associated primary resistance mutation, was selected after IVRS with MK-2048, suggesting similar mechanisms of resistance to RAL and MK-2048. This was confirmed by phenotypic analysis of 766 clonal viruses harboring IN sequences isolated at the point of virological failure from 106 patients on HAART (including RAL), where mutation Q148H/K/R together with additional secondary mutations conferred reduced susceptibility to both RAL and MK-2048. A homology model of full length HIV-1 integrase complexed with viral DNA and RAL or MK-2048, based on an X-ray structure of the prototype foamy virus integrase-DNA complex, was used to explain resistance to RAL and cross-resistance to MK-2048. These findings will be important for the further discovery and profiling of next-generation INSTIs. PMID- 21669230 TI - Topical cream-based oxyresveratrol in the treatment of cutaneous HSV-1 infection in mice. AB - Anti-herpes simplex virus (HSV) activities of oxyresveratrol in vitro and topical administration in cutaneous HSV-1 infection in mice were examined. The inhibitory concentrations for 50% plaque formation (IC(50)) of oxyresveratrol against HSV-1 clinical isolates and HSV-2 clinical isolates were 20.9-29.5 and 22.2-27.5 MUg/ml, respectively. In topical administration in cutaneous HSV-1 infection in mice, 2.5%, 5%, 10% and 20% oxyresveratrol in cream vehicle applied three times daily for 7 days after infection were evaluated and 10% and 20% oxyresveratrol cream were significantly effective in delaying the development of skin lesions and protection from death (P < 0.01). The concentration of 10% oxyresveratrol in cream was significantly more effective than that of 30% oxyresveratrol in vaseline applied three times daily (P < 0.01). Oxyresveratrol cream at 20% was as effective as 5% ACV cream applied three times daily (P < 0.01). Both 10% and 20% oxyresveratrol cream were as effective as that of 5% ACV cream applied two times daily (P > 0.05). Therapeutic efficacy of oxyresveratrol in cream vehicle was dose-dependent and the maximum efficacy observed on day 6 after infection was shown at 10% oxyresveratrol in cream applied three times daily. The frequency of application of 10% oxyresveratrol cream at three, four and five times daily was as effective as that of 5% ACV cream applied five times daily (P > 0.05). These results demonstrated that topical administration of oxyresveratrol in novel cream vehicle reduced the concentration of oxyresveratrol to 10% and was suitable for cutaneous HSV infection. PMID- 21669229 TI - HPV episome levels are potently decreased by pyrrole-imidazole polyamides. AB - Human papillomavirus (HPV) causes cervical cancer and other hyperproliferative diseases. There currently are no approved antiviral drugs for HPV that directly decrease viral DNA load and that have low toxicity. We report the potent anti-HPV activity of two N-methylpyrrole-imidazole polyamides of the hairpin type, polyamide 1 (PA1) and polyamide 25 (PA25). Both polyamides have potent anti-HPV activity against three different genotypes when tested on cells maintaining HPV episomes. The compounds were tested against HPV16 (in W12 cells), HPV18 (in Ker4 18 cells), and HPV31 (in HPV31 maintaining cells). From a library of polyamides designed to recognize AT-rich DNA sequences such as those in or near E1 or E2 binding sites of the HPV16 origin of replication (ori), four polyamides were identified that possessed apparent IC(50)s<=150nM with no evidence of cytotoxicity. We report two highly-active compounds here. Treatment of epithelia engineered in organotypic cultures with these compounds also causes a dose dependent loss of HPV episomal DNA that correlates with accumulation of compounds in the nucleus. Bromodeoxyuridine (BrdU) incorporation demonstrates that DNA synthesis in organotypic cultures is suppressed upon compound treatment, correlating with a loss of HPV16 and HPV18 episomes. PA1 and PA25 are currently in preclinical development as antiviral compounds for treatment of HPV-related disease, including cervical dysplasia. PA1, PA25, and related polyamides offer promise as antiviral agents and as tools to regulate HPV episomal levels in cells for the study of HPV biology. We also report that anti-HPV16 activity for Distamycin A, a natural product related to our polyamides, is accompanied by significant cellular toxicity. PMID- 21669231 TI - Lopinavir shows greater specificity than zinc finger ejecting compounds as a potential treatment for human papillomavirus-related lesions. AB - Non-surgical, antiviral treatment options are desirable for HPV-related lesions within the genitourinary and upper digestive tract. We compared the toxicity of three zinc finger-ejecting (ZFE) compounds (4,4-dithiodimorpholine, azodicarbonamide, and diamide) to the HIV protease inhibitor lopinavir using HPV positive SiHa, CaSki, HeLa, ME180, and HPV-negative C33A cervical carcinoma cell lines as well as primary human foreskin keratinocytes (PHFKs). Colorimetric growth assays revealed selective toxicity when treated with lopinavir. All carcinoma cell lines, except CaSki, were sensitive to 20 MUM lopinavir whereas primary PHFKs were highly resistant. In contrast, 4,4-dithiodimorpholine was uniformly toxic to all cells tested while azodicarbonamide and diamide showed no effect at all. It is concluded that lopinavir may be an attractive candidate to treat pre-cancerous and cancerous HPV-positive lesions. PMID- 21669232 TI - Ablation of the hypothalamic neuropeptide melanin concentrating hormone is associated with behavioral abnormalities that reflect impaired olfactory integration. AB - Melanin-concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide. At least one receptor, MCH receptor 1 (MCHR1), is present in all mammals and is expressed widely throughout the brain, including cortex, striatum and structures implicated in the integration of olfactory cues such as the piriform cortex and olfactory bulb. Consistent with a potential role for MCH in mediating olfactory function, MCH knockout mice demonstrate abnormal olfactory behaviors. These behaviors include impaired food seeking by both genders in the context of normal levels of exploratory behavior, suggesting impaired olfaction. Males also exhibit increased aggression while females show defects in several olfactory mediated behaviors including mating, estrous cycle synchronization and maternal behavior. These findings suggest that hypothalamic inputs through MCH play an important role in regulating sensory integration from olfactory pathways. PMID- 21669233 TI - Antipsychotic drugs reverse MK-801-induced cognitive and social interaction deficits in zebrafish (Danio rerio). AB - Schizophrenia is a severe mental illness characterized by positive and negative symptoms and cognitive deficits. Reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. Modeling social interaction and cognitive impairment in animals can be of great benefit in the effort to develop novel treatments for negative and cognitive symptoms of schizophrenia. Studies have demonstrated that these behavioral changes are, in some cases, sensitive to remediation by antipsychotic drugs. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs and to discover new pharmacological targets. In the current study we investigated the ability of antipsychotic drugs to reverse schizophrenia-like symptoms produced by the NMDA receptor antagonist MK-801. Results showed that MK-801 (5MUM) given pre training hindered memory formation while both atypical antipsychotics sulpiride (250MUM) and olanzapine (50MUM) improved MK-801-induced amnesia. The same change was observed in the social interaction task, where atypical antipsychotics reversed the MK-801-induced social interaction deficit whereas the typical antipsychotic haloperidol (9MUM) was ineffective to reverse those behavioral deficits. Therefore, MK-801-treated zebrafish showed some behavioral features observed in schizophrenia, such as cognitive and social interaction deficits, which were reverted by current available atypical drugs. PMID- 21669234 TI - Neonatal exposure to lipopolysaccharide enhances methamphetamine-induced reinstated behavioral sensitization in adult rats. AB - Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in long-lasting dopaminergic injury and enhanced methamphetamine (METH)-induced increase of locomotion in the adult male rat. To further investigate the effect of neonatal LPS exposure-induced dopaminergic injury, we used our neonatal rat model of LPS exposure (1mg/kg, intracerebral injection in postnatal day 5, P5, rats) to examine the METH sensitization as an indicator of drug addiction in the adult rats. On P70, animals began a treatment schedule of 5 daily subcutaneous (s.c.) administration of METH (0.5mg/kg) or saline (P70-P74) to induce behavioral sensitization. Ninety-six hours after the 5th treatment with METH or saline (P78), animals received a single dose of 0.5mg/kg METH (s.c.) or saline. Neonatal LPS exposure enhanced the level of development of behavioral sensitization including distance traveled, rearing events and stereotypy to METH administration in both male and female rats. Neonatal LPS exposure also enhanced the reinstated behavioral sensitization in both male and female rats after the administration had ceased for 96h. However, neonatal LPS exposure induced alteration in the reinstated behaviors sensitization of distance traveled and rearing events to METH administration appears to be greater in male than in female rats. These results indicate that neonatal brain LPS exposure produces a persistent lesion in the dopaminergic system, as indicated by enhanced METH induced locomotor and stereotyped behavioral sensitization in later life. These findings show that early-life brain inflammation may enhance susceptibility to the development of drug addiction in later life. PMID- 21669235 TI - Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. AB - A growing body of evidence has suggested that the dysfunction of glutamatergic systems plays a pivotal role in major depressive disorder (MDD). In clinical studies, an N-methyl-d-aspartate receptor antagonist, ketamine, was shown to exert both rapid and sustained antidepressant effects in patients with treatment resistant MDD. The objective of the present study was to confirm the rapid onset of action of ketamine and to investigate the mechanisms underlying both the rapid and sustained antidepressant-like effects of ketamine in rodent models of depression. The intraperitoneal administration of ketamine (10mg/kg) 30min prior to testing significantly reduced the number of escape failures in the learned helplessness (LH) paradigm in rats in which currently prescribed antidepressants exerted an effect only after repeated administrations. Ketamine also significantly reduced the immobility time in the tail suspension test (TST), and this effect lasted for 72h, indicating that ketamine may possess a sustained antidepressant-like effect. The rapid antidepressant-like effects of ketamine in both the LH paradigm and the TST were significantly blocked by subcutaneous treatment with 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX), an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist. In addition, the sustained antidepressant-like effect of ketamine in the TST was partially abolished by treatment with NBQX. In conclusion, we confirmed the faster onset of the action of ketamine, compared with clinically prescribed antidepressants. Moreover, the present results suggested that direct AMPA receptor activation may play an important role in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression, although other mechanisms might be involved in the sustained action. PMID- 21669236 TI - Adult hippocampal neurogenesis and memory interference. AB - Rats, subjected to low-dose irradiation that suppressed hippocampal neurogenesis, or a sham treatment, were administered a visual discrimination task under conditions of high, or low interference. Half of the rats engaged in running activity and the other half did not. In the non-runners, there was no effect of irradiation on learning, or remembering the discrimination response under low interference, but irradiation treatment increased their susceptibility to interference, resulting in loss of memory for the previously learned discrimination. Irradiated rats that engaged in running activity exhibited increased neuronal growth and protection from memory impairment. The results, which show that hippocampal cells generated in adulthood play a role in differentiating between conflicting, context-dependent memories, provide further evidence of the importance of neurogenesis in hippocampus-sensitive memory tasks. The results are consistent with computational models of hippocampal function that specify a central role for neurogenesis in the modulation of interfering influences during learning and memory. PMID- 21669238 TI - Auditory deviance detection revisited: evidence for a hierarchical novelty system. AB - The fast detection of novel or deviant stimuli is a striking property of the auditory processing which reflects basic organizational principles of the auditory system and at the same time is of high practical significance. In human electrophysiology, deviance detection has been related to the occurrence of the mismatch negativity (MMN)--a component of the event-related potential (ERP) evoked 100 to 250 ms after the occurrence of a rare irregular sound. Recently, it has been shown in animal studies that a considerable portion of neurons in the auditory pathway exhibits a property called stimulus-specific adaptation enabling them to encode inter-sound relationships and to discharge at higher rates to rare changes in the acoustic stimulation. These neural responses have been linked to the deviant-evoked potential measured at the human scalp, but such responses occur at lower levels anatomically (e.g. the primary auditory cortex as well as the inferior colliculi) and are elicited earlier (20-30 ms after sound onset) in comparison to MMN. Further, they are not considerable enough in size to be interpreted as a direct neural correlate of the MMN. We review here a series of recent findings that provides a first step toward filling this gap between animal and human recordings by showing that comparably early modulations due to a sound's deviancy can be observed in humans, particularly in the middle-latency portion of the ERP within the first 50 ms after sound onset. The existence of those early indices of deviance detection preceding the well-studied MMN component strongly supports the idea that the encoding of regularities and the detection of violations is a basic principle of human auditory processing acting on multiple levels. This sustains the notion of a hierarchically organized novelty and deviance detection system in the human auditory system. PMID- 21669237 TI - A transmembrane domain containing pellicle protein of Toxoplasma gondii enhances virulence and invasion after extracellular stress. AB - To identify Toxoplasma gondii genes important in the establishment of a persistent infection, we previously used signature-tagged mutagenesis to identify mutants with reduced cyst numbers in the brains of mice. One of the mutants, 95C5, has an insertion within a predicted six transmembrane domain protein, which localizes to the parasite pellicle, thus we named it transmembrane pellicle protein 1 (TgTPP1). Although the 95C5 mutant was found be reduced in its ability to form brain cysts, it is defective during acute infection. Addition of TgTPP1 expressed from its endogenous promoter restored the acute lethality of the 95C5 mutant to parental levels. The 95C5 mutant does not have a growth defect in standard tissue culture conditions; however, we found a significant defect in host cell penetration after extracellular stress. Overall, TgTPP1 may function during acute infection by enhancing the parasites ability to invade after extracellular stress. PMID- 21669239 TI - Complement activation by carbon nanotubes. AB - Carbon nanotube interaction with an important part of the innate immune system, complement, needs to be taken into account when envisaging their use in biomedical applications. Carbon nanotubes (CNTs) and other synthetic materials are recognized by various components of the complement system in human or mammalian blood and also collectins in the lungs. Modification of the surface chemistry of CNTs alters their interactions with complement proteins and collectins. Functionalizations of CNTs which have been tested so far do not completely prevent complement activation or plasma protein binding. The interaction of the functionalized CNTs with the complement system proteins in blood may influence the adhesion of CNTs to phagocytic cells and red blood cells. Excessive activation of complement can have a harmful effect on human tissues and therefore significantly limit CNT applications in biomedicine. PMID- 21669240 TI - Lymphatic drug delivery: therapy, imaging and nanotechnology. Preface. PMID- 21669241 TI - Foods that are perceived as healthy or unhealthy differentially alter young women's state body image. AB - Body image can be influenced by day-to-day events, including food intake. The present study investigated the effects of foods typically perceived as "healthy" or "unhealthy" on state body image and mood. College-aged women were told the experiment was designed to assess the effects of food on cognition. Using a between-subjects design, participants consumed isocaloric amounts of foods perceived to be healthy (banana) or unhealthy (donut) or ate nothing. Next, participants completed three cognitive tasks. Prior to eating and following the cognitive tests, participants completed the BISS, POMS, the Figure Rating Scale, and the Restraint Scale. Body satisfaction decreased following intake of a donut, but was not altered in the other conditions. Depression scores significantly decreased after intake of either a donut or banana, but did not decrease in the no-food condition. Tension scores decreased significantly after consumption of a banana and in the no-food condition, but did not decrease following consumption of a donut. These results indicate that intake of a food that is perceived as unhealthy negatively affects state body image. PMID- 21669242 TI - A possible pivotal role of mitochondrial free calcium in neurotoxicity mediated by N-methyl-d-aspartate receptors in cultured rat hippocampal neurons. AB - We have previously shown that mitochondrial membrane potential disruption is involved in mechanisms underlying differential vulnerabilities to the excitotoxicity mediated by N-methyl-d-aspartate (NMDA) receptors between primary cultured neurons prepared from rat cortex and hippocampus. To further elucidate the role of mitochondria in the excitotoxicity after activation of NMDA receptors, neurons were loaded with the fluorescent dye calcein diffusible in the cytoplasm and organelles for determination of the activity of mitochondrial permeability transition pore (mPTP) responsible for the leakage of different mitochondrial molecules. The addition of CoCl(2) similarly quenched the intracellular fluorescence except mitochondria in both cultured neurons, while further addition of NMDA led to a leakage of the dye into the cytoplasm in hippocampal neurons only. An mPTP inhibitor prevented the NMDA-induced loss of viability in hippocampal neurons, while an activator of mPTP induced a similarly potent loss of viability in cortical and hippocampal neurons. Although NMDA was more effective in increasing rhodamine-2 fluorescence as a mitochondrial calcium indicator in hippocampal than cortical neurons, a mitochondrial calcium uniporter inhibitor significantly prevented the NMDA-induced loss of viability in hippocampal neurons. Expression of mRNA was significantly higher for the putative uniporter uncoupling protein-2 in hippocampal than cortical neurons. These results suggest that mitochondrial calcium uniporter would be at least in part responsible for the NMDA neurotoxicity through a mechanism relevant to promotion of mPTP orchestration in hippocampal neurons. PMID- 21669243 TI - CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer. AB - Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA 4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60) (rs3087243), CTLA-4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T>C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA 4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA-4c.49A>G[A] allele and CTLA-4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles CTLA-4c.49A>G[A]/CT60[G]/CD28c.17+3T>C[T]/ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold (p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C>T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC. PMID- 21669244 TI - Studying the genetic predisposing factors in the pathogenesis of acne vulgaris. AB - Acne is one of the most common dermatologic diseases in the developed regions of the world, affecting a large percentage of the population. Despite the great improvement in the number and quality of studies of the molecular etiology of this disease in the past 3 decades, the detailed molecular pathogenesis and the cause of the large individual variations in severity of skin symptoms remain unknown. The roles of genetic inheritance and special genetic susceptibility and protective factors have been suggested for over 100 years, but their identification and determination started only in the 1990s. To date, only a small number of genetic polymorphisms affecting the expression and/or function of a handful of genes have been investigated. This review surveys the major findings of the classic and molecular genetic studies that have been conducted in this field, draws conclusions, and indicates how the available data help our current understanding of the pathogenesis of this common skin disease. PMID- 21669245 TI - Low CD40L levels and relative lymphopenia in narcoleptic patients. AB - Narcolepsy has been studied as a possible autoimmune disease for many years, and recent findings lend more credence to this belief. Although recent and important advances have been done, no study has analyzed the role of the CD40L in patients with narcolepsy. The purpose of this study was to assess CD40L levels, CD3, TCD4, TCD8, CD19, and CD56 lymphocytes, as well as levels of tumor necrosis factor alpha and interleukin-6 in narcoleptic patients. We quantified the levels of CD40L, different types of lymphocytes, and levels of tumor necrosis factor-alpha and interleukin-6 in narcoleptic patients and control subjects. Narcoleptic patients had lower levels of CD40L. Total lymphocytes; CD3, and TCD4 were lower than in the control group. Our findings highlight the important role of CD40L in narcolepsy. PMID- 21669246 TI - Surfactant protein C is an essential constituent for mucosal adjuvanticity of Surfacten, acting as an antigen delivery vehicle and inducing both local and systemic immunity. AB - We have reported that Surfacten((r)) (St), a bovine pulmonary surfactant free of antigenic c-type lectins, is a useful mucosal adjuvant for nasal vaccination. To prepare ample supplies a synthetic adjuvant that mimics St, we analyzed essential constituents of St for mucosal adjuvanticity. Intranasal inoculation of influenza virus hemagglutinin (HA) vaccine combined with St free of surfactant protein (SP) C resulted in failure of HA vaccine delivery to dendritic cells and loss of local and systemic immune responses. Naive bovine SP-C, synthetic human or bovine SP-C peptide reconstituted with three major St lipids restored delivery activity and local and systemic immune responses to levels similar to those of St and provided almost complete protection against lethal doses of influenza virus challenge in mice. The delivery of fluoresceinated HA vaccine to cultured dendritic cells was significantly enhanced by co-administration of St or synthetic adjuvant, and moderately stimulated the expression of MHC class II and CD86. In addition, both St and synthetic adjuvant markedly sustained HA vaccine and achieved a wide antigen distribution in murine nasal cavity. These results suggest that synthetic mucosal adjuvant reconstituted with SP-C peptide and major St lipids is useful for ample supply of the potent mucosal adjuvant as an antigen delivery vehicle for intranasal vaccination. PMID- 21669247 TI - Impact of infant and preschool pertussis vaccinations on memory B-cell responses in children at 4 years of age. AB - Whooping cough, caused by Bordetella pertussis, is reemerging in the vaccinated population. Antibody levels to pertussis antigens wane rapidly after both whole cell (wP) and acellular pertussis (aP) vaccination and protection may largely depend on long-term B- and T-cell immunity. We studied the effect of wP and aP infant priming at 2, 3, 4 and 11 months according to the Dutch immunization program on pertussis-specific memory B-cell responses before and after a booster vaccination with either a high- or low-pertussis dose vaccine at 4 years of age. Purified B-cells were characterized by FACS-analysis and after polyclonal stimulation, memory B-cells were detected by ELISPOT-assays specific for pertussis toxin, filamentous haemagglutinin and pertactin. Before and after the booster, higher memory B-cell responses were measured in aP primed children compared with wP primed children. In contrast with antibody levels, no dose effect was observed on the numbers of memory B-cell responses. In aP primed children a fifth high-dose aP vaccination tended to induce even lower memory B cell responses than a low-dose aP booster. In both wP and aP primed children, the number of memory B-cells increased after the booster and correlated with the pertussis-specific antibody concentrations and observed affinity maturation. This study indicates that aP vaccinations in the first year of life induce higher pertussis-specific memory B-cell responses in children 4 years of age compared with Dutch wP primary vaccinations. Since infant aP vaccinations have improved protection against whooping cough in children despite waning antibody levels, this suggests that an enhanced memory B-cell pool induction may have an important role in protection. However, the pertussis-dose of the preschool booster needs to be considered depending on the vaccine used for priming to optimize long-term protection against whooping cough. PMID- 21669248 TI - Sample characterization: a priori to evaluating absorption, distribution, and metabolism. PMID- 21669250 TI - Two genetic codes, one genome: frameshifted primate mitochondrial genes code for additional proteins in presence of antisense antitermination tRNAs. AB - Genomic amino acid usages coevolve with cloverleaf formation capacities of corresponding primate mitochondrial tRNAs, also for antisense tRNAs, suggesting translational function for sense and antisense tRNAs. Some antisense tRNAs are antitermination tRNAs (anticodons match stops (UAR: UAA, UAG; AGR: AGA, AGG)). Genomes possessing antitermination tRNAs avoid corresponding stops in frames 0 and +1, preventing translational antitermination. In frame +2, AGR stop frequencies and corresponding antisense antitermination tRNAs coevolve positively. This suggests expression of frameshifted overlapping genes, potentially shortening genomes, increasing metabolic efficiency. Blast analyses of hypothetical proteins translated from one and seven +1, respectively, +2 frameshifted human mitochondrial protein coding genes align with eleven GenBank sequences (31% of the mitochondrial coding regions). These putative overlap genes contain few UARs, AGRs align with arginine. Overlap gene numbers increase in presence of, and with time since evolution of antitermination tRNA AGR in 57 primate mitochondrial genomes. Numbers of putative proteins translated from antisense protein coding sequences and detected by blast also coevolve positively with antitermination tRNAs; expression of two of these 'antisense' mRNAs increases under low resource availability. Although more direct evidence is still lacking for the existence of proteins translated from overlapping mitochondrial genes and for antisense tRNAs activity, coevolutions between predicted overlap genes and the antitermination tRNAs required to translate them suggest expression of overlapping genes by an overlapping genetic code. Functions of overlapping genes remain unknown, perhaps originating from dual lifestyles of ancestral free living-parasitic mitochondria. Their amino acid composition suggests expression under anaerobic conditions. PMID- 21669251 TI - Vitamin D metabolism in mammary gland and breast cancer. AB - 1alpha,25-Dihydroxycholecalciferol (1,25D) mediates growth inhibition and terminal differentiation in mammary epithelial cells via interaction with the vitamin D receptor (VDR). This review focuses on the concept that cells in the mammary gland express the vitamin D metabolizing enzyme CYP27B1 which converts the circulating vitamin D metabolite 25D to the active metabolite 1,25D. In support of this concept, CYP27B1 is developmentally regulated in mouse mammary gland, with highest levels found during pregnancy and lactation. In addition, human mammary cells cultured from normal breast tissue express VDR, CYP27B1 and the megalin-cubilin complex that facilitates internalization of 25D complexed with the vitamin D binding protein. When incubated with physiological concentrations of 25D, human mammary cells synthesize 1,25D in sufficient quantities to mediate growth inhibition. However, emerging evidence suggests that deregulation of VDR and CYP27B1 occurs during cancer development and contributes to abrogation of the tumor suppressive effects triggered by 25D. PMID- 21669252 TI - Age related changes in the myelinated fibers of corpus callosum. AB - Efficient and unbiased stereological methods were used to study the age-related changes of corpus callosum and the age-related changes of the myelinated fibers in the corpus callosum. There existed age-related atrophy of rat corpus callosum. The total volume of the myelinated fibers and the total volume of the myelin sheathes in the corpus callosum of aged rat were significantly decreased when compared to young rat. The age-related changes of corpus callosum were primarily due to the loss of the myelinated fibers with small diameters. PMID- 21669253 TI - Loss of CNS IL-2 gene expression modifies brain T lymphocyte trafficking: response of normal versus autoreactive Treg-deficient T cells. AB - Emerging data from our lab and others suggested that dysregulation of the brain's endogenous neuroimmunological milieu may occur with the loss of brain IL-2 gene expression and be involved in initiating processes that lead to CNS autoimmunity. We sought to test our working hypothesis that IL-2 deficiency induces endogenous changes in the CNS that play a key role in eliciting T cell homing into the brain. To accomplish this goal, we used an experimental approach that combined mouse congenic breeding and immune reconstitution. In congenic mice without brain IL-2 (two IL-2 KO alleles) that were reconstituted with a normal wild-type immune system, the loss of brain IL-2 doubled the number of T cells that trafficked into the brain in all regions quantified (hippocampus, septum, and cerebellum) compared to mice with two wild-type brain IL-2 alleles and a wild-type peripheral immune system. Congenic mice with normal brain IL-2 (two wild-type IL-2 alleles) that were immune reconstituted with autoreactive Treg-deficient T cells from IL-2 KO mice developed the expected peripheral autoimmunity (splenomegaly) and had a comparable doubling of T cell trafficking into the hippocampus and septum, whereas they exhibited an additional twofold proclivity for the cerebellum over the septohippocampal regions. Unlike brain trafficking of wild-type T cells, the increased homing of IL-2 KO T cells to the cerebellum was independent of brain IL 2 gene expression. These findings demonstrate that brain IL-2 deficiency induces endogenous CNS changes that may lead to the development of brain autoimmunity, and that autoreactive Treg-deficient IL-2 KO T cells trafficking to the brain could have a proclivity to induce cerebellar neuropathology. PMID- 21669254 TI - Novelty response of rats determines the effect of prefrontal alpha-2 adrenoceptor modulation on anxiety. AB - In this study we provide evidence that animals of the same population, although identical in age and sex, have individual reactions to the prefrontal modulation of adrenoceptors. We have examined the dose-dependent action of alpha(2) adrenoceptor agents on the anxiety of rats with different response to novelty in the elevated plus maze (EPM) apparatus. Rats were divided into high (HR) and low responder (LR) groups based on their locomotor activity in a novel open field environment. HR rats also showed increased locomotion and low anxiety in the EPM. Prefrontal injection of alpha(2)-receptor antagonist yohimbine, BRL44408 or imiloxan caused anxiety only in HR rats. The alpha(2A/D)-receptor agonist guanfacine increased anxiety levels of both groups. However, the effective dose was lower in HR rats. The present results propose different prefrontal adrenoceptor sensitivity of rats showing distinct baseline activity levels. PMID- 21669255 TI - Oligodendrocyte vulnerability following traumatic brain injury in rats. AB - Experimental and clinical findings demonstrate that traumatic brain injury (TBI) results in injury to both gray and white matter structures. The purpose of this study was to document patterns of oligodendrocyte vulnerability to TBI. Sprague Dawley rats underwent sham operated procedures or moderate fluid percussion brain injury. Quantitative immunohistochemical analysis was performed on animals perfusion-fixed at 3 (n=9) or 7 (n=9) days post-surgery. Within the ipsilateral external capsule and corpus callosum, numbers of APC-CC1 immunoreactive oligodendrocytes were significantly decreased at 3 or 7 days post-TBI compared to sham rats (p<0.03). At both posttraumatic survival periods, double-labeling studies indicated that oligodendrocytes showed increased Caspase 3 activation compared to sham. These data demonstrate regional patterns of oligodendrocyte vulnerability after TBI and that oligodendrocyte cell loss may be due to Caspase 3-mediated cell death mechanisms. Further studies are needed to test therapeutic interventions that prevent trauma-induced oligodendrocyte cell death, subsequent demyelination and circuit dysfunction. PMID- 21669256 TI - Embryonic exposure to thimerosal, an organomercury compound, causes abnormal early development of serotonergic neurons. AB - Even though neuronal toxicity due to organomercury compounds is well known, thimerosal, an organomercury compound, is widely used in pediatric vaccine preservation. In the present study, we examined whether embryonic exposure to thimerosal affects early development of serotonergic neurons. Thimerosal (1mg Hg/kg) was intramuscularly administered to pregnant rats on gestational day 9 (susceptible time window for development of fetal serotonergic system), and fetal serotonergic neurons were assessed at embryonic day 15 using anti-serotonin antibodies. A dramatic increase in the number of serotonergic neurons localized to the lateral portion of the caudal raphe was observed in thimerosal group (1.9 fold increase, p<0.01 compared to control). These results indicate that embryonic exposure to thimerosal affects early development of serotonergic neurons. PMID- 21669258 TI - Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A(2A) receptors. AB - G-protein coupled receptors interact to provide additional regulatory mechanisms for neurotransmitter signaling. Adenosine A(2A) receptors are expressed at a high density in striatal neurons, where they closely interact with dopamine D2 receptors and modulate effects of dopamine and responses to psychostimulants. A(2A) receptors are expressed at much lower densities in other forebrain neurons but play a more prominent yet opposing role to striatal receptors in response to psychostimulants in mice. It is, therefore, possible that A(2A) receptors expressed at low levels elsewhere in the brain may also regulate neurotransmitter systems and modulate neuronal functions. Dopamine D2 receptors play an important role in autoinhibition of neuronal firing in dopamine neurons of the ventral tegmental area (VTA) and dopamine release in other brain areas. Here, we examined the effect of A(2A) receptor deletion on D2 receptor-mediated inhibition of neuronal firing in dopamine neurons in the VTA. Spontaneous activity of dopamine neurons was recorded in midbrain slices, and concentration-dependent effects of the dopamine D2 receptor agonist, quinpirole, was compared between wild-type and A(2A) knockout mice. The potency of quinpirole applied in single concentrations and the expression of D2 receptors were not altered in the VTA of the knockout mice. However, quinpirole applied in stepwise escalating concentrations caused significantly reduced maximal inhibition in A(2A) knockout mice, indicating an enhanced agonist-induced desensitization of D2 receptors in the absence of A(2A) receptors. The A(2A) receptor agonist, CGS21680, did not exert any effect on dopamine neuron firing or response to quinpirole, revealing a novel non pharmacological interaction between adenosine A(2A) receptors and dopaminergic neurotransmission in midbrain dopamine neurons. Altered D2 receptor desensitization may result in changes in dopamine neuron firing rate and pattern and dopamine release in other brain areas in response to persistent dopamine release and administration of psychostimulants. PMID- 21669259 TI - Neuroprotective effect of levetiracetam on hippocampal sclerosis-like change in spontaneously epileptic rats. AB - The spontaneously epileptic rat (SER) begins to exhibit both tonic convulsions and absence seizures from 6 weeks of age and SERs have stable seizures after 10 weeks of age. Low-dose administrations of levetiracetam (LEV) for 4- to 5-weeks old SERs which did not show spontaneous seizures reduced both seizures 5 weeks after termination of administration. The hippocampus of SER exhibited decreased CA3 neurons, sprouting of mossy fibers, and hyperexpression of the brain-derived neurotrophic factor (BDNF). We attempted prophylactic LEV administrations in preseizure-manifesting SERs to evaluate if such a treatment regimen would protect the hippocampal sclerosis-like changes observed in SERs. The osmotic mini-pump administered LEV dissolved in saline to 4-weeks-old SERs for 4 weeks at 2.5 MUl/h. LEV was administered at 420 mg/ml for 4 weeks in Group A. In Group B, LEV was given at 420 mg/ml for the first 2 weeks followed by doubling the dosage (840 mg/ml) in the following 2 weeks. LEV administrations in preseizure-manifesting SERs reduced the decrease of CA3 neurons and mossy fibers sprouting at 10-11 weeks of age in both group A and B. LEV attenuated BDNF expression in inner molecular layers of the dentate gyrus, striatum radiatum, and CA3 in 10- to 11- and 14- to 15-weeks-old SERs. In group B, LEV decreased BDNF expression in hilus and CA1 of 10- to 11- weeks-old SER. The present results suggest that prophylactic treatment with LEV in preseizure-manifesting SERs inhibits hippocampal sclerosis-like neuronal degeneration and/or regeneration. PMID- 21669260 TI - C-Phycocyanin is neuroprotective against global cerebral ischemia/reperfusion injury in gerbils. AB - Although the huge economic and social impact and the predicted incidence increase, neuroprotection for ischemic stroke remains as a therapeutically empty niche. In the present study, we investigated the rationale of the C-Phycocyanin (C-PC) treatment on global cerebral ischemia/reperfusion (I/R) injury in gerbils. We demonstrated that C-PC given either prophylactically or therapeutically was able to significantly reduce the infarct volume as assessed by triphenyltetrazolium chloride (TTC) staining and the neurological deficit score 24h post-stroke. In addition, C-PC exhibited a protective effect against hippocampus neuronal cell death, and significantly improved the functional outcome (locomotor behavior) and gerbil survival after 7 days of reperfusion. Malondialdehyde (MDA), peroxidation potential (PP) and ferric reducing ability of plasma (FRAP) were assayed in serum and brain homogenates to evaluate the redox status 24h post-stroke. The treatment with C-PC prevented the lipid peroxidation and the increase of FRAP in both tissue compartments. These results suggest that the protective effects of C-PC are most likely due to its antioxidant activity, although its anti-inflammatory and immuno-modulatory properties reported elsewhere could also contribute to neuroprotection. To our knowledge, this is the first report of the neuroprotective effect of C-PC in an experimental model of global cerebral I/R damage, and strongly indicates that C-PC may represent a potential preventive and acute disease modifying pharmacological agent for stroke therapy. PMID- 21669257 TI - Lithium pilocarpine-induced status epilepticus in postnatal day 20 rats results in greater neuronal injury in ventral versus dorsal hippocampus. AB - Many quantitative animal studies examining the possible relationship between hippocampal neuronal loss and the development of epilepsy have examined only the dorsal hippocampus. The ventral hippocampus, however, represents the more homologous structure to the anterior hippocampus in humans, which is the area associated with the maximal damage in patients with temporal lobe epilepsy. This study tested the hypothesis that the ventral hippocampus has greater neuronal injury than the dorsal hippocampus in an animal model of chemoconvulsant-status epilepticus at postnatal day 20. Status epilepticus was induced in postnatal day 20 Sprague-Dawley rat pups with the chemoconvulsant lithium-pilocarpine and brain tissue was examined with Fluoro-Jade B. Horizontal sections (n=7) favoring a visualization of the ventral hippocampus showed marked Fluoro-Jade B staining in CA1, CA3, and hilar region. Coronal sections favoring a visualization of the dorsal hippocampus did not consistently show as robust a staining pattern in these regions. In coronal sections where both the dorsal and ventral hippocampus could be viewed, greater staining was always seen in ventral versus dorsal hippocampus. Quantitative analysis of cell counts demonstrated a significant difference between ventral and dorsal hippocampus in CA1 and CA3, but not hilus. These results demonstrate that in ventral hippocampus, lithium pilocarpine induced status epilepticus consistently results in hippocampal neuronal injury in postnatal day 20 rats. This study shows the importance of including the ventral hippocampus in any analysis of seizure-induced hippocampal neuronal injury, and raises concerns about the accuracy of studies quantifying hippocampal neuronal loss when only the dorsal hippocampus is examined. PMID- 21669261 TI - Special aspects of cosmetic spray safety evaluations: principles on inhalation risk assessment. AB - The consumer exposure to the vast majority of cosmetic products is limited to dermal contact. Even spray applications tend to be topically exposed to skin or hair. Besides this skin contact, spray products require additional considerations in regard to potential inhalation for building a robust and reliable safety assessment. Over the years, cosmetic industry developed prediction models for the best estimate of inhalation exposure combining data from computer simulation programs available in the market, individual real measured data and last but not least the experience from the market. Such attempt is driven by the toxicological profile of individual used ingredients. The focus of this review is on the determination of inhalation exposure, and the derivation of safe exposure levels for cosmetic spray products. Many of the methods employed to ensure product safety of cosmetic sprays in accordance with the general requirements of the EC Cosmetics Directive are based on industry experience which are not necessarily consistent across companies. This paper presents an approach to compile common principles for risk assessment and thus contribute to standardisation of safety assessment methodologies utilized for spray product evaluation without interfering with the flexibility of the individual safety assessor. It is based on the experience within the author's companies and may be useful as a support document as well for SME (Small and Medium Enterprises) companies safety assessors. In this respect it can be seen as one fundamental step in a tiered approach of cosmetic spray safety evaluation. PMID- 21669262 TI - Comparison of manganese oxide nanoparticles and manganese sulfate with regard to oxidative stress, uptake and apoptosis in alveolar epithelial cells. AB - Due to their physicochemical characteristics, metal oxide nanoparticles (NPs) interact differently with cells compared to larger particles or soluble metals. Oxidative stress and cellular metal uptake were quantified in rat type II alveolar epithelial cells in culture exposed to three different NPs: manganese(II,III) oxide nanoparticles (Mn(3)O(4)-NPs), the soluble manganese sulfate (Mn-salt) at corresponding equivalent doses, titanium dioxide (TiO(2) NPs) and cerium dioxide nanoparticles (CeO(2)-NPs). In the presence of reactive oxygen species an increased apoptosis rate was hypothesized. Oxidative stress was assessed by detection of fluorescently labeled reactive oxygen species and by measuring intracellular oxidized glutathione. Catalytic activity was determined by measuring catalyst-dependent oxidation of thiols (DTT-assay) in a cell free environment. Inductively coupled plasma mass spectrometry was used to quantify cellular metal uptake. Apoptosis rate was determined assessing the activity of caspase-3 and by fluorescence microscopic quantification of apoptotic nuclei. Reactive oxygen species were mainly generated in cells treated with Mn(3)O(4) NPs. Only Mn(3)O(4)-NPs oxidized intracellular glutathione. Catalytic activity could be exclusively shown for Mn(3)O(4)-NPs. Cellular metal uptake was similar for all particles, whereas Mn-salt could hardly be detected within the cell. Apoptosis was induced by both, Mn(3)O(4)-NPs and Mn-salt. The combination of catalytic activity and capability of passing the cell membrane contributes to the toxicity of Mn(3)O(4)-NPs. Apoptosis of samples treated with Mn-salt is triggered by different, potentially extracellular mechanisms. PMID- 21669263 TI - Sunscreen products: what do they protect us from? AB - Whereas for fifty or so years acquiring a tan has been the trend for aesthetic reasons relating to current beauty criteria, the health authorities are now advocating vigilance in this area, prompted by the knowledge of the harmful effects of the sun, especially from its ultra-violet rays. In the European Union, sunscreen products are considered cosmetics and tests on their effectiveness can be performed in vivo or in vitro to determine four effectiveness indicators: the SPF (Sun Protection Factor), the PF-UVA (UVA Protection Factor), the SPF/PF-UVA ratio and the critical wave length. It is the erythemal SPF which is measured in the vast majority of cases: it can therefore be confirmed that sunscreen products protect us from sunburn under good conditions of use. We thought it would be interesting to calculate other indicators to assess protection against non melanoma skin cancers (NMSC) and to quantify the effectiveness of the product against UVA1 or UVA2. To characterize the products tested, we have determined in vitro different SPF and PF-UVA values, by using not just the erythemal weighting factor but also the weighting factor relating to the non-melanocytic skin cancer (SPF(cnm) and PF-UVA(cnm)), by getting away from any weighting factor (SPF(m) and PF-UVA(m)) and lastly, by varying the integration limits to quantify the effectiveness of the tested product in the UVB (290-320 nm), UVA1 (340-400 nm) and UVA2 320-340 nm) fields. In this way, and using these new indicators, we have been able to qualify eleven commercial products-ten cosmetic products and one medical device. It can be interesting to take into account the non-melanocytic skin cancer protection in order to qualify the sunscreen products. PMID- 21669264 TI - Synergistic effect of 1,4-cyclohexanediol and 1,2-hexanediol on percutaneous absorption and penetration of metronidazole. AB - The objective of this study was to investigate the percutaneous absorption of metronidazole (MTZ) in the topical formulations containing a combination of 1,4 cyclohexanediol and 1,2-hexanediol. Six formulations were studied in an in vitro hairless mouse skin model using Franz Diffusion Cell. MTZ was applied at infinite doses (50mg and 100mg of the formulations, which correspond to 375 and 750 MUg of MTZ, respectively). Based on the flux values and retardation ratio (RR), a synergistic retardation effect on percutaneous absorption of MTZ was observed for the formulations containing a combination of 1,4-cyclohexanediol and 1,2 hexanediol (RRs are 0.40 for 375 MUg dose and 0.69 for 750 MUg dose, respectively). Interestingly, retention of MTZ in epidermis and dermis layer showed no significant differences (p>0.05) between the formulations containing the retardant combination and control formulations. In other words, the retardant combination in the formulation decreases MTZ fluxes while maintaining similar level of retention in epidermis and dermis layer when compared to the control formulations. These observations provide insight in formulating superior topical formulations with minimized potential systematic toxicity while maintaining therapeutic efficiency. A mechanistic explanation of the observed synergistic effect is proposed. PMID- 21669265 TI - Gold nanorod mediated plasmonic photothermal therapy: a tool to enhance macromolecular delivery. AB - Plasmonic photothermal therapy (PPTT) with gold nanostructures has been used to generate significant heat within tumors to ablate vasculature. Here we report the use of gold nanorod (GNR) mediated PPTT to induce moderate hyperthermia as a tool to enhance the delivery of macromolecules. GNRs were injected intravenously in a mouse sarcoma (S-180) tumor model. After 24h Evans blue dye (EBD) was injected and the right tumor was radiated with a laser diode for 10 min. EBD content in the right and left tumors were extracted in formamide, measured spectrophotometrically and expressed as a thermal enhancement ratio (TER). Enhanced delivery of EBD was observed (up to 1.8-fold) when tumor temperatures reached 43 degrees C or 46 degrees C. No statistical difference was observed between tumors at these two temperatures, though significant hemorrhage was observed in tumors and surrounding areas receiving the higher thermal dose (46 degrees C). These results indicate that tumor directed PPTT may be used to induce moderate hyperthermia and therefore selectively increase the delivery of macromolecules with therapeutic anticancer drugs. PMID- 21669266 TI - Paclitaxel conjugation with the analog of the gonadotropin-releasing hormone as a targeting moiety. AB - A new targeted conjugates in which paclitaxel was used as a cytostatic compound and an analog of the gonadotropin-releasing hormone (GnRH) as a targeting moiety were synthesized. The molecule of the peptide hormone GnRH was modified to allow its connection to paclitaxel via spacer. The conjugates were prepared as prodrugs using 2'-hydroxyl group of paclitaxel. 4-Maleimidobutyric acid and chloroacetic acid served as spacers. The structures of the prepared derivatives were analysed by NMR and HR-MS. The conjugates MP264 and MP265 were chosen and their antiproliferative effect was tested in the breast cancer cell line MCF-7 using the MTT test of cell viability and neutral red uptake test. In MCF-7 cells, conjugate MP265 showed higher antiproliferative effect than paclitaxel alone. Receptor saturation tests showed that the unconjugated peptide analog of GnRH decreased efficacy of conjugate MP265 in concentration- and time-dependent manner. In conclusion, the paclitaxel conjugate with the analog of GnRH exhibited targeted antiproliferative effect for which its further testing will be implemented. PMID- 21669268 TI - Distribution of glucocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase isoforms in the rat inner ear. AB - 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is an enzyme complex responsible for the conversion of hormonally active cortisol to inactive cortisone, and two isoforms of the enzyme (11beta-HSD1 and 11beta-HSD2) have been cloned and characterized. An immunohistochemical study was performed to determine the precise distribution of glucocorticoid receptors (GRs) and the isoforms of 11beta HSD in the rat (postnatal day 1, 4, 10, and adult). Immunoreactivity of GRs was detected in the stria vascularis (SV), the outer hair cells (OHCs), the inner hair cells (IHCs), the spiral ligament (SLig), the spiral limbus (SLib), the spiral ganglion cells (SGCs), Reissner's membrane (RM), the cochlear nerve (CN), the vestibular hair cells (VHCs), the dark cells (DCs), and the vestibular nerve (VN) in the rats. Immunostaining of 11beta-HSD1 was observed in almost all the tissues in the cochlea and the vestibule except SLig, SLib, SGCs, CN, VHCs, and VN during all developmental stages, whereas, immunoreactivity of 11beta-HSD2 was not detected in any of the inner ear tissues. A polymerase chain reaction (PCR) study was also performed on GRs, 11beta-HSD1, and 11beta-HSD2 in the OC, SV and vestibule of the postnatal rats, and revealed that mRNAs were detected in all those and tissues in all the developmental days of postnatal days 1, 4, and 10. This data indicates that expression of GRs and 11beta-HSD isoforms in the inner ear is tissue and age-specific, and that different local steroid regulation by GRs and the isoforms of 11beta-HSD is present in each part of the inner ear. PMID- 21669267 TI - Hearing loss associated with enlargement of the vestibular aqueduct: mechanistic insights from clinical phenotypes, genotypes, and mouse models. AB - Enlargement of the vestibular aqueduct (EVA) is one of the most common inner ear malformations associated with sensorineural hearing loss in children. The delayed onset and progressive nature of this phenotype offer a window of opportunity to prevent or retard progression of hearing loss. EVA is not the direct cause of hearing loss in these patients, but rather is a radiologic marker for some underlying pathogenetic defect. Mutations of the SLC26A4 gene are a common cause of EVA. Studies of an Slc26a4 knockout mouse demonstrate that acidification and enlargement of the scala media are early events in the pathogenesis of deafness. The enlargement is driven by fluid secretion in the vestibular labyrinth and a failure of fluid absorption in the embryonic endolymphatic sac. Elucidating the mechanism of hearing loss may offer clues to potential therapeutic strategies. PMID- 21669269 TI - Assessment of auditory nonlinearity for listeners with different hearing losses using temporal masking and categorical loudness scaling. AB - A dysfunction or loss of outer hair cells (OHC) and inner hair cells (IHC), assumed to be present in sensorineural hearing-impaired listeners, affects the processing of sound both at and above the listeners' hearing threshold. A loss of OHC may be responsible for a reduction of cochlear gain, apparent in the input/output function of the basilar membrane and steeper-than-normal growth of loudness with level (recruitment). IHC loss is typically assumed to cause a level independent loss of sensitivity. In the current study, parameters reflecting individual auditory processing were estimated using two psychoacoustic measurement techniques. Hearing loss presumably attributable to IHC damage and low-level (cochlear) gain were estimated using temporal masking curves (TMC). Hearing loss attributable to OHC (HL(OHC)) was estimated using adaptive categorical loudness scaling (ACALOS) and by fitting a loudness model to measured loudness functions. In a group of listeners with thresholds ranging from normal to mild-to-moderately impaired, the loss in low-level gain derived from TMC was found to be equivalent with HL(OHC) estimates inferred from ACALOS. Furthermore, HL(OHC) estimates obtained using both measurement techniques were highly consistent. Overall, the two methods provide consistent measures of auditory nonlinearity in individual listeners, with ACALOS offering better time efficiency. PMID- 21669270 TI - Anti-inflammatory activity of Eupatorium perfoliatum L. extracts, eupafolin, and dimeric guaianolide via iNOS inhibitory activity and modulation of inflammation related cytokines and chemokines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eupatorium perfoliatum L. has been used traditionally for the treatment of fever, malaria and inflammation-associated diseases. Nowadays it is mostly used as immune activating remedy. The following study was performed to evaluate extracts with different polarity and defined lead compounds from the herbal material on potential in vitro activities concerning immune cell activation, phagocytosis, and inflammation-related processes. MATERIALS AND METHODS: MeOH-, EtOH-, and DCM extracts, beside several subfractions and isolated polysaccharides, sesquiterpene lactones and flavonoids were prepared and characterized analytically from the aerial parts of E. perfoliatum. Immunological activity was tested within lymphocyte transformation test on PBMC, test on enhancement of phagocytosis and of NO-production by murine RAW 264.7 macrophages. Anti-inflammatory effects were assessed from LPS stimulated RAW 264.7 cells by NO/iNOS quantification, gene array, real-time PCR and ELISA. RESULTS: No stimulatory activity was found within lymphocyte transformation test, for phagocytic activity and NO formation in macrophages. MeOH-, EtOH- and DCM extracts showed anti-inflammatory activity against LPS stimulated macrophages by inhibition of NO release (IC(50)>100, 89, 19 MUg/mL resp.) with eupafolin and a dimeric guaianolide having prominent NO inhibiting activity (IC(50) 6 resp. 16 MUM). Anti-inflammatory activity was found on gene and protein level by significant down-regulation of cytokines CSF-3, IL-1alpha, IL-1beta, and chemokines CCL2, CCL22 and CXCL10. Also TNF was down-regulated moderately (-17%). CONCLUSIONS: Although the postulated immunostimulating properties of E. perfoliatum have not been confirmed, the anti-inflammatory effects can be seen as a verification of the traditional use against inflammatory diseases. PMID- 21669271 TI - Anti-hyaluronidase and anti-elastase activity screening of tannin-rich plant materials used in traditional Polish medicine for external treatment of diseases with inflammatory background. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aim of the study was to examine extracts from twelve tannin-rich plant materials used in traditional Polish medicine for external treatment of skin and mucosa diseases considering their ability to inhibit hyaluronidase activity and elastase release from stimulated neutrophils in vitro. MATERIALS AND METHODS: In vitro anti-hyaluronidase and anti-elastase assays together with phytochemical qualitative and quantitative screening were performed. RESULTS: The strongest inhibition of hyaluronidase was observed for extract from Lythri herba, with IC(50) value 8.1 +/- 0.8 MUg/mL. The most active extract towards elastase release was from Hippocastani cortex which at concentration 10 MUg/mL showed 62.0 +/- 6.9% inhibition. CONCLUSION: Anti hyaluronidase and anti-elastase activity of chosen tannin-rich plant materials can support their traditional use in folk medicine. Strong inhibition of both enzymes by extract from Lythri herba makes this pharmacopeial plant material an interesting topic for further biological and phytochemical examination. PMID- 21669272 TI - Effects of the Chinese Yi-Qi-Bu-Shen Recipe extract on brainstem auditory evoked potential in rats with diabetes. AB - This study was designed to investigate the effects of the Chinese Yi-Qi-Bu-Shen Recipe (YB) on brain stem auditory evoked potential (BAEP) in diabetic rats and on the protection of the diabetic rat brain's functional lesion. Thirty-three male rats were randomly divided into three groups: the normal control group (NC), the diabetic group (DM), and the diabetic rats treated with YB group (DM+YB). Blood glucose and body weight were measured every three weeks. After six weeks, the serum insulin, blood biochemical indices, superoxide dismutase, malondialdehyde, monoamine neurotransmitters, and BAEP were measured. Compared with the NC group, the waves III, V PLs, and the I-III, I-V IPLs of BAEP in the DM group were significantly delayed (all P<0.05). However, YB-treated diabetic rats maintained a normal brainstem function over the experimental period. Compared with the NC group, the waves I, III, V PL, and waves I-III, III-V and I V IPLs of BAEP in the DM+YB group were very close (all P>0.05). On the other hand, compared with the DM group, the III, V PLs and the I-III, I-V IPLs of BAEP in the DM+YB group were significantly improved. It was discovered that the central conduction time of rats with diabetes had a close correlation with serum insulin, blood glucose, malondialdehyde, and insulin resistance index. Our results suggest that YB extract has a beneficial effect in preserving the brain's electrophysiological function in diabetic rats, likely through its antihyperglycemic activity, ability to reduce insulin resistance, and antioxidant activity. PMID- 21669273 TI - Achyranthes bidentata root extract prevent OVX-induced osteoporosis in rats. AB - AIM: The objective of the present study was to systematically investigate the effects of Achyranthes bidentata root extract (ABRE) on postmenopausal osteoporosis. MATERIALS AND METHODS: Eighty 3-month-old female Sprague-Dawley rats were used and randomly assigned into sham-operated group (SHAM) and five ovariectomy (OVX) subgroups, i.e. OVX with vehicle (OVX); OVX with 17 beta ethinylestradiol (E(2), 25 MUg/kg/day); OVX with ABRE of graded doses (100, 300, or 500 mg/kg/day). Daily oral administration of ABRE or E(2) started on week 4 after OVX for 16 weeks. Bone mass, bone turnover and strength were analyzed by dual-energy X-ray absorptiometry (DEXA), biochemical markers and three-point bending test. The trabecular bone microarchitecture was evaluated by microcomputed tomography (MUCT). RESULTS: 16 weeks treatment of ABRE slowed down the body weight gain and prevented the loss of bone mass induced by the OVX. The prevention effect on bone loss was due to altering the rate of bone remodeling, which could be inferred from the decreased level of bone turnover markers, such as serum alkaline phosphatase (ALP), osteocalcin (OC) and urinary deoxypyridinoline (DPD). The changes of urinary calcium and phosphorus excretion provided the same evidence. The treatment could also enhance the bone strength and prevent the deterioration of trabecular microarchitecture. CONCLUSIONS: We conclude that 16 weeks of ABRE treatment improve bone biomechanical quality through modifications of bone mineral density (BMD), and trabecular microarchitecture without hyperplastic effect on uterus, and it might be a potential alternative medicine for treatment of postmenopausal osteoporosis. PMID- 21669274 TI - South African plants used in traditional medicine to treat epilepsy have an antagonistic effect on NMDA receptor currents. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Several Searsia species (Anacardiaceae), including Searsia dentata and Searsia pyroides, are used in South Africa traditional medicine to treat epilepsy. Ethanol leaf extracts of these plants have been shown to act as possible antagonists of N-methyl-d-aspartate (NMDA) type glutamate receptors. MATERIALS AND METHODS: Leaf material of three Searsia species were collected from the Botanical Garden at the University of KwaZulu Natal, Pietermaritzburg; dried and extracted with ethanol in an ultrasound bath. Filtered and dried extracts were resuspended in DMSO (100mg/ml) and diluted in the recording solution. The effect of Searsia dentata, Searsia pyroides and Searsia glauca extracts was investigated in dissociated cerebellar granule cells (CGCs) from 8-day-old rats and in transiently transfected HEK (human embryonic kidney) 293 cells (HEK), expressing either NR1a/NR2A or NR1a/NR2B receptors. In both systems we measured whole-cell currents elicited by 0.5mM NMDA (CGCs) or 50 MUM glutamic acid (HEK) at -60 mV in 0Mg and 30 MUM glycine and NMDA driven Ca influx in Fura2-loaded CGC. RESULTS: Searsia dentata and Searsia pyroides ethanol extracts caused a dose-dependent decrease of NR current with ED(50) close to 0.03 mg/ml in CGC and a similar inhibition (80% with 1mg/ml) in HEK cells, while Searsia glauca was much less effective. The inhibition was dependent on time of incubation and slightly favored by opening of the NR channel. It was hardly reversible during the recording time, but was not caused by accelerated run-down or by interaction with the modulatory redox site. Searsia pyroides ethanol extract also depressed the NMDA stimulated increase in intracellular Ca. CONCLUSIONS: The data confirm the specificity of Searsia dentata and Searsia pyroides and justify their use in traditional medicine. These plants may combine one or more gamma-aminobutyric acid (GABA)(A) agonists with one or more NMDA antagonists, thus representing an efficient treatment for epilepsy. PMID- 21669275 TI - Calycosin protects HUVECs from advanced glycation end products-induced macrophage infiltration. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Astragali radix is a traditional Chinese medicine that has long been used for treatment of diabetes and diabetes-associated disease, but its active component and mechanism on the disease is not well defined. AIM OF THE STUDY: Infiltration of leukocytes within the glomeruli and vasculature is one of the early and characteristic features of diabetic nephropathy. Advanced glycation end products (AGEs) play pivotal role in the progression of diabetic-associated diseases. The present study was designed to explore the therapeutic effect of calycosin, an active component from A. radix, on AGEs-induced macrophages infiltration in HUVECs. MATERIALS AND METHODS: Transwell HUVEC-macrophage co-culture system was established to evaluate macrophage migration and adhesion. Immunocytochemistry was applied to examine TGF beta1, ICAM-1 and RAGE protein expressions; real-time PCR was carried out to determine mRNA expression of TGF-beta1, ICAM-1 and RAGE. Immunofluorescence was carried out to observe estrogen receptor-alpha, ICAM-1, RAGE expression and the phosphorylation status of ERK1/2 and NF-kappaB. RESULTS: Calycosin significantly reduced AGEs-induced macrophage migration and adhesion to HUVEC. Pre-treatment with calycosin strikingly down-regulated HUVEC TGF-beta1, ICAM-1 and RAGE expressions in both protein and mRNA levels. Furthermore, calycosin incubation significantly increased estrogen receptor expression and reversed AGEs-induced ERK1/2 and NF-kappaB phosphorylation and nuclear translocation in HUVEC, and this effect of calycosin could be inhibited by estrogen receptor inhibitor, ICI182780. CONCLUSIONS: These findings suggest that calycosin can reduce AGEs-induced macrophage migration and adhesion to endothelial cells and relieve the local inflammation; furthermore, this effect was via estrogen receptor-ERK1/2-NF-kappaB pathway. PMID- 21669276 TI - Typha latifolia L. fruit polysaccharides induce the differentiation and stimulate the proliferation of human keratinocytes in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Northern America Typha latifolia L. (Typhaceae) fruits are used for more than 4000 years for treatment of skin disorders, burns and as wound dressing to absorb the ichors. AIM OF THE STUDY: The following studies attempted to characterize water-soluble polysaccharides from aqueous Typha latifolia extracts and to investigate the influence of the polymers on cell physiology of human dermal fibroblasts (NHDF) and epidermal keratinocytes (NHEK). MATERIALS AND METHODS: Water-soluble raw polysaccharides (RPS) were isolated from Typha latifolia fruits and fractionated by anion exchange chromatography (AEC) and size exclusion chromatography (GPC). Fractions obtained were characterized concerning monosaccharide composition by HPAEC-PAD. The bioactivity of the polysaccharides was investigated on cell viability, proliferation, differentiation and gene expression NHDF of NHEK. RESULTS: RPS was fractionated into 5 heterodisperse fractions (TL1-TL5). The polysaccharides were composed mainly of glucose (more than 50% in RPS and TL4), galactose, xylose, mannose, glucuronic acid, galacturonic acid, arabinose, ribose, fucose, rhamnose, and fructose with differing amounts concerning to RPS and AEC-fractions. Proteins were detected in the RPS (10%) and to a less extend in TL1-TL3 (1-3%). TL1-TL3 significantly increased the proliferation of keratinocytes, whereas TL4 was shown to be a potent inductor of the early differentiation process of keratinocytes. Gene expression analysis supported these results since Smad3 and PKC-alpha, known to be part of signal pathways leading to cell differentiation, were significantly up regulated. Effects on fibroblasts were not observed, indicating cell specific activity of the polysaccharides. CONCLUSION: The results clearly indicate a rationale for the traditional use of Typha latifolia fruits extracts for wound healing to the strong stimulatory activity of the polysaccharides on keratinocytes proliferation and early differentiation, major activities necessary for potent wound-healing agents. PMID- 21669277 TI - Differential effects of anti-metastatic mechanism of Tian-Xian liquid (TXL) and its bioactive fractions on human colorectal cancer models. AB - AIM OF STUDY: This study aimed to elucidate and compare the anti-metastatic mechanism of Tian-Xian liquid (TXL) and its bioactive components namely butanol (BU), ethyl-acetate (EA) and aqueous (WA) fractions on human colorectal cancer in vitro (HT-29 cancer cells) and in vivo (nude mouse xenografts). MATERIALS AND METHODS: The anti-proliferative effects of TXL and its bioactive components in HT 29 cells were determined by MTT assay. Their modulations on the potential angiogenic and metastatic marker expressions on HT-29 cells and xenografts were investigated by real-time PCR and Western blot at transcriptional and translational levels, respectively. For the in vitro study, migration abilities of HT-29 cells were determined using wound healing assay. For the in vivo study, daily measurements of the tumor size and volume of the xenografts were also performed. RESULTS: TXL, BU, EA and WA effectively inhibited the proliferation of HT-29 cells in a dose- and time-dependent manner. The IC(50) value of TXL on HT 29 cells was obtained after incubation with 1% (v/v) TXL for 4h; whereas IC(50) values were obtained for the following bioactive components: BU at 1.25% (v/v); EA at 5% (v/v); and WA at 0.3125% (v/v). It was found that 1% (v/v) TXL significantly down-regulated MMP2 and MMP7 expression at both transcriptional and translational levels and it reduced MMP9 and VEGF protein expression in vitro. TXL decreased the metastatic ability of HT-29 cells as demonstrated by wound healing assay. TXL and its bioactive fractions caused no significant changes in the body weight indicating lack of toxicity to the xenografts. CONCLUSIONS: In summary, TXL multi-targeted to down-regulate the metastatic markers in both in vitro and in vivo models. However, the effects of its bioactive fractions were not obvious. This study profoundly elucidated the anti-proliferative mechanism of TXL, which is vital for the development of future anti-cancer regime in Chinese medicinal formulations. PMID- 21669278 TI - Effects of Atractylodes macrocephala Koidzumi rhizome on 3T3-L1 adipogenesis and an animal model of obesity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodes macrocephala Koidzumi (AMK) is an herbal medicine traditionally used for treatment of abdominal pain, gastrointestinal disease, obesity, and related complications. AIM OF THE STUDY: We investigated the effects and molecular mechanism of AMK rhizome water extract on 3T3-L1 adipogenesis and an animal model of obesity. MATERIALS AND METHODS: To study the effect of AMK on adipogenesis in vitro, differentiating 3T3-L1 cells were treated every two days with AMK at various concentrations (1-25MUg/ml) for eight days. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the inhibitory mechanism of AMK on adipogenesis, phosphorylation levels of Akt and expression of perilipin, were analyzed by Western blotting. AMK was administered orally to high fat diet (HFD)-induced obese rats to confirm its effect in vivo. RESULTS: AMK inhibited 3T3-L1 adipocyte differentiation in a dose-dependent manner without cellular toxicity. Phospho-Akt expression was highly decreased by AMK treatment, whereas there was no significant change in perilipin expression. AMK administration significantly reduced the body weight of rats fed a HFD. Plasma triglyceride levels were significantly lower in the AMK-treated HFD group than those in the HFD control group or normal diet (ND) group, although serum total, HDL- and LDL-cholesterol levels did not differ between the groups. CONCLUSION: These results demonstrate an inhibitory effect of AMK on adipogenesis through reduction of an adipogenic factor, phospho-Akt. AMK had a beneficial effect, reducing body weight gain in a HFD-induced animal model of obesity. PMID- 21669279 TI - Interesting anticandidal effects of anisic aldehydes on growth and proton-pumping ATPase-targeted activity. AB - Attention has been drawn to evaluate the antifungal activity of p-anisaldehyde (1), o-anisaldehyde (2) and m-anisaldehyde (3). To put forward this approach, antifungal activity has been assessed in thirty six fluconazole-sensitive and eleven fluconazole-resistant Candida isolates. Growth and sensitivity of the organisms were significantly effected by test compounds at different concentrations. The rapid irreversible action of compound-1, compound-2 and compound-3 on fungal cells suggested a membrane-located target for their action. We investigated their effect on H(+) ATPase mediated H(+)-pumping by various Candida species. All the compounds inhibit H(+)- ATPase activity at their respective MIC(90) values. Inhibition of H(+) ATPase leads to intracellular acidification and cell death. Scanning electron microscopy analysis revealed deep wrinkles, deformity and flowed content. Furthermore, it was also observed that position of methoxy group attached to the benzene ring decides antifungal activity of the compound. The present study indicates that compound-1, compound-2 and compound-3 have significant antifungal activity against Candida, including azole-resistant strains, advocating further investigation for clinical applications in the treatment of fungal infections. PMID- 21669281 TI - Neuroprotection effects of retained acupuncture in neurotoxin-induced Parkinson's disease mice. AB - The aim of this study was to investigate the role of retained acupuncture (RA) in neurotoxin-induced Parkinson's disease (PD) mice. Male C57BL/6 mice were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce the PD model. The mice were divided into four groups, namely, (1) normal; (2) MPTP+retained acupuncture (RA); (3) MPTP+electroacupuncture (EA); (4) MPTP+sham acupuncture (SA). After mice being manipulated with/without acupuncture at acupoints (Daling, PC 7), groups 2-4 were injected with MPTP (15 mg/kg/d). The mice were evaluated for behavioral changes, in terms of time of landing, after acupuncture treatment. The animals were sacrificed and their brains assayed for dopamine and its metabolites and tyrosine hydroxylase (TH) expression by using HPLC and immunohistochemistry/Western blotting, respectively. [(123)I] IBZM-SPECT imaging between SA and RA groups were compared. The results showed that the time of landing of the three groups with treatment was significant longer than group 1 (normal) (4.33+/-0.15 s). Nonetheless, group 2 (RA) (7.13+/-0.20 s) had a shorter time of landing than group 4 (SA) (7.89+/-0.46 s). The number of TH (+) neurons and the expression of TH proteins were significantly higher in the RA group than in the SA/EA groups. RA also increased the uptake of [(123)I] IBZM into the triatum compared to the SA group. We conclude that RA possibly attenuates neuronal damage in MPTP-induced PD mice, which suggests RA may be useful as a complementary strategy when treating human PD. PMID- 21669280 TI - Intralaboratory validation of four in vitro assays for the prediction of the skin sensitizing potential of chemicals. AB - Allergic contact dermatitis is induced by repeated skin contact with an allergen. Assessment of the skin sensitizing potential of chemicals, agrochemicals, and especially cosmetic ingredients is currently performed with the use of animals. Animal welfare and EU legislation demand animal-free alternatives reflected in a testing and marketing ban for cosmetic ingredients beginning in 2013. The underlying mechanisms of induction and elicitation of skin sensitization are complex and a chemical needs to comply several properties being skin sensitizing. To account for the multitude of events in the induction of skin sensitization an in vitro test system will consist of a battery of various tests. Currently, we performed intralaboratory validations of four assays addressing three different events during induction of skin sensitization. (1) The Direct Peptide Reactivity Assay (DPRA) according to Gerberick and co-workers (Gerberick et al., 2004) using synthetic peptides and HPLC analysis. (2) Two dendritic cell activation assays based on the dendritic cell like cell lines U-937 and THP-1 and flow cytometric detection of the maturation markers CD54 and/or CD86 (Ashikaga et al., 2006; Python et al., 2007; Sakaguchi et al., 2006). (3) Antioxidant response element (ARE)-dependent gene activity in a HaCaT reporter gene cell line (Emter et al., 2010). We present the results of our intralaboratory validation of these assays with 23 substances of known sensitizing potential. The sensitivity, specificity, and accuracy of the individual tests were obtained by comparison to human epidemiological data as well as to data from animal tests such as the local lymph node assay. PMID- 21669282 TI - The relationships between blood lead levels and serum follicle stimulating hormone and luteinizing hormone in the National Health and Nutrition Examination Survey 1999-2002. AB - The relationships between blood lead levels and serum follicle stimulating hormone and luteinizing hormone were assessed in a nationally representative sample of women, 35-60 years old, from the National Health and Nutrition Examination Survey 1999-2002. The blood lead levels of the women ranged from 0.2 to 17.0 MUg/dL. The estimated geometric mean was 1.4 MUg/dL, and the estimated arithmetic mean was 1.6 MUg/dL. As the blood lead level increased, the concentration of serum follicle stimulating hormone increased in post-menopausal women, women who had both ovaries removed, and pre-menopausal women. The concentration of luteinizing hormone increased as blood lead level increased in post-menopausal women and women who had both ovaries removed. The lowest concentrations of blood lead at which a relationship was detected were 0.9 MUg/dL for follicle stimulating hormone and 3.2 MUg/dL for luteinizing hormone. Lead may act directly or indirectly at ovarian and non-ovarian sites to increase the concentrations of follicle stimulating hormone and luteinizing hormone. PMID- 21669284 TI - Temperature-controlled micro-TLC: a versatile green chemistry and fast analytical tool for separation and preliminary screening of steroids fraction from biological and environmental samples. AB - This paper is a continuation of our previous research focusing on development of micro-TLC methodology under temperature-controlled conditions. The main goal of present paper is to demonstrate separation and detection capability of micro-TLC technique involving simple analytical protocols without multi-steps sample pre purification. One of the advantages of planar chromatography over its column counterpart is that each TLC run can be performed using non-previously used stationary phase. Therefore, it is possible to fractionate or separate complex samples characterized by heavy biological matrix loading. In present studies components of interest, mainly steroids, were isolated from biological samples like fish bile using single pre-treatment steps involving direct organic liquid extraction and/or deproteinization by freeze-drying method. Low-molecular mass compounds with polarity ranging from estetrol to progesterone derived from the environmental samples (lake water, untreated and treated sewage waters) were concentrated using optimized solid-phase extraction (SPE). Specific bands patterns for samples derived from surface water of the Middle Pomerania in northern part of Poland can be easily observed on obtained micro-TLC chromatograms. This approach can be useful as simple and non-expensive complementary method for fast control and screening of treated sewage water discharged by the municipal wastewater treatment plants. Moreover, our experimental results show the potential of micro-TLC as an efficient tool for retention measurements of a wide range of steroids under reversed-phase (RP) chromatographic conditions. These data can be used for further optimalization of SPE or HPLC systems working under RP conditions. Furthermore, we also demonstrated that micro-TLC based analytical approach can be applied as an effective method for the internal standard (IS) substance search. Generally, described methodology can be applied for fast fractionation or screening of the whole range of target substances as well as chemo-taxonomic studies and fingerprinting of complex mixtures, which are present in biological or environmental samples. Due to low consumption of eluent (usually 0.3-1mL/run) mainly composed of water-alcohol binary mixtures, this method can be considered as environmentally friendly and green chemistry focused analytical tool, supplementary to analytical protocols involving column chromatography or planar micro-fluidic devices. PMID- 21669283 TI - Upregulation of select rab GTPases in cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease. AB - Endocytic system dysfunction is one of the earliest disturbances that occur in Alzheimer's disease (AD), and may underlie the selective vulnerability of cholinergic basal forebrain (CBF) neurons during the progression of dementia. Herein we report that genes regulating early and late endosomes are selectively upregulated within CBF neurons in mild cognitive impairment (MCI) and AD. Specifically, upregulation of rab4, rab5, rab7, and rab27 was observed in CBF neurons microdissected from postmortem brains of individuals with MCI and AD compared to age-matched control subjects with no cognitive impairment (NCI). Upregulated expression of rab4, rab5, rab7, and rab27 correlated with antemortem measures of cognitive decline in individuals with MCI and AD. qPCR validated upregulation of these select rab GTPases within microdissected samples of the basal forebrain. Moreover, quantitative immunoblot analysis demonstrated upregulation of rab5 protein expression in the basal forebrain of subjects with MCI and AD. The elevation of rab4, rab5, and rab7 expression is consistent with our recent observations in CA1 pyramidal neurons in MCI and AD. These findings provide further support that endosomal pathology accelerates endocytosis and endosome recycling, which may promote aberrant endosomal signaling and neurodegeneration throughout the progression of AD. PMID- 21669285 TI - Proteomic identification of hippocampal proteins vulnerable to oxidative stress in excitotoxin-induced acute neuronal injury. AB - Excitotoxicity is involved in seizure-induced acute neuronal death, hypoxic ischemic encephalopathy, and chronic neurodegenerative conditions such as Alzheimer's disease. Although oxidative stress has been implicated in excitotoxicity, the target proteins of oxidative damage during the course of excitotoxic cell death are still unclear. In the present study, we performed 2D oxyblot analysis and mass spectrometric amino acid sequencing to identify proteins that were vulnerable to oxidative damage in the rat hippocampus during kainic acid (KA)-induced status epilepticus. We first investigated the time course in which oxidative protein damage occurred using immunohistochemistry. Carbonylated proteins, a manifestation of protein oxidation, were detected in hippocampal neurons as early as 3h after KA administration. Immunoreactivity for 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also elevated at the same time point. The increase in oxidative damage to proteins and DNA occurred concomitantly with the early morphological changes in KA-treated rat hippocampus, i.e., changes in chromatin distribution and swelling of rough endoplasmic reticulum and mitochondria, which preceded the appearance of morphological features of neuronal death such as pyknotic nuclei and hypereosinophilic cytoplasm. Proteomic analysis revealed that several hippocampal proteins were consistently carbonylated at this time point, including heat shock 70kDa protein 4, valosin-containing protein, mitochondrial inner membrane protein (mitofilin), alpha-internexin, and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (14-3-3 protein). We propose that oxidative damage to these proteins may be one of the upstream events in the molecular pathway leading to excitotoxic cell death in KA-treated rat hippocampus, and these proteins may be targets of therapeutic intervention for seizure-induced neuronal death. PMID- 21669286 TI - Gene expression profiling of peripheral blood leukocytes identifies and validates ABCB1 as a novel biomarker for Alzheimer's disease. AB - Increasing evidence has shown that the immunological reaction of leukocytes plays a crucial role in the development of neurodegenerative disorders. We conducted transcriptome analysis of leukocytes from patients of mild cognitive impairment (MCI), Alzheimer's disease (AD), as well as normal controls (NC) by oligonucleotide microarray. The differentially expressed genes of interest were selected by pathway-based functional enrichment and were then validated in 60 subjects (17 NC, 20 MCI and 23 AD) by quantitative PCR (QRT-PCR). Thirty-four differentially expressed genes between NC and AD were enriched in ATP-binding cassette (ABC) transporters, ascorbate and aldarate metabolism, Gly/Ser/Thr metabolism, transforming growth factor-beta signaling, and extracellular matrix (ECM)-receptor interaction pathways (Welch t-test; p < 0.05). Comparison of NC, MCI and AD transcriptomes identified 8 genes significantly associated with purine metabolism and the ABC transporters. Furthermore, 13 out of 18 genes selected from the above lists were successfully validated by QRT-PCR (Mann-Whitney U test), and only ABCB1 gene exhibited significantly positive correlation with MMSE scores among NC, MCI, and AD subjects (r = 0.3858, p = 0.0011). With a limited number of study population, our study may provide a novel direction for evaluating diagnostic biomarkers in monitoring AD progression. PMID- 21669287 TI - Evaluation of spontaneous propulsive movement as a screening tool to detect rescue of Parkinsonism phenotypes in zebrafish models. AB - Zebrafish models of human neuropsychiatric diseases offer opportunities to identify novel therapeutic targets and treatments through phenotype-based genetic or chemical modifier screens. In order to develop an assay to detect rescue of zebrafish models of Parkinsonism, we characterized spontaneous zebrafish larval motor behavior from 3 to 9 days post fertilization in a microtiter plate format suitable for screening, and clarified the role of dopaminergic signaling in its regulation. The proportion of time that larvae spent moving increased progressively between 3 and 9 dpf, whereas their active velocity decreased between 5 and 6 dpf as sporadic burst movements gave way to a more mature beat and-glide pattern. Spontaneous movement varied between larvae and during the course of recordings as a result of intrinsic larval factors including genetic background. Variability decreased with age, such that small differences between groups of larvae exposed to different experimental conditions could be detected robustly by 6 to 7 dpf. Suppression of endogenous dopaminergic signaling by exposure to MPP(+), haloperidol or chlorpromazine reduced mean velocity by decreasing the frequency with which spontaneous movements were initiated, but did not alter active velocity. The variability of mean velocity assays could be reduced by analyzing groups of larvae for each data point, yielding acceptable screening window coefficients; the sample size required in each group was determined by the magnitude of the motor phenotype in different models. For chlorpromazine exposure, samples of four larvae allowed robust separation of treated and untreated data points (Z=0.42), whereas the milder impairment provoked by MPP(+) necessitated groups of eight larvae in order to provide a useful discovery assay (Z=0.13). Quantification of spontaneous larval movement offers a simple method to determine functional integrity of motor systems, and may be a useful tool to isolate novel molecular modulators of Parkinsonism phenotypes. PMID- 21669288 TI - Ion mobility mass spectrometry for peptide analysis. AB - The use of ion mobility mass spectrometry has grown rapidly over the last two decades. This powerful analytical platform now forms an attractive prospect for comprehensive analysis of many different molecular species, including chemically complex biological molecules. This paper describes the application of IM-MS to the study of peptides. We focus on three different ion mobility devices that are most frequently found in tandem with mass spectrometers. These are instruments using linear drift tubes (LDT), those using travelling wave ion guides (TWIGS) and those employing high field asymmetric ion mobility spectrometry (FAIMS). Each technique is described. Examples are given on the use of IM-MS for the determination of peptide structure, the study of peptides that form amyloid fibrils, and the study of complex peptide mixtures in proteomic investigations. We describe and comment on the methodologies used and the outlook for this developing analytical technique. PMID- 21669289 TI - Probiotics and herbal mixtures enhance the growth, blood constituents, and nonspecific immune response in Paralichthys olivaceus against Streptococcus parauberis. AB - The present study was reported the effect of probiotics and herbals mixture supplementation diet on growth, blood constituents, and nonspecific immune response in olive flounder Paralichthys olivaceus against Streptococcus parauberis on weeks 1, 2, 4, 6, 8, 10, and 12 after injected intraperitoneally (i.p.) with 50 MUl of PBS (phosphate buffer saline) containing S. parauberis (2.1 * 107 CFU ml-1). The initial weight did not significantly increased in supplementation diet group from 1 to 4 weeks, whereas it was significantly increased from weeks 6 to 12 as compared to fish fed without supplementation diet. The serum aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) activities significantly increased from weeks 4 to 12 in infected fish fed with supplementation diet compared to fish fed without supplementation diet. However, the total protein (TP) and glucose (GLU) levels were significantly increased in infected fish fed with supplementation diet after 6 weeks. The phagocytic, respiratory burst, complement, and lysozyme activities significantly enhanced in infected fish fed with supplementation diet from weeks 4 to 12 as compared to fish fed without supplementation diet. These results suggested that different probiotics and herbals mixture supplementation diet enhanced the growth, blood biochemical constituents, and nonspecific immunity in olive flounder against S. parauberis. PMID- 21669290 TI - Molecular cloning, characterization and expression of a C-type lectin cDNA in Chinese mitten crab, Eriocheir sinensis. AB - C-type lectins are pattern-recognition proteins which are functionally important for pathogen recognition and immune regulation in vertebrates and invertebrates. In this study, a lectin cDNA named as Es-Lectin was cloned and characterized from the Chinese mitten crab, Eriocheir sinensis. The full-length sequence of this Es Lectin cDNA was 651 bp, including an open reading frame of 483 bp encoding 160 amino acids. The predicted molecular weight of the Es-Lectin was 11.8 kDa. A typical signal peptide of 21 amino acids was deduced at the N-terminus of the predicted protein. This Es-Lectin belongs to a C-type lectin and contains six cysteines, a conserved EPN motif (Glu-Pro-Asn) and an imperfect WND (Trp-Asn-Asp) motif (FND, Phe-Asn-Asp). This Es-Lectin had 55% and 32% identity with other two C-type lectins in E. sinensis, and 29-36% homology with decapods. Although the Es Lectin was also expressed in gill, hepatopancreas, intestine, muscle and stomach, its expression in haemocytes was the greatest. The expression of Es-Lectins in haemocytes increased at 1.5 h after the Aeromonas hydrophila challenge. After a slight decrease, the Es-Lectin expression in haemocytes significantly increased at 48 h post-challenge. The diverse distribution of Es-Lectin and its enhancement by bacterial challenge indicate that C-type lectins are important in the innate immune response to bacterial infection, and can be activated for innate immune response in crab at the initial stage after pathogen infection. PMID- 21669291 TI - Fear is only as deep as the mind allows: a coordinate-based meta-analysis of neuroimaging studies on the regulation of negative affect. AB - Humans have the ability to control negative affect and perceived fear. Nevertheless, it is still unclear whether this affect regulation capacity relies on a common neural mechanism in different experimental domains. Here, we sought to identify commonalities in regulatory brain activation in the domains of fear extinction, placebo, and cognitive emotion regulation. Using coordinate-based activation-likelihood estimation meta-analysis we intended to elucidate concordant hyperactivations and the associated deactivations in the three experimental domains, when human subjects successfully diminished negative affect. Our data show that only one region in the ventromedial prefrontal cortex (VMPFC) controlled negative affective responses and reduced the degree of subjectively perceived unpleasantness independent of the experimental domain. This down-regulation of negative affect was further accompanied by a concordant reduction of activation in the left amygdala. Finally, the soothing effect of placebo treatments and cognitive reappraisal strategies, but not extinction retrieval, was specifically accompanied by a coherent hyperactivation in the anterior cingulate and the insular cortex. Collectively, our data strongly imply that the human VMPFC may represent a domain-general controller of perceived fear and aversiveness that modulates negative affective responses in phylogenetically older structures of the emotion processing system. In addition, higher-level regulation strategies may further engage complementary neural resources to effectively deal with the emotion-eliciting events. PMID- 21669293 TI - Reconciling gene trees of eastern North American minnows. AB - Most eastern North American cyprinid fishes belong to a clade known as the "open posterior myodome" (OPM) minnows, but phylogenetic relationships within this clade have been difficult to ascertain. Previous attempts to resolve relationships among the generally benthic "chubs" and the more pelagic "shiners", that constitute the majority of OPM minnows, have led to highly discordant phylogenetic hypotheses. To further examine relationships among the OPM minnows, we utilized both a concatenated Bayesian approach and a coalescent-based species tree method to analyze data from six protein coding nuclear loci (Enc1, Ptr, Ryr3, Sh3px3, Tbr1, and Zic1), as well as the mitochondrial locus (Cytb). We focused our analyses on the chub-like genus Phenacobius, a group that has drifted topologically between other benthic chubs and the more pelagic shiners, and also included exemplar taxa from 11 other OPM lineages. Individual gene trees were highly discordant regarding relationships within Phenacobius and across the OPM clade. The concatenated Bayesian analysis and coalescent-based species tree reconstruction recovered slightly different phylogenetic topologies. Additionally, the posterior support values for clades using the coalescent-based approach were consistently lower than the concatenated analysis. However, Phenacobius was resolved as monophyletic and as the sister lineage to Erimystax regardless of the combined data approach taken. Furthermore, Phenacobius+Erimystax was recovered as more closely related to the shiners we examined than to other chubs. Relationships within Phenacobius varied depending on the combined phylogenetic method utilized. Our results highlight the importance of multi-locus, coalescent-based approaches for resolving the phylogeny of diverse clades like the eastern North American OPM minnows. PMID- 21669294 TI - Insights into the evolution of freshwater sponges (Porifera: Demospongiae: Spongillina): Barcoding and phylogenetic data from Lake Tanganyika endemics indicate multiple invasions and unsettle existing taxonomy. AB - Sponges are a conspicuous element in many benthic habitats including in Africa's oldest, deepest lake, Lake Tanganyika. Despite their prevalence and pivotal ecological role as filter feeders, knowledge of the evolutionary history of sponges is in its infancy. Here, we provide the first molecular analysis targeting the evolution of sponges from Lake Tanganyika. Independent markers indicate the occurrence of several colonisation events which have shaped the current Tanganyikan lacustrine sponge biodiversity. This is in contrast to a range of previously studied organisms that have diversified within the lake from single lineages. Our tree reconstructions indicate the presence of two genera, Oncosclera and Eunapius, which are globally distributed. Therefore, we reject the hypothesis of monophyly for the sponges from Lake Tanganyika and challenge existing higher taxonomic structure for freshwater sponges. PMID- 21669295 TI - A phylogenetic revision of the Glaucopsyche section (Lepidoptera: Lycaenidae), with special focus on the Phengaris-Maculinea clade. AB - Despite much research on the socially parasitic large blue butterflies (genus Maculinea) in the past 40 years, their relationship to their closest relatives, Phengaris, is controversial and the relationships among the remaining genera in the Glaucopsyche section are largely unresolved. The evolutionary history of this butterfly section is particularly important to understand the evolution of life history diversity connected to food-plant and host-ant associations in the larval stage. In the present study, we use a combination of four nuclear and two mitochondrial genes to reconstruct the phylogeny of the Glaucopsyche section, and in particular, to study the relationships among and within the Phengaris Maculinea species. We find a clear pattern between the clades recovered in the Glaucopsyche section phylogeny and their food-plant associations, with only the Phengaris-Maculinea clade utilising more than one plant family. Maculinea is, for the first time, recovered with strong support as a monophyletic group nested within Phengaris, with the closest relative being the rare genus Caerulea. The genus Glaucopsyche is polyphyletic, including the genera Sinia and Iolana. Interestingly, we find evidence for additional potential cryptic species within the highly endangered Maculinea, which has long been suspected from morphological, ecological and molecular studies. PMID- 21669292 TI - A theoretical framework for estimating cerebral oxygen metabolism changes using the calibrated-BOLD method: modeling the effects of blood volume distribution, hematocrit, oxygen extraction fraction, and tissue signal properties on the BOLD signal. AB - Calibrated blood oxygenation level dependent (BOLD) imaging, a technique used to measure changes in cerebral O(2) metabolism, depends on an accurate model of how the BOLD signal is affected by the mismatch between changes in cerebral blood flow (CBF) and cerebral metabolic rate of O(2) (CMRO(2)). However, other factors such as the cerebral blood volume (CBV) distribution at rest and with activation also affect the BOLD signal. The Davis model originally proposed for calibrated BOLD studies (Davis et al., 1998) is widely used because of its simplicity, but it assumes CBV changes are uniformly distributed across vascular compartments, neglects intravascular signal changes, and ignores blood-tissue signal exchange effects as CBV increases and supplants tissue volume. More recent studies suggest that venous CBV changes are smaller than arterial changes, and that intravascular signal changes and CBV exchange effects can bias estimated CMRO(2). In this paper, recent experimental results for the relationship between deoxyhemoglobin and BOLD signal changes are integrated in order to simulate the BOLD signal in detail by expanding a previous model to include a tissue compartment and three blood compartments rather than only the venous blood compartment. The simulated data were then used to test the accuracy of the Davis model of calibrated BOLD, demonstrating that the errors in estimated CMRO(2) responses across the typical CBF-CMRO(2) coupling range are modest despite the simplicity of the assumptions underlying the original derivation of the model. Nevertheless, the accuracy of the model can be improved by abandoning the original physical meaning of the two parameters alpha and beta and treating them as adjustable parameters that capture several physical effects. For a 3Tesla field and a dominant arterial volume change with activation, the accuracy of the Davis model is improved with new values of alpha=0.14 and beta=0.91. PMID- 21669296 TI - Microbial ecology of the watery ecosystems of Evros river in North Eastern Greece and its influence upon the cultivated soil ecosystem. AB - The aim of the present study was to evaluate the microbial ecosystem of cultivated soils along the Evros river in NE Greece. Evros river together with its derivative rivers constitute the capital source of life and sustainable development of the area. Along this riverside watery ecosystem systematic agro cultures were developed such as wheat, corn and vegetable cultures. The evaluation of the ecosystem microbial charge was conducted in both axes which are the watery ecosystem and the riverside cultivated soil area. Considerable discrimination of water quality was observed when considering chemical and microbiological parameters of the Evros river ecosystem. Ardas river possesses a better water quality than Evros and Erythropotamos, which is mainly due to the higher quantities that these two rivers accumulate from industrial, farming and urban residues leading to higher degree of pollution. An increased microbial pollution was recorded in two of the three rivers monitored and a direct relation in microbial and chemical charging between water and cultivated-soil ecosystems was observed. The protection of these ecosystems with appropriate cultivated practices and control of human and animal activities will define the homeostasis of the environmental area. PMID- 21669297 TI - Multi-locus variable number tandem repeat analysis for investigation of the genetic association of Clostridium difficile isolates from food, food animals and humans. AB - Clostridium difficile is the primary known cause of antibiotic-associated diarrhea. Diarrheal disease in food animals due to C. difficile infection has been well documented. Recently, reports of C. difficile infections in patients with no known risk factors for disease have raised concern of community acquisition through food animals and food. In this study, multi-locus variable number tandem repeat analysis (MLVA) was performed on a collection of 97C. difficile isolates of human, animal and food origin belonging to either the North American pulsed-field type (NAP) 1 or NAP7/NAP8. MLVA discriminated between NAP1 and NAP7/NAP8 populations. Three clusters of food, food animal and human NAP1 isolates were highly related by MLVA. These data suggest the possibility of either laboratory contamination or widespread distribution of clonal C. difficile populations. Community-associated NAP1 isolates were unrelated to NAP1 food and food animal isolates. Two MLVA loci were absent and 1 was invariant in all NAP7/NAP8 isolates. Therefore, MLVA discrimination was not sufficient to make assessments regarding the genetic associations among food, food animal and human isolates belonging to the NAP7/NAP8 pulsovar. Rigorous epidemiologic and laboratory investigations that employ highly discriminatory genotyping methods are necessary to compare C. difficile isolates from food and food animals to those from humans. PMID- 21669299 TI - Lipid metabolism in mammalian tissues and its control by retinoic acid. AB - Evidence has accumulated that specific retinoids impact on developmental and biochemical processes influencing mammalian adiposity including adipogenesis, lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with retinoic acid, in particular, has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents by enhancing fat mobilization and energy utilization systemically, in tissues including brown and white adipose tissues, skeletal muscle and the liver. Nevertheless, controversial data have been reported, particularly regarding retinoids' effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported activities of retinoids on different aspects of lipid metabolism in key tissues, focusing on retinoic acid. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. PMID- 21669300 TI - Computational approaches to the rational design of nanoemulsions, polymeric micelles, and dendrimers for drug delivery. AB - Nanoparticles are promising drug delivery systems whose selection and optimization can be gainfully conducted by theoretical methods. This review is targeted to experimentalists who are interested in enhancing their time and cost efficiency through the incorporation of theoretical approaches. This review thus begins with a brief overview of theoretical approaches available to the development of contemporary drug delivery systems. Approaches include solubility parameters, Flory-Huggins theory, analytical predictions of partition coefficients, and molecular simulations. These methods are then compared as they relate to the optimization of drug-material pairs using important performance related parameters including the size of the delivery particles, their surface properties, and the compatibility of the materials with the drug to be sequestered. Next, this review explores contemporary efforts to optimize a selection of existing nanoparticle platforms, including nanoemulsions, linear and star-shaped block co-polymer micelles, and dendrimers. The review concludes with an outlook on the challenges remaining in the successful application of these theoretical methods to the development of new drug formulations. FROM THE CLINICAL EDITOR: This paper is a comprehensive review of the many approaches available to assist the optimization of nanoparticle drug delivery vehicles, including a detailed discussion of methodological applicability, a survey of contemporary efforts to optimize a selection of frequently used nanoparticle subtypes. PMID- 21669298 TI - Early and late extensive chronic graft-versus-host disease in children is characterized by different Th1/Th2 cytokine profiles: findings of the Children's Oncology Group Study ASCT0031. AB - Numerous mechanisms underlie chronic graft-versus-host disease (cGVHD), including skewing of Th1/Th2 cytokine expression. There are biological differences between early-onset and late-onset cGVHD. To test whether different Th1/Th2 cytokines are associated with early- or late-onset cGVHD, peripheral blood was collected from 63 children enrolled on the Children's Oncology Group Phase III trial ASCT0031 evaluating hydroxychloroquine therapy for newly diagnosed extensive cGVHD. mRNA expression of interferon (IFN)-gamma and interleukin (IL)-2, -4, and -10 from stimulated peripheral blood mononuclear cells was evaluated by quantitative polymerase chain reaction. Early-onset cGVHD (n = 33) was characterized by decreased expression of IFN-gamma and IL-2 mRNA after nonspecific phorbol 12 myristate 13-acetate-ionomycin stimulation. In contrast, late-onset cGVHD (n = 11) was characterized by decreased expression of IL-4 and IL-2 mRNA after anti CD3 stimulation of T cells. Receiver-operating characteristic curve analysis revealed that IFN-gamma expression was correlated with the absence of early cGVHD (area under the curve [AUC] = 0.77) and that IL-4 (AUC = 0.89) and IL-2 (AUC = 0.84) expression was correlated with the absence of late cGVHD. There was no correlation between cytokine expression and a specific immune cell subset. Increased expression of Foxp3 mRNA was seen in early-onset cGVHD and late controls. The different time-dependent cytokine profiles in patients with newly diagnosed cGVHD suggests that the mechanisms underlying cGVHD are temporally regulated. Although larger validation studies are needed, our data suggest that cytokine profiles have a potential use as biomarkers for the diagnosis of cGVHD. PMID- 21669302 TI - Dynamic mechanical stimulations induce anisotropy and improve the tensile properties of engineered tissues produced without exogenous scaffolding. AB - Mechanical strength and the production of extracellular matrix (ECM) are essential characteristics for engineered tissues designed to repair and replace connective tissues that are subject to stress and strain. In this study, dynamic mechanical stimulation (DMS) was investigated as a method to improve the mechanical properties of engineered tissues produced without the use of an exogenous scaffold, referred to as the self-assembly approach. This method, based exclusively on the use of human cells without any exogenous scaffolding, allows for the production of a tissue sheet comprised of cells and ECM components synthesized by dermal fibroblasts in vitro. A bioreactor chamber was designed to apply cyclic strain to engineered tissues in order to determine if dynamic culture had an impact on their mechanical properties and ECM organization. Fibroblasts were cultured in the presence of ascorbic acid for 35 days to promote ECM production and allow the formation of a tissue sheet. This sheet was grown on a custom-built anchoring system allowing for easy manipulation and fixation of the tissue in the bioreactor. Following the 35 day period, tissues were maintained for 3 days in static culture (SC), or subjected either to a static mechanical stimulation of 10% strain, or a dynamic DMS with a duty cycle of 10% uniaxial cyclic strain at 1Hz. ECM was characterized by histology, immunofluorescence labeling and Western blotting. Both static and dynamic mechanical stimulation induced the alignment of assessed cytoskeletal proteins and ECM components parallel to the axis of applied strain and increased the ECM content of the tissues compared to SC. Measurement of the tensile mechanical properties revealed that mechanical stimulation significantly increases both the ultimate tensile strength and tensile modulus of the engineered tissues when compared to the non-stimulated control. Moreover, we demonstrated that cyclic strain significantly increases these parameters when compared to a static-loading stimulation and that mechanical stimulation contributes to the establishment of anisotropy in the structural and mechanical properties of self-assembled tissue sheets. PMID- 21669304 TI - Two-dimensional gel electrophoresis in proteomics: a tutorial. AB - Two-dimensional electrophoresis of proteins has preceded, and accompanied, the birth of proteomics. Although it is no longer the only experimental scheme used in modern proteomics, it still has distinct features and advantages. The purpose of this tutorial paper is to guide the reader through the history of the field, then through the main steps of the process, from sample preparation to in-gel detection of proteins, commenting the constraints and caveats of the technique. Then the limitations and positive features of two-dimensional electrophoresis are discussed (e.g. its unique ability to separate complete proteins and its easy interfacing with immunoblotting techniques), so that the optimal type of applications of this technique in current and future proteomics can be perceived. This is illustrated by a detailed example taken from the literature and commented in detail. This Tutorial is part of the International Proteomics Tutorial Programme (IPTP 2). PMID- 21669303 TI - Identification of carbonylated peptides by tandem mass spectrometry using a precursor ion-like scan in negative ion mode. AB - Reactive oxygen species (ROS) can oxidize proteins at almost any amino acid residue. Whereas some modifications are reversible within the cells, the higher oxidation states are especially irreversible. These irreversible post translational modifications are widely used as biomarkers of oxidative stress, such as protein carbonylation, which refers to aldehydes, ketones and lactams as 'reactive carbonyl groups'. This study relied on a set of synthetic peptides containing a C-terminal aldehyde (arginal) or modification with pyruvic acid (ketone) or 4-hydroxynonenal (aldehyde) at lysine or histidine residues, as well as peptides containing pyroglutamic acid (oxidation product of proline) and 2 amino-3-butyric acid (oxidation product of threonine). The carbonylation sites were specifically derivatized with 2,4-dinitrophenylhydrazine (DNPH) and the fragmentation behavior of the products investigated in electrospray ionization (ESI-) MS. Importantly, the DNPH-labeled carbonylated peptides showed favorable ionization behaviors in negative ion mode ESI, providing a sensitive detection method. Regular peptides were mostly discriminated under these conditions. Among the fragmentation techniques tested for the negatively charged ions, pulsed Q dissociation provided three diagnostic ions at m/z values 152.0, 163.1 and 179.0, specific for DNPH-modified peptides. These marker ions were successfully applied to detect the carbonylated model peptides in a spiked tryptic digest of bovine serum albumin and a complex protein mixture obtained from HeLa cells. PMID- 21669301 TI - Long-term molecular surveillance of multidrug-resistant tuberculosis in Spain. AB - The data presented here span 11 years (1998-2008) of monitoring of multidrug resistant tuberculosis (MDR-TB) clustering through molecular typing techniques in Spain. The molecular and epidemiological data of 480 multidrug-resistant Mycobacterium tuberculosis complex isolates were analyzed. Thirty-one clusters involving 157 (32.7%) patients were identified. The proportion of immigrants increased substantially over the study period reaching 65% in 2008; however, the clustering rate remained stable indicating that local transmission was little influenced by imported MDR-TB. The three major clusters respond to the persistence of two autochthonous strains throughout the study period and an extensively drug-resistant (XDR) Mycobacterium bovis outbreak with only two cases was reported since 2002. Molecular and epidemiological evidence for the importation of new strains and their spread within the community was found. Immigrant-only clusters most often grouped patients infected abroad with strains belonging to rare spoligotypes. Conversely, widespread spoligotypes of the Latin American and Mediterranean (LAM) and Haarlem families were responsible for the majority of the MDR-TB local transmission. The demonstration of clusters spanning several Spanish regions that have been ongoing throughout the study period makes it advisable to maintain a continuous molecular surveillance in order to monitor the spread of MDR-TB. PMID- 21669312 TI - The continuum of pediatric medical education and life-long learning. PMID- 21669316 TI - One in six children with initial urinary tract infection will have renal scarring on follow-up. PMID- 21669317 TI - Adjunct corticosteroids may benefit children admitted with community-acquired pneumonia who are wheezing. PMID- 21669318 TI - Lactobacillus GG may improve frequency and severity of pain in children with functional abdominal pain. PMID- 21669319 TI - Oral rehydration solution with zinc and prebiotics decreases duration of acute diarrhea in children. PMID- 21669320 TI - Adding intranasal lidocaine to midazolam may benefit children undergoing procedural sedation. PMID- 21669322 TI - More evidence on the use of parenteral omega-3 lipids in pediatric intestinal failure. PMID- 21669323 TI - A review of the impact of climate change on future nitrate concentrations in groundwater of the UK. AB - This paper reviews the potential impacts of climate change on nitrate concentrations in groundwater of the UK using a Source-Pathway-Receptor framework. Changes in temperature, precipitation quantity and distribution, and atmospheric carbon dioxide concentrations will affect the agricultural nitrate source term through changes in both soil processes and agricultural productivity. Non-agricultural source terms, such as urban areas and atmospheric deposition, are also expected to be affected. The implications for the rate of nitrate leaching to groundwater as a result of these changes are not yet fully understood but predictions suggest that leaching rate may increase under future climate scenarios. Climate change will affect the hydrological cycle with changes to recharge, groundwater levels and resources and flow processes. These changes will impact on concentrations of nitrate in abstracted water and other receptors, such as surface water and groundwater-fed wetlands. The implications for nitrate leaching to groundwater as a result of climate changes are not yet well enough understood to be able to make useful predictions without more site-specific data. The few studies which address the whole cycle show likely changes in nitrate leaching ranging from limited increases to a possible doubling of aquifer concentrations by 2100. These changes may be masked by nitrate reductions from improved agricultural practices, but a range of adaption measures need to be identified. Future impact may also be driven by economic responses to climate change. PMID- 21669324 TI - Persistent organochlorine compounds in fetal and maternal tissues: evaluation of their potential influence on several indicators of fetal growth and health. AB - Some organochlorine compounds, such as polychlorinated biphenyls (PCBs), have a tendency to bioaccumulate in humans and predators at the top of the food chain. We have recently confirmed the transplacental transfer of these compounds and the present study has been designed on the same material with the aim of investigating their potential health effects on newborns from 70 pregnant women, resident in a Northern Italy industrial town. Organochlorine compounds [namely, p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT), p,p' dichlorodiphenyldichloroethene (p,p'-DDE), hexachlorobenzene (HCB), and PCBs] have been analyzed both in cord and maternal serum, placenta, and maternal subcutaneous adipose tissue by GC-MSD. p,p'-DDT levels in the adipose tissue resulted significantly (p<0.05) related to birth length. Mothers of neonates born by preterm programmed caesarean delivery showed significantly (p<0.005 for both) higher serum p,p'-DDE serum concentrations and p,p'-DDT levels in the adipose tissue, as compared to mothers delivering at term. PMID- 21669325 TI - Antibiotic contamination and occurrence of antibiotic-resistant bacteria in aquatic environments of northern Vietnam. AB - The ubiquitous application and release of antibiotics to the environment can result in bacterial antibiotic resistance, which in turn can be a serious risk to humans and other animals. Southeast Asian countries commonly apply an integrated recycling farm system called VAC (Vegetable, Aquaculture and Caged animal). In the VAC environment, antibiotics are released from animal and human origins, which would cause antibiotic-resistant bacteria (ARB). This study evaluated occurrence of ARB in the VAC environment in northern Vietnam, with quantitative analysis of antibiotic pollution. We found that sulfonamides were commonly detected at all sites. In dry season, while sulfamethazine was a major contaminant in pig farm pond (475-6662 ng/l) and less common in city canal and aquaculture sites, sulfamethoxazole was a major one in city canal (612-4330 ng/l). Erythromycin (154-2246 ng/l) and clarithromycin (2.8-778 ng/ml) were the common macrolides in city canal, but very low concentrations in pig farm pond and aquaculture sites. High frequencies of sulfamethoxazole-resistant bacteria (2.14 94.44%) were found whereas the occurrence rates of erythromycin-resistant bacteria were lower (<0.01-38.8%). A positive correlation was found between sulfamethoxazole concentration and occurrence of sulfamethoxazole-resistant bacteria in dry season. The sulfamethoxazole-resistant isolates were found to belong to 25 genera. Acinetobacter and Aeromonas were the major genera. Twenty three of 25 genera contained sul genes. This study showed specific contamination patterns in city and VAC environments and concluded that ARB occurred not only within contaminated sites but also those less contaminated. Various species can obtain resistance in VAC environment, which would be reservoir of drug resistance genes. Occurrence of ARB is suggested to relate with rainfall condition and horizontal gene transfer in diverse microbial community. PMID- 21669326 TI - Relative importance of wastewater treatment plants and non-point sources of perfluorinated compounds to Washington State rivers. AB - Perfluorinated compounds (PFCs) were measured in 10 Washington State rivers and 4 wastewater treatment plants (WWTPs) under periods of low and high flows to investigate the relative importance of point and non-point sources to rivers. PFCs were detected in all samples with summed values ranging from 1.11 to 74.9 ng/L in surface waters and 62.3-418 ng/L in WWTP effluent. Concentrations in 6 of the 10 rivers exhibited a positive relationship with flow, indicating runoff as a contributing source, with PFC loads greatest at all 10 waterbodies during high flows. Perfluoroheptanoic acid:perfluorooctanoic acid homologue ratios suggest atmospheric contributions to the waterbodies are important throughout the year. Principal component analysis (PCA) indicated distinct homologue profiles for high flow, low flow, and effluent samples. The PCA demonstrates that during the spring when flows and loads are at their greatest; WWTP discharges are not the primary sources of PFCs to the river systems. Taken together, the evidence provided signifies non-point inputs are a major pathway for PFCs to surface waters in Washington State. PMID- 21669327 TI - Chemical and biological recovery of Lake Saudlandsvatn, a formerly highly acidified lake in southernmost Norway, in response to decreased acid deposition. AB - We studied acid-sensitive organisms in Lake Saudlandsvatn in southernmost Norway in relation to acidification: brown trout (Salmo trutta), the caddisfly Hydropsyche siltalai and the zooplankter Daphnia longispina. The study lake was highly acidified with episodic pH depressions <5.0 in the 1970s and 1980s, and sulphur (S) deposition five times greater than the critical load. Chemical recovery following reduced deposition of S became evident in the late 1990s, when the pH increased to 5.5-6.0. By 2000, S deposition had decreased to the critical load. The lake sustained a good brown trout population until the early 1980s, but then it started to decline and nearly went extinct ten years later. Severe recruitment failures were found in most years prior to 1995, both in the inlet and outlet stream. However, since 2003 a marked recovery of the brown trout population has occurred in the lake. During the 1980s, the H. siltalai disappeared from the lake tributaries. In 1996, the species reappeared, and increased highly in abundance from 2000 and onwards. The first post-acidification record of D. longispina from net hauls in Lake Saudlandsvatn was in 2002. Palaeolimnological data confirmed their presence prior to acidification. Any significant recovery in all three organism groups coincided with an acid neutralizing capacity (ANC) of >20 MUeq L-1 and toxic inorganic aluminium of <30 MUg L-1. Projections made with the MAGIC model indicate that unless further reductions in deposition of S are made, the ANC will fluctuate around the ANC survival threshold for the biological elements described. Thus, full biological recovery will not occur in the near future. PMID- 21669328 TI - Atmospheric concentrations and air-soil gas exchange of polycyclic aromatic hydrocarbons (PAHs) in remote, rural village and urban areas of Beijing-Tianjin region, North China. AB - Forty passive air samplers were deployed to study the occurrence of gas and particulate phase PAHs in remote, rural village and urban areas of Beijing Tianjin region, North China for four seasons (spring, summer, fall and winter) from 2007 to 2008. The influence of emissions on the spatial distribution pattern of air PAH concentrations was addressed. In addition, the air-soil gas exchange of PAHs was studied using fugacity calculations. The median gaseous and particulate phase PAH concentrations were 222 ng/m3 and 114 ng/m3, respectively, with a median total PAH concentration of 349 ng/m3. Higher PAH concentrations were measured in winter than in other seasons. Air PAH concentrations measured at the rural villages and urban sites in the northern mountain region were significantly lower than those measured at sites in the southern plain during all seasons. However, there was no significant difference in PAH concentrations between the rural villages and urban sites in the northern and southern areas. This urban-rural PAH distribution pattern was related to the location of PAH emission sources and the population distribution. The location of PAH emission sources explained 56%-77% of the spatial variation in ambient air PAH concentrations. The annual median air-soil gas exchange flux of PAHs was 42.2 ng/m2/day from soil to air. Among the 15 PAHs measured, acenaphthylene (ACY) and acenaphthene (ACE) contributed to more than half of the total exchange flux. Furthermore, the air-soil gas exchange fluxes of PAHs at the urban sites were higher than those at the remote and rural sites. In summer, more gaseous PAHs volatilized from soil to air because of higher temperatures and increased rainfall. However, in winter, more gaseous PAHs deposited from air to soil due to higher PAH emissions and lower temperatures. The soil TOC concentration had no significant influence on the air-soil gas exchange of PAHs. PMID- 21669329 TI - A parameterization of dust concentration (PM10) of dust events observed at Erdene in Mongolia using the monitored tower data. AB - Hourly mean time series of dust concentration (PM10) measured at 3m high and a sonic-anemometer measured momentum and kinematic heat fluxes at 8m high above the surface have been obtained from a 20-m monitoring tower located at Erdene in the Asian dust source region of Mongolia for years of 2009 and 2010. These time series were used to identify dust events and to develop optimal regression equations for the dust concentration of dust events with the friction velocity (u(*)) and the convective velocity scale (w(*)). In total, 68 dust events were identified in 2009 (except for November) and 43 dust events for the period from March to August in 2010. The duration of each dust event ranged from 3-29 h in 2009 and 5-35 h in 2010. The maximum hourly mean dust concentration of the dust event was found to be 4,107 MUg m-3 in May in 2009 and 4,708 MUg m-3 in March in 2010 while a minimum of 251 MUg m-3 in August in 2009 and 662 MUg m-3 in June in 2010. The optimal regression equation for the dust concentration (C) of dust events was found to have the form of log C=a+b(u(*)+cw(*))(n), where a, b, c and n are constants that vary month to month. The convective velocity scale (w(*)) that has not been taken into account in most dust modelings was found to enhance the dust concentration of dust events during the cold period from December to March when the soil temperature was below the freezing level for both the stable (w(*)<0) and unstable (w(*)>0) stratifications, whereas the convective velocity caused a reduction in the dust concentrations during the warm period from April to October, suggesting the importance of the convective velocity to estimate dust concentration of dust events. PMID- 21669330 TI - Characterisation of acid mine drainage in a high rainfall mountain environment, New Zealand. AB - The Stockton coal mine lies at 700-1100 m above sea level in a mountainous orographic precipitation zone on the West Coast of the South Island of New Zealand. Rainfall exceeds 6000 mm/year and arrives with frequent flood events that can deliver > 200 mm/day. Streams vary in discharges by up to two orders of magnitude over a time scale of hours. Pyritic waste rock at the mine interacts chemically with even the most intense rainfall, and almost all runoff is acidic to some degree. In the most intense rain event recorded in this study (> 10 mm/hour), dilution of acid mine drainage (AMD) occurred and pH rose from 3 to >5 over several hours, with stream discharge at a monitoring point rising from <0.5 to >100 cumecs. However, most rain events of similar magnitude are less intense, longer duration, and only raise AMD pH to ~4 with similar high discharges. Results presented here for Stockton confirm that it is the intensity of rain events on the hourly scale, rather than the total amount of rainwater delivered to the site, that governs the amount and composition of AMD generated during flood events. Stream discharge loads of dissolved iron and aluminium range from ~20 to 1000 kg/hour. Dissolved sulfate and acidity loads are typically ~500 kg/hour but can exceed 20 tonnes/hour in rain events. First flush effects observable elsewhere around the world involving peak metal loads following dry periods or seasonal changes are not obvious at Stockton due to the high and variable rainfall environment. Dissolved Fe concentrations may be limited in runoff waters by precipitation of jarosite and schwertmannite, especially when rainfall is sufficiently intense to raise pH to 4 or higher. These minerals are widespread in the exposed waste rock on site. Likewise, precipitation of alunite may occur as pH rises in rain events, but no field evidence for this has been observed. PMID- 21669331 TI - Elimination of oxide interferences and determination of ultra-trace silver in soils by ICP-MS with ion-molecule reactions. AB - Silver is subject to significant spectral interferences caused by high concentrations of Zr, Nb, Mo and Y in inductively coupled plasma mass spectrometry (ICP-MS) analysis for soil or sediment samples. In this study, the Zr, Nb, and Mo based oxide and/or hydroxide polyatomic interferences were successfully eliminated by ion-molecule reactions in a dynamic reaction cell (DRC). These potentially interfering ions 93Nb16O+, 92Zr16OH+ and 92Mo16OH+ on 109Ag+ were rapidly oxidized to higher oxides 93NbO2+, 92ZrO2H+/92ZrO2H+ and 92MoO2H+ by O2 as the reaction gas in DRC. However, interfering ions 89Y18O+ and 91Zr16O+ on 107Ag cannot be removed by this method, because the reaction rates of ZrO+ and YO+ to ZrO2+/ZrO3+ and YO2+/YO3+ were too low. Under the optimized O2 flow rate (2.4 mL min-1) and DRC rejection parameter q (Rpq, 0.75), the background signal was reduced by up to 100-fold at m/z 109 and the limit of quantitation (LOQ, 10sigma) for 109Ag was 0.5 ng g-1. The proposed method was used to determine the concentration of Ag in twenty-eight soil standard reference materials (SRMs). The accuracy of the results suggests that the method has great potential for the direct determination of trace or ultra-trace levels of Ag in various environmental samples. PMID- 21669332 TI - Determination of arsenic leaching from glazed and non-glazed Turkish traditional earthenware. AB - Glazed and non-glazed earthenware is traditionally and widely used in Turkey and most of the Mediterranean and the Middle East countries for cooking and conservation of foodstuff. Acid-leaching tests have been carried out to determine whether the use of glazed and non-glazed earthenware may constitute a human health hazard risk to the consumers. Earthenware was leached with 4% acetic acid and 1% citric acid solutions, and arsenic in the leachates was measured using hydride generation atomic absorption spectrometry. Arsenic concentrations in the leach solution of non-glazed potteries varied from 30.9 to 800 MUg L-1, while the glazed potteries varied generally from below the limit of detection (0.5 MUg L-1) to 30.6 MUg L-1, but in one poorly glazed series it reached to 110 MUg L-1. Therefore, the risk of arsenic poisoning by poorly glazed and non-glazed potteries is high enough to be of concern. It appears that this is the first study reporting arsenic release from earthenware into food. PMID- 21669333 TI - Epigenetic mechanisms in Alzheimer's disease: progress but much to do. AB - The interesting review from Mastroeni and colleagues highlights recent progress on epigenetic analysis of Alzheimer's disease, but it also illustrates how much we still need to do. PMID- 21669334 TI - Presence: brain, virtual reality and robots. PMID- 21669335 TI - Foreword. Hallux rigidus. PMID- 21669336 TI - Preface. PMID- 21669337 TI - Etiology, pathophysiology, and staging of hallux rigidus. AB - The condition of hallux limitus is well understood and agreed on as visualized histologically and radiographically. But the historically described pathophysiology and anatomy that predisposes to hallux limitus has been challenged. Numerous investigators have proposed anatomic abnormalities of the foot as a primary cause of this condition, but perhaps trauma is the only unanimously agreed on cause. However, this accounts for only a small percentage of cases. To strive for better treatment outcomes, understanding the pathophysiology, assessing patient risk factors, and recognizing causative agents can better equip the foot and ankle surgeon in managing this condition. PMID- 21669338 TI - Evaluation and biomechanics of the first ray in the patient with limited motion. AB - Adequate first ray function is essential to healthy human gait. Controversies still exist about aspects of human structure and function and many newer answers and theories have been proposed by a new generation of experts. Examples include the sagittal plane facilitation, tissue stress, and preferred movement pathway theories. This article also presents a summary of how to provide a thorough, detailed, and accurate first ray examination on the individual with limited motion. This article explores functional first ray mechanics in both a theoretic and biomechanical perspective, as well as a practical, hands-on examination perspective. PMID- 21669339 TI - Sesamoid disorders of the first metatarsophalangeal joint. AB - The sesamoid complex is located centrally and plantar to the first metatarsal head, where they are imbedded within the plantar plate, which transmits 50% of body weight and more than 300% during push-off, is susceptible to numerous pathologies. These pathologies include sesamoiditis, stress fracture, avascular necrosis, osteochondral fractures, and chondromalacia, and are secondary to these large weight-bearing loads. This article discusses sesamoid conditions and their relationship with hallux limitus, and reviews the conditions that predispose the first metatarsophalangeal joint to osteoarthritic changes. PMID- 21669340 TI - Modern techniques in hallux abducto valgus surgery. AB - Hallux abducto valgus surgery is in a constant state of evolution. Innovation is driven by surgeons pursuing the perfect procedure for any clinical scenario. The end point is to eliminate complications and produce satisfied patients. Medical device technology has helped pave the way for some recent advances in bunion surgery. The use of opening base wedge plates, locking plates for the Lapidus fusion, suture endobuttons, and staples for the Akin procedure are the focus in this review of modern techniques. PMID- 21669341 TI - The cheilectomy and its modifications. AB - Hallux rigidus occurs in 10% of persons aged 20 to 34 years but in as much as 44% of people older than 80 years. Surgical intervention has been suggested for cases of hallux rigidus that have failed using conservative methods. The modified cheilectomy is considered by many the first-line treatment for this disease, given the procedure's inherent ability to eliminate degenerate bone and cartilage and decompress the intra-articular space, while sparing considerable cubic content of bone. Once the cheilectomy has been performed, there remains a sufficient volume of bone to perform a more definitive reconstruction if necessary. PMID- 21669342 TI - Multiplanar phalangeal and metatarsal osteotomies for hallux rigidus. AB - Many articles have been published on the various treatments of hallux rigidus/limitus but few, if any, have focused solely on the osteotomies performed in the treatment of this disorder and provided a thorough review of the literature and critique of the procedures. Here, we describe the most commonly used, most widely accepted, and most effective osteotomies in the treatment of hallux limitus/rigidus. Along with this discussion are figures and tables to make the information accessible and user friendly. Among the procedures discussed are Keller arthroplasty, Keller interpositional arthroplasty, Bonney-Kessel, Mayo Stone, Regnauld, Youngswick, Watermann, Watermann-Green, tricorrectional metatarsal osteotomy, sagittal V, LADO (long-arm decompression osteotomy), Drago, Lambrinudi (plantarflexory closing base wedge osteotomy), sagittal Scarf/sagittal Z, and Weil/Mau/distal oblique osteotomy. PMID- 21669343 TI - Technique and pearls in performing the first metatarsal phalangeal joint arthrodesis. AB - When there is a considerable loss of first metatarsal phalangeal joint (MTPJ) motion and/or ankylosis is apparent then a joint preservation procedure may not be feasible. For end-stage degenerative change within the MTPJ, nonreducible joint incongruity, or instability of the first MTPJ, an arthrodesis can provide the most predictable and, arguably, the most definitive correction of the deformity, especially in patients with higher functional demands. This article discusses principles of techniques with an emphasis on the procedure to prepare a successful arthrodesis, and expounds on technical nuances including those associated with fixation devices. PMID- 21669344 TI - Modern techniques in hallux rigidus surgery. AB - This article is a review of the history, etiology, and clinical and radiographic presentations of hallux rigidus. The focus is on current treatment options being offered for the treatment of hallux rigidus. PMID- 21669345 TI - Hallux rigidus: what lies beyond fusion, resectional arthroplasty, and implants. AB - Hallux rigidus (HR) is the limitation of motion at the first metatarsophalangeal (MTP) joint, most commonly secondary to degenerative arthritis. Surgical options for treating HR include 2 general categories: joint salvage and joint destruction. A hybrid of techniques from the 2 categories has emerged: cartilage resurfacing, interpositional arthroplasty, and arthrodiastasis. These procedures address the pathologic condition of the first MTP joint more directly than joint salvage and avoid many of the negative complications, consequences, and connotations of joint destruction procedures. Alternative surgical options for the treatment of recalcitrant pain associated with HR are evolving and are discussed in this review. PMID- 21669346 TI - First metatarsophalangeal joint arthrodesis: current fixation options. AB - This article reviews the current literature on first metatarsophalangeal joint arthrodesis rates using various forms of fixation, as well as reviewing biomechanical studies comparing the strengths of the different fixation options that are available. PMID- 21669347 TI - Primary arthrodesis and sural artery flap coverage for subtalar joint osteomyelitis in a diabetic patient. AB - Diabetic chronic wounds with joint sepsis and osteomyelitis of the hindfoot can be difficult pathologic entities to treat. Limb salvage approaches are based on careful preoperative evaluation, surgical technique, and postoperative care. This article reviews the overall management of subtalar joint osteomyelitis with a case report showing primary arthrodesis with external fixation and soft tissue coverage with a reverse sural artery neurofasciocutaneous flap. PMID- 21669348 TI - Significance of finding micropapillary DCIS on core needle biopsy. PMID- 21669350 TI - Reproducibility and repeatability of volumetric measurements for olfactory bulb volumetry: which method is appropriate? An update using 3 Tesla MRI. AB - RATIONALE AND OBJECTIVES: The aim of this study was to compare different sequences for olfactory bulb volumetry using 3-T magnetic resonance imaging, evaluating reproducibility, repeatability, and systematic biases. MATERIALS AND METHODS: Twenty-two volunteers underwent 3-T magnetic resonance imaging of the frontal skull base in this prospective study. Imaging included constructive interference in steady state (CISS), T2-weighted (T2w) three-dimensional (3D) sampling perfection with application-optimized contrasts using different flip angle evolutions, and T2w two-dimensional (2D) turbo spin-echo sequences. Two observers independently performed two olfactory bulb volumetric studies per bulb and sequence. Intraobserver and interobserver reliability was assessed using intraclass correlation coefficients. For the evaluation of reproducibility, concordance correlation coefficients were determined, and for repeatability and systematic biases, Bland-Altman plots were analyzed. RESULTS: Intraclass correlation coefficient analysis of the specialized observer yielded almost perfect results for intraobserver reliability (0.94, 0.85, and 0.93 for the CISS, T2w 3D, and T2w 2D sequences, respectively). For the less experienced observer, the results were 0.86 0.78, and 0.74 for the CISS, T2w 3D, and T2w 2D sequences, respectively. Interobserver reliability showed almost perfect agreement for all sequences (0.92, 0.86, and 0.86, respectively). The CISS sequence yielded the highest concordance correlation coefficient (0.84), precision (0.85), and accuracy (0.99). Bland-Altman plot analyses revealed the lowest repeatability coefficients for the T2w 2D sequence. Volumetric measurements of T2w 2D imaging showed systematically lower volumetric results compared to the CISS sequence ( 22.7%) and the T2w 3D sequence (-8.3%). CONCLUSIONS: Comparison of three imaging sequences for olfactory bulb volumetry yielded the best values for the CISS sequence in terms of intraobserver and interobserver reliability, reproducibility, accuracy, and precision. Given that even less experienced observers achieve almost perfect results, the CISS sequence is recommended for olfactory bulb volumetry. PMID- 21669349 TI - Intraprocedural transcatheter intra-arterial perfusion MRI as a predictor of tumor response to chemoembolization for hepatocellular carcinoma. AB - RATIONALE AND OBJECTIVES: To prospectively test the hypothesis that transcatheter intraarterial perfusion magnetic resonance imaging (TRIP-MRI) measured semiquantitative perfusion reductions during transcatheter arterial chemoembolization of hepatocellular carcinoma (HCC) are associated with tumor response. MATERIALS AND METHODS: Twenty-eight patients (mean age 63 years; range 47-87 years) with 29 tumors underwent chemoembolization in a combined magnetic resonance interventional radiology suite. Intraprocedural tumor perfusion reductions during chemoembolization were monitored using TRIP-MRI. Pre- and postchemoembolization semiquantitative area under the time-signal enhancement curve (AUC) tumor perfusion was measured. Mean tumor perfusion pre- and postchemoembolization were compared using a paired t-test. Imaging follow-up was performed 1-3 months after chemoembolization. We studied the relationship between short-term tumor imaging response and intraprocedural perfusion reductions using univariate and multivariate analysis. RESULTS: Intraprocedural AUC perfusion value decreased significantly after chemoembolization (342.1 vs. 158.6 arbitrary unit, P < .001). Twenty-six patients with 27 HCCs (n = 27) had follow-up imaging at mean 39 days postchemoembolization. Favorable response was present in 67% of these treated tumors according to necrosis criteria. Fifteen of 16 (94%) tumors with 25%-75% perfusion reductions showed necrosis treatment response compared to only 3 of 11 (27%) tumors with perfusion reductions outside the above range (P = .001). Multivariate logistic regression indicated that intraprocedural tumor perfusion reduction and Child-Pugh class were independent factors associated significantly with tumor response (P = .012 and .047, respectively). CONCLUSION: TRIP-MRI can successfully measure semiquantitative changes in HCC perfusion during chemoembolization. Intraprocedural tumor perfusion reductions are associated with future tumor response. PMID- 21669351 TI - Can non-calcified coronary artery plaques be detected on non-contrast CT calcium scoring studies? AB - RATIONALE AND OBJECTIVES: Coronary computed tomographic (CT) angiography has been shown to detect noncalcified coronary artery plaque. Depending on tissue composition, noncalcified plaque differs in CT attenuation from blood and epicardial fat. The aim of this study was to determine whether noncalcified plaque can be visually detected on non-contrast-enhanced CT calcium scoring studies. MATERIALS AND METHODS: A total of 106 patients (40 women; mean age, 59 years) who underwent coronary calcium scoring, coronary CT angiography, and quantitative catheter angiography were prospectively investigated. Two blinded observers independently reviewed calcium scoring studies for positive vascular remodeling and hypoattenuation within the vessel wall, suggestive of noncalcified plaque. Findings on calcium scoring studies were compared with those on coronary CT angiography and quantitative catheter angiography. RESULTS: The mean Agatston score was 515.8 +/- 826.8. Overall interobserver agreement for the identification of noncalcified lesions was substantial (kappa = 0.69). Observer 1 and observer 2 identified 21 and 17 patients, respectively, with 38 and 35 lesions suggestive of noncalcified plaque. Coronary CT angiography confirmed noncalcified plaque in 33 of 38 (86.8%; observer 1) and 31 of 35 (88.6%; observer 2) lesions. Thus, the overall positive predictive value for correct identification of noncalcified plaque on calcium scoring studies was 0.88, although overall sensitivity was low at 0.39. CONCLUSIONS: Noncalcified plaque can be visually detected on calcium scoring studies. Review of calcium scoring studies for features of noncalcified plaque may enhance the identification of patients with more active disease and higher cardiovascular risk. PMID- 21669352 TI - Spatial resolution limits of multislice computed tomography (MS-CT), C-arm-CT, and flat panel-CT (FP-CT) compared to MicroCT for visualization of a small metallic stent. AB - RATIONALE AND OBJECTIVES: Small metallic stents are increasingly used in the treatment of cerebral aneurysms and for revascularization in ischemic strokes. Realistic three-dimensional datasets of a stent were obtained by using three x ray-based imaging methods in current clinical use. Multislice-CT (MS-CT), C-arm flat detector-CT (C-arm CT, ACT), and flat panel-CT (FP-CT) were compared with high-resolution laboratory MicroCT scans that served as a reference standard. The purpose was to assess and compare the quality and accuracy of current clinical three-dimensional reconstructions of a vascular stents. MATERIAL & METHODS: A 3 * 20 mm Cypher stent was deployed in a straight polytetrafluoroethylene tube and filled with nondiluted iodine contrast and BaSO(4). MS-CT images of the static tube phantom and stent were acquired using GE LightSpeed VCT Series, C-arm CT images were obtained using Artis (DynaCT, Siemens), FP-CT were obtained using a preclinical research CT (GE), and MicroCT images were obtained using eXplore Locus SP (GE). DICOM datasets were analyzed using Amira and Matlab. RESULTS: Because of blooming effects, the maximum intensity projections (MIPs) and volume renderings generated from MS-CT showed significantly increased strut dimensions with no distinction between the regular struts and connector struts while the lumen diameter is artificially reduced. The shape of the reconstructed stent surface differed remarkably from the real stent. C-arm CT and FP-CT volume renderings more accurately represented the struts. Consistently capturing the structure of the connectors and the strut shape definition was highly threshold dependent. The stent lumen was about 30% underestimated by MS-CT when compared to MicroCT. CONCLUSION: The spatial resolution of current clinical CT for imaging of small metallic stents is insufficient to visualize fine geometrical details. Further improvement in the spatial resolution of clinical imaging technologies combined with better software and hardware for image postprocessing will be necessary for detailed structural analysis, evaluation of the stent lumen in vivo, and to permit accurate assessment of stent patency and early detection potential in-stent stenosis. PMID- 21669353 TI - Effect of segmental bronchoalveolar lavage on quantitative computed tomography of the lung. AB - RATIONALE AND OBJECTIVES: With employment of both multidetector computed tomography (MDCT) and endobronchial procedures in multicenter studies, effects of timing of endobronchial procedures on quantitative imaging (Q-MDCT) metrics is a question of increasing importance. MATERIALS AND METHODS: Six subjects were studied via MDCT at baseline, immediately following and at 4 hours and 24 hours post-bronchoalveolar lavage (BAL) (right middle lobe and lingula). Through quantitative image analysis, non-air, or "tissue" volume (TV) in each lung and lobe was recorded. Change in TV from baseline was used to infer retention and redistribution of lavage fluid. RESULTS: Bronchoscopist reported unrecovered BAL volume correlated well with Q-MDCT for whole lung measures, but less well with individual lobes indicating redistribution. TV in all lobes except the right lower lobe differed significantly (P < .05) from baseline immediately post lavage. At 24 hours, all lobes except the left lower lobe (small 1% mean difference at 24 hours) returned to baseline. CONCLUSIONS: These findings suggest fluid movement affecting Q-MDCT metrics between lobes and between lungs before eventual resolution, and preclude protocols involving the lavage of one lung and imaging of the other to avoid interactions. We demonstrate that Q-MDCT is sensitive to lavage fluid retention and redistribution, and endobronchial procedures should not precede Q-MDCT imaging by less than 24 hours. PMID- 21669354 TI - How to do Medicare. PMID- 21669355 TI - Extraction of four wisdom teeth in a patient with congenital factor V deficiency hemophilia. AB - Congenital factor V deficiency was first described by Owren in 1947.(1) It is thought to be transmitted by an autosomal recessive gene (q23-24)(2) found in 1 out of every 1 million population and usually with no gender or race correlation.(3) To date, ~150 cases have been reported in the world literature.(3) The description of rare case of this disease is justified, because they may add further information about the condition of the hemorrhagic tendency. The object of the present paper was to report the bleeding control for extraction of 4 wisdom teeth with congenital factor V deficiency hemophilia and review the literature. PMID- 21669356 TI - Oral melanotic macule and primary oral malignant melanoma: epidemiology, location involved, and clinical implications. AB - BACKGROUND: Oral malignant melanoma must be differentiated from melanotic macule. STUDY DESIGN: Retrospective review of 2 series of oral melanotic macule (n = 52) and oral melanoma (n = 130) were conducted to investigate the epidemiology and location involved and assess their differences. RESULTS: The mean age of oral melanotic macule patients was 47.3 years, with female:male ratio 2.1 and the lower lip being the predominant location. The mean age of oral melanoma patients was 53.8 years, with no observed sex predilection and the main locations being palate and gingiva. Differences between the 2 cohorts in age (P = .006), gender (P = .014), and lesion site (P < .001) were noted. In this review, 1 case of oral melanotic macule was found to subsequently develop into melanoma. CONCLUSIONS: Oral melanotic macule may possess malignant potential. Biopsy is recommended to differentiate oral melanoma from melanotic macule for male patients >60 years old with suspected melanotic macule lesion located on the palate. PMID- 21669357 TI - Hyalinizing clear cell carcinoma: a case report and review of the literature. AB - Hyalinizing clear cell carcinoma (HCCC) is a low-grade malignancy with infiltrative growth pattern. It affects mainly the minor salivary glands of adult women. The most frequent locations of this tumor are the palate and tongue. HCCC shows a poorly circumscribed, infiltrative, and essentially monomorphic population of clear cells with few mitoses and almost no nuclear or cellular pleomorphism. These cells form trabeculae, cords, islands, and/or nests, circumscribed by variable amounts of hyalinized fibrous bands with foci of myxohyaline stroma. S-100 protein, muscle-specific actin, smooth muscle actin, myosin, and calponin are consistently negative, which strongly indicates the absence of myoepithelial cell differentiation in this tumor. We present a case of HCCC affecting the upper vestibule in a 53-year-old man. The patient was treated by surgery and postoperative radiation and did not show recurrence or distant metastases 3 years after treatment. Discussed also are the clinical and pathologic features of this tumor along with the differential diagnosis and a literature review. PMID- 21669358 TI - Traumatic pseudoaneurysm of the facial artery: late complication and effects on local blood flow. AB - OBJECTIVE: Pseudoaneurysms are vascular injuries resulting from a rupture of the vessel walls with blood extravasation into perivascular tissues. Proper treatment is required to prevent rupture and intense bleeding. This article reports a case of pseudoaneurysm of the facial artery that evolved to a late complication, presenting dehiscence of suture and exposure of the wound and bleeding after the initial injury and also discusses the effects of vascular response from the involved vessels by comparing them against the contralateral side. CASE REPORT: A healthy 17-year-old male was admitted with an injury of approximately 35 mm in length in the right cheek with an exposed clot inside the injury and local bleeding after a stabbing 11 days before. CT angiography showed rupture of the facial artery and formation of a pseudoaneurysm with an organized clot. The patient was treated by means of surgery under local anesthesia and intravenous sedation. The facial artery was located and attached by suture. The wound was explored and clots were removed. The patient was discharged on the first postoperative day and he had an excellent scarring standard with no unfavorable event. CONCLUSIONS: The authors conclude that this surgical technique is an effective method for treating such injuries, as it is easily performed and can be conducted by the oral and maxillofacial surgeon assistant. PMID- 21669359 TI - Are we doing enough? PMID- 21669360 TI - The importance of using diagnostic codes. PMID- 21669362 TI - Fibrodysplasia ossificans progressiva (FOP) in South Africa: dental implications in 5 cases. AB - Fibrodysplasia ossificans progressiva (FOP) is a severe genetic disorder in which progressive ossification of subcutaneous tissues leads to immobility and profound physical handicap. Dental management of affected persons may be constrained by impaired mobility of the temporomandibular joints. Equally, the traumatic aspects of dental intervention can exacerbate the ossification process. In the later stages of the disorder, thoracic immobility impairs pulmonary ventilation and compromises dental anesthesia. We have undertaken dental appraisal and treatment of 5 South Africans with FOP, with ages ranging from 2 to 52 years. The age relationship of the manifestations of FOP was apparent in these persons, as were the dental problems that emerged. These dental observations illustrate the importance of accurate diagnosis and the awareness of potential complications that may be encountered in dental management. Our observations are presented and discussed in this article. PMID- 21669363 TI - Taking conjoint analysis to task. PMID- 21669364 TI - Conjoint analysis applications in health--a checklist: a report of the ISPOR Good Research Practices for Conjoint Analysis Task Force. AB - BACKGROUND: The application of conjoint analysis (including discrete-choice experiments and other multiattribute stated-preference methods) in health has increased rapidly over the past decade. A wider acceptance of these methods is limited by an absence of consensus-based methodological standards. OBJECTIVE: The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Good Research Practices for Conjoint Analysis Task Force was established to identify good research practices for conjoint-analysis applications in health. METHODS: The task force met regularly to identify the important steps in a conjoint analysis, to discuss good research practices for conjoint analysis, and to develop and refine the key criteria for identifying good research practices. ISPOR members contributed to this process through an extensive consultation process. A final consensus meeting was held to revise the article using these comments, and those of a number of international reviewers. RESULTS: Task force findings are presented as a 10-item checklist covering: 1) research question; 2) attributes and levels; 3) construction of tasks; 4) experimental design; 5) preference elicitation; 6) instrument design; 7) data-collection plan; 8) statistical analyses; 9) results and conclusions; and 10) study presentation. A primary question relating to each of the 10 items is posed, and three sub questions examine finer issues within items. CONCLUSIONS: Although the checklist should not be interpreted as endorsing any specific methodological approach to conjoint analysis, it can facilitate future training activities and discussions of good research practices for the application of conjoint-analysis methods in health care studies. PMID- 21669365 TI - ISPOR states its position on network meta-analysis. PMID- 21669366 TI - Interpreting indirect treatment comparisons and network meta-analysis for health care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 1. AB - Evidence-based health-care decision making requires comparisons of all relevant competing interventions. In the absence of randomized, controlled trials involving a direct comparison of all treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best choice(s) of treatment. Mixed treatment comparisons, a special case of network meta-analysis, combine direct and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than a traditional meta-analysis. This report from the ISPOR Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on the interpretation of indirect treatment comparisons and network meta analysis to assist policymakers and health-care professionals in using its findings for decision making. We start with an overview of how networks of randomized, controlled trials allow multiple treatment comparisons of competing interventions. Next, an introduction to the synthesis of the available evidence with a focus on terminology, assumptions, validity, and statistical methods is provided, followed by advice on critically reviewing and interpreting an indirect treatment comparison or network meta-analysis to inform decision making. We finish with a discussion of what to do if there are no direct or indirect treatment comparisons of randomized, controlled trials possible and a health-care decision still needs to be made. PMID- 21669367 TI - Conducting indirect-treatment-comparison and network-meta-analysis studies: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 2. AB - Evidence-based health care decision making requires comparison of all relevant competing interventions. In the absence of randomized controlled trials involving a direct comparison of all treatments of interest, indirect treatment comparisons and network meta-analysis provide useful evidence for judiciously selecting the best treatment(s). Mixed treatment comparisons, a special case of network meta analysis, combine direct evidence and indirect evidence for particular pairwise comparisons, thereby synthesizing a greater share of the available evidence than traditional meta-analysis. This report from the International Society for Pharmacoeconomics and Outcomes Research Indirect Treatment Comparisons Good Research Practices Task Force provides guidance on technical aspects of conducting network meta-analyses (our use of this term includes most methods that involve meta-analysis in the context of a network of evidence). We start with a discussion of strategies for developing networks of evidence. Next we briefly review assumptions of network meta-analysis. Then we focus on the statistical analysis of the data: objectives, models (fixed-effects and random-effects), frequentist versus Bayesian approaches, and model validation. A checklist highlights key components of network meta-analysis, and substantial examples illustrate indirect treatment comparisons (both frequentist and Bayesian approaches) and network meta-analysis. A further section discusses eight key areas for future research. PMID- 21669368 TI - Practical implications of differential discounting in cost-effectiveness analyses with varying numbers of cohorts. AB - OBJECTIVE: To call attention to the influence of the number of birth-cohorts used in cost-effectiveness analysis (CEA) models on incremental cost-effectiveness ratios (ICERs) under differential discounting. METHODS: The consequences of increasing the number of birth-cohorts are demonstrated using a CEA of cervical cancer prevention as an example. The cost-effectiveness of vaccinating 12-year old girls against the human papillomavirus is estimated with the MISCAN microsimulation screening analysis model for 1, 10, 20, and 30 birth-cohorts. Costs and health effects are discounted with equal rates of 4% and alternatively with differential rates of 4% and 1.5% respectively. The effects of increasing the number of cohorts are shown by comparing the ICERs under equal and differential discounting. RESULTS: The ICER decreases as the number of cohorts increases under differential discounting, but not under equal discounting. CONCLUSIONS: The variation of ICERs with the number of cohorts under differential discounting prompts questions regarding the appropriate specification of CEA models and interpretation of their results. In particular, it raises concerns that arbitrary variation in study specification leads to arbitrary variation in results. Such variations could lead to erroneous policy decisions. These findings are relevant to CEA guidance authorities, CEA practitioners, and decision makers. Our results do not imply a problem with differential discounting per se, yet they highlight the need for practical guidance for its use. PMID- 21669370 TI - The use of quality-adjusted life-years in the economic evaluation of health technologies in Spain: a review of the 1990-2009 literature. AB - OBJECTIVE: To appraise economic evaluations of health technologies that included quality-adjusted life-years (QALYs) as an outcome measure conducted over the past 20 years in Spain. METHODS: A systematic review of the literature was conducted. Economic evaluations that included QALYs as an outcome measure, conducted in Spain and published between January 1990 and December 2009 were identified. Primary and gray literature sources were reviewed. RESULTS: A total of 60 articles and 4 health technology assessment reports were included. Key findings were 1) the vast majority of articles (77.1%) referred to therapeutic interventions; 2) 63.2% dealt with pharmaceutical products and much fewer with preventive strategies, medical devices, or diagnostic interventions; 3) most evaluations referred to cardiovascular- (19.8%), respiratory- (16.3%), and cancer (13.0%) related processes; 4) 80.3% were based on a theoretical model, most commonly Markov models (71.4%); 5) 67.3% adopted the National Health System perspective; 6) information on the methods used to describe the health states was given in 45.1% of studies; 7) 40.3% used the EuroQoL-5D to elicit preferences, whereas 66.1% gave no details on the methods applied to determine patients' choices; 8) it was possible to state who completed the questionnaires in only 17.7% of studies; 9) 77.1% of the interventions assessed were below the ?30,000/QALY suggested affordable threshold in Spain. CONCLUSIONS: An increasing number of economic evaluations using QALYs had been conducted. Most of them relied on theoretical models. Several methodological issues remain unsolved. Great disparity exists regarding the reporting of the methods used to determine health states and utility values. PMID- 21669371 TI - Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis for febrile neutropenia in breast cancer in the United Kingdom. AB - OBJECTIVE: We report a cost-effectiveness evaluation of granulocyte colony stimulating factors (G-CSFs) for the prevention of febrile neutropenia (FN) after chemotherapy in the United Kingdom (UK). METHODS: A mathematical model was constructed simulating the experience of women with breast cancer undergoing chemotherapy. Three strategies were modeled: primary prophylaxis (G-CSFs administered in all cycles), secondary prophylaxis (G-CSFs administered in all cycles after an FN event), and no G-CSF prophylaxis. Three G-CSFs were considered: filgrastim, lenograstim, and pegfilgrastim. Costs were taken from UK databases and utility values from published sources. A systematic review provided data on G-CSF efficacy. Probabilistic sensitivity analyses examined the effects of uncertainty in model parameters. RESULTS: In the UK, base-case analysis with a willingness-to-pay (WTP) threshold of L20K per quality-adjusted life year gained and also using list prices, the most cost-effective strategy was primary prophylaxis with pegfilgrastim for a patient with baseline FN risk greater than 38%, secondary prophylaxis with pegfilgrastim for baseline FN risk 11% to 37%, and no G-CSFs for baseline FN risk less than 11%. Using a WTP threshold of L30K and list prices, primary prophylaxis with pegfilgrastim was cost-effective for baseline FN risks greater than 29%. In all analyses, pegfilgrastim dominated filgrastim and lenograstim. Sensitivity analyses demonstrated that higher WTP threshold, younger age, earlier stage at diagnosis, or reduced G-CSF prices result in G-CSF prophylaxis being cost-effective at lower baseline FN risk levels. CONCLUSION: Pegfilgrastim was the most cost-effective G-CSF. The most cost-effective strategy (primary or secondary prophylaxis) was dependent on the FN risk level for an individual patient, patient age and stage at diagnosis, and G-CSF price. PMID- 21669372 TI - Impact of depression on work productivity and its improvement after outpatient treatment with antidepressants. AB - OBJECTIVE: Depressive disorders influence socioeconomic burden at both the individual and organizational levels. This study estimates the lost productive time (LPT) and its resulting cost among workers with major depressive disorder (MDD) compared with a comparison group. It also estimates the change in productivity after 8 weeks of outpatient psychiatric treatment with antidepressants. METHODS: Working patients diagnosed with MDD without other major physical or mental disorders were recruited (n = 102), along with age- and sex matched healthy controls from the Seoul Metropolitan area (n = 91). The World Health Organization's Health and Work Performance Questionnaire and the Hamilton Rating Scale for Depression were utilized to measure productivity and severity of depression, respectively, at baseline and at 8 weeks of treatment. RESULTS: The LPT from absenteeism and presenteeism (reduced performance while present at work) was significantly higher among the MDD group. Workers with MDD averaged costs due to LPT at 33.4% of their average annual salary, whereas the comparison group averaged costs of 2.5% of annual salary. After 8 weeks of treatment, absenteeism and clinical symptoms of depression were significantly reduced and associated with significant improvement in self-rated job performance (31.8%) or cost savings of $7508 per employee per year. CONCLUSIONS: We confirmed that significant productivity loss arises from MDD and that this loss can be reduced with psychiatric intervention after a time period as short as 8 weeks. Mental health professionals should work with employers to devise a cost-effective system to provide workers with accessible quality care. PMID- 21669369 TI - Economic evaluation of reamed versus unreamed intramedullary nailing in patients with closed and open tibial fractures: results from the study to prospectively evaluate reamed intramedullary nails in patients with tibial fractures (SPRINT). AB - INTRODUCTION: Recently, results from the large, randomized study to prospectively evaluate reamed intramedullary nails in patients with tibial fractures (SPRINT) trial suggested a benefit for reamed intramedullary nail insertion in patients with closed tibial shaft fractures largely based on cost-neutral autodynamizations and a potential advantage for unreamed intramedullary nailing in open fractures. We performed an economic evaluation to compare resource use and effectiveness of reamed and unreamed intramedullary nailing using a cost utility analysis. METHODS: We calculated quality-adjusted life years (QALYs) for each patient from a self-administered health utility index 3 questionnaire for the first 12 months following the intramedullary nailing. A convenience sample of 235 SPRINT patients provided data on costs associated with health care resource utilization. All costs are reported in Canadian dollars for the 2008 financial year. RESULTS: We found incremental effects of -0.017 (95% confidence interval [CI] -0.021-0.058) and -0.002 (95% CI -0.060-0.062) QALYs for patients treated with reamed compared with unreamed intramedullary nails in closed and open fractures, respectively. The incremental costs for reamed compared with unreamed intramedullary nailing were $51 Canadian dollars (95% CI -$2298-$2400) in closed tibial fractures and $2546 Canadian dollars (95%CI -$1773-$6864) in open tibial fractures. Unreamed nailing dominated reamed nailing for both closed and open tibial fractures; however, the cost and the utility results had high variability. CONCLUSION: Our economic analysis from a governmental perspective suggests small differences in both cost and effectiveness with large uncertainty between reamed and unreamed intramedullary nailing. PMID- 21669374 TI - Economic impact of nonpersistence with antidepressant treatment in the adult population of Quebec: a comparative cost-effectiveness approach. AB - BACKGROUND: Although for the great majority of indications, practice guidelines recommend that antidepressants (ADs) be used for at least 6 months, premature discontinuation is very frequent in a "real-life" setting. Previous studies have assessed the economic impact of such nonpersistence, but differences across antidepressant products remain inadequately explored. OBJECTIVE: To compare treatment persistence and incremental cost/persistence ratios (ICPRs) across individual new ADs (selective serotonin reuptake inhibitors and atypical ADs) as well as the associated direct health-care costs in the adult population covered by the public drug program of Quebec. METHODS: A retrospective cohort study was conducted in 13,936 adults aged 18 to 64 years who started an AD treatment in 2003. Persistence was defined as treatment duration of at least 6 months regardless of whether a product switch had occurred. Economic impact was assessed over the first year of treatment through drug, medical services, hospitalization, and total health-care costs. Comparisons across products were conducted using the ICPR. RESULTS: Adjusting for confounders, treatment nonpersistence ranged from 60.4% (paroxetine) to 65.1% (citalopram). The product associated with the highest total health-care costs was citalopram (CDN$2653) and the lowest was venlafaxine (CDN$2168). Fluvoxamine had the lowest mean AD costs (CDN$215) and venlafaxine (CDN$309) the highest. CONCLUSIONS: Total health-care costs were similar across products except for citalopram, which was more costly. Comparisons based on the ICPR revealed that paroxetine, fluoxetine, and venlafaxine were more favorable than the other AD alternatives. PMID- 21669373 TI - Ticagrelor versus genotype-driven antiplatelet therapy for secondary prevention after acute coronary syndrome: a cost-effectiveness analysis. AB - BACKGROUND: Clopidogrel's effectiveness is likely reduced significantly for prevention of thrombotic events after acute coronary syndrome (ACS) in patients exhibiting a decreased ability to metabolize clopidogrel into its active form. A genetic mutation responsible for this reduced effectiveness is detectable by genotyping. Ticagrelor is not dependent on gene-based metabolic activation and demonstrated greater clinical efficacy than clopidogrel in a recent secondary prevention trial. In 2011, clopidogrel will lose its patent protection and likely will be substantially less expensive than ticagrelor. OBJECTIVE: To determine the cost-effectiveness of ticagrelor compared with a genotype-driven selection of antiplatelet agents. METHODS: A hybrid decision tree/Markov model was used to estimate the 5-year medical costs (in 2009 US$) and outcomes for a cohort of ACS patients enrolled in Medicare receiving either genotype-driven or ticagrelor-only treatment. Outcomes included life years and quality-adjusted life years (QALYs) gained. Data comparing the clinical performance of ticagrelor and clopidogrel were derived from the Platelet Inhibition and Patient Outcomes trial. RESULTS: The incremental cost-effectiveness ratio (ICER) for universal ticagrelor was $10,059 per QALY compared to genotype-driven treatment, and was most sensitive to the price of ticagrelor and the hazard ratio for death for ticagrelor compared with clopidogrel. The ICER remained below $50,000 per QALY until a monthly ticagrelor price of $693 or a 0.93 hazard ratio for death for ticagrelor relative to clopidogrel. In probabilistic analyses, universal ticagrelor was below $50,000 per QALY in 97.7% of simulations. CONCLUSION: Prescribing ticagrelor universally increases quality-adjusted life years for ACS patients at a cost below a typically accepted threshold. PMID- 21669375 TI - Hospital resource utilization and treatment cost of skeletal-related events in patients with metastatic breast or prostate cancer: estimation for the Portuguese National Health System. AB - BACKGROUND: Skeletal-related events (SREs) occur frequently in patients with bone metastases as a result of breast (BC) and prostate (PC) cancers. They increase both morbidity and mortality and lead to extensive health-care resource utilization. METHODS: Health care resource utilization by BC/PC patients with at least one SRE during the preceding 12 months was assessed through retrospective chart review. SRE-treatment costs were estimated using the Portuguese Ministry of Health cost database and analyzed using generalized linear models. RESULTS: This study included 152 patients from nine hospitals. The mean (SD) annual SRE treatment cost per patient was ?5963 (?3646) and ?5711 (?4347), for BC (n=121) and PC (n=31) patients, respectively. Mean cost per single episode ranged between ?1485 (radiotherapy) and ?13,203 (spinal cord compression). Early onset of bone metastasis (P = 0.03) and diagnosis of bone metastases at or after the occurrence of the first SRE (P < 0.001) were associated with higher SRE-treatment costs. CONCLUSION: These results reveal the high hospital SRE-treatment costs, highlighting the need for early diagnosis and treatment, and identify key factors determining the economic value of therapies for patients with skeletal metastases. PMID- 21669376 TI - Examining web equivalence and risk factor sensitivity of the COPD population screener. AB - OBJECTIVES: The primary aim was to assess the equivalence of an Internet-based chronic obstructive pulmonary disease-population screener (COPD-PS) relative to a validated paper-and-pencil version. A secondary aim was to compare groups based on known COPD risk factors, such as smoking status and gender. METHODS: Using an online panel survey organization, participants were randomized to internet or paper-and-pencil assessment where they completed the COPD-PS and other study forms. A subset of respondents also completed a test-retest reliability assessment. Finally, several thousand additional online respondents completed the COPD-PS for risk factor analyses. RESULTS: A total of 1006 adults completed the randomized study (N = 504 online, N = 502 by mail). There were no differences between the arms in mean COPD-PS scores (mean difference: 0.12; 95% confidence interval: -0.14-+0.37; P = 0.365). In the web arm, 106/504 (21.0%) exceeded the screening cut-off compared to 101/502 (20.1%) in the paper-administration arm (difference in proportions: 0.9%; 95% confidence interval: -4.1%-+5.9%; P = 0.720). Subgroup analyses on a separate cohort of 3001 adults demonstrated hypothesized differences between groups defined by smoking status, presence of COPD, and shortness of breath. CONCLUSION: The methods of administration that were evaluated in this study (internet vs. paper and pencil) resulted in no significant differences in COPD-PS mean scores. Furthermore, the predictive utility of the COPD-PS was not different between methods of administration, even after accounting for age and smoking status. PMID- 21669377 TI - The association between statin use and outcomes potentially attributable to an unhealthy lifestyle in older adults. AB - OBJECTIVE: To explore the "healthy user" and "healthy adherer" effects hypothetical sources of bias thought to arise when patients who initiate and adhere to preventive therapies are more likely to engage in healthy behaviors than are other subjects. METHODS: The authors examined the association between statin initiation and adherence, and the subsequent use of preventive health services and incidence of clinical outcomes unlikely to be associated with the need for, or use of, a statin among older enrollees in two state-sponsored drug benefit programs. RESULTS: After adjustment for demographic and clinical covariates, patients who initiated statin use were more likely to receive recommended preventive services than noninitiators matched on age, sex, and state (hazard ratio [HR]: 1.10, 1.06-1.14 for males, HR: 1.09, 1.07-1.11 for females) and appeared to have a lower risk of a range of adverse outcomes (HR: 0.87, 0.85 0.89) thought to be unrelated to statin use. Adherence to a statin regimen was also associated with increased rates of preventive service use and a decreased rate of adverse clinical outcomes (HR: 0.93, 0.88-0.99). CONCLUSIONS: These results suggest that patients initiating and adhering to chronic preventive drug therapies are more likely to engage in other health-promoting behaviors. Failure to account for this relationship may introduce bias in any epidemiologic study evaluating the effect of a preventive therapy on clinical outcomes. PMID- 21669378 TI - Using health state utility values from the general population to approximate baselines in decision analytic models when condition-specific data are not available. AB - BACKGROUND: Decision analytic models in health care require baseline health related quality of life data to accurately assess the benefits of interventions. The use of inappropriate baselines such as assuming the value of perfect health (EQ-5D = 1) for not having a condition may overestimate the benefits of some treatment and thus distort policy decisions informed by cost per quality adjusted life years thresholds. OBJECTIVE: The primary objective was to determine if data from the general population are appropriate for baseline health state utility values (HSUVs) when condition specific data are not available. METHODS: Data from four consecutive Health Surveys for England were pooled. Self-reported health status and EQ-5D data were extracted and used to generate mean HSUVs for cohorts with or without prevalent health conditions. These were compared with mean HSUVs from all respondents irrespective of health status. RESULTS: More than 45% of respondents (n = 41,174) reported at least one condition and almost 20% reported at least two. Our results suggest that data from the general population could be used to approximate baseline HSUVs in some analyses, but not all. In particular, HSUVs from the general population would not be an appropriate baseline for cohorts who have just one condition. In these instances, if condition specific data are not available, data from respondents who report they do not have any prevalent health condition may be more appropriate. Exploratory analyses suggest the decrement on health-related quality of life may not be constant across ages for all conditions and these relationships may be condition specific. Additional research is required to validate our findings. PMID- 21669379 TI - Development of the EXACT-U: a preference-based measure to report COPD exacerbation utilities. AB - BACKGROUND: The exacerbations of chronic obstructive pulmonary disease tool (EXACT) is a condition-specific daily diary recently developed to evaluate the frequency, severity, and duration of chronic obstructive pulmonary disease (COPD) exacerbations. A preference-based algorithm for the EXACT would allow utilities to be reported from patients during an exacerbation when EQ-5D data are not available. OBJECTIVE: To develop the exacerbations of chronic obstructive pulmonary disease tool-utility (EXACT-U), a condition-specific preference-based measure to report utilities from the EXACT for use in cost-effectiveness studies. METHODS: Five items with three to five levels comprise the EXACT-U. Two groups of health states and respondents were constructed to allow for model development (Development group) and predictive validity testing (Validation group) using independent samples. Members of the UK general public each valued 11 randomized health states using time trade-offs (TTOs) scaled from full health/dead with 10 year durations. Regression models estimated from the Development group using individual data, mean data, and panel designs. Models assessed by number of inconsistent coefficients estimated and R(2) and tested against observed utilities from the Validation group using mean absolute error (MAE) and root mean squared error (RMSE). RESULTS: A total of 55 health states, including the best and worst states, were valued in TTO interviews conducted with 400 respondents. Ten models were developed. The final preferred model contained no logical inconsistencies and found MAE = 0.04 and RMSE = 0.05 with a predicted utility range from 0.09 to 0.95. CONCLUSIONS: The EXACT-U is a condition-specific preference-based measure with strong predictive validity to report daily utilities during an exacerbation. PMID- 21669380 TI - Health utilities associated with hemoglobin levels and blood loss in postmenopausal women: the Women's Health Initiative. AB - OBJECTIVES: The purpose of our study was to use health-related quality of life data from the Women's Health Initiative to calculate health-related utility weights and examine differences in these health utility weights across different hemoglobin (Hgb) levels. These utility weights could then be used in future cost effectiveness studies. METHODS: Health utility weights were measured by the Short Form-6D (SF-6D), a health utility index derived from the Short Form Medical Outcomes questionnaire. Adjusted least square means were calculated for each level of Hgb at baseline and in longitudinal regression analysis the relationship between change in Hgb and change in the SF-6D was examined. Both baseline and longitudinal analyses were performed for all postmenopausal women and separately for those with self-reported heart failure, cancer, and osteoarthritis. RESULTS: Women with Hgb in the anemic range had lower health utility weights than those with higher Hgb levels. Longitudinally, a loss of of 2 g/dl Hgb or more was associated with a statistically significant and clinically meaningfully decline in SF-6D in all participants and also in the group of participants with cancer and osteoarthritis, but not in those with heart failure. CONCLUSIONS: Lower levels of Hgb and a loss of Hgb are associated with a statistically significant and clinically meaningful decrement in health utility in all postmenopausal women we studied and also in those with chronic conditions. PMID- 21669381 TI - Estimation of a multiattribute utility function for the Spanish version of the TooL questionnaire. AB - OBJECTIVES: To estimate and assess the psychometric properties of a multiattribute utility function (MAUF) for the Spanish version of the Tolerability and Quality of Life (TooL questionnaire). METHODS: Balanced data on 243 patients diagnosed with schizophrenia or bipolar disorder were gathered. In addition to the demographic and clinical variables and the usual generic health related quality of life (HRQoL) questionnaires (EuroQol-5D [EQ-5D] and Short Form 6D [SF-6D]), instruments considered included the Spanish versions of the Positive and Negative Symptoms of Schizophrenia Scale (PANSS), Young Mania Rating Scale (YMRS), Montgomery-Asberg Depression Rating Scale (MADRS), Udvalg for Kliniske Undersogelser (UKU), and Clinical Global Impression Severity (CGIS) scale. MAUF parameters estimation involved a number of visual analogue scale (VAS) and time trade-off (TTO) ratings that proved difficult to be performed by the patients. After checking for inconsistencies in patient responses, the original sample was reduced to a still balanced subsample of 70 individuals. A multiplicative-form MAUF was estimated following the standard methodology. RESULTS: Good convergent validity was demonstrated because utility estimates from the MAUF presented strong correlations with utilities from the generic HRQoL instruments included: SF-6D (0.66, P < 0.01), EQ-5D (0.69, P < 0.01), and moderate correlations with the rest of instruments considered: PANSS (-0.27, P = 0.10), YMRS (-0.30, P = 0.08), MADRS (-0.48, P < 0.01), UKU (-0.35, P < 0.01). Criterion validity was also met because differences in mean utilities by clinical severity were found (P < 0.01). Utilities from the MAUF covered a wider range of health states [0.04,1.00] than those from the SF-6D [0.53,1.00] and EQ-5D [0.23,0.96]. CONCLUSIONS: Utilities from the MAUF showed good psychometric properties, serving as a complement to generic health utilities. If misapplied, however, utilities from this instrument might favor the positive evaluation of drugs showing fewer associated side effects. PMID- 21669382 TI - A meta-analysis of osteoporotic fracture risk with medication nonadherence. AB - OBJECTIVES: Therapy for osteoporosis reduces the risk of fracture in clinical trials; real-world adherence to therapy is suboptimal and may reduce the effectiveness of intervention. The objective was to assess the fracture risk among patients nonadherent versus adherent to therapy for osteoporosis. METHODS: Medline, Embase, and CINAHL were searched for English-language publications of observational studies (January 1998-February 2009). Proceedings from two recent meetings of five relevant conferences were hand searched. Prospective and retrospective observational studies of patients with osteoporosis receiving bisphosphonates, parathyroid hormone, or selective estrogen receptor modulators denosumab were included. Studies were required to consider both fracture risk and adherence (compliance and/or persistence); any definition of adherence/fracture was acceptable. Data were analyzed using pooled comparisons of the odds and hazard ratios of fracture in noncompliance versus compliance and nonpersistence versus persistence. Sensitivity analyses were conducted to determine the effect of clinical heterogeneity on the results. RESULTS: Twenty-seven citations were identified, the majority of which were retrospective database analyses considering the effect of adherence to bisphosphonate therapy on fracture at any skeletal site. The absolute frequency of fracture ranged from 6% to 38% with noncompliance and from 5% to 19% with nonpersistence (104-159 weeks). Meta analysis indicates that fracture risk increases by approximately 30% with noncompliance (odds ratio [95% confidence interval] 1.29 [1.22-1.38]; hazard ratio 1.28 [1.18-1.38]) and by 30% to 40% with nonpersistence (odds ratio 1.40 [1.29-1.52]; hazard ratio 1.32 [1.23-1.42]). CONCLUSIONS: Poor medication adherence is associated with a significantly increased risk of fracture versus optimal adherence. Improving medication adherence in patients with osteoporosis may lead to a greater reduction in fracture. PMID- 21669383 TI - Utility scores and treatment preferences for clinical early-stage cervical cancer. AB - OBJECTIVES: To determine utility scores for health states relevant to the treatment of early-stage, high-risk cervical cancer. METHODS: Seven descriptive health states incorporating the physical and emotional aspects of medical treatment, recovery, and prognosis were developed. Forty-five female volunteers valuated each health state using the visual analogue score (VAS) and time trade off (TTO) methods. Treatment options were ranked by mean and median TTO scores. The 95% confidence intervals were calculated to determine the statistical significance of ranking preferences. The Wilcoxon rank-sum test was used to compare central tendencies related to age, race, parity, and subject history of abnormal cervical cytology. RESULTS: VAS and TTO scores were highly correlated. Volunteers ranked minimally invasive radical hysterectomy with low-risk features as most preferred (mean TTO = 0.96; median TTO = 1.00) and aborted radical hysterectomy followed by chemoradiation as least preferred (mean TTO = 0.69; median TTO = 0.83). Health states that included radical surgery were ranked higher than those that included chemoradiation, either in the adjuvant or primary setting. When survival was comparable, volunteers rated radical hysterectomy with high-risk pathology followed by adjuvant chemoradiation (mean TTO = 0.78; median TTO = 0.92; 95% CI: 0.69-0.87) similarly to chemoradiation alone (mean TTO = 0.76; median TTO 0.90; 95% CI: 0.66-0.86; p = NS). Utility scores for the majority of health states were not significantly associated with age, race, parity, or subject history of abnormal cervical cytology. CONCLUSION: Subjects consistently preferred surgical excision to treat early-stage, high-risk cervical cancer and chose a minimally invasive approach. Such utility scores can be used to incorporate quality-of-life effects into comparative-effectiveness models for cervical cancer. PMID- 21669384 TI - Pharmaceutical priority setting and the use of health economic evaluations: a systematic literature review. AB - OBJECTIVES: To investigate which factors and criteria are used in priority setting of pharmaceuticals, in what contexts health economic evaluations are used, and barriers to the use of health economic evaluations at micro, meso, and macro health-care levels. METHODS: The search for empirical articles was based on the MeSH index (Medical Substance Heading), including the search terms "economic evaluation," "cost-effectiveness analysis," "cost-utility analysis," "cost benefit analysis," "pharmacoeconomic," AND "drug cost(s)," AND "eligibility determination," AND "decision-making," AND "rationing," AND formulary. The following databases were searched: PubMed, EconLit, Cochrane, Web of Science, CINAHL, and PsycINFO. More than 3100 studies were identified, 31 of which were included in this review. RESULTS: The use of health economic evaluations at all three health-care levels was investigated in three countries (United States [US], United Kingdom [UK], and Sweden). Postal and telephone survey methods dominated (n = 17) followed by interviews (n = 13), document analysis (n = 10), and observations of group deliberations (n = 9). The cost-effectiveness criterion was most important at the macro level. A number of contextual uses of health economic evaluations were identified, including importantly the legitimizing of decisions, structuring the priority-setting process, and requesting additional budgets to finance expensive pharmaceuticals. CONCLUSION: Factors that seem to support the increased use of health economic evaluations are well-developed frameworks for evaluations, the presence of health economic skills, and an explicit priority setting process. Differences in how economic evaluations are used at macro, meso, and micro levels are attributed to differences in the preconditions at each level. PMID- 21669385 TI - Trends in health care utilization in British Columbia following public coverage for tiotropium. AB - OBJECTIVES: To examine the use and cost of health-care services in British Columbia, Canada, before and after public drug coverage for tiotropium bromide. METHODS: A time series analysis was performed using data from British Columbia's centralized administrative health-care databases. Linear regression on data from a stable 3-year prepolicy period was used to predict future use of inhaled anticholinergic (IAC) medications, visits to physicians, emergency hospitalizations, and costs. For each use measure, we estimated the policy effect as the difference between observed use in the postpolicy period and predicted use obtained from the prepolicy period. RESULTS: In total, over the 2.5-year period after public coverage, tiotropium use increased by 24.4% more than predicted (95% confidence interval [CI] 23.9%-24.8%). Visits to physicians were unchanged, but there were between 596 and 948 more emergency admissions for chronic obstructive pulmonary disease, and between 582 and 1940 more hospital admissions of any kind than were predicted from prepolicy data. Total cost of inhaled IAC medications increased slightly more than predicted, by between an additional CDN$1.30 million and CDN$1.71 million, but total out-of-pocket spending by patients on IAC medications was reduced by between CDN$2.83 million and CDN$3.11 million because of public coverage. Hospital costs were between CDN$3.88 million and CDN$12.93 million greater than anticipated based on prepolicy data. CONCLUSIONS: Public drug plan coverage for tiotropium in British Columbia reduced out-of-pocket costs for patients and their private insurers. Before versus after time series analysis did not show a reduction in hospitalizations or physician visits, or costs associated with those services. PMID- 21669386 TI - Perspectives on "early dialogue" between a manufacturer and health technology assessment agencies. PMID- 21669387 TI - Early dialogue between the developers of new technologies and pricing and reimbursement agencies: a pilot study. AB - It is common practice for developers of new health care technologies to engage in early dialogue with the major regulatory agencies; such discussions frequently center around the proposed clinical trial designs to support the registration of new interventions and suggestions on their improvement. Pricing and reimbursement agencies are increasingly using the results from health technology assessments to inform their decision making for new technologies. Such assessments are invariably underpinned by the phase 3 clinical trial evidence which may not provide answers to the key questions. Technology developers are beginning to realize that direct, early dialogue on the evidence requirements of the major pricing and reimbursement agencies, before phase 3 clinical trial designs for their key development compounds have been finalized, may be beneficial. This article reports on the pioneering efforts of one technology developer in seeking early dialogue with seven pricing and reimbursement agencies in five countries globally in 2007-2008 on their likely evidence requirements for a new oral treatment for patients with chronic plaque psoriasis. The pilot project demonstrated that a feasible process of early dialogue could be established, through a face-to-face meeting with prior circulation of a briefing book. Although there was some variation in the advice the similarities far outweighed the differences. More experience of early dialogue needs to be accumulated, involving a wider range of pricing and reimbursement agencies and compounds. The conclusion of this study, however, was that early dialogue can be a worthwhile process for all parties and can lead to a common understanding about evidence development for market access. PMID- 21669388 TI - The chimera of population norms. PMID- 21669390 TI - Editorial. The 21st International Conference on Information Processing in Medical Imaging (IPMI). July 5-10, 2009, College of William and Mary, Williamsburg, Virginia. PMID- 21669391 TI - Macrophages as a battleground for toxoplasma pathogenesis. AB - In this issue of Cell Host & Microbe, Jensen et al. (2011) show that clonal lineages of Toxoplasma gondii have evolved distinct ways of subverting their favored host cell, the macrophage. The results suggest that T. gondii and the ROP kinases can be used to probe immune signaling pathways. PMID- 21669392 TI - KAPs off for HIV-1 integration. AB - Integration of reverse transcribed HIV-1 DNA into the host genome, catalyzed by HIV-1 integrase, represents an obligate step in establishing productive viral infection. Allouch et al. (2011) identify KAP1 (TRIM28) as an interaction partner of acetylated integrase. KAP1, in complex with HDAC1, represses HIV-1 integration through specific deacetylation of HIV-1 integrase. PMID- 21669393 TI - Shigella gets captured to gain entry. AB - The type III secretion system-dependent epithelial invasion and dissemination of Shigella is stimulated by ATP released through hemichannels. Romero et al. (2011) show that prior to epithelial contact, Shigella is captured by nanometer-thin micropodial extensions at a distance from the cell surface, in a process involving ATP and connexin-mediated signaling. PMID- 21669394 TI - Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites. AB - While subunit vaccines have shown partial efficacy in clinical trials, radiation attenuated sporozoites (RAS) remain the "gold standard" for sterilizing protection against Plasmodium infection in human vaccinees. The variability in immunogenicity and replication introduced by the extensive, random DNA damage necessary to generate RAS could be overcome by genetically attenuated parasites (GAP) designed via gene deletion to arrest at defined points during liver-stage development. Here, we demonstrate the principle that late liver stage-arresting GAP induce larger and broader CD8 T cell responses that provide superior protection in inbred and outbred mice compared to RAS or early-arresting GAP immunizations. Late liver stage-arresting GAP also engender high levels of cross stage and cross-species protection and complete protection when administered by translationally relevant intradermal or subcutaneous routes. Collectively, our results underscore the potential utility of late liver stage-arresting GAP as broadly protective next-generation live-attenuated malaria vaccines and support their potential as a powerful model for identifying antigens to generate cross stage protection. PMID- 21669395 TI - Leishmania promotes its own virulence by inducing expression of the host immune inhibitory ligand CD200. AB - Leishmania parasites infect macrophages, cells normally involved in innate defense against pathogens. Leishmania amazonensis and Leishmania major cause severe or mild disease, respectively, consistent with each parasite's ability to survive within activated macrophages. The mechanisms underlying increased virulence of L. amazonensis are mostly unknown. We show that L. amazonensis promotes its own survival by inducing expression of CD200, an immunoregulatory molecule that inhibits macrophage activation. L. amazonensis does not form typical nonhealing lesions in CD200(-/-) mice and cannot replicate in CD200(-/-) macrophages, an effect reversed by exogenous administration of soluble CD200-Fc. The less virulent L. major does not induce CD200 expression and forms small, self healing lesions in both wild-type and CD200(-/-) mice. Notably, CD200-Fc injection transforms the course of L. major infection to one resembling L. amazonensis, with large, nonhealing lesions. CD200-dependent iNOS inhibition allows parasite growth in macrophages, identifying a mechanism for the increased virulence of L. amazonensis. PMID- 21669396 TI - Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. AB - European and North American strains of the parasite Toxoplasma gondii belong to three distinct clonal lineages, type I, type II, and type III, which differ in virulence. Understanding the basis of Toxoplasma strain differences and how secreted effectors work to achieve chronic infection is a major goal of current research. Here we show that type I and III infected macrophages, a cell type required for host immunity to Toxoplasma, are alternatively activated, while type II infected macrophages are classically activated. The Toxoplasma rhoptry kinase ROP16, which activates STAT6, is responsible for alternative activation. The Toxoplasma dense granule protein GRA15, which activates NF-kappaB, promotes classical activation by type II parasites. These effectors antagonistically regulate many of the same genes, and mice infected with type II parasites expressing type I ROP16 are protected against Toxoplasma-induced ileitis. Thus, polymorphisms in determinants that modulate macrophage activation influence the ability of Toxoplasma to establish a chronic infection. PMID- 21669397 TI - The TRIM family protein KAP1 inhibits HIV-1 integration. AB - The integration of viral cDNA into the host genome is a critical step in the life cycle of HIV-1. This step is catalyzed by integrase (IN), a viral enzyme that is positively regulated by acetylation via the cellular histone acetyl transferase (HAT) p300. To investigate the relevance of IN acetylation, we searched for cellular proteins that selectively bind acetylated IN and identified KAP1, a protein belonging to the TRIM family of antiviral proteins. KAP1 binds acetylated IN and induces its deacetylation through the formation of a protein complex which includes the deacetylase HDAC1. Modulation of intracellular KAP1 levels in different cell types including T cells, the primary HIV-1 target, revealed that KAP1 curtails viral infectivity by selectively affecting HIV-1 integration. This study identifies KAP1 as a cellular factor restricting HIV-1 infection and underscores the relevance of IN acetylation as a crucial step in the viral infectious cycle. PMID- 21669398 TI - Viral infection augments Nod1/2 signaling to potentiate lethality associated with secondary bacterial infections. AB - Secondary bacterial infection is a common sequela to viral infection and is associated with increased lethality and morbidity. However, the underlying mechanisms remain poorly understood. We show that the TLR3/MDA5 agonist poly I:C or viral infection dramatically augments signaling via the NLRs Nod1 and Nod2 and enhances the production of proinflammatory cytokines. Enhanced Nod1 and Nod2 signaling by poly I:C required the TLR3/MDA5 adaptors TRIF and IPS-1 and was mediated by type I IFNs. Mechanistically, poly I:C or IFN-beta induced the expression of Nod1, Nod2, and the Nod-signaling adaptor Rip2. Systemic administration of poly I:C or IFN-beta or infection with murine norovirus-1 promoted inflammation and lethality in mice superinfected with E. coli, which was independent of bacterial burden but attenuated in the absence of Nod1/Nod2 or Rip2. Thus, crosstalk between type I IFNs and Nod1/Nod2 signaling promotes bacterial recognition, but induces harmful effects in the virally infected host. PMID- 21669399 TI - ATP-mediated Erk1/2 activation stimulates bacterial capture by filopodia, which precedes Shigella invasion of epithelial cells. AB - Shigella, the causative agent of bacillary dysentery in humans, invades epithelial cells, using a type III secretory system (T3SS) to inject bacterial effectors into host cells and remodel the actin cytoskeleton. ATP released through connexin hemichanels on the epithelial membrane stimulates Shigella invasion and dissemination in epithelial cells. Here, we show that prior to contact with the cell body, Shigella is captured by nanometer-thin micropodial extensions (NMEs) at a distance from the cell surface, in a process involving the T3SS tip complex proteins and stimulated by ATP- and connexin-mediated signaling. Upon bacterial contact, NMEs retract, bringing bacteria in contact with the cell body, where invasion occurs. ATP stimulates Erk1/2 activation, which controls actin retrograde flow in NMEs and their retraction. These findings reveal previously unappreciated facets of interaction of an invasive bacterium with host cells and a prominent role for Erk1/2 in the control of filopodial dynamics. PMID- 21669400 TI - Serine phosphorylation of cortactin controls focal adhesion kinase activity and cell scattering induced by Helicobacter pylori. AB - Cell migration and invasion require the coordinated regulation of cytoskeletal architectural changes by signaling factors, including the actin-binding protein cortactin. Bacterial and viral pathogens subvert these signaling factors to promote their uptake, spread and dissemination. We show that the gastric pathogen Helicobacter pylori (Hp) targets cortactin by two independent processes leading to its tyrosine dephosphorylation and serine phosphorylation to regulate cell scattering and elongation. The phosphorylation status of cortactin dictates its subcellular localization and signaling partners. Upon infection, cortactin was found to interact with and stimulate the kinase activity of focal adhesion kinase (FAK). This interaction required the SH3 domain and phosphorylation of cortactin at serine 405 and a proline-rich sequence in FAK. Using Hp as a model, this study unravels a previously unrecognized FAK activation pathway. We propose that Hp targets cortactin to protect the gastric epithelium from excessive cell lifting and ensure sustained infection in the stomach. PMID- 21669401 TI - Industrial wastes as low-cost potential adsorbents for the treatment of wastewater laden with heavy metals. AB - Industrial wastes, such as, fly ash, blast furnace slag and sludge, black liquor lignin, red mud, and waste slurry, etc. are currently being investigated as potential adsorbents for the removal of the heavy metals from wastewater. It was found that modified industrial wastes showed higher adsorption capacity. The application of low-cost adsorbents obtained from the industrial wastes as a replacement for costly conventional methods of removing heavy metal ions from wastewater has been reviewed. The adsorption mechanism, influencing factors, favorable conditions, and competitive ions etc. on the adsorption of heavy metals have also been discussed in this article. From the review, it is evident that certain industrial waste materials have demonstrated high removal capacities for the heavy metals laden with wastewater. However, it is to be mentioned that adsorption capacities of the adsorbents vary depending on the characteristics of the adsorbents, the extent of chemical modification and the concentration of adsorbates. There are also few issues and drawbacks on the utilization of industrial wastes as low-cost adsorbents that have been addressed. In order to find out the practical utilization of industrial waste as low-cost adsorbents on the commercial scale, more research should be conducted in this direction. PMID- 21669402 TI - Foveal microstructure on spectral-domain optical coherence tomographic images and visual function after macular hole surgery. AB - PURPOSE: To determine the correlation between the recovery of foveal microstructure and the visual acuity or the foveal sensitivity after idiopathic macular hole (MH) closure. DESIGN: Prospective, consecutive, observational case series. METHODS: We studied 43 eyes of 43 patients before and 1, 3, and 6 months after MH surgery. The best-corrected visual acuity (BCVA), the foveal sensitivity measured by MP1 microperimetry, and the photoreceptor inner and outer segment (IS/OS) junction and the external limiting membrane (ELM) determined by spectral domain optical coherence tomography were investigated. RESULTS: Preoperatively, the lengths of the IS/OS junction defect and the ELM defect were significantly correlated with only the foveal sensitivity (P<.0001). At all postoperative times, the lengths of both the IS/OS and ELM defects were significantly correlated with both the BCVA and the foveal sensitivity (P<.05 for all). The preoperative lengths of both the IS/OS and ELM defects were significantly correlated with the foveal sensitivity at 6 months after surgery (P=.0022, P=.0031, respectively). The IS/OS junction defect was significantly correlated with the ELM defect at all times (P<.0001 for all). No restoration of the IS/OS junction was observed in eyes without the ELM restoration. CONCLUSIONS: The restoration of the ELM is closely associated with that of the IS/OS junction. The preoperative IS/OS or ELM defect was associated with the postoperative foveal sensitivity. The restoration of not only the IS/OS junction but also the ELM may reflect the morphologic and functional recovery of the foveal photoreceptors in surgically closed MHs. PMID- 21669403 TI - Characteristics of intranasal structures for endonasal dacryocystorhinostomy in asians. AB - PURPOSE: To describe the anatomic characteristics of structures adjacent to the lacrimal sac fossa and the standardized osteotomy method for endonasal dacryocystorhinostomy in Asians. DESIGN: Retrospective noncomparative observational case series study. MATERIALS AND METHODS: One hundred fifty-two eyes of 76 patients who had normal orbit computed tomographic scans were enrolled. The relationships of the uncinate process, the operculum of the middle turbinate, and the agger nasi cell to the lacrimal sac fossa were analyzed. Bone thickness and proportion of the frontal process of the maxilla in the lacrimal sac fossa was also evaluated. RESULTS: The uncinate process was attached to the lacrimal sac fossa in 152 cases (100%) at the lower level of the fossa. The operculum of the middle turbinate was attached to the lacrimal sac fossa in 142 cases (93.4%), with wide positional variation. The agger nasi cell was adjacent to the lacrimal sac fossa in 118 cases (77.6%). The descent of the operculum of the middle turbinate relative to the lacrimal fossa had a strong correlation with the descent of the agger nasi cell (P < .001). The height and length of the nasal bone had a significant negative correlation with the thickness of the frontal process of the maxillary bone (P < .001). CONCLUSION: The uncinate process, operculum of the middle turbinate, and agger nasi cell should be removed for sufficient osteotomy in a significant portion of Asian patients during dacryocystorhinostomy. A thick frontal process of the maxilla can be anticipated for the patient with a low nasal bridge. Further studies on the variation in intranasal procedures and the success rate of endonasal dacryocystorhinostomy need to be established. PMID- 21669404 TI - Implication of CD21, CD35, and CD55 in the pathogenesis of age-related macular degeneration. AB - PURPOSE: To determine a possible implication of CD21, CD35, and CD55 in the pathogenesis of age-related macular degeneration (AMD) by assessing the difference in expression rates of these factors on AMD patients and a control group. DESIGN: Case-control study. METHODS: Fifty unrelated AMD patients and 48 unrelated sex- and age-matched control subjects participated in this case-control study. Samples of fresh EDTA-blood were stained and flow cytometry was chosen to measure fluorescence emissions. The association between exudative AMD and CD21, CD35, and CD55 was evaluated from all patients who completed the study. RESULTS: Our study shows CD35 to be expressed in a significantly higher frequency in AMD patients on monocytes (P = .00586), lymphocytes (P = .000605), and granulocytes (P < .000033). In contrast, the expression rate of CD21 (P > .05) and CD55 (P > .05) are similar in both groups. CONCLUSION: More regulative factors of the complement system are involved in pathogenesis of AMD. Our study underlines the key role of the complement system in AMD and shows the involvement of the whole immune system through more regulative factors. PMID- 21669405 TI - Strabismus precipitated by monovision. AB - PURPOSE: To present patients who had the onset of strabismus or the recurrence of strabismus after converting to a monovision system of seeing. DESIGN: Retrospective interventional case series. METHODS: Clinical records of 12 patients from the private practice of the corresponding author of this paper (Z.F.P.) were reviewed. Patients obtaining monovision via contact lenses, LASIK, and cataract surgery with posterior chamber intraocular lenses were studied if their monovision produced a new strabismus or was related to the recurrence of a previous strabismus. RESULTS: All patients were first treated by converting the monofixing near eye to distance vision and then using reading glasses for near work. Of the 12 patients, 7 regained their fusion by doing away with monovision and 5 required surgery to reestablish motor or sensory control. All of the surgery patients obtained an excellent alignment but 1 did not regain sensory fusion. CONCLUSION: Monovision is successful for the far majority of patients who try it. However, in patients with a previous history of strabismus or those with significant phorias, caution should be used in recommending monovision, and if monovision is elected, keeping the anisometropia to small levels such as 1.25 to 1.50 diopters (D) might lessen the chance of producing strabismus post monovision. The majority of our patients developed strabismus after 2 years of monovision, telling us that while a trial of monovision with a contact lens prior to surgery may suggest that the patient could tolerate monovision, it is not a guarantee. PMID- 21669406 TI - Hypothyroidism attenuates SCH 23390-mediated depression of breathing and decreases D1 receptor expression in carotid bodies, PVN and striatum of hamsters. AB - Hypothyroidism can lead to depressed breathing. We determined if propylthiouracil (PTU)-induced hypothyroidismin hamsters (HH) altered dopamine D1 receptor expression, D1 receptor-modulated ventilation, and ventilatory chemoreflex activation by hypoxia or hypercapnia. Hypothyroidism was induced by administering 0.04% PTU in drinking water for 3 months. Ventilation was evaluated following saline or 0.25mg/kg SCH 23390,a D1 receptor antagonist, while awake hamsters breathed normoxic (21% O(2) in N(2)), hypoxic (10% O(2)in N(2)) and hypercapnic (5% CO(2) in O(2))air. Relative to euthyroid hamsters (EH), HH exhibited decreased D1 receptor protein levels in carotid bodies, striatum, and hypothalamic paraventricular nucleus, but not in the nucleus tractus solitarius. Relative to EH, HH exhibited lower ventilation during exposure to normoxia, hypoxia, or hypercapnia, but comparable ventilatory responsiveness to chemoreflex activation. SCH23390 decreased ventilation of EH hamsters exposed to normoxia, hypoxia, and hypercapnia. In HH SCH23390 increased ventilation during baseline normoxia and did not affect ventilation during exposure to hypoxia and hypercapnia, resulting in reduced ventilatory responsivess to chemoreflex activation by hypoxia and hypercapnia. Furthermore, in HH D1 receptor protein levels are decreased in several brain regions and within the carotid bodies. Moreover, D1 receptor-modulation of breathing at rest and during gas exposures were depressed in EH but not HH. PMID- 21669407 TI - Distinct resting-state brain activities in heroin-dependent individuals. AB - Previous functional imaging studies on heroin addicts have focused on abnormal brain functions based on specific tasks, while few fMRI studies concentrated on the resting-state abnormalities of heroin-dependent individuals. In the current study, we applied the pattern classification technique, which employs the feature extraction method of non-negative matrix factorization (NMF) and a support vector machine (SVM) classifier. Its main purpose was to characterize the discrepancy in activation patterns between heroin-dependent individuals and healthy subjects during the resting state. The results displayed a high accuracy in the activation pattern differences of the two groups, which included the orbitofrontal cortex (OFC), cingulate gyrus, frontal and para-limbic regions such as the anterior cingulate cortex (ACC), hippocampal/parahippocampal region, amygdala, caudate, putamen, as well as the posterior insula and thalamus. These findings indicate that significant biomarkers exist among the network of circuits that are involved in drug abuse. The implications from our study may help explain the behavioral and neuropsychological deficits in heroin-dependent individuals and shed light on the mechanisms underlying heroin addiction. PMID- 21669409 TI - Interaction and representational integration: evidence from speech errors. AB - We examine the mechanisms that support interaction between lexical, phonological and phonetic processes during language production. Studies of the phonetics of speech errors have provided evidence that partially activated lexical and phonological representations influence phonetic processing. We examine how these interactive effects are modulated by lexical frequency. Previous research has demonstrated that during lexical access, the processing of high frequency words is facilitated; in contrast, during phonetic encoding, the properties of low frequency words are enhanced. These contrasting effects provide the opportunity to distinguish two theoretical perspectives on how interaction between processing levels can be increased. A theory in which cascading activation is used to increase interaction predicts that the facilitation of high frequency words will enhance their influence on the phonetic properties of speech errors. Alternatively, if interaction is increased by integrating levels of representation, the phonetics of speech errors will reflect the retrieval of enhanced phonetic properties for low frequency words. Utilizing a novel statistical analysis method, we show that in experimentally induced speech errors low lexical frequency targets and outcomes exhibit enhanced phonetic processing. We sketch an interactive model of lexical, phonological and phonetic processing that accounts for the conflicting effects of lexical frequency on lexical access and phonetic processing. PMID- 21669408 TI - Anterior and posterior cingulate cortex volume in healthy adults: effects of aging and gender differences. AB - The cingulate cortex frequently shows gray matter loss with age as well as gender differences in structure and function, but little is known about whether individual cingulate Brodmann areas show gender-specific patterns of age-related volume decline. This study examined age-related changes, gender differences, and the interaction of age and gender in the relative volume of cingulate gray matter in areas 25, 24, 31, 23, and 29, over seven decades of adulthood. Participants included healthy, age-matched men and women, aged 20-87 (n=70). Main findings were as follows: (1) The whole cingulate showed significant age-related volume declines (averaging 5.54% decline between decades, 20s-80s). Each of the five cingulate areas also showed a significant decline with age, and individual areas showed different patterns of decline across the decades: Smaller volume with age was most evident in area 31, followed by 25 and 24. (2) Women had relatively larger cingulate gray matter volume than men overall and in area 24. (3) Men and women showed different patterns of age-related volume decline in area 31, at midlife and late in life. By delineating normal gender differences and age related morphometric changes in the cingulate cortex over seven decades of adulthood, this study improves the baseline for comparison with structural irregularities in the cingulate cortex associated with psychopathology. The Brodmann area-based approach also facilitates comparisons across studies that aim to draw inferences between age- and gender-related structural differences in the cingulate gyrus and corresponding differences in cingulate function. PMID- 21669410 TI - Abnormal expression of growth differentiation factor 9 and bone morphogenetic protein 15 in stimulated oocytes during maturation from women with polycystic ovary syndrome. AB - OBJECTIVE: To investigate the expression pattern of two oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BM15) during oocyte maturation in women with polycystic ovary syndrome (PCOS) and in controls and to evaluate the expression differences in oocytes between the two groups. DESIGN: Case-control study. SETTING: University-affiliated hospital. PATIENT(S): Twenty-five oocytes were obtained from 12 patients with PCOS and 82 oocytes from 56 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The abundance of GDF9 and BMP15 mRNA in oocytes of the germinal vesicle (GV), metaphase I (MI), and MII stage. RESULT(S): The expression of GDF9 and BMP15 mRNA displayed dynamic changes during oocyte maturation in controls after ovarian stimulation, with a decline at the MI stage and an increase to the peak at the MII stage. However, their expression in oocytes from patients with PCOS demonstrated a reduced state without any dynamic change. CONCLUSION(S): The results suggest that the expression of GDF9 and BMP15 in oocytes from patients with PCOS cannot reach the normal level even after ovarian stimulation and that the expression pattern is abnormal during oocyte maturation, which may be associated with impaired oocyte quality and developmental competence in PCOS. PMID- 21669412 TI - To add GnRH antagonists to controlled ovarian stimulation in management of subfertile couples with IUI may not have additional effect in terms of clinical pregnancy rates. PMID- 21669414 TI - Outcome of cycles of oocyte in vitro maturation requiring testicular sperm extraction for nonobstructive azoospermia. AB - OBJECTIVE: To assess the applicability of oocyte IVM in case of nonobstructive azoospermia (NOA). DESIGN: Case series. SETTING: Private IVF unit. PATIENT(S): All male partners were affected by NOA. Twenty-one women (20 normo-ovulatory and 1 with polycystic ovary) underwent 27 IVM treatments. The outcome of controlled ovarian stimulation (COS) cycles in normo-ovulatory women whose partners were affected by NOA was assessed for comparison. INTERVENTION(S): Spermatozoa from testicular sperm extraction (TESE) samples were retrieved and cryopreserved before treatment. MAIN OUTCOME MEASURE(S): Rates of fertilization, pregnancy per cycle and transfer, and implantation. RESULT(S): Twenty-seven IVM-TESE cycles were carried out in 21 women. Fertilization rate was 64.4%. In compliance with national legislation, no more than three oocytes were inseminated in each cycle and all developing embryos were transferred. Six single clinical pregnancies were ascertained (22.2% and 27.3% pregnancy rates per cycle and per transfer, respectively). One pregnancy ended in abortion. The others developed to term and gave rise to five healthy babies. Sixty couples underwent standard COS-TESE treatment. Rates of fertilization, clinical pregnancy per cycle, implantation, and abortion were 64.6%, 20.0%, 11.3%, and 16.7%, respectively. Eleven babies were born from ten pregnancies. CONCLUSION(S): Oocyte IVM may represent an option in NOA cases. PMID- 21669413 TI - Role of tissue digestion and extensive sperm search after microdissection testicular sperm extraction. AB - OBJECTIVE: To report the chance of sperm discovery in the laboratory when sperm were not identified in the operating room (OR). DESIGN: Clinical retrospective study. SETTING: Department of urology at a tertiary university hospital. PATIENT(S): A total of 1,054 men with nonobstructive azoospermia who underwent microdissection testicular sperm extraction. INTERVENTION(S): Preoperative and intraoperative parameters were analyzed relative to the chance of sperm identification using a tissue digestion protocol in the laboratory if no sperm were observed in the OR. MAIN OUTCOME MEASURE(S): Sperm retrieval, clinical pregnancy, and live birth rates. RESULT(S): Sperm were found in the OR in 52.5% of the 1,054 men. Of the 501 men for whom sperm were not identified by andrologists in the OR, sperm were found in the laboratory for an additional 35 (7%). On multivariable logistic regression analysis, the presence of germ cells intraoperatively was the only predictor of identifying sperm in the laboratory after tissue digestion. CONCLUSION(S): In men undergoing microdissection testicular sperm extraction, when sperm were not observed in the OR despite extensive mechanical processing, sperm were observed in the laboratory for 7% of the men. This information is valuable in counseling couples in the immediate postoperative period when no sperm were identified intraoperatively. PMID- 21669415 TI - Resectoscopic treatment of ectopic pregnancy in previous cesarean delivery scar defect with vasopressin injection. AB - OBJECTIVE: To describe resectoscopic treatment with vasopressin injection as an effective surgical intervention for ectopic pregnancy in previous cesarean delivery scar (PCDS) defect. DESIGN: Case report. SETTING: University hospital. PATIENT(S): Two women with ectopic pregnancy in PCDS defect. INTERVENTION(S): The patients underwent transvaginal ultrasound examination, followed by operative hysteroscopy with vasopressin injection for evacuating the ectopic pregnancy in PCDS defect. MAIN OUTCOME MEASURE(S): Conservation of the uterus. RESULT(S): Successful resectoscopic treatment of ectopic pregnancy in PCDS defect. CONCLUSION(S): Resectoscopic treatment of ectopic pregnancy in PCDS defect is a safe and efficient technique that has the advantage of a rapid return to normal levels of beta-hCG. Intracervical vasopressin administration could decrease intraoperative bleeding and provide a clear view during the operation. PMID- 21669416 TI - Changes in the management and outcome of central nervous system involvement from ovarian cancer since 1994. AB - OBJECTIVE: To identify differences in the management and outcome of patients with central nervous system metastases from epithelial ovarian cancer. METHODS: The clinical and pathologic characteristics, treatment, and outcome of 23 patients with brain metastases from epithelial ovarian cancer who were treated during 1982 1994 were compared with those of 20 patients treated during 1995-2010 at the same center. RESULTS: No differences were found in terms of primary tumor characteristics, time interval from ovarian cancer diagnosis to brain involvement diagnosis, sites of metastasis, and presence of extracranial disease. The main difference between the 2 groups was the therapeutic approach. During 1982-1994, most patients received radiotherapy only, whereas most patients during 1995-2010 underwent surgical resection followed by radiotherapy and/or chemotherapy. The duration of survival during 1982-1994 was 5 months, which was significantly shorter than the duration of survival (18 months) during 1995-2010. CONCLUSION: An aggressive multimodal treatment approach might prolong the survival of patients with brain involvement from ovarian cancer. PMID- 21669417 TI - Comparison of quality-of-life changes in patients with stress urinary incontinence after midurethral sling placement. AB - OBJECTIVE: To compare changes in quality of life for women undergoing either suprapubic or transvaginal midurethral sling placement for stress urinary incontinence (SUI). METHODS: A retrospective cohort study was conducted involving 113 patients who underwent transvaginal or suprapubic midurethral sling placement for SUI over 2 years at a US institution. All patients completed a short form of the urogenital distress inventory (UDI-6) questionnaire preoperatively and postoperatively. Preoperative and postoperative UDI-6 scores were compared between the 2 groups. Data were analyzed using the Mann-Whitney U test and the Fisher exact test. RESULTS: A midurethral sling was placed using the suprapubic approach in 70 patients, and 43 patients underwent the procedure using the transvaginal approach. Preoperatively, there was no statistical difference between mean UDI-6 scores for the suprapubic versus the transvaginal group (48.5 versus 51.0 P = 0.9). Postoperatively, patients who underwent a suprapubic procedure had significantly lower mean UDI-6 scores than those who underwent a transvaginal procedure (10.6 versus 17.0; P < 0.005). CONCLUSION: Suprapubic midurethral sling placement was associated with a significantly greater quality of life postoperatively compared with the transvaginal procedure. PMID- 21669418 TI - Pregnancy outcomes after surgical treatment of ovarian pregnancy. AB - OBJECTIVE: To investigate pregnancy outcomes subsequent to ovarian pregnancy treated by surgery. METHODS: A retrospective analysis was conducted of ovarian pregnancies that were treated by surgery at a hospital in Korea between January 1996 and December 2009. RESULTS: Forty-nine women with ovarian pregnancies (1.6% of all ectopic pregnancies) were treated; 28 of these patients who were followed up for more than a year were included in the study. The most common risk factor for ovarian pregnancy was endometriosis (42.9%). Accurate diagnosis of ovarian pregnancy was made preoperatively in 7 patients (25%). Of the 28 patients, 16 (57.1%) had subsequent pregnancies: 13 (46.4%) were intrauterine pregnancies and 3 (10.7%) were tubal pregnancies. However, no subsequent ovarian pregnancies occurred. In addition, only 1 patient had secondary infertility after surgery for ovarian pregnancy. CONCLUSIONS: After an ovarian pregnancy treated by surgery, the outcome of a subsequent pregnancy is reasonable; there is a high rate of successful subsequent pregnancy and a low rate of subsequent ectopic pregnancy or of infertility. PMID- 21669419 TI - Antifungal efficacy of propolis against fluconazole-resistant Candida glabrata isolates obtained from women with recurrent vulvovaginal candidiasis. PMID- 21669420 TI - Condom nonuse among female sex workers in Chennai, India. PMID- 21669421 TI - Human papillomavirus genotype distribution among French women with and without cervical abnormalities. AB - OBJECTIVE: To assess human papillomavirus (HPV) prevalence and distribution among French women with normal and pathologic cytology findings. METHODS: A genomic DNA microarray assay enabling the detection of 35 different HPV genotypes was used for in vitro diagnosis, as a complement to Papanicolaou screening, to test 785 women who attended the gynecology department of a hospital in Lyon, France. RESULTS: Pathologic and normal cytology findings were obtained for 260 (33.1%) and 302 (38.5%) of the 785 women, respectively, whereas 223 (28.4%) results were inconclusive. HPV infection and multiple infection were significantly more prevalent (P<0.001) in the population with pathologic findings (90.0% and 41.9%, respectively) than in the population with normal cytology findings (48.3% and 20.2%, respectively). Overall, the 4 most frequent HPV genotypes were HPV-16 (14.8%), HPV-53 (9.0%), HPV-31 (8.7%), and HPV-51 (7.5%), whereas HPV-18 (3.8%), HPV-6 (2.9%), and HPV-11 (0.4%) were less common. The HPV genotypes included in the quadrivalent vaccination had a prevalence of 20.6% among all women and 30.4% among those with pathologic findings. CONCLUSION: The present data indicate a reduced direct impact of HPV vaccination in the study population owing to a low prevalence of HPV-18 and a high prevalence of HPV-53, HPV-31, and HPV-51. PMID- 21669422 TI - Cervical and vaginal cancer in a woman with chronic graft-versus-host disease. PMID- 21669424 TI - Treatment of recurrent vaginal eversion after previous Le Fort colpocleisis. PMID- 21669423 TI - Invasive vulvar carcinoma and the question of the surgical margin. AB - OBJECTIVE: To assess the discrepancy between width of surgical margin measured with the naked eye/ruler by a surgeon before removing an invasive vulvar carcinoma, and width of margin measured under microscope by pathologist after fixation of the resected lesion with formalin. Potential relationships between discrepancy and disease recurrence were also investigated. METHODS: This prospective study was conducted with resected lesions from 86 women who underwent surgery for primary/recurrent invasive vulvar carcinoma. After the surgeon removed the lesions surrounded by 1-2-cm margins, the pathologist determined margin width at the 4 cardinal points of 86 lesions (for a total of 344 margin assessments), first macroscopically and then under the microscope. RESULTS: A safety margin of 0.8 cm on microscopic view was achieved in 83% of cases (112 of 135) when the macroscopic measurement was 1cm, in 91% of cases (58 of 64) when it was 1.5 cm, and 98% of cases (105 of 107) when it was 2 cm. CONCLUSION: There was a small discrepancy between the surgeon's intent and the microscopic margin measurement, mostly related to tissue shrinkage. A 1-cm surgical margin corresponded to a 0.8-cm margin in microscopic view (the "safe margin") in most cases. PMID- 21669425 TI - IPA, ICM, and FIGO joint statement on breastfeeding, including breastfeeding by HIV-infected mothers. PMID- 21669426 TI - Combined contraceptive ring versus combined oral contraceptive (30-MUg ethinylestradiol and 3-mg drospirenone). AB - OBJECTIVES: To compare the adverse effects, cycle control, and metabolic effects of NuvaRing and a combined oral contraceptive (COC). METHODS: Women seeking contraception received NuvaRing (n = 300) or a COC (n = 300) for 12 cycles in a randomized, open-label trial. RESULTS: The total number of women with adverse effects did not differ significantly between the 2 groups. Leucorrhea, vaginitis, decreased libido, and ring-related problems were more common with NuvaRing, whereas weight increase, acne, and emotional lability were more common with the COC. Breakthrough bleeding occurred in 11.3% of women receiving NuvaRing and in 14.7% of women receiving the COC; 2.1% and 2.9% of women, respectively, had no withdrawal bleeding. Differences in blood pressure, blood sugar levels, lipid profile, liver enzyme activity, and anticoagulant activity were not statistically significant, with the exception of low-density lipoprotein levels measured at 6 and 12 months, which were significantly lower in the NuvaRing group than in the COC group. CONCLUSIONS: NuvaRing is a good alternative to a COC. It is associated with a slightly reduced incidence of breakthrough bleeding and there were no clinically relevant adverse effects or changes in blood pressure, blood sugar levels, lipid profile, or anticoagulant activity when compared with the COC. PMID- 21669427 TI - Availability and distribution of, and geographic access to emergency obstetric care in Zambia. AB - OBJECTIVE: To assess the availability and coverage of emergency obstetric care (EmOC) services in Zambia. METHODS: Reported provision of EmOC signal functions in the Zambian Health Facility Census and additional criteria on staffing, opening hours, and referral capacity were used to classify all Zambian health facilities as providing comprehensive EmOC, basic EmOC, or more limited care. Geographic accessibility of EmOC services was estimated by linking health facility data with data from the Zambian population census. RESULTS: Few Zambian health facilities provided all basic EmOC signal functions and had qualified health professionals available on a 24-hour basis. Of the 1131 Zambian delivery facilities, 135 (12%) were classified as providing EmOC. Zambia nearly met the UN EmOC density benchmarks nationally, but EmOC facilities and health professionals were unevenly distributed between provinces. Geographic access to EmOC services in rural areas was low; in most provinces, less than 25% of the population lived within 15 km of an EmOC facility. CONCLUSION: A national Health Facility Census with geographic information is a valuable tool for assessing service availability and coverage at national and subnational levels. Simultaneously assessing health worker density and geographic access adds crucial information. PMID- 21669428 TI - Assessing women's willingness to collect their own cervical samples for HPV testing as part of the ASPIRE cervical cancer screening project in Uganda. AB - OBJECTIVE: To assess women's willingness to collect their own samples for HPV testing as the first part of a screening program for cervical cancer in Uganda. METHODS: In March and April 2010, trained assistants from Kisenyi interviewed 300 women aged 30 to 65 years who lived and/or worked in this community. Descriptive data and multivariate modeling were used to identify the predictors of the women's willingness to collect their own cervical samples. RESULTS: More than 80% of the 300 participants were willing to collect their own samples. In multivariate modeling, factors positively associated with this willingness were agreement to let outreach workers deliver the necessary swab at their homes (adjusted odds ratio [AOR], 4.10; 95% confidence interval [CI], 1.83-9.18) and willingness to undergo a pelvic examination if the sample was abnormal (AOR, 3.91; 95% CI,1.03-14.90). Factors negatively associated were embarrassment at collecting the sample at home where they lacked privacy (AOR, 0.09; 95% CI, 0.03 0.29) and concern of not collecting the sample properly (AOR, 0.1; 95% CI, 0.05 0.3). CONCLUSION: Self-collection is an option in impoverished settings in Africa. To improve acceptability, women should be taught how to properly collect their own cervical sample and encouraged to find ways to make the collection less embarrassing. PMID- 21669429 TI - Effects of the Kampo medication keishibukuryogan on blood pressure in perimenopausal and postmenopausal women. AB - OBJECTIVE: To examine the effects of keishibukuryogan (TJ-25)-a medicine of the Kampo tradition (the Japanese adaptation of Chinese herbal medicine)-on middle aged women with high blood pressure. METHODS: The records of 77 peri- and postmenopausal women with high-normal blood pressure or hypertension were analyzed retrospectively. The women had participated in the Systematic Health and Nutrition Education Program at the Tokyo Medical and Dental University in Tokyo, Japan, and had received education only (controls; n = 47) or education and treatment with TJ-25 (n = 30). RESULTS: The baseline characteristics of the 2 groups were comparable. After approximately 6 months, women in the TJ-25 group showed significant reductions in their systolic blood pressure (from 148.4mm Hg to 134.8mm Hg), diastolic blood pressure (from 89.7 mm Hg to 83.7 mm Hg), pulse rate (from 79.5 beats/min to 73.5 beats/min), and resting energy expenditure (from 1552 kcal/day to 1373 kcal/day). Several menopausal symptoms including perspiration, difficulty in initiating sleep, nonrestorative sleep, and headaches/dizziness were also improved. In addition, women in the TJ-25 group had increased health-related quality of life scores in the domains of physical health and life satisfaction. CONCLUSION: TJ-25 alleviates menopausal symptoms and concurrently lowers the blood pressure of middle-aged women with high blood pressure. PMID- 21669430 TI - Chemical neurolysis of the superior hypogastric plexus for chronic non-cancer pelvic pain. PMID- 21669431 TI - Vaginal support as determined by levator ani defect status 6 weeks after primary surgery for pelvic organ prolapse. AB - OBJECTIVE: To evaluate whether major levator ani muscle defects were associated with differences in postoperative vaginal support after primary surgery for pelvic organ prolapse (POP). METHODS: A retrospective chart review of a subgroup of patients in the Organ Prolapse and Levator (OPAL) study. Of the 247 women recruited into OPAL, 107 underwent surgery for prolapse and were the cohort for the present analysis. Major levator ani defects were diagnosed when more than 50% of the pubovisceral muscle was missing on MRI. Postoperative vaginal support was assessed via POP-quantification system. Postoperative anatomic outcome was analyzed according to levator ani defect status, as determined by MRI. RESULTS: Support of the anterior vaginal wall 2 cm above the hymen occurred among 62% of women with normal levator ani muscles/minor defects and 35% of those with major defects. Support of the anterior wall 1cm above the hymen occurred among 32% women with normal muscles /minor defects and 59% of those with major defects. Levator ani defects were not associated with differences in postoperative apical/posterior vaginal support. CONCLUSION: Six weeks after primary surgery for prolapse, women with normal levator ani muscles/minor defects had better anterior vaginal support than those with major levator defects. PMID- 21669432 TI - Evaluation of a caregiver education program to support memory and communication in dementia: a controlled pretest-posttest study with nursing home staff. AB - BACKGROUND: There is a need for simple multimedia training programs designed to upskill the dementia care workforce. A DVD-based training program entitled RECAPS and MESSAGE has been designed to provide caregivers with strategies to support memory and communication in people with dementia. OBJECTIVES: The aims of this study were: (1) to evaluate the effects of the RECAPS and MESSAGE training on knowledge of support strategies, and caregiver satisfaction, in nursing home care staff, and (2) to evaluate staff opinion of the training. DESIGN: A multi-centre controlled pretest-posttest trial was conducted between June 2009 and January 2010, with baseline, immediately post-training and 3-month follow-up assessment. SETTING: Four nursing homes in Queensland, Australia. PARTICIPANTS: All care staff were invited to participate. Of the 68 participants who entered the study, 52 (37 training participants and 15 controls) completed outcome measures at baseline and 3-month follow-up. 63.5% of participants were nursing assistants, 25% were qualified nurses and 11.5% were recreational/activities officers. METHODS: The training and control groups were compared on the following outcomes: (1) knowledge of memory and communication support strategies, and (2) caregiver satisfaction. In the training group, the immediate effects of training on knowledge, and the effects of role (nurse, nursing assistant, recreational staff) on both outcome measures, were also examined. Staff opinion of the training was assessed immediately post-training and at 3-month follow-up. RESULTS: The training group showed a significant improvement in knowledge of support strategies from baseline to immediately post-training (p=0.001). Comparison of the training and control groups revealed a significant increase in knowledge for the training group (p=0.011), but not for the control group (p=0.33), between baseline and 3-month follow-up. Examination of caregiver satisfaction by care staff role in the training group revealed that only the qualified nurses showed higher levels of caregiver satisfaction at 3-month follow-up (p=0.013). Staff rated the training positively both for usefulness and applicability. CONCLUSION: The RECAPS and MESSAGE training improved nursing home care staff's knowledge of support strategies for memory and communication, and gains were maintained at 3 month follow-up. Moreover, the training was well received by staff. PMID- 21669433 TI - The role of documents and documentation in communication failure across the perioperative pathway. A literature review. AB - OBJECTIVE: Communication practices of healthcare professionals have been strongly implicated in the cascade of events that unfold into poor outcomes for surgical patients. The purpose of this paper is to explore the role of documents and documentation in communication failure among healthcare professionals across the perioperative pathway. The perioperative pathway consists of 3 interconnecting, but geographically distinct domains: preoperative, intraoperative and postoperative. DESIGN: A comprehensive search of the literature was undertaken to provide a focused analysis and appraisal of past research. DATA SOURCES: Electronic databases searched included the Cochrane Database of Systematic Reviews, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), Medline and PsycINFO from 1990 to end February 2011. Additionally, references of retrieved articles were manually examined for papers not revealed via electronic searches. REVIEW METHODS: Content analysis was used to draw out major themes and summarise the information. RESULTS: Fifty-nine papers were selected based on their relevance to the topic. The results highlight that documentation such as surgeons' operation notes, anaesthetists' records and nurses' perioperative notes, deficient in the areas of design, quality, accuracy and function, contributed to the development of communication failure among healthcare professionals across the perioperative pathway. The consequences of communication failure attributable to documentation ranged from inefficiency, delays and increased workload, through to serious adverse patient events such as wrong site surgery. Documents that involve the coordination of verbal communication of multidisciplinary surgical teams, such as preoperative checklists, also influenced communication and surgical patient outcomes. CONCLUSIONS: Effective communication among healthcare professionals is vital to the delivery of safe patient care. Multiple documents utilised across the perioperative pathway have a critical role in the communication of information essential to the immediate and ongoing care of surgical patients. Failure in the communicative function of documents and documentation impedes the transfer of information and contributes to the cascade of events that results in compromised patient safety and potentially adverse patient outcomes. PMID- 21669434 TI - Learning from prevented suicide in psychiatric inpatient care: an analysis of data from the National Patient Safety Agency. AB - BACKGROUND: Inpatient suicide is a tragedy, and removal of the means is only a partially effective strategy. OBJECTIVES: To identify the mechanisms by which attempted inpatient suicides are prevented, so that their use can become more widespread. METHOD: Analysis of one year of nationally reported suicide attempts on inpatient psychiatric wards from the National Patient Safety Agency. RESULTS: Patients are discovered in the act by staff checks (medication rounds, meals, routine activities, and intermittent observation) and by staff being caringly vigilant and inquisitive (noticing the absence of patients, their psychological distress, physical state, responding to unusual noises, etc.). CONCLUSIONS: The use of intermittent observation and other patient checks should be increased, and particularly directed to private areas of the ward. All staff should act on any sense of unease or feeling that something about a patient, their behaviour, or noises on the ward, are not right. PMID- 21669435 TI - Triazole-forming waterborne polyurethane composites fabricated with silane coupling agent functionalized nano-silica. AB - In the research work, "click" chemistry was used to modify waterborne polyurethane (WPU) with silane coupling agent (SiCA) functionalized nano-silica. The modified WPU (CWPU) was characterized by FTIR, scanning electron microscope (SEM), thermogravimetric analysis (TGA) and contact angle measurement. The experiment results show that the modification can improve the thermal stability, hardness, and water or weather resistance of CWPU. PMID- 21669436 TI - A proton NMR study on the specific sorption of yttrium(III) and europium(III) on gamma-alumina [gamma-Al2O3]. AB - The specific sorption of Eu(III) and Y(III) on gamma-alumina was investigated with solid-state (1)H NMR. Solution pH was shown to influence the recorded (1)H NMR spectra of gamma-alumina, and thus, metal ion-containing samples were prepared under constant pH conditions, 8.00+/-0.05. The metal ion concentration in the samples was varied between 6.58*10(-7) M - 3.95*10(-4) M in case of Y(3+) and 6.58*10(-8) M - 1.32*10(-4) M in case of Eu(3+). The mineral concentration was kept constant at 4 g/l. After separation of the liquid phase, the samples were dried under vacuum to remove physisorbed water from the mineral surface. However, even after 48 h of drying at 150 degrees C and 20 mTorr, water was still detected in the proton spectra as two distinct peaks with chemical shifts at 1.3 and 0.9 ppm. The europium addition to the gamma-alumina samples induced significant spectral changes in comparison with yttrium-containing samples. These changes were attributed to the paramagnetism of europium rather than to complexation reactions occurring on the mineral surface. Proton spectra obtained for yttrium samples were therefore used to detect the spectral changes induced by the sorption reaction itself. The results revealed a large distribution of protons being removed from the mineral surface upon yttrium complexation. Removed protons were assigned to both bridging surface hydroxyls such as (Al(VI))(2)-OH as well as to terminal hydroxyls, e.g., of type Al(VI)-OH. Acidic protons belonging to (Al(VI))(3)-OH groups were not observed to participate in the surface reaction. PMID- 21669437 TI - Effect of structural isomerism and polymer end group on the pH-stability of hydrogen-bonded multilayers. AB - Association of tannic acid (TA) with structurally isomeric poly(N isopropylacrylamide) (PNIPAM) and poly(2-isopropyl-2-oxazoline) (PIPOX) has been examined at surfaces to understand the effect of different molecular arrangements in a polymer repeating unit of structural isomers on the construction and pH stability of hydrogen-bonded multilayers. Films were fabricated using layer-by layer (LbL) technique through hydrogen-bonding interactions primarily between carbonyl groups of neutral polymers and hydroxyl groups of TA molecules at pH 2. PIPOX and TA formed thinner and more stable films in the pH scale with a critical dissolution pH of 9 when compared to films of PNIPAM and TA with a critical pH of 8. The differences in the thickness and pH-stability were due to different conformational behavior of PNIPAM and PIPOX in water which affects the accessibility of carbonyl groups for participation in the hydrogen bonding and the number of binding sites between the polymer pairs. Addition of electrostatic interactions by introducing amino groups only at the PIPOX chain end shifted the critical dissolution pH to higher values and resulted in gradual dissolution of the films in a wide pH range of 9-12. Such films hold promise for use in biomedical field due to biocompatibility and lower critical solution temperature (LCST) behavior at near physiological temperature of PNIPAM and PIPOX together with the pH-response of the hydrogen-bonded films. PMID- 21669438 TI - Nanostructured functional co-polymers bioconjugate integrin inhibitors. AB - Synthesis and properties of bioconjugates based on functionalized polymeric nanoparticles (PNs) and monoclonal anti-Integrin alphaV CD51 (aI) antibody were investigated. Polymeric and co-polymeric colloidal nanoparticles with different functionalities, i.e., acid, amine, or thiol, namely poly(methylmethacrylate-co acrylic acid) [P(MMA-co-AA)], poly(methylmethacrylate-co-dimethylpropargylamine) [P(MMA-co-DMPA)], poly(methylmethacrylate-co-allil mercaptane) [P(MMA-co-AM)], were obtained by tailoring emulsion synthesis and fully characterized by means of spectroscopic techniques and scanning electron microscopy (SEM). Bioconjugates (PN/aI) based on P(MMA) or P(MMA-co-AA) were obtained by loading the polymeric nanoparticles with the antibody anti-Integrin with a simple and straightforward immobilization strategy. Bioconjugates qualitative and quantitative loading analyses were carried out by means of polyacrylamide gel electrophoresis 1D-PAGE, MALDI-TOF, and LC/ESI-MS/MS investigations. The biological efficacy of bioconjugates was confirmed by the reduced migration potential of PN/aI-treated human kidney cells (HEK293). The easy immobilization procedure and high immobilization capacity of polymeric nanoparticles together with tuneable chemical functionalities and dimension of the polymeric nanoparticles open applicative perspectives for targeted delivery. PMID- 21669439 TI - Adsorption-stress relationship in drying of silica/PVA suspensions. AB - In this study, we investigated drying process of silica/PVA suspensions. After measuring the amount of polymer adsorption and the stress evolution of a film during drying process, we could find a quantitative relationship between polymer adsorption and stress development, for silica/PVA suspensions of different pH and mixing time. For all the suspensions of different pH, both the amount of polymer adsorption (Gamma) and the plateau stress of dry film (sigma(p)) could be scaled onto a single master curve as a function of mixing time (t(m)). The scaling of mixing time for both Gamma and sigma(p) could be performed by the same scale factor, which implies that there is a one to one correlation between adsorption and stress. This correlation implies that we can control the microstructure and performance of dry film by adjusting the amount of polymer adsorption. The origin of adsorption kinetics of silica/PVA suspension was also discussed in terms of saponification of acetate groups in PVA, which facilitates hydrogen bonding between silica and PVA. PMID- 21669440 TI - Activated carbon fibers with a high content of surface functional groups by phosphoric acid activation of PPTA. AB - Activated carbon fibers (ACFs) were prepared by chemical activation of poly(p phenylene terephthalamide (PPTA) with phosphoric acid, with a particular focus on the effects of impregnation ratio and carbonization temperature on both surface chemistry and porous texture. Thermogravimetric studies of the pyrolysis of PPTA impregnated with different amounts of phosphoric acid indicated that this reagent has a strong influence on the thermal degradation of the polymer, lowering the decomposition temperature and increasing the carbon yield. As concerns surface chemistry, TPD and chemical analysis results indicated that the addition of phosphoric acid increases the concentration of oxygenated surface groups, with a maximum at an impregnation ratio of 100 wt.%. The resulting materials present uncommon properties, namely a large amount of oxygen- and phosphorus-containing surface groups and a high nitrogen content. Porosity development following H(3)PO(4) activation was very significant, with values close to 1700 m(2)/g and 0.80 cm(3)/g being reached for the BET surface area and total pore volume, respectively. The pore size distributions remained confined to the micropore and narrow mesopore (<10 nm) range. PMID- 21669441 TI - Micellisation of triblock copolymers of ethylene oxide and 1,2-butylene oxide: effect of B-block length. AB - We have used pyrene fluorescence spectroscopy and isothermal titration calorimetry (ITC) to investigate the effect of hydrophobic-block length on values of the critical micelle concentration (cmc) for aqueous solutions of triblock poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers (B(n)E(m)B(n), where m and n denote the respective block lengths) with hydrophobic block lengths in the range n=12-21. Combined with results from previous work on B(n)E(m)B(n) copolymers with shorter B blocks, plots of log(10)(cmc) (cmc in molar units and reduced to a common E-block length) against total number of B units (n(t)=n for diblock or n(t)=2n for triblock copolymers) display transitions in the slopes of the two plots, which indicate changes in the micellisation equilibrium. These occur at values of n(t)which can be assigned to the onset and completion of collapse of the hydrophobic B blocks, an effect not previously observed for reverse triblock copolymers. The results are compared with related data for diblock E(m)B(n) copolymers. PMID- 21669442 TI - Preparation of rattle-type magnetic mesoporous carbon spheres and their highly efficient adsorption and separation. AB - Novel rattle-type magnetic mesoporous carbon spheres are successfully prepared using composite spheres with Fe(3)O(4) as core and mesoporous SiO(2) as shell plus solid SiO(2) as a middle layer as templates. These rattle-type spheres possess the magnetization strength of as high as 37.5 emu/g, high and tunable specific surface areas (382-512.6 m(2)/g) due to mesoporous carbon shells. This magnetic rattle-type structure and the readily accessible mesoporous shell are very favoring for the fast adsorption and release of guest objects triggered by external stimulus, for example, the spheres showed very good adsorptive property to dye. PMID- 21669443 TI - An investigation of the stable orientations of orthorhombic particles in a thin film and their effect on its critical failure pressure. AB - The effects of shape and contact angle on the behaviour of orthorhombic particles at an interface and in thin films were investigated using Surface Evolver. It is shown that the energetically stable orientations of the particle change with its aspect ratio. Long, wide, flat particles with low contact angles are more stable in flat orientations, i.e. with two faces parallel to the flat film surface. More cubic particles with higher contact angles are more stable in twisted orientations, where the opposite sides of the film can be drawn together at the sharp edges of the particle. The combination of contact angle and orientation has been found to have a large effect on the capillary pressure required to rupture the film. A film containing a particle in a flat orientation will rupture at a capillary pressure up to three times greater than one containing an identical particle in a twisted orientation. Wider, flatter particles with low contact angles stabilise thin liquid films to a greater extent than cubic particles with high contact angles. PMID- 21669444 TI - Coating typologies and constrained swelling of hyaluronic acid gels within scaffold pores. AB - A set of elastomeric scaffolds with a well defined porous structure was prepared with a template leaching procedure and coated with hyaluronic acid solutions. Depending on the coating process parameters the hyaluronic acid deposited on the pores had configurations ranging from thin disconnected aggregates to a thick continuous layer on the pore surface. The development of the coating layer was studied by scanning electron microscopy and the materials were subjected to dynamical and equilibrium swelling experiments in a water vapor ambient of fixed activity. The porosity change due to coating and to swelling of the coating layer were determined. The hyaluronic acid coating the pores has a different swelling capacity depending on the type of layer formed, as a consequence of the scaffold constraint and of the layer typology. These factors were investigated analytically by modifying the standard theory of gel swelling. An experimental quantity is introduced which reflects the constrainment build-up on gel swelling. PMID- 21669445 TI - The population attributable fraction of stroke associated with high blood pressure in the Middle East and North Africa. AB - BACKGROUND: Hypertension and the prevalence of stroke are increasing in the Middle East and North Africa. This study aims to quantify the contribution of hypertension to the development of stroke at the country-level by calculating the sex-specific population attributable fraction (PAFs). METHODS: The most recent sex-specific prevalence data was used, along with age-adjusted hazard ratio (HR) estimates for ischemic and hemorrhagic stroke associated with hypertension from the Asia Pacific Cohort Studies Collaboration (APCSC). HR estimates and prevalence data were then used to calculate the PAFs for each country in the region with the relevant data. RESULTS: In the 10 countries with nationally representative data, the PAFs in men ranged from 16.3% in Kuwait to 60.7% in Morocco for hemorrhagic stroke and 7.2% in Kuwait to 38% in Morocco for ischemic stroke. The equivalent PAFs for stroke deaths related to hypertension in women ranged from 12.4% in United Arab Emirates to 48.6% in Bahrain for hemorrhagic stroke and from 10.3% in UAE to 46% in Morocco for ischemic stroke. CONCLUSION: Overall, up to 60% of stroke can be attributed to the high blood pressure in the Middle East. Stroke is a preventative disease, with this information and better prevention strategies, this region can aim to lower the prevalence of stroke. PMID- 21669446 TI - Do benthic biofilters contribute to sustainability and restoration of the benthic environment impacted by offshore cage finfish aquaculture? AB - Benthic biofilters were deployed under a cage fish farm and in two reference locations to assess the influence of the farm on the biofilters and the surroundings, as well as to verify the usefulness of this technology as a mitigation tool. The biofilters underneath the farm recruited a fouling community practically identical to that of the control biofilters, which included a variety of trophic strategies. The former showed a higher 15N enrichment, indicating that fouling beneath the farm was benefiting from the farm waste. The waste retention efficiency was low (0.02 g N m(-2) month(-1)) beneath the farm. Benthic biofilters aggregated demersal wild fish around and within them. Pelagic wild fish also frequently used the biofilters beneath the farm, forming compact shoals around them. The increased complexity of the habitat below the fish farm enhanced biodiversity, but this improvement did not lead to the recovery of the sediments around the biofilters. PMID- 21669447 TI - Identification of beta-1 adrenergic receptor polymorphisms in cats. AB - In human beings, genetic polymorphisms within the beta-1 adrenergic receptor (ADRB1) gene have been associated with variable pharmacologic responses to beta blocker therapy. Beta-blockers are commonly given to cats with heart disease, particularly hypertrophic cardiomyopathy, a common cause of feline heart disease. We hypothesized that polymorphisms are present in the feline ADRB1 gene, which could result in an altered pharmacologic response to beta-blocker therapy. We sequenced the feline ADRB1 gene in 42 cats of five breeds. We identified three polymorphisms within the ADRB1 gene. Two polymorphisms did not change the amino acid produced and are unlikely to be clinically significant. A third polymorphism identified was an AA/CC substitution at the 830-831 base pair sites. This alteration changed the amino acid produced from proline to glutamine at position 277 and computer modeling predicts an altered protein structure. Further study is warranted to determine if this polymorphism alters response to beta blocker therapy. PMID- 21669448 TI - Fatal bronchopneumonia in a Metastrongylus elongatus and Porcine circovirus type 2 co-infected pig. AB - Porcine circovirus type 2 (PCV2) infection is distributed worldwide and PCV2 associated disease (PCVAD) is considered among the most economically relevant ones to the global swine industry. PCV2 is known to play a causal role in the porcine respiratory disease complex, usually in close association with a large plethora of other biologic agents. We describe herein a case of fatal parasitic bronchopneumonia by Metastrongylus elongatus in a PCV2-infected pig. Metastrongylosis may still represent a major concern for outdoor herds. Our recent experience suggests that a concurrent PCVAD condition may trigger metastrongylosis, which may subsequently result, at its turn, in severe, sometimes fatal, pulmonary disease. PMID- 21669450 TI - Ultrasonic system for accurate distance measurement in the air. AB - This paper presents a system that accurately measures the distance travelled by ultrasound waves through the air. The simple design of the system and its obtained accuracy provide a tool for non-contact distance measurements required in the laser's optical system that investigates the surface of the eyeball. PMID- 21669449 TI - Relationship between teat-end condition, udder cleanliness and bovine subclinical mastitis. AB - The aims of the present study were to relate intramammary infection (IMI) occurrence and somatic cell count (SCC) with teat-end condition (TEC) and udder cleanliness (UC). Milk samples from 1931 teats were evaluated according to the presence of IMI and SCC. Scores were applied to teats according to the TEC and to UC. Teats ends with a very rough ring had the largest number of IMI when compared to the other three categories, as well as animals with dirtier udders. The change in a TEC score increased by around 30% the chance of IMI. Also, the chance of the animal developing IMI increased by approximately 47% when the UC score increased. No significant association between both scores and quarter SCC was found. It can be concluded that animals with very rough teat end rings and very dirty udders have a greater predisposition to IMI. PMID- 21669451 TI - Feasibility study of complex wavefield retrieval in off-axis acoustic holography employing an acousto-optic sensor. AB - We propose and experimentally demonstrate a new method for complex-valued wavefield retrieval in off-axis acoustic holography. The method involves use of an intensity-sensitive acousto-optic (AO) sensor, optimized for use at 3.3 MHz, to record the acoustic hologram and a computational method for reconstruction of the object wavefield. The proposed method may circumvent limitations of conventional implementations of acoustic holography and may facilitate the development of acoustic-holography-based biomedical imaging methods. PMID- 21669452 TI - In situ aquatic bioassessment of pesticides applied on rice fields using a microalga and daphnids. AB - This study assessed the effects of episodic contamination on a drainage canal adjacent to an area of intensive rice production (Coimbra, Portugal). Four monitoring periods were considered [i) before herbicide application (day-14), ii) at the first application day (day 0), iii) 3 or 5 and iv) 6days after]. Each one consisted in three complementary evaluation lines: a) physico-chemical analyses, b) whole effluent toxicity (WET) assays with Pseudokirchneriella subcapitata, c) in situ bioassays to assess microalgae (P. subcapitata) growth, and the feeding rate and survival of Daphnia longispina and Daphnia magna. Study sites were located upstream, in a protected wetland (L1), and downstream, in the vicinity of rice fields (L2). Along with the application of agrochemicals, there was a general decrease of the water quality, especially in L2, due to nutrient and herbicide inputs. Herbicide peaks (on days 0, 5 and 6) in L2 water samples were recorded concomitantly or immediately after their application. Regarding the in situ bioassessment, the algae growth decrease from day 0 onwards in L1, whilst in L2 its inhibition was generally coherent with the decline of the water quality. Apparently, WET tests indicated that the limitation of nutrients could be affecting algae growth in L1, however, conclusions should be cautious. The feeding depression of daphnids occurred on days 0 and 5 for D. longispina and only on day 0 for D. magna, while significant reductions on survival were restricted to day 0 for both species. The impairments occurring on day 0 were linked to a potential increased toxicity driven by the ingestion of particle bound herbicides and suspended particles. The feeding rate of daphnids provided an earlier indication of toxic impairments, though it is prompted the use of complementary endpoints and trophic levels in order to understand the cumulative effects due to various herbicide pulses. PMID- 21669453 TI - Genotype-independent in vivo oxidative stress following a methionine loading test: maximal platelet activation in subjects with early-onset thrombosis. AB - BACKGROUND: Methionine ingestion (100mg/kg) identifies subjects in whom fasting total homocysteine (tHcy) may be normal but the post-methionine load (PML) tHcy is abnormally high. METHODS: In 96 subjects [54 M/42 F, 40.4 +/- 12.3 yrs old; 28 with the 68 bp844 ins of the cystathionine-beta-synthase gene (CBSins+); 20 homozygotes for the C677T mutation of the methylene-tetrahydrofolate reductase gene (MTHFR++); 13 with the combination of the two, and 35 without any of them], we have evaluated in vivo oxidative stress and platelet activation, as reflected by urinary excretions of 8-iso-PGF(2alpha) and of 11-dehydro-TXB(2) respectively, before and after a methionine load test (PML). A history of early-onset thrombosis (18 arterial, 32 venous, 2 both) was present in 52/96 of them. RESULTS: Baseline; tHcy was highest in MTHFR++ carriers (p < 0,05); 8-iso PGF(2alpha) and 11-dehydro-TXB(2) levels were independent of sex, MTHFR++ and/or CBSins + (p > 0.05). PML; The ~3-fold increase (p < 0.01 vs baseline) in tHcy reached a plateau within 6-8 hrs. Mean PML tHcy was maximal in MTHFR++ carriers (p = 0.000). 8-iso-PGF(2alpha) and 11-dehydro-TXB(2) increase reached a maximum within 4 hrs. 11-dehydro-TXB(2) increase was highest (p = 0.023 vs baseline) in subjects with a history of thrombosis. Baseline 11-dehydro-TXB(2) and a history of thrombosis independently predicted PML 11-dehydro-TXB(2) (beta = 0.287, p = 0.000 and beta = 0.308, p = 0.026, respectively).The PML increase in 8-iso PGF(2alpha) or in 11-dehydro-TXB(2) were comparable in the different genotypes (p > 0.05). CONCLUSION: Regardless genotypes associated with moderate hyperhomocysteinemia, following a methionine loading test, in vivo oxidative stress and platelet activation occur, being the latter maximal in subjects with a history of early-onset thrombosis. PMID- 21669454 TI - Don't trust anyone over 30: parental legitimacy as a mediator between parenting style and changes in delinquent behavior over time. AB - Both law and society scholars and developmental psychologists have focused on the legitimacy of authority figures, although in different domains (police versus parents). The purpose of the current research is to bridge these two fields by examining the relations among parenting style (i.e., authoritarian, authoritative, permissive), the perception of parental legitimacy, and changes in delinquency over time. It is hypothesized that parental legitimacy mediates the relation between parenting style and future delinquent behavior. Middle school and high school students completed questionnaires three times over a period of 18 months. Parenting style and delinquent behavior were measured at time 1, parental legitimacy at time 2, and delinquency again at time 3. The results show that authoritative parenting was positively related to parental legitimacy, while authoritarian parenting was negatively associated with parental legitimacy. Furthermore, parental legitimacy was negatively associated with future delinquency. Structural equation modeling indicated that parental legitimacy mediated the relation between parenting styles and changes in delinquency over the 18-month time period. The implications for parenting style and parental legitimacy affecting delinquent behavior are discussed. PMID- 21669455 TI - Directed cell attachment by tropoelastin on masked plasma immersion ion implantation treated PTFE. AB - The ability to generate cell patterns on polymer surfaces is critical for the detailed study of cellular biology, the fabrication of cell-based biosensors, cell separation techniques and for tissue engineering. In this study contact tape masking and steel shadow masks were used to exclude plasma immersion ion implantation (PIII) treatment from defined areas of polytetrafluoroethylene (PTFE) surfaces. This process enabled patterned covalent binding of the cell adhesive protein, tropoelastin, without employing chemical linking molecules. Tropoelastin coating rendered the untreated regions cell adhesive and the PIII treated area non-adhesive, allowing very fine patterning of cell adhesion to PTFE surfaces. A blocking step, such as with BSA or PEG, was not required to prevent cell binding to the underlying PIII-treated regions as tropoelastin coating alone performed this blocking function. Although tropoelastin coated the entire PTFE surface, the cell binding C-terminus of tropoelastin was markedly less solvent exposed on the PIII-treated, hydrophilic regions. The differential exposure of the C-terminus correlated with the patterned distribution of tropoelastin mediated cell adhesion. This new methodology specifically enables directed cell behavior on a polymer surface using a simple one-step treatment process, by modulating the adhesive activity of a single extracellular matrix protein. PMID- 21669456 TI - A highly radiopaque vertebroplasty cement using tetraiodinated o-carborane additive. AB - Bone cements for vertebroplasty must have a much better radiocontrast level than cements for knee or hip arthroplasty. This is generally accomplished by adding a relatively large portion of BaSO(4), although this affects the physical mechanical and biological properties of the cement. This prompted us to develop an alternative radiopaque cement, on the basis of unique highly radiopaque methacrylic microspheres. These contain iodine in two modalities: (i) covalently linked to the methacrylic polymer, and (ii) as constituent of the stable tetraiodocarborane 8,9,10,12-I(4)-1,2-closo-C(2)B(10)H(8). The total iodine content in these particles exceeded 30% by mass. These radiopaque microspheres as well as the cement made thereof were characterized extensively, e.g., by scanning electron microscopy, X-ray contrast measurements, X-ray photoelectron spectroscopy, measurements of compressive strength, infrared spectroscopy, and solid state (11)B{(1)H} NMR spectroscopy. Furthermore, the new cement was subjected to several biocompatibility tests in vitro. The results show that the new bone cement fulfills all physico-chemical criteria for use in vertebroplasty. Further data on the cement's biocompatibility (in vitro), as well as on the handling parameters and doughviscosity, indicate that this material has a potential to become an alternative to vertebroplasty cements with a high BaSO(4) content. The new cement provides two significant advantages: (i) controlled viscosity in the dough phase, which facilitates precise injection during the vertebroplasty procedure; (ii) excellent structural stability, which precludes leaching of contrast post-implantation. PMID- 21669457 TI - Biological and mechanical implications of PEGylating proteins into hydrogel biomaterials. AB - Protein PEGylation has been successfully applied in pharmaceuticals and more recently in biomaterials development for making bioactive and structurally versatile hydrogels. Despite many advantages in this regard, PEGylation of proteins is also known to alter biological activity and modify biophysical characteristics in ways that may be detrimental to cells. The aim of this study was to evaluate the relative loss of biological compatibility associated with PEGylating a fibrinogen precursor into a hydrogel scaffold, in comparison to thrombin cross-linked fibrin hydrogels. Specifically, we investigated the consequences of conjugating fibrinogen with linear polyethtylene glycol (PEG) polymer chains (10 kDa) on the ability to cultivate neonatal human foreskin fibroblasts (HFFs) in 3-D. For this purpose, thrombin cross-linked fibrin (TCL Fib) and PEGylated fibrinogen (PEG-Fib) gels were prepared with HFFs and cultured for up to seven days. The benchmark biological compatibility test was based on a combined assessment of cellular morphology, proliferation, actin expression, and matrix metalloproteinase (MMP) expression in the 3-D culture systems. The results showed correlations between modulus and proteolytic biodegradation in both materials, but no correlation between the mechanical properties and the ability of HFFs to remodel the microenvironment. A slight reduction of actin, MMPs, and spindled morphology of the cells in the PEG-Fib hydrogels indicated that the PEGylation process altered the biological compatibility of the fibrin. Nevertheless, the overall benchmark performance of the two materials demonstrated that PEGylated fibrinogen hydrogels still retains much to the inherent biofunctionality of the fibrin precursor when used as a scaffold for 3-D cell cultivation. PMID- 21669458 TI - The role of adipose-derived stem cells engineered with the persistently expressing hybrid baculovirus in the healing of massive bone defects. AB - Massive segmental defects arising from trauma or tumor resection remain a challenging clinical problem. To repair large, segmental bone defects using adipose-derived stem cells (ASCs) which alone cannot heal massive defects, we hypothesized that sustained expression of factors promoting osteogenesis (BMP2) and angiogenesis (VEGF) provides continuous stimuli to augment the healing. Baculovirus is a vector for gene delivery into stem cells, but it only mediates transient expression. Therefore we developed a dual system whereby one baculovirus expressed FLP recombinase (BacFLP) while the other hybrid baculovirus harbored an Frt-flanking transgene cassette. Within the ASCs transduced with BacFLP and the hybrid baculovirus, the transduction efficiency reached 98% and the FLP/Frt-mediated recombination efficiency approached 46%, leading to cassette excision off the baculovirus genome, enabling transgene persistence in episomal form and prolonging the expression to >28 days. ASCs engineered by the conventional baculovirus transiently expressing BMP2/VEGF (S group) only healed the critical-size (10mm) segmental femoral bone defects in 40% of New Zealand White rabbits at 12 weeks post-implantation, whereas ASCs engineered by the hybrid vectors persistently expressing BMP2/VEGF (L group) healed the critical size defects in 12 out of 12 animals in 8 weeks. Compared with the S group, the L group not only accelerated the healing, but also ameliorated the bone quality (metabolism, volume, density, mechanical properties) and angiogenesis, thereby attesting our hypothesis that persistent BMP2/VEGF expression is essential. Use of ASCs engineered by the hybrid BV vector thus holds promise to treat massive segmental defects necessitating sustained stimuli. PMID- 21669459 TI - Reduced expression of gap junction gene connexin 43 in recurrent early pregnancy loss patients. AB - Connexin 43 (Cx43) gap junctions play an important role in development and differentiation of endometrium and placenta. Therefore, aberrant expression of Cx43 could result in altered physiological and pathological processes leading to recurrent early pregnancy loss (REPL). To investigate if expression of Cx43 is effected in REPL patients as compared to controls, Cx43 expression was compared in the chorionic villi and uterine decidua samples of 15 REPL patients and 15 induced abortion subjects as controls. Cx43 levels were evaluated using semi quantitative RT-PCR, quantitative Real-time PCR and by western blot. Cx43 expression at mRNA and protein level was significantly decreased in both chorionic villi and decidua (p < 0.05) of REPL patients. Reduced expression of Cx43 transcript and protein in fetal chorionic villi and maternal decidua indicate the key role of Cx43 in REPL risk. PMID- 21669460 TI - Characterization of receptors for murine pregnancy specific glycoproteins 17 and 23. AB - In primates and rodents, trophoblast cells synthesize and secrete into the maternal circulation a family of proteins known as pregnancy specific glycoproteins (PSG). The current study was undertaken to characterize the receptor for two members of the murine PSG family, PSG17 and PSG23. Binding of recombinant PSG17 and PSG23 to CHO-K1 and L929 cells and their derived mutants was performed to determine whether these proteins bound to cell surface proteoglycans. We also examined binding of these proteins to cells transfected with syndecans and glypican-1 by flow cytometry. The interaction with glycosaminoglycans was confirmed in solid phase assays. Our results show that PSG17 binds to CD9 and to cell surface proteoglycans while PSG23 binds only to the latter. We found that the amino acids involved in CD9 binding reside in the region of highest divergence between the N1-domains of murine PSGs. For both proteins, the N-terminal domain (designated as N1) is sufficient for binding to cells and the ability to bind cell surface proteoglycans is affected by the cell line employed to generate the recombinant proteins. We conclude that while substantially different at the amino acid level, some murine PSGs share with human PSG1 the ability to bind to cell surface proteoglycans and that at least one PSG binds to more than one type of molecule on the cell surface. PMID- 21669461 TI - Predicting future depression in adolescents using the Short Mood and Feelings Questionnaire: a two-nation study. AB - BACKGROUND: Adolescence is a key life period for the development of depression. Predicting the development of depression in adolescence through detecting specific early symptoms may aid in the development of timely screening and intervention programmes. METHODS: We administered the Short Mood and Feelings Questionnaire (SMFQ) to 5769 American and Australian students aged 10 to 15 years, at two time points, separated by 12 months. We attempted to predict high levels of depression symptoms at 12 months from symptoms at baseline, using statistical approaches based upon the quality, as well as the quantity, of depression symptoms present. These approaches included classification and regression trees (CART) and logistic regression. RESULTS: A classification tree employing four SMFQ items, such as feelings of self-hatred and of being unloved, performed almost as well as all 13 SMFQ items at predicting subsequent depression symptomatology. LIMITATIONS: Depression was measured using a self-report instrument, rather than a criterion standard diagnostic interview. CONCLUSION: Further validation on other populations of adolescents is required: however the results suggest that several symptoms of depression, especially feelings of self hatred, and being unloved, are associated with increased levels of self-reported depression at 12 months post baseline. Although screening for depression can be problematic, symptoms such as the ones above should be considered for inclusion in screening tests for adolescents. PMID- 21669463 TI - The meanings of delusions in dementia: a preliminary study. AB - One of the common symptoms of dementia is delusions. Due to a biological conceptualization of the behaviors represented as delusions, these are classified as psychotic symptoms. This is a qualitative and quantitative study aiming to describe the delusions experienced by older persons with dementia and the context of occurrence, and to elucidate their etiology. Participants were 74 nursing home residents aged 65 and over, diagnosed with dementia, from nine nursing homes in Israel. Participants with delusions were found to have significantly more difficulties in performing ADLs, and poorer vision and hearing. Based on assessment using the BEHAVE-AD, six categories of delusions were examined: 1. One's house is not one's home, 2. Theft, 3. Danger, 4. Abandonment, 5. Misidentification, and 6. Other non-paranoid. Common themes appeared across delusions including reality, disorientation, re-experience of past events, loneliness and insecurity, boredom, and trigger. Current results suggest that delusions may not represent psychotic symptoms for most participants, because they sometimes represented reality, or were neither firm nor incontrovertible. Thus, utilizing the term delusion relegates the person's behavior to the domain of severe psychiatric phenomena and precludes understanding its true meaning. PMID- 21669462 TI - Neuropsychological performance in patients with schizophrenia and controls as a function of cigarette smoking status. AB - Schizophrenia is associated with many neurocognitive deficits, some of which are improved by nicotine and cigarette smoking. To better understand the relationship between smoking and cognitive function in schizophrenia, cross-sectional assessment of neuropsychological performance as a function of smoking status (smoker or non-smoker) and smoking history (current, former or never-smoker) in clinically stable outpatients with schizophrenia and controls was evaluated. Subjects (n=140) were divided into subgroups on the basis of self-report and biochemical verification of smoking history. Current smokers with schizophrenia (n=38), former smokers with schizophrenia (n=17), never-smokers with schizophrenia (n=12), control smokers (n=31), control former smokers (n=16), and control never-smokers (n=26) were administered a comprehensive neuropsychological battery. Smokers were studied under non-deprivation conditions. Comparison of neuropsychological performance in schizophrenia and control subjects revealed significant main effects of diagnosis. Analysis of the data as a function of smoking history demonstrated that never-smokers with schizophrenia performed the poorest on measures of sustained attention, processing speed and response inhibition, when compared to the other schizophrenia subgroups. Cigarette smoking did not alter neuropsychological performance in controls. Our findings suggest that smoking status and history differentially alters neuropsychological outcomes in schizophrenia compared to non-psychiatric controls, and that never-smokers may present with more severe neurocognitive impairments. PMID- 21669464 TI - Concomitant autoimmunity in myasthenia gravis--lack of association with IgA deficiency. AB - A marked increase in concomitant autoimmune diseases has previously been noted in patients with myasthenia gravis (MG). We show that these diseases occur both before and after the onset of MG and that the process is not influenced by thymectomy. IgA deficiency (IgAD), which is strongly associated with the same HLA haplotype as early onset MG, has recently been suggested to be an autoimmune disease. However, there was no increase in the prevalence of IgAD in a large cohort of Swedish MG patients. PMID- 21669465 TI - The preventive effect of N-nitro L-arginine methyl ester in experimentally induced myringosclerosis. AB - OBJECTIVE: The purpose of this study was to investigate the antiinflammatory and antifibrotic effects of N-nitro L-arginine methyl ester (L-name) in experimentally induced myringosclerosis. METHODS: Twenty Wistar albino rats were bilaterally myringotomized and divided randomly into four groups, each including five rats. Group I received no treatment, Group II was treated with topical saline solution, Group III received topical L-NAME and Group IV received intraperitoneally administered L-NAME. After 2 weeks, the tympanic membranes were examined and scored by otomicroscopy regarding the extent of the myringosclerosis. Then the tympanic membranes were harvested and evaluated histopathologically by light microscopy. The intensity of inflammation and degree of myringosclerosis were evaluated, the mean thickness of tympanic membranes were also measured. RESULTS: The tympanic membranes of Groups I and II showed extensive myringosclerosis in contrast to those of Groups III and IV which had significantly less or no changes (p < 0.05). The inflammation and fibroblastic activity of the lamina propria in the tympanic membranes of Groups III and IV were found to be significantly less pronounced (p < 0.05). The tympanic membranes were found to be significantly thicker in Groups I and II when compared with Groups III and IV (p < 0.05). CONCLUSION: Our results showed that both topical and intraperitoneal applications of L-NAME supressed inflammation, reduced fibroblastic proliferation and decreased the formation of myringosclerosis in myringotomized rat tympanic membranes. PMID- 21669466 TI - Relationship between memory age identity (MAI) and cognition in Korean elders. AB - Relatively few studies have examined the psychological predictors of cognitive functions in the elderly. We aimed to investigate the relationship between MAI and cognition in the non-cognitively impaired (NCI) elderly. Data obtained from 1345 Korean subjects aged 60+ years were analyzed. MAI was defined as the discrepancy between subjective memory age and chronological age. We conducted the analysis of covariance (ANCOVA) to demonstrate the relationship between MAI and Korean version-Mini Mental State Examination (K-MMSE). There were significant differences in the estimated means of K-MMSE score among the 4 quartile groups of MAI (Q1-Q2>Q3>Q4, F=13.12, p<0.0001). These results suggested that MAI may be associated with cognitive function in the NCI elderly. PMID- 21669467 TI - The effect of mandibular anterior teeth on the hypermobile tissue in the anterior part of the maxilla. AB - The absence of posterior occlusal contacts may result in increased anterior occlusal contacts and forces between natural mandibular dentition and artificial maxillary dentition. The impact of natural mandibular anterior teeth on the development of hypermobile tissues in the anterior part of the edentulous maxillary alveolar ridge was investigated in this study. The study group consisted of 410 patients with maxillary complete dentures and various mandibular dentitions from seven rest homes in Istanbul. The data; including hypermobile tissue in the anterior part of the maxilla, occlusal relationship, nocturnal wear, denture age, and duration of the maxillary full edentulism period were recorded. A chi-square test was performed to analyze the effects of following data: Existence of mandibular anterior teeth, poor adaptation of the dentures, nocturnal wear, types of occlusal contacts, and gender, on the resorption of the anterior part of the maxilla. To examine the effects of the presence of anterior mandibular teeth and early maxillary edentulism on bone resorption in the anterior part of the maxilla, a logistic regression analysis was performed. The results reveal that patients with edentulous maxilla and natural mandibular anterior teeth are approximately twice more likely to show risk of hypermobile tissue in the anterior part of the maxilla than are full edentulous patients. Further, edentulous periods exceeding 30 years in maxilla seem to increase this risk approximately 4 times. PMID- 21669468 TI - Tactical pattern recognition in soccer games by means of special self-organizing maps. AB - Increasing amounts of data are collected in sports due to technological progress. From a typical soccer game, for instance, the positions of the 22 players and the ball can be recorded 25 times per second, resulting in approximately 135.000 datasets. Without computational assistance it is almost impossible to extract relevant information from the complete data. This contribution introduces a hierarchical architecture of artificial neural networks to find tactical patterns in those positional data. The results from the classification using the hierarchical setup were compared to the results gained by an expert manually classifying the different categories. Short and long game initiations can be detected with relative high accuracy leading to the conclusion that the hierarchical architecture is capable of recognizing different tactical patterns and variations in these patterns. Remaining problems are discussed and ideas concerning further improvements of classification are indicated. PMID- 21669469 TI - Dynamics of the ankle joint analyzed through moment-angle loops during human walking: gender and age effects. AB - Aim of this study was to provide a non-invasive assessment of the dynamic properties of the ankle joint during human locomotion, with specific focus on the effects of gender and age. Accordingly, flexion-extension angles and moments, obtained through gait analysis, were used to generate moment-angle loops at the ankle joint in 120 healthy subjects walking at a same normalized speed. Four reproducible types of loops were identified: Typical Loops, Narrow, Large and Yielding loops. No significant changes in the slopes of the main loop phases were observed as a function of gender and age, with the exception of a relative increase in the slope of the descending phase in elderly males compared to adult females. As for the ergometric parameters, the peak ankle moment, work produced and net work along the cycle were slightly, but significantly affected, with progressively decrease in the following order: Adult Males, Adult Females, Elderly Males and Elderly Females. The evidence that only few of the quantitative aspects of moment-angle loops were affected suggests that the control strategy which regulates the biomechanical properties of the ankle joint during walking is rather robust and qualitatively consistent across genders and age. PMID- 21669470 TI - Involvement of Clostridium gasigenes and C. algidicarnis in 'blown pack' spoilage of Brazilian vacuum-packed beef. AB - The objectives of this study were to isolate psychrotrophic clostridia from Brazilian vacuum-packed beef cuts (spoiled or not) and to identify the isolates by using 16S rRNA gene sequencing. Anaerobic psychrotrophic microorganisms were also enumerated and samples were collected to verify the incidence of psychrotrophic clostridia in the abattoir environment. Vacuum-packed beef cuts (n=8 grossly distended and n=5 non-spoiled) and environmental samples were obtained from a beef packing plant located in the state of Sao Paulo, Brazil. Each sample was divided in three subsamples (exudate, beef surface and beef core) that were analyzed for vegetative forms, total spore-forming, and sulfide reducing spore-forming, both activated by alcohol and heat. Biochemical profiles of the isolates were obtained using API20A, with further identification using 16S rRNA gene sequencing. The growth temperature and the pH range were also assessed. Populations of psychrotrophic anaerobic vegetative microorganisms of up to 10(10)CFU/(g, mL or 100 cm(2)) were found in 'blown pack' samples, while in non spoiled samples populations of 10(5)CFU/(g, CFU/mL or CFU/100 cm(2)) was found. Overall, a higher population of total spores and sulfide reducing spores activated by heat in spoiled samples was found. Clostridium gasigenes (n=10) and C. algidicarnis (n=2) were identified using 16S rRNA gene sequencing. Among the ten C. gasigenes isolates, six were from spoiled samples (C1, C2 and C9), two were isolated from non-spoiled samples (C4 and C5) and two were isolated from the hide and the abattoir corridor/beef cut conveyor belt. C. algidicarnis was recovered from spoiled beef packs (C2). Although some samples (C3, C7, C10 and C14) presented signs of 'blown pack' spoilage, Clostridium was not recovered. C. algidicarnis (n=1) and C. gasigenes (n=9) isolates have shown a psychrotrophic behavior, grew in the range 6.2-8.2. This is the first report on the isolation of psychrotrophic Clostridium (C. gasigenes and C. algidicarnis) in Brazil. This study shows that psychrotrophic Clostridium may pose a risk for the stability of vacuum-packed beef produced in tropical countries during shelf-life and highlights the need of adopting control measures to reduce their incidence in abattoir and the occurrence of 'blown pack' spoilage. PMID- 21669471 TI - Technique for preprocessing of digital mammogram. AB - Digital mammogram has emerged as the most popular screening technique for early detection of breast cancer and other abnormalities in human breast tissue. It provides us opportunities to develop algorithms for computer aided detection (CAD). In this paper we have proposed three distinct steps. The initial step involves contrast enhancement by using the contrast limited adaptive histogram equalization (CLAHE) technique. Then define the rectangle to isolate the pectoral muscle from the region of interest (ROI) and finally suppress the pectoral muscle using our proposed modified seeded region growing (SRG) algorithm. The proposed algorithms were extensively applied on all the 322 mammogram images in MIAS database resulting in complete pectoral muscle suppression in most of the images. Our proposed algorithm is compared with other segmentation methods showing superior results in comparison. PMID- 21669472 TI - Determination of spatially-resolved porosity, tracer distributions and diffusion coefficients in porous media using MRI measurements and numerical simulations. AB - This work is focused on measuring the concentration distribution of a conservative tracer in a homogeneous synthetic porous material and in heterogeneous natural sandstone using MRI techniques, and on the use of spatially resolved porosity data to define spatially variable diffusion coefficients in heterogeneous media. The measurements are made by employing SPRITE, a fast MRI method that yields quantitative, spatially-resolved tracer concentrations in porous media. Diffusion experiments involving the migration of H(2)O into D(2)O saturated porous media are conducted. One-dimensional spatial distributions of H(2)O-tracer concentrations acquired from experiments with the homogeneous synthetic calcium silicate are fitted with the one-dimensional analytical solution of Fick's second law to confirm that the experimental method provides results that are consistent with expectations for Fickian diffusion in porous media. The MRI-measured concentration profiles match well with the solution for Fick's second law and provide a pore-water diffusion coefficient of 1.75*10( 9)m(2)s(-1). The experimental approach was then extended to evaluate diffusion in a heterogeneous natural sandstone in three dimensions. The relatively high hydraulic conductivity of the sandstone, and the contrast in fluid density between the H(2)O tracer and the D(2)O pore fluid, lead to solute transport by a combination of diffusion and density-driven advection. The MRI measurements of spatially distributed tracer concentration, combined with numerical simulations allow for the identification of the respective influences of advection and diffusion. The experimental data are interpreted with the aid of MIN3P-D - a multicomponent reactive transport code that includes the coupled processes of diffusion and density-driven advection. The model defines local diffusion coefficients as a function of spatially resolved porosity measurements. The D(e) values calculated for the heterogeneous sandstone and used to simulate diffusive and advective transport range from 5.4*10(-12) to 1.0*10(-10)m(2)s(-1). These methods have broad applicability to studies of contaminant migration in geological materials. PMID- 21669473 TI - Dermal dendritic cells in psoriasis, nummular dermatitis, and normal-appearing skin. AB - BACKGROUND: The reason psoriasis (PSO) favors extensor skin is unknown. We hypothesized that PSO may involve extensor skin preferentially because of differences in the number or type of dermal dendritic cells (dDCs) between flexural and extensor skin. OBJECTIVE: We sought to compare dDC type and distribution in normal-appearing flexural and extensor skin, PSO, and nummular dermatitis (ND). METHODS: Using immunohistochemical markers, the number, distribution, and type of Langerhans cells, myeloid dendritic cells (DCs), and plasmacytoid DCs was compared in normal-appearing skin, PSO, and ND. RESULTS: Significant differences in dDC density were not identified between flexural and extensor skin, although extensor skin contained fewer CD11a(+) and CD11c(+) cells. Compared with normal-appearing skin, cells expressing CD11a, CD11c, CD123, CD303, and CD207 were increased in PSO. ND lesions showed similar increases. No significant difference between PSO and ND was evident with the exception of decreased S100A6(+) cells in PSO. LIMITATIONS: We did not study seasonal variation in DC density or assess nonlesional skin from patients with PSO. CONCLUSIONS: The data did not support the hypothesis that PSO favors extensor skin because of differences in DC localization. However, dDCs were significantly increased in PSO by comparison with normal-appearing skin, supporting existing evidence that they are involved in the overall pathogenesis of PSO. PMID- 21669474 TI - Role of oligomers in the amyloidogenesis of primary cutaneous amyloidosis. AB - BACKGROUND: Primary cutaneous amyloidosis (PCA) describes a heterogeneous group of cutaneous diseases characterized by amyloid deposition; this may manifest as macules, papules, or nodules, depending on the subtype involved. To date, relatively little is known about the process of amyloidogenesis in the skin; however, investigators recently have identified small amyloid species, known as oligomers, which give rise to large amyloid fibrillar aggregates. OBJECTIVE: The purpose of the current study was to identify small oligomers in patients with PCA using novel immunohistochemical techniques and to examine our findings in light of previous hypotheses of amyloid formation in these diseases. METHODS: Six cases of PCA were analyzed using Congo red, thioflavin S, and hematoxylin-eosin. We also analyzed these samples with the novel oligomer-specific conformational antibody I-11 to detect the small, misfolded protein oligomers. Semiquantitative analysis was performed on these samples to grade the amount of amyloid aggregates and oligomers detected in the skin samples with light and polarized microscopy. RESULTS: In the cases examined, we detected intracellular oligomers in the basal cell layer of the epidermis and the surrounding cells in the dermis. We also were able to detect large aggregates of amyloid in our samples and to correlate the relationship of oligomers to amyloid aggregates in accordance with previous studies on cutaneous amyloidosis and other amyloid-related diseases. LIMITATIONS: Small sample size is a limitation. CONCLUSIONS: PCA is an amyloid-related disease that likely follows a similar mechanism as other more intensively studied amyloid diseases. PMID- 21669475 TI - Sebaceous gland loss and inflammation in scarring alopecia: a potential role in pathogenesis. AB - BACKGROUND: Primary scarring alopecia (SA) comprises a group of disorders with poorly defined origins. Improving diagnostic and therapeutic capabilities requires a better understanding of their pathogenesis. OBJECTIVES: We sought to assess the frequency of sebaceous gland loss in SA and to identify the role of sebaceous gland and sebaceous gland duct inflammation in the pathogenesis of SA. METHODS: Ninety specimens submitted with a clinical history of alopecia, both scarring and nonscarring, were reviewed. Samples were scored based on sebaceous gland, sebaceous duct, and follicle inflammation. RESULTS: Sebaceous gland loss was much more common in cases of SA (>53% of follicles on average) than non-SA (<5% of follicles on average). Many cases of SA showed residual affected follicles with an absence of sebaceous glands. Sebaceous gland duct inflammation was often more frequent and severe than gland inflammation in SA. LIMITATIONS: Sample size was limited in some alopecia entities. Inflammation was graded by means of subjective observation. CONCLUSIONS: This study demonstrates that sebaceous gland loss is a common and early finding among SA. In addition, sebaceous gland and/or duct inflammation may play a role in initiating or accelerating follicular damage during the development of SA. PMID- 21669476 TI - Impact of a blood culture collection kit on the quality of blood culture sampling: fear and the law of unintended consequences. AB - Blood culture is a vital investigation and can be the first step in obtaining a definitive diagnosis in a patient with presumed sepsis, but can also have serious adverse consequences for the patient. The aim of this study was to evaluate the extent of the blood culture contamination problem at the Lancashire Teaching Hospitals (LTH) and to assess the impact of the introduction of a new blood culture collection kit on the contamination rate. Blood culture contamination rate at the LTH before the introduction of the blood culture collection kit was 9.2%. A fall in contamination rate was observed after kit introduction, to 3.8%, a proportion approaching the American Society of Microbiologists' recommended standard of <=3%. The reduction in contamination was associated with an unintended, yet sustained, reduction in the total number of blood culture sets collected and an unwanted reduction in the number of genuine Gram-negative bacteraemias. This reduction may reflect education and training issues at the time of the introduction. In the era of 'route cause analyses', it may also reflect fears by junior colleagues of the consequences of being found responsible for a blood culture contaminant. The study recommended continuing with the blood culture kit, but ensuring regular training and education sessions, carried out in a non-blame manner. PMID- 21669477 TI - Synthesis and structure of new bicopper(II) complexes bridged by N-(2- aminopropyl)-N'-(2-oxidophenyl)oxamide: the effects of terminal ligands on structures, anticancer activities and DNA-binding properties. AB - A novel dissymmetrical N,N'-bis(substituted)oxamide ligand, N-(2-aminopropyl)-N' (2-oxido- phenyl)oxamide (H(3)apopoxd) (L), and its three bicopper(II) complexes, [Cu(2)(apopoxd)(bpy)]- (ClO(4)).H(2)O (1), [Cu(2)(apopoxd)(dabt)](ClO(4)).2H(2)O (2), and [Cu(2)(apopoxd)(phen)(2)](ClO(4)) (3) (bpy = 2,2'-bipyridine; dabt = 2,2'-diamino-4,4'-bithiazole; phen = 1,10-phenanthroline) have been synthesized and characterized. The crystal structures of the three bicopper(II) complexes have been determined by X-ray single-crystal diffraction. In complexes 1 and 2, the cis-apopoxd(3-) ligands bridge two copper(II) ions in square-planar geometries with the corresponding separations of 5.1868(3) and 5.2016(4) A, respectively. While in complex 3, the apopoxd(3-) ligand adopting a trans conformation bridges the two copper(II) ions in distorted square-pyramid environments with a Cu . . . Cu distance of 5.2508(7) A. The anticancer activities and DNA-binding properties of L and the three complexes were investigated. PMID- 21669478 TI - Design, synthesis and biological evaluation of novel desmuramyldipeptide analogs. AB - A series of novel desmuramyldipeptides have been designed and synthesized as part of our search for therapeutically useful muramyldipeptide (MDP) analogs. Their immunomodulatory properties were initially assessed in vitro, evaluating their effect on lipopolysaccharide (LPS)-induced cytokine release in THP-1 cells. Following the initial screening, selected compounds were further investigated for immunomodulatory properties using LPS and phorbol 12-myristate 13-acetate (PMA)/ionomycin-stimulated human peripheral blood mononuclear cells. The results confirmed the immunomodulatory properties of some of the synthesized desmuramyldipeptide analogs. Taken together, presented data confirmed the immunostimulatory effect of compound 44, MDP derivative incorporating a pyrido fused [1,2]-benzisothiazole moiety, while for compounds 32 and 39, indole scaffold-based derivatives of MDP, an immunosuppressive effect was observed. Further studies will be necessary to address their potential therapeutic use as immunomodulatory drugs, both as immunostimulants or anti-inflammatory agents. PMID- 21669479 TI - Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease. AB - The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine 3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22-25. Compounds of type II were prepared by Friedlander type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1 yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one (31). The biological evaluation of molecules 1-11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a EeAChE mixed type inhibitor (IC(50) = 16 +/- 2; Ki = 12 +/- 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11, as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer's disease. PMID- 21669481 TI - Regional dynamics of persistent organic pollutants (POPs) in the Pearl River Delta, China: implications and perspectives. AB - The mass transport budgets of 1,1,1-trichloro-2,2-bis(chlorophenyl)ethane (p,p' DDT) and decabromodiphenyl ether (BDE-209) in the Pearl River Delta, South China were calculated based on previously collected data. Residual p,p'-DDT, mostly related to historical use, has largely settled into soil (780,000 kg), while the soil BDE-209 inventory (44,000 kg) is considerably smaller. Conversely, large amounts of BDE-209 currently used in numerous commercial products have resulted in a much higher atmospheric depositional flux of BDE-209 (28,100 kg/yr) relative to p,p'-DDT (310 kg/yr). The soil inventory of p,p'-DDT is predicted to decrease to half of its current value after 22 years, and the percent area containing soil p,p'-DDT at levels exceeding the effects range-medium (27 ng/g) will decrease from 40% to 20%. Finally, soil BDE-209 inventory will reach an equilibrium value of 940 tons in ~60 years, when BDE-209 levels in 50% of soil will be above an equivalent risk guideline value (125 ng/g). PMID- 21669482 TI - The neighborhood context of relative position, trust, and self-rated health. AB - The relative position hypothesis proposes that an individual's relative position in a community or population influences their health because (1) unfavorable comparisons lead those with a lower position to experience negative emotions that cause stress and detrimentally impact health and well-being, and (2) individuals with different statuses are less likely to develop trust and cohesion with one another. These processes are important for individual health and also because their results may detract from community level social resources. Surprisingly little work has investigated this hypothesis within small units of analysis such as neighborhoods. In this research, logistic regression analyses were conducted on data from the Los Angeles Family and Neighborhood Survey to test the relative position hypothesis as it applies to distrust of neighbors and fair or poor self rated health, and whether the relationship varies across neighborhood income inequality. Results indicate that relative position significantly predicts distrust, such that those with higher local position are more likely to distrust their comparatively lower income neighbors. Relative position was not significantly associated with self-rated health, but lack of trust of neighbors was significantly and positively associated with below average self-rated health. The effect of relative position did not vary across neighborhood income inequality for either outcome. Implications for theories of income inequality and health are discussed. PMID- 21669483 TI - Diagnosis and nosology in primary care. AB - Diagnosis in contemporary medicine is made using an underlying classification system or nosology, the basis of which was first laid down at the end of the 18th century. The International Classification of Disease (ICD) was constructed to formalise this nosology and successive revisions have attempted to capture technical developments and new discoveries across the diagnostic landscape. The ICD has proved particularly applicable in hospital practice where a selected patient population and access to comprehensive diagnostic aids enables a pathology-based diagnosis. When it came to be applied to primary care in the middle of the 20th century, however, it encountered major problems as general practice struggled to marry a classification of disease to the rawness of undifferentiated human illness and distress. Eventually a classification based on the reason the patient consulted emerged to replace that based on pathology defined disease. Analysis of the frontier zone where a dominant classification system struggles to maintain order reveals the ways in which medical nosologies, through their application in the process of diagnosis, attempt to promote and maintain a certain medical reality. PMID- 21669484 TI - Protecting the health of employees caring for family members with special health care needs. AB - Over half of American workers are holding a paid job while also providing unpaid assistance and support to a family member. Research shows that family members who provide care to children or adults with special health care needs are themselves at risk of physical and mental health problems. Yet, little research has explored how the work environment mediates the effects of caregiving on caregivers' mental and physical health. With a sample of 2455 currently employed U.S. adults from the Work, Family, Community Nexus (WFCN) survey, a random-digit dial, nationally representative survey of Americans aged 18-69, we examine whether paid leave and flexibility policies mediate the relationship between caregiving and health. In Ordinary Least Squares regression models, we find that paid leave to address family members' health was associated with better mental health status as measured by the 5-item Mental Health Inventory and paid sick leave with better physical health status as measured by self-rated overall health status. A supportive supervisor was also associated with improvements in mental and physical health. For both men and women, paid leave and a supervisor's support offset some or all of the negative effects of caregiving, but for women, the buffering effects of working conditions are slightly larger. Enhancing the unpaid leave guaranteed in the U.S. Family and Medical Leave Act so that it is paid and passing national paid sick days legislation will help ensure that employed caregivers can retain their jobs, receive needed income, and meet their own mental and physical health needs. PMID- 21669486 TI - Optimizing voluntary compliance in marine protected areas: a comparison of recreational fisher and enforcement officer perspectives using multi-criteria analysis. AB - A comprehensive list of planning criteria for optimizing compliance in Marine Protected Areas (MPAs) was compiled and used to compare the views of recreational fishers and compliance officers for facilitating voluntary compliance in the Port Stephens - Great Lakes Marine Park (PSGLMP). Expert working groups were tasked separately with: 1) criteria identification and weighting; 2) scoring of no-take zones; 3) prioritizing and determining uncertainty; and 4) analysis of results and sensitivity testing. Multi-Criteria Analysis (MCA) revealed that both groups had similar perspectives and recommendations, despite weighting the individual planning criteria differently. Significantly, "manageability" scores for no-take zones from MCA appeared to correlate well with past numbers of enforcement actions recorded for each zone. This provides empirical evidence that adopting manageability criteria during the planning of MPAs could lead to a marked increase in voluntary compliance. As a result, greater consideration to compliance planning during MPA design and zoning is recommended in order to optimize voluntary compliance. Whilst the majority of no-take zones in the PSGLMP case study were evaluated as being relatively effective in terms of optimizing voluntary compliance, there remains considerable potential to improve design, management and use of the poorer performing zones. Finally, the study highlighted the value of recreational fisher engagement in MPA planning processes to maximize voluntary compliance and manageability. PMID- 21669485 TI - Axillary lymph node dissection in the case of sentinel lymph node micrometastatic invasion: evaluation of three predictive models. AB - OBJECTIVE: To evaluate three predictive risk models of non-sentinel lymph node (NSLN) involvement in the case of micrometastatic sentinel node (SLN) involvement for breast cancer. STUDY DESIGN: This retrospective study included 72 successive patients with micrometastatic SLN involvement who had surgery between March 1996 and October 2007. All patients had undergone immediate or delayed axillary lymph node dissection (ALND). The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram, the Stanford nomogram and the Tenon score were applied to the population to calculate the probability of NSLN involvement. RESULTS: For the MSKCC nomogram with a threshold value of 10%, sensitivity was 50%, specificity was 70% and the negative predictive value (NPV) was 89%. The area under the receiver operating characteristic curve (AUC) was 0.6 (significant). Use of this nomogram would have avoided ALND in 49 out of 72 (68%) patients, but five out of 10 (50%) patients with NSLN involvement would not have been detected. With a threshold value of 7%, the AUC was 0.69, sensitivity was 90% and NPV was 97%. ALND would have been avoided in 31 out of 72 (43%) patients, with a 3% chance of leaving metastases when abstaining from ALND. For the Tenon score with a threshold value of 3.5, sensitivity was 50%, specificity was 72% and the AUC was 0.62. This was not clinically applicable because eight out of 10 (80%) patients with NSLN involvement would not have been detected. For the Stanford nomogram, the results could not be interpreted because the AUC was not significant. CONCLUSION: None of the tested models are sufficiently reliable for use in daily practice. The MSKCC nomogram showed the most encouraging results, especially for a threshold value of 7%, but this has not been validated in the literature. Complete axillary dissection should be performed in the case of micrometastatic SLN involvement until more data become available. PMID- 21669487 TI - Hepatocellular carcinoma with progenitor cell features distinguishable by the hepatic stem/progenitor cell marker NCAM. AB - We analyzed hepatocellular carcinoma (HCC) with progenitor cell features using hepatic stem/progenitor cell marker neural cell adhesion molecule (NCAM). Approximately 8.3% of the operated HCC cases expressed NCAM, and 22.3% of the HCC patients had soluble NCAM levels >1000ng/ml (the "highly soluble" NCAM group). Soluble NCAM status was a significant independent factor predictive of long-term survival in patients with HCC, and high levels of soluble NCAM were significantly related to intrahepatic metastasis. The 140-kDa NCAM isoform was specifically detected in the "highly soluble" NCAM group of HCC patients andits related signals are potential drug targets for NCAM+ HCC. PMID- 21669488 TI - N-nitroso compound exposure-associated transcriptomic profiles are indicative of an increased risk for colorectal cancer. AB - Endogenous formation of N-nitroso compounds (NOCs), which are known animal carcinogens, could contribute to human carcinogenesis but definitive evidence is still lacking. To investigate the relevance of NOCs in human colorectal cancer (CRC) development, we analyzed whole genome gene expression modifications in human colon biopsies in relation to fecal NOC exposure. We had a particular interest in patients suffering from intestinal inflammation as this may stimulate endogenous NOC formation, and consequently predispose to CRC risk. Inflammatory bowel disease (IBD) patients diagnosed with ulcerative colitis and irritable bowel syndrome patients without inflammation, serving as controls, were therefore recruited. Fecal NOC were demonstrated in the majority of subjects. By associating gene expression levels of all subjects to fecal NOC levels, we identified a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may potentially induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending NOC-induced carcinogenesis. In addition, pro-inflammatory transcriptomic modifications were identified in visually non-inflamed regions of the IBD colon. However, fecal NOC levels were slightly but not significantly increased in IBD patients, suggesting that inflammation did not strongly stimulate NOC formation. We conclude that NOC exposure is associated with gene expression modifications in the human colon that may suggest a potential role of these compounds in CRC development. PMID- 21669489 TI - Hypoxia-induced cisplatin resistance is reversible and growth rate independent in lung cancer cells. AB - Hypoxia frequently occurs in solid tumors and is known to contribute to chemotherapy resistance. However, the mechanisms leading to chemotherapy resistance are not entirely known. We investigated hypoxia-induced resistance to cisplatin in NSCLC cell lines. We show that chronic moderate hypoxia induced resistance to cisplatin in NSCLC cells without involvement of selection pressure. Our data suggest that stabilization of the hypoxia-inducible factor 1 alpha and down-regulation of the pro-apoptotic protein BAX play a role in this process. Furthermore, we provide evidence that hypoxia-induced resistance to cisplatin is not due to the reduced growth rate of cancer cells under hypoxic conditions. PMID- 21669490 TI - Adenovirus-mediated transfer of tris-shRNAs induced apoptosis of nasopharyngeal carcinoma cell in vitro and in vivo. AB - RNA interference (RNAi) is an evolutionary conserved mechanism for specific gene silencing. There are currently numerous cancer therapy clinical trials based on RNAi technology. Using an adenoviral system as a delivery mediator of RNAi, we investigated the therapeutic effects of targeting three genes simultaneously in vitro and in vivo. In this study, we constructed an recombinant adenoviral shRNA expression system as Adv-pEGFP-shVEGF-shTERT-shBcl-xl for multi-genes silencing. Our results showed that the adenoviral vector can achieve above 90% of transfection efficiency and induced obvious apoptosis in CNE-2 cell both in vitro and in vivo compared with targeting the TERT alone or controlled group. PMID- 21669491 TI - SUMO-specific protease 1 regulates the in vitro and in vivo growth of colon cancer cells with the upregulated expression of CDK inhibitors. AB - SUMO conjugation emerges as an important mechanism in regulating protein localization, stability and activity. SUMOylation is a dynamic process and can be reversed by a family of sentrin/SUMO-specific proteases (SENPs). However, the biological roles of SENPs in cellular processes are largely unknown. Here, we show that SENP1, a member of SENP family, is overexpressed in most of colon cancer tissues. Silencing of SENP1 expression inhibits cell growth with G(1) arrest in vitro and in nude mice and colony formation in colon cancer cell line DLD-1, suggesting that SENP1 is essential for cell growth in the colon cancer cell line. Accordingly, silencing of SENP1 results in upregulation of CDK inhibitors such as p16, p19, p21 and p27. These results suggest that SENP1 might play a role in cell cycle regulation of colon cancer cells. PMID- 21669492 TI - Spatiotemporal and anatomical analyses of P2X receptor-mediated neuronal and glial processing of sensory signals in the rat dorsal horn. AB - Extracellularly released adenosine triphosphate (ATP) modulates sensory signaling in the spinal cord. We analyzed the spatiotemporal profiles of P2X receptor mediated neuronal and glial processing of sensory signals and the distribution of P2X receptor subunits in the rat dorsal horn. Voltage imaging of spinal cord slices revealed that extracellularly applied ATP (5-500 MUM), which was degraded to adenosine and acting on P1 receptors, inhibited depolarizing signals and that it also enhanced long-lasting slow depolarization, which was potentiated after ATP was washed out. This post-ATP rebound potentiation was mediated by P2X receptors and was more prominent in the deep than in the superficial layer. Patch clamp recording of neurons in the superficial layer revealed long-lasting enhancement of depolarization by ATP through P2X receptors during the slow repolarization phase at a single neuron level. This depolarization pattern was different from that in voltage imaging, which reflects both neuronal and glial activities. By immunohistochemistry, P2X(1) and P2X(3) subunits were detected in neuropils in the superficial layer. The P2X(5) subunit was found in neuronal somata. The P2X(6) subunit was widely expressed in neuropils in the whole gray matter except for the dorsal superficial layer. Astrocytes expressed the P2X(7) subunit. These findings indicate that extracellular ATP is degraded into adenosine and prevents overexcitation of the sensory system, and that ATP acts on pre- and partly on postsynaptic neuronal P2X receptors and enhances synaptic transmission, predominantly in the deep layer. Astrocytes are involved in sensitization of sensory network activity more importantly in the superficial than in the deep layer. PMID- 21669493 TI - Acupuncture review skepticism. PMID- 21669494 TI - Using the theory of planned behaviour and prototype willingness model to target binge drinking in female undergraduate university students. AB - The current study investigated whether binge drinking in female undergraduates could be reduced by the mere measurement effect (MME), and by altering binge drinker prototypes from the prototype willingness model (PWM). Whether willingness added to the theory of planned behaviour (TPB) was also explored. Female undergraduates aged 17-25 (N=122) were randomly allocated to a prototype manipulation, mere measurement, or control group, and completed two online questionnaires separated by 14-21 days. Controlling for past behaviour, MME group consumed less alcohol than the control group, and this effect was more extreme for those who previously consumed more alcohol. However, the prototype manipulation had no effect. The TPB variables were predictive of intentions and behaviour, but willingness was not. Despite limitations, the MME could be utilised to reduce binge drinking in female undergraduates. The TPB appears to model binge drinking in female undergraduates better than the PWM, implying that binge drinking can be a reasoned behaviour. PMID- 21669495 TI - Ehrlichia and bone marrow cells: could Ehrlichial infection explain the unsuspected etiology of some diseases of the immune system? AB - A large group of diseases of unknown etiology, including leukemia, systemic lupus erythematosus, myelodysplastic disease, multiple sclerosis, amyotrophic lateral sclerosis, and rheumatoid arthritis, all present with some elements of immune system disturbance. The Ehrlichia/anaplasma (EA) are an obscure group of obligate parasitic intracellular pathogens that excrete intracellularly a substance called host transcriptional protein, which can alter transcription in cell division. Infection with EA may lead to changes in transcription in proliferating cells, such as those in the marrow, and alter the biology of the products such as T and B cells. Normally 60% of B cells produced in the marrow may be self reactive, but are eliminated before release from the marrow. Changes in transcription could allow self reactive cells to escape into the peripheral circulation and injure normal tissue, creating the dysfunctions which characterize the different immune system diseases and give them their separate identities. A number of studies previously published, and new information presented here, suggest that EA infections may be an underlying, undiagnosed cause for these and other immune system diseases. This hypothesis, long overlooked, has never been subjected to adequate, rigorous study sufficient to prove or disprove its truth. If so, patients may be treated with antibiotics, and marrow transplant manipulations already used in treatment of diseases such as lupus and leukemia may become more effective. PMID- 21669496 TI - Reprogramming neurons by microRNAs into iPSCs to treat Parkinson's disease. PMID- 21669497 TI - Effect of polymorphisms at the ghrelin gene locus on carcass, microstructure and physicochemical properties of longissimus lumborum muscle of Polish Landrace pigs. AB - The influence of RFLP-BsrI polymorphisms at the ghrelin gene locus on carcass, meat quality parameters and muscle fiber characteristics of longissimus lumborum was studied in 168 barrows of the Polish Landrace breed. Analysis revealed a high frequency of the 1 allele (0.60) with the frequencies of the 11, 12 and 22 genotypes being 0.45, 0.30 and 0.25, respectively. The most favorable parameters of meat traits were characteristic of pigs with the 22 genotype, together with a higher carcass and loin weight and lower thermal loss compared to 12 heterozygotes. The highest fat content was found in pigs with the 11 genotype, which had the highest abdominal fat weight and mean backfat thickness. Meanwhile, the 12 heterozygotes were characterized by the largest loin eye areas, highest lightness (L*) and yellowness (b*) values, and lowest redness (a*) values, as well as the greatest hardness and chewiness and largest diameter of type IIB muscle fibers compared to the other genotypes. PMID- 21669498 TI - Antioxidant and other quality properties of reindeer muscle from two different Norwegian regions. AB - The effects of origin, gender, age, and muscle type on chemical composition, colour, antioxidant status and sensory profile of reindeer muscles Longissimus dorsi (LD) and Semimembranosus (SM) from two production regions were investigated. For some variables, the comparison between reindeer and beef muscles was also included. Muscles from North Norway (NN) were darker and contained more myoglobin and moisture, and less protein and fat than muscles from Mid Norway (MN). Oxygen radical absorbance capacity (ORAC) was significantly higher in these muscles while the levels of antioxidant enzymes were significantly lower in contrast to MN muscles. Relative to male reindeer, muscles from females contained significantly more total phenols and showed higher antiradical power (ARP). Carcass weight and the sensory attributes colour, sharp and bitter flavour had higher scores for older animals. Considerable differences between LD and SM were revealed in sensory assessment. In comparison to beef reindeer meat was darker, had more myoglobin, total phenols, antioxidant enzymes, and higher ARP and ORAC values. PMID- 21669499 TI - Effects of the addition of mechanically deboned poultry meat and collagen fibers on quality characteristics of frankfurter-type sausages. AB - The effects of mechanically deboned poultry meat (MDPM) and levels of collagen fibers on comminuted, cooked sausage quality characteristics were investigated using the central composite rotatable design of response surface methodology (RSM). Use of collagen fiber as an additive affected the sausage characteristics, but the effect depended on the amount of the MDPM used. While MDPM additions resulted in higher cooking loss and darker and redder frankfurters, the addition of collagen fibers improved cooking yields and contributed to the lightness of the final product. Higher collagen fiber content was also accompanied by a significant increase in frankfurter hardness regardless of the MDPM content. Use of collagen fibers countered the negative effects of MDPM on sausage quality attributes, especially on cooking yields and final product color. PMID- 21669500 TI - Shelf life and stability traits of traditionally and modified atmosphere packaged ground beef patties treated with lactic acid bacteria, rosemary oleoresin, or both prior to retail display. AB - Previous research indicates that lactic acid bacteria (LAB) can inhibit pathogenic bacteria. This research evaluated effects of LAB inclusion on the shelf life of traditionally packaged ground beef patties; as well as the effects and possible interaction of LAB and rosemary oleoresin (RO) on the stability of high oxygen MAP ground beef during display. In both package types, trained and consumer evaluations indicated no effect (P>0.05) of LAB on lean color and off odor. Display affected trained and consumer sensory evaluations and indicated declined stability over time. Thiobarbituric acid values were lower for traditionally packaged ground beef with LAB (P<0.05) and MAP ground beef with RO or RO and LAB (P<0.05). Overall, LAB had no effect on the shelf life and stability of traditionally or high-oxygen MAP packaged ground beef patties. Therefore, utilization of LAB in ground beef to reduce pathogenic bacteria is viable without alteration of spoilage indicators. PMID- 21669501 TI - Bifocal intracranial germinoma: a retrospective analysis of treatment outcomes in 20 patients and review of the literature. AB - PURPOSE: Bifocal germinoma (BFG) is a rare intracranial neoplasm for which the choice of radiation therapy (RT) field is controversial. Some believe that BFG represents disseminated disease requiring craniospinal irradiation (CSI), whereas others believe that BFG represents localized disease and advocate for more limited fields. METHODS AND MATERIALS: We analyzed 20 BFG patients at our institutions with classic bifocal lesions (pineal gland and suprasellar region). In addition, we identified 60 BFG patients from the literature. The RT fields, use of chemotherapy and extent of disease were recorded and analyzed for each patient. RESULTS: There were 55 patients with bifocal lesions only (Group I), and 25 with bifocal lesions plus ventricular and/or CSF positive disease (Group II). The 5-year progression-free survival was 95% for Group I and 80% for Group II. In Group I, there were no failures in patients receiving CSI (n = 11), two spinal failures in those treated with more limited RT fields without chemotherapy (n = 17), and one spinal failure with chemotherapy (n = 23). In Group II, there were no failures in patients receiving CSI (n = 11), but four spinal failures were observed in patients receiving more limited RT fields with chemotherapy (n = 13); 1 patient who received whole-brain RT without chemotherapy experienced failure in the spine and brain. CONCLUSIONS: CSI is associated with excellent PFS in BFG. In Group I BFG patients, omission of spinal irradiation appears to be a reasonable approach, especially when chemotherapy is used. Patients with Group II BFG are best treated with CSI. PMID- 21669502 TI - Correlating computed tomography perfusion changes in the pharyngeal constrictor muscles during head-and-neck radiotherapy to dysphagia outcome. AB - PURPOSE: To measure changes in perfusion of the pharyngeal constrictor muscles (PCM) using CT perfusion (CTP) imaging during a course of definitive radiotherapy (RT) in head-and-neck cancer (HNC) patients and correlate with dysphagia outcome after RT. METHODS AND MATERIALS: Fifteen HNC patients underwent CTP imaging of the PCM at baseline and Weeks 2, 4, and 6 during RT and 6 weeks after RT. Blood flow and blood volume were measured in the PCM, and percentage change from baseline scan was determined. A single physician-based assessment of dysphagia was performed every 3 months after RT using the Common Terminology Criteria for Adverse Events, version 3.0 grading system. RESULTS: With a median follow-up of 28 months (range, 6-44 months), Grade 3 dysphagia was present in 7 of 15 patients, and 8 patients experienced Grade 0-2 dysphagia. The CTP parameters at Week 2 of RT demonstrated an increase in mean PCM blood flow of 161.9% vs. 12.3% (p = 0.007) and an increase in mean PCM blood volume of 96.6% vs. 8.7% (p = 0.039) in patients with 6-month post-RT Grade 3 dysphagia and Grade 0-2 dysphagia, respectively. On multivariate analysis, when adjusting for smoking history, tumor volume, and baseline dysphagia status, an increase in blood flow in the second week of RT was significant for 3- and 6-month Grade 3 dysphagia (p < 0.05). CONCLUSIONS: Perfusion changes in the PCM during Week 2 of RT in the PCM may predict the severity of dysphagia after HNC RT. PMID- 21669503 TI - Technological advancements and error rates in radiation therapy delivery. AB - PURPOSE: Technological advances in radiation therapy (RT) delivery have the potential to reduce errors via increased automation and built-in quality assurance (QA) safeguards, yet may also introduce new types of errors. Intensity modulated RT (IMRT) is an increasingly used technology that is more technically complex than three-dimensional (3D)-conformal RT and conventional RT. We determined the rate of reported errors in RT delivery among IMRT and 3D/conventional RT treatments and characterized the errors associated with the respective techniques to improve existing QA processes. METHODS AND MATERIALS: All errors in external beam RT delivery were prospectively recorded via a nonpunitive error-reporting system at Brigham & Women's Hospital/Dana Farber Cancer Institute. Errors are defined as any unplanned deviation from the intended RT treatment and are reviewed during monthly departmental quality improvement meetings. We analyzed all reported errors since the routine use of IMRT in our department, from January 2004 to July 2009. Fisher's exact test was used to determine the association between treatment technique (IMRT vs. 3D/conventional) and specific error types. Effect estimates were computed using logistic regression. RESULTS: There were 155 errors in RT delivery among 241,546 fractions (0.06%), and none were clinically significant. IMRT was commonly associated with errors in machine parameters (nine of 19 errors) and data entry and interpretation (six of 19 errors). IMRT was associated with a lower rate of reported errors compared with 3D/conventional RT (0.03% vs. 0.07%, p = 0.001) and specifically fewer accessory errors (odds ratio, 0.11; 95% confidence interval, 0.01-0.78) and setup errors (odds ratio, 0.24; 95% confidence interval, 0.08 0.79). CONCLUSIONS: The rate of errors in RT delivery is low. The types of errors differ significantly between IMRT and 3D/conventional RT, suggesting that QA processes must be uniquely adapted for each technique. There was a lower error rate with IMRT compared with 3D/conventional RT, highlighting the need for sustained vigilance against errors common to more traditional treatment techniques. PMID- 21669504 TI - Quantification of organ motion during chemoradiotherapy of rectal cancer using cone-beam computed tomography. AB - PURPOSE: There has been no previously published data related to the quantification of rectal motion using cone-beam computed tomography (CBCT) during standard conformal long-course chemoradiotherapy. The purpose of the present study was to quantify the interfractional changes in rectal movement and dimensions and rectal and bladder volume using CBCT and to quantify the bony anatomy displacements to calculate the margins required to account for systematic (Sigma) and random (sigma) setup errors. METHODS AND MATERIALS: CBCT images were acquired from 16 patients on the first 3 days of treatment and weekly thereafter. The rectum and bladder were outlined on all CBCT images. The interfraction movement was measured using fixed bony landmarks as references to define the rectal location (upper, mid, and low), The maximal rectal diameter at the three rectal locations was also measured. The bony anatomy displacements were quantified, allowing the calculation of systematic (Sigma) and random (sigma) setup errors. RESULTS: A total of 123 CBCT data sets were analyzed. Analysis of variance for standard deviation from planning scans showed that rectal anterior and lateral wall movement differed significantly by rectal location. Anterior and lateral rectal wall movements were larger in the mid and upper rectum compared with the low rectum. The posterior rectal wall movement did not change significantly with the rectal location. The rectal diameter changed more in the mid and upper than in the low rectum. No consistent relationship was found between the rectal and bladder volume and time, nor was a significant relationship found between the rectal volume and bladder volume. CONCLUSIONS: In the present study, the anterior and lateral rectal movement and rectal diameter were found to change most in the upper rectum, followed by the mid rectum, with the smallest changes seen in the low rectum. Asymmetric margins are warranted to ensure phase 2 coverage. PMID- 21669505 TI - Clinical use of the Utrecht applicator for combined intracavitary/interstitial brachytherapy treatment in locally advanced cervical cancer. AB - PURPOSE: The aims of this study were to investigate the benefit of the Utrecht interstitial CT/MR applicator for combined intracavitary/interstitial (IC/IS) approach, using magnetic resonance imaging-guided brachytherapy, over the intracavitary approach alone in patients with locally advanced cervical cancer and to analyze the clinical use of needles. METHODS AND MATERIALS: This study includes the first 20 patients treated with the new applicator. Brachytherapy consisted of two pulsed dose rate applications, and the second application was performed with the IC/IS approach. The number of needles, chosen guiding holes through the ovoids, and insertion depths were based on the dose distribution and dosimetric shortcomings of the first application (IC alone). We investigated the dosimetric gain by comparing the clinical interstitial optimized plan (IC/IS(clinical)) with an additionally generated optimized plan without needle use (IC(study)). Furthermore, we studied the relation of the inserted needles and their source loading patterns with the high-risk clinical target volume (HR-CTV). RESULTS: A total of 54 needles (range, 1-6 per application) were applied with an average depth of 25 mm. The chosen needle positions corresponded with the location of the HR-CTV extensions. The total and individual needle treatment times per application were on average 19% (range, 4-35%) and 7% (range, 2-14%) of the implant treatment time, respectively. The total (external-beam radiotherapy + brachytherapy) D90 HR-CTV for the IC(study) and the IC/IS(clinical) were on average 79.5 (SD 7.4) Gy(alpha/beta10) and 83.9 (SD 6.7) Gy(alpha/beta10), respectively, with an average gain of 4.4 (SD 2.3) Gy(alpha/beta10) for the second application. CONCLUSIONS: Needle placement was feasible in all patients and resulted in a gain in dose and better coverage of HR-CTV. Defining the location of HR-CTV protrusions and analyzing the associated needles has given us deeper understanding of the possibilities in magnetic resonance imaging-guided (pre)treatment planning with the IC/IS Utrecht applicator. PMID- 21669506 TI - Neuropathology of fetal stage Seckel syndrome: a case report providing a morphological correlate for the emerging molecular mechanisms. AB - Seckel syndrome is a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly and mental retardation. Pathological descriptions of fetal stage Seckel syndrome are rare and pre-date the evolving understanding of the genetic and molecular mechanisms involved. The autopsy findings in a case of fetal Seckel syndrome at 30 weeks gestation are presented, with detailed description of the neuropathological findings. Severe neurological abnormalities in a male fetus were observed that included microencephaly, cortical neuronal migration disorder, white matter tract hypoplasia/aplasia, premature depletion of the germinal matrix with cystic transformation and patchy absence of the external granular cell layer of the cerebellum. The striking neuropathological finding in this case was evidence of failure of the developing brain's germinal elements, providing rare morphological insight into the abnormal development of the Seckel syndrome fetal brain. The selective failure of this proliferating cell population correlates with the emerging molecular evidence that Seckel syndrome is caused by defects in ATR dependent DNA damage signaling with resultant premature death of proliferating cells. PMID- 21669507 TI - Abnormal brain MRI signal in 18q-syndrome not due to dysmyelination. AB - BACKGROUND: 18q-Syndrome is a chromosomal disorder exhibiting various symptoms arising from the central nervous system. Brain magnetic resonance imaging (MRI) of patients with this syndrome usually demonstrates abnormal white matter intensities. This is widely believed to be due to impaired myelin formation because this syndrome involves the deletion of the myelin basic protein (MBP) gene in 18q23. However, this hypothesis has not been confirmed by actual pathology because early death is unusual and autopsy rarely performed. PATIENT: A 6-year-old boy with ring chromosome 18 syndrome was examined by genetic analysis for the MBP gene, brain MRI, and autopsy. RESULTS: Haploinsufficiency of the MBP gene was confirmed. T(2)-weighted MRI revealed diffuse high intensities throughout the cerebral white matter. Pathological examination showed the cerebral white matter to be uniformly stained by Kluver-Barrera and MBP immunohistochemical staining. Oligodendrocytes were immunoreactive for proteolipid protein and ferritin but not MBP. Electron microscopy revealed clusters of axons wrapped in compact myelin sheaths with distinct major dense lines. Holzer and immunohistochemical staining for glial fibrillary acidic protein showed extensive staining of the white matter and an increased number of glial filaments. CONCLUSIONS: This pathological study demonstrated that in this disorder, the brain was well myelinated, contrary to established hypotheses about this disorder. The MRI signal abnormalities in 18q-syndrome could be attributed to gliosis and not to dysmyelination. PMID- 21669508 TI - Violence and abuse faced by junior physicians in the emergency department from patients and their caretakers: a nationwide study from Pakistan. AB - BACKGROUND: Across the globe, physicians in the emergency department (ED) are subject to violence by patients and visitors. This has been shown to have negative effects on patient care and physician performance. STUDY OBJECTIVES: This study was conducted to determine the magnitude of the problem in a developing country, to examine the effects of ED violence on physician satisfaction and performance, and to identify underlying etiologies and potential solutions. METHODS AND SETTING: This nationwide cross-sectional study examined physicians-in-training (n = 675) in the EDs of nine major tertiary care hospitals in Pakistan. RESULTS: The study reveals a significant problem, with 76.9% of physicians facing verbal (65.0%) or physical (11.9%) abuse from patients or their caretakers in the previous 2 months. Male physicians were more likely than female physicians to be victims of such episodes (p < 0.05), as were physicians who had spent more than 60 h in the ED in the past 2 months (p < 0.0001). Reduced job satisfaction and a decline in the quality of job performance were reported by 40.7% and 44.3% of physicians, respectively. Junior trainee physicians were more likely to report impairment in job performance when compared to their senior colleagues (p = 0.014). Patients' lack of education, overcrowding in the ED, and lack of coverage by security staff were identified as the major areas that need attention to address the problem. CONCLUSION: This study provides further evidence of the global prevalence of the problem, with the first nationwide epidemiological study performed in a developing country. PMID- 21669509 TI - Risk factors for complications after a foreign body is retained in the esophagus. AB - BACKGROUND: Foreign body (FB) ingestion is a common problem presenting to the emergency department (ED). The standard treatment, removal by endoscopy, is well established. However, some patients may refuse this invasive procedure due to their fear of an uncomfortable or painful experience. Obtaining hard evidence of potential complications of not having the FB removed by endoscopy would be helpful in convincing patients to have the procedure. OBJECTIVES: The aim of this study was to identify the risk factors for developing complications after FB ingestion. MATERIALS AND METHODS: The study was conducted over a period of 1 year (April 1, 2006 through March 31, 2007) at a referral medical center. Potential risk factors for developing complications (e.g., age, gender, type of FB, positive finding on radiography) were retrospectively evaluated in patients presenting with esophageal FBs and analyzed using chi-squared or Fisher's exact test and logistic regression. RESULTS: A total of 225 patients were included. Fish bones were found to be the most common FBs (73.4%). The most commonly affected site was the oropharynx (64.5%). The complication rate was 9.7%. Risk factors for complications after FB ingestion were: 1) time interval over 24 h between FB ingestion and presenting to the ED; 2) a positive radiographic finding; 3) age > 50 years. CONCLUSION: If a patient presents to the ED with at least one of the three risk factors identified, it is strongly suggested that the patient undergo endoscopy to remove the FB due to a higher risk for developing complications. PMID- 21669510 TI - Cricoid pressure provides incomplete esophageal occlusion associated with lateral deviation: a magnetic resonance imaging study. AB - BACKGROUND: Cricoid pressure is a routine component of rapid sequence induction and is designed to reduce the risk of reflux and its associated morbidity. Recent studies have raised questions regarding the efficacy of cricoid pressure in terms of changes in the pharyngeal and esophageal anatomy. OBJECTIVE: This current descriptive study was designed to observe the anatomical effect of cricoid pressure on the occlusion of esophageal lumen in conscious volunteers using magnetic resonance imaging (MRI). METHODS: We quantitatively assessed esophageal patency before and during application of cricoid pressure in 20 awake volunteers utilizing MRI. RESULTS: Target cricoid pressure was achieved in 16 of 20 individuals, corresponding to a mean percentage reduction in cricovertebral distance of 43% (range 25-80%). Cricoid pressure was applied incorrectly in 4 (20%) individuals as evidenced by no change in the cricovertebral distance. Incomplete esophageal occlusion was seen in 10 of 16, or 62.5% (95% confidence interval 35-85%) of individuals when appropriate cricoid pressure was applied. Incomplete esophageal occlusion was always associated with a lateral deviation of the esophagus. None of the 6 subjects with complete occlusion had esophageal deviation during the appropriate application of cricoid pressure. CONCLUSION: Effective application of cricoid pressure by an experienced operator frequently resulted in lateral deviation of the esophagus and incomplete occlusion of esophageal lumen. Reliance on cricoid pressure for esophageal occlusion requires further evaluation utilizing functional studies. PMID- 21669512 TI - The relation between objective and subjective domains of recovery among persons with schizophrenia-related disorders. AB - In recent years, growing emphasis has been placed on the vision of recovery, which is broadly organized into two types: clinical objective versus personal subjective. The purpose of the present study was to investigate the relation between objective clinical recovery as defined by symptom severity and level of functioning, and subjective personal recovery as defined by quality of life, domains of personal confidence and hope, willingness to ask for help, reliance on others and no domination by symptoms. One hundred and fifty-nine persons diagnosed with schizophrenia or schizoaffective disorder completed measures of recovery, quality of life, perceived social support and emotional loneliness. Clinicians used the Modified Brief Psychiatric Rating Scale and the Global Assessment Functioning Scale to assess the severity of symptoms and level of functioning. Results revealed no direct correlation between total score of observer ratings of symptoms and total score of subjective self-report of being in recovery. The relationship between total score of symptoms and total score of subjective self-report of recovery was moderated by the age of onset. Magnitude of the self-report of subjective recovery was related to higher levels of reported social support and lower levels of reported loneliness. Finally, analyses suggested that the impact of social support and loneliness upon self reported recovery was mediated by quality of life. Taken together, results are consistent with literature suggesting that clinical objective recovery is not synonymous with personal subjective recovery yet can be conceptualized as complementary. PMID- 21669513 TI - Theta burst stimulation in the negative symptoms of schizophrenia and striatal dopamine release. An iTBS-[11C]raclopride PET case study. PMID- 21669514 TI - The socioeconomic consequences of multiple sclerosis: a controlled national study. AB - Multiple sclerosis (MS) has serious negative effects on health-, social-, and work-related issues for the patients and their families, thus causing significant socioeconomic burden. The objective of the study was to determine healthcare costs and indirect illness costs in MS patient in a national sample. We used all national records from the Danish National Patient Registry (1998-2006), and identified 10,849 MS patients which were compared with 43,396 randomly age-, sex- and social matched citizens. Healthcare sector costs included frequencies and costs of hospitalizations and weighted outpatient use, frequencies of visits and hospitalizations and costs from primary sectors, and the use and costs of drugs. Productivity costs (the value of lost productivity from time off from work due to illness) and all social transfer payments were also calculated. Patients with MS had significantly higher rates of health-related contact and medication use and very low employment rate which incurred a higher socioeconomic cost. The income level of employed MS patients was significantly lower than that of control subjects. The annual total health sector costs and productivity costs were ?14,575 for MS patients vs. ?1163 for control subjects (p<0.001), corresponding to an annual mean excess health-related cost of ?13,413 for each patient with MS. In addition, the MS patients received an annual mean excess social transfer income of ?6843. MS present social and economical consequences more than eight years before diagnosis. We conclude that MS causes major socioeconomic consequences for the individual patient and for society. Productivity costs are a far more important economic factor, especially due to reduced employment, which are enhanced by the early age of diagnose onset. PMID- 21669511 TI - The International Classification of Functioning, Disability and Health: development of capacity and performance scales. AB - OBJECTIVE: There has been no attempt to obtain a continuous summary measure of disability from the checklist of the International Classification of Functioning, Disability and Health (ICF). Our objective was to assess whether valid scales of Capacity and Performance could be developed from the "Activities and Participation" domain of the ICF checklist. STUDY DESIGN AND SETTING: A multicenter, observational study of 1,092 patients with 12 different chronic conditions from five European countries was conducted. Exploratory and confirmatory factor analyses were performed to assess the underlying factor structure. Reliability and validity of the Capacity and Performance scales were evaluated. Construct validity was assessed calculating effect size coefficients between extreme severity groups (discriminant ability). RESULTS: The good fit of the confirmatory factor model supported the global scales of Capacity and Performance and their "Psychosocial" and "Physical" subscales. Reliability was excellent (coefficients=0.79-0.92). Effect sizes of most conditions were large for the Capacity global scale (0.50-3.05), and slightly lower for the Performance global scale (0.45-2.57). CONCLUSIONS: Our findings support the measurement model, reliability, and validity of the Capacity and Performance scales. Summary measures of functioning based on the ICF can be obtained using these scales, which should facilitate their incorporation in clinical and epidemiological studies. PMID- 21669515 TI - Child and adolescent neuropsychopharmacology: now or never. PMID- 21669516 TI - Airway vascular damage in elite swimmers. AB - We postulated that high level swimming can promote airway inflammation and thus asthma by enhancing local vascular permeability. We aimed to test this hypothesis by a cross-sectional study comparing swimmers (n = 13, 17 +/- 3 years, competing 7 +/- 4 years, training 18 +/- 3 h per week), asthmatic-swimmers (n = 6, 17 +/- 2 years, competing 8 +/- 3 years, training 16 +/- 4 h per week), and asthmatics (n = 19, 14 +/- 3 years). Subjects performed induced sputum and had exhaled nitric oxide, lung volumes, and airway responsiveness determined. Airway vascular permeability index was defined as the ratio of albumin in sputum and serum. Results from the multiple linear regression showed each unit change in airway vascular permeability index was associated with an increase of 0.97% (95%CI: 0.02 to 1.92; p = 0.047) in sputum eosinophilis, and of 2.64% (95%CI:0.96 to 4.31; p = 0.006) in sputum neutrophils after adjustment for confounders. In a general linear model no significant differences between airway vascular permeability between index study groups existed, after controlling for sputum eosinophilis and neutrophils. In conclusion, competitive swimmers training in chlorine-rich pools have similar levels of airway vascular permeability than asthmatics. Although competitive swimming has been associated with asthma, airway inflammation and airway hyperesponsiveness do not seem to be dependent on increased airway vascular permeability. PMID- 21669517 TI - Factors affecting treatment choices in paediatric palliative care: comparing parents and health professionals. AB - STUDY AIM: When children with cancer are no longer curable, parents often need to decide between further aggressive treatments or symptom relief alone. Objectives were to: (1) Describe and compare factors influencing parent and healthcare professional (HCP) decision-making regarding the choice between chemotherapy versus supportive care alone in paediatric palliative care; and (2) Describe how these factors influence this choice. METHODS: Participants included parents of children with cancer without a reasonable chance of cure and health care professionals in paediatric oncology. Respondents were asked to indicate the preferred option and to report what factors affected their choice. Each factor was then rated on an importance visual analogue scale (VAS) ranging from 0 to 10. The importance scales were compared between parents and HCPs and the influence of importance ratings on preferred option was examined. RESULTS: A total of 77 parents and 128 health care professionals participated. For parents the median importance scores for hope, increased survival time and child quality of life were rated as most important (VAS score=10). Parents rated these factors to be significantly more important than HCPs. Conversely, HCPs rated financial considerations more important than parents. For HCPs, stronger importance ranking for parent opinion was associated with stronger preference for aggressive chemotherapy. CONCLUSION: Hope, increased survival time and child quality of life are all more important factors to parents when decision-making at end-of-life compared to HCPs. Conversely, HCPs place greater emphasis on the families' financial considerations than parents. Understanding these differences may aid in communication and improve end-of-life care for children with cancer. PMID- 21669519 TI - Nutrient removal of effluent from quail farm through cultivation of Wolffia arrhiza. AB - The objective of this work was to study the nutrient removal using the Wolffiaarrhiza during the treatment of laying quails farm effluent. The relationship between W. arrhiza biomass and treatment time, the change in water qualities, and nitrogen-balance (N-balance) were evaluated. The results showed that a biomass of 12.0g of W. arrhiza per liter of effluent and a treatment period of 30 days were found to provide the best conditions for W. arrhiza's growth and the quality of the treated effluent in terms of biological oxygen demand, suspended solids, total phosphorus, nitrate, total ammonia nitrogen and total Kjeldahl nitrogen. The pH and salinity were similar for each level of biomass. The W. arrhiza biomasses of 4.00-12.0g/l of effluent were suitable for W. arrhiza survival over time. Since W. arrhiza can fix N in the atmosphere, it can grow very well in effluent containing a low level of N. PMID- 21669518 TI - Studies of laccase from Trametes versicolor in aqueous solutions of several methylimidazolium ionic liquids. AB - Stability and kinetic behavior of laccase from Trametes versicolor in the presence of several ionic liquids from the methylimidazolium family have been investigated. In general laccase stability diminished as the size of the alkylic substitute in the methylimidazolium ring increased. Higher concentrations of ionic liquids caused more destabilization than lower ones. Thus, low concentrations of [C(2)mim(+)][EtSO(4)(-)] allowed maintaining enzymatic stability. [C(4)mim(+)][Cl(-)] appeared to have a stabilizing effect on laccase, as little activity decay was observed within three weeks. Kinetic studies indicated that both [C(2)mim(+)][EtSO(4)(-)] and [C(4)mim(+)][Cl(-)] inhibited laccase activity, although 10-fold more [C(2)mim(+)][EtSO(4)(-)] than [C(4)mim(+)][Cl(-)] was required to cause the same degree of inhibition. A kinetic model was developed to represent the experimental data. PMID- 21669520 TI - Substituent effect on the preferred DNA binding mode and affinity of a homologous series of naphthalene diimides. AB - A combination of isothermal titration calorimetry (ITC), topoisomerase I DNA unwinding assays, and ethidium bromide displacement studies were employed to investigate the binding of a homologous series of naphthalene diimides (NDI) to DNA. Our results suggest that the nature of the substituent plays a significant role in both the preferred binding mode and relative binding affinity of the compounds of this study. Only intercalative-type binding (K=15+/-3*10(6)M(-1)) was observed for the NDI with the smallest substituent (trimethyl-ethylamino), while larger members of the series (diethylmethyl-, dipropylmethyl- and dibutylmethyl-ethylamino substituents) adopted an additional binding mode of higher affinity (K(1)=31-78*10(6)M(-1)). PMID- 21669521 TI - Selective non zinc binding inhibitors of MMP13. AB - Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom. PMID- 21669522 TI - In vitro inhibition of alpha-carbonic anhydrase isozymes by some phenolic compounds. AB - Carbonic anhydrase inhibitors (CAIs) are a class of pharmaceuticals used as antiglaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, gastric and duodenal ulcers, neurological disorders or osteoporosis. We report here the inhibitory capacities of some phenolic compounds against three human CA isozymes (hCA I, hCA II, and hCA VI) and the gill carbonic anhydrase of the teleost fish Dicentrarchus labrax (European seabass) (dCA). The isozymes showed quite diverse inhibition profiles with these compounds. These data may lead to design novel CAIs with a diverse inhibition mechanism compared to sulfonamide/sulfamate inhibitors. PMID- 21669523 TI - Synthesis of useful fragments in drug discovery: 2-Amino-5-tert-butylpyridine and its oxidised analogues. AB - A novel and robust synthesis of the fragment, 2-amino-5-tert-butylpyridine, has been described, which has been shown to have improved physicochemical properties over 4-tert-butylaniline, when considering drug-like properties. The synthesis also yields fragments containing more highly oxidised precursors to the tert butyl group as intermediates. These fragments can be incorporated into final target molecules, yielding pharmaceutical compounds and their putative CYP mediated oxidative metabolites, which can aid in elucidation of metabolic clearance processes. PMID- 21669524 TI - Antihyperglycemic and neuroprotective effects of one novel Cu-Zn SOD mimetic. AB - Increasing evidence supports that OS plays important roles in diabetes mellitus and cerebral ischemia. This suggests that recovering an impaired endogenous superoxide dismutase (SOD) enzyme system induced by OS with a mimetic would be beneficial and protective for these diseases. In present study, one nonpeptidyl small molecular weight compound (D34) was synthesized. Its SOD mimetic activity and the potential therapeutic actions were also evaluated both in vivo and in vitro. The in vitro nitro blue tetrazolium (NBT) assay indicated that D34 presents an SOD mimetic activity. D34 (20MUmol/kg) exhibited significant antihyperglycemic activity in alloxan-diabetic mice. D34 could also ameliorate the cerebral neuronal death in hippocampus of global cerebral ischemia mice. Furthermore, the D34 treatment significantly decreased malondialdehyde (MDA) contents and increased SOD activities in brains or livers of diabetes mice or cerebral ischemic mice. In conclusion, these preliminary findings support that D34 exhibits SOD mimetic activity and possesses significant antihyperglycemic and neuroprotective effects. PMID- 21669526 TI - Anti-resorptive activity and pharmacokinetic study of N(1),N(1)-diisopropyl-N(2) (diphenylphosphoryl)-2-(4-nitrophenyl)acetamidine. AB - In vitro anti-resorptive activity, mechanism of action, pharmacokinetic profile and in vivo anti-resorptive activity of N(1),N(1)-diisopropyl-N(2) (diphenylphosphoryl)-2-(4-nitrophenyl)acetamidine (1) were evaluated. PMID- 21669525 TI - Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening. AB - SHP2, encoded by PTPN11, is a non-receptor protein tyrosine phosphatase (PTP) containing two tandem Src homology-2 (SH2) domains. It is expressed ubiquitously and plays critical roles in growth factor mediated processes, primarily by promoting the activation of the RAS/ERK signaling pathway. Genetic and biochemical studies have identified SHP2 as the first bona fide oncoprotein in the PTP superfamily, and a promising target for anti-cancer and anti-leukemia therapy. Here, we report a structure-based approach to identify SHP2 inhibitors with a novel scaffold. Through sequential virtual screenings and in vitro inhibition assays, a reversible competitive SHP2 inhibitor (C21) was identified. C21 is structurally distinct from all known SHP2 inhibitors. Combining molecular dynamics simulation and binding free energy calculation, a most likely binding mode of C21 with SHP2 is proposed, and further validated by site-directed mutagenesis and structure-activity relationship studies. This binding mode is consistent with the observed potency and specificity of C21, and reveals the molecular determinants for further optimization based on the new scaffold. PMID- 21669527 TI - Targeted and armed oncolytic adenovirus via chemoselective modification. AB - Oncolytic adenoviruses (Ads) are an emerging alternative therapy for cancer; however, clinical trial have not yet demonstrated sufficient efficacy. When oncolytic Ads are used in combination with taxoids a synergistic increase in both cytotoxicity and viral replication is observed. In order to generate a next generation oncolytic adenovirus, virion were physically conjugated to a highly potent taxoid, SB-T-1214, and a folate targeting motif. Conjugation was enabled via the metabolic incorporation of non-canonical monosaccharides (O-GlcNAz) and amino acids (homopropargylglycine), which served as sites for chemoselective modification. PMID- 21669528 TI - Identification of non-amidine inhibitors of acid-sensing ion channel-3 (ASIC3). AB - A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition. PMID- 21669529 TI - Discovery of a new type inhibitor of human glyoxalase I by myricetin-based 4 point pharmacophore. AB - The human glyoxalase I (hGLO I), which is a rate-limiting enzyme in the pathway for detoxification of apoptosis-inducible methylglyoxal (MG), has been expected as an attractive target for the development of new anti-cancer drugs. We have previously identified a natural compound myricetin as a substrate transition state (Zn(2+)-bound MG-glutathione (GSH) hemithioacetal) mimetic inhibitor of hGLO I. Here, we constructed a hGLO I/inhibitor 4-point pharmacophore based on the binding mode of myricetin to hGLO I. Using this pharmacophore, in silico screening of chemical library was performed by docking study. Consequently, a new type of compound, which has a unique benzothiazole ring with a carboxyl group, named TLSC702, was found to inhibit hGLO I more effectively than S-p bromobenzylglutathione (BBG), a well-known GSH analog inhibitor. The computational simulation of the binding mode indicates the contribution of Zn(2+) chelating carboxyl group of TLSC702 to the hGLO I inhibitory activity. This implies an important scaffold-hopping of myricetin to TLSC702. Thus, TLSC702 may be a valuable seed compound for the generation of a new lead of anti-cancer pharmaceuticals targeting hGLO I. PMID- 21669530 TI - Synthesis and activities of naphthalimide azoles as a new type of antibacterial and antifungal agents. AB - Naphthalimide-derived azoles as a new type of antimicrobial agents were synthesized and evaluated for their efficiency in vitro against eight bacteria and two fungi by two fold serial dilution technique. Most title compounds exhibited good antimicrobial potency with low MIC values ranging from 1 to 16MUg/mL. Notably, some synthesized compounds displayed comparable or even better antibacterial and antifungal activities against some tested strains than the reference drugs Orbifloxacin, Chloromycin and Fluconazole, respectively. PMID- 21669532 TI - Identification of lysine acetyltransferase p300 substrates using 4-pentynoyl coenzyme A and bioorthogonal proteomics. AB - Proteomic studies have identified a plethora of lysine acetylated proteins in eukaryotes and bacteria. Determining the individual lysine acetyltransferases responsible for each protein acetylation mark is crucial for elucidating the underlying regulatory mechanisms, but has been challenging due to limited biochemical methods. Here, we describe the application of a bioorthogonal chemical proteomics method to profile and identify substrates of individual lysine acetyltransferases. Addition of 4-pentynoyl-coenzyme A, an alkynyl chemical reporter for protein acetylation, to cell extracts, together with purified lysine acetyltransferase p300, enabled the fluorescent profiling and identification of protein substrates via Cu(I)-catalyzed alkyne-azide cycloaddition. We identified several known protein substrates of the acetyltransferase p300 as well as the lysine residues that were modified. Interestingly, several new candidate p300 substrates and their sites of acetylation were also discovered using this approach. Our results demonstrate that bioorthogonal chemical proteomics allows the rapid substrate identification of individual protein acetyltransferases in vitro. PMID- 21669531 TI - Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system x(c)(-). AB - Evidence was acquired prior to suggest that the vesicular glutamate transporter (VGLUT) but not other glutamate transporters were inhibited by structures containing a weakly basic alpha-amino group. To test this hypothesis, a series of analogs using a hydantoin (pK(a)~9.1) isostere were synthesized and analyzed as inhibitors of VGLUT and the obligate cystine-glutamate transporter (system x(c)( )). Of the hydantoin analogs tested, a thiophene-5-carboxaldehyde analog 2l and a bis-hydantoin 4b were relatively strong inhibitors of VGLUT reducing uptake to less than 6% of control at 5mM but few inhibited system x(c)(-) greater than 50% of control. The benzene-2,4-disulfonic acid analog 2b and p-diaminobenzene analog 2e were also good hydantoin-based inhibitors of VGLUT reducing uptake by 11% and 23% of control, respectively, but neither analog was effective as a system x(c)( ) inhibitor. In sum, a hydantoin isostere adds the requisite chemical properties needed to produce selective inhibitors of VGLUT. PMID- 21669533 TI - Optimisation of a novel series of selective CNS penetrant CB(2) agonists. AB - A series of benzimidazole CB(2) receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB(2) full agonist (EC(50) 2.7nM) with excellent selectivity over the CB(1) receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat. PMID- 21669534 TI - Intra-articular local anaesthetic on the day after surgery improves pain and patient satisfaction after Unicompartmental Knee Replacement: a randomised controlled trial. AB - Intra-operative local anaesthetic infiltration provides good early pain relief after Unicompartmental Knee Replacement (UKR). However, appreciable pain may occur on the day after surgery. The purpose of this double-blinded, prospective randomised controlled trial was to evaluate the effectiveness of a bolus of local intra-articular anaesthetic given early on the day after surgery. Forty-four patients were randomised to receive an intra-articular injection, via an epidural catheter inserted at operation, of either 20 ml 0.5% plain bupivacaine or 20 ml normal saline. All patients received a femoral nerve block with 20 ml prilocaine 1% and local anaesthetic infiltration by the surgeon. Patients injected with bupivacaine had significantly less (p<0.001) pain than control patients immediately (mean pain score 1.82 v 6.1) and 6 hours (2.5 v 5.7) after injection. Patient satisfaction was also significantly greater (p<0.001) in the local anaesthetic group. We conclude that a bolus dose of intra-articular bupivacaine early on the day after surgery dramatically improves pain control after UKR and improves patient satisfaction. PMID- 21669535 TI - 4-alkoxy-3-arylfuran-2(5H)-ones as inhibitors of tyrosyl-tRNA synthetase: synthesis, molecular docking and antibacterial evaluation. AB - A series of novel 4-alkoxy-3-arylfuran-2(5H)-ones as tyrosyl-tRNA synthetase inhibitors were synthesized. Of these compounds, 3-(4-hydroxyphenyl)-4-(2 morpholinoethoxy)furan-2(5H)-one (27) was the most potent. The binding model and structure-activity relationship indicate that replacement of morpholine-ring in the side chain of 27 with a substituent containing more hydrophilic groups would be more suitable for further modification. Antibacterial assay revealed that the synthetic compounds are effective against growth of Gram-positive organisms, and 27 is the most potent agent against Staphylococcus aureus ATCC 25923 with MIC(50) value of 0.23 MUg/mL. PMID- 21669536 TI - Mapping the intestinal alpha-glucogenic enzyme specificities of starch digesting maltase-glucoamylase and sucrase-isomaltase. AB - Inhibition of intestinal alpha-glucosidases and pancreatic alpha-amylases is an approach to controlling blood glucose and serum insulin levels in individuals with Type II diabetes. The two human intestinal glucosidases are maltase glucoamylase and sucrase-isomaltase. Each incorporates two family 31 glycoside hydrolases responsible for the final step of starch hydrolysis. Here we compare the inhibition profiles of the individual N- and C-terminal catalytic subunits of both glucosidases by clinical glucosidase inhibitors, acarbose and miglitol, and newly discovered glucosidase inhibitors from an Ayurvedic remedy used for the treatment of Type II diabetes. We show that features of the compounds introduce selectivity towards the subunits. Together with structural data, the results enhance the understanding of the role of each catalytic subunit in starch digestion, helping to guide the development of new compounds with subunit specific antidiabetic activity. The results may also have relevance to other metabolic diseases such as obesity and cardiovascular disease. PMID- 21669538 TI - Peak triceps surae muscle activity is not specific to knee flexion angles during MVIC. AB - There is limited research on peak activity of the separate triceps surae muscles in select knee flexion (KF) positions during a maximum voluntary isometric contraction (MVIC) used to normalize EMG signals. The aim of this study was to determine how frequent peak activity occurred during an MVIC for soleus (SOL), gastrocnemius medialis (GM), and gastrocnemius lateralis (GL) in select KF positions, and if these peaks were recorded in similar KF positions. Forty-eight healthy individuals performed unilateral plantar-flexion MVIC in standing with 0 degrees KF and 45 degrees KF, and in sitting with 90 degrees KF. Surface EMG of SOL, GM, and GL were collected and processed in 250 ms epochs to determine peak root-mean-square amplitude. Peak activity was most frequently captured in standing and rarely in sitting, with no position selective to SOL, GM or GL activity. Peak GM and GL activity was more frequent in 0 degrees KF than 45 degrees KF, and more often in similar KF positions than not. Peak SOL activity was just as likely in 45 degrees KF as 0 degrees KF, and more in positions similar to GM, but not GL. The EMG amplitudes were at least 20% greater in positions that captured peak activity over those that did not. The overall findings support performing an MVIC in more than one KF position to normalize triceps surae EMG. It is emphasized that no KF position is selective to SOL, GM, or GL alone. PMID- 21669537 TI - Francisella tularensis LVS-induced Interleukin-12 p40 cytokine production mediates dendritic cell migration through IL-12 Receptor beta1. AB - Three cytokines use the IL-12p40 cytokine subunit namely: IL-12p70 (IL-12 comprised of IL-12p40 and IL-12p35), IL-23 (comprised of the IL-12p40 and IL 23p19 subunits) and homodimeric IL-12p40 (IL-12(p40)(2)). Following activation, immature dendritic cells (DCs) upregulate the chemokine receptor Chemokine-C Receptor 7 (CCR7), and migrate in response to homeostatic chemokines such as chemokine (C-C motif) ligand 19 (CCL19). Induction of the cytokine IL-12p40 in response to pathogen-exposure, likely in its homodimeric form, is one of the primary events that mediates migration of DCs in response to CCL19. Here we show that following exposure to Francisella tularensis Live Vaccine Strain (LVS), DCs produce IL-12p40 and promote the migration of DCs to the chemokine CCL19 in an IL 12Rbeta1- and IL-12p(40)(2)-dependent manner. Induction of IL-12p40 and resulting chemokine responsiveness in DCs is TLR2-dependent and coincides with the uptake of F. tularensis LVS and activation of DCs. Importantly, we show that IL-12Rbeta1 signaling is required for DC migration from the lung to the draining lymph node following F. tularensis LVS exposure and coincides with accumulation of IL-12p40 expressing DCs in the draining lymph nodes. Together, these findings illustrate that IL-12p40 is induced rapidly in response to F. tularensis LVS and is required for DC migration through an IL-12Rbeta1-IL-12(p40)(2) dependent mechanism. PMID- 21669539 TI - EMG-based muscle fatigue assessment during dynamic contractions using principal component analysis. AB - A novel approach to fatigue assessment during dynamic contractions was proposed which projected multiple surface myoelectric parameters onto the vector connecting the temporal start and end points in feature-space in order to extract the long-term trend information. The proposed end to end (ETE) projection was compared to traditional principal component analysis (PCA) as well as neural network implementations of linear (LPCA) and non-linear PCA (NLPCA). Nine healthy participants completed two repetitions of fatigue tests during isometric, cyclic and random fatiguing contractions of the biceps brachii. The fatigue assessments were evaluated in terms of a modified sensitivity to variability ratio (SVR) and each method used a set of time-domain and frequency-domain features which maximized the SVR. It was shown that there was no statistical difference among ETE, PCA and LPCA (p>0.99) and that all three outperformed NLPCA (p<0.0022). Future work will include a broader comparison of these methods to other new and established fatigue indices. PMID- 21669540 TI - HIV risk reduction intervention among traditionally circumcised young men in South Africa: a cluster randomized control trial. AB - The aim of this study was to test a 180-minute group HIV risk-reduction counseling intervention trial with men undergoing traditional circumcision in South Africa to reduce behavioral disinhibition (false security) as a result of the procedure. A cluster randomized controlled trial design was employed using a sample of 160 men, 80 in the experimental group and 80 in the control group. Comparisons between baseline and 3-month follow-up assessments on key behavioral outcomes were completed. We found that behavioral intentions, risk-reduction skills, and male role norms did not change in the experimental compared to the control condition. However, HIV-related stigma beliefs were significantly reduced in both conditions over time. These findings show that one small-group HIV risk reduction intervention did not reduce sexual risk behaviors in recently traditionally circumcised men at high risk for behavioral disinhibition. PMID- 21669541 TI - Insurance claims after vascular surgery in Sweden. AB - OBJECTIVES: The study aimed to estimate the incidence and causes of insurance claims (IC) after vascular surgery (VS) reported to the Swedish Medical Injury Insurance (SMII); and to validate the registration of complications in the National Vascular Registry (Swedvasc). METHODS: The medical records of all IC in VS in Sweden reported to the SMII 2002-2007 were scrutinised and cross-referenced against Swedvasc. RESULTS: There were 193 claims after VS: varicose-veins (66), lower extremity (45), aortic (31) or carotid artery (21), access (19) or other VS (11). Frequent causes of claims were peripheral nerve injury (76), wound infection (22) and cranial nerve injury (15). More than half of the patients suffered permanent injuries, three died. As many as 55 (28%) received economic compensation (an average of 45% of all ICs in SMII). The highest frequency of compensated claims (1:650 yearly procedures) was for carotid artery surgery. Of the procedures, 187 were elective. Compared with the Swedvasc, claudication was a more common indication (28% vs. 12%). Nearly one-fifth (18%) were incorrectly registered in Swedvasc. CONCLUSIONS: The most common causes of insurance claims were peripheral nerve injuries and infections. Patients raising insurance claims after vascular surgery undergo acute procedures less frequently, and are correctly registered in the Swedvasc in 82% of cases. PMID- 21669542 TI - Identification of two novel PBGD mutations in acute intermittent porphyria patients accompanying anemia in mainland China. PMID- 21669543 TI - Are emotion regulation skills related to adjustment among people with chronic pain, independent of pain coping? AB - Although emotion regulation capacities have been linked to adjustment among people with chronic pain, researchers have yet to determine whether these capacities are related to functioning independent of established facets of pain coping. The present study was designed to address this gap. A sample 128 Australian adults with chronic pain (44 men, 84 women) completed self-report measures of adjustment (quality of life, negative affect, and pain-related disability), pain coping, and features of emotion regulation (emotion appraisal, perceived efficacy in emotion regulation, emotion utilization). Hierarchical multiple regression analyses indicated that efficacy in emotion regulation was related to quality of life and reduced negative affect even after statistically controlling for effects of other measures of adjustment, pain coping efficacy, and pain coping. Conversely, features of emotion regulation did not improve the prediction model for pain-related disability. Findings suggest emotion regulation capacities may have a unique role in the prediction of specific facets of adjustment among people with chronic pain. PMID- 21669544 TI - Effect of sonication on eliminating of phorate in apple juice. AB - The degradation of phorate in apple juice by sonication was investigated in the present study. Results showed that sonication was effective in eliminating phorate in apple juice, and the ultrasonic power and sonication time significantly influenced the degradation of phorate (p<0.05). The degradation of phorate followed the first-order kinetics model well. Phorate-oxon and phorate sulfoxide were identified as the degradation products of phorate by gas chromatography-mass spectrometry (GC-MS). Moreover, the toxicity of apple juice samples spiked with phorate was significantly reduced by sonication (p<0.05). The quality indexes of apple juice including pH, titratable acidity (TA), electrical conductivity (EC), total soluble solids (TSS), and the contents of sucrose, glucose and fructose were not affected by sonication, and no visible difference in color was observed between the sonicated samples and the control. PMID- 21669545 TI - The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinson's disease. AB - OBJECTIVE: To evaluate the impact of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on the prevalence of non-motor symptoms reported by Parkinson's disease (PD) patients one year following surgery and to examine whether there was an association between number of non-motor symptoms reported and quality of life (QoL). METHODS: Twenty-four patients who received bilateral STN DBS and had follow-up evaluations one year after surgery were included in this study. Patients' motor function was evaluated with the Unified Parkinson's Disease Rating Scale, non-motor symptoms were assessed with the Non-Motor Symptom questionnaire (NMSQuest) and quality of life was assessed with the PDQ-39. RESULTS: There was a mean of 12 non-motor symptoms reported prior to surgery which was significantly reduced to a mean of 7 symptoms one year after surgery. Autonomic symptoms were the most frequently reported and demonstrated the greatest reductions following surgery. Twenty-seven of the 30 items represented in the NMSQuest were reported less frequently one year after surgery compared to before surgery. The reduction in non-motor symptoms was significantly correlated with total QoL scores and the subscales of mobility, activities of daily living, cognition and bodily discomfort. CONCLUSIONS: Non-motor symptoms are common in patients with advanced PD. The number of non-motor symptoms was significantly decreased one year following bilateral STN DBS which was associated with a significant improvement in QoL. Further studies focused on specific non-motor symptoms are warranted in order to fully understand the impact and mechanisms of STN DBS on these symptoms. PMID- 21669546 TI - Apraxia of eyelid closure in autopsy-confirmed vascular progressive supranuclear palsy. PMID- 21669547 TI - Anisotropic path searching for automatic neuron reconstruction. AB - Full reconstruction of neuron morphology is of fundamental interest for the analysis and understanding of their functioning. We have developed a novel method capable of automatically tracing neurons in three-dimensional microscopy data. In contrast to template-based methods, the proposed approach makes no assumptions about the shape or appearance of neurite structure. Instead, an efficient seeding approach is applied to capture complex neuronal structures and the tracing problem is solved by computing the optimal reconstruction with a weighted graph. The optimality is determined by the cost function designed for the path between each pair of seeds and by topological constraints defining the component interrelations and completeness. In addition, an automated neuron comparison method is introduced for performance evaluation and structure analysis. The proposed algorithm is computationally efficient and has been validated using different types of microscopy data sets including Drosophila's projection neurons and fly neurons with presynaptic sites. In all cases, the approach yielded promising results. PMID- 21669548 TI - Fluorescence and DNA-binding properties of neodymium(III) and praseodymium(III) complexes containing 1,10-phenanthroline. AB - The binding of neodymium(III) and praseodymium(III) complexes containing 1,10 phenanthroline, [M(phen)2Cl3.OH2] (M=Nd (1), Pr (2)), to DNA has been investigated by absorption, emission, and viscosity measurements. The complexes show absorption decreasing in charge transfer band, fluorescence decrement when bound to DNA. The binding constant Kb has been determined by absorption measurement for both complexes and found to be (6.76+/-0.12)*10(4) for 1 and (1.83+/-0.15)*10(4)M(-1), for 2. The fluorescence of [M(phen)2Cl3.OH2] (M=Nd (1), Pr (2)) has been studied in detail. The results of fluorescence titration reveal that DNA has the strong ability to quenching the intrinsic fluorescence of Nd(III) and Pr(III) complexes through the static quenching procedure. The binding site number n, apparent binding constant Kb and the Stern-Volmer constant kSV are determined. Thermodynamic parameters, enthalpy change (DeltaH degrees ) and entropy change (DeltaS degrees ), are calculated according to relevant fluorescent data and Van't Hoff equation. The experimental data suggest that the complexes bind to DNA by non-intercalative mode. Major groove binding is the preferred mode of interaction for [M(phen)2Cl3.OH2] (M=Nd (1), Pr (2)) with DNA. PMID- 21669549 TI - Evoked potential study of hippocampal efferent projections in the human brain. AB - OBJECTIVE: To explore in human potential hippocampal projections within and outside the temporal lobe. METHODS: We performed intra-cerebral electrical stimulations in seven patients investigated by depth electrodes for refractory epilepsy and analyzed the presence of evoked potentials (EPs) in all brain regions explored. Bipolar electrical stimulations, consisting of two series of 25 pulses of 1 ms duration, 0.2 Hz frequency, and 3 mA intensity, were delivered in a total of 36 hippocampal stimulations sites. RESULTS: Reproducible EPs were recorded in several brain regions with variable latencies, amplitudes and morphologies. Within the temporal lobe, EPs were present in the amygdala, entorhinal cortex, temporal pole and temporal neocortex. EPs were also observed in the frontal lobe, anterior cingulate gyrus and orbito-frontal cortex, midcingulate and posterior cingulate gyrus, insula and thalamic pulvinar nucleus. CONCLUSION: Our results demonstrate a large distribution of direct or indirect hippocampal projections. SIGNIFICANCE: This widespread connectivity supports the previous definition of different networks involved mainly in memory and behavioral processes, implicating the temporal lobe, the cingulate gyrus or the prefrontal region. Our data provide some clues to further evaluate potential pathways of propagation of mesial temporal lobe seizure, via the insula or the pulvinar nucleus. PMID- 21669550 TI - Detecting weak protein-protein interactions by modified far-western blotting. AB - We developed a cross-linking far-western blotting (WB) technique to detect weak protein-protein interactions. In addition, by comparison of the banding patterns resulting from the conventional and cross-linking methods, weak interactions can be identified by monitoring the enhancement of band intensities. PMID- 21669551 TI - Relation between morningness-eveningness score and depressive symptoms among patients with delayed sleep phase syndrome. AB - OBJECTIVES: Depressive symptoms are observed in a relatively large series of patients with delayed sleep phase syndrome (DSPS). This study was undertaken to investigate the prevalence, characteristics, and factors associated with depressive symptoms among DSPS patients. METHODS: This study targeted 90 consecutive patients (54 men, 27.1+/-9.2 years old) diagnosed as having DSPS. Demographic and clinical characteristics were assessed at their initial visit, including application of the Zung self-rating depression scale (SDS) and morningness-eveningness questionnaire. A series of logistic regression analyses were conducted to determine the factors associated with depressive symptoms (determined as SDS?48). RESULTS: Sixty-four percent of the DSPS patients were in a moderate or severe depressive state. Diurnal variation, sleep disturbance, fatigue, and psychomotor retardation were the main depressive symptom items on SDS in the DSPS patients. Logistic regression analyses showed that SDS?48 was significantly associated with moderate and definite evening chronotype. In contrast, self-reported nocturnal sleep onset and offset times were not associated with depressive symptoms. CONCLUSIONS: There is a high prevalence of depressive symptoms among the DSPS patients. The symptomatic structure of depressive symptoms in this population appears to differ from those of typical depression. Moreover, results of our study suggest that depressive symptoms are more associated with the preference of the evening chronotype rather than sleep wake phase among DSPS patients. PMID- 21669552 TI - Feasibility and reliability of pain pressure threshold measurements in patellar tendinopathy. AB - Patellar tendinopathy is a common and often difficult to treat overuse injury which is characterized by activity-related anterior knee and focal palpation tenderness of the patellar tendon. The clinical diagnosis is mainly based on clinical examination, in which the yardstick is a non-standardized manual palpation. To standardize this palpation procedure the use of an algometer seems applicable. The purpose of this study was to investigate the feasibility and reliability of the algometer in patellar tendinopathy. A cross sectional study was carried out.The algometer was applied to the patellar tendon in 20 asymptomatic volleyball players to measure the 'normal' pressure pain threshold. The inter-rater reliability was analyzed in 54 athletes with symptomatic patellar tendinopathy, the intra-rater reliability was analyzed in 48 athletes with symptomatic patellar tendinopathy. During the procedure difficulties were described, the SEM, intra class correlations and limits of agreement were determined using the Bland and Altman method. The feasibility of the algometer is adequate. The PPT of asymptomatic athletes differs significantly (p<.001) from athletes with a diagnosis of patellar tendinopathy. The inter-rater (ICC 0.93) and intra-rater (ICC 0.60) reliability of the pain pressure threshold are adequate to moderate. Although further research is warranted PPT algometry seems to be a feasible, reliable and useful tool in the diagnosis and treatment evaluation of athletes with patellar tendinopathy. PMID- 21669553 TI - Fingolimod in multiple sclerosis: mechanisms of action and clinical efficacy. AB - Fingolimod, also known as FTY720, has recently been approved by the regulatory authorities in the US, EU, Australia, Russia, among others, for the treatment of relapsing-remitting multiple sclerosis. Fingolimod therefore represents the first oral drug for the treatment of this autoimmune disease of the central nervous system. Fingolimod modulates sphingosine-1 phosphate receptors and has unique immunoregulatory properties. Mechanistic studies from animal models have shown that fingolimod prevents immune cells from exiting from the lymphoid tissue and reaching the inflammatory tissue. Indeed, two phase III studies that laid the basis for fingolimod's approval demonstrated that fingolimod efficiently improves the relapse rate compared to both placebo and one of the standard MS medications. In this review, we will summarize the immunological profile of fingolimod, discuss the possible direct neurobiological effects that have been suggested recently and present the clinical data regarding the efficacy and safety profiles of this promising new drug. PMID- 21669554 TI - ATM protects against oxidative stress induced by oxidized low-density lipoprotein. AB - Chronic oxidative stress is involved in the pathogenesis of multiple inflammatory diseases, including cardiovascular disease and atherosclerosis. The rare autosomal recessive disorder Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia secondary to Purkinje cell death, immunodeficiency, and increased cancer incidence. ATM, the protein mutated in A-T, plays a key role in cellular DNA-damage responses. A-T cells show poor cellular anti-oxidant defences and increased oxidant sensitivity compared to normal cells, and ATM functions, in part, as an oxidative stress sensor. The oxidation of low-density lipoprotein (oxLDL) and its uptake by macrophages is an initiating step in the development of atherosclerosis. We demonstrate that oxLDL activates ATM and downstream p21 expression in normal fibroblasts and endothelial cells. In ATM deficient fibroblasts oxLDL induces DNA double-strand breaks, micronuclei formation and causes chromosome breaks. Furthermore, oxLDL decreases cell viability and inhibits colony formation in A-T fibroblasts more effectively as compared to normal controls. Formation of oxLDL-induced reactive oxygen species is significantly higher in A-T, than normal fibroblasts. Last, pre-treatment of cells with ammonium pyrrolidine dithiocarbamate, a potent antioxidant and inhibitor of transcription factor nuclear factor kappaB, reduces oxLDL-induced reactive oxygen species formation. Our data indicates that ATM functions in the defence against oxLDL-mediated cytotoxicity. PMID- 21669555 TI - Early lymph-drainage massage using a cosmetic roller after lymphatico-venous anastomosis compared to manual lymph drainage: a case report. AB - Conservative and surgical treatment for lymphedema are performed independently, and combined treatment with lymphatico-venous anastomosis (LVA) followed by manual massage is increasingly reported. However, a problem with this approach is that manual massage cannot be initiated immediately after LVA because of concerns of injuring surgical wounds and anastomosed regions. To overcome this problem, we developed a treatment method using a cosmetic roller instead of manual massage, which allows lymph drainage to be initiated immediately after surgery. In this study, we treated a patient with bilateral lower limb lymphedema using this method. Conventional manual massage starting 3 weeks after surgery was used for the left lower limb, while early massage using a cosmetic roller was used for the right lower limb from the day after surgery. A higher therapeutic effect was obtained in the right lower limb compared to that in the left lower limb. The results in this case suggest that further studies should be performed to examine the new method in various types of patients. PMID- 21669556 TI - Global methylation in exposure biology and translational medical science. AB - BACKGROUND: Many groups are actively investigating how the epigenetic state relates to environmental exposures and development of disease, including cancer. There are myriad choices for capturing and measuring the epigenetic state of a tissue, ranging from assessing the total methyl-CpG content to array-based platforms that simultaneously probe hundreds of thousands of CpG loci. There is an emerging literature that uses CpG methylation at repetitive sequences, including LINE-1 (long interspersed nuclear element-1) elements, to capture the epigenomic state. OBJECTIVES: We explored the complexity of using CpG methylation at repetitive sequences in epidemiology and translational medical research and suggest needed avenues of research to clarify its meaning and utility. CONCLUSIONS: Among the most urgent avenues of research is the need for prospective studies to eliminate the possibilities of reverse causality, and development of new LINE-1 assays that capture both class of LINE-1 element and copy number. PMID- 21669558 TI - All children who experience epileptic falls do not necessarily have Lennox Gastaut syndrome... but many do. AB - Lennox-Gastaut syndrome (LGS) is a severe, chronic, epileptic encephalopathy, primarily with childhood onset, which is characterised by a triad of features: multiple seizure types, including tonic seizures that may appear late in the course of the disorder; abnormal EEG features with slow spike-wave discharges; and cognitive impairment. Recognition of LGS is problematic, since the seizure types and EEG features that characterise it are not pathognomonic and often change over time. Furthermore, although seizures associated with LGS may occur de novo, the appearance of core LGS seizures may be preceded by prolonged periods of other seizure types, including myoclonic seizures, partial seizures, or infantile spasms. This has led some authors to postulate that a continuum between LGS and other types of childhood epilepsy may exist. Accurate diagnosis requires careful assessment of both clinical and EEG features, in order to distinguish LGS from other childhood epilepsy syndromes, such as atypical benign partial epilepsy of childhood, Dravet syndrome or epilepsies with predominantly myoclonic-astatic seizures. Since there is no biological marker that can be used to confirm diagnosis of LGS and because of the multiple aetiologies that could lead to its development, early referral to a specialist team may prove to be crucial for facilitating both diagnosis and management. Such an approach ensures that patients receive the appropriate treatment at the correct time, providing the best opportunity for the clinical course and overall prognosis to be improved. Effective management of LGS requires regular reappraisal of the evolving symptoms and features, and adjustment of the treatment accordingly. PMID- 21669557 TI - Intervention to lower household wood smoke exposure in Guatemala reduces ST segment depression on electrocardiograms. AB - BACKGROUND: A large body of evidence suggests that fine particulate matter (PM) air pollution is a cause of cardiovascular disease, but little is known in particular about the cardiovascular effects of indoor air pollution from household use of solid fuels in developing countries. RESPIRE (Randomized Exposure Study of Pollution Indoors and Respiratory Effects) was a randomized trial of a chimney woodstove that reduces wood smoke exposure. OBJECTIVES: We tested the hypotheses that the stove intervention, compared with open fire use, would reduce ST-segment depression and increase heart rate variability (HRV). METHODS: We used two complementary study designs: a) between-groups comparisons based on randomized stove assignment, and b) before-and-after comparisons within control subjects who used open fires during the trial and received chimney stoves after the trial. Electrocardiogram sessions that lasted 20 hr were repeated up to three times among 49 intervention and 70 control women 38-84 years of age, and 55 control subjects were also assessed after receiving stoves. HRV and ST-segment values were assessed for each 30-min period. ST-segment depression was defined as an average value below -1.00 mm. Personal fine PM [aerodynamic diameter <= 2.5 MUm (PM2.5] exposures were measured for 24 hr before each electrocardiogram. RESULTS: PM2.5 exposure means were 266 and 102 MUg/m3 during the trial period in the control and intervention groups, respectively. During the trial, the stove intervention was associated with an odds ratio of 0.26 (95% confidence interval, 0.08-0.90) for ST-segment depression. We found similar associations with the before-and-after comparison. The intervention was not significantly associated with HRV. CONCLUSIONS: The stove intervention was associated with reduced occurrence of nonspecific ST-segment depression, suggesting that household wood smoke exposures affect ventricular repolarization and potentially cardiovascular health. PMID- 21669559 TI - Evolution and management of Lennox-Gastaut syndrome through adolescence and into adulthood: are seizures always the primary issue? AB - Although Lennox-Gastaut syndrome (LGS) typically begins during childhood, it frequently persists through adolescence and on into adulthood. It may also, rarely, have late onset during adolescence or adulthood. Longitudinal studies have highlighted that the "typical" features of LGS observed during childhood evolve and change over time, so that by adulthood it might be difficult to recognise LGS in previously undiagnosed patients. Approaches to treatment must therefore adapt to the changes in a patient's condition as they progress through life. Effective management of LGS requires a global approach to care that not only encompasses seizure control, but also the management of co-morbidities associated with the condition, such as cognitive and behavioural problems, sleep disturbances and physical disability, together with the specific educational and psychosocial needs of the individual. This is particularly relevant during adolescence, when patients have to cope with a host of additional issues alongside those relating to their epilepsy. During all stages of life, management of LGS must carefully balance the need for treatment against its side effects, with the patient's overall quality of life always being the primary focus. The transition of care from paediatric to adult services presents important challenges for patients, their families and healthcare providers, and requires particular consideration to ensure that it is as smooth as possible. It also presents an important opportunity to review and reappraise a patient's condition, treatment and other longer-term needs as they journey into adulthood. PMID- 21669560 TI - Rufinamide from clinical trials to clinical practice in the United States and Europe. AB - Rufinamide is a triazole derivative structurally unrelated to other antiepileptic drugs that is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged >=4 years. Originally granted orphan drug status, marketing authorisation was obtained on the basis of a randomised, double-blind, placebo-controlled trial conducted in 138 LGS patients. An open-label extension study subsequently demonstrated that rufinamide's efficacy and tolerability were maintained over the longer term (median duration of treatment, 432 days). Recently published reports from Europe and the United States have described the use of adjunctive rufinamide to treat LGS in clinical practice. These data complement the clinical trial results, by providing information on the efficacy and tolerability of rufinamide when used on an individualised basis in real-world practice, under less tightly restricted conditions in terms of patient population and dosing strategies. A comparison of the data reveals that a "lower and slower" dosing strategy tends to be adopted in clinical practice, in comparison with the clinical trial, which does not appear to compromise efficacy, but may provide improvements in tolerability. Individual case reports provide additional valuable information on how rufinamide is being used to treat different seizure types associated with LGS. Since clinical experience with rufinamide is currently at an early stage, there are still unanswered questions relating to its use, and it is likely that its place in the adjunctive treatment of LGS will evolve as further data emerge. PMID- 21669561 TI - [KIT and KIT: from biology to clinical use]. AB - Scientific knowledge on gastrointestinal stromal tumors (GIST) has highly progressed over the last 10 years. The molecular bases of oncogenic transformation, KIT activating mutations, were identified in 1998 by Hirota et al. The product of KIT proto-oncogene, KIT protein, is a transmembrane receptor with tyrosine kinase activity. Tyrosine kinase inhibitors targeting these mutated activated kinases, namely imatinib and more recently sunitinib, nilotinib, masitinib or sorafenib, have deeply modified GIST prognosis. Molecular biology in GIST is now becoming a routine tool for treatment selection. In patients with advanced GIST, imatinib should be given until progression, and then, other tyrosine kinase inhibitors targeting KIT should be used. In the adjuvant setting, the optimal duration of imatinib treatment remains unknown. PMID- 21669562 TI - New adipocytokines (vaspin, apelin, visfatin, adiponectin) levels in children treated with valproic acid. AB - AIM: To investigate the relationship between the newly discovered adipocytokines and increasing body weight (paralleled by increased insulin resistance), and antiepileptic drug therapy with valproic acid (VPA). DESIGN AND METHODS: 44 children with idiopathic, generalized epilepsy treated with valproic acid (VPA), and 40 control group children were included in this study. RESULTS: Both the VPA treated group and the control group showed no significant difference in terms of age, total cholesterol and LDL-cholesterol. Subjects in the VPA group had significantly higher BMI-SDS than control subjects (2.3+/-0.15 vs -0.04+/-0.8, p<0.001). HOMA-IR, apelin and visfatin levels were significantly increased (4.95+/-2.07 vs 1.46 vs 0.6, p<0.001; 2.21+/-1.14 vs 0.57+/-0.15, p<0.001; 31+/ 12 vs 18.4+/-10.4, p<0.001; respectively), and adiponectin levels were significantly lower in the VPA group (2.02+/-1.03 vs 12.4+/-6.1, p<0.001). Triglyceride levels were significantly increased (126+/-70 vs 80+/-40 mg/dL, p=0.001), and HDL-cholesterol levels were significantly lower in the VPA group. Vaspin levels were higher in the VPA group than the control group, but the difference was not significant. CONCLUSION: Based on the findings of this study, apelin, visfatin and adiponectin levels may be considered as potential regulators of glucose and fat metabolism during valproic acid therapy. PMID- 21669563 TI - [Cell cycle, mitosis and therapeutic applications]. AB - Genomic DNA is constantly under stress of endogenous and exogenous DNA damaging agents. Without proper care, the DNA damage causes an alteration of the genomic structure and can lead to cell death or the occurrence of mutations involved in tumorigenesis. During the process of evolution, organisms have acquired a series of response mechanisms and repair of DNA damage, thereby ensuring the maintenance of genome stability and faithful transmission of genetic information. The checkpoints are the major mechanisms by which a cell can respond to DNA damage, either by actively stopping the cell cycle or by induction of apoptosis. Two parallel signalling pathways, ATM and ATR respond to genotoxic stress by activating their downstream target proteins including the two effectors kinases CHK1 and CHK2. Promising preliminary data render these proteins potential targets for therapeutic development against cancer. PMID- 21669564 TI - Liver transplantation for hepatocellular carcinoma: an update. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with multiple etiologies, high incidence, and high mortality. The standard surgical management for patients with HCC consists of locoregional ablation, surgical resection, or liver transplantation, depending on the background state of the liver. Eighty percent of patients initially presenting with HCC are unresectable, either due to the extent of tumor or the level of underlying hepatic dysfunction. While in patients with no evidence of cirrhosis and good hepatic function resection has been the surgical treatment of choice, it is contraindicated in patients with moderate to severe cirrhosis. Liver transplantation is the optimal surgical treatment. DATA SOURCES: PubMed search of recent articles (from January 2000 to March 2011) was performed looking for relevant articles about hepatocellular carcinoma and its treatment. Additional articles were identified by evaluating references from selected articles. RESULTS: Here we review criteria for transplantation, the types, indications, and role of locoregional therapy in treating the cancer and in downstaging for possible later transplantation. We also summarize the contribution of immunosuppression and adjuvant chemotherapy in the management and prevention of HCC recurrence. Finally we discuss recent advances in imaging, tumor biology, and genomics as we delineate the remaining challenges for the diagnosis and treatment of this disease. CONCLUSIONS: Much can be improved in the diagnosis and treatment of HCC. A great challenge will be to improve patient selection to criteria based on tumor biology. Another will be to incorporate systemic agents post-operatively in patients at high risk for recurrence, paying close attention to efficacy and safety. The future direction of the effort in treating HCC will be to stimulate prospective trials, develop molecular imaging of lymphovascular invasion, to improve recipient selection, and to investigate biomarkers of tumor biology. PMID- 21669565 TI - Current surgical management of pancreatic endocrine tumor liver metastases. AB - BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved. DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery. RESULTS: The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important. Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time, but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors. The combination of chemoembolization and systemic chemotherapy results in better response and survival rates. Other local destructive techniques include ethanol injection, cryotherapy and radiofrequency ablation. CONCLUSION: It seems that the current management of PETs can achieve important improvements, even in advanced cases. PMID- 21669566 TI - Predictors of patient survival following living donor liver transplantation. AB - BACKGROUND: Living donor liver transplantation (LDLT) is considered to be the alterative choice in light of the great shortage of cadaveric donors. However, the characteristics of the patients who will benefit from LDLT have not been well identified. The aim of this study was to define the pre- and intra-operative factors that may influence patient outcome. METHODS: The data from 102 LDLT patients who had operations between 2002 and 2009 were collected and analyzed retrospectively. Data were analyzed using uni- and multi-variate analysis according to factors that are known to be associated with outcome in these patients. RESULTS: Overall, the accurate survival rate of recipients at 1, 3, and 5 years was 84%, 76%, and 70%, respectively. The independent risk factors, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male match (donor to recipient matching), were identified by Cox regression analysis. The pre-transplant model for end stage liver disease score and a graft to recipient weight ratio of less than 0.8% were not predictive of outcome. The overall 1-, 3-, and 5-year survival of patients with one or no risk factors and two or more risk factors were 91%, 86%, and 83% and 67%, 56%, and 47%, respectively (P<0.0001). CONCLUSIONS: In our retrospective study, preoperative renal dysfunction, intraoperative red blood cell transfusions of greater than 5 units, and female to male gender match were independent risk factors for LDLT recipient outcome. Two or more of these risk factors may contribute to poor outcome. PMID- 21669567 TI - Necessity and indications of invasive treatment for Budd-Chiari syndrome. AB - BACKGROUND: The development of collaterals in Budd-Chiari syndrome has been described and these collaterals play an important role in the presentation of this disease. These collaterals are diagnostic and their use in management strategy has never been evaluated. This study aimed to investigate the indications, feasibility and necessity of invasive treatment for patients with Budd-Chiari syndrome and to determine whether such a strategy is necessary for optimal management. METHODS: Twenty-nine patients who had been treated at our unit were enrolled in this study. Based on physical and biochemical examination, and hemodynamic compensation by collaterals, 18 patients underwent radiological intervention (group A), while the other 11 had no invasive treatment (group B). The related hemodynamic parameters were acquired when percutaneous angiography was performed. RESULTS: In group A, all patients underwent successfully inferior vena cava (IVC) balloon angioplasty with or without stenting. Four patients also underwent hepatic vein angioplasty. In these patients, the mean IVC pressure before and after treatment was statistically different (29.3+/-9.2 vs 15.1+/-4.6 mmHg, P<0.01). The mean IVC pressure was much lower in group B than in group A (12.9+/-2.4 vs 29.3+/-9.2 mmHg, P<0.01), but there was no difference from that of the patients after radiological treatment (12.9+/-2.4 vs 15.1+/-4.6 mmHg, P>0.05). Median follow-up was 32.3 months (mean 21.3 months; range 3-61 months). In the course of follow-up, the patients in group A survived with good systemic status except for re-stenosis in one patient who underwent re-canalization of the IVC. In group B, 10 patients had good systemic status except one patient who had a meso-caval shunt because of deterioration. CONCLUSIONS: The rationale of "early diagnosis and early treatment" is not suitable for all patients with Budd-Chiari syndrome. Satisfactory survival can be achieved in some patients without invasive treatment, who are completely compensated by rich collaterals. Nonetheless, a positive treatment procedure should be performed if the patient's situation worsens in the course of regular follow-up. PMID- 21669568 TI - Clinical features and treatment of sump syndrome following hepaticojejunostomy. AB - BACKGROUND: Cholangitis after Roux-en-Y hepaticojejunostomy is usually caused by anastomotic stricture. A small number of cases present without evidence of obstruction and are ascribed to reflux of gastro-intestinal content into the biliary tree above the anastomosis (sump syndrome). Despite prophylactic rotating antibiotic therapy, the cholangitic episode may be severe and life-threatening. METHODS: From 2001 to 2006, six patients who had undergone an end-to-side hepaticojejunostomy presented to our institution with recurrent episodes of biliary sepsis. Anastomotic stricture was excluded by liver MRI/MRCP and percutaneous transhepatic cholangiogram (PTC). Barium meal showed reflux of contrast into the biliary tree in all patients. Three patients had a short jejunal Roux limb (less than 50 cm) on pre-operative imaging. RESULTS: Five patients underwent surgery and two of them had two operations. One patient had a Tsuchida antireflux valve and subsequently underwent lengthening of the Roux loop. Three patients had lengthening of the Roux loop; one underwent re-do hepaticojejunostomy and one had concomitant revision of the hepaticojejunostomy and lengthening of the Roux loop. The latter underwent further lengthening of the Roux loop. Three patients are cholangitis-free 6, 36 and 60 months after surgery; two still experience mild episodes of cholangitis. CONCLUSIONS: An adequate length of the Roux loop is important to prevent reflux. However, Roux loop lengthening to 70 cm or more does not always resolve the problem and cholangitis, although generally less frequent and severe, may recur despite appropriate reconstructive or antireflux surgery. In these cases, life-long rotating antibiotics is the only available measure. PMID- 21669569 TI - A new scoring system for assessment of liver function after successful hepatectomy in patients with hepatocellular carcinoma. AB - BACKGROUND: Whether a major liver resection is safe has been judged mainly from the patient's hepatic reserve. However, a safe limit for liver resection does not exist yet. This study aimed to construct a new scoring system as a guide to determine a safe limit for liver resection and avoid liver dysfunction after hepatectomy. METHODS: Eighty-six patients with hepatocellular carcinoma who had undergone hepatectomy in West China Hospital from March 2007 to June 2010 were reviewed. The patients were classified according to the levels of total bilirubin after hepatectomy and the parameters in the perioperative period were compared. Receiver operating characteristic (ROC) analysis was made to assess the liver function compensatory (LFC) value to predict liver dysfunction of the patients after hepatectomy. LFC value is defined as the preoperative K(ICG) value x 22.487 + standard remnant liver volume (SRLV) x 0.020. RESULTS: Patients were classified into group I (normal group, n=69) and group II (with total bilirubin >85.5 MUmol/L for 7 days after hepatectomy, n=17) based on the levels of total bilirubin after hepatectomy. Group II was further divided into two subgroups: recovered subgroup (n=14) and fatal subgroup (n=3). There were no significant differences in preoperative data or intraoperative findings except the indocyanine green test parameters (K(ICG) and ICG R15) and SRLV. ROC analysis showed that the sensitivity and specificity of an LFC value <=13.01 were 94.1% and 82.6% respectively for predicting liver dysfunction of the patients after hepatectomy. CONCLUSIONS: The LFC value appears to be a good predictor of postoperative liver dysfunction in patients who undergo hepatectomy for HCC. An expected LFC value of 13.01 seems to be a safe limit for liver resection. PMID- 21669570 TI - Iron overload and HFE gene mutations in Polish patients with liver cirrhosis. AB - BACKGROUND: Increased liver iron stores may contribute to the progression of liver injury and fibrosis, and are associated with a higher risk of hepatocellular carcinoma development. Pre-transplant symptoms of iron overload in patients with liver cirrhosis are associated with higher risk of infectious and malignant complications in liver transplant recipients. HFE gene mutations may be involved in the pathogenesis of liver iron overload and influence the progression of chronic liver diseases of different origins. This study was designed to determine the prevalence of iron overload in relation to HFE gene mutations among Polish patients with liver cirrhosis. METHODS: Sixty-one patients with liver cirrhosis included in the study were compared with a control group of 42 consecutive patients subjected to liver biopsy because of chronic liver diseases. Liver function tests and serum iron markers were assessed in both groups. All patients were screened for HFE mutations (C282Y, H63D, S65C). Thirty-six of 61 patients from the study group and all controls had liver biopsy performed with semiquantitative assessment of iron deposits in hepatocytes. RESULTS: The biochemical markers of iron overload and iron deposits in the liver were detected with a higher frequency (70% and 47% respectively) in patients with liver cirrhosis. There were no differences in the prevalence of all HFE mutations in both groups. In patients with a diagnosis of hepatocellular carcinoma, no significant associations with iron disorders and HFE gene mutations were found. CONCLUSIONS: Iron disorders were detected in patients with liver cirrhosis frequently but without significant association with HFE gene mutations. Only the homozygous C282Y mutation seems to occur more frequently in the selected population of patients with liver cirrhosis. As elevated biochemical iron indices accompanied liver iron deposits more frequently in liver cirrhosis compared to controls with chronic liver disease, there is a need for more extensive studies searching for the possible influence of non-HFE iron homeostasis regulators and their modulation on the course of chronic liver disease and liver cirrhosis. PMID- 21669571 TI - Relationship between alcohol consumption and clinical manifestation of patients with fatty liver: a single-center study. AB - BACKGROUND: Fatty liver is a common chronic liver disease worldwide. It is associated with an increasing morbidity in China in recent years. The aim of this study was to analyze the effect of drinking alcohol on the hemoglobin and biochemical values of patients with fatty liver. METHODS: We investigated the clinical and laboratory data of 669 patients with fatty liver. Of the 669 patients, 166 consumed alcohol more than 60 g per week for at least 2 years, and 503 did not have a history of long-term alcohol consumption. We further analyzed the relationship between alcohol consumption and clinical characteristics of these patients. RESULTS: The values of aspartate transaminase (AST), gamma glutamyl transpeptidase (GGT), and hemoglobin in the long-term consumption group were significantly higher than those in the non long-term consumption group (P<0.05). In the patients without long-term alcohol consumption, the values of GGT and hemoglobin in patients with light alcohol consumption were significantly higher than those in non alcohol consumers (P<0.05). CONCLUSION: Alcohol consumption is associated with significantly increased values of AST, GGT, and hemoglobin in patients with fatty liver, suggesting their potential roles in hepatic steatosis. PMID- 21669572 TI - Cytokine and apoptosis gene polymorphisms influence the outcome of hepatitis C virus infection. AB - BACKGROUND: Hepatitis C virus (HCV) infection is thought to be chronic and the factors leading to viral clearance or persistence are poorly understood. This study was undertaken to investigate the possibility of a significant relationship between the spontaneous clearance or the persistence of hepatitis C virus (HCV) infection and cytokine and apoptosis gene polymorphisms in Tunisian patients on hemodialysis. METHODS: Polymorphisms of the genes IL-1 (-889 IL-1alpha, -511 and +3954 IL-1beta, IL-1Ra), IL-18 (-137 and -607), IL-12 (-1188) and Apo1/Fas (-670) were determined by PCR-RFLP, PCR-SSP and PCR-VNTR in 100 healthy blood donors and 100 patients infected with HCV and undergoing hemodialysis. The patients were classified into two groups: G1 consisted of 76 active chronic hepatitis patients (positive for HCV RNA) and G2 consisted of 24 hemodialysed patients who spontaneously eliminated the virus (negative for HCV RNA). RESULTS: The frequency of genotype association [-137GC/-607CA] IL-18 was higher in G2 (41.7%) than in G1 (15.8%) (P=0.008; OR=0.26; 95% CI, 0.10-0.73). We also found a higher frequency of the AA genotype of the Apo1/Fas gene in G2 (41.6%) than in G1 (17.5%) (P=0.026; OR=3.49; 95% CI, 1.13-10.69). Adjustment for known covariate factors (age, gender and genotype) confirmed these univariate findings and revealed that the genotype association GC-CA of the (-137 and -607) IL-18 gene and the AA genotype of the Apo1/Fas gene were associated with the clearance of HCV (P=0.041 and 0.017, respectively). CONCLUSION: The two genotypes GC-CA of the (-137 and 607) IL-18 polymorphism and the AA genotype of the Apo1/Fas gene influence the outcome of HCV infection in Tunisian patients on hemodialysis. PMID- 21669573 TI - Oncofetal antigen glypican-3 as a promising early diagnostic marker for hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by a multi-cause, multi-stage and multi-focus process of tumor progression. Its prognosis is poor and early diagnosis is of utmost importance. This study was undertaken to investigate the dynamic expression of oncofetal antigen glypican-3 (GPC-3) and GPC-3 mRNA in hepatocarcinogenesis and to explore their early diagnostic value for HCC. METHODS: A hepatoma model was induced in male Sprague-Dawley rats with 0.05% 2-fluorenylacetamide and confirmed by hematoxylin and eosin staining and gamma-glutamyltransferase (GGT) expression. Total RNA was purified and transcribed into cDNA by reverse transcription. Fragments of the GPC-3 gene were amplified by nested RT-PCR, and confirmed by sequencing. GPC-3 was analyzed by immunohistochemistry, Western blotting or ELISA. RESULTS: Positive GPC-3 expression showed as brown granule-like staining localized in the cytoplasm. Histological examination of hepatocytes revealed three morphological stages of granule-like degeneration, atypical hyperplasia (precancerous), and cancer formation, with a progressive increase of liver total RNA and GGT expression. The incidence of liver GPC-3 mRNA and GPC-3, and serum GPC-3 was 100%, 100% and 77.8% in the HCC group, 100%, 100%, and 66.7% in the precancerous group, 83.3%, 83.3%, and 38.9% in the degeneration group, and no expression in the liver or blood of the control group, respectively. There was a positive correlation between liver GPC-3 mRNA and total RNA level (r=0.475, P<0.05) or liver GPC-3 (r=1.0, P<0.001) or serum GPC-3 (r=0.994, P<0.001). CONCLUSION: Abnormal oncofetal antigen GPC-3 and GPC-3 mRNA expression in hepatocarcinogenesis may be promising molecular markers for early diagnosis of HCC. PMID- 21669574 TI - Evaluation of hepatitis B viral replication and proteomic analysis of HepG2.2.15 cell line after knockdown of HBx. AB - BACKGROUND: Hepatitis B virus (HBV) is one of the major pathogens of human liver disease. Studies have shown that HBV X protein (HBx) plays an important role in promoting viral gene expression and replication. In this study we performed a global proteomic profiling to identify the downstream functional proteins of HBx, thereby detecting the mechanisms of action of HBx on virion replication. METHODS: HBx in the HepG2.2.15 cell line was knocked down by the transfection of small interfering RNA (siRNA). The replication level of HBV was evaluated by microparticle enzyme immunoassay analysis of HBsAg and HBeAg in the culture supernatant, and real-time quantitative PCR analysis of HBV DNA. Two-dimensional electrophoresis combined with MALDI-TOF/TOF was performed to analyze the changes in protein expression profile after treatment with HBx siRNA. RESULTS: Knockdown of HBx disturbed HBV replication in vitro. HBx target siRNA significantly inhibited the expression of HBsAg, HBeAg and the replication of HBV DNA. Twelve significantly changed proteins (7 upregulated and 5 downregulated) were successfully identified by MALDI-TOF/TOF using proteomics differential expression analysis after the knockdown of HBx. Among these identified proteins, HSP70 was validated by Western blotting. CONCLUSION: The results of the study indicated the positive effect of HBx on HBV replication, and a group of downstream target proteins of HBx may be responsible for this effect. PMID- 21669575 TI - Hepatocellular carcinoma HepG2 cell apoptosis and caspase-8 and Bcl-2 expression induced by injectable seed extract of Coix lacryma-jobi. AB - BACKGROUND: Many Chinese herbs, especially herbal injections, have been shown to have anti-tumor effects in recent years. However, since most reports focus on the clinical effectiveness of these herbs, their mechanisms of action are not well understood. In this study, we assessed apoptosis in the hepatocellular carcinoma (HCC) cell line HepG2 induced by an injectable extract from the seed of Coix lacryma-jobi (Semen coicis, SC), and monitored the expression of Bcl-2 and caspase-8. METHODS: Injectable SC was applied to HepG2 cells at different concentrations and the cells were collected 12, 24 and 48 hours later. 5 fluorouracil was used as a positive control group, and fluorescence-activated cell-sorting cytometry was used to measure the apoptosis rate of HepG2 cells and the expression of Bcl-2 and caspase-8 proteins. RESULTS: SC induced apoptosis in HepG2 cells in a concentration- and time-dependent manner, and the expression of caspase-8 was elevated and prolonged. However, it did not significantly influence the expression of Bcl-2. CONCLUSION: Injectable SC may induce apoptosis in HCC cells by regulating the expression of caspase-8. PMID- 21669576 TI - Predictive value and main determinants of abnormal features of intraoperative cholangiography during cholecystectomy. AB - BACKGROUND: The major issue with intraoperative cholangiography (IOC) is whether its diagnostic accuracy for common bile duct (CBD) stones matches that of other diagnostic procedures, and thus, whether it will become a routine diagnostic procedure. The current study aimed to address the main determinants of CBD stone diagnosis in IOC among an Iranian population. METHODS: In a retrospective review database-based study conducted in Taleghani Hospital in Tehran between 2006 and 2008, baseline data and perioperative information of 2060 patients (male to female ratio 542:1518, mean age 53.7 years) who were candidates for cholecystectomy and underwent concomitant IOC for confirming CBD stones were reviewed. The predictive power of this procedure for diagnosis of abnormal biliary ducts with the focus on biliary stones was determined. RESULTS: Overall mortality and morbidity following cholecystectomy in the study population were 0.6% and 2.6%, respectively. Both early mortality and morbidity due to cholecystectomy were higher in male than female. The prevalence of CBD stones in IOC was 3.4% (5.2% in male and 2.8% in female, P=0.008). Among those without gallstones, 8.7% had CBD stones and only 3.1% had concomitant gallstones and CBD stones. The main predictors of stone appearance as an abnormal feature of IOC during cholecystectomy were: advanced age (OR=1.022, P=0.001), male gender (OR=1.498, P=0.050), history of abdominal surgery (OR=1.543, P=0.040) and preoperative endoscopic retrograde cholangiopancreatography (OR=5.400, P<0.001). CONCLUSIONS: IOC is a safe and accurate method for the assessment of bile duct anatomy and stones. Therefore, the routine use of IOC within cholecystectomy seems reasonable and is recommended. PMID- 21669577 TI - Dose requirement and complications of diluted and undiluted propofol for deep sedation in endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: In general, the dose requirement and complications of propofol are lower when used in the diluted form than in the undiluted form. The aim of this study was to determine the dose requirement and complications of diluted and undiluted propofol for deep sedation in endoscopic retrograde cholangiopancreatography. METHODS: Eighty-six patients were randomly assigned to either group D (diluted propofol) or U (undiluted propofol). All patients were sedated with 0.02-0.03 mg/kg midazolam (total dose <=2 mg for age <70 years and 1 mg for age >=70) and 0.5-1 MUg/kg fentanyl (total dose <=75 MUg for age <70 and <=50 MUg for age >=70). Patients in group U (42) were sedated with standard undiluted propofol (10 mg/mL). Patients in group D (44) were sedated with diluted propofol (5 mg/mL). All patients in both groups were monitored for the depth of sedation using the Narcotrend system. The primary outcome variable was the total dose of propofol used during the procedure. The secondary outcome variables were complications during and immediately after the procedure, and recovery time. RESULTS: All endoscopies were completed successfully. Mean propofol doses per body weight and per body weight per hour in groups D and U were 3.0 mg/kg, 6.2 mg/kg per hour and 4.7 mg/kg, 8.0 mg/kg per hour, respectively. The mean dose of propofol, expressed as total dose, dose/kg or dose/kg per hour and the recovery time were not significantly different between the two groups. Sedation-related adverse events during and immediately after the procedure were higher in group U (42.9%) than in group D (18.2%) (P=0.013). CONCLUSIONS: Propofol requirement and recovery time in the diluted and undiluted propofol groups were comparable. However, the sedation-related hypotension was significantly lower in the diluted group than the undiluted group. PMID- 21669578 TI - Borderline resectable pancreatic tumors: is there a need for further refinement of this stage? AB - BACKGROUND: The ideal treatment of patients with "borderline resectable pancreatic tumors (BRTs)" needs to be established. Current protocols advise neoadjuvant chemo(radio)therapy, although some patients may appear to have BRT on preoperative imaging and a complete resection may be achieved without the need for vascular resection. The aim of the present study was to identify specific findings on preoperative imaging that could help predict in which patients with BRT a complete resection, with or without vascular resection (VR), could be achieved. METHODS: Twelve patients with BRTs were identified. Tumor location, maximum degree of circumferential contact (CC), length of contact of the tumor with major vessels (LC), and luminal narrowing of vessels at the point of contact with the tumor (venous deformity, VD) were graded on preoperatively acquired multidetector computed tomography (MDCT) images and then compared with the intraoperative findings and need for VR. RESULTS: A complete resection (R0) was achieved in 10 patients with 2 having microscopic positive margins (R1) on histopathology at the uncinate margin. Four of the 10 patients required VR (40%). In 3 of the 4 patients whose tumors required VRs, CC was >=grade III and VD was grade 2. LC did not influence the need for VR. CONCLUSIONS: It is possible to achieve a complete resection at the first instance in patients found to have BRTs on preoperative imaging. Preoperative MDCT-based grading systems and our proposed criteria may help identify such patients, thus avoiding any delay in curative resections in such patients. PMID- 21669579 TI - Emergency re-routing of anterior sector venous outflow for right lobe living donor liver transplantation including the middle hepatic vein. AB - BACKGROUND: Controversy remains over whether the middle hepatic vein should be included in the liver graft in right liver living donor liver transplantation. Congestion in the anterior sector of a right liver graft can cause graft malfunction, which is especially devastating in the case of a graft with marginal size in relation to recipient body size on top of poor pre-transplant recipient status. The case we report here highlighted the importance of the middle hepatic vein in right liver living donor liver transplantation. METHODS: We illustrated the rectification of outflow obstruction of the middle hepatic vein in the anterior sector of right liver graft caused by technical error during transplantation. The rectification was performed with emergency re-routing using an artificial conduit. RESULT: Congestion in the anterior sector of the graft improved immediately and the patient's postoperative liver function test results improved gradually. CONCLUSIONS: The middle hepatic vein is important for effective drainage of the anterior sector of a right liver graft. The re-routing technique described in the report can also be applied to cases in which the middle hepatic vein is injured during hepatectomy requiring immediate reconstruction. PMID- 21669580 TI - Persistent port-site sinus in a patient after laparoscopic cholecystectomy: watch out for gallbladder tuberculosis. AB - BACKGROUND: The gallbladder is rarely affected by mycobacterium tuberculosis. The diagnosis of gallbladder tuberculosis is often not suspected prior to surgery or biopsy. METHOD: A young female patient underwent laparoscopic cholecystectomy but presented with a persistently discharging sinus from the port site. RESULTS: The gallbladder biopsy revealed granulomas typical of chronic granulomatous tuberculosis. The condition of the patient was improved by antitubercular treatment. CONCLUSIONS: Presentation of gallbladder tuberculosis as a persistent discharging sinus at the port site in a patient who has undergone a laparoscopic cholecystectomy is extremely rare. The diagnosis was reached by histopathology only. The rarity of the presentation prompted us to report the case. PMID- 21669581 TI - Long-term survival of a patient after resection of a gastrointestinal stromal tumor arising from the pancreas. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) may arise in any part of the gastrointestinal tract; extra-gastrointestinal locations are extremely rare. Only a few cases of extragastrointestinal stromal tumor arising from the pancreas were reported. None of the reports described a long-term follow-up of the patients. METHOD: This report describes an interesting and unusual case of GIST arising from the pancreas. RESULTS: A 74-year-old female presented with a palpable abdominal mass. CT scan showed a large mass 11 x 8 x 4 cm originating from the tail of the pancreas. Percutaneous biopsy revealed a GIST predominantly with spindle cells, but some parts also contained epitheloid cells. The patient was treated by distal pancreatic resection with splenectomy. Immunohistochemistry of the tumor showed a staining pattern characteristic of GIST. The patient has achieved a long-term survival of five years and six months without any sign of recurrence of the disease. CONCLUSION: This is the first reported case of an extra-gastrointestinal stromal tumor arising from the pancreas treated surgically, with a long-term survival. PMID- 21669582 TI - Enteral nutrition is superior to total parenteral nutrition for pancreatic cancer patients who underwent pancreaticoduodenectomy. AB - OBJECTIVE: To determine the effects of total parenteral nutrition (TPN) and enteral nutrition (EN) on biochemical and clinical outcomes in pancreatic cancer patients who underwent pancreaticoduodenectomy. METHODS: From the year 2006 to 2008, 60 patients who underwent pancreaticoduodenectomy in Tianjin Third Central Hospital were enrolled in this study. They were randomly divided into the EN group and the TPN group. The biochemical and clinical parameters were recorded and analyzed between the two groups. RESULTS: There was no significant difference in the nutritional status, liver and kidney function, and blood glucose levels between the TPN and EN groups on the preoperative day, the 1st and 3 rd postoperative days. However, on the 7th postoperative day, there was significant difference between the two groups in 24 h urinary nitrogen, serum levels of, total protein (TP), transferrin (TF), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptadase (GGT), blood urea nitrogen (BUN) and creatinine (Cr). On the 14th postoperative day, there was a significant difference between the two groups in terms of urinary levels of 24 h nitrogen, TP, TF, retinol binding protein, ALT, AST, ALP, GGT, total bilirubin, direct bilirubin, BUN, Cr, and glucose. The incidence of delayed gastric emptying in the EN and TPN groups was 0% and 20%, respectively. Moreover, the incidence of pancreatic fistulas and hemorrhages in the EN group were 3.6% and 3.6%, versus 26.7% and 30% in the TPN group, respectively. CONCLUSIONS: EN is better than TPN for pancreatic cancer patients who received pancreaticoduodenectomy. PMID- 21669583 TI - A simple meal plan of 'eating vegetables before carbohydrate' was more effective for achieving glycemic control than an exchange-based meal plan in Japanese patients with type 2 diabetes. AB - This study aimed to determine whether educating diabetic patients to 'eat vegetables before carbohydrate' was as effective on long-term glycemic control as a traditional exchange-based meal plan. To test this hypothesis, we carried out a randomized, controlled trial in patients with type 2 diabetes that compared changes in HbA1c as the primary outcome. A total of 101 patients were stratified according to sex, age, BMI, duration of diabetes, and HbA1c, and then randomized to receive instructions to eat either vegetables before carbohydrate (VBC, n=69) or an exchange-based meal plan (EXB, n=32). The impact of the two plans on glycemic control was compared over 24 months of follow-up. Significant improvements in HbA1c over 24 months were observed in both groups (VBC, 8.3 to 6.8% vs EXB, 8.2 to 7.3%). HbA1c levels were significantly lower in the VBC group than in the EXB group after 6, 9, 12 and 24 months of the study. Both groups exhibited similar improvements in dietary practices with respect to intake of carbohydrate, fats and sweets, while the VBC group had a significant increase in consumption of green vegetables and a significant decrease in fruit consumption. A simple meal plan of 'eating vegetables before carbohydrate' achieved better glycemic control than an exchange-based meal plan in Japanese patients with type 2 diabetes over a 24-month period. PMID- 21669584 TI - Effect of kiwifruit consumption on sleep quality in adults with sleep problems. AB - Numerous studies have revealed that kiwifruit contains many medicinally useful compounds, among which antioxidants and serotonin may be beneficial in the treatment of the sleep disorders. The aim of this study was to evaluate the effects of kiwifruit on sleep patterns, including sleep onset, duration, and quality. In this study, we applied a free-living, self-controlled diet design. Twenty-four subjects (2 males, 22 females) 20 to 55 years of age consumed 2 kiwifruits 1 hour before bedtime nightly for 4 weeks. The Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), a 3-day sleep diary, and the Actigraph sleep/activity logger watch were used to assess the subjective and objective parameters of sleep quality, including time to bed, time of sleep onset, waking time after sleep onset, time of getting up, total sleep time, and self-reported sleep quality and sleep onset latency, waking time after sleep onset, total sleep time, and sleep efficiency before and after the intervention. After 4 weeks of kiwifruit consumption, the subjective CPSQI score, waking time after sleep onset, and sleep onset latency were significantly decreased (42.4%, 28.9%, and 35.4%, respectively). Total sleep time and sleep efficiency were significantly increased (13.4% and 5.41%, respectively). Kiwifruit consumption may improve sleep onset, duration, and efficiency in adults with self-reported sleep disturbances. Further investigation of the sleep-promoting properties of kiwifruit may be warranted. PMID- 21669585 TI - Testing the acceptability of liquid fish oil in older adults. AB - Inflammatory conditions likely to benefit from fish oil therapy are prevalent in older adults however acceptability in this group is uncertain. This study aimed to assess the palatability of a range of liquid fish oil concentrations, the frequency and extent of side effects, and to summarise any effects on adherence to fish oil therapy in older adults. One hundred patients (>=60 years) completed a randomised, single-blind palatability study, conducted in two parts. In part one, 50 subjects, blinded to random sample order, consumed multiple liquid fish oil samples (2x10%, 40% and 100%). In part two, 50 subjects tasted one concentration, or 100% extra light olive oil (control). Pleasantness of taste was scored on a 5-point Likert scale. Side effects were recorded 24-hr post-tasting. Results of part one showed that 9/50 participants reported increasingly unpleasant taste with increasing fish oil concentration. 14/50 reported unpleasant taste for 100% fish oil vs 7/50 for 10%. 14/50 reported side effects which would not affect compliance with therapy. For part two, 1/12 reported unpleasant taste for 100% vs 0/13 for 10% fish oil or control. 4/50 reported side effects and 2/4 indicated these would prevent ongoing fish oil therapy. The authors conclude that taste itself is not a deterrent to fish oil therapy. Furthermore, reported adverse effects may not be a true reaction to fish oil, or dissuade patients from compliance. Liquid fish oil supplements are acceptable to older adults, therefore should be investigated as a therapy for geriatric conditions. PMID- 21669586 TI - Secular changes in growth among Japanese children over 100 years (1900-2000). AB - Human growth is associated with complex interactions between genetic and environmental factors. While research has reported increased body size and body mass index (BMI) of Japanese children, few studies have compared the magnitude of increments in growth before and after World War II (WW II) and also considered other social and economical events that may have influenced the growth of children. The current study assessed the secular change in growth in Japanese children and adolescents aged between 6 and 17 years using data from the School Health Statistics Survey conducted between 1900 and 2000 with consideration of key social changes during the 20th Century. Over the 100-year period, Japanese boys had height and weight increments of 1.0-2.0 cm per decade and 0.4-1.7 kg per decade whereas girls had rates of 1.1-1.9 cm and 0.4-1.5 kg per decade, respectively. The rates of height increment were significantly (p<0.05) different between pre-, during and post-WW II periods. While Japanese children were considerably larger in 2000 compared to 1900, increments between 1950 and 1960 reflected catch-up growth to restore physical size seen in children prior to WW II. The increments in body size continued after 1960 with greatest changes seen across the pubertal years. While increments in BMI were evident in most age groups, the BMI of 17-year-old girls was consistent over the 100 years. Results clarified secular changes in growth in Japanese school children across the 20th Century and possible factors contributing to these changes. PMID- 21669587 TI - Coconut oil is associated with a beneficial lipid profile in pre-menopausal women in the Philippines. AB - Coconut oil is a common edible oil in many countries, and there is mixed evidence for its effects on lipid profiles and cardiovascular disease risk. Here we examine the association between coconut oil consumption and lipid profiles in a cohort of 1,839 Filipino women (age 35-69 years) participating in the Cebu Longitudinal Health and Nutrition Survey, a community based study in Metropolitan Cebu. Coconut oil intake was estimated using the mean of two 24-hour dietary recalls (9.5+/-8.9 grams). Lipid profiles were measured in morning plasma samples collected after an overnight fast. Linear regression models were used to estimate the association between coconut oil intake and each plasma lipid outcome after adjusting for total energy intake, age, body mass index (BMI), number of pregnancies, education, menopausal status, household assets and urban residency. Dietary coconut oil intake was positively associated with high density lipoprotein cholesterol especially among pre-menopausal women, suggesting that coconut oil intake is associated with beneficial lipid profiles. Coconut oil consumption was not significantly associated with low density lipoprotein cholesterol or triglyceride values. The relationship of coconut oil to cholesterol profiles needs further study in populations in which coconut oil consumption is common. PMID- 21669588 TI - Survey on eating disorders related thoughts, behaviors and dietary intake in female junior high school students in Taiwan. AB - OBJECTIVE: The purpose of this study was to investigate body weight satisfaction, eating attitudes and dietary intake related to eating disorders of female junior high school students in Taiwan. METHODS: In a cross-sectional survey, 835 female junior high school students participated in this study. The questionnaire items included respondents' demographic information as well as weight and body image concerns. Developmental and attitudinal scales such as the body shape-related teasing scale, Pubertal Development Scale, Eating Attitudes Test-26 (EAT-26) and 24-hour dietary recall were also used to collect data. Data were analyzed using a Student's t test, chi-square test and logistic regression. RESULTS: Disturbed eating attitudes and behaviors were found in 10.4 % of participants (measured by EAT-26?20). The multivariate logistic regressions showed that disturbed eating attitudes and behaviors were associated with weight/shape-related teasing experiences and dissatisfaction with body weight. The reported intakes of energy, protein, fat, carbohydrate, cholesterol, zinc and vitamins B-6, B-12, were significantly lower in participants with disturbed eating patterns than in participants without disturbed eating. Conversely, participants with disturbed eating patterns had higher dietary and crude fiber intake than participates without disturbed eating. CONCLUSION: Disturbed eating behaviors exist among female adolescents in Taiwan, and these behaviors jeopardize their necessary dietary intake requirements. More research using the EAT-26 as a measure to predict the quality and quantity of food intake among female adolescents warrants further study. PMID- 21669589 TI - Nutritional adequacy of energy restricted diets for young obese women. AB - AIM: Energy restricted meal plans may compromise nutrient intake. This study used diet modelling to assess the nutritional adequacy of energy restricted meal plans designed for weight management in young obese women. METHODS: Diet modelling of 6000 kJ/d animal protein based meal plans was performed using Australian nutrient databases with adequacy compared to the Australian Nutrient Reference Values (NRVs) for women (19-30 years). One diet plan was based on the higher carbohydrate (HC) version of the Australian Guide to Healthy Eating for women 19 60 years. An alternative higher protein (HP) plan was adapted from the CSIRO Total Wellbeing Diet. Vegan and lacto-ovo versions of these plans were also modelled and compared to the appropriate vegetarian NRVs. RESULTS: Both animal protein diets met the estimated average requirement (EAR) or adequate intake (AI) for all nutrients analysed. The recommended dietary intake (RDI) was also satisfied, except for iron. HC met 75+/-30% and HP 81+/-31% of the iron RDI when red meat and iron fortified cereal were both included three days a week, and remained below the RDI even when red meat was increased to seven days. Iron for the modified vegan (57+/-5% HC; 66+/-4% HP) and lacto-ovo (48+/-6% HC; 59+/-7% HP) plans was below the RDI and zinc below the EAR for the vegan (76+/-8% HC; 84+/-9% HP) plans. CONCLUSION: The 6000 kJ/d animal protein meal plans met the RDI for all nutrients except iron. Iron and zinc failed to meet the vegetarian RDI and EAR respectively for the vegan plans. PMID- 21669590 TI - Attitudes toward pregnancy related changes and self-judged dieting behavior. AB - Adequate weight gain in pregnancy is essential for the health of the mother and developing fetus. However, a woman's self-beliefs regarding body shape and weight gain may become a driving force toward unnecessary dietary restriction during pregnancy. In order to assess the current status of self-beliefs, attitudes toward pregnancy related changes, and dieting behavior in pregnant women, a questionnaire survey was conducted at a prenatal clinic in Tokyo. A self administered questionnaire was distributed to 500 women and 248 women responded with eligible data. Nearly all respondents (91.5%) stated that they knew their own weight gain targets. Thirty-four women (13.7%) reported dieting before being pregnant, and 88 women (35.5%) reported current dieting. Seventy-eight of the current dieters were doing so based on self-judgment, and only fifteen were following a dietician's advice. The majority of the respondents (69.0%) believed that smaller babies would help a smooth delivery. From multivariable logistic regression analysis, the odds ratio (OR) for current self-judged dieting was significant in women who had dieted before pregnancy (OR: 4.67, 95% confidence intervals (CI): 2.10-10.4), and those who desired smaller babies for a smooth delivery (OR: 2.73, 95% CI: 1.35-5.52). Obstetricians, midwives, and dieticians should be aware of previous dieting history and self-beliefs in pregnant women, in order to give professional advice about the importance of adequate weight gains. PMID- 21669591 TI - Relation of plasma somatostatin levels with malondialdehyde in hyperlipidemic patients. AB - Somatostatin (SST) may protect organism from overnutrition-induced insulin resistance and oxidative stress by inhibiting pancreatic endocrine and exocrine secretion, gastrointestinal digestion and absorption. Many studies clearly show its release becomes perturbed in diabetes and obesity. Therefore, in the present study we first aimed to investigate whether or not plasma somatostatin level was different in patients with hyperlipidemia and normolipidemic controls. We also assessed the relationship between plasma somatostatin levels with atherosclerotic index (AI) and malondialdehyde (MDA) in non-diabetic dyslipidemic patients. Subjects with hyperlipidemia have insulin resistance and high levels of oxidative stress. Median somatostatin (57.2+/-19.2 vs 68.0+/-21.9 pg/mL; p<0.05) levels were lower in hyperlipidemic than in normolipidemic subjects. Significant inverse relationships between SST level and AI (r=-0.21, p< 0.05), or MDA (r=-0.31, p<0.01) were observed. These results suggest a possible protective role of endogenous SST, at least on hyperlipidemia and atherosclerosis that are attributed to excess energy intake and physical inactivity. Of course these preliminary results should be supported by prospective studies. PMID- 21669592 TI - Design and sample characteristics of the 2005-2008 Nutrition and Health Survey in Taiwan. AB - The Nutrition and Health Survey in Taiwan (NAHSIT) 2005-2008 was funded by the Department of Health to provide continued assessment of health and nutrition of the people in Taiwan. This household survey collected data from children aged less than 6 years and adults aged 19 years and above, and adopted a three-stage stratified, clustered sampling scheme similar to that used in the NAHSIT 1993 1996. Four samples were produced. One sample with five geographical strata was selected for inference to the whole of Taiwan, while the other three samples, including Hakka, Penghu and mountainous areas were produced for inference to each cultural stratum. A total of 6,189 household interviews and 3,670 health examinations were completed. Interview data included household information, socio demographics, 24-hour dietary recall, food frequency and habits, dietary and nutritional knowledge, attitudes and behaviors, physical activity, medical history and bone health. Health exam data included anthropometry, blood pressure, physical fitness, bone density, as well as blood and urine collection. Response rate for the household interview was 65%. Of these household interviews, 59% participated in the health exam. Only in a few age subgroups were there significant differences in sex, age, education, or ethnicity distribution between respondents and non-respondents. For the health exam, certain significant differences between participants and non-participants were mostly observed in those aged 19-64 years. The results of this survey will be of benefit to researchers, policy makers and the public to understand and improve the nutrition and health status of pre-school children and adults in Taiwan. PMID- 21669593 TI - Diet and health trends in Taiwan: comparison of two nutrition and health surveys from 1993-1996 and 2005-2008. AB - The availability of new food choices has increased dramatically in recent times, whilst increasingly sedentary lifestyles have reduced calorie intake requirements. The present study uses 24 hour dietary recall data, and biochemical and anthropometric measurements from the 1993-1996 and 2005-2008 Nutrition and Health Surveys in Taiwan (NAHSIT) to investigate trends in dietary habits, and cardiovascular and metabolic disease markers in Taiwanese persons aged 19 years and above. We found that dietary habits in Taiwan are changing, particularly in regards to intakes of cakes and sweets, and sugary drinks. Energy intakes in young people have increased, and combined with an increasingly sedentary lifestyle, this may have led to the increase in obesity and associated metabolic diseases. Large increases in the prevalence of the metabolic syndrome, diabetes, hypertriglyceridemia and gout have been observed. Fortunately, some positive dietary and behavioral changes have also been observed; including an increased avoidance of products made from animal fats and oils' and a concomitant increase in the use of vegetable oil. Intakes of fruit and vegetables, soy products, fish, whole grains, nuts and seeds have also increased; and intakes of red meat, carbohydrates and sodium containing foods have decreased. These positive dietary changes could explain the lack of large changes in the prevalence of hypertension and hypercholesterolemia, and the decrease in prevalence of hyperuricemia. Intake of dairy products remains low, and continues to be an important dietary issue in Taiwan. PMID- 21669594 TI - Trends in nutrient and dietary intake among adults and the elderly: from NAHSIT 1993-1996 to 2005-2008. AB - The aim of this study was to investigate trends in nutrients and sources of dietary intake for Taiwanese people from the Nutrition and Health Survey in Taiwan (NAHSIT) 1993-1996 to 2005-2008. Twenty-four hour dietary recall data were obtained from the 2005-2008 NAHSIT. The results showed that intake of cereals and grains, and dietary fiber has decreased, whereas intake of carbohydrate rich convenience foods has increased. As a result, 10-20 g of dietary fat is now obtained from carbohydrate rich foods. A greater proportion of Taiwanese are choosing low-fat meat products, however, excessive intake of meat by men and women aged 19 to 64 years is resulting in excessive intakes of protein, cholesterol and saturated fat. Men and women aged 19 to 30 years had insufficient intakes of fruit and vegetables. Consumption of fruit, dairy/products, and nuts was low in all age groups. We recommend strengthening public nutrition education and changing diet related environment to improve dietary quality and food group distributions. Issues of concern include excessive intakes of energy and the soybean/fish/meat/eggs food group in all subjects, high amount of processed foods and refined-carbohydrate rich foods in men aged 19 to 64 years and women aged 19 30 years, as well as intakes below the DRI for a variety of nutrients in elderly persons. PMID- 21669595 TI - Trends and nutritional status for magnesium in Taiwan from NAHSIT 1993 to 2008. AB - Data from nationwide population-based nutrition surveys in Taiwan were used to investigate trends and nutritional status for magnesium from 1993 to 2008. Dietary magnesium intake was estimated from 24-hour dietary recalls. Serum and urinary magnesium were also measured. In Nutrition and Health Survey in Taiwan (NAHSIT) 2005-2008, average magnesium intake was 305 mg and 259 mg for adult males and females, respectively, which is equivalent to 82-85% of relevant Taiwanese Dietary Reference Intakes (DRIs). After correcting intra-individual variation, 74-81% of adult subjects' dietary magnesium was estimated as sub optimal. Mean serum magnesium concentration was 0.866 mmol/L and 0.861 mmol/L for the males and females, respectively. The prevalence of low serum magnesium (<0.8 mmol/L) was 12.3% and 23.7% for the males and females, respectively. There was positive association among dietary magnesium, blood magnesium, and urinary magnesium/creatinine ratio. From NAHSIT 1993-1996 to NAHSIT 2005-2008, dietary magnesium significantly increased (p<0.05), the blood magnesium and urinary magnesium/creatinine ratio decreased (p<0.05). The findings suggest that the relationships between dietary magnesium and biochemical markers among different nutrition and health surveys are not straightforward and need to be further clarified. PMID- 21669596 TI - Trends in folate status in the Taiwanese population aged 19 years and older from the Nutrition and Health Survey in Taiwan 1993-1996 to 2005-2008. AB - To investigate ten year trends in folate status in Taiwanese aged >=19 yrs by three Nutrition and Health Survey in Taiwan (NAHSIT) in 1993-1996, 1999-2000 and 2005-2008. Women had higher blood folate levels than men in all three surveys. The prevalence of folate deficiency (5.2% <3 ng/mL) and insufficiency (34.1% <=6 ng/mL) in men was highest in 2005-2008. Adults aged 19-30 yrs had the lowest blood levels and the highest prevalence of deficiency (8.1% in men; 3.5% in women) and insufficiency (48.6% in men; 25% in women) as compared to other age groups in 2005-2008. Folate insufficiency rate in those aged 31-44 yrs was twice as high in men and three times as high in women in 2005-2008 compared to 1993 1996. In the elderly, folate insufficiency rate (28%) in 2005-2008 was not higher than that of 1993-1996, although it was higher than that found in 1999-2000 (18.4%). Men aged >=80 yrs had the poorest folate status in 2005-2008, and men were twice as likely to have inadequate status as women. Plasma homocysteine (Hcy) levels were higher in older men than older women in both surveys. The elderly had significantly higher plasma tHcy in 2005-2008 compared to the 1999 2000 survey. Dark green vegetables and fruit intake frequency in young adults (19 30 yrs) was the lowest among all age groups. This study suggests that folate status in Taiwan has not improved during the past fifteen years, and has worsened in the young population. PMID- 21669597 TI - Bone mineral density in adults in Taiwan: results of the Nutrition and Health Survey in Taiwan 2005-2008 (NAHSIT 2005-2008). AB - Osteoporosis is one of the most prevalent global health problems in the elderly. A nationwide representative sample of 1121 adult subjects, aged 19 years and older, were scanned by a dual-energy X-ray absorptiometry in the third survey year of Nutrition and Health Survey in Taiwan 2005-2008. There was an apparent gender difference in the trend of bone mineral density (BMD) with age. In males, the decrease in BMD with age at lumbar spine and at femoral neck were statistically significant in those younger than 50 years, whereas the decrease in BMD at forearm was significant only in those aged 50 years and older (beta= 0.005, p<0.0001). In females there was a significant negative correlation between BMD at femoral neck and age (beta= -0.004, p<0.0001). In the 236 subjects aged 50 years and older, the prevalence rates of osteoporosis were 4.3% at lumbar spine, 12.0% at femoral neck, and 11.6% at forearm in males, and 12.6% at lumbar spine, 18.1% at femoral neck, and 25.0% at forearm in females, respectively. The prevalence rates of osteoporosis at any site were 23.9% in males and 38.3% in females, respectively. The prevalence rates of low bone mass at lumbar spine, femoral neck, and forearm were 28.8%, 57.5%, and 22.7% in males and 34.7%, 45.9%, and 26.1% in females, respectively. Effective measures to maintain bone health and/or to reduce excessive bone loss may be important in the prevention of osteoporotic fractures in Taiwanese adults. PMID- 21669598 TI - Time trend of obesity, the metabolic syndrome and related dietary pattern in Taiwan: from NAHSIT 1993-1996 to NAHSIT 2005-2008. AB - Obesity and the metabolic syndrome (MetS) are challenging public health issues as globesity popularizes. The present study illustrates the trend of obesity and MetS for the last 12 years in Taiwan based on the analysis of Nutrition and Health Survey in Taiwan. Between the two surveys, a large growth on MetS prevalence was observed, from 13.6% to 25.5%. In NAHSIT 2005-2008, the prevalence of MetS in females exceeded that of males in people older than the age of 45. With regard to regional differences, the growing prevalence of obesity and the metabolic syndromes alleviated in the northern area level one, the most urbanized and dense area. Prevalence of obesity and MetS in Hakka, central, and southern areas increased rapidly. Aboriginal areas had the highest prevalence, which increased modestly. Prevalence of MetS rose fast among males, but much slower among females. Comparing the Taiwanese data with other countries, obesity prevalence in Taiwan was higher than in many of Asian countries, but less than in the West. The prevalence of MetS in Taiwanese females reached levels close to that of the West. Reduced rank regression analysis was used to extract a risk reducing dietary pattern in women, featured by not only more vegetables, fruit, lean meat, and fish, but also some specific Taiwanese dietary items including mushrooms, seaweed, and soybean. No apparent increase in intake of certain healthy foods including lean meat, milk, dark-green vegetables, and fruit in the last 12 years, challenges future strategies to promote health. PMID- 21669599 TI - Trends in hyperuricemia and gout prevalence: Nutrition and Health Survey in Taiwan from 1993-1996 to 2005-2008. AB - Hyperuricemia is a recognized risk factor for cardiovascular disease. This study investigated trends in uric acid levels, hyperuricemia and gout among adults in Taiwan from 1993-1996 to 2005-2008, using data collection from, Nutrition and health surveys in Taiwan (NAHSIT) conducted in 1993-1996 and 2005-2008. Information on food frequency, medical history, physical measures and fasting blood parameters were analyzed. Mean uric acid levels decreased between 1993-1996 and 2005-2008 in both genders (6.77 vs 6.59 mg/dL in men and 5.33 vs 4.97 mg/dL in women) and the prevalence of hyperuricemia declined from 25.3% to 22.0% in men (p<0.0001) and from 16.7% to 9.7% in women (p<0.0001). However, the prevalence of gout (self-reported) increased (4.74% vs 8.21% in men and 2.19% vs 2.33% in women, p<0.0001). Reduced rank regression was used to identify dietary patterns that explained significant amounts of variance in uric acid. Frequency of consumption of lean meat, soy products and soymilk, milk, eggs, vegetables, carrots, mushrooms, fruit and coffee were negatively associated with hyperuricemia, whereas consumption of organ meats, bamboo shoots, and soft drinks were positively associated with hyperuricemia. The dietary factor score (DFS) composed of the frequency of above food items decreased from -5.40 to -6.00 between the two surveys (p<0.0001). In conclusion, uric acid levels and prevalence of hyperuricemia both declined, whilst self-reported gout increased between 1993-1996 and 2005-2008. Changes in dietary patterns may in part explain the decrease in uric acid levels between the two national surveys. PMID- 21669600 TI - 2005-2008 Nutrition and Health Survey in Taiwan: the nutrition knowledge, attitude and behavior of 19-64 year old adults. AB - The purpose of this study is to understand nutrition knowledge, attitude, and behavior in Taiwanese adults. Results indicated that adults' knowledge on 'relationship between diet and disease' and 'comparison of foods in terms of specific nutrients' is acceptable. However, they lack knowledge on 'daily serving requirements' and 'weight and weight loss'. Although they recognize the importance of nutrition, nutrition was not the major concern of food selection. Significant differences were found among gender and age groups. Females of most age groups are better than males in many aspects of nutrition knowledge, attitude and behavior except emotional and external eating behavior. Young (age 19-30) and prime (age 31-44) adults have better knowledge than that of middle adults (age 45 64), while prime adults hold a more positive attitude than young adults. As for nutrition behavior, prime and middle adults are better than young adults. Nutrition knowledge and attitude of adults in urban areas is generally better than those in suburban and remote areas. However, adults in urban areas perform 'emotional and external cued eating' more frequently than those in suburban and remote areas. There are significantly positive correlations among nutrition knowledge, attitude and behavior; and attitude has stronger correlation (r=0.42) with behavior than knowledge does (r=0.27). Therefore, to achieve desirable eating behaviors, the adult nutrition education program should include knowledge of what constitutes a balanced diet and what constitutes being overweight. Proper strategies to enhance the behavioral motivation of healthy food selection must also not be neglected. PMID- 21669601 TI - Use of supplements by Taiwanese adults aged 19-44 during 2005-2008. AB - The aim of the study was to understand the use of supplements in Taiwan. Data used in this study came from the 2005-2008 Nutrition and Health Survey in Taiwan. The total sample available for analysis of supplement use included 973 adults (485 men and 488 women), aged 19-44 years. Survey data were weighted to adjust for the survey design effect and to make the sample nationally representative. Our results showed that 33.2% of Taiwanese adults aged 19-44 took supplements (26.6% of men and 40.0% of women). Gender was the only demographic factor found to be associated with the total number of supplement types taken. Men were more likely to take only one supplement. In contrast, women were 2.6 times more likely than men to take two or more supplements. The most commonly taken supplements by adults were multivitamins and minerals (35.8%), followed by vitamin B group (20.6%) and calcium (9.3%). We found that in both men and women, nutrient intakes from supplements exceeded DRIs for vitamins A, D, E, B-1, B-2, B-6, B-12, pantothenic acid and biotin. Men were more likely than women to take excess iron. Women were more likely than men to take excess vitamin C and niacin. Our study results may be used by government agencies to develop policies regarding supplement use in Taiwan. PMID- 21669602 TI - Dietary supplements usage among elderly Taiwanese during 2005-2008. AB - This study describes dietary supplement consumption practices among the Taiwanese population over the age of 65. Data for the analyses were derived from the 2005 2008 Nutrition and Health Survey in Taiwan. Data from a total of 914 participants (456 men and 458 women) was collected in the study to delineate patterns of supplement usage. The results indicated that the percentage of individuals taking supplements was 45.7% for men and 52.2% for women. There were no significant differences in supplement use by gender, age group, geographic stratum, current employment status, household monthly income, self-reported health status or marital status, except for higher education and adequate perceived financial resources. Half of both men and women chose to take only one supplement. In addition, as the number of supplements taken increased, the number of people decreased. The elderly with higher education levels were more likely to take two kinds of supplements. The top five supplements consumed from highest to lowest were: glucosamine, multivitamins and minerals, calcium, fish oil and vitamin B complex. The major reason for supplements use for men was to supplement an unbalanced diet, and that for women was to prevent joint degeneration. The main factor influencing choice of supplements in the elderly was receiving the supplement as a gift from another person. Note that mean intakes of vitamins A, C, E, B-1, B-2, B-6, B-12, biotin, niacin, and pantothenic acid from supplements over-exceeded DRIs in Taiwan. PMID- 21669603 TI - Practice to introduce complementary foods to infants in Taiwan--changes from 1997 to 2008. AB - The purpose of the study was to understand present infant complementary foods eating and compare trends over the past 10 years in Taiwan. We investigated the methods used to introduce infants to complementary foods, difficulties encountered, sources of information and the principle caregiver's knowledge about infant feeding. This study focused on findings from the 2005-2008 Nutrition and Health Survey in Taiwan (NAHSIT) and compared with those from the 1997-1999 Child NAHSIT. Interviews in both surveys were carried out by trained interviewers. In 2005-2008 survey, 50% of infants aged 7-12 months had started eating baby cereals or juice at age 4-6 months as recommended. The proportions of infants aged 10-12 months who were introduced to particular complementary foods at recommended periods varied from biscuits (51.1%) to tofu (1.1%). The proportions were higher in 2005-2008 than in 1997-1999 for only 3 items. In both survey, more than 80% of mothers were the one who made the decision to introduce their children to complementary foods. More than 75% of caregivers fed baby cereals to their babies from milk bottles. In 2005-2008, the most commonly encountered problem was that the child wouldn't eat. Nutrition knowledge of the caregivers have improved since 1999, but still needs fostering. The timing to introduce complementary foods become later than ten years ago. Whether the delay will affect the normal dietary intakes of children after one year of age needs attention. The government should not only promote breastfeeding, but also reevaluate current evidence-based recommendation on complementary food introduction time. PMID- 21669604 TI - The science of plant morphology: definition, history, and role in modern biology. AB - As a scientific discipline, plant morphology is 211 yr old, originated by Goethe in 1790. It is a discipline that has largely been Germanic in practice. Because it took its origins from the study of the natural history of plants and the United States is principally an engineering society, the discipline of plant morphology in its pure form has never been widely practiced in this country. What has been labeled "plant morphology" in the United States has served largely as a handmaiden for systematics, using morphological characteristics to carve up diversity into its systematic subunits. Because the heart of plant morphology as a science is a focus on the convergences rather than the homologies in a phylogenetic sense, the German tradition of plant morphology is a unifying science that focuses on fundamental themes that transcend systematic boundaries. This paper traces the history of the science of plant morphology through the lineage of its principal practitioners: Goethe, Hofmeister, von Goebel, and Troll. It also evaluates the principles of plant morphology by applying them to the phyletically diverse Pteridophytes, showing that contemporary members of that group exhibit levels of shoot organization comparable to that of seed plants and discusses the implications of these findings. PMID- 21669605 TI - Characterization of mycobiont adaptations in the foliose lichen Xanthoparmelia chlorochroa (Parmeliaceae). AB - A cross section of the vagrant soil lichen Xanthoparmelia chlorochroa was analyzed using proton microprobe PIXE. Data were used to generate quantitative, two-dimensional element distribution maps for Al, Si, P, S, Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, As, and Sr. Element maps show differential element partitioning between the stratified layers of the thallus. These data document transfer of inorganic nutrients across the thallus to the algal layer. Inorganic particle entrapment was also evident in the element maps. Dense accumulations of calcium oxalate at the junction of the medulla and the algal layer on the order of 10% by dry mass were discovered. Scanning electron microscopy and thermogravimetric analyses were used to characterize the calcium oxalate region. These data provide evidence for possible functional roles of the calcium oxalate layer, including regulation of water and light. Data also provide support for a mutualistic interpretation of the lichen association. PMID- 21669606 TI - Population genetic study in the Balearic endemic plant species Digitalis minor (Scrophulariaceae) using RAPD markers. AB - Digitalis minor (Scrophulariaceae) is a cardenolide-producing plant endemic to the eastern Balearic Islands (Mallorca, Menorca, and Cabrera) that occurs in two morphologically distinct varieties: D. minor var. minor (pubescent) and D. minor var. palaui (glabrous). Levels and patterns of genetic diversity in 162 individuals from 17 D. minor populations across the entire geographic range were assessed using random amplified polymorphic DNA (RAPD) markers. Comigrating RAPD fragments tested were found to be homologous by Southern hybridization in both var. minor and var. palaui. To avoid bias in parameter estimation, analyses of population genetic structure were restricted to those RAPD bands that fulfilled the 3/N criterion (observed frequencies were less than 1 - [3/N] in each population) either among or within each island. Analyses of molecular variance (AMOVAs) with distances among individuals corrected for the dominant nature of RAPD (genotypic analysis) showed low values (1.57-17.55%) of between-population variability, indicating a relatively restricted population differentiation as expected for an outcrossing species such as D. minor. Nested AMOVAs demonstrated, however, a not significant partitioning of genetic diversity among Mallorca, Menorca, and Cabrera islands. Estimates of the Wright, Weir, and Cockerham and the Lynch and Milligan F(ST) from null allele frequencies corroborated AMOVA partitioning and provided evidence for population differentiation in D. minor. Our RAPD data did not show significant differences between pubescent and glabrous populations of D. minor, suggesting a failure to find a correlation between the RAPD loci and this morphological trait. PMID- 21669607 TI - Reproductive biology and natural hybridization between two endemic species of Pitcairnia (Bromeliaceae). AB - We investigated pollination biology and breeding systems in hybridizing populations of Pitcairnia albiflos and P. staminea; both species are endemic to rocky outcrops at Rio de Janeiro, Brazil. These species are morphologically distinct and easily recognized by floral color: white in P. albiflos and red in P. staminea. Putative hybrids show a large range of intermediate pink floral colors. The showy hermaphroditic flowers offer pollen and nectar that attract many visitors including bees, butterflies, hawk moths, and bats. Although the flowers of both parental species and hybrids open at night, only P. albiflos had other adaptations for nocturnal pollination. Flowering times overlapped during three consecutive years of observation. Bees visited both species and putative hybrids. Cross-pollinations were performed within and among parental species and hybrids in a greenhouse using plants transplanted from the field. Pitcairnia staminea and hybrids are self-compatible and could be spontaneously self pollinated, whereas P. albiflos, though self-compatible, needs pollinators' services for self-pollination. Facultative agamospermy was found in the parental species. Prezygotic and postzygotic reproductive barriers between these taxa were weak. Reciprocal hand-pollinations between parental species and with hybrids yielded high fruit sets with viable seeds. Evaluations of fruit set, seed set, seed germination, and pollen viability were undertaken to compare the fitness of the hybrids relative to their parents. The hybrids showed equivalent fitness, except for lower pollen viability. Some conservation implications are noted. PMID- 21669608 TI - Rodent pollination in the African lily Massonia depressa (Hyacinthaceae). AB - Field studies in the semiarid Succulent Karoo region of South Africa showed that flowers of Massonia depressa (Hyacinthaceae) are visited at night by at least four rodent species, including two gerbil species. Live-trapped rodents were found to carry Massonia pollen on their snouts; they also had large quantities of Massonia pollen in their feces as a result of grooming their fur. Visits by insects to the flowers were infrequent at one site and apparently absent at another site. Plants enclosed in large-mesh wire cages, which excluded rodents but not insects, set very few seeds relative to open controls. Our initial hypothesis of rodent-pollination in M. depressa was based on the striking similarity of its flowers to those of unrelated, rodent-pollinated Protea species. Convergent traits include dull-colored and very robust flowers situated at ground level, a strong yeasty odor, and secretion of copious amounts of sucrose-dominant nectar during the evening when rodents are active. Despite having a low sugar concentration (~20%), the nectar of M. depressa is almost 400 times as viscous as an equivalent sugar solution. The jelly-like constituent in the nectar may discourage robbing by insects, while also facilitating lapping by rodents. Our findings illustrate the utility of floral syndromes for generating testable predictions about pollination systems. PMID- 21669609 TI - Flowering dynamics in Arum italicum (Araceae): relative role of inflorescence traits, flowering synchrony, and pollination context on fruit initiation. AB - We studied the relative role of inflorescence traits, flowering synchrony, and pollination context for infructescence and fruit initiation in two Spanish populations of Arum italicum, a species in which inflorescences are the pollination unit. In this species, a specialized inflorescence organ, the appendix, is important for pollinator attraction. However, the short floral longevity and the production of mostly one inflorescence per plant make its pollination potentially dependent on strong flowering synchrony and on external factors not controlled by the plant (the pollination context). The flowering period in both sites lasted >3 mo. Day-to-day variation in simultaneous antheses was high, and 11-50% of antheses occurred on days during which no pollen donor was present. Inflorescence traits, flowering synchrony, and between-plant distance all influenced infructescence and fruit initiation, but their relative importance differed between sites. In one large population, infructescence initiation was positively related to inflorescence traits; in a smaller population infructescence initiation increased with the number of donor inflorescences. In both sites, percentage of fruits initiated per infructescence was dependent on a combination of inflorescence traits, flowering synchrony, and between-plant distance. Plants producing 2-4 inflorescences had higher probability of infructescence initiation and overlapped their antheses with more plants than single-inflorescence ones. PMID- 21669610 TI - Sexual mass allocation in species with inflorescences as pollination units: a comparison between Arum italicum and Arisaema (Araceae). AB - Sex allocation models predict that cosexuality is stabilized by high allocation to attractive structures in pollen-limited species or by high allocation to shared structures that contribute to both genders. High investment in unilateral fixed costs favor the evolution of dioecy or gender change. With these predictions in mind, I studied sexual mass allocation at flowering in the monoecious Arum italicum (Araceae) and compared it with information available for its sex labile relative Arisaema dracontium. In A. italicum, 68% of biomass was allocated to structures believed to be involved in pollinator attraction and capture. This allocation pattern contrasts with that of Arisaema dracontium, in which 70% of biomass was allocated to scape, considered to be a unilateral fixed cost. The importance of attractive structures in A. italicum was further supported by a disproportionate increased allocation, in larger inflorescences, to the appendix (an attractive structure) compared to fertile flowers. In addition, an increase in inflorescence mass involved a disproportionate increase in mass allocation to male, rather than female, flowers. This pattern also contrasts with a size-related gender change from male to female in Arisaema species. These findings were consistent with sex allocation model predictions and shed light on the evolution of sex lability in Arisaema species. PMID- 21669611 TI - Effects of mycorrhizal infection and soil phosphorus availability on in vitro and in vivo pollen performance in Lycopersicon esculentum (Solanaceae). AB - The effects of mycorrhizal infection and soil P availability on in vitro and in vivo pollen performance were studied in two cultivars of tomato (Lycopersicon esculentum). In the first study, plants were grown in a greenhouse under three treatment combinations: nonmycorrhizal, low P (NMPO); nonmycorrhizal, high P (NMP3); and mycorrhizal, low P (MPO). Mycorrhizal infection and high soil P conditions significantly increased in vitro pollen tube growth rates but not percentage of germination. In addition, pollen from NMP3 and MPO plants sired significantly more seeds than pollen from NMPO plants in pollen mixture studies. In the second study, plants were grown initially in a greenhouse under two treatment combinations: NMPO and MPO. After all plants began to flower, they were placed in experimental arrays in the field. Under open pollination, pollen from MPO plants sired significantly more seeds than pollen from NMPO plants. This result was primarily attributed to increased flower production (and thus pollen production) in MPO plants. Thus, mycorrhizal infection and high soil P conditions can increase pollen quality (in vitro and in vivo pollen performance) as well as pollen quantity, thereby enhancing fitness through the male function. Anthocyanin production (used to determine paternity) also affected pollen performance. PMID- 21669612 TI - Reproductive assurance and the evolutionary ecology of self-pollination in Clarkia xantiana (Onagraceae). AB - The reproductive assurance hypothesis posits that selection favors self pollination in flowering plants where mates and/or pollinators are scarce. A corollary is that self-pollinating populations are expected to be superior colonizers of mate- and pollinator-scarce environments. The California annual Clarkia xantiana includes outcrossing populations (ssp. xantiana) and autogamously self-pollinating populations (ssp. parviflora). Outcrossing is ancestral, and the subspecies have parapatric distributions with a narrow contact zone. We tested aspects of the reproductive assurance hypothesis by examining geographic and subspecies variation in the densities of mates and pollinators (native bees) and the density dependence of pollinator visitation and pollen receipt. Plant and flower densities, pollinator density, and pollinator visitation rates were lowest in the region of exclusively self-pollinating populations. Pollinator assemblages there lacked Clarkia-associated pollinator taxa that were common elsewhere. Self-pollinating populations in the contact zone generally had densities and visitation rates intermediate between allopatric self pollinating populations and outcrossing populations. Visitation rate and pollen receipt increased significantly with plant density. These findings suggest that selection for reproductive assurance influenced the origin of self-pollination and/or that reproductive assurance influenced the geographic distribution of self pollination. Geographic variation in pollinator assemblages may have generated variation in the value of reproductive assurance. PMID- 21669613 TI - Seedling functional types in a lowland rain forest in Mexico. AB - Seedling morphology of 210 species (173 trees and 37 lianas) was studied from a community perspective to identify major patterns of seedling functional types in a Mexican rain forest. Five types of seedlings were distinguished: cryptocotylar with reserve storage or absorption cotyledons (epigeal [CER] and hypogeal [CHR]), phanerocotylar epigeal, either with photosynthetic cotyledons (PEF) or with reserve storage or absorption cotyledons (PER), and phanerocotylar hypogeal with reserve cotyledons (PHR). The most common seedling type was PEF (49.5%), followed by CHR (31.4%), PER (9.5%), PHR (7.2%), and CER (2.4%). Excepting the CER type, seedling type frequencies did not differ between trees and lianas. The PEF seedlings had the lightest seeds, whereas CHR seedlings had the heaviest ones. Pioneer trees showed lighter seeds than persistent trees or lianas in species with PEF but not in species with PER. Pioneer trees (38 species) showed three seedling types and the most common was PEF (82%). Persistent trees (135 species) showed the five seedling types but PEF (43%) and CHR (37%) were the most frequent. Seedling type frequencies differed among dispersal syndrome groups. The animal dispersal syndrome was significantly more frequent in species with CHR. Our results show an evolutionary convergence of seedling types at the community level worldwide and the existence of a phylogenetic inertia in the evolution of initial seedling morphology. A comparison among eight tropical communities indicated on average that PEF is the most frequent type and CER the least common, although the relative frequency of each seedling type differs among communities, particularly between Neotropical and Paleotropical sites. PMID- 21669614 TI - Persistence of seed bank under thick volcanic deposits twenty years after eruptions of Mount Usu, Hokkaido Island, Japan. AB - The topsoil that contained the seed bank became buried under thick tephra after the eruptions of Mount Usu during 1977 and 1978. To determine the seed bank potential of the topsoil 20 yr after the eruptions, i.e., in 1998, 408 100-cm(3) samples were excavated under 115-185 cm of volcanic deposits. The topsoil was collected at 10-cm intervals along the horizontal scale and was divided into a 0 5 cm deep upper layer and a 5-10 cm deep lower layer. The seed bank was estimated by both the germination (GM) and flotation (FM) methods. In total, 23 species with an average seed density of 1317 seeds/m(2) were identified by GM, and 30 species with a density of 2986 seeds/m(2) were extracted by FM. The dominant species was Rumex obtusifolius, and perennial herbs, such as Carex oxyandra, Viola grypoceras, and Poa pratensis, were common. For nine species this study provided the first records for field seed longevity >20 yr. The seed density in the upper layer was double that in the lower layer, and the horizontal distribution was heterogeneous even at 10-cm intervals. We concluded that the seed bank has retained the original structure of the seed bank under the tephra and will persist longer with soil water content between 20 and 40%, no light, and low temperature fluctuations (+/-0.17 degrees C of standard deviation in a day). PMID- 21669615 TI - C3 woody plant expansion in a C4 grassland: are grasses and shrubs functionally distinct? AB - The expansion of C(3) shrubs into C(4)-dominated tallgrass prairies represents a fundamental shift in growth-form dominance accompanied by changes in resource acquisition and use. We assessed these changes by comparing the ecophysiological traits of the dominant C(4) grass Andropogon gerardii, with traits of three C(3) invasive shrub species, Cornus drummondii, Prunus americana, and Rhus glabra. We tested the hypothesis that ecophysiological traits of the shrubs would be similar within this growth form but distinct from grasses and that these species would conform to the two-layer soil water model. Photosynthetic rates in R. glabra were similar to A. gerardii and higher than in the other two shrubs, while water use efficiency was markedly greater in A. gerardii. Among all species, midday xylem pressure potentials (XPP) were distinctly lower (70%) for P. americana, but were similar among the other species. Predawn XPP was related to soil water at shallow depths for A. gerardii (r(2) = 0.59) and P. americana (r(2) = 0.62), and to deeper soil moisture for R. glabra (r(2) = 0.63); there was no relationship for C. drummondii at any soil depth. Thus, a simple two-layer soil water model for partitioning shrub/grass resource acquisition was not appropriate for this grassland. We conclude that these shrubs could not be considered functional equivalents from an ecophysiological perspective, nor were they, as a group, distinct from A. gerardii in resource acquisition and use. PMID- 21669616 TI - Occurrence of arbuscular mycorrhizal fungi in a phosphorus-poor wetland and mycorrhizal response to phosphorus fertilization. AB - The presence of arbuscular mycorrhizas in fens has received little attention, but because fen plants are often phosphorus limited, the plant-fungus interaction could be an important factor in plant competition for phosphorus. In this field study, we determined mycorrhizal colonization rates for 18 fen plant species. Also in the field, we examined the effect of four different forms of phosphorus on the percentage colonization for one fen plant species, Solidago patula. We found that in a species-rich, phosphorus-poor wetland both mycorrhizal and nonmycorrhizal species were common. Nine of ten dicotyledonous species examined formed arbuscular mycorrhizas, while all monocotyledonous species were at most very weakly mycorrhizal. A morphological explanation for this pattern is that the monocots in our study have more extensive aerenchyma, especially in coarse roots. Therefore, monocots are able to transport oxygen to their roots more effectively than dicots. In the organic wetland soil, additional oxygen in the rhizosphere promotes phosphorus mineralization and availability. Two of the monocot species (Typha latifolia and Carex lasiocarpa), which have been described previously as mycorrhizal in other wetland types, are surprisingly nonmycorrhizal in our phosphorus-poor study site, suggesting that a mycorrhizal association would not offer improved phosphorus nutrition to these species. In contrast, our field phosphorus addition decreased mycorrhizal colonization in S. patula, suggesting that one benefit to S. patula of the mycorrhizas is phosphorus uptake. PMID- 21669617 TI - Phylogeny of Malpighiaceae: evidence from chloroplast ndhF and trnl-F nucleotide sequences. AB - The Malpighiaceae are a family of ~1250 species of predominantly New World tropical flowering plants. Infrafamilial classification has long been based on fruit characters. Phylogenetic analyses of chloroplast DNA nucleotide sequences were analyzed to help resolve the phylogeny of Malpighiaceae. A total of 79 species, representing 58 of the 65 currently recognized genera, were studied. The 3' region of the gene ndhF was sequenced for 77 species and the noncoding intergenic spacer region trnL-F was sequenced for 65 species; both sequences were obtained for the outgroup, Humiria (Humiriaceae). Phylogenetic relationships inferred from these data sets are largely congruent with one another and with results from combined analyses. The family is divided into two major clades, recognized here as the subfamilies Byrsonimoideae (New World only) and Malpighioideae (New World and Old World). Niedenzu's tribes are all polyphyletic, suggesting extensive convergence on similar fruit types; only de Jussieu's tribe Gaudichaudieae and Anderson's tribes Acmanthereae and Galphimieae are monophyletic. Fleshy fruits evolved three times in the family and bristly fruits at least three times. Among the wing-fruited vines, which constitute more than half the diversity in the family, genera with dorsal-winged samaras are fairly well resolved, while the resolution of taxa with lateral-winged samaras is poor. The trees suggest a shift from radially symmetrical pollen arrangement to globally symmetrical pollen at the base of one of the clades within the Malpighioideae. The Old World taxa fall into at least six and as many as nine clades. PMID- 21669618 TI - Molecular systematics of Malpighiaceae: evidence from plastid rbcL and matK sequences. AB - Phylogenetic analyses of DNA nucleotide sequences from the plastid genes rbcL and matK were employed to investigate intergeneric relationships within Malpighiaceae. Cladistic relationships generated from the independent data matrices for the family are generally in agreement with those from the combined matrix. At the base of Malpighiaceae are several clades mostly representing genera from a paraphyletic subfamily Byrsonimoideae. Intergeneric relationships among these byrsonimoid malpighs are well supported by the bootstrap, and the tribe Galphimeae is monophyletic. There is also a well-supported clade of genera corresponding to tribes Banisterieae plus Gaudichaudieae present in all trees, and many of the relationships among these banisterioid malpighs are well supported by the bootstrap. However, tribes Hiraeae and Tricomarieae (the hiraeoid malpighs) are paraphyletic and largely unresolved. Species of Mascagnia are distributed throughout these hiraeoid clades, confirming the suspected polyphyly of this large genus. Optimization of selected morphological characters on these trees demonstrates clear phylogenetic trends such as the evolution of globally symmetrical from radially symmetrical pollen, increased modification and sterilization of stamens, and switch from base chromosome number n = 6 to n = 10. PMID- 21669619 TI - Origin and genetic diversity of Spartina anglica (Poaceae) using nuclear DNA markers. AB - Spartina alterniflora, introduced into the UK in the 1800s, was the seed parent in an interspecific hybridization with S. maritima. The sterile F1 hybrid S. *townsendii gave rise to the fertile allopolyploid S. anglica by chromosomal doubling. Previous chromosome, isozyme, and cpDNA surveys did not reveal notable genetic variation within either the parental or the hybrid species. We used nuclear DNA markers (random amplified polymorphic DNA ([RAPD]) and inter-simple sequence repeats (ISSR) to further explore the origin, diversity, and parentage of S. anglica. We found DNA fragments in S. *townsendii were the aggregate of diagnostic DNA fragments from S. maritima and S. alterniflora, thus confirming its hybrid origin. The S. *townsendii genotype was identical to most of the S. anglica individuals analyzed, establishing the genetic concordance of these two taxa. We found widespread genetic variation within S. anglica. This could indicate that S. anglica arose several times, from different S. maritima sires. Alternatively, alleles could have been lost through recombination and/or through loss of entire chromosomes in S. anglica. Finally, all but one S. anglica individual had a S. alterniflora component that was indistinguishable from a S. alterniflora plant extant in Marchwood, UK, leaving open the possibility that this plant is the actual seed parent of S. anglica. PMID- 21669620 TI - Amplified fragment length polymorphisms (AFLP) reveal details of polyploid evolution in Dactylorhiza (Orchidaceae). AB - The utility of the PCR-based AFLP technique (polymerase chain reaction; amplified fragment length polymorphisms) was explored in elucidating details of polyploid evolution in the Eurasian orchid genus Dactylorhiza. We emphasized Swedish taxa but also included some material from the British Isles and elsewhere in Europe. Three different sets of primers, amplifying different subsets of restriction fragments, independently revealed similar patterns for relationships among the Dactylorhiza samples investigated. The AFLP data support the general picture of polyploid evolution in Dactylorhiza, i.e., that allotetraploid derivatives have arisen repeatedly as a result of hybridization beween the two parental groups D. incarnata s.l. (sensu lato; diploid marsh orchids) and the D. maculata group (spotted orchids). Within the incarnata s.l. group, morphologically defined varieties were interdigitated. The D. maculata group consisted of two distinct subgroups, one containing autotetraploid D. maculata subsp. maculata and the other containing diploid D. maculata subsp. fuchsii. Allotetraploids showed a high degree of additivity for the putative parental genomes, and relationships among them were partly correlated to morphologically based entities, but also to geographic distribution. Thus, allotetraploid taxa from the British Isles clustered together, rather than with morphologically similar plants from other areas. PMID- 21669621 TI - Species relationships in Lactuca s.l. (Lactuceae, Asteraceae) inferred from AFLP fingerprints. AB - An AFLP data set comprising 95 accessions from 20 species of Lactuca s.l. (sensu lato) and related genera was generated using the primer combinations E35/M48 and E35/M49. In phenetic analyses of a data subset, clustering with UPGMA based on Jaccard's similarity coefficient resulted in the highest cophenetic correlation, and the results were comparable to those of a principal coordinates analysis. In analyses of the total data set, phenetic and cladistic analyses showed similar tree topologies for the well-supported parts of the trees. The validity of cladistic analysis of AFLP data is discussed. The results do not support a distinction among the serriola-like species L. sativa, L. serriola, L. dregeana, and L. altaica, which is in line with previous results. Therefore, we postulate that these species are conspecific. The serriola-like species L. aculeata occupies a clearly separate position, making it an ideal outgroup for studies of the closest relatives of L. sativa. The subsect. Lactuca as a group is well supported by our data, but the positions of L. saligna and L. virosa relative to the serriola-like species remain unclear. The close relationship between the sect. Mulgedium species L. tatarica and L. sibirica is corroborated by the present AFLP results and by additional crossability data. PMID- 21669622 TI - Granule-bound starch synthase (GBSSI) gene phylogeny of wild tomatoes (Solanum L. section Lycopersicon [Mill.] Wettst. subsection Lycopersicon). AB - Eight wild tomato species are native to western South America and one to the Galapagos Islands. Different classifications of tomatoes have been based on morphological or biological criteria. Our primary goal was to examine the phylogenetic relationships of all nine wild tomato species and closely related outgroups, with a concentration on the most widespread and variable tomato species Solanum peruvianum, using DNA sequences of the structural gene granule bound starch synthase (GBSSI, or waxy). Results show some concordance with previous morphology-based classifications and new relationships. The ingroup comprised a basal polytomy composed of the self-incompatible green-fruited species S. chilense and the central to southern Peruvian populations of S. peruvianum, S. habrochaites, and S. pennellii. A derived clade contains the northern Peruvian populations of S. peruvianum (also self-incompatible, green fruited), S. chmielewskii, and S. neorickii (self-compatible, green-fruited), and the self-compatible and red- to orange- to yellow-fruited species S. cheesmaniae, S. lycopersicum, and S. pimpinellifolium. Outgroup relationships are largely concordant with prior chloroplast DNA restriction site phylogenies, support S. juglandifolium and S. ochranthum as the closest outgroup to tomatoes with S. lycopersicoides and S. sitiens as basal to these, and support allogamy, self incompatibility, and green fruits as primitive in the tomato clade. PMID- 21669623 TI - A phylogenetic analysis of Diurideae (Orchidaceae) based on plastid DNA sequence data. AB - DNA sequence data from plastid matK and trnL-F regions were used in phylogenetic analyses of Diurideae, which indicate that Diurideae are not monophyletic as currently delimited. However, if Chloraeinae and Pterostylidinae are excluded from Diurideae, the remaining subtribes form a well-supported, monophyletic group that is sister to a "spiranthid" clade. Chloraea, Gavilea, and Megastylis pro parte (Chloraeinae) are all placed among the spiranthid orchids and form a grade with Pterostylis leading to a monophyletic Cranichideae. Codonorchis, previously included among Chloraeinae, is sister to Orchideae. Within the more narrowly delimited Diurideae two major lineages are apparent. One includes Diuridinae, Cryptostylidinae, Thelymitrinae, and an expanded Drakaeinae; the other includes Caladeniinae s.s., Prasophyllinae, and Acianthinae. The achlorophyllous subtribe Rhizanthellinae is a member of Diurideae, but its placement is otherwise uncertain. The sequence-based trees indicate that some morphological characters used in previous classifications, such as subterranean storage organs, anther position, growth habit, fungal symbionts, and pollination syndromes have more complex evolutionary histories than previously hypothesized. Treatments based upon these characters have produced conflicting classifications, and molecular data offer a tool for reevaluating these phylogenetic hypotheses. PMID- 21669624 TI - Molecular phylogeny of Coelogyne (Epidendroideae; Orchidaceae) based on plastid RFLPS, matK, and nuclear ribosomal ITS sequences: evidence for polyphyly. AB - To evaluate the monophyly of Coelogyne (Epidendroideae; Orchidaceae) and reveal sectional relationships and relations to allied genera in subtribe Coelogyninae, we collected PCR (polymerase chain reaction) amplified restriction fragment length polymorphisms (RFLPs) from 11 plastid regions for 42 taxa (28 Coelogyne species and 14 representatives of other genera) and three outgroups from Bletiinae and Thuniinae. We also sequenced a large portion of the plastid trnK intron (mostly matK) and the nuclear ribosomal DNA internal transcribed spacers ITS1 and ITS2 (including the 5.8S gene). Separate phylogenetic analyses on each data set using maximum parsimony produced mainly congruent (except for the position of Panisea) but weakly supported clades. Parsimony analysis of the combined data clearly identified three main clades in Coelogyninae. Whereas Coelogyninae are monophyletic, Coelogyne is polyphyletic, with species falling into at least two well-supported clades. The utility of morphological characters used in previous classifications was explored by reconstructing character state evolution on one of the four molecular trees. Lip base and petal shape were homoplasious, whereas ovary indumentum and flower number were congruent with well supported groups. The implications of our results for the classification of Coelogyne are discussed, and a reorganization of the genus by including Neogyna and Pholidota and removing several species is proposed. PMID- 21669625 TI - Erratum. PMID- 21669626 TI - Structure and ultrastructure of leaf and calyx glands in Galphimia brasiliensis (Malpighiaceae). AB - The present study describes the anatomical structure of calyx and leaf glands in Galphimia brasiliensis and analyzes the mechanism of secretion. The glands are marginal and suprabasal, cup-shaped, sessile, and scarcely visible with the naked eye. Light microscopy reveals the following features: a thin, smooth cuticle; unistratified secretory cells; subglandular parenchyma; and vascular bundle supply composed of phloem and xylem with abundant druses of calcium oxalate. Transmission electron microscopy reveals the presence of secretory cells with conspicuous nuclei, dense cytoplasm, lipid droplets, numerous vesicles, mitochondria, Golgi, rough endoplasmic reticulum (RER), and elongated plastids with osmiophilic contents. The secretion reaches the apoplastic space and accumulates beneath the cuticle. Finally, the viscous, translucent exudate is eliminated by mechanical rupture of the cuticle. Histochemical analysis confirms that lipids are the main constituent. Small amounts of polysaccharides were also identified. PMID- 21669627 TI - Analysis of shoot apical organization in six species of the Cupressaceae based on chimeric behavior. AB - Six species of the Cupressaceae, the variegated Leyland cypress (Cupressocyparis leylandii 'Silver Dust'), savin (Juniperus sabina variegata Laws), davurian juniper (Juniperus davurica 'expansa variegata'), California incense cedar (Calocedrus decurrens 'Aureovariegata'), the American arbor vitae (Thuja occidentalis 'lutae zebrina' Kent), and the sawara false cypress (Chamaecyparis pisifera 'nana aureovariegata') were examined for the behavior of albino-green shoot chimeras. The fate of the variegations in these six plants is the same in two important respects. First, the majority (89%) of sprays with an original sector become completely white. Second, sectorial branch sprays of the original sectorial sprays become either completely green or white in a 1 : 1 ratio. Based on the first finding it is concluded that there is one rather than the two to four apical initials in the shoot apex, as generally postulated. This single apical initial, actually an apical cell lineage, residing in the tunica layer can both form the leaf epidermis and by rare periclinal divisions form sectorial chimeras. The second finding is that there is no selection advantage of either type, a feature also postulated by others. PMID- 21669628 TI - The role of breeding system and inbreeding depression in the maintenance of an outcrossing mating strategy in Silene virginica (Caryophyllaceae). AB - The goal of this study was to understand the interaction among breeding system, mating system, and expression of inbreeding depression in the hermaphroditic, primarily hummingbird-pollinated, iteroparous, short-lived perennial Silene virginica. We performed hand-selfed and hand-outcrossed pollinations in the field, conducted detailed floral observations within individual flowers and plants, and assayed adult tissue from flowering plants for a genetic estimate of population outcrossing rate. We quantified the opportunity for geitonogamy as the proportion of days each plant exhibited simultaneous male and female function, i.e., asynchronous expression of male- and female-phased flowers. Expression of cumulative inbreeding depression based on germination rate and total flower production in the glasshouse was ~40% and was congruent with the estimated high outcrossing rate of 0.89. Floral observations demonstrated strong temporal protandry within each flower (dichogamy) as well as complete spatial separation between male and female function within each flower (herkogamy). On average, 29% of the time there were both male- and female-phased flowers present on an individual plant. We conclude that our estimate of inbreeding depression is compatible with a largely outcrossing mating system and the amount of selfing observed, likely results from geitonogamy. This study illustrates the utility of examining both the causes and the consequences of inbreeding via selfing to provide additional insights into the evolution of plant mating systems. PMID- 21669629 TI - The effects of a bumble bee nectar robber on plant reproductive success and pollinator behavior. AB - Interactions between a plant species (Corydalis caseana), a bumble bee nectar robber (Bombus occidentalis), and a bumble bee pollinator (B. appositus) were studied. There were no significant differences between naturally robbed and unrobbed flowers in fruit set or mean seed set per fruit. Plots of C. caseana plants were subjected to treatments of robbing and no robbing using commercially available colonies of B. occidentalis. Robbers did not pollinate the flowers. Pollinator behavior was observed to determine (1) the number of bees attracted to each plot, (2) the number of inflorescences visited in a plot, (3) the number of flowers visited on each inflorescence, and (4) the distance flown between inflorescences. There were no significant differences in the number of inflorescences visited per bee or the number of flowers visited per inflorescence per bee when robbed and unrobbed treatments were compared. Of the parameters measured, only distance flown between inflorescences differed in the robbed and the unrobbed treatments. Bees flew significantly further between inflorescences in the robbed plots than in the unrobbed plots. The results indicate that the nectar robbers have no negative effect on fruit set or seed set in C. caseana and that they may cause increased pollen flow distances by changing the behavior of the pollinator. PMID- 21669630 TI - Reproductive biology of henequen (Agave fourcroydes) and its wild ancestor Agave Angustifolia (Agavaceae). i. Gametophyte development. AB - The pathways of micro- and megagametophyte development in Agave fourcroydes (henequen) and A. angustifolia were studied. We used histology and light microscopy to observe anther ontogeny and ovary differentiation in relation to flower bud size. Both species have the same sexual reproductive strategies and gametophyte development that may be divided into three phases: (1) premeiotic, which includes the establishment of the megaspore mother cell and the pollen mother cell; (2) meiotic, the formation of mature microspores and functional megaspores; (3) postmeiotic, which encompasses the development of mature pollen grains and the formation of the embryo sac. A successive type microsporogenesis was found in both species with formation of T-shaped tetrads and binuclear pollen grains. In vitro germination tests revealed very low pollen fertility. The female gametophyte is formed from two micropylar megaspore cells after the first meiotic division (bisporic type). Male and female gametogenesis occur asynchronously with microsporogenesis finishing before macrosporogenesis. The results so far show that the formation of male and female gametophytes in henequen is affected at different stages and that these alterations might be responsible for the low fertility shown by this species. PMID- 21669631 TI - Genetic diversity and the mating system of a rare Mexican pinon, Pinus pinceana, and a comparison with Pinus maximartinezii (Pinaceae). AB - Weeping pinon (Pinus pinceana) has a restricted and fragmented range, trees are widely scattered within populations, and reproduction is limited. Nevertheless, genetic diversity was high; based on 27 isozyme loci in 18 enzyme systems, unbiased expected heterozygosity averaged 0.174. Differentiation also was high (F(ST) = 0.152), reflecting isolation between southern, central, and northern fragments of the range. Among populations in the northern fragment, F(ST) was only 0.056, and the number of migrants per generation (Nm) was 4.21, which should preclude fixation. Nm between central and southern populations or between them and populations in the northern fragment was lower, 0.99-1.66, indicating a degree of genetic isolation. Multilocus outcrossing rates (t(m)) ranged from 0.836 in the south to 0.897 in the north. Therefore, selfing is low but statistically significant. The equilibrium inbreeding coefficient (F(e)) calculated from t(m) was in good agreement with observed inbreeding coefficients, suggesting that weeping pinon may be near equilibrium with respect to inbreeding and selection against selfed trees. Weeping pinon was variable at all loci polymorphic in maxipinon (Pinus maximartinezii) and, therefore, qualifies as a possible progenitor of maxipinon. Because of the high level of diversity, reasonable levels of gene flow within the northern fragment of weeping pinon's range, high rates of outcrossing, and, perhaps, only weak selection against inbred trees, protection in reserves would be a viable option for conservation. PMID- 21669632 TI - Phylogenetics of paniceae (poaceae). AB - Paniceae demonstrate unique variability of photosynthetic physiology and anatomy, including both non-Kranz and Kranz species and all subtypes of the latter. This variability suggests hypotheses of independent origin or reversals (e.g., from C(4) to C(3)). These hypotheses can be tested by phylogenetic analysis of independent molecular characters. The molecular phylogeny of 57 species of Paniceae was explored using sequences from the grass-specific insert found in the plastid locus rpoC2. Phylogenetic analyses confirmed some long-recognized alliances in Paniceae, some recent molecular phylogenetic results, and suggested new relationships. Broadly, Paniceae were found to be paraphyletic with Andropogoneae, Panicum was found to be polyphyletic, and Oplismenus hirtellus was resolved as the sister group to the remaining ingroup species. A particularly well-supported clade in the rpoC2 tree included four genera with non-Kranz species and three with distinctively keeled paleas. As previously suggested, the PCK (phosphoenol pyruvate carboxykinase) C(4) subtype arose once within Paniceae. All clades with non-Kranz species had Kranz ancestors or sister taxa suggesting repeated loss of the Kranz syndrome. PMID- 21669633 TI - A molecular phylogeny of the grass subfamily Panicoideae (Poaceae) shows multiple origins of C4 photosynthesis. AB - DNA sequence data from the chloroplast gene ndhF were analyzed to estimate the phylogeny of the subfamily Panicoideae, with emphasis on the tribe Paniceae. Our data suggest that the subfamily is divided into three strongly supported clades, corresponding to groups with largely identical base chromosome numbers. Relationships among the three clades are unclear. In unweighted parsimony analyses, the two major clades with x = 10 (Andropogoneae and x = 10 Paniceae) are weakly supported as sister taxa. The third large clade corresponds to x = 9 Paniceae. In analyses under implied weight, the two clades of Paniceae are sisters, making the tribe monophyletic. Neither resolution is strongly supported.Our molecular phylogenies are not congruent with previous classifications of tribes or subtribes. Based on this sample of species, we infer that C(4) photosynthesis has evolved independently several times, although a single origin with multiple reversals and several reacquisitions is only slightly less parsimonious. The phosphoenol pyruvate carboxykinase (PCK) subtype of C(4) photosynthesis has evolved only once, as has the NAD-malic enzyme (ME) subtype; all other origins are NADP-ME. Inflorescence bristles are apparently homologous in the genera Setaria and Pennisetum, contrary to opinions of most previous authors. Some genera, such as Digitaria, Echinochloa, and Homolepis are supported as monophyletic. The large genus Paspalum is shown to be paraphyletic, with Thrasya derived from within it. As expected, Panicum is polyphyletic, with lineages derived from multiple ancestors across the tree. Panicum subg. Panicum is monophyletic. Panicum subg. Dichanthelium, subg. Agrostoides, and subg. Phanopyrum are unrelated to each other, and none is monophyletic. Only Panicum subg. Dichanthelium sect. Dichanthelium, represented by P. sabulorum and P. koolauense, is monophyletic. Panicum subg. Megathyrsus, a monotypic subgenus including only the species P. maximum, is better placed in Urochloa, as suggested by other authors. PMID- 21669634 TI - Myrtaceae revisited: a reassessment of infrafamilial groups. AB - Cladistic analyses are presented of matK sequence data as well as a nonmolecular database for an identical set of exemplar species chosen to represent the core genera or groups of genera in Myrtaceae. Eleven robust clades are recognized on the molecular data. Polyphyly of the previously recognized Metrosideros and Leptospermum alliances is confirmed, and several smaller informal taxonomic groupings are recognized from among the members of the former alliance, i.e., the Tristania, Tristaniopsis, Metrosideros, and Lophostemon groups. The nonmolecular analysis provides only limited resolution of relationships. A degree of congruence exists between the two analyses in that two separate fleshy-fruited clades, the Acmena and Myrtoid groups, are identified, as are the Eucalypt and Tristania groups, and Psiloxylon and Heteropyxis are the first lineages to diverge in both analyses. A combined analysis recognized all 11 clades that received strong support from the molecular data. A high level of homoplasy is revealed in many of the nonmolecular characters when they are examined against the combined estimate of phylogeny. PMID- 21669635 TI - A Dendroctonus bark engraving (Coleoptera: Scolytidae) from a middle Eocene Larix (Coniferales: Pinaceae): early or delayed colonization? AB - An engraving made by a scolytid bark beetle, assigned to the genus Dendroctonus of the tribe Tomicini, has been identified on a mummified, middle Eocene (45 Ma) specimen of Larix altoborealis wood from the Canadian High Arctic. Larix altoborealis is the earliest known species of Larix, a distinctive lineage of pinaceous conifers that is taxonomically identifiable by the middle Eocene and achieved a broad continental distribution in northern North America and Eurasia during the late Cenozoic. Dendroctonus currently consists of three highly host specific lineages that have pinaceous hosts: a basal monospecific clade on Pinoideae (Pinus) and two sister clades that consist of a speciose clade associated exclusively with Pinoideae and six species that breed overwhelmingly in Piceoideae (Picea) and Laricoideae (Pseudotsuga and Larix). The middle Eocene engraving in L. altoborealis represents an early member of Dendroctonus that is ancestral to other congeneric species that colonized a short-bracted species of Larix. This fossil occurrence, buttressed by recent data on the phylogeny of Pinaceae subfamilies and Dendroctonus species, indicates that there was phylogenetically congruent colonization by these bark-beetle lineages of a Pinoideae + (Piceoideae + Laricoideae) host-plant sequence. Based on all available evidence, an hypothesis of a geochronologically early invasion during the Early Cretaceous is supported over an alternative view of late Cenozoic cladogenesis by bark beetles onto the Pinaceae. These data also suggest that host plant chemistry may be an effective species barrier to colonization by some bark beetle taxa over geologically long time scales. PMID- 21669636 TI - Isozyme variation and genetic relationships among taxa in the Asplenium obovatum group (Aspleniaceae, Pteridophyta). AB - The Asplenium obovatum group consists of diploid and tetraploid taxa; the origin of the tetraploid A. obovatum subsp. lanceolatum was previously considered to have occurred via autopolyploidy, involving one of the diploids of the group, either A. obovatum subsp. obovatum var. obovatum or var. protobillotii. To test this hypothesis, electrophoretic analyses of eight enzyme systems encoded by fourteen putative loci and cytological studies of the artificial hybrid between both diploid varieties were conducted. Alleles of the loci Lap-1, Mdh-2, Mdh-3, Pgm-1, Pgm-1', and 6Pgd-1 emerged as genetic markers for the diploids and were present in an additive pattern in most of the analyzed individuals of the tetraploid. Cytological results indicated a high degree of genomic homology between the diploids. These results indicated that the tetraploid behaves as a segmental allopolyploid. Our results showed that both diploids were involved in the origin of the tetraploid. We propose the new combination Asplenium obovatum subsp. protobillotii for one of the diploids. PMID- 21669637 TI - Chloroplast DNA phylogeny and biogeography of Lepidium (Brassicaceae). AB - Two intergenic spacers, trnT-trnL and trnL-trnF, and the trnL intron of cpDNA were sequenced to study phylogenetic relationships and biogeography of 73 Lepidium taxa. Insertions/deletions of >=3 bp (base pairs) provided reliable phylogenetic information whereas indels <=2 bp, probably originating from slipped strand mispairing, are prone to parallelism in the context of our phylogenetic framework. For the first time, an hypothesis of the genus Lepidium is proposed based on molecular phylogeny, in contrast to previous classification schemes into sections and greges (the latter category represents groups of related species within a given geographic region), which are based mainly on fruit characters. Only a few of the taxa as delimited in the traditional systems represent monophyletic lineages. The proposed phylogeny would suggest three main lineages, corresponding to (1) sections Lepia and Cardaria, (2) grex Monoplocoidea from Australia, and (3) remaining taxa, representing the bulk of Lepidium species with more or less resolved sublineages that sometimes represent geographical correspondence. The fossil data, easily dispersible mucilaginous seeds, widespread autogamous breeding systems, and low levels of sequence divergence between species from different continents or islands suggest a rapid radiation of Lepidium by long-distance dispersal in the Pliocene/Pleistocene. As a consequence of climatic changes in this geological epoch, arid/semiarid areas were established, providing favorable conditions for the radiation of Lepidium by which the genus attained its worldwide distribution. PMID- 21669638 TI - A molecular phylogenetic study of the subtribe Glycininae (Leguminosae) derived from the chloroplast DNA rps16 intron sequences. AB - Phylogenetic relationships among 13 genera of the subtribe Glycininae, two genera of the allied subtribe Diocleinae that were included within Glycininae by Polhill, and two genera of the subtribe Erythrininae as outgroups were inferred from chloroplast DNA rps16 intron sequence variation. Pairwise sequence divergence values ranged from identity between Teramnus mollis and T. micans and between T. flexilis and T. labialis to 7.89% between Pueraria wallichii and Pseudeminia comosa across all accessions. Phylogenies estimated using parsimony and neighbor-joining methods revealed that (1) Glycininae is monophyletic if Pachyrhizus and Calopogonium (both Diocleinae) are included within Glycininae; (2) the genus Teramnus is closely related to Glycine, and Amphicarpaea showed a sister relationship to the clade comprising Teramnus and Glycine; (3) the expanded Glycininae including two genera of Diocleinae is divided into three branches, temporarily named I (comprising the rest of the examined taxa), II (Pueraria wallichii), and III (Mastersia), but their relationships are equivocal; and (4) the genus Pueraria, regarded as a closely related genus to Glycine, is not monophyletic and should be divided into at least four genera (a hypothesis supported previously by Lackey). PMID- 21669639 TI - Molecular systematics of Iridaceae: evidence from four plastid DNA regions. AB - Iridaceae are one of the largest families of Lilianae and probably also among the best studied of monocotyledons. To further evaluate generic, tribal, and subfamilial relationships we have produced four plastid DNA data sets for 57 genera of Iridaceae plus outgroups: rps4, rbcL (both protein-coding genes), the trnL intron, and the trnL-F intergenic spacer. All four matrices produce similar although not identical trees, and we thus analyzed them in a combined analysis, which produced a highly resolved and well-supported topology, in spite of the fact that the partition homogeneity test indicated strong incongruence. In each of the individual trees, some genera or groups of genera are misplaced relative to morphological cladistic studies, but the combined analysis produced a pattern much more similar to these previous ideas of relationships. In the combined tree, all subfamilies were resolved as monophyletic, except Nivenioideae that formed a grade in which Ixioideae were embedded. Achlorophyllous Geosiris (sometimes referred to Geosiridaceae or Burmanniaceae) fell within the nivenioid grade. Most of the tribes were monophyletic, and Isophysis (Tasmanian) was sister to the rest of the family; Diplarrhena (Australian) fell in a well-supported position as sister to Irideae/Sisyrinchieae/Tigridieae/Mariceae (i.e., Iridoideae); Bobartia of Sisyrinchieae is supported as a member of Irideae. The paraphyly of Nivenioideae is suspicious due to extremely high levels of sequence divergence, and when they were constrained to be monophyletic the resulting trees were only slightly less parsimonious (<1.0%). However, this subfamily also lacks clear morphological synapomorphies and is highly heterogeneous, so it is difficult to develop a strong case on nonmolecular grounds for their monophyly. PMID- 21669640 TI - Phylogenetic relationships in Disa based on non-coding trnL-trnF chloroplast sequences: evidence of numerous repeat regions. AB - Sequence data from the intron and spacer of the trnL-F chloroplast region elucidate the phylogenetic relationships of the tribe Diseae (Orchidoideae: Orchidaceae). Within Diseae, 41 species of Disa, two of Brownleea, three of Satyrium, and two of Corycium were included, with five species of Habenaria sensu lato (Orchideae) and one epidendroid as outgroups. The sequences revealed substitutions and considerable length variation, due mainly to the presence of repeat motifs. Phylogenetic analysis using parsimony revealed five distinct clades. The branching order of the five weakly supported the paraphyly of Diseae, with the successive divergence of Brownleea, Corycium, Habenaria, Satyrium, and Disa. Within the monophyletic Disa, three main groupings appeared, two strongly supported clades representing sect. Racemosae and sect. Coryphaea and the third grouping containing several clades currently grouped into sections based on morphological phylogenies. Some discrepancies between the molecular phylogeny and the phylogeny based on morphological characters may require reevaluation of some of the morphological characters. The presence of different numbers of repeat motifs, both among different taxa and within taxa, indicates that these characters may be phylogenetically informative at the population level. PMID- 21669641 TI - Geographic distribution of wild potato species. AB - The geographic distribution of wild potatoes (Solanaceae sect. Petota) was analyzed using a database of 6073 georeferenced observations. Wild potatoes occur in 16 countries, but 88% of the observations are from Argentina, Bolivia, Mexico, and Peru. Most species are rare and narrowly endemic: for 77 species the largest distance between two observations of the same species is <100 km. Peru has the highest number of species (93), followed by Bolivia (39). A grid of 50 * 50 km cells and a circular neighborhood with a radius of 50 km to assign points to grid cells was used to map species richness. High species richness occurs in northern Argentina, central Bolivia, central Ecuador, central Mexico, and south and north central Peru. The highest number of species in a grid cell (22) occurs in southern Peru. To include all species at least once, 59 grid cells need to be selected (out of 1317 cells with observations). Wild potatoes occur between 38 degrees N and 41 degrees S, with more species in the southern hemisphere. Species richness is highest between 8 degrees and 20 degrees S and around 20 degrees N. Wild potatoes typically occur between 2000 and 4000 m altitude. PMID- 21669642 TI - Pollen load size, reproductive success, and progeny kinship of naturally pollinated flowers of the tropical dry forest tree Pachira quinata (Bombacaceae). AB - Several studies have demonstrated, using controlled pollinations, that the number and identity of pollen grains deposited onto a flower's stigma affect the reproductive success of plants. However, few studies have shown this relationship under conditions of natural pollination. Using the tropical dry forest tree Pachira quinata, we evaluated the relationship between the number of microgametophytes per pistil and the number of sires with respect to the production of fruits and seeds in a natural population of Pachira quinata. Our study demonstrates that fruit and seed production are directly related to the number of microgametophytes per pistil in natural populations of P. quinata. Only 6% of the marked flowers developed into mature fruits and 10% of the marked flowers initiated fruits but later aborted them. A mean of 23 pollen grains were required to produce a seed. Flowers with >400 pollen grains on the stigma always developed into mature fruits, whereas flowers that received <200 grains never matured fruits. Half of the pollen grains transferred to a flower stigma germinated and developed pollen tubes to the base of the style. The number of pollen grains on a stigma explained 34% of the variation in seed number per fruit, and the number of seeds produced per fruit is positively correlated with the size of the seeds. The population of P. quinata studied is predominantly outcrossing, and seeds within fruits are sired by one or a few donors. The total seed crop within trees was sired by three to five donors. Our study examined the implications of the variation in size of microgametophyte loads per pistil with respect to the breeding system and the paternity of progeny under natural conditions. The competitive ability of pollen and pollen tube attrition are important factors regulating fruit production in P. quinata. PMID- 21669643 TI - Productivity and species richness across an environmental gradient in a fire dependent ecosystem. AB - The fire-dependent longleaf pine-wiregrass (Pinus palustris Mill.-Aristida beyrichiana Trin. & Rupr.) savannas of the southeastern United States provide a unique opportunity to examine the relationship between productivity and species richness in a natural ecosystem because of the extremely high number of species and their range across a wide ecological amplitude (sandhills to edges of wetlands). We used a natural gradient to examine how plant species richness and plant community structure vary with standing crop biomass (which in this system is proportional to annual net productivity) as a function of soil moisture and nitrogen mineralization rates in a frequently burned longleaf pine-wiregrass savanna. Highest ground cover biomass and highest species richness were found at the same position along the gradient, the wet-mesic sites. Relative differences in species richness among site types were independent of scale, ranging from 0.01 m(2) to 100 m(2). Nitrogen availability was negatively correlated with species richness. Dominance of wiregrass (in terms of biomass) was consistent across the gradient and not correlated with species richness. Regardless of site type, the community structure of the savannas was characterized by many perennial species with infrequent occurrences, a factor in the low temporal heterogeneity (percent similarity between seasons and years) and high within-site spatial heterogeneity (percent dissimilarity of vegetation composition). The coexistence of numerous species is likely due to the high frequency of fire that removes competing hardwood vegetation and litter and to the suite of fire-adapted perennial species that, once established, are able to persist. Our results suggest that soil moisture is an important factor regulating both the number of species present and community production within the defined gradient of this study. PMID- 21669644 TI - A survey of bryophytes for presence of cholinesterase activity. AB - The neurotransmitter acetylcholine (ACh) is present in plants including bryophytes. The first biochemical evidence for ACh hydrolysis by enzyme cholinesterase (ChE) in bryophytes is presented. Thirty-nine species belonging to 16 families of bryophytes were surveyed for ChE activity. Thirty species belonging to 13 families showed ChE activity. Of the bryophytes tested, Anoectangium bicolor showed the highest ChE activity. Widespread distribution of ChE in bryophytes indicates their suitability as a system to study the role of ACh in plants. PMID- 21669645 TI - A soybean plastid-targeted NADH-malate dehydrogenase: cloning and expression analyses. AB - A typical soybean (Glycine max) plant assimilates nitrogen rapidly both in active root nodules and in developing seeds and pods. Oxaloacetate and 2-ketoglutarate are major acceptors of ammonia during rapid nitrogen assimilation. Oxaloacetate can be derived from the tricarboxylic acid (TCA) cycle, and it also can be synthesized from phosphoenolpyruvate and carbon dioxide by phosphoenolpyruvate carboxylase. An active malate dehydrogenase is required to facilitate carbon flow from phosphoenolpyruvate to oxaloacetate. We report the cloning and sequence analyses of a complete and novel malate dehydrogenase gene in soybean. The derived amino acid sequence was highly similar to the nodule-enhanced malate dehydrogenases from Medicago sativa and Pisum sativum in terms of the transit peptide and the mature subunit (i.e., the functional enzyme). Furthermore, the mature subunit exhibited a very high homology to the plastid-localized NAD dependent malate dehydrogenase from Arabidopsis thaliana, which has a completely different transit peptide. In addition, the soybean nodule-enhanced malate dehydrogenase was abundant in both immature soybean seeds and pods. Only trace amounts of the enzyme were found in leaves and nonnodulated roots. In vitro synthesized labeled precursor protein was imported into the stroma of spinach chloroplasts and processed to the mature subunit, which has a molecular mass of ~34 kDa. We propose that this new malate dehydrogenase facilitates rapid nitrogen assimilation both in soybean root nodules and in developing soybean seeds, which are rich in protein. In addition, the complete coding region of a geranylgeranyl hydrogenase gene, which is essential for chlorophyll synthesis, was found immediately upstream from the new malate dehydrogenase gene. PMID- 21669646 TI - The questionable affinities of Lactoris: evidence from branching pattern, inflorescence morphology, and stipule development. AB - The phylogenetically ambivalent monotypic genus Lactoris presents sympodial (determinate) branching, as a terminal flower is present on each main branch. The synflorescence is thyrsoid. Partial inflorescences are rhipidia with up to three flowers. The ochrealike stipule is formed by the fusion of two lateral stipules, which forms an adaxial ligule-like structure and a two-flanked leaf sheath that encircles the parental axis. The leaf sheath elongates with the growth of the preceding internode. Although sympodial growth and a sheathing leaf base are present in all Piperales (Aristolochiaceae, Lactoridaceae, Piperaceae, and Saururaceae), the presence of stipules is confined to Lactoris, Saururaceae, and some Piperaceae. These characters are consistent with the placement of Lactoris within Piperales, although its phylogenetic position within the order remains equivocal, except for the possible sister group relationship suggested by the presence of cymose inflorescences in both Lactoris and Aristolochiaceae. PMID- 21669647 TI - Anatomical and chemical analyses of leaf secretory cavities of Rustia formosa (Rubiaceae). AB - Foliar secretory cavities, commonly called leaf pellucid glands, have been reported in many families of vascular plants. In the Rubiaceae, these structures have only been found in the sister genera Rustia and Tresanthera, which are also anomalous within the family because they have poricidal anthers, and in the distantly related Heterophyllaea. General leaf anatomy, with particular attention to secretory cavities, as well as the chemical analysis of the secreted substances of Rustia formosa, is presented here for the first time. The secretory structures have been found in the lamina between the palisade and spongy parenchymas and in the cortical region of the petiole. The chemical analysis showed that the essential oil secreted is a complex mixture of at least 75 components, mostly of sesquiterpenoid composition. Illustrations of the leaf anatomy, details of the secretory structures of Rustia formosa, a gas chromatogram, and a table of the principal components of the leaf essential oil are included. PMID- 21669648 TI - Leaf shape and anatomy as indicators of phase change in the grasses: comparison of maize, rice, and bluegrass. AB - Leaf morphology and anatomy during vegetative phase change was compared in bluegrass, rice, and maize. Maize juvenile leaves are coated with epicuticular wax, lack specialized cells, such as trichomes and bulliform cells, and epidermal cell walls stain a uniform purple color. Adult maize leaves are pubescent, lack epicuticular waxes, and have crenulated epidermal cell walls that stain purple and blue. All bluegrass and rice blades are pubescent, coated with epicuticular waxes, and show purple and blue wall staining. In all three grasses, blade width steadily increases at each node until a threshold size is achieved several nodes before reproductive competence is acquired. Blade-to-sheath length showed a similar trend of continuous change followed by discontinuous change prior to reproduction. Analysis of leaf development demonstrated that maize primordia initiate more rapidly relative to blade and sheath growth than do either bluegrass or rice. We conclude that leaf shape, as defined by blade width and blade-to-sheath ratio, is a reliable indicator of phase, whereas anatomy is not a universal indicator of phase change in the grasses. We speculate that different growth patterns among these grasses may be attributed to changes in the timing of embryonic and postembryonic development. PMID- 21669649 TI - Multiple origins of sequestrate fungi related to Cortinarius (Cortinariaceae). AB - The aim of the present study was to investigate the phylogeny and evolution of sequestrate fungi (with gastroid or partially exposed basidiomes) in relation to their gilled relatives from the Cortinariaceae (Basidiomycetes). Phylogenetic analyses of 151 ITS sequences from 77 gilled species and 37 sequestrate taxa were performed using maximum parsimony and maximum likelihood methods. Results show that sequestrate basidiome forms occur in all three major ectomycorrhizal lineages of Cortinariaceae: the clades Cortinarius, Hebeloma/Hymenogaster/Naucoria, and Descolea. However, these forms do not appear within the saprobic outgroup Gymnopilus, indicating multiple origins of sequestrate forms from ectomycorrhizal ancestors. Additionally, within the Cortinarius clade sequestrate forms have multiple origins: emergent Cortinarius spp., Thaxterogaster, Quadrispora, Protoglossum, and two Hymenogaster spp. (H. remyi, H. sublilacinus) share common ancestors with Cortinarius spp., but these sequestrate genera are not closely related to each other (with exception of Thaxterogaster and Quadrispora). Hymenogaster sensu stricto, Setchelliogaster, and Descomyces were placed in the two other major clades. Thus, sequestrate taxa evolved independently many times within brown-spored Agaricales. Furthermore, emergent, secotioid, and gastroid forms have evolved independently from each other, and so are not necessarily intermediate forms. After their establishment, these apparently morphologically stable taxa show a tendency to radiate. PMID- 21669650 TI - Genetic structure of three orchid species with contrasting breeding systems using RAPD and allozyme markers. AB - Zeuxine gracilis, Zeuxine strateumatica, and Eulophia sinensis are wild orchids with different breeding systems and colonizing abilities. Zeuxine gracilis is an outcrosser with restricted distribution, whereas S. strateumatica is an apomictic colonizer found only in newly available open habitats. Eulophia sinensis is an outcrossing colonizer. This study investigates the levels of genetic variation and patterns of population structure in these wild orchids to provide genetic information for the development of suitable conservation strategies. Lack of allozyme variation was characteristic of all three species, especially in populations of the two colonizing orchids, Z. strateumatica and E. sinensis. More variable markers, randomly amplified polymorphic DNAs (RAPDs), were further employed to characterize population structure of these species. Substantial genetic variation was found at the RAPD loci within populations of Z. gracilis (p = 21.65 +/- 15.88%, A = 1.217 +/- 0.159, and H = 0.076 +/- 0.054) and E. sinensis (p = 17.82 +/- 20.97%, A = 1.179 +/- 0.209, and H = 0.070 +/- 0.084), but little variation existed within populations of Z. strateumatica (p = 2.84 +/- 2.58%, A = 1.029 +/- 0.026, and H = 0.011 +/- 0.011). Regardless of the breeding system, the total gene diversity at the species level was partitioned primarily between populations, as shown by high G(ST) values, in all three species. An extremely high level of population differentiation (G(ST) = 0.924) was found in the apomictic colonizer Z. strateumatica. The patterns of genetic variation in these wild orchids are apparently related to their differences in breeding system and colonizing ability. Different conservation strategies are needed for the long term survival of these species. PMID- 21669651 TI - Genetic differentiation within and among island populations of the endangered plant Aster miyagii (Asteraceae), an endemic to the Ryukyu Islands. AB - Genetic diversity was examined at 17 putative allozyme loci in 18 populations of the insular endemic plant Aster miyagii (Asteraceae). This species is geographically restricted to only three islands of the Ryukyu Islands and is on the federal list of threatened plants. Genetic differentiation within an island is small, suggesting that gene flow among populations on the same island is sufficiently large to prevent divergence. By contrast, genetic differentiation among islands is large, especially between Amamioshima Island and the other two islands, suggesting that gene flow between the islands is highly restricted. Two unique alleles are nearly fixed in populations on Amamioshima Island, which is the southernmost island of the three. Comparatively, genetic diversity is the smallest on Amamioshima Island. This genetic paucity on Amamioshima Island is probably a result of a population bottleneck at colonization or the small effective population size on this island. Genetic diversity at the species level of A. miyagii is larger than those of the species with a similar life history and of the congeneric widespread species, suggesting that the species has an old origin as an insular endemic species. PMID- 21669652 TI - Allozyme diversity in endemic flowering plant species of the Juan Fernandez Archipelago, Chile: ecological and historical factors with implications for conservation. AB - The level and apportionment of allozyme diversity were determined for 29 endemic (and 1 native) species from the Juan Fernandez Islands, Chile. Mean diversities at the species level (H(es) = 0.065) are low but comparable to those measured for other insular endemics in the Pacific. A high mean proportion (0.338) of species level diversity resides among populations. Diversity statistics were compared for species in different ecological-life history trait categories and abundance classes. Species occurring in large populations and those present in scattered small populations have higher diversities than species occurring in one or two populations. Although not significant with the conservative statistical test employed, lower diversity was found in highly selfing species as compared to animal- or wind-pollinated species. The apportionment of genetic diversity within and among populations (G(ST) values) is not significantly different for any of the species categories. Of particular interest is the lack of difference between animal- and wind-pollinated species because previous analyses of large data sets showed higher differentiation between populations of animal- than wind-pollinated species. Historical factors, both ecological and phylogenetic in nature, can influence the level and apportionment of diversity within insular endemics, and thus ecological correlates of diversity seen in many continental species may not apply to endemics. The results have several conservation implications. The preservation of large populations or several small populations is important for conserving diversity within species because when species are reduced to one or two populations, allozyme diversity is sharply reduced. High mean G(ST) values for the species examined illustrate the need for conserving as many populations as possible, either in the wild or in the garden, to preserve maximal diversity within species. Effective conservation strategies require empirical knowledge of each species. PMID- 21669653 TI - Functional analysis of synchronous dichogamy in flowering rush, Butomus umbellatus (Butomaceae). AB - Dichogamy is one of the most widespread floral mechanisms in flowering plants and is thought to have evolved to reduce interference between pollen import and export within flowers, especially self-pollination. Self-pollination between flowers may also be reduced if dichogamy is synchronous among flowers on an inflorescence. The analysis of dichogamy at both levels requires that the sexual phases of individual flowers be defined functionally in terms of pollen deposition and removal. We conducted morphological and functional analyses to investigate the degree of dichogamy within flowers and the synchronicity of dichogamy between flowers within inflorescences in an emergent, aquatic monocot, flowering rush (Butomus umbellatus). Based on daily observations of the development of marked flowers, data on the schedule of anther dehiscence within flowers, and repeat surveys of floral sex ratios in three populations, individual flowers appear to be strictly protandrous. On average, each flower spends ~1 d in each of male and female phases with an intervening 1-d neuter phase during which there is no available pollen in anthers and stigmas are not yet exposed to receive pollen. Morphological criteria used to delimit the beginning and end of each of these three sex phases were validated by quantifying the temporal schedule of pollen removal from anthers and pollen deposition on stigmas. Experimental pollinations showed that the morphological changes marking the end of female phase are hastened by pollen deposition. At the umbel level, synchronous development within sequential cohorts of flowers reduced overlap of male and female sexual phases between flowers. On average (+/-1 SE), 72 +/- 3% of flowers completed their female phase while no other flowers on the same umbel were in male phase. Computer simulations of umbel development showed that this value is significantly higher than expected if the timing of flower development within umbels was random (30 +/- 1%). Surveys of floral sex ratios in three populations revealed that 87% of umbels were either unisexual male or female at any given time. Pollinators usually visited more than one flower in sequence when foraging on umbels, suggesting that synchronous dichogamy may be an adaptation to avoid geitonogamy. The adaptiveness of both flower- and umbel-level dichogamy is also suggested because both traits are expressed to a lesser extent in obligately clonal, triploid populations, where flowers do not make seeds and hence floral adaptations are not maintained by natural selection. PMID- 21669654 TI - Carbon allocation to volatiles and other reproductive components in male Ficus carica (Moraceae). AB - Volatile compounds are often mediators of plant-pollinator interactions. Their emission is presumed to be costly, but this cost has seldom been quantified. Figs of Ficus carica (a dioecious species) release volatile compounds when receptive, thus attracting the agaonid wasp Blastophaga psenes. In dioecious fig species, wasps lay eggs inside male figs and pollinate female ones. For a male tree, we estimated carbon allocation to reproduction using the annual growth module (AGM) as the unit of measurement. Over the growing season, leaf and fig carbon exchange and construction costs were measured, as well as carbon investment in stamens, provisioning pollinators, and biosynthesis and release of volatile compounds. Representativity of the tree studied was evaluated by measuring some of these parameters on seven other male fig trees. The results show that 7.6-16.4% of the carbon assimilated by leaves and figs was invested in reproduction. Of the carbon invested in reproduction, pollinator attraction and feeding represented only 0.08 0.12% and 1.84-2.33%, respectively, while pollinator sheltering (fig construction and respiration) represented 97.6-98.0%. In this strict and coevolved plant pollinator association, the main male reproductive investment was thus in the structures sheltering the associated pollinators. PMID- 21669655 TI - Floral stages, ovule development, and ovule and fruit success in Iris tenax, focusing on var. gormanii, a taxon with low seed set. AB - Ovule development and ovule and fruit success were investigated in Iris tenax var. tenax and I. tenax var. gormanii. Ovule development, including megasporogenesis and initial stages of megagametogenesis, occurred while flowers were still in bud. Final maturation of the seven-celled embryo sac occurred during the male phase of flowering. An earlier report that synergids persist after fertilization, and that nucellar nuclei migrate into the developing megagametophyte in I. tenax var. tenax, was not supported in the present study. Reproductive studies used two pollination treatments: outcrossing and selfing. Treatment results were compared with results from open pollination. Both varieties of I. tenax are self-compatible. Results showed that <5% of I. tenax var. gormanii ovules develop into seeds with open pollination, supporting earlier reports of low seed set. Hand pollinations improved reproductive success, suggesting that pollen may be limiting in nature. PMID- 21669656 TI - Does differential seed siring success change over time or with pollination history in wild radish, Raphanus sativus (Brassicaceae)? AB - Previous work with wild radish has shown that pollen donors sire different numbers of seeds and that the condition of the maternal tissue affects seed paternity, suggesting that both pollen donor characteristics and maternal tissue affect mating. However, because these results are from the greenhouse, it is difficult to know whether they would hold true in the field. Here, we performed hundreds of crosses on several maternal plants to simulate changes during the flowering season of field plants. During the experiment, maternal resource availability changed due to the costs of producing fruits, and we determined the pollination history of a plant by performing crosses in specific orders. Examination of seed paternity showed that there were small differences in pollen donor success at the beginning of the experiment when maternal resources were abundant. Differential pollen donor success was greatest slightly later in the flowering period, but declined toward the end of the experiment. Thus, maternal plants may distinguish most among pollen donors when they have both abundant resources and experience with the differences in quality of available pollen donors. In contrast, there were few significant effects of the recent pollination history of plants on pollen donor success. Finally, despite the changes in mating performance over time, there were strong overall differences in pollen donor success, suggesting that seasonal changes in the field will not eliminate the potential for nonrandom mating. PMID- 21669657 TI - Evidence for a switch in the reproductive biology of Rubus alceifolius (Rosaceae) towards apomixis, between its native range and its area of introduction. AB - We compared the reproductive system of Rubus alceifolius in its native range in Southeast Asia, in Madagascar, where the plant was introduced apparently some centuries ago, and in La Reunion, an Indian Ocean island onto which R. alceifolius was introduced (from Madagascan source populations) around 1850. While tetraploidy makes it impossible to analyze variation in R. alceifolius using classical methods of population genetics, both the patterns of genetic diversity (as revealed by AFLP [amplified fragment length polymorphism] markers) and differences between half-sib progeny and their maternal parents (revealed by microsatellite markers) show that in the plant's native range in southeast Asia, seeds are produced sexually. In contrast, in Madagascar sexual reproduction cannot alone account for the genetic patterns observed with microsatellite markers. Over 85% of the half-sib progeny resulting from open pollination gave multilocus genotypes identical to those of their respective maternal parents, despite the fact that the latter had alleles that were rare in the population. The other progeny differed in having an allele with one motif more or less than that of the maternal parent. Seeds thus appear to be produced mostly or exclusively by apomixis in Madagascar. We present findings suggesting that Madagascan populations result from hybridization of introduced R. alceifolius and native populations of R. roridus, a closely related species of Rubus subgenus Malachobatus, and suggest that apomixis was a consequence of this hybridization. In Reunionese populations of R. alceifolius (derived from Madagascan populations), seeds obtained in controlled pollination experiments were all genetically identical to maternal parents. While genetic variation (microsatellite markers) in Reunionese populations was low, it was sufficient to allow us to demonstrate that seeds could not have resulted from fertilization by the pollen donors chosen for controlled pollinations, or from autogamy, and were produced exclusively by apomixis. PMID- 21669658 TI - Construction cost and invasive potential: comparing Lythrum salicaria (Lythraceae) with co-occurring native species along pond banks. AB - Lythrum salicaria (purple loosestrife) is a nonindigenous invasive species characterized by prolific growth and abundance in marshy and riparian habitats across North America. Given its invasive success, we hypothesized this species may require less energy and/or use energy more efficiently for biomass construction than co-occurring noninvasive plant species. We measured leaf construction cost (CC), leaf mass per unit area (LMA), and leaf organic nitrogen and carbon content of L. salicaria and the five most abundant co-occurring species, Parthenocissus quinquefolia, Erigeron philadelphicus, Asclepias syriaca, Spiraea latifolia, and Solidago graminifolia, along dammed ponds in the Black Rock Forest, Cornwall, New York, USA. Lythrum salicaria, which was highly abundant (2.52 individuals/m(2)), exhibited significantly lower area-based leaf CC (44.47 +/- 4.24 g glucose/m(2) leaf) than relatively less abundant species, suggesting energetics may influence its invasive success. Conversely, least abundant Solidago graminifolia (0.67 individuals/m(2)) exhibited the significantly highest leaf CC per unit leaf area (141.87 +/- 39.21 g glucose/m(2) leaf). Overall, a negative correlation between species abundance and area-based leaf CC (r(2) = 0.73) indicated low energy requirements and/or high energy efficiency may influence relative abundance in the plant species studied. As it correlates with species abundance in this study, CC may be a useful tool for evaluating invasive potential. PMID- 21669659 TI - Multiple origin of the tropical forest tree family Icacinaceae. AB - Analyses of DNA sequences from four genes (ndhF, rbcL, atpB, and 18S rDNA) and morphological data show that the members of the tropical forest tree family Icacinaceae do not have a common origin. All of the genera earlier placed in Icacinaceae are euasterids but placed in the following three different orders: Garryales, Aquifoliales, and Apiales. Icacina and related genera are members of Garryales and, pending more data, are still best treated as Icacinaceae (sensu stricto). The genera related to Aquifoliales are placed in Cardiopteridaceae and a new family, Stemonuraceae. The genus Pennantia is a member of Apiales and the family Pennantiaceae is recognized. Morphological characters delimiting these groups are discussed. Twenty-six new ndhF sequences were obtained for the study (25 from former Icacinaceae and 1 from Cardiopteris). PMID- 21669660 TI - Molecular phylogeny of the Magnoliaceae: the biogeography of tropical and temperate disjunctions. AB - The boreotropical flora concept suggests that relictual tropical disjunctions between Asia and the Americas are a result of the expansion of the circumboreal tropical flora from the middle to the close of the Eocene. Subsequently, temperate species diverged at high latitudes and migrated to other continents. To test this concept, we conducted a molecular phylogenetic analysis (using cpDNA) of the Magnoliaceae, a former boreotropical element that currently contains both tropical and temperate disjuncts. Divergence times of the clades were estimated using sequences of matK and two intergenic regions consisting of psbA-trnH and atpB-rbcL. Results indicate the tropical American section Talauma branched first, followed by the tropical Asian clade and the West Indies clade. Within the remaining taxa, two temperate disjunctions were formed. Assuming the temperate disjunction of Magnolia acuminata and Asian relatives occurred 25 mya (late Oligocene; based on seed fossil records), section Talauma diverged 42 mya (mid Eocene), and tropical Asian and the West Indies clades 36 mya (late Eocene). These events correlate with cooling temperatures during the middle to late Eocene and probably caused the tropical disjunctions. PMID- 21669661 TI - Phylogenetic relationships in Pleurothallidinae (Orchidaceae): combined evidence from nuclear and plastid DNA sequences. AB - To evaluate the monophyly of subtribe Pleurothallidinae (Epidendreae: Orchidaceae) and the component genera and to reveal evolutionary relationships and trends, we sequenced the nuclear ribosomal DNA internal transcribed spacers (ITS1 and ITS2) and 5.8S gene for 185 taxa. In addition, to improve the overall assessments along the spine of the topology, we added plastid sequences from matK, the trnL intron, and the trnL-F intergenic spacer for a representative subset of those taxa in the ITS study. All results were highly congruent, and so we then combined the sequence data from all three data sets in a separate analysis of 58 representative taxa. There is strong support in most analyses for the monophyly of Pleurothallidinae and in some for inclusion of Dilomilis and Neocognauxia of Laeliinae. Although most genera in the nine clades identified in the analyses are monophyletic, all data sets are highly congruent in revealing the polyphyly of Pleurothallis and its constitutent subgenera as presently understood. The high degree of homoplasy in morphological characters, especially floral characters, limits their usefulness in phylogenetic reconstruction of the subtribe. PMID- 21669662 TI - Phylogenetic relationships of Theaceae inferred from chloroplast DNA sequence data. AB - Tribal and generic relationships within Theaceae were investigated using cladistic analyses of chloroplast-encoded rbcL and matK + flanking intergenic spacer region data. Molecular data were employed because recent morphological and anatomical studies of tea (Camellia sinensis) and related plant species provide conflicting support for tribal and generic relationships within the family. Parsimony analyses of separate and combined data consistently identify three strongly supported lineages: Theeae, Stewartieae, and Gordonieae. These data support the broad generic circumscription of Camellia and Stewartia but do not support the recognition of Gordonia sensu lato. Gordonia lasianthus and Gordonia brandegeei are the basal clade in Gordonieae, a position far removed from all other representatives of Gordonia sensu lato (Polyspora and Laplacea) included in this study. This phylogeny most closely mirrors Airy-Shaw's tribe Camellieae [= Theeae] and his two subtribes Stewartiinae and Gordoniinae, first published in 1936. We recognize all three major lineages at the tribal level, although there is weak statistical support for a sister relationship between Gordonieae and Theeae. We also find statistical support for the recognition of the two former subfamilies Theoideae and Ternstroemioideae as two separate families, Theaceae and Ternstroemiaceae. PMID- 21669663 TI - Phylogeny of Amaryllidaceae tribe Amaryllideae based on nrDNA ITS sequences and morphology. AB - We present the results of cladistic analyses of morphology, nrDNA ITS sequences, and a combination of the two for tribe Amaryllideae of the Amaryllidaceae. The morphologically based analysis supports the recognition of Amaryllis as sister to two major clades, equivalent to Snijman and Linder's (1996, Annals of the Missouri Botanical Garden 83: 362-386) Crininae and Amaryllidinae (less Amaryllis). A single tree is found with a successively weighted ITS sequence matrix. Amaryllis and Boophone form a grade at the base of the tree. All the other genera are included in two clades conforming to Snijman and Linder's (1996) subtribes Amaryllidinae (less Amaryllis, thus now Strumariinae) and Crininae (less Boophone). Within Strumariinae, Strumaria sensu lato is resolved as polyphyletic. Strumaria subg. Gemmaria is sister to the rest of the subtribe. Hessea is monophyletic only if Namaquanula is excluded. The monotypic Carpolyza is embedded within Strumaria sensu stricto. The consensus of the combined analysis is highly resolved, and most similar to the sequence topology. Based on the results of the combined analyses, the major clades are recognized as subtribes, and Carpolyza is placed into synonymy under Strumaria. PMID- 21669664 TI - Phylogeny and quaternary history of the European montane/alpine endemic Soldanella (Primulaceae) based on ITS and AFLP variation. AB - Soldanella contains 16 species of herbaceous perennials that are endemic to the central and south European high mountains. The genus is ecogeographically subdivided into forest/montane and alpine species. Evolutionary relationships and large-scale biogeographic patterns were inferred from parsimony analyses of the internal transcribed spacer (ITS) regions of nuclear ribosomal DNA, and genetic distance analyses based on amplified fragment length polymorphism (AFLP) markers. The ITS region proved useful for examining subgeneric relationships and testing hypotheses on genus-wide divergence times, whereas the AFLP markers were suitable for studying relationships among closely related taxa and biogeographic patterns of divergence. Neither ITS nor AFLP data supported sectional delimitations, particularly those related to the grouping of S. alpina (sect. Soldanella) with S. pusilla (sect. Tubiflores), which may be the result of hybridization. Additional results and conclusions drawn are (1) Soldanella is derived from an ancestor of Asian origin with a montane ecology; (2) estimates of divergence times suggest a late Quaternary origin of the genus; (3) alpine species of sect. Tubiflores diverged from within a paraphyletic sect. Soldanella of mainly montane species; (4) alpine and montane species of Soldanella experienced different cycles of range expansion and contraction during late Quaternary climatic changes, resulting in differential patterns of geographic distribution; and (5) AFLP divergence among montane species from eastern Europe was lower than between alpine species; we hypothesize that the latter differentiated in allopatric regions of expansion during glacials, while the former experienced secondary contact at lower elevations in more southern refugia. PMID- 21669665 TI - Erratum. PMID- 21669666 TI - The evolution of minor vein phloem and phloem loading. AB - Phylogenetic analysis provides a rational basis for comparative studies of phloem structure and phloem loading. Although several types of minor vein companion cell have been identified, and progress has been made in correlating structural features of these cells with loading mechanisms, little is known about the phylogenetic relationships of the different types. To add to the available data on companion cells, we analyzed the ultrastructure of minor veins in Euonymus fortunei and Celastrus orbiculatis (Celastraceae) leaves and determined that in these species they are specialized as intermediary cells. This cell type has been implicated in symplastic phloem loading. The data were added to published data sets on minor vein phloem characteristics, which were then mapped to a well supported molecular tree. The analysis indicates that extensive plasmodesmatal continuity between minor vein phloem and surrounding cells is ancestral in the angiosperms. Reduction in plasmodesmatal frequency at this interface is a general evolutionary trend, punctuated by instances of the reverse. This is especially true in the case of intermediary cells that have many plasmodesmata, but other distinguishing characteristics as well, and have arisen independently at least four, and probably six, times in derived lineages. The character of highly reduced plasmodesmatal frequency in minor vein phloem, common in crop plants, has several points of origin in the tree. Thus, caution should be exercised in generalizing results on apoplastic phloem loading obtained from model species. Transfer cells have many independent points of origin, not always from lineages with reduced plasmodesmatal frequency. PMID- 21669667 TI - Heteroblasty and preformation in mayapple, Podophyllum Peltatum (Berberidaceae): developmental flexibility and morphological constraint. AB - Developmental preformation can constrain growth responses of shoots to current conditions, but there is potential for flexibility in development preceding formation of the preformed organs. Mayapple (Podophyllum peltatum) is strongly heteroblastic, producing rhizome scales, bud scales, and either a single vegetative foliage leaf or two foliage leaves on a sexual shoot. To understand how and when preformation constrains growth responses, we compare (1) how leaf homologs of the renewal shoot differ in development, (2) whether there are differences in shoot development that occur in advance of morphological determination of shoot type, and (3) whether there are points of developmental flexibility in renewal shoot growth prior to preformation of the foliage and floral organs. We use scanning electron microscopy and histology to show that the three vegetative leaves (both types of scale leaves and the vegetative foliage leaf) are similar in the initial establishment of an encircling and overarching leaf base. Differences among them are found in the timing of differentiation of the leaf base and in the relative timing and degree of growth of the lamina and petiole. In contrast, foliage leaves on sexual shoots show less expression of the leaf base and precocious growth of the lamina and petiole. Prior to shoot type determination, there are no morphological differences in the sequence or position of leaf homologs that predict final shoot type. In this colony, leaves at positions 12 and 13, on average, appear to be identical in development until they are between 700 and 800 MUm in length, when it becomes possible to distinguish leaves that will become vegetative foliage leaves from additional bud scale leaves on vegetative or sexual shoots. We suggest that late developmental determination of leaves at positions 12 and 13 reflects ontogenetic sensitivity to a transition to flowering. Thus, in mayapple, heteroblasty appears to facilitate developmental flexibility prior to the point where shoot growth becomes constrained by preformation of determined aerial structures. PMID- 21669668 TI - Rice and Phragmites: effects of organic acids on growth, root permeability, and radial oxygen loss to the rhizosphere. AB - Young Phragmites plants were grown in two cocktails of monocarboxylic acids (C(1) C(5)) at pH 6, where the concentration of each acid was innocuous and the total undissociated (potentially toxic) concentrations were 0.35 mmol/L and 0.42 mmol/L. Rice plants were subjected to 1.5 mmol/L acetic acid at pH 4.5 (undissociated concentration = 1.05 mmol/L). In Phragmites, each cocktail curtailed root growth especially and induced premature shoot senescence. In both species, after 3-5 d of treatment, radial oxygen loss (ROL) from apical regions of adventitious roots, and from Phragmites laterals, was reduced to very low values and associated with cell wall lignification and suberization in the surface cell layers. At later stages of treatment, rice responded to acetic acid in similar ways to Phragmites, with the development of intercellular and callus type occlusions in the gas space system, vascular blockages, and the failure of laterals to emerge. The results are relevant to the supply of oxygen from Phragmites roots to sediments for the phytopurification of waste waters, to the efflux of methane and carbon dioxide from wetlands, and to rice cultivation. PMID- 21669669 TI - Hydrophobic trichome layers and epicuticular wax powders in Bromeliaceae. AB - The distinctive foliar trichome of Bromeliaceae has promoted the evolution of an epiphytic habit in certain taxa by allowing the shoot to assume a significant role in the uptake of water and mineral nutrients. Despite the profound ecophysiological and taxonomic importance of this epidermal structure, the functions of nonabsorbent trichomes in remaining Bromeliaceae are not fully understood. The hypothesis that light reflection from these trichome layers provides photoprotection was not supported by spectroradiometry and fluorimetry in the present study; the mean reflectance of visible light from trichome layers did not exceed 6.4% on the adaxial surfaces of species representing a range of ecophysiological types nor was significant photoprotection provided by their presence. Several reports suggesting water repellency in some terrestrial Bromeliaceae were investigated. Scanning electron microscopy (SEM) and a new technique-fluorographic dimensional imaging (FDI)-were used to assess the interaction between aqueous droplets and the leaf surfaces of 86 species from 25 genera. In the majority of cases a dense layer of overlapping, stellate or peltate trichomes held water off the leaf epidermis proper. In the case of hydrophobic tank-forming tillandsioideae, a powdery epicuticular wax layer provided water repellency. The irregular architecture of these indumenta resulted in relatively little contact with water droplets. Most mesic terrestrial Pitcairnioideae examined either possessed glabrous leaf blades or hydrophobic layers of confluent trichomes on the abaxial surface. Thus, the present study indicates that an important ancestral function of the foliar trichome in Bromeliaceae was water repellency. The ecophysiological consequences of hydrophobia are discussed. PMID- 21669670 TI - Ribosomal DNA phylogeny of the Bangiophycidae (Rhodophyta) and the origin of secondary plastids. AB - We sequenced the nuclear small subunit ribosomal DNA coding region from 20 members of the Bangiophycidae and from two members of the Florideophycidae to gain insights into red algal evolution. A combined alignment of nuclear and plastid small subunit rDNA and a data set of Rubisco protein sequences were also studied to complement the understanding of bangiophyte phylogeny and to address red algal secondary symbiosis. Our results are consistent with a monophyletic origin of the Florideophycidae, which form a sister-group to the Bangiales. Bangiales monophyly is strongly supported, although Porphyra is polyphyletic within Bangia. Bangiophycidae orders such as the Porphyridiales are distributed over three independent red algal lineages. The Compsopogonales sensu stricto, consisting of two freshwater families, Compsopogonaceae and Boldiaceae, forms a well-supported monophyletic grouping. The single taxon within the Rhodochaetales, Rhodochaete parvula, is positioned within a cluster containing members of the Erythropeltidales. Analyses of Rubisco sequences show that the plastids of the heterokonts are most closely related to members of the Cyanidiales and are not directly related to cryptophyte and haptophyte plastid genomes. Our results support the independent origins of these secondary algal plastids from different members of the Bangiophycidae. PMID- 21669671 TI - Susceptibility to UV damage in Impatiens capensis (Balsaminaceae): testing for opportunity costs to shade-avoidance and population differentiation. AB - Plastic increases in leaf secondary compounds may be an adaptive strategy that reduces the damaging effects of high-energy, ultraviolet radiation (UV). Here, we examine (1) the relationship between fitness and anthocyanin and flavonoid concentrations in experimental, UV environments, (2) the effects of UV on Impatiens capensis plants derived from woodland and clearing sites, and (3) whether susceptibility to UV damage is reduced by exposure to high ratios of red : far-red wavelengths (R : FR), which also stimulate the production of leaf compounds. Seedlings from each site were exposed to either high R : FR typical of sunlight or low R : FR characteristic of foliar shade, after which plants were moved into ambient UV or UV-removal treatments. Ultraviolet radiation stimulated the production of anthocyanins and flavonoids. However, higher anthocyanin concentrations were associated with lower biomass in the UV environment. Relative to the clearing population, reproductive output of the woodland population was more detrimentally affected by exposure to UV, despite its higher concentration of anthocyanins. Increased anthocyanin production may therefore be a stress response rather than an adaptive one. The greater tolerance of the clearing population to UV suggests that populations with an evolutionary history of UV exposure evolve mechanisms to limit damage. The R : FR pretreatments did not influence susceptibility to UV damage. PMID- 21669672 TI - Partitioning and diversity of nuclear and organelle markers in native and introduced populations of Epipactis helleborine (Orchidaceae). AB - Variability of allozymes (1170 individuals, 47 populations) and chloroplast DNA (692 individuals, 29 populations) was examined in native European and introduced North American populations of Epipactis helleborine (Orchidaceae). At the species level, the percentage of allozyme loci that were polymorphic (P(99)) was 67%, with a mean of 2.11 alleles (A) per locus, and an expected heterozygosity (H(exp)) of 0.294. At the population level, mean P(99) = 56%, mean A = 1.81, and mean H(exp) = 0.231. Although field observations suggest that self-pollination occurs frequently, populations had a genetic structure consistent with Hardy Weinberg expectations and random mating (mean F(IS) = 0.002). There was significant deviation from panmixia associated with population differentiation (mean F(ST) = 0.206). The distribution of two chloroplast haplotypes showed that 15 of the 29 populations were polymorphic. Using both nuclear and organelle F(ST) estimates, a pollen to seed flow ratio of 1.43 : 1 was calculated. This is very low compared with published estimates for other plant groups, consistent with the high dispersability of orchid seeds. Finally, there was no evidence for a genetic bottleneck associated with the introduction of E. helleborine to North America. PMID- 21669673 TI - A rare continual flowering strategy and its influence on offspring quality in a gynodioecious plant. AB - The majority of angiosperms have a single annual bout of reproduction; species that flower continually throughout the year are rare. Ochradenus baccatus is a gynodioecious, desert shrub whose principal flowering period is associated with the winter rains, although large individuals also remain in flower during the hot, dry summer. The goal of this study was to examine the reproductive consequences of continual flowering in a large population of O. baccatus in Israel. Over the two years of this study, 60% of individuals flowered continuously. The number of fruit and seeds per fruit were greater in winter. Winter seeds were ~12% heavier than summer seeds and had significantly higher germination rates (80 vs. 60%, respectively). Although summer seeds were smaller and less likely to germinate, we propose that the benefit derived from their production lies in their ability to capitalize on the first winter rains. These early rain events provide a head start on establishment and growth in the hostile desert environment. Plants that delay reproduction until the onset of rains risk having their offspring face the dry conditions of spring and summer. PMID- 21669674 TI - Inbreeding depression under intraspecific competition in a highly outcrossing population of Crepis sancta (Asteraceae): evidence for frequency-dependent variation. AB - Inbreeding depression is a major selective factor acting to maintain outcrossing in hermaphroditic plants. Recently it has been shown that environmental conditions may greatly affect the levels of inbreeding depression. In this study, the effects of intraspecific competition, from either crossed or inbred progeny, and plant density on the expression of inbreeding depression were estimated for the allogamous colonizing plant Crepis sancta (Asteraceae). The population used in this experiment showed a very high outcrossing rate (t = 0.99). Inbreeding depression was measured for germination, survival to reproduction, number of capitula, and a multiplicative fitness estimate. We found that inbreeding depression on survival, the number of capitula, and total fitness was the greatest when inbred plants compete with outbred plants. The effect of density on inbreeding depression was less evident. The major implication of our study is that the relative fitness of selfed progeny is strongly influenced by the type of competitors (outbred or inbred). These results support the hypothesis that inbreeding depression varies according to the density and frequency of outbred plants and suggest that it could be considered as a density- and frequency dependent phenomenon. PMID- 21669675 TI - Response to ammonium and nitrate by a mycorrhizal annual invasive grass and native shrub in southern California. AB - The goal of this study was to determine the interaction of mycorrhizae and two N sources, ammonium (NH(4)(+)) and nitrate (NO(3)(-)), on the growth of a coastal sage scrub (CSS) species, Artemisia californica, and an exotic annual grass, Bromus madritensis ssp. rubens. Anthropogenic nitrogen deposition may be influencing the decline of CSS and replacement by exotic grasses, but the extent to which mycorrhizae are involved in shrubland decline is unknown. NO(3)(-) is the dominant form of deposition in southern California, although the native, uneutrophied soils have a greater concentration of NH(4)(+). Seeds of each species were germinated in pots of sterile soil, inoculated with native soil containing mycorrhizal spores and infective root fragments, and fertilized with 50 MUg/g of either NO(3)(-) or NH(4)(+). NH(4)(+) enhanced the growth of both mycorrhizal species, while NO(3)(-) did not. Control plants of B. madritensis under low N had a significant response to mycorrhizae, but A. californica did not. Nitrate increased the growth of nonmycorrhizal A. californica as much as the mycorrhizal NH(4)(+)-treated plants. There is no evidence in this study to suggest that the decline of A. californica or increase in B. madritensis is due to a mycorrhizal response to NO(3)(-). Other life history traits of the two species must be used to explain the invasive behavior of the annual grass. Mycorrhizae may be more important in controlling plant growth in native uneutrophied soils dominated by NH(4)(+) rather than NO(3)(-). PMID- 21669676 TI - Sex-biased seed predation and the maintenance of females in a gynodioecious plant. AB - We investigated genetic and ecological factors contributing to the maintenance of females in populations of the gynodioecious plant, Sidalcea hendersonii (Malvaceae). Our crossing experiments indicated that male sterility is controlled by a dominant nuclear allele. Nuclear determination of sex theoretically requires much higher female fitness to account for the high frequency of female plants often observed during surveys of S. hendersonii populations. Females were, in fact, shown to have higher fitness in an experimental population, producing more viable seed and surviving offspring than hermaphrodite plants. In natural populations, however, differences in viable seed production were not evident unless seed predation was considered. Sex-biased seed predation appears to play an important role in the maintenance of gynodioecy in S. hendersonii. In populations with high female frequencies, weevil larvae destroyed significantly more seeds from hermaphrodite plants than females, substantially reducing their seed production. To our knowledge, this study provides the first evidence that sex-biased predation may be responsible for high female frequencies in natural populations of a gynodioecious species. PMID- 21669677 TI - Dormancy-breaking and germination requirements for seeds of Symphoricarpos orbiculatus (Caprifoliaceae). AB - Fruits (drupes) of Symphoricarpos orbiculatus ripen in autumn and are dispersed from autumn to spring. Seeds (true seed plus fibrous endocarp) are dormant at maturity, and they have a small, linear embryo that is underdeveloped. In contrast to previous reports, the endocarp and seed coat of S. orbiculatus are permeable to water; thus, seeds do not have physical dormancy. No fresh seeds germinated during 2 wk of incubation over a 15 degrees /6 degrees -35 degrees /20 degrees C range of thermoperiods in light (14-h photoperiod); gibberellic acid and warm or cold stratification alone did not overcome dormancy. One hundred percent of the seeds incubated in a simulated summer -> autumn -> winter -> spring sequence of temperature regimes germinated, whereas none of those subjected to a winter -> spring sequence did so. That is, cold stratification is effective in breaking dormancy only after seeds first are exposed to a period of warm temperatures. Likewise, embryos grew at cold temperatures only after seeds were exposed to warm temperatures. Thus, the seeds of S. orbiculatus have nondeep complex morphophysiological dormancy. As a result of dispersal phenology and dormancy-breaking requirements, in nature most seeds that germinate do so the second spring following maturity; a low to moderate percentage of the seeds may germinate the third spring. Seeds can germinate to high percentages under Quercus leaf litter and while buried in soil; they have little or no potential to form a long-lived soil seed bank. PMID- 21669678 TI - Effects of mycorrhizae on growth and demography of tallgrass prairie forbs. AB - The effects of arbuscular mycorrhizal (AM) symbiosis on ramet and genet densities, vegetative growth rates, and flowering of three forb species were studied in native tallgrass prairie in northeastern Kansas. Mycorrhizal activity was experimentally suppressed for six growing seasons on replicate plots in an annually burned and an infrequently burned watershed with the fungicide benomyl. Benomyl reduced mycorrhizal root colonization to an average of 4.2%, approximately a two-thirds reduction relative to controls (13.7% colonization). Mycorrhizae influenced the population structure of these forbs. Although mycorrhizal suppression had no long-term effect on genet densities and no effect on ramet survivorship throughout the growing season, the number of ramets per individual was significantly increased such that ramet densities of all three species were approximately doubled in response to long-term mycorrhizal suppression. Effects of mycorrhizae on ramet growth and reproduction varied among species. Ramet growth rates, biomass, and flowering of Salvia azurea were greater in plots with active mycorrhizal symbiosis, whereas mycorrhizae reduced ramet growth rates and biomass of Artemesia ludoviciana. Aster sericeus ramet growth rates and biomass were unaffected by the fungicide applications, but its flowering was reduced.The pattern of responses of these three species to mycorrhizae differed considerably between the two sites of contrasting fire regime, indicating that the interaction of fire-induced shifts in resource availability and mycorrhizal symbiosis together modulates plant responses and the intensity and patterns of interspecific competition between and among tallgrass prairie grass and forb species. Further, the results indicate that effects of mycorrhizae on community structure are a result of interspecific differences in the balance between direct positive effects of the symbiosis on host plant performance and indirect negative effects mediated through altered competitive interactions. PMID- 21669679 TI - Is breaking up hard to do? Breakage, growth, and survival in the parasitic clonal plant Cuscuta corymbosa (Convolvulaceae). AB - In a tripartite exploration of the effects of traumatic breakage in the parasitic clonal plant Cuscuta corymbosa, experimental breakage had significant negative effects upon stem extension of ramets distal to a break and the level of that effect depended upon the number of ramets in the severed fragment. Regular monitoring of clonal individuals transplanted onto naturally occurring, native host species revealed that breakage in individuals growing under natural conditions ranged from 2 to 66% of all interramet connections and significantly affected distance between ramets and stolon generation in ramets associated with a break. Simulations revealed that these responses to breakage would significantly change the "shape" of a clonal individual in a manner capable of affecting probabilities of encounter with patchily distributed resources. Nonetheless, the observed levels of breakage had no discernible effect on biomass accumulation, although individuals that survived into the dry season and thus gained the potential to reproduce in additional seasons had a significantly lower rate of breakage than those that did not. We suggest that the lack of a relationship between breakage and within-season biomass accumulation is an indication that parasite response to breakage is gauged to expected levels of breakage for the habitat. We note that the capacity of ramets to survive disconnection significantly decreased the loss of tissue that would occur if subunits did not possess the potential to function independently. PMID- 21669680 TI - Heterophylly in the yellow waterlily, Nuphar variegata (Nymphaeaceae): effects of [CO2], natural sediment type, and water depth. AB - We transplanted Nuphar variegata with submersed leaves only into natural lake sediments in pH-, [CO(2)]-, depth-, and temperature-controlled greenhouse tanks to test the hypotheses that more fertile sediment, lower free [CO(2)], and shallower depth would all stimulate the development of floating leaves. Sediment higher in porewater [NH(4)(+)] favored floating leaf development. Low CO(2)-grown plants initiated floating leaf development significantly earlier than high CO(2) grown plants, which produced significantly more submersed leaves and fewer floating leaves. Mean floating leaf biomass was significantly greater than mean submersed leaf biomass but was not influenced by CO(2) enrichment, whereas mean submersed leaf biomass increased 88% at high [CO(2)]. At the shallower depth (35 cm), floating leaves required 50% less biomass investment per leaf than at 70 cm, and a significantly greater proportion of plants had floating leaves (70 vs. 23 43% at 35 vs. 70 cm, respectively) for the last three of the eight leaf censuses. Sediment type, water depth, and especially free [CO(2)] all can influence leaf morphogenesis in Nuphar variegata, and the development of more and larger submersed leaves with CO(2) enrichment favors the exploitation of high [CO(2)] when it is present in the water column. PMID- 21669681 TI - Evolution of Caulanthus amplexicaulis var. barbarae (Brassicaceae), a rare serpentine endemic plant: a molecular phylogenetic perspective. AB - Intra- and interspecific phylogenetic relationships of the rare serpentine endemic taxon Caulanthus amplexicaulus var. barbarae and related taxa in the "Streptanthoid Complex" of genera (Streptanthus, Caulanthus, Guillenia) were examined using nuclear ribosomal internal transcribed spacer (ITS) and chloroplast trnL intron sequences. Phylogenetic hypotheses generated from 81 variable ITS nucleotide sites and six variable trnL nucleotide sites indicate that Streptanthus and Caulanthus are nonmonophyletic groups. Caulanthus amplexicaulis var. barbarae and its more widespread nonserpentine sister taxon Caulanthus amplexicaulis var. amplexicaulis formed a distinct monophyletic group. Among the taxa in our study, C. amplexicaulis was most closely related to Streptanthus tortuosus. The ITS sequences supported monophyly of subgenus Euclesia, which includes the bulk of the serpentine endemics in the Streptanthoid Complex. The serpentine taxa were nonmonophyletic, occurring in at least three distinct clades, suggesting that tolerance to serpentine may be gained or lost through relatively few genetic changes. Intraspecific ITS1 and ITS2 sequence divergence within C. amplexicaulis (1.3-1.8%) was higher than in comparable species (0.0-0.3%); implications of this genetic differentiation for the conservation status of C. amplexicaulis var. barbarae are discussed. Evidence is presented that supports a "biotype depletion" model for the origin of this rare endemic taxon. PMID- 21669682 TI - Algal switching among lichen symbioses. AB - Lichens are intimate and long-term symbioses of algae and fungi. Such intimate associations are often hypothesized to have undergone long periods of symbiotic interdependence and coevolution. However, coevolution has not been rigorously tested for lichen associations. In the present study we compared the nuclear internal transcribed spacer (ITS) phylogenies of algal and fungal partners from 33 natural lichen associations to test two aspects of coevolution, cospeciation and parallel cladogenesis. Since statistically significant incongruence between symbiont phylogenies rejected parallel cladogenesis and minimized cospeciation events, we conclude that switching of highly selected algal genotypes occurs repeatedly among these symbiotic lichen associations. PMID- 21669683 TI - Sources of error and confidence intervals in estimating the age of angiosperms from rbcL and 18S rDNA data. AB - Molecular estimates of the age of angiosperms have varied widely, and many greatly predate the Early Cretaceous appearance of angiosperms in the fossil record, but there have been few attempts to assess confidence limits on ages. Experiments with rbcL and 18S data using maximum likelihood suggest that previous angiosperm age estimates were too old because they assumed equal rates across sites-use of a gamma distribution of rates to correct for site-to-site variation gives 10-30 my (million years) younger ages-and relied on herbaceous angiosperm taxa with high rates of molecular evolution. Ages based on first and second codon positions of rbcL are markedly older than those based on third positions, which conflict with the fossil record in being too young, but all examined data partitions of rbcL and 18S depart substantially from a molecular clock. Age estimates are surprisingly insensitive to different views on seed-plant relationships. Randomization schemes were used to quantify confidence intervals due to phylogenetic uncertainty, substitutional noise, and lineage effects (deviations from a molecular clock). Estimates of the age of crown-group angiosperms range from 68 to 281 mya (million years ago), depending on data, tree, and assumptions, with most ~140-190 mya (Early Jurassic-earliest Cretaceous). Approximate 95% confidence intervals on ages are wider for rbcL than 18S, ranging up to 160 my for phylogenetic uncertainty, 90 my for substitutional noise, and 70 my for lineage effects. These intervals overlap the oldest occurrences of angiosperms in the fossil record, as well as some estimates from previous molecular studies. PMID- 21669684 TI - Molecular systematics of the Asplenium nidus complex from Mt. Halimun National Park, Indonesia: evidence for reproductive isolation among three sympatric rbcL sequence types. AB - Asplenium nidus is an epiphytic fern with large simple leaves. Because A. nidus lacks the good taxonomic characters available for species recognition, multiple cryptic species may exist within A. nidus. In Mt. Halimun National Park, West Java, Indonesia, three rbcL sequence types of A. nidus were recorded. All plants regardless of rbcL sequence were 2n = 144. Crossing experiments among these rbcL types were conducted, and it was observed that the molecularly distinct types were reproductively isolated because hybrids failed to form between at least two pairs of rbcL types. These results suggest that these rbcL types are cryptic species because they are reproductively isolated but they are difficult to distinguish morphologically. Thus, the characters of DNA sequences information are useful in the discovery of cryptic species in ferns. PMID- 21669685 TI - Thrips pollination of androdioecious Castilla elastica (Moraceae) in a seasonal tropical forest. AB - Androdioecy is a rare sexual system in nature, as predicted theoretically. Among the androecious species reported so far, Castilla elastica (Moraceae) is unique in that flowers are unisexual and staminate and pistillate flowers on cosexual plants are produced on different inflorescences. In addition, inflorescence structure of staminate inflorescences on males and staminate and pistillate inflorescences on cosexes is markedly different. Staminate inflorescences on males are bivalvate, while staminate inflorescences on cosexes are "fig-like" and urceolate. Pistillate inflorescences are discoidal. The difference may reflect different roles and requirements of the three inflorescences in pollination and protection from herbivores. This study reports thrips pollination of C. elastica, demonstrated by a pollinator introduction experiment. Thrips pollination of the species may be an example of mutualism originating from plant-herbivore interactions. In the Moraceae, shifts from simple herbivores on flowers to pollinators might have occurred many times, evolving into diverse pollination systems including the fig-fig wasp mutualism. The family, of which little is known about pollination systems, provides interesting and unique opportunities to study evolution of pollination systems and roles of nonpollinating associates of inflorescences. PMID- 21669686 TI - Life history of Acrosiphonia (Codiolales, Chlorophyta) in southwestern British Columbia, Canada. AB - This study establishes the phenology of the alternate life history phases of the green alga Acrosiphonia in British Columbia, Canada. Free-living, filamentous plants are seasonal, March-July, with peak percent cover (10%) in April. Plants are fertile immediately after establishment. The unicells, previously identified as Chlorochytrium inclusum and Codiolum petrocelidis, are the sporophyte phase of Acrosiphonia. 'Chlorochytrium,' spherical and 160-280 MUm in diameter, colonizes the foliose red alga Mazzaella splendens 1 mo after filamentous Acrosiphonia plants appear. Maximum density (53 'Chlorochytrium' cells/cm(2) of blade) was recorded in May. 'Codiolum,' on the other hand, is stalked (the vesicle measures 150 * 50 MUm) and colonizes the red algal crust Petrocelis. Peak density (22 400 'Codiolum' cells/cm(2) of crust) was recorded 2 mo after 'Chlorochytrium' density peaked. The endophytes survive high summer temperatures, which correlate with death of the free-living plants, and overwinter in their hosts. Zoospore release in late winter corresponds to decreased host abundance, suggesting the endophytes have evolved a strategy whereby duration in the host is synchronized with host seasonality. A bet-hedging strategy is proposed for Acrosiphonia's life history: two morphologically different phases have adapted to a seasonally variable environment, with the sporophyte phase capable of colonizing two different hosts. PMID- 21669687 TI - Studies in Neotropical Paleobotany. XV. A Mio-Pliocene palynoflora from the Eastern Cordillera, Bolivia: implications for the uplift history of the Central Andes. AB - An assemblage of 33 fossil pollen and spores, recovered from the 3600-m high Pislepampa locality of E. W. Berry, Eastern Cordillera, Bolivia, adds considerably to our knowledge of three aspects of the region in late Neogene time: (1) the paleovegetation, (2) the paleoclimate, and (3) the paleoelevation of the Central Andes. The plant microfossils recognized are Isoetes, Lycopodium (three types), Cnemidaria, Cyathea (three types), Grammitis, Hymenophyllum, Pteris, trilete fern spores (two types), Danaea, monolete fern spores (four types), Podocarpus, Gramineae, Palmae, Ilex, cf. Oreopanax, Cavanillesia, cf. Pereskia, Compositae (three types), Ericaceae, Tetrorchidium, and unknowns (three types). The diversity of the Compositae suggest that this flora has a maximum age around the Miocene-Pliocene boundary, that is, 6-7 million years. All members of the paleocommunity presently grow in the bosque montano humedo (cloud forest) along the eastern slope of the Central Andes of Bolivia, which occurs between MATs (mean annual temperatures) of ~10 degrees and 20 degrees C. The Pislepampa flora probably represents the lower limits of this forest because the fossil leaves collected by Berry from the same locality all have entire margins, suggesting that the flora grew near the cloud forest-tropical forest transition. Presently, the lower limit of the cloud forest forest has MATs of ~20 degrees C, a mean annual precipitation between 1000 and 1500 mm, and that part containing most of the identified genera of fossil pollen is found at elevations ~1200-1400 m. These conditions are thus inferred for the Pislepampa flora; however, because of the uncertainty of the magnitude of global climate change and of possible changes in the ecological range of plant genera, we estimate an error of at least +/-1000 m for the paleoelevation estimate. When the total uplift is corrected for probable amounts of erosionally driven isostatic rebound, the paleoelevation estimate suggests that from one-third to one-half of the uplift of the Eastern Cordillera had occurred by the beginning of the Pliocene. This estimate is consistent with other paleoelevation estimates from the Central Andes. PMID- 21669688 TI - A filmy fern from the Upper Triassic of North Carolina (USA). AB - Modern cladistic analyses support earlier suggestions that the Hymenophyllaceae (the "filmy ferns") are basal filicaleans. However, the fossil record of the family is ambiguous. A new fossil fern, Hopetedia praetermissa gen. et sp. nov., from the Upper Triassic Pekin Formation of North Carolina (USA), is described and interpreted as the oldest unequivocal representative of the Hymenophyllaceae based primarily on general frond morphology, indirect evidence for a filmy (membranaceous) habit, and soral position and morphology. Particularly compelling as evidence for the hymenophyllaceous affinity of H. praetermissa is the funneliform structure of the indusium (involucre), which is similar to that found primarilly in the extant Trichomanes (sensu lato) clade. However, the receptacle in H. praetermissa is relatively short and, thus, more like most representatives of the Hymenophyllum (sensu lato) clade. The Triassic age of this fossil is consistent with the basal or near basal position of the Hymenophyllaceae in all recent phylogenetic analyses of the filicalean ferns. Hopetedia preatermissa is evaluated in relationship to several previous reports of fossil Hymenophyllaceae. PMID- 21669689 TI - Functional significance of variation in bryophyte canopy structure. AB - In most bryophytes, the thickness of boundary layers (i.e., unstirred layers) that surrounds plant surfaces governs rates of water loss. Architectural features of canopies that influence boundary layer thickness affect the water balance of bryophytes. Using field samples (9.3 cm diameter cushions) from 12 populations (11 species) of mosses and liverworts, we evaluated the relationship between canopy structure and boundary layer properties. Canopy structure was characterized using a contact surface probe to measure canopy depth along perpendicular transects at spatial scales ranging from 0.8 to 30 mm on 186 points per sample. Semivariance in depth measurements at different spatial scales was used to estimate three architectural properties: surface roughness (L(r)), the scale of roughness elements (S(r)), and fine-scale surface texture, the latter characterized by the fractal dimension (D) of the canopy profile. Boundary layer properties were assessed by evaporation of ethanol from samples in a wind-tunnel at wind speeds from 0.6 to 4.2 m/s and applied to characterize mass transfer using principles of dynamic similarity (i.e., using dimensionless representations of conductance and flow). In addition, particle image velocimetry (PIV) was used to visualize and quantify flow over two species. All cushions exhibited the characteristics of turbulent as opposed to laminar boundary layers, and conductance increased with surface roughness. Bryophyte canopies with higher L(r) had greater conductances at all wind speeds. Particle image velocimetry analysis verified that roughness elements interacted with flow and caused turbulent eddies to enter canopies, enhancing evaporation. All three morphological features were significantly associated with evaporation. When L(r), S(r), and D were incorporated with a flow parameter into a conductance model using multiple linear regression, the model accounted for 91% of the variation in mass transfer. PMID- 21669690 TI - Sources of phenotypic variation in floral traits in wild radish, Raphanus raphanistrum (Brassicaceae). AB - Pollinator-mediated natural selection has been shown to act on phenotypic variation in floral morphology, and this variation has often been demonstrated to be heritable, but few details are available concerning the sources of floral variation. We examined phenotypic variation in seven floral traits in wild radish (Raphanus raphanistrum) at six levels: between two populations grown in a common garden, among plants within populations, among flowers measured on different weeks, between flowers on two flowering stalks measured on the same day, between adjacent flowers on a flowering stalk, and within individual flowers. There were no significant differences between plants derived from the two source populations, which were ~800 km apart. Most of the variance was within individual plants; repeatabilities were all <0.35. There were highly significant differences between flowers measured in different weeks and also highly significant plant by week interactions, indicating that the among-plant variation was not consistent over time. There was substantial variance among adjacent flowers on the same stalk, particularly in the gynoecium. This high within-plant variance is partly responsible for the low heritability of floral traits in the field and the weak selection on floral traits found in previous studies of wild radish. PMID- 21669691 TI - Allozyme diversity in three endemic species of Cistus (Cistaceae) from the Canary Islands: intraspecific and interspecific comparisons and implications for genetic conservation. AB - Patterns of variation at 13 isozyme loci were examined in 11 populations in three Cistus species strictly endemic to the Canary Islands. Cistus osbaeckiaefolius and C. chinamadensis display low levels of isozyme variation associated with moderate to high interpopulation differentiation, which probably arose through historical bottlenecks in a landscape of habitat fragmentation, grazing, and human influence. By contrast, C. symphytifolius ranks among the subset of narrow endemics with high levels of isozyme variation and features different degrees of genetic structuring that are closely associated with taxonomic ascription. Low interpopulation differentiation in var. leucophyllus is possibly a reflection of its recent origin or of moderate levels of gene flow between its populations. High interpopulation differentiation in var. symphytifolius probably arose due to slight ecological differences between populations coupled with low levels of gene flow. Interpretation of neighbor-joining trees in the light of geological data substantiates the hypothesis that C. symphytifolius (or a very close relative) might be the ancestor of the other stands of Cistus in the islands. Conservation implications of our survey are the identification of the two populations of C. chinamadensis with the highest allele and genotype richness for preservation on genetic grounds and advice to prevent artificial gene flow in this taxon lest it might disrupt locally adapted gene combinations. All populations of C. osbaeckiaefolius should be given conservation priority on ecological grounds despite their genetic depauperation. PMID- 21669692 TI - Adaptation of Senecio vulgaris (Asteraceae) to ruderal and agricultural habitats. AB - Adaptation of the annual plant Senecio vulgaris to ruderal and agricultural habitats was investigated. We expected S. vulgaris to be adapted to the agricultural habitat through nutrient-specific differentiation of relatively few genotypes responding to the generally high homogenous nutrient levels at the agricultural habitat caused by constant fertilization. To assess adaptation of S. vulgaris, vegetative and reproductive responses of seed families from various populations of agricultural and ruderal habitats, grown in the greenhouse at high and low nutrient levels, were compared. Data were analyzed with a three-level nested ANOVA based on the levels habitat, population, and family. A significant habitat effect indicated that S. vulgaris from ruderal and agricultural habitats were genetically different with plants from the agricultural habitat having larger leaves and a higher reproduction. A significant habitat by nutrient effect showed a stronger response of reproduction to nutrients at the agricultural habitat, suggesting that genetic differentiation among habitats is nutrient specific. Contrary to expectations, only the agricultural habitat showed genetic diversity of S. vulgaris. Results suggest that nutrient levels at the agricultural habitat are more heterogeneous as generally proposed leading to a relatively high genetic variation. PMID- 21669693 TI - Variation in the breeding behavior of the dry forest tree Enterolobium cyclocarpum (guanacaste) in Costa Rica. AB - We studied the breeding systems of four populations of Enterolobium cyclocarpum (guanacaste, earpod tree) in Costa Rica. Multilocus estimates of the outcrossing rate indicate that E. cyclocarpum is a predominant outcrossing species (t(m) ranged between 0.881 and 0.901) and biparental inbreeding is low (range between 0.058 and 0.079). Overall, our analyses showed significant differences in the gene frequencies between pollen and ovules and significant differences in pollen gene frequencies between the four populations. We also found significant differences in the pollen gene frequencies calculated for single trees in the same population. Outcrossing rates and pollen gene frequencies varied in two consecutive years in two populations of E. cyclocarpum. The correlated mating model revealed that there are differences in the correlation of paternity between populations and years. These findings indicate that there is variation in the average number of trees that father the seed crop of each tree and/or that some fathers are overrepresented in the seed crop of each tree. The implication of these findings for the development of strategies for conservation and management of this species are discussed. PMID- 21669694 TI - Reproductive biology of the dry forest tree Enterolobium cyclocarpum (guanacaste) in Costa Rica: a comparison between trees left in pastures and trees in continuous forest. AB - We compared the rate of pollen deposition, the likelihood of fruit production, the number of seeds per fruit, the outcrossing rate, and the progeny vigor of the tropical dry forest tree Enterolobium cyclocarpum for individuals in pastures vs. individuals in continuous forest. We found that flowers from trees growing in continuous forests were more likely to have pollen deposited on their stigmas than flowers from trees in pastures (52.1 vs. 32.3%, respectively). We also found that trees from continuous forests were almost six times more likely to set fruits and produce more seeds per fruit than trees in pastures. Morever, progeny from trees in continuous forests were, on average, more vigorous than the progeny from trees in pastures, as indicated by 12 of 16 indicators of plant vigor. However, there was no significant difference in the multilocus estimate of the outcrossing rate between the two groups of trees (tm = 1.00 and 0.99 for trees from continuous forest and trees from pastures, respectively). But there are differences in the correlation of paternity between the progeny of the two groups, where the progeny from trees in pastures showed a lower correlation of paternity than progeny of trees from continuous forests (r(p) = 0.104 and r(p) = 0.189, respectively). We argue that the mechanisms that regulate progeny vigor are disrupted in trees from pastures. We discuss the implications of these findings for the conservation of E. cyclocarpum. PMID- 21669695 TI - Pollination limitation to reproductive success in the Missouri evening primrose, Oenothera macrocarpa (Onagraceae). AB - Habitat fragmentation may result in plant populations that are less attractive to pollinators and thus susceptible to reduced reproductive output due to pollination limitation. Pollination limitation was investigated in three Missouri populations of Oenothera macrocarpa, a hawk-moth-pollinated, perennial herb. The populations represented extremes in size and habitat quality. Following supplemental pollination, mean fertilization success (proportion of ovules fertilized) across populations increased from 24.3 to 44.8% and mean seed set (proportion of ovules that matured into seed) increased from 14.7 to 27.9%. These increases were statistically significant in two of the three populations. Failure to achieve 100% fertilization and seed set following supplementation indicates that other factors, in addition to pollination, were limiting to female reproductive success. Fruit set was pollination limited in only one population. Fruits matured with as few as one seed, suggesting that fruit set was not resource limited. The degree of pollination limitation was greatest in the most disturbed population. The population located in the highest-quality habitat was not significantly pollination limited. This suggests that pollination limitation is occurring, at least in part, because of reduced pollinator activity in degraded habitats. PMID- 21669696 TI - Pollination, breeding system, and genetic structure in two sympatric Delphinium (Ranunculaceae) species. AB - Two sympatric Delphinium species, D. barbeyi and D. nuttallianum, are ecologically and morphologically similar. However, D. barbeyi has multiple, large inflorescences while D. nuttallianum has a single, small inflorescence. These differences in floral display should result in greater intraplant pollen transfer in D. barbeyi, leading to higher rates of self-pollination through geitonogamy. Reduced gene flow by pollen should in turn produce greater population differentiation among populations of D. barbeyi relative to D. nuttallianum. We tested these predictions by comparing pollinator behavior, breeding systems, outcrossing rates, and population genetic structure of sympatric populations of the two species in Colorado. Bumble bee and hummingbird pollinators visit more flowers and inflorescences per foraging bout in D. barbeyi than in D. nuttallianum. The species differed in breeding system; D. barbeyi produced more seeds by autogamy (9 vs. 2%) than D. nuttallianum and suffered no reduction in seed set in hand-self vs. outcross pollinations, in contrast to a 41% decline in D. nuttallianum. The outcrossing rate in one D. barbeyi population was 55%, but ranged from 87 to 97% in four D. nuttallianum populations. Genetic differentiation among population subdivisions estimated by hierarchical F statistics was >10 times greater in D. barbeyi ( = 0.055-0.126) than D. nuttallianum ( = 0.004-0.009) at spatial scales ranging from metres to 3.5 km. Spatial autocorrelation analysis also indicated more pronounced local genetic structure in D. barbeyi than D. nuttallianum populations. Fixation indices (F(IS)) of D. barbeyi adults were much lower than expected based on mating system equilibrium and suggest that differences in the degree of self-compatibility and/or the timing of postpollination selection/inbreeding depression between the two species further contribute to the genetic differences between them. PMID- 21669697 TI - Temporal vegetation dynamics and recolonization mechanisms on different-sized soil disturbances in tallgrass prairie. AB - Assessing the various mechanisms by which plants revegetate disturbances is important for understanding the effects of disturbances on plant population dynamics, plant community structure, community assembly processes, and ecosystem function. We initiated a 2-yr experiment examining temporal vegetation dynamics and mechanisms of recolonization on different-sized soil disturbances created to simulate pocket gopher mounds in North American tallgrass prairie. Treatments were designed to assess potential contributions of the seed rain, soil seed bank, clonal propagation from the edges of a soil mound, and regrowth of buried plants. Small mounds were more rapidly recolonized than large mounds. Vegetative regrowth strategies were the dominant recolonization mechanisms, while the seed rain was considerably less important in maintaining the diversity of forbs and annuals than previously believed. All recolonization mechanisms influenced plant succession, but stem densities and plant mass on soil mounds remained significantly lower than undisturbed controls after two growing seasons. Because natural pocket gopher mounds are indistinguishable from undisturbed areas after two seasons, these results suggest that multiple modes of recruitment concurrently, albeit differentially, contribute to the recolonization of soil disturbances and influence tallgrass prairie plant community structure and successional dynamics. PMID- 21669698 TI - Comparative vessel anatomy of arctic deciduous and evergreen dicots. AB - Arctic tundra plant species exhibit striking variation in leaf character and growth form. Both are likely related to differences in vessel anatomy, and all may affect responses to climate changes in the Arctic. To investigate the relationships among leaf character, growth form, vessel anatomy, and susceptibility to freeze-thaw-induced xylem cavitation, xylem vessel characteristics were compared among six deciduous and six evergreen arctic dicot species of erect and prostrate growth forms. We hypothesized that deciduous and erect species would have larger and longer vessels than evergreen and cushion/mat forming species. Vessel lengths, diameters, and densities were measured for each species. Theoretical vessel flow rates were calculated using Poiseuille's law for ideal capillaries. Flow rates were used to determine the susceptibility of vessels to cavitation induced by freeze-thaw events that may become more frequent with global warming. Vessel diameters were larger in deciduous species compared to evergreens, and in shrubs/trees vs. cushion/mat-forming plants. Vessel length distributions, however, did not differ for growth form or leaf character. Vessel density was greater in cushion/mat-forming species than in shrub/tree species. Deciduous plants showed a greater contribution to total conductivity by relatively larger vessels than evergreens. One of the deciduous species, Vaccinium uliginosum, is predicted to be susceptible to freeze-thaw-induced cavitation. These results have important implications for future arctic species composition and plant community structure. PMID- 21669699 TI - Evidence of a mycorrhizal mechanism for the adaptation of Andropogon gerardii (Poaceae) to high- and low-nutrient prairies. AB - Andropogon gerardii seed obtained from Kansas and Illinois was grown in a controlled environment in their own and each other's soils, with and without arbuscular mycorrhizal fungi (AMF). Each ecotype grew comparatively better in its own soil indicating adaptation to its soil of origin. Overall, A. gerardii benefited more from AMF in low-nutrient Kansas soil than Illinois soil. The two ecotypes, however, did not benefit equally from mycorrhizal infection. The Kansas ecotype was three times more responsive to mycorrhizal infection in the Kansas soil than was the Illinois ecotype. Our results indicate that plant adaptation to the nutrient levels of their local soils is likely to be due, at least in part, to a shift in their dependence on mycorrhizal fungi. The Illinois ecotype of A. gerardii has evolved a reduced dependence upon these fungi and greater reliance on a more highly branched root system. In contrast, the Kansas ecotype had a significantly coarser root system and invested proportionately greater carbon in the symbiotic association with AMF as measured by spore production. This study provides the first demonstration that plants can adapt to changing soil nutrient levels by shifting their dependence on AMF. This result has broad implications for our understanding of the role of these fungi in agricultural systems. PMID- 21669700 TI - Generic circumscription and relationships in the tribe Melanthieae (Liliales, Melanthiaceae), with emphasis on Zigadenus: evidence from ITS and trnL-F sequence data. AB - The circumscription and relationships of genera within the tribe Melanthieae (29 representative taxa) were evaluated using parsimony analyses of ITS (nuclear ribosomal) and trnL-F (plastid) DNA sequence data, alone and in combination. Proposed new generic circumscriptions, strongly supported by the tree statistics and topologies in all analyses, are correlated with potential morphological synapomorphies at the proper level of universality. Based on the molecular cladograms, Stenanthium is biphyletic, and the traditional Zigadenus s.l. (sensu lato) is polyphyletic. Amianthium and Schoenocaulon are distinct entities; the Veratrum complex is conservatively treated as one large monophyletic genus (including Melanthium). Although some generic relationships are not highly resolved, the analyses provide strong support for Zigadenus glaberrimus as sister to the rest of the tribe, and Amianthium muscitoxicum as closely related to Veratrum s.l. As a result of these analyses, seven genera (some with novel circumscription) are recognized within the tribe Melanthieae: Amianthium, Anticlea, Schoenocaulon, Stenanthium, Toxicoscordion, Veratrum, and Zigadenus. PMID- 21669701 TI - Morphological interpretation of the spikelet in Digitaria atra (Poaceae: Panicoideae: Paniceae) and emended generic description. AB - Digitaria atra is illustrated for the first time and the original description is emended. The diagnosis of the genus Digitaria is completed by introducing modifications related to the spikelet's morphology and the lower lemma's consistency. Some remarks about the lower palea are included. The unusual morphological characteristics of the spikelet of D. atra are compared with the tribe Isachneae and some genera of Paniceae. PMID- 21669702 TI - A molecular phylogeny of the endemic Australian genus Gastrolobium (Fabaceae: Mirbelieae) and allied genera using chloroplast and nuclear markers. AB - Gastrolobium (Fabaceae: Mirbelieae) is an endemic Australian genus that produces toxic sodium monofluoroacetate. A phylogenetic reconstruction of Gastrolobium and the related genera Brachysema, Callistachys, Jansonia, Nemcia, Oxylobium, and Podolobium is presented, using sequence data from three regions-the psbA-trnH intergenic spacer and the trnK 5' intron from chloroplast DNA and the 3' end of the external transcribed spacer (ETS) from nuclear ribosomal DNA. Gastrolobium is shown to be paraphyletic, with Brachysema, Jansonia, Nemcia, and Oxylobium lineare nesting within it, and Nemcia is shown to be polyphyletic within Gastrolobium. Past key morphological characters, such as fluoroacetate content and characters associated with pollination syndrome, are shown to be homoplastic, with fluoroacetate possibly a plesiomorphic condition lost in more derived species. Podolobium is also shown to be polyphyletic, with the P. ilicifolium group sister to Gastrolobium and the P. alpestre group sister to Callistachys, a member of the Oxylobium group. It is recommended that Gastrolobium be expanded to include Brachysema, Jansonia, Nemcia, and Oxylobium lineare, while further work is required to test the sister-group relationship between Podolobium s.s. (sensu stricto) and Gastrolobium. PMID- 21669703 TI - Assessment of hybridization and introgression in lava-colonizing Hawaiian Dubautia (Asteraceae: Madiinae) using RAPD markers. AB - Hybridization between Dubautia ciliolata and D. scabra occurring on a mosaic of lava flows of 1855 and 1935 on the island of Hawai'i was examined using random amplified polymorphic DNA (RAPD) markers. The RAPD data indicate that D. ciliolata plants, nearly restricted to the 1855 lava flow, contain higher levels of genetic variation than do D. scabra plants occurring on the 1935 lava flow. Seventy-one markers were specific to D. ciliolata and 60 to D. scabra; 40 of these were "constant" (found in all individuals) in one or the other species. Hybrids sampled were determined to represent F(1), filial hybrids beyond the F(1), and backcross progeny. All backcrosses were unidirectional with D. ciliolata acting as the recurrent parent. No hybrid, including an artificially produced F(1), had all 40 constant markers, suggesting that at least some loci for these markers were heterozygous in the parents. However, several hybrids exhibited a loss of many of the species markers, suggesting that they were later filial hybrid generation plants. The apparent occurrence of unidirectional introgression at the study site may be providing D. ciliolata plants with genetic plasticity to colonize the new lava flow previously occupied only by D. scabra. PMID- 21669704 TI - Age and biogeography of major clades in Liliales. AB - A robust phylogeny of 40 genera and all seven families of the Liliales based on rbcL sequences was dated by the mean branch-length method of Bremer and Gustafsson and by Sanderson's nonparametric rate smoothing. The basal node was set to 82 million years (my) from the results of a previous more extensive dating involving all monocots. Confidence intervals for the age estimates were generated by bootstrap analysis. The results indicate that four well-supported clades of Liliales date back to the Cretaceous ~65 million years ago (mya), Campynemataceae, Melanthiaceae, Smilacaceae + Liliaceae, and Alstroemeriaceae + Luzuriagaceae + Colchicaceae. Aspects of historical biogeography were investigated by dispersal-vicariance analysis. Several dispersal and vicariance events were found to coincide with Late Cretaceous-Early Tertiary changes in continental interconnections. The study contains the first published sequence of Campynemanthe, supporting the Campynemataceae as a monophyletic group. PMID- 21669705 TI - Bt corn has a higher lignin content than non-Bt corn. AB - Bt corn has been genetically modified to express the Cry1Ab protein of Bacillus thuringiensis to kill lepidopteran pests. Fluorescence microscopy and staining with toluidine blue indicated a higher content of lignin in the vascular bundle sheaths and in the sclerenchyma cells surrounding the vascular bundle in all ten Bt corn hybrids, representing three different transformation events, studied than of their respective non-Bt isolines. Chemical analysis confirmed that the lignin content of all hybrids of Bt corn, whether grown in a plant growth room or in the field, was significantly higher (33-97% higher) than that of their respective non Bt isolines. As lignin is a major structural component of plant cells, modifications in lignin content may have ecological implications. PMID- 21669706 TI - Oscillation frequencies of tapered plant stems. AB - Free oscillations of upright plant stems, or in technical terms, slender tapered rods with one end free, can be described by considering the equilibrium between bending moments in the form of a differential equation with appropriate boundary conditions. For stems with apical loads, where the mass of the stem is negligible, Mathematica 4.0 returns solutions for tapering modes alpha = 0, 0.5, and 1. For other values of alpha, including cases where the modulus of elasticity varies over the length of the stem, approximations leading to an upper and a lower estimate of the frequency of oscillation can be derived. For the limiting case of omega = 0, the differential equation is identical with Greenhill's equation for the stability against Euler buckling of a top-loaded slender pole. For stems without top loads, Mathematica 4.0 returns solutions only for two limiting cases, zero gravity (realized approximately for oscillations in a horizontal orientation of the stem) and for omega = 0 (Greenhill's equation). Approximations can be derived for all other cases. As an example, the oscillation of an Arundo donax plant stem is described. PMID- 21669707 TI - The biomechanics of Pachycereus pringlei root systems. AB - We report on the root system of the large columnar cactus species Pachycereus pringlei to explore the hypothesis that increasing plant size decreases the ability to resist wind-throw but increases the capacity to absorb and store nutrients in roots (i.e., plant size limits the performance of these functions and may shift the performance of one function in favor of another as size increases). Based on 18 plants differing in size, the root system is characterized by a broad and deep bayonet-like root central to a shallow and extensive lateral system of root elements bearing sinker roots near the stem base. All root types have a living secondary cortex and contain wood with a large volume fraction of ray tissues that increases toward the stem base. Wood stiffness and tensile strength are correlated negatively with the ray tissue volume fraction and thus decrease toward the stem base in lateral and bayonet roots. Calculations show that the ability of the bayonet and proximal lateral root elements to resist wind-throw decreases with increasing plant size, whereas the nutrient absorption/storage capacity of the total root system increases with plant size (i.e., a size-dependent shift between these two root functions occurs). PMID- 21669708 TI - The application of SSRs characterized for grape (Vitis vinifera) to conservation studies in Vitaceae. AB - The use of microsatellite loci developed from a single plant species across a number of related taxa is becoming increasingly widespread. This approach can provide highly informative markers even for species for which microsatellites have not been characterized. As a number of expressed sequence tag (EST)-derived and enrichment-derived microsatellites are available for grape (Vitis vinifera), this study set out to assess transferability of nine such loci across 25 species from five different Vitaceae genera. Intergeneric transfer success in Vitaceae was high (51.1%) and EST-derived loci performed better than enrichment-derived loci. Six loci were further tested across two Australian native species, Cissus hypoglauca and C. sterculiifolia, in order to assess the conservation of microsatellite repeats and their flanking sequences. Polymorphism of these selected loci was successfully tested for each species across a small, isolated rain forest population from northern New South Wales (Australia). Results from this preliminary investigation suggest that it is possible to use grape-derived simple sequence repeats (SSR) loci for population studies on Vitaceae. As Vitaceae are an important component of rain forest flora, the availability of such highly informative loci will be beneficial to future studies aimed at determining the genetic consequences of rain forest fragmentation. PMID- 21669709 TI - Stratified analysis of the soil seed bank in the cedar glade endemic Astragalus bibullatus: evidence for historical changes in genetic structure. AB - Persistent seed banks may provide information on historical changes in the genetic composition of populations. We used stratified sampling of the soil seed bank of Astragalus bibullatus (Pyne's ground plum) to assess levels of temporal variation in population genetic structure and to infer historical changes in the levels of inbreeding and relative gene flow. This species has an extremely limited distribution in the Central Basin of Tennessee, where it is found in open areas and along the edges of cedar glades. Protein electrophoresis was conducted on seedlings grown from seeds that had been recovered from three successive 1 cm thick layers of soil sampled from six sites. Analyses of seven polymorphic allozyme loci indicated that there were substantial levels of genetic differentiation among soil layers and sites. Higher levels of genetic diversity were found in seed than in vegetative populations that had been sampled in a previous study. Seed populations from the uppermost soil layer had higher heterozygote deficiencies, displayed higher levels of differentiation among sites, and had higher private allele frequencies than seed populations from the lower two layers. The change in heterozygosity and distribution of genetic variation among sites for the youngest soil layer is consistent with a pattern of increased selfing, sib mating, and decreased gene flow among populations. These changes in inbreeding and relative levels of gene flow are corroborated by information on historical land use practices in the region and support the hypothesis that loss of appropriate habitat has led to smaller population sizes and a more fragmented distribution of this cedar glade endemic. PMID- 21669710 TI - Comparative analysis of late floral development and mating-system evolution in tribe Collinsieae (Scrophulariaceae s.l.). AB - Species of Collinsia and Tonella, the two sister genera of self-compatible annuals that constitute tribe Collinsieae, show extensive variation in floral size and morphology and in patterns of stamen and style elongation during the life of the flower (anthesis). We used a nuclear ribosomal ITS phylogeny, independent contrasts, and phylogenetically corrected path analysis to explore the patterns of covariance of the developmental and morphological traits potentially influencing mating system. Large-flowered taxa maintain herkogamy (spatial separation of anthers and stigmas) early in anthesis by differential elongation of staminal filaments, which positions each of the four anthers at the tip of the "keel" upon dehiscence. Small-flowered taxa do not show this pattern of filament elongation. The styles of large-flowered taxa elongate late in the 2 5 d of anthesis, resulting in late anther-stigma contact and delayed self pollination. Anther-stigma contact and self-pollination occur early in anthesis in small-flowered species/populations. Thus, we found complex covariation of morphological and developmental traits that can be interpreted as the result of multitrait adaptation for early selfing and high levels of autogamy, delayed selfing and higher levels of outcrossing, or intermediate levels of outcrossing. Continuous variation in these traits suggests the operation of continuous variation in selective optima or the combined effects of divergent selection and phylogenetic inertia. PMID- 21669711 TI - Thrips pollination of the dioecious ant plant Macaranga hullettii (Euphorbiaceae) in Southeast Asia. AB - Discussion about thrips (Thysanoptera) as main pollinators has been controversial in the past because thrips do not fit the preconception of an effective pollinator. In this study, we present evidence for thrips pollination in the dioecious pioneer tree genus Macaranga (Euphorbiaceae). Macaranga hullettii is pollinated predominantly by one thrips species, Neoheegeria sp. (Phlaeothripidae, Thysanoptera). As a reward for pollinators, the protective floral bracteoles function as breeding sites for thrips and trichomal nectaries on the adaxial surface of the floral bracteoles provide alimentation. Flowering phenology of both staminate and pistillate trees was highly synchronized within 3-4 wk periods. In contrast to pistillate trees, staminate trees start to breed the thrips inside the developing inflorescences ~2 wk before anthesis. Breeding of Neoheegeria sp. in the laboratory indicates that the thrips development is completed within ~17 d. Thus, staminate trees offer breeding sites for one thrips generation until the onset of pollen presentation. Intraspecific pollen transfer by thrips was proved by pollen loads of thrips taken from receptive pistillate inflorescences of M. hullettii. Bagging experiments of different mesh sizes showed that seed set reached almost the level of open-pollinated flowers when exclusively tiny insects like thrips were able to enter the net bags, but no apomictic seed set occurred when no insect access was given to the flowers. PMID- 21669712 TI - Multiple factors contribute to outcrossing in a tropical emergent Dipterocarpus tempehes, including a new pollen-tube guidance mechanism for self incompatibility. AB - The self-rejection system of Dipterocarpus tempehes (Dipterocarpaceae), an emergent tree of the lowland tropical forests of Borneo, were studied by means of pollination experiments, fluorescence microscopy of pollen tubes, and monitoring of ovary maturation patterns. Fruit set was higher in cross-pollinated flowers than in control and self-pollinated flowers, indicating the existence of pollen limitation and a self-rejection system. Although the adhesion and the germination of self-pollen and the growth of self-pollen tubes were not inhibited, the proportion of cross-pollen tubes that entered the style was 1.7-2.3 times higher than that of self-pollen tubes, indicating a partial self-incompatibility that inhibits self-pollen tubes from entering the style hollow. These results suggest, for the first time, that self-incompatibility is caused by a defect of pollen tube guidance. We also suggest a threshold effect in number of pollen tubes or late-acting self-incompatibility to fully explain the drastic and uniform selection against self-pollinated flowers before ovary swelling. After that, maternal selection and/or inbreeding depression caused the abortion and delayed maturation of self-pollinated flowers. The advantages of the self-rejection process composed of partial early-acting self-incompatibility and relatively strong delayed abortion is discussed with respect to the general-flowering phenomenon in lowland dipterocarp forests. PMID- 21669713 TI - Many to flower, few to fruit: the reproductive biology of Hamamelis virginiana (Hamamelidaceae). AB - Hamamelis virginiana flowers from late September to late November. In 1977, we began studying the reproductive biology of this eastern North American arborescent shrub by examining floral phenology and rewards, pollen-ovule ratios, breeding system, pollination, pollinator and resource limitation, and seed dispersal. The homogamous, self-incompatible flowers emit a faint odor, bear nectar with sucrose ratios typical of bee- and fly-pollinated flowers, and produce abundant sticky pollen. Flowers were visited infrequently by insects representing six orders. Flies were the most common floral visitors, specifically members of the genus Bradysia, but small bees also carried high percentages of Hamamelis pollen. Despite high pollen/ovule ratios (11 445 grains/ovule), bees and flies are likely pollinators, as experiments indicate wind pollination is less likely. Pollen quantity and resource availability did not appear to limit reproductive output, but pollen quality did. Tests of >40 000 flowers showed natural fruit set to be <1%. The flowering time, breeding system, and clumped distribution of plants, likely due in part to limited seed dispersal, combine to yield this remarkably low fruit set. Because all other species of Hamamelis flower from late winter to early summer, it may be that H. virginiana evolved a fall flowering phenology to avoid competition for pollinators with the closely related H. vernalis. PMID- 21669714 TI - Changes in the risk of fine-root mortality with age: a case study in peach, Prunus persica (Rosaceae). AB - Previous studies suggest that younger roots are more vulnerable to mortality than older roots. We analyzed minirhizotron data using a mixed-age, proportional hazards regression approach to determine whether the risk of mortality (or "hazard") was higher for younger roots than for older roots in a West Virginia peach orchard. While root age apparently had a strong effect on the hazard when considered alone, this effect was largely due to different rates of mortality among roots of different orders, diameters, and depths. Roots with dependent laterals (higher order roots) had a lower hazard than first-order roots in 1996 and 1997. Greater root diameter was also associated with a decreased hazard in both 1996 and 1997. In both years, there was a significant decrease in the hazard with depth. When considered alone, age appeared to be a strong predictor of risk: a 1-d increase in initial root age was associated with a 1.26-2.62% decrease in the hazard. However, when diameter, order, and depth were incorporated into the model, the effect of root age disappeared or was greatly reduced. Baseline hazard function plots revealed that the timing of high-risk periods was generally related to seasonal factors rather than individual root age. PMID- 21669715 TI - Spectral reflectance and photosynthetic properties of Betula papyrifera (Betulaceae) leaves along an elevational gradient on Mt. Mansfield, Vermont, USA. AB - We studied relationships between spectral reflectance and photosynthesis of mountain paper birch, Betula papyrifera var. cordifolia (Regel) Fern., leaves from three different elevations on Mt. Mansfield (summit elevation 1339 m above sea level) in the Green Mountains of Vermont, USA. The different reflectance indices we used all suggested progressively increasing stress with increasing elevation. The photochemical reflectance index (PRI) indicated lower photosynthetic radiation use efficiency at higher elevations, the red edge position (lambdaRE) indicated lower chlorophyll concentrations at higher elevations, and the structure-independent pigment index (SIPI) indicated a higher carotenoid : chlorophyll a ratio at higher elevations. The rate of change in these indices with changes in elevation was much higher than we have observed in our studies of red spruce and balsam fir reflectance along a similar elevational gradient; we take this to be an indicator of the greater susceptibility of paper birch to elevation-related stressors compared to the very stress-tolerant conifers. At all light levels, photosynthesis decreased with increasing elevation; this pattern was most noticeable in the light-saturated rate of photosynthesis (A(sat)), which was nearly twice as high in low-elevation leaves (17.0 +/- 1.0 MUmol.m(-2).s(-1)) than in high-elevation leaves. The quantum yield of photosynthesis (Phi) exhibited a similar trend. Furthermore, the highest elevation leaves showed a much sharper transition from the light-limited to the light-saturated part of the light response curve than did the lowest elevation leaves. The photochemical reflectance index was highly correlated with A(sat) (r(2) = 0.99) and Phi (r(2) = 0.96). In addition to contributing to our knowledge of the ecophysiology of paper birch along a steep environmental gradient, these results are further evidence of the usefulness of reflectance measures for the rapid and noninvasive detection of plant stress, especially when used in conjunction with direct measurements of photosynthesis. PMID- 21669716 TI - Host compatibility of the cloud forest mistletoe Psittacanthus schiedeanus (Loranthaceae) in Central Veracruz, Mexico. AB - The consequences of the seed deposition of the parasitic mistletoe Psittacanthus schiedeanus were evaluated in a 32-mo study. We conducted a field seed inoculation experiment to determine variation in seed adhesion, seed germination, seedling establishment, and plant survival to reproduction among five host species and to evaluate whether these post-dispersal processes explain mistletoe prevalence and specificity at the regional scale. Seeds without an exocarp were inoculated onto branches of individuals of the five most common host species identified in nature in central Veracruz, Mexico. Seed fate was monitored for 2 yr, at weekly intervals for the first 2 mo and at 2-mo intervals thereafter. The height and diameter of experimental host branches and canopy cover above them were measured to see if these factors affected mistletoe establishment. Significant differences in seed attachment and seed germination were found among host species. Fewer seeds remained attached on experimental branches of Quercus germana than those of Liquidambar styraciflua, Acacia pennatula, and Platanus mexicana. Although significant differences in seed germination were observed among species (significantly greater on A. pennatula), >70% of mistletoe seeds germinated within the first 5 wk on all host species. Towards the end of the inoculation experiment, more mistletoe seedlings survived, grew, and then flowered on Liquidambar styraciflua than on A. pennatula, P. mexicana, Q. germana, or Q. leiophylla. Host branch initial height and diameter did not affect seedling survival, but seedlings survived better on trees where the canopy was more open. Our results suggest that Liquidambar styraciflua is the most compatible host species with P. schiedeanus in central Veracruz. Not surprisingly, Liquidambar is by far the most common host tree for P. schiedeanus in this area as well. We suggest that the observed local specialization is a result of seed dispersal as consequence of bird foraging and territorial behavior, host abundance, and host species compatibility. PMID- 21669717 TI - The effects of ultraviolet-B radiation and intraspecific competition on growth, pollination success, and lifetime female fitness in Phacelia campanularia and P. purshii (Hydrophyllaceae). AB - While a considerable amount of attention has been devoted to the effects that increased ultraviolet-B (UV-B) radiation has on vegetative plant growth and physiological function, the impact that UV-B may have on plant fitness has been the focus of fewer studies, with attention given primarily to a few crop species. Further, the possible interactions between UV-B and additional potential stresses found in natural environments have rarely been studied experimentally. Because the reported effects of increased UV-B on plant growth and fitness have been highly variable, studies that focus on factors that may lead to these differences in results are important for the formulation of accurate predictions about future plant success under varying UV-B levels. We examined the effects of UV-B dose and intraspecific competition on growth, phenology, pollen production, pollination success, fruit and seed production, and offspring quality in two species of Phacelia. Increased UV-B was neutral or beneficial for all traits, while competition was neutral or detrimental. There were no significant interactions between UV-B and competition in the parental generation. Phacelia campanularia offspring were unaffected by parental competition, but derived indirect beneficial effects on germination, growth, and fitness traits from parental enhanced UV-B. PMID- 21669718 TI - Dynamic nectar replenishment in flowers of Penstemon (Scrophulariaceae). AB - Plants that experience variation in pollinator visitation rates or fluctuations in weather conditions may be expected to have evolved homeostatic mechanisms that regulate their nectar offerings, thereby providing a more constant reward to the pollinators. A limited degree of such nectar homeostasis is reported here for Penstemon. First, nectar removal stimulates replenishment: when nectar was removed hourly for 6 h from P. speciosus, twice as much nectar was secreted cumulatively as when nectar was removed only at the beginning and end of the same 6-h period. Second, replacing artificial nectar in the nectaries of P. speciosus prevents replenishment. Third, the hummingbird-adapted P. barbatus made more nectar before leveling off than the bee-adapted P. strictus. Our work and previous studies with other plants imply mechanisms for dynamic regulation of nectar offerings, at least within broad limits. We speculate about the proximate physiology underlying this behavior and its evolutionary significance. PMID- 21669719 TI - Post-fire recovery of acorn production by four oak species in southern ridge sandhill association in south-central Florida. AB - We examined post-fire recovery of two components of acorn production (percentage of bearing ramets [stems] and number of acorns per bearing ramet) for four species of oaks in southern ridge sandhill vegetation in south-central peninsular Florida. Annual counts of acorns on two white oaks (Quercus chapmanii and Q. geminata) and two red oaks (Q. laevis and Q. myrtifolia) were conducted annually (except in 1991) on two 2.7-ha grids from 1969 to 1998. A prescribed burn was conducted on one of the grids in May 1993. Newly sprouted ramets of both white oaks produced acorns during the first year following the fire, whereas red oaks required 3 yr (Q. myrtifolia) or 4 yr (Q. laevis) to produce acorns. The difference in the timing of post-fire acorn production between the white and red oak species reflected the difference in the number of years from flower bud initiation to mature acorns in the two groups, with the additional year-long lag in Q. laevis probably attributable to the fact that it is typically a tree rather than a shrub species. The data suggested that percentage of bearing ramets in the smallest size class of the two white oak species was markedly lower in the burned than unburned grid in the first year of post-fire acorn production and higher in the fifth year, but these trends were not evident for the red oaks. Among all four species, differences between mean number of acorns in burned and unburned grids were significant in only two cases (the largest size class of both white oak species in the fifth year). There was no evidence of recruitment from acorns on the burned grid, possibly due to the rapid redevelopment of the shrub layer because of low mortality of the extensive clonal root systems. Rapid post-fire recovery of acorn production in xeric fire-prone habitats is presumably the result of selection to increase the probability of recovery and persistence following sufficiently intense fires that result in high oak mortality. The timing and magnitude of post-fire acorn production in sandhill and other xeric Florida associations has a potential impact on a wide variety of insects, birds, and mammals that feed on acorns, as well as on the species with which they interact. PMID- 21669720 TI - Relation of ramet size to acorn production in five oak species of xeric upland habitats in south-central Florida. AB - This study examined variation in two components of acorn production. Percentage of bearing ramets (stems) and number of acorns per bearing ramet were examined in five clonal oaks in three xeric habitats of south-central peninsular Florida in relation to ramet size within and between species and vegetative associations. Counts of acorns on two white oaks (Quercus chapmanii and Q. geminata) and three red oaks (Q. inopina, Q. laevis, and Q. myrtifolia) were conducted annually from 1969 to 1996 (except in 1991) on permanent grids in southern ridge sandhill, sand pine scrub, and scrubby flatwoods associations at the Archbold Biological Station, Florida, USA. Percentage of bearing individuals and mean number of acorns per bearing individual increased with increasing ramet size for all species across all vegetation associations. However, in Q. geminata and Q. myrtifolia, acorn production declined in the largest size class (>3.2 m), implying that larger individuals of these clonal species may become senescent. All oak species in sand pine scrub, which had a nearly closed overstory, had lower frequencies of bearing oaks and mean numbers of acorns compared with similar-sized individuals of the same species in the more open-canopied southern ridge sandhill and scrubby flatwoods associations, suggesting light limitation. The annual production of acorns by a given oak species was correlated across vegetative associations and annual acorn production of oak species was correlated for species within the same section. Intermediate-size class oaks contributed the most acorns per unit area, suggesting that stands managed with short fire-return times will provide fewer acorns to wildlife than stands managed to produce more variable distributions of oak size classes. However, our study suggests that long unburned stands, such as those studied here, will maintain relatively constant levels of acorn production as a consequence of ramet replacement within the clones of these shrubby oaks to create a variable distribution of size classes. Of the oak species studied, Q. myrtifolia had the highest acorn production and the smallest acorns, while Q. laevis had the lowest acorn production and the largest acorns, suggesting an allocation trade-off between acorn numbers and size. PMID- 21669721 TI - Molecular phylogenetics of Caryophyllales based on nuclear 18S rDNA and plastid rbcL, atpB, and matK DNA sequences. AB - To study the inter- and infrafamilial phylogenetic relationships in the order Caryophyllales sensu lato (s.l.), ~930 base pairs of the matK plastid gene have been sequenced and analyzed for 127 taxa. In addition, these sequences have been combined with the rbcL plastid gene for 53 taxa and with the rbcL and atpB plastid genes as well as the nuclear 18S rDNA for 26 taxa to provide increased support for deeper branches. The red pigments of Corbichonia, Lophiocarpus, and Sarcobatus have been tested and shown to belong to the betacyanin class of compounds. Most taxa of the order are clearly grouped into two main clades (i.e., "core" and "noncore" Caryophyllales) which are, in turn, divided into well defined subunits. Phytolaccaceae and Molluginaceae are polyphyletic, and Portulacaceae are paraphyletic, whereas Agdestidaceae, Barbeuiaceae, Petiveriaceae, and Sarcobataceae should be given familial recognition. Two additional lineages are potentially appropriate to be elevated to the family level in the future: the genera Lophiocarpus and Corbichonia form a well supported clade on the basis of molecular and chemical evidence, and Limeum appears to be separated from other Molluginaceae based on both molecular and ultrastructural data. PMID- 21669722 TI - A trnL-F cpDNA sequence study of the Condamineeae-Rondeletieae-Sipaneeae complex with implications on the phylogeny of the Rubiaceae. AB - DNA sequences from the chloroplast trnL-F region of 154 Rubiaceae and 11 outgroup taxa were analyzed cladistically. An emphasis was placed on the tribes Rondeletieae, Sipaneeae, and Condamineeae. Sipaneeae are not close to Rondeletieae and belong in the Ixoroideae. There is no support for a widely distributed Rondeletieae in a broad sense. Instead, Rondeletieae sensu stricto form an almost entirely Antillean clade. Support was found for the separation of Arachnothryx, Rogiera, Roigella, and Suberanthus from Rondeletia. The Guettardeae as well as Gonzalagunia are found close to a complex formed by Arachnothryx, Javorkaea, and Rogiera. Condamineeae, in a strict sense, belongs in the Ixoroideae. A number of Rondeletieae genera should be transferred to Condamineeae or other parts of Ixoroideae. Support is found for an emended tribe Naucleeae, comprising several genera with spherical pseudanthia. For the first time, tribal or subfamilial affiliation based on molecular sequence data is suggested for Allenanthus, Blepharidium, Chione, Coutaportla, Dolichodelphys, Mazaea, Neobertiera, Neoblakea, Phialanthus, Phyllacanthus, Phyllomelia, Schmidtottia, and Suberanthus. PMID- 21669723 TI - Phylogeny of Stephanomeria and related genera (compositae-lactuceae) based on analysis of 18S-26S nuclear rDNA ITS and ETS sequences. AB - A phylogenetic analysis of DNA sequences from the internal transcribed spacer (ITS), the external transcribed spacer (ETS), and the 5.8S regions of 18S-26S nuclear rDNA from all diploid species of Stephanomeria and related genera shows that Stephanomeria does not include either Munzothamnus blairii (previously S. blairii) or Pleiacanthus spinosus (previously S. spinosa). Without these two taxa, Stephanomeria is a well-supported (100% bootstrap), monophyletic group of ten perennial and six annual species. Munzothamnus blairii and Pleiacanthus spinosus, both now considered members of monotypic genera, had been placed in Stephanomeria primarily because they have the same chromosome number as Stephanomeria and similar pollen surface features, but many disparities were ignored in previous classifications. Within Stephanomeria, an unsuspected sister relationship was detected between the montane S. lactucina and coastal S. cichoriacea. A second clade contained all the annual taxa and five of the perennial species. Among the annuals, strong bootstrap support was obtained for the previously recognized relationships between S. diegensis and S. exigua (98%) and between S. malheurensis and its progenitor, S. exigua subsp. coronaria (96%). Among the five perennial species that constitute a clade with the annuals, the recently described S. fluminea was shown to be sister to S. runcinata, and both of them were closely allied to S. tenuifolia and S. thurberi. The clade including the annuals (and five of the perennial species) was subtended by perennial lineages and pairwise divergence values among the annual taxa were much lower than among the perennial taxa as a group (though not too different than among the perennials in the same clade). The annuals probably originated recently within the genus. PMID- 21669724 TI - A new rain-operated seed dispersal mechanism in Bertolonia mosenii (Melastomataceae), a Neotropical rainforest herb. AB - Although widespread among fungi, lichens, liverworts, and mosses, seed dispersal mechanisms operated by rain are unusual among flowering plants. Generally speaking, two mechanisms are involved in seed dispersal by rains: the splash-cup and the springboard. Here we describe a new seed dispersal mechanism operated by rain in a Neotropical rainforest herb Bertolonia mosenii Cogniaux (Melastomataceae). The study was carried out at the lowland Atlantic rainforest, southeastern Brazil. We experimentally demonstrate that rain is necessary to release the seeds from the capsules through what we call "squirt-corner" seed dispersal mechanism: when a raindrop strikes the mature fruit, the water droplet forces the seeds outward to the angles (corners) of the triangular capsule and the seeds are released. As far as we know squirt-corner represents a new rain operated seed dispersal mechanism, and a novel seed dispersal mode both for Melastomataceae and for flowering plants from Neotropical forests. PMID- 21669725 TI - Erratum. PMID- 21669726 TI - The tracheid-vessel element transition in angiosperms involves multiple independent features: cladistic consequences. AB - Current definitions of tracheids and vessel elements are overly simple. These definitions are based on light microscope studies and have not incorporated information gained with scanning electron microscopy (SEM) or transmission electron microscopy (TEM). Current definitions are based primarily on angiosperms, especially eudicots, and were devised before many basal angiosperms were carefully studied. When all sources of information are taken into account, one can recognize changes in six characters in the evolution of tracheids into vessel elements in angiosperms (or vice versa) as well as in other groups of vascular plants. There is an appreciable number of taxa in which all criteria for vessel origin are not met, and thus incipient vessels are present. At the very least, vessel presence or absence should not be treated as a single binary character state change in construction of cladistic matrices. Increase in conductive area of an end wall by means of lysis of progressively greater areas of pit membrane and increase in pit area on the end wall (as compared to pit area on equivalent portions of lateral walls) are considered the most important usable criteria for recognizing intermediacy between tracheids and vessel elements. Primitive character states in vessel elements are briefly discussed to differentiate them from changes in character states that can be regarded as intermediate between tracheids and vessel elements. PMID- 21669727 TI - Xylem of rattans: vessel dimensions in climbing palms. AB - We examined 11 species in four genera of rattans (Calamus, Daemonorops, Korthalsia, Plectocomia) growing in their native rainforest habitat in Singapore. Using aqueous safranin dye, we found that >95% of all vascular bundles at the base of a mature stem were functioning to transport water. We determined the frequency of vessel lengths in the long stems of these climbing palms by infiltration with dilute latex paint. Separate length distributions were made for metaxylem and protoxylem vessels; in both, there were many short and a few long vessels. The longest protoxylem vessels ranged from 7.5 to 62 cm in length, but one stem had an exceptional protoxylem vessel measuring 3.0 m. Maximum metaxylem vessel diameters were positively correlated to maximum vessel lengths in these species. The longest metaxylem vessel was found in K. rigida and was 3.96 m in length and was constructed from ~1200 vessel elements (cells). The widest vessel in that same stem was 532 MUm in diameter. Long, wide vessels decrease resistance and increase water transport efficiency. In addition, we suggest that wide metaxylem vessels may have an important function in water storage. PMID- 21669728 TI - The maize mutant barren stalk1 is defective in axillary meristem development. AB - barren stalk1 is a recessive mutant of maize that has no tassel branches, spikelets, tillers, or ears. Here we present a detailed characterization of the ba1 mutant phenotype, including scanning electron microscopy of developing inflorescences, in situ hybridization analysis using a meristem marker, molecular mapping, and genetic analysis demonstrating an epistatic relationship between ba1 and teosinte branched1 (tb1). These data show that the primary defect in the ba1 mutant is a failure in axillary meristem development. PMID- 21669729 TI - Evolutionary implications of substitution patterns in prolamin genes of Oryza glaberrima (African rice, Poaceae) and related species. AB - Patterns of sequence variation of nuclear genes encoding 10-kDa and 16-kDa prolamin seed storage proteins were examined in Oryza glaberrima (African rice, Poaceae) and O. barthii and compared to available sequences for the genus to assess potential application of these gene families in evolutionary studies. Sequence variation among species in 10-kDa genes was very low. In contrast, the 16-kDa genes have undergone rapid evolution, displaying a larger number of length and point mutations that in some cases result in frame shift or produce truncated protein or pseudogenes. The proportion of nonsynonymous substitution is high in both genes. Although nonsynonymous mutations did not alter the overall profile of the protein, pronounced shifts in proportions of some amino acids were evident and could have systematic application. The data provide support for a proposed direct evolution of the Asian (O. sativa) and African rice from O. rufipogon and O. barthii, respectively. Patterns of amino acid frequencies of the 10-kDa genes show the distinctness of O. rufipogon and O. longistaminata from the other species. The study underscores the potential application of the prolamin genes as markers from the nuclear genome for evolutionary studies in grasses at different taxonomic levels. PMID- 21669730 TI - Morphology and development of the female flowers in Geonoma interrupta (Arecaceae). AB - Morphology and development of the female flowers in Geonoma interrupta are described and compared with other taxa within Arecaceae. Inflorescences are pleiothyrses. Cincinni are immersed in pits and arranged according to the Fibonacci pattern along the rachillae. The gynoecium is composed of three free carpels in early stages and later becomes pseudomonomerous. Two carpels are sterile; they develop to different degrees and are commonly unequal in size. The fertile carpel contains a single, crassinucellate, anatropous ovule. Styles are formed in each carpel. The style of the fertile carpel becomes basifixed as the ovary enlarges. The stigmas remain free and plicate during development and expose unicellular papillae at anthesis. Pollen tube transmitting tracts and a compitum are present in the ventral slits of the stigmas and the postgenitally united styles during anthesis. A septal nectary is formed by incomplete union of the flanks of the carpels at the base of the gynoecium, and nectar is secreted from an epithelium. It is suggested that in Geonoma as a whole, the attraction of pollinators to female flowers is due to a combination of nectar reward and partial mimicry of male flowers. PMID- 21669731 TI - Phytochrome photoreceptors mediate plasticity to light quality in flowers of the Brassicaceae. AB - The family of phytochrome photoreceptors mediates stem-elongation responses to ambient ratios of red : far-red light (R : FR). Although phytochrome genes are expressed in flowers in addition to vegetative parts, nothing is known about floral plasticity to R : FR or the pleiotropic effects of phytochrome genes on flowers. Here, the following floral morphologies were compared: (1) wild-type Arabidopsis thaliana and Brassica rapa plants experiencing high R : FR characteristic of sunlight vs. low R : FR typical of foliar shade and (2) wild type and phytochrome-deficient A. thaliana plants. Wild-type A. thaliana exposed to low R : FR had diminished petal and pistil lengths but longer filaments for a given petal size than plants experiencing high R : FR. Brassica rapa plants had qualitatively similar responses. In comparison to wild-type A. thaliana, mutants lacking phytochrome A had smaller flowers (smaller petals, pistils, and filaments), whereas phytochrome B-deficient mutants exhibited longer filament lengths. These results provide the first evidence that R : FR and phytochromes affect floral phenotypes in addition to vegetative ones. Although the ecological relevance remains to be established, the observed plasticity of flowers to R : FR may be relevant to individual fitness in some species because stigma and filament positions can affect pollen removal and levels of self-pollination. PMID- 21669732 TI - Long-living lotus: germination and soil {gamma}-irradiation of centuries-old fruits, and cultivation, growth, and phenotypic abnormalities of offspring. AB - Sacred lotus (Nelumbo nucifera) has been cultivated as a crop in Asia for thousands of years. An ~1300-yr-old lotus fruit, recovered from an originally cultivated but now dry lakebed in northeastern China, is the oldest germinated and directly (14)C-dated fruit known. In 1996, we traveled to the dry lake at Xipaozi Village, China, the source of the old viable fruits. We identified all of the landmarks recorded by botanist Ichiro Ohga some 80 yr ago when he first studied the deposit, but found that the fruits are now rare. We (1) cataloged a total of 60 lotus fruits; (2) germinated four fruits having physical ages of 200 500 yr by (14)C dating; (3) measured the rapid germination of the old fruits and the initially fast growth and short dormancy of their seedlings; (4) recorded abnormal phenotypes in their leaves, stalks, roots, and rhizomes; (5) determined gamma-radiation of ~2.0 mGy/yr in the lotus-bearing beds; and (6) measured stratigraphic sequences of the lakebed strata. The total gamma-irradiation of the old fruits of 0.1-3 Gy (gray, the unit of absorbed dosage defined as 1 joule/kg; 1 Gy = 100 rad), evidently resulting in certain of the abnormal phenotypes noted in their seedlings, represents the longest natural radiobiology experiment yet recorded. Most of the lotus abnormalities resemble those of chronically irradiated plants exposed to much higher irradiances. Though the chronic exposure of the old fruits to low-dose gamma-radiation may be responsible in part for the notably weak growth and mutant phenotypes of the seedlings, it has not affected seed viability. All seeds presumably repair cellular damage before germination. Understanding of repair mechanisms in the old lotus seeds may provide insight to the aging process applicable also to other organisms. PMID- 21669733 TI - Collection and storage of pollen from Salix (Salicaceae). AB - Genetic improvement of willows through traditional breeding can be facilitated by pollen collection and storage so that female flower receptivity need not be synchronized with pollen shed for breeding. Two experiments were completed to test the effectiveness of various organic solvents for willow pollen collection. In the first experiment, seven pollen collection treatments and an untreated control were tested with two willow clones. The other experiment tested three treatments that showed promise in the initial experiment and an untreated control with eight willow clones. Toluene and carbon tetrachloride were effective for pollen extraction, with average pollen germination percentages that were >15%, but both chemicals reduced pollen viability by 10-20% compared with an untreated control based on in vitro germination tests. Pollen extracted with carbon tetrachloride or toluene was successfully used in controlled pollination, and >100 new families were produced with this technique. Pollen viability remained high after 18 mo of storage at -20 degrees C. Based on our results, toluene is the preferred solvent for future willow pollen extractions because it is as effective as carbon tetrachloride, is not a known carcinogen, and is less expensive. PMID- 21669734 TI - Enantiostyly in Wachendorfia (Haemodoraceae): the influence of reproductive systems on the maintenance of the polymorphism. AB - Enantiostyly is a form of directional asymmetry in plants in which the style is deflected away from the main axis of the flower, either to the left or right side. In Wachendorfia (Haemodoraceae), a small genus of insect-pollinated geophytes restricted to the Cape Province of South Africa, populations are usually polymorphic for asymmetry. Here we investigate dimorphic enantiostyly in the four species of Wachendorfia to determine whether variation in their reproductive systems influences the maintenance of this genetic polymorphism. Experimental field pollinations of W. paniculata and W. thyrsiflora indicated higher fertility for cross- than for self-pollinations, whereas in W. brachyandra, these types of pollination produced similar levels of fertility. Outcrossing rates were highest in W. paniculata (t = 0.78-0.98), with W. brachyandra (t = 0.39-0.79) and W. thyrsiflora (t = 0.76) exhibiting mixed mating systems. Outcrossing rates in two populations of W. parviflora varied from mixed mating (t = 0.61) to predominant selfing (t = 0.07). Population style-morph ratios ranged from 1 : 1 in outcrossing W. paniculata to monomorphism in selfing W. parviflora and clonal W. thyrsiflora. In W. brachyandra, a species with delayed selfing, morph ratios were usually biased. The maintenance of enantiostyly in Wachendorfia appears to be strongly influenced by levels of disassortative mating and the balance between sexual and clonal recruitment. PMID- 21669735 TI - The role of autonomous self-pollination in floral longevity in varieties of Impatiens hypophylla (Balsaminaceae). AB - The floral longevity of unpollinated, hand self-, and hand cross-pollinated flowers was compared in two varieties of Impatiens hypophylla, which contrasts with their mating systems. When flowers were emasculated and hand-pollinated every day after anthesis, their longevity was reduced. In the absence of emasculation and hand pollination, the staminate phase of the flowers of both varieties was 1 d longer. After the staminate phase, flowers of the outcrossing variety dropped their androecium, exposing the stigma and initiating the pistillate phase, which lasted for ~2 d. In contrast, flowers of the mixed-mating variety self-pollinated autonomously and then terminated their flowering. Under great seasonal variation in the pollinator visitation rate, which was observed in their natural populations, the outcrossing variety should maximize expected outcross success through the phenology of floral sex phases, whereas the mixed mating variety self-pollinated ovules that were not outcrossed within the staminate phase. Based on these results, I suggest that the autonomous self pollination in I. hypophylla induced differences both in the selfing coefficient and in floral longevity between the varieties. PMID- 21669736 TI - Vascular architecture and patchy nutrient availability generate within-plant heterogeneity in plant traits important to herbivores. AB - Within-plant heterogeneity in growth, morphology, and chemistry is ubiquitous, and is commonly attributed to differences in tissue age, light availability, or previous damage by herbivores. Although these factors are important, we argue that plant vascular architecture is an underappreciated determinant of heterogeneity. Vascular architecture can restrict the transport of resources (nutrients, photosynthate, hormones, etc.) to within specific sectors of the plant: this is referred to as sectoriality. Although studies have documented sectoriality in the transport of isotopes and dyes from roots to shoots, the ecological consequences of this sectoriality remain poorly understood. We tested the hypothesis that spatial variation in belowground nutrient availability combined with sectorial transport results in localized "fertilization" of aboveground plant parts and generates heterogeneity in traits important to herbivores. Our split-root experiments with tomato (Lycopersicon esculentum Mill) clearly demonstrate that fertilization to isolated lateral roots generates heterogeneity in leaf morphology, phenolic chemistry, and side-shoot growth. Specifically, leaflets with direct connections to these lateral roots were larger and had lower levels of rutin and chlorogenic acid than did leaflets in other sectors lacking direct vascular connections. Moreover, side-shoot production was greater in the connected sectors. We discuss the implications of this heterogeneity for plant-herbivore interactions. PMID- 21669737 TI - The use of dna sequencing (ITS and trnL-F), AFLP, and fluorescent in situ hybridization to study allopolyploid Miscanthus (Poaceae). AB - Two clones of Miscanthus, grown under the names M. *giganteus and M. sacchariflorus, have been used in biomass trials in Europe, but neither the identity of these clones nor their origin has been established. DNA sequencing, amplified fragment length polymorphism (AFLP), and chromosome studies confirm that M. *giganteus is an allotriploid (2n = 3x = 57) combining genomes from M. sinensis (2n = 2x = 38) and M. sacchariflorus (2n = 38 or 76). Two alleles of the internal transcribed spacer of 18S-25S nuclear ribosomal DNA (ITS) were discovered in polymerase chain reaction products of M. *giganteus. Cloning of these revealed that one matched M. sinensis and the other M. sacchariflorus. Plastid trnL intron and trnL-F spacer sequences showed that the maternal lineage of M. *giganteus was M. sacchariflorus. Fluorescent in situ hybridization, FISH, was used to investigate genome organization in Miscanthus but was unable to differentiate between the different parental genomes present in M. *giganteus, indicating that two parental genomes are still extremely similar at the repetitive DNA level. This study is an example in which rDNA sequences and AFLP fingerprints permit identification of the parental genomes in a hybrid, but FISH methods, at the repetitive DNA level (including genomic in situ hybridization, GISH), were unable to do so because their sequences remain too similar. PMID- 21669738 TI - A systematic analysis of Heliotropium, Tournefortia, and allied taxa of the Heliotropiaceae (Boraginales) based on ITS1 sequences and morphological data. AB - The relationships of Heliotropium, Tournefortia, Schleidenia, Ixorhea, and Ceballosia of the Heliotropiaceae (Boraginaceae in the traditional sense, Boraginales) are investigated using molecular data (ITS1). These genera form a monophyletic group. Five clades can be distinguished on the basis of molecular data, morphological traits, and distribution. In their current circumscription, Tournefortia is polyphyletic and Heliotropium is paraphyletic. Tournefortia section Cyphocyema is the sister group to all other ingroup taxa. Heliotropium section Orthostachys including Schleidenia sensu lato is the well supported sister group of a clade comprising the other species of Heliotropium sensu stricto (s.s.), Tournefortia section Tournefortia, and Ceballosia. Heliotropium s.s. forms two clades: one clade includes all species of the Old World and represents the only monophylum of Heliotropium s.s. The other clade consists of all Heliotropium s.s. species of the New World but also includes Tournefortia section Tournefortia and Ceballosia. The results suggest that taxonomic changes are inevitable. PMID- 21669739 TI - Phylogenetic relationships in the Gesnerioideae (Gesneriaceae) based on nrDNA ITS and cpDNA trnL-F and trnE-T spacer region sequences. AB - The Gesnerioideae includes most of the New World members of the Gesneriaceae family and is currently considered to include five tribes: Beslerieae, Episcieae, Gesnerieae, Gloxinieae, and Napeantheae. This study presents maximum parsimony and maximum likelihood phylogenetic analyses of nuclear ribosomal DNA internal transcribed spacer regions (ITS), and the chloroplast DNA trnL intron, trnL-trnF intergenic spacer region, and trnE-trnT intergenic spacer region sequences. The ITS and cpDNA data sets strongly support the monophyly of a Beslerieae/Napeantheae clade; an Episcieae clade; a Gesnerieae clade; a Gloxinieae clade minus Sinningia, Sinningia relatives, and Gloxinia sarmentiana; and a Sinningia/Paliavana/Vanhouttea clade. This is the first study to provide strong statistical support for these tribes/clades. These analyses suggest that Sinningia and relatives should be considered as a separate tribe. Additionally, generic relationships are explored, including the apparent polyphyly of Gloxinia. Chromosome number changes are minimized on the proposed phylogeny, with the exception of the n = 11 taxa of the Gloxinieae. Scaly rhizomes appear to have been derived once in the Gloxinieae sensu stricto. The number of derivations of the inferior ovary is unclear: either there was one derivation with a reversal to a superior ovary in the Episcieae, or there were multiple independent derivations of the inferior ovary. PMID- 21669740 TI - Phylogenetic relationships in the cactus family (Cactaceae) based on evidence from trnK/ matK and trnL-trnF sequences. AB - Cacti are a large and diverse group of stem succulents predominantly occurring in warm and arid North and South America. Chloroplast DNA sequences of the trnK intron, including the matK gene, were sequenced for 70 ingroup taxa and two outgroups from the Portulacaceae. In order to improve resolution in three major groups of Cactoideae, trnL-trnF sequences from members of these clades were added to a combined analysis. The three exemplars of Pereskia did not form a monophyletic group but a basal grade. The well-supported subfamilies Cactoideae and Opuntioideae and the genus Maihuenia formed a weakly supported clade sister to Pereskia. The parsimony analysis supported a sister group relationship of Maihuenia and Opuntioideae, although the likelihood analysis did not. Blossfeldia, a monotypic genus of morphologically modified and ecologically specialized cacti, was identified as the sister group to all other Cactoideae. The tribe Cacteae was found to be sister to a largely unresolved clade comprising the genera Calymmanthium, Copiapoa, and Frailea, as well as two large and well supported clades. Browningia sensu stricto (excluding Castellanosia), the two tribes Cereeae and Trichocereeae, and parts of the tribes Notocacteae and Rhipsalideae formed one clade. The distribution of this group is largely restricted to South America. The other clade consists of the columnar cacti of Notocacteae, various genera of Browningieae, Echinocereeae, and Leptocereeae, the tribes Hylocereeae and Pachycereeae, and Pfeiffera. A large portion of this latter group occurs in Central and North America and the Caribbean. PMID- 21669741 TI - Phylogenetic relationships within the blueberry tribe (Vaccinieae, Ericaceae) based on sequence data from MATK and nuclear ribosomal ITS regions, with comments on the placement of Satyria. AB - The blueberry tribe (Vaccinieae) is a large and morphologically diverse group that is widespread in the temperate and tropical zones of most continents. The greatest species diversity is in the tropics, where Vaccinieae are a major component of montane cloud forests. Generic limits are poorly understood, and many of the characters traditionally used fail to adequately distinguish among taxa. This study analyzed sequence data from the chloroplast matK gene and the nrITS region for 93 species of Vaccinieae, representing 28 genera, and 16 sections (of the ~33 currently recognized) of Vaccinium. Results indicated that, in general, traditional generic circumscriptions were not corroborated, but several well-supported clades were found: an Andean clade (including at least some members of 18 of the 23 Neotropical genera sampled), a Meso American/Caribbean clade, an East Malesian clade (including the Old World taxa Paphia and Dimorphanthera), an Agapetes clade comprised of some Asian Vaccinium and Agapetes, and a Bracteata-Oarianthe clade (Vaccinium spp.). This study is the first to address phylogenetic relationships among members of Vaccinieae on a worldwide basis and the results indicate that the large genus Vaccinium is not monophyletic, but likely represents a grade group out of which several more specialized clades evolved. PMID- 21669742 TI - Mycorrhizal dependency of some endemic and endangered Hawaiian plant species. AB - Four endemic species of Hawaiian plants were tested for their response to inoculation with a Hawaiian isolate of Glomus aggregatum (an arbuscular mycorrhizal fungus [AMF]) when grown in a native soil with or without P added to achieve different soil-solution P levels. The endangered species (Sesbania tomentosa [Fabaceae] and Colubrina oppositifolia [Rhamnaceae]) and two nonendangered species (Bidens sandvicensis and B. asymmetrica * sandvicensis [Asteraceae]) were tested. When soil-solution P levels in greenhouse trials were similar to unfertilized field soils (e.g., 0.005-0.020 mg P/L), shoots of inoculated plants were 2.1 to 7.0 times larger than noninoculated plants. Leaf tissue P levels and root biomass in these species showed similar responses to inoculation. Mycorrhizal dependencies ranging from 44 to 88% were measured when plants were grown in low-P soils and were -4-42% in soil with P levels typical of highly productive agricultural soils. A survey of P levels in a variety of native (nonagricultural) Hawaiian soils indicated the widespread occurrence of P-limited sites (mean = 0.010 mg P/L, range = <0.001-0.030 mg P/L; N = 41). The terms "ecological mycorrhizal dependency" (EMD) and "agricultural mycorrhizal dependency" (AMD) are introduced to refine the concept of mycorrhizal dependency. PMID- 21669743 TI - Aluminum in the opal silica reticule of phytoliths: a new tool in palaeoecological studies. AB - X-ray microanalysis was employed to screen biogenic plant silica extracted from the aboveground tissues of 20 species (Gramineae, Cyperaceae, Ericaceae, and Coniferae) occurring in subalpine and alpine grasslands, heaths, and woodlands on siliceous bedrock in the Valaisan Swiss Alps. Among the taxa investigated, only woody species produced a high proportion of phytoliths containing aluminum in the form of aluminosilicates. This difference between the chemical composition of wood and that of herbaceous phytoliths has important implications for the sourcing of phytoliths. As applications for palaeoenvironmental studies can be expected to be far-reaching, the potential of this microanalytical technique is discussed. PMID- 21669744 TI - Ashicaulis woolfei n. sp.: additional evidence for the antiquity of osmundaceous ferns from the Triassic of Antarctica. AB - Numerous small fern trunks and dispersed osmundaceous frond fragments occur within a Middle Triassic silicified peat near Fremouw Peak in the Transantarctic Mountains of Antarctica. These specimens form the basis of a new species of osmundaceous ferns that further helps to characterize the early Mesozoic vegetation of high latitude Gondwana. Ashicaulis woolfei n. sp. consists of small, upright trunks with a persistent armor of frond bases, adventitious roots, and vegetative frond parts. In cross section the trunks are ~2.5 cm in diameter and include up to 45 frond bases. Stems range from 5 to 8 mm in diameter with a xylem cylinder of 8-9 xylem segments separated by leaf gaps. Phyllotaxy is variable, approaching 2/5 or 3/8, with 10-12 frond traces in the cortex. Stipes have parenchymatous, stipular wings that are usually devoid of sclerenchyma; fronds are pinnate with alternate-subopposite pinnatifid pinnules. Although the absence of fertile pinnules and sporangia precludes assigning the fossils to a living genus, this species demonstrates that ferns with stelar architecture and histology similar to Osmunda subgenus Osmundastrum (Osmundaceae) were present in the Southern Hemisphere by the mid-Triassic. PMID- 21669745 TI - Fringe Science: are the corollas of Nymphoides (Menyanthaceae) flowers adapted for surface tension interactions? AB - Attractive features of flowers are adaptations for biotic interactions, and a few floral adaptations are for interactions with the physical environment. Marginal corollar appendages of Nymphoides (Menyanthaceae) can be membranous, a fringe of trichomes, or a ruffle. Although clearly enhancing display, a fringed corollar margin might function by generating a significant upward force through surface tension, an interaction adaptive in an aquatic environment. The force needed to dunk flowers with an intact corollar fringe and those whose fringe had been trimmed showed a significant difference. The fringe added a mean of 10.4% to the floral mass, but the upward force generated increased by nearly 50%, a significant difference from the predicted change based upon buoyancy alone. A correlation between plant form and type of corolla margin supports the surface tension hypothesis. The membranous and ruffled corollar margins were found in species whose flowers had less risk of contacting the water's surface. PMID- 21669746 TI - Green light reversal of blue-light-stimulated stomatal opening is found in a diversity of plant species. AB - Reversal by green light of blue-light-stimulated stomatal opening was found across a number of plant species, including leguminous and nonleguminous dicots and grass and nongrass monocots. Simultaneous exposure to equal fluence rates of blue and green light resulted in ~50% reversal of normal blue light opening. Complete reversal occurred when the fluence rate of green light was approximately twice that of blue light. These results suggest that blue-green reversibility of stomatal opening is a basic photobiological property of guard cells. The blue green reversibility of stomatal opening has been hypothesized to ensue from the cycling of two interconvertible, isomeric forms of the blue-light photoreceptor, zeaxanthin. Testing of blue-green reversibility could provide a valuable diagnostic tool for zeaxanthin-mediated blue-light photoperception. PMID- 21669747 TI - Key transitions in animal evolution. AB - In order to address this subject further and to assess progress in the examination of animal origins and transitions, an international group of scientists was convened at the Society for Comparative Biology meeting in January 2007. PMID- 21669748 TI - Can we ever identify the Urmetazoan? AB - Unraveling the root of the metazoan tree of life has been a difficult task since the time of Haeckel and the invention of phylogenetics. Even considerable amounts of recent molecular data have not provided a generally accepted answer. Here, we review the major problems of this phylogenetic conundrum and provide some directions for solving it. PMID- 21669749 TI - Field biology of placozoans (Trichoplax): distribution, diversity, biotic interactions. AB - The goal of this review is to highlight what little is known, and point to the bulk of what is yet to be learned, about the natural history of placozoans in the field-in order to stimulate a broader search for placozoans and a fuller exploration of their distribution, diversity, and all other aspects of their enigmatic lives. The documented geographic distribution of placozoans lies mostly in the nearshore, warm, marine waters of the tropics and subtropics. Although placozoans have long been viewed as benthic organisms, they can be more readily collected from the water column, well above the sea bottom. The full life-history of placozoans is unknown, including the nature of this abundant pelagic phase and all details of sexual reproduction and development. We note observations on the biota associated with placozoans in field collections, in particular the other regular members of the microcommunity in which placozoans occur on our collecting plates and on some factors influencing this assemblage. Among the animals found are some potential predators against which placozoans appear to be defended, although the mechanisms are still to be examined. Also yet to be uncovered is the full breadth of diversity in this phylum, certainly underrepresented by its single named species. We report here greatly expanded distributions for known haplotypes and fresh specimens that include a new haplotype, and we review the evidence that many more almost certainly await discovery. We also describe some methods for collecting and handling these small, fragile animals. PMID- 21669750 TI - Cnidarian milestones in metazoan evolution. AB - Cnidarians display most of the characters considered as milestones of metazoan evolution. Whereas a tissue-level organization was probably already present in the multicellular common ancestor of all animals, the Urmetazoa, the emergence of important animal features such as bilateral symmetry, triploblasty, a polarized nervous system, sense organs (eyes, statocysts), and a (chitinous or calcium based) continuous skeleton can be traced back before the divergence between cnidarians and bilaterians. Modularity and metamery might be also regarded as two faces of the same medal, likely involving conserved molecular mechanisms ruling animal body architectures through regional specification of iterated units. Available evidence indicates that the common ancestor of cnidarians and bilaterians, the UrEumetazoa, was a surprisingly complex animal with nerve cell differentiation. We suggest that paedomorphic events in descendants of this ancestor led to the array of diversity seen in the main extant animal phyla. The use of molecular analyses and identifying the genetic determinants of anatomical organizations can provide an integrative test of hypotheses of homologies and independent evidence of the evolutionary relationships among extant taxa. PMID- 21669751 TI - Implications of cnidarian gene expression patterns for the origins of bilaterality is the glass half full or half empty? AB - The past two years have seen a dramatic increase in the available data on gene sequence and gene expression for cnidarians and other "lower" Metazoa, and a flurry of recent papers has drawn on these to address the origins of bilaterality. Cnidarian homologs of many genes that play key roles in the specification of both the A/P and D/V axes of bilaterians have been characterized, and their patterns of expression determined. Some of these expression patterns are consistent with the possibility of conservation of function between Cnidaria and Bilateria, but others clearly differ. Moreover, in some cases very different interpretations have been made on the basis of the same, or similar, data. In part, these differences reflect the inevitable uncertainties associated with the depth of the divergence between cnidarians and bilaterians. In this article, we briefly summarize the cnidarian data on gene expression and organization relevant to axis formation, the varying interpretations of these data, and where they conflict. Our conclusion is that the presently available data do not allow us to unequivocally homologize the single overt axis of cnidarians with either of the bilaterian axes. PMID- 21669752 TI - Evolution of sensory structures in basal metazoa. AB - Cnidaria have traditionally been viewed as the most basal animals with complex, organ-like multicellular structures dedicated to sensory perception. However, sponges also have a surprising range of the genes required for sensory and neural functions in Bilateria. Here, we: (1) discuss "sense organ" regulatory genes, including; sine oculis, Brain 3, and eyes absent, that are expressed in cnidarian sense organs; (2) assess the sensory features of the planula, polyp, and medusa life-history stages of Cnidaria; and (3) discuss physiological and molecular data that suggest sensory and "neural" processes in sponges. We then develop arguments explaining the shared aspects of developmental regulation across sense organs and between sense organs and other structures. We focus on explanations involving divergent evolution from a common ancestral condition. In Bilateria, distinct sense-organ types share components of developmental-gene regulation. These regulators are also present in basal metazoans, suggesting evolution of multiple bilaterian organs from fewer antecedent sensory structures in a metazoan ancestor. More broadly, we hypothesize that developmental genetic similarities between sense organs and appendages may reflect descent from closely associated structures, or a composite organ, in the common ancestor of Cnidaria and Bilateria, and we argue that such similarities between bilaterian sense organs and kidneys may derive from a multifunctional aggregations of choanocyte-like cells in a metazoan ancestor. We hope these speculative arguments presented here will stimulate further discussion of these and related questions. PMID- 21669753 TI - A food's-eye view of the transition from basal metazoans to bilaterians. AB - Living things invariably consist of some kind of compartmentalized redox chemistry. Signaling pathways mediated by oxidation and reduction thus derive from the nature of life itself. The role of such redox or metabolic signaling broadened with major transitions in the history of life. Prokaryotes often use redox signals to deploy one or more variant electron carriers and associated enzymes to better utilize environmental energy sources. Eukaryotes transcend the strong surface-to-volume constraints inherent in prokaryotic cells by moving chemiosmotic membranes internally. As a consequence, eukaryotic redox signaling is frequently between these organelle membranes and the nucleus, thus potentially involving levels-of-selection synergies and antagonisms. Gradients of oxygen and substrate in simple multicellular organisms similarly associated metabolic signaling with levels of selection, now at the level of the cell and the organism. By allowing sequestration of large amounts of food, the evolution of the animal mouth was a pivotal event in metabolic signaling, leading to "multicellular" redox regulation. Because concentrated food resources may be patchy in time and space, long-lived sedentary animals with mouths employ such metabolic signaling and phenotypic plasticity in ways that adapt them to the changing availability of food. Alternatively, if the mouth is coupled to a battery of sensory equipment, the organism can actively seek out and sequester patches of food. In these early bilaterians, competition for food resources may have favored rapid development with little subsequent plasticity and metabolic signaling. With rapid dispersal and colonization, such "assembly-line" animals could effectively compete for patchy resources. Limiting metabolic signaling, however, resulted in a cascade of seemingly unrelated changes. These changes derive from the effectiveness of metabolic signaling in policing variation at the cellular level. If the signals an organism uses to control cellular replication are the same as the signals a cell uses to control its own metabolism, then cells that ignore these signals and carry out selfish replication will pay a fitness cost in terms of inefficient metabolism. Bilaterians with limited metabolic signaling thus require other mechanisms to police cell-level variation. Bilaterian features such as restricted somatic cell potency, a sequestered germ line, and determinate growth should be viewed in this context. Bilaterian senescence evolved as a by-product of restricted potency of somatic cells, itself a mechanism of cell policing required by limited metabolic signaling. PMID- 21669754 TI - Key transitions in animal evolution: a mitochondrial DNA perspective. AB - Animal mitochondrial DNA (mtDNA) is usually depicted as a small and very economically organized molecule with almost invariable gene content, stable gene order, a high rate of sequence evolution, and several unorthodox genetic features. Sampling across different animal phyla reveals that such a description applies primarily to mtDNA of bilaterian animals (such as arthropods or chordates). By contrast, mitochondrial genomes of nonbilaterian animals (phyla Cnidaria, Placozoa, and Porifera) display more variation in size and gene content and, in most cases, lack the genetic novelties associated with bilaterian mtDNA. Outside the Metazoa, mtDNA of the choanoflagellate Monosiga brevicollis, the closest unicellular out-group, is a much larger molecule that contains a large proportion of noncoding DNA, 1.5 times more genes, as well as several introns. Thus, changes in animal mtDNA organization appear to correlate with two main transitions in animal evolution: the origin of multicellularity and the origin of the Bilateria. Studies of mtDNA in nonbilaterian animals provide valuable insights into these transitions in the organization of mtDNA and also supply data for phylogenetic analyses of the relationships of early animals. Here I review recent progress in the understanding of nonbilaterian mtDNA and discuss the advantages and limitations of mitochondrial data sets for inferences about the phylogeny and evolution of animals. PMID- 21669755 TI - Fossils and phylogenies: integrating multiple lines of evidence to investigate the origin of early major metazoan lineages. AB - Understanding the nature and timing of metazoan origins is one of the most important, yet elusive, questions in evolutionary biology. Fossil data provide the most tangible evidence for the origin of early animal lineages, although additional evidence from molecular phylogenetics, molecular clock studies, and development has contributed to our current understanding. We review several lines of evidence to explore the nature and timing of early metazoan evolution and discuss how these data, when considered together, provide a more cohesive picture of the origin of animal diversity. We discuss how trace fossils and biomarkers provide compelling evidence for the origins of Bilateria and siliceous sponges. Using a molecular phylogenetic framework for metazoans, we discuss how fossils can be used to date the origin of clades. We use these fossil dates to perform a relaxed molecular clock analysis for estimating dates of nodes when no fossils are available. We also discuss current data from developmental biology that suggest that early metazoans possessed a sophisticated molecular toolkit for building complex body plans. We conclude that the best evidence for the origin of major metazoan lineages lies in the careful interpretation of the fossil record and that these data, when considered with phylogenetic and developmental evidence, support the notion that the Cambrian radiation is a real phenomenon that marks a critically important time in the history of life. PMID- 21669756 TI - Origin and evolution of a myxozoan worm. AB - Buddenbrockia plumatellae is an active, muscular, worm-shaped parasite of freshwater bryozoans. This rare and enigmatic animal has been assigned to the Myxozoa on the basis of 18S ribosomal DNA sequences and the presence of malacosporean spores. Here we report cloning of four homologous protein-coding genes from Buddenbrockia worms, the putatively conspecific sac-shaped parasite originally described as Tetracapsula bryozoides and the related sac-shaped parasite Tetracapsuloides bryosalmonae, the causative agent of proliferative kidney disease in salmonid fish. Analyses are consistent with the hypothesis that Buddenbrockia is indeed a malacosporean myxozoan, but do not provide support for conspecificity with either T. bryozoides or T. bryosalmonae. Implications for the evolution of worm-like body plans in the Myxozoa are discussed. PMID- 21669757 TI - Key transitions during the evolution of animal phototransduction: novelty, "tree thinking," co-option, and co-duplication. AB - Biologists are amazed by the intricacy and complexity of biological interactions between molecules, cells, organisms, and ecosystems. Yet underlying all this biodiversity is a universal common ancestry. How does evolution proceed from common starting points to generate the riotous biodiversity we see today? This "novelty problem"-understanding how novelty and common ancestry relate-has become of critical importance, especially since the realization that genes and developmental processes are often conserved across vast phylogenetic distances. In particular, two processes have emerged as the primary generators of diversity in organismal form: duplication plus divergence and co-option. In this article, we first illustrate how phylogenetic methodology and "tree-thinking" can be used to distinguish duplication plus divergence from co-option. Second, we review two case studies in photoreceptor evolution-one suggesting a role for duplication plus divergence, the other exemplifying how co-option can shape evolutionary change. Finally, we discuss how our tree-thinking approach differs from other treatments of the origin of novelty that utilized a "linear-thinking" approach in which evolution is viewed as a linear and gradual progression, often from simple to complex phenotype, driven by natural selection. PMID- 21669758 TI - Evolution of the bilaterian germ line: lineage origin and modulation of specification mechanisms. AB - A key focus of evolutionary developmental biology (evo-devo) in recent years has been to elucidate the evolution of developmental mechanisms as a means of reconstructing the hypothetical last common ancestors of various clades. Prominent among such reconstructions have been proposals as to the nature of the mysterious "Urbilateria," originally defined as the last common ancestor of the extant Bilateria (protostomes and deuterostomes). Indeed, drawings of this animal can now be found, as well as detailed information on the genetics and morphological processes that it used to construct its gut, heart, eyes, appendages, segments, and body regions. Perhaps surprisingly, however, no explanations have yet been offered as to how this animal might have achieved the successful reproduction that must have been necessary for it to give rise to those lineages that are ancestral to today's diverse clades. The present article examines the comparative data available to date on the specification of the only cells containing the genetic hereditary material, the germ cells, and speculates on the possible evolutionary and developmental origin of the Urbilaterian germ line. PMID- 21669759 TI - Does new technology inspire new directions? Examples drawn from pelagic visual ecology. AB - Oceanography has seen the recent development of many new tools and techniques. The subfield of pelagic visual ecology in particular has benefited from the development of more reliable, portable, and economic tools and techniques that can be taken to sea including spectrometers, microspectrophotometery, electroretinography, and ultraviolet and polarization imaging systems. These advances have led to a relative wealth of data on the visual physiology of pelagic species and on the optical properties of these species and their environment. These data, particularly in combination with computational methods, have tested long-standing hypotheses in pelagic ecology and led to new hypotheses and research directions. While the ability to study pelagic species still lags far behind what is possible in terrestrial and coastal environments, a renaissance may be developing in the study of the integrative biology of pelagic species. PMID- 21669760 TI - Comparative visual acuity of coleoid cephalopods. AB - The pelagic realm of the ocean is characterized by extremely clear water and a lack of surfaces. Adaptations to the visual ecology of this environment include transparency, fluorescence, bioluminescence, and deep red or black pigmentation. While the signals that pelagic organisms send are increasingly well-understood, the optical capabilities of their viewers, especially for predators with camera like vision such as fish and squid, are almost unknown. Aquatic camera-like vision is characterized by a spherical lens focusing an image on the retina. Here, we measured the resolving power of the lenses of eight species of pelagic cephalopods to obtain an approximation of their visual capabilities. We did this by focusing a standard resolution target through dissected lenses and calculating their modulation transfer functions. The modulation transfer function (MTF) is the single most complete expression of the resolving capabilities of a lens. Since the optical and retinal capabilities of an eye are generally well-matched, we considered our measurements of cephalopod lens MTF to be a good proxy for their visual capabilities in vivo. In general, squid have optical capabilities comparable to other organisms generally assumed to have good vision, such as fish and birds. Surprisingly, the optical capability of the eye of Vampyroteuthis infernalis rivals that of humans. PMID- 21669761 TI - Phylogenetic analysis of lineage relationships among hyperiid amphipods as revealed by examination of the mitochondrial gene, cytochrome oxidase I (COI). AB - Among metazoans, crustaceans display the greatest disparity between body plans and are second only to the insects in overall species diversity. Within the crustaceans, the Amphipoda rank as one of the most speciose extant orders. Amphipods have successfully invaded a variety of ecosystems, including the pelagic midwater environment. Despite their abundance in varied and dissimilar habitats, and the use of traditional morphological and systematic comparative analyses, phylogenetic relationships among amphipods remain uncertain. The pelagic amphipods, hyperiids, have highly divergent life histories and morphological attributes in comparison to more familiar benthic, nearshore, intertidal, and terrestrial amphipods. Some of these adaptations are likely correlated with their pelagic life history and include features such as hypertrophied olfactory and visual systems, duplications of the eyes, and an array of modifications to the appendages. Many of these morphological features may represent homoplasies, thus masking the true phylogenetic relationships among extant hyperiid amphipods. Here, we sample a wide range of amphipod taxa for the COI gene and present the first preliminary molecular phylogeny among the hyperiids. PMID- 21669762 TI - The prevalence and implications of copepod behavioral responses to oceanographic gradients and biological patchiness. AB - Several species and developmental stages of calanoid copepods were tested for responses to environmental cues in a laboratory apparatus that mimicked conditions commonly associated with patches of food in the ocean. All species responded to the presence of phytoplankton by feeding. All species responded by increasing proportional residence time in one, but not both, of the treatments defined by gradients of velocity or density. Most species increased swimming speed and frequency of turning in response to the presence of chemical exudates or gradients of velocity. Only one species, Eurytemora affinis, increased proportional time of residence in response to gradients in density of the water. Responses of E. affinis to combined cues did not definitively demonstrate a hierarchical use of different cues as previously observed for Temora longicornis and Acartia tonsa. A simple foraging simulation was developed to assess the applicability in the field of the behavioral results observed in the laboratory. These simulations suggest that observed fine-scale behaviors could lead to copepod aggregations observed in situ. The present study demonstrates that behavioral response to cues associated with fine-scale oceanographic gradients and biological patchiness is functionally important and prevalent among copepods and likely has significant impacts on larger-scale distributional patterns. PMID- 21669763 TI - Comparative feeding behavior of planktonic ctenophores. AB - The phylum Ctenophora (known as comb jellies) consists of gelatinous marine carnivores found from the surface to several thousand meters depth. Their morphology can be simple or complex, ranging from a sac-like shape with no tentacles to large lobed forms with sinuous "auricles," papillae, and two different kinds of tentacles. This diversity appears to reflect adaptations to many different diets. For example, some species can continuously "graze" on small crustaceans or larvae, others engulf larger jellies, and some are able to snare individual larger prey through a variety of strategies. Thus feeding behavior can help explain the high morphological diversity in this relatively small phylum. Because of their fragility, comb jellies are difficult to study alive and the natural histories of many types, especially those found in the deep sea, have not been examined. This account categorizes ctenophore feeding methods using published reports as well as new observations using submersibles and blue-water scuba diving. PMID- 21669764 TI - The Hox gene complement of a pelagic chaetognath, Flaccisagitta enflata. AB - Chaetognaths are transparent marine animals that are ubiquitous and abundant members of oceanic zooplanktonic communities. Their phylogenetic position within the Metazoa, however, has remained obscure since their discovery. Morphology and embryology have traditionally allied chaetognaths with deuterostomes, but molecular evidence suggests otherwise. Two recent multigene expressed sequence tag (EST) molecular phylogenomic studies suggest that chaetognaths are either sister to the Lophotrochozoa (Matus et al. 2006) or to all protostomes (Marletaz et al. 2006). We have isolated eight Hox genes, one Parahox gene, and Mox, a related homeodomain gene, from the pelagic chaetognath, Flaccisagitta enflata. Although chaetognath central class Hox genes lack the Lox5 or "spiralian" parapeptide, a diagnostic amino-acid motif that has been utilized previously to assign lophotrochozoan affinity, they do possess a central class Hox gene that has a partial "Ubd-A peptide" found in both ecdysozoan and lophotrochozoan Ubx/Abd-A/Lox2/Lox4 genes. Additionally, we report the presence of two distinct chaetognath posterior Hox genes that possess both ecdysozoan and lophotrochozoan signature amino-acid motifs. The phylogenetic position of chaetognaths, as well as the evolution of the Hox cluster, is discussed in light of these data. PMID- 21669765 TI - Homology of ciliary bands in Spiralian Trochophores. AB - A number of hypotheses have been presented regarding the origins of the metazoans and, more specifically, the Bilateria. Using various phylogenetic analyses, characteristics have been mapped on phylogenetic trees to infer ancestral body plans and life history strategies of those ancestors. Many arguments on the evolution of the Bilateria are based on the presumed homology of certain characteristics of extant larva and adults, including various ciliated bands involved in feeding and locomotion. This article considers a recent study indicating that the second, downstream-collecting, ciliated band in the veliger larva of the gastropod mollusc, Crepidula fornicata, is actually derived from secondary trochoblasts (derived from second quartet micromeres), that normally form part of the prototrochal band found in other spiralian phyla (Hejnol et al. 2007). Despite previous arguments, these new findings suggest that the second ciliated band in the veliger larva is not homologous to the metatroch found in the trochophore larva of some other spiralians, such as the annelid, Polygordius lacteus. In the latter case, the metatroch was reported to be formed by a different set of lineage precursors (derived from third quartet micromeres) (Woltereck 1904). These findings have important implications for the interpretation of various hypotheses related to the evolution of metazoan phyla. PMID- 21669766 TI - A brief review of holopelagic annelids. AB - Annelids are one of the most successful major animal lineages in terms of number of species and of habitats occupied. Despite annelids being common in terrestrial, aquatic, and marine environments, only a limited number of lineages have evolved a holopelagic existence. Most of these holopelagic lineages belong to Phyllodocida (nereidids, syllids, scale worms, and jawed worms) and more particularly often within the family Phyllodocidae. These worms generally appear to retain many characteristics of adult annelids. Moreover, we provide molecular evidence showing that the well-known alciopids are derived from within Phyllodocidae. In contrast, at least two lineages, Poeobius meseres/Flota flabelligera and probably Chaetopterus pugaporcinus, are derived through paedomorphic processes acting on larvae from lineages that have sedentary adult forms. Herein, we will briefly review the known diversity of holopelagic annelids with discussion of their evolutionary origins. PMID- 21669767 TI - Metabolic temperature compensation and coevolution of locomotory performance in pteropod molluscs. AB - Gymnosomatous pteropods are highly specialized planktonic predators that feed exclusively on their thecosomatous relatives. Feeding behavior and the morphology of gymnosome feeding structures are diverse and have evolved in concert with the size, shape, and consistency of the thecosome shell. Here, we show that the metabolic capacity and locomotory behaviors of gymnosomes are similarly diverse and vary with those of their prey. Both gymnosomes and thecosomes range from gelatinous sit-and-wait forms to active predators with high-performance locomotory muscles. We find more than 10-fold variation in size-adjusted and temperature-adjusted metabolic rates within both the Gymnosomata and Thecosomata and a strong correlation between the metabolic rates of predators and of prey. Furthermore, these characteristics are strongly influenced by environmental parameters and predator and prey converge upon similar physiological capacities under similar selection. For example, compensation of locomotory capacity in cold waters leads to elevated metabolic rates in polar species. This highly coevolved system is discussed in terms of a predator-prey "arms race" and the impending loss of both predator and prey as elevated atmospheric carbon dioxide levels threaten to dissolve prey shells via oceanic acidification. PMID- 21669768 TI - Aeroecology: probing and modeling the aerosphere. AB - Aeroecology is a discipline that embraces and integrates the domains of atmospheric science, ecology, earth science, geography, computer science, computational biology, and engineering. The unifying concept that underlies this emerging discipline is its focus on the planetary boundary layer, or aerosphere, and the myriad of organisms that, in large part, depend upon this environment for their existence. The aerosphere influences both daily and seasonal movements of organisms, and its effects have both short- and long-term consequences for species that use this environment. The biotic interactions and physical conditions in the aerosphere represent important selection pressures that influence traits such as size and shape of organisms, which in turn facilitate both passive and active displacements. The aerosphere also influences the evolution of behavioral, sensory, metabolic, and respiratory functions of organisms in a myriad of ways. In contrast to organisms that depend strictly on terrestrial or aquatic existence, those that routinely use the aerosphere are almost immediately influenced by changing atmospheric conditions (e.g., winds, air density, precipitation, air temperature), sunlight, polarized light, moon light, and geomagnetic and gravitational forces. The aerosphere has direct and indirect effects on organisms, which often are more strongly influenced than those that spend significant amounts of time on land or in water. Future advances in aeroecology will be made when research conducted by biologists is more fully integrated across temporal and spatial scales in concert with advances made by atmospheric scientists and mathematical modelers. Ultimately, understanding how organisms such as arthropods, birds, and bats aloft are influenced by a dynamic aerosphere will be of importance for assessing, and maintaining ecosystem health, human health, and biodiversity. PMID- 21669769 TI - Detection and discrimination of fauna in the aerosphere using Doppler weather surveillance radar. AB - Organisms in the aerosphere have been detected by radar since its development in the 1940s. The national network of Doppler weather radars (WSR-88D) in the United States can readily detect birds, bats, and insects aloft. Level-II data from the radar contain information on the reflectivity and radial velocity of targets and on width of the spectrum (SD of radial velocities in a radar pulse volume). Information on reflectivity can be used to quantify density of organisms aloft and radial velocity can be used to discriminate different types of targets based on their air speeds. Spectral width can also provide some useful information when organisms with very different air speeds are aloft. Recent work with dual polarization radar suggests that it may be useful for discriminating birds from insects in the aerosphere, but more development and biological validation are required. PMID- 21669770 TI - Analyzing NEXRAD doppler radar images to assess nightly dispersal patterns and population trends in Brazilian free-tailed bats (Tadarida brasiliensis). AB - Operators of early weather-surveillance radars often observed echoes on their displays that did not behave like weather pattern, including expanding ring-like shapes they called angels. These echoes were caused by high-flying insects, migrating birds, and large colonies of bats emerging from roosts to feed. Modern weather-surveillance radar stations in the United States (NEXt-generation RADar or NEXRAD) provide detailed images that clearly show evening bat emergences from large colonies. These images can be used to investigate the flight behavior of groups of bats and population trends in large colonies of Brazilian free-tailed bats (Tadarida brasiliensis) in south-central Texas which are clearly imaged by local NEXRAD radar stations. In this study, we used radar reflectivity data from the New Braunfels, Texas NEXRAD station to examine relative colony size, direction of movement, speed of dispersion, and altitude gradients of bats from these colonies following evening emergence. Base reflectivity clear-air-mode Level-II images were geo-referenced and compiled in a GIS along with locations of colonies and features on the landscape. Temporal sequences of images were filtered for the activity of bats, and from this, the relative size of bat colonies, and the speed and heading of bat emergences were calculated. Our results indicate cyclical changes in colony size from year to year and that initial headings taken by bats during emergence flights are highly directional. We found that NEXRAD data can be an effective tool for monitoring the nightly behavior and seasonal changes in these large colonies. Understanding the distribution of a large regional bat population on a landscape scale has important implications for agricultural pest management and conservation efforts. PMID- 21669771 TI - Evidence for widely dispersed birds migrating together at night. AB - Lore and indirect evidence from previous studies suggest that nocturnally migrating vertebrates (perhaps bats but mostly birds) sometimes fly widely dispersed from each other, but in flocks. The observations include stationary and scanning radars, recordings of flight calls, and watching the moon with telescopes. Direct observations of such flocks have been lacking. This article presents data from novel tracking of nocturnal aggregations of radar targets. Statistical analysis of straight, detailed flight paths supported the hypothesis that vertebrates, almost certainly birds, flying within about 200-300 m of each other fly parallel (in the same direction at the same speed) more often than do vertebrates flying farther apart. This inference was strengthened by comparisons with a partial control for wind and for small-scale atmospheric structure: namely, small nocturnal arthropods tracked by the identical method did not fly parallel. Radar data also indicated that birds flying together may have similar wing beats, suggesting taxonomic similarity between birds flying parallel. Possible functions include not only mutual benefits on the ground during migratory stopover (habitat use, avoidance of predators, and social feeding) but also in-flight sharing of information about orientation. PMID- 21669772 TI - Applications of thermal infrared imaging for research in aeroecology. AB - The night sky remains a largely unexplored frontier for biologists studying the behavior and physiology of free-ranging, nocturnal organisms. Conventional imaging tools and techniques such as night-vision scopes, infrared-reflectance cameras, flash cameras, and radar provide insufficient detail for the scale and resolution demanded by field researchers. A new tool is needed that is capable of imaging noninvasively in the dark at high-temporal and spatial resolution. Thermal infrared imaging represents the most promising such technology that is poised to revolutionize our ability to observe and document the behavior of free ranging organisms in the dark. Herein we present several examples from our research on free-ranging bats that highlight the power and potential of thermal infrared imaging for the study of animal behavior, energetics and censusing of large colonies, among others. Using never-before-seen video footage and data, we have begun to answer questions that have puzzled biologists for decades, as well as to generate new hypotheses and insight. As we begin to appreciate the functional significance of the aerosphere as a dynamic environment that affects organisms at different spatial and temporal scales, thermal infrared imaging can be at the forefront of the effort to explore this next frontier. PMID- 21669773 TI - Flying high--assessing the use of the aerosphere by bats. AB - Bats feature prominently among organisms that occupy the aerosphere as they extensively use this environment for foraging, but also for dispersal, migration, and behavioral interactions. Differential use of the aerosphere is an important factor structuring bat assemblages, with species exhibiting distinct morphological, physiological, and sensory adaptations to different habitat types. This necessitates comprehensive sampling methodologies such as combined ground level and canopy-level mist netting as well as acoustic monitoring to assess the presence, diversity, and activity of different functional groups of species adequately. Recent technological advances in acoustic detection and in methods of analysis, coupled with the expansion of libraries of echolocation calls for species identification, now allow for the reliable quantification of species numbers and activity of the scarcely known group of aerial insectivorous bats, particularly in species-rich tropical assemblages. We provide a brief, exemplary overview of recent studies on bats conducted in Panama to demonstrate the necessity of comprehensive sampling methods and application of new technologies in order to adequately depict assemblage composition and responses of bats to structural changes in habitats induced by fragmentation. In addition to acoustic methods, miniaturization of radio transmitters has provided new insights into the patterns of spatial use of the aerosphere by bats and has identified species specific differences in mobility as one of the important traits that determines bats' reactions to anthropogenic alterations of the landscape. Following the goals of the symposium on aeroecology, we propose new avenues of research for probing the aerosphere. We discuss how integration of a diverse array of remote sensing tools with data on species distribution and species traits, such as mobility and edge-sensitivity, might provide novel opportunities for the development, and application of conservation-oriented monitoring systems. PMID- 21669774 TI - Understanding signal design during the pursuit of aerial insects by echolocating bats: tools and applications. AB - Bats are among the few predators that can exploit the large quantities of aerial insects active at night. They do this by using echolocation to detect, localize, and classify targets in the dark. Echolocation calls are shaped by natural selection to match ecological challenges. For example, bats flying in open habitats typically emit calls of long duration, with long pulse intervals, shallow frequency modulation, and containing low frequencies-all these are adaptations for long-range detection. As obstacles or prey are approached, call structure changes in predictable ways for several reasons: calls become shorter, thereby reducing overlap between pulse and echo, and calls change in shape in ways that minimize localization errors. At the same time, such changes are believed to support recognition of objects. Echolocation and flight are closely synchronized: we have monitored both features simultaneously by using stereo photogrammetry and videogrammetry, and by acoustic tracking of flight paths. These methods have allowed us to quantify the intensity of signals used by free living bats, and illustrate systematic changes in signal design in relation to obstacle proximity. We show how signals emitted by aerial feeding bats can be among the most intense airborne sounds in nature. Wideband ambiguity functions developed in the processing of signals produce two-dimensional functions showing trade-offs between resolution of time and velocity, and illustrate costs and benefits associated with Doppler sensitivity and range resolution in echolocation. Remarkably, bats that emit broadband calls can adjust signal design so that Doppler-related overestimation of range compensates for underestimation of range caused by the bat's movement in flight. We show the potential of our methods for understanding interactions between echolocating bats and those prey that have evolved ears that detect bat calls. PMID- 21669775 TI - Aeromechanics in aeroecology: flight biology in the aerosphere. AB - The physical environment of the aerosphere is both complex and dynamic, and poses many challenges to the locomotor systems of the three extant evolutionary lineages of flying animals. Many features of the aerosphere, operating over spatial and temporal scales of many orders of magnitude, have the potential to be important influences on animal flight, and much as marine ecologists have studied the relationship between physical oceanography and swimming locomotion, a subfield of aeroecology can focus attention on the ways the biology of flight is influenced by these characteristics. Airflows are altered and modulated by motion over and around natural and human-engineered structures, and both vortical flow structures and turbulence are introduced to the aerial environment by technologies such as aircraft and wind farms. Diverse aspects of the biology of flight may be better understood with reference to an aeroecological approach, particularly the mechanics and energetics of flight, the sensing of aerial flows, and the motor control of flight. Moreover, not only does the abiotic world influence the aerospheric conditions in which animals fly, but flying animals also, in turn, change the flow environment in their immediate vicinity, which can include the air through which other animals fly, particularly when animals fly in groups. Flight biologists can offer considerable insight into the ecology of the aerial world, and an aeroecological approach holds great promise for stimulating and enriching the study of the biology of flight. PMID- 21669776 TI - Noctuid migration in Texas within the nocturnal aeroecological boundary layer. AB - Long-distance migration of adult corn earworm moths (Helicoverpa zea), and several other noctuid moth species, facilitates seasonal expansion of pest populations and consequent increased infestations of agricultural crops on a continental scale in North America. Long-term field studies of population dynamics and migratory flights of H. zea and fall armyworm (Spodoptera frugiperda) in the United States were evaluated using X-band radar observations and profiles of atmospheric conditions. These studies identified characteristic patterns of migratory flight that are largely associated with vertical profiles of temperature and wind speed. Collective patterns of moth migrations were generally highly correlated with wind headings, but often at a significant angular deviation. Preliminary analyses are presented between moth distributions in the aerosphere estimated from discrete moth counts using X-band radar and bulk reflectivity data from NEXRAD Doppler radar. Identification of associations between atmospheric factors and noctuid population dynamics and migratory flights will improve the ability to predict infestations by pest species throughout their broad seasonal range expansion. PMID- 21669777 TI - Brazilian free-tailed bats (Tadarida brasiliensis: Molossidae, Chiroptera) at high altitude: links to migratory insect populations. AB - Existing information on the activity of bats in the aerosphere is restricted almost exclusively to altitudes that are within a few tens of meters above the ground. We report a total of 50.2 h of ultrasonic recordings made using radio microphonic bat detectors suspended from free-floating helium balloons and from kites. The data include a total of 22 353 echolocative calls from ground-level to 1118 m above ground level (AGL). These calls are attributed to Brazilian free tailed bats based on acoustic features and the large numbers and high-altitude aerial dispersion of these bats over the local landscape. Bat activity varied significantly throughout the air column and was greatest at 400-500 m AGL and near ground level. Feeding buzzes, indicating feeding on aerial prey, were most abundant near ground level and at 400-500 m, and were detected to altitudes of ~ 900 m AGL. The peak activity of bats at 400-500 m AGL is concordant with the altitude of the atmospheric boundary layer and the seasonal formation of the low elevation southerly wind jet that has been identified as a major aeroecological corridor for the nocturnal dispersal of noctuid moths and other insects. PMID- 21669778 TI - Optimal strategies for insects migrating in the flight boundary layer: mechanisms and consequences. AB - Directed aerial displacement requires that a volant organism's airspeed exceeds ambient wind speed. For biologically relevant altitudes, wind speed increases exponentially with increased height above the ground. Thus, dispersal of most insects is influenced by atmospheric conditions. However, insects that fly close to the Earth's surface displace within the flight boundary layer where insect airspeeds are relatively high. Over the past 17 years, we have studied boundary layer insects by following individuals as they migrate across the Caribbean Sea and the Panama Canal. Although most migrants evade either drought or cold, nymphalid and pierid butterflies migrate across Panama near the onset of the rainy season. Dragonflies of the genus Pantala migrate in October concurrently with frontal weather systems. Migrating the furthest and thereby being the most difficult to study, the diurnal moth Urania fulgens migrates between Central and South America. Migratory butterflies and dragonflies are capable of directed movement towards a preferred compass direction in variable winds, whereas the moths drift with winds over water. Butterflies orient using both global and local cues. Consistent with optimal migration theory, butterflies and dragonflies adjust their flight speeds in ways that maximize migratory distance traveled per unit fuel, whereas the moths do not. Moreover, only butterflies adjust their flight speed in relation to endogenous fat reserves. It is likely that these insects use optic flow to gauge their speed and drift, and thus must migrate where sufficient detail in the Earth's surface is visible to them. The abilities of butterflies and dragonflies to adjust their airspeed over water indicate sophisticated control and guidance systems pertaining to migration. PMID- 21669779 TI - Wingbeat frequency and flap-pause ratio during natural migratory flight in thrushes. AB - Powered flapping flight has evolved independently in many different taxa. For flapping fliers, wingbeat parameters such as frequency and amplitude are the primary determinants of these animals' energetic expenditure during flight. Here we present data on wingbeat frequency and amplitude for three New World thrush species during 15 entire nocturnal migratory flights over the Midwestern United States. Using continuous (non-pulsing) radio transmitters, we were able to measure wingbeat frequency and relative amplitude of wingbeats as well as the characteristics of flap-pauses. Contrary to previous telemetric findings, all of the individuals we followed used both flapping-only and flap-pause flight. During migratory flights, wingbeat frequency, effective wingbeat frequency, and amplitude were highest during initial ascent. Effective wingbeat frequency and amplitude were lowest during final descent. We show that identification of species based solely on characteristics of the wingbeat e.g., during radar studies, can be difficult because variables such as wingbeat frequency and amplitude, wingbeat pausing, and pattern of beats and pauses vary between individuals of the same species and even within individual flights. We also show that observed wingbeat frequencies were lower than those predicted by theoretical models. We speculate that this may be because theoretical predictions are generally based on (1) data from larger birds and (2) data from diurnal flights. We found that diurnal wingbeat frequencies of thrushes were generally higher than were those during nocturnal migratory flight. Finally, we suggest that rather than remaining at a single altitude during flight or climbing slightly as theoretical models predict, thrushes often moved up and down in the air column, perhaps searching for favorable atmospheric conditions. PMID- 21669780 TI - Effect of a refuge from persistent male courtship in the Drosophila laboratory environment. AB - The Drosophila melanogaster laboratory model has been used extensively in studies of sexual conflict because during the process of courtship and mating, males impose several costs upon females (e.g., reduced fecundity). One important difference between the laboratory and the wild is that females in the laboratory lack a spatial refuge from persistent male courtship. Here, we describe two experiments that examine the potential consequences of a spatial refuge for females. In the first experiment, we examined the influence of a spatial refuge on mating rate of females, and in the second one we examined its influence on females' lifetime fecundity. We found that females mated about 25% less often when a spatial refuge was available, but that the absence of a spatial refuge did not substantially increase the level of male-induced harm to females (i.e., sexual conflict). PMID- 21669781 TI - Teaching evolution: challenging religious preconceptions. AB - Teaching college students about the nature of science should not be a controversial exercise. College students are expected to distinguish between astronomy and astrology, chemistry and alchemy, evolution and creationism. In practice, however, the conflict between creationism and the nature of science may create controversy in the classroom, even walkouts, when the subject of evolution is raised. The authors have grappled with the meaning of such behaviors. They surveyed 538 students in a public, liberal arts college. Pre/post course surveys were analyzed to track changes in student responses to questions that were either consistent or inconsistent with the Theory of Evolution after a semester of instruction in a college biology or zoology course in which evolution was taught. Many students who were initially undecided about issues regarding evolution had shifted in their viewpoints by the end of the course. It was found that more education about the evidence for and the mechanics of evolutionary processes did not necessarily move students toward a scientific viewpoint. The authors also discovered a "wedge" effect among students who were undecided about questions pertaining to human ancestry at the beginning of the course. About half of these students shifted to a scientific viewpoint at the end of the course; the other half shifted toward agreement with statements consistent with creationism. PMID- 21669782 TI - Trickle-down evolution: an approach to getting major evolutionary adaptive changes into textbooks and curricula. AB - Although contemporary high school and college textbooks of biology generally cover the principles and data of microevolution (genetic and populational change) and speciation rather well, coverage of what is known of the major changes in evolution (macroevolution), and how the evidence is understood is generally poor to nonexistent. It is critical to improve this because acceptance of evolution by the American public rests on the understanding of how we know what we know about the emergence of major new taxonomic groups, and about their adaptations, behaviors, and ecologies in geologic time. An efficient approach to this problem is to improve the illustrations in college textbooks to show the consilience of different lines of fossil, morphological, and molecular evidence mapped on phylogenies. Such "evograms" will markedly improve traditional illustrations of phylogenies, "menageries," and "companatomies." If "evograms" are installed at the college level, the basic principles and evidence of macroevolution will be more likely taught in K-12, thus providing an essential missing piece in biological education. PMID- 21669783 TI - Still creationism after all these years: understanding and counteracting intelligent design. AB - Despite denials by proponents of intelligent design (ID) that ID is creationism, critical analysis by scientists and scholars, as well as statements by the proponents of ID themselves, has established beyond any doubt ID's true identity as neo-creationism. Despite de-emphasizing elements of earlier creationism such as belief in a young earth and "flood geology," ID bears marks of its descent from "creation science" and is defined by its leading proponents in overtly religious, and specifically Christian, terms. These facts enabled the plaintiffs in the first ID legal case, Kitzmiller et al. v. Dover Area School District (2005), to win a decisive victory over the Dover, PA, school board, which had required that a pro-ID statement be read to biology students at Dover High School. Kitzmiller was also a defeat for ID proponents at the Discovery Institute's Center for Science and Culture (CSC). Yet, although the CSC continues efforts to undermine the teaching of evolution even in the wake of this defeat, their tactics are increasingly stale and transparent. Their current strategy, disguising pro-ID policy proposals with code language to avoid using the term "intelligent design," is yet another tactic used by earlier creationists after consistent legal defeats. Moreover, the ID movement's continued execution of their agenda has enabled ID critics to compile an ever-lengthening list of further congruencies between ID and creation science. Such powerful evidence of ID's identity as neo-creationism, combined with modest but promising demographic changes in the United States, suggest that increased public support for teaching evolution is possible through effective outreach to the relevant demographic groups. Scientists must take advantage of this opportunity to cultivate such support and to counteract ID by engaging in pro-science activism, making use of the many resources available to support their efforts. PMID- 21669784 TI - Thomism and science education: history informs a modern debate. AB - There is no debate over the Theory of Evolution. Among biologists the Theory of Evolution is a settled principle. Yet, the issue is far from settled in the larger context of society; between sectors of lay society and biological scientists in the United States there is evidence of a deep divide. Faith and reason, religion, and science at odds-that is hardly a recent divide. It is the premise of the author that the origin of the current conflict over the teaching of evolution stems from a fundamental philosophical divide that began long before Darwin first proposed his Theory of Evolution. It predates the inclusion of physical and biological sciences in the curriculum of western universities. It is older than either Islam or Christianity. The conflict goes back to Plato's Academy in 385 BC where the schools of Idealism and Realism first emerged as two distinct philosophical systems. Idealism and Realism diverged over essential issues of philosophy: What are we, what is true, and how do we know? Answers to these questions about the natural order are framed within philosophical constructs, themselves based upon essential assumptions about the essence of being, the essence of truth, and the nature of learning. Idealism and Realism developed independently for over 1500 years into two competing schools: the Augustinians (fundamentally Idealists) and the Latin Averroists (fundamentally Realists). It was over the place of natural philosophy in the curriculum that these two competing schools collided violently at the University of Paris in 1252. It was Thomas Aquinas who brokered a ceasefire between two embattled schools. Aquinas forged a philosophical system, called Thomism, that allowed the two schools to agree to disagree to the extent that in the graduate curriculum of the University Natural Philosophy could be taught apart from theology. This separation of secular or natural philosophy from theology opened the way for the development of the empirical sciences, the effects of which are evident today. All but forgotten, however, is that Thomism provided a system for resolving the disparities between these two separate ways of knowing, not by compartmentalizing them into separate domains, but by proving the domains to be philosophically complementary, creating a holistic framework in which to reconcile apparent conflicts between theology (religion) and natural philosophy (science). The essence of this historic compromise and its implications for the teaching of the Theory of Evolution form the core of this article. PMID- 21669785 TI - Teaching evolution (and all of biology) more effectively: Strategies for engagement, critical reasoning, and confronting misconceptions. AB - The strength of the evidence supporting evolution has increased markedly since the discovery of DNA but, paradoxically, public resistance to accepting evolution seems to have become stronger. A key dilemma is that science faculty have often continued to teach evolution ineffectively, even as the evidence that traditional ways of teaching are inferior has become stronger and stronger. Three pedagogical strategies that together can make a large difference in students' understanding and acceptance of evolution are extensive use of interactive engagement, a focus on critical thinking in science (especially on comparisons and explicit criteria) and using both of these in helping the students actively compare their initial conceptions (and publicly popular misconceptions) with more fully scientific conceptions. The conclusion that students' misconceptions must be dealt with systematically can be difficult for faculty who are teaching evolution since much of the students' resistance is framed in religious terms and one might be reluctant to address religious ideas in class. Applications to teaching evolution are illustrated with examples that address criteria and critical thinking, standard geology versus flood geology, evolutionary developmental biology versus organs of extreme perfection, and the importance of using humans as a central example. It is also helpful to bridge the false dichotomy, seen by many students, between atheistic evolution versus religious creationism. These applications are developed in detail and are intended to be sufficient to allow others to use these approaches in their teaching. Students and other faculty were quite supportive of these approaches as implemented in my classes. PMID- 21669786 TI - Curricular reform and inquiry teaching in biology: where are our efforts most fruitfully invested? AB - University faculty often express frustration with the accuracy of students' understanding of science in general and of evolution in particular. A rich research literature suggests that inquiry-based pedagogies are more effective in producing meaningful learning than are traditional, didactic approaches. A pragmatic investigation into the efficacy of inquiry-based curricular reforms compared to traditional laboratory activities was undertaken in the introductory biology course for majors at a large state university in the southeastern United States. The topics of the course focused on biodiversity, evolution, and plant and animal anatomy and physiology. Students' learning in the inquiry versus traditional units was compared using both a test of pre-post content knowledge as well as open-ended written responses in which students described events in which there was meaningful learning and conceptual changes. The pre-post tests were replicated over five semesters of the same course (n = 1493 students). Students' misconceptions as well as examples of meaningful learning were gathered for two semesters in the same course (n = 518 students). Results consistently revealed that descriptive, concrete topics such as anatomy can be taught effectively using traditional didactic methods; average effect sizes (a measure of the difference between pretest scores and posttest scores) range from 1.8 to 2.1. The inquiry units also increased knowledge of content on the topics of evolution and biodiversity by a significant degree (average effect sizes range from 1.0 to 1.1), despite the fact that students spent less than half the instructional time on these units compared to the didactic units. In addition, a literature review indicated that highly abstract or mathematical concepts such as evolution or geologic time require greater formal reasoning ability and that students often show lesser gains in these areas compared to more concrete topics. It was therefore especially notable that the frequency of meaningful learning events was significantly higher in the units on evolution compared to the traditional units (chi(2) P < 0.5 to 0.001). A catalog of students' misconceptions (some of which were quite unexpected) was also generated and found useful for future teaching. Therefore, we feel that when time and resources for curricular reform are limited, those efforts should prioritize abstract and foundational topics such as evolution. Didactic teaching appears sufficient for more concrete topics such as anatomy. PMID- 21669787 TI - Symposium introduction: electromyography interpretation and limitations in functional analyses of musculoskeletal systems. PMID- 21669788 TI - Congruence between muscle activity and kinematics in a convergently derived prey processing behavior. AB - Quantification of anatomical and physiological characteristics of the function of a musculoskeletal system may yield a detailed understanding of how the organizational levels of morphology, biomechanics, kinematics, and muscle activity patterns (MAPs) influence behavioral diversity. Using separate analyses of these organizational levels in representative study taxa, we sought patterns of congruence in how organizational levels drive behavioral modulation in a novel raking prey-processing behavior found in teleosts belonging to two evolutionarily distinct lineages. Biomechanically divergent prey (elusive, robust goldfish and sedentary, malleable earthworms) were fed to knifefish, Chitala ornata (Osteoglossomorpha) and brook trout, Salvelinus fontinalis (Salmoniformes). Electromyography recorded MAPs from the hyoid protractor, jaw adductor, sternohyoideus, epaxialis, and hypaxialis musculature, while sonomicrometry sampled deep basihyal kinesis and contractile length dynamics in the basihyal protractor and retractor muscles. Syntheses of our results with recent analyses of cranial morphology and raking kinematics showed that raking in Salvelinus relies on an elongated cranial out lever, extensive cranial elevation and a curved cleithrobranchial ligament (CBL), and that both raking MAPs and kinematics remain entirely unmodulated-a highly unusual trait, particularly among feeding generalists. Chitala had a shorter CBL and a raking power stroke involving increased retraction of the elongated pectoral girdle during raking on goldfish. The raking MAP was also modulated in Chitala, involving an extensive overlap between muscle activity of the preparatory and power stroke phases, driven by shifts in hypaxial timing and recruitment of the hyoid protractor muscle. Sonomicrometry revealed that the protractor hyoideus muscle stored energy from retraction of the pectoral girdle for ca. 5-20 ms after onset of the power stroke and then hyper-extended. This mechanism of elastic recoil in Chitala, which amplifies retraction of the basihyal during raking on goldfish without a significant increase in recruitment of the hypaxialis, suggests a unique mechanism of modulation based on performance-enhancing changes in the design and function of the musculoskeletal system. PMID- 21669789 TI - Electromyography and the evolution of motor control: limitations and insights. AB - Electromyography (EMG), or the study of muscle activation patterns, has long been used to infer central nervous system (CNS) control of the musculoskeletal system and the evolution of that control. As the activation of the muscles at the level of the periphery is a reflection of the interaction of descending influences and local reflex control, EMG is an important tool in integrated investigations of the evolution of coordination in complex, musculoskeletal systems. Yet, the use of EMG as a tool to understand the evolution of motor control has its limitations. We here review the potential limitations and opportunities of the use of EMG in studying the evolution of motor control in vertebrates and provide original previously unpublished data to illustrate this. The relative timing of activation of a set of muscles can be used to evaluate CNS coordination of the components in a musculoskeletal system. Studies of relative timing reveal task dependent variability in the recruitment of different populations of muscle fibers (i.e., different fiber types) within a single muscle, and left-right asymmetries in activation that need to be taken into account in comparative studies. The magnitude of muscle recruitment is strongly influenced by the instantaneous demands imposed on the system, and is likely determined by local reflex-control systems. Consequently, using EMG to make meaningful inferences about evolutionary changes in musculoskeletal control requires comparisons across similar functional tasks. Moreover, our data show that inferences about the evolution of motor control are limited in their explanatory power without proper insights into the kinematics and dynamics of a system. PMID- 21669790 TI - Evolution of asynchronous motor activity in paired muscles: effects of ecology, morphology, and phylogeny. AB - Many studies of feeding behavior have implanted electrodes unilaterally (in muscles on only one side of the head) to determine the basic motor patterns of muscles controlling the jaws. However, bilateral implantation has the potential to achieve a more comprehensive understanding of modification of the motor activity that may be occurring between the left and right sides of the head. In particular, complex processing of prey is often characterized by bilaterally asynchronous and even unilateral activation of the jaw musculature. In this study, we bilaterally implant feeding muscles in species from four orders of elasmobranchs (Squaliformes, Orectolobiformes, Carcharhiniformes, Rajoidea) in order to characterize the effects of type of prey, feeding behavior, and phylogeny on the degree of asynchronous muscle activation. Electrodes were implanted in three of the jaw adductors, two divisions of the quadratomandibularis and the preorbitalis, as well as in a cranial elevator in sharks, the epaxialis. The asynchrony of feeding events (measured as the degree to which activity of members of a muscle pair is out of phase) was compared across species for capture versus processing and simple versus complex prey, then interpreted in the contexts of phylogeny, morphology, and ecology to clarify determinants of asynchronous activity. Whereas capture and processing of prey were characterized by statistically similar degrees of asynchrony for data pooled across species, events involving complex prey were more asynchronous than were those involving simple prey. The two trophic generalists, Squalus acanthias and Leucoraja erinacea, modulated the degree of asynchrony according to type of prey, whereas the two behavioral specialists, Chiloscyllium plagiosum and Mustelus canis, activated the cranial muscles synchronously regardless of type of prey. These differences in jaw muscle activity would not have been detected with unilateral implantation. Therefore, we advocate bilateral implantation in studies of cranial muscle function in fishes, particularly when investigating behaviors associated with processing complex prey. Incorporating this methodology will provide a more detailed understanding of the coordination and evolution of paired muscle function in the feeding apparatus relative to behavioral and ecological performance. PMID- 21669791 TI - Variation in EMG activity: a hierarchical approach. AB - Recordings of naturally occurring Electromyographic (EMG) signals are variable. One of the first formal and successful attempts to quantify variation in EMG signals was Shaffer and Lauder's (1985) study examining several levels of variation but not within muscle. The goal of the current study was to quantify the variation that exists at different levels, using more detailed measures of EMG activity than did Shaffer and Lauder (1985). The importance of accounting for different levels of variation in an EMG study is both biological and statistical. Signal variation within the same muscle for a stereotyped action suggests that each recording represents a sample drawn from a pool of a large number of motor units that, while biologically functioning in an integrated fashion, showed statistical variation. Different levels of variation for different muscles could be related to different functions or different tasks of those muscles. The statistical impact of unaccounted or inappropriately analyzed variation can lead to false rejection (type I error) or false acceptance (type II error) of the null hypothesis. Type II errors occur because such variation will accrue to the error, reducing power, and producing an artificially low F-value. Type I errors are associated with pseudoreplication, in which the replicated units are not truly independent, thereby leading to inflated degrees of freedom, and an underestimate of the error mean square. To address these problems, we used a repeated measures, nested multifactor model to measure the relative contribution of different hierarchical levels of variation to the total variation in EMG signals during swallowing. We found that variation at all levels, among electrodes in the same muscle, in sequences of the same animal, and among individuals and between differently named muscles, was significant. These findings suggest that a single intramuscular electrode, recording from a limited sample of the motor units, cannot be relied upon to characterize the activity of an entire muscle. Furthermore, the use of both a repeated-measures model, to avoid pseudoreplication, and a nested model, to account for variation, is critical for a correct testing of biological hypotheses about differences in EMG signals. PMID- 21669792 TI - Patterns of variation across primates in jaw-muscle electromyography during mastication. AB - Biologists that study mammals continue to discuss the evolution of and functional variation in jaw-muscle activity during chewing. A major barrier to addressing these issues is collecting sufficient in vivo data to adequately capture neuromuscular variation in a clade. We combine data on jaw-muscle electromyography (EMG) collected during mastication from 14 species of primates and one of treeshrews to assess patterns of neuromuscular variation in primates. All data were collected and analyzed using the same methods. We examine the variance components for EMG parameters using a nested ANOVA design across successive hierarchical factors from chewing cycle through species for eight locations in the masseter and temporalis muscles. Variation in jaw-muscle EMGs was not distributed equally across hierarchical levels. The timing of peak EMG activity showed the largest variance components among chewing cycles. Relative levels of recruitment of jaw muscles showed the largest variance components among chewing sequences and cycles. We attribute variation among chewing cycles to (1) changes in food properties throughout the chewing sequence, (2) variation in bite location, and (3) the multiple ways jaw muscles can produce submaximal bite forces. We hypothesize that variation among chewing sequences is primarily related to variation in properties of food. The significant proportion of variation in EMGs potentially linked to food properties suggests that experimental biologists must pay close attention to foods given to research subjects in laboratory-based studies of feeding. The jaw muscles exhibit markedly different variance components among species suggesting that primate jaw muscles have evolved as distinct functional units. The balancing-side deep masseter (BDM) exhibits the most variation among species. This observation supports previous hypotheses linking variation in the timing and activation of the BDM to symphyseal fusion in anthropoid primates and in strepsirrhines with robust symphyses. The working-side anterior temporalis shows a contrasting pattern with little variation in timing and relative activation across primates. The consistent recruitment of this muscle suggests that primates have maintained their ability to produce vertical jaw movements and force in contrast to the evolutionary changes in transverse occlusal forces driven by the varying patterns of activation in the BDM. PMID- 21669793 TI - Interpreting muscle function from EMG: lessons learned from direct measurements of muscle force. AB - Electromyography is often used to infer the pattern of production of force by skeletal muscles. The interpretation of muscle function from the electromyogram (EMG) is challenged by the fact that factors such as type of muscle fiber, muscle length, and muscle velocity can all influence the relationship between electrical and mechanical activity of a muscle. Simultaneous measurements of EMG, muscle force, and fascicle length in hindlimb muscles of wild turkeys allow us to probe the quantitative link between force and EMG. We examined two features of the force-EMG relationship. First, we measured the relaxation electromechanical delay (r-EMD) as the time from the end of the EMG signal to time of the end of force. This delay varied with locomotor speed in the lateral gastrocnemius (LG); it was longer at slow walking speeds than for running. This variation in r-EMD was not explained by differences in muscle length trajectory, as the magnitude of r-EMD was not correlated with the velocity of shortening of the muscle during relaxation. We speculate that the longer relaxation times at slow walking speeds compared with running may reflect the longer time course of relaxation in slower muscles fibers. We also examined the relationship between magnitude of force and EMG across a range of walking and running speeds. We analyzed the force-EMG relationship during the swing phase separately from the force-EMG relationship during stance phase. During stance, force amplitude (average force) was linearly related to mean EMG amplitude (average EMG). Forces during swing phase were lower than predicted from the stance phase force-EMG relationship. The different force EMG relationships during the stance and swing phases may reflect the contribution of passive structures to the development of force, or a nonlinear force-EMG relationship at low levels of muscle activity. Together the results suggest that any inference of force from EMG must be done cautiously when a broad range of activities is considered. PMID- 21669794 TI - Building a better organismal model: The role of the mouse--Introduction to the symposium. PMID- 21669795 TI - Of "mice" and mammals: utilizing classical inbred mice to study the genetic architecture of function and performance in mammals. AB - The house mouse is one of the most successful mammals and the premier research animal in mammalian biology. The classical inbred strains of house mice have been artificially modified to facilitate identification of the genetic factors underlying phenotypic variation among these strains. Despite their widespread use in basic and biomedical research, functional and evolutionary morphologists have not taken full advantage of inbred mice as a model for studying the genetic architecture of form, function, and performance in mammals. We illustrate the potential of inbred mice as a model for mammalian functional morphology by examining the genetic architecture of maximum jaw-opening performance, or maximum gape, across 21 classical inbred strains. We find that variation in maximum gape among these strains is heritable, providing the first evidence of a genetic contribution to maximum jaw-opening performance in mammals. Maximum gape exhibits a significant genetic correlation with body size across strains, raising the possibility that evolutionary increases in size frequently resulted in correlated increases in maximum gape (within the constraints of existing craniofacial form) during mammalian evolution. Several craniofacial features that influence maximum gape share significant phenotypic and genetic correlations with jaw-opening ability across these inbred strains. The significant genetic correlations indicate the potential for coordinated evolution of craniofacial form and jaw opening performance, as hypothesized in several comparative analyses of mammals linking skull form to variation in jaw-opening ability. Functional studies of mammalian locomotion and feeding have only rarely examined the genetic basis of functional and performance traits. The classical inbred strains of house mice offer a powerful tool for exploring this genetic architecture and furthering our understanding of how form, function, and performance have evolved in mammals. PMID- 21669796 TI - Enlargement of the temporalis muscle and alterations in the lateral cranial vault. AB - The purpose of this study was to test the hypothesis that increased masticatory muscle accompanied morphologic changes in the temporal bone and squamosal suture. Ten mice deficient for the protein myostatin (Mstn -/-) had significantly increased skeletal muscle mass and were compared with nine controls (Mstn +/+). Variables measured include linear and areal metrics describing temporal size and temporal bone shape as well as the extent of the area of the squamosal suture that overlaps, or bevels, with parietal bones. Mstn-/- mice showed significantly larger temporalis muscles. Their temporal bones showed significantly decreased size as well as decreased beveling of the squamosal suture. These decreases were absolute as well as relative and were not restricted to either vertical or horizontal axes. The increased masticatory musculature of Myostatin-null mice had a shrinking effect on the temporal aspect of the cranium. These results are inconsistent with the interpretation that increased temporalis mass induces morphologic changes in temporal bone that compensate for putative increases in compressive forces transduced at this region. Rather than increase in the area of overlap between two calvarial bones, potential increase in biomechanical loading along the temporal squama led to a smaller bevel which would presumably weaken this joint. It is unclear why this is so. Either compressive forces are not anabolic to suture beveling or they do upregulate growth of the suture bevel, with compression not being the primary loading regime at this suture. PMID- 21669797 TI - Using "Mighty Mouse" to understand masticatory plasticity: myostatin-deficient mice and musculoskeletal function. AB - Knockout mice lacking myostatin (Mstn), a negative regulator of the growth of skeletal muscle, develop significant increases in the relative mass of masticatory muscles as well as the ability to generate higher maximal muscle forces. Wild-type and Mstn-deficient mice were compared to investigate the postnatal influence of elevated masticatory loads due to increased jaw-adductor and bite forces on the biomineralization of mandibular articular and cortical bone, the internal structure of the jaw joints, and the composition of temporomandibular joint (TMJ) articular cartilage. To provide an interspecific perspective on the long-term responses of mammalian jaw joints to altered loading conditions, the findings on mice were compared to similar data for growing rabbits subjected to long-term dietary manipulation. Statistically significant differences in joint proportions and bone mineral density between normal and Mstn deficient mice, which are similar to those observed between rabbit loading cohorts, underscore the need for a comprehensive analysis of masticatory tissue plasticity vis-a-vis altered mechanical loads, one in which variation in external and internal structure are considered. Differences in the expression of proteoglycans and type-II collagen in TMJ articular cartilage between the mouse and rabbit comparisons suggest that the duration and magnitude of the loading stimulus will significantly affect patterns of adaptive and degradative responses. These data on mammals subjected to long-term loading conditions offer novel insights regarding variation in ontogeny, life history, and the ecomorphology of the feeding apparatus. PMID- 21669798 TI - A novel transgenic mouse model of fetal encephalization and craniofacial development. AB - There are surprisingly few experimental models of neural growth and cranial integration. This, and the dearth of information regarding fetal brain development, detracts from a mechanistic understanding of cranial integration and its relevance to the ontogenetic and interspecific patterning of the form of the skull. To address this shortcoming, our research uses transgenic mice expressing a stabilized form of beta-catenin to isolate the effects of encephalization on the development of the basi- and neuro-cranium. These mice develop highly enlarged brains due to an increase in neural precursor cells, and differences between transgenic and wild-type mice are predicted to result solely from variation in relative brain size. By focusing on prenatal growth, this project adds to our understanding of a critically important period when major structural and functional interrelationships are established in the skull. Comparisons of wild-type and transgenic mice were performed using microcomputed tomography (microCT) and magnetic resonance imaging (MRI). These analyses show that the larger brains of the transgenic mice are associated with a larger neurocranium and an altered basicranial morphology. However, body size and postcranial ossification do not seem to be affected by the transgene. Comparisons of the rate of postcranial and cranial ossification also point to an unexpected effect of neural growth on skull development: increased fetal encephalization may result in a compensatory decrease in the level of cranial ossification. Therefore, if other life-history factors are held constant, the ontogeny of a metabolically costly structure, such as a brain, may occur at the expense of other cranial structures. These analyses indicate the benefits of a multifactorial approach to cranial integration using a mouse model. PMID- 21669799 TI - Mouse models and the evolutionary developmental biology of the skull. AB - Understanding development is relevant to understanding evolution because developmental processes structure the expression of phenotypic variation upon which natural selection acts. Advances in developmental biology are fueling a new synthesis of developmental and evolutionary biology, but it remains unclear how to use developmental information that largely derives from a few model organisms to test hypotheses about the evolutionary developmental biology of taxa such as humans and other primates that have not been or are not amenable to direct study through experimental developmental biology. In this article, we discuss how and when model organisms like mice are useful for studying the evolutionary developmental biology of even rather distantly related and morphologically different groups like primates. A productive approach is to focus on processes that are likely to play key roles in producing evolutionarily significant phenotypic variation across a large phylogenetic range. We illustrate this approach by applying the analysis of craniofacial variation in mouse mutant models to primate and human evolution. PMID- 21669800 TI - Do different locomotor modes during growth modulate trabecular architecture in the murine hind limb? AB - Vertebrate morphologists often implicate functional adaptations of bone to mechanical milieus when comparing animals with distinct behavioral repertoires. Functional morphologists frequently use comparative osteology and locomotor behavior to construct correlative form-function relationships. While some experimental work has investigated functional adaptations of bone elicited by specific locomotor behaviors, these studies usually manipulate repertoires by introducing artificial situations (e.g., treadmills) or creating differences in the level of activity (i.e., exercise), either of which can compromise extrapolations to free-ranging animals. Here, we present trabecular bone morphology and microarchitecture from an inbred mouse model in which components of naturalistic locomotor repertoires were accentuated. Using inbred mice, we control for genetic variability, further isolating the osteogenic responses to these behaviors. Single female (BALB/cByJ) mice (n = 10 per group) were housed for 8 weeks beginning at 30 days postbirth in custom-designed cages that accentuated either linear quadrupedalism or turning. Concurrently, mice in a control group were housed singly in open cages. The distal femoral metaphysis was scanned by micro-computed tomography at the end of the 8-week experiment protocol. The experimental groups, particularly the "linear" group, differed significantly from the control group (simulated "free-ranging" condition) in several variables: bone volume fraction ("linear" 42% less than controls; "turning" 24% less than controls), trabecular number ("linear" 12% less than controls; "turning" 9% less than controls), connectivity density ("linear" 43% less than controls; "turning" 35% less than controls), and a characterization of trabecular surfaces ("linear" 15% greater than controls; "turning" 11% greater than controls). No differences in the degree of anisotropy were observed among groups, and generally, "linear" and "turning" groups did not differ significantly from one another in any measures of trabecular microarchitecture. Considering the distinct differences in locomotor behaviors between the "linear" quadrupedalism and "turning" groups, these data suggest that comparisons at the distal femoral metaphysis of trabecular microarchitecture or orientation between different groups of animals may be somewhat limited in accurately reconstructing the loading conditions associated with different locomotor modes. PMID- 21669801 TI - Selective breeding as a tool to probe skeletal response to high voluntary locomotor activity in mice. AB - We present a novel mouse-model for the study of skeletal structure and evolution, based on selective breeding for high levels of voluntary wheel running. Whereas traditional models (originally inbred strains, more recently knockouts and transgenics) rely on the study of mutant or laboratory-manipulated phenotypes, we have studied changes in skeletal morphometrics resulting from many generations of artificial selection for high activity in the form of wheel running, in which mice engage voluntarily. Mice from the four replicate High Runner (HR) lines run nearly three times as many revolutions during days 5 and 6 of a 6-day exposure to wheels (1.12 m circumference). We have found significant changes in skeletal dimensions of the hind limbs, including decreased directional asymmetry, larger femoral heads, and wider distal femora. The latter two have been hypothesized as evolutionary adaptations for long-distance locomotion in hominids. Exercise training studies involving experimental groups with and without access to wheels have shown increased diameters of both femora and tibiafibulae, and suggest genetic effects on trainability (genotype-by-environment interactions). Reanalysis of previously published data on bone masses of hind limbs revealed novel patterns of change in bone mass associated with access to wheels for 2 months. Without access to wheels, HR mice have significantly heavier tibiafibulae and foot bones, whereas with chronic access to wheels, a significant increase in foot bone mass that was linearly related to increases in daily wheel running was observed. Mice exhibiting a recently discovered small-muscle phenotype ("mini muscle," [MM] caused by a Mendelian recessive gene), in which the mass of the triceps surae muscle complex is ~50% lower than in normal individuals, have significantly longer and thinner bones in the hind limb. We present new data for the ontogenetic development of muscle mass in Control, HR, and MM phenotypes in mice of 1-7 weeks postnatal age. Statistical comparisons reveal highly significant differences both in triceps surae mass and mass-corrected triceps surae mass between normal and MM mice at all but the postnatal age of 1 week. Based on previously observed differences in distributions of myosin isoforms in adult MM mice, we hypothesize that a reduction of myosin heavy-chain type-IIb isoforms with accounts for our observed ontogenetic changes in muscle mass. PMID- 21669802 TI - Toward a dynamic model of deposition and utilization of yolk steroids. AB - The discovery by Schwabl that maternal steroid hormones are transferred to the egg yolk and have effects on the phenotype of offspring revealed a new pathway for non-genetic maternal effects. The initial model relied on passive transfer. The thinking was that steroids passively entered the lipophillic yolk during yolk deposition and then were deposited in the yolk until they were passively delivered to the embryo as the yolk was used. Subsequent studies revealed that the system is much more dynamic than that. Here, we explore questions about how dynamic the system really is and look at questions like: Is transfer of maternal steroids to the yolk passive or is it actively regulated? At what stages of the maternal reproductive cycle are steroids transferred? During reproduction, how dynamic are the levels of yolk steroids? Especially in the case of potentially deleterious steroids (e.g., androgens in female offspring; glucocorticoids), once deposited can they come out of the yolk over time? Can they be metabolized by the yolk or by the embryo? During incubation, how much do steroid levels in the yolk change? Can steroids diffuse from the yolk to the embryo prior to yolk utilization? Does the embryo contribute to yolk steroid levels as it develops? We believe that comprehensive answers to questions like these will eventually allow us to generate a much more accurate and complete model of the transfer and utilization of yolk steroids and that this model will be much more dynamic and active than the one initially proposed. PMID- 21669803 TI - A proposed role of the sulfotransferase/sulfatase pathway in modulating yolk steroid effects. AB - Steroid hormones have long been studied by behavioral ecologists as a nongenetic means whereby females can influence the development of their offspring. In oviparous vertebrates, steroids are present in the yolk at the time of oviposition and have been shown to affect numerous traits of the offspring. To date, most studies have focused on the functional relationship between yolk steroids and offspring development. In this article we used a mechanistic approach to investigate the effects of yolk steroids in an attempt to decipher how lipophilic steroids may make it from the lipid-rich yolk to the developing embryo. First, we examined the distribution of radioactive and nonradioactive estradiol following the exogenous application of each to developing eggs of the red-eared slider. Second, we quantified sulfotransferase activity in various components of the egg as a potential mechanism for the metabolism of steroids. Results indicate that exogenous estradiol is converted to a water-soluble form during the first 15 days of development, concurrent with an increase of sulfotransferase activity in the yolk and extra-embryonic membranes. Based on these data, we propose a mechanistic model based upon the sulfotransferase/sulfatase pathway as a means through which developing eggs can convert steroids to a water-soluble form that can be transported to the embryo. These sulfonated steroids may then serve as precursors for subsequent steroid production via sulfatase activity. This model utilizes a mechanism known to be important for the modulation of maternal steroid signals in placental mammals, at the same time addressing several previously unanswered questions regarding the mechanisms underlying the effects of yolk steroids. PMID- 21669804 TI - The effects of diet on plasma and yolk steroids in lizards (Anolis carolinensis). AB - Steroids present in egg yolk have been shown to vary as a result of numerous social and environmental influences and to produce both positive and negative phenotypic outcomes in offspring. In the present study, we examined how quality of the diet affects plasma and yolk steroids in the green anole (Anolis carolinensis), a lizard species with genotypic sex determination. We documented the effects of body condition on plasma testosterone (T) and corticosterone (CORT)-steroids with frequently opposing effects-in breeding females and on the T and CORT content of their eggs. We chose to manipulate body condition via diet because resource availability is a relevant, fluctuating variable in the environment to which females can be expected to respond. Field-collected females were housed in the laboratory and kept on either a reduced, standard, or enhanced diet (differing in nutritional quality and/or quantity) for ten weeks. Although females did not differ in body condition at the beginning of the study, we found these diet regimes effective in producing females that differed in condition by the end of the study. Females on diets of enhanced quality were in better condition, produced more, but not heavier, eggs, and had higher plasma T concentrations than did females on a standard diet or one of reduced quality. There was also a significant positive relationship between laying sequence of eggs and yolk T for females on diets of enhanced quality, but not for the females on diets of standard or reduced quality. There were no effects of quality of diet on CORT in plasma or yolk, but yolk T and yolk CORT exhibited a strong positive correlation irrespective of treatment. Females on diets of reduced quality did not differ from females on standard diets either with respect to reproductive output or to endocrine profiles, in spite of being in worse body condition. These results demonstrate that females' body condition, physiology, and reproductive output can be manipulated by quality of diet, and that changes in deposition of yolk steroids in response to diet may be minimal. PMID- 21669806 TI - Turtle isochore structure is intermediate between amphibians and other amniotes. AB - Vertebrate genomes are comprised of isochores that are relatively long (>100 kb) regions with a relatively homogenous (either GC-rich or AT-rich) base composition and with rather sharp boundaries with neighboring isochores. Mammals and living archosaurs (birds and crocodilians) have heterogeneous genomes that include very GC-rich isochores. In sharp contrast, the genomes of amphibians and fishes are more homogeneous and they have a lower overall GC content. Because DNA with higher GC content is more thermostable, the elevated GC content of mammalian and archosaurian DNA has been hypothesized to be an adaptation to higher body temperatures. This hypothesis can be tested by examining structure of isochores across the reptilian clade, which includes the archosaurs, testudines (turtles), and lepidosaurs (lizards and snakes), because reptiles exhibit diverse body sizes, metabolic rates, and patterns of thermoregulation. This study focuses on a comparative analysis of a new set of expressed genes of the red-eared slider turtle and orthologs of the turtle genes in mammalian (human, mouse, dog, and opossum), archosaurian (chicken and alligator), and amphibian (western clawed frog) genomes. EST (expressed sequence tag) data from a turtle cDNA library enriched for genes that have specialized functions (developmental genes) revealed using the GC content of the third-codon-position to examine isochore structure requires careful consideration of the types of genes examined. The more highly expressed genes (e.g., housekeeping genes) are more likely to be GC-rich than are genes with specialized functions. However, the set of highly expressed turtle genes demonstrated that the turtle genome has a GC content that is intermediate between the GC-poor amphibians and the GC-rich mammals and archosaurs. There was a strong correlation between the GC content of all turtle genes and the GC content of other vertebrate genes, with the slope of the line describing this relationship also indicating that the isochore structure of turtles is intermediate between that of amphibians and other amniotes. These data are consistent with some thermal hypotheses of isochore evolution, but we believe that the credible set of models for isochore evolution still includes a variety of models. These data expand the amount of genomic data available from reptiles upon which future studies of reptilian genomics can build. PMID- 21669805 TI - New resources inform study of genome size, content, and organization in nonavian reptiles. AB - Genomic resources for studies of nonavian reptiles have recently improved and will reach a new level of access once the genomes of the painted turtle (Chrysemys picta) and the green anole (Anolis carolinensis) have been published. Eleven speakers gathered for a symposium on reptilian genomics and evolutionary genetics at the 2008 meeting of the Society for Integrative and Comparative Biology in San Antonio, Texas. Presentations described results of reptilian genetic studies concerning molecular evolution, chromosomal evolution, genomic architecture, population dynamics, endocrinology and endocrine disruption, and the evolution of developmental mechanisms. The presented studies took advantage of the recent generation of genetic and genomic tools and resources. Novel findings demonstrated the positive impact made by the improved availability of resources like genome annotations and bacterial artificial chromosomes (BACs). The symposium was timely and important because it provided a vehicle for the dissemination of novel findings that advance the field. Moreover, this meeting fostered the synergistic interaction of the participants as a group, which is anticipated to encourage the funding and creation of further resources such as additional BAC libraries and genomic projects. Novel data have already been collected and studies like those presented in this symposium promise to shape and improve our understanding of overall amniote evolution. Additional reptilian taxa such as the American alligator (Alligator mississippiensis), tuatara (Sphenodon punctatus), and garter snake (Thamnophis sirtalis) should be the foci of future genomic projects. We hope that the following articles in this volume will help promote these efforts by describing the conclusions and the potential that the improvement of genomic resources for nonavian reptiles can continue having in this important area of integrative and comparative biology. PMID- 21669807 TI - Evolutionary relationships among copies of feather beta ({beta}) keratin genes from several avian orders. AB - The feather beta (beta) keratins of the white leghorn chicken (order Galliformes, Gallus gallus domesticus) are the products of a multigene family that includes claw, feather, feather-like, and scale genes (Presland et al. 1989a). Here we characterize the feather beta-keratin genes in additional bird species. We designed primers for polymerase chain reactions (PCR) using sequences available from chicken, cloned the resulting amplicons to isolate individual copies, and sequenced multiple clones from each PCR reaction for which we obtained amplicons of the expected size. Feather beta-keratins of 18 species from eight avian orders demonstrate DNA sequence variation within and among taxa, even in the protein coding regions of the genes. Phylogenies of these data suggest that Galliformes (fowl-like birds), Psittaciformes (parrots), and possibly Falconiformes (birds of prey) existed as separate lineages before duplication of the feather beta-keratin gene began in Ciconiiformes (herons, storks, and allies), Gruiformes (cranes, rails, and allies), and Piciformes (woodpeckers and allies). Sequences from single species of Coraciiformes (kingfishers) and Columbiformes (pigeons) are monophyletic and strikingly divergent, suggesting feather beta-keratin genes in these birds also diverged after these species last shared a common ancestor with the other taxa investigated. Overall, these data demonstrate considerable variation in this structural protein in the relatively recent history of birds, and raise questions concerning the origin and homology of claw, feather-like, and scale beta-keratins of birds and the reptilian beta-keratins. PMID- 21669808 TI - Evolution of the gene network underlying gonadogenesis in turtles with temperature-dependent and genotypic sex determination. AB - The evolution of sex determination has long fascinated biologists, as it has paramount consequences for the evolution of a multitude of traits, from sex allocation to speciation and extinction. Explaining the diversity of sex determining systems found in vertebrates (genotypic or GSD and temperature dependent or TSD) requires a comprehensive and integrative examination from both a functional and an evolutionary perspective. Particularly revealing is the examination of the gene network that regulates gonadogenesis. Here, I review some advances in this field and propose some additional hypotheses about the composition of the gene network underlying sexual development, the functional links among some of its elements and their evolution in turtles. I focus on several pending questions about: (1) What renders TSD systems thermo-sensitive? (2) Is there one developmentally conserved or multiple TSD mechanisms? (3) Have evolutionarily derived GSD species lost all ancestral thermal-sensitivity? New data are presented on embryonic expression of Dax1 (the dosage-sensitive sex reversal adrenal hypoplasia congenital on the X chromosome gene in the turtles Chrysemys picta (TSD) and Apalone mutica (GSD). No differential Dax1 expression was detected in C. picta at any of the stages examined, consistent with reports on two other TSD turtles and alligators. Notably, significantly higher Dax1 expression was found at 30 degrees C than at 25 degrees C at stage 15 in A. mutica (GSD), likely caused by Wt1's identical expression pattern previously reported. Because Sf1 is an immediate downstream target of Dax1 and its expression is not affected by temperature, it is proposed that Sf1 renders Dax1's differential signal ineffective to induce biased sex ratios in A. mutica, as previously proposed for Wt1's thermosensitive expression. Thus, it is hypothesized that Sf1 plays a major role in the lack of response of sex ratio to temperature of A. mutica, and may function as a sex-determining gene in this GSD species. These and previous data permit formulating several mechanistic hypotheses: (1) the postulation of Wt1 as a candidate thermal master switch alone, or in combination with Sf1, in the TSD turtle C. picta; (2) the proposition of Sf1 as a sex-determining gene in the GSD turtle A. mutica; and (3) the hypothesis that differing patterns of gene expression among TSD taxa reflect multiple traits from a developmental perspective. Moreover, the recent finding of relic differential Wt1 expression in A. mutica and the results for Dax1 in this species provide empirical evidence that GSD taxa can harbor thermal sensitivity at the level of gene expression, potentially co-optable during TSD evolution. PMID- 21669809 TI - Trends in the evolution of reptilian chromosomes. AB - Reptiles are a karyologically heterogeneous group, where some orders and suborders exhibit characteristics similar to those of anamniotes and others share similarities with homeotherms. The class also shows different evolutionary trends, for instance in genome and chromosome size and composition. The turtle DNA base composition is similar to that of mammals, whereas that of lizards and snakes is more similar to that of anamniotes. The major karyological differences between turtles and squamates are the size and composition of the genome and the rate at which chromosomes change. Turtles have larger and more variable genome sizes, and a greater amount of middle repetitive DNA that differs even among related species. In lizards and snakes size of the genome are smaller, single copy DNA is constant within each suborder, and differences in repetitive DNA involve fractions that become increasingly heterogeneous with widening phylogenetic distance. With regard to variation in karyotype morphology, turtles and crocodiles show low variability in chromosome number, morphology, and G banding pattern. Greater variability is found among squamates, which have a similar degree of karyotypic change-as do some mammals, such as carnivores and bats-and in which there are also differences among congeneric species. An interesting relationship has been highlighted in the entire class Reptilia between rates of change in chromosomes, number of living species, and rate of extinction. However, different situations obtain in turtles and crocodiles on the one hand, and squamates on the other. In the former, the rate of change in chromosomes is lower and the various evolutionary steps do not seem to have entailed marked chromosomal variation, whereas squamates have a higher rate of change in chromosomes clearly related to the number of living species, and chromosomal variation seems to have played an important role in the evolution of several taxa. The different evolutionary trends in chromosomes observed between turtles and crocodiles on the one hand and squamates on the other might depend on their different patterns of G-banding. PMID- 21669811 TI - Characterization, chromosomal location, and genomic neighborhood of a ratite ortholog of a gene with gonadal expression in mammals. AB - A locus that we name SubA was discovered during large-scale sequencing and characterization of a bacterial artificial chromosome library from an emu, Dromaius novaehollandiae. This locus yields a significantly negative Tajima's D in emus and is conserved across emu, chicken, mouse, and human. Expression of SubA orthologs has been reported in human ovaries and in mouse testes, but remains unknown in emus. The locus was physically mapped onto a pair of microchromosomes in emus by fluorescent in situ hybridization and also in chicken as previously reported. By characterizing emu SubA in this article, we aim to improve current descriptions of the cascade of genes associated with avian sex differentiation. Future experimentation will report the expression of SubA in ratites, other birds, and nonavian reptiles. PMID- 21669810 TI - Three tiers of genome evolution in reptiles. AB - Characterization of reptilian genomes is essential for understanding the overall diversity and evolution of amniote genomes, because reptiles, which include birds, constitute a major fraction of the amniote evolutionary tree. To better understand the evolution and diversity of genomic characteristics in Reptilia, we conducted comparative analyses of online sequence data from Alligator mississippiensis (alligator) and Sphenodon punctatus (tuatara) as well as genome size and karyological data from a wide range of reptilian species. At the whole genome and chromosomal tiers of organization, we find that reptilian genome size distribution is consistent with a model of continuous gradual evolution while genomic compartmentalization, as manifested in the number of microchromosomes and macrochromosomes, appears to have undergone early rapid change. At the sequence level, the third genomic tier, we find that exon size in Alligator is distributed in a pattern matching that of exons in Gallus (chicken), especially in the 101 200 bp size class. A small spike in the fraction of exons in the 301 bp-1 kb size class is also observed for Alligator, but more so for Sphenodon. For introns, we find that members of Reptilia have a larger fraction of introns within the 101 bp 2 kb size class and a lower fraction of introns within the 5-30 kb size class than do mammals. These findings suggest that the mode of reptilian genome evolution varies across three hierarchical levels of the genome, a pattern consistent with a mosaic model of genomic evolution. PMID- 21669813 TI - Exploiting genomic resources in studies of speciation and adaptive radiation of lizards in the genus Anolis. AB - Lizards in the genus Anolis have radiated extensively within and among islands in the Caribbean. Here, I provide a prospectus for identifying genes underlying adaptive phenotypic traits in anoles. First I review patterns of diversification in Anolis and the important morphological axes along which divergence occurs. Then I discuss two features of anole diversification, the repeated, convergent evolution of ecomorphs, and phenotypic divergence among populations within species, that provide opportunities to identify genes underlying adaptive phenotypic variation. While small clutch size and difficulty with captive rearing currently limit the utility of quantitative trait locus analyses, comparative analyses of gene expression, and population genomic approaches are promising. PMID- 21669812 TI - Evolution of sex chromosomes in Sauropsida. AB - Reptiles (sauropsids) represent the sister group to mammals, and the basal members of Reptilia may provide a good model for the condition of the common ancestor of both groups. Sex-determining mechanisms (SDM) and organizations of sex chromosomes among genotypically sex-determining (GSD) species vary widely across reptiles. Birds and snakes, for example, are entirely GSD whereas other reptiles, like all crocodilians, exhibit temperature-dependent sex determination (TSD). Here we explore the evolution of sex chromosomes and SDM within reptiles, using family-level analyses of character evolution and applying parsimony, likelihood, Bayesian, and stochastic methods. We find support for the common ancestor of amphisbaenians and whiptail lizards (Laterata) possessing the XY (male heterogametic) GSD mechanism, while the ancestors of Testudines and Crocodylia, as well as the larger group Archosauromorpha (here containing turtles) are inferred to have exhibited TSD. We also find evidence consistent with the hypothesis that the XY system is more labile and evolves faster than does the ZW (female heterogametic) system. Phylogenetic-based speciation tests do not support an association between GSD and speciation, and reject the hypothesis that the presence of the XY system is associated with speciation in reptiles. PMID- 21669815 TI - Advances in neurobiology: an introduction. PMID- 21669814 TI - Novel approaches for the study of vertebrate steroid hormone receptors. AB - Steroid hormones are essential for the normal function of most organ systems in vertebrates. Reproductive activities in females and males, such as the differentiation, growth and maintenance of the reproductive system, require signaling by sex steroid hormones. Although extensively studied in mammals and a few fish and bird species, the evolution and molecular mechanisms associated with the nuclear steroid hormone receptors are still poorly understood in amphibians and reptiles. Given our interest in environmental signaling of sex determination as well as a major interest in environmental contaminants that can mimic steroid hormone signaling, we have established an approach to study the molecular function (ligand binding and trans-activation) of steroid hormone receptors cloned from reptiles. This approach involves molecular cloning and sequencing of steroid hormone receptors, phylogenic analysis and in vitro trans-activation assays using endogenous or exogenous ligands. Comparing the in vitro trans activation induced by different ligands with receptors cloned from different species would develop additional functional relationships (classification) among steroid hormone receptors. This approach can provide insight into understanding why each species could have different responses to exogenous ligands. Further, we have developed a novel and less invasive approach to obtaining mRNA for molecular cloning and sequencing of steroid hormone receptors in reptiles and other non mammalian species, using blood cells as a source of genetic material. For example, white blood cells (WBCs) and red blood cells (RBCs) of the American alligator both express steroid hormone receptors and have adequate amounts of mRNA for molecular cloning. This approach would allow us to analyze components of endocrine function of steroid hormones without sacrificing animals. Especially in endangered species, this approach could provide an understanding of endocrine functions, elucidate the phylogenic relationships of various receptors in vitro, such as the steroid hormone receptors, and determine possible effects of environmental contaminants in a minimally invasive manner. PMID- 21669816 TI - Emerging methodologies for the study of hypothalamic gonadotropin-releasing hormone (GnRH) neurons. AB - Gonadotropin-releasing-hormone (GnRH) neurons form part of a central neural oscillator that controls sexual reproduction through intermittent release of the GnRH peptide. Activity of GnRH neurons, and by extension release of GnRH, has been proposed to reflect intrinsic properties and synaptic input of GnRH neurons. To study GnRH neurons, we used traditional electrophysiology and computational methods. These emerging methodologies enhance the elucidation of processing in GnRH neurons. We used dynamic current-clamping to understand how living GnRH somata process input from glutamate and GABA, two key neurotransmitters in the neuroendocrine hypothalamus. In order to study the impact of synaptic integration in dendrites and neuronal morphology, we have developed full-morphology models of GnRH neurons. Using dynamic clamping, we have demonstrated that small-amplitude glutamatergic currents can drive repetitive firing in GnRH neurons. Furthermore, application of simulated GABAergic synapses with a depolarized reversal potential have revealed two functional subpopulations of GnRH neurons: one population in which GABA chronically depolarizes membrane potential (without inducing action potentials) and a second population in which GABAergic excitation results in slow spiking. Finally, when AMPA-type and GABA-type simulated inputs are applied together, action potentials occur when the AMPA-type conductance occurs during the descending phase of GABAergic excitation and at the nadir of GABAergic inhibition. Compartmental computer models have shown that excitatory synapses at >300 microns from somtata are unable to drive spiking with purely passive dendrites. In models with active dendrites, distal synapses are more efficient at driving spiking than somatic inputs. We then used our models to extend the results from dynamic current clamping at GnRH somata to distribute synaptic inputs along the dendrite. We show that propagation delays for dendritic synapses alter synaptic integration in GnRH neurons by widening the temporal window of interaction for the generation of action potentials. Finally, we have shown that changes in dendrite morphology can modulate the output of GnRH neurons by altering the efficacy of action potential generation in response to after depolarization potentials (ADPs). Taken together, the methodologies of dynamic current clamping and multi-compartmental modeling can make major contributions to the study of synaptic integration and structure-function relationships in hypothalamic GnRH neurons. Use of these methodological approaches will continue to provide keen insights leading to conceptual advances in our understanding of reproductive hormone secretion in normal and pathological physiology and open the door to understanding whether the mechanisms of pulsatile GnRH release are conserved across species. PMID- 21669817 TI - Four functional GnRH receptors in zebrafish: analysis of structure, signaling, synteny and phylogeny. AB - Reproduction in all vertebrates requires the brain hormone gonadotropin-releasing hormone (GnRH) to activate a cascade of events leading to gametogenesis. All vertebrates studied to date have one to three forms of GnRH in specific but different neurons in the brain. In addition, at least one type of GnRH receptor is present in each vertebrate for activation of specific physiological events within a target cell. Humans possess two types of GnRH (GnRH1 and GnRH2) but only one functional GnRH receptor. Zebrafish, Danio rerio, also have two types of GnRH (GnRH2 and GnRH3), although in contrast to humans, zebrafish appear to have four different GnRH receptors in their genome. To characterize the biological significance of multiple GnRH receptors within a single species, we cloned four GnRH receptor cDNAs from zebrafish and compared their structures, expression, and cell physiology. The zebrafish receptors are 7-transmembrane G-protein coupled receptors with amino-acid sequence identities ranging from 45 to 71% among the four receptors. High sequence similarity was observed among the seven helices of zebrafish GnRHRs compared with the human GnRHR, the green monkey type II GnRHR, and the two goldfish GnRHRs. Also, key amino acids for putative ligand binding, disulfide bond formation, N-glycosylation, and G-protein coupling were present in the extracellular and intracellular domains. The four zebrafish receptors were expressed in a variety of tissues including the brain, eye, and gonads. In an inositol phosphate assay, each receptor was functional as shown by its response to physiological doses of native GnRH peptides; two receptors showed selectivity between GnRH2 and GnRH3. Each of the four receptor genes was mapped to distinct chromosomes. Our phylogenetic and syntenic analysis segregated the four zebrafish GnRH receptors into two distinct phylogenetic groups that are separate gene lineages conserved throughout vertebrate evolution. We suggest the maintenance of four functional GnRH receptors in zebrafish compared with only one in humans may depend either on subfunctionalization or neofunctionalization in fish compared with mammalian GnRH receptors. The differences in structure, location, and response to GnRH forms strongly suggests that the four zebrafish GnRH receptors have novel functions in addition to the conventional activation of the pituitary gland in the reproductive axis. PMID- 21669818 TI - Gonadotropin-releasing hormone II: a multi-purpose neuropeptide. AB - Close to 30 forms of gonadotropin releasing hormone (GnRH) and at least five GnRH receptors have been identified in a wide variety of vertebrates and some invertebrates. One form, now called GnRH II, has the broadest distribution and the most ancient and conserved phylogeny. The distribution of the neurons that produce this peptide are completely nonoverlapping with any other GnRH forms. Fibers that project from these neurons overlap with GnRH I cells and/or fibers in a few regions, but are primarily divergent. The musk shrew (Suncus murinus) continues to be the most tractable mammalian species to use for studies of the function of GnRH II. The brain of the musk shrew has two GnRH genes (I and II), two GnRH receptors (types-1 and -2), and two different behaviors can be influenced by central infusion of GnRH II, but not by GnRH I; receptivity and feeding. Here, we summarize research on the musk shrew relative to the behavioral functions of GnRH II. First, female musk shrews are continually sexually receptive by virtue of their lack of an ovarian and/or behavioral estrus cycle. This feature of their reproductive ecology may be related to their semi-tropical distribution and their breeding season is highly dependent on changes in the availability of food. When food is not abundant, females stop mating, but brief bouts of feeding reinstate reproductive behavior. Likewise, intake of food is related to GnRH II mRNA and peptide content in the brain; after mild food restriction both decline. When GnRH II is infused centrally, at times when its content is low, it can both enhance receptivity and inhibit food intake. Simultaneous administration of a type-1 antagonist does not change the effect of GnRH II and use of an analog (135-18) that is a specific GnRH II agonist as well as a type-1 antagonist has the same effect as the endogenous GnRH II peptide. We propose that GnRH II plays a critical role by orchestrating the coordination of reproduction with the availability of nutritional support for these activities. Humans are bombarded with copious nutritional opportunities and at present obesity is a larger threat to health in many parts of the world than is under nutrition. It is our hope that understanding neuropeptides such as GnRH II that regulate food intake can ultimately lead to products that may curb appetite and thus decrease obesity and related risks to health. PMID- 21669819 TI - How do social dominance and social information influence reproduction and the brain? AB - How does living in a social environment influence the brain? In particular, we ask the following questions: How do animals perceive and use social information? How does the perception of social information influence the reproductive system? Where is this represented in the brain? We present a model system in which these questions can be addressed, focusing on the brain's role in integrating information. In the social fish, Astatotilapia burtoni (Haplochromis), the relationship between social status and gonadotropin-releasing hormone (GnRH1) has been well established. Change in status results in numerous changes in the physiology of A. burtoni at every level of organization. Social status can regulate reproduction via the hypothalamic-pituitary-gonadal (HPG) axis. GnRH1 is used by the brain to signal the pituitary about reproductive state so reproductive control depends on regulation of this signaling peptide. In this fish, social dominance is tightly coupled to fertility. Here, we have exploited this link to understand the regulatory systems from circulating hormones, brain volume to gene expression. PMID- 21669820 TI - Historical hypotheses regarding segmentation of the vertebrate head. AB - The morphology of the vertebrate head is extremely complex and comprises numerous iterative structures that arise from each of the embryonic germ layers. The search for a fundamental plan uniting all of these serial structures spans ~200 years. The earliest attempt to identify a common plan was J. W. Goethe's vertebral theory of skull organization, in which the skull was interpreted as being formed by a series of trunk vertebrae. This theory was rejected by T. H. Huxley in the 1858 Croonian Lecture and was replaced by the segmented mesodermal model of Francis Balfour, which was elaborated subsequently by A. Marshall, Gavin de Beer, and Edwin Goodrich. This model assumes that the head of the earliest vertebrates consisted of eight segments. It further assumes that each segment contained dorsal muscles arising from the somitic mesoderm, and ventral muscles arising from lateral plate mesoderm, except for the first segment, which lacked ventral muscles derived from the lateral plate mesoderm. The muscles of each head segment were believed to be innervated by two pairs of cranial nerves, homologous to the dorsal and ventral spinal nerves of lampreys. The validity of this theory, known as the Goodrich model, came into question, however, after the discovery that the branchiomeric muscles associated with each pharyngeal arch do not arise from lateral plate mesoderm, as initially proposed by Marshall and subsequently accepted by Goodrich and de Beer, but, rather, arise from paraxial mesoderm. Furthermore, segmentation of the brain into some 14 neuromeres cannot be accommodated by any model involving eight segments. Finally, there is also clear evidence that at least one, if not two, additional series of placodally derived sensory nerves occurs in the head and has no counterpart in the trunk. At present, there is no theory of segmentation that can account for all cephalic iterative structures. PMID- 21669821 TI - Head organization and the head/trunk relationship in protochordates: problems and prospects. AB - The fossil record has been an invaluable aid for reconstructing the major events of vertebrate evolution. There is no comparable record for protochordates, however, which severely limits our knowledge of their ancestral morphology, habits, and mode of life. The alternative is inference based on an interpretation of living protochordates but this is fraught with problems, not least being our own biases of what we think an ancestral chordate ought to look like. Relevant to the present symposium is the problem of head/trunk relationships and whether or not the myotomes of the trunk originally extended into the head in vertebrates. I will review what is currently known of patterns of innervation in tunicates and amphioxus in relation to Romer's somaticovisceral concept of the vertebrate body to show how little progress has been made in resolving this problem. There are, in contrast, surprisingly good prospects for solving some other puzzles concerning chordate origins. Dorsoventral inversion provides a good example. A consensus is now emerging, based largely on molecular data from hemichordates that casts new light on the asymmetry of the head in amphioxus. Specifically, the morphogenetic growth process that reestablishes symmetry in late-stage larvae can now be seen, at least in part, as a recapitulation of past evolutionary events, and this has important implications for the origin and basic organization of the brain. PMID- 21669822 TI - Amphioxus and the evolution of head segmentation. AB - Whether or not the vertebrate head is fundamentally segmented has been controversial for over 150 years. Beginning in the late 19th century, segmentalist theories proposed that the vertebrate head evolved from an amphioxus like ancestor in which mesodermal somites extended the full length of the body with remnants of segmentation persisting as the mesodermal head cavities of sharks and lampreys. Antisegmentalists generally argued either that the vertebrate ancestors never had any mesodermal segmentation anteriorly or that they lost it before the origin of the vertebrates; in either case, the earliest vertebrates had an unsegmented head and the embryonic cranial mesoderm of vertebrates is at best pseudo-segmented, evolving independently of any pre vertebrate segmental pattern. Recent morphologic studies have generally confirmed the accuracy of the major classical studies of head development in lampreys and sharks, yet disagree with their theoretical conclusions regarding the evolution of head segmentation. Studies of developmental genes in amphioxus and vertebrates, which have demonstrated conservation of the mechanisms of anterior posterior patterning in the two groups, have shed new light on this controversy. Most pertinently, some homologs of genes expressed in the anterior amphioxus somites, which form as outpocketings of the gut, are also expressed in the walls of the head cavities of lampreys, which form similarly, and in their major derivatives (the velar muscles) as well as in the eye and jaw muscles of bony gnathostomes, which derive from unsegmented head mesoderm. These muscles share gene expression with the corresponding muscles of the shark, which derive from the walls of head cavities that form, not as outpocketings of the gut, but as secondary cavities within solid blocks of tissue. While molecular data that can be compared across all the relevant taxa remain limited, they are consistent with an evolutionary scenario in which the cranial paraxial mesoderm of the lamprey and shark evolved from the anterior somites of an amphioxus-like ancestor. Although, bony vertebrates have lost the mesodermal head segments present in the shark and lamprey, their remnants persist in the muscles of the eye and jaw. PMID- 21669824 TI - Segmentation of the vertebrate skull: neural-crest derivation of adult cartilages in the clawed frog, Xenopus laevis. AB - We utilize a novel, transgenic cell-labeling system to assess the embryonic derivation of cartilages in the post-metamorphic skull of anuran amphibians. Many of these cartilages form de novo at metamorphosis and have no obvious precursors within the larval skeleton. Most adult cartilages are derived from mandibular- or hyoid-stream neural crest, either individually or in combination; branchial stream neural crest makes a modest contribution. Each stream also contributes to at least one cartilage in the middle ear or external ear. Four cartilages are composite elements; each is derived from at least two distinct cell populations. Many boundaries between adjacent neural-crest territories are cryptic insofar as they do not coincide with anatomical boundaries. The system of adult cranial segmentation revealed by these fate-mapping results differs in important respects from both the segmentation of the ontogenetically earlier larval skull and the cranial segmentation in amniotes. Most striking is the rostral "inversion" of neural-crest-derived cartilages in Xenopus, such that mandibular stream-derived elements are deployed caudal to those derived from the hyoid stream, which predominate anteriorly. This novel pattern of rostral segmentation may be a consequence of the complex, biphasic life history that is characteristic of most species of living amphibians, and especially anurans, in which cranial architecture is significantly reconfigured at metamorphosis. Neural-crest derivation of the vertebrate skull is not invariant; instead, embryonic derivation of individual components of the cranial skeleton may vary widely among species. PMID- 21669823 TI - Anterior-posterior patterning and segmentation of the vertebrate head. AB - Segmentation of the vertebrate head emerges out of earlier processes that establish the anterior-posterior (A-P) axis. Recent genetic studies and comparisons across species have led to a better understanding of the links between A-P patterning and segmentation. These point to similar signals acting on both head and trunk, such as retinoic acid and fibroblast growth factors. These form interacting networks of diffusible morphogen gradients that pattern both hindbrain rhombomeres and mesodermal somites. New computational models, particularly for retinoic acid, have revealed how morphogen gradients are established and made robust to changes in signaling levels. However, the orientations of these gradients, as well as how they interact to generate segments, differ remarkably between germ layers and body regions. Thus, the vertebrate head is, in part, built through modifications of the same processes that link A-P patterning and segmentation in the trunk, but fundamental differences in how these processes are deployed lend further doubt to the notion that head and trunk segments are homologous. PMID- 21669825 TI - Going with the flow: ecomorphological variation across aquatic flow regimes: an introduction to the symposium. PMID- 21669826 TI - Modes and scaling in aquatic locomotion. AB - Organisms spanning a 10(7)-fold range in length of the body engage in aquatic propulsion-swimming; they do so with several kinds of propulsors and take advantage of several different fluid mechanical mechanisms. A hierarchical classification of swimming modes can impose some order on this complexity. More difficult are the issues surrounding the different kinds of propulsive devices used by different organisms. These issues can be in part exposed by an examination of how speeds and accelerations scale with changes in body length, both for different lineages of swimmers and for all swimmers collectively. Clearly, fluid mechanical factors impose general rules and constraints; just as clearly, these only roughly anticipate actual scaling. Indeed, collections of data on scaling can serve as useful correctives for assumptions about functional mechanisms. They can also reveal size-dependent constraints on biological designs. PMID- 21669827 TI - The role of spatial and ontogenetic morphological variation in the expansion of the geographic range of the tropical brown alga, Turbinaria ornata. AB - Like many reefs worldwide, reefs in French Polynesia are experiencing a shift from coral-dominated to algal-dominated systems. The macroalga Turbinaria ornata comprises the majority of the increasing algal biomass on the barrier reefs surrounding these islands, and its distribution is increasing throughout this region. Aspects of the ecomorphology of Turbinaria make it ideally suited to thrive under the physical conditions found across barrier reefs throughout French Polynesia. Spatial morphological variation allows Turbinaria to produce morphotypes that are suited either to the calm, unidirectional, slowly flowing water in the backreef or to the high-energy wave-driven flow of the forereef. Backreef plants are flexible and produce airbladders that make them buoyant, whereas forereef plants are not buoyant, but strong and stiff. Production of bladders and resulting buoyancy has been found to be a phenotypically plastic trait in response to movement of water and confers advantages to backreef plants and plays an important role in dispersal. Ontogenetic variation of buoyancy, material properties, and reproductive capacity is part of a dispersal strategy whereby fertile, buoyant fronds drift between oceanic islands and form new populations, thereby contributing to the recent expansion of range of T. ornata across French Polynesia. PMID- 21669828 TI - Swimming dynamics and propulsive efficiency of squids throughout ontogeny. AB - Squids encounter vastly different flow regimes throughout ontogeny as they undergo critical morphological changes to their two locomotive systems: the fins and jet. Squid hatchlings (paralarvae) operate at low and intermediate Reynolds numbers (Re) and typically have rounded bodies, small fins, and relatively large funnel apertures, whereas juveniles and adults operate at higher Re and generally have more streamlined bodies, larger fins, and relatively small funnel apertures. These morphological changes and varying flow conditions affect swimming performance in squids. To determine how swimming dynamics and propulsive efficiency change throughout ontogeny, digital particle image velocimetry (DPIV) and kinematic data were collected from an ontogenetic range of long-finned squid Doryteuthis pealeii and brief squid Lolliguncula brevis swimming in a holding chamber or water tunnel (Re = 20-20 000). Jet and fin wake bulk properties were quantified, and propulsive efficiency was computed based on measurements of impulse and excess kinetic energy in the wakes. Paralarvae relied predominantly on a vertically directed, high frequency, low velocity jet as they bobbed up and down in the water column. Although some spherical vortex rings were observed, most paralarval jets consisted of an elongated vortical region of variable length with no clear pinch-off of a vortex ring from the trailing tail component. Compared with paralarvae, juvenile and adult squid exhibited a more diverse range of swimming strategies, involving greater overall locomotive fin reliance and multiple fin and jet wake modes with better defined vortex rings. Despite greater locomotive flexibility, jet propulsive efficiency of juveniles/adults was significantly lower than that of paralarvae, even when juvenile/adults employed their highest efficiency jet mode involving the production of periodic isolated vortex rings with each jet pulse. When the fins were considered together with the jet for several juvenile/adult swimming sequences, overall propulsive efficiency increased, suggesting that fin contributions are important and should not be overlooked in analyses of the swimming performance of squids. The fins produced significant thrust and consistently had higher propulsive efficiency than did the jet. One particularly important area of future study is the determination of coordinated jet/fin wake modes that have the greatest impact on propulsive efficiency. Although such research would be technically challenging, requiring new, powerful, 3D approaches, it is necessary for a more comprehensive assessment of propulsive efficiency of the squid dual-mode locomotive system. PMID- 21669829 TI - Morphological selection in an extreme flow environment: body shape and waterfall climbing success in the Hawaiian stream fish Sicyopterus stimpsoni. AB - Flow characteristics are a prominent factor determining body shapes in aquatic organisms, and correlations between body shape and ambient flow regimes have been established for many fish species. In this study, we investigated the potential for a brief period of extreme flow to exert selection on the body shape of juvenile climbing Hawaiian gobiid fishes. Because of an amphidromous life history, juvenile gobies that complete an oceanic larval phase return to freshwater habitats, where they become adults. Returning juveniles often must scale waterfalls (typically with the use of a ventral sucker) in order to reach the habitats they will use as adults, thereby exposing these animals to brief periods of extreme velocities of flow. Hydrodynamic theory predicts that bodies with larger suckers and with lower heights that reduce drag would have improved climbing success and, thus, be well suited to meet the demands of the flows in waterfalls. To test the potential for the flow environment of waterfalls to impose selection that could contribute to differences in body shape between islands, we subjected juvenile Sicyopterus stimpsoni to climbing trials up artificial waterfalls (~100 body lengths) and measured differences in body shape between successful and unsuccessful climbers. Waterfalls appear to represent a significant selective barrier to these fishes, as nearly 30% failed our climbing test. However, the effects of selection on morphology were not straightforward, as significant differences in shape between successful and unsuccessful climbers did not always match hydrodynamic predictions. In both selection experiments and in adult fish collected from habitats with different prevailing conditions of flow (the islands of Hawai'i versus Kaua'i), lower head heights were associated with exposure to high-flow regimes, as predicted by hydrodynamic theory. Thus, a premium appears to be placed on the reduction of drag via head morphology throughout the ontogeny of this species. The congruence of phenotypic selection patterns observed in our experiments, with morphological character divergence documented among adult fish from Hawai'i and Kaua'i, suggests that differences in morphology between subpopulations of adult climbing gobies may result, at least in part, from the selective pressures of high-velocity flows encountered by migrating juveniles. PMID- 21669830 TI - Predictability of phenotypic differentiation across flow regimes in fishes. AB - Fish inhabit environments greatly varying in intensity of water velocity, and these flow regimes are generally believed to be of major evolutionary significance. To what extent does water flow drive repeatable and predictable phenotypic differentiation? Although many investigators have examined phenotypic variation across flow gradients in fishes, no clear consensus regarding the nature of water velocity's effects on phenotypic diversity has yet emerged. Here, I describe a generalized model that produces testable hypotheses of morphological and locomotor differentiation between flow regimes in fishes. The model combines biomechanical information (describing how fish morphology determines locomotor abilities) with ecological information (describing how locomotor performance influences fitness) to yield predictions of divergent natural selection and phenotypic differentiation between low-flow and high-flow environments. To test the model's predictions of phenotypic differentiation, I synthesized the existing literature and conducted a meta-analysis. Based on results gathered from 80 studies, providing 115 tests of predictions, the model produced some accurate results across both intraspecific and interspecific scales, as differences in body shape, caudal fin shape, and steady-swimming performance strongly matched predictions. These results suggest that water flow drives predictable phenotypic variation in disparate groups of fish based on a common, generalized model, and that microevolutionary processes might often scale up to generate broader, interspecific patterns. However, too few studies have examined differentiation in body stiffness, muscle architecture, or unsteady-swimming performance to draw clear conclusions for those traits. The analysis revealed that, at the intraspecific scale, both genetic divergence and phenotypic plasticity play important roles in phenotypic differentiation across flow regimes, but we do not yet know the relative importance of these two sources of phenotypic variation. Moreover, while major patterns within and between species were predictable, we have little direct evidence regarding the role of water flow in driving speciation or generating broad, macroevolutionary patterns, as too few studies have addressed these topics or conducted analyses within a phylogenetic framework. Thus, flow regime does indeed drive some predictable phenotypic outcomes, but many questions remain unanswered. This study establishes a general model for predicting phenotypic differentiation across flow regimes in fishes, and should help guide future studies in fruitful directions, thereby enhancing our understanding of the predictability of phenotypic variation in nature. PMID- 21669831 TI - Ecomorphological variation in shell shape of the freshwater turtle Pseudemys concinna inhabiting different aquatic flow regimes. AB - Populations of species that inhabit a range of environments frequently display divergent morphologies that correlate with differences in ecological parameters. The velocity of water flow (i.e., flow velocity) is a critical feature of aquatic environments that has been shown to influence morphology in a broad range of taxa. The focus of this study was to evaluate the relationship between flow velocity and shell morphology for males and females of the semi-aquatic freshwater turtle Pseudemys concinna. For both sexes, the carapace and plastron show significant morphological differences between habitats characterized by slow flowing (i.e., lentic) and fast-flowing (i.e., lotic) water. In general, the most prominent pattern for both sexes is that the shells of individuals from lotic habitats are more streamlined (small height-to-length ratio) than the shells of individuals from lentic habitats. Of the two shell components (carapace and plastron), the carapace shows greater divergence between habitats, particularly for males. These results are consistent with adaptations to flow velocity, and suggest that variation in shape may be more constrained in females. I also provide empirical evidence for an adaptive benefit of the observed shape change (i.e., drag reduction) and a brief comment on the relative roles of genetic divergence and phenotypic plasticity in generating shape differences observed in this species. PMID- 21669832 TI - Hydrodynamic flow control in marine mammals. AB - The ability to control the flow of water around the body dictates the performance of marine mammals in the aquatic environment. Morphological specializations of marine mammals afford mechanisms for passive flow control. Aside from the design of the body, which minimizes drag, the morphology of the appendages provides hydrodynamic advantages with respect to drag, lift, thrust, and stall. The flukes of cetaceans and sirenians and flippers of pinnipeds possess geometries with flexibility, which enhance thrust production for high efficiency swimming. The pectoral flippers provide hydrodynamic lift for maneuvering. The design of the flippers is constrained by performance associated with stall. Delay of stall can be accomplished passively by modification of the flipper leading edge. Such a design is exhibited by the leading edge tubercles on the flippers of humpback whales (Megaptera novaeangliae). These novel morphological structures induce a spanwise flow field of separated vortices alternating with regions of accelerated flow. The coupled flow regions maintain areas of attached flow and delay stall to high angles of attack. The delay of stall permits enhanced turning performance with respect to both agility and maneuverability. The morphological features of marine mammals for flow control can be utilized in the biomimetic design of engineered structures for increased power production and increased efficiency. PMID- 21669833 TI - Mussel attachment on rocky shores: the effect of flow on byssus production. AB - Mussels rely on a strong byssal attachment to persist in a range of habitats with differing rates of water flow. Recent studies, however, suggest that the ability of one mussel species to sense and respond adaptively to the flow in its environment is limited under even modest flow conditions because the process of byssal thread formation is disrupted. This study extends these findings to four mussel species, Mytilus trossulus, M. galloprovincialis, M. californianus, and Modiolus modiolus. Collectively, the response of byssal thread formation decreased with rates of flow above ~25 cm/s and the critical flow threshold was estimated to be <50 cm/s. How can mussels persist on shores where flow is an order of magnitude higher? Using a combination of techniques for measuring flow, velocity profiles were obtained above and within mussel aggregations in the laboratory and in the field. Flow was greatly reduced within mussel aggregations, ranging from 0.1% to 10% of free-stream velocity. These results suggest one key to the success of mussels in habitats with high rates of flow is the ability to form aggregations that ameliorate flows to a level that is conducive to byssal thread formation. PMID- 21669834 TI - Living where the flow is right: How flow affects feeding in bryozoans. AB - Bryozoans are suspension feeding colonial animals that remain attached to the substratum or other surfaces. How well a bryozoan can feed in a particular flow regime could help determine the distribution and abundance of that bryozoan. I tested how velocity of flow affects feeding rate in four species of bryozoans in the laboratory and how these species perform in different flow regimes in the field. I found that one species, Membranipora membranacea, had a higher ingestion rate than did the other three species at all velocities of flow tested. Membranipora also had a higher rate of ingestion at intermediate velocities, while velocity did not have as strong an effect on ingestion rate in the other three species. As predicted from the feeding experiments, all four species generally had greater abundance, attained a larger size, grew faster, and survived longer in flow regimes in which feeding is higher. Also as predicted, Membranipora had greater abundance, attained a larger size, grew faster, and survived longer than did the other three species both in slower and faster flow regimes in the field. Understanding how flow affects feeding can help predict the distribution and abundance of bryozoans in the field. Because especially efficient filterers like Membranipora can grow faster and have higher survival under a wide range of conditions of flow, this species may be able to outcompete many other species or take advantage of ephemeral habitats, thereby becoming a potentially effective invasive species as has been seen in the Gulf of Maine. PMID- 21669835 TI - Do antennule and aesthetasc structure in the crayfish Orconectes virilis correlate with flow habitat? AB - The local flow environment affects the shape of waterborne chemical signals through a variety of physical mechanisms and at several scales. Since crayfish rely on these chemical signals to extract information about predators, prey, and mates, one might expect the chemical sensors (aesthetascs) on crayfish antennules to be physically tuned to the presentation of chemical cues by the flow environment. This hypothesis was tested by comparing length, diameter, and spacing of antennules and aesthetascs among geographically distinct populations of Orconectes virilis. Crayfish were collected from the Chagrin river, Hebron hatchery, and Burt lake. In addition, antennules were sampled from 43 museum populations representing 12 lake, 10 creek, and 21 river populations from multiple states and river drainages. Mean velocities from the collection sites were either measured directly or calculated from United States Geological Survey (USGS) historical data. Structural parameters were measured using Scion Image software on Scanning electron microscope micrographs, and analyses of variance were performed using StatView. Structural parameters of aesthetascs were found to vary with flow environment. Aesthetascs from lake populations were inserted at a larger angle, extended out farther from the supporting antennule relative to the width of the antennule, and were more widely spaced than aesthetascs from creek, hatchery, and river populations. PMID- 21669836 TI - How kelp produce blade shapes suited to different flow regimes: A new wrinkle. AB - Many species of macroalgae have flat, strap-like blades in habitats exposed to rapidly flowing water, but have wide, ruffled "undulate" blades at protected sites. We used the giant bull kelp, Nereocystis luetkeana, to investigate how these ecomorphological differences are produced. The undulate blades of N. luetkeana from sites with low flow remain spread out and flutter erratically in moving water, thereby not only enhancing interception of light, but also increasing drag. In contrast, strap-like blades of kelp from habitats with rapid flow collapse into streamlined bundles and flutter at low amplitude in flowing water, thus reducing both drag and interception of light. Transplant experiments in the field revealed that shape of the blade in N. luetkeana is a plastic trait. Laboratory experiments in which growing blades from different sites were subjected to tensile forces that mimicked the hydrodynamic drag experienced by blades in different flow regimes showed that change in shape is induced by mechanical stress. During growth experiments in the field and laboratory, we mapped the spatial distribution of growth in both undulate and strap-like blades to determine how these different morphologies were produced. The highest growth rates occur near the proximal ends of N. luetkeana blades of both morphologies, but the rates of transverse growth of narrow, strap-like blades are lower than those of wide, undulate blades. If rates of longitudinal growth at the edges of a blade exceed the rate of longitudinal growth along the midline of the blade, ruffles along the edges of the blade are produced by elastic buckling. In contrast, flat blades are produced when rates of longitudinal growth are similar across the width of a blade. Because ruffles are the result of elastic buckling, a compliant undulate N. luetkeana blade can easily be pushed into different configurations (e.g., the wavelengths of the ruffles along the edges of the blade can change, and the whole blade can twist into left- and right-handed helicoidal shapes), which may enhance movements of the blade in flowing water that reduce self-shading and increase mass exchange along blade surfaces. PMID- 21669837 TI - Recent advances in crustacean genomics. AB - Crustaceans are a diverse and ancient group of arthropods that have long been studied as interesting model systems in biology, especially for understanding animal evolution and physiology and for environmentally relevant studies. Like many model systems, advances in DNA-sequencing methodologies have led to a large amount of genomics-related projects. The purpose of this article is to highlight the genome projects and functional genomics (transcriptomics) projects that are currently underway in crustacean biology. Specifically, we have surveyed the amount of publicly available DNA sequence data (both genomic and EST data) across all crustacean taxa for which a significant number of DNA sequences have been generated. Several ongoing projects are presented including the ecology of invasive species, thermal physiology, ion and water balance, ecology and evolutionary biology, and developmental biology. PMID- 21669838 TI - Awards, scholarships and grants awarded at the SICB Meeting in January 2009. PMID- 21669839 TI - Announcement of a new Honorary International Associate of the Editorial Board. PMID- 21669840 TI - Grand challenges. PMID- 21669841 TI - Grand challenges in organismal biology. AB - A renaissance in organismal biology has been sparked by recent conceptual, theoretical, methodological, and computational advances in the life sciences, along with an unprecedented interdisciplinary integration with Mathematics, Engineering, and the physical sciences. Despite a decades-long trend toward reductionist approaches to biological problems, it is increasingly recognized that whole organisms play a central role in organizing and interpreting information from across the biological spectrum. Organisms represent the nexus where sub- and supra-organismal processes meet, and it is the performance of organisms within the environment that provides the material for natural selection. Here, we identify five "grand challenges" for future research in organismal biology. It is intended that these challenges will spark further discussion in the broader community and identify future research priorities, opportunities, and directions, which will ultimately help to guide the allocation of support for and training in organismal biology. PMID- 21669842 TI - Biomaterials: Properties, variation and evolution. PMID- 21669843 TI - The evolution of complex biomaterial performance: The case of spider silk. AB - Spider silk is a high-performance biomaterial with exceptional mechanical properties and over half a century of research into its mechanics, structure, and biology. Recent research demonstrates that it is a highly variable class of materials that differs across species and individuals in complex and interesting ways. Here, we review recent literature on mechanical variation and evolution in spider silk. We then present new data on material properties of silk from nine species of spiders in the Mesothelae and Mygalomorphae, the two basal clades of spiders. Silk from spiders in the Araneomorphae (true spiders where most previous research on silk has focused) is significantly stronger and therefore much tougher than the silk produced by spiders in the basal groups. These data support the hypothesis that the success and diversity seen in araneomorph spiders is associated with the evolution of this high-performance fiber. This comparative approach shows promise as a way to understand complex, high-performance biomaterials. PMID- 21669844 TI - From ultra-soft slime to hard {alpha}-keratins: The many lives of intermediate filaments. AB - Intermediate filaments are filaments 10 nm in diameter that make up an important component of the cytoskeleton in most metazoan taxa. They are most familiar for their role as the fibrous component of alpha-keratins such as skin, hair, nail, and horn but are also abundant within living cells. Although they are almost exclusively intracellular in their distribution, in the case of the defensive slime produced by hagfishes, they are secreted. This article surveys the impressive diversity of biomaterials that animals construct from intermediate filaments and will focus on the mechanisms by which the mechanical properties of these materials are achieved. Hagfish slime is a dilute network of hydrated mucus and compliant intermediate filament bundles with ultrasoft material properties. Within the cytoplasm of living cells, networks of intermediate filaments form soft gels whose elasticity arises via entropic mechanisms. Single intermediate filaments or bundles are also elastic, but substantially stiffer, exhibiting modulus values similar to that of rubber. Hard alpha-keratins like wool are stiffer still, an effect that is likely achieved via dehydration of the intermediate filaments in these epidermal appendages. The diverse mechanisms described here have been employed by animals to generate materials with stiffness values that span an impressive eleven orders of magnitude. PMID- 21669845 TI - Nonlinear viscoelastic biomaterials: meaningful characterization and engineering inspiration. AB - Nonlinear mechanical properties play an important role in numerous biological functions, for instance the locomotion strategy used by terrestrial gastropods. We discuss the progress made toward bioinspired snail-like locomotion and the pursuit of an engineered fluid that imitates the nonlinear viscoelastic properties of native gastropod pedal mucus. The rheological behavior of native pedal mucus is characterized using an oscillatory deformation protocol known as large amplitude oscillatory shear, and we review recently developed techniques for appropriately describing nonlinear viscoelastic behavior. Although materials that exhibit purely elastic and purely viscous nonlinearities are amenable to standard techniques for characterization, pedal mucus samples (and biomaterials in general) are viscoelastic, exhibiting both elastic and viscous nonlinear responses simultaneously and requiring advanced techniques for characterization. We reveal the utility of these new methods by examining trail mucus from the terrestrial slug Limax maximus using oscillatory shear rheology. Material responses which previously could only be described mathematically, with little physical insight, can now be interpreted with familiar language such as strain stiffening/softening and shear-thickening/thinning. The new methodology is applicable to any complex material that can be tested using imposed oscillatory deformations. We have developed data-analysis software to enable wider use of this framework within and beyond the biomaterials community. The functionality of this software is outlined here. PMID- 21669846 TI - Correlations between indentation modulus and mineral density in bone-fracture calluses. AB - The mechanical properties of a healing bone fracture depend not only on the geometry of the fracture callus but also on the material properties of the callus tissues. Despite the biomechanical importance of callus tissues in restoring mechanical integrity to the injured bone, little is known about the material properties of these tissues and whether these properties can be estimated non invasively. This study used nanoindentation to quantify the spatial variations in indentation modulus throughout the fracture callus and correlated the measurements of modulus with measurements of tissue mineral density (TMD) obtained from images from micro-computed tomography (uCT). Fracture calluses were harvested from rats 24 days following creation of a full-thickness, transverse osteotomy in the femoral mid-diaphysis. Calluses were imaged using uCT, and the average TMD and the median grayvalue (X-ray attenuation) of five, pre-defined volumes of interest (VOIs) in each callus were computed. Nanoindentation was then performed at multiple, regularly spaced locations across 150 um-thick, sagittal sections of the calluses. The indentation modulus ranged from 0.51 to 1680 MPa throughout the callus, with the highest moduli in the center of the fracture gap and the lowest in the periphery of the gap (P < 0.05). TMD was also highest in the center of the gap (P < 0.05). An increasing trend in both modulus and TMD was observed in the regions of the callus adjacent to the periosteal surfaces of the cortex. While no correlation was found between the average indentation modulus in a given VOI and the median grayvalue of that VOI, the average indentation modulus and the average TMD were positively correlated (R = 0.70, P < 0.05). Together, these findings establish the spatial heterogeneity in the mechanical behavior of tissues in fracture calluses and indicate that the indentation modulus of these tissues can be estimated by non-invasive measurements of tissue mineralization. PMID- 21669847 TI - Plants control the properties and actuation of their organs through the orientation of cellulose fibrils in their cell walls. AB - Plants use the orientation of cellulose microfibrils to create cell walls with anisotropic properties related to specific functions. This enables organisms to control the shape and size of cells during growth, to adjust the mechanical performance of tissues, and to perform bending movements of organs. We review the key function of cellulose orientation in defining structural-functional relationships in cell walls from a biomechanics perspective, and illustrate this by examples mainly from our own work. First, primary cell-wall expansion largely depends on the organization of cellulose microfibrils in newly deposited tissue and model calculations allow an estimate of how their passive re-orientation may influence the growth of cells. Moreover, mechanical properties of secondary cell walls depend to a large extent on the orientation of cellulose fibrils and we discuss strategies whereby plants utilize this interrelationship for adaptation. Lastly, we address the question of how plants regulate complex organ movements by designing appropriate supramolecular architectures at the level of the cell wall. Several examples, from trees to grasses, show that the cellulose architecture in the cell wall may be used to direct the swelling or shrinking of cell walls and thereby generate internal growth stress or movement of organs. PMID- 21669848 TI - The black box, the creature from the Black Lagoon, August Krogh, and the dominant animal. PMID- 21669849 TI - Introduction to the first symposium on the biology of the parasitic Crustacea. PMID- 21669850 TI - A review of bopyrid isopods infesting crabs from China. AB - Isopod parasites of the subfamilies Ioninae and Pseudioninae infest the branchial chambers of brachyuran crabs. In total, 19 species of parasitic isopods infest crabs from China; they belong to 6 genera from the Ioninae and 1 genus from the Pseudioninae. Specifically, the following genera are represented: Allokepon Markham, 1982 (three species), Apocepon Nierstrasz and Brender a Brandis, 1930 (three species), Cancricepon Giard and Bonnier, 1887 (one species), Dactylokepon Stebbing, 1910 (four species), Gigantione Kossmann, 1881 (four species), Onkokepon, An et al. 2006 (two species) and Tylokepon Stebbing, 1906 (two species). The new species Tylokepon biturus from Menaethius monoceros (Latreille) collected in China is distinguished from other members of the genus by the striking shape of the head, two mid-dorsal projections on Pereomere 6, and entire pleopods and uropods without any tubercules on their surface. A list of all bopyrid species (19 species in seven families) along with their hosts and localities, is presented. PMID- 21669851 TI - Serratotantulus chertoprudae gen. et sp. n. (Crustacea, Tantulocarida, Basipodellidae): A new tantulocaridan from the abyssal depths of the Indian Ocean. AB - A single tantulus larva was found at the abyssal depth of the Indian Ocean attached to a harpacticoid host of the family Cletodidae. It represents a new genus and species of Tantulocarida, family Basipodellidae. Its ultrastructure was studied with SEM. This genus can be easily distinguished from the other genera of Basipodellidae by the pore pattern, bilobed oral disk with strong longitudinal ridges and the posterior projection of the cephalic shield. A morphological analysis of two related families Basipodellidae and Deothertridae shows that they represent polyphyletic taxa and need further revision. PMID- 21669852 TI - The cryptogenic parasitic isopod Orthione griffenis Markham, 2004 from the eastern and western Pacific. AB - The parasitic isopod Orthione griffenis Markham, 2004 was originally described from thalassinid mud shrimp hosts collected in Oregon. Subsequently, O. griffenis has been cited as a non-indigenous species in estuaries of the Pacific Northwest of North America; however, no taxonomic work has provided evidence that specimens from the western coast of the United States and other localities are conspecific. We report the first record of O. griffenis from Chinese waters based on collections made in the 1950s, which pre-date any records of the species from the United States by at least 20 years. Females of the Chinese specimens match the original description except in the number of articles on antennae 2 (six and five articles in the Chinese material and holotype, respectively). However, newly examined material from the United States showed females are variable in this character, exhibiting 5-6 articles on antennae 2. Although males of O. griffenis from Oregon were originally described as having second antennae with five articles, reexamination of the allotype showed that antennae 2 were damaged and missing terminal articles. Thus, the number of articles in the second antennae of males is six, as found in both the Chinese and new samples from the United States. Scanning electron microscopy (SEM) of males from USA and China revealed curled setae on the distolateral margins of the uropods, which were not reported in the original description. In China the species is found on Austinogebia wuhsienweni (Yu) from Shandong province, whereas along the western coast of North America the species extends from British Columbia to California on Upogebia pugettensis (Dana) and U. macginitieorum Williams (the latter species replacing U. pugettensis south of Pt. Conception, California). Orthione griffenis has also been reported from Japan on Upogebia issaeffi (Balss) and Austinogebia narutensis (Sakai). In Coos Bay, Oregon, the prevalence of the species was ~65% in the mature U. pugettensis. The species was presumably introduced as larvae released in ballast water from ships originating in Asia. The epicaridium larvae of O. griffenis were examined with SEM, and aspects of the life history of the species are reviewed. PMID- 21669853 TI - Parasitic crustaceans as vectors of viruses, with an emphasis on three penaeid viruses. AB - Parasitic crustaceans serve as both hosts and vectors of viruses as well as of parasites and other microbial pathogenic agents. Few of the presumably numerous associations are known, but many can be anticipated. Recently, branchiurans and gnathiid isopods have been documented to host helminths and blood parasites. Because the agents can be observed readily with a microscope, these are better recognized than are the smaller viral, bacterial, and fungal agents. Some agents are harmful to the host of the crustacean parasite and others are not. Viruses probably fit both these categories, since viruses that do not appear pathogenic are often seen in ultrastructural images from a range of invertebrate hosts, including crustaceans. Some viruses have been implicated in causing disease in the host, at least under appropriate conditions. For example, lymphocystis virus may possibly be transmitted to the dermis of its fish hosts by copepods and to the visceral organs by a cymothoid isopod. Similarly, argulid branchiurans seem to transmit the viral agent of spring viremia of carp as well as carp pox, and copepods have been implicated in transmitting infectious hematopoietic necrosis, infectious salmon anemia, and infectious pancreatic necrosis to salmon. Other viruses can be vectored to their hosts through an additional animal. We exposed three viruses, Taura syndrome virus (TSV), white spot syndrome virus (WSSV), and yellowhead virus (YHV), all of which cause mortalities in wild and cultured penaeid shrimps, to crustacean parasites on fish and crabs. Using real-time polymerase chain reaction analysis, we show that TSV in the cyclopoid copepod Ergasilus manicatus on the gill filaments of the Gulf killifish, Fundulus grandis, the acorn barnacle Chelonibia patula on the carapace of the blue crab, Callinectes sapidus, and gooseneck barnacle Octolasmis muelleri on the gills of C. sapidus, can replicate for at least 2 weeks and establish what should be an infective dose. This result was additionally supported by positive in situ hybridization reactions. All three parasites are the first known non-penaeid hosts in which replication occurs. The mean log copy number of WSSV also suggested that replication occurred in E. manicatus. The mean log copy number of YHV gradually decreased in all three parasites and both hosts over the 2-week period. The vector relationships indicate an additional potential means of transmitting and disseminating the disease-causing agents to the highly susceptible and economically valuable penaeid shrimp hosts. PMID- 21669854 TI - Evolutionary roots of iodine and thyroid hormones in cell-cell signaling. AB - In vertebrates, thyroid hormones (THs, thyroxine, and triiodothyronine) are critical cell signaling molecules. THs regulate and coordinate physiology within and between cells, tissues, and whole organisms, in addition to controlling embryonic growth and development, via dose-dependent regulatory effects on essential genes. While invertebrates and plants do not have thyroid glands, many utilize THs for development, while others store iodine as TH derivatives or TH precursor molecules (iodotyrosines)-or produce similar hormones that act in analogous ways. Such common developmental roles for iodotyrosines across kingdoms suggest that a common endocrine signaling mechanism may account for coordinated evolutionary change in all multi-cellular organisms. Here, I expand my earlier hypothesis for the role of THs in vertebrate evolution by proposing a critical evolutionary role for iodine, the essential ingredient in all iodotyrosines and THs. Iodine is known to be crucial for life in many unicellular organisms (including evolutionarily ancient cyanobacteria), in part, because it acts as a powerful antioxidant. I propose that during the last 3-4 billion years, the ease with which various iodine species become volatile, react with simple organic compounds, and catalyze biochemical reactions explains why iodine became an essential constituent of life and the Earth's atmosphere-and a potential marker for the origins of life. From an initial role as membrane antioxidant and biochemical catalyst, spontaneous coupling of iodine with tyrosine appears to have created a versatile, highly reactive and mobile molecule, which over time became integrated into the machinery of energy production, gene function, and DNA replication in mitochondria. Iodotyrosines later coupled together to form THs, the ubiquitous cell-signaling molecules used by all vertebrates. Thus, due to their evolutionary history, THs, and their derivative and precursors molecules not only became essential for communicating within and between cells, tissues and organs, and for coordinating development and whole-body physiology in vertebrates, but they can also be shared between organisms from different kingdoms. PMID- 21669855 TI - Epithelia and integration in sponges. AB - An epithelium is important for integrity, homeostasis, communication and co ordination, and its development must have been a fundamental step in the evolution of modern metazoan body plans. Sponges are metazoans that are often said to lack a true epithelium. We assess the properties of epithelia, and review the history of studies on sponge epithelia, focusing on their homology to bilaterian epithelia, their ultrastructure, and on their ability to seal. Electron micrographs show that adherens-type junctions are present in sponges but they can appear much slighter than equivalent junctions in other metazoans. Fine septae are seen in junctions of all sponge groups, but distinct septate junctions are only known from Calcarea. Similarly, all sponges can have collagenous sheets underlying their epithelia, but only homoscleromorphs are established to have a distinct basal lamina. The presence of most, but not all, gene families known to be involved in epithelial development and function also suggests that sponge epithelia function like, and are homologous to, bilaterian epithelia. However, physiological evidence that sponge epithelia regulate their internal environment is so far lacking. Given that up to six differentiated epithelia can be recognized in sponges, distinct physiological roles are expected. Recognition that sponges have epithelia challenges the perception that sponges are only loose associations of cells, and helps to relate the biology and physiology of the body plan of the adult sponge to the biology of other metazoans. PMID- 21669856 TI - An evo-devo view on the origin of the backbone: evolutionary development of the vertebrae. AB - Vertebral columns are a group of diverse axial structures that define the vertebrates and provide supportive, locomotive, protective, and other important functions. The embryonic origin of the first vertebral element in this subphylum, the lamprey arcualia, has remained a puzzle for more than a century although much developmental and genetic progress has been made. The comparative approach is a very powerful tool for studying vertebrate morphological variation and understanding how the novel structures were generated during evolution. Here, I first briefly describe the vertebral structures and their developmental processes in major taxa, and then analyze the most recently published data on the basal vertebrates. Finally, an ontogenetic and phylogenetic origin is proposed. The lamprey may have already evolved a sclerotome, which gave rise to arcualia ontogenetically; whole genome duplications likely promoted the establishment of sclerotomal core genetic program by gene co-options. PMID- 21669857 TI - Plasticity of the immunoglobulin domain in the evolution of immunity. AB - Immune receptors are omnipresent in multicellular organisms and comprise a vast array of molecular structures that serve to detect and eliminate pathogenic threats. The immunoglobulin (Ig) domain, a central structural feature of the antigen binding receptors that mediate adaptive immunity in jawed vertebrates, appears to play a particularly widespread role in metazoan immunity. Recent reports also have implicated Ig domains in the immune responses of protostomes such as flies and snails. Our research has focused on understanding the utilization of the Ig domain in the immunity of chordates and has identified numerous multigene families of Ig domain-containing receptors that appear to serve roles distinct from the adaptive antigen-binding receptors. Three families have received particular focus: novel immune-type receptors (NITRs) of bony fish, modular domain immune-type receptors (MDIRs) of cartilaginous fish and variable region-containing chitin-binding proteins (VCBPs) of amphioxus. NITRs and MDIRs are encoded in large multigene families of highly diversified forms and exhibit a striking dichotomy of an apparently ubiquitous presence but extensive diversification of sequence both within and among the particular taxonomic groups in which they are found. Crystal structures of VCBPs and NITRs demonstrate significant similarity to those of antigen-binding receptors but at the same time exhibit key differences that imply acquisition of separate and distinct ligand binding functions. The tremendous plasticity of the Ig domain makes it a strong focus for studies of evolutionary events that have shaped modern integrated immune systems. Current data are consistent with a model of extremely rapid emergence and divergence of immune receptors, perhaps specific to individual species, as organisms contend with environments in which pathogens are continually selected for variation of their own molecular signatures. PMID- 21669858 TI - Environmental surfaces and the compression of perceived visual space. AB - The present study examined whether the compression of perceived visual space varies according to the type of environmental surface being viewed. To examine this issue, observers made exocentric distance judgments when viewing simulated 3D scenes. In 4 experiments, observers viewed ground and ceiling surfaces and performed either an L-shaped matching task (Experiments 1, 3, and 4) or a bisection task (Experiment 2). Overall, we found considerable compression of perceived exocentric distance on both ground and ceiling surfaces. However, the perceived exocentric distance was less compressed on a ground surface than on a ceiling surface. In addition, this ground surface advantage did not vary systematically as a function of the distance in the scene. These results suggest that the perceived visual space when viewing a ground surface is less compressed than the perceived visual space when viewing a ceiling surface and that the perceived layout of a surface varies as a function of the type of the surface. PMID- 21669860 TI - A multivariate logistic regression. PMID- 21669859 TI - Sandwich masking eliminates both visual awareness of faces and face-specific brain activity through a feedforward mechanism. AB - It is generally agreed that considerable amounts of low-level sensory processing of visual stimuli can occur without conscious awareness. On the other hand, the degree of higher level visual processing that occurs in the absence of awareness is as yet unclear. Here, event-related potential (ERP) measures of brain activity were recorded during a sandwich-masking paradigm, a commonly used approach for attenuating conscious awareness of visual stimulus content. In particular, the present study used a combination of ERP activation contrasts to track both early sensory-processing ERP components and face-specific N170 ERP activations, in trials with versus without awareness. The electrophysiological measures revealed that the sandwich masking abolished the early face-specific N170 neural response (peaking at ~170 ms post-stimulus), an effect that paralleled the abolition of awareness of face versus non-face image content. Furthermore, however, the masking appeared to render a strong attenuation of earlier feedforward visual sensory-processing signals. This early attenuation presumably resulted in insufficient information being fed into the higher level visual system pathways specific to object category processing, thus leading to unawareness of the visual object content. These results support a coupling of visual awareness and neural indices of face processing, while also demonstrating an early low-level mechanism of interference in sandwich masking. PMID- 21669861 TI - Retrograde supra-aortic stent placement combined with open carotid or subclavian artery revascularization. AB - PURPOSE: To review the outcomes of retrograde supra-aortic vessel stent (RSAS) placement combined with open carotid or subclavian artery revascularization. METHODS: Retrospective review of all consecutive patients between 1995 and 2010, excluding transfemoral procedures or isolated retrograde stent placement. RESULTS: There were 11 patients (9 females, mean age 65 years). Open revascularization included carotid endarterectomy in 6 patients, carotid subclavian bypass in 3, and carotid-carotid bypass in 2 patients. There were no operative deaths or neurological events. All symptomatic patients improved. Over a mean follow-up of 24 months, One patient developed common carotid artery (CCA) in-stent dissection and symptomatic restenosis treated with subclavian-carotid bypass. Another 3 patients had asymptomatic restenosis of the carotid bifurcation but required no intervention. CONCLUSIONS: Retrograde stenting of the common carotid or innominate artery is a safe and effective method to provide inflow in selected patients with severe supra-aortic vessel disease who require concomitant open carotid or subclavian artery reconstructions. PMID- 21669862 TI - Variations in anatomy of the popliteal artery and its side branches. AB - Knowledge of anatomic variations of the popliteal artery is essential for the management of peripheral vascular disease and in orthopedic surgery. The aim of this study was to perform an overview of the literature describing variations of the popliteal artery. To identify relevant literature, we performed a systematic search on MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews. We included 4 studies of anatomic dissections and 11 radiologic retrospective series, comprising 7671 limbs, and a variation in popliteal branching was seen in almost 10%. The 3 most frequent variations in branching are a high origin of the anterior tibial artery, the trifurcation of the anterior tibial artery, peroneal artery, and posterior tibial artery, and a hypoplastic or aplastic posterior tibial artery. Awareness of the terminal branching pattern of the popliteal artery before intervention enhances the planning for successful operations and may reduce the incidence of serious, unexpected arterial injury. PMID- 21669863 TI - Results with Viabahn-assisted subintimal recanalization for TASC C and TASC D superficial femoral artery occlusive disease. AB - OBJECTIVES: Many investigators including TransAtlantic Inter-Society Consensus (TASC) recommend against primary endovascular treatment for severe (TASC C and D) superficial femoral artery (SFA) disease. Vein bypass is preferable but may not be appropriate due to comorbidities or lack of suitable vein. This study reviews our results with Viabahn stent graft-assisted subintimal recanalization (VASIR) for TASC C and D SFA atherosclerosis. METHODS: In all, 13 males and 14 females, mean age 72 +/- 11 years underwent 28 VASIR for severe (TASC C 8 of 28, TASC D 20 of 28, and 5 of 28 no continuous infrapopliteal runoff artery) SFA disease. Indications were claudication (14 of 28 limbs), ischemic rest pain (6 of 28), and tissue loss (8 of 28). Viabahn stent graft-assisted subintimal recanalization was chosen instead of bypass due to comorbidities or lack of vein. Patients received aspirin and, if not already taking warfarin, they also received clopidogrel. Patients were examined with Ankle-brachial Index (ABI) and duplex scan at 1 month, then every 3 months after VASIR. RESULTS: Viabahn stent graft-assisted subintimal recanalization was technically successful in all. Ankle-brachial Index averaged 0.47 +/- 0.17 preprocedure, 0.89 +/- 0.20 postprocedure, and increased by 0.15 or more in every case. Median follow-up is 20 months. There were 3 perioperative (<30 days) and 7 later failures including revision prior to any thrombosis. One patient required amputation. Four have died, 2 with patent grafts, none from causes related to VASIR, all more than 30 days post-VASIR. Estimated 1-year primary and secondary patency were 70% +/- 11% and 73% +/- 10%. Failure was not significantly associated with indications, comorbidities, or runoff status. There was a clear distinction between patients with early failure and the rest of the patients. None of the 8 patients with failure in the first 8 months after surgery has a patent graft. However, of 17 grafts primarily patent at 8 months, only 2 have failed (1 thrombosed and 1 required preemptive balloon angioplasty). There was a strong trend toward better patency with 6 and 7 mm diameter compared to 5 mm diameter stent grafts. Furthermore, although warfarin was not prescribed as part of the protocol, no patient taking warfarin before and who resumed warfarin after VASIR (n=4) suffered failure. CONCLUSIONS: Despite significant early failures, we found VASIR to be durable in those who did not have early failure. Viabahn stent graft-assisted subintimal recanalization is an acceptable alternative to vein bypass in selected patients with severe SFA disease. Smaller arterial or stent graft diameter may be associated with poorer results. Warfarin may be valuable to reduce the risk of failure after VASIR. PMID- 21669864 TI - Short- to mid-term results using autologous bone-marrow mononuclear cell implantation therapy as a limb salvage procedure in patients with severe peripheral arterial disease. AB - Short- to mid-term results of a prospective study evaluating dual intramuscular and intra-arterial autologous bone-marrow mononuclear cell (BM-MNC) implantation for the treatment of patients with severe peripheral arterial occlusive disease (PAD) in whom amputation was considered the only viable treatment option are presented. Ankle-brachial indices (ABIs), rest pain, and ulcer healing were assessed at 3 months. Success was defined as improvement in ABI measurements; absence of rest pain; absence of ulcers; and absence of major limb amputations. Twenty patients (21 limbs) have been enrolled. Three-month follow-up evaluation accounting included 18 patients (19 limbs). Four (22.2%) major and 2 (11.1%) minor amputations were performed within 3 months postoperatively. With 17 (94.4%) of 18 limbs demonstrating at least one criterion for success and major amputation avoided in 14 (77.8%) of 18 limbs at the 3-month evaluation, this specific BM-MNC implantation technique is an effective limb salvage strategy for patients with severe PAD. PMID- 21669865 TI - Synthetic reversal of epigenetic silencing. AB - Controlling cell fate-determining gene expression is key to stem cell differentiation, tissue regeneration, and cancer therapy. To date, custom-built transcription factors recognize the information encoded in specific DNA sequences. Chromatin proteins undergo covalent modifications and form complexes that encode a second layer of information that determines proximal gene activity. Here, we employ a novel gene-targeting approach that exploits a specific chromatin modification to reactivate silenced loci in human cells. We used the human Polycomb chromatin protein and homologues from other species to construct modular synthetic transcription factors, called Pc-TFs, that recognize the repressive trimethyl-histone H3 lysine 27 (H3K27me3) signal and switch silenced genes to an active state. Pc-TF expression in U2OS osteosarcoma cells leads to increased transcription of the senescence locus CDKN2A (p16) and other loci in a chromodomain- and activation module-dependent manner, a switch to a senescence phenotype, and reduced cell proliferation. These results indicate that silenced developmental regulators can be reactivated by a synthetic transcription factor that interacts with chromatin rather than DNA, resulting in an altered cell state. As such, our work extends the flexibility of transcription factor engineering and is the first example of chromatin-mediated synthetic transcription factor targeting. PMID- 21669866 TI - Selenoprotein-dependent up-regulation of hematopoietic prostaglandin D2 synthase in macrophages is mediated through the activation of peroxisome proliferator activated receptor (PPAR) gamma. AB - The plasticity of macrophages is evident from their dual role in inflammation and resolution of inflammation that are accompanied by changes in the transcriptome and metabolome. Along these lines, we have previously demonstrated that the micronutrient selenium increases macrophage production of arachidonic acid (AA) derived anti-inflammatory 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and decreases the proinflammatory PGE(2). Here, we hypothesized that selenium modulated the metabolism of AA by a differential regulation of various prostaglandin (PG) synthases favoring the production of PGD(2) metabolites, Delta(12)-PGJ(2) and 15d-PGJ(2). A dose-dependent increase in the expression of hematopoietic-PGD(2) synthase (H-PGDS) by selenium and a corresponding increase in Delta(12)-PGJ(2) and 15d-PGJ(2) in RAW264.7 macrophages and primary bone marrow-derived macrophages was observed. Studies with organic non-bioavailable forms of selenium and the genetic manipulation of cellular selenium incorporation machinery indicated that selenoproteins were necessary for H-PGDS expression and 15d-PGJ(2) production. Treatment of selenium-deficient macrophages with rosiglitazone, a peroxisome proliferator-activated receptor gamma ligand, up regulated H-PGDS. Furthermore, electrophoretic mobility shift assays indicated the presence of an active peroxisome proliferator-activated receptor-response element in murine Hpgds promoter suggesting a positive feedback mechanism of H PGDS expression. Alternatively, the expression of nuclear factor-kappaB-dependent thromboxane synthase and microsomal PGE(2) synthase was down-regulated by selenium. Using a Friend virus infection model of murine leukemia, the onset of leukemia was observed only in selenium-deficient and indomethacin-treated selenium-supplemented mice but not in the selenium-supplemented group or those treated with 15d-PGJ(2). These results suggest the importance of selenium in the shunting of AA metabolism toward the production of PGD(2) metabolites, which may have clinical implications. PMID- 21669867 TI - Ca2+/Calmodulin-dependent protein kinase kinase beta is regulated by multisite phosphorylation. AB - Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) is a serine/threonine-directed kinase that is activated following increases in intracellular Ca(2+). CaMKKbeta activates Ca(2+)/calmodulin-dependent protein kinase I, Ca(2+)/calmodulin-dependent protein kinase IV, and the AMP-dependent protein kinase in a number of physiological pathways, including learning and memory formation, neuronal differentiation, and regulation of energy balance. Here, we report the novel regulation of CaMKKbeta activity by multisite phosphorylation. We identify three phosphorylation sites in the N terminus of CaMKKbeta, which regulate its Ca(2+)/calmodulin-independent autonomous activity. We then identify the kinases responsible for these phosphorylations as cyclin dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3). In addition to regulation of autonomous activity, we find that phosphorylation of CaMKKbeta regulates its half-life. We find that cellular levels of CaMKKbeta correlate with CDK5 activity and are regulated developmentally in neurons. Finally, we demonstrate that appropriate phosphorylation of CaMKKbeta is critical for its role in neurite development. These results reveal a novel regulatory mechanism for CaMKKbeta-dependent signaling cascades. PMID- 21669868 TI - Protein kinase Ctheta is a specific target for inhibition of the HIV type 1 replication in CD4+ T lymphocytes. AB - Integration of HIV-1 genome in CD4(+) T cells produces latent reservoirs with long half-life that impedes the eradication of the infection. Control of viral replication is essential to reduce the size of latent reservoirs, mainly during primary infection when HIV-1 infects CD4(+) T cells massively. The addition of immunosuppressive agents to highly active antiretroviral therapy during primary infection would suppress HIV-1 replication by limiting T cell activation, but these agents show potential risk for causing lymphoproliferative disorders. Selective inhibition of PKC, crucial for T cell function, would limit T cell activation and HIV-1 replication without causing general immunosuppression due to PKC being mostly expressed in T cells. Accordingly, the effect of rottlerin, a dose-dependent PKC inhibitor, on HIV-1 replication was analyzed in T cells. Rottlerin was able to reduce HIV-1 replication more than 20-fold in MT-2 (IC(50) = 5.2 MUM) and Jurkat (IC(50) = 2.2 MUM) cells and more than 4-fold in peripheral blood lymphocytes (IC(50) = 4.4 MUM). Selective inhibition of PKC, but not PKCdelta or -zeta, was observed at <6.0 MUM, decreasing the phosphorylation at residue Thr(538) on the kinase catalytic domain activation loop and avoiding PKC translocation to the lipid rafts. Consequently, the main effector at the end of PKC pathway, NF-kappaB, was repressed. Rottlerin also caused a significant inhibition of HIV-1 integration. Recently, several specific PKC inhibitors have been designed for the treatment of autoimmune diseases. Using these inhibitors in combination with highly active antiretroviral therapy during primary infection could be helpful to avoid massive viral infection and replication from infected CD4(+) T cells, reducing the reservoir size at early stages of the infection. PMID- 21669869 TI - An undecided coiled coil: the leucine zipper of Nek2 kinase exhibits atypical conformational exchange dynamics. AB - Leucine zippers are oligomerization domains used in a wide range of proteins. Their structure is based on a highly conserved heptad repeat sequence in which two key positions are occupied by leucines. The leucine zipper of the cell cycle regulated Nek2 kinase is important for its dimerization and activation. However, the sequence of this leucine zipper is most unusual in that leucines occupy only one of the two hydrophobic positions. The other position, depending on the register of the heptad repeat, is occupied by either acidic or basic residues. Using NMR spectroscopy, we show that this leucine zipper exists in two conformations of almost equal population that exchange with a rate of 17 s(-1). We propose that the two conformations correspond to the two possible registers of the heptad repeat. This hypothesis is supported by a cysteine mutant that locks the protein in one of the two conformations. NMR spectra of this mutant showed the predicted 2-fold reduction of peaks in the (15)N HSQC spectrum and the complete removal of cross peaks in exchange spectra. It is possible that interconversion of these two conformations may be triggered by external signals in a manner similar to that proposed recently for the microtubule binding domain of dynein and the HAMP domain. As a result, the leucine zipper of Nek2 kinase is the first example where the frameshift of coiled-coil heptad repeats has been directly observed experimentally. PMID- 21669870 TI - Signaling events involved in interleukin 27 (IL-27)-induced proliferation of human naive CD4+ T cells and B cells. AB - IL-27 induces stronger proliferation of naive than memory human B cells and CD4(+) T cells. In B cells, this differential response is associated with similar levels of IL-27 receptor chains, IL-27Ralpha and gp130, in both subsets and stronger STAT1 and STAT3 activation by IL-27 in naive B cells. Here, we show that the stronger proliferative response of CD3-stimulated naive CD4(+) T cells to IL 27 is associated with lower levels of IL-27Ralpha but higher levels of gp130 compared with memory CD4(+) T cells. IL-27 signaling differs between naive and memory CD4(+) T cells, as shown by more sustained STAT1, -3, and -5 activation and weaker activation of SHP-2 in naive CD4(+) T cells. In the latter, IL-27 increases G0/G1 to S phase transition, cell division and, in some cases, cell survival. IL-27 proliferative effect on naive CD4(+) T cells is independent of MAPK, but is dependent on c-Myc and Pim-1 induction by IL-27 and is associated with induction of cyclin D2, cyclin D3, and CDK4 by IL-27 in a c-Myc and Pim-1 dependent manner. In BCR-stimulated naive B cells, IL-27 only increases entry in the S phase and induces the expression of Pim-1 and of cyclins A, D2, and D3. In these cells, inhibition of Pim-1 inhibits IL-27 effect on proliferation and cyclin induction. Altogether, these data indicate that IL-27 mediates proliferation of naive CD4(+) T cells and B cells through induction of both common and distinct sets of cell cycle regulators. PMID- 21669871 TI - Interaction of actin with carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) receptor in liposomes is Ca2+- and phospholipid-dependent. AB - The regulation of binding of G-actin to cytoplasmic domains of cell surface receptors is a common mechanism to control diverse biological processes. To model the regulation of G-actin binding to a cell surface receptor we used the cell cell adhesion molecule carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1-S) in which G-actin binds to its short cytoplasmic domain (12 amino acids; Chen, C. J., Kirshner, J., Sherman, M. A., Hu, W., Nguyen, T., and Shively, J. E. (2007) J. Biol. Chem. 282, 5749-5760). A liposome model system demonstrates that G-actin binds to the cytosolic domain peptide of CEACAM1-S in the presence of negatively charged palmitoyl-oleoyl phosphatidylserine (POPS) liposomes and Ca(2+). In contrast, no binding of G-actin was observed in palmitoyl-oleoyl phosphatidylcholine (POPC) liposomes or when a key residue in the peptide, Phe-454, is replaced with Ala. Molecular Dynamics simulations on CEACAM1-S in an asymmetric phospholipid bilayer show migration of Ca(2+) ions to the lipid leaflet containing POPS and reveal two conformations for Phe-454 explaining the reversible availability of this residue for G-actin binding. NMR transverse relaxation optimized spectroscopic analysis of (13)C-labeled Phe-454 CEACAM1-S peptide in liposomes plus actin further confirmed the existence of two peptide conformers and the Ca(2+) dependence of actin binding. These findings explain how a receptor with a short cytoplasmic domain can recruit a cytosolic protein in a phospholipid and Ca(2+)-specific manner. In addition, this model system provides a powerful approach that can be applied to study other membrane protein interactions with their cytosolic targets. PMID- 21669872 TI - Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase/Akt pathway. AB - Inflammatory processes play essential roles in the pathogenesis of tendinitis and tendinopathy. These events are accompanied by catabolic processes initiated by pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Pharmacological treatments for tendinitis are restricted to the use of non-steroidal anti-inflammatory drugs. Recent studies in various cell models have demonstrated that curcumin targets the NF-kappaB signaling pathway. However, its potential for the treatment of tendinitis has not been explored. Herein, we used an in vitro model of human tenocytes to study the mechanism of curcumin action on IL-1beta-mediated inflammatory signaling. Curcumin at concentrations of 5-20 MUm inhibited IL-1beta-induced inflammation and apoptosis in cultures of human tenocytes. The anti-inflammatory effects of curcumin included down-regulation of gene products that mediate matrix degradation (matrix metalloproteinase-1, -9, and -13), prostanoid production (cyclooxygenase-2), apoptosis (Bax and activated caspase-3), and stimulation of cell survival (Bcl-2), all known to be regulated by NF-kappaB. Furthermore, curcumin suppressed IL-1beta-induced NF-kappaB activation via inhibition of phosphorylation and degradation of inhibitor of kappaBalpha, inhibition of inhibitor of kappaB-kinase activity, and inhibition of nuclear translocation of NF-kappaB. Furthermore, the effects of IL-1beta were abrogated by wortmannin, suggesting a role for the phosphatidylinositol 3-kinase (PI-3K) pathway in IL 1beta signaling. Curcumin suppressed IL-1beta-induced PI-3K p85/Akt activation and its association with IKK. These results demonstrate, for the first time, a potential role for curcumin in treating tendon inflammation through modulation of NF-kappaB signaling, which involves PI-3K/Akt and the tendon-specific transcription factor scleraxis in tenocytes. PMID- 21669873 TI - Shortened engineered human antibody CH2 domains: increased stability and binding to the human neonatal Fc receptor. AB - The immunoglobulin (Ig) constant CH2 domain is critical for antibody effector functions. Isolated CH2 domains are promising scaffolds for construction of libraries containing diverse binders that could also confer some effector functions. We have shown previously that an isolated human CH2 domain is relatively unstable to thermally induced unfolding, but its stability can be improved by engineering an additional disulfide bond (Gong, R., Vu, B. K., Feng, Y., Prieto, D. A., Dyba, M. A., Walsh, J. D., Prabakaran, P., Veenstra, T. D., Tarasov, S. G., Ishima, R., and Dimitrov, D. S. (2009) J. Biol. Chem. 284, 14203 14210). We have hypothesized that the stability of this engineered antibody domain could be further increased by removing unstructured residues. To test our hypothesis, we removed the seven N-terminal residues that are in a random coil as suggested by our analysis of the isolated CH2 crystal structure and NMR data. The resulting shortened engineered CH2 (m01s) was highly soluble, monomeric, and remarkably stable, with a melting temperature (T(m)) of 82.6 degrees C, which is about 10 and 30 degrees C higher than those of the original stabilized CH2 (m01) and CH2, respectively. m01s and m01 were more resistant to protease digestion than CH2. A newly identified anti-CH2 antibody that recognizes a conformational epitope bound to m01s significantly better (>10-fold higher affinity) than to CH2 and slightly better than to m01. m01s bound to a recombinant soluble human neonatal Fc receptor at pH 6.0 more strongly than CH2. These data suggest that shortening the m01 N terminus significantly increases stability without disrupting its conformation and that our approach for increasing stability and decreasing size by removing unstructured regions may also apply to other proteins. PMID- 21669874 TI - SKAP1 protein PH domain determines RapL membrane localization and Rap1 protein complex formation for T cell receptor (TCR) activation of LFA-1. AB - Although essential for T cell function, the identity of the T cell receptor (TCR) "inside-out" pathway for the activation of lymphocyte function-associated antigen 1 (LFA-1) is unclear. SKAP1 (SKAP-55) is the upstream regulator needed for TCR induced RapL-Rap1 complex formation and LFA-1 activation. In this paper, we show that SKAP1 is needed for RapL binding to membranes in a manner dependent on the PH domain of SKAP1 and the PI3K pathway. A SKAP1 PH domain-inactivating mutation (i.e. R131M) markedly impaired RapL translocation to membranes for Rap1 and LFA-1 binding and the up-regulation of LFA-1-intercellular adhesion molecule 1 (ICAM-1) binding. Further, N-terminal myr-tagged SKAP1 for membrane binding facilitated constitutive RapL membrane and Rap1 binding and effectively substituted for PI3K and TCR ligation in the activation of LFA-1 in T cells. PMID- 21669875 TI - Retinoic acid signaling sequentially controls visceral and heart laterality in zebrafish. AB - During zebrafish development, the left-right (LR) asymmetric signals are first established around the Kupffer vesicle (KV), a ciliated organ generating directional fluid flow. Then, LR asymmetry is conveyed and stabilized in the lateral plate mesoderm. Although numerous molecules and signaling pathways are involved in controlling LR asymmetry, mechanistic difference and concordance between different organs during LR patterning are poorly understood. Here we show that RA signaling regulates laterality decisions at two stages in zebrafish. Before the 2-somite stage (2So), inhibition of RA signaling leads to randomized visceral laterality through bilateral expression of nodal/spaw in the lateral plate mesoderm, which is mediated by increases in cilia length and defective directional fluid flow in KV. Fgf8 is required for the regulation of cilia length by RA signaling. Blockage of RA signaling before 2So also leads to mild defects of heart laterality, which become much more severe through perturbation of cardiac bmp4 asymmetry when RA signaling is blocked after 2So. At this stage, visceral laterality and the left-sided Nodal remain unaffected. These findings suggest that RA signaling controls visceral laterality through the left-sided Nodal signal before 2So, and regulates heart laterality through cardiac bmp4 mainly after 2So, first identifying sequential control and concordance of visceral and heart laterality. PMID- 21669876 TI - Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts. AB - We previously reported that partial disruption of the Ankrd26 gene in mice leads to hyperphagia and leptin-resistant obesity. To determine whether the Ankrd26 mutation can affect the development of adipocytes, we studied mouse embryo fibroblasts (MEFs) from the mutant mice. We found that Ankrd26(-/-) MEFs have a higher rate of spontaneous adipogenesis than normal MEFs and that adipocyte formation is greatly increased when the cells are induced with troglitazone alone or with a mixture of troglitazone, insulin, dexamethasone, and methylisobutylxanthine. Increased adipogenesis was detected as an increase in lipid droplet formation and in the expression of several markers of adipogenesis. There was an increase in expression of early stage adipogenesis genes such as Krox20, KLF5, C/EBPbeta, C/EBPdelta, and late stage adipogenesis regulators KLF15, C/EBPalpha, PPARgamma, and aP2. There was also an increase in adipocyte stem cell markers CD34 and Sca-1 and preadipocyte markers Gata2 and Pref-1, indicating an increase in both stem cells and progenitor cells in the mutant MEFs. Furthermore, ERK was found constitutively activated in Anrd26(-/-) MEFs, and the addition of MEK inhibitors to mutant cells blocked ERK activation, decreased adipogenesis induction, and significantly reduced expression of C/EBPdelta, KLF15, PPARgamma2, CD34, and Pref-1 genes. We conclude that Ankrd26 gene disruption promotes adipocyte differentiation at both the progenitor commitment and differentiation steps and that ERK activation plays a role in this process. PMID- 21669877 TI - Global identification of SMAD2 target genes reveals a role for multiple co regulatory factors in zebrafish early gastrulas. AB - Nodal and Smad2/3 signals play pivotal roles in mesendoderm induction and axis determination during late blastulation and early gastrulation in vertebrate embryos. However, Smad2/3 direct target genes during those critical developmental stages have not been systematically identified. Here, through ChIP-chip assay, we show that the promoter/enhancer regions of 679 genes are bound by Smad2 in the zebrafish early gastrulas. Expression analyses confirm that a significant proportion of Smad2 targets are indeed subjected to Nodal/Smad2 regulation at the onset of gastrulation. The co-existence of DNA-binding sites of other transcription factors in the Smad2-bound regions allows the identification of well known Smad2-binding partners, such as FoxH1 and Lef1/beta-catenin, as well as many previously unknown Smad2 partners, including Oct1 and Gata6, during embryogenesis. We demonstrate that Oct1 physically associates with and enhances the transcription and mesendodermal induction activity of Smad2, whereas Gata6 exerts an inhibitory role in Smad2 signaling and mesendodermal induction. Thus, our study systemically uncovers a large number of Smad2 targets in early gastrulas and suggests cooperative roles of Smad2 and other transcription factors in controlling target gene transcription, which will be valuable for studying regulatory cascades during germ layer formation and patterning of vertebrate embryos. PMID- 21669878 TI - Consequences of loss of Vph1 protein-containing vacuolar ATPases (V-ATPases) for overall cellular pH homeostasis. AB - In yeast cells, subunit a of the vacuolar proton pump (V-ATPase) is encoded by two organelle-specific isoforms, VPH1 and STV1. V-ATPases containing Vph1 and Stv1 localize predominantly to the vacuole and the Golgi apparatus/endosomes, respectively. Ratiometric measurements of vacuolar pH confirm that loss of STV1 has little effect on vacuolar pH. Loss of VPH1 results in vacuolar alkalinization that is even more rapid and pronounced than in vma mutants, which lack all V ATPase activity. Cytosolic pH responses to glucose addition in the vph1Delta mutant are similar to those in vma mutants. The extended cytosolic acidification in these mutants arises from reduced activity of the plasma membrane proton pump, Pma1p. Pma1p is mislocalized in vma mutants but remains at the plasma membrane in both vph1Delta and stv1Delta mutants, suggesting multiple mechanisms for limiting Pma1 activity when organelle acidification is compromised. pH measurements in early prevacuolar compartments via a pHluorin fusion to the Golgi protein Gef1 demonstrate that pH responses of these compartments parallel cytosolic pH changes. Surprisingly, these compartments remain acidic even in the absence of V ATPase function, possibly as a result of cytosolic acidification. These results emphasize that loss of a single subunit isoform may have effects far beyond the organelle where it resides. PMID- 21669880 TI - How agro-ecological research helps to address food security issues under new IPM and pesticide reduction policies for global crop production systems. AB - Drivers behind food security and crop protection issues are discussed in relation to food losses caused by pests. Pests globally consume food estimated to feed an additional one billion people. Key drivers include rapid human population increase, climate change, loss of beneficial on-farm biodiversity, reduction in per capita cropped land, water shortages, and EU pesticide withdrawals under policies relating to 91/414 EEC. IPM (Integrated Pest Management) will be compulsory for all EU agriculture by 2014 and is also being widely adopted globally. IPM offers a 'toolbox' of complementary crop- and region-specific crop protection solutions to address these rising pressures. IPM aims for more sustainable solutions by using complementary technologies. The applied research challenge now is to reduce selection pressure on single solution strategies, by creating additive/synergistic interactions between IPM components. IPM is compatible with organic, conventional, and GM cropping systems and is flexible, allowing regional fine-tuning. It reduces pests below economic thresholds utilizing key 'ecological services', particularly biocontrol. A recent global review demonstrates that IPM can reduce pesticide use and increase yields of most of the major crops studied. Landscape scale 'ecological engineering', together with genetic improvement of new crop varieties, will enhance the durability of pest-resistant cultivars (conventional and GM). IPM will also promote compatibility with semiochemicals, biopesticides, precision pest monitoring tools, and rapid diagnostics. These combined strategies are urgently needed and are best achieved via multi-disciplinary research, including complex spatio temporal modelling at farm and landscape scales. Integrative and synergistic use of existing and new IPM technologies will help meet future food production needs more sustainably in developed and developing countries, in an era of reduced pesticide availability. Current IPM research gaps are identified and discussed. PMID- 21669879 TI - Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes. AB - Lipid microdomains or caveolae, small invaginations of plasma membrane, have emerged as important elements for lipid uptake and glucose homeostasis. Sphingomyelin (SM) is one of the major phospholipids of the lipid microdomains. In this study, we investigated the physiological function of sphingomyelin synthase 2 (SMS2) using SMS2 knock-out mice, and we found that SMS2 deficiency prevents high fat diet-induced obesity and insulin resistance. Interestingly, in the liver of SMS2 knock-out mice, large and mature lipid droplets were scarcely observed. Treatment with siRNA for SMS2 also decreased the large lipid droplets in HepG2 cells. Additionally, the siRNA of SMS2 decreased the accumulation of triglyceride in liver of leptin-deficient (ob/ob) mice, strongly suggesting that SMS2 is involved in lipid droplet formation. Furthermore, we found that SMS2 exists in lipid microdomains and partially associates with the fatty acid transporter CD36/FAT and with caveolin 1, a scaffolding protein of caveolae. Because CD36/FAT and caveolin 1 exist in lipid microdomains and are coordinately involved in lipid droplet formation, SMS2 is implicated in the modulation of the SM in lipid microdomains, resulting in the regulation of CD36/FAT and caveolae. Here, we established new cell lines, in which we can completely distinguish SMS2 activity from SMS1 activity, and we demonstrated that SMS2 could convert ceramide produced in the outer leaflet of the plasma membrane into SM. Our findings demonstrate the novel and dynamic regulation of lipid microdomains via conformational changes in lipids on the plasma membrane by SMS2, which is responsible for obesity and type 2 diabetes. PMID- 21669881 TI - Exploration of the difference in incidence of renal replacement therapy between Flanders and the Netherlands--investigation of explanatory variables. AB - AIM: This study investigates the difference in the incidence of renal replacement therapy (RRT) between Flanders and the Netherlands and possible explanations for this difference. METHODS: End-stage renal disease incidence data were obtained from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA). Additional sources were the National Institute of Statistics (NIS), the Central Bureau of Statistics (CBS), the Organisation for Economic Cooperation and Development (OECD) health data and the WHO Health For All database (WHO-HFA). RESULTS: There is remarkable difference in incidence rate of RRT between Flanders and the Netherlands, with a higher rate in Flanders. This difference is already present in patients aged 45-64 years and increases with age, being >2-fold higher in subjects of >= 75 years. With respect to the renal diagnoses leading to need for RRT, a higher share of especially diabetes mellitus type 2 and renovascular disease was observed in Flanders. Remarkably, the difference in incidence rate of RRT is not associated with a difference in survival on RRT, not even in the elderly, arguing against a restricted access to RRT in the Netherlands. In the general population, the expected number of healthy life years at birth is lower in Belgium than in the Netherlands, and in Belgium, the hospital discharge rates for diabetes, acute myocardial infarction and cerebrovascular accident and the number of coronary bypass procedures and percutaneous coronary interventions per capitum is higher, as is the prevalence of obesity. CONCLUSION: Our data do not support the assumption that the differences in RRT incidence in the elderly between Flanders and the Netherlands are due to a more restricted access to RRT in the Netherlands but may be due to differences in underlying comorbidity and life style between the two populations. PMID- 21669882 TI - Higher hemoglobin level is associated with subtle declines in renal function and presence of cardiorenal risk factors in early CKD stages. AB - BACKGROUND: Patients with advanced renal dysfunction have comorbidities, including anemia, as a consequence of reduced production of erythropoietin. However, little is known about the renal response to early decreases in estimated glomerular filtration rate (eGFR) before the onset of anemia. We therefore investigated the hemoglobin concentration across subtle declines in renal function stratified by cardiorenal risk factors, in subjects with eGFR >=50 mL/min/1.73 m(2). METHODS: Based on the data from routine health checkups in tertiary university hospitals during the last 15 years, 145 865 adult subjects were identified. RESULTS: Hemoglobin levels among eGFR Groups 2-6 (50 <= eGFR < 100 mL/min/1.73m(2)) were significantly higher compared to eGFR group >=100 mL/min/1.73m(2) (P < 0.001), and the highest level of mean hemoglobin was seen at eGFR 50-59 mL/min/1.73m(2). The mean hemoglobin level of subjects with eGFR 50-59 mL/min/1.73m(2) and eGFR >= 100 mL/min/1.73m(2) were 13.36 [95% confidence interval (CI): 13.33-13.40] g/dL versus 12.92 (95% CI: 12.88-12.95) g/dL in women (P < 0.001); in men, 15.60 (95% CI: 15.57-15.63) g/dL versus 15.15 (95% CI: 15.11 15.18) g/dL (P < 0.001). Among each eGFR group, hemoglobin levels were higher in subjects with hypertension (P < 0.001 in both genders), diabetes mellitus (P < 0.001 in both genders) and components of MS (P < 0.003 in both genders) compared to subjects without these conditions. CONCLUSION: Hemoglobin concentration may be slightly higher across subtle declines in renal function and the presence of cardiorenal risk factors in early CKD stages. PMID- 21669883 TI - Atrial natriuretic peptide ameliorates peritoneal fibrosis in rat peritonitis model. AB - BACKGROUND: Atrial natriuretic peptide (ANP) was recently reported to ameliorate fibrosis in the heart and experimental renal diseases and vascular thickening after balloon injury. Peritoneal fibrosis is an important complication of long term peritoneal dialysis, and peritonitis is a factor in its onset. In the present study, we investigated the effects of ANP in a rat peritonitis-induced peritoneal fibrosis model. METHODS: As pretreatment, an osmotic pump containing vehicle (saline) or ANP (0.15 or 0.3 MUg/min) was inserted through the carotid vein in male Sprague-Dawley rats. ANP or saline was continuously infused using the osmotic pump. Three days after administration of ANP or saline, rats underwent peritoneal scraping in a blind manner and were sacrificed on Day 14. The effects of ANP were evaluated based on peritoneal thickness, immunohistochemistry and real-time polymerase chain reaction. In each experiment, we evaluated messenger RNA (mRNA) expression of the ANP receptor natriuretic peptide receptor A (NPR-A) in the peritoneum after scraping. The effects of ANP were also studied in cultured peritoneal fibroblasts and mesothelial cells. RESULTS: We observed a significant increase in NPR-A mRNA in the peritoneum. Peritoneal thickness increased with time and peaked on Day 14, but ANP significantly reduced peritoneal thickness. Parameters such as number of macrophages and CD-31-positive vessels and expression of type III collagen/transforming growth factor-beta/plasminogen activator inhibitor-1 (PAI 1)/connective tissue growth factor (CTGF) were significantly suppressed by ANP. In cultured peritoneal fibroblasts and mesothelial cells, ANP suppressed angiotensin II-induced upregulation of CTGF and PAI-1. CONCLUSIONS: Our results suggest that ANP is useful in preventing inflammation-induced peritoneal fibrosis. PMID- 21669884 TI - Long-term retinal, renal and cardiovascular outcomes in diabetic chronic kidney disease without proteinuria. AB - BACKGROUND: Patients with diabetes mellitus (DM) with chronic kidney disease (CKD) often have no proteinuria. METHODS: To compare the characteristics that differ between DM + CKD patients with and without proteinuria, we conducted a cross-sectional study followed by surveillance over a decade for 'hard' cardiovascular, renal and retinal outcomes. Groups were stratified by presence (n = 129) and absence (n = 284) of DM. Each stratum had three groups: no CKD, CKD without proteinuria and CKD with proteinuria. RESULTS: Compared to DM + CKD + proteinuria patients, those with DM + CKD but without proteinuria had similar clinical characteristics including estimated glomerular filtration rate. However, they had lower 24-h ambulatory systolic and diastolic blood pressure. Crude all cause mortality rates per 1000 patient-years in the nondiabetic group with no CKD, CKD with no proteinuria and CKD with overt proteinuria were 29.3, 68.5 and 111.1, respectively. Respective rates in the diabetic group were 50.1, 105.7 and 136.8. Diabetes increased the risk of coronary (P = 0.01) and end-stage renal disease (ESRD) events (P = 0.05) even after multivariate adjustments. Proteinuria aggravated the risk of cardiovascular events, ESRD, death and time to first of these events similarly among diabetics with CKD compared to nondiabetics with CKD. Diabetic patients with CKD but no overt proteinuria were much more likely than nondiabetics to progress to overt proteinuria [adjusted hazard ratio 5.28 (95% confidence interval 1.64-17.02), P < 0.01). CKD was a risk factor for prevalent retinopathy and proteinuria was a risk factor for incident diabetic retinopathy. CONCLUSIONS: To protect sight, those with proteinuria and DM need regular retinal examinations. Since diabetic CKD patients without proteinuria are more likely to develop overt proteinuria, close follow-up and risk factor management among these patients appear to be more important than among nondiabetic patients with CKD and no proteinuria. PMID- 21669885 TI - Clinical and molecular characterization of Turkish patients with familial hypomagnesaemia: novel mutations in TRPM6 and CLDN16 genes. AB - BACKGROUND: Recent identification and characterization of novel renal Mg(2+) transporters and ion channels have greatly increased our understanding of the normal physiology of renal magnesium handling. METHODS: The present study deals with the clinical and molecular characterization of eight Turkish children (median age 10.6 years, range 3-16.2 years, five boys and three girls) with primary hypomagnesaemia from six families. RESULTS: All patients initially presented with tetany and convulsions. Laboratory evaluation yielded severely low serum magnesium levels and low serum calcium levels in all patients. While six patients exhibited inadequately low parathyroid hormone levels, the two remaining patients showed hyperparathyroidism, hypercalciuria and nephrocalcinosis. Genetic studies revealed familial hypomagnesaemia with secondary hypocalcaemia (HSH) due to a TRPM6 mutation in six patients and familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) due to a CLDN16 mutation in one patient. CONCLUSIONS: Among recently identified magnesium-wasting disorders, HSH and FHHNC represent two major entities also in the Turkish population. Besides clinical course and laboratory diagnosis of hypomagnesaemia, the detection of renal calcium wasting and parathyroid function are crucial to differentiate between these most prevalent forms of hereditary magnesium deficiency. While TRPM6 mutations underlying HSH almost uniformly lead to a complete loss of function of the TRPM6 protein, the severity of FHHNC phenotype depends on the residual function of the mutated claudin-16 protein. PMID- 21669887 TI - Peritoneal dialysis in infants: the experience of the Italian Registry of Paediatric Chronic Dialysis. AB - BACKGROUND: Although chronic peritoneal dialysis (CPD) is considered the replacement therapy of choice for infants with end-stage renal failure, many questions persist about treatment risks and outcomes. METHODS: We present data on 84 infants who started CPD at <1 year of age; these patients represent 12% of the total population of the Italian Registry of Paediatric Chronic Dialysis. We analysed patient records from all children consecutively treated with CPD between 1995 and 2007 in Italy. Growth data analysis was performed only in infants with complete auxological parameters at 0, 6 and 12 months of follow-up. RESULTS: Median age at the start of CPD was 6.9 months, weight was 6.1 kg and length 63.6 cm. In one-half of the study population diagnosis leading to renal failure was congenital nephrouropathy. Twenty-eight per cent of the children had at least one pre-existing comorbidity. The mean height standard deviation score was -1.65 at the start of CPD, -1.82 after 12 months and -1.53 after 24 months. Catch-up growth was documented in 50% of patients during dialysis. A positive correlation was observed between longitudinal growth and both exchange volume (R(2) = 0.36) and dialysis session length (R(2) = 0.35), while a negative association was found with the number of peritonitis cases (P = 0.003). Peritonitis incidence was 1:20.7 episode:CPD-months (1:28.3 in the older children from the same registry) and was significantly higher in children with oligoanuria (1:15.5 episode:CPD months) compared to infants with residual renal function (1:37.4 episode:CPD months). Catheter survival rate was 70% at 12 months and 51% at 24 months. Catheter-related complications were similar in infants and older children (1:20.5 versus 1:19.8 episode:CPD-months), while clinical complications were more frequent in children under 1 year of age (1:18.3 versus 1:25.2 episode:CPD months; P < 0.05). During the follow-up period, 33 patients were transplanted (39.3%), 18 were shifted to haemodialysis (21.4%) and 8 died (9.5%). The mortality rate was 4-fold greater than in older children (2.3%). CONCLUSIONS: Our data confirm that infants on CPD represent a high-risk group; however, our experience demonstrated that growth was acceptable and a large portion was successfully transplanted. Increased efforts should be aimed at optimizing dialysis efficiency and preventing peritonitis. The higher mortality rate in infants was largely caused by comorbidities. PMID- 21669886 TI - A prospective evaluation of urine microscopy in septic and non-septic acute kidney injury. AB - BACKGROUND: Sepsis is the most common trigger for acute kidney injury (AKI) in critically ill patients. We sought to determine whether there are unique patterns to urine sediment in septic compared with non-septic AKI. METHODS: Prospective two center cohort study of adult critically ill patients with septic and non septic AKI, defined by the RIFLE criteria. Eligible patients had clinical, physiologic and laboratory data extracted. Blood and urine were sampled for urine biochemistry, microscopy and neutrophil gelatinase-associated lipocalin (NGAL). A urine microscopy score (UMS) was derived based on the observed quantification of renal tubular cells and casts in the sediment. The UMS was compared between septic and non-septic AKI and correlated with NGAL, worsening AKI, renal replacement therapy (RRT) and hospital mortality. RESULTS: Eighty-three patients were enrolled. Mean (SD) age was 64.3 (16.6) years, 60.2% were male, Charlson comorbidity score was 3.3 (2.8) and Acute Physiology and Chronic Health Evaluation II score was 21.4 (7.6). Septic AKI was present in 43 patients (51.8%). RIFLE class at enrollment was not different between groups (P = 0.43). Septic AKI was associated with higher UMS compared with non-septic AKI (P = 0.001). There was no correlation between UMS and fractional excretion of sodium (FeNa) or fractional excretion of urea (FeU). Elevated urine NGAL (uNGAL) correlated with higher UMS (P = 0.0003), while correlation with plasma NGAL was modest (P = 0.05). Worsening AKI occurred in 22.9% with no difference between septic and non-septic groups. A UMS score >= 3 was associated with increased odds of worsening AKI [adjusted odds ratio 8.0; 95% confidence intervals (CI), 1.03 62.5, P = 0.046]. For a UMS >=3, sensitivity and specificity were 0.67 (95% CI, 0.39-0.86) and 0.95 (0.84-0.99) and positive and negative predictive values we re 0.80 (0.49-0.94) and 0.91 (0.78-0.96) for detecting worsening AKI, respectively. While there were no differences between septic and non-septic AKI, higher UMS correlated with need for RRT (15.7%, P = 0.02) and in-hospital death (30.1%, P = 0.01); however, this did not persist in multivariable analysis. CONCLUSIONS: Septic AKI is associated with greater urine microscopy evidence of kidney injury compared with non-septic AKI, despite similar severity of AKI. A UMS >= 3 correlated with higher uNGAL and was predictive of worsening AKI. Urine microscopy may have a complementary role for discerning septic from non-septic AKI, discriminating severity and predicting worsening AKI in critically ill patients. PMID- 21669888 TI - Puberty and influencing factors in schoolgirls living in Istanbul: end of the secular trend? AB - OBJECTIVE: To (1) establish the median ages at menarche and pubertal stages and investigate influential factors and (2) assess the secular trend in reaching puberty in a transitional society. MATERIALS AND METHODS: A probit method was used to calculate the median age at menarche and pubertal stages from a cross sectional study of 4868 healthy schoolgirls (aged 6-18 years) in Istanbul, Turkey. The findings were compared with those from a similar study performed 4 decades earlier. Logistic regression was used to analyze the associations between the odds of attaining puberty stages and putatively influential factors. Simple statistical models were used to test the effects of BMI and consumption of certain foods on the onset of menarche. RESULTS: The median age at menarche is 12.74 years. The median ages at breast stages 2 through 5 are 9.65, 10.10, 11.75, and 14.17 years, respectively, and at pubic-hair stages 2 through 5 are 10.09, 11.19, 12.33, and 14.68 years, respectively. Girls from upper socioeconomic classes are more likely to reach menarche and B4 and B5 stages. Higher BMI seems to be a promoting factor for attaining menarche. Intrauterine growth and gestational age had no effect. The average age at menarche was not associated with the consumption of milk, eggs, chicken, or fish. CONCLUSIONS: The secular trend in puberty is probably about to end in Turkey. Although the median ages at the breast stages show a decreasing trend, the median age at menarche is approximately the same as it was 4 decades ago. Socioeconomic status and BMI are important, and related, factors that affect the age at menarche and pubertal stages. PMID- 21669889 TI - Prenatal exposure to organochlorine compounds and birth size. AB - OBJECTIVE: To investigate the possible association between birth size and cord concentrations of some organochlorine compounds (OCs), including 4,4' dichlorodiphenyltrichloroethane (DDT), 4,4'-1,1-dichloro-2,2-bis(p dichlorodiphenyl)ethylene (DDE), hexachlorobenzene (HCB), beta hexachlorocyclohexane (beta-HCH), 4 polychlorinated biphenyl (PCB) congeners (118, 138, 153, and 180), and their sum (SigmaPCBs) in a birth cohort in Valencia, Spain. STUDY DESIGN: A total of 494 mothers and their newborns (born 2003-2006) participated in the study. Multivariate linear regression analyses were performed between birth weight, length, or head circumference and OC concentrations. RESULTS: Median concentrations of 4,4'-DDT, 4,4'-DDE, HCB, beta HCH, and SigmaPCBs were 0.02, 0.46, 0.22, 0.09, and 0.35 ng/mL, respectively. For birth weight there was a significant decrease of 63 and 107 g for each 10-fold increase in cord serum 4,4'-DDT and 4,4'-DDE concentrations, and a marginally significant decrease of 79 and 53 g for each 10-fold increase in HCB and beta-HCH concentrations. A significant decrease of 0.39 cm in birth length was found for each 10-fold increase in HCB concentrations. For newborns with cord 4,4'-DDT concentrations above the median there was a significant decrease of 0.26 cm in birth head circumference. CONCLUSIONS: These results reveal that prenatal exposure to some OCs could impair the anthropometric development of the fetus, reducing the birth weight, length, and head circumference. PMID- 21669890 TI - Promoting best-care practices in childhood asthma: quality improvement in community health centers. AB - OBJECTIVE: Outpatient asthma management remains suboptimal. We previously reported significant improvements in asthma guideline adherence and outcomes in children by using quality-improvement processes and community health workers. We hypothesized that a larger project could achieve comparable outcome improvements with streamlined quality-improvement processes and decreased technical assistance. METHODS: Seventeen clinics treating 12 000 children with asthma were evaluated through interviews of a subset of patients with persistent or high-risk asthma (n=761) at baseline and at 12 and 21 months and chart reviews randomly selected from all patients with asthma at baseline and 12 and 24 months (n=2040). Multidisciplinary teams developed data-driven continuous quality-improvement activities. Asthma coordinators provided patient education and were active team members. RESULTS: Study children were predominantly Hispanic (77%) and black (11%); 60% were enrolled in Medicaid, and 9% were uninsured. Comparing results between baseline and the 21-month follow-up, significantly fewer families reported emergency-department visits (29.6% vs 9.3%), hospitalizations (10.9% vs 3.4%), frequent daytime symptoms (44.0% vs 11.7%), and missed school days (28.7% vs 13.6%); significantly more reported confidence in asthma management (70.6% vs 95.5%); and quality-of-life scores increased significantly for both children and caregivers (all P<.05). Cross-sectional data revealed significant clinic-wide improvements in symptom documentation, health care use, and review of action plans. CONCLUSIONS: On a larger scale, this approach realized impressive changes in provider clinical practice associated with major improvements in health outcomes. It holds great potential for significantly reducing asthma-related morbidity among low-income children. PMID- 21669891 TI - Computer-assisted management of attention-deficit/hyperactivity disorder. AB - OBJECTIVES: Medication management of attention-deficit/hyperactivity disorder (ADHD) is often suboptimal. We examined whether (1) brief physician training plus computer-assisted medication management led to greater reduction in ADHD symptoms and (2) adherence to the recommended titration protocol produced greater symptomatic improvement. METHODS: A randomized medication trial was conducted that included 24 pediatric practices. Children who met criteria for ADHD were randomly assigned by practice to treatment-as-usual or a specialized care group in which physicians received 2 hours of didactic training on medication management of ADHD plus training on a software program to assist in monitoring improvement. Parent and teacher reports were obtained before treatment and 4, 9, and 12 months after starting medication. RESULTS: Children in both specialized care and treatment-as-usual groups improved on the ADHD Rating Scales and SNAP IV, but there were no group differences in improvement rates. Brief physician training alone did not produce improvements. When recommended titration procedures were followed, however, outcomes were better for total and inattentive ADHD symptoms on both the ADHD Rating Scales and SNAP-IV parent and teacher scales. Results were not attributable to discontinuation because of adverse effects or failure to find an effective medication dose. CONCLUSIONS: Brief physician training alone did not lead to reductions in ADHD symptoms, but adherence to a protocol that involved titration until the child's symptoms were in the average range and had shown a reliable change led to better symptom reduction. Computer-assisted medication management can contribute to better treatment outcomes in primary care medication treatment of ADHD. PMID- 21669892 TI - Breastfeeding and reduced risk of sudden infant death syndrome: a meta-analysis. AB - CONTEXT: Benefits of breastfeeding include lower risk of postneonatal mortality. However, it is unclear whether breastfeeding specifically lowers sudden infant death syndrome (SIDS) risk, because study results have been conflicting. OBJECTIVE: To perform a meta-analysis to measure the association between breastfeeding and SIDS. METHODS: We identified 288 studies with data on breastfeeding and SIDS through a Medline search (1966-2009), review articles, and meta-analyses. Twenty-four original case-control studies were identified that provided data on the relationship between breastfeeding and SIDS risk. Two teams of 2 reviewers evaluated study quality according to preset criteria; 6 studies were excluded, which resulted in 18 studies for analysis. Univariable and multivariable odds ratios were extracted. A summary odds ratio (SOR) was calculated for the odds ratios by using the fixed-effect and random-effect inverse-variance methods of meta-analysis. The Breslow-Day test for heterogeneity was performed. RESULTS: For infants who received any amount of breast milk for any duration, the univariable SOR was 0.40 (95% confidence interval [CI]: 0.35 0.44), and the multivariable SOR was 0.55 (95% CI: 0.44-0.69). For any breastfeeding at 2 months of age or older, the univariable SOR was 0.38 (95% CI: 0.27-0.54). The univariable SOR for exclusive breastfeeding of any duration was 0.27 (95% CI: 0.24-0.31). CONCLUSIONS: Breastfeeding is protective against SIDS, and this effect is stronger when breastfeeding is exclusive. The recommendation to breastfeed infants should be included with other SIDS risk-reduction messages to both reduce the risk of SIDS and promote breastfeeding for its many other infant and maternal health benefits. PMID- 21669893 TI - Impact of implementing 5 potentially better respiratory practices on neonatal outcomes and costs. AB - OBJECTIVE: We implemented 5 potentially better practices to limit mechanical ventilation (MV), supplemental oxygen, and bronchopulmonary dysplasia in newborn infants born before 33 weeks' gestation. METHODS: The methods used in this study included (1) exclusive use of bubble continuous positive airway pressure (bCPAP), (2) provision of bCPAP in the delivery room, (3) strict intubation criteria, (4) strict extubation criteria, and (5) prolonged CPAP to avoid supplemental oxygen. We excluded outborn infants and those with major anomalies and obstetric complications from analysis. RESULTS: Demographics were similar in 61 infants born before and 60 born after implementation. For infants born at 26 to 32(6/7) weeks' gestation, intubation (first 72 hours) decreased from 52% to 11% (P < .0001) and surfactant use decreased from 48% to 14% (P=.0001). In all infants, the mean +/- SD fraction of inspired oxygen requirement (first 24 hours) decreased from 0.27 +/- 0.08 to 0.24 +/- 0.05 (P=.0005), days of oxygen decreased from 23.5 +/- 44.5 to 9.3 +/- 22.0 (P=.04), and days of MV decreased from 8.8 +/- 27.8 to 2.2 +/- 6.2 (P=.005). Hypotension decreased from 33% to 15% (P=.03). The percentage of infants with bronchopulmonary dysplasia was 17% before and 8% after (P=.27). Nurse staffing ratios remained unchanged. CONCLUSIONS: Implementation of these potentially better practices reduced the need for MV, surfactant, and supplemental oxygen as well as reduced hypotension among infants born before 33 weeks' gestation without adverse consequences. The costs for equipment and surfactant were lower. PMID- 21669894 TI - Analgesic effects of EMLA cream and oral sucrose during venipuncture in preterm infants. AB - OBJECTIVE: The goal of this study was to compare the analgesic effect of sucrose with that of the combination of sucrose and the local anesthetic cream EMLA during venipuncture in preterm neonates. METHODS: This randomized, double-blind prospective study included infants younger than 37 weeks' gestational age during 1 routine venipuncture for blood sampling. Each child randomly received either sucrose plus application of a placebo cream (S group) or sucrose plus EMLA cream (S+E group) before venipuncture. Venipuncture-induced pain was assessed through videotapes of the procedures by using the Douleur Aigue Nouveau-ne (DAN) behavioral scale. Pain was assessed at 2 phases: during venipuncture (from needle introduction to its removal) and during the recovery period (30 seconds after needle removal). Pain scores over time and between treatments were compared by using repeated-measures analysis of variance. RESULTS: The study included 76 children (37 in the S group, 39 in the S+E group). Mean (SD) DAN pain scores for the S group and the S+E group were 7.7 (2.1) and 6.4 (2.5), respectively, during venipuncture and 7.1 (2.8) and 5.7 (3.3) during the postinjection period. A significant time and treatment effect in favor of the S+E group was observed. CONCLUSION: The combination of sucrose and EMLA cream revealed a higher analgesic effect than sucrose alone during venipuncture in these preterm infants. PMID- 21669895 TI - Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. AB - Screened for by all state newborn screening (NBS) programs in the United States, mitochondrial acetoacetyl-coenzyme A thiolase (T2), or beta-ketothiolase, deficiency is a rare autosomal recessive disorder that causes ketoacidosis and hypoglycemia/hyperglycemia. Outcomes vary from normal development to severe cognitive impairment or even death after an acute episode of ketoacidosis. The classical biochemical profile of T2 deficiency is a result of null mutations in both alleles of the ACAT1 gene and consists of persistently increased urinary excretion of ketones, characteristic organic acids, and tiglylglycine as well as abnormal blood or plasma acylcarnitine profiles in acute and stable conditions. Early diagnosis and aggressive management can prevent further episodes of ketoacidosis and lead to normal development. We report the cases of 3 children, all subsequently found to have mutations predicted to be associated with no residual T2 enzymatic activity, but only 1 was identified by NBS in Minnesota since 2001. To our knowledge, this is the first description of compound heterozygotes for null mutations associated with no enzymatic activity exhibiting normal urinary organic acid, blood, and plasma acylcarnitine profiles when clinically well, thereby explaining the false-negative NBS results. We suggest that T2 deficiency may be underrecognized, because the incidence of T2 deficiency in Minnesota, on the basis of these 3 cases, is 1 in 232 000, higher than the reported <1 in 1 million incidence. Our cases emphasize that T2 deficiency must be considered in patients who present with ketoacidosis disproportionately severe to the triggering illness despite normal NBS results or nonspecific biochemical findings in blood and urine during asymptomatic periods. PMID- 21669896 TI - Early autism detection: are we ready for routine screening? AB - BACKGROUND. Autism is a serious neurodevelopmental disorder that has a reportedly rising prevalence rate. The American Academy of Pediatrics recommends that screening for autism be incorporated into routine practice. It is important to consider the pros and cons of conducting autism screening as part of routine practice and its implications on the community. We have explored this question in the context of screening from a scientific point of view. METHOD: A literature search was conducted to assess the effectiveness of community screening programs for autism. RESULTS: Judged against critical questions about autism, screening programs failed to fulfill most criteria. Good screening tools and efficacious treatment are lacking, and there is no evidence yet that such a program would do more good than harm. CONCLUSIONS: On the basis of the available research, we believe that we do not have enough sound evidence to support the implementation of a routine population-based screening program for autism. Ongoing research in this field is certainly needed, including the development of excellent screening instruments and demonstrating with clinical trials that such programs work and do more good than harm. PMID- 21669897 TI - Maternal depressive symptoms and child care during toddlerhood relate to child behavior at age 5 years. AB - BACKGROUND: Disentangling the effects of maternal depression in toddlerhood from concurrent maternal depression on child behavior is difficult from previous research. Child care may modify any effects of maternal depression on subsequent child behavior, but this has not been widely investigated. METHODS: We examined the influence of maternal depressive symptoms during toddlerhood on children's behavior at the age of 5 years and investigated if formal or informal child care during toddlerhood modified any relationship observed. RESULTS: Data were available from 438 mothers and their children (227 girls and 211 boys); the mothers who completed questionnaires during the children's infancy, in toddlerhood, and at the age of 5 years. Recurrent maternal depressive symptoms in toddlerhood (when study children were aged 2 and 31/2 years) was a significant risk factor for internalizing, externalizing, and total behavior problems when children were aged 5 years. Intermittent maternal depressive symptoms (study child age 2 or 31/2 years) did not significantly affect child behavior problems. Formal child care at the age of 2 years modified the effect of recurrent maternal depressive symptoms on total behavior problems at age 5 years. Informal child care in toddlerhood did not significantly affect child behavior problems. CONCLUSIONS: Recurrent, but not intermittent, maternal depressive symptoms when children were toddlers were associated with child behavior problems at age 5 years. As little as half a day in formal child care at the age of 2 years significantly modified the effect of recurrent maternal depressive symptoms on total behavior problems. Formal child care for toddlers of depressed mothers may have positive benefits for the child's subsequent behavior. PMID- 21669898 TI - "Vodka energy": too much for the adolescent nephron? AB - We report here the case of a 17-year-old boy who suffered acute renal failure after consuming 3 L of energy drink (ED) in combination with 1 L of vodka amounting to 4600 mg of taurine and 780 mg of caffeine mixed with 380 g of alcohol. The consumption of this mixture is extremely popular in adolescents, because the joint effects of caffeine and taurine reduce the effect of alcohol. Although there have been case reports of deaths linked to the consumption of EDs with and without alcohol, awareness of the possible dangers is still low. The fact that athletes and major sports events are sponsored by ED manufacturers implies that they may even be healthy and performance-enhancing. PMID- 21669901 TI - A child with sudden vision loss in one eye. PMID- 21669900 TI - Acute Tc-99m DMSA scan for identifying dilating vesicoureteral reflux in children: a meta-analysis. AB - Controversy exists regarding the type and/or sequence of imaging studies needed during the first febrile urinary tract infection (UTI) in young children. Several investigators have claimed that because acute-phase Tc-99m dimercaptosuccinic acid (DMSA) renal-scan results are abnormal in the presence of dilating vesicoureteral reflux, a normal DMSA-scan result makes voiding cystourethrography (VCUG) unnecessary in the primary examination of infants with UTI. To evaluate the accuracy of acute-phase DMSA scanning in identifying dilating (grades III through V) vesicoureteral reflux documented by VCUG in children with a first febrile UTI, we performed a meta-analysis of the accuracy of diagnostic tests as reported from relevant studies identified through the PubMed and Scopus databases. Patient-based and renal unit-based analyses were performed. Overall, 13 cohort studies were identified. Nine studies involved patients younger than 2 years, 3 involved children aged 16 years or younger, and 1 involved exclusively neonates. Girls constituted 22% to 85% of the involved children. Pooled (95% confidence intervals) sensitivity and specificity rates of DMSA scanning were 79% and 53%, respectively, for the patient-based analysis (8 studies) and 60% and 65% for the renal unit-based analysis (5 studies). The respective areas under the hierarchical summary receiver operating curves were 0.71 and 0.67. Marked statistical heterogeneity was observed in both analyses, as indicated by I(2) test values of 91% and 87%, respectively. Acute-phase DMSA renal scanning cannot be recommended as replacement for VCUG in the evaluation of young children with a first febrile UTI. PMID- 21669902 TI - Disseminated mycobacterium avium complex infection in a pediatric renal transplant recipient. PMID- 21669903 TI - The morphology and haemodynamics of the rabbit renal artery: evaluation by conventional and contrast-enhanced ultrasonography. AB - The purpose of this study was to test the morphology and haemodynamics of the renal artery in the rabbit as evaluated by conventional and contrast-enhanced ultrasonography (CEUS). The morphology and haemodynamics of the rabbit renal artery, including the diameter, which were measured using B-mode ultrasonography (US), colour Doppler US and CEUS, and systolic velocity, diastolic velocity and resistive index (RI) were measured using pulsed wave Doppler US. CEUS was used to measure the renal artery diameter: 0.21 +/- 0.04 cm (right) and 0.21 +/- 0.03 cm (left). Values of the main renal artery diameter obtained from CEUS significantly correlated with those of digital subtraction angiography. The blood flow velocity of the right main renal artery was 44.20 +/- 8.71/18.92 +/- 6.26 cm/s (systolic/diastolic) and 36.30 +/- 6.89/17.64 +/- 5.58 cm/s (systolic/diastolic), at its origin from the aorta and at the renal hilus, respectively. The blood flow velocity of the left main renal artery was 45.10 +/- 8.49/19.00 +/- 6.80 cm/s (systolic/diastolic) and 41.70 +/- 10.25/19.55 +/- 7.90 cm/s (systolic/diastolic), at its origin from the aorta and at the renal hilus, respectively. Conventional US provides a more feasible modality for measuring the morphology and haemodynamics of the rabbit renal artery. CEUS is a more accurate method for measuring diameter. This information on the morphology and haemodynamics of the rabbit renal artery might be helpful for researchers. PMID- 21669904 TI - Relationship between production of acute-phase proteins and strength of inflammatory stimulation in rats. AB - The relationship between intensity of inflammatory stimulation and production of alpha(2)-macroglobulin (alpha2M) and alpha(1)-acid glycoprotein (AAG) in rats was investigated. Sprague-Dawley rats were injected with turpentine oil at doses of 0.05, 0.2 or 0.4 mL/rat. Serum levels of alpha2M, interleukin (IL)-6 and cytokine induced neutrophil chemoattractant-1 (CINC-1) were measured by enzyme-linked immunosorbent assay, and AAG was measured by single radial immunodiffusion. Peak serum levels of alpha2M and AAG in rats injected at 0.05 mL/rat were significantly lower than those at 0.2 or 0.4 mL/rat. However, no significant differences were observed for peak serum levels of these acute-phase proteins between 0.2 and 0.4 mL/rat. Furthermore, peak serum levels of IL-6 and CINC-1 in rats injected at 0.05 mL/rat were significantly lower than those at 0.2 or 0.4 mL/rat. Thus, the production of these acute-phase proteins has upper limits, even under increased strength of inflammatory stimulation in rats injected with turpentine oil. PMID- 21669899 TI - Predictive value of an early amplitude integrated electroencephalogram and neurologic examination. AB - OBJECTIVE: To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia. DESIGN: Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months. RESULTS: There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n=12) or discontinuous normal voltage (n=12), or abnormal, with burst suppression (n=22), continuous low voltage (n=26), or flat tracing (n=36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P=.19). CONCLUSIONS: The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE. PMID- 21669906 TI - Determination of clothing evaporative resistance on a sweating thermal manikin in an isothermal condition: heat loss method or mass loss method? AB - This paper addresses selection between two calculation options, i.e heat loss option and mass loss option, for thermal manikin measurements on clothing evaporative resistance conducted in an isothermal condition (T(manikin) = T(a) = T(r)). Five vocational clothing ensembles with a thermal insulation range of 1.05 2.58 clo were selected and measured on a sweating thermal manikin 'Tore'. The reasons why the isothermal heat loss method generates a higher evaporative resistance than that of the mass loss method were thoroughly investigated. In addition, an indirect approach was applied to determine the amount of evaporative heat energy taken from the environment. It was found that clothing evaporative resistance values by the heat loss option were 11.2-37.1% greater than those based on the mass loss option. The percentage of evaporative heat loss taken from the environment (H(e,env)) for all test scenarios ranged from 10.9 to 23.8%. The real evaporative cooling efficiency ranged from 0.762 to 0.891, respectively. Furthermore, it is evident that the evaporative heat loss difference introduced by those two options was equal to the heat energy taken from the environment. In order to eliminate the combined effects of dry heat transfer, condensation, and heat pipe on clothing evaporative resistance, it is suggested that manikin measurements on the determination of clothing evaporative resistance should be performed in an isothermal condition. Moreover, the mass loss method should be applied to calculate clothing evaporative resistance. The isothermal heat loss method would appear to overestimate heat stress and thus should be corrected before use. PMID- 21669905 TI - Thyroid status of female rhesus monkeys and preliminary information on impact of perchlorate administration. AB - Thyroid status was assessed in adult female rhesus monkey breeders at the California National Primate Research Center at the beginning of the breeding season. The 95% confidence intervals for thyrotropin (TSH), thyroxine (T(4)) and triiodothyronine (T(3)) (n = 66-80) were similar to those previously reported in smaller samples of macaque monkeys. Based on human criteria, 10 of 80 monkeys (12%) were hypothyroid (TSH > 2.0 uIU/mL). Because hypothyroxinaemia can be a risk factor in pregnancy, T(4) status was compared with past breeding history, breeding outcome for that season and general health records in a subset of 42 breeders. Age, weight and parity did not differ between monkeys in the lowest T(4) quartile as compared with those in the upper three quartiles. However, T(4) concentrations were significantly associated with the number of missed menstrual cycles during the previous breeding season. In additional work, three healthy lactating rhesus monkeys were given three different doses of environmental contaminant and thyroid iodine uptake inhibitor, ammonium perchlorate (0.006, 0.34, 12.8 mg/kg/day, respectively) in food for two weeks. Thyroid status variables (TSH, T(4), T(3), thyroid radioactive iodine uptake) were then measured. In the monkey receiving the highest perchlorate dose, iodine uptake was suppressed relative to baseline. The study shows the availability of tools to study thyroid status in rhesus monkeys, the variability of thyroid status in the breeder colony and the potential ability of environmental factors to influence thyroid status. PMID- 21669907 TI - The effect of two sock fabrics on physiological parameters associated with blister incidence: a laboratory study. AB - The goal of the present study was to investigate physiological effects, mainly at the level of the foot, of two sock fabrics with distinct moisture properties. Twelve participants wore two different socks, one on each foot. The following two sock types were used: PP: 99.6% polypropylene and 0.4% elastane and BLEND: 50% Merino wool, 33% polypropylene, and 17% polyamide. The participants walked three times on a treadmill at 5 km h(-1), with no gradient for the first and third phase and a 10% upward inclination for the second walking phase. The microclimate temperature between the boot and foot was measured during walking. Preceding and following the walking phases, additional measurements were carried out at the level of the foot, i.e. skin temperature and skin hydration on three locations and skin friction between the posterior surface of the calcaneus and a glass plate. In addition, the moisture absorption of boots and socks was determined. Differences between the sock fabrics were found for weight gain and microclimate temperature: (i) PP tended to hold less water compared to BLEND, (ii) the boot's microclimate temperature resulted in larger values for BLEND measured at the dorsal surface at the level of the third metatarsal, and (iii) warmer microclimates of the boot were measured for PP compared to BLEND at the distal anterior end of the tibia. The established differences in moisture behavior of both socks did not result in detectable differences in parameters measured on the skin of the foot. PMID- 21669908 TI - Comment on Strupp papers on beryllium metal toxicity. PMID- 21669910 TI - Field assessment of stratified aged-refuse-based reactor for landfill leachate treatment. AB - The aim of this study was to investigate the engineering applicability of the stratified aged-refuse-based process for landfill leachate treatment. In this work, a pilot-scale (10m(3)day(-1)) and a demonstration-scale (200m(3)day(-1)) stratified reactor, containing the aged refuse excavated from an 8-year-old closed landfill cell, were used as a medium by which to treat landfill leachate generated in the Shanghai Refuse Landfill (SRL). The preliminary-treated leachate with initial CODcr, NH(3)-N and total-N concentrations of 2387-8592, 1431-2145 and 1290-2188 mgL(-1), respectively, was intermittently sprayed over the refuse surface eight times a day with 3 h per interval in the pilot study. The results from the pilot operation showed that on average 89.5% of COD, 98.8% of NH(3)-N and 52.6% of total N could be removed from a hydraulic load of 0.267-0.444m(3)m( 3)refuseday(-1). Additionally, similar results were observed for the demonstration system even with the leachate of low BOD(5)/COD ratios (0.17-0.19). The investment and operational costs of this stratified process were about 20000yuan (?2200) and 1-2 yuan (?0.11-0.22) per m(3) leachate treated, respectively. Taken together, the stratified process has some significant advantages including low operation cost, easy maintenance and good adaptability to the leachate of variable quality, which makes this process a viable alternative for the treatment of landfill leachate. PMID- 21669911 TI - Optic neuropathy as a presenting feature of systemic lupus erythematosus: two case reports and literature review. AB - Systemic lupus erythematosus (SLE) may affect the eyes and/or visual system in up to a third of patients; however, optic nerve involvement has been rarely reported. SLE presenting as optic neuropathy is exceptional. We report two new cases of optic neuropathy as a presenting feature of SLE. The first patient presented with an ischemic optic neuropathy and antiphospholipid antibodies, and the second presented with optic neuritis. A literature review for previous cases of SLE presenting as optic neuropathy was performed. Early diagnosis of SLE associated optic neuropathy is warranted and leads to a better prognosis. PMID- 21669912 TI - Acute cerebellar ataxia in lupus. AB - Acute cerebellar ataxia in patients with lupus is rare and occurs early in the course of disease. We report a case of acute cerebellar ataxia in a young adult female who recovered completely with intravenous high-dose steroid therapy. PMID- 21669913 TI - Antiphospholipid syndrome and rheumatic fever: a case spanning three decades of changing concepts and common immunological mechanisms. AB - We present a case of primary antiphospholipid syndrome (APS), initially diagnosed as acute rheumatic fever, resulting in severe mitral valve incompetence. This case raises questions of the specificity of the Jones diagnostic criteria for rheumatic fever in a population where it is infrequently encountered. There are similarities in clinical, pathological and echocardiographic presentations between rheumatic fever and APS, in addition to common immunological mechanisms. Our case highlights the possibility that rather than rheumatic fever being primarily responsible for her recurrent attacks of chorea and arthritis, the streptococcal infections in our patient occurred either in the setting of underlying antiphospholipid antibodies ('second hit' phenomenon), or may have triggered the development of pathogenic antibodies (molecular mimicry), subsequently leading to the clinical evolution of APS. During the three decades of our patient and her recurrent problems, there has been an evolving knowledge of the mechanisms of APS and rheumatic fever, allowing us to extend our understanding beyond symptoms and syndromes, to a better realization of the underlying immunological relationship between the two. PMID- 21669914 TI - Human neutrophil peptides 1, 2 and 3 (HNP 1-3): elevated serum levels in colorectal cancer and novel marker of lymphatic and hepatic metastasis. AB - OBJECTIVE: Biological levels of localized colon tumors are needed for the diagnosis and prevention of colon cancer. Numerous biomarker studies are produced currently through research. We investigated some peptides with the aim of identifying biomarkers for colorectal cancer and lymphatic and hepatic metastasis. MATERIALS AND METHODS: A total of 100 patients with histologically proven colorectal cancer and 60 normal volunteers were included in this study. Preoperative serum was collected for analysis. Human neutrophil peptides levels (HNP) were assayed by solid phase RIA (Radio Immun Assay) based on monoclonal antibodies. RESULTS: The HNP-1, -2 and -3-also known as alpha-defensin-1, -2 and 3-are present in elevated concentrations in the plasma from colorectal cancer patients. CONCLUSION: Preoperative high plasma HNP 1-3 levels are associated with colorectal cancer. The HNP 1-3 levels may procure information on patients with lymph node or hepatic metastasis. PMID- 21669915 TI - Flammeovirga pacifica sp. nov., isolated from deep-sea sediment. AB - Strain WPAGA1T was isolated from marine sediment of the west Pacific Ocean. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belonged to the genus Flammeovirga. Strain WPAGA1T exhibited highest 16S rRNA gene sequence similarity with Flammeovirga yaeyamensis NBRC 100898(T) (98.1 %) and lower sequence similarity with Flammeovirga arenaria IFO 15982T (94.6 %) and other members of the genus Flammeovirga (<94.2 %). DNA-DNA relatedness studies showed that strain WPAGA1T was distinct from F. yaeyamensis NBRC 100898T and F. arenaria NBRC 15982T (43+/-4 % and 32+/-2 % relatedness values, respectively). Strain WPAGA1T could be distinguished from all known members of the genus Flammeovirga by a number of phenotypic features. However, the dominant fatty acids of strain WPAGA1T (iso-C15:0, C16:0 and C20:4omega6,9,12,15c), the major polyamine (cadaverine) and the G+C content of the chromosomal DNA (32.9 mol%) were consistent with those of members of the genus Flammeovirga. Based on phenotypic and chemotaxonomic features and 16S rRNA gene sequences, strain WPAGA1T can be assigned to the genus Flammeovirga as a representative of a novel species, for which the name Flammeovirga pacifica sp. nov. is proposed; the type strain is WPAGA1T (=CCTCC AB 2010364T=LMG 26175T=DSM 24597T=MCCC 1A06425T). PMID- 21669916 TI - Bacillus daliensis sp. nov., an alkaliphilic, Gram-positive bacterium isolated from a soda lake. AB - A Gram-positive, alkaliphilic bacterium, designated strain DLS13T, was isolated from Dali Lake in Inner Mongolia Autonomous Region, China. The isolate was able to grow at pH 7.5-11.0 (optimum at pH 9), in 0-8 % (w/v) NaCl (optimum at 2 %, w/v) and at 10-45 degrees C (optimum at 30 degrees C). Cells of the isolate were facultatively anaerobic, spore-forming rods with peritrichous flagella. The predominant isoprenoid quinone was MK-7 and its cell wall peptidoglycan contained meso-diaminopimelic acid. The major polar lipids consisted of phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. The major cellular fatty acids were anteiso-C15:0, anteiso-C17:0 and iso-C15:0. The genomic DNA G+C content of the isolate was 43.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain DLS13T was a member of the genus Bacillus and most closely related to Bacillus saliphilus DSM 15402T (96.9 % similarity). The DNA-DNA relatedness value between strain DLS13T and B. saliphilus DSM 15402T was 38.7+/-1.9 %. Comparative analysis of genotypic and phenotypic features indicated that strain DLS13T represents a novel species of the genus Bacillus, for which the name Bacillus daliensis sp. nov. is proposed; the type strain is DLS13T (=CGMCC 1.10369T=JCM 17097T=NBRC 107572T). PMID- 21669917 TI - Roseovarius halocynthiae sp. nov., isolated from the sea squirt Halocynthia roretzi. AB - A Gram-negative, motile, ovoid- to rod-shaped bacterial strain, designated MA1 10T, was isolated from a sea squirt (Halocynthia roretzi) collected from the South Sea, Korea. Strain MA1-10T grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2 % (w/v) NaCl. In the neighbour-joining phylogenetic tree based on 16S rRNA gene sequences, strain MA1-10T clustered with Roseovarius crassostreae CV919-312T, with which it exhibited 97.1 % sequence similarity, at a bootstrap resampling value of 96.2 %. It exhibited 93.3-95.8 % 16S rRNA gene sequence similarity to the type strains of other recognized Roseovarius species. Strain MA1-10T contained Q-10 as the predominant ubiquinone and C18:1omega7c as the major fatty acid, which is consistent with data for the genus Roseovarius. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, an unidentified aminolipid and an unidentified lipid. The DNA G+C content of strain MA1-10T was 55.4 mol%. Mean DNA-DNA relatedness between strain MA1-10T and R. crassostreae DSM 16950T was 13 %. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, demonstrated that strain MA1-10T could be distinguished from all recognized Roseovarius species. On the basis of the data presented, strain MA1 10T is considered to represent a novel species of the genus Roseovarius, for which the name Roseovarius halocynthiae sp. nov. is proposed; the type strain is MA1-10T (=KCTC 23462T=CCUG 60745T). PMID- 21669918 TI - Salinactinospora qingdaonensis gen. nov., sp. nov., a halophilic actinomycete isolated from a salt pond. AB - A novel halophilic, filamentous, actinomycete strain, designated CXB832T, was isolated from a salt pond in Qingdao, China. Optimal growth occurred at 37 degrees C, pH 7.0-8.0 and 9-12 % (w/v) NaCl. Strain CXB832T formed pale yellow to deep yellow branched substrate mycelium without fragmentation. Abundant white aerial mycelium differentiated into long chains of spores and the spores were rod shaped with smooth surfaces. Strain CXB832T contained meso-diaminopimelic acid as the diagnostic diamino acid of the cell-wall peptidoglycan, and glucose and xylose as the major whole-cell sugars. The phospholipids were diphosphatidylglycerol, phosphatidylglycerol, phospholipids, glycolipid and unidentified lipids. MK-10(H8), MK-9(H8), MK-10(H2) and MK-10(H6) were the predominant menaquinones. The major fatty acids were i-C16:0 (30.71 %), ai-C17:0 (13.31 %) and C16:0 (11.28 %). The G+C content of the DNA was 60.1 mol%. Comparative analysis of 16S rRNA gene sequences showed that the novel strain was most closely related to genera within the family Nocardiopsaceae, but formed a separate lineage. The highest sequence similarities were to Nocardiopsis arabia DSM 45083T (95.4 %) and Haloactinospora alba DSM 45015T (94.9 %). On the basis of phenotypic, chemotaxonomic and phylogenetic distinctiveness, strain CXB832T represents a new genus and novel species in the family Nocardiopsaceae, for which the name Salinactinospora qingdaonensis gen. nov., sp. nov. is proposed. The type strain of the type species is CXB832T (=DSM 45442T=LMG 25567T). PMID- 21669919 TI - 'Candidatus Phytoplasma sudamericanum', a novel taxon, and strain PassWB-Br4, a new subgroup 16SrIII-V phytoplasma, from diseased passion fruit (Passiflora edulis f. flavicarpa Deg.). AB - Symptoms of abnormal proliferation of shoots resulting in formation of witches' broom growths were observed on diseased plants of passion fruit (Passiflora edulis f. flavicarpa Deg.) in Brazil. RFLP analysis of 16S rRNA gene sequences amplified in PCRs containing template DNAs extracted from diseased plants collected in Bonito (Pernambuco) and Vicosa (Minas Gerais) Brazil, indicated that such symptoms were associated with infections by two mutually distinct phytoplasmas. One phytoplasma, PassWB-Br4 from Bonito, represents a new subgroup, 16SrIII-V, in the X-disease phytoplasma group ('Candidatus Phytoplasma pruni' related strains). The second phytoplasma, PassWB-Br3 from Vicosa, represents a previously undescribed subgroup in group 16SrVI. Phylogenetic analyses of 16S rRNA gene sequences were consistent with the hypothesis that strain PassWB-Br3 is distinct from previously described 'Ca. Phytoplasma' species. Nucleotide sequence alignments revealed that strain PassWB-Br3 shared less than 97.5 % 16S rRNA gene sequence similarity with previously described 'Ca. Phytoplasma' species. The unique properties of its DNA, in addition to natural host and geographical occurrence, support the recognition of strain PassWB-Br3 as a representative of a novel taxon, 'Candidatus Phytoplasma sudamericanum'. PMID- 21669921 TI - Erwinia typographi sp. nov., isolated from bark beetle (Ips typographus) gut. AB - Gram-negative-staining bacteria that were resistant to monoterpene myrcene (7 methyl-3-methylene-1.6-octadiene, C10H16, at concentrations of up to 10 ul ml(-1) in TSB) were isolated from the gut contents of adult bark beetles Ips typographus (Coleoptera, Scolytidae). The beetles were collected from the bark of Norway spruce (Picea abies) in Lithuania. Bark beetles feed on conifers, which produce myrcene among many other defensive compounds. It has been suggested that the micro-organisms present within the beetles' guts could be involved in their resistance towards this plant defensive compound. The most resistant bacterial strains were isolated and characterized by phenotypic assays as well as fatty acid analysis, 16S rRNA gene sequencing, multilocus sequence analyses (MLSA) based on the rpoB, atpD and infB genes and DNA-DNA hybridization. Biochemical characterization indicated that the bacteria belonged to the family Enterobacteriaceae. Phylogenetic analyses of the 16S rRNA gene sequences and MLSA of the novel strains revealed that they belonged to the genus Erwinia, but represented a novel species. The dominant cellular fatty acids were C16:0 and C17:0 cyclo. The DNA G+C content was 49.1 mol%. The results obtained in this study indicated that these bacteria from the bark beetle gut represented a novel species, for which the name Erwinia typographi sp. nov. is proposed, with the type strain DSM 22678T (=Y1T=LMG 25347T). PMID- 21669920 TI - Isoptericola nanjingensis sp. nov., a mineral-weathering bacterium. AB - A Gram-positive-staining, non-motile, rod- or coccoid-shaped actinobacterium, designated strain H17T, was isolated from a soil sample from Nanjing, Jiangsu Province, PR China. The organism grew optimally at 30 degrees C, pH 7.0 and with 3 % NaCl (w/v). Strain H17T contained L-Lys-D-Asp as the cell-wall peptidoglycan type and galactose, xylose and mannose as the whole-cell sugars. The major fatty acids were anteiso-C15:0 and iso-C15:0. The total polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phospholipids, phosphatidylinositol, phosphoglycolipid, one unidentified glycolipid and one unidentified lipid. The menaquinone was MK9(H4). Mycolic acids were not detected. The DNA G+C content was 72.4 mol%. Phylogenetic analysis of this strain based on 16S rRNA gene sequences revealed 97.8-99.6 % similarity to recognized species of the genus Isoptericola. The low level of DNA-DNA relatedness to other species of the genus Isoptericola and the many phenotypic properties that distinguished strain H17T from recognized species of this genus demonstrated that isolate H17T should be classified as representing a novel species of the genus Isoptericola. The name Isoptericola nanjingensis sp. nov. is proposed for this novel species. The type strain is H17T (=DSM 24300T=CCTCC AB 2011005T). PMID- 21669922 TI - Aureitalea marina gen. nov., sp. nov., a member of the family Flavobacteriaceae, isolated from seawater. AB - An irregular rod-shaped, non-gliding, yellow-pigmented bacterium was isolated from seawater from the western North Pacific Ocean near Japan. The strain, designated S1-66T, was Gram-negative, obligately aerobic, heterotrophic and oxidase-positive. Growth occurred in the presence of 1-4 % NaCl, with optimum growth at 2 % NaCl. The strain grew at 15-30 degrees C, with optimum growth at 20-25 degrees C. The G+C content of genomic DNA was 48.1 mol% (HPLC). The predominant isoprenoid quinone was MK-6 and the major cellular fatty acids were iso-C15:0 (26.4 %), iso-C15:1 (20.3 %) and iso-C17:0 3-OH (14.2 %). Phylogenetic trees generated by using 16S rRNA gene sequences revealed that strain S1-66T belongs to the family Flavobacteriaceae and showed 94.2 % sequence similarity to the most closely related type strain, Ulvibacter antarcticus IMCC3101T. On the basis of phenotypic and phylogenetic features, S1-66T is classified in a novel genus and species within the family Flavobacteriaceae, for which the name Aureitalea marina gen. nov., sp. nov. is proposed. The type strain of Aureitalea marina is S1-66T (=NBRC 107741T=KCTC 23434T). PMID- 21669923 TI - Ruegeria halocynthiae sp. nov., isolated from the sea squirt Halocynthia roretzi. AB - A Gram-negative, non-motile, rod-shaped bacterial strain, designated MA1-6T, was isolated from a sea squirt (Halocynthia roretzi) collected from the South Sea, Korea, and was characterized to determine its taxonomic position. Strain MA1-6T grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2-3 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain MA1-6T fell within the clade comprising Ruegeria species and exhibited 95.3-96.5 % similarity to the type strains of recognized Ruegeria species. Strain MA1-6T contained Q-10 as the predominant ubiquinone and C18:1omega7c as the major fatty acid, which is consistent with data for Ruegeria species. The major polar lipids detected in strain MA1-6T and Ruegeria atlantica KCTC 12424T were phosphatidylcholine, phosphatidylglycerol, an unidentified aminolipid and an unidentified lipid. The DNA G+C content of strain MA1-6T was 58.6 mol%. Differential phenotypic properties, together with phylogenetic distinctiveness, demonstrated that strain MA1-6T can be distinguished from recognized Ruegeria species. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain MA1-6T is considered to represent a novel species of the genus Ruegeria, for which the name Ruegeria halocynthiae sp. nov. is proposed; the type strain is MA1 6T (=KCTC 23463T=CCUG 60744T). PMID- 21669924 TI - Phenylobacterium muchangponense sp. nov., isolated from beach soil, and emended description of the genus Phenylobacterium. AB - A Gram-staining-negative, non-motile, aerobic bacterium, designated strain A8T, was isolated from the beach soil of Muchangpo, Korea. Cells were rod-shaped (0.5 0.6*0.7-1.3 um) and colonies were colourless, circular with entire edges and had a glistening surface. The isolate grew optimally at 25-35 degrees C and did not require NaCl for growth. Strain A8T could not assimilate acetate, DL-lactate, succinate, antipyrine or chloridazon, but weakly assimilated L-phenylalanine. Major fatty acids were summed feature 7 (comprising C18:1omega7c/omega9t/omega12t), C16:0 and summed feature 4 (comprising C16:1omega7c/ iso-C15:0 2-OH). The major isoprenoid quinone was ubiquinone-10 and the DNA G+C content was 72.3 mol%. Comparative 16S rRNA gene sequence studies showed that strain A8T belonged to the family Caulobacteraceae, class Alphaproteobacteria and was most closely related to type strains of members of the genus Phenylobacterium (95.7-97.1 % similarity). Signature nucleotides and phylogenetic analysis of the 16S rRNA gene sequence also suggested that strain A8T was affiliated with the genus Phenylobacterium. Low DNA-DNA relatedness values (3.0+/-1.8-11.5+/-3.2 %) indicated that strain A8T represented a distinct species that was separated from other type strains in the genus Phenylobacterium. On the basis of evidence from a polyphasic study, it is proposed that strain A8T (=KACC 15042T=LMG 25973T) represents the type strain of a novel species, Phenylobacterium muchangponense sp. nov. An emended description of the genus Phenylobacterium is also presented. PMID- 21669925 TI - Streptomyces staurosporininus sp. nov., a staurosporine-producing actinomycete. AB - The taxonomic position of a staurosporine-producing actinomycete isolated from a hay meadow soil was determined using a polyphasic approach. The organism had chemical and morphological characteristics consistent with its classification in the genus Streptomyces and formed a distinct branch between the Streptomyces lydicus and Streptomyces noursei clades in the 16S rRNA Streptomyces gene tree. DNA-DNA relatedness values between the isolate and its nearest phylogenetic neighbours, namely Streptomyces lydicus NBRC 13058T and Streptomyces chattanoogensis NBRC 12754T, were 53 % and 40 %, respectively. The isolate was also readily distinguished from the type strains of these species using a combination of morphological and other phenotypic properties. On the basis of these results, it is proposed that isolate BK179T (=KACC 20912T=NRRL B-24850T) be classified as the type strain of Streptomyces staurosporininus sp. nov. PMID- 21669926 TI - Actinoplanes abujensis sp. nov., isolated from Nigerian arid soil. AB - A novel actinobacterial strain, A4029T, isolated from arid soil of Abuja, Nigeria, and provisionally assigned to the genus Actinoplanes, was subjected to a polyphasic taxonomic study. 16S rRNA gene sequence similarity studies showed that strain A4029T belonged to the genus Actinoplanes, being most closely related to Actinoplanes brasiliensis DSM 43805T (98.9 %) and Actinoplanes deccanensis DSM 43806T (98.0 %); similarity to other type strains of the genus Actinoplanes ranged from 96.2 to 97.9 %. Chemotaxonomic data [major menaquinone MK-9(H4); major polar lipids phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol; characteristic sugars arabinose and xylose; major fatty acids iso-C15:0, anteiso-C15:0, iso-C16:0, C17:1omega9c and iso-C14:0] confirmed the affiliation of strain A4029T to the genus Actinoplanes. The results of DNA-DNA hybridizations and phylogenetic analysis, together with phenotypic and biochemical test data, allowed strain A4029T to be differentiated from strains of other Actinoplanes species. Therefore, strain A4029T represents a novel species, for which the name Actinoplanes abujensis sp. nov. is proposed, with A4029T (=DSM 45518T=NRRL B-24835T=KCTC 19984T) as the type strain. PMID- 21669927 TI - Methylobacterium cerastii sp. nov., isolated from the leaf surface of Cerastium holosteoides. AB - Two Gram-stain-negative, non-endospore-forming, rod-like strains, designated C15T and C44, were isolated from the phyllosphere of Cerastium holosteoides and were studied in detail in order to assess their taxonomic position. 16S rRNA gene sequence analysis allocated both isolates clearly to the genus Methylobacterium. Both strains showed the highest 16S rRNA gene sequence similarity to Methylobacterium marchantiae JT1T (97.5 %) and Methylobacterium jeotgali S2R03-9T (97.4 %). The fatty acid profiles contained major amounts of C16:0, C18:1omega7c and C16:1omega7c/iso-C15:0 2-OH (summed feature 3), which supported the grouping of the isolates in the genus Methylobacterium. Physiological/biochemical characterization and DNA-DNA hybridizations with the type strains of the most closely related species allowed a clear phenotypic and genotypic differentiation of the strains. For this reason, we propose for strain C15T (=DSM 23679T=CCUG 60040T=CCM 7788T) a novel species with the name Methylobacterium cerastii sp. nov. Strain C44 (=DSM 23675=CCM 7789) is an additional strain of M. cerastii. PMID- 21669928 TI - Simiduia areninigrae sp. nov., an agarolytic bacterium isolated from sea sand. AB - During a study intended to screen for agar-degrading bacteria, strain M2-5T was isolated from black sand off the shore of Jeju Island, Republic of Korea. Strain M2-5T exhibited agarase activity; the beta-agarase gene of the isolate had 62 % amino acid sequence identity to the beta-agarase gene of Microbulbifer thermotolerans JAMB A94T. The isolate was closely related to members of the genus Simiduia but was clearly discernible from reported Simiduia species, based on a polyphasic analysis. Cells of strain M2-5T were Gram-negative, catalase- and oxidase-positive, motile rods. The DNA G+C content was 53.3 mol%. The predominant isoprenoid quinone was Q-8. The major cellular fatty acids were C17:1omega8c (25.9 %), summed feature 3 (iso-C(15 : 0) 2-OH and/or C16:1omega7c; 17.2 %) and C17:0 (15.0 %). Phylogenetic analysis using 16S rRNA gene sequences showed that strain M2-5T had 96.6 % gene sequence similarity to Simiduia agarivorans SA1T, the most closely related type strain of the genus Simiduia. These results suggest that strain M2-5T represents a novel species in the genus Simiduia, for which the name Simiduia areninigrae sp. nov. is proposed; the type strain is M2-5T (=KCTC 23293T=NCAIM B 02424T). PMID- 21669929 TI - The endocannabinoid system in critical neurodevelopmental periods: sex differences and neuropsychiatric implications. AB - This review focuses on the endocannabinoid system as a crucial player during critical periods of brain development, and how its disturbance either by early life stressful events or cannabis consumption may lead to important neuropsychiatric signs and symptoms. First we discuss the advantages and limitations of animal models within the framework of neuropsychiatric research and the crucial role of genetic and environmental factors for the establishment of vulnerable phenotypes. We are becoming aware of important sex differences that have emerged in relation to the psychobiology of cannabinoids. We will discuss sexual dimorphisms observed within the endogenous cannabinoid system, as well as those observed with exogenously administered cannabinoids. We start with how the expression of cannabinoid CB(1) receptors is regulated throughout development. Then, we discuss recent results showing how an experimental model of early maternal deprivation, which induces long-term neuropsychiatric symptoms, interacts in a sex-dependent manner with the brain endocannabinoid system during development. This is followed by a discussion of differential vulnerability to the pathological sequelae stemming from cannabinoid exposure during adolescence. Next we talk about sex differences in the interactions between cannabinoids and other drugs of abuse. Finally, we discuss the potential implications that organizational and activational actions of gonadal steroids may have in establishing and maintaining sex dependence in the neurobiological actions of cannabinoids and their interaction with stress. PMID- 21669930 TI - A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders. AB - Human peroxisome biogenesis disorders are lethal genetic diseases in which abnormal peroxisome assembly compromises overall peroxisome and cellular function. Peroxisomes are ubiquitous membrane-bound organelles involved in several important biochemical processes, notably lipid metabolism and the use of reactive oxygen species for detoxification. Using cultured cells, we systematically characterized the peroxisome assembly phenotypes associated with dsRNA-mediated knockdown of 14 predicted Drosophila homologs of PEX genes (encoding peroxins; required for peroxisome assembly and linked to peroxisome biogenesis disorders), and confirmed that at least 13 of them are required for normal peroxisome assembly. We also demonstrate the relevance of Drosophila as a genetic model for the early developmental defects associated with the human peroxisome biogenesis disorders. Mutation of the PEX1 gene is the most common cause of peroxisome biogenesis disorders and is one of the causes of the most severe form of the disease, Zellweger syndrome. Inherited mutations in Drosophila Pex1 correlate with reproducible defects during early development. Notably, Pex1 mutant larvae exhibit abnormalities that are analogous to those exhibited by Zellweger syndrome patients, including developmental delay, poor feeding, severe structural abnormalities in the peripheral and central nervous systems, and early death. Finally, microarray analysis defined several clusters of genes whose expression varied significantly between wild-type and mutant larvae, implicating peroxisomal function in neuronal development, innate immunity, lipid and protein metabolism, gamete formation, and meiosis. PMID- 21669931 TI - Neural circuit architecture defects in a Drosophila model of Fragile X syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase. AB - Fragile X syndrome (FXS), caused by loss of the fragile X mental retardation 1 (FMR1) product (FMRP), is the most common cause of inherited intellectual disability and autism spectrum disorders. FXS patients suffer multiple behavioral symptoms, including hyperactivity, disrupted circadian cycles, and learning and memory deficits. Recently, a study in the mouse FXS model showed that the tetracycline derivative minocycline effectively remediates the disease state via a proposed matrix metalloproteinase (MMP) inhibition mechanism. Here, we use the well-characterized Drosophila FXS model to assess the effects of minocycline treatment on multiple neural circuit morphological defects and to investigate the MMP hypothesis. We first treat Drosophila Fmr1 (dfmr1) null animals with minocycline to assay the effects on mutant synaptic architecture in three disparate locations: the neuromuscular junction (NMJ), clock neurons in the circadian activity circuit and Kenyon cells in the mushroom body learning and memory center. We find that minocycline effectively restores normal synaptic structure in all three circuits, promising therapeutic potential for FXS treatment. We next tested the MMP hypothesis by assaying the effects of overexpressing the sole Drosophila tissue inhibitor of MMP (TIMP) in dfmr1 null mutants. We find that TIMP overexpression effectively prevents defects in the NMJ synaptic architecture in dfmr1 mutants. Moreover, co-removal of dfmr1 similarly rescues TIMP overexpression phenotypes, including cellular tracheal defects and lethality. To further test the MMP hypothesis, we generated dfmr1;mmp1 double null mutants. Null mmp1 mutants are 100% lethal and display cellular tracheal defects, but co-removal of dfmr1 allows adult viability and prevents tracheal defects. Conversely, co-removal of mmp1 ameliorates the NMJ synaptic architecture defects in dfmr1 null mutants, despite the lack of detectable difference in MMP1 expression or gelatinase activity between the single dfmr1 mutants and controls. These results support minocycline as a promising potential FXS treatment and suggest that it might act via MMP inhibition. We conclude that FMRP and TIMP pathways interact in a reciprocal, bidirectional manner. PMID- 21669932 TI - Drosophila: a model for studying genetic and molecular aspects of haematopoiesis and associated leukaemias. AB - Vertebrate haematopoietic stem cells (HSCs) give rise to a hierarchically organised set of progenitors for erythroid, myeloid, lymphoid and megakaryocyte lineages, and are responsible for lifelong maintenance of the blood system. Dysregulation of the haematopoietic differentiation programme is at the origin of numerous pathologies, including leukaemias. With the discoveries that many transcriptional regulators and signalling pathways controlling blood cell development are conserved between humans and Drosophila melanogaster, the fruit fly has become a good model for investigating the mechanisms underlying the generation of blood cell lineages and blood cell homeostasis. In this review article, we discuss how genetic and molecular studies of Drosophila haematopoiesis can contribute to our understanding of the haematopoietic niche, as well as of the origin and/or progression of haematopoietic malignancies in humans. PMID- 21669934 TI - Multiple sclerosis incidence in the Faroe Islands. PMID- 21669935 TI - The differential diagnosis of longitudinally extensive transverse myelitis. AB - Longitudinally extensive transverse myelitis refers to florid and widespread inflammation of the spinal cord causing T2 hyperintensity on spinal magnetic resonance imaging that is seen to extend over three or more vertebral segments. Whilst rare, longitudinally extensive transverse myelitis is clinically important as it can lead to catastrophic morbidity, and a group of these patients are at risk of further attacks. Early identification and establishment of the underlying aetiology is vital in order to initiate appropriate therapy and optimize outcomes. Whilst longitudinally extensive transverse myelitis is classically associated with neuromyelitis optica, there are many other causes. These include other inflammatory aetiologies, infection, malignancy and metabolic disturbance. Some of these are readily treatable. Laboratory and radiological investigations can help to differentiate these causes. Treatment of longitudinally extensive transverse myelitis hinges on distinguishing inflammatory and non-inflammatory aetiologies and identifying patients who are at high risk of a recurrent course. PMID- 21669933 TI - Worms, flies and four-legged friends: the applicability of biological models to the understanding of intestinal inflammatory diseases. AB - Diseases of intestinal inflammation, including Crohn's disease, ulcerative colitis and necrotizing enterocolitis, cause substantial acute and chronic disability in a large proportion of the population. Crohn's disease and ulcerative colitis, which are collectively referred to as inflammatory bowel disease (IBD), lead to recurrent episodes of intestinal dysfunction and systemic illness, whereas necrotizing enterocolitis is characterized by the development of dramatic and all too often fatal intestinal necrosis in infants. To determine the molecular underpinnings of these disorders, investigators have explored a variety of animal models that vary widely in their complexity. These experimental systems include the invertebrate nematode Caenorhabditis elegans, the more complex invertebrate Drosophila melanogaster, and vertebrate systems including mice, rats and other mammals. This review explores the experimental models that are used to mimic and evaluate the pathogenic mechanisms leading to these diseases of intestinal inflammation. We then highlight, as an example, how the use of different experimental models that focus on the role of Toll-like receptor 4 (TLR4) signaling in the gut has revealed important distinctions between the pathogenesis of IBD and necrotizing enterocolitis. Specifically, TLR4-mediated signaling plays a protective role in the development of Crohn's disease and ulcerative colitis, whereas this signaling pathway plays a causative role in the development of necrotizing enterocolitis in the newborn small intestine by adversely affecting intestinal injury and repair mechanisms. PMID- 21669936 TI - Patient characteristics and determinants of quality of life in an international population with multiple sclerosis: assessment using the MusiQoL and SF-36 questionnaires. AB - BACKGROUND: Multiple sclerosis (MS) can have psychological and socioeconomic consequences that affect patients' health-related quality of life (HRQoL) as much as physical disability. OBJECTIVE: To determine the clinical and sociodemographic factors affecting HRQoL in a large international study using the MS International QoL (MusiQoL) questionnaire. METHODS: Patients aged >18 years with a diagnosis of MS for >6 months or clinically isolated syndrome (CIS) were enrolled. Sociodemographic and clinical data were recorded, and patients completed the MusiQoL and 36-item short form (SF-36) health survey questionnaires. RESULTS: In total, 1992 patients from 15 countries were enrolled (mean [standard deviation] age: 42.3 [12.5] years; 70.5% women; 70.4% with relapsing-remitting MS). Multivariate multiple regression analyses identified lower educational level, higher Expanded Disability Status Scale (EDSS) score, cognitive impairment, being single and shorter time since last relapse as significant predictors of lower MusiQoL global index scores (p < 0.05). Older age, female sex, higher EDSS score, shorter time since last relapse and receiving current MS treatment were significant predictors of lower SF-36 physical component summary scores (p < 0.05). The SF-36 mental component summary score was linked to occupational status, inpatient/outpatient status, time since last relapse, and whether the patient was receiving MS treatment (p < 0.05). CONCLUSION: Sociodemographic and clinical factors are linked to HRQoL in patients with MS. Interventions that affect these factors might be expected to influence HRQoL. PMID- 21669937 TI - Dramatic worsening following plasma exchange in severe post-natalizumab withdrawal multiple sclerosis relapse. AB - We report the case of a young woman with multiple sclerosis who discontinued natalizumab twice and experienced a severe relapse following each natalizumab withdrawal. The first relapse was successfully treated by intravenous methylprednisolone (IVMP). In contrast the second relapse was unresponsive to IVMP. Subsequent treatment by plasma exchanges (PLEX) was followed by a dramatic neurological worsening. This case suggests that PLEX after natalizumab discontinuation may increase relapse severity. PMID- 21669938 TI - Micronucleus frequencies in peripheral blood lymphocytes of children with chronic kidney disease. AB - One of the crucial adverse effects of chronic kidney disease (CKD) and its treatment is an elevated cancer risk. There are no data on cytogenetic effects in children with CKD or children undergoing dialysis or those who have received a transplant. In this study, cytogenetic effects in children with CKD in pre dialysis (PreD) stage, on regular haemodialysis (HD) and transplanted (Tx) compared with a control group of healthy children has been investigated using the cytokinesis-blocked micronucleus (CBMN) assay and fluorescence in situ hybridisation (FISH) combined with CBMN (CBMN-FISH) in peripheral blood lymphocytes. The results revealed a significant increase (P < 0.001) in micronucleus (MN) frequencies [mean +/- SD (n)] in the PreD, HD and Tx groups versus the control group [CBMN assay; 9.19 +/- 2.61 (16), 9.07 +/- 4.86 (15), 6.12 +/- 5.33 (17) versus 1.60 +/- 0.99 (20), respectively]. Moreover, centromere negative micronucleus (C- MN) and centromere positive micronucleus (C+ MN) frequencies were significantly higher in each subgroup children (PreD, HD and Tx) than in the control group (P < 0.01) although children in Tx group had lower C- MN frequencies than PreD and lower C+ MN frequencies than PreD and HD groups (P < 0.05). Additionally, MN frequencies in mononuclear cells, nucleoplasmic bridges and nuclear buds in binucleated cells were increased in children with CKD (P < 0.001, P < 0.001, P > 0.05, respectively). The nuclear division index significantly decreased in Tx group relative to the control, PreD and HD groups (P < 0.001). Associations between cytogenetic parameters and creatinine or blood urea nitrogen were found (P < 0.05). To provide longer and better life expectancy of children with CKD and treatment modes, further research is needed to better understand and avoid these effects. PMID- 21669940 TI - Radon in earthquake prediction research. AB - The observation of anomalies in the radon concentration in soil gas and ground water before earthquakes initiated systematic investigations on earthquake precursor phenomena. The question what is needed for a meaningful earthquake prediction as well as what types of precursory effects can be expected is shortly discussed. The basic ideas of the dilatancy theory are presented which in principle can explain the occurrence of earthquake forerunners. The reasons for radon anomalies in soil gas and in ground water are clarified and a possible classification of radon anomalies is given. PMID- 21669939 TI - The resveratrol analogue, 2,3',4,5'-tetramethoxystilbene, does not inhibit CYP gene expression, enzyme activity and benzo[a]pyrene-DNA adduct formation in MCF-7 cells exposed to benzo[a]pyrene. AB - Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) induces cytochrome P450 (CYP) 1A1 and 1B1 enzymes, which biotransform PAHs resulting in the formation of DNA adducts. We hypothesised that 2,3',4,5'-tetramethoxystilbene (TMS), an analogue of resveratrol and a potent CYP1B1 inhibitor, may inhibit r7, t8, t9-trihydroxy-c-10-(N(2)deoxyguanosyl)-7,8,9,10-tetrahydro-benzo[a]pyrene (BPdG) adduct formation in cells exposed to benzo[a]pyrene (BP). To address this, MCF-7 cells were cultured for 96 h in the presence of 1 MUM BP, 1 MUM BP + 1 MUM TMS or 1 MUM BP + 4 MUM TMS. Cells were assayed at 2-12 h intervals for: BPdG adducts by r7, t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) DNA chemiluminescence immunoassay; CYP1A1 and 1B1 gene expression changes by relative real-time polymerase chain reaction; and CYP1A1/1B1 enzyme activity by ethoxyresorufin-O-deethylase (EROD) assay. Whereas maximal BPdG levels were similar for all exposure groups, the times at which the maxima were reached increased by 16 and 24 h with the addition of 1 and 4 MUM TMS, respectively. The maximal expression of CYP1A1 and CYP1B1 occurred at 16, 24 and 48 h, but the maximal level for EROD-specific activity was reached at 24, 48 and 60 h, in cells exposed to 1 MUM BP, 1 MUM BP + 1 MUM TMS or 1 MUM BP + 4 MUM TMS, respectively. The area under the curve from 4 to 96 h of exposure (AUC(4-)(96 h)) for BPdG adduct formation was not increased in the presence of TMS, but for CYP1A1 and CYP1B1 expression fold increase AUC(4-)(96 h) and EROD-specific activity AUC(4 )(96 h), there were significant (P < 0.05) increases in the presence of 4 MUM TMS. Therefore, during 96 h of exposure in MCF-7 cells, the combination of BP plus TMS caused a slowing of BP biotransformation, with an increase in CYP1A1 and CYP1B1 expression and EROD activity, and a slowing, but no change in magnitude of BPdG formation. PMID- 21669941 TI - Use of parks or playgrounds: reported access to drinking water fountains among US adults, 2009. AB - BACKGROUND: As a first step to determining the public availability of drinking water, self-reported access to water fountains in parks and playgrounds was examined. METHODS: A cross-sectional analysis was conducted on a convenience sample of 4163 US adults (aged >= 18 years) using the 2009 HealthStyles Survey. The outcome measure was reported access to water fountains in parks/playgrounds. Among those who reported using parks/playgrounds, multivariable logistic regression was used to examine the associations between sociodemographic variables and reported access to water fountains. RESULTS: About half (54.7%) of participants used parks/playgrounds. Among those, 55.0% reported access to water fountains. Factors significantly associated with reported access to water fountains were being male [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.09, 1.85] and living in the Pacific region (versus East North Central region, OR = 2.56; 95% CI = 1.61, 4.06). Age, race/ethnicity, household income, marital status, education, smoking and physical activity were not significantly associated with reported access to water fountains. CONCLUSIONS: Among 54.7% of adults using parks/playgrounds, reported access to water fountains was significantly differed by sex and region. This study provides information that can be considered when developing interventions to increase access to drinking water in public facilities. PMID- 21669942 TI - Applications of post-translational modifications of FoxO family proteins in biological functions. AB - The functions of the FoxO family proteins, in particular their transcriptional activities, are modulated by post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. These PTMs occur in response to different cellular stresses, which in turn regulate the subcellular localization of FoxO family proteins, as well as their half-life, DNA binding, transcriptional activity and ability to interact with other cellular proteins. In this review, we summarize the role of PTMs of FoxO family proteins in linking their biological and functional relevance with various diseases. PMID- 21669943 TI - Sirt2 is a novel in vivo downstream target of Nkx2.2 and enhances oligodendroglial cell differentiation. AB - Although Sirt2 is primarily expressed in oligodendrocytes of the central nervous system, its role in oligodendroglial lineage differentiation is not fully understood. Our findings demonstrate that the transcription factor Nkx2.2 binds to the Sirt2 promoter via histone deacetylase 1 (HDAC-1), the binding site for Nkx2.2 maps close to the start codon of the Sirt2 gene, and Nkx2.2 negatively regulates Sirt2 expression in CG4 cells, an oligodendroglial precursor cell line. HDAC-1 knock-down not only significantly attenuates the binding capacity of Nkx2.2 to the Sirt2 promoter but also releases repression of Sirt2 expression by Nkx2.2. Nkx2.2 over-expression down-regulates Sirt2 expression and delays differentiation of CG4 cells; in contrast, up-regulation of Sirt2 does not impact Nkx2.2 expression level. Sirt2 knock-down via RNAi or inhibition of Sirt2 by sirtinol, a Sirt2 activity inhibitor, blocks CG4 cell differentiation. Over expression of Sirt2 facilitates CG4 cell differentiation at both molecular and cellular levels, enhancing expression of myelin basic protein and facilitating the growth of cell processes. We have conclusively demonstrated that Sirt2 enhances CG4 oligodendroglial differentiation and report a novel mechanism through which Nkx2.2 represses CG4 oligodendroglial differentiation via Sirt2. PMID- 21669944 TI - Altered expression of matrix metalloproteinases and their tissue inhibitors in matured rat adipocytes in vitro. AB - Obesity is recognized as a risk factor for delayed cutaneous wound healing. The authors hypothesized that the secretion of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) from subcutaneous adipose tissue correlates with disorder of the healing process in obese subjects. Findings from previous studies on the expression of MMPs and TIMPs in obese adipose tissue are inconsistent. Since these conflicting results could be due to the effect of several intrinsic factors, the authors conducted a simple in vitro experiment to clarify the change in profile of MMPs and TIMPs in excessively matured adipocytes. The authors cultured the induced adipocytes under conditions of high or low glucose and with or without insulin supplementation. Oil red O staining and its dye extraction assay revealed excessive lipid accumulation in high glucose and insulin supplemented adipocytes. Additionally, there was altered expression of adipokines, similar to the change in adipose tissue in obese subjects. Under these conditions, the expression/activity of MMP8 was promoted and the expression of MMP3 and TIMP3 was inhibited. Further studies to determine the effect of other obesity-related factors, such as insulin resistance, on MMPs and TIMPs are required. PMID- 21669945 TI - Spinal cord stimulation for cancer-related low back pain. AB - OBJECTIVE: At least one third of patients with cancer have pain at the time of their diagnosis. In an attempt to provide increased pain relief for patients with intractable cancer pain, unconventional agents and interventional procedures including spinal cord stimulation (SCS) have received considerable attention. METHODS: Patients with cancer-related low back pain underwent an uneventful SCS trial with percutaneous placement of 2 temporary 8-electrode leads placed at the level of T8-T9-T10. RESULTS: After experiencing excellent pain relief during the 2-day trial, patients were subsequently implanted with permanent leads and generator with sustained pain relief at 12 months postoperation. CONCLUSION: Spinal cord stimulation provides an effective, alternative treatment option for select patients with cancer-related pain who have failed conservative treatment. PMID- 21669946 TI - National survey of Escherichia coli causing extraintestinal infections reveals the spread of drug-resistant clonal groups O25b:H4-B2-ST131, O15:H1-D-ST393 and CGA-D-ST69 with high virulence gene content in Spain. AB - OBJECTIVES: To evaluate the current prevalence of the three clonal groups O25b:H4 B2-ST131, O15:H1-D-ST393 and CGA-D-ST69 (where ST stands for sequence type) among Escherichia coli isolates causing extraintestinal infections in Spain and to characterize their virulence background, 500 consecutive non-duplicate E. coli isolates causing extraintestinal infections were analysed. METHODS: The 500 isolates were collected during February 2009 from five hospitals in different Spanish regions. Phylogenetic groups, STs, serotypes, virulence genes, PFGE profiles, antimicrobial resistance and extended-spectrum beta-lactamase (ESBL) enzymes were determined. RESULTS: The three clonal groups accounted for 19% of the 500 isolates. Furthermore, they accounted for 37% of the isolates exhibiting trimethoprim/sulfamethoxazole plus ciprofloxacin resistance, 34% of aminoglycoside-resistant isolates and 30% of multidrug-resistant isolates. Clonal group ST131 was the most prevalent, and accounted for 12% of isolates overall and for 23% of multidrug-resistant isolates. The ST131 isolates exhibited a significantly higher virulence score (mean of virulence genes 8.1) compared with the ST393 (6.0) and ST69 (5.4) isolates. The prevalence of ESBL-producing isolates was 7%. Six (10%) of the 59 ST131 isolates were positive for CTX-M-15 and one (6%) of the 16 ST393 isolates was positive for CTX-M-14, whereas none of the 22 ST69 isolates produced ESBL enzymes. CONCLUSIONS: The three clonal groups investigated accounted for 30% of the multidrug-resistant isolates, which gives evidence of an important clonal component in the emergence of resistances among extraintestinal pathogenic E. coli. Notably, a single high virulence clonal group (O25b:H4-B2-ST131) causes approximately 1 in every 10 extraintestinal infections in Spain, representing an important public health threat. A new variant of the ST131 clonal group, which is non-ESBL-producing but trimethoprim/sulfamethoxazole resistant and with high virulence content, is reported. PMID- 21669947 TI - Phylogenetic diversity of Escherichia coli strains producing NDM-type carbapenemases. AB - BACKGROUND: The global accumulation of Escherichia coli with CTX-M extended spectrum beta-lactamases partly reflects the dissemination of clonal lineages, notably ST131 and ST405. More recently, E. coli have emerged that produce NDM carbapenemase. We sought to determine the clonal diversity of E. coli with this enzyme from English hospitals, and to compare them with isolates from Pakistan and India. METHODS: The 18 NDM-positive E. coli were from hospitals in England (n = 10), Pakistan (n = 7) and India (n = 1). Isolates were compared by phylogenetic grouping, multilocus sequence typing and PFGE of XbaI-digested DNA. Isolates were screened by PCR for acquired AmpC genes, bla(CTX-M), and the 16S rRNA methylase genes armA and rmtC. RESULTS: Most of the isolates belonged to phylogenetic groups B1 (n = 9) or D (n = 7); two were group A and none was group B2. Nine isolates from England and Pakistan belonged to the B1 lineage ST101, with seven of these clustering at >77% similarity by PFGE. Other lineages included ST405 (n = 3, group D), ST648 (n = 3, group D), the ST23 complex (one each of ST90 and ST410, both group A) and ST156 (n = 1, group D). Sixteen of 18 isolates had a group 1 CTX-M gene, 13 had a CIT-type acquired AmpC, and 16 had either or both of armA and rmtC. CONCLUSIONS: The E. coli isolates producing NDM-1 carbapenemase belonged to six sequence types and included diverse clonal lineages. Nevertheless, isolates of B1-ST101 accounted for half the collection, and included isolates from both England and Pakistan. None of the isolates belonged to ST131 or to phylogroup B2. PMID- 21669949 TI - Doctor who complained to regulator about weight loss product is sued for libel. PMID- 21669948 TI - GP consortiums must learn from US experience, says expert. PMID- 21669951 TI - "No decisions about us without us"? Individual healthcare rationing in a fiscal ice age. PMID- 21669952 TI - Five year survival from breast cancer is lower in deprived areas, says UK report. PMID- 21669953 TI - London hospital says it will continue to offer HIV tests to all accident and emergency patients after trial. PMID- 21669950 TI - Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study. AB - OBJECTIVES: To assess the compliance of Asian intensive care units and hospitals to the Surviving Sepsis Campaign's resuscitation and management bundles. Secondary objectives were to evaluate the impact of compliance on mortality and the organisational characteristics of hospitals that were associated with higher compliance. DESIGN: Prospective cohort study. SETTING: 150 intensive care units in 16 Asian countries. PARTICIPANTS: 1285 adult patients with severe sepsis admitted to these intensive care units in July 2009. The organisational characteristics of participating centres, the patients' baseline characteristics, the achievement of targets within the resuscitation and management bundles, and outcome data were recorded. MAIN OUTCOME MEASURE: Compliance with the Surviving Sepsis Campaign's resuscitation (six hours) and management (24 hours) bundles. RESULTS: Hospital mortality was 44.5% (572/1285). Compliance rates for the resuscitation and management bundles were 7.6% (98/1285) and 3.5% (45/1285), respectively. On logistic regression analysis, compliance with the following bundle targets independently predicted decreased mortality: blood cultures (achieved in 803/1285; 62.5%, 95% confidence interval 59.8% to 65.1%), broad spectrum antibiotics (achieved in 821/1285; 63.9%, 61.3% to 66.5%), and central venous pressure (achieved in 345/870; 39.7%, 36.4% to 42.9%). High income countries, university hospitals, intensive care units with an accredited fellowship programme, and surgical intensive care units were more likely to be compliant with the resuscitation bundle. CONCLUSIONS: While mortality from severe sepsis is high, compliance with resuscitation and management bundles is generally poor in much of Asia. As the centres included in this study might not be fully representative, achievement rates reported might overestimate the true degree of compliance with recommended care and should be interpreted with caution. Achievement of targets for blood cultures, antibiotics, and central venous pressure was independently associated with improved survival. PMID- 21669954 TI - Dose ranging study on the effect of preoperative dexamethasone on postoperative quality of recovery and opioid consumption after ambulatory gynaecological surgery. AB - BACKGROUND: Glucocorticoids are commonly administered before ambulatory surgery, although their effects on quality of recovery are not well characterized. The purpose of this study was to evaluate the dose-dependent effects of dexamethasone on patient recovery using the Quality of Recovery 40 questionnaire (QoR-40) after ambulatory surgery. METHODS: This prospective, double-blind trial studied 106 female subjects undergoing outpatient gynaecological laparoscopy. Subjects were randomized to receive saline, dexamethasone 0.05 mg kg(-1) or dexamethasone 0.1 mg kg(-1) before induction. The primary outcome was global QoR-40 at 24 h. Postoperative pain, analgesic consumption, side-effects, and discharge time were also evaluated. RESULTS: Global median (IQR) QoR-40 after dexamethasone 0.1 mg kg(-1) 193 (192-195) was greater than dexamethasone 0.05 mg kg(-1) 179 (175-185) (P=0.004) or saline, 171 (160-182) (P<0.005). Median (IQR) morphine equivalents administered before discharge were 2.7 (0-6.3) mg after dexamethasone 0.1 mg kg( 1) compared with 5.3 (2.4-8.8) mg and 5.3 (2.7-7.8) mg after dexamethasone 0.05 mg kg(-1) and saline (P=0.02). Time to meet discharge criteria was 30 min shorter after dexamethasone 0.1 mg kg(-1) compared with saline (P=0.005). At 24 h, subjects receiving dexamethasone 0.1 mg kg(-1) had consumed less opioid analgesics, reported less sore throat, muscle pain, confusion, difficulty in falling asleep, and nausea compared with dexamethasone 0.05 mg kg(-1) and saline. CONCLUSIONS: Dexamethasone demonstrated dose-dependent effects on quality of recovery. Dexamethasone 0.1 mg kg(-1) reduced opioid consumption compared with dexamethasone 0.05 mg kg(-1), which may be beneficial for improving recovery after ambulatory gynaecological surgery. PMID- 21669955 TI - Protein stabilization in a highly knotted protein polymer. AB - The polypeptide backbones of a few proteins are tied in a knot. The biophysical effects and potential biological roles of knots are not well understood. Here, we test the consequences of protein knotting by taking a monomeric protein, carbonic anhydrase II, whose native structure contains a shallow knot, and polymerizing it end-to-end to form a deeply and multiply knotted polymeric filament. Thermal stability experiments show that the polymer is stabilized against loss of structure and aggregation by the presence of deep knots. PMID- 21669956 TI - Peptides specific for Mycobacterium avium subspecies paratuberculosis infection: diagnostic potential. AB - Mycobacterium avium subspecies paratuberculosis (Map) is the causative agent of Johne's disease (JD). Current serological diagnostic tests for JD are limited by their sensitivity when used in sub-clinical stages of the disease. Our objective was to identify peptides that mimic diagnostically important Map epitopes that might be incorporated into a new-generation JD diagnostic. Four peptides were isolated from a phage-displayed random peptide library by screening on antibodies derived from Map-infected goats. The peptides were recognised by antibodies from Map-infected goats but not by antibodies from uninfected goats. The peptides elicited immune responses in rabbits, which reacted strongly with bona fide Map antigens proving the peptides were true epitope mimics. To assess the diagnostic value a panel of goat sera was screened for reactivity's with peptides. The peptides were recognised by antibodies from a proportion of goats infected with Map compared with control animals with a diagnostic specificity of 100% and the sensitivity ranged from 50 to 75%. Combinations of any two peptides improved sensitivity 62.5-87.5% and 100% sensitivity was achieved with three of the four peptides in combination. These data suggest peptides representing diagnostically important Map epitopes could be incorporated into a sensitive diagnostic test. PMID- 21669957 TI - Differences in cigarette smoking behaviors among heroin inhalers versus heroin injectors. AB - INTRODUCTION: The high prevalence of cigarette smoking among heroin users has triggered many studies to explore possible interactions between cigarette smoking and heroin addiction; however, little is known about the relationship between cigarette smoking behaviors and routes of heroin administration. The present study provided the first examination of cigarette smoking status, motivation, and cigarette smoking cue reactivity among injecting or inhaling heroin users. METHODS: Forty-six heroin-dependent patients were recruited in the present study. A battery of self-report questionnaires was used to assess cigarette smoking status and the reasons for smoking. In the clinical laboratory study, participants completed a cue-reactivity procedure that involved collecting psychophysical and motivational data in response to cigarette smoking slides. RESULTS: The average number of cigarette per day among heroin inhalers was higher than that among heroin injectors. Most heroin inhalers reported that the primary reason for smoking was "maintaining drug pleasure," whereas heroin injectors reported that the primary smoking reason was "nicotine pleasure." Compared with heroin injectors, heroin inhalers provided increased ratings of heroin craving and desire to heroin use when exposed to cigarette smoking cues. Number of cigarettes per day was significantly correlated with cue-induced overall mean motivation in heroin inhalers but not in heroin injectors. CONCLUSIONS: Cigarette smoking behaviors were different among heroin inhalers from among heroin injectors. These results emphasize the stronger association between cigarette smoking and heroin inhaling. PMID- 21669958 TI - Efficacy of cell phone-delivered smoking cessation counseling for persons living with HIV/AIDS: 3-month outcomes. AB - INTRODUCTION: Substantial evidence indicates that cigarette smoking among people living with HIV/AIDS (PLWHA) represents a significant public health concern. However, few efforts to assess smoking cessation interventions targeting this population have been reported. In this brief report, 3-month outcomes from an ongoing treatment trial for PLWHA who smoke are described. METHODS: Study participants were recruited from a large HIV care center serving a diverse population of PLWHA. A two-group randomized design was used to compare the efficacy of usual-care (UC) smoking cessation treatment versus a cell phone intervention (CPI). Follow-ups were conducted at the HIV clinic 3 months postenrollment. Using an intent-to-treat approach, a series of multiple regression models were used to compare smoking outcomes in the 2 groups. RESULTS: Four hundred and seventy-four participants were enrolled and randomized, UC (n = 238) and CPI (n = 236). Mean age in the sample was 44.8 (SD = 8.1) years, and the majority were male (70.0%), Black (76.6%), and had an education level of high school or less (77.5%). At follow-up, participants in the CPI group were 4.3 (95% CI = 1.9, 9.8) times more likely to be abstinent (7 day) compared with those in the UC group. Similarly, significant point estimates were observed for the other smoking outcomes of interest. CONCLUSIONS: Findings from this preliminary report indicate that a smoking cessation intervention for PLWHA consisting of cell phone delivered proactive counseling results in significantly higher abstinence rates compared with a standard care approach. Evaluation of the long-term (6-month and 12-month) efficacy of the CPI approach is ongoing. PMID- 21669959 TI - Secondhand smoke risk in infants discharged from an NICU: potential for significant health disparities? AB - INTRODUCTION: Secondhand smoke exposure (SHSe) threatens fragile infants discharged from a neonatal intensive care unit (NICU). Smoking practices were examined in families with a high respiratory risk infant (born at very low birth weight; ventilated > 12 hr) in a Houston, Texas, NICU. Socioeconomic status, race, and mental health status were hypothesized to be related to SHSe and household smoking bans. METHODS: Data were collected as part of The Baby's Breath Project, a hospital-based SHSe intervention trial targeting parents with a high risk infant in the NICU who reported a smoker in the household (N = 99). Measures of sociodemographics, smoking, home and car smoking bans, and depression were collected. RESULTS: Overall, 26% of all families with a high-risk infant in the NICU reported a household smoker. Almost half of the families with a smoker reported an annual income of less than $25,000. 46.2% of families reported having a total smoking ban in place in both their homes and cars. Only 27.8% families earning less than $25,000 reported having a total smoking ban in place relative to almost 60% of families earning more (p < .01). African American and Caucasian families were less likely to have a smoking ban compared with Hispanics (p < .05). Mothers who reported no smoking ban were more depressed than those who had a household smoking ban (p < .02). CONCLUSIONS: The most disadvantaged families were least likely to have protective health behaviors in place to reduce SHSe and, consequently, are most at-risk for tobacco exposure and subsequent tobacco related health disparities. Innovative SHSe interventions for this vulnerable population are sorely needed. PMID- 21669960 TI - Safety, efficacy, and performance of new discrimination algorithms to reduce inappropriate and unnecessary shocks: the PainFree SST clinical study design. AB - INTRODUCTION: Implantable cardioverter defibrillator (ICD) shock therapy improves survival of patients at risk for sudden cardiac death. The high sensitivity of ICDs to detect tachycardia events is accompanied by reduced specificity resulting in inappropriate and unnecessary shocks. Up to 30% of ICD patients may experience inappropriate shocks, which are most commonly caused by lead noise, oversensing of T-waves, and supraventricular tachycardias. The new Protecta ICD and cardiac resynchronization therapy devices have been designed to minimize inappropriate and unnecessary shocks through novel SmartShock(TM) technology algorithms targeting these causes. METHODS: The PainFree SST study is a prospective, multicentre clinical trial, which will be conducted in two consecutive phases. Phase I will assess safety and any delay that may arise in ventricular fibrillation (VF) arrhythmia detection time using new algorithms. Phase II will evaluate reduction of inappropriate and unnecessary shocks at 1 year of follow up. Additional objectives will include Quality of Life, healthcare utilization, safety of extending the ventricular tachyarrhythmia/VF interval detection duration (18 out of 24 vs. 30 out of 40 intervals), and reasons for inappropriate shock. Up to 2000 subjects in 150 centres worldwide will be enrolled with a follow-up of at least 1 year. Subjects enrolled in Phase I will continue in Phase II of the study and data from all enrolled subjects will contribute to the analysis of Phase II objectives. CONCLUSION: Inappropriate and unnecessary shock delivery remains a significant clinical issue for patients receiving device therapies, which has considerable consequences for patients and the healthcare system. The PainFree SST study will investigate the ability of new algorithms to reduce inappropriate shocks. Results from this study are expected in mid-2013. PMID- 21669961 TI - Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. AB - AIMS: Advanced glycation endproducts (AGEs) have been associated with the development and progression of chronic heart failure (CHF). Advanced glycation endproducts-crosslink breakers might be of benefit in HF, but only small-scale and uncontrolled data are available. Our aim was to conduct a prospective, randomized, double-blind, placebo-controlled study to examine the effects of the AGE-breaker alagebrium on exercise capacity and cardiac function in patients with HF. METHODS AND RESULTS: One hundred and two patients with HF (78% male, aged 62 +/- 11 years), and a left ventricular ejection fraction (LVEF) <=0.45, were randomized to either 200 mg alagebrium twice daily or placebo. After 36 weeks, the primary efficacy end-point peak VO(2) had changed by (mean +/- SEM) -2.1 +/- 0.5 mL/min/kg in alagebrium vs. -0.5 +/- 0.7 mL/min/kg in placebo-treated patients (P= 0.06). No significant changes were observed in a number of secondary end-points, including diastolic function (mean E': P= 0.32; E/E': P= 0.81), systolic function (LVEF: P= 0.43), AGE accumulation (skin-autofluorescence: P= 0.42), N-terminal pro brain natriuretic peptide, P= 0.20); New York Heart Association functional class (P= 0.73), patient global assessment (P= 0.32), physicians global assessment (P= 0.76), and the Minnesota Living with Heart Failure Questionnaire score (P= 0.38). Overall alagebrium was reasonably well tolerated. CONCLUSION: In the present proof-of-concept study, the AGE-breaker alagebrium did not improve exercise tolerance in patients with HF and systolic dysfunction, and no changes were observed in a number of secondary endpoints. The present data therefore do not support earlier data which suggested a beneficial effect of alagebrium in systolic HF. CLINICAL TRIAL REGISTRATION INFORMATION: NCT00516646 (http://clinicaltrials.gov). PMID- 21669962 TI - An EST-SSR linkage map of Raphanus sativus and comparative genomics of the Brassicaceae. AB - Raphanus sativus (2n = 2x = 18) is a widely cultivated member of the family Brassicaceae, for which genomic resources are available only to a limited extent in comparison to many other members of the family. To promote more genetic and genomic studies and to enhance breeding programmes of R. sativus, we have prepared genetic resources such as complementary DNA libraries, expressed sequences tags (ESTs), simple sequence repeat (SSR) markers and a genetic linkage map. A total of 26 606 ESTs have been collected from seedlings, roots, leaves, and flowers, and clustered into 10 381 unigenes. Similarities were observed between the expression patterns of transcripts from R. sativus and those from representative members of the genera Arabidopsis and Brassica, indicating their functional relatedness. The EST sequence data were used to design 3800 SSR markers and consequently 630 polymorphic SSR loci and 213 reported marker loci have been mapped onto nine linkage groups, covering 1129.2 cM with an average distance of 1.3 cM between loci. Comparison of the mapped EST-SSR marker positions in R. sativus with the genome sequence of A. thaliana indicated that the Brassicaceae members have evolved from a common ancestor. It appears that genomic fragments corresponding to those of A. thaliana have been doubled and tripled in R. sativus. The genetic map developed here is expected to provide a standard map for the genetics, genomics, and molecular breeding of R. sativus as well as of related species. The resources are available at http://marker.kazusa.or.jp/Daikon. PMID- 21669963 TI - Abnormal expression of the ERG transcription factor in prostate cancer cells activates osteopontin. AB - Osteopontin (OPN) is an extracellular matrix glycophosphoprotein that plays a key role in the metastasis of a wide variety of cancers. The high level of OPN expression in prostate cells is associated with malignancy and reduced survival of the patient. Recent studies on prostate cancer (PCa) tissue have revealed recurrent genomic rearrangements involving the fusion of the 5' untranslated region of a prostate-specific androgen-responsive gene with a gene coding for transcription factors from the ETS family. The most frequently identified fusion gene is TMPRSS2:ERG, which causes ERG protein overexpression in PCa cells. ERG is a transcription factor linked to skeletogenesis. This study was designed to test whether ERG and the product of the TMPRSS2:ERG fusion gene modulate OPN gene expression in PCa cells. To characterize ERG and TMPRSS2:ERG transcriptional activity of OPN, we focused on ETS binding sites (EBS) localized in conserved regions of the promoter. Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt -115 to -118) in the OPN promoter. Moreover, stable transfection of prostate tumor cell lines by TMPRSS2:ERG upregulates endogenous OPN expression. Finally, in human prostate tumor samples, detection of the TMPRSS2:ERG fusion gene was significantly associated with OPN overexpression. Taken together, these data suggest that OPN is an ERG-target gene in PCa where the abnormal expression of the transcription factor ERG, due to the TMPRSS2:ERG fusion, disturbs the expression of genes that play an important role in PCa cells and associated metastases. PMID- 21669964 TI - The a3 isoform vacuolar type H+-ATPase promotes distant metastasis in the mouse B16 melanoma cells. AB - Accumulating evidence indicates that the acidic microenvironments critically influence malignant behaviors of cancer including invasiveness, metastasis, and chemoresistance. Because the vacuolar-type H(+)-ATPase (V-ATPase) has been shown to cause extracellular acidification by pumping protons, we studied the role of V ATPase in distant metastasis. Real-time PCR analysis revealed that the high metastatic B16-F10 melanoma cells strongly expressed the a3 isoform V-ATPase compared to the low-metastatic B16 parental cells. Consistent with this, B16-F10 cells created acidic environments in lung metastases by acridine orange staining and strong a3 V-ATPase expression in bone metastases by immunohistochemistry. Immunocytochemical analysis showed B16-F10 cells expressed a3 V-ATPase not only in cytoplasm but also plasma membrane, whereas B16 parental cells exhibited its expression only in cytoplasm. Of note, knockdown of a3 V-ATPase suppressed invasiveness and migration with reduced MMP-2 and MMP-9 expression in B16-F10 cells and significantly decreased lung and bone metastases, despite that tumor growth was not altered. Importantly, administration of a specific V-ATPase a3 inhibitor FR167356 reduced bone metastasis of B16-F10 cells. These results suggest that a3 V-ATPase promotes distant metastasis of B16-F10 cells by creating acidic environments via proton secretion. Our results also suggest that inhibition of the development of cancer-associated acidic environments by suppressing a3 V-ATPase could be a novel therapeutic approach for the treatment of cancer metastasis. PMID- 21669965 TI - "Scratching" beneath the surface: an integrative psychosocial approach to pediatric pruritus and pain. AB - Pruritus is prevalent in children with atopic dermatitis and associated with effects on mood, quality of life, sleep, scholastic performance, social and family functioning. In this study a 7-year-old African American female with severe atopic dermatitis, itching and pain refractory to multiple systemic and topical medications was referred for treatment. At baseline, the patient scratched to the point of bleeding, despite maximal doses of anti-histamines, antidepressant and topical therapies. The patient became progressively shy, anxious, and her scholastic performance suffered. A literature review prompted the implementation of a multi-modal program of family cognitive behavioral therapy, imagery, aromatherapy, drawing, and biofeedback. The results were that decreased itch, scratching, pain, and anxiety were seen within the first month. Fewer lesions and episodes of bleeding were observed with almost complete skin clearance by the fourth month. The article concludes that a short-term, integrative program including psychological, complementary and alternative medicine (CAM), and medical therapies may represent a novel, efficacious approach for children suffering from severe atopic dermatitis. PMID- 21669967 TI - Time trends in the natural dizygotic twinning rate. AB - BACKGROUND: The natural dizygotic (DZ) twinning rate has been proposed as a reliable and useful measure of human fecundity, if adjusted for maternal age at twin birth. The aim of this study was to analyze age-adjusted trends in natural DZ twinning rates over the past 40 years using data from the 'East Flanders Prospective Twin Survey (EFPTS)'. METHODS: This study involved 4835 naturally conceived twin pregnancies between 1969 and 2009 from the population-based Belgian 'EFPTS'. Age-adjusted trends in the incidence of natural DZ twin pregnancies were calculated using a generalized linear model with Poisson distribution. RESULTS: Both the natural DZ twinning rates and maternal age at twin birth increased in a linear fashion from 1969 to 2009. When age-adjusted, we found that the trend in the natural DZ twinning rate was stable during the whole time period. CONCLUSIONS: According to our population-based data and after age adjustment, a stable natural DZ twinning rate could be observed over the last four decades. Under the assumption that the spontaneous DZ twinning rate is a sensor of fecundity, this indicates a stable 'high' fecundity for this population. PMID- 21669966 TI - Animal age, weight and estrus cycle stage impact the quality of in vitro grown follicles. AB - BACKGROUND: Ovarian tissue cryopreservation is an emerging fertility preservation option, and culturing follicles isolated from this tissue to obtain mature gametes may ultimately be the best solution for patients for whom transplantation is contraindicated. It is unclear, however, how patient-specific variables (including age, weight and menstrual cycle stage) impact follicle growth and quality during three-dimensional culture. METHODS: We used a mouse model to systematically determine how these variables impact in vitro follicle growth. We characterized metabolic and hormonal profiles of mice at specific ages, weights and cycle stages and secondary follicles from these cohorts were isolated and cultured. We then assessed follicle survival, growth and function, as well as meiotic competence and spindle morphology of the resulting oocytes. RESULTS: We found that older mice and mice with increased body weight had higher serum cholesterol, abnormal glucose tolerance and lower levels of circulating Anti Mullerian hormone compared with younger and leaner controls. Secondary follicles isolated from different cohorts and grown in vitro had indistinguishable growth trajectories. However, the follicles isolated from older and heavier mice and those in diestrus had altered hormone profiles. These follicles contained oocytes with reduced meiotic competence and produced oocytes with greater spindle defects. CONCLUSIONS: These results suggest that the original physical environment of the follicle within the ovary can impact its function when isolated and cultured. These findings are valuable as we begin to use in vitro follicle growth technology for a heterogeneous fertility preservation patient population. PMID- 21669968 TI - Idiopathic primary ovarian insufficiency: a study of serial hormonal profiles to assess ovarian follicular activity. AB - BACKGROUND: Ovarian follicular activity in serial hormone profiles has been reported in up to 86% of patients with primary ovarian insufficiency (POI). In most of these studies, patients had a short duration of amenorrhea or irregular menstrual cycles which could influence the occurrence of spontaneous follicular activity. The aim was to study the incidence of follicular activity in serial hormonal profiles of women with spontaneous POI and amenorrhea of 1 year duration. METHODS: This observational study involved 20 patients with spontaneous POI, amenorrhea of >1 year duration and normal karyotype. Serum measurements of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone, free T3, free T4, thyroid-stimulating hormone and anti thyroperoxidase antibodies, taken in the absence of estrogen replacement, were followed by weekly measurements of serum E2, FSH, LH and progesterone for 1 month then monthly measurements for 2 months. Increases in serum E2 >184 pmol/l and serum progesterone >10 nmol/l were taken as evidence of follicular activity and ovulation, respectively. RESULTS: A rise in serum E2 >184 pmol/l was noted in 2/18 subjects [11.1%; 95% confidence interval (CI): 1.4-34.7%]. Though the corresponding serum FSH levels showed a decline, the values remained >40 IU/l. None of the subjects had serum progesterone levels >10 nmol/l, return of menses or pregnancy. CONCLUSION: Endogenous ovarian follicular function is intermittently present in only 11.1% of Asian Indian women with POI. However, the 95% CI (1.4-34.7%) was large due to a small sample size. PMID- 21669969 TI - Incident reporting culture: scale development with validation and reliability and assessment of hospital nurses in Taiwan. AB - OBJECTIVE: To examine the psychometric validity and reliability of the incident reporting culture questionnaire (IRCQ; in Chinese) following an exploration of the reporting culture perceived by hospital nurses in Taiwan. DESIGN: Scale development with psychometric examination and a cross-sectional study. SETTING: Ten teaching hospitals. PARTICIPANTS: A total of 1064 nurses participated with an average response rate of 83% between November 2008 and June 2009. MAIN OUTCOME MEASURES: The factorial construct, criterion-related validity, homogeneity and stability of the IRCQ were evaluated. The nurses' perceptions of the IRCQ were also explored. RESULTS: The four-factor structure of the 20-item IRCQ had satisfactory construct validity (explained variance: 49.37%), criterion-related validity (r = 0.42; P = 0.001), reliability (Cronbach's alpha: 0.83) and stability (3-week-interval correlation: r = 0.80; P = 0.001). These factors included 'application of learning from errors', 'readiness to provide feedback on incident reports', 'collegial atmospheres of unpleasantness and punishment' (CA) and 'incident management: confidential and system driven'. The nurses perceived a moderate overall reporting culture (mean positive response = 49.25%; range: 67.2 24.94%). They weakly agreed on the CA factor of five items (mean positive response = 24.94%; range: 33.0-17.2%). CONCLUSIONS: This study provides empirical evidence for the psychometric properties of the IRCQ and the reporting culture which nurses perceive in Taiwan. To Taiwanese nurses, the reporting culture within their work environments especially as it relates to coworker relations, inter-professional collaboration and non-punitive atmosphere is their major concern. Healthcare administrators should consider nurses' perceptions related to incident reporting when managing underreporting issues. PMID- 21669970 TI - Inappropriate hospitalization days in Korean oriental medicine hospitals. AB - OBJECTIVE: To examine the extent of inappropriate hospitalization days in Korean oriental medicine (OM) hospitals and to determine the factors associated with inappropriate stays. DESIGN: Cross-sectional study design using concurrent and retrospective medical record reviews. SETTING: Two teaching OM hospitals in Korea. PARTICIPANTS: Patients (n = 256) consecutively discharged from general care units in two OM hospitals in 1 month. INTERVENTION: The appropriateness of each hospitalization day was assessed using a modified appropriateness evaluation protocol. Patient and healthcare use characteristics were also reviewed. Multiple regression analyses were performed to determine factors associated with inappropriate stay. MAIN OUTCOME MEASURE: Rate of inappropriate hospitalization days. RESULTS: Overall, 14.9% (691/4644) of hospitalization days reviewed were judged inappropriate with a mean of 18.3% (95% confidence interval = 14.6-22.0) per patient. Approximately half of patients (n = 126, 49.2%) had at least 1 inappropriate hospitalization day. Factors associated with inappropriate hospitalization days were admission method and number of types of OM therapies. Patients admitted to hospitals on foot without assistance had more inappropriate hospitalization days than those admitted by stretcher cart. Those who underwent several types of OM therapies during hospitalization had fewer inappropriate hospitalization days. CONCLUSIONS: A substantial proportion of hospitalization days were evaluated as inappropriate. Patient condition at admission and types of OM therapies required should be taken into account to reduce unnecessary stays in OM hospitals. Additionally, availability of OM services, especially for patients with limited motor functions, needs to be improved outside hospitals. PMID- 21669971 TI - Utilization and perceptions of neonatal healthcare providers in rural Uttar Pradesh, India. AB - OBJECTIVE: To describe the utilization and perceptions of existing neonatal health services in rural Uttar Pradesh, India. DESIGN: A prospective observational study. SETTING: The study was located in Shivgarh, a rural block of Uttar Pradesh, India. PARTICIPANTS: One hundred and fifty-three households that utilized a healthcare provider for their sick neonates. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Perceived neonatal health improvement after utilization of neonatal health services; satisfaction with aspects of neonatal health services: 'overall care', 'interaction with provider', 'waiting time' and 'explanations of immediate care and follow-up care'. RESULTS: Unqualified allopathically oriented providers (UAOPs) were utilized by 110 households (71.8%), while qualified allopathically oriented providers (QAOPs) by 43 households (28.2%). The odds of perceived neonatal health improvement were significantly higher among households utilizing UAOPs (n = 88/110, 80.0%) than those using QAOPs (n = 23/43, 53.5%) [adjusted odds ratio (OR): 3.3, 95% confidence interval (CI): 1.5-7.5]. The median healthcare fee charged was higher for UAOPs (Rs. 25) than those for QAOPs (Rs. 1). Household satisfaction with 'overall care' of neonatal health service was significantly higher among households that utilized UAOPs compared with those that used QAOPs (OR: 2.4, 95% CI: 1.2-5.0). CONCLUSION: Households that utilized UAOPs reported better perceived neonatal health outcomes and higher satisfaction levels than those that used QAOPs, despite higher costs for the former. Future research should assess what dimensions of neonatal care are important to households and identify incentive structures that promote healthcare providers to deliver better perceived care in high-mortality settings such as rural Uttar Pradesh, India. PMID- 21669973 TI - Fostering in mice induces cardiovascular and metabolic dysfunction in adulthood. AB - Cross-fostering is widely used in developmental programming studies to determine the relative contribution of the in utero and suckling periods in establishing the adult offspring phenotype in response to an environmental challenge. We have investigated whether the process of fostering per se influences cardiovascular and metabolic function in adult offspring of C57BL/6J mice in comparison with animals suckled by their biological dams. Cross-fostered (CF) mice demonstrated juvenile onset hyperphagia and significantly higher body weight (from weaning to 12 weeks: male control (CON) vs. CF: P < 0.01, female CON vs. CF: P < 0.001; RM ANOVA) accompanied by increased abdominal adiposity in males only (white adipose tissue mass (mg): CON 280.5 +/- 13.4 [mean +/- SEM] (n = 7) vs. CF, 549.8 +/- 99.3 (n = 8), P < 0.01). Both male and female CF mice demonstrated significantly enhanced glucose tolerance. A marked increase in systolic blood pressure (SBP) was observed in male CF mice (SBP (mmHg), day: CON 100.5 +/- 1.4 (n = 6) vs. CF 114.3 +/- 0.7 (n = 6), P < 0.001; night: CON 108.0 +/- 2.0 (n = 6) vs. CF 123.2 +/- 1.1 (n = 6), P < 0.001). Endothelium-dependent relaxation was enhanced in male CF mice, and renal noradrenaline was increased in female CF mice. Concentration of serum triglycerides, cholesterol, insulin and leptin were increased in CF vs. CON. The process of cross-fostering profoundly affects cardiovascular and metabolic phenotype in mice. The findings have implications for the inclusion of appropriate controls in the design of future studies and in the interpretation of previous cross-fostering studies in mice. PMID- 21669974 TI - The spatio-temporal characteristics of action potential initiation in layer 5 pyramidal neurons: a voltage imaging study. AB - The spatial pattern of Na(+) channel clustering in the axon initial segment (AIS) plays a critical role in tuning neuronal computations, and changes in Na(+) channel distribution have been shown to mediate novel forms of neuronal plasticity in the axon. However, immunocytochemical data on channel distribution may not directly predict spatio-temporal characteristics of action potential initiation, and prior electrophysiological measures are either indirect (extracellular) or lack sufficient spatial resolution (intracellular) to directly characterize the spike trigger zone (TZ). We took advantage of a critical methodological improvement in the high sensitivity membrane potential imaging (V(m) imaging) technique to directly determine the location and length of the spike TZ as defined in functional terms. The results show that in mature axons of mouse cortical layer 5 pyramidal cells, action potentials initiate in a region ~20 MUm in length centred between 20 and 40 MUm from the soma. From this region, the AP depolarizing wave invades initial nodes of Ranvier within a fraction of a millisecond and propagates in a saltatory fashion into axonal collaterals without failure at all physiologically relevant frequencies. We further demonstrate that, in contrast to the saltatory conduction in mature axons, AP propagation is non saltatory (monotonic) in immature axons prior to myelination. PMID- 21669975 TI - Novel events in the molecular regulation of muscle mass in critically ill patients. AB - Critically ill patients experience marked skeletal muscle atrophy, but the molecular mechanisms responsible for this are largely unresolved. Therefore, we investigated key genes and proteins, identified from cell and animal studies to control protein synthesis and breakdown, in vastus lateralis biopsy samples obtained from 10 patients and 10 age- and sex-matched healthy controls. Muscle cytokines IL-6 and TNF-alpha mRNA were higher in patients than in controls(6.5 fold; P < 0.001 and 2-fold; P < 0.01). From the perspective of muscle protein breakdown, muscle-specific E3-ligases (MAFbx and MuRF1) were higher in patients at mRNA (4.5-fold; P < 0.05 and 2.5-fold; P < 0.05) and protein (5-fold; P < 0.001 and 4.5-fold; P < 0.001) level. Furthermore, 20S proteasome mRNA and protein were higher in patients (5-fold; P < 0.001 and 2.5-fold; P < 0.01). Cathepsin-L mRNA was 2-fold higher (P < 0.01), whilst calpain-3 mRNA(2-fold; P < 0.01) and protein (4-fold; P < 0.01)were lower inpatients. Another novel observation was the 3-fold (P < 0.05) and 8.5-fold (P < 0.001) higher expression of myostatin mRNA and protein in patients. Widespread dephosphorylation (inactivation) of proteins regulating translation initiation factor activation and protein synthesis (Akt1, GSK3alpha,beta, mTOR, p70S6K and 4E-BP1) was observed in patients, which was paralleled by increases in their mRNAs. Finally, PDK4 mRNA and protein was 2-fold (P < 0.05) and 2.6-fold (P < 0.01), respectively, higher inpatients. In conclusion, we showed comprehensive alterations in molecular events thought to reduce muscle mass and carbohydrate (CHO) oxidation in critically ill patients. Nevertheless,these catabolic events were matched by a cellular programme of anabolic restoration at the transcriptional level. This shows a high molecular plasticity in the muscle of patients, and strategies to preserve muscle mass and metabolic function should focus on maintaining Akt phosphorylation and inhibiting myostatin expression.C PMID- 21669976 TI - O-glycosylation of the cardiac I(Ks) complex. AB - Post-translational modifications of the KCNQ1-KCNE1 (Kv7) K+ channel complex are vital for regulation of the cardiac IKs current and action potential duration. Here, we show the KCNE1 regulatory subunit is O-glycosylated with mucin-type glycans in vivo. As O-linked glycosylation sites are not recognizable by sequence gazing, we designed a novel set of glycosylation mutants and KCNE chimeras and analysed their glycan content using deglycosylation enzymes. Our results show that KCNE1 is exclusively O-glycosylated at Thr-7, which is also required for N glycosylation at Asn-5. For wild type KCNE1, the overlapping N- and O glycosylation sites are innocuous for subunit biogenesis; however, mutation of Thr-7 to a non-hydroxylated residue yielded mostly unglycosylated protein and a small fraction of mono-N-glycosylated protein. The compounded hypoglycosylation was equally deleterious for KCNQ1-KCNE1 cell surface expression, demonstrating that KCNE1 O-glycosylation is a post-translational modification that is integral for the proper biogenesis and anterograde trafficking of the cardiac IKs complex. The enzymatic assays and panel of glycosylation mutants used here will be valuable for identifying the different KCNE1 glycoforms in native cells and determining the roles N- and O-glycosylation play in KCNQ1-KCNE1 function and localization in cardiomyocytes, PMID- 21669978 TI - The retinal hypercircuit: a repeating synaptic interactive motif underlying visual function. AB - The vertebrate retina generates a stack of about a dozen different movies that represent the visual world as dynamic neural images or movies. The stack is embodied as separate strata that span the inner plexiform layer (IPL). At each stratum, ganglion cell dendrites reach up to read out inhibitory interactions between three different amacrine cell classes that shape bipolar-to-ganglion cell transmission. The nexus of these five cell classes represents a functional module, a retinal 'hypercircuit', that is repeated across the surface of each of the dozen strata that span the depth of the IPL. Individual differences in the characteristics of each cell class at each stratum lead to the unique processing characteristics of each neural image throughout the stack. This review shows how the interactions between the morphological and physiological characteristics of each cell class generate many of the known retinal visual functions including motion detection, directional selectivity, local edge detection, looming detection, object motion and looming detection. PMID- 21669977 TI - Mast cells drive mesenteric afferent signalling during acute intestinal ischaemia. AB - Acute intestinal ischaemia stimulates visceral afferent nerves but the mechanisms responsible for this excitation are not fully understood. Mast cells may participate in this process as they are known to signal to mesenteric afferents during intestinal anaphylaxis and contribute to early inflammation and neuronal damage in response to cerebral ischaemia. We therefore hypothesised that mast cells are early responders to acute intestinal ischaemia and their activation initiates rapid signalling to the CNS via the excitation of mesenteric afferents. Primary afferent firing was recorded from a mesenteric nerve bundle supplying a segment of jejunum in anaesthetized adult rats. Acute focal ischaemia was produced by clamping theme senteric vessels for 8 min, and reperfusion followed removal of the vessel clip. Two episodes of ischaemia-reperfusion (I-R) separated by a 30 min interval were performed. Drugs or their vehicles were administered 10 min before the 2nd I-R episode. Ischaemia caused a reproducible, intense and biphasic afferent firing that was temporally dissociated from the concomitantly triggered complex pattern of intestinal motor activity. The L-type calcium channel blocker, nifedipine, significantly attenuated this afferent firing by a mechanism independent of its action on intestinal tone. Ischaemia-induced afferent firing was also abrogated by the mast cell stabilizer, doxantrazole, and the H1 histamine receptor antagonist, pyrilamine. In contrast, the nicotinic receptor antagonist, hexamethonium, and the N-type calcium channel toxin, omega conotoxin GVIA, each reduced the ischaemia-evoked motor inhibition but not the concurrent afferent discharge. Similarly, the cyclooxygenase inhibitor, naproxen, had no effect on the ischaemic afferent response but reduced the intestinal tone shortly from the onset of ischaemia to the early period of reperfusion. These data support a critical role for mast cell-derived histamine in the direct chemoexcitation of mesenteric afferents during acute intestinal ischaemia, whereas enteric reflex mechanisms and cyclooxygenase products contribute primarily to ischaemia-induced changes in intestinal motility. Therefore, targeting mast cells may provide benefits in patients with abdominal pain resulting from an ischaemic insult to the gastrointestinal tract. PMID- 21669979 TI - The cerebellar network: revisiting the critical issues. PMID- 21669980 TI - Alternative splicing determines mRNA translation initiation and function of human K(2P)10.1 K+ channels. AB - Potassium-selective ion channels regulate cardiac and neuronal excitability by stabilizing the resting membrane potential and by modulating shape and frequency of action potentials. The delicate control of membrane voltage requires structural and functional diversity of K+ channel subunits expressed in a given cell. Here we reveal a previously unrecognized biological mechanism. Tissue specific mRNA splicing regulates alternative translation initiation (ATI) of human K(2P)10.1 K+ background channels via recombination of 5 nucleotide motifs. ATI-dependent expression of full-length protein or truncated subunits initiated from two downstream start codons determines macroscopic current amplitudes and biophysical properties of hK(2P)10.1 channels. The interaction between hK(2P)10.1 mRNA splicing, translation and function increases K+ channel complexity and is expected to contribute to electrophysiological plasticity of excitable cells. PMID- 21669981 TI - Multiple extra-synaptic spillover mechanisms regulate prolonged activity in cerebellar Golgi cell-granule cell loops. AB - Despite a wealth of in vitro and modelling studies it remains unclear how neuronal populations in the cerebellum interact in vivo. We address the issue of how the cerebellar input layer processes sensory information, with particular focus on the granule cells (input relays) and their counterpart inhibitory interneurones, Golgi cells. Based on the textbook view, granule cells excite Golgi cells via glutamate forming a negative feedback loop. However, Golgi cells express inhibitory mGluR2 receptors suggesting an inhibitory role for glutamate. We set out to test this glutamatergic paradox in Golgi cells. Here we show that granule cells and Golgi cells interact through extra-synaptic signalling mechanisms during sensory information processing, as well as synaptic mechanisms. We demonstrate that such interactions depend on granule cell-derived glutamate acting via inhibitory mGluR2 receptors leading causally to the suppression of Golgi cell activity for several hundreds of milliseconds. We further show that granule cell-derived inhibition of Golgi cell activity is regulated by GABA dependent extra-synaptic Golgi cell inhibition of granule cells, identifying a regulatory loop in which glutamate and GABA may be critical regulators of Golgi cell-granule cell functional activity. Thus, granule cells may promote their own prolonged activity via paradoxical feed-forward inhibition of Golgi cells, thereby enabling information processing over long timescales. PMID- 21669982 TI - Human stem cell research and regenerative medicine--present and future. AB - INTRODUCTION: Stem cells are cells with the ability to grow and differentiate into more than 200 cell types. SOURCES OF DATA: We review here the characteristics and potential of human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs). AREAS OF AGREEMENT: The differentiation ability of all stem cell types could be stimulated to obtain specialized cells that represent renewable sources of functional cells useful for cell-based therapy. AREAS OF CONTROVERSY: The proof of functional differentiated cells needs to be investigated in more detail using both in vitro and in vivo assays including animal disease models and clinical studies. GROWING POINTS: Much progress has been made in the ASCs-based therapies. Meanwhile hESCs and iPSCs have dramatically emerged as novel approaches to understand pathogenesis of different diseases. AREAS TIMELY FOR DEVELOPING RESEARCH: A number of new strategies become very important in regenerative medicine. However, we discuss the limitations of stem cells and latest development in the reprogramming research. PMID- 21669983 TI - Small noncoding RNAs in the germline. AB - Small noncoding RNAs have emerged as potent regulators of gene expression, especially in the germline. We review the biogenesis and regulatory function of three major small noncoding RNA pathways in the germline: The small interfering RNA (siRNA) pathway that leads to the degradation of target mRNAs, the microRNA (miRNA) pathway that mostly represses the translation of target mRNAs, and the newly discovered Piwi-interacting RNA (piRNA) pathway that appears to have diverse functions in epigenetic programming, transposon silencing, and the regulation of mRNA translation and stability. The siRNA and miRNA pathways are present in the germline as well as many somatic tissues, whereas the piRNA pathway is predominantly confined to the germline. Investigation of the three small RNA pathways has started to reveal a new dimension of gene regulation with defining roles in germline specification and development. PMID- 21669984 TI - Germ cell intercellular bridges. AB - Stable intercellular bridges are a conserved feature of gametogenesis in multicellular animals observed more than 100 years ago, but their function was unknown. Many of the components necessary for this structure have been identified through the study of cytokinesis in Drosophila; however, mammalian intercellular bridges have distinct properties from those of insects. Mammalian germ cell intercellular bridges are composed of general cytokinesis components with additional germ cell-specific factors including TEX14. TEX14 is an inactive kinase essential for the maintenance of stable intercellular bridges in gametes of both sexes but whose loss specifically impairs male meiosis. TEX14 acts to impede the terminal steps of abscission by competing for essential component CEP55, blocking its interaction in nongerm cells with ALIX and TSG101. Additionally, TEX14-interacting protein RBM44, whose localization in stabile intercellular bridges is limited to pachytene and secondary spermatocytes, may participate in processes such as RNA transport but is nonessential to the maintenance of intercellular bridge stability. PMID- 21670063 TI - 3,5-Diiodo-L-thyronine prevents high-fat-diet-induced insulin resistance in rat skeletal muscle through metabolic and structural adaptations. AB - The worldwide prevalence of obesity-associated pathologies, including type 2 diabetes, requires thorough investigation of mechanisms and interventions. Recent studies have highlighted thyroid hormone analogs and derivatives as potential agents able to counteract such pathologies. In this study, in rats receiving a high-fat diet (HFD), we analyzed the effects of a 4-wk daily administration of a naturally occurring iodothyronine, 3,5-diiodo-L-thyronine (T2), on the gastrocnemius muscle metabolic/structural phenotype and insulin signaling. The HFD-induced increases in muscle levels of fatty acid translocase (3-fold; P<0.05) and TGs (2-fold, P<0.05) were prevented by T2 (each; P<0.05 vs. HFD). T2 increased insulin-stimulated Akt phosphorylation levels (~2.5-fold; P<0.05 vs. HFD). T2 induced these effects while sparing muscle mass and without cardiac hypertrophy. T2 increased the muscle contents of fast/glycolytic fibers (2-fold; P<0.05 vs. HFD) and sarcolemmal glucose transporter 4 (3-fold; P<0.05 vs. HFD). Adipocyte differentiation-related protein was predominantly present within the slow/oxidative fibers in HFD-T2. In T2-treated rats (vs. HFD), glycolytic enzymes and associated components were up-regulated (proteomic analysis, significance limit: 2-fold; P<0.05), as was phosphofructokinase activity (by 1.3-fold; P<0.05), supporting the metabolic shift toward a more glycolytic phenotype. These results highlight T2 as a potential therapeutic approach to the treatment of diet induced metabolic dysfunctions. PMID- 21670064 TI - Perinatal undernutrition affects the methylation and expression of the leptin gene in adults: implication for the understanding of metabolic syndrome. AB - Transient environmental influences, such as perinatal nutritional stress, may induce deleterious metabolic symptoms that last for the entire life of individuals, implying that epigenetic modifications play an important role in this process. We have investigated, in mice, the consequences of maternal undernutrition during gestation and lactation on DNA methylation and expression of the leptin gene, which plays a major regulatory role in coordinating nutritional state with many aspects of mammalian biology. We show that animals born to mothers fed a low-protein-diet (F1-LPD group) have a lower body weight/adiposity and exhibit a higher food intake than animals born to mothers fed a control diet (F1-CD group). These modifications persisted throughout life and were associated with lower levels of leptin mRNA and protein in starved F1 LPD mice, emphasizing that maternal protein-undernutrition affects the balance between food intake and energy expenditure in adults. Moreover, this nutritional stress resulted in the removal of methyls at CpGs located in the promoter of leptin, causing a permanent specific modification in the dynamics of the expression of leptin, which exhibits a stronger induction in the F1-LPD than in F1-CD mice in response to a meal. This study is an example of a molecular rationale linking transient environmental influences to permanent phenotypic consequences. PMID- 21670065 TI - A substrate-based approach to convert SerpinB1 into a specific inhibitor of proteinase 3, the Wegener's granulomatosis autoantigen. AB - The physiological and pathological functions of proteinase 3 (PR3) are not well understood due to its close similarity to human neutrophil elastase (HNE) and the lack of a specific inhibitor. Based on structural analysis of the active sites of PR3 and HNE, we generated mutants derived from the polyvalent inhibitor SerpinB1 (monocyte/neutrophil elastase inhibitor) that specifically inhibit PR3 and that differ from wt-SerpinB1 by only 3 or 4 residues in the reactive center loop. The rate constant of association between the best SerpinB1 mutant and PR3 is 1.4 * 107 M-1 . s-1, which is ~100-fold higher than that observed with wt-SerpinB1 and compares with that of alpha1-protease inhibitor (alpha1-PI) toward HNE. SerpinB1(S/DAR) is cleaved by HNE, but due to differences in rate, inhibition of PR3 by SerpinB1(S/DAR) is only minimally affected by the presence of HNE even when the latter is in excess. SerpinB1(S/DAR) inhibits soluble PR3 and also membrane-bound PR3 at the surface of activated neutrophils. Moreover, SerpinB1(S/DAR) clears induced PR3 from the surface of activated neutrophils. Overall, these specific inhibitors of PR3 will be valuable for defining biological functions of the protease and may prove useful as therapeutics for PR3 related inflammatory diseases, such as Wegener's granulomatosis. PMID- 21669985 TI - Fluorescence techniques to study lipid dynamics. AB - Biological research has always tremendously benefited from the development of key methodology. In fact, it was the advent of microscopy that shaped our understanding of cells as the fundamental units of life. Microscopic techniques are still central to the elucidation of biological units and processes, but equally important are methods that allow access to the dimension of time, to investigate the dynamics of molecular functions and interactions. Here, fluorescence spectroscopy with its sensitivity to access the single-molecule level, and its large temporal resolution, has been opening up fully new perspectives for cell biology. Here we summarize the key fluorescent techniques used to study cellular dynamics, with the focus on lipid and membrane systems. PMID- 21670067 TI - A redox switch in C-reactive protein modulates activation of endothelial cells. AB - C-reactive protein (CRP) has been implicated in the regulation of inflammation underlying coronary artery disease; however, little is known about the molecular mechanisms responsible for the expression of its pro- or anti-inflammatory activities. Here, we have identified the intrasubunit disulfide bond as a conserved switch that controls the structure and functions of CRP. Conformational rearrangement in human pentameric CRP to monomeric CRP (mCRP) is the prerequisite for this switch to be activated by reducing agents, including thioredoxin. Immunohistochemical analysis revealed 36-79% colocalization of thioredoxin and mCRP in human advanced coronary atherosclerotic lesions. Nonreduced mCRP was largely inert in activating human coronary artery endothelial cells (HCAECs), whereas reduced or cysteine-mutated mCRP evoked marked release of IL-8 and monocyte chemoattractant protein-1 from HCAECs, with ~50% increase at a concentration of 1 MUg/ml. Reduced mCRP was ~4 to 40-fold more potent than mCRP in up-regulating adhesion molecule expression, promoting U937 monocyte adhesion to HCAECs, and inducing cytokine release from rabbit arteries ex vivo and in mice. These actions were primarily due to unlocking the lipid raft interaction motif. Therefore, expression of proinflammatory properties of CRP on endothelial cells requires sequential conformational changes, i.e., loss of pentameric symmetry followed by reduction of the intrasubunit disulfide bond. PMID- 21670066 TI - Interaction between amyloid precursor protein and Nogo receptors regulates amyloid deposition. AB - Excessive production or accumulation of beta-amyloid (Abeta) peptides in human brains leads to increased amyloid deposition and cognitive dysfunction, which are invariable pathological features in patients with Alzheimer's disease (AD). Many cellular factors can regulate the production of Abeta. In this study, we show that a family of proteins named Nogo receptor proteins (NgR1 to NgR3) regulates Abeta production via interaction with amyloid precursor protein (APP). Further mapping of the interacting domain indicates that a small region adjacent to the BACE1 cleavage site of APP mediates interaction of APP with Nogo receptor proteins. Our results also indicate that increased interaction between Nogo receptor and APP reduces surface expression of APP and favors processing of APP by BACE1. When NgR2 was ablated in AD transgenic mice expressing Swedish APP and PS1DeltaE9, amyloid deposition was clearly reduced (0.66% of total measured area in APP(swe)/PS1DeltaE9/NgR2(-/-) mice vs. 0.76% of total measured area in APP(swe)/PS1DeltaE9 mice). Our results demonstrate that down-regulation of NgR expression is a potential approach for inhibiting amyloid deposition in AD patients. PMID- 21670068 TI - Trpv5/6 is vital for epithelial calcium uptake and bone formation. AB - Calcium is an essential ion serving a multitude of physiological roles. Aside from its role as a second messenger, it is an essential component of the vertebrate bone matrix. Efficient uptake and storage of calcium are therefore indispensable for all vertebrates. Transient receptor potential family, vanilloid type (TRPV)5 and TRPV6 channels are known players in transcellular calcium uptake, but the exact contribution of this pathway is unclear. We used forward genetic screening in zebrafish (Danio rerio) to identify genes essential in bone formation and identified a lethal zebrafish mutant (matt-und-schlapp) with severe defects in bone formation, including lack of ossification of the vertebral column and craniofacial structures. Mutant embryos show a 68% reduction in calcium content, and systemic calcium homeostasis is disturbed when compared with siblings. The phenotype can be partially rescued by increasing ambient calcium levels to 25 mM. We identified the mutation as a loss-of-function mutation in the single orthologue of TRPV5 and 6, trpv5/6. Expression in HEK293 cells showed that Trpv5/6 is a calcium-selective channel capable of inward calcium transport at physiological concentrations whereas the mutant channel is not. Taken together, this study provides both genetic and functional evidence that transcellular epithelial calcium uptake is vital to sustain life and enable bone formation. PMID- 21670069 TI - Incidence of sudden cardiac death in athletes: where did the science go? PMID- 21670070 TI - Management of orbital inflammation. PMID- 21670071 TI - Association between firearm ownership, firearm-related risk and risk reduction behaviours and alcohol-related risk behaviours. AB - Alcohol use and firearm ownership are risk factors for violent injury and death. To determine whether firearm ownership and specific firearm-related behaviours are associated with alcohol-related risk behaviours, the author conducted a cross sectional study using Behavioral Risk Factor Surveillance System data for eight states in the USA from 1996 to 1997 (the most recent data available). Altogether, 15 474 respondents provided information on firearm exposure. After adjustment for demographics and state of residence, firearm owners were more likely than those with no firearms at home to have >=5 drinks on one occasion (OR 1.32; 95% CI 1.16 to 1.50), to drink and drive (OR 1.79; 95% CI 1.34 to 2.39) and to have >=60 drinks per month (OR 1.45; 95% CI 1.14 to 1.83). Heavy alcohol use was most common among firearm owners who also engaged in behaviours such as carrying a firearm for protection against other people and keeping a firearm at home that was both loaded and not locked away. The author concludes that firearm ownership and specific firearm-related behaviours are associated with alcohol-related risk behaviours. PMID- 21670072 TI - Preventing bath water scalds: a cost-effectiveness analysis of introducing bath thermostatic mixer valves in social housing. AB - AIMS: To assess the cost-effectiveness of installing thermostatic mixer valves (TMVs) in reducing risks of bath water scalds and estimate the costs of avoiding bath water scalds. METHODS: The evaluation was undertaken from the perspective of the UK public sector, and conducted in conjunction with a randomised control trial of TMVs installed in social housing in Glasgow. Installation costs were borne by the social housing organisation, while support materials were provided by the UK NHS. Effectiveness was represented by the number of families with at risk bath water temperatures pre- and post-installation, and the number of bath scalds avoided as a result of installation. Differences in the number of families with at-risk temperatures between groups were derived from the RCT. Cost effectiveness was assessed and a series of one-way sensitivity analyses were conducted. RESULTS: Unit costs associated with installation were calculated to be L13.68, while costs associated with treating bath water scalds ranged from L25,226 to L71,902. The cost of an avoided bath water scald ranged from net savings to public purse of L1887 to L75,520 and at baseline produced a net saving of L3,229,008; that is, L1.41 saved for every L1 spent. CONCLUSION: It is very likely that installing TMVs as standard in social housing in new buildings and major refurbishments accompanied by educational information represents value for money. PMID- 21670073 TI - Meta-analysis of controlled studies on immunotherapy in severe scorpion envenomation: a commentary. PMID- 21670075 TI - More than 500 trillion molecules of strong carcinogens per cigarette: use in product labelling? PMID- 21670074 TI - Diagnostic accuracy of transient elastography (FibroScan) versus the aspartate transaminase to platelet ratio index in assessing liver fibrosis in chronic hepatitis B: the role in primary care setting. AB - BACKGROUND: A non-invasive method to assess liver fibrosis by measuring liver stiffness with transient elastography (TE) has been recently introduced. The role of TE among chronic hepatitis B (CHB) patients in starting antiviral therapy in the primary care setting is still controversial because of its high cost. The AST to platelet ratio index (APRI) could be a much cheaper alternative. OBJECTIVES: This study compares the diagnostic accuracy of TE and APRI in assessing liver fibrosis in CHB patients. PATIENTS AND METHODS: A cross-sectional study in CHB patients intending to start antiviral treatment. Liver fibrosis was staged according to the METAVIR scoring system. Liver stiffness was measured by TE performed on the same day with liver biopsy, while APRI was calculated as follows: APRI=(AST/upper limit of normal)*100/platelet count (10(9)/l). Cutoff levels of liver stiffness and APRI were calculated by using the receiver operating characteristic curve to detect significant liver fibrosis, defined as fibrosis stage F2 or more. RESULTS: 117 patients were enrolled in the study; their mean age was 40.6+/-10.97 years. The median liver stiffness was 5.9 kPa (2.5-48 kPa) and the median APRI was 0.239 (0.09-2.73). The cutoff level of liver stiffness was 5.85 kPa for >=F2 with an AUC of 0.614, 60.3% sensitivity, 63.6% specificity, 73.3% PPV, 49.1% NPV and a LR+ of 1.66. The APRI cutoff level was 0.235 for F>=2 with an AUC of 0.693, 64.4% sensitivity, 70.5% specificity, 78.3% PPV, 54.4% NPV and a LR+ of 2.18. Both methods gave comparable diagnostic accuracy. CONCLUSION: APRI is a useful marker to screen liver fibrosis in the primary care setting when TE is not available. PMID- 21670076 TI - Variation in partner notification outcomes for chlamydia in UK genitourinary medicine clinics: multilevel study. AB - OBJECTIVES: To compare different ways of measuring partner notification (PN) outcomes with published audit standards, examine variability between clinics and examine factors contributing to variation in PN outcomes in genitourinary medicine (GUM) clinics in the UK. METHODS: Reanalysis of the 2007 BASHH national chlamydia audit. The primary outcome was the number of partners per index case tested for chlamydia, as verified by a healthcare worker or, if missing, reported by the patient. Control charts were used to examine variation between clinics considering missing values as zero or excluding missing values. Hierarchical logistic regression was used to investigate factors contributing to variation in outcomes. RESULTS: Data from 4616 individuals in 169 genitourinary medicine clinics were analysed. There was no information about the primary outcome in 41% of records. The mean number of partners tested for chlamydia ranged from 0 to 1.5 per index case per clinic. The median across all clinics was 0.47 when missing values were assumed to be zero and 0.92 per index case when missing values were excluded. Men who have sex with men were less likely than heterosexual men and patients with symptoms (4-week look-back period) were less likely than asymptomatic patients (6-month look-back) to report having one or more partners tested for chlamydia. There was no association between the primary outcome and the type of the health professional giving the PN advice. CONCLUSIONS: The completeness of PN outcomes recorded in clinical notes needs to improve. Further research is needed to identify auditable measures that are associated with successful PN that prevents repeated chlamydia in index cases. PMID- 21670077 TI - Urinary dysfunction in early and untreated Parkinson's disease. AB - BACKGROUND: Urinary dysfunction is common in Parkinson's disease (PD); however, little is known about urinary dysfunction in early and untreated PD patients. METHODS: Fifty consecutive untreated PD patients (mean age, 66.7; mean disease duration, 23.6 months; and mean Hoehn & Yahr scale, 1.9) were recruited; those with other conditions that might have influenced urinary function were excluded. Patients were evaluated using a urinary questionnaire and urodynamic studies. RESULTS: Sixty-four per cent complained of urinary symptoms (storage, 64.0%; voiding, 28.0%). Urodynamic studies showed abnormal findings in the storage phase in 84%, with detrusor overactivity (DO) and increased bladder sensation without DO in 58.0% and 12.0% of patients, respectively. In the voiding phase, detrusor underactivity, impaired urethral relaxation such as detrusor sphincter dyssynergia, and bladder outlet obstruction were present in 50.0%, 8.0% and 16% of patients, respectively. In patients with both storage and voiding phase abnormalities, DO+detrusor underactivity was the most common finding. Few patients experienced urge incontinence and/or quality-of-life impairment owing to urinary dysfunction; none had low-compliance bladder or abnormal anal-sphincter motor unit potential. These urinary symptoms and urodynamic findings were not correlated with gender, disease severity or motor symptom type. CONCLUSION: Urinary dysfunction, manifested primarily as storage disorders with subclinical voiding disorders and normal anal-sphincter electromyography, occurs in early and untreated PD patients. In cases with severe voiding disorder and/or abnormal anal sphincter electromyography, other diagnoses should be considered. PMID- 21670078 TI - Exosome targeting of tumor antigens expressed by cancer vaccines can improve antigen immunogenicity and therapeutic efficacy. AB - MVA-BN-PRO (BN ImmunoTherapeutics) is a candidate immunotherapy product for the treatment of prostate cancer. It encodes 2 tumor-associated antigens, prostate specific antigen (PSA), and prostatic acid phosphatase (PAP), and is derived from the highly attenuated modified vaccinia Ankara (MVA) virus stock known as MVA-BN. Past work has shown that the immunogenicity of antigens can be improved by targeting their localization to exosomes, which are small, 50- to 100-nm diameter vesicles secreted by most cell types. Exosome targeting is achieved by fusing the antigen to the C1C2 domain of the lactadherin protein. To test whether exosome targeting would improve the immunogenicity of PSA and PAP, 2 additional versions of MVA-BN-PRO were produced, targeting either PSA (MVA-BN-PSA-C1C2) or PAP (MVA BN-PAP-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN-PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10- to 100-fold higher than those for mice treated with MVA-BN PRO. Furthermore, treatment with MVA-BN-PAP-C1C2 increased the frequency of PAP specific T cells 5-fold compared with mice treated with MVA-BN-PRO. These improvements translated into a greater frequency of tumor rejection in a PAP expressing solid tumor model. Likewise, treatment with MVA-BN-PSA-C1C2 increased the antigenicity of PSA compared with treatment with MVA-BN-PRO and resulted in a trend of improved antitumor efficacy in a PSA-expressing tumor model. These experiments confirm that targeting antigen localization to exosomes is a viable approach for improving the therapeutic potential of MVA-BN-PRO in humans. PMID- 21670079 TI - Inhibition of miR-193a expression by Max and RXRalpha activates K-Ras and PLAU to mediate distinct aspects of cellular transformation. AB - MicroRNA profiling in isogenic models of cellular transformation involving either breast epithelial cells or fibroblasts reveals that expression of miR-193a is lower in transformed cells than in nontransformed cells. The transcription factors Max and RXRalpha bind directly to the miR-193a promoter and inhibit miR 193a expression during transformation. miR-193a inhibits cellular transformation by directly targeting the 3' untranslated regions of PLAU and K-Ras. Interestingly, miR-193a controls anchorage-independent growth in soft agar through K-Ras, whereas it affects invasive growth through PLAU. miR-193a overexpression inhibits the tumorigenicity of developmentally diverse but not all cancer cell types, and it inhibits tumor growth in colon- and breast-derived xenografts. Finally, expression of miR-193a is inversely correlated with PLAU and K-Ras in human colon adenocarcinomas. Thus, a pathway in which Max and RXRalpha inhibit miR-193a expression, thereby activating the PLAU and K-Ras oncogenes is important for distinct aspects of cellular transformation, as well as tumor growth and colon (and perhaps other types of) cancer. PMID- 21670080 TI - Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition. AB - Most cancer cells utilize aerobic glycolysis, and activation of the phosphoinositide 3-kinase/Akt/mTOR pathway can promote this metabolic program to render cells glucose dependent. Although manipulation of glucose metabolism may provide a means to specifically eliminate cancer cells, mechanistic links between cell metabolism and apoptosis remain poorly understood. Here, we examined the role and metabolic regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in cell death upon inhibition of Akt-induced aerobic glycolysis. In the presence of adequate glucose, activated Akt prevented the loss of Mcl-1 expression and protected cells from growth factor deprivation-induced apoptosis. Mcl-1 associated with and inhibited the proapoptotic Bcl-2 family protein Bim, contributing to cell survival. However, suppression of glucose metabolism led to induction of Bim, decreased expression of Mcl-1, and apoptosis. The proapoptotic Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, shows clinical promise, but Mcl-1 upregulation can promote resistance. Importantly, inhibition of glucose metabolism or mTORC1 overcame Mcl-1-mediated resistance in diffuse large B cell leukemic cells. Together these data show that Mcl-1 protein synthesis is tightly controlled by metabolism and that manipulation of glucose metabolism may provide a mechanism to suppress Mcl-1 expression and sensitize cancer cells to apoptosis. PMID- 21670081 TI - BMP4 promotes prostate tumor growth in bone through osteogenesis. AB - Induction of new bone formation is frequently seen in the bone lesions from prostate cancer. However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, 2 xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from prostate cancer bone metastases. When implanted subcutaneously in severe combined immunodeficient (SCID) mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (secretome) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of bone morphogenetic protein BMP4 and several cytokines including interleukin-8, growth-related protein (GRO), and CCL2. We showed that BMP4 secreted from MDA-PCa 118b contributed to about a third of the osteogenic differentiation seen in MDA PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treatment with BMP4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN 193189. BMP4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of prostate cancer in bone. PMID- 21670082 TI - Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. AB - Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised severe combined immunodeficient (SCID) mice. Furthermore, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of proangiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell-derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression. PMID- 21670084 TI - Inhibition of SRC family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors. AB - Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) alpha and beta, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale. PMID- 21670083 TI - Substitution patterns are GC-biased in divergent sequences across the metazoans. AB - The fastest-evolving regions in the human and chimpanzee genomes show a remarkable excess of weak (A,T) to strong (G,C) nucleotide substitutions since divergence from their common ancestor. We investigated the phylogenetic extent and possible causes of this weak to strong (W -> S) bias in divergent sequences (BDS) using recently sequenced genomes and recombination maps from eight trios of eukaryotic species. To quantify evidence for BDS, we inferred substitution histories using an efficient maximum likelihood approach with a context-dependent evolutionary model. We then annotated all lineage-specific substitutions in terms of W -> S bias and density on the chromosomes. Finally, we used the inferred substitutions to calculate a BDS score-a log odds ratio between substitution type and density-and assessed its statistical significance with Fisher's exact test. Applying this approach, we found significant BDS in the coding and noncoding sequence of human, mouse, dog, stickleback, fruit fly, and worm. We also observed a significant lack of W -> S BDS in chicken and yeast. The BDS score varies between species and across the chromosomes within each species. It is most strongly correlated with different genomic features in different species, but a strong correlation with recombination rates is found in several species. Our results demonstrate that a W -> S substitution bias in fast-evolving sequences is a widespread phenomenon. The patterns of BDS observed suggest that a recombination-associated process, such as GC-biased gene conversion, is involved in the production of the bias in many species, but the strength of the BDS likely depends on many factors, including genome stability, variability in recombination rate over time and across the genome, the frequency of meiosis, and the amount of outcrossing in each species. PMID- 21670085 TI - New strategies in metastatic melanoma: oncogene-defined taxonomy leads to therapeutic advances. AB - The discovery of BRAF and KIT mutations provided the first basis for a molecular classification of cutaneous melanoma on therapeutic grounds. As BRAF-targeted therapy quickly moves toward regulatory approval and incorporation as standard therapy for patients with metastatic disease, proof of concept has also been established for targeting mutated KIT in melanoma. NRAS mutations have long been known to be present in a subset of melanomas and represent an elusive subgroup for targeted therapies. Matching patient subgroups defined by genetic aberrations in the phosphoinositide 3-kinase and p16/cyclin dependent kinase 4 (CDK4) pathways with appropriate targeted therapies has not yet been realized. And, an increasing understanding of lineage-specific transcriptional regulators, most notably MITF, and how they may play a role in melanoma pathophysiology, has provided another axis to approach with therapies. The foundation has been established for individual oncogene targeting, and current investigations seek to understand the intersection of these susceptibilities and other described potential targets and pathways. The melanoma field stands poised to take the lead among cancer subtypes in advancing combination therapy strategies that simultaneously target multiple biologic underpinnings of the disease. PMID- 21670086 TI - Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer? AB - Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer. PMID- 21670087 TI - A random effects branch-site model for detecting episodic diversifying selection. AB - Adaptive evolution frequently occurs in episodic bursts, localized to a few sites in a gene, and to a small number of lineages in a phylogenetic tree. A popular class of "branch-site" evolutionary models provides a statistical framework to search for evidence of such episodic selection. For computational tractability, current branch-site models unrealistically assume that all branches in the tree can be partitioned a priori into two rigid classes--"foreground" branches that are allowed to undergo diversifying selective bursts and "background" branches that are negatively selected or neutral. We demonstrate that this assumption leads to unacceptably high rates of false positives or false negatives when the evolutionary process along background branches strongly deviates from modeling assumptions. To address this problem, we extend Felsenstein's pruning algorithm to allow efficient likelihood computations for models in which variation over branches (and not just sites) is described in the random effects likelihood framework. This enables us to model the process at every branch-site combination as a mixture of three Markov substitution models--our model treats the selective class of every branch at a particular site as an unobserved state that is chosen independently of that at any other branch. When benchmarked on a previously published set of simulated sequences, our method consistently matched or outperformed existing branch-site tests in terms of power and error rates. Using three empirical data sets, previously analyzed for episodic selection, we discuss how modeling assumptions can influence inference in practical situations. PMID- 21670089 TI - Expression and function of toll-like receptors in peripheral blood mononuclear cells of patients with polymyalgia rheumatica and giant cell arteritis. AB - OBJECTIVE: To investigate the expression and function of the Toll-like receptor (TLR) family in peripheral blood mononuclear cells (PBMCs) of patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). METHODS: The authors analysed 70 patients with PMR, 20 with GCA, and 24 healthy controls (HC). TLR expression was assessed by flow cytometry. TLR function was assessed by stimulating PBMCs with specific ligands. RESULTS: A significantly increased expression of TLR7 in PBMCs of patients with active disease compared with HC was found. Despite increased expression of TLR7, circulating monocytes from patients showed a significantly lower in vitro response to TLR7 agonists. No amino acid substitutions predicted to be functionally damaging were found in TLR7. A normal response to specific TLR7 agonists in patients in complete remission eliminated a genetic defect. TLR expression and function were also affected to some degree in other diseases characterised by a strong acute phase response. CONCLUSION: These data suggest activation of TLR7 during the active phase of PMR and GCA which resolves with complete disease remission. Whether this finding is the consequence of the marked inflammatory process in these disorders or activation by natural ligands remains to be explored. PMID- 21670090 TI - Sepsis bundles and compliance with clinical guidelines. AB - Realizing the vast medical benefits of validated protocols, recommendations and practice guidelines requires acceptance and implementation by frontline care providers. Knowledge translation is the science of accelerating the transfer of knowledge to practice by understanding and creatively addressing the barriers that prevent adoption of new professional standards. In an attempt to improve patient care and reduce mortality, the Surviving Sepsis Campaign and The Institute for Healthcare Improvement created the resuscitation and management bundles for patients with severe sepsis and septic shock. These bundles have been accepted as best practice by many clinicians since multiple clinical trials have produced similar positive results when they were implemented. However, transferring these research outcomes-based guidelines to the clinical practice arena has been associated with poor compliance due to important barriers to implementation. Delays in the adoption of sepsis bundles are not surprising since the time from validation to implementation of a new clinical practice is typically 17 years. Using sepsis bundles as a model, this article explores why guidelines are important, examines physician adherence to protocols, and reviews the literature on strategies to improve clinical compliance and enhance knowledge translation. PMID- 21670088 TI - High plasma leptin levels confer increased risk of atherosclerosis in women with systemic lupus erythematosus, and are associated with inflammatory oxidised lipids. AB - BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors. High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population. OBJECTIVE: To examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis. METHODS: Carotid ultrasonography was performed in 250 women with SLE and 122 controls. Plasma leptin and adiponectin levels were measured. Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed. RESULTS: Leptin levels were significantly higher in patients with SLE than in controls (23.7+/-28.0 vs 13.3+/-12.9 ng/ml, p<0.001). Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4+/-32.3 vs 20.9+/-26.4 ng/ml, p=0.002). After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (>=29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01). Adiponectin levels were not significantly associated with plaque in our cohort. A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present. CONCLUSIONS: High leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100. High leptin levels may help to identify patients with SLE at risk of atherosclerosis. PMID- 21670091 TI - Surviving sepsis guidelines and scientific evidence? PMID- 21670092 TI - Age-related medical decision limits for urinary free (unconjugated) metadrenalines, catecholamines and metabolites in random urine specimens from children. AB - BACKGROUND: Neuroblastoma is the most common extracranial solid tumour in childhood (8% of all childhood cancers), the most frequently diagnosed in infancy, and has one of the highest death rates, while chromaffin tumours rarely present in childhood. Both tumour types produce catecholamines and their metabolites. It is difficult to produce reference ranges for tests in children, and currently, no age-related medical decision limits for free metadrenalines (free metanephrines) in random urine specimens exist in the paediatric literature. METHODS: Results of vanillylmandelic acid (VMA), 5 hydroxyindoleacetic acid, homovanillic acid (HVA), noradrenaline (NA), adrenaline, dopamine (DA), free normetadrenaline (fNMA), free metadrenaline and free 3-methoxytyramine (f3MT) in 1658 random urines obtained from infants, children and young adults were measured by high performance liquid chromatography with electrochemical detection. Specimens were excluded from consideration if obtained from the following categories, i.e. (a) harbouring neuroblastic, chromaffin, carcinoid or other tumours or malignancies; (b) medical conditions having known association with excess catecholamine excretion; (c) patients administered catecholamine or paracetamol; (d) overly dilute urine; and (e) manifesting outlying values following visual inspection. RESULTS: There remained 872 specimens that were grouped into seven age ranges (<1; 1 or 2; 3 or 4; 5-7; 8 10; 11-13; 14-19 y) for which medical decision limits were determined for each analyte. There was no significant difference between the results for boys or girls. In 55 patients harbouring neuroblastic tumours, HVA (54/55), f3MT (14/16), VMA (45/53) and DA (43/53) were the most frequently elevated analytes at time of diagnosis. In 11 patients presenting in childhood with chromaffin tumours, fNMA (11/11) followed by NA (10/11) were the most frequently elevated. Discussion The likely reasons for outlying or missing values, together with the reasons for variation in the distinctive biochemical patterns of analytes exhibited in individuals harbouring either neuroblastic or chromaffin tumours are discussed. PMID- 21670093 TI - Quantitating nocturia: a study into the recording of solute and water excretion to determine causation. AB - BACKGROUND: Nocturia is common but the clinical assessment of its severity and cause rarely involves any biochemical analysis. Investigating the cause of nocturia needs to be informed by the overall 24 h fluid and solute excretion patterns. The aim of this study was to establish a practical method of monitoring the renal excretion of water and solutes over a complete 24 h cycle. METHODS: The excretion patterns of sodium, volume and osmoles were assessed in 89 healthy control subjects over a 24 h period by sampling each voiding from the 24 h collection and then using the total urine creatinine as the denominator. A group of 21 patients under investigation for sleep-disordered breathing (SDB: a group of disorders known to increase the risk of nocturia) were also studied to determine comparative excretion patterns. RESULTS: Reference excretion patterns of sodium, volume and osmoles were described. Patients under investigation for SDB had overall a significant (P < 0.001) increase in urine sodium excretion at night (nocturnal natriuresis) matched by an increased osmotic excretion and accompanied by a significantly increased nocturnal urine volume (P < 0.001). CONCLUSION: Breaking down a 24 h urine collection into voided aliquots provides practical information on the pattern of water and solute excretion. Such patterns may assist in identifying the underlying mechanism of significant nocturia in individual patients presenting with this symptom, and could be used as a method of monitoring treatment. PMID- 21670094 TI - A national survey of interpretative reporting in the UK. AB - AIMS: There is still debate as to whether the addition of interpretative comments to laboratory reports can influence the management of patients. Little is known about the extent of this activity in individual laboratories throughout the UK and so this national survey aimed to establish the prevalence. METHODS: An electronic questionnaire was sent to 196 NHS laboratories in the UK asking whether 17 commonly requested groups of tests were reported with interpretative comments and, if so, how laboratory computers and/or humans were involved in the process. Enquiries were also made of the grades of staff performing the process and of any 'vignette' examples where interpretative reporting had improved the clinical outcome for the patient. RESULTS: A total of 138 of the 196 laboratories (70%) responded. Only two laboratories did not have staff adding interpretative comments to any of the 17 tests. Consultant laboratory staff reporting predominated in all tests with a significant minority also being added by biomedical scientists. High-volume requests usually had staff adding comments to results selected by computer rules whereas more of the specialist endocrine tests tended to be considered for comment. Only six of 71 vignettes referred specifically to 'routine' biochemistry. CONCLUSIONS: The addition of interpretative comments onto clinical biochemistry reports is widespread throughout the UK. This service is largely consultant led. There is anecdotal evidence that the process can influence the clinical management of patients. PMID- 21670095 TI - Statistically optimal integration of biased sensory estimates. AB - Experimental investigations of cue combination typically assume that individual cues provide noisy but unbiased sensory information about world properties. However, in numerous instances, including real-world settings, observers systematically misestimate properties of the world from sensory information. Two such instances are the estimation of shape from stereo and motion cues. Bias in single-cue estimates, therefore poses a problem for cue combination if the visual system is to maintain accuracy with respect to the world, particularly because knowledge about the magnitude of bias in individual cues is typically unknown. Here, we show that observers fail to take account of the magnitude of bias in each cue during combination and instead combine cues in proportion to their reliability so as to increase the precision of the combined-cue estimate. This suggests that observers were unaware of the bias in their sensory estimates. Our analysis of cue combination shows that there is a definable range of circumstances in which combining information from biased cues, rather than vetoing one or other cue, can still be beneficial, by reducing error in the final estimate. PMID- 21670096 TI - Attentional selection of relative SF mediates global versus local processing: evidence from EEG. AB - Previous research on functional hemispheric differences in visual processing has associated global perception with low spatial frequency (LSF) processing biases of the right hemisphere (RH) and local perception with high spatial frequency (HSF) processing biases of the left hemisphere (LH). The Double Filtering by Frequency (DFF) theory expanded this hypothesis by proposing that visual attention selects and is directed to relatively LSFs by the RH and relatively HSFs by the LH, suggesting a direct causal relationship between SF selection and global versus local perception. We tested this idea in the current experiment by comparing activity in the EEG recorded at posterior right and posterior left hemisphere sites while participants' attention was directed to global or local levels of processing after selection of relatively LSFs versus HSFs in a previous stimulus. Hemispheric asymmetry in the alpha band (8-12 Hz) during preparation for global versus local processing was modulated by the selected SF. In contrast, preparatory activity associated with selection of SF was not modulated by the previously attended level (global/local). These results support the DFF theory that top-down attentional selection of SF mediates global and local processing. PMID- 21670097 TI - Category-selective background connectivity in ventral visual cortex. AB - Ventral visual cortex contains specialized regions for particular object categories, but little is known about how these regions interact during object recognition. Here we examine how the face-selective fusiform gyrus (FG) and the scene-selective parahippocampal cortex (PHC) interact with each other and with the rest of the brain during different visual tasks. To assess these interactions, we developed a novel approach for identifying patterns of connectivity associated with specific task sets, independent of stimulus-evoked responses. We tested whether this "background connectivity" between the FG and PHC was modulated when subjects engaged in face and scene processing tasks. In contrast to what would be predicted from biased competition or intrinsic activity accounts, we found that the strength of FG-PHC background connectivity depended on which category was task relevant: connectivity increased when subjects attended to scenes (irrespective of whether a competing face was present) and decreased when subjects attended to faces (irrespective of competing scenes). We further discovered that posterior occipital cortex was correlated selectively with the FG during face tasks and the PHC during scene tasks. These results suggest that category specificity exists not only in which regions respond most strongly but also in how these and other regions interact. PMID- 21670098 TI - Pontine reference frames for the sensory guidance of movement. AB - The pontine nuclei (PN) are the major intermediary elements in the corticopontocerebellar pathway. Here we asked if the PN may help to adapt the spatial reference frames used by cerebrocortical neurons involved in the sensory guidance of movement to a format potentially more appropriate for the cerebellum. To this end, we studied movement-related neurons in the dorsal PN (DPN) of monkeys, most probably projecting to the cerebellum, executing fixed vector saccades or, alternatively, fixed vector hand reaches from different starting positions. The 83 task-related neurons considered fired movement-related bursts before saccades (saccade-related) or before hand movements (hand movement related). About 40% of the SR neurons were "oculocentric," whereas the others were modulated by eye starting position. A third of the HMR neurons encoded hand reaches in hand-centered coordinates, whereas the remainder exhibited different types of dependencies on starting positions, reminiscent in general of cortical responses. All in all, pontine reference frames for the sensory guidance of movement seem to be very similar to those in cortex. Specifically, the frequency of orbital position gain fields of SR neurons is identical in the DPN and in one of their major cortical inputs, lateral intraparietal area (LIP). PMID- 21670099 TI - The brain structural hub of interhemispheric information integration for visual motion perception. AB - We investigated the key anatomical structures mediating interhemispheric integration during the perception of apparent motion across the retinal midline. Previous studies of commissurotomized patients suggest that subcortical structures mediate interhemispheric transmission but the specific regions involved remain unclear. Here, we exploit interindividual variations in the propensity of normal subjects to perceive horizontal motion, in relation to vertical motion. We characterize these differences psychophysically using a Dynamic Dot Quartet (an ambiguous stimulus that induces illusory motion). We then tested for correlations between a tendency to perceive horizontal motion and fractional anisotropy (FA) (from structural diffusion tensor imaging), over subjects. FA is an indirect measure of the orientation and integrity of white matter tracts. Subjects who found it easy to perceive horizontal motion showed significantly higher FA values in the pulvinar. Furthermore, fiber tracking from an independently identified (subject-specific) visual motion area converged on the pulvinar nucleus. These results suggest that the pulvinar is an anatomical hub and may play a central role in interhemispheric integration. PMID- 21670101 TI - Noradrenergic neurons of the locus coeruleus are phase locked to cortical up-down states during sleep. AB - Nonrapid eye movement (NREM) sleep is characterized by periodic changes in cortical excitability that are reflected in the electroencephalography (EEG) as high-amplitude slow oscillations, indicative of cortical Up/Down states. These slow oscillations are thought to be involved in NREM sleep-dependent memory consolidation. Although the locus coeruleus (LC) noradrenergic system is known to play a role in off-line memory consolidation (that may occur during NREM sleep), cortico-coerulear interactions during NREM sleep have not yet been studied in detail. Here, we investigated the timing of LC spikes as a function of sleep associated slow oscillations. Cortical EEG was monitored, along with activity of LC neurons recorded extracellularly, in nonanesthetized naturally sleeping rats. LC spike-triggered averaging of EEG, together with phase-locking analysis, revealed preferential firing of LC neurons along the ascending edge of the EEG slow oscillation, correlating with Down-to-Up state transition. LC neurons were locked best when spikes were shifted forward ~50 ms in time with respect to the EEG slow oscillation. These results suggest that during NREM sleep, firing of LC neurons may contribute to the rising phase of the EEG slow wave by providing a neuromodulatory input that increases cortical excitability, thereby promoting plasticity within these circuits. PMID- 21670100 TI - Emerging cerebral connectivity in the human fetal brain: an MR tractography study. AB - Cerebral axonal connections begin to develop before birth during radial migration in each brain area. A number of theories are still actively debated regarding the link between neuronal migration, developing connectivity, and gyrification. Here, we used high angular resolution diffusion tractography on postmortem fetal human brains (postconception week (W) 17-40) to document the regression of radial and tangential organization likely to represent migration pathways and the emergence of corticocortical organization and gyrification. The dominant radial organization at W17 gradually diminished first in dorsal parieto-occipital and later in ventral frontotemporal regions with regional variation: radial organization persisted longer in the crests of gyri than at the depths of sulci. The dominant tangential organization of the ganglionic eminence at W17 also gradually disappeared by term, together with the disappearance of the ganglionic eminence. A few immature long-range association pathways were visible at W17, gradually became evident by term. Short-range corticocortical tracts emerged prior to gyrification in regions where sulci later developed. Our results suggest that the regional regression of radial organization and regional emergence of fetal brain connectivity proceeds in general from posterodorsal to anteroventral with local variations. PMID- 21670102 TI - Medicare physician payment rules for 2011: a primer for the neurointerventionalist. AB - Physicians generally have been affected by significant changes in the patterns of medical practice evolving over the past several decades. The Patient Protection and Affordable Care Act of 2010, also called ACA for short, impacts physician professional practice dramatically. Physicians are paid in the USA for their personal services. The payment system is highly variable in the private insurance market; however, governmental systems have a formula based payment, mostly based on the Medicare payment system. Physician services are billed under part B. The Neurointerventional practice is typically performed in a hospital setting. The VA system is a frequently cited successful implementation of a government supported health care program. Availability of neurointerventional services at many VA medical centers is limited. Since the inception of the Medicare program in 1965, several methods have been used to determine the amounts paid to physicians for each covered service. Initially, the payment systems compensated physicians on the basis of their charges. In 1975, just over 10 years after the inception of the Medicare program, payments changed so as not to exceed the increase in medical economic index. The involvement of medical economic index failed to curb increases in costs, leading to the determination of a yearly change in fees by legislation from 1984 to 1991. In 1992, the fee schedule essentially replaced the prior payment system that was based on the physician's charges, which also failed to curb the growth in spending. Thus, in 1998, the sustainable growth rate system was introduced. In 2009, multiple unsuccessful attempts were made by Congress to repeal the formula. The mechanism of the sustainable growth rate includes three components that are incorporated into a statutory formula: expenditure targets, growth rate period and annual adjustments of payment rates for physician services. PMID- 21670103 TI - Activation of cannabinoid type 2 receptors inhibits HIV-1 envelope glycoprotein gp120-induced synapse loss. AB - HIV-1 infection of the central nervous system is associated with dendritic and synaptic damage that correlates with cognitive decline in patients with HIV-1 associated dementia (HAD). HAD is due in part to the release of viral proteins from infected cells. Because cannabinoids modulate neurotoxic and inflammatory processes, we investigated their effects on changes in synaptic connections induced by the HIV-1 envelope glycoprotein gp120. Morphology and synapses between cultured hippocampal neurons were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP). Twenty-four-hour treatment with gp120 IIIB decreased the number of PSD95-GFP puncta by 37 +/- 4%. The decrease was concentration-dependent (EC50 = 153 +/- 50 pM). Synapse loss preceded cell death as defined by retention of DsRed2 fluorescence gp120 activated CXCR4 on microglia to evoke interleukin 1beta (IL-1beta) release. Pharmacological studies determined that sequential activation of CXCR4, the IL-1beta receptor, and the N-methyl-d-aspartate receptor was required. Expression of alternative reading frame polypeptide, which inhibits the ubiquitin ligase murine double minute 2, protected synapses, implicating the ubiquitin-proteasome pathway. Cannabimimetic drugs are of particular relevance to HAD because of their clinical and illicit use in patients with AIDS. The cannabinoid receptor full agonist [(R)-(+)-[2,3-dihydro-5-methyl-3[(4 morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt] (Win55,212-2) inhibited gp120-induced IL-1beta production and synapse in a manner reversed by a cannabinoid type 2 receptor antagonist. In contrast, Win55,212-2 did not inhibit synapse loss elicited by exposure to the HIV-1 protein Tat. These results indicate that cannabinoids prevent the impairment of network function produced by gp120 and, thus, might have therapeutic potential in HAD. PMID- 21670105 TI - Hypokalemic nephropathy in anorexia nervosa. PMID- 21670104 TI - Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor. AB - The ability of dopamine receptors to interact with other receptor subtypes may provide mechanisms for modulating dopamine-related functions and behaviors. In particular, there is evidence suggesting that the trace amine-associated receptor 1 (TAAR1) affects the dopaminergic system by regulating the firing rate of dopaminergic neurons or by altering dopamine D2 receptor (D2R) responsiveness to ligands. TAAR1 is a Galpha(s) protein-coupled receptor that is activated by biogenic amines, "trace amines," such as beta-phenylethylamine (beta-PEA) and tyramine that are normally found at low concentrations in the mammalian brain. In the present study, we investigated the biochemical mechanism of interaction between TAAR1 and D2R and the role this interaction plays in D2R-related signaling and behaviors. Using a bioluminescence resonance energy transfer biosensor for cAMP, we demonstrated that the D2R antagonists haloperidol, raclopride, and amisulpride were able to enhance selectively a TAAR1-mediated beta-PEA increase of cAMP. Moreover, TAAR1 and D2R were able to form heterodimers when coexpressed in human embryonic kidney 293 cells, and this direct interaction was disrupted in the presence of haloperidol. In addition, in mice lacking TAAR1, haloperidol-induced striatal c-Fos expression and catalepsy were significantly reduced. Taken together, these data suggest that TAAR1 and D2R have functional and physical interactions that could be critical for the modulation of the dopaminergic system by TAAR1 in vivo. PMID- 21670106 TI - The Cedar Project: risk factors for transition to injection drug use among young, urban Aboriginal people. AB - BACKGROUND: Studies suggest that Aboriginal people in Canada are over-represented among people using injection drugs. The factors associated with transitioning to the use of injection drugs among young Aboriginal people in Canada are not well understood. METHODS: The Cedar Project is a prospective cohort study (2003-2007) involving young Aboriginal people in Vancouver and Prince George, British Columbia, who use illicit drugs. Participants' venous blood samples were tested for antibodies to HIV and the hepatitis C virus, and drug use was confirmed using saliva screens. The primary outcomes were use of injection drugs at baseline and tranisition to injection drug use in the six months before each follow-up interview. RESULTS: Of 605 participants, 335 (55.4%) reported using injection drugs at baseline. Young people who used injection drugs tended to be older than those who did not, female and in a relationship. Participants who injected drugs were also more likely than those who did not to have been denied shelter because of their drug use, to have been incarcerated, to have a mental illness and to have been involved in sex work. Transition to injection drug use occurred among 39 (14.4%) participants, yielding a crude incidence rate of 19.8% and an incidence density of 11.5 participants per 100 person-years. In unadjusted analysis, transition to injection drug use was associated with being female (odds ratio [OR] 1.98, 95% confidence interval (CI) 1.06-3.72), involved in sex work (OR 3.35, 95% CI 1.75-6.40), having a history of sexually transmitted infection (OR 2.01, 95% CI 1.07-3.78) and using drugs with sex-work clients (OR 2.51, 95% CI 1.19-5.32). In adjusted analysis, transition to injection drug use remained associated with involvement in sex work (adjusted OR 3.94, 95% CI 1.45-10.71). INTERPRETATION: The initiation rate for injection drug use of 11.5 participants per 100 person-years among participants in the Cedar Project is distressing. Young Aboriginal women in our study were twice as likely to inject drugs as men, and participants who injected drugs at baseline were more than twice as likely as those who did not to be involved in sex work. PMID- 21670108 TI - Disparate prescriptions in desperate times. PMID- 21670107 TI - Accuracy of administrative claims data for polypectomy. AB - BACKGROUND: The frequency of polypectomy is an important indicator of quality assurance for population-based colorectal cancer screening programs. Although administrative databases of physician claims provide population-level data on the performance of polypectomy, the accuracy of the procedure codes has not been examined. We determined the level of agreement between physician claims for polypectomy and documentation of the procedure in endoscopy reports. METHODS: We conducted a retrospective cohort study involving patients aged 50-80 years who underwent colonoscopy at seven study sites in Montreal, Que., between January and March 2007. We obtained data on physician claims for polypectomy from the Regie de l'Assurance Maladie du Quebec (RAMQ) database. We evaluated the accuracy of the RAMQ data against information in the endoscopy reports. RESULTS: We collected data on 689 patients who underwent colonoscopy during the study period. The sensitivity of physician claims for polypectomy in the administrative database was 84.7% (95% confidence interval [CI] 78.6%-89.4%), the specificity was 99.0% (95% CI 97.5%-99.6%), concordance was 95.1% (95% CI 93.1%-96.5%), and the kappa value was 0.87 (95% CI 0.83-0.91). INTERPRETATION: Despite providing a reasonably accurate estimate of the frequency of polypectomy, physician claims underestimated the number of procedures performed by more than 15%. Such differences could affect conclusions regarding quality assurance if used to evaluate population-based screening programs for colorectal cancer. Even when a high level of accuracy is anticipated, validating physician claims data from administrative databases is recommended. PMID- 21670109 TI - Curricula reform needed to develop more tech-savvy physicians. PMID- 21670110 TI - Conservative treatment of chronic Achilles tendinopathy. PMID- 21670112 TI - Self-injury rates indicate Canadian mental health services are inadequate. PMID- 21670113 TI - United States proposes universal labelling standards for prescriptions. PMID- 21670114 TI - Ontario health records proposal would breach privacy, experts say. PMID- 21670115 TI - Attenuated but live: a pelvic abscess caused by bacille Calmette-Guerin. PMID- 21670116 TI - The microbes are coming. PMID- 21670117 TI - Using administrative health data for the surveillance of interventions for alcohol-related harm among young people. PMID- 21670118 TI - Industry's neglect of prescribing information for children. PMID- 21670120 TI - Fighting colorectal cancer with information technology. PMID- 21670121 TI - Angiotensin-receptor-blocker research blocked by too many assumptions. PMID- 21670122 TI - Tuberculosis in Nunavut: a socioeconomic tragedy. PMID- 21670123 TI - Cognitive impairment behind the wheel. PMID- 21670124 TI - Radiology overlooked in pancreatitis review. PMID- 21670125 TI - Dynamics of flagellar force generated by a hyperactivated spermatozoon. AB - The flagellar force generated by a hyperactivated monkey spermatozoon was evaluated using the resistive force theory applied to the activated (nonhyperactivated) and hyperactivated flagellar waves that were obtained using high-speed video microscopy and digital image processing in order to clarify the mechanism of sperm penetration through the zona pellucida. No difference in the maximum propulsive force, which was parallel to the longitudinal sperm head axis, was found between the activated and hyperactivated spermatozoa. The maximum transverse force (45 pN), which was perpendicular to the longitudinal sperm head axis, of the hyperactivated spermatozoon was ~2.5 times its propulsive force. As the beat frequency of the flagellar beating remarkably decreased during the hyperactivation, the slowly oscillating transverse force (5 Hz) by the hyperactivated spermatozoon seems to be most effective for sperm penetration through the zona pellucida. PMID- 21670126 TI - Roosters affected by epididymal lithiasis present local alteration in vitamin D3, testosterone and estradiol levels as well as estrogen receptor 2 (beta) expression. AB - Epididymal lithiasis is a reproductive dysfunction of roosters that is associated with loss of fertility and is characterized by the formation of calcium stones in the lumen of the efferent ductules of the epididymal region. The efferent ductules of birds are responsible for the reabsorption of the fluid coming from the testis as well as luminal calcium. It has been hypothesized that the epididymal stone formation may be related to the impairment of local fluid or calcium homeostasis, which depends on hormones such as estradiol (E(2)). Therefore, this study aimed to investigate possible alterations in the expression of ERalpha (ESR1) and ERbeta (ESR2) in the epididymal region of roosters affected by epididymal lithiasis. The study was performed by immunohistochemistry and western blotting assays. In addition, the concentrations of E(2), vitamin D3, and testosterone, which are also key hormones in maintenance of calcium homeostasis, were determined in the plasma and epididymal region, by ELISA. It was observed that ESR2 expression is increased in all segments of the epididymal region of affected roosters, whereas ESR1 levels are not altered. Moreover, the hormone concentration profiles were changed, as in the epididymal region of roosters with lithiasis the E(2) levels were increased and vitamin D3 as well as testosterone concentrations were significantly decreased. These results suggest that a hormonal imbalance may be involved with the origin and progression of the epididymal lithiasis, possibly by affecting the local fluid or calcium homeostasis. PMID- 21670127 TI - Peripheral kisspeptin reverses short photoperiod-induced gonadal regression in Syrian hamsters by promoting GNRH release. AB - In seasonal breeders, reproduction is synchronised by day length via the pineal hormone melatonin. In short winter days (short day, SD), the Syrian hamster displays a complete gonadal atrophy together with a marked reduction in expression of kisspeptins (Kp), a family of potent hypothalamic stimulators of GNRH neurons. Both central and peripheral acute injections of Kp have been reported to activate the gonadotropic axis in mammals. The aim of this study was to determine if and how peripheral administration of Kp54 could restore gonadal function in photo-inhibited hamsters. Testicular activity of hamsters kept in SD was reactivated by two daily i.p. injections of Kp54 but not by chronic subcutaneous delivery of the same peptide via mini-pumps. Acute i.p. injection of Kp54-induced FOS (c-Fos) expression in a large number of GNRH neurons and pituitary gonadotrophs together with a strong increase in circulating testosterone. The activation of pituitary cells by Kp was inhibited by preadministration of the GNRH receptor antagonist acyline. Altogether, our results demonstrate that peripheral Kp54 activates the gonadotropic axis by stimulating GNRH release and indicate that an appropriate protocol of long-term systemic Kp administration can recrudesce a photo-inhibited reproductive axis. PMID- 21670128 TI - Sedation in a radiology department--do radiologists follow their own guidelines? AB - The Royal College of Radiologists (RCR) published guidelines in 2003 which aimed to standardise and improve the safety of sedation in the modern Radiology department. As sedation requirements increase, we decided to audit our own departments understandings and practice with respect to sedation. A repeat audit cycle was performed following a re-educational lecture, one year later. Three common sedation case scenarios were incorporated into a questionnaire which detailed questioning on requirements for fasting, monitoring and the order and use of sedation drugs alongside analgesics. These were compared to the 2003 RCR guidelines. The audit was recycled at one year. Despite the RCR guidelines, freely available on the RCR website, there was a persisting variation in practice which revealed a lack of awareness of the requirements for adequate fasting and the importance of giving the opiate before the benzodiazepine (sedative) agent in cases where a combination are chosen. The audit did show a trend towards using shorter acting benzodiazepines, which is in keeping with the guidelines. Monitoring of vital signs was generally, well carried out. General awareness of the RCR guidelines for safe sedation in the Radiology department was initially low and practice found to be variable. Re-education saw some improvements but also, some persisting habitual deviations from the guidelines, particularly with respect to the order in which the opiate and sedative benzodiazepine were given. PMID- 21670129 TI - The evolution of laparoscopic antireflux surgery and its influence on postoperative stay. AB - Laparoscopic fundoplication is an established treatment for refractory gastro oesophageal reflux disease. This study aims to compare the outcome of two laparoscopic antireflux techniques in a regional specialist unit. A sequential audit was carried out on patients undergoing laparoscopic Nissen (LN: performed May 1994 to November 2000) or laparoscopic anterior (LA: performed March 2001 to December 2004) fundoplication. Patient satisfaction was assessed by postal questionnaire. The cohorts undergoing each operation were also divided into two chronological groups of 51 patients, to study the effect of possible learning curve progression on the number of nights spent in the hospital postoperatively. In all, 142/204 (70%) questionnaires were returned from patients with follow-up ranging from 5 to 40 months postoperation. Overall, 102/142 (72%) reported a good or excellent outcome. Patients who underwent LA had a higher rate of antacid medication use (LN 17.4% versus LA 34.2%, P = 0.036) but there was a higher score for inability to belch following LN (LN 2.03 versus LA 1.53, P = 0.034). When comparing the chronologically divided cohorts, LN was associated with a significantly longer hospital stay than LA (P < 0.001, Mann-Whitney U test). There was a significant decrease in hospital stay from the first to second group of 51 LNs (P < 0.001, Mann-Whitney U test) and a further significant reduction in hospital stay from the first 51 to second 51 LAs (P < 0.001, Mann-Whitney U test). In conclusion, both procedures provide good symptom control. Increased requirement for acid suppression following LA and inability to belch following LN, may suggest more long-term durability of the LN wrap. The decrease in the number of nights spent in hospital may be related to the procedure performed but seems more likely to be an effect of increasing volume of surgical experience. PMID- 21670130 TI - Bile vomiting in paediatrics: what do we really know? AB - Bile vomiting is clinically significant in neonates and children, indicating intestinal obstruction until proven otherwise. The aim of this study was to assess whether nursing staff within a children's hospital were able to accurately identify bilious vomiting and if a deficiency existed, whether educational posters could rectify this problem. A primary audit was conducted in the Royal Aberdeen Children's Hospital evaluating the ability of nursing staff to identify bile vomit and its significance. Educational posters were distributed and a secondary audit was conducted after six months to complete the audit cycle. The second audit also compared the knowledge of different medical professionals. In the primary audit, 41% of nurses selected the colour yellow, compared with 18% of nurses in the second audit with approximately 70% selecting dark-green. Thirty three percent of nurses in the primary audit confirmed intestinal obstruction as the cause of bile vomiting, compared with 64% of nurses in the secondary audit. In conclusion, this study identified a deficiency in the recognition of bile vomiting among nurses, but demonstrates that the use of educational posters can significantly improve knowledge. This can be beneficial in the early recognition of this potential surgical emergency. PMID- 21670131 TI - Supporting trainees in difficulty: a new approach for Scotland. AB - National Health Service (NHS) Education for Scotland (NES) works with NHS and University employers, through the four Postgraduate Deaneries to provide education and training for medical trainees from graduation to completion of specialist and general practice training. Most trainees make good progress through the relevant curriculum supported by a managed system of supervision with regular appraisal and feedback. Similarly most trainees demonstrate their progression to Certificate of Completion of Training through the assessment process that is defined in each specialty curriculum. However a small number of trainees each year will experience difficulties sufficient to impact on their progress and when this occurs, a clear plan of investigation, support and management is required. These activities now have to be robust, and are subject to quality management locally and also external scrutiny by Postgraduate Medical Education and Training Board. Therefore, there is a need for the management process to be clear and consistent, and easily accessible to both trainees and their consultant supervisors. NES has introduced a new infrastructure for Scotland which is described in this paper. The paper also discusses training of educational supervisors, best use of national training and remediation resources and how a national advisory group might contribute. PMID- 21670132 TI - Do waiting list initiatives discriminate in favour of those in a higher socioeconomic group? AB - The UK has a publicly funded health care system with open access to all. In the past, demand for services overwhelmed the resources available. Recent government initiatives have attempted to address this. To achieve shorter waiting times (and guaranteed waiting times), access to additional services has been purchased from the private sector under short-term initiatives, often at sites firth of the home health board. There has been a suspicion that patients from higher socioeconomic groups have benefited differentially from this by rapid access to private health care facilities, due to ease of transport. The aim of this study was to analyse whether a patient's socioeconomic group influenced their access to, and place of, surgery. Patients undergoing a primary total hip or knee arthroplasty in a single health region over a three-year period were identified and their social group was determined by postcode address. Analysis of 3888 patients operated on in four different treatment centres comparing the distribution of patients according to their social group, revealed no bias in the provision of treatment. The study group was comparable to the control population in that health region. In conclusion, the introduction of health policies to reduce time to orthopaedic treatment within one health board area has not resulted in patient bias. PMID- 21670133 TI - The role of a paediatric day surgery unit at the Royal Hospital for Sick Children, Glasgow between 1993 and 2006. AB - A retrospective analysis was carried out on all day surgery admissions at Glasgow's Royal Hospital for Sick Children between 1993 and 2006. The aim of the study was to analyse the total number of operations per day, month and year; specialties involved; and age range of the children admitted, to examine how these factors changed over the 13-year study period. We also studied the specific operations performed in 2006 by each specialty. PMID- 21670134 TI - Late diagnosis of HIV: could this be avoided? AB - Many patients with HIV infection present at a late stage of disease. Late diagnosis is associated with increased morbidity and mortality. One strategy to encourage earlier HIV diagnosis is the promotion of HIV testing outside of a specialist HIV setting. This study aimed to determine whether the diagnosis of HIV could be made sooner by non-HIV specialists consulting HIV-positive patients in the year preceding diagnosis. A case note review of all newly diagnosed HIV positive patients seen over a 12-month period ending in September 2006, was performed to analyse whether patients had consulted a doctor in the year prior to diagnosis, whether they were offered HIV testing and whether they had symptoms or risk factors suggesting HIV infection. Fifty-one newly diagnosed HIV-positive patients were seen during the study period. Twenty-nine of these patients had consulted a doctor in the year prior to diagnosis. Of these, 10 were offered HIV testing and 19 were not. All patients who were not offered HIV testing had risk factors for-, or symptoms of HIV infection. The majority of newly diagnosed HIV patients had consulted a doctor in the year prior to diagnosis. Most were not offered HIV testing despite having risk factors for HIV infection. HIV diagnosis may have been made earlier by testing for HIV outside of a specialist setting. PMID- 21670135 TI - Is Foundation training producing competent doctors? What do Foundation trainees, educational supervisors and nurses in Scotland have to say? AB - The aim of this paper is to examine perceptions of Foundation Year trainees, consultants and senior nurses about the introduction of the Foundation Programme. Specifically, to examine whether Foundation trainees acquire appropriate skills, experience and responsibility. Semi-structured interviews were conducted with 23 F1 doctors, 22 F2 doctors, 23 consultants and 25 nurses from across Scotland in a broad range of specialties. In the summer of 2007 trainees, consultants and nurses broadly agreed that Foundation offers good experience but some issues were highlighted. Certain specialties were seen as offering insufficiently generic experience and consultants, in particular, were concerned that four-month rotations are too short. Frequent moving around for trainees was seen as detrimental for seeing cases through and continuity of care was now perceived to be provided by nurses and consultants rather than junior doctors. Levels of responsibility could vary widely from post to post and tended to be specialty dependent. As a result, some F2s reported frustration that they were not given sufficient responsibility for their stage of training. Nights were recognized as a valuable learning opportunity and most trainees were supportive of night work being made available in F1 and F2. In conclusion, in order to maximize the possibilities of the Foundation years and ensure that trainees can meet the required Foundation competencies, specialties that offer narrow experience need to be matched with 'busy' specialties that can offer broader experience. Night work should be retained, but perhaps not introduced right at the start of F1. Trainees feeling that they are being given insufficient experience, particularly in the F2 year, need to be proactive in addressing this if possible. There is a perception among some consultants and nurses that a process of 'delayed skilling' is taking place, attributable more to reduced hours than Foundation per se. There is a need to follow trainees through to specialty training to ascertain if Foundation has adequately prepared them for run-through training. PMID- 21670136 TI - Antidepressants for mothers: what are we prescribing? AB - Prescribing in the perinatal period is based on a risk-benefit analysis, in the context of a limited evidence base, composed primarily of case series and reports. Mothers with depressive illness often present first in the community and effective treatment is paramount for the wellbeing of both mother and child. We aimed at investigating current prescribing practices among general practitioners (GPs) of antidepressants to mothers presenting in first trimester of pregnancy and during breastfeeding. This qualitative study was conducted by way of postal survey to 78 GPs within South Central Edinburgh catchment area. All responses were anonymous and confidential. We discovered inconsistent prescribing patterns among GPs to both pregnant and breastfeeding mothers. Only one GP suggested consulting clinical guidelines when making prescribing choices. There was no mention of the continuation of an antidepressant from pregnancy into breastfeeding as a reason of choice. Inconsistent prescribing patterns among GPs could have implications for the wellbeing of mother and child, and may be reflective of an underlying educational need among GPs. PMID- 21670137 TI - The prevalence of ear, nose and throat disorders in preschool children with Down's syndrome in Glasgow. AB - Guidelines suggest that all children with Down's syndrome have hearing testing on a regular basis. Since 2004, the ear, nose and throat (ENT), audiology and education services have conducted a joint clinic for annual ENT health and hearing surveillance of all preschool children with Down's syndrome in Greater Glasgow. The aim of this study is to report the prevalence of ENT problems in this well-defined birth cohort, and the proportion of children for whom ENT surgery is required. A prospective database has been kept since 2004, detailing the ENT health status of every child attending the community-based surveillance clinic. Between September 2004 and September 2008, 87 preschool (aged 9 months to 6 years) children with Down's syndrome were sent appointments for the clinic. Of these, 48 (55%) were female and 39 were male. Data were available for 79 (91%). Over the course of the study, 37% were listed for surgery at some point, either adenotonsillectomy for obstructive symptoms or grommet insertion for otitis media with effusion (OME). The prevalence of OME was 93% at age 1, falling to 68% by age 5. None had significant sensorineural hearing impairment. Obstructive symptoms were also common, with 79% of children having either currently symptomatic upper airways obstruction or a history of adenotonsillectomy by age 5. One child had laryngomalacia and two had symptomatic congenital subglottic stenosis. The prevalence of ENT problems in these children is high. Surgical intervention is frequently required. We advocate a proactive approach of regular ENT and audiology surveillance leading to early intervention, with the aim of maximizing health and educational achievement in the long term. PMID- 21670138 TI - Simulation in surgery: a review. AB - The ability to acquire surgical skills requires consistent practice, and evidence suggests that many of these technical skills can be learnt away from the operating theatre. The aim of this review article is to discuss the importance of surgical simulation today and its various types, exploring the effectiveness of simulation in the clinical setting and its challenges for the future. Surgical simulation offers the opportunity for trainees to practise their surgical skills prior to entering the operating theatre, allowing detailed feedback and objective assessment of their performance. This enables better patient safety and standards of care. Surgical simulators can be divided into organic or inorganic simulators. Organic simulators, consisting of live animal and fresh human cadaver models, are considered to be of high-fidelity. Inorganic simulators comprise virtual reality simulators and synthetic bench models. Current evidence suggests that skills acquired through training with simulators, positively transfers to the clinical setting and improves operative outcome. The major challenge for the future revolves around understanding the value of this new technology and developing an educational curriculum that can incorporate surgical simulators. PMID- 21670139 TI - Mary Seacole: forgotten hero? PMID- 21670140 TI - Compliance to oseltamivir and subsequent occurrence of self-reported adverse drug reactions among nursery and primary school children following exposure to Influenza A(H1N1)v. AB - During the containment phase of Influenza A(H1N1)v, a nursery, a primary school and an afterschool club were closed after two pupils were found confirmed cases. Classmates were prescribed postexposure oseltamivir. Compliance was expected to be low. The objective of this study was to assess compliance, the number of children developing adverse drug reactions (ADRs) and the reasons for stopping the course prematurely. We conducted a survey among parents of all classmates of the two cases. Parents were asked about compliance and adverse drug events in a questionnaire or underwent a telephone interview. Response was high, 88%. Seventy nine percent of the children were compliant to the prescribed dose of oseltamivir. One in four children experienced at least one ADR. Children who took a higher daily dose (treatment dose) developed significantly more often ADRs. No children developed Influenza A(H1N1)v. We found that a high overall compliance to prescribed oseltamivir can be achieved in very young children (1-11 years). The proportion of children developing ADRs was much lower than described in two other recent UK investigations. Possibly, this is related to the socioeconomic status of the population under investigation. PMID- 21670141 TI - Thrombolysis of acute ischaemic stroke in a district general hospital: are we doing enough? AB - Thrombolysis of acute ischaemic stroke is safe, efficacious and licensed for use in the UK. To date, few studies have looked at the rates of thrombolysis within a district general hospital setting. The aim of the study was to identify whether local thrombolysis protocols for stroke are adhered to; the rate of thrombolysis and strategies for implementation focused at improving the provision of thrombolysis of patients with acute ischaemic stroke. The methodology involved in this was a retrospective study within a district general hospital in the South of England. Data on patients admitted between 15 April 2008 and 14 April 2009 including demographics, use of the local thrombolysis protocol and reasons for non-thrombolysis were collected and analysed. Out of a total of 599 patients with a primary presentation of acute stroke, 18 were considered for thrombolysis. Six patients out of these 18 were thrombolysed without complications. Four out of these six patients had an improved National Institutes of Health Stroke Scale (NIHSS) post-thrombolysis and one eventually died due to the extensiveness of the stroke sustained, despite a slightly improved NIHSS. The rate of thrombolysis of acute ischaemic stroke is low in this hospital (1.001%). Various measures will need to be considered for implementation in order to improve the provision of this service. PMID- 21670144 TI - Reply to "Reversal and prevention of arsenic-induced human bronchial epithelial cell malignant transformation by microRNA-200b". PMID- 21670145 TI - Complex formation and interactions between transcription factors essential for human prolactin receptor gene transcription. AB - The protein association of estrogen receptor alpha ERalpha with DNA-bound SP1 and C/EBPbeta is essential for the 17beta-estradiol (E2)-induced activation of human prolactin receptor (hPRLR) gene transcription. Protein-protein interaction and complex formation at the hPIII promoter of hPRLR was investigated. The basic region and leucine zipper (bZIP) of C/EBPbeta, zinc finger (ZF) motifs of SP1, and the DNA binding domain of ERalpha were identified as regions responsible for the interactions between transfactors. The E2-induced interaction was confirmed by bioluminescence resonance energy transfer (BRET) assays of live cells. The combination of BRET/bimolecular luminescence complementation assay revealed that ERalpha exists as a constitutive homodimer, and E2 induced a change(s) in ERalpha homodimer conformation favorable for its association with C/EBPbeta and SP1. Chromatin immunoprecipitation and small interfering RNA knockdown of members of the complex in breast cancer cells demonstrated the endogenous recruitment of components of the complex onto the hPIII promoter of the hPRLR gene. SP1 is the preferred transfactor for the recruitment of ERalpha to the complex that facilitates the C/EBPbeta association. The E2/ERalpha-induced hPRLR transcription was demonstrated in ERalpha-negative breast cancer cells. This study indicates that the enhanced complex formation of ERalpha dimer with SP1 and C/EBPbeta by E2 has an essential role in the transcriptional activation of the hPRLR gene. PMID- 21670146 TI - PINCH proteins regulate cardiac contractility by modulating integrin-linked kinase-protein kinase B signaling. AB - Integrin-linked kinase (ILK) is an essential component of the cardiac mechanical stretch sensor and is bound in a protein complex with parvin and PINCH proteins, the so-called ILK-PINCH-parvin (IPP) complex. We have recently shown that inactivation of ILK or beta-parvin activity leads to heart failure in zebrafish via reduced protein kinase B (PKB/Akt) activation. Here, we show that PINCH proteins localize at sarcomeric Z disks and costameres in the zebrafish heart and skeletal muscle. To investigate the in vivo role of PINCH proteins for IPP complex stability and PKB signaling within the vertebrate heart, we inactivated PINCH1 and PINCH2 in zebrafish. Inactivation of either PINCH isoform independently leads to instability of ILK, loss of stretch-responsive anf and vegf expression, and progressive heart failure. The predominant cause of heart failure in PINCH morphants seems to be loss of PKB activity, since PKB phosphorylation at serine 473 is significantly reduced in PINCH-deficient hearts and overexpression of constitutively active PKB reconstitutes cardiac function in PINCH morphants. These findings highlight the essential function of PINCH proteins in controlling cardiac contractility by granting IPP/PKB-mediated signaling. PMID- 21670147 TI - Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. AB - AMP-activated protein kinase (AMPK) is an energy sensor activated by increases in [AMP] or by oxidant stress (reactive oxygen species [ROS]). Hypoxia increases cellular ROS signaling, but the pathways underlying subsequent AMPK activation are not known. We tested the hypothesis that hypoxia activates AMPK by ROS mediated opening of calcium release-activated calcium (CRAC) channels. Hypoxia (1.5% O(2)) augments cellular ROS as detected by the redox-sensitive green fluorescent protein (roGFP) but does not increase the [AMP]/[ATP] ratio. Increases in intracellular calcium during hypoxia were detected with Fura2 and the calcium-calmodulin fluorescence resonance energy transfer (FRET) sensor YC2.3. Antioxidant treatment or removal of extracellular calcium abrogates hypoxia-induced calcium signaling and subsequent AMPK phosphorylation during hypoxia. Oxidant stress triggers relocation of stromal interaction molecule 1 (STIM1), the endoplasmic reticulum (ER) Ca(2+) sensor, to the plasma membrane. Knockdown of STIM1 by short interfering RNA (siRNA) attenuates the calcium responses to hypoxia and subsequent AMPK phosphorylation, while inhibition of L type calcium channels has no effect. Knockdown of the AMPK upstream kinase LKB1 by siRNA does not prevent AMPK activation during hypoxia, but knockdown of CaMKKbeta abolishes the AMPK response. These findings reveal that hypoxia can trigger AMPK activation in the apparent absence of increased [AMP] through ROS dependent CRAC channel activation, leading to increases in cytosolic calcium that activate the AMPK upstream kinase CaMKKbeta. PMID- 21670148 TI - Talin1 regulates integrin turnover to promote embryonic epithelial morphogenesis. AB - Talin is a cytoskeletal protein that binds to integrin beta cytoplasmic tails and regulates integrin activation. Talin1 ablation in mice disrupts gastrulation and causes embryonic lethality. However, the role of talin in mammalian epithelial morphogenesis is poorly understood. Here we demonstrate that embryoid bodies (EBs) differentiated from talin1-null embryonic stem cells are defective in integrin adhesion complex assembly, epiblast elongation, and lineage differentiation. These defects are accompanied by a significant reduction in integrin beta1 protein levels due to accelerated degradation through an MG-132 sensitive proteasomal pathway. Overexpression of integrin beta1 or MG-132 treatment in mutant EBs largely rescues the phenotype. In addition, epiblast cells isolated from talin1-null EBs exhibit impaired cell spreading and focal adhesion formation. Transfection of the mutant cells with green fluorescent protein (GFP)-tagged wild-type but not mutant talin1 that is defective in integrin binding normalizes integrin beta1 protein levels and restores focal adhesion formation. Significantly, cell adhesion and spreading are also improved by overexpression of integrin beta1. All together, these results suggest that talin1 binding to integrin promotes epiblast adhesion and morphogenesis in part by preventing integrin beta1 degradation. PMID- 21670150 TI - Cdc25A regulates matrix metalloprotease 1 through Foxo1 and mediates metastasis of breast cancer cells. AB - Cdc25A is a cell cycle-activating phosphatase, and its overexpression in breast cancers has been shown to correlate with poor prognosis. Most recent studies related to Cdc25A and tumor progression have focused on its role in regulating cell cycle progression. However, less is known about how Cdc25A modulates the metastasis of breast cancer cells. In this study, we revealed that Cdc25A enhances Foxo1 stability by dephosphorylating Cdk2, and Foxo1 was shown to directly regulate transcription of the metastatic factor MMP1. Further studies have shown that overexpression of Cdc25A in breast cancer cells enhances metastasis, whereas its downmodulation inhibits metastasis in mouse models, and the effects of Cdc25A on breast cancer cell metastasis are independent of cell proliferation and apoptosis. Furthermore, we have demonstrated that aberrant Cdc25A in breast cancer patient samples directly correlates with the metastatic phenotype. Further insights into this critical role of Cdc25A in the metastasis of breast cancer cells and the trial of an anti-Cdc25A strategy in mouse models may reveal its therapeutic potential in prevention and treatment of breast cancer cell dissemination. PMID- 21670149 TI - Nuclear receptors TR2 and TR4 recruit multiple epigenetic transcriptional corepressors that associate specifically with the embryonic beta-type globin promoters in differentiated adult erythroid cells. AB - Nuclear receptors TR2 and TR4 (TR2/TR4) were previously shown to bind in vitro to direct repeat elements in the mouse and human embryonic and fetal beta-type globin gene promoters and to play critical roles in the silencing of these genes. By chromatin immunoprecipitation (ChIP) we show that, in adult erythroid cells, TR2/TR4 bind to the embryonic beta-type globin promoters but not to the adult beta-globin promoter. We purified protein complexes containing biotin-tagged TR2/TR4 from adult erythroid cells and identified DNMT1, NuRD, and LSD1/CoREST repressor complexes, as well as HDAC3 and TIF1beta, all known to confer epigenetic gene silencing, as potential corepressors of TR2/TR4. Coimmunoprecipitation assays of endogenous abundance proteins indicated that TR2/TR4 complexes consist of at least four distinct molecular species. In ChIP assays we found that, in undifferentiated murine adult erythroid cells, many of these corepressors associate with both the embryonic and the adult beta-type globin promoters but, upon terminal differentiation, they specifically dissociate only from the adult beta-globin promoter concomitant with its activation but remain bound to the silenced embryonic globin gene promoters. These data suggest that TR2/TR4 recruit an array of transcriptional corepressors to elicit adult stage-specific silencing of the embryonic beta-type globin genes through coordinated epigenetic chromatin modifications. PMID- 21670151 TI - The defective nuclear lamina in Hutchinson-gilford progeria syndrome disrupts the nucleocytoplasmic Ran gradient and inhibits nuclear localization of Ubc9. AB - The mutant form of lamin A responsible for the premature aging disease Hutchinson Gilford progeria syndrome (termed progerin) acts as a dominant negative protein that changes the structure of the nuclear lamina. How the perturbation of the nuclear lamina in progeria is transduced into cellular changes is undefined. Using patient fibroblasts and a variety of cell-based assays, we determined that progerin expression in Hutchinson-Gilford progeria syndrome inhibits the nucleocytoplasmic transport of several factors with key roles in nuclear function. We found that progerin reduces the nuclear/cytoplasmic concentration of the Ran GTPase and inhibits the nuclear localization of Ubc9, the sole E2 for SUMOylation, and of TPR, the nucleoporin that forms the basket on the nuclear side of the nuclear pore complex. Forcing the nuclear localization of Ubc9 in progerin-expressing cells rescues the Ran gradient and TPR import, indicating that these pathways are linked. Reducing nuclear SUMOylation decreases the nuclear mobility of the Ran nucleotide exchange factor RCC1 in vivo, and the addition of SUMO E1 and E2 promotes the dissociation of RCC1 and Ran from chromatin in vitro. Our data suggest that the cellular effects of progerin are transduced, at least in part, through reduced function of the Ran GTPase and SUMOylation pathways. PMID- 21670152 TI - Sequestration of toxic oligomers by HspB1 as a cytoprotective mechanism. AB - Small heat shock proteins (sHsps) are molecular chaperones that protect cells from cytotoxic effects of protein misfolding and aggregation. HspB1, an sHsp commonly associated with senile plaques in Alzheimer's disease (AD), prevents the toxic effects of Abeta aggregates in vitro. However, the mechanism of this chaperone activity is poorly understood. Here, we observed that in two distinct transgenic mouse models of AD, mouse HspB1 (Hsp25) localized to the penumbral areas of plaques. We have demonstrated that substoichiometric amounts of human HspB1 (Hsp27) abolish the toxicity of Abeta oligomers on N2a (mouse neuroblastoma) cells. Using biochemical methods, spectroscopy, light scattering, and microscopy methods, we found that HspB1 sequesters toxic Abeta oligomers and converts them into large nontoxic aggregates. HspB1 was overexpressed in N2a cells in response to treatment with Abeta oligomers. Cultured neurons from HspB1 deficient mice were more sensitive to oligomer-mediated toxicity than were those from wild-type mice. Our results suggest that sequestration of oligomers by HspB1 constitutes a novel cytoprotective mechanism of proteostasis. Whether chaperone mediated cytoprotective sequestration of toxic aggregates may bear clues to plaque deposition and may have potential therapeutic implications must be investigated in the future. PMID- 21670153 TI - CrbpI modulates glucose homeostasis and pancreas 9-cis-retinoic acid concentrations. AB - Cellular retinol-binding protein type I (CrbpI), encoded by Rpb1, serves as a chaperone of retinol homeostasis, but its physiological effects remain incompletely understood. We show here that the Rbp1(-/-) mouse has disrupted retinoid homeostasis in multiple tissues, with abnormally high 9-cis-retinoic acid (9cRA), a pancreas autacoid that attenuates glucose-stimulated insulin secretion. The Rbp1(-/-) pancreas has increased retinol and intense ectopic expression of Rpb2 mRNA, which encodes CrbpII: both would contribute to increased beta-cell 9cRA biosynthesis. 9cRA in Rbp1(-/-) pancreas resists postprandial and glucose-induced decreases. Rbp1(-/-) mice have defective islet expression of genes involved in glucose sensing and insulin secretion, as well as islet alpha cell infiltration, which contribute to reduced glucose-stimulated insulin secretion, high glucagon secretion, an abnormally high rate of gluconeogenesis, and hyperglycemia. A diet rich in vitamin A (as in a standard chow diet) increases pancreas 9cRA and impairs glucose tolerance. Crbp1 attenuates the negative impact of vitamin A (retinol) on glucose tolerance, regardless of the dietary retinol content. Rbp1(-/-) mice have an increased rate of fatty acid oxidation and resist obesity when fed a high-fat diet. Thus, glucose homeostasis and energy metabolism rely on Rbp1 expression and its moderation of pancreas retinol and of the autacoid 9cRA. PMID- 21670154 TI - LMO7 mediates cell-specific activation of the Rho-myocardin-related transcription factor-serum response factor pathway and plays an important role in breast cancer cell migration. AB - Serum response factor (SRF) is a ubiquitously expressed transcription factor that regulates cell-specific functions such as muscle development and breast cancer metastasis. The myocardin-related transcription factors (MRTFs), which are transcriptional coactivators mediating cell-specific functions of SRF, are also ubiquitously expressed. How MRTFs and SRF drive cell-specific transcription is still not fully understood. Here we show that LIM domain only 7 (LMO7) is a cell specific regulator of MRTFs and plays an important role in breast cancer cell migration. LMO7 activates MRTFs by relieving actin-mediated inhibition in a manner that requires, and is synergistic with, Rho GTPase. Whereas Rho is required for LMO7 to activate full-length MRTFs that have three RPEL actin binding motifs, the disruption of individual actin-RPEL interactions is sufficient to eliminate the Rho dependency and to allow the strong Rho independent function of LMO7. Mechanistically, we show that LMO7 colocalizes with F-actin and reduces the G-actin/F-actin ratio via a Rho-independent mechanism. The knockdown of LMO7 in HeLa and MDA-MB-231 cells compromises both basal and Rho stimulated MRTF activities and impairs the migration of MDA-MB-231 breast cancer cells. We also show that LMO7 is upregulated in the stroma of invasive breast carcinoma in a manner that correlates with the increased expression of SRF target genes that regulate muscle and actin cytoskeleton functions. Together, this study reveals a novel cell-specific mechanism regulating Rho-MRTF-SRF signaling and breast cancer cell migration and identifies a role for actin-RPEL interactions in integrating Rho and cell-specific signals to achieve both the synergistic and Rho dependent activation of MRTFs. PMID- 21670155 TI - Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. AB - Disruption of the BRCA1 tumor suppressor can be caused not only by inherited mutations in familial cancers but also by BRCA1 gene silencing in sporadic cancers. Hypoxia, a key feature of the tumor microenvironment, has been shown to downregulate BRCA1 at the transcriptional level via repressive E2F4/p130 complexes. Here we showed that hypoxia also drives epigenetic modification of the BRCA1 promoter, with decreased H3K4 methylation as a key repressive modification produced by the lysine-specific histone demethylase LSD1. We also observed increased H3K9 methylation coupled with decreased H3K9 acetylation. Similar modifications were seen in the RAD51 promoter, which is also downregulated by hypoxia, whereas exactly opposite changes were seen in the promoter of the hypoxia-inducible gene VEGF. In cells containing the BRCA1 promoter driving a selectable HPRT gene, long-term silencing of the promoter was observed following exposure to hypoxic stress. Clones with silenced BRCA1 promoters were detected at frequencies of 2% or more following hypoxia, but at less than 6 * 10(-5) without hypoxia. The silenced clones showed decreased H3K4 methylation and decreased H3K9 acetylation in the BRCA1 promoters, consistent with the acute effects of hypoxic stress. Hypoxia-induced BRCA1 promoter silencing persisted in subsequent normoxic conditions but could be reversed by treatment with a histone deacetylase (HDAC) inhibitor but not with a DNA methylation inhibitor. Interestingly, treatment of cells with inhibitors of poly(ADP-ribose) polymerase (PARP) can cause short-term repression of BRCA1 expression, but such treatment does not produce H3K4 or H3K9 histone modification or BRCA1 promoter silencing. These results suggest that hypoxia is a driving force for long-term silencing of BRCA1, thereby promoting genome instability and tumor progression. PMID- 21670156 TI - A small, glutamine-free domain propagates the [SWI(+)] prion in budding yeast. AB - Yeast prions are self-propagating protein conformations that transmit heritable phenotypes in an epigenetic manner. The recently identified yeast prion [SWI(+)] is an alternative conformation of Swi1, a component of the evolutionarily conserved SWI/SNF chromatin-remodeling complex. Formation of the [SWI(+)] prion results in a partial loss-of-function phenotype for Swi1. The amino-terminal region of Swi1 is dispensable for its normal function but is required for [SWI(+)] formation and propagation; however, the precise prion domain (PrD) of Swi1 has not been elucidated. Here, we define the minimal Swi1 PrD as the first 37 amino acids of the protein. This region is extremely asparagine rich but, unexpectedly, contains no glutamine residues. This unusually small prion domain is sufficient for aggregation, propagation, and transmission of the [SWI(+)] prion. Because of its unusual size and composition, the Swi1 prion domain defined here has important implications for describing and identifying novel prions. PMID- 21670157 TI - The RPB2 flap loop of human RNA polymerase II is dispensable for transcription initiation and elongation. AB - The flap domain of multisubunit RNA polymerases (RNAPs), also called the wall, forms one side of the RNA exit channel. In bacterial RNAP, the mobile part of the flap is called the flap tip and makes essential contacts with initiation and elongation factors. Cocrystal structures suggest that the orthologous part of eukaryotic RNAPII, called the flap loop, contacts transcription factor IIB (TFIIB), but the function of the flap loop has not been assessed. We constructed and tested a deletion of the flap loop in human RNAPII (subunit RPB2 Delta873 884) that removes the flap loop interaction interface with TFIIB. Genome-wide analysis of the distribution of the RNAPII with the flap loop deletion expressed in a human embryonic kidney cell line (HEK 293) revealed no effect of the flap loop on global transcription initiation, RNAPII occupancy within genes, or the efficiency of promoter escape and productive elongation. In vitro, the flap loop deletion had no effect on promoter binding, abortive initiation or promoter escape, TFIIS-stimulated transcript cleavage, or inhibition of transcript elongation by the complex of negative elongation factor (NELF) and 5,6-dichloro-1 beta-d-ribofuranosylbenzimidazole (DRB) sensitivity-inducing factor (DSIF). A modest effect on transcript elongation and pausing was suppressed by TFIIF. Although similar to the flap tip of bacterial RNAP, the RNAPII flap loop is not equivalently essential. PMID- 21670158 TI - The role of culture in parents' socialization of children's emotional development. AB - Parents' emotion coaching of children and modeling of effective emotional responses are associated with children's positive emotional development. However, much of the research in this area has been with European American families. This study examined parents' self-reports about their emotion regulation patterns and coaching their children about emotions, across three racial and ethnic groups (African American, European American, and Multiracial), to determine how well these parental behaviors predicted their children's self-reports of depressive and anxiety symptoms 18 to 24 months later (N = 99). For the African American families, a higher level of coaching about anger and sadness by mothers was linked with lower depressive symptoms in their children. A higher level of anger coaching by fathers within the Multiracial group was also associated with lower anxiety and depressive symptoms. This study supports the importance of cultural values, within racial and ethnic groups, in parenting approaches associated with children's mental health outcomes. PMID- 21670159 TI - Systems: What's in a name? PMID- 21670161 TI - The transcriptional control of lymphatic vascular development. AB - More than 100 years ago, Florence Sabin suggested that lymphatic vessels develop by sprouting from preexisting blood vessels, but it is only over the past decade that the molecular mechanisms underpinning lymphatic vascular development have begun to be elucidated. Genetic manipulations in mice have identified a transcriptional hub comprised of Prox1, CoupTFII, and Sox18 that is essential for lymphatic endothelial cell fate specification. Recent work has identified a number of additional transcription factors that regulate later stages of lymphatic vessel differentiation and maturation. This review highlights recent advances in our understanding of the transcriptional control of lymphatic vascular development and reflects on efforts to better understand the activities of transcriptional networks during this discrete developmental process. Finally, we highlight the transcription factors associated with human lymphatic vascular disorders, demonstrating the importance of understanding how the activity of these key molecules is regulated, with a view toward the development of innovative therapeutic avenues. PMID- 21670162 TI - Regulation of smooth muscle contraction by the epithelium: role of prostaglandins. AB - As an analog to the endothelium situated next to the vascular smooth muscle, the epithelium is emerging as an important regulator of smooth muscle contraction in many vital organs/tissues by interacting with other cell types and releasing epithelium-derived factors, among which prostaglandins have been demonstrated to play a versatile role in governing smooth muscle contraction essential to the physiological and pathophysiological processes in a wide range of organ systems. PMID- 21670163 TI - Cell polarity and migration: emerging role for the endosomal sorting machinery. AB - The endosomal sorting complex required for transport (ESCRT) machinery has been implicated in the regulation of endosomal sorting, cell division, viral budding, autophagy, and cell signaling. Here, we review recent evidence that implicates ESCRTs in cell polarity and cell migration, and discuss the potential role of ESCRTs as tumor suppressors. PMID- 21670160 TI - Vascular effects of exercise: endothelial adaptations beyond active muscle beds. AB - Endothelial adaptations to exercise training are not exclusively conferred within the active muscle beds. Herein, we summarize key studies that have evaluated the impact of chronic exercise on the endothelium of vasculatures perfusing nonworking skeletal muscle, brain, viscera, and skin, concluding with discussion of potential mechanisms driving these endothelial adaptations. PMID- 21670164 TI - Membrane proteins as 14-3-3 clients in functional regulation and intracellular transport. AB - 14-3-3 proteins regulate the function and subcellular sorting of membrane proteins. Often, 14-3-3 binding to client proteins requires phosphorylation of the client, but the relevant kinase is unknown in most cases. We summarize current progress in identifying kinases that target membrane proteins with 14-3-3 binding sites and discuss the molecular mechanisms of 14-3-3 action. One of the kinases involved is Akt/PKB, which has recently been shown to activate the 14-3-3 dependent switch in a number of client membrane proteins. PMID- 21670165 TI - The regulation and physiology of mitochondrial proton leak. AB - Mitochondria couple respiration to ATP synthesis through an electrochemical proton gradient. Proton leak across the inner membrane allows adjustment of the coupling efficiency. The aim of this review is threefold: 1) introduce the unfamiliar reader to proton leak and its physiological significance, 2) review the role and regulation of uncoupling proteins, and 3) outline the prospects of proton leak as an avenue to treat obesity, diabetes, and age-related disease. PMID- 21670166 TI - Medroxyprogesterone acetate aggravates oxidative stress and left ventricular dysfunction in rats with chronic myocardial infarction. AB - The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17beta estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI). To address this issue, we evaluated clinical signs of heart failure as well as left ventricular (LV) dysfunction and remodeling in ovariectomized rats subjected to chronic MI receiving E2 or E2 plus MPA. After eight weeks MI E2 showed no effects. Adding MPA to E2 aggravated LV remodeling and dysfunction as judged by increased heart weight, elevated myocyte cross sectional areas, increased elevated left ventricle end diastolic pressure, and decreased LV fractional shortening. Impaired LV function in rats receiving MPA plus E2 was associated with increased cardiac reactive oxygen species generation and myocardial expression levels of NADPH oxidase subunits. These results support the interpretation that adding MPA to an E2 treatment complicates cardiovascular injury damage post-MI and therefore contributes to explain the adverse outcome of prospective clinical studies. PMID- 21670167 TI - Well-differentiated teratoma in a mouse uterus. AB - Teratomas commonly occur in the testis and ovary, whereas in the uterus they are rare. The authors report findings for a mass detected in the uterus of a 26-week old mouse in a colony of C57BL/6 bred in their laboratory. The mass was located in the endometrium and protruded into the lumen. Histopathologically, it consisted of abnormal diploblastic or triploblastic tissues. Bone with a growth plate and myeloid cells, as well as cartilage, was mainly observed. It also included melanocytes, exocrine gland-like cells, striated muscle, and neuron-like cells. While these tissues were accompanied by extensive necrosis, all of them were well differentiated and lacked features of malignancy, such as invasion and metastasis. This mouse had experienced parturition, but fetal tissue was not observed in the lesion. Therefore, the lesion was diagnosed as a benign teratoma, which was spontaneously developed in the uterus. PMID- 21670168 TI - Analysis of the HD-GYP domain cyclic dimeric GMP phosphodiesterase reveals a role in motility and the enzootic life cycle of Borrelia burgdorferi. AB - HD-GYP domain cyclic dimeric GMP (c-di-GMP) phosphodiesterases are implicated in motility and virulence in bacteria. Borrelia burgdorferi possesses a single set of c-di-GMP-metabolizing enzymes, including a putative HD-GYP domain protein, BB0374. Recently, we characterized the EAL domain phosphodiesterase PdeA. A mutation in pdeA resulted in cells that were defective in motility and virulence. Here we demonstrate that BB0374/PdeB specifically hydrolyzed c-di-GMP with a K(m) of 2.9 nM, confirming that it is a functional phosphodiesterase. Furthermore, by measuring phosphodiesterase enzyme activity in extracts from cells containing the pdeA pdeB double mutant, we demonstrate that no additional phosphodiesterases are present in B. burgdorferi. pdeB single mutant cells exhibit significantly increased flexing, indicating a role for c-di-GMP in motility. Constructing and analyzing a pilZ pdeB double mutant suggests that PilZ likely interacts with chemotaxis signaling. While virulence in needle-inoculated C3H/HeN mice did not appear to be altered significantly in pdeB mutant cells, these cells exhibited a reduced ability to survive in Ixodes scapularis ticks. Consequently, those ticks were unable to transmit the infection to naive mice. All of these phenotypes were restored when the mutant was complemented. Identification of this role of pdeB increases our understanding of the c-di-GMP signaling network in motility regulation and the life cycle of B. burgdorferi. PMID- 21670169 TI - Chitin-induced carbotype conversion in Vibrio vulnificus. AB - As an etiological agent of bacterial sepsis and wound infections, Vibrio vulnificus is unique among the Vibrionaceae. The most intensely studied of its virulence factors is the capsular polysaccharide (CPS). Over 100 CPS types have been identified, yet little is known about the genetic mechanisms that drive such diversity. Chitin, the second-most-abundant polysaccharide in nature, is known to induce competence in Vibrio species. Here, we show that the frequency of chitin induced transformation in V. vulnificus varies by strain and that (GlcNAc)(2) is the shortest chitin-derived polymer capable of inducing competence. Transformation frequencies (TFs) increased 8-fold when mixed-culture biofilms were exposed to a strain-specific lytic phage, suggesting that the lysis of dead cells during lytic infection increased the amount of extracellular DNA within the biofilm that was available for transfer. Furthermore, we show that V. vulnificus can undergo chitin-dependent carbotype conversion following the uptake and recombination of complete cps loci from exogenous genomic DNA (gDNA). The acquisition of a partial locus was also demonstrated when internal regions of homology between the endogenous and exogenous loci existed. This suggested that the same mechanism governing the transfer of complete cps loci also contributed to their evolution by generating novel combinations of CPS biosynthesis genes. Since no evidence that cps loci were preferentially acquired during natural transformation (random transposon-tagged DNA was readily taken up in chitin transformation assays) exists, the phenomenon of chitin-induced transformation likely plays an important but general role in the evolution of this genetically promiscuous genus. PMID- 21670170 TI - Regulation of type VI secretion system during Burkholderia pseudomallei infection. AB - Type III and type VI secretion systems (T3SSs and T6SSs, respectively) are critical virulence determinants in several Gram-negative pathogens. In Burkholderia pseudomallei, the T3SS-3 and T6SS-1 clusters have been implicated in bacterial virulence in mammalian hosts. We recently discovered a regulatory cascade that coordinately controls the expression of T3SS-3 and T6SS-1. BsaN is a central regulator located within T3SS-3 for the expression of T3SS-3 effectors and regulators for T6SS-1 such as VirA-VirG (VirAG) and BprC. Whereas T6SS-1 gene expression was completely dependent on BprC when bacteria were grown in medium, the expression inside host cells was dependent on the two-component sensor regulator VirAG, with the exception of the tssAB operon, which was dependent primarily on BprC. VirAG and BprC initiate different transcriptional start sites within T6SS-1, and VirAG is able to activate the hcp1 promoter directly. We also provided novel evidence that virAG, bprC, and tssAB are critical for T6SS-1 function in macrophages. Furthermore, virAG and bprC regulator mutants were avirulent in mice, demonstrating the absolute dependence of T6SS-1 expression on these regulators in vivo. PMID- 21670172 TI - A dispersal-dependent zone of introgressive hybridization between weakfish, Cynoscion regalis, and sand seatrout, C. arenarius, (Sciaenidae) in the Florida Atlantic. AB - Five diagnostic codominant nuclear DNA markers and a diagnostic mitochondrial DNA marker were used to survey weakfish (Cynoscion regalis) and sand seatrout (C. arenarius), with particular focus on heretofore uncharacterized juvenile populations along the Florida (FL) Atlantic coast. Geographic and reproductive ranges of weakfish and sand seatrout were shown to overlap on the Atlantic coast along north and central FL. An active bidirectional zone of introgressive hybridization exists between these taxa, centered in the St Johns River, FL. Strong patterns of Hardy-Weinberg, linkage, and cytonuclear disequilibrium and a bimodal hybrid index distribution were observed for juvenile cohorts in the zone center, coupled with narrow (~240 km) concordant clines. Parental forms had disparate habitat preferences; hybrid forms occurred predominantly in intermediate habitats. All genetic data were consistent with the hypothesis that the C. arenarius-C. regalis hybrid zone is maintained by a dynamic equilibrium between continued interspecific gene flow and one or more opposing forces. Cytonuclear analyses indicated that parental forms mate assortatively in the zone but that mate recognition was imperfect. Ethological mating dynamics are likely stabilized by some form of endogenous or exogenous postfertilization selection against hybrids such that parental taxa will likely continue to evolve independently. PMID- 21670171 TI - A Francisella tularensis locus required for spermine responsiveness is necessary for virulence. AB - Tularemia is a debilitating febrile illness caused by the category A biodefense agent Francisella tularensis. This pathogen infects over 250 different hosts, has a low infectious dose, and causes high morbidity and mortality. Our understanding of the mechanisms by which F. tularensis senses and adapts to host environments is incomplete. Polyamines, including spermine, regulate the interactions of F. tularensis with host cells. However, it is not known whether responsiveness to polyamines is necessary for the virulence of the organism. Through transposon mutagenesis of F. tularensis subsp. holarctica live vaccine strain (LVS), we identified FTL_0883 as a gene important for spermine responsiveness. In-frame deletion mutants of FTL_0883 and FTT_0615c, the homologue of FTL_0883 in F. tularensis subsp. tularensis Schu S4 (Schu S4), elicited higher levels of cytokines from human and murine macrophages compared to wild-type strains. Although deletion of FTL_0883 attenuated LVS replication within macrophages in vitro, the Schu S4 mutant with a deletion in FTT_0615c replicated similarly to wild-type Schu S4. Nevertheless, both the LVS and the Schu S4 mutants were significantly attenuated in vivo. Growth and dissemination of the Schu S4 mutant was severely reduced in the murine model of pneumonic tularemia. This attenuation depended on host responses to elevated levels of proinflammatory cytokines. These data associate responsiveness to polyamines with tularemia pathogenesis and define FTL_0883/FTT_0615c as an F. tularensis gene important for virulence and evasion of the host immune response. PMID- 21670173 TI - The 5S rDNA gene family in mollusks: characterization of transcriptional regulatory regions, prediction of secondary structures, and long-term evolution, with special attention to Mytilidae mussels. AB - Several reports on the characterization of 5S ribosomal DNA (5S rDNA) in various animal groups have been published to date, but there is a lack of studies analyzing this gene family in a much broader context. Here, we have studied 5S rDNA variation in several molluskan species, including bivalves, gastropods, and cephalopods. The degree of conservation of transcriptional regulatory regions was analyzed in these lineages, revealing a conserved TATA-like box in the upstream region. The evolution of the 120 bp coding region (5S) was also studied, suggesting the occurrence of paralogue groups in razor clams, clams, and cockles. In addition, 5S rDNA sequences from 11 species and 7 genus of Mytilidae Rafinesque, 1815 mussels were sampled and studied in detail. Four different 5S rDNA types, based on the nontranscribed spacer region were identified. The phylogenetic analyses performed within each type showed a between-species gene clustering pattern, suggesting ancestral polymorphism. Moreover, some putative pseudogenized 5S copies were also identified. Our report, together with previous studies that found high degree of intragenomic divergence in bivalve species, suggests that birth-and-death evolution may be the main force driving the evolution of 5S rDNA in these animals, even at the genus level. PMID- 21670174 TI - Evaluating the utility of microsatellites for investigations of autopolyploid taxa. AB - Autopolyploid taxa present numerous challenges for population genetic analyses due to difficulties determining allele dosage. Dosage ambiguity hinders accurate assessment of allele frequencies, multilocus genotypes (MLGTs), as well as levels and patterns of clonality. The pervasiveness of polyploidy in the evolutionary history of plant taxa makes this a recurring problem. Whereas diploidization of loci may occur over time, duplication of at least some loci is still frequently evident. Fortunately, with high-quality allozyme gels, it is possible to accurately infer allele dosage and, thus, determine exact MLGTs. However, accurately assessing dosage of microsatellite peaks is nearly impossible when studying wild populations with a large number of alleles per locus. Even if precise knowledge of genotypes is not required, for comparable numbers of alleles per locus and loci, the number of "phenotypes" is always lower with microsatellites than allozymes due to the inability to assess allele dosage. Microsatellite loci typically have more alleles per locus relative to allozymes although fewer loci are generally employed. Here, we present a mathematical model for comparing the relative utility of simple sequence repeat (SSR) versus allozyme markers to discriminate MLGTs. For example, the average plant allozyme study (2.6 alleles per locus, 10 polymorphic loci) has better discriminating power than SSR markers with 10 alleles at each of 3 loci, 9 alleles at 4 loci, 6 alleles at 5 loci, 5 alleles at 6 loci, and 4 alleles at 8 loci, demonstrating the value of assessing the relative discriminating power of these markers. PMID- 21670175 TI - CONGEN-2010: A semester in a fortnight. PMID- 21670176 TI - LEADER Program results for 2009: an activity and spectrum analysis of linezolid using 6,414 clinical isolates from 56 medical centers in the United States. AB - The LEADER Program monitors the in vitro activity of linezolid in sampled U.S. medical centers using reference broth microdilution methods with supporting molecular investigations in a central laboratory design. This report summarizes data obtained in 2009, the 6th consecutive year of this longitudinal study. A total of 6,414 isolates from 56 medical centers in all nine Census regions across the United States participated in 2009. For the six leading species/groups, the following linezolid MIC(90) values were observed: Staphylococcus aureus, 2 MUg/ml; coagulase-negative staphylococci (CoNS), 1 MUg/ml; Enterococcus spp., 2 MUg/ml; Streptococcus pneumoniae, 1 MUg/ml; viridans group streptococci, 1 MUg/ml; and beta-hemolytic streptococci, 1 MUg/ml. Linezolid resistance was only 0.34% overall, with no evidence of significant increase in the LEADER Program since 2006. The predominant linezolid resistant mechanism found was a G2576T mutation in the 23S rRNA. L3/L4 riboprotein mutations were also found. The mobile multidrug-resistant cfr gene was found in four strains (two S. aureus strains and one strain each of S. epidermidis and S. capitis) from four different states, suggesting persistence but a lack of dissemination. Linezolid continues to exhibit excellent activity and spectrum, and this study documents the need for continued monitoring of emerging mechanisms of resistance over a wide geographic area. PMID- 21670178 TI - Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease. AB - We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram negative pathogens were also calculated. The mean peak (maximum) concentration (C(max)) and trough (minimum) concentration in plasma were 5.37 +/- 1.57 and 1 +/ 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC(0-24)) were 169.87 +/- 84.11 liters, 26.96 +/- 8.86 liters/h, 5.35 +/- 2.21 h, and 47.41 +/- 17.02 mg . h/liter, respectively. In bronchial secretions, a mean C(max) of 3.08 +/- 1.21 mg/liter was achieved in 3.12 +/- 1.01 h, and the penetration ratio was 1.16 +/- 0.59. The target of AUC(0-24)/MIC of >=125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 MUg/ml, respectively. Slightly better results were obtained for the ratio C(max)/MIC of >=10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of >=0.5 MUg/ml. PMID- 21670177 TI - Pharmacokinetic and pharmacodynamic characteristics of a new pediatric formulation of artemether-lumefantrine in African children with uncomplicated Plasmodium falciparum malaria. AB - The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n = 91) and crushed (n = 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (C(max)) for the different body weight groups, with overall means of 175 +/- 168 and 190 +/- 168 ng/ml, respectively, for artemether and 64.7 +/- 58.1 and 63.7 +/- 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population C(max) were 6.3 MUg/ml (dispersible tablet) and 7.7 MUg/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 MUg . h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA C(max) and parasite clearance time or between the lumefantrine C(max) and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria. PMID- 21670179 TI - Antivirulence potential of TR-700 and clindamycin on clinical isolates of Staphylococcus aureus producing phenol-soluble modulins. AB - Staphylococcus aureus strains (n = 50) causing complicated skin and skin structure infections produced various levels of phenol-soluble modulin alpha-type (PSMalpha) peptides; some produced more than twice that produced by the control strain (LAC USA300). TR-700 (oxazolidinone) and clindamycin strongly inhibited PSM production at one-half the MIC but exhibited weak to modest induction at one fourth and one-eighth the MICs, primarily in low producers. Adequate dosing of these agents is emphasized to minimize the potential for paradoxical induction of virulence. PMID- 21670180 TI - A fluoroquinolone-resistant Escherichia coli clinical isolate without quinolone resistance-determining region mutations found in Japan. PMID- 21670181 TI - Pharmacokinetics/pharmacodynamics of colistin and imipenem on mucoid and nonmucoid Pseudomonas aeruginosa biofilms. AB - The time course of activity of colistin and imipenem against mucoid and nonmucoid Pseudomonas aeruginosa growing in a biofilm showed that compared with those for planktonic bacteria, the kinetics of colistin and imipenem retained the concentration- and time-dependent killing, respectively, but higher doses of antibiotics and longer dosing periods were required for biofilm eradication. Biofilms of mucoid P. aeruginosa were more difficult to eradicate than nonmucoid biofilms. PMID- 21670182 TI - Steady-state pharmacokinetics of tenofovir-based regimens in HIV-infected pediatric patients. AB - HIV-infected children are treated with tenofovir in combination with other, potentially interacting, antiretroviral agents. We report the pharmacokinetic parameters of tenofovir in combination with efavirenz, darunavir-ritonavir, or atazanavir-ritonavir in HIV-infected children. HIV-infected patients 8 to 18 years of age receiving a tenofovir (300 mg)-based regimen containing efavirenz (300 or 600 mg) once daily (group 1), darunavir (300 or 600 mg)-ritonavir (100 mg) twice daily (group 2), or atazanavir (150 to 400 mg)-ritonavir (100 mg) once daily (group 3) were enrolled. Plasma samples were collected over a 24-h time interval. The 90% confidence intervals (90% CI) of the geometric means for the area under the plasma concentration-time curve (AUC) and the minimum concentration of drug in serum (C(min)) of each antiretroviral were computed and checked for overlap with intervals bracketing published values obtained in adult or pediatric studies demonstrating safety and/or efficacy. Group 1 efavirenz plasma concentrations were observed to be higher in patients receiving fixed-dose combination tablets compared with subjects receiving the individual formulation. In group 2, tenofovir and darunavir exposure was observed to be lower than expected. In group 3, tenofovir and atazanavir administered concomitantly produced exposures similar to those published for adult patients. The 90% CI of AUC and C(min) for tenofovir overlapped the target range for all combinations. Informal comparisons of treatment groups did not indicate any advantage to any combination with respect to tenofovir exposure. Further study of exposures achieved with antiretrovirals administered in combination is warranted. PMID- 21670183 TI - The 8-aminoquinoline analogue sitamaquine causes oxidative stress in Leishmania donovani promastigotes by targeting succinate dehydrogenase. AB - The 8-aminoquinoline analogue sitamaquine (SQ) is an oral antileishmanial drug currently undergoing phase 2b clinical trials for the treatment of visceral leishmaniasis. In the present study, we investigated the mechanism of action of this drug in Leishmania donovani promastigotes. SQ causes a dose-dependent inhibition of complex II (succinate dehydrogenase) of the respiratory chain in digitonin-permeabilized promastigotes, together with a drop in intracellular ATP levels and a decrease of the mitochondrial electrochemical potential. This is associated with increases of reactive oxygen species and intracellular Ca(2+) levels, a higher percentage of the population with sub-G(1) DNA content, and exposure of phosphatidylserine. Taken together, these results support a lethal mechanism for SQ that involves inhibition of the respiratory chain complex II, which in turn triggers oxidative stress and finally leads to an apoptosis-like death of Leishmania parasites. PMID- 21670184 TI - Efficacy of human simulated exposures of ceftaroline administered at 600 milligrams every 12 hours against phenotypically diverse Staphylococcus aureus isolates. AB - Ceftaroline exhibits bactericidal activity against Gram-positive pathogens, including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus, as well as common Gram-negative pathogens. This study evaluated the efficacy of human simulated exposures of ceftaroline against S. aureus in both the neutropenic and immunocompetent mouse thigh infection models. Twenty-six S. aureus isolates (4 MSSA, 22 MRSA) with ceftaroline MICs ranging from 0.125 to 4 MUg/ml were collected. All isolates were tested in the neutropenic model and a subset of 13 MRSA isolates were tested in the immunocompetent model. Two hours after inoculation, a ceftaroline regimen that simulated the percentage of the dosing interval that free-drug concentrations remained above the MIC of the infecting organism (fT>MIC) of humans administered ceftaroline at 600 mg every 12 h (q12h) infused over 1 h was given. The change in log(10) CFU/ml after 24 h of treatment was analyzed relative to the 0- and 24-h controls for neutropenic and immunocompetent mice, respectively. The human simulated regimen resulted in efficacy against all isolates tested in both infection models. In the neutropenic model, a 0.95 to 3.28 log(10) CFU/ml reduction was observed when compared with the 0-h control, whereas for the immunocompetent model, all isolates obtained a >1 log(10) CFU/ml reduction (log(10) CFU/ml reduction range: 1.06 to 2.43) in bacterial density. Irrespective of immune competency, a reduction in bacterial density was observed at the highest MIC of 4 MUg/ml (fT>MIC of 27.5%). Human simulated exposures of ceftaroline 600 mg q12h provided predictable efficacy against all tested S. aureus isolates in the mouse thigh model independent of immune status. These data support the clinical utility of ceftaroline against S. aureus, including MRSA, with MICs of <=4 MUg/ml. PMID- 21670185 TI - Antimicrobial susceptibilities of commonly encountered bacterial isolates to fosfomycin determined by agar dilution and disk diffusion methods. AB - We studied the antimicrobial activity of fosfomycin against 960 strains of commonly encountered bacteria associated with urinary tract infection using standard agar dilution and disk diffusion methods. Species studied included 3 common species of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia; methicillin-susceptible and resistant Staphylococcus aureus; and vancomycin-susceptible and resistant Enterococcus faecalis and E. faecium. MICs and inhibition zone diameters were interpreted in accordance with both the currently recommended Clinical and Laboratory Standards Institute (CLSI) criteria for urinary tract isolates of Escherichia coli and Enterococcus faecalis and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria for Enterobacteriaceae. Tentative zone diameter interpretive criteria were developed for species not currently published by CLSI or EUCAST. Escherichia coli was uniformly susceptible to fosfomycin, as were most strains of Klebsiella pneumoniae and Enterobacter cloacae. A. baumannii was resistant to fosfomycin, while the prevalence of resistance in P. aeruginosa and S. maltophilia was greatly affected by the choice of MIC breakpoint. New tentative zone diameter criteria for K. pneumoniae, E. cloacae, S. aureus, and E. faecium were able to be set, providing some interim laboratory guidance for disk diffusion until further breakpoint evaluations are undertaken by CLSI and EUCAST. PMID- 21670186 TI - Investigation of the efficacy of micafungin in the treatment of histoplasmosis using two North American strains of Histoplasma capsulatum. AB - Micafungin alone and combined with liposomal amphotericin B was evaluated against two strains of Histoplasma capsulatum. Micafungin was active in vitro against the mold but not the yeast form but was ineffective in vivo. Micafungin appears to be ineffective in treatment of histoplasmosis. PMID- 21670187 TI - In vitro echinocandin susceptibility of Aspergillus isolates from patients enrolled in the Transplant-Associated Infection Surveillance Network. AB - We determined the echinocandin minimum effective concentration (MEC) values for caspofungin, micafungin, and anidulafungin against 288 Aspergillus isolates prospectively collected from transplant patients with proven or probable invasive aspergillosis between 2001 and 2006 as part of the Transplant-Associated Infection Surveillance Network (TRANSNET). We demonstrated that the vast majority of Aspergillus isolates had MEC values at or below the epidemiological cutoff values for caspofungin, micafungin, and anidulafungin, including those from patients who had received caspofungin. PMID- 21670188 TI - Pharmacokinetics and diffusion into sputum of oseltamivir and oseltamivir carboxylate in adults with cystic fibrosis. AB - Oseltamivir is a prodrug of oseltamivir carboxylate (OC), a neuraminidase inhibitor used for treatment and prevention of influenza. The pharmacokinetics of these 2 compounds were investigated after a single 75-mg oseltamivir dose in 6 patients with cystic fibrosis (CF). Means +/- standard deviations of the area under the curve from time zero to infinity (AUC) were 173 +/- 58 MUg . h/liter for oseltamivir and 2,256 +/- 394 MUg . h/liter for OC. The concentrations of OC in sputum 4 to 6 h and 22 to 26 h after the intake ranged from 4.1 to 62.2 MUg/liter. The AUC of OC was approximately 30% lower than and significantly different from published values for volunteers. On the basis of the present results and because the anti-A/H1N1 influenza virus efficacy of OC is related to its AUC/50% effective concentration (EC(50)) ratio, an increase in the oseltamivir unitary dose could be considered for the treatment of influenza in CF patients. This should nevertheless be confirmed by a controlled pharmacokinetic study performed on a larger number of patients. PMID- 21670189 TI - Simplified estimation of aminoglycoside pharmacokinetics in underweight and obese adult patients. AB - Aminoglycosides are an important class of agents that are used in combination antimicrobial regimens to treat bacterial pathogens. Dosing of aminoglycosides is typically based on total body weight. However, the most appropriate alternative body size descriptor for dosing aminoglycosides at the extremes of weight (underweight and obese) is not known. Also, the predictive performance of newer formulas to assess kidney function, such as the modification of diet in renal disease (MDRD) and chronic kidney disease-epidemiology (CKD-EPI) equations compared to the Cockcroft-Gault equation to predict aminoglycoside clearance, is not known. We sought to examine dosing of aminoglycosides across the extremes of weight using a variety of formulas to assess kidney function. Pharmacokinetic data were obtained from a set of prospectively collected data (1982 to 2003) of 2,073 (53.5% male) adult patients that included 497 tobramycin- and 1,576 gentamicin-treated cases. The median (minimum, maximum) age, weight, and body mass index were 66 (18, 98) years, 70.0 (29.7, 206.7) kg, and 24.4 (11.3, 73.8) kg/m(2), respectively. The percentage of underweight, normal-weight, overweight, and obese cases based on the World Health Organization classification were 8.8%, 45.5%, 26.5%, and 19.2%, respectively. The aminoglycoside volume of distribution was normalized to several alternative body size descriptors. Only lean body weight estimated by the method of S. Janmahasatian et al. (Clin. Pharmacokinet. 44:1051-1065, 2005) normalized the volume of distribution for both tobramycin and gentamicin across all weight strata, with the estimate being approximately 0.45 liter/kg. Aminoglycoside dosing can be simplified across all weight strata with the use of lean body weight. The CKD-EPI equation best predicts aminoglycoside clearance. PMID- 21670190 TI - Sequence type ST405 Escherichia coli isolate producing QepA1, CTX-M-15, and RmtB from Detroit, Michigan. PMID- 21670191 TI - Refining vancomycin protein binding estimates: identification of clinical factors that influence protein binding. AB - While current data indicate only free (unbound) drug is pharmacologically active and is most predictive of response, pharmacodynamic studies of vancomycin have been limited to measurement of total concentrations. The protein binding of vancomycin is thought to be approximately 50%, but considerable variability surrounds this estimate. The present study sought to determine the extent of vancomycin protein binding, to identify factors that modulate its binding, and to create and validate a prediction tool to estimate the extent of protein binding based on individual clinical factors. This single-site prospective cohort study included hospitalized adult patients treated with vancomycin and with a vancomycin serum concentration determination available. Linear regression was used to predict the free vancomycin concentration (f[vanco]) and to determine the clinical factors modulating vancomycin protein binding. Among the 50 patients in the study, the mean protein binding was 41.5%. The strongest predictor of f[vanco] was the total vancomycin concentration (total [vanco]), and this was modified by dialysis and total protein of >=6.7 g/dl as covariates. The algebraic expression from the final prediction model was f[vanco] = 0.643 + 0.560 * total [vanco] - {0.067 * total [vanco] * D} - {0.071 * total [vanco] * TP} where D = 1 if dialysis dependent or 0 if not dialysis dependent, and TP = 1 if total protein is >=6.7 g/dl or 0 if total protein is <6.7 g/dl. The R(2) of the final prediction model was 0.959 (P < 0.001). Validation of our model was performed in 13 patients, and the predictive performance was highly favorable (R(2) was 0.9, and bias and precision were 0.18 and 0.18, respectively). Prediction models such as ours can be utilized in future pharmacokinetics and pharmacodynamics studies evaluating the exposure-response profile and to determine the pharmacodynamic target of interest as it relates to the free concentration. PMID- 21670192 TI - Susceptibility of Klebsiella pneumoniae isolates from intra-abdominal infections and molecular characterization of ertapenem-resistant isolates. AB - A total of 2,841 clinical isolates of Klebsiella pneumoniae from intra-abdominal infections worldwide were collected in the Study for Monitoring Antimicrobial Resistance Trends (SMART) during 2008 and 2009. Overall, 22.4% of isolates had extended-spectrum beta-lactamases (ESBLs). The most active antibiotics among the 11 tested were imipenem, amikacin, and ertapenem, though even these, like all other comparators, were less consistently active against ESBL-positive isolates than against ESBL-negative isolates. Globally, 6.5% of isolates were ertapenem resistant based on the June 2010 clinical breakpoints published by the Clinical and Laboratory Standards Institute, with MICs of >=1 MUg/ml. Molecular characterization of 43 isolates with ertapenem MICs of >=4 MUg/ml showed that they variously produced CTX-M or SHV ESBLs combined with altered impermeability and/or had KPC (n = 28), OXA-48 (n = 3), or VIM (n = 1) carbapenemases. Further monitoring of ertapenem susceptibility and molecular characterization of ertapenem-resistant isolates are needed. PMID- 21670193 TI - Development of chronic and acute golden Syrian hamster infection models with Leptospira borgpetersenii serovar Hardjo. AB - The golden Syrian hamster (Mesocricetus auratus) is frequently used as a model to study virulence for several Leptospira species. Onset of an acute lethal infection following inoculation with several pathogenic Leptospira species has been widely adopted for pathogenesis studies. An important exception is the outcome following inoculation of hamsters with live L. borgpetersenii serovar Hardjo, the primary cause of bovine leptospirosis and a cause of human infections. Typically, inoculation of hamsters with L. borgpetersenii serovar Hardjo fails to induce clinical signs of infection. In this study, the authors defined LD(50) and ID(50) for 2 strains of L. borgpetersenii serovar Hardjo: JB197 and 203. Both strains infected hamsters with ID(50) values of approximately 1.5 * 10(2) bacteria yet differed in tissue invasion and interaction with leukocytes, resulting in widely divergent clinical outcomes. Hamsters infected with strain 203 established renal colonization within 4 days postinfection and remained asymptomatic with chronic renal infections similar to cattle infected with serovar Hardjo. In contrast, hamsters infected with strain JB197 developed a rapidly debilitating disease typical of acute leptospirosis common in accidental hosts (eg, humans) with an LD(50) of 3.6 * 10(4) bacteria. Evidence that strain JB197 resides in both extracellular and intracellular environments during hamster infection was obtained. Development of models that result in chronic and acute forms of leptospirosis provides a platform to study L. borgpetersenii pathogenesis and to test vaccines for the prevention of leptospirosis. PMID- 21670194 TI - A retrospective study of those histopathologic parameters predictive of invasion of the lymphatic system by canine mammary carcinomas. AB - The aim of the present study was to determine which histopathologic parameters of primary canine mammary carcinomas (CMCs) could predict metastatic spread via the lymphatic system. A modification of the World Health Organization classification was applied to 245 CMCs. In addition to tumor subtype, neoplastic infiltration of the surrounding mammary stroma, vasculogenic mimicry, and micropapillary pattern were evaluated, and 2 histologic grading systems were used for each sample. A statistical analysis was undertaken to determine the relationship between these histopathologic parameters and the detection of lymphatic vessels invasion (LVI) and regional lymph node metastases (RLM). To compare the predictive value for lymphatic spread of the 2 histologic grading systems, the Akaike information criterion was measured. The classification into tumor subtypes was significant (P < .01) in predicting the risk of LVI and RLM. Peripheral infiltration, vasculogenic mimicry, and micropapillary pattern were found in 170 of 245 (69.4%), 32 of 245 (13.1%), and 54 of 245 (22.0%) CMCs. The presence of peripheral infiltration was significantly associated (P < .001) with both LVI and RLM, and a similar relation (P < .05) was found for the micropapillary pattern. Vasculogenic mimicry was not predictive of invasion of the lymphatic system. Both histologic grading systems were significant predictors (P < .001) of the risk of LVI and RLM. The grading system that included a more rigorous evaluation of the neoplastic mitotic activity had the lower Akaike information criterion values, thus indicating a better predictive ability. The study confirms the significant prognostic role for the modified World Health Organization classification of CMCs and the prognostic value of additional histopathologic parameters. PMID- 21670195 TI - Necropsy or autopsy? It's all about communication! PMID- 21670196 TI - Hematologic changes after total body irradiation and autologous transplantation of hematopoietic peripheral blood progenitor cells in dogs with lymphoma. AB - Dogs with and without lymphoma have undergone hematopoietic cell transplantation in a research setting for decades. North Carolina State University is currently treating dogs with B- and T-cell lymphoma in a clinical setting with autologous peripheral blood progenitor cell transplants, using peripheral blood CD34+ progenitor cells harvested using an apheresis machine. Complete blood counts were performed daily for 15 to 19 days posttransplantation to monitor peripheral blood cell nadirs and subsequent CD34+ cell engraftment. This study documents the hematologic toxicities of total body irradiation in 10 dogs and the subsequent recovery of the affected cell lines after peripheral blood progenitor cell transplant, indicating successful CD34+ engraftment. All peripheral blood cell lines, excluding red blood cells, experienced grade 4 toxicities. All dogs had >= 500 neutrophils/MUl by day 12, while thrombocytopenia persisted for many weeks. All dogs were clinically normal at discharge. PMID- 21670197 TI - Aquaporins at a glance. PMID- 21670199 TI - Drosophila 14-3-3epsilon has a crucial role in anti-microbial peptide secretion and innate immunity. AB - The secretion of anti-microbial peptides is recognised as an essential step in innate immunity, but there is limited knowledge of the molecular mechanism controlling the release of these effectors from immune response cells. Here, we report that Drosophila 14-3-3epsilon mutants exhibit reduced survival when infected with either Gram-positive or Gram-negative bacteria, indicating a functional role for 14-3-3epsilon in innate immunity. In 14-3-3epsilon mutants, there was a reduced release of the anti-microbial peptide Drosomycin into the haemolymph, which correlated with an accumulation of Drosomycin-containing vesicles near the plasma membrane of cells isolated from immune response tissues. Drosomycin appeared to be delivered towards the plasma membrane in Rab4- and Rab11-positive vesicles and smaller Rab11-positive vesicles. RNAi silencing of Rab11 and Rab4 significantly blocked the anterograde delivery of Drosomycin from the perinuclear region to the plasma membrane. However, in 14-3-3epsilon mutants there was an accumulation of small Rab11-positive vesicles near the plasma membrane. This vesicular phenotype was similar to that observed in response to the depletion of the vesicular Syntaxin protein Syx1a. In wild-type Drosophila immune tissue, 14-3-3epsilon was detected adjacent to Rab11, and partially overlapping with Syx1a, on vesicles near the plasma membrane. We conclude that 14 3-3epsilon is required for Rab11-positive vesicle function, which in turn enables antimicrobial peptide secretion during an innate immune response. PMID- 21670198 TI - Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. AB - We have shown previously that distinct Mena isoforms are expressed in invasive and migratory tumor cells in vivo and that the invasion isoform (Mena(INV)) potentiates carcinoma cell metastasis in murine models of breast cancer. However, the specific step of metastatic progression affected by this isoform and the effects on metastasis of the Mena11a isoform, expressed in primary tumor cells, are largely unknown. Here, we provide evidence that elevated Mena(INV) increases coordinated streaming motility, and enhances transendothelial migration and intravasation of tumor cells. We demonstrate that promotion of these early stages of metastasis by Mena(INV) is dependent on a macrophage-tumor cell paracrine loop. Our studies also show that increased Mena11a expression correlates with decreased expression of colony-stimulating factor 1 and a dramatically decreased ability to participate in paracrine-mediated invasion and intravasation. Our results illustrate the importance of paracrine-mediated cell streaming and intravasation on tumor cell dissemination, and demonstrate that the relative abundance of Mena(INV) and Mena11a helps to regulate these key stages of metastatic progression in breast cancer cells. PMID- 21670200 TI - Proteolytically cleaved MLL subunits are susceptible to distinct degradation pathways. AB - The mixed lineage leukemia (MLL) proto-oncogenic protein is a histone-lysine N methyltransferase that is produced by proteolytic cleavage and self-association of the respective functionally distinct subunits (MLL(N) and MLL(C)) to form a holocomplex involved in epigenetic transcriptional regulation. On the basis of studies in Drosophila it has been suggested that the separated subunits might also have distinct functions. In this study, we used a genetically engineered mouse line that lacked MLL(C) to show that the MLL(N)-MLL(C) holocomplex is responsible for MLL functions in various developmental processes. The stability of MLL(N) is dependent on its intramolecular interaction with MLL(C), which is mediated through the first and fourth plant homeodomain (PHD) fingers (PHD1 and PHD4) and the phenylalanine/tyrosine-rich (FYRN) domain of MLL(N). Free MLL(N) is destroyed by a mechanism that targets the FYRN domain, whereas free MLL(C) is exported to the cytoplasm and degraded by the proteasome. PHD1 is encoded by an alternatively spliced exon that is occasionally deleted in T-cell leukemia, and its absence produces an MLL mutant protein that is deficient for holocomplex formation. Therefore, this should be a loss-of-function mutant allele, suggesting that the known tumor suppression role of MLL may also apply to the T-cell lineage. Our data demonstrate that the dissociated MLL subunits are subjected to distinct degradation pathways and thus not likely to have separate functions unless the degradation mechanisms are inhibited. PMID- 21670201 TI - Wnt controls the transcriptional activity of Kaiso through CK1epsilon-dependent phosphorylation of p120-catenin. AB - p120-catenin is an E-cadherin-associated protein that modulates E-cadherin function and stability. In response to Wnt3a, p120-catenin is phosphorylated at Ser268 and Ser269, disrupting its interaction with E-cadherin. Here, we describe that Wnt-induced p120-catenin phosphorylation at Ser268 and Ser269 also enhances its binding to the transcriptional factor Kaiso, preventing Kaiso-mediated inhibition of the beta-catenin-Tcf-4 transcriptional complex. Kaiso-mediated repression of this complex is due to its association not only with Tcf-4 but also with beta-catenin. Disruption of Tcf-4-Kaiso and beta-catenin-Kaiso interactions by p120-catenin not only releases Tcf-4 and beta-catenin enabling its mutual association and the formation of the transcriptional complex but also permits Kaiso binding to methylated CpG islands, an interaction that is weakly inhibited by p120-catenin. Consequently, Wnt stimulates Kaiso association to the CDKN2A promoter, which contains CpG sequences, in cells where these sequences are extensively methylated, such as HT-29 M6, an effect accompanied by decreased expression of its gene product. These results indicate that, when released from E cadherin by Wnt3a-stimulated phosphorylation, p120-catenin controls the activity of the Kaiso transcriptional factor, enhancing its binding to repressed promoters and relieving its inhibition of the beta-catenin-Tcf-4 transcriptional complex. PMID- 21670202 TI - Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. AB - The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains <20 clonally represented gene alterations/case, including predominantly nonsilent mutations, and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. Although most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance. PMID- 21670204 TI - ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18. AB - The ROP18 kinase has been identified as a key virulence determinant conferring a high mortality phenotype characteristic of type I Toxoplasma gondii strains. This major effector molecule is secreted by the rhoptries into the host cells during invasion; however, the molecular mechanisms by which this kinase exerts its pathogenic action remain poorly understood. In this study, we show that ROP18 targets the host endoplasmic reticulum-bound transcription factor ATF6beta. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6beta-dependent pathogenicity by interacting with ATF6beta and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6beta and for parasite virulence. Consistent with a key role for ATF6beta in resistance against this intracellular pathogen, ATF6beta-deficient mice exhibit a high susceptibility to infection by ROP18-deficient parasites. The results reveal that interference with ATF6beta dependent immune responses is a novel pathogenic mechanism induced by ROP18. PMID- 21670203 TI - Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth. AB - Regulatory T cells (T reg cells) are characterized by the expression of the forkhead lineage-specific transcription factor Foxp3, and their main function is to suppress T cells. While evaluating T reg cells, we identified a population of Foxp3-positive cells that were CD11b(+)F4/80(+)CD68(+), indicating macrophage origin. These cells were observed in spleen, lymph nodes, bone marrow, thymus, liver, and other tissues of naive animals. To characterize this subpopulation of macrophages, we devised a strategy to purify CD11b(+)F4/80(+)Foxp3(+) macrophages using Foxp3-GFP mice. Analysis of CD11b(+)F4/80(+)Foxp3(+) macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3( ) macrophages did not. Suppression of T cell proliferation was mediated through soluble factors. Foxp3(-) macrophages acquired Foxp3 expression after activation, which conferred inhibitory properties that were indistinguishable from natural Foxp3(+) macrophages. The cytokine and transcriptional profiles of Foxp3(+) macrophages were distinct from those of Foxp3(-) macrophages, indicating that these cells have different biological functions. Functional in vivo analyses indicated that CD11b(+)F4/80(+)Foxp3(+) macrophages are important in tumor promotion and the induction of T reg cell conversion. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells in which expression of Foxp3 correlates with suppressive function. PMID- 21670205 TI - Relationships between resting conductances, excitability, and t-system ionic homeostasis in skeletal muscle. AB - Activation of skeletal muscle fibers requires rapid sarcolemmal action potential (AP) conduction to ensure uniform excitation along the fiber length, as well as successful tubular excitation to initiate excitation-contraction coupling. In our companion paper in this issue, Pedersen et al. (2011. J. Gen. Physiol. doi:10.1085/jgp.201010510) quantify, for subthreshold stimuli, the influence upon both surface conduction velocity and tubular (t)-system excitation of the large changes in resting membrane conductance (G(M)) that occur during repetitive AP firing. The present work extends the analysis by developing a multi-compartment modification of the charge-difference model of Fraser and Huang to provide a quantitative description of the conduction velocity of actively propagated APs; the influence of voltage-gated ion channels within the t-system; the influence of t-system APs on ionic homeostasis within the t-system; the influence of t-system ion concentration changes on membrane potentials; and the influence of Phase I and Phase II G(M) changes on these relationships. Passive conduction properties of the novel model agreed with established linear circuit analysis and previous experimental results, while key simulations of AP firing were tested against focused experimental microelectrode measurements of membrane potential. This study thereby first quantified the effects of the t-system luminal resistance and voltage-gated Na(+) channel density on surface AP propagation and the resultant electrical response of the t-system. Second, it demonstrated the influence of G(M) changes during repetitive AP firing upon surface and t-system excitability. Third, it showed that significant K(+) accumulation occurs within the t-system during repetitive AP firing and produces a baseline depolarization of the surface membrane potential. Finally, it indicated that G(M) changes during repetitive AP firing significantly influence both t-system K(+) accumulation and its influence on the resting membrane potential. Thus, the present study emerges with a quantitative description of the changes in membrane potential, excitability, and t-system ionic homeostasis that occur during repetitive AP firing in skeletal muscle. PMID- 21670206 TI - Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors. AB - The voltage-activated sodium (Nav) channel Nav1.9 is expressed in dorsal root ganglion (DRG) neurons where it is believed to play an important role in nociception. Progress in revealing the functional properties and pharmacological sensitivities of this non-canonical Nav channel has been slow because attempts to express this channel in a heterologous expression system have been unsuccessful. Here, we use a protein engineering approach to dissect the contributions of the four Nav1.9 voltage sensors to channel function and pharmacology. We define individual S3b-S4 paddle motifs within each voltage sensor, and show that they can sense changes in membrane voltage and drive voltage sensor activation when transplanted into voltage-activated potassium channels. We also find that the paddle motifs in Nav1.9 are targeted by animal toxins, and that these toxins alter Nav1.9-mediated currents in DRG neurons. Our results demonstrate that slowly activating and inactivating Nav1.9 channels have functional and pharmacological properties in common with canonical Nav channels, but also show distinctive pharmacological sensitivities that can potentially be exploited for developing novel treatments for pain. PMID- 21670207 TI - The pathway and spatial scale for MscS inactivation. AB - The mechanosensitive channel of small conductance (MscS) is a bacterial tension driven osmolyte release valve with homologues in many walled eukaryotic organisms. When stimulated by steps of tension in excised patches, Escherichia coli MscS exhibits transient opening followed by reversible adaptation and then complete inactivation. Here, we study properties of the inactivation transition, which renders MscS nonconductive and tension insensitive. Using special pressure protocols we demonstrate that adaptation and inactivation are sequential processes with opposite tension dependencies. In contrast to many eukaryotic channels, which inactivate from the open state, MscS inactivates primarily from the closed state because full openings by preconditioning pulses do not influence the degree of inactivation, and saturating tensions keeping channels open prevent inactivation. The easily opened A98S mutant lacks inactivation completely, whereas the L111S mutant with a right-shifted activation curve inactivates silently before reaching the threshold for opening. This suggests that opening and inactivation are two independent tension-driven pathways, both starting from the closed state. Analysis of tension dependencies for inactivation and recovery rates estimated the in-plane expansion (DeltaA) associated with inactivation as 8.5 nm(2), which is about half of the area change for opening. Given that the interhelical contact between the outer TM1-TM2 pairs and the core TM3s is the force-transmitting path from the periphery to the gate, the determined DeltaA now can be used as a constraining parameter for the models of the inactivated state in which the lipid-facing TM1-TM2 pairs are displaced and uncoupled from the gate. PMID- 21670208 TI - An analysis of the relationships between subthreshold electrical properties and excitability in skeletal muscle. AB - Skeletal muscle activation requires action potential (AP) initiation followed by its sarcolemmal propagation and tubular excitation to trigger Ca(2+) release and contraction. Recent studies demonstrate that ion channels underlying the resting membrane conductance (G(M)) of fast-twitch mammalian muscle fibers are highly regulated during muscle activity. Thus, onset of activity reduces G(M), whereas prolonged activity can markedly elevate G(M). Although these observations implicate G(M) regulation in control of muscle excitability, classical theoretical studies in un-myelinated axons predict little influence of G(M) on membrane excitability. However, surface membrane morphologies differ markedly between un-myelinated axons and muscle fibers, predominantly because of the tubular (t)-system of muscle fibers. This study develops a linear circuit model of mammalian muscle fiber and uses this to assess the role of subthreshold electrical properties, including G(M) changes during muscle activity, for AP initiation, AP propagation, and t-system excitation. Experimental observations of frequency-dependent length constant and membrane-phase properties in fast-twitch rat fibers could only be replicated by models that included t-system luminal resistances. Having quantified these resistances, the resulting models showed enhanced conduction velocity of passive current flow also implicating elevated AP propagation velocity. Furthermore, the resistances filter passive currents such that higher frequency current components would determine sarcolemma AP conduction velocity, whereas lower frequency components excite t-system APs. Because G(M) modulation affects only the low-frequency membrane impedance, the G(M) changes in active muscle would predominantly affect neuromuscular transmission and low frequency t-system excitation while exerting little influence on the high frequency process of sarcolemmal AP propagation. This physiological role of G(M) regulation was increased by high Cl(-) permeability, as in muscle endplate regions, and by increased extracellular [K(+)], as observed in working muscle. Thus, reduced G(M) at the onset of exercise would enhance t-system excitation and neuromuscular transmission, whereas elevated G(M) after sustained activity would inhibit these processes and thereby accentuate muscle fatigue. PMID- 21670209 TI - David Bilder: Getting to know epithelia inside and out. Interviewed by Caitlin Sedwick. PMID- 21670210 TI - Septin pairs, a complex choreography. AB - Septins form a filamentous collar at the mother-bud neck in budding yeast. In cytokinesis, this collar splits into two rings and the septin complexes undergo a dramatic reorientation. Using fluorescence polarization microscopy, DeMay et al. (2011. J. Cell Biol. doi:10.1083/jcb.201012143) now demonstrate that septin complexes assemble as paired filaments in vivo and reveal new insights into septin organization during cytokinesis. PMID- 21670211 TI - Evolution: On a bender--BARs, ESCRTs, COPs, and finally getting your coat. AB - Tremendous variety in form and function is displayed among the intracellular membrane systems of different eukaryotes. Until recently, few clues existed as to how these internal membrane systems had originated and diversified. However, proteomic, structural, and comparative genomics studies together have revealed extensive similarities among many of the protein complexes used in controlling the morphology and trafficking of intracellular membranes. These new insights have had a profound impact on our understanding of the evolutionary origins of the internal architecture of the eukaryotic cell. PMID- 21670212 TI - PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth. AB - The induction of neurite outgrowth and arborization is critical for developmental and regenerative processes. In this paper, we report that the BTB-kelch protein KLHL20 promoted neurite outgrowth and arborization in hippocampal and cortical neurons through its interaction with Cullin3 to form a ubiquitin ligase complex. This complex targeted PDZ-Rho guanine nucleotide exchange factor (RhoGEF), a protein abundantly expressed in the brain, for ubiquitin-dependent proteolysis, thereby restricting RhoA activity and facilitating growth cone spreading and neurite outgrowth. Importantly, targeting PDZ-RhoGEF to KLHL20 required PDZ RhoGEF phosphorylation by p38 mitogen-activated protein kinase. In response to p38-activating neurotrophins, such as brain-derived neurotrophic factor and neurotrophin-3, KLHL20-mediated PDZ-RhoGEF destruction was potentiated, leading to neurotrophin-induced neurite outgrowth. Our study identified a ubiquitin dependent pathway that targets PDZ-RhoGEF destruction to facilitate neurite outgrowth and indicates a key role of this pathway in neurotrophin-induced neuronal morphogenesis. PMID- 21670213 TI - The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity. AB - Cyclic adenosine monophosphate (cAMP) is a second messenger that relays a wide range of hormone responses. In this paper, we demonstrate that the nuclear pore component RanBP2 acts as a negative regulator of cAMP signaling through Epac1, a cAMP-regulated guanine nucleotide exchange factor for Rap. We show that Epac1 directly interacts with the zinc fingers (ZNFs) of RanBP2, tethering Epac1 to the nuclear pore complex (NPC). RanBP2 inhibits the catalytic activity of Epac1 in vitro by binding to its catalytic CDC25 homology domain. Accordingly, cellular depletion of RanBP2 releases Epac1 from the NPC and enhances cAMP-induced Rap activation and cell adhesion. Epac1 also is released upon phosphorylation of the ZNFs of RanBP2, demonstrating that the interaction can be regulated by posttranslational modification. These results reveal a novel mechanism of Epac1 regulation and elucidate an unexpected link between the NPC and cAMP signaling. PMID- 21670214 TI - Aurora A kinase activity influences calcium signaling in kidney cells. AB - Most studies of Aurora A (AurA) describe it as a mitotic centrosomal kinase. However, we and others have recently identified AurA functions as diverse as control of ciliary resorption, cell differentiation, and cell polarity control in interphase cells. In these activities, AurA is transiently activated by noncanonical signals, including Ca(2+)-dependent calmodulin binding. These and other observations suggested that AurA might be involved in pathological conditions, such as polycystic kidney disease (PKD). In this paper, we show that AurA is abundant in normal kidney tissue but is also abnormally expressed and activated in cells lining PKD-associated renal cysts. PKD arises from mutations in the PKD1 or PKD2 genes, encoding polycystins 1 and 2 (PC1 and PC2). AurA binds, phosphorylates, and reduces the activity of PC2, a Ca(2+)-permeable nonselective cation channel and, thus, limits the amplitude of Ca(2+) release from the endoplasmic reticulum. These and other findings suggest AurA may be a relevant new biomarker or target in the therapy of PKD. PMID- 21670215 TI - The cortical protein Lte1 promotes mitotic exit by inhibiting the spindle position checkpoint kinase Kin4. AB - The spindle position checkpoint (SPOC) is an essential surveillance mechanism that allows mitotic exit only when the spindle is correctly oriented along the cell axis. Key SPOC components are the kinase Kin4 and the Bub2-Bfa1 GAP complex that inhibit the mitotic exit-promoting GTPase Tem1. During an unperturbed cell cycle, Kin4 associates with the mother spindle pole body (mSPB), whereas Bub2 Bfa1 is at the daughter SPB (dSPB). When the spindle is mispositioned, Bub2-Bfa1 and Kin4 bind to both SPBs, which enables Kin4 to phosphorylate Bfa1 and thereby block mitotic exit. Here, we show that the daughter cell protein Lte1 physically interacts with Kin4 and inhibits Kin4 kinase activity. Specifically, Lte1 binds to catalytically active Kin4 and promotes Kin4 hyperphosphorylation, which restricts Kin4 binding to the mSPB. This Lte1-mediated exclusion of Kin4 from the dSPB is essential for proper mitotic exit of cells with a correctly aligned spindle. Therefore, Lte1 promotes mitotic exit by inhibiting Kin4 activity at the dSPB. PMID- 21670216 TI - Septin filaments exhibit a dynamic, paired organization that is conserved from yeast to mammals. AB - The septins are conserved, GTP-binding proteins important for cytokinesis, membrane compartmentalization, and exocytosis. However, it is unknown how septins are arranged within higher-order structures in cells. To determine the organization of septins in live cells, we developed a polarized fluorescence microscopy system to monitor the orientation of GFP dipole moments with high spatial and temporal resolution. When GFP was fused to septins, the arrangement of GFP dipoles reflected the underlying septin organization. We demonstrated in a filamentous fungus, a budding yeast, and a mammalian epithelial cell line that septin proteins were organized in an identical highly ordered fashion. Fluorescence anisotropy measurements indicated that septin filaments organized into pairs within live cells, just as has been observed in vitro. Additional support for the formation of pairs came from the observation of paired filaments at the cortex of cells using electron microscopy. Furthermore, we found that highly ordered septin structures exchanged subunits and rapidly rearranged. We conclude that septins assemble into dynamic, paired filaments in vivo and that this organization is conserved from yeast to mammals. PMID- 21670219 TI - Disposition and metabolism of ticagrelor, a novel P2Y12 receptor antagonist, in mice, rats, and marmosets. AB - Ticagrelor is a reversibly binding and selective oral P2Y(12) antagonist, developed for the prevention of atherothrombotic events in patients with acute coronary syndromes. The disposition and metabolism of [(14)C]ticagrelor was investigated in mice, rats, and marmosets to demonstrate that these preclinical toxicity species showed similar metabolic profiles to human. Incubations with hepatocytes or microsomes from multiple species were also studied to compare with in vivo metabolic profiles. The routes of excretion were similar for both oral and intravenous administration in mice, rats, and marmosets with fecal excretion being the major elimination pathway accounting for 59 to 96% of the total radioactivity administered. Urinary excretion of drug-related material accounted for only 1 to 15% of the total radioactivity administered. Milk samples from lactating rats displayed significantly higher levels of total radioactivity than plasma after oral administration of ticagrelor. This demonstrated that ticagrelor and/or its metabolites were readily transferred into rat milk and that neonatal rats could be exposed to ticagrelor-related compounds via maternal milk. Ticagrelor and active metabolite AR-C124910 (loss of hydroxyethyl side chain) were the major components in plasma from all species studied and similar to human plasma profiles. The primary metabolite of ticagrelor excreted in urine across all species was an inactive metabolite, AR-C133913 (loss of difluorophenylcyclopropyl group). Ticagrelor, AR-C124910, and AR-C133913 were the major components found in feces from the three species examined. Overall, in vivo metabolite profiles were qualitatively similar across all species and consistent with in vitro results. PMID- 21670218 TI - Type XII collagen regulates osteoblast polarity and communication during bone formation. AB - Differentiated osteoblasts are polarized in regions of bone deposition, demonstrate extensive cell interaction and communication, and are responsible for bone formation and quality. Type XII collagen is a fibril-associated collagen with interrupted triple helices and has been implicated in the osteoblast response to mechanical forces. Type XII collagen is expressed by osteoblasts and localizes to areas of bone formation. A transgenic mouse null for type XII collagen exhibits skeletal abnormalities including shorter, more slender long bones with decreased mechanical strength as well as altered vertebrae structure compared with wild-type mice. Col12a(-/-) osteoblasts have decreased bone matrix deposition with delayed maturation indicated by decreased bone matrix protein expression. Compared with controls, Col12a(-/-) osteoblasts are disorganized and less polarized with disrupted cell-cell interactions, decreased connexin43 expression, and impaired gap junction function. The data demonstrate important regulatory roles for type XII collagen in osteoblast differentiation and bone matrix formation. PMID- 21670217 TI - Cbp3-Cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly. AB - Mitochondria contain their own genetic system to express a small number of hydrophobic polypeptides, including cytochrome b, an essential subunit of the bc(1) complex of the respiratory chain. In this paper, we show in yeast that Cbp3, a bc(1) complex assembly factor, and Cbp6, a regulator of cytochrome b translation, form a complex that associates with the polypeptide tunnel exit of mitochondrial ribosomes and that exhibits two important functions in the biogenesis of cytochrome b. On the one hand, the interaction of Cbp3 and Cbp6 with mitochondrial ribosomes is necessary for efficient translation of cytochrome b transcript [corrected]. On the other hand, the Cbp3-Cbp6 complex interacts directly with newly synthesized cytochrome b in an assembly intermediate that is not ribosome bound and that contains the assembly factor Cbp4. Our results suggest that synthesis of cytochrome b occurs preferentially on those ribosomes that have the Cbp3-Cbp6 complex bound to their tunnel exit, an arrangement that may ensure tight coordination of cytochrome b synthesis and assembly. PMID- 21670220 TI - Maintaining close relationships: gratitude as a motivator and a detector of maintenance behavior. AB - This research examined the dual function of gratitude for relationship maintenance in close relationships. In a longitudinal study among married couples, the authors tested the dyadic effects of gratitude over three time points for approximately 4 years following marriage. They found that feelings of gratitude toward a partner stem from the partner's relationship maintenance behaviors, partly because such behaviors create the perception of responsiveness to one's needs. In turn, gratitude motivates partners to engage in relationship maintenance. Hence, the present model emphasizes that gratitude between close partners (a) originates from partners' relationship maintenance behaviors and the perception of a partner's responsiveness and (b) promotes a partner's reciprocal maintenance behaviors. Thus, the authors' findings add credence to their model, in that gratitude contributes to a reciprocal process of relationship maintenance, whereby each partner's maintenance behaviors, perceptions of responsiveness, and feelings of gratitude feed back on and influence the other's behaviors, perceptions, and feelings. PMID- 21670221 TI - The role of sensory fiber demography in trigeminal and postherpetic neuralgias. AB - In this study, we systematically investigated fiber demography, based on function and distribution, from the periphery to their destinations in the various central (sub) nuclei in the trigeminal brainstem nuclear sensory complex. Conventional and novel compelling information is provided, demonstrating that the ratio and somatotopy of types A and C sensory fibers at the site of a lesion can elucidate important puzzles in TNP disorders. For instance, we explain how of a major shift in the fibers' direction and ratio at the level of the trigeminal root entry zone (REZ) influences the pathophysiology of pre- and typical trigeminal neuralgia. As a result, there is a high A/C ratio of oral and peri-oral fibers in the supero medial region of the REZ, which is mostly susceptible to vascular compression. However, this A/C ratio varies considerably at lower proportions in other areas along the peripheral trigeminal pathway, where an injury (viral, vessel compression, or trauma) can lead to a broader spectrum of fiber involvement and, consequently, pain outcome. In summary, we explain how fiber demography can influence pain quality, location, temporal features, progress, and treatment prognosis of TNP in those patients who develop it. PMID- 21670222 TI - Proline accumulation is inhibitory to Arabidopsis seedlings during heat stress. AB - The effect of proline (Pro) accumulation on heat sensitivity was investigated using transgenic Arabidopsis (Arabidopsis thaliana) plants ectopically expressing the Delta(1)-pyrroline-5-carboxylate synthetase 1 gene (AtP5CS1) under the control of a heat shock protein 17.6II gene promoter. During heat stress, the heat-inducible expression of the AtP5CS1 transgene was capable of enhancing Pro biosynthesis. Twelve-day-old seedlings were first treated with heat at 37 degrees C for 24 h to induce Pro and then were stressed at 50 degrees C for 4 h. After recovery at 22 degrees C for 96 h, the growth of Pro-overproducing plants was significantly more inhibited than that of control plants that do not accumulate Pro, manifested by lower survival rate, higher ion leakage, higher reactive oxygen species (ROS) and malondialdehyde levels, and increased activity of the Pro/P5C cycle. The activities of antioxidant enzymes superoxide dismutase, guaiacol peroxidase, and catalase, but not those of glutathione reductase and ascorbate peroxidase, increased in all lines after heat treatment, but the increase was more significant in Pro-overproducing seedlings. Staining with MitoSox-Red, reported for being able to specifically detect superoxide formed in mitochondria, showed that Pro accumulation during heat stress resulted in elevated levels of ROS in mitochondria. Interestingly, exogenous abscisic acid (ABA) and ethylene were found to partially rescue the heat-sensitive phenotype of Pro-overproducing seedlings. Measurement of ethylene and ABA levels further confirmed that these two hormones are negatively affected in Pro-overproducing seedlings during heat stress. Our results indicated that Pro accumulation under heat stress decreases the thermotolerance, probably by increased ROS production via the Pro/P5C cycle and inhibition of ABA and ethylene biosynthesis. PMID- 21670223 TI - Overexpression of Arabidopsis ACBP3 enhances NPR1-dependent plant resistance to Pseudomonas syringe pv tomato DC3000. AB - ACBP3 is one of six Arabidopsis (Arabidopsis thaliana) genes, designated ACBP1 to ACBP6, that encode acyl-coenzyme A (CoA)-binding proteins (ACBPs). These ACBPs bind long-chain acyl-CoA esters and phospholipids and are involved in diverse cellular functions, including acyl-CoA homeostasis, development, and stress tolerance. Recombinant ACBP3 binds polyunsaturated acyl-CoA esters and phospholipids in vitro. Here, we show that ACBP3 plays a role in the plant defense response to the bacterial pathogen Pseudomonas syringae pv tomato DC3000. ACBP3 mRNA was up-regulated upon pathogen infection and treatments using pathogen elicitors and defense-related phytohormones. Transgenic Arabidopsis ACBP3 overexpressors (ACBP3-OEs) showed constitutive expression of pathogenesis-related genes (PR1, PR2, and PR5), cell death, and hydrogen peroxide accumulation in leaves. Consequently, ACBP3-OEs displayed enhanced resistance to the bacterial pathogen P. syringae DC3000. In contrast, the acbp3 T-DNA insertional mutant was more susceptible and exhibited lower PR gene transcript levels upon infection. Using the ACBP3 OE-1 line in combination with nonexpressor of PR genes1 (npr1-5) or coronatine-insensitive1 (coi1-2), we concluded that the enhanced PR gene expression and P. syringae DC3000 resistance in the ACBP3-OEs are dependent on the NPR1-mediated, but not the COI1-mediated, signaling pathway. Given that ACBP3 OEs showed greater susceptibility to infection by the necrotrophic fungus Botrytis cinerea while the acbp3 mutant was less susceptible, we suggest that ACBP3 plays a role in the plant defense response against biotrophic pathogens that is distinct from necrotrophic pathogens. ACBP3 function in plant defense was supported further by bioinformatics data showing up-regulation of many biotic and abiotic stress-related genes in ACBP3 OE-1 in comparison with the wild type. PMID- 21670224 TI - Altering trehalose-6-phosphate content in transgenic potato tubers affects tuber growth and alters responsiveness to hormones during sprouting. AB - Trehalose-6-phosphate (T6P) is a signaling metabolite that regulates carbon metabolism, developmental processes, and growth in plants. In Arabidopsis (Arabidopsis thaliana), T6P signaling is, at least in part, mediated through inhibition of the SNF1-related protein kinase SnRK1. To investigate the role of T6P signaling in a heterotrophic, starch-accumulating storage organ, transgenic potato (Solanum tuberosum) plants with altered T6P levels specifically in their tubers were generated. Transgenic lines with elevated T6P levels (B33-TPS, expressing Escherichia coli osmoregulatory trehalose synthesis A [OtsA], which encodes a T6P synthase) displayed reduced starch content, decreased ATP contents, and increased respiration rate diagnostic for high metabolic activity. On the other hand, lines with significantly reduced T6P (B33-TPP, expressing E. coli OtsB, which encodes a T6P phosphatase) showed accumulation of soluble carbohydrates, hexose phosphates, and ATP, no change in starch when calculated on a fresh weight basis, and a strongly reduced tuber yield. [14C]glucose feeding to transgenic tubers indicated that carbon partitioning between starch and soluble carbohydrates was not altered. Transcriptional profiling of B33-TPP tubers revealed that target genes of SnRK1 were strongly up-regulated and that T6P inhibited potato tuber SnRK1 activity in vitro. Among the SnRK1 target genes in B33-TPP tubers, those involved in the promotion of cell proliferation and growth were down-regulated, while an inhibitor of cell cycle progression was up regulated. T6P-accumulating tubers were strongly delayed in sprouting, while those with reduced T6P sprouted earlier than the wild type. Early sprouting of B33-TPP tubers correlated with a reduced abscisic acid content. Collectively, our data indicate that T6P plays an important role for potato tuber growth. PMID- 21670226 TI - ACCF/AHA/AMA-PCPI 2011 performance measures for adults with coronary artery disease and hypertension: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures and the American Medical Association-Physician Consortium for Performance Improvement. PMID- 21670227 TI - Puma deletion delays cardiac dysfunction in murine heart failure models through attenuation of apoptosis. AB - BACKGROUND: Puma (p53-upregulated modulator of apoptosis) is a proapoptotic Bcl-2 family protein that serves as a general sensor in response to pathological apoptotic stimuli. In previous work, we demonstrated that puma ablation protects the heart from reperfusion injury in a Langendorff setting. Consistent with this, downregulation of Puma in isolated cardiac myocytes prevented apoptosis induced by different proapoptotic agents. Here, we extended our research to investigate the role of Puma, a downstream mediator of p53, in the development of heart failure using Puma(-/-) mice. METHODS AND RESULTS: Mice underwent transverse aortic constriction, and the characteristics of cardiac remodeling were analyzed by echocardiography, histology, and gene expression at multiple time points after surgery. Four weeks after the operation, puma deletion attenuated pressure overload-induced apoptosis and fibrosis; however, it did not affect hypertrophy and angiogenesis and maintained functional performance (fractional shortening, 39% versus 25.2% in Puma(-/-) versus WT mice, respectively). Even at 12 weeks after transverse aortic constriction, Puma(-/-) mice displayed only slightly reduced contractility. In addition, transverse aortic constriction induced puma expression in a partially p53-dependent manner. To corroborate these findings, we studied another heart failure model in which heart-specific mdm4 deletion leads to p53 activation and dilated cardiomyopathy. In these mice, Puma was upregulated and its deletion rescued the cardiomyopathy phenotype. CONCLUSIONS: Our data indicate that Puma might be a critical component of the apoptotic signaling pathways that contribute to ventricular remodeling and heart failure. Therefore, Puma inactivation may serve as a preferential target to prevent heart failure induced by cellular stress. PMID- 21670225 TI - Light history influences the response of the marine cyanobacterium Synechococcus sp. WH7803 to oxidative stress. AB - Marine Synechococcus undergo a wide range of environmental stressors, especially high and variable irradiance, which may induce oxidative stress through the generation of reactive oxygen species (ROS). While light and ROS could act synergistically on the impairment of photosynthesis, inducing photodamage and inhibiting photosystem II repair, acclimation to high irradiance is also thought to confer resistance to other stressors. To identify the respective roles of light and ROS in the photoinhibition process and detect a possible light-driven tolerance to oxidative stress, we compared the photophysiological and transcriptomic responses of Synechococcus sp. WH7803 acclimated to low light (LL) or high light (HL) to oxidative stress, induced by hydrogen peroxide (H2O2) or methylviologen. While photosynthetic activity was much more affected in HL than in LL cells, only HL cells were able to recover growth and photosynthesis after the addition of 25 MUM H2O2. Depending upon light conditions and H2O2 concentration, the latter oxidizing agent induced photosystem II inactivation through both direct damage to the reaction centers and inhibition of its repair cycle. Although the global transcriptome response appeared similar in LL and HL cells, some processes were specifically induced in HL cells that seemingly helped them withstand oxidative stress, including enhancement of photoprotection and ROS detoxification, repair of ROS-driven damage, and regulation of redox state. Detection of putative LexA binding sites allowed the identification of the putative LexA regulon, which was down-regulated in HL compared with LL cells but up-regulated by oxidative stress under both growth irradiances. PMID- 21670228 TI - Increased adipose tissue oxygen tension in obese compared with lean men is accompanied by insulin resistance, impaired adipose tissue capillarization, and inflammation. AB - BACKGROUND: Adipose tissue (AT) dysfunction in obesity contributes to chronic, low-grade inflammation that predisposes to type 2 diabetes mellitus and cardiovascular disease. Recent in vitro studies suggest that AT hypoxia may induce inflammation. We hypothesized that adipose tissue blood flow (ATBF) regulates AT oxygen partial pressure (AT P(O2)), thereby affecting AT inflammation and insulin sensitivity. METHODS AND RESULTS: We developed an optochemical measurement system for continuous monitoring of AT P(O2) using microdialysis. The effect of alterations in ATBF on AT P(O2) was investigated in lean and obese subjects with both pharmacological and physiological approaches to manipulate ATBF. Local administration of angiotensin II (vasoconstrictor) in abdominal subcutaneous AT decreased ATBF and AT P(O2), whereas infusion of isoprenaline (vasodilator) evoked opposite effects. Ingestion of a glucose drink increased ATBF and AT P(O2) in lean subjects, but these responses were blunted in obese individuals. However, AT P(O2) was higher (hyperoxia) in obese subjects despite lower ATBF, which appears to be explained by lower AT oxygen consumption. This was accompanied by insulin resistance, lower AT capillarization, lower AT expression of genes encoding proteins involved in mitochondrial biogenesis and function, and higher AT gene expression of macrophage infiltration and inflammatory markers. CONCLUSIONS: Our findings establish ATBF as an important regulator of AT P(O2). Nevertheless, obese individuals exhibit AT hyperoxia despite lower ATBF, which seems to be explained by lower AT oxygen consumption. This is accompanied by insulin resistance, impaired AT capillarization, and higher AT gene expression of inflammatory cell markers. CLINICAL TRIAL REGISTRATION- URL: http://www.trialregister.nl. Unique identifier: NTR2451. PMID- 21670229 TI - Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community. AB - BACKGROUND: Heart failure (HF) is a clinical syndrome characterized by signs and symptoms involving multiple organ systems. Longitudinal data demonstrating that asymptomatic cardiac dysfunction precedes overt HF are scarce, and the contribution of noncardiac dysfunction to HF progression is unclear. We hypothesized that subclinical cardiac and noncardiac organ dysfunction would accelerate the manifestation of HF. METHODS AND RESULTS: We studied 1038 participants of the Framingham Heart Study original cohort (mean age, 76+/-5 years; 39% men) with routine assessment of left ventricular systolic and diastolic function. Major noncardiac organ systems were assessed with the use of serum creatinine (renal), serum albumin (hepatic), ratio of forced expiratory volume in 1 second to forced vital capacity (FEV(1):FVC ratio; pulmonary), hemoglobin concentration (hematologic/oxygen-carrying capacity), and white blood cell count (systemic inflammation). On follow-up (mean, 11 years), there were 248 incident HF events (146 in women). After adjustment for established HF risk factors, antecedent left ventricular systolic dysfunction (hazard ratio, 2.33; 95% confidence interval, 1.43 to 3.78) and diastolic dysfunction (hazard ratio, 1.32; 95% confidence interval, 1.01 to 1.71) were associated with increased HF risk. After adjustment for cardiac dysfunction, higher serum creatinine, lower FEV1:FVC ratios, and lower hemoglobin concentrations were associated with increased HF risk (all P<0.05); serum albumin and white blood cell count were not. Subclinical dysfunction in each noncardiac organ system was associated with a 30% increased risk of HF (P=0.013). CONCLUSIONS: Antecedent cardiac dysfunction and noncardiac organ dysfunction are associated with increased incidence of HF, supporting the notion that HF is a progressive syndrome and underscoring the importance of noncardiac factors in its occurrence. PMID- 21670230 TI - Loss of methyl-CpG-binding domain protein 2 enhances endothelial angiogenesis and protects mice against hind-limb ischemic injury. AB - BACKGROUND: Despite intensive investigation, how DNA methylation influences endothelial function remains poorly understood. We used methyl-CpG-binding domain protein 2 (MBD2), an interpreter for DNA methylome-encoded information, to dissect the impact of DNA methylation on endothelial function in both physiological and pathophysiological states. METHODS AND RESULTS: Human umbilical vein endothelial cells under normal conditions express moderate levels of MBD2, but knockdown of MBD2 by siRNA significantly enhanced angiogenesis and provided protection against H(2)O(2)-induced apoptosis. Remarkably, Mbd2(-/-) mice were protected against hind-limb ischemia evidenced by the significant improvement in perfusion recovery, along with increased capillary and arteriole formation. Loss of MBD2 activated endothelial survival and proangiogenic signals downstream of vascular endothelial growth factor signaling characterized by an increase in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor receptor 2 expression, along with enhanced extracellular signal-regulated kinase 1/2 activation and BCL-2 expression. Mechanistic studies confirmed the methylation of CpG elements in the eNOS and vascular endothelial growth factor receptor 2 promoter. MBD2 binds to these methylated CpG elements and suppresses eNOS promoter activity. On ischemic insult, key endothelial genes such as eNOS and vascular endothelial growth factor receptor 2 undergo a DNA methylation turnover, and MBD2 interprets the changes of DNA methylation to suppress their expressions. Moreover, MBD2 modulation of eNOS expression is likely confined to endothelial cells because nonendothelial cells such as splenocytes fail to express eNOS after loss of MBD2. CONCLUSIONS: We provided direct evidence supporting that DNA methylation regulates endothelial function, which forms the molecular basis for understanding how environmental insults (epigenetic factor) affect the genome to modify disease susceptibility. Because MBD2 itself does not affect the methylation of DNA and is dispensable for normal physiology in mice, it could be a viable epigenetic target for modulating endothelial function in disease states. PMID- 21670232 TI - Extracorporeal membrane oxygenation for bridge to heart transplantation among children in the United States: analysis of data from the Organ Procurement and Transplant Network and Extracorporeal Life Support Organization Registry. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has served for >2 decades as the standard of care for US children requiring mechanical support as a bridge to heart transplantation. Objective data on the safety and efficacy of ECMO for this indication are limited. We describe the outcomes of ECMO as a bridge to heart transplantation to serve as performance benchmarks for emerging miniaturized assist devices intended to replace ECMO. METHODS AND RESULTS: Data from the Extracorporeal Life Support Organization Registry and the Organ Procurement Transplant Network database were merged to identify children supported with ECMO and listed for heart transplantation from 1994 to 2009. Independent predictors of wait-list and posttransplantation in-hospital mortality were identified. Objective performance goals for ECMO were developed. Of 773 children, the median age was 6 months (interquartile range, 1 to 44 months); 28% had cardiomyopathy; and in 38%, a bridge to transplantation was intended at ECMO initiation. Overall, 45% of subjects reached transplantation, although one third of those transplanted died before discharge; overall survival to hospital discharge was 47%. Wait-list mortality was independently associated with congenital heart disease, cardiopulmonary resuscitation before ECMO, and renal dysfunction. Posttransplantation mortality was associated with congenital heart disease, renal dysfunction, ECMO duration of >14 days, and initial ECMO indication as a bridge to recovery. In the objective performance goal cohort (n=485), patients with cardiomyopathy had the highest survival to hospital discharge (63%), followed by patients with myocarditis (59%), 2-ventricle congenital heart disease (44%) and 1-ventricle congenital heart disease (33%). CONCLUSION: Although ECMO is effective for short-term circulatory support, it is not reliable for the long-term circulatory support necessary for children awaiting heart transplantation. Fewer than half of patients bridged with ECMO survive to hospital discharge. More effective modalities for chronic circulatory support in children are urgently needed. PMID- 21670231 TI - Nonmuscle myosin light-chain kinase deficiency attenuates atherosclerosis in apolipoprotein E-deficient mice via reduced endothelial barrier dysfunction and monocyte migration. AB - BACKGROUND: Endothelial dysfunction and monocyte migration are key events in the pathogenesis of atherosclerosis. Nonmuscle myosin light-chain kinase (nmMLCK), the predominant MLCK isoform in endothelial cells, has been shown to contribute to vascular inflammation by altering endothelial barrier function. However, its impact on atherogenesis remains unknown. METHODS AND RESULTS: We investigated the role of nmMLCK in the development of atherosclerotic lesions in apolipoprotein E deficient (apoE(-/-)) mice fed an atherogenic diet for 12 weeks. Histopathological examination demonstrated that nmMLCK deficiency (apoE(-/ )nmmlck(-/-)) reduced the size of aortic lesions by 53%, lipid contents by 44%, and macrophage deposition by 40%. Western blotting and reverse-transcription polymerase chain reaction revealed the expression of nmMLCK in aortic endothelial cells and peripheral blood monocytes. Measurements of transendothelial electric resistance indicated that nmMLCK deficiency attenuated endothelial barrier dysfunction caused by thrombin, oxidized low-density lipoprotein, and tumor necrosis factor alpha. In monocytes, nmMLCK deficiency reduced their migration in response to the chemokine monocyte chemoattractant protein-1. Further mechanistic studies showed that nmMLCK acted through both myosin light chain phosphorylation coupled and -uncoupled pathways; the latter involved Rous sacracoma virus homolog genes-encoded tyrosine kinases (Src) signaling. Moreover, depletion of Src via gene silencing, site-specific mutagenesis, or pharmacological inhibition of Src greatly attenuated nmMLCK-dependent endothelial barrier dysfunction and monocyte migration. CONCLUSIONS: Nonmuscle myosin light-chain kinase contributes to atherosclerosis by regulating endothelial barrier function and monocyte migration via mechanisms involving not only kinase-mediated MLC phosphorylation but also Src activation. PMID- 21670233 TI - Epigenetic control of angiogenesis via DNA methylation. PMID- 21670234 TI - Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. AB - BACKGROUND: Whether morphological abnormalities of the mitral valve represent part of the hypertrophic cardiomyopathy (HCM) disease process is unresolved. Therefore, we applied cardiovascular magnetic resonance to characterize mitral valve morphology in a large HCM cohort. METHODS AND RESULTS: Cine cardiac magnetic resonance images were obtained in 172 HCM patients (age, 42+/-18 years; 62% men) and 172 control subjects. In addition, 15 HCM gene-positive/phenotype negative relatives were studied. Anterior mitral leaflet (AML) and posterior mitral leaflet lengths were greater in HCM patients than in control subjects (26+/-5 versus 19+/-5 mm, P<0.001; and 14+/-4 versus 10+/-3 mm, P<0.001, respectively), including 59 patients (34%) in whom AML length alone, posterior mitral leaflet length alone, or both were particularly substantial (>2 SDs above controls). Leaflet length was increased compared with controls in virtually all HCM age groups, including young patients 15 to 20 years of age (AML, 26+/-5 versus 21+/-4 mm; P=0.0002) and those >=60 years of age (AML, 26+/-4 versus 19+/ 2 mm; P<0.001). No relation was evident between mitral leaflet length and LV thickness or mass index (P=0.09 and P=0.16, respectively). A ratio of AML length to LV outflow tract diameter of >2.0 was associated with subaortic obstruction (P=0.001). In addition, AML length in 15 genotype-positive relatives without LV hypertrophy exceeded that of matched control subjects (21+/-3 versus 18+/-3 mm; P<0.01). CONCLUSIONS: In HCM, mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease, and are an important morphological abnormality responsible for LV outflow obstruction in combination with small outflow tract dimension. These findings suggest a novel role for cardiac magnetic resonance in the assessment of HCM. PMID- 21670235 TI - Neutralizing monoclonal antibody to periostin inhibits ovarian tumor growth and metastasis. AB - Periostin, an extracellular matrix protein, is reported to be overexpressed in a variety of human cancers and its functions seem to be linked to tumor metastasis. Our previous results show that engineered periostin overexpression promotes ovarian tumor growth and dissemination in vivo. In this study, we developed a neutralizing monoclonal antibody to periostin, named MZ-1, and investigated its effects on human ovarian tumor growth and metastasis. Our in vivo studies showed significant growth inhibition by MZ-1 on both subcutaneous and intraperitoneal (i.p.) tumors derived from the periostin-expressing ovarian cancer cell line A2780. In addition, MZ-1 treatment led to a reduction of the metastatic potential of these A2780 i.p. tumors. The in vivo antitumor effects of MZ-1 were linked to its specific inhibition of anchorage-independent growth and survival of periostin expressing cells, as well as its neutralizing effects on periostin-induced cancer cell migration and invasion. The data suggest that blocking periostin expression may be a novel approach for treating the subset of invasive ovarian tumors that overexpress periostin protein. PMID- 21670236 TI - Heart failure in a patient with Noonan syndrome. PMID- 21670237 TI - Letter by Gloekler et al regarding article, "Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study". PMID- 21670238 TI - Letter by Schuster et al regarding article, "Selecting a noninvasive imaging study after an inconclusive exercise test". PMID- 21670239 TI - Arrhythmogenic right ventricular dysplasia/cardiomyopathy: a family affair. PMID- 21670240 TI - Bleeding Academic Research Consortium consensus report: the Food and Drug Administration perspective. PMID- 21670241 TI - Athlete's heart and cardiovascular care of the athlete: scientific and clinical update. PMID- 21670242 TI - Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. PMID- 21670243 TI - Decapitate or strangulate? PMID- 21670245 TI - Discriminating between climate observations in terms of their ability to improve an ensemble of climate predictions. AB - In view of the cost and complexity of climate-observing systems, it is a matter of concern to know which measurements, by satellite or in situ, can best improve the accuracy and precision of long-term ensembles of climate projections. We follow a statistical procedure to evaluate the relative capabilities of a wide variety of observable data types for improving the accuracy and precision of an ensemble of Intergovernmental Panel on Climate Change (IPCC) models. Thirty-two data types are evaluated for their potential for improving a 50-y surface air temperature trend prediction with data from earlier periods, with an emphasis on 20 y. Data types can be ordered in terms of their ability to increase the precision of a forecast. Results show that important conclusions can follow from this ordering. The small size of the IPCC model ensemble (20 members) creates uncertainties in these conclusions, which need to be substantiated with the larger ensembles expected in the future. But the larger issue of whether the methodology can provide useful answers is demonstrated. PMID- 21670244 TI - Structural and kinetic mapping of side-chain exposure onto the protein energy landscape. AB - Identification and characterization of structural fluctuations that occur under native conditions is crucial for understanding protein folding and function, but such fluctuations are often rare and transient, making them difficult to study. Native-state hydrogen exchange (NSHX) has been a powerful tool for identifying such rarely populated conformations, but it generally reveals no information about the placement of these species along the folding reaction coordinate or the barriers separating them from the folded state and provides little insight into side-chain packing. To complement such studies, we have performed native-state alkyl-proton exchange, a method analogous to NSHX that monitors cysteine modification rather than backbone amide exchange, to examine the folding landscape of Escherichia coli ribonuclease H, a protein well characterized by hydrogen exchange. We have chosen experimental conditions such that the rate limiting barrier acts as a kinetic partition: residues that become exposed only upon crossing the unfolding barrier are modified in the EX1 regime (alkylation rates report on the rate of unfolding), while those exposed on the native side of the barrier are modified predominantly in the EX2 regime (alkylation rates report on equilibrium populations). This kinetic partitioning allows for identification and placement of partially unfolded forms along the reaction coordinate. Using this approach we detect previously unidentified, rarely populated conformations residing on the native side of the barrier and identify side chains that are modified only upon crossing the unfolding barrier. Thus, in a single experiment under native conditions, both sides of the rate-limiting barrier are investigated. PMID- 21670246 TI - The Legionella HtrA homologue DegQ is a self-compartmentizing protease that forms large 12-meric assemblies. AB - Proteases of the HtrA family are key factors dealing with folding stress in the periplasmatic compartment of prokaryotes. In Escherichia coli, the well characterized HtrA family members DegS and DegP counteract the accumulation of unfolded outer-membrane proteins under stress conditions. Whereas DegS serves as a folding-stress sensor, DegP is a chaperone-protease facilitating refolding or degradation of defective outer-membrane proteins. Here, we report the 2.15-A resolution crystal structure of the second major chaperone-protease of the periplasm, DegQ from Legionella fallonii. DegQ assembles into large, cage-like 12 mers that form independently of unfolded substrate proteins. We provide evidence that 12-mer formation is essential for the degradation of substrate proteins but not for the chaperone activity of DegQ. In the current model for the regulation of periplasmatic chaperone-proteases, 6-meric assemblies represent important protease-resting states. However, DegQ is unable to form such 6-mers, suggesting divergent regulatory mechanisms for DegQ and DegP. To understand how the protease activity of DegQ is controlled, we probed its functional properties employing designed protein variants. Combining crystallographic, biochemical, and mutagenic data, we present a mechanistic model that suggests how protease activity of DegQ 12-mers is intrinsically regulated and how deleterious proteolysis by free DegQ 3 mers is prevented. Our study sheds light on a previously uncharacterized component of the prokaryotic stress-response system with implications for other members of the HtrA family. PMID- 21670247 TI - Calculated vibrational properties of pigments in protein binding sites. AB - FTIR difference spectroscopy is widely used to probe molecular bonding interactions of protein-bound electron transfer cofactors. The technique is particularly attractive because it provides information on both neutral and radical cofactor states. Such dual information is not easily obtainable using other techniques. Although FTIR difference spectroscopy has been used to study cofactors in biological protein complexes, in nearly all cases interpretation of the spectra has been purely qualitative. Virtually no computational work has been undertaken in an attempt to model the spectra. To address this problem we have developed the use of ONIOM (our own N-layered integrated molecular Orbital + Molecular mechanics package) (quantum mechanical:molecular mechanics) methods to calculate FTIR difference spectra associated with protein-bound cofactors. As a specific example showing the utility of the approach we have calculated isotope edited FTIR difference spectra associated with unlabeled and labeled ubiquinones in the Q(A) binding site in Rhodobacter sphaeroides photosynthetic reaction centers. The calculated spectra are in remarkable agreement with experiment. Such agreement cannot be obtained by considering ubiquinone molecules in the gas phase or in solution. A calculation including the protein environment is required. The ONIOM calculated spectra agree well with experiment but indicate a very different interpretation of the experimental data compared to that proposed previously. In particular the calculations do not predict that one of the carbonyl groups of Q(A) is very strongly hydrogen bonded. We show that a computational-based interpretation of FTIR difference spectra associated with protein-bound cofactors is now possible. This approach will be applicable to FTIR studies of many cofactor-containing proteins. PMID- 21670248 TI - Antisense RNA polymerase II divergent transcripts are P-TEFb dependent and substrates for the RNA exosome. AB - Divergent transcription occurs at the majority of RNA polymerase II (RNAPII) promoters in mouse embryonic stem cells (mESCs), and this activity correlates with CpG islands. Here we report the characterization of upstream antisense transcription in regions encoding transcription start site associated RNAs (TSSa RNAs) at four divergent CpG island promoters: Isg20l1, Tcea1, Txn1, and Sf3b1. We find that upstream antisense RNAs (uaRNAs) have distinct capped 5' termini and heterogeneous nonpolyadenylated 3' ends. uaRNAs are short-lived with average half lives of 18 minutes and are present at 1-4 copies per cell, approximately one RNA per DNA template. Exosome depletion stabilizes uaRNAs. These uaRNAs are probably initiation products because their capped termini correlate with peaks of paused RNAPII. The pausing factors NELF and DSIF are associated with these antisense polymerases and their sense partners. Knockdown of either NELF or DSIF results in an increase in the levels of uaRNAs. Consistent with P-TEFb controlling release from pausing, treatment with its inhibitor, flavopiridol, decreases uaRNA and nascent mRNA transcripts with similar kinetics. Finally, Isg20l1 induction reveals equivalent increases in transcriptional activity in sense and antisense directions. Together these data show divergent polymerases are regulated after P TEFb recruitment with uaRNA levels controlled by the exosome. PMID- 21670249 TI - Instant fabrication and selection of folded structures using drop impact. AB - A drop impacting a target cutout in a thin polymer film is wrapped by the film in a dynamic sequence involving both capillary forces and inertia. Different 3D structures can be produced from a given target by slightly varying the impact parameters. A simplified model for a nonlinear dynamic Elastica coupled with a drop successfully explains this shape selection and yields detailed quantitative agreement with experiments. This first venture into the largely unexplored dynamics of elastocapillary assemblies opens up the perspective of mass production of 3D packages with individual shape selection. PMID- 21670250 TI - Site-specific protein modifications through pyrroline-carboxy-lysine residues. AB - Pyrroline-carboxy-lysine (Pcl) is a demethylated form of pyrrolysine that is generated by the pyrrolysine biosynthetic enzymes when the growth media is supplemented with D-ornithine. Pcl is readily incorporated by the unmodified pyrrolysyl-tRNA/tRNA synthetase pair into proteins expressed in Escherichia coli and in mammalian cells. Here, we describe a broadly applicable conjugation chemistry that is specific for Pcl and orthogonal to all other reactive groups on proteins. The reaction of Pcl with 2-amino-benzaldehyde or 2-amino-acetophenone reagents proceeds to near completion at neutral pH with high efficiency. We illustrate the versatility of the chemistry by conjugating Pcl proteins with poly(ethylene glycol)s, peptides, oligosaccharides, oligonucleotides, fluorescence, and biotin labels and other small molecules. Because Pcl is genetically encoded by TAG codons, this conjugation chemistry enables enhancements of the pharmacology and functionality of proteins through site specific conjugation. PMID- 21670251 TI - Aggregation of gamma-crystallins associated with human cataracts via domain swapping at the C-terminal beta-strands. AB - The prevalent eye disease age-onset cataract is associated with aggregation of human gammaD-crystallins, one of the longest-lived proteins. Identification of the gamma-crystallin precursors to aggregates is crucial for developing strategies to prevent and reverse cataract. Our microseconds of atomistic molecular dynamics simulations uncover the molecular structure of the experimentally detected aggregation-prone folding intermediate species of monomeric native gammaD-crystallin with a largely folded C-terminal domain and a mostly unfolded N-terminal domain. About 30 residues including a, b, and c strands from the Greek Key motif 4 of the C-terminal domain experience strong solvent exposure of hydrophobic residues as well as partial unstructuring upon N terminal domain unfolding. Those strands comprise the domain-domain interface crucial for unusually high stability of gammaD-crystallin. We further simulate the intermolecular linkage of these monomeric aggregation precursors, which reveals domain-swapped dimeric structures. In the simulated dimeric structures, the N-terminal domain of one monomer is frequently found in contact with residues 135-164 encompassing the a, b, and c strands of the Greek Key motif 4 of the second molecule. The present results suggest that gammaD-crystallin may polymerize through successive domain swapping of those three C-terminal beta strands leading to age-onset cataract, as an evolutionary cost of its very high stability. Alanine substitutions of the hydrophobic residues in those aggregation prone beta-strands, such as L145 and M147, hinder domain swapping as a pathway toward dimerization. These findings thus provide critical molecular insights onto the initial stages of age-onset cataract, which is important for understanding protein aggregation diseases. PMID- 21670252 TI - Role of antibiotic ligand in nascent peptide-dependent ribosome stalling. AB - Specific nascent peptides in the ribosome exit tunnel can elicit translation arrest. Such ribosome stalling is used for regulation of expression of some bacterial and eukaryotic genes. The stalling is sensitive to additional cellular cues, most commonly the binding of specific small-molecular-weight cofactors to the ribosome. The role of cofactors in programmed translation arrest is unknown. By analyzing nascent peptide- and antibiotic-dependent ribosome stalling that controls inducible expression of antibiotic resistance genes in bacteria, we have found that the antibiotic is directly recognized as a part of the translation modulating signal. Even minute structural alterations preclude it from assisting in ribosome stalling, indicating the importance of precise molecular interactions of the drug with the ribosome. One of the sensors that monitor the structure of the antibiotic is the 23S rRNA residue C2610, whose mutation reduces the efficiency of nascent peptide- and antibiotic-dependent ribosome stalling. These findings establish a new paradigm of the role of the cofactor in programmed translation arrest in which a small molecule is recognized along with specific nascent peptide sequences as a composite structure that provokes arrest of translation. A similar mechanism could be used by the ribosome to sense a variety of cellular metabolites. PMID- 21670253 TI - Unique scorpion toxin with a putative ancestral fold provides insight into evolution of the inhibitor cystine knot motif. AB - The three-disulfide inhibitor cystine knot (ICK) motif is a fold common to venom peptides from spiders, scorpions, and aquatic cone snails. Over a decade ago it was proposed that the ICK motif is an elaboration of an ancestral two-disulfide fold coined the disulfide-directed beta-hairpin (DDH). Here we report the isolation, characterization, and structure of a novel toxin [U(1)-liotoxin-Lw1a (U(1)-LITX-Lw1a)] from the venom of the scorpion Liocheles waigiensis that is the first example of a native peptide that adopts the DDH fold. U(1)-LITX-Lw1a not only represents the discovery of a missing link in venom protein evolution, it is the first member of a fourth structural fold to be adopted by scorpion-venom peptides. Additionally, we show that U(1)-LITX-Lw1a has potent insecticidal activity across a broad range of insect pest species, thereby providing a unique structural scaffold for bioinsecticide development. PMID- 21670254 TI - Retrograde nuclear import of tRNA precursors is required for modified base biogenesis in yeast. AB - The retrograde movement of tRNAs from the cytoplasm to the nucleus occurs constitutively in eukaryotic cells but its functional significance remains unclear. We show evidence suggesting that in Saccharomyces cerevisiae, a spliced tRNA precursor must be imported into the nucleus before the biogenesis of a modified base can occur. Wybutosine (yW) is a modified base adjacent to the anticodon of tRNA(Phe) and is required for accurate decoding. Glucose starvation or overexpression of the nuclear tRNA binding protein Trz1p both caused nuclear retention of cytoplasmic tRNAs, impaired the yW synthesis, and induced the accumulation of its intermediate, N(1)-methylgunanosine (m(1)G), showing that the postspliced tRNA(Phe) is imported to the nucleus, where m(1)G is formed by Trm5p, after which it is reexported to the cytoplasm, where the yW synthesis is completed by cytoplasmic enzymes. PMID- 21670255 TI - Pressure-induced reversible amorphization and an amorphous-amorphous transition in Ge2Sb2Te5 phase-change memory material. AB - Ge(2)Sb(2)Te(5) (GST) is a technologically very important phase-change material that is used in digital versatile disks-random access memory and is currently studied for the use in phase-change random access memory devices. This type of data storage is achieved by the fast reversible phase transition between amorphous and crystalline GST upon heat pulse. Here we report pressure-induced reversible crystalline-amorphous and polymorphic amorphous transitions in NaCl structured GST by ab initio molecular dynamics calculations. We have showed that the onset amorphization of GST starts at approximately 18 GPa and the system become completely random at approximately 22 GPa. This amorphous state has a cubic framework (c-amorphous) of sixfold coordinations. With further increasing pressure, the c-amorphous transforms to a high-density amorphous structure with trigonal framework (t-amorphous) and an average coordination number of eight. The pressure-induced amorphization is investigated to be due to large displacements of Te atoms for which weak Te-Te bonds exist or vacancies are nearby. Upon decompressing to ambient conditions, the original cubic crystalline structure is restored for c-amorphous, whereas t-amorphous transforms to another amorphous phase that is similar to the melt-quenched amorphous GST. PMID- 21670256 TI - Direct visualization at the single-cell level of siRNA electrotransfer into cancer cells. AB - The RNA interference-mediated gene silencing approach is promising for therapies based on the targeted inhibition of disease-relevant genes. Electropermeabilization is one of the nonviral methods successfully used to transfer siRNA into living cells in vitro and in vivo. Although this approach is effective in the field of gene silencing by RNA interference, very little is known about the basic processes supporting siRNA transfer. In this study, we investigated, by direct visualization at the single-cell level, the delivery of Alexa Fluor 546-labeled siRNA into murine melanoma cells stably expressing the enhanced green fluorescent protein (EGFP) as a target gene. The electrotransfer of siRNA was quantified by time lapse fluorescence microscopy and was correlated with the silencing of egfp expression. A direct transfer into the cell cytoplasm of the negatively charged siRNA was observed across the plasma membrane exclusively on the side facing the cathode. When added after electropulsation, the siRNA was inefficient for gene silencing because it did not penetrate the cells. Therefore, we report that an electric field acts on both the permeabilization of the cell plasma membrane and on the electrophoretic drag of the negatively charged siRNA molecules from the bulk phase into the cytoplasm. The transfer kinetics of siRNA are compatible with the creation of nanopores, which are described with the technique of synthetic nanopores. The mechanism involved was clearly specific for the physico-chemical properties of the electrotransferred molecule and was different from that observed with small molecules or plasmid DNA. PMID- 21670257 TI - Two classes of BRC repeats in BRCA2 promote RAD51 nucleoprotein filament function by distinct mechanisms. AB - The human tumor suppressor protein BRCA2 plays a key role in recombinational DNA repair. BRCA2 recruits RAD51 to sites of DNA damage through interaction with eight conserved motifs of approximately 35 amino acids, the BRC repeats; however, the specific function of each repeat remains unclear. Here, we investigated the function of the individual BRC repeats by systematically analyzing their effects on RAD51 activities. Our results reveal the existence of two categories of BRC repeats that display unique functional characteristics. One group, comprising BRC1, -2, -3, and -4, binds to free RAD51 with high affinity. The second group, comprising BRC5, -6, -7, and -8, binds to free RAD51 with low affinity but binds to the RAD51-ssDNA filament with high affinity. Each member of the first group reduces the ATPase activity of RAD51, whereas none of the BRC repeats of the second group affects this activity. Thus, through different mechanisms, both types of BRC repeats bind to and stabilize the RAD51 nucleoprotein filament on ssDNA. In addition, members of the first group limit binding of RAD51 to duplex DNA, where members of the second group do not. Only the first group enhances DNA strand exchange by RAD51. Our results suggest that the two groups of BRC repeats have differentially evolved to ensure efficient formation of a nascent RAD51 filament on ssDNA by promoting its nucleation and growth, respectively. We propose that the BRC repeats cooperate in a partially redundant but reinforcing manner to ensure a high probability of RAD51 filament formation. PMID- 21670258 TI - Impaired protein conformational landscapes as revealed in anomalous Arrhenius prefactors. AB - A growing body of data supports a role for protein motion in enzyme catalysis. In particular, the ability of enzymes to sample catalytically relevant conformational substates has been invoked to model kinetic and spectroscopic data. However, direct experimental links between rapidly interconverting conformations and the chemical steps of catalysis remain rare. We report here on the kinetic analysis and characterization of the hydride transfer step catalyzed by a series of mutant thermophilic alcohol dehydrogenases (ht-ADH), presenting evidence for Arrhenius prefactor values that become enormously elevated above an expected value of approximately 10(13) s(-1) when the enzyme operates below its optimal temperature range. Restoration of normal Arrhenius behavior in the ht-ADH reaction occurs at elevated temperatures. A simple model, in which reduced temperature alters the ability of the ht-ADH variants to sample the catalytically relevant region of conformational space, can reproduce the available data. These findings indicate an impaired landscape that has been generated by the combined condition of reduced temperature and mutation at a single, active-site hydrophobic side chain. The broader implication is that optimal enzyme function requires the maintenance of a relatively smooth landscape that minimizes low energy traps. PMID- 21670259 TI - Metabolic principles of river basin organization. AB - The metabolism of a river basin is defined as the set of processes through which the basin maintains its structure and responds to its environment. Green (or biotic) metabolism is measured via transpiration and blue (or abiotic) metabolism through runoff. A principle of equal metabolic rate per unit area throughout the basin structure is developed and tested in a river basin characterized by large heterogeneities in precipitation, vegetation, soil, and geomorphology. This principle is suggested to have profound implications for the spatial organization of river basin hydrologic dynamics, including the minimization of energy expenditure known to control the scale-invariant characteristics of river networks over several orders of magnitude. Empirically derived, remarkably constant rates of average transpiration per unit area through the basin structure lead to a power law for the probability distribution of transpiration from a randomly chosen subbasin. The average runoff per unit area, evaluated for subbasins of a wide range of topological magnitudes, is also shown to be remarkably constant independently of size. A similar result is found for the rainfall after accounting for canopy interception. Allometric scaling of metabolic rates with size, variously addressed in the biological literature and network theory under the label of Kleiber's law, is similarly derived. The empirical evidence suggests that river basin metabolic activity is linked with the spatial organization that takes place around the drainage network and therefore with the mechanisms responsible for the fractal geometry of the network, suggesting a new coevolutionary framework for biological, geomorphological, and hydrologic dynamics. PMID- 21670260 TI - Methionine sulfoxide reductase A is a stereospecific methionine oxidase. AB - Methionine sulfoxide reductase A (MsrA) catalyzes the reduction of methionine sulfoxide to methionine and is specific for the S epimer of methionine sulfoxide. The enzyme participates in defense against oxidative stresses by reducing methionine sulfoxide residues in proteins back to methionine. Because oxidation of methionine residues is reversible, this covalent modification could also function as a mechanism for cellular regulation, provided there exists a stereospecific methionine oxidase. We show that MsrA itself is a stereospecific methionine oxidase, producing S-methionine sulfoxide as its product. MsrA catalyzes its own autooxidation as well as oxidation of free methionine and methionine residues in peptides and proteins. When functioning as a reductase, MsrA fully reverses the oxidations which it catalyzes. PMID- 21670261 TI - A model of cytoplasmically driven microtubule-based motion in the single-celled Caenorhabditis elegans embryo. AB - We present a model of cytoplasmically driven microtubule-based pronuclear motion in the single-celled Caenorhabditis elegans embryo. In this model, a centrosome pair at the male pronucleus initiates stochastic microtubule (MT) growth. These MTs encounter motor proteins, distributed throughout the cytoplasm, that attach and exert a pulling force. The consequent MT-length-dependent pulling forces drag the pronucleus through the cytoplasm. On physical grounds, we assume that the motor proteins also exert equal and opposite forces on the surrounding viscous cytoplasm, here modeled as an incompressible Newtonian fluid constrained within an ellipsoidal eggshell. This naturally leads to streaming flows along the MTs. Our computational method is based on an immersed boundary formulation that allows for the simultaneous treatment of fluid flow and the dynamics of structures immersed within. Our simulations demonstrate that the balance of MT pulling forces and viscous nuclear drag is sufficient to move the pronucleus, while simultaneously generating minus-end directed flows along MTs that are similar to the observed movement of yolk granules toward the center of asters. Our simulations show pronuclear migration, and moreover, a robust pronuclear centration and rotation very similar to that observed in vivo. We find also that the confinement provided by the eggshell significantly affects the internal dynamics of the cytoplasm, increasing by an order of magnitude the forces necessary to translocate and center the pronucleus. PMID- 21670262 TI - Solid-state NMR of proteins sedimented by ultracentrifugation. AB - Relatively large proteins in solution, spun in NMR rotors for solid samples at typical ultracentrifugation speeds, sediment at the rotor wall. The sedimented proteins provide high-quality solid-state-like NMR spectra suitable for structural investigation. The proteins fully revert to the native solution state when spinning is stopped, allowing one to study them in both conditions. Transiently sedimented proteins can be considered a novel phase as far as NMR is concerned. NMR of transiently sedimented molecules under fast magic angle spinning has the advantage of overcoming protein size limitations of solution NMR without the need of sample crystallization/precipitation required by solid-state NMR. PMID- 21670263 TI - Structural and functional characterization of an atypical activation domain in erythroid Kruppel-like factor (EKLF). AB - Erythroid Kruppel-like factor (EKLF) plays an important role in erythroid development by stimulating beta-globin gene expression. We have examined the details by which the minimal transactivation domain (TAD) of EKLF (EKLFTAD) interacts with several transcriptional regulatory factors. We report that EKLFTAD displays homology to the p53TAD and, like the p53TAD, can be divided into two functional subdomains (EKLFTAD1 and EKLFTAD2). Based on sequence analysis, we found that EKLFTAD2 is conserved in KLF2, KLF4, KLF5, and KLF15. In addition, we demonstrate that EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300. The solution structure of the EKLFTAD2/Tfb1PH complex indicates that EKLFTAD2 binds Tfb1PH in an extended conformation, which is in contrast to the alpha helical conformation seen for p53TAD2 in complex with Tfb1PH. These studies provide detailed mechanistic information into EKLFTAD functions as well as insights into potential interactions of the TADs of other KLF proteins. In addition, they suggest that not only have acidic TADs evolved so that they bind using different conformations on a common target, but that transitioning from a disordered to a more ordered state is not a requirement for their ability to bind multiple partners. PMID- 21670264 TI - In vitro assembly of physiological cohesin/DNA complexes. AB - Cohesin is a member of the Smc family of protein complexes that mediates higher order chromosome structure by tethering different regions of chromatin. We present a new in vitro system that assembles cohesin-DNA complexes with in vivo properties. The assembly of these physiological salt-resistant complexes requires the cohesin holo-complex, its ability to bind ATP, the cohesin loader Scc2p and a closed DNA topology. Both the number of cohesin molecules bound to the DNA substrate and their distribution on the DNA substrate are limited. Cohesin and Scc2p bind preferentially to cohesin associated regions (CARs), DNA sequences with enriched cohesin binding in vivo. A subsequence of CARC1 promotes cohesin binding to neighboring sequences within CARC1. The enhancer-like function of this sequence is validated by in vivo deletion analysis. By demonstrating the physiological relevance of these in vitro assembled cohesin-DNA complexes, we establish our in vitro system as a powerful tool to elucidate the mechanism of cohesin and other Smc complexes. PMID- 21670265 TI - Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. AB - Polycystic kidney disease (PKD) is a genetic disorder that is characterized by cyst formation in kidney tubules. PKD arises from abnormalities of the primary cilium, a sensory organelle located on the cell surface. Here, we show that the primary cilium of renal epithelial cells contains a protein complex comprising adenylyl cyclase 5/6 (AC5/6), A-kinase anchoring protein 150 (AKAP150), and protein kinase A. Loss of primary cilia caused by deletion of Kif3a results in activation of AC5 and increased cAMP levels. Polycystin-2 (PC2), a ciliary calcium channel that is mutated in human PKD, interacts with AC5/6 through its C terminus. Deletion of PC2 increases cAMP levels, which can be corrected by reexpression of wild-type PC2 but not by a mutant lacking calcium channel activity. Phosphodiesterase 4C (PDE4C), which catabolizes cAMP, is also located in renal primary cilia and interacts with the AKAP150 complex. Expression of PDE4C is regulated by the transcription factor hepatocyte nuclear factor-1beta (HNF-1beta), mutations of which produce kidney cysts. PDE4C is down-regulated and cAMP levels are increased in HNF-1beta mutant kidney cells and mice. Collectively, these findings identify PC2 and PDE4C as unique components of an AKAP complex in primary cilia and reveal a common mechanism for dysregulation of cAMP signaling in cystic kidney diseases arising from different gene mutations. PMID- 21670266 TI - Fundamental relationship between operon organization and gene expression. AB - Half a century has passed since the discovery of operons (groups of genes that are transcribed together as a single mRNA). Despite the importance of operons in bacterial gene networks, the relationship between their organization and gene expression remains poorly understood. Here we show using synthetic operons in Escherichia coli that the expression of a given gene increases with the length of the operon and as its position moves farther from the end of the operon. These findings can be explained by a common mechanism; increasing the distance from the start of a gene to the end of the operon (termed the "transcription distance") provides more time for translation to occur during transcription, resulting in increased expression. We confirmed experimentally that the increased expression is indeed due to increased translation. Furthermore our analysis indicates the translation initiation rate for an mRNA is sixfold greater during transcription than after its release, which amplifies the impact of the transcription distance on gene expression. As a result of these mechanisms, gene expression increases by ~40% for each 1,000 nucleotides of transcription distance. In summary, we demonstrate that a fundamental relationship exists between gene expression and the number, length, and order of the genes in an operon. This relationship has important implications for understanding the functional basis of genome organization and practical applications for synthetic biology. PMID- 21670267 TI - Effector-triggered immunity blocks pathogen degradation of an immunity-associated vesicle traffic regulator in Arabidopsis. AB - Innate immunity in plants can be triggered by microbe- and pathogen-associated molecular patterns. The pathogen-associated molecular pattern-triggered immunity (PTI) is often suppressed by pathogen effectors delivered into the host cell. Plants can overcome pathogen suppression of PTI and reestablish pathogen resistance through effector-triggered immunity (ETI). An unanswered question is how plants might overcome pathogen-suppression of PTI during ETI. Findings described in this paper suggest a possible mechanism. During Pseudomonas syringae pathovar tomato (Pst) DC3000 infection of Arabidopsis, a host ADP ribosylation factor guanine nucleotide exchange factor, AtMIN7, is destabilized by the pathogen effector HopM1 through the host 26S proteasome. In this study, we discovered that AtMIN7 is required for not only PTI, consistent with the notion that Pst DC3000 degrades AtMIN7 to suppress PTI, but also ETI. The AtMIN7 level in healthy plants is low, but increases posttranscriptionally in response to activation of PTI. Whereas DC3000 infection led to degradation of AtMIN7, activation of ETI by three different effectors, AvrRpt2, AvrPphB, and HopA1, in Col-0 plants blocks the ability of Pst DC3000 to destabilize AtMIN7. Further analyses of bacterial translocation of HopM1 and AtMIN7 stability in HopM1 transgenic plants show that ETI prevents HopM1-mediated degradation of AtMIN7 inside the plant cell. Both AtMIN7 and HopM1 are localized to the trans-Golgi network/early endosome, a subcellular compartment that is not previously known to be associated with bacterial pathogenesis in plants. Thus, blocking pathogen degradation of trans-Golgi network/early endosome-associated AtMIN7 is a critical part of the ETI mechanism to counter bacterial suppression of PTI. PMID- 21670268 TI - MicroRNA-mediated posttranscriptional regulation is required for maintaining undifferentiated properties of blastoderm and primordial germ cells in chickens. AB - MicroRNAs (miRNAs) play a critical role in determining the differentiation fate of pluripotent stem cells and germ cells in mammals. However, the mechanism(s) of miRNA-mediated posttranscriptional regulation with regard to lineage specification and differentiation in chick development require further investigation. Therefore, we conducted miRNA expression profiling to explore specific miRNA signatures in undifferentiated blastoderm and primordial germ cells (PGCs). We identified seven miRNAs that are highly expressed in blastoderm and 10 that are highly expressed in PGCs. In this study, miR-302a and miR-456 for blastoderm and miR-181a* for PGCs were analyzed further for their target transcripts and regulatory pathways. Both miR-302a and miR-456 bound directly to the sex-determining region Y box 11 transcript and could act as posttranscriptional coregulators to maintain the undifferentiated state of the chicken blastoderm through the suppression of somatic gene expression and differentiation. Moreover, miR-181a* showed a bifunctional role in PGCs by binding to two different transcripts. miR-181a* inhibited the somatic differentiation of PGCs by silencing homeobox A1 expression. Additionally, miR 181a* prevented PGCs from entering meiosis through the repression of the nuclear receptor subfamily 6, group A, member 1 transcript. Collectively, our data demonstrate that in chickens miRNAs intrinsically regulate the differentiation fate of blastoderms and PGCs and that the specific timing of germ cell meiosis is controlled through miRNA expression. PMID- 21670269 TI - An antigenic peptide produced by reverse splicing and double asparagine deamidation. AB - A variety of unconventional translational and posttranslational mechanisms contribute to the production of antigenic peptides, thereby increasing the diversity of the peptide repertoire presented by MHC class I molecules. Here, we describe a class I-restricted peptide that combines several posttranslational modifications. It is derived from tyrosinase and recognized by tumor-infiltrating lymphocytes isolated from a melanoma patient. This unusual antigenic peptide is made of two noncontiguous tyrosinase fragments that are spliced together in the reverse order. In addition, it contains two aspartate residues that replace the asparagines encoded in the tyrosinase sequence. We confirmed that this peptide is naturally presented at the surface of melanoma cells, and we showed that its processing sequentially requires translation of tyrosinase into the endoplasmic reticulum and its retrotranslocation into the cytosol, where deglycosylation of the two asparagines by peptide-N-glycanase turns them into aspartates by deamidation. This process is followed by cleavage and splicing of the appropriate fragments by the standard proteasome and additional transport of the resulting peptide into the endoplasmic reticulum through the transporter associated with antigen processing (TAP). PMID- 21670270 TI - Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF beta and integrin/focal adhesion kinase (FAK) signaling. AB - Cancer stem cells (CSCs) sustain tumor growth through their ability to self-renew and to generate differentiated progeny. These functions endow CSCs with the potential to initiate secondary tumors bearing characteristics similar to those of the parent. Recently the hair follicle stem cell marker CD34 was used to purify a CSC-like cell population from early skin tumors arising from treatment with 7,12-dimethylbenz[alpha]anthracene/12-o-tetradecanoylphorbol-13-acetate, which typically generates benign papillomas that occasionally progress to squamous cell carcinomas (SCCs). In the present study, we identify and characterize CSCs purified from malignant SCCs. We show that SCCs contain two highly tumorigenic CSC populations that differ in CD34 levels but are enriched for integrins and coexist at the SCC-stroma interface. Intriguingly, whether CD34(lo) or CD34(hi), alpha6(hi)beta1(hi) populations can initiate secondary tumors by serial limit-dilution transplantation assays, but alpha6(lo)beta1(lo) populations cannot. Moreover, secondary tumors generated from a single CSC of either subtype contain both CD34(lo) and CD34(hi) alpha6(hi)beta1(hi)CSCs, indicating their nonhierarchical organization. Genomic profiling and hierarchical cluster analysis show that these two CSC subtypes share a molecular signature distinct from either the CD34(-) epidermal or the CD34(hi) hair follicle stem cell signature. Although closely related, alpha6(hi)beta1(hi)CD34(lo) and alpha6(hi)beta1(hi)CD34(hi) CSCs differ in cell-cycle gene expression and proliferation characteristics. Indeed, proliferation and expansion of alpha6(hi)beta1(hi)CD34(hi) CSCs is sensitive to whether they can initiate a TGF beta receptor II-mediated response to counterbalance elevated focal adhesion kinase-mediated integrin signaling within the tumor. Overall, the coexistence and interconvertibility of CSCs with differing sensitivities to their microenvironment pose challenges and opportunities for SCC cancer therapies. PMID- 21670271 TI - Short- and long-term benefits of cognitive training. AB - Does cognitive training work? There are numerous commercial training interventions claiming to improve general mental capacity; however, the scientific evidence for such claims is sparse. Nevertheless, there is accumulating evidence that certain cognitive interventions are effective. Here we provide evidence for the effectiveness of cognitive (often called "brain") training. However, we demonstrate that there are important individual differences that determine training and transfer. We trained elementary and middle school children by means of a videogame-like working memory task. We found that only children who considerably improved on the training task showed a performance increase on untrained fluid intelligence tasks. This improvement was larger than the improvement of a control group who trained on a knowledge-based task that did not engage working memory; further, this differential pattern remained intact even after a 3-mo hiatus from training. We conclude that cognitive training can be effective and long-lasting, but that there are limiting factors that must be considered to evaluate the effects of this training, one of which is individual differences in training performance. We propose that future research should not investigate whether cognitive training works, but rather should determine what training regimens and what training conditions result in the best transfer effects, investigate the underlying neural and cognitive mechanisms, and finally, investigate for whom cognitive training is most useful. PMID- 21670272 TI - Chemical genetic screen identifies Toxoplasma DJ-1 as a regulator of parasite secretion, attachment, and invasion. AB - Toxoplasma gondii is a member of the phylum Apicomplexa that includes several important human pathogens, such as Cryptosporidium and Plasmodium falciparum, the causative agent of human malaria. It is an obligate intracellular parasite that can cause severe disease in congenitally infected neonates and immunocompromised individuals. Despite the importance of attachment and invasion to the success of the parasite, little is known about the underlying mechanisms that drive these processes. Here we describe a screen to identify small molecules that block the process of host cell invasion by the T. gondii parasite. We identified a small molecule that specifically and irreversibly blocks parasite attachment and subsequent invasion of host cells. Using tandem orthogonal proteolysis-activity based protein profiling, we determined that this compound covalently modifies a single cysteine residue in a poorly characterized protein homologous to the human protein DJ-1. Mutation of this key cysteine residue in the native gene sequence resulted in parasites that were resistant to inhibition of host cell attachment and invasion by the compound. Further analysis of the invasion phenotype confirmed that modification of Cys127 on TgDJ-1 resulted in a block of microneme secretion and motility, even in the presence of direct stimulators of calcium release. Together, our results suggest that TgDJ-1 plays an important role that is likely downstream of the calcium flux required for microneme secretion, parasite motility, and subsequent invasion of host cells. PMID- 21670273 TI - We choose to go to the membrane. PMID- 21670274 TI - A cascade of coregulating enhancer binding proteins initiates and propagates a multicellular developmental program. AB - The signal transduction networks that initiate multicellular development in bacteria remain largely undefined. Here, we report that Myxococcus xanthus regulates entry into its multicellular developmental program using a novel strategy: a cascade of transcriptional activators known as enhancer binding proteins (EBPs). The EBPs in the cascade function in sequential stages of early development, and several lines of evidence indicate that the cascade is propagated when EBPs that function at one stage of development directly regulate transcription of an EBP gene important for the next developmental stage. We also show that the regulatory cascade is designed in a novel way that extensively expands on the typical use of EBPs: Instead of using only one EBP to regulate a particular gene or group of genes, which is the norm in other bacterial systems, the cascade uses multiple EBPs to regulate EBP genes that are positioned at key transition points in early development. Based on the locations of the putative EBP promoter binding sites, several different mechanisms of EBP coregulation are possible, including the formation of coregulating EBP transcriptional complexes. We propose that M. xanthus uses an EBP coregulation strategy to make expression of EBP genes that modulate stage-stage transitions responsive to multiple signal transduction pathways, which provide information that is important for a coordinated decision to advance the developmental process. PMID- 21670275 TI - Isoform-specific regulation of Akt by PDGF-induced reactive oxygen species. AB - Isoform-specific signaling of Akt, a major signaling hub and a prominent therapeutic target, remained poorly defined until recently. Subcellular distribution, tissue-specific expression, substrate specificity, and posttranslational modifications are believed to underlie isoform-specific signaling of Akt. The studies reported here show inhibition of Akt2 activity under physiologically relevant conditions of oxidation created by PDGF-induced reactive oxygen species. Combined MS and functional assays identified Cys124 located in the linker region between the N-terminal pleckstrin homology domain and the catalytic kinase domain as one of the unique regulatory redox sites in Akt2 with functional consequence on PDGF-stimulated glucose uptake. A model is proposed describing the consequence of increased endogenous oxidation induced by extracellular cues such as PDGF on Akt2 activity. PMID- 21670276 TI - HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8+ T lymphocytes. AB - HLA-E is a nonclassical HLA class I molecule, which differs from classical HLA molecules by its nonpolymorphic, conserved nature. Expression and function of HLA E in normal tissues and solid tumors is not fully understood. We investigated HLA E protein expression on tissue sections of 420 ovarian and cervical cancers and found equal or higher levels than normal counterpart epithelia in 80% of the tumors. Expression was strongly associated with components of the antigen presentation pathway, e.g., transporter associated with antigen processing (TAP), endoplasmic reticulum aminopeptide (ERAP), beta2 microglobulin (beta2m), HLA classes I and II, and for ovarian cancer with tumor infiltrating CD8(+) T lymphocytes (CTLs). This association argues against the idea that HLA-E would compensate for the loss of classical HLA in tumors. In situ detection of HLA-E interacting receptors revealed a very low infiltrate of natural killer (NK) cells, but up to 50% of intraepithelial CTLs expressed the inhibiting CD94/NKG2A receptor. In cervical cancer, HLA-E expression did not alter the prognostic effect of CTLs, most likely due to very high infiltrating CTL numbers in this virus-induced tumor. Overall survival of ovarian cancer patients, however, was strongly influenced by HLA-E, because the beneficial effect of high CTL infiltration was completely neutralized in the subpopulation with strong HLA-E expression. Interestingly, these results indicate that CTL infiltration in ovarian cancer is associated with better survival only when HLA-E expression is low and that intratumoral CTLs are inhibited by CD94/NKG2A receptors on CTLs in the tumor microenvironment. PMID- 21670277 TI - Perturbation of thymocyte development in nonsense-mediated decay (NMD)-deficient mice. AB - The random nature of T-cell receptor-beta (TCR-beta) recombination needed to generate immunological diversity dictates that two-thirds of alleles will be out of-frame. Transcripts derived from nonproductive rearrangements are cleared by the nonsense-mediated mRNA decay (NMD) pathway, the process by which cells selectively degrade transcripts harboring premature termination codons. Here, we demonstrate that the fetal thymus in transgenic mice that ubiquitously express a dominant-negative form of Rent1/hUpf1, an essential trans-effector of NMD, shows decreased cell number, reduced CD4CD8 double-positive thymocytes, diminished expression of TCR-beta, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous Vbeta-to-DbetaJbeta rearrangements, whereas Dbeta-to-Jbeta rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-beta rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-beta transgene that precludes generation of out-of-frame transcripts, suggesting direct mRNA-mediated trans-dominant effects. These data document that NMD has been functionally incorporated into developmental programs during eukaryotic evolution. PMID- 21670278 TI - Tudor domain containing 7 (Tdrd7) is essential for dynamic ribonucleoprotein (RNP) remodeling of chromatoid bodies during spermatogenesis. AB - In the male germline in mammals, chromatoid bodies, a specialized assembly of cytoplasmic ribonucleoprotein (RNP), are structurally evident during meiosis and haploidgenesis, but their developmental origin and regulation remain elusive. The tudor domain containing proteins constitute a conserved class of chromatoid body components. We show that tudor domain containing 7 (Tdrd7), the deficiency of which causes male sterility and age-related cataract (as well as glaucoma), is essential for haploid spermatid development and defines, in concert with Tdrd6, key biogenesis processes of chromatoid bodies. Single and double knockouts of Tdrd7 and Tdrd6 demonstrated that these spermiogenic tudor genes orchestrate developmental programs for ordered remodeling of chromatoid bodies, including the initial establishment, subsequent RNP fusion with ubiquitous processing bodies/GW bodies and later structural maintenance. Tdrd7 suppresses LINE1 retrotransposons independently of piwi-interacting RNA (piRNA) biogenesis wherein Tdrd1 and Tdrd9 operate, indicating that distinct Tdrd pathways act against retrotransposons in the male germline. Tdrd6, in contrast, does not affect retrotransposons but functions at a later stage of spermiogenesis when chromatoid bodies exhibit aggresome-like properties. Our results delineate that chromatoid bodies assemble as an integrated compartment incorporating both germline and ubiquitous features as spermatogenesis proceeds and that the conserved tudor family genes act as master regulators of this unique RNP remodeling, which is genetically linked to the male germline integrity in mammals. PMID- 21670279 TI - Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production. AB - B-lymphocyte development is dictated by the protein products of functionally rearranged Ig heavy (H) and light (L) chain genes. Ig rearrangement begins in pro B cells at the IgH locus. If pro-B cells generate a productive allele, they assemble a pre-B cell receptor complex, which signals their differentiation into pre-B cells and their clonal expansion. Pre-B cell receptor signals are also thought to contribute to allelic exclusion by preventing further IgH rearrangements. Here we show in two independent mouse models that the accumulation of a stabilized MUH mRNA that does not encode MUH chain protein specifically impairs pro-B cell differentiation and reduces the frequency of rearranged IgH genes in a dose-dependent manner. Because noncoding IgH mRNA is usually rapidly degraded by the nonsense-mediated mRNA decay machinery, we propose that the difference in mRNA stability allows pro-B cells to distinguish between productive and nonproductive Ig gene rearrangements and that MUH mRNA may thus contribute to efficient H chain allelic exclusion. PMID- 21670280 TI - Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. AB - Evidence of endoplasmic reticulum (ER) stress has been found in lungs of patients with familial and sporadic idiopathic pulmonary fibrosis. We tested whether ER stress causes or exacerbates lung fibrosis by (i) conditional expression of a mutant form of surfactant protein C (L188Q SFTPC) found in familial interstitial pneumonia and (ii) intratracheal treatment with the protein misfolding agent tunicamycin. We developed transgenic mice expressing L188Q SFTPC exclusively in type II alveolar epithelium by using the Tet-On system. Expression of L188Q SFTPC induced ER stress, as determined by increased expression of heavy-chain Ig binding protein (BiP) and splicing of X-box binding protein 1 (XBP1) mRNA, but no lung fibrosis was identified in the absence of a second profibrotic stimulus. After intratracheal bleomycin, L188Q SFTPC-expressing mice developed exaggerated lung fibrosis and reduced static lung compliance compared with controls. Bleomycin-treated L188Q SFTPC mice also demonstrated increased apoptosis of alveolar epithelial cells and greater numbers of fibroblasts in the lungs. With a complementary model, intratracheal tunicamycin treatment failed to induce lung remodeling yet resulted in augmentation of bleomycin-induced fibrosis. These data support the concept that ER stress produces a dysfunctional epithelial cell phenotype that facilitates fibrotic remodeling. ER stress pathways may serve as important therapeutic targets in idiopathic pulmonary fibrosis. PMID- 21670281 TI - Reshuffling genomic landscapes to study the regulatory evolution of Hox gene clusters. AB - The emergence of Vertebrata was accompanied by two rounds of whole-genome duplications. This enabled paralogous genes to acquire novel functions with high evolutionary potential, a process suggested to occur mostly by changes in gene regulation, rather than in protein sequences. In the case of Hox gene clusters, such duplications favored the appearance of distinct global regulations. To assess the impact of such "regulatory evolution" upon neo-functionalization, we developed PANTHERE (PAN-genomic Translocation for Heterologous Enhancer RE shuffling) to bring the entire megabase-scale HoxD regulatory landscape in front of the HoxC gene cluster via a targeted translocation in vivo. At this chimeric locus, Hoxc genes could both interpret this foreign regulation and functionally substitute for their Hoxd counterparts. Our results emphasize the importance of evolving regulatory modules rather than their target genes in the process of neo functionalization and offer a genetic tool to study the complexity of the vertebrate regulatory genome. PMID- 21670282 TI - Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature. AB - Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension. WNK4 regulates diverse ion transporters in the kidney, and dysregulation of renal transporters is considered the main cause of the WNK4 mutation-associated hypertension. Another determinant of hypertension is vascular tone that is regulated by Ca(2+)-dependent blood vessel constriction. However, the role of WNK4 in vasoconstriction as part of its function to regulate blood pressure is not known. Here, we report that WNK4 is a unique modulator of blood pressure by restricting Ca(2+) influx via the transient receptor potential canonical 3 (TRPC3) channel in the vasculature. Loss of WNK4 markedly augmented TRPC3 mediated Ca(2+) influx in vascular smooth muscle cells (VSMCs) in response to alpha-adrenoreceptor stimulation, which is the pathological hallmark of hypertension in resistance arteries. Notably, WNK4 depletion induced hypertrophic cell growth in VSMCs and increased vasoconstriction in small mesenteric arteries via TRPC3-mediated Ca(2+) influx. In addition, WNK4 mutants harboring the Q562E PHAII-causing or the D318A kinase-inactive mutation failed to mediate TRPC3 inhibition. These results define a previously undescribed function of WNK4 and reveal a unique therapeutic target to control blood pressure in WNK4-related hypertension. PMID- 21670283 TI - Using implementation intentions prompts to enhance influenza vaccination rates. AB - We evaluate the results of a field experiment designed to measure the effect of prompts to form implementation intentions on realized behavioral outcomes. The outcome of interest is influenza vaccination receipt at free on-site clinics offered by a large firm to its employees. All employees eligible for study participation received reminder mailings that listed the times and locations of the relevant vaccination clinics. Mailings to employees randomly assigned to the treatment conditions additionally included a prompt to write down either (i) the date the employee planned to be vaccinated or (ii) the date and time the employee planned to be vaccinated. Vaccination rates increased when these implementation intentions prompts were included in the mailing. The vaccination rate among control condition employees was 33.1%. Employees who received the prompt to write down just a date had a vaccination rate 1.5 percentage points higher than the control group, a difference that is not statistically significant. Employees who received the more specific prompt to write down both a date and a time had a 4.2 percentage point higher vaccination rate, a difference that is both statistically significant and of meaningful magnitude. PMID- 21670284 TI - Near-UV cyanobacteriochrome signaling system elicits negative phototaxis in the cyanobacterium Synechocystis sp. PCC 6803. AB - Positive phototaxis systems have been well studied in bacteria; however, the photoreceptor(s) and their downstream signaling components that are responsible for negative phototaxis are poorly understood. Negative phototaxis sensory systems are important for cyanobacteria, oxygenic photosynthetic organisms that must contend with reactive oxygen species generated by an abundance of pigment photosensitizers. The unicellular cyanobacterium Synechocystis sp. PCC6803 exhibits type IV pilus-dependent negative phototaxis in response to unidirectional UV-A illumination. Using a reverse genetic approach, together with biochemical, molecular genetic, and RNA expression profiling analyses, we show that the cyanobacteriochrome locus (slr1212/uirS) of Synechocystis and two adjacent response regulator loci (slr1213/uirR and the PatA-type regulator slr1214/lsiR) encode a UV-A-activated signaling system that is required for negative phototaxis. We propose that UirS, which is membrane-associated via its ETR1 domain, functions as a UV-A photosensor directing expression of lsiR via release of bound UirR, which targets the lsiR promoter. Constitutive expression of LsiR induces negative phototaxis under conditions that normally promote positive phototaxis. Also induced by other stresses, LsiR thus integrates light inputs from multiple photosensors to determine the direction of movement. PMID- 21670285 TI - Punishment sustains large-scale cooperation in prestate warfare. AB - Understanding cooperation and punishment in small-scale societies is crucial for explaining the origins of human cooperation. We studied warfare among the Turkana, a politically uncentralized, egalitarian, nomadic pastoral society in East Africa. Based on a representative sample of 88 recent raids, we show that the Turkana sustain costly cooperation in combat at a remarkably large scale, at least in part, through punishment of free-riders. Raiding parties comprised several hundred warriors and participants are not kin or day-to-day interactants. Warriors incur substantial risk of death and produce collective benefits. Cowardice and desertions occur, and are punished by community-imposed sanctions, including collective corporal punishment and fines. Furthermore, Turkana norms governing warfare benefit the ethnolinguistic group, a population of a half million people, at the expense of smaller social groupings. These results challenge current views that punishment is unimportant in small-scale societies and that human cooperation evolved in small groups of kin and familiar individuals. Instead, these results suggest that cooperation at the larger scale of ethnolinguistic units enforced by third-party sanctions could have a deep evolutionary history in the human species. PMID- 21670286 TI - Osmotic stress triggers toxin production by the dinoflagellate Karenia brevis. AB - With the increase in frequency of harmful algal blooms (HABs) worldwide, a better understanding of the mechanisms that influence toxin production is needed. Karenia brevis, the major HAB dinoflagellate in the Gulf of Mexico, produces potent neurotoxins, known as brevetoxins. Human health is directly impacted by blooms of K. brevis through consumption of shellfish contaminated by accumulated brevetoxins (neurotoxic shellfish poisoning) or from aerosolized brevetoxins in sea spray (reduced respiratory function); however, the reason for brevetoxin production has remained a mystery. Here we show that brevetoxin production increased dramatically in response to osmotic stress in three of the four K. brevis clones examined. By rapidly changing salinity to simulate a shift from oceanic conditions to a decreased salinity typical of coastal conditions, brevetoxin production was triggered. As a result, brevetoxin cell quota increased by >14-fold, while growth rate remained unchanged. Live images of K. brevis cells were also examined to assess changes in cell volume. In the K. brevis Wilson clone, cells responded quickly to hypoosmotic stress by increasing their brevetoxin cell quota from ~10 to 160 pg of brevetoxin per cell, while cell volume remained stable. In contrast, the K. brevis SP1 clone, which has a consistently low brevetoxin cell quota (<1 pg per cell), was unable to balance the hypoosmotic stress, and although brevetoxin production remained low, average cell volume increased. Our findings close a critical gap in knowledge regarding mechanisms for toxin production in K. brevis by providing an explanation for toxin production in this harmful dinoflagellate. PMID- 21670287 TI - Prestimulus theta activity predicts correct source memory retrieval. AB - Recent evidence indicates that the processing of a stimulus can be influenced by preceding patterns of brain activity. Here we examine whether prestimulus oscillatory brain activity can influence the ability to retrieve episodic memories. Neural activity in the theta-frequency band (4-8 Hz) was enhanced before presentation of test items which elicited accurate recollection of contextual details of the prior study episode ("source retrieval"), relative to trials for which item recognition was successful but source retrieval failed. Poststimulus theta activity was also related to source retrieval, and the magnitude of poststimulus theta was predicted by the magnitude of the prestimulus theta effects. The results suggest that ongoing neural processes occurring before stimulus onset might play a critical role in readying the brain for successful memory retrieval. PMID- 21670288 TI - Female extrapair mating behavior can evolve via indirect selection on males. AB - In many species that form socially monogamous pair bonds, a considerable proportion of the offspring is sired by extrapair males. This observation has remained a puzzle for evolutionary biologists: although mating outside the pair bond can obviously increase the offspring production of males, the benefits of such behavior to females are less clear, yet females are known to actively solicit extrapair copulations. For more than two decades adaptionist explanations have dominated the discussions, yet remain controversial, and genetic constraint arguments have been dismissed without much consideration. An intriguing but still untested hypothesis states that extrapair mating behavior by females may be affected by the same genetic variants (alleles) as extrapair mating behavior by males, such that the female behavior could evolve through indirect selection on the male behavior. Here we show that in the socially monogamous zebra finch, individual differences in extrapair mating behavior have a hereditary component. Intriguingly, this genetic basis is shared between the sexes, as shown by a strong genetic correlation between male and female measurements of extrapair mating behavior. Hence, positive selection on males to sire extrapair young will lead to increased extrapair mating by females as a correlated evolutionary response. This behavior leads to a fundamentally different view of female extrapair mating: it may exist even if females obtain no net benefit from it, simply because the corresponding alleles were positively selected in the male ancestors. PMID- 21670290 TI - Lowering apolipoprotein CIII delays onset of type 1 diabetes. AB - Serum levels of apolipoprotein CIII (apoCIII) are increased in type 1 diabetic patients, and when beta cells are exposed to these diabetic sera, apoptosis occurs, an effect abolished by an antibody against apoCIII. We have investigated the BB rat, an animal model that develops a human-like type 1 diabetes, and found that apoCIII was also increased in sera from prediabetic rats. This increase in apoCIII promoted beta-cell death. The endogenous levels of apoCIII were reduced by treating prediabetic animals with an antisense against this apolipoprotein, resulting in a significantly delayed onset of diabetes. ApoCIII thus serves as a diabetogenic factor, and intervention with this apolipoprotein in the prediabetic state can arrest disease progression. These findings suggest apoCIII as a target for the treatment of type 1 diabetes. PMID- 21670292 TI - Replication and segregation of an Escherichia coli chromosome with two replication origins. AB - Characterized bacteria, unlike eukaryotes and some archaea, initiate replication bidirectionally from a single replication origin contained within a circular or linear chromosome. We constructed Escherichia coli cells with two WT origins separated by 1 Mb in their 4.64-Mb chromosome. Productive bidirectional replication initiated synchronously at both spatially separate origins. Newly replicated DNA from both origins was segregated sequentially as replication progressed, with two temporally and spatially separate replication termination events. Replication initiation occurred at a cell volume identical to that of cells with a single WT origin, showing that initiation control is independent of cellular and chromosomal oriC concentration. Cells containing just the ectopic origin initiated bidirectional replication at the expected cell mass and at the normal cellular location of that region. In all strains, spatial separation of sister loci adjacent to active origins occurred shortly after their replication, independently of whether replication initiated at the normal origin, the ectopic origin, or both origins. PMID- 21670291 TI - Crystal structure of mouse coronavirus receptor-binding domain complexed with its murine receptor. AB - Coronaviruses have evolved diverse mechanisms to recognize different receptors for their cross-species transmission and host-range expansion. Mouse hepatitis coronavirus (MHV) uses the N-terminal domain (NTD) of its spike protein as its receptor-binding domain. Here we present the crystal structure of MHV NTD complexed with its receptor murine carcinoembryonic antigen-related cell adhesion molecule 1a (mCEACAM1a). Unexpectedly, MHV NTD contains a core structure that has the same beta-sandwich fold as human galectins (S-lectins) and additional structural motifs that bind to the N-terminal Ig-like domain of mCEACAM1a. Despite its galectin fold, MHV NTD does not bind sugars, but instead binds mCEACAM1a through exclusive protein-protein interactions. Critical contacts at the interface have been confirmed by mutagenesis, providing a structural basis for viral and host specificities of coronavirus/CEACAM1 interactions. Sugar binding assays reveal that galectin-like NTDs of some coronaviruses such as human coronavirus OC43 and bovine coronavirus bind sugars. Structural analysis and mutagenesis localize the sugar-binding site in coronavirus NTDs to be above the beta-sandwich core. We propose that coronavirus NTDs originated from a host galectin and retained sugar-binding functions in some contemporary coronaviruses, but evolved new structural features in MHV for mCEACAM1a binding. PMID- 21670289 TI - Genetic calibration of species diversity among North America's freshwater fishes. AB - Freshwater ecosystems are being heavily exploited and degraded by human activities all over the world, including in North America, where fishes and fisheries are strongly affected. Despite centuries of taxonomic inquiry, problems inherent to species identification continue to hamper the conservation of North American freshwater fishes. Indeed, nearly 10% of species diversity is thought to remain undescribed. To provide an independent calibration of taxonomic uncertainty and to establish a more accessible molecular identification key for its application, we generated a standard reference library of mtDNA sequences (DNA barcodes) derived from expert-identified museum specimens for 752 North American freshwater fish species. This study demonstrates that 90% of known species can be delineated using barcodes. Moreover, it reveals numerous genetic discontinuities indicative of independently evolving lineages within described species, which points to the presence of morphologically cryptic diversity. From the 752 species analyzed, our survey flagged 138 named species that represent as many as 347 candidate species, which suggests a 28% increase in species diversity. In contrast, several species of parasitic and nonparasitic lampreys lack such discontinuity and may represent alternative life history strategies within single species. Therefore, it appears that the current North American freshwater fish taxonomy at the species level significantly conceals diversity in some groups, although artificially creating diversity in others. In addition to providing an easily accessible digital identification system, this study identifies 151 fish species for which taxonomic revision is required. PMID- 21670293 TI - Differential curvature sensing and generating activities of dynamin isoforms provide opportunities for tissue-specific regulation. AB - Dynamin 1 (Dyn1) and Dyn2 are neuronal and ubiquitously expressed isoforms, respectively, of the multidomain GTPase required for clathrin-mediated endocytosis (CME). Although they are 79% identical, Dyn1 and Dyn2 are not fully functionally redundant. Through direct measurements of basal and assembly stimulated GTPase activities, membrane binding, self-assembly, and membrane fission on planar and curved templates, we have shown that Dyn1 is an efficient curvature generator, whereas Dyn2 is primarily a curvature sensor. Using Dyn1/Dyn2 chimeras, we identified the lipid-binding pleckstrin homology domain as being responsible for the differential in vitro properties of these two isoforms. Remarkably, their in vitro activities were reversed by a single amino acid change in the membrane-binding variable loop 3. Reconstitution of KO mouse embryo fibroblasts showed that both the pleckstrin homology and the Pro/Arg-rich domains determine the differential abilities of these two isoforms to support CME. These domains are specific to classical dynamins and are involved in regulating their activity. Our findings reveal opportunities for fundamental differences in the regulation of Dyn1, which mediates rapid endocytosis at the synapse, vs. Dyn2, which regulates early and late events in CME in nonneuronal cells. PMID- 21670294 TI - Metabolomic analysis of Arabidopsis reveals hemiterpenoid glycosides as products of a nitrate ion-regulated, carbon flux overflow. AB - An understanding of the balance between carbon and nitrogen assimilation in plants is key to future bioengineering for a range of applications. Metabolomic analysis of the model plant, Arabidopsis thaliana, using combined NMR-MS revealed the presence of two hemiterpenoid glycosides that accumulated in leaf tissue, to ~1% dry weight under repeated nitrate-deficient conditions. The formation of these isoprenoids was correlated with leaf nitrate concentrations that could also be assayed in the metabolomic data using a unique flavonoid-nitrate mass spectral adduct. Analysis of leaf and root tissue from plants grown in hydroponics with a variety of root stressors identified the conditions under which the isoprenoid pathway in leaves was diverted to the hemiterpenoids. These compounds were strongly induced by root wounding or oxidative stress and weakly induced by potassium deficiency. Other stresses such as cold, saline, and osmotic stress did not induce the compounds. Replacement of nitrate with ammonia failed to suppress the formation of the hemiterpenoids, indicating that nitrate sensing was a key factor. Feeding of intermediates was used to study aspects of 2-C-methyl-d erythritol-4-phosphate pathway regulation leading to hemiterpenoid formation. The formation of the hemiterpenoids in leaves was strongly correlated with the induction of the phenylpropanoids scopolin and coniferin in roots of the same plants. These shunts of photosynthetic carbon flow are discussed in terms of overflow mechanisms that have some parallels with isoprene production in tree species. PMID- 21670295 TI - Boundary cap cells are peripheral nervous system stem cells that can be redirected into central nervous system lineages. AB - Boundary cap cells (BC), which express the transcription factor Krox20, participate in the formation of the boundary between the central nervous system and the peripheral nervous system. To study BC stemness, we developed a method to purify and amplify BC in vitro from Krox20(Cre/+), R26R(YFP/+) mouse embryos. We show that BC progeny are EGF/FGF2-responsive, form spheres, and express neural crest markers. Upon growth factor withdrawal, BC progeny gave rise to multiple neural crest and CNS lineages. Transplanted into the developing murine forebrain, they successfully survived, migrated, and integrated within the host environment. Surprisingly, BC progeny generated exclusively CNS cells, including neurons, astrocytes, and myelin-forming oligodendrocytes. In vitro experiments indicated that a sequential combination of ventralizing morphogens and glial growth factors was necessary to reprogram BC into oligodendrocytes. Thus, BC progeny are endowed with differentiation plasticity beyond the peripheral nervous system. The demonstration that CNS developmental cues can reprogram neural crest-derived stem cells into CNS derivatives suggests that BC could serve as a source of cell type specific lineages, including oligodendrocytes, for cell-based therapies to treat CNS disorders. PMID- 21670296 TI - Beta oscillations in the monkey sensorimotor network reflect somatosensory decision making. AB - The neuronal correlate of perceptual decision making has been extensively studied in the monkey somatosensory system by using a vibrotactile discrimination task, showing that stimulus encoding, retention, and comparison are widely distributed across cortical areas. However, from a network perspective, it is not known what role oscillations play in this task. We recorded local field potentials (LFPs) from diverse cortical areas of the sensorimotor system while one monkey performed the vibrotactile discrimination task. Exclusively during stimulus presentation, a periodic response reflecting the stimulus frequency was observed in the somatosensory regions, suggesting that after initial processing, the frequency content of the stimulus is coded in some other way than entrainment. Interestingly, we found that oscillatory activity in the beta band reflected the dynamics of decision making in the monkey sensorimotor network. During the comparison and decision period, beta activity showed a categorical response that reflected the decision of the monkey and distinguished correct from incorrect responses. Importantly, this differential activity was absent in a control condition that involved the same stimulation and response but no decision making required, suggesting it does not merely reflect the maintenance of a motor plan. We conclude that beta band oscillations reflect the temporal and spatial dynamics of the accumulation and processing of evidence in the sensorimotor network leading to the decision outcome. PMID- 21670297 TI - Profile of David M. Hillis. Interview by Sujata Gupta. PMID- 21670298 TI - Unconventional myristoylation of large-conductance Ca2+-activated K+ channel (Slo1) via serine/threonine residues regulates channel surface expression. AB - Protein myristoylation is a means by which cells anchor proteins into membranes. The most common type of myristoylation occurs at an N-terminal glycine. However, myristoylation rarely occurs at an internal amino acid residue. Here we tested whether the alpha-subunit of the human large-conductance voltage- and Ca(2+) activated K(+) channel (hSlo1) might undergo internal myristoylation. hSlo1 expressed in HEK293T cells incorporated [(3)H]myristic acid via a posttranslational mechanism, which is insensitive to cycloheximide, an inhibitor of protein biosynthesis. In-gel hydrolysis of [(3)H]myristoyl-hSlo1 with alkaline NH(2)OH (which cleaves hydroxyesters) but not neutral NH(2)OH (which cleaves thioesters) completely removed [(3)H]myristate from hSlo1, suggesting the involvement of a hydroxyester bond between hSlo1's hydroxyl-bearing serine, threonine, and/or tyrosine residues and myristic acid; this type of esterification was further confirmed by its resistance to alkaline Tris.HCl. Treatment of cells expressing hSlo1 with 100 MUM myristic acid caused alteration of hSlo1 activation kinetics and a 40% decrease in hSlo1 current density from 20 to 12 nA*MOmega. Immunocytochemistry confirmed a decrease in hSlo1 plasmalemma localization by myristic acid. Replacement of the six serines or the seven threonines (but not of the single tyrosine) of hSlo1 intracellular loops 1 and 3 with alanines decreased hSlo1 direct myristoylation by 40-44%, whereas in combination decreased myristoylation by nearly 90% and abolished the myristic acid-induced change in current density. Our data demonstrate that an ion channel, hSlo1, is internally and posttranslationally myristoylated. Myristoylation occurs mainly at hSlo1 intracellular loop 1 or 3, and is an additional mechanism for channel surface expression regulation. PMID- 21670299 TI - The transcriptional repressor Blimp1/Prdm1 regulates postnatal reprogramming of intestinal enterocytes. AB - Female mammals produce milk to feed their newborn offspring before teeth develop and permit the consumption of solid food. Intestinal enterocytes dramatically alter their biochemical signature during the suckling-to-weaning transition. The transcriptional repressor Blimp1 is strongly expressed in immature enterocytes in utero, but these are gradually replaced by Blimp1(-) crypt-derived adult enterocytes. Here we used a conditional inactivation strategy to eliminate Blimp1 function in the developing intestinal epithelium. There was no noticeable effect on gross morphology or formation of mature cell types before birth. However, survival of mutant neonates was severely compromised. Transcriptional profiling experiments reveal global changes in gene expression patterns. Key components of the adult enterocyte biochemical signature were substantially and prematurely activated. In contrast, those required for processing maternal milk were markedly reduced. Thus, we conclude Blimp1 governs the developmental switch responsible for postnatal intestinal maturation. PMID- 21670300 TI - Structural vaccinology to thwart antigenic variation in microbial pathogens. PMID- 21670301 TI - Coarse to fine dynamics of monocular and binocular processing in human pattern vision. AB - Biological image processing has been hypothesized to adopt a coarse to fine strategy: the image is initially analyzed at a coarse spatial scale, and this analysis is then used to guide subsequent inspection at a finer scale. Neurons in visual cortex often display response characteristics that are consistent with this hypothesis for both monocular and binocular signals. Puzzlingly, measurements in human observers have failed to expose similar coarse to fine dynamics for human pattern vision, questioning the applicability of direct parallels between single neurons and perception. We performed a series of measurements using experimental protocols that were specifically designed to examine this question in more detail. We were able to confirm that, when the analysis is restricted to the linear properties of the perceptual process, no coarse to fine dynamics were evident in the data. However, when the analysis was extended to nonlinear descriptors, a clear coarse to fine structure emerged that consisted of two processes: an early nonlinear process operating on a coarse spatial scale followed by a linear process operating on a fine spatial scale. These results potentially serve to reduce the gap between the electrophysiological and behavioral findings. PMID- 21670302 TI - Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca2+/Calmodulin-dependent protein kinase II. AB - The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted. PMID- 21670303 TI - Four amino acids guide the assembly or disassembly of Arabidopsis histone H3.3 containing nucleosomes. AB - The histone variant H3.3 and the canonical histone H3.1, which differ in only 4- to 5-aa positions, are coexpressed in complex multicellular eukaryotes from fly to human and plant. H3.3 is mainly associated with active chromatin by replacing H3.1 through chaperones such as histone regulator A, death domain associated protein DAXX, thalassemia/mental retardation syndrome X-linked homolog ATRX, or proto-oncogene protein DEK and plays important roles in the germline, epigenetic memory, and reprogramming. However, the signals within H3.3 that serve as a guide for its dynamic deposition or depletion in plant chromatin are not clear. Here, we show that Arabidopsis histone H3.3 differs from H3.1 by 4-aa sites: amino acids 31, 41, 87, and 90. Although histone H3.1 is highly enriched in chromocenters, H3.3 is present in nucleolar foci in addition to being diffusely distributed in the nucleoplasm. We have evaluated the function of the 4 aa that differ between H3.1 and H3.3. We show that amino acid residue 87, and to some extent residue 90, of Arabidopsis histone H3.3 are critical for its deposition into rDNA arrays. When RNA polymerase I-directed nucleolar transcription is inhibited, wild type H3.3, but not H3.3 containing mutations at residues 31 and 41, is depleted from the rDNA arrays. Together, our results are consistent with a model in which amino acids 87 and 90 in the core domain of H3.3 guide nucleosome assembly, whereas amino acids 31 and 41 in the N-terminal tail of Arabidopsis H3.3 guide nucleosome disassembly in nucleolar rDNA. PMID- 21670304 TI - B regulatory cells and the tumor-promoting actions of TNF-alpha during squamous carcinogenesis. AB - The inflammatory cytokine TNF-alpha has been recognized as a critical tumor promoter, but the effector cells that mediate its action have not been fully characterized. Because B cells regulate squamous and prostate carcinogenesis, and Tnf(-/-) mice harbor B-cell defects, we investigated the hypothesis that B cells are important effector cells for TNF-alpha-mediated promotion of cancer development. Using an adoptive transfer strategy and the 7,12 dimethylbenz[alpha]anthracene/terephthalic acid (DMBA/TPA) two-stage model of skin carcinogenesis, we found that both B cells and TNF-alpha are critical for the development of DMBA/TPA-induced papilloma. Transfer of B cells from DMBA/TPA treated wild-type mice to Tnf(-/-) mice rescued papilloma development to a wild type level, a result not observed when B cells from Tnf(-/-) mice were transferred to Rag2(-/-) mice or when TNF-alpha was eliminated selectively in B cells. Resistance to papilloma development in Tnf(-/-) mice was associated with increased IFN-gamma and CD8(+) T cells in skin and a significant reduction in IL 10-producing B regulatory cells alongside an increase in IFN-gamma-producing CD8(+) T cells in the spleen. These data indicate that during DMBA/TPA-induced squamous carcinogenesis TNF-alpha mediates tumor-promoting activity via regulatory B cells that repress antitumor immunity. PMID- 21670305 TI - Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways. AB - Signaling pathways essential for axon regeneration, but not for neuron development or function, are particularly well suited targets for therapeutic intervention. We find that the parallel PMK-3(p38) and KGB-1(JNK) MAPK pathways must be coordinately activated to promote axon regeneration. Axon regeneration fails if the activity of either pathway is absent. These two MAPKs are coregulated by the E3 ubiquitin ligase RPM-1(Phr1) via targeted degradation of the MAPKKKs DLK-1 and MLK-1 and by the MAPK phosphatase VHP-1(MKP7), which negatively regulates both PMK-3(p38) and KGB-1(JNK). PMID- 21670306 TI - Mitochondrial complex II has a key role in mitochondrial-derived reactive oxygen species influence on plant stress gene regulation and defense. AB - Mitochondria are both a source of ATP and a site of reactive oxygen species (ROS) production. However, there is little information on the sites of mitochondrial ROS (mROS) production or the biological role of such mROS in plants. We provide genetic proof that mitochondrial complex II (Complex II) of the electron transport chain contributes to localized mROS that regulates plant stress and defense responses. We identify an Arabidopsis mutant in the Complex II subunit, SDH1-1, through a screen for mutants lacking GSTF8 gene expression in response to salicylic acid (SA). GSTF8 is an early stress-responsive gene whose transcription is induced by biotic and abiotic stresses, and its expression is commonly used as a marker of early stress and defense responses. Transcriptional analysis of this mutant, disrupted in stress responses 1 (dsr1), showed that it had altered SA mediated gene expression for specific downstream stress and defense genes, and it exhibited increased susceptibility to specific fungal and bacterial pathogens. The dsr1 mutant also showed significantly reduced succinate dehydrogenase activity. Using in vivo fluorescence assays, we demonstrated that root cell ROS production occurred primarily from mitochondria and was lower in the mutant in response to SA. In addition, leaf ROS production was lower in the mutant after avirulent bacterial infection. This mutation, in a conserved region of SDH1-1, is a unique plant mitochondrial mutant that exhibits phenotypes associated with lowered mROS production. It provides critical insights into Complex II function with implications for understanding Complex II's role in mitochondrial diseases across eukaryotes. PMID- 21670307 TI - Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. AB - Interaction of cell surface glycoproteins with endogenous lectins on the cell surface regulates formation and maintenance of plasma membrane domains, clusters signaling complexes, and controls the residency time of glycoproteins on the plasma membrane. Galectin-9 is a soluble, secreted lectin that binds to glycoprotein receptors to form galectin-glycoprotein lattices on the cell surface. Whereas galectin-9 binding to specific glycoprotein receptors induces death of CD4 Th1 cells, CD4 Th2 cells are resistant to galectin-9 death due to alternative glycosylation. On Th2 cells, galectin-9 binds cell surface protein disulfide isomerase (PDI), increasing retention of PDI on the cell surface and altering the redox status at the plasma membrane. Cell surface PDI regulates integrin function on platelets and also enhances susceptibility of T cells to infection with HIV. We find that galectin-9 binding to PDI on Th2 cells results in increased cell migration through extracellular matrix via beta3 integrins, identifying a unique mechanism to regulate T-cell migration. In addition, galectin-9 binding to PDI on T cells potentiates infection with HIV. We identify a mechanism for regulating cell surface redox status via a galectin-glycoprotein lattice, to regulate distinct T-cell functions. PMID- 21670309 TI - Global standards and local knowledge building: upgrading small producers in developing countries. AB - Local knowledge building is a crucial factor for upgrading small producers and improving their market competitiveness and livelihoods. The rise of global standards affecting food safety and environmental sustainability in agriculture sparks debates on the impact on smallholders in developing countries. This article presents a perspective on the links of international standards to knowledge and institution building for developing the capabilities of small producers. Interacting with global practices, indigenous private and public actors create local institutions to develop capabilities for product and process innovations that contribute to economic development and enhance food security. Local innovation depends on collective strategic efforts through increasing networks among small producers and other organizations, including firms, nongovernmental organizations, and government, that foster knowledge circulation and bring diverse resources and support to build local capabilities. PMID- 21670308 TI - Disentangling pleasure from incentive salience and learning signals in brain reward circuitry. AB - Multiple signals for reward-hedonic impact, motivation, and learned associative prediction-are funneled through brain mesocorticolimbic circuits involving the nucleus accumbens and ventral pallidum. Here, we show how the hedonic "liking" and motivation "wanting" signals for a sweet reward are distinctly modulated and tracked in this circuit separately from signals for Pavlovian predictions (learning). Animals first learned to associate a fixed sequence of Pavlovian cues with sucrose reward. Subsequent intraaccumbens microinjections of an opioid stimulating drug increased the hedonic liking impact of sucrose in behavior and firing signals of ventral pallidum neurons, and likewise, they increased incentive salience signals in firing to the reward-proximal incentive cue (but did not alter firing signals to the learned prediction value of a reward-distal cue). Microinjection of a dopamine-stimulating drug instead enhanced only the motivation component but did not alter hedonic impact or learned prediction signals. Different dedicated neuronal subpopulations in the ventral pallidum tracked signal enhancements for hedonic impact vs. incentive salience, and a faster firing pattern also distinguished incentive signals from slower hedonic signals, even for a third overlapping population. These results reveal separate neural representations of wanting, liking, and prediction components of the same reward within the nucleus accumbens to ventral pallidum segment of mesocorticolimbic circuitry. PMID- 21670310 TI - The Pif1 family in prokaryotes: what are our helicases doing in your bacteria? AB - Pif1 family helicases, which are found in nearly all eukaryotes, have important roles in both nuclear and mitochondrial genome maintenance. Recently, the increasing availability of genome sequences has revealed that Pif1 helicases are also widely found in diverse prokaryotes, but it is currently unknown what physiological function(s) prokaryotic Pif1 helicases might perform. This Perspective aims to briefly introduce the reader to the well-studied eukaryotic Pif1 family helicases and speculate on what roles such enzymes may play in bacteria. On the basis of our hypotheses, we predict that Pif1 family helicases are important for resolving common issues that arise during DNA replication, recombination, and repair rather than functioning in a eukaryotic-specific manner. PMID- 21670311 TI - Stimulated gammadelta T cells increase the in vivo efficacy of trastuzumab in HER 2+ breast cancer. AB - One fourth of women with HER-2(+) metastatic breast carcinoma are treated with a combination regimen with trastuzumab, but the frequent resistance to this Ab requires definition of new means to improve its bioactivity. The mechanisms of action of trastuzumab involve several pathways including Ab-dependent cellular cytotoxicity. Because human gammadelta T lymphocytes mediate Ab-dependent cellular cytotoxicity and can be activated further by phosphoantigens, these cells are prone to improve the efficacy of Abs, as recently demonstrated for CD20(+) B cell lymphomas. Whether this concept applies as well with carcinomas remained to be demonstrated in vivo, however. In this study, we asked whether a combination of trastuzumab and phosphoantigen-stimulated gammadelta lymphocytes increases the efficacy of trastuzumab against HER-2(+) breast carcinoma cell lines in vivo. We report that repeated infusions of this combination had a better efficacy than that of trastuzumab alone against HER-2(+) mammary carcinoma xenografts in mice. In these models, reduction of tumor growth was observed together with trastuzumab opsonization of HER-2(+) cells and tumor infiltration by gammadelta lymphocytes. In addition in humans, the mammary carcinomas of 27 of 30 patients showed significant gammadelta T cell infiltrates. Altogether, these findings indicate that combination of trastuzumab and stimulated gammadelta cells represents a new strategy to improve the efficacy of Herceptin (trastuzumab) in HER-2(+) breast cancer. PMID- 21670312 TI - Endoplasmic reticulum calcium depletion impacts chaperone secretion, innate immunity, and phagocytic uptake of cells. AB - A number of immunological functions are ascribed to cell surface-expressed forms of the endoplasmic reticulum (ER) chaperone calreticulin (CRT). In this study, we examined the impact of ER stress-inducing drugs upon cell surface CRT induction and the resulting immunological consequences. We showed that cell surface expression of CRT and secretion of CRT, BiP, gp96, and PDI were induced by thapsigargin (THP) treatment, which depletes ER calcium, but not by tunicamycin treatment, which inhibits protein glycosylation. Surface expression of CRT in viable, THP-treated fibroblasts correlated with their enhanced phagocytic uptake by bone marrow-derived dendritic cells. Incubation of bone marrow-derived dendritic cells with THP-treated fibroblasts enhanced sterile IL-6 production and LPS-induced generation of IL-1beta, IL-12, IL-23, and TNF-alpha. However, extracellular CRT is not required for enhanced proinflammatory responses. Furthermore, the pattern of proinflammatory cytokine induction by THP-treated cells and cell supernatants resembled that induced by THP itself and indicated that other ER chaperones present in supernatants of THP-treated cells also do not contribute to induction of the innate immune response. Thus, secretion of various ER chaperones, including CRT, is induced by ER calcium depletion. CRT, previously suggested as an eat-me signal in dead and dying cellular contexts, can also promote phagocytic uptake of cells subject to ER calcium depletion. Finally, there is a strong synergy between calcium depletion in the ER and sterile IL-6, as well as LPS-dependent IL-1beta, IL-12, IL-23, and TNF-alpha innate responses, findings that have implications for understanding inflammatory diseases that originate in the ER. PMID- 21670313 TI - Multilayered defense in HLA-B51-associated HIV viral control. AB - Polymorphism in the HLA region of a chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, -B27, and -B51. Taking advantage of a unique cohort infected with clade B' HIV-1 through contaminated blood, in which many variables such as the length of infection, the infecting viral strain, and host genetic background are controlled, we performed a comprehensive study to understand HLA-B51-associated HIV-1 control. We focused on the T cell responses against three dominant HLA-B51 restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI, and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in position 1 of epitope LI9 was seen in most B51(+) individuals, followed by V289X in position 8 of the TI8, and then, A328S, in position 2 of the NI9 epitope, was also seen in some B51(+) individuals. Good control of viral load and higher CD4(+) counts were significantly associated with at least one detectable T cell response to unmutated epitopes, whereas lower CD4(+) counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defense against the development of immune escape mutations. PMID- 21670314 TI - TNF mediates the sustained activation of Nrf2 in human monocytes. AB - Modulation of monocyte function is a critical factor in the resolution of inflammatory responses. This role is mediated mainly by the production of TNF alpha. Investigations of the actions of TNF have mostly focused on acute activation of other cell types such as fibroblasts and endothelial cells. Less is known about the effects of TNF on monocytes themselves, and little is known about the regulation of cell responses to TNF beyond the activation of NF-kappaB. In this study, we investigated the regulation of NF-E2-related factor 2 (Nrf2) cyctoprotective responses to TNF in human monocytes. We found that in monocytes TNF induces sustained Nrf2 activation and Nrf2 cytoprotective gene induction in a TNFR1-dependent manner. Under TNF activation, monocytes increased their expression of Nrf2-dependent genes, including NAD(P)H:quinone oxidoreductase 1 and glutamyl cysteine ligase modulatory, but not heme oxygenase-1. We also showed that autocrine TNF secretion was responsible for this sustained Nrf2 response and that Nrf2 activation by TNF was mediated by the generation of reactive oxygen species. Moreover, we showed that Nrf2-mediated gene induction can modulate TNF induced NF-kappaB activation. These results show for the first time, to our knowledge, that TNF modulates prolonged Nrf2-induced gene expression, which in turn regulates TNF-induced inflammatory responses. PMID- 21670316 TI - NTPDase1 controls IL-8 production by human neutrophils. AB - The ectonucleotidase NTPDase1 (CD39) terminates P2 receptor activation by the hydrolysis of extracellular nucleotides (i.e., the P2 receptor ligands). In agreement with that role, exacerbated inflammation has been observed in NTPDase1 deficient mice. In this study, we extend these observations by showing that inhibition of NTPDase1 markedly increases IL-8 production by TLR-stimulated human neutrophils. First, immunolabeling of human blood neutrophils and neutrophil-like HL60 cells displayed the expression of NTPDase1 protein, which correlated with the hydrolysis of ATP at their surface. NTPDase1 inhibitors (e.g., NF279 and ARL 67156) as well as NTPDase1-specific small interfering RNAs markedly increased IL 8 production in neutrophils stimulated with LPS and Pam(3)CSK(4) (agonists of TLR4 and TLR1/2, respectively) but not with flagellin (TLR5) and gardiquimod (TLR7 and 8). This increase in IL-8 release was due to the synergy between TLRs and P2 receptors. Indeed, ATP was released from neutrophils constitutively and accumulated in the medium upon NTPDase1 inhibition by NF279. Likewise, both human blood neutrophils and neutrophil-like HL60 cells produced IL-8 in response to exogenous nucleotides, ATP being the most potent inducer. In agreement, P2Y(2) receptor knockdown in neutrophil-like HL60 cells markedly decreased LPS- and Pam(3)CSK(4)-induced IL-8 production. In line with these in vitro results, injection of LPS in the air pouches of NTPDase1-deficient mice triggered an increased production of the chemokines MIP-2 and keratinocyte-derived chemokine (i.e., the rodent counterparts of human IL-8) compared with that in wild-type mice. In summary, NTPDase1 controls IL-8 production by human neutrophils via the regulation of P2Y(2) activation. PMID- 21670315 TI - Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. AB - Attempts to cure breast cancer by adoptive cellular therapy (ACT) have not been successful. This is primarily due to the presence of tumor-induced immune suppressive mechanisms as well as the failure of tumor-reactive T cells to provide long-term memory responses in vivo. To address these clinically important challenges, we developed an ex vivo protocol for the expansion of tumor-reactive immune cells obtained from tumor-bearing animals prior to or after local radiation therapy. We used an Ag-free protocol that included bryostatin 1/ionomycin and sequential common gamma-chain cytokines (IL-7/IL-15 + IL-2). The proposed protocol expanded tumor-reactive T cells as well as activated non-T cells, including NKT cells, NK cells, and IFN-gamma-producing killer dendritic cells. Antitumor efficacy of T cells depended on the presence of non-T cells. The effector non-T cells also rendered T cells resistant to myeloid-derived suppressor cells. Radiation therapy altered phenotypic distribution and differentiation of T cells as well as their ability to generate central memory T cells. ACT by means of the expanded cells protected animals from tumor challenge and generated long-term memory responses against the tumor, provided that leukocytes were derived from tumor-bearing animals prior to radiation therapy. The ex vivo protocol was also able to expand HER-2/neu-specific T cells derived from the PBMC of a single patient with breast carcinoma. These data suggest that the proposed ACT protocol should be studied further in breast cancer patients. PMID- 21670317 TI - IL-23 is critical for induction of arthritis, osteoclast formation, and maintenance of bone mass. AB - The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4(+) T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23-induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19(-/-) mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19( /-) mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides. PMID- 21670319 TI - Obstetrician-gynaecologists' opinions about conscientious refusal of a request for abortion: results from a national vignette experiment. AB - BACKGROUND AND OBJECTIVES: Conscientious refusal of abortion has been discussed widely by medical ethicists but little information on practitioners' opinions exists. The American College of Obstetricians and Gynecologists (ACOG) issued recommendations about conscientious refusal. We used a vignette experiment to examine obstetrician-gynecologists' (OB/GYN) support for the recommendations. DESIGN: A national survey of OB/GYN physicians contained a vignette experiment in which an OB/GYN doctor refused a requested elective abortion. The vignette varied two issues recently addressed by the ACOG ethics committee--whether the doctor referred and whether the doctor disclosed their objection to the abortion. PARTICIPANTS AND SETTING: 1800 OB/GYN randomly selected physicians were asked to complete a mail survey containing the vignette. The response rate was 66% (n=1154) after excluding 40 ineligible cases. MEASUREMENT: Physicians indicated their approval for the vignette doctor's decision. MAIN RESULTS: Overall, 43% of OB/GYN physicians responded that the conscientious refusal exercised by the vignette physician was appropriate. 70% rated the vignette doctor as acting appropriately when a referral was made. This dropped to 51% when the doctor disclosed objections to the patient, and to 12% when the doctor disclosed objections and refused to make a referral. Consistent with previous research, males were more likely to support disclosure and refusal to refer. Highly religious physicians supported non-referral but not disclosure. CONCLUSION: OB/GYN physicians are less likely to support conscientious refusal of abortion if physicians disclose their objections to patients. This is at odds with ACOG recommendations and with some models of the doctor-patient relationship. PMID- 21670318 TI - Loss of T cell CD98 H chain specifically ablates T cell clonal expansion and protects from autoimmunity. AB - CD98 H chain (4F2 Ag, Slc3a2) was discovered as a lymphocyte-activation Ag. Deletion of CD98 H chain in B cells leads to complete failure of B cell proliferation, plasma cell formation, and Ab secretion. In this study, we examined the role of T cell CD98 in cell-mediated immunity and autoimmune disease pathogenesis by specifically deleting it in murine T cells. Deletion of T cell CD98 prevented experimental autoimmune diabetes associated with dramatically reduced T cell clonal expansion. Nevertheless, initial T cell homing to pancreatic islets was unimpaired. In sharp contrast to B cells, CD98-null T cells showed only modestly impaired Ag-driven proliferation and nearly normal homeostatic proliferation. Furthermore, these cells were activated by Ag, leading to cytokine production (CD4) and efficient cytolytic killing of targets (CD8). The integrin-binding domain of CD98 was necessary and sufficient for full clonal expansion, pointing to a role for adhesive signaling in T cell proliferation and autoimmune disease. When we expanded CD98-null T cells in vitro, they adoptively transferred diabetes, establishing that impaired clonal expansion was responsible for protection from disease. Thus, the integrin-binding domain of CD98 is required for Ag-driven T cell clonal expansion in the pathogenesis of an autoimmune disease and may represent a useful therapeutic target. PMID- 21670320 TI - Lost property? Legal compensation for destroyed sperm: a reflection and comparison drawing on UK and French perspectives. AB - In a recent case in the UK, six men stored their sperm before undergoing chemotherapy treatment for cancer in case they proved to be infertile after the treatment. The sperm was not properly stored and as a result was inadvertently destroyed. The men sued the NHS Trust that stored the sperm and were in the end successful. This paper questions the basis on which the judgement was made and the rationale behind it, namely that the men 'had ownership' of the sperm, and that compensation was thus due on the grounds that the men's property had been destroyed. We first argue that the claim is erroneous and enhances the tendency towards the commodification of body parts. We then suggest that the men could have been compensated for the harm done to them without granting property rights, and that this would, at least in philosophical and ethical terms, have been more appropriate. To help illustrate this, we draw on a parallel case in French law in which a couple whose embryos had been destroyed were overtly denied ownership rights in them. Finally, we suggest some possible ethical and practical problems if the proprietary view expressed in the UK ruling were to become dominant in law, with particular focus on the storing of genetic information in biobanks. We conclude that, although compensation claims should not necessarily be ruled out, a 'no property in the body' approach should be the default position in cases of detached bodily materials, the alternative being significantly ethically problematic. PMID- 21670321 TI - Acceptability of financial incentives to improve health outcomes in UK and US samples. AB - In an online study conducted separately in the UK and the US, participants rated the acceptability and fairness of four interventions: two types of financial incentives (rewards and penalties) and two types of medical interventions (pills and injections). These were stated to be equally effective in improving outcomes in five contexts: (a) weight loss and (b) smoking cessation programmes, and adherence in treatment programmes for (c) drug addiction, (d) serious mental illness and (e) physiotherapy after surgery. Financial incentives (weekly rewards and penalties) were judged less acceptable and to be less fair than medical interventions (weekly pill or injection) across all five contexts. Context moderated the relative preference between rewards and penalties: participants from both countries favoured rewards over penalties in weight loss and treatment for serious mental illness. Only among US participants was this relative preference moderated by perceived responsibility of the target group. Overall, participants supported funding more strongly for interventions when they judged members of the target group to be less responsible for their condition, and vice versa. These results reveal a striking similarity in negative attitudes towards the use of financial incentives, rewards as well as penalties, in improving outcomes across a range of contexts, in the UK and the USA. The basis for such negative attitudes awaits further study. PMID- 21670322 TI - Mechanistic causality and counterfactual-manipulative causality: recent insights from philosophy of science. AB - Current epidemiological and statistical theory about research methods and how to elicit causation from epidemiological studies is strongly influenced by counterfactual-manipulative thinking. However, thinking about how disease states develop is rooted in mechanistic 'webs of causes'. After a tremendous growth of research in molecular biology, biochemistry and genetics, attention has increasingly been paid to environmental and socioeconomic factors as determinants of diseases. This led to conceiving of most pathologies as caused by multilevel mechanical systems. The nature of 'mechanisms' has been the subject of extensive philosophical reflection over the past couple of decades. The present paper will first present some of today's philosophical insights in what are called biologic or other 'mechanisms' and thereafter show how these concepts can be linked to counterfactual-manipulative views. PMID- 21670323 TI - Ethnic mortality differentials in Lithuania: contradictory evidence from census linked and unlinked mortality estimates. AB - BACKGROUND: This study examines discrepancies between census and death registry information in the reporting of the ethnicity of the deceased in Lithuania and shows how these reporting differences influence estimates of mortality inequality by ethnicity. METHODS: This study uses a census-linked dataset provided by Statistics Lithuania. The data include all deaths and population exposures between 1 July 2001 and 31 December 2004. The information on the ethnicity of the deceased was available from both the census and the death records. The Poisson regression was applied (1) to measure the effects of socio-demographic variables on the misreporting of ethnicity on death records and (2) to estimate mortality rate ratios by ethnicity based on census-linked and unlinked data. RESULTS: The death-record-based information on ethnicity under-reports the deaths of people of Russian, Polish and other ethnicities and over-reports the deaths of people of Lithuanian ethnicity. This leads both to the underestimation of mortality in the three ethnic minority groups and to biased mortality rate ratios. The misreporting is higher in death records for women, persons younger than 80 years, divorced persons, urban residents and those dying from ill-defined causes. CONCLUSION: Studies based on unlinked data may provide biased estimates of ethnic mortality differences. PMID- 21670324 TI - A diagnosis of sarcoid arthritis: 'check the tattoos'. PMID- 21670325 TI - NICE guidelines for the investigation of stable chest pain: what are the implications for cardiac imaging? PMID- 21670326 TI - Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications. AB - OBJECTIVE: To describe treatment complications following intra-arterial chemotherapy (IAC) for retinoblastoma. METHODS: A retrospective interventional series of ophthalmic artery cannulation for IAC injection (3 planned sessions at 1-month intervals) was undertaken. Thirty-eight catheterizations of 17 eyes of 17 patients were performed from September 2008 to September 2010. Fluoroscopy of the ophthalmic artery was performed before and immediately after treatment. Heparin was given during the procedure and aspirin (40 mg) was given orally for 1 week. The treatment complications were determined. RESULTS: Only 17 of 190 children were selected for treatment with IAC during this period. Following successful ophthalmic artery cannulation in 16 cases, there was no evidence of metastasis, stroke, brain injury, or persistent systemic toxic effects. Fluoroscopy demonstrated patent ophthalmic artery immediately before and after IAC injection in each case. Following therapy, orbital and adnexal findings at 1 month included eyelid edema (n = 13), blepharoptosis (n = 10), cilia loss (n = 1), and orbital congestion with temporary dysmotility (n = 12). These findings resolved within 6 months in all cases. Following therapy, vascular findings included ophthalmic artery stenosis (permanent in 3 cases, temporary in 1 case), confirmed on fluoroscopy in 3 cases. Concomitant central or branch retinal artery occlusion was noted (permanent in 2 cases, temporary in 1 case). Subtle retinal pigment epithelial mottling in 9 cases that slowly evolved to later-onset underlying choroidal atrophy in 5 cases was noted. CONCLUSIONS: Treatment with IAC for retinoblastoma can lead to mild and severe short-term ocular complications, including eyelid edema as well as potentially blinding vascular obstruction. This procedure should be used with caution. PMID- 21670327 TI - The expanded spectrum of focal choroidal excavation. AB - OBJECTIVE: To describe the clinical and imaging findings in patients with focal choroidal excavation. METHODS: Retrospective observational case series. The medical records of 12 patients (13 eyes) with focal choroidal excavation were reviewed. Clinical histories and imaging findings (including color photography, fundus autofluorescence imaging, fluorescein angiography, indocyanine green angiography, spectral-domain optical coherence tomography, and enhanced depth imaging spectral-domain optical coherence tomography) were analyzed. RESULTS: The mean age of the patients was 45 years (range, 22-62 years). Four patients were Asian. Mean visual acuity was 20/31 (range, 20/20 to 20/100). Mean refractive error was -3.54 diopters (D) (range, 6.00 to -8.00 D). One patient had bilateral involvement. All patients manifested varying degrees of foveal pigmentary changes that were usually hypoautofluorescent on fundus autofluorescence images. Fluorescein angiographic findings varied with degree of retinal pigment epithelial alterations. Indocyanine green angiography revealed relative hypofluorescence. In 7 eyes, spectral-domain optical coherence tomography revealed outer retinal layers conforming to retinal pigment epithelial alterations within the excavation. In the other 6 eyes, spectral-domain optical coherence tomography revealed a separation between the outer retina and the retinal pigment epithelium within the excavation. In 7 eyes studied with enhanced depth imaging spectral-domain optical coherence tomography, there was no evidence of scleral ectasia. Mean choroidal thickness of the uninvolved choroid was thicker than normal at 319 MUm (range, 244-439 MUm). All lesions remained stable except for in 1 eye, which had findings of central serous chorioretinopathy and secondary type 2 (subretinal) neovascularization. CONCLUSION: Focal choroidal excavation is a newly described idiopathic entity in eyes having 1 or more focal areas of choroidal excavation. In some patients, there may be an association with central serous chorioretinopathy. Although most lesions remain stable, secondary choroidal neovascularization may occur. PMID- 21670328 TI - Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds. AB - OBJECTIVE: To describe tumor control following intra-arterial chemotherapy (IAC) for retinoblastoma. METHODS: A retrospective interventional series in which 17 patients were treated with ophthalmic artery injection of melphalan, 5 mg, was undertaken to determine retinoblastoma control. RESULTS: Of 190 children with retinoblastoma, 17 (9%) were treated with IAC. Catheterization was successful in 37 of 38 attempts. The treatment was primary in 13 cases (1 failed catheterization) and secondary in 4. The median retinoblastoma base was 20 mm and the median retinoblastoma thickness was 9.0 mm. Iris neovascularization was present in 5 cases. Following IAC, complete response of the main tumor was found in 14 cases (88%) and partial response was found in 2 (12%). Eyes with complete response and followed up for a minimum of 1 year (n = 10) showed no solid tumor recurrence. Of 11 eyes with subretinal seeds, 9 (82%) had complete response, 1 (9%) had partial response, and 1 (9%) had recurrence. Of 9 eyes with vitreous seeds, 6 (67%) had complete response, 2 (22%) had partial response, and 1 (11%) had recurrence. Globe salvage was achieved in 8 of 12 eyes (67%) treated with primary IAC, including 2 of 2 group C eyes, 4 of 4 group D eyes, and 2 of 6 group E eyes according to the International Classification of Retinoblastoma. Globe salvage was achieved in 2 of 4 eyes (50%) treated secondarily after failure of other methods. CONCLUSIONS: Of 12 eyes managed with IAC as primary treatment, globe salvage was achieved in 67%. Eyes classified as group C or D showed 100% globe salvage, whereas group E had 33% salvage. Of 4 eyes managed with IAC as secondary treatment, globe salvage was achieved in 50%. PMID- 21670329 TI - Trends in glaucoma medication expenditure: Medical Expenditure Panel Survey 2001 2006. AB - OBJECTIVE: To study trends of glaucoma medication expenditure from 2001 to 2006 using a nationally representative sample of US adults. METHODS: We analyzed glaucoma medication expenditure trends among participants of the 2001-2006 Medical Expenditure Panel Survey, a subsample of the National Health Interview Survey, which is a continuous multipurpose, multistage area probability survey of the US civilian noninstitutionalized population. After adjusting for survey design and inflation using the 2009 inflation index, data from 1404 participants 18 years and older using glaucoma medication were analyzed. RESULTS: Mean annual glaucoma medication expenditure per subject increased from $445 in 2001 to $557 in 2006 (slope = 20.8; P < .001). Subgroup analysis showed expenditure increased significantly in women (P = .02), those with public-only insurance (P < .001), and those with less than a high school education (P < .008). Over the survey period, a significant decrease in expenditures on beta-blockers (P = .048) and significant increases in expenditures on prostaglandin analogs (P = .01) and alpha-agonists (P = .01) were found. CONCLUSIONS: Factors associated with increasing glaucoma medication expenditure trends include the increasing use of prostaglandin analogs, changes in insurance coverage, and possibly more aggressive glaucoma treatment. The findings are pertinent to the development of cost-effective strategies that optimize treatment and reduce expenditures. PMID- 21670330 TI - Rhetorical techniques used in the reporting of cardiac resynchronization trials. PMID- 21670331 TI - Principles of conservative prescribing. AB - Judicious prescribing is a prerequisite for safe and appropriate medication use. Based on evidence and lessons from recent studies demonstrating problems with widely prescribed medications, we offer a series of principles as a prescription for more cautious and conservative prescribing. These principles urge clinicians to (1) think beyond drugs (consider nondrug therapy, treatable underlying causes, and prevention); (2) practice more strategic prescribing (defer nonurgent drug treatment; avoid unwarranted drug switching; be circumspect about unproven drug uses; and start treatment with only 1 new drug at a time); (3) maintain heightened vigilance regarding adverse effects (suspect drug reactions; be aware of withdrawal syndromes; and educate patients to anticipate reactions); (4) exercise caution and skepticism regarding new drugs (seek out unbiased information; wait until drugs have sufficient time on the market; be skeptical about surrogate rather than true clinical outcomes; avoid stretching indications; avoid seduction by elegant molecular pharmacology; beware of selective drug trial reporting); (5) work with patients for a shared agenda (do not automatically accede to drug requests; consider nonadherence before adding drugs to regimen; avoid restarting previously unsuccessful drug treatment; discontinue treatment with unneeded medications; and respect patients' reservations about drugs); and (6) consider long-term, broader impacts (weigh long-term outcomes, and recognize that improved systems may outweigh marginal benefits of new drugs). PMID- 21670332 TI - "A little learning is a dangerous thing". PMID- 21670333 TI - Opioids for chronic pain. PMID- 21670334 TI - CRT--less is more: comment on "Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy". PMID- 21670335 TI - Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is effective in reducing clinical events in patients with heart failure and prolonged QRS interval. Studies using surrogate measures and subgroup analysis of large trials suggest that only patients with severely prolonged QRS benefit from CRT. Our objective was to determine whether the effect of CRT on adverse clinical events (eg, death, hospitalizations) is different in patients with moderately (ie, 120 to 149 milliseconds) [corrected] vs severely (ie, >=150 milliseconds) prolonged QRS duration. METHODS: Searches of MEDLINE, SCOPUS, and Cochrane databases were conducted for randomized controlled CRT trials. Trials reporting clinical events according to different QRS ranges were identified. Five randomized trials fulfilling the inclusion criteria (total patients, n = 5813) were included in the meta-analysis. RESULTS: In patients with severely prolonged QRS, there was a reduction in composite clinical events with CRT (risk ratio, 0.60; 95% confidence interval [CI], 0.53-0.67) (P < .001). In contrast, there was no benefit of CRT in patients with moderately prolonged QRS (RR, 0.95; 95% CI, 0.82-1.10) (P = .49), resulting in a significantly different impact of CRT in the 2 QRS groups (P < .001). There was a significant relationship between baseline QRS duration and risk ratio (P < .001) with benefit of CRT appearing at a QRS of approximately 150 milliseconds and above. The differential response of the 2 QRS groups was evident for all New York Heart Association classes. CONCLUSIONS: Cardiac resynchronization therapy was effective in reducing adverse clinical events in patients with heart failure and a baseline QRS interval of 150 milliseconds or greater, but CRT did not reduce events in patients with a QRS of less than 150 milliseconds. These findings have implications for the selection of patients for CRT. PMID- 21670336 TI - Intraocular pressure response to selective laser trabeculoplasty in the first treated eye vs the fellow eye. AB - OBJECTIVE: To determine if the intraocular pressure (IOP) response to selective laser trabeculoplasty (SLT) in one eye predicts long-term response to SLT in the fellow eye. METHODS: A retrospective medical record review was performed of patients who underwent SLT as primary treatment in both eyes and who completed at least 30 months of follow-up visits. Pearson product moment correlation analysis was performed to determine correlations between the 3-month percentage of IOP reduction in the first treated eye and long-term percentages of IOP reduction in the fellow eye. RESULTS: Medical records of 80 eyes in 40 patients were reviewed. In patients with ocular hypertension, the 3-month percentage of IOP reduction in the first treated eye correlated strongly with long-term percentages of IOP reduction in the fellow eye (r > 0.652). In patients with primary open-angle glaucoma, the 3-month percentage of IOP reduction in the first treated eye correlated moderately with percentages of IOP reduction in the fellow eye up to 9 months (r > 0.367). CONCLUSIONS: In patients with ocular hypertension, the 3 month percentage of IOP reduction in the first treated eye in response to SLT was predictive of response in the fellow eye up to 30 months. In patients with primary open-angle glaucoma, the 3-month percentage of IOP reduction in the first treated eye in response to SLT was predictive of response in the fellow eye up to 9 months. PMID- 21670337 TI - Estimated cases of legal blindness and visual impairment avoided using ranibizumab for choroidal neovascularization: non-Hispanic white population in the United States with age-related macular degeneration. AB - OBJECTIVE: To estimate the number of non-Hispanic white individuals in the United States avoiding legal blindness and visual impairment from neovascular age related macular degeneration (AMD) with ranibizumab availability. METHODS: Modeling of visual acuity outcomes from phase 3 ranibizumab trials to incidence rates of neovascular AMD from population-based studies. RESULTS: If no treatment were given, of the 103 582 individuals developing neovascular AMD for which ranibizumab would be indicated and available, 16 268 would become legally blind in 2 years. Monthly ranibizumab would reduce the incidence of legal blindness in 2 years by 72% (95% confidence interval [CI], 70% to 74%) to 4484 individuals. If no treatment were given, 34 702 would become visually impaired. Monthly ranibizumab would reduce the incidence of visual impairment in 2 years by 37% (95% CI, 35% to 39%) to 21 919 cases. CONCLUSIONS: Ranibizumab should have a substantial effect on reducing the magnitude of legal blindness and visual impairment within 2 years after diagnosis of neovascular AMD among non-Hispanic white individuals in the United States. Although racial subgroups other than non Hispanic whites were not considered (because there is limited information in the literature regarding incidence rates of choroidal neovascularization in other populations) and although these results assume access to and application of monthly ranibizumab for 2 years, the number of individuals developing legal blindness or vision impairment from neovascular AMD should be reduced dramatically if monthly ranibizumab is applied when indicated. PMID- 21670338 TI - Comparison of digital and film grading of diabetic retinopathy severity in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. AB - OBJECTIVE: To compare diabetic retinopathy (DR) severity as evaluated by digital and film images in a long-term multicenter study, as the obsolescence of film forced the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) to transition to digital after 25 years. METHODS: At 20 clinics from 2007 through 2009, 310 participants with type 1 diabetes with a broad range of DR were imaged, per the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, with both film and digital cameras. Severity of DR was assessed centrally from film and tonally standardized digital cameras. For retinopathy outcomes with greater than 10% prevalence, we had 85% or greater power to detect an agreement kappa of 0.7 or lower from our target of 0.9. RESULTS: Comparing DR severity, digital vs film yielded a weighted kappa of 0.74 for eye level and 0.73 for patient level ("substantial"). Overall, digital grading did not systematically underestimate or overestimate severity (McNemar bias test, P = .14). For major DR outcomes (>=3-step progression on the ETDRS scale and disease presence at ascending thresholds), digital vs film kappa values ranged from 0.69 to 0.96 ("substantial" to "nearly perfect"). Agreement was 86% to 99%; sensitivity, 75% to 98%; and specificity, 72% to 99%. Major conclusions were similar with digital vs film gradings (odds reductions with intensive diabetes therapy for proliferative DR at EDIC years 14 to 16: 65.5% digital vs 64.3% film). CONCLUSION: Digital and film evaluations of DR were comparable for ETDRS severity levels, DCCT/EDIC design outcomes, and major study conclusions, indicating that switching media should not adversely affect ongoing studies. PMID- 21670339 TI - Evolution in regression patterns following chemoreduction for retinoblastoma. AB - OBJECTIVE: To evaluate the change in regression pattern following chemoreduction and tumor consolidation therapy (thermotherapy or cryotherapy) for retinoblastoma METHODS: Retrospective medical record analysis was completed for 557 retinoblastomas (239 eyes of 157 patients) that were treated with chemoreduction and showed regression to 1 of 5 patterns (type 0, no visible remnant; type 1, completely calcified remnant; type 2, completely noncalcified remnant; type 3, partially calcified remnant; and type 4, atrophic chorioretinal flat scar). Evolution of these regression patterns was observed over time. RESULTS: Immediately following 6 cycles of chemoreduction, types 0 (2%), 1 (30%), 2 (3%), 3 (33%), and 4 (32%) regression patterns were found. During a mean follow-up period of 56 months (median, 48 months; range, 18-145 months), there was no change in regression patterns classified as type 0, 1, or 4. However, there was evolution of regression pattern types 2 and 3. Over time, type 2 tumor scars either remained stable (41%) or evolved to type 4 (41%), 3 (9%), or 1 (9%) scars. Type 3 tumor scars remained stable (74%) or evolved to type 1 (26%) scars. CONCLUSION: Following chemoreduction and tumor consolidation therapy, retinoblastoma regression patterns types 2 and 3 can slowly evolve over time into a slightly different appearance, even without additional treatment. Ophthalmologists should be familiar with these regression patterns and their evolution. PMID- 21670340 TI - Periocular topotecan for intraocular retinoblastoma. AB - OBJECTIVE: To review the effectiveness and toxicity of periocular topotecan hydrochloride in fibrin sealant (Tisseel) for the control of intraocular retinoblastoma. METHODS: Retrospective medical record review of visually threatening or recurrent intraocular retinoblastoma treated with periocular topotecan. RESULTS: Eight children (10 eyes) received 1 to 4 injections of periocular topotecan in fibrin sealant, without or with concomitant laser and/or single freeze-thaw prechemotherapy cryotherapy. Median dose was 0.18 mg/kg (3.72 mg/m(2)). The 6 children who responded to treatment had small discrete tumors (8 International Intraocular Retinoblastoma Classification group A or B eyes). Of these, prior primary treatment for 3 children (3 eyes) was laser; for 1 child (2 eyes), systemic chemotherapy with focal laser; and for 2 children (3 eyes), periocular topotecan. In 4 children (4 eyes), tumor regression was sufficient for effective focal therapy, but in 2 children (4 eyes), long-term control required systemic chemotherapy. The 2 children who did not respond each had an International Intraocular Retinoblastoma Classification group D eye treated primarily with systemic chemotherapy, focal laser, and cryotherapy and recurrent disease that was not controlled by periocular topotecan; both eyes were eventually enucleated. No ocular and minimal hematological toxic effects were observed. At 11 months' median follow-up after topotecan treatment (18 months since diagnosis), all 8 group A and B eyes were retained with ongoing focal therapy required in only 1 group B eye; the 2 group D eyes were enucleated. CONCLUSION: Periocular topotecan in fibrin sealant can achieve volume reduction of small and recurrent retinoblastoma sufficient to allow successful focal therapy. PMID- 21670341 TI - Phacomatosis pigmentovascularis of cesioflammea type in 7 patients: combination of ocular pigmentation (melanocytosis or melanosis) and nevus flammeus with risk for melanoma. AB - OBJECTIVE: To describe the features of phacomatosis pigmentovascularis (cesioflammea type). DESIGN: Noninterventional retrospective case series composed of 7 patients. RESULTS: Nevus flammeus combined with ipsilateral ocular melanocytosis or melanosis was seen in all 7 patients. Additional contralateral nevus flammeus was observed in 3 patients. Nevus flammeus (unilateral in 4 patients and bilateral in 3 patients) was distributed in trigeminal nerves V1 (n = 3), V2 (n = 7), and V3 (n = 5). Related findings included diffuse choroidal hemangioma (n = 1) and glaucoma (n = 1), with no patients having brain hemangioma or seizures. Ocular pigmentary abnormalities (unilateral in all 7 patients) included congenital ocular melanocytosis (n = 6) and conjunctival acquired melanosis (n = 1). Pigmentation was sectorial (partial) in 5 patients and complete in 2 patients. Melanocytosis involved the periocular skin in 1 patient, sclera in 2 patients, iris in 2 patients, and choroid in 4 patients. In 3 of 6 patients, melanocytosis was visible in the choroid only on dilated fundus evaluation. Related tumors included choroidal melanoma (n = 3), optic disc melanocytoma (n = 1), and conjunctival melanoma in situ (primary acquired melanosis) (n = 1). Melanoma metastasis developed in 1 patient. CONCLUSIONS: Phacomatosis pigmentovascularis shows features of nevus flammeus and more serious ocular pigmentary abnormalities (uveoscleral melanocytosis and conjunctival melanosis). Melanocytosis may be detected only by dilated ocular fundus examination, as found in 3 of 6 patients. Furthermore, choroidal melanoma can develop from melanocytosis, as noted in 3 of our 6 patients (50%). All patients with nevus flammeus should be examined for phacomatosis pigmentovascularis by an ophthalmologist because ocular melanocytosis and uveal melanoma may remain hidden within the eye. PMID- 21670342 TI - Influence of elevated intraocular pressure on the posterior chamber-anterior hyaloid membrane barrier during cataract operations. AB - OBJECTIVE: To investigate the influence of elevated intraocular pressure on the posterior chamber-anterior hyaloid membrane (PC-AHM) barrier during cataract operations in ex vivo porcine eyes. METHODS: A pressure transducer was connected to porcine eye anterior chambers (ACs). In experiment 1, ACs were perfused for 20 seconds with balanced salt solution containing 1.0-MUm fluorescein beads (10 eyes per bottle height: 45, 85, 145, and 285 cm). In experiment 2, 5 ophthalmic viscosurgical devices with different molecular weights and sodium hyaluronate concentrations were infused into the ACs (20 eyes per ophthalmic viscosurgical device). After continuous curvilinear capsulorrhexis, hydrodissection was performed. After both experiments, PC-AHM barrier staining was evaluated through the Miyake-Apple view. RESULTS: Types of fluorescein staining patterns were classified as AC, zonule of Zinn, AHM, AHM tear, and ruptured capsule. In experiment 1, plateau intraocular pressure and staining type were positively correlated (Spearman rank correlation; r = 0.703, P < .001). In experiment 2, mean peak intraocular pressure was significantly greater in the ruptured capsule type eyes than in the AC-, zonule of Zinn-, AHM (P < .001), or AHM-tear-(P = .02) type eyes, as well as in the AHM- and AHM-tear-type eyes compared with the AC and zonule of Zinn type eyes (P < .001). Intraocular pressure was significantly higher in eyes infused with ophthalmic viscosurgical devices with a higher molecular weight or sodium hyaluronate concentration (P < .05). CONCLUSIONS: Stress on the PC-AHM barrier increases as intraocular pressure increases. Ophthalmic viscosurgical devices with a higher molecular weight or sodium hyaluronate concentration might induce increased IOP during cataract operations. CLINICAL RELEVANCE: To maintain normal PC-AHM barrier function, excessive intraocular pressure should be avoided during cataract operations. PMID- 21670343 TI - Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and omega-3 fatty acids: the Rotterdam study. AB - OBJECTIVE: To investigate whether dietary nutrients can reduce the genetic risk of early age-related macular degeneration (AMD) conferred by the genetic variants CFH Y402H and LOC387715 A69S in a nested case-control study. METHODS: For 2167 individuals (>=55 years) from the population-based Rotterdam Study at risk of AMD, dietary intake was assessed at baseline using a semiquantitative food frequency questionnaire and genetic variants were determined using TaqMan assay. Incident early AMD was determined on fundus photographs at 3 follow-up visits (median follow-up, 8.6 years). The synergy index was used to evaluate biological interaction between risk factors; hazard ratios were calculated to estimate risk of early AMD in strata of nutrient intake and genotypes. RESULTS: Five hundred seventeen participants developed early AMD. Significant synergy indices supported the possibility of biological interaction between CFH Y402H and zinc, beta carotene, lutein/zeaxanthin, and eicosapentaenoic/docosahexaenoic acid (EPA/DHA) and between LOC387715 A69S and zinc and EPA/DHA (all P < .05). Homozygotes of CFH Y402H with dietary intake of zinc in the highest tertile reduced their hazard ratio of early AMD from 2.25 to 1.27. For intakes of beta-carotene, lutein/zeaxanthin, and EPA/DHA, these risk reductions were from 2.54 to 1.47, 2.63 to 1.72, and 1.97 to 1.30, respectively. Carriers of LOC387715 A69S with the highest intake of zinc and EPA/DHA reduced their risk from 1.70 to 1.17 and 1.59 to 0.95, respectively (all P trends <.05). CONCLUSIONS: High dietary intake of nutrients with antioxidant properties reduces the risk of early AMD in those at high genetic risk. Therefore, clinicians should provide dietary advice to young susceptible individuals to postpone or prevent the vision-disabling consequences of AMD. PMID- 21670345 TI - Oculodentodigital dysplasia: new ocular findings and a novel connexin 43 mutation. AB - OBJECTIVES: To describe new ocular findings associated with oculodentodigital dysplasia (ODDD) and a novel mutation in the connexin 43 transmembrane domain. DESIGN: Oculodentodigital dysplasia is a rare autosomal dominant disease characterized by multiple systemic abnormalities, most commonly of the ocular, nasal, dental, and limb structures. Herein, we studied 2 patients with ODDD. We describe their clinical findings and 2 ocular abnormalities not previously emphasized or reported. RESULTS: Optic nerve and retinal dysplasia was observed in both patients, and ciliary body cysts were observed in 1 patient. Both patients carried isolated in-frame deletion and missense mutations of the GJA1 gene on chromosome 6. CONCLUSIONS: Optic nerve and retinal dysplasia had not been emphasized as ocular manifestations of ODDD. Ciliary body cysts have not previously been reported in association with ODDD. CLINICAL RELEVANCE: Our findings support the potential significance of connexin 43 in the retina, optic nerve, and ciliary body. Retinal and optic nerve dysplasia may be more common than previously appreciated and may be associated with reduced vision. In addition, the ciliary body cysts observed in 1 patient may be secondary to weakened cellular adhesions between ciliary body pigmented and nonpigmented epithelium associated with the in-frame deletion identified in the affected patient. The presence of these cysts may exacerbate glaucoma or complicate its management. PMID- 21670346 TI - Ocular hypertension and normal-tension glaucoma: time for banishment and burial. PMID- 21670344 TI - Endothelial nitric oxide synthase gene variants and primary open-angle glaucoma: interactions with hypertension, alcohol intake, and cigarette smoking. AB - OBJECTIVE: To evaluate whether an association between risk of any of the factors of hypertension, alcohol intake, and cigarette smoking and the risk of primary open-angle glaucoma (POAG) depended on nitric oxide synthase 3 (NOS3) gene variants. METHODS: Two functional single-nucleotide polymorphisms (SNPs) (T-786C [rs2070744] and Glu298Asp [rs1799983]) and 2 tagging SNPs (rs7830 and rs3918188) were evaluated in nested case-control studies from the Nurses' Health Study (1980 2002) and the Health Professionals' Follow-up Study (1986-2002). Participants were 40 years of age or older and white, and were followed up biennially. We included 527 incident case patients with POAG and 1539 control participants, matched by cohort, age, and eye examination at the matched case patients' diagnosis dates. Cohort-specific relative risks were estimated using multivariable conditional logistic regression and were pooled using meta-analytic methods. RESULTS: The association between hypertension and POAG depended on T 786C SNP variants. Compared with TT homozygotes without hypertension, the TT homozygotes with hypertension were at significantly higher risk of POAG (relative risk,1.45 [95% confidence interval, 1.01-2.08]); however, among carriers of the variant (C) allele, hypertension was not associated with POAG (P interaction = .007). Similarly, compared with CC homozygotes with the rs7830 tagging SNP who never smoked, CC homozygotes who were past or current smokers were at significantly higher risk of POAG (relative risk, 1.63 [95% confidence interval, 1.15-2.31]); however, among carriers of the variant allele (A), smoking was not associated with POAG (P interaction = .004). Interactions were not observed with alcohol intake. CONCLUSIONS: The associations between hypertension and cigarette smoking in relation to POAG depended on NOS3 SNPs. PMID- 21670347 TI - Importance of the NHANES 2005-2008 diabetic retinopathy data. PMID- 21670348 TI - The first Western-style hospital in China. AB - Peter Parker (1804-1888), a Yale University--trained missionary and physician, founded the first Western-style hospital in China, the Ophthalmic Hospital in Canton (now known as Guangzhou), on November 4, 1835. During its first 3 months, Parker treated 1061 patients, of whom 1020 (96.1%) had ocular illnesses. Since then, the Ophthalmic Hospital in Canton has become a comprehensive institution that is affiliated with Sun Yat-sen University and is one of the largest hospitals in China. In 1965, the Department of Ophthalmology, which originally employed only 2 ophthalmologists, expanded to become an ophthalmic hospital. In 1983, it joined the Eye Research Institute and the Office of Prevention of Blindness to form the Zhongshan Ophthalmic Center. The center currently employs nearly 800 staff members and provides care to more than 500 000 patients annually. The first Western-style hospital in China has survived and thrived; it is now one of the most prestigious ophthalmic institutes in the world. PMID- 21670349 TI - Ocular surface disease secondary to vitamin A deficiency in the developed world: it still exists. PMID- 21670350 TI - Retinal dystrophy in 2 brothers with alpha-Mannosidosis. PMID- 21670351 TI - Spontaneous regression of small melanocytic choroidal tumor. PMID- 21670352 TI - Posterior microphthalmos as a genetically heterogeneous condition that can be allelic to nanophthalmos. PMID- 21670353 TI - Subclinical facioscapulohumeral muscular dystrophy masquerading as bilateral Coats disease in a woman. PMID- 21670354 TI - Three-dimensional reconstruction and analysis of vitreomacular traction: quantification of cyst volume and vitreoretinal interface area. PMID- 21670355 TI - Commercial air travel with a small intravitreous gas bubble. PMID- 21670356 TI - Complete, pupil-sparing third nerve palsy in a patient with a malignant peripheral nerve sheath tumor. PMID- 21670358 TI - Natamycin and voriconazole in fungal keratitis. PMID- 21670360 TI - Vitamin E and age-related cataracts. PMID- 21670362 TI - Immune choroiditis following acute retinal necrosis. PMID- 21670364 TI - Cystic macular lesions in patients with retinitis pigmentosa. PMID- 21670365 TI - Ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder and Graves ophthalmopathy. PMID- 21670366 TI - Norrie disease vs familial exudative vitreoretinopathy. PMID- 21670368 TI - Sustained ventricular fibrillation in a conscious patient. PMID- 21670370 TI - Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalized patients. AB - BACKGROUND: Previous studies have not demonstrated a consistent association between potentially inappropriate medicines (PIMs) in older patients as defined by Beers criteria and avoidable adverse drug events (ADEs). This study aimed to assess whether PIMs defined by new STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions) criteria are significantly associated with ADEs in older people with acute illness. METHODS: We prospectively studied 600 consecutive patients 65 years or older who were admitted with acute illness to a university teaching hospital over a 4-month interval. Potentially inappropriate medicines were defined by both Beers and STOPP criteria. Adverse drug events were defined by World Health Organization-Uppsala Monitoring Centre criteria and verified by a local expert consensus panel, which also assessed whether ADEs were causal or contributory to current hospitalization. Hallas criteria defined ADE avoidability. We compared the proportions of patients taking Beers criteria PIMs and STOPP criteria PIMs with avoidable ADEs that were causal or contributory to admission. RESULTS: A total of 329 ADEs were detected in 158 of 600 patients (26.3%); 219 of 329 ADEs (66.6%) were considered causal or contributory to admission. Of the 219 ADEs, 151 (68.9%) considered causal or contributory to admission were avoidable or potentially avoidable. After adjusting for age, sex, comorbidity, dementia, baseline activities of daily living function, and number of medications, the likelihood of a serious avoidable ADE increased significantly when STOPP PIMs were prescribed (odds ratio, 1.847; 95% confidence interval [CI], 1.506-2.264; P < .001); prescription of Beers criteria PIMs did not significantly increase ADE risk (odds ratio, 1.276; 95% CI, 0.945-1.722; P = .11). CONCLUSION: STOPP criteria PIMs, unlike Beers criteria PIMs, are significantly associated with avoidable ADEs in older people that cause or contribute to urgent hospitalization. PMID- 21670371 TI - Medication safety: are we there yet?: Comment on "Potentially inappropriate medications defined by STOPP criteria and the risk of adverse drug events in older hospitalized patients". PMID- 21670372 TI - Inappropriate medications in elderly ICU survivors: where to intervene? PMID- 21670373 TI - Nonmedical use of opioid analgesics obtained directly from physicians: prevalence and correlates. PMID- 21670374 TI - Effect of computerized physician order entry on radiologic examination order indication quality. PMID- 21670375 TI - Resident time spent in clinical and educational activities at home: implications for duty hours. PMID- 21670376 TI - Lack of cardiovascular disease among old order amish with familial defective apolipoprotein B. PMID- 21670377 TI - Depression and type 2 diabetes mellitus: a call to explore the common cause hypothesis. PMID- 21670378 TI - Low serum 25-hydroxyvitamin D levels and the bidirectional association between depression and type 2 diabetes mellitus in women. PMID- 21670379 TI - Levels of evidence needed for changing indications, contraindications, and Food and Drug Administration labeling: the case of metformin. PMID- 21670380 TI - FDA recalls not as alarming as they seem. PMID- 21670381 TI - Inverse association between duration of use of acid-suppressive medications and fracture risk. PMID- 21670382 TI - Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. AB - OBJECTIVE: To perform a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, which tested the effect of treatment with atorvastatin in reducing stroke in subjects with a recent stroke or transient ischemic attack, to explore the effects of treatment in subjects with type 2 diabetes mellitus or metabolic syndrome (MetS). METHODS: The 4731 subjects enrolled in the SPARCL trial were classified as having type 2 diabetes mellitus at enrollment (n = 794), MetS retrospectively (n = 642), or neither diabetes nor MetS (n = 3295, the reference group) based on data collected at baseline. Cox regression models were used to determine whether the effect of treatment on the primary end point (combined risk of nonfatal and fatal stroke) and secondary end points (major coronary events, major cardiovascular events, any coronary heart disease event, and any revascularization procedure) varied based on the presence of type 2 diabetes mellitus or MetS. RESULTS: Subjects with type 2 diabetes mellitus had increased risks of stroke (hazard ratio [HR] = 1.62; 95% confidence interval [CI], 1.33-1.98; P < .001), major cardiovascular events (HR = 1.66; 95% CI, 1.39-1.97; P < .001), and revascularization procedures (HR = 2.39; 95% CI, 1.78-3.19; P < .001) compared with the reference group. Subjects with MetS were not at increased risk for stroke (P = .78) or major cardiovascular events (P = .38) but more frequently had revascularization procedures (HR = 1.78; 95% CI, 1.26-2.5; P = .001). There were no treatment * subgroup interactions for the SPARCL primary end point (P = .47). CONCLUSIONS: The SPARCL subjects with type 2 diabetes were at higher risk for recurrent stroke and cardiovascular events. This exploratory analysis found no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or MetS. Trial Registration clinicaltrials.gov Identifier: NCT00147602. PMID- 21670383 TI - Treat Alzheimer disease before it is symptomatic. PMID- 21670384 TI - Yellow fever vaccination and increased relapse rate in travelers with multiple sclerosis. AB - OBJECTIVE: To investigate the effect of yellow fever (YF) immunization on the subsequent multiple sclerosis (MS) relapse risk. DESIGN: Self-controlled case series study. SETTING: An MS outpatient clinic. PATIENTS: Seven patients with clinical relapsing-remitting MS traveling to endemic YF areas who received the YF 17D-204 vaccine were studied. INTERVENTION: The YF 17D-204 vaccine. MAIN OUTCOME MEASURE: Number of relapses. Secondary outcomes included the number of new lesions on magnetic resonance imaging and peripheral mononuclear cell cytokine and chemokine production. RESULTS: The annual exacerbation rate during risk periods following immunization was 8.57, while the relapse rate outside the risk period was only 0.67 (rate ratio = 12.778; P < .001). Three months after immunization, patients showed a significant increase in new or enlarging T2 weighted lesions and gadolinium-enhancing lesions compared with 12 months prior to vaccination and 9 months after immunization (both P < .001). Moreover, blood myelin basic protein and myelin oligodendrocyte glycoprotein responses showed significant increases in interferon gamma-induced protein 10 kDa-, interferon gamma-, interleukin 1alpha-, interleukin 1beta-, and tumor necrosis factor secreting cell numbers as well as complement component C1qB production after YF vaccination in patients with MS compared with unvaccinated patients with MS, patients with MS vaccinated against influenza, and healthy control subjects (P = .01 and P < .001, respectively). CONCLUSION: For patients with MS traveling to endemic YF areas, vaccination should be recommended on the basis of carefully weighing the risk of exacerbation against the likelihood of exposure to the YF virus. PMID- 21670385 TI - Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations. AB - OBJECTIVE: To determine the frequency of malformations among infants born to women who had taken lamotrigine or carbamazepine as part of polytherapy during the first trimester of pregnancy. DESIGN: A cohort of women enrolled during pregnancy in the North American AED (Antiepileptic Drug) Pregnancy Registry between February 1, 1997, and June 1, 2010. Information on AED use and demographic characteristics was collected in 3 telephone interviews. SETTING: United States and Canada. PATIENTS: A total of 6857 pregnant women taking an AED for any reason. MAIN OUTCOME MEASURES: Major congenital malformations were identified at birth and through the first 12 weeks after delivery. Diagnoses were based on the mother's report and confirmed by medical records. The risks of malformations were compared between polytherapy and monotherapy groups, using exact odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The risk of malformations was 1.9% among infants exposed to lamotrigine as monotherapy (n = 1441). Among the infants exposed to lamotrigine as polytherapy (n = 505), the risks were 9.1% for lamotrigine plus valproate sodium (OR, 5.0; 95% CI, 1.5-14.0) and 2.9% for lamotrigine plus any other AEDs (1.5; 0.7-3.0). The risk of malformations was 2.9% for the infants exposed to carbamazepine monotherapy (n = 1012). For the infants exposed to carbamazepine as polytherapy (n = 365), the risks were 15.4% for carbamazepine plus valproate (OR, 6.2; 95% CI, 2.0-16.5) and 2.5% for carbamazepine plus any other AEDs (0.8; 0.3-1.9). Confounding by factors such as periconceptional vitamin use, cigarette smoking, alcohol use, and chronic maternal diseases did not explain the results. CONCLUSIONS: The risk of malformations among infants exposed to lamotrigine and carbamazepine as polytherapy was higher than the corresponding monotherapies only when the polytherapy includes valproate. These findings suggest that counseling for fetal risks from AED polytherapy should be based on the specific drugs included. PMID- 21670387 TI - Purkinje cell cytoplasmic autoantibody type 1 accompaniments: the cerebellum and beyond. AB - OBJECTIVE: To investigate the full extent of Purkinje cell cytoplasmic autoantibody type 1 autoimmunity (classically associated with paraneoplastic cerebellar degeneration) from clinical, immunohistochemical, and neuropathological perspectives. DESIGN: Case series. SETTING: Mayo Clinics, 3 sites (Minnesota, Arizona, and Florida). PATIENTS: Of 133,138 patients tested over a 21-year period, 83 (0.06%) were identified as seropositive for Purkinje cell cytoplasmic autoantibody type 1 IgG. MAIN OUTCOME MEASURES: The frequency of cerebellar and noncerebellar disorders and the clinical outcomes (neurological and oncological) of the patients. RESULTS: All patients were women. At initial presentation, 64 patients (77%) had a cerebellar disorder, and 19 patients (23%) had an extracerebellar disorder. Over the clinical course, neurological symptoms and signs were multifocal in 50 patients (60%), and they involved the cerebellum (89% of patients), the pyramidal tract (30%), the brainstem (13%), and the spinal anterior horn cells or peripheral nerve (10%; frequently upper limb predominant); 11% of patients did not develop cerebellar ataxia. Serological and neuropathological findings were observed in the cerebellum, the brainstem, the spinal cord, the anterior horn, and the dorsal root ganglion that paralleled the diversity of clinical signs. After a median follow-up of 18 months, 1 or more carcinomas had been detected in 88% of patients: ovarian epithelial cancer (53%), breast cancer (22%), fallopian tubal cancer (11%), primary peritoneal cancer (5%), metastases of unknown primary cancer (4%), and other cancers (4%). Sustained improvement was reported in 15% of patients following oncological or immunological therapies. Voltage-gated calcium channel antibodies coexisted in 23 patients (28%). CONCLUSIONS: Purkinje cell cytoplasmic autoantibody type 1 autoimmunity most commonly affects the cerebellum, but the spectrum of neurological symptoms and presentations is broad. Neurological outcomes are usually poor, even when cancer remission is achieved. PMID- 21670388 TI - Visual attention study in youth with spastic cerebral palsy using the event related potential method. AB - Youth with mild spastic cerebral palsy (n = 14) and a peer control group were compared on an oddball paradigm. Here, visual stimuli were presented with low and high probability and participants were instructed to count in silence the number of rare stimuli. The infrequent stimulus typically elicits an enhanced frontal central N2 and a centroparietal P300 event-related brain potential, reflecting orientation and evaluation of stimulus novelty. No differences in latency and amplitude of the N2-P300 complex were found between the 2 groups, indicating that some fundamental attention processes are intact in youth with mild spastic cerebral palsy. PMID- 21670389 TI - Primary leptomeningeal melanocytosis in a 10-year-old girl: a challenging diagnosis with a poor prognosis. AB - Primary leptomeningeal melanocytosis is rarely encountered in the pediatric population. Despite being considered a nonmalignant condition, it uniformly carries a poor prognosis given the ineluctable progression of meningeal infiltration. The case of a previously healthy 10-year-old girl who was first thought to suffer from recurrent hemiplegic migraine is reported. She later developed insidious subacute hydrocephalus. Meningeal biopsy performed during shunt insertion demonstrated an unexpectedly large number of melanocytes consistent with meningeal melanocytosis. Subsequently, the child developed recurrent shunt dysfunction and showed evidence of malignant transformation. The steps to reaching the proper diagnosis are discussed, and the current literature on this rare clinical entity as well as on related central nervous system melanocytic lesions that can occur in the pediatric population is reviewed. PMID- 21670390 TI - Magnetic resonance imaging (MRI) as a translational tool for the study of neonatal stroke. AB - More than half of neonatal stroke survivors have long-term sequelae, including seizures and neurological deficits. Although the immature brain has tremendous potential for recovery, mechanisms governing repair are essentially unexplored. We investigated whether magnetic resonance imaging (MRI) early or late after transient middle cerebral arterial occlusion in postnatal day (P) 10 rats can serve as an intermediate endpoint for long-term studies. Injured animals selected by diffusion-weighted MRI during middle cerebral arterial occlusion were scanned using T2-weighted MRI at P18 and P25 (injury volumes on MRI and histology were compared) or were subjected to contrast-enhanced MRI at P13 to characterize cerebral microcirculatory disturbances and blood-brain barrier leakage. Injury volume during middle cerebral artery occlusion did not predict histological outcome at 2 weeks. Major reductions in injury volume occurred by P18, with no further changes by P25 and correlated with histological injury. Cerebral perfusion was significantly reduced in the injured caudate but blood-brain barrier leakage was small. Therefore, conventional T2-weighted MRI performed during a subchronic injury phase predicts a long-term histological outcome after experimental neonatal focal stroke. PMID- 21670392 TI - Aicardi-Goutieres syndrome and systemic lupus erythematosus (SLE) in a 12-year old boy with SAMHD1 mutations. AB - Aicardi-Goutieres syndrome is an early-onset encephalopathy with a presumed immune pathogenesis caused by inherited defects in nucleic acid metabolism. The clinical picture resembles a congenital viral infection despite negative investigations for common viruses. In addition to leukoencephalopathy with calcifications of basal ganglia, patients show increased levels of the antiviral cytokine interferon-alpha in cerebrospinal fluid. We report on a 12-year-old boy with Aicardi-Goutieres syndrome and systemic lupus erythematosus (SLE) due to mutations in the SAMHD1 (sterile alpha motif domain and HD domain-containing protein 1) gene, illustrating an emerging pattern of the natural history of Aicardi-Goutieres syndrome characterized by neurological disease followed by symptoms of systemic autoimmunity. Thus, Aicardi-Goutieres syndrome constitutes a model disease for systemic autoimmunity triggered by the activation of the innate immune system. Recognition of the etiologic link between Aicardi-Goutieres syndrome and systemic lupus erythematosus has direct implications on therapeutic management and suggests that early immune modulatory intervention can improve neurological outcome. PMID- 21670393 TI - Sleep in children with cerebral palsy: a review. AB - Children with neurodevelopmental disabilities, such as cerebral palsy, are considered to be a population at risk for the occurrence of sleep problems. Moreover, recent studies on children with cerebral palsy seem to indicate that this population is at higher risk for sleep disorders. The importance of the recognition and treatment of sleep problems in children with cerebral palsy cannot be overemphasized. It is well known that the consequences of sleep disorders in children are broad and affect both the child and family. This review article explores the types and possible risk factors associated with the development of sleep problems in children with cerebral palsy and the impact of this disorder on the child and family. In addition, a brief summary of current diagnostic and treatment modalities is provided. Finally, the characteristics, diagnostic techniques, and management of sleep-related breathing disorders in children with cerebral palsy are discussed. PMID- 21670386 TI - Longitudinal change of biomarkers in cognitive decline. AB - OBJECTIVE: To delineate the trajectories of Abeta42 level in cerebrospinal fluid (CSF), fludeoxyglucose F18 (FDG) uptake using positron emission tomography, and hippocampal volume using magnetic resonance imaging and their relative associations with cognitive change at different stages in aging and Alzheimer disease (AD). DESIGN: Cohort study. SETTING: The 59 study sites for the Alzheimer's Disease Neuroimaging Initiative. PARTICIPANTS: A total of 819 participants 55 to 90 years of age with normal cognition, mild cognitive impairment, and AD who were followed up during the period from 2005 to 2007. MAIN OUTCOME MEASURES: Rates of change in level of Abeta42 in CSF, FDG uptake, hippocampal volume, and the Alzheimer Disease's Assessment Scale-cognitive subscale score during up to 36 months of follow-up by diagnostic group as well as prediction of cognitive change by each biomarker. RESULTS: Reductions in the level of Abeta42 in CSF were numerically greater in participants with normal cognition than in participants with mild cognitive impairment or AD; whereas both glucose metabolic decline and hippocampal atrophy were significantly slower in participants with normal cognition than in participants with mild cognitive impairment or AD. Positive APOE4 status accelerated hippocampal atrophic changes in participants with mild cognitive impairment or AD, but did not modify rates of change in level of Abeta42 in CSF or FDG uptake. The Alzheimer Disease's Assessment Scale-cognitive subscale scores were related only to the baseline level of Abeta42 in CSF and the baseline FDG uptake in participants with normal cognition, which were about equally associated with change in FDG uptake and hippocampal volume in participants with mild cognitive impairment and best modeled by change in FDG uptake in participants with AD. CONCLUSION: Trajectories of Abeta42 level in CSF, FDG uptake, and hippocampal volume vary across different cognitive stages. The longitudinal patterns support a hypothetical sequence of AD pathology in which amyloid deposition is an early event before hypometabolism or hippocampal atrophy, suggesting that biomarker prediction for cognitive change is stage dependent. PMID- 21670391 TI - The black box of perinatal ischemic stroke pathogenesis. AB - An improved understanding of perinatal stroke epidemiology, classification, neuroimaging, and outcomes has emerged in recent years. Despite this, little is known regarding the pathophysiological mechanisms responsible for most cases. A multitude of possible associations and putative risk factors have been reported, but most lack definitive empirical evidence supporting primary causation. These include obstetrical and maternal factors, perinatal conditions, infectious diseases, prothrombotic abnormalities, cardiac disorders, medications, and many others. The bulk of evidence is weak, dominated by case reports and retrospective case series. Findings from the small number of case-control and cohort studies that exist are limited by heterogeneous populations and methodologies. The single largest barrier to ultimately understanding and potentially improving outcomes from this common and disabling condition is the lack of comprehensive, fully powered risk factor studies required to definitively describe perinatal stroke pathogenesis. This review summarizes current evidence and suggests future directions for research. PMID- 21670394 TI - Another good reason to consider surgical treatment for epilepsy more often and sooner. PMID- 21670395 TI - Movement disorders emergencies Part 2: hyperkinetic disorders. AB - Although movement disorders do not usually present as neurologic emergencies, there are times when the abrupt onset of an unusual movement abnormality results in emergency department or intensive care unit consultations. Part 1 of this review discussed hypokinetic movement disorders emergencies. Part 2 provides a diagnostic approach to the recognition and treatment of hyperkinetic movement disorders emergencies by identifying phenomenology and reviewing common etiologies. PMID- 21670396 TI - Sleep manifestations of voltage-gated potassium channel complex autoimmunity. AB - OBJECTIVE: To identify the spectrum of sleep disorders associated with autoantibodies reactive with voltage-gated potassium channel (VGKC) complexes. DESIGN: Case series of all patients with neurologic disorders of VGKC autoimmunity evaluated in the Mayo Clinic Center for Sleep Medicine (Rochester, Minnesota) between January 1, 1994, and February 1, 2010. SETTING: Academic referral center. PATIENTS: Fifteen consecutive patients were identified with limbic encephalitis (n = 5), Morvan syndrome (n = 4), and overlapping features (n = 6). INTERVENTION: Ten patients received immunotherapy (corticosteroids, cyclophosphamide, or mycophenolate mofetil). MAIN OUTCOME MEASURE: Response to immunotherapy. RESULTS: The median VGKC autoantibody value at presentation was 1.51 nmol/L (range, 0.09-4.86 nmol/L). Neoplasms were discovered in 5 patients (33%) (thymoma [n = 2], prostate adenocarcinoma, colon adenocarcinoma, and melanoma). In 14 patients (93%), serious sleep disturbances were identified (insomnia, dream enactment behavior, suspected nocturnal epilepsy, and hypersomnia). Severe insomnia occurred in 9 patients (60%), regardless of neurologic presentation. Polysomnography at presentation (7 patients) revealed a mean sleep efficiency of 19% (4 patients had complete absence of sleep). Dream enactment behavior occurred in 8 patients (53%), including 3 of 5 with limbic encephalitis and all 4 with Morvan syndrome. Two of 7 polysomnograms demonstrated loss of rapid eye movement sleep muscle atonia; absent or minimal rapid eye movement sleep precluded interpretation in 4 patients. Sleep disorders resolved completely or almost completely in 8 of 10 patients who received immunotherapy. CONCLUSIONS: Sleep disorders are cardinal manifestations of VGKC complex autoimmunity in association with a spectrum of neurologic presentations. They may respond favorably to immunotherapy. PMID- 21670397 TI - Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. AB - OBJECTIVE: To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS. DESIGN: Case-control study. SETTING: France and Quebec, Canada. PARTICIPANTS: A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French Canadian origin. RESULTS: We observed a significant association between ATXN2 high-length alleles (>=29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (>=32 CAG repeats) in both familial and sporadic ALS cases. CONCLUSIONS: Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS. PMID- 21670399 TI - Clinical correlates of white matter tract degeneration in progressive supranuclear palsy. AB - OBJECTIVES: To use diffusion tensor imaging to assess white matter tract degeneration in progressive supranuclear palsy (PSP) and to investigate correlates between tract integrity and clinical measures. DESIGN: Case-control study. SETTING: Tertiary care medical center. PATIENTS/PARTICIPANTS: Twenty patients with probable PSP and 20 age- and sex-matched healthy controls were enrolled. All patients with PSP underwent standardized clinical testing, including the Frontal Behavioral Inventory and Frontal Assessment Battery to assess behavioral change, the PSP Rating Scale to measure disease severity, the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (parts II and III) to measure motor function, and the PSP Saccadic Impairment Scale to measure eye movement abnormalities. METHODS: Fractional anisotropy and mean diffusivity were measured using region of interest analysis and tract-based spatial statistics. RESULTS: Compared with controls, abnormal diffusivity was observed predominantly in the superior cerebellar peduncles, body of the corpus callosum, inferior longitudinal fasciculus, and superior longitudinal fasciculus in patients with PSP. Fractional anisotropy values in the superior cerebellar peduncles correlated with disease severity (r = -0.59, P = .006), inferior longitudinal fasciculus correlated with motor function (r = 0.51, P = .02), and superior longitudinal fasciculus correlated with severity of saccadic impairments (r = -0.45, P = .047). CONCLUSIONS: The results of this study demonstrate that PSP is associated with degeneration of the brainstem, association, and commissural fibers and that this degeneration likely plays an important role in clinical dysfunction. PMID- 21670398 TI - Diet intervention and cerebrospinal fluid biomarkers in amnestic mild cognitive impairment. AB - OBJECTIVE: To compare the effects of a 4-week high-saturated fat/high-glycemic index (HIGH) diet with a low-saturated fat/low-glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI). DESIGN: Randomized controlled trial. SETTING: Veterans Affairs Medical Center clinical research unit. PARTICIPANTS: Forty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years). INTERVENTION: Participants received the HIGH diet (fat, 45% [saturated fat, > 25%]; carbohydrates, 35%-40% [glycemic index, > 70]; and protein, 15%-20%) or the LOW diet (fat, 25%; [saturated fat, < 7%]; carbohydrates, 55%-60% [glycemic index, < 55]; and protein, 15%-20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet. MAIN OUTCOME MEASURES: The CSF concentrations of beta-amyloid (Abeta42 and Abeta40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition. RESULTS: For the aMCI group, the LOW diet increased CSF Abeta42 concentrations, contrary to the pathologic pattern of lowered CSF Abeta42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Abeta42, whereas the HIGH diet increased CSF Abeta42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2 isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet. CONCLUSION: Our results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of Abeta42, lipoproteins, oxidative stress, and insulin. PMID- 21670400 TI - Outcomes of mild cognitive impairment by definition: a population study. AB - BACKGROUND: Mild cognitive impairment (MCI) has been defined in several ways. OBJECTIVE: To determine the 1-year outcomes of MCI by different definitions at the population level. DESIGN: Inception cohort with 1-year follow-up. Participants were classified as having MCI using the following definitions operationalized for this study: amnestic MCI by Mayo criteria, expanded MCI by International Working Group criteria, Clinical Dementia Rating (CDR) = 0.5, and a purely cognitive classification into amnestic and nonamnestic MCI. SETTING: General community. PARTICIPANTS: Stratified random population-based sample of 1982 individuals 65 years and older. MAIN OUTCOME MEASURES: For each MCI definition, there were 3 possible outcomes: worsening (progression to dementia [CDR >= 1] or severe cognitive impairment), improvement (reversion to CDR = 0 or normal cognition), and stability (unchanged CDR or cognitive status). RESULTS: Regardless of MCI definition, over 1 year, a small proportion of participants progressed to CDR > 1 (range, 0%-3%) or severe cognitive impairment (0%-20%) at rates higher than their cognitively normal peers. Somewhat larger proportions of participants improved or reverted to normal (6%-53%). Most participants remained stable (29%-92%). Where definitions focused on memory impairment and on multiple cognitive domains, higher proportions progressed and lower proportions reverted on the CDR. CONCLUSIONS: As ascertained by several operational definitions, MCI is a heterogeneous entity at the population level but progresses to dementia at rates higher than in normal elderly individuals. Proportions of participants progressing to dementia are lower and proportions reverting to normal are higher than in clinical populations. Memory impairments and impairments in multiple domains lead to greater progression and lesser improvement. Research criteria may benefit from validation at the community level before incorporation into clinical practice. PMID- 21670402 TI - Reliability of seizure semiology in patients with 2 seizure foci. AB - OBJECTIVE: To determine whether seizure semiology is reliable in localizing and distinguishing seizures at 2 independent brain foci in the same patient. DESIGN: Two masked reviewers localized seizures from 2 foci by their clinical semiology and intracranial electroencephalograms (EEGs). SETTING: Epilepsy monitoring unit of referral comprehensive epilepsy program. PATIENTS: Seventeen consecutive patients (51 seizures) with sufficient video and intracranial EEG data were identified by reviewing medical records of 366 patients older than 10 years. MAIN OUTCOME MEASURES: The primary outcome measures were interobserver agreement between the 2 masked reviewers; the proportion of seizures localized by semiology; the proportion of localized seizures concordant with intracranial EEG localization; and comparison between concordant and nonconcordant seizures in latency of intracranial EEG seizure spread. RESULTS: Interobserver agreement was 41% (kappa score, 0.16). Only 30 of 51 seizures (59%) were localized by seizure semiology. The focus localized by semiology was concordant with the location of intracranial EEG seizure onset in 16 of 30 seizures (53%). No significant difference was observed between concordant and nonconcordant seizures in relation to the speed with which the EEG discharge spread from the location of seizure onset to another lobar region (P = .09, Wilcoxon rank sum test). CONCLUSION: Clinical seizure semiology is not as useful as intracranial EEG in localizing seizure onset in patients with dual seizure foci. PMID- 21670401 TI - Positron emission tomography of brain beta-amyloid and tau levels in adults with Down syndrome. AB - OBJECTIVES: To determine the neuropathological load in the living brain of nondemented adults with Down syndrome using positron emission tomography with 2 (1-{6-[(2-fluorine 18-labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([(18)F]FDDNP) and to assess the influence of age and cognitive and behavioral functioning. For reference, [(18)F]FDDNP binding values and patterns were compared with those from patients with Alzheimer disease and cognitively intact control participants. DESIGN: Cross-sectional clinical study. PARTICIPANTS: Volunteer sample of 19 persons with Down syndrome without dementia (mean age, 36.7 years), 10 patients with Alzheimer disease (mean age, 66.5 years), and 10 controls (mean age, 43.8 years). MAIN OUTCOME MEASURES: Binding of [(18)F]FDDNP in brain regions of interest, including the parietal, medial temporal, lateral temporal, and frontal lobes and posterior cingulate gyrus, and the average of all regions (global binding). RESULTS: The [(18)F]FDDNP binding values were higher in all brain regions in the Down syndrome group than in controls. Compared with the Alzheimer disease group, the Down syndrome group had higher [(18)F]FDDNP binding values in the parietal and frontal regions, whereas binding levels in other regions were comparable. Within the Down syndrome group, age correlated with [(18)F]FDDNP binding values in all regions except the posterior cingulate, and several measures of behavioral dysfunction showed positive correlations with global, frontal, parietal, and posterior cingulate [(18)F]FDDNP binding. CONCLUSIONS: Consistent with neuropathological findings from postmortem studies, [(18)F]FDDNP positron emission tomography shows high binding levels in Down syndrome comparable to Alzheimer disease and greater levels than in members of a control group. The positive associations between [(18)F]FDDNP binding levels and age as well as behavioral dysfunction in Down syndrome are consistent with the age-related progression of Alzheimer-type neuropathological findings in this population. PMID- 21670403 TI - Stroke and Alzheimer disease: fellow travelers or partners in crime? PMID- 21670404 TI - Plasma beta-amyloid linked to cognitive decline. PMID- 21670405 TI - Novel POLG splice site mutation and optic atrophy. AB - OBJECTIVE: To investigate the molecular etiology of 2 unrelated patients with a multisystem mitochondrial disorder accompanied by optic atrophy in one of them. DESIGN: Clinical examination and neurophysiological, radiological, morphological, and molecular analyses. SETTING: Tertiary care neuromuscular clinic and molecular genetics laboratory. PATIENTS: A 65-year-old man (patient 1) with dyschromatopsia and vision loss since childhood developed progressive external ophthalmoplegia, ptosis, and myopathy in the seventh decade of life and was found to have optic atrophy. A 63-year-old man (patient 2) with a similar phenotype, without visual symptoms, experienced also hearing loss and parkinsonism. MAIN OUTCOME MEASURES: Description of the clinical and molecular findings. RESULTS: A muscle biopsy specimen showed ragged-red, ragged-blue, and cytochrome c oxidase-negative fibers in both patients. Because optic atrophy in patient 1 suggested an autosomal dominant OPA1-related disorder, the OPA1 gene was first sequenced, the results of which did not detect any mutations. Southern blot and polymerase chain reaction analyses of muscle mitochondrial DNA revealed multiple deletions. Sequencing of POLG detected a novel variant, c.3104 + 3A>T, in both patients. Patient 1 was compound heterozygous for a known p.F749S mutation; patient 2 had p.G848S as the second mutation. Analysis of POLG complementary DNA showed that c.3104 + 3A>T results in skipping of exon 18. CONCLUSION: Early-onset dyschromatopsia and optic atrophy can occur not only in OPA1-related but also in POLG-related disorders with significant impact on genetic counseling. PMID- 21670406 TI - Mutation of SCARB2 in a patient with progressive myoclonus epilepsy and demyelinating peripheral neuropathy. AB - OBJECTIVE: To report the detection of mutations in the SCARB2 gene in a previously described patient with progressive myoclonus epilepsy (PME) and demyelinating peripheral neuropathy. DESIGN: Case report. SETTING: Epilepsy Genetics Research Laboratory and Epilepsy Service in a tertiary care center. PATIENT: A 27-year old male patient with PME with preserved intellect and peripheral neuropathy. RESULTS: We have solved a previously reported case of PME, preserved intellect, and demyelinating peripheral neuropathy. The patient is a compound heterozygote for 2 mutations in the SCARB2 gene, which has recently been found to be a cause of PME. CONCLUSIONS: Demyelinating neuropathy is a clinical clue to the presence of SCARB2 mutations in PME. PMID- 21670408 TI - Vein of Galen aneurysmal malformation. PMID- 21670407 TI - Neuropathy in a human without the PMP22 gene. AB - BACKGROUND: Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies. However, the biological functions of the PMP22 protein in humans have largely been unexplored owing to the absence of patients with PMP22-null mutations. OBJECTIVE: To investigate the function of PMP22 in the peripheral nervous system by studying a boy without the PMP22 gene and mice without the Pmp22 gene. DESIGN: The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. SETTING: Clinical evaluation was performed at tertiary hospitals in the United Kingdom. Molecular diagnosis was performed at the West Midlands Regional Genetics Laboratory. Immunohistochemistry and electron microscopy analyses were conducted at Wayne State University, Detroit, Michigan. Analysis of the Pmp22 +/- and null mice was performed at Vanderbilt University, Nashville, Tennessee. PARTICIPANT: A 7-year-old boy without the PMP22 gene. RESULTS: Motor and sensory deficits in the proband were nonlength-dependent. Weakness was found in cranial muscles but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and dorsal root ganglia during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells; these defects were more significant in motor nerve fibers than in sensory nerve fibers. CONCLUSIONS: Taken together, the data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with an absence of PMP22. PMID- 21670409 TI - Prominent forehead scalp arteries a diagnostic clue to unruptured anterior cranial fossa dural arteriovenous fistula. PMID- 21670410 TI - Magnetic resonance imaging characteristics at onset of spontaneous intracerebral hemorrhage. PMID- 21670411 TI - A dramatic case of intraventricular cysticercosis. PMID- 21670412 TI - Dissection or hemorrhage into arteriosclerotic plaque. PMID- 21670413 TI - Ethnic differences in aortic pulse wave velocity occur in the descending aorta and may be related to vitamin D. AB - We studied aortic pulse wave velocity (aPWV), a predictor of cardiovascular events independent of blood pressure, in a multiethnic sample of British men, to investigate the roles for blood levels of vitamin D and aldosterone in total and regional aortic stiffness. Total aPWV was estimated noninvasively by the Arteriograph device (aPWV(AG)) in 198 men, with its length measure calibrated by magnetic resonance. PWVs over the aortic arch and descending aorta were measured by magnetic resonance in a subsample (n=47). Mean (SE) aPWV(AG) in South Asians (n=68; age 55+/-10 years), at known higher coronary disease risk than other groups, was 0.5 m/s (0.2 m/s) higher than in African Caribbeans (n=67; 55+/-10 years), at lowest coronary disease risk here, and Europeans (n=63; 57+/-8 years), adjusted for age, systolic blood pressure, and diabetes mellitus (P=0.01). By magnetic resonance, PWV over the descending aorta in South Asians was 0.7 m/s (0.3 m/s) and 0.8 m/s (0.3 m/s) higher than in African Caribbeans and Europeans, respectively; PWV over the aortic arch was not different. South Asians and African Caribbeans had 21 nmol/L (3 nmol/L) and 14 nmol/L (3 nmol/L) lower mean (SE) 25(OH)D than Europeans (P<0.001). Unlike aldosterone, 25(OH)D was negatively correlated with aPWV(AG) adjusted for age and systolic blood pressure, as well as weakened or removed ethnic differences in aPWV(AG) in regression models. These data suggest that aortic stiffness as aPWV parallels coronary disease risk in ethnic groups, descending aortic but not arch PWV has this feature, and serum 25(OH)D is an independent negative correlate of aPWV and may partly account for ethnicity-related differences in aPWV and coronary disease risk. PMID- 21670414 TI - Magnesium and vascular dysfunction in malignant hypertension. PMID- 21670415 TI - Acute change in vascular tone alters intima-media thickness. AB - Atherosclerosis is a lifelong process involving artery wall thickening. Increased wall thickness has been widely adopted as a preclinical surrogate marker of atherosclerosis. A prerequisite for such a surrogate marker is that it is a structural characteristic of the vessel wall that is not subject to acute changes. The purpose of this study was to examine the acute effects of vasodilator drug administration on wall thickness of the carotid and superficial femoral arteries. High-resolution ultrasound was used to examine carotid and femoral artery diameters and wall thickness in 15 young (25+/-4 years of age) and 15 older (70+/-6 years of age) healthy men who were administered sublingual glyceryl trinitrate. Diameter and wall thickness were collected before and across a 10-minute period after glyceryl trinitrate administration. Glyceryl trinitrate induced a significant increase in carotid and femoral artery diameter and a decrease in wall thickness in both young and older men (both P<0.001). The latter was significantly larger than in young men (both P<0.01). The changes in carotid artery wall thickness in both young (35+/-23 MUm) and older men (71+/-46 MUm) approximate those considered prognostically relevant. Collectively, our data suggest that vasodilator drug administration induces a rapid and marked decrease in wall thickness, which mirrors conduit artery vasodilation in both young and older men. This finding confirms the presence of acute changes in wall thickness and has important implications for future studies that assess artery wall characteristics as a surrogate measure of atherosclerosis. PMID- 21670417 TI - Unmasking true resistant hypertension: is the real-world resistance just revealed? PMID- 21670416 TI - Relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. AB - We demonstrated previously that the blood pressure of patients with IgA nephropathy becomes salt sensitive as renal damage progresses. We also showed that increased urinary angiotensinogen levels in such patients closely correlate with augmented renal tissue angiotensinogen gene expression and angiotensin II levels. Here, we investigated the relationship between urinary angiotensinogen and salt sensitivity of blood pressure in patients with IgA nephropathy. Forty one patients with IgA nephropathy consumed an ordinary salt diet (12 g/d of NaCl) for 1 week and a low-salt diet (5 g/d of NaCl) for 1 week in random order. The salt-sensitivity index was calculated as the reciprocal of the slope of the pressure-natriuresis curve drawn by linking 2 data points obtained during consumption of each diet. The urinary angiotensinogen:creatinine ratio was significantly higher in patients who consumed the ordinary salt diet compared with the low-salt diet (17.5 MUg/g [range: 7.3 to 35.6 MUg/g] versus 7.9 MUg/g [range: 3.1 to 14.2 MUg/g] of creatinine, respectively; P<0.001). The sodium sensitivity index in our patients positively correlated with the glomerulosclerosis score (r=0.43; P=0.008) and changes in logarithmic urinary angiotensinogen:creatinine ratio (r=0.37; P=0.017) but not with changes in urinary protein excretion (r=0.18; P=0.49). In contrast, changes in sodium intake did not alter the urinary angiotensinogen:creatinine ratio in patients with Meniere disease and normal renal function (n=9). These data suggest that the inappropriate augmentation of intrarenal angiotensinogen induced by salt and associated renal damage contribute to the development of salt-sensitive hypertension in patients with IgA nephropathy. PMID- 21670418 TI - Hepatocyte growth factor attenuates transforming growth factor-beta-angiotensin II crosstalk through inhibition of the PTEN/Akt pathway. AB - Both angiotensin II (Ang II) and transforming growth factor (TGF)-beta1 are thought to be involved in the progression of chronic kidney disease. In contrast, hepatocyte growth factor (HGF) counteracts the actions of Ang II and TGF-beta1. Therefore, in this study, we investigated the molecular mechanisms of how HGF antagonizes the Ang II-TGF-beta axis in renal cells. In cultured human mesangial cells, TGF-beta1 increased angiotensin type 1 receptor (AT(1)R) mRNA, mainly dependent on the Akt/phosphatidylinositol 3-kinase signaling pathway. Furthermore, TGF-beta1 decreased the expression and phosphatase activity of phosphatase and tensin homolog, deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. These data revealed positive feedback of the Ang II-TGF-beta pathway, because Ang II increased TGF beta expression. In contrast, HGF significantly attenuated the increase in AT(1)R gene expression, and inhibited the decrease in PTEN induced by TGF-beta1. Of importance, a PTEN-specific inhibitor significantly attenuated the reduction in TGF-beta1-induced AT(1)R expression by HGF. These data suggest that HGF attenuated TGF-beta1-induced AT(1)R expression through the PTEN/Akt pathway. To investigate this hypothesis, we performed in vivo experiments in mice with increased circulating levels of HGF produced by transgenically expressing HGF under control of a cardiac-specific transgene (HGF-Tg). In HGF-Tg mice, renal injury and fibrosis were significantly decreased, associated with reduction in AT(1)R expression and increase in PTEN after Ang II infusion, as compared with control mice. Moreover, these renal protective effects were abrogated by a neutralizing antibody against HGF. Thus, the present study demonstrated that HGF counteracts the vicious cycle of Ang II-TGF-beta1-AT(1)R, mediating the inhibition of PTEN. PMID- 21670419 TI - Relaxin ameliorates hypertension and increases nitric oxide metabolite excretion in angiotensin II but not N(omega)-nitro-L-arginine methyl ester hypertensive rats. AB - Previous findings suggest a potential therapeutic action of relaxin, the putative vasodilatory signal of normal pregnancy, in some forms of cardiovascular disease. However, the mechanisms underlying the beneficial effects of relaxin have not been fully elucidated. The purpose of this study was to determine whether the vasodilatory effects of relaxin are dependent on activation of NO synthase. We examined the effect of relaxin in male Sprague-Dawley rats given angiotensin II (Ang II; 200 ng/kg per minute SC by minipump), the NO synthase inhibitor N(omega) nitro-l-arginine methyl ester (l-NAME; 1.5 mg/100 g IV followed by 150 mg/L in drinking water), or vehicle for 3 weeks. After 7 days of Ang II or l-NAME, mean arterial pressure was elevated compared with baseline. Relaxin was administered (4 MUg/h, SC by minipump) for the next 2 weeks of Ang II, l-NAME, or vehicle treatment. Two-week relaxin treatment alone slightly reduced mean arterial pressure in normotensive rats. Three weeks of either Ang II or l-NAME treatment alone produced hypertension, albuminuria, mild glomerular sclerosis, reduced nitric oxide metabolite excretion, and increased oxidative stress (excretion of hydrogen peroxide and thiobarbituric acid reactive substances and renal cortex nitrotyrosine abundance). Relaxin reduced mean arterial pressure, albumin excretion, and oxidative stress markers and preserved glomerular structure and nitric oxide metabolite excretion in Ang II-treated rats; however, relaxin did not attenuate these changes in the rats treated with l-NAME. None of the treatments affected protein abundance of neuronal or endothelial NO synthase in the kidney cortex. These data suggest that the vasodilatory effects of relaxin are dependent on a functional NO synthase system and increased NO bioavailability possibly because of a reduction in oxidative stress. PMID- 21670420 TI - Angiotensin (1-7) induces MAS receptor internalization. AB - Angiotensin (Ang) (1-7) is the endogenous ligand for the G protein-coupled receptor Mas, a receptor associated with cardiac, renal, and cerebral protective responses. Physiological evidence suggests that Mas receptor (MasR) undergoes agonist-dependent desensitization, but the underlying molecular mechanism regulating receptor activity is unknown. We investigated the hypothesis that MasR desensitizes and internalizes on stimulation with Ang-(1-7). For this purpose, we generated a chimera between the MasR and the yellow fluorescent protein (YFP; MasR-YFP). MasR-YFP-transfected HEK 293T cells were incubated with Ang-(1-7), and the relative cellular distribution of MasR-YFP was observed by confocal microscopy. In resting cells, MasR-YFP was mostly localized to the cell membrane. Ang-(1-7) induced a redistribution of MasR-YFP to intracellular vesicles of various sizes after 5 minutes. Following the time course of [(125)I]Ang-(1-7) endocytosis, we observed that half of MasR-YFP underwent endocytosis after 10 minutes, and this was blocked by a MasR antagonist. MasR-YFP colocalized with Rab5, the early endosome antigen 1, and the adaptor protein complex 2, indicating that the R is internalized through a clathrin-mediated pathway and targeted to early endosomes after Ang-(1-7) stimulation. A fraction of MasR-YFP also colocalized with caveolin 1, suggesting that at some point MasR-YFP traverses caveolin 1-positive compartments. In conclusion, MasR undergoes endocytosis on stimulation with Ang-(1-7), and this event may explain the desensitization of MasR responsiveness. In this way, MasR activity and density may be tightly controlled by the cell. PMID- 21670421 TI - The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system. AB - Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (DeltaBP: 31.6+/-0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (DeltaBP: 12.3+/-1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (DeltaBP: 25.9+/-2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib induced hypertension. PMID- 21670422 TI - Personalized medicine and cancer supportive care: appropriate use of colony stimulating factor support of chemotherapy. PMID- 21670423 TI - Use of colony-stimulating factors with chemotherapy: opportunities for cost savings and improved outcomes. AB - Myeloid colony-stimulating factors (CSFs) decrease the risk of febrile neutropenia (FN) from high-risk chemotherapy regimens administered to patients at 20% or greater risk of FN, but little is known about their use in clinical practice. We evaluated CSF use in a multiregional population-based cohort of lung and colorectal cancer patients (N = 1849). Only 17% (95% confidence interval [CI] = 8% to 26%) patients treated with high-risk chemotherapy regimens received CSFs, compared with 18% (95% CI = 16% to 20%) and 10% (95% CI = 8% to 12%) of patients treated with intermediate- (10%-20% risk of FN) and low-risk (<10% risk of FN) chemotherapy regimens, respectively. Using a generalized estimating equation model, we found that enrollment in a health maintenance organization (HMO) was strongly associated with a lower adjusted odds of discretionary CSF use, compared with non-HMO patients (odds ratio = 0.44, 95% CI = 0.32 to 0.60, P < .001). All statistical tests were two-sided. Overall, 96% (95% CI = 93% to 98%) of CSFs were administered in scenarios where CSF therapy is not recommended by evidence-based guidelines. This finding suggests that policies to decrease CSF use in patients at lower or intermediate risk of FN may yield substantial cost savings without compromising patient outcomes. PMID- 21670424 TI - Frontotemporal dementia: what can the behavioral variant teach us about human brain organization? AB - The behavioral variant of frontotemporal dementia (bvFTD) slowly undermines emotion, social behavior, personal conduct, and decision making. These deficits occur in concert with focal neurodegeneration that can be quantified with modern structural and functional imaging and neuropathological methods. As a result, studies of bvFTD have helped to clarify brain structures, networks, and neurons that prove critical for normal social-emotional functioning. In this article, the authors review the evolving bvFTD literature and propose a simple, testable network-based working model for understanding bvFTD. PMID- 21670425 TI - Gerstmann meets Geschwind: a crossing (or kissing) variant of a subcortical disconnection syndrome? AB - That disconnection causes clinical symptoms is a very influential concept in behavioral neurology. Criteria for subcortical disconnection usually are symptoms that are distinct from those following cortical lesions and damage to a single, long-range fiber tract. Yet, a recent study combining functional magnetic resonance imaging and fiber tracking concluded that a focal lesion in left parietal white matter provides the only tenable explanation for pure Gerstmann's syndrome, an enigmatic tetrad of acalculia, agraphia, finger agnosia, and left right disorientation. Such a lesion would affect not only a single fiber tract but crossing or "kissing" of different fiber tracts and hence disconnect separate cortical networks. As fiber crossing is prominent in the cerebral white matter, the authors propose an extension to the subcortical disconnection framework that opens the door to ascribing a more diversified clinical phenomenology to white matter damage and ensuing disconnection than has been the case so far. PMID- 21670426 TI - Structural modulation of dendritic spines during synaptic plasticity. AB - The majority of excitatory synaptic input in the brain is received by small bulbous actin-rich protrusions residing on the dendrites of glutamatergic neurons. These dendritic spines are the major sites of information processing in the brain. This conclusion is reinforced by the observation that many higher cognitive disorders, such as mental retardation, Rett syndrome, and autism, are associated with aberrant spine morphology. Mechanisms that regulate the maturation and plasticity of dendritic spines are therefore fundamental to understanding higher brain functions including learning and memory. It is well known that activity-driven changes in synaptic efficacy modulate spine morphology due to alterations in the underlying actin cytoskeleton. Recent studies have elucidated numerous molecular regulators that directly alter actin dynamics within dendritic spines. This review will emphasize activity-dependent changes in spine morphology and highlight likely roles of these actin-binding proteins. PMID- 21670427 TI - Anticipatory anxiety hinders detection of a second target in dual-target search. AB - Professional visual searches (e.g., baggage screenings, military searches, radiological examinations) are often conducted in high-pressure environments and require focus on multiple visual targets. Yet laboratory studies of visual search tend to be conducted in emotionally neutral settings with only one possible target per display. In the experiment reported here, we looked to better emulate high-pressure search conditions by presenting searchers with arrays that contained between zero and two targets while inducing anticipatory anxiety via a threat-of-shock paradigm. Under conditions of anticipatory anxiety, dual-target performance was negatively affected, but single-target performance and time on task were unaffected. These results suggest that multiple-target searches may be a more sensitive instrument to measure the effect of environmental factors on visual cognition than single-target searches are. Further, the effect of anticipatory anxiety was modulated by individual differences in state anxiety levels of participants prior to the experiment. These results have implications for both the laboratory study of visual search and the management and assessment of professional searchers. PMID- 21670428 TI - Mating interest improves women's accuracy in judging male sexual orientation. AB - People can accurately infer others' traits and group memberships across several domains. We examined heterosexual women's accuracy in judging male sexual orientation across the fertility cycle (Study 1) and found that women's accuracy was significantly greater the nearer they were to peak ovulation. In contrast, women's accuracy was not related to their fertility when they judged the sexual orientations of other women (Study 2). Increased sexual interest brought about by the increased likelihood of conception near ovulation may therefore influence women's sensitivity to male sexual orientation. To test this hypothesis, we manipulated women's interest in mating using an unobtrusive priming task (Study 3). Women primed with romantic thoughts showed significantly greater accuracy in their categorizations of male sexual orientation (but not female sexual orientation) compared with women who were not primed. The accuracy of judgments of male sexual orientation therefore appears to be influenced by both natural variations in female perceivers' fertility and experimentally manipulated cognitive frames. PMID- 21670429 TI - Teaching NeuroImages: primary progressive aphasia: PET demonstration. PMID- 21670430 TI - Teaching NeuroImages: Isolated bilateral trigeminal nerve palsy. PMID- 21670431 TI - Love, lies, bleeding (with apologies to Lynne Truss). PMID- 21670432 TI - Will my baby walk?: The predictive value of cranial imaging. PMID- 21670433 TI - The consequences of optic neuritis: more than meets the eye. PMID- 21670434 TI - Predicting motor outcome and death in term hypoxic-ischemic encephalopathy. AB - OBJECTIVES: Central gray matter damage, the hallmark of term acute perinatal hypoxia-ischemia, frequently leads to severe cerebral palsy and sometimes death. The precision with which these outcomes can be determined from neonatal imaging has not been fully explored. We evaluated the accuracy of early brain MRI for predicting death, the presence and severity of motor impairment, and ability to walk at 2 years in term infants with hypoxic-ischemic encephalopathy (HIE) and basal ganglia-thalamic (BGT) lesions. METHODS: From 1993 to 2007, 175 term infants with evidence of perinatal asphyxia, HIE, and BGT injury seen on early MRI scans were studied. BGT, white matter, posterior limb of the internal capsule (PLIC), and cortex and brainstem abnormality were classified by severity. Motor impairment was staged using the Gross Motor Function Classification System. RESULTS: The severity of BGT lesions was strongly associated with the severity of motor impairment (Spearman rank correlation 0.77; p < 0.001). The association between white matter, cortical, and brainstem injury and motor impairment was less strong and only BGT injury correlated significantly in a logistic regression model. The predictive accuracy of severe BGT lesions for severe motor impairment was 0.89 (95% confidence interval 0.83-0.96). Abnormal PLIC signal intensity predicted the inability to walk independently by 2 years (sensitivity 0.92, specificity 0.77, positive predictive value 0.88, negative predictive value 0.85). Brainstem injury was the only factor with an independent association with death. CONCLUSION: We have shown that in term newborns with HIE and BGT injury, early MRI can be used to predict death and specific motor outcomes. PMID- 21670436 TI - SEPN1-related myopathies: clinical course in a large cohort of patients. AB - OBJECTIVE: To assess the clinical course and genotype-phenotype correlations in patients with selenoprotein-related myopathy (SEPN1-RM) due to selenoprotein N1 gene (SEPN1) mutations for a retrospective cross-sectional study. METHODS: Forty one patients aged 1-60 years were included. Clinical data including scoliosis, respiratory function, and growth measurements were collected by case note review. RESULTS: Mean age at onset was 2.7 years, ranging from birth to the second decade of life. All but 2 remained independently ambulant: one lost ambulation at age 5 years and another in his late 50s. The mean age of starting nocturnal noninvasive ventilation (NIV) was 13.9 years. One child required full-time NIV at the age of 1 year while in 2 cases NIV was started at 33 years. Two patients died from respiratory failure at the age of 10 and 22 years, respectively. The mean age at scoliosis onset was 10 years, in most cases preceded by rigidity of the spine. Fourteen patients had successful spinal surgery (mean age 13.9 years). Twenty-one were underweight; however, overt feeding difficulties were not a feature. CONCLUSIONS: This study describes the largest population affected by SEPN1-RM reported so far. Our findings show that the spectrum of severity is wider than previously reported. Respiratory insufficiency generally develops by 14 years but may occur as early as in infancy or not until the fourth decade. Motor abilities remain essentially static over time even in patients with early presentation. Most adult patients remain ambulant and fully employed. PMID- 21670437 TI - Type I interferon and Toll-like receptor expression characterizes inflammatory myopathies. AB - OBJECTIVES: Juvenile dermatomyositis (JDM), adult dermatomyositis, and polymyositis (PM) are idiopathic inflammatory myopathies (IIMs) characterized by muscle infiltration and specific muscle fiber alterations. They are thought to have an autoimmune etiology, but triggering factors, and how immunologic attack induces muscle weakness, remain unknown. Recent evidence suggests a key role for type I interferon (IFN)-mediated innate immunity in dermatomyositis, which we explored in JDM, dermatomyositis, and PM by gene expression profiling, and other methods. METHODS: Ten IIM and 5 control muscle biopsies were assessed for expression of approximately 16,000 genes by microarray; 37 additional IIM, 10 dystrophinopathic, and 14 nonmyopathic control muscles were studied for type I IFN-dependent genes, and Toll-like receptor (TLR) expression by immunochemistry and PCR. RESULTS: Type I IFN-dependent transcripts were significantly upregulated in IIM muscles compared to controls; in JDM the most expressed were ISG15 (408 fold), IFIT3 (261-fold), MX1 (99-fold), and IRF7 (37-fold). IFN-beta (but not IFN alpha) transcripts were upregulated in PM as well as dermatomyositis/JDM. TLR3 was upregulated particularly in JDM, being localized on vascular endothelial cells, muscle infiltrating cells (mainly myeloid dendritic cells), and regenerating myofibers; TLR7 and TLR9 proteins were present in IIM (prominently in PM), mainly on cell infiltrates, particularly plasma cells, and on some injured myofibers. CONCLUSIONS: IFN-beta and type I IFN-induced molecules are involved in PM as well as JDM/dermatomyositis. Endosomal TLRs (effectors of innate immunity) are also involved (but differently) in the 3 conditions, further suggesting viral involvement, although TLR activation could be secondary to tissue damage. PMID- 21670438 TI - Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. AB - OBJECTIVE: To report the clinical phenotype and outcome of isolated paraneoplastic myelopathy. METHODS: We systematically reviewed clinical, serologic, and MRI data for 31 patients (20 female) who presented with an isolated myelopathy and coexisting cancer: carcinoma (lung, 9; breast, 7; kidney, 2; thyroid, 2; ovary/endometrium, 2), melanoma (2), or other cancer (3), or a paraneoplastic autoantibody with strong cancer association (amphiphysin immunoglobulin G [IgG], 9; collapsin response-mediator protein 5-IgG, 9; Purkinje cell cytoplasmic autoantibody type 1, 2; antineuronal nuclear autoantibody [ANNA] 1, 1; ANNA-3, 1). RESULTS: Of 31 patients who presented with a progressive myelopathy, symptom onset was subacute in 16 (52%). The median age was 62 years. CSF abnormalities included elevated protein (>45 mg/dL), 22; pleocytosis, 15; excess oligoclonal bands (normal <4), 7. MRI cord abnormalities identified in 20 patients were longitudinally extensive (>3 vertebral segments), 14; symmetric tract or gray matter-specific signal abnormality, 15 (enhancing in 13). Myelopathy preceded cancer diagnosis in 18 patients (median interval 12 months; range 2-44). After myelopathy onset, 26 patients underwent oncologic treatment, immunosuppressive treatment (median delay to commencing immunotherapy 9.5 months [range 1-54]), or both; only 8 improved (31%). At last neurologic evaluation (median interval after onset 17 months; range 1-165 months), 16 patients (52%) were wheelchair-dependent (median time from onset to wheelchair 9 months [range 1 21]). Ten patients died after a median of 38 months from symptom onset (range 7 152). CONCLUSION: Symmetric, longitudinally extensive tract or gray matter specific changes on spinal MRI should raise suspicion for a paraneoplastic myelopathy. Resulting disability is often severe. Only a minority of patients improve with treatment. PMID- 21670439 TI - A multicenter assessment of cervical cord atrophy among MS clinical phenotypes. AB - OBJECTIVE: In this multicenter study, a new semiautomatic method for segmenting the cervical cord from C2 to C5 was used to investigate the correlation between cord atrophy and clinical disability in a large sample of patients with multiple sclerosis (MS). METHODS: T2 and 3-dimensional T1-weighted cervical cord scans and dual-echo brain scans were acquired from 143 healthy controls, 22 patients with clinically isolated syndromes (CIS), 101 patients with relapsing-remitting MS (RRMS), 79 patients with secondary progressive MS (SPMS), 58 patients with benign MS (BMS), and 75 patients with primary progressive MS (PPMS) in 3 European centers. Normalized cervical cord cross-sectional area (CSAn) was measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of CSA along the cervical cord. RESULTS: Cord CSAn was significantly lower in PPMS vs healthy controls, BMS vs RRMS, SPMS vs BMS, and RRMS. From C2 to C5, a net separation and definition of the plots of patients with BMS, PPMS, and SPMS was seen with respect to those of the other study groups. CSAn was correlated with Expanded Disability Status Scale (r = -0.49, p < 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS or in BMS; association in RRMS (r = -0.30, p = 0.001), SPMS (r = -0.34, p = 0.001), and PPMS (r = -0.27, p = 0.01). CONCLUSIONS: Cervical cord atrophy provides a relevant and useful marker for the characterization of clinical heterogeneity of patients with MS. The stability of this measure among different centers supports its use as potential outcome measure to monitor disease progression in multicenter trials. PMID- 21670440 TI - Sustained motion perception deficit following optic neuritis: Behavioral and cortical evidence. AB - OBJECTIVE: To assess the recovery process in patients after an acute optic neuritis (ON) attack, comparing static and dynamic visual functions. METHODS: In this prospective controlled study, 21 patients with unilateral, first-ever ON were followed over the course of 1 year. Standard visual tests, visual evoked potentials, and optical coherence tomography were assessed repeatedly. In addition, we developed a novel set of motion perceptual tasks to test dynamic visual deficits. fMRI examinations were performed to study the neuronal correlates for the behavioral findings. RESULTS: Four months after the acute phase, the affected eyes had returned to normal performance levels in the routine visual testing. However, motion perception remained impaired throughout the 12 month period. In agreement with the clinical findings, fMRI studies showed recovery in cortical activation during static object recognition, as opposed to sustained deficit in tasks that require motion perception. CONCLUSIONS: Sustained motion perception deficit following ON may explain the continued visual complaints of patients long after recovery of visual acuity. Cortical activation patterns suggest that if plastic processes in higher visual regions contribute to the recovery of vision, this may be limited to static visual functions. Alternatively, cortical activation may reflect the visual percept (intact for visual acuity and impaired for motion perception), rather than demonstrating plastic processes. We suggest that motion perception should be included in the routine ophthalmologic tests following ON. PMID- 21670442 TI - Problem neurology residents: a national survey. AB - OBJECTIVES: Problem residents are found across most medical specialties at a prevalence of about 10%. This study was designed to explore the prevalence and causes of problem neurology residents and to compare neurology programs' responses and outcomes. METHODS: Directors of 126 US neurology residency programs were sent an electronic survey. We collected data on demographics, first and all "identifiers" of problem residents, and year of training in which the problem was found. We asked about observable signs, etiology, and who performed remediation. We asked what resources were used and what outcomes occurred. RESULTS: Ninety five program directors completed surveys (75% response rate). Almost all neurology programs have problem residents (81%). Age, sex, marital status, being a US native, or attending a US medical school had no effect on problem status. Being a parent carried a lower likelihood of problems (32%). Most commonly the problem is acted on during the first year of training. Faculty members without defined educational roles were the most frequent first identifiers. Program directors were the most common remediators. The most common remediation techniques were increasing supervision and assigning a faculty mentor. Graduate medical education office and psychiatric or psychological counseling services were most often used. Eleven percent of problem residents required a program for impaired physicians and 14% required a leave of absence. Sixteen percent were dismissed from their programs. CONCLUSIONS: The prevalence of problem residents in neurology is similar to other disciplines, and various resources are available to remediate them. PMID- 21670444 TI - Aorto-left-ventricular tunnel: A rare cause of cardioembolic stroke in a 42-year old patient. PMID- 21670443 TI - Interleukin-7 receptor alpha gene polymorphism influences multiple sclerosis risk in Asians. PMID- 21670445 TI - Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. PMID- 21670446 TI - Multiple osteolytic bone lesions 3 years after ovarian cancer: benign or malignant? PMID- 21670447 TI - Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial. AB - PURPOSE: Radiochemotherapy of head and neck cancer causes severe mucositis in most patients. We investigated whether palifermin reduces this debilitating sequela. METHODS: We conducted a multicenter, double-blind, randomized, placebo controlled trial in 186 patients with stages II to IVB carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received 60 or 66 Gy after complete (R0) or incomplete resection (R1), respectively, at 2 Gy/fraction and five fractions per week. Cisplatin 100 mg/m(2) was administered on days 1 and 22 (and on day 43 with R1). Patients were randomly assigned to receive weekly palifermin 120 MUg/kg or placebo from 3 days before and continuing throughout radiochemotherapy. Trained evaluators performed oral assessments twice weekly. The primary end point was the incidence of severe oral mucositis (WHO grades 3 to 4). Overall survival and time to locoregional progression were also assessed. Analysis was by intention to treat. RESULTS: Severe oral mucositis was seen in 47 (51%) of 92 patients administered palifermin and 63 (67%) of 94 administered placebo (P = .027). Palifermin decreased the duration (median, 4.5 v 22.0 days) and prolonged the time to develop (median, 45 v 32 days) severe mucositis. Neither patient-reported mouth and throat soreness scores nor treatment breaks differed between treatment arms. After median follow-up of 32.8 months, 23 deaths (25%) had occurred in both treatment arms, and disease had recurred in 25 (27%) and 22 (24%) of palifermin- and placebo-treated patients, respectively. CONCLUSION: Palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. Additional clinical exploration of palifermin with postoperative radiochemotherapy would be useful. PMID- 21670448 TI - Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. AB - PURPOSE: To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. PATIENTS AND METHODS: A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). RESULTS: DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. CONCLUSION: DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis. PMID- 21670449 TI - Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial. AB - PURPOSE: Imatinib is the standard of care in adults with chronic myeloid leukemia (CML) in chronic phase (CP). Only a few studies to assess efficacy in children have been performed. We report on the results of the French prospective trial (ClinicalTrials.gov identifier NCT00845221) conducted in children and adolescents with newly diagnosed CML in CP. PATIENTS AND METHODS: A total of 44 patients from age 10 months to 17 years with newly diagnosed CML in CP received daily imatinib 260 mg/m(2). Progression-free survival, responses, and tolerance were evaluated. RESULTS: With a median follow-up times of 31 months (range, 11 to 64 months), the estimated progression-free survival rate at 36 months was 98% (95% CI, 85% to 100%). A complete hematologic response was achieved in 98% of the patients. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were 61% and 31% at 12 months, respectively. During follow-up, CCyR and MMR were achieved in 36 children (77%) and 25 children (57%), respectively. Overall, 30% of the patients discontinued imatinib, mainly because of unsatisfactory response. The most common adverse events were neutropenia and musculoskeletal events. CONCLUSION: Imatinib is effective in children with CML in CP with response rates similar to rates reported in adults. The adverse effects are acceptable, but longer follow-up studies are required to fully assess the long-term impact. PMID- 21670450 TI - Rare phenomenon: liver metastases from glioblastoma multiforme. PMID- 21670451 TI - Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy. AB - PURPOSE: To evaluate the risk of locoregional recurrence (LRR) associated with locoregional treatment of women with primary breast cancer tumors negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (triple-negative breast cancer [TNBC]). PATIENTS AND METHODS: Patients diagnosed with TNBC were identified from a cancer registry in a single institution (n=768). LRR-free survival was estimated using Kaplan-Meier analysis. The Cox proportional hazards regression model was used to determine risk of LRR on the basis of locoregional management: breast-conserving therapy (BCT; ie, lumpectomy and adjuvant radiation therapy [RT]) and modified radical mastectomy (MRM) in the TNBC population and T1-2N0 subgroup. RESULTS: At a median follow-up of 7.2 years, 77 patients (10%) with TNBC developed LRR. Five-year LRR-free survival was 94%, 85%, and 87% in the BCT, MRM, and MRM + RT groups, respectively (P < .001). In multivariate analysis, MRM (compared with BCT), lymphovascular invasion and lymph node positivity were associated with increased LRR. Conversely, adjuvant chemotherapy was associated with decreased risk of LRR. For patients with T1-2N0 tumors, 5-year LRR-free survival was 96% and 90% in the BCT and MRM groups, respectively (P = .027), and MRM was the only independent prognostic factor associated with increased LRR compared with BCT (hazard ratio, 2.53; 95% CI, 1.12 to 5.75; P = .0264). CONCLUSION: Women with T1-2N0 TNBC treated with MRM without RT have a significant increased risk of LRR compared with those treated with BCT. Prospective studies are warranted to investigate the benefit of adjuvant RT after MRM in TNBC. PMID- 21670452 TI - Molecular selection trumps clinical selection. PMID- 21670453 TI - Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. AB - PURPOSE: Oral mucositis (OM) is a debilitating toxicity of chemoradiotherapy for head and neck cancer (HNC). This randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of palifermin to reduce OM associated with definitive chemoradiotherapy for locally advanced HNC. PATIENTS AND METHODS: Patients receiving conventionally fractionated radiotherapy (2.0 Gy/d, 5 days/wk to 70 Gy) with cisplatin (100 mg/m(2) on days 1, 22, and 43) received palifermin (180 MUg/kg) or placebo before starting chemoradiotherapy and then once weekly for 7 weeks. The primary end point was the incidence of severe, observable, and functional OM (WHO grade 3 to 4). RESULTS: The palifermin (n = 94) and placebo (n = 94) arms were well balanced. The incidence of severe OM was significantly lower for palifermin than for placebo (54% v 69%; P = .041). In the palifermin arm, median time to severe OM was delayed (47 v 35 days), median duration of severe OM was shortened (5 v 26 days), and the incidence of xerostomia grade >= 2 was lower (67% v 80%), favoring palifermin; however, the differences were not significant after multiplicity adjustment. Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms. Adverse events were similar between arms (98%, palifermin; 93%, placebo). The most common study drug-related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between treatment arms. CONCLUSION: Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemoradiotherapy remains to be elucidated. PMID- 21670454 TI - Assessment of PTEN and PI3K status in primary breast cancer and corresponding metastases: is it worthwhile? PMID- 21670455 TI - Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia (IPASS). AB - PURPOSE: The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. PATIENTS AND METHODS: In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. RESULTS: OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). CONCLUSION: EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment. PMID- 21670456 TI - Palliative care and the quality of life. PMID- 21670457 TI - Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial. AB - PURPOSE: Many nonrandomized studies have suggested better outcome for patients with breast cancer who undergo surgery during the luteal (progestogenic) phase of their menstrual cycle, but this is controversial. We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial (ClinicalTrials.gov identifier, NCT00123669). PATIENTS AND METHODS: One thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An analysis by axillary lymph node status was preplanned. RESULTS: At a median follow-up of 65 months among 976 eligible patients, 273 recurrences and 202 deaths were recorded. In the progesterone group versus control group, 5-year DFS and OS rates were 73.9% v 70.2% (hazard ratio [HR], 0.87; 95% CI, 0.68 to 1.09; P = .23) and 80.2% v 78.4% (HR, 0.92; 95% CI, 0.69 to 1.21; P = .53), respectively. In 471 node-positive patients, the 5-year DFS and OS rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P = .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P = .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P = .02), whereas there was no significant effect in node-negative patients (P for interaction = .04). CONCLUSION: A single injection of hydroxyprogesterone before surgery did not improve outcomes in all women with OBC. This intervention showed significant improvement in node-positive women that may be considered hypothesis generating. If replicated in other studies, this could be a simple and inexpensive intervention, especially in developing countries where the incidence of lymph node metastasis is high. PMID- 21670458 TI - Carboplatin does not prevent contralateral testicular tumors in patients with seminoma. PMID- 21670459 TI - Is breast conservation therapy superior to mastectomy for women with triple negative breast cancers? PMID- 21670460 TI - Does topoisomerase II-alpha gene amplification provide useful information for treatment selection in patients with breast carcinoma? PMID- 21670461 TI - Presurgical progesterone in early breast cancer: so much for so little? PMID- 21670462 TI - Interpretation in consultations with immigrant patients with cancer: how accurate is it? AB - PURPOSE: Immigrants with cancer often have professional and/or family interpreters to overcome challenges communicating with their health team. This study explored the rate and consequences of nonequivalent interpretation in medical oncology consultations. PATIENTS AND METHODS: Consecutive immigrant patients with newly diagnosed with incurable cancer, who spoke Arabic, Cantonese, Mandarin, or Greek, were recruited from the practices of 10 medical oncologists in nine hospitals. Their first two consultations were audio taped, transcribed, translated into English and coded. RESULTS: Thirty-two of 78 participants had an interpreter at 49 consultations; 43% of interpreters were family, 35% professional, 18% both a professional and family, and 4% a health professional. Sixty-five percent of professional interpretations were equivalent to the original speech versus 50% for family interpreters (P= .02). Seventy percent of nonequivalent interpretations were inconsequential or positive; however, 10% could result in misunderstanding, in 5% the tone was more authoritarian than originally intended, and in 3% more certainty was conveyed. There were no significant differences in interpreter type for equivalency of interpretations. CONCLUSION: Nonequivalent interpretation is common, and not always innocuous. Our study suggests that there may remain a role for family or telephone versus face to-face professional interpreters. PRACTICE IMPLICATIONS: careful communication between oncologists and interpreters is required to ensure optimal communication with the patient. PMID- 21670463 TI - Biology and clinical relevance of the micropthalmia family of transcription factors in human cancer. AB - Members of the micropthalmia (MiT) family of transcription factors (MITF, TFE3, TFEB, and TFEC) are physiologic regulators of cell growth, differentiation, and survival in several tissue types. Because their dysregulation can lead to melanoma, renal cell carcinoma, and some sarcomas, understanding why these genes are co-opted in carcinogenesis may be of general utility. Here we describe the structure of the MiT family of proteins, the ways in which they are aberrantly activated, and the molecular mechanisms by which they promote oncogenesis. We discuss how meaningful understanding of these mechanisms can be used to elucidate the oncogenic process. Because the expression of these proteins is essential for initiating and maintaining the oncogenic state in some cancer types, we propose ways that they can be exploited to prevent, diagnose, and rationally treat these malignancies. PMID- 21670465 TI - Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. AB - The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy. PMID- 21670466 TI - How I treat Gaucher disease. AB - This review presents a cohesive approach to treating patients with Gaucher disease. The spectrum of the clinical presentation of the disease is broad, yet heretofore there was only one disease-specific treatment. In the past 2 years, a global shortage of this product has resulted in reassessment of the "one enzyme one disease-one therapy" mantra. It has also showcased the multiple levels that engage the patient, the treating physician, and the third-party insurer in providing adequate treatment to all symptomatic patients. The key points summarizing the way I manage my patients include accurate enzymatic diagnosis with mutation analysis (for some prognostication and better carrier detection in the family), a detailed follow-up every 6-12 months (with an option to see consultants and attention to comorbidities), and initiation of enzyme replacement therapy according to symptoms or deterioration in clinically significant features or both. I do not treat patients with very mild disease, but I consider presymptomatic therapy for patients at risk, including young women with poor obstetric history. I prefer the minimal-effective dose rather than the maximally tolerated dose, and when the difference between high-dose and lower-dose regimens is (merely statistically significant but) clinically meaningless, minimizing the burden on society by advocating less-expensive treatments is ethically justified. PMID- 21670467 TI - Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche. AB - Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or up-regulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfa(delta/delta), where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfa(delta/delta) mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-VEGFA axis. PMID- 21670468 TI - Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy largely caused by aberrant activation of the TAL1/SCL, LMO1/2, and NOTCH1 oncogenes. Approximately 30% of T-ALL patients relapse, and evidence is emerging that relapse may result from a failure to eliminate leukemia-initiating cells (LICs). Thymic expression of the Tal1 and Lmo2 oncogenes in mice results in rapid development of T-ALL; and similar to T-ALL patients, more than half the leukemic mice develop spontaneous mutations in Notch1. Using this mouse model, we demonstrate that mouse T-ALLs are immunophenotypically and functionally heterogeneous with approximately 1 of 10,000 leukemic cells capable of initiating disease on transplantation. Our preleukemic studies reveal expansion of Notch active double-negative thymic progenitors, and we find the leukemic DN3 population enriched in disease potential. To examine the role of Notch1 in LIC function, we measured LIC activity in leukemic mice treated with vehicle or with a gamma-secretase inhibitor. In 4 of 5 leukemias examined, Notch inhibition significantly reduced or eliminated LICs and extended survival. Remarkably, in 2 mice, gamma-secretase inhibitor treatment reduced LIC frequency below the limits of detection of this assay, and all transplanted mice failed to develop disease. These data support the continued development of Notch1 therapeutics as antileukemia agents. PMID- 21670469 TI - Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment. AB - Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL. PMID- 21670470 TI - Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. AB - Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes. PMID- 21670471 TI - Thalidomide for previously untreated elderly patients with multiple myeloma: meta analysis of 1685 individual patient data from 6 randomized clinical trials. AB - The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%. PMID- 21670472 TI - Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. AB - Despite increasing use of prothrombin complex concentrate (PCC) to treat hemorrhage-associated coagulopathy, few studies have investigated PCC in trauma, and there is a particular lack of safety data. This study was performed to evaluate PCC therapy in a porcine model of coagulopathy with blunt liver injury. Coagulopathy was induced in 27 anesthetized pigs by replacing approximately 70% blood volume with hydroxyethyl starch 130/0.4 and Ringer's lactate solution; erythrocytes were collected and retransfused. Ten minutes after trauma, animals randomly received PCC (35 or 50 IU/kg) or saline. Coagulation parameters including thromboelastometry, thrombin generation, and blood loss were monitored for 2 hours. Internal organs were examined macroscopically and histologically to determine the presence of emboli and assess liver injury. Total blood loss was significantly lower and survival was higher in both PCC groups versus the control group (P < .05). These outcomes appeared to be dose-independent. Thromboembolism was found in all animals treated with 50 IU/kg PCC; 44% also showed signs of disseminated intravascular coagulation. Liver injury was similar in all animals. In conclusion, 35 IU/kg PCC safely improved coagulation and attenuated blood loss. However, the higher dose of PCC (50 IU/kg) appeared to increase the risk of thromboembolism and disseminated intravascular coagulation. PMID- 21670474 TI - Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment. AB - Clonal evolution of the leukemogenic compartment may contribute to alter the therapeutic response in acute lymphoblastic leukemia (ALL). Using xenotransplantation of primary leukemia cells, we evaluated the phenotypic and genetic composition of de novo resistant very high risk precursor B-cell ALL, a subgroup defined by the persistence of minimal residual disease despite intensive chemotherapy. Analysis of copy number alterations (CNAs) showed that the xenografted leukemia, even when reconstituted from 100 cells, remained highly related to the diagnostic sample, with minor changes in CNAs, mostly deletions, emerging in most cases in the first passage into mice. At the single-cell level, the pattern of monoallelic and biallelic deletions of the CDKN2A locus revealed distinct leukemia subpopulations, which were reproducibly tracked in xenografts. In most very high risk ALL cases, the predominant diagnostic clones were reconstituted in xenografts, as shown by multiplex polymerase chain reaction analysis of immunoglobulin and T-cell receptor loci. In other cases, the pattern in CNAs and immunoglobulin and T-cell receptor rearrangement was less concordant in xenografts, suggesting the outgrowth of subclones. These results unequivocally demonstrate the existence of clonally closely related but distinct subsets of leukemia initiating cells in ALL, which has important implications for drug development and preclinical disease modeling. PMID- 21670475 TI - GATA3 is redundant for maintenance and self-renewal of hematopoietic stem cells. AB - GATA3 has been identified as a master regulator of T helper cells, as well as being important for early thymic progenitors and T-cell commitment. However, Gata3 expression initiates already at the hematopoietic stem cell (HSC) level, implicating a potential role also in the regulation of HSCs. Herein we used a conditional Gata3 knockout strategy in which Gata3 expression was completely deleted from the earliest stage of embryonic hematopoietic development after emergence of HSCs from hemogenic endothelium. Through a detailed analysis of HSCs at the phenotypic and functional level, we demonstrate that steady-state levels of HSCs are normal in Gata3(fl/fl)Vav-Cre(tg/+) mice. Moreover, through long-term primary and secondary transplantation experiments, we also unequivocally demonstrate that Gata3 has a redundant role in post-transplantation HSC self renewal. PMID- 21670473 TI - A critical role for SHP2 in STAT5 activation and growth factor-mediated proliferation, survival, and differentiation of human CD34+ cells. AB - SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, plays a critical role in developmental hematopoiesis in the mouse, and gain-of function mutations of SHP2 are associated with hematopoietic malignancies. However, the role of SHP2 in adult hematopoiesis has not been addressed in previous studies. In addition, the role of SHP2 in human hematopoiesis has not been described. These questions are of considerable importance given the interest in development of SHP2 inhibitors for cancer treatment. We used shRNA-mediated inhibition of SHP2 expression to investigate the function of SHP2 in growth factor (GF) signaling in normal human CD34(+) cells. SHP2 knockdown resulted in markedly reduced proliferation and survival of cells cultured with GF, and reduced colony-forming cell growth. Cells expressing gain-of-function SHP2 mutations demonstrated increased dependency on SHP2 expression for survival compared with cells expressing wild-type SHP2. SHP2 knockdown was associated with significantly reduced myeloid and erythroid differentiation with retention of CD34(+) progenitors with enhanced proliferative capacity. Inhibition of SHP2 expression initially enhanced and later inhibited STAT5 phosphorylation and reduced expression of the antiapoptotic genes MCL1 and BCLXL. These results indicate an important role for SHP2 in STAT5 activation and GF-mediated proliferation, survival, and differentiation of human progenitor cells. PMID- 21670476 TI - Functional and survival outcomes in patients undergoing total glossectomy compared with total laryngoglossectomy. AB - OBJECTIVE: To compare functional and survival outcomes for patients undergoing total glossectomy (TG) or total glossectomy plus laryngectomy (TGL) for advanced squamous cell carcinoma (SCC) of the tongue. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary referral center. SUBJECTS AND METHODS: There were 30 included patients (20 TG, 10 TGL). Outcomes included tumor recurrence, disease-free survival, and functional data (swallowing, gastrostomy tube dependence, speech, airway). RESULTS: Mean patient age was 56 years with a male predominance (90%). Compared with TG, TGL was more commonly performed for recurrent tumors (90% vs 55%, P = .06). Perineural invasion and extracapsular extension occurred more commonly in the TGL group (80% vs 50%, P = .12). At 12 months postoperatively, 61% of TG patients had disease recurrence compared with 40% of TGL patients (P = .43), and 12-month disease-free survival was 40% (TG) and 50% (TGL). Functionally, more TG patients were totally gastrostomy tube dependent (70% vs 30%, P = .04), and 50% of TG patients were also tracheostomy dependent. Intelligible speech was achieved by 30% of TG and 10% of TGL patients (P = .68). CONCLUSION: Patients undergoing TGL had similar functional and survival outcomes to patients undergoing TG alone despite the presence of more locally advanced disease with greater adverse pathological features. Following TG alone, positive or close margins occurred most commonly at the inferior margin of resection (hyoid/valleculae), which could explain why TGL in patients with advanced tongue SCC may improve local disease control. PMID- 21670478 TI - Innate resistance of corneas to pathogen infections. PMID- 21670477 TI - Tumor satellite in predicting occult nodal metastasis of tongue cancer. AB - OBJECTIVE: Tongue cancer is well known to have a high potential for locoregional metastasis. However, controversy about electively treating the neck in early stage tongue cancer remains. Although many risk factors related to cervical occult nodal metastasis (ONM) have been investigated, the ability of the tumor to spread, a phenomenon that results from the intrinsic property of the tumor and its interaction with the surrounding environment, has seldom been addressed. STUDY DESIGN: Retrospective case series with chart review. SETTING: Tertiary referral hospital of university. SUBJECTS: Patients with early-stage squamous cell carcinoma of the oral tongue. RESULTS: In 71 eligible enrolled patients, ONM was detected in 19 (27%) patients, while the results were negative (ONM(-)) in 52 (73%) patients. The average tumor satellite distance (TSD) in the ONM(+) group was 4.1 +/- 4.3 mm, in contrast to that in the ONM(-) group (1.0 +/- 1.5 mm; P < .001). When stratified by increased TSD values, the significance of the difference between the 2 groups increased. For clinical applications, the optimal TSD threshold for determining the ONM probability was 3.5 mm. Multivariate analyses demonstrated that TSD was an independent prognosticator. CONCLUSIONS: The results indicate that TSD is a feasible pathological parameter that is useful for determining the status of cervical nodal metastasis. It can be used as an indicator of potential cervical subclinical disease and as a guideline for deciding the necessity and modality of neck treatment. PMID- 21670479 TI - A real-time deformable detector. AB - We propose a new learning strategy for object detection. The proposed scheme forgoes the need to train a collection of detectors dedicated to homogeneous families of poses, and instead learns a single classifier that has the inherent ability to deform based on the signal of interest. We train a detector with a standard AdaBoost procedure by using combinations of pose-indexed features and pose estimators. This allows the learning process to select and combine various estimates of the pose with features able to compensate for variations in pose without the need to label data for training or explore the pose space in testing. We validate our framework on three types of data: hand video sequences, aerial images of cars, and face images. We compare our method to a standard boosting framework, with access to the same ground truth, and show a reduction in the false alarm rate of up to an order of magnitude. Where possible, we compare our method to the state of the art, which requires pose annotations of the training data, and demonstrate comparable performance. PMID- 21670480 TI - Object-graphs for context-aware visual category discovery. AB - How can knowing about some categories help us to discover new ones in unlabeled images? Unsupervised visual category discovery is useful to mine for recurring objects without human supervision, but existing methods assume no prior information and thus tend to perform poorly for cluttered scenes with multiple objects. We propose to leverage knowledge about previously learned categories to enable more accurate discovery, and address challenges in estimating their familiarity in unsegmented, unlabeled images. We introduce two variants of a novel object-graph descriptor to encode the 2D and 3D spatial layout of object level co-occurrence patterns relative to an unfamiliar region and show that by using them to model the interaction between an image's known and unknown objects, we can better detect new visual categories. Rather than mine for all categories from scratch, our method identifies new objects while drawing on useful cues from familiar ones. We evaluate our approach on several benchmark data sets and demonstrate clear improvements in discovery over conventional purely appearance based baselines. PMID- 21670481 TI - Efficient feedforward categorization of objects and human postures with address event image sensors. AB - This paper proposes an algorithm for feedforward categorization of objects and, in particular, human postures in real-time video sequences from address-event temporal-difference image sensors. The system employs an innovative combination of event based hardware and bio-inspired software architecture. An event-based temporal difference image sensor is used to provide input video sequences, while a software module extracts size and position invariant line features inspired by models of the primate visual cortex. The detected line features are organized into vectorial segments. After feature extraction, a modified line segment Hausdorff distance classifier combined with on-the-fly cluster-based size and position invariant categorization. The system can achieve about 90 percent average success rate in the categorization of human postures, while using only a small number of training samples. Compared to state-of-the-art bio-inspired categorization methods, the proposed algorithm requires less hardware resource, reduces the computation complexity by at least five times, and is an ideal candidate for hardware implementation with event-based circuits. PMID- 21670482 TI - A tree-based context model for object recognition. AB - There has been a growing interest in exploiting contextual information in addition to local features to detect and localize multiple object categories in an image. A context model can rule out some unlikely combinations or locations of objects and guide detectors to produce a semantically coherent interpretation of a scene. However, the performance benefit of context models has been limited because most of the previous methods were tested on data sets with only a few object categories, in which most images contain one or two object categories. In this paper, we introduce a new data set with images that contain many instances of different object categories, and propose an efficient model that captures the contextual information among more than a hundred object categories using a tree structure. Our model incorporates global image features, dependencies between object categories, and outputs of local detectors into one probabilistic framework. We demonstrate that our context model improves object recognition performance and provides a coherent interpretation of a scene, which enables a reliable image querying system by multiple object categories. In addition, our model can be applied to scene understanding tasks that local detectors alone cannot solve, such as detecting objects out of context or querying for the most typical and the least typical scenes in a data set. PMID- 21670483 TI - On the Duality of Forward and Inverse Light Transport. AB - Inverse light transport seeks to undo global illumination effects, such as interreflections, that pervade images of most scenes. This paper presents the theoretical and computational foundations for inverse light transport as a dual of forward rendering. Mathematically, this duality is established through the existence of underlying Neumann series expansions. Physically, it can be shown that each term of our inverse series cancels an interreflection bounce, just as the forward series adds them. While the convergence properties of the forward series are well known, we show that the oscillatory convergence of the inverse series leads to more interesting conditions on material reflectance. Conceptually, the inverse problem requires the inversion of a large light transport matrix, which is impractical for realistic resolutions using standard techniques. A natural consequence of our theoretical framework is a suite of fast computational algorithms for light transport inversion--analogous to finite element radiosity, Monte Carlo and wavelet-based methods in forward rendering- that rely at most on matrix-vector multiplications. We demonstrate two practical applications, namely, separation of individual bounces of the light transport and fast projector radiometric compensation, to display images free of global illumination artifacts in real-world environments. PMID- 21670484 TI - Computing the Inner Distances of Volumetric Models for Articulated Shape Description with a Visibility Graph. AB - A new visibility graph-based algorithm is presented for computing the inner distances of a 3D shape represented by a volumetric model. The inner distance is defined as the length of the shortest path between landmark points within the shape. The inner distance is robust to articulation and can reflect the deformation of a shape structure well without an explicit decomposition. Our method is based on the visibility graph approach. To check the visibility between pairwise points, we propose a novel, fast, and robust visibility checking algorithm based on a clustering technique which operates directly on the volumetric model without any surface reconstruction procedure, where an octree is used for accelerating the computation. The inner distance can be used as a replacement for other distance measures to build a more accurate description for complex shapes, especially for those with articulated parts. The binary executable program for the Windows platform is available from https://engineering.purdue.edu/PRECISE/VMID. PMID- 21670485 TI - Adaptive manifold learning. AB - Manifold learning algorithms seek to find a low-dimensional parameterization of high-dimensional data. They heavily rely on the notion of what can be considered as local, how accurately the manifold can be approximated locally, and, last but not least, how the local structures can be patched together to produce the global parameterization. In this paper, we develop algorithms that address two key issues in manifold learning: 1) the adaptive selection of the local neighborhood sizes when imposing a connectivity structure on the given set of high-dimensional data points and 2) the adaptive bias reduction in the local low-dimensional embedding by accounting for the variations in the curvature of the manifold as well as its interplay with the sampling density of the data set. We demonstrate the effectiveness of our methods for improving the performance of manifold learning algorithms using both synthetic and real-world data sets. PMID- 21670486 TI - Curved glide-reflection symmetry detection. AB - We generalize the concept of bilateral reflection symmetry to curved glide reflection symmetry in 2D euclidean space, such that classic reflection symmetry becomes one of its six special cases. We propose a local feature-based approach for curved glidereflection symmetry detection from real, unsegmented 2D images. Furthermore, we apply curved glide-reflection axis detection for curved reflection surface detection in 3D images. Our method discovers, groups, and connects statistically dominant local glidereflection axes in an Axis-Parameter Space (APS) without preassumptions on the types of reflection symmetries. Quantitative evaluations and comparisons against state-of-the-art algorithms on a diverse 64-test-image set and 1,125 Swedish leaf-data images show a promising average detection rate of the proposed algorithm at 80 and 40 percent, respectively, and superior performance over existing reflection symmetry detection algorithms. Potential applications in computer vision, particularly biomedical imaging, include saliency detection from unsegmented images and quantification of deviations from normality. We make our 64-test-image set publicly available. PMID- 21670487 TI - Unconstrained Pose-Invariant Face Recognition Using 3D Generic Elastic Models. AB - Classical face recognition techniques have been successful at operating under well-controlled conditions; however, they have difficulty in robustly performing recognition in uncontrolled real-world scenarios where variations in pose, illumination, and expression are encountered. In this paper, we propose a new method for real-world unconstrained pose-invariant face recognition. We first construct a 3D model for each subject in our database using only a single 2D image by applying the 3D Generic Elastic Model (3D GEM) approach. These 3D models comprise an intermediate gallery database from which novel 2D pose views are synthesized for matching. Before matching, an initial estimate of the pose of the test query is obtained using a linear regression approach based on automatic facial landmark annotation. Each 3D model is subsequently rendered at different poses within a limited search space about the estimated pose, and the resulting images are matched against the test query. Finally, we compute the distances between the synthesized images and test query by using a simple normalized correlation matcher to show the effectiveness of our pose synthesis method to real-world data. We present convincing results on challenging data sets and video sequences demonstrating high recognition accuracy under controlled as well as unseen, uncontrolled real-world scenarios using a fast implementation. PMID- 21670488 TI - Fast Inference with Min-Sum Matrix Product. AB - The MAP inference problem in many graphical models can be solved efficiently using a fast algorithm for computing min-sum products of n * n matrices. The class of models in question includes cyclic and skip-chain models that arise in many applications. Although the worst-case complexity of the min-sum product operation is not known to be much better than O(n(3)), an O(n(2.5)) expected time algorithm was recently given, subject to some constraints on the input matrices. In this paper, we give an algorithm that runs in O(n(2) log n) expected time, assuming that the entries in the input matrices are independent samples from a uniform distribution. We also show that two variants of our algorithm are quite fast for inputs that arise in several applications. This leads to significant performance gains over previous methods in applications within computer vision and natural language processing. PMID- 21670489 TI - Efficient Volume Exploration Using the Gaussian Mixture Model. AB - The multidimensional transfer function is a flexible and effective tool for exploring volume data. However, designing an appropriate transfer function is a trial-and-error process and remains a challenge. In this paper, we propose a novel volume exploration scheme that explores volumetric structures in the feature space by modeling the space using the Gaussian mixture model (GMM). Our new approach has three distinctive advantages. First, an initial feature separation can be automatically achieved through GMM estimation. Second, the calculated Gaussians can be directly mapped to a set of elliptical transfer functions (ETFs), facilitating a fast pre-integrated volume rendering process. Third, an inexperienced user can flexibly manipulate the ETFs with the assistance of a suite of simple widgets, and discover potential features with several interactions. We further extend the GMM-based exploration scheme to time-varying data sets using an incremental GMM estimation algorithm. The algorithm estimates the GMM for one time step by using itself and the GMM generated from its previous steps. Sequentially applying the incremental algorithm to all time steps in a selected time interval yields a preliminary classification for each time step. In addition, the computed ETFs can be freely adjusted. The adjustments are then automatically propagated to other time steps. In this way, coherent user-guided exploration of a given time interval is achieved. Our GPU implementation demonstrates interactive performance and good scalability. The effectiveness of our approach is verified on several data sets. PMID- 21670491 TI - Phosphorylation of AKT: a mutational analysis. AB - Akt (cellular homolog of murine thymoma virus akt8 oncogene) is an essential component of the PI3K (phosphatidylinositol 3-kinase) pathway. Its activity is stimulated by receptor tyrosine kinases and G-protein coupled receptors and plays a critical role in the regulation of cell proliferation, differentiation and apoptosis. A gain of function in Akt can lead to uncontrolled cell proliferation and resistance to apoptosis, both hallmarks of oncogenic transformation. In this communication, we have investigated the phosphorylation at the Akt residues T308, S473 and T450 and their roles in oncogenic transformation and signaling. We find that T450 phosphorylation has only a minimal part in these activities. In contrast, the phosphorylation of T308 and of S473 fulfills essential, distinct, and non-overlapping functions that we define with inactivating and with phosphomimetic mutations of these sites. PMID- 21670492 TI - What information do Karman streets offer to flow sensing? AB - In this work, we focus on biomimetic lateral line sensing in Karman vortex streets. After generating a Karman street in a controlled environment, we examine the hydrodynamic images obtained with digital particle image velocimetry (DPIV). On the grounds that positioning in the flow and interaction with the vortices govern bio-inspired underwater locomotion, we inspect the fluid in the swimming robot frame of reference. We spatially subsample the flow field obtained using DPIV to emulate the local flow around the body. In particular, we look at various sensor configurations in order to reliably identify the vortex shedding frequency, wake wavelength and downstream flow speed. Moreover, we propose methods that differentiate between being in and out of the Karman street with >70% accuracy, distinguish right from left with respect to Karman vortex street centreline (>80%) and highlight when the sensor system enters the vortex formation zone (>75%). Finally, we present a method that estimates the relative position of a sensor array with respect to the vortex formation point within 15% error margin. PMID- 21670490 TI - RIP kinase-mediated necrosis as an alternative mechanisms of photoreceptor death. AB - Photoreceptor cell death is the terminal event in a variety of retinal disorders including age-related macular degeneration, retinitis pigmentosa, and retinal detachment. Apoptosis has been thought to be the major form of cell death in these diseases, however accumulating evidence suggests that another pathway, programmed necrosis is also important. Recent studies have shown that, when caspase pathways are blocked, receptor interacting protein (RIP) kinases promote necrosis and overcome apoptosis inhibition. Therefore, targeting of both caspase and RIP kinase pathways are required for effective photoreceptor protection. Here, we summarize the current knowledge of RIP kinase-mediated necrotic signaling and its contribution to photoreceptor death. PMID- 21670493 TI - An octopus-bioinspired solution to movement and manipulation for soft robots. AB - Soft robotics is a challenging and promising branch of robotics. It can drive significant improvements across various fields of traditional robotics, and contribute solutions to basic problems such as locomotion and manipulation in unstructured environments. A challenging task for soft robotics is to build and control soft robots able to exert effective forces. In recent years, biology has inspired several solutions to such complex problems. This study aims at investigating the smart solution that the Octopus vulgaris adopts to perform a crawling movement, with the same limbs used for grasping and manipulation. An ad hoc robot was designed and built taking as a reference a biological hypothesis on crawling. A silicone arm with cables embedded to replicate the functionality of the arm muscles of the octopus was built. This novel arm is capable of pushing based locomotion and object grasping, mimicking the movements that octopuses adopt when crawling. The results support the biological observations and clearly show a suitable way to build a more complex soft robot that, with minimum control, can perform diverse tasks. PMID- 21670494 TI - Discrete breathers in a realistic coarse-grained model of proteins. AB - We report the results of molecular dynamics simulations of an off-lattice protein model featuring a physical force-field and amino-acid sequence. We show that localized modes of nonlinear origin, discrete breathers (DBs), emerge naturally as continuations of a subset of high-frequency normal modes residing at specific sites dictated by the native fold. DBs are time-periodic, space-localized vibrational modes that exist generically in nonlinear discrete systems and are known for their resilience and ability to concentrate energy for long times. In the case of the small beta-barrel structure that we consider, DB-mediated localization occurs on the turns connecting the strands. At high energies, DBs stabilize the structure by concentrating energy on a few sites, while their collapse marks the onset of large-amplitude fluctuations of the protein. Furthermore, we show how breathers develop as energy-accumulating centres following perturbations even at distant locations, thus mediating efficient and irreversible energy transfers. Remarkably, due to the presence of angular potentials, the breather induces a local static distortion of the native fold. Altogether, the combination of these two nonlinear effects may provide a ready means for remotely controlling local conformational changes in proteins. PMID- 21670495 TI - P2X7 receptor signaling contributes to tissue factor-dependent thrombosis in mice. AB - Thrombosis is initiated by tissue factor (TF), a coagulation cofactor/receptor expressed in the vessel wall, on myeloid cells, and on microparticles (MPs) with variable procoagulant activity. However, the molecular pathways that generate prothrombotic TF in vivo are poorly defined. The oxidoreductase protein disulfide isomerase (PDI) is thought to be involved in the activation of TF. Here, we found that in mouse myeloid cells, ATP-triggered signaling through purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7 receptor; encoded by P2rx7) induced activation (decryption) of TF procoagulant activity and promoted release of TF+ MPs from macrophages and SMCs. The generation of prothrombotic MPs required P2X7 receptor-dependent production of ROS leading to increased availability of solvent accessible extracellular thiols. An antibody to PDI with antithrombotic activity in vivo attenuated the release of procoagulant MPs. In addition, P2rx7-/- mice were protected from TF-dependent FeCl3-induced carotid artery thrombosis. BM chimeras revealed that P2X7 receptor prothrombotic function was present in both hematopoietic and vessel wall compartments. In contrast, an alternative anti-PDI antibody showed activities consistent with cellular activation typically induced by P2X7 receptor signaling. This anti-PDI antibody restored TF-dependent thrombosis in P2rx7-/- mice. These data suggest that PDI regulates a critical P2X7 receptor-dependent signaling pathway that generates prothrombotic TF, defining a link between inflammation and thrombosis with potential implications for antithrombotic therapy. PMID- 21670496 TI - The homeobox transcription factor VentX controls human macrophage terminal differentiation and proinflammatory activation. AB - Macrophages are critical players in both innate and adaptive immunity. While the exogenous signaling events leading to the terminal differentiation of macrophages from monocytes have been studied extensively, the underlying intracellular transcriptional mechanisms remain poorly understood. Here we report that the homeobox transcription factor VentX plays a pivotal role in human macrophage terminal differentiation and proinflammatory function. Our study showed that VentX expression was upregulated upon human primary monocyte-to-macrophage differentiation induced by cytokines such as M-CSF, GM-CSF, and IL-3. Moreover, ablation of VentX expression in primary monocytes profoundly impaired their differentiation to macrophages, and ectopic expression of VentX in a myeloid progenitor cell line triggered its differentiation with prominent macrophage features. Further analysis revealed that VentX was pivotal for the proinflammatory response of terminally differentiated macrophages. Mechanistically, VentX was found to control expression of proteins key to macrophage differentiation and activation, including M-CSF receptor. Importantly, preliminary analysis of gene expression in leukocytes from patients with autoimmune diseases revealed a strong correlation between levels of VentX and those of proinflammatory cytokines. Our results provide mechanistic insight into the crucial roles of VentX in macrophage differentiation and proinflammatory activation and suggest that dysregulation of VentX may play a role in the pathogenesis of autoimmune diseases. PMID- 21670497 TI - Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. AB - Nanoparticle-based materials, such as drug delivery vehicles and diagnostic probes, currently under evaluation in oncology clinical trials are largely not tumor selective. To be clinically successful, the next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations. Here, we describe our full characterization of an approximately 7-nm diameter multimodal silica nanoparticle, exhibiting what we believe to be a unique combination of structural, optical, and biological properties. This ultrasmall cancer-selective silica particle was recently approved for a first-in-human clinical trial. Optimized for efficient renal clearance, it concurrently achieved specific tumor targeting. Dye-encapsulating particles, surface functionalized with cyclic arginine-glycine-aspartic acid peptide ligands and radioiodine, exhibited high affinity/avidity binding, favorable tumor-to-blood residence time ratios, and enhanced tumor-selective accumulation in alphavbeta3 integrin-expressing melanoma xenografts in mice. Further, the sensitive, real-time detection and imaging of lymphatic drainage patterns, particle clearance rates, nodal metastases, and differential tumor burden in a large-animal model of melanoma highlighted the distinct potential advantage of this multimodal platform for staging metastatic disease in the clinical setting. PMID- 21670498 TI - Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. AB - Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process. PMID- 21670499 TI - Inhibition of MRP4 prevents and reverses pulmonary hypertension in mice. AB - Multidrug resistance-associated protein 4 (MRP4, also known as Abcc4) regulates intracellular levels of cAMP and cGMP in arterial SMCs. Here, we report our studies of the role of MRP4 in the development and progression of pulmonary arterial hypertension (PAH), a severe vascular disease characterized by chronically elevated pulmonary artery pressure and accompanied by remodeling of the small pulmonary arteries as a prelude to right heart failure and premature death. MRP4 expression was increased in pulmonary arteries from patients with idiopathic PAH as well as in WT mice exposed to hypoxic conditions. Consistent with a pathogenic role for MRP4 in PAH, WT mice exposed to hypoxia for 3 weeks showed reversal of hypoxic pulmonary hypertension (PH) following oral administration of the MRP4 inhibitor MK571, and Mrp4-/- mice were protected from hypoxic PH. Inhibition of MRP4 in vitro was accompanied by increased intracellular cAMP and cGMP levels and PKA and PKG activities, implicating cyclic nucleotide-related signaling pathways in the mechanism underlying the protective effects of MRP4 inhibition. Our data suggest that MRP4 could represent a potential target for therapeutic intervention in PAH. PMID- 21670500 TI - The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction. AB - Impaired cardiac function is associated with myocardial triglyceride accumulation, but it is not clear how the lipids accumulate or whether this accumulation is detrimental. Here we show that hypoxia/ischemia-induced accumulation of lipids in HL-1 cardiomyocytes and mouse hearts is dependent on expression of the VLDL receptor (VLDLR). Hypoxia-induced VLDLR expression in HL-1 cells was dependent on HIF-1alpha through its interaction with a hypoxia responsive element in the Vldlr promoter, and VLDLR promoted the endocytosis of lipoproteins. Furthermore, VLDLR expression was higher in ischemic compared with nonischemic left ventricles from human hearts and was correlated with the total lipid droplet area in the cardiomyocytes. Importantly, Vldlr-/- mice showed improved survival and decreased infarct area following an induced myocardial infarction. ER stress, which leads to apoptosis, is known to be involved in ischemic heart disease. We found that ischemia-induced ER stress and apoptosis in mouse hearts were reduced in Vldlr-/- mice and in mice treated with antibodies specific for VLDLR. These findings suggest that VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis. PMID- 21670501 TI - Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions. AB - Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) - adult stem cells from human nasal olfactory lamina propria - migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies. PMID- 21670502 TI - Kruppel-like factor 4 regulates macrophage polarization. AB - Current paradigms suggest that two macrophage subsets, termed M1 and M2, are involved in inflammation and host defense. While the distinct functions of M1 and M2 macrophages have been intensively studied - the former are considered proinflammatory and the latter antiinflammatory - the determinants of their speciation are incompletely understood. Here we report our studies that identify Kruppel-like factor 4 (KLF4) as a critical regulator of macrophage polarization. Macrophage KLF4 expression was robustly induced in M2 macrophages and strongly reduced in M1 macrophages, observations that were recapitulated in human inflammatory paradigms in vivo. Mechanistically, KLF4 was found to cooperate with Stat6 to induce an M2 genetic program and inhibit M1 targets via sequestration of coactivators required for NF-kappaB activation. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. Furthermore, mice bearing myeloid-specific deletion of KLF4 exhibited delayed wound healing and were predisposed to developing diet-induced obesity, glucose intolerance, and insulin resistance. Collectively, these data identify KLF4 as what we believe to be a novel regulator of macrophage polarization. PMID- 21670503 TI - Phosphodiesterase 4B in the cardiac L-type Ca2+ channel complex regulates Ca2+ current and protects against ventricular arrhythmias in mice. AB - beta-Adrenergic receptors (beta-ARs) enhance cardiac contractility by increasing cAMP levels and activating PKA. PKA increases Ca2+-induced Ca2+ release via phosphorylation of L-type Ca2+ channels (LTCCs) and ryanodine receptor 2. Multiple cyclic nucleotide phosphodiesterases (PDEs) regulate local cAMP concentration in cardiomyocytes, with PDE4 being predominant for the control of beta-AR-dependent cAMP signals. Three genes encoding PDE4 are expressed in mouse heart: Pde4a, Pde4b, and Pde4d. Here we show that both PDE4B and PDE4D are tethered to the LTCC in the mouse heart but that beta-AR stimulation of the L type Ca2+ current (ICa,L) is increased only in Pde4b-/- mice. A fraction of PDE4B colocalized with the LTCC along T-tubules in the mouse heart. Under beta-AR stimulation, Ca2+ transients, cell contraction, and spontaneous Ca2+ release events were increased in Pde4b-/- and Pde4d-/- myocytes compared with those in WT myocytes. In vivo, after intraperitoneal injection of isoprenaline, catheter mediated burst pacing triggered ventricular tachycardia in Pde4b-/- mice but not in WT mice. These results identify PDE4B in the CaV1.2 complex as a critical regulator of ICa,L during beta-AR stimulation and suggest that distinct PDE4 subtypes are important for normal regulation of Ca2+-induced Ca2+ release in cardiomyocytes. PMID- 21670505 TI - Molecular cloning and mRNA expression of the liver-specific cathepsin L1 gene of the olive flounder, Paralichthys olivaceus. AB - We isolated a homolog of cathepsin L from a cDNA library of the olive flounder liver. The flounder cathepsin L1 transcript consisted of 1,221 bp that encoded a polypeptide of 334 amino acids. The overall identity between flounder cathepsin L1 and other cathepsin Ls was 50-64%, and flounder cathepsin L1 contained the highly conserved ERFNIN-motif. A phylogenetic tree indicated that flounder cathepsin L1 is in the same monophyletic group as zebrafish cathepsin Lc. RT-PCR analysis revealed that cathepsin L1 transcripts were expressed only in the liver. They were detected from 28 d post-hatching. Under starvation conditions, cathepsin L1 expression was decreased at 30 d. PMID- 21670504 TI - Absence of Stat1 in donor CD4+ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice. AB - STAT1 is the main signal transducer for type I and II IFNs and plays a central role in the regulation of innate and adaptive immune responses. We used Stat1 deficient mice to test the role of donor Stat1 in MHC-matched minor histocompatibility antigen-mismatched (mHA-mismatched) and fully MHC-mismatched models of bone marrow transplantation. Lack of Stat1 in donor splenocytes reduced graft-versus-host disease (GVHD) in both immunogenetic disparities, leading to substantially attenuated morbidity and mortality. Donor Stat1 deficiency resulted in reduced alloantigen-induced activation and expansion of donor T cells and correlated with the expansion of CD4+CD25+Foxp3+ Tregs in vivo. This expansion of Tregs was further confirmed by studies showing that Stat1 deficiency promoted the proliferation, while inhibiting the apoptosis, of natural Tregs, and that absence of Stat1 enhanced the induction of inducible Tregs both in vitro and in vivo. Ex vivo expanded Stat1-/- Tregs were superior to wild-type Tregs in suppressing alloantigen-driven expansion of T cells in vitro and in inhibiting the development of GVHD. These observations demonstrate that Stat1 is a regulator of Tregs and that targeting Stat1 in CD4+ T cells may facilitate in vitro and in vivo expansion of Tregs for therapeutic use. PMID- 21670506 TI - Rice ABCG43 is Cd inducible and confers Cd tolerance on yeast. AB - An understanding of the cadmium (Cd) transport system in rice can serve as a basis for coping with Cd-related problems in rice and human health. To identify a new gene involved in Cd transport in rice, we screened our yeast library, expressing 140 kinds of rice ATP binding cassette (ABC)-type transporters. From the screening, we found that OsABCG43/PDR5 conferred high Cd tolerance on yeast. The Cd concentration of yeast carrying OsABCG43 was similar to that of the vector control. The OsABCG43 transcript was detected both in shoots and roots. Accumulation of it was elevated by Cd treatment in the roots but not in the shoots. This study indicates that OsABCG43 is a Cd inducible-transporter gene capable of conferring Cd tolerance on yeast. PMID- 21670507 TI - Biochemical characterization of deblocking aminopeptidases from the hyperthermophilic archaeon Thermococcus kodakarensis KOD1. AB - Deblocking aminopeptidase (DAP) is an exoprotease that can release N-terminal amino acids from blocked peptides. Three DAP homologous (TkDAP1, TkDAP2, and TkDAP3) are annotated in the genome data base of Thermococcus kodakarensis KOD1. TkDAP2 and TkDAP3 were identified as proteins that are overexpressed in response to heat and oxidative stress by two-dimensional electrophoresis. In this study, the TkDAP1 and TkDAP2 genes were cloned and expressed in Escherichia coli. The two proteins were purified homogeneity and analyzed by gel filtration chromatography and electron microscopy. TkDAP1 showed two oligomers, which were identified as an octodecimer and a dodecamer. TkDAP2 produced three native forms: octodecimer, dodecamer, and trimer. Dodecamer assembly was the main form in the two proteins. Finally, TkDAP1 was found to have higher deblocking aminopeptidase activity on the substrates of Ac-Leu-pNA and Ac-Ala-Ala-Ala, while TkDAP2 had higher aminopeptidase activity on the substrates of Leu-pNA and Ala-Ala-Ala-pNA. PMID- 21670508 TI - New neuritogenic steroidal saponin from Ophiopogon japonicus (Thunb.) Ker-Gawl. AB - A new steroidal saponin was isolated from Ophiopogon japonicus. This saponin possesses a modification by 2-hydroxy-3-methylvalerylation of the hydroxyl group at C-4' of the sugar, linked to C-1 of the aglycone. It exhibited significant neuritogenic activity for PC12 cells. The structure-activity relationship revealed the aglycone, rather than the sugar moieties and acylation, to be important for the neuritogenic activity. PMID- 21670509 TI - Inhibitory effect of a hot water extract of coffee "silverskin" on hyaluronidase. AB - Coffee "silverskin" (CS) is a by-product of the roasting procedure for coffee beans. A CS extract (CS-ext) was found to have a high inhibitory effect against hyaluronidase. It seems that the higher-molecular-weight substances in CS-ext contributed most to the hyaluronidase inhibition, while acidic polysaccharides mainly composed of uronic acid played a major role in this hyaluronidase inhibition by CS-ext. PMID- 21670510 TI - Network structure and forces involved in perilla globulin gelation: comparison with sesame globulin. AB - Scanning electron micrographs show that perilla globulin gel had a finer network structure than sesame alpha-globulin gel. The effects of various reagents on the gel formation and solubility of perilla and sesame gels were compared. The contribution of disulfide bonds to the formation and stability of perilla gel was greater than to sesame gel, despite having the same subunit structure. PMID- 21670511 TI - Enzymatic properties of recombinant kojibiose phosphorylase from Caldicellulosiruptor saccharolyticus ATCC43494. AB - One kojibiose phoshorylase (KP) homolog gene was cloned from Caldicellulosiruptor saccharolyticus ATCC43494. Recombinant KP from C. saccharolyticus (Cs-KP) expressed in Escherichia coli showed highest activity at pH 6.0 at 85 degrees C, and was stable from pH 3.5 to 10.0 and up to 85 degrees C for phosphorolysis. Cs KP showed higher productivity of kojioligosaccharides of DP ? 4 than KP from Thermoanaerobacter brockii ATCC35047. PMID- 21670512 TI - Human bitter taste receptors hTAS2R8 and hTAS2R39 with differential functions to recognize bitter peptides. AB - The strong bitter peptide, Phe-Phe-Pro-Arg, activated cultured cells expressing either of the known human bitter taste receptors, hTAS2R8 and hTAS2R39. The partial structure of Pro-Arg activated hTAS2R39, but did not activate hTAS2R8. These receptors may not indiscriminately recognize bitter peptides, but have a differential function in their recognition. PMID- 21670513 TI - Characterization of 2-octenoyl-CoA carboxylase/reductase utilizing pteB from Streptomyce avermitilis. AB - The filipin biosynthetic gene cluster of Streptomyces avermitilis contains pteB, a homolog of crotonyl-CoA carboxylase/reductase. PteB was predicted to be 2 octenoyl-CoA carboxylase/reductase, supplying hexylmalonyl-CoA to filipin biosynthesis. Recombinant PteB displayed selective reductase activity toward 2 octenoyl-CoA while generating a broad range of alkylmalonyl-CoAs in the presence of bicarbonate. PMID- 21670514 TI - Pulsed-field gel electrophoretic analysis and some characteristics of Staphylococcus aureus isolated from retail foods and human hands. AB - This study investigates whether there is a predominant Staphylococcus aureus strain in retail foods and healthy human hands, and examines the relationship between pulsed-field gel electrophoresis (PFGE) banding patterns and the S. aureus characteristics of staphylococcal enterotoxin (SE) type, coagulase type, and beta-lactamase activity. Ninety-four strains of S. aureus isolated from retail foods and healthy human hands were analyzed by PFGE. Several strains isolated from the same shop or a chain store showed identical patterns, indicating that the origins of these strains were identical. After excluding these strains showing identical patterns, 54 strains were used for the PFGE analysis. No spread of a particular clone in the environment surrounding the food was apparent. The PFGE analysis of these 54 strains was classified in 6 lineages (L1-L6). There was no relationship between the PFGE banding pattern and coagulase type or SE type. Eleven (84.6%) of the 13 isolates in PFGE banding pattern L5 did not produce beta-lactamase, suggesting that the production of beta-lactamase influenced a specific PFGE banding pattern. PMID- 21670515 TI - Production of a recombinant full-length prion protein in a soluble form without refolding or detergents. AB - Recombinant prion protein has been produced in insoluble form and refolded following solubilization with denaturants. It is, however, preferable to use a soluble recombinant protein prepared without artificial solubilization. In this study, a soluble recombinant prion protein was produced in Escherichia coli cells by coexpression of neuregulin I-beta1 and purified to high purity. PMID- 21670516 TI - Cloning and expression of a beta-galactosidase gene of Bacillus circulans. AB - A gene of beta-galactosidase from Bacillus circulans ATCC 31382 was cloned and sequenced on the basis of N-terminal and internal peptide sequences isolated from a commercial enzyme preparation, Biolacta((r)). Using the cloned gene, recombinant beta-galactosidase and its deletion mutants were overexpressed as His tagged proteins in Escherichia coli cells and the enzymes expressed were characterized. PMID- 21670517 TI - Effects of anaerobic processing of soybean seeds on the properties of tofu. AB - Oxygenation of lipids during the processing soybeans affects the flavor properties of soy products. We prepared tofu under anaerobic conditions and then evaluated its sensory properties and the compositions of volatiles and oxidized lipids. Anaerobic processing resulted in tofu with less intense richness (kokumi) concomitant with reductions in the amounts of oxidized lipids and volatile compounds. PMID- 21670518 TI - Synthesis and biological evaluation of the 12,12-dimethyl derivative of Aplog-1, an anti-proliferative analog of tumor-promoting aplysiatoxin. AB - Aplog-1 is a unique analog of tumor-promoting aplysiatoxin that inhibits tumor promotion by phorbol diesters and proliferation of tumor cells. While the structural features relevant to the biological activities of Aplog-1 remain to be identified, recent studies by us have suggested that local hydrophobicity around the spiroketal moiety of Aplog-1 is a crucial determinant of its anti proliferative activity. This hypothesis led us to design 12,12-dimethyl-Aplog-1 (3), in which a hydrophobic geminal dimethyl group is installed proximal to the spiroketal moiety to improve biological potency. As expected, 3 was more effective than Aplog-1 in inhibiting cancer cell growth and binding to protein kinase Cdelta, a putative receptor responsible for the biological response of Aplog-1. Moreover, an induction test on Epstein-Barr virus early antigen demonstrated 3 to be a better anti-tumor promoter than Aplog-1. These results indicate that 3 is a superior derivative of Aplog-1, and thus a more promising lead for anti-cancer drugs. PMID- 21670519 TI - Selenite reduction by the thioredoxin system: kinetics and identification of protein-bound selenide. AB - Selenite (SeO(3)(2-)) assimilation into a bacterial selenoprotein depends on thioredoxin (trx) reductase in Esherichia coli, but the molecular mechanism has not been elucidated. The mineral-oil overlay method made it possible to carry out anaerobic enzyme assay, which demonstrated an initial lag-phase followed by time dependent steady NADPH consumption with a positive cooperativity toward selenite and trx. SDS-PAGE/autoradiography using (75)Se-labeled selenite as substrate revealed the formation of trx-bound selenium in the reaction mixture. The protein bound selenium has metabolic significance in being stabilized in the divalent state, and it also produced the selenopersulfide (-S-SeH) form by the catalysis of E. coli trx reductase (TrxB). PMID- 21670520 TI - Increased monocytic adhesion by senescence in human umbilical vein endothelial cells. AB - We investigated whether replicative senescence of endothelial cells contributed to the pathogenesis of atherosclerosis in human umbilical vein endothelial cells (HUVECs). HUVECs at a population-doubling level of 30 (PDL30) divided much more slowly than those at PDL9. The percentage of SA-beta-Gal-positive cells and the mRNA expression levels of PAI-1 and p21 at PDL30 were significantly higher than those at PDL9. The changes induced by aging were evaluated according to the mRNA expression level of genes related to the endothelial cell function. The expression level of many adhesion molecules promoting monocytic adhesion was significantly increased, and monocytic adhesion on HUVECs was found to be significantly promoted by aging. Monocytic adhesion is an essential early event in the development of atherosclerosis, and our results suggest that replicative senescence of the vascular endothelial cells induced increased expression of adhesion molecules. The consequent increase in monocytic adhesion may then promote the pathogenesis of atherosclerosis. PMID- 21670521 TI - Apoptotic cell death in the fission yeast Schizosaccharomyces pombe induced by valproic acid and its extreme susceptibility to pH change. AB - Schizosaccharomyces pombe treated with valproic acid died with apoptotic markers such as DNA fragmentation, loss of a mitochondrial electrochemical gradient and chromatin condensation, independently of metacaspase, a yeast homolog of metazoan caspase. Sensitivity to valproic acid was strongly dependent on growth phase. Cells in a later growth phase were much more sensitive to valproic acid than those in an earlier one. Altering the pH of the medium with HCl and with NaOH also caused remarkable changes in sensitivity. Cells in an acidic medium were more sensitive to valproic acid. This pH-dependent change in sensitivity did not require de novo protein synthesis, and a change in pH 60 min after the administration of valproic acid affected sensitivity. These results suggest that the intracellular cell death process was susceptible to extracellular pH. Although a sir2 mutant of Saccharomyces cerevisiae has been reported to be resistant to valproic acid, mutations in sir2 did not affect the sensitivity to valproic acid of S. pombe. PMID- 21670522 TI - Ethanol production from xylo-oligosaccharides by xylose-fermenting Saccharomyces cerevisiae expressing beta-xylosidase. AB - Construction of xylose- and xylo-oligosaccharide-fermenting Saccharomyces cerevisiae strains is important, because hydrolysates derived from lignocellulosic biomass contain significant amounts of these sugars. We have obtained recombinant S. cerevisiae strain MA-D4 (D-XKXDHXR), expressing xylose reductase, xylitol dehydrogenase and xylulokinase. In the present study, we generated recombinant strain D-XSD/XKXDHXR by transforming MA-D4 with a beta xylosidase gene cloned from the filamentous fungus Trichoderma reesei. The intracellular beta-xylosidase-specific activity of D-XSD/XKXDHXR was high, while that of the control strain was under the limit of detection. D-XSD/XKXDHXR produced ethanol, and xylose accumulated in the culture supernatant under fermentation in a medium containing xylo-oligosaccharides as sole carbon source. beta-Xylosidase-specific activity in D-XSD/XKXDHXR declined due to xylose both in vivo and in vitro. D-XSD/XKXDHXR converted xylo-oligosaccharides in an enzymatic hydrolysate of eucalyptus to ethanol. These results indicate that D-XSD/XKXDHXR efficiently converted xylo-oligosaccharides to xylose and subsequently to ethanol. PMID- 21670523 TI - A novel small protein of Bacillus subtilis involved in spore germination and spore coat assembly. AB - Two small genes named sscA (previously yhzE) and orf-62, located in the prsA-yhaK intergenic region of the Bacillus subtilis genome, were transcribed by SigK and GerE in the mother cells during the later stages of sporulation. The SscA-FLAG fusion protein was produced from T(5) of sporulation and incorporated into mature spores. sscA mutant spores exhibited poor germination, and Tricine-SDS-PAGE analysis showed that the coat protein profile of the mutant differed from that of the wild type. Bands corresponding to proteins at 59, 36, 5, and 3 kDa were reduced in the sscA null mutant. Western blot analysis of anti-CotB and anti-CotG antibodies showed reductions of the proteins at 59 kDa and 36 kDa in the sscA mutant spores. These proteins correspond to CotB and CotG. By immunoblot analysis of an anti-CotH antibody, we also observed that CotH was markedly reduced in the sscA mutant spores. It appears that SscA is a novel spore protein involved in the assembly of several components of the spore coat, including CotB, CotG, and CotH, and is associated with spore germination. PMID- 21670524 TI - Optimization of xylanase production from Aspergillus niger for biobleaching of eucalyptus pulp. AB - A crude endo-xylanase produced by Aspergillus niger BCC14405 was investigated for its potential in pre-bleaching of chemical pulp from eucalyptus. The optimal fermentation conditions on the basis of optimization using response surface methodology included cultivation in a complex medium comprising wheat bran, rice bran, and soybean meal supplemented with yeast extract, glucose, peptone, and lactose with a starting pH of 6.0 for 7 d. This resulted in production of 89.5 IU/mL of xylanase with minor cellulase activity. Proteomic analysis using LC/MS/MS revealed that the crude enzyme was a composite of hemicellulolytic enzymes, including endo-beta-1,4-xylanase and other hemicellulolytic enzymes attacking arabinoxylan and mannan. Pretreatment of the pulp at a xylanase dosage of 10 IU/g increased the brightness ceiling after the C-Eop-H bleaching step up to 3.0% using a chlorine charge with a C-factor of 0.16-0.20. Xylanase treatment also led to reduction in chlorine charge of at least 20%, with an acceptable brightness level. The enzyme pretreatment resulted in a slight increase in pulp viscosity, suggesting an increase in relative cellulose content. The crude enzyme was potent in the enzyme-aided bleaching of chemical pulp in an environmentally friendly pulping process. PMID- 21670525 TI - An active part of Artemisia sacrorum Ledeb. suppresses gluconeogenesis through AMPK mediated GSK3beta and CREB phosphorylation in human HepG2 cells. AB - In this study, we investigated the effects of a petroleum ether fraction of Artemisia sacrorum Ledeb. (Compositae) (PEASL) on glucose production through AMP activated protein kinase (AMPK) activation in human HepG2 cells. PEASL significantly inhibited glucose production in a concentration-dependent manner, and this effect was reversed in the presence of compound C, a selective AMPK inhibitor. PEASL markedly induced the phosphorylation of AMPK and downstream acetyl-CoA carboxylase (ACC) in a time- and concentration-dependent manner. In addition, it markedly increased the phosphorylations of glycogen synthase kinase 3beta (GSK3beta) in a concentration-dependent manner. In contrast, cAMP response element binding protein (CREB), a key transcription factor for gluconeogenic enzyme phosphorylation, decreased in a concentration-dependent manner. PEASL downregulated the gluconeogenesis gene expression of peroxisome proliferation activated receptor-gamma coactivator-1alpha (PGC-1alpha), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) in a concentration dependent manner. In addition, the gene expression of orphan nuclear receptor small heterodimer partner (SHP) increased, also in a concentration-dependent manner. These effects were also abolished by pretreatment with compound C, an AMPK inhibitor. This indicates that PEASL inhibited glucose production via the AMPK-GSK-CREB pathway in HepG2 cells, and these effects appeared to be capable of revealing anti-diabetic mechanism of PEASL in HepG2 cells. PMID- 21670526 TI - pSLA2-M of Streptomyces rochei is a composite linear plasmid characterized by self-defense genes and homology with pSLA2-L. AB - The 113,463-bp nucleotide sequence of the linear plasmid pSLA2-M of Streptomyces rochei 7434AN4 was determined. pSLA2-M had a 69.7% overall GC content, 352-bp terminal inverted repeats with 91% (321/352) identity at both ends, and 121 open reading frames. The rightmost 14.6-kb sequence was almost (14,550/14,555) identical to that of the coexisting 211-kb linear plasmid pSLA2-L. Adjacent to this homologous region an 11.8-kb CRISPR cluster was identified, which is known to function against phage infection in prokaryotes. This cluster region as well as another one containing two large membrane protein genes (orf78 and orf79) were flanked by direct repeats of 194 and 566 bp respectively. Hence the insertion of circular DNAs containing each cluster by homologous recombination was suggested. In addition, the orf71 encoded a Ku70/Ku80-like protein, known to function in the repair of double-strand DNA breaks in eukaryotes, but disruption of it did not affect the radiation sensitivity of the mutant. A pair of replication initiation genes (orf1-orf2) were identified at the extreme left end. Thus, pSLA2-M proved to be a composite linear plasmid characterized by self-defense genes and homology with pSLA2-L that might have been generated by multiple recombination events. PMID- 21670527 TI - Metabolic profiling and predicting the free radical scavenging activity of guava (Psidium guajava L.) leaves according to harvest time by 1H-nuclear magnetic resonance spectroscopy. AB - Guava leaves were classified and the free radical scavenging activity (FRSA) evaluated according to different harvest times by using the (1)H-NMR-based metabolomic technique. A principal component analysis (PCA) of (1)H-NMR data from the guava leaves provided clear clusters according to the harvesting time. A partial least squares (PLS) analysis indicated a correlation between the metabolic profile and FRSA. FRSA levels of the guava leaves harvested during May and August were high, and those leaves contained higher amounts of 3 hydroxybutyric acid, acetic acid, glutamic acid, asparagine, citric acid, malonic acid, trans-aconitic acid, ascorbic acid, maleic acid, cis-aconitic acid, epicatechin, protocatechuic acid, and xanthine than the leaves harvested during October and December. Epicatechin and protocatechuic acid among those compounds seem to have enhanced FRSA of the guava leaf samples harvested in May and August. A PLS regression model was established to predict guava leaf FRSA at different harvesting times by using a (1)H-NMR data set. The predictability of the PLS model was then tested by internal and external validation. The results of this study indicate that (1)H-NMR-based metabolomic data could usefully characterize guava leaves according to their time of harvesting. PMID- 21670528 TI - Genotypic variations in non-structural carbohydrate and cell-wall components of the stem in rice, sorghum, and sugar vane. AB - We evaluated genetic variations in the non-structural carbohydrate (NSC) and the cell-wall components of stem in rice, sorghum, and sugar cane to assess the potential suitability of these gramineous crops for bioethanol production. For NSC, the maximum soluble sugar concentration was highest in sugar cane, followed by sorghum with sucrose. The major NSC in rice was starch, but there were wide variations in the starch to soluble sugar ratios among the cultivars. The total concentration of cell-wall components was negatively correlated with the NSC concentration, indicating competition for carbon sources. Among the cell-wall components, lignin was relatively stable within each group. The major sugar species composing hemicellulose was xylose in all crop groups, but there were differences in composition, with a higher fraction of arabinose and glucose in rice as compared to the other crops. In rice, there was less lignin than in sorghum or sugar cane; this might be advantageous for the efficient saccharification of cellulose. PMID- 21670529 TI - Surface plasmon resonance analysis of interactions between diacylglycerol acyltransferase and its interacting molecules. AB - To measure the interactions of diacylglycerol acyltransferase (DGAT) by surface plasmon resonance (SPR), we immobilized Saccharomyces cerevisiae DGAT2 encoded by DGA1 on a BIACORE sensor chip surface. We used N-terminally truncated Dga1p with a FLAG tag at the C-terminus, which was purified to apparent homogeneity, maintaining significant DGAT activity (Kamisaka et al., Appl. Microbiol. Biotechnol., 88, 105-115 (2010)). Truncated Dga1p with a FLAG tag was immobilized with an anti-FLAG antibody that had been coupled with an L1 chip surface consisting of a carboxymethyl dextran matrix with additional hydrophobic alkane groups. The Dga1p-immobilized chip surface was analyzed for interactions of Dga1p with oleoyl-CoA, its substrate, and anti-Dga1p IgG, its interacting protein, by SPR. The binding of these analytes with the Dga1p-immobilized chip surface was specific, because butyryl-CoA, which cannot be used as a substrate for DGAT, and anti-glyceraldehyde-3-phosphate dehydrogenase IgG, did not induce any signals on SPR. Furthermore, injection of organic compounds such as xanthohumol, a DGAT inhibitor, into the Dga1p-immobilized chip surface induced significant SPR signals, probably due to interaction with DGAT. Another DGAT inhibitor, piperine, did not induce SPR signals on application, but induced them due to piperine on application together with oleoyl-CoA, in which piperine can be incorporated into the micelles of oleoyl-CoA. The results indicate that the Dga1p-immobilized L1 chip surface recognized DGAT inhibitors. Taking all this together, SPR measurement using the Dga1p-immobilized L1 chip surface provided a useful system to elucidate the structure-function relationships of DGAT and screen DGAT inhibitors. PMID- 21670530 TI - Purification and characterization of porcine skeletal muscle aminopeptidase T, a novel metallopeptidase homologous to leukotriene A4 hydrolase. AB - A novel aminopeptidase, Aminopeptidase T (APase T), was purified from porcine skeletal muscle following successive column chromatography: twice on DEAE cellulose, hydroxyapatite, and Sephacryl S-200 HR using Leu-beta-naphthylamide (LeuNap) as a substrate. The molecular mass of the enzyme was 69 kDa on SDS-PAGE. The optimum pH towards LeuNap of the enzyme was about 7. The enzyme activity was strongly inhibited by bestatin and was negatively affected by ethylenediaminetetraacetic acid (EDTA). Chlorine-activated APase T liberated Leu, Ala, Met, Pro, and Arg from Nap derivatives. The APase T gene consisted of an ORF of 1,836 bp encoding a protein of 611 amino acid residues. The APase T was highly homologous to bovine, human, and mouse Leukotriene A(4) hydrolase (LTA(4)H), a bifunctional enzyme which exhibits APase and epoxide hydrolase activity. PMID- 21670531 TI - Effects of creatine and its analog, beta-guanidinopropionic acid, on the differentiation of and nucleoli in myoblasts. AB - The effects of supplementation with creatine (Cr) and its analog, beta guanidinopropionic acid (beta-GPA), on the differentiation of myoblasts and the numbers of nucleoli were studied in C2C12 cells. The cells were cultured in differentiation medium for 4 d. Then Cr (1 mM) or beta-GPA (1 mM) was added to the cells, and the mixture was cultured for an additional 2 d. Although the number of myotubes was not different among the groups, myotube diameters and nuclear numbers in myotubes were increased by Cr and beta-GPA treatment respectively. The expression of differentiation marker proteins, myogenin, and the myosine heavy chain, was increased in the beta-GPA group. Supplementation with beta-GPA also increased the percentage of p21 (inhibitor for cell cycle progression)-positive myoblasts. Supplementation with Cr inhibited the decrease in nucleoli numbers, whereas beta-GPA increased nucleolar sizes in the myotubes. These results suggest that beta-GPA supplementation stimulated the differentiation of myoblasts into multi-nucleated myotubes through induction of p21 expression. PMID- 21670532 TI - FXYD6, a Na,K-ATPase regulator, is expressed in type II taste cells. AB - Taste buds contain three types of taste cells. Each type can respond to taste stimulation, and type II and III taste cells are electrically excitable. However, there are differences between the properties of type II and III taste cells. In this study, we found that Fxyd6, an Na,K-ATPase regulator gene, is expressed in type II taste cells in the taste buds of mice. Double-labeled in situ hybridization analysis showed that Fxyd6 was coexpressed with transient receptor potential cation channel, subfamily M, member 5 (Trpm5), a critical component of the sweet, bitter, and umami taste signal transduction pathways and that it was specifically expressed in type II taste cells. We also found that taste cells frequently coexpressed Fxyd6 and Na,K-ATPase beta1. These results indicate the presence of an inherent mechanism that regulated transmembrane Na(+) dynamics in type II taste cells. PMID- 21670533 TI - Purification and characterization of an NADH-dependent alcohol dehydrogenase from Candida maris for the synthesis of optically active 1-(pyridyl)ethanol derivatives. AB - A novel (R)-specific alcohol dehydrogenase (AFPDH) produced by Candida maris IFO10003 was purified to homogeneity by ammonium sulfate fractionation, DEAE Toyopearl, and Phenyl-Toyopearl, and characterized. The relative molecular mass of the native enzyme was found to be 59,900 by gel filtration, and that of the subunit was estimated to be 28,900 on SDS-polyacrylamide gel electrophoresis. These results suggest that the enzyme is a homodimer. It required NADH as a cofactor and reduced various kinds of carbonyl compounds, including ketones and aldehydes. AFPDH reduced acetylpyridine derivatives, beta-keto esters, and some ketone compounds with high enantioselectivity. This is the first report of an NADH-dependent, highly enantioselective (R)-specific alcohol dehydrogenase isolated from a yeast. AFPDH is a very useful enzyme for the preparation of various kinds of chiral alcohols. PMID- 21670534 TI - ABC transporters involved in the biogenesis of the outer membrane in gram negative bacteria. AB - The outer membrane of gram-negative bacteria is an asymmetric lipid bilayer with phospholipids and lipopolysaccharides (LPSs). beta-Barreled outer membrane proteins and lipoproteins are embedded in the outer membrane. All of these constituents are essential to the function of the outer membrane. The transport systems for lipoproteins have been characterized in detail. An ATP-binding cassette (ABC) transporter, LolCDE, initiates sorting by mediating the detachment of lipoproteins from the inner membrane to form a water-soluble lipoprotein-LolA complex in the periplasm. Lipoproteins are then transferred to LolB at the outer membrane and are incorporated into the lipid bilayer. A model analogous to the Lol system has been suggested for the transport of LPS, where an ABC transporter, LptBFG, mediates the detachment of LPS from the inner membrane. Recent developments in the functional characterization of ABC transporters involved in the biogenesis of the outer membrane in gram-negative bacteria are discussed. PMID- 21670535 TI - Diet and atherosclerosis in apolipoprotein E-deficient mice. AB - Atherosclerosis is a multifactorial, long-lasting process in humans. Accordingly, animal models in which more rapid changes occur can be useful for the study of this process. Among such models are apolipoprotein E-deficient (apoE-/-) mice, which give insight into the human process. ApoE-/- mice show impaired clearing of plasma lipoproteins and develop atherosclerosis in a short time, and hence they are an excellent model in which to assess the impact of dietary factors. This review considers lipid metabolism and inflammation as well as nutritional constituents affecting atherosclerosis, with reference to apoE-/- mice, and discusses the mechanisms through which they act. PMID- 21670536 TI - Inhibitory effect of [6]-gingerol on melanogenesis in B16F10 melanoma cells and a possible mechanism of action. AB - [6]-Gingerol is an active component of ginger that shows antipyretic and anti inflammation activities. To find a novel skin-whitening agent, the melanogeneis inhibitory effects and action mechanisms of [6]-gingerol were investigated. In the present study, the effects of [6]-gingerol on mushroom tyrosinase, tyrosinase activity, and melanin content were determined spectrophotometrically, and the expression of tyrosinase and related proteins in B16F10 murine melanoma cells was evaluated by Western blotting. Furthermore, a possible signaling pathway involved in [6]-gingerolmediated depigmentation was investigated by means of specific inhibitors. The results revealed that [6]-gingerol (25-100 uM) effectively suppresses murine tyrosinase activity and decreases the amount of melanin in a dose-dependent manner. Additionally, it also effectively decreased the intracellular reactive oxygen species (ROS) level in a dose-dependent pattern in the same dose range. Our results indicate that [6]-gingerol inhibits melanogenesis of B16F10 melanoma and can function as a good skinwhitening agent. PMID- 21670537 TI - Effects of magnesium sulfate on the luminescence of Vibrio fischeri under nutrient-starved conditions. AB - In this study, we investigated the relationship between MgSO(4) and luminescence in Vibrio fischeri under nutrient-starved conditions. When V. fischeri was cultured in an artificial seawater medium, the luminescence intensity was low relative to that observed under normal growth conditions. It decreased during the initial 14 h, and then increased slightly at 24 h. This regulation of luminescence was not dependent on the quorum-sensing mechanism, because the cell densities had not reached a critical threshold concentration. Under MgSO(4) starved conditions, luminescence was not fully induced at 14 h, and decreased at 24 h. In contrast, induction of luminescence occurred under MgSO(4)-supplemented conditions, but MgSO(4) alone was insufficient to induce luminescence, and required NaHCO(3) or KCl. These results suggest that the luminescence of V. fischeri is controlled by an exogenous sulfur source under nutrient-starved conditions. In addition, they indicate that the induction of sulfur-dependent luminescence is regulated by the NaHCO(3) or KCl concentration. PMID- 21670538 TI - An overview of a wide range of functions of ZnT and Zip zinc transporters in the secretory pathway. AB - Zinc plays essential roles in the early secretory pathway for a number of secretory, membrane-bound, and endosome/lysosome-resident enzymes. It enables the enzymes to fold properly and become functional, by binding as a structural or catalytic component. Moreover, zinc secreted from the secretory vesicles/granules into the extracellular space has a pivotal role as a signaling molecule for various physiological functions. Zinc transporters of the Slc30a/ZnT and Slc39a/Zip families play crucial roles in these functions, mediating zinc influx to and efflux from the lumen of the secretory pathway, constitutively or in a cell-specific manner. This paper reviews current knowledge of the ways these two zinc transporters perform these tasks by manipulating zinc homeostasis in the secretory pathway. Recent questions concerning zinc released into the cytoplasm from the secretory pathway, which then functions as an intracellular signaling molecule, are also briefly reviewed, emphasizing zinc transporter functions. PMID- 21670540 TI - Effect of long-term nitrate treatment on cardiac events in patients with vasospastic angina. AB - BACKGROUND: Nitrates have been widely used as anti-ischemic drugs in patients with vasospastic angina (VSA). However, the effect of long-term nitrate treatment on cardiac events in VSA patients remains unclear. METHODS AND RESULTS: Two hundred and thirty-one patients with VSA who had not been receiving any antiischemic drugs, including calcium channel blockers (CCBs), nitrates, nicorandil, or any combination of these medications were prospectively enrolled in the present study. All patients had a positive acetylcholine provocation test with normal coronary angiograms, and they received CCBs after enrollment. They were divided into 2 groups based on whether nitrates were included in the treatment: a nitrate group (n=86) and a without nitrate group (n=145). The baseline clinical characteristics and frequency of anginal attacks within 48h before enrollment were similar between the 2 groups. With a median follow-up period of 70.5 months, 29 patients developed cardiac events, including 7 sudden cardiac deaths and 22 re-admissions for acute coronary syndrome. Cardiac events occurred in 19.8% of the nitrate group and in only 8.3% of the patients who were not taking nitrates (P=0.015). In a multivariate analysis, long-term nitrate treatment (hazard ratio 5.18, 95% confidence interval: 1.69-15.89, P=0.004) was an independent predictor of cardiac events. CONCLUSIONS: These data indicate that long-term nitrate treatment in addition to CCBs might not reduce cardiac events in VSA patients. PMID- 21670539 TI - Effect of pretreatment with pioglitazone on reperfusion injury in diabetic patients with acute myocardial infarction. AB - BACKGROUND: Pioglitazone (PIO) is a new class of anti-diabetic agent with an anti inflammatory effect. In the experimental studies, pretreatment with PIO before ischemia/reperfusion reduced ischemia-reperfusion injury and myocardial infarct size. However, the clinical efficacy of this therapy in patients with acute myocardial infarction (AMI) remains unknown. METHODS AND RESULTS: Three hundred and nineteen diabetic patients with ST-segment elevation AMI, treated with bare metal stent within 24h from the onset of AMI were examined. Myocardial blush grade, ST-segment resolution, peak creatine kinase (CK) level, and left ventricular ejection fraction (LVEF) were compared between PIO group (pretreatment with PIO [+]; n=26) and non-PIO group (pretreatment with PIO [-]; n=293). The PIO group showed a significantly higher incidence of blush score >= 2 and complete ST-segment resolution (blush score >= 2; 38% vs. 71%, P=0.04, ST segment resolution; 44% vs. 71%, P=0.04). Besides, slow flow/no-reflow phenomenon and reperfusion arrhythmia did not occur in this group. Better improvement of LVEF and lower peak CK level was observed in this group, although these were not statistically significant (LVEF 48% vs. 41%, P=0.10, peak CK level 2,041 vs. 3,207, P=0.06). CONCLUSIONS: Pretreatment with PIO in diabetic patients with AMI resulted in better myocardial perfusion with less reperfusion injury. PMID- 21670541 TI - Histological characteristics of glistening yellow coronary plaques seen on angioscopy. -With special reference to vulnerable plaques-. AB - BACKGROUND: Glistening yellow coronary plaques (GY) seen on angioscopy are considered vulnerable to disruption. Collagen fiber (CF) is the main substance that protects coronary plaques against mechanical stress. Therefore, whether angioscopically defined vulnerable plaques correlate with those defined histologically was investigated. METHODS AND RESULTS: One hundred and thirty-two excised human coronary plaques were classified by angioscopy into 19 GY, 49 non glistening yellow plaques (non-GY) and 64 white plaques, and their relation to CF density was examined. CF-dense (>15/100 um), CF-loose (>5 and <15/100 um), and CF scanty (<5/100 um) plaques were hypothesized to be stable, relatively stable, and vulnerable, respectively. Histologically the plaques were classified into non lipid deposition, superficial lipid deposition and diffuse lipid deposition groups; the diffuse lipid deposition group was classified into necrotic core (NC) and non-NC types. Nineteen GY were composed of 4 with superficial lipid deposition, 4 with non-NC type of diffuse lipid deposition, and 11 with NC type. Sixteen (84%) of these were CF scanty. Forty-nine (100%) of non-GY and 57 (89%) of white plaques were CF dense or CF loose The sensitivity, specificity and predictive value of GY in detecting histologically vulnerable plaques were 90%, 97% and 84%, respectively, indicating that GY represented histologically vulnerable plaques. CONCLUSIONS: These pathohistological characteristics might indicate that GY, less-protected plaques against mechanical stress, are vulnerable plaques. PMID- 21670542 TI - Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. -The ARISTOTLE-J study-. AB - BACKGROUND: Guidelines recommend warfarin as the standard of care for patients with atrial fibrillation (AF) at moderate or high risk for stroke. This phase II study assessed the effects of 2 doses of the factor Xa inhibitor apixaban vs. warfarin in Japanese patients with non-valvular AF. The composite primary endpoint was major and clinically relevant non-major (CRNM) bleeding. METHODS AND RESULTS: Two hundred and twenty-two patients with AF and 1 or more additional risk factors for stroke were randomized (1:1:1) to double-blind apixaban 2.5 or 5mg b.i.d. or open-label warfarin (target international normalized ratio 2.0-3.0; 2.0-2.6 if age >= 70 years) for 12 weeks. The primary endpoint occurred in 1 patient (1.4%) in each apixaban group and 4 (5.3%) warfarin patients. There were no strokes, systemic emboli, myocardial infarctions, or deaths in either apixaban group. The warfarin group had 2 ischemic strokes and 1 subarachnoid hemorrhage, but there were no deaths. Major and CRNM bleeds each occurred with higher frequency in the warfarin group vs. either apixaban group. Most adverse events were mild or moderate. No patients had hepatic aminotransferase elevations greater than 3 times the upper limit of normal. CONCLUSIONS: In Japanese patients with AF, apixaban 2.5 and 5mg b.i.d. were well tolerated over 12 weeks. A global phase III trial, which includes Japanese patients, is ongoing (ClinicalTrials.gov Identifier NCT00787150). PMID- 21670543 TI - A 1H NMR-based metabolomics approach for mechanistic insight into acetaminophen induced hepatotoxicity. AB - The widely used analgesic-antipyretic drug acetaminophen (APAP) is known to cause serious liver necrosis at high doses in man and experimental animals. For studies of toxic processes, 1H NMR spectroscopy of biofluids allows monitoring of endogenous metabolite profiles that alter characteristically in response to changes in physiological status. Herein, a 1H NMR metabolomics approach was applied to the investigation of APAP toxicity in rats and the effect of phenobarbital (PB) on APAP-induced hepatotoxicity. Metabolite differences due to hepatotoxicity were observed in 1H NMR spectra of serum and urine, and enhanced APAP hepatotoxicity by pretreatment with PB was clearly shown by a principal components analysis of the spectral data. NMR spectra of APAP-dosed rat urine provided profiles of APAP-related compounds together with endogenous metabolites. By comparison of endogenous and APAP-related metabolite spectra with those from rats pretreated with PB, it was possible to show the importance of oxidative metabolism of APAP to N-acetyl-p-benzoquinone, an essential step in APAP hepatotoxicity. PMID- 21670544 TI - Our experience of treatment of cribriform morular variant of papillary thyroid carcinoma; difference in clinicopathological features of FAP-associated and sporadic patients. AB - Cribriform-morular variant (CMV) is a comparably rare histological subtype of papillary thyroid carcinoma (PTC). This can be associated with familial adenomatous polyposis (FAP) due to APC gene mutations. In this study, we investigated the difference in the biological characteristics between FAP associated and sporadic CMV. Between 1991 and 2010, 32 patients with CMV were treated in Kuma Hospital. Thirty-one of these underwent initial surgery for CMV in Kuma Hospital. Twelve patients were FAP-associated and the remaining 19 were sporadic CMV. All patients were female. Tumors of FAP-associated CMV were more frequently multiple than those of sporadic CMV. Patient age and tumor size did not differ between the two groups. Of 12 FAP-associated CMV, 5 were detected by thyroid nodule (thyroid precedent group) and 7 were detected by FAP (polyposis precedent group) as an initial manifestation. Patient age was younger and tumor size was smaller in the polyposis group than in the thyroid nodule group. All patients lacked extrathyroid extension on intraoperative finding and were node negative on pathological examination. To date, two patients with FAP-associated CMV who initially underwent hemithyroidectomy (one in Kuma Hospital and one in another hospital) showed recurrence to the remnant thyroid during follow-up. None of the patients showed recurrence to other regions or died of carcinoma. Taken together, CMV is considered an indolent disease in our series. FAP-associated CMV showed multiple tumors more frequently than sporadic CMV. Total thyroidectomy is recommended for FAP-associated CMV, but extensive lymph node dissection is not necessary. PMID- 21670546 TI - Boundaries of transcriptionally silent chromatin in Saccharomyces cerevisiae. AB - In the budding yeast Saccharomyces cerevisiae, heterochromatic gene silencing has been found within HMR and HML silent mating type loci, the telomeres, and the rRNA-encoding DNA. There may be boundary elements that regulate the spread of silencing to protect genes adjacent to silenced domains from this epigenetic repressive effect. Many assays show that specific DNA regulatory elements separate a euchromatic locus from a neighboring heterochromatic domain and thereby function as a boundary. Alternatively, DNA-independent mechanisms such as competition between acetylated and deacetylated histones are also reported to contribute to gene insulation. However, the mechanism by which boundaries are formed is not clear. Here, the characteristics and functions of boundaries at silenced domains in S. cerevisiae are discussed. PMID- 21670545 TI - Efficacy analysis of the lipid-lowering and renoprotective effects of rosuvastatin in patients with chronic kidney disease. AB - We aimed to assess the effects of rosuvastatin treatment on lipid levels, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label, study of 91 patients with CKD, low density lipoprotein cholesterol (LDL-C) levels > 120 mg/dL, and well-controlled blood pressure who were undergoing treatment with renin-angiotensin system inhibitors. Subjects were treated with 2.5 mg/day rosuvastatin, which was increased to 10 mg/day for the 24-week study period. Rosuvastatin effectively reduced total cholesterol, LDL-C, triglycerides, non-high density lipoprotein cholesterol (non-HDL-C) levels, and the LDL-C/HDL-C ratio. Although there was no significant change in the estimated glomerular filtration rate (eGFR), serum cystatin C levels and urinary albumin/creatinine ratio were significantly decreased. Subjects were divided into 2 groups: with and without diabetes mellitus (DM). Percent changes of HDL-C, C-reactive protein (CRP), and malondialdehyde-modified (MDA)-LDL were significantly higher in the DM group than in the non-DM group. Furthermore, when the subjects were divided into 2 groups based on eGFR levels (60 mL/min/1.73 m(2) or more, normal-GFR group; less than 60 mL/min/1.73 m(2), decreased-GFR group), the percent reduction of non-HDL-C, CRP, MDA-LDL levels, and albuminuria of DM subjects in the decreased-GFR group were significantly higher than those in the non-DM subjects. Multivariate analysis identified a change in cystatin C to be associated with decreased albuminuria during rosuvastatin treatment. Rosuvastatin administration reduced albuminuria, serum cystatin C levels, and inflammation, and improved lipid profiles, regardless of the presence or absence of DM, and the degree of the eGFR. PMID- 21670547 TI - Fission yeast homologs of human XPC and CSB, rhp41 and rhp26, are involved in transcription-coupled repair of methyl methanesulfonate-induced DNA damage. AB - Methyl methanesulfonate (MMS) methylates nitrogen atoms in purines, and predominantly produces 7-methylguanine and 3-methyladenine (3-meA). Previously, we showed that base excision repair (BER) and nucleotide excision repair (NER) synergistically function to repair MMS-induced DNA damage in the fission yeast Schizosaccharomyces pombe. Here, we studied the roles of NER components in repair of 3-meA and BER intermediates such as the AP site and single strand breaks. Mutants of rhp41 (XPC homolog) and rhp26 (CSB homolog) exhibited moderate sensitivity to MMS. Transcription of the fbp1 gene, which is induced by glucose starvation, was strongly inhibited by MMS damage in rhp41Delta and rhp26Delta strains but not in wild type and 3-meA DNA glycosylase-deficient cells. The results indicate that Rhp41p and Rhp26p are involved in transcription-coupled repair (TCR) of MMS-induced DNA damage. In the BER pathway of S. pombe, AP lyase activity of Nth1p mainly incises the AP site to generate a 3'-blocked end, which is in turn converted to 3'-OH by Apn2p. Deletion of rad16 or rhp26 in the nth1Delta strain greatly enhanced MMS sensitivity, suggesting that the AP site could also be corrected by TCR. Double mutant apn2Delta/rad16Delta exhibited hypersensitivity to MMS, implying that Rad16p provides a backup pathway for removal of the 3'-blocked end. Moreover, an rhp51Delta strain was extremely sensitive to MMS and double mutants of nth1Delta/rhp51Delta and apn2Delta/rhp51Delta increased the sensitivity, suggesting that homologous recombination is necessary for repair of three different types of lesions, 3-meA, AP sites and 3'-blocked ends. PMID- 21670548 TI - A Phalaenopsis variety with floral organs showing C class homeotic transformation and its revertant may enable Phalaenopsis as a potential molecular genetic material. AB - The Orchidaceae is one of the most famous garden plants, and improvement of the orchid is very important in horticulture field. However, molecular information is largely unknown. We found a Phalaenopsis variety harboring floral organs showing C class homeotic change. Column is composed of the anthers with the receptive stigmatic surface just underneath them in wild type. However the C class variety produced column with sepal or petal like structure at the abaxial side. This is the typical abnormality as C class mutants in plants. Further, wild type looking revertant was found from the meristem tissue cultured population. This result strongly indicates the existence of active transposable element in Phalaenopsis genome. This transposon may enable Phalaenopsis as a good material for molecular genetic analysis in Orchidaceae. PMID- 21670549 TI - Sperm of the wasted mutant are wasted when females utilize the stored sperm in Drosophila melanogaster. AB - Females of many animal species store sperm after copulation for use in fertilization, but the mechanisms controlling sperm storage and utilization are largely unknown. Here we describe a novel male sterile mutation of Drosophila melanogaster, wasted (wst), which shows defects in various processes of sperm utilization. The sperm of wst mutant males are stored like those of wild-type males in the female sperm storage organs, the spermathecae and seminal receptacles, after copulation and are released at each ovulation. However, an average of thirteen times more wst sperm than wild type sperm are released at each ovulation, resulting in rapid loss of sperm stored in seminal receptacles within a few days after copulation. wst sperm can enter eggs efficiently at 5 hr after copulation, but the efficiency of sperm entry decreases significantly by 24 hr after copulation, suggesting that wst sperm lose their ability to enter eggs during storage. Furthermore, wst sperm fail to undergo nuclear decondensation, which prevents the process of fertilization even when sperm enter eggs. Our results indicate that the wst gene is essential for independent processes in the utilization of stored sperm; namely, regulation of sperm release from female storage organs, maintenance of sperm efficiency for entry into eggs, and formation of the male pronucleus in the egg at fertilization. PMID- 21670550 TI - Evolution of the CYP2D gene cluster in humans and four non-human primates. AB - The human cytochrome P450 2D6 (CYP2D6) is a primary enzyme involved in the metabolism of about 25% of commonly used therapeutic drugs. CYP2D6 belongs to the CYP2D subfamily, a gene cluster located on chromosome 22, which comprises the CYP2D6 gene and pseudogenes CYP2D7P and CYP2D8P. Although the chemical and physiological properties of CYP2D6 have been extensively studied, there has been no study to date on molecular evolution of the CYP2D subfamily in the human genome. Such knowledge could greatly contribute to the understanding of drug metabolism in humans because it makes us to know when and how the current metabolic system has been constructed. The knowledge moreover can be useful to find differences in exogenous substrates in a particular metabolism between human and other animals such as experimental animals. Here, we conducted a preliminary study to investigate the evolution and gene organization of the CYP2D subfamily, focused on humans and four non-human primates (chimpanzees, orangutans, rhesus monkeys, and common marmosets). Our results indicate that CYP2D7P has been duplicated from CYP2D6 before the divergence between humans and great apes, whereas CYP2D6 and CYP2D8P have been already present in the stem lineages of New World monkeys and Catarrhini. Furthermore, the origin of the CYP2D subfamily in the human genome can be traced back to before the divergence between amniotes and amphibians. Our analyses also show that reported chimeric sequences of the CYP2D6 and CYP2D7 genes in the chimpanzee genome appear to be exchanged in its genome database. PMID- 21670551 TI - Genome-wide SNP-based linkage analysis for ADNSHL families identifies novel susceptibility loci with positive evidence for linkage. AB - The linkage search for susceptibility loci using SNP markers in hereditary hearing loss has proven challenging due to genetic heterogeneity. We conducted a genome-wide linkage analysis using high-density SNP markers in two Korean families (families coded SD-J and SR-167) with autosomal dominant non-syndromic hearing loss (ADNSHL). Evidence was found of linkage at 8q24.13~q24.3 and 10p11.21~q22.2 (LOD 3.01) in the SD-J family. In the case of family SR-167, which had the most affected members, the parametric LOD score was low owing to the lack of power for linkage analysis. However, using non-parametric linkage analysis, it was possible to obtain significant evidence for linkage at 10q22.1~q23.31 (LOD 1.79; NPL 6.47, P<0.00001). There is an overlapping region with a significant LOD score between the SD-J and SR-167 families, which encompasses 4 cM at 10q22.1~22.2. Interestingly, the characteristics of hearing loss in both families were similar, and the haplotype within overlapping region was shared in the affected individuals of the two families. We performed direct sequencing of the candidate genes that are thought to be causing the condition, but no disease causing mutations were identified. PMID- 21670552 TI - Overestimation of nonsynonymous/synonymous rate ratio by reverse-translation of aligned amino acid sequences. AB - In the analysis of protein-coding nucleotide sequences, the ratio of the number of nonsynonymous substitutions to that of synonymous substitutions (d(N)/d(S)) is used as an indicator for the direction and magnitude of natural selection operating at the amino acid sequence level. The d(S) and d(N) values are estimated based on the comparison of homologous codons, which are often identified by converting (reverse-translating) aligned amino acid sequences into codon sequences. In this method, however, homologous codons may be mis-identified when frame-shifts occurred or amino acid sequences were mis-aligned, which may lead to overestimation of the d(N)/d(S) ratio. Here the effect of reverse translating aligned amino acid sequences on the estimation of d(N)/d(S) ratio was examined through a large-scale analysis of protein-coding nucleotide sequences from vertebrate species. Apparently, 1-9% of codon sites that were identified as homologous with reverse-translation contained non-homologous codons, where the d(N)/d(S) ratio was unduly high. By correcting the d(N)/d(S) ratio for these codon sites, it was inferred that the ratio was 5-43% overestimated with reverse translation. These results suggest that caution should be exerted in the study of natural selection using the d(N)/d(S) ratio by reverse-translating aligned amino acid sequences. PMID- 21670553 TI - Characterization of two putative cytokine receptors, gp130 and ciliary neurotrophic factor receptor, from terrestrial salamanders. AB - Cytokines of the gp130 family are fundamental regulators of immune responses and signal through multimeric receptors to initiate intracellular second-messenger cascades. Here, we provide the first characterization of two full-length gp130 cytokine receptors from the cDNA of the red-legged salamander (Plethodon shermani). The first, gp130 (2745 bp), is a common signaling receptor for several multi-functional cytokines in vertebrates. We also isolated the full-length (1104 bp) sequence of the ciliary neurotrophic factor receptor (CNTFR), which forms a heteromeric signaling complex with gp130. The open reading frames of both receptors were predicted to contain many of the conserved features found in mammalian gp130s, such as cytokine binding homology regions and residues known to form disulfide bonds. Finally, we used RT-PCR to show that gp130 and CNTFR were expressed in most P. shermani tissues, including brain, intestine and muscle. The expression profiles, along with the structural predictions, show that gp130, CNTFR, and their cytokine ligands are parts of the immune system of P. shermani and other caudate amphibians. PMID- 21670554 TI - Circulatory and central nervous system responses to different types of mental stress. AB - The purpose of the present study was to compare the physiological responses to different types of mental stress encountered in the workplace. Circulatory and central nervous system responses were examined in 8 healthy males by exposing them to 20-min of white noise (80 dB(A)) and 20-min of computer-based mental arithmetic tasks as models of vascular and cardiac stress, respectively. The results indicated that both cardiac and vascular stresses increased blood pressure and showed a cumulative effect as exposure period was extended. Heart rate and prefrontal oxygenated hemoglobin levels (measured by NIRS) increased in the face of cardiac stress but were not clearly altered by vascular stress and indicated that cardiac stress higher cardiac response and requires more oxygen supply to the brain. As the central nervous system responded, an event-related potential P300 component was elicited by an auditory oddball task presented before and after each stress. The P300 amplitude increased for both stresses. However, P300 latency increased in response to cardiac stress but decreased with vascular stress in the left prefrontal. Thus, the circulatory and central nervous system responses to cardiac stress and to vascular stress may have different underlying mechanisms, and measuring physiological indices appears to be an effective method by which to evaluate the influence of mental stress. PMID- 21670555 TI - Measuring exposed magnetic fields of welders in working time. AB - The assessment of the occupational electromagnetic field exposure of welders is of great importance, especially in shielded-arc welding, which uses relatively high electric currents of up to several hundred amperes. In the present study, we measured the magnetic field exposure level of welders in the course of working. A 3-axis Hall magnetometer was attached to a subject's wrist in order to place the sensor probe at the closest position to the magnetic source (a cable from the current source). Data was acquired every 5 s from the beginning of the work time. The maximum exposed field was 0.35-3.35 mT (Mean +/- SD: 1.55 +/- 0.93 mT, N=17) and the average value per day was 0.04-0.12 mT (Mean +/- SD: 0.07 +/- 0.02 mT, N=17). We also conducted a finite element method-based analysis of human hand tissue for the electromagnetic field dosimetry. In addition, the magnetic field associated with grinders, an air hammer, and a drill using electromagnetic anchorage were measured; however, the magnetic fields were much lower than those generated in the welding process. These results agreed well with the results of the electromagnetic field dosimetry (1.49 mT at the wrist position), and the calculated eddy current (4.28 mA/m(2)) was much lower than the well-known guideline thresholds for electrical nerve or muscular stimulation. PMID- 21670556 TI - Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. AB - AIM: Endothelial cell (EC) dysfunction contributes to insulin resistance in diabetes and is characterized by reduced nitric oxide (NO) release, increased nitroxidative stress and enhanced inflammation. The purpose of this study was to test the effect of improved postprandial glucose control on EC function in insulin-resistant rats as compared to fasting glucose (FG) changes. METHODS: Obese Zucker rats were treated with 10 mg/kg/day saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, for 4 or 8 weeks and compared to lean rats. NO and peroxynitrite (ONOO(-)) release from aortic and glomerular ECs was measured ex vivo using amperometric approaches and correlated with FG, postprandial glucose, insulin, soluble CD40 (sCD40) and L-citrulline levels. RESULTS: Saxagliptin treatment improved NO production and reduced ONOO(-) release prior to any observed changes in FG levels. In untreated obese animals, NO release from aortic and glomerular ECs decreased by 22% and 31%, respectively, while ONOO(-) release increased by 26% and 40%. Saxagliptin increased aortic and glomerular NO release by 18% and 31%, respectively, with comparable reductions in ONOO(-) levels; the NO/ONOO(-) ratio, an indicator of NO synthase coupling, increased by >40%. Improved glycemic control was further associated with a reduction in sCD40 levels by more than ten-fold (from 300 +/- 206 to 22 +/- 22 pg/mL, p < 0.001). CONCLUSION: These findings indicate that enhanced glycemic control with DPP4 inhibition improved NO release and reduced inflammation in a manner not predicted by FG changes alone. PMID- 21670557 TI - Relationship between waist circumferences measured at the umbilical level and midway between the ribs and iliac crest - a solution to the debate on optimal waist circumference standards in the diagnostic criteria of metabolic syndrome in Japan. AB - AIM: The waist circumference (WC) cut-off values in the diagnostic criteria of metabolic syndrome (MetS) established in Japan (Japanese criteria) differ from those established by the International Diabetes Federation (IDF) for Asians (IDF criteria). METHODS: To settle this contradiction, a cross-sectional study of Japanese aged 20-65 years was performed. After excluding subjects suffering from significant diseases other than those constituting MetS, excessive drinkers, and regular smokers, 835 males and 1,304 females were examined. WC was measured at the umbilical level (UWC) and midway between the ribs and iliac crest (MWC) according to both criteria in each subject. RESULTS: Upper limits of reference intervals of MWC estimated in subjects free from MetS were 84.6 and 84.3 cm in older (40-65 years) and younger (20-39) males, and 78.4 and 70.5 cm in older and younger females, respectively; those of UWC were 86.4, 86.2, 87.9 and 78.9 cm, respectively. Receiver operating characteristic (ROC) curves for MWC to predict UWC reproduced the relationships of the two types of cut-off values in each population. CONCLUSION: WC cut-off values in the Japanese and IDF criteria have the potential to be valid as cut-off values of UWC and MWC in Japanese, respectively. Their difference can be explained by the variation in the WC definition, and they can stand together without inconsistency. Acceptance of the recently prevailing view that the WC standard in IDF for Asian males should be 85 cm and the introduction of new criteria for younger females in consideration of their generation differences in both criteria could facilitate their higher compatibility. PMID- 21670558 TI - Elevated antibody titers to Porphyromonas gingivalis as a possible predictor of ischemic vascular disease - results from the Tokamachi-Nakasato cohort study. AB - AIM: Limited epidemiological studies have investigated the relationship between ischemic vascular disease and periodontitis in non-Western populations. We investigated this relationship in a Japanese cohort by measuring serum titers of antibodies to periodontopathic bacteria. METHODS: As part of the Tokamachi Nakasato cohort study, we followed up 7021 participants regarding cardiovascular events over 5 years, and observed 99 ischemic vascular events: 66 cerebral infarctions and 33 cases of ischemic heart disease (IHD). For a nested case control study, we selected 495 sex- and age-matched control subjects. Conditional logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of ischemic vascular events associated with antibody titers to Porphyromonas gingivalis FDC381 and SU63. Multivariable models were adjusted for traditional cardiovascular risk factors using propensity scores. RESULTS: The highest tertile category of antibody titers to P. gingivalis FDC381 in men was significantly associated with an increased risk of cerebral infarction in only the crude model. The 2nd and 3rd tertile categories of antibody titers to P. gingivalis SU63 were significantly associated with an increased risk of cerebral infarction in men (multivariable ORs (95% CIs) were 7.12 (1.51-33.5) and 9.03 (1.97-41.5), respectively). The association was not appreciably modified when we further adjusted for serum high-sensitivity C-reactive protein levels. Antibody titers to P. gingivalis were not dose-dependently associated with the risk of IHD. CONCLUSION: High serum antibody titers to P. gingivalis SU63 could be a predictor of cerebral infarction in Japanese men independent of traditional risk factors and inflammation. PMID- 21670559 TI - AOPPs inhibits cholesterol efflux by down-regulating ABCA1 expression in a JAK/STAT signaling pathway-dependent manner. AB - AIMS: Advanced oxidation protein products (AOPPs) are new independent risk factor for coronary artery disease. This study was to determine the effects and potential mechanisms of AOPPs on cholesterol efflux from human macrophage foam cells. METHODS: Human THP-1 monocytes were preincubated with Phorbol-12-myristate 13-acetate (PMA) and oxidized low density lipoprotein (ox-LDL) to form foam cells. The protein and mRNA expression were examined by western immunoblotting assays and real-time quantitative PCR, respectively. Cellular cholesterol content was measured by HPLC. The cholesterol efflux was assessed by liquid scintillation counting. RESULTS: AOPPs significantly decreased the expression of ATP-binding membrane cassette transporter A-1 (ABCA1) and liver X receptor alpha (LXRalpha) and reduced cholesterol efflux from THP-1 macrophage- derived foam cells. AOPPs substantially activated NADPH oxidase and activated Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal pathway in THP-1 derived foam-like cells. Inhibiting NADPH oxidase by diphenyliodonium (DPI) effectively abolished the AOPPs-induced decrease in cholesterol efflux and the expression of ABCA1. Inhibiting JAK/STAT activation by its specific inhibitor AG 490 or by siRNA could also block AOPPs action on THP-1 cells. CONCLUSIONS: AOPPs may first down-regulate the expression of LXRalpha and ABCA1 through JAK/STAT signal pathway activation and then inhibit cholesterol efflux in THP-1-derived foam-like cells; therefore, our study may be useful for understanding the critical effects of AOPPs on the pathogenesis of atherosclerosis. PMID- 21670560 TI - Significance of a novel apolipoprotein E variant, ApoE Osaka/Kurashiki, in lipoprotein glomerulopathy. PMID- 21670561 TI - Expression of heme oxygenase-1 in the lungs of rats exposed to potassium octatitanate whiskers. AB - OBJECTIVES: Oxidative stress is thought to be the pathogenesis of pulmonary fibrosis induced by asbestos, and heme oxygenase-1 (HO-1) protects lung tissue against oxidative stress. We hypothesized that HO-1 is also associated with oxidative lung injury caused by exposure to potassium octatitanate whiskers (PT1), which is one of the asbestos substitutes. METHODS: Male Wistar rats were administered 1 mg or 2 mg PT1 suspended in saline by a single intratracheal instillation and were sacrificed after recovery for 3 days, 1 wk, 1 mo, 3 mo or 6 mo. Gene expression of HO-1 protein and mRNA and immunostaining were investigated in rat lungs. RESULTS: HO-1 protein expression was increased from 3 days to 1 mo and at 6 mo in the 1 or 2 mg PT1-exposed groups, and the gene expression of HO-1 mRNA was also increased at 3 days and from 1 mo to 6 mo. HO-1-positive cells were mainly found in the alveolar macrophages and the bronchial epithelial cells in immunostaining. CONCLUSIONS: These findings suggest that HO-1 is involved in lung damage caused by PT1. PMID- 21670562 TI - The association between impaired fasting glucose and noise-induced hearing loss. AB - OBJECTIVES: This study was performed to determine whether there is an association between impaired fasting glucose and noise-induced hearing loss. METHODS: The study subjects were workers in one automobile manufacturing company. The data were obtained from results of health examinations during 2005 and 2009. The factors analyzed were age, smoking and alcohol history, work duration, environmental noise level, hearing thresholds, blood pressure, serum creatinine, initial hearing threshold and fasting glucose. RESULTS: The hearing thresholds at 4,000 Hz frequencies for both ears were significantly higher in 2009 than those in 2005. The changes in the hearing thresholds of the subjects with an impaired fasting glucose (100-125 mg/dl) and diabetes (>=126 mg/dl) were greater than those of the normal (<100 mg/dl) group. After adjusting for variables such as age, smoking and alcohol history, environmental noise, hypertension and serum creatinine, fasting glucose was found to be a significant variable. Impaired fasting glucose (100-125 mg/dl) was significant (beta=1.339, p=0.002) for the right ear, whereas it was not significant (beta=0.639, p=0.121) for the left ear. CONCLUSIONS: Impaired fasting glucose, as well as diabetes, might be risk factors for hearing loss in individuals with exposure to certain noise levels. The results of this study suggest that impaired fasting glucose should be considered a risk factor for hearing loss. PMID- 21670563 TI - Injury of cell tight junctions and changes of actin level in acute lung injury caused by the perfluoroisobutylene exposure and the role of Myosin light chain kinase. AB - OBJECTIVES: To investigate the injury of cell tight junctions and change in actin level in the alveolus epithelial cells of the lung after perfluoroisobutylene (PFIB) exposure and the role of myosin light chain kinase (MLCK) in the injury. METHODS: Rats and mice were exposed to a sublethal dose of PFIB. The changes in tight junction zonula occludens-1 (ZO-1), actin and myosin light chain kinase (MLCK) were detected by immunofluorescence at 30 min, 1, 2, 4, 8, 16, 24, 48 and 72 h after PFIB exposure. The role of MLCK was analyzed by lung indices and the actin level. RESULTS: The normal ZO-1 immunofluorescence density and those after PFIB exposure were 71.63, 39.41, 37.59, 35.71, 33.22, 31.34, 31.61, 24.51, 40.03 and 44.71 respectively, The normal actin immunofluorescence density and those after PFIB exposure were 31.82, 36.46, 36.57, 41.60, 40.95, 35.41, 30.69, 19.96, 29.30 and 33.00 respectively, The normal MLCK immunofluorescence density and those after PFIB exposure were 61.21, 50.87, 48.37, 43.65, 41.96, 35.44, 31.77, 30.85, 33.10 and 38.20 respectively. When the MLCK inhibitor ML-7 was given in advance, pulmonary edema and actin degradation were suppressed. CONCLUSIONS: At an earlier stage, the increased permeability of the blood-air barrier after PFIB exposure is probably the result of injury of cell tight junctions that acts in concert with later changes in actin, resulting in an increase in permeability. MLCK could be a potential target for novel drug development for relief of acute lung injury. PMID- 21670564 TI - Effect of soil type and fertilizer management on archaeal community in upland field soils. AB - The effects of soil and fertilizer types on archaeal communities were evaluated by real-time PCR and PCR-denaturing gradient gel electrophoresis (DGGE) targeting the 16S rRNA gene of total DNA directly extracted from upland field soils. Twelve experimental upland field plots containing four different soil types, i.e., Cumulic Andosol, Low-humic Andosol, Yellow Soil and Gray Lowland Soil, were maintained under three different fertilizer management systems for 8 years (chemical fertilizer, rice husks and cow manure, and pig manure, respectively). Two-way ANOVA and RDA analyses showed that the copy number and PCR-DGGE profile of archaeal 16S rRNA gene were affected mainly by soil type, especially between Andosol and non-Andosol, but were also influenced by fertilizer type. Among several soil chemical properties, total N content showed a significant correlation to archaeal community. Sequence analyses showed that most of the major DGGE bands corresponded to uncultured Crenarchaeota of Group I.1b that contained ammonia-oxidizing archaea (AOA). These sequences were separated into two clusters in the phylogenetic tree and each lineage showed a different response to total N content. PMID- 21670565 TI - Fungal assemblages in the rhizosphere and rhizoplane of grasses of the subfamily Panicoideae in the Lakkavalli region of Karnataka, India. AB - Fungal communities associated with roots play an important role in nutrient cycling, supporting plant growth and the biocontrol of plant diseases. Experiments were conducted in 2004-2006 to isolate and characterize, based on their morphological features, rhizosphere and rhizoplane fungi from perennial grasses of the subfamily Panicoideae growing in forests of the Western Ghats in India. Fungal species were isolated on potato dextrose, czapeck dox and water agar, in different locations and seasons. The results obtained on PDA were used for detailed analysis since most fungi occurred in high percentages. While certain grasses harbored diverse fungal species, others supported only a few species. Most fungi were isolated during winter followed by the rainy and summer seasons. The species richness, diversity and evenness of fungal assemblages in the rhizosphere and rhizoplane depended on the grass species and season. Ascomycetes were isolated in large numbers in most grass species. Species of Aspergillus, Chaetomium, Penicillium and Trichoderma occurred frequently. Certain others and non-sporulating fungi were grass species-specific. Most fungal species colonized the middle of the root more than the root tip or root base. Results suggest that perennial grasses harbor diverse fungal communities whose potential could be tapped for producing secondary metabolites and managing plant diseases. PMID- 21670567 TI - Development of miracle medicines from sialic acids. AB - Sialic acids are electronegatively charged C9-sugars and are considered to play important roles in higher animals and some microorganisms. Denoting their significance, understanding and exploiting the complexity of the sialic acids has been referred to as the "the third language of life". In essence, "sialic acid derivatives possess a harmonious shape and good balance between two opposing hydrophilic and hydrophobic parts, meaning that they should display various kinds of potentially unique and possibly conflicting physiological activities (glycolipoids)". Consequently, there are good omens that unprecedented 'miracle' medicines could be developed from sialic acid derivatives. In this review, the first problem, the preparation of sialic acids, is covered, the synthesis of sialic acid derivatives and confirmation of their structures obviously being of critical significance. In addition we needed to confirm their precise stereochemistry and a hydrolysis method has been developed for confirmation of the anomeric position. Several of the compounds have already demonstrated interesting bioactivity. PMID- 21670568 TI - New way to produce dense double-antikaonic dibaryon system, KKNN, through Lambda(1405)-doorway sticking in p+p collisions. AB - A recent successful observation of a dense and deeply bound K nuclear system, K pp, in the p+p->K++K-pp reaction in a DISTO experiment indicates that the double K dibaryon, K-K-pp, which was predicted to be a dense nuclear system, can also be formed in p+p collisions. We find theoretically that the K--K- repulsion plays no significant role in reducing the density and binding energy of K-K-pp and that, when two Lambda(1405) resonances are produced simultaneously in a short-range p+p collision, they act as doorways to copious formation of K-K-pp, if and only if K K-pp is a dense object, as predicted. PMID- 21670569 TI - [Issue to be addressed in Japan when considering working hour restrictions for physicians and the anticipated responses of hospitals]. PMID- 21670570 TI - Higher serum free triiodothyronine levels within the normal range are associated with metabolic syndrome components in type 2 diabetic subjects with euthyroidism. AB - Associations of thyroid hormones with visceral obesity and insulin resistance in obese subjects with euthyroidism have been reported. However, there are no such reports in subjects with type 2 diabetes. The purpose of our study is to observe a relationship between thyroid hormones and components of metabolic syndrome (MetS) in type 2 diabetic subjects with euthyroidism defined by normal thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels. Subjects were 301 Japanese patients with type 2 diabetes. Serum TSH, FT4, free triiodothyronine (FT3), and variables related to MetS were measured. MetS was defined by the Japanese criteria and the criteria of the National Cholesterol Education Program modified for Asians. We found that serum FT3 levels were significantly and positively associated with BMI, visceral fat area, systolic and diastolic blood pressure, estimated glomerular filtration rate, serum triglyceride, and urine C peptide as a marker of insulin production, whereas negatively with age and HbA1c. In contrast, fewer numbers of variables were associated with serum TSH and FT4 levels. By a multiple regression analysis, FT3 level was independently associated with components of MetS such as visceral fat area, systolic blood pressure, and fasting blood glucose levels. On the other hand, the presence of these MetS components was independently associated with FT3 levels and urine C peptide. In conclusion, these results suggest a significant relationship between serum FT3 levels and components of MetS in type 2 diabetic subjects with euthyroidism, and imply a role of FT3 in MetS in type 2 diabetes. PMID- 21670571 TI - Honest signaling and the uses of prey coloration. AB - Abstract Although signal reliability is of fundamental importance to the understanding of animal communication, the extent of signal honesty in relation to antipredator warning signals has received relatively little attention. A recent theoretical model that assumed a physiological linkage between pigmentation and toxicity suggested that (aposematic) warning signals may often be reliable, in the sense that brightness and toxicity are positively correlated within prey populations. Two shortcomings of the model were (1) the requirement among predators for an innate aversion to brightly colored prey and (2) the assumption that prey can generate only bright coloration and not cryptic coloration. We evaluated the generality of predictions of reliable signaling when these shortcomings were removed. Without innate avoidance of bright prey, we found a positive brightness-toxin correlation when conspicuous prey coloration provided an additional fitness benefit unrelated to predation. Initially, this correlation could evolve for reasons unrelated to prey signaling; hence, aposematism might represent a striking example of exaptation. Given a choice between using pigmentation for bright or for cryptic coloration, crypsis was favored only in conditions of very low or very high resource levels. In the latter case, toxicity correlated positively with degree of cryptic coloration. Predictions of toxin-signal correlation appear robust, but we can identify interesting conditions in which signal reliability is not predicted. PMID- 21670566 TI - Calpain chronicle--an enzyme family under multidisciplinary characterization. AB - Calpain is an intracellular Ca2+-dependent cysteine protease (EC 3.4.22.17; Clan CA, family C02) discovered in 1964. It was also called CANP (Ca2+-activated neutral protease) as well as CASF, CDP, KAF, etc. until 1990. Calpains are found in almost all eukaryotes and a few bacteria, but not in archaebacteria. Calpains have a limited proteolytic activity, and function to transform or modulate their substrates' structures and activities; they are therefore called, "modulator proteases." In the human genome, 15 genes--CAPN1, CAPN2, etc.--encode a calpain like protease domain. Their products are calpain homologs with divergent structures and various combinations of functional domains, including Ca2+-binding and microtubule-interaction domains. Genetic studies have linked calpain deficiencies to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy, and diabetes. This review of the study of calpains focuses especially on recent findings about their structure function relationships. These discoveries have been greatly aided by the development of 3D structural studies and genetic models. PMID- 21670572 TI - Comparative methods as a statistical fix: the dangers of ignoring an evolutionary model. AB - Abstract Comparative methods are widely used in ecology and evolution. The most frequently used comparative methods are based on an explicit evolutionary model. However, recent approaches have been popularized that are without an evolutionary basis or an underlying null model. Here we highlight the limitations of such techniques in comparative analyses by using simulations to compare two commonly used comparative methods with and without evolutionary basis, respectively: generalized least squares (GLS) and phylogenetic eigenvector regression (PVR). We find that GLS methods are more efficient at estimating model parameters and produce lower variance in parameter estimates, lower phylogenetic signal in residuals, and lower Type I error rates than PVR methods. These results can very likely be generalized to eigenvector methods that control for space and both space and phylogeny. We highlight that GLS methods can be adapted in numerous ways and that the variance structure used in these models can be flexibly optimized to each data set. PMID- 21670573 TI - Negotiation, sanctions, and context dependency in the legume-Rhizobium mutualism. AB - Two important questions about mutualisms are how the fitness costs and benefits to the mutualist partners are determined and how these mechanisms affect the evolutionary dynamics of the mutualism. We tackle these questions with a model of the legume-rhizobium symbiosis that regards the mutualism outcome as a result of biochemical negotiations between the plant and its nodules. We explore the fitness consequences of this mechanism to the plant and rhizobia and obtain four main results. First, negotiations permit the plant to differentially reward more cooperative rhizobia--a phenomenon termed "plant sanctions"--but only when more cooperative rhizobia also provide the plant with good outside options during negotiations with other nodules. Second, negotiations may result in seemingly paradoxical cases where the plant is worse off when it has a "choice" between two strains of rhizobia than when infected by either strain alone. Third, even when sanctions are effective, they are by themselves not sufficient to maintain cooperative rhizobia in a population: less cooperative strains always have an advantage at the population level. Finally, partner fidelity feedback, together with genetic correlations between a rhizobium strain's cooperativeness and the outside options it provides, can maintain cooperative rhizobia. Our results show how joint control over the outcome of a mutualism through the proximate mechanism of negotiation can affect the evolutionary dynamics of interspecific cooperation. PMID- 21670575 TI - Developing dynamic mechanistic species distribution models: predicting bird mediated spread of invasive plants across northeastern North America. AB - Species distribution models are a fundamental tool in ecology, conservation biology, and biogeography and typically identify potential species distributions using static phenomenological models. We demonstrate the importance of complementing these popular models with spatially explicit, dynamic mechanistic models that link potential and realized distributions. We develop general grid based, pattern-oriented spread models incorporating three mechanisms--plant population growth, local dispersal, and long-distance dispersal--to predict broadscale spread patterns in heterogeneous landscapes. We use the model to examine the spread of the invasive Celastrus orbiculatus (Oriental bittersweet) by Sturnus vulgaris (European starling) across northeastern North America. We find excellent quantitative agreement with historical spread records over the last century that are critically linked to the geometry of heterogeneous landscapes and each of the explanatory mechanisms considered. Spread of bittersweet before 1960 was primarily driven by high growth rates in developed and agricultural landscapes, while subsequent spread was mediated by expansion into deciduous and coniferous forests. Large, continuous patches of coniferous forests may substantially impede invasion. The success of C. orbiculatus and its potential mutualism with S. vulgaris suggest troubling predictions for the spread of other invasive, fleshy-fruited plant species across northeastern North America. PMID- 21670574 TI - The effect of travel loss on evolutionarily stable distributions of populations in space. AB - A key assumption of the ideal free distribution (IFD) is that there are no costs in moving between habitat patches. However, because many populations exhibit more or less continuous population movement between patches and traveling cost is a frequent factor, it is important to determine the effects of costs on expected population movement patterns and spatial distributions. We consider a food chain (tritrophic or bitrophic) in which one species moves between patches, with energy cost or mortality risk in movement. In the two-patch case, assuming forced movement in one direction, an evolutionarily stable strategy requires bidirectional movement, even if costs during movement are high. In the N-patch case, assuming that at least one patch is linked bidirectionally to all other patches, optimal movement rates can lead to source-sink dynamics where patches with negative growth rates are maintained by other patches with positive growth rates. As well, dispersal between patches is not balanced (even in the two-patch case), leading to a deviation from the IFD. Our results indicate that cost associated forced movement can have important consequences for spatial metapopulation dynamics. Relevance to marine reserve design and the study of stream communities subject to drift is discussed. PMID- 21670576 TI - Fitness benefits and costs of cold acclimation in Arabidopsis thaliana. AB - Abstract When resources are limited, there is a trade-off between growth/reproduction and stress defense in plants. Most temperate plant species, including Arabidopsis thaliana, can enhance freezing tolerance through cold acclimation at low but nonfreezing temperatures. Induction of the cold acclimation pathway should be beneficial in environments where plants frequently encounter freezing stress, but it might represent a cost in environments where freezing events are rare. In A. thaliana, induction of the cold acclimation pathway critically involves a small subfamily of genes known as the CBFs. Here we test for a cost of cold acclimation by utilizing (1) natural accessions of A. thaliana that originate from different regions of the species' native range and that have experienced different patterns of historical selection on their CBF genes and (2) transgenic CBF overexpression and T-DNA insertion (knockdown/knockout) lines. While benefits of cold acclimation in the presence of freezing stress were confirmed, no cost of cold acclimation was detected in the absence of freezing stress. These findings suggest that cold acclimation is unlikely to be selected against in warmer environments and that naturally occurring mutations disrupting CBF function in the southern part of the species range are likely to be selectively neutral. An unanticipated finding was that cold acclimation in the absence of a subsequent freezing stress resulted in increased fruit production, that is, fitness. PMID- 21670577 TI - Female, but not male, tropical sparrows respond more strongly to the local song dialect: implications for population divergence. AB - In addition to the observed high diversity of species in the tropics, divergence among populations of the same species exists over short geographic distances in both phenotypic traits and neutral genetic markers. Divergence among populations suggests great potential for the evolution of reproductive isolation and eventual speciation. In birds, song can evolve quickly through cultural transmission and result in regional dialects, which can be a critical component of reproductive isolation through variation in female preference. We examined female and male behavioral responses to local and nonlocal dialects in two allopatric populations of rufous-collared sparrows (Zonotrichia capensis) in the Andes Mountains of Ecuador. Here we show that female sparrows prefer their natal song dialect to the dialect of an allopatric population that is just 25 km away and separated by an unsuitable higher-elevation habitat (pass of 4,200 m), thus providing evidence of prezygotic reproductive isolation among populations. Males showed similar territorial responses to all conspecific dialects with no consistent difference with respect to distance, making male territoriality uninformative for estimating reproductive isolation. This study provides novel evidence for culturally based prezygotic isolation over very short distances in a tropical bird. PMID- 21670578 TI - Differential maternal testosterone allocation among siblings benefits both mother and offspring in the zebra finch Taeniopygia guttata. AB - Parents are selected to preferentially invest in the offspring with highest reproductive value. One mechanism for achieving this is the modification of competitive asymmetries between siblings by maternal hormones. In many organisms, offspring value varies according to birth position in the brood, which determines survival chances and competitive advantage over access to resources. In birds, variation in yolk androgen allocation over the laying sequence is thought to modulate dominance of senior chicks over junior brood mates. We tested this hypothesis in zebra finches, which show a naturally decreasing pattern of within clutch testosterone allocation. We abolished these within-clutch differences by experimentally elevating yolk testosterone levels in eggs 2-6 to the level of egg 1, and we assessed fitness measures for junior offspring (eggs 2-6), senior offspring (egg 1), and their mothers. Testosterone-injected eggs hatched later than control eggs. Junior, but not senior, chicks in testosterone-treated broods attained poorer phenotypic quality compared to control broods, which was not compensated for by positive effects on seniors. Mothers were generally unaffected by clutch treatment. Thus, naturally decreasing within-clutch yolk testosterone allocation appears to benefit all family members and does not generally enhance brood reduction by favoring senior chicks, in contrast to the widely held assumption. PMID- 21670579 TI - Linking the spatial scale of environmental variation and the evolution of phenotypic plasticity: selection favors adaptive plasticity in fine-grained environments. AB - Adaptive phenotypic plasticity and adaptive genetic differentiation enable plant lineages to maximize their fitness in response to environmental heterogeneity. The spatial scale of environmental variation relative to the average dispersal distance of a species determines whether selection will favor plasticity, local adaptation, or an intermediate strategy. Habitats where the spatial scale of environmental variation is less than the dispersal distance of a species are fine grained and should favor the expression of adaptive plasticity, while coarse grained habitats, where environmental variation occurs on spatial scales greater than dispersal, should favor adaptive genetic differentiation. However, there is relatively little information available characterizing the link between the spatial scale of environmental variation and patterns of selection on plasticity measured in the field. I examined patterns of spatial environmental variation within a serpentine mosaic grassland and selection on an annual plant (Erodium cicutarium) within that landscape. Results indicate that serpentine soil patches are a significantly finer-grained habitat than non-serpentine patches. Additionally, selection generally favored increased plasticity on serpentine soils and diminished plasticity on non-serpentine soils. This is the first empirical example of differential selection for phenotypic plasticity in the field as a result of strong differences in the grain of environmental heterogeneity within habitats. PMID- 21670580 TI - Facilitation within species: a possible origin of group-selected superorganisms. AB - Facilitation (positive interactions) has emerged as a dominant ecological mechanism in many ecosystems. Its importance has recently been expanded to include intraspecific interactions, creating the potential for higher-level natural selection within species. Using multiple lines of evidence, we show that conspecific facilitation within the southern beech tree, Nothofagus pumilio, appears to overcome competition in two life phases. In a seedling experiment addressing stress and planting-density effects, we found that mortality was lowest (~0%) where there was no stress and was indistinguishable across densities. Furthermore, in mature forests (45 years old), genetically variable, merged individuals had lower mortality (-50%) than unmerged individuals in locations without identifiable stress. Thus, a full understanding of the occurrence of facilitation may require a more general model of resource improvements than the commonly cited stress gradient hypothesis. Additionally, the merged trees showed a density-dependent mortality pattern at the level of the group. These data demonstrate a potential mechanism (facilitation) driving natural selection at this higher level, via stem merging. These merged "superorganisms" would confirm theoretical predictions whereby facilitation acts as an ecological mechanism driving group selection. PMID- 21670581 TI - Biophysical aspects of resource acquisition and competition in algal mixotrophs. AB - Mixotrophic organisms combine autotrophic and heterotrophic nutrition and are abundant in both freshwater and marine environments. Recent observations indicate that mixotrophs constitute a large fraction of the biomass, bacterivory, and primary production in oligotrophic environments. While mixotrophy allows greater flexibility in terms of resource acquisition, any advantage must be traded off against an associated increase in metabolic costs, which appear to make mixotrophs uncompetitive relative to obligate autotrophs and heterotrophs. Using an idealized model of cell physiology and community competition, we identify one mechanism by which mixotrophs can effectively outcompete specialists for nutrient elements. At low resource concentrations, when the uptake of nutrients is limited by diffusion toward the cell, the investment in cell membrane transporters can be minimized. In this situation, mixotrophs can acquire limiting elements in both organic and inorganic forms, outcompeting their specialist competitors that can utilize only one of these forms. This advantage can be enough to offset as much as a twofold increase in additional metabolic costs incurred by mixotrophs. This mechanism is particularly relevant for the maintenance of mixotrophic populations and productivity in the highly oligotrophic subtropical oceans. PMID- 21670582 TI - Characteristic spatial and temporal scales unify models of animal movement. AB - Animal movements have been modeled with diffusion at large scales and with more detailed movement models at smaller scales. We argue that the biologically relevant behavior of a wide class of movement models can be efficiently summarized with two parameters: the characteristic temporal and spatial scales of movement. We define these scales so that they describe movement behavior both at short scales (through the velocity autocorrelation function) and at long scales (through the diffusion coefficient). We derive these scales for two types of commonly used movement models: the discrete-step correlated random walk, with either constant or random step intervals, and the continuous-time correlated velocity model. For a given set of characteristic scales, the models produce very similar trajectories and encounter rates between moving searchers and stationary targets. Thus, we argue that characteristic scales provide a unifying currency that can be used to parameterize a wide range of ecological phenomena related to movement. PMID- 21670583 TI - Is the evolution of inaccurate mimicry a result of selection by a suite of predators? A case study using myrmecomorphic spiders. AB - Several hypotheses have been put forward to explain the evolution of inaccurate mimicry. Here we investigated the novel hypothesis that inaccurate mimicry (in color and shape) is maintained by opposing selective pressures from a suite of different predators: model-aversive visually oriented predators and model- and mimic-specialized predators indifferent to mimetic cues. We hypothesize that spiders resembling ants in color and shape escape predators that typically avoid ants but fall prey to ant-eating predators. We tested whether inaccurate myrmecomorphic spiders are perceived as their models by two types of predators and whether they can escape from these predators. We found that model-specialized (ant-eating) predators captured mimics significantly less frequently than their ant models, because mimics changed their behavior by fleeing predatory attacks. The fastest escape was found in less accurate mimics, indicating a negative association between visual resemblance and effectiveness of defenses. In trials with spider-eating predators, mimics were not captured more frequently than their models. The quality of defensive mechanisms appears to result from opposing selection forces exerted by the predator complex: mimics are more accurate (in color and shape) in microhabitats dominated by model-aversive predators and less accurate in microhabitats with model- and mimic-specialized predators. PMID- 21670584 TI - Are pollination "syndromes" predictive? Asian dalechampia fit neotropical models. AB - Using pollination syndrome parameters and pollinator correlations with floral phenotype from the Neotropics, we predicted that Dalechampia bidentata Blume (Euphorbiaceae) in southern China would be pollinated by female resin-collecting bees between 12 and 20 mm in length. Observations in southwestern Yunnan Province, China, revealed pollination primarily by resin-collecting female Megachile (Callomegachile) faceta Bingham (Hymenoptera: Megachilidae). These bees, at 14 mm in length, were in the predicted size range, confirming the utility of syndromes and models developed in distant regions. Phenotypic selection analyses and estimation of adaptive surfaces and adaptive accuracies together suggest that the blossoms of D. bidentata are well adapted to pollination by their most common floral visitors. PMID- 21670585 TI - Association of angiotensin I converting enzyme, angiotensin II type 1 receptor and angiotensin I converting enzyme 2 gene polymorphisms with the dyslipidemia in type 2 diabetic patients of Chinese Han origin. AB - OBJECTIVE: To investigate whether the genetic polymorphisms in the angiotensin I converting enzyme (ACE) (insertion/ deletion, or I/D), angiotensin II type 1 receptor (AT1R) (rs5186), and ACE2 (rs2285666) could be associated with dyslipidemia in Type 2 diabetic (T2D) patients of Chinese Han origin. DESIGN AND METHODS: The above 3 polymorphisms were genotyped in a total of 282 patients with T2D and dyslipidemia (Group A), 182 patients with T2D but without dyslipidemia (Group B), and 324 healthy controls. The association between a certain polymorphism and each group was assessed by an odds ratio (OR). RESULTS: The D allele of the ACE (I/D) was significantly associated with the risk of T2D accompanying dyslipidemia between group A and controls [OR=1.37, 95% confidence interval (CI)=1.08-1.74; p=0.010], and significant association of the D allele with dyslipidemia was also observed in diabetic patients (OR=1.88, 95% CI=1.40 2.54; p<0.001). Furthermore, the ID genotype had a decreased risk of developing T2D without dyslipidemia as compared with controls (OR=0.52, 95% CI=0.32-0.82; p=0.0060). The distributions of the AT1R (rs5186) and ACE2 (rs2285666) genotypes and alleles did not differ between T2D patients with or without dyslipidemia and the controls. CONCLUSIONS: This study demonstrates that the ACE (I/D) polymorphism is associated with T2D, regardless of the absence or presence of dyslipidemia. The polymorphisms in the AT1R (rs5186) and ACE2 (rs2285666) seem to play lesser roles in the development of T2D. PMID- 21670586 TI - Nanoengineering bactericidal nitric oxide therapies. PMID- 21670589 TI - Resetting gene expression in chronic Chagas heart disease. PMID- 21670587 TI - Identification and functional analysis of Joka2, a tobacco member of the family of selective autophagy cargo receptors. AB - Two main mechanisms of protein turnover exist in eukaryotic cells: the ubiquitin proteasome system and the autophagy-lysosomal pathway. Autophagy is an emerging important constituent of many physiological and pathological processes, such as response to nutrient deficiency, programmed cell death and innate immune response. In mammalian cells the selectivity of autophagy is ensured by the presence of cargo receptors, such as p62/SQSTM1 and NBR1, responsible for sequestration of the ubiquitinated proteins. In plants no selective cargo receptors have been identified yet. The present report indicates that structural and functional homologs of p62 and NBR1 proteins exist in plants. The tobacco protein, named Joka2, has been identified in yeast two-hybrid search as a binding partner of a small coiled-coil protein, a member of UP9/LSU family of unknown function, encoded by the UP9C gene strongly and specifically induced during sulfur deficiency. The typical domains of p62 and NBR1 are conserved in Joka2. Similarly to p62, Joka2-YFP has dual localization (cytosolic speckles and the nucleus); it forms homodimers and interacts with a member of the ATG8 family. Increased expression of Joka2 and ATG8f was observed in roots of tobacco plants grown for two days in nutrient-deficient conditions. Constitutive ectopic expression of Joka2-YFP in tobacco resulted in attenuated response (manifested by lesser yellowing of the leaves) to nutrient deficiency. In conclusion, Joka2, and presumably the process of selective autophagy, might constitute an important part of plant response to environmental stresses. PMID- 21670588 TI - Caveolin-2-deficient mice show increased sensitivity to endotoxemia. AB - Caveolin proteins are structural components of caveolae and are involved in the regulation of many biological processes. Recent studies have shown that caveolin 1 modulates inflammatory responses and is important for sepsis development. In the present study, we show that caveolin-1 and caveolin-2 have opposite roles in lipopolysaccharide (LPS)-induced sepsis using caveolin-deficient (Cav-1 (-/-) and Cav-2 (-/-) ) mice for each of these proteins. While Cav-1 (-/-) mice displayed delayed mortality following challenge with LPS, Cav-2 (-/-) mice were more sensitive to LPS compared to wild-type (WT). With Cav-2 (-/-) mice, this effect was associated with increased intestinal injury and increased intestinal permeability. This negative outcome was also correlated with enhanced expression of iNOS in epithelial intestinal cells, and enhanced production of nitric oxide (NO). By contrast, Cav-1 (-/-) mice demonstrated a decrease in iNOS expression with decreased NO production, but no alteration in intestinal permeability. The differential expression of iNOS was associated with a significant increase of STAT-1 activation in these mice. Intestinal cells of Cav-2 (-/-) mice showed increased phosphorylation of STAT-1 at tyrosine 701 compared to wild-type. However, Cav-1 (-/-) mice-derived intestinal cells showed decreased levels of phosphorylation of STAT-1 at tyrosine 701. Since caveolin-2 is almost completely absent in Cav-1 (-/-) mice, we conclude that it is not just the absence of caveolin-2 that is responsible for the observed effects, but that the balance between caveolin-1 and caveolin-2 is important for iNOS expression and ultimately for sepsis outcome. PMID- 21670590 TI - Timeless makes some time for itself. PMID- 21670591 TI - Dynamic regulation of hematopoietic stem cell cycling. PMID- 21670592 TI - Epigenetic Nanog regulation and the role of functional heterogeneity. PMID- 21670594 TI - An Ezh way to turn off Nanog. PMID- 21670593 TI - Chromium induces chromosomal instability, which is partly due to deregulation of BubR1 and Emi1, two APC/C inhibitors. AB - Disruption of cell cycle checkpoints and interference with the normal cell cycle progression frequently result in cell death or malignant transformation. Hexavalent chromium [Cr(VI)] is a well-known carcinogen that has been implicated in the occurrence of many types of human malignancies, including lung cancer. However, the exact mechanism by which Cr(VI) causes malignant transformation in the lung remains unknown. We have demonstrated that chronic exposure to a non cytotoxic concentration of Cr(VI) induced a variety of chromosomal abnormalities, including premature sister chromatid separation, chromosomal breakage and the presence of lagging/misaligned chromosomes. After treatment with nocodazole, both HeLa and normal lung bronchial epithelial cells were arrested at mitosis. However, Cr(VI) significantly compromised M-phase arrest induced by nocodazole. Cr(VI) suppressed BubR1 activation and reduced expression of Emi1, leading to an unscheduled activation of APC/C. Consistent with this observation, Cr(VI) treatment caused enhanced polyubiquitination of geminin during mitotic release, while it deregulated the activity of Cdt1, a DNA replication licensing factor. Combined, these results suggest that Cr(VI)-induced chromosomal instability is partly due to a perturbation of APC/C activities, leading to chromosomal instability. PMID- 21670595 TI - Surviving without oxygen: hypoxia regulation of mammary morphogenesis and anoikis. AB - Tumor hypoxia correlates with resistance to chemotherapy, increased incidence of metastasis and poor clinical prognosis. Early breast cancer lesions, such as carcinoma in situ, characterized by filled lumens, are often associated with hypoxic markers. However, the contribution of hypoxia to changes in tissue architecture in early pre-malignant lesions is not well defined. Using three dimensional basement membrane cultures of mammary epithelial cells, we recently reported that acini-like structures exposed to hypoxia display epithelial disorganization and delayed lumen formation. We found that hypoxia, via HIF 1alpha, targets signaling pathways, specifically the Erk-Bim axis, to suppress anoikis-cell death in a 3D acinar model. Here, we discuss these findings further and present additional data, indicating that hypoxia-mediated alterations in acinar architecture and anoikis-associated Erk-Bim signaling are maintained in mammary epithelial cells after reoxygenation. Taken together, these findings may offer new insight into the contribution of hypoxia-mediated signaling in the progression of early breast cancer lesions and possible treatment of hypoxic cancers. PMID- 21670597 TI - Sub-nuclear compartmentalization of core promoter factors and target genes. PMID- 21670598 TI - When every minute counts: the enzymatic complexity associated with the activation of hormone-dependent genes. PMID- 21670599 TI - Recording cellular experiences of DNA damage. PMID- 21670596 TI - mTOR complex 2 signaling and functions. AB - The mechanistic target of rapamycin (mTOR) plays a central role in cellular growth and metabolism. mTOR forms two distinct protein complexes, mTORC1 and mTORC2. Much is known about the regulation and functions of mTORC1 due to availability of a natural compound, rapamycin, that inhibits this complex. Studies that define mTORC2 cellular functions and signaling have lagged behind. The development of pharmacological inhibitors that block mTOR kinase activity, and thereby inhibit both mTOR complexes, along with availability of mice with genetic knockouts in mTOR complex components have now provided new insights on mTORC2 function and regulation. Since prolonged effects of rapamycin can also disrupt mTORC2, it is worth re-evaluating the contribution of this less-studied mTOR complex in cancer, metabolic disorders and aging. In this review, we focus on recent developments on mammalian mTORC2 signaling mechanisms and its cellular and tissue-specific functions. PMID- 21670600 TI - Rheb: enrichment beyond the brain. PMID- 21670601 TI - Same stem cells but different: Isogenic embryonic stem cells harboring different p53 mutants. PMID- 21670603 TI - Photoreceptors and neural circuitry underlying phototaxis in insects. AB - Visual behavior of insects has long been studied, but it is only recently that a wide variety of genetic tools has become available for its analysis. Perhaps the most basic visual behaviour is phototaxis, locomotion towards a source of light. It is known in many insects and has been studied for over a century but the neural network underlying it is little understood. We recently described in the fruit fly Drosophila how different photoreceptor types contribute to phototaxis. By blocking subsets of them we showed that at least four of the five types are involved. In this short review, we compare phototactic behaviour in fruit flies and other insects (especially honeybees), and discuss what is known about the underlying neural circuitry. : PMID- 21670602 TI - Scleroderma-like properties of skin from caveolin-1-deficient mice: implications for new treatment strategies in patients with fibrosis and systemic sclerosis. AB - Caveolin-1 (Cav-1), the principal structural component of caveolae, participates in the pathogenesis of several fibrotic diseases, including systemic sclerosis (SSc). Interestingly, affected skin and lung samples from patients with SSc show reduced levels of Cav-1, as compared to normal skin. In addition, restoration of Cav-1 function in skin fibroblasts from SSc patients reversed their pro-fibrotic phenotype. Here, we further investigated whether Cav-1 mice are a useful pre clinical model for studying the pathogenesis of SSc. For this purpose, we performed quantitative transmission electron microscopy, as well as biochemical and immuno-histochemical analysis, of the skin from Cav-1 (-/-) null mice. Using these complementary approaches, we now show that skin from Cav-1 null mice exhibits many of the same characteristics as SSc skin from patients, including a decrease in collagen fiber diameter, increased tensile strength, and stiffness, as well as mononuclear cell infiltration. Furthermore, an increase in autophagy/mitophagy was observed in the stromal cells of the dermis from Cav-1 ( /-) mice. These findings suggest that changes in cellular energy metabolism (e.g., a shift towards aerobic glycolysis) in these stromal cells may be a survival mechanism in this "hostile" or pro-inflammatory microenvironment. Taken together, our results demonstrate that Cav-1 (-/-) null mice are a valuable new pre-clinical model for studying scleroderma. Most importantly, our results suggest that inhibition of autophagy and/or aerobic glycolysis may represent a new promising therapeutic strategy for halting fibrosis in SSc patients. Finally, Cav-1 (-/-) null mice are also a pre-clinical model for a "lethal" tumor micro environment, possibly explaining the link between fibrosis, tumor progression, and cancer metastasis. PMID- 21670604 TI - Spinophilin loss contributes to tumorigenesis in vivo. AB - The scaffold protein spinophilin (SPN, PPP1R9B) is a regulatory subunit of phosphatase-1a located at 17q21.31. This region is frequently associated with microsatellite instability and LOH and contains a relatively high density of known tumor suppressor genes (such as BRCA1), putative tumor suppressor genes and several unidentified candidate tumor suppressor genes located distal to BRCA1. Spn is located distal to BRCA1, and we have previously shown that the loss of Spn contributes to human tumorigenesis in the absence of p53 function. In this work, we explore the role of Spn as putative tumor suppressor in in vivo models using genetically modified mice. Spn-knockout mice had decreased lifespan with increased cellular proliferation in tissues such as the mammary ducts and early appearance of tumors, such as lymphoma. Furthermore, the combined loss of Spn and mutant p53 activity led to increased mammary carcinomas, confirming the functional relationship between p53 and Spn. We suggest that Spn may be a novel tumor suppressor located at 17q21. PMID- 21670609 TI - Indications for free-tissue transfer in cleft palate reconstruction. PMID- 21670606 TI - The psychological effects of breast cancer and reconstruction: "A stroll down mammary lane"--A patient's artistic journal. AB - One in 8 women will develop invasive breast cancer. Nationally, it is estimated that about 200,000 women in the United States are diagnosed annually, and approximately 40,000 women die from the disease each year. A diagnosis of breast cancer forces women to consider living without their gender-defining curves, reevaluate their lives, and live with a 1 in 33 possibility of their mortality. Although medical science has made advances in the treatment of breast carcinoma and breast reconstruction, it currently does not adequately address the psychological effects that this disease and its treatment have on its patients. This discussion of a patient's postmastectomy drawings and creative writing sheds some light on one woman's personal battle with breast carcinoma, from diagnosis through breast reconstruction. PMID- 21670610 TI - Understanding the reasonable, but limited benefits of the CPM strategy. PMID- 21670611 TI - Intraperitoneal local anesthetic improves recovery after colon resection: a double-blinded randomized controlled trial. AB - BACKGROUND: Two wounds are created after abdominal surgery. The surgical insult to the peritoneal cavity and viscera has not been emphasized as a target for interventions. In animal models vagotomy blunts the intraperitoneal response to induced inflammation. This is not feasible in humans. However a transient chemical afferentectomy after colectomy by using neuraxial blockade (epidural) and intraperitoneal blockade may be possible. We investigated the effects of intraoperative instillation and postoperative infusion of intraperitoneal local anesthetic (IPLA) on recovery parameters after colectomy, in the setting of an established enhanced recovery after surgery (ERAS) program. METHODS: Double blinded, randomized, placebo controlled design. The study group (IPLA) received instillation of intraperitoneal ropivacaine (75 mg) before dissection and postoperative infusion of 0.2% solution at 4 mL/hour for 3 days continuously. The placebo group (NS) was treated as above with 0.9% saline solution. All patients were cared for under ERAS standardized perioperative care. Epidural infusion was stopped on day 2. Patients were discharged from day 3 onwards once criteria met. Perioperative data, surgical recovery score (SRS), complications, and length of stay were recorded. Systemic cytokines response, neuroendocrine parameters, pain measures and opioid use data were collected. Patients were followed up for 60 days. RESULTS: Sixty patients were recruited. Patients were equivalently matched at baseline. There were no local anesthetic related adverse events. The complication rate, including anastomotic leak rate, was equivalent between groups. IPLA group had better SRS scores for the duration of intraperitoneal infusion. Pain and opioid use was reduced in the IPLA group. Systemic cytokine and cortisol response was diminished in the IPLA group. IPLA group had consistently higher systemic ropivacaine levels than placebo group. CONCLUSION: Instillation and infusion of intraperitoneal ropivacaine after colectomy improves early surgical recovery. This was associated with a blunting of postsurgical systemic cytokines and cortisol. Patients also had significantly reduced pain and opioid use over and above the effect of an epidural infusion. Therefore a transient chemical afferentectomy with clinical benefit is possible with this method. A longer IPLA infusion duration needs to be studied. This study is registered at clinicaltrials.gov and carries the ID number NCT00722709. PMID- 21670612 TI - Tumor biology influences the prognosis of nephroblastoma patients with primary pulmonary metastases: results from SIOP 93-01/GPOH and SIOP 2001/GPOH. AB - OBJECTIVE: To analyze the outcome of Wilms' tumor patients with primary lung metastases. SUMMARY BACKGROUND DATA: Radiotherapy and/or surgery are used for local control of primary pulmonary Wilms' tumor metastases. A widely accepted treatment standardization is still lacking. METHODS: Data for 210 patients with Wilms' tumor and primary lung metastases from the collaborative multicenter trials SIOP 93-01/GPOH and SIOP 2001/GPOH of the German Society of Pediatric Oncology and Hematology were reviewed. Analyses included patient data, tumor characteristics, local treatment, outcome and possible prognostic factors. RESULTS: Five-year overall survival (OS) was 83.3% and 5-year event free survival (EFS) was 72.3% for all children. Survival was significantly poorer in children with high risk primary tumor histology (OS 44.4%) compared to low risk (OS 100.0%) and intermediate risk histology (OS 89.2%, P < 0.001). Within the high risk group, tumors of the blastemal subtype (OS 56.5%) were associated with a significantly better outcome than those presenting with diffuse anaplasia (OS 22.2%, P = 0.02). Further, prognostic markers were lacking response to chemotherapy (P = 0.011), persistence of metastases after local treatment (P = 0.007), and vitality of metastases (P = 0.01). CONCLUSIONS: The prognosis of children with primary Wilms' tumor lung metastases mainly depends on the biology of primary tumors and metastases and is excellent with adequate treatment. Pulmonary metastasectomy is indicated if complete remission can be achieved to avoid lung irradiation. In the future a standardized local approach to nonresponding lung metastases (metastasectomy, irradiation, or both) will have to be prospectively evaluated regarding outcome, acute toxicity, and late effects. PMID- 21670614 TI - Technology and its many applications to caring for the patient in the intensive care environment. Foreword. PMID- 21670615 TI - Using the Tele-ICU care delivery model to build organizational performance, part 1. AB - The paradigm has shifted in care delivery models to effect improvements in both the quality and safety of patient care. Tele-Health integration is one example. By using mobile devices and the expertise of experienced clinicians in a remote location, bedside caregivers now can receive real-time assistance for patient management. The Tele-ICU is one example of an application of a technological model that accelerates clinical problem solving and decision-making, resulting in expediting critical care delivery and ultimately enhancing outcomes. PMID- 21670616 TI - Tele-ICUs, part 2: Adding value to the health care equation. PMID- 21670617 TI - An innovative approach to meeting early goal-directed therapy using telemedicine. AB - Severe sepsis and septic shock is a major health concern. A key component in the treatment of severe sepsis and septic shock is optimization of the septic patient's abnormal physiology. However, following the evidence based guidelines present many unique challenges. The article presents the challenges and how a 5 hospital system in San Antonio, Texas uses a telemedicine approach to help comply with the sepsis bundles. A multidisciplinary sepsis team meets regularly to assess compliance and review data. The processes and tools continue to be changed accordingly, to improve adherence to best evidence practice for the severe septic and septic shock patient. PMID- 21670618 TI - Demystifying ventricular assist devices. AB - Many people throughout the world are living with heart disease and advanced heart failure. They may be in need of a heart transplant, but because of the limited amount of donor hearts available, other options need to be available. Because of the advancement of technology, there are now other options, and one option available would be a mechanical circulatory and cardiac support device. Ventricular assist devices (VADs) have been developed over the past 30 years. From larger, earlier pulsatile devices to smaller, hand-held, newer axial flow or rotary pump devices, VADs are implanted cardiac assist devices. They are implanted to provide cardiac support and can be used temporarily as a bridge to transplant (for those awaiting a heart transplant) or implanted permanently, which is known as destination therapy. With the changes in the size of device, decrease in the size of drive line, increased length of battery life, as well as length of device life, thousands of people now have these implanted VAD devices and are living quality lives and functioning at high levels. Currently, there are 3 generations of the left ventricular assist devices being used throughout the world. Five of the most well-known type of left ventricular assist devices are discussed in this article. PMID- 21670619 TI - Implementing electronic documentation. AB - Implementing health information technology is a major strategic objective. Health care organizations must meet "meaningful use" through the implementation of a certified electronic medical record. It is the imperative to secure leadership support in the project. Communication, accountability, and clinical champions are vital elements for successful implementation. PMID- 21670621 TI - Ischemic middle cerebral artery stroke: a case study. AB - Stroke is the third leading cause of death, ranking lower only to cardiac disease and cancer. Patients with stroke involving large vessels, including the middle cerebral artery, account for almost half of all patients with ischemic strokes and have an increased risk for poor outcomes and mortality at 6 months. Despite the availability and use of published guidelines for the early management of ischemic stroke, evidence to support treatment modalities for cerebral edema is still lacking. This case presentation will include the pathophysiology of an ischemic stroke and outline the established management guidelines. Literature related to the management of cerebral edema will also be discussed. PMID- 21670620 TI - Reiki therapy: a nursing intervention for critical care. AB - Complementary and alternative medicine (CAM) is not generally associated with the complexity and intensity of critical care. Most CAM therapies involve slow, calming techniques that seem to be in direct contrast with the fast-paced, highly technical nature of critical care. However, patients in critical care often find themselves coping with the pain and stress of their illness exacerbated by the stress of the critical care environment. Complementary and alternative medicine related research reveals that complementary therapies, such as Reiki, relieve pain and anxiety and reduce symptoms of stress such as elevated blood pressure and pulse rates. Patients and health care professionals alike have become increasingly interested in complementary and alternative therapies that do not rely on expensive, invasive technology, and are holistic in focus. Reiki is cost effective, noninvasive, and can easily be incorporated into patient care. The purpose of this article is to examine the science of Reiki therapy and to explore Reiki as a valuable nursing intervention. PMID- 21670622 TI - Compassion satisfaction, burnout, and secondary traumatic stress in heart and vascular nurses. AB - Objectives for this project were to determine the prevalence of compassion satisfaction (CS), burnout, and secondary traumatic stress (STS) in heart and vascular nurses to confirm whether differences exist between intensive care and intermediate care nurses. The Professional Quality of Life Scale Compassion Satisfaction and Compassion Fatigue: Version 5 developed by Stamm (2009) was used. Results showed that nurses who work in the heart and vascular intermediate care unit had average to high scores of CS, low to average levels of burnout, and low to average levels of STS. Nurses who work in the heart and vascular intensive care unit had average to high levels of CS, low to average levels of burnout, and low to average levels of STS. These findings suggest that leadership should be aware of the prevalence of STS and burnout in heart and vascular nurses. Raising awareness of STS and burnout in intensive care and intermediate care nurses can help in targeting more specific strategies that may prevent the onset of developing these symptoms. PMID- 21670623 TI - A review of the literature on heart failure and discharge education. AB - The Centers for Medicare and Medicaid Services (CMS) have proposed changes in the health care reimbursement for patients diagnosed with heart failure (HF) if readmission to a hospital occurs within 30 days of their discharge. The Joint Commission (TJC) has identified 6 key education topics for HF patients with their families that can result in decreased readmissions. Though the patient may be too ill, critical care nurses have an opportunity to begin the discharge education process immediately with families or caregivers. This literature review discusses studies focused on discharge education in general and then those studies specific to HF discharge education. This review reports on what is known or supported by evidence within 8 major topics. Finally, the discussion section summarizes the evidence for discharge education by answering 6 questions that address the "who and when" as well as the "what" of discharge education. PMID- 21670624 TI - Using QRS morphology and QTc interval to prevent complications and cardiac death. AB - Prevention of cardiac complications including death is influenced by the availability of diagnostic tools and technological advances. Cardiac telemetry as a diagnostic tool is widely used in hospitals because of an increased severity of illness and complex modality of treatments. QTc interval abnormalities in the electrocardiogram have been long recognized as a predictive precursor for life threatening cardiac arrhythmias and cardiac arrest. QRS morphology has also been recognized as a reliable marker to prevent cardiac events in outpatient settings. However, the QTc and QRS morphology as electrocardiogram predictors are not routinely assessed in daily practice for hospitalized patients because of the slow advancement of technology in bedside monitoring systems and inadequate staff preparation. This article discusses the role of QRS morphology and QTc interval assessment in predicting risk of complications. The article also explores the need for further research and advancement in technology to overcome barriers to integrating these predictors into routine nursing practice. PMID- 21670625 TI - Streamlining the handling of administrative paperwork. AB - Many new nursing leaders assuming deanships, assistant, or interim deanships have limited education, experience, or background to prepare them for the job. To assist new deans and those aspiring to be deans, the authors of this department, 2 deans, offer survival tips based on their experiences and insights. They address common issues, challenges, and opportunities that face academic executive teams, such as negotiating an executive contract, obtaining faculty lines, building effective work teams, managing difficult employees, and creating nimble organizational structure to respond to changing consumer, healthcare delivery, and community needs. The authors welcome counterpoint discussions with readers. PMID- 21670626 TI - Teaching with technology: free Web resources for teaching and learning. AB - In this bimonthly series, the department editor examines how nurse educators can use Internet and Web-based computer technologies such as search, communication, collaborative writing tools; social networking, and social bookmarking sites; virtual worlds; and Web-based teaching and learning programs. In this article, the department editor and her coauthor describe free Web-based resources that can be used to support teaching and learning. PMID- 21670627 TI - Why can't we all just get along? A Civility Journal Club intervention. PMID- 21670628 TI - A pathophysiology bank: investing in clinical nursing education. PMID- 21670630 TI - Psychomotor skills acquisition of novice learners: a case for contextual learning. AB - Deficiencies in procedural competency compromise patient safety and the quality of care provided. Educators in prelicensure nursing programs are challenged to design effective instruction to develop psychomotor skills abilities among novice learners. Highly contextualized learning and frequent opportunities for performance rehearsal promote knowledge retention and procedural competence. The author discusses data from an evaluation study that explored students' perceptions of the effectiveness of skills instruction and suggests strategies for curricular integration and effective instruction. PMID- 21670631 TI - Engaging students in an undergraduate research course. AB - Nursing educators must be creative and dynamic in course design and seek to adopt pedagogical strategies that promote learner outcomes. Using multiple teaching strategies and experiential methods, the author describes one such attempt to engage students enrolled in an undergraduate nursing research course. PMID- 21670632 TI - A hybrid course for the RN-to-baccalaureate curriculum: patient-centered care and quality. AB - Teaching RN-to-baccalaureate nursing students to incorporate patient-centered care and quality concepts into the practice environment presents challenges and opportunities for nurse educators. The authors describe development, deployment, and evaluation of an RN-to-baccalaureate hybrid course focused on patient centered care and quality improvement. Course teaching strategies and evaluation of student learning and the efficacy of using a hybrid instructional design are discussed. PMID- 21670633 TI - Refresh your radiation knowledge. PMID- 21670634 TI - Student engagement through podcasting. AB - Nursing faculty investigated the use of a preclass podcast compared with lecture to deliver electrocardiogram interpretation content to facilitate student learning through learner-centered, faculty-guided practice during scheduled class time. Pretest-posttest comparisons of 2 groups revealed the podcast/engaged group scored just as high, but no higher, than the lecture group. However, further analysis determined that only 28% of the engaged group had actually watched the podcast in its entirety. The results may indicate that formal presentation of content in this study was not as effective as originally considered and that it was learner-centered engagement that actually contributed to student learning. PMID- 21670636 TI - Using experienced clinicians to facilitate clinical education. AB - Dedicated education units (DEUs) teach nursing students how to provide professional, competent, and safe nursing care using staff nurses as educators and reduce the number of adjunct clinical faculty required by schools of nursing. The authors describe a collaborative clinical partnership between a pediatric healthcare system and a school of nursing to pilot the use of a DEU for one-on one clinical education of students with expert pediatric nurses. PMID- 21670638 TI - Admission criteria for undergraduate nursing programs: a systematic review. AB - A concise, systematic review of commonly used admission criteria for prelicensure nursing programs is presented in this article. Admission criteria include grades in prenursing college courses, standardized preadmission tests, essays, personal interviews, and volunteerism. Literature is reviewed regarding the relationships between admission criteria and success in undergraduate nursing programs. Gaps in the literature and future research needs are described. PMID- 21670639 TI - Promoting interdisciplinary care of patients and families: a classroom project. AB - Interdisciplinary educational experiences provide opportunities for nursing students to gain knowledge regarding the contributions of other healthcare providers in ensuring quality patient care. The project, part of a family health course, brought together students from 5 disciplines to heighten awareness of the necessity of, and the call for, interdisciplinary education. The authors discuss the project and its structure to provide ideas to other educators who may want to integrate an innovative interdisciplinary experience into their course. PMID- 21670644 TI - Every nurse can be "green". PMID- 21670640 TI - Education protects babies from HIV infection. PMID- 21670645 TI - Demystifying skin tears, part 2. PMID- 21670648 TI - Preparing your patient for a trip to India. PMID- 21670651 TI - Chest tubes. PMID- 21670647 TI - Managing osteoarthritis pain in patients with von Willebrand disease. PMID- 21670653 TI - Call a code. PMID- 21670654 TI - Balancing act: Na+ sodium K+ potassium. PMID- 21670655 TI - Take the "hyper" out of pharmacotherapy. PMID- 21670656 TI - Showcase your talents with a career portfolio. PMID- 21670657 TI - What you need to know about genital herpes. PMID- 21670658 TI - Listen closely to detect healthcare-associated pneumonia. PMID- 21670660 TI - Impaled object. PMID- 21670661 TI - Empathy decline and its reasons: a systematic review of studies with medical students and residents. AB - PURPOSE: Empathy is a key element of patient-physician communication; it is relevant to and positively influences patients' health. The authors systematically reviewed the literature to investigate changes in trainee empathy and reasons for those changes during medical school and residency. METHOD: The authors conducted a systematic search of studies concerning trainee empathy published from January 1990 to January 2010, using manual methods and the PubMed, EMBASE, and PsycINFO databases. They independently reviewed and selected quantitative and qualitative studies for inclusion. Intervention studies, those that evaluated psychometric properties of self-assessment tools, and those with a sample size <30 were excluded. RESULTS: Eighteen studies met the inclusion criteria: 11 on medical students and 7 on residents. Three longitudinal and six cross-sectional studies of medical students demonstrated a significant decrease in empathy during medical school; one cross-sectional study found a tendency toward a decrease, and another suggested stable scores. The five longitudinal and two cross-sectional studies of residents showed a decrease in empathy during residency. The studies pointed to the clinical practice phase of training and the distress produced by aspects of the "hidden," "formal," and "informal" curricula as main reasons for empathy decline. CONCLUSIONS: The results of the reviewed studies, especially those with longitudinal data, suggest that empathy decline during medical school and residency compromises striving toward professionalism and may threaten health care quality. Theory-based investigations of the factors that contribute to empathy decline among trainees and improvement of the validity of self-assessment methods are necessary for further research. PMID- 21670662 TI - Biphasic activation of extracellular signal-regulated kinase in anterior cingulate cortex distinctly regulates the development of pain-related anxiety and mechanical hypersensitivity in rats after incision. AB - BACKGROUND: A recent study has demonstrated that surgical incision induces an anxiety-like behavior but its relationship with incision-evoked mechanical hypersensitivity remains elusive. Extracellular signal-regulated kinase (ERK) activity in the anterior cingulate cortex (ACC) is important for the affective pain. The current study aims to explore ERK1/2 activity in the ACC and its role in the development of anxiety and mechanical hypersensitivity after incision. METHODS: Anxiety-like behavior was measured by elevated plus maze experiment and open field test after hind paw incision. ERK1/2 phosphorylation was determined by immunohistochemistry and Western blot. Cannulae were implanted into the bilateral ACC for the intra-ACC injection of ERK inhibitors PD98059 and U0126. Brushing (innocuous stimulus) was used to investigate its effect on ERK activation under the incision-evoked painful condition. RESULTS: The anxiety-like behavior induced by the hind paw incision persisted longer than mechanical hypersensitivity. One hind paw incision resulted in a biphasic ERK activation in bilateral ACC. Inhibiting ERK activation in the early phase attenuated pain-related anxiety and mechanical hypersensitivity whereas inhibiting ERK activation in the late phase only reduced the anxiety-like behavior. During the time interval between two phases of ERK activation, brushing the incised skin dramatically increased ERK phosphorylation in the ACC. CONCLUSIONS: These data suggest that in the early phase of postoperative pain, pain-related anxiety and mechanical hypersensitivity are tightly linked and regulated by the ERK activation in the ACC. However, in the late phase of postoperative pain, ERK activation in the ACC is only required for the expression of pain-related anxiety but not mechanical hypersensitivity. PMID- 21670663 TI - Activation of coagulation by a thalidomide-based regimen. AB - Combining thalidomide (Thal) with chemotherapeutic agents or steroid preparations led to improved response rates in the treatment of multiple myeloma. However, deep vein thrombosis (DVT) is one of the most serious side-effects noted with this regimen, and how a Thal-based regimen causes DVT is unclear. We investigated the procoagulant effects of Thal when combined with chemotherapeutic agents in vitro, focusing on tissue factor (TF) and phosphatidylserine. We examined the effects of the chemotherapeutic doxorubicin hydrochloride (Dox) and the steroid dexamethasone (Dex), with or without Thal. Our study used the human vascular endothelial, monocytic, and myeloma cell lines, EAhy926, THP-1, and RPMI8226, respectively. In EAhy926 and THP-1, Dex treatment increased expression of TF, which may induce procoagulant activity (PCA). Upregulation of TF mRNA correlated with activation of the Egr-1 pathway. In Thal and Dex treatments, the increase of PCA induction from phosphatidylserine exposure was modest. In contrast, Dox and Thal-Dox increased phosphatidylserine exposure in both cell types. In THP-1 cells, cell surface phosphatidylserine exposure correlated with increased PCA by Dox. Thal alone showed a modest increase in phosphatidylserine exposure in endothelial cells and monocytes. When Thal is given in combination with chemotherapies or Dex, endothelial cell and monocyte PCA may be induced through phosphatidylserine exposure, or TF expression. Induction may be protracted by Thal, which has an antiangiogenic activity. Therefore, prophylactic anticoagulant strategies should be considered in Thal-based combination regimens. PMID- 21670664 TI - Recurrent ischemic stroke in a patient with ulcerative colitis and high levels of lipoprotein (a). AB - Cerebral infarction associated with ulcerative colitis is particularly rare, but clinically important because of its high morbidity and mortality. The pathogenesis of thrombosis in ulcerative colitis remains unclear even if platelet and coagulation cascade abnormalities, systemic inflammation, and the presence of other well recognized vascular risk factors are likely to play a key role in clot formation. We report a case of a young woman with recurrent ischemic stroke secondary to the interaction between ulcerative colitis-related dysbalanced hemostasis and high levels of lipoprotein (a). PMID- 21670666 TI - Evidence for phenotype-driven treatment in asthmatic patients. AB - PURPOSE OF REVIEW: Asthma is a complex inflammatory disease and current therapy remains inadequate in many sufferers. There is phenotypic heterogeneity in its clinical expression as a consequence of gene-environment interactions and heterogeneity in response to therapy. This review summarizes the current state of knowledge on phenotype-driven treatment of asthma. RECENT FINDINGS: Evidence is accumulating that even standard therapies such as inhaled corticosteroids benefit some groups of asthmatic patients more than others. Macrolide antibiotics and antifungal agents are examples of drugs that have established indications outside the field of airways disease but which may benefit a subset of patients with asthma. Finally, new and expensive biological therapies for asthma are emerging that may be highly efficacious, but only for a selected group of patients. SUMMARY: The emergence of novel therapies, in particular highly specific treatments, bring the promise of improving healthcare in asthma but present the challenge of choosing the right therapy for the right patient. Phenotype-driven treatment of asthma is emerging as a potential reality and will pave the way for personalized healthcare. PMID- 21670665 TI - Intensive care unit discharge to the ward with a tracheostomy cannula as a risk factor for mortality: a prospective, multicenter propensity analysis. AB - OBJECTIVE: To analyze the impact of decannulation before intensive care unit discharge on ward survival in nonexperimental conditions. DESIGN: Prospective, observational survey. SETTING: Thirty-one intensive care units throughout Spain. PATIENTS: All patients admitted from March 1, 2008 to May 31, 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At intensive care unit discharge, we recorded demographic variables, severity score, and intensive care unit treatments, with special attention to tracheostomy. After intensive care unit discharge, we recorded intensive care unit readmission and hospital survival. STATISTICS: Multivariate analyses for ward mortality, with Cox proportional hazard ratio adjusted for propensity score for intensive care unit decannulation. We included 4,132 patients, 1,996 of whom needed mechanical ventilation. Of these, 260 (13%) were tracheostomized and 59 (23%) died in the intensive care unit. Of the 201 intensive care unit tracheostomized survivors, 60 were decannulated in the intensive care unit and 141 were discharged to the ward with cannulae in place. Variables associated with intensive care unit decannulation (non-neurologic disease [85% vs. 64%], vasoactive drugs [90% vs. 76%], parenteral nutrition [55% vs. 33%], acute renal failure [37% vs. 23%], and good prognosis at intensive care unit discharge [40% vs. 18%]) were included in a propensity score model for decannulation. Crude ward mortality was similar in decannulated and nondecannulated patients (22% vs. 23%); however, after adjustment for the propensity score and Sabadell Score, the presence of a tracheostomy cannula was not associated with any survival disadvantage with an odds ratio of 0.6 [0.3-1.2] (p=.1). CONCLUSION: In our multicenter setting, intensive care unit discharge before decannulation is not a risk factor. PMID- 21670667 TI - An evidence-based appraisal of the surrogate markers of efficacy of allergen immunotherapy. AB - PURPOSE OF REVIEW: The assessment of clinical efficacy of immunotherapy in patients with respiratory allergy is highly affected by variability and lack of validated outcome measures such as symptom and medication scores. At the same time, there is a need to identify reliable predictive surrogate markers or biomarkers that may correlate with real clinical endpoints and lead to individually tailored immunotherapy treatment. RECENT FINDINGS: In-vivo markers, such as early and late skin reaction as well as immunological parameters such as IgE levels, IgG subclasses, mucosal IgA, lymphocyte subsets, cytokines and local and systemic inflammatory markers, have been proposed as potential surrogate markers. SUMMARY: Given the poor reproducibility and surrogacy to clinical outcomes shown in various clinical trials, the decreased availability in daily practice and anticipated high costs, an ideal surrogate marker is still not available to allergists. PMID- 21670668 TI - Risk to and resilience of the coronary heart disease patient during surgery. AB - PURPOSE OF REVIEW: Three topics are at the forefront of the investigation and treatment of patients with coronary artery disease (CAD) undergoing major noncardiac surgery: prophylactic perioperative beta-blockade (PPBB), prophylactic statins and prophylactic preoperative coronary revascularization (PCR). The purpose of the review is to summarize the investigational efforts in each one of these fields and to provide a subjective evaluation as to their impact on perioperative patient care. RECENT FINDINGS: The data on PPBB are still controversial. Most recent studies are observational with contradicting results on whether PPBB improves perioperative survival and whether chronic beta-blockade is better than beta-blockers added acutely postoperatively. The data on statins are still evolving and the main question remains whether the proven long-term pleiotrophic, plaque-stabilizing effects of statins translate into measurable improvements in hard outcome in the acute, perioperative setting. The data on PCR are also incomplete. The study that previously reported lack of any perioperative benefit to PCR now provides data that in selected patients PCR may nevertheless improve outcome. SUMMARY: These topics demonstrate how difficult it is to prove a significant change in outcome in high-risk CAD patients by prophylactic preoperative measures and that there is no alternative to clinical judgment and individualized patient care. PMID- 21670669 TI - Rare roentgenologic manifestations of pulmonary edema. AB - PURPOSE OF REVIEW: Unilateral pulmonary edema (UPE) is an unusual manifestation of pulmonary edema that is frequently confused with other causes of unilateral alveolar and interstitial infiltrates. Until now limited data existed regarding the prevalence, cause, and outcome of patients presenting with cardiogenic UPE. The purpose of this review is to give insights into this rare entity. RECENT FINDINGS: In a recent retrospective study, the prevalence of UPE was 2.1% of all cases of cardiogenic pulmonary edema. UPE was right-sided in 89%. All patients with UPE had severe mitral regurgitation. In patients with UPE, blood pressure was significantly lower, whereas noninvasive or invasive ventilation and catecholamines were used more frequently compared with patients with bilateral pulmonary edema. In-hospital mortality was higher for patients with UPE (39 vs. 8% for bilateral pulmonary edema) and UPE was independently related to death (a 6.5-fold higher risk of death). Delayed treatment of UPE could be one of the explanations for this increased mortality. SUMMARY: UPE is not that rare as considered to be and is mostly related to severe organic or functional mitral regurgitation. Probably because of initial misdiagnosis and delayed appropriate treatment, UPE is related to increased mortality. History, absence of signs of infection, and elevated serum cardiac markers such as B-natriuretic peptide may help to differentiate UPE from other diagnoses. The key examination remains bedside transthoracic echocardiography, although transesophageal echocardiography can also provide additional information regarding the severity and mechanism of mitral regurgitation and documentation of the differential pressure between the right and left pulmonary veins. PMID- 21670670 TI - Cardiovascular risk factors in inflammatory arthritis. AB - PURPOSE OF REVIEW: To assess factors that promote atherogenesis and cardiovascular disease (CVD) in rheumatoid arthritis (RA). Also, to determine how control of inflammation with conventional and biological antirheumatic drugs affects cardiovascular risk. RECENT FINDINGS: An excess risk of CVD occurs early in the RA disease course and indeed may predate disease onset. Inflammation is a key driver of CVD risk as it adversely affects body composition, glucose handling and lipid function, especially the atheroprotective role of high-density lipoprotein. Therapies for RA, especially hydroxychloroquine and methotrexate (MTX) have positive effects on cardiovascular risk factors such as glycaemic control and reverse cholesterol transport. MTX and antitumour necrosis factor alpha drugs also appear to have beneficial effect on CVD event risk, although the data on MTX appears more consistently to favour such a benefit. SUMMARY: Future work needs to understand which aspects of the inflammatory state contribute most to CVD risk and whether specific anti-inflammatory agents, either alone or in combination, afford maximal CVD protection in RA. PMID- 21670671 TI - Aging and antihypertensive medication-related complications in the chronic kidney disease patient. AB - PURPOSE OF REVIEW: We have reviewed the recent literature to describe the potential medication errors and adverse drug events (ADEs) associated with antihypertensives among older adults with chronic kidney disease (CKD). RECENT FINDINGS: Overall, few studies have been published describing ADEs in older adults with CKD. Several examined hyperkalemia associated with angiotensin converting enzyme (ACE)-inhibitor/angiotensin II receptor blocker (ARB), diuretic (potassium-sparing), and beta-blocker use. Additional studies described acute kidney injury (AKI) most commonly with ACE-inhibitor/ARB therapy. Finally, orthostatic hypotension was evaluated in those taking ACE-inhibitor/ARB, beta blocker, or calcium-channel blocker therapy. In the absence of robust literature examining these events in this understudied population, one must consider age related antihypertensive pharmacokinetic/pharmacodynamic profiles concomitantly with the patient's comorbidities and other medications in order to minimize the risk for potential medication errors, drug-drug interactions, and ADEs. SUMMARY: Some of the most common ADEs associated with antihypertensive use in older adults with CKD include hyperkalemia, AKI, and orthostatic hypotension. Diligent monitoring of laboratory data, vital signs, and potential drug-drug interactions may mitigate serious ADEs caused by antihypertensives in this high-risk patient population. PMID- 21670672 TI - Physiological regulation of epithelial sodium channel by proteolysis. AB - PURPOSE OF REVIEW: Activation of epithelial sodium channel (ENaC) by proteolysis appears to be relevant for day-to-day physiological regulation of channel activity in kidney and other epithelial tissues. Pathophysiogical, proteolytic activation of ENaC in kidney has been demonstrated in proteinuric disease. RECENT FINDINGS: A variation in sodium and potassium intake or plasma aldosterone changes the number of cleaved alpha and gamma-ENaC subunits and is associated with changes in ENaC currents. The protease furin mediates intracellular cleavage, whereas the channel-activating protease prostasin (CAP-1), which is glycophosphatidylinositol-anchored to the apical cell surface, mediates important extracellular cleavage. Soluble protease activity is very low in urine under physiological conditions but rises in proteinuria. In nephrotic syndrome, the dominant soluble protease activity is plasmin, which is formed from filtered plasminogen via urokinase-type plasminogen activator. Plasmin activates ENaC directly at high concentrations and through prostasin at lower concentrations. SUMMARY: The discovery of serine protease-mediated activation of renal ENaC in physiological and pathophysiological conditions opens the way for new understanding of the pathogenesis of proteinuric sodium retention, which may involve plasmin and present several potential new drug targets. PMID- 21670673 TI - Regulation of ion transport by microRNAs. AB - PURPOSE OF REVIEW: This review aims to describe the recent findings obtained on the regulation of ion transport by microRNAs in physiological and pathological situations in different organs and organisms. RECENT FINDINGS: The number of ion channels or transporters can be regulated by increasing or decreasing the transcription and/or translation of the corresponding genes. In this context, a new class of regulators of gene expression has emerged as an important modulator of ion transport. microRNAs are short noncoding RNAs which inhibit gene expression by enhancing the degradation or inhibiting the translation of their targets. Most of the studies published so far describe their roles during embryonic development and tumorigenesis. However, recent studies have started to unravel how microRNA-mediated modulation of ion transport could contribute not only to the development of pathological states, such as heart disease, but also to the osmotic regulation of various organisms. SUMMARY: The contribution of microRNAs to the regulation of ion transport has only begun to be unraveled, mostly in cardiomyocytes. Only a few studies have focused on the kidney but they strongly suggest that microRNAs could play an important role in the regulation of renal ion transport in response to variation in daily food intake. PMID- 21670675 TI - Luminal nucleotides are tonic inhibitors of renal tubular transport. AB - PURPOSE OF REVIEW: Extracellular ATP is an essential local signaling molecule in all organ systems. In the kidney, purinergic signaling is involved in an array of functions and this review highlights those of relevance for renal tubular transport. RECENT FINDINGS: Purinergic receptors are expressed in all renal tubular segments and their stimulation generally leads to transport inhibition. Recent evidence has identified the tubular lumen as a restricted space for purinergic signaling. The concentrations of ATP in the luminal fluids are sufficiently high to inflict a tonic inhibition of renal tubular absorption via P2 receptors. The apical P2Y2 receptor plays a crucial role in this process. ATP is released continuously into the tubular lumen. The release is augmented in response to an increase of tubular flow and after stimulation of G-protein coupled receptors. The primary cilium appears necessary for flow-stimulated luminal ATP release. Tubular ATP secretion may occur via nonjunctional connexin hemichannels (connexin 30), which are strategically placed in the apical membrane of distal tubular intercalated cells and can be activated by tubular flow. SUMMARY: The tubular lumen has been discovered as an important signaling compartment in which local purinergic signaling determines an inhibitory tone for renal tubular transport. Blocking components of this system leads to tubular hyper-absorption, volume retention and elevated blood pressure. PMID- 21670674 TI - Role of BK channels in hypertension and potassium secretion. AB - PURPOSE OF REVIEW: This review summarizes recent studies of hypertension associated with a defect in renal K excretion due to genetic deletions of various components of the large, Ca-activated K channel (BK), and describes new evidence and theories regarding K secretory roles of BK in intercalated cells. RECENT FINDINGS: Isolated perfused tubule methods have revealed the importance of BK in flow-induced K secretion. Subsequently, mice with genetically deleted BK subunits revealed the complexities of BK-mediated K secretion. Deletion of BKalpha results in extreme aldosteronism, hypertension, and an absence of flow-induced K secretion. Deletion of the BKbeta1 ancillary subunit results in decreased handling of a K load, increased plasma K, mild aldosteronism and hypertension that is exacerbated by a high K diet. Deletion of BKbeta4 (beta4KO) leads to insufficient K handling, high plasma K, fluid retention, but with milder hypertension. Fluid retention in beta4KO may be the result of insufficient flow induced secretion of adenosine triphosphate (ATP), which normally inhibits epithelial Na channels (ENaCs). SUMMARY: Classical physiological analysis of electrolyte handling in knockout mice has enlightened our understanding of the mechanism of handling K loads by renal K channels. Studies have focused on the different roles of BK-alpha/beta1 and BK-alpha/beta4 in the kidney. BKbeta1 hypertension may be a 'three-hit' hypertension, involving a K secretory defect, elevated production of aldosterone, and increased vascular tone. The disorders observed in BK knockout mice have shed new insights on the importance of proper renal K handling for maintaining volume balance and blood pressure. PMID- 21670676 TI - Indications and guidelines for pectus excavatum repair. AB - PURPOSE OF REVIEW: The introduction of the Nuss procedure in 1997 for treatment of pectus excavatum, in conjunction with the ever-expanding body of medical information available on the internet, significantly raised the level of awareness for this deformity as both an anatomic and a functional problem. The subsequent increase in referrals for pectus excavatum repair provided large patient series for clinical analyses to better define underlying physiologic impairments and stimulated surgeons to develop technical improvements to enhance the safety and effectiveness of pectus excavatum repair. RECENT FINDINGS: Clinical assessment, diagnostic imaging, and cardiorespiratory testing of patients with pectus excavatum have helped to characterize physiologic impairments associated with severe pectus excavatum and to define inclusion criteria for surgical repair. Appropriate timing of repair is important to minimize complications, especially recurrence. Evidence of improved cardiorespiratory function after pectus excavatum repair has been presented. As a result of numerous technical improvements, safe and effective operative correction of pectus excavatum has been reported for both the Nuss procedure and open repair. SUMMARY: The findings presented in this review provide objective evidence of the cardiorespiratory impairment associated with severe pectus excavatum. Clinical identification of affected patients should prompt timely work up and referral for pectus excavatum repair if inclusion criteria are met. Regular follow-up through pubertal growth is recommended. PMID- 21670677 TI - Disorders of selenium metabolism and selenoprotein function. AB - PURPOSE OF REVIEW: Inborn errors of metabolism are increasingly recognized as underlying causes in pediatric diseases. Selenium and selenoproteins have only recently been identified as causes of inherited defects. Respective case reports have broadened our understanding of selenoprotein function and their developmental importance. This review presents the characterized defects and tries to attract attention to the spectrum of potential phenotypes. RECENT FINDINGS: The characterization of patients with inherited mutations in selenoprotein N has corroborated the physiological importance of selenium for muscle function. Individuals with inherited defects in selenocysteine insertion sequence (SECIS)-binding protein 2 display a syndrome of selenoprotein-related defects including abnormal thyroid hormone metabolism, delayed bone maturation, and other more individual phenotypes. The recent identification of mutations in selenocysteine synthase causing progressive cerebello-cerebral atrophy underlines the central role of selenoproteins in brain development and protection from neurodegeneration. SUMMARY: The spectrum of diseases related to inborn defects of selenium utilization, transport, and metabolism is expanding. However, only few examples are already known, resulting from defects in one selenoprotein gene and two genes involved in selenoprotein biosynthesis, respectively. Complex syndromes with impaired muscle function, stunted growth, neurosensory and/or immune defects may point to the involvement of impaired selenium metabolism and selenoprotein function, necessitating specific diagnostic procedures. PMID- 21670678 TI - Endocrinology and metabolism 2011. PMID- 21670679 TI - Understanding teen dating violence: practical screening and intervention strategies for pediatric and adolescent healthcare providers. AB - PURPOSE OF REVIEW: Teen dating violence (TDV) is a serious and potentially lethal form of relationship violence in adolescence. TDV is highly correlated with several outcomes related to poor physical and mental health. Although incidence and prevalence data indicate high rates of exposure to TDV among adolescents throughout the United States, significant confusion remains in healthcare communities concerning the definition and implications of TDV. Additionally, healthcare providers are uncertain about effective screening and intervention methods. The article will review the definition and epidemiology of TDV and discuss possible screening and intervention strategies. RECENT FINDINGS: TDV research is a relatively new addition to the field of relationship violence. Although some confusion remains, the definition and epidemiology of TDV are better understood, which has greatly led to effective ways in which to screen and intervene when such violence is detected. Universal screening with a focus on high-risk subgroups combined with referrals to local and national support services are key steps in reducing both primary and secondary exposure. SUMMARY: TDV is a widespread public health crisis with serious short-term and long-term implications. It is necessary for pediatric and adolescent healthcare providers to be aware of TDV and its potential repercussions, as well as possible methods for screening and intervention. More research is needed to better understand TDV as well as to further define effective screening and intervention protocol for the clinical environment. PMID- 21670680 TI - Refeeding in anorexia nervosa: increased safety and efficiency through understanding the pathophysiology of protein calorie malnutrition. AB - PURPOSE OF REVIEW: This paper reviews recent publications about the physiology associated with adaptation to malnutrition and refeeding (including the refeeding syndrome) and clinical outcomes of refeeding paradigms. RECENT FINDINGS: A number of recent reviews and original publications have highlighted important differences from the assumptions underpinning the current refeeding guidelines for patients with anorexia nervosa. The notion of 'starting low and going slow' with the prescription of daily calories seems unlikely to be important in preventing refeeding syndrome. Recent publications suggest this approach does not necessarily add to safety in the refeeding process but rather the contrary. It typically results in weight loss and protracts hospitalization and nutritional recovery. Rather, the composition of macronutrients, in particular avoiding a high proportion of calories from carbohydrates, appears to be more important than the absolute number of calories. The means of initial refeeding appears increasingly important in this process, particularly following descriptions of postprandial hypoglycemia. SUMMARY: The study supports a review of the current guidelines. Evidence for the use of continuous feeding strategies with less than 40% of calories from carbohydrates is presented. This approach has important implications for the prevention of the refeeding syndrome as well as the safety and efficiency with which refeeding may occur for children and adolescents with anorexia nervosa in hospital. PMID- 21670681 TI - Approach to psychosomatic illness in adolescents. AB - PURPOSE OF REVIEW: Due to the increased prevalence of psychosomatic presentations and the difficulty of managing such patients, this article summarizes the latest findings for identifying individual and family risk factors, and new trends in the evaluation and management of pediatric patients with psychosomatic illness. RECENT FINDINGS: Up to 50% of patients in pediatric care will complain of medically unexplained symptoms with significant functional and emotional impairment. Such patients place heavy burdens on the healthcare system (frequent utilization of health resources and hospitalizations, specialist consultations, unnecessary investigations, and treatments). Somatoform disorders in pediatric care are associated with risks for psychiatric co-morbidity (anxiety and depressive disorders), family conflict, parent-perceived ill health, and school problems/absenteeism. SUMMARY: Gaining expertise in addressing pediatric psychosomatic illness can make a great difference in patients' life and in physicians' professional satisfaction. Effective treatment approaches involve a multidisciplinary approach to consolidate care and facilitate communication, target the patient/family's understanding of the mind-body relationship and their acceptance of the bio-psycho-social formulation and treatment, and utilize functional rehabilitation and cognitive behavioral therapy for the individual and family and management guidance for schools. PMID- 21670682 TI - Pediatric dermatology emergencies. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize recent advances in the diagnosis and treatment of several severe skin diseases seen in children. RECENT FINDINGS: Several articles published recently added significantly to our understanding of drug reaction with eosinophilia and systemic symptoms (DRESS), eczema herpeticum, staphylococcal scalded skin syndrome and inherited ichthyosis. A review of 60 patients with DRESS showed 80% with hepatic involvement, 40% with renal involvement, 33% with pulmonary involvement and 50% with hematologic abnormalities. A review on eczema herpeticum describes several clinical scenarios in which it is vital to keep that diagnosis in mind. Another review on severe staphylococcal skin infections reminds us of the importance of covering for methicillin-resistant Staphylococcus aureus in all such cases until cultures and sensitivities show otherwise. The results of an international consensus conference on ichthyosis published this year will help all of us to better characterize these complicated patients. Additionally, the first case of hypothyroidism associated with a collodion baby was reported, as was the finding of an increased incidence of atypical nevi in patients with inherited ichthyosis. SUMMARY: Although all of the conditions discussed in this article are relatively rare, it is important that they be kept on the differential diagnosis for sick infants and children with cutaneous findings, as early diagnosis and treatment of some of these conditions can be life saving. PMID- 21670683 TI - Cosmetic procedures in children. AB - PURPOSE OF REVIEW: Cosmetic procedures are being performed with increased frequency in the United States and worldwide. Many of these procedures are being performed on children for aesthetic reasons and for the management of dermatological conditions such as psoriasis and vitiligo. This review serves as an overview of selected cosmetic procedures with pediatric applications. RECENT FINDINGS: Recent developments in laser technology have improved our ability to treat a large number of pediatric cutaneous disorders. The vast majority of these technologies were first developed for aesthetic dermatology in adults. Collagen stimulatory agents such as poly-L-lactic acid were first approved for lipoatrophy associated with human immunodeficiency virus. Poly-L-lactic acid and dermal fillers have potential therapeutic applications in children with atrophic disorders such as lipoatrophy and morphea. Injection of botulinum toxin is very successful in the treatment of hyperhidrosis in adults and can be utilized to improve quality of life in children with hyperhidrosis. SUMMARY: The field of cosmetic dermatology is evolving quickly, with limited safety and efficacy studies in the pediatric age group. Children may benefit from thoughtful application of these technologies. PMID- 21670684 TI - Adult women with 21-hydroxylase deficient congenital adrenal hyperplasia, surgical and psychological aspects. AB - PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency results in prenatal androgen exposure and virilization of the external genitalia. The surgical procedures, indications, timing, and methods used have come under debate during the past decade. The androgen effect on later behaviors adds to the complexity of the situation for these women. The purpose of this review is to update physicians on recent findings regarding the outcome of feminizing surgery, infertility, quality of life (QoL), and psychosexual aspects in women with CAH. RECENT FINDINGS: Surgical outcome, also for the more modern techniques used today, has not been entirely satisfactory and QoL assessments paint a dark picture. All psychological effects assessed show a spectrum of severity correlating with the CYP21A2 genotype or disease severity. The prevailing recommendation for sex of rearing is to let all patients with the 46,XX karyotype grow up as girls. This notion has now been challenged regarding patients with the most extreme virilization of genitalia. SUMMARY: There are large differences in outcome depending on the severity of the disease or CYP21A2 mutation. Care needs to be individualized and centralized to specialized multidisciplinary teams. Feminizing surgery is still not satisfactory for all patients. More studies regarding sex identity are needed. PMID- 21670685 TI - Perspectives of intellectual disability in the People's Republic of China: epidemiology, policy, services for children and adults. AB - PURPOSE OF REVIEW: This review aims to provide an overview of the current status and recent developments in epidemiology, public policy and services for children and adults with intellectual disability in China. RECENT FINDINGS: The most recent national survey on disability conducted in 2006 estimated that the prevalence of intellectual disability was 0.75% in China. People with intellectual disability accounted for 11.9% of all the people with disabilities and they have an uneven geographical distribution. The prevalence in urban areas was 0.4%, whereas that in rural areas was 1.02%. The Constitution of the People's Republic of China stated that people with disabilities have the right to receive assistance from the state and society. Based on this, laws have been formulated and revised to protect people with disabilities in areas of education, employment and rehabilitation. The variety, capacity and quality of services for people with intellectual disability are steadily increasing or improving, but there are still gaps and deficiencies such as mental health care and professional services. SUMMARY: Supported by the Central Government of the People's Republic of China, there has been remarkable progress in the formulation of policies and provision of services for people with intellectual disability in recent years. However, there continue to be a lot of unmet needs among this population, particularly those living in rural areas. Therefore, further commitment, coordination and resource allocation are required to improve the lives of people with intellectual disability in China. PMID- 21670687 TI - Perspectives of intellectual disability in Serbia and Bulgaria: epidemiology, policy and services for children and adults. AB - PURPOSE OF REVIEW: The review aims to summarize data published in scientific journals and available from official websites on epidemiology, policies and services for children and adults with intellectual disability in Serbia and Bulgaria, countries which are in the process of rapid political, economic and social changes. RECENT FINDINGS: The estimated prevalence of intellectual disability is between 1 and 3%, as in other south-east European countries, but evidence-based publications on epidemiology of intellectual disability are lacking.A shift from biomedical to social model of disability has inspired the policies, legislation and programs for persons with intellectual disability adopted in the last few years. Deinstitutionalization and development of community-based services for children and adults with intellectual disability are a great challenge. Biomedical and particularly molecular genetic studies are prevailing in research, but psychosocial studies have received increased attention recently. SUMMARY: There has been encouraging progress in policies and services aimed to improve the well being and respect of human rights of persons with intellectual disability in Serbia and Bulgaria, but well designed and methodologically rigourous scientific studies are needed to inform the future policies and practice for the benefit of people with intellectual disability. PMID- 21670686 TI - Perspectives of intellectual disability in Greece: epidemiology, policy, services for children and adults. AB - PURPOSE OF REVIEW: The purpose of this review is to investigate the existing situation regarding how people with intellectual disability are treated in contemporary Greece. RECENT FINDINGS: The legal rights of people with intellectual disability are fully protected. Steady improvement of special education, along with development of educational services. Greater access of people with intellectual disability is being developed. There is, however, a lack of specialized health services. A relatively adequate social and financial support of families of individuals with severe intellectual disability. There is very limited access to employment for people with intellectual disability. Lack of rigorous research and representative studies on intellectual disability and insufficient epidemiological data. SUMMARY: The main conclusion of this review is that, since 1980, the situation of people with intellectual disability has been steadily improving in the areas of civil rights, social support, special education, and use of health services. However, the deficiency of official national data on intellectual disability does not allow a complete and documented evaluation of the situation in the country. Furthermore, the lack of epidemiological data undermines the development and establishment of evidence based public policies. PMID- 21670688 TI - Bilateral postoperative brachial plexus palsy and longlasting surgery. PMID- 21670689 TI - Endotracheal kinking of a double-lumen tube: a potential complication of inappropriate size tube selection. PMID- 21670690 TI - Ultraviolet radiation and the anterior eye. AB - The eye is on the one hand dependent on visible light energy and on the other hand can be damaged by these and the contiguous ultraviolet (UV) and infrared wavelengths. Diseases of the eye in which sunlight has been implicated have been termed the ophthalmohelioses, and these conditions pose a significant problem to the eye health of many communities. The ophthalmohelioses have a tremendous impact on patients' quality of life and have significant implications on the cost of health care. Although cataract is not entirely caused by insolation, it now seems certain that sunlight plays a contributory role-cataract extraction is one of the, if not the most, commonly performed surgical procedures in many societies. Pterygium, typically afflicting a younger population, adds a tremendous burden, both human and financial, in many countries. We review evidence that peripheral light focusing by the anterior eye to the sites of usual locations of pterygium and cataract plays a role in the pathogenesis of these conditions. Recognition of the light pathways involved with foci at stem cell niches has directed our investigations into inflammatory and matrix metalloproteinase-related pathophysiologic mechanisms. An understanding of the intracellular mechanisms involved has provided some insight into how medical treatments have been developed for the effective management of ocular surface squamous neoplasia. The concept of peripheral light focusing has also provided direction in the prevention of these diseases. This has resulted in improved sunglass design and the further development of UV-blocking contact lenses. With the development of ocular UV fluorescence photographic techniques, we have been able to demonstrate preclinical ocular surface evidence of solar damage. Evidence that diet may play a role in the development of certain conditions is reviewed. The conundrum of the public health message about solar exposure is also reviewed, and in this context, the potential role of vitamin D deficiency is summarized. The eye may play a role in the development of individualized assessment techniques of solar damage, perhaps allowing us to provide better advice to both individuals and populations. PMID- 21670691 TI - Intraocular and crystalline lens protection from ultraviolet damage. AB - OBJECTIVES: Although the risks of excess solar ultraviolet (UV) exposure of the skin are well recognized, the need for eye protection is frequently overlooked, or when sunglasses are also recommended, specific guidance is wrong or is not explained. Guidance from the World Health Organization at its InterSun webpage advises people to wear "wrap-around" sunglasses under many conditions. The objective of this study was to examine the need for UV filtration in prescription lenses, contact lenses, and sunglasses. METHODS: The geometry of UV exposure of both eyes, solar position, ground reflection, pupil size, and lid opening were studied. Because an accurate determination of cumulative ocular exposure is difficult, the cornea itself can serve as a biologic dosimeter, because photokeratitis is not experienced on a daily basis but does under certain ground surface and sunlight conditions. From a knowledge of the UV-threshold dose required to produce photokeratitis, we have an upper level of routine ocular exposure to ambient UV. RESULTS: From ambient UV measurements and observed photokeratitis, the upper limits of UV exposure of the crystalline lens or an intraocular lens implant are estimated. The risk of excess UV exposure of the germinative cells of the lens is greatest from the side. Sunglasses can actually increase UV exposure of the germinative region of the crystalline lens and the corneal limbus by disabling the eyes' natural protective mechanisms of lid closure and pupil constriction! The level of UV-A risk is difficult to define. CONCLUSIONS: Proper UV-absorbing contact lenses offer the best mode for filtering needless exposure of UV radiation of the lens and limbus. PMID- 21670693 TI - An epidemiological perspective of ultraviolet exposure--public health concerns. AB - Over the last 30 years, many countries have developed strong sun protection programs, spurred on by rapidly increasing skin cancer incidence and concerns about stratospheric ozone depletion. More recently, considerable concern has arisen about widespread vitamin D insufficiency, creating a "sun exposure dilemma," since in most regions vitamin D predominantly derives from endogenous synthesis in the skin initiated by exposure to ultraviolet (UV) radiation. Little attention has been paid to whether a similar dilemma exists for UV-related eye conditions.For the eyes, to our current knowledge, exposure to UV radiation has only adverse effects. There is strong evidence that acute high dose exposure to UV radiation causes photokeratitis and photoconjunctivitis, while even low dose chronic exposure to UV radiation is a risk factor for cataract, pterygium, and squamous cell carcinoma of the cornea and conjunctiva. There is weaker evidence in relation to other conditions, including ocular melanoma and age-related macular degeneration. Ultraviolet radiation-related eye diseases are common, disabling, and cause a considerable disease burden worldwide.The "correct" public health message for optimal sun exposure is not clear cut, with too many variables ambient UV radiation, personal skin type, age, weight, clothing habits, medication, and others-for a blanket sun safety message. In addition, there remain many unknowns, including strong evidence supporting or refuting the very many proposed health benefits of vitamin D. More evidence is required to define disease burdens for UV-induced eye diseases, to evaluate the decrease in disease burden from sun protective measures and to elucidate any beneficial effects of exposure of the eye to UV radiation, to provide appropriate advice to the public. PMID- 21670694 TI - Does the eye benefit from wearing ultraviolet-blocking contact lenses? AB - OBJECTIVES: The human eye is exposed to toxic ultraviolet radiation (UVR) from sunlight and artificial sources. The UVR-induced damage occurs in ocular tissues from the corneal surface to the retina. Although the cornea and crystalline lens provide inherent UVR protection, the anterior ocular surface and the limbus, which contains stem cells, receive toxic levels of UVR from relatively short solar exposures. METHODS: Shading headwear and some UVR-blocking sunglasses are designed to reduce direct solar exposure but may not protect the eye from diffuse ambient and surface reflected light. If the squint mechanism is reduced because of the reduction of visible light, the ocular surface is then exposed to ambient and reflected UVR. In addition, laterally incident radiation that is focused across the cornea onto the limbus, a phenomenon known as peripheral light focusing, can increase the dose at the nasal limbus by a factor of 20. RESULTS: The UVR-blocking contact lenses that cover the limbus provide protection from all sources of ocularly incident UVR. Although directly relating solar UVR dose to ocular damage is epidemiologically challenging, irradiation of ocular cell cultures can estimate the toxic effects of UVR exposure. The use of UVR-blocking contact lenses greatly increases the time the wearer can be exposed to solar UVR before a toxic ocular dose is reached. CONCLUSIONS: There is a need for the development of a scientifically rigorous, clinically applicable ocular protection factor metric, based not only on the transmittance of eyewear but on the protection afforded from the total UVR field and the length of that exposure. PMID- 21670695 TI - Ozone depletion and solar ultraviolet radiation: ocular effects, a United nations environment programme perspective. AB - PURPOSE: To describe he role played by the United Nations Environmental Effects Panel with respect to the ocular effects of stratospheric ozone depletion and present the essence of the Health Chapter of the 2010 Assessment. METHODS: A consideration of solar ultraviolet radiation (UVR) at the Earth's surface as it is affected by atmospheric changes and how these influence sunlight-related eye diseases. A review of the current Assessment with emphasis on pterygium, cataract, ocular melanoma, and age-related macular degeneration. RESULTS: Although the ozone layer is projected to recover slowly in the coming decades, continuing vigilance is required regarding exposure to the sun. Evidence implicating solar UVR, especially UVB, in every tissue of the eye continues to be amassed. CONCLUSION: The need for ocular UV protection existed before the discovery of the depletion of the ozone layer and will continue even when the layer fully recovers in approximately 2100. PMID- 21670692 TI - Ultraviolet radiation: cellular antioxidant response and the role of ocular aldehyde dehydrogenase enzymes. AB - Solar ultraviolet radiation (UVR) exposes the human eye to near constant oxidative stress. Evidence suggests that UVR is the most important environmental insult leading to the development of a variety of ophthalmoheliosis disorders. UVR-induced reactive oxygen species (ROS) are highly reactive with DNA, proteins, and cellular membranes, resulting in cellular and tissue damage. Antioxidant defense systems present in ocular tissues function to combat ROS and protect the eye from oxidative damage. Important enzymatic antioxidants are the superoxide dismutases, catalase, glutathione peroxidases, glutathione reductase, and members of the aldehyde dehydrogenase (ALDH) superfamily. Glutathione, ascorbic and uric acids, alpha-tocopherol, nicotinamide-adenine dinucleotide phosphate, and ferritin serve as small molecule, nonenzymatic antioxidants. Ocular tissues have high levels of these antioxidants, which are essential for the maintenance of reduction-oxidation homeostasis in the eye and protection against oxidative damage. ALDH1A1 and ALDH3A1, present abundantly in the cornea and lens, have been shown to have unique roles in the defense against UVR and the downstream effects of oxidative stress. This review presents the properties and functions of ocular antioxidants that play critical roles in the cellular response to UVR exposure, including a focused discussion of the unique roles that the ALDH1A1 and ALDH3A1 enzymes have as multifunctional ocular antioxidants. PMID- 21670696 TI - UV-B exposure to the eye depending on solar altitude. AB - PURPOSE: To assess the validity of the solar ultraviolet index (UVI) as a determiner of eye risk under different conditions of facial profiles and orientation, and reflected light. METHODS: Ocular UV radiation (UVR) exposure was measured as a function of the time of the day (solar altitude) using a two-dummy type mannequin dosimetry system with embedded UVR (260-310 nm) sensors, in September and November in Kanazawa, Japan, on a motorized sun-tracking mount with one dummy face directed toward the sun and the other away from the sun. RESULTS: A bimodal distribution of UV-B exposure was found in September for the face directed toward the sun, which differed dramatically from the pattern of ambient UVR exposure and measurements taken on the top of the head and those for the eye taken later in the year. Although the overall level was lower, a higher solar altitude is associated with higher UVR exposure in the condition facing away from the sun. CONCLUSIONS: The UVI is based on ambient solar radiation on an unobstructed horizontal plane similar to our measures taken on the top of the head, which differed so much from our measures of ocular exposure that UVI as a determiner of eye risk is deemed invalid. The use of the UVI as an indicator for the need for eye protection can be seriously misleading. Doctors should caution patients with regard to this problem, and eye protection may be warranted throughout the year. PMID- 21670697 TI - Role of ultraviolet irradiation and oxidative stress in cataract formation medical prevention by nutritional antioxidants and metabolic agonists. AB - PURPOSE: Cataract is a significant cause of visual disability with relatively high incidence. It has been proposed that such high incidence is related to oxidative stress induced by continued intraocular penetration of light and consequent photochemical generation of reactive oxygen species, such as superoxide and singlet oxygen and their derivatization to other oxidants, such as hydrogen peroxide and hydroxyl radical. The latter two can also interact to generate singlet oxygen by Haber-Weiss reaction. It has been proposed that in addition to the endogenous enzymatic antioxidant enzymes, the process can be inhibited by many nutritional and metabolic oxyradical scavengers, such as ascorbate, vitamin E, pyruvate, and xanthine alkaloids, such as caffeine. METHODS: Initial verification of the hypothesis has been done primarily by rat and mouse lens organ culture studies under ambient as well as ultraviolet (UV) light irradiation and determining the effect of such irradiation on its physiology in terms of its efficiency of active membrane transport activity and the levels of certain metabolites such as glutathione and adenosine triphosphate as well as in terms of apoptotic cell death. In vivo studies on the possible prevention of oxidative stress and cataract formation have been conducted by administering pyruvate and caffeine orally in drinking water and by their topical application using diabetic and galactosemic animal models. RESULTS: Photosensitized damage to lens caused by exposure to visible light and UVA has been found to be significantly prevented by ascorbate and pyruvate. Caffeine has been found be effective against UVA and UVB. Oral or topical application of pyruvate has been found to inhibit the formation of cataracts induced by diabetes and galactosemia. Caffeine has also been found to inhibit cataract induced by sodium selenite and high levels of galactose. Studies with diabetes are in progress. CONCLUSIONS: Various in vitro and in vivo studies summarized in this review strongly support the hypothesis that light penetration into the eye is a significant contributory factor in the genesis of cataracts. The major effect is through photochemical generation of reactive oxygen species and consequent oxidative stress to the tissue. The results demonstrate that this can be averted by the use of various antioxidants administered preferably by topical route. That they will be so effective is strongly suggested by the effectiveness of pyruvate and caffeine administered topically to diabetic and galactosemic animals. PMID- 21670698 TI - Association of inhibitor of differentiation 1 expression with human papillomaviruses infections in cervical carcinoma. AB - BACKGROUND: Our recent study has shown that inhibitor of differentiation 1 (Id-1) is overexpressed in cervical carcinoma. However, the relationship between Id-1 expression and human papillomavirus (HPV) infection has not been elucidated. In this study, we investigate the association of Id-1 protein expression and HPV infection in cervical carcinoma tissues. METHODS: A total of 56 paraffin-embedded and 12 fresh cervical carcinoma tissues were collected for Id-1 and HPV detection. The Id-1 protein was detected by immunohistochemistry and Western blot in paraffin-embedded and fresh carcinoma tissues. Human papillomavirus DNA was detected and genotyped by using an oligonucleotide microarray and polymerase chain reaction. RESULTS: The overall HPV prevalence was 82.1%, whereas that of HPV type 16 (HPV-16) was 62.5% in cervical carcinoma. The HPV-positive samples showed higher Id-1 expression levels than the HPV-negative ones (Cochran-Mantel Haenszel chi test [chiCMH] = 4.39, P < 0.05). The HPV-16-infected samples had higher Id-1 expression levels than the samples with infection of other single HPV genotypes (chiCMH = 6.42, P < 0.02). The results of Western blot were correlated to the immunohistochemistry results, showing a higher Id-1 expression level in HPV-infected especially HPV-16-infected carcinoma tissues. CONCLUSIONS: Inhibitor of differentiation 1 expression is correlated to HPV infection in cervical carcinoma, suggesting that Id-1 plays a role in HPV-related cervical carcinogenesis. PMID- 21670699 TI - Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical pathological protocol. AB - BACKGROUND: Women carriers of BRCA mutations often have occult malignancy found at the time of risk-reducing bilateral salpingo-oophorectomy (RRSO). We report outcomes in 111 consecutive BRCA-positive women who had RRSO using a rigorous surgical-pathological protocol from 1996 to 2008. METHOD: We identified risk factors associated with finding an occult malignancy at RRSO with outcomes followed for a median of 61 months. RESULTS: A total of 111 BRCA carriers elected RRSO, 10 patients [9.1%] had 14 sites of occult neoplasia. Two patients had invasive serous fallopian tube carcinoma (TSC) only, 1 patient had invasive serous ovarian carcinoma (OSC) only, 5 patients had tubal intraepithelial carcinoma (TIC) only, and 2 patients had multifocal lesions of the ovary (OSC) and TIC. Occult ovarian carcinomas were only detected in BRCA1 patients, and all BRCA2 carcinomas involved only the fallopian tube. The odds of finding occult carcinoma is 4 times greater (odds ratio, 4.3; 95% confidence interval, 1.06 20.7) in women older than 50 than in younger ones (P=0.023). A history of invasive breast cancer was associated with a reduced risk of occult carcinoma (odds ratio, 0.2; 95% confidence interval, 0.05-0.85). In median follow-up of 5 years, recurrence rate after detection of an occult carcinoma was 10% and the risk for primary peritoneal carcinoma was less than 1%. CONCLUSION: A rigorous surgical protocol with meticulous pathologic review at RRSO yielded an overall detection rate of 9.1% for occult gynecological carcinoma in BRCA mutation carriers followed by a multidisciplinary team at a single institution. Primary peritoneal carcinoma after RRSO is rare. PMID- 21670700 TI - Expression of HOXA10 in endometrial hyperplasia and adenocarcinoma and regulation by sex hormones in vitro. AB - OBJECTIVE: The objective of the study was to determine the expression of HOXA10 in human endometrial tissue in endometrial hyperplasia and carcinomas, and regulation by sex steroids in Ishikawa cells. METHODS: Endometrial tissue was obtained from 133 subjects with normal endometria, endometrial hyperplasia, or endometrial adenocarcinoma. Among 133 specimens, 20 were normal endometria, 19 were simple hyperplasias without atypia, 20 were complex hyperplasias without atypia, 33 were atypical hyperplasias, and 41 were endometrial adenocarcinomas. The expression of HOXA10 was analyzed by immunohistochemistry. Ishikawa cell lines were incubated with 17beta estradiol (10-8 mol/L) alone, medroxyprogesterone acetate (10-6 mol/L) alone, or the combination of estrogen and progesterone for 48 hours, respectively. In certain experiments, the antiprogestin antagonist, RU486 (10-5 mol/L), was also added to Ishikawa cells along with estradiol and medroxyprogesterone acetate for 48 hours. The expression of HOXA10 gene was detected by reverse transcriptase-polymerase chain reaction and Western blotting. RESULTS: HOXA10 was expressed in both normal and neoplastic endometria. No significant difference in HOXA10 expression was found between normal and hyperplastic endometrial tissues. The expression of HOXA10 was decreased in endometrial adenocarcinomas compared with normal endometria. Estrogen alone, progestin alone, or progestin combined with estrogen could significantly increase the expression of HOXA10 gene (P<0.05). RU486 could inhibit the effect of up-regulation of HOXA10 expression by progestin. CONCLUSIONS: The expression of HOXA10 was deregulated in endometrial carcinomas and up-regulated by sex hormones. PMID- 21670701 TI - An uncommon presentation of acute type A aortic dissection: left main coronary artery obstruction. AB - Acute aortic dissection presents with a wide range of manifestations. Sometimes an acute coronary syndrome is diagnosed instead of aortic dissection leading to inappropriate treatment. We describe a case of acute aortic dissection with the uncommon involvement of the left main coronary artery. A 64-year-old man was referred to our hospital for primary coronary intervention because ECG demonstrated ST elevation in the aVR lead with diffuse ST-segment depression. Coronary angiography was performed to treat the culprit lesion but the left main coronary artery could not be catheterized. Aortography and transesophageal echocardiography confirmed Stanford type A aortic dissection. The patient died of cardiac arrest in spite of cardiopulmonary resuscitation. This case also illustrates how Stanford type A aortic dissection can present with left main coronary artery obstruction. PMID- 21670702 TI - From SYNTAX to FAME, a paradigm shift in revascularization strategies: the key role of fractional flow reserve in guiding myocardial revascularization. AB - In patients with chest pain, noninvasive functional assessment prior to cardiac catheterization is often missing or it is inadequate to guide percutaneous coronary revascularization. This is particularly frequent in patients with complex coronary atherosclerotic disease, such as left main stenosis or multivessel disease. Interventional cardiologists are therefore often confronted with diagnostic dilemmas as to which revascularization strategy should be adopted in these patients. A revascularization strategy based on drug-eluting stent (DES) implantation of all the lesions deemed anatomically significant has been increasingly adopted, thanks to the availability of DESs. The down side of this strategy is that DESs are being liberally used even to treat lesions that are not responsible for patients' symptoms (e.g. not ischemic), just on the basis of their angiographic appearance. An alternative approach consists in limiting DES implantation to only the lesions that are indeed responsible for patients' symptoms, like those inducing ischemia, on the basis of fractional flow reserve (FFR). Following the results of important randomized clinical trials, this article discusses the pros and cons of both strategies, underscoring the key role of functional assessment of coronary stenosis severity by FFR. PMID- 21670703 TI - Immediate evidence of the benefit of distal protection in vein graft intervention. AB - Percutaneous intervention carries a higher risk of distal embolization and fatal outcome in saphenous vein grafts (SVG) than in native coronary vessels. Most of these adverse clinical events, predominantly myocardial infarction and reduced antegrade flow (no reflow phenomenon), are due to distal embolization of atherothrombotic debris and distal microvascular occlusion. For this reason, in current interventional practice, the use of distal protection devices is mandatory. Our case report provides direct and dramatic evidence of the usefulness of a low-profile filter device in the setting of massively thrombotic SVG. PMID- 21670704 TI - When job stress threatens Chinese workers: combination of job stress models can improve the risk estimation for coronary heart disease--the BADCAR study. AB - OBJECTIVE: To examine the association between job stress assessed by job demand control (JDC) model and effort-reward imbalance (ERI) model, and coronary heart disease (CHD) among Chinese workers. METHODS: The study enrolled 388 subjects undergoing angiography. Job stress was assessed by JDC and ERI models. The association between job stress and CHD was analyzed by logistic regression. RESULTS: Compared with low level group, high strain, especially high demand in JDC model, increased CHD risk with odds ratio of 2.0 (P < 0.05), and 5.0 (P < 0.001), respectively; by combing exposure to both high job strain and high ERI, a substantially increased CHD risk was observed (adjusted odds ratio = 6.1, P = 0.001). CONCLUSIONS: High job strain and demand increased the risk of CHD among Chinese workers. The combination of information from the two job stress models (JDC and ERI) substantially improved the risk estimation for CHD. PMID- 21670705 TI - Effectiveness of a workplace wellness program for maintaining health and promoting healthy behaviors. AB - This study assessed the effectiveness of a worksite wellness program. A within group study design was conducted. Assessment was based on 3737 continuously employed workers at a large agribusiness during 2007-2009. More than 80% of employees participated in the program, with a higher percentage of women participating. Clinically significant improvements occurred in those who were underweight, those with high systolic or diastolic blood pressure, high total cholesterol, high low-density lipoprotein, low high-density lipoprotein, high triglycerides, and high glucose. Among obese employee participants, significant improvements occurred in selected mental health and dietary variables. Among those who lowered their BMI, significant decrease occurred in fat intake, and significant increase resulted in weekly aerobic exercise and feelings of calmness and peace, happiness, ability to cope with stress, and more physical energy. PMID- 21670706 TI - Evaluation of popliteal artery injury risk with locked lateral plating of the tibial plateau. AB - OBJECTIVES: This study was undertaken to determine if there is increased likelihood of popliteal artery injury as one places a fixed-angle lateral proximal tibia locking plate with posterior plate lift off and or anterior plate translation from the ideal position. METHODS: A Synthes (Synthes USA, West Chester, PA) 3.5-mm and 4.5-mm lateral proximal tibia locking plate was placed consecutively on each of six specimens in the straight lateral (SL) position. Screw position with respect to the medial cortex was recorded as well as the distance of the posterior most screw tip to the popliteal artery. Next a 3-mm shim was placed under the posterior edge of the same plate to mimic posterior plate lift off (LO) followed by placement of a 6-mm shim. The same experiment was repeated with the plate translated 5 mm anteriorly (AT). RESULTS: The popliteal artery was injured in zero of six specimens using the 3.5-mm plate. The popliteal artery was injured in six of six specimens using the 4.5-mm plate in the 5-mm AT 6-mm LO position, five of six with 5-mm AT and 3-mm LO, two of six with only 5-mm AT, four of six with SL and 6-mm LO, two of six with SL and 3-mm LO, and zero of six with SL. CONCLUSION: The Synthes 4.5-mm plate can put the popliteal artery at risk with as little as 3-mm posterior liftoff in the intended straight lateral position or with 5-mm anterior plate translation with no posterior liftoff. Therefore, placement of the 4.5-mm plate in the proper position and confirmation of its position with a true lateral radiograph is paramount to avoid injury to the popliteal artery. PMID- 21670707 TI - Medial joint space widening of the ankle in displaced Tillaux and Triplane fractures in children. AB - OBJECTIVES: Tillaux and Triplane fractures occur in children predominantly from external rotation mechanism. We hypothesized that in displaced fractures, the talus would shift laterally along with the distal fibula and the distal tibial epiphyseal fragment increasing the medial joint space. DESIGN: Consecutive cases evaluated retrospectively. SETTING: Level I and Level II centers. PATIENTS: Twenty-two skeletally immature patients with 14 displaced Triplane fractures and eight displaced Tillaux fractures were evaluated for medial joint space widening. INTERVENTION: Measurement of fracture displacement and medial joint space widening before and after intervention. RESULTS: Thirteen Triplane and six Tillaux fractures (86%) showed medial space widening of 1 to 9 mm and equal to the amount of fracture displacement. Reduction of the fracture reduced the medial space to normal. There were no known complications. CONCLUSIONS: Medial space widening of the ankle may be a sign of ankle fracture displacement. Anatomic reduction of the fracture reduces the medial space and may improve the results in Tillaux and Triplane fractures. PMID- 21670708 TI - Pathophysiology of fat embolism: a rabbit model. AB - OBJECTIVES: The objective of this study was to assess the effects of fat embolism on rabbit physiology. METHODS: After anesthetic administration, both femoral condyles of the right knee only of 23 New Zealand white rabbits were exposed through a medial parapatellar approach to the knee. In the pulmonary fat embolism group (n = 15), the femoral canal was drilled in a retrograde fashion and then reamed and pressurized with a 1- to 1.5-mL cement injection. In the no pressurization group (n = 4), after reaming, no cement was injected. In the control group (n = 4), the knee incision was immediately closed. Animals were then observed for 5 hours. Hemodynamics and blood gases were recorded at standard intervals. Postmortem, the lungs were removed en bloc and fixed for histologic assessment and quantitative histomorphometry. RESULTS: Four intraoperative deaths occurred in the pulmonary fat embolism group immediately after pressurization and may have been associated with hypotension and cardiac arrest. In the pulmonary fat embolism group, pulmonary artery pressure increased, and both mean arterial pressure and PaO2 decreased after pressurization. Approximately 2% of lung volume was occupied by intravascular fat and there were no signs of perivascular inflammation. Control and no-pressurization animals remained stable throughout the experiment. CONCLUSIONS: This model simulates pulmonary fat embolism after long-bone fractures. Despite cardiorespiratory dysfunction, there was no evidence of fat initiating pulmonary inflammation based on histologic data within the timeframe of the investigation. PMID- 21670709 TI - Are polyaxially locked screws advantageous in the plate osteosynthesis of proximal humeral fractures in the elderly? A prospective randomized clinical observational study. AB - OBJECTIVES: To evaluate the results of plate osteosynthesis using either polyaxial or nonpolyaxially locked screw-plate systems in proximal humeral fractures in the elderly. DESIGN: Prospective, randomized. SETTING: Level I trauma center. METHODS: Fifty-six patients (older than 60 years) with isolated, displaced three- and four-part fractures were included. Twenty-five patients (median age, 75.5 years) were randomized to a polyaxial locking screw plate (Group 1), whereas 31 patients (median age, 72 years) were treated with a locking screw plate (Group 2). Follow-up evaluations were performed 3, 6, and 12 months postoperatively using the Simple Shoulder Test, Disabilities of the Arm, Shoulder and Hand score, and Constant score as well as radiographs. The results and the complications were compared between both groups. RESULTS: Forty-eight patients were available for follow-up (Group 1, 20 of 25; Group 2, 28 of 31). The Simple Shoulder Test, Disabilities of the Arm, Shoulder and Hand, and Constant score improved significantly from 3 to 12 months and did not differ between groups. Twelve months after the index procedure, the Simple Shoulder Test score was 8.6 +/- 3.2 points in Group 1 and 9.7 +/- 1.8 points in Group 2. The Disabilities of the Arm, Shoulder and Hand score was 17.8 +/- 16.2 in Group 1 and 15.7 +/- 11.8 in Group 2. The mean Constant score amounted to 73% +/- 17% in Group 1 and 81% +/ 13% in Group 2. There were six complications in Group 1 and eight in Group 2. CONCLUSIONS: Both the functional outcomes and the rate of complications after polyaxial locked plate osteosynthesis of proximal humeral fractures in elderly patients were comparable to those treated with nonpolyaxial implants. Despite the theoretical advantages of polyaxial locked plating in proximal humerus fractures, this study could not show a verifiable clinical advantage of these plates. PMID- 21670710 TI - Celiac disease in normal-weight and overweight children: clinical features and growth outcomes following a gluten-free diet. AB - OBJECTIVES: There are few data on pediatric celiac disease in the United States. The aim of our study was to describe the presentation of celiac disease among children with a normal and an elevated body mass index (BMI) for age, and to study their BMI changes following a gluten-free diet (GFD). PATIENTS AND METHODS: One hundred forty-two children (age 13 months-19 years) with biopsy-proven celiac disease, contained in a registry of patients studied at our center from 2000 to 2008, had follow-up growth data available. Patients' height, weight, and BMI were converted to z scores for age and grouped by BMI as underweight, normal, and overweight. Compliance was confirmed using results of serological assays, and data of noncompliant patients were analyzed separately. Data were analyzed during the observation period and were expressed as change in height, weight, and BMI z score per month of dietary treatment. RESULTS: Nearly 19% of patients had an elevated BMI at diagnosis (12.6% overweight, 6% obese) and 74.5% presented with a normal BMI. The mean duration of follow-up was 35.6 months. Seventy-five percent of patients with an elevated BMI at diagnosis decreased their BMI z scores significantly after adherence to a GFD, normalizing it in 44% of cases. Of patients with a normal BMI at diagnosis, weight z scores increased significantly after treatment, and 13% became overweight. CONCLUSIONS: Both normal weight and overweight frequently occur in North American children presenting with celiac disease. A GFD may have a beneficial effect upon the BMI of overweight and obese children with celiac disease. PMID- 21670711 TI - Long-term changes in food consumption trends in overweight children in the HIKCUPS intervention. AB - BACKGROUND AND AIM: Energy intake is a major contributor to energy imbalance and is a key modifiable factor for successful treatment of obesity. Long-term changes in dietary intake from pediatric obesity treatment programs are rarely reported. The aim of this study was to describe the changes in food intake of children from all intervention groups from baseline to 2-year follow-up after a 6-month obesity intervention. SUBJECTS AND METHODS: Overweight children (n = 160, 5-9 years), 58% girls and body mass index z score (mean +/- SD) 2.89 +/- 0.79, were recruited to the Hunter Illawarra Kids Challenge using the Parent Support randomized controlled trial. Dietary intake was reported by parents for children at baseline and 2-year follow-up (n = 87) using a food frequency questionnaire. Linear mixed models were used to determine differences by time. RESULTS: Parents reported decreases in total energy (total kcal, kcal/kg), child percentage of total energy from energy-dense, nutrient-poor foods (sweetened drinks, potato crisps, sweets, and carry-out foods) from 42% +/- 1.0% at baseline to 34.8% +/- 1.0% at 2 years (P < 0.001), with an increase in percentage of energy from nutrient-dense foods (fruits, vegetables, dairy, breads, and cereals) from 57% +/- 0.9% at baseline to 65% +/- 1.0% at 2 years (P < 0.001). CONCLUSIONS: This is the only one of a few studies that report dietary data of overweight children who participated in a treatment program with long-term follow-up. It provides evidence that improvements in food intake can be sustained up to 2 years through decreased consumption of energy-dense, nutrient-poor foods, particularly sweetened drinks, and increased consumption of core foods following an intervention. PMID- 21670712 TI - Management of children who have eosinophilic esophagitis. PMID- 21670713 TI - The risk of squamous cell carcinoma in persistent vulvar ulcers. AB - OBJECTIVE: The standard evaluation for vulvar ulcers includes an office biopsy. There are limited data regarding the false-negative rate of a punch biopsy in detecting squamous cell carcinoma of the vulva. This study reports on pathologic discrepancies between office biopsy and subsequent wide local excision for nonhealing vulvar ulcers. METHODS: A retrospective review of the surgical records of 118 consecutive vulvar procedures was performed. Eleven women with persistent vulvar ulcers in the absence of a mass or pigmented lesion were identified. Patient demographics, physical examination, office evaluation, and surgical and pathology reports for these 11 women were reviewed. RESULTS: A persistent vulvar ulcer was the presenting complaint in 11 (13.8%) of 80 women with squamous cell disease. Most women were postmenopausal, with a median age of 72 years. Nine of the 11 women had an office biopsy performed before consultation with a gynecologic oncologist. Five (55%) of these specimens had benign findings on office biopsy but revealed invasive squamous cell carcinoma after subsequent excision. Three of four women with prior diagnosis of lichen sclerosis had ulcers harboring invasive carcinoma. CONCLUSIONS: Vulvar ulceration may be the only presenting symptom in women with vulvar squamous cell carcinoma especially in postmenopausal women. Prompt office biopsy should remain part of the standard diagnostic evaluation; however, cancer should be suspected even with a negative biopsy result if ulcerations persist. More extensive tissue sampling in the operating room should be considered for these women. PMID- 21670714 TI - A randomized and blinded single-center trial comparing the effect of intracranial pressure and intracranial pressure wave amplitude-guided intensive care management on early clinical state and 12-month outcome in patients with aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: In patients with aneurysmal subarachnoid hemorrhage (SAH), preliminary results indicate that the amplitude of the single intracranial pressure (ICP) wave is a better predictor of the early clinical state and 6-month outcome than the mean ICP. OBJECTIVE: To perform a randomized and blinded single center trial comparing the effect of mean ICP vs mean ICP wave amplitude (MWA) guided intensive care management on early clinical state and outcome in patients with aneurysmal SAH. METHODS: Patients were randomized to 2 different types of ICP management: maintenance of mean ICP less than 20 mm Hg and MWA less than 5 mm Hg. Early clinical state was assessed daily using the Glasgow Coma Scale. The primary efficacy variable was 12-month outcome in terms of the Rankin Stroke Score. RESULTS: Ninety-seven patients were included in the study. There were no significant differences in treatment between the 2 groups apart from a larger volume of cerebrospinal fluid drained during week 1 in the MWA group. There was a tendency toward higher Glasgow Coma Scale scores in the MWA group during weeks 1 (P = .08) and 2 (P = .07). Outcome in terms of Rankin Stroke Score at 12 months was significantly better in the MWA group (P < .05). CONCLUSION: This randomized and blinded trial disclosed a significant better primary efficacy variable (Rankin Stroke Score after 12 months) in the MWA patient group. We suggest that proactive intensive care management with MWA-tailored cerebrospinal fluid drainage during the first week improves aneurysmal SAH outcome. PMID- 21670715 TI - Results of the prospective, randomized, multicenter clinical trial evaluating a biosynthesized cellulose graft for repair of dural defects. AB - BACKGROUND: After intradural cranial surgery, a dural substitute is often required for dural closure. Although preferred, limitations of autograft include local availability and additional surgical site morbidity. Thus, allografts, xenografts, and synthetics are frequently used. OBJECTIVE: To report 6-month results of a randomized, controlled trial of a biosynthesized cellulose (BSC) composed duraplasty device compared with commercially available dural replacements. METHODS: A total of 99 patients (62 BSC; 37 control) were treated on protocol, using a 2:1 (BSC:control) blocked randomization schedule. Physical examinations were performed pre- and postoperatively within 10 days and at 1, 3, and 6 months. Magnetic resonance imaging was performed preoperatively and at 6 months. The primary study endpoint was the absence of pseudomeningocele and extracerebral fluid collection confirmed radiographically and the absence of cerebrospinal fluid fistula at 6 months. RESULTS: At 6 months, the primary hypothesis, noninferiority of the BSC implant compared with the control group, was confirmed (P = .0206). Overall success was achieved by 96.6% of BSC and 97.1% of control patients. No significant difference was revealed between treatment groups for surgical site infection (P = 1.0000) or wound healing assessment (P >= .3685) outcomes, or radiologic endpoints (P >= .4061). Device strength and seal quality favored BSC. CONCLUSION: This randomized, controlled trial establishes BSC as noninferior to commercially available dural replacement devices. BSC offers a hypothetical advantage concerning prion and other infectious agent exposure; superior handling qualities are evident. Longer term data are necessary to identify limitations of BSC and its potential equivalence to the gold standard of pericranium. PMID- 21670716 TI - Neurocritical care monitoring correlates with neuropathology in a swine model of pediatric traumatic brain injury. AB - BACKGROUND: Small-animal models have been used in traumatic brain injury (TBI) research to investigate the basic mechanisms and pathology of TBI. Unfortunately, successful TBI investigations in small-animal models have not resulted in marked improvements in clinical outcomes of TBI patients. OBJECTIVE: To develop a clinically relevant immature large-animal model of pediatric neurocritical care following TBI. METHODS: Eleven 4-week-old piglets were randomly assigned to either rapid axial head rotation without impact (n = 6) or instrumented sham (n = 5). All animals had an intracranial pressure monitor, brain tissue oxygen tension (Pbto(2)) probe, and cerebral microdialysis probe placed in the frontal lobe and data collected for 6 hours following injury. RESULTS: Injured animals had sustained elevations in intracranial pressure and lactate-pyruvate ratio (LPR), and decreased Pbto(2) compared with sham. Pbto(2) and LPR from separate frontal lobes had strong linear correlation in both sham and injured animals. Neuropathologic examination demonstrated significant axonal injury and infarct volumes in injured animals compared with sham at 6 hours postinjury. Averaged over time, Pbto(2) in both injured and sham animals had a strong inverse correlation with total injury volume. Average LPR had a strong correlation with total injury volume. CONCLUSION: LPR and Pbto(2) can be utilized as serial nonterminal secondary markers in our injury model for neuropathology, and as evaluation metrics for novel interventions and therapeutics in the acute postinjury period. This translational model bridges a vital gap in knowledge between TBI studies in small-animal models and clinical trials in the pediatric TBI population. PMID- 21670717 TI - Risk factors for heparin-induced thrombocytopenia type II in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Heparin-induced thrombocytopenia type II (HIT II) correlates with a higher incidence of thromboembolic complications and unfavorable outcome. OBJECTIVE: To examine the risk factors and outcomes for patients with HIT II with aneurysmal subarachnoid hemorrhage. METHODS: Demographics, risk factors, treatments, and outcomes data of 600 aneurysmal subarachnoid hemorrhage patients admitted to the University of Illinois Medical Center in Chicago between June 2002 and July 2007 were retrospectively reviewed. Patients meeting the clinical criteria for HIT II were compared with those who did not develop thrombocytopenia. RESULTS: Twenty-five patients (6%) met the clinical criteria for HIT II, and 396 (94%) did not develop thrombocytopenia. Both groups were the same with respect to age, Hunt-Hess score and Fisher grade on admission, medical conditions, and social risk factors. The HIT II patients had significantly more unfavorable outcomes (modified Rankin Scale score >3), deep vein thrombosis, stroke, pulmonary embolism, and death. Development of HIT II was strongly associated with symptomatic vasospasm (odds ratio, 5.7; 95% confidence interval, 2.5-13.1; P < .001) and number of angiographic procedures (odds ratio, 1.7; 95% confidence interval, 1.3-2.2; P < .001). Forward buildup selection modeling demonstrated the latter to be the strongest predictor for HIT II development (odds ratio, 2.3; 95% confidence interval, 1.7-3.2; P = .02). CONCLUSION: Heparin induced thrombocytopenia type II correlates with a worse outcome and higher risk of thromboembolic complications in aneurysmal subarachnoid hemorrhage patients. In addition, HIT II was strongly associated with the number of angiographic procedures performed during the same hospitalization. PMID- 21670718 TI - Delayed thrombosis or stenosis following enterprise-assisted stent-coiling: is it safe? Midterm results of the interstate collaboration of enterprise stent coiling. AB - BACKGROUND: Stent-assisted coiling of intracranial aneurysms with self-expanding stents has widened the applicability of neuroendovascular therapies to those aneurysms previously considered "uncoilable" because of poor morphology. The Enterprise Vascular Reconstruction Device and Delivery System (Cordis) has demonstrated promising initial short-term results. However, the rates of delayed in-stent stenosis or thrombosis are not known. OBJECTIVE: To report midterm results of the Enterprise stent system. METHODS: A 10-center registry was created to provide a large volume of data on the safety and efficacy of the Enterprise stent system. Pooled data were compiled for consecutive patients undergoing Enterprise stent-assisted coiling at each institution. Available follow-up data were evaluated for the incidence of in-stent stenosis, thrombosis, and aneurysm occlusion. RESULTS: In total, 213 patients (176 females) with 219 aneurysms were treated with the Enterprise stent. One hundred ten patients had undergone delayed angiography (>= 30 days from stent placement, mean follow-up 174.6 days). Forty percent of patients demonstrated total occlusion with 88% having >= 90% aneurysm occlusion. Six percent of patients had delayed (>30 days) angiographic findings, of which 3% demonstrated significant (>= 50%) in-stent stenosis or occlusion. Seven delayed thrombotic events occurred (3%), along with 2 additional immediate periprocedural events. All 7 delayed events were concomitant to cessation of double-antiplatelet therapy. CONCLUSION: Midterm occlusion rates are excellent, and stenosis and thrombosis rates are comparable to other available neurovascular stents. Interruption of antiplatelet therapy appears to be a factor in those developing delayed stenosis or thrombosis. PMID- 21670719 TI - Outcome after delayed Oberlin transfer in brachial plexus injury. AB - BACKGROUND: Nerve transfers following traumatic brachial plexus injuries are infrequently operated on after 6 months of injury because myoneural degeneration may set in before nerve regeneration can occur. An exception may lie in transferring healthy donor nerve fascicles directly onto an injured recipient nerve close to the motor point. This is especially true of the Oberlin transfer in which ulnar nerve fascicle(s) are transferred onto the damaged nerve to the biceps. OBJECTIVE: This retrospective observational study evaluated the outcome of the Oberlin transfer on bicipital power in patients with upper trunk/C5,6,7 root level injuries operated on after 6 months of injury. METHODS: Using a standard infraclavicular exposure, the musculocutaneous nerve was followed to its branch to the biceps. Distal to this, the ulnar nerve was skeletonized and a constituent motor fascicle was transferred onto the nerve to biceps. Medical Research Council (MRC) motor power grading was assessed every 3 months following surgery. Patients with a follow-up less than 12 months were excluded. RESULTS: Nine patients operated on after an average of 12.2 months (range, 7-24 months) following injury qualified for the study. At an average follow-up of 26.7 months (range, 12-41 months), all patients had >= 2/5 biceps power. Seven patients (77.8%) had useful biceps function >= 3/5 MRC score. A single patient operated on 24 months after injury gained 4/5 MRC biceps power. CONCLUSION: The Oberlin transfer is a useful salvage procedure in patients presenting after 6 months of a brachial plexus injury. PMID- 21670720 TI - Medical liability reform: a case study of Mississippi. AB - Mississippi enacted medical negligence and other tort reform legislation that generally became effective for causes of action filed on or after January 1, 2003, and September 1, 2004. Data regarding lawsuits against physicians insured by the Medical Assurance Company of Mississippi (MACM), the largest medical liability insurer in the state, and MACM-insured Obstetrician-gynecologists (ob gyns) in particular, were compared by year from 1986 to 2010. The data encompassed the periods before and after the implementation of Mississippi's tort reform legislation. In addition, MACM medical liability premiums were compared by year from 2000 to 2010. Mississippi's tort reform laws were associated with a steep drop in lawsuits against MACM-insured physicians, particularly MACM-insured ob-gyns, as well as medical liability premium reductions and refunds. PMID- 21670721 TI - Cytomegalovirus infection presenting as isolated inflammatory polyps of the gastrointestinal tract. AB - BACKGROUND: Gastrointestinal involvement by cytomegalovirus (CMV) infection is a well recognised complication in patients taking steroid/immunosuppressive therapy or suffering from immunodeficiency and debilitating diseases. Rarely, CMV may affect immunocompetent healthy individuals. However, CMV infection presenting as isolated inflammatory polyps is unusual. METHODS: We describe five patients (1 infant and 4 adults 56-80 years of age) with CMV-associated polyps that posed diagnostic difficulty. Four lesions were initially misdiagnosed as inflammatory fibroid polyp (n = 2), atypical/suspicious lymphoproliferative (n = 1) and mesenchymal (n = 1) lesion. RESULTS: Underlying diseases were kidney transplantation (1), ulcerative colitis (1), and HIV infection (1). One elderly patient had pseudomembranous colitis but no significant co-morbidity. One patient had no relevant diseases. The lesions affected the colon (3), small intestine (1) and gastric antrum (1); one was multifocal. The size ranged from 0.3 cm to 2.0 cm. Histologically, all lesions showed extensive surface ulceration and abundant capillary-rich granulation tissue containing activated lymphoid cells, plasma cells, granulocytes, enlarged histiocytes and atypical fibroblasts. Eosinophils were prominent in two cases. Immunohistochemistry showed unequivocal intranuclear CMV inclusions. CONCLUSION: These cases widen the spectrum of endoscopic and histological appearance of gastrointestinal CMV infection. Awareness of these unusual lesions should enhance detection and proper classification of this probably under-recognised CMV presentation. PMID- 21670722 TI - Gastrointestinal Foxp3 expression in normal, inflammatory and neoplastic conditions. AB - BACKGROUND: Foxp3(+) regulatory T lymphocytes (T-regs) represent an important regulatory cell subset in inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract. METHODS: Inflammatory, preneoplastic and neoplastic conditions of the gastrointestinal tract (189 cases) were studied with the evaluation of Foxp3 regulatory T cells based on immunohistochemistry. RESULTS: Few Foxp3(+) cells were found in controls and inflammatory conditions (oesophagitis, gastritis, coeliac disease, inflammatory bowel disease); in preneoplastic and neoplastic conditions the number of Foxp3(+) cells was significatively increased. CONCLUSIONS: In normal conditions the number of mucosal lymphocytes is very low throughout the gastro-intestinal tract; in active coeliac disease patients or on a gluten-free diet, only a slight increase in Foxp3(+) cells may be found. Gastrointestinal cancers are associated with higher Foxp3(+) cell proportion, compared with microscopically normal tissue and with precancerous conditions. However, it is uncertain whether the increase in these regulatory cells is a cause or a consequence of tumour progression. PMID- 21670723 TI - Genotyping of human adenoviruses using a PCR-based reverse line blot hybridisation assay. AB - OBJECTIVES: Human adenoviruses are common pathogens associated with a broad spectrum of disease. There is a growing clinical interest in typing clinical isolates since it is becoming increasingly clear that individual serotypes are associated with different disease spectra, virulence, severity of consequences, and outbreaks. Current methods cannot detect all known adenoviruses simultaneously and rapidly. We designed a practical adenovirus typing method with polymerase chain reaction (PCR)-based reverse line blot hybridisation assay (RLB) using hypervariable region-7 (HVR-7) in the hexon gene. METHODS: A PCR-RLB assay was developed based on HVR-7 in the hexon region for potentially genotyping 51 adenovirus serotypes by hybridisation of 62 genotype-specific probes using amplicons generated from one genus-specific primer pair. Single PCR and sequencing were performed for confirmation of RLB results. Eighty-seven previously serotyped clinical isolates (representing 28 serotypes) were studied. RESULTS: Thirty-two different genotypes were detected by RLB from 87 adenovirus isolates, of which 82 isolates showed consistent results with sequencing. Another five isolates revealed evidence by RLB of co-infection, and were confirmed with a combination of genotype-specific single PCR and sequencing. CONCLUSIONS: In comparison to sequencing and serological methods, the advantages of the RLB assay include: (1) rapid genotyping of multiple samples in a single run; (2) successful detection of co-infection; (3) detection of subgenotype variants. This will allow rapid and inexpensive characterisation of adenovirus infections and outbreaks. PMID- 21670724 TI - Human epidermal growth factor receptor 2 (HER2) in salivary gland carcinomas. AB - BACKGROUND: HER2 is a target for antibody-based treatment of breast and gastric carcinoma which is highly successful in advanced disease as well as in the adjuvant setting. To determine the potential applicability of such therapies, salivary gland tumours were analysed for HER2 overexpression/amplification in this study. METHODS: A tissue microarray (TMA) was constructed from 994 carcinomas and 205 adenomas of the salivary gland. Slides were analysed for HER2 overexpression and gene amplification using FDA approved reagents for immunohistochemistry (IHC; Hercep-Test; Dako) and fluorescence in situ hybridisation (FISH; PathVysion; Vysis-Abbott). RESULTS: HER2 was found overexpressed in 39 of 915 (4.26%) and amplified in nine of 915 interpretable salivary gland carcinomas (0.98%). HER2 overexpression was mostly found in salivary duct carcinoma. All other entities were mainly HER2 negative. HER2 was overexpressed in 34 of 319 (10.65%) mucoepidermoid carcinomas, one of 170 (0.59%) acinic cell adenocarcinomas and three of 14 (21.43%) salivary duct carcinomas. HER2 amplification was seen in three of 294 (1.01%) mucoepidermoid carcinomas, three of 14 (21.43%) salivary duct carcinomas, one of 81 (1.23%) adenocarcinomas (NOS), one of 12 (8.33%) cystadenocarcinomas and one of 19 (2.08%) myoepithelial carcinomas. HER2 amplification was found in seven of 39 immunohistochemically HER2 positive (2+ and 3+) tumours (17.95%) but in only two of 849 (0.24%) IHC negative tumours (p < 0.0001). No amplification/overexpression was found in adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, polymorphous low grade carcinoma, basal cell carcinoma, myoepithelial carcinoma, cystadenocarcinoma and oncocytic carcinoma. CONCLUSION: HER2 overexpression caused by gene amplification was observed in about 20% of patients with salivary duct cancers but was rare in salivary adenomas and other carcinomas. Therefore, anti-HER2 therapy may represent a therapeutic option only in a small subgroup of salivary gland tumours. PMID- 21670725 TI - Expression of BDNF, TrkB, and p53 in early-stage squamous cell carcinoma of the uterine cervix. AB - AIMS: TrkB and BDNF play a critical role in cancer invasion and metastasis. We investigated the potential role of these proteins, together with p53, in squamous cell carcinoma (SCC) of the uterine cervix by focusing on the clinicopathological correlation and outcome. METHODS: We performed RT-PCR analysis of TrkB and BDNF mRNA expression in cervical cancer cell lines, as well as tumour and normal tissue of the cervix. We analysed TrkB, BDNF, and p53 protein expression using immunohistochemistry in 80 patients with cervical SCC. RESULTS: The expression of BDNF and TrkB mRNA was higher in human cervical cancer cell lines and SCC tissues than in normal tissues. Positive TrkB expression was significantly correlated with low FIGO stage (p = 0.032), low T stage (p = 0.027), less than 1/2 stromal invasion of the cervix (p = 0.018), 4 cm or smaller for the greatest dimension of the tumour (p = 0.015) and absent lymphatic invasion (p = 0.032). Positive BDNF expression was significantly related to low FIGO stage (p = 0.001), less than 1/2 stromal invasion of the cervix (p = 0.040), absent lymphatic invasion (p = 0.026), and absent lymph node metastasis (p = 0.003). In contrast, p53 expression was significantly related to advanced T stage (p = 0.001), greater than 4 cm for the greatest dimension of the tumour (p = 0.002), more than 1/2 stromal invasion of the cervix (p = 0.005), and poor survival (p = 0.0218). CONCLUSIONS: TrkB and BDNF expression might play a significant role in the early events in tumorigenesis of cervical SCC. However, p53 is involved late in the process of tumour progression and therefore is predictive of a poor prognosis in SCC. PMID- 21670726 TI - Overexpression of P53 protein and local hGH, IGF-I, IGFBP-3, IGFBP-2 and PRL secretion by human breast cancer explants. AB - BACKGROUND: Insulin-like growth factor-I (IGF-I) in concert with insulin-like binding protein 3 (IGFBP-3), insulin-like binding protein 2 (IGFBP-2), human growth hormone (GH) and P53 protein is involved in autocrine/paracrine growth signaling pathways as an adaptive response to environmental stimuli. OBJECTIVE: The study evaluated the local secretion of PRL, hGH, IGF-I, IGFBP-2 and IGFBP-3 by breast cancer tissue explants in relation to the overexpression of P53 protein in breast cancer tissue. MATERIALS AND METHODS: Breast cancer explants were obtained during radical mastectomies. The overexpression of P53 protein was assessed immunohistochemically using monoclonal antibody (DAKO, Anti-Human P53 protein, clone DO-7); the results of the reaction were stratified into 5 groups. The lack of P53 protein overexpression was defined as 0% of cells that overexpressed P53 protein. IGF-I, IGFBP-3, IGFBP-2, and hGH levels were measured with RIA kits, and prolactin was measured with the MEIA kit. RESULTS: The local secretion of hGH by tumour explants - presenting a positive immunohistochemical reaction (IHCR) to the product of P53 gene - was twice as high as those with no IHCR to product of P53 gene; the opposite was noted in the case of IGF-I, IGFBP-2 and IGFBP-3 secretion. In both cases, the level of hGH, IGF-I and IGFBP-3 secretion did not correlate with the ratio of cells overexpressing P53 protein. There was a significant decrease in local, basic IGFBP-2 secretion along with an increased ratio of cells with positive IHCR to product of P53 gene. Furthermore, local PRL secretion was not correlated with the ratio of cells overexpressing P53 protein in breast cancer tissue. Prolactin also exerts no influence on IGF-I secretion. CONCLUSION: Our results may suggest the presence of local hGH/IGF-I feedback in breast tissue as well as the possibility of P53/hGH/IGF-I/IGFBP-3 but not P53/PRL/IGF-I axis. PMID- 21670727 TI - Beneficial influence of postmenopausal estrogen therapy on serum adhesion molecules is independent of the route and dose of administration. AB - OBJECTIVE: In current literature, the immune-inflammatory theory of atherosclerosis is widely discussed. The role of how adhesion molecules contribute to the development of atheromatic plaques is especially underlined. MATERIAL AND METHODS: 120 females in menopausal age were included in the study between 2004 and 2009. All the women were of menopausal age (51+/-3 years), from southern Poland, with FSH levels above 30 mIU/ml, and complaining of menopausal symptoms that disturbed normal daily activity. The study was conducted over a 6 month period. Three groups of 40 randomized patients were selected. The control group consisted of 40 volunteers, who were also from southern Poland, in good health, without menopausal symptoms, or menstrual periods in the last 6 months. Control subjects were match according to age and weight, with FSH levels above 25 mIU/ml and normal TSH and prolactin values. All patients, in the treatment and control groups were seronegative for Chlamydia pneumonia throughout the duration of the study. RESULTS: After 6 months, hormonal therapy was found to significantly reduce levels of sICAM-1 and sVCAM-1 in all treated groups compared to the control group and the results were statistically significant. Alternatively, in the latter group, we observed increased levels of the investigated adhesion molecules (group I: 37.5 ug/24h transdermal estradiol + dydrogesteron; group II 50 ug/24h transdermal estradiol + medroxyprogesteron; group III 1mg of oral estradiol + noretisteron sICAM-1 and control group; using paired Wilcoxon test). CONCLUSION: All of the investigated estrogen therapy schemas have a favorable impact on the blood levels of sICAM-1 and sVCAM-1 in postmenopausal women without cardiovascular risk factors, reducing their concentration. PMID- 21670728 TI - Aspirin resistance may be associated with adverse pregnancy outcomes. AB - OBJECTIVE: Verify that resistance to aspirin may have an impact on pregnancy and neonatal outcome. METHODS: We enrolled 43 pregnant women, aged 30.7 +/- 4.0 years regularly taking 75 mg of aspirin daily and 32 (aged 30.8 +/- 4 years) pregnant women not receiving aspirin who served as control group. Laboratory tests were performed at 18 to 22 weeks of gestation, 28 to 32 weeks of gestation and 16 to 32 weeks after delivery. Resistance to aspirin was defined as urinary 11 dehydrothromboxane B2 (u11-dTXB2) concentrations in the highest quartile and additionally, as the resistance index (RI) calculated for each woman, defined as the difference between u11-dTXB2 concentration of each woman treated with aspirin and the median value at the same time point measured in the control group. RESULTS: Women taking aspirin in the highest quartile of u11-dTXB2 delivered prematurely (35.8+/-3.4 vs 38.1+/-1.7 weeks, p=0.02). Delivery of small for gestational age (SGA) newborns (p=0.003) as well as fetal distress (p=0.014) and preeclampsia (p=0.003) occured more frequently in aspirin-resistant women. Resistance to aspirin based on the RI value was also associated with higher prevalence of preeclampsia (p=0.02) and SGA newborns delivery (p=0.01). The two groups resistant to ASA designed on the basis of both (RI and u11-dTXB2 urine levels) methods compared with ASA sensitive group differed in frequency of SLE prevalence. CONCLUSION: Aspirin resistance may be associated with increased risk of adverse pregnancy outcomes including preeclampsia, premature delivery and delivery of SGA newborns. PMID- 21670730 TI - Evidence-based psychiatric genetics, AKA the false dichotomy between common and rare variant hypotheses. AB - In this article, we review some of the data that contribute to our understanding of the genetic architecture of psychiatric disorders. These include results from evolutionary modelling (hence no data), the observed recurrence risk to relatives and data from molecular markers. We briefly discuss the common-disease common variant hypothesis, the success (or otherwise) of genome-wide association studies, the evidence for polygenic variance and the likely success of exome and whole-genome sequencing studies. We conclude that the perceived dichotomy between 'common' and 'rare' variants is not only false, but unhelpful in making progress towards increasing our understanding of the genetic basis of psychiatric disorders. Strong evidence has been accumulated that is consistent with the contribution of many genes to risk of disease, across a wide range of allele frequencies and with a substantial proportion of genetic variation in the population in linkage disequilibrium with single-nucleotide polymorphisms (SNPs) on commercial genotyping arrays. At the same time, most causal variants that segregate in the population are likely to be rare and in total these variants also explain a significant proportion of genetic variation. It is the combination of allele frequency, effect size and functional characteristics that will determine the success of new experimental paradigms such as whole exome/genome sequencing to detect such loci. Empirical results suggest that roughly half the genetic variance is tagged by SNPs on commercial genome-wide chips, but that individual causal variants have a small effect size, on average. We conclude that larger experimental sample sizes are essential to further our understanding of the biology underlying psychiatric disorders. PMID- 21670729 TI - Levels of explanation in psychiatric and substance use disorders: implications for the development of an etiologically based nosology. AB - The soft medical model for psychiatric illness, which was operationalized in DSM III, defines psychiatric disorders as syndromes with shared symptoms, signs, course of illness and response to treatment. Many in our field want to move to a hard medical model based on etiological mechanisms. This essay explores the feasibility of this move and asks whether psychiatric disorders have the needed single clear level of explanation for an etiologically based nosology. I propose seven criteria for a good explanation: (i) strength, (ii) causal confidence, (iii) generalizability, (iv) specificity, (v) manipulability, (vi) proximity and (vii) generativity. Applying them to cystic fibrosis, a gene-level approach to etiology performs well across the board. By contrast, a detailed review of alcohol dependence and a briefer review of major depression suggests that psychiatric disorders have multiple explanatory perspectives no one of which can be privileged over others using scientific data alone. Therefore, a move toward an etiologically based diagnostic system cannot assume that one level of explanation will stand out as the obvious candidate on which to base the nosology. This leaves two options. Either a hard medical model will be implemented that will require a consensus about a preferred level of explanation which must reflect value judgments as well as science. To take this approach, we need to agree on what we most want from our explanations. Alternatively, we will need to move away from the traditional hard medical model that requires that we ground our diagnoses in single biological essences, and focus instead on fuzzy, cross-level mechanisms, which may more realistically capture the true nature of psychiatric disorders. PMID- 21670731 TI - Identifying false, but apparently plausible, explanations for the onset of psychiatric disorder. PMID- 21670732 TI - Identification of tag haplotypes for 5HTTLPR for different genome-wide SNP platforms. PMID- 21670737 TI - Chromatin: positioning the players. PMID- 21670733 TI - Basolateral amygdala regulation of adult hippocampal neurogenesis and fear related activation of newborn neurons. AB - Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contribute to support emotional memory, and that regulation of hippocampal neurogenesis is implicated in depressive disorders. How emotional information affects newborn neurons in adults is not clear. Given the role of the BLA in hippocampus-dependent emotional memory, we investigated whether hippocampal neurogenesis was sensitive to emotional stimuli from the BLA. We show that BLA lesions suppress adult neurogenesis, while lesions of the central nucleus of the amygdala do not. Similarly, we show that reducing BLA activity through viral vector-mediated overexpression of an outwardly rectifying potassium channel suppresses neurogenesis. We also show that BLA lesions prevent selective activation of immature newborn neurons in response to a fear conditioning task. These results demonstrate that BLA activity regulates adult hippocampal neurogenesis and the fear context-specific activation of newborn neurons. Together, these findings denote functional implications for proliferation and recruitment of new neurons into emotional memory circuits. PMID- 21670736 TI - Mission impossible? Urological management of patients with spinal cord injury during pregnancy: a systematic review. AB - STUDY DESIGN: A systematic literature review. OBJECTIVES: To systematically assess the existing knowledge about treatment of neurogenic lower urinary tract dysfunction (NLUTD) in pregnant women with traumatic spinal cord injury (SCI), as urologic management of these patients is mandatory, but no guidelines are available. SETTING: Paraplegic center in Switzerland. METHODS: Studies were identified by electronic search of PubMed and MedLine. Data were pooled and analyzed quantitatively. RESULTS: The evidence level of all 14 reports (163 patients, 226 pregnancies) included was low. In 13 studies, information was gathered by a retrospective review of the medical records or by questionnaires. In all studies, reported data were incomplete. SCI was cervical in 34.7%, thoracic in 61.2% and lumbar in 4.1% of the pregnant women. In all 34.7% of the women used indwelling catheters, 25% performed intermittent catheterization, 11.5% used the Crede maneuver and 28.8% voided spontaneously. A total of 64% of the patients had at least one symptomatic urinary tract infection (UTI) during pregnancy. UTIs were more common in women with indwelling catheters (100%) than in those performing intermittent catheterization (38.5%), using the Crede technique (17%) or voiding spontaneously (53.3%). One study demonstrated a significant reduction in UTI during pregnancy without complications in mothers or infants. CONCLUSION: No evidence-based recommendations can be drawn from the existing literature to guide urologists in the management of NLUTD in pregnant women with SCI. The number of studies is small, and data acquisition and presentation are often inadequate. Thus, further research is urgently needed. PMID- 21670739 TI - ESAT6 differentially inhibits IFN-gamma-inducible class II transactivator isoforms in both a TLR2-dependent and -independent manner. AB - Mycobacterium tuberculosis (Mtb) downregulates the surface expression of major histocompatibility class II (MHC II) molecules on macrophages via modulating class II transactivator (CIITA) protein of the host cell. This results in decreased effector function of CD4(+) T cells. In macrophages, CIITA is transcribed by the promoters I (pI) and IV (pIV) and the corresponding gene products are referred to as type I and type IV CIITA, respectively. Earlier studies have mainly focused on CIITA transcribed by pIV; however, these studies also showed that type IV CIITA expression was transient and dispensable for MHC II expression. In the present study, we observed that the Mtb 6-kDa, early secreted antigen (ESAT6) inhibited interferon (IFN)-gamma-induced type I as well as type IV CIITA, but, interestingly, inhibition of type I CIITA was found to be independent of Toll-like receptor-2 (TLR2), whereas that of type IV was TLR2 dependent. Moreover, we also present evidence to show that ESAT6-mediated inhibition was regulated via remodeling of the chromatin. We found that ESAT6 caused a decrease in the IFN-gamma-stimulated methylation of the histone H3K4, as well as in the levels of histone acetylation at the CIITA pI locus in macrophages. We also found the involvement of mitogen-activated protein kinases ERK1/2 and p38 in the regulation of CIITA by ESAT6. In conclusion, our studies suggest that ESAT6 could inhibit the expression of type I and type IV CIITA through different pathways. Furthermore, ESAT6 could signal through putative receptors other than TLR2, and that the inhibition of IFN-gamma-stimulated CIITA by ESAT6 was regulated at the chromatin level. PMID- 21670738 TI - LPS hypersensitivity of gp130 mutant mice is independent of elevated haemopoietic TLR4 signaling. AB - Among the many inflammatory mediators induced by the prototypical inflammatory stimulus lipopolysaccharide (LPS), which signals via Toll-like receptor (TLR)-4, interleukin (IL)-6 has recently been shown to feedback and augment TLR4 signaling when overproduced in LPS hypersensitive gp130(F/F) mice. This regulation by IL-6 in gp130(F/F) mice requires hyperactivation of the latent transcription factor signal transducer and activator of transcription (STAT) 3 via the IL-6 signaling receptor subunit gp130. However, the identity of LPS/TLR4-responsive inflammatory signaling pathways and gene networks, which are modulated by IL-6 (via gp130/STAT3), and the extent to which the tissue and cellular context of this regulation contributes to LPS-induced endotoxic shock in gp130(F/F) mice, are unknown. We report here that in LPS-treated macrophages from gp130(F/F) mice, gp130 hyperactivation upregulated the LPS-induced expression of inflammatory mediators downstream of Janus kinase (JAK)/STAT, nuclear factor kappa-light-chain enhancer of activated B cells, interferon regulatory factor and c-Jun N-terminal kinase/p38 mitogen-activated protein kinase pathways. Notably, however, LPS administration to bone marrow chimeras indicated that heightened LPS/TLR4 signaling in haemopoietic-derived gp130(F/F) immune cells is dispensable for the hypersensitivity of gp130(F/F) mice to LPS-induced endotoxemia. To understand the molecular consequences of gp130 hyperactivity in non-haemopoietic tissue on LPS induced systemic inflammation, global gene expression profiling of livers from LPS-treated gp130(F/F) mice was performed and identified 264 hepatic LPS responsive genes, which are differentially regulated by hyperactive gp130 signaling. Collectively, the substantial transcriptional reprogramming of LPS responsive genes in gp130(F/F) mice emphasizes non-haemopoietic gp130 signaling as a key regulator of systemic inflammatory responses during LPS-induced endotoxemia. PMID- 21670740 TI - Human cytomegalovirus UL7, a homologue of the SLAM-family receptor CD229, impairs cytokine production. AB - Human cytomegalovirus (HCMV), the beta-herpesvirus prototype, has evolved a wide spectrum of mechanisms to counteract host immunity. Among them, HCMV uses cellular captured genes encoding molecules capable of interfering with the original host function or of fulfilling new immunomodulatory tasks. Here, we report on UL7, a novel HCMV heavily glycosylated transmembrane protein, containing an Ig-like domain that exhibits remarkable amino acid similarity to CD229, a cell-surface molecule of the signalling lymphocyte-activation molecule (SLAM) family involved in leukocyte activation. The UL7 Ig-like domain, which is well-preserved in all HCMV strains, structurally resembles the SLAM-family N terminal Ig-variable domain responsible for the homophilic and heterophilic interactions that trigger signalling. UL7 is transcribed with early-late kinetics during the lytic infectious cycle. Using a mAb generated against the viral protein, we show that it is constitutively shed, through its mucine-like stalk, from the cell-surface. Production of soluble UL7 is enhanced by PMA and reduced by a broad-spectrum metalloproteinase inhibitor. Although UL7 does not hold the ability to interact with CD229 or other SLAM-family members, it shares with them the capacity to mediate adhesion to leukocytes, specifically to monocyte-derived DCs. Furthermore, we demonstrate that UL7 expression attenuates the production of proinflammatory cytokines TNF, IL-8 and IL-6 in DCs and myeloid cell lines. Thus, the ability of UL7 to interfere with cellular proinflammatory responses may contribute to viral persistence. These results enhance our understanding of those HCMV-encoded molecules involved in sustaining the balance between HCMV and the host immune system. PMID- 21670742 TI - AKNA: another AT-hook transcription factor "hooking-up" with inflammation. PMID- 21670741 TI - The AP-3 adaptor complex is required for vacuolar function in Arabidopsis. AB - Subcellular trafficking is required for a multitude of functions in eukaryotic cells. It involves regulation of cargo sorting, vesicle formation, trafficking and fusion processes at multiple levels. Adaptor protein (AP) complexes are key regulators of cargo sorting into vesicles in yeast and mammals but their existence and function in plants have not been demonstrated. Here we report the identification of the protein-affected trafficking 4 (pat4) mutant defective in the putative delta subunit of the AP-3 complex. pat4 and pat2, a mutant isolated from the same GFP imaging-based forward genetic screen that lacks a functional putative AP-3 beta, as well as dominant negative AP-3 MU transgenic lines display undistinguishable phenotypes characterized by largely normal morphology and development, but strong intracellular accumulation of membrane proteins in aberrant vacuolar structures. All mutants are defective in morphology and function of lytic and protein storage vacuoles (PSVs) but show normal sorting of reserve proteins to PSVs. Immunoprecipitation experiments and genetic studies revealed tight functional and physical associations of putative AP-3 beta and AP 3 delta subunits. Furthermore, both proteins are closely linked with putative AP 3 MU and sigma subunits and several components of the clathrin and dynamin machineries. Taken together, these results demonstrate that AP complexes, similar to those in other eukaryotes, exist in plants, and that AP-3 plays a specific role in the regulation of biogenesis and function of vacuoles in plant cells. PMID- 21670743 TI - The heterogeneity and dynamic equilibrium of rat embryonic stem cells. PMID- 21670744 TI - Long-term survival of exogenous embryonic stem cells in adult bone marrow. PMID- 21670745 TI - Childhood obesity and cardiovascular disease: links and prevention strategies. AB - The prevalence and severity of pediatric obesity have dramatically increased since the late 1980s, raising concerns about a subsequent increase in cardiovascular outcomes. Strong evidence, particularly from autopsy studies, supports the concept that precursors of adult cardiovascular disease (CVD) begin in childhood, and that pediatric obesity has an important influence on overall CVD risk. Lifestyle patterns also begin early and impact CVD risk. In addition, obesity and other CVD risk factors tend to persist over time. However, whether childhood obesity causes adult CVD directly, or does so by persisting as adult obesity, or both, is less clear. Regardless, sufficient data exist to warrant early implementation of both obesity prevention and treatment in youth and adults. In this Review, we examine the evidence supporting the impact of childhood obesity on adult obesity, surrogate markers of CVD, components of the metabolic syndrome, and the development of CVD. We also evaluate how obesity treatment strategies can improve risk factors and, ultimately, adverse clinical outcomes. PMID- 21670748 TI - Screening: Quantitative is better than qualitative. PMID- 21670746 TI - Peripheral artery disease. Part 2: medical and endovascular treatment. AB - The treatment of peripheral artery disease (PAD) focuses on risk factor modification, cardiovascular event reduction, limb viability, and symptom improvement. Hypertension, hyperlipidemia, and diabetes mellitus should all be controlled to recommended target levels, and smoking cessation is vital. Antiplatelet therapies, such as aspirin or clopidogrel, should be administered in all patients unless contraindicated. Whenever possible, patients who present with claudication should be offered a regimen comprised of both medical and exercise therapy, which often results in substantial improvement in symptoms. For patients presenting with more-advanced disease, such as acute limb ischemia, critical limb ischemia, and severely-limiting symptoms of PAD, revascularization is often necessary. As a result of the rapid evolution in endovascular revascularization technology and expertise, many patients with PAD can be treated percutaneously. Therefore, in this Review, we will focus on medical therapy and endovascular revascularization of patients with PAD, with reference to surgical bypass in specific clinical scenarios. PMID- 21670747 TI - Assessment of left ventricular function in aortic stenosis. AB - Degenerative aortic stenosis (AS) has become the most common valvular heart disease and the definitive treatment of symptomatic, severe AS is surgical valve replacement. In the absence of symptoms, the presence of left ventricular (LV) systolic dysfunction is pivotal in making treatment decisions for patients with AS. However, the LV ejection fraction is not a sensitive marker of global LV systolic function in the presence of LV hypertrophy, implying that asymptomatic patients with AS can have myocardial dysfunction with preserved LV ejection fraction. Abnormal myocardial mechanics might explain the pathophysiological processes underlying chronic pressure overload in AS. In this article, we review how new echocardiographic deformation parameters--such as myocardial strain, strain rate, and twist measurements--offer the potential for clinicians to monitor the course of LV dysfunction in patients with AS. Quantifying disturbances in LV function might provide insight into the timing of aortic valve replacement and into the improvement of LV systolic and diastolic properties through regression of LV hypertrophy and fibrosis after valve implantation. PMID- 21670749 TI - Experimental therapies: I've got you under my skin. PMID- 21670750 TI - Bladder cancer: are provider volumes a suitable measure of quality of care? PMID- 21670751 TI - Bladder cancer: Predicting response to BCG. PMID- 21670752 TI - Radiation therapy for prostate cancer after prostatectomy: adjuvant or salvage? AB - Approximately 15-25% of men who undergo radical prostatectomy for localized prostate cancer will experience a PSA-defined biochemical recurrence (BCR) of their cancer--men with poorly differentiated cancer, non-organ-confined disease, and positive surgical margins are at the highest risk. Accumulating evidence indicates that postoperative radiation therapy to the prostate bed favorably influences the course of disease in men with pathological features of poor prognosis. Three phase III randomized trials of adjuvant radiotherapy versus observation have reported improved freedom from BCR, and one study has reported improved metastasis-free survival and overall survival. Similar evidence from randomized trials for salvage radiotherapy is lacking; however, several observational studies have reported durable responses to salvage radiotherapy and reduced cancer-specific mortality in a substantial proportion of high-risk patients, provided that it is administered at the earliest evidence of BCR. The appeal of salvage radiotherapy is that a substantial proportion of patients with non-organ-confined cancer or positive surgical margins are cured after radical prostatectomy alone, thereby limiting the adverse effects of postoperative radiotherapy--which include urinary and bowel dysfunction, sexual dysfunction and secondary pelvic malignancies--to only those whose cancer was not cured by surgery. In the absence of data from randomized trials demonstrating the superiority of adjuvant radiotherapy over a surveillance strategy (with planned salvage radiotherapy at the earliest evidence of BCR), we advocate shared decision making between physicians and patients, based on the relative advantages and disadvantages of each approach. PMID- 21670753 TI - Prostate cancer: What is the cost of modern cancer treatment? PMID- 21670754 TI - BPH: Lift and separate to relieve LUTS. PMID- 21670755 TI - TRAIL-mediated signaling in prostate, bladder and renal cancer. AB - Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a death receptor ligand that has the ability to preferentially initiate apoptosis in malignant cells with minimal toxicity to normal cells. TRAIL-based therapeutics, including recombinant TRAIL, TRAIL-receptor agonistic antibodies and TRAIL gene therapy, have now entered clinical trials. Although these therapeutics are promising, concerns regarding TRAIL resistance are causing research efforts to shift towards the identification of effective combination therapies. Small molecule inhibitors, natural compounds, and drugs approved for treatment of diseases other than cancer have been shown to affect TRAIL receptors, antiapoptotic proteins and survival pathways in prostate, bladder and renal cell lines and in preclinical models. Changes in endogenous TRAIL and TRAIL receptor expression during the development of genitourinary malignancies and the way in which the expression pattern is affected by treatment are of great interest, and understanding the biological consequences of such changes will be important to maximize the potential of TRAIL-based therapeutics. PMID- 21670756 TI - Pharmacotherapy: Levothyroxine in the elderly-finding the breaking point. PMID- 21670758 TI - Reproductive Endocrinology: Androgens inversely related to depression in PCOS. PMID- 21670759 TI - Pain: MAPK inhibitor shows promise in clinical trial for neuropathic pain. PMID- 21670760 TI - Stroke: do statins improve outcomes after acute ischemic stroke? PMID- 21670761 TI - Neurodegenerative disease: functional networks are altered in mild cognitive impairment. PMID- 21670763 TI - Stroke: are antihypertensives beneficial in acute stroke? PMID- 21670757 TI - New perspectives on osteogenesis imperfecta. AB - A new paradigm has emerged for osteogenesis imperfecta as a collagen-related disorder. The more prevalent autosomal dominant forms of osteogenesis imperfecta are caused by primary defects in type I collagen, whereas autosomal recessive forms are caused by deficiency of proteins which interact with type I procollagen for post-translational modification and/or folding. Factors that contribute to the mechanism of dominant osteogenesis imperfecta include intracellular stress, disruption of interactions between collagen and noncollagenous proteins, compromised matrix structure, abnormal cell-cell and cell-matrix interactions and tissue mineralization. Recessive osteogenesis imperfecta is caused by deficiency of any of the three components of the collagen prolyl 3-hydroxylation complex. Absence of 3-hydroxylation is associated with increased modification of the collagen helix, consistent with delayed collagen folding. Other causes of recessive osteogenesis imperfecta include deficiency of the collagen chaperones FKBP10 or Serpin H1. Murine models are crucial to uncovering the common pathways in dominant and recessive osteogenesis imperfecta bone dysplasia. Clinical management of osteogenesis imperfecta is multidisciplinary, encompassing substantial progress in physical rehabilitation and surgical procedures, management of hearing, dental and pulmonary abnormalities, as well as drugs, such as bisphosphonates and recombinant human growth hormone. Novel treatments using cell therapy or new drug regimens hold promise for the future. PMID- 21670764 TI - Parkinson disease: protein-based stem cells generate healthy dopamine neurons. PMID- 21670766 TI - How to make better use of thrombolytic therapy in acute ischemic stroke. AB - Around 15 years have now elapsed since thrombolysis was first shown to be effective for treating acute ischemic stroke, but therapeutic uptake has been modest. As outlined in this Review, research efforts are being directed towards rectifying this situation in a number of ways. First, strategies to enhance thrombolytic efficacy are being tested; these include intravenous and intra arterial bridging protocols, sonothrombolysis, and the use of alternative thrombolytic agents. Second, means of extending the 4.5-h therapeutic time window up to 6 h, or even up to 9 h in patients selected on the basis of imaging, are being investigated in clinical trials. Prolongation of the time window using neuroprotection to 'freeze' penumbral tissue is also being attempted. Third, attempts are underway to reduce the risk of symptomatic intracerebral hemorrhage (currently affecting about 7% of cases) by refining imaging selection criteria, and through the use of alternative thrombolytic agents, lower doses of tissue plasminogen activator, blood-based biomarkers, and neuroprotectants. Last, in an effort to include more people within the currently accepted therapeutic time window, improvements in prehospital management strategies are being introduced. Elimination of prehospital and in-hospital delays is an urgent priority. PMID- 21670767 TI - The epidemiology of early inflammatory arthritis. AB - Various early arthritis clinics have provided extensive data on presentation, disease course and outcomes of early inflammatory arthritis (EIA). The present Review summarizes the epidemiological data from these early arthritis cohorts (EACs), which provide information about the frequency of, risk factors for, and outcomes of EIA and undifferentiated arthritis (UA). The studies demonstrate the large variation in selection criteria and outcome definitions in EACs, which demands careful interpretation of the results. The annual incidence of EIA ranges from 115 to 271 per 100,000 adults, and the incidence of UA ranges from 41 to 149 per 100,000 adults. Depending on the selection criteria used by the specific EACs, 13-54% of patients with UA will develop rheumatoid arthritis (RA) and in 21 87% UA will persist. Epidemiological data from the various EACs has enabled the development of prediction models for persistent and erosive arthritis. These data formed the basis of new classification criteria developed in 2010, which could enable earlier diagnosis and treatment. Future clinical research should focus on the role of imaging techniques in the early detection of synovitis and on the effect of early treatment on the outcomes of EIA. PMID- 21670768 TI - Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. AB - Bone remodeling consists of two phases--bone resorption and bone formation--that are normally balanced. When bone resorption exceeds bone formation, pathologic processes, such as osteoporosis, can result. Cathepsin K is a member of the papain family of cysteine proteases that is highly expressed by activated osteoclasts. Cathepsin K readily degrades type I collagen, the major component of the organic bone matrix. With such a major role in the initial process of bone resorption, cathepsin K has become a therapeutic target in osteoporosis. The antiresorptive properties of cathepsin K inhibitors have been studied in phase I and phase II clinical trials. Phase III studies are currently underway for odanacatib, a selective cathepsin K inhibitor. PMID- 21670769 TI - Autoimmunity: Does autoantigen complementarity underlie PR3-ANCA AAV? PMID- 21670770 TI - Randomized comparison of three palliative regimens including brachytherapy, photodynamic therapy, and APC in patients with malignant dysphagia (CONSORT 1a) (Revised II). AB - OBJECTIVES: Because most esophageal cancers are diagnosed at an advanced stage, a majority of patients require palliative dysphagia treatment. Dysphagia severity and the need for repeated re-canalization procedures significantly affect patients' quality of life (QoL). The aim of this study was to establish whether combining argon plasma coagulation (APC) of the neoplastic esophageal tissue with another re-canalization method results in a longer dysphagia-free period compared with APC alone. METHODS: We conducted a randomized trial in 93 patients with malignant dysphagia. Patients were followed until death. We compared three regimens of esophageal re-canalization; APC combined with high dose rate (HDR) brachytherapy, APC combined with photodynamic therapy (PDT), and APC alone. The primary outcome measure was the dysphagia-free period following randomization. Secondary measures were survival, QoL, treatment-associated complications, and treatment tolerance. A per-protocol analysis was carried out. RESULTS: The time to first dysphagia recurrence was significantly different between each combination treatment group and the control group (overall test: P=0.006; HDR vs. control, log-rank P=0.002, PDT vs. control, log-rank P=0.036), but not different between the combination groups (HDR vs. PDT, log-rank P=0.36). The median time to first dysphagia recurrence was 88, 59, and 35 days in the HDR, PDT, and control groups, respectively. There was no difference in overall survival between the study groups (P=0.27). No deaths, perforations, hemorrhages, or fistula formations were attributed to treatment. The only major complication was fever, occurring in three PDT patients. Minor complications were observed significantly more often in the combination treatment groups and included pain in both groups, transient dysphagia worsening, and skin sensitivity in the PDT group. The QoL 30 days after treatment in the HDR group was significantly better than in the other groups. CONCLUSIONS: In patients with inoperable esophageal cancer, palliative combination treatment of dysphagia with APC and HDR or PDT was significantly more efficient than APC alone, and was safe and well tolerated. APC combined with HDR resulted in fewer complications and better QoL than APC with PDT or APC alone (CONSORT 1b). PMID- 21670771 TI - Elevated levels of neutrophil gelatinase-associated lipocalin in bile from patients with malignant pancreatobiliary disease. AB - OBJECTIVES: Accurate differentiation between benign and malignant causes of biliary obstruction remains challenging and reliable biomarkers are urgently needed. Bile is a potential source of such biomarkers. Our aim was to apply a proteomic approach to identify a potential biomarker in bile that differentiates between malignant and benign disease, and to assess its diagnostic accuracy. Neutrophil gelatinase-associated lipocalin (NGAL) is multi-functional protein, released from activated neutrophils, with roles in inflammation, immune function, and carcinogenesis. It has not previously been described in bile. METHODS: Bile, urine, and serum were collected prospectively from 38 patients undergoing endoscopic retrograde cholangiopancreatography ("discovery" cohort); 22 had benign and 16 had malignant pancreatobiliary disease. Initially, label-free proteomics and immunoblotting were performed in samples from a subset of these patients. Enzyme-linked immunosorbent assay was then performed for NGAL as a potential biomarker on all samples in this cohort. The diagnostic performance of biliary NGAL was then validated in a second, independent group ("validation" cohort) of 21 patients with pancreatobiliary disease (benign n=14, malignant n=7). RESULTS: NGAL levels were significantly raised in bile from the malignant disease group, compared with bile from the benign disease group in the discovery cohort (median 1,556 vs. 480 ng/ml, P=0.007). Biliary NGAL levels had a receiver operating characteristic area under curve of 0.76, sensitivity 94%, specificity 55%, positive predictive value 60%, and negative predictive value 92% for distinguishing malignant from benign causes. Biliary NGAL was independent of serum biochemistry and carbohydrate antigen 19-9 (CA 19-9) in differentiating between underlying benign and malignant disease. No significant differences in serum and urine NGAL levels were found between benign and malignant disease. Combining biliary NGAL and serum CA 19-9 improved diagnostic accuracy for malignancy (sensitivity 85%, specificity 82%, positive predictive value 79%, and negative predictive value 87%). The diagnostic accuracy of biliary NGAL was confirmed in the second independent validation cohort. CONCLUSIONS: NGAL in bile is a novel potential biomarker to help distinguish benign from malignant biliary obstruction. PMID- 21670772 TI - Importance of host genetic factors HLA and IL28B as predictors of response to pegylated interferon and ribavirin. AB - OBJECTIVES: Viral factors are considered the best predictors of response to treatment for chronic hepatitis C (CHC), but genetic factors are known to have an important role in this respect. This paper investigates the relationships among the host genetic factors HLA and IL28B, viral factors, and the outcome of combination therapy. METHODS: A multicenter retrospective cohort of 428 previously untreated CHC patients was treated with pegylated interferon/ribavirin (pegIFN/RBV) for 48 weeks. In all, 378 (88%) of these patients were genotype 1 or 4, and 50 (12%) were genotype 2 or 3. RESULTS: Multivariate logistic regression showed the rs12979860 CC genotype (adjusted odds ratio (aOR)=4.3, 95% confidence interval (95% CI): 2.6-7), the HLA-DQB1*0301 allele (aOR=2.08, 95% CI: 1.2-3.5) and age, viral genotype, and viral load levels to be significantly associated with sustained virological response (SVR). When the variable rs12979860 was eliminated, the area under the receiver operating characteristic (ROC) curve (AUC) decreased significantly (0.76 vs. 0.69; P=0.03). AUC values derived from viral factors were lower than those corresponding to host genetic factors (0.67 vs. 0.72, respectively; P=0.04). The HLA-DQB1*0301 and A*0201 alleles were associated with rs12979860 CC genotype and SVR (P<0.0001). CONCLUSIONS: The HLA DQB1*0301 allele and IL28B genotype are factors that are associated independently with SVR. There is a synergism between the HLA-DQB1*0301 and HLA-A*0201 alleles with polymorphism rs12979860 CC, which increases the SVR rate. IL28B genotype is the best predictor of SVR. PMID- 21670773 TI - Impact of a population-based colorectal cancer screening program on local health services demand in Italy: a 7-year survey in a northern province. AB - OBJECTIVES: In 2005, the National Health Service recommended a population-based colorectal cancer (CRC) screening program using biennial fecal occult blood testing (FOBT), followed by total colonoscopy in positive patients. So far, no studies have been performed to evaluate the impact of a mass-screening CRC campaign on the health system services at the community level in Italy. We have therefore assessed the workload generated by the first two biennial rounds of screening program on the activity of hospital services involved in CRC diagnosis in the Lecco province. METHODS: Routine data from all hospital services of our province were collected on activity levels related to CRC diagnosis from January 2003 to December 2009. This time span covered the 2 years prior to, as well as the two biennial rounds of the CRC screening program. In particular, we focused on the volume of outpatient FOBTs and colonoscopies (both diagnostic and interventional) performed among subjects outside the screening program. Joinpoint models were used to test whether an apparent change in trend of examination over time was statistically significant in different age cohorts of the population (<50 years, 50-69 years, and >=70 years). RESULTS: The volume of "extra screening" per-patient/FOBTs and colonoscopies increased significantly over the evaluated periods in all ages, until year 2008, when a steady trend was beginning; the AAPCs (average of the annual percent changes) values were 5.7, 3.1, and 8.4 for FOBT and 14.6, 13.4, and 16.7 for colonoscopy in the three age cohorts, respectively. However, the increase in both FOBT and colonoscopy demand was maximal in the cohort >=70 years, where three statistically significant annual percent changes (APCs) were identified (in 2003-2005, 2005-2006, and 2006 2007 APCs were 12.3, 14.9, and 15.9 for FOBT, and 18.7, 36.8, and 25.4 for colonoscopy, respectively). CONCLUSIONS: After the implementation of a FOBT-based mass-screening program for CRC, careful consideration must be given to the significant increase in the workload of hospital services involved in CRC diagnosis, outside the screening campaign. The extra-work mainly involves gastroenterologists performing colonoscopy, whose activity increased over the 5 year period by 118%, as well as laboratory services, where the demand of FOBTs rose by 40%. This phenomenon, mainly attributable to a profound change in the attitude toward CRC screening by those age cohorts outside the program, covers a time span of two full rounds of screening, whereupon a steady trend for colonoscopy is apparent. PMID- 21670774 TI - Prevalence of chronic bronchitis and tobacco smoking in some rural communities in Ekiti state, Nigeria. AB - AIMS AND OBJECTIVES: The objective of this study was to determine the prevalence of chronic bronchitis (CB) and its association with sociodemographic factors and tobacco smoking in some rural communities in Ekiti state, Nigeria. SUBJECTS AND METHODS: This is a cross sectional study among adults aged e" 35 years in the three selected rural communities in Ekiti state, South West, Nigeria from January 2009 to March 2009.The subjects were selected by multistage cluster sampling method. The European Coal and Steel Community (ECSC) questionnaire was adapted and administered by trained health workers to obtain sociodemographic information, respiratory symptoms, history of tobacco smoking, occupational exposure to dust and housing. RESULTS: Of the 391 subjects that participated in the study, 135(34.5%) were males and 256(65.5%) were females; the mean age of the subjects was 55.5 +/- 10.2 year. Twenty two subjects (5.6%) met the case definition of CB. Nine (6.7%) of the 22 were males and 13(5.1%) were female. None of the current smokers had CB, while 36.4% of those with CB were former smokers. The multivariate logistic regression analysis showed that aged 65-74 (OR= 9.66, 95% C.I 3.43-27.20), aged e"75 years (OR= 3.88, 95% C.I 1.08-13.98) and tobacco smoking (OR= 6.37 95% C.I 2.12-19.14) had the strongest association with CB. Poor housing (OR=1.80; 95% C.I 0.56-6.51), occupational exposure to organic and inorganic dust (OR= 1.74; 95% C.I 0.67-4.60) and Low socioeconomic status (OR=1.72; 95% C.I 0.29-10.88) were also independently associated with CB. Sex and level of education were not associated with CB. CONCLUSION: The prevalence of chronic bronchitis in this study was 5.6% and is comparable to previous studies worldwide. Apart from old age which is not modifiable, other associated factors with CB like tobacco smoking, low socioeconomic status, poor housing and exposure to dusts can be modified to prevent the disease. PMID- 21670775 TI - Prostate diseases in Lagos, Nigeria: a histologic study with tPSA correlation. AB - OBJECTIVE: To present a 10year retrospective histologic study of prostate diseases in Lagos, Nigeria. The aim is to document the prevalence, histologic pattern, age distribution and PSA values of prostatic diseases. MATERIALS AND METHODS: The materials consisted of slides, paraffin embedded tissue blocks, patients case files and histology request forms of all prostatic biopsies received at the Morbid Anatomy department of Lagos University Teaching Hospital Idi-Araba, Lagos from 1999 to 2008. Each sample represents a different patient. RESULTS: Prostatic biopsies comprised 3.6 % of all biopsies in LUTH. BPH was the commonest prostatic lesion and accounted for 70.9% of all cases. The age range was 40 to 94 years with a mean of 67 years and a peak age group at 60-69 years. Stromoglandular pattern was the most common histological type of BPH accounting for 72.2 %( 393) of the cases. Malignant tumours constituted 28.9% of all prostatic biopsies. Most (93.7%) of these malignancies were seen in trucut biopsies. Adenocarcinoma accounted for 99.1% of the total 222 malignant tumours. It showed an age range of 40 to 98 years, a mean age of 66 years and peak prevalence in the 60-69 year age group. Gleason score nine was the most frequent (16.8%) in occurrence. Most adenocarcinomas were poorly differentiated (40%). Incidental carcinoma was seen in 4.2% of prostatectomy samples. High grade PIN was seen in 19.1% of adenocarcinoma cases. The most common inflammatory lesion was chronic non-specific prostatitis accounting for 76.4% of all inflammatory lesions. Malignant and benign lesions were accountable for PSA levels of 1 to 49.9ng/ml while values of 50ng/ml and above were seen exclusively in malignant lesions. CONCLUSION: Prostatic lesions constitute a significant source of morbidity among adult males in Lagos. Adenocarcinoma is the commonest histologic subtype of prostatic cancer and most are of poorly differentiated variety. Elevated levels of tPSA in Nigerian males may be as a result prostate cancer, BPH or BPH with prostatitis. PSA should in our opinion be used as a component of a strategy integrating multiple diagnostic approaches for prostate cancer screening and not to be used alone in our environment. PMID- 21670777 TI - Effect of the aqueous extract of entandrophragma utile bark on gastric acid secretion in ghosh and schild rat preparations. AB - AIMS AND OBJECTIVES: The reduction of aggressive factors such as gastric acid is considered a key target of gastrointestinal protection. We investigated the antisecretory effect of the aqueous bark extract of E. utile, a Nigerian traditional medicinal preparation used for ulcers. METHODS: Male rats were anesthetized and cannulated for intragastric perfusion of saline and test agents as well as for infusion of histamine into the jugular vein. Gastric effluents were collected every 30 min and 10 ml aliquots were titrated against 0.01 N NaOH using phenol red indicator. Gastric acidity was deduced from titre values. Histamine in saline was infused for 2 h at a rate of 1 x 10(-4) g kg-1 min -1 to stimulate acid secretion. In one set of animals, cimetidine in saline was simultaneously perfused intragastrically for 2 h at the rate of 2.5 x 10(-3) g kg(-1) h(-1). Similarly, rats in other sets were simultaneously perfused intragastrically with either the aqueous fresh bark extract of E.utile or the decolorized extract for 2 h at a rate of 1.5 x 10(-3) g kg(-1) h(-1). The extract was also perfused in rats that had established peak gastric acid output with prior infusion of histamine. RESULTS: Mean basal acid output per 0.5 h was 20.2 +/- 1.9 mEq. Peak measurement fluctuated within a range of 114 - 117 mEq 0.5h(-1) and was maintained for more than 5 h. Cimetidine or E. utile prevented the rise to peak output that histamine produces. Using the 2-tailed paired t-test, the inhibitory effects of either cimetidine or E. utile was significant (p<0.05) at 60 min. E. utile significantly caused greater inhibition of histamine stimulated gastric acid output than cimetidine at 120 min (p<0.05). When the extract was given after establishment of peak output, the gastric acidity dramatically fell to below the basal level. CONCLUSION: The aqueous bark extract of E. utile contains one or more active component(s) that can be developed as antisecretory medication for hypersecretory states or for protection of the compromised gastrointestinal mucosa. PMID- 21670776 TI - Prophylaxis versus pre-emptive antibiotics in third molar surgery: a randomised control study. AB - OBJECTIVES: This study was carried out to compare the efficacy of preoperative single bolus antibiotics with a 5 day- postoperative antibiotic regimen in reducing pain, swelling, and trismus, surgical site infection (SSI) and alveolar osteitis (AO) after third molar surgery. PATIENTS AND METHODS: A randomised experiment was done involving eighty-four patients. The patients were divided into two groups consisting of 42 patients each. A preoperative group was given an oral bolus of 2g amoxycillin capsules and 1g metronidazole tablets one hour before extraction, while those in the postoperative group were given a five-day regimen oral 500mg amoxycillin capsules thrice daily and 400mg metronidazole tablets thrice daily. The occurrence of postoperative pain, swelling, trismus, SSI and AO were compared between the groups. RESULTS: Seventy-nine patients completed the study; 38 patients in the preoperative group and 41 patients in the postoperative group. There was no difference between the groups in respect of the inflammatory complications. The four cases of AO occurred in the preoperative group. CONCLUSION: Single bolus antibiotic prophylaxis should be adequate for most cases of third molar surgery as the degree of degree of postoperative pain, swelling and trismus was similar in both groups. The use of single bolus antibiotic prophylaxis would also help reduce the cost of treatment in developing countries as well as reduce the risk of development of resistant strains. However, a five-day postoperative antibiotic regimen is advised in patient with risk factors for AO. PMID- 21670778 TI - Observations on early and delayed colostomy closure. AB - BACKGROUND: Traditional treatment of a variety of colorectal pathologies had included a diverting colostomy that was closed eight or more weeks later during a readmission. AIMS AND OBJECTIVES: The aim of this retrospective study was to determine the outcomes of early colostomy closure and delayed colostomy closure in patients with temporary colostomies following traumatic and non-traumatic colorectal pathologies. In this study early colostomy closure was the closure of a colostomy within three weeks of its construction, while delayed colostomy closure referred to closure after 3 weeks. PATIENTS AND METHODS: Complete records of the 37 adult patients who had temporary colostomy constructed and closed between Jan. 1997 December 2003 for various colorectal pathologies were studied. RESULTS: Fourteen patients had early colostomy closure while 23 had delayed closure. In the early colostomy closure group there were 10 men and 4 women. The mean age of the patients was 28yr with a range of 18-65yr. Colostomies were closed 9-18 days after initial colostomy construction. There was no mortality. Morbidity rate 28.6% (4 out of 14). There were two faecal fistulas (14.3%). Twenty-three patients had delayed colostomy closure 8 weeks to 18 months after initial colostomy construction. These were patients unfit for early surgery after initial colostomy construction because of carcinoma, significant weight loss, or sepsis. There was no mortality. Morbidity rate was 26.1%. There were 3 faecal fistulas (13.2%). CONCLUSION: Outcomes following early colostomy closure and delayed closure were comparable. Patients fit for surgery should have early closure whilst patients who may have compromised health should have delayed closure. PMID- 21670779 TI - Knowledge and Attitude of PLWHA concerning oral lesions of HIV/AIDS among patients of PEPFAR clinic in Lagos University Teaching Hospital (LUTH) Lagos, Nigeria. AB - INTRODUCTION: Oral manifestations in Human Immunodeficiency virus/Acquired Immunodeficiency Disease Syndrome (HIV/AIDS) are associated with adverse effects on quality of life such as pain, difficulty in eating, bad breath, altered taste and sometimes altered appearance. There is also a predisposition to poor nutrition which confers an additional burden on the body's immune defences and the ability to fight off infections. Knowledge of the oral lesions will enable People Living with HIV/AIDS (PLWA) to seek dental treatment on time. AIMS AND OBJECTIVES: To assess the general knowledge of HIV/AIDS, its oral manifestations and willingness to know more about its oral lesions among people living with HIV/AIDS (PLWHA) in Lagos, Nigeria. PATIENTS AND METHODS: A structured questionnaire was administered to two hundred and thirty-five patients (235) who were randomly selected from attendees at an NGO clinic supporting PLWHA in Lagos. RESULTS: Majority of the participants exhibited poor knowledge of the oral manifestations of HIV/AIDS although many of them had fair knowledge of the general symptoms of HIV/AIDS. The high educational status of the subjects seemed to play little role in awareness of oral manifestations in HIV/AIDS as only 45(21.4%) of the participants had good overall knowledge having a range of 25-31 correct answers out of 210 participants. Many of the respondents (145, 69%) wish to know more about oral lesion of HIV/AIDS. CONCLUSION: Although there is a high awareness of the general symptoms of HIV/AIDS in the study group, there is poor awareness of the oral manifestations, their presentations and management. The study also showed that PLWHA would be willing to know more about the oral manifestations of HIV/AIDS and seek dental care for their management. PMID- 21670780 TI - Symphysiotomy- a dying art: the experience at Federal Medical Centre Umuahia Nigeria. AB - AIMS AND OBJECTIVES: To review the indications, outcome and complications of symphysiotomy done in Federal Medical Centre Umuahia during the study period. PATIENTS AND METHODS: This study is a 5-year review of all women who had symphysiotomy at Federal Medical Centre Umuahia. The total number of the procedure performed, and all the deliveries conducted at the hospital in the study period were obtained from the labour ward register. The case notes of the patients were then retrieved and their biodata and other relevant information were obtained and summarized in frequency tables and percentages. RESULTS: Ten (10) symphysiotomies were performed among 3702 deliveries conducted during the period under review giving a rate of 0.27%. Seventy per cent of the patients were aged 30 years and below, mean age was 26 (+/- SD4.9) years. Most of the patients were multiparous women, only one was grandmultiparous. All were for mild to moderate cephalopelvic disproportion (CPD). In one particular case, the patient also presented with retained second twin. They were all unbooked patients. Main complication was pelvic and leg pain but there were two cases of vesicovaginal fistula which may be a complication of obstructed labour since leakage of urine did not start immediately after the procedure. The birth weight of the babies ranged from 3kg to 4.2kg. There was no maternal mortality but two fresh stillbirths were recorded giving a perinatal mortality rate of 200 per 1000 total births. CONCLUSION: Symphysiotomy if done by a trained person, in well selected patients is still safe and can be life saving in environments where caesarean delivery is not well accepted and late presentation is common. PMID- 21670781 TI - Bacterial isolates in blood cultures of children with suspected septicaemia in Kano: a two-year study. AB - AIMS AND OBJECTIVE: Septicaemia is a common condition in children with a resultant high morbidity and mortality. The gold standard for diagnosis of septicaemia is the isolation of bacterial agents from blood cultures. The study was done to determine the common aetiology of septicaemia in children and their antibiotic susceptibility pattern in Kano, Nigeria. MATERIALS AND METHODS: A retrospective study with a review of blood culture reports of paediatric patients aged 0-15 years, suspected of septicaemia, from October 2006 to October 2008 in the Medical Microbiology department of Aminu Kano Teaching Hospital Kano. Kano. Nigeria was carried out. RESULTS: Out of a total of 3840 blood culture samples, only 18.2% (n=700) was culture positive. Gram-negative and gram - positive bacteria constituted 69.3% (n=2661) and 30.7% (n=1179) respectively. The most prevalent bacterial isolates were Escherichia coli with 44.3% (n=310/700) and Staphylococcus aureus 30.7% (n=215/700). Escherichia coli were sensitive to ceftriaxone, ciprofloxacin, gentamicin and clavulinate - amoxyl. CONCLUSION: The commonest bacterial isolate from blood culture of children with suspected septicaemia in Kano is Escherichia coli. The most sensitive and preferable among the tested antibiotics is ceftriaxone. Rational use of antibiotics with regular antibiotic susceptibility surveillance studies is recommended to maintain high antibiotic therapeutic profile. PMID- 21670782 TI - Bowel preparation for colonoscopy: enema versus sodium phosphate. AB - BACKGROUND: Colonoscopy is considered to be the gold standard investigation for assessing the colonic mucosa. Good bowel preparation is essential in order to achieve optimal visualisation of the mucosa. Traditionally water enema is used for bowel preparation in most centres in Nigeria. This prospective study was performed at the Gastrointestinal Endoscopy Unit of Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria between July 2008 and June 2009. AIMS AND OBJECTIVES: This study compared patients' tolerability, adverse effects, efficacy and mean duration of colonoscopy of water enema and sodium phosphate (NaP) for bowel preparation toward colonoscopy. PATIENTS AND METHODS: Standard structured questionnaire was completed by 64 patients and the colonoscopist assessing tolerability, adverse effect, efficacy and mean duration of the procedure. RESULTS: There were sixty four patients aged between 22 to 86 years. The mean age was 58.16 +/- 15.790. Thirty eight (59.4%) patients were in patients and 26 (40.6%) were out patients. Forty one (64.1%) patients had water enema while 23 (35.9%) patients were included in the NaP group. The median age for patients in both groups was 62.0 years. Patients in NaP group rated their bowel preparation as more tolerable and found the dietary restriction much easier than those in water enema group (p < 0.0001). Better colon cleansing score was found in patient in NaP group as compared with those in water enema group in all region of the colon. The procedure took significantly longer time in patients in water enema group as compared with those in NaP group (p < 0.0001). CONCLUSION: NaP has a better bowel cleansing score for colonoscopy than water. It has better tolerability, side effect profile, efficacy and gives a shorter mean duration for the procedure. PMID- 21670783 TI - Awareness and practice of safety precautions among healthcare workers in the laboratories of two public health facilities in Nigeria. AB - AIMS AND OBJECTIVES: To determine the level of awareness and practice of SP among laboratory workers at two tertiary public health facilities in Nigeria. METHODS: A semi-structured, self-administered questionnaire was used to assess the awareness, attitude and adherence to SP among laboratory workers. Information on the availability of safety equipment was also sought. The laboratory safety practice of respondents was assessed based on self-reported observance of basic principles of universal precautions in clinical settings. RESULTS: Study participants were 130, mean age: 28.2 years (SD+/-6.6), number of years in hospital employment: 3.7 years (SD+/-2.4) and the male to female ratio was 1.8:1. Many (41.5%) were unaware and 25.4% do not observe SP. Participants attest to availability of various safety devices and equipment including hand gloves (86.2%), disinfectants (84.6%), HBV immunisation (46.2%) and post exposure prophylaxis (PEP) for HIV and HBV (79.6%). Attitude to safety is unsatisfactory as 60.0% eat and drink in the laboratory, 50.8% recap needles and 56.9% use sharps box. Even though 83.1% are willing to take PEP, only 1.5% will present self following laboratory injury. CONCLUSION: This study shows the deficit in the awareness of SP among laboratory personnel and demonstrates that attitude and practice of safety rules are unsatisfactory. Training and re-training on SP is therefore desired. Counselling to induce a positive attitudinal change on HBV immunisation and PEP is similarly necessary. PMID- 21670784 TI - Stroke mimics which complicate the clinical management of 'stroke patients'. AB - Not all patients presenting as 'stroke patients' have cerebrovascular disease, as some conditions mimic stroke clinically. A significant degree of misdiagnosis of stroke has been documented. Clinical presentation of patients with stroke mimics can confound emergency care physicians and lead to significant morbidity and mortality for the patient, if unrecognised. We highlight some conditions that can mimic stroke emphasising ways in which these stroke mimics can be differentiated from stroke. Correct identification and management of these conditions can reduce morbidity and mortality in 'stroke patients. PMID- 21670785 TI - An overview of cleft care in Nigeria. AB - This is an overview of the present state of cleft lip and palate care in Nigeria. The aim is to stimulate further discussions on the need to improve standard of care and quality of life in patients with cleft lip and palate deformities. The number of cleft surgeries and surgeons involved in cleft repairs across Nigeria is increasing due to availability of free treatment grants provided by non governmental organisation; therefore, it has become imperative to assess the quality of surgery and quality of cleft care. It is expected that as the number of repaired cleft lip/palate increases, more patients will require secondary repair, speech therapy, and orthodontics therapy and orthognathic surgery. The following recommendations are made to improve the standard of cleft care in Nigeria: establishment of multidisciplinary team approach, formulation of policy on quality control, establishment of fellowship training in cleft care and establishment of regional specialised cleft care centre. PMID- 21670786 TI - Migrating foreign body in the tracheobronchial tree of childen: report of two cases. AB - Tracheobronchial foreign bodies (FBs) especially in infants and children can cause respiratory obstruction and can lead to death if intervention is delayed. Two cases of migrating FBs in the tracheobronchial (T-b) tree with fatal outcome are reported: Case 1 was an 11-year-old girl with a ten-week history of episodes of fever, cough, breathlessness and progressive weight loss. No positive history of FB aspiration. She was cachetic and febrile with short attention span, dyspnoeic, a flattened left upper hemithorax, mediastinal shift and evidence of atelectasis. Case 2, a 5-year-old girl with a three-month history of aspiration of a tiny toy. She developed fever, cough and marked weight loss, developed severe respiratory distress three days prior to presentation. She was febrile, had grade II finger clubbing, markedly dyspnoeic, left mediastinal shift, and evidence of left sided atelectasis. X-ray films in Case 1 showed evidence of FB at various locations in the T-b tree, and complete opacification and atelectasis of left hemithorax in Case 2. Planned bronchoscopy could not be done as both patients were adjudged to be too severely ill for the procedure. Both patients died after 9 days and 8 hours of hospital stay, respectively. Postmortem revealed FB in right main bronchus in both patients (tooth and toy, respectively) and evidence of tuberculosis in Case 2. Fatal outcome is attributed to inappropriate healthcare seeking behaviour, lack of medical expertise and material resources in our health facilities. PMID- 21670788 TI - E-infrastructure technologies triggering of Bioinformatics development. PMID- 21670787 TI - Non puerperal uterine inversion due to submucous fibroid: a case report. AB - An unusual case of non-puerperal uterine inversion is presented. The patient, a 37 year old multipara who had been earlier diagnosed with uterine fibroids, subsequently developed a protrusion from the vagina having declined surgery. The mass had become necrotic and infected at the time of presentation. Uterine inversion was diagnosed clinically and further confirmed at surgery where a vaginal hysterectomy was carried out. Uterine inversion is a rare condition not encountered by most gynaecologists. Diagnosis and treatment could thus be challenging. The literature on non-puerperal uterine inversion regarding the evaluation and management is reviewed. PMID- 21670789 TI - Mining for single nucleotide polymorphisms and insertions / deletions in expressed sequence tag libraries of oil palm. AB - The oil palm is a tropical oil bearing tree. Recently EST-derived SNPs and SSRs are a free by-product of the currently expanding EST (Expressed Sequence Tag) data bases. The development of high-throughput methods for the detection of SNPs (Single Nucleotide Polymorphism) and small indels (insertion / deletion) has led to a revolution in their use as molecular markers. Available (5452) Oil palm EST sequences were mined from dbEST of NCBI. CAP3 program was used to assemble EST sequences into contigs. Candidate SNPs and Indel polymorphisms were detected using the perl script auto_snip version 1.0 which has used 576 ESTs for detecting SNPs and Indel sites. We found 1180 SNP sites and 137 indel polymorphisms with frequency 1.36 SNPs / 100 bp. Among the six tissues from which the EST libraries had been generated, mesocarp had high frequency of 2.91 SNPs and indels per 100 bp whereas the zygotic embryos had lowest frequency of 0.15 per 100 bp. We also used the Shannon index to analyze the proportion of ten possible types of SNP/indels. ESTs from tissues of normal apex showed highest values of Shannon index (0.60) whereas abnormal apex had least value (0.02). The present report deals the use of Shannon index for comparing SNP/ indel frequencies mined from ESTlibraries and also confirm that the frequency of SNP occurrence in oil palm to use them as markers for genetic studies. PMID- 21670790 TI - Integrating information from existing databases for enhanced function annotation of genes, genomes and networks. AB - Uncovering functional associations for genes and gene products remains one of the most significant challenges in biology. The classical approaches, such as homology detection, are mainly suited for predicting approximate molecular function of a protein and should be used in context with other methods. Several studies have emerged that employ knowledge-based procedures to extract functional data for genes from a variety of biological sources. However, data derived from a single biological resource often provides only a limited perspective on their functional associations largely due to systematic bias in the underlying data. The post-genomic era has witnessed the emergence of knowledge-based studies that aim to decipher functional associations by combining several biological evidence types. These are expected to provide better insights into the functional aspects of diverse genes, genomes and networks. PMID- 21670791 TI - Towards reconstructing a metabolic tree of life. AB - Using information from several metabolic databases, we have built our own metabolic database containing 434 pathways and 1157 different enzymes. We have used this information to construct a dendrogram that demonstrates the metabolic similarities between 282 species. The resulting species distribution and the clusters defined in the tree show a certain taxonomic congruence, especially in recent relationships between species. This dendrogram is another representation of the tree of life, based on metabolism that may complement the trees constructed by other methods. For example, the metabolic dissimilarity we demonstrate between Symbiobacterium thermophilum (previously defined as Actinobacteria) and the other Actinobacteria species, and the metabolic similarity between S. thermophilum and Clostridia, combined with other evidence, suggest that S. thermophilum may be re-classified as Firmicutes, Clostridia. PMID- 21670792 TI - Comparative sequence analysis of acid sensitive/resistance proteins in Escherichia coli and Shigella flexneri. AB - The molecular basis for the survival of bacteria under extreme conditions in which growth is inhibited is a question of great current interest. A preliminary study was carried out to determine residue pattern conservation among the antiporters of enteric bacteria, responsible for extreme acid sensitivity especially in Escherichia coli and Shigella flexneri. Here we found the molecular evidence that proved the relationship between E. coli and S. flexneri. Multiple sequence alignment of the gadC coded acid sensitive antiporter showed many conserved residue patterns at regular intervals at the N-terminal region. It was observed that as the alignment approaches towards the C-terminal, the number of conserved residues decreases, indicating that the N-terminal region of this protein has much active role when compared to the carboxyl terminal. The motif, FHLVFFLLLGG, is well conserved within the entire gadC coded protein at the amino terminal. The motif is also partially conserved among other antiporters (which are not coded by gadC) but involved in acid sensitive/resistance mechanism. Phylogenetic cluster analysis proves the relationship of Escherichia coli and Shigella flexneri. The gadC coded proteins are converged as a clade and diverged from other antiporters belongs to the amino acid-polyamine-organocation (APC) superfamily. PMID- 21670793 TI - Database of neurodegenerative disorders. AB - A neurological disorder is a disorder caused by the deterioration of certain nerve cells called neurons. Changes in these cells cause them to function abnormally, eventually bringing about their death. In this paper we present a comprehensive database for neurodegenerative diseases, a first-of-its kind covering all known or suspected genes, proteins, pathways related to neurodegenerative diseases. This dynamically compiled database allows researchers to link neurological disorders to the candidate genes & proteins. It serves as a tool to navigate potential gene-protein-pathway relationships in the context of neurodegenerative diseases. The neurodegenerative disorder database covers more then 100 disease concepts including synonyms and research topics. The current version of the database provides links to 728 abstracts and over 203 unique genes/proteins with 137 drugs. Also it is integrated well with other related databases. The aim of this database is to provide the researcher with a quick overview of potential links between genes and proteins with related neurodegenerative diseases. Thus DND providing a user-friendly interface is designed as a source to enhance research on neurodegenerative disorders. AVAILABILITY: http://www.bioinfosastra.com/services/dnd/dnd.html. PMID- 21670794 TI - Alternative splicing: a paradoxical qudo in eukaryotic genomes. AB - One of the most remarkable observations stemming from the sequencing of genomes of diverse species is that the number of protein-coding genes in an organism does not correlate with its overall cellular complexity. Alternative splicing, a key mechanism for generating protein complexity, has been suggested as one of the major explanation for this discrepancy between the number of genes and genome complexity. Determining the extent and importance of alternative splicing required the confluence of critical advances in data acquisition, improved understanding of biological processes and the development of fast and accurate computational analysis tools. Although many model organisms have now been completely sequenced, we are still very far from understanding the exact frequency of alternative splicing from these sequenced genomes.This paper will highlight some recent progress and future challenges for functional genomics and bioinformatics in this rapidly developing area. PMID- 21670795 TI - Insilco analysis of functionally important residues in folate receptors. AB - Lack of crystal structure data of folate binding proteins has left so many questions unanswered (for example, important residues in active site, binding domain, important amino acid residues involved in interactions between ligand and receptor). With sequence alignment and PROSITE motif identification, we attempted to answer evolutionarily significant residues that are of functional importance for ligand binding and that form catalytic sites. We have analyzed 46 different FRs and FBP sequences of various organisms obtained from Genbank. Multiple sequence alignment identified 44 highly conserved identical amino acid residues with 10 cysteine residues and 12 motifs including ECSPNLGPW (which might help in the structural stability of FR). PMID- 21670796 TI - CliniProteus: A flexible clinical trials information management system. AB - Clinical trials involve multi-site heterogeneous data generation with complex data input-formats and forms. The data should be captured and queried in an integrated fashion to facilitate further analysis. Electronic case-report forms (eCRF) are gaining popularity since it allows capture of clinical information in a rapid manner. We have designed and developed an XML based flexible clinical trials data management framework in .NET environment that can be used for efficient design and deployment of eCRFs to efficiently collate data and analyze information from multi-site clinical trials. The main components of our system include an XML form designer, a Patient registration eForm, reusable eForms, multiple-visit data capture and consolidated reports. A unique id is used for tracking the trial, site of occurrence, the patient and the year of recruitment. AVAILABILITY: http://www.rfdn.org/bioinfo/CTMS/ctms.html. PMID- 21670797 TI - A comparison of four pair-wise sequence alignment methods. AB - Protein sequence alignment has become an essential task in modern molecular biology research. A number of alignment techniques have been documented in literature and their corresponding tools are made available as freeware and commercial software. The choice and use of these tools for sequence alignment through the complete interpretation of alignment results is often considered non trivial by end-users with limited skill in Bioinformatics algorithm development. Here, we discuss the comparison of sequence alignment techniques based on dynamic programming (N-W, S-W) and heuristics (LFASTA, BL2SEQ) for four sets of sequence data towards an educational purpose. The analysis suggests that heuristics based methods are faster than dynamic programming methods in alignment speed. PMID- 21670798 TI - Photosensitizing catalysis of the B12 complex without an additional photosensitizer. AB - A cobalamin derivative, heptamethyl cobyrinate perchlorate, was activated by UV light irradiation to form a Co(I) species in the presence of triethanolamine and used for a dechlorination reaction, and this photochemical reaction was accelerated in an ionic liquid. PMID- 21670799 TI - Stereoselective self-sorting in the self-assembly of a Phe-Phe extended guanidiniocarbonyl pyrrole carboxylate zwitterion: formation of two diastereomeric dimers with significantly different stabilities. AB - The 'dipeptide extended' guanidiniocarbonyl pyrrole carboxylate zwitterion GCP Phe-Phe 1 forms stable dimers in DMSO. However, dimerization is highly stereoselective. Only homochiral dimers are formed and the (L,L).(L,L) dimer (K(dim) > 10(5) M(-1)) is significantly more stable by a factor of 10(3) than the diastereomeric (D,L).(D,L) dimer (K(dim) = 120 M(-1)). PMID- 21670800 TI - High performance supercapacitors based on highly conductive nitrogen-doped graphene sheets. AB - Thermal nitridation of reduced graphene oxide sheets yields highly conductive (~1000-3000 S m(-1)) N-doped graphene sheets, as a result of the restoration of the graphene network by the formation of C-N bonded groups and N-doping. Even without carbon additives, supercapacitors made of the N-doped graphene electrodes can deliver remarkable energy and power when operated at higher voltages, in the range of 0-4 V. PMID- 21670801 TI - Plant volatiles: production, function and pharmacology. AB - Plant volatiles typically occur as a complex mixture of low-molecular weight lipophilic compounds derived from different biosynthetic pathways, and are seemingly produced as part of a defense strategy against biotic and abiotic stress, as well as contributing to various physiological functions of the producer organism. The biochemistry and molecular biology of plant volatiles is complex, and involves the interplay of several biochemical pathways and hundreds of genes. All plants are able to store and emit volatile organic compounds (VOCs), but the process shows remarkable genotypic variation and phenotypic plasticity. From a physiological standpoint, plant volatiles are involved in three critical processes, namely plant-plant interaction, the signaling between symbiotic organisms, and the attraction of pollinating insects. Their role in these ''housekeeping'' activities underlies agricultural applications that range from the search for sustainable methods for pest control to the production of flavors and fragrances. On the other hand, there is also growing evidence that VOCs are endowed with a range of biological activities in mammals, and that they represent a substantially under-exploited and still largely untapped source of novel drugs and drug leads. This review summarizes recent major developments in the study of biosynthesis, ecological functions and medicinal applications of plant VOCs. PMID- 21670802 TI - On-surface synthesis of cyclic organic molecules. AB - Creating or connecting together large organic molecules, as polycyclic aromatic hydrocarbons (PAH), by chemical reactions readily on surfaces is the first step to a true advance in the field of molecular electronics. On-surface synthesis can be regarded as an efficient means to build new molecular species by using bottom up strategies. Recently, a collection of different reactions leading to large tailor-made organic molecules on single-crystal metal surfaces has been reported. The fundamental mechanisms controlling these reactions can be investigated from a surface science perspective. This discipline skillfully combines the use of characterization techniques at the nanoscale, with single-crystal metallic surfaces able to catalyse these reactions. We present a tutorial review that highlights the relevance of the new bottom up strategies and classifies most of the different molecular on-surface reactions involving aromatic organic molecules that have been published up to date. PMID- 21670803 TI - The effect of neat ionic liquid on the folding of short peptides. AB - Using circular dichroism spectroscopy, we show evidence of unusual folding behaviour for several designed peptides in neat ionic liquid. Helical peptides, AKA(2) and Trp-cage, exhibit heat-induced folding, with stable helical structure persisting to 96 degrees C, whereas the beta-hairpin Trpzip4 is destabilized by the neat [C(4)mpy][Tf(2)N]. PMID- 21670804 TI - A method for the calculation of the adsorbed phase volume and pseudo-saturation pressure from adsorption isotherm data on activated carbon. AB - We propose a new method for evaluating the adsorbed phase volume during physisorption of several gases on activated carbon specimens. We treat the adsorbed phase as another equilibrium phase which satisfies the Gibbs equation and hence assume that the law of rectilinear diameters is applicable. Since invariably the bulk gas phase densities are known along measured isotherms, the constants of the adsorbed phase volume can be regressed from the experimental data. We take the Dubinin-Astakhov isotherm as the model for verifying our hypothesis since it is one of the few equations that accounts for adsorbed phase volume changes. In addition, the pseudo-saturation pressure in the supercritical region is calculated by letting the index of the temperature term in Dubinin's equation to be temperature dependent. Based on over 50 combinations of activated carbons and adsorbates (nitrogen, oxygen, argon, carbon dioxide, hydrocarbons and halocarbon refrigerants) it is observed that the proposed changes fit experimental data quite well. PMID- 21670805 TI - Designing neutral metallophilic hydrogels from di- and tripeptides. AB - Here we report the metallophilic attraction driven gel-forming capability of four cysteine-containing short peptides at neutral pH. Such peptides were designed to have an isoelectric point (pI) close to 7, aided by the introduction of an arginine unit with its highly basic guanidinium group. PMID- 21670806 TI - Synthesis of uniformly 13C-labeled polycyclic aromatic hydrocarbons. AB - Convergent synthetic pathways were devised for efficient synthesis of a series of uniformly (13)C labeled polycyclic aromatic hydrocarbons de novo from U-(13)C benzene and other simple commercially-available (13)C-starting compounds. All target products were obtained in excellent yields, including the alternant PAH U (13)C-naphthalene, U-(13)C-phenanthrene, U-(13)C-anthracene, U-(13)C benz[a]anthracene, U-(13)C-pyrene and the nonalternant PAH U-(13)C-fluoranthene. PMID- 21670807 TI - Agonist responses of (R)- and (S)-3-fluoro-gamma-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABA(C) receptors. AB - The enantiomers of 3F-GABA were evaluated on GABA(C) receptors. Both enantiomers were agonists, with the (R)-enantiomer being an order of magnitude more potent. This result is consistent with a folded binding mode for GABA, a conclusion which suggests a different binding mode to that found in the related but pharmacologically distinct GABA(A) receptors. PMID- 21670808 TI - Supramolecular organization of calix[4]pyrrole with a methyl-trialkylammonium anion exchanger leads to remarkable reversal of selectivity for sulfate extraction vs. nitrate. AB - meso-Octamethylcalix[4]pyrrole (C4P) enhances sulfate selectivity in solvent extraction by Aliquat(r) 336N, an effect ascribed to the supramolecular preorganization and thermodynamic stability imparted by insertion of the methyl group of the Aliquat cation into the cup of C4P in its cone conformation. PMID- 21670809 TI - Light induced photoreactions with plasmid DNA by Cu/Ru and Cu/Ru/Pt multi metallic porphyrins. AB - Coordination of two [Ru(bipy)(2)Cl](+) moieties (where bipy = 2,2'-bipyridine) to the pyridyl nitrogens in the 5,10-positions of meso-5,10,15-(4-Pyridyl)-20 (pentafluorophenyl)porphyrin gives the diruthenium porphyrin complex II. Insertion of copper(II) into the porphyrin center allows for the third pyridyl nitrogen to coordinate to Pt(dmso)Cl(2). Electronic transitions associated with the ruthenium porphyrin include an intense Soret band and four less intense Q bands in the visible region of the spectrum. An intense pi-pi* transition in the UV region associated with the bipyridyl groups and a metal to ligand charge transfer (MLCT) band appearing as a shoulder to the Soret band are also observed. A slight blue shift of the Soret band and collapse of the Q-bands into one band is observed upon insertion of Cu(II) into the porphyrin center. No change in the electronic spectrum is observed upon coordination of the Pt(dmso)Cl(2) moiety. Electrochemical properties associated with the complexes include a redox couple in the cathodic region attributed to the porphyrin and a redox couple in the anodic region due to the Ru(III/II) couple. DNA titrations of the Cu/Ru and Cu/Ru/Pt porphyrins indicate that both complexes interact strongly with DNA potentially through a partial intercalation mechanism. Gel electrophoresis studies indicate that the Cu/Ru/Pt porphyrin has a greater effect on DNA migration through the gel than the well known DNA binding agent cis-platin. Irradiation of aqueous solutions of the Cu/Ru porphyrin and supercoiled DNA at a 5:1 base pair to complex ratio (in the absence of oxygen) with visible light above 400 nm shows a nicking of the DNA. Repeat experiments in the presence of oxygen show that the Cu/Ru porphyrin photocleaves the DNA, giving the linear form, as evidenced by gel electrophoresis. PMID- 21670810 TI - Nitrogen cation-pi interactions in asymmetric organocatalytic synthesis. AB - Cation-pi interactions have been widely exploited and utilised in the structural biology arena, their fundamental importance in supramolecular chemistry and the pivotal role they play in host guest chemistry has rapidly expanded. In terms of organic synthesis pi-pi, CH-pi and cation-pi interactions are often invoked providing hypotheses for observed selectivities and reaction outcomes although fundamental studies of these interactions are less well reported, especially in the organic synthesis arena. This article considers cation-pi interactions in the field of asymmetric organocatalysis and provides a summary of cases where such interactions may play an important role. Importantly this article sets out to highlight where such interactions could be operating in order to highlight the potential wealth of investigations to be had in this area rather than categorically claiming such interactions are in operation. For asymmetric catalysis this is particularly important as the geometry of a transition state dictates the stereochemical outcome of the reaction, this article provides a perspective on such phenomena. PMID- 21670811 TI - A divalent metal-dependent self-cleaving DNAzyme with a tyrosine side chain. AB - The enzymatic incorporation of a phenol-modified 2'-deoxyuridine triphosphate gave rise to a modified DNA library that was subsequently used in an in vitro selection for ribophosphodiester-cleaving DNAzymes in the presence of divalent zinc and magnesium cations. After 11 rounds of selection, cloning and sequencing resulted in 14 distinct sequences, the most active of which was Dz11-17PheO. Dz11 17PheO self-cleaved an embedded ribocytidine with an observed rate constant of 0.20 +/- 0.02 min(-1) in the presence of 10 mM Mg(2+) and 1 mM Zn(2+) at room temperature. The activity was inhibited at low concentrations of Hg(2+) cations and somewhat higher concentrations of Eu(3+) cations. PMID- 21670821 TI - Durable electrocatalytic-activity of Pt-Au/C cathode in PEMFCs. AB - Longevity remains as one of the central issues in the successful commercialization of polymer electrolyte membrane fuel cells (PEMFCs) and primarily hinges on the durability of the cathode. Incorporation of gold (Au) to platinum (Pt) is known to ameliorate both the electrocatalytic activity and stability of cathode in relation to pristine Pt-cathodes that are currently being used in PEMFCs. In this study, an accelerated stress test (AST) is conducted to simulate prolonged fuel-cell operating conditions by potential cycling the carbon supported Pt-Au (Pt-Au/C) cathode. The loss in performance of PEMFC with Pt-Au/C cathode is found to be ~10% after 7000 accelerated potential-cycles as against ~60% for Pt/C cathode under similar conditions. These data are in conformity with the electrochemical surface-area values. PEMFC with Pt-Au/C cathode can withstand >10,000 potential cycles with very little effect on its performance. X-ray diffraction and transmission electron microscopy studies on the catalyst before and after AST suggest that incorporating Au with Pt helps mitigate aggregation of Pt particles during prolonged fuel-cell operations while X-ray photoelectron spectroscopy reflects that the metallic nature of Pt is retained in the Pt-Au catalyst during AST in comparison to Pt/C that shows a major portion of Pt to be present as oxidic platinum. Field-emission scanning electron microscopy conducted on the membrane electrode assembly before and after AST suggests that incorporating Au with Pt helps mitigating deformations in the catalyst layer. PMID- 21670820 TI - Imidazolium ylides from a conjugate addition-proton transfer route and their cycloaddition reactions. AB - 4,5-Dihydroimidazolium ylides formed by conjugate addition-proton transfer from dihydroimidazoles and doubly-activated electron-deficient alkenes afford 2:1 cycloadducts in a one-pot process wherein the alkene also acts as a dipolarophile. PMID- 21670822 TI - Effective interaction between charged nanoparticles and DNA. AB - We investigate the effective interaction mediated by salt ions between charged nanoparticles (NPs) and DNA. DNA is modeled as an infinite cylinder with a constant surface charge in an implicit solvent. Monte Carlo simulations are used to compute the free energy of the system described in the framework of the primitive model of electrolytes, which accounts for excluded volumes of salt ions. A mean-field Poisson-Boltzmann theory also allows us to compute the free energy and provides us with explicit formulae for its main characteristics (position and depth of the minimum). We intend here to identify the physical parameters that have a major impact on the NP-DNA interaction, in an attempt to evaluate physico-chemical properties which could play a role in genotoxicity or, which could be exploited for therapeutic use. Thus, we investigate the influence on the effective interaction of: the shape of the nanoparticle, the magnitude of the nanoparticle charge and its distribution, the value of the pH of the solution, the magnitude of Van der Waals interactions depending on the nature of the constitutive material of the NP (metal vs. dielectric). We show that for positively charged concave NPs the effective interaction is repulsive at short distance, so that it presents a minimum at distance from the DNA. This short range repulsion is specific to indented particles and is a robust property that holds for a large range of materials and charge densities. PMID- 21670823 TI - Raman spectra of long chain hydrocarbons: anharmonic calculations, experiment and implications for imaging of biomembranes. AB - First-principles anharmonic vibrational calculations are carried out for the Raman spectrum of the C-H stretching bands in dodecane, and for the C-D bands in the deuterated molecule. The calculations use the Vibrational Self-Consistent Field (VSCF) algorithm. The results are compared with liquid-state experiments, after smoothing the isolated-molecule sharp-line computed spectra. Very good agreement between the computed and experimental results is found for the two systems. The combined theoretical and experimental results provide insights into the spectrum, elucidating the roles of symmetric and asymmetric CH(3) and CH(2) hydrogenic stretches. This is expected to be very useful for the interpretation of spectra of long-chain hydrocarbons. The results show that anharmonic effects on the spectrum are large. On the other hand, vibrational degeneracy effects seem to be rather modest at the resolution of the experiments. The degeneracy effects may have more pronounced manifestations in higher-resolution experiments. The results show that first-principles anharmonic vibrational calculations for hydrocarbons are feasible, in good agreement with experiment, opening the way for applications to many similar systems. The results may be useful for the analysis of CARS imaging of lipids, for which dodecane is a representative molecule. It is suggested that first-principles vibrational calculations may be useful also for CARS imaging of other systems. PMID- 21670824 TI - Polyoxoniobate chemistry in the 21st century. AB - Polyoxometalate (POM) chemistry of W, Mo and V is rich and diverse; and new discoveries are frequent and abundant. The prolificacy of this POM chemistry is attributed to rich redox chemistry, an acidic nature that is compatible with addendum metal cations, and most importantly an understanding and ability to control solution behavior. In contrast, the POM chemistry of Nb and Ta (PONb, POTa) is hindered by minimal redox chemistry, alkalinity that is incompatible with the solubility of most metal cations, and a relatively poor understanding of the behavior in aqueous media. Despite these hurdles, considerable advancements in PONb chemistry (and to a much lesser extent POTa chemistry) have been made in the last decade. These include synthesis of the first heteropolyniobate Keggin derivatives, utilization of organic countercations to obtain unprecedented PONb geometries and compositions, and investigation of PONb solution behavior using advanced techniques such as nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry (ESI MS) and small-angle X-ray scattering (SAXS). This Perspective article summarizes the recent successes, continued shortcomings, and some unique and potentially exploitable features of PONb chemistry. More importantly, this annotated compilation of recent PONb literature has revealed the most logical and promising directions for the continued growth of the most challenging of polyoxometalate chemistries. PMID- 21670825 TI - Probing liquid surfaces under vacuum using SEM and ToF-SIMS. AB - We report a newly developed self-contained interface for high-vapor pressure liquid surfaces to vacuum-based analytical instruments. It requires no wires or tubing connections to the outside of the instrument and uses a microfluidic channel with a 3 MUm diameter window into the flowing fluid beneath it. This window supports the liquid against the vacuum by the liquid's surface tension and limits the high-density vapor region traversed by the probe beams to only a few microns. We demonstrate this microfluidic interface for in situ liquid surfaces in a time-of-flight secondary ion mass spectrometer (ToF-SIMS) and a scanning electron microscope (SEM) with chemical analysis. PMID- 21670826 TI - Integrated prediction of protein folding and unfolding rates from only size and structural class. AB - Protein stability, folding and unfolding rates are all determined by the multidimensional folding free energy surface, which in turn is dictated by factors such as size, structure, and amino-acid sequence. Work over the last 15 years has highlighted the role of size and 3D structure in determining folding rates, resulting in many procedures for their prediction. In contrast, unfolding rates are thought to depend on sequence specifics and be much more difficult to predict. Here we introduce a minimalist physics-based model that computes one dimensional folding free energy surfaces using the number of aminoacids (N) and the structural class (alpha-helical, all-beta, or alpha-beta) as only protein specific input. In this model N sets the overall cost in conformational entropy and the net stabilization energy, whereas the structural class defines the partitioning of the stabilization energy between local and non-local interactions. To test its predictive power, we calibrated the model empirically and implemented it into an algorithm for the PREdiction of Folding and Unfolding Rates (PREFUR). We found that PREFUR predicts the absolute folding and unfolding rates of an experimental database of 52 proteins with accuracies of +/-0.7 and +/ 1.4 orders of magnitude, respectively (relative to experimental spans of 6 and 8 orders of magnitude). Such prediction uncertainty for proteins vastly varying in size and structure is only two-fold larger than the differences in folding (+/ 0.34) and unfolding rates (+/-0.7) caused by single-point mutations. Moreover, PREFUR predicts protein stability with an accuracy of +/-6.3 kJ mol(-1), relative to the 5 kJ mol(-1) average perturbation induced by single-point mutations. The remarkable performance of our simplistic model demonstrates that size and structural class are the major determinants of the folding landscapes of natural proteins, whereas sequence variability only provides the final 10-20% tuning. PREFUR is thus a powerful bioinformatic tool for the prediction of folding properties and analysis of experimental data. PMID- 21670827 TI - The role of low levels of water in the electrochemical oxidation of alpha tocopherol (vitamin E) and other phenols in acetonitrile. AB - The phenol, alpha-tocopherol, can be electrochemically oxidised in a -2e(-)/-H(+) process to form a diamagnetic cation that is long-lived in dry organic solvents such as acetonitrile and dichloromethane, but in the presence of water quickly reacts to form a hemiketal. Variable scan rate cyclic voltammetry experiments in acetonitrile with carefully controlled amounts of water between 0.010 M-0.6 M were performed in order to determine the rate of reaction of the diamagnetic cation with water. The water content of the solvent was accurately determined by Karl Fischer coulometric titrations and the voltammetric data were modelled using digital simulation techniques. The oxidation peak potential of alpha-tocopherol measured during cyclic voltammetry experiments was found to shift to less positive potentials as increasing amounts of water (0.01-0.6 M) were added to the acetonitrile, which was interpreted based on hydrogen-bonding interactions between the phenolic hydrogen atom and water. Several other phenols were examined and they displayed similar voltammetric features to alpha-tocopherol, suggesting that interactions of phenols with trace amounts of water were a common occurrence in acetonitrile. The H-bonding interactions of alpha-tocopherol with water were also examined via NMR and UV-vis spectroscopies, with the voltammetric and spectroscopic studies extended to include other coordinating solvents (dimethyl sulfoxide and pyridine). PMID- 21670828 TI - Structure prediction, disorder and dynamics in a DMSO solvate of carbamazepine. AB - We have applied crystal structure prediction methods to understand and predict the formation of a DMSO solvate of the anti-convulsant drug carbamazepine (CBZ), in which the DMSO molecules are disordered. Crystal structure prediction calculations on the 1:1 CBZ:DMSO solvate revealed the generation of two similar low energy structures which differ only in the orientation of the DMSO molecules. Analysis of crystal energy landscapes generated at 0 K suggests the possibility of solvent disorder. A combined computational and experimental study of the changes in the orientation of the DMSO within the crystal structure revealed that the nature of the disorder changes with temperature. At low temperature, the DMSO disorder is static whilst at high temperature the DMSO configurations can interconvert by a 180 degrees rotation of the DMSO molecules within the lattice. This 180 degrees rotation of the DMSO molecules drives a phase change from a high temperature dynamically disordered phase to a low temperature phase with static disorder. Crystallisation of a DMSO solvate of the related molecule epoxycarbamazepine resulted in a different degree of DMSO disorder in the crystal structure, despite the similarity of the carbamazepine and epoxycarbamazepine molecules. We believe consideration of disorder and its contribution to entropy and crystal free energies at temperature other than 0 K is fundamental for the accuracy of future energy rankings in crystal structure prediction calculations of similar solvated structures. PMID- 21670829 TI - Phthalide-derived novel fluoroionophores incorporating picolylamino receptors: synthesis and response to metal cations. AB - Phthalide derivatives incorporating mono- and di-picolylamino functionalities at the 6-position have been prepared as novel fluoroionophores and their fluorescence responses to metal cations have been investigated. These phthalides not only exhibited efficient fluorescence in an aqueous medium but also displayed fluorescence on-off response upon addition of transition-metal cations, namely Cu(2+). The 6-aminophthalide fluorophore served as the core of the fluorescent probes although it has rarely been applied to a chemosensor. To the best of our knowledge, these modified phthalides are the first 6-aminophthalide-derived fluorometric probes for metal cations, namely Cu(2+). PMID- 21670830 TI - Antimicrobial graphene polymer (PVK-GO) nanocomposite films. AB - The first report on the fabrication and application of a nanocomposite containing poly-N-vinyl carbazole (PVK) polymer and graphene oxide (GO) as an antimicrobial film was demonstrated. The antimicrobial film was 90% more effective in preventing bacterial colonization relative to the unmodified surface. More importantly, the nanocomposite thin film showed higher bacterial toxicity than pure GO-modified surface. PMID- 21670831 TI - Capsulation of carbon nanotubes on top of colloidally templated and electropolymerized polythiophene arrays. AB - We describe the capsulation of colloidally templated polythiophene (P3-TAA) arrays with multi-walled carbon nanotubes (MWNTs) after colloidal template electropolymerization. The dissolution of the polystyrene (PS) particle templates, which were assembled via the Langmuir-Blodgett (LB)-like technique, allowed the formation of hollow-shell Janus type arrays. PMID- 21670832 TI - Preparation of high-performance hydroxide exchange membrane by a novel ablation restriction plasma polymerization approach. AB - A novel approach of ablation restriction plasma polymerization has been successfully demonstrated for the first time in hydroxide exchange membrane synthesis. The membrane possesses high hydroxide conductivity, alkaline stability, and the ability of fully encompassing catalyst particles, without solubility in low boiling point water-soluble solvents. PMID- 21670833 TI - Convenient synthesis of nucleoside 5'-triphosphates for RNA transcription. AB - By generating a selective phosphitylating reagent in situ, nucleoside 5' triphosphates can be conveniently synthesized in one pot. This novel strategy without nucleoside protection has been developed to largely simplify synthesis of the nucleoside triphosphates. This demonstrated principle can be applied to the 5'-triphosphate synthesis of both native and modified nucleosides. PMID- 21670834 TI - Hofmeister effects: interplay of hydration, nonelectrostatic potentials, and ion size. AB - The classical Derjaguin-Landau-Verwey-Overbeek (DLVO) theory of colloids, and corresponding theories of electrolytes, are unable to explain ion specific forces between colloidal particles quantitatively. The same is true generally, for surfactant aggregates, lipids, proteins, for zeta and membrane potentials and in adsorption phenomena. Even with fitting parameters the theory is not predictive. The classical theories of interactions begin with continuum solvent electrostatic (double layer) forces. Extensions to include surface hydration are taken care of with concepts like inner and outer Helmholtz planes, and "dressed" ion sizes. The opposing quantum mechanical attractive forces (variously termed van der Waals, Hamaker, Lifshitz, dispersion, nonelectrostatic forces) are treated separately from electrostatic forces. The ansatz that separates electrostatic and quantum forces can be shown to be thermodynamically inconsistent. Hofmeister or specific ion effects usually show up above ~10(-2) molar salt. Parameters to accommodate these in terms of hydration and ion size had to be invoked, specific to each case. Ionic dispersion forces, between ions and solvent, for ion-ion and ion surface interactions are not explicit in classical theories that use "effective" potentials. It can be shown that the missing ionic quantum fluctuation forces have a large role to play in specific ion effects, and in hydration. In a consistent predictive theory they have to be included at the same level as the nonlinear electrostatic forces that form the skeletal framework of standard theory. This poses a challenge. The challenges go further than academic theory and have implications for the interpretation and meaning of concepts like pH, buffers and membrane potentials, and for their experimental interpretation. In this article we overview recent quantitative developments in our evolving understanding of the theoretical origins of specific ion, or Hofmeister effects. These are demonstrated through an analysis that incorporates nonelectrostatic ion surface and ion-ion dispersion interactions. This is based on ab initio ionic polarisabilities, and finite ion sizes quantified through recent ab initio work. We underline the central role of ionic polarisabilities and of ion size in the nonelectrostatic interactions that involve ions, solvent molecules and interfaces. Examples of mechanisms through which they operate are discussed in detail. An ab initio hydration model that accounts for polarisabilities of the tightly held hydration shell of "cosmotropic" ions is introduced. It is shown how Hofmeister effects depend on an interplay between specific surface chemistry, surface charge density, pH, buffer, and counterion with polarisabilities and ion size. We also discuss how the most recent theories on surface hydration combined with hydrated nonelectrostatic potentials may predict experimental zeta potentials and hydration forces. PMID- 21670836 TI - A new method for non-labeling attomolar detection of diseases based on an individual gold nanorod immunosensor. AB - Herein, we present the use of a single gold nanorod sensor for detection of diseases on an antibody-functionalized surface, based on antibody-antigen interaction and the localized surface plasmon resonance (LSPR) lambda(max) shifts of the resonant Rayleigh light scattering spectra. By replacing the cetyltrimethylammonium bromide (CTAB), a tightly packed self-assembled monolayer of HS(CH(2))(11)(OCH(2)CH(2))(6)OCH(2)COOH(OEG(6)) has been successfully formed on the gold nanorod surface prior to the LSPR sensing, leading to the successful fabrication of individual gold nanorod immunosensors. Using prostate specific antigen (PSA) as a protein biomarker, the lowest concentration experimentally detected was as low as 111 aM, corresponding to a 2.79 nm LSPR lambda(max) shift. These results indicate that the detection platform is very sensitive and outperforms detection limits of commercial tests for PSA so far. Correlatively, its detection limit can be equally compared to the assays based on DNA biobarcodes. This study shows that a gold nanorod has been used as a single nanobiosensor to detect antigens for the first time; and the detection method based on the resonant Rayleigh scattering spectrum of individual gold nanorods enables a simple, label-free detection with ultrahigh sensitivity. PMID- 21670835 TI - The contribution of roadside soil to phosphorus loading in the eutrophic Lagos Lagoon, Nigeria. AB - Roadside soils were sampled from the Lagos Lagoon catchment during the wet and dry seasons over the period 2005-2009. Lagoon sediment samples were also collected within the same period. All samples were digested with aqua regia to determine total phosphorus and extracted with 0.5 M sodium bicarbonate to determine the bioavailable fraction (Olsen-P). A segmented flow analyser method was used for analysis and good accuracy was demonstrated for two reference soils (SO-2 from CCMET and SRM 2711 from NIST). The Lagos Lagoon is a hypereutrophic water body (1270 +/- 1170 MUg P L(-1)), with significant areas of anoxia and water hyacinth growth. The total phosphorus concentrations in roadside soils (16 sites; mean +/- 2 S.D.) were 285 +/- 279 mg kg(-1) in the wet season and 424 +/- 629 mg kg(-1) in the dry season, indicating that rainwater leaching is a major source of phosphorus in the lagoon. The bioavailable fractions were 5.17 +/- 3.47 mg kg(-1) (2.1 +/- 1.5% of the total) in the wet season and 13.0 +/- 8.7 mg kg( 1) (4.3 +/- 4.5% of the total) in the dry season. PMID- 21670837 TI - Tunable 3D droplet self-assembly for ultra-high-density digital micro-reactor arrays. AB - We present a tunable three-dimensional (3D) self-assembled droplet packing method to achieve high-density micro-reactor arrays for greater imaging efficiency and higher-throughput chemical and biological assays. We demonstrate the capability of this platform's high-density imaging method by performing single molecule quantification using digital polymerase chain reaction, or digital PCR, in multiple self-assembled colloid-like crystal lattice configurations. By controlling chamber height to droplet diameter ratios we predictively control three-dimensional packing configurations with varying degrees of droplet overlap to increase droplet density and imaging sensor area coverage efficiency. Fluorescence imaging of the densely packed 3D reactor arrays, up to three layers high, demonstrates high throughput quantitative analysis of single-molecule reactions. Now a greater number of microreactors can be observed and studied in a single picture frame without the need for confocal imaging, slide scanners, or complicated image processing techniques. Compared to 2D designs, tunable 3D reactor arrays yield up to a threefold increase in density and use 100% of the sensor's imaging area to enable simultaneous imaging a larger number of reactions without sacrificing digital quantification performance. This novel approach provides an important advancement for ultra-high-density reactor arrays. PMID- 21670838 TI - An ultrasensitive electrochemical biosensor for detection of DNA species related to oral cancer based on nuclease-assisted target recycling and amplification of DNAzyme. AB - A simple, label-free, ultra-highly sensitive and selective electrochemical sensor based on nuclease-assisted target recycling and DNAzyme for the detection of DNA species related to oral cancer in saliva is developed. PMID- 21670839 TI - Different crystal morphologies lead to slightly different conformations of light harvesting complex II as monitored by variations of the intrinsic fluorescence lifetime. AB - In 2005, it was found that the fluorescence of crystals of the major light harvesting complex LHCII of green plants is significantly quenched when compared to the fluorescence of isolated LHCII (A. A. Pascal et al., Nature, 2005, 436, 134-137). The Raman spectrum of crystallized LHCII was also found to be different from that of isolated LHCII but very similar to that of aggregated LHCII, which has often been considered a good model system for studying nonphotochemical quenching (NPQ), the major protection mechanism of plants against photodamage in high light. It was proposed that in the crystal LHCII adopts a similar (quenching) conformation as during NPQ and indeed similar changes in the Raman spectrum were observed during NPQ in vivo (A. V. Ruban et al., Nature, 2007, 450, 575-579). We now compared the fluorescence of various types of crystals, differing in morphology and age. Each type gave rise to its own characteristic mono-exponential fluorescence lifetime, which was 5 to 10 times shorter than that of isolated LHCII. This indicates that fluorescence is not quenched by random impurities and packing defects (as proposed recently by T. Barros et al., EMBO Journal, 2009, 28, 298-306), but that LHCII adopts a particular structure in each crystal type, that leads to fluorescence quenching. Most interestingly, the extent of quenching appears to depend on the crystal morphology, indicating that also the crystal structure depends on this crystal morphology but at the moment no data are available to correlate the crystals' structural changes to changes in fluorescence lifetime. PMID- 21670840 TI - A [Pd]-mediated omega-alkynone cycloisomerization approach for the central tetrahydropyran unit and the synthesis of C(31)-C(48) fragment of aflastatin A. AB - A concise assembly of the central tetrahydropyran unit of aflastatin A featuring a Pd-mediated alkynone cycloisomerization to provide a glycal and its subsequent stereoselective hydroboration to deliver the requisite stereochemistry at C(33) and C(34) centers is documented. PMID- 21670841 TI - Highly stereoselective reduction of prochiral ketones by a bacterial reductase coupled with cofactor regeneration. AB - A carbonyl reductase gene (yueD) from Bacillus sp. ECU0013 was heterologously overexpressed in Escherichia coli, and the encoded protein (BYueD) was purified to homogeneity and characterized. The NADPH-dependent reductase showed a broad substrate spectrum towards different aromatic ketones, and alpha- and beta ketoesters. Although the enantioselectivity was high to moderate for the reduction of alpha-ketoesters, all the tested beta-ketoesters and aromatic ketones were reduced to the corresponding chiral alcohols in enantiomerically pure forms. Furthermore, the practical applicability of this enzyme was evaluated for the reduction of ethyl 4-chloro-3-oxobutanoate (1a). Using Escherichia coli cells coexpressing BYueD and glucose dehydrogenase, 215 g L(-1) (1.3 M) of 1a was stoichiometrically converted to ethyl (R)-4-chloro-3-hydroxybutanoate ((R)-1b) in an aqueous-toluene biphasic system by using a substrate fed-batch strategy, resulting in an overall hydroxyl product yield of 91.7% with enantiomeric purity of 99.6% ee. PMID- 21670842 TI - Trp-Trp pairs as beta-hairpin stabilisers: hydrogen-bonded versus non-hydrogen bonded sites. AB - Trp-Trp pairs have emerged as a successful strategy for beta-hairpin stabilization. Using loop 3 of Vammin as a template, we experimentally demonstrate that the contribution of Trp-Trp pairs to beta-hairpin stability depends on beta-sheet periodicity, that is, they are stabilising at non-hydrogen bonded sites, but not at hydrogen-bonded positions. PMID- 21670843 TI - Recent advances and perspectives in four-component Dirac-Kohn-Sham calculations. AB - We review recent theoretical and computational advances in the full relativistic four-component Dirac-Kohn-Sham (DKS) approach and its application to the calculation of the electronic structure of chemical systems containing many heavy atoms. We describe our implementation of an all-electron DKS approach based on the use of G-spinor basis sets, Hermite Gaussian functions, state-of-the-art density-fitting techniques and memory distributed parallelism. This approach has enormously extended the applicability of the DKS method, including for example large clusters of heavy atoms, and opens the way for future key developments. We examine the current limitations and future possible applications of the DKS approach, including the implementation of four-current density functionals and real-time propagation schemes. This would make possible to describe molecules in strong fields, accurately accounting for relativistic kinematic effects and spin orbit coupling. PMID- 21670844 TI - Absence of "rebound" platelet hyperreactivity following cessation of prasugrel. PMID- 21670845 TI - Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. AB - Plaque rupture and subsequent thrombotic occlusion of the coronary artery account for as many as three quarters of myocardial infarctions. The concept of plaque stabilisation emerged about 20 years ago to explain the discrepancy between the reduction of cardiovascular events in patients receiving lipid lowering therapy and the small decrease seen in angiographic evaluation of atherosclerosis. Since then, the concept of a vulnerable plaque has received a lot of attention in basic and clinical research leading to a better understanding of the pathophysiology of the vulnerable plaque and acute coronary syndromes. From pathological and clinical observations, plaques that have recently ruptured have thin fibrous caps, large lipid cores, exhibit outward remodelling and invasion by vasa vasorum. Ruptured plaques are also focally inflamed and this may be a common denominator of the other pathological features. Plaques with similar characteristics, but which have not yet ruptured, are believed to be vulnerable to rupture. Experimental studies strongly support the validity of anti inflammatory approaches to promote plaque stability. Unfortunately, reliable non invasive methods for imaging and detection of such plaques are not yet readily available. There is a strong biological basis and supportive clinical evidence that low-density lipoprotein lowering with statins is useful for the stabilisation of vulnerable plaques. There is also some clinical evidence for the usefulness of antiplatelet agents, beta blockers and renin-angiotensin aldosterone system inhibitors for plaque stabilisation. Determining the causes of plaque rupture and designing diagnostics and interventions to prevent them are urgent priorities for current basic and clinical research in cardiovascular area. PMID- 21670846 TI - Use of statins and recurrence of atrial fibrillation after catheter ablation or electrical cardioversion: an old question revisited. PMID- 21670847 TI - Myeloid angiogenic cells act as alternative M2 macrophages and modulate angiogenesis through interleukin-8. AB - Endothelial progenitor cells (EPCs) promote angiogenesis, and clinical trials have shown such cell therapy to be feasible for treating ischemic disease. However, clinical outcomes have been contradictory owing to the diverse range of EPC types used. We recently characterized two EPC subtypes, and identified outgrowth endothelial cells as the only EPC type with true progenitor and endothelial characteristics. By contrast, myeloid angiogenic cells (MACs) were shown to be monocytic cells without endothelial characteristics despite being widely described as "EPCs." In the current study we demonstrated that although MACs do not become endothelial cells or directly incorporate into a microvascular network, they can significantly induce endothelial tube formation in vitro and vascular repair in vivo. MAC-derived interleukin-8 (IL-8) was identified as a key paracrine factor, and blockade of IL-8 but not vascular endothelial growth factor (VEGF) prevented MAC-induced angiogenesis. Extracellular IL-8 transactivates VEGFR2 and induces phosphorylation of extracellular signal-regulated kinases. Further transcriptomic and immunophenotypic analysis indicates that MACs represent alternative activated M2 macrophages. Our findings demonstrate an unequivocal role for MACs in angiogenesis, which is linked to paracrine release of cytokines such as IL-8. We also show, for the first time, the true identity of these cells as alternative M2 macrophages with proangiogenic, antiinflammatory and pro-tissue-repair properties. PMID- 21670848 TI - alpha-1-antitrypsin gene delivery reduces inflammation, increases T-regulatory cell population size and prevents islet allograft rejection. AB - Antiinflammatory clinical-grade, plasma-derived human alpha-1 antitrypsin (hAAT) protects islets from allorejection as well as from autoimmune destruction. hAAT also interferes with disease progression in experimental autoimmune encephalomyelitis (EAE) and in collagen-induced arthritis (CIA) mouse models. hAAT increases IL-1 receptor antagonist expression in human mononuclear cells and T-regulatory (Treg) cell population size in animal models. Clinical-grade hAAT contains plasma impurities, multiple hAAT isoforms and various states of inactive hAAT. We thus wished to establish islet-protective activities and effect on Treg cells of plasmid-derived circulating hAAT in whole animals. Islet function was assessed in mice that received allogeneic islet transplants after mice were given hydrodynamic tail-vein injection with pEF-hAAT, a previously described Epstein Barr virus (EBV) plasmid construct containing the EBV nuclear antigen 1 (EBNA1) and the family of repeat EBNA1 binding site components (designated "EF") alongside the hAAT gene. Sera collected from hAAT-expressing mice were added to lipopolysaccharide (LPS)-stimulated macrophages to assess macrophage responsiveness. Also, maturation of peritoneal cells from hAAT-expressing mice was evaluated. hAAT-expressing mice accepted islet allografts (n = 11), whereas phosphate-buffered saline-injected animals (n = 11), as well as mice treated with truncated-hAAT-plasmid (n = 6) and untreated animals (n = 20) rapidly rejected islet allografts. In hAAT-expressing animals, local Treg cells were abundant at graft sites, and the IL-1 receptor antagonist was elevated in grafts and circulation. Sera from hAAT-expressing mice, but not control mice, inhibited macrophage responses. Finally, peritoneal cells from hAAT-expressing mice exhibited a semimature phenotype. We conclude that plasmid-derived circulating hAAT protects islet allografts from acute rejection, and human plasma impurities are unrelated to islet protection. Future studies may use this in vivo approach to examine the structure-function characteristics of the protective activities of AAT by manipulation of the hAAT plasmid. PMID- 21670849 TI - BRAP Activates Inflammatory Cascades and Increases the Risk for Carotid Atherosclerosis. AB - The BRCA-1 associated protein gene (BRAP) was recently identified as a susceptibility gene for myocardial infarction (MI). In the present study we aimed to decipher the association between the BRAP polymorphism and carotid atherosclerosis and the mechanism underlying its proatherogenic effect. A total of 1749 stroke/MI-free volunteers received carotid ultrasonic examinations for the measurement of intima-medial thickness (IMT) and plaque. The promoter polymorphism rs11066001 was selected because it affects the transcription of BRAP. We found that the GG genotype was associated with a 1.58-fold increased risk for having at least one plaque compared to carrying the A allele (P = 0.021). When subjects were divided by the cutoff value of IMT above the mean plus 1 standard deviation, there was an overrepresentation of the GG genotype in the subjects with thicker IMT (P = 0.004). The expression of BRAP increased significantly when human aortic smooth muscle cells (HASMCs) were treated with lipopolysaccharide (LPS). HASMCs were transfected with small interfering RNA against BRAP or scrambled sequences before treatment with LPS. Knockdown of BRAP led to attenuated HASMC proliferation and reduced secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in response to LPS. Downregulation of BRAP did not affect the protein levels of nuclear factor-kappaB (NF-kappaB), but prohibited its nuclear translocation. Coimmunoprecipitation experiments confirmed an interaction between BRAP and the two major components of the IKK signalosome, IkappaBbeta and IKKbeta. Collectively, BRAP conferred a risk for carotid plaque and IMT. Inflammatory stimuli upregulated BRAP expression, and BRAP activated inflammatory cascades by regulating NF-kappaB nuclear translocation. PMID- 21670852 TI - Effectiveness of gutta-percha and Resilon in filling lateral root canals using the Obtura II system. AB - The aim of this study was to evaluate the effectiveness of gutta-percha and Resilon in filling lateral root canals by using the Obtura II system. Root canals of artificial teeth were prepared using a standard protocol, and lateral canals were made in three thirds of the root canal. The root canals were filled with either Obtura gutta-percha (OB), Endo-points flow gutta-percha (ED), or Resilon (RE) by using the Obtura II system. The fillings were evaluated using digitized radiographs and analyzed by using Image Tool software. Outlines of the total areas of the lateral canals and the filled areas were used to determine the percentage of filling in each lateral canal. Data were analyzed with the Kruskal Wallis and Dunn tests at a 5% significance level. RE and ED showed better results than OB did in the three thirds of the root canals. When the root canal thirds were compared, OB and RE were more effective in the cervical third than in the apical third (p < 0.05). In conclusion, Resilon and EndoFlow gutta-percha were effective in filling lateral canals by using the Obtura II system. PMID- 21670851 TI - A map of Brazilian dental research in the last decade. AB - The aim of the present study was to analyze dental research trends in Brazil over the past nine years. All abstracts presented at the 26th Annual Meeting of the Brazilian Society for Dental Research in 2009 (n = 2648) were classified based on field of knowledge, home institution and geographic region. Data were compared with those previously published based on abstracts presented at various meetings. Between 2001 and 2006, five fields of knowledge had a greater than 10% representation among the total number of studies. These fields included restorative dentistry/dental materials (RD/DM), periodontics, endodontics, pediatric dentistry and population-based oral health. In 2009, only RD/DM maintained a greater than 10% proportion of meeting abstracts, and basic fields comprised the second position among those fields with greater representation (9.8%). The majority of research studies were performed at public institutions, and the number of abstracts per state increased significantly in 2009 (Wilcoxon test, p < 0.001). The southeastern region of Brazil submitted the greatest number of abstracts; however, other regions also demonstrated increased participation in research (11%). The percentage distribution of abstracts between states remained constant (Wilcoxon test, p = 0.255; r s = 0.873). The results of the present study suggest a slight shift in the scientific research profile in Brazilian dentistry: fields related to professional disciplines have declined in relative research participation, while increasing interest has been observed in basic fields and new specialties. PMID- 21670853 TI - Experimental model of distraction osteogenesis in edentulous rats. AB - Distraction osteogenesis (DO) is a surgical technique producing bone lengthening by distraction of the fracture callus. Although a large number of experimental studies on the events associated with DO of craniofacial skeleton have been reported, the few employing rat mandibular bone DO used complicated designs and produced a small volume of newly formed bone. Thus, this study aims to present an original experimental model of mandibular DO in edentulous rats that produces a sufficient quantity and quality of intramembranous bone. Eight male Wistar rats, weighing 75 g, underwent extraction of lower molars. With rats weighing 350 g, right mandibular osteotomy was performed and the distraction device was placed. The distraction device was custom made using micro-implants, expansion screws, and acrylic resin. STUDY PROTOCOL: latency: 6 days, distraction: 1/4 turn (0.175 mm) once a day during 6 d, consolidation: 28 d after distraction phase, sacrifice. DO-treated and contralateral hemimandibles were dissected and compared macroscopically and using radiographic studies. Histological sections were obtained and stained with H&E. A distraction gap filled with newly formed and mature bone tissue was obtained. This model of mandibular DO proved useful to obtain adequate quantity and quality of bone to study bone regeneration. PMID- 21670854 TI - Vimentin expression and the influence of Matrigel in cell lines of head and neck squamous cell carcinoma. AB - Vimentin is a cytoeskeletal intermediate filament protein commonly observed in mesenchymal cells; however, it can also be found in malignant epithelial cells. It is demonstrated in several carcinomas, such as those of the cervix, breast and bladder, in which it is widely used as a marker of the epithelial to mesenchymal transition that takes place during embryogenesis and metastasis. Vimentin is associated with tumors that show a high degree of invasiveness, being detected in invasion front cells. Its expression seems to be influenced by the tumor microenvironment. The aim of this study was to evaluate vimentin expression in head and neck squamous cell carcinoma (HNSCC) cell lines, and to investigate the contribution of the microenvironment to its expression. HNSCC cell lines (HN6, HN30 and HN31) and an immortalized nontumorigenic cell line (HaCaT) were submitted to a three-dimensional assay with Matrigel. Cytoplasmatic staining of the HN6 cell line cultured without Matrigel and of the HN30 and HN31 cell lines cultured with Matrigel was demonstrated through immunohistochemistry. Western Blotting revealed a significant decrease in vimentin expression for the HN6 cell line and a significant increase for the HN30 and HN31 cell lines cultured with Matrigel. The results suggest that vimentin can be expressed in HNSCC cells and its presence is influenced by the microenvironment of a tumor. PMID- 21670855 TI - Effects of age and gender on upper airway, lower airway and upper lip growth. AB - The aim of the present retrospective study was to evaluate the influence of age and gender on upper and lower airway width and upper lip length. In this study, 390 lateral cephalograms were divided into 13 age groups (ranging from 6 to 18 years) and were analyzed. The intergroup differences were analyzed using a MANOVA (Multivariate Analysis of the Variance), and the intragroup differences were analyzed using an ANOVA (Analysis of the Variance) and Tukey's test. The results of the present study indicated that although the airway width and the upper lip length increased with age, the lower airway width exhibited variable growth between the ages of six and eighteen years. The airway width was significantly greater in females than males, whereas the upper airway width was similar between these two genders. The lip length was significantly shorter in females than males. The lower airway width and upper lip length were significantly different between males and females, whereas the upper airway width was similar for the genders. The upper airway width and upper lip exhibited incremental growth between the ages of six and eighteen years. The upper lip closely followed the growth pattern of the upper airway width; the growth plateaued between the ages of 6 and 9 years, increased from 9 to 16 years and plateaued from 16 to 18 years. PMID- 21670856 TI - Obstetricians' knowledge of periodontal disease as a potential risk factor for preterm delivery and low birth weight. AB - There is little information about the knowledge and attitudes of physicians regarding oral care. This study aimed to assess the knowledge and attitudes of obstetricians about the relationship between periodontal disease and preterm/low birth weight. A questionnaire was emailed to members of the Brazilian Federation of Gynecology and Obstetrics (FEBRASGO). The questionnaire elicited both personal information and knowledge and attitudes regarding the relationship between periodontal diseases and preterm labor. A total of 875 obstetricians responded to the questionnaire. The majority of respondents were female (54.1%), resided in the Southeast (45.6%), worked in both the public and private sectors (61.4%), and had over 15 years of experience in obstetrics (48.9%). A large proportion of obstetricians (93.4%) stated that bacteria were associated with periodontal disease, and 94% reported that periodontitis was a condition more severe than gingivitis. In total, over 80% of participating obstetricians reported smoking, preeclampsia, bacterial vaginosis and periodontal disease as risk factors or possible risk factors for preterm birth or low birth weight. A correlation between the experience of the obstetricians and referral of their patients for dental examinations (p < 0.001) was observed. Also, obstetricians who had had their own dental visits more recently were more likely to recommend the same for their patients (p < 0.001). It is concluded that, although obstetricians were aware of the association between gingival inflammation and adverse obstetric outcomes, the attitudes of these professionals were not in agreement with their apparent knowledge regarding periodontal diseases and their possible repercussions. PMID- 21670857 TI - Langerhans cells in periodontal disease of HIV- and HIV+ patients undergoing highly active antiretroviral therapy. AB - The aim of this study was to assess and compare quantitatively the presence of S100+ Langerhans cells (LC) by immunochemistry techniques in HIV+ and HIV- gingivitis and periodontitis subjects. Additionally, it aimed to evaluate the correlation among densities of these cells with CD4+ and CD8+ T cells, and viral load levels in HIV+ subjects, all using Highly Active Antiretroviral Therapy (HAART). The samples were allocated into four groups: 1) 15 subjects with moderate chronic periodontitis (MCP), HIV+; 2) 15 subjects with MCP, HIV-; 3) 10 subjects with gingivitis (G), HIV+; and 4) 10 subjects with G, HIV-. The S100+ cells were assessed in the pocket epithelium, gingival epithelium, and lamina propria. A statistically significant increase of total S100+ cells in HIV+ periodontitis subjects was observed in relation to HIV- periodontitis subjects. No increase of S100+ cells with increased inflammation was observed. No statistically significant correlation among S100+ cells and blood levels of CD4, CD8, and viral load was observed. In conclusion, the use of HAART can aid in achieving viral loads, and it is suggested that it may prevent the destruction of the LC. PMID- 21670858 TI - Influence of marginal fit and cement types on microleakage of all-ceramic crown systems. AB - The purpose of this study was to evaluate the effects of both marginal fit and cementing with different luting agents on the microleakage of all-ceramic crown systems. Thirty-six extracted upper central incisors were prepared for full coverage crowns and were divided into three groups. Group 1: CAD/CAM-fabricated ZrO2, Group 2: Heat-pressed lithium-disilicate, and Group 3: Cast Cr-Co copings as the control group. Copings were made following standard techniques, and groups were assigned cementation with either self-adhesive resin cement (A) or glass ionomer luting cement (B). The specimens were subjected to thermocycling, immersed in basic fuchsin solution, sectioned mesiodistally and buccolingually. The surface of each section was digitally photographed under a stereomicroscope. Microleakage was scored using a five-point scale, and the marginal gap was measured using image analysis software. Data were statistically analyzed using 2 way ANOVA, Kruskal-Wallis, and Mann-Whitney U tests (alpha: 0.05). The marginal discrepancy of each group was 82.7 +/- 7 um, 92.6 +/- 4 um and 96.5 +/- 7 um respectively. Group 1 showed significantly smaller gaps than Group 3 (P = 0.042). Self-adhesive resin cement (A) showed a lower level of microleakage than glass ionomer luting cement (B) in all groups (P = 0.029). Microleakage scores of '0' were 83% for 1A, 50% for 1B, 50% for 2A, 16% for 2B, 33% for 3A and none for 3B. Marginal discrepancy and cement type both had significant effects on microleakage. Lower levels of microleakage were recorded with self-adhesive resin cement, while CAD/CAM-fabricated ZrO2 copings showed smaller marginal discrepancy and less microleakage in comparison to cast Cr-Co. PMID- 21670859 TI - Knoop microhardness and FT-Raman evaluation of composite resins: influence of opacity and photoactivation source. AB - The aim of this study was to evaluate the degree of conversion by Knoop microhardness (KHN) and FT-Raman spectroscopy (FTIR) of one nanofilled (Filtek Supreme-3M-ESPE [FS]) and one microhybrid composite (Charisma-Heraeus-Kulzer [CH]), each with different opacities, namely enamel, dentin, and translucent, which were photo-activated by a quartz-tungsten-halogen lamp (QTH) and a light emitting diode (LED). Resin was bulk inserted into a disc-shaped mold that was 2.0 mm thick and 4 mm in diameter, obtaining 10 samples per group. KHN and FTIR values were analyzed by two-way ANOVA and Tukey's tests (alpha = 0.05). Nanofilled resin activated by a LED presented higher microhardness values than samples activated by a QTH for dentin opacity (p < 0.05). The microhybrid resin showed no differences in KHN or FTIR values with different activation sources or opacity. The nanofilled dentin and enamel resins showed lower FTIR values than the translucent resin. The KHN values of the translucent resins were not influenced by the light source. PMID- 21670860 TI - Micromorphological and hardness analyses of human and bovine sclerotic dentin: a comparative study. AB - The purpose of this study was to test the hypothesis that both human and bovine sclerotic dentin have similar hardness properties, in addition to similar micromorphological characteristics. Sixteen teeth (8 human and 8 bovine) exhibiting exposed dentin in the incisal edge and showing characteristics typical of sclerosis were used. Vickers surface microhardness testing was conducted. Three areas of the dentin surface of each specimen were selected. All teeth were processed for scanning electron microscopy in order to estimate the amount (in percentage) of solid dentin on the sclerotic dentin surface. The data were compared by Student's t test (alpha = 0.05). The micromorphological and microhardness data were compared by Pearson's linear correlation test (alpha = 0.05). The mean percentages of solid dentin of human and bovine sclerotic dentin were similar (human 90.71 +/- 0.83 and bovine 89.08 +/- 0.81, p = 0.18). The mean microhardness value (VHN) of human sclerotic dentin was significantly higher than that of bovine sclerotic dentin (human 45.26 +/- 2.92 and bovine 29.93 +/- 3.83, p = 0.006). No correlation was found between the microhardness values and the amount of solid dentin in the sclerotic dentin, irrespective of the species considered (human R2 = 0.0240, p = 0.714; bovine R2 = 0.0017, p = 0.923; and combined R2 = 0.038, p = 0.46). We concluded that although both bovine and human sclerotic dentin present a similar amount of solid tissue, human sclerotic dentin presents higher microhardness than bovine sclerotic dentin. PMID- 21670861 TI - Longitudinal anthropometric assessment of infants born to HIV-1-infected mothers, Belo Horizonte, Southeastern Brazil. AB - OBJECTIVE: To evaluate the growth parameters in infants who were born to HIV-1 infected mothers. METHODS: The study was a longitudinal evaluation of the z scores for the weight-for-age (WAZ), weight-for-length (WLZ) and length-for-age (LAZ) data collected from a cohort. A total of 97 non-infected and 33 HIV infected infants born to HIV-1-infected mothers in Belo Horizonte, Southeastern Brazil, between 1995 and 2003 was studied. The average follow-up period for the infected and non-infected children was 15.8 months (variation: 6.8 to 18.0 months) and 14.3 months (variation: 6.3 to 18.6 months), respectively. A mixed effects linear regression model was used and was fitted using a restricted maximum likelihood. RESULTS: There was an observed decrease over time in the WAZ, LAZ and WLZ among the infected infants. At six months of age, the mean differences in the WAZ, LAZ and WLZ between the HIV-infected and non-infected infants were 1.02, 0.59, and 0.63 standard deviations, respectively. At 12 months, the mean differences in the WAZ, LAZ and WLZ between the HIV-infected and non-infected infants were 1.15, 1.01, and 0.87 standard deviations, respectively. CONCLUSIONS: The precocious and increasing deterioration of the HIV-infected infants' anthropometric indicators demonstrates the importance of the early identification of HIV-infected infants who are at nutritional risk and the importance of the continuous assessment of nutritional interventions for these infants. PMID- 21670862 TI - Patterns of deliveries in a Brazilian birth cohort: almost universal cesarean sections for the better-off. AB - OBJECTIVE: To describe the patterns of deliveries in a birth cohort and to compare vaginal and cesarean section deliveries. METHODS: All children born to mothers from the urban area of Pelotas, Brazil, in 2004, were recruited for a birth cohort study. Mothers were contacted and interviewed during their hospital stay when extensive information on the gestation, the birth and the newborn, along with maternal health history and family characteristics was collected. Maternal characteristics and childbirth care financing - either private or public healthcare (SUS) patients - were the main factors investigated along with a description of C-sections distribution according to day of the week and delivery time. Standard descriptive techniques, Chi2 tests for comparing proportions and Poisson regression to explore the independent effect of C-section predictors were the methods used. RESULTS: The overall C-section rate was 45%, 36% among SUS and 81% among private patients, where 35% of C-sections were reported elective. C sections were more frequent on Tuesdays and Wednesdays, reducing by about a third on Sundays, while normal deliveries had a uniform distribution along the week. Delivery time for C-sections was markedly different among public and private patients. Maternal schooling was positively associated with C-section among SUS patients, but not among private patients. CONCLUSIONS: C-sections were almost universal among the wealthier mothers, and strongly related to maternal education among SUS patients. The patterns we describe are compatible with the idea that C sections are largely done to suit the doctor's schedule. Drastic action is called for to change the current situation. PMID- 21670863 TI - Gender differences in the field of sexology: new contexts and old definitions. AB - OBJECTIVE: To analyze concepts of gender and sexuality present in the field of sex therapeutic interventions. METHODOLOGICAL PROCEDURES: An ethnographic observation was conducted, and it was completed with the analysis of printed material originated from the X Congresso Brasileiro de Sexualidade Humana (10th Brazilian Congress on Human Sexuality), promoted by the Sociedade Brasileira de Estudos em Sexualidade Humana (Brazilian Society of Human Sexuality Studies), and the VIII Congresso Brasileiro sobre Inadequacoes Sexuais (8th Brazilian Congress on Sexual Inadequacies), promoted by the Associacao Brasileira para o Estudo das Inadequacoes Sexuais (Brazilian Association of Sexual Inadequacy Studies), both held in 2005. The analysis emphasized the interaction between the quantitative perspective in the processing of the variables (participants' gender and profession and lecture topics) and the qualitative perspective in the analysis and interpretation of the more general set of data. RESULTS: The topics of sessions and focus of presentations suggest that the field is divided by the contrast between two medical specialties: gynecology and urology, the former is aimed at female and couple dysfunctions, while the latter is aimed at male dysfunctions. CONCLUSIONS: Male sexuality is approached from the predominantly biomedical perspective, centered on the physiology of erection and drug prescription, whereas female sexuality is considered to be conditioned by relationship problems, when psychological intervention is more adequate. PMID- 21670864 TI - Infestation by triatomine bugs in indigenous communities of Valledupar, Colombia. AB - OBJECTIVE: To calculate triatomine infestation indices in indigenous communities in Colombia. METHODS: A descriptive study was carried out in 19 communities in Valledupar Municipality, Cesar Department, Colombia. During June to December, 2007, triatromine bugs were collected from their resting places in households. Taxonomic identification was made according to the keys by Lent & Wygodzinsky. An infection process in animal model and isozyme analysis of triatomine feces were performed. RESULTS: Rhodnius prolixus showed a density index of 154.7%, for Triatoma dimidiata was 102.45%, T. maculata 109.25% and Panstrogylus geniculatus 0.3%. The mean infestation index was 40.54%, and mean Trypanosoma infection index was 9.4%. Of five hemocultures positive for T. cruzi, three were enzimatically identified as T. cruzi group I. Biopsies revealed few pathologic characteristics of infective process with these strains isolated from domiciliary triatomine bugs. CONCLUSIONS: The high triatomine infestation indices in households and the T. cruzi infection index are evidence of active transmission of Chagas disease. The situation merits a vector control program and serological survey of the population at risk. The genetic characterization of T. cruzi strains as group I agrees with other findings on strains in this region of Colombia. PMID- 21670866 TI - E Schistosoma mansoni at the molecular and cellular biology of helminth parasites VI meeting. PMID- 21670865 TI - Self-rated health conditions of the adult population, Southern Brazil. AB - The study aimed to estimate how the adult population (20 to 59 years) of Joacaba, Southern Brazil, rates its health status. A cross-sectional study involving a representative sample (n=707) was carried out in 2006. The questionnaire surveyed sociodemographic conditions, restriction on daily activities, medical consultation, hospitalization and self-rated health. A hierarchical multiple logistic regression analysis was performed. It was verified that 74.7% of the individuals perceived their health as good and 3.9% perceived it as poor/very poor. Being unemployed at the moment of the interview and ceasing to perform daily activities due to health problems significantly increased the chance of poor /very poor self-rated health. PMID- 21670869 TI - Biogeochemical processes and the diversity of Nhecolandia lakes, Brazil. AB - The Pantanal of Nhecolandia, the world's largest and most diversified field of tropical lakes, comprises approximately 10,000 lakes, which cover an area of 24,000 km(2) and vary greatly in salinity, pH, alkalinity, colour, physiography and biological activity. The hyposaline lakes have variable pHs, low alkalinity, macrophytes and low phytoplankton densities. The saline lakes have pHs above 9 or 10, high alkalinity, a high density of phytoplankton and sand beaches. The cause of the diversity of these lakes has been an open question, which we have addressed in our research. Here we propose a hybrid process, both geochemical and biological, as the main cause, including (1) a climate with an important water deficit and poverty in Ca(2+) in both superficial and phreatic waters; and (2) an elevation of pH during cyanobacteria blooms. These two aspects destabilise the general tendency of Earth's surface waters towards a neutral pH. This imbalance results in an increase in the pH and dissolution of previously precipitated amorphous silica and quartzose sand. During extreme droughts, amorphous silica precipitates in the inter-granular spaces of the lake bottom sediment, increasing the isolation of the lake from the phreatic level. This paper discusses this biogeochemical problem in the light of physicochemical, chemical, altimetric and phytoplankton data. PMID- 21670871 TI - Nutrient budgets (C, N and P) and trophic dynamics of a Brazilian tropical estuary: Barra das Jangadas. AB - This paper focuses on the nutrient dynamics of a tropical estuary on the northeastern Brazilian coast, studied using the LOICZ biogeochemical budgeting protocol. We describe the methodology and assumptions underlying this model. Input data (monthly for rainfall, evaporation, river discharge, and concentrations of salt, phosphorus and nitrogen) were obtained during field campaigns in the Barra das Jangadas Estuary (BJE) over a 5 years period (1999 to 2003). Mass balance results indicate large inputs of nutrients to the system. The model shows that the seasonal variation of the Net Ecosystem Metabolism (NEM) indicates that the system passes from a stage of organic matter liquid production and mineralization during the dry season (-0.5 mmoles C m(-2) d(-1)) to liquid mineralization during the rainy season (-19 mmoles C m(-2) d(-1)). We suggest that the system varies slightly between autotrophy and heterotrophy during the year due to the rainfall regime, human activities in the basin (density population and sugarcane plantations), and associated DIP riverine loads. High per capita loads of N and P indicate a high population density and high runoff. The application of flux balance modeling was useful to understand the nutrient dynamics of this typical small tropical estuary. PMID- 21670872 TI - Geochemical behavior of heavy metals in differents environments in Rodrigo de Freitas lagoon - RJ/Brazil. AB - The accelerated urbanisation without a planning, brought several environmental problems to Rio de Janeiro coastal zone, especially in areas such as Rodrigo de Freitas lagoon, which receives a great amount of untreated sewage every day. To assess the nature, potentially sources and extent of heavy metal pollution in the lagoon, sediments from the surrounding streets, from the entrance of the main canal that drains to the lagoon and from the bottom of the lagoon were collected and analysed by a modified selective extraction procedure in order to study the geochemical partitioning and bioavailability of Zn, Cu, Cr, Ni and Pb in these three compartments. The present study verified an increase in the Cu, Pb and Zn concentrations in the north of the Rodrigo de Freitas lagoon. Despite the different levels of oxidation between the sediments accumulated in the streets and in the bottom of the lagoon, the geochemical partitioning of the heavy metals did not show any pattern of variation for the metals, except for the element Cu. No concentrations were found in the soluble phase of samples collected in the surfacial sediments of the lagoon, suggesting no bioavailability of heavy metals. PMID- 21670874 TI - Taxonomic review and phylogenetic analysis of Enchodontoidei. AB - Enchodontoidei are extinct marine teleost fishes with a long temporal range and a wide geographic distribution. As there has been no comprehensive phylogenetic study of this taxon, we performed a parsimony analysis using a data matrix with 87 characters, 31 terminal taxa for ingroup, and three taxa for outgroup. The analysis produced 93 equally parsimonious trees (L = 437 steps; CI = 0. 24; RI = 0. 49). The topology of the majority rule consensus tree was: (Sardinioides + Hemisaurida + (Nardorex + (Atolvorator + (Protostomias + Yabrudichthys ) + (Apateopholis + (Serrilepis + (Halec + Phylactocephalus ) + (Cimolichthys + (Prionolepis + ( (Eurypholis + Saurorhamphus ) + (Enchodus + (Paleolycus + Parenchodus ))))))) + ( (Ichthyotringa + Apateodus ) + (Rharbichthys + (Trachinocephalus + ( (Apuliadercetis + Brazilodercetis ) + (Benthesikyme + (Cyranichthys + Robertichthys ) + (Dercetis + Ophidercetis )) + (Caudadercetis + (Pelargorhynchus + (Nardodercetis + (Rhynchodercetis + (Dercetoides + Hastichthys )))))). The group Enchodontoidei is not monophyletic. Dercetidae form a clade supported by the presence of very reduced neural spines and possess a new composition. Enchodontidae are monophyletic by the presence of middorsal scutes, and Rharbichthys was excluded. Halecidae possess a new composition, with the exclusion of Hemisaurida. This taxon and Nardorex are Aulopiformes incertae sedis. PMID- 21670875 TI - Ethnoecological knowledge of the artisan fishermen of octopi in the community of Coroa Vermelha. AB - Coral reefs are quite diverse ecosystems that carry out several ecological functions and plays a relevant socioeconomic role. The artisan fishing of octopi (Octopus spp.) is practiced for the survival of part of the inhabitants of Coroa Vermelha community, in the south of the state of Bahia. We intended to study the knowledge of the octopi fishermen of Coroa Vermelha using the comprehensive ethnoecological proposal of Marques. The data were collected between July, 2006 and April, 2008 through direct observation and from interviews with fishermen met by chance and through the "native specialists" criterion. Twenty semi-structured interviews were carried out following an itinerary of pre-established questions about the activity of octopi capture, and the biological and ecological aspects of the resource. The data showed that the fishermen have knowledge about biological and ecological aspects of the octopi. Two capture techniques are used: octopus fishing (polvejamento) in the reefs and through diving. Two specific folk are recognized: the "normal octopus" (Octopus insularis) and the "east octopus" (Octopus macropus (?)). The intervieews demonstrated ecological knowledge sometimes compatible with the scientific literature, mainly in which concerns the trophic ecology and behavior of the octopi. PMID- 21670876 TI - Nutritional reserves of Vochysiaceae seeds: chemical diversity and potential economic uses. AB - Contents of proteins, carbohydrates and oil of seeds of 57 individuals of Vochysiaceae, involving one species of Callisthene, six of Qualea, one of Salvertia and eight of Vochysia were determined. The main nutritional reserves of Vochysiaceae seeds are proteins (20% in average) and oils (21. 6%). Mean of carbohydrate contents was 5. 8%. Callisthene showed the lowest protein content (16. 9%), while Q. cordata was the species with the highest content (30% in average). The contents of ethanol soluble carbohydrates were much higher than those of water soluble carbohydrates. Oil contents lay above 20% for most species (30. 4% in V. pygmaea and V. pyramidalis seeds). The predominant fatty acids are lauric (Q. grandiflora), oleic (Qualea and Salvertia) or acids with longer carbon chains (Salvertia and a group of Vochysia species). The distribution of Vochysiaceae fatty acids suggests for seeds of some species an exploitation as food sources (predominance of oleic acid), for other species an alternative to cocoa butter (high contents or predominance of stearic acid) or the production of lubricants, surfactants, detergents, cosmetics and plastic (predominance of acids with C(20) or C(22) chains) or biodiesel (predominance of monounsaturated acids). The possibility of exploitation of Vochysiaceae products in a cultivation regimen and in extractive reserves is discussed. PMID- 21670877 TI - Occurrence of the Indo-Pacific freshwater prawn Macrobrachium equidens Dana 1852 on the coast of Brazilian Amazonia, with notes on its reproductive biology. AB - The freshwater prawn Macrobrachium equidens, which is native species of the Indo Pacific Region, was recorded for the first time on the Amazon coast of Brazil. This species was found to inhabit the same environment as two native Macrobrachium species, M. amazonicum and M. acanthurus, and is morphologically very similar to the latter. The identification of the species was confirmed by the genetic analysis of sequences of the mitochondrial Cytochrome Oxidase (COI) gene. A detailed description of the morphological features and reproductive biology of M. equidens in this new environment is presented. PMID- 21670878 TI - Neuronal changes caused by Trypanosoma cruzi: an experimental model. AB - Define an experimental model by evaluating quantitative and morphometric changes in myenteric neurons of the colon of mice infected with Trypanosoma cruzi. Twenty eight Swiss male mice were distributed into groups: control (CG, n=9) and inoculated with 100 (IG(100), n=9) and 1000 (IG(1000), n=10) blood trypomastigotes, Y strain-T. cruzi II. Parasitemia was evaluated from 3-25 days post inoculation (dpi) with parasites peak of 7.7 * 10(6) and 8.4 * 10(6) trypomastigotes/mL at 8(th) dpi (p>0.05) in IG(100) and IG(1000), respectively. Chronic phase of the infection was obtained with two doses of 100mg/Kg/weight and one dose of 250mg/Kg/weight of Benznidazole on 11, 16 and 18 dpi. Three animals from each group were euthanized at 18, 30 and 75 dpi. The colon was stained with Giemsa. The quantitative and morphometric analysis of neurons revealed that the infection caused a decrease of neuronal density on 30(th) dpi (p<0.05) and 75 dpi (p<0.05) in IG(100) and IG(1000). Infection caused death and neuronal hypertrophy in the 75(th) dpi in IG(100) and IG(1000) (p<0.05, p<0.01). The changes observed in myenteric neurons were directly related to the inoculate and the time of infection. PMID- 21670879 TI - Variability in the trophic position of larval fishes in the upper Parana floodplain based on delta15N. AB - The upper Parana River floodplain is composed of several marginal lagoons, making it a natural breeding ground for many fish species at developmental stages. The aim of this study is to estimate the trophic positions of these fishes based on feed intake (measured via diet) and nitrogen assimilation (measured via delta(15)N). The monthly samplings were concentrated during the spawning season in the Ivinheima River, which is located in the upper Parana River floodplain. The specimens were grouped into preflexion, flexion and postflexion stages. Trophic positions were estimated based on the isotope value of nitrogen and on diet. During the developmental stages of P. squamosissimus, there were significant differences in the isotope values of delta(15)N; for H. edentatus, however, no significant differences were found. During the developmental stages, both species were classified as either at or above the third trophic level. Once this information is obtained for other species and components of the ecosystem, it will not only provide a more precise view of the energy allocation and flow in the ecosystem, but will also make possible for management measures to promote sustainability in this environment. PMID- 21670880 TI - The holoplankton of the Santa Catarina coast, southern Brazil. AB - This paper presents information from different sampling surveys carried out along the Santa Catarina coast in order to outline the biogeographical characteristics of the zooplankton in this region and identify species or groups of species with potential use as bioindicators. Based on a checklist of species of the zooplankton community in the state, it was observed that, in the warmer months of the year, the fauna is similar to that of the states of Parana and Sao Paulo (e.g. Creseis virgula f. virgula, Penilia avirostris; Acartia lilljeborgi and Oithona oswaldocruzi), while in the colder months there are coastal representatives of the fauna of Rio Grande do Sul (e.g. Acartia tonsa). However, the zooplankton consists predominantly of warm water species for most of the year, which is typical of Tropical Shelf Waters. Various species of zooplankton can be used as hydrological indicators, enabling a distinction to be made between coastal waters which are influenced by continental inputs (e.g. Paracalanus quasimodo and Parvocalanus crassirostris), common in the north of the state, and processes of upwelling (e.g. Podon intermedius) and the influence of the Subtropical Shelf Front (e.g. Pleopis polyphemoides), coming from the south. The different environments investigated present a zooplankton abundance that depends on the influence of continental inputs and the possibility of their retaining and contribution for the coastal enrichment, which varies seasonally. PMID- 21670881 TI - Constitution of ethnozoological semantic domains: meaning and inclusiveness of the lexeme "insect" for the inhabitants of the county of Pedra Branca, Bahia State, Brazil. AB - This article deals with the sociocultural construction of the 'insect' and 'animal' domains by the inhabitants of the county of Pedra Branca (municipality of Santa Terezinha, Bahia State, Brazil). The fieldwork was performed from September 2006 to July 2007. The data was obtained by means of open-ended interviews of 74 individuals of both genders whose ages ranged from 4 to 89 years old. The results show that the interviewees were unable to say in an accurate and secure way a specific definition for each domain. Depending on how a given animal is culturally interpreted, it could belong to the semantic domain 'animal' or 'insect', being representative of one or another group. However, in practice, such a distinction between these two semantic domains appears as something tenuous and ambiguous. Researchers who carry out biodiversity inventories should pay attention to the ethnocategory 'insect' during their studies, especially if these involve the participation of traditional community representatives. PMID- 21670882 TI - Whole blood transfusion in small animals: indications and effects. AB - Transfusion therapy is a major resource that can improve the patient's capability to overcome the underlying disease. However, the effects of whole blood infusion, and how they affect the patient's outcome, are not yet clear. For this study, a protocol was developed in order to monitor a group of 15 animals (9 dogs, 6 cats) that received a total of 19 transfusions; 3 animals received more than one transfusion each. The most common indications for blood transfusion included acute blood loss (47%), coagulopathy (33%) and other anaemias (20%). The mean pre transfusion packed cell volume (PCV) of animals with acute blood loss (18%) was higher than in the group of coagulopathy (15%) or other anaemias (15%). The survival rates at 6 days after transfusion were greater in the coagulopathy (80.0%) and other anaemias (66.7%) than in the group of acute blood loss (42.9%). After transfusion, pulse rate ( p <0.01) and platelet count ( p <0.05) decreased significantly, and there was a significant increase in body temperature of the animals that suffered from hypothermia before the transfusion ( p <0.05). Overall survival was predictable based upon posttransfusion body temperature, observed PCV change, the difference between the obtained and the calculated PCV, and administered transfusion volume ( p <0.05). PMID- 21670883 TI - Schistosoma mansoni Polo-like kinases and their function in control of mitosis and parasite reproduction. AB - Polo-like kinases are important regulators of cell cycle progression and mitosis. They constitute a family of conserved serine/threonine kinases which are highly related in their catalytic domains and contain polo boxes involved in protein protein interactions and subcellular localization. In mammals, five Plks (Plk 1 5) encompass diverse roles in centrosome dynamics, spindle formation, intra S phase and G2/M checkpoints and DNA damage response. Plk1 is a key positive regulator of mitosis and is overexpressed in various types of cancers. Plk4 is a divergent member of the Plk family, with essential functions in centriole duplication. Homozygous disruption of Plk1 or Plk4 in mice is lethal in embryos. Two Plk members SmPlk1 and SmSak, homologous to Plk1 and Plk4 respectively, are present in the parasitic platyhelminth Schistosoma mansoni. Structural and functional analyses of SmPlk1 have demonstrated its conserved function in the regulation of cell cycle G2/M transition in Xenopus oocytes. The anti-cancer drug BI 2536 (the most potent and selective Plk1 inhibitor) inhibits specifically the catalytic activity of SmPlk1 and induced profound alterations in schistosome gonads, indicating a role of SmPlk1 in parasite gametogenesis and its potential as a novel chemotherapeutic target against schistosomiasis. Functions of SmSak in cell cycle regulation and schistosome gonad development are currently investigated. PMID- 21670884 TI - Characterization of the cGMP-dependent protein kinase SmcGK1 of Schistosoma mansoni. AB - Schistosomes are trematode parasites and of worldwide medical importance for humans and animals. Growth and development of these parasites require a specific host environment, but also permanent communication processes between the two genders. Accumulating molecular evidence indicates that the responsible interactions are mediated by signal transduction processes. Conserved signaling molecules were identified, and first approaches made for their characterization. However, no representative of the conserved family of cGMP-dependent protein kinases (cGKs) has been described in this parasite yet. Within the Schistosoma mansoni genome data-set we identified cGK homologs, of which one was investigated in more detail in this study. We present the cloning of SmcGK1, whose sequence shows homology to cGKs of higher eukaryotes. SmcGK1 was found to be gender independently transcribed in adult schistosomes. The occurrence of SmcGK1 sense and antisense transcripts suggests that the expression of this gene is controlled at the post-transcriptional level. In situ hybridization experiments demonstrated a gonad-preferential expression profile in both genders indicating a role of SmcGK1, at least during sexual development of schistosomes. Using a cGK-specific inhibitor to treat adult schistosomes in vitro finally resulted in a multifaceted phenotype including slow motion, oocyte congestion, and reduced egg production. PMID- 21670885 TI - Cross-disciplinary approaches for measuring parasitic helminth viability and phenotype. AB - Parasitic worms (helminths) within the Phyla Nematoda and Platyhelminthes are responsible for some of the most debilitating and chronic infectious diseases of human and animal populations across the globe. As no subunit vaccine for any parasitic helminth is close to being developed, the frontline strategy for intervention is administration of therapeutic, anthelmintic drugs. Worryingly, and unsurprising due to co-evolutionary mechanisms, many of these worms are developing resistance to the limited compound classes currently being used. This unfortunate reality has led to a renaissance in next generation anthelmintic discovery within both academic and industrial sectors. However, a major bottleneck in this process is the lack of quantitative methods for screening large numbers of small molecules for their effects on the whole organism. Development of methodologies that can objectively and rapidly distinguish helminth viability or phenotype would be an invaluable tool in the anthelmintic discovery pipeline. Towards this end, we describe how several basic techniques currently used to assess single cell eukaryote viability have been successfully applied to parasitic helminths. We additionally demonstrate how some of these methodologies have been adopted for high-throughput use and further modified for assessing worm phenotype. Continued development in this area is aimed at increasing the rate by which novel anthelmintics are identified and subsequently translated into everyday, practical applications. PMID- 21670887 TI - Non-coding RNAs in schistosomes: an unexplored world. AB - Non-coding RNAs (ncRNAs) were recently given much higher attention due to technical advances in sequencing which expanded the characterization of transcriptomes in different organisms. ncRNAs have different lengths (22 nt to >1,000 nt) and mechanisms of action that essentially comprise a sophisticated gene expression regulation network. Recent publication of schistosome genomes and transcriptomes has increased the description and characterization of a large number of parasite genes. Here we review the number of predicted genes and the coverage of genomic bases in face of the public ESTs dataset available, including a critical appraisal of the evidence and characterization of ncRNAs in schistosomes. We show expression data for ncRNAs in Schistosoma mansoni. We analyze three different microarray experiment datasets: (1) adult worms' large scale expression measurements; (2) differentially expressed S. mansoni genes regulated by a human cytokine (TNF-alpha) in a parasite culture; and (3) a stage specific expression of ncRNAs. All these data point to ncRNAs involved in different biological processes and physiological responses that suggest functionality of these new players in the parasite's biology. Exploring this world is a challenge for the scientists under a new molecular perspective of host parasite interactions and parasite development. PMID- 21670886 TI - Schistosome serine protease inhibitors: parasite defense or homeostasis? AB - Serpins are a structurally conserved family of macromolecular inhibitors found in numerous biological systems. The completion and annotation of the genomes of Schistosoma mansoni and Schistosoma japonicum has enabled the identification by phylogenetic analysis of two major serpin clades. S. mansoni shows a greater multiplicity of serpin genes, perhaps reflecting adaptation to infection of a human host. Putative targets of schistosome serpins can be predicted from the sequence of the reactive center loop (RCL). Schistosome serpins may play important roles in both post-translational regulation of schistosome-derived proteases, as well as parasite defense mechanisms against the action of host proteases. PMID- 21670888 TI - Physio-anatomic aspects on the initial growth of Guazuma ulmifolia Lam. seedlings. AB - This paper aimed to evaluate the initial growth of "mutambo" seedlings in different conditions of light intensity and treatments with gibberellic acid (GA). The seedlings were kept under full sun and 50% of shading. Sixty days after the emergence, seedlings were sprayed with: 1) 100 mg L(-1) GA(3); 2) 200 mg L( 1) GA(3); 3) control. At the end of the appraisals, seedlings height under 50% of shading was compared to the height that were growing under full sun with 200 mg L(-1) GA. Stem diameter was lower under shading. Leaf area did not vary among the treatments, but the root system growth was higher under full sun and did not vary among GA levels. The number of stomata, trichomes and epidermal cells on adaxial and abaxial sides was higher under full sun. Total dry masses of leaf and root were highe runder full sun and with 200 mg L(-1) GA application. "Mutambo" seedlings presented a higher initial growth under full sun, although with a lower height, diameter, and lenght of the largest root and total dry masses of leaf and root were higher. A concentration with 200 mg L(-1) promoted a higher growth. PMID- 21670889 TI - Economic analysis of cucumber and lettuce intercropping under greenhouse in the winter-spring. AB - The economical analysis complements the evaluation of the intercrop systems efficiency, considering besides the physical production of crops, the price of products according to their quality classification and time of the year. Intercropping systems of lettuce and cucumber in two plant populations under greenhouse were economically evaluated in winter-spring, in Jaboticabal City, Sao Paulo State, Brazil. The total operating cost (TOC) of cucumber and lettuce as sole crop and intercropping were estimated, as well as gross revenue (GR) and operating profit (OP). The labor for the crops was the component with greater participation in the TOC of crops in intercropping and single crop. Greater GR and OP were observed in intercrops established by transplanting lettuce and cucumbers on the same day. Considering the operating profit and the land efficient ratio, it is recommended the intercropping of lettuce transplanted until 10 days after the transplanting (DAT) of cucumber with two rows per plot, and at 0 DAT of cucumber grown with a row plot. PMID- 21670890 TI - Intellectual property rights related to the genetically modified glyphosate tolerant soybeans in Brazil. AB - The present work analyzes the different modalities of protection of the intellectual creations in the biotechnology agricultural field. Regarding the Brazilian legislations related to the theme (the Industrial Property Law - no. 9. 279/96 and the Plant Variety Protection Law - no. 9. 456/97), and based in the international treaties signed by Brazil, the present work points to the inclusions of each of them, as well as to their interfaces using as reference the case study of glyphosate tolerant genetically modified soybean. For this case study, Monsanto's pipelines patents were searched and used to analyze the limits of patent protection in respect to others related to the Intellectual Property (IP) laws. Thus, it was possible to elucidate the complex scenario of the Intellectual Property of the glyphosate tolerant soybeans, since for the farmer it is hard to correlate the royalties payment with the IP enterprise's rights. PMID- 21670891 TI - Human mobility on the Brazilian coast: an analysis of strontium isotopes in archaeological human remains from Forte Marechal Luz Sambaqui. AB - This study investigated strontium isotopes in the dental enamel of 32 human skeletons from Forte Marechal Luz sambaqui (shellmound), Santa Catarina, Brazil, aiming at identifying local and non-local individuals. The archeological site presents pot sherds in the uppermost archeological layers. Dental enamel was also examined from specimens of terrestrial fauna ((87)Sr/(86)Sr = 0.71046 to 0.71273) and marine fauna ((87)Sr/(86)Sr = 0.70917). The (87)Sr/(86)Sr isotope ratio for individuals classified as locals ranged from 0. 70905 to 0. 71064 and was closer to the isotope ratio of the seawater than to the ratio of the terrestrial fauna, indicating a strong influence of marine strontium on the inhabitants of this sambaqui. The results indicate the existence of three non-local individuals ((87)Sr/(86)Sr = 0.70761 to 0.70835), buried in both the level without pottery and the layer with pottery, possibly originated from the Santa Catarina Plateau, close to the municipality of Lages, or from the Curitiba Plateau. The occurrence of a slight difference between the isotope ratios of local individuals buried in the archeological layer without pottery, when compared to those in the layer with pottery, suggests a possible change in dietary patterns between these two moments in the site's occupation. PMID- 21670893 TI - Drag reduction by polyethylene glycol in the tail arterial bed of normotensive and hypertensive rats. AB - This study was designed to evaluate the effect of drag reducer polymers (DRP) on arteries from normotensive (Wistar) and spontaneously hypertensive rats (SHR). Polyethylene glycol (PEG 4000 at 5000 ppm) was perfused in the tail arterial bed with (E+) and without endothelium (E-) from male, adult Wistar (N = 14) and SHR (N = 13) animals under basal conditions (constant flow at 2.5 mL/min). In these preparations, flow-pressure curves (1.5 to 10 mL/min) were constructed before and 1 h after PEG 4000 perfusion. Afterwards, the tail arterial bed was fixed and the internal diameters of the arteries were then measured by microscopy and drag reduction was assessed based on the values of wall shear stress (WSS) by computational simulation. In Wistar and SHR groups, perfusion of PEG 4000 significantly reduced pulsatile pressure (Wistar/E+: 17.5 +/- 2.8; SHR/E+: 16.3 +/- 2.7%), WSS (Wistar/E+: 36; SHR/E+: 40%) and the flow-pressure response. The E reduced the effects of PEG 4000 on arteries from both groups, suggesting that endothelial damage decreased the effect of PEG 4000 as a DRP. Moreover, the effects of PEG 4000 were more pronounced in the tail arterial bed from SHR compared to Wistar rats. In conclusion, these data demonstrated for the first time that PEG 4000 was more effective in reducing the pressure-flow response as well as WSS in the tail arterial bed of hypertensive than of normotensive rats and these effects were amplified by, but not dependent on, endothelial integrity. Thus, these results show an additional mechanism of action of this polymer besides its mechanical effect through the release and/or bioavailability of endothelial factors. PMID- 21670894 TI - Inhibition of cytohesin-1 by siRNA leads to reduced IGFR signaling in prostate cancer. AB - To explore how cytohesin-1 (CYTH-1) small interfering RNA (siRNA) influences the insulin-like growth factor receptor (IGFR)-associated signal transduction in prostate cancer, we transfected human prostate cancer PC-3 cell lines with liposome-encapsulated CYTH-1 siRNA in serum-free medium and exposed the cells to 100 nM IGF-1. The mRNA and protein levels of the signal molecules involved in the IGFR signaling pathways were determined by real-time PCR and detected by Western blotting. The relative mRNA levels of CYTH-1, c-Myc, cyclinD1 and IGF-1R (CYTH-1 siRNA group vs scrambled siRNA group) were 0.26 vs 0.97, 0.34 vs 1.06, 0.10 vs 0.95, and 0.27 vs 0.41 (P < 0.05 for all), respectively. The relative protein levels of CYTH-1, pIGF-1R, pIRS1, pAkt1, pErk1, c-Myc, and cyclinD1 (CYTH-1 siRNA group vs scrambled siRNA group) were 0.10 vs 1.00 (30 min), 0.10 vs 0.98 (30 min), 0.04 vs 0.50 (30 min), 0.10 vs 1.00 (30 min), 0.10 vs 1.00 (30 min), 0.13 vs 0.85 (5 h), and 0.08 vs 0.80 (7 h), respectively. The tyrosine kinase activity of IGF-1R was associated with CYTH-1. The proliferative activity of PC-3 cells transfected with CYTH-1 siRNA was significantly lower than that of cells transfected with scrambled siRNA at 48 h (40.5 vs 87.6%, P < 0.05) and at 72 h (34.5 vs 93.5%, P < 0.05). In conclusion, the interference of siRNA with cytohesin-1 leads to reduced IGFR signaling in prostate cancer; therefore, CYTH-1 might serve as a new molecular target for the treatment of prostate cancer. PMID- 21670895 TI - Ergoreflex activity in heart failure. AB - A large body of evidence has suggested the existence of a reflex network that becomes hyperactive secondary to musculoskeletal alterations that occur in heart failure (HF) syndrome. Together with sympathoinhibitory cardiovascular reflexes, suppressed in the presence of the syndrome, heart failure can contribute to physical exercise intolerance. The hyperactivation of signals originated from receptors located in skeletal muscles (mechanoreceptors - metaboreceptors) is a recently proposed hypothesis to explain the origin of fatigue and dyspnea symptoms in HF. In HF, other alterations in the reflex control system, which are not mutually exclusive, contribute to dyspnea. The inappropriate stimulation of the arterial baroreceptors, with the consequent lack of inhibition of the muscle metaboreflex and carotid chemoreflex unloading and the increase in the renal vasoconstriction with angiotensin II release can also be considered. Although the functional alterations of the reflexes were used independently to illustrate the sympathetic excitation observed in HF, the interaction between these reflexes under normal and pathological conditions, especially its contribution to the sympathoexcitatory state found in HF, has not been broadly investigated. Therefore, questions about a possible association between the muscle receptors (mechano and metaboreceptors) in the genesis of the ergoreflex exacerbation, observed in HF, remain. Thus, the objective of this review was to integrate the knowledge on the mechano and metaboreflex (ergoreflex) in HF syndrome, as well as to clarify the influence of HF drug therapy on the ergoreflex. PMID- 21670896 TI - Ventricular dyssynchrony and increased BNP levels in right ventricular apical pacing. AB - BACKGROUND: Long-term right ventricular apical pacing can cause ventricular dyssynchrony and, secondarily, neurohumoral alterations and increase in cardiac morbimortality. OBJECTIVE: To analyze ventricular dyssynchrony and its effects on BNP levels in patients with pacemakers and long-term right ventricular (RV) apex pacing. METHODS: Cross-sectional study of 85 patients with single or dual chamber pacemaker, NYHA functional class I or II and left ventricular ejection fraction (LVEF) >= 35%. The dyssynchrony assessment was carried out using several echocardiographic techniques, including Tissue Synchronization Imaging (TSI), with the analysis of the 12 segments. BNP was measured at the same time when the echocardiogram was performed, but the examiner was blinded to the results. RESULTS: Forty-six women and 39 men, aged 58 +/- 12 years, with Chagas' disease (56%) and controlled hypertensive individuals (62%), were included in the study. LVEF was 52 +/- 8% and the mean QRS duration was 139 ms (120-180 ms). BNP levels were altered in 36.5% of the sample (cutoff = 60 pg/ml). At the multivariate linear regression analysis, BNP was correlated with age (p = 0.024), LVEF (p < 0.0001) and left ventricular (LV) pre-ejection time (p = 0.009), which is an intraventricular dyssynchrony index. CONCLUSION: In clinically stable patients receiving conventional cardiac pacing, the intraventricular dyssynchrony was an independent predictor of BNP level increase after adjusted for age and LVEF. PMID- 21670897 TI - Validity and equivalence of the Portuguese version of the Veterans Specific Activity Questionnaire. AB - BACKGROUND: The Veterans Specific Activity Questionnaire (VSAQ) has been used to individualize exercise testing (ET) and to indirectly assess cardiorespiratory fitness (CRF) in epidemiological studies. Nevertheless, there is no validated Portuguese version. OBJECTIVE: To verify the criterion-related validity and the measurement equivalence of a Portuguese version of VSAQ in 95 individuals, 8 women (aged 69 +/- 7 years) referred to ET. METHODS: The subjects performed a cardiopulmonary test with incremental to maximal exercise on a cycle ergometer. The correlation between VSAQ score and Maximum Measured and Estimated METs was compared to results from other studies. The VSAQ Nomogram was calculated and its results were compared to CRF real values by linear regression. Limits of concordance and mean differences (biases) were assessed according to the Bland Altman methodology. RESULTS: The VSAQ scores were significantly correlated to the Measured METs (r = 0.64) and Estimated METs (r = 0.67), results that were equivalent to those obtained by the original versions. The VSAQ Nomogram presented multiple R of 0.78 (Measured MET) and 0.80 (Estimated MET). However, the Nomogram seems to have underestimated CRF values greater than 6 METs. CONCLUSION: The VSAQ version confirmed its validity and equivalence to the original version, especially when evaluating individuals with coronary heart disease and older adults. PMID- 21670898 TI - Keratoprosthesis in the fight against corneal blindness in developing countries. PMID- 21670899 TI - Epidemiology and medical prediction of microbial keratitis in southeast Brazil. AB - PURPOSE: The goals of the study were the following: 1) to show the epidemiology of microbial keratitis (MK) in the southeast Brazil, 2) to compare the epidemiological differences between fungal (FK) and bacterial keratitis (BK), and 3) to evaluate the frequency which ophthalmologists accurately differentiate bacterial keratitis from fungal keratitis based on clinical diagnosis. METHODS: A retrospective chart analysis of all clinically diagnosed microbial keratitis patients presenting between October, 2003 and September, 2006 was performed. Demographic features, ocular and laboratory findings, and information regarding the risk factors and clinical evolution were recorded. RESULTS: Among 118 consecutive patients with a clinical diagnosis of microbial keratitis, the positive culture rate was 61%. The predominant bacterial and fungal pathogens isolated were S. epidermidis and Fusarium spp. Prior corneal injury was more frequent among fungal keratitis than bacterial keratitis cases (p<0.0001). Coexisting systemic diseases, ocular diseases, and previous ocular surgery were more frequent among BK cases (p=0.001; p=0.001; p=0.004; respectively). The following clinical findings were more frequent in bacterial keratitis: hypopion, corneal peripheral superficial vascularisation, and ulceration area >20 mm2 (p<0.05). The diagnosis was predicted correctly in 81.6% of bacterial keratitis cases and in 48.1% of fungal keratitis cases. CONCLUSION: Medical judgment of microbial keratitis agent is possible based on clinical and epidemiological data, but it is more difficult for fungal infection. Thus, such data cannot be the only basis for the diagnosis of suspected microbial keratitis, but oriented clinical suspicion based on these data may be beneficial for guiding antimicrobial treatment and earlier therapy. PMID- 21670900 TI - Corneal biomechanical evaluation in healthy thin corneas compared with matched keratoconus cases. AB - PURPOSE: To evaluate and compare corneal hysteresis (CH) and corneal resistance factor (CRF) in healthy eyes with a central corneal thickness (CCT) < 505 um with CH and CRF in gender-, age-, and CCT-matched keratoconus cases, and to estimate the sensitivity and specificity of these parameters for discriminating between the two groups. METHODS: Prospective, comparative case series. In total 46 eyes from 30 healthy patients with CCT < 505 um, and 42 eyes from 30 CCT-, gender- and age-matched keratoconus cases were enrolled. Biomechanical metrics (CH and CRF) were measured using the Ocular Response Analyzer (ORA) and then compared. A receiver operating characteristic (ROC) curve was used to identify cut-off points to maximize the sensitivity and specificity for discriminating between the groups. RESULTS: The CCT was 485.96 +/- 17.61 um (range, 438 - 505) in healthy thin corneas and 483.64 +/- 16.19 um (range, 452 - 505) in keratoconus; p=0.5225. CH was 8.63 +/- 1.23 mmHg (range, 5.95 - 12.2) and 8.07 +/- 1.17 mmHg (range, 4.9 - 9.85), respectively; p=0.0312. CRF was 8.43 +/- 1.29 mmHg (range, 5.45 - 11.10) and 7.22 +/- 1.34 mmHg (range, 4.7 - 9.45), respectively; p<0.001. ROC curve analysis showed a poor overall predictive accuracy of CH (cut-off, 8.95 mmHg; sensitivity, 63%; specificity, 23.8%; test accuracy, 44.30%) and CRF (cut-off, 7.4 mmHg; sensitivity, 28.3%; specificity, 40.5%; test accuracy, 34.12%) for detecting keratoconus in the eyes studied. CONCLUSION: CH and CRF were statistically lower in keratoconus than in healthy thin corneas. However, CH and CRF offered very low sensitivity and specificity for discriminating the groups. PMID- 21670901 TI - [Characteristics of corneal donors in the Cascavel Eye Bank: impact of the anti HBc test for hepatitis B]. AB - PURPOSE: To describe the characteristics of human ocular tissue donors from the Cascavel Eye Bank in the State of Parana (PR) and investigate the impact of hepatitis B serologic test positivity on discarded ocular tissues. METHODS: Cross sectional study of data collected between March 2006 and April 2007 at the Cascavel Eye Bank. Information such as age, gender, cause of death, time between death and enucleation, and serologic tests results was collected. Data were used to characterize the study population and stratified according to hepatitis B (anti-HBc) status. RESULTS: Mean age of donors was 54.2 +/- 20.6 years and a greater proportion of men (64,7%) was observed. Mean time between death and enucleation was 3.8 +/- 2.4 hours, cardiovascular diseases were the main cause of death (34.5%). Positivity of anti-HBc and HBsAg tests was 47.4% and 1.5%, respectively. Hepatitis B was the main reason for discarding corneas. Donors whose serologic tests were positive for anti-HBc had higher mean age compared to those with negative tests (p<0.001). Only 0.8% of all donations tested positive for hepatitis C and donors with positive HIV test were not seen in our study. CONCLUSIONS: Activities of the Cascavel Eye Bank significantly increased the availability of corneas for transplant in the State of Parana. The main contraindication for availability of ocular tissues was positivity of serologic tests for anti-HBc. Biosafety studies should be performed in order to investigate the potential transmission of hepatitis B virus for donors with positive tests for anti-HBc. The inclusion of these donors would increase the number of corneas available for transplant. PMID- 21670902 TI - Incidence of epithelial lesions of the conjunctiva in a review of 12,102 specimens in Canada (Quebec). AB - PURPOSE: The purpose of this study was to assess the relative frequency of epithelial lesions of the conjunctiva in Canada. METHODS: A retrospective study of 12,102 consecutive cases received during 16 years (1993-2009) at the Henry C. Witelson Ocular Pathology Laboratory in Montreal, Canada, was performed. Demographic data was retrieved from histopathological request forms and specimens were categorized and analyzed by mean percentage. The relative frequency of epithelial lesions of the conjunctiva from a single center in Canada, representing the province of Quebec was reviewed. RESULTS: Of the 12,102 specimens reviewed, 273 were conjunctival lesions (2.25%), including 86 epithelial tumors (0.71%) of the conjunctiva that comprised the studied sample. The average age of these patients was 59.9 +/- 17.6 years, and gender distribution was 66 (69%) males and 30 (31%) females. Fifteen lesions (17.4%) were classified as squamous cell papillomas (mean age, 57.3 +/- 16.7 years). Within the ocular surface squamous neoplasia (OSSN) spectrum, there were 10 (11.6%) actinic keratosis (63.8 +/- 17.6 years), 27 (31.3%) cases of conjunctival intraepithelial neoplasia (CIN) with variable degrees of atypia (mild to moderate) (63.9 +/- 15.3 years), 15 (17.4%) carcinomas in situ (66.7 +/- 18.0 years), and 17 (19.7%) squamous cell carcinomas (SCC) (56.2 +/- 19.4 years). Two other rare cases of malignant tumors included one basal cell carcinoma and one mucoepidermoid carcinoma. CONCLUSIONS: The distribution of our sample is similar to the one reported by the American Forces Institute of Pathology (AFIP) in 1994. When we compare our sample to others coming from countries with high levels of sunlight exposure, we found a lower incidence of ocular surface squamous neoplasia, including squamous cell carcinomas in Canada. PMID- 21670903 TI - [Variations of postoperative ocular alignment in patients submitted to strabismus surgery]. AB - PURPOSE: To determine the drift variations of the postoperative alignment in patients who underwent strabismus surgery and to identify possible risk factors associated with such occurrence. PATIENTS AND METHODS: We reviewed the variations in postoperative alignment drift of 819 patients who underwent rectus muscle surgery from January, 1995 to December, 2005 at the Hospital de Clinicas da Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo. The patients were divided into four groups according to the type of deviation (alternating esotropia, monocular esotropia, alternating exotropia and monocular exotropia). Changes in eye positioning were quantified in each group. RESULTS: The prevalence of variations in the postoperative angle (considering variations more than 10 ?) among the total of studied patients was 33.5% (274 patients). In those patients, a higher frequency was found in the exotropic direction (178 patients or 65.0%) than in the esotropic direction (96 patients or 35,0%), and this difference was statistically significant (chi-square test; p<0.001). CONCLUSIONS: Eye positioning instability can occur over time in patients who underwent strabismus surgery. This incident reinforces the need for the development of alternative therapies in order to provide greater stability to the oculomotor system in the follow-up of strabismus surgery. PMID- 21670904 TI - [Main pathogens and in vitro antimicrobial susceptibility in bacterial keratitis: 5-year study, 2005-2009]. AB - PURPOSE: To determine the most common pathogens involved in the etiology of bacterial keratitis at the Sorocaba Ophthalmological Hospital and the in vitro susceptibility of main antimicrobial used in the treatment of this pathology. METHODS: Retrospective study of all patients suspected of infectious keratitis that underwent microbiological exam at the Sorocaba Ophthalmological Hospital, between 2005 and 2009. To test susceptibility of antimicrobial drugs, antibiograms were made through the standard method of discs diffusion and interpretation following the National Committee on Clinical Laboratory Standards (NCCLS, Villanova, PA, USA). RESULTS: 963 samples were obtained in this period and 278 (28.86%) were positive for some pathogen. Among the positive for bacteria, the most common were Staphylococcus aureus (30.56%), Staphylococcus epidermidis (30.56%), Streptococcus sp (9.43%) and Pseudomonas sp (9.43%). Dividing in Gram's method, 191 (72.08%) were Gram-positive and 74 (27.92%) were Gram-negative. Analyzing in vitro antimicrobial effectiveness, the majority presented good susceptibility rates, beyond 85%, except cephalotin which presented 53.13%. At the same analysis, higher resistance rates with cephalotin (33.47%) and ciprofloxacin (11.36%) were noted. CONCLUSION: Gram-positive bacteria were the most common pathogen isolated at microbiologic exams, especially staphylococci. despite the increasing number of isolated Gram-negative bacteria, meanly represented by Pseudomonas, related with the widespread use of contact lenses. Laboratorial exam revealed high sensibility values for most of antibiotics (more than 85%), except for cephalotin (53.13%). Higher resistance values were observed with cephalotin (33.47%) and ciprofloxacin (11.36%). With all these important variability of antibiotic susceptibility and pathogens involved in bacterial keratitis etiology, it is very important to know the specific characteristics of each infection for a better patient care. PMID- 21670905 TI - [Visual behavior and socioeconomic and demographic profile of the premature newborns from Federal University of Pernambuco Maternity (UFPE)]. AB - OBJECTIVE: To characterize the behavior of premature newborns in the first year of chronological age. METHODS: This is a cross-sectional descriptive study, bound to a longitudinal study titled: "Comparison of visual behavior on the first quarter of year of life of premature nursling born at two maternities of Recife/PE." The sample was composed by 52 premature newborns selected from June, 2007 to June, 2008 from the Maternity of the Federal University of Pernambuco (UFPE). Biological, socioeconomic and demographic data was collected through medical records and interviews with progeny. Newborns were evaluated by the Assessment Guide of Visual Ability in Infants. RESULTS: Most of the newborns were male at a gestational period between 33 weeks and 36 weeks and 6 days, showed a good visual behavior development for the age researched, and most of the families showed good socioeconomical and demographic profile. Besides, it was possible to detect ocular signs in 19% of sample, that were referred to an Ophthalmology Service. CONCLUSION: This study results point out the method like an important key in the early detection and visual screening for premature nursling since the first month of life and it led us to believe that clinical view for occupational therapy intervention must be focused not only on biological risks but also at the influence environment in newborn performance. PMID- 21670906 TI - Axonal electrovisiogram as an electrophysiological test to evaluate optic nerve and inner retina electrical potentials: findings in normal subjects. AB - PURPOSES: To standardize and validate the technique of axonal electrovisiogram (AxEvg), defining its normative values and parameters and characterizing its findings in normal individuals. METHODS: We enrolled 140 normal individuals (280 eyes) divided into seven groups according to age, each one with 10 males and 10 females. The technique was based on monocular visual stimulation by a 0 dB intensity bright flash on Ganzfeld bowl at a presentation rate of 1.4 Hz. Golden cup electrodes were used and electrical waves were acquired after artifact rejection. For each amplitude and implicit time peak we calculated the mean, median, pattern deviation, minimum and maximum values and 95% confidence interval. RESULTS: Monocular visual stimulation with bright flash under mesopic conditions was the standard technical procedure established. The normal AxEvg waveform consists of an initial positive wave (named P1, with mean amplitude of 2.0 mV and mean implicit time peak of 23.1 ms) followed by a negative wave (named N1, with mean amplitude of -3.9 mV and mean implicit time peak of 41.4 ms). No significant differences were observed between males and females or between right and left eyes, but there was an increased P1 and N1 implicit time peaks according to age. Implicit time characteristics suggest that P1 wave represents an optic nerve electrical potential and N1 wave represents an inner retinal layers potential. CONCLUSIONS: AxEvg can be considered a pre-chiasmatic visual evoked potential capable to reliably record the electrical activity of optic nerve and inner retina. The findings suggest that AxEvg may be useful as an electrophysiological test in the diagnosis of neuroretinal diseases. PMID- 21670907 TI - [Treatment of tear trough deformity with hyaluronic acid gel filler]. AB - BACKGROUND: Volume loss and muscular hyperactivity are two major components of the aging process that contribute to the formation of the folds and wrinkles. Tear trough deformity is one of the most difficult depressions to correct surgically. PURPOSE: The aim of this study was to evaluate the results of ten patients submitted to periorbital filling with hyaluronic acid gel filler. METHODS: Between June and August, 2008, 10 patients have had their tears troughs treated with hyaluronic acid gel filler. The filler was introduced by a serial puncture technique and approximately 0.1 ml was injected at each pass. The filler was placed in the pre-periosteal tissue. Patients photographs before and after the procedure were reviewed to assess the outcomes. RESULTS: The mean volume per side needed to achieve correction was on the right side 0.61 ml (SD=0.25) and on the left side 0.65 ml (SD=0.26). The most common complications were bruising, erythema, local swelling, and pain at the injection site. The effect of treatment lasted up to 12 months. CONCLUSIONS: This pilot study showed that the treatment of tear trough deformity with hyaluronic acid gel filler was feasible, predictable and effective. All patients were very satisfied with their results. PMID- 21670908 TI - [Effect of subconjunctival bevacizumab on corneal neovascularization and reepithelization 25 days after chemical burn]. AB - PURPOSES: To evaluate the effect of subconjunctival bevacizumab in an experimental model of neovascularization in rabbit cornea. Determine its effect on vessels extension, inflammation, epithelialization of the cornea and whether the evaluation method used is appropriate to compare neovascular models. METHODS: Experimental, prospective, randomized, blinded study in twenty rabbits subjected to chemical trauma with sodium hydroxide at 1N divided into two groups. The study group received subconjunctival injection of 0.15 ml (3.75 mg) of bevacizumab and was compared with the control group that received subconjunctival injection of 0.15 ml saline solution. After 25 days, digital photographic analysis was performed to assess the vessel's extension and inflammation/diameter according to pre-established criteria. Histopathology of the cornea, which evaluated the state of the epithelium and the number of polymorphonuclear cells was also studied. RESULTS: The length of the neovessels was greater in the control group compared to the study group (P=<0.001). There was no difference in inflammation/vessel diameter between groups. Histopathology analysis showed that there was no difference between groups for the variables state of the epithelium and number of polymorphonuclear cells. The concordance analysis for the variable extension of the vessels and the variable inflammation/vessel diameter was estimated with Kappa coefficients of 0.705 and 0.500 respectively, indicating a good level of agreement in different evaluations and validating the method. CONCLUSIONS: The experimental model is adequate and can be reproduced to evaluate other drugs in the cornea. Bevacizumab inhibit the neovessels' growth but was not effective in preventing the inflammatory response. The drug did not delay the reepithelialization of the cornea. PMID- 21670909 TI - Posterior scleral tuberculoma: case report. AB - Posterior scleral tuberculoma formation is an extremely rare condition. The few reports on scleral involvement in tuberculosis refer to cases of anterior scleritis. In the present manuscript we describe a patient who had rheumatoid arthritis and developed a large posterior scleral tuberculoma. The lesion provoked retinal detachment and visual loss and was diagnosed only after enucleation due to a misdiagnosis of choroidal melanoma. PMID- 21670910 TI - Ichthyosis follicularis, alopecia and photophobia syndrome (IFAP): report of the first case with ocular and cutaneous manifestations in Brazil with a favorable response to treatment. AB - Ichthyosis follicular, alopecia, and photophobia (IFAP) syndrome is a rare disease, with possible X-linked mode of inheritance. The patient presented with ocular findings of photophobia, corneal scarring and erosions, superficial and deep corneal vascularization and myopia. He was treated with artificial tears and punctal occlusion with small improvement of photophobia. After three months using systemic retinoid (Acitretina) and posterior amniotic membrane transplantation in the left eye, there was a significant improvement of photophobia, corneal erosions and neuropsychomotor development. PMID- 21670911 TI - Management of globe luxation followed by traumatic liquoric fistula: case report. AB - This report describes the only case in the literature of globe luxation due to traumatic cerebrospinal fluid fistula to the orbit caused by fire gun with ocular globe maintenance. E.N., female, white, 7 months, admitted with left orbitocranial injury by fire gun. Ocular globe luxation was detected with complete ocular motility restriction and absence of pupillary reflex in the left orbit. Computed tomography showed fracture of the medial orbital wall; bone fragments near the apex of the orbit and a stretched optic nerve. Surgical exploration was performed, showing liquor fistula through the ethmoid-sphenoid wall that was blocked with sponge (Gelfoam(r)) plus organic glue in the left orbit posterior wall, with immediate resolution of the proptosis and ocular integrity maintenance. Although controversial, maintenance of the ocular globe instead of enucleation was performed due to the integrity of the globe in this case. Despite the blindness, we considered the result to the proposed treatment excellent, once the maintenance of the ocular globe provides a good appearance and will contribute to an adequate facial bone development. PMID- 21670912 TI - Bilateral nonarteritic anterior ischemic neuropathy following acute angle-closure glaucoma in a patient with iridoschisis: case report. AB - A 55-year-old woman was referred to our clinic because of a one-week history of visual loss and raised intraocular pressure in the left eye followed 4 days later by visual loss in the right eye. Slit-lamp examination showed bilateral conjunctival hyperemia, slight diffuse corneal edema, shallow anterior chamber and fixed and dilated pupil in both eyes. Splitting of the anterior layers of the iris with fibrillar degeneration extending for approximately one quadrant inferiorly was presented in each eye. Fundus examination showed optic disc edema with no vascular tortuosity and no cup in both eyes. The condition was treated as bilateral acute angle-closure glaucoma in a patient with irisdoschisis. After medical treatment and improvement of visual acuity, perimetry revealed a significant visual field defect especially in left eye; this case represents a rare concurrence of acute angle-closure glaucoma and bilateral nonarteritic ischemic optic neuropathy. Although most cases of elevated intraocular pressure, including acute angle-closure glaucoma, do not result in optic disc edema and irreversible vision loss, variations in the vascular supply of the nerve optic head along with others ocular systemic risk factors, may predispose certain individuals to nonarteritic ischemic optic neuropathy during periods of elevated intraocular pressure. PMID- 21670913 TI - Floppy eyelid syndrome: review. AB - Floppy eyelid syndrome is characterized by the easy evertion of the upper eyelid which occurs spontaneously during the sleep, causing the exposure of the eye surface and chronic papillary conjunctivitis. Its pathogenesis is not totally defined yet: it is usually more frequent in middle-aged, male obese patients and it is associated with systemic disorders such as obstructive sleep apnea, high blood pressure and diabetes. On the occasions which conservative treatment fails, surgical procedures present good results, including surgical techniques which are constantly evolving. PMID- 21670914 TI - [Cross-linking and intrastromal corneal ring segment]. AB - Corneal cross-linking is a procedure used for stabilizing the cornea in patients with progressive keratoconus by increasing corneal rigidity, and it is also used in corneal inflammatory melting process. The intrastromal corneal ring segments act by flattening the center of the cornea. Originally designed for the correction of mild myopia, the segments are now being used for reduction of keratoconus in order to improve the uncorrected visual acuity, the best spectacle corrected visual acuity, to allow good tolerance to the use of contact lenses and delay the need for corneal grafting procedures. The present text presents a review of corneal cross-linking and insertion of intrastromal corneal ring segments, emphasizing their indications, results and complications related until now. PMID- 21670915 TI - Staphylococcus aureus regulates secretion of interleukin-6 and monocyte chemoattractant protein-1 through activation of nuclear factor kappaB signaling pathway in human osteoblasts. AB - OBJECTIVE: Activation of nuclear factor kappaB by diverse bacteria regulates the secretion of chemokines and cytokines. Staphylococcus aureus (S. aureus)-infected osteoblasts can significantly increase the secretion of interleukin-6 and monocyte chemoattractant protein-1. The aim of this study was to investigate whether S. aureus can activate nuclear factor kappaB in human osteoblasts, and whether the activation of nuclear factor kappaB by S. aureus regulates the secretion of interleukin-6 and monocyte chemoattractant protein-1. METHODS: Immunoblot and electrophoretic mobility shift assay were used to detect the degradation of IkappaBa and activation of nuclear factor kappaB in human osteoblasts in response to S. aureus, respectively. Enzyme-linked immunosorbent assay was used to measure the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants. Lastly, carbobenzoxyl-l-leucinyl-l leucinyl-l-leucinal, an inhibitor of the nuclear factor kappaB, was used to determine if activation of nuclear factor kappaB by S. aureus in human osteoblasts regulates the secretions of interleukin-6 and monocyte chemoattractant protein-1. RESULTS: Our results for the first time demonstrated that S. aureus can induce the degradation of IkappaBa and activation of nuclear factor kappaB in human osteoblasts in a time and dose-dependent manner. In addition, inhibition of nuclear factor kappaB by carbobenzoxyl-l-leucinyl-l leucinyl-l-leucinal suppressed the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants of S. aureus-infected human osteoblasts in a dose-dependent manner. CONCLUSION: These findings suggest that S. aureus can activate nuclear factor kappaB in human osteoblasts, and subsequently regulate the secretion of interleukin-6 and monocyte chemoattractant protein-1. The nuclear factor kappaB transcription factor regulates a number of genes involved in a wide variety of biological processes. Further study of the effects of nuclear factor kappaB activation on S. aureus-infected human osteoblast may provide us new insights into discovery of the immune mechanisms in osteomyelitis. PMID- 21670916 TI - Metallo-beta-lactamase and genetic diversity of Pseudomonas aeruginosa in intensive care units in Campo Grande, MS, Brazil. AB - Infection by Pseudomonas aeruginosa has spread worldwide, with limited options for treatment. The purpose of this study was to investigate metallo-beta lactamase-producing P. aeruginosa strains and compare their genetic profile using samples collected from patients in intensive care units. Forty P. aeruginosa strains were isolated from two public hospitals in Campo Grande, Mato Grosso do Sul State, from January 1st, 2007 to June 31st, 2008. Profiles of antimicrobial susceptibility were determined using the agar diffusion method. Metallo-beta lactamase was investigated using the double-disk diffusion test and PCR. Molecular typing was performed by pulsed-field gel electrophoresis (PFGE). Respiratory and urinary tracts were the most common isolation sites. Of the 40 samples tested, 72.5% (29/40) were resistant to ceftazidime and 92.5% (37/40) to imipenem, whereas 65% (26/40) were resistant to both antimicrobials. Fifteen pan resistant samples were found. Five percent (2/40) of samples were positive for metallo-beta-lactamase on the phenotype test. No metallo-beta-lactamase subtype was detected by PCR. Macrorestriction analysis revealed 14 distinct genetic patterns. Based on the superior accuracy of PCR, it can be inferred that P. aeruginosa isolates from the investigated hospitals have alternative mechanisms of carbapenem resistance. The results also suggest clonal spread of P. aeruginosa between the studied hospitals. PMID- 21670917 TI - Biocide activity of microfiber mops with and without silver after contamination. AB - OBJECTIVE: The purpose of the present research was to compare the residual microbial load in Solo System microfiber mops with silver and in normal microfiber mops without silver to see whether those with the silver prevent bacterial proliferation and spread more effectively during normal cleaning operations. METHODS: Mops with and without silver were experimentally contaminated with suspension of Staphylococcus aureus ATCC 6538. The bioburden was evaluated by a filtering procedure according to UNI EN 1174 after contamination, after washing and after different times of impregnation in an alcohol-base detergent. RESULTS AND DISCUSSION: The results obtained lead to the conclusion that silver microfiber mop was significantly more effective in reducing bacterial load despite initial high level contamination (106-107 CFU/50 cm2). Indeed, after low temperature washing, the bacterial load was already completely eliminated while the mop without silver still presented relatively high levels of the microorganism (approximately 102 CFU/50 cm2) even after being soaked for 8 hours in a detergent/disinfectant. PMID- 21670918 TI - Comparison of different primes for PCR-based diagnosis of cutaneous leishmaniasis. AB - OBJECTIVE: The objective of this study was to analyze different primers that are commonly used in epidemiological studies for the detection of Leishmania DNA by PCR, and to compare them to the conventional direct parasite search for American cutaneous leishmaniasis (ACL) diagnosis. MATERIAL AND METHODS: Five pairs of primers, four of them derived from Leishmania kDNA sequences (MP3H-MP1L; B1-B2; LBF1-LBR1; 13A-13B), and one derived from the SL RNA (mini-exon) gene repeat (LU5A-LB3C), reported previously, were used. RESULTS: The MP3H-MP1L primers were the best at amplifying the DNA, detecting 2 fg of Leishmania spp. DNA. The 13A 13B primers presented the worst performance, detecting 512 x 103 fg of DNA. CONCLUSION: The wide variation in the analytical sensitivity of the primers used in the PCR, and the significant differences from the conventional method of ACL diagnosis found in this study, emphasize the importance of standardizing the PCR technique, analyzing sensitivity, and selecting suitable oligonucleotide primers. PMID- 21670919 TI - Diagnosis and quantitative detection of HSV DNA in samples from patients with suspected herpes simplex encephalitis. AB - Diagnosis of herpes simplex encephalitis (HSE) is based on the detection of herpes simplex virus (HSV) DNA in patients' CSF samples. HSV DNA quantitation has the potential for estimating the effects of antiviral therapy. The aim of this study was to diagnose HSV DNA in HSE suspected patients and the quantitative analysis of its genome using real-time PCR to assess the value of the viral load in the course of antiviral treatment. The CSF samples were collected from 236 consecutive HSE suspected patients from November 2004 to May 2008. Upon DNA extraction, the samples were analyzed by Real-Time PCR assay. A set of primers amplified a common sequence of HSV glycoprotein B gene. The copy numbers of unknown samples were expressed via a standard curve drawn with a known amount of amplified cloned plasmid. Of the 236 samples, 137 (58%) came from males and 99 (42%) from females. The HSV genome was detected in 22 (9.3%) patients by PCR, 13 males/ 9 females. Serial CSF samples were available from 10 of the 22 patients. The range of the HSV DNA copy numbers in the clinical samples ranged from 2.5 * 102 to 1.7 * 106 copies/mL of CSF. Quantitative PCR results can be helpful in evaluating the efficacy of antiviral therapy in the above-mentioned patients. There is an association between the initial viral load and the duration of treatment course. PMID- 21670920 TI - Rotavirus infection in a tertiary hospital: laboratory diagnosis and impact of immunization on pediatric hospitalization. AB - BACKGROUND AND OBJECTIVES: Rotavirus (RV) is the main etiological agent of diarrhea in childhood; its laboratory diagnosis is crucial to guide the clinical management and prevention of its spread. RV immunization was introduced in Brazilian 6-month-old children in 2006. The present study was aimed to evaluate three methodologies used for human RV detection in stool samples obtained from patients hospitalized due to gastroenteritis in a teaching hospital and report the impact of RV immunization in hospitalization by diarrhea. METHODS: 293 stool samples collected in the 2001-2008 period were analyzed by enzyme immunoassay (EIA), latex agglutination (LA) and polyacrylamide gel electrophoresis (PAGE). RESULTS: Rotavirus was detected in 34.8% of samples by LA assay, 28.3% of samples by EIA assay and in 25.6% of samples by PAGE assay. Considering the PAGE method as gold standard, the sensitivity, specificity and accuracy of EIA were 94.6%, 94.4% and 94.5%, and to LA were 82.6%, 81.6% and 81.9%, respectively. CONCLUSION: These results indicate that antigen detection by EIA is a rapid, sensitive and specific method, and could be used in large-scale applications for screening stool samples suspected of RV infection. This study showed decreased incidence of RV infection in hospitalized children prior to the implementation of the national immunization program against RV. PMID- 21670921 TI - Respiratory virus infections among hospitalized patients with suspected influenza A H1N1 2009 virus during the first pandemic wave in Brazil. AB - INTRODUCTION: During the first pandemic wave of the influenza A H1N1 2009 virus, morbidity was particularly high in Brazil. Hospitalizations resulting from severe respiratory disease due to suspected influenza-like illness created an opportunity to identify other respiratory viruses causing lower respiratory infections. OBJECTIVE: The purpose of this study was to assess viral etiologies among samples collected during the first pandemic wave of H1N1 2009 from hospitalized patients with suspected cases in a Brazilian Sentinel Hospital. PATIENTS AND METHODS: Viral etiologies were investigated in samples from 98 children and 61 adults with fever, cough and dyspnea who were admitted to Sao Paulo Sentinel Hospital with suspected H1N1 infection. RESULTS: From August to November 2009, in 19.5% (31/159) of the samples 2009 H1N1 virus was detected with 23% (14/61) in adults (median age 25 years, range: 14-55 years) and 18.4% (17/92) in children (median age 5 years, range: 4 months - 11 years). Among the negative samples, a wide range of causative etiologic agents was identified. Human rhinovirus was the most frequent virus (23.91%) in children and human metapneumovirus (11.48%) was the second most frequent in adults, following 2009 H1N1 virus (22.95%). CONCLUSION: These data highlight the need to diagnose other viral infections that can co-circulate with influenza and may have been neglected by physicians as causes of severe respiratory diseases. PMID- 21670922 TI - Cost-effectiveness of telbivudine versus lamivudine for chronic hepatitis B. AB - BACKGROUND AND AIM: Chronic hepatitis B is a highly prevalent disease worldwide, leading to serious consequences if not properly treated. Six treatment options for chronic hepatitis B are currently provided by the Brazilian public health system. Telbivudine is a nucleoside analogue that is neither included in the Brazilian clinical protocol nor in the therapeutic guidelines for chronic hepatitis B. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of telbivudine for the viewpoint of the Brazilian public system, comparing it to lamivudine. METHODS: A Markov model was used to project lifetime complications and costs of treatment with lamivudine or telbivudine for chronic hepatitis B in both HBeAg-positive and HBeAg-negative patients. To evaluate disease progression, probabilities and utilities of virologic response, virologic resistance, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, treatment, interruption of treatment, death and seroconversion were collected in systematic reviews. Costs were collected in DATASUS, ABC da Saude and scientific literature. RESULTS: Higher rate of virologic response and seroconversion was obtained with telbivudine, and also higher values of quality adjusted life years. However lamivudine is associated with lower costs and also lower cost-effectiveness values. The incremental cost-effectiveness ratios for telbivudine, when compared with lamivudine, were US$ 30,575 and US$ 40,457, respectively for HBeAg-positive and HBeAg-negative patients. CONCLUSION: In chronic hepatitis B lamivudine is a more cost-effective or even cost-saving strategy when compared with telbivudine. PMID- 21670923 TI - TNF -308G > a promoter polymorphism (rs1800629) and outcome from critical illness. AB - BACKGROUND: The susceptibility to adverse outcome from critical illness (occurrence of sepsis, septic shock, organ dysfunction/failure, and mortality) varies dramatically due to different degrees of inflammatory response. An over expression of tumor necrosis factor alpha (TNF-alpha) can lead to the progression of the inflammatory condition. OBJECTIVE: We assessed the relationship of the genotype distribution of -308G >A TNF-alpha polymorphism with regard to the development of sepsis, septic shock, higher organ dysfunction or mortality in critically ill patients. METHODS: Observational, hospital-based cohort study of 520 critically ill Caucasian patients from southern Brazil admitted to the general ICU of Sao Lucas Hospital, Porto Alegre, Brazil. Patients were monitored daily from the ICU admission day to hospital discharge or death, measuring SOFA score, sepsis, and septic shock occurrences. The -308G >A TNF-alpha SNP effect was analyzed in the entire patient group, in patients with sepsis (349/520), and in those who developed septic shock (248/520). RESULTS: The genotypic and allelic frequencies were -308GG = 0.72; -308GA = 0.27; -308AA = 0.01; -308G = 0.85; -308A = 0.15. No associations were found with sepsis, septic shock, organ dysfunction, and/or mortality rates among the TNF-alpha genotypes. Our results reveal that the -308G >A TNF-alpha SNP alone was not predictive of severe outcomes in critically ill patients. CONCLUSION: The principal novel input of this study was the larger sample size in an investigation with -308G > A TNF-alpha SNP. The presence of 308A allele is not associated with sepsis, septic shock, higher organ dysfunction or mortality in critically ill patients. PMID- 21670925 TI - Prevalence and factors associated with darunavir resistance mutations in multi experienced HIV-1-infected patients failing other protease inhibitors in a referral teaching center in Brazil. AB - Information about resistance profile of darunavir (DRV) is scarce in Brazil. Our objectives were to estimate the prevalence of DRV resistance mutations in patients failing protease inhibitors (PI) and to identify factors associated with having more DRV resistance mutations. All HIV-infected patients failing PI-based regimens with genotyping performed between 2007 and 2008 in a referral teaching center in Sao Paulo, Brazil, were included. DRV-specific resistance mutations listed by December 2008 IAS-USA panel update were considered. Two Poisson regression models were constructed to assess factors related to the presence of more DRV resistance mutations. A total of 171 HIV-infected patients with available genotyping were included. The number of patients with lopinavir, saquinavir, and amprenavir used in previous regimen were 130 (76%), 83 (49%), and 35 (20%), respectively. The prevalence of major DRV resistance mutations was 50V: 5%; 54M: 1%; 76V: 4%; 84V: 15%. For minor mutations, the rates were 11I: 3%; 32I: 7%; 33F: 23%; 47V: 6%; 54L: 6%; 74P: 3%; 89V: 6%. Only 11 (6%) of the genotypes had > 3 DRV resistance mutations. In the clinical model, time of HIV infection of > 10 years and use of amprenavir were independently associated with having more DRV resistance mutations. In the genotyping-based model, only total number of PI resistance mutations was associated with our outcome. In conclusion, the prevalence of DRV mutations was low. Time of HIV infection, use of amprenavir and total number of PI resistance mutations were associated with having more DRV mutations. PMID- 21670924 TI - Candida species isolated from the vaginal mucosa of HIV-infected women in Salvador, Bahia, Brazil. AB - BACKGROUND: Vulvovaginal candidiasis (VVC) is the second most common vaginal infection. HIV-infection is a risk factor for this infection. OBJECTIVE: To determine the frequency of VVC and to describe the main Candida species isolated and their susceptibility to antifungal drugs in HIV-infected patients, compared to HIV-uninfected women in Salvador, Brazil. METHODS: Cross-sectional study including a group of 64 HIV-infected women and 76 uninfected women, followed up at the AIDS reference center and at the Gynecological Clinic of Escola Bahiana de Medicina e Saude Publica (Salvador, Bahia, Brazil). RESULTS: Frequency of Candida spp. was higher in HIV-infected women (29.7%) than in HIV-uninfected controls (14.5%) (p = 0.02). The odds ratio value for vulvovaginal candidiasis in HIV infected patients was 2.6 (95% CI: 1.07 - 6.32 p = 0.03). Candida albicans was the most commonly isolated species in both HIV-infected (52.3%) and uninfected women (85.7%), followed by C. parapsolis in 17.6% and 14.3%, respectively. In HIV infected women, C. glabrata, C. parapsilosis, and a coinfection of C. albicans and C. glabrata were also identified. There was no significant difference between Candida species isolated from the vaginal mucosa of women with VVC and colonization of the vaginal mucosa of HIV-infected and HIV-uninfected women. One C. glabrata isolate from an HIV-infected patient was resistant to fluconazole and other two isolates exhibited a dose-dependent susceptibility. CONCLUSION: Our results confirm a higher frequency of Candida spp. isolated from the vaginal mucosa of HIV-infected women and a broader spectrum of species involved. Only Candida glabrata isolates showed decreased susceptibility to fluconazole. PMID- 21670926 TI - Physician adherence to guidelines for tuberculosis and HIV care in Rio de Janeiro, Brazil. AB - BACKGROUND: Tuberculosis is the most common opportunistic infection among HIV infected patients in Brazil. Brazil's national policy for HIV care recommends screening for latent tuberculosis (TB) and implementing isoniazid preventive therapy (IPT). OBJECTIVES: We compared physician adherence to TB screening and other prevention and care policies among HIV primary care clinics in Rio de Janeiro City. METHODS: Data on performance of CD4 counts, viral load testing, tuberculin skin testing (TST) and IPT were abstracted from patient charts at 29 HIV clinics in Rio de Janeiro as part of the TB/HIV in Rio (THRio) study. Data on use of pneumocystis jiroveci pneumonia (PCP) prophylaxis were also abstracted from a convenience sample of 150 patient charts at 10 HIV clinics. Comparisons were made between rates of adherence to TB guidelines and other HIV care guidelines. RESULTS: Among the subset of 150 patients with confirmed HIV infection in 2003, 96% had at least one reported CD4 counts result; 93% had at least one viral load result reported; and, PCP prophylaxis was prescribed for 97% of patients with CD4 counts < 200 cells/mm3 or when clinically indicated. In contrast, 67 patients (45%) had a TST performed (all eligible); and only 11% (17) of eligible patients started IPT. Among 12,027 THRio cohort participants between 2003 and 2005, the mean number of CD4 counts and viral load counts was 2.5 and 1.9, respectively, per patient per year. In contrast, 49% of 8,703 eligible patients in THRio had a TST ever performed and only 53% of eligible patients started IPT. CONCLUSION: Physicians are substantially more compliant with HIV monitoring and PCP prophylaxis than with TB prophylaxis guidelines. Efforts to improve TB control in HIV patients are badly needed. PMID- 21670928 TI - Impact of macrolide therapy on mortality of HIV-infected patients with community acquired pneumonia in a tertiary teaching hospital. AB - BACKGROUND: Bacterial pneumonia is one of the main causes of morbidity and mortality in patients infected by the human immunodeficiency virus (HIV). The main objective of this study was to evaluate the effect of macrolide therapy in combination with a beta-lactam based empiric regimen for inpatients with community-acquired pneumonia and HIV. METHODS: This is a retrospective cohort study of hospitalized patients. Adult patients who had received treatment with ceftriaxone or ceftriaxone plus clarithromycin were included. RESULTS: 76 patients met the inclusion criteria. Among baseline characteristics analyzed, only respiratory rate showed significant difference: patients who had received clarithromycin were more likely to have a respiratory rate > 30/min than patients who received only ceftriaxone (64% versus 36%, p = 0.03). ICU admission was the only outcome that showed a significant difference, more frequent in the ceftriaxone plus clarithromycin group (45% versus 20%, p = 0.03). CONCLUSIONS: This study does not support the addition of a macrolide to a beta-lactam based regimen in HIV-infected patients. This is probably related to the patients' immunodeficiency status, which impairs the immunomodulatory properties of the macrolides. PMID- 21670927 TI - Lopinavir/ritonavir dosing during pregnancy in Brazil and maternal/infant laboratory abnormalities. AB - OBJECTIVES: To describe laboratory abnormalities among HIV-infected women and their infants with standard and increased lopinavir/ritonavir (LPV/r) dosing during the third trimester of pregnancy. METHODS: We evaluated data on pregnant women from NISDI cohorts (2002-2009) enrolled in Brazil, who received at least 28 days of LPV/r during the third pregnancy trimester and gave birth to singleton infants. RESULTS: 164 women received LPV/r standard dosing [(798/198 or 800/200 mg/day) (Group 1)] and 70 increased dosing [(> 800/200 mg/day) (Group 2)]. Group 1 was more likely to have advanced clinical disease and to use ARVs for treatment, and less likely to have CD4 counts > 500 cells/mm3. Mean plasma viral load was higher in Group 2. There were statistically significant, but not clinically meaningful, differences between groups in mean AST, ALT, cholesterol, and triglycerides. The proportion of women with Grade 3 or 4 adverse events was very low, with no statistically significant differences between groups in severe adverse events related to ALT, AST, total bilirubin, cholesterol, or triglycerides. There were statistically significant, but not clinically meaningful, differences between infant groups in ALT and creatinine. The proportion of infants with Grade 3 or 4 adverse events was very low, and there were no statistically significant differences in severe adverse events related to ALT, AST, BUN, or creatinine. CONCLUSION: The proportions of women and infants with severe laboratory adverse events were very low. Increased LPV/r dosing during the third trimester of pregnancy appears to be safe for HIV-infected women and their infants. PMID- 21670929 TI - Seroprevalence of hepatitis A immunity among brazilian adult patients with liver cirrhosis: is HAV vaccination necessary? AB - BACKGROUND: Patients with chronic liver disease have a higher risk of fulminant hepatitis when infected with hepatitis A virus, and vaccination of these patients against such infection is recommended. In Brazil, mainly in the South and Southeast regions, the epidemiology of hepatitis A (HA) has shifted from high to intermediate endemicity, which would have implication on policy of HA vaccination for these populations. OBJECTIVE: To verify the prevalence of HA immunity in adult patients with liver cirrhosis (LC), in Uberlandia MG, a city of Southeastern Brazil. METHODS: Between December 2005 and December 2006, 106 patients with LC were consecutively evaluated. In addition, 75 individuals without LC or alcoholism were evaluated (control group - CG). RESULTS: Total anti HAV (ELISA methods) was positive in 104 (98.1%) patients with LC (82 men, 24 women; mean age, 53.3 +/- 11.9 years) and in 74 (98.7%) individuals of the CG (55 men, 20 women; mean age, 47 +/- 11.6 years), p > 0.05. CONCLUSIONS: For patients with chronic liver disease, in the geographic regions and age groups evaluated, routine vaccination against hepatitis A is not recommended. Moreover, the serum determination of total anti-HAV, used to assess immunity, is five times cheaper than vaccination against hepatitis A and, for this reason, should precede vaccination. PMID- 21670930 TI - Seroepidemiological survey of transmissible infectious diseases in a portuguese prison establishment. AB - A cross-sectional study was conducted in 151 (71.6%) of 211 male inmates of a regional Portuguese prison in order to establish the seroprevalence for viral hepatitis (HAV, HBV, HCV), human immunodeficiency virus (HIV), syphilis and herpes simplex virus (HSV-1 and HSV-2) and to analyze some psychosocial and criminal characteristics. Mean age was 34 years. Anti-HAV was positive in 69.5% (n = 105) and in 34.4% (n = 52) for anti-HCV. One (0.7%) person had HBsAg and 29 (19.2%) had laboratory markers of past HBV infection. Non-immune inmates for HBV were 40.4% (n = 61). Syphilis was diagnosed in 6.0% (n = 9). The rate of HIV infection was 6.6% (n = 10; all HIV-1). The seropositivity of HSV-2 was 19.9% (n = 30) and of HSV-1 was 82.1% (n = 124). Alcohol dependence was reported by 26.5% (n = 40). Excluding tobacco and prescription medication, 73.5% (n = 111) reported drug use in prison. The most commonly used drugs were: cannabis (100%; n = 111) followed by heroin (56.7%; n = 63). Anti-HCV rate was noteworthy. The HIV infection rate (6.6%) in this regional prison is at least 13 to 22 times greater than in general population. As the inmate return to the community increases the risk of disease exposure for the general population, early detection and counseling is urgently needed for prisoners. PMID- 21670931 TI - Polyoma BK virus: an emerging opportunistic infectious agent of the human central nervous system. AB - BK virus, a double-stranded DNA virus, is a member of the Polyomaviridae family which is known to infect humans. Clinical evidence of disease is mostly encountered in immunosuppressed individuals such as AIDS patients or those who undergo renal or bone marrow transplantation where complications associated with BKV infection manifest commonly as a polyomavirus nephropathy or hemorrhagic cystitis, respectively. Recent evidence suggests that in addition to the JC virus (the other member of the same family known to be strongly neurotropic and responsible for the progressive multifocal leukoencephalopathy), BK virus can infect and cause clinically relevant disease in the human central nervous system. In this mini-review, an analysis of the literature is made. A special focus is given to alert clinicians to the possibility of this association during the differential diagnosis of infections of the central nervous system in the immunocompromised host. PMID- 21670932 TI - Fatal adenoviral necrotizing bronchiolitis case in a post-cardiac surgery intensive care unit. AB - We report a case of a 67 year-old-male patient admitted to the intensive care unit in the post-coronary bypass surgery period who presented cardiogenic shock, acute renal failure and three episodes of sepsis, the latter with pulmonary distress at the 30th post-operative day. The patient expired within five days in spite of treatment with vancomycin, imipenem, colistimethate and amphotericin B. At autopsy severe adenovirus pneumonia was found. Viral pulmonary infections following cardiovascular surgery are uncommon. We highlight the importance of etiological diagnosis to a correct treatment approach. PMID- 21670933 TI - Infection of the lymphatic system by Aureobasidium pullulans in a patient with erythema nodosum leprosum. AB - Aureobasidium pullulans is a causal agent of phaeohyphomycosis, occasionally found in men and animals. As an agent of different opportunistic fungal processes, it may cause fungemia, systemic infections and abscesses in different viscera. This paper aims to report a case of a patient with infection of the lymphatic system by A. pullulans. A 23-year-old patient being treated for erythema nodosum leprosum presented a 60-day complaint of daily fever, hoarseness, odynophagia and weight loss. Laboratory tests showed pancytopenia with severe neutropenia, cervical adenomegaly and solid contrast uptake lesion in the oropharyngeal region. Due to neutropenia and sepsis the patient was initially treated with cefepime and vancomycin, but there was no clinical improvement. Lymph node puncture-aspiration showed yeast-form fungus identified as A. pullulans by sequencing ITS region. The patient was treated with amphotericin B deoxycholate, leading to complete recovery of bone marrow function and regression of adenomegaly and the oropharyngeal lesion. PMID- 21670934 TI - Methicillin-resistant Staphylococcus lugdunensis carrying SCCmec type V misidentified as MRSA. AB - Staphylococcus lugdunensis is a rare cause of severe infections and clinical manifestations are similar to those related to S. aureus infection. We describe a hospital-acquired bacteremia due to methicillin-resistant Staphylococcus lugdunensis, misidentified as methicillin-resistant S. aureus. The oxacillin MIC was 16 ug/mL and the mecA gene and SCCmec type V were determined by PCR. Although treatment had been appropriated, the patient died after rapid progressive respiratory failure and another nosocomial sepsis. It is important not only to identify S. lugdunensis in view of its clinical course, but also to determine its susceptibility to oxacillin by detecting the mecA gene or its product. PMID- 21670935 TI - Surveys of catheter-associated urinary tract infection in a university hospital intensive care unit in China. PMID- 21670936 TI - Hantavirus pulmonary syndrome: when should you consider this diagnosis? PMID- 21670937 TI - HCV genotype 4 circulating in the city of Franca, Sao Paulo state, Brazil. PMID- 21670938 TI - Cell therapy in dilated cardiomyopathy: back to the right scientific track? PMID- 21670939 TI - Authors' reply to "Cell therapy in dilated cardiomyopathy: back to the right scientific track?". PMID- 21670940 TI - GM1 improves neurofascin155 association with lipid rafts and prevents rat brain myelin injury after hypoxia-ischemia. AB - White matter injury characterized by damage to myelin is an important process in hypoxic-ischemic brain damage (HIBD). Because the oligodendrocyte-specific isoform of neurofascin, neurofascin 155 (NF155), and its association with lipid rafts are essential for the establishment and stabilization of the paranodal junction, which is required for tight interaction between myelin and axons, we analyzed the effect of monosialotetrahexosyl ganglioside (GM1) on NF155 expression and its association with lipid rafts after HIBD in Sprague-Dawley rats, weighing 12-15 g, on day 7 post-partum (P7; N = 20 per group). HIBD was induced on P7 and the rats were divided into two groups: one group received an intraperitoneal injection of 50 mg/kg GM1 three times and the other group an injection of saline. There was also a group of 20 sham-operated rats. After sacrifice, the brains of the rats were removed on P30 and studied by immunochemistry, SDS-PAGE, Western blot analysis, and electron microscopy. Staining showed that the saline group had definite rarefaction and fragmentation of brain myelin sheaths, whereas the GM1 group had no obvious structural changes. The GM1 group had 1.9-2.9-fold more GM1 in lipid rafts than the saline group (fraction 3-6; all P < 0.05) and 0.5-2.4-fold higher expression of NF155 in lipid rafts (fraction 3-5; all P < 0.05). Injection of GM1 increased the content of GM1 in lipid rafts as well as NF155 expression and its lipid raft association in HIBD rat brains. GM1 may repair the structure of lipid rafts, promote the association of NF155 (or other important proteins) with lipid rafts, stabilize the structure of paranodes, and eventually prevent myelin sheath damage, suggesting a novel mechanism for its neuroprotective properties. PMID- 21670941 TI - Work-related falls from ladders--a follow-back study of US emergency department cases. AB - OBJECTIVES: Ladder falls comprise 16% of all US workplace fall-related fatalities, and ladder use may be particularly hazardous among older workers. This follow-back study of injured workers from a nationally representative sample of US emergency departments (ED) focused on factors related to ladder falls in three domains of the work environment: work equipment, work practices, and worker related factors. Risk factors for fractures, the most frequent and severe outcome, were also evaluated. METHODS: Workers injured from a ladder fall, treated in one of the 65 participating ED in the occupational National Electronic Injury Surveillance System (NEISS) were asked to participate. The questionnaire included worker demographics, injury, ladder and work equipment and environment characteristics, work tasks, and activities. Multivariate logistic regression models estimated odds ratios and 95% confidence intervals of a work-related fracture. RESULTS: Three-hundred and six workers experiencing an injury from an- on average--7.5-foot-fall from a step, extension, or straight ladder were interviewed primarily from construction, installation, maintenance, and repair professions. Injuries were most frequently to the arm, elbow or shoulder; head, neck, or face with diagnoses were primarily fracture, strain, sprain, contusion or abrasion. Workers were most frequently standing or sitting on the ladder while installing, hanging an item, or performing a repair when they fell. Ladder movement was the mechanism in 40% of falls. Environmental conditions played a role in <10% of cases. There was a significant association between fracture risk and fall height while working on the ladder that was also influenced by older work age. CONCLUSIONS: This study advances knowledge of falls from ladders to support those who specify means and methods, select equipment, and plan, supervise, or manage the performance of employees working at heights. PMID- 21670942 TI - Feasibility and effects of a physical exercise programme in adults with myotonic dystrophy type 1: a randomized controlled pilot study. AB - OBJECTIVE: To investigate the feasibility and effects of a physical exercise programme on functioning and health-related quality of life in adults with myotonic dystrophy type 1. DESIGN: A randomized controlled trial. SUBJECTS: Thirty-five adults with myotonic dystrophy type 1. METHODS: After stratification for level of functioning, study participants were assigned by lot to either a training group or a control group. Training-group participants attended a 60 minute comprehensive group-training programme, Friskis&Svettis(r) Open Doors, twice a week for 14 weeks. The six-minute walk test was the primary outcome measure and the timed-stands test, the timed up-and-go test, the Epworth sleepiness scale and the Short Form-36 health survey were secondary outcome measures. RESULTS: Intention-to-treat analyses revealed no significant differences in any outcome measures, except for an increased between-group difference after intervention in the Short Form-36 mental health subscale and a decrease in the vitality subscale for the control group. The programme was well tolerated and many training-group participants perceived subjective changes for the better. No negative effects were reported. CONCLUSION: The Friskis&Svettis(r) Open Doors programme was feasible for adults with myotonic dystrophy type 1 who had been screened for cardiac involvement, had distal or mild-to-moderate proximal muscle impairment, and no severe cognitive impairments. No beneficial or detrimental effects were evident. PMID- 21670943 TI - The anatomic and radiographic measurement of C2 lamina in Chinese population. AB - OBJECTIVE: In this study, we performed anatomic and computed tomography (CT) measurements of C2 lamina in Chinese people in order to provide the anatomic and radiographic data, and to verify the clinical applicability of trans-lamina screws to this population. METHODS: The anatomic and radiographic measurement was conducted on two separate groups, group A and group B. In group A, a total of 96 human adult (male 51, female 45) cadaver spines were included. The minimal height (H1), thickness (T), length (L1) of C2 lamina, height of the root of lamina (H2), distance from the entry point to the lateral rim of lamina (L2) and to the lateral rim of lateral mass (L3) were bilaterally measured using high precision calipers. The spino-laminar angles (angle A) were also included. In group B, a total of 112 volunteers (male 58, female 54) without upper cervical abnormality were enrolled. Angle A, H1, T, L1, H2, L2 and L3 were bilaterally measured using plain X-rays and reconstruction CT. All measurements were taken at the thinnest part of the lamina in the axial and coronal plane. RESULTS: All the measurements (except angle A) in males were significantly higher than those in females (P < 0.05). There was no significant difference in the values of bilateral laminae between group A and group B (P > 0.05). The thickness of 45% specimens was less than 6 mm. The length of lamina in all specimens was less than 2.5 cm, while only 5% of the specimens had a length of >3 cm from the entry point to the rim of lamina. The length from the entry point to the lateral rim of lateral mass was between 2.5 and 4.6 cm. In contrast, the length of only 5% specimens was longer than 4 cm. CONCLUSIONS: The preoperative radiographic evaluation is very important to determine the suitable size of screws. The diameter of screws is mainly restricted by the thickness of C2 lamina. It is safe to use screws with a length of 2.5-3.0 cm for Chinese people. The radiographic measurement method we used is simple, accurate and reliable for preoperative measurement. PMID- 21670944 TI - Validation of the Korean version of the Scoliosis Research Society-22 questionnaire. AB - INTRODUCTION: We evaluated the reliability and validity of an adapted Korean version of the Scoliosis Research Society-22 (SRS-22) questionnaire. MATERIALS AND METHODS: Translation/retranslation of the English version of SRS-22 was conducted, and all steps of the cross-cultural adaptation process were performed. The Korean version of the SRS-22 questionnaire and the previously validated Short Form-36 (SF-36) outcome instruments were mailed to 102 patients who had been treated surgically for idiopathic scoliosis. Eighty-two patients responded to the first mailing of questionnaires and 64 of the first-time responders returned their second survey. The average age of the 64 patients (56 females and 8 males) was 18.3 years. Reliability assessment was determined by estimating Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Concurrent validity was evaluated by comparing SRS-22 domains with relevant domains in the SF-36 questionnaire using Pearson's correlation coefficient. RESULTS: The study demonstrated satisfactory internal consistency (Cronbach's alpha = 0.80-0.89) for function/activity, pain and mental health, and good consistency (Cronbach's alpha = 0.50-0.79) for the remaining domains. The ICC of all domains demonstrated excellent test/retest reproducibility. Considering concurrent validity, 3 domains showed excellent correlation, 9 domains good, 25 domains moderate, and 3 domains poor. CONCLUSION: The adapted Korean version of the SRS-22 questionnaire was successfully translated and showed acceptable measurement properties, and as such, is considered suitable for treatment outcome assessments in the Korean speaking patients with idiopathic scoliosis. PMID- 21670945 TI - The analysis of segmental mobility with different lumbar radiographs in symptomatic patients with a spondylolisthesis. AB - PURPOSE: Lumbar flexion-extension radiographs in standing position (SFE) are the most commonly used imaging method to evaluate segmental mobility. Many surgeons use SFE to disclose abnormal vertebral motion and base their decision for surgical fusion on its results. We tested the hypothesis that imaging in standing and recumbent position (SRP) reveals a higher sagittal translation (ST) and sagittal rotation (SR) in symptomatic patients than with SFE. MATERIALS AND METHODS: We analysed images of 100 symptomatic patients with a low-grade spondylolisthesis that underwent surgical fusion. To determine the ST and SR in SRP, we compared the images taken in the recumbent position in the CT with images taken in the standing position during the routine plain radiography. RESULTS: The measurement of ST revealed an absolute value of 2.3 +/- 1.5 mm in SFE and 4.0 +/- 2.0 mm in SRP and differed significantly (p = 0.001). The analysis of the relative value showed an ST of 5.9 +/- 3.9% in SFE and 7.8 +/- 5.4% in SRP (p = 0.008). The assessment of ST in flexion and in a recumbent position (FRP) revealed the highest ST (4.6 +/- 2.5 mm or 9.2 +/- 5.7%). Comparison of SR showed the highest rotation in SFE (6.1 degrees +/- 3.8 degrees ), however, compared to SRP (5.4 degrees +/- 3.3 degrees ), it missed the level of significance (p = 0.051). CONCLUSIONS: For evaluation of ST in symptomatic patients with spondylolisthesis SRP appears to be more suitable than SFE, while a pathological SR is better revealed in SFE. The analysis of SRP might offer a complementary method to detect or exclude pathological mobility in more cases. PMID- 21670947 TI - Aversive learning overcomes appetitive innate responding in honeybees. AB - Despite their miniature brain, honeybees have emerged as a powerful model for the study of learning and memory. Yet, they also exhibit innate responses to biologically relevant social signals such as pheromones. Here, we asked whether the bees' developed learning capabilities allow them to overcome hardwired appetitive responses. Can they learn that attractant pheromones, that are not normally associated with a noxious stimulation in nature, predict the punishment of an electric shock? Immobilized honeybees were trained to discriminate two odorants, one that was paired with a shock and another that had no consequences. We measured whether they learned to produce aversive sting extension responses to the punished but not the non-punished odorant. One odorant was a neutral odor without innate value while the other was either an attractive pheromone (geraniol or citral) or an attractive floral odorant (phenylacetaldehyde). In all cases, bees developed a conditioned aversive response to the punished odorant, be it pheromone or not, and efficiently retrieved this information 1 h later. No learning asymmetries between odors were found. Thus, associative aversive learning in bees is strong enough to override preprogrammed responding, thus reflecting an impressive behavioral flexibility. PMID- 21670948 TI - Variance-sensitive choice in lemurs: constancy trumps quantity. AB - Numerous studies have demonstrated that animals' tolerance for risk when foraging can be affected by changes in metabolic state. Specifically, animals on a negative energy budget increase their preferences for risk, while animals on a positive energy budget are typically risk-averse. The malleability of these preferences may be evolutionarily advantageous, and important for maximizing chances of survival during brief periods of energetic stress. However, animals adapted to living in unpredictable conditions are unlikely to benefit from risk seeking strategies, and instead are expected to reduce energetic demands while maintaining risk-aversion. We measured risk preferences in lemurs, a group of primates restricted to the island of Madagascar. Lemurs have evolved diverse anatomical and behavioral traits for survival in a harsh and unpredictable ecology, and these traits have been explained as forms of anatomical and behavioral risk reduction. We therefore predicted that lemurs would also be risk averse in a behavioral task that offered subjects a choice between a small certain reward, and an uncertain but potentially large reward. In Experiment 1, the average rewards associated with the constant and variable options were equal and lemurs exhibited high levels of risk-aversion, replicating a phenomenon that has been demonstrated in dozens of taxa. In Experiment 2, we gradually increased the average value of the variable option relative to the constant option. Lemurs' preferences tracked these changes and subjects became more risk-seeking as the risk premium increased. However, many subjects maintained high levels of risk aversion even when the average payout of the variable option yielded double that of the constant option. These results are consistent with the notion that lemur cognition has evolved to minimize risk in an unpredictable island environment. PMID- 21670949 TI - Erratum to: N-Glycosylation profiling of recombinant mouse extracellular superoxide dismutase produced in Chinese hamster ovary cells. PMID- 21670950 TI - Reactivity of pulmonary circulation and right ventricle function to inhaled nitric oxide in systemic sclerosis patients. AB - Systemic sclerosis (SSc) is complicated by pulmonary hypertension and right ventricle (RV) failure in approximately 10% of the patients. Factors influencing the reactivity of pulmonary circulation to vasodilators are not established, while the examination of vasoreactivity is important in determining the treatment, because systemic administration of oral vasodilators can induce severe adverse events in nonresponders. The mechanism of RV failure in SSc is unclear and may result either from increased RV afterload or intrinsic myocardial disease. The aim of the study was to assess the reactivity of pulmonary circulation to inhaled nitric oxide (iNO) and to evaluate its influence on RV function in SSc patients with elevated right ventricle systolic pressure (RVSP). In 60 SSc patients aged 24-73 (58 females, two males; 33 patients with limited SSc and 27 with diffuse SSc), echocardiographic examination with tissue Doppler echocardiography (TDE) was performed. RV function was measured by systolic (S) and early diastolic (E) velocity of tricuspid annulus by TDE. In patients with RVSP >45 mmHg, the reactivity of pulmonary circulation was assessed by iNO test. High-resolution computerized tomography (HRCT) was performed to assess the extent of pulmonary fibrosis. Of 14 SSc subjects with elevated RVSP (13 females, one male; RVSP 47-62 mmHg), positive reaction to iNO was observed in five (RVSP decreased from 51.6 +/- 3.7 to 32.24 +/- 2.3 mmHg); nine patients were not reactive (RVSP 53.5 +/- 5.7 mmHg before iNO vs. 49.6 +/- 6.7 mmHg). RV systolic function was decreased in patients with elevated RVSP as compared to the patients with normal pulmonary pressure (S velocity 13.2 +/- 1.3 vs. 14.4 +/- 1.6 cm/s, respectively, p < 0.05). Significant increase of RV systolic function during iNO test was found in reactive patients only (S velocity before iNO 12.8 +/- 1.2 cm/s, during iNO 14.5 +/- 1.5 cm/s, p < 0.01). RVSP decrease strongly correlated with S velocity increase (r = 0.95, p < 0.0001). Response to iNO was found only in limited form of SSc; diffuse SSc patients showed no response. Pulmonary fibrosis on HRCT was more frequent in subjects nonreactive to iNO (67% of patients) than in the reactive group (40% of patients). The reactivity of pulmonary circulation to iNO in SSc patients with elevated RVSP was found predominantly in limited form of the disease. Pulmonary fibrosis typical for diffuse SSc was more frequent in nonreactive subjects. Elevated pulmonary pressure plays an important role in RV systolic dysfunction. Pulmonary pressure decrease during iNO test leads to the improvement of RV systolic function. Therapy for right-heart failure in reactive SSc patients should be directed, if possible, at the decrease in pulmonary resistance. PMID- 21670951 TI - Clinical significance and diagnostic usefulness of anti-centromere antibody in Sjogren's syndrome. AB - Anti-SS-A/Ro antibody (SS-A) and anti-SS-B/La antibody (SS-B) are important serologic markers in the diagnostic criteria for Primary Sjogren's syndrome (SS). Although anti-centromere antibody (ACA)-positive SS is frequently experienced, ACA is not included in these criteria. The purpose of this study was to identify the clinical features of ACA-positive SS and discuss the usefulness of ACA in diagnosing SS. Forty-five patients with SS were divided into the following three groups: SS-A only-positive group (n = 17), SS-A and SS-B both-positive group (n = 18), and ACA only-positive group (n = 10). As a control, 54 patients without SS who were negative for antinuclear antibodies were also evaluated. The following items were compared among groups: Saxon's test, unstimulated whole salivary flow (UWSF), salivary gland scintigraphy (SGS), histopathologic examination of the minor salivary glands, Schirmer's test, and fluorescein staining of the cornea. In the ACA only-positive group, Saxon's test was 0.21 +/- 0.26 g/2 min (mean +/- SD) and UWSF was 0.16 +/- 0.25 ml/10 min (mean +/- SD), showing a significant decrease in salivary secretion (p < 0.05; vs. non-SS). On SGS, accumulation and disappearance of (99m)TcO (4) (-) were significantly decreased (p < 0.05; vs. non SS). Histopathologic examination showed moderate or severe lymphocytic infiltration and tissue destruction in all cases, similar to that in the SS-A- and/or SS-B-positive groups. Schirmer's test and fluorescein staining were positive in 60% and 80%, respectively. Impaired lacrimal secretion and keratoconjunctivitis sicca were similar to those in SS-A- and/or SS-B-positive groups. These results suggest that ACA is an autoantibody reflecting impairment in the salivary and lacrimal glands and may be a useful serologic marker for SS. PMID- 21670952 TI - Psychometric properties of self-administered Lequesne Algofunctional Indexes in patients with hip and knee osteoarthritis: an evaluation using classical test theory and Rasch analysis. AB - The aim of this study is to perform a psychometric analysis of the Lequesne Algofunctional Indexes (LAI) for the severity of osteoarthritis (OA) of the hip (LAI-hip) and knee (LAI-knee), using classical test theory (CTT) and Rasch analysis. Questionnaires were completed by 1,214 patients with symptomatic OA of the knee (n = 697) and hip (n = 517). Internal consistency was evaluated using Cronbach's alpha and an item-to-total correlation. Dimensionality was investigated with a factor analysis. Raw scores underwent Rasch analysis. Cronbach's alpha was 0.84 for LAI-hip and 0.82 for LAI-knee. LAI-hip resulted in unidimensionality according to the factor analysis, while LAI-knee supported both a single and a two-factor solution (items 1-6b and 7-10, respectively). At Rasch analysis, the rating categories of item 'maximum distance walked' did not comply with the criteria for category functioning in either LAI-hip or LAI-knee. A test of the residual correlation showed item dependency in both LAI-hip and LAI-knee. Misfitting items were present in both the scales. According to both CTT and Rasch analysis, in our two samples representing a wide spectrum of both hip and knee OA severity the LAI-hip and LAI-knee showed a series of drawbacks, which rendered both questionnaires inadequate in relation to their metric properties and severely limit their ability to perform, as a composite measure, in line with the main aims of their developers. PMID- 21670953 TI - Keiji Sano--memories of meetings. PMID- 21670954 TI - Posterior petrous bone meningiomas: surgical experience in 53 patients and literature review. AB - Meningiomas of the posterior fossa represent a heterogeneous group of tumors regarding difficulty of resection and functional outcome. The aim of this review was to focus on tumors located mainly on the posterior surface of the petrous bone and threatening hearing and facial functions. An anatomical classification was used to evaluate surgical outcome depending on the relationship of the tumor to the internal auditory meatus. The authors performed a retrospective chart review of 53 consecutive patients operated on for a posterior petrous bone meningioma in a tertiary referral center and a literature review. Tumors were classified in four groups according to the modified Desgeorges and Sterkers classification: posterior petrous (P; 17 tumors), meatus and internal auditory canal (M; 12 tumors), petrous apex without invasion of the internal auditory canal (A; 9 tumors), and cerebellopontine angle with invasion of the internal auditory canal (AMP; 15 tumors). The facial function was preserved in 100% of P and A tumors, 75% of group M tumors, and 53% of AMP tumors. Hearing preservation was attempted only in P, A, and M groups where rates of serviceable hearing preservation were 82%, 80%, and 66%, respectively. The cumulative rate of hearing preservation for AMP tumors was 45% in our literature review. The increased facial morbidity associated with AMP tumors compared with other groups was also confirmed by the review of the literature. In conclusion, this study shows that among posterior petrous bone meningiomas, tumors invading the internal auditory canal present with increased postoperative functional morbidity in spite of a tailored approach regarding dural insertion. PMID- 21670955 TI - Preoperative nodal staging of uterine cancer: is contrast-enhanced PET/CT more accurate than non-enhanced PET/CT or enhanced CT alone? AB - OBJECTIVE: To determine whether contrast-enhanced PET/CT is more accurate than either non-enhanced PET/CT or enhanced CT alone for nodal staging of uterine cancer. METHODS: Forty patients with endometrial cancer and cervical cancer underwent conventional PET/CT scan with low-dose CT (ldCT), followed by full-dose CT with IV contrast (ceCT) before radical hysterectomy with pelvic and, when applicable, para-aortic lymphadenectomy. Three data sets of PET/ldCT, PET/ceCT, and enhanced CT images were interpreted separately by two readers. For region specific comparisons, para-aortic and pelvic lymph nodes were divided into the bilateral para-aortic, common iliac, external iliac, internal iliac, and obturator areas. Based on histopathological findings as the gold standard, we compared the diagnostic accuracy between the three methods using McNemar test with Bonferroni's adjustment. RESULTS: Of the 40 patients, 21 underwent pelvic lymphadenectomy only. Region-based analysis showed that the sensitivity, specificity, and accuracy of PET/ceCT were 61.4% (27/44), 98.1% (308/314), and 93.6% (335/358), respectively, whereas those of PET/ldCT were 52.3% (23/44), 96.8% (304/314), and 91.3% (327/358), respectively, and those of enhanced CT were 40.9% (18/44), 97.8% (307/314), and 90.8% (325/358), respectively. Although PET/ceCT had the best sensitivity among the three imaging modalities, a significant difference was observed only between PET/ceCT and enhanced CT (p = 0.0027). Although PET/ceCT had better sensitivity and accuracy than PET/ldCT, the differences between the two imaging methods did not reach statistical significance (p = 0.046 and p = 0.047, respectively). CONCLUSION: PET/ceCT is slightly but not significantly superior to PET/ldCT for nodal staging of uterine cancer. Nodal metastasis cannot be excluded even if PET/ceCT gives negative findings. PMID- 21670956 TI - DNA repair genes polymorphism (XPG and XRCC1) and association of prostate cancer in a north Indian population. AB - Prostate cancer is the most commonly diagnosed cancer in men worldwide and is the second leading cause of cancer related mortality. Genetic background may account for the difference in susceptibility of individuals to different diseases and the relationship between genetic polymorphism and some diseases has been extensively studied. There are several common polymorphisms in genes encoding DNA repair enzymes, some of these polymorphisms are reported to result in subtle structural alterations of the repair enzyme and modulation of the repair capacity. The aim of the present study was to analyze the effect of XPG Asp 1104His and XRCC1 Arg309Gln polymorphisms on risk of prostate cancer in north Indian population. Statistically significant increased risk of prostate cancer was observed on individuals that posses His/His genotype of XPG (OR 2.53, 95% CI 0.99-6.56, P = 0.031). In this study 150 prostate cancer diagnosed patients, 150 healthy controls and 150 BPH (benign prostate hyper plasia) were recruited from north Indian population. Moreover, individuals that carried the Gln/Gln genotype of XRCC1 also showed statistically increased risk of prostate cancer (OR 2.06, 95% CI 1.07-4.00, P = 0.033). The Asp/Asp of XPG and Gln/Gln of XRCC1 in combination showed statistically increased risk of prostate cancer in cases (OR 3.29, 95% CI 1.09-10.16, P = 0.032). PMID- 21670957 TI - Association of FANCC polymorphisms with FEV1 decline in aspirin exacerbated respiratory disease. AB - Aspirin exacerbated respiratory disease (AERD) is a clinical condition characterized by severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. The exacerbated inflammatory response in Fancc-deficient mice has been reported to be associated with hemopoietic responses that are also related to AERD pathogenesis. To investigate associations of FANCC polymorphisms with AERD and related phenotypes, this study genotyped 25 common single nucleotide polymorphisms (SNPs) in a total of 592 Korean asthmatics including 163 AERD and 429 aspirin-tolerant asthma (ATA) subjects. Logistic analysis revealed that genetic polymorphisms of the FANCC gene might not be directly related to AERD development and nasal polyposis (P > 0.05). However, the FEV1 decline by aspirin provocation showed significant associations with FANCC polymorphisms (P = 0.006-0.04) and a haplotype (unique to rs4647416G > A, P = 0.01 under co dominant, P = 0.006 under recessive model). In silico analysis showed that the "A" allele of rs4647376C > A, which was more prevalent in AERD than in ATA, could act as a potential branch point (BP) site for alternative splicing (BP score = 4.16). Although replications in independent cohorts and further functional evaluations are still needed, our preliminary findings suggest that FANCC polymorphisms might be associated with the obstructive symptoms in allergic diseases. PMID- 21670958 TI - DNA barcoding of nymphalid butterflies (Nymphalidae: Lepidoptera) from Western Ghats of India. AB - We have checked the utility of DNA barcoding for species identification of nymphalid butterflies from Western Ghats of India by using 650 bp sequence of mitochondrial gene cytochrome c oxidase subunit I. Distinct DNA barcoding gap (i.e. difference between intraspecies and interspecies nucleotide divergence), exists between species studied here. When our sequences were compared with the sequences of the conspecifics submitted from different geographic regions, nine cases of deep intraspecies nucleotide divergences were observed. In spite of this, NJ (Neighbour Joining) clustering analysis successfully discriminated all species. Observed cases of deep intraspecies nucleotide divergences certainly warrant further study. PMID- 21670959 TI - Clinical implications of activated leukocyte cell adhesion molecule expression in breast cancer. AB - In the study, we enrolled 150 breast cancer cases to investigate the expression status of activated leukocyte cell adhesion molecule (ALCAM), and the relationships between ALCAM expression and clinical-pathological characteristics and prognosis of breast cancer. It was observed that ALCAM was expressed at higher levels in breast cancer tissue compared to levels observed for tumor adjacent tissue. Compared to cancers with low membranous ALCAM expression, cancers with high membranous ALCAM expression were prone to lymph node metastasis (chi2=15.910, P=0.010) and metastasis in general (chi2=5.211, P=0.029). High cytoplasmic ALCAM expression was noticeably correlated with local recurrence (chi2=7.379, P=0.012), especially for short-term recurrence (interval<2 years) (chi2=5.562, P=0.037), while not associated to long-term local recurrence (interval>2 years). The content of ALCAM protein is closely associated with the expression of estrogen receptor (ER) (P=0.024). The disease-free survival of patients with high cytoplasmic ALCAM expression was significantly shorter compared to the cases with low cytoplasmic ALCAM expression (P=0.036). In conclusion, ALCAM expressed at high levels in breast cancer. High membranous expression of ALCAM probably resulted in weakened adherent ability and metastasis. In addition, high cytoplasmic ALCAM expression strengthened invasive ability of malignant cells and then promoted tumor development. PMID- 21670960 TI - The complete mitochondrial genome of the oriental fruit moth Grapholita molesta (Busck) (Lepidoptera: Tortricidae). AB - The oriental fruit moth, Grapholita molesta (Busck) (Lepidoptera: Tortricidae) currently is one of the economically most destructive pest species of stone and pome fruits worldwide. Here we sequenced the complete mitochondrial genome of this pest. This genome is 15,776 bp long, with an A + T content of 81.24%, containing 37 typical animal mitochondrial genes and an A + T-rich region. All gene are arranged as hypothesized ancestral gene order of insects except for trnM, which was shuffled from 3' downstream of trnQ to 5' upstream of trnI. cox1 gene uses unusual CGA start codon, as that in all other sequenced lepidopteran mitochondrial genome. The secondary structures for the two rRNA genes were predicted. All helices typically present in insect mitochondrial rRNA genes are generated. A microsatellite sequence was inserted into the region of H2347 in rrnL in G. molesta and two other sequenced tortricid mitochondrial genomes, indicating that the insertion event in this helix might occurred anciently in family Tortricidae. All of the 22 typical animal tRNA genes have a typical cloverleaf structure except for trnS2, in which the D-stem pairings in the DHU arm are absent. An intergenic sequence is present between trnQ and nad2 as well as in other sequenced lepidopteran mitochondrial genomes, which was presumed to be a remnant of trnM gene and its boundary sequences after the duplication of trnM to the upstream of trnI in Lepidoptera. The A + T-rich region is 836 bp, containing six repeat sequences of "TTATTATTATTATTAAATA(G)TTT." PMID- 21670961 TI - CREB-binding protein silencing inhibits thrombin-induced endothelial progenitor cells angiogenesis. AB - Endothelial progenitor cells (EPCs) are known to promote neovascularization in ischemic diseases. Recent evidence from our group suggested that CREB-binding protein (CBP) plays an important role in thrombin-induced EPCs migration. However, whether CBP could regulate EPCs angiogenic properties is unknown. In the present study, we investigated whether CBP silencing could inhibit thrombin induced EPCs angiogenesis. EPCs isolated from the bone marrow of Sprague-Dawley rats were cultured and identified, and then were treated by thrombin alone or combined with CBP-shRNA lentivirus. The effect of CBP silencing on EPCs proliferation was assessed using BrdU incorporation assay. Cell adhesion and tube formation were detected to evaluate the angiogenic functions. Finally, mRNA and protein expression of relevant angiogenic genes were examined by real-time PCR, western-blot, and enzyme-linked immunoassay respectively. Luciferase reporter gene assay was performed to evaluate NF-kappaB activity. Administration of thrombin significantly promoted EPCs proliferation and adhesion. Thrombin also increased the tube formation in Matrigel assay. However, these effects of thrombin were abolished by CBP gene silencing. CBP silencing also abrogated thrombin-induced increases of integrin beta2 expression. In thrombin-induced EPCs, CBP silencing significantly decreased the secretion of VEGF, IL-6 and suppressed NF-kappaB activity. In conclusion, thrombin-induced EPCs proliferation, adhesion, and tube formation were inhibited by CBP silencing, indicating that CBP plays an important role in thrombin-induced EPCs neovascularization. PMID- 21670962 TI - Chemicobiological effects of herbicide MCPA-Na on plasma proteins. AB - Under physiological conditions, the potential hematological toxicity of herbicide 2-methyl-4-chlorophenoxyacetic acid sodium (MCPA-Na) was discussed by fluorescence probe technology and spectroscopy methods including three dimensional (3D) fluorescence, UV absorption and circular dichroism (CD) spectra. In vitro, MCPA-Na bound with bovine serum albumin (BSA) and formed new complex at ground state by electrostatic force and hydrogen bond. During the process, non radiation energy transfer from BSA to MCPA-Na occurred and the distance r between donor and acceptor was obtained based on Forster theory. The binding site was investigated by fluorescence probe method and the results implied MCPA-Na was absorbed on domain II of BSA molecule. The enthalpy change (DeltaH(theta)), Gibbs free energy change (DeltaG(theta)) and entropy change (DeltaS(theta)) were calculated at four different temperatures according to Van't Hoff isobar equation and Gibbs-Helmholtz equation. Negative value of DeltaG(theta) indicated the process of binding was a spontaneous and irreversible process, which gave a broad hint that MCPA-Na was likely to be poisonous. CD spectra exhibited significant changes of secondary structures in BSA molecule and three-dimensional fluorescence spectra indicated the tryptophan residue in BSA was placed in a less hydrophobic environment, which presented additional evidence to caution the danger of MCPA-Na residue in food. Meanwhile, the mechanism and geometry of the binding was analyzed at molecular level. PMID- 21670963 TI - DJ-1 may contribute to metastasis of non-small cell lung cancer. AB - Lung cancer is a leading cause of cancer-related death, about 40% human non-small cell lung cancer (NSCLC) patients showed lymph node involvements. However, the precise mechanism for the metastasis is still not fully understood. This study was to analyze the potential molecular mechanism for lung cancer metastasis. In the current study, proteomics analysis by two-dimensional electrophoresis (2-DE) was performed first to identify the differentially expressed protein between the higher metastasis lung adenocarcinoma cell line Anip973 and the lower metastasis lung adenocarcinoma cell line AGZY83-a. We confirmed the result by RT-PCR, immunoblotting and immunocytochemistry analyses in these two cell lines. Then we examined the expression of the differentially expressed protein in tumor tissues of NSCLC patients by immunoblotting and immunohistochemistry analyses. Using 2-DE analysis, we have identified DJ-1 was expressed higher in the higher metastasis Anip973 compared to the parental cell line AGZY83-a, that was confirmed by RT PCR, immunoblotting and immunocytochemistry analyses. In NSCLC patients' tumor tissues study, immunoblotting data showed that, DJ-1 expression level was significantly higher in 72.2% (13/18) of NSCLC tissue samples compared to that in paired normal lung tissues (P = 0.044). Immunohistochemistry analysis demonstrated increased DJ-1 expression in 85 NSCLC tumor tissue samples compared with 7 normal lung tissue samples (P = 0.044). DJ-1 expression was also found to be significantly correlated with cancer lymphatic metastasis (P = 0.039). DJ-1 might contribute to the metastasis of NSCLC. PMID- 21670964 TI - Association between TNF-alpha polymorphisms and cervical cancer risk: a meta analysis. AB - Tumor necrosis factor alpha (TNF-alpha) is a vital cytokine involved in inflammation, immunity, and cellular organization. The TNFA-308G/A (rs1800629) and -238G/A (rs361525) polymorphisms are two widely investigated variants for their associations with risk of cervical cancer, but the results are conflicting. Here, we performed a meta-analysis to pool the data and evaluate the between studies heterogeneity. All the case-control studies published from January 1989 to October 2010 on the association between the two polymorphisms of TNFA and cervical cancer risk were identified by searching the electronic literature Medline. The cervical cancer risk associated with the two polymorphisms of TNFA gene was estimated for each study by OR together with its 95% CI, respectively, by using the Review Manager 4.2 software. It was showed that the variant homozygote -308AA was associated with a significantly increased risk of cervical cancer (AA vs. GG: OR = 1.41, 95% CI = 1.03-1.92, P = 0.033; AA vs. GA/GG: OR = 1.39, 95% CI = 1.02-1.90, P = 0.036), and the effect was more evident among Asians (AA vs. GA/GG: OR = 3.67, 95% CI = 1.25-10.81, P = 0.018). We also found that the variant genotypes -238GA/AA was associated with a significantly decreased risk of cervical cancer (GA/AA vs. GG: OR = 0.55, 95% CI = 0.41-0.74, P < 0.001). The results suggested that TNFA-308G/A and -238G/A may contribute to cervical cancer susceptibility. PMID- 21670965 TI - SULT1A1 Arg213His polymorphism and susceptibility of environment-related cancers: a meta analysis of 5,915 cases and 7,900 controls. AB - The common genetic polymorphism for SULT1A1 is Arg213His polymorphism, which may affect the sulfation process of various environmental carcinogens and thus is suggested to be related to susceptibility of several cancers. However, studies on the association between SULT1A1 Arg213His polymorphism and cancer susceptibility are inconsistent. To assess the relationship between Arg213His polymorphism and environmental-related cancers systematically, we performed a meta analysis from 20 case-control studies including 5,915 cases and 7,900 controls. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the strength of risk, we found a significant association between SULT1A1 Arg213His polymorphism and environment-related cancers (for dominant model: OR 1.22, 95% CI 1.07-1.39, P = 0.003). When stratified by ethnicity, a significant risk was observed in Asian cases, compared with controls (for dominant model: OR 1.69, 95% CI 1.17-2.43, P = 0.005). When we chose only smokers in our analysis, we also found a significantly increased risk between Arg213His polymorphism and susceptibility of environment related cancers for participants exposed to a smoking environment. In conclusion, SULT1A1 Arg213His polymorphism, ethnicity, smoking may modulate environment related cancer risk. Studies on gene-gene interactions in the sequential or concurrent metabolic pathway and gene-environment interactions need to be further conducted to explore the susceptibility of cancer occurrence. PMID- 21670966 TI - Identification of MicroRNAs and their targets in Helianthus. AB - MicroRNAs (miRNAs) are small non-coding RNAs about 20-24 nucleotides long, playing regulatory role. The conserved nature among the various organisms makes them a good source of new miRNAs discovery by comparative genomics approach using bioinformatic tools. A systematic search approach was used for inter-species homologs of miRNA precursors (pre-miRNAs), from known Helianthus expressed sequence tags (ESTs). The study resulted in 61 novel miRNAs belonging to 34 families from Helianthus ESTs. The 28 miRNA families; mir 159,160, 164, 170, 390, 393, 413, 415, 419, 426, 446, 530, 822, 842, 846, 1310, 1888, 2086, 2657, 2667, 2678, 2659, 2911, 2938, 3440, 3521, 3623, and 3630 are reporting for the first time in Helianthus. In the 61 new miRNAs, 20 are from H. tuberosus, 17 miRNAs belong to H. annus, 8 are from H. ciliaris, 5 to H. exilis, 4 is from H. argophyllous, H. petiolaris each and 3 are from H. paradoxus. All the pre-miRNAs form stable minimum free energy (mfe) stem-loop structure as their orthologues form and the mature miRNAs reside in the stem portion of the stem-loop structures. Their targets consist of growth and development related, transcription factors, signalling pathway kinases, stress resistant proteins and transport related proteins. PMID- 21670967 TI - Adult-onset Still's disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept. AB - We report a 16-year-old female case of intractable adult-onset Still's disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease. PMID- 21670968 TI - Abrogation of Treg function deteriorates rheumatoid arthritis. AB - An early prognostic indicator which warns of progressive joint destruction of rheumatoid arthritis (RA) was explored using a novel suspension-array technique in moderate (Steinbrocker stage I and II) and severe (Steinbrocker stage IV) RA patients. DNA microarray analysis of peripheral blood lymphocytes showed significant increase of interleukin (IL)-2 receptor alpha-chain (CD25) gene expression, a regulatory T cell (Treg) surface marker in severe RA patients. In contrast, suspension array, a comprehensive bead-based enzyme-linked immunosorbent assay (ELISA), revealed decreased production of IL-10 and increased production of interferon (IFN)-gamma in sera in the incipient stage of the aggressive disease process. Both in moderate and in severe RA patients, the IFN gamma/IL-10 ratio indicated deterioration of the disease with universal validity. Fluorescence-activated cell sorting (FACS) and reverse-transcription polymerase chain reaction (RT-PCR) analysis showed extant CD4+CD25+ regulatory T cells in severe RA patients, however Foxp3, a regulatory T cell-specific transcription factor, gene expression was absent, while glucocorticoid-induced tumor necrosis factor (TNF) receptor family-related protein (GITR), which transmits a signal that abrogates regulatory T cell functions, was elevated. In the current study, we showed the validity of suspension-array analysis for enabling more complete understanding of RA, and showed that IFN-gamma/IL-10 ratio can be a prognostic tool for early lesion and more aggressive RA. PMID- 21670969 TI - Intraoperative injuries during liver resection: analysis of 1,005 procedures. AB - PURPOSE: Risk of liver resection has been well investigated in many studies. However, the problem of intraoperative injuries is rarely mentioned. The aim of this study was to assess the incidence, the type, and management of intraoperative injuries during liver resection. METHODS: A total of 1,005 liver resections between 2004 and 2009 were included in this retrospective investigation. We analyzed the incidence of intraoperative injuries, risk factors, and an impact on patients' clinical outcome. RESULTS: The overall incidence of intraoperative injuries was 4.4% (44 of 1,005). Injuries of the diaphragm (1.6%, 16 of 1,005) and hepatocaval junction (1%, 10 of 1,005) were the most frequent. In multivariate analysis, tumor recurrence (p = 0.0199) and tumor size (p = 0.0317) were the only independent risk factors for diaphragm injuries, whereas the extent of resection (p = 0.0007) was the only independent risk factor for caval or hepatic vein injuries. Injuries of the inferior vena cava or hepatic veins significantly increased perioperative mortality (p = 0.0005). CONCLUSIONS: Minor injuries causing no significant complications were the most frequent. However, prevention and proper management of the rare injuries of hepatocaval junction are essential to avoid increased mortality in major liver resections. PMID- 21670970 TI - Hepatitis B virus reactivation in patients receiving cancer chemotherapy: natural history, pathogenesis, and management. AB - Chronic hepatitis B virus (HBV) infection is endemic in the Asian-Pacific region, and reactivation of HBV post-cancer chemotherapy has become an emerging clinical challenge. Patients with detectable serum HBV DNA before chemotherapy and those receiving intensive chemotherapy are particularly at a risk of HBV reactivation. Most patients with HBV reactivation are positive for hepatitis B surface antigen (HBsAg) and are, therefore, easily identified by recommended serological screening before chemotherapy. However, a small, but significant proportion of subjects who have apparently recovered from HBV infection as reflected by HBsAg negativity and hepatitis B core antibody positivity in HBV endemic areas may also experience reactivation when host immunity is severely compromised by cancer chemotherapy. Serum alanine aminotransferase, HBsAg, and/or HBV DNA should be monitored closely in these subjects and antiviral therapy should be administered immediately when any evidence of HBV reactivation is detected during chemotherapy. The prophylactic use of nucleos(t)ide analogs before chemotherapy and its continuation until reconstitution of host immunity remain the mainstay of effective prevention of hepatitis B reactivation in this special clinical entity. PMID- 21670971 TI - The role of CXCR2 chemokine receptors in the oral squamous cell carcinoma. AB - This study evaluated the relevance of CXCR2 chemokine receptors in oral squamous cell carcinoma, by means of in vitro and in vivo approaches. The in vitro incubation of the selective and non-peptide CXCR2 receptor antagonist N-(2 hydroxy-4-nitrophenyl)-N9-(2-bromophenyl) Urea (SB225002; 25 to 800 nM) produced a time- and concentration-dependent inhibition of SCC158 (rat) and HN30 (human) cell lines viability. Conversely, this antagonist did not significantly affect the viability of the immortalized keratinocyte lineage, HaCaT. Additionally, the incubation of human IL-8 and rat CINC-1 CXCR2 agonists produced a concentration related increase on HN30 and SCC158 proliferation. The submucosal injection of SCC158 cells (5 * 10(6) cells) into the tongue of Fischer 344 rats induced tumor development, which displayed typical clinical features. Immunohistochemical analysis of rat tongue biopsies revealed a marked increase of CXCR2 receptor immunoreactivity, which was accompanied by augumented expression of VEGF and caspase-3. Our data suggests an important role for CXCR2 receptors in oral squamous cell carcinoma. PMID- 21670972 TI - Phase I study of axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer. AB - PURPOSE: Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. PATIENTS AND METHODS: Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m(2)), C1D14 (steady state, axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state axitinib). Adverse events were monitored weekly at the clinic. RESULTS: Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. CONCLUSIONS: Axitinib (5 mg BID) and gemcitabine (1,000 mg/m(2)) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity. PMID- 21670973 TI - The impact of treatment, socio-demographic and clinical characteristics on health related quality of life among Hodgkin's and non-Hodgkin's lymphoma survivors: a systematic review. AB - Cancer survivors are at risk of experiencing adverse physical and psychosocial effects of their cancer and its treatment. Both Hodgkin's lymphoma (HL) and non Hodgkin's lymphoma (NHL) survivors face problems that can affect their health related quality of life (HRQoL). The authors systematically reviewed the literature on HRQoL among HL and NHL survivors. A PubMed and PsychINFO literature search for original articles published until May 2011 was performed. Twenty-four articles, which met the predefined inclusion criteria, were subjected to a quality checklist. HL survivors showed the most problems in (role) physical, social and cognitive functioning, general health, fatigue and financial problems. In addition, HL survivors treated with a combination of therapies, with older age and female sex reported worse HRQoL. NHL survivors showed the most problems in physical functioning, appetite loss, vitality and financial problems. Having had chemotherapy was negatively associated with HRQoL, but no differences in chemotherapy regimens were found. Furthermore, in NHL survivors not meeting public exercise guidelines, HRQoL is low but can be improved with more exercise. More research on the longitudinal comparison between HL and NHL survivors and healthy controls should be performed in order to better understand the long-term (side) effects of treatment on HRQoL and possibilities to alleviate these. PMID- 21670974 TI - Risk of bleeding with oral anticoagulants: an updated systematic review and performance analysis of clinical prediction rules. AB - This study aimed to determine whether progress in developing bleeding risk estimation tools for patients on oral anticoagulant therapy has been made since 2006 when we last systematically reviewed this topic, and to refresh previously published quantitative evaluations of the clinical prediction rules (CPRs) available for estimating bleeding risk in patients on oral anticoagulant therapy. A systematic review of English language literature published since December 2006 was conducted when our previous systematic review ended. Studies were analyzed for predictive performance using likelihood ratios. Six studies detailed CPRs used to assess risk of bleeding prior to commencing warfarin therapy, four of which were included in the analysis. Three studies evaluated new CPRs ("RIETE" and "HAS-BLED"). One of the studies was a further validation of the modified outpatient bleeding risk index (mOBRI) in patients with atrial fibrillation. Individual trial and pooled analyses using likelihood ratios for mOBRI and HAS BLED showed they have weak predictive accuracy. A RIETE score of 0 point was moderately predictive of the absence of major bleeding. None of the CPRs exhibited sufficient predictive accuracy or had sufficient validation to be recommended for routine use in practice. None of the available CPRs exhibit sufficient predictive accuracy or have trials evaluating the impact of their use on patient outcomes. Hence, no existing oral anticoagulation major bleeding CPR can be recommended for routine use in practice at present. PMID- 21670975 TI - Response of methanotrophs and methane oxidation on ammonium application in landfill soils. AB - To test the dose effect of ammonium (NH4+) fertilization on soil methane (CH4) oxidation by methanotrophic communities, batch incubations were conducted at a wide scale of NH4+ amendments: 0, 100, 250, 500, and 1,000 mg Nkg(dry soil(-1)). Denaturing gradient gel electrophoresis and real-time quantitative PCR analysis were conducted to investigate the correlation between the CH4 oxidation capacity and methanotrophic communities. Immediately after the addition of NH4+, temporal inhibition of CH4 oxidation occurred, and this might have been due to the non specific salt effect (osmotic stress). After a lag phase, the CH4 oxidation rates of the soils with NH4+ fertilization were promoted to levels higher than those of the controls. More than 100 mg Nkg(dry soil(-1)) of NH4+ addition resulted in the reduction of type II/type I MOB ratios and an obvious evolution of type II MOB communities, while less than 100 mg Nkg(dry soil(-1)) of NH4+ addition induced nearly no change of methanotrophic community compositions. The NH(4+)-derived stimulation after the lag phase was attributed to the improvement of N availability for type I MOB. Compared with the controls, 100 mg Nkg(dry soil(-1)) of NH(4) (+) addition doubled the CH(4) oxidation peak value to more than 20 mg CH4kg(dry soil(-1)) h(-1). Therefore, an appropriate amount of leachate irrigation on the landfill cover layer might efficiently mitigate the CH4 emissions. PMID- 21670976 TI - Selectively inducing the synthesis of a key structural exopolysaccharide in aerobic granules by enriching for Candidatus "Competibacter phosphatis". AB - A gel-forming exopolysaccharide was previously shown to play an important structural role in aerobic granules treating nutrient-rich industrial wastewater. To identify whether this exopolysaccharide performs a similar role in other granular biomass and if conditions favouring its production can be more precisely elucidated, extracellular polymeric substances (EPS) were extracted from granules grown under four different operating conditions. (1)H nuclear magnetic resonance (NMR) spectroscopy of their EPS indicated that the gel-forming exopolysaccharide was expressed in two granular sludges both enriched in Candidatus "Competibacter phosphatis". In contrast, it was not expressed in granules performing denitrification with methanol as a carbon source and nitrate as the electron acceptor or granules enriched in Candidatus "Accumulibacter phosphatis" performing enhanced biological phosphorus removal from synthetic wastewater. In one of the first two sludges, the exopolysaccharide contained in the seeding granular sludge continued to be a major component of the granule EPS while Competibacter was being enriched. In the second sludge, a floccular sludge not containing the gel-forming exopolysaccharide initially was also enriched for Competibacter. In this sludge, an increase in particle size was detected coinciding with a yield increase of EPS. NMR spectroscopy confirmed its yield increase to be attributable to the production of this structural gel-forming exopolysaccharide. The results show that (1) the particular gel-forming exopolysaccharide previously identified is not necessarily a key structural exopolysaccharide for all granule types, and (2) synthesis of this exopolysaccharide is induced under conditions favouring the selective enrichment of Competibacter. This indicates that Competibacter may be involved in its production. PMID- 21670977 TI - Transformation of prednisolone to a 20beta-hydroxy prednisolone compound by Streptomyces roseochromogenes TS79. AB - Prednisolone represents an important compound in pharmaceutical preparations. To obtain more bioactive prednisolone derivatives, the microbial transformation of prednisolone was carried out. The steroid products were assigned by an interpretation of their spectral data using mass spectrometry and proton nuclear magnetic resonance ((1)H NMR) analyses. The product was assigned the chemical structure of 11beta, 17alpha, 20beta, 21-tetrahydroxypregna-1,4-diene-3-one (named as 20beta-hydroxy prednisolone). The conversion of prednisolone to 20beta hydroxy prednisolone by Streptomyces roseochromogenes TS79 was different from a previous study on the microbial transformation of steroid by this organism, which usually generates a 16alpha-hydroxy steroid product. The different reaction parameters for maximum conversion of prednisolone were optimized. The analysis revealed that the optimum values of the tested variables were 7.5 mg/ml prednisolone dissolved in DMSO and added to the 24-h pre-culture fermentation culture containing 0.05% MgSO(4) and incubated for 24 h. A conversion of 95.1% of prednisolone was observed, which has the potential to be used in industrial production. PMID- 21670978 TI - Progress on plague vaccine development. AB - Yersinia pestis (YP), the gram-negative plague bacterium, has shaped human history unlike any other pathogen known to mankind. YP (transmitted by the bite of an infected flea) diverged only recently from the related enteric pathogen Yersinia pseudotuberculosis but causes radically different diseases. Three forms of plague exist in humans: bubonic (swollen lymph nodes or bubos), septicemic (spread of YP through the lymphatics or bloodstream from the bubos to other organs), and contagious, pneumonic plague which can be communicated via YP charged respiratory droplets resulting in person-person transmission and rapid death if left untreated (50-90% mortality). Despite the potential threat of weaponized YP being employed in bioterrorism and YP infections remaining prevalent in endemic regions of the world where rodent populations are high (including the four corner regions of the USA), an efficacious vaccine that confers immunoprotection has yet to be developed. This review article will describe the current vaccine candidates being evaluated in various model systems and provide an overall summary on the progress of this important endeavor. PMID- 21670979 TI - Synthesis and biotransformation of 2-alkyl-4(1H)-quinolones by recombinant Pseudomonas putida KT2440. AB - 2-Alkyl-4(1H)-quinolones (AQs) and related derivatives, which exhibit a variety of biological properties, are secondary metabolites produced by, e.g., Pseudomonas and Burkholderia spp. Due to their main role as signaling molecules in the quorum sensing system of Pseudomonas aeruginosa, 2-heptyl-4(1H)-quinolone (HHQ) and its 3-hydroxy derivative, termed the "Pseudomonas quinolone signal" (PQS), have received considerable attention. Since chemical synthesis of different AQs is complex, we assessed the applicability of recombinant P. putida KT2440 strains for the biosynthetic production of AQs. In mineral salts medium supplemented with octanoate and anthranilate, batch cultures of P. putida KT2440 [pBBR-pqsABCD] produced about 45 MUM HHQ, 30% and 70% of which were localized in the culture supernatant and methanolic cell extract, respectively. 2,4 Dihydroxyquinoline and minor amounts of C3- to C13-saturated and C7:1 to C13:1 monounsaturated AQs were formed as by-products. Mass spectrometry and nuclear magnetic resonance analyses spectroscopy indicated that unsaturated AQs having the same molecular mass are cis and trans isomers rather than position isomers, with the double bond located between the alpha and beta carbon of the alkyl chain. Supplementing the cultures with hexanoate instead of octanoate shifted the AQ profile towards increased formation of C5-AQ. Individual AQs can be prepared from concentrated methanolic extracts by preparative high-performance liquid chromatography (HPLC). Regioselective hydroxylation of HHQ to PQS can be achieved in > 90% yield by biotransformation with P. putida KT2440 [pBBR-pqsH]. PQS can be isolated from methanolic cell extracts by HPLC, or be precipitated as Fe(III)-PQS complex. Preparation of a library of AQs will facilitate studies on the biological functions of these compounds. PMID- 21670980 TI - Dynamics of bacterial communities during solid-state fermentation using agro industrial wastes to produce poly-gamma-glutamic acid, revealed by real-time PCR and denaturing gradient gel electrophoresis (DGGE). AB - The dynamics of bacterial communities play an important role in solid-state fermentation (SSF). Poly-gamma-glutamic acid (gamma-PGA) was produced by Bacillus amyloliquefaciens C1 in SSF using dairy manure compost and monosodium glutamate production residuals as basic substrates. The production of gamma-PGA reached a maximum of 0.6% after 20 days fermentation. Real-time polymerase chain reaction showed the amount of total bacteria reached 3.95 * 10(9) 16S rDNA copies/g sample after 30 days, which was in good accordance with the 4.80 * 10(9) CFU/g obtained by plate counting. Denaturing gradient gel electrophoresis profile showed a reduction of microbial diversity during fermentation, while the inoculum, B. amyloliquefaciens C1, was detected as the dominant organism through the whole process. In the mesophilic phase of SSF, Proteobacteria was the dominant microbial, which was replaced by Firmicutes and Actinobacteria in the thermophilic phase. The molecular analysis of the bacterial diversity has significant potential for instructing the maturing process of SSF to produce gamma-PGA at a large-scale level, which could be a benefit in the production of high quality and stable SSF products. PMID- 21670981 TI - Increased NADPH availability in Escherichia coli: improvement of the product per glucose ratio in reductive whole-cell biotransformation. AB - A basic requirement for the efficiency of reductive whole-cell biotransformations is the reducing capacity of the host. Here, the pentose phosphate pathway (PPP) was applied for NADPH regeneration with glucose as the electron-donating co substrate using Escherichia coli as host. Reduction of the prochiral beta-keto ester methyl acetoacetate to the chiral hydroxy ester (R)-methyl 3 hydroxybutyrate (MHB) served as a model reaction, catalyzed by an R-specific alcohol dehydrogenase. The main focus was maximization of the reduced product per glucose yield of this pathway-coupled cofactor regeneration with resting cells. With a strain lacking the phosphoglucose isomerase, the yield of the reference strain was increased from 2.44 to 3.78 mol MHB/mol glucose. Even higher yields were obtained with strains lacking either phosphofructokinase I (4.79 mol MHB/mol glucose) or phosphofructokinase I and II (5.46 mol MHB/mol glucose). These results persuasively demonstrate the potential of NADPH generation by the PPP in whole-cell biotransformations. PMID- 21670982 TI - The importance of testing PET-directed therapy in patients with Hodgkin lymphoma. AB - Measuring the rapidity of response by PET scan and changing the treatment regimen in slow responders may lead to an improved outcome. Ongoing studies addressing this possibility have the potential to answer this question and need to be supported. PMID- 21670983 TI - Effect of thermal cycling on the bond strength of self-adhesive cements to fiber posts. AB - The aim of this study was to assess the push-out bond strengths of self-adhesive resin cements to epoxy resin-based fiber posts after challenging by thermocycling. Thirty-six single-rooted premolars were endodontically treated, and the post-spaces were drilled to receive RelyX Fiber posts #1. Three self adhesive resin cements (RelyX Unicem, G-Cem, and Breeze) were used for luting fiber posts. The bonded specimens were either stored for 1 month in a moist field (37 degrees C) or submitted to thermocycling (5,000 times) prior to push-out test. The maximum force required to dislodge the post via an apical-coronal direction was recorded (megapascal). The data were statistically analyzed with two-way ANOVA and Tukey tests (p < 0.05). The factors "luting cement" and "thermocycling" significantly influenced bond strengths. The initial push-out values of RelyX Unicem and Breeze were higher than those of G-Cem. After thermocycling, the bond strength of G-Cem increased and no differences were found between groups. RelyX Unicem and Breeze bond strengths were not affected by the thermal challenge. Thermal cycling and cement type differently influence the bond strengths of self-adhesive resin cements. Self-adhesive cements can represent an option for luting fiber posts into root canal. PMID- 21670984 TI - Plasma citrulline as surrogate marker of intestinal inflammation in pediatric and adolescent with Crohn's disease: preliminary report. AB - PURPOSE: Several researchers have found that plasma citrulline could be a marker of reduced enterocyte mass. The aim of this study was to assess the relationship between plasma citrulline and bowel inflammation and/or disease location in pediatric and adolescent Crohn's disease (CD) patients. METHODS: Between January 2008 and January 2010, 31 CD patients and 44 controls were included in our study, and 15 out of the 31 CD patients continued a prospective survey. We evaluated the differences between groups, at baseline, in plasma citrulline and glutamine and between their baseline and final values during the prospective survey, and correlation between baseline values of citrulline and duration of disease, C reactive protein, and fecal calprotectin. RESULTS: Mean citrulline value was 33.0 +/- 7.5 MUmol/L in controls and 23.5 +/- 8.4 MUmol/L in CD patients (P < 0.0001). Plasma citrulline was significantly lower in patients with small bowel (SB) location than in patient with only ileo-colon disease (14.2 +/- 5.5 and 24.7 +/- 8.0, respectively; P = 0.0037). Citrulline <=22 MUmol/L reached sensitivity of 100% (95% confidence interval (CI) 54-100) and specificity of 98% (CI 89-99) in differentiating control subjects from CD with SB location. CONCLUSIONS: CD patients have reduced concentration of plasma citrulline than controls. Intestinal damage rather than inflammation seems to be responsible for the reduced biosynthesis of citrulline, which decreases particularly in CD patients with SB location. This finding suggests the potential role of citrulline as marker of disease location, but future works will be needed to confirm this suggestion. PMID- 21670985 TI - Isolation and characterization of spheroid cells from the HT29 colon cancer cell line. AB - BACKGROUND: Colorectal cancer stem cells (Cr-CSCs) are involved in the growth of colon cancer, but their specific role in tumor biology, including metastasis, is still unclear. Currently, methods for sorting Cr-CSCs are based on the expression of surface markers (e.g., CD133(+), CD44(+), and aldehyde dehydrogenase 1 (ALDH1(+))); however, the specificity of these markers for Cr-CSCs is uncertain. PURPOSE: This study aimed to develop more effective ways of isolating and purifying Cr-CSCs. METHODS: Suspension culture was used for isolation of Cr-CSCs. And spheroid cells were performed by side population technology, and the putative molecular marker analysis of colorectal cancer stem cell. Migration assay and chemoresistance experiment were conducted between the adherent cells and spheroid cells. RESULTS: HT29 colon cancer cells grew well in suspension culture. The percentage of CD44(+) cancer cell of spheroid cells was 68 times higher than that of adherent cells (89.5% vs. 1.3%), but there was no obvious difference in the percentage of CD133(+) cells (6.25% vs. 5.6%). Moreover, it is worth noting that the percent of CD133 (+)/CD44(+) cells remarkably rose (from 0.6% to 5.4%). The expression of ALDH1 was markedly increased (7.5% vs. 20.5%) for the spheroid cells than the adherent cells. The side population within the spheroid population dramatically increased from 0.2% to 6.3%. The resistance of spheroid cells to 5 FU was higher than that of adherent cells, as was their ability to migrate in the presence of SDF-1alpha. CONCLUSION: Suspension culture is an effective approach for enriching Cr-CSCs and can provide an inexhaustible supply of genetically stable colon cancer stem cells for targeted Cr-CSC studies. Spheroid cell models also enable the study of colon cancer chemoresistance and metastasis and may help to elucidate the role of cancer stem cells in colon cancer. PMID- 21670986 TI - Subjective assessment of right ventricle enlargement from computed tomography pulmonary angiography images. AB - To retrospectively evaluate prognostic accuracy of subjective assessment of right ventricle (RV) enlargement on CT pulmonary angiography (CTPA) images in comparison with objective measures of RV enlargement in patients with acute pulmonary embolism (PE). For 200 consecutive patients with acute PE, two readers blinded to patient outcomes subjectively determined whether the maximum RV diameter was greater than that of the left ventricle (LV) using axial CTPA images. For the objective measurements, RV/LV diameter ratios were calculated using axial images and 4-chamber reformatted images. For all assessments, sensitivities and specificities for predicting PE-related death within 30-days and a composite outcome including PE-related death or the need for intensive therapies were compared. The agreement between two readers was 91.5% (kappa = 0.83) and all other assessments had pair-wise agreement over 75% (kappa = 0.53 0.72). There was no significant difference in sensitivity between the subjective and objective methods for predicting both outcomes. The specificity for subjective RV enlargement (55.4-67.7%) was significantly higher than objective measures (45.8-53.1%), except for the 4-chamber views where, for one reader, the specificity of the subjective evaluation was higher but did not reach statistical significance. Complex measurements of RV/LV diameter ratios may not be needed to maximize the prognostic value from CTPA. The radiologist who interprets the CTPA images should report RV enlargement when the RV diameter subjectively appears larger than the LV. PMID- 21670987 TI - Assessment of potable water quality including organic, inorganic, and trace metal concentrations. AB - The quality of drinking water (tap, ground, and spring) in Toyama Prefecture, Japan was assessed by studying quality indicators including major ions, total carbon, and trace metal levels. The physicochemical properties of the water tested were different depending on the water source. Major ion concentrations (Ca(2+), K(+), Si(4+), Mg(2+), Na(+), SO(4)(2-), HCO(3)(-), NO(3)(-), and Cl(-)) were determined by ion chromatography, and the results were used to generate Stiff diagrams in order to visually identify different water masses. Major ion concentrations were higher in ground water than in spring and tap water. The relationship between alkaline metals (Na(+) and K(+)), alkaline-earth metals (Ca(2+) and Mg(2+)), and HCO(3)(-) showed little difference between deep and shallow ground water. Toyama ground, spring, and tap water were all the same type of water mass, called Ca-HCO(3). The calculated total dissolved solid values were below 300 mg/L for all water sources and met World Health Organization (WHO) water quality guidelines. Trace levels of As, Cd, Cr, Co, Cu, Fe, Pb, Mn, Mo, Ni, V, Zn, Sr, and Hg were detected in ground, spring, and tap water sources using inductively coupled plasma atomic emission spectrometry, and their levels were below WHO and Japanese water quality standard limits. Volatile organic carbon compounds were quantified by headspace gas chromatography-mass spectrometry, and the measured concentrations met WHO and Japanese water quality guidelines. Total trihalomethanes (THMs) were the major contaminant detected in all natural drinking water sources, but the concentration was highest in tap water (37.27 +/- 0.05 MUg/L). Notably, THMs concentrations reached up to 1.1 +/- 0.05 MUg/L in deep ground water. The proposed model gives an accurate description of the organic, inorganic, and trace heavy metal indicators studied here and may be used in natural clean water quality management. PMID- 21670988 TI - Cytogenetic characterization and mapping of rDNAs, core histone genes and telomeric sequences in Venerupis aurea and Tapes rhomboides (Bivalvia: Veneridae). AB - We describe the chromosomal location of GC-rich regions, 28S and 5S rDNA, core histone genes, and telomeric sequences in the veneroid bivalve species Venerupis aurea and Tapes (Venerupis) rhomboides, using fluorochrome staining with propidium iodide, DAPI and chromomycin A3 (CMA) and fluorescent in situ hybridization (FISH). DAPI dull/CMA bright bands were coincident with the chromosomal location of 28S rDNA in both species. The major rDNA was interstitially clustered at a single locus on the short arms of the metacentric chromosome pair 5 in V. aurea, whereas in T. rhomboides it was subtelomerically clustered on the long arms of the subtelocentric chromosome pair 17. 5S rDNA also was a single subtelomeric cluster on the long arms of subtelocentric pair 17 in V. aurea and on the short arms of the metacentric pair 9 in T. rhomboides. Furthermore, V. aurea showed four telomeric histone gene clusters on three metacentric pairs, at both ends of chromosome 2 and on the long arms of chromosomes 3 and 8, whereas histone genes in T. rhomboides clustered interstitially on the long arms of the metacentric pair 5 and proximally on the long arms of the subtelocentric pair 12. Double and triple FISH experiments demonstrated that rDNA and H3 histone genes localized on different chromosome pairs in the two clam species. Telomeric signals were found at both ends of every single chromosome in both species. Chromosomal location of these three gene families in two species of Veneridae provides a clue to karyotype evolution in this commercially important bivalve family. PMID- 21670989 TI - The origin of natural tetraploid loach Misgurnus anguillicaudatus (Teleostei: Cobitidae) inferred from meiotic chromosome configurations. AB - In the loach, or Oriental weatherfish Misgurnus anguillicaudatus (Teleostei: Cobitidae), diploid (2n = 50) and tetraploid individuals (4n = 100) are often sympatric in central China. The evolutionary mechanism of this tetraploidization was analyzed with the observation of meiotic behavior of chromosomes in both the germinal vesicles of mature oocytes and the primary spermatocytes in diploid and tetraploid loaches. Whereas diploid specimens usually showed 25 bivalents in meiotic cells, tetraploid loaches exhibited 0-6 quadrivalents and 38-50 bivalents in both sexes, with the modal number of quadrivalents as three in females and four in males. In the diploid specimens, the two largest metacentric chromosomes bearing nucleolar organizing regions (NORs) identified by chromomycin A(3) staining and fluorescence in situ hybridization with a 5.8S + 28S rDNA probe formed one bivalent with terminal association. In the tetraploids, four NOR bearing chromosomes never formed a quadrivalent, but were organized into two terminally-associated bivalents. These findings suggest an autotetraploid origin of the natural tetraploid loach and subsequent rediploidization of whole genome. The latter process, however, seems still in progress as inferred from the concurrence of up-to several quadrivalents and the majority of bivalents. PMID- 21670990 TI - Rosuvastatin beneficially alters the glomerular structure of kidneys from spontaneously hypertensive rats (SHRs). AB - The incidence of chronic renal diseases is increasing worldwide, and there is a great need to identify therapies capable of arresting or reducing disease progression. The current treatment of chronic nephropathies is limited to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, but increasing clinical and experimental evidence suggests that statins could play a therapeutic role. Ultrastructural studies have shown the presence of gap junctions within all the cells of the glomerulus and podocytes have been found to contain primarily connexin-43. The present study aims to observe the beneficial effects of rosuvastatin on structural and ultrastructural renal morphology and on glomerular connexin-43 expression in normotensive rats and spontaneously hypertensive rats (SHR). Rats were randomly allocated into four groups: WKY-C: normotensive animals no receiving rosuvastatin; WKY-ROS: normotensive animals receiving rosuvastatin; SHR-C: hypertensive animals no receiving rosuvastatin; SHR-ROS: hypertensive animals receiving rosuvastatin. Our results show no differences in blood urea, creatinine, uric acid and creatine phosphokinase levels between the groups, however, there was an decreasing of 24-h protein excretion in SHR-ROS. Capsular area in SHR-ROS was decreased, however, there was no alteration in urinary space. By transmission electron microscopy the slit diaphragm and podocyte foot processes were more preserved in SHR-ROS. By scanning electron microscopy the podocyte foot processes were more preserved in SHR-ROS. Increased connexin-43 immunofluorescence was observed in glomeruli of WKY-ROS and SHR-ROS. In conclusion, we hypothesize that renal pleiotropic effect of rosuvastatin can be a therapeutic tool for improving kidney ultrastructure and, consequently, renal function in hypertensive individuals. PMID- 21670991 TI - Replica exchange molecular dynamics simulation of structure variation from alpha/4beta-fold to 3alpha-fold protein. AB - Replica exchange molecular dynamics (REMD) simulation provides an efficient conformational sampling tool for the study of protein folding. In this study, we explore the mechanism directing the structure variation from alpha/4beta-fold protein to 3alpha-fold protein after mutation by conducting REMD simulation on 42 replicas with temperatures ranging from 270 K to 710 K. The simulation began from a protein possessing the primary structure of GA88 but the tertiary structure of GB88, two G proteins with "high sequence identity." Albeit the large Calpha-root mean square deviation (RMSD) of the folded protein (4.34 A at 270 K and 4.75 A at 304 K), a variation in tertiary structure was observed. Together with the analysis of secondary structure assignment, cluster analysis and principal component, it provides insights to the folding and unfolding pathway of 3alpha fold protein and alpha/4beta-fold protein respectively paving the way toward the understanding of the ongoings during conformational variation. PMID- 21670992 TI - Improving the desolvation penalty in empirical protein pKa modeling. AB - Unlike atomistic and continuum models, empirical pk(a) predicting methods need to include desolvation contributions explicitly. This study describes a new empirical desolvation method based on the Born solvation model. The new desolvation model was evaluated by high-level Poisson-Boltzmann calculations, and discussed and compared with the current desolvation model in PROPKA-one of the most widely used empirical protein pK(a) predictors. The new desolvation model was found to remove artificial erratic behavior due to discontinuous jumps from man-made first-shell cutoffs, and thus improves the desolvation description significantly. PMID- 21670993 TI - Substrate binding and translocation of the serotonin transporter studied by docking and molecular dynamics simulations. AB - The serotonin (5-HT) transporter (SERT) plays an important role in the termination of 5-HT-mediated neurotransmission by transporting 5-HT away from the synaptic cleft and into the presynaptic neuron. In addition, SERT is the main target for antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs). The three-dimensional (3D) structure of SERT has not yet been determined, and little is known about the molecular mechanisms of substrate binding and transport, though such information is very important for the development of new antidepressant drugs. In this study, a homology model of SERT was constructed based on the 3D structure of a prokaryotic homologous leucine transporter (LeuT) (PDB id: 2A65). Eleven tryptamine derivates (including 5-HT) and the SSRI (S)-citalopram were docked into the putative substrate binding site, and two possible binding modes of the ligands were found. To study the conformational effect that ligand binding may have on SERT, two SERT-5-HT and two SERT-(S)-citalopram complexes, as well as the SERT apo structure, were embedded in POPC lipid bilayers and comparative molecular dynamics (MD) simulations were performed. Our results show that 5-HT in the SERT-5-HT(B) complex induced larger conformational changes in the cytoplasmic parts of the transmembrane helices of SERT than any of the other ligands. Based on these results, we suggest that the formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation. PMID- 21670994 TI - Probing the structural requirements of A-type Aurora kinase inhibitors using 3D QSAR and molecular docking analysis. AB - Aurora-A, the most widely studied isoform of Aurora kinase overexpressed aberrantly in a wide variety of tumors, has been implicated in early mitotic entry, degradation of natural tumor suppressor p53 and centrosome maturation and separation; hence, potent inhibitors of Aurora-A may be therapeutically useful drugs in the treatment of various forms of cancer. Here, we report an in silico study on a group of 220 reported Aurora-A inhibitors with six different substructures. Three-dimensional quantitative structure-activity relationship (3D QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on this series of molecules. The resultant optimum 3D-QSAR models exhibited an r (cv) (2) value of 0.404-0.582 and their predictive ability was validated using an independent test set, ending in r (pred) (2) 0.512-0.985. In addition, docking studies were employed to explore these protein-inhibitor interactions at the molecular level. The results of 3D-QSAR and docking analyses validated each other, and the key structural requirements affecting Aurora-A inhibitory activities, and the influential amino acids involved were identified. To the best of our knowledge, this is the first report on 3D-QSAR modeling of Aurora-A inhibitors, and the results can be used to accurately predict the binding affinity of related analogues and also facilitate the rational design of novel inhibitors with more potent biological activities. PMID- 21670995 TI - Quantification of vital adherent Streptococcus sanguinis cells on protein-coated titanium after disinfectant treatment. AB - The quantification of vital adherent bacteria is challenging, especially when efficacy of antimicrobial agents is to be evaluated. In this study three different methods were compared in order to quantify vital adherent Streptococcus sanguinis cells after exposure to disinfectants. An anaerobic flow chamber model accomplished initial adhesion of S. sanguinis on protein-coated titanium. Effects of chlorhexidine, Betadine(r), Octenidol(r), and ProntOral(r) were assessed by quantifying vital cells using Live/Dead BacLightTM, conventional culturing and isothermal microcalorimetry (IMC). Results were analysed by Kruskal-Wallis one way analysis of variance. Live/dead staining revealed highest vital cell counts (P < 0.05) and demonstrated dose-dependent effect for all disinfectants. Microcalorimetry showed time-delayed heat flow peaks that were proportioned to the remaining number of viable cells. Over 48 h there was no difference in total heat between treated and untreated samples (P > 0.05), indicating equivalent numbers of bacteria were created and disinfectants delayed growth but did not eliminate it. In conclusion, contrary to culturing, live/dead staining enables detection of cells that may be viable but non-cultivable. Microcalorimetry allows unique evaluation of relative disinfectant effects by quantifying differences in time delay of regrowth of remaining vital cells. PMID- 21670996 TI - Nanostructured positively charged bioactive TiO2 layer formed on Ti metal by NaOH, acid and heat treatments. AB - Nanometer-scale roughness was generated on the surface of titanium (Ti) metal by NaOH treatment and remained after subsequent acid treatment with HCl, HNO(3) or H(2)SO(4) solution, as long as the acid concentration was not high. It also remained after heat treatment. Sodium hydrogen titanate produced by NaOH treatment was transformed into hydrogen titanate after subsequent acid treatment as long as the acid concentration was not high. The hydrogen titanate was then transformed into titanium oxide (TiO(2)) of anatase and rutile by heat treatment. Treated Ti metals exhibited high apatite-forming abilities in a simulated body fluid especially when the acid concentration was greater than 10 mM, irrespective of the type of acid solutions used. This high apatite-forming ability was maintained in humid environments for long periods. The high apatite-forming ability was attributed to the positive surface charge that formed on the TiO(2) layer and not to the surface roughness or a specific crystalline phase. This positively charged TiO(2) induced apatite formation by first selectively adsorbing negatively charged phosphate ions followed by positively charged calcium ions. Apatite formation is expected on the surfaces of such treated Ti metals after short periods, even in living systems. The bonding of metal to living bone is also expected to take place through this apatite layer. PMID- 21670997 TI - Raman spectroscopy of primary bovine aortic endothelial cells: a comparison of single cell and cell cluster analysis. AB - There are many techniques that allow in vitro interactions among cells and their environment to be monitored, including molecular, biochemical and immunochemical techniques. Traditional techniques for the analysis of cells often require fixation or lysis from substrates; however, use of such destructive methods is not feasible where the expanded cell cultures are required to be used for clinical implantation. Several studies have previously highlighted the potential of Raman spectroscopy to provide useful information on key biochemical markers within cells. As such, we highlight the capability of Raman spectroscopy with different laser spot sizes for use as a non-invasive, rapid, and specific method to perform in situ analysis of primary bovine aortic endothelial cells (BAECs). Raman spectra were collected from both individual live cells cultured on fused silica substrates and on clusters of live cells placed on fused silica substrates, measured at 532 and 785 nm. The results obtained show notable spectral differences in DNA/RNA region indicative of the relative cytoplasm and nucleus contributions. Raman spectra of cell clusters show slight variations in the intensity of the phenylalanine peak (1004 cm(-1)) indicating variations in protein contribution. These spectra also highlight contributions from other cellular components such as, proteins, lipids, nucleic acids and carbohydrates, respectively. PMID- 21670998 TI - Fabrication and characterization of interconnected porous biodegradable poly(epsilon-caprolactone) load bearing scaffolds. AB - In this study, poly(epsilon-caprolactone) (PCL)/poly(ethylene oxide) (PEO) (50:50 wt%) immiscible blend was used as a model system to investigate the feasibility of a novel solventless fabrication approach that combines cryomilling, compression molding and porogen leaching techniques to prepare interconnected porous scaffolds for tissue engineering. PCL was cryomilled with PEO to form blend powders. Compression molding was used to consolidate and anneal the cryomilled powders. Selective dissolution of the PEO with water resulted in interconnected porous scaffolds. Sodium chloride salt (NaCl) was subsequently added to cryomilled powder to increase the porosity of scaffolds. The prepared scaffolds had homogeneous pore structures, a porosity of ~50% which was increased by mixing salt with the blend (~70% for 60% wt% NaCl), and a compressive modulus and strength (epsilon = 10%) of 60 and 2.8 MPa, respectively. The results of the study confirm that this novel approach offers a viable alternative to fabricate scaffolds. PMID- 21670999 TI - Characterization of an antimicrobial dental resin adhesive containing zinc methacrylate. AB - This study evaluates the effect of zinc methacrylate (ZM) on the degree of conversion (DC), cytotoxicity and antimicrobial activity (AA) of an experimental resin. Tetraethyleneglycol dimethacrylate was used as the experimental resin and it was photo activated using camphoroquinone and ethyl 4-dimethylamine benzoate. Additionally, 1.0, 2.5, 5.0, 10, 20 and 30 wt% of ZM was added to the various experimental resins. The DC was accessed by Fourier Transform infrared spectroscopy. For cytotoxicity, immortalized mouse fibroblasts were exposed to the experimental resin extracts. An MTT assay was used to access the cytotoxicity. The AA against Streptococcus mutans UA159 was accessed by the agar diffusion method. An improvement in the DC in all concentrations of ZM was observed. The greater the amount of ZM on the experimental resin, the less the cytotoxicity was provoked. Three ZM concentrations showed AA that exhibited various inhibition growth zones with 10, 20 (10 mm) and 30 wt% (15 mm). PMID- 21671000 TI - Electrodeposition of chitosan-glucose oxidase biocomposite onto Pt-Pb nanoparticles modified stainless steel needle electrode for amperometric glucose biosensor. AB - A glucose biosensor was fabricated by electrodepositing chitosan (CS)-glucose oxidase(GOD) biocomposite onto the stainless steel needle electrode (SSN electrode) modified by Pt-Pb nanoparticles (Pt-Pb/SSN electrode). Firstly, Pt-Pb nanoparticles were deposited onto the SSN electrode and then CS-GOD biocomposite was co-electrodeposited onto the Pt-Pb/SSN electrode in a mixed solution containing p-benzoquinone (p-BQ), CS and GOD. The electrochemical results showed that the Pt-Pb nanoparticles can accelerate the electron transfer and improve the effective surface area of the SSN electrode. As a result, the detection range of the proposed biosensor was from 0.03 to 9 mM with a current sensitivity of 0.4485 MUA/mM and a response time of 15 s. The Michaelis constant value was calculated to be 4.9837 mM. The cell test results indicated that the electrodes have a low cytotoxicity. This work provided a suitable technology for the fabrication of the needle-type glucose biosensor. PMID- 21671001 TI - Composites for bone repair: phosphate glass fibre reinforced PLA with varying fibre architecture. AB - Internal fixation for bone fractures with rigid metallic plates, screws and pins is a proven operative technique. However, refracture's have been observed after rigid internal fixation with metal plates and plate fixation has been known to cause localised osteopenia under and near the plate. In the present study, resorbable composites comprising a PLA matrix reinforced with iron doped phosphate glass fibres were investigated. Non-woven random mat laminates of approximately 30% and 45% fibre volume fraction (V(f)) were produced, along with unidirectional and 0 degrees -90 degrees samples of approximately 20% V(f). The non-woven composite laminates achieved maximum values of 10 GPa modulus and 120 MPa strength. The 0-90o samples showed unexpectedly low strengths close to matrix value (~50 MPa) although with a modulus of 7 GPa. The UD specimens exhibited values of 130 MPa and 11.5 GPa for strength and modulus respectively. All the modulus values observed were close to that expected from the rule of mixtures. Samples immersed in deionised water at 37 degrees C revealed rapid mechanical property loss, more so for the UD and 0-90o samples. It was suggested that continuous fibres wicked the degradation media into the composite plates which sped up the deterioration of the fibre-matrix interface. The effect was less pronounced in the non-woven random mat laminates due to the discontinuous arrangement of fibres within the composite, making it less prone to wicking. Random mat composites revealed a higher mass loss than the UD and 0 degrees -90 degrees specimens, it was suggested this was due to the higher fibre volume fractions of these composites and SEM studies revealed voidage around the fibres by day 3. Studies of pH of the degradation media showed similar profiles for all the composites investigated. An initial decrease in pH was attributed to the release of phosphate ions into solution followed by a gradual return back to neutral. PMID- 21671003 TI - Neuregulin-1beta prevents Ca(2+) overloading and apoptosis through PI3K/Akt activation in cultured dorsal root ganglion neurons with excitotoxicity induced by glutamate. AB - Neuregulin (NRG) plays an important role on the genesis and differentiation of neurons in the dorsal root ganglion (DRG). Whether NRG-1beta regulates Ca(2+) homeostasis and apoptosis of cultured DRG neurons with excitotoxicity induced by Glu remains unknown. In this study, primary cultured DRG neurons were used to determine the effects of NRG-1beta on Ca(2+) overload and apoptosis of DRG sensory neurons with excitotoxicity induced by Glu. The primary cultured DRG neurons at 48 h of culture age were then exposed to Glu (0.2 mmol/l), Glu (0.2 mmol/l) plus NRG-1beta (20 nmol/l), or Glu (0.2 mmol/l) plus NRG-1beta (20 nmol/l) and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 MUmol/l) for additional 12 h. After that, intracellular Ca(2+) concentration ([Ca(2+)](i)) in isolated DRG neurons using the fluorescent Ca(2+) indicator fluo-3 was measured by confocal laser scanning microscope. Apoptotic neurons were monitored by Hoechst 33342 staining. Expression of caspase-3, procaspase-3, and pAkt was detected by Western blot assay. Administration of 0.2 mmol/l Glu evoked an increase in [Ca(2+)](i), confirming the excitatory effect of Glu. Compared with the control group, apoptotic (condensed and fragmented nuclei) neurons were observed in Glu-treated cells after Hoechst 33342 staining. The increase caspase 3 of and decrease of procaspase-3 expression levels after administration of 0.2 mmol/l Glu suggested the apoptotic effects of Glu. These effects could be inhibited by the presence of NRG-1beta. The effects of NRG-1beta could be blocked by PI3K inhibitor LY294002. These results implicated that NRG-1beta could prevents Ca(2+) overload and apoptosis by activating PI3K/Akt pathway of primary cultured DRG neurons with excitotoxicity induced by Glu. PMID- 21671004 TI - Associations between effortful control, psychological control and proactive and reactive aggression. AB - The current study examined relations between effortful control (ones ability to focus and shift attention in an adaptive manner), psychological control (caregiver attempts to manipulate the child's internal world) and proactive and reactive aggression. Participants were 69 children (54% male) ranging from 9 to 12 years of age (M = 10.35, SD = 1.14) and their primary caregivers from a community-recruited sample. Results indicate that psychological control and effortful control interacted and contributed to proactive aggression. At high levels of effortful control psychological control was positively associated with proactive aggression, whereas at low levels of effortful control psychological control was unrelated to proactive aggression. In contrast, although both effortful control and psychological control were correlated with reactive aggression, only effortful control was uniquely negatively associated with reactive aggression. Implications for prevention and intervention are discussed. PMID- 21671005 TI - Emotional and behavioral functioning of offspring of African American mothers with depression. AB - Extensive research demonstrates the negative impact of maternal depression on their offspring. Unfortunately, few studies have been explored in African American families. This study examined emotional and behavioral functioning among children of African American mothers with depression. African American mothers (n = 63), with a past year diagnosis of a depressive disorder, and one of their children (ages 7-14) completed behavioral rating scales in a cross-sectional design. Results showed that 6.5 and 15% scored within the clinical range for depression and anxiety symptoms, respectively. Approximately a third of the offspring reported suicidal ideation. Based on mothers' report, 25.4 and 20.6% of the offspring exhibited internalizing and externalizing symptoms in the clinical range, respectively. Offspring whose mothers were in treatment exhibited higher levels of self-reported anxiety symptoms. Offspring of African American mothers with depression were exhibiting socioemotional problems in ways that are similar to offspring of European American mothers with depression. PMID- 21671006 TI - The role of IL-1beta in nicotine-induced immunosuppression and neuroimmune communication. AB - Although a number of inflammatory cytokines are increased during sepsis, the clinical trials aimed at down-regulating these mediators have not improved the outcome. These paradoxical results are attributed to loss of the "tolerance" phase that normally follows the proinflammatory response. Chronic nicotine (NT) suppresses both adaptive and innate immune responses, and the effects are partly mediated by the nicotinic acetylcholine receptors in the brain; however, the mechanism of neuroimmune communication is not clear. Here, we present evidence that, in rats and mice, NT initially increases IL-1beta in the brain, but the expression is downregulated within 1-2 week of chronic exposure, and the animals become resistant to proinflammatory/pyrogenic stimuli. To examine the relationship between NT, IL-1beta, and immunosuppression, we hypothesized that NT induces IL-1beta in the brain, and its constant presence produces immunological "tolerance". Indeed, unlike wild-type C57BL/6 mice, chronic NT failed to induce immunosuppression or downregulation of IL-1beta expression in IL-1beta-receptor knockout mice. Moreover, while acute intracerebroventricular administration of IL 1beta in Lewis (LEW) rats activated Fyn and protein tyrosine kinase activities in the spleen, chronic administration of low levels of IL-1beta progressively diminished the pyrogenic and T cell proliferative responses of treated animals. Thus, IL-1beta may play a critical role in the perception of inflammation by the CNS and the induction of an immunologic "tolerant" state. Moreover, the immunosuppressive effects of NT might be at least partly mediated through its effects on the brain IL-1beta. This represents a novel mechanism for neuroimmune communication. PMID- 21671007 TI - Role of Bim in apoptosis induced in H460 lung tumor cells by the spindle poison Combretastatin-A4. AB - The BH3-only Bcl-2 subfamily member Bim is a well known apoptosis promoting protein. However, the mechanisms upstream of mitochondrion membrane permeability by which Bim is involved in apoptosis have been poorly investigated, particularly in response to agents capable of interfering with the cytoskeleton architecture and arresting cells in mitosis. Based on the observation that Bim is sequestered on the microtubule-array by interaction with the light chain of dynein, we have investigated upon depolymerisation, whether Bim could be involved in the commitment of apoptosis. With this purpose H460 Non Small Lung Cancer Cells (NSLC) were treated with the microtubule damaging agent combretastatin-A4 (CA-4) (7.5 nM; 8-48 h), and various parameters were investigated. Upon treatment, cells arrested in mitosis and died through a caspase-3-dependent mitotic catastrophe. Transient knock down of Bim drastically reduced apoptosis, indicating that this protein was involved in cell death as induced by microtubules disorganisation. In response to increasing conditions of microtubules depolymerisation, we found that the protein level of Bim was strongly upregulated in a time-dependent manner at transcriptional level. Furthermore, Bim was released from microtubule-associated components. Bim was translocated to mitochondria, even in a condition of protein synthesis inhibition, where it showed a markedly increased interaction with Bcl 2. In turn, the fraction of Bax bound to Bcl-2 decreases in response to treatment, thereby indicating that Bim possibly promotes Bax release from the pro survival protein Bcl-2. Overall, we demonstrated that Bim is required for the CA 4-induced cell death in the H460 lung cancer cell line via activation of the mitochondrial signalling pathway. Defining the contribution of Bim to the mechanism of apoptosis may offer some different clues in view of developing new strategies for chemotherapy with CA-4, underlining the relevance of the cytoskeleton integrity in the apoptotic response. PMID- 21671008 TI - Insulin receptor signaling activated by penta-O-galloyl-alpha-D: -glucopyranose induces p53 and apoptosis in cancer cells. AB - p53 is essential for cell cycle arrest and apoptosis induction while insulin receptor (IR) signaling is important for cell metabolism and proliferation and found upregulated in cancers. While IR has recently been found to be involved in apoptosis, p53 induction or apoptosis mediated through IR signaling activation has never been documented. Here, we report that the IR signaling pathway, particularly the IR-MEK pathway, mediates biological and biochemical changes in p53 and apoptosis in tumor cells. Specifically, natural compound penta-O-galloyl alpha-D: -glucopyranose (alpha-PGG), a previously characterized IR signaling activator, induced apoptosis in RKO cells without significantly affecting its normal counterpart FHC cells. alpha-PGG induced apoptosis in RKO cells through p53, Bax and caspase 3. Importantly, alpha-PGG's ability to elevate p53 was diminished by IR inhibitor and IR-siRNA, suggesting a non-conventional role of IR as being involved in p53 induction. Further studies revealed that alpha-PGG activated MEK, a downstream signaling factor of IR. Blocking MEK significantly suppressed alpha-PGG-induced p53 and Bax elevation. All these results suggested that alpha-PGG induced p53, Bax, and apoptosis through the IR-MEK signaling pathway. The unique activity of alpha-PGG, a novel IR phosphorylation and apoptosis inducer, may offer a new therapeutic strategy for eliciting apoptotic signal and inhibiting cancer growth. PMID- 21671009 TI - Trajectories of attention deficit hyperactivity disorder and oppositional defiant disorder symptoms as precursors of borderline personality disorder symptoms in adolescent girls. AB - Little empirical evidence exists regarding the developmental links between childhood psychopathology and borderline personality disorder (BPD) in adolescence. The current study addresses this gap by examining symptoms of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) as potential precursors. ADHD and BPD share clinical features of impulsivity, poor self-regulation, and executive dysfunction, while ODD and BPD share features of anger and interpersonal turmoil. The study is based on annual, longitudinal data from the two oldest cohorts in the Pittsburgh Girls Study (N = 1,233). We used piecewise latent growth curve models of ADHD and ODD scores from age 8 to 10 and 10 to 13 years to examine the prospective associations between dual trajectories of ADHD and ODD symptom severity and later BPD symptoms at age 14 in girls. To examine the specificity of these associations, we also included conduct disorder and depression symptom severity at age 14 as additional outcomes. We found that higher levels of ADHD and ODD scores at age 8 uniquely predicted BPD symptoms at age 14. Additionally, the rate of growth in ADHD scores from age 10 to 13 and the rate of growth in ODD scores from 8 to 10 uniquely predicted higher BPD symptoms at age 14. This study adds to the literature on the early development of BPD by providing the first longitudinal study to examine ADHD and ODD symptom trajectories as specific childhood precursors of BPD symptoms in adolescent girls. PMID- 21671010 TI - Inflammatory biomarkers in depression: an opportunity for novel therapeutic interventions. AB - Currently available antidepressants are effective in less than two thirds of depressed patients, with even lower remission rates in the context of co-morbid medical illness. A rapidly expanding evidence base suggests that maladaptive inflammatory immune responses may be a common pathophysiology underlying depression, particularly in the presence of a general medical condition. The inflammatory hypothesis of depression marks a significant shift away from monoamine-based approaches and is a major step towards developing novel treatments that directly target causal factors of depression. Many antidepressants exert anti-inflammatory effects and there is an emerging literature documenting the efficacy of anti-inflammatory agents as adjunctive treatments for depression. Identification of inflammatory biomarkers in depression will require a re-conceptualization of both the diagnostic phenomenology and the experimental approaches to studying multi-determined psychiatric disorders. In addition to their application in diagnosis, predicting prognosis, and monitoring severity and response to treatment, inflammatory biomarkers may serve as novel therapeutic targets in the treatment of depression. PMID- 21671012 TI - Mutations to the probe of Cobas TaqMan HIV-1 ver. 1.0 assay causing undetectable viral load in a patient with acute HIV-1 infection. AB - We encountered a human immunodeficiency virus (HIV)-1 in which the viral load was undetectable with the Cobas TaqMan HIV-1 ver. 1.0 (CTM v.1.0) in a patient with acute HIV-1 infection. The CTM v.1.0 assay showed more than 1,000-fold underestimation compared with the subsequent Cobas Amplicor Monitor v.1.5 assay. Because five mismatches to the CTM v.1.0 assay probe in the HIV-1 virus in the patient were disclosed by the manufacturer, partial gag regions of the HIV genome were directly sequenced from the patient's plasma viral RNA. The detected single nucleotide point mutations were located near the 5'-end of the Cobas Amplicor Monitor probe. Clinicians should be very careful in making interpretations when indeterminate Western blot analysis results and a low or even undetectable HIV-1 viral load are encountered with the CTM HIV-1 ver. 1.0 assay in patients with suspected acute HIV infection. Repeating Western blot analysis is essential before considering a low HIV-1 viral load to be a false-positive result. PMID- 21671011 TI - Validation of the Insomnia Treatment Acceptability Scale (ITAS) in primary care. AB - Patients with insomnia respond best to cognitive-behavioral treatments (CBT) if they find the approach acceptable. One tool, the Insomnia Treatment Acceptability Scale (ITAS), has been used to identify such patients, however, its reliability and validity has not been well established especially in primary care. The purpose of this study was to assess the reliability and validity of the ITAS in a primary care setting. A cross-sectional survey was conducted with 236 primary care patients, aged 18 and above, with clinically significant insomnia (Insomnia Severity Index >=8). Descriptive and summary statistics, Cronbach's alpha, Principal Axis Factor analysis with Promax rotation, and comparison of ITAS subscale scores with self-reported treatment preferences (Chi-Square) are included. Factor analysis identified two factor solutions for the ITAS subscales. The ITAS was shown to be a reliable and valid tool that can be used to facilitate psychological practice and research on interdisciplinary behavioral-medical care. PMID- 21671013 TI - Heavy metal pollution of ambient air in Nagpur City. AB - Heavy metals released from different sources in urban environment get adsorbed on respirable particulate matter less than 10 MUm in size (PM(10)) and are important from public health point of view causing morbidity and mortality. Therefore, the ambient air quality monitoring was carried out to study the temporal and special pattern in the distribution of PM(10) and associated heavy metal content in the atmosphere of Nagpur, Maharashtra State, India during 2001 as well as in 2006. PM(10) fraction was observed to exceed the stipulated standards in both years. It was also observed that minimum range of PM(10) was observed to be increased in 2006 indicating increase in human activity during nighttime also. Six heavy metals were analyzed and were observed to occur in the order Zn > Fe > Pb > Ni > Cd > Cr in 2006, similar to the trend in other metro cities in India. Lead and Nickel were observed to be within the stipulated standards. Poor correlation coefficient (R(2)) between lead and PM(10) indicated that automobile exhaust is not the source of metals to air pollution. Commercial and industrial activity as well as geological composition may be the potential sources of heavy metal pollution. Total load of heavy metals was found to be increased in 2006 with prominent increase in zinc, lead, and nickel in the environment. Public health impacts of heavy metals as well as certain preventive measures to mitigate the impact of heavy metals on public health are also summarized. PMID- 21671014 TI - Atorvastatin protects against ischemia-reperfusion injury in fructose-induced insulin resistant rats. AB - PURPOSE: High fructose (HFr) intake is known to cause insulin resistance syndrome (IRS), however its effect against acute coronary events remains elusive. The present study was undertaken to evaluate the effect of HFr (60%) diet on myocardial ischemia-reperfusion (MI-RP) injury and its modulation by atorvastatin treatment. METHODS: Wistar rats kept on HFr/chow feeding for 10 weeks, received atorvastatin (30 mg/kg, per oral) or vehicle for two additional weeks followed by MI-RP injury. RESULTS: MI-RP injury was significantly augmented in HFr fed rats, as evident by the increase in infarct size (IS, 65 +/- 5% vs. 43 +/- 7%) and activities of cardiac injury biomarkers [serum lactate dehydrogenase (LDH, 698 +/ 57 vs. 444 +/- 26 U/L), creatinine kinase (CK-MB, 584 +/- 58 vs. 435 +/- 28 U/L) and tissue myeloperoxidase (MPO, 235 +/- 15 vs. 101 +/- 11 MUM/min/100 mg tissue)]. Insulin resistance (plasma glucose, 64 +/- 5 vs. 100 +/- 5 mg/dl; AUC (0-120 min), p < 0.05), MI-RP injury (IS 20 +/- 5%, LDH 292 +/- 28 U/L, CK-MB 257 +/- 13 U/L, MPO 95 +/- 5 MUM/min/100 mg tissue) and triglyceride (TG) level were significantly reduced, while myocardial Akt, p-Akt, eNOS, p-eNOS and iNOS protein expression were significantly enhanced following atorvastatin treatment in comparison to HFr fed rats. Oxidative stress marker, malondialdehyde and circulating levels of inflammatory cytokines (CRP, IL-6, IFN-gamma and TNF) were significantly reduced, while total nitrite content in the tissue and plasma was significantly augmented in atorvastatin treated rats. Atorvastatin also ameliorated endothelial dysfunction and significantly enhanced aortic Akt and eNOS protein expression. CONCLUSION: Atorvastatin conferred significant protection against MI-RP injury and alleviated HFr induced IRS possibly by increasing NOS expression through Akt dependent pathway. PMID- 21671015 TI - LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome. AB - Interactions between kinases and the estrogen receptor alpha (ERalpha) are thought to be a critical signaling pathway in the majority of human breast cancers. We have recently identified a previously uncharacterized molecule, lemur tyrosine kinase-3 (LMTK3) as a prognostic and predictive oncogenic ERalpha regulator with a central role in endocrine resistance. Unusually this protein has undergone Darwinian positive selection between Chimpanzees and humans suggesting it may contribute to human susceptibility to ERalpha-positive tumors. Using over 600 European primary breast cancer cases, we wished to establish tumor characteristics associated with both cytoplasmic and nuclear LMTK3 expression, and then externally validate our observed European clinical outcomes with samples from Asian individuals receiving chemotherapy. Both nuclear and cytoplasmic expression correlated with tumor grade (P < 0.001) and in the Asian cohort, independent blinded analyses demonstrated that high basal LMTK3 expression was associated with advanced stage of primary breast cancers as well as decreased overall (P = 0.03) and disease-free survival (P = 0.006). In summary, higher LMTK3 expression is associated with more aggressive cancers. These data support our previous findings and suggest LMTK3 expression may be a reliable new biomarker in breast cancer. PMID- 21671016 TI - The prognostic significance of B lymphocytes in invasive carcinoma of the breast. AB - Although the favourable role of T lymphocyte populations in different tumour types is established, that of B cells is still a matter of debate and needs further clarification. The presence of tumour-infiltrating B cells may represent an antibody response against breast tumour antigens. We used immunohistochemistry to investigate the density and localisation of B lymphocytes infiltrating 1470 breast tumours and to identify any prognostic significance and relationship to various clinicopathological factors. Higher numbers of CD20(+) cells were found in the stroma away from the carcinoma (mean 12 cells) compared with either intratumoural or adjacent stromal compartments (mean 1 cell). The majority of tumours showed a diffuse pattern of B cells rather than aggregates. There was a positive correlation between higher numbers of total CD20(+) B cells and higher tumour grade (r (s) = 0.20, P < 0.001), ER and PgR negativity (P < 0.001), and basal phenotype (P < 0.001) subclass. In univariate survival analysis, higher total number of infiltrating CD20(+) cells, irrespective of location, was associated with significantly better BCSS (P = 0.037) and longer DFI (P = 0.001). In multivariate analysis, total CD20(+) B cell count (HR = 0.75, 95% CI = 0.58 0.96 for BCSS and HR = 0.72, 95% CI = 0.58-0.89, for DFI), tumour size, nodal stage, grade, vascular invasion, HER-2 status, and total CD8(+) T cell count were independently associated with outcome. This suggests that humoral immunity, in addition to the cell mediated immunity, may be important in breast cancer. This should be considered in breast cancer immunotherapy and vaccine strategies. PMID- 21671017 TI - Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. AB - The ability to predict metastatic potential could be of great clinical importance, however, it is uncertain if predicting metastasis to specific vital organs is feasible. As a first step in evaluating metastatic predictions, we analyzed multiple primary tumors and metastasis pairs and determined that >90% of 298 gene expression signatures were found to be similarly expressed between matched pairs of tumors and metastases; therefore, primary tumors may be a good predictor of metastatic propensity. Next, using a dataset of >1,000 human breast tumor gene expression microarrays we determined that HER2-enriched subtype tumors aggressively spread to the liver, while basal-like and claudin-low subtypes colonize the brain and lung. Correspondingly, brain and lung metastasis signatures, along with embryonic stem cell, tumor initiating cell, and hypoxia signatures, were also strongly expressed in the basal-like and claudin-low tumors. Interestingly, low "Differentiation Scores," or high expression of the aforementioned signatures, further predicted for brain and lung metastases. In total, these data identify that depending upon the organ of relapse, a combination of gene expression signatures most accurately predicts metastatic behavior. PMID- 21671018 TI - Prognosis of metachronous contralateral breast cancer: importance of stage, age and interval time between the two diagnoses. AB - Studies comparing the prognosis after contralateral breast cancer (CBC) with that after unilateral breast cancer (UBC) shows conflicting results. We assessed the risk of breast cancer-specific death for women with metachronous CBC compared to those with a UBC in 8,478 women with invasive primary breast cancer registered in the Guy's and St. Thomas' Breast Cancer Tissue and Data Bank. Risk factors associated with breast cancer-specific death for women with CBC were estimated using Cox proportional hazards modelling. Prognoses after UBC and CBC were compared, with survival time for women with CBC calculated: (i) from CBC, (ii) from the initial cancer with CBC as a time-dependent covariate. Women diagnosed with CBC within 5 years after the initial primary breast cancer had a worse prognosis than those with CBC after 5 years and those with UBC. Women with CBC who had positive lymph nodes at the initial breast cancer diagnosis were at an increased risk of dying from breast cancer compared to those without [HR 2.5 (95% CI 1.5-4.0)]. For all stages of the initial breast cancer, a worse prognosis was observed after CBC. CBC increased the hazard originating from the initial cancer at any follow-up time, but the highest hazards were associated with a short interval to CBC. Metachronous CBC adds to the risk of dying from breast cancer. The risk increases substantially when it occurs shortly after the initial cancer, indicating a CBC in some instances may be an indicator of active distant disease. The occurrence of CBC implies a new surveillance and therapeutic situation. PMID- 21671019 TI - Polymorphisms of matrix metalloproteinases (MMP) gene and breast cancer risk: appraisal of a recent meta-analysis. PMID- 21671020 TI - Effect of the overexpression of BRCA2 unclassified missense variants on spontaneous homologous recombination in human cells. AB - Breast Cancer 2 gene (BRCA2) mutation carriers have a 45% chance of developing breast cancer and a 11% risk of developing ovarian cancer by the age of 70. While hundreds of BRCA2-truncating mutations have been associated with an increased cancer risk in carriers, the contribution of unclassified variants (UCVs) to cancer risk remains largely undefined. BRCA2-defective cells show a high degree of chromosome instability. Although a functional assay based on the BRCA2 capability to stimulate DSB-induced homologous recombination (HR) as a way to classify UCVs has been proposed, so far no data are available concerning the effect of BRCA2 UCVs on spontaneous HR. In this study, we proposed a novel functional HR-based assay that determines the effect of the transient overexpression of the BRCA2 variant on spontaneous HR. This assay will help one in the difficult task of classifying UCVs, and it will give more information on how BRCA2 may induce genome instability and on the basic mechanism of BRCA2 induced tumourigenesis. We chose 11 BRCA2 UCVs not previously described or classified in other articles, and distributed along the entire BRCA2-coding region. They are as follows: G173V, D191V, S286P, M927V, T1011R, L1019V, N1878K, S2006R, R2108C, G2353R and V3091I. Basically, because the expression of BRCA2wt and the neutral variants did not increase spontaneous HR, we classified the variants G173V, S286P, M927V, T1011R and L1019V as HR-negative and presumed that they were not pathogenic. The HR-positive variants, D191V, N1878K, S2006R, R2108C, G2353R, and V3091I, which increased HR as much as the cancer-associated variant G2748D, could probably be classified as pathogenic. We observed that all our variants in the C-terminus of the protein behaved differently from the wt, suggesting a role for this protein region in spontaneous HR. PMID- 21671021 TI - Evaluation of medication safety in the discharge medication of 509 surgical inpatients using electronic prescription support software and an extended operational interaction classification. AB - PURPOSE: Our aim was to study drug interactions and dose adjustments in patients with renal impairment in the discharge medication of surgical inpatients and to evaluate the strengths and limitations of clinical decision support software (CDSS) for this task. METHODS: This was a cross-sectional study involving 509 surgical patients of a primary care hospital. We developed a customized interface for the CDSS MediQ, which we used for automated retrospective identification of drug interactions in the patients' discharge medication. The clinical relevance of the interactions was evaluated based on the Zurich Interaction System (ZHIAS) that incorporates the operational classification of drug interactions (ORCA). Prescriptions were further analyzed for recommended dose adjustments in patients with a glomerular filtration rate <60 ml/min. RESULTS: For the total of 2,729 prescriptions written for the 509 patients enrolled in the study, MediQ generated 2,558 interaction alerts and 1,849 comments. Among these were ten "high danger" and 551 "average danger" alerts that we reclassified according to ORCA criteria. This reclassification resulted in ten contraindicated combinations, 77 provisionally contraindicated combinations, and 310 with a conditional and 164 with a minimal risk of adverse outcomes. The ZHIAS classification also provides categorical information on expected adverse outcomes and management recommendations, which are presented in detail. We identified 56 prescriptions without a recommended dose adjustment for impaired renal function. CONCLUSIONS: CDSS identified a large number of drug interactions in surgical discharge medication, but according to ZHIAS criteria only a minor fraction of these appeared to involve a substantial risk to the patient. CDSS should therefore aim at reducing over-alerting and improve usability in order to become more efficacious in terms of the prevention of adverse drug events in clinical practice. PMID- 21671022 TI - Demand and supply of N in seed production of soybean (Glycine max) at different N fertilization levels after flowering. AB - Nitrogen (N) has been suggested as a determinant of seed production especially in species with high seed N content. Assuming that seed yield was determined as the balance between N demand and supply for seed production, we studied the effect of N fertilization after flowering on soybean (Glycine max L. Merr.) yield. Seed N concentration was nearly constant irrespective of N fertilization, indicating that seed production was proportional to the amount of N available for seed growth. N demand for seed production was analyzed as the product of seed number, the rate of N filling in individual seeds, and the length of the reproductive period. N fertilization increased seed number and the reproductive period, but did not influence the N filling rate. Seed number was positively correlated with dry mass productivity after flowering. Three N sources were distinguished: mineral N uptake, symbiotic N(2) fixation and N remobilization from vegetative body. N fertilization increased N uptake and N remobilization, but lowered N(2) fixation. We concluded that N availability in the reproductive period determined seed yield directly through increasing N supply for seed growth and indirectly through increasing seed N demand with enhanced plant dry mass productivity. PMID- 21671023 TI - Digestive enzyme activities during early ontogeny in Common snook (Centropomus undecimalis). AB - Common snook (Centropomus undecimalis) is one of the most important marine species under commercial exploitation in the Gulf of Mexico; for this reason, interest in developing its culture is a priority. However, larviculture remains as the main bottleneck for massive production. In this sense, our objective was to determine the changes of digestive enzymes activities using biochemical and electrophoretic techniques during 36 days of Common snook larviculture fed with live preys (microalgae, rotifers, and Artemia). During larviculture, all digestive enzymatic activities were detected with low values since yolk absorption, 2 days after hatching (dah) onwards. However, the maximum values for alkaline protease (6,500 U mg protein(-1)), trypsin (0.053 mU * 10(-3) mg protein(-1)), and Leucine aminopeptidase (1.4 * 10(-3) mU mg protein(-1)) were detected at 12 dah; for chymotrypsin at 25 dah (3.8 * 10(-3) mU mg protein(-1)), for carboxypeptidase A (280 mU mg protein(-1)) and lipase at 36 dah (480 U mg protein(-1)), for alpha-amylase at 7 dah (1.5 U mg protein(-1)), for acid phosphatases at 34 dah (5.5 U mg protein(-1)), and finally for alkaline phosphatase at 25 dah (70 U mg protein(-1)). The alkaline protease zymogram showed two active bands, the first (26.3 kDa) at 25 dah onwards, and the second (51.6 kDa) at 36 dah. The acid protease zymogram showed two bands (RF = 0.32 and 0.51, respectively) at 34 dah. The digestive enzymatic ontogeny of C. undecimalis is very similar to other strictly marine carnivorous fish, and we suggest that weaning process should be started at 34 dah. PMID- 21671024 TI - Effects of dietary nucleotides supplementation on rainbow trout (Oncorhynchus mykiss) performance and acute stress response. AB - This experiment was conducted to examine the effect of dietary nucleotides (NT) on fish performance and acute stress response on fingerling rainbow trout (23 g +/- 0.01, mean weight +/- SEM). Five experimental diets according to different levels of supplemented nucleotides (0, 0.05, 0.1, 0.15, and 0.2%) were assayed on experimental fish for 8 weeks. Growth, hematological parameters (hematocrit, hemoglobin, erythrocyte, lymphocyte, and neutrophil count), serum proteins (globulin, albumin), and plasma enzymatic activity (alkaline phosphatase, ALP; aspartate transaminase, AST; lactate dehydrogenase, LDH; alanine transaminase, ALT) were assayed. At the end of feeding trial, fish fed the control and 0.2% diets were subjected to handling and crowding stress. Modulatory effects of nucleotides on acute stress response (cortisol and glucose) and plasma electrolytes (Na(+), Cl(-), K(+), and Ca(2+)) were studied. The percentage of body weight gain (WG) and feed efficiency (FE) of fish were better when the fish were fed 0.15-0.2% diets. Fish fed the nucleotide-supplemented diets tended to have lower levels of serum enzymes including ALP, AST, LDH, and ALT. Plasma cortisol levels of fish fed on 0.2% diet under handling and crowding stress were significantly lower than fish fed the control diet at all post-stress time intervals. In our study, fish fed nucleotide-supplemented diet had significantly lower concentrations of glucose compared to those fed the basal diet. The concentrations of sodium, chloride, calcium, and potassium of fish fed the control diet were significantly lower than in fish fed nucleotide-supplemented diet. Dietary nucleotides administration seems to promote growth and to enhance resistance against handling and crowding stress in fingerling rainbow trout. PMID- 21671025 TI - Does feeding time affect fish welfare? AB - Increased aquaculture production has raised concerns about managing protocols to safeguard the welfare of farmed fish, as consumers demand responsible aquaculture practices to provide 'welfare friendly' products. Feeding is one of the largest production cost in a fish farm and can be one of the biggest stressors for fish. Under farming conditions, fish are challenged with artificial diets and feeding regimes, and inadequate feeding conditions cause stress, alteration of normal behavioural patterns, poor performance and eventually diseases and death, which are by no means acceptable neither economically nor ethically. This review aims to highlight the impact of feeding rhythms and feeding time upon physiological and behavioural welfare indicators, which show circadian rhythms as well. Therefore, all these variables should be considered when designing feeding strategies in farming conditions and assessing the welfare state of cultured fish. PMID- 21671027 TI - Risk assessment in fish welfare, applications and limitations. AB - The Treaty of Amsterdam, in force since 1 May 1999, has established new ground rules for the actions of the European Union (EU) on animal welfare. It recognizes that animals are sentient beings and obliges the European Institutions to pay full regard to the welfare requirements of animals when formulating and implementing Community legislation. In order to properly address welfare issues, these need to be assessed in a scientific and transparent way. The principles of risk assessment in terms of transparency and use of available scientific data are probably well suited for this area. The application of risk assessment for terrestrial and aquatic animal welfare is a relatively new area. This paper describes the work developed in the context of the European Food Safety Authority (EFSA) opinions on the application of a risk assessment methodology to fish welfare. Risk assessment is a scientifically based process that seeks to determine the likelihood and consequences of an adverse event, which is referred to as a hazard. It generally consists of the following steps: (i) hazard identification, (ii) hazard characterisation, (iii) exposure assessment and (iv) risk characterisation. Different approaches can be used for risk assessments, such as qualitative, semi-quantitative and quantitative approaches. These are discussed in the context of fish welfare, using examples from assessments done to aquaculture husbandry systems and stunning/killing methods for farmed fish. A critical review of the applications and limitations of the risk methodology in fish welfare is given. There is a need to develop appropriate indicators of fish welfare. Yet, risk assessment methodology provides a transparent approach to identify significant hazards and support recommendations for improved welfare. PMID- 21671028 TI - Novel developments in thrombotic microangiopathies: is there a common link between hemolytic uremic syndrome and thrombotic thrombocytic purpura? AB - Thrombotic microangiopathies (TMA) represent a spectrum of related disorders associated with newly formed thrombi that block perfusion and thus affect the function of either renal or neurological organs and tissue. Recent years have seen a dramatic development in the field of TMA and for the two major forms hemolytic uremic syndrome (HUS) and thrombocytopenic purpura (TTP), new genetic causes and also autoimmune forms have been identified. This development indicates a similar pathophysiology and suggests that the two acute disorders are based on common principles. HUS is primarily a kidney disease and TTP also develops in the kidney and at neurological sites. In HUS thrombi formation is likely due to a deregulated complement activation and inappropriate platelet activity. In TTP thrombi formation occurs because of inappropriate processing of released multimers of von Willebrand Factor (vWF). Defining both the similarities and the unique features of each disorder will open up new ways and concepts that are relevant for diagnosis, for therapy, and for the prognostic outcome of kidney transplantations. Here we summarize the most relevant topics and timely issues that were presented and discussed at the 4th International Workshop on Thrombotic Microangiopathies held in Weimar in October 2009 (www.hus-ttp.de). PMID- 21671026 TI - Fish welfare and genomics. AB - There is a considerable public and scientific debate concerning welfare of fish in aquaculture. In this review, we will consider fish welfare as an integration of physiological, behavioral, and cognitive/emotional responses, all of which are essentially adaptative responses to stressful situations. An overview of fish welfare in this context suggests that understanding will rely on knowledge of all components of allostatic responses to stress and environmental perturbations. The development of genomic technologies provides new approaches to this task, exemplified by how genome-wide analysis of genetic structures and corresponding expression patterns can lead to the discovery of new aspects of adaptative responses. We will illustrate how the genomic approach may give rise to new biomarkers for fish welfare and also increase our understanding of the interaction between physiological, behavioral, and emotional responses. In a first part, we present data on expression of candidate genes selected a priori. This is a common avenue to develop molecular biomarkers capable of diagnosing a stress condition at its earliest onset, in order to allow quick corrective intervention in an aquaculture setting. However, most of these studies address isolated physiological functions and stress responses that may not be truly indicative of animal welfare, and there is only rudimentary understanding of genes related to possible cognitive and emotional responses in fish. We also present an overview on transcriptomic analysis related to the effect of aquaculture stressors, environmental changes (temperature, salinity, hypoxia), or concerning specific behavioral patterns. These studies illustrate the potential of genomic approaches to characterize the complexity of the molecular mechanisms which underlies not only physiological but also behavioral responses in relation to fish welfare. Thirdly, we address proteomic studies on biological responses to stressors such as salinity change and hypoxia. We will also consider proteomic studies developed in mammals in relation to anxiety and depressive status which may lead to new potential candidates in fish. Finally, in the conclusion, we will suggest new developments to facilitate an integrated view of fish welfare. This includes use of laser microdissection in the transcriptomic/proteomic studies, development of meta-analysis methods for extracting information from genomic data sets, and implementation of technological advances for high-throughput proteomic studies. Development of these new approaches should be as productive for our understanding of the biological processes underlying fish welfare as it has been for the progress of pathophysiological research. PMID- 21671029 TI - From Markovian to pairwise epidemic models and the performance of moment closure approximations. AB - Many if not all models of disease transmission on networks can be linked to the exact state-based Markovian formulation. However the large number of equations for any system of realistic size limits their applicability to small populations. As a result, most modelling work relies on simulation and pairwise models. In this paper, for a simple SIS dynamics on an arbitrary network, we formalise the link between a well known pairwise model and the exact Markovian formulation. This involves the rigorous derivation of the exact ODE model at the level of pairs in terms of the expected number of pairs and triples. The exact system is then closed using two different closures, one well established and one that has been recently proposed. A new interpretation of both closures is presented, which explains several of their previously observed properties. The closed dynamical systems are solved numerically and the results are compared to output from individual-based stochastic simulations. This is done for a range of networks with the same average degree and clustering coefficient but generated using different algorithms. It is shown that the ability of the pairwise system to accurately model an epidemic is fundamentally dependent on the underlying large scale network structure. We show that the existing pairwise models are a good fit for certain types of network but have to be used with caution as higher-order network structures may compromise their effectiveness. PMID- 21671030 TI - Competition in the presence of a virus in an aquatic system: an SIS model in the chemostat. AB - Recent research indicates that viruses are much more prevalent in aquatic environments than previously imagined. We derive a model of competition between two populations of bacteria for a single limiting nutrient in a chemostat where a virus is present. It is assumed that the virus can only infect one of the populations, the population that would be a more efficient consumer of the resource in a virus free environment, in order to determine whether introduction of a virus can result in coexistence of the competing populations. We also analyze the subsystem that results when the resistant competitor is absent. The model takes the form of an SIS epidemic model. Criteria for the global stability of the disease free and endemic steady states are obtained for both the subsystem as well as for the full competition model. However, for certain parameter ranges, bi-stability, and/or multiple periodic orbits is possible and both disease induced oscillations and competition induced oscillations are possible. It is proved that persistence of the vulnerable and resistant populations can occur, but only when the disease is endemic in the population. It is also shown that it is possible to have multiple attracting endemic steady states, oscillatory behavior involving Hopf, saddle-node, and homoclinic bifurcations, and a hysteresis effect. An explicit expression for the basic reproduction number for the epidemic is given in terms of biologically meaningful parameters. Mathematical tools that are used include Lyapunov functions, persistence theory, and bifurcation analysis. PMID- 21671031 TI - The effects of density on the topological structure of the mitochondrial DNA from trypanosomes. AB - Trypanosomatida parasites, such as trypanosoma and lishmania, are the cause of deadly diseases in many third world countries. A distinctive feature of these organisms is the three dimensional organization of their mitochondrial DNA into maxi and minicircles. In some of these organisms minicircles are confined into a small disk volume and are topologically linked, forming a gigantic linked network. The origins of such a network as well as of its topological properties are mostly unknown. In this paper we quantify the effects of the confinement on the topology of such a minicircle network. We introduce a simple mathematical model in which a collection of randomly oriented minicircles are spread over a rectangular grid. We present analytical and computational results showing that a finite positive critical percolation density exists, that the probability of formation of a highly linked network increases exponentially fast when minicircles are confined, and that the mean minicircle valence (the number of minicircles that a particular minicircle is linked to) increases linearly with density. When these results are interpreted in the context of the mitochondrial DNA of the trypanosome they suggest that confinement plays a key role on the formation of the linked network. This hypothesis is supported by the agreement of our simulations with experimental results that show that the valence grows linearly with density. Our model predicts the existence of a percolation density and that the distribution of minicircle valences is more heterogeneous than initially thought. PMID- 21671032 TI - The Markovian binary tree applied to demography. AB - We apply matrix analytic methods and branching processes theory to a comparison of female populations in different countries. We show how the same mathematical model allows us to determine characteristics about individual women, such as the distribution of her lifetime, the time until her first and her last daughter, and the number of daughters, as well as to analyze properties of the whole female family generated by a first woman, such as the extinction probability of the family, the distributions of the time until extinction, of the family size at any given time and of the total progeny. PMID- 21671033 TI - Joint effects of mitosis and intracellular delay on viral dynamics: two-parameter bifurcation analysis. AB - To understand joint effects of logistic growth in target cells and intracellular delay on viral dynamics in vivo, we carry out two-parameter bifurcation analysis of an in-host model that describes infections of many viruses including HIV-I, HBV and HTLV-I. The bifurcation parameters are the mitosis rate r of the target cells and an intracellular delay tau in the incidence of viral infection. We describe the stability region of the chronic-infection equilibrium E* in the two dimensional (r, tau) parameter space, as well as the global Hopf bifurcation curves as each of tau and r varies. Our analysis shows that, while both tau and r can destabilize E* and cause Hopf bifurcations, they do behave differently. The intracellular delay tau can cause Hopf bifurcations only when r is positive and sufficiently large, while r can cause Hopf bifurcations even when tau = 0. Intracellular delay tau can cause stability switches in E* while r does not. PMID- 21671034 TI - Genes are differentially expressed at transcriptional level of Neocaridina denticulata following short-term exposure to nonylphenol. AB - To assess the toxicity of nonylphenol towards aquatic crustaceans, Neocaridina denticulata were exposed short-term to sublethal concentration (0.001-0.5 mg/L). Following treatment, differentially expressed genes were identified using suppression subtractive hybridization on samples prepared from whole specimens. There were 20 differentially expressed sequence tags that corresponded to known genes and could be divided into six functional classes: defence, translation, metabolism, ribosomal gene expression, respiration, and genes involved in the stress response. Using semi-quantitative RT-PCR, we found that 14 of the differentially expressed sequence tags significantly responded to nonylphenol, including six at a nominal concentration of 0.01 mg/L; among them, 12 genes were down-regulated. These results suggest that under non-lethal concentrations of nonylphenol, the polluted aquatic environment may still present a potential risk to N. denticulata. PMID- 21671037 TI - Sentinel lymph node biopsy in breast cancer patients with previous breast augmentation surgery. AB - The number of breast augmentation surgeries (BAS) has increased. Therefore, the number of breast cancer patients with history of BAS has also increased. In this paper, we present two cases of sentinel lymph node biopsy (SLNB) in patients with previous BAS who were diagnosed with breast cancer. The patients were augmented using different approach; the first case was augmented through transaxillary incision, whereas the second case was augmented through periareolar incision. Lymphoscintigraphy (LPG) was performed on the patients 1 day prior to operation, enabling confirmation of lymphatic flow and SLN in both patients. SLNB was successfully performed in both cases. In one patient, SLNB was performed using indocyanine green (ICG) fluorescence and the Photodynamic Eye (PDE) system. Regardless of history of BAS, ICG and PDE system showed lymphatic flow and SLN in real time. LPG and ICG fluorescence were useful methods for SLN detection in patients with previous BAS, being able to confirm lymph flow before operation. Biopsy methods using LPG and PDE system were considered useful for difficult confirmation of lymph flow after breast augmentation. This is the first report of SLNB using ICG and PDE system for patients with previous BAS. PMID- 21671035 TI - ES cells overexpressing microRNA-1 attenuate apoptosis in the injured myocardium. AB - MicroRNAs (miRs) are small, single-stranded, noncoding RNA's involved in post transcriptional negative gene regulation. Recent investigations have underscored the integral role of miRs in various biological processes including innate immunity, cell-cycle regulation, metabolism, differentiation, and cell death. In the present study, we overexpressed miR-1, a muscle-specific miR, in embryonic stem cells (miR-1-ES cells), transplanted them into the infarcted myocardium, and evaluated their impact on cardiac apoptosis and function. We provide evidence demonstrating reduced apoptosis following transplantation of miR-1-ES cells 4 weeks post-myocardial infarction as compared to respective controls assessed by TUNEL staining and a capsase-3 activity assay. Moreover, we show significant elevation in p-Akt levels and diminished PTEN levels in hearts transplanted with miR-1-ES cells as determined by enzyme-linked immunoassays. Finally, using echocardiography, we reveal mice receiving miR-1-ES cell transplantation post myocardial infarction had significantly improved fractional shortening and ejection fraction compared with respective controls. Our data suggest transplanted miR-1-ES cells inhibit apoptosis, mediated through the PTEN/Akt pathway, leading to improved cardiac function in the infarcted myocardium. PMID- 21671039 TI - Does avian malaria infection affect feather stable isotope signatures? AB - It is widely accepted that stable isotope ratios in inert tissues such as feather keratin reflect the dietary isotopic signature at the time of the tissue synthesis. However, some elements such as stable nitrogen isotopes can be affected by individual physiological state and nutritional stress. Using malaria infection experiment protocols, we estimated the possible effect of malaria parasite infections on feather carbon (delta(13)C) and nitrogen (delta(15)N) isotope signatures in juvenile common crossbills Loxia curvirostra. The birds were experimentally infected with Plasmodium relictum (lineage SGS1) and P. ashfordi (GRW2), two widespread parasites of passerines. Experimental birds developed heavy parasitemia of both parasites and maintained high levels throughout the experiment (33 days). We found no significant difference between experimental and control birds in both delta(13)C and delta(15)N values of feathers re-grown. The study shows that even heavy primary infections of malaria parasites do not affect feather delta(13)C and delta(15)N isotopic signatures. The results of this experiment demonstrate that feather isotope values of wild caught birds accurately reflect the dietary isotopic sources at the time of tissue synthesis even when the animal's immune system might be challenged due to parasitic infection. PMID- 21671040 TI - Morbillivirus infection in pilot whales: strict protein requirement drives genetic conservation. AB - Morbillivirus infection of marine mammals has been documented across all of the world's oceans. Whilst infection is generally demonstrated using a variety of histopathological and serological techniques, where possible, the use of molecular techniques is being used to enable accurate genetic typing of virus strains through sequence analysis. Here, we present genetic data from dolphins and pilot whales affected by morbillivirus infection in the recent outbreak in the Mediterranean Sea during a six-month period from the end of October 2006 to April 2007. To date, very few studies have looked at characterizing outbreaks of morbillivirus infections in whale species at the molecular level. Here, we provide a full sequence for the haemagglutinin (H) gene from material derived from both a dolphin and a pilot whale from the 2007 outbreak in the Mediterranean Sea and show this virus to be 100% identical across the region analysed. Furthermore, we compare partial sequence data from the nucleocapsid (N) gene of the pilot whale material with previously published data and show evidence for strong protein conservation between these different isolates. Finally, we discuss the current classification of cetacean morbilliviruses as a single species. PMID- 21671041 TI - The P7-1 protein of southern rice black-streaked dwarf virus, a fijivirus, induces the formation of tubular structures in insect cells. AB - Southern rice black-streaked dwarf virus (SRBSDV), an insect- and plant-infecting reovirus of the genus Fijivirus, induced the formation of virus-containing tubules in infected plant and insect vector cells. Expression of the nonstructural protein P7-1 of SRBSDV in insect cells by a recombinant baculovirus resulted in the formation of tubules with dimensions and appearance similar to those found in SRBSDV-infected cells. These tubules protruded from the cell surface, supporting the hypothesis that the P7-1 protein contains two putative transmembrane domains that are necessary for the formation of tubules. Furthermore, the self-interaction of SRBSDV P7-1 protein indicates that this protein has the capacity to form homodimers or oligomers to assemble the proposed helical symmetry structure of tubules. Taken together, our results indicate that SRBSDV P7-1 has the intrinsic ability of self-interaction to form tubules growing from the cell surface in the absence of other viral proteins. PMID- 21671042 TI - A gluten metabolism study in healthy individuals shows the presence of faecal glutenasic activity. AB - PURPOSE: To study the gluten metabolism in healthy individuals and its effect over the intestinal microbial activity. METHODS: The faeces of eleven healthy subjects were analysed under 4 diet regimens: their normal gluten diet, a strict gluten-free diet (GFD), a GFD with a supplemental intake of 9 g gluten/day and a GFD with a supplemental intake of 30 g gluten/day. Gluten content, faecal tryptic activity (FTA), short-chain fatty acids (SCFAs) and faecal glutenasic activity (FGA) were analysed in faecal samples. RESULTS: Faecal gluten contents, FTA, SCFAs and FGA varied significantly with different levels of gluten intake in the diet. When high gluten doses (30 g/day) were administered in the diet, SCFA concentrations (70.5 mmoles/kg faeces) were significantly different from those from the GFD period (33.8 mmoles/kg faeces) of the experiment. However, the FTA showed significant differences between the GFD (34 units) and the normal gluten containing diet (60 units) and also between the GFD and the GFD + 30 g of gluten/day (67 units). When gluten was present in the diet, gluten was detected in the faeces, showing that at least a portion of the gluten ingested is eliminated in the large intestine, providing a substrate for intestinal microbial proteases. We have also shown the presence of faecal glutenasic activity that increased proportionally with the gluten intake in the diet, showing an enzymatic activity of 993 units in DSG, 2,063 units in DSG + 9 g and 6,090 units in DSG + 30 g. CONCLUSIONS: The activity of the intestinal microbiota is modified by gluten intake in the diet. The incorporation of gluten in the diet increases the activity of a gluten proteolytic activity in the faeces. PMID- 21671043 TI - Small bowel adenocarcinoma in Crohn disease: CT-enterography features with pathological correlation. AB - PURPOSE: The aim of this study was to analyze the clinical, pathological, and CT enterography findings of small bowel adenocarcinomas in Crohn disease patients. MATERIALS AND METHODS: Clinical, histopathological, and imaging findings were retrospectively evaluated in seven Crohn disease patients with small bowel adenocarcinoma. CT-enterography examinations were reviewed for morphologic features and location of tumor, presence of stratification, luminal stenosis, proximal dilatation, adjacent lymph nodes, and correlated with findings at histological examination. RESULTS: The tumor was located in the terminal (n = 6) or distal (n = 1) ileum. On CT-enterography, the tumor was visible in five patients, whereas two patients had no visible tumor. Four different patterns were individualized including small bowel mass (n = 2), long stenosis with heterogeneous submucosal layer (n = 2), short and severe stenosis with proximal small bowel dilatation (n = 2), and sacculated small bowel loop with irregular and asymmetric circumferential thickening (n = 1). Stratification, fat stranding, and comb sign were present in two, two, and one patients, respectively. CONCLUSION: Identification of a mass being clearly visible suggests strongly the presence of small bowel adenocarcinoma in Crohn disease patients but adenocarcinoma may be completely indistinguishable from benign fibrotic or acute inflammatory stricture. Knowledge of these findings is critical to help suggest the diagnosis of this rare but severe complication of Crohn disease. PMID- 21671045 TI - Variables influencing the neural correlates of perceived risk of physical harm. AB - Many human activities involve a risk of physical harm. However, not much is known about the specific brain regions involved in decision making regarding these risks. To explore the neural correlates of risk perception for physical harms, 19 participants took part in an event-related fMRI study while rating risky activities. The scenarios varied in level of potential harm (e.g., paralysis vs. stubbed toe), likelihood of injury (e.g., 1 chance in 100 vs. 1 chance in 1,000), and format (frequency vs. probability). Networks of brain regions were responsive to different aspects of risk information. Cortical language- processing areas, the middle temporal gyrus, and a region around the bed nucleus of stria terminalis responded more strongly to high- harm conditions. Prefrontal areas, along with subcortical ventral striatum, responded preferentially to high- likelihood conditions. Participants rated identical risks to be greater when information was presented in frequency format rather than probability format. These findings indicate that risk assessments for physical harm engage a broad network of brain regions that are sensitive to the severity of harm, the likelihood of risk, and the framing of risk information. PMID- 21671044 TI - Telomere dysfunction and cell cycle checkpoints in hematopoietic stem cell aging. AB - Stem cells are believed to be closely associated with tissue degeneration during aging. Studies of human genetic diseases and gene-targeted animal models have provided evidence that functional decline of telomeres and deregulation of cell cycle checkpoints contribute to the aging process of tissue stem cells. Telomere dysfunction can induce DNA damage response via key cell cycle checkpoints, leading to cellular senescence or apoptosis depending on the tissue type and developmental stage of a specific stem cell compartment. Telomerase mutation and telomere shortening have been observed in a variety of hematological disorders, such as dyskeratosis congenital, aplastic anemia, myelodysplastic syndromes and leukemia, in which the hematopoietic stem cells (HSC) are a major target during the pathogenesis. Moreover, telomere dysfunction is able to induce both cell intrinsic checkpoints and environmental factors limiting the self-renewal capacity and differentiation potential of HSCs. Crucial components in the cascade of DNA damage response, including ataxia telangiectasia mutated, CHK2, p53, p21 and p16/p19(ARF), play important roles in HSC maintenance and self-renewal in the scenarios of both sufficient telomere reserve and dysfunctional telomere. Therefore, a further understanding of the molecular mechanisms underlying HSC aging may help identity new therapeutic targets for stem cell-based regenerative medicine. PMID- 21671046 TI - Usefulness of transnasal endoscopy where endoscopic submucosal dissection is difficult. AB - BACKGROUND: Early gastric cancer located from the pyloric ring to inside the duodenal bulb (DB) is not easily treated by endoscopic submucosal dissection (ESD). The endoscope needs to be reversed inside the DB to set the resection line at a safe distance from the anal side. Because of the space limitations and limited flexibility of conventional endoscopy (CE), there have been increasing possibilities of complications. Here we report a new ESD technique using a transnasal endoscope (TN-E) that is reversed inside the DB. METHODS: The subjects were 5 patients with early gastric cancer or adenoma, at locations ranging from the pyloric ring to inside the DB, who were all treated by ESD. We compared results in these patients (TN-E group) with results in five patients with similar disease characteristics who were treated by ESD before July 2008, when the TN-E treatment method was introduced (CE group). In the TN-E group, after marking by CE, we switched the endoscope to the TN-E, and performed the reversing procedure inside the DB, and cut the anal side of the lesion in a semicircle. We switched back to CE to dissect the remaining half on the oral side. We compared the average resection time, en-bloc resection rate, and safety margin between the TN E and CE groups. RESULTS: Reversing inside the DB and the anal-side procedures proved easy and there were no complications. No bleeding or perforation occurred. The average resection times and en-bloc resection rates were not different between the two groups. All the resections by the TN-E were more than 5 mm away from the tumor margin, whereas a resection rate with a safety margin of more than 5 mm was 80% by CE. CONCLUSIONS: In conclusion, the TN-E was safe and effective for use inside the DB. ESD using the TN-E contributed to accurate pathological diagnosis, because the size of the resected specimen was sufficient to prevent the burning effect caused by the ESD. PMID- 21671047 TI - Early gastric cancer combined with multiple metachronous osteosclerotic bone and bone marrow metastases that responded to chemoradiotherapy. AB - We report a 75-year-old woman who suffered multiple metachronous osteosclerotic bone metastases 4 years after a distal gastrectomy for early gastric cancer (EGC). The primary tumor was a poorly differentiated adenocarcinoma, which had invaded the submucosal layer, and only one lymph node metastasis was noted. To the best of our knowledge, cases of EGC combined with metachronous osteosclerotic multiple bone and bone marrow metastases that respond to chemoradiotherapy are very rare. In this case, the multiple bone metastases were diagnosed 4 years after surgery. The patient's metastatic tumor was successfully treated using S-1, paclitaxel, and camptothecin, with subsequent irradiation. The patient survived for 24 months after the treatment, without having any major symptoms. PMID- 21671048 TI - Language and sociability: insights from Williams syndrome. AB - One of the most compelling features of Williams syndrome (WS) is the widely reported excessive sociability, accompanied by a relative proficiency in expressive language, which stands in stark contrast with significant intellectual and nonverbal impairments. It has been proposed that the unique language skills observed in WS are implicated in the strong drive to interact and communicate with others, which has been widely documented in WS. Nevertheless, this proposition has yet to be empirically examined. The present study aimed at investigating the relationship between a brain index of language processing and judgments of approachability of faces, as a proxy for sociability, in individuals with WS as contrasted to typical controls. Results revealed a significant and substantial association between the two in the WS, but not in the control group, supporting the hitherto untested notion that language use in WS might be uniquely related to their excessive social drive. PMID- 21671049 TI - Treatment effects of stimulant medication in young boys with fragile X syndrome. AB - Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is caused by a CGG repeat expansion at Xq27.3 on the FMR1 gene. The majority of young boys with FXS display poor attention and hyperactivity that is disproportionate to their cognitive disability, and approximately 70% meet diagnostic criteria for attention-deficit/hyperactivity disorder. Psychopharmacology is employed with 82% of young males 5-17 years of age, with stimulant medication as the most common medication prescribed. This study evaluated the effects of stimulant medication on the academic performance, attention, motor activity, and psychophysiological arousal of boys with FXS, as well as the concordance of effects within individuals. Participants in this study included 12 boys with FXS who were treated with stimulants. Participants completed videotaped academic testing on two consecutive days and were randomly assigned to be off stimulants for 1 day and on stimulants the other day. On each day, multiple measures including academic performance, behavior regulation, and psychophysiological arousal were collected. Approximately 75% of participants performed better on attention and academic measures, and 70% showed improved physiological regulation while on stimulant medication. A high degree of concordance among measures was found. Lower intelligence quotient (IQ), but not age, correlated with greater improvements in in-seat behavior. IQ and age did not relate to on-task behaviors. The frequency and magnitude of response to stimulant medication in boys with FXS is higher than those reported for most children with non-specific intellectual disabilities and autism spectrum disorder. PMID- 21671050 TI - Central retinal artery originating from the temporal short posterior ciliary artery associated with intraorbital external-to-internal carotid arterial anastomoses. AB - Although variations in the peripapillary division pattern of the central retinal artery (CRA) are common, variations in the origin of this artery are seldom reported in the literature. Herein, the authors report a variant of the CRA that originated from the temporal short posterior ciliary artery. Two intraorbital anastomoses were also noted between the internal and external carotid arterial systems: one through the lacrimal artery-middle meningeal artery to the ophthalmic artery and the other through supraorbital artery-recurrent meningeal artery to the ophthalmic artery. A brief review of CRA variations and potential clinical significances of the observed variant are discussed. PMID- 21671052 TI - Gastric bypass and copper deficiency: a possible overlooked consequence. PMID- 21671053 TI - Anticoagulant, antiherpetic and antibacterial activities of sulphated polysaccharide from Indian medicinal plant Tridax procumbens L. (Asteraceae). AB - The sulphated polysaccharide from the widespread Tridax procumbens plant was studied for the anticoagulant, antiherpetic and antibacterial activity. The anticoagulant activity was determined by the activated partial thromboplastin time assay. The sulphated polysaccharide from T. procumbens represented potent anticoagulant reaching the efficacy to heparin and chondroitin sulphate. Moreover, the sulphated polysaccharide extracted from T. procumbens was found non toxic on Vero cell lines up to the concentration of 200 MUg/ml. Sulphated polysaccharide exhibited detectable antiviral effect towards HSV-1 with IC(50) value 100-150 MUg/ml. Furthermore, sulphated polysaccharide from T. procumbens was highly inhibitory against the bacterial strains Vibrio alginolyticus and Vibrio harveyi isolated from oil sardine. PMID- 21671054 TI - Searching of predictors to predict pH optimum of cellulases. AB - The optimal working conditions for enzymes are very much elegant, and their determination is often through experimental approach, which generally is costly and time-consuming. Therefore, it is important to develop methods to use as simple as possible information to predict the optimal working condition for enzymes. Cellulase is a very important enzyme widely used in industries. In this study, we attempted to use a 20-1 feedforward backpropagation neural network to screen 24 amino acid properties related to the primary structure of cellulases as predictors to predict the pH optimum in cellulases. The results show that some predictors can predict the pH, especially amino acid distribution probability. PMID- 21671055 TI - Evaluation of ethanol production from corncob using Scheffersomyces (Pichia) stipitis CBS 6054 by volumetric scale-up. AB - In scale-up, the potential of ethanol production by dilute sulfuric acid pretreatment using corncob was investigated. Pretreatments were performed at 170 degrees C with various acid concentrations ranging from 0% to 1.656% based on oven dry weight. Following pretreatment, pretreated biomass yield ranged from 59% to 67%. More than 90% of xylan was removed at 0.828% of sulfuric acid. At same pretreatment condition, the highest glucose yield obtained from pretreated biomass by enzymatic hydrolysis was about 76%, based on a glucan content of 37/100 g. In hydrolysate obtained by pretreatment, glucose concentration was low, while xylose concentration was significantly increased above 0.368% of sulfuric acid. At 1.656% of sulfuric acid, xylose and glucose concentration was highest. In subsequent, fermentation with hydrolysate, maximal ethanol yield was attained after 24 h with 0.368% of sulfuric acid. The fermentation efficiency of hydrolysate obtained by enzymatic hydrolysis reached a maximum of 75% at an acid charge of 0.368%. PMID- 21671056 TI - Pelvic floor disorders: role of new ultrasonographic techniques. AB - The paper presents the role of various ultrasound modalities in the diagnostics of female pelvic floor disorders (PFD). It describes the use of two/three/four dimensional transperineal ultrasound and endocavitary transducers, which, up to now, have been used for proctological examinations and prostate cancer brachytherapy. Ultrasonography is the most widely available imaging modality. As a result of technical progress, novel transducers and more sophisticated software have recently been introduced to the market providing more information about the anatomy of pelvic organs. Some features of these transducers, such as higher frequency and multiplanar imaging, enable better visualisation of pelvic floor organs. In-depth knowledge of the technical and physical properties of modern ultrasonography, as well as its advantages and limitations, could provide an integrated approach to imaging of PFD. Technical modalities, the wide availability of ultrasonographic techniques, and an understanding of the imaging possible with modern ultrasonography could improve our understanding of PFD and allow better assessment in pre- and post-surgical management. PMID- 21671057 TI - Occurrence of lymph node metastasis in early-stage parotid gland cancer. AB - Lymph node metastasis is one of the most important factors in therapy and prognosis for patients with parotid gland cancer. Nevertheless, the extent of the primary tumor resection and the necessity of a neck dissection still is a common issue. Since little is known about lymph node metastasis in early-stage parotid gland cancer, the purpose of the present study was to evaluate the occurrence of lymph node metastases in T1 and T2 carcinomas and its impact on local control and survival. We retrospectively analyzed 70 patients with early-stage (T1 and T2) primary parotid gland cancer. All patients were treated with parotidectomy and an ipsilateral neck dissection from 1987 to 2009. Clinicopathological and survival parameters were calculated. The median follow-up time was 51.7 months. A positive pathological lymph node stage (pN+) was found in 21.4% of patients with a significant correlation to the clinical lymph node stage (cN) (p = 0.061). There were no differences in the clinical and histopathological data between pN- and pN+ patients. In 73.3% of pN+ patients, the metastases were located intraparotideal. The incidence of occult metastases (pN+/cN-) was 17.2%. Of all patients with occult metastases, 30.0% had extraparotideal lymphatic spread. A positive lymph node stage significantly indicated a poorer 5-year overall as well as 5-year disease-free survival rate compared to pN- patients (p = 0.048; p = 0.011). We propose total parotidectomy in combination with at least a level II III selective neck dissection in any case of early-stage parotid gland cancer. PMID- 21671058 TI - Human umbilical cord Wharton's jelly stem cells undergo enhanced chondrogenic differentiation when grown on nanofibrous scaffolds and in a sequential two-stage culture medium environment. AB - The current treatments used for osteoarthritis from cartilage damage have their disadvantages of donor site morbidity, complicated surgical interventions and risks of infection and graft rejection. Recent advances in tissue engineering have offered much promise in cartilage repair but the best cell source and in vitro system have not as yet been optimised. Human bone marrow mesenchymal stem cells (hBMSCs) have thus far been the cell of choice. However, we derived a unique stem cell from the human umbilical cord Wharton's jelly (hWJSC) that has properties superior to hBMSCs in terms of ready availability, prolonged stemness characteristics in vitro, high proliferation rates, wide multipotency, non tumorigenicity and tolerance in allogeneic transplantation. We observed enhanced cell attachment, cell proliferation and chondrogenesis of hWJSCs over hBMSCs when grown on PCL/Collagen nanoscaffolds in the presence of a two-stage sequential complex/chondrogenic medium for 21 days. Improvement of these three parameters were confirmed via inverted optics, field emission scanning electron microscopy (FESEM), MTT assay, pellet diameters, Alcian blue histology and staining, glycosaminglycans (GAG) and hyaluronic acid production and expression of key chondrogenic genes (SOX9, Collagen type II, COMP, FMOD) using immunohistochemistry and real-time polymerase chain reaction (qRT-PCR). In separate experiments we demonstrated that the 16 ng/ml of basic fibroblast growth factor (bFGF) present in the complex medium may have contributed to driving chondrogenesis. We conclude that hWJSCs are an attractive stem cell source for inducing chondrogenesis in vitro when grown on nanoscaffolds and exposed sequentially first to complex medium and then followed by chondrogenic medium. PMID- 21671059 TI - The procurement of cells for the derivation of human embryonic stem cell lines for therapeutic use: recommendations for good practice. AB - The donation of human embryos for the derivation of embryonic stem cell lines that may be used in the development of therapeutic products raises more complex ethical, practical and regulatory problems than the donation of embryos for non clinical research. This review considers these issues and offers recommendations for good practice. PMID- 21671060 TI - Functional and transcriptomic recovery of infarcted mouse myocardium treated with bone marrow mononuclear cells. AB - Although bone marrow-derived mononuclear cells (BMNC) have been extensively used in cell therapy for cardiac diseases, little mechanistic information is available to support reports of their efficacy. To address this shortcoming, we compared structural and functional recovery and associated global gene expression profiles in post-ischaemic myocardium treated with BMNC transplantation. BMNC suspensions were injected into cardiac scar tissue 10 days after experimental myocardial infarction. Six weeks later, mice undergoing BMNC therapy were found to have normalized antibody repertoire and improved cardiac performance measured by ECG, treadmill exercise time and echocardiography. After functional testing, gene expression profiles in cardiac tissue were evaluated using high-density oligonucleotide arrays. Expression of more than 18% of the 11981 quantified unigenes was significantly altered in the infarcted hearts. BMNC therapy restored expression of 2099 (96.2%) of the genes that were altered by infarction but led to altered expression of 286 other genes, considered to be a side effect of the treatment. Transcriptional therapeutic efficacy, a metric calculated using a formula that incorporates both recovery and side effect of treatment, was 73%. In conclusion, our results confirm a beneficial role for bone marrow-derived cell therapy and provide new information on molecular mechanisms operating after BMNC transplantation on post ischemic heart failure in mice. PMID- 21671062 TI - Endoscopic ultrasonographic study of autoimmune pancreatitis and the effect of steroid therapy. AB - BACKGROUND: Recently, endoscopic ultrasonography (EUS) has been used for the diagnosis of chronic pancreatitis (CP); however, EUS diagnosis of autoimmune pancreatitis (AIP) varies among different researchers. We investigated EUS findings in AIP and retrospectively analyzed them before and after steroid therapy. PATIENTS AND METHODS: The subjects were 32 patients with AIP and the EUS images of the pancreatic parenchyma were evaluated with reference to the Sahai criteria. Patients' background factors detected by EUS were analyzed statistically. Peroral steroid was given to 23 of the 32 patients. EUS was also performed 2 weeks after the initiation of therapy in 14 of the 23 patients, and the changes in EUS were investigated. Microscope images were compared with EUS images in one patient who underwent surgical resection. RESULTS: EUS results included hyperechoic strands in 26 (81.3%) and lobularity in 17 (53.1%) patients. The patients' background factors included the presence of splenic and/or portal vein occlusion or narrowing around the pancreas in patients who had neither hyperechoic strands nor lobularity (p = 0.002, p = 0.004). The numbers of EUS findings before versus after steroid therapy were 11 versus 5 for hyperechoic strands and 7 versus 2 for lobularity. Microscope images showed the coexistence of relatively well-maintained lobular structures of pancreatic acini and almost complete loss of such structures. CONCLUSION: EUS findings in AIP were similar to those in early-stage CP, and hyperechoic strands and lobularity seem to suggest a condition under which the histology of lobular structures of the pancreatic acini is relatively well-maintained. EUS results had improved within about 2 weeks of steroid therapy. PMID- 21671061 TI - Induced pluripotent stem cells: fundamentals and applications of the reprogramming process and its ramifications on regenerative medicine. AB - OBJECTIVE: To provide a comprehensive source of information about the reprogramming process and induced pluripotency. BACKGROUND: The ability of stem cells to renew their own population and to differentiate into specialized cell types has always attracted researchers looking to exploit this potential for cellular replacement therapies, pharmaceutical testing and studying developmental pathways. While adult stem cell therapy has already been brought to the clinic, embryonic stem cell research has been beset with legal and ethical impediments. FOCUS: The conversion of human somatic cells to human induced pluripotent stem cells (hiPSCs), which are equivalent to human embryonic stem cells (hESCs), provides a system to sidestep these barriers and expedite pluripotent stem cell research for the aforementioned purposes. However, being a very recent discovery, iPSCs have yet to overcome many other obstacles and criticism to be proven safe and feasible for clinical use. METHODOLOGY: This review introduces iPSC, the various methods that have been used to generate them and their pros and cons. It also covers in detail the pluripotency factors responsible for iPSC generation as well as the signaling pathways, epigenetic modifications and miRNA regulation implicated in the reprogramming process. The known molecular crosstalk between these reprogramming regulators is also illuminated. We will also mention the molecular compounds which have been shown to either replace one or more genetic factors or improve overall efficiency and kinetics of iPSC induction. CONCLUSION: To conclude, we will briefly discuss the current problems that hinder bench to bedside translation of iPSC research as well as the possible steps that can bring iPSC therapy and other potential applications closer to fruition. PMID- 21671063 TI - The efficacy of the levonorgestrel-releasing intrauterine system in perimenopausal women with menorrhagia or dysmenorrhea. AB - OBJECTIVE: To evaluate the hysterectomy rates and the risk factors for hysterectomy during the first 2 years of use of a levonorgestrel-releasing intrauterine system (LNG-IUS) in perimenopausal women who had complaints of either menorrhagia or dysmenorrhea. METHODS: One hundred ninety-two women over 40 years old were retrospectively analyzed for a 2-year follow-up period. The changes in the amount and duration of bleeding and the pain scores were checked at 3, 6, 12 and 24 months. RESULTS: Twenty-six (13.5%) women failed with LNG-IUS treatment and they received hysterectomy. Age, parity, the type of diseases, the amount of menstrual bleeding, the mean duration of persisted menorrhagia and the severity of pain before treatment were not the factors affecting removal of the LNG-IUS and undergoing hysterectomy. However, the pain score of the third month and the amount of bleeding on the sixth month were the factors affecting undergoing hysterectomy (P < 0.05). When hysterectomy was performed, the average duration from LNG-IUS insertion to hysterectomy was 8.9 months. The participants who persisted with the LNG-IUS treatment for 24 months showed a success rate of 80.7%. CONCLUSION: LNG-IUS is an effective device for the treatment of perimenopausal women who have complaints of either menorrhagia or dysmenorrhea. Insufficient reduction of pain score during the first 3 months and menstrual blood loss during the first 6 months after insertion of the LNG-IUS were important factors that affected undergoing hysterectomy. PMID- 21671064 TI - Effect of apoptosis-inducing antitumor agents on endocardial endothelial cells. AB - Chemotherapy is one of the common treatment modalities for cancer. Some of the antineoplastic drugs have, however, been found to be toxic for vascular endothelium, resulting in complications such as endothelial dysfunction, thromboembolism, heart failure, and cardiomyopathy. In this study, we investigated the cytotoxic effect of widely used antitumor agents doxorubicin, camptothecin, and thapsigargin on primary and immortalized porcine endocardial endothelial cells and compared with the effects of these agents on human umbilical vein endothelial cells, human aortic endothelial cells, and EA.hy926 cells. Our study revealed that endocardial endothelial cells are relatively resistant to apoptosis induced by these drugs. Interestingly, our study indicates that response to antitumor agents greatly differs depending on the site of origin of endothelial cells. Doxorubicin, camptothecin, and thapsigargin induce mitochondrial-dependent cell death following loss of mitochondrial membrane potential (MMP) in vascular endothelial cells, with subsequent increase in sub-G0 population. In endocardial endothelial cells, there was no MMP loss; and only cell cycle arrest either at G1 or S phases was observed when the cells were treated with doxorubicin, camptothecin, and thapsigargin. PMID- 21671065 TI - Frontal lobe and posterior parietal contributions to the cortico-cerebellar system. AB - Our growing understanding of how cerebral cortical areas communicate with the cerebellum in primates has enriched our understanding of the data that cerebellar circuits can access, and the neocortical areas that cerebellar activity can influence. The cerebellum is part of some large-scale networks involving several parts of the neocortex including association areas in the frontal lobe and the posterior parietal cortex that are known for their contributions to higher cognitive function. Understanding their connections with the cerebellum informs the debates around the role of the cerebellum in higher cognitive functions because they provide mechanisms through which association areas and the cerebellum can influence each others' operations. In recent years, evidence from connectional anatomy and human neuroimaging have comprehensively overturned the view that the cerebellum contributes only to motor control. The aim of this review is to examine our changing perspectives on the nature of cortico cerebellar anatomy and the ways in which it continues to shape our views on its contributions to function. The review considers the anatomical connectivity of the cerebellar cortex with frontal lobe areas and the posterior parietal cortex. It will first focus on the anatomical organisation of these circuits in non-human primates before discussing new findings about this system in the human brain. It has been suggested that in non-human primates "although there is a modest input from medial prefrontal cortex, there is very little or none from the more lateral prefrontal areas" [33]. This review discusses anatomical investigations that challenge this claim. It also attempts to dispel the misconception that prefrontal projections to the cerebellum are from areas concerned only with the kinematic control of eye movements. Finally, I argue that our revised understanding of anatomy compels us to reconsider conventional views of how these systems operate in the human brain. PMID- 21671066 TI - Anti-inflammatory effects of glyceollins derived from soybean by elicitation with Aspergillus sojae. AB - OBJECTIVE: Given the preventive effect of soy intake against several chronic diseases, this study was conducted to investigate the inhibitory activity against inflammatory response of phytoalexins glyceollins derived from soybean isoflavones by treatment with a biotic elicitor. METHODS: Using RAW264.7 cells, we examined the effects of glyceollins on production of nitric oxide (NO) and inflammatory cytokines, expression of inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2, and activation of NF-kB, induced by lipopolysaccharide (LPS). RESULTS: Our data showed that glyceollins effectively inhibited NO production, IL-6 release, and expression of iNOS and COX-2 induced by LPS. In particular, glyceollins suppressed the LPS-induced phosphorylation of NF-kB p65, suggesting that the compounds inhibit the production of NO and transcriptional activation of COX-2 by regulating NF-kB activity. In another experiment we found that glyceollins enhanced the expression of heme oxygenase 1 in LPS-treated RAW264.7 cells. Glyceollins also reduced TPA-induced skin inflammation in a mouse model, confirming the anti-inflammatory activity of glyceollins in an in-vivo system as well as in a cell culture system. CONCLUSION: Glyceollins exert an anti inflammatory effect, which is mediated through the inhibition of NF-kappaB activation in LPS-activated murine RAW264.7 cells. Glyceollins merit further study as potential therapeutic agents for inflammatory disorders. PMID- 21671067 TI - Molecular mapping for resistance to pea rust caused by Uromyces fabae (Pers.) de Bary. AB - Pea rust caused by Uromyces fabae (Pers.) de-Bary is a major problem in warm humid regions causing huge economic losses. A mapping population of 136 F(6:7) recombinant inbred lines (RILs) derived from the cross between pea genotypes, HUVP 1 (susceptible) and FC 1 (resistant) was evaluated in polyhouse as well as under field conditions during two consecutive years. Infection frequency (IF) and area under disease progress curve (AUDPC) were used for evaluation of rust reaction of the RILs. A linkage map was constructed with 57 polymorphic loci selected from 148 simple sequence repeats (SSRs), 3 sequence tagged sites (STS), and 2 random amplified polymorphic (RAPD) markers covering 634 cM of genetic distance on the seven linkage groups of pea with an average interval length of 11.3 cM. Composite interval mapping (CIM) revealed one major (Qruf) and one minor (Qruf1) QTL for rust resistance on LGVII. The LOD (5.2-15.8) peak for Qruf was flanked by SSR markers, AA505 and AA446 (10.8 cM), explaining 22.2-42.4% and 23.5 58.8% of the total phenotypic variation for IF and AUDPC, respectively. The minor QTL was environment-specific, and it was detected only in the polyhouse (LOD values 4.2 and 4.8). It was flanked by SSR markers, AD146 and AA416 (7.3 cM), and explained 11.2-12.4% of the total phenotypic variation. The major QTL Qruf was consistently identified across all the four environments. Therefore, the SSR markers flanking Qruf would be useful for marker-assisted selection for pea rust (U. fabae) resistance. PMID- 21671069 TI - Decision support algorithm for diagnosis of ADHD using electroencephalograms. AB - Attention deficit hyperactivity disorder is a complex brain disorder which is usually difficult to diagnose. As a result many literature reports about the increasing rate of misdiagnosis of ADHD disorder with other types of brain disorder. There is also a risk of normal children to be associated with ADHD if practical diagnostic criteria are not supported. To this end we propose a decision support system in diagnosing of ADHD disorder through brain electroencephalographic signals. Subjects of 10 children participated in this study, 7 of them were diagnosed with ADHD disorder and remaining 3 children are normal group. Our main goal of this sthudy is to present a supporting diagnostic tool that uses signal processing for feature selection and machine learning algorithms for diagnosis.Particularly, for a feature selection we propose information theoretic which is based on entropy and mutual information measure. We propose a maximal discrepancy criterion for selecting distinct (most distinguishing) features of two groups as well as a semi-supervised formulation for efficiently updating the training set. Further, support vector machine classifier trained and tested for identification of robust marker of EEG patterns for accurate diagnosis of ADHD group. We demonstrate that the applicability of the proposed approach provides higher accuracy in diagnostic process of ADHD disorder than the few currently available methods. PMID- 21671070 TI - Characterizing mammography reports for health analytics. AB - As massive collections of digital health data are becoming available, the opportunities for large-scale automated analysis increase. In particular, the widespread collection of detailed health information is expected to help realize a vision of evidence-based public health and patient-centric health care. Within such a framework for large scale health analytics we describe the transformation of a large data set of mostly unlabeled and free-text mammography data into a searchable and accessible collection, usable for analytics. We also describe several methods to characterize and analyze the data, including their temporal aspects, using information retrieval, supervised learning, and classical statistical techniques. We present experimental results that demonstrate the validity and usefulness of the approach, since the results are consistent with the known features of the data, provide novel insights about it, and can be used in specific applications. Additionally, based on the process of going from raw data to results from analysis, we present the architecture of a generic system for health analytics from clinical notes. PMID- 21671068 TI - MusaDHN-1, a novel multiple stress-inducible SK(3)-type dehydrin gene, contributes affirmatively to drought- and salt-stress tolerance in banana. AB - Dehydrins are highly hydrophilic proteins involved in playing key adaptive roles in response to abiotic stress conditions having dehydration as a common component. In the present study, a novel banana SK(3)-type dehydrin, MusaDHN-1, was identified and later characterized using transgenic banana plants to investigate its functions in abiotic stress tolerance. Expression profiling in native banana plants demonstrated that MusaDHN-1 was induced in leaves by drought, salinity, cold, oxidative and heavy metal stress as well as by treatment with signalling molecules like abscisic acid, ethylene and methyl jasmonate. Promoter analysis carried out by making a MusaDHN-1 promoter: beta-glucuronidase fusion construct reconfirmed the abiotic stress inducibility of MusaDHN-1. Transgenic banana plants constitutively overexpressing MusaDHN-1 were phenotypically normal and displayed improved tolerance to drought and salt-stress treatments in both in vitro and ex vitro assays. Enhanced accumulation of proline and reduced malondialdehyde levels in drought and salt-stressed MusaDHN-1 overexpressing plants further established their superior performance in stressed conditions. This study is the first to report generation of transgenic banana plants engineered for improved drought and salt-stress tolerance. PMID- 21671071 TI - Left atrial volume and dominant frequency of atrial fibrillation in patients undergoing catheter ablation of persistent atrial fibrillation. AB - BACKGROUND: Prior studies have suggested that left atrial (LA) volume and frequency of atrial fibrillation (AF) are associated with suboptimal outcomes in patients undergoing catheter ablation of AF. However, the interaction of these factors and their relative impact on outcome are not clear. METHODS: Seventy-nine consecutive patients underwent catheter ablation of persistent AF. LA volume was determined by echocardiography. Electrograms from the LA appendage (LAA), coronary sinus (CS), and lead V(1) were obtained before ablation, and the dominant frequency (DF) was determined by fast Fourier transformation. The ablation strategy consisted of pulmonary vein isolation, electrogram-guided, and linear ablation. RESULTS: The mean LA volume indexed, LA voltage, and DF in the LAA were 48 +/- 16 mL/m(2), 0.58 +/- 0.20 mV, and 6.3 +/- 0.8 Hz, respectively. There was a significant inverse correlation between LA volume and DF in the CS (P < 0.0001, R = -0.51). The mean LA amplitude also correlated with DF in the LAA (P = 0.0008, R = 0.37). In 38 patients (48%), AF terminated during catheter ablation. Sixty-six of the 79 patients (84%) are arrhythmia-free without antiarrhythmic drugs at a mean follow-up of 14 +/- 7 months after the last procedure. Advancing age was associated with recurrence (odds ratio (OR), 1.2; 95% confidence interval (CI), 1.02 to 1.42; P = 0.02), and duration of radiofrequency energy delivery was associated with a favorable outcome (OR, 0.93; 95% CI, 0.86 to 0.99; P = 0.04). CONCLUSION: Atrial enlargement is associated with a lower AF frequency. Age and RF duration seem to be better predictors of outcome than LA volume or AF frequency. PMID- 21671072 TI - High-energy defibrillation increases the dispersion of regional ventricular repolarization. AB - PURPOSE: This study evaluated the effects of shock energy on the dispersion of regional ventricular repolarization (DRVR), post-shock rhythm and sinus recovery time (SRT), and the relationship between DRVR and post-shock ventricular arrhythmias. MATERIALS AND METHODS: Ten open-chest dogs were anesthetized. Ventricular fibrillation (VF) was electrically induced and recorded from a 6 * 6 unipolar electrode plaque (4 mm spacing) sutured on the left ventricular epicardium. Defibrillation threshold (DFT) was determined after 20 s of VF. DRVR was measured before VF, during the earliest post-shock sinus rhythm, and during sinus rhythm 30 s following shocks. Post-shock rhythm and SRT were evaluated after energies of 100% DFT, 125% DFT, 175% DFT, and 250% DFT. RESULTS: In the100% DFT group, the DRVR of the earliest sinus rhythm and 30 s after successful defibrillation was not significantly different than that before VF. But the DRVRs were significantly increased in 125% DFT, 175% DFT, and 250% DFT group. DRVR after defibrillation in the 250% DFT group was higher than those in the 100% DFT and 125% DFT groups. SRT in the 250% DFT group was significantly longer than that in the other groups .The incidence of post-shock ventricular tachycardia was increased when a high-shock energy was applied (P = 0.041). CONCLUSION: DRVR was increased by application of high-energy defibrillation associated with SRT prolongation. The increased DRVR may play an important role in the onset of post shock ventricular tachycardia. PMID- 21671073 TI - Transgenic Nicotiana tabacum plants expressing a fungal copper transporter gene show enhanced acquisition of copper. AB - The diets of two-thirds of the world's population are deficient in one or more essential elements and one of the approaches to enhance the levels of mineral elements in food crops is by developing plants with ability to accumulate them in edible parts. Besides conventional methods, transgenic technology can be used for enhancing metal acquisition in plants. Copper is an essential element, which is often deficient in human diet. With the objective of developing plants with improved copper acquisition, a high-affinity copper transporter gene (tcu-1) was cloned from fungus Neurospora crassa and introduced into a model plant (Nicotiana tabacum). Integration of the transgene was confirmed by Southern blot hybridization. Transgenic tobacco plants (T(0) and T(1)) expressing tcu-1, when grown in hydroponic medium spiked with different concentrations of copper, showed higher acquisition of copper (up to 3.1 times) compared with control plants. Transgenic plants grown in soil spiked with copper could also take up more copper compared with wild-type plants. Supplementation of other divalent cations such as Cd(2+) and Zn(2+) did not alter uptake of Cu by transgenic plants. The present study has shown that expression of a heterologous copper transporter in tobacco could enhance acquisition of copper. PMID- 21671074 TI - Hallucinogen persisting perception disorder in neuronal networks with adaptation. AB - We study the spatiotemporal dynamics of neuronal networks with spike frequency adaptation. In particular, we compare the effects of adaptation being either a linear or nonlinear function of neural activity. We find that altering parameters controlling the strength of synaptic connections in the network can lead to spatially structured activity suggestive of symptoms of hallucinogen persisting perception disorder (HPPD). First, we study how both networks track spatially homogeneous flickering stimuli, and find input is encoded as continuous at lower flicker frequencies when the network's synapses exhibit more net excitation. Mainly, we study instabilities of stimulus-driven traveling pulse solutions, representative of visual trailing phenomena common to HPPD patients. Visual trails are reported as discrete afterimages in the wake of a moving input. Thus, we analyze several solutions arising in response to moving inputs in both networks: an ON state, stimulus-locked pulses, and traveling breathers. We find traveling breathers can arise in both networks when an input moves beyond a critical speed. These possible neural substrates of visual trails occur at slower speeds when the modulation of synaptic connectivity is increased. PMID- 21671075 TI - The role of the TCF4 gene in the phenotype of individuals with 18q segmental deletions. AB - The goal of this study is to define the effects of TCF4 hemizygosity in the context of a larger segmental deletion of chromosome 18q. Our cohort included 37 individuals with deletions of 18q. Twenty-seven had deletions including TCF4 (TCF4 (+/-)); nine had deletions that did not include TCF4 (TCF4 (+/+)); and one individual had a microdeletion that included only the TCF4 gene. We compared phenotypic data from the participants' medical records, survey responses, and in person evaluations. Features unique to the TCF4 (+/-) individuals included abnormal corpus callosum, short neck, small penis, accessory and wide-spaced nipples, broad or clubbed fingers, and sacral dimple. The developmental data revealed that TCF4 (+/+) individuals were only moderately developmentally delayed while TCF4 (+/-) individuals failed to reach developmental milestones beyond those typically acquired by 12 months of age. TCF4 hemizygosity also conferred an increased risk of early death principally due to aspiration-related complications. Hemizygosity for TCF4 confers a significant impact primarily with regard to cognitive and motor development, resulting in a very different prognosis for individuals hemizygous for TCF4 when compared to individuals hemizygous for other regions of distal 18q. PMID- 21671076 TI - The influence of foot geometry on the calcaneal osteotomy angle based on two dimensional static force analyses. AB - BACKGROUND: Malalignment of the hindfoot can be corrected with a calcaneal osteotomy (CO). A well-selected osteotomy angle in the sagittal plane will reduce the shear force in the osteotomy plane while walking. The purpose was to determine the presence of a relationship between the foot geometry and loading of the calcaneus, which influences the choice of the preferred CO angle. METHODS: A static free body force analysis was made of the posterior calcaneal fragment in the second half of the stance phase to determine the main loads: the plantar apeunorosis (PA) and Achilles tendon (AT). The third load is on the osteotomy surface which should be oriented such that the shear component of the force is zero. The force direction of the PA and AT was measured on 58 MRIs of the foot, and the force ratio between both structures was taken from the literature. In addition the PA-to-AT force ratio was estimated for different foot geometries to identify the relationship. RESULTS: Based on the wish to minimize the shear force during walking, a mean CO angle was determined to be 33 degrees (SD8) relative to the foot sole. In pes planus foot geometry, the angle should be higher than the mean. In pes cavus foot geometry, the angle should be smaller. CONCLUSION: Foot geometry, in particular the relative foot heights is a determinant for the individual angle in performing the sliding calcaneal osteotomy. It is recommended to take into account the foot geometry (arch) when deciding on the CO angle for hindfoot correction. PMID- 21671077 TI - Painful lumbar spondylolysis among pediatric sports players: a pilot MRI study. AB - INTRODUCTION: For children and adolescents who are very active athletes, fresh lumbar spondylolysis is the main pathologic cause of lower back pain (LBP). However, regarding the terminal-stage spondylolysis (pars defect), there have been few studies to clarify the pathomechanism of LBP. The purpose of this study is to clarify the cause of LBP associated with pars defects in athletes. This is the first report showing a possible pathomechanism of LBP in active athletes with painful pars defect. METHOD: Six pediatric athletes (5 boys and 1 girl) below 18 years old with painful bilateral lumbar spondylolysis were evaluated. In all cases, spondylolysis was identified as terminal stage (pseudoarthrosis) on CT scan. To evaluate the inflammation around the pars defects, short time inversion recovery (STIR) MRI was performed along with the sagittal section. Fluid collection, which is an indicator of inflammatory events, was evaluated in 12 pars defects as well as in 12 cranial and caudal adjoining facet joints. RESULTS: Inflammation (i.e., fluid collection) was observed in all 12 pars defects in six subjects at the pseudoarthrotic pars defects. In terms of facet joints, 7 of 12 (58%) pars defects showed fluid collection at the cranial and/or caudal adjoining joints on STIR MRI. CONCLUSION: The present study showed that inflammation was always present at the pars defects and in some cases at the adjoining facet joints. Thus, it is not difficult to understand how, during sports activity, inflammation may first occur at the pseudoarthrotic site and then spread to the adjoining facet joints. This mechanism could cause LBP associated with terminal stage (pseudoarthrotics) spondylolysis in athletes. PMID- 21671078 TI - Intraoperative subcutaneous wound closing culture sample: a predicting factor for periprosthetic infection after hip- and knee-replacement? AB - INTRODUCTION: It is unknown whether intraoperative subcutaneous wound closing culture samples (WCCS) are useful to predict periprosthetic joint infection (PJI). METHOD: Here we prospectively followed 167 out of a total of 175 consecutive patients with primary total hip (THR) or knee replacement (TKR) between 01/2002 and 12/2002 for a mean follow-up period of 5 years; of those patients, n = 159 (96.8%) underwent WCCS. RESULTS: The results showed a positive WCCS in n = 9 cases (5.8%). Nine patients developed postoperative wound complication and required revision surgery. Two patients developed signs of a deep periprosthetic infection; however, only one out of nine patients had initial positive WCCS. CONCLUSION: Our results thus indicate that WCCS during primary joint replacement is not an appropriate predictive method to identify patients at risk for periprosthetic joint infections. PMID- 21671079 TI - Increasing incidence of Barrett's oesophagus: a population-based study. AB - Oesophageal adenocarcinoma, a highly fatal cancer, has risen in incidence in Western societies, but it is unclear whether this is due to increasing incidence of its pre-cursor condition, Barrett's oesophagus (BO) or whether the proportion of BO patients undergoing malignant progression has increased in the face of unchanged BO incidence. Data from population-based studies of BO incidence is limited, with equivocal results to date difficult to distinguish from changes in endoscopic practices. The aim of this study was to assess population trends in Barrett's oesophagus (BO) diagnoses in relation to endoscopy and biopsy rates over a 13 year period. The Northern Ireland Barrett's oesophagus Register (NIBR) is a population-based register of all 9,329 adults diagnosed with columnar epithelium of the oesophagus in Northern Ireland between 1993 and 2005, of whom 58.3% were male. European age-standardised annual BO incidence rates were calculated per 100,000 of the population, per 100 endoscopies and per 100 endoscopies including an oesophageal biopsy. Average annual BO incidence rates rose by 159% during the study period, increasing from 23.9/100,000 during 1993 1997 to 62.0/100,000 during 2002-2005. This elevation far exceeded corresponding increases in rates of endoscopies and oesophageal biopsies being conducted. BO incidence increased most markedly in individuals aged < 60 years, and most notably amongst males aged < 40 years. This study points towards a true increase in the incidence of BO which would appear to be most marked in young males. These findings have significant implications for future rates of oesophageal adenocarcinoma and surveillance programmes. PMID- 21671080 TI - Shortening of gestational length among native-born and immigrants in Spain (1997 2008). AB - During the last decade there have been significant socio-demographic changes in Spain with potential impact on gestational length. The aim of the study was to describe the evolution of gestational age during 1997-2008, separately for native born and immigrant population, in order to assess their contribution to the overall pattern of gestational length. A cross-sectional study of 5,018,229 singleton births born between 1997 and 2008 was carried out. The annual mean of gestational age was calculated and compared by means of ANOVA test, globally and also separately for natives and immigrants. Proportions of deliveries by gestational age and maternal characteristics were calculated in 4 periods and compared by means of Chi-square tests. Crude and adjusted multinomial logistic regression models were fitted separately for native-born and immigrant women. Our results show that in the last 12 years a progressive shortening in the mean gestational age has taken place in Spain. While the overall decrease of gestational length along the period was 1.5 days, closer to that in Spanish women (1.3 days), it was 2.3 days among immigrants. In both groups this shortening was mainly due to an increase in the proportion of 37-39 weeks deliveries at the expense of a substantial decrease in those with 40 weeks. These trends remained after controlling for known confounding variables such as maternal age, parity and occupation. Further analysis of its causes and public health implications are recommended. PMID- 21671081 TI - Familial colorectal cancer: eleven years of data from a registry program in Switzerland. AB - Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n = 134, 57%) or MMR-deficient (n = 101, 43%). In 81 of the latter kindreds, deleterious germ-line MMR-gene variants have already been found (62 different variants, including 13 that have not been previously reported), confirming the diagnosis of Lynch syndrome. Compared with MMR-deficient kindreds, the 134 who were MMR proficient were less likely to meet the Amsterdam Criteria II regarding autosomal dominant transmission. They also had primary cancers with later onset and colon-segment distribution patterns resembling those of sporadic colorectal cancers, and they had lower frequencies of metachronous colorectal cancers and extracolonic cancers in general. Although the predisposition to colorectal cancer in these kindreds is probably etiologically heterogeneous, we were unable to identify distinct phenotypic subgroups solely on the basis of the clinical data collected in this study. Further insight, however, is expected to emerge from the molecular characterization of their tumors. PMID- 21671082 TI - Up-regulation of lipoxygenase, phospholipase, and oxylipin-production in the induced chemical defense of the red alga Gracilaria chilensis against epiphytes. AB - The red alga Gracilaria chilensis is commercially farmed for the production of agar hydrocolloids, but some susceptible algae in farms suffer from intense epiphyte growth. We investigated the induced chemical defense response of G. chilensis against epiphytes and demonstrated that an extract of an epiphyte challenged alga can trigger a defense response. The hormonally active metabolites were purified by RP-HPLC. Treatment with the extract or the purified fraction changed the chemical profile of the alga and increased resistance against epiphyte spores. Semi-quantitative RT-PCR and enzyme assays demonstrated that this metabolic response occurs after an increase in lipoxygenase and phospholipase A2 activity. Although this suggests the involvement of regulatory oxylipins, neither jasmonic acid nor the algal metabolite prostaglandin E2 triggers comparable defense responses. PMID- 21671083 TI - Identification of semiochemicals released by cotton, Gossypium hirsutum, upon infestation by the cotton aphid, Aphis gossypii. AB - The cotton aphid, Aphis gossypii (Homoptera: Aphididae), is increasing in importance as a pest worldwide since the introduction of Bt-cotton, which controls lepidopteran but not homopteran pests. The chemical ecology of interactions between cotton, Gossypium hirsutum (Malvaceae), A. gossypii, and the predatory lacewing Chrysoperla lucasina (Neuroptera: Chrysopidae), was investigated with a view to providing new pest management strategies. Behavioral tests using a four-arm (Pettersson) olfactometer showed that alate A. gossypii spent significantly more time in the presence of odor from uninfested cotton seedlings compared to clean air, but significantly less time in the presence of odor from A. gossypii infested plants. A. gossypii also spent significantly more time in the presence of headspace samples of volatile organic compounds (VOCs) obtained from uninfested cotton seedlings, but significantly less time with those from A. gossypii infested plants. VOCs from uninfested and A. gossypii infested cotton seedlings were analyzed by gas chromatography (GC) and coupled GC-mass spectrometry (GC-MS), leading to the identification of (Z)-3-hexenyl acetate, (E) 4,8-dimethyl-1,3,7-nonatriene (DMNT), methyl salicylate, and (E,E)-4,8,12 trimethyl-1,3,7,11-tridecatetraene (TMTT), which were produced in larger amounts from A. gossypii infested plants compared to uninfested plants. In behavioral tests, A. gossypii spent significantly more time in the control (solvent) arms when presented with a synthetic blend of these four compounds, with and without the presence of VOCs from uninfested cotton. Coupled GC-electroantennogram (EAG) recordings with the lacewing C. lucasina showed significant antennal responses to VOCs from A. gossypii infested cotton, suggesting they have a role in indirect defense and indicating a likely behavioral role for these compounds for the predator as well as the aphid. PMID- 21671084 TI - Modifications of neuroactive steroid levels in an experimental model of nigrostriatal degeneration: potential relevance to the pathophysiology of Parkinson's disease. AB - An important link between neuroactive steroids and neurodegenerative disorders has recently been suggested. Indeed, in several neurodegenerative experimental models the levels of neuroactive steroids are affected and their administration exerts neuroprotective effects. However, scarce information has so far been obtained on the neuroactive steroid levels present in Parkinson's disease. To this aim, using an experimental model of loss of nigrostriatal dopaminergic neurons obtained by stereotaxic injection of the neurotoxin 6-hydroxydopamine (6 OHDA), we evaluated by liquid chromatography tandem mass spectrometry the levels of several neuroactive steroids in the striatum and cerebral cortex of 6-OHDA lesioned male rats. Among the neuroactive steroid levels assessed (i.e., pregnenolone, progesterone, dihydroprogesterone, tetrahydroprogesterone, isopregnanolone, testosterone, dihydrotestosterone, 3alpha-diol, dehydroepiandrosterone, 17alpha-estradiol, and 17beta-estradiol), we observed a significant decrease of pregnenolone in the striatum. A similar effect was also observed on the levels of dihydroprogesterone present in this cerebral area and also in the cerebral cortex. Interestingly, an increase of isopregnanolone also occurred in the striatum and in the cerebral cortex. Altogether, these results suggesting that progesterone metabolism is affected in an experimental model of Parkinson's disease further highlight the link between neuroactive steroids and the neurodegenerative diseases. PMID- 21671085 TI - Lithium and other elements in scalp hair of residents of Tokyo Prefecture as investigational predictors of suicide risk. AB - The high suicide rates in Japan and several reports of inverse associations of suicide rates with the levels of lithium (Li) in drinking water prompted determinations of Li along with other elements in samples of scalp hair of 100 male and 100 female residents of Tokyo Prefecture. In more than half of the samples of both genders, Li levels were below the instrumental detection limit or below or the lower limit of the laboratory reference ranges. Among other elements, the concentrations namely of cobalt were also frequently below the laboratory reference range, suggesting that low circulating levels of vitamin B(12) were common in this study population. As vitamin B(12) deficiency is associated with depression and other psychiatric conditions, and there is evidence of interactions between Li and vitamin B(12), Li deficiency as well as suboptimal vitamin B(12) status must be considered as potential suicide risk factors. In view of its established positive effects on mood and brain function, an adequate supply of selenium (Se) is important as well. Although the analytical results suggested that the Se status of the subjects was generally adequate, as seafood was a major dietary source of Se, much of it was actually sequestered by mercury and only a fraction was bio-available. In addition, the hair samples were found to contain not insignificant levels of As, Cd, Ni, and Pb, arising from the adventitious presence of these elements in foods and the environment. As these elements also interact with Se in vivo and are known to adversely affect mood and behavior, in investigational studies, subjects at risk need to be evaluated also with respect to these elements. PMID- 21671086 TI - Acute phase response of selenium status and glutathione peroxidase activity in blood plasma before and after total knee arthroplasty surgery. AB - Several studies show the consistent results of the decrease in plasma or serum selenium (Se) after surgery, and the change is suggested to be a negative acute phase response of Se to the surgical inflammation. Plasma glutathione peroxidase (GPx), which is included in the acute phase response proteins, is a selenoenzyme. However, previous studies failed to show any changes in GPx activity before and after surgery. In the present study, we investigated the Se- and selenoenzyme responses that accompany the acute inflammatory reactions during and following major surgery. Patients who underwent elective total knee arthroplasty surgery due to knee osteoarthritis at the Department of Orthopaedic Surgery at Gunma University Hospital in Japan were studied. The plasma Se concentration was determined, and the activity of plasma GPx was measured. C-reactive protein (CRP), albumin, blood urea nitrogen (BUN), and white blood cell (WBC) count were also analysed. Increases in the inflammatory biomarkers of CRP and WBC showed inflammatory reactions with the surgery. A significant increase in plasma GPx activity (p < 0.05) and decreases in the plasma Se concentration (p < 0.05) and in serum albumin (p < 0.05) after surgery were observed. Since albumin is a Se containing protein and represents a negative acute phase protein that provides amino acids for the production of other series of acute phase proteins, the present results suggest that there is a redistribution of plasma Se to GPx that occurs as an acute phase response, and the source of Se for GPx could be, at least partly, from albumin. PMID- 21671087 TI - Background values for essential and toxic elements in children's nails and correlation with hair levels. AB - Human nails are an attractive matrix for assessing environmental exposures to toxic elements as well as the deficiency of essential elements since it is noninvasively collected and can be stored at room temperature. However, reference or baseline levels in nonexposed and healthy populations are not yet established. Then, the aims of this study were (a) to estimate background values for essential and toxic elements in nails from a healthy young population in southern Brazil and (b) to evaluate possible correlations between essential and toxic elements in nails. Furthermore, this report took part of a recent study of background values in the hair of a young population. Thus, correlations between chemical elements in nails and hair were also evaluated. Nails were collected from healthy children (n = 126), and element concentrations were determined by inductively coupled plasma mass spectrometry. This study provides new and reliable reference concentrations for toxic and essential elements in children's nails. The results can be used as reference values for epidemiological or clinical investigations based on trace elements in nails. Additionally, we also showed weak to strong correlations between Cu, Mg, Mn, Se, and Zn levels in nails and hair. PMID- 21671088 TI - Manganese regulates manganese-containing superoxide dismutase (MnSOD) expression in the primary broiler myocardial cells. AB - Previous studies showed that dietary manganese can increase the MnSOD mRNA expression in a dose-dependent manner in the heart of broilers. In order to explore the specific mechanism of the MnSOD expression induced by manganese, a model of MnSOD expression was developed with primary cultured broiler myocardial cells. The objective of the present study was to investigate whether the model was working or not and to determine how manganese affects the expression of the enzyme in broiler myocardial cells in vitro. In experiment 1, various amount of manganese (0, 0.25, 0.5, 1, 2, and 4 mM) were added into the cultures for 24-h incubation to investigate MnSOD expression and for 0-, 6-, 12-, 24-, 36-, and 48 h incubation to measure the cell viability. In experiment 2, the most suitable Mn supplementation based on the results of experiment 1 was added into cultures for 6-, 12-, 24-, and 48-h incubation. The results showed that MnSOD mRNA, MnSOD protein, and MnSOD activity were induced by manganese in dose- and time-dependent manner. Manganese regulates MnSOD expression not only at transcriptional level but also at translational and/or posttranslational levels. PMID- 21671089 TI - Correlation between serum testosterone level and concentrations of copper and zinc in hair tissue. AB - Testosterone deficiency is associated with late-onset hypogonadism. Micronutrients including copper (Cu) and zinc (Zn) influence testosterone synthesis. The association between micronutrient concentrations in hair tissue and serum testosterone was studied in Korean men. The subjects were 88 men 40-60 years of age who visited the health promotion center and an outpatient clinic of family medicine at a university hospital from March 2006 to February 2008. Population sociological features of the subjects were acquired by self administered surveys and interview, height and weight were measured, serum total testosterone was determined in the morning, and Cu and Zn were quantified from hair tissue collected in the morning. Subjects with normal testosterone group had a significantly higher Zn level compared to low testosterone group (P = 0.003). Significant negative correlations were evident between total testosterone and Cu level (r = -0.252, P = 0.022), and the Cu/Zn ratio (r = -0.288, P = 0.008). Normal testosterone is associated with a higher Zn level. Decreased serum testosterone is significantly associated with a high level of Cu and elevated Cu/Zn ratio in hair tissue. PMID- 21671090 TI - Sustaining fidelity following the nationwide PMTOTM implementation in Norway. AB - This report describes three studies from the nationwide Norwegian implementation of Parent Management Training-Oregon Model (PMTOTM), an empirically supported treatment for families of children with behavior problems (Forgatch and Patterson 2010). Separate stages of the implementation were evaluated using a fidelity measure based on direct observation of intervention sessions. Study 1 assessed growth in fidelity observed early, mid, and late in the training of a group of practitioners. We hypothesized increased fidelity and decreased variability in practice. Study 2 evaluated method fidelity over the course of three generations of practitioners trained in PMTO. Generation 1 (G1) was trained by the PMTO developer/purveyors; Generation 2 (G2) was trained by selected G1 Norwegian trainers; and Generation 3 (G3) was trained by G1 and G2 trainers. We hypothesized decrease in fidelity with each generation. Study 3 tested the predictive validity of fidelity in a cross-cultural replication, hypothesizing that higher fidelity scores would correlate with improved parenting practices observed in parent-child interactions before and after treatment. In Study 1, trainees' performance improved and became more homogeneous as predicted. In Study 2, a small decline in fidelity followed the transfer from the purveyor trainers to Norwegian trainers in G2, but G3 scores were equivalent to those attained by G1. Thus, the hypothesis was not fully supported. Finally, the FIMP validity model replicated; PMTO fidelity significantly contributed to improvements in parenting practices from pre- to post-treatment. The data indicate that PMTO was transferred successfully to Norwegian implementation with sustained fidelity and cross-cultural generalization. PMID- 21671091 TI - Lysinibacillus sphaericus S-layer protein toxicity against Culex quinquefasciatus. AB - The main toxicity mechanism of Lysinibacillus sphaericus, which is used in the control of mosquitoes, is its binary toxin produced during sporulation; additionally the Mtx1, Mtx2 and Mtx 3 toxins are expressed in vegetative cells. Mosquito larvicidal potency of the S-layer protein that is expressed in vegetative cells has been determined. The protein is similar to other S-layer proteins of mosquitocidal L. sphaericus strains. The LC50 values of the S-layer protein of the L. sphaericus OT4b25, OT4b26, and III(3)7 strains against third instar larvae of Culex quinquefasciatus were 8.7, 24 and 0.68 MUg/ml, respectively. To our knowledge this is the first study showing the mosquito larvicidal potency of the S-layer protein from Lysinibacillus sphaericus. PMID- 21671092 TI - Purification and characterization of arabinofuranosidase from the corn endophyte Acremonium zeae. AB - Acremonium zeae, one of the most prevalent fungal colonists of preharvest corn, possesses a suite of hemicellulolytic activities including xylanase, xylosidase, and arabinofuranosidase. Two enzymes with arabinofuranosidase activity were purified from cell-free culture supernatants of A. zeae grown on oat spelt xylan. A 47 kDa enzyme (AF47) was optimally active at 37 degrees C and pH 6.0, and had a specific activity for 4-nitrophenyl-alpha-L-arabinofuranoside (4NPA) of 6.2 U/mg. A 30 kDa enzyme (AF30) was optimally active at 50 degrees C and pH 4.5, and had a specific activity for 4NPA of 12.4 U/mg. AF47 hydrolyzed 4-nitrophenyl beta-D-xylopyranoside, 4-nitrophenyl-beta-D-glucopyranoside, and 4-nitrophenyl beta-D-cellobioside, as well as producing reducing sugars from corn fiber, wheat, and oat spelt arabinoxylan. AF30 had little detectable activity on the 4 nitrophenyl substrates, except for 4NPA, but activity on arabinoxylans from corn fiber, wheat, and oat spelt was at least 7-fold higher than AF47, with specific activities of 109, 358, and 153 U/mg, respectively. A combination of the two enzymes released 61 and 88% of the total arabinose from corn fiber and wheat arabinoxylans. The arabinofuranosidases produced by A. zeae may have industrial application for the enzymatic hydrolysis of recalcitrant lignocellulosic feedstocks such as corn fiber and wheat straw. PMID- 21671093 TI - Remodeling of the infarct territory in the time course of infarct healing in humans. AB - OBJECT: To analyze the remodeling processes of the infarct territory in the time course of infarct healing. MATERIALS AND METHODS: Serial late enhancement (LE) studies were performed in 30 patients following reperfused myocardial infarction (MI) in the first and second week post-MI and after 3 months. To characterize infarct remodeling over time, the following variables were derived and analyzed in a blinded fashion: Infarct size (IS, in mm(3)), maximum infarct thickness (IT(max), mm), mean infarct thickness (IT(mean), mm) and the variability of infarct thickness (VIT=IT(max)/IT(mean)). Further, a new parameter for the assessment of infarct remodeling, the infarct extent (IE, mm(2)) was computed. IE quantifies IS in two dimensions along the heart's circumferential and longitudinal directions. IS was divided by the IE to obtain IT(mean). RESULTS: Overall infarct thickness was highly variable. Infarct shrinkage due to infarct thinning and IE reduction was found in the first months of healing. IS, IT(mean) and IT(max) significantly decreased during follow-up. There was a less consistent change of the IE: IE decreased in 75% of all infarcts from the first week up to 3 months post-MI, whereas 25% of infarcts expanded. Infarct thinning was found in almost all patients (92%), hence occurring in patients with infarct expansion and in patients without infarct expansion. CONCLUSION: Infarct thinning and-to a lesser extent-IE reduction, contribute to infarct shrinkage in the time course of infarct healing. Infarct thinning may occur without infarct expansion. PMID- 21671094 TI - Nasopharyngeal carcinoma segmentation using a region growing technique. AB - PURPOSE: This paper proposes a new image segmentation technique for identifying nasopharyngeal tumor regions in CT images. The technique is modified from the seeded region growing (SRG) approach that is simple but sensitive to image intensity of the initial seed. METHODS: CT images of patients with nasopharyngeal carcinoma (NPC) were collected from Ramathibodi hospital, Thailand. Tumor regions in the images were separately drawn by three experienced radiologists. The images are used as standard ground truth for performance evaluation. From the ground truth images, common sites of nasopharyngeal tumor regions are different from head to neck. Before the segmentation, each CT image is localized: above supraorbital foramen (Group I), below oropharynx (Group III), or between these parts (Group II). Representatives of the CT images in each part are separately generated based on the Self-Organizing Map (SOM) technique. The representative images contain invariant features of similar NPC images. For a given CT slice, a possible tumor region can be approximately determined from the best matching representative image. Mode intensity within this region is identified and used in the SRG technique. RESULTS: From 6,606 CT images of 31 NPC patients, 578 images contained the tumors. Because NPC images above the supraorbital foremen were insufficient for study (6 images from 1 subject), they were excluded from the analysis. The CT images with inconsistent standard ground truth images, metastasis cases, and bone invasion were also disregarded. Finally, 245 CT images were taken into account. The segmented results showed that the proposed technique was efficient for nasopharyngeal tumor region identification. For two seed generation, average corresponding ratios (CRs) were 0.67 and 0.69 for Group II and Group III, correspondingly. Average PMs were 78.17 and 82.47%, respectively. The results were compared with that of the traditional SRG approach. The segmentation performances of the proposed technique were obviously superior to the other one. This is because possible tumor regions are accurately determined. Mode intensity, which is used in place of the seed pixel intensity, is less sensitive to the initial seed location. Searching nearby tumor pixels is more efficient than the traditional technique. CONCLUSION: A modified SRG technique based on the SOM approach is presented in this paper. Initially, a possible tumor region in a CT image of interest is approximately localized. Mode intensity within this region is determined and used in place of the seed pixel intensity. The tumor region is then searched and subsequently grown. The experimental results showed that the proposed technique is efficient and superior to the traditional SRG approach. PMID- 21671095 TI - Building an ensemble system for diagnosing masses in mammograms. AB - PURPOSE: Classification of a suspicious mass (region of interest, ROI) in a mammogram as malignant or benign may be achieved using mass shape features. An ensemble system was built for this purpose and tested. METHODS: Multiple contours were generated from a single ROI using various parameter settings of the image enhancement functions for the segmentation. For each segmented contour, the mass shape features were computed. For classification, the dataset was partitioned into four subsets based on the patient age (young/old) and the ROI size (large/small). We built an ensemble learning system consisting of four single classifiers, where each classifier is a specialist, trained specifically for one of the subsets. Those specialist classifiers are also an optimal classifier for the subset, selected from several candidate classifiers through preliminary experiment. In this scheme, the final diagnosis (malignant or benign) of an instance is the classification produced by the classifier trained for the subset to which the instance belongs. RESULTS: The Digital Database for Screening Mammography (DDSM) from the University of South Florida was used to test the ensemble system for classification of masses, which achieved a 72% overall accuracy. This ensemble of specialist classifiers achieved better performance than single classification (56%). CONCLUSION: An ensemble classifier for mammography-detected masses may provide superior performance to any single classifier in distinguishing benign from malignant cases. PMID- 21671096 TI - Web-based bone age assessment by content-based image retrieval for case-based reasoning. AB - PURPOSE: Maturity estimation by radiological bone age assessment (BAA) is a frequent task for pediatric radiologists. Following Greulich and Pyle, all hand bones are compared with a standard atlas, or a subset of bones is examined according to Tanner and Whitehouse. We support BAA comparing the epiphyses of a current case to similar cases with validated bone age by content-based image retrieval (CBIR). METHODS: A web-based prototype case-based retrieval system for BAA was developed and is publicly available. Hand radiographs from the USC database or user uploads may be retrieved by image-based query. The ten best matching cases for each epiphysis are retrieved by CBIR and displayed with their BAA, similarity score, and the derived age estimate. The similarity is approximated by cross-correlation. The USC hand database includes 1,101 cases comprising four ethnic groups of both genders between zero and 18 years of chronological age with radiographs and two annotated BAA. The USC image data have been enriched by marking the epiphyseal centers between metacarpals and distal phalanges. RESULTS: Leave-one-out experiments yielded a mean error rate of 0.99 years and a standard deviation of 0.76 years in comparison with the mean USC-BAA. The research prototype enables radiologists to judge their agreement based on similarity of retrieved cases and the derived age. CONCLUSIONS: CBIR provides support to the radiologist with a second opinion for BAA. Self-explanatory web applications can be established to support workflow integration. Enhancements in similarity computation and interface usability may further improve the system. PMID- 21671098 TI - Bilateral pertrochanteric fractures with bilateral patellar fractures with missed medial process fracture of talus in a young adult: a case report and review of literature. AB - Management of polytrauma patients is one the most difficult and challenging tasks for an orthopaedic surgeon, and it includes different aspects of intervention: emergent resuscitative care, early surgical care, post-operative care and delayed rehabilitative care. We report an interesting case of multiple skeletal injuries with a coexisting pattern of fractures of bilateral patellae with bilateral pertrochanteric fractures of femur with a missed talar fracture following a dashboard type of injury in a road traffic accident. We are not aware of a similar case reported in literature in the past. We highlight the management protocol in such a case and review the available literature regarding such a presentation. PMID- 21671097 TI - Accuracy considerations in image-guided cardiac interventions: experience and lessons learned. AB - MOTIVATION: Medical imaging and its application in interventional guidance has revolutionized the development of minimally invasive surgical procedures leading to reduced patient trauma, fewer risks, and shorter recovery times. However, a frequently posed question with regard to an image guidance system is "how accurate is it?" On one hand, the accuracy challenge can be posed in terms of the tolerable clinical error associated with the procedure; on the other hand, accuracy is bound by the limitations of the system's components, including modeling, patient registration, and surgical instrument tracking, all of which ultimately impact the overall targeting capabilities of the system. METHODS: While these processes are not unique to any interventional specialty, this paper discusses them in the context of two different cardiac image guidance platforms: a model-enhanced ultrasound platform for intracardiac interventions and a prototype system for advanced visualization in image-guided cardiac ablation therapy. RESULTS: Pre-operative modeling techniques involving manual, semi automatic and registration-based segmentation are discussed. The performance and limitations of clinically feasible approaches for patient registration evaluated both in the laboratory and in the operating room are presented. Our experience with two different magnetic tracking systems for instrument and ultrasound transducer localization is reported. Ultimately, the overall accuracy of the systems is discussed based on both in vitro and preliminary in vivo experience. CONCLUSION: While clinical accuracy is specific to a particular patient and procedure and vastly dependent on the surgeon's experience, the system's engineering limitations are critical to determine whether the clinical requirements can be met. PMID- 21671099 TI - Sequelae of an undiagnosed unilateral congenital fixed anterior shoulder dislocation in a 40-year-old female. AB - Congenital shoulder dislocation is a rare condition. A review of the literature showed that 0.018-0.07% of newborns suffer from shoulder dislocations. There have been only few reports about this entity, clinic and radiologic features, treatment, and etiology of this condition remains unclear. We report a case of undiagnosed unilateral congenital fixed anterior shoulder dislocation in a 40 year-old female, which affected the day quality of life. Pediatrists and orthopaedic surgeons should know this rare condition and the importance of a proper diagnosis in the early childhood when an appropriate treatment could be performed. PMID- 21671100 TI - Extracorporeal shock waves in articular cartilage defects in the rats. AB - Thirty adult Sprague-Dawley rats were used to assess the nature of healing tissues in hyaline cartilage defects and to compare the healing in defects treated with shock waves, with those in defects without treatment. A 2 * 2 mm cartilage defect with exposed cancellous bone was created in a nonweight-bearing area of each medial femoral condyle. Each right knee defect was received extracorporeal shock waves (Swiss Dolorclast) of 500 impulses in 5 min at 2 bar (comparative to 0.09 mJ/mm(2)), and the left knee defects were assigned as controls. The rat groups were sacrificed at 6 and 12 weeks postsurgery. Sections from each knee were stained with hematoxylin-eosin to analyze synovial adhesion, synovial thickness, bone maturation, and chondroid metaplasia and with masson trichrome to analyze collagen fiber intensity. There was not a significant difference found between the study and control groups (P > 0.05). Extracorporeal shock waves did not effect healing of the chondral defects. PMID- 21671101 TI - Effect of cold acclimatization on exercise economy in the cold. AB - We sought to determine if cold acclimatized men display higher economy (i.e. lower oxygen consumption at a given workload) during graded cycle ergometry in the cold (5 degrees C). After completing a familiarization trial 1 week prior, five cold weather athletes (CWA) and eight physically active men (NON) underwent graded exercise tests to volitional fatigue in 5 degrees C. The protocol always started at 60 W and increased by 20 W each minute. Oxygen consumption (VO(2)), respiration rate (RR), tidal volume (TV), and respiratory exchange ratio (RER) were determined via open circuit spirometry. Individuals were matched for body size and minutes of weekly physical activity. Repeated measures analyses of variance were conducted across time (workload) and cold acclimatization was entered as a between subjects factor. VO(2) peak was not different between groups but CWA had lower VO(2) at 60 and 240 W. CWA also had lower RR at 180 and 260 W as well as lower RER at 240 and 260 W. At submaximal workloads, cold acclimatized men have higher exercise economy than non-acclimatized men. This could have implications for those who work in this context. PMID- 21671102 TI - Practice makes transfer of motor skills imperfect. AB - We investigated the practice-effects on motor skill transfer and the associated representational memory changes that occur during the within-practice and between practice phases. In two experiments, participants produced extension-flexion movements with their dominant right arm for a limited or prolonged practice session arranged in either a single- or multi-session format. We tested the ability of participants to transfer the original pattern (extrinsic transformation) or the mirrored one (intrinsic transformation) to the non dominant left arm, 10 min and 24 h after the practice sessions. Results showed that practice induces rapid motor skill improvements that are non-transferable irrespective of the amount of acquisition trials. Furthermore, the extrinsic component of the skill develops early and remains the dominant coding system during practice. Conversely, we found distinct between-practice memory changes: a limited practice induces an off-line development of the extrinsic component, whereas a prolonged practice session subserves the off-line development of the intrinsic component (experiment 2). We provided further evidence that the long term representation of the motor skill also depends on the nature of the practice session itself: the parsing of practice into multiple sessions narrows the effector-transfer capacities in comparison to a single session (experiment 1). These findings yield theoretical and practical implications that are discussed in the context of recent motor skill learning models. PMID- 21671103 TI - Apamin increases post-spike excitability of supraoptic nucleus neurons in anaesthetized morphine-naive rats and morphine-dependent rats: consequences for morphine withdrawal excitation. AB - Supraoptic nucleus (SON) oxytocin neurons develop morphine dependence when chronically exposed to this opiate and undergo excitation when morphine is subsequently withdrawn. Morphine withdrawal excitation is evident as an increased action potential (spike) firing rate and is associated with an increased post spike excitability that is consistent with the expression of an enhanced post spike afterdepolarization (ADP) during withdrawal. Here, we administered apamin (which inhibits the medium afterhyperpolarization [mAHP] in vitro and unmasks an ADP) into the SON of urethane-anaesthetized rats to determine its effects on oxytocin neurons in vivo. As predicted, intra-SON apamin administration increased the propensity to fire a spike soon (<100 ms) after each spike (post-spike excitability) more in oxytocin neurons recorded from morphine-treated rats than in morphine-naive rats. However, intra-SON apamin did not alter the overall firing rate of oxytocin neurons recorded from morphine-treated rats or morphine naive rats, indicating that an increase in post-spike excitability alone is not sufficient to trigger withdrawal excitation of oxytocin neurons. Nevertheless, bilateral intra-SON apamin infusion increased oxytocin secretion (which depends on firing pattern as well as firing rate) by 90 +/- 46% in morphine-dependent rats (P < 0.01 compared to aCSF). Hence, an increase in post-spike excitability does not appear to drive morphine withdrawal-induced increases in oxytocin neuron firing rate, but does contribute to withdrawal-induced hyper-secretion of oxytocin. PMID- 21671105 TI - Stimulus-response bindings code both abstract and specific representations of stimuli: evidence from a classification priming design that reverses multiple levels of response representation. AB - Repetition priming can be caused by the rapid retrieval of previously encoded stimulus-response (S-R) bindings. S-R bindings have recently been shown to simultaneously code multiple levels of response representation, from specific Motor-actions to more abstract Decisions ("yes"/"no") and Classifications (e.g., "man-made"/"natural"). Using an experimental design that reverses responses at all of these levels, we assessed whether S-R bindings also code multiple levels of stimulus representation. Across two experiments, we found effects of response reversal on priming when switching between object pictures and object names, consistent with S-R bindings that code stimuli at an abstract level. Nonetheless, the size of this reversal effect was smaller for such across-format (e.g., word picture) repetition than for within-format (e.g., picture-picture) repetition, suggesting additional coding of format-specific stimulus representations. We conclude that S-R bindings simultaneously represent both stimuli and responses at multiple levels of abstraction. PMID- 21671104 TI - Evaluation of exposure biomarkers in offshore workers exposed to low benzene and toluene concentrations. AB - PURPOSE: Characterize ethylbenzene and xylene air concentrations, and explore the biological exposure markers (urinary t,t-muconic acid (t,t-MA) and unmetabolized toluene) among petroleum workers offshore. Offshore workers have increased health risks due to simultaneous exposures to several hydrocarbons present in crude oil. We discuss the pooled benzene exposure results from our previous and current studies and possible co-exposure interactions. METHODS: BTEX air concentrations were measured during three consecutive 12-h work shifts among 10 tank workers, 15 process operators, and 18 controls. Biological samples were collected pre-shift on the first day of study and post-shift on the third day of the study. RESULTS: The geometric mean exposure over the three work shifts were 0.02 ppm benzene, 0.05 ppm toluene, 0.03 ppm ethylbenzene, and 0.06 ppm xylene. Benzene in air was significantly correlated with unmetabolized benzene in blood (r = 0.69, p < 0.001) and urine (r = 0.64, p < 0.001), but not with urinary t,t-MA (r = 0.27, p = 0.20). Toluene in air was highly correlated with the internal dose of toluene in both blood (r = 0.70, p < 0.001) and urine (r = 0.73, p < 0.001). Co-exposures were present; however, an interaction of metabolism was not likely at these low benzene and toluene exposures. CONCLUSION: Urinary benzene, but not t,t-MA, was a reliable biomarker for benzene at low exposure levels. Urinary toluene was a useful biomarker for toluene exposure. Xylene and ethylbenzene air levels were low. Dermal exposure assessment needs to be performed in future studies among these workers. PMID- 21671106 TI - Cytolytic effects and apoptosis induction of Newcastle disease virus strain AF2240 on anaplastic astrocytoma brain tumor cell line. AB - Newcastle disease virus (NDV) is a member of genus Avulavirus within the family Paramyxoviridae. Interest of using NDV as an anticancer agent has arisen from its ability to kill tumor cells with limited toxicity to normal cells. In this investigation, the cytotolytic properties of NDV strain AF2240 were evaluated on brain tumor cell line, anaplastic astrocytoma (U-87MG), by using MTT assay. Cytological observations were studied using fluorescence microscopy and transmission electron microscopy to show the apoptogenic features of NDV on U 87MG. DNA laddering in agarose gel electrophoresis and terminal deoxyribonucleotide transferase-mediated dUTP-X nick end-labeling staining assay confirmed that the mode of cell death was by apoptosis. However, analysis of the cellular DNA content by flowcytometery showed that there was a loss of treated U 87MG cells in all cell cycle phases (G1, S and G2/M) accompanied with increasing in sub-G1 region (apoptosis peak). Early apoptosis was observed 6 h post inoculation by annexin-V flow-cytometry method. It could be concluded that NDV strain AF2240 is a potent antitumor agent that induce apoptosis and its cytotoxicity increasing while increasing of time and virus titer. PMID- 21671108 TI - An empirical examination of women's empowerment and transformative change in the context of international development. AB - This paper responds to calls from social scientists in the area of globalization and women's empowerment to test a model that investigates both structural and individual components of women's empowerment in the context of globalization. The investigation uses a liberation psychology framework by taking into account the effects of globalization, human rights discourse, and women's activism within social movements to identify how structural inequities may be related to empowerment. Surveys conducted in rural Nicaragua revealed that land ownership and organizational participation among women were related to more progressive gender ideology, and in turn, women's power and control within the marital relationship, individual levels of agency, and subjective well-being. The study demonstrates that psychology can bridge the theoretical arguments surrounding human rights with the practical implementation of development interventions, and provide empirical support that has yet to be demonstrated elsewhere. The findings have important implications for strategies and interventions that can improve conditions for women and contribute to the aims of social justice articulated in the Beijing Platform for Action. PMID- 21671107 TI - Differential pharmacological actions of methadone and buprenorphine in human embryonic kidney 293 cells coexpressing human MU-opioid and opioid receptor-like 1 receptors. AB - Methadone and buprenorphine are used in maintenance therapy for heroin addicts. In this study, we compared their effects on adenylate cyclase (AC) activity in human embryonic kidney (HEK) 293 cells stably overexpressing human MU-opioid receptor (MOR) and nociceptin/opioid receptor-like 1 receptor (ORL1) simultaneously. After acute exposure, methadone inhibited AC activity; however, buprenorphine induced compromised AC inhibition. When naloxone was introduced after 30 min incubation with methadone, the AC activity was enhanced. This was not observed in the case of buprenorphine. Enhancement of the AC activity was more significant when the incubation lasted for 4 h, and prolonged exposure to buprenorphine elevated the AC activity as well. The removal of methadone and buprenorphine by washing also obtained similar AC superactivation as that revealed by naloxone challenge. The study demonstrated that methadone and buprenorphine exert initially different yet eventually convergent adaptive changes of AC activity in cells coexpressing human MOR and ORL1 receptors. PMID- 21671109 TI - Diverse perceptions of the informed consent process: implications for the recruitment and participation of diverse communities in the National Children's Study. AB - We examined the experiences, perceptions, and values that are brought to bear when individuals from different ethnic and cultural backgrounds consider participating in health research. Fifty-three women from Latino, Asian American, Middle Eastern, or Non-Latino, White backgrounds participated in seven English or Spanish focus groups facilitated by trained investigators using a standard protocol. Investigators described the National Children's Study (NCS) and then asked questions to elicit potential concerns, expectations, and informational needs. Group sessions were audio-recorded, transcribed verbatim, and analyzed using qualitative thematic methods. A major theme that emerged during focus groups was participant self-identification as a member of a cultural group or community when raising issues that would influence their decision to participate in research. A related theme was the belief by some that communities may differ in the ease of participation in the NCS. Identified themes related to the informed consent process included perceived risks, anticipated burden, perceived benefits, informational needs, and decision-making strategies. Although themes were shared across groups, there were cultural differences within themes. Findings indicated that individuals from diverse backgrounds may have different perspectives on and expectations for the research process. To effectively recruit representative samples, it will be important to address a range of issues relevant for informed consent and to consider the impact of participation on both individuals and communities. PMID- 21671110 TI - Sterility of the personal protection system in total joint arthroplasty. AB - BACKGROUND: Bacteria shed by operating room personnel is a source of wound contamination and postoperative infections. The personal protection system (PPS) was designed to decrease airborne bacteria and intraoperative contamination in total joint arthroplasty. QUESTIONS/PURPOSES: We determined the microbial contamination rate of the PPS and incidence of contamination with key pathogens, Staphylococcus aureus and coagulase-negative staphylococci. PATIENTS AND METHODS: We prospectively evaluated PPS contamination in 61 primary THAs and 41 TKAs. The PPS were assumed to be sterile before opening the packs. The initial culture was taken immediately after the hood was placed over the helmet. Four cultures were collected at the conclusion of the procedure. Plates were examined and colonies were classified according to Gram stain results and biochemical tests. S. aureus was classified as methicillin-resistant or -susceptible. RESULTS: At time zero, 22 of 102 cultures isolated an organism, accounting for a contamination rate of 22%. The bacterial contamination rate of the PPS at the conclusion of the procedure was 47% (48 of 102). The relative percentage of the various organisms found was coagulase-negative staphylococci 50%, Micrococcus sp. 20%, methicillin susceptible S. aureus 11%, and methicillin-resistant S. aureus (MRSA) 1%. CONCLUSIONS: The external surface of the PPS cannot be assumed to be sterile after its removal from the original packaging. Of all the PPS studied, the potential pathogens coagulase-negative staphylococcus, S. aureus, and MRSA were found in 43%. This study supports the need to change gloves if the PPS is touched or adjusted during the procedure. PMID- 21671111 TI - CT-based myocardial perfusion imaging-practical considerations: acquisition, image analysis, interpretation, and challenges. AB - Methods for non-invasive, cardiac risk assessment have historically relied on exercise stress testing with or without echocardiography or radionuclide imaging and pharmacological stress testing when appropriate. More recently, CT-based modalities like CT angiography (CTA) have been shown to reliably differentiate low from high-risk coronary disease. The advent of newer CT technology now allows for CT-based myocardial perfusion imaging (CTP) that provides functional information, that when analyzed with anatomic data from CTA, can provide a comprehensive risk assessment strategy. In this review, we discuss the research and implementation; as well as the quantitative, semiquantitative, and qualitative methods of image analysis of CT-based perfusion. We also discuss the present state of technology and challenges associated with the methodology. In each section, when appropriate, we provide some information regarding the translation of these methods being utilized in the international, multicenter CORE320 study that is evaluating the combined CT-based imaging (CTA and CTP) strategy of risk assessment in comparison to the combined reference standard of radionuclide myocardial perfusion imaging and invasive angiography. PMID- 21671113 TI - Effect of TachoSil patch in prevention of postoperative pancreatic fistula. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is a severe complication after pancreatic resections. The aim was to assess if application of TachoSil(r) patch could reduce incidence of postoperative fistulas after laparoscopic distal pancreatic resections. METHODS: This is a retrospective study of prospectively collected data after enucleations and distal pancreatic resections. Patients were divided in two groups: with or without application of TachoSil(r) patch. Demographic and surgical data were analyzed. RESULTS: One hundred twenty-one patients with distal pancreatic resections without additional resections were identified among 230 patients operated by laparoscopic approach at our institution since 1998. They were divided into two groups. In group 1 (n = 48), TachoSil(r) patch was not applied while in group 2 (n = 73), the pancreatic stump was covered with TachoSil(r). Postoperative fistulas were registered in 8% (4/48) and 12% (9/73) in groups 1 and 2, respectively. The median duration of postoperative hospital stay in group 1 was 5.5 (2-35) days compared with 5 (2-16) days in group 2. No significant difference in surgical outcomes was found. CONCLUSIONS: The application of the TachoSil(r) patch did not affect either occurrence of POPF or duration of postoperative hospital stay. Routine use of TachoSil(r) patch to prevent pancreatic fistulas does not provide clinically significant benefit. PMID- 21671112 TI - Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. AB - INTRODUCTION: Hyperinsulinemic hypoglycemia with severe neuroglycopenia has been identified as a late complication of Roux-en-Y gastric bypass (RYGB) in a small number of patients. DISCUSSION: The rapid resolution of type 2 diabetes mellitus after RYGB is probably related to increased secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and patients with post-RYGB hypoglycemia demonstrate prolonged elevations of GIP and GLP-1 compared to non-hypoglycemic post-RYGB patients. Nesidioblastosis has been identified in some patients with post-RYGB hypoglycemia and is likely due to the trophic effects of GIP and GLP-1 on pancreatic islets. CONCLUSIONS: Treatment of hypoglycemia after RYGB should begin with strict dietary (low carbohydrate) alteration and may require a trial of diazoxide, octreotide, or calcium-channel antagonists, among other drugs. Surgical therapy should include consideration of a restrictive form of bariatric procedure, with or without reconstitution of gastrointestinal continuity. Partial or total pancreatic resection should be avoided. PMID- 21671114 TI - Transmediastinal endoscopic intervention. PMID- 21671115 TI - Prevention of leaks in esophageal surgery. PMID- 21671116 TI - Perception of dialect variation by young adults with high-functioning autism. AB - The linguistic profile of people with Autism spectrum disorders typically involves intact perceptual processing, accompanied by deficits in the social functions of language. In a series of three experiments, the impact of this profile on the perception of regional dialect was examined. Young adults with High-Functioning Autism exhibited similar performance to a typically developing comparison group in regional dialect classification and localness rating tasks, suggesting that they can use indexical information in speech to make judgments about the regional background of unfamiliar talkers. However, the participants with High-Functioning Autism were less able to differentiate among the dialects in a language attitudes task, suggesting that they do not share social stereotypes related to dialect variation with the typically developing comparison group. PMID- 21671117 TI - Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: implications for structure-based design of novel mosquito repellents. AB - Insect odorant binding proteins (OBPs) are the first components of the olfactory system to encounter and bind attractant and repellent odors emanating from various sources for presentation to olfactory receptors, which trigger relevant signal transduction cascades culminating in specific physiological and behavioral responses. For disease vectors, particularly hematophagous mosquitoes, repellents represent important defenses against parasitic diseases because they effect a reduction in the rate of contact between the vectors and humans. OBPs are targets for structure-based rational approaches for the discovery of new repellent or other olfaction inhibitory compounds with desirable features. Thus, a study was conducted to characterize the high resolution crystal structure of an OBP of Anopheles gambiae, the African malaria mosquito vector, in complex with N,N diethyl-m-toluamide (DEET), one of the most effective repellents that has been in worldwide use for six decades. We found that DEET binds at the edge of a long hydrophobic tunnel by exploiting numerous non-polar interactions and one hydrogen bond, which is perceived to be critical for DEET's recognition. Based on the experimentally determined affinity of AgamOBP1 for DEET (K (d) of 31.3 MUMU) and our structural data, we modeled the interactions for this protein with 29 promising leads reported in the literature to have significant repellent activities, and carried out fluorescence binding studies with four highly ranked ligands. Our experimental results confirmed the modeling predictions indicating that structure-based modeling could facilitate the design of novel repellents with enhanced binding affinity and selectivity. PMID- 21671118 TI - Mechanisms regulating cilia growth and cilia function in endothelial cells. AB - The primary cilium is an important sensory organelle present in most mammalian cells. Our current studies aim at examining intracellular molecules that regulate cilia length and/or cilia function in vitro and ex vivo. For the first time, we show that intracellular cAMP and cAMP-dependent protein kinase (PKA) regulate both cilia length and function in vascular endothelial cells. Although calcium dependent protein kinase modulates cilia length, it does not play a significant role in cilia function. Cilia length regulation also involves mitogen-activated protein kinase (MAPK), protein phosphatase-1 (PP-1), and cofilin. Furthermore, cofilin regulates cilia length through actin rearrangement. Overall, our study suggests that the molecular interactions between cilia function and length can be independent of one another. Although PKA regulates both cilia length and function, changes in cilia length by MAPK, PP-1, or cofilin do not have a direct correlation to changes in cilia function. We propose that cilia length and function are regulated by distinct, yet complex intertwined signaling pathways. PMID- 21671119 TI - An abundant, truncated human sulfonylurea receptor 1 splice variant has prodiabetic properties and impairs sulfonylurea action. AB - An alternatively spliced form of human sulfonylurea receptor (SUR) 1 mRNA lacking exon 2 (SUR1Delta2) has been identified. The omission of exon 2 caused a frame shift and an immediate stop codon in exon 3 leading to translation of a 5.6-kDa peptide that comprises the N-terminal extracellular domain and the first transmembrane helix of SUR1. Based on a weak first splice acceptor site in the human SUR1 gene (ABCC8), RT-PCR revealed a concurrent expression of SUR1Delta2 and SUR1. The SUR1Delta2/(SUR1 + SUR1Delta2) mRNA ratio differed between tissues, and was lowest in pancreas (46%), highest in heart (88%) and negatively correlated with alternative splice factor/splicing factor 2 (ASF/SF2) expression. In COS-7 cells triple transfected with SUR1Delta2/SUR1/Kir6.2, the SUR1Delta2 peptide co-immunoprecipitated with Kir6.2, thereby displacing two of four SUR1 subunits on the cell surface. The ATP sensitivity of these hybrid ATP-sensitive potassium channels (K(ATP)) channels was reduced by about sixfold, as shown with single-channel recordings. RINm5f rat insulinoma cells, which genuinely express SUR1 but not SUR1Delta2, exhibited a strongly increased K(ATP) channel current upon transfection with SUR1Delta2. This led to inhibition of glucose-induced depolarization, calcium flux, insulin release and glibenclamide action. A non mutagenic SNP on nucleotide position 333 (Pro69Pro) added another exonic splicing enhancer sequence detected by ASF/SF2, reduced relative abundance of SUR1Delta2 and slightly protected from non-insulin dependent diabetes in homozygotic individuals. Thus, SUR1Delta2 represents an endogenous K(ATP)-channel modulator with prodiabetic properties in islet cells. Its predominance in heart may explain why high-affinity sulfonylurea receptors are not found in human cardiac tissue. PMID- 21671121 TI - Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection. AB - In vivo and ex vivo models of reoviral encephalitis were utilized to delineate the contribution of type I interferon (IFN) to the host's defense against local central nervous system (CNS) viral infection and systemic viral spread. Following intracranial (i.c.) inoculation with either serotype 3 (T3) or serotype 1 (T1) reovirus, increased expression of IFN-alpha, IFN-beta, and myxovirus-resistance protein (Mx1; a prototypical IFN stimulated gene) was observed in mouse brain tissue. Type I IFN receptor deficient mice (IFNAR(-/-)) had accelerated lethality, compared to wildtype (B6wt) controls, following i.c. T1 or T3 challenge. Although viral titers in the brain and eyes of reovirus infected IFNAR(-/-) mice were significantly increased, these mice did not develop neurologic signs or brain injury. In contrast, increased reovirus titers in peripheral tissues (liver, spleen, kidney, heart, and blood) of IFNAR(-/-) mice were associated with severe intestinal and liver injury. These results suggest that reovirus-infected IFNAR(-/-) mice succumb to peripheral disease rather than encephalitis per se. To investigate the potential role of type I IFN in brain tissue, brain slice cultures (BSCs) were prepared from IFNAR(-/-) mice and B6wt controls for ex vivo T3 reovirus infection. Compared to B6wt controls, reoviral replication and virus-induced apoptosis were enhanced in IFNAR(-/-) BSCs indicating that a type I IFN response, initiated by resident CNS cells, mediates innate viral immunity within the brain. T3 reovirus tropism was extended in IFNAR(-/-) brains to include dentate neurons, ependymal cells, and meningeal cells indicating that reovirus tropism within the CNS is dependent upon type I interferon signaling. PMID- 21671120 TI - CD8(+) Tregs in autoimmunity: learning "self"-control from experience. AB - Autoreactive CD8(+) regulatory T cells (Tregs) play important roles as modulators of immune responses against self, and numerical and functional defects in CD8(+) Tregs have been linked to autoimmunity. Several subsets of CD8(+) Tregs have been described. However, the origin of these T cells and how they participate in the natural progression of autoimmunity remain poorly defined. We discuss several lines of evidence suggesting that the autoimmune process itself promotes the development of autoregulatory CD8(+) T cells. We posit that chronic autoantigenic exposure fosters the differentiation of non-pathogenic autoreactive CD8(+) T cells into antigen-experienced, memory-like autoregulatory T cells, to generate a "negative feedback" regulatory loop capable of countering pathogenic autoreactive effectors. This hypothesis predicts that approaches capable of boosting autoregulatory T cell memory will be able to blunt autoimmunity without compromising systemic immunity. PMID- 21671122 TI - Genetic structure of Marchalina hellenica (Hemiptera: Margarodidae) populations from Turkey: preliminary mtDNA sequencing data. AB - The scale insect Marchalina hellenica (Gennadius) (Hemiptera: Margarodidae) contributes to the production of pine honey in Turkey and Greece via the honeydew excreted when it feeds on pine trees. Although it is an insect of prime economic importance, there is no information on its genetic structure. Preliminary data were obtained based on sequencing analysis of 12s rDNA and COI mtDNA gene segments from samples from four areas of Turkey. Sequences of the 12s rDNA gene segment from Greek samples available in GenBank were also included. No variability was detected concerning the COI mtDNA gene segment analysis, although 13 haplotypes were revealed based on the 12s rDNA gene segment. The most distant population was from Mudanya-Bursa Province (Turkey). Further research is necessary on the genetic structure and variability of M. hellenica populations from the two neighboring countries. PMID- 21671123 TI - Blood biomarkers of ischemic stroke. AB - This review provides a summary of the protein and RNA biomarkers that have been studied for the diagnosis and assessment of ischemic stroke. Many of the biomarkers identified relate to the pathophysiology of ischemic stroke, including ischemia of CNS tissue, acute thrombosis and inflammatory response. These biomarkers are summarized by their intended clinical application in ischemic stroke including diagnosis, prediction of stroke severity and outcome, and stratification of patients for stroke therapy. Among the biomarkers discussed are recent whole genome studies using RNA expression profiles to diagnose ischemic stroke and stroke etiology. Though many candidate blood based biomarkers for ischemic stroke have been identified, none are currently used in clinical practice. With further well designed study and careful validation, the development of blood biomarkers to improve the care of patients with ischemic stroke may be achieved. PMID- 21671125 TI - Gaze training enhances laparoscopic technical skill acquisition and multi-tasking performance: a randomized, controlled study. AB - BACKGROUND: The operating room environment is replete with stressors and distractions that increase the attention demands of what are already complex psychomotor procedures. Contemporary research in other fields (e.g., sport) has revealed that gaze training interventions may support the development of robust movement skills. This current study was designed to examine the utility of gaze training for technical laparoscopic skills and to test performance under multitasking conditions. METHODS: Thirty medical trainees with no laparoscopic experience were divided randomly into one of three treatment groups: gaze trained (GAZE), movement trained (MOVE), and discovery learning/control (DISCOVERY). Participants were fitted with a Mobile Eye gaze registration system, which measures eye-line of gaze at 25 Hz. Training consisted of ten repetitions of the "eye-hand coordination" task from the LAP Mentor VR laparoscopic surgical simulator while receiving instruction and video feedback (specific to each treatment condition). After training, all participants completed a control test (designed to assess learning) and a multitasking transfer test, in which they completed the procedure while performing a concurrent tone counting task. RESULTS: Not only did the GAZE group learn more quickly than the MOVE and DISCOVERY groups (faster completion times in the control test), but the performance difference was even more pronounced when multitasking. Differences in gaze control (target locking fixations), rather than tool movement measures (tool path length), underpinned this performance advantage for GAZE training. CONCLUSIONS: These results suggest that although the GAZE intervention focused on training gaze behavior only, there were indirect benefits for movement behaviors and performance efficiency. Additionally, focusing on a single external target when learning, rather than on complex movement patterns, may have freed-up attentional resources that could be applied to concurrent cognitive tasks. PMID- 21671126 TI - Efficacy of turmeric (curcumin) in pain and postoperative fatigue after laparoscopic cholecystectomy: a double-blind, randomized placebo-controlled study. AB - OBJECTIVE: Better patient-reported outcomes (PROs) of laparoscopic cholecystectomy (LC) are premised upon PROs such as postoperative pain and fatigue. These PROs are indices of convalescence and return to normal activity. Curcumin (turmeric) is used in India for traumatic pain and fatigue for its anti inflammatory/antioxidant and tissue modulation/healing properties. We studied the effect of curcumin on pain and postoperative fatigue in patients of LC. METHODS AND PROCEDURES: From July to September 2009, 50 consecutive day-care LC candidates were enrolled for a prospective, double-blind randomized placebo controlled study. A uniform general anesthesia and analgesia protocol was followed. Curcumin/placebo and rescue analgesic were prescribed at discharge. Patients were told to maintain pain/fatigue/adverse event diaries based upon 100 point visual analog pain scale (VAS) and 10-point interval rating fatigue scale (IRS). Patients were followed up at third day (D3), first week (W1), second week (W2), and third week (W3). The blind labels were opened at the end of study. RESULTS: Demographic characteristics, comorbidity, and gallbladder pathology profiles were comparable in the study (n = 25) and control groups (n = 25). There was no adverse surgical outcome, adverse PRO or withdrawal. Pain and fatigue scores at D3 were similar in the two groups. At W1 and W2, the study group showed significantly lower (p value 0.000) mean pain scores, i.e., 15 +/- 5.204 versus 30 +/- 13 in controls. Fatigue scores at W1, W2, and W3 were significantly lower (p value 0.000) in the study group, i.e., 2.16 +/- 1.748, 1, and 0, respectively, versus 5.16 +/- 1.375, 4.20 +/- 1.633, and 1 in controls. All patients were pain free at W3. Analgesic tablet usage was significantly lower (p value 0.000) in the study group, i.e., 6.96 +/- 1.837 versus 39.32 +/- 16.509 in controls. CONCLUSIONS: Turmeric (curcumin) improves postoperative pain- and fatigue-related PROs following LC. PMID- 21671127 TI - Rapid disease progression in HIV-1-infected men who have sex with men is negatively correlated with peripheral plasmacytoid dendritic cell counts at the early stage of primary infection. AB - To explore the relationship between absolute dendritic cell (DC) counts at the early stage of primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) and subsequent disease progression, we performed a prospective study of 16 rapid progressors (RPs) and 12 typical progressors (TPs) from a PHI cohort of men who have sex with men. Significantly decreased plasmacytoid DC (pDC) and myeloid DC (mDC) counts in the blood of RPs were observed at study entry as compared with TPs and healthy HIV-1-negative subjects. Low baseline pDC counts were significantly associated with rapid disease progression after adjustment for baseline CD4(+) T cell counts, mDC counts, and HIV-1 load. Kaplan-Meier survival analysis showed that low pDC counts were strongly associated with rapid disease progression. Our findings demonstrated the predictive value of blood absolute pDC counts at baseline in PHI for HIV-1 disease progression. Further studies are required to confirm this notion. PMID- 21671128 TI - Defective T cell chemotaxis to sphingosine 1-phosphate and chemokine CCL21 in idiopathic T lymphocytopenia. AB - T cell chemotaxis to sphingosine 1-phosphate (S1P) and the chemokines CCL21 and CCL5 was studied in ten adults with T lymphocytopenia, other immunological abnormalities (nine of ten), and frequent bacterial infections (seven of ten). Mean chemotactic responses to S1P of CD4 T cells from CD4 T lymphocytopenic patients and of CD8 T cells from CD8 T lymphocytopenic patients were significantly lower than those of healthy matched controls. Chemotaxis to CCL21 was lower than that of controls for CD4 T cells of three CD4 T lymphocytopenic patients and for CD8 T cells of three CD8 T lymphocytopenic patients, but none of the T cells of patients had diminished chemotaxis to CCL5. Defective T cell chemotactic responses to S1P and some chemokines may lead to subset-selective abnormal T cell trafficking and chronic T cell lymphocytopenia. PMID- 21671129 TI - The possible roles of OPN-regulated CEACAM1 expression in promoting the survival of activated T cells and the apoptosis of oral keratinocytes in oral lichen planus patients. AB - Oral lichen planus is a chronic inflammatory disorder of the oral mucosa that represents T cell-mediated autoimmune diseases. The regulation and roles of carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), a novel immune molecule, in the immunopathogenesis of T cell-mediated autoimmune diseases remain unclear. In the current paper, CEACAM1 was found to be overexpressed in peripheral T cells and epithelial cells in oral lichen planus patients. A fraction of infiltrating inflammatory mononuclear cells in the lamina propria of the oral lichen planus mucosa also expressed CEACAM1. Importantly, for the first time, CEACAM1 expression in T cells and in normal human oral keratinocytes was demonstrated to be regulated differently by osteopontin in vitro. Furthermore, the apoptosis of oral keratinocytes and activated T cells can be markedly suppressed by CEACAM1-specific monoclonal antibodies. In conclusion, OPN regulated CEACAM1 expression may play a critical role in the immunopathogenesis of oral lichen planus. PMID- 21671130 TI - Pharmaceutical industry gifts to physicians: patient beliefs and trust in physicians and the health care system. AB - BACKGROUND: Pharmaceutical industry gifts to physicians are common and influence physician behavior. Little is known about patient beliefs about the prevalence of these gifts and how these beliefs may influence trust in physicians and the health care system. OBJECTIVE: To measure patient perceptions about the prevalence of industry gifts and their relationship to trust in doctors and the health care system. DESIGN: Cross sectional random digit dial telephone survey. PARTICIPANTS: African-American and White adults in 40 large metropolitan areas. MAIN MEASURES: Respondents' beliefs about whether their physician and physicians in general receive industry gifts, physician trust, and health care system distrust. KEY RESULTS: Overall, 55% of respondents believe their physician receives gifts, and 34% believe almost all doctors receive gifts. Respondents of higher socioeconomic status (income, education) and younger age were more likely to believe their physician receives gifts. In multivariate analyses, those that believe their personal physician receives gifts were more likely to report low physician trust (OR 2.26, 95% CI 1.56-3.30) and high health care system distrust (OR 2.03, 95% CI 1.49-2.77). Similarly, those that believe almost all doctors accept gifts were more likely to report low physician trust (OR 1.69, 95% CI 1.25 2.29) and high health care system distrust (OR 2.57, 95% CI 1.82-3.62). CONCLUSIONS: Patients perceive physician-industry gift relationships as common. Patients that believe gift relationships exist report lower levels of physician trust and higher rates of health care system distrust. Greater efforts to limit industry-physician gifts could have positive effects beyond reducing influences on physician behavior. PMID- 21671131 TI - Scabies crustosa in a 61-year-old kidney-transplanted patient. PMID- 21671132 TI - Racial and ethnic differences in longitudinal blood pressure control in veterans with type 2 diabetes mellitus. AB - BACKGROUND: Few studies have examined racial/ethnic differences in blood pressure (BP) control over time, especially in an equal access system. We examined racial/ethnic differences in longitudinal BP control in Veterans with type 2 diabetes. METHODS: We collected data on a retrospective cohort of 5,319 Veterans with type 2 diabetes and initially uncontrolled BP followed from 1996 to 2006 at a Veterans Administration (VA) facility in the southeastern United States. The mean blood pressure value for each subject for each year was used for the analysis with BP control defined as <140/<90 mmHg. The primary outcome measure was proportion with controlled BP. The main predictor variable was race/ethnicity categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic/Other (H/O). Other covariates included age, gender, employment, marital status, service connectedness, and ICD-9 coded medical and psychiatric comorbidities. Generalized linear mixed models were used to assess the relationship between race/ethnicity and BP control after adjusting for covariates. RESULTS: Mean follow-up was 5.0 years. The sample was 46% NHW, 26% NHB, 19% H/O, and 9% unknown. The average age was 68 years. In the final model, after adjusting for covariates, NHB race (OR = 1.38, 95%CI: 1.2, 1.6) and H/O race (OR = 1.57, 95% CI: 1.3, 1.8) were associated with increased likelihood of poor BP control (>140/>90 mmHg) over time compared to NHW patients. CONCLUSION: Ethnic minority Veterans with type 2 diabetes have significantly increased odds of poor BP control over ~5 years of follow-up compared to their non-Hispanic White counterparts independent of sociodemographic factors and comorbidity patterns. PMID- 21671133 TI - Enhanced topical and transdermal delivery of antineoplastic and antiviral acyclic nucleoside phosphonate cPr-PMEDAP. AB - PURPOSE: Acyclic nucleoside phosphonates possess unique antiviral and antineoplastic activities; however, their polar phosphonate moiety is associated with low ability to cross biological membranes. We explored the potential of transdermal and topical delivery of 2,6-diaminopurine derivative cPr-PMEDAP. METHODS: In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin. RESULTS: Ability of 0.1-5% cPr-PMEDAP to cross human skin barrier was very low with flux values ~40 ng/cm(2)/h, the majority of compound found in the stratum corneum. The highest permeation rates were found at pH 6; increased donor concentration had no influence. The permeation enhancer dodecyl 6 dimethylaminohexanoate (DDAK, 1%) increased flux of cPr-PMEDAP (up to 61 times) and its concentration in nucleated epidermis (up to ~0.5 mg of cPr-PMEDAP/g of the tissue). No deamination of cPr-PMEDAP into PMEG occurred during permeation studies, but N-dealkylation into PMEDAP mediated by skin microflora was observed. CONCLUSIONS: Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound. PMID- 21671135 TI - Disulfide scrambling in IgG2 monoclonal antibodies: insights from molecular dynamics simulations. AB - PURPOSE: To explore potential non-canonical disulfide linkages feasible in human IgG2 mAbs via molecular dynamics simulations of a model system, Hinge(++). METHODS: Hinge(++) is derived from the crystal structure of a full-length murine IgG2a antibody by replacing its core hinge region with human IgG2 hinge. Fv and C(H)3 domains were discarded to speed up calculations. Eight independent simulations, grouped in four sets, were performed. In the control set, disulfide bonding is identical to canonical human IgG2 mAb. Different numbers of disulfide bonds were broken in the remaining three sets. RESULTS: Two Fabs move towards Fc asymmetrically repeatedly leading to spatial proximity of LC.Cys214 and HC.Cys128 residues in one Fab with Cys residues in the upper hinge region, which could initiate disulfide scrambling. Local dynamics place the eight hinge region Cys residues in a large number of proximal positions which could facilitate non canonical inter- and intra- heavy chain disulfide linkages in the hinge region. CONCLUSION: Consistent with experimental studies, our simulations indicate inter chain disulfide linkages in human IgG2 mAbs are degenerate. Potential rational design strategies to devise hinge stabilized human IgG2 mAbs are gleaned. PMID- 21671134 TI - Novel mitochondria-targeted antioxidants: plastoquinone conjugated with cationic plant alkaloids berberine and palmatine. AB - PURPOSE: To develop effective mitochondria-targeted antioxidants composed entirely of natural constituents. METHODS: Novel mitochondria-targeted antioxidants were synthesized containing plant electron carrier and antioxidant plastoquinone conjugated by nonyloxycarbonylmethyl residue with berberine or palmatine, penetrating cations of plant origin. These compounds, SkQBerb and SkQPalm, were tested in model planar phospholipid membranes and micelles, liposomes, isolated mitochondria and living cells. RESULTS: SkQBerb and SkQPalm penetrated across planar bilayer phospholipid membrane in their cationic forms and accumulated in mitochondria isolated or in living human cells in culture. Reduced forms of SkQBerb and SkQPalm as well as C10Berb and C10Palm (SkQBerb and SkQPalm analogs lacking plastoquinol moiety) revealed radical scavenging activity in lipid micelles and liposomes, while oxidized forms were inactive. In isolated mitochondria and in living cells, berberine and palmatine moieties were not reduced, so antioxidant activity of C10Berb and C10Palm was not detected. SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations; their prooxidant effect was observed at 1,000 times higher concentrations. In human cell cuture, nanomolar SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by exogenous hydrogen peroxide. CONCLUSION: This is the first successful attempt to construct mitochondria-targeted antioxidants composed entirely of natural components, namely plastoquinone, nonyl, acetyl and berberine or palmatine residues. PMID- 21671136 TI - A new method of producing monoclinic paracetamol suitable for direct compression. AB - PURPOSE: To develop a technique of obtaining monoclinic polymorph of paracetamol suitable for direct compression without excipients. METHODS: Preparation of spongy monoclinic paracetamol was based on quench-cooling of paracetamol solutions in water-acetone mixtures sprayed into a vessel with liquid nitrogen followed by removal of solvents by freeze-drying. X-ray powder diffraction was used to study annealing of quench-cooled solutions in "paracetamol-acetone-water" and "acetone-water" systems and to find optimum conditions for obtaining fine particles of pure monoclinic paracetamol. Samples were characterized by electron microscopy; compression properties were measured. RESULTS: The preparation technique gave fine monoclinic paracetamol powder containing agglomerates (30-200 MUm) composed of flat particles (linear sizes 1-10 MUm, the thickness 60-150 nm). The spongy sample was suitable for direct compression without excipients, stable on storage, and mechanically robust. Mechanically stable tablets pressed from the spongy sample were better soluble in water than commercially available tablets of paracetamol with excipients. CONCLUSIONS: The proposed method gave spongy monoclinic paracetamol samples with improved properties. For inexpensive paracetamol, the method may not yield economic advantage. However, the same method based on freeze-drying solutions in mixed aqueous-organic solvents can be used to prepare new improved forms of other molecular solids for pharmaceutical applications. PMID- 21671137 TI - Potential of amino acid/dipeptide monoester prodrugs of floxuridine in facilitating enhanced delivery of active drug to interior sites of tumors: a two tier monolayer in vitro study. AB - PURPOSE: To evaluate the advantages of amino acid/dipeptide monoester prodrugs for cancer treatments by assessing the uptake and cytotoxic effects of floxuridine prodrugs in a secondary cancer cell monolayer following permeation across a primary cancer cell monolayer. METHODS: The first Capan-2 monolayer was grown on membrane transwell inserts; the second monolayer was grown at the bottom of a plate. The permeation of floxuridine and its prodrugs across the first monolayer and the uptake and cell proliferation assay on secondary layer were sequentially determined. RESULTS: All floxuridine prodrugs exhibited greater permeation across the first Capan-2 monolayer than the parent drug. The correlation between uptake and growth inhibition in the second monolayer with intact prodrug permeating the first monolayer suggests that permeability and enzymatic stability are essential for sustained action of prodrugs in deeper layers of tumors. The correlation of uptake and growth inhibition were vastly superior for dipeptide prodrugs to those obtained with mono amino acid prodrugs. CONCLUSIONS: Although a tentative general overall correlation between intact prodrug and uptake or cytotoxic action was obtained, it appears that a mixture of floxuridine prodrugs with varying beneficial characteristics may be more effective in treating tumors. PMID- 21671138 TI - Testing the accuracy of the retrospective recall method used in expertise research. AB - Expertise typically develops slowly over years, and controlled experiments to study its development may be impractical. Researchers often use a correlational, retrospective recall method in which participants recall career data, sometimes over many years before. However, recall accuracy is uncertain. The present study investigated the accuracy of recalled career data for up to 38 years, in over 600 international chess players. Participants' estimates of their entry year into international chess, total career games played, and number of games in a typical year were compared with the known true values. Entry year typically was recalled fairly accurately, and accuracy did not diminish systematically with time since list entry from 10 years earlier to 25 or more years earlier. On average, games count estimates were reasonably accurate. However, some participants were very inaccurate, and some were more inaccurate in their total-games counts and entry year estimates. The retrospective recall method yields usable data but may have some accuracy problems. Possible remedies are outlined. PMID- 21671139 TI - Effects of skewness and kurtosis on normal-theory based maximum likelihood test statistic in multilevel structural equation modeling. AB - A simulation study investigated the effects of skewness and kurtosis on level specific maximum likelihood (ML) test statistics based on normal theory in multilevel structural equation models. The levels of skewness and kurtosis at each level were manipulated in multilevel data, and the effects of skewness and kurtosis on level-specific ML test statistics were examined. When the assumption of multivariate normality was violated, the level-specific ML test statistics were inflated, resulting in Type I error rates that were higher than the nominal level for the correctly specified model. Q-Q plots of the test statistics against a theoretical chi-square distribution showed that skewness led to a thicker upper tail and kurtosis led to a longer upper tail of the observed distribution of the level-specific ML test statistic for the correctly specified model. PMID- 21671141 TI - Continuous intrathecal glyceryl trinitrate prevents delayed cerebral vasospasm in the single-SAH rabbit model in vivo. AB - BACKGROUND: Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of high morbidity and mortality. The reduced availability of nitric oxide (NO) in blood and cerebrospinal fluid (CSF) is well established as a key mechanism of vasospasm. Systemic administration of glyceryl trinitrate (GTN), an NO donor also known as nitroglycerin, has failed to be established in clinical settings to prevent vasospasm because of its adverse effects, particularly hypotension. The purpose of this study was to analyze the effect of intrathecally administered GTN on vasospasm after experimental SAH in the rabbit basilar artery. METHODS: A single-hemorrhage model of SAH in rabbits was used to induce vasospasm. GTN (0.5 mg/ml) or saline was infused via a subcutaneous implanted osmotic pump with continuous drug release into the cerebellomedullary cistern over 5 days. The degree of vasospasm in the basilar artery was recorded with angiography on day 5 after SAH and was compared to baseline angiography on day 0. FINDINGS: Significant reduction of basilar artery diameter was observed in the SAH group with saline infusion compared to sham-operated animals. Intrathecally administered GTN had no effect on the vessel diameter in sham operated animals, whereas it significantly prevented vasospasm in the SAH group. Intrathecal GTN infusion did not affect arterial blood pressure. CONCLUSIONS: Prophylactic, continuous intrathecal administration of GTN prevents vasospasm of the basilar artery in the rabbit SAH model. No toxic effects could be demonstrated in this study. The clinical safety and feasibility of this strategy need to be further investigated. PMID- 21671140 TI - Immunohistochemical study of the angiogenetic network of VEGF, HIF1alpha, VEGFR-2 and endothelial nitric oxide synthase (eNOS) in human breast cancer. AB - BACKGROUND: The role of Nitric Oxide (NO) in angiogenesis has not been fully clarified yet. A dual role for NO, either inductive or inhibitory, has been proposed on the basis of different effects that high or low concentrations of NO may exert on the angiogenic process. Additionally, it has been referred that NO may induce VEGF production, while VEGF may induce NO production via up-regulation of the endothelial nitric oxide synthase (eNOS), the two pathways being reverse. The aim of the current study was to investigate the expression of key molecules involved in these opposite pathways in primary breast cancer. METHODS: Representative tumor samples from 242 patients with early-stage breast cancer (invasive ductal breast carcinomas) were investigated for the expression of VEGF, VEGFR-2, HIF1alpha, iNOS, and eNOS using immunohistochemistry. RESULTS: Endothelial NOS was found in 159 cases, VEGF in 131 cases, HIF-1alpha in 139 cases, VEGFR2 in 185 cases and inducible NOS (iNOS) in 22 cases. There was a significant correlation between the expression of VEGF and VEGFR-2, eNOS and VEGF, eNOS and VEGFR-2, eNOS and HIF1alpha. No statistically significant correlation was found between iNOS and the rest of the studied molecules. CONCLUSIONS: In breast cancer cases, the major molecules regulating NO and VEGF production can be co-expressed in the individual carcinomas implying a possibility for the relevant pathways to be active; however appropriate functional experiments remain to be conducted to prove such a hypothesis. PMID- 21671142 TI - Ultrasound-guided medial mid-thigh approach to sciatic nerve block with a patient in a supine position. AB - We report the use of a 'medial mid-thigh approach (medial approach),' a new approach for performing ultrasound-guided sciatic nerve blockade (SNB) with patients in a supine position. Fifty-four patients undergoing knee surgery under general anesthesia and a combined femoral nerve block (FNB) and SNB were included in the study. After FNB, an ultrasound-guided medial approach was used to perform the SNB. The patient was placed in a supine position, and the hip and knee joints were flexed with the leg rotating externally. A linear ultrasound transducer was positioned perpendicular to the skin at the level of the upper mid-thigh. The sciatic nerve was identified in all patients using ultrasound imaging, and the distance to the nerve was 3.0-5.5 cm. A combined ultrasound- and nerve stimulator guided SNB was then performed, and 0.375% ropivacaine was administered. The block was successful in all patients, and the mean duration of the sensory and motor blockade was 11.9 and 8.2 h, respectively. In this study, the medial approach was highly successful and easy to perform. As performing a simultaneous FNB and SNB with patients in a supine position has several potential advantages, future studies should compare this approach with other more proximal approaches for performing SNB. PMID- 21671143 TI - Vaccinomics: current findings, challenges and novel approaches for vaccine development. AB - Recent years have witnessed a growing interest in a field of vaccinology that we have named vaccinomics. The overall idea behind vaccinomics is to identify genetic and other mechanisms and pathways that determine immune responses, and thereby provide new candidate vaccine approaches. Considerable data show that host genetic polymorphisms act as important determinants of innate and adaptive immunity to vaccines. This review highlights examples of the role of immunogenetics and immunogenomics in understanding immune responses to vaccination, which are highly variable across the population. The influence of HLA genes, non-HLA, and innate genes in inter-individual variations in immune responses to viral vaccines are examined using population-based gene/SNP association studies. The ability to understand relationships between immune response gene variants and vaccine-specific immunity may assist in designing new vaccines. At the same time, application of state-of-the-art next-generation sequencing technology (and bioinformatics) is desired to provide new genetic information and its relationship to the immune response. PMID- 21671144 TI - Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer's dementia. AB - The aim of the study was to compare the long-term efficacy of high versus low frequency repetitive transcranial magnetic stimulation (rTMS), applied bilaterally over the dorsolateral prefrontal cortex (DLPFC), on cognitive function and cortical excitability of patients with Alzheimer's disease (AD). Forty-five AD patients were randomly classified into three groups. The first two groups received real rTMS over the DLPFC (20 and 1 Hz, respectively) while the third group received sham stimulation. All patients received one session daily for five consecutive days. In each session, rTMS was applied first over the right DLPFC, immediately followed by rTMS over the left DLPFC. Mini Mental State Examination (MMSE), Instrumental Daily Living Activity (IADL) scale and the Geriatric Depression Scale (GDS) were assessed before, after the last (fifth) session, and then followed up at 1 and 3 months. Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), and the duration of transcallosal inhibition (TI) before and after the end of the treatment sessions. At base line assessment there were no significant differences between groups in any of the rating scales. The high frequency rTMS group improved significantly more than the low frequency and sham groups in all rating scales (MMSE, IADL, and GDS) and at all time points after treatment. Measures of cortical excitability immediately after the last treatment session showed that treatment with 20 Hz rTMS reduced TI duration. These results confirm that five daily sessions of high frequency rTMS over the left and then the right DLPFC improves cognitive function in patients with mild to moderate degree of AD. This improvement was maintained for 3 months. High frequency rTMS may be a useful addition to therapy for the treatment of AD. PMID- 21671145 TI - Left ventricular dyssynchrony assessment by phase analysis from gated PET-FDG scans. AB - BACKGROUND: The outcome of patients with severe ischaemic left ventricular (LV) dysfunction is determined by the extent of myocardial viability and the presence of LV dyssynchrony. We aimed at assessing both parameters from the same imaging method, i.e. gated positron emission tomography (PET) F18-fluorodeoxyglucose (FDG) scans. METHODS: Phase analysis from Emory Cardiac Toolbox was applied on gated PET-FDG scans to assess histogram bandwidth and standard deviation (SD) as a measure of LV dyssynchrony in 30 heart failure patients (mean ejection fraction: 30.2% +/- 13.8%) referred for the evaluation of myocardial viability. Cut-off values from single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) best predicting cardiac resynchronization therapy (CRT) response served as standard of reference (bandwidth < 135 degrees ; phase SD < 43 degrees ). Severe LV dyssynchrony was diagnosed if both SPECT-MPI values were above these limits. Intraclass correlation and clinical agreement in detection of severe LV dyssynchrony by PET vs SPECT were assessed. RESULTS: There was a significant correlation between PET-FDG and SPECT-MPI for bandwidth (r = 0.88, P < .001) and phase SD (r = 0.88, P < .001) resulting in an excellent clinical agreement between the two methods of 93%. CONCLUSIONS: Accurate LV dyssynchrony assessment by phase analysis of gated PET-FDG scans is feasible, allowing assessing myocardial viability and severe LV dyssynchrony in one scan. PMID- 21671146 TI - Predictors of an ischemic electrocardiographic response in patients with exercise induced myocardial ischemia. AB - BACKGROUND: The determinants of an ischemic electrocardiographic (ECG) response in patients with exercise-induced ischemia on single-photon emission computed tomography (SPECT) remain poorly defined. Specifically, it is unknown whether the occurrence of an ischemic ECG response is related to the extent and/or severity of SPECT ischemia. METHODS AND RESULTS: Among 3,294 patients who underwent exercise SPECT using a rest thallium-201/exercise Tc-99m sestamibi protocol, 699 (21%) patients had myocardial ischemia defined as summed difference score (SDS) >=2. The extent of SPECT ischemia was further defined as the total number of segments with difference score >=1, and severity of ischemia as the largest difference score among all segments. Patients with ischemic ECG changes (n = 315) were significantly older and had a significantly greater prevalence of hyperlipidemia. SDS (7.4 +/- 2.2 vs 4.7 +/- 1.9, P < .0001), extent (4.2 +/- 2.6 vs 2.9 +/- 1.7, P < .0001), and severity (2.8 +/- 0.9 vs 2.3 +/- 0.8, P < .0001) of SPECT ischemia were greater among patients with ischemic ECG changes. In multivariate analysis, age and SDS (which is a composite of the extent and severity of ischemia) were associated with ischemic ECG. When analyzed in a separate model which did not include SDS, both severity of SPECT ischemia (OR 1.42, CI 1.13-1.79) and extent of SPECT ischemia (OR 1.21, CI 1.10-1.33) were independently associated with ischemic ECG. CONCLUSIONS: Among patients with exercise-induced myocardial ischemia by SPECT, age and SDS were associated with ischemic ECG changes. When analyzed separately, the severity and extent of SPECT ischemia were both independent predictors of ischemic ECG changes. PMID- 21671147 TI - Incremental prognostic value of coronary flow reserve assessed with single-photon emission computed tomography. PMID- 21671149 TI - Patchouli alcohol: in vitro direct anti-influenza virus sesquiterpene in Pogostemon cablin Benth. AB - During the screening of anti-influenza virus substances from traditional herbal medicines, the methanol extract from the leaves of Pogostemon cablin Benth. showed potent in vitro antiviral activity (99.8% inhibition at a concentration of 10 MUg/mL) against influenza virus A/PR/8/34 (H1N1). The anti-influenza virus principle was isolated from the hexane-soluble fraction, through solvent fractionation, repeated silica gel column chromatography, and reversed-phase HPLC. The major active principle was a volatile substance that was identified as a sesquiterpene, patchouli alcohol (1), on the basis of its spectral analyses. When anti-influenza virus activity against A/PR/8/34 was evaluated by the plaque forming assay, patchouli alcohol reduced the number of plaques by 75% at 2 MUg/mL and 89% at 10 MUg/mL. Patchouli alcohol showed dose-dependent anti-influenza virus activity, and its IC(50) value was estimated to be 2.635 MUM. Although 11 different sesquiterpenes were tested for antiviral activity against influenza virus A/PR/8/34, no or negligible activity was observed except for patchouli alcohol. Patchouli alcohol did not show anti-influenza virus activity against A/Guizhou/54/89 (H3N2), but showed weak activity against B/Ibaraki/2/85 (IC(50) = 40.82 MUM). Patchouli alcohol did not show inhibitory activity against influenza virus neuraminidase. PMID- 21671150 TI - Stereotactic radiofrequency ablation (SRFA) of liver lesions: technique effectiveness, safety, and interoperator performance. AB - PURPOSE: To evaluate technique effectiveness, safety, and interoperator performance of stereotactic radiofrequency ablation (SRFA) of liver lesions. METHODS: Retrospective review including 90 consecutive patients from January 2008 to January 2010 with 106 computed tomography-guided SRFA sessions using both single and multiple electrodes for the treatment of 177 lesions: 72 hepatocellular carcinoma (HCC) and 105 metastases with a mean size of 2.9 cm (range 0.5-11 cm). Technique effectiveness and 1-year local recurrence were evaluated by computed tomographic scans. Complications, mortality, and hospital days were recorded. The performance between an experienced and inexperienced interventional radiologist was compared. RESULTS: The overall technique effectiveness after a single SRFA was 95.5% (93.1% for HCC and 97.1% for metastases). Four of the eight unsuccessfully treated lesions could be retreated (secondary technique effectiveness of 97.7%). Local recurrence at 1 year was 2.9%. Technique effectiveness was significantly different for lesions<5 cm (96.7%) and >5 cm (87.5%) (P=0.044) but not for lesions<3 cm (95.9%) and 3-5 cm (100%). Compared to clear parenchymal property (97.3%), vessel vicinity (93.3%) (P=0.349) and subcapsular (95.2%) (P=0.532) had no, but hollow viscera vicinity (83.3%) had a significantly lower technique effectiveness (P=0.020). Mortality rate was 0.9%. Major complications and hospital days were higher for cirrhosis Child-Pugh B (20%, 7.2 days) than Child-Pugh A (3.1%, 4.7 days) patients and for metastases (5.1%, 4.3 days). There was no significant difference in interoperator performance. CONCLUSION: SRFA allowed for efficient, reliable, and safe ablation of large-volume liver disease. PMID- 21671151 TI - Combination therapy of transcatheter arterial chemoembolization and arterial administration of antiangiogenesis on VX2 liver tumor. AB - PURPOSE: This study was designed to evaluate the antitumorigenic efficiency of Endostar (an antiangiogenic agent) arterially administrated combined with transcatheter arterial chemoembolization (TACE) on liver tumor, and validation of perfusion CT for quantitative measurements of the results. EXPERIMENTAL DESIGN: Thirty rabbits bearing VX2 liver tumors were randomly and equally distributed into three groups. One of the following treatment protocols was performed in each group: 1) group 1 was treated with TACE and simultaneously arterially administrated Endostar; 2) group 2 with TACE alone, and 3) a control group that had saline injected through hepatic artery. Routine CT scan was performed before treatment, and perfusion CT imaging was performed 2 weeks after treatment. Immunohistochemical biomarkers of microvascular density (MVD) and the expression of vascular endothelial growth factor (VEGF) were measured for assessments of angiogenesis. RESULTS: We observed a statistically significant reduction from the control in the volume, growth rate, and size of the tumor 2 weeks after treatment with both TACE plus Endostar and with TACE alone (P < 0.01). Although there was no statistically significant difference in tumor size between the group with TACE plus Endostar and the group with TACE alone (P > 0.05), MVD and VEGF were significantly less expressed in the TACE plus Endostar group than both groups with TACE alone and the control group (P < 0.01). Blood flow (BF), blood volume (BV), and permeability-surface area products (PS) in the group with TACE plus Endostar on perfusion CT were significantly higher than other two groups (P < 0.05), which were positively correlated with the MVD and VEGF values (P < 0.05). CONCLUSIONS: TACE with arterial administration of Endostar simultaneously significantly inhibited the angiogenesis biomarkers associated with TACE in a rabbit model bearing VX2 liver tumor, which indicates that the combined treatment protocol may have potential synergistic effects on liver cancer. It also is suggested that perfusion CT may be useful for monitoring antiangiogenic/antivascular treatment in the liver tumors. PMID- 21671152 TI - Effect of dehydroleucodine on intestinal transit: structural basis of the interaction with the alpha(2)-adrenergic receptor. AB - The activity of dehydroleucodine, a sesquiterpene lactone obtained from Artemisia douglasiana, was studied in mice small intestinal transit. Its mechanism was evaluated in the presence of several adrenergic and cholinergic antagonist drugs and one opioid antagonist. Docking of dehydroleucodine into the homology model of the alpha2-adrenergic receptor allowed us to analyze the structural basis of their interactions. The experiments showed that dehydroleucodine delayed intestinal transit. The docking of dehydroleucodine showed a unique binding site, equivalent to the binding site of carozolol in the beta-adrenergic receptor. The results suggested that dehydroleucodine produced an inhibitory effect on intestinal transit. Its action could be mediated, at least in part, through the alpha2-adrenergic receptor. PMID- 21671153 TI - Blindness enhances tactile acuity and haptic 3-D shape discrimination. AB - This study compared the sensory and perceptual abilities of the blind and sighted. The 32 participants were required to perform two tasks: tactile grating orientation discrimination (to determine tactile acuity) and haptic three dimensional (3-D) shape discrimination. The results indicated that the blind outperformed their sighted counterparts (individually matched for both age and sex) on both tactile tasks. The improvements in tactile acuity that accompanied blindness occurred for all blind groups (congenital, early, and late). However, the improvements in haptic 3-D shape discrimination only occurred for the early onset and late-onset blindness groups; the performance of the congenitally blind was no better than that of the sighted controls. The results of the present study demonstrate that blindness does lead to an enhancement of tactile abilities, but they also suggest that early visual experience may play a role in facilitating haptic 3-D shape discrimination. PMID- 21671154 TI - The interplay of spatial attention and memory: evidence for memory-driven spatial compatibility effects, but not for a facilitating role of attention in memory retrieval. AB - The visual indexing theory proposed by Zenon Pylyshyn (Cognition, 32, 65-97, 1989) predicts that visual attention mechanisms are employed when mental images are projected onto a visual scene. Recent eye-tracking studies have supported this hypothesis by showing that people tend to look at empty places where requested information has been previously presented. However, it has remained unclear to what extent this behavior is related to memory performance. The aim of the present study was to explore whether the manipulation of spatial attention can facilitate memory retrieval. In two experiments, participants were asked first to memorize a set of four objects and then to determine whether a probe word referred to any of the objects. The results of both experiments indicate that memory accuracy is not affected by the current focus of attention and that all the effects of directing attention to specific locations on response times can be explained in terms of stimulus-stimulus and stimulus-response spatial compatibility. PMID- 21671155 TI - Stimulus-specific learning: disrupting the bow effect in absolute identification. AB - The bow effect is ubiquitous in standard absolute identification experiments; stimuli at the center of the stimulus-set range elicit slower and less accurate responses than do others. This effect has motivated various theoretical accounts of performance, often involving the idea that end-of-range stimuli have privileged roles. Two other phenomena (practice effects and improved performance for frequently-presented stimuli) have an important but less explored consequence for the bow effect: Standard within-subjects manipulations of set size could disrupt the bow effect. We found this disruption for stimulus types that support practice effects (line length and tone frequency), suggesting that the bow effect is more fragile than has been thought. Our results also have implications for theoretical accounts of absolute identification, which currently do not include mechanisms for practice effects, and provide results consistent with those in the literature on stimulus-specific learning. PMID- 21671157 TI - Spatial working memory load affects counting but not subitizing in enumeration. AB - The present study investigated whether subitizing reflects capacity limitations associated with two types of working memory tasks. Under a dual-task situation, participants performed an enumeration task in conjunction with either a spatial (Experiment 1) or a nonspatial visual (Experiment 2) working memory task. Experiment 1 showed that spatial working memory load affected the slope of a counting function but did not affect subitizing performance or subitizing range. Experiment 2 showed that nonspatial visual working memory load affected neither enumeration efficiency nor subitizing range. Furthermore, in both spatial and nonspatial memory tasks, neither subitizing efficiency nor subitizing range was affected by amount of imposed memory load. In all the experiments, working memory load failed to influence slope, subitizing range, or overall reaction time. These findings suggest that subitizing is performed without either spatial or nonspatial working memory. A possible mechanism of subitizing with independent capacity of working memory is discussed. PMID- 21671156 TI - Visual search for arbitrary objects in real scenes. AB - How efficient is visual search in real scenes? In searches for targets among arrays of randomly placed distractors, efficiency is often indexed by the slope of the reaction time (RT) * Set Size function. However, it may be impossible to define set size for real scenes. As an approximation, we hand-labeled 100 indoor scenes and used the number of labeled regions as a surrogate for set size. In Experiment 1, observers searched for named objects (a chair, bowl, etc.). With set size defined as the number of labeled regions, search was very efficient (~5 ms/item). When we controlled for a possible guessing strategy in Experiment 2, slopes increased somewhat (~15 ms/item), but they were much shallower than search for a random object among other distinctive objects outside of a scene setting (Exp. 3: ~40 ms/item). In Experiments 4-6, observers searched repeatedly through the same scene for different objects. Increased familiarity with scenes had modest effects on RTs, while repetition of target items had large effects (>500 ms). We propose that visual search in scenes is efficient because scene-specific forms of attentional guidance can eliminate most regions from the "functional set size" of items that could possibly be the target. PMID- 21671159 TI - Heat-shock response and antioxidant defense during air exposure in Patagonian shallow-water limpets from different climatic habitats. AB - Climate warming involves not only a rise of air temperature means, but also more frequent heat waves in many regions on earth, and is predicted to intensify physiological stress especially in extremely changeable habitats like the intertidal. We investigated the heat-shock response (HSR) and enzymatic antioxidant defense levels of Patagonian shallow-water limpets, adapted to distinct tidal exposure conditions in the sub- and intertidal. Limpets were sampled in the temperate Northern Patagonia and the subpolar Magellan region. Expression levels of two Hsp70 genes and activities of the antioxidants superoxide dismutase (SOD) and catalase (CAT) were measured in submerged and 2- and 12-h air-exposed specimens. Air-exposed Patagonian limpets showed a tiered HSR increasing from South to North on the latitudinal gradient and from high to low shore levels on a tidal gradient. SOD activities in the Magellan region correlated with the tidal rhythm and were higher after 2 and 12 h when the tide was low at the experimental site compared to the 6 h value taken at high tide. This pattern was observed in intertidal and subtidal specimens, although subtidal individuals are little affected by tides. Our study shows that long-term thermal adaptation shapes the HSR in limpets, while the oxidative stress response is linked to the tidal rhythm. Close to the warm border of their distribution range, energy expenses to cope with stress might become overwhelming and represent one cause why the limpets are unable to colonize the shallow intertidal zone. PMID- 21671160 TI - Prognostic value of HER2-positive circulating tumor cells in patients with metastatic breast cancer. AB - BACKGROUNDS: The presence of >=5 circulating tumor cells (CTCs) in 7.5 ml blood is a poor prognostic marker in metastatic breast cancer (MBC). However, the role of human epidermal growth factor receptor 2 (HER2) status in CTCs is not known. METHODS: We prospectively assessed the prognostic value of this parameter for patients with MBC who started a new line of systemic therapy. The CTC count (>=5 or <5) and the HER2 status in CTCs at the initiation of the therapy and 3-4 weeks later (first follow-up) were determined. RESULTS: The median follow-up time of the 52 enrolled patients was 655.0 days (18-1,275 days). HER2-positive CTCs were present in 14 of the 52 patients (26.9%) during the study period. Eight of 33 patients (24.2%) with HER2-negative primary tumors had HER2-positive CTCs during the study period. At first follow-up, patients with HER2-positive CTCs had significantly shorter progression-free (n = 6; P = 0.001) and overall (P = 0.013) survival than did patients without HER2-positive CTCs (n = 43) in log-rank analysis. In multivariate analysis, HER2-positive CTCs at first follow-up (P = 0.029) and the number of therapies patients received before this study (P = 0.006) were independent prognostic factors in terms of progression-free survival. The number of therapies (P = 0.001) and a count of >=5 CTCs (P = 0.043) at baseline were independent prognostic factors in terms of overall survival. CONCLUSIONS: We showed that HER2 status in CTCs may be a prognostic factor for MBC. Well-powered prospective studies are necessary to determine the potential role of HER2-targeted therapies for patients with HER2-positive CTCs and HER2 negative primary tumors. PMID- 21671161 TI - A case of hypokalemia-induced fatal arrhythmia caused by indapamide in an anorexic elderly patient. AB - An 84-year-old man was referred to our hospital for atrioventricular block and severe hypokalemia. He had been treated for hypertension since 2007 with indapamide, a thiazide-like diuretic. His laboratory data had not been tested for a long time. One week before his first visit, he suffered from a common cold and anorexia. He was admitted to our hospital because his electrocardiogram showed ventricular flutter, and pulmonary arrest occurred at the time of his visit. Cardiopulmonary resuscitation was successfully performed. Hypokalemia (K, 1.7 mEq/L) was considered as the cause of acute cardiopulmonary failure. His oral intake of potassium decreased, but potassium loss from the kidney persisted (urinary potassium, 14.0 mEq/L; transtubular potassium gradient, 5.00). These results suggested that although hypokalemia was suspected to have been present for a long time due to indapamide, severe hypokalemia was induced during the period of anorexia. After discontinuation of indapamide and intravenous administration of potassium L: -aspartate for potassium supplementation, the patient's serum potassium levels increased and his general condition improved. Although it is well known that hypokalemia is caused by indapamide, the incidence is not frequent and if observed is not severe. However, we experienced an unusual case of hypokalemia-induced fatal arrhythmia caused by indapamide. Hence, the serum potassium concentration of patients under the drug, especially anorexic elderly patients, should be monitored. PMID- 21671162 TI - Advances in epigenetics and epigenomics for neurodegenerative diseases. AB - In the post-genomic era, epigenetic factors-literally those that are "over" or "above" genetic ones and responsible for controlling the expression and function of genes-have emerged as important mediators of development and aging; gene-gene and gene-environmental interactions; and the pathophysiology of complex disease states. Here, we provide a brief overview of the major epigenetic mechanisms (ie, DNA methylation, histone modifications and chromatin remodeling, and non-coding RNA regulation). We highlight the nearly ubiquitous profiles of epigenetic dysregulation that have been found in Alzheimer's and other neurodegenerative diseases. We also review innovative methods and technologies that enable the characterization of individual epigenetic modifications and more widespread epigenomic states at high resolution. We conclude that, together with complementary genetic, genomic, and related approaches, interrogating epigenetic and epigenomic profiles in neurodegenerative diseases represent important and increasingly practical strategies for advancing our understanding of and the diagnosis and treatment of these disorders. PMID- 21671163 TI - Anti-mullerian hormone as a predictive marker for the selection of women for oocyte in vitro maturation treatment. AB - PURPOSE: In oocyte in-vitro maturation (IVM) treatments, the chances to achieve a pregnancy are critically dependent on the retrieval of a suitable number of oocytes. In this study, we assessed the ability of circulating levels of anti mullerian hormone (AMH) to identify normo-ovulatory women suitable for IVM treatment on the basis of the number of retrieved oocytes. METHOD: Serum AMH was quantified in normo-ovulatory women younger than 39 years undergoing IVM treatment. After immature oocyte retrieval and IVM, maximum 3 mature oocytes were used for treatment and all resulting embryos were transferred, as established by law. From 177 cycles, 991 oocytes were recovered. Following IVM, 484 mature oocytes were obtained (50.1%). RESULTS: The overall pregnancy rate per embryo transfer was 16.6% (25/151) and the implantation rate was 10.9% (30/278). Linear regression and receiver operating characteristic (ROC) analyses were applied to identify independent variables and quantify a cut-off AMH value able to identify patients suitable for IVM treatment. An AMH value of 1.28 ng/ml was identified as a threshold for the prediction of the retrieval of at least 5 oocytes, with a sensitivity of 93.4% and a specificity of 33.8%. Positive and negative predictive values were 67.6% and 75.0%, respectively. CONCLUSIONS: AMH can be adopted to identify women candidate for an IVM treatment from whom a suitable number of oocytes may be retrieved. This is of crucial significance during a non-stimulated cycle, in order to prevent an insufficient oocyte collection and rescue the treatment by implementing a conventional controlled ovarian stimulation. PMID- 21671164 TI - Perioperative care of the infant with single ventricle physiology. AB - OPINION STATEMENT: Among patients with congenital heart defects, neonates with single ventricle disease continue to challenge clinicians despite significant improvements in survival over the past 30 years. The cardiac anatomical variants associated with the term "single ventricle" are characterized by severe hypoplasia (or absence) of either ventricle, typically in association with obstruction or atresia of either the pulmonary or systemic outflow tracts. Physiologically, the single ventricle receives both pulmonary and systemic venous blood and ejects simultaneously into the pulmonary and systemic circulations, a pattern commonly referred to as single ventricle physiology. Medical and surgical management strategies, though palliative, are aimed at achieving the optimal balance of systemic blood flow and pulmonary blood flow to maximize oxygen delivery. Patients with single ventricle physiology have a greater risk of dying than those with biventricular circulations and are generally committed to multiple palliative interventions throughout childhood with considerable risk. Surgical intervention in the newborn period involves Norwood Stage I palliation, placement of a systemic-to-pulmonary artery shunt, or banding of the pulmonary artery, depending on the status of the outflow tracts. Heart transplantation is offered as the initial approach in some centers. The management strategy and the actual delivery of care from the time of birth (or at time of diagnosis) through the postoperative period is crucial to optimize the short-term and long-term outcomes. Whereas survival following initial palliation in experienced centers is as high as 95%, emphasis is now appropriately shifting toward the control of in hospital morbidity and optimizing long-term functional outcome. Centers are continually striving to gather and apply new knowledge related to the underlying anatomical and physiologic problems while seeking to improve decision making and care of the patient with single ventricle physiology. PMID- 21671165 TI - Murine cytomegalovirus IE3 protein interacts with Ankrd17. AB - Murine cytomegalovirus (MCMV) IE3 protein is a multifunctional viral protein that interacts with several target proteins of both viral and host cellular origin. To investigate the biological function of IE3 in the pathogenesis of the brain disorders caused by CMV, a screening for host cellular proteins that could interact with IE3 was performed. By yeast two-hybrid screening, ankyrin repeats domain 17 (Ankrd17, also known as Gtar) was identified as a host factor that could interact with IE3. This interaction was verified by yeast two-hybrid assay and chemiluminescent co-immunoprecipitaion. Mapping analysis suggested that the 1 148 residues of IE3 were responsible for the interaction. These results suggested that the interaction between Ankrd17 and IE3 may play a key role in the pathogenesis of MCMV-associated disease. PMID- 21671166 TI - Cellular oxidative damage of HEK293T cells induced by combination of CdCl(2) and nano-TiO (2). AB - This study investigated the conjoined cellular oxidative damage of human embryo kidney 293T (HEK293T) cells induced by cadmium chloride (CdCl(2)) and nanometer titanium dioxide (nano-TiO(2)). RT-PCR technique was used to detect the expressions of Heme oxygenase-1 (HO-1) and 8-oxoguanine DNA glycosylase (OGG1). The activities of superoxide dismutase (SOD) and catalase enzyme (CAT) and concentrations of reactive oxygen species (ROS) and maldondialdehyde (MDA) were measured by different approaches. The results showed that CdCl(2) and nano-TiO(2) at a low concentration of 0.75 total toxic unit (TU) exerted an additive effects on HO-1 gene expression, CAT activities and MDA concentrations. When the total TU was increased to 1 or 1.25 TU, the interaction was synergetic. Moreover, the mixture with high proportion of CdCl(2) produced an additive effect on the OGG1 gene expression, and the interaction was changed to be synergetic when the concentration of CdCl(2) was lower than or equal to that of nano-TiO(2). Synergetic effects of CdCl(2) and nano-TiO(2) on cellular oxidative damage of HEK293T cells were found as indicated by the changes in the SOD activities and ROS concentrations. It was concluded that CdCl(2) and nano-TiO(2) exerts synergistic effects on the cellular oxidative damage of HEK293T cells, and the sensitivity of these indicators of oxidative damage varies with the proportion of CdCl(2) and nano-TiO(2) in the mixture. PMID- 21671167 TI - Lack of association of common polymorphism of LRP1 gene with myocardial infarction in a Chinese Han population. AB - This study examined the association of a common polymorphic allele (25G) of the low-density lipoprotein receptor-related protein1 (LRP1) gene with myocardial infarction (MI). The genotypes of LRP1 25CG (rs35282763) were determined in 347 MI patients and 347 age- and sex-frequency-matched controls from an unrelated Chinese Han population. Factor VIII (FVIII) levels were measured in the MI patients and controls by chromogenic assay and enzyme-linked immunosorbent assay (ELISA). The results showed that LRP1 25CG (rs35282763) genotype distribution did not differ significantly between patients (n=206 for 25CC, n=122 for 25CG) and controls (n=191 for 25CC, n=126 for 25CG; P>0.05). The 25G allele was not associated with a reduced risk of MI (P>0.05). Further stratifications for age, sex, and other cardiovascular risk factors did not affect the negative findings. It was concluded that the presence of the G allele at the 25CG (rs35282763) polymorphism of the LRP1 is not associated with a reduced risk of MI, and genotyping for LRP1 25CG (rs35282763) polymorphism is not useful in assessing the individual risk of MI. PMID- 21671168 TI - Association of polymorphisms in angiotensin II receptor genes with aldosterone producing adenoma. AB - This study examined the association of polymorphisms in angiotensin II receptor genes (AT (1) R and AT (2) R) with the risk for aldosterone-producing adenoma (APA) in a Chinese Han population. Four polymorphisms including rs5182 (573T/C) in exon 4, rs5186 (1166A/C) in 3'-untranslated region (3'-UTR) in AT (1) R gene and rs5194 (2274G/A) in 3'-UTR, rs1403543 (1675G/A) in intron 1 in AT (2) R gene were detected in 148 APA patients and 192 normal subjects (serving as control) by using a MGB-Taqman probe. The distribution of genotypes of each locus was in accordance with Hardy-Weinberg Equilibrium (HWE) in the APA and control groups (P>0.05). The allele A frequency at rs5194 was significantly higher in the APA group (0.49) than in the control group (0.35) (chi (2)=12.08, P=0.001). Subjects with homozygotic genotype AA and heterozygotic genotype GA were at an increased risk for APA as compared to those with GG genotype (OR=2.66, 95% CI=1.45-4.87; OR=1.67, 95% CI=1.02-2.74). Furthermore, rs5194 single-nucleotide polymorphism (SNP) at AT (2) R gene was significantly associated with APA in additive (OR=1.64, 95% CI=1.21-2.20, P=0.001), dominant (OR=1.94, 95% CI=1.23-3.06, P=0.003), and recessive model (OR=2.01, 95% CI=1.17-3.45, P=0.01). It was concluded that rs5194 polymorphism at AT (2) R gene was associated with the risk for APA, which may constitute a genetic marker of APA. PMID- 21671169 TI - Association of SUMO4 Met55Val variation with increased insulin resistance in newly diagnosed type 2 diabetes in a Chinese population. AB - SUMO4 Met55Val variation was shown to be related to type 2 diabetes susceptibility and the vascular complications in Asian people. To further examine the related mechanisms, this study was designed to evaluate the association of SUMO4 Met55Val polymorphism with insulin resistance and beta cell function in newly diagnosed type 2 diabetic patients in a Chinese population. Four hundred and twenty seven newly diagnosed type 2 diabetic patients were selected for SUMO4 Met55Val polymorphism genotype analysis. All subjects underwent a 75-g oral glucose tolerance test (OGTT) to estimate the insulin sensitivity and beta cell function. Anthropometrics and a metabolic profile were used for phenotyping analysis. The results showed that the SUMO4 Met55Val polymorphism was associated with higher insulin resistance (P<0.001) and lower insulin sensitivity (P<0.001). Patients with GG genotype had higher levels of plasma glucose, insulin and C peptide. Insulin sensitivity index (ISI) was closely correlated with body mass index (BMI) in patients with GG genotype in comparison to the counterparts with AG or AA genotype (r= -0.504 vs. r= -0.430 vs. r= -0.340). Multiple regression linear analysis showed that SUMO4 Met55Val polymorphism was an independent determinant for insulin sensitivity (P=0.001), which, along with triglyceride, BMI and sex, could account for 20.1% of the variation in ISI. The result remained the same after adjusting for BMI and sex. No association was found between SUMO4 Met55Val polymorphism and beta cell function (all P>0.05). It was concluded that SUMO4 Met55Val variant was associated with increased insulin resistance in Chinese patients with newly diagnosed type 2 diabetes. PMID- 21671170 TI - Variation of serum monocyte chemoattractant protein-1 in patients with diabetes and metabolic syndrome. AB - This study investigated the variation of serum monocyte chemoattractant protein-1 (MCP-1) in patients with both diabetes mellitus (DM) and metabolic syndrome (MS). Based on the International Diabetes Federation (IDF) diagnostic criteria, 93 patients enrolled in this study were divided into four groups: normal control (NC), simple DM, simple MS, and DM plus MS (DM-MS) groups. The main measures included height, weight, waist circumference (WC), hip circumference, blood pressure, fasting blood glucose, insulin resistance index (HOMA-IR), serum triglyceride (TG), HDL-ch, LDL-ch, and MCP-1. The results showed that the serum levels of MCP-1 in the DM-MS group were significantly increased as compared with those in the DM and MS groups (P<0.05), and the increase in the MCP-1 level in the DM group was much higher than in the MS group (P<0.05). The DM-MS group had the highest HOMA-IR levels, followed by MS, DM and NC groups (P<0.05). Correlation tests showed that the association of MCP-1 with age, HDL-ch, or LDL ch was insignificant, whereas that of MCP-1 with body mass index (BMI), waist hip rate (WHR), WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), TG, and HOMA-IR was significantly positive. It was concluded that circulating MCP 1 was substantially increased in patients with both DM and MS as compared with that in the patients with DM or MS alone, and the central obese state may contribute to a more vicious proinflammatory condition and insulin resistance in patients with diabetes. PMID- 21671171 TI - Telmisartan protects against insulin resistance by attenuating inflammatory response in rats. AB - This study investigated the effects of telmisartan on insulin resistance in high fat diet-treated rats and the possible mechanism. A total of 40 male Sprague Dawley rats enrolled in the study were divided into 4 groups at random: ND group (n=10) and HD group (n=10), in which the rats were given a normal chow diet or a high-fat diet for 20 weeks following a one-week adaptation; ND+telmisartan (n=10) group and HD+telmisartan group (n=10), in which the rats were initially administered in the same way as the ND or HD group, and then they were orally gavaged with telmisartan (5 mg/kg daily) additionally for 5 weeks. Related inflammatory factors were measured by ELISA. Monocyte chemotactic protein 1 (MCP 1), phosphorylated JNK and IkappaB-alpha expressions in both adipose and liver were detected by Western blotting. CRP and angiotensin II receptor 1 (AT1) mRNA expressions in both adipose and liver were determined by RT-PCR. The results showed that telmisartan administration in vivo reversed insulin resistance as evidenced by a decrease in plasma fasting glucose levels, plasma fasting insulin levels and homeostasis model of assessment-insulin resistance (HOMA-IR). Furthermore, telmisartan administration significantly reduced serum CRP, TNF alpha and IL-1beta levels, and elevated serum IL-10 levels. It was also found to hamper the high-fat diet-induced increase in CRP mRNA, AT1 mRNA and MCP-1, and decrease in IkappaB-alpha in both adipose and liver. It was concluded that telmisartan administration in vivo may improve insulin resistance through attenuated inflammatory response pathways. PMID- 21671172 TI - Influence of silencing soluble epoxide hydrolase with RNA interference on cardiomyocytes apoptosis induced by doxorubicin. AB - In order to investigate the influence of silencing soluble epoxide hydrolase (sEH) with double-stranded small interfering RNA (siRNA) on cardiomyocytes apoptosis induced by doxorubicin (DOX), two plasmids containing siRNA sequences specific to sEH were constructed and transfected into the primary cultured cardiomyocytes by using FuGENE HD transfection agents. The mRNA and protein expression levels of sEH were detected by semiquantitative RT-PCR and Western blotting respectively, and the plasmids that silenced sEH most significantly were selected, and renamed EH-R. The plasmids carrying a nonspecific siRNA coding sequence (PCN) served as the negative control. Cardiomyocytes were divided into four groups: control group, DOX group, PCN+DOX group, and EH-R+DOX group. Apoptosis of cardiomyocytes was induced by DOX at a concentration of 1 MUmol/L. Apoptosis rate of cardiomyocytes was determined by flow cytometery. The protein expression levels of Bcl-2 and Bax were detected by Western blotting. The results showed that the expression of sEH was down-regulated by EH-R plasmid. The expression levels of sEH mRNA and protein in the EH-R+DOX group were significantly decreased as compared with other groups (P<0.01). As compared with the control group, the apoptosis rate of cardiomyocytes in three DOX-treated groups was obviously increased, the expression levels of Bax increased, and those of Bcl-2 decreased (P<0.01). However, the expression levels of Bax were decreased, those of Bcl-2 increased and the apoptosis rate of cardiomyocytes obviously decreased in EH-R+DOX group when compared with those in the DOX group and the PCN+DOX group (P<0.01 for each). It was concluded that the recombinant plasmids could be successfully constructed, and transfected into the primary cultured cardiomyocytes. They could ameliorate the DOX-induced cardiomyocytes apoptosis by selectively inhibiting the expression of sEH with RNAi and increasing the expression of Bcl-2. PMID- 21671173 TI - Protective effects of eplerenone on podocyte injury in adriamycin nephropathy rats. AB - To investigate the protective effects of eplerenone on adriamycin-induced renal injury and the possible mechanisms involved, 36 male Sprague-Dawley rats were randomly divided into control group, adriamycin nephropathy (AN) group and eplerenone-treated group (100 mg.kg(-1).d(-1) eplerenone). Blood pressure, 24-h urinary protein, serum potassium, sodium and creatinine were measured 28 days after adriamycin injection (a single tail intravenous injection of 6.5 mg/kg adriamycin). The morphological changes of renal tissues were observed by light and electron microscopy. Immunohistochemistry and Western blotting were performed to examine the expression of TGF-beta(1) and desmin in renal cortex. The results showed that 28 days after adriamycin injection, there were no significant changes in the level of serum potassium, sodium, creatinine concentrations and blood pressure values in the rats of the three groups. Meanwhile, the 24-h proteinuria excretion in the AN group was significantly higher than that in the control group (P<0.01), but that in the eplerenone-treated group was substantially reduced when compared with that in the AN group (P<0.05). Mild mesangial cell proliferation and matrix expansion, diffuse deformation and confluence of foot processes in podocytes were found in the AN group. By contrast, rats in the eplerenone-treated group exhibited obvious attenuation of these morphological lesions. The protein expression of TGF-beta(1) and desmin in the AN group was markedly up-regulated in contrast to that in the control group (P<0.01), whereas that in the eplerenone treated group was much lower than in the AN group (P<0.05). It was concluded that eplerenone may ameliorate the proteinuria and the development of pathological alteration in adriamycin-induced nephropathy presumably via the inhibition of cytokine release, and restore the morphology of podocytes independent of its blood pressure-lowing effects. PMID- 21671174 TI - Role of reactive oxygen species in triptolide-induced apoptosis of renal tubular cells and renal injury in rats. AB - This study investigated the role of reactive oxygen species (ROS) in the pathogenesis of triptolide-induced renal injury in vivo. Rats were randomly divided into 4 groups (n=5 in each): triptolide group in which the rats were intraperitoneally injected with triptolide solution at a dose of 1 mg/kg of body weight on day 8; control group in which the rats received a single intraperitoneal injection of 0.9% physiological saline on day 8; vitamin C group in which the rats were pretreated with vitamin C by gavage at a dose of 250 mg/kg of body weight per day for 7 days before the same treatment as the control group on day 8; triptolide+vitamin C group in which the rats were first subjected to an oral administration of vitamin C at a dose of 250 mg/kg of body weight per day for 7 days, and then to the same treatment as the triptolide group on day 8. All the rats were sacrificed on day 10. Blood samples were collected for detection of plasma creatinine (Pcr) and plasma urea nitrogen (PUN) concentrations. Both kidneys were removed. The histological changes were measured by haematoxylin eosin (HE) staining. The production of ROS was determined by detecting the fluorescent intensity of the oxidation-sensitive probe rhodamine 123 in renal tissue. Renal malondialdehyde (MDA) content was measured to evaluate lipid peroxidation level in renal tissue. TUNEL staining was performed to assess apoptosis of renal tubular cells. Renal expression of apoptosis-related proteins Bcl-2, Bax, Bid, Bad, Fas and FasL, as well as corresponding encoding genes were assessed by Western Blotting and real-time PCR. The results showed that triptolide treatment promoted the generation of a great amount of ROS, up regulated the expression of Bax, Bid, Bad, Fas and FasL at both protein and mRNA levels, as well as the ratio of Bax to Bcl-2, and caused the apoptosis of renal tubular cells and renal injury. However, pretreatment with an antioxidant, vitamin C, significantly reduced the generation of ROS and effectively inhibited the triptolide-induced apoptosis of renal tubular cells and renal injury. It was concluded that ROS plays a critical role in triptolide-induced apoptosis of renal tubular cells and renal injury. The protective administration of vitamin C may help alleviate triptolide-induced renal injury and nephrotoxicity. PMID- 21671175 TI - Role of RANTES and its receptor in gastric cancer metastasis. AB - This study examined the role of regulated upon activation normal T cell expressed and secreted (RANTES) and its receptor C-C chemokine receptor type 5 (CCR5) in gastric cancer metastasis and the associated mechanism. The expression of RANTES and CCR5 was detected by using immunohistochemical staining and Western blotting in the gastric cancer tissues obtained from 60 gastric cancer patients with or without lymph node metastasis (n=30 in each). The results showed that the expression levels of RANTES and CCR5 were higher in gastric cancer with lymph node metastasis than in that without metastasis (P<0.05). The expression levels of RANTES in 30 lymph nodes with cancerous invasion were higher than in 30 normal lymph nodes (P<0.05). Chemotactic test revealed that the number of migrating gastric cancer cells (n=295.0 +/- 54.6) induced by the protein of cancer-invading lymph nodes was greater than that by the protein mixture from cancer-invading lymph nodes and RANTES antibody (n=42.5 +/- 11.6) (P<0.05). RT-PCR showed that the expression levels of the main Th1 cytokines (IL-2, Gamma-IFN) were lower in gastric cancer with lymph node metastasis (2.22 +/- 0.90, 3.26 +/- 1.15 respectively) than in that without metastasis (3.07 +/- 1.67, 4.77 +/- 1.52 respectively) (P<0.05), but the expression level of the main Th 2 cytokine (IL 10) was higher in gastric cancer with lymph nodes metastasis (6.06 +/- 2.04) than in that without metastasis (4.88 +/- 1.87) (P<0.05). It was concluded that RANTES and its receptor CCR5 may contribute to gastric cancer metastasis through influencing the balance of Th1/Th2. RANTES and CCR5 may become a marker of gastric cancer metastasis. PMID- 21671176 TI - Targeted silencing of heparanase gene by small interfering RNA inhibits invasiveness and metastasis of osteosarcoma cells. AB - The effects of targeted silencing of heparanase gene by small interfering RNA (siRNA) on invasiveness and metastasis of osteosarcoma cells (MG63 cells) were investigated in the present study. Two complementary oligonucleotide strands were synthesized and inserted into pGenesil-1 vector based on the mRNA sequence of heparanase gene. The expression vector containing short hairpin RNA (pGenesil shRNA) was constructed successfully. MG63 cells were randomly allocated into 3 groups: blank group, empty vector (pGenesil) transfected group and expression vector (pGenesil-shRNA) transfected group. Under the induction of Lipofectamine 2000, the recombinants were transfected into MG63 cells. Heparanase gene expression level was detected by RT-PCR and Western blotting. Cell proliferation was measured by MTT assay. Cell invasiveness and metastasis were examined by cell adhesion and Transwell-ECM assays. HUVECs migration assay was applied for the detection of angiogenesis. As compared with negative controls, the mRNA and protein expression levels of heparanase were down-regulated by 76.1% (P<0.01) and 75.3% (P<0.01) respectively in the pGenesil-shRNA transfected group. Meanwhile, the proliferation, adhesiveness, invasiveness and angiogenesis properties of MG63 cells were all significantly inhibited. It was suggested that targeted silencing of heparanase gene by siRNA could dramatically inhibit the invasiveness and metastasis of osteosarcoma cells. PMID- 21671177 TI - Influence of beta-catenin small interfering RNA on human osteosarcoma cells. AB - This study examined the effect of small interfering RNA-mediated beta-catenin knockdown on the survival, invasion and chemosensitivity of human osteosarcoma cells (U2-OS cells). The siRNA against beta-catenin was constructed and transfected into U2-OS cells. The expression of beta-catenin was detected by qRT PCR and Western blotting. Cell growth and apoptosis was detected in the presence or absence of doxorubicin by MTT and flow cytometry, respectively. Cell invasion ability was measured by transwell assay. The results showed that the transfection of beta-catenin siRNA resulted in decreased expression of beta-catenin, suppression of invasion and motility of U2-OS cells, reduced chemosensitivity to doxorubicin in vitro, and little change in cell growth and apoptosis. Additionally, down-regulated MT1-MMP expression was found after transfection. It was concluded that knockdown of beta-catenin gene may decrease the invasive ability of human osteosarcoma cells through down-regulated MT1-MMP expression, and the chemosensitivity of osteosarcoma cells against doxorubicin. PMID- 21671178 TI - Contribution of decreased expression of Ku70 to enhanced radiosensitivity by sodium butyrate in glioblastoma cell line (U251). AB - The present study investigated the enhanced radiosensitivity of U-251 cells induced by sodium butyrate (NaB) and its possible mechanisms. Increased radiosensitivity of U251 cells was examined by clonogenic cell survival assays. The expression of Ku70 mRNA and protein was detected by using RT-PCR and Western blotting respectively. gamma-H2AX foci were measured at different time points after ionizing irradiation alone or combined with NaB treatment. The results showed that cell survival rate was significantly reduced, both D0 and Dq values were decreased (D0: 1.43 Gy vs. 1.76 Gy; Dq: 1.22 Gy vs. 2.05 Gy) after the combined treatment as compared with irradiation alone, and sensitivity enhancing ratio (SER) reached 1.23. The average number of gamma-H2AX foci per cell receiving the combined treatment was significantly increased at different time points, and the expression levels of Ku70 mRNA and protein were suppressed by NaB in a dose-dependent manner. It was concluded that enhanced radiosensitivity induced by NaB involves an inhibited expression of Ku70 and an increase in gamma H2AX foci, which suggests decreased ability in DSB repair. PMID- 21671179 TI - Leptin activates STAT3 and ERK1/2 pathways and induces endometrial cancer cell proliferation. AB - Obesity is an established risk factor for endometrial cancer. Leptin, a secreted protein of the ob gene by white adipose tissue, plays an important role in the regulation of food intake and energy consumption in the brain and acts as a potential growth stimulator in normal and neoplastic cancer cells. However, a direct role for leptin in endometrial cancer has not been demonstrated. In the present study, the effect of leptin on the proliferation of Ishikawa endometrial cancer cells was investigated as well as the possible mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. The expression of leptin receptor (ObRb) in Ishikawa cells was detected by RT-PCR and Western blotting. The cells after serum starvation, were treated by leptin with various concentrations (0, 10, 50, 100, 150 ng/mL) for different durations (6, 12, 24 h). The effect of leptin treatment on cell proliferation was examined by MTT assay. Meanwhile, inhibitory effect of Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) inhibitor AG490 or extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 on the proliferation of Ishikawa cells induced by leptin was also studied. Ishikawa cells were treated with 100 ng/mL leptin for various periods (0, 20, 40, 60 min), and the levels of STAT3 phosphorylation and ERK1/2 phosphorylation were examined by Western blotting. The results showed that leptin induced the phosphorylation of STAT3 and the activation of ERK1/2 in a time- and dose-dependent manner in the Ishikawa endometrial cancer cells. Blocking STAT3 phosphorylation with the inhibitor AG490, or blocking ERK1/2 activation by the specific ERK1/2 kinase inhibitor, PD98059, abolished leptin-induced proliferation of Ishikawa cells. In addition, leptin was found to potently induce the invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of STAT3 (AG490) and ERK1/2 kinase (PD98059). These results suggested that leptin promotes endometrial cancer growth and invasiveness by activating STAT3 and ERK1/2 signaling pathways and therefore blocking its action at the receptor level can be a rational therapeutic strategy. PMID- 21671180 TI - Long-term impact of intrauterine MCMV infection on development of offspring nervous system. AB - This study examined the impacts of intrauterine murine cytomegalovirus (MCMV) infection on the long-term learning and memory of offspring. Sexually matured male and female BALB/C mice without MCMV infection were identified by ELISA and then mated. Seventy pregnant mice were randomly divided into the virus group (n=40) and the control group (n=30), in which the pregnant mice were subjected to placenta inoculation of MCMV suspension (1 MUL, 1*106 PFU) or the same amount of cell culture medium, respectively, at gestational age of 12.5 days. Some pregnant mice [virus group (n=20), control group (n=15)] were sacrificed by cervical dislocation at gestational age of 18.5 days, and the head circumference and brain weight of the mouse fetuses were measured, and the MCMV infection in their brain tissues was detected by PCR. The other pregnant mice [virus group (n=20), control group (n=15)] delivered naturally, and the learning and memory capability of the offspring at 70-day-old was analyzed by Morris water maze test. The results showed that 28.57% mouse fetuses in the virus group developed viral infection in the brain. Their head circumference and brain weight were significantly reduced as compared with those in the control group (P<0.01). The Morris water maze test revealed that the mouse offspring in the control group found the platform with straight-line trajectories after training. In contrast, the counterparts in the virus group intended to enter the central area, but looked for the platform with a circular trajectory. And the infected mice exhibited prolonged swimming distance and swimming latency (P<0.01). It was concluded that: (1) placenta inoculation of MCMV can cause fetal brain infection and intrauterine development retardation; (2) the offspring of MCMV placenta inoculation mice showed a long term decline in learning and memory capability. PMID- 21671181 TI - Effect of sublingual immunotherapy on level of cytokines in PBMCs of patients with allergic asthma. AB - This study examined the possible mechanism of sublingual immunotherapy (SLIT) in the treatment of allergic asthma. Forty asthma patients allergic to dust mite were enrolled. They received SLIT with dermatophagoides farinae (Der. f) drops for one year. Thirty healthy subjects served as controls. The levels of IL-4 and IFN-gamma of peripheral blood mononuclear cells (PBMCs) were determined in allergic asthma patients before and after the SLIT as well as the healthy subjects. The results showed that the level of IL-4 was substantially increased and that of IFN-gamma remarkably decreased in the patients before the SLIT as compared with those in the healthy subjects (P<0.05). After the SLIT, the level of IL-4 was significantly reduced and that of IFN-gamma elevated in these allergic asthma patients. It was concluded that sublingual immunotherapy is effective for patients with allergic asthma. And it may work by regulating the balance of Th1/Th2 through changing the expression of IL-4 and IFN-gamma in PBMCs. PMID- 21671182 TI - Effects of cinnamon granules on pharmacokinetics of berberine in Rhizoma Coptidis granules in healthy male volunteers. AB - The effects of Cinnamon granules on pharmacokinetics of berberine in Rhizoma Coptidis granules in healthy male volunteers, and the compatibility mechanism of Jiao-Tai-Wan (JTW) composed of Rhizoma Coptidis granules and Cinnamon granules were investigated. The concentration of berberine in plasma of healthy male volunteers was determined directly by high performance liquid chromatography (HPLC) after an oral administration of Rhizoma Coptidis granules alone or combined with Cinnamon granules (JTW). The plasma concentration-time curves of berberine were plotted. The data were analyzed with Drug and Statistics (DAS) 2.0 pharmacokinetic program (Chinese Pharmacology Society) to obtain the main pharmacokinetic parameters. The results showed that the plasma concentration-time curve of berberine was described by a two-compartment model. The C(max), T(max), t(1/2) and CLz/F of berberine in Rhizoma Coptidis granules were 360.883 MUg/L, 2.0 h, 3.882 h, 119.320 L.h(-1).kg(-1) respectively, and those of berberine in JTW were 396.124 MUg/L, 1.5 h, 4.727 h, 57.709 L.h(-1).kg(-1) respectively. It was suggested that Rhizoma Coptidis granules combined with Cinnamon granules could increase the plasma concentration of berberine, promote berberine absorption and lengthen the detention time of berberine in healthy male volunteers. PMID- 21671183 TI - Clinical characteristics and gene mutation analysis of methylmalonic aciduria. AB - Methylmalonic aciduria (MMA) is a common inherited autosomal recessive disorder resulting from defects in the enzyme methylmalonyl CoA mutase (MCM, mut complementation group) or in the synthesis of the MCM cofactor adenosylcobalamin (cbl complementation groups). The defects in the mut complementation group accounts for the largest number of patients with isolated MMA. At least 200 mutations in the MUT gene on chromosome 6p12 have been identified in MMA patients until now. This study aimed to investigate the clinical characteristics of MMA and genomic variations in the MUT gene of Chinese patients. Genomic DNA was extracted from 18 patients who were diagnosed as having isolated MMA by gas chromatography/mass spectrometry (GC-MS), and from some of their parents as well. Amplification and direct sequencing of the MUT coding regions (exon 2-13) and their adjacent intronic consensus splice sites were performed in order to identify the disease causing mutations. In this group, six novel mutations in the MUT gene, c.424A>G (p.T142A), c.786T>G (p.S262R), c.808G>C (p.G270R), c.1323_1324insA, c.1445-1G>A and c.1676+77A>C were identified. p.T142A and p.G270R were respectively detected at a heterozygous level in one patient. Two previously reported mutations, c.682C>T (p.R228X) and c.323G>A (p.R108H) were also found in this study. In addition, six previously described single nucleotide polymorphism (SNP), c.636A>G (p.K212K), c.1495G>A (p.A499T), c.1595A>G (p.H532R), c.1992G>A (p.A664A), c.2011G>A (p.V671I) and c.1677-53A>G were identified. In this study, we updated the spectrum of MUT mutations and identified the main MMA causing mutations in Chinese MMA patients. PMID- 21671184 TI - Non-thermal plasma suppresses bacterial colonization on skin wound and promotes wound healing in mice. AB - The present study evaluated the effect of non-thermal plasma on skin wound healing in BalB/c mice. Two 6-mm wounds along the both sides of the spine were created on the back of each mouse (n=80) by using a punch biopsy. The mice were assigned randomly into two groups, with 40 animals in each group: a non-thermal plasma group in which the mice were treated with the non-thermal plasma; a control group in which the mice were left to heal naturally. Wound healing was evaluated on postoperative days (POD) 4, 7, 10 and 14 (n=5 per group in each POD) by percentage of wound closure. The mice was euthanized on POD 1, 4, 7, 10, 14, 21, 28 and 35 (n=1 in each POD). The wounds were removed, routinely fixed, paraffin-embedded, sectioned and HE-stained. A modified scoring system was used to evaluate the wounds. The results showed that acute inflammation peaked on POD 4 in non-thermal plasma group, earlier than in control group in which acute inflammation reached a peak on POD 7, and the acute inflammation scores were much lower in non-thermal group than in control group on POD 7 (P<0.05). The amount of granular tissue was greater on POD 4 and 7 in non-thermal group than in control group (P<0.05). The re-epithelialization score and the neovasularization score were increased significantly in non-thermal group when compared with control group on POD 7 and 10 (P<0.05 for all). The count of bacterial colonies was 10(3) CFU/mL on POD 4 and <20 CFU/mL on POD 7, significantly lower than that in control group (10(9) CFU/mL on POD 4 and >10(12) CFU/mL on the POD 7) (P<0.05). It was suggested that the non-thermal plasma facilitates the wound healing by suppressing bacterial colonization. PMID- 21671185 TI - Analgesic effect of diprospan in rats with trigeminal neuralgia. AB - This study examined the analgesic effect of diprospan in rats with trigeminal neuralgia. Rat model of trigeminal neuralgic pain was established by loosely ligating the left infraorbital branch of the trigeminal nerve. After allodynia developed, the rats were randomly divided into 2 groups (n=20 in each): diprospan group, in which the rats received diprospan (7 mg/mL, 0.1 mL) injected to the left infraorbital foramen area; control group, in which saline (0.1 mL) was administered as the same manner as the diprospan group. The pain threshold (PT) in the left infraorbital area was measured before and 2, 6, and 8 weeks after the administration. The expression of neuropeptides [substance P, preprotachykinin A (PPTA), calcitonin gene-related peptide (CGRP)] in the trigeminal nerve was detected at the same time points as the PT measurement by immunohistochemistry or in situ hybridization method. The results showed that in the diprospan group, the PT was 10.65 +/- 1.26, 10.77 +/- 1.19 and 14.13 +/- 1.34 g 2, 6, and 8 weeks after the administration respectively, significantly higher than that before the administration (PT value: 0.36 +/- 0.11) (P<0.05 for each). In the saline group, the PT was 0.37 +/- 0.13, 0.66 +/- 0.09, 4.45 +/- 1.29 and 13.72 +/- 1.72 g before and 2, 6, and 8 weeks after the administration respectively with differences being significant between before and 6, 8 weeks after the administration (P<0.01). No significant difference existed in the PT between the diprospan group and the saline group at pre-administration (P>0.05). The PT in the diprospan group was significantly greater than that in the saline group 2 and 6 weeks post-administration (P<0.05). In the diprospan group, the expression levels of neuropeptides were significantly reduced as compared with those in the saline group 2 and 6 weeks post-administration (P<0.05). It was concluded that diprospan has an obvious analgesic effect on the trigeminal neuropathic pain partly by reducing the expression of neuropeptides in the trigeminal ganglia. PMID- 21671186 TI - Culture of rat retinal ganglion cells. AB - This study aimed to modify the mixed and purified culture of rat retinal ganglion cells (RGCs) in vitro. The retinae of 1-3 day old Sprague-Dawley (SD) rats were separated bluntly into two layers: inner layer and outer layer, under a surgical microscope. Retinal cells isolated from different layers (inner layer, outer layer and whole retinal tissue) by using enzyme dissociation method were cultured in F12/DMEM medium containing 15% FBS. After 3-day culture, the RGCs in the retinal cells obtained from mixed culture of inner, outer, and whole retinal tissue were identified by immunocytochemical staining of Thy-1.1, and the rate of RGCs to retinal cells (RGCs%) was calculated. Two monoclonal antibodies, anti macrophages/granulocytes (OX-41) against rat macrophage and antibody against rat Thy-1.1 (OX-7), were used to purify RGCs by either a conventional or modified two stepped immunopanning procedure (purification in situ). Purified RGCs were seeded at different cell density and cultured in F12/DMEM medium containing 15% FBS. Immunocytochemical staining for Thy-1.1, MTT, and PI-Hoechst33342 fluorescence imaging were used to identify the purity and the viability of RGCs in purified culture of RGCs. The results showed: (1) Immunocytochemistry of different retinal tissue layers culture revealed that the RGCs% was (19.9 +/- 1.2)%, (0.5 +/- 0.2)%, and (6.2 +/- 1.7)% respectively in the mixed culture of inner, outer, and whole retinal tissue, with differences being significant (P<0.05); (2) fluorescent double staining of Hoechst33342 and PI indicated that with the same RGCs%, RGCs obtained from purification in situ grew well with more neurite outgrowth than those by the conventional two-stepped immunopanning method; (3) the viability of purified RGCs seeded at high density was increased and the cells developed complex intercellular networks. The viability of RGCs was declined with the decreasing seeding density, and most cells presented round or oval in shape with thin neurites. It was concluded that: (1) RGCs% in the inner layer retina was higher than that in the outer layer retina; (2) RGCs obtained by in situ purification had more neurite outgrowth and lower mortality than those by conventional two-stepped immunopanning procedure; (3) the viability of purified RGCs could be increased by increasing cell seeding density to some extent. PMID- 21671187 TI - Surgical treatment for complications of congenital retinoschisis. AB - This study examined the clinical features of complications of congenital retinoschisis and the clinical efficacy of vitreoretinal surgery in the treatment of these complications. The clinical efficacy of surgical treatments was retrospectively analyzed in 10 patients with congenital retinoschisis (10 eyes) complicated with rhegmatogenous retinal detachment (n=5), vitreous hemorrhage (n=2) and macula- involving schisis (n=1). All the patients suffered foveal and peripheral schisis. They were treated with scleral buckling (n=1) or vitrectomy (n=9). After the surgical treatment, the retina was reattached in patients with rhegmatogenous retinal detachment; the refractive media became transparent in those with vitreous hemorrhage; the visual acuity in 80% of patients was improved; no remarkable progression of schisis was found; no severe operative complications occurred. It was concluded that vitreoretinal surgery in the treatment of complications of congenital retinoschisis is safe and effective, and helps improve and maintain the visual function. PMID- 21671188 TI - Correlation between distribution of Helicobacter pylori in oral cavity and chronic stomach conditions. AB - In this study, the colonization and distribution of Helicobacter pylori (Hp) in patients with chronic gastric diseases were investigated and the relationship between the periodontal initial treatment and presence of Hp in oral cavity was examined to better understand the connection between Hp infection and chronic diseases. Primers for PCR amplification were designed according to ureC gene and cagA genes of Hp. Specimens were harvested from different sites of 96 patients with chronic gastric diseases and the specimens of dental plaques, gargles and dorsal mucosa were tested for Hp. The 96 patients were treated by bismuth triple therapy and among them, 52 subjects were additionally given periodontal initial therapy. The eradication rate of gastric Hp and oral Hp detection rate were determined 4 weeks and 1 year after the treatment. The results showed that the detection rates of oral specimens were in the order of dental plaques (82.3%), gargles (51.1%) and scrapings of dorsal mucosa of tongue (37.5%). One year after bismuth triple therapy or the triple therapy in combination with periodontal initial treatment, the eradication rate of gastric Hp was significantly higher in the combination treatment group than in group treated by the triple therapy alone (62.8% vs. 32.4%, P<0. 05). Moreover, the Hp detection rate was significantly lower in the combination group than in the group treated only with the triple therapy. We are led to conclude that Hp is present at various parts of oral cavity, oral Hp might be an important source of gastric Hp and the triple therapy plus periodontal initial treatment can enhance the long-term eradication rate of gastric Hp in patient with both chronic gastric diseases and chronic periodontitis. PMID- 21671189 TI - Evaluation of airway obstruction at soft palate level in male patients with obstructive sleep apnea/hypopnea syndrome: dynamic 3-dimensional CT imaging of upper airway. AB - This study examined the dynamic characteristics of upper airway collapse at soft palate level in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) by using dynamic 3-Dimensional (3-D) CT imaging. A total of 41 male patients who presented with 2 of the following symptoms, i.e., daytime sleepiness and fatigue, frequent snoring, and apnea with witness, were diagnosed as having OSAHS. They underwent full-night polysomnography and then dynamic 3-D CT imaging of the upper airway during quiet breathing and in Muller's maneuver. The soft palate length (SPL), the minimal cross-sectional area of the retropalatal region (mXSA-RP), and the vertical distance from the hard palate to the upper posterior part of the hyoid (hhL) were compared between the two breathing states. These parameters, together with hard palate length (HPL), were also compared between mild/moderate and severe OSAHS groups. Association of these parameters with the severity of OSAHS [as reflected by apnea hypopnea index (AHI) and the lowest saturation of blood oxygen (LSaO(2))] was examined. The results showed that 31 patients had severe OSAHS, and 10 mild/moderate OSAHS. All the patients had airway obstruction at soft palate level. mXSA-RP was significantly decreased and SPL remarkably increased during Muller's maneuver as compared with the quiet breathing state. There were no significant differences in these airway parameters (except the position of the hyoid bone) between severe and mild/moderate OSAHS groups. And no significant correlation between these airway parameters and the severity of OSAHS was found. The position of hyoid was lower in the severe OSAHS group than in the mild/moderate OSAHS group. The patients in group with body mass index (BMI)>=26 had higher collapse ratio of mXSA-RP, greater neck circumference and smaller mXSA RP in the Muller's maneuver than those in group with BMI<26 (P<0.05 for all). It was concluded that dynamic 3-D CT imaging could dynamically show the upper airway changes at soft palate level in OSAHS patients. All the OSAHS patients had airway obstruction of various degrees at soft palate level. But no correlation was observed between the airway change at soft palate level and the severity of OSAHS. The patients in group with BMI>=26 were more likely to develop airway obstruction at soft palate level than those with BMI<26. PMID- 21671190 TI - Neuroanatomical changes associated with cognitive aging. AB - The literature on the neuroanatomical changes that occur during normal, non demented aging is reviewed here with an emphasis on the improved accuracy of studies that use stereological techniques. Loss of neural tissue involved in cognition occurs during aging of humans as well as the other mammals that have been examined. There is considerable regional specificity within the cerebral cortex and the hippocampus in both the degree and cellular basis for loss. The anatomy of the prefrontal cortex is especially vulnerable to the effects of aging while the major subfields of the hippocampus are not. A loss of neurons, dendrites and synapses has been documented, as well as changes in neurotransmitter systems, in some regions of the cortex and hippocampus but not others. Species differences are also apparent in the cortical white matter and the corpus callosum where there are indications of loss of myelin in humans, but most evidence favors preservation in rats. The examination of whether the course of neuroanatomical aging is altered by hormone replacement in females is just beginning. When hormone replacement is started close to the time of cycle cessation, there are indications in humans and rats that replacement can preserve neural tissue but there is some variability due to the type of hormones and regimen of administration. PMID- 21671191 TI - The challenge of studying parallel behaviors in humans and animal models. AB - The use of animal models is essential in carrying out research into clinical phenomena such as addiction. However, the complexity of the clinical condition inevitably means that even the best animal models are inadequate representations of the condition they seek to mimic. Such mismatches may account for apparent inconsistencies between discoveries in animal models, including the identification of potential novel therapies, and the translation of such discoveries to the clinic. We argue that it is overambitious to attempt to model human disorders such as addiction in animals, and especially in rodents, where "validity" of such models is often limited to superficial similarities, referred to as "face validity" that reflect quite different underlying phenomena and biological processes from the clinical situation. Instead, we suggest a more profitable approach may be to identify (a) well-defined intermediate human behavioral phenotypes that reflect defined, limited aspects of the human clinical disorder, and (b) to develop animal models that are homologous with those discrete human behavioral phenotypes in terms of psychological processes, and underlying neurobiological mechanisms. Examples of current weaknesses and suggestions for more limited approaches that may allow better homology between the test animal and human condition are made. PMID- 21671192 TI - Evaluation of the use of recN sequence analysis in the phylogeny of the genus Amycolatopsis. AB - Partial recN gene sequences (>1 kb) were obtained from 35 type strains of the genus Amycolatopsis. Phylogenetic trees were constructed to determine the effectiveness of using this gene to predict taxonomic relationships within the genus. The use of recN sequence analysis as an alternative to DNA-DNA hybridization (DDH) for distinguishing closely related species was also assessed. The recN based phylogeny mostly confirmed the conventional 16S rRNA and gyrB gene based phylogenies and thus provides further support for these phylogenetic groupings. As is the case for the gyrB gene, pairwise recN sequence similarities cannot be used to predict the DNA relatedness between type strains but the recN genetic distance can be used as a means to assess quickly whether an isolate is likely to represent a new species in the genus Amycolatopsis. A recN genetic distance of >0.04 between two Amycolatopsis strains is proposed to provide a good indication that they belong to different species (and that polyphasic taxonomic characterization of the unknown strain is worth undertaking). PMID- 21671193 TI - A new methanol assimilating yeast, Ogataea parapolymorpha, the ascosporic state of Candida parapolymorpha. AB - Ogataea parapolymorpha sp. n. (NRRL YB-1982, CBS 12304, type strain), the ascosporic state of Candida parapolymorpha, is described. The species appears homothallic, assimilates methanol as is typical of most Ogataea species and forms hat-shaped ascospores in asci that become deliquescent. O. parapolymorpha is closely related to Ogataea angusta and Ogataea polymorpha. The three species can be resolved from gene sequence analyses but are unresolved from fermentation and growth reactions that are typically used for yeast identification. On the basis of multiple isolates, O. angusta is known only from California, USA, in association with Drosophila and Aulacigaster flies, O. parapolymorpha is predominantly associated with insect frass from trees in the eastern USA but O. polymorpha has been isolated from various substrates in the USA, Brazil, Spain and Costa Rica. PMID- 21671194 TI - Bacillus rhizosphaerae sp. nov., an novel diazotrophic bacterium isolated from sugarcane rhizosphere soil. AB - A Gram-positive, non-pigmented, rod-shaped, diazotrophic bacterial strain, designated SC-N012(T), was isolated from rhizosphere soil of sugarcane and was subjected to a polyphasic taxonomic study. The strain exhibited phenotypic properties that included chemotaxonomic characteristics consistent with its classification in the genus Bacillus. Sequence analysis of the 16S rRNA gene of SC-N012(T) revealed the closest match (98.9% pair wise similarity) with Bacillus clausii DSM 8716(T). However, DNA-DNA hybridization experiments indicated low levels of genomic relatedness (32%) with this strain. The major components of the fatty acid profile are iso-C(15:0), anteiso-C(15:0), iso-C(17:0) and anteiso C(17:0). The diagnostic cell-wall diamino acid was meso-diaminopimelic acid. The G+C content of the genomic DNA is 43.0 mol%. The lipids present in strain SC N012(T) are diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol and two unknown phospholipids. Their predominant respiratory quinone was MK-7. Studies of DNA-DNA relatedness, morphological, physiological and chemotaxonomic analyses and phylogenetic data based on 16S rRNA gene sequencing allowed strain SC-N012(T) to be described as members of novel species of the genus Bacillus, for which the name Bacillus rhizosphaerae sp. nov. is proposed. The type strain is SC-N012(T) (=DSM 21911(T) = NCCB 100267(T)). PMID- 21671195 TI - Isolation and characterisation of bacteria from the Eastern Mediterranean deep sea. AB - The Eastern Mediterranean deep sea is one of the most oligotrophic regions in the world's ocean. With the aim to classify bacteria from this special environment we isolated 107 strains affiliating to the Gammaproteobacteria, Alphaproteobacteria, Firmicutes, Actinobacteria and Bacteroidetes from sediments of the Eastern Mediterranean Sea. As determined by 16S rRNA gene sequence analysis, Actinobacteria and Firmicutes, in particular members of the genus Bacillus, were dominant and represented a remarkable diversity with 27 out of a total of 33 operational taxonomic units obtained from the untreated sediment. The considerable percentage of operational taxonomic units (42%) which may be considered to be new species underlines the uniqueness of the studied environment. In order to selectively enrich bacteria which are adapted to the deep-sea conditions and tolerate broad pressure ranges, enrichments were set up with a sediment sample under in situ pressure and temperature (28 MPa, 13.5 degrees C) using N-acetyl-D: -glucosamine as substrate. Interestingly Gammaproteobacteria were significantly enriched and dominant among the strains isolated after pressure pre-incubation. Obviously, Gammaproteobacteria have a selective advantage under the enrichment conditions applied mimicking nutrient supply under pressure conditions and cope well with sudden changes of hydrostatic pressure. However, under the continued low nutrient situation in the Eastern Mediterranean deep-sea sediments apparently Firmicutes and Actinobacteria have a clear adaptative advantage. PMID- 21671196 TI - Nocardiopsis yanglingensis sp. nov., a thermophilic strain isolated from a compost of button mushrooms. AB - A strain named A18 was recovered from a compost of button mushrooms. It was characterized using a polyphasic approach. On the basis of 16S rRNA gene sequence comparison, it belonged to the genus Nocardiopsis and was most closely related to the type strains of Nocardiopsis flavescens (sequence similarity 98.0%), Nocardiopsis prasina (97.5%), Nocardiopsis metallicus (97.4%), Nocardiopsis alba (97.3%). The combination of phylogenetic analysis, DNA-DNA hybridization, phenotypic characteristics and chemotaxonomic data supported the proposal that strain A18 represents a new species of the genus Nocardiopsis, for which the name Nocardiopsis yanglingensis sp. nov. was proposed (type strain A18(T) = KCTC 19723(T) = CCTCC 209063(T)). PMID- 21671197 TI - Oxidative stress in older adults: effects of physical fitness. AB - Acute exercise results in transient change in redox balance. High concentrations of reactive oxygen species (ROS) can lead to oxidative damage to macromolecules. However, moderate periodic increases in ROS, such as experienced with habitual exercise, may activate signal transduction pathways which stimulate increases in endogenous antioxidant systems. This study tested the hypothesis that physically fit older adults would have less oxidative stress than unfit age-matched controls, due to greater circulating concentrations of non-enzymatic antioxidants and greater capacity to upregulate antioxidant enzymes. We compared 37 fit (mean age 65.2 +/- 5 years) and 35 unfit (mean age 67.7 +/- 4 years) men and women. Fitness status was classified by VO(2 max) and maximal leg power. Basal levels of oxidative stress were assessed by measuring urinary markers of nucleic acid damage and lipid peroxidation. Antioxidant status was assessed by measuring total antioxidant power and ratios of reduced to oxidized glutathione in plasma, at rest. The capacity to counteract an oxidative insult was assessed by measuring changes in plasma F(2)-isoprostanes in response to forearm ischemia-reperfusion. The fit individuals had significantly lower levels of urinary markers of oxidative damage (all P <0.05) and lower F(2)-isoprostane response to the oxidative challenge (P < 0.05), but there were no group differences in antioxidant status. The lower levels of oxidative stress in the fit individuals were not mediated by known effects of exercise training such as adiposity, HDL concentrations, or small molecular weight antioxidants. These data suggest that reduced oxidative stress associated with physical fitness results from differences in activity of antioxidant enzymes. PMID- 21671198 TI - The evolution of family complexity from the perspective of nonmarital children. AB - We document the incidence and evolution of family complexity from the perspective of children. Following a cohort of firstborn children whose mothers were not married at the time of their birth, we consider family structure changes over the first 10 years of the child's life-considering both full and half-siblings who are coresidential or who live in another household. We rely on detailed longitudinal administrative data from Wisconsin that include information on the timing of subsequent births to the mother and father, and detailed information on earnings, child support, and welfare. We find that 60% of firstborn children of unmarried mothers have at least one half-sibling by age 10. Our results highlight the importance of having fertility information for both fathers and mothers: estimates of the proportion of children with half-siblings would be qualitatively lower if we had fertility information on only one parent. Complex family structures are more likely for children of parents who are younger or who have low earnings and for those in larger urban areas. Children who have half-siblings on their mother's side are also more likely to have half-siblings on their father's side, and vice versa, contributing to very complex family structures-and potential child support arrangements-for some children. PMID- 21671199 TI - Nanovesicular formulation of brimonidine tartrate for the management of glaucoma: in vitro and in vivo evaluation. AB - In this study, nanovesicles were developed for brimonidine tartrate by film hydration technique and dispersed in viscous carbopol solution for ocular delivery. Scanning electron microscopy revealed spherical shape of the vesicles. As high as 32.27% drug entrapment efficiency was achieved depending upon the surfactant/cholesterol molar ratio (7:4 to 7:8). The vesicles were in the size range of 298.0-587.9 nm. Release study showed a biphasic drug-release pattern for the lyophilized vesicular formulation in buffered saline solution, i.e., initial burst release followed by gradual release over the period of 8 h. On contrary, the isolated vesicles reduced the burst effect in 3 h by two to three times and the drug release was comparatively slower at the intermediate ratio in both cases. With variation in cholesterol content, the drug release followed either first order or Higuchi's kinetics. Physically the lyophilized vesicular formulations were more stable at refrigerated temperature. DSC and X-RD analyses indicated loss of drug crystallinity in the vesicles. FTIR spectroscopy did not reveal any interaction between drug and excipients. The lyophilized formulation showed better ocular hypotensive activity than marketed drops on albino rabbits and in vivo efficacy was sustained up to 7.5 h. Furthermore, the formulation was found to be non-irritant to the rabbit eye. Hence, the lyophilized vesicles, when dispersed in viscous carbopol solution, had the potential in reducing dosing frequency and could improve patient compliance. PMID- 21671200 TI - Polymorph transformation in paracetamol monitored by in-line NIR spectroscopy during a cooling crystallization process. AB - The reliable in-line monitoring of pharmaceutical processes has been regarded as a key tool toward the full implementation of process analytical technology. In this study, near-infrared (NIR) spectroscopy was examined for use as an in-line monitoring method of the paracetamol cooling crystallization process. The drug powder was dissolved in ethanol-based cosolvent at 60 degrees C and was cooled by 1 degrees C/min for crystallization. NIR spectra acquired by in-line measurement were interpreted by principal component analysis combined with off-line characterizations via X-ray diffraction, optical microscopy, and transmission electron microscopy. The whole crystallization process appeared to take place in three steps. A metastable form II polymorph of paracetamol was formed and transformed into the stable form I polymorph on the way to the growth of pure form I by cooling crystallization. These observations are consistent with a previous focused beam reflectance method-based study (Barthe et al., Cryst Growth Des 8:3316-3322, 2008). PMID- 21671201 TI - The effect of sterilization methods on the physical properties of silk sericin scaffolds. AB - Protein-based biomaterials respond differently to sterilization methods. Since protein is a complex structure, heat, or irradiation may result in the loss of its physical or biological properties. Recent investigations have shown that sericin, a degumming silk protein, can be successfully formed into a 3-D scaffolds after mixing with other polymers which can be applied in skin tissue engineering. The objective of this study was to investigate the effectiveness of ethanol, ethylene oxide (EtO) and gamma irradiation on the sterilization of sericin scaffolds. The influence of these sterilization methods on the physical properties such as pore size, scaffold dimensions, swelling and mechanical properties, as well as the amount of sericin released from sericin/polyvinyl alcohol/glycerin scaffolds, were also investigated. Ethanol treatment was ineffective for sericin scaffold sterilization whereas gamma irradiation was the most effective technique for scaffold sterilization. Moreover, ethanol also caused significant changes in pore size resulting from shrinkage of the scaffold. Gamma-irradiated samples exhibited the highest swelling property, but they also lost the greatest amount of weight after immersion for 24 h compared with scaffolds obtained from other sterilization methods. The results of the maximum stress test and Young's modulus showed that gamma-irradiated and ethanol-treated scaffolds are more flexible than the EtO-treated and untreated scaffolds. The amount of sericin released, which was related to its collagen promoting effect, was highest from the gamma-irradiated scaffold. The results of this study indicate that gamma irradiation should have the greatest potential for sterilizing sericin scaffolds for skin tissue engineering. PMID- 21671202 TI - The re-shaping of the life-world: male British Bangladeshi smokers and the English smoke-free legislation. AB - OBJECTIVE: To explore how male Bangladeshi smokers adapted to the English smoke free legislation. DESIGN: We draw on data derived from the Evaluation of Smoke free England (ESME), a qualitative, longitudinal study conducted between 2007 and 2008 in two English metropolitan areas. Repeat interviews (n = 34) were conducted before and after the legislation with 15 male Bangladeshi panel informants and from two focus groups: one with Bangladeshi men and the other with Bangladeshi women. RESULTS: Bangladeshi smokers who participated in this study had largely accommodated to the smoke-free legislation and most had reduced their consumption of cigarettes, albeit to a modest degree. However, at the same time some Bangladeshi smokers appeared to have increased their use of shisha, a popular alternative method of smoking tobacco in this community. Smoke-free legislation also had an impact on the social and cultural forces that shape smoking behaviour in this group. In particular, family homes continued to be a key space where tobacco is consumed, although the legislation may have helped to shift the balance in favour of forces that oppose smoking and against enduring cultural pro smoking norms. Smoking in public was also less socially acceptable, especially in the vicinity of local mosques and at community events. In some older groups, however, smoking remains a deeply embedded social habit which can undermine smokers' efforts to quit. CONCLUSION: For maximum impact, tobacco control interventions aimed at whole populations may need to be supplemented by culturally sensitive measures in local areas where there is a high concentration of Bangladeshi people. Similar considerations may apply to other minority communities with a high prevalence of smoking. PMID- 21671203 TI - Apostolic faith church organization contexts for health and wellbeing in women and children. AB - OBJECTIVE: The study explored contexts for health and wellbeing for women and children influenced by the structural behavior of an Apostolic faith church organization in Zimbabwe. METHODS: Twenty-three purposively selected members of an African indigenous Apostolic church (males = 12; females = 11; age range 22-95 years) were informants to a focus group discussion session. They provided data on the institutional behaviors that were culturally-historically embedded in the organization's activities. Data were analyzed thematically and using cultural historical activity theory (CHAT) to foreground essential themes. RESULTS: The church organization provided social capital to support health and wellbeing in members. However, the culturally embedded practices to minimize decision making by women and child members potentially compromised their health and wellbeing. CONCLUSION: The findings suggest that the structural activities of the church for health and wellbeing could also have the paradoxical effect of exposing women and children to health risks from obligatory roles. PMID- 21671205 TI - Framing effects: the influence of handedness and access to right hemisphere processing. AB - Changing how information is framed, such that the same critical information is cast in a positive or negative light, has a powerful impact on judgements and decision making. Research indicates that the influence of frames may be driven by participants' initial affective response and that the right hemisphere is sensitive to the emotional connotation of stimuli. While previous research tested the effects of hemispheric differences on framing effects by inducing asymmetrical activation, the current study explored how stable brain differences may account for differences in susceptibility to framing effects. Because mixed degree of handedness is associated with increased access to right hemisphere processes, mixed-handed participants were expected to be more susceptible to the effects of framing than strong-handed participants. Participants responded to the Asian disease problem and completed as assessment of handedness. Although mixed- and strong-handed participants were affected differently, the results were not consistent with the hypothesis. Mixed-handed participants conformed to risky choice framing effects when options were framed negatively and showed no effect of the positive frame. Strong-handed participants conformed to positively framed options and showed no effect of the negative frame. Possible explanations are discussed. PMID- 21671204 TI - Molecular detection of Pseudomonas aeruginosa in recreational water. AB - The aim of this study was the development of a new molecular assay for Pseudomonas aeruginosa identification in recreational water. The method includes bacterial cell concentration through membrane filtration, a short (6 h) culture enrichment step, DNA extraction and its amplification through a Real-Time PCR assay. The performance of the molecular approach was evaluated on 44 samples of swimming pool water and compared with the reference method UNI EN ISO 16266:2008. Positivity rates of 6% and 74% in pool and inlet water, respectively, with the standard culture method, and of 23% and 74% with the molecular method were found. Statistical analysis indicated "substantial agreement" (Cohen's Kappa index: 0.6831) between the two approaches. RAPD typing of P. aeruginosa isolates showed identical fingerprint profiles, indicating their epidemiological correlation. The developed protocol showed very high specificity and a detection limit of 10 genomic units. This technique has the potential to screen large numbers of environmental samples, and could be proposed as part of a self-monitoring plan for recreational facilities, improving surveillance and early warning systems. PMID- 21671206 TI - Triterpenoids with neurotrophic activity from Ganoderma lucidum. AB - A new triterpenoid, 4,4,14alpha-trimethyl-5alpha-chol-7,9(11)-dien-3-oxo-24-oic acid (1), together with seven known triterpenoids, were isolated from the dried fruiting bodies of Ganoderma lucidum. Their structures were elucidated by extensive spectroscopic analyses. Bioassay results revealed that compounds 1 and methyl ganoderic acid B (5) had nerve growth factor-like neuronal survival promoting effects, whereas compounds 1, and 4-7 showed brain-derived neurotrophic factor-like neuronal survival-promoting activities. PMID- 21671207 TI - Purification and anticancer activity investigation of pentacyclic triterpenoids from the leaves of Sinojackia sarcocarpa L.Q. Luo by high-speed counter-current chromatography. AB - Sinojackia sarcocarpa L.Q. Luo has high aesthetic value, which is clinically used to treat diseases such as the variations of arthritis, thromboangiitis obliterans, angina pectoris as well as many other diseases. Pentacyclic triterpenoids are the main pharmacological effective compounds. High-speed counter-current chromatography method was performed on a Midi-DE centrifuge at 25 degrees C. The solvent system was n-hexane-ethylacetate-methanol-water (10:5:3:1, v/v). Peak fractions were collected according to the elution profile for subsequent high-performance liquid chromatography analysis. The structure identification was performed by ultraviolet, infrared, mass spectrometry, (1)H NMR and (13)C-NMR. Compound 2alpha,3alpha,19beta,23beta-tetrahydroxyurs-12-en-28 oic acid and 2alpha,3alpha,23beta-trihydroxyurs-12-en-28-oic acid were purified from the plant of Styracaceaen genius for the first time, whose purities were 96.57% and 97.33%, respectively. Compared with the same dose of oral 5 fluorouracil with 57.6% inhibition rate, the S(180) tumour inhibition rates of 20 mg kg(-1)d(-1) two compounds were 59.5% and 48.9%, respectively. PMID- 21671218 TI - The ability of phased-array MRI in preoperative staging of primary rectal cancer: correlation with histopathological results. AB - PURPOSE: This study evaluated the accuracy of phased-array magnetic resonance imaging (MRI) for preoperative local tumor staging in primary rectal cancer and emphasized the importance of the preoperative differentiation of T2 tumors from T3 tumors so the appropriate treatment can be applied. MATERIALS AND METHODS: Twenty-four patients with primary rectal cancer were examined preoperatively using 1.5 T MRI with a phased-array coil. Multiplanar T2-weighted images were obtained. Rectum anatomy, depth of tumor invasion, mesorectal involvement and lymph nodes were assessed. All patients underwent radical surgery. The histological sections were evaluated microscopically. The correlation of magnetic resonance imaging and histopathology was assessed using the kappa statistic. Overstaging with MRI was compared with Fischer's exact test. RESULTS: Histopathological examination of the tumors revealed adenocarcinoma. When the tumors were staged, there was one patient with a pT1 tumor, six patients with pT2 tumors, and 17 patients with pT3 tumors. Using MRI, four patients with pT2 were overstaged as T3, and one patient with pT3 was overstaged as T4. In the remaining cases (one pT1, two pT2, and 16 pT3), MRI correctly assessed the stage of transmural invasion. The accuracy of T staging and metastatic lymph node detection with MRI was calculated as 79.2% and 58.5%, respectively. CONCLUSION: Phased-array MRI is a valuable technique for the preoperative staging of rectal cancer, especially in the differentiation of T2 and T3 tumors. PMID- 21671219 TI - Drosophila mechanoreceptors as a model for studying asymmetric cell division. AB - Asymmetric cell division (ACD) is one of the processes creating the overall diversity of cell types in multicellular organisms. The essence of this process is that the daughter cells exit from it being different from both the parental cell and one another in their ability to further differentiation and specialization. The large bristles (macrochaetae) that are regularly arranged on the surface of the Drosophila adult function as mechanoreceptors, and since their development requires ACD, they have been extensively used as a model system for studying the genetic control of this process. Each macrochaete is composed of four specialized cells, the progeny resulting from several ACDs from a single sensory organ precursor (SOP) cell, which differentiates from the ectodermal cells of the wing imaginal disc in the third-instar larva and pupa. In this paper we review the experimental data on the genes and their products controlling the ACDs of the SOP cell and its daughter cells, and their further specialization. We discuss the main mechanisms determining the time when the cell enters ACD, as well as the mechanisms providing for the structural characteristics of asymmetric division, namely, polar distribution of protein determinants (Numb and Neuralized), orientation of the division spindle relative to these determinants, and unequal segregation of the determinants specifying the direction of daughter cell development. PMID- 21671220 TI - Could modifications of signalling pathways activated after ICSI induce a potential risk of epigenetic defects? AB - A calcium signal during oocyte or egg activation is a conserved event in virtually all species analyzed so far. This signal, that is in the form of calcium oscillations in mammals, is spatially and temporally controlled and is mainly supported by calcium release from internal calcium stores, but how it is triggered after fertilization is far from understood. The sperm factor hypothesis of egg activation postulates that sperm delivers a calcium-releasing factor into the egg following sperm-egg fusion. Among the many potential sperm factors, PLCzeta is the strongest bona fide sperm factor candidate. However, how sperm oocyte fusion occurs prior to PLCzeta delivery and oocyte activation is not entirely known. We propose in the first part of this review the possibility that other pathways such as those involving G-proteins, tyrosine kinases or integrins could be activated besides sperm factor injection and could be upstream mechanisms involved in later embryonic development. Among different assisted reproductive technologies (ARTs), intracytoplasmic sperm injection (ICSI) is considered as the best and easiest therapeutic technique to circumvent severe male infertility. Although most reports are reassuring, some recent data suggest a greater incidence of abnormalities in children conceived by ART compared with those conceived normally. Spatio-temporal signals may be missing or abnormal during ICSI, perhaps because membrane fusion and signalling events are bypassed. We discuss in the second part of this review the hypothesis that potential perturbations during the ICSI procedure may have repercussions on epigenetic processes, inducing not only alterations of embryonic development, but also diseases in young children and, perhaps, in adults. PMID- 21671221 TI - Altered patterns of differentiation in karyotypically abnormal human embryonic stem cells. AB - Upon prolonged culture, human embryonic stem (hES) cells undergo adaptation, exhibiting decreased population doubling times and increased cloning efficiencies, often associated with karyotypic changes. To test whether culture adaptation influences the patterns of differentiation of hES cells, we compared the expression of genes indicative of distinct embryonic lineages in the embryoid bodies produced from two early passage, karyotypically normal hES cell lines, and two late passage, karyotypically abnormal hES cell lines. One of the abnormal lines was a subline of one of the normal early passage lines. The embryoid bodies from each of the lines showed evidence of extensive differentiation. However, there were differences in the expression of several genes, indicating that the culture adapted hES cells show altered patterns of differentiation compared to karyotypically normal hES cells. The loss of induction of alphafetoprotein in the culture-adapted cells was especially marked, suggesting that they had a reduced capacity to produce extra-embryonic endoderm. These changes may contribute to the growth advantages of genetically variant cells, not only by reflecting an increased tendency to self renewal rather than to differentiate, but also by reducing spontaneous differentiation to derivatives that themselves may produce factors that could induce further differentiation of undifferentiated stem cells. PMID- 21671222 TI - Induced in vitro differentiation of neural-like cells from human exfoliated deciduous teeth-derived stem cells. AB - Stem cells from human exfoliated deciduous teeth (SHED) are highly proliferative, clonogenic and multipotent stem cells with a neural crest cell origin. Additionally, they can be collected with minimal invasiveness in comparison with other sources of mesenchymal stem cells (MSCs). Therefore, SHED could be a desirable option for potential therapeutic applications. In this study, SHEDs were established from enzyme-disaggregated deciduous dental pulp obtained from 6 to 9 year-old children. The cells had typical fibroblastoid morphology and expressed antigens characteristic of MSCs, STRO1, CD146, CD45, CD90, CD106 and CD166, but not the hematopoietic and endothelial markers, CD34 and CD31, as assessed by FACS analysis. Differentiation assessment revealed a strong osteogenic and adipogenic potential of SHEDs. In order to further evaluate the in vitro differentiation potential of SHED into neural cells, a simple short time growth factor-mediated induction was used. Immunofluorescence staining and flow cytometric analysis revealed that SHED rapidly expressed nestin and b-III tubulin, and later expressed intermediate neural markers. In addition, the intensity and percentages of nestin and b-III tubulin and mature neural markers (PSA-NCAM, NeuN, Tau, TH, or GFAP) increased significantly following treatment. Moreover, RT-PCR and Western blot analyses showed that the neural markers were strongly up-regulated after induction. In conclusion, these results provide evidence that SHED can differentiate into neural cells by the expression of a comprehensive set of genes and proteins that define neural-like cells in vitro. SHED cells might be considered as new candidates for the autologous transplantation of a wide variety of neurological diseases and neurotraumatic injuries. PMID- 21671223 TI - A SET/MYND chromatin re-modelling protein regulates Dictyostelium prespore patterning. AB - SmdA is a Dictyostelium orthologue of the SET/MYND chromatin re-modelling proteins. In developing structures derived from a null mutant for smdA (a smdA- strain), prestalk patterning is normal, but using a prespore lacZ reporter fusion, there is ectopic accumulation of beta-galactosidase in the prestalk region. As wild type slugs migrate, there is continual forward movement and re differentiation of prespore cells into prestalk cells. Thus, a potential explanation for the ectopic reporter localization in smdA null prestalk cells is an increased rate of re-differentiation and anterior movement of prespore cells. In support of this notion, analysis of an unstable lacZ reporter, driven by the prespore promoter, reveals a normal staining pattern in the smdA- strain. We suggest that one or more genes regulated by SmdA acts to repress prespore re specification. PMID- 21671224 TI - Impaired meiotic competence in putative primordial germ cells produced from mouse embryonic stem cells. AB - There are still several unanswered questions and problems about the recently claimed possibility of producing functional germ cells in vitro from pluripotent embryonic stem cells (ESCs). In the present paper, we compared by single-cell analysis the capability of putative primordial germ cells (PGCs), produced in vitro from ESCs, and that of endogenous PGCs isolated from embryos, to enter and progress through meiotic prophase I. Using a protocol previously reported to be suitable to produce female germ cells from mouse ESC monolayers, we first identified putative PGCs by analysing the expression pattern of several markers such as SSEA1, APase, OCT4, NANOG, MVH and SCP3 of pre- and post migratory PGCs. Next, after isolation of such cells from culture, we tested their meiotic capability. The evaluation at 2-5 days of culture of the number of cells showing meiotic nuclear SCP3 staining in cytospreads showed that it remained nearly constant in the putative PGCs, whereas it increased markedly in endogenous PGCs. Moreover, we observed that in putative PGCs, the nuclear distribution or expression of SCP3 and other meiotic markers such as DMC1, gH2AX and SCP1 were always highly abnormal in comparison to that observed in endogenous cultured PGCs. We conclude that although the formation of cells showing characteristics of PGCs can occur efficiently from ESCs in vitro, these cells possess impaired capability to enter and progress through meiotic prophase I. PMID- 21671225 TI - Spatially controlled expression of the Drosophila pseudouridine synthase RluA-1. AB - Pseudouridine (Psi) synthases function in the formation of Psi, the most abundant of the modified RNA residues. All Psi synthases in E. coli are classified into one of five families according to their sequences. Among them, members of the RluA Psi synthase family catalyze certain Psi formations in ribosomal RNA. RluA family members are required for ribosomal assembly and bacterial growth. None of the RluA in multicellular organisms has been studied. In the Drosophila peripheral nervous system, multiple dendritic (MD) neurons are recognized by their dendritic arbors. MD neurons can also be identified by using the enhancer trap line E7-2-36, which expresses the lacZ gene in MD neurons. Here, we show that the P-element of E7-2-36 inserts into the Drosophila RluA-1 gene. RluA-1 is homologous to E. coli RluA family members and is evolutionarily conserved in multicellular organisms. In situ hybridization and immunocytochemistry revealed that RluA-1 is expressed in MD neurons. We investigated the RluA-1 enhancer responsible for MD expression and found that the membrane-tethered green fluorescent protein driven by RluA-1-GAL4 was expressed in the dendritic arbors of MD neurons, confirming that RluA-1 is indeed expressed in MD neurons. Thus, the expression of RluA-1 is spatially controlled during development. PMID- 21671226 TI - Predicting accelerated aggregation rates for monoclonal antibody formulations, and challenges for low-temperature predictions. AB - Nonnative aggregation is a common degradation route for therapeutic proteins. Control of aggregate levels inherently requires control and/or prediction of aggregation rates at formulation conditions and storage temperatures of practical interest. Additionally, formulation screening often involves generation of accelerated stability data at one or more temperatures. A temperature-scanning approach for measuring nonnative aggregation rates as a function of temperature is proposed and evaluated here for a monoclonal antibody across different formulation conditions. Observed rate coefficients of aggregation (kobs ) were determined from isothermal kinetic studies for a range of pH and salt conditions at several temperatures, corresponding to shelf lives spanning multiple orders of magnitude. Isothermal kobs values were efficiently and quantitatively predicted by the temperature-scanning monomer loss (TSML) approach at accelerated conditions (half lives of the order 10(-1) -10(2) h). At lower temperatures, non Arrhenius behavior was apparent in some cases, and was semi-quantitatively described by nonlinear van't Hoff contributions to monomer unfolding free energies. Overall, the results demonstrate a novel strategy to quantitatively determine aggregation rates at time scales of industrial interest, based on kobs values from TSML, which are sample- and time-sparing as compared with traditional isothermal approaches, and illustrate challenges for shelf-life prediction with non-Arrhenius kinetics. PMID- 21671227 TI - Alternatives to conventional suspensions for pulmonary drug delivery by nebulisers: a review. AB - This review discusses the reports of alternative dosage forms to suspension formulations of hydrophobic drugs for nebulisers. Suspensions for nebulisers, although widely used over recent years, have several limitations which have led to pharmaceutical researchers looking for alternative, better performing preparations. Particular attention has been directed towards the use of nanoparticles as carriers of hydrophobic active ingredients. Several nanoformulations have been prepared and compared in vitro and/or in vivo with the corresponding microsuspension formulation. It is also clear that future studies in this field should address the parallel important aspects of safety and economical aspects of nanoparticualte formulations. PMID- 21671228 TI - Application of FTIR spectroscopic imaging to study the effects of modifying the pH microenvironment on the dissolution of ibuprofen from HPMC matrices. AB - This work presents the novel application of attenuated total reflection-Fourier transform infrared spectroscopic (ATR-FTIR) imaging to study the dissolution of ibuprofen form tablets in which the internal pH of the matrix has been modified by addition of acidic and basic powders to the formulations. Acidic additives to the matrix retarded the dissolution of crystalline ibuprofen domains. Basic additives formed both soluble and insoluble salts with the ibuprofen depending on the pH modifier added. Tablets consisting of hydroxypropyl methylcellulose, ibuprofen, and an acidic or basic additive were studied. FTIR imaging in ATR mode was used for analysis of water ingress into the tablet and the presence, distribution, and chemical state of the drug. The FTIR imaging data showed distinct changes in the dissolution of crystalline ibuprofen between the formulations with different pH modifiers. In the basic formulations, FTIR imaging identified the formation of salts. The sodium salt formed was highly soluble and enhanced dissolution, whereas the calcium salt was highly insoluble and slowed the dissolution. FTIR imaging has produced important data concerning the internal matrix dissolution performance. PMID- 21671229 TI - Antibiotic prophylaxis in uncontaminated neck dissection. AB - OBJECTIVES/HYPOTHESIS: To describe our institution's experience with antibiotic prophylaxis in uncontaminated neck dissection and to identify risk factors associated with postoperative wound infection. STUDY DESIGN: Retrospective chart review. METHODS: Between April 2006 and June 2010, 244 patients underwent 273 uncontaminated neck dissections at a single tertiary care center. Patient factors, operative details, and postoperative complications were recorded. Patients were separated into three groups: no prophylactic antibiotics, intraoperative antibiotics only, and intra- and postoperative antibiotics. RESULTS: Wound infections occurred after nine of the 273 procedures (3.3%). All of the wound infections occurred in patients receiving intraoperative antibiotics only (4 of 157) or intra- and postoperative antibiotics (5 of 75) (P = .11). The development of a wound infection was not associated with age, sex, history of tobacco and alcohol use, history of head and neck surgery, or history of radiation or chemotherapy. Wound infection was independently associated with operative time (adjusted odds ratio, 1.35; 95% confidence interval, 1.07-1.71; P = .011, for each additional hour of surgery) and with radical or extended neck dissection (adjusted odds ratio, 14.61; 95% confidence interval, 2.37-90.01, P = .004). CONCLUSIONS: Our data did not support the use of antibiotic prophylaxis in routine uncontaminated neck dissection. Prophylactic antibiotics, however, may be indicated for more extensive lymphadenectomy procedures. PMID- 21671230 TI - Surgical anatomy of transcanal endoscopic approach to the tympanic facial nerve. AB - OBJECTIVES/HYPOTHESIS: Until recently, tympanic facial nerve surgery had been performed using microscopic approaches, but in recent years, exclusive endoscopic approaches to the middle ear have increasingly been used, particularly in cholesteatoma surgery. The aim of this report was to illustrate the surgical anatomy of the facial nerve during an exclusive endoscopic transcanal approach. STUDY DESIGN: Retrospective video review of cadaveric dissections and operations on living patients in a tertiary university referral center. METHODS: Between November 2008 and July 2010, a total of 12 endoscopic cadaveric dissections were performed by an exclusive endoscopic transcanal approach. All dissections were recorded and stored in a database. In July 2010, video recordings from those dissections were reviewed, and the anatomic variations and accessibility of the tympanic facial nerve were studied and noted. Two further video recordings from living patients affected by middle ear chronic disease were also included in our study. RESULTS: In all 14 subjects, the transcanal endoscopic approach guaranteed direct access to the entire tympanic segment of the facial nerve after ossicular chain removal, allowing decompression of the nerve from the geniculate ganglion and the greater petrosal nerve to the second genu of the facial nerve. As in microscopic techniques, the cochleariform process and transverse crest (cog) may represent useful landmarks. CONCLUSIONS: The tympanic facial nerve can be thoroughly visualized by an exclusive endoscopic transcanal approach, even in poorly accessible regions such as the second genu and geniculate ganglion. Further clinically based reports may strengthen our preliminary results. PMID- 21671231 TI - The Triological Society 2011 presidential address. AB - The Triological Society 2011 Presidential Address was presented at The Triological Society's 2011 Combined Sections Meeting in Scottsdale, Arizona, Thursday January 27-29, 2011, by Gerald Berke, MD. The address captures the president's inspiration for the annual address as the past, present, and future of otolaryngology. A review of the financing and economics of health care in the United States over time is presented, and the future of health care with reference to otolaryngology is discussed. The address focused on the percentage increase in gross domestic product assigned to medical care in the United States owing to the emergence, adoption, and widespread diffusion of new medical technologies and services. It showed that a significant proportion of the expense goes to hospitals and physician/clinical services. It refuted many of the current criticisms of medical care in the United States, pointing out that neonatal death rates in the United States include all gestational ages, but many countries only use full-term births in their statistics; also, longevity is excellent when deaths due to motor vehicle accidents and homicides are adjusted. Furthermore, survival rates for common malignancies and myocardial infarctions are better in the United States than in many countries. The address related the president's memories of medical care in the United States as an intern and young resident. It went on to discuss the concept of treating diseased organs ex vivo and reimplanting them without systemic side effects within the next 25 years but cautioned that future medical advances may be moderated by a reliance on evidence based studies before new technologies can be adopted. Finally, it emphasized physician's altruistic motivations for choosing this profession despite future economic realities in coming years. PMID- 21671232 TI - Temporal bone histopathology in neurofibromatosis type 2. AB - OBJECTIVES/HYPOTHESIS: To describe the histopathologic findings in the temporal bone in patients with neurofibromatosis type 2 (NF2). The literature contains limited data on otopathology of NF2. STUDY DESIGN: Basic science study. METHODS: Twenty-six temporal bones from 16 patients with NF2 were examined by light microscopy. The diagnosis of NF2 was made on the basis of bilateral cochleovestibular schwannomas. Clinical information was obtained from review of the medical records. RESULTS: The tumors were multicentric in origin in 19 of 26 (73%) ears. Typically, tumors were seen arising within the internal auditory canal and from various locations within the labyrinth. The majority of schwannomas showed high cellularity with involvement of the labyrinth. Most cases showed significant degrees of degeneration of sensory and neural elements within the cochlea. Fusion tumors were sometimes seen as a result of a schwannoma merging with an adjacent meningioma. Fifteen of 26 (58%) ears showed facial nerve involvement by schwannoma. CONCLUSIONS: Cochleovestibular schwannomas in NF2 are aggressive neoplasms; they are often multicentric and demonstrate a propensity to involve the labyrinth. There is often associated secondary degeneration within the cochlea. These features make total removal of these tumors and their removal with preservation of hearing more difficult than with sporadic unilateral cochleovestibular schwannoma. PMID- 21671233 TI - Change in Epworth Sleepiness Scale after surgical treatment of obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: To evaluate the effect of surgical intervention for obstructive sleep apnea (OSA) on patients' level of excessive daytime sleepiness as determined by the Epworth Sleepiness Scale (ESS). The ESS questionnaire is a validated measure of subjective daytime sleepiness. There have been several studies that have shown that continuous positive airway pressure (CPAP) improves excessive daytime sleepiness in OSA patients as measured by the ESS. STUDY DESIGN: Retrospective case series. METHODS: This is a study of patients who had uvulopalatopharyngoplasty (UPPP); UPPP and tonsillectomy; or UPPP, tonsillectomy, and radiofrequency ablation of the base of the tongue for OSA between January 2007 and December 2009. Forty patients were identified who met the criteria of having had an ESS evaluation and polysomnography prior to surgery for OSA. RESULTS: Across all of the patients there was a mean reduction of their ESS by 5.6 +/- 4.1; t = 8.82, P < .001. Only three of the patients did not improve in their ESS scores after surgical treatment for OSA. CONCLUSIONS: Surgical intervention for OSA significantly improves sleepiness in OSA patients as measured by the ESS. Two meta-analyses of multiple, randomized, controlled studies showed patients with mild to moderate OSA treated with CPAP demonstrated an improvement in the ESS score of 1.2 points (95% confidence interval, 0.05-1.9, P = .001) and 2.94 points for patients with mild to severe OSA treated with CPAP. The results of this study show an improvement in ESS after surgery that is substantially higher than previously reported with CPAP for all categories of OSA. PMID- 21671235 TI - The bipedicled anterior septal flap: a radioanatomic and cadaveric study. AB - OBJECTIVES/HYPOTHESIS: Pedicled mucosal flaps are the preferred method of endoscopic skull base reconstruction. Vascularized coverage of the anterior and posterior frontal tables remains a challenge given the lack of large caliber vessels supplying the anterior septum. The objective of this study was to define a novel bipedicled anterior septal (BAS) flap that is hypothesized to be capable of providing reproducible coverage of these difficult areas. STUDY DESIGN: Radioanatomic and cadaveric study. METHODS: The flap outline was superimposed over nine midline sagittal computed tomography images. The pedicles are comprised of the septal branch of the superior labial artery and the nasopalatine artery. The flap length subtended the distance from the incisive canal to the sphenoid face at the level of the choanal arch. Radiometric analysis of the flap length to base ratio and anterior/posterior frontal table coverage were calculated. These projected values were confirmed in four cadaveric dissection specimens. RESULTS: The mean flap length was 39.64 +/- 4.26 mm with a mean length:base ratio of 3.29 +/- 0.70 and a total surface area of 916.46 +/- 262.66 mm(2) . The flap was estimated to provide coverage of 100.31 +/- 21.34% of the frontal beak and 50.74 +/- 32.54% of the posterior frontal table. In all cadaveric specimens the flap extended beyond the superior aspect of the frontal beak and at least 50% of the posterior table. CONCLUSIONS: The BAS flap represents a novel septal mucosal flap based on two well-defined arterial inputs. This flap is capable of providing reliable vascularized coverage of the posterior frontal table and the frontal beak following frontal drillout. PMID- 21671234 TI - Systematic review and meta-analyses of randomized controlled trials examining tinnitus management. AB - OBJECTIVES/HYPOTHESIS: To evaluate the existing level of evidence for tinnitus management strategies identified in the UK Department of Health's Good Practice Guideline. STUDY DESIGN: Systematic review of peer-reviewed literature and meta analyses. METHODS: Searches were conducted in PubMed, Cambridge Scientific Abstracts, Web of Science, and EMBASE (earliest to August 2010), supplemented by hand searches in October 2010. Only randomized controlled trials that used validated questionnaire measures of symptoms (i.e., measures of tinnitus distress, anxiety, depression) were included. RESULTS: Twenty-eight randomized controlled trials met our inclusion criteria, most of which provide moderate levels of evidence for the effects they reported. Levels of evidence were generally limited by the lack of blinding, lack of power calculations, and incomplete data reporting in these studies. Only studies examining cognitive behavioral therapy were numerous and similar enough to perform meta-analysis, from which the efficacy of cognitive behavioral therapy (moderate effect size) appears to be reasonably established. Antidepressants were the only drug class to show any evidence of potential benefit. CONCLUSIONS: The efficacy of most interventions for tinnitus benefit remains to be demonstrated conclusively. In particular, high-level assessment of the benefit derived from those interventions most commonly used in practice, namely hearing aids, maskers, and tinnitus retraining therapy needs to be performed. PMID- 21671236 TI - Management of complex tympanojugular paragangliomas including endovascular intervention. AB - OBJECTIVES/HYPOTHESIS: To identify complex cases of tympanojugular paraganglioma (TJP) and to analyze their management and surgical outcome. To present strategy and guidelines on how to deal with the perioperative complicating factors. STUDY DESIGN: Retrospective analysis. METHODS: We retrospectively studied 212 TJP patients to identify the complex cases and analyzed their management and surgical outcome. The criteria for complex TJP are: 1) very large size; 2) large intradural extension (IDE); 3) extension to the cavernous sinus, foramen magnum, and clivus; 4) significant involvement of the internal carotid artery (ICA); 5) a solitary ICA on the lesion side; 6) involvement of the vertebral artery; 7) dominant or unilateral sigmoid sinus on the lesion side; 8) bilateral or multiple paragangliomas; and 9) recurrence. RESULTS: Sixty patients were classified as complex. Forty-five patients had tumors with IDE. Twenty patients with tumor involving ICA underwent preoperative endovascular intervention. Two patients had a solitary ICA and two others unilateral sigmoid sinus on the lesion side. Thirteen patients had multicentric tumors, and three patients had bilateral ones. The main procedure was the infratemporal fossa approach type A. Total removal was achieved in 46 patients, and five of them experienced recurrence. CONCLUSIONS: It is essential to carefully investigate the hemodynamics of the brain in planning surgery. A proper preoperative endovascular intervention facilitates gross total tumor removal. In bilateral paragangliomas, lower cranial nerves' function should be preserved at least unilaterally. Staged removal is recommended for a tumor with a large intradural component. PMID- 21671237 TI - Variables related to recurrence of pleomorphic adenomas: outcome of parotid surgery in 182 cases. AB - OBJECTIVE: We present our experience in parotid surgery for pleomorphic adenomas; analyzing a prospectively recorded database of parotidectomy; aiming to identify independent variables related to adenoma recurrence. STUDY DESIGN: Prospective case series. METHODS: Data of 182 patients; 164 new tumors and 18 revision parotidectomies were analyzed. The main outcome measure was tumor recurrence; the analyzed variables were age, gender, tumor size and site, safety margin, tumor puncture, spillage, adherence to facial nerve, surgical procedure, and follow-up period. RESULTS: Five new patients had a recurrence, two revision cases had second recurrence (11%), the overall recurrence rate was 3.8%. Recurrence rate was not related to age, gender, or duration of follow-up. Recurrence was related to larger tumors, tumors less than 30 mm in diameter are unlikely to recur. Tumor recurrence was inversely related to safety margin. Tumors with a diameter of 4 cm or more have no margins. All the seven tumors that recurred were punctured. Spillage was reported in five patients, four had a recurrence (80%). Tumor capsules were related to facial nerve in 75 cases; 6 of them had a recurrence (8%). CONCLUSIONS: Tumor puncture and spillage were the only variables that have an independent effect on recurrence, 26.9% of punctured tumors and 80% of cases of spillage recurred (P = .043 and P = .035, respectively). Although tumor size, safety margin, and adherence to facial nerve are related to recurrence, logistic regression suggests that these are confounding variables influencing recurrence through effect on puncture and spillage rates. PMID- 21671238 TI - Preliminary evaluation of junior medical students' exposure and comfort with performing the basic head and neck examination. AB - OBJECTIVE: To assess junior medical students' comfort levels in performing the head and neck physical examination (H&NPE) and perception of the importance of otolaryngology--head and neck surgery (OTO-HNS) in medical training before and after undergoing a department-led teaching session. DESIGN: Anonymous cross sectional survey study, before and after educational intervention. METHODS: One hundred one second-year medical students participated in an H&NPE teaching session as part of their preclinical curriculum. Students first watched a 25 minute H&NPE instructional video. Students then participated in lectures (90 minutes) on OTO-HNS subspecialties and faculty- and resident-led group H&NPE instruction (five to six students each, 90 minutes) with practice on student partners. Students rated their comfort levels (0-5 point Likert scale) in performing the H&NPE and the importance of OTO-HNS rotations throughout medical training before and after the session. RESULTS: Ninety-five and 77 medical students completed presurveys and postsurveys, respectively. Before the teaching session, students reported an average comfort level of 2.1 in performing the complete H&NPE, which increased to 3.4 (P < .0001) after the session. Similar changes were observed for the individual ear, nose, mouth, and neck exams. CONCLUSIONS: A specialized teaching session significantly improved medical students' comfort levels in performing the H&NPE and increased their awareness of the importance of OTO-HNS in medical training immediately after the session. PMID- 21671239 TI - Swallowing disturbance questionnaire for detecting dysphagia. AB - OBJECTIVES: To assess the accuracy of the swallowing disturbance questionnaire (SDQ) that had originally been designed and validated for detecting swallowing problems among patients with Parkinson's disease and was now applied for identifying patients with dysphagia associated with various other etiologies. STUDY DESIGN: Prospective. METHODS: One-hundred patients with the complaint of swallowing disturbances who underwent a full swallowing survey at the Tel-Aviv Voice and Swallowing Disorder Clinic participated. They all filled in the SDQ. The collected data included patient characteristics, medical history, and the results of an oromotor examination and a fiberoptic endoscopic evaluation of swallowing (FEES). The SDQ results were compared to the FEES and oromotor examination findings. RESULTS: The responses to the questions in the SDQ were highly correlated with the findings of the oral part of the oromotor examination (85.71% sensitivity, 87.6% specificity). Items on the laryngopharyngeal phase reliably assessed dysphagia symptoms in correlation to the FEES examination (67.3% sensitivity, 76.7% specificity). The total SDQ score correlated with the total oromotor and the FEES scores (79.7% sensitivity, 73% specificity). CONCLUSIONS: The SDQ is a sensitive and accurate tool for identifying patients with true swallowing disturbances arising from different etiologies and for indicating the need for more in-depth instrumental swallowing evaluations. PMID- 21671240 TI - Can ultrasonography of the placenta previa predict antenatal bleeding? AB - PURPOSE: To evaluate the abnormal sonographic (US) findings in patients with placenta previa and bleeding. METHODS: A total of 182 cases of singleton pregnancies with placenta previa were reviewed. The US findings including the type of placenta previa, placental location, presence of placenta lacunae, lack of clear zone, sinus venosus at the margin of the placenta, velamentous cord insertion, sponge-like echo in the cervix and cervical length were evaluated in relation to episodes of bleeding that required in-patient treatment during pregnancy and/or emergency cesarean section. RESULTS: Episodes of antenatal bleeding occurred in 102/182 (56%) patients with placenta previa. An emergency cesarean section was performed in 66 (64.7%) of these 102 patients. In the 80 patients without episodes of antenatal bleeding, an emergency cesarean section was performed in only 1 (1.3%). Detection of US findings just prior to cesarean section was not associated with the need for emergency cesarean section due to uncontrollable bleeding from the placenta previa. Frequencies of each US finding at 20 weeks of gestation were not different between the patients who underwent emergency cesarean sections and the others. Frequency of marginal sinus was slightly higher in cases with bleeding episode (16% versus 0%, p < 0.05), but the other US findings were not associated with the occurrence of bleeding episodes during pregnancy. CONCLUSIONS: No US finding could predict bleeding episodes and the eventual need for an emergency cesarean section. The obstetrician should be aware that sudden bleeding during pregnancy may occur in patients with placenta previa, even in the absence of any other US findings. PMID- 21671241 TI - Stepwise disproportionation in polyelectrolyte complexes. AB - Structural properties and the topology of polyelectrolyte complexes (PECs) formed in solution have been investigated under different conditions by Monte Carlo simulations using a coarse-grained model. The extension of individual polyions has been characterized by their radius of gyration, whereas the composition of the complexes has been investigated by their net charge and their internal topological structure by a novel analysis describing how the shorter polycations link to monomers of the longer polyanion. Conditions have been found at which the polyanion and a given number of polycations form distinguishable complexes differing in (i) the polyanion conformation and (ii) the fraction of polycations being in extended and collapsed states. Thus, at equilibrium, these PECs display a stepwise variation of the degree of intrachain disproportionation within the polyanion (also referred to as intrachain segregation), concomitant with the interchain disproportionation of the polycations, which is in agreement with previous theoretical predictions. The coexistence of the different polyelectrolyte complex structures appears, generally, at mixing ratios close to but different from charge equivalence and, as a consequence, broad polyelectrolyte size distributions are commonly obtained. PMID- 21671242 TI - A computational study of unique properties of pillar[n]quinones: self-assembly to tubular structures and potential applications as electron acceptors and anion recognizers. AB - Density functional theory has been used to calculate the thermodynamic properties and molecular orbitals of pillar[n]quinones. Pillar[n]quinones are expected to be effective electron acceptors and the ability to accept more than one electron increases with the size of the interior cavity. Pillar[5]quinone and pillar[7]quinone show a great intramolecular charge transfer upon the electron excitation from highest occupied molecular orbital (HOMO) to lowest unoccupied molecular orbital (LUMO) as indicated by a large difference of electron distributions between their HOMO and LUMO and a notable dipole moment difference between the ground and first triplet excited state. The aggregation of pillar[n]quinones leads to tubular dimeric structures joined by 2n C?H...O nonclassical hydrogen bonds (HBs) with binding energies about 2 kcal/mol per HB. The longitudinal extension of the supramolecular self-assembly of pillar[n]quinone may be adjustable through forming and breaking their HBs by controlling the surrounding environment. The tunability of the diameter of the tubular structures can be achieved by changing the number of quinone units in the pillar[n]quinone. The electrostatic potential maps of pillar[n]quinones indicate that the positive charge in the interior cavity decreases as the number of quinone units increases. Chloride and bromide anions are chosen to examine the noncovalent anion-pi interactions between pillar[n]quinones and captured anions. The calculations show that the better compatibility of the effective radius of the anions with the interior dimension of pillar[n]quinone leads to larger stabilization energy. The selectivity of spatial matching and specific interaction of pillar[n]quinone is believed to possibly serve as a candidate for ionic and molecular recognition. PMID- 21671244 TI - Protein kinase B/Akt may regulate G2/M transition in the fertilized mouse egg by changing the localization of p21(Cip1/WAF1). AB - Protein kinase B (PKB, also called Akt) is known as a serine/threonine protein kinase. Some studies indicate that the Akt signalling pathway strongly promotes G2/M transition in mammalian cell cycle progression, but the mechanism remains to be clarified, especially in the fertilized mouse egg. Here, we report that the expression of Akt at both the protein and mRNA level was highest in G2 phase, accompanied by a peak of Akt activity. In addition, the subcellular localization of p21(Cip1/WAF1) has been proposed to be critical in the cell cycle. Hence, we detected the expression and localization of p21(Cip1/WAF1) after injecting fertilized mouse eggs with Akt mRNA. In one-cell stage fertilized embryos microinjected with mRNA coding for a constitutively active myristoylated Akt (myr Akt), p21(Cip1/WAF1) was retained in the cytoplasm. Microinjection of mRNA of kinase-deficient Akt(Akt-KD) resulted in nuclear localization of p21(Cip1/WAF1) . Meanwhile, microinjection of different types of Akt mRNA affected the phosphorylation status of p21(Cip1/WAF1) . However, there was no obvious difference in the protein expression of p21(Cip1/WAF1) . Therefore, Akt controls the cell cycle by changing the subcellular localization of p21(Cip1/WAF1) , most likely by affecting the phosphorylation status of p21(Cip1/WAF1) . PMID- 21671245 TI - Comparing EndoPAT and BIOPAC measurement of vascular responses to mental stress. AB - There are currently no comparison measurements of stress-induced changes in vascular function during acute mental stress tests to measurements made by BIOPAC MP150 systems technology, a standard polygraph device used to detect deception during polygraph examinations in military or law enforcement applications. Vascular responses to reactive hyperaemia and acute mental stress in 25 healthy subjects were measured by both peripheral arterial tonometry (EndoPAT) and a blood pressure cuff attached to a pressure transducer (BIOPAC) and compared. Reactive hyperaemia was performed at baseline and following three acute mental stress tests. There was no difference in vascular reactivity at baseline and following acute mental stress, as measured by EndoPAT or BIOPAC systems (p > 0.05). Mental stress ratios measured by EndoPAT were significantly different than those measured by BIOPAC (p < 0.01). These data suggest that EndoPAT measurements of vascular responses to acute mental stress may be more specific and sensitive than measurements using the BIOPAC system. PMID- 21671246 TI - Regional distribution of neuroendocrine cells in the urogenital duct system of the male rat. AB - BACKGROUND: Neuroendocrine (NE) cells are frequently present in the human prostate and urethra, whereas they are lacking in the other urogenital organs. This study was undertaken as there are only few detailed studies available on the distribution, form and function of NE cells and the structure of excretory ducts of the accessory sex organs in the male rat. METHODS: Systematic gross anatomical dissections were combined with immunohistochemical and electron microscopic studies of the excretory ducts of the urogenital glands in male rats, with particular focus on the distribution and ultrastructure of the NE cells. RESULTS: The topography and structure of the excretory ducts of the different glands were characterized in detail and analyzed for the distribution of NE cells. These are present (in falling frequencies) in the ducts of seminal vesicles and ventral and lateral prostate and are rare in ducts of coagulating gland, dorsal prostate, urethral epithelium, and excretory ducts of the (bulbo) urethral glands. They are absent in the respective glands proper, the deferent duct and ejaculatory ampulla. Approximately 40% of the NE cells of the ventral prostate ducts are of the "open" type, whereas these are less frequent (14%) in the seminal vesicle ducts, where the "closed" type prevails. CONCLUSIONS: NE cells are present in unequal quantities in the excretory ducts of the accessory sex glands, but they are absent in the glands proper and the deferent ducts. This distribution pattern points to a strictly localized function and differentiation potency of NE precursor cells. PMID- 21671249 TI - An elaboration of "proof" of peritoneal mesothelioma from tremolite free chrysotile. PMID- 21671247 TI - Association of prostate cancer risk with SNPs in regions containing androgen receptor binding sites captured by ChIP-On-chip analyses. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified approximately three dozen single nucleotide polymorphisms (SNPs) consistently associated with prostate cancer (PCa) risk. Despite the reproducibility of these associations, the molecular mechanism for most of these SNPs has not been well elaborated as most lie within non-coding regions of the genome. Androgens play a key role in prostate carcinogenesis. Recently, using ChIP-on-chip technology, 22,447 androgen receptor (AR) binding sites have been mapped throughout the genome, greatly expanding the genomic regions potentially involved in androgen-mediated activity. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that sequence variants in AR binding sites are associated with PCa risk, we performed a systematic evaluation among two existing PCa GWAS cohorts; the Johns Hopkins Hospital and the Cancer Genetic Markers of Susceptibility (CGEMS) study population. We demonstrate that regions containing AR binding sites are significantly enriched for PCa risk-associated SNPs, that is, more than expected by chance alone. In addition, compared with the entire genome, these newly observed risk-associated SNPs in these regions are significantly more likely to overlap with established PCa risk-associated SNPs from previous GWAS. These results are consistent with our previous finding from a bioinformatics analysis that one-third of the 33 known PCa risk-associated SNPs discovered by GWAS are located in regions of the genome containing AR binding sites. CONCLUSIONS/SIGNIFICANCE: The results to date provide novel statistical evidence suggesting an androgen-mediated mechanism by which some PCa associated SNPs act to influence PCa risk. However, these results are hypothesis generating and ultimately warrant testing through in-depth molecular analyses. PMID- 21671250 TI - A few remarks on 'Statistical distribution of the difference of two proportions' by Nadarajah and Kotz, Statistics in Medicine 2007; 26(18):3518-3523. PMID- 21671251 TI - Response to 'A few remarks on Statistical distribution of the difference of two proportions' by Chen and Luo. PMID- 21671252 TI - On fitting generalized linear mixed-effects models for binary responses using different statistical packages. AB - The generalized linear mixed-effects model (GLMM) is a popular paradigm to extend models for cross-sectional data to a longitudinal setting. When applied to modeling binary responses, different software packages and even different procedures within a package may give quite different results. In this report, we describe the statistical approaches that underlie these different procedures and discuss their strengths and weaknesses when applied to fit correlated binary responses. We then illustrate these considerations by applying these procedures implemented in some popular software packages to simulated and real study data. Our simulation results indicate a lack of reliability for most of the procedures considered, which carries significant implications for applying such popular software packages in practice. PMID- 21671253 TI - Del(13q14.3) length matters: an integrated analysis of genomic, fluorescence in situ hybridization and clinical data in 169 chronic lymphocytic leukaemia patients with 13q deletion alone or a normal karyotype. PMID- 21671254 TI - Inhibition of cyclin-dependent kinase 5 but not of glycogen synthase kinase 3 beta prevents neurite retraction and tau hyperphosphorylation caused by secretable products of human T-cell leukemia virus type I-infected lymphocytes. AB - Human T-cell leukemia virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease characterized by selective loss of axons and myelin in the corticospinal tracts. This central axonopathy may originate from the impairment of anterograde axoplasmic transport. Previous work showed tau hyperphosphorylation at T(181) in cerebrospinal fluid of HAM/TSP patients. Similar hyperphosphorylation occurs in SH-SY5Y cells incubated with supernatant from MT-2 cells (HTLV-I-infected lymphocytes secreting viral proteins, including Tax) that produce neurite shortening. Tau phosphorylation at T(181) is attributable to glycogen synthase kinase 3-beta (GSK3-beta) and cyclin dependent kinase 5 (CDK5) activation. Here we investigate whether neurite retraction in the SH-SY5Y model associates with concurrent changes in other tau hyperphosphorylable residues. Threonine 181 turned out to be the only tau hyperphosphorylated residue. We also evaluate the role of GSK3-beta and CDK5 in this process by using specific kinase inhibitors (LiCl, TDZD-8, and roscovitine). Changes in both GSK3-beta active and inactive forms were followed by measuring the regulatory phosphorylable sites (S(9) and Y(216) , inactivating and activating phosphorylation, respectively) together with changes in beta-catenin protein levels. Our results showed that LiCl and TDZD-8 were unable to prevent MT 2 supernatant-mediated neurite retraction and also that neither Y(216) nor S(9) phosphorylations were changed in GSK3-beta. Thus, GSK3-beta seems not to play a role in T(181) hyperphosphorylation. On the other hand, the CDK5 involvement in tau phosphorylation was confirmed by both the increase in its enzymatic activity and the absence of MT-2 neurite retraction in the presence of roscovitine or CDK5 siRNA transfection. PMID- 21671255 TI - Neuroprotective effect of guanosine against glutamate-induced cell death in rat hippocampal slices is mediated by the phosphatidylinositol-3 kinase/Akt/ glycogen synthase kinase 3beta pathway activation and inducible nitric oxide synthase inhibition. AB - Excitotoxicity and cell death induced by glutamate are involved in many neurodegenerative disorders. We have previously demonstrated that excitotoxicity induced by millimolar concentrations of glutamate in hippocampal slices involves apoptotic features and glutamate-induced glutamate release. Guanosine, an endogenous guanine nucleoside, prevents excitotoxicity by its ability to modulate glutamate transport. In this study, we have evaluated the neuroprotective effect of guanosine against glutamate-induced toxicity in hippocampal slices and the mechanism involved in such an effect. We have found that guanosine (100 MUM) was neuroprotective against 1 mM glutamate-induced cell death through the inhibition of glutamate release induced by glutamate. Guanosine also induced the phosphorylation and, thus, activation of protein kinase B (PKB/Akt), a downstream target of phosphatidylinositol-3 kinase (PI3K), as well as phosphorylation of glycogen synthase kinase 3beta, which has been reported to be inactivated by Akt after phosphorylation at Ser9. Glutamate treated hippocampal slices showed increased inducible nitric oxide synthase (iNOS) expression that was prevented by guanosine. Slices preincubated with SNAP (an NO donor), inhibited the protective effect of guanosine. LY294002 (30 MUM), a PI3K inhibitor, attenuated guanosine induced neuroprotection, guanosine prevention of glutamate release, and guanosine induced GSK3beta(Ser9) phosphorylation but not guanosine reduction of glutamate induced iNOS expression. Taken together, the results of this study show that guanosine protects hippocampal slices by a mechanism that involves the PI3K/Akt/GSK3beta(Ser9) pathway and prevention of glutamate-induced glutamate release. Furthermore, guanosine also reduces glutamate-induced iNOS by a PI3K/Akt independent mechanism. PMID- 21671256 TI - Purkinje cell protein 4 positively regulates neurite outgrowth and neurotransmitter release. AB - Purkinje cell protein 4 (PCP4), also called brain-specific polypeptide 19 (PEP19), is a neurospecific, small calmodulin-binding protein that binds both calcium-free and calcium-binding calmodulin to regulate the calmodulin-mediated signal. The expression level of this molecule is decreased in the brain in Alzheimer's disease, Huntington's disease, and alcoholism. However, little is known of the function of PCP4 regarding neuronal or neuroendocrine cell differentiation and neurotransmitter release. To address this, we established a PCP4 tetracycline-inducible rat chromaffin cell line, PC12. When PCP4 expression was induced with doxcycline, neurite outgrowth was significantly advanced in the presence of nerve growth factor (NGF) and dibutyryl cAMP, which was inhibited by W-7, a calmodulin inhibitor, and PD98059, an ERK inhibitor. In addition, size of the cell body also was increased by treatment with NGF in the PCP4-induced PC12 cells. Constitutive and potassium-evoked release of acetylcholine and dopamine was increased and apoptosis induced by hydrogen peroxide (H(2)O(2)) was inhibited in PCP4-induced PC12 cells. On the other hand, knockdown of PCP4 by siRNA transfection decreased neurite outgrowth and dopamine release and increased H(2)O(2)-induced apoptosis in PC12 cells. These results indicate that PCP4 promotes neuroendocrine cell differentiation and neurotransmitter release by activating calmodulin function. PMID- 21671257 TI - Cyanidin-3-glucoside ameliorates ethanol neurotoxicity in the developing brain. AB - Ethanol exposure induces neurodegeneration in the developing central nervous system (CNS). Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during pregnancy and are the most common nonhereditary cause of mental retardation. It is important to identify agents that provide neuroprotection against ethanol neurotoxicity. Multiple mechanisms have been proposed for ethanol induced neurodegeneration, and oxidative stress is one of the most important mechanisms. Recent evidence indicates that glycogen synthase kinase 3beta (GSK3beta) is a potential mediator of ethanol-mediated neuronal death. Cyanidin-3 glucoside (C3G), a member of the anthocyanin family, is a potent natural antioxidant. Our previous study suggested that C3G inhibited GSK3beta activity in neurons. Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that C3G can ameliorate ethanol-induced neuronal death in the developing brain. Intraperitoneal injection of C3G reduced ethanol-meditated caspase-3 activation, neurodegeneration, and microglial activation in the cerebral cortex of 7-day-old mice. C3G blocked ethanol-mediated GSK3beta activation by inducing phosphorylation at serine 9 while reducing the phosphorylation at tyrosine 216. C3G also inhibited ethanol-stimulated expression of malondialdehyde (MDA) and p47phox, indicating that C3G alleviated ethanol induced oxidative stress. These results provide important insight into the therapeutic potential of C3G. PMID- 21671258 TI - Temporal evaluation of effects of a model 3beta-hydroxysteroid dehydrogenase inhibitor on endocrine function in the fathead minnow. AB - Inhibition of enzymes involved in the synthesis of sex steroids can substantially impact developmental and reproductive processes controlled by the hypothalmic pituitary-gonadal (HPG) axis. A key steroidogenic enzyme that has received little attention from a toxicological perspective is 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In these studies, we exposed reproductively-active fathead minnows (Pimephales promelas) to the model 3beta-HSD inhibitor trilostane at two test concentrations (300 and 1,500 ug/L) over a 16-d period that included both 8-d exposure and 8-d recovery phases. Plasma concentrations of 17beta-estradiol (E2) in females were depressed within hours of exposure to the drug and remained decreased at the highest trilostane concentration throughout the 8-d exposure. Reductions in E2 were accompanied by decreases in plasma concentrations of the estrogen-responsive protein vitellogenin (VTG). During the recovery phase of the test, plasma E2 and VTG concentrations returned to levels comparable to those of controls, in the case of E2 within 1 d. Up-regulation of ovarian expression of gene products for follicle-stimulating hormone receptor (fshr) and aromatase (cyp19a1a) suggested active compensation in trilostane-exposed animals. Effects of trilostane on HPG-related endpoints in exposed males were less pronounced, although, as in females, up-regulation of gonadal fshr was seen. Data from these time-course studies provide insights as to direct impacts, compensatory responses, and recovery from effects associated with perturbation of a comparatively poorly characterized enzyme/pathway critical to sex steroid synthesis. This information is important to the design and interpretation of approaches for assessing the occurrence and effects of HPG-active chemicals in both the laboratory and the field. PMID- 21671259 TI - Chronic zebrafish PFOS exposure alters sex ratio and maternal related effects in F1 offspring. AB - Perfluorooctanesulfonic acid (PFOS) is an organic contaminant ubiquitous in the environment, wildlife, and humans. Few studies have assessed its chronic toxicity on aquatic organisms. The present study defined the effects of long-term exposure to PFOS on zebrafish development and reproduction. Specifically, zebrafish at 8 h postfertilization (hpf) were exposed to PFOS at 0, 5, 50, and 250 ug/L for five months. Growth suppression was observed in the 250 ug/L PFOS-treated group. The sex ratio was altered, with a significant female dominance in the high-dose PFOS group. Male gonad development was also impaired in a dose-dependent manner by PFOS exposure. Although female fecundity was not impacted, the F1 embryos derived from high-dose exposed females paired with males without PFOS exposure developed severe deformity at early development stages and resulted in 100% larval mortality at 7 d postfertilization (dpf). Perfluorooctanesulfonic acid quantification in embryos indicated that decreased larval survival in F1 offspring was directly correlated to the PFOS body burden, and larval lethality was attributable to maternal transfer of PFOS to the eggs. Lower-dose parental PFOS exposure did not result in decreased F1 survival; however, the offspring displayed hyperactivity of basal swimming speed in a light-to-dark behavior assessment test. These findings demonstrate that chronic exposure to PFOS adversely impacts embryonic growth, reproduction, and subsequent offspring development. PMID- 21671260 TI - Hip osteoarthritis susceptibility is associated with IL1B -511(G>A) and IL1 RN (VNTR) genotypic polymorphisms in Croatian Caucasian population. AB - Among the predisposing factors to osteoarthritis (OA), a frequent destructive joint disease, is the complex genetic heritage including the interleukin-1 family members like the IL1beta (IL1B) and the IL1 receptor antagonist (IL1RN) genes. The aim of this study was to investigate allelic and genotypic frequencies of the IL1B gene single nucleotide polymorphism (SNP) at -511(G>A) and the variable number tandem repeat (VNTR) in the IL1RN gene in a Croatian Caucasian population of hip OA (HOA) cases and healthy controls. A total of 259 HOA patients with total hip replacement (THR) and 518 healthy blood donors as controls were genotyped for IL1B gene SNP -511(G>A) and the VNTR in the IL1RN gene associated with HOA. The genotype G/A (1/2) at IL1B was significantly associated with the protection of the HOA (p < 0.036, OR = 0.72, 95% CI = 0.52-0.99). The genotype G/G (1/1) had only a trend towards the susceptibility (p = 0.053, OR = 1.35, 95% CI = 0.98-1.86) to disease. None of the haplotypes IL1B -511(G>A) and IL1RN (VNTR) were found associated with the HOA. The haplotype 1-2 at these loci had only a trend to susceptibility (p = 0.065). Haplotype 1-3 had a significant male bias in diseased. Furthermore, genotype comprising 2-1/2-2 haplotypes was found significantly associated with predisposition to HOA (p = 0.027, OR = 2.23, 95% CI = 1.03-4.88), whereas genotype 1-1/2-2 with protection to disease (p = 0.028, OR = 0.65, 95% CI = 0.43-0.97). Our findings suggest that HOA in Croatian population might have a different genetic risk regarding the IL1 locus than has been reported for other Caucasian populations previously. PMID- 21671261 TI - Depth of subchondral perforation influences the outcome of bone marrow stimulation cartilage repair. AB - Subchondral drilling and microfracture are bone marrow stimulation techniques commonly used for the treatment of cartilage defects. Few studies to date have examined the technical variants which may influence the success of the cartilage repair procedures. This study compared the effect of hole depth (6 mm vs. 2 mm) and hole type (drill vs. microfracture) on chondral defect repair using a mature rabbit model. Results from quantitative histomorphometry and histological scoring showed that deeper versus shallower drilling elicited a greater fill of the cartilage defect with a more hyaline character in the repair matrix indicated by significant improvement (p = 0.021) in the aggregate measure of increased cartilage defect fill, increased glycosaminoglycan and type II collagen content and reduced type I collagen content of total soft repair tissue. Compared to microfracture at the same 2 mm depth, drilling to 2 mm produced a similar quantity and quality of cartilage repair (p = 0.120) according to the aggregate indicator described above. We conclude that the depth of bone marrow stimulation can exert important influences on cartilage repair outcomes. PMID- 21671262 TI - Humeral cementless surface replacement arthroplasties of the shoulder: an experimental investigation on their initial fixation. AB - Cementless surface replacement arthroplasties are increasingly being used to treat arthritic humeral heads. These implants are designed to provide narrow bone resection, making a later revision easier. However, no clear evidence exists as to whether their initial fixation is sufficient for bony ingrowth. The aim of our in vitro study was to characterize the relative micromotion of two resurfacing implants with essentially different bone-facing geometries. Both systems were implanted into 10 human humeral specimens and micromotion was measured under a cyclic torque application of up to +/-1.75 Nm. The mean relative rotary motion resulted in a significant difference (p = 0.036), which was attributed to design differences of central stabilizers featuring both implants. A conversion of rotary motions into relative micromotions, using recently measured moments acting on these implants during daily activities of living, nullified this difference (p = 0.088). However, depending on the shoulder load case considered, a clear difference appeared (p = 0.031-0.045). In conclusion, both resurfacing implants are capable of achieving sufficient initial fixation on the humeral head and perform relative micromotions in a range considered safe for bony ingrowth. Patient-related parameters do not appear to influence the initial fixation of these implants. PMID- 21671264 TI - New treatment for peripheral nerve defects: reconstruction of a 2 cm, monkey median nerve gap by direct lengthening of both nerve stumps. AB - We have developed a new treatment for peripheral nerve defects: nerve-lengthening method, and confirmed the efficacy and safety of our method using cynomolgus monkeys. A 20-mm defect in the median nerve of monkey's forearms was repaired through the simultaneous lengthening of both nerve stumps with original nerve lengthening device. To evaluate nerve regeneration after neurorrhaphy, electrophysiological, histological, and functional recovery were examined and compared to the standard autografting. Nerve conduction velocity, axon maturation, and the result of functional test were superior in the nerve lengthening method than in the autografting. And there were no adverse events associated with our method. We concluded that this method is practical for clinical application. PMID- 21671263 TI - Determination of annulus fibrosus cell response to tensile strain as a function of duration, magnitude, and frequency. AB - As clinical evidence suggests that mechanical forces can have both reparative and traumatic effects on the spine, we investigated responses to different magnitudes, frequencies, and durations of applied tensile strain in an in vitro system. We examined the interactions of inflammatory and mechanical stimuli on cells isolated from the annulus fibrosus. Rabbit annulus fibrosus fibrochondrocytes were cultured in the presence or absence of an inflammatory stimulus. Cells were exposed to various magnitudes and frequencies of tensile strain for 4 or 24 h, and mRNA expression of catabolic mediators of inflammation and matrix degradation was measured by quantitative real time PCR and compared to control cells. Conditioned media were analyzed for matrix metalloprotease activity and production of prostaglandin E(2) . Application of low magnitudes and frequencies of tensile strain resulted in down-regulation of catabolic mediators, particularly under inflammatory stress. However, loss of this protective effect was observed at higher frequency and magnitude, and after prolonged duration. These in vitro data confirm the existence of magnitude, frequency, and duration based effects, which determine biochemical response of disc tissue resulting in either anti- or pro-catabolic outcomes. This may help to explain the beneficial effects of motion-based therapies as well as the destructive effect of traumatic levels of applied strain. PMID- 21671265 TI - Contrast at high field: relaxation times, magnetization transfer and phase in the rat brain at 16.4 T. AB - As field strength increases, the magnetic resonance imaging contrast parameters like relaxation times, magnetization transfer or image phase change, causing variations in contrast and signal-to-noise ratio. To obtain reliable data for these parameters at 16.4 T, high-resolution measurements of the relaxation times T(1), T(2) and T(2)*, as well as of the magnetization transfer ratio and the local frequency in the rat brain were performed. Tissue-specific values were obtained for up to 17 brain structures to assess image contrast. The measured parameters were compared to those found at different field strengths to estimate contrast and signal behavior at increasing field. T(1) values were relatively long with (2272 +/- 113) ms in cortex and (2073 +/- 97) ms in white matter, but did not show a tendency to converge, leading to an almost linear increase in signal-to-noise ratio and still growing contrast-to-noise ratio. T(2) was short with (25 +/- 2) ms in cortex and (20 +/- 1) ms in white matter. Magnetization transfer effects increase by around 25% compared to published 4.7 T data, which leads to improved contrast. The image phase, as novel and high-field specific contrast mechanism, is shown to obtain good contrast in deep brain regions with increasing signal-to-noise ratio up to high field strengths. PMID- 21671267 TI - Multi-contrast reconstruction with Bayesian compressed sensing. AB - Clinical imaging with structural MRI routinely relies on multiple acquisitions of the same region of interest under several different contrast preparations. This work presents a reconstruction algorithm based on Bayesian compressed sensing to jointly reconstruct a set of images from undersampled k-space data with higher fidelity than when the images are reconstructed either individually or jointly by a previously proposed algorithm, M-FOCUSS. The joint inference problem is formulated in a hierarchical Bayesian setting, wherein solving each of the inverse problems corresponds to finding the parameters (here, image gradient coefficients) associated with each of the images. The variance of image gradients across contrasts for a single volumetric spatial position is a single hyperparameter. All of the images from the same anatomical region, but with different contrast properties, contribute to the estimation of the hyperparameters, and once they are found, the k-space data belonging to each image are used independently to infer the image gradients. Thus, commonality of image spatial structure across contrasts is exploited without the problematic assumption of correlation across contrasts. Examples demonstrate improved reconstruction quality (up to a factor of 4 in root-mean-square error) compared with previous compressed sensing algorithms and show the benefit of joint inversion under a hierarchical Bayesian model. PMID- 21671266 TI - Compressed-sensing motion compensation (CosMo): a joint prospective-retrospective respiratory navigator for coronary MRI. AB - Prospective right hemidiaphragm navigator (NAV) is commonly used in free breathing coronary MRI. The NAV results in an increase in acquisition time to allow for resampling of the motion-corrupted k-space data. In this study, we are presenting a joint prospective-retrospective NAV motion compensation algorithm called compressed-sensing motion compensation (CosMo). The inner k-space region is acquired using a prospective NAV; for the outer k-space, a NAV is only used to reject the motion-corrupted data without reacquiring them. Subsequently, those unfilled k-space lines are retrospectively estimated using compressed sensing reconstruction. We imaged right coronary artery in nine healthy adult subjects. An undersampling probability map and sidelobe-to-peak ratio were calculated to study the pattern of undersampling, generated by NAV. Right coronary artery images were then retrospectively reconstructed using compressed-sensing motion compensation for gating windows between 3 and 10 mm and compared with the ones fully acquired within the gating windows. Qualitative imaging score and quantitative vessel sharpness were calculated for each reconstruction. The probability map and sidelobe-to-peak ratio show that the NAV generates a random undersampling k-space pattern. There were no statistically significant differences between the vessel sharpness and subjective score of the two reconstructions. Compressed-sensing motion compensation could be an alternative motion compensation technique for free-breathing coronary MRI that can be used to reduce scan time. PMID- 21671268 TI - Serial MRI characterization of the functional and morphological changes in mouse lung in response to cardiac remodeling following myocardial infarction. AB - The temporal evolution of heart failure and associated pulmonary congestion in rodent heart failure models has not yet been characterized simultaneously and noninvasively. In this study, MRI was used to assess the serial progression of left-ventricular dysfunction and lung congestion in mice following myocardial infarction (MI). Cardiac and lung (1) H MRI was performed at baseline and every 3 days up to 13 days postsurgery in sham and MI mice. Respiratory parameters and terminal lung mechanics were assessed followed by histological analysis. MRI revealed that the MI induced significant pulmonary congestion/edema as detected by increased MRI signal intensity and was associated with increased lung volume and reduced cardiac contractility. Pulmonary function was also depressed in MI mice, reflected by a reduced tidal volume and a low minute ventilation rate. Additionally, MI significantly increased lung resistance, markedly reduced lung compliance and total lung capacity and significantly increased lung weights by 57%. Significant correlations were observed between the MRI measured lung congestion, lung volume, ejection fraction, and lung wet-weight parameters. This study demonstrates that MRI may be of significant value in evaluating therapies aimed at primary intervention for lung congestion and secondary prevention of unfavorable cardiac remodeling. PMID- 21671269 TI - Whole brain susceptibility mapping using compressed sensing. AB - The derivation of susceptibility from image phase is hampered by the ill conditioned filter inversion in certain k-space regions. In this article, compressed sensing is used to compensate for the k-space regions where direct filter inversion is unstable. A significantly lower level of streaking artifacts is produced in the resulting susceptibility maps for both simulated and in vivo data sets compared to outcomes obtained using the direct threshold method. It is also demonstrated that the compressed sensing based method outperforms regularization based methods. The key difference between the regularized inversions and compressed sensing compensated inversions is that, in the former case, the entire k-space spectrum estimation is affected by the ill-conditioned filter inversion in certain k-space regions, whereas in the compressed sensing based method only the ill-conditioned k-space regions are estimated. In the susceptibility map calculated from the phase measurement obtained using a 3T scanner, not only are the iron-rich regions well depicted, but good contrast between white and gray matter interfaces that feature a low level of susceptibility variations are also obtained. The correlation between the iron content and the susceptibility levels in iron-rich deep nucleus regions is studied, and strong linear relationships are observed which agree with previous findings. PMID- 21671270 TI - Benzodiazepine prescription among patients with severe mental illness and co occurring alcohol abuse/dependence in Taiwan. AB - OBJECTIVE: Because benzodiazepines (BZDs) may be abused, prescribing them is debatable. The purpose of this study was to investigate the prescription of BZDs to explore the current status of BZD use at discharge and at 4 months after discharge. METHODS: From 1 January 2006 to 31 December 2006, prescribed doses for BZDs at discharge and at 4 months after discharge were recorded for all discharged inpatients with schizophrenia, bipolar I disorder, and major depressive disorder. Two-way analysis of variance was used to analyze the effects of severe mental illness and co-occurring alcohol abuse/dependence on BZD doses at discharge and at 4 months after discharge. RESULTS: Patients with severe mental illness prescribed with significantly higher rates and higher doses of BZDs at discharge and at 4 months after discharge are more likely to have major depressive disorder and to have co-occurring alcohol abuse/dependence problems. No significant interactions were found between severe mental illness and co occurring alcohol abuse/dependence. CONCLUSIONS: These findings suggest that caution should be applied in prescribing BZDs to patients with severe mental illness, particularly those with major depressive disorder and co-occurring alcohol abuse/dependence. Future studies require being conducted in many different mental health-care systems in Taiwan to generalize the findings. PMID- 21671271 TI - Analysis of protein function and its prediction from amino acid sequence. AB - Understanding protein function is one of the keys to understanding life at the molecular level. It is also important in the context of human disease because many conditions arise as a consequence of alterations of protein function. The recent availability of relatively inexpensive sequencing technology has resulted in thousands of complete or partially sequenced genomes with millions of functionally uncharacterized proteins. Such a large volume of data, combined with the lack of high-throughput experimental assays to functionally annotate proteins, attributes to the growing importance of automated function prediction. Here, we study proteins annotated by Gene Ontology (GO) terms and estimate the accuracy of functional transfer from protein sequence only. We find that the transfer of GO terms by pairwise sequence alignments is only moderately accurate, showing a surprisingly small influence of sequence identity (SID) in a broad range (30-100%). We developed and evaluated a new predictor of protein function, functional annotator (FANN), from amino acid sequence. The predictor exploits a multioutput neural network framework which is well suited to simultaneously modeling dependencies between functional terms. Experiments provide evidence that FANN-GO (predictor of GO terms; available from http://www.informatics.indiana.edu/predrag) outperforms standard methods such as transfer by global or local SID as well as GOtcha, a method that incorporates the structure of GO. PMID- 21671272 TI - Is the research on continuing education of health professionals underutilized? PMID- 21671273 TI - How mentoring relationships evolve: a longitudinal study of academic pediatricians in a physician educator faculty development program. AB - INTRODUCTION: Mentoring is increasingly recognized as central to career development. Less attention has been paid, however, to how mentoring relationships evolve over time. To provide a more complete picture of these complex relationships, the authors explored mentoring from a mentee's perspective within the context of a three-year faculty development program in which the mentor provided specific expertise to assist the mentee in completing a scholarly educational project. METHODS: Using an evolving focus group design, the authors interviewed mentee groups in 2007-2009 inclusive. Transcripts were coded inductively; codes were revised as data patterns became more apparent. Preliminary assertions about the answers to guiding questions were made; the trustworthiness of the assertions was assessed via member check. RESULTS: Mentees offered a variety of reasons for choosing their project mentor, including proximity, familiarity, and mentor expertise. There was a dyadic relationship with the project mentor in year 1, a broader collaboration with multiple senior mentors in year 2, and mentoring among program peers in year 3. Mentees benefitted from mentors' supportive behaviors and, to a lesser extent, mentors' challenging behaviors. CONCLUSION: Mentoring relationships, in the context of this faculty development program, tended not to be an exclusive dyadic connection but rather a constellation of relationships that evolved over time and included peer mentoring. The complex reality of these relationships challenges the application of traditional mentoring models and suggests unique considerations in developing mentoring programs designed to meet the needs of faculty in academic medicine. PMID- 21671274 TI - How do physicians assess their family physician colleagues' performance?: creating a rubric to inform assessment and feedback. AB - INTRODUCTION: The Colleges of Physicians and Surgeons of Alberta and Nova Scotia (CPSNS) use a standardized multisource feedback program, the Physician Achievement Review (PAR/NSPAR), to provide physicians with performance assessment data via questionnaires from medical colleagues, coworkers, and patients on 5 practice domains: consultation communication, patient interaction, professional self-management, clinical competence, and psychosocial management of patients. Physicians receive a confidential report; the intent is practice improvement. However, research indicates that feedback from medical colleagues appears to be less understood than that from coworkers or patients, due to a lack of specificity and concerns regarding feedback credibility. The purpose of this study was to determine how physicians make decisions about performance ratings for family physician (FP) colleagues in the 5 practice domains. METHODS: This was an exploratory qualitative study using focus groups-one with 11 family physicians and one with 12 specialists-who had served as NSPAR "medical colleague'' reviewers. We analyzed focus group transcripts using content analysis. RESULTS: Family and specialist physicians provided examples of behaviors indicative of both high- and low-scoring performance for items within the 5 practice domains. From these, an assessment rubric was created to inform both external reviewers and the physicians being reviewed of performance expectations. Reviewers reported using varied sources of information to make assessments, including shared patients, medical records, referral letters, feedback from others, and self reference. DISCUSSION: The CPSNS has used the assessment rubric to create an online resource to inform medical colleague assessment and enhance the usefulness of their NSPAR scores. Further research will be required to determine its impact. PMID- 21671275 TI - Can criteria for identifying educational influentials in developed countries be applied to other countries? A study in Iran. AB - INTRODUCTION: There are published criteria for identifying educational influentials (EIs). These criteria are based on studies that have been performed in developed countries. This study was performed to identify criteria and characteristics of EIs in Iran. METHODS: The study was conducted on residents, interns, and clerks at a major educational hospital in Iran. This study had 3 stages: (1) preparation of an inclusive list of EI characteristics through 3 focus group discussions with 22 individuals, in which 30 primary characteristics of EIs were found; (2) reducing the number of characteristics by examining 154 individuals for exploratory factor analysis and internal consistency evaluation by Cronbach's alpha, after which the characteristics were reduced to 25; (3) finalizing the criteria through discriminant validity. RESULTS: Fifteen characteristics were identified in 4 domains: (1) knowledge (high level of clinical knowledge, being up-to-date and an expert, high level of clinical skills); (2) communication skills (good communication with others, easily accessible, good public relations, and oratory); (3) taking into account the stakeholders (involving patients in decision making, allowing students to identify problems, delivering decisions to others, and interest in transfer of material); and (4) professional ethics (pursuing the patients' maximum benefit, observing ethics in education and research). Overall, they have a sensitivity and specificity of 87% and 74%, respectively. DISCUSSION: Three of the four domains we found were already identified in other studies; however, the "taking into account the stakeholders" domain has not been previously reported. The other domains and criteria were similar to those found in developed countries. PMID- 21671276 TI - Impact on clinical behavior of face-to-face continuing medical education blended with online spaced education: a randomized controlled trial. AB - BACKGROUND: Spaced education (SE) is a novel, evidence-based form of online learning. We investigated whether an SE program following a face-to-face continuing medical education (CME) course could enhance the course's impact on providers' clinical behaviors. METHODS: This randomized controlled trial was conducted from March 2009 to April 2010, immediately following the Current Clinical Issues in Primary Care (Pri-Med) CME conference in Houston, Texas. Enrolled providers were randomized to receive the SE program immediately after the live CME event or 18 weeks later (wait-list controls). The SE program consisted of 40 validated questions and explanations covering 4 clinical topics. The repetition intervals were adapted to each provider based on his or her performance (8- and 16-day intervals for incorrect and correct answers, respectively). Questions were retired when answered correctly twice in a row. At week 18, a behavior change survey instrument was administered simultaneously to providers in both cohorts. RESULTS: Seventy-four percent of participants (181/246) completed the SE program. Of these, 97% (176/181) submitted the behavior change survey. Across all 4 clinical topics, providers who received SE reported significantly greater change in their global clinical behaviors as a result of the CME program (p-values .013 to < .001; effect size 0.7). Ninety seven percent (175/179) requested to participate in future SE supplements to live CME courses. Eighty-six percent (156/179) agreed or strongly agreed that the SE program enhanced the impact of the live CME conference. DISCUSSION: Online spaced education following a live CME course can significantly increase the impact of a face-to-face course on providers' self-reported global clinical behaviors. PMID- 21671277 TI - Controlling quality in CME/CPD by measuring and illuminating bias. AB - INTRODUCTION: There has been a surge of interest in the area of bias in industry supported continuing medical education/continuing professional development (CME/CPD) activities. In 2007, we published our first study on measuring bias in CME, demonstrating that our assessment tool was valid and reliable. In light of the increasing interest in this area, and building on our experience, we wanted to further understand the application of this tool in different environments. We invited other CME/CPD providers from multiple sites in Canada to participate in a second CME bias study. METHODS: A new steering committee was established with representatives from 5 academic CME/CPD offices nationally, the Royal College of Physicians and Surgeons, and the College of Family Physicians of Canada to outline the project in terms of review of the literature, refining items on the tool, updating the training guide for implementation, and establishing a resource Web site for reviewers. Training involved a train-the-trainer session with the event coordinators at each of the 5 participating centers via videoconferencing. RESULTS: The content reviews from the study showed moderate inter-rater reliability (ICC = 0.54), and the live reviews showed poor overall inter-rater reliability; however, one center achieved substantial inter-rater reliability (ICC = 0.68). DISCUSSION: The analysis from this study suggests that the tool can be used as a part of a multistage process to introduce quality control mechanisms to help raise standards for CME/CPD. It is imperative to develop a cost-effective standardized training protocol that can be implemented at all sites to maximize the reliability of the tool. PMID- 21671278 TI - Guiding principles for physician reentry programs. AB - Physician reentry is defined by the American Medical Association (AMA) as: "A return to clinical practice in the discipline in which one has been trained or certified following an extended period of clinical inactivity not resulting from discipline or impairment." Physician reentry programs are creating an avenue for physicians who have left medicine in good standing to return to clinical practice. To date, however, programs have developed independently, with little coordination among them. If, as predicted, more physicians seek to reenter practice and more programs are developed in response, the need for information on program outcomes will grow. Valid assessment tools should be developed and shared across reentry programs to assess individual learner outcomes. This discussion paper sets forth Guiding Principles for Physician Reentry Programs as a step toward a more coordinated approach to physician reentry education and training. They serve as a reference for setting priorities and standards for action and, more specifically, offer a foundation from which programs can be planned, evaluated, and monitored. In addition to the guiding principles, an overview of physician reentry is provided including information on reentry physicians and physician reentry programs as well as a definition of physician reentry, reasons for taking leave and returning to clinical practice, and barriers physicians face as they seek to reenter clinical care. PMID- 21671279 TI - Enhancing practice improvement by facilitating practitioner interactivity: new roles for providers of continuing medical education. AB - Research into networking and interactivity among practitioners is providing new information that has the potential to enhance the effectiveness of practice improvement initiatives. This commentary reviews the evidence that practitioner interactivity can facilitate emergent learning and behavior change that lead to practice improvements. Insights from learning theories provide a framework for understanding emergent learning as the product of interactions between individuals in trusted relationships, such as occurs in communities of practice. This framework helps explain why some groups respond more favorably to improvement initiatives than others. Failure to take advantage of practitioner interactivity may explain in part the disappointingly low mean rates of practice improvement reported in studies of the effectiveness of practice improvement projects. Examples of improvement models in primary care settings that explicitly use relationship building and facilitation techniques to enhance practitioner interactivity are provided. Ingredients of a curriculum to teach relationship building in communities of practice and facilitation skills to enhance learning in small group education sessions are explored. Sufficient evidence exists to support the roles of relationships and interactivity in practice improvement initiatives such that we recommend the development of training programs to teach these skills to CME providers. PMID- 21671280 TI - Web-based morbidity and mortality conferencing: a model for rural medical education. AB - Transfer of patients from rural emergency departments to tertiary centers can improve outcomes. The transfer process is complex and often ad hoc, inefficient, duplicative, and frustrating to both patients and providers. Suboptimal transfer undermines quality of care, raises costs, and delays services. Unfortunately, the same barriers that make transfer necessary (limited resources, geographic isolation) also hamper effective review. In this article, we describe a Web based, interactive morbidity and mortality conference series in which providers reviewed cases transferred from rural emergency departments to a tertiary center. Six case-review conferences were conducted over 8 months. Each involved an average of 20 providers representing a total of 7 hospitals. Learning resources (ie, care protocols, best practice reviews, literature reviews) were developed collaboratively and disseminated among participating hospitals following the case review conferences. Participant responses were highly favorable: 100% found the case reviews "very useful" or "useful" and 100% strongly agreed that the reviews would improve quality of patient care. We conclude that Web-based technology can efficiently facilitate review of transfers and has the potential to positively impact patient care. Future studies should utilize standard validated survey instruments of a larger number of participants to better understand the impact of this intervention. PMID- 21671281 TI - Presentation of the microscopic vascular architecture of the radial head using a sequential plastination technique. AB - The purpose of this study was to demonstrate the peri- and intraosseous vascular architecture of the radial head and vascular interaction with surgical implants. Seventeen fresh human cadaveric elbows were sequentially plastinated beginning with arterial injection, followed by block and slice plastination of the whole elbow. With this technique, we obtained completely transparent cadaveric slices in which the peri- and intraosseous vascular architecture could be studied in its neutral position. In six of these elbows, radial head osteosynthesis was imitated with miniplates or fine threaded K-wires. Vascularization of the radial head occurred via branches of the radial recurrent artery on the ventral, lateral, and dorsal sides of the radial head and a branch of the ulnar artery--ramus periostalis ulnaris--medially and dorsomedially. Both arteries create a pericervical arterial ring around the radial neck. A branch of the interosseous artery--R. interosseous recurrence--supports the ventral and dorsal sides of the radial neck and the final branches of the nutrient artery support intraosseous vascularization. Vascular structures were damaged more severely by plates than by screws. The peri- and intraosseous vascularization of the radial head and the interaction between vascularization and the implants was shown. Plate fixation of radial head fractures leads to a higher level of implant-related destruction of the periosseous vascularization than screw fixation. Besides devascularization of the radial head due to the injury leading to a certain risk of fracture nonunion, additional implant-related injuries to the blood supply might increase the chance of radial head fracture non-union. PMID- 21671282 TI - Variant origin of the superior thyroid artery in a Kenyan population. AB - Variant anatomy of the superior thyroid artery is important during surgical procedures, interpretation of angiograms, and interventional radiography in the neck. Pattern of the variations shows population differences but there is no data from the Kenyan population. This study therefore investigated the variations in origin of the superior thyroid artery in a Kenyan population. Forty six necks (36 males and 10 females) from 46 cadavers of black Kenyans in Department of Human Anatomy University of Nairobi, Kenya were bilaterally dissected to expose the origin of the superior thyroid artery. Pattern of origin of the vessel was determined on both sides in males and females. It originated from the external carotid artery common carotid artery and linguo-facial trunk in 80%, 13%, and 6.5% of the cadavers respectively on the right side. All but one of the superior thyroid arteries were ventral branches. There was asymmetric origin in 6.5% of cases. Origin from the common carotid artery was associated with high carotid bifurcation. Nearly 20% of superior thyroid arteries showed variant origin. Of these, 6.5% arose from the linguo-facial trunk, much higher than in the Caucasian and Oriental populations. Origin from common carotid artery is substantially lower than prevailing figures from other populations. These findings support ethnic variations. Preoperative angiographic evaluation is recommended. PMID- 21671283 TI - Anatomical variations of the lateral nasal wall: The secondary and accessory middle turbinates. AB - The aim of the current anatomical and clinical study was to audit our cases of patients who presented with secondary and/or accessory middle turbinates during a two-year period. We investigated the incidence and the clinical impact of these variations. Twenty-eight patients, 19 males and 9 females with a mean age of 41.5 years, representing different ethnic origins, were diagnosed with double middle turbinates based on endoscopic examination. Of those, 92.8% had a main symptom of refractory frontal headache. A secondary nasal symptom was sensation of blocked nose. Patients who underwent endoscopic surgery (n = 13) for reduction of the extra turbinate, reported significant symptom scores improvement (P < 0.0001) of frontal headache and blocked nose, from means of 9.07 +/- 0.26 and 8.57 +/- 1.39 to 1 +/- 0.31, and 1.42 +/- 0.35, respectively. Our results indicate that double middle turbinates may be encountered in rhinology practice (2%). Clinically they may present with refractory headache and blocked nose. Endoscopic surgical approach seems to be an effective way of improving the symptoms. PMID- 21671284 TI - Parotidectomy--Anatomical considerations. AB - The parotid glands are paired major salivary glands and are located in the preauricular region. Parotidectomy is a surgical procedure that entails removal of all or a portion of the parotid gland. The most common indications for this operative procedure are a neoplasm of the parotid gland or metastases to parotid lymph nodes. An intimate knowledge of the anatomy of the parotid gland and related structures is necessary for the performance of safe and successful parotid surgery. This report will discuss the anatomy of the parotid gland as it pertains to parotid surgery and the avoidance of complications related to this surgery. PMID- 21671285 TI - Mapping a muscle with magnetic resonance imaging. PMID- 21671286 TI - Nerve root to lumbar disc relationships at the intervertebral foramen from a surgical viewpoint: An anatomical study. AB - The objective of this study was to analyze relationship of the intervertebral disc to the nerve root in the intervertebral foramen. Fourteen formalin-fixed cadavers were studied and measurements were performed. At the medial line of the neural foramen, the disc-root distance gradually increased from L1-L2 to L5-S1. The shortest distance between the disc to nerve root was L1-L2 (mean, 8.2 mm) and the greatest distance was found at L3-L4 (mean, 10.5 mm). In the mid-foramen, the disc-root distance decreased from L1-2 to L5-S1. The shortest distance from the disc to nerve root was found at L5-S1 (mean, 0.4 mm); and the greatest distance, at L1-L2 (mean, 3.8 mm). For the lateral line, the distance between an intersection point between the medial edge of the nerve root and the superior edge of the disc and lateral line of the foramen consistently increased from L1 L2 to L5-S1. The shortest distance from nerve root to the lateral border of the foramen, at the point where the nerve root crosses disc was at level L1-L2 (mean, 2.6 mm), the greatest distance, L5-S1 (mean, 8.8 mm). The width of the foramina progressively increased in a craniocaudal direction (mean, 8.3-17.8 mm from L1-2 to L5-S1, respectively). The mean height of the foramina was more or less the same for disc levels (range, 19.3-21.5). The results showed that nerve roots at lower levels traveled closer to the midline of the foramen. This morphometric information may be helpful in minimizing the incidence of injury to the lumbar nerve root during foraminal and extraforaminal approaches. PMID- 21671287 TI - Stereoselective determination of the epimer mixtures of itraconazole in human blood plasma using HPLC and fluorescence detection. AB - Itraconazole is an antifungal drug widely used in a variety of fungal infections, which have become a significant public-health problem in recent decades. Itraconazole is a chiral drug consisting of two diastereoisomeric racemates, i.e., four stereoisomers. Data in the literature suggests that stereochemistry may play a significant role in the action and disposition of the drug and therefore stereoselective analytical methods for the determination of the drug in biological fluids are needed for the elucidation of that role. We report a stereoselective HPLC method that incorporates solvent extraction, the use of an internal standard, two chiral stationary phases in series, and fluorescence detection. The procedure is enantioselective and partially diastereoselective and provides the concentrations in blood plasma of the two epimer mixtures 2R,4S,2'R/2R,4S2'S and 2S,4R,2'R/2S,4R,2'S, respectively, each of which is a combination of the two epimers that differ in the configuration at the sec-butyl group. The analytical method has suitable sensitivity, recovery, precision, and accuracy. Analysis of the plasma of a human subject six hours after the oral administration of a single 200-mg dose of itraconazole showed a 3.4-fold difference between the concentrations of the epimer mixtures. The method has certain advantages over the published alternative procedure that uses LC-MS. PMID- 21671288 TI - Peripheral substitution of a near-IR-absorbing soluble phthalocyanine using "click" chemistry. AB - A series of near-IR-absorbing soluble phthalocyanines (Pcs) with eight alkyne moieties as side chains of the chromophore have been synthesized. One of these Pcs has been used as a scaffold for functional group modification using alkyne azide click chemistry with various azides. This led to a small library of Pcs with photo and thermal crosslinkable, dendritic, and hydrophilic moieties starting from a single Pc molecule. A patterned thin film was fabricated by photocrosslinking one of these Pc derivatives. PMID- 21671289 TI - Synthesis and photochemical investigations of tetrasubstituted alkenes as molecular switches--the effect of substituents. AB - Molecular switches based on helical tetrasubstituted alkenes, substituted with either electron-withdrawing (CF(3), F, CN; 2a-c, 3a,c) or -donating substituents (Me, OMe; 2d,e), have been synthesized from acyclic precursors 4 and 5 in a domino carbopalladation/Stille reaction. This palladium-catalyzed process allowed the rapid assembly of two C-C bonds, two six-membered rings, and the tetrasubstituted double bond in a completely diastereoselective fashion. The electronic effects of the substituents on the overall switching process were investigated by alternating irradiation of two different wavelength regions. Although the substituents had only a small influence on the absorption maxima, drastic differences in the switching behavior were observed. PMID- 21671290 TI - Structural characterization of phosphorus-based networks and clusters: 31P MAS NMR spectroscopy and magnetic shielding calculations on Hittorf's phosphorus. AB - The (31)P MAS NMR spectrum of Hittorf's phosphorus has been measured and assigned to the 21 crystallographically distinct phosphorus atoms based on two-dimensional dipolar correlation spectroscopies. Application of such 2D techniques to phosphorus-based networks is particularly challenging owing to the wide chemical shift dispersions, rapid irreversible decay of transverse magnetization, and extremely slow spin-lattice relaxation in these systems. Nevertheless, a complete assignment was possible by using the combination of correlated spectroscopy (COSY) and radiofrequency-driven dipolar recoupling (RFDR). The assignment is supported further by DFT-based ab initio chemical shift calculations using a cluster-model approach, which gives good agreement between experimental and calculated chemical shift values. The (31)P chemical shifts appear to be strongly correlated with the average P-P bond lengths within the P(P(1/3))(3) coordination environments, whereas no clear dependence on average P-P-P bond angles can be detected. Calculations of localized Kohn-Sham orbitals reveal that this bond length dependence is reflected in energy variations in the corresponding localized p-p-sigma orbitals influencing the paramagnetic deshielding contribution in Ramsey's equation. In contrast, the contributions of the lone pairs to shielding differences are small and/or do not vary in a systematic manner for the different crystallographically distinct phosphorus sites. The combined spectroscopic and quantum chemical approach applied here and the increased theoretical understanding of (31)P chemical shifts will facilitate the structural elucidation of other phosphorus-based clusters and networks. PMID- 21671291 TI - High-intensity fluorescence imaging and sensitive electrochemical detection of cancer cells by using an extracellular supramolecular reticular DNA-quantum dot sheath. AB - Acting as a cage-type cellular probe, an extracellular supramolecular reticular DNA-quantum dot (QD) sheath has been developed for high-intensity fluorescence microscopy imaging and the sensitive electrochemical detection of Ramos cells. The extracellular supramolecular reticular DNA-QD sheath is constructed from layer-by-layer self-assembly of DNA-CdTe QD probes and DNA nanowire frameworks functionalized with a Ramos cell-binding aptamer. The DNA-QD sheath forms specifically and quickly on the surface of Ramos cells at physiological temperature, and the assembly of large numbers of DNA-CdTe QD probes on the surface of Ramos cells produces exceedingly high fluorescence intensity. Using the extracellular supramolecular reticular DNA-QD sheath as the cellular probe, Ramos cells can be clearly observed and easily distinguished from a mixture of multiple cancer cells by fluorescence microscopy imaging. Using the new cage-type cellular probe, a sensitive sandwich-type electrochemical strategy has also been developed to achieve accurate quantitative analysis of Ramos cells. Under the optimized conditions, Ramos cells can be detected quantitatively in a range from 10 to 1000 cells with a detection limit of 10 cells. This strategy presents a promising platform for highly sensitive and convenient evaluation of cancer cell levels. PMID- 21671292 TI - Total synthesis of (+)-(2'S,3'R)-zoapatanol exploiting the B-alkyl Suzuki reaction and the nucleophilic potential of the sulfinyl group. AB - A stereoselective synthesis of the diterpenoid oxepane (+)-zoapatanol is described. The key steps include a B-alkyl Suzuki cross-coupling reaction for the stereoselective synthesis of trisubstituted alkenes, creation of the two stereogenic centers on the oxepane ring by heterofunctionalization of an alkene through substrate control exploiting the nucleophilic potential of an intramolecular sulfinyl group, and transformation of a beta-hydroxy sulfoxide into a terminal alkene. PMID- 21671293 TI - Microenvironment engineering in ortho- and para-dendronized metalloporphyrin fullerene conjugates involving a trans-2-bisaddition pattern. AB - A new series of dendronized metalloporphyrin-fullerene conjugates as photosynthetic reaction center mimics was developed in a highly regioselective fashion through tether-controlled synthesis. The microenvironment around the porphyrin core is dependent on the spatial substitution pattern and the nature and generation number of the dendrons, which was proven by cyclic voltammetry. PMID- 21671294 TI - MRI-guided neutron capture therapy by use of a dual gadolinium/boron agent targeted at tumour cells through upregulated low-density lipoprotein transporters. AB - The upregulation of low-density lipoprotein (LDL) transporters in tumour cells has been exploited to deliver a sufficient amount of gadolinium/boron/ligand (Gd/B/L) probes for neutron capture therapy, a binary chemio-radiotherapy for cancer treatment. The Gd/B/L probe consists of a carborane unit (ten B atoms) bearing an aliphatic chain on one side (to bind LDL particles), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other (for detection by magnetic resonance imaging (MRI)). Up to 190 Gd/B/L probes were loaded per LDL particle. The uptake from tumour cells was initially assessed on cell cultures of human hepatoma (HepG2), murine melanoma (B16), and human glioblastoma (U87). The MRI assessment of the amount of Gd/B/L taken up by tumour cells was validated by inductively coupled plasma-mass-spectrometric measurements of the Gd and B content. Measurements were undertaken in vivo on mice bearing tumours in which B16 tumour cells were inoculated at the base of the neck. From the acquisition of magnetic resonance images, it was established that after 4-6 hours from the administration of the Gd/B/L-LDL particles (0.1 and 1 mmol kg(-1) of Gd and (10)B, respectively) the amount of boron taken up in the tumour region is above the threshold required for successful NCT treatment. After neutron irradiation, tumour growth was followed for 20 days by MRI. The group of treated mice showed markedly lower tumour growth with respect to the control group. PMID- 21671295 TI - Stereoselective conjugate addition reactions to phenylglycinol-derived, unsaturated oxazolopiperidone lactams. AB - Phenylglycinol-derived, unsaturated oxazolopiperidone lactams are extremely useful building blocks that undergo stereoselective conjugate addition reactions with organocuprates, enolates, and sulfur-stabilized anions, allowing the stereocontrolled introduction of substituents at the piperidine 4-position. The factors governing the exo- or endo-facial selectivity are discussed. The methodology can be used for the preparation of a variety of enantiopure piperidines, including pharmaceuticals, alkaloids precursors, piperidine-fused derivatives, as well as complex piperidine-containing natural products. PMID- 21671297 TI - A molecular pair of [GdNi3] tetrahedra bridged by water molecules. PMID- 21671296 TI - Sequence-controlled oligomers fold into nanosolenoids and impart unusual optical properties. AB - Controlled syntheses give unique block oligomers with alternating flexible ethylene glycol and rigid perylenetetracarboxylic diimide (PDI) units. The number of rigid units vary from n=1 to 10. PDI units were stitched together by using efficient phosphoramidite chemistry. The resulting oligomers undergo folding in most solvents, including chloroform. In their ground state, these folded oligomers were characterized by using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), NMR spectroscopy, and electronic absorption spectroscopy. FTICR-MS revealed the exact masses of these sequence-controlled oligomers, which confirmed the chemical composition and validated the synthetic strategy. The NMR neighboring ring-current effect (NRE) indicates the formation of cofacial pi stacks; the stacked aromatic rings have nearly coaxial alignment akin to a nanosoleniod. Nanosolenoidal shielding in pi stacks causes all aromatic protons to shift upfield, whereas NOE in a cyclic hetero-chromophoric dimer supports a rotated, cofacial pi-stacking orientation separated by about 3.5 A. Electron-phonon coupling is much stronger than excitonic coupling in these self folded PDI oligomers; thus, Franck-Condon factors dictate the observed spectral features in visible spectra. The absorbance spectrum exhibits weak hypochromism due to pi stacking with increasing stacking units n. Finally, ab initio calculations support the experimental observations, indicating 3.5 A cofacial spacing in which one molecule is rotated 30 degrees from the eclipsed orientation and higher oligomers can adopt, without a compensating energy penalty, either the right/left-handed helices or the 1,3-eclipsed structures. Both theory and experiments validate the nano-pi-solenoids and their novel photophysical properties. PMID- 21671298 TI - Stereoselective synthesis of 4alpha-alkyloxy-2-alpha/beta-bromopodophyllotoxin derivatives as insecticidal agents. PMID- 21671299 TI - DNA-templated photonic arrays and assemblies: design principles and future opportunities. AB - Molecular photonics is a rapidly developing and multi-disciplinary field of research involving the construction of molecular assemblies comprising photoactive building blocks that are responsive to a light stimulus. A salient challenge in this field is the controlled assembly of these building blocks with nanoscale precision. DNA exhibits considerable promise as an architecture for the templated assembly of photoactive materials. In this Concept Article we describe the progress that has been made in the area of DNA photonics, in which DNA acts as a platform for the construction of optoelectronic assemblies, thin films and devices. PMID- 21671300 TI - Water-based hydrogen-atom wires as mediators in long-range proton-coupled electron transfer in enzymes: a new twist on water reactivity. PMID- 21671301 TI - Retrieving the most prevalent small fullerene C56. PMID- 21671304 TI - The Edmonton Symptom Assessment System, a proposed tool for distress screening in cancer patients: development and refinement. AB - OBJECTIVE: The Edmonton Symptom Assessment System (ESAS) has been proposed as one element of a distress screening strategy in cancer patients. It consists of 11 point numerical rating scales for self-report of nine common symptoms of cancer, with a 10th scale for a patient-specific symptom. The ESAS has undergone widespread adoption internationally for clinical, research and administrative purposes. Despite its rapid uptake, validity evidence has lagged behind, and concerns have been raised about feasibility and usefulness. The objective of this paper is to provide a synthesis of a program of research focusing on the psychometric properties of the ESAS. METHODS: We describe and discuss a series of three ESAS studies undertaken by our group: (i) a review of ESAS validation studies (1991-2006); (ii) a think-aloud study conducted in 20 advanced cancer patients; and (iii) a prospective multicenter study conducted in 160 patients in different palliative care settings, comparing the ESAS with a revised version (ESAS-r). RESULTS: The review identified 13 articles focusing on gathering reliability and/or validity evidence; the need to standardize the ESAS and conduct further validation research was apparent. The think-aloud study elucidated the complex cognitive processes by which patients arrive at symptom ratings and areas of potential difficulty in understanding and completing the ESAS. The multicenter study demonstrated that the ESAS-r was significantly easier for patients to understand. CONCLUSIONS: Overall, our findings support consideration of the ESAS and its successor, the ESAS-r, for use in distress screening in cancer patients. Areas for future research will be presented. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21671303 TI - The choice of detecting Down syndrome: does money matter? AB - The prenatal diagnosis of Down syndrome (amniocentesis) presents parents with a complex dilemma which requires comparing the risk of giving birth to an affected child and the risk of losing an unaffected child through amniocentesis-related miscarriage. Building on the specific features of the French Health insurance system, this paper shows that variation in the monetary costs of the diagnosis procedure may have a very significant impact on how parents solve this ethical dilemma. The French institutions make it possible to compare otherwise similar women facing very different reimbursement schemes and we find that eligibility to full reimbursement has a largely positive effect on the probability of taking an amniocentesis test. By contrast, the sole fact of being labelled 'high-risk' by the Health system seems to have, as such, only a modest effect on subsequent choices. Finally, building on available information on post-amniocentesis outcomes, we report new evidence suggesting that amniocentesis increases the risk of premature birth and low weight at birth. PMID- 21671302 TI - Genetic modifications of pigs for medicine and agriculture. AB - Genetically modified swine hold great promise in the fields of agriculture and medicine. Currently, these swine are being used to optimize production of quality meat, to improve our understanding of the biology of disease resistance, and to reduced waste. In the field of biomedicine, swine are anatomically and physiologically analogous to humans. Alterations of key swine genes in disease pathways provide model animals to improve our understanding of the causes and potential treatments of many human genetic disorders. The completed sequencing of the swine genome will significantly enhance the specificity of genetic modifications, and allow for more accurate representations of human disease based on syntenic genes between the two species. Improvements in both methods of gene alteration and efficiency of model animal production are key to enabling routine use of these swine models in medicine and agriculture. PMID- 21671305 TI - Chemotherapy and information-seeking behaviour: characteristics of patients using mass-media information sources. AB - OBJECTIVE: Fulfilling patients' information needs can help them cope with illness and improve their well-being. Little research has been conducted on the characteristics of patients using different information sources. This study aims to get insight into which information sources patients receiving chemotherapy for the first time use and which factors (background characteristics, psychological factors, information needs and source reliability) explain the use of different mass-media information sources. METHODS: Three hundred forty-five patients receiving chemotherapy in ten hospitals in the Netherlands completed a questionnaire. Use of 16 sources (mass-media and interpersonal) was measured with a five-point Likert scale. Regression analyses were conducted to test whether use of the three most frequently used mass-media sources could be explained by socio demographic, medical and psychological factors, unfulfilled information needs and perceived reliability of the source. RESULTS: Treatment guide, brochures and Internet were the most frequently used mass-media sources. Medical specialists, nurses, and family and/or friends were the most common interpersonal sources. Using the treatment guide was found to be associated with treatment goal, unfulfilled information needs and source reliability. Using brochures was associated with cancer-related stress responses, coping style and source reliability. Using Internet was associated with age, education, coping style and source reliability. CONCLUSIONS: This study developed a model to explain the use of mass-media information sources by patients with cancer receiving chemotherapy. The use of different information sources is associated with different factors, indicating that each source offers specific opportunities to tailor information to the patient's needs. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21671306 TI - Toxic effects of lead and nickel nitrate on rat liver chromatin components. AB - The biological activity of heavy metals is related to their physicochemical interaction with biological receptors. In the present study, the effect of low concentrations of nickel nitrate and lead nitrate (<0.3 mM) on rat liver soluble chromatin and histone proteins was examined. The results showed that addition of various concentrations of metals to chromatin solution preceded the chromatin into aggregation and precipitation in a dose-dependant manner; however, the extent of absorbance changes at 260 and 400 nm was different between two metals. Gel electrophoresis of histone proteins and DNA of the supernatants obtained from the metal-treated chromatin and the controls revealed higher affinity of lead nitrate to chromatin compared to nickel nitrate. Also, the binding affinity of lead nitrate to histone proteins free in solution was higher than nickel. On the basis of the results, it is concluded that lead reacts with chromatin components even at very low concentrations and induce chromatin aggregation through histone DNA cross-links. Whereas, nickel nitrate is less effective on chromatin at low concentrations, suggesting higher toxicity of lead nitrate on chromatin compared to nickel. PMID- 21671307 TI - Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats. AB - The present study was designed to evaluate the preventive effects of N-acetyl cysteine on lipid peroxide metabolism in isoproterenol (ISO) induced myocardial infarcted rats. Male albino Wistar rats were pretreated with N-acetyl cysteine (5 and 10 mg/kg) daily for a period of 14 days. After the pretreatment period, ISO (100 mg/kg) was subcutaneously injected to rats twice at an interval of 24 h. Increased activities of serum creatine kinase, creatine kinase-MB, lactate dehydrogenase, and increased intensities of serum lactate dehydrogenase-isoenzyme bands (LDH-1, LDH-2) were observed in ISO-induced rats. The heart lipid peroxidation products were significantly increased, and the antioxidant system was significantly reduced in ISO-induced rats. Pretreatment with N-acetyl cysteine (5 and 10 mg/kg) to ISO-induced rats showed significant effects on all the biochemical parameters studied. Histopathological findings of the myocardium also showed the protective role of N-acetyl cysteine in ISO-induced rats. Furthermore, in vitro study confirmed the potent-free radical scavenging activity of N-acetyl cysteine. The effect at a dose of 10 mg/kg of N-acetyl cysteine was more pronounced than the dose, 5 mg/kg. The results of our study show that N acetyl cysteine protects the heart against ISO-induced myocardial infarction by its free radical scavenging effect. PMID- 21671308 TI - Inhibitory effect of ganglioside on mastoparan-induced cytotoxicity and degranulation in lipid raft of connective tissue type mast cell. AB - Antihistamine, the most important drug for Hymenoptera stinging, cannot attenuate cytotoxicity and mast cell direct activation by mastoparan that is the most abundant polypeptides in the venoms of social wasps. The aim of this study was to investigate whether gangliosides inhibit the effect of mastoparan on mast cells activation. The degranulation and cytotoxicity in canine cutaneous mastocytoma cells (CM-MC) were done by measurement of beta-hexosaminidase release and MTT assay. Lipid raft was isolated with discontinuous sucrose gradient centrifuge for the analysis of distribution of Galpha(q) and Galpha(i) protein by western blotting. We found that mastoparan induced the degranulation in (CM-MC) via direct activation of Galpha(i) and Galpha(q) with a decrease in their amount in lipid raft. Ganglioside G(D1a) (disialoganglioside) and G(M1) (monosialoganglioside) strongly reduced the degranulation and cytotoxicity through stabilizing the structure of lipid raft domain. In addition, mastoparan generated intracellular reactive oxygen species (ROS) independently from cytotoxicity, through arachidonic cascade but not G-protein activations. Crude wasp venom showed cytotoxicity and induction of the release from CM-MC, which were potently reduced by gangliosides. We show here that mastoparan activates both Galpha(i) and Galpha(q) protein and that the exogenous ganglioside G(D1a) and G(M1) inhibit the degranulation and cytotoxicity through stabilizing lipid raft. Gangliosides have potentials to be therapeutic tool or clinical prophylaxis for wasp stinging. PMID- 21671309 TI - A comparative study of DNA binding and cell cycle phase perturbation by the dinuclear complex of Cd(II) with the condensation product of 2-acetylpyridine and malonic acid dihydrazide N',N'(2) -bis[(1E)-1-(2 pyridyl)ethylidene]propanedihydrazide. AB - Organometallic Cd(II) compounds have recently attracted attention for their anticancer activity. The interaction of the dinuclear complex of Cd(II) with the condensation product of 2-acetylpyridine and malonic acid dihydrazide, N',N'(2) bis[(1E)-1-(2-pyridyl)ethylidene]propanedihydrazide (Cd(II)H(2) L), with calf thymus DNA (CT-DNA) was monitored by blue shift in UV-vis spectra of the complex. The binding constant of Cd(II)H(2) L complex with CT-DNA was determined (K(B) = 1.8 * 10(4) M(-1) ) and was indicative of minor groove binding. Agarose gel electrophoretic changes in mobility of supercoiled and circular forms of pBR322 and pUC18 plasmids in the presence of the complex suggest that conformational changes in the plasmids occur upon binding of the Cd(II)H(2) L complex. The Cd(II)H(2) L complex induced perturbation of the cell cycle phase distribution and an increase in the percentage of cells in the sub-G1 phase of human cervical cancer HeLa cell line and murine melanoma B16 cell line. Immunoblotting analysis showed the overexpression of Bcl-2 protein with the Cd(II)H(2) L complex. PMID- 21671310 TI - Gene expression-based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development. AB - We have analyzed gene expression and histopathology of rat liver treated with a histamine-3 receptor inverse agonist under development for the treatment of obesity 24 h after a single acute administration. While histopathology did not identify a clear liver toxicity, analysis of gene changes strongly suggested the development of toxicity. This prediction was confirmed in a 2-week repeat-dose rat study where prominent liver pathology occurred, while gene changes that lead to the prediction persisted. A subset of these genes was analyzed in vitro in both rat and human hepatocytes to reveal the potential relevancy of the findings for the situation in humans. This comprehensive analysis of the development compound at the gene expression level allowed interpretation of findings of the follow-up compound in a frontloaded 24-h single-dose acute study that was initiated before regular 2-week repeat-dose studies started. The high similarity of the follow-up compound to the lead compound based on gene expression lead to the immediate termination of the development program for this compound series. Our data demonstrate the value of genomics-based early toxicity prediction in short-term in vivo studies for the characterization of compounds to allow prioritization and selection of suited candidates before compound-, animal-, and cost-intensive longer term studies are undertaken. PMID- 21671311 TI - Effects of the Crotalus durissus terrificus snake venom on hepatic metabolism and oxidative stress. AB - Snake venoms present different action mechanisms because of their complex composition, represented mainly by toxins and enzymes. This work aimed to investigate the effects of the Crotalus durissus terrificus(Cdt) venom in the liver. Wistar rats were inoculated intraperitoneally with saline (control) or Cdt venom. After 3, 4, or 6 h, the following parameters were analyzed: (a) hepatic function, (b) oxidative stress parameters, and (c) the metabolism of alanine in the isolated perfused liver. Plasma activities of alanine aminotransferase and aspartate aminotransferase and hepatic glutathione S-transferase and catalase presented significant elevation in rats inoculated with 300 MUg ? kg(-1) Cdt venom. Liver lipoperoxidation was enormously increased by venom doses of 100, 200, and 300 MUg ?kg(-1) , whereas glutathione S-transferase was not changed. Perfused livers from rats inoculated with 1500 MUg ?kg(-1) venom showed increased production of lactate, pyruvate, and ammonia when alanine was the metabolic substrate. These results demonstrate that the Cdt venom can produce several changes in hepatocytes. The causes of the changes are possibly related to the disequilibrium in the redox homeostasis but also to specific needs of the poisoned organism, for example, an increased supply of lactate and pyruvate in response to an increased activity of the Cori cycle. PMID- 21671312 TI - Coexistence of metamagnetism and slow relaxation of the magnetization in a cobalt thiocyanate 2D coordination network. PMID- 21671313 TI - Janus-like 3D tectons: self-assembled 2D arrays of functional units at a defined distance from the substrate. PMID- 21671314 TI - The conformation of ATP within the Na,K-ATPase nucleotide site: a statistically constrained analysis of REDOR solid-state NMR data. PMID- 21671315 TI - Disulfide bonds reduce the toxicity of the amyloid fibrils formed by an extracellular protein. PMID- 21671317 TI - Gold-catalyzed 1,3-acyloxy migration/5-exo-dig cyclization/1,5-acyl migration of diynyl esters. PMID- 21671318 TI - Two-coordinate transition-metal centers with metal-metal bonds. PMID- 21671316 TI - Light-activated gene editing with a photocaged zinc-finger nuclease. PMID- 21671319 TI - Conformational effects on the dynamics of internal conversion in boron dipyrromethene dyes in solution. PMID- 21671320 TI - Star-polymer-catalyzed living radical polymerization: microgel-core reaction vessel by tandem catalyst interchange. PMID- 21671321 TI - Copper-catalyzed dehydrogenative cross-coupling reactions of N-para-tolylamides through successive C-H activation: synthesis of 4H-3,1-benzoxazines. PMID- 21671323 TI - A soft chemistry approach to coating of LiFePO4 with a conducting polymer. PMID- 21671322 TI - Oxygen-independent decarbonylation of aldehydes by cyanobacterial aldehyde decarbonylase: a new reaction of diiron enzymes. PMID- 21671324 TI - Cobalt-phenanthroline catalysts for the ortho alkylation of aromatic imines under mild reaction conditions. PMID- 21671325 TI - The catalytic enantioselective total synthesis of (+)-liphagal. PMID- 21671328 TI - SeSaM-Tv-II generates a protein sequence space that is unobtainable by epPCR. AB - Generating high-quality mutant libraries in which each amino acid is equally targeted and substituted in a chemically diverse manner is crucial to obtain improved variants in small mutant libraries. The sequence saturation mutagenesis method (SeSaM-Tv(+) ) offers the opportunity to generate such high-quality mutant libraries by introducing consecutive mutations and by enriching transversions. In this study, automated gel electrophoresis, real-time quantitative PCR, and a phosphorimager quantification system were developed and employed to optimize each step of previously reported SeSaM-Tv(+) method. Advancements of the SeSaM-Tv(+) protocol and the use of a novel DNA polymerase quadrupled the number of transversions, by doubling the fraction of consecutive mutations (from 16.7 to 37.1 %). About 33 % of all amino acid substitutions observed in a model library are rarely introduced by epPCR methods, and around 10 % of all clones carried amino acid substitutions that are unobtainable by epPCR. PMID- 21671329 TI - An engineered methionyl-tRNA synthetase enables azidonorleucine incorporation in methionine prototrophic bacteria. PMID- 21671327 TI - Triptolide directly inhibits dCTP pyrophosphatase. AB - Triptolide is a potent natural product, with documented antiproliferative, immunosuppressive, anti-inflammatory, antifertility, and antipolycystic kidney disease effects. Despite a wealth of knowledge about the biology of this compound, direct intracellular target proteins have remained elusive. We synthesized a biotinylated photoaffinity derivative of triptolide, and used it to identify dCTP pyrophosphatase 1 (DCTPP1) as a triptolide-interacting protein. Free triptolide interacts directly with recombinant DCTPP1, and inhibits the enzymatic activity of this protein. Triptolide is thus the first dCTP pyrophosphatase inhibitor identified, and DCTPP1 is a biophysically validated target of triptolide. PMID- 21671330 TI - Revisiting the mechanism of the triosephosphate isomerase reaction: the role of the fully conserved glutamic acid 97 residue. AB - An analysis of 503 available triosephosphate isomerase sequences revealed nine fully conserved residues. Of these, four residues-K12, H95, E97 and E165-are capable of proton transfer and are all arrayed around the dihydroxyacetone phosphate substrate in the three-dimensional structure. Specific roles have been assigned to the residues K12, H95 and E165, but the nature of the involvement of E97 has not been established. Kinetic and structural characterization is reported for the E97Q and E97D mutants of Plasmodium falciparum triosephosphate isomerase (Pf TIM). A 4000-fold reduction in k(cat) is observed for E97Q, whereas the E97D mutant shows a 100-fold reduction. The control mutant, E165A, which lacks the key catalytic base, shows an approximately 9000-fold drop in activity. The integrity of the overall fold and stability of the dimeric structure have been demonstrated by biophysical studies. Crystal structures of E97Q and E97D mutants have been determined at 2.0 A resolution. In the case of the isosteric replacement of glutamic acid by glutamine in the E97Q mutant a large conformational change for the critical K12 side chain is observed, corresponding to a trans-to-gauche transition about the Cgamma-Cdelta (chi(3)) bond. In the E97D mutant, the K12 side chain maintains the wild-type orientation, but the hydrogen bond between K12 and D97 is lost. The results are interpreted as a direct role for E97 in the catalytic proton transfer cycle. The proposed mechanism eliminates the need to invoke the formation of the energetically unfavourable imidazolate anion at H95, a key feature of the classical mechanism. PMID- 21671332 TI - Hyperconjugation contributes to the bimodal distribution of glycine conformations observed in protein three-dimensional structures. PMID- 21671331 TI - Polyphenolic glycosides and aglycones utilize opposing pathways to selectively remodel and inactivate toxic oligomers of amyloid beta. AB - Substantial evidence suggests that soluble prefibrillar oligomers of the Abeta42 peptide associated with Alzheimer's disease are the most cytotoxic aggregated Abeta isoform. Limited previous work has revealed that aromatic compounds capable of remodeling Abeta oligomers into nontoxic conformers typically do so by converting them into off-pathway aggregates instead of dissociating them into monomers. Towards identifying small-molecule antagonists capable of selectively dissociating toxic Abeta oligomers into soluble peptide at substoichiometric concentrations, we have investigated the pathways used by polyphenol aglycones and their glycosides to remodel Abeta soluble oligomers. We find that eleven polyphenol aglycones of variable size and structure utilize the same remodeling pathway whereby Abeta oligomers are rapidly converted into large, off-pathway aggregates. Strikingly, we find that glycosides of these polyphenols all utilize a distinct remodeling pathway in which Abeta oligomers are rapidly dissociated into soluble, disaggregated peptide. This disaggregation activity is a synergistic combination of the aglycone and glycone moieties because combinations of polyphenols and sugars fail to disaggregate Abeta oligomers. We also find that polyphenolic glycosides and aglycones use the same opposing pathways to remodel Abeta fibrils. Importantly, both classes of polyphenols fail to remodel nontoxic Abeta oligomers (which are indistinguishable in size and morphology to Abeta soluble oligomers) or promote aggregation of freshly disaggregated Abeta peptide; thus revealing that they are specific for remodeling toxic Abeta conformers. We expect that these and related small molecules will be powerful chemical probes for investigating the conformational and cellular underpinnings of Abeta-mediated toxicity. PMID- 21671333 TI - AuaA, a membrane-bound farnesyltransferase from Stigmatella aurantiaca, catalyzes the prenylation of 2-methyl-4-hydroxyquinoline in the biosynthesis of aurachins. AB - Aurachins are quinoline alkaloids isolated from the myxobacterium Stigmatella aurantiaca. They are substituted with an isoprenoid side chain and act as potent inhibitors in the electron transport chain. A biosynthetic gene cluster that contains at least five genes (auaA-auaE) has been identified for aurachin biosynthesis. In this study, auaA, the gene encoding a putative prenyltransferase of 326 amino acids, was cloned and overexpressed in Escherichia coli. Biochemical investigations showed that AuaA catalyzes the prenylation of 2-methyl-4 hydroxyquinoline in the presence of farnesyl diphosphate (FPP), thereby resulting in the formation of aurachin D. The hydroxyl group at position C4 of the quinoline ring is essential for an acceptance by AuaA; this was concluded by testing 18 quinoline derivatives or analogues with AuaA and FPP. (1) H NMR and HR EI-MS analyses of six isolated enzyme products revealed the presence of a farnesyl moiety at position C3 of the quinoline ring. K(M) values of 43 and 270 MUM were determined for FPP and 2-methyl-4-hydroxyquinoline, respectively. Like other known membrane-bound prenyltransferases, the reaction catalyzed by AuaA is dependent on the presence of metal ions such as Mg(2+) , Mn(2+) and Co(2+) , although no typical (N/D)DXXD binding motif was found in the sequence. PMID- 21671334 TI - Hydration is required in DNA G-quadruplex-protein binding. PMID- 21671335 TI - Linking spectral and electrochemical analysis to monitor c-type cytochrome redox status in living Geobacter sulfurreducens biofilms. PMID- 21671336 TI - An exploration of the support person's perceptions and experiences of complex regional pain syndrome and the rehabilitation process. AB - We explored the perceptions and experiences of those who support a relative or friend with complex regional pain syndrome (CRPS), a chronic pain condition of unknown aetiology usually affecting a single limb. Semi-structured interviews were analysed using interpretative phenomenological analysis, and four superordinate themes are presented here. These themes describe the efforts of carers to make sense of CRPS and the rehabilitation process, to be sensitive to the discomfort of the person with CRPS and to respond in an attuned and helpful way. CRPS had become integrated into the carers' lives as they sought to monitor, protect and motivate the person they supported. The themes are discussed in relation to each other and to extant literature, including work on social support and adjustment to chronic illness, and the clinical implications are explored. PMID- 21671337 TI - Twenty-one reasons to care about the psychological basis of ownership. AB - The psychological basis of ownership is a neglected area of research; the authors consider twenty-one disparate reasons why it is worth investigating. PMID- 21671339 TI - Possession and morality in early development. AB - From the moment children say "mine!" by two years of age, objects of possession change progressively from being experienced as primarily unalienable property (i.e., something that is absolute or nonnegotiable), to being alienable (i.e., something that is negotiable in reciprocal exchanges). As possession begins to be experienced as alienable, the child enters "moral space," a socially normative and evaluative space made of perceived values that are either good or less good, and where accountability and reputation begin to play a prominent role. The aim of this chapter is to show the close developmental link between possession and morality. PMID- 21671338 TI - Property in nonhuman primates. AB - Property is rare in most nonhuman primates, most likely because their lifestyles are not conducive to it. Nonetheless, just because these species do not frequently maintain property does not mean that they lack the propensity to do so. Primates show respect for possession, as well as behaviors related to property, such as irrational decision making regarding property (e.g., the endowment effect) and barter. The limiting factor in species other than humans is likely the lack of social and institutional controls for maintaining property. By comparing primates and humans, we gain a better understanding of how human property concepts have evolved. PMID- 21671340 TI - Early representations of ownership. AB - To navigate a world filled with private property, children must be able to assign ownership information to objects and update that information when appropriate. In this chapter, the authors propose that children include ownership as an attribute of their object representations. Children can learn about ownership attributes either by witnessing owners acting on their property, a visual source, or by receiving information from the testimony of others, a verbal source. The authors consider the differences between these two forms of information and how they might conflict at the representational level, leading to difficulties in learning about ownership. PMID- 21671341 TI - Property rights and the resolution of social conflict. AB - It has long been argued that ownership depends upon social groups' establishing and adhering to rights such as the right to use and to exclude others from using one's own property. The authors consider the application of such rights in the interactions of young peers and siblings, and the extent to which parents support their children in establishing and maintaining the entitlement of owners. They show that children, but not their parents, give priority to ownership in settling property disputes, and argue that diverging models of children's relationships account for these differing perspectives of children and parents. PMID- 21671342 TI - Ownership as a social status. AB - The authors suggest that ownership may be one of the critical entry points into thinking about social constructions, a kind of laboratory for understanding status. They discuss the features of ownership that make it an interesting case to study developmentally. In particular, ownership is a consequential social fact that is alterable by an individual, even a child. Children experience changes in ownership in a way they do not experience changes in other social facts (such as word meanings or social norms). Ownership is also an individual rather than a general property; two objects can be identical, but differ in ownership. PMID- 21671343 TI - Ownership and object history. AB - Appropriate behavior in relation to an object often requires judging whether it is owned and, if so, by whom. The authors propose accounts of how people make these judgments. Our central claim is that both judgments often involve making inferences about object history. In judging whether objects are owned, people may assume that artifacts (e.g., chairs) are owned and that natural objects (e.g., pinecones) are not. However, people may override these assumptions by inferring the history of intentional acts made in relation to objects. In judging who owns an object, people may often consider which person likely possessed the object in the past--such reasoning may be responsible for people's bias to assume that the first person known to possess an object is its owner. PMID- 21671344 TI - Exploring ownership in a developmental context. AB - Ownership and economic behaviors are highly salient elements of the human social landscape. Indeed, the human world is literally constructed of property. Individuals perceive and manipulate a complex web of people and property that is largely invisible and abstract. In this chapter, the authors focus on drawing together information from a variety of disciplines, including legal theory, philosophy, psychology, and economics, to begin creating a coherent picture of the cognitive architecture that underlies ownership concepts. In doing so, the authors review theories of ownership and discuss recent research that highlights the unique contributions garnered by studying ownership in a developmental context. PMID- 21671346 TI - Highlighted article: "Generation of transgenic dogs that conditionally express green fluorescent protein" by M.J. Kim et al. PMID- 21671347 TI - Efficient inducible Pan-neuronal cre-mediated recombination in SLICK-H transgenic mice. AB - Large-scale functional genomics in mice is becoming feasible through projects to develop conditional knockout alleles for every gene. Inducible neuron-specific gene knockout in such mice will permit the analysis of neuronal phenotypes while circumventing developmental defects or embryonic lethality. Here we describe a transgenic line, termed SLICK-H, that facilitates widespread inducible conditional genetic manipulation within most populations of projection neurons. In SLICK-H mice, the Thy1 promoter drives robust and relatively uniform expression of a drug-inducible form of cre recombinase throughout the peripheral and central nervous system. This permits efficient induction of cre-mediated genetic manipulation upon tamoxifen administration in adult mice. Importantly, cre activity in the absence of tamoxifen is minimal, permitting tight control of recombination. In the present study, we catalog in detail the transgene expression patterns and recombination efficiencies in SLICK-H mice. Our results highlight the utility of SLICK-H mice for functional genomics in the nervous system. PMID- 21671348 TI - Position matters: variability in the spatial pattern of BMP modulators generates functional diversity. AB - Bone morphogenetic proteins (BMPs) perform a variety of functions during development. Considering a single BMP, what enables its multiple roles in tissues of varied sizes and shapes? What regulates the spatial distribution and activity patterns of the BMP in these different developmental contexts? Some BMP functions require controlling spread of the BMP morphogen, while others require formation of localized, high concentration peaks of BMP activity. Here we review work in Drosophila that describes spatial regulation of the BMP encoded by decapentaplegic (dpp) in different developmental contexts. We concentrate on extracellular modulation of BMP function and discuss the mechanisms that generate concentrated peaks of Dpp activity, subdivide territories of different activity levels or regulate spread of the Dpp morphogen from a point source. We compare these findings with data from vertebrates and non-model organisms to discuss how changes in the regulation of Dpp distribution by extracellular modulators may lead to variability in dpp function in different species. PMID- 21671349 TI - Does adiponectin benefit steatotic liver transplantation? AB - Strategies for improving the viability of steatotic donor livers could increase the number of organs suitable for transplantation. There is evidence that adiponectin, the most abundant adipose-specific adipokine, acts as an anti obesity and anti-inflammatory hormone. Here we review the signaling pathways of adiponectin and the possible therapies based on adiponectin regulation that have been examined or applied clinically. Recent studies on the role of adiponectin in steatotic livers subjected to ischemia/reperfusion are discussed. The data suggest that further investigations are required to determine whether adiponectin is a potential therapeutic target in liver transplantation. PMID- 21671350 TI - Cyclic adenosine 3',5'-monophosphate in rat steatotic liver transplantation. AB - Numerous steatotic livers are discarded as unsuitable for transplantation (TR) because of their poor tolerance of ischemia/reperfusion (I/R). Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents protect against I/R injury both in nonsteatotic livers that have been removed from non-heart-beating donors and subjected to warm ischemia or cold ischemia (CIS) and in perfused, isolated livers. Ischemic preconditioning (PC), which is based on brief periods of I/R, protects steatotic liver grafts, but the mechanism that is responsible is poorly understood. This study examines the role of cAMP in the vulnerability shown by steatotic livers to TR-associated I/R injury and the benefits of PC in this situation. Steatotic livers with or without PC were transplanted into Zucker rats. The hepatic levels of cAMP were measured and altered pharmacologically. Our results indicate that the cAMP levels in the nonsteatotic liver grafts were similar to those found in a sham group. However, high cAMP levels were observed in steatotic liver grafts. The blockage of cAMP generation by adenylate cyclase inhibitor pre-treatment or PC had the following results: reduced hepatic injury and increased survival of steatotic graft recipients; greater preservation of adenosine triphosphate (ATP) and reduced lactate accumulation throughout CI. This blockade of cAMP by a nitric oxide-dependent mechanism protected steatotic liver grafts against oxidative stress and microvascular disorders after reperfusion. In conclusion, cAMP blocking-based strategies could protect patients against the inherent risk of steatotic liver failure after TR. PMID- 21671351 TI - Developmental toxicity screening in zebrafish. AB - Given the ever-increasing toxic exposure ubiquitously present in our environment as well as emerging evidence that these exposures are hazardous to human health, the current rodent-based regulations are proving inadequate. In the process of overhauling risk assessment methodology, a nonrodent test organism, the zebrafish, is emerging as tractable for medium- and high-throughput assessments, which may help to accelerate the restructuring of standards. Zebrafish have high developmental similarity to mammals in most aspects of embryo development, including early embryonic processes, and on cardiovascular, somite, muscular, skeletal, and neuronal systems. Here, we briefly describe the development of these systems and then chronicle the toxic impacts assessed following chemical exposure. We also compare the available data in zebrafish toxicity assays with two databases containing mammalian toxicity data. Finally, we identify gaps in our collective knowledge that are ripe for future studies. PMID- 21671352 TI - Zebrafish embryos and larvae: a new generation of disease models and drug screens. AB - Technological innovation has helped the zebrafish embryo gain ground as a disease model and an assay system for drug screening. Here, we review the use of zebrafish embryos and early larvae in applied biomedical research, using selected cases. We look at the use of zebrafish embryos as disease models, taking fetal alcohol syndrome and tuberculosis as examples. We discuss advances in imaging, in culture techniques (including microfluidics), and in drug delivery (including new techniques for the robotic injection of compounds into the egg). The use of zebrafish embryos in early stages of drug safety-screening is discussed. So too are the new behavioral assays that are being adapted from rodent research for use in zebrafish embryos, and which may become relevant in validating the effects of neuroactive compounds such as anxiolytics and antidepressants. Readouts, such as morphological screening and cardiac function, are examined. There are several drawbacks in the zebrafish model. One is its very rapid development, which means that screening with zebrafish is analogous to "screening on a run-away train." Therefore, we argue that zebrafish embryos need to be precisely staged when used in acute assays, so as to ensure a consistent window of developmental exposure. We believe that zebrafish embryo screens can be used in the pre-regulatory phases of drug development, although more validation studies are needed to overcome industry scepticism. Finally, the zebrafish poses no challenge to the position of rodent models: it is complementary to them, especially in early stages of drug research. PMID- 21671353 TI - Molecular control of vascular development in the zebrafish. AB - The zebrafish is emerging as a novel model for the study of embryonic vascular development. In this review we summarize the advantages of this intriguing experimental system and the advances in our understanding of the molecular control of vascular development it has allowed. PMID- 21671355 TI - Liver development and cancer formation in zebrafish. AB - Liver is the largest organ in the human body, and it regulates many physiological processes. Many studies on liver development in different model organisms have demonstrated that the mechanism of hepatogenesis is conserved in vertebrates. The identification of the genes and regulatory pathways involved in liver formation provides a basis for the diagnosis of liver diseases and therapeutic interventions. Hepatocellular carcinoma is the third leading cause of mortality worldwide. In the last decade, genetic alterations, which include the gain and loss of DNA, as well as mutations and epigenomic changes, have been identified as important factors in liver cancer. Many genetic pathways are dysregulated during carcinogenesis. Here, we review the gene regulatory networks that underlie liver organogenesis and the dysregulation of these pathways in liver cancer. The genes and pathways involved in hepatogenesis and liver cancer are largely conserved between zebrafish and humans, making this an ideal model organism for the study of this disease. A better understanding of liver development may aid in the development of new diagnostic and therapeutic approaches to liver cancer. PMID- 21671356 TI - One step forward: the use of transgenic zebrafish tumor model in drug screens. AB - The zebrafish (Danio rerio) has been an experimental model in the developmental biology and toxicology since the 1950s. In recent years, with the aid of transgenic technology, it has also gained an increasing popularity to model human diseases, including various cancers. As a feasible vertebrate model for large scale chemical screens, the zebrafish has also given us a new option for the search of potential anticancer drugs. It is hopeful that in the near future with automation and analytical tools, drug development processes will be significantly shortened for quick and effective identification of candidate drugs. PMID- 21671354 TI - Zebrafish kidney development: basic science to translational research. AB - The zebrafish has become a significant model system for studying renal organogenesis and disease, as well as for the quest for new therapeutics, because of the structural and functional simplicity of the embryonic kidney. Inroads to the nature and disease states of kidney-related ciliopathies and acute kidney injury (AKI) have been advanced by zebrafish studies. This model organism has been instrumental in the analysis of mutant gene function for human disease with respect to ciliopathies. Additionally, in the AKI field, recent work in the zebrafish has identified a bona fide adult zebrafish renal progenitor (stem) cell that is required for neo-nephrogenesis, both during the normal lifespan and in response to renal injury. Taken together, these studies solidify the zebrafish as a successful model system for studying the broad spectrum of ciliopathies and AKI that affect millions of humans worldwide, and point to a very promising future of zebrafish drug discovery. The emphasis of this review will be on the role of the zebrafish as a model for human kidney-related ciliopathies and AKI, and how our understanding of these complex pathologies is being furthered by this tiny teleost. PMID- 21671357 TI - Zebrafish models to study hypoxia-induced pathological angiogenesis in malignant and nonmalignant diseases. AB - Most in vivo preclinical disease models are based on mouse and other mammalian systems. However, these rodent-based model systems have considerable limitations to recapitulate clinical situations in human patients. Zebrafish have been widely used to study embryonic development, behavior, tissue regeneration, and genetic defects. Additionally, zebrafish also provides an opportunity to screen chemical compounds that target a specific cell population for drug development. Owing to the availability of various genetically manipulated strains of zebrafish, immune privilege during early embryonic development, transparency of the embryos, and easy and precise setup of hypoxia equipment, we have developed several disease models in both embryonic and adult zebrafish, focusing on studying the role of angiogenesis in pathological settings. These zebrafish disease models are complementary to the existing mouse models, allowing us to study clinically relevant processes in cancer and nonmalignant diseases, which otherwise would be difficult to study in mice. For example, dissemination and invasion of single human or mouse tumor cells from the primary site in association with tumor angiogenesis can be studied under normoxia or hypoxia in zebrafish embryos. Hypoxia-induced retinopathy in the adult zebrafish recapitulates the clinical situation of retinopathy development in diabetic patients or age-related macular degeneration. These zebrafish disease models offer exciting opportunities to understand the mechanisms of disease development, progression, and development of more effective drugs for therapeutic intervention. PMID- 21671359 TI - Is the number of blood products transfused associated with lower survival in children with acute lymphoblastic leukemia? AB - BACKGROUND: Blood transfusion during acute lymphoblastic leukemia (ALL) of childhood is scarcely documented. Children with ALL are immunosuppressed by both the disease and its therapy. Transfusion may contribute to the course of ALL through its transfusion-related immunomodulation (TRIM) effect. PROCEDURE: Blood transfusion history and response to therapy for 108 children <16 years of age at the time of ALL diagnosis was documented. Clinical files, electronic records, and blood bank registries were scrutinized. Overall survival (OS) and event-free survival (EFS) in relation to blood product type and number of transfusions was determined. Hazard ratios (HR) for death and relapse were estimated through uni- and multivariate Cox regression analysis. RESULTS: One hundred eight ALL patients were included. Median age was 6 years (range: 0-15 years). Ninety-seven patients (89.8%) were transfused. Median number of transfused products was seven (range: 0 345). After multivariate analysis, transfusion of >5 packed red blood cells (PRBC) remained a significant predictor for death (P = 0.003) and relapse (P = 0.011). For platelets, maximal significance was observed when >30 platelet concentrates (PC) were transfused (P < 0.001). When both, PRBC and PC were considered, maximal significance for predicting death was observed with transfusion of >30 blood products (P < 0.001). CONCLUSIONS: The number of blood products transfused to children with ALL appears to be significantly associated with lower survival rates. This may reflect both the severity of the disease and the TRIM effect, which may decrease immune surveillance capacity and the probability of leukemic clone eradication. PMID- 21671358 TI - Epigenetics, development, and cancer: zebrafish make their mark.. AB - Zebrafish embryos are an exceptional system for studying vertebrate development. Historically, studies using zebrafish to uncover key players in developmentally regulated gene expression have entailed detailed analysis of transcription factors. It is now apparent that epigenetic modifications of both DNA and histone tails are equally important in the regulation of gene expression during development. As such, blocking the function of key epigenetic modifiers impairs development, albeit with surprising tissue specificity. For instance, DNA methylation is an important epigenetic mark that is depleted in embryos lacking dnmt1 and uhrf1. These embryos display developmental defects in the eye, liver, pancreas, and larval lethality. Interestingly, human tumors derived from these same organs have aberrant changes in DNA methylation and altered expression of genes that are thought to contribute to formation of these cancers. These observations have provided a mechanistic basis for treating cancer with drugs that block the enzymes that facilitate DNA and histone modifications. Thus, it is important to understand the consequences of targeting these factors in a whole animal. We review the use of zebrafish for probing the genetic, cellular, and physiological response to alterations in the epigenome and highlight exciting data illustrating that epigenetic studies using zebrafish can inform and impact cancer biology. PMID- 21671360 TI - Magnetic resonance imaging in childhood leukemia survivors treated with cranial radiotherapy: a cross sectional, single center study. AB - BACKGROUND: Children treated with cranial radiotherapy (CRT) for leukemia are at risk of developing central nervous system injuries. Magnetic resonance imaging (MRI) represents the examination method of choice for evaluating radiation induced brain complications. The purpose of this report is to describe the spectrum of MRI abnormalities detected in a group of survivors of leukemia treated with cranial irradiation. PROCEDURES: In this cross-sectional, single center study, 56 patients (median age at follow-up 19 years) receiving CRT as cranial prophylaxis (CP) included in the leukemia protocol (total dose 1,800 2,400 cGy) and/or in the total body irradiation regimen (990-1,200 cGy) before hematopoietic stem cell transplant, were evaluated by MRI after a median interval of 11 years (range 2-27) following CRT. RESULTS: Fifty-nine MRI abnormalities (32 cavernomas, nine focal areas of gliosis, seven dystrophic mineralizations, five cerebral atrophies, four pituitary atrophies, one diffuse radiation leukoencephalopathy, and one meningioma) were found in 43 patients. The longest interval between CRT and MRI and oldest age at follow-up represented the two risk factors that were statistically associated with MRI lesions (P = 0.032 and 0.033, respectively). Cerebral cavernomas (CC) were the most frequent MRI abnormalities (57%). All patients with CC were asymptomatic at diagnosis and during follow-up, except one who had aspecific neurological manifestations and micro hemorrhages. CONCLUSIONS: These results confirm that total doses and modalities of fractionation dose of CRT were not significantly associated with MRI abnormalities. Moreover, in our experience none of the patients developed neurological symptoms related to MRI abnormalities, and furthermore, the CC remained substantially stable during follow-up. PMID- 21671361 TI - Definitive radiotherapy for unresectable pediatric and young adult nonrhabdomyosarcoma soft tissue sarcoma. AB - BACKGROUND: Few published articles describe outcomes following definitive radiation for unresectable pediatric and young adult nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). The purpose of this study is to evaluate the prognostic factors, outcomes, and complications in patients age 30 years or younger with NRSTS treated at the University of Florida from 1973 to 2002. PROCEDURE: Nineteen pediatric and young adult patients with NRSTS were treated with radiotherapy after biopsy. Thirteen patients had high-grade tumors. The median age at radiotherapy was 19.6 years; the median dose was 55.2 Gy. Twelve patients received chemotherapy. Prognostic factors for local recurrence, distant metastases, and survival were analyzed. RESULTS: Median follow-up was 2.6 years. The 5-year local-control rate was 40%. Nine out of 13 local failures occurred in the absence of metastatic disease. All patients with local failures died of their cancer, and 8 patients died without evidence of distant metastases. There was a trend toward improved local control with low/intermediate-grade tumors. Freedom from distant metastases at 5 years was 68%. Fourteen patients died of their disease. The 5-year overall survival was 37%. There was one grade 4 complication based on NCI Common Terminology Criteria for Adverse Events version 3. CONCLUSION: Young patients with unresectable NRSTS have a poor outcome thereby justifying current study efforts focused on treatment intensification. By demonstrating that all patients with local recurrence died of disease and more than half of these deaths occurred in the absence of distant spread, these results suggests that improved means of local control may translate into improvement in survival. PMID- 21671362 TI - Dactinomycin and vincristine toxicity in the treatment of childhood cancer: a retrospective study from the Children's Oncology Group. AB - BACKGROUND: Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence-based dosing guidance is lacking. METHODS: Patient AMD and VCR dose and drug-related adverse event (AE) information from four rhabdomyosarcoma (RMS) and two Wilms tumor (WT) studies were assembled. Statistical modeling was used to account for differences in AE data collection across studies, develop rate models for grade 3/4 CTCAE v3 hepatic- (AMD) and neuro- (VCR) toxicity, assess variation in toxicity rates over age and other factors, and predict toxicity risk under current dosing guidelines. RESULTS: For the same dose/body size, AMD toxicity rates were higher in patients <1 year than older patients and VCR toxicity rates increased with age. The statistical model provided estimates for AMD and VCR toxicity risk under current dosing schedules and indicated that patients of smaller body size were at lower risk of VCR toxicity than larger patients of the same age. The rate of AMD toxicity was highest early in treatment and was lower in patients who tolerated initial AMD without toxicity. CONCLUSION: The observed decrease in AMD toxicity rate with cumulative dose may indicate sensitivity in a subgroup of patients while the observed increase in VCR toxicity risk with age may indicate changing sensitivity to VCR. Current dosing practices result in a fairly uniform toxicity profile within age group. However, PK/PD studies should be done to provide further provide further information on best dosing guidelines. PMID- 21671364 TI - Antibiotic resistance is associated with longer bacteremic episodes and worse outcome in febrile neutropenic children with cancer. AB - PURPOSE: With the increasing emergence of multiresistant pathogens, better understanding of these infections is necessary. The aim of the present study was to evaluate the risk factors associated with isolating a multiresistant organism (MRO) from a positive blood culture in pediatric cancer patients with febrile neutropenia (F&N), and to study its impact on clinical course and outcome of febrile episodes. PATIENTS AND METHODS: The association between MRO with underlying malignancy, age, disease status, hospitalization during episode, absolute neutrophil count, absolute monocyte count, clinical foci of infection, and pathogens isolated was assessed in bacteremic pediatric cancer patients. The MRO phenotype was defined as diminished susceptibility to >=3 of the broad spectrum antibody classes. RESULTS: Among 239 episodes of blood stream infections (BSI), Gram-positive, and Gram-negative organisms were detected in 180 (75%), and 59(25%) episodes, respectively; with 38% of isolates showing multiresistance (n = 92). Significant risk factors (P < 0.05) for MRO were hospitalization, Gram negative organisms, presence of clinical focus of infection, reduced ANC, prolonged duration of neutropenia, and previous intake of antibiotics. Of the episodes with prolonged duration of fever extending for more than 7 days 62% (64|93) were associated with a multiresistant phenotype, while it accompanied 72% (18|25) of the cases with an unfavorable outcome; P-value <0.001. CONCLUSION: Isolation of MRO is more likely to be associated with a prolonged course and an unfavorable outcome. Continuous multidisciplinary surveillance of BSI is warranted to develop strategies for antimicrobial resistance control. PMID- 21671363 TI - A phase I study of zoledronic acid and low-dose cyclophosphamide in recurrent/refractory neuroblastoma: a new approaches to neuroblastoma therapy (NANT) study. AB - BACKGROUND: Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. PROCEDURE: Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m(2)/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated. RESULTS: Twenty-one patients, median age 7.5 (range 0.8-25.6) years were treated with 2 mg/m(2) (n = 4), 3 mg/m(2) (n = 3), or 4 mg/m(2) (n = 14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1-18) courses was given. Two dose limiting toxicities (grade 3 hypophosphatemia) occurred at 4 mg/m(2) zoledronic acid. Other grades 3-4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 1), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3-18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL-6 levels decreased with therapy. CONCLUSIONS: Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m(2) every 28 days. PMID- 21671365 TI - Acute chest syndrome is associated with history of asthma in hemoglobin SC disease. AB - BACKGROUND: Acute chest syndrome (ACS) is a frequent cause of morbidity and leading cause of death among individuals with sickle cell disease. Yet, ACS in hemoglobin SC disease is not well characterized. The objective of this study was to compare the presentation and clinical course of ACS in individuals with hemoglobin SC disease to that observed in individuals with hemoglobin SS disease. PROCEDURE: We retrospectively reviewed 71 inpatient episodes of ACS in patients with hemoglobin SC disease over a 20-year period. Continuous and categorical data from index cases were compared with that from 71 control cases of ACS in patients with hemoglobin SS disease. RESULTS: Median length of hospitalization was shorter for hemoglobin SC episodes when compared to hemoglobin SS episodes (3.0 vs. 5.0 days, P < 0.001). In comparison to hemoglobin SS patients, a greater proportion of hemoglobin SC patients had a previous history of asthma or wheezing (50.7 vs. 33.8%, OR = 2.01 [1.02-3.96], P = 0.041) and a respiratory complaint of wheeze (11.3 vs. 2.8%, OR = 4.38 [0.90-21.4], P = 0.049). In our multivariate regression model, time to ACS diagnosis and total number of days of oxygen supplementation were independent predictors of length of hospitalization in both hemoglobin SC and SS episodes of ACS. CONCLUSIONS: ACS appears to be less severe in children with hemoglobin SC disease compared to that in children with SS disease. Asthma and wheezing may represent more significant risk factors for the development of ACS in children with hemoglobin SC disease. PMID- 21671366 TI - Neurocognitive deficits in children with sickle cell disease are associated with the severity of anemia. AB - BACKGROUND: Although neurocognitive deficits in children with sickle cell disease (SCD) have been well documented, the etiology of these deficits has not been completely clarified. The aim of this study was to investigate the association of laboratory markers of disease severity and radiological parameters with neurocognitive functioning in children with SCD. DESIGN AND METHODS: Participants were 37 children with SCD ((HbSS or HbS-beta(0)-thalassemia) aged 6-18 years. All participants underwent extensive neurocognitive assessment. Further data (TCD values, laboratory test results, and MRI data) were obtained from medical charts. Associations were analyzed by hierarchical regression analysis. RESULTS: Hemoglobin was associated with a decrease in verbal short-term memory. There was no association between TCD velocities and neurocognitive functioning, when controlled for age. Children with silent infarcts did not differ from children with normal MRI in neurocognitive functioning. Children with right-left asymmetries in cerebral blood flow as measured by continuous arterial spin labelling (CASL) MRI had better sustained attention than children without asymmetries. CONCLUSIONS: Neurocognitive deficits are associated with the severity of anemia, indicating reduced oxygen delivery to the brain as an etiological mechanism. This implies that children with SCD and normal MRIs may still suffer from neurocognitive impairments, possibly affecting their academic development and full participation in society. PMID- 21671367 TI - Neutrophil functions in patients with inherited bone marrow failure syndromes. AB - BACKGROUND: The inherited bone marrow failure syndromes (IBMFS) include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome (SDS). Previous studies reported decreased neutrophil chemotaxis in patients with SDS; there are no reports of neutrophil function in other IBMFS. In this study we examined neutrophil respiratory burst function in IBMFS patients. PROCEDURE: Samples from 43 IBMFS patients and 61 healthy family members were collected, shipped, and analyzed within 24 hr. We also studied samples from 12 healthy control persons immediately after collection. Neutrophils were stimulated with phorbol 12-myristate acetate (PMA) and N-formyl-methyonyl-leucyl phenylalanine (fMLP), and respiratory burst analyzed by reduction of dihydro rhodamine and cytochrome c. RESULTS: There was no significant difference in the degree of fMLP or PMA-driven respiratory burst activity between each of the IBMFS subgroups and their respective family members. There was also no difference in respiratory burst activity between any IBMFS, pooled group of all healthy family members and healthy controls. CONCLUSIONS: Neutrophil respiratory burst activity from IBMFS patients does not differ from that of healthy family members and controls. PMID- 21671368 TI - Disseminated intravascular coagulation due to IgM-mediated autoimmune hemolytic anemia. AB - Disseminated intravascular coagulation (DIC) due to red cell hemolysis has been previously attributed to transfusion-related hemolytic reactions, but not to autoimmune hemolytic anemia. We report a case of DIC in a child with complement fixing IgM-mediated cold-agglutinin autoimmune hemolysis, which resulted in arterial thrombosis and gangrene of the upper and lower extremities. PMID- 21671369 TI - Long-term survival in a pediatric patient with supratentorial primitive neuro ectodermal tumor and extraneural metastasis at diagnosis. AB - Extraneural metastases of central nervous system (CNS) tumors are rare occurrences most commonly observed in medulloblastomas. Survival outcomes are generally dismal. Supratentorial primitive neuroectodermal tumors (stPNET) are rare childhood tumors with few documented cases of extraneural metastases. We present a rare occurrence of a 23-month-old patient with long-term survival after diagnosis of stPNET with metastases to the lungs. This patient was treated with surgical resection, induction chemotherapy, tandem autologous hematopoietic cell rescues, and focal radiotherapy. We report long-term survival for a patient with a stPNET and extraneural metastases at diagnosis following an intensive approach to treatment. PMID- 21671370 TI - Treatment with oral ribavirin and IVIG of severe human metapneumovirus pneumonia (HMPV) in immune compromised child. PMID- 21671371 TI - Pancreatic exocrine function and cardiac iron in patients with iron overload and with thalassemia. AB - Patients with beta-thalassemia major at risk of cardiac iron overload have to be identified to undergo myocardial iron measurements by magnetic resonance imaging (MRI), especially, in areas and centers with restricted access to MRI. Measurements of heart iron, liver iron, and pancreatic exocrine function were performed in 44 patients by MRI-R2* [the transverse relaxation rate R2* (= 1/T2*) characterizes the magnetic resonance decay from protons not being in phase with each other in contrast to R2 (= 1/T2)], biomagnetic liver susceptometry (LIC), and pancreatic serum amylase (PAM) and lipase (LIP), respectively. ROC analysis (area: 0.88) for detecting patients with cardiac R2* > 50 sec(-1) (T2* < 20 msec) by LIP revealed a cut-off level of 19 U/L. In conclusion, patients at risk of elevated cardiac iron levels could be identified by the exocrine pancreatic lipase and amylase function parameters. PMID- 21671372 TI - Mental retardation, congenital heart malformation, and myelodysplasia in a patient with a complex chromosomal rearrangement involving the critical region 21q22. AB - The region 21q22 is considered crucial for the pathogenesis of both Down syndrome (DS) and the partial monosomy 21q syndrome. Haploinsufficiency of the RUNX-1 gene, mapping at 21q22 is responsible for a platelet disorder and causes predisposition to myelodysplastic syndrome (MDS). We describe a 3-year-old girl with mental retardation, congenital heart malformation, and subtle dysmorphic facial features. The patient developed thrombocytopenia when she was 2 years old. Bone marrow smear led to the diagnosis of myelodysplasia. Prenatal karyotyping had shown chromosome 21 pericentric inversion. Postnatally the array-CGH revealed duplication at bands 21q11.2-21q21.1 and a simultaneous deletion involving the region 21q22.13-21q22.3. RUNX-1 mRNA levels analyzed in patient's skin fibroblasts were reduced. In this child the monosomy of the region 21q22 likely had the main role in determining the phenotype. Although the RUNX-1 gene is localized outside the deleted region, we speculate that RUNX-1 reduced expression, is probably due to the deletion of regulatory factors and caused the hematologic disorder in the patient. The present report underlines also the importance of array-CGH in characterizing patients with a complex phenotype. PMID- 21671373 TI - Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome): report of three affected sibs. AB - The Wiedemann-Rautenstrauch syndrome (WRS) (OMIM 264090) is a rare progeroid entity. WRS patients are characterized by premature aging present at birth including pseudohydrocephalus, cranio-facial disproportion, reduced subcutaneous fat, thin skin, rigid and thick joints, and neonatal teeth in some cases. Here we describe three sibs with WRS from unaffected parents and without consanguinity. Our findings support autosomal recessive inheritance in WRS and support the possibility of homozygocity mapping as a good approach to find the causative gene. PMID- 21671374 TI - Methotrexate and misoprostol teratogenicity: further expansion of the clinical manifestations. AB - We describe a boy who was exposed to misoprostol and methotrexate in the first trimester of gestation as a result of a failed medical abortion. He presented with severe growth retardation, skull defects, proptotic eyes, cleft palate, and severe micrognathia. There were bilateral defects of the upper and lower extremities, missing and hypoplastic ribs, and undescended testicles. He had clinical features of pulmonary hypoplasia with severe persistent pulmonary hypertension and remained ventilator-dependent until he expired. An autopsy revealed brain anomalies consistent with arrhinencephaly. Methotrexate is frequently used in conjunction with misoprostol to induce medical abortion, an off-label use as abortifacient. Both of these medications are well-established teratogens and have an X classification during pregnancy. Data from eight patients who were exposed to both medications in the first trimester indicate a significant teratogenic risk to the developing fetus. Reported anomalies include growth retardation, absence or hypoplasia of the frontal bones, craniosynostosis, large fontanelle, ocular hypertelorism, short palpebral fissures, wide nasal bridge, malformed and low-set ears, and micrognathia. Skeletal anomalies are frequent consisting of syndactyly, mesomelic shortening of the forearms, missing ribs, dislocated hips, and talipes equinovarus. The findings in our case are consistent with the pattern of abnormalities that have been reported in the literature. In addition, our patient had severe pulmonary hypoplasia and arrhinencephaly, anomalies that have not been described previously. This case adds to the documentation of the teratogenic effects of methotrexate and misoprostol on the developing fetus. PMID- 21671376 TI - Delineation of a less than 200 kb minimal deleted region for cardiac malformations on chromosome 7p22. AB - Cardiac malformations are commonly seen in individuals with terminal and interstitial deletions involving chromosome band 7p22. Although these malformations represent a significant cause of morbidity, the dosage-sensitive gene(s) that underlie these defects have yet to be identified. In this report, we describe a 16-month-old male with tetralogy of Fallot, bilateral second branchial arch remnants, and mild dysmorphic features. Array comparative genomic hybridization analysis revealed a less than 400 kb interstitial deletion on chromosome 7p22. The deletion was confirmed by real-time quantitative PCR and FISH analyses and was not detected in samples obtained from the child's parents. Molecular data from this de novo deletion, in combination with data from other isolated 7p deletions in the literature, can be used to define a less than 200 kb minimal deleted region for cardiac malformations on 7p22. This minimal deleted region spans all, or portions, of the coding regions of four known genes-MAD1L1, FTSJ2, NUDT1, and SNX8-and may include upstream regulatory elements of EIF3B. It is likely that one or more of these five genes, alone or in combination, plays an important, yet previously uncharacterized, role in cardiac development. PMID- 21671375 TI - Desmosterolosis-phenotypic and molecular characterization of a third case and review of the literature. AB - Desmosterolosis, a rare disorder of cholesterol biosynthesis, is caused by mutations in DHCR24, the gene encoding the enzyme 24-dehydrocholesterol reductase (DHCR24). To date, desmosterolosis has been described in only two patients. Here we report on a third patient with desmosterolosis who presented after delivery with relative macrocephaly, mild arthrogryposis, and dysmorphic facial features. Brain MRI revealed hydrocephalus, thickening of the tectum and massa intermedia, mildly effaced gyral pattern, underopercularization, and a thin corpus callosum. The diagnosis of desmosterolosis was established by detection of significant elevation of plasma desmosterol levels and reduced enzyme activity of DHCR24 upon expression of the patient's DHCR24 cDNA in yeast. The patient was found to be a compound heterozygote for c.281G>A (p.R94H) and c.1438G>A (p.E480K) mutations. Structural and evolutionary analyses showed that residue R94 resides at the flavin adenine dinucleotide (FAD) binding site and is strictly conserved throughout evolution, while residue E480 is less conserved, but the charge shift substitution is accompanied by drastic changes in the local protein environment of that residue. We compare the phenotype of our patient with previously reported cases. PMID- 21671377 TI - Genomic characterization of prenatally detected chromosomal structural abnormalities using oligonucleotide array comparative genomic hybridization. AB - Detection of chromosomal structural abnormalities using conventional cytogenetic methods poses a challenge for prenatal genetic counseling due to unpredictable clinical outcomes and risk of recurrence. Of the 1,726 prenatal cases in a 3-year period, we performed oligonucleotide array comparative genomic hybridization (aCGH) analysis on 11 cases detected with various structural chromosomal abnormalities. In nine cases, genomic aberrations and gene contents involving a 3p distal deletion, a marker chromosome from chromosome 4, a derivative chromosome 5 from a 5p/7q translocation, a de novo distal 6q deletion, a recombinant chromosome 8 comprised of an 8p duplication and an 8q deletion, an extra derivative chromosome 9 from an 8p/9q translocation, mosaicism for chromosome 12q with added material of initially unknown origin, an unbalanced 13q/15q rearrangement, and a distal 18q duplication and deletion were delineated. An absence of pathogenic copy number changes was noted in one case with a de novo 11q/14q translocation and in another with a familial insertion of 21q into a 19q. Genomic characterization of the structural abnormalities aided in the prediction of clinical outcomes. These results demonstrated the value of aCGH analysis in prenatal cases with subtle or complex chromosomal rearrangements. Furthermore, a retrospective analysis of clinical indications of our prenatal cases showed that approximately 20% of them had abnormal ultrasound findings and should be considered as high risk pregnancies for a combined chromosome and aCGH analysis. PMID- 21671379 TI - Efficacy of modafinil on excessive daytime sleepiness in Prader-Willi syndrome. AB - Excessive daytime sleepiness is a frequent and a highly disruptive symptom to the daily routine of children with Prader-Willi Syndrome (PWS) and their families. The objective of the study was to evaluate the efficacy of modafinil, a central stimulant, on excessive daytime sleepiness in children and adolescents with PWS. The efficacy of modafinil was evaluated in this open label pilot study comparing the Epworth sleepiness scale before and after treatment. Ten patients with molecularly confirmed PWS and a complaint of excessive daytime sleepiness underwent a night-time sleep recording and multiple sleep latency tests. One patient was excluded because of severe obstructive sleep apnea syndrome. Nine patients (4 males) with median age of 16 years (8-21) received modafinil at a starting dose of 100 mg/day. We found that all patients had excessive daytime sleepiness with an Epworth sleepiness scale at 14 (11-20) and mean sleep latency on multiple sleep latency tests at 5 (3-6) minutes. Moreover, six patients had at least two sleep-onset rapid eye movement periods showing a narcolepsy-like phenotype. Modafinil significantly improved sleepiness in all patients on the Epworth sleepiness scale from 14 (11-20) to 4 (3-12), (P = 0.007). Body mass index of the patients did not change significantly under treatment. No side effects were reported, and the drug was well-tolerated. We posit that this open label case series shows good efficacy of modafinil in nine children and adolescents with PWS. PMID- 21671378 TI - Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up. AB - Reports of birth defects rates may focus on defects observed in the newborn period or include defects diagnosed at older ages. However, little information is available on the rates of additional anomalies detected after birth or on the ages at which such anomalies are diagnosed. The aims of this work were to describe the initial diagnoses of oral clefts, isolated or associated with other defects, in newborn infants ascertained in hospitals of the ECLAMC network, and diagnostic changes that occurred due to detection of additional defects during a 1-year follow-up period. Seven hundred ten liveborn infants with cleft lip only (CLO), cleft lip with cleft palate (CLP), or cleft palate (CP) were ascertained between 2003 and 2005. Prevalence estimates of isolated and associated (ASO) clefts, diagnoses in infants with associated clefts, and the percentage of isolated clefts that were reclassified as associated were established. Birth prevalence estimates (per 1,000) were as follows: Total: 1.7; CLP: 0.94 (ASO = 23.5%); CP: 0.46 (ASO = 42.3%); CLO: 0.28 (ASO = 7.6%). Initial diagnoses in infants with associated clefts included 38 infants with chromosomal abnormalities, 33 with non-chromosomal syndromes, 16 with malformation sequences, and 98 with multiple anomalies of unknown etiology. Seven percent of newborns initially classified as isolated were later reclassified as associated. Ten infants without associated defects or clinically suspected syndromes were diagnosed as syndromic only through laboratory findings or family history, illustrating the difference between the terms associated versus isolated, which refers to presence or absence of associated anomalies, and syndromic versus non syndromic, which refers to etiology. PMID- 21671380 TI - Phenotypic variability of distal 22q11.2 copy number abnormalities. AB - The availability of microarray technology has led to the recent recognition of copy number abnormalities of distal chromosome 22q11.2 that are distinct from the better-characterized deletions and duplications of the proximal region. This report describes five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2. We report on novel phenotypic features including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome; and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. We describe the third distal chromosome 22q11.2 microdeletion patient with Goldenhar syndrome. Patients with distal chromosome 22q11.2 copy number abnormalities exhibit inter- and intra familial phenotypic variability, and challenge our ability to draw meaningful genotype-phenotype correlations. PMID- 21671381 TI - Early ultrasound suspect of thanatophoric dysplasia followed by first trimester molecular diagnosis. PMID- 21671382 TI - Residual activity and proteasomal degradation of p.Ser298Pro sulfamidase identified in patients with a mild clinical phenotype of Sanfilippo A syndrome. AB - Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo syndrome) is a fatal inherited lysosomal storage disease accompanied by progressive neurologic degeneration. The gene underlying MPS IIIA, SGSH, encodes a lysosomal enzyme, N sulfoglucosamine sulfohydrolase (sulfamidase). Mutational analysis of a large cohort of MPS IIIA patients showed a correlation of the missense mutation p.Ser298Pro and a slowly progressive course of the disease. We report here on the expression of the mutant p.Ser298Pro sulfamidase in BHK cells retaining low residual activity. Pulse-chase experiments showed that rapid degradation is responsible for the low steady state level of the mutant protein. Processing and secretion of p.Ser298Pro sulfamidase suggests that small amounts of the newly synthesized enzyme are transported to lysosomes. Most of the mutant sulfamidase exits the endoplasmic reticulum for proteasomal degradation. The ability to predict the clinical course of MPS IIIA in patients with the p.Ser298Pro mutation, as well as the residual enzymatic activity, and the reduced stability of the mutant sulfamidase suggest that this subgroup of patients is especially well suited to early sulfamidase replacement therapy or treatment with selective pharmacological chaperones. PMID- 21671384 TI - Avascular necrosis of the femoral head due to a novel C propeptide mutation in COL2A1. PMID- 21671383 TI - Fetal pads as a clue to the diagnosis of Pitt-Hopkins syndrome. AB - Pitt-Hopkins syndrome (PHS) is characterized by severe mental retardation, characteristic facial features including a wide mouth and intermittent overbreathing. It is due to abnormalities of the TCF4 gene at 18q21.1 and over 50 cases have now been reported in the literature. The clinical features overlap significantly with those of Angelman, Rett, and Mowat-Wilson syndromes. We have observed prominent fetal pads as a feature in several individuals with PHS and suggested that this is a useful clinical sign which helps to distinguish PHS from other conditions in the differential diagnosis and may guide genetic testing. PMID- 21671385 TI - Adults with Rubinstein-Taybi syndrome. AB - Information in the medical literature regarding adults with genetic syndromes is limited, making the care of these patients challenging. We conducted a questionnaire study of adults with Rubinstein-Taybi syndrome that addressed medical problems, education, independence, and behavior. The most common medical problems included short stature, obesity, visual difficulties, keloids, eating problems, spine curvature, and joint problems. The adults had typically moderate mental retardation, but most achieved some independence in self-care and communication; many participated in supported work situations. However, approximately one-third were said to have some decreased abilities over time. Behavior problems were common and often worsened with age. Very few of the study participants were seeing a geneticist as an adult. Long-term involvement of geneticists and education of adult primary care providers may help with many of the challenges facing adults with RTS and their families. PMID- 21671386 TI - Microdeletion 20p12.3 involving BMP2 contributes to syndromic forms of cleft palate. AB - Orofacial clefts of the lip and/or palate comprise one of the most common craniofacial birth defects in humans. Though a majority of cleft lip and/or cleft palate (CL/P) occurs as isolated congenital anomalies, there exist a large number of Mendelian disorders in which orofacial clefting is part of the clinical phenotype. Here we report on two individuals and one multi-generational family with microdeletions at 20p12.3 that include the bone morphogenetic protein 2 (BMP2) gene. In two propositi the deletion was almost identical at ~600 kb in size, and BMP2 was the only gene deleted; the third case had a ~5.5-Mb deletion (20p13p12.2) that encompassed at least 20 genes including BMP2. Clinical features were significant for cleft palate and facial dysmorphism in all three patients, including Pierre-Robin sequence in two. Microdeletion 20p13p12 involving BMP2 is rare and has been implicated in Wolff-Parkinson-White (WPW) syndrome with neurocognitive deficits and with Alagille syndrome when the deletion includes the neighboring JAG1 gene in addition to BMP2. Despite a significant role for the BMPs in orofacial development, heterozygous loss of BMP2 has not been previously reported in patients with syndromic clefting defects. Because BMP2 was the sole deleted gene in Patients 1 and 2 and one of the genes deleted in Patient 3, all of whom had clinical features in common, we suggest that haploinsufficiency for BMP2 is a crucial event that predisposes to cleft palate and additional anomalies. Lack of significant phenotypic components in family members of Patient 1 suggests variable expressivity for the phenotype. PMID- 21671387 TI - Homozygous PTEN deletion in neuroblastoma arising in a child with Cowden syndrome. PMID- 21671389 TI - Adults with congenital heart disease: patients' knowledge and concerns about inheritance. AB - With recent advances in medical and surgical management, most patients with congenital heart disease (CHD) survive to reproductive age. Current guidelines recommend counseling about inheritance and transmission of CHD to offspring. We evaluated whether adult CHD patients recalled having received information about the inheritance of their CHD, patients' knowledge about inheritance and their concerns in this regard. A questionnaire was sent to 486 non-syndromic CHD patients aged 20-45 years. We received 332 useful questionnaires (response rate 68%). One-third (33%) of patients recalled receiving information about inheritance of CHD from their cardiologist, and 13% had consulted a clinical geneticist. Eight percent of patients who were considering having children estimated the recurrence risk for their own offspring to be 1% or lower, whereas one-fourth (25%) estimated it to be higher than 10%. According to our classification, 44% estimated the recurrence risk in a correct range of magnitude. Additional information about inheritance of CHD was desired by 41% of patients. Forty-two percent of patients considering having children reported concerns about transmitting CHD to offspring. We conclude that a substantial proportion of adult CHD patients lacks knowledge and desires more information about inheritance, indicating a need for better patient education. Current guidelines and/or their implementation do not seem to meet the needs of these patients. A dedicated program of counseling for adults with CHD has to be developed to optimize knowledge and satisfaction with information provision and to reduce or manage concerns regarding inheritance of CHD. PMID- 21671388 TI - Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment : Summary of the 2010 PXE International Research Meeting. AB - Pseudoxanthoma elasticum (PXE), a prototypic heritable disorder with ectopic mineralization, manifests with characteristic skin findings, ocular involvement, and cardiovascular problems. The classic forms of PXE are due to loss-of-function mutations in the ABCC6 gene, which encodes ABCC6, a putative transmembrane efflux transporter expressed primarily in the liver. While considerable progress has recently been made in understanding the molecular genetics and pathomechanisms of PXE, no effective or specific treatment is currently available for this disorder. PXE International, the premiere patient advocacy organization, organized a workshop in November 2010 to assess the current state of diagnostics and research to develop an agenda towards treatment of PXE. This overview summarizes the progress in PXE research, with emphasis on molecular therapies for this, currently intractable, disorder. PMID- 21671391 TI - The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria. AB - Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin. PMID- 21671392 TI - A loss of function mutation in the COL9A2 gene causes autosomal recessive Stickler syndrome. AB - Stickler syndrome is characterized by ocular, auditory, skeletal, and orofacial abnormalities. We describe a family with autosomal recessive Stickler syndrome. The main clinical findings consisted of high myopia, vitreoretinal degeneration, retinal detachment, hearing loss, and short stature. Affected family members were found to have a homozygous loss-of-function mutation in COL9A2, c.843_c.846 + 4del8. A family with autosomal recessive Stickler syndrome was previously described and found to have a homozygous loss-of-function mutation in COL9A1. COL9A1, COL9A2, and COL9A3 code for collagen IX. All three collagen IX alpha chains, alpha1, alpha2, and alpha3, are needed for formation of functional collagen IX molecule. In dogs, two causative loci have been identified in autosomal recessive oculoskeletal dysplasia. This dysplasia resembles Stickler syndrome. Recently, homozygous loss-of-function mutations in COL9A2 and COL9A3 were found to co-segregate with the loci. Together the data from the present study and the previous studies suggest that loss-of-function mutations in any of the collagen IX genes can cause autosomal recessive Stickler syndrome. PMID- 21671393 TI - Partial trisomy 8 mosaicism due to a pseudoisodicentric chromosome 8. AB - Chromosome 8 is the largest autosome in which mosaic trisomy is compatible with life. Constitutional trisomy 8 (T8) is estimated to occur in approximately 0.1% of all recognized pregnancies. The estimated frequency of trisomy 8 mosaicism (T8M), also known as Warkany syndrome, is about 1/25,000 to 50,000 liveborns, and is found to be more prevalent in males than females, 5:1. T8M is known to demonstrate extreme clinical variability affecting multiple systems including central nervous, ocular, cardiac, gastrointestinal, genitourinary, and musculoskeletal. There appears to be little correlation between the level of mosaicism and the extent of the clinical phenotype. Additionally, the exact mechanism that causes the severity of phenotype in patients with T8M remains unknown. We report on a mildly dysmorphic male patient with partial low-level T8M due to a pseudoisodicentric chromosome 8 with normal 6.0 SNP microarray and high resolution chromosome analyses in lymphocytes. The aneuploidy was detected in fibroblasts and confirmed by FISH in lymphocytes. This report elaborates further the clinical variability seen in trisomy 8 mosaicism. PMID- 21671394 TI - Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. AB - Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome. PMID- 21671395 TI - Lateral meningocele syndrome and Hajdu-Cheney syndrome: different disorders with overlapping phenotypes. PMID- 21671396 TI - Are genetic counselors just misunderstood? Thoughts on "the relationship between the genetic counseling profession and the disability community: a commentary". PMID- 21671397 TI - Trisomy 13 and 18 and quality of life: treading "softly". PMID- 21671399 TI - Trisomy 18: experience of a reference hospital from the south of Brazil. AB - Trisomy 18 is a chromosomal syndrome characterized by a broad clinical picture, as well as a very reserved prognosis. The aim of our study was to verify the clinical characteristics and survival of patients diagnosed in a referral hospital in southern Brazil. Our sample consisted of 31 patients, 22 were female (71%), ages ranging from 1 to 1,395 days (median 14 days). The majority had a single cell lineage with full trisomy of chromosome 18 (94%). Concerning pregnancy complications, pre-eclampsia was the main abnormality described (17%). Fetal ultrasound was performed in 23 cases, and the most frequent abnormalities were polyhydramnios (41%) and intrauterine growth retardation (27%). There were no reports of prenatal identification of the syndrome. Most patients were born by cesarean due to pregnancy and fetal complications and about half of the cases were premature. Congenital heart defects represented the main major malformation observed (94%). Thirty patients (97%) progressed to death (survival ranged from 2 to 780 days, and 87% died within the first 6 months of life). Trisomy 18 is a serious chromosomal disorder with limited survival. Abnormalities of pregnancy appear to be frequent, which can lead to complications for both fetus and mother. The prenatal identification of these patients in our country is still inadequate, resulting in important implications for genetic counseling and management of these patients and their families. And this makes the possibility of interruption of pregnancy, regardless of ethical factors involved, an unlikely option. PMID- 21671402 TI - Automated classification of multicolored rolling circle products in dual-channel wide-field fluorescence microscopy. AB - Specific single-molecule detection opens new possibilities in genomics and proteomics, and automated image analysis is needed for accurate quantification. This work presents image analysis methods for the detection and classification of single molecules and single-molecule interactions detected using padlock probes or proximity ligation. We use simple, widespread, and cost-efficient wide-field microscopy and increase detection multiplexity by labeling detection events with combinations of fluorescence dyes. The mathematical model presented herein can classify the resulting point-like signals in dual-channel images by spectral angles without discriminating between low and high intensity. We evaluate the methods on experiments with known signal classes and compare to classical classification algorithms based on intensity thresholding. We also demonstrate how the methods can be used as tools to evaluate biochemical protocols by measuring detection probe quality and accuracy. Finally, the method is used to evaluate single-molecule detection events in situ. PMID- 21671404 TI - Organocatalytic approach for the syntheses of corynantheidol, dihydrocorynantheol, protoemetinol, protoemetine, and mitragynine. AB - O-Trimethylsilyl (TMS)-protected diphenylprolinol-catalyzed Michael addition of a functionalized alkylidene malonate and n-butanal affords an aldehyde. This adduct can serve as the common intermediate for the assembly of secologanin tryptamine and dopamine alkaloids; this is demonstrated by the total syntheses of corynantheidol, dihydrocorynantheol, protoemetinol, and protoemetine, and the formal synthesis of mitragynine. The key steps include reductive amination of this aldehyde with tryptamine, condensation of this aldehyde with 4 methoxytryptamine, condensation of dimethoxyphenethylamine with a lactone derived from this aldehyde, and subsequent Bischler-Napieralski cyclization and reduction. PMID- 21671403 TI - Oxime-based click chemistry in the development of 3-isoxazolecarboxylic acid containing inhibitors of Yersinia pestis protein tyrosine phosphatase, YopH. AB - The pathogenicity of Yersinia pestis relies on several effector proteins including YopH, a protein tyrosine phosphatase (PTP). We previously screened a library of analogues based on the ubiquitous PTP substrate para nitrophenylphosphate (pNPP) and found that incorporation of a 3-phenyl substituent to give 6-nitro-[1,1'-biphenyl]-3-yldihydrogen phosphate (1) enhanced affinity. Herein we report the conversion of 1 from a substrate into an inhibitor by replacing the hydrolysable phosphoryl group with a 3-isoxazolecarboxylic acid moiety and by introduction of an aminooxy group and subsequent diversification using oxime-based click chemistry. This approach led to the identification of non promiscuous bidentate YopH inhibitors with affinity in the low micromolar range. PMID- 21671405 TI - Metallic impurities are responsible for electrocatalytic behavior of carbon nanotubes towards sulfides. PMID- 21671406 TI - Carbon nanotubes for sustainable energy applications. AB - The grand challenge of a sustainable production and use of energy has focused research on the nanostructure of materials. This aspect is considered of critical importance for improving the performance of advanced materials and electrodes to meet demanding expectations. Carbon nanotubes (CNTs) are the first and most successful example of nanomaterials, and play a central role in the development of advanced solutions for sustainable energy applications. However, notwithstanding the rising scientific and technological interest in CNTs, their use is still largely based on phenomenological observations that miss the complexities of the nanostructure and characteristics of these materials. This Concept paper addresses the need for a rational design of CNTs for energy applications, based on an understanding of the key aspects to be considered for their optimization in different applications such as lithium ion batteries, supercapacitors, solar cells, and fuel cells. PMID- 21671407 TI - Mesenchymal stem cells injection in degenerated intervertebral disc: cell leakage may induce osteophyte formation. AB - Recent studies have shown that mesenchymal stem cell (MSC)-based therapy might be an effective approach for the treatment of intervertebral disc degeneration (IDD). However, many unanswered questions remain before clinical translation, such as the most effective stem cell type, a reliable transplantation method, including the carrier choice, and the fate of stem cells after misdirected delivery, among others. The objective of the study was to evaluate the fate and effect of allogenic bone marrow MSCs after transplantation into an IDD model. The L2-3, L3-4 and L4-5 intervertebral discs (IVDs) of four rabbits were stabbed to create IDD. Rabbit MSCs were expanded in vitro and in part transduced with retrovirus/eGFP. After 3 weeks, 1 * 10(5) MSCs were injected into the IVDs. The rabbits were followed by X-ray and MRI 3 and 9 weeks after injection. Then the animals were sacrificed and the spines analysed histologically. MRI showed no signs of regeneration. X-ray and gross anatomy inspection demonstrated large anterolateral osteophytes. Histological analysis showed that the osteophytes were composed of mineralized tissue surrounded by chondrocytes, with the labelled MSCs among the osteophyte-forming cells. The labelled MSCs were not found in the nucleus. Inflammatory cells were not observed in any injected IVDs. These results raise concern that MSCs can migrate out of the nucleus and undesirable bone formation may occur. While cause cannot be inferred from this study, the presence of MSCs in the osteophytes suggests a potential side-effect with this approach. IVD regeneration strategies need to focus on cell carrier systems and annulus sealing technologies to avoid pitfalls. PMID- 21671408 TI - Oncostatin M regulates neural precursor activity in the adult brain. AB - The regulation of neural precursor cell (NPC) activity is the major determinant of the rate of neuronal production in neurogenic regions of the adult brain. Here, we show that Oncostatin M (Osm) and its receptor, OsmRbeta, are both expressed in the subventricular zone (SVZ) and that in contradistinction to leukemia inhibitory factor and ciliary neutrophic factor, Osm directly inhibits the proliferation of adult NPCs as measured by a decreased level of neurosphere formation in vitro. Similarly, intraventricular infusion of Osm dramatically decreases the pool of NPCs in both the SVZ and the hippocampus. In keeping with the inhibitory action of Osm, we reveal that mice lacking OsmRbeta have substantially more NPCs in the SVZ, the hippocampus and the olfactory bulb, demonstrating that endogenous Osm signaling is important for NPC homeostasis. Finally, we show that Osm can also inhibit clonal growth of glioblastoma-derived neurospheres, further supporting the close link between NPCs and tumor stem cells. PMID- 21671409 TI - Cytologists battle cruel killer in Peru: volunteers take on one of the world's highest cervical cancer rates. PMID- 21671410 TI - The "Cancer of Machismo" in Mexico: a personal battle with breast cancer becomes a public fight against a deadly stigma. PMID- 21671411 TI - Evaluation of a scoring system for predicting lymph node malignancy in ultrasound guided fine needle aspiration practice. AB - Ultrasound-guided fine needle aspiration (USG-FNA) has enabled cytopathologists to accurately diagnose smaller or non-palpable lymph nodes (LN) on a regular basis. Pre-FNA clinical and ultrasonographic factors, such as a patient's age, ratio of short to long axis diameter (S/L ratio), internal echogenicity, and the vascular pattern of a LN, are reported to be able to predict the benign or malignant nature of a LN. This study is designed to test the formula "0.06 * (age) + 4.76 * (S/L ratio) + 2.15 * (internal echo) + 1.80 * (vascular pattern)" generated from the study of Liao et al. as a scoring system for predicting LN malignancy in a cytopathologist operated USG-FNA practice. Eighty-three reports of USG-FNA of LNs issued between 7/1/2008 and 4/28/2010 were reviewed. Patient's age, S/L ratio, internal echo, and vascular pattern were used to generate scores based on the aforementioned formula. A score of seven was used as a cutoff for predicting benign (<7) and malignant (>7) LNs. FNA cytology diagnosis, flow cytometric analysis as well as subsequent surgical diagnosis in some cases served as gold standard for statistical analysis. Among 46 USG-FNA of LNs with scores > 7, 38 were malignant and eight were benign. All 37 USG-FNA of LNs with scores < 7 were proven to be benign. The scoring system achieved 100% sensitivity, 82% specificity, 83% positive predictive value, 100% negative predictive value, and 90% accuracy. Further study of the eight "false-positive" cases revealed that three of them (37.5%) were found to be malignant in follow-up FNA and/or surgical biopsy. This scoring system may serve as a complementary tool in determining how aggressive a FNA procedure should be performed, how a FNA sample of LN should be triaged for ancillary study, and how closely a patient with lymphadenopathy should be followed up. PMID- 21671412 TI - Role of fine-needle aspiration cytology in the prompt diagnosis of recurrence of visceral leishmaniasis presented as isolated cervical leishmanial lymphadenopathy. AB - We report a case of isolated cervical leishmanial lymphadenopathy diagnosed by fine-needle aspiration cytology (FNAC) in apparently cured case of visceral leishmaniasis. A 28-year-old female presented with cervical lymphnode enlargement to surgery outpatient department and was subjected for FNAC. Smear showed numerous Leishmania donovani bodies in the cytoplasm of macrophages and giant cells, and extracellular spaces. She was treated by Amphotericin B for alternate 14 days and the size of the lymphnode regressed. She was found asymptomatic for 1 year of follow-up. PMID- 21671413 TI - Are the benefits of a high-intensity progressive resistance training program sustained in rheumatoid arthritis patients? A 3-year followup study. AB - OBJECTIVE: Rheumatoid arthritis (RA) patients were reassessed for body composition and physical function mean +/- SD 39 +/- 6 months after commencing a randomized controlled trial involving 24 weeks of either high-intensity progressive resistance training (PRT) or low-intensity range of movement exercise (control) to determine whether the benefits of PRT (i.e., reduced fat mass [FM], increased lean mass [LM], and improved function) were retained. METHODS: Nine PRT and 9 control subjects were reassessed for body composition (dual x-ray absorptiometry) and function (knee extensor strength, chair test, arm curl test, 50-foot walk) approximately 3 years after resuming normal activity following the exercise intervention. RESULTS: At followup, PRT subjects remained significantly leaner than control subjects (P = 0.03), who conversely had accumulated considerable FM during the study period (approximately -1.0 kg versus +2.4 kg, PRT versus controls). PRT subjects also retained most of the improvement in walking speed gained from training (P = 0.03 versus controls at followup). In contrast, the PRT-induced gains in LM and strength-related function were completely lost. Data from the controls suggest that established and stable RA patients have similar rates of LM loss but elevated rates of FM accretion relative to age-matched sedentary non-RA controls. CONCLUSION: We found that long term resumption of normal activity resulted in loss of PRT-induced improvements in LM and strength-related function, but substantial retention of the benefits in FM reduction and walking ability. The relatively long-term benefit of reduced adiposity, in particular, is likely to be clinically significant, as obesity is very prevalent among RA patients and is associated with their disability and exacerbated cardiovascular disease risk. PMID- 21671414 TI - Racial and ethnic disparities in disease activity and function among persons with rheumatoid arthritis from university-affiliated clinics. AB - OBJECTIVE: Health outcomes in rheumatoid arthritis (RA) have improved significantly over the past 2 decades. However, research suggests that disparities exist by race/ethnicity and socioeconomic status, with certain vulnerable populations remaining understudied. Our objective was to assess disparities in disease activity and function by race/ethnicity and explore the impact of language and immigrant status at clinics serving diverse populations. METHODS: We examined a cross-sectional study of 498 adults with confirmed RA at 2 rheumatology clinics: a university hospital clinic and a public county hospital clinic. Outcomes included the Disease Activity Score in 28 joints (DAS28) and its components, and the Health Assessment Questionnaire (HAQ), a measure of function. We estimated multivariable linear regression models including interaction terms for race/ethnicity and clinic site. RESULTS: After adjusting for age, sex, education, disease duration, rheumatoid factor status, and medication use, clinically meaningful and statistically significant differences in DAS28 and HAQ scores were seen by race/ethnicity, language, and immigrant status. Lower disease activity and better function was observed among whites compared to nonwhites at the university hospital. This same pattern was observed for disease activity by language (English compared to non-English) and immigrant status (US-born compared to immigrant) at the university clinic. No significant differences in outcomes were found at the county clinic. CONCLUSION: The relationship between social determinants and RA disease activity varied significantly across clinic setting with pronounced variation at the university, but not at the county clinic. These disparities may be a result of events that preceded access to subspecialty care, poor adherence, or health care delivery system differences. PMID- 21671415 TI - Six-year course and prognosis of nontraumatic knee symptoms in adults in general practice: a prospective cohort study. AB - OBJECTIVE: To examine the 6-year course of nontraumatic knee symptoms in adults in general practice, to identify prognostic factors for unfavorable outcome, and to develop a clinical prediction rule. METHODS: Adults (ages >35 years) with incident nontraumatic knee symptoms (n = 549) were followed for 6 years. Multivariable logistic regression analysis was used to identify prognostic factors associated with an unfavorable outcome, the area under the receiver operating curve (AUC) was calculated to determine discriminative ability, and a clinical prediction rule was developed. Unfavorable outcome is defined as persistent knee symptoms at 6-year followup or having undergone knee replacement surgery during followup. RESULTS: At 6-year followup, 42.1% of patients had an unfavorable outcome. Having persistent knee symptoms (odds ratio [OR] 5.31, 95% confidence interval [95% CI] 3.27-8.61) and fulfilling the clinical American College of Rheumatology (ACR) criteria for osteoarthritis (OA; OR 2.65, 95% CI 1.48-4.73) at 1-year followup were significantly associated with unfavorable outcome, while fulfilling the clinical ACR criteria for OA at baseline was not. Baseline factors independently associated with an unfavorable outcome were low/middle education level, comorbidity of the skeletal system, duration of knee symptoms of >3 months, bilateral knee symptoms, self-reported warm knee, history of nontraumatic knee symptoms, valgus alignment, pain at passive knee flexion/extension, and bony enlargement of the knee joint (AUC 0.80). CONCLUSION: Nontraumatic knee symptoms in adults in general practice appear to become a chronic disorder in nearly half of the patients. The developed clinical prediction rule with 10 baseline prognostic factors can be used to select high risk patients for an unfavorable outcome at long-term followup. PMID- 21671416 TI - Recommendations for juvenile idiopathic arthritis by the American College of Rheumatology: comment on the article by Beukelman et al. PMID- 21671419 TI - Predicting response to a cognitive-behavioral approach to treating low back pain: Secondary analysis of the BeST data set. AB - OBJECTIVE: Identifying factors that predict who is likely to gain the greatest benefit from different treatments for low back pain is an important research priority. Here we report moderator analyses of the Back Skills Training Trial (BeST) that tested a cognitive-behavioral approach for low back pain. METHODS: We recruited 701 participants ages >=18 years with at least moderately troublesome low back pain present for >6 weeks from 56 general practices in 7 localities across England to a trial adding a group cognitive-behavioral approach to active management advice. The cognitive-behavioral package had a moderate effect on primary outcomes (Roland Morris Disability Questionnaire [RMDQ] and modified Von Korff scales). At 12-month followup, we tested for interaction between randomized groups on 2 prespecified baseline variables (troublesomeness and fear avoidance) and 10 post hoc (exploratory) variables identified from previous studies. RESULTS: Neither troublesomeness nor fear avoidance moderated treatment effect on any of our primary outcomes. In the final model, the only moderation by baseline variables of the effect of randomization was on the RMDQ outcome. Being younger and currently working both moderated treatment effect, resulting in larger improvements as a response to treatment. CONCLUSION: Although BeST is one of the larger trials of back pain treatment, it is still too small to reliably detect moderation if it exists. Since the significant moderation effects were only observed for 1 outcome measure in 3 of 10 post-hoc analyses, we cannot conclude that these are true moderation effects. PMID- 21671418 TI - Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To assess the effect of vitamin C supplementation on serum uric acid (SUA) by pooling the findings from published randomized controlled trials (RCTs). METHODS: A total of 2,082 publications identified through systematic search were subjected to the following inclusion criteria: 1) RCTs conducted on human subjects, 2) reported end-trial SUA means and variance, 3) study design with oral vitamin C supplementation and concurrent control groups, and 4) trial duration of at least 1 week. Trials that enrolled children or patients receiving dialysis were excluded. Two investigators independently abstracted trial and participant characteristics. SUA effects were pooled by random-effects models and weighted by inverse variance. RESULTS: Thirteen RCTs were identified in the Medline, EMBase, and Cochrane Central Register of Controlled Trials databases. The total number of participants was 556, the median dosage of vitamin C was 500 mg/day, trial size ranged from 8-184 participants, and the median study duration was 30 days. Pretreatment SUA values ranged from 2.9-7.0 mg/dl (Systeme International d'Unites [SI units]: 172.5-416.4 MUmoles/liter). The combined effect of these trials was a significant reduction in SUA of -0.35 mg/dl (95% confidence interval -0.66, -0.03 [P = 0.032]; SI units: -20.8 MUmoles/liter). Trial heterogeneity was significant (I(2) = 77%, P < 0.01). Subgroup analyses based on trial characteristics indicated larger reductions in uric acid in trials that were placebo controlled. CONCLUSIONS: In aggregate, vitamin C supplementation significantly lowered SUA. Future trials are needed to determine whether vitamin C supplementation can reduce hyperuricemia or prevent incident and recurrent gout. PMID- 21671420 TI - Radiographic prognosis of finger joint damage predicted by early alteration in synovial vascularity in patients with rheumatoid arthritis: Potential utility of power doppler sonography in clinical practice. AB - OBJECTIVE: To investigate the relationship between synovial vascularity and progression of structural bone damage in each finger joint in patients with rheumatoid arthritis (RA) and to demonstrate synovial vascularity as a potential therapeutic marker. METHODS: We studied 250 metacarpophalangeal (MCP) and 250 proximal interphalangeal (PIP) joints of 25 patients with active RA who were administered adalimumab or tocilizumab. Patients were examined with clinical and laboratory assessments. Power Doppler sonography was performed at baseline and at the fourth and eighth weeks. Synovial vascularity was evaluated according to quantitative measurement. Hand and foot radiography was performed at baseline and the twentieth week. RESULTS: Clinical indices such as the 28-joint Disease Activity Score, the Clinical Disease Activity Index, and the Simplified Disease Activity Index were significantly decreased by biologic agents. The MCP and PIP joints with no response in synovial vascularity between baseline and the eighth week (vascularity improvement of <=70% at the eighth week) showed a higher risk of radiographic progression compared with responsive joints (vascularity improvement of >70% at the eighth week; relative risk 2.33-9). Radiographic progression at the twentieth week was significantly lower in responsive joints than in nonresponsive joints. CONCLUSION: The improvement of synovial vascularity following treatment with biologic agents led to suppression of radiographic progression of RA in each finger joint. The alteration in synovial vascularity numerically reflected therapeutic efficacy. Using vascularity as a marker to determine the most suitable therapeutic approach would be beneficial for patients with active RA. PMID- 21671422 TI - Pain as a quality of care measure in juvenile idiopathic arthritis: one step forward, but is it the best foot? Comment on the article by Lovell et al. PMID- 21671421 TI - Suicidal ideation among adults with arthritis: prevalence and subgroups at highest risk. Data from the 2007-2008 National Health and Nutrition Examination Survey. AB - OBJECTIVE: To evaluate the prevalence, correlates, and subgroups at highest risk for suicidal ideation among adults with arthritis. METHODS: We used data on US adults with arthritis, ages >=40 years, participating in the 2007-2008 National Health and Nutrition Examination Survey. Suicidal ideation was assessed by item 9 of the Patient Health Questionnaire 9 (PHQ-9). Sociodemographic factors, health behaviors, and comorbid conditions were examined as potential correlates. Depression was measured by the PHQ-8 score (range 1-24). We used random forests to identify subgroups at highest risk for suicidal ideation. To determine if any correlates were unique to arthritis, we compared results to those for persons with diabetes mellitus and cancer. RESULTS: The prevalence +/- SEM of suicidal ideation was 5.6% +/- 0.8% among persons with arthritis and 2.4% +/- 0.4% among those without. The most important correlates for suicidal ideation in adults with arthritis were depression, anxiety, duration of arthritis, age, income:poverty ratio, number of close friends, pain, alcohol, excessive daytime sleepiness, and comorbidities. Eleven of the 16 most important contributors for suicidal ideation among adults with arthritis were also important for people with diabetes mellitus and cancer. Among persons with arthritis, subgroups at highest risk for suicidal ideation were those with a PHQ-8 score between 18 and 24 and less than 4.5 years of arthritis (96.5%), and those with a PHQ-8 score between 7 and 17, >=1.24 days of binges/month, and either an income of >=$45,000/year (85.4%) or an income of <$45,000/year and >3 comorbidities (70.8%). CONCLUSION: Depression, short duration of arthritis, binge drinking, income, and >3 comorbidities identified subgroups of adults with arthritis at greatest risk for suicidal ideation. PMID- 21671423 TI - "It looks after me": how older patients make decisions about analgesics for osteoarthritis. AB - OBJECTIVE: To explore the key motivators behind selection of analgesics (nonsteroidal antiinflammatory drugs [NSAIDs], acetaminophen, and complementary medications [CMs]) by patients with osteoarthritis (OA). METHODS: We performed a qualitative study in which in-depth semistructured interviews were conducted with 15 OA patients recruited from 4 general practices in Sydney, Australia. Patients were ages >=65 years, and were currently taking or had recently taken an NSAID for OA. RESULTS: Three key themes emerged from the data: reliance, routine, and pill load. Patients were strongly reliant upon NSAIDs because they consistently satisfied their needs. By contrast, they were much less reliant upon acetaminophen because of uncertainty or skepticism about its effectiveness. They were not reliant upon CMs but were willing to take them indefinitely because they were perceived as being without risk. Many patients took an NSAID as well as CMs as part of a "daily routine." By contrast, patients had difficulty developing a routine around using acetaminophen at the recommended maximum dose because of the implicit frequency of dosing required and an aversion to the associated "pill load." CONCLUSION: The results highlight the importance of exploring the perceptions and preferences of patients with regard to analgesics for OA. Clinician advice regarding analgesia for OA should take account of the possible reliance of the patient upon an NSAID, their medicine routines, and their potential concern about the pill load associated, in particular, with acetaminophen. PMID- 21671425 TI - A sensitive flow injection chemiluminescence method for the determination of progesterone. AB - A sensitive flow injection (FI) chemiluminescence (CL) method was developed for the determination of trace amounts of progesterone. This method was based on the luminescent properties of the tris(1,10-phenanthroline) ruthenium(II) - potassium permanganate (KMnO4 ) - progesterone in acidic medium sensitized by Na2 SO3 . With the peak height as a quantitative parameter applying optimum conditions, the relative CL intensity was linear with progesterone concentration in the range of 1.0 * 10(-10) ~ 6.0 * 10(-9) g.ml(-1) and 6.0 * 10(-9) ~ 4.0 * 10(-8) g.ml(-1) with a detection limit of 7.1 * 10(-11) g.ml(-1) . The relative standard deviation (RSD) was 2.79% for 1.0 * 10(-8) g.ml(-1) progesterone (n = 11). The proposed method held low detection limit and was successfully applied to determination of progesterone in pharmaceutical preparations. The possible CL reaction mechanism was also discussed. PMID- 21671426 TI - Development and validation of an LC-UV method for the determination of sulfonamides in animal feeds. AB - A simple LC-UV method was developed for the determination of residues of eight sulfonamides (sulfachloropyridazine, sulfadiazine, sulfadimidine, sulfadoxine, sulfamethoxypyridazine, sulfaquinoxaline, sulfamethoxazole, and sulfadimethoxine) in six types of animal feed. C18, Oasis HLB, Plexa and Plexa PCX stationary phases were assessed for the clean-up step and the latter was chosen as it showed greater efficiency in the clean-up of interferences. Feed samples spiked with sulfonamides at 2 mg/kg were used to assess the trueness (recovery %) and precision of the method. Mean recovery values ranged from 47% to 66%, intra-day precision (RSD %) from 4% to 15% and inter-day precision (RSD %) from 7% to 18% in pig feed. Recoveries and intra-day precisions were also evaluated in rabbit, hen, cow, chicken and piglet feed matrices. Calibration curves with standards prepared in mobile phase and matrix-matched calibration curves were compared and the matrix effects were ascertained. The limits of detection and quantification in the feeds ranged from 74 to 265 ug/kg and from 265 to 868 ug/kg, respectively. PMID- 21671427 TI - In vitro approaches to studying the metabolism of new psychoactive compounds. AB - In the last two decades, a large number of new drugs from several drug classes have appeared on the illicit drug market. While some of these compounds have meanwhile been scheduled as controlled substances, the majority of them are (still) sold as so-called 'legal highs', mostly via the Internet. At the time they appear on the market the metabolism of these drugs is generally unknown. Therefore, it must be studied in order to obtain data necessary for analytical method development as well as toxicological risk assessment. In vitro metabolism studies of new designer drugs can be performed for identification and structure elucidation of new designer drug metabolites or to assess the qualitative and quantitative involvement of certain enzymes in the metabolism of a particular drug. In this review, the value of the following enzyme preparations for in vitro metabolism studies of new designer drugs will be discussed: liver microsomes, recombinant cDNA-expressed enzymes, liver cytosol, S9 mix, and hepatocytes. This will cover the major metabolic enzymes: cytochrome P450 monooxygenases, flavin monooxygenases, monoamine oxidases, UDP-glucuronyltransferases, sulfotransferases, and catechol-O-methyltransferases. Important analytical aspects such as the value of mass spectrometric techniques will also be covered. PMID- 21671428 TI - Impact of physical activity and doping on epigenetic gene regulation. AB - To achieve success in sports, many athletes consume doping substances, such as anabolic androgenic steroids and growth hormones, and ignore the negative influence of these drugs on their health. Apart from the unethical aspect of doping in sports, it is essential to consider the tremendous risk it represents to their physical condition. The abuse of pharmaceuticals which improve athletic performance may alter the expression of specific genes involved in muscle and bone metabolism by epigenetic mechanisms, such as DNA methylation and histone modifications. Moreover, excessive and relentless training to increase the muscle mass, may also have an influence on the health of the athletes. This stress releases neurotransmitters and growth factors, and may affect the expression of endogenous genes by DNA methylation, too. This paper focuses on the relationship between epigenetic mechanisms and sports, highlights the potential consequences of abuse of doping drugs on gene expression, and describes methods to molecularly detect epigenetic changes of gene markers reflecting the physiological or metabolic effects of doping agents. PMID- 21671429 TI - Optical detection of protein in complex media with plasmonic nanoparticle dimers. PMID- 21671430 TI - Templated synthesis of shape-controlled, ordered TiO2 cage structures. PMID- 21671431 TI - Nanoscale origami for 3D optics. PMID- 21671433 TI - EcoRI-modified gold nanoparticles for dual-mode colorimetric detection of magnesium and pyrophosphate ions. PMID- 21671434 TI - On the lifecycle of nanocomposites: comparing released fragments and their in vivo hazards from three release mechanisms and four nanocomposites. AB - Nanocomposites are the dominating class of nanomaterials to come into consumer contact, and were in general assumed to pose low risk. The first data is now emerging on the exposure from nanocomposites, but little is yet known about their hypothetical nanospecific physiological effects, giving ample room for speculation. For the first time, this comprehensive study addresses these aspects in a systematic series of thermoplastic and cementitious nanocomposite materials. Earlier reports that 'chalking', the release of pigments from weathered paints, also occurs for nanocomposites, are confirmed. In contrast, mechanical forces by normal consumer use or do-it-yourself sanding do not disrupt nanofillers (nanoparticles or nanofibers) from the matrix. Detailed evidence is provided for the nature of the degradation products: no free nanofillers are detected up to the detection threshold of 100 ppm. Sanding powders measuring 1 to 80 MUm in diameter are identified with the original material, still containing the nanofillers. The potential hazard from aerosols generated by sanding nanocomposites up to the nuisance dust limit is also investigated. In-vivo instillation in rats is used to quantify physiological effects on degradation products from abraded nanocomposites, in comparison to the abraded matrix without nanofiller and to the pure nanofiller. In this pioneering and preliminary evaluation, the hazards cannot be distinguished with or without nanofiller. PMID- 21671435 TI - Systemic mastocytosis in a child with t(8;21) acute myeloid leukemia. AB - Mastocytosis is primarily limited to the cutaneous variant in pediatric patients. Systemic mastocytosis (SM) has been associated with t(8;21) acute myeloid leukemia (AML) in adults. We provide the first report of a child with t(8;21) AML, diagnosed with asymptomatic SM following four cycles of chemotherapy. Unlike most adults with SM/AML, she was not found to have a c-KIT (D816V) mutation. SM persisted in the bone marrow after completion of chemotherapy, and her AML relapsed 9 months off-treatment. Although she achieved a second remission, mastocytosis persists in the marrow. Pediatric patients with t(8;21) AML/SM may represent a high-risk group despite favorable cytogenetics. PMID- 21671436 TI - 'Standing on our own two feet': a report of the West Midlands Rheumatology Forum Autumn meeting 2010. PMID- 21671432 TI - Beauty is skin deep: a surface monolayer perspective on nanoparticle interactions with cells and bio-macromolecules. AB - Surface recognition of biosystems is a critical component in the development of novel biosensors and delivery vehicles, and for the therapeutic regulation of biological processes. Monolayer-protected nanoparticles present a highly versatile scaffold for selective interaction with bio-macromolecules and cells. Through the engineering of the monolayer surface, nanoparticles can be tailored for surface recognition of biomolecules and cells. This review highlights recent progress in nanoparticle-bio-macromolecule/cellular interactions, emphasizing the effect of the surface monolayer structure on the interactions with proteins, DNA, and cell surfaces. The extension of these tailored interactions to hybrid nanomaterials, biosensing platforms, and delivery vehicles is also discussed. PMID- 21671437 TI - Structural identification of SAR-943 metabolites generated by human liver microsomes in vitro using mass spectrometry in combination with analysis of fragmentation patterns. AB - SAR-943 (32-deoxo rapamycin) is a proliferation signal inhibitor via interaction with the mammalian target of rapamycin (mTOR). Most importantly, SAR-943 has improved chemical stability compared to rapamycin (sirolimus) and is currently under investigation as a drug coated on coronary stents. It was the goal of this study to identify the SAR-943 metabolites generated after incubation with human liver microsomes using high-resolution mass spectrometry (MS) and MS/iontrap (MS(n)) and comparison of fragmentation patterns of the metabolites with those of SAR-943 and other known rapamycin derivatives. Our study showed that SAR-943 is mainly hydroxylated and/or demethylated by human liver microsomes. The structures of the following metabolites were identified: O-demethylated metabolites: 39-O desmethyl, 16-O-desmethyl and 27-O-desmethyl SAR-943; hydroxylated metabolites: hydroxy piperidine SAR-943, 11-hydroxy, 12-hydroxy, 14-hydroxy, 23-hydroxy, 24 hydroxy, 25-hydroxy, 46-hydroxy and 49-hydroxy SAR-943; didemethylated metabolites: 16,39-O-didesmethyl and 27,39-O-didesmethyl SAR-943; demethylated hydroxylated metabolites: 39-O-desmethyl, 23- or 24-hydroxy and 39-O-desmethyl, hydroxy piperidine SAR-943 and dihydroxylated metabolites: 12-,23- or 24 dihydroxy SAR-943. In addition, several other demethylated-hydroxylated and dihydroxylated metabolites were detected. However, their exact structures could not be identified. PMID- 21671438 TI - Photofragmentation of the K-shell excited perfluorocyclobutane: anisotropies in the fragments and breakdown pathways. AB - Total ion yield spectrum of perfluorocyclobutane (c-C(4)F(8)) has been measured in the C and F K-shell excitation regions. The peak assignments are presented based on angle-resolved photofragment ion mass spectrometry. The peaks at 291.34 and 688.5 eV are found to come from the transitions from the C 1s and the F 1s to the lowest unoccupied b(2)sigma(CF)* orbital, respectively. A photoelectron photoion-photoion coincidence spectrum is acquired at 700.1 eV for clarifying the breakdown pathways of c-C(4)F(8)(2+). Two series of the pathways are identified; fission of F atom(s) followed by charge separation and elimination of CF(2) or CF(3) followed by charge separation. PMID- 21671439 TI - On the way to understand antioxidants: chromanol and dimethoxyphenols gas-phase acidities. AB - Some antioxidant mechanisms displayed by several phenolic compounds relate with OH bond dissociation energy. One way for its determination, in the gas-phase, relies on acidity measurements. Gas-phase acidities were determined experimentally, applying the kinetic method, for chromanol and four dimethoxyphenols, and theoretically through quantum chemical DFT calculations for chromanol, six dimethoxyphenols and 3,4,5-trimethoxyphenol. The experimental acidity order, 2,3-dimethoxyphenol > 3,5-dimethoxyphenol > 2,6-dimethoxyphenol > 3,4-dimethoxyphenol ~ phenol > chromanol shows good agreement with the theoretical acidity order, 2,5-dimethoxyphenol > 2,3-dimethoxyphenol > 3,4,5 trimethoxyphenol > 3,5-dimethoxyphenol ~ 2,4-dimethoxyphenol > 2,6 dimethoxyphenol > 3,4-dimethoxyphenol > phenol > chromanol. These acidity trends were rationalized in terms of the substituent effects on the thermodynamic stabilities both of the parent phenols and the corresponding phenoxide ions. DFT calculations also evidenced the occurrence of intramolecular C-H...O hydrogen bonds whenever there are vicinal substituents (either OH, O(-) or OCH(3)) which induce further stabilization of the geometries. PMID- 21671440 TI - The use of medications with anticholinergic properties and risk factors for their use in hospitalised elderly patients. AB - PURPOSE: The aims of the present study were to evaluate the use of drugs with anticholinergic properties in elderly patients and to identify risk factors that increase the patient's chance of being given such medications. METHODS: The study was performed on a sample of 1636 patients aged >=65 years hospitalised during the period between 1 January 2008 and 31 December 2009 in three municipal hospitals. To evaluate the factors influencing the use of anticholinergic medications, we compared two groups-users and non-users of such drugs-in terms of sociodemographic and clinical characteristics as well as comorbid conditions. The most important risk factors were identified using the binary logistic regression model. RESULTS: Hospitalisation led to a significant increase in the prevalence of anticholinergic medication users, when comparing their occurrence at the time of hospital admission and discharge (10.5% and 14.2%, respectively; p < 0.001). A significantly higher total number of prescribed drugs were found in the group of users compared with non-users, at both hospital admission (7.2 +/- 3.5 vs 5.7 +/- 3.1; p < 0.001) and discharge (8.7 +/- 3.1 vs 7.5 +/- 2.9; p < 0.001). Immobilisation, urinary incontinence and retention, constipation, gastroduodenal ulcer disease as well as neurologic and psychiatric comorbidities (depression, Parkinson's disease, epilepsy) appeared as the most important risk factors of using anticholinergic medications. CONCLUSIONS: Physicians should be aware of the greater risk of adverse anticholinergic effects of drugs in certain therapeutic classes in the elderly. In patients with risk factors mentioned previously, special attention should be paid to active identification of anticholinergic effects of medications. PMID- 21671441 TI - Thiazolidinediones and the risk of incident congestive heart failure among patients with type 2 diabetes mellitus. AB - BACKGROUND: Clinical trials suggest that thiazolidinediones (TZDs) may increase the risk of congestive heart failure (CHF). However, their effect on the risk of incident CHF in unselected populations has not been thoroughly investigated. METHODS: Using data from the UK's General Practice Research Database, we conducted a case-control study within a population-based cohort of patients with type 2 diabetes. Cases were identified by a clinical diagnosis of incident CHF and were then classified as possible or probable cases using prescription data. A 90-day drug exposure window was used in the primary analysis, which compared patients prescribed TZDs with those with no prescriptions for anti-diabetic medications. RESULTS: We identified 3405 incident cases (2632 probable and 773 possible) of CHF and 32,042 corresponding controls. TZDs were prescribed in 6.4% of cases and 6.3% of controls. Prescription of TZDs was associated with an increased rate of possible or probable CHF (adjusted rate ratio (RR) = 1.24, 95% CI = 1.01, 1.54 and adjusted RR = 1.24, 95% CI = 0.98, 1.58, respectively). Similar results were obtained when using a 180-day exposure window (RR = 1.38, 95% CI = 1.11, 1.72 and RR = 1.44, 95% CI = 1.12, 1.84, respectively). CONCLUSIONS: Given the totality of the evidence from this and previous studies, the probability of an increased risk for CHF with these agents remains high. However, any increase in CHF risk associated with TZDs may be lower than previously reported. PMID- 21671442 TI - Why do covariates defined by International Classification of Diseases codes fail to remove confounding in pharmacoepidemiologic studies among seniors? AB - PURPOSE: The common practice of using administrative diagnosis codes as the sole source of data on potential confounders in pharmacoepidemiologic studies has been shown to leave substantial residual confounding. We explored reasons why adjustment for comorbid illness defined from International Classification of Diseases (ICD) codes fails to remove confounding. METHODS: We used data from a case-control study among immunocompetent seniors enrolled in Group Health to estimate bias in the estimated association between receipt of influenza vaccine and the risk of community-acquired pneumonia during non-influenza control periods and to estimate the effects of adjusting for comorbid illnesses defined from either ICD codes or the medical record. We also estimated the accuracy of ICD codes for identifying comorbid illnesses compared with the gold standard of medical record review. RESULTS: Sensitivity of ICD codes for illnesses recorded in the medical record ranged from 59 to 97% (median, 76%). Strong confounding was present in the vaccine/pneumonia association, as evidenced by the non-null odds ratio of 0.60 (95% confidence interval, 0.38-0.95) during this control period. Adjusting for the presence/absence of comorbid illnesses defined from either medical record review (odds ratio, 0.73) or from ICD codes (odds ratio, 0.68) left considerable residual confounding. CONCLUSIONS: ICD codes may fail to control for confounding because they often lack sensitivity for detecting comorbid illnesses and because measures of the presence/absence of comorbid illnesses may be insufficient to remove confounding. These findings call for caution in the use of ICD codes to control for confounding. PMID- 21671443 TI - Graft-crosslinked copolymers based on poly(arylene ether ketone)-gc-sulfonated poly(arylene ether sulfone) for PEMFC applications. AB - Novel poly(arylene ether ketone) polymers with fluorophenyl pendants and phenoxide-terminated wholly sulfonated poly(arylene ether sulfone) oligomers are prepared via Ni(0)-catalyzed and nucleophilic polymerization, respectively, and subsequently used as starting materials to obtain graft-crosslinked membranes as polymer electrolyte membranes. The phenoxide-terminated sulfonated moieties are introduced as hydrophilic parts as well as crosslinking units. The chemical structure and morphology of the obtained membranes are confirmed by (1) H NMR and tapping-mode AFM. The properties required for fuel cell applications, including water uptake and dimensional change, as well as proton conductivity, are investigated. AFM results show a clear nanoscale phase-separation microstructure of the obtained membranes. The membranes show good dimensional stability and reasonably high proton conductivities under 30-90% relative humidity. The anisotropic proton conductivity ratios (sigma(formula see text) ) of the membranes in water are in the range 0.65-0.92, and increase with an increase in hydrophilic block length. The results indicate that the graft-crosslinked membranes are promising candidates for applications as polymer electrolyte membranes. PMID- 21671444 TI - Psychological distress and experience of sexual and physical assault among Australian prisoners. AB - BACKGROUND: Prison populations are made up of individuals from disadvantaged, often abusive backgrounds, who are more likely to suffer from psychological problems than the general community. AIM: This study aimed to determine associations between current psychological distress and history of having experienced sexual coercion and/or physical assault among prisoners in two Australian states (Queensland and New South Wales). METHODS: We conducted a random sample survey of prisoners by computer-assisted telephone interview. Prisoners were asked about forced sexual encounters in or outside prison, and physical assault in prison. Psychological distress was estimated using a dichotomised score obtained from the Kessler 6-Item Psychological Distress Scale (K6), and a logistic regression analysis was employed to investigate associations. RESULTS: A total of 2426 prisoners were interviewed of 3055 prisoners invited to participate, a response rate of 79%. We categorised 236 men (12%) and 63 women (19%) as 'severely' psychologically distressed according to the K6, and 13% of the men and 60% of the women reported that they had been sexually coerced prior to imprisonment. Physical assault in prison was common, reported by 34% of the men and 24% of the women. On multivariate analysis, prisoners were more likely to be psychologically distressed if they had ever been threatened with sexual assault in prison or physically assaulted in prison. Sexual coercion outside prison was an important associate of psychological distress among men but not among women. CONCLUSIONS: As psychological distress and experiences of assault are closely statistically linked among male prisoners and both are very common among female prisoners, their screening for psychological distress should include efforts to find out about sexual and violent assaults against them both before and during imprisonment. Further, longitudinal research with prisoners is required to establish causal relationships. PMID- 21671445 TI - Cytophilic fluorescent bioprobes for long-term cell tracking. PMID- 21671446 TI - Dual-gate thin-film transistors, integrated circuits and sensors. AB - The first dual-gate thin-film transistor (DGTFT) was reported in 1981 with CdSe as the semiconductor. Other TFT technologies such as a-Si:H and organic semiconductors have led to additional ways of making DGTFTs. DGTFTs contain a second gate dielectric with a second gate positioned opposite of the first gate. The main advantage is that the threshold voltage can be set as a function of the applied second gate bias. The shift depends on the ratio of the capacitances of the two gate dielectrics. Here we review the fast growing field of DGTFTs. We summarize the reported operational mechanisms, and the application in logic gates and integrated circuits. The second emerging application of DGTFTs is sensitivity enhancement of existing ion-sensitive field-effect transistors (ISFET). The reported sensing mechanism is discussed and an outlook is presented. PMID- 21671447 TI - Reduction of lattice thermal conductivity in single Bi-Te core/shell nanowires with rough interface. PMID- 21671448 TI - Melanin layer on silicon: an attractive structure for a possible exploitation in bio-polymer based metal-insulator-silicon devices. PMID- 21671449 TI - Improving device efficiency of polymer/fullerene bulk heterojunction solar cells through enhanced crystallinity and reduced grain boundaries induced by solvent additives. PMID- 21671450 TI - Electronic transport in organic materials: comparison of band theory with percolation/(variable range) hopping theory. PMID- 21671451 TI - Resolving bulk and grain boundary transport properties of TiO2 thin films enabled by laser-induced anisotropic morphology. PMID- 21671452 TI - In situ observation of voltage-induced multilevel resistive switching in solid electrolyte memory. PMID- 21671453 TI - Superstrong ultralong carbon nanotubes for mechanical energy storage. PMID- 21671454 TI - "Marking" the nitrogen atoms of phenyl-(2-pyridyl)-(3-pyridyl)-(4-pyridyl) methane. Synthesis and absolute configuration of the corresponding tris(pyridine N-oxide). AB - To "mark" the nitrogen atoms in phenyl-(2-pyridyl)-(3-pyridyl)-(4-pyridyl)methane (1), we have synthesized the corresponding tris(pyridine N-oxide) 2 by oxidation of 1 with m-chloroperbenzoic acid. The nitrogen atoms of 2 are unequivocally determined by the X-ray crystal analysis of a single crystal of rac-2 whereas the nitrogen atoms cannot be assigned at all in the case of rac-1. N-Oxide 2 can be resolved by chiral high-performance liquid chromatography under similar conditions to those used for the resolution of 1. The calculated circular dichroism (CD) curve for (R)-2 on the basis of time-dependent density functional theory reproduces the experimental spectra very well to suggest that the second eluted fraction ([CD(+)283]-2) is the R isomer, namely (R)-[CD(+)283]-2. The independent absolute configuration determinations for 1 and 2 are in keeping with the chemical correlation between the two compounds by oxidation of (R)-1 into (R) 2. PMID- 21671455 TI - Internal organization of large protein families: relationship between the sequence, structure, and function-based clustering. AB - The protein universe can be organized in families that group proteins sharing common ancestry. Such families display variable levels of structural and functional divergence, from homogenous families, where all members have the same function and very similar structure, to very divergent families, where large variations in function and structure are observed. For practical purposes of structure and function prediction, it would be beneficial to identify sub-groups of proteins with highly similar structures (iso-structural) and/or functions (iso functional) within divergent protein families. We compared three algorithms in their ability to cluster large protein families and discuss whether any of these methods could reliably identify such iso-structural or iso-functional groups. We show that clustering using profile-sequence and profile-profile comparison methods closely reproduces clusters based on similarities between 3D structures or clusters of proteins with similar biological functions. In contrast, the still commonly used sequence-based methods with fixed thresholds result in vast overestimates of structural and functional diversity in protein families. As a result, these methods also overestimate the number of protein structures that have to be determined to fully characterize structural space of such families. The fact that one can build reliable models based on apparently distantly related templates is crucial for extracting maximal amount of information from new sequencing projects. PMID- 21671456 TI - A randomized, double-blind, placebo-controlled, crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a history of recreational cannabis use. AB - OBJECTIVE: This study aimed to evaluate the abuse potential and cognitive effects of nabiximols (Sativex, GW Pharma Ltd. Salisbury, UK), an oromucosal spray primarily containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). METHODS: This was a single-dose, randomized, double-blind, crossover study comparing nabiximols (4, 8, and 16 consecutive sprays: 10.8, 21.6, and 43.2 mg THC, respectively) with dronabinol 20 and 40 mg (synthetic THC: Marinol, Solvay Pharmaceuticals, Brussels, Belgium) and matching placebos in 23 recreational cannabis users. Subjective and cognitive/psychomotor measures were administered over 24 h post-dose. RESULTS: Dronabinol was significantly different from placebo on abuse potential measures, thereby confirming study validity. Nabiximols 10.8 mg was not significantly different from placebo on primary measures but was different on some secondary measures. Nabiximols 21.6 mg was significantly greater than placebo on some primary/secondary measures, whereas nabiximols 43.2 mg showed significant effects on most measures. Nabiximols 10.8 mg was significantly lower than dronabinol doses on most measures ( p < 0.05). Dronabinol 20 mg effects were numerically higher than nabiximols 21.6 mg but were statistically significant only for some measures. Dronabinol 40 mg and nabiximols 43.2 mg were generally not statistically different. CONCLUSIONS: Both dronabinol and nabiximols had significant abuse potential compared with placebo at higher doses. Nabiximols showed similar or slightly less abuse potential compared with dronabinol. Therefore, the abuse potential of nabiximols should be no higher than that of dronabinol. PMID- 21671457 TI - Translating visions of transparency and quality development: the transformation of clinical databases in the Danish hospital field. AB - One of the most significant developments in the quest for quality, transparency, and accountability in healthcare is the construction and the implementation of indicator-based technologies. In Denmark, this development has been relatively pronounced, and based on an extensive document study supplemented by qualitative interviews, this paper articulates a policy history of the clinical databases for quality from the early 1990s to the present. First, the paper outlines how, in the early 1990s, the National Board of Health and representatives from the medical profession place the clinical databases on the quality agenda in healthcare. Second, the paper shows that, in spite of an initial alignment between governmental and professional interests, the establishment of national clinical databases for quality turns out to be a difficult enterprise. Third, the paper elaborates how the public authorities respond to the challenges by re designing the governance framework for the databases. The transformations are characterized by increased centralization, standardization, specialization and regulative pressure. Finally, it is pointed out that although the course of events does constitute an increased institutionalization of the clinical databases, large variations exist and several databases have not yet realized the ambitions of transparency and quality improvement. PMID- 21671458 TI - Serotonin transporter binding after recovery from bulimia nervosa. AB - OBJECTIVE: Physiological and pharmacological studies indicate that altered brain serotonin (5-HT) activity could contribute to a susceptibility to develop appetitive and behavioral alterations that are characteristic of bulimia nervosa (BN). METHOD: Eight individuals recovered from BN (REC BN) and eight healthy control women were scanned with [11C]DASB and positron emission tomography imaging of the 5-HT transporter (5-HTT). Logan graphical analysis was applied, and parametric binding potential (BP(nondisplaceable (ND)) ) images were generated. Voxel-by-voxel t-tests and a region of interest (ROI) analysis were conducted. RESULTS: REC BN had significantly lower [11C]DASB BP(ND) in midbrain, superior and inferior cingulate and significantly higher [11C]DASB BP(ND) in anterior cingulate and superior temporal gyrus in the voxel-based analysis. ROI analysis indicated lower [11C]DASB BP(ND) in midbrain (p = .07), containing the dorsal raphe, in REC BN, consistent with our earlier studies. DISCUSSION: These preliminary findings of a small-scale study confirm and extend previous data suggesting that ill and recovered BN have altered 5-HTT measures, which potentially contribute to BN symptomatology and/or differential responses to medication. PMID- 21671459 TI - Occupational vs. industry sector classification of the US workforce: which approach is more strongly associated with worker health outcomes? AB - OBJECTIVES: Through use of a nationally representative database, we examined the variability in both self-rated health and overall mortality risk within occupations across the National Occupational Research Agenda (NORA) Industry Sectors, as well as between the occupations within the NORA Industry sectors. METHODS: Using multiple waves of the National Health Interview Survey (NHIS) representing an estimated 119,343,749 US workers per year from 1986 to 2004, age adjusted self-rated health and overall mortality rates were examined by occupation and by NORA Industry Sector. RESULTS: There was considerable variability in the prevalence rate of age-adjusted self-rated poor/fair health and overall mortality rates for all US workers. The variability was greatest when examining these data by the Industry Sectors. In addition, we identified an overall pattern of increased poor/fair self-reported health and increased mortality rates concentrated among particular occupations and particular Industry Sectors. CONCLUSIONS: This study suggests that using occupational categories within and across Industry Sectors would improve the characterization of the health status and health disparities of many subpopulations of workers within these Industry Sectors. PMID- 21671460 TI - Fetal surgery for cardiac lesions. AB - Intrauterine dilation of critical fetal aortic stenosis (AS) and pulmonary stenosis or atresia has the potential to change the natural course of these congenital heart defects preventing progression to a single ventricle circulation. This article reviews the world experience in fetal cardiac interventions. In carefully selected cases, fetal cardiac surgery can reverse end stage heart failure and can provide biventricular outcome postnatally in about two thirds of the cases with successful interventions. PMID- 21671461 TI - Tracheal diameter at birth in severe congenital diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. AB - OBJECTIVE: To investigate tracheal dimensional differences seen at birth following fetal endoscopic tracheal occlusion (FETO) in cases of severe congenital diaphragmatic hernia (CDH) and to report on their clinical follow-up. PATIENTS AND METHODS: In chest X-rays, taken within 48 h after birth, we measured the tracheal diameter at the level of the tracheal entry into the chest, 1 cm above the level of the carina and at middistance between these sites in 37 fetuses with severe CDH treated by FETO. These measurements were compared with those in 74 preterm and term neonates with no congenital lung abnormalities. RESULTS: In the CDH group, compared to the controls, the tracheal diameter corrected for gestational age was significantly larger at all three levels of the trachea. Regression analysis showed that significant predictors of the tracheal diameter at the level of tracheal entry into the chest were the observed to expected (o/e) lung area to head circumference ratio (LHR) and the duration of tracheal occlusion. In the CDH group, postnatal follow-up until the age of 22 months (1-70) showed that 5 of 24 neonates had an effort-induced barking cough. CONCLUSION: A large number of infants with severe CDH surviving after FETO have a degree of tracheomegaly that is associated with the severity of CDH as assessed by pre-FETO LHR. This tracheomegaly does not constitute an obvious clinical problem. PMID- 21671462 TI - Clinical implication of FDG-PET in advanced gastric cancer with signet ring cell histology. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to investigate the role of the standardized uptake values (SUV), a semi-quantitative assessment of tumor FDG uptake, as a prognosticator for advanced signet ring cell carcinoma (SRC). METHODS: We reviewed the files of 41 patients who underwent curative gastrectomy for advanced SRC and who had an FDG-PET at initial presentation between September 2003 and December 2007. RESULTS: The median follow-up period was 30.9 months (range: 4.0-70.3). We found a correlation between the SUVmax and TNM stage. When the patients were divided into two groups (low vs. high SUVmax) based on a median SUVmax of 3.80, the high-SUVmax group showed more aggressive tumor behavior than did the low SUVmax group. In addition, the high SUVmax group showed more postoperative recurrence (P = 0.028), shorter relapse-free survival (P = 0.004), and lower 30-month cancer-specific survival rates (40.0% vs. 69.3%, P = 0.008). However, in multivariate analysis, SUVmax failed to be an independent predictor of overall survival. CONCLUSIONS: Although SUVmax of initial PET scan was not an independent predictor of patient outcomes after curative surgery, higher SUVmax is associated with more advanced stage and indicates more aggressive tumor biology in advanced SRC. PMID- 21671463 TI - The status of EGFR-associated genes could predict the outcome and tumor response of chemo-refractory metastatic colorectal patients using cetuximab and chemotherapy. AB - PURPOSE: This study was designed to analyze the impacts of status of EGFR associated genes on the outcome of chemo-refractory mCRC patients using cetuximab. MATERIALS AND METHODS: We collected samples from 42 metastatic CRC patients refractory to FOLFOX or FOLFIRI. Mutation profiles of KRAS, BRAF, PTEN, and PI3KCA and the copy numbers of EGFR and PTEN were analyzed. Overall survival and tumor response between various statuses of EGFR-associated genes were compared. RESULTS: Eleven patients had a partial response to cetuximab with chemotherapy. Sixteen (38.1%) tumors had KRAS mutations. Three (7.1%) had BRAF mutations (V600E) and three (7.1%) had PTEN mutations. No PIK3CA mutation was found. Of 26 wild-KRAS tumors, nine (34.6%) had a partial response to cetuximab: this was higher than that of KRAS-mutated tumors (12.5%). Five patients with BRAF or PTEN mutations did not response to cetuximab. Response rate increased to 45% in patients with all wild-type KRAS, BRAF, and PTEN tumors. Of 16 tumors with high EGFR copy number, eight (50%) responded to cetuximab, a higher response rate than that of tumors with normal EGFR copy number (3/26, P = 0.011). Overall survival of patients was associated with high EGFR copy number and all wild-type tumors. CONCLUSION: EFGR copy number and mutation in EGFR-associated genes could be selective markers in mCRC patients using cetuximab. PMID- 21671464 TI - Heat shock protein-60 expression was significantly correlated with the prognosis of lung adenocarcinoma. AB - BACKGROUND: The purpose of this study was to investigate the role of heat shock protein 60 (HSP60) in the clinical pathology of lung adenocarcinoma, and to explore whether the expression of HSP60 can act as an independent predictor for tumor relapse and prognosis after radical resection of lung adenocarcinoma. METHODS: Paraffin sections of lung adenocarcinoma tumor tissues were collected from 103 patients. Using immunohistochemistry, the expression levels of HSP60 in lung adenocarcinoma were detected. The correlations between HSP60 expression and clinicopathological parameters as well as prognosis were statistically analyzed. RESULTS: Of the 103 specimens, 70 cases (68.0%) showed a strongly positive expression of HSP60, five cases (4.8%) showed a negative expression, and 28 cases (27.2%) showed a weakly positive expression. The level of HSP60 expression was significantly correlated with TNM stage of the tumor (P = 0.015), and Eastern Cooperative Oncology Group (ECOG) performance status (P = 0.027). Multivariate statistical analysis showed that patient age, pathological T stage, N stage, and HSP60 expression were independent prognostic influence on disease-free survival (P = 0.008, 0.011, 0.010, and <0.001, respectively). CONCLUSIONS: HSP60 may be a good biomarker to be applied in clinic to predict the prognosis of patients with lung adenocarcinoma. PMID- 21671465 TI - Totally implantable central venous access ports. Analysis of 700 cases. AB - BACKGROUND AND OBJECTIVES: Vascular access has great importance in the treatment of patients submitted to prolonged chemotherapy. Purpose of this study is to assess the efficacy and safety of the percutaneous insertion and use of totally implantable central venous access ports (TICVAP). METHODS: During a 10-year period, 700 TICVAP were inserted into cancer patients for chemotherapy. Early and late complications and their management were recorded and analyzed. RESULTS: Of the 700 catheters implanted, 126 (18%) presented one or more types of early and late complication. Removal of 262 catheters was performed, of which 216 (82.4%) were elective indications due to the termination of the treatment and 46 (17.6%) resulted from complications that could not be controlled using clinical measures. In 280 patients (40%), the catheter remained functional until the patient's death, and 158 patients (22.5%) are still making use of their catheters for clinical treatment. CONCLUSIONS: The low rate of complications according to this study confirms the safety and convenience of the percutaneous insertion and use of TICVAP in patients undergoing prolonged chemotherapy regimens and explains the increasing use of these devices in current medical oncology practice. PMID- 21671466 TI - Intraoperative mapping with isosulfan blue of lymphatic leakage during inguinal lymph node dissection (ILND) for skin cancer for the prevention of postoperative lymphocele. AB - BACKGROUND: Inguinal lymphocele is a well-known complication of inguinal lymph node dissection. Isosulfan blue has been used to identify and treat lymphoceles arising from lymphatics injured during surgery of the groin. However, the preventive use at the time of lymph node dissection has not been reported. OBJECTIVES: We evaluated the potential role of intraoperative injection of isosulfan blue during inguinal lymph node dissection for the prevention of postoperative lymphocele. METHODS: We performed 43 conventional inguinal lymph node dissections (group A) and 7 inguinal lymph node dissections using isosulfan blue injection around the dissected inguinal region (group B) to identify lymphatic leakage intraoperatively. RESULTS: Lymphoceles were observed in 13 of 43 dissections (30.23%) in group A and in 0 of 7 dissections (0%) in group B. The number of detected injured lymphatics ranged from 0 to 6 (mean 3.3) in group B. The mean postoperative lymphatic drainage output was less in group B than in group A. The mean number of days of suction catheter insertion was 4.43 days in group B, and 7.98 days in group A. CONCLUSIONS: The technique during inguinal lymph node dissection presented herein is useful for the prevention of postoperative lymphocele. PMID- 21671467 TI - miR-338-3p suppresses invasion of liver cancer cell by targeting smoothened. AB - MicroRNAs are involved in human carcinogenesis and cancer progression. Our previous study has shown that loss of miR-338-3p expression is associated with clinical aggressiveness of hepatocellular carcinoma (HCC). However, the exact roles and mechanisms of miR-338-3p remain unknown in HCC. To determine whether and how miR-338-3p influences liver cancer cell invasion, we studied miR-338-3p in the liver cancer cell lines, and we found that miR-338-3p is down-regulated in treated cells. Forced expression of miR-338-3p in SK-HEP-1 cells suppressed cell migration and invasion, whereas inhibition of miR-338-3p in SMMC-7721 cells induced cell migration and invasion. Furthermore, smoothened (SMO) was identified as a direct target of miR-338-3p. Forced expression of miR-338-3p down-regulated SMO and matrix metalloproteinase (MMP)-9 expression, but inhibition of miR-338-3p up-regulated SMO and MMP9 expression. However, small interfering RNA targeted SMO reversed the effects induced by blockade of miR-338-3p. SMO and MMP9 were overexpressed and associated with invasion and metastasis in HCC tissues. These data indicate that miR-338-3p suppresses cell invasion by targeting the smoothened gene in liver cancer in vitro and miR-338-3p might be a novel potential strategy for liver cancer treatment. PMID- 21671468 TI - Histone deacetylase inhibition as an anticancer telomerase-targeting strategy. AB - Aberrant epigenetic regulation of gene expression contributes to tumor initiation and progression. Studies from a plethora of hematologic and solid tumors support the use of histone deacetylase inhibitors (HDACi) as potent anticancer agents. The mechanism(s) of HDACi-induced cancer growth inhibition and cell death are complex and incompletely elucidated. Here, we discuss erroneous epigenetic regulation of hTERT transcription in cancer cells and propose that alleviation of an improper acetylation-deacetylation balance at the hTERT promoter, is one mode by which HDACi induces anticancer effects. We conclude with some pertinent questions and future perspectives arising from the recent impetus in HDACi preclinical and early clinical studies, with particular attention to the cancer stem cell therapeutic paradigm and its relevance to tumor resistance. PMID- 21671469 TI - The cancer burden in the United Kingdom in 2007 due to radiotherapy. AB - The number of long-term cancer survivors in the general population of the UK is substantial and increasing rapidly. Many cancer survivors have been treated with radiotherapy but the likely number of radiotherapy-related second cancers has not previously been estimated. We used estimates of the numbers of cancer survivors in the UK at the beginning of 2007, in conjunction with estimates of the relative risk of a second primary cancer associated with previous radiotherapy from the United States Surveillance Epidemiology and End Results (SEER) programme, to estimate the numbers of incident cancers in the UK in 2007 that were associated with radiotherapy for a previous cancer and that may have been caused by it. We estimated that 1,346 cases of cancer, or about 0.45% of the 298,000 new cancers registered in the UK in 2007, were associated with radiotherapy for a previous cancer. The largest numbers of radiotherapy-related second cancers were lung cancer (23.7% of the total), oesophageal cancer (13.3%), and female breast cancer (10.6%); 54% of radiotherapy-related second cancers were in individuals aged 75 or over. The highest percentages of second cancers related to radiotherapy were among survivors of Hodgkin's disease and cancers of the oral cavity and pharynx and cervix uteri; over 15% of second cancers among these survivors were associated with radiotherapy for the first cancer. These calculations, which involve a number of assumptions and approximations, provide a reasonable, if conservative, estimate of the fraction of incident cancers in the UK that are attributable to past radiation therapy. PMID- 21671470 TI - Novel senescence associated gene, YPEL3, is repressed by estrogen in ER+ mammary tumor cells and required for tamoxifen-induced cellular senescence. AB - Estrogen signaling plays an important role in breast carcinogenesis. An increased understanding of estrogen gene targets and their effects will allow for more directed and effective therapies for individuals with breast cancer, particularly those with estrogen receptor positive tumors resistant to tamoxifen therapy. Here, we identify YPEL3 as a growth suppressive protein downregulated by estrogen in estrogen receptor positive breast cancer cell lines. Estrogen repression of YPEL3 expression was found to be independent of p53 but dependent on estrogen receptor alpha expression. Importantly, YPEL3 expression, which is induced by the removal of estrogen or treatment with tamoxifen triggers cellular senescence in MCF-7 cells while loss of YPEL3 increases the growth rate of MCF-7 cells. Taken together these findings suggest that YPEL3 may represent a potential target for directed hormonal therapy for estrogen receptor positive breast cancer patients. PMID- 21671471 TI - B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes. AB - B7-H3, an immunoregulatory protein, is known to play a role in tumor progression. In many cancer types, observed correlations between high B7-H3 expression and poor prognosis have been attributed to involvement in antitumor immunity. However, here we demonstrate a nonimmunological alternative function of B7-H3 in cancer metastasis. Since advanced malignant melanoma is a disease with a poor survival rate and a broad pattern of metastasis, we used this disease as a model in our studies. We found that shRNA silencing of B7-H3 reduced the in vitro migratory potential and matrigel invasiveness of MDA-MB-435 and FEMX-I melanoma cells. In an experimental metastasis model in vivo, B7-H3 silencing of MDA-MB-435 cells resulted in reduced metastatic capacity and significantly increased the median symptom-free survival of nude mice (147 vs. 65 days, p < 0.001) and rats (53 vs. 42 days, p = 0.025) injected with MDA-MB-435 cells. Furthermore, a smaller fraction of mice had microscopically detectable metastases compared to control animals, and the pattern of metastases was slightly different between the two groups but with the brain as the predominant organ. Immunohistochemistry on samples from two melanoma patients showed strong B7-H3 staining in both a primary tumor and metastases. Notably, the metastasis-associated proteins, matrix metalloproteinase (MMP)-2, signal transducer and activator of transcription 3 (Stat3), and the level of secreted interleukin-8 (IL-8) were reduced in the B7-H3 knock-down cell variants, whereas tissue inhibitor of metalloproteinase (TIMP)-1 and-2 levels were increased. Taken together, our findings indicate a novel role for B7-H3 in the regulation of the metastatic capacity of melanoma cells and it might be a potential therapeutic target for anti-metastasis therapy. PMID- 21671472 TI - Occupation and risk of upper aerodigestive tract cancer: the ARCAGE study. AB - We investigated the association between occupational history and upper aerodigestive tract (UADT) cancer risk in the ARCAGE European case-control study. The study included 1,851 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1,949 controls. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ever employment in 283 occupations and 172 industries, adjusting for smoking and alcohol. Men (1,457 cases) and women (394 cases) were analyzed separately and we incorporated a semi Bayes adjustment approach for multiple comparisons. Among men, we found increased risks for occupational categories previously reported to be associated with at least one type of UADT cancer, including painters (OR = 1.74, 95% CI: 1.01-3.00), bricklayers (1.58, 1.05-2.37), workers employed in the erection of roofs and frames (2.62, 1.08-6.36), reinforced concreters (3.46, 1.11-10.8), dockers (2.91, 1.05-8.05) and workers employed in the construction of roads (3.03, 1.23-7.46), general construction of buildings (1.44, 1.12-1.85) and cargo handling (2.60, 1.17-5.75). With the exception of the first three categories, risks both increased when restricting to long duration of employment and remained elevated after semi-Bayes adjustment. Increased risks were also found for loggers (3.56, 1.20-10.5) and cattle and dairy farming (3.60, 1.15-11.2). Among women, there was no clear evidence of increased risks of UADT cancer in association with occupations or industrial activities. This study provides evidence of an association between some occupational categories and UADT cancer risk among men. The most consistent findings, also supported by previous studies, were obtained for specific workers employed in the construction industry. PMID- 21671473 TI - Menopausal hormone therapy and risk of gastrointestinal cancer: nested case control study within a prospective cohort, and meta-analysis. AB - Use of menopausal hormone therapy (HT) has been associated with reduced risk of colorectal cancer; evidence for its effect on other gastrointestinal cancers is limited. We conducted a nested case-control study within a UK cohort, and meta analyses combining our results with those from published studies. Our study included women aged 50+ in the UK General Practice Research Database (GPRD): 1,054 with oesophageal, 750 with gastric and 4,708 with colorectal cancer, and 5 age- and practice-matched controls per case. Relative risks (RRs) and 95% confidence intervals (CIs) for cancer in relation to prospectively-recorded HT prescriptions were estimated by conditional logistic regression. Women prescribed HT had a reduced risk of oesophageal cancer (adjusted RR for 1+ vs. no HT prescriptions, 0.68, 95% CI 0.53-0.88; p = 0.004), gastric cancer (0.75, 0.54 1.05; p = 0.1) and colorectal cancer (0.81, 0.73-0.90; p < 0.001). There were no significant differences in cancer risk by HT type, estimated duration of HT use or between past and current users. In meta-analyses, risks for ever vs. never use of HT were significantly reduced for all three cancers (summary RR for oesophageal cancer, 0.68, 0.55-0.84, p < 0.001; for gastric cancer, 0.78, 0.65 0.94, p = 0.008; for colorectal cancer, 0.84, 0.81-0.88, p < 0.001). In high income countries, estimated incidence over 5 years of these three cancers combined in women aged 50-64 was 2.9/1,000 in HT users and 3.6/1,000 in never users. The absolute reduction in risk of these cancers in HT users is small compared to the HT-associated increased risk of breast cancer. PMID- 21671474 TI - Adjuvant and neoadjuvant imatinib therapy: current role in the management of gastrointestinal stromal tumors. AB - Although surgery remains the mainstay for the treatment of primary gastrointestinal stromal tumors (GIST), a significant number of patients experience disease recurrence within 5 years of surgery. The emergence of imatinib therapy for the treatment of patients with advanced GIST has offered unprecedented improvements in clinical outcomes for these patients. Prospective clinical trials have supported the efficacy and safety of imatinib before and after surgical resection of GIST. The American College of Surgeons Oncology Group Z9001 pivotal trial revealed that 1 year of adjuvant imatinib therapy provides significantly superior recurrence-free survival in patients with GIST after surgical resection, when compared to placebo. Additional trials and case studies have also begun to define the potential clinical benefit of imatinib in the neoadjuvant setting. Optimized risk stratification paradigms will be required to ensure the appropriate selection of patients to undergo treatment with imatinib in these settings. Risk stratification schemes are evolving that potentially will include mutation status and tumor rupture, and predictive nomograms have recently been proposed. The recent European Society of Medical Oncology and National Comprehensive Cancer Network guidelines mention use of adjuvant imatinib for >= 1 year in patients with KIT(+) , resectable GIST at high risk of recurrence. Moreover, the guidelines support the use of neoadjuvant imatinib in cases of limited disease if it would facilitate less extensive surgery and organ sparing. This article reviews pivotal efficacy and safety data for adjuvant imatinib and explores the potential clinical benefit of neoadjuvant imatinib in patients with GIST. PMID- 21671476 TI - Candidate microRNA biomarkers in human colorectal cancer: systematic review profiling studies and experimental validation. AB - Colorectal cancer (CRC) is a major cause of cancer mortality worldwide. There is an urgent need to search for specific and sensitive biomarkers for early diagnosis of CRC. We carried out a comprehensive systematic review of published studies that compared the miRNA expression profiles between CRC tissue and paired neighboring noncancerous colorectal tissue to determine candidate miRNA biomarkers for CRC. A miRNA ranking system that takes the number of comparisons in agreement, total study sizes and direction of differential expression into the consideration was devised and used. One of the most up-regulated miRNAs, miRNA 106a, was consistently reported to be differentially expressed in six studies and the five most down-regulated miRNAs, miR-30a-3p, miR-139, miR-145, miR-125a and miR-133a, were consistently reported to be differentially expressed in four studies. Moreover, we further validated five miRNAs in a clinical setting using qRT-PCR, which demonstrated that miR-106a expression was increased, whereas the expression of miR-30a-3p, miR-145, miR-125a and miR-133a was decreased in the CRC tissues. Therefore, these miRNAs may be the candidates to develop a panel of biomarkers with sufficient sensitivity and specificity for the diagnosis of CRC in a clinical setting. PMID- 21671475 TI - An American founder mutation in MLH1. AB - Mutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the MLH1 gene (c.589-2A>G) had been observed in four ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1,803 cases tested for MLH1 mutations by the German HNPCC consortium, while it occurred in three probands and an additional five family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (~4.8 Mb) shared haplotype that also harbors the variant c.2146G>A, which predicts a missense change in codon 716 referred to here as V716M. In Italy, it occurs on a different, shorter shared haplotype (~2.2 Mb) that does not carry V716M. The V716M variant was found to be present by itself in the U.S., German and Italian populations with individuals sharing a common haplotype of 280 kb, allowing us to calculate that the variant arose around 5,600 years ago (225 generations; 95% confidence interval 183-272). The splice site mutation in America arose or was introduced some 450 years ago (18 generations; 95% confidence interval 14-23); it accounts for 1.0% all LS in the Unites States and can be readily screened for. PMID- 21671477 TI - Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations. AB - Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families. We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (-)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. p-Values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p = 0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p = 0.0006). 28 ~ 56% of genotyped SNPs in these genes had single SNP p < 0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (-) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations. PMID- 21671478 TI - Versican V1 isoform regulates cell-associated matrix formation and cell behavior differentially from aggrecan in Swarm rat chondrosarcoma cells. AB - Versican, a large chondroitin sulfate proteoglycan that binds hyaluronan and is composed of large extracellular matrix aggregates, has been shown to correlate with tumor progression. No studies have examined the roles of versican in chondrosarcoma nor compared them to those of aggrecan. In clinical specimens of human chondromatous tumors, versican expression was significantly increased in malignant tumors, moreover, as the tumor grade increased. To clarify the roles of versican in chondrosarcoma, versican splicing variant 1, variant 3 or only GFP was stably transfected to Swarm rat chondrosarcoma cells with Trap-In System. Forced expression of versican V1 isoform in Swarm rat chondrosarcoma cells induced a marked increase of cell-associated matrix compared to V3-, GFP- transfected or RCS cells. Versican was immunolocalized in a fashion similar to that of hyaluronan and more diffusively than aggrecan. Anchor-dependent and independent growth was not affected by versican isoform expression, whereas cell motility and migration were significantly enhanced by V1 isoform transfection. Tumors formed in vivo with V1-transfected cells exhibited more myxomatous area and included more spindle shaped cells. These results support the concept that versican has the capacity to form more extensive cell-associated matrix than aggrecan, and the prominent matrix formation alters the cell behavior of chondrosarcoma more aggressively. These observations suggest that versican expression may serve as a marker of tumor grade determination in chondrosarcoma and possibly help to decide on therapeutic targets in higher grades of chondrosarcoma. PMID- 21671479 TI - Prior chemoradiotherapy adversely impacts outcomes of recurrent and second primary head and neck cancer treated with concurrent chemotherapy and reirradiation. AB - BACKGROUND: It has been shown that concomitant chemotherapy (C) with reirradiation (ReRT) is feasible and effective for select patients with recurrent or second primary head and neck cancer (HNC). To examine potential prognostic factors associated with survival, the authors of this report retrospectively reviewed the outcomes of patients who received CReRT. METHODS: The study cohort comprised previously irradiated patients with nonmetastatic disease from 9 consecutive phase 1 and 2 protocols for poor-prognosis HNC. For all patients, reirradiation (ReRT) was delivered with concurrent chemotherapy. Chemotherapy generally was 5-fluorouracil, hydroxyurea, and a third agent. RESULTS: One hundred sixty-six patients were identified, including 81 patients who underwent surgical resection or debulking before enrollment. The median ReRT dose was 66 gray. After a median follow-up of 53 months among surviving patients, the median overall survival (OS) was 10.3 months. The 2-year rates for OS, disease-free survival, locoregional control, and freedom from distant metastasis were 24.8%, 19.9%, 50.7%, and 61.4%, respectively. Thirty-three patients (19.9%) died of treatment-related toxicity. In subgroup analysis, survival was significantly reduced in patients who received previous concurrent chemoradiotherapy (CRT) compared with patients who were naive to CRT (2-year OS rate, 10.8% vs 28.4%; P = .0043). In multivariable analysis, prior CRT was associated independently with OS along with surgery before protocol treatment, full-dose ReRT, and radiotherapy interval. CONCLUSIONS: CReRT achieved a long-term cure for a small group of patients with recurrent or second primary HNC. Previous treatment with CRT was among the important prognostic factors for survival. Because of the associated risk of severe toxicity, CReRT should be limited only to carefully selected patients. PMID- 21671480 TI - [Screening strategies for colorectal cancer]. PMID- 21671481 TI - [Screening of Tag SNPs and prediction of their potential function in genetic studies of complex diseases]. AB - We applied public databases of single nucleotide polymorphism (SNP) to screen complex disease-related SNPs and assessed the potential functions of selected SNPs through SNP function prediction software, including FastSNP, SNP Function Prediction, F-SNP. We selected Tag SNP in HapMap database and compared all results with above software. With above strategies we screened IGFBP7 gene and obtained total 47 SNPs, including 11 TFBS SNPs, 31 intronic enhancer SNPs, 4 intronic enhancer and TFBS SNPs and 1 splicing sites SNPs. PMID- 21671482 TI - [Expression of caspase apoptosis pathway genes mRNA in colorectal cancer and polyps]. AB - OBJECTIVE: To investigate mRNA expression of caspase apoptosis pathway genes in colorectal cancer, polyps and normal mucosa. METHODS: Nineteen patients with colorectal cancer, 86 patients with polyps and 10 normal controls were enrolled from 2008 to 2010. Fluorescence quantitative RT-PCR was performed to detect the mRNA expression of caspase apoptosis pathway genes (caspase-2,-3,-6,-7,-8,-9 and 10) in colorectal cancer, polyps and normal mucosa. RESULT: There were no statistically significant differences of demographic characteristics between patients with colorectal cancer, patients with polyps and normal controls. Compared with normal control group, the mRNA expression of all selected genes except for caspase-3 were lower; however, the P values did not reach statistic significance. Highly positive correlations were observed between mRNA expression of all selected genes except caspase-9. CONCLUSION: There are no significant changes in mRNA expression levels of caspase apoptosis pathway genes from normal mucosa to polyps to cancer. The mRNA expressions of most caspase pathway genes are highly correlated with each other. PMID- 21671483 TI - [Association of XPC gene polymorphisms with breast cancer risk]. AB - OBJECTIVE: To access the association of xeroderma pigmentosum group C (XPC) Lys939Gln (A/C) and Ala499Val (C/T) polymorphisms with breast cancer risk in a Chinese Han population. METHODS: 173 patients with breast cancer and 171 matched controls in terms of habitation and age (+/-5 years) were included in this population-based case-control study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was employed to genotyping the Lys939Gln and Ala499Val polymorphisms. Associations of genotypes of Lys939Gln and Ala499Val with breast cancer risk were evaluated using unconditional logistic regression model. Associations between XPC haplotypes and breast cancer risk were estimated by Haplo. Stats package. RESULT: No significant associations were observed both in individual SNPs and haplotype analyses. However, there was a significant interaction between XPC Lys939Gln polymorphism and menopausal status (P=0.032). CONCLUSION: The XPC Lys939Gln polymorphism may modulate breast cancer susceptibility jointly with the menopausal status. PMID- 21671484 TI - [Association of CASP3 polymorphisms and its haplotypes with susceptibility of breast cancer]. AB - OBJECTIVE: To investigate the association of Caspase3 (CASP3) polymorphisms with susceptibility of breast cancer in Chinese Han population. METHODS: In this population-based case-control study, 251 cases with breast cancers and 251 matched controls in terms of habitation and age (+/-5 years) were recruited. Rs4647693, rs2696056, rs4647610 were selected as TagSNPs in CASP3 gene and genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The haplotype distribution was estimated and compared by PHASE software. RESULT: There was significant association between menarche age and breast cancer (P=0.007), as well as the early pregnancy age and breast cancer (P=0.002). No significant differences were detected in the distribution of CASP3 genotype and haplotype frequencies between breast cancer patients and controls. The GGA was the most common haplotype both in cases and controls. CONCLUSION: CASP3 polymorphisms and its haplotypes were not related to the susceptibility of breast cancer. PMID- 21671485 TI - [Association of miR-605 and miR-149 genetic polymorphisms with related risk factors of lung cancer susceptibility]. AB - OBJECTIVE: To explore association of miR-149 and miR-605 polymorphisms with other risk factors of lung cancer susceptibility among Chinese population. METHODS: Two hundred and forty-four patients with lung cancer and 243 cancer-free controls matched by age and sex were enrolled from 2002 to 2008. Peripheral venous blood samples were collected from all subjects. Single nucleotide polymorphisms (SNPs) of miR-149 and miR-605 were genotyped by PCR-RFLP. Multiple-variable logistic regression model was used to assess the association of SNPs and cancer related risk factors for lung cancer. RESULT: There was not significant association of SNPs of miR-149 and miR-605 with lung cancer. A marginal significance was observed while the males with at least one G allele of miR-605 had higher risk of lung cancer (OR=1.5, 95% CI:1.0-2.3) than those with AA genotype. Increased frequency of smoking was associated with lung cancer risk. Compared with no smoker, the subjects with <20 and >20 cigarettes/day had higher risk of lung cancer: OR (95%CI)=1.7(1.0-3.0) for <20 cigarettes, OR (95%CI)=4.2(2.3-7.6) for >20 cigarettes. There was no interaction between two genes and smoking on lung cancer. CONCLUSION: miR-149 polymorphisms may not affect lung cancer susceptibility. miR-605 gene mutant might be increase the risk of lung cancer among males. Cigarette smoking increased a risk of lung cancer, but there were not interactive effects between two gene and smoking on lung cancer. PMID- 21671486 TI - [Optimization of sequential screening scheme in prevention of colorectal neoplasm]. AB - OBJECTIVE: To improve early diagnosis rate and reduce the incidence rate of colorectal cancer, through the application of optimized sequential screening scheme for colorectal neoplasm in general population. METHODS: Quantitative risk assessment by questionnaires survey and fecal occult blood test (FOBT) were used to proceed preliminary screening among people aged 40 to 74. Electronic colonoscopy was applied to examine the whole colon and rectum among identified high-risk subjects. The detected cases received treatment for colorectal cancer, adenomatous polyps or non-adenomatous polyps. The early diagnosis rate and incidence rate of colorectal cancer were evaluated and compared with those before screening. RESULT: With application of optimized sequential screening schemes, various types of colorectal lesions were detected in 1 117 subjects, including 69 cases of colorectal cancer, 701 cases of colorectal adenoma and 211 cases of advanced adenoma. The early diagnosis rate of colorectal cancer was increased by 58.19%, and its incidence rate also decreased significantly. CONCLUSION: The optimized sequential screening scheme is simple, economical, efficient in colorectal cancer screening of general population. PMID- 21671487 TI - [Comparison of mail and meeting forms in evaluation of Delphi study]. AB - OBJECTIVE: To evaluate and compare mail and meeting forms in evaluation of Delphi study. METHODS: Delphi study by mail and meeting approaches was used to determine the health information dataset. Experts were required to grade the listed items through three indexes: importance, necessity and availability. Study duration, coefficient of variation of items, authority coefficient and coordination coefficient of the experts' opinion of two forms of study were calculated and compared. RESULT: The study duration was four months through mail form and 2 days through meeting. Compared with the first round, the coefficient of variation decreased (P<0.001, all of the three indexes by two forms), and the cooperation index increased (P<0.005) in the second round. The experts' opinions were easier to be consistent through meeting than through mail(P<0.033). And the authority coefficient by meeting consultation (0.83 +/- 0.05) was higher than that by mail (0.77 +/- 0.03) (P=0.001). CONCLUSION: Both mail and meeting forms of Delphi study can determine the health information dataset,but meeting consultation is better and requires shorter study duration. PMID- 21671488 TI - [Acceptability of pre-exposure prophylaxis among female sex workers in Xinjiang]. AB - OBJECTIVE: To assess the acceptability of pre-exposure prophylaxis (Pr-EP) among the female sex workers in Xinjiang. METHODS: A volunteer-based, anonymous and one to-one questionnaire survey was conducted in 762 female sex workers (FSW) in Urumqi and Kelamayi of Xinjiang Uyghur Autonomous Region. RESULT: Among 762 FSW surveyed, 673 (88.32%) was not aware of pre-exposure prophylaxis with an awareness rate of 11.55%. The awareness rate of FSWs working in high-end entertainment venues was higher than that of FSWs working in medium-low end entertainment venues(P<0.001). Five hundred and twenty eight FSWs (69.29%) were willing to take Pr-EP, 145 (19.03%) were unwilling to take the medicine and 89 (11.68%) were possible to use the Pr-EP. There was no significant difference in willingness of using Pr-EP among FSWs working in high and medium-low end entertainment venuew (P=0.285). The subjects who were willing to take Pr-EP mainly concerned of the drug security, effectiveness and cost. The main reasons for not willing to take Pr-EP were: not having risk of infecting HIV, suspecting effectiveness of Pr-EP and worrying about side effects. CONCLUSION: The acceptability to use Pr-EP in female sex workers of Xinjiang is relatively high and the drug security, effectiveness and cost will influence the promotion and application of Pr-EP in the future. PMID- 21671489 TI - [Repetitive transcranial magnetic stimulation combined with antidepressant medication in treatment of first-episode patients with major depression]. AB - OBJECTIVE: To assess the early therapeutic and cognitive effect of repetitive transcranial magnetic stimulation (rTMS) combined with antidepressant medication in treatment of first-episode patients with major depression. METHODS: Sixty first-episode depressed inpatients aged 18-45 y, who met the DSM-IV clinical criteria for major depressive episode were randomly assigned to citalopram treatment (20 mg/d) in combination with a two-week period of either rTMS (study group)or sham procedure (control group) on left dorsal-lateral prefrontal cortex (10 Hz, 90% motor threshold). The Hamilton Depression Rating Scale (HAMD) was used to assess the severity of depression. The Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) were used to assess cognitive function of depression. RESULT: The response rate was significantly greater in the study group compared to the control group after treatment (57% compared with 29%,P<0.05). The HAMD scores significantly declined after treatment in two groups, and the study group showed lower scores compared to the control group after 2 weeks (P<0.01). Neuropsychological assessments showed that there was no significant difference between the two groups except for the significant improvement in the categories on WCST in study group compared to the baseline (P<0.05) and the control group (P<0.05)after 2 weeks treatment. No serious event occurred in the patients during the rTMS study. CONCLUSION: 10 Hz rTMS enhances early effects of citalopram and improves cognitive function in first-episode major depressive patients. PMID- 21671490 TI - [Construction and expression of recombinant adenovirus containing human catalase gene in vitro]. AB - OBJECTIVE: To construct the adenovirus vector containing recombinant human catalase (CAT) and to express the recombinant gene in vitro. METHODS: Total RNA was extracted from human leukocytes and full-length human CAT cDNA was obtained with RT-PCR method. The CAT gene was cloned into pcDNA3.1(+) vector and pcDNA3.1(+)CAT was constructed. The positive clones were confirmed by the restriction enzyme digestion and gene sequencing. The CAT gene was cloned into the entry vector pENTR1A, and pENTR1A-CAT vector was constructed. By LR reaction pENTR1A-CAT and pAd/CMV/V5-DEST was recombined in vitro, and the recombinant adenovirus pAd/CMV/V5-DEST-CAT was obtained. The positive pAd/CMV/V5-DEST-CAT was confirmed by sequencing and transfected into 293A cells with Pac I linearization and Lipofectamine 2 000, and the recombinant virus particles were packaged and amplified in the cells. The expression of CAT protein and CAT enzyme activities of the recombinant virus were determined by Western blot and 240 nm UV absorption methods. RESULT: High expression of recombinant adenovirus was obtained and the expressed human catalase had high enzyme activity. CONCLUSION: Ad/CMV/V5-DEST-CAT vector containing human catalase gene has been constructed successfully; and the expressed enzyme in 293A cells has high activity. PMID- 21671491 TI - [Codon optimization of recombinant staphylococcal enterotoxin O enhances the expression level in Escherichia coli]. AB - OBJECTIVE: To enhance the expression level of staphylococcal enterotoxin O (SEO) by optimization of rare codons. METHODS: The gene of mature SEO (His-tag included) was cloned to pET28a, and 15 rare codons on the gene were optimized by PCR technology. These recombinant plasmids then were transformed into E.coli BL21(DE3), respectively. After IPTG induced, the expression levels of those mutants were analyzed by SDS-PAGE. The proteins were purified and their bioactivities were determined. RESULT: After the optimization of rare codons, the expression levels were increased from 7.49% to 19.8% in total cell proteins. The optimized SEO had bioactivity to stimulate the proliferation of murine lymphocytes, which was equivalent to that of non-optimized SEO in vitro. CONCLUSION: Optimization of rare codons can enhance the expression of SEO effectively. PMID- 21671492 TI - [Role of mitochondrial calcium uniporter in cardioprotection induced by ischemic postconditioning in isolated rat heart]. AB - OBJECTIVE: To investigate the role of mitochondrial calcium uniporter in cardioprotection elicited by ischemic postconditioning (Postcond). METHODS: Male Sprague-Dawley rats were used for Langendorff isolated heart perfusion. The hearts subjected to global ischemia for 30 min followed by 120 min of reperfusion. Left ventricular developed pressure (LVDP), maximal rise/fall rate of left ventricular pressure (+/- dP/dtmax) were measured. The level of lactate dehydrogenase (LDH) in the coronary effluent was measured spectrophotometrically, the content of formazan of myocardium was also measured at the end of reperfusion. RESULT: Compared to I/R group, Postcond had an significant increase in the mechanical function of the left ventricle, with LDH release reduced and the content of formazan increased. Spermine, the opener of mitochondrial calcium uniporter, deteriorated the mechanical function of left ventricle and decreased the formazan content, and increased LDH release. Ruthenium red, the inhibitor of mitochondrial calcium uniporter, increased the mechanical function of the left ventricle, decreased the LDH release, but the content of formazan was not increased. CONCLUSION: The inhibition of mitochondrial calcium uniporter is involved in the mechanisms of ischemic postconditioning. PMID- 21671493 TI - [DNA methylation of ZIC1 and KLOTHO gene promoters in colorectal carcinomas and its clinicopathological significance]. AB - OBJECTIVE: To determine DNA methylation status of ZIC1 and KLOTHO gene in colorectal carcinomas and its relationship with clinicopathological features of patients. METHODS: The mRNA expression of ZIC1 and KLOTHO genes in colorectal carcinomas was detected by real-time quantitative RT-PCR, and the promoter methylation status was detected by methylation specific PCR (MSP). The relationship of ZIC1 and KLOTHO methylation status with clinicopathological features of colorectal carcinoma was analyzed. RESULT: The mRNA expression levels of ZIC1 and KLOTHO genes were significantly down-regulated in tumor tissues when compared to adjacent nontumor tissues (P<0.001). ZIC1 and KLOTHO methylation was detected in 80.0%(20/25) and 76.0%(19/25) of colorectal tumor tissues, respectively, and the both positive rate was 64.0%(16/25). CONCLUSION: The down regulated expression of ZIC1 and KLOTHO in colorectal carcinoma may relate to promoter methylation. The detection of methylation of ZIC1 and KLOTHO gene potentially provides biomarkers for diagnosis of colorectal carcinoma. PMID- 21671494 TI - [Effects of mice body temperature on pressure inside plethysmograph]. AB - OBJECTIVE: To observe temperature and pressure changes inside plethysmograph produced by body temperature of anesthetized mice. METHODS: The temperature and pressure changes inside whole body plethysmograph generated from anesthetized mice were compared with those from dead mice. The temperature and pressure changes inside body chamber and head chamber of double-chamber with anesthetized mice in body chamber were synchronously measured. The respiratory frequencies and amplitudes of mice inside two kinds of head-out plethysmographs were synchronously measured. One of these two plethysmographs kept sealed all the time and the other was opened to the atmosphere for 1 min every 2 min. RESULT: Temperature and pressure of air in the anesthetized mice chamber increased 1.18 degree and 2.710 mmHg within 6 min, and data from dead mice were 1.17 degree and 2.671 mmHg. There were no significant differences between these two groups. The temperature inside body chamber increased 1.92 degree in 20 min and the pressure was 5.554 mmHg, which were significantly higher than those of head chamber (0.09 degree and 0.627 mmHg). The respiratory frequencies of mice in the sealed head out plethysmograph increased from 125.04 per min to 168.45 per min, and amplitudes of pressure changes generated from mice breath decreased from 1.090 mmHg to 0.883 mmHg. Significant differences occurred between different observation time points. Meanwhile respiratory frequencies in the open head-out plethysmograph were around 120 per min and amplitude of pressure changes kept about 1 mmHg. There were no significant differences between different time points. CONCLUSION: Increase of temperature and pressure inside pressure whole body plethysmograph are mainly from body temperature of mice, and the increased pressure significantly influences respiration of mice. PMID- 21671495 TI - [Clinical characteristics and in vivo confocal microscopic imaging of Fleck corneal dystrophy]. AB - OBJECTIVE: To investigate the clinical characteristics and the corneal morphological abnormalities in Fleck corneal dystrophy. METHODS: Eighteen eyes with Fleck corneal dystrophy of 9 patients from two unrelated families were examined by slit-lamp biomicroscopy, Cochet-Bonnet esthesiometer and in vivo confocal microscopy. The corneal cells, nerves and stromal deposits were analyzed quantitatively with NAVIS software. RESULT: Slit-lamp biomicroscopy of the Fleck corneal dystrophy revealed that bilateral small grey-white fleck-like or wreath like opacities were scattered in all layer of the corneal stroma from the center to the periphery, the intervening stroma between the lesions was clear. In vivo confocal microscopy identified that the opacities appeared as doughnut-like or nephroid-like deposits approximately 70.6 MUm * 110.3 MUm in size, (1.6 +/- 0.4)/frame in density and involved about (438.4 +/- 22.0) MUm of the corneal stroma, with hyper reflective dot-like intracellular particles,measuring 2 to 18 MUm in diameter. In two eyes of 1 patient associated with decreased corneal sensation, confocal images showed that abnormal hyper reflective deposits involved the Bowman's layer and the branch and density of the subbasal nerve was reduced. The other eyes with normal corneal sensation appeared normal in the morphology and the density of the corneal nerves. CONCLUSION: Fleck corneal dystrophy has typical clinical characteristics. In vivo confocal microscopy allows to study the morphological changes of the cornea at cellular level, which is valuable for the clinical diagnosis and evaluation of the corneal dystrophy. Decreased corneal sensitivity in Fleck corneal dystrophy is probably caused by corneal stromal deposits involved in the Bowman's layer. PMID- 21671496 TI - [Efficacy of bismuth-based quadruple therapy as first-line treatment for Helicobacter pylori infection]. AB - OBJECTIVE: To evaluate the efficacy of bismuth-based quadruple therapy as the first-line treatment for H.pylori infection. METHODS: A total of 136 patients with H.pylori related peptic ulcer or chronic gastritis were randomized into two groups: 67 patients in bismuth-based quadruple group received esomeprazole 20 mg, clarithromycin 0.5 g,amoxicillin 1.0 g,and bismuth potassium citrate 220 mg for 7 d; 69 patients in standard triple group received esomeprazole 20 mg, clarithromycin 0.5 g and amoxicillin 1.0 g for 7 d. Outcome of eradication therapy was assessed by (14)C-UBT. On ITT and PP analysis, calculating the cost effectiveness ratio (C/E) and the incremental cost-effectiveness ratio (delta C/delta E). RESULT: On ITT and PP analysis, the eradication rates of the quadruple therapy group were 82.09% and 88.71%, and those of the triple therapy group were 66.67% and 73.02% (P<0.05). The cost-effectiveness ratio of two groups was 4.15 and 4.82; The incremental cost-effectiveness ratio of quadruple therapy group was 1.02 as against triple therapy group. CONCLUSION: Compared to the standard triple therapy regimen, the bismuth-containing quadruple therapy regimen has higher eradication rate and cost-effectiveness, which can be recommended as the fist-line treatment for H.pylori infection. PMID- 21671498 TI - [Research progress on living quality of children conceived by assisted reproductive technology]. AB - With the development of assisted reproductive technique (ART), children born following ART now form a sizeable subgroup of the population, so assessment for the safety of ART becomes more urgent than ever before. The health problems about living quality of children conceived by ART mainly focus on perinatal outcome and short-term follow-up study, including multiple pregnancies, low birth weight and prematurity in singleton births, congenital malformations, imprinting disorders, neurodevelopmental outcome, neonatal outcomes, physical and mental health, as well as cancer risks. In this review, we will discuss the health problems of these children, to provide data for further study. PMID- 21671497 TI - [Research progress on barrel cortex and its plasticity]. AB - Synaptic plasticity of barrel cortex is one of the most widely studied topics in neuroscience in recent years. The primary somatosensory cortex of the rodent has a good topology character,which provides an ideal experimental model for plasticity study. This system displays very strong experience-dependent plasticity both during development and in adulthood. The changes of sensory cortex's neural circuit can induce experience-dependent plasticity. In the synaptic level,thalamocortical synapse is considered to be the main location of plasticity. In the circuit level,both synapses from layer 4 to layer 2/3 and those within layer 2/3 are also the necessary parts of achieving synaptic plasticity in primary somatosensory cortex. The GABAergic inhibitory circuit may be involved in this plasticity of S1, but the exact mechanism remains unknown. PMID- 21671500 TI - [Treatment of epithelial implantation cyst of iris by penetrating keratoplasty: report of one case]. PMID- 21671499 TI - [Early lung cancer complicated with lungs embolism: a case report]. PMID- 21671501 TI - Field study of hydrogeologic characterization methods in a heterogeneous aquifer. AB - Hydraulic conductivity (K) and specific storage (S(s)) are required parameters when designing transient groundwater flow models. The purpose of this study was to evaluate the ability of commonly used hydrogeologic characterization approaches to accurately delineate the distribution of hydraulic properties in a highly heterogeneous glaciofluvial deposit. The metric used to compare the various approaches was the prediction of drawdown responses from three separate pumping tests. The study was conducted at a field site, where a 15 m * 15 m area was instrumented with four 18-m deep Continuous Multichannel Tubing (CMT) wells. Each CMT well contained seven 17 cm * 1.9 cm monitoring ports equally spaced every 2 m down each CMT system. An 18-m deep pumping well with eight separate 1-m long screens spaced every 2 m was also placed in the center of the square pattern. In each of these boreholes, cores were collected and characterized using the Unified Soil Classification System, grain size analysis, and permeameter tests. To date, 471 K estimates have been obtained through permeameter analyses and 270 K estimates from empirical relationships. Geostatistical analysis of the small-scale K data yielded strongly heterogeneous K fields in three-dimensions. Additional K estimates were obtained through slug tests in 28 ports of the four CMT wells. Several pumping tests were conducted using the multiscreen and CMT wells to obtain larger scale estimates of both K and S(s). The various K and S(s) estimates were then quantitatively evaluated by simulating transient drawdown data from three pumping tests using a 3D forward numerical model constructed using HydroGeoSphere (Therrien et al. 2005). Results showed that, while drawdown predictions generally improved as more complexity was introduced into the model, the ability to make accurate drawdown predictions at all CMT ports was inconsistent. PMID- 21671502 TI - Field verification of stable perched groundwater in layered bedrock uplands. AB - Data substantiating perched conditions in layered bedrock uplands are rare and have not been widely reported. Field observations in layered sedimentary bedrock in southwestern Wisconsin, USA, provide evidence of a stable, laterally extensive perched aquifer. Data from a densely instrumented field site show a perched aquifer in shallow dolomite, underlain by a shale-and-dolomite aquitard approximately 25 m thick, which is in turn underlain by sandstone containing a 30 m-thick unsaturated zone above a regional aquifer. Heads in water supply wells indicate that perched conditions extend at least several kilometers into hillsides, which is consistent with published modeling studies. Observations of unsaturated conditions in the sandstone over a 4-year period, historical development of the perched aquifer, and perennial flow from upland springs emanating from the shallow dolomite suggest that perched groundwater is a stable hydrogeologic feature under current climate conditions. Water-table hydrographs exhibit apparent differences in the amount and timing of recharge to the perched and regional flow systems; steep hydraulic gradients and tritium and chloride concentrations suggest there is limited hydraulic connection between the two. Recognition and characterization of perched flow systems have practical importance because their groundwater flow and transport pathways may differ significantly from those in underlying flow systems. Construction of multi aquifer wells and groundwater withdrawal in perched systems can further alter such pathways. PMID- 21671503 TI - The socioeconomic origin of the students has a major influence on the ability to integrate medical studies. PMID- 21671504 TI - Empathy integration: a two way street between medical students and standardized patients. PMID- 21671505 TI - An international comparison of professional attitudes among medical students in Ireland. PMID- 21671506 TI - Teaching faculty to teach: a new approach to global awareness. PMID- 21671507 TI - Error reduction/recovery more empirical evidence needed. PMID- 21671508 TI - The risk of valvular regurgitation in patients with Parkinson's disease treated with dopamine receptor agonists. AB - OBJECTIVES: Several observational studies suggest an association between treatment with ergoline-derived dopamine agonists and valvular regurgitation. In this article, we present an overview of the literature and conduct a meta analysis. METHODS: Observational studies addressing the frequency of moderate or severe valvular regurgitation among ergoline-treated patients with Parkinson's disease were considered for a meta-analysis. Pooled risk estimates and the risk of increased pulmonary artery pressure were calculated. RESULTS: The pooling of data from well-designed observational studies documented that both pergolide (RR = 3.05 [1.71-5.44]) and cabergoline (RR = 6.38 [3.17-12.81]) represent a substantially increased risk of developing moderate to severe valvular regurgitation. In addition, pergolide, but not cabergoline, was associated with an increase in pulmonary artery pressure. CONCLUSIONS: The present meta-analysis confirmed a statistically significant association between pergolide and cabergoline treatment and the risk of moderate to severe valvular regurgitation. An association between bromocriptine and valvular regurgitation cannot be entirely ruled out. PMID- 21671509 TI - Parkin inactivation via PARIS (ZNF746) may lead to neurodegeneration in Parkinson's disease. PMID- 21671510 TI - A novel protein degradation system in young-onset Parkinson's disease: mitophagy is a therapeutic target as a quality control for damaged mitochondria. PMID- 21671511 TI - alpha-synuclein, a prion-like protein. PMID- 21671512 TI - Germany reels in the wake of E coli outbreak. PMID- 21671513 TI - Anti-abortion laws gain more ground in the USA. PMID- 21671514 TI - State policies worsen HIV/AIDS crisis in Mississippi. PMID- 21671515 TI - Retraining the King's left hand. PMID- 21671516 TI - Management of metabolic acidosis. PMID- 21671517 TI - Natural history of Crohn's disease: is the tide beginning to turn? PMID- 21671518 TI - Procedural training in neonatal care. PMID- 21671519 TI - Against female genital mutilation. PMID- 21671520 TI - Stand together and be vocal! PMID- 21671521 TI - Teething and the use of systemic analgesia. PMID- 21671522 TI - Screening for diabetes in an African American community: identifying characteristics associated with abnormal blood glucose readings. AB - OBJECTIVE: To identify characteristics associated with abnormal blood glucose readings among African Americans and to determine the potential value of a more targeted approach to community-based screenings for type 2 diabetes. METHODS: Data were collected from 7113 participants with no previous diagnosis of diabetes at mobile screening events in Detroit, Michigan. Data collected included gender, race, age, self-reported height and weight, total diabetes risk score, blood pressure, and random capillary blood glucose. RESULTS: Nearly 9% of participants had abnormal random plasma glucose readings (RPG>or=160 mg/dL). Results indicated that higher age, elevated blood pressure, and body mass index (BMI) were significantly associated with abnormal glucose readings. CONCLUSION: These findings suggest that community-based screenings for diabetes that are targeted to adults aged more than 50 years who have high blood pressure or a BMI of at least 25 may enhance detection of abnormal glucose levels among African Americans. PMID- 21671523 TI - Translation of the National Institutes of Health Diabetes Prevention Program in African American churches. AB - OBJECTIVE: To translate the Diabetes Prevention Program (DPP) for delivery in African American churches. METHODS: Two churches participated in a 6-week church based DPP and 3 churches participated in a 16-week church-based DPP, with follow up at 6 and 12 months. The primary outcomes were changes in fasting glucose and weight. RESULTS: There were a total of 37 participants; 17 participated in the 6 session program and 20 participated in the 16-session program. Overall, the fasting glucose decreased from 108.1 to 101.7 mg/dL post intervention (p=.037), and this reduction persisted at the 12-month follow-up without any planned maintenance following the intervention. Weight decreased 1.7 kg post intervention with 0.9 kg regained at 12 months. Body mass index (BMI) decreased from 33.2 to 32.6 kg/m2 post intervention with a final mean BMI of 32.9 kg/m2 at the 12-month check (P<.05). Both the 6- and 16-session programs demonstrated similar reductions in glucose and weight; however, the material costs of implementing the modified 6-session DPP were $934.27 compared to $1075.09 for the modified 16 session DPP. CONCLUSION: Translation of DPP can be achieved in at-risk African Americans if research teams build successful community-based relationships with members of African American churches. The 6-session modified DPP was associated with decreased fasting glucose and weight similar to the 16-session program, with lowered material costs for implementation. Further trials are needed to test the costs and effectiveness of church-based DPPs across different at-risk populations. PMID- 21671524 TI - Beliefs, behaviors, and modifications of type 2 diabetes self-management among African American women. AB - Among African Americans, behaviors and beliefs about management of disease constitute an important component of self-management of type 2 diabetes (diabetes mellitus). The purpose of this study was to explore and identify health beliefs and health behaviors affecting diabetes self-management among African American women with type 2 diabetes. Twenty-five African American women aged 46 to 87 years, participated in the study. Community-based women in Pinellas County, Florida, completed semistructured, in-depth interviews, a self-management questionnaire, and a demographic profile. Participant observation occurred at a cross-section of 5 diabetes self-management education classes. Participants were asked about nutritional changes, physical activity, medication use, blood glucose monitoring, physician-patient interaction, support systems, and patient education/knowledge. Findings indicated that a majority of participants used regular exercise, medications, and dietary modifications as a core components model of diabetes self-management. Successful self-management was affected by diabetes beliefs, types of behaviors initiated, and available support systems and resources. Difficulties experienced that affected behavioral outcomes included access to care, costs of medications, pain, testing supplies, and nutritional changes. Findings suggest that modifications to the recommended regimen support or impede participants' efficient self-management of clinically recommended behaviors. Thus, for African American women managing type 2 diabetes, the regimen may necessitate modification models of diabetes self-management, day-to-day behavioral lifestyle adjustments to the biomedically recommended self-management regimen. PMID- 21671525 TI - Implications of the new definition of diabetes for health disparities. AB - In July 2009, an international committee announced a new diagnostic criterion for diabetes based on hemoglobin Alc (HbA1c) values. Our objective was to estimate how the new diabetes diagnostic criterion will affect the prevalence of diabetes among different race, age, and gender subpopulations, compared to the previously used fasting plasma glucose (FPG) criterion. We analyzed nationally representative data from The National Health and Nutrition Examination Survey (NHANES), aggregated from 1999 to 2006. We estimated the prevalence of known diabetes (prevalence static across either diagnostic criterion), unknown, and no diabetes (prevalence variable by criterion). We tested statistical significance of prevalence differences for unknown diabetes between the prior diagnostic criterion--FPG of at least 126 mg/dL--and the new diagnostic criterion--HbA1c of at least 6.5%--using conditional logistic regression. We further tested the association of these differences with demographic factors. The new HbA1c diagnostic criterion differentially affects different racial/ethnic groups. For non-Hispanic whites, the prevalence of undiagnosed diabetes was more than halved from 2.6% (95% confidence interval [CI], 2.2-3.1) with FPG diagnosis to 1.3% (95% CI, 1.0-1.7), P<.001 with HbAic diagnosis. For Hispanics and non-Hispanic blacks, the differences in prevalence by the 2 criteria were smaller and nonsignificant. Racial differences by diagnostic criteria were most pronounced among people aged over 55 years. Overall, the new definition of diabetes differentially affects ethnic groups, especially for older people. If the new criterion is widely adopted, over time, we may see an apparent widening of racial/ethnic disparities in diabetes prevalence. PMID- 21671527 TI - Progression of type 2 diabetes and insulin initiation. AB - The prevalence of type 2 diabetes is significantly greater among African Americans compared to some other ethnic groups. The reasons for this increased incidence are due at least in part to the increased frequency of obesity, especially among African American women. The onset of hyperglycemia, after many years of insulin resistance, is due to beta cell dysfunction that slowly progresses to beta cell failure, necessitating insulin replacement. The timely initiation of insulin therapy is a critical clinical decision for treating physicians managing patients, especially when the patient is hesitant to begin insulin therapy. The availability of various insulin formulations gives the opportunity to tailor insulin therapy based on a patient's personal insulin requirements and lifestyle. Specific issues related to insulin therapy such as patient preferences, quality of life, barriers to the addition of insulin to the treatment regimen, and the effectiveness of insulin therapy are illustrated using a case study. PMID- 21671526 TI - Patient complexity and diabetes quality of care in rural settings. AB - PURPOSE: Even though pay-for-performance programs are being rapidly implemented, little is known about how patient complexity affects practice-level performance assessment in rural settings. We sought to determine the association between patient complexity and practice-level performance in the rural United States. BASIC PROCEDURES: Using baseline data from a trial aimed at improving diabetes care, we determined factors associated with a practice's proportion of patients having controlled diabetes (hemoglobin A1c(3)F(4), blue), Tb(3+) ((5)D(4) >(7)F(5), green), and Eu(3+) ((5)D(0)->(7)F(2), red), respectively. By adjusting the doping concentration of Eu(3+) ions in Sr(3)AlO(4)F:0.10Tm(3+), 0.10Tb(3+), zEu(3+), a white emission in a single composition was obtained under the excitation of 360 nm, in which an energy transfer from Tb(3+) to Eu(3+) was observed. For Sr(3)AlO(4)F:Ce(3+),Tb(3+) samples, the energy transfer from Ce(3+) to Tb(3+) is efficient and demonstrated to be a resonant type via a dipole quadrupole interaction by comparing the experimental data and theoretical calculation. Furthermore, the critical distance of the Ce(3+) and Tb(3+) ions has also been calculated to be 9.05 A. The corresponding luminescence and energy transfer mechanisms have been proposed in detail. These phosphors might be promising for use in near-UV LEDs. PMID- 21671556 TI - Scientific discovery and challenges for an editor. PMID- 21671557 TI - Enhancing protease activity assay in droplet-based microfluidics using a biomolecule concentrator. AB - We introduce an integrated microfluidic device consisting of a biomolecule concentrator and a microdroplet generator, which enhances the limited sensitivity of low-abundance enzyme assays by concentrating biomolecules before encapsulating them into droplet microreactors. We used this platform to detect ultralow levels of matrix metalloproteinases (MMPs) from diluted cellular supernatant and showed that it significantly (~10-fold) reduced the time required to complete the assay and the sample volume used. PMID- 21671558 TI - Metabolic profiling uncovers a phenotypic signature of small for gestational age in early pregnancy. AB - Being born small for gestational age (SGA) confers increased risks of perinatal morbidity and mortality and increases the risk of cardiovascular complications and diabetes in later life. Accumulating evidence suggests that the etiology of SGA is usually associated with poor placental vascular development in early pregnancy. We examined metabolomic profiles using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) in three independent studies: (a) venous cord plasma from normal and SGA babies, (b) plasma from a rat model of placental insufficiency and controls, and (c) early pregnancy peripheral plasma samples from women who subsequently delivered a SGA baby and controls. Multivariate analysis by cross-validated Partial Least Squares Discriminant Analysis (PLS-DA) of all 3 studies showed a comprehensive and similar disruption of plasma metabolism. A multivariate predictive model combining 19 metabolites produced by a Genetic Algorithm-based search program gave an Odds Ratio for developing SGA of 44, with an area under the Receiver Operator Characteristic curve of 0.9. Sphingolipids, phospholipids, carnitines, and fatty acids were among this panel of metabolites. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of SGA offers insight into disease pathogenesis and offers the promise of a robust presymptomatic screening test. PMID- 21671559 TI - Synthesis of hierarchical hollow silica microspheres containing surface nanoparticles employing the quasi-hard template of poly(4-vinylpyridine) microspheres. AB - A facile method of preparing hierarchical hollow silica microspheres containing surface silica nanoparticles (HHSMs) through the sol-gel process of tetraethylorthosilicate employing a quasi-hard template of non-cross-linking poly(4-vinylpyridine) microspheres is proposed. The quasi-hard template contains the inherent catalyst of the basic pyridine group, and a few of the polymer chains can escape from the template matrix into the aqueous phase, which initiates the sol-gel process spontaneously both on the surface of the template used to prepare the hollow silica shell and in the aqueous phase to produce the surface silica nanoparticles. By tuning the weight ratio of the silica precursor to the quasi-hard template, HHSMs with a size of about 180 nm and a shell thickness ranging from 14 to 32 nm and surface silica nanoparticles ranging from 17 to 36 nm are produced initially through the deposition of surface silica nanoparticles onto the silica shell, followed by template removal either by calcination or solvent extraction. The synthesized HHSMs are characterized, and a possible mechanism for the synthesis of HHSMs is proposed. PMID- 21671560 TI - Rapid assembly of colloidal monolayer for the synthesis of surface anisotropic particles. AB - A facile and efficient technique for synthesizing rapid and large-scale colloidal monolayer is introduced to obtain surface anisotropic particles. Silica particles grafted with long alkyl chains are rapidly organized into monolayer assemblies by implementing water-film climbing and convective particle assembly on glass slides. Assembled particles are modified into surface-anisotropic particles utilizing physical vapor deposition with a magnetically active material. The magnetic hemisphere enables separation of modified and unmodified surface anisotropic particles. The proposed methodology can lead to a large-scale production opportunity for surface-anisotropic particles. PMID- 21671561 TI - Hydrogen-bonded assemblies of two-electron reduced mixed-valence [XMo12O40] (X = P and Si) with p-phenylenediamines. AB - Hydrogen-bonded assemblies of the two-electron reduced mixed-valence Keggin clusters [PMo(12)O(40)](5-) and [SiMo(12)O(40)](6-) were obtained by the one-pot electron-transfer reactions between p-phenylenediamine (PPD) or 2,3,5,6 tetramethyl-PPD (TMPPD) (donors) and H(+)(3)[PMo(12)O(40)](3-) or H(+)(4)[SiMo(12)O(40)](4-) (acceptors) in CH(3)CN. The redox states of the [PMo(12)O(40)](5-) and [SiMo(12)O(40)](6-) clusters were confirmed by the redox titrations and electronic absorption measurements. In (HPPD(+))(3)(H(+))(2)[PMo(12)O(40)](5-)(CH(3)CN)(3-6) (1), the N-H ~ O hydrogen bonded interactions between the monoprotonated HPPD(+) (or diprotonated H2PPD(2+)) and the [PMo(12)O(40)](5-) resulted in a windmill-like assembly and hydrophilic one-dimensional channels are formed with a cross-sectional area of 0.065 nm(2), and these are filled by the CH(3)CN molecules. Also, the CH(3)CN molecules in salt 1 were removed by immersing the single crystals of 1 into H(2)O, CH(3)OH, and C(2)H(5)OH solvents. In the compound, (HTMPPD(+))(6)[SiMo(12)O(40)](6-)(CH(3)CN)(6) (2), the N-H ~ O hydrogen-bonded interactions between the monoprotonated HTMPPD(+) molecules and the [SiMo(12)O(40)](6-) formed a "Saturn-ring"-like assembly. Each Saturn-ring was arranged into an hexagonally packed array via hydrogen-bonded and pi-stacking interactions of HTMPPD(+), while the CH(3)CN solvent present in salt 2 are only found in the zero-dimensional isolated cavities. PMID- 21671562 TI - Theoretical investigation into the mechanism of reductive elimination from bimetallic palladium complexes. AB - Reductive elimination of C-Cl and C-C bonds from binuclear organopalladium complexes containing Pd-Pd bonds with overall formal oxidation state +III are explored by density functional theory for dichloromethane and acetonitrile solvent environments. An X-ray crystallographically authenticated neutral complex, [(L-C,N)ClPd(MU-O(2)CMe)](2) (L = benzo[h]quinolinyl) (I), is examined for C-Cl coupling, and the proposed cation, [(L-C,N)PhPd(1)(MU-O(2)CMe)(2)Pd(2)(L C,N)](+) (II), examined for C-C coupling together with (L-C,N)PhPd(1)(MU O(2)CMe)(2)Pd(2)Cl(L-C,N) (III) as a neutral analogue of II. In both polar and nonpolar solvents, reaction from III via chloride dissociation from Pd(2) to form II is predicted to be favored. Cation II undergoes Ph-C coupling at Pd(1) with concomitant Pd(1)-Pd(2) lengthening and shortening of the Pd(1)-O bond trans to the carbon atom of L; natural bond orbital analysis indicates that reductive coupling from II involves depopulation of the d(x(2)-y(2)) orbital of Pd(1) and population of the d(z(2)) orbitals of Pd(1) and Pd(2) as the Pd-Pd bond lengthens. Calculations for the symmetrical dichloro complex I indicate that a similar dissociative pathway for C-Cl coupling is competitive with a direct (nondissociative) pathway in acetonitrile, but the direct pathway is favored in dichloromethane. In contrast to the dissociative mechanism, direct coupling for I involves population of the d(x(2)-y(2)) orbital of Pd(1) with Pd(1)-O(1) lengthening, significantly less population occurs for the d(z(2)) orbital of Pd(1) than for the dissociative pathway, and d(z(2)) at Pd(2) is only marginally populated resulting in an intermediate that is formally a Pd(1)(I)-Pd(2)(III) species, (L-Cl-N,Cl)Pd(1)(MU-O(2)CMe)Pd(2)Cl(O(2)CMe)(L-C,N) that releases chloride from Pd(2) with loss of Pd(I)-Pd(III) bonding to form a Pd(II) species. A similar process is formulated for the less competitive direct pathway for C-C coupling from III, in this case involving decreased population of the d(z(2)) orbital of Pd(2) and strengthening of the Pd(I)-Pd(III) interaction in the analogous intermediate with eta(2)-coordination at Pd(1) by L-Ph-N, C(1)-C(2). PMID- 21671563 TI - Discovery and characterization of heme enzymes from unsequenced bacteria: application to microbial lignin degradation. AB - Bacteria and other living organisms offer a potentially unlimited resource for the discovery of new chemical catalysts, but many interesting reaction phenotypes observed at the whole organism level remain difficult to elucidate down to the molecular level. A key challenge in the discovery process is the identification of discrete molecular players involved in complex biological transformations because multiple cryptic genetic components often work in concert to elicit an overall chemical phenotype. We now report a rapid pipeline for the discovery of new enzymes of interest from unsequenced bacterial hosts based on laboratory scale methods for the de novo assembly of bacterial genome sequences using short reads. We have applied this approach to the biomass-degrading soil bacterium Amycolatopsis sp. 75iv2 ATCC 39116 (formerly Streptomyces setonii and S. griseus 75vi2) to discover and biochemically characterize two new heme proteins comprising the most abundant members of the extracellular oxidative system under lignin-reactive growth conditions. PMID- 21671564 TI - Effect of high pressure on the organocatalytic asymmetric Michael reaction: highly enantioselective synthesis of gamma-nitroketones with quaternary stereogenic centers. AB - The significant effect of hydrostatic pressure on the difficult organocatalytic 1,4-conjugate addition of nitroalkanes to prochiral sterically congested beta,beta-disubstituted enones is demonstrated. This approach allows for the synthesis of gamma-nitroketones containing quaternary stereogenic centers with good yields, excellent enantioselectivity, and low loading (1-5 mol %) of simple chiral primary amine catalysts. PMID- 21671565 TI - Influence of calcium-induced aggregation on the sensitivity of aminobis(methylenephosphonate)-containing potential MRI contrast agents. AB - A novel class of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenecarboxylic) acid (DO3A)-based lanthanide complexes with relaxometric response to Ca(2+) was synthesized, and their physicochemical properties were investigated. Four macrocyclic ligands containing an alkyl-aminobis(methylenephosphonate) side chain for Ca(2+)-chelation have been studied (alkyl is propyl, butyl, pentyl, and hexyl for L(1), L(2), L(3), and L(4), respectively). Upon addition of Ca(2+), the r(1) relaxivity of their Gd(3+) complexes decreased up to 61% of the initial value for the best compounds GdL(3) and GdL(4). The relaxivity of the complexes was concentration dependent (it decreases with increasing concentration). Diffusion NMR studies on the Y(3+) analogues evidenced the formation of agglomerates at higher concentrations; the aggregation becomes even more important in the presence of Ca(2+). (31)P NMR experiments on EuL(1) and EuL(4) indicated the coordination of a phosphonate to the Ln(3+) for the ligand with a propyl chain, while phosphonate coordination was not observed for the analogue bearing a hexyl linker. Potentiometric titrations yielded protonation constants of the Gd(3+) complexes. log K(H1) values for all complexes lie between 6.12 and 7.11 whereas log K(H2) values are between 4.61 and 5.87. Luminescence emission spectra recorded on the Eu(3+) complexes confirmed the coordination of a phosphonate group to the Ln(3+) center in EuL(1). Luminescence lifetime measurements showed that Ca-induced agglomeration reduces the hydration number which is the main cause for the change in r(1). Variable temperature (17)O NMR experiments evidenced high water exchange rates on GdL(1), GdL(2), and GdL(3) comparable to that of the aqua ion. PMID- 21671567 TI - Multiprotein interactions during surface adsorption: a molecular dynamics study of lysozyme aggregation at a charged solid surface. AB - Multiprotein adsorption of hen egg white lysozyme at a model charged ionic surface is studied using fully atomistic molecular dynamics simulations. Simulations with two, three, and five proteins, in various orientations with respect the surface, are performed over a 100 ns time scale. Mutated proteins with point mutations at the major (Arg128 and Arg125) and minor (Arg68) surface adsorption sites are also studied. The 100 ns time scale used is sufficient to observe protein translations, rotations, adsorption, and aggregation. Two competing processes of particular interest are observed, namely surface adsorption and protein-protein aggregation. At low protein concentration, the proteins first adsorb in isolation and can then reorientate on the surface to aggregate. At high concentration, the proteins aggregate in the solution and then adsorb in nonspecific ways. This work demonstrates the role of protein concentration in adsorption, indicates the residues involved in both types of interaction (protein-protein and protein-surface), and gives an insight into processes to be considered in the development of new functionalized material systems. PMID- 21671566 TI - Ternary dinuclear copper(II) complexes of a hydroxybenzamide ligand with diimine coligands: the 5,6-dmp ligand enhances DNA binding and cleavage and induces apoptosis. AB - The dinuclear copper(II) complexes [Cu(2)(LH)(2)(diimine)(2)(ClO(4))(2)](ClO(4))(2) (1-4), where LH = 2-hydroxy-N-[2 (methylamino)ethyl]benzamide and diimine = 2,2'-bipyridine (bpy; 1), 1,10 phenanthroline (phen; 2), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp; 3), and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq; 4), have been isolated and characterized. The X-ray crystal structure of complex 1 contains two copper(II) centers bridged by the phenolate moiety of the amide ligand. All of the complexes display a ligand-field band (630-655 nm) and the PhO(-)-to-Cu(II) ligand-to-metal charge-transfer band (405-420 nm) in solution. Absorption and emission spectral studies and viscosity measurements indicate that complex 4 interacts with calf thymus DNA more strongly than all of the other complexes through strong partial intercalation of the extended planar ring (dpq) with a DNA base stack. Interestingly, 3 exhibits a DNA binding affinity higher than 2, suggesting the involvement in hydrophobic interaction of coordinated 5,6-dmp with the DNA surface. In contrast to the increase in relative viscosities of DNA bound to 2-4, a decrease in viscosity of DNA bound to 1 is observed, indicating a shortening of the DNA chain length through formation of kinks or bends. All of the complexes exhibit an ability to cleave DNA (pUC19 DNA) in a 5% DMF/5 mM Tris-HCl/50 mM NaCl buffer at pH 7.1 in the absence of an oxidant at 100 MUM complex concentration, which varies as 4 > 2 > 1 > 3. The order of DNA the cleavage ability at 30 MUM concentration in the presence ascorbic acid is 4 > 2 > 1 > 3, and, interestingly, 4 alone shows an ability to convert supercoiled DNA into nicked-coiled DNA even at 6 MUM concentration, beyond which complete degradation is observed and the pathway of oxidative DNA cleavage involves hydroxyl radicals. In the presence of distamycin, all of the complexes, except 3, show decreased DNA cleavage activity, suggesting that the complexes prefer to bind in the DNA minor groove. All of the complexes exhibit prominent DNA cleavage even at very low concentrations (nM) in the presence of H(2)O(2) as an activator, with the order of cleavage efficiency being 3 > 2 > 4 > 1. Studies on the anticancer activity toward HEp-2 human larynx cell lines reveal that the ability of the complexes to kill the cancer cell lines varies as 3 > 4 > 2 > 1. Also, interestingly, the IC(50) value of 3 is lower than that of cisplatin, suggesting that the hydrophobicity of methyl groups on the 5 and 6 positions of the complex enhances the anticancer activity. The mode of cell death effected by the complex has been explored by using various biochemical techniques like comet assay, mitochondrial membrane potency, and Western blotting. The complex has been found to induce nuclear condensation and fragmentation in cell lines. Also, it triggers activation of caspases by releasing cytochrome c from mitochondria to cytosol, suggesting that it induces apoptosis in cells via the mitochondrial pathway. PMID- 21671568 TI - Modeling the tetraphenylalanine-PEG hybrid amphiphile: from DFT calculations on the peptide to molecular dynamics simulations on the conjugate. AB - The conformational properties of the hybrid amphiphile formed by the conjugation of a hydrophobic peptide with four phenylalanine (Phe) residues and hydrophilic poly(ethylene glycol), have been investigated using quantum mechanical calculations and atomistic molecular dynamics simulations. The intrinsic conformational preferences of the peptide were examined using the building-up search procedure combined with B3LYP/6-31G(d) geometry optimizations, which led to the identification of 78, 78, and 92 minimum energy structures for the peptides containing one, two, and four Phe residues. These peptides tend to adopt regular organizations involving turn-like motifs that define ribbon or helical like arrangements. Furthermore, calculations indicate that backbone...side chain interactions involving the N-H of the amide groups and the pi clouds of the aromatic rings play a crucial role in Phe-containing peptides. On the other hand, MD simulations on the complete amphiphile in aqueous solution showed that the polymer fragment rapidly unfolds maximizing the contacts with the polar solvent, even though the hydrophobic peptide reduce the number of waters of hydration with respect to an individual polymer chain of equivalent molecular weight. In spite of the small effect of the peptide in the hydrodynamic properties of the polymer, we conclude that the two counterparts of the amphiphile tend to organize as independent modules. PMID- 21671569 TI - Unexpected cycloisomerizations of nonclassical carbocation intermediates in gold(I)-catalyzed homo-Rautenstrauch cyclizations. AB - An unexpected gold(I)-catalyzed homo-Rautenstrauch rearrangement of 1-cyclopropyl propargylic esters to cyclohexenones is disclosed. This rearrangement represents new evidence for the recently discussed gold-stabilized nonclassical carbocation character of intermediates in gold catalysis. A mechanistic study proved partial chirality transfer from optically active propargyl acetates. PMID- 21671570 TI - Low sensitivity of acoustic breathing mode frequency in Co nanocrystals upon change in nanocrystallinity. AB - Cobalt nanocrystals (NCs) with narrow size distribution and polycrystalline structure in their native form are synthesized in reverse micelles. After annealing at 350 degrees C, these NCs are transformed into single crystalline phase with hexagonal close-packed structure. The vibrational dynamics of NCs differing by their nanocrystallinity is studied by femtosecond pump-probe spectroscopy. By recording the differential reflectivity signal in the native and annealed Co NCs, the frequency of their fundamental breathing acoustic mode can be measured in the time domain. A small decrease of the breathing mode frequency is observed in single crystalline Co NCs compared to that measured in polycrystals, indicating low sensitivity of their fundamental radial mode upon change in crystallinity. This result is in agreement with predictions from calculations using the resonant ultrasound approach. PMID- 21671571 TI - Structures of glycosylated mammalian glutaminyl cyclases reveal conformational variability near the active center. AB - Formation of N-terminal pyroglutamate (pGlu or pE) from glutaminyl or glutamyl precursors is catalyzed by glutaminyl cyclases (QC). As the formation of pGlu amyloid has been linked with Alzheimer's disease, inhibitors of QCs are currently the subject of intense development. Here, we report three crystal structures of N glycosylated mammalian QC from humans (hQC) and mice (mQC). Whereas the overall structures of the enzymes are similar to those reported previously, two surface loops in the neighborhood of the active center exhibit conformational variability. Furthermore, two conserved cysteine residues form a disulfide bond at the base of the active center that was not present in previous reports of hQC structure. Site-directed mutagenesis suggests a structure-stabilizing role of the disulfide bond. At the entrance to the active center, the conserved tryptophan residue, W(207), which displayed multiple orientations in previous structure, shows a single conformation in both glycosylated human and murine QCs. Although mutagenesis of W(207) into leucine or glutamine altered substrate conversion significantly, the binding constants of inhibitors such as the highly potent PQ50 (PBD150) were minimally affected. The crystal structure of PQ50 bound to the active center of murine QC reveals principal binding determinants provided by the catalytic zinc ion and a hydrophobic funnel. This study presents a first comparison of two mammalian QCs containing typical, conserved post-translational modifications. PMID- 21671572 TI - New insight in protein-ligand interactions. 2. Stability and properties of two mutant forms of the D-galactose/D-glucose-binding protein from E. coli. AB - The galactose/glucose-binding protein from E. coli (GGBP) is a 32 kDa protein possessing the typical two-domains structure of the ligand-binding proteins family. GGBP is characterized by low dissociation constant values with respect to glucose binding, displaying an affinity constant for glucose in micromolar range. This feature makes GGBP unsuitable as a sensitive probe for continuous glucose monitoring in blood of diabetic patients. In this work we designed, produced, and characterized two mutant forms of GGBP carrying the following amino acid substitutions in the active center of the protein: W183A or F16A. The two mutant GGBP forms retained a globular structure similar to that of the wild-type GGBP and displayed an affinity for glucose lower than the wild-type GGBP. A deep inspection of the entire set of the obtained results pointed out that the N- and C-terminal domains of GGBP-W183A in the absence of glucose have a stability lower than that of the wild-type protein. In the presence of glucose, the two domains of GGBP-W183A were tightly bound, making the protein structure more stable to the action of denaturing agents. On the contrary, the mutant form GGBP-F16A possesses a very restricted structural stability both in the absence and in the presence of glucose. In this work the role of Phe 16 and W 183 are discussed with regard to the structural and functional features of GGBP. In addition, some general guidelines are reported for the design of a novel glucose biosensor based on the use of GGBP. PMID- 21671573 TI - Systematic study of aggregation structure and thermal behavior of a series of unique H-shape alkane molecules. AB - The H-shape alkanes of various arm lengths have been synthesized successfully through the Grignard reaction. The detailed investigation of these novel compounds may allow us to widen the topological chemistry field furthermore. The molecular form and molecular packing structure in the crystal lattice have been revealed successfully on the basis of X-ray structure analysis as well as the analysis of Raman longitudinal acoustic modes (LAM) sensitive to the alkyl zigzag chain segments. The molecular conformation in the crystal lattice is deformed markedly from the originally imagined H-shape. In the cases of C3HOH to C6HOH, for example, the molecules are packed in a complicated manner and the OH...O hydrogen bonds govern the whole intermolecular interactions mainly. Since the alkyl segmental length is not very long, the conformational change is not very drastic, i.e., the small configurational entropy. Synergic effect of the hydrogen bonds and the small configurational entropy gives the higher melting point as known from the thermal data. On the other hand, in the cases of C10HOH and C12HOH, one of the long alkyl chain arms is found to be bent by 90 degrees so that all of the alky chain segments of planar-zigzag conformation can be packed as closely as possible, and the intermolecular OH...O hydrogen bonds are also formed effectively without any mistake. As a result, the contribution of nonbonded intra- and intermolecular van der Waals interactions between the trans zigzag alkyl chain segments become major, and the coupling of this enthalpy effect with the larger configurational entropy effect of the molecular shape results in the decrement of the melting point which approaches gradually that of longer n-alkane compound. In this way a sensitive balance between the nonbonded van der Waals interactions, the OH...O hydrogen bonds, as well as the configurational entropy effect gives the characteristic thermal behavior of the H shape compounds. The thus-newly synthesized H-shape alkane compounds should give us new insight into the packing topology of complicated molecules, leading to the development of new functionality unexpected for normal linear alkane compounds. PMID- 21671574 TI - Alkylnaphthalenes: priority pollutants or minor contributors to the poor health of marine mussels? AB - Alkylnaphthalenes (AN) are relatively water-soluble hydrocarbons which, following spillages of crude oils, have been widely reported in contaminated marine organisms such as mussels. In the present report we show, by tandem-gas chromatography-time-of-flight-mass spectrometry (GC * GC-ToF-MS), that the range of AN in contaminated wild mussels from the UK extends beyond the previously GC resolved isomers to those with at least seven substituent carbon atoms. Since surprisingly little information on AN toxicity to such marine organisms has been reported we synthesized two C(8) AN and measured the toxicity of C(2-8) AN to mussels (clearance rate assay). C(2-3) AN were appreciably toxic (concentration for 50% clearance rate inhibition, 48 h IC(50) 1.4-2.6 MUmol g(-1) dry weight tissue), but several C(4), (6) and C(8) AN, including branched isomers expected to be resistant to biodegradation and more accumulative, were relatively nontoxic (48 h IC(50) > 10 MUmol g(-1)) and longer term exposure (8d) failed to elicit a greater toxic response. The accumulation profiles of AN in laboratory mussels exposed to oil were similar to those of the wild mussels. Moreover, laboratory oil-exposed mussels depurated toxic C(2-3) AN within 5 days in clean water and clearance rates recovered. The latter might imply that, in contrast with branched alkyl benzenes tested previously, AN are of less toxic concern, but such a straightforward conclusion cannot necessarily be drawn; a synthetic branched C(8) AN persisted following depuration and was as toxic to mussels as a C(3) AN (IC(50) 1.3 MUmol g(-1)). This indicates that the structures of AN are also important. PMID- 21671575 TI - Denaturation behaviors of two-state and non-two-state proteins examined by an interruption-incubation protocol. AB - We established an interruption-incubation protocol to study the denaturation and aggregation behaviors of two-state and non-two-state proteins, represented by hen egg-white lysozyme (lysozyme) and bovine serum albumin (BSA), by differential scanning calorimetry (DSC) and Fourier-transform infrared (FTIR) spectroscopy. After incubation at selected interrupting temperatures (T(int)), the onset temperature (T(onset)) and denaturation temperature (T(d)) of the reheating scans were found to pose distinct contrasts between the two proteins. BSA shows increasing T(onset) and T(d) as T(int) increases, whereas lysozyme exhibits invariable T(onset) and T(d). After long-time incubation, the reheating scans of BSA still show residual peaks in the DSC curves. Moderate aggregation upon incubation restricts the refolding of the thermodynamically stable unfolding intermediates in the denaturation of BSA. On the contrary, prolonged incubation at selected T(int) causes complete denaturation of lysozyme. The results were also supported by FTIR experiments. It is concluded that the variable T(onset) and T(d) indicate the unfolding of the "trapped" intermediates in the second heating scans, and the invariable T(onset) and T(d) values indicate the nonexistence of such intermediates. The examination of two additional proteins, ribonuclease A and gamma-globulin, shows a similar phenomenon. The results may represent the general features of two-state and non-two-state denaturations and the protocol would serve to study protein denaturation cooperativity. PMID- 21671576 TI - Solid-phase synthesis of a library of amphipatic hydantoins. Discovery of new hits for TRPV1 blockade. AB - Some heterocyclic systems, called privileged scaffolds, appear frequently in bioactive products and marketed drugs. The combination of a recognized privileged scaffold (hydantoin) and a functional group with high incidence in bioactive molecules (guanidine) guided the design of a library of amphipatic compounds, which allowed the discovery of novel TRPV1 ion channel blockers. The library was synthesized by parallel solid-phase synthesis from an orthogonally protected resin-bound Lys-Lys skeleton. Key steps of the synthetic procedure were the construction of the hydantoin ring, by reaction of the N-terminal amino group with N,N-disuccinimidyl carbonate (DSC) and subsequent base-induced cyclization, and the guanidinylation of the C-terminal Lys side-chain after removal of the Alloc protecting-group. The preliminary biological studies have allowed the identification of some of the key structural features directing the blockage of capsaicin-induced Ca(2+) influx through TRPV1 channels, particularly, the strong preference showed for highly lipophilic acyl groups and substituted guanidine moieties. Active compounds based on this new pharmacophoric scaffold that display in vitro and in vivo inhibitory activity. PMID- 21671577 TI - Resonance energy transfer (RET)-Induced intermolecular pairing force: a tunable weak interaction and its application in SWNT separation. AB - This paper explores evidence of an optically mediated interaction that is active in the separation mechanism of certain selective agents through consideration of the contrasting selective behaviors of two conjugated polymers with distinct optical properties. The involvement of a RET-induced intermolecular pairing force is implied by the different illumination response behaviors. The magnitude of this interaction scales with the external stimulus parameter, the illumination irradiance (I), and thus is tunable. This suggests a facile technique to modify the selectivity of polymers toward specific SWNT species by altering the polymer structure to adjust the corresponding intermolecular interaction. This is the first experimental verification and application of a RET-induced intermolecular pairing force to SWNT separation. With this kind of interaction taken into account, reasonable interpretation of some conflicting data, especially PLE maps, can be easily made. The above conclusion can be applied to other substances as long as they are electrically neutral and there is photon-induced RET between them. The significant magnitude of this interaction makes direct manipulation of molecules/particles possible and is expected to have applications in molecular engineering. PMID- 21671578 TI - Flexible electrically conductive nanocomposite membrane based on bacterial cellulose and polyaniline. AB - The novel conductive polyaniline/bacterial cellulose (PANI/BC) nanocomposite membranes have been synthesized in situ by oxidative polymerization of aniline with ammonium persulfate as an oxidant and BC as a template. The resulting PANI coated BC nanofibrils formed a uniform and flexible membrane. It was found that the PANI nanoparticles deposited on the surface of BC connected to form a continuous nanosheath by taking along the BC template, which greatly increases the thermal stability of BC. The content of PANI and the electrical conductivity of composites increased with increasing reaction time from 30 to 90 min, while the conductivity decreased because of the aggregation of PANI particles by further prolonging the reaction time. In addition, the acids remarkably improve the accessibility and reactivity of the hydroxyl groups of BC. The results indicate that the composites exhibit excellent electrical conductivity (the highest value was 5.0 * 10(-2) S/cm) and good mechanical properties (Young's modulus was 5.6 GPa and tensile strength was 95.7 MPa). Moreover, the electrical conductivity of the membrane is sensitive to the strain. This work provides a straightforward method to prepare flexible films with high conductivity and good mechanical properties, which could be applied in sensors, flexible electrodes, and flexible displays. It also opens a new field of potential applications of BC materials. PMID- 21671579 TI - Efficient transport of gold atoms with a scanning tunneling microscopy tip and a linker molecule. AB - A thiophene-containing molecule attached to a scanning tunneling microscopy (STM) tip is used to transport gold atoms on a Au(111) surface. The molecule contains eight thiophene rings and therefore has sulfur atoms that are known to bind to gold atoms. Using a gold-coated tip, the molecules previously deposited on the surface bind to the lower-coordination gold atoms of the tip. When that tip is used to scan the surface, the still free thiophene rings (not all of the sulfur atoms bind to the tip) can attach to gold atoms from the surface and drag them along the scanning direction, depositing them either at the position where the tip changes its scanning direction or where the tip encounters an "up step", whichever event occurs first. PMID- 21671580 TI - Multimodal image-guided photothermal therapy mediated by 188Re-labeled micelles containing a cyanine-type photosensitizer. AB - Multifunctional micelles loaded with the near-infrared (NIR) dye and labeled with the radionuclide rhenium-188 ((188)Re) have been developed to provide multimodalities for NIR fluorescence and nuclear imaging and for photothermal therapy (PTT) of cancer. The NIR dye, IR-780 iodide, allowed the micelles to have dual functions in cancer NIR imaging and PTT. The (188)Re-labeled IR-780 micelles enabled imaging by NIR fluorescence and by microSPECT to guide the delivery of drugs and to monitor in real-time the tumor accumulation, intratumoral distribution, and kinetics of drug release, which serve as a basis of specific photothermal injury to the targeted tissue. We also investigated the biodistribution, generation of heat, and photothermal cancer ablation of IR-780 micelles of both in vitro and in vivo xenografts. Histopathology observed irreversible tissue damage, such as necrotic features, decreased cell proliferation, increased apoptosis of cells, and increased expression of heat shock proteins in the PTT-treated tumors. The (188)Re-labeled IR-780 micelles offer multifunctional modalities for NIR fluorescence and nuclear imaging and for PTT of cancer. PMID- 21671581 TI - N-Methyl inversion and structure of six-membered heterocyclic rings: rotational spectrum of 1-methyl-4-piperidone. AB - The conformational and structural properties of the six-membered heterocyclic ring of 1-methyl-4-piperidone have been observed in a jet-cooled supersonic expansion using Fourier transform microwave spectroscopy (FT-MW). The rotational spectrum evidenced two different conformations originated by nitrogen inversion, with the N-methyl group in either equatorial (most stable) or axial position. Additional observation of the rotational spectra for all possible carbon, nitrogen, and oxygen monosubstituted species (4 * (13)C, (15)N, (18)O) in natural abundance allowed us to determine substitution (r(s)) and effective structures (r(0)) for the equatorial conformer. Additional ab initio and DFT calculations provided comparative rotational parameters, structural data, conformational energies, and the axial-equatorial interconversion barrier. The structural data were compared with the related azabicycle of tropinone, revealing the molecular changes and structural relaxation associated with the presence of the two-carbon bridge in the latter molecule. PMID- 21671582 TI - Doping effects on structural and electronic properties of ladderanes and ladder polysilanes: a density functional theory investigation. AB - Doping effects on the structural and electronic properties of ladderanes and ladder polysilanes have been studied using density functional theory. Two types of doping: substitution with isoelectronic atoms or heteroatoms (or radicals), have been used to design low band gap ladderanes. It is found that the B-doped [n]-ladderanes and 1,2 P-doped [n]-silaladderanes exhibit a very noticeable bent conformation, whereas the 1,2 and 1,3 N-doped ladderanes, P-doped ladderanes, and silaladderanes keep the relatively straight ladder shapes. The isoelectronic atom doping reduces the HOMO-LUMO (H-L) gaps of [n]-ladderanes but increases those of [n]-silaladderanes with n > 5. The present results show that isoelectronic atom doping is not an effective way to decrease the H-L gaps of ladderanes and silaladderanes. Heteroatom doping has a more pronounced effect than the isoelectronic atom doping. The HOMOs of heteroatom-doped ladderanes and silaladderanes are destabilized and LUMOs are stabilized, leading to significant reduction of H-L gaps. Most of the B-, N-, and P-doped [n]-silaladderanes we designed have H-L gaps below 1.5 eV. Therefore, it is expected that these silaladderanes are promising candidates of conductive or semiconductive materials. The heteroatom doping is a viable approach to reduce H-L gaps for the silaladderanes. In addition, it is found that nine different density functionals, including B3LYP, SVWN LDA, four pure GGAs, and three hybrid GGAs, as well as the time-dependent B3LYP method, all lead to the same predictions on the H-L gaps of ladderanes, silaladderanes, as well as their doped derivatives. PMID- 21671586 TI - Functional role of a conserved arginine residue located on a mobile loop of alkanesulfonate monooxygenase. AB - The structure of the flavin-dependent alkanesulfonate monooxygenase (SsuD) exists as a TIM-barrel structure with an insertion region located over the active site that contains a conserved arginine (Arg297) residue present in all SsuD homologues. Substitution of Arg297 with alanine (R297A SsuD) or lysine (R297K SsuD) was performed to determine the functional role of this conserved residue in SsuD catalysis. While the more conservative R297K SsuD possessed a lower k(cat)/K(m) value (0.04 +/- 0.01 MUM(-1) min(-1)) relative to wild-type (1.17 +/- 0.22 MUM(-1) min(-1)), there was no activity observed with the R297A SsuD variant. Each of the arginine variants had similar K(d) values for flavin binding as wild-type SsuD (0.32 +/- 0.15 MUM), but there was no measurable binding of octanesulfonate. The low levels of activity for the R297A and R297K SsuD variants correlated with the absence of any detectable C4a-(peroxy)flavin formation in stopped-flow kinetic studies. Single-turnover experiments were performed in the presence of SsuE to evaluate both the reductive and oxidative half-reaction. With wild-type SsuD a lag phase is observed following the reductive half-reaction by SsuE that represents flavin transfer or conformational changes associated with the binding of substrates. Evaluation of the Arg297 SsuD variants in the presence of SsuE showed no lag phase following reduction by SsuE, and the flavin was oxidized immediately following the reductive half-reaction. These results corresponded with a lack of detectable changes in the proteolytic susceptibility of R297A and R297K SsuD in the presence of reduced flavin and/or octanesulfonate, signifying the absence of a conformational change in these variants with the substitution of Arg297. PMID- 21671587 TI - Intramolecular charge transfer and Z-scan studies of a semiorganic nonlinear optical material sodium acid phthalate hemihydrate: a vibrational spectroscopic study. AB - FT-IR and Raman spectra of the nonlinear optical material sodium acid phthalate hemihydrate crystal have been recorded and analyzed. The equilibrium geometry, bonding features, and harmonic vibrational wavenumbers have been investigated with the help of the B3LYP density functional theory method. A detailed interpretation of the vibrational spectra was carried out with the aid of normal coordinate analysis following the scaled quantum mechanical force field methodology. The natural bond orbital analysis confirms the occurrence of strong intermolecular hydrogen bonding in the molecule. Nonlinear optical absorption of the sample has been studied at 532 nm using single 5 ns laser pulses, employing the open-aperture Z-scan technique. It is found that the NaAPH molecule is a potential candidate for optical limiting applications. PMID- 21671584 TI - Friedreich's ataxia variants I154F and W155R diminish frataxin-based activation of the iron-sulfur cluster assembly complex. AB - Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that has been linked to defects in the protein frataxin (Fxn). Most FRDA patients have a GAA expansion in the first intron of their Fxn gene that decreases protein expression. Some FRDA patients have a GAA expansion on one allele and a missense mutation on the other allele. Few functional details are known for the ~15 different missense mutations identified in FRDA patients. Here in vitro evidence is presented that indicates the FRDA I154F and W155R variants bind more weakly to the complex of Nfs1, Isd11, and Isu2 and thereby are defective in forming the four-component SDUF complex that constitutes the core of the Fe-S cluster assembly machine. The binding affinities follow the trend Fxn ~ I154F > W155F > W155A ~ W155R. The Fxn variants also have diminished ability to function as part of the SDUF complex to stimulate the cysteine desulfurase reaction and facilitate Fe-S cluster assembly. Four crystal structures, including the first for a FRDA variant, reveal specific rearrangements associated with the loss of function and lead to a model for Fxn-based activation of the Fe-S cluster assembly complex. Importantly, the weaker binding and lower activity for FRDA variants correlate with the severity of disease progression. Together, these results suggest that Fxn facilitates sulfur transfer from Nfs1 to Isu2 and that these in vitro assays are sensitive and appropriate for deciphering functional defects and mechanistic details for human Fe-S cluster biosynthesis. PMID- 21671588 TI - Effective improvement of water-retention in nanocomposite membranes using novel organo-modified clays as fillers for high temperature PEMFCs. AB - Toward an enhanced water-retention of polymer electrolyte membranes at high temperatures, novel organo-modified clays were prepared and tested as fillers for the creation of hybrid Nafion nanocomposites. Two smectite clays (Laponite and montmorillonite), with different structural and physical parameters, were loaded with various cationic organic molecules bearing several hydrophilic functional groups (-NH(2), -OH, -SO(3)H) and incorporated in Nafion by solution intercalation. The resulted hybrid membranes were characterized by a combination of powder X-ray diffraction, FTIR spectroscopy, and thermal analysis (DTA/TGA) showing that highly homogeneous exfoliated nanocomposites were created where the individual organoclay layers are uniformly dispersed in the continuous polymeric matrix. In this paper, water-transport properties were investigated by NMR spectroscopy, including pulsed-field-gradient spin-echo diffusion and spectral measurements conducted under variable temperature. Organo-montmorillonite nanofillers demonstrate a considerable effect on the Nafion polymer in terms both of water absorption/retention and water mobility with a remarkable behavior in the region of high temperatures (100-130 degrees C), denoting that the surface modifications of this clay with acid organic molecules significantly improve the performance of the final composite membrane. (1)H NMR spectral analysis allowed a general description of the water distribution in the system and an estimation of the number of water molecules involved in the hydration shell of the sulfonic groups as well as that absorbed on the organoclay particles. PMID- 21671589 TI - Intracellular O2 sensing probe based on cell-penetrating phosphorescent nanoparticles. AB - A new intracellular O(2) (icO(2)) sensing probe is presented, which comprises a nanoparticle (NP) formulation of a cationic polymer Eudragit RL-100 and a hydrophobic phosphorescent dye Pt(II)-tetrakis(pentafluorophenyl)porphyrin (PtPFPP). Using the time-resolved fluorescence (TR-F) plate reader set-up, cell loading was investigated in detail, particularly the effects of probe concentration, loading time, serum content in the medium, cell type, density, etc. The use of a fluorescent analogue of the probe in conjunction with confocal microscopy and flow cytometry analysis, revealed that cellular uptake of the NPs is driven by nonspecific energy-dependent endocytosis and that the probe localizes inside the cell close to the nucleus. Probe calibration in biological environment was performed, which allowed conversion of measured phosphorescence lifetime signals into icO(2) concentration (MUM). Its analytical performance in icO(2) sensing experiments was demonstrated by monitoring metabolic responses of mouse embryonic fibroblast cells under ambient and hypoxic macroenvironment. The NP probe was seen to generate stable and reproducible signals in different types of mammalian cells and robust responses to their metabolic stimulation, thus allowing accurate quantitative analysis. High brightness and photostability allow its use in screening experiments with cell populations on a commercial TR-F reader, and for single cell analysis on a fluorescent microscope. PMID- 21671590 TI - Holographic control of motive shape in plasmonic nanogap arrays. AB - Here we demonstrate that 4-beam holographic lithography can be utilized to create plasmonic nanogaps that are 70 times smaller than the laser wavelength (488 nm). This was achieved by controlling phase, polarization, and laser beam intensity in order to tune the relative spacing of the two sublattices in the interference pattern of a compound-lattice in combination with the nonlinear resist response. Exemplarily, twin and triplet motive features were designed and patterned into polymer in a single exposure step and then transferred into gold nanogap arrays resulting in an average gap size of 22 nm and smallest features down to 7 nm. These results extend the utility of high-throughput, wafer-scale holographic lithography into the realm of nanoplasmonics. PMID- 21671591 TI - Total synthesis of (+/-)-trigonoliimine C via oxidative rearrangement of an unsymmetrical bis-tryptamine. AB - We report the first total synthesis of (+/-)-trigonoliimine C, a member of a family of structurally complex alkaloids, in 10 steps from tryptamine and 6 methoxytryptamine. Our convergent synthetic strategy relies on a selective oxidative rearrangement of an unsymmetrical 2,2'-bis-tryptamine. PMID- 21671592 TI - Capacities of membrane lipids to accumulate neutral organic chemicals. AB - Lipids have been considered as the predominant components for bioaccumulation of organic chemicals. However, differences in accumulation properties between different types of lipid (e.g., storage and membrane lipids) have rarely been considered. Moreover, in view of toxic effects on organisms, chemical accumulation specifically in biological membranes is of particular importance. In this review article, partition coefficients of 240 neutral organic compounds between liposomes (phospholipid membrane vesicles) and water (K(lipw)), reported in the literature or measured additionally for this work, were evaluated. Values of log K(lipw) and log K(ow) (octanol-water partition coefficients) differ by 0.4 on average. Polyparameter linear free energy relationships (PP-LFERs) can describe the log K(lipw) data even better (standard deviations = 0.28-0.31) than the log K(ow) model. Recent experimental data for highly hydrophobic compounds fit well to the PP-LFERs and do not indicate the existence of a previously postulated "hydrophobicity cutoff". Predictive approaches based only on the molecular structure (KOWWIN, SPARC, COSMOthermX, COSMOmic) were also evaluated for K(lipw) prediction. The PP-LFERs revealed that partition coefficients into membrane lipids can be two log units higher than those into storage lipids for H bond donor compounds, suggesting that distinguishing between the two lipids is necessary to account for the bioaccumulation of these compounds, and that tissues rich in membrane lipids (e.g., kidneys, liver) instead of fat tissue can be the primary phase for accumulation. PMID- 21671593 TI - Formal enantioselective total synthesis of schulzeines A-C via Pd-catalyzed intramolecular asymmetric allylic amination. AB - Formal enantioselective total synthesis of schulzeines A-C was accomplished, featuring highly efficient Pd-catalyzed asymmetric allylic amination using novel diphosphonite ligands (BOPs) to provide 1-vinyltetrahydroisoquinoline key intermediates, as well as Ru-catalyzed ring-closing metathesis reaction to construct the key tricyclic cores in enantiopure form with correct absolute configurations. PMID- 21671594 TI - Asymmetric synthesis of beta2-tryptophan analogues via Friedel-Crafts alkylation of indoles with a chiral nitroacrylate. AB - The asymmetric Friedel-Crafts alkylation of various indoles with a chiral nitroacrylate provides optically active beta-tryptophan analogues after reduction of the nitro group and removal of the chiral auxiliary. This reaction generally occurs in good yield and high diastereoselectivity (up to 90:10). PMID- 21671595 TI - Computational study of cycloaddition reactions of 16-electron d8 ML4 complexes with C60. AB - The potential energy surfaces of the cycloaddition reactions M(CO)(4) + C(60) -> (CO)(4)M(C(60)) (M = Fe, Ru, and Os) have been studied at the B3LYP/LANL2DZ level of theory. It has been found that these reactions have two competing pathways, which can be classified as a [6,5]-attack (path A) and a [6,6]-attack (path B). Our B3LYP results suggest that, given the same reaction conditions, the [6,6] attack is more favorable than the [6,5]-attack both kinetically and thermodynamically. A qualitative model based on the theory of Pross and Shaik has been used to develop an explanation for the barrier heights. As a consequence, the theoretical findings indicate that the singlet-triplet splitting DeltaE(st) (=E(triplet) - E(singlet)) of the 16-electron d(8) M(CO)(4) and C(60) species can be used as a guide to predict their reactivity toward cycloaddition. Our computational results reveal that the reactivity of d(8) M(CO)(4) cycloaddition to C(60) decreases in the order Fe(CO)(4) > Os(CO)(4) > Ru(CO)(4). Accordingly, we demonstrate that both electronic and geometric effects play a crucial role in determining the energy barriers as well as the reaction enthalpy. PMID- 21671596 TI - Novel reversible chemosensory material based on conjugated side-chain polymer containing fluorescent pyridyl receptor pendants. AB - A novel light-emitting monomer M1 and its side-chain polymer P1 containing three conjugated aromatic pendants, including one pyridyl terminus, were successfully synthesized via Wittig and Pd-catalyzed Heck coupling reactions. The fluorescence of polymer P1 was efficiently quenched upon addition of different metal ions due to the facile energy transfers from the pendent groups of polymer P1 to specific metal ions. Among these metal ions, P1 exhibited extraordinary sensory selectivities for Ni(2+) and Cu(2+) ions over the other metal ions due to the stronger binding capabilities of Ni(2+) and Cu(2+) ions with polymer P1. From the time-resolved fluorescence (TRF) signals in photoluminescence spectra, the emergences of tau(1) decay components in polymer complexes (P1+Ni(2+)) and (P1+Cu(2+)) clearly indicated that their TRF traces consisted of two contributions, one from the complexes (tau(1)) and the other from free polymer P1 (tau(2)). Upon addition of Ni(2+) and Cu(2+) ions, polymer P1 showed faster decay time constants (tau(1)) of metal ion quenching on TRF signals (i.e., better quenching efficiencies on photoluminescence) than its monomer M1. Furthermore, the on-off-on fluorescent switching behavior by adding a tridentate ligand 1,1,4,7,7-pentamethyldiethylenetriamine (PMDTA) to the polymer complex (P1+Cu(2+)) for several successive cycles demonstrated a superior reusable chemosensor of P1 for further applications. PMID- 21671597 TI - Reversible tuning of the wettability of carbon nanotube arrays: the effect of ultraviolet/ozone and vacuum pyrolysis treatments. AB - Among diverse types of synthetic materials, arrays of vertically aligned carbon nanotubes have attracted the most attention, mainly because of their exceptional mechanical, electrical, optical, and thermal properties. However, their wetting properties are yet to be understood. In this present study, oxygenated surface functional groups have been identified as a vital factor in controlling the wetting properties of carbon nanotube arrays. The results presented herein indeed show that a combination of ultraviolet/ozone and vacuum pyrolysis treatments can be used to vary the surface concentration of these functional groups such that the carbon nanotube array can be repeatedly switched between hydrophilic and hydrophobic. PMID- 21671598 TI - Preparation and characterization of amino-linked heterocyclic carbene palladium, gold, and silver complexes and their use as anticancer agents that act by triggering apoptotic cell death. AB - Transition metal complexes bearing amino linked N-heterocyclic carbenes (NHC) were prepared and evaluated for their antiproliferative activities in human cancer cells. The optimum antiproliferative activity, observed for the gold complex 3 in U-87 MG cells, was found to involve S-phase arrest of the cell cycle. The results indicate that 3 induces apoptosis through a p53-bak pathway, a finding that could serve as a new strategy to reduce the resistance of cancer cells to p53-induced apoptosis. PMID- 21671599 TI - Theoretical study for pyridinium-based ionic liquid 1-ethylpyridinium trifluoroacetate: synthesis mechanism, electronic structure, and catalytic reactivity. AB - By performing density functional theory calculations, we have studied the synthesis mechanism, electronic structure, and catalytic reactivity of a pyridinium-based ionic liquid, 1-ethylpyridinium trifluoroacetate ([epy](+)[CF(3)COO](-)). It is found that the synthesis of the pyridinium salt follows a S(N)2 mechanism. The electronic structural analyses show that multiple H bonds are generally involved in the pyridinium-based ionic liquid, which may play a decisive role for stabilizing the ionic liquid. The cation-anion interaction mainly involves electron transfer between the lone pair of the oxygen atom in the anion and the antibonding orbital of the C*-H bond (C* denotes the carbon atom at the ortho-position of nitrogen atom in the cation). This present work has also given clearly the catalytic mechanism of [epy](+)[CF(3)COO](-) toward to the Diels-Alder (D-A) reaction of acrylonitrile with 2-methyl-1,3 butadiene. Both the cation and anion are shown to play important roles in promoting the D-A reaction. The cation [epy](+), as a Lewis acid, associates the C=N group by C=N...H H bond to increase the polarity of the C?C double bond in acrylonitrile, while the anion CF(3)COO(-) links with the methyl group in 2 methyl-1,3-butadiene by C-H...O H bond, which weakens the electron-donating capability of methyl and thereby lowers the energy barrier of the D-A reaction. The present results are expected to provide valuable information for the design and application of pyridinium-based ionic liquids. PMID- 21671601 TI - Surprising effect of uncompensated resistance on the cyclic voltammetric responses for a reversible surface-confined and uniformly accessible redox couple. AB - A traditional diagnostic for cyclic voltammetric responses is the plot of the peak current i(peak) vs the scan rate |v| or vs |v|(1/2). For a reversible redox couple with redox moieties freely diffusing in bulk solution, a plot of i(peak) vs |v|(1/2) will be linear; for a surface-confined and uniformly accessible reversible couple, a plot of i(peak) vs |v| will be linear; however, if there is significant uncompensated resistance, it is the plot of i(peak) vs |v|(1/2) that will be linear even if the redox species are surface confined. The present work offers a theoretical basis for this result. PMID- 21671600 TI - Using covalent dimers of human carbonic anhydrase II to model bivalency in immunoglobulins. AB - This paper describes the development of a new bivalent system comprising synthetic dimers of carbonic anhydrase linked chemically through thiol groups of cysteine residues introduced by site-directed mutagenesis. These compounds serve as models with which to study the interaction of bivalent proteins with ligands presented at the surface of mixed self-assembled monolayers (SAMs). Monovalent carbonic anhydrase (CA) binds to benzenesulfonamide ligands presented on the surface of the SAM with K(d)(surf) = 89 nM. The synthetic bivalent proteins- inspired by the structure of immunoglobulins--bind bivalently to the sulfonamide functionalized SAMs with low nanomolar avidities (K(d)(avidity,surf) = 1-3 nM); this difference represents a ~50-fold enhancement of bivalent over monovalent association. The paper describes dimers of CA having (i) different lengths of the covalent linker that joined the two proteins and (ii) different points of attachment of the linker to the protein (either near the active site (C133) or distal to the active site (C185)). Comparison of the thermodynamics of their interactions with SAMs presenting arylsulfonamide groups demonstrated that varying the length of the linker between the molecules of CA had virtually no effect on the rate of association, or on the avidity of these dimers with ligand presenting surfaces. Varying the point of attachment of the linker between monomeric CA's also had almost no effect on the avidity of the dimers, although changing the point of attachment affected the rates of binding and unbinding. These observations indicate that the avidities of these bivalent proteins, and by inference the avidities of structurally similar bivalent proteins such as IgG, are unexpectedly insensitive to the structure of the linker connecting them. PMID- 21671602 TI - Effect of the molecular structure on the hierarchical self-assembly of semifluorinated alkanes at the air/water interface. AB - Semifluorinated alkanes (C(n)F(2n+1)C(m)H(2m+1)), short FnHm display local phase separation of mutually incompatible hydrocarbon and fluorocarbon chain moieties, which has been utilized as a structure-forming motif in supramolecular architectures. The packing of semifluorinated alkanes, nominally based on dodecyl subunits, such as perfluoro(dodecyl)dodecane (F12H12) and perfluoro(dodecyl)eicosane (F12H20), as well as a core extended analogue, 1,4 dibromo-2-((perfluoroundecyl)methoxy)-5-(dodecyloxy)benzene) (F11H1-core-H12), was studied at the air/water interface. Langmuir monolayers were investigated by means of neutron reflectivity directly at the air/water interface and scanning force microscopy after transfer to silicon wafers. Narrowly disperse surface micelles formed in all three cases; however, they were found to bear different morphologies with respect to molecular orientation and assembly dimensionality, which gives rise to different hierarchical aggregate topologies. For F12H12, micelles of ca. 30 nm in diameter, composed of several circular or "spherical cap" substructures, were observed and a monolayer model with the fluorocarbon block oriented toward air is proposed. F12H20 molecules formed larger (ca. 50 nm diameter) hexagonally shaped surface micelles that were hexagonally, densely packed, besides more elongated but tightly interlocked wormlike structures. Conversely, F11H1-core-H12 films organized into linear rows of elongated surface micelles with comparable width, but an average length of ca. 400 nm, apparently formed by antiparallel molecular packing. PMID- 21671603 TI - Hydrogen-bond-directed 2-D sheet assemblies of sulfamide derivatives: formation of giant vesicles with patchwork-like surface pattern. AB - Sulfamide derivatives showed high ability to form hydrogen-bond-directed two dimensional (2-D) sheet assemblies of nanometer thickness. Further, fine-tuning of the side chain structures and preparation conditions allowed for the formation of micrometer-sized giant vesicles of 4b in water by the simple injection method. IR and XRD studies indicated that 4b having tetradecyl and oxyethylene-terminated alkyl side chains formed hydrogen-bond-directed 2-D nanosheet pairs. SEM, AFM, and TEM observation of the dried vesicles revealed that the vesicle membrane was composed of several lamellar-stacked layers of 2-D nanosheets and showed a characteristic patchwork-like pattern on the surface. PMID- 21671604 TI - Nanodrop of an Ising magnetic fluid on a solid surface. AB - The density functional theory of inhomogeneous simple fluids is extended to an Ising magnetic fluid in contact with a solid surface, which is subjected to an external uniform or nonuniform magnetic field. The system is described by two coupled integral equations regarding the magnetic moment and fluid density distributions. The dependence of the contact angle that a nanodrop makes with the solid surface on the parameters involved in the magnetic interactions between the molecules of fluid and between the molecules of fluid and an external magnetic field is calculated. For the uniform magnetic field, the contact angle increases with increasing magnetic field, approaching an asymptotic value that depends on the strength of the fluid-fluid magnetic interactions. In the nonuniform field generated by a permanent magnet, the contact angle first increases with increasing magnetic field B(M) and then decreases, with the decrease being almost linear for large values of B(M). The obtained results are in qualitative agreement with the experimental data on the contact angle of magnetic drops on a solid surface available in the literature. PMID- 21671605 TI - Specific ion effects on adsorption at the solid/electrolyte interface: a probe into the concentration limit. AB - Adsorption of organic acid at the mineral oxide-electrolyte interface has been explored. The adsorption of 2,4-dihydroxybenzoic acid onto alpha-alumina illustrates that specific ion effects show up at very low salt concentration (<0.05 mM). These surprising Hofmeister effects occur at salt concentrations an order of magnitude lower than in a previous study ( J. Colloid Interface Sci. 2010, 344, 482 ). Salts enhance adsorption and specifically at <=0.05 mM. With increasing concentration of ion, the adsorption density decreases. The results are accounted for by incorporating the ion size and dispersion forces in the theoretical modeling based on ab initio calculations of polarizabilities. The order appears to be governed by ion size, determining the maximum concentration that ions can attain near the surface due to close packing. PMID- 21671606 TI - Mimicking natural fibrous structures of opals by means of a microemulsion mediated hydrothermal method. AB - Silica-based nanomaterials are of great interest because of their potential applications in constructing electronic and optoelectronic nanodevices. Especially significant are those that combine the properties of photonic crystal with a fibrous semiconductor structure. Here we report the use of microemulsion droplet systems as a simple and controllable route for the synthesis of 3D opals materials with an unusual fibrous microstructure similar to those that exist in nature. By this method, we demonstrate the creation of very long fibrils of 30-50 nm diameter and more than 20 MUm length showing simultaneous short and long wavelength light emissions and band gap values (5.50 and 4.41 eV) comparable to those obtained for silicon-based metal oxide semiconductors. PMID- 21671607 TI - Novel application of square-wave adsorptive-stripping voltammetry for the determination of xanthohumol in spent hops. AB - This paper reports the development of a novel electrochemical assay for xanthohumol (XN) by square-wave adsorptive-stripping voltammetry (SWAdSV) with a hanging mercury drop electrode. The method showed good repeatability (CV < 2%) and linearity (between 10 and 250 MUg L(-1)), as well as suitable limits of detection (2.6 MUg L(-1)) and quantification (8.8 MUg L(-1)). The method was applied for the quantification of this compound in spent hops, and the results obtained were compared with the HPLC-UV method. XN contents determined by the SWAdSV method were 16 +/- 1 and 100 +/- 4 MUg L(-1) for aqueous and methanolic extracts, respectively. The developed new methodology considerably reduces the analysis time, approximately from 25 min (HPLC-UV method) to 7 min, enabling a high sample throughput. In addition, the detection and quantification limits were approximately 5-fold lower than those obtained with the chromatographic method. PMID- 21671608 TI - Nickel-catalyzed synthesis of 1,3,5-trisubstituted hydantoins from acrylates and isocyanates. AB - One molecule of acrylate reacts with two molecules of isocyanate in the presence of a nickel(0)/SIPr catalyst to give a 1,3,5-trisubstituted hydantoin. Two processes operate in sequence, the first, regioselective formation of N substituted fumaramate from acrylate and isocyanate and, the second, ring closure of the fumaramate with incorporation of another molecule of isocyanate. PMID- 21671609 TI - Toxicity and internalization of CuO nanoparticles to prokaryotic alga Microcystis aeruginosa as affected by dissolved organic matter. AB - This is the first study investigating the toxicity of nanoparticles (NPs) to algae in the presence of dissolved organic matter (DOM). Suwannee river fulvic acid (SRFA), a type of DOM, could significantly increase the toxicity of CuO NPs to prokaryotic alga Microcystis aeruginosa. Internalization of CuO NPs was observed for the first time in the intact algal cells using high resolution transmission electron microscopy (HRTEM), and the cell uptake was enhanced by SRFA. A fast Fourier transformation (FFT)/inversed FFT (IFFT) process revealed that a main form of intracellular NPs was Cu(2)O, and an intracellular environment may reduce CuO into Cu(2)O. The internalization behavior alone did not seem to pose a hazard to membrane integrity as shown from the flow cytometry data. Elevated CuO nanotoxicity by SRFA was related to a combination of a lesser degree of aggregation, higher Cu(2+) release, and enhanced internalization of CuO NPs. PMID- 21671610 TI - The benzyne Fischer-indole reaction. AB - A new approach to the Fischer-indole synthesis is reported that uses the reactive intermediate benzyne. The addition of N-tosyl hydrazones to arynes, generated through fluoride activation of 2-(trimethylsilyl)phenyl triflate precursors, leads to efficient N-arylation. Addition of a Lewis acid to the same reaction pot then affords N-tosylindole products via Fischer cyclization. PMID- 21671611 TI - Filter-feeding bivalves store and biodeposit colloidally stable gold nanoparticles. AB - Nanoparticles resistant to salt-induced aggregation are continually being developed for biomedical and industrial applications. Because of their colloidal stability these functionalized nanoparticles are anticipated to be persistent aquatic contaminants. Here, we show that Corbicula fluminea, a globally distributed clam that is a known sentinel of aquatic ecosystem contamination, can uptake and biodeposit bovine serum albumin (BSA) stabilized gold nanoparticles. Nanoparticle clearance rates from suspension were dictated by diameter and concentration, with the largest particles cleared most quickly on a mass basis. Particle capture facilitates size-selective 'biopurification' of particle suspensions with nanoscale resolution. Nanoparticles were retained either within the clam digestive tract or excreted in feces. Our results suggest that biotransformation and biodeposition will play a significant role in the fate and transport of persistent nanoparticles in aquatic systems. PMID- 21671612 TI - Highly efficient synthesis of ketoheptoses. AB - A reliable, facile, high overall yielding and diastereoselective synthesis of ketoheptoses was developed and applied for preparation of the two most diabetogenic ketoheptoses as well as in a modified version for the synthesis of kamusol. PMID- 21671613 TI - Quantifying the dynamics of bacterial secondary metabolites by spectral multiphoton microscopy. AB - Phenazines, a group of fluorescent small molecules produced by the bacterium Pseudomonas aeruginosa, play a role in maintaining cellular redox homeostasis. Phenazines have been challenging to study in vivo due to their redox activity, presence both intra- and extracellularly, and their diverse chemical properties. Here, we describe a noninvasive in vivo optical technique to monitor phenazine concentrations within bacterial cells using time-lapsed spectral multiphoton fluorescence microscopy. This technique enables simultaneous monitoring of multiple weakly fluorescent molecules (phenazines, siderophores, NAD(P)H) expressed by bacteria in culture. This work provides the first in vivo measurements of reduced phenazine concentration as well as the first description of the temporal dynamics of the phenazine-NAD(P)H redox system in Pseudomonas aeruginosa, illuminating an unanticipated role for 1-hydroxyphenazine. Similar approaches could be used to study the abundance and redox dynamics of a wide range of small molecules within bacteria, both as single cells and in communities. PMID- 21671614 TI - Site-specific protein modification with a dirhodium metallopeptide catalyst. AB - A new method for chemical protein modification is presented utilizing a dirhodium metallopeptide catalyst. The combination of peptide-based molecular recognition and a dirhodium catalyst with broad side-chain scope enables site-specific protein functionalization. The scope and utility of dirhodium-catalyzed biomolecule modification is expanded to allow reaction at physiological pH and in biologically relevant buffer solutions. Specific protein modification is possible directly in E. coli lysate, demonstrating the remarkable activity and specificity of the designed metallopeptide catalyst. Furthermore, a new biotin-diazo conjugate 1b is presented that allows affinity tagging of target proteins. PMID- 21671615 TI - Hole transparent and hole blocking transport in single-crystal-like organic heterojunction: when rods hold up disks. AB - Single-crystal-like organic heterojuntions are fabricated with disk-like molecules and different rodlike molecules. Hole transparent and blocking transport are demonstrated with photoemission spectroscopy and field-effect transistors. These results demonstrate a route to utilize adjustable interfacial electronic structure and control transport behavior in developing functional organic crystalline devices and crystalline nanocircuits. PMID- 21671616 TI - Dissipation and distribution behavior of azoxystrobin, carbendazim, and difenoconazole in pomegranate fruits. AB - The dissipation behavior and degradation kinetics of azoxystrobin, carbendazim, and difenoconazole in pomegranate are reported. Twenty fruits/hectare (5 kg) were collected at random, ensuring sample-to-sample relative standard deviation (RSD) within 20-25%. Each fruit was cut into eight equal portions, and two diagonal pieces per fruit were drawn and combined to constitute the laboratory sample, resulting in RSDs <6% (n = 6). Crushed sample (15 g) was extracted with 10 mL of ethyl acetate (+ 10 g Na(2)SO(4)), cleaned by dispersive solid phase extraction on primary secondary amine (25 mg) and C(18) (25 mg), and measured by liquid chromatography tandem mass spectrometry. The limit of quantification was <=0.0025 MUg g(-1) for all the three fungicides, with calibration linearity in the concentration range of 0.001-0.025 MUg mL(-1) (r(2) >= 0.999). The recoveries of each chemical were 75-110% at 0.0025, 0.005, and 0.010 MUg g(-1) with intralaboratory Horwitz ratio <0.32 at 0.0025 MUg g(-1). Variable matrix effects were recorded in different fruit parts viz rind, albedo, membrane, and arils, which could be correlated to their biochemical constituents as evidenced from accurate mass measurements on a Q-ToF LC-MS. The residues of carbendazim and difenoconazole were confined within the outer rind of pomegranate; however, azoxystrobin penetrated into the inner fruit parts. The dissipation of azoxystrobin, carbendazim, and difenoconazole followed first + first order kinetics at both standard and double doses, with preharvest intervals being 9, 60, and 26 days at standard dose. At double dose, the preharvest intervals extended to 20.5, 100, and 60 days, respectively. PMID- 21671617 TI - Multiresidue pesticide analysis of agricultural commodities using acetonitrile salt-out extraction, dispersive solid-phase sample clean-up, and high-performance liquid chromatography-tandem mass spectrometry. AB - A multiresidue method analyzing 209 pesticides in 24 agricultural commodities has been developed and validated using the original Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) procedure and high performance liquid chromatography positive electrospray ionization-tandem mass spectrometry (LC-MS/MS) analysis. Using solvent-only calibration standards (SOCSs) and matrix-matched calibration standards (MMCSs), it was demonstrated that a minimal concentration of 5-10 MUg/kg (part per billion, ppb) of analytes in matrix is required for the consistent identification of targeted pesticides with two MRM transitions. Method performance was validated by the precision and accuracy results obtained from fortification studies at 10, 25, 100, and 500 ppb and MMCSs. The method was demonstrated to achieve an average recovery of 100 +/- 20% (n = 4) for >75% of evaluated pesticides at the low fortification level (10 ppb) and improved to >84% at the higher fortification concentrations in all 24 matrices. Matrix effects in LC-MS/MS analysis were studied by evaluating the slope ratios of calibration curves (1.0-100 ng/mL) obtained from the SOCSs and MMCSs. Principal component analysis (PCA) of LC-MS/MS and method validation data confirmed that each matrix exerts its specific effect during the sample preparation and LC-MS/MS analysis. The matrix effect is primarily dependent on the matrix type, pesticide type and concentration. Some caution is warranted when using matrix matched calibration curves for the quantitation of pesticides to alleviate concerns on matrix effects. The QuEChERS method with LC-MS/MS was used to identify and quantitate pesticides residues, with concentrations ranging from 2.5 to >1000 ppb in a variety of agricultural samples, demonstrating fitness for screening and surveillance applications. PMID- 21671618 TI - Electroosmotic velocity and electric conductivity in a fibrous porous medium in the transverse direction. AB - The steady electroosmosis and electric conduction in a fibrous medium constructed by a homogeneous array of parallel, identical, charged, circular cylinders filled with an electrolyte solution is analytically examined. The imposed electric field is constant and normal to the axes of the cylinders. The electric double layer surrounding each dielectric cylinder may have an arbitrary thickness relative to the radius of the cylinder. A unit cell model that allows for the overlap of the double layers of adjacent cylinders is employed. The electrokinetic equations that govern the ionic concentration distributions, the electrostatic potential profile, and the fluid flow field in the electrolyte solution surrounding the charged cylinder in a cylindrical cell are linearized assuming that the system is only slightly distorted from equilibrium. Through the use of a regular perturbation method, these linearized equations are solved with the surface charge density (or zeta potential) of the cylinder as the small perturbation parameter. Analytical expressions for the electroosmotic velocity of the fluid solution and the effective electric conductivity in the array of cylinders are obtained in closed forms as functions of the porosity of the fiber matrix and other characteristics of the porous system. Comparisons of the results of the cell model with different conditions at the outer boundary of the cell are made. The cell model predicts that, under otherwise identical conditions, the electric conductivity in a porous medium composed of an array of parallel cylinders in the transverse direction in general is smaller than that of a suspension of spheres, but there are some exceptions. The effect of interactions among the cylinders or spheres on the effective conductivity can be significant under appropriate conditions. PMID- 21671619 TI - Radical reaction of [60]fullerene with phosphorus compounds mediated by manganese(III) acetate. AB - Radical reaction of [60]fullerene with phosphonates or phosphine oxide mediated by manganese(III) acetate dihydrate in chlorobenzene under three different conditions afforded three different types of phosphorylated fullerenes: singly bonded fullerene dimers 2, hydrophosphorylated fullerenes 3, and acetoxylated fullerene derivatives 4. In addition, interconversions among the three types of phosphorylated fullerene derivatives have also been investigated. A possible reaction mechanism was proposed to explain experimental results. PMID- 21671620 TI - Electronic structure and thermochemical properties of small neutral and cationic lithium clusters and boron-doped lithium clusters: Li(n)(0/+) and Li(n)B(0/+) (n = 1-8). AB - The stability, electronic structure, and thermochemical properties of the pure Li(n) and boron-doped Li(n)B (n = 1-8) clusters in both neutral and cationic states are studied using electronic structure methods. The global equilibrium structures are established, and their heats of formation are evaluated using the G3B3 and CCSD(T)/CBS methods based on the density functional theory geometries. Theoretical adiabatic ionization energies (IE(a)) for the Li(n) clusters are in good agreement with experiment: Li(2) (G3B3, 5.21 eV; CCSD(T), 5.14 eV; expt, 5.1127 +/- 0.0003 eV), Li(3) (4.16, 4.11, 4.08 +/- 0.10), Li(4) (4.76, 4.68, 4.70 +/- 0.05), Li(5) (4.11, 4.06, 4.02 +/- 0.10), Li(6) (4.46, 4.32, 4.20 +/- 0.10), Li(7) (4.07, 3.99, 3.94 +/- 0.10), and Li(8) (4.49, 4.31, 4.16 +/- 0.10). The Li(4) experimental IE(a) has been revised on the basis of the Franck-Condon simulations. Species Li(5)B, Li(6)B(+), Li(7)B, and Li(8)B(+) exhibit high stability as compared to their neighbors, which can be understood by considering the magic numbers of the phenomenological shell model (PSM). PMID- 21671621 TI - Monovalent, clickable, uncharged, water-soluble perylenediimide-cored dendrimers for target-specific fluorescent biolabeling. AB - Herein we report the synthesis of water-soluble polyglycerol-dendronized perylenediimides with a single reactive group that undergoes high-yielding click reactions. Single-molecule studies and target-specific biolabeling are reported, including the highly specific labeling of proteins on the surface of living bacterial and mammalian cells. PMID- 21671622 TI - Identification of Ustilago maydis Aurora kinase as a novel antifungal target. AB - Infestation of crops by pathogenic fungi has continued to have a major impact by reducing yield and quality, emphasizing the need to identify new targets and develop new agents to improve methods of crop protection. Here we present Aurora kinase from the phytopathogenic fungus Ustilago maydis as a novel target for N substituted diaminopyrimidines, a class of small-molecule kinase inhibitors. We show that Aurora kinase is essential in U. maydis and that diaminopyrimidines inhibit its activity in vitro. Furthermore, we observed an overall good correlation between in vitro inhibition of Aurora kinase and growth inhibition of diverse fungi in vivo. In vitro inhibition assays with Ustilago and human Aurora kinases indicate that some compounds of the N-substituted diaminopyrimidine class show specificity for the Ustilago enzyme, thus revealing their potential as selective fungicides. PMID- 21671624 TI - Super flexibility of a 2D Cu-based porous coordination framework on gas adsorption in comparison with a 3D framework of identical composition: framework dimensionality-dependent gas adsorptivities. AB - Selective synthetic routes to coordination polymers [Cu(bpy)(2)(OTf)(2)](n) (bpy = 4,4'-bipyridine, OTf = trifluoromethanesulfonate) with 2- and 3 dimensionalities of the frameworks were established by properly choosing each different solvent-solution system. They show a quite similar local coordination environment around the Cu(II) centers, but these assemble in a different way leading to the 2D and 3D building-up structures. Although the two kinds of porous coordination polymers (PCPs) both have flexible frameworks, the 2D shows more marked flexibility than the 3D, giving rise to different flexibility-associated gas adsorption behaviors. All adsorption isotherms for N(2), CO(2), and Ar on the 3D PCP are of type I, whereas the 2D PCP has stepwise gas adsorption isotherms, also for CH(4) and water, in addition to these gases. The 3D structure, having hydrophilic and hydrophobic pores, shows the size-selective and quadrupole surface electrical field interaction dependent adsorption. Remarkably, the 2D structure can accommodate greater amounts of gas molecules than that corresponding to the inherent crystallographic void volume through framework structural changes. In alcohol adsorption isotherms, however, the 2D PCP changes its framework structure through the guest accommodation, leading to no stepwise adsorption isotherms. The structural diversity of the 2D PCP stems from the breathing phenomenon and expansion/shrinkage modulation. PMID- 21671623 TI - Probing the reaction mechanism of spore photoproduct lyase (SPL) via diastereoselectively labeled dinucleotide SP TpT substrates. AB - 5-Thyminyl-5,6-dihydrothymine (commonly called spore photoproduct or SP) is the exclusive DNA photodamage product in bacterial endospores. It is generated in the bacterial sporulation phase and repaired by a radical SAM enzyme, spore photoproduct lyase (SPL), at the early germination phase. SPL utilizes a special [4Fe-4S] cluster to reductively cleave S-adenosylmethionine (SAM) to generate a reactive 5'-dA radical. The 5'-dA radical is proposed to abstract one of the two H-atoms at the C6 carbon of SP to initiate the repair process. Via organic synthesis and DNA photochemistry, we selectively labeled the 6-H(proS) or 6 H(proR) position with a deuterium in a dinucleotide SP TpT substrate. Monitoring the deuterium migration in enzyme catalysis (employing Bacillus subtilis SPL) revealed that it is the 6-H(proR) atom of SP that is abstracted by the 5'-dA radical. Surprisingly, the abstracted deuterium was not returned to the resulting TpT after enzymatic catalysis; an H-atom from the aqueous buffer was incorporated into TpT instead. This result questions the currently hypothesized SPL mechanism which excludes the involvement of protein residue(s) in SPL reaction, suggesting that some protein residue(s), which is capable of exchanging a proton with the aqueous buffer, is involved in the enzyme catalysis. Moreover, evidence has been obtained for a possible SAM regeneration after each catalytic cycle; however, such a regeneration process is more complex than currently thought, with one or even more protein residues involved as well. These observations have enabled us to propose a modified reaction mechanism for this intriguing DNA repair enzyme. PMID- 21671628 TI - Stabilization principles for polar surfaces of ZnO. AB - ZnO is a wide band gap metal oxide with a very interesting combination of semiconducting, transparent optical and catalytic properties. Recently, an amplified interest in ZnO has appeared due to the impressive progress made in nanofabrication of tailored ZnO nanostructures and functional surfaces. However, the fundamental principles governing the structure of even the clean low-index ZnO surfaces have not been adequately explained. From an interplay of high resolution scanning probe microscopy (SPM), X-ray photoelectron spectroscopy (XPS), near edge X-ray absorption fine structure (NEXAFS) spectroscopy experiments, and density functional theory (DFT) calculations, we identify here a group of hitherto unresolved surface structures which stabilize the clean polar O terminated ZnO(0001) surface. The found honeycomb structures are truly remarkable since their existence deviates from expectations using a conventional electrostatic model which applies to the opposite Zn-terminated (0001) surface. As a common principle, the differences for the clean polar ZnO surfaces are explained by a higher bonding flexibility of the exposed 3-fold coordinated surface Zn atoms as compared to O atoms. PMID- 21671629 TI - Evaluating microcystin exposure risk through fish consumption. AB - Microcystin is a cyanobacterial hepatotoxin that is found worldwide, and poses a serious threat to the ecological communities in which it is found as well as to those who rely on these waters for drinking, sanitation, or as a food source. Microcystin is known to accumulate in fish and other aquatic biota, however the prevalence of microcystin in fish tissue and the human health risks posed by microcystin exposure through fish consumption remain poorly resolved. Here we show that microcystin is pervasive in water and fish from several tropical (Ugandan) and temperate (North American) lakes, including lakes that support some of the largest freshwater fisheries in the world. We establish that fish consumption can be an important and sometimes dominant route of microcystin exposure for humans, and can cause consumers to exceed recommended total daily intake guidelines for microcystin. These results highlight the importance of monitoring microcystin concentrations in fish, and the need to consider potential exposure to microcystin through fish consumption in order to adequately assess human exposure risk. PMID- 21671630 TI - sp3 C-H bond activation with ruthenium(II) catalysts and C(3)-alkylation of cyclic amines. AB - A selective C(3)-alkylation via activation/functionalization of sp(3) C-H bond of saturated cyclic amines was promoted by (arene)ruthenium(II) complexes featuring a bidentate phosphino-sulfonate ligand upon reaction with aldehydes. This highly regioselective sustainable transformation takes place via initial dehydrogenation of cyclic amines and hydrogen autotransfer processes. PMID- 21671631 TI - Fast nuclear spin conversion in water clusters and ices: a matrix isolation study. AB - Single water molecules have been isolated in solid Ar matrices at 4 K and studied by rovibrational spectroscopy using FTIR in the regions of the nu(1), nu(2), and nu(3) modes. Upon nuclear spin conversion at 4 K, essentially pure para-H(2)O was prepared, followed by subsequent fast annealing generating ice particles. FTIR studies of the vapor above the condensed water upon annealing to T >= 250 K indicate fast reconversion of nuclear spin to equilibrium conditions. Our results indicate that nuclear spin conversion is fast in water dimers and larger clusters, which preclude preparation of concentrated samples of para-H(2)O, such as in ice or vapor. PMID- 21671632 TI - Asymmetric synthesis of chiral delta-lactones containing multiple contiguous stereocenters. AB - A versatile methodology for the asymmetric synthesis of chiral delta-lactones containing multiple contiguous stereocenters has been developed that relies on a series of Evans' aldol, hydroxyl-directed cyclopropanation, methanolysis, and Hg(II) mediated cyclopropane ring-opening reactions for stereocontrol. PMID- 21671633 TI - Chemistry-based risk assessment for skin sensitization: quantitative mechanistic modeling for the S(N)Ar domain. AB - There is a strong impetus to develop nonanimal based methods to predict skin sensitization potency. An approach based on physical organic chemistry, whereby chemicals are classified into reaction mechanistic domains and quantitative models or read-across methods are derived for each domain, has been the basis of several recent publications. This article is concerned with the S(N)Ar reaction mechanistic domain. Electrophiles able to react by the S(N)Ar mechanism have long been recognized as skin sensitizers and have been used extensively in research studies on the biology of skin sensitization. Although qualitative discriminant analysis approaches have been developed for estimating the sensitization potential for S(N)Ar electrophiles on a yes/no qualitative basis, no quantitative mechanistic model (QMM) has so far been developed for this domain. Here, we derive a QMM that correlates skin sensitization potency, quantified by murine local lymph node assay (LLNA) EC3 data on a range of S(N)Ar electrophiles. It is based on the Hammett sigma(-) values for the activating groups and the Taft sigma* value for the leaving group. The model takes the form pEC3=2.48 Sigmasigma(-) + 0.60 sigma* - 4.51. This QMM, generated from mouse LLNA data, provides a reactivity parameter 2.48 Sigmasigma(-) + 0.60 sigma*, which was applied to a set of 20 compounds for which guinea pig test results were available in the literature and was found to successfully discriminate the sensitizers from the nonsensitizers. The reactivity parameter correctly predicted a known human sensitizer 2,4-dichloropyrimidine. New LLNA data on two further S(N)Ar electrophiles are consistent with the QMM. PMID- 21671634 TI - Supplementation of hydroxypropyl methylcellulose into yeast leavened all-whole grain barley bread potentiates cholesterol-lowering effect. AB - We investigated in Syrian Golden hamsters the biological impact and its underlying mechanism of single whole grain breads supplemented with 2-3% hydroxypropyl methylcellulose (HPMC), a semisynthetic viscous soluble dietary fiber (SDF) as a substitute for gluten. Hamsters were fed high-fat diets supplemented with 48-65% (w/w) differently ground, freeze-dried single grain breads including whole grain wheat, barley, barley supplemented with HPMC, debranned oat, and oat supplemented with HPMC which were compared to a diet containing microcrystalline cellulose (control). All single grain breads significantly lowered plasma LDL-cholesterol concentrations compared to the control. Enrichment with HPMC further lowered plasma and hepatic cholesterol concentrations. Despite the reduced molecular weight of naturally occurring soluble (1--->3),(1--->4)-beta-d-glucan (beta-glucan) caused by the bread-making process, whole grain barley breads downregulated hepatic expression of CYP7A1 and HMG-CoAR genes that are responsible for bile acid and cholesterol synthesis, suggesting a possible role of bioactive compounds such as short-chain fatty acids and phenolic compounds from barley bread. Barley bread enriched with HPMC downregulated expression of ABCG5 gene. Taken together, it appears that distinctive modulation of synthesis and excretion of hepatic cholesterol and bile acid contributes to the cholesterol-lowering properties of whole grain barley breads and breads enriched with HPMC. These data suggests that alternative whole grain breads supplemented with HPMC may provide consumers with a staple food that can assist in cholesterol management. PMID- 21671635 TI - A computational approach to design and evaluate enzymatic reaction pathways: application to 1-butanol production from pyruvate. AB - We present a new computational strategy for the design and evaluation of novel enzymatic pathways for the biosynthesis of fuels and chemicals. The approach combines the use of the Biochemical Network Integrated Computational Explorer (BNICE) framework and a structure-based screening method for rapid generation and evaluation of novel enzymatic reactions and pathways. The strategy is applied to a case study of 1-butanol production from pyruvate, which yielded nine novel biosynthetic pathways. Using screening criteria based on pathway length, thermodynamic feasibility, and metabolic flux analysis, all nine novel pathways were deemed to be attractive candidates. To further assess their feasibility of implementation, we introduced a new screening criterion based on structural complementarity using molecular docking methods. We show that this approach correctly reproduces the native binding poses for a wide range of enzymes in key classes related to 1-butanol production and provides qualitative agreement with experimental measures of catalytic activity for different substrates. In addition, we show that the structure-based methods can be used to select specific proteins that may be promising candidates to catalyze novel reactions. PMID- 21671636 TI - Controlling the facial selectivity of asymmetric [4+2] cyclo-additions: a concise synthesis of the cis-decalin core structure of superstolides A and B. AB - Regio-, stereo-, and facial selective [4 + 2] cycloadditions between highly activated vinyl sulfones and 1,3-dienes derived from (R)-4-tert butyldimethylsilyloxy-2-cyclohexen-1-one provide a powerful approach for the asymmetric synthesis of compounds containing the bicyclo[2.2.2]octanone carbon skeleton. This new methodology has been successfully applied to the asymmetric synthesis of the cis-decalin core structure of the potent anticancer marine natural products superstolides A and B. PMID- 21671637 TI - Post-self-assembly covalent chemistry of discrete multicomponent metallosupramolecular hexagonal prisms. AB - The multicomponent coordination-driven self-assembly of hexakis[4-(4 pyridyl)phenyl]benzene, cis-(PEt(3))(2)Pt(II)(OTf)(2), and amine- or maleimide functionalized isophthalate forms discrete hexagonal prisms as single reaction products. The amino or maleimide groups decorating the isophthalate pillars of the prisms provide reactive sites for post-self-asssembly modifications. In this communication, we demonstrate that the hexagonal prisms can be functionalized without disrupting the prismatic cores, enabling the incorporation of new functionalities under mild conditions. PMID- 21671638 TI - Pd-catalyzed intramolecular oxidative C-H amination: synthesis of carbazoles. AB - A Pd-catalyzed oxidative C-H amination of N-Ts-2-arylanilines under ambient temperature using Oxone as an inexpensive, safe, and easy-to-handle oxidant has been developed. This process represents a green and practical method for the facile construction of carbazoles with a broad substrate scope and wide functional group tolerance. PMID- 21671639 TI - Ab initio study of hydroxyl torsional barriers and molecular properties of mono- and di-iodotyrosine. AB - Phenol rings with one or two iodine atoms bonded to ortho carbons are the essential organic source of iodine for living organisms. The salvage of this halogen fundamental for a variety of biological functions is accomplished through enzymatic processes that rely on recognition of mono- and di-iodotyrosine (MIT and DIT, respectively). Ab initio quantum calculations are used to investigate molecular properties of MIT and DIT associated with their recognition by cognate proteins. Energies, electron density properties, atomic charges, and electrostatic potentials are analyzed in relation with the presence of one or two iodine atoms and internal rotation of hydroxyl hydrogen. The formation of an intramolecular hydrogen bond at some conformations has little effect on the properties that might affect the recognition and further deiodination of MIT and DIT. Polarizability of iodine and the reactive nature of iodinated tyrosines as nucleophilic targets are the essential features revealed in this work. PMID- 21671640 TI - Size-dependent hydrogen storage properties of Mg nanocrystals prepared from solution. AB - Mg nanocrystals of controllable sizes were prepared in gram quantities by chemical reduction of magnesocene using a reducing solution of potassium with an aromatic hydrocarbon (either biphenyl, phenanthrene, or naphthalene). The hydrogen sorption kinetics were shown to be dramatically faster for nanocrystals with smaller diameters, although the activation energies calculated for hydrogen absorption (115-122 kJ/mol) and desorption (126-160 kJ/mol) were within previously measured values for bulk Mg. This large rate enhancement cannot be explained by the decrease in particle size alone but is likely due to an increase in the defect density present in smaller nanocrystals. PMID- 21671641 TI - Redox control for electrochemical dechlorination of trichloroethylene in bicarbonate aqueous media. AB - The role of iron anode on electrochemical dechlorination of aqueous trichloroethylene (TCE) is evaluated using batch mixed-electrolyte experiments. A significantly higher dechlorination rate, up to 99%, is reported when iron anode and copper foam cathodes are used. In contrast to the oxygen-releasing inert anode, the cast iron anode generates ferrous species, which regulate the electrolyte to a reducing condition (low ORP value) and favor the reduction of TCE. The main products of TCE electrochemical reduction on copper foam cathode include ethene and ethane. The ratio of these two hydrocarbons gases varied with the electrolyte ORP condition and current density as more ethane gas generates at more reducing electrolyte condition and at higher current condition. A pseudofirst-order model is used to describe the degradation of TCE; the first order rate constant (k) increases with the current applied but exhibits a negative relation with initial concentration. Depending on the current, electrolysis by iron anode causes a reduction in the ORP and an increase in the pH of the mixed electrolyte. Enhanced reaction rates in this investigation indicate that the electrochemical reduction using copper foam and iron anode may be a promising process for remediation of groundwater contaminated with chlorinated organic compounds. PMID- 21671643 TI - Reactive tracer test to evaluate the fate of pharmaceuticals in rivers. AB - The fate of pharmaceutically active substances in rivers is still only incompletely understood, especially as the knowledge transfer from laboratory experiments to the real world is complicated by factors like turbidity, hydrodynamics, or heterogeneity. Therefore, we performed a tracer test with pharmaceutically active substances to study their fate and the importance of individual attenuation mechanisms in situ. The experiment was carried out at a small stream in central Sweden. Two dye tracers and six pharmaceuticals were injected as Dirac pulse and water was sampled at five downstream sites along a 16 km-long river reach. Ibuprofen and clofibric acid were the only compounds which were eliminated along the study reach at half-life times of 10 h and 2.5 d, respectively. Based on the shape of the breakthrough curves and the low hydraulic conductivity of the river bed, we can assume that exchange of river water with the hyporheic zone was minor. Thus, the contribution of processes in the hyporheic zone to the attenuation of pharmaceuticals was low. We hypothesize that ibuprofen and clofibric acid were transformed by in-stream biofilms growing on submerged macrophytes and at the water-sediment interface. Phototransformation and sorption were ruled out as major attenuation processes. No attenuation of bezafibrate, diclofenac, metoprolol, and naproxen was observed. PMID- 21671642 TI - Drug-induced protein free radical formation is attenuated by unsaturated fatty acids by scavenging drug-derived phenyl radical metabolites. AB - Aromatic amine drugs like aminoglutethimide (AG) and related congeners have been shown to produce phenyl radicals through metabolism by myeloperoxidase (MPO)/H(2)O(2), which has been proposed to play a role in drug-induced agranulocytosis. AG has also been shown to induce MPO protein radical formation, but the ultimate fate of these metabolically generated phenyl radicals is still unknown. We tested the reactivity of linoleic acid (LA) and GSH with aniline based compounds in the presence of horseradish peroxidase (HRP)/H(2)O(2) by measuring oxygen consumption. We found a qualitative correlation between drugs or xenobiotics that formed phenyl radical metabolites with the cooxidation of LA. Most compounds that reacted with LA did not react with GSH. Furthermore, an AG derived phenyl radical was detected by EPR spin-trapping with MNP (2-methyl-2 nitrosopropane), in a reaction containing AG and HRP/H(2)O(2); these spectra were attenuated in the presence of LA and docosahexaenoic acid (DHA) indicating that phenyl radical scavenging occurred. Since it has been proposed that the phenyl radical metabolite leads to protein radical formation on MPO, we investigated the effect of LA and DHA in immuno-spin trapping experiments with MPO-containing HL 60 cell lysate. Using anti-DMPO, a protein radical was detected on a putative MPO fragment from the reaction of DMPO, AG, and glucose/glucose oxidase. When LA or DHA was included in this reaction, protein radical formation was significantly inhibited. Our results show that certain polyunsaturated fatty acids (PUFAs) act as scavengers of aromatic amine drug-derived phenyl radicals which in turn prevent protein radical formation. However, the interaction of phenyl radical drug metabolites with PUFAs will be dictated by their relative concentrations compared to those of other targets. Most importantly, it is possible to differentiate peroxidase substrates that generate phenyl radical metabolites from N-centered radicals on the basis of their reactivity toward GSH vs PUFAs, and PUFAs are targets for metabolically generated phenyl radicals. PMID- 21671644 TI - Hydrothermal carbonization of municipal waste streams. AB - Hydrothermal carbonization (HTC) is a novel thermal conversion process that can be used to convert municipal waste streams into sterilized, value-added hydrochar. HTC has been mostly applied and studied on a limited number of feedstocks, ranging from pure substances to slightly more complex biomass such as wood, with an emphasis on nanostructure generation. There has been little work exploring the carbonization of complex waste streams or of utilizing HTC as a sustainable waste management technique. The objectives of this study were to evaluate the environmental implications associated with the carbonization of representative municipal waste streams (including gas and liquid products), to evaluate the physical, chemical, and thermal properties of the produced hydrochar, and to determine carbonization energetics associated with each waste stream. Results from batch carbonization experiments indicate 49-75% of the initially present carbon is retained within the char, while 20-37% and 2-11% of the carbon is transferred to the liquid- and gas-phases, respectively. The composition of the produced hydrochar suggests both dehydration and decarboxylation occur during carbonization, resulting in structures with high aromaticities. Process energetics suggest feedstock carbonization is exothermic. PMID- 21671645 TI - Spatiotemporal aspects of real-time PM(2.5): low- and middle-income neighborhoods in Bangalore, India. AB - We measured outdoor fine particulate matter (PM(2.5)) concentrations in a low- and a nearby middle-income neighborhood in Bangalore, India. Each neighborhood included sampling locations near and not near a major road. One-minute average concentrations were recorded for 168 days during September 2008 to May 2009 using a gravimetric-corrected nephelometer. We also measured wind speed and direction, and PM(2.5) concentration as a function of distance from road. Average concentrations are 21-46% higher in the low- than in the middle-income neighborhood, and exhibit differing spatiotemporal patterns. For example, in the middle-income neighborhood, median concentrations are higher near-road than not near-road (56 versus 50 MUg m(-3)); in the low-income neighborhood, the reverse holds (68 MUg m(-3) near-road, 74 MUg m(-3) not near-road), likely because of within-neighborhood residential emissions (e.g., cooking; trash combustion). A moving-average subtraction method used to infer local- versus urban-scale emissions confirms that local emissions are greater in the low-income neighborhood than in the middle-income neighborhood; however, relative contributions from local sources vary by time-of-day. Real-time relative humidity correction factors are important for accurately interpreting real-time nephelometer data. PMID- 21671646 TI - Environmental consequences of future biogas technologies based on separated slurry. AB - This consequential life cycle assessment study highlights the key environmental aspects of producing biogas from separated pig and cow slurry, a relatively new but probable scenario for future biogas production, as it avoids the reliance on constrained carbon cosubstrates. Three scenarios involving different slurry separation technologies have been assessed and compared to a business-as-usual reference slurry management scenario. The results show that the environmental benefits of such biogas production are highly dependent upon the efficiency of the separation technology used to concentrate the volatile solids in the solid fraction. The biogas scenario involving the most efficient separation technology resulted in a dry matter separation efficiency of 87% and allowed a net reduction of the global warming potential of 40%, compared to the reference slurry management. This figure comprises the whole slurry life cycle, including the flows bypassing the biogas plant. This study includes soil carbon balances and a method for quantifying the changes in yield resulting from increased nitrogen availability as well as for quantifying mineral fertilizers displacement. Soil carbon balances showed that between 13 and 50% less carbon ends up in the soil pool with the different biogas alternatives, as opposed to the reference slurry management. PMID- 21671647 TI - Carbon dioxide capture by functionalized solid amine sorbents with simulated flue gas conditions. AB - A novel solid amine sorbent was prepared using KIT-6-type mesoporous silica modified with tetraethylenepentamine (TEPA). Its adsorption behavior toward CO(2) from simulated flue gases is investigated using an adsorption column. The adsorption capacities at temperatures of 303, 313, 333, 343, and 353 K are 2.10, 2.29, 2.58, 2.85, and 2.71 mmol g(-1), respectively. Experimental adsorption isotherms were obtained, and the average isosteric heat of adsorption was 43.8 kJ/mol. The adsorption capacity increases to 3.2 mmol g(-1) when the relative humidity (RH) of the simulated flue gas reaches 37%. The adsorption capacity is inhibited slightly by the presence of SO(2) at concentrations lower than 300 ppm but is not significantly influenced by NO at concentrations up to 400 ppm. The adsorbent is completely regenerated in 10 min at 393 K and a pressure of 5 KPa, with expected consumption energy of about 1.41 MJ kg(-1) CO(2). The adsorption capacity remains almost the same after 10 cycles of adsorption/regeneration with adsorption conditions of 10 vol % CO(2), 100 ppm SO(2), 200 ppm NO, 100% relative humidity, and a temperature of 393 K. The solid amine sorbent, KIT-6(TEPA), performs excellently for CO(2) capture and its separation from flue gas. PMID- 21671648 TI - Photo retro-Diels-Alder reactions. AB - Photo-retro-Diels-Alder (PrDA) reactions of a variety of Diels-Alder (DA) adducts were studied. Experimental results showed that the photoreactivity (quantum yield) depends on the electron-donating ability of the diene component and the electron-withdrawing ability of the dienophile component. The mechanism was studied by trapping the reaction intermediate, O(2) quenching, time-resolved absorption, and fluorescence spectroscopy. All the results support a mechanism that involves a charge-separated intermediate generated from a singlet excited state. The PrDA reaction may find applications in photoresponsive materials, photolithography, drug delivery, and mechanistic research. PMID- 21671649 TI - On-site measurement of trace-level sulfide in natural waters by vapor generation and microchannel collection. AB - Aqueous sulfide plays an important role in the environment even at low concentrations. However, it is unstable, which means field samples cannot be transported to the laboratory for analysis without fixation. In this work, a novel method was developed to determine trace levels of sulfide on site. This method is based on vapor generation and collection in a special microchannel device followed by fluorescence measurement (VG-MUGAS). The microchannel scrubber gave a high enrichment factor, and a high sensitivity was achieved, which allowed measurement of nanomolar (nM) levels of sulfide. The theoretical approach to vapor generation for several compounds is discussed to evaluate the applicability of the method to these analytes, and compounds having a low Henry's law constant (<1 M atm(-1)) are suitable to measure by VG-MUGAS. Under optimized conditions, concentrations of 1.0-100 nM of sulfide could be measured. The sulfide contents of hot spring, aquarium, pond, and seawater were successfully measured by this method. Nanomolar levels of sulfide could be measured on site without loss of analyte, and results were obtained instantly in the field, both of which are advantageous for effective field surveys. The method was also applied to field measurements of aqueous sulfide in the Ariake Sea and Lake Baikal. PMID- 21671650 TI - Measuring electron and hole transfer in core/shell nanoheterostructures. AB - Using femtosecond transient absorption and time-resolved photoluminescence spectroscopy, we studied the electron versus hole dynamics in photoexcited quasi type-II heterostructured nanocrystals with fixed CdTe core radii and varying CdSe shell coverage. By choosing the pump wavelength in resonance with the core or the shell states, respectively, we were able to measure the excited electron and hole dynamics selectively. Both, the core- and the shell-excited CdTe/CdSe nanocrystals showed the same spectral emission and photoluminescence lifetimes, indicating that ultrafast electron and hole transfer across the core/shell interface resulted in the identical long-lived charge transfer state. Both charge carriers have subpicosecond transfer rates through the interface, but the subsequent relaxation rates of the hole (tau(dec) ~ 800 ps) and electron (tau(avg) ~ 8 ps) are extremely different. On the basis of the presented transient absorption measurements and fitting of the steady-state spectra, we find that the electron transfer occurs in the Marcus inverted region and mixing between the CdTe exciton and charge transfer states takes place and therefore needs to be considered in the analysis. PMID- 21671651 TI - Remediation of contaminated marine sediment using thin-layer capping with activated carbon--a field experiment in Trondheim harbor, Norway. AB - In situ amendment of contaminated sediments using activated carbon (AC) is a recent remediation technique, where the strong sorption of contaminants to added AC reduces their release from sediments and uptake into organisms. The current study describes a marine underwater field pilot study in Trondheim harbor, Norway, in which powdered AC alone or in combination with sand or clay was tested as a thin-layer capping material for polycyclic aromatic hydrocarbon (PAH) contaminated sediment. Several novel elements were included, such as measuring PAH fluxes, no active mixing of AC into the sediment, and the testing of new manners of placing a thin AC cap on sediment, such as AC+clay and AC+sand combinations. Innovative chemical and biological monitoring methods were deployed to test capping effectiveness. In situ sediment-to-water PAH fluxes were measured using recently developed benthic flux chambers. Compared to the reference field, AC capping reduced fluxes by a factor of 2-10. Pore water PAH concentration profiles were measured in situ using a new passive sampler technique, and yielded a reduction factor of 2-3 compared to the reference field. The benthic macrofauna composition and biodiversity were affected by the AC amendments, AC + clay having a lower impact on the benthic taxa than AC-only or AC + sand. In addition, AC + clay gave the highest AC recoveries (60% vs 30% for AC-only and AC + sand) and strongest reductions in sediment-to-water PAH fluxes and porewater concentrations. Thus, application of an AC-clay mixture is recommended as the optimal choice of the currently tested thin-layer capping methods for PAHs, and more research on optimizing its implementation is needed. PMID- 21671652 TI - Morphology-controllable synthesis of cobalt oxalates and their conversion to mesoporous Co3O4 nanostructures for application in supercapacitors. AB - In this work, one-dimensional and layered parallel folding of cobalt oxalate nanostructures have been selectively prepared by a one-step, template-free, water controlled precipitation approach by simply altering the solvents used at ambient temperature and pressure. Encouragingly, the feeding order of solutions played an extraordinary role in the synthesis of nanorods and nanowires. After calcination in air, the as-prepared cobalt oxalate nanostructures were converted to mesoporous Co(3)O(4) nanostructures while their original frame structures were well maintained. The phase composition, morphology, and structure of the as obtained products were studied in detail. Electrochemical properties of the Co(3)O(4) electrodes were carried out using cyclic voltammetry (CV) and galvanostatic charge-discharge measurements by a three-electrode system. The electrochemical experiments revealed that the layered parallel folding structure of mesoporous Co(3)O(4) exhibited higher capacitance compared to that of the nanorods and nanowires. A maximum specific capacitance of 202.5 F g (-1) has been obtained in 2 M KOH aqueous electrolyte at a current density of 1 A g(-1) with a voltage window from 0 to 0.40 V. Furthermore, the specific capacitance decay after 1000 continuous charge-discharge cycles was negligible, revealing the excellent stability of the electrode. These characteristics indicate that the mesoporous Co(3)O(4) nanostructures are promising electrode materials for supercapacitors. PMID- 21671653 TI - Triangular trinuclear metal-N4 complexes with high electrocatalytic activity for oxygen reduction. AB - A new class of macrocyclic metal-N(4) complexes [MN(4)](n) (M = Co and Fe) were designed and synthesized based on a triangular ligand. Their unique triangular trinuclear structure provides a high density of active sites and facilitates the reduction of dioxygen via a four-electron pathway. Among them, a [CoN(4)](3)/C catalyst (20 wt %) exhibits high catalytic activity and long-time stability for the oxygen reduction reaction (ORR) in alkaline conditions, superior to the commercial Pt/C catalyst. Such structurally well-defined [MN(4)](n) complexes provide a platform for a new generation of nonprecious metal catalysts (NPMCs) for fuel cell applications. PMID- 21671654 TI - Conformational partitioning in pH-induced fluorescence of the kindling fluorescent protein (KFP). AB - Kindling fluorescent protein (KFP) is considered as a prospective fluorophore for high-resolution nanoscopy. Analysis of pH dependence of the absorption and fluorescence spectra of KFP in aqueous solutions prompted us to assume that a shift in conformational equilibrium is responsible for substantial enhancement of red fluorescence in KFP at alkaline pH. Variations in pH also resulted in noticeable shifts in band maxima for absorption, fluorescence excitation, and fluorescence emission. These observations can be interpreted as an appearance of pH-induced fluorescent conformational states of the protein. On the basis of the available crystal structures of the protein and the results of molecular modeling, we suggest that appearance of these pH-induced fluorescent states is due to changes in the hydrogen bond network around the chromophore moiety (but not the cromophore itself), especially those associated with the side chains of Cys62 and Ser158. We hypothesize that conformational partitioning and fluctuations in protein ionization at alkali pH play an essential role in the appearance of fluorescent properties of KFP. PMID- 21671655 TI - Detection of multiple disease indicators by an autonomous biomolecular computer. AB - The promise of biomolecular computers is their ability to interact with naturally occurring biomolecules, enabling in the future the development of context dependent programmable drugs. Here we show a context-sensing mechanism of a biomolecular automaton that can simultaneously sense different types of molecules, allowing future integration of biomedical knowledge on a broad range of molecular disease symptoms in the decision of a biomolecular computer to release a drug molecule. PMID- 21671656 TI - Reversible (de)protonation-induced valence inversion in mixed-valent diiron(II,III) complexes. AB - The coupling of electron and proton transfers is currently under intense scrutiny. This Communication reports a new kind of proton-coupled electron transfer within a homodinuclear first-row transition-metal complex. The triply bridged complex [Fe(III)(MU-OPh)(MU(2)-mpdp)Fe(II)(NH(2)Bn)] (1; mpdp(2-) = m phenylenedipropionate) bearing a terminal aminobenzyl ligand can be reversibly deprotonated to the anilinate complex 2 whose core [Fe(II)(MU-OPh)(MU(2) mpdp)Fe(III)(NHBn)] features an inversion of the iron valences. This observation is supported by a combination of UV-visible, (1)H NMR, and Mossbauer spectroscopic studies. PMID- 21671657 TI - Direct synthesis of Rev peptide-conjugated gold nanoparticles and their application in cancer therapeutics. AB - We have developed a simple approach for generating peptide-conjugated gold nanoparticles (AuNPs) from the Rev peptide and gold aqueous solution. The peptide functions as both a reducing agent and a capping molecule. AuNPs of various sizes (20-300 nm) and shapes (spheres, triangular plates, and polygons) can be obtained upon modulating the ratio of gold ions to the Rev peptide. Transmission electron microscopy, X-ray diffraction, and UV-vis spectroscopy were utilized to characterize these nanoparticles. Fourier-transform infrared and X-ray photoelectron spectroscopy measurements were performed to investigate chemical interactions between the Rev peptide and AuNPs. Lactate dehydrogenase and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays revealed that the Rev peptide-AuNP nanocomposites exhibited exceptionally high cytotoxic effects toward mouse ovarian surface epithelial cell lines, relative to the effects of equal doses of the free Rev peptide. Our study suggests a new way of utilizing biomolecule-conjugated AuNPs as potentially effective anticancer drugs. PMID- 21671658 TI - Comparative study of the phototoxicity of long-wavelength photosensitizers targeted by the MornigaG lectin. AB - Morniga G is a plant lectin selective for high density of tumor-associated carbohydrate T and Tn antigens on the surface of cells. The interaction of the protein with Tn induces its cell penetration. This property was used for targeting photosensitizers (consisting of the porphyrins TrMPyP and TPPS, the Al(III)-phthalocyanin AlPcS(4), and the chlorin e6) against leukemic Jurkat T cells after covalent coupling to the protein. The control of MornigaG/photosensitizer loading allowed the comparison of the toxicity of the different photosensitizer conjugates. Conjugate including a single AlPcS(4) per protein appeared promising, since it is poorly toxic when irradiated under white light, while it shows a strong phototoxicity (LD(50) = 4 nM) when irradiated in the therapeutic window, it preferentially kills cancerous lymphocytes, and the sugar binding specificity of the lectin part of the molecule remains unaltered. PMID- 21671659 TI - Graphene actuators: quantum-mechanical and electrostatic double-layer effects. AB - The electrochemical actuation of covalent carbon materials, such as graphene, immersed in liquid electrolytes has shown immense promise for a myriad of applications. To realize this potential, an intimate understanding of the physics behind the actuation is essential. With the use of ab initio density functional calculations, it is shown that the strain induced in monolayer graphene by the formation of an electrostatic double-layer (DL) is the dominant actuation mechanism. The DL-induced strain (~1%) is found to exceed the quantum-mechanical strain (~0.2%) due to charge injection only, for charges and electric potentials of greater than -0.08 e/C-atom and 1 V, respectively. Various methods of calculating the graphene atomic charges based on first principle charge densities are compared and contrasted. The electrochemical charge-strain and potential strain relationships for monolayer graphene are shown to be parabolic in nature. This study proves that the origin of the high electrochemical strains in covalent carbon materials is the electrostatic DL potential, and demonstrates the true viability of using monolayer graphene for nanoelectromechanical systems (NEMS) actuators. PMID- 21671660 TI - Visualizing zeptomole (electro)catalysis at single nanoparticles within an ensemble. AB - The relationship between the structural properties, such as the size and the shape, of a catalytic nanoparticle and its reactivity is a key concept in (electro)catalysis. Current understanding of this relationship is mainly derived from studies involving large ensembles of nanoparticles (NPs). However, the results necessarily reflect the average catalytic behavior of an ensemble, even though the properties of individual particles may vary widely. Here, we demonstrate a novel approach using scanning electrochemical cell microscopy (SECCM) to locate and map the reactivity of individual NPs within an electrocatalytic ensemble, consisting of platinum NPs supported on a single carbon nanotube. Significantly, our studies show that subtle variations in the morphology of NPs lead to dramatic changes in (potential-dependent) reactivity, which has important implications for the design and assessment of NP catalysts. The instrumental approach described is general and opens up new avenues of research in functional imaging, nanoscale electron transfer, and catalysis. PMID- 21671661 TI - Resolving the mystery of aqueous solutions of tertiary butyl alcohol. AB - We have resolved a long-standing issue in the discussion on the origin of the mesoscale inhomogeneities observed in aqueous solutions of tertiary butyl alcohol (TBA). We have shown that the formation of stable mesoscale particles (of about 100 nm in size) can be triggered by the addition of trace amounts of propylene oxide (an impurity expected to be present in all commercial samples of TBA) to a solution, which was previously filtered at a low temperature to remove these inhomogeneities. We hypothesize that these particles are aggregates of mixed clathrate-hydrates that are formed through the stabilization of fluctuations of the intrinsic structure in TBA aqueous solutions by the clathrate-forming ability of propylene oxide. PMID- 21671662 TI - Identification of calmodulin and MlcC as light chains for Dictyostelium myosin-I isozymes. AB - Dictyostelium discoideum express seven single-headed myosin-I isozymes (MyoA-MyoE and MyoK) that drive motile processes at the cell membrane. The light chains for MyoA and MyoE were identified by expressing Flag-tagged constructs consisting of the motor domain and the two IQ motifs in the neck region in Dictyostelium. The MyoA and MyoE constructs both copurified with calmodulin. Isothermal titration calorimetry (ITC) showed that apo-calmodulin bound to peptides corresponding to the MyoA and MyoE IQ motifs with micromolar affinity. In the presence of calcium, calmodulin cross-linked two IQ motif peptides, with one domain binding with nanomolar affinity and the other with micromolar affinity. The IQ motifs were required for the actin-activated MgATPase activity of MyoA but not MyoE; however, neither myosin exhibited calcium-dependent activity. A Flag-tagged construct consisting of the MyoC motor domain and the three IQ motifs in the adjacent neck region bound a novel 8.6 kDa two EF-hand protein named MlcC, for myosin light chain for MyoC. MlcC is most similar to the C-terminal domain of calmodulin but does not bind calcium. ITC studies showed that MlcC binds IQ1 and IQ2 but not IQ3 of MyoC. IQ3 contains a proline residue that may render it nonfunctional. Each long-tailed Dictyostelium myosin-I has now been shown to have a unique light chain (MyoB-MlcB, MyoC-MlcC, and MyoD-MlcD), whereas the short-tailed myosins-I, MyoA and MyoE, have the multifunctional calmodulin as a light chain. The diversity in light chain composition is likely to contribute to the distinct cellular functions of each myosin-I isozyme. PMID- 21671663 TI - Fingerprints for main varieties of argentinean wines: terroir differentiation by inorganic, organic, and stable isotopic analyses coupled to chemometrics. AB - Our main goal was to investigate if robust chemical fingerprints could be developed for three Argentinean red wines based on organic, inorganic, and isotopic patterns, in relation to the regional soil composition. Soils and wines from three regions (Mendoza, San Juan, and Cordoba) and three varieties (Cabernet Sauvignon, Malbec, and Syrah) were collected. The phenolic profile was determined by HPLC-MS/MS and multielemental composition by ICP-MS; (87)Sr/(86)Sr and delta(13)C were determined by TIMS and IRMS, respectively. Chemometrics allowed robust differentiation between regions, wine varieties, and the same variety from different regions. Among phenolic compounds, resveratrol concentration was the most useful marker for wine differentiation, whereas Mg, K/Rb, Ca/Sr, and (87)Sr/(86)Sr were the main inorganic and isotopic parameters selected. Generalized Procrustes analysis (GPA) using two studied matrices (wine and soil) shows consensus between them and clear differences between studied areas. Finally, we applied a canonical correlation analysis, demonstrating significant correlation (r = 0.99; p < 0.001) between soil and wine composition. To our knowledge this is the first report combining independent variables, constructing a fingerprint including elemental composition, isotopic, and polyphenol patterns to differentiate wines, matching part of this fingerprint with the soil provenance. PMID- 21671664 TI - Rheology of heterotypic collagen networks. AB - Collagen fibrils are the main structural element of connective tissues. In many tissues, these fibrils contain two fibrillar collagens (types I and V) in a ratio that changes during tissue development, regeneration, and various diseases. Here we investigate the influence of collagen composition on the structure and rheology of networks of purified collagen I and V, combining fluorescence and atomic force microscopy, turbidimetry, and rheometry. We demonstrate that the network stiffness strongly decreases with increasing collagen V content, even though the network structure does not substantially change. We compare the rheological data with theoretical models for rigid polymers and find that the elasticity is dominated by nonaffine deformations. There is no analytical theory describing this regime, hampering a quantitative interpretation of the influence of collagen V. Our findings are relevant for understanding molecular origins of tissue biomechanics and for guiding rational design of collagenous biomaterials for biomedical applications. PMID- 21671665 TI - Introducing a decomposition rate modifier in the Rothamsted Carbon Model to predict soil organic carbon stocks in saline soils. AB - Soil organic carbon (SOC) models such as the Rothamsted Carbon Model (RothC) have been used to estimate SOC dynamics in soils over different time scales but, until recently, their ability to accurately predict SOC stocks/carbon dioxide (CO(2)) emissions from salt-affected soils has not been assessed. Given the large extent of salt-affected soils (19% of the 20.8 billion ha of arable land on Earth), this may lead to miss-estimation of CO(2) release. Using soils from two salt-affected regions (one in Punjab, India and one in South Australia), an incubation study was carried out measuring CO(2) release over 120 days. The soils varied both in salinity (measured as electrical conductivity (EC) and calculated as osmotic potential using EC and water content) and sodicity (measured as sodium adsorption ratio, SAR). For soils from both regions, the osmotic potential had a significant positive relationship with CO(2)-C release, but no significant relationship was found between SAR and CO(2)-C release. The monthly cumulative CO(2)-C was simulated using RothC. RothC was modified to take into account reductions in plant inputs due to salinity. A subset of non-salt-affected soils was used to derive an equation for a "lab-effect" modifier to account for changes in decomposition under lab conditions and this modifier was significantly related with pH. Using a subset of salt-affected soils, a decomposition rate modifier (as a function of osmotic potential) was developed to match measured and modelled CO(2)-C release after correcting for the lab effect. Using this decomposition rate modifier, we found an agreement (R(2) = 0.92) between modelled and independently measured data for a set of soils from the incubation experiment. RothC, modified by including reduced plant inputs due to salinity and the salinity decomposition rate modifier, was used to predict SOC stocks of soils in a field in South Australia. The predictions clearly showed that SOC stocks are reduced in saline soils. Therefore both the decomposition rate modifier and plant input modifier should be taken into account when accounting for SOC turnover in saline soils. Since modeling has previously not accounted for the impact of salinity, our results suggest that previous predictions may have overestimated SOC stocks. PMID- 21671667 TI - Tributes to Victoria Buch. PMID- 21671666 TI - Long-wavelength absorbing and fluorescent chameleon labels for proteins, peptides, and amines. AB - Long-wavelength absorbing labels that change their color and fluorescence upon conjugation to proteins and other biomolecules provide two critical advantages over the wealth of conventional amine-reactive labels. At first, the progress of the labeling reaction can be monitored continuously either visually or by spectrometry without prior purification. Then, the labeled biomolecule can be investigated with red or near-infrared light, which minimizes background interference in biological samples. These unique characteristics are met by a group of long-wavelength absorbing cyanine dyes carrying a reactive chloro substituent for nucleophilic substitution with primary amines, which is accompanied by a color change from green to blue. In addition to this so-called chameleon effect, the dyes display an increase in fluorescence during the labeling reaction. Despite their structural similarity, the reactivity of the dyes differs strongly. The fastest labeling kinetics is observed with dye S 0378 as its five-membered ring affords a stabilizing effect on the intermediate carbocation during an S(N)1-type of nucleophilic substitution. The reaction mechanism of the amine-reactive cyanine dyes provides a blueprint for the design of future long-wavelength absorbing chameleon dyes. PMID- 21671668 TI - My sister Victoria. PMID- 21671671 TI - Non-joule heating of ice in an electric field. AB - We theoretically predict and calculate non-Joule heating/cooling caused by a direct electric current in ordinary crystalline ice Ih. The cause of this effect is related to partial ordering/disordering occurring in the proton subsystem of ice when protons either drift or diffuse in the ice. Depending on relative directions of the electric current and the configuration vector of ice, the non Joule effect can be either positive, that is, heat generation, or negative, that is, heat absorption, and its absolute magnitude is usually comparable with that of normal Joule heating. The magnitude of this phenomenon is also approximately inversely proportional to the ice temperature and, thus, is more pronounced at low temperatures. PMID- 21671672 TI - Diastereoselective aziridination of chiral electron-deficient olefins with N chloro-N-sodiocarbamates catalyzed by chiral quaternary ammonium salts. AB - Chiral quaternary ammonium salt-catalyzed diastereoselective aziridination of electron-deficient olefins that possess a chiral auxiliary with N-chloro-N sodiocarbamates was developed. The key to high stereoselectivity was found to be the employment of the "matching" stereochemical combination of chiral auxiliary/ammonium salt. For example, when 3-phenyl-(4R,7S)-4-methyl-7-isopropyl 4,5,6,7-tetrahydroindazole (L-menthopyrazole) as a chiral auxiliary and a cinchonidine-derived chiral ammonium salt as a catalyst were applied to the reaction system, perfect diastereoselectivity was realized. Furthermore, the preparation of enantiomerically pure aziridines by removal of the chiral auxiliary was demonstrated. PMID- 21671673 TI - Structure of long human telomeric RNA (TERRA): G-quadruplexes formed by four and eight UUAGGG repeats are stable building blocks. AB - The discovery of long RNA transcripts of telomeric repeats (TERRA) and their potential to form G-quadruplexes stimulated studies on the possible arrangements of G-quadruplexes along TERRA. Here we performed ribonuclease protection assay to investigate the structures formed by long human TERRA. We found that G quadruplexes comprising four and eight UUAGGG repeats were most resistant to RNase T1 digestion, presumably with the former adopting an all-parallel-stranded propeller-type conformation and the latter forming a structure with two tandemly stacked G-quadruplex subunits each containing three G-tetrad layers. Molecular dynamics simulations of eight-repeat human TERRA sequences consisting of different stacking interfaces between the two G-quadruplex subunits, i.e., 5'-5', 3'-3', 3'-5', and 5'-3', demonstrated stacking feasibility for all but the 5'-3' arrangement. A continuous stacking of the loop bases from one G-quadruplex subunit to the next was observed for the 5'-5' stacking conformation. We also put forward other possible stacking arrangements that involve more than one linker connecting the two G-quadruplex subunits. On the basis of these results, we propose a "beads-on-a-string"-like arrangement along human TERRA, whereby each bead is made up of either four or eight UUAGGG repeats in a one- or two-block G quadruplex arrangement, respectively. PMID- 21671674 TI - Introduction to enzymes in synthesis. PMID- 21671675 TI - Energy-water nexus for mass cultivation of algae. AB - Microalgae are currently considered a potential feedstock for the production of biofuels. This work addresses the energy needed to manage the water used in the mass cultivation of saline, eukaryotic algae grown in open pond systems. Estimates of both direct and upstream energy requirements for obtaining, containing, and circulating water within algae cultivation systems are developed. Potential productivities are calculated for each of the 48 states within the continental U.S. based on theoretical photosynthetic efficiencies, growing season, and total available land area. Energy output in the form of algal biodiesel and the total energy content of algal biomass are compared to energy inputs required for water management. The analysis indicates that, for current technologies, energy required for water management alone is approximately seven times greater than energy output in the form of biodiesel and more than double that contained within the entire algal biomass. While this analysis addresses only currently identified species grown in an open-pond system, the water management requirements of any algae system will be substantial; therefore, it is critical that an energy assessment of water management requirements be performed for any cultivation technology and algal type in order to fully understand the energy balance of algae-derived biofuels. PMID- 21671676 TI - Series assembly of microbial desalination cells containing stacked electrodialysis cells for partial or complete seawater desalination. AB - A microbial desalination cell (MDC) is a new approach for desalinating water based on using the electrical current generated by exoelectrogenic bacteria. Previously developed MDCs have used only one or two desalination chambers with substantial internal resistance, and used low salinity catholytes containing a buffered or acid solution. Here we show that substantially improved MDC performance can be obtained even with a nonbuffered, saline catholyte, by using an electrodialysis stack consisting of 5 pairs of desalting and concentrating cells. When 4 stacked MDCs were used in series (20 total pairs of desalination chambers), the salinity of 0.06 L of synthetic seawater (35 g/L NaCl) was reduced by 44% using 0.12 L of anode solution (2:1). The resistive loss in the electrodialysis stack was negligible due to minimization of the intermembrane distances, and therefore the power densities produced by the MDC were similar to those produced by single chamber microbial fuel cells (MFCs) lacking desalination chambers. The observed current efficiency was 86%, indicating separation of 4.3 pairs of sodium and chloride ions for every electron transferred through the circuit. With two additional stages (total of 3.8 L of anolyte), desalination was increased to 98% salt removal, producing 0.3 L of fresh water (12.6:1). These results demonstrate that stacked MDCs can be used for efficient desalination of seawater while at the same time achieving power densities comparable to those obtained in MFCs. PMID- 21671677 TI - Gravimetric analysis of the adsorption and desorption of CO2 on amine functionalized mesoporous silica mounted on a microcantilever array. AB - The kinetics of CO(2) adsorption and desorption over amine-functionalized mesoporous silica were investigated using silicon microcantilever arrays. Three types of mesoporous silica with different pore sizes were synthesized and functionalized with a variety of amine molecules. After depositing the silica sorbents onto the free end of each cantilever in an array, mass changes due to the adsorption and desorption of CO(2) were determined in situ with picogram sensitivity by measuring variations in the cantilever frequencies. The adsorption and desorption kinetics were found to be diffusion-controlled, and the kinetics were accelerated by increasing the temperature and pore size. The activation energies for adsorption and desorption of CO(2) were determined from Arrhenius plots. PMID- 21671678 TI - Biological mechanism for the toxicity of haloacetic acid drinking water disinfection byproducts. AB - The halogenated acetic acids are a major class of drinking water disinfection byproducts (DBPs) with five haloacetic acids regulated by the U.S. EPA. These agents are cytotoxic, genotoxic, mutagenic, and teratogenic. The decreasing toxicity rank order of the monohalogenated acetic acids (monoHAAs) is iodo- > bromo- >> chloroacetic acid. We present data that the monoHAAs inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity in a concentration dependent manner with the same rank order as above. The rate of inhibition of GAPDH and the toxic potency of the monoHAAs are highly correlated with their alkylating potential and the propensity of the halogen leaving group. This strong association between GAPDH inhibition and the monoHAA toxic potency supports a comprehensive mechanism for the adverse biological effects by this widely occurring class of regulated DBPs. PMID- 21671679 TI - Distinguishing homogeneous from heterogeneous catalysis in electrode-driven water oxidation with molecular iridium complexes. AB - Molecular water-oxidation catalysts can deactivate by side reactions or decompose to secondary materials over time due to the harsh, oxidizing conditions required to drive oxygen evolution. Distinguishing electrode surface-bound heterogeneous catalysts (such as iridium oxide) from homogeneous molecular catalysts is often difficult. Using an electrochemical quartz crystal nanobalance (EQCN), we report a method for probing electrodeposition of metal oxide materials from molecular precursors. Using the previously reported [Cp*Ir(H(2)O)(3)](2+) complex, we monitor deposition of a heterogeneous water oxidation catalyst by measuring the electrode mass in real time with piezoelectric gravimetry. Conversely, we do not observe deposition for homogeneous catalysts, such as the water-soluble complex Cp*Ir(pyr-CMe(2)O)X reported in this work. Rotating ring-disk electrode electrochemistry and Clark-type electrode studies show that this complex is a catalyst for water oxidation with oxygen produced as the product. For the heterogeneous, surface-attached material generated from [Cp*Ir(H(2)O)(3)](2+), we can estimate the percentage of electroactive metal centers in the surface layer. We monitor electrode composition dynamically during catalytic turnover, providing new information on catalytic performance. Together, these data suggest that EQCN can directly probe the homogeneity of molecular water-oxidation catalysts over short times. PMID- 21671680 TI - Stepwise synthesis of metal-organic frameworks: replacement of structural organic linkers. AB - We demonstrate how a single-crystal to single-crystal transformation resulting from bridging-linker replacement is possible in extended 2D and 3D metal-organic frameworks (MOFs) by introducing pillared paddlewheel MOF structures into a solution containing dipyridyl linkers. No lateral movement of the layers was observed during this transformation, creating a templating effect from the "parent" structure to the "daughter" structure. A previously unattainable structure was obtained by a two-step synthetic method utilizing the bridging linker replacement transformation method. Additionally, a bridging-linker insertion was observed when excess linker was used with the 2D MOF structure, inducing an overall 2D to 3D transformation. PMID- 21671681 TI - Thallium chalcohalides for X-ray and gamma-ray detection. AB - We report that the chalcohalide compound Tl(6)SeI(4) is a promising material for efficient X-ray and gamma-ray detection. This material has a higher figure of merit than the current state-of-the-art material for room-temperature operation, Cd(0.9)Zn(0.1)Te (CZT). We have synthesized high-quality single-crystalline wafers of Tl(6)SeI(4) with detector-grade resistivities and good carrier transport of both electrons and holes. We demonstrate that pulse height spectra recorded using Co-57 radiation show an energy resolution matching that of a commercial CZT detector material. PMID- 21671682 TI - Reaction-based fluorescent probes for selective imaging of hydrogen sulfide in living cells. AB - Hydrogen sulfide (H(2)S) is emerging as an important mediator of human physiology and pathology but remains difficult to study, in large part because of the lack of methods for selective monitoring of this small signaling molecule in live biological specimens. We now report a pair of new reaction-based fluorescent probes for selective imaging of H(2)S in living cells that exploit the H(2)S mediated reduction of azides to fluorescent amines. Sulfidefluor-1 (SF1) and Sulfidefluor-2 (SF2) respond to H(2)S by a turn-on fluorescence signal enhancement and display high selectivity for H(2)S over other biologically relevant reactive sulfur, oxygen, and nitrogen species. In addition, SF1 and SF2 can be used to detect H(2)S in both water and live cells, providing a potentially powerful approach for probing H(2)S chemistry in biological systems. PMID- 21671683 TI - Charge recombination time distributions in photosynthetic reaction centers exposed to alternating intervals of photoexcitation and dark relaxation. AB - The charge recombination lifetime of photosynthetic reaction centers (RCs) increases significantly upon lengthy illumination, revealing nonequilibrium structural transitions in the protein-cofactor system. This paper analyzes the charge recombination kinetics measured in isolated RCs following a systematic variation of actinic illumination times (pulses) from 0.1 s to hundreds of seconds. The maximum entropy method (MEM) was utilized for optimizing the fitting procedure to retrieve the relaxation spectrum from the experimental recombination kinetics curves. The MEM-assisted analysis reveals that each relaxation curve contains at least three peaks in the relaxation time-distribution domain. Two peaks are always observed, one near 0.1 s and the other near 1 s recombination times. A third peak appears after prolonged photoexcitation with a relaxation time significantly greater than 1 s, and the time of this peak increases further in recombination time as the photoexcitation pulse duration is increased. In addition to the shifts of the time constant distributions, the amplitudes of the distributions in the time domain spectrum demonstrate a variation in the quinone occupancy of the RCs. The results reported here support our previous claim that accumulation of slow conformational changes, triggered by charge separation events in the RCs, controls system dynamics and favors stabilization of more efficient functioning regimes of the RCs. PMID- 21671684 TI - Steric effect in the energy transfer reaction of oriented CO (a 3Pi, v'=0, Omega=1 and 2) + NO (X 2Pi) -> NO (A 2Sigma+, B 2Pi) + CO (X 1Sigma+). AB - The oriented CO (a (3)Pi, v' = 0, Omega = 1 and 2) beam has been prepared by using an electric hexapole and applied to the energy transfer reaction of CO (a (3)Pi, v' = 0, Omega = 1 and 2) + NO (X (2)Pi) -> NO (A (2)Sigma(+), B (2)Pi) + CO (X (1)Sigma(+)). The emission spectra of NO (A (2)Sigma(+), B(2)Pi) have been measured at three orientation configurations (C-end, O-end, random). The shape of the emission spectra (and/or the internal excitation of products) turns out to be insensitive to the molecular orientation. The vibrational distributions of NO (A (2)Sigma(+), v' = 0-2) and NO (B (2)Pi, v' = 0-2) are determined to be N(v'=0):N(v'=1):N(v'=2) = 1:0.40 +/- 0.05:0.10 +/- 0.05 and N(v'=0):N(v'=1):N(v'= 2) = 1:0.6 +/- 0.1:0.7 +/- 0.1, respectively, and the branching ratio gamma/beta [=NO (A (2)Sigma(+))/NO (B (2)Pi)] is estimated to be gamma/beta ~ 0.3 +/- 0.1 by means of spectral simulation. These vibrational distributions of NO (A, B) can be essentially attributed to the product-pair correlations between CO (X, v") and NO (A (2)Sigma(+), v' = 0-2), NO (B (2)Pi, v' = 0-2) due to energetic restriction under the vibrational distribution of CO (X, v") produced from the vertical transition of CO (a (3)Pi, v' = 0) -> CO (X, v") in the course of energy transfer. The steric opacity function has been determined at two wavelength regions: 220 < lambda < 290 nm [NO (A -> X) is dominant]; 320 < lambda < 400 nm [NO (B -> X) is dominant]. For both channels NO (A (2)Sigma(+), B(2)Pi), a significant CO (a (3)Pi) alignment effect is recognized; the largest reactivity at the sideways direction with the small reactivity at the molecular axis direction is observed. These CO (a (3)Pi) alignment effects can be essentially attributed to the steric asymmetry on two sets of molecular orbital overlap, [CO (2pi) + NO (6sigma (2pi))] and [CO (5sigma) + NO (1pi (2pi))]. All experimental observations support the electron exchange mechanism that is operative through the formation of a weakly bound complex OCNO. PMID- 21671685 TI - Reflections on the changing face of German pharmaceutical policy: how far is Germany from value-based pricing? PMID- 21671686 TI - Presenting evidence and summary measures to best inform societal decisions when comparing multiple strategies. AB - Multiple strategy comparisons in health technology assessment (HTA) are becoming increasingly important, with multiple alternative therapeutic actions, combinations of therapies and diagnostic and genetic testing alternatives. Comparison under uncertainty of incremental cost, effects and cost effectiveness across more than two strategies is conceptually and practically very different from that for two strategies, where all evidence can be summarized in a single bivariate distribution on the incremental cost-effectiveness plane. Alternative methods for comparing multiple strategies in HTA have been developed in (i) presenting cost and effects on the cost-disutility plane and (ii) summarizing evidence with multiple strategy cost-effectiveness acceptability (CEA) and expected net loss (ENL) curves and frontiers. However, critical questions remain for the analyst and decision maker of how these techniques can be best employed across multiple strategies to (i) inform clinical and cost inference in presenting evidence, and (ii) summarize evidence of cost effectiveness to inform societal reimbursement decisions where preferences may be risk neutral or somewhat risk averse under the Arrow-Lind theorem. We critically consider how evidence across multiple strategies can be best presented and summarized to inform inference and societal reimbursement decisions, given currently available methods. In the process, we make a number of important original findings. First, in presenting evidence for multiple strategies, the joint distribution of costs and effects on the cost-disutility plane with associated flexible comparators varying across replicates for cost and effect axes ensure full cost and effect inference. Such inference is usually confounded on the cost-effectiveness plane with comparison relative to a fixed origin and axes. Second, in summarizing evidence for risk-neutral societal decision making, ENL curves and frontiers are shown to have advantages over the CEA frontier in directly presenting differences in expected net benefit (ENB). The CEA frontier, while identifying strategies that maximize ENB, only presents their probability of maximizing net benefit (NB) and, hence, fails to explain why strategies maximize ENB at any given threshold value. Third, in summarizing evidence for somewhat risk-averse societal decision making, trade-offs between the strategy maximizing ENB and other potentially optimal strategies with higher probability of maximizing NB should be presented over discrete threshold values where they arise. However, the probabilities informing these trade-offs and associated discrete threshold value regions should be derived from bilateral CEA curves to prevent confounding by other strategies inherent in multiple strategy CEA curves. Based on these findings, a series of recommendations are made for best presenting and summarizing cost-effectiveness evidence for reimbursement decisions when comparing multiple strategies, which are contrasted with advice for comparing two strategies. Implications for joint research and reimbursement decisions are also discussed. PMID- 21671687 TI - Unit costs for delivery of antiretroviral treatment and prevention of mother-to child transmission of HIV: a systematic review for low- and middle-income countries. AB - As antiretroviral treatment (ART) for HIV/AIDS is scaled up globally, information on per-person costs is critical to improve efficiency in service delivery and to maximize coverage and health impact. The objective of this study was to review studies on unit costs for delivery of adult and paediatric ART per patient-year, and prevention of mother-to-child transmission (PMTCT) interventions per mother infant pair screened or treated, in low- and middle-income countries. A systematic review was conducted of English, French and Spanish publications from 2001 to 2009, reporting empirical costing that accounted for at least antiretroviral (ARV) medicines, laboratory testing and personnel. Expenditures were analysed by country-income level and cost component. All costs were standardized to $US, year 2009 values. Several sensitivity analyses were conducted. Analyses covered 29 eligible, comprehensive, costing studies. In the base case, in low-income countries (LIC), median ART cost per patient-year was $US792 (mean: 839, range: 682-1089); for lower-middle-income countries (LMIC), the median was $US932 (mean: 1246, range: 156-3904); and, for upper-middle-income countries (UMIC), the median was $US1454 (mean: 2783, range: 1230-5667). ARV drugs were the largest component of overall ART costs in all settings (64%, 50% and 47% in LIC, LMIC and UMIC, respectively). Of 26 ART studies, 14 reported the drug regimes used, and only one study explicitly reported second-line treatment costs. The second cost driver was laboratory cost in LIC and LMIC (14% and 20%), and personnel costs in UMIC (26%). Two ART studies specified the types of laboratory tests costed, and three studies specifically included above facility level personnel costs. Three studies reported detailed PMTCT costs, and three studies reported on paediatric ART. There is a paucity of data on the full unit costs for delivery of ART and PMTCT, particularly for LIC and middle-income countries. Heterogeneity in activities costed, and insufficient detail regarding components included in the costing, hampers standardization of unit cost measures. Evaluation of programme-level unit costs would benefit from international guidance on standardized costing methods, and expenditure categories and definitions. Future work should help elucidate the sources of the large variations in delivery unit costs across settings with similar income and epidemiological characteristics. PMID- 21671690 TI - Stimulating pharmaceutical innovation in the EU. PMID- 21671688 TI - A review of the costs and cost effectiveness of interventions in chronic kidney disease: implications for policy. AB - Given rising healthcare costs and a growing population of patients with chronic kidney disease (CKD), there is an urgent need to identify health interventions that provide good value for money. For this review, the English-language literature was searched for studies of interventions in CKD reporting an original incremental cost-utility (cost per QALY) or cost-effectiveness (cost per life year) ratio. Published cost studies that did not report cost-effectiveness or cost-utility ratios were also reviewed. League tables were then created for both cost-utility and cost-effectiveness ratios to assess interventions in patients with stage 1-4 CKD, waitlist and transplant patients and those with end-stage renal disease (ESRD). In addition, the percentage of cost-saving or dominant interventions (those that save money and improve health) was compared across these three disease categories. A total of 84 studies were included, contributing 72 cost-utility ratios, 20 cost-effectiveness ratios and 42 other cost measures. Many of the interventions were dominant over the comparator, indicating better health outcomes and lower costs. For the three disease categories, the greatest number of dominant or cost-saving interventions was reported for stage 1-4 CKD patients, followed by waitlist and transplant recipients and those with ESRD (91%, 87% and 55% of studies reporting a dominant or cost-saving intervention, respectively). There is evidence of opportunities to lower costs in the treatment of patients with CKD, while either improving or maintaining the quality of care. In order to realize these cost savings, efforts will be required to promote and effectively implement changes in treatment practices. PMID- 21671692 TI - Assessment of parents' preferences for the treatment of school-age children with ADHD: a discrete choice experiment. AB - OBJECTIVES: Treatment decisions for children with attention-deficit/hyperactivity disorder (ADHD) should include parents' preferences, since parents' acceptance and support are crucial for ensuring treatment adherence and, as a consequence, good clinical outcomes. Discrete choice experiments (DCEs, also known as conjoint experiences) are an important technique for identification and assessment of preferences for different treatment characteristics. In this study, a DCE was performed to analyze and to discuss parents' preferences regarding ADHD treatment for their school-aged children. METHODS: This article presents a mixed-method approach; qualitative and quantitative methods were used to ascertain the attributes that might influence a parent's choices for the optimal management of their child with ADHD. Parents of patients with ADHD in Germany completed a self administered survey. Relevant characteristics of an ideal ADHD treatment were collected by reviewing the literature and by conducting a qualitative study with focus groups. The study involved a subgroup of parents of school-age children aged 6-14 years (n = 121). Attitudes were measured and analyzed using a classic rating scale (5-point Likert format). Preferences were elicited using a DCE; scenarios were analyzed using a random-effects logit model. RESULTS: A total of 121 questionnaires were completed by caregivers (101 mothers, 16 fathers and four others) on behalf of their school-age children (6-14 years, 87% male). Six main attributes were investigated regarding their impact on parent preferences for ADHD treatment. While all were statistically significant in the DCE, improvements in the child's social situation (coefficient: 2.812; odds ratio: 16.64) and emotional state (coefficient: 1.610; odds ratio: 5.00) were rated as the most important by parents. CONCLUSION: The study provides a valuable insight into parents' preferences regarding treatment for their child with ADHD. If physicians can incorporate this information into their treatment plans for children with ADHD, greater concordance regarding treatment goals, adherence with therapy and, ultimately, clinical outcomes may be achieved. PMID- 21671689 TI - Long-term efficacy and tolerability of a fixed-dose combination of antihypertensive agents: an open-label surveillance study in China. AB - BACKGROUND: A fixed-dose combination (FDC) of four compounds, hydrochlorothiazide 12.5 mg, triamterene 12.5 mg, dihydralazine 12.5 mg and reserpine 0.1 mg (HTDR), is widely used as an antihypertensive treatment in China. Although HTDR has been used in China for more than 30 years, there have been few comprehensive evaluations of this treatment. OBJECTIVE: The aim of this study was to investigate the long-term efficacy and tolerability of HTDR in Chinese patients with essential hypertension. METHODS: This was a 36-month, community-based, open label surveillance study, conducted in the Huangpu District (Shanghai, China). The study was based in local primary healthcare settings. Subjects were recruited if they had essential hypertension, were aged >=35 years at the time of enrolment, were expected to remain in the area for 3 years, and were able to provide informed consent. Patients who had secondary hypertension, myocardial infarction or stroke within 6 months of screening, impaired renal or hepatic function, history of cardiomyopathy or chronic heart failure, or were pregnant or lactating were excluded. HTDR was administered as one or two tablets per day in the morning. If necessary, additional hydrochlorothiazide was added. Blood pressure (BP) was measured at baseline and throughout the 36-month surveillance period every 3 months. Biochemical indicators (e.g. fasting blood glucose, plasma lipid parameters, plasma sodium and potassium, plasma uric acid and serum creatinine) were also measured, and adverse events were noted. BP reductions and the rate at which patients achieved BP targets (systolic BP [SBP] <140 mmHg and diastolic BP [DBP] <90 mmHg) throughout the period were determined. Subgroup analyses by sex and age were also conducted. RESULTS: A total of 1529 patients (550 male, 979 female; mean age 65.7 years) entered the study. After the 36-month treatment period, 93.1% of patients had achieved the SBP target, 97.9% had achieved the DBP target, and 92.1% had achieved both. The mean decreases in SBP and DBP were 15.3 mmHg and 9.9 mmHg, respectively. Overall, 127 adverse events in 119 patients (7.8%) occurred during the follow-up period, most of which were mild to moderate. Plasma lipid profiles were improved after 24 months of treatment. In addition, a significant increase in plasma potassium and a significant reduction in plasma uric acid were seen. CONCLUSION: HTDR was found to have good long-term efficacy and tolerability in Chinese patients with essential hypertension. PMID- 21671693 TI - Pharmacoeconomic evidence of bosentan for pulmonary arterial hypertension. AB - In this article, we review randomized controlled trials, open-label trials and pharmacoeconomic models of bosentan for the management of patients with pulmonary arterial hypertension. Bosentan consistently improves WHO functional class and quality of life, slows clinical worsening and is associated with improved survival compared with historical treatment. Although head-to-head trials are scarce, data directly comparing bosentan with sildenafil indicate no clinically significant differences between treatments as measured by the 6-min walk distance alone. Compared with historical care, bosentan treatment, over a 15-30-year period, increases the number of quality-adjusted life years (3.49 years). Economic modeling suggests that the cost-effectiveness of bosentan is similar to that of ambrisentan (US$43,725-57,778 per quality-adjusted life year), not as cost effective as sildenafil (at 20 mg three-times daily) and more cost effective than iloprost. More randomized controlled trials of longer duration are required to confirm the results from these economic models. PMID- 21671694 TI - Second Conference of the African Health Economics and Policy Association: towards universal healthcare coverage in Africa. AB - This report discusses the key messages coming out of the papers presented at the second African Health Economics and Policy Association conference, with a particular focus on innovative and recent research results of interest to a wider audience. It also covers the scientific structure and organization of the conference, including the various sessions and key note speeches. The 3-day conference discussed the definition and scope as well as the key issues concerned, the challenges involved, and the role of leadership and country ownership in achieving universal health coverage in low-income countries. A special effort was also made to link the research outputs of the conference to policy-making in the region, through the participation of high-level decision makers from countries as well as the production of policy briefs targeting policy makers and based on the conference outputs and relevant research. Sub-themes of the conference included user fee removal and exemptions, covering those outside the formal sector, improved domestic funding of healthcare, purchasing of services and policy processes. The conference was attended by approximately 230 participants drawn from over 30 African countries as well as abroad, mostly from academia, research institutions, Ministries of Health and other relevant Government agencies, as well as donor and technical partners. PMID- 21671695 TI - Development and validation of a novel idiographic measure of cystectomy patients' goals and concerns before surgery. AB - Evaluation of: Morganstern BM, Bochner B, Dalbagni G, Shabsigh A, Rapkin B. The psychological context of quality of life: a psychometric analysis of a novel idiographic measure of bladder cancer patients' personal goals and concerns prior to surgery. Health Qual. Life Outcomes 9:10 (2011). Morganstern et al. presented a brief quality-of-life appraisal profile (BQOLAP) to measure the unique quality of-life concerns and issues of preoperative bladder cancer patients, setting the stage for future studies that would compare quality of life outcomes following reconstructive cystectomy surgery. Results from 50 patients with bladder cancer revealed 503 goal statements that were coded and developed into 40 content categories based on several overarching domains: motivational themes; health and treatment; functioning; mental health and perceptions; comfort and lifestyle; events; responsibilities; relationship and family; home and community; problems and conflicts; and other/nonanswer. Drawing from measures developed by Rapkin and colleagues, the BQOLAP was designed to prompt patients to create their own unique goals and activity statements and their subsequent ratings of goal-attainment activities, difficulty reaching their goals, support needed to reach their goals and self-ratings of how close they were to reaching their goals. PMID- 21671696 TI - Comparing meta-analyses for chronic obstructive pulmonary disease. AB - Evaluation of: Oppe M, Al M, Rutten-van Molken M. Comparing methods of data synthesis. Re-estimating parameters of an existing probabilistic cost effectiveness model. Pharmacoeconomics 29(3), 239-250 (2011). In the paper by Oppe et al., a cost-effectiveness analysis of alternative treatments for chronic obstructive pulmonary disease (COPD), based on data from four different trials, is considered. The goal is to compare the usual (frequentist and Bayesian) fixed effects (FE) and random-effects (RE) normal model for carrying out meta-analysis. Under RE and FE models, the meta-estimation of some quantities of interest for the disease are also carried out using three out of the four trials, and afterwards data from the fourth are incorporated into the meta-estimation. From these sequential estimators, some conclusions on the FE and RE procedures are drawn. Furthermore, as far as the cost-effectiveness is concerned, the main conclusion of the paper is that the Bayesian RE procedure overrides the Bayesian FE and frequentist methods for cost-effectiveness meta-analysis. PMID- 21671697 TI - Information disclosure to cancer patients: EORTC QLQ-INFO25 questionnaire. AB - Information is one of the main interventions given to cancer patients. Important research into information disclosure has been conducted and major advances have been made. We present the main theoretical models used to understand the information field and describe the current situation regarding the principal factors related to information: patients' needs, coping strategies, illness representations, cross-cultural differences, the role of the family, and strategies to enhance information giving, such as professional training and patient-targeted interventions. We highlight the need to assess patients' characteristics and desires through questionnaires and interviews and present the European Organisation for Research and Treatment of Cancer Quality of Life Group information questionnaire (EORTC QLQ-INFO 25). This instrument evaluates the level of information patients have received in different areas of their disease, treatment and care, and evaluates qualitative aspects. Finally, we describe the key areas of the information field and discuss how these areas could change in the future. PMID- 21671698 TI - Quality of life of women with lower-limb lymphedema following gynecological cancer. AB - Secondary lower-limb lymphedema can develop following treatment for gynecological cancers, and has debilitating effects on quality of life (QoL). Lymphedema can limit mobility and ability to perform daily activities, and have adverse effects on psychological and social wellbeing. When assessing the effect of lymphedema treatment methods, the focus is on change in clinically measured lymphedema status, rather than QoL outcomes. Considering that treatment for lymphedema involves a significant and ongoing commitment from patients, it is essential to determine whether the benefits to patients outweigh the burden associated with treatment. This article summarizes the results of studies assessing the impact of lower-limb lymphedema on QoL in women with gynecological cancer, evaluates their methodologies and discusses limitations and priorities for future research. PMID- 21671699 TI - Economic impact of venous thromboembolism after hip and knee arthroplasty: potential impact of rivaroxaban. AB - The number of total hip and knee arthroplasties is increasing, with a consequent rise in the number of patients at risk of venous thromboembolism. Each such event is associated with the risk of morbidity and mortality, plus substantial healthcare costs. Consequently, the American College of Chest Physicians guidelines recommend low-molecular-weight heparins, fondaparinux or vitamin K antagonists (usually warfarin) after total hip and knee arthroplasty. However, such agents are also associated with healthcare costs for administration and monitoring. New oral anticoagulants in development may reduce post-arthroplasty symptomatic thromboembolic events and produce potential savings for the healthcare system. This brief article outlines such potential savings with rivaroxaban based on the results of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) program. PMID- 21671700 TI - Trends in translation requests and arising issues regarding cultural adaptation. AB - Quality of life has become an important end point in clinical trials and academic studies. The questionnaires developed by the European Organisation for Research and Treatment of Cancer Quality of Life Group are widely used to measure quality of life in cancer patients. The expanding geographical coverage of current studies and trials implies a continuous rise in requests for new language versions of the questionnaires. Together with normal linguistic problems in translation, cultural differences come into play, especially in translations into non-European languages. Two types of such problems can be differentiated: first, specific issues related to culturally dependent activities or phenomena; second, topical issues related to taboos. These translation challenges have to be carefully addressed to ensure the equivalence and validity of the final questionnaires. PMID- 21671701 TI - Better guidelines for better care: enhancing the implementability of clinical practice guidelines. AB - The potential of clinical practice guidelines to promote evidence-based care has not been consistently realized. This article outlines how modifying guidelines, and specifically their implementability (the perceived characteristics that influence their use in practice), could be an inexpensive way to improve care. The article uses a planned action model, Graham's knowledge-to-action framework, to illustrate how this framework can be applied in the context of an ongoing research initiative. It describes each step from knowledge synthesis, to barrier analysis, intervention development and evaluation of a guideline implementability tool that could facilitate uptake of guidelines in clinical practice. This tool targets guideline developers, so that better guidelines may result in better care. PMID- 21671702 TI - Clinical and health economic outcomes of alternative HER2 test strategies for guiding adjuvant trastuzumab therapy. AB - AIM: To evaluate the clinical outcomes and cost-effectiveness of human epidermal growth factor receptor 2 (HER2) testing strategies to guide adjuvant trastuzumab (AT) therapy in women with HER2-positive breast cancer. METHODS: A literature review produced 72 studies comparing HER2 test methods, and we computed concordance (assuming fluorescence in situ hybridization [FISH] as a reference assay) to assess performance relative to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. An economic analysis provided cost-effectiveness of alternative strategies, including a Monte Carlo simulation to vary key assumptions such as test price and performance. RESULTS: Of 46 studies comparing immunohistochemistry (IHC) and FISH, only seven met the ASCO/CAP guideline of 95% or better concordance. A total of 14 out of 21 studies comparing chromogenic in situ hybridization and three out of five studies comparing silver-enhanced in situ hybridization met the guideline. Confirmation of IHC 2+ and 3+ and primary FISH strategies are likely to reduce costs and improve quality of life relative to confirmation of IHC 2+ only. Initial testing with a gene amplification-based assay is probably a cost-effective alternative to confirmation of IHC 2+ and 3+. The results are not sensitive to varying test price but are sensitive to test accuracy below 98%. CONCLUSION: Using a primary gene amplification-based assay to guide AT therapy for HER2-positive breast cancer probably results in lower US medical costs, increased life-years and increased quality of life compared with confirmation of IHC 2+ with a gene amplification-based assay. We recommend the ASCO/CAP guidelines reflect 98% or greater concordance relative to a reference assay. Additional research regarding therapy response is required to further differentiate between gene amplification based assays. PMID- 21671703 TI - European countries with small populations can obtain low prices for drugs: Lithuania as a case history. AB - OBJECTIVES: Assess whether European countries with smaller populations can obtain appreciable discounts for generics, similar to some of the larger European countries, to investigate the validity of recently published hypotheses. METHODS: Observational study involving all 3.4 million ambulatory care patients currently contained within the compulsory health insurance system in Lithuania among four drug classes, with a particular focus on generics. Utilization measured in defined daily doses (DDDs). Prices in terms of reimbursed expenditure/DDD. Reductions in reimbursed expenditure/DDD for generic proton pump inhibitors, statins, angiotensin-converting enzyme inhibitors and selective serotonin reuptake inhibitors in either 2007 or 2009 were compared with 2000 or 2001 originator prices, as well as a range of European countries. RESULTS: There was an appreciable reduction in reimbursed expenditure/DDD for generics in each drug class in Lithuania, such as 56% reduction for generic omeprazole, 65% for generic ramipril, 83% for generic simvastatin, 85% for generic sertraline and 87% for generic atorvastatin. This is despite appreciably lower utilization of proton pump inhibitors, statins and antidepressants in Lithuania versus Western European countries. Reductions in generic prices were similar to those among a range of European countries, with no apparent correlation between the number of competitors and price reductions in practice. CONCLUSION: European countries with smaller populations can obtain substantial reductions in prices of generics versus originators. This was seen in Lithuania among classes with currently limited utilization versus Western European countries, as well as those with similar utilization patterns. In addition, matching price reductions for generics were seen among Western European countries. Overall, our findings demonstrate that it is possible for European countries with smaller populations to engineer low prices with manufacturers. PMID- 21671704 TI - Willingness to pay to reduce alcohol-related harm in Australian rural communities. AB - A common metric is needed to compare the benefits of interventions to reduce alcohol misuse. Monetary value is one such metric that can be elicited using willingness to pay (WTP). This paper explores household WTP for reductions in alcohol-related harm in 20 rural Australian communities. Data were obtained from both postal and face-to-face questionnaires. The results indicate that those with friends or family drinking too much are willing to pay more to reduce alcohol caused harm, but there was no evidence to suggest those causing and experiencing the most alcohol-caused harm (drinking at high frequency and intensity) had a higher WTP. These findings can be compared with the cost of implementing interventions to determine whether they are likely to be welfare enhancing. PMID- 21671708 TI - The emerging role of the intestine in metabolic diseases. AB - The intestine is an important metabolic organ that has gained attention in recent years for the newly identified role that it plays in the pathophysiology of various metabolic diseases including obesity, insulin resistance and diabetes. Recent insights regarding the role of enteroendocrine hormones, such as GIP, GLP 1, and PYY in metabolic diseases, as well as the emerging role of the gut microbial community and gastric bypass bariatric surgeries in modulating metabolic function and dysfunction have sparked a wave of interest in understanding the mechanisms involved, in an effort to identify new therapeutics and novel regulators of metabolism. This review summarizes the current evidence that the gastrointestinal tract has a key role in the development of obesity, inflammation, insulin resistance and diabetes and discusses the possible players that can be targeted for therapeutic intervention. PMID- 21671709 TI - Mitochondrial pathophysiology and type 2 diabetes mellitus. AB - Over the last decades, substantial progress has been made in defining the molecular events and relevant tissues controlling insulin action and the potential defects that lead to insulin resistance and later on Type 2 diabetes mellitus (T2DM). Mitochondrial dysfunction has been postulated as a common mechanism implicated in the development of insulin resistance and T2DM aetiology. Since then there has been growing interest in this area of research and many studies have addressed whether mitochondrial function/dysfunction is implicated in the progression of T2DM or if it is just a consequence. Mitochondria are adjusted to the specific needs of the tissue and to the environmental interactions or pathophysiological state that it encounters. This review offers a current state of the subject in a tissue specific approach. We will focus our attention on skeletal muscle, liver, and white adipose tissue as the main insulin sensitive organs. Hypothalamic mitochondrial function will be also discussed. PMID- 21671710 TI - Eltrombopag for the treatment of immune thrombocytopenia. AB - Chronic immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a low platelet count that has persisted for more than 12 months. Patients with severe, symptomatic disease may have significant morbidity and require treatment. Historically, the underlying cause of ITP was believed to be accelerated platelet destruction by antiplatelet antibodies. Treatment options were therefore focused on reducing platelet autoantibody production or inhibiting macrophage-mediated platelet destruction. These treatments are not always effective or, at best, only have a transient effect and treatment-related adverse events often preclude their long-term use. Recently, impaired platelet production was observed in many ITP patients. Therefore, growth factor or growth factor analogs that stimulate megakaryopoiesis may be useful in ITP treatment. This article presents data on the pharmacology, clinical efficacy, safety profile and future roles of eltrombopag, an orally bioavailable, low-molecular-weight, synthetic nonpeptide thrombopoietin receptor agonist, in the treatment of ITP. PMID- 21671711 TI - Analysis of maxillary arch force/couple systems for a simulated high canine malocclusion: Part 2. Elastic ligation. AB - OBJECTIVE: To better understand the mechanics of bracket/archwire interaction through analysis of force and couple distribution along the maxillary arch using elastic ligation and to compare these results with passive ligation. MATERIALS AND METHODS: An orthodontic simulator was used to study a high canine malocclusion. Force and couple distributions produced by elastic ligation and round wire were measured. Forces and couples were referenced to the center of resistance of each tooth. Tests were repeated for 12 bracket sets with 12 wires per set. Data were compared with those derived from similar tests for passive ligation. RESULTS: Propagation of the force/couple systems around the arch using elastic ligation was extensive. Elastic ligation produced significantly more resistance to sliding, contributing to higher forces and couples at the center of resistance than were observed for passive ligation. CONCLUSIONS: The results of this study suggest some potential mechanical advantages of passive over elastic ligation. In particular, limited propagation around the arch in passive ligation reduces the occurrence of unwanted force/couple systems compared with elastic ligation. These advantages may not transfer to a clinical setting because of the conditions of the tests; additional testing would be required to determine whether these advantages can be generalized. PMID- 21671712 TI - Effects of cyclic loading on the bond strength of metal orthodontic brackets bonded to a porcelain surface using different conditioning protocols. AB - OBJECTIVE: To evaluate cyclic and static shear bond strengths (SSBSs) of metal orthodontic brackets bonded to a porcelain surface using different conditioning protocols. MATERIALS AND METHODS: A total of 100 feldspathic porcelain disks were fabricated. The specimens were divided into four equal groups. Porcelain surfaces were conditioned with different protocols. In group 1, hydrofluoric acid and Embrace First-Coat primer were used. In group 2, hydrofluoric acid and silane were utilized. In groups 3 and 4, sandblasting with aluminum oxide powder was done instead of etching. Metal brackets were bonded to the porcelain surfaces using Transbond XT adhesive. SSBS testing was carried out in 10 specimens, while cyclic shear bond strength (CSBS) testing was done in 15 specimens from each group. The data were subjected to analysis of variance, least significant difference post hoc, and Student's t-tests. RESULTS: Embrace First-Coat and silane exhibited a comparable SSBS. The sandblasting process significantly increased SSBS. No significant difference was found in bond SSBS utilizing either hydrofluoric acid and Embrace First-Coat or sandblasting and silane. With regard to CSBS, the use of sandblasting and Embrace First-Coat revealed the highest significant CSBS value, followed by sandblasting and silane. Etching with hydrofluoric acid prior to application of either primer exhibited the least CSBS values; however, no significant difference was found between them. The SSBS was significantly higher than CSBS. CONCLUSION: Embrace First-Coat could be used successfully as an alternative to silane. Sandblasting provides higher bond strength than did hydrofluoric acid. Cyclic loading significantly decreased bond strength. PMID- 21671713 TI - Effects of laser-aided circumferential supracrestal fiberotomy on root surfaces. AB - OBJECTIVE: To evaluate and compare the effects of circumferential supracrestal fiberotomy in vivo (using diode, CO(2), and Er?YAG lasers) on the morphology and chemical composition of the root surface. MATERIALS AND METHODS: Forty healthy premolar teeth, intended for extraction for orthodontic reasons, were used in this study. Root surfaces were treated using different laser methods, as follows: (1) control; (2) Er?YAG laser (2.94 um, 100 mJ, 10 Hz); (3) diode laser (808 nm, 1.2 W, continuous wave); and (4) CO(2) laser (10.6 um, 3 W, continuous wave). Subsequently, the teeth were removed and subjected to scanning electron microscopic (SEM) examination and energy dispersive x-ray (EDX) spectrometric analysis. RESULTS: SEM analysis indicated that no thermal changes, including melting or carbonization, were observed following the lasing procedures. EDX analysis showed that the laser procedures resulted in similar mineral contents (weight % of calcium and phosphate) as compared to those in the control group. CONCLUSION: Based on these findings, we concluded that laser-aided procedures, when used at appropriate laser settings, preserve the original morphology and chemical composition of cementum. PMID- 21671714 TI - Use of 18F-fluoride PET to determine the appropriate tissue sampling region for improved sensitivity of tissue examinations in cases of suspected periprosthetic infection after total hip arthroplasty. AB - BACKGROUND AND PURPOSE: The accurate diagnosis of periprosthetic infection requires assessment of intraoperative tissues. These must be sampled from the appropriate sites. We used (18)F-fluoride positron emission tomography (PET) to identify sites of inflammation in order to improve the sensitivity of histopathology, microbiological culture, and real-time PCR in total hip arthroplasty (THA) patients. PATIENTS AND METHODS: 23 THA patients (23 hips) scheduled for revision surgery (the revision group) and 17 uninfected THA patients (23 hips; control group) were enrolled. Uptake was classified into major, minor, and no uptake. To evaluate the association between the (18)F fluoride uptake and intraoperative tissue results in the revision group, we calculated their sensitivity on each of the major, minor, and no-uptake sides. RESULTS: 17 revision patients showed major uptake and all were diagnosed as having septic loosening from intraoperative tissue results. Minor uptake was observed in the other 6 revision patients and all were diagnosed as having aseptic loosening. Apart from 3 cases that showed minor uptake regions, control subjects showed no uptake. In the revision group, the sensitivities of histopathology, microbiological culture, real-time PCR separately and also in combination were 0.78, 0.58, 0.96, and 0.96, respectively, on the major (18)F fluoride uptake sides, 0.0, 0.0, 0.1, and 0.1 on the minor-uptake sides, and 0, 0, 0.18, and 0.18 on the no-uptake sides. INTERPRETATION: Our findings suggest that preoperative assessment of major uptake of (18)F-fluoride markedly improves the accuracy of tissue sampling, and thus the sensitivity of subsequent tissue examinations. More definitive diagnosis of periprosthetic infection is therefore possible. PMID- 21671715 TI - Sphaeridiotrema globulus and Sphaeridiotrema pseudoglobulus (Digenea): species differentiation based on mtDNA (Barcode) and partial LSU-rDNA sequences. AB - Flukes belonging to Sphaeridiotrema are important parasites of waterfowl, and 2 morphologically similar species Sphaeridiotrema globulus and Sphaeridiotrema pseudoglobulus, have been implicated in waterfowl mortality in North America. Cytochrome oxidase I (barcode region) and partial LSU-rDNA sequences from specimens of S. globulus and S. pseudoglobulus, obtained from naturally and experimentally infected hosts from New Jersey and Quebec, respectively, confirmed that these species were distinct. Barcode sequences of the 2 species differed at 92 of 590 nucleotide positions (15.6%) and the translated sequences differed by 13 amino acid residues. Partial LSU-rDNA sequences differed at 29 of 1,208 nucleotide positions (2.4%). Additional barcode sequences from specimens collected from waterfowl in Wisconsin and Minnesota and morphometric data obtained from specimens acquired along the north shore of Lake Superior revealed the presence of S. pseudoglobulus in these areas. Although morphometric data suggested the presence of S. globulus in the Lake Superior sample, it was not found among the specimens sequenced from Wisconsin or Minnesota. PMID- 21671716 TI - Paleoparasitological finding of eggs of nematodes in rodent coprolites dated at the early Holocene from the archaeological site Cerro Casa de Piedra 7, Santa Cruz, Argentina. AB - The aim of the present study was to examine the parasite remains present in rodent coprolites collected from the archaeological site Cerro Casa de Piedra 7 (CCP7), located in the Perito Moreno National Park (47 degrees 57'S, 72 degrees 05'W), Santa Cruz Province, Argentina. Eight coprolites obtained from the layer 17, dated at 10,620 +/- 40 to 9,390 +/- 40 yr B.P., were examined for parasites. Feces were processed whole, rehydrated, homogenized, subjected to spontaneous sedimentation, and examined via light microscopy. Eggs of parasites were measured and photographed. Seven of 8 coprolites possessed 199 eggs of 2, probably new, species of nematodes, including 43 eggs of Heteroxynema sp. Hall, 1916 (Cavioxyura sp. Quentin, 1975) (Oxyurida, Heteroxynematidae), and 156 eggs of Trichuris sp. Roederer, 1761 (Trichinellida, Trichuridae). Heteroxynema sp. is cited for the first time from ancient material worldwide. The finding of Trichuris spp. in both rodents and other host samples from the area under study is indicative of the stability of the biological and environmental conditions for this nematode genus to establish in the Patagonian Early Holocene. The rodent host was assigned to an unknown species of Caviomorpha (Hystricognathi) that lived during the Pleistocenic transition in Patagonia. PMID- 21671717 TI - Host size- and habitat-dependent intensity of Heliconema longissimum (Nematoda: Physalopteridae) in the Japanese eel (Anguilla japonica). AB - Heliconema longissimum (Ortlepp, 1923) is an ecologically poorly known nematode found in the stomach of Japanese eels, Anguilla japonica Temminck and Schlegel. The occurrence of this nematode in Japanese eels was surveyed in 2 contiguous brackish-water areas (Misho Cove and the lower Renjoji River) of Ehime Prefecture, western Japan, during April 2008 to March 2009. The factors associated with the nematode intensity were also assessed by applying generalized additive models (GAM). Heliconema longissimum exhibited nearly 100% prevalence in both areas, but its intensity differed. The heavier infection in the cove eels indicates that H. longissimum is mainly distributed in the cove, which supports the past speculation for this nematode as a brackish-water parasite. The intensity also increased with the body size of eels. This tendency suggests that the eels inhabiting the cove consume, as they grow, a greater quantity of crustaceans that presumably serve as the nematode's intermediate hosts. PMID- 21671718 TI - Presence of Ctenocephalides canis (Curtis) and Ctenocephalides felis (Bouche) infesting dogs in the city of Aguascalientes, Mexico. AB - Prevalence and seasonal distribution of Ctenocephalides canis (Curtis) and Ctenocephalides felis (Bouche) infestations in urban dogs of the city of Aguascalientes, Mexico, were studied. Between January and December 2007, 863 dogs in the Municipal Canine and Feline Control Center were examined. Overall prevalence of infestation was 12% (95% CI 10-14). Seasonal distribution revealed that prevalences in spring and summer were highest, while autumn and winter had lower prevalences. Two infestation peaks were observed, i.e., in April (17.7%) and July (18.9%). A positive correlation was detected between prevalence and temperature during the winter season (P < 0.05). Prevalence in relation to gender showed that males were more frequently infested, 14% (95% CI 11-17), than females, 9.4% (95% CI 7-13); hair length did not affect differences in prevalence. Six hundred twenty-nine fleas were examined; 62% were C. canis and 38% C. felis . Dogs infested with only C. canis were 48% (95% CI 38-58), while 18% were infested only with C. felis (95% CI 11-27); the remainder, 34% (95% CI 24-44), had mixed infestations. PMID- 21671719 TI - Dispersal in the acanthocephalan Acanthocephalus dirus. AB - In acanthocephalans, dispersal typically occurs when eggs that have been released in the intestines of definitive hosts are expelled with the feces. We examined whether the acanthocephalan Acanthocephalus dirus adopts a strategy of dispersal in which eggs are carried into the environment by gravid females. Using a combination of field surveys and lab-based experiments, we showed that the A. dirus female retained eggs as they passed out of the intestines and that these eggs could develop in intermediate hosts (sediment-dwelling isopods). Lab-based behavioral experiments revealed that the bodies of gravid females were attractive to foraging isopods. We propose that a strategy of egg dispersal could occur in A. dirus in which eggs are carried into the environment by females. This strategy could increase transmission success by dispersing eggs closer to the sediment, rather than in the water column, and by directing the feeding behavior of target hosts. PMID- 21671720 TI - New species of Acanthochondria (Copepoda: Chondracanthidae) infecting the longtail southern cod, Patagonotothen ramsayi (Perciformes: Nototheniidae), from Patagonian waters, Argentina. AB - Acanthochondria lilianae n. sp. (Copepoda: Chondracanthidae) is described and illustrated based on specimens of both sexes collected from inner surface of the operculum of the longtail southern cod, Patagonotothen ramsayi (Regan) (Perciformes: Nototheniidae), from the Patagonian Shelf, Argentina (42-48 degrees S, 60-63 degrees W). Acanthochondria lilianae n. sp. is characterized by the combination of a Type B-III antennule and Type A leg 2, in addition to both the cephalosome and the trunk being wider than long. The new species most closely resembles Acanthochondria incisa Shiino, 1955, Acanthochondria ophidii (Kroyer, 1863), Acanthochondria priacanthi Shiino, 1964, and Acanthochondria tasmaniae Heegaard, 1962, but differs from these species in the general measurements and proportions of the body, shape and size of head, shape and size of genitoabdomen, and fine details of appendages such as the armature of antennule, ornamentation of both pairs of legs, number of teeth on mandible and maxilla, and ornamentation on maxilliped. This is the first Acanthochondria species recorded from a nototheniid and the second southernmost record of a species of this genus in the southwestern Atlantic Ocean. PMID- 21671721 TI - Experimental exposure of Helisoma trivolvis and Biomphalaria glabrata (Gastropoda) to Ribeiroia ondatrae (Trematoda). AB - Experimental infections provide an important foundation for understanding host responses to parasites. While infections with Ribeiroia ondatrae cause mortality and malformations in a wide range of amphibian second intermediate host species, little is known about how the parasite affects its snail first intermediate hosts or even what species can support infection. In this study, we experimentally exposed Helisoma trivolvis, a commonly reported host of R. ondatrae, and Biomphalaria glabrata, a confamilial snail known to host Ribeiroia marini, to increasing concentrations of embryonated eggs of R. ondatrae obtained from surrogate definitive hosts. Over the course of 8 wk, we examined the effect of parasite exposure on infection status, time-to-cercariae release, host size, and mortality of both snail species. Helisoma trivolvis was a highly competent host for R. ondatrae infection, with over 93% infection in all exposed snails, regardless of egg exposure level. However, no infections were detected among exposed B. glabrata, despite previous accounts of this snail hosting a congener parasite. Among exposed H. trivolvis, high parasite exposure reduced growth, decreased time-to-cercariae release, and caused marginally significant increases in mortality. Interestingly, while B. glabrata snails did not become infected with R. ondatrae, individuals exposed to 650 R. ondatrae eggs grew less rapidly than unexposed snails, suggesting a sub-lethal energetic cost associated with parasite exposure. Our results highlight the importance of using experimental infections to understand the effects of parasite exposure on host- and non-host species, each of which can be affected by exposure. PMID- 21671722 TI - Molecular prevalence of different genotypes of Theileria orientalis detected from cattle and water buffaloes in Thailand. AB - Here we report on an epidemiological study regarding the molecular prevalence of different genotypes of Theileria orientalis present among domestic cattle and water buffalo populations bred in Thailand. A phylogenetic analysis based on the parasitic gene encoding a major piroplasm surface protein revealed the presence of 5 genotypes (Types 1, 3, 5, 7, and N-3) in cattle and 7 genotypes (Types 1, 3, 4, 5, 7, N-2, and N-3) in water buffaloes. Types 4, 7, and N-3 of T. orientalis were reported for the first time in water buffaloes. The previously reported C and Thai types from Thailand clustered as types 7 and 6, respectively, in the present analysis. Great similarities were observed among nucleotide sequences of isolates of the same genotype from cattle and water buffaloes, and, therefore, water buffaloes were considered to serve as a reservoir for these genotypes of T. orientalis in Thailand. In conclusion, T. orientalis parasites circulating in Thailand are more diverse in their genetic characters than previously anticipated. PMID- 21671723 TI - A description of mature Oncicola venezuelensis (Acanthocephala: Oligacanthorhynchidae) from a feral house cat in the U. S. Virgin Islands. AB - A road-killed feral house cat from the U.S. Virgin Islands was parasitized by 87 acanthocephalans of the species Oncicola venezuelensis Marteau, 1977. The finding allowed for the documentation of a suitable definitive host for the species in the Virgin Islands and permits a more comprehensive description of the species, including the first of fully mature adults and completely formed eggs. Sexually mature males from the cat were 6.5-8.4 (8.0) mm long; gravid females were 13.2 18.3 (15.5) mm long. Fully formed eggs dissected from the trunk of females were 67-72 (69) um long by 43-50 (47) um wide. The life cycle of O. venezuelensis in the Virgin Islands is now apparent, i.e., termites serve as intermediate hosts, lizards and birds as paratenic hosts, and domestic cats as definitive hosts. Extra-intestinal infections in mongooses are likely incidental. PMID- 21671724 TI - Introduction of Bruce M. Christensen, recipient of the 2011 Clark P. Read Mentor Award. PMID- 21671726 TI - Features of diaphragmatic myositis in a case of sudden infant death. PMID- 21671727 TI - Sex, the underestimated potential determining factor in brain tissue repair strategy. AB - Neural stem cells (NSCs) hold a lot of potential for the development of brain repair strategies. However, difficulties in clinical translation suggest that improving the "know how" demands that we improve our fundamental knowledge on mechanisms that regulate NSC transplantation outcome. In this article, we will focus on recent works conducted in our laboratory and by others supporting the fact that the sex of NSCs (the donor) may be a determining factor in the outcome of NSCs grafts. In particular, we will discuss the intrinsic sexual dimorphism recently reported in NSCs showing a differential expression of estrogen receptor alpha and beta as well as aromatase and how it affected NSCs transplantation outcome. An emphasis will be put on the importance of taking such sexual dimorphism into consideration for the design of future brain repair strategies. PMID- 21671725 TI - Developmental regulation of TAC1 in peptidergic-induced human mesenchymal stem cells: implication for spinal cord injury in zebrafish. AB - Human mesenchymal stem cells (MSCs) are easy to expand, are relatively safe, and can be transplanted in allogeneic recipients as off-the-shelf cells. MSCs can be induced to form functional peptidergic neurons and express the neurotransmitter gene, TAC1. Expression of TAC1 requires that the repressor gene, RE-1 silencing transcription factor (REST), is decreased. This study investigated the molecular pathway in TAC1 induction as MSCs differentiated into neurons and then applied the findings in a model of spinal cord injury (SCI) in zebrafish. We studied the developmental roles of the 2 cAMP response element (CRE) sites: CRE1 and CRE2. Activator protein-1 (AP-1) binding site overlaps with CRE2 (CRE2/AP-1). Reporter gene studies with the 5' regulatory region of TAC1 containing wild-type or mutant CRE sites and, parallel studies with ectopically expressed inhibitor of cAMP proteins (inducible cAMP early repressor) indicated that CRE1 and CRE2/AP-1 are activated at days 6 and 12, respectively. Studies with protein kinase-A (PKA) and Jun N-terminal kinase (JNK) inhibitors in the reporter gene studies, chromatin immunoprecipation assay, and ectopic expression of REST indicated the following pathways: Decrease of REST activated upstream c-Jun N-terminal kinase (JNK). In turn, JNK activated ATF-2 and AP-1 for interaction with CRE1 and CRE2/AP-1, respectively. To apply the finding to SCI, we transplanted 6-day-induced MSCs in transgenic HB9-GFP zebrafish larvae with SCI, in the presence or absence of JNK inhibitors. Imaging and functional studies showed significant improvement in the fish. The repair mechanism involved the activation of JNK. The findings have long term implications for SCI repair with MSCs. PMID- 21671728 TI - The adaptation of human embryonic stem cells to different feeder-free culture conditions is accompanied by a mitochondrial response. AB - The mitochondrial contribution to the maintenance of human embryonic stem cell (hESC) pluripotency and culture homeostasis remains poorly understood. Here, we sought to determine whether hESC adaptation to different feeder-free culture conditions is linked to a mitochondrial adaptation. The expression of ESC pluripotency factors and parameters of mitochondrial contribution including mitochondrial membrane potential, mtDNA content, and the expression of master mitochondrial genes implicated in replication, transcription, and biogenesis were determined in 8 hESC lines maintained in 2 distinct human feeders-conditioned media (CM): human foreskin fibroblast-CM (HFF-CM) and mesenchymal stem cell-CM (MSC-CM). We show a robust parallel trend between the expression of ESC pluripotency factors and the mitochondrial contribution depending on the culture conditions employed to maintain the hESCs, with those in MSC-CM consistently displaying increased levels of pluripotency markers associated to an enhanced mitochondrial contribution. The differences in the mitochondrial status between hESCs maintained in MSC-CM versus HFF-CM respond to coordinated changes in mitochondrial gene expression and biogenesis. Importantly, the culture conditions determine the mitochondrial distribution within the stage-specific embryonic antigen 3 positive (SSEA3(+)) and negative (SSEA3(-)) isolated cell subsets. hESC colonies in MSC-CM display an "intrinsic" high mitochondrial status which may suffice to support undifferentiated growth, whereas hESC colonies maintained in HFF-CM show low mitochondrial status, possibly relying on the production of autologous niche with higher mitochondrial status to support pluripotency and culture homeostasis. Pluripotency markers and mitochondrial status are concomitantly reverted on changing the culture conditions, supporting an unrecognized role of the mitochondria in response to hESC culture adaptation. We provide the first evidence supporting that hESCs adaptation to different feeder free culture systems relies on a mitochondrial response. PMID- 21671729 TI - Ex vivoimaging of injured arteries in rabbits using fluorescence-labelled glycoprotein VI-Fc. AB - Vascular lesion formation and collagen presentation are key events leading to the development of vulnerable plaques. Glycoprotein VI (GPVI) significantly contributes to plaque-associated collagen binding and thrombus formation. The aim of this study was to image endothelial injury using fluorescence-labelled GPVI-Fc (Fc, fragment crystallized), a soluble form of GPVI that was generated by cloning and fusing GPVI to an Fc-domain, in an ex-vivo rabbit model. This study serves as a proof-of-principle study to demonstrate that GPVI-Fc is a useful tool for detecting endothelial damage. The carotid and femoral arteries and the aorta abdominalis were isolated from rabbits and perfused with phosphate buffered saline (PBS) to remove all blood, and a catheter was placed into the vessels in situ. Endothelial damage was achieved by pulling an inflated balloon approximately 1 inch through the vessels, while control vessels were not balloon treated. After balloon deflation, the catheter was removed. Fluorescence-labelled GPVI-Fc (50 ug/mL) was injected into the injured and control intact vessels, and the opened vessels were sealed by clamps. After incubation, the vessels were rinsed with PBS, and optical imaging was performed to measure GPVI-Fc binding to injured endothelium. The optical data corresponding to the mean detected optical signal of the regions of interest were corrected by subtracting the mean data of the background fluorescence (arbitrary units). After denudation, fluorescence was enhanced in injured femoral and carotid arteries when compared to intact femoral (41.1 +/- 17.5 vs. 14.6 +/- 6.5; P = 0.021) and carotid (30.2 +/- 7.6 vs. 7.9 +/- 3.9; P = 0.005) arteries. This preclinical GPVI-Fc-based vascular lesion imaging approach may be the first step towards a method that allows identification of vascular lesions in vivo. PMID- 21671730 TI - Decompressive craniectomy for cerebral venous thrombosis. PMID- 21671732 TI - Can we remember future actions yet forget the last two minutes? Study in transient global amnesia. AB - Transient global amnesia (TGA) is a clinical syndrome characterized by the abrupt onset of a massive episodic memory deficit that spares other cognitive functions. If the anterograde dimension is known to be impaired in TGA, researchers have yet to investigate prospective memory (PM)--which involves remembering to perform an intended action at some point in the future--in this syndrome. Furthermore, as executive functions are thought to be spared in this syndrome, TGA provides an opportunity to examine the impact of a massive "pure" memory impairment on PM. We assessed 38 patients with a newly designed protocol that distinguished between the prospective (remembering to do something at the appropriate time) and retrospective (remembering what has to be done) components of PM. Moreover, we investigated episodic memory with an anterograde memory task and assessed executive functions, anxiety and mood, as well as their links with PM. We demonstrated that PM is impaired during TGA, with a greater deficit for the retrospective component than for the prospective component. Furthermore, we highlighted a strong link between these two components. Anterograde episodic memory impairments were correlated with retrospective component deficits in TGA patients, although we were able to confirm that executive functions are globally spared. We discuss this pattern of results within the theoretical framework of PM, putting forward new arguments in favor of the idea that PM deficits can occur mainly because of a massive anterograde memory deficit. The clinical consequences of PM impairment in TGA are examined. PMID- 21671731 TI - Behavioral interpretations of intrinsic connectivity networks. AB - An increasingly large number of neuroimaging studies have investigated functionally connected networks during rest, providing insight into human brain architecture. Assessment of the functional qualities of resting state networks has been limited by the task-independent state, which results in an inability to relate these networks to specific mental functions. However, it was recently demonstrated that similar brain networks can be extracted from resting state data and data extracted from thousands of task-based neuroimaging experiments archived in the BrainMap database. Here, we present a full functional explication of these intrinsic connectivity networks at a standard low order decomposition using a neuroinformatics approach based on the BrainMap behavioral taxonomy as well as a stratified, data-driven ordering of cognitive processes. Our results serve as a resource for functional interpretations of brain networks in resting state studies and future investigations into mental operations and the tasks that drive them. PMID- 21671733 TI - Neural encoding of objects relevant for navigation and resting state correlations with navigational ability. AB - Objects along a route can help us to successfully navigate through our surroundings. Previous neuroimaging research has shown that the parahippocampal gyrus (PHG) distinguishes between objects that were previously encountered at navigationally relevant locations (decision points) and irrelevant locations (nondecision points) during simple object recognition. This study aimed at unraveling how this neural marking of objects relevant for navigation is established during learning and postlearning rest. Twenty-four participants were scanned using fMRI while they were viewing a route through a virtual environment. Eye movements were measured, and brain responses were time-locked to viewing each object. The PHG showed increased responses to decision point objects compared with nondecision point objects during route learning. We compared functional connectivity between the PHG and the rest of the brain in a resting state scan postlearning with such a scan prelearning. Results show that functional connectivity between the PHG and the hippocampus is positively related to participants' self-reported navigational ability. On the other hand, connectivity with the caudate nucleus correlated negatively with navigational ability. These results are in line with a distinction between egocentric and allocentric spatial representations in the caudate nucleus and the hippocampus, respectively. Our results thus suggest a relation between navigational ability and a neural preference for a specific type of spatial representation. Together, these results show that the PHG is immediately involved in the encoding of navigationally relevant object information. Furthermore, they provide insight into the neural correlates of individual differences in spatial ability. PMID- 21671734 TI - Working memory and the hippocampus. AB - A number of studies suggest an important role for the hippocampus in tasks involving visuospatial or relational working memory. We test the generality of this proposal across tasks using a battery designed to investigate the various components of working memory, studying the working memory performance of Jon, who shows a bilateral reduction in hippocampal volume of approximately 50%, comparing him to a group of 48 college students. We measure performance on four complex working memory span measures based on combining visuospatial and verbal storage with visuospatial or verbal concurrent processing as well as measuring Jon's ability to carry out the component storage and processing aspects of these tasks. Jon performed at a consistently high level across our range of tasks. Possible reasons for the apparent disparity between our own findings and earlier studies showing a hippocampal deficit are discussed in terms of both the potential differences in the demands placed on relational memory and of the proposed distinction between egocentric and allocentric visuospatial processing. PMID- 21671735 TI - "She" is not like "I": the tie between language and action is in our imagination. AB - Embodied theories hold that understanding what another person is doing requires the observer to map that action directly onto his or her own motor representation and simulate it internally. The human motor system may, thus, be endowed with a "mirror matching" device through which the same motor representation is activated, when the subject is either the performer or the observer of another's action ("self-other shared representation"). It is suggested that understanding action verbs relies upon the same mechanism; this implies that motor responses to these words are automatic and independent of the subject of the verb. In the current study, participants were requested to read silently and decide on the syntactic subject of action and nonaction verbs, presented in first (1P) or third (3P) person, while TMS was applied to the left hand primary motor cortex (M1). TMS-induced motor-evoked potentials were recorded from hand muscles as a measure of cortico-spinal excitability. Motor-evoked potentials increased for 1P, but not for 3P, action verbs or 1P and 3P nonaction verbs. We provide novel demonstration that the motor simulation is triggered only when the conceptual representation of a word integrates the action with the self as the agent of that action. This questions the core principle of "mirror matching" and opens to alternative interpretations of the relationship between conceptual and sensorimotor processes. PMID- 21671736 TI - Eye can see what you want: posterior intraparietal sulcus encodes the object of an actor's gaze. AB - In a social setting, seeing Sally look at a clock means something different to seeing her gaze longingly at a slice of chocolate cake. In both cases, her eyes and face might be turned rightward, but the information conveyed is markedly different, depending on the object of her gaze. Numerous studies have examined brain systems underlying the perception of gaze direction, but less is known about the neural basis of perceiving gaze shifts to specific objects. During fMRI, participants observed an actor look toward one of two objects, each occupying a distinct location. Video stimuli were sequenced to obtain repetition suppression (RS) for object identity, independent of spatial location. In a control condition, a spotlight highlighted one of the objects, but no actor was present. Observation of the human actor's gaze compared with the spotlight engaged frontal, parietal, and temporal cortices, consistent with a broad action observation network. RS for gazed object in the human condition was found in posterior intraparietal sulcus (pIPS). RS for highlighted object in the spotlight condition was found in middle occipital, inferior temporal, medial fusiform gyri, and superior parietal lobule. These results suggest that human pIPS is specifically sensitive to the type object that an observed actor looks at (tool vs. food), irrespective of the observed actor's gaze location (left vs. right). A general attention or lower-level object feature processing mechanism cannot account for the findings because a very different response pattern was seen in the spotlight control condition. Our results suggest that, in addition to spatial orienting, human pIPS has an important role in object-centered social orienting. PMID- 21671737 TI - Oscillatory brain activity in the time frequency domain associated to change blindness and change detection awareness. AB - Despite the importance of change detection (CD) for visual perception and for performance in our environment, observers often miss changes that should be easily noticed. In the present study, we employed time-frequency analysis to investigate the neural activity associated with CD and change blindness (CB). Observers were presented with two successive visual displays and had to look for a change in orientation in any one of four sinusoid gratings between both displays. Theta power increased widely over the scalp after the second display when a change was consciously detected. Relative to no-change and CD, CB was associated with a pronounced theta power enhancement at parietal-occipital and occipital sites and broadly distributed alpha power suppression during the processing of the prechange display. Finally, power suppressions in the beta band following the second display show that, even when a change is not consciously detected, it might be represented to a certain degree. These results show the potential of time-frequency analysis to deepen our knowledge of the temporal curse of the neural events underlying CD. The results further reveal that the process resulting in CB begins even before the occurrence of the change itself. PMID- 21671738 TI - Activation of fusiform face area by Greebles is related to face similarity but not expertise. AB - Some of the brain areas in the ventral temporal lobe, such as the fusiform face area (FFA), are critical for face perception in humans, but what determines this specialization is a matter of debate. The face specificity hypothesis claims that faces are processed in a domain-specific way. Alternatively, the expertise hypothesis states that the FFA is specialized in processing objects of expertise. To disentangle these views, some previous experiments used an artificial class of novel objects called Greebles. These experiments combined a learning and fMRI paradigm. Given the high impact of the results in the literature, we replicated and further investigated this paradigm. In our experiment, eight participants were trained for ten 1-hr sessions at identifying Greebles. We scanned participants before and after training and examined responses in FFA and lateral occipital complex. Most importantly and in contrast to previous reports, we found a neural inversion effect for Greebles before training. This result suggests that people process the "novel" Greebles as faces, even before training. This prediction was confirmed in a postexperimental debriefing. In addition, we did not find an increase of the inversion effect for Greebles in the FFA after training. This indicates that the activity in the FFA for Greebles does not depend on the degree of expertise acquired with the objects but on the interpretation of the stimuli as face-related. PMID- 21671739 TI - Neural correlates of subsecond time distortion in the middle temporal area of visual cortex. AB - How does the brain represent the passage of time at the subsecond scale? Although different conceptual models for time perception have been proposed, its neurophysiological basis remains unknown. We took advantage of a visual duration illusion produced by stimulus novelty to link changes in cortical activity in monkeys with distortions of duration perception in humans. We found that human subjects perceived the duration of a subsecond motion pulse with a novel direction longer than a motion pulse with a repeated direction. Recording from monkeys viewing identical motion stimuli but performing a different behavioral task, we found that both the duration and amplitude of the neural response in the middle temporal area of visual cortex were positively correlated with the degree of novelty of the motion direction. In contrast to previous accounts that attribute distortions in duration perception to changes in the speed of a putative internal clock, our results suggest that the known adaptive properties of neural activity in visual cortex contributes to subsecond temporal distortions. PMID- 21671740 TI - Study-test congruency affects encoding-related brain activity for some but not all stimulus materials. AB - Memory improves when encoding and retrieval processes overlap. Here, we investigated how the neural bases of long-term memory encoding vary as a function of the degree to which functional processes engaged at study are engaged again at test. In an incidental learning paradigm, electrical brain activity was recorded from the scalps of healthy adults while they made size judgments on intermixed series of pictures and words. After a 1-hr delay, memory for the items was tested with a recognition task incorporating remember/know judgments. In different groups of participants, studied items were either probed in the same mode of presentation (word-word; picture-picture) or in the alternative mode of presentation (word-picture; picture-word). Activity over anterior scalp sites predicted later memory of words, irrespective of type of test probe. Encoding related activity for pictures, by contrast, differed qualitatively depending on how an item was cued at test. When a picture was probed with a picture, activity over anterior scalp sites predicted encoding success. When a picture was probed with a word, encoding-related activity was instead maximal over posterior sites. Activity differed according to study-test congruency from around 100 msec after picture onset. These findings indicate that electrophysiological correlates of encoding are sensitive to the similarity between processes engaged at study and test. The time course supports a direct and not merely consequential role of encoding-retrieval overlap in encoding. However, because congruency only affected one type of stimulus material, encoding-retrieval overlap may not be a universal organizing principle of neural correlates of memory. PMID- 21671741 TI - What does ipsilateral delay activity reflect? Inferences from slow potentials in a lateralized visual working memory task. AB - In the lateralized change detection task, two item arrays are presented, one on each side of the display. Participants have to remember the items in the relevant hemifield and ignore the items in the irrelevant hemifield. A difference wave between contralateral and ipsilateral slow potentials with respect to the relevant items, the contralateral delay activity, can be calculated. As its amplitude varies with the number of items held in working memory (WM) and reaches its asymptote with WM capacity, it is considered a pure neural correlate of visual WM load. However, in addition to this contralateral delay activity, load dependent activity has also been observed over the hemisphere ipsilateral to the relevant hemifield, suggesting that the ipsilateral hemisphere is also involved in memory-related processes. This ipsilateral activity might either reflect a bilateral processing of relevant or else a lateralized processing of irrelevant, to-be-filtered-out items. As in the lateralized change detection task, the number of items on both sides of the display is typically identical, it was not possible to decide between these alternatives yet. To disentangle the influence of relevant and irrelevant items, we orthogonally varied the number of both types of items. Processing of relevant items caused purely contralateral load-dependent activity. Ipsilateral slow potentials were influenced by the number of irrelevant items only if visual WM load was low, but not if it was high. This suggests that whether irrelevant items are processed or filtered out depends on visual WM load. PMID- 21671742 TI - Rapid and highly resolving: affective evaluation of olfactorily conditioned faces. AB - Evidence from hemodynamic and electrophysiological measures suggests that the processing of emotionally relevant information occurs in a spatially and temporally distributed affective network. ERP studies of emotional stimulus processing frequently report differential responses to emotional stimuli starting around 120 msec. However, the involvement of structures that seem to become activated at earlier latencies (i.e., amygdala and OFC) would allow for more rapid modulations, even in distant cortical areas. Consistent with this notion, recent ERP studies investigating associative learning have provided evidence for rapid modulations in sensory areas earlier than 120 msec, but these studies either used simple and/or very few stimuli. The present study used high-density whole-head magneto-encephalography to measure brain responses to a multitude of neutral facial stimuli, which were associated with an aversive or neutral odor. Significant emotional modulations were observed at intervals of 50-80 and 130-190 msec in frontal and occipito-temporal regions, respectively. In the absence of contingency awareness and with only two learning instances, a remarkable capacity for emotional learning is observed. PMID- 21671743 TI - Influence of aging on the neural correlates of autobiographical, episodic, and semantic memory retrieval. AB - We used fMRI to assess the neural correlates of autobiographical, semantic, and episodic memory retrieval in healthy young and older adults. Participants were tested with an event-related paradigm in which retrieval demand was the only factor varying between trials. A spatio-temporal partial least square analysis was conducted to identify the main patterns of activity characterizing the groups across conditions. We identified brain regions activated by all three memory conditions relative to a control condition. This pattern was expressed equally in both age groups and replicated previous findings obtained in a separate group of younger adults. We also identified regions whose activity differentiated among the different memory conditions. These patterns of differentiation were expressed less strongly in the older adults than in the young adults, a finding that was further confirmed by a barycentric discriminant analysis. This analysis showed an age-related dedifferentiation in autobiographical and episodic memory tasks but not in the semantic memory task or the control condition. These findings suggest that the activation of a common memory retrieval network is maintained with age, whereas the specific aspects of brain activity that differ with memory content are more vulnerable and less selectively engaged in older adults. Our results provide a potential neural mechanism for the well-known age differences in episodic/autobiographical memory, and preserved semantic memory, observed when older adults are compared with younger adults. PMID- 21671745 TI - Prediction error associated with the perceptual segmentation of naturalistic events. AB - Predicting the near future is important for survival and plays a central role in theories of perception, language processing, and learning. Prediction failures may be particularly important for initiating the updating of perceptual and memory systems and, thus, for the subjective experience of events. Here, we asked observers to make predictions about what would happen 5 sec later in a movie of an everyday activity. Those points where prediction was more difficult corresponded with subjective boundaries in the stream of experience. At points of unpredictability, midbrain and striatal regions associated with the phasic release of the neurotransmitter dopamine transiently increased in activity. This activity could provide a global updating signal, cuing other brain systems that a significant new event has begun. PMID- 21671744 TI - Bounded empathy: neural responses to outgroup targets' (mis)fortunes. AB - The current study investigates whether mere stereotypes are sufficient to modulate empathic responses to other people's (mis)fortunes, how these modulations manifest in the brain, and whether affective and neural responses relate to endorsing harm against different outgroup targets. Participants feel least bad when misfortunes befall envied targets and worst when misfortunes befall pitied targets, as compared with ingroup targets. Participants are also least willing to endorse harming pitied targets, despite pitied targets being outgroup members. However, those participants who exhibit increased activation in functionally defined insula/middle frontal gyrus when viewing pity targets experience positive events not only report feeling worse about those events but also more willing to harm pity targets in a tradeoff scenario. Similarly, increased activation in anatomically defined bilateral anterior insula, in response to positive events, predicts increased willingness to harm envy targets, but decreased willingness to harm ingroup targets, above and beyond self-reported affect in response to the events. Stereotypes' specific content and not just outgroup membership modulates empathic responses and related behavioral consequences including harm. PMID- 21671746 TI - Timing spatial conflict within the parietal cortex: a TMS study. AB - Orienting and motor attention are known to recruit different regions within right and left parietal lobes. However, the time course and the role played by these modules when visual information competes for different motor response are still unknown. To deal with this issue, single-pulse TMS was applied over the angular (AG) and the supramarginal (SMG) gyri of both hemispheres at several time intervals during the execution of a Simon task. Suppression of the conflict between stimulus and response positions (i.e., the Simon effect) was found when TMS pulse was applied 130 msec after stimulus onset over the right AG and after 160 msec when applied over the left AG and SMG. Interestingly, only stimulation of the left SMG suppressed the asymmetry in conflict magnitude between left- and right-hand responses, usually observed in the Simon task. The present data show that orienting attention and motor attention processes are temporally, functionally, and spatially separated in the posterior parietal cortex, and both contribute to prime motor response during spatial conflict. PMID- 21671747 TI - Pigment epithelial-derived factor and melanoma differentiation associated gene-7 cytokine gene therapies delivered by adipose-derived stromal/mesenchymal stem cells are effective in reducing prostate cancer cell growth. AB - Adipose-derived stromal/mesenchymal stem cells (ASC) have gained interest as promising tools for delivering cancer therapy. Adipose tissue can be obtained readily in amounts sufficient for ASC isolation, which can be expanded rapidly, allowing its use at low passage numbers, and can be transduced by viral and nonviral means. Our goal was to examine the potential of ASC to deliver cytokine gene therapies melanoma differentiation associated gene-7 (MDA-7) or pigment epithelial-derived factor (PEDF) to cancer cells. These novel cytokines are a potent proapoptotic and an antiangiogenesis mediator, respectively, with potential as antitumor agents. Expression of cytokine therapies did not adversely affect ASC biology, and these cells were still able to differentiate and retain normal viability. The ASC cytokine therapies were efficient in reducing tumor cell growth in coculture and also in suppressing in vitro angiogenesis phenotypes. We also observed that ASC retained their innate ability to migrate toward tumor cells in coculture, and this ability could be blocked by inhibition of CXCR4 signaling. The ASC were found to be nontumorigenic in vitro using a soft agar assay, as well as in vivo, utilizing 2 prostate cancer xenograft models. The ASC-MDA7 only reduced tumor growth in the TRAMP-C2-Ras (TC2Ras) prostate cancer model. The ASC-PEDF, however, reduced growth in both the TC2Ras and the PC3 highly aggressive prostate cancer models, and it was able to completely prevent prostate tumor establishment in vivo. In conclusion, ASC expressing PEDF and MDA7 could effectively reduce prostate tumor growth in vivo, suggesting ASC-cytokine therapies might have translational applications, especially the PEDF modality. PMID- 21671748 TI - Utility of spatially-resolved atmospheric pressure surface sampling and ionization techniques as alternatives to mass spectrometric imaging (MSI) in drug metabolism. AB - Tissue distribution studies of drug molecules play an essential role in the pharmaceutical industry and are commonly undertaken using quantitative whole body autoradiography (QWBA) methods. The growing need for complementary methods to address some scientific gaps around radiography methods has led to increased use of mass spectrometric imaging (MSI) technology over the last 5 to 10 years. More recently, the development of novel mass spectrometric techniques for ambient surface sampling has redefined what can be regarded as "fit-for-purpose" for MSI in a drug metabolism and disposition arena. Together with a review of these novel alternatives, this paper details the use of two liquid microjunction (LMJ)-based mass spectrometric surface sampling technologies. These approaches are used to provide qualitative determination of parent drug in rat liver tissue slices using liquid extraction surface analysis (LESA) and to assess the performance of a LMJ surface sampling probe (LMJ-SSP) interface for quantitative assessment of parent drug in brain, liver and muscle tissue slices. An assessment of the utility of these spatially-resolved sampling methods is given, showing interdependence between mass spectrometric and QWBA methods, in particular there emerges a reason to question typical MSI workflows for drug metabolism; suggesting the expedient use of profile or region analysis may be more appropriate, rather than generating time-intensive molecular images of the entire tissue section. PMID- 21671751 TI - Relation between humidity and size of exhaled particles. AB - BACKGROUND: Aerosol particles are generated in human airways, and leave the body with exhaled air. These particles may carry indicators of various lung conditions. To fully utilize the information provided by endogenously produced exhaled particles, it is important to understand their formation mechanism and physical properties. The scope of this work was to measure number size distributions of exhaled aerosol particles at various surrounding relative humidities (RH) in order to gain some knowledge of the size distribution at the point of particle generation. METHODS: Number size distributions of exhaled particles were measured at various RHs, using an optical particle counter. Breathing with airway closure was employed. RESULTS: A relation between particle volume and RH was fitted to experimental data and used to predict how exhaled droplets behave at RHs not easily accessible by experiments. The diameter of an exhaled particle is reduced by a factor of 0.42 when the RH is changed from 99.5 to 75% at 309 K. Calculations also show that the droplets are concentrated solutions near saturation at 75% RH. CONCLUSIONS: It is concluded that the particles are supersaturated liquid particles, rather than crystalline solids, in ambient air with RH below 75%. A size distribution related to the aerosol at the moment of formation is given. A successful detailed formation mechanism should be able to accommodate the size distribution predicted at 99.5% RH. PMID- 21671750 TI - Vertebral defects in patients with Peters plus syndrome and mutations in B3GALTL. PMID- 21671749 TI - Distinct functional effects for dynamin 3 during megakaryocytopoiesis. AB - Dynamin 3 (DNM3) is a member of a family of motor proteins that participate in a number of membrane rearrangements such as cytokinesis, budding of transport vesicles, phagocytosis, and cell motility. Recently, DNM3 was implicated as having a role in megakaryocyte (MK) development. To further investigate the functional role of DNM3 during megakaryocytopoiesis, we introduced sequence specific short hairpin RNAs (shRNAs) into developing MKs. The results showed that knockdown of DNM3 inhibited a stage of MK development that involved progenitor amplification. This was evident by significant decreases in the number of colony forming unit-megakaryocytes, the total number of nucleated cells, and the number of CD41(+) and CD61(+) MKs produced in culture. Using a styrl membrane dye to quantify the demarcation membrane system (DMS) of terminally differentiated MKs, we found that DNM3 co-localized with the DMS and that DNM3 lentiviral shRNAs precluded the formation of the DMS. Knockdown of dynamin 3 in murine MKs also caused a decrease in the number of morphologically large MKs and the overall size of large MKs was decreased relative to controls. MK protein lysates were used in overlay blots to show that both DNM3 and actin bind to nonmuscle myosin IIA (MYH9). Consistent with these observations, immunofluorescence studies of MKs and proplatelet processes showed co-localization of DNM3 with MYH9. Overall, these studies demonstrate that DNM3 not only participates in MK progenitor amplification, but is also involved in cytoplasmic enlargement and the formation of the DMS. PMID- 21671752 TI - Comparative pulmonary function and pharmacokinetics of fluticasone propionate and salmeterol xinafoate delivered by two dry powder inhalers to patients with asthma. AB - BACKGROUND: This report presents results of the first human study of a new dry powder inhaler (DPI-C). DPI-C uses reverse flow cyclone technology to retain larger particles in the device and to increase efficiency of respirable drug release. The study was conducted to determine comparative pharmacokinetics (not bioequivalence) of DPI-C and DPI-A (Advair Diskus(r), GlaxoSmithKline) and to establish preliminary efficacy and safety of DPI-C. METHODS: Nineteen patients with mild-moderate asthma received two treatments (randomized crossover design). Treatments were one inhalation from DPI-A labeled to deliver 100 MUg fluticasone propionate and 50 MUg salmeterol, or one inhalation from DPI-C which contained ~10% less of each drug per metered dose. Prior to dosing, 10 g of charcoal was administered. FEV1 increase over baseline (measured over 12 h), plasma concentrations of fluticasone and salmeterol (measured over 12.5 h), and occurrence of adverse events were the primary measures of device performance and safety. RESULTS: Seventeen patients were evaluable. Response profiles of percent increase in FEV1 over baseline showed no statistically significant differences between devices. Peak plasma concentrations of both fluticasone (p=0.003) and salmeterol (p=0.084) were higher from DPI-C. Mean extent of absorption [area under the curve (AUC)] of fluticasone was approximately 30% greater with DPI-C, whereas AUC of salmeterol was approximately 40% greater with DPI-A. CONCLUSIONS: DPI-C provided similar improvement in pulmonary function compared with DPI-A. Pharmacokinetic results showed a greater initial absorption of salmeterol with DPI-C but greater continued absorption and a 40% greater AUC with DPI-A, which we attribute to slower but more extensive oral absorption because of the greater mass of swallowed large particles of salmeterol generated by DPI-A. No patient reported any treatment-related adverse event or use of rescue medication during this study. Determination of the significance of the observed differences in pharmacokinetics from this single-dose study requires further exploration in studies using clinically relevant dosing regimens. PMID- 21671753 TI - An in vitro assessment of aerosol delivery through patient breathing circuits used with medical air or a helium-oxygen mixture. AB - BACKGROUND: The bench experiments presented herein were conducted in order to investigate the influence of carrier gas, either medical air or a helium-oxygen mixture (78% He, 22% O2), on the droplet size distribution and aerosol mass delivered from a vibrating mesh nebulizer through a patient breathing circuit. METHODS: Droplet size distributions at the exit of the nebulizer T-piece and at the patient end of the breathing circuit were determined by laser diffraction. Additional experiments were performed to determine the effects on measured size distributions of gas humidity and of the droplet residence time during transport from the nebulizer to the laser diffraction measurement volume. Aerosol deposition in the nebulizer, breathing circuit, and on expiratory and patient filters was determined by photometry following nebulization of sodium fluoride solutions into the breathing circuit during simulated patient breathing. RESULTS: With no humidification of the carrier gas, droplet volume median diameter (VMD) at the exit of the nebulizer T-piece was 5.5+/-0.1 MUm for medical air, and 4.3+/ 0.1 MUm for helium-oxygen. Varying the aerosol residence time between the nebulizer and the measurement volume did not affect the measured size distributions; however, humidification of the carrier gases reduced differences in VMD at the nebulizer exit between medical air and helium-oxygen. At the patient end of the breathing circuit, droplet VMDs were 1.8+/-0.1 MUm for medical air and 2.2+/-0.1 MUm for helium-oxygen. The percentages of sodium fluoride recovered from the nebulizer, breathing circuit, patient filter, and expiratory filter were, respectively, 29.9+/-8.3, 40.4+/-5.6, 8.3+/-1.5, and 21.5+/-2.1% for air, and 32.6+/-2.2, 36.3+/-0.7, 12.0+/-1.4, and 19.1+/-1.1% for helium-oxygen. CONCLUSIONS: Ventilation with helium-oxygen in place of air-oxygen mixtures can influence both the droplet size distribution and mass of nebulized aerosol delivered through patient breathing circuits. Assessment of these effects on aerosol delivery is important when incorporating helium-oxygen into patient ventilation strategies. PMID- 21671754 TI - The oxidative folding and misfolding of human leukocyte antigen-b27. AB - The major histocompatibility complex class I molecule human leukocyte antigen (HLA)-B27 is strongly associated with a group of inflammatory arthritic disorders known as the spondyloarthropathies. Many autoimmune diseases exhibit associations with major histocompatibility complex molecules encoded within the class II locus with defined immune responses either mediated by T or B-lymphocytes. Despite the association being known for over 30 years, no defined immune response and target autoantigens have been characterized for the spondyloarthropathies. Thus, the mechanism and role of HLA-B27 in disease pathogenesis remains undetermined. One hypothesis that has recently received much attention has focused around the enhanced propensity for HLA-B27 to misfold and the increased tendency of the heavy chain to dimerize. The misfolding of HLA-B27 has been associated with its redox status and this is postulated to be involved in disease development. Here we discuss the impact of the redox status on HLA-B27 biosynthesis and function. PMID- 21671755 TI - Photodynamic therapy using methylene blue to treat cutaneous leishmaniasis. AB - OBJECTIVE: The purpose of this study was to show the efficiency and underlying mechanism of action of photodynamic therapy (PDT) using methylene blue (MB) and non-coherent light sources to treat cutaneous leishmaniasis (CL). BACKGROUND DATA: Systemic treatment can cause severe side effects, and PDT using porphyrin precursors as sensitizers has been used as an alternative to treat CL. MB has been used under illumination or in the dark to treat a wide range of medical conditions, and it exhibits antimicrobial activity against protozoa and viruses. METHODS: In in vitro tests, the cell viability (via a MTT colorimetric assay) of Leishmania amazonensis parasites was evaluated as a function of MB concentration. In in vivo experiments, we analyzed the treatment of two lesions from a patient with leishmaniasis. The patient received a low dose of pentavalent antimony (SbV), and one lesion was treated with PDT. RESULTS: We observed IC(50) decreases from 100 to 20 MUM in response to PDT when MB was used in different concentrations in in vitro tests. Use of SbV in combination with the PDT protocol produced faster wound recovery when compared with the use of SbV alone. CONCLUSIONS: The in vitro experiments and the results from the clinical case suggest that the inexpensive PDT protocol that is based on MB and RL50(r) may be used to treat CL caused by L. amazonensis. PMID- 21671756 TI - "Positive Examples": a bottom-up approach to identifying best practices in HIV care and treatment based on the experiences of peer educators. AB - Literature describing the roles and activities of peers working in HIV care is limited. Evaluations of the impact of peer-based behavior-change interventions reveal mixed results, due in part to varied program aims, structure, evaluation mechanisms, and training. Peers themselves are important resources to address these concerns and lay the groundwork for developing improved programs and evaluation strategies. This qualitative article describes peer support in HIV care and treatment from the perspective of 23 HIV-positive peers across the United States. Peers reported that peer characteristics (HIV-status, common experiences, and self-care) enable them to engage clients. Peers also required flexibility to respond to client needs, and their activities spanned four types of social support: informational, emotional, instrumental, and affiliational. We recommend peer programs and evaluations accommodate the broad scope of peer work by acknowledging the need for flexibility and activities that are not always directly related to clients' HIV care and treatment. PMID- 21671757 TI - Improved targeting of radio-frequency ablation probes and thermal sensors: a preliminary investigation of flat-panel CT-guided ablation of renal tumors performed in the cardiac catheterization laboratory. AB - Flat-panel detector CT (FD-CT) provides cross-sectional CT-images while offering an improved workspace using fluoroscopic guidance for thermal probe placement such as for radiofrequency ablation (RFA) needles and thermal sensors. The purpose of this article is to test the feasibility of FD-CT in the application of renal tumor ablation in a "hybrid operating room" environment. Eleven patients with renal masses diagnosed preprocedurally with contrast-enhanced CT scan underwent core biopsy and simultaneous CT-RFA under general anesthesia with FD-CT guidance in the cardiac catheterization laboratory. Scans were taken preablation for tumor targeting, intermittently for probe placement and guidance of temperature sensors, and postablation. Perioperative and postoperative outcomes, pathologic results, and radiographic follow-up were recorded for each patient. Target temperatures >60 degrees C to guide treatment end point were reached for each tumor periphery. Biopsy pathology showed 6/11 (55%) to be renal-cell carcinoma, and 2/11 (18%) to be benign; 3/11 (27%) had an indeterminate biopsy result. Three Clavien grade I complications occurred. One patient showed evidence of recurrent disease on postoperative CT scan. In our experience, we have found FD-CT-guided ablation of small renal tumors to be feasible using this advanced targeting system. PMID- 21671758 TI - Functional and oncologic outcomes of bilateral open partial nephrectomy versus bilateral laparoscopic partial nephrectomy. AB - PURPOSE: This study compared operative data and outcomes in patients undergoing either bilateral open partial nephrectomy (BOPN) or bilateral laparoscopic partial nephrectomy (BLPN) for synchronous bilateral kidney tumors. PATIENTS AND METHODS: Patients who had undergone bilateral partial nephrectomy at our institution between 1992 and 2008 were reviewed retrospectively; 114 patients underwent either BOPN or BLPN. Ischemia time, tumor size, and renal function outcomes immediately after each surgery, at an intermediate time point (<=12 months), and at a late time point (>12 months) were compared. Oncologic outcomes were also evaluated using Kaplan-Meier analysis. RESULTS: BOPN and BLPN were conducted in 92 and 22 patients, respectively. Average tumor size was larger in the BOPN group (4.1 vs 2.7 cm; P=0.001); however, pathologic stage was equivalent (P=0.52). Hospital stay was longer in the BOPN group (5.6 vs 4.0 d; P<0.001). Preoperative estimated glomerular filtration rates (eGFR) in the BOPN and BLPN groups were both >=60 mL/min/1.73 m(2). Percent decrease in eGFR between the two groups was 38% in the BLPN group and 27% in the BOPN group (P=0.03). Cancer specific and recurrence-free survival rates were equivalent between groups over a mean follow-up of 5.5 years. CONCLUSIONS: BOPN and BLPN resulted in equivalent intermediate-term oncologic control. BLPN was associated with a larger percent decrease in eGFR. As ischemia times shorten for contemporary laparoscopic partial nephrectomies, it is expected that functional outcomes will be equivalent. PMID- 21671759 TI - Laparoscopic orchidopexy in boys with prune belly syndrome--outcome and technical considerations. AB - BACKGROUND AND PURPOSE: Cryptorchidism is an ubiquitous feature in prune belly syndrome (PBS). Laparoscopic orchidopexy allows dissection of the spermatic cord with minimal morbidity. We discuss the technical difficulties and outcome of three boys with PBS who underwent two-stage laparoscopic Fowler-Stephens orchidopexy (F-SO). PATIENTS AND METHODS: Three boys, ages 1, 2, and 4, underwent laparoscopic F-SO. All boys had viable testes that were found within 3 cm of the deep inguinal ring. The testicular vessels were either ligated bilaterally with 4/0 polyglactin or monopolar diathermy was used and the vessels divided. Bilateral second-stage F-SO was performed within 6 months in two boys and limited to one side in the third boy. One boy awaits the contralateral second stage. RESULTS: All three boys have adequately sized gonads. Based on our experience, the port incisions should be smaller than routine practice to prevent air leak in PBS. Although the intra-abdominal pressure of 12 mm Hg did not vary from our normal practice, a high flow rate is necessary after initial insufflation (6 L/min) to compensate for inevitable gas leaks because the abdominal wall is so thin. Risk of diathermy injury to the thin abdominal wall and the vessels is significant. Laparoscopy enables easy visualization of the ureter, testes, and testicular vessels and permits complete dissection of testicular vessels. It is easier to maintain integrity of spermatic vessels. CONCLUSION: Use of radially expanding trocars, small incisions, and high gas flow rates permit this procedure to be performed safely with good outcome and cosmetic results in this challenging group of boys. PMID- 21671761 TI - Conversions in laparoscopic renal surgery: causes and outcomes. AB - PURPOSE: We examined conversions in laparoscopic renal surgery, evaluating the causes and outcomes. PATIENTS AND METHODS: A single institution review of all laparoscopic renal surgeries, excluding renal donors, over a nine-year period was performed. Cases were evaluated for intraoperative results, conversions, and complications. RESULTS: 399 laparoscopic renal surgeries were identified (394 available for review) with 41 conversions (31 open, 8 hand-assisted, 2 retroperitoneal). Intraoperative and postoperative complications occurred in 3.0% and 12.2%, respectively. The most common reason for conversion was a lack of progress (20), followed by difficult anatomy (8), tumor thrombus (5), and bleeding (4). Open conversion rates for hand-assisted laparoscopic (HAL), transperitoneal laparoscopic, retroperitoneal laparoscopic (RPL), and robot assisted were 17.1%, 6.9%, 13.2%, and 1.8%, respectively, although HAL and RPL were more often used for bilateral procedures, previous abdominal surgery, and large specimens (P<0.05). Surgical indication significantly impacted perioperative outcome, where autosomal dominant polycystic kidney disease and partial nephrectomy were associated with the highest rate of open conversion (13%), while nephroureterectomy had the highest rate of complications (40%). Cases in which there were large specimens weighing over 1500 g were converted in 40% of cases vs 8.2% for smaller specimens, P<0.001. Previous abdominal surgery did not impact conversion rate (11.9% without vs 9.3% with previous surgery, P=0.401). Cases that were converted had a significantly higher blood loss, operative time, transfusion rate, hospital stay, and complication rate (P<0.05). CONCLUSIONS: Rate of conversion to an open procedure is significantly impacted by surgical indication, specimen size, and surgical technique. Any conversion is associated with an increased perioperative morbidity. PMID- 21671762 TI - A system for laparoscopic surgery ergonomics and skills evaluation. AB - This article presents a system for tracking, recording, and analysis of instrument and surgeon's arm motion in minimally invasive surgeries. The captured trajectories can be objectively analyzed for both ergonomic assessment and skills evaluation. The system consists of two special infrared (IR) markers that are used for 6 degrees of freedom (DOF) laparoscopic instrument tracking and a set of 3DOF IR markers attached to elbows and shoulders. A compact IR camera tracks and records the markers during a standardized training task (eg, suturing). The instrument markers were purposely designed to provide good tracking while minimizing their volume. The accuracy of the instrument markers was evaluated showing a root mean square error of 0.61 mm, 1.0 mm, and 2.4 mm at distances from the camera of 0.5 m, 0.68 m, and 1 m respectively. Furthermore, some sample trajectories were recorded during an in-trainer suturing task. The Results section presents the values of basic skills metrics computed from the acquired data. PMID- 21671763 TI - Adsorption of amino acids (ALA, CYS, HIS, MET) on zeolites: fourier transform infrared and Raman spectroscopy investigations. AB - Minerals adsorb more amino acids with charged R-groups than amino acids with uncharged R-groups. Thus, the peptides that form from the condensation of amino acids on the surface of minerals should be composed of amino acid residues that are more charged than uncharged. However, most of the amino acids (74%) in today's proteins have an uncharged R-group. One mechanism with which to solve this paradox is the use of organophilic minerals such as zeolites. Over the range of pH (pH 2.66-4.50) used in these experiments, the R-group of histidine (His) is positively charged and neutral for alanine (Ala), cysteine (Cys), and methionine (Met). In acidic hydrothermal environments, the pH could be even lower than those used in this study. For the pH range studied, the zeolites were negatively charged, and the overall charge of all amino acids was positive. The conditions used here approximate those of prebiotic Earth. The most important finding of this work is that the relative concentrations of each amino acid (X=His, Met, Cys) to alanine (X/Ala) are close to 1.00. This is an important result with regard to prebiotic chemistry because it could be a solution for the paradox stated above. Pore size did not affect the adsorption of Cys and Met on zeolites, and the Si/Al ratio did not affect the adsorption of Cys, His, and Met. ZSM-5 could be used for the purification of Cys from other amino acids (Student-Newman Keuls test, p<0.05), and mordenite could be used for separation of amino acids from each other (Student-Newman-Keuls test, p<0.05). As shown by Fourier transform infrared (FT-IR) spectra, Ala interacts with zeolites through the [Formula: see text] group, and methionine-zeolite interactions involve the COO, [Formula: see text], and CH(3) groups. FT-IR spectra show that the interaction between the zeolites and His is weak. Cys showed higher adsorption on all zeolites; however, the hydrophobic Van der Waals interaction between zeolites and Cys is too weak to produce any structural changes in the Cys groups (amine, carboxylic, sulfhydryl, etc.); thus, the FT-IR and Raman spectra are the same as those of solid Cys. PMID- 21671764 TI - Mineral-enhanced hydrothermal oligopeptide formation at the second time scale. AB - Accumulation of biopolymers should have been an essential step for the emergence of life on primitive Earth. However, experimental simulations for submarine hydrothermal vent systems in which high-temperature water spouts through minerals within a short time scale have not been attempted. Here, we show that enhancement of hydrothermal oligopeptide elongation by naturally occurring minerals was successfully verified for the first time by using a mineral-mediated hydrothermal flow reactor system (MMHF). MMHF consists of a narrow tubular reactor packed with mineral particles, and the enhancement or inhibitory activities of 10 types of naturally occurring minerals were successfully evaluated for an elongation reaction from (Ala)(4) to (Ala)(5) and higher oligopeptides in the absence of condensation reagents. It was unexpected that calcite and dolomite facilitated the elongation from (Ala)(4) to (Ala)(5) and higher oligopeptides with 28% yield at pH 7, while tourmaline, galena, apatite, mica, sphalerite, quartz, chalcopyrite, and pyrite did not show enhancement activities. These facts suggest the importance of carbonate minerals for the accumulation of peptide in primitive Earth environments. PMID- 21671765 TI - Pregnancy intention, demographic differences, and psychosocial health. AB - OBJECTIVES: We explore the psychosocial, demographic, and maternal characteristics across wanted, mistimed, and unwanted pregnancies. METHODS: Data from 1321 women from a prospective cohort study of pregnant women in Durham, NC, are analyzed. Psychosocial correlates were obtained through prenatal surveys; electronic medical records were used to ascertain maternal health and pregnancy outcomes. RESULTS: Sixty-two percent of the women indicated an unintended pregnancy, with 44% (578) mistimed and 18% (245) unwanted. Only 38% of the pregnancies were characterized as wanted. Women with unwanted and with mistimed pregnancies were similar demographically, but they differed significantly on psychosocial profiles and maternal characteristics. Women with mistimed and with wanted pregnancies differed in demographics and psychosocial profiles. Wanted pregnancies had the healthiest, mistimed an intermediate, and unwanted the poorest psychosocial profile. Women with unwanted pregnancies had the highest depression, perceived stress, and negative paternal support scores (p<0.05) and the lowest self-efficacy, social support, and positive paternal support scores (p<0.05). In multivariate analyses, women with riskier psychosocial profiles had higher odds of being in the unwanted category. Controlling for psychosocial and demographic variables, perceived stress and positive paternal support remained significant predictors of belonging to the unwanted and mistimed groups. CONCLUSIONS: Fully characterizing pregnancy intention and its relationship to psychosocial profiles may provide a basis for identifying women with highest risk during pregnancy and early motherhood. Women with unwanted and mistimed pregnancies may appear similar demographically but are different psychosocially. Women with unwanted pregnancies have multiple risk factors and would benefit from targeted interventions. PMID- 21671766 TI - Cystitis: symptomatology in women with suspected uncomplicated urinary tract infection. AB - BACKGROUND: Although cystitis in women is very common in general practice, its evolution in symptoms has not been clearly studied. Qualitative research has pointed to other than the classic symptomatology. METHODS: This was a prospective observational study of the symptomatology at presentation and the evolution of the symptoms in treated women with suspected uncomplicated urinary tract infection (UTI). Women consulting their general practitioner (GP) for dysuria, urgency, or frequency produced a urine sample (for bacteriologic processing) and kept a diary until the end of the symptoms. Exclusion criteria included complaints >1 week, fever, vaginal discharge, and known pathology. RESULTS: Of the 300 asked to participate, 148 (49%) returned the diary. Although none of the patients developed acute pyelonephritis, a substantial number of the women had such complaints as feeling feverish (33% in culture-positive group, 38% in culture-negative group), back pains (44% vs. 56%), and feeling weak and tired (71% vs. 65%). Differences between the culture-positive and culture-negative groups were not statistically significant except for the duration of symptoms, which was shorter in the culture-positive group (4 vs. 6 days). More severe symptoms at inclusion were correlated with a longer duration of these symptoms. CONCLUSIONS: The spectrum of complaints in women with suspected uncomplicated UTI is broad and comprises a number of symptoms usually associated with an upper UTI. The occurrence of these symptoms should not automatically prompt GPs to prescribe broad-spectrum antibiotics. Moreover, the duration of symptoms exceeding the recommended duration of antibiotic therapy does not indicate therapy failure and, thus, the need for changing antibiotic therapy. PMID- 21671767 TI - Comparing screening and preventive health behaviors in two study populations: daughters of mothers with breast cancer and women responding to the behavioral risk factor surveillance system survey. AB - BACKGROUND: Studies show that daughters of mothers with breast cancer may be at increased risk for developing the disease. However, daughters' adherence to health behavior and screening recommendations, compared to the general population, is unknown. METHODS: Telephone interviews explored characteristics of adult daughters (n=147), including primary and secondary preventive behaviors, body mass index (BMI, kg/m(2)), physical activity, fruit/vegetable intake, alcohol intake, smoking, and mammography. Daughters of mothers with breast cancer were recruited from the community and were compared with Virginia women (n=2528) from the 2005 Behavioral Risk Factor Surveillance System (BRFSS) survey. Differences were examined using logistic regression, adjusting for demographic covariates. RESULTS: Daughters were younger (p<0.001), more highly educated (p<0.001), and more likely to never have been married (p<0.001) than BRFSS participants, but groups were similar by race. In adjusted analyses, daughters were significantly more likely to have ever had a mammogram (p<0.001) and to have had one recently (p=0.001). Daughters also were significantly less likely to consume>3 fruit/vegetable servings daily (p=0.032) compared to BRFSS results. There were no differences in BMI, smoking rates, alcohol consumption, or level of physical activity at work. CONCLUSIONS: Daughters with familial breast cancer risk were more likely to receive mammography screening than BRFSS participants, but they were no different in BMI, physical activity at work, exercise, or smoking than BRFSS participants and were less likely to consume more fruits and vegetables. More research is needed to explore group differences in screening practices compared to modifiable health behaviors in daughters of mothers with breast cancer. PMID- 21671768 TI - Thirty years of research on atrial natriuretic factor: historical background and emerging concepts. AB - The discovery of the natriuretic properties of atrial muscle extracts pointed to the existence of an endocrine function of the heart that is now known to be mediated by the polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). On the basis of such a finding, approximately 27 000 publications to date have described a wide variety of biological properties of the heart hormones as well as their application as therapeutic agents and biomarkers of cardiac disease. Stimulation of secretion of ANF and BNP from the atria is mediated through mechanisms involving G proteins of the G(q) or G(o) types. We showed that the latter type underlies the transduction of muscle stretch into stimulated secretion and that it is more highly abundant in atria than in ventricles. The Galpha(o)()-1 subunit appears to play a key role in the biogenesis of atrial granules and in the intracellular targeting of their contents. Protein interaction studies using a yeast two-hybrid approach showed interactions between Galpha(o)()-1, proANF, and the intermediate conductance, calcium-activated K(+) channel SK4. Pharmacological inhibition of this channel decreases ANF secretion. Unpublished studies using in vitro knockdowns suggest interdependency in granule protein expression levels. These studies suggest previously unknown mechanisms of intracellular targeting and secretion control of the heart hormones that may find an application in the therapeutic manipulation of circulating ANF and BNP. PMID- 21671770 TI - Roles of guanylyl cyclase--a signaling in the cardiovascular system. AB - Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are cardiac hormones synthesized in and secreted from the heart. ANP and BNP bind the common receptor guanylyl cyclase-A (GC-A) and possess biological actions. Based on their diuretic, natriuretic, and vasodilating activities, they are now widely used as therapeutic agents for heart failure. Roles of endogenous ANP and BNP have been investigated using mice lacking the gene encoding GC-A. Here we describe the recent understanding of roles of GC-A in the cardiovascular system. PMID- 21671769 TI - Reported symptoms before and one year after hysterectomy in African American and white women. AB - PURPOSE: Although African American women are more likely than white women to undergo hysterectomy, there are few data describing their symptoms before and after surgery. This report compares reported symptoms in white and African American women before and 1-year after having a hysterectomy with at least one ovary retained. METHODS: Using data from a prospective cohort study, we compared self-reported symptoms at baseline and 1-year follow-up among 382 women undergoing hysterectomy without bilateral oophorectomy (197 African American and 185 white) and 448 controls (199 African American and 249 white). Symptoms were assessed using an 11-item scale with questions on somatic, psychologic, and urogenital symptoms. RESULTS: Women undergoing hysterectomy had more severe symptom scores before surgery than controls, but no significant racial differences were found. At follow-up, total scores for women with hysterectomies were comparable to those of control women, but some differences were observed within individual domains. Urogenital scores were worse for women with hysterectomies for both African American and white women. African American women with hysterectomies had better scores in the psychologic domain than either controls or white women with hysterectomies. CONCLUSIONS: African American women, despite having such characteristics as larger uterine weight and lower hemoglobin that might suggest they would have more severe symptoms, had scores that were no worse than white women both before and after hysterectomy. PMID- 21671771 TI - Expression of hypoxia-inducible factors, regulators, and target genes in congenital diaphragmatic hernia patients. AB - Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia and pulmonary hypertension and has high morbidity and mortality rates. The cause and pathophysiology of CDH are not fully understood. However, impaired angiogenesis appears to play an important role in the pathophysiology of CDH. Therefore, we examined different components of an important pathway in angiogenesis: hypoxia inducible factors (HIFs); HIF regulators von Hippel-Lindau (VHL) and prolyl 3 hydroxylase (PHD3); and HIF target genes vascular endothelial growth factor A ( VEGF-A ) and vascular endothelial growth factor receptor 2 ( VEGFR-2 ). Quantitative polymerase chain reaction of lung tissue showed a significantly decreased expression of VEGF-A mRNA in the alveolar stage of lung development in CDH patients compared with matched control patients. In the canalicular stage, no differences for VEGF-A were seen between the lungs of CDH patients and those of control patients. Other components of angiogenesis (VHL, HIF-1alpha, HIF-2alpha, HIF-3alpha, VEGFR-2 mRNA, PHD3 protein) that were analyzed showed no differences in expression between CDH and control patients, independent of the developmental stage. A lower expression of VEGF mRNA in CDH patients in the alveolar stage, possibly as a result of downregulation of HIF-2alpha might indicate a role for these factors in the pathophysiology of CDH. PMID- 21671772 TI - U.S. medical eligibility criteria for contraceptive use, 2010. AB - Abstract unintended pregnancy may worsen the condition and carry even greater risk of adverse pregnancy outcomes, including maternal and perinatal death. Although safe and highly effective contraceptive methods are available to prevent unintended pregnancy, there may be concerns about the safety of contraceptive methods among women with medical conditions. The Centers for Disease Control and Prevention (CDC) has recently developed the U.S. Medical Eligibility Criteria for Contraceptive Use, 2010, which provides evidence-based recommendations for the safety of contraceptive use among women with medical conditions. Most women, even those with medical conditions, can safely use most methods of contraception. PMID- 21671773 TI - After inclusion, information and inference: reporting on clinical trials results after 15 years of monitoring inclusion of women. AB - OBJECTIVE: The objectives of this report are to review the publications resulting from National Institutes of Health (NIH)-funded phase 3 trials monitored by NIH for inclusion and to address the quality of the research conducted and the validity of the sex/gender-specific or sex/gender difference analyses reported. METHODS: For intervention trials enrolling both women and men, this review links reports to NIH of completed enrollment to publications of trial results. Each publication was then reviewed for a variety of reported characteristics based on established measures of quality, bearing on whether or not the research will permit valid analyses of sex/gender differences. RESULTS: Publications from 268 trials reported an overall average enrollment of 37% (+/-6% standard deviation [SD]) women, at an increasing rate over the years 1995-2010. Only 28% of the publications either made some reference to sex/gender-specific results in the text or provided detailed results including sex/gender-specific estimates of effect or tests of interaction. CONCLUSIONS: Efforts at including women in clinical research have increased the information captured relative to women's health. Sex/gender-specific information has been captured and should be available to other researchers for further analysis, including individual patient data meta analyses. Improved reporting and disseminating sex/gender-specific results will allow sex/gender-specific inferences and healthcare decisions. PMID- 21671774 TI - Eating disorders and trauma history in women with perinatal depression. AB - OBJECTIVE: Although the prevalence of perinatal depression (depression occurring during pregnancy and postpartum) is 10%, little is known about psychiatric comorbidity in these women. We examined the prevalence of comorbid eating disorders (ED) and trauma history in women with perinatal depression. METHODS: A research questionnaire was administered to 158 consecutive patients seen in a perinatal psychiatry clinic during pregnancy (n=99) or postpartum (n=59). Measures included Structured Clinical Interview for DSM (SCID) IV-based questions for lifetime eating psychopathology and assessments of comorbid psychiatric illness including the State/Trait Anxiety Inventory (STAI), Patient Health Questionnaire (PHQ-9), Edinburgh Postnatal Depression Scale (EPDS), and Trauma Inventory. RESULTS: In this cohort, 37.1% reported a putative lifetime ED history; 10.1% reported anorexia nervosa (AN), 10.1% reported bulimia nervosa (BN), 10.1% reported ED not otherwise specified-purging subtype (EDNOS-P), and 7.0% reported binge eating disorder (BED). Women with BN reported more severe depression (EPDS score, 19.1, standard deviation [SD 4.3], p=0.02; PHQ-severity 14.5, SD 7.4, p=0.02) than the referent group of women with perinatal depression and no ED history (EPDS 13.3, SD=6.1; PHQ 9.0, SD=6.2). Women with AN were more likely to report sexual trauma history than the referent group (62.5% vs. 29.3%, p<0.05), and those with BN were more likely report physical (50.0%, p<0.05) and sexual (66.7%, p<0.05) trauma histories. CONCLUSIONS: ED histories were present in over one third of admissions to a perinatal psychiatry clinic. Women with BN reported more severe depression and histories of physical and sexual trauma. Screening for histories of eating psychopathology is important in women with perinatal depression. PMID- 21671776 TI - Serum micronutrient concentrations and risk of uterine fibroids. AB - BACKGROUND: Although uterine fibroids are among the most common gynecologic conditions affecting women in the United States, research on uterine fibroids is sparse. This study explored the association between micronutrients and uterine fibroids. METHODS: We conducted a population-based, cross-sectional analysis of 887 women aged 20-49 who participated in the 2003-2004 National Health and Nutrition Examination Survey (NHANES). Serum micronutrient levels were collected during the health examinations, and information on uterine fibroids was assessed on self-reported questionnaires. Multivariate logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) while controlling for confounders. RESULTS: A statistically significant dose-response relationship was observed between vitamin A and uterine fibroids, after adjustment for age, race, education, body mass index (BMI), and oral contraceptive (OC) use (middle vs. low: OR 2.43, 95% CI 1.35-4.37; high vs. low: OR 2.66, 95% CI 1.16-6.10, p for trend=0.02). After adjustment, a dose-response relationship also emerged for vitamin C, although these associations were not statistically significant. CONCLUSIONS: It is possible that certain micronutrients affect uterine fibroid development. If this is confirmed in large prospective studies, clinicians could advise susceptible populations on dietary changes to reduce their risk of uterine fibroids. PMID- 21671775 TI - Predictors of drinking during pregnancy: a systematic review. AB - BACKGROUND: Many pregnant women continue to drink alcohol despite clinical recommendations and public health campaigns about the risks associated with alcohol use during pregnancy. This review examines the predictors of prenatal alcohol use, with the long-term goal of developing more effective preventive efforts. METHODS: A literature search of several databases for relevant articles was undertaken. Studies were included if they occurred in the context of antenatal care, collected data during the woman's pregnancy (between 1999 and 2009), investigated predictors of any drinking, had a population-based orientation (e.g., did not focus only on high-risk drinkers), and were published in English in a scientific peer-reviewed journal between 1999 and 2009. RESULTS: Fourteen studies published between 2002 and 2009 fulfilled the inclusion criteria (United States, 4; Europe, 4; Australia and New Zealand, 3; Japan, 2; and Uganda, 1). The predictors of prenatal alcohol use most consistently identified were prepregnancy alcohol consumption and having been abused or exposed to violence. Less consistent predictors of drinking during pregnancy were high income/social class and positive dependence screen. Unemployment, marital status, and education level were examined in many studies but found to be predictive only infrequently. CONCLUSIONS: Women's prepregnancy alcohol consumption (i.e., quantity and frequency of typical drinking) and exposure to abuse or violence were consistently associated with drinking during pregnancy. Antenatal care providers should assess these factors for improved detection of women at risk for alcohol exposed pregnancies. PMID- 21671778 TI - HIV testing among midlife women in the deep south: an analysis of the 2008 Behavioral Risk Factor Surveillance System survey data. AB - OBJECTIVE AND BACKGROUND: Our objective was to examine HIV testing uptake among postmenopausal women. Many women are routinely tested for HIV during pregnancy. Disproportionate numbers of women beyond reproductive age are diagnosed HIV positive late in the disease course. Some older women and healthcare providers have dismissed early AIDS symptoms as signs of aging. This has resulted in missed opportunities for early initiation of effective antiretroviral therapy. METHODS: Behavioral Risk Factor Surveillance System (BRFSS) 2008 data were analyzed for non-Hispanic white and non-Hispanic black women (50-64 years) from six deep south states. Logistic regression models examined associations between uptake of HIV testing and population/behavioral characteristics. RESULTS: More than half of our sample (1091 of 2027) had an HIV test during their postreproductive years (>45 years old). Women 50-54 years old were about 40% as likely to have been tested for HIV during their postreproductive years as those 60-64 years old (adjusted odds ratio [AOR] 0.62, 95% confidence interval [CI] 0.45-0.84). Population characteristics, such as race/ethnicity, family poverty status, and urbanization, as well as HIV exposure risk, were all potential confounders of this relationship. CONCLUSIONS: Routine HIV testing is underused among women during their postreproductive years. HIV prevention messages that target midlife women are needed to reduce the prevalence of HIV/AIDS and disproportionate burden of late diagnosed HIV infection in this population. PMID- 21671777 TI - Lifetime discrimination associated with greater likelihood of premenstrual dysphoric disorder. AB - OBJECTIVES: To evaluate whether the stressor of perceived discrimination was associated with premenstrual dysphoric disorder (PMDD) and premenstrual symptoms among minority women. This study builds on previous research that found perceived discrimination was positively associated with other psychiatric illnesses. METHODS: Participants were 2718 Asian, Latina, and black premenopausal women aged 18-40 years who completed the World Mental Health Composite International Diagnostic Interview for the National Latino and Asian American Survey or the National Survey of American Life. Perceived discrimination was assessed with the Everyday Discrimination Scale. DSM-IV-based diagnostic algorithms generated a provisional lifetime diagnosis of PMDD. RESULTS: Eighty-three percent of the participants reported experiencing discrimination (due to race, gender, age, height or weight, or other reasons) in their lifetimes. The frequency of perceived discrimination was positively associated with PMDD (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10) and premenstrual symptoms (OR 1.04, 95% CI 1.02-1.05), independent of demographic covariates and social desirability. Women reporting gender discrimination (OR 5.18, 95% CI 1.80-14.90), race discrimination (OR 4.14, 95% CI 1.54-11.11), and other forms of discrimination (OR 6.43, 95% CI 2.11-19.65) were significantly more likely than women without experiences of discrimination to have PMDD. Subtle discrimination was more strongly associated with PMDD (OR 1.12, 95% CI 1.01-1.23) than was blatant discrimination (OR 1.04, 95% CI 0.94-1.15). CONCLUSIONS: This study is the first to demonstrate that perceived discrimination is associated with PMDD and premenstrual symptoms. These findings suggest that the prevalence of these conditions may be lessened by reducing discrimination in women's lives. PMID- 21671779 TI - Knowledge, attitudes, and demographic factors influencing cervical cancer screening behavior of Zimbabwean women. AB - AIMS: The aims of this study were (1) to estimate what proportion of rural females had received cervical screening, (2) to assess knowledge, beliefs, attitudes, and demographics that influence cervical screening, and (3) to predict cervical screening accessibility based on demographic factors, knowledge, beliefs, and attitudes that influence cervical screening. METHODS: The study sample consisted of randomly selected, sexually active, rural females between 12 and 84 years of age. Five hundred fourteen females responded to an individually administered questionnaire. RESULTS: Of the 514 participants, 91% had never had cervical screening and 81% had no previous knowledge of cervical screening tests; 80% of the group expressed positive beliefs about cervical screening tests after an educational intervention. Females who were financially independent were 6.61% more likely to access cervical screening compared with those who were dependent on their husbands. Females in mining villages were 4.47% more likely to access cervical screening than those in traditional rural reserve villages. Females in resettlement villages were 20% less likely to access cervical screening than those in traditional rural reserve villages. CONCLUSIONS: Accessibility of screening services could be improved through planning and implementation of screening programs involving community leaders and culturally appropriate messages. The government should incorporate the human papillomavirus (HPV) vaccine in its immunization program for adolescents, and health education should be intensified to encourage women and their partners to comply with diagnostic and treatment regimens. PMID- 21671780 TI - Lengthened predelivery stay and antepartum complications in women with depressive symptoms during pregnancy. AB - Abstract Background: It is crucial to understand the timing and mechanisms behind depression's effect on peripartum stay because attempts to intervene will vary based on the time period involved. We designed this study to compare predelivery and postdelivery length of stay in women with and without elevated depressive symptoms during pregnancy. METHODS: This study involved secondary data analysis of a larger study exploring antepartum depression. Each subject completed the Center for Epidemiological Studies Depression Scale (CES-D) during pregnancy at a mean of 25.8 weeks' gestation. We used time-stamped data to compare total peripartum, predelivery, and postdelivery lengths of stay in women with and without elevated depressive symptoms during pregnancy. In addition, we used a Cox proportional hazards regression model to evaluate potential mechanisms for depression's effect on length of stay. RESULTS: The study sample included 802 pregnant women. Overall, 18% of study subjects scored >=16 on the CES-D. Bivariate analyses demonstrated a significant association between elevated depressive symptoms and longer predelivery stays (time from admission to delivery). Interaction analyses demonstrated a significant interaction effect between depressive symptoms and parity, such that depressive symptoms were significantly associated with predelivery length of stay in multiparas but not so in primiparous subjects. In a multivariate model of multiparous subjects, depression's effect on length of stay was partially influenced by sociodemographic confounders but remained significant until antepartum complications were added to the model. CONCLUSIONS: Depressive symptoms during pregnancy are significantly associated with a subsequent increase in predelivery length of stay, and this association is mediated in part by antepartum complications, even after controlling for sociodemographic factors. These longer hospital stays can present significant burdens to the patient, her family, and the healthcare system. Future studies should evaluate whether interventions for depression during pregnancy can impact this relationship among depressive symptoms during pregnancy, antepartum complications, and extensive predelivery hospitalizations. PMID- 21671781 TI - Inverse association between total bilirubin and metabolic syndrome in rural korean women. AB - Abstract Background: Chronic inflammation and oxidative stress are associated with the development of metabolic syndrome (MetS). Bilirubin is an antioxidant and has a protective effect against cardiovascular disease (CVD). The purpose of this study was to examine the association between total bilirubin levels and the prevalence of MetS in rural Korean women. METHODS: This cross-sectional study included 5,266 women (>40 years) enrolled in the Korean Genomic Rural Cohort (KGRC). MetS was defined using the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) guidelines. Total bilirubin levels were categorized into quartiles. RESULTS: Subjects in the upper quartiles of total bilirubin were younger and had lower waist circumferences, systolic blood pressure, and triglyceride levels and higher high-density lipoprotein cholesterol (HDL-C) concentrations. The overall prevalence of MetS was 39.0%. When the participants were categorized into quartiles by total bilirubin level, the prevalence of MetS according to increasing total bilirubin quartiles was 47.9%, 41.2%, 34.3%, and 32.7%, respectively. By comparison to the lowest quartile of total bilirubin (<0.61 mg/dL), the odds ratio (OR) (95% confidence interval [CI]) for MetS in the highest quartile of total bilirubin (>=0.94 mg/dL) was 0.63 (0.52 0.77) after adjusting for menopausal status, C-reactive protein (CRP) levels, insulin resistance, and other covariates. CONCLUSIONS: Total bilirubin level appears to be inversely associated with the prevalence of MetS in rural Korean women >40 years of age in the KGRC, even after adjusting for risk factors of MetS, including body mass index (BMI), menopausal status, CRP levels, and homeostasis model assessment of insulin resistance (HOMA-IR). PMID- 21671782 TI - The incretin effect and secretion in obese and lean women with polycystic ovary syndrome: a pilot study. AB - BACKGROUND: Insulin resistance is considered to play an important role in the pathogenesis of polycystic ovary syndrome (PCOS) and in the progression to type 2 diabetes. Recent reports concentrate on a possible relationship between incretin secretion and beta-cell function in PCOS. The aim of the present study is to investigate the incretin effect in obese and lean women with PCOS. METHODS: Twenty women with PCOS and ten age-matched healthy women were recruited in the study. The oral glucose tolerance test (OGTT) and isoglycemic test were carried out on each participant after an overnight fast at 2-weeks interval. Plasma levels of insulin, glucose, C-peptide, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) were assayed. RESULTS: Obese women with PCOS demonstrated lower GIP concentrations (area under the curve [AUC]) in response to OGTT compared to the control group. The incretin effect was found significantly augmented in the obese women with PCOS compared to controls. This finding remained robust in the subgroup analysis including only body mass index (BMI)-matched healthy women. CONCLUSIONS: Increased insulinotropic effect could counteract the blunted GIP response to OGTT in obese women with PCOS. It is suggested that the pathology of PCOS may also include impaired activity of the enteroinsular axis. PMID- 21671784 TI - Invariant object recognition and pose estimation with slow feature analysis. AB - Primates are very good at recognizing objects independent of viewing angle or retinal position, and they outperform existing computer vision systems by far. But invariant object recognition is only one prerequisite for successful interaction with the environment. An animal also needs to assess an object's position and relative rotational angle. We propose here a model that is able to extract object identity, position, and rotation angles. We demonstrate the model behavior on complex three-dimensional objects under translation and rotation in depth on a homogeneous background. A similar model has previously been shown to extract hippocampal spatial codes from quasi-natural videos. The framework for mathematical analysis of this earlier application carries over to the scenario of invariant object recognition. Thus, the simulation results can be explained analytically even for the complex high-dimensional data we employed. PMID- 21671783 TI - Odd-skipped related genes regulate differentiation of embryonic limb mesenchyme and bone marrow mesenchymal stromal cells. AB - The regulation of progenitor cell differentiation to a specific tissue type is one of the fundamental questions of biology. Here, we identify Osr1 and Osr2, 2 closely related genes encoding zinc finger transcription factors, as being strongly expressed in irregular connective tissue (ICT) fibroblasts in the chicken embryo, suitable as a developmental marker. We provide evidence that both Osr1 and Osr2 regulate mesenchymal cell-type differentiation. Both Osr1 and Osr2 can promote the formation of ICT, a cell type of so far unknown molecular specification, while suppressing differentiation of other tissues such as cartilage and tendon from uncommitted progenitors. Conversely, knockdown of either Osr gene alone or in combination reverses this effect, thereby leading to decreased differentiation of ICT fibroblasts and increased chondrogenesis in vitro. This indicates that Osr genes play a pivotal role in ICT fibroblast differentiation. Undifferentiated mesenchymal cells reside in the adult body in the form of mesenchymal stem cells in the bone marrow cavity. Using bone marrow stromal cells (BMSCs) isolated from chicken fetal long bones, we show that Osr1 and Osr2 have an intrinsic role in BMSC differentiation similar to their role in early embryonic development, that is, the enforcement of CT fibroblast differentiation and the repression of other cell types as exemplified here by osteoblast differentiation. PMID- 21671785 TI - Automated parameter estimation of the Hodgkin-Huxley model using the differential evolution algorithm: application to neuromimetic analog integrated circuits. AB - We propose a new estimation method for the characterization of the Hodgkin-Huxley formalism. This method is an alternative technique to the classical estimation methods associated with voltage clamp measurements. It uses voltage clamp type recordings, but is based on the differential evolution algorithm. The parameters of an ionic channel are estimated simultaneously, such that the usual approximations of classical methods are avoided and all the parameters of the model, including the time constant, can be correctly optimized. In a second step, this new estimation technique is applied to the automated tuning of neuromimetic analog integrated circuits designed by our research group. We present a tuning example of a fast spiking neuron, which reproduces the frequency-current characteristics of the reference data, as well as the membrane voltage behavior. The final goal of this tuning is to interconnect neuromimetic chips as neural networks, with specific cellular properties, for future theoretical studies in neuroscience. PMID- 21671788 TI - A low-order model of biological neural networks. AB - A biologically plausible low-order model (LOM) of biological neural networks is proposed. LOM is a recurrent hierarchical network of models of dendritic nodes and trees; spiking and nonspiking neurons; unsupervised, supervised covariance and accumulative learning mechanisms; feedback connections; and a scheme for maximal generalization. These component models are motivated and necessitated by making LOM learn and retrieve easily without differentiation, optimization, or iteration, and cluster, detect, and recognize multiple and hierarchical corrupted, distorted, and occluded temporal and spatial patterns. Four models of dendritic nodes are given that are all described as a hyperbolic polynomial that acts like an exclusive-OR logic gate when the model dendritic nodes input two binary digits. A model dendritic encoder that is a network of model dendritic nodes encodes its inputs such that the resultant codes have an orthogonality property. Such codes are stored in synapses by unsupervised covariance learning, supervised covariance learning, or unsupervised accumulative learning, depending on the type of postsynaptic neuron. A masking matrix for a dendritic tree, whose upper part comprises model dendritic encoders, enables maximal generalization on corrupted, distorted, and occluded data. It is a mathematical organization and idealization of dendritic trees with overlapped and nested input vectors. A model nonspiking neuron transmits inhibitory graded signals to modulate its neighboring model spiking neurons. Model spiking neurons evaluate the subjective probability distribution (SPD) of the labels of the inputs to model dendritic encoders and generate spike trains with such SPDs as firing rates. Feedback connections from the same or higher layers with different numbers of unit-delay devices reflect different signal traveling times, enabling LOM to fully utilize temporally and spatially associated information. Biological plausibility of the component models is discussed. Numerical examples are given to demonstrate how LOM operates in retrieving, generalizing, and unsupervised and supervised learning. PMID- 21671786 TI - Finding the event structure of neuronal spike trains. AB - Neurons in sensory systems convey information about physical stimuli in their spike trains. In vitro, single neurons respond precisely and reliably to the repeated injection of the same fluctuating current, producing regions of elevated firing rate, termed events. Analysis of these spike trains reveals that multiple distinct spike patterns can be identified as trial-to-trial correlations between spike times (Fellous, Tiesinga, Thomas, & Sejnowski, 2004 ). Finding events in data with realistic spiking statistics is challenging because events belonging to different spike patterns may overlap. We propose a method for finding spiking events that uses contextual information to disambiguate which pattern a trial belongs to. The procedure can be applied to spike trains of the same neuron across multiple trials to detect and separate responses obtained during different brain states. The procedure can also be applied to spike trains from multiple simultaneously recorded neurons in order to identify volleys of near-synchronous activity or to distinguish between excitatory and inhibitory neurons. The procedure was tested using artificial data as well as recordings in vitro in response to fluctuating current waveforms. PMID- 21671789 TI - Principles and typical computational limitations of sparse speaker separation based on deterministic speech features. AB - The separation of mixed auditory signals into their sources is an eminent neuroscience and engineering challenge. We reveal the principles underlying a deterministic, neural network-like solution to this problem. This approach is orthogonal to ICA/PCA that views the signal constituents as independent realizations of random processes. We demonstrate exemplarily that in the absence of salient frequency modulations, the decomposition of speech signals into local cosine packets allows for a sparse, noise-robust speaker separation. As the main result, we present analytical limitations inherent in the approach, where we propose strategies of how to deal with this situation. Our results offer new perspectives toward efficient noise cleaning and auditory signal separation and provide a new perspective of how the brain might achieve these tasks. PMID- 21671790 TI - Kernels for longitudinal data with variable sequence length and sampling intervals. AB - We develop several kernel methods for classification of longitudinal data and apply them to detect cognitive decline in the elderly. We first develop mixed effects models, a type of hierarchical empirical Bayes generative models, for the time series. After demonstrating their utility in likelihood ratio classifiers (and the improvement over standard regression models for such classifiers), we develop novel Fisher kernels based on mixture of mixed-effects models and use them in support vector machine classifiers. The hierarchical generative model allows us to handle variations in sequence length and sampling interval gracefully. We also give nonparametric kernels not based on generative models, but rather on the reproducing kernel Hilbert space. We apply the methods to detecting cognitive decline from longitudinal clinical data on motor and neuropsychological tests. The likelihood ratio classifiers based on the neuropsychological tests perform better than than classifiers based on the motor behavior. Discriminant classifiers performed better than likelihood ratio classifiers for the motor behavior tests. PMID- 21671791 TI - A differential model of the complex cell. AB - The receptive fields of simple cells in the visual cortex can be understood as linear filters. These filters can be modeled by Gabor functions or gaussian derivatives. Gabor functions can also be combined in an energy model of the complex cell response. This letter proposes an alternative model of the complex cell, based on gaussian derivatives. It is most important to account for the insensitivity of the complex response to small shifts of the image. The new model uses a linear combination of the first few derivative filters, at a single position, to approximate the first derivative filter, at a series of adjacent positions. The maximum response, over all positions, gives a signal that is insensitive to small shifts of the image. This model, unlike previous approaches, is based on the scale space theory of visual processing. In particular, the complex cell is built from filters that respond to the 2D differential structure of the image. The computational aspects of the new model are studied in one and two dimensions, using the steerability of the gaussian derivatives. The response of the model to basic images, such as edges and gratings, is derived formally. The response to natural images is also evaluated, using statistical measures of shift insensitivity. The neural implementation and predictions of the model are discussed. PMID- 21671792 TI - The dependence of spike field coherence on expected intensity. AB - The coherence between neural spike trains and local-field potential recordings, called spike-field coherence, is of key importance in many neuroscience studies. In this work, aside from questions of estimator performance, we demonstrate that theoretical spike-field coherence for a broad class of spiking models depends on the expected rate of spiking. This rate dependence confounds the phase locking of spike events to field-potential oscillations with overall neuron activity and is demonstrated analytically, for a large class of stochastic models, and in simulation. Finally, the relationship between the spike-field coherence and the intensity field coherence is detailed analytically. This latter quantity is independent of neuron firing rate and, under commonly found conditions, is proportional to the probability that a neuron spikes at a specific phase of field oscillation. Hence, intensity field coherence is a rate-independent measure and a candidate on which to base the appropriate statistical inference of spike field synchrony. PMID- 21671794 TI - Active data collection for efficient estimation and comparison of nonlinear neural models. AB - The stimulus-response relationship of many sensory neurons is nonlinear, but fully quantifying this relationship by a complex nonlinear model may require too much data to be experimentally tractable. Here we present a theoretical study of a general two-stage computational method that may help to significantly reduce the number of stimuli needed to obtain an accurate mathematical description of nonlinear neural responses. Our method of active data collection first adaptively generates stimuli that are optimal for estimating the parameters of competing nonlinear models and then uses these estimates to generate stimuli online that are optimal for discriminating these models. We applied our method to simple hierarchical circuit models, including nonlinear networks built on the spatiotemporal or spectral-temporal receptive fields, and confirmed that collecting data using our two-stage adaptive algorithm was far more effective for estimating and comparing competing nonlinear sensory processing models than standard nonadaptive methods using random stimuli. PMID- 21671795 TI - Transplanted L1 expressing radial glia and astrocytes enhance recovery after spinal cord injury. AB - A major obstacle for the transplantation of neural stem cells (NSCs) into the lesioned spinal cord is their predominant astrocytic differentiation after transplantation. We took advantage of this predominant astrocytic differentiation of NSCs and expressed the paradigmatic beneficial neural cell adhesion molecule L1 in radial glial cells and reactive and nonreactive astrocytes as novel cellular vehicles to express L1 under the control of the promoter for the human glial fibrillary acidic protein (GFAP-L1 NSCs). Behavioral analysis and electrophysiological H-reflex recordings revealed that mice transplanted with GFAP-L1 NSCs showed enhanced locomotor recovery in comparison to mice injected with wild type (WT) NSCs or control mice injected with phosphate-buffered saline (PBS). This functional recovery was further accelerated in mice transplanted with L1-expressing radial glial cells that had been immunoisolated from GFAP-L1 NSCs (GFAP-L1-i cells). Morphological analysis revealed that mice grafted with GFAP-L1 NSCs exhibited increased neuronal differentiation and migration of transplanted cells, as well as increased soma size and cholinergic synaptic coverage of host motoneurons and increased numbers of endogenous catecholaminergic nerve fibers caudal to the lesion site. These findings show that L1-expressing astrocytes and radial glial cells isolated from GFAP-L1 NSC cultures represent a novel strategy for improving functional recovery after spinal cord injury, encouraging the use of the human GFAP promoter to target beneficial transgene expression in transplanted stem cells. PMID- 21671796 TI - Structured assessment of hypopituitarism after traumatic brain injury and aneurysmal subarachnoid hemorrhage in 1242 patients: the German interdisciplinary database. AB - Clinical studies have demonstrated that traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) are frequent causes of long-term disturbances of hypothalamo-pituitary function. This study aimed to assess the prevalence and associated factors of post-traumatic hypopituitarism in a large national registry of patients with TBI and SAH. Data were collected from 14 centers in Germany and Austria treating patients for TBI or SAH and performing endocrine assessments. Data were collected using a structured, internet-based study sheet, obtaining information on clinical, radiological, and hormonal parameters. A total of 1242 patients (825 TBI, age 43.5+/-19.7 years; 417 SAH, age 49.7+/-11.8 years) were included. We studied the prevalence of hypopituitarism reported based on different definitions of laboratory values and stimulation tests. Stimulation tests for the corticotropic and somatotropic axes were performed in 26% and 22% of the patients, respectively. The prevalence of hypopituitarism in the chronic phase (at least 5 months after the event) by laboratory values, physician diagnoses, and stimulation tests, was 35%, 36%, and 70%, respectively. Hypopituitarism was less common in the acute phase. According to the frequency of endocrine dysfunction, pituitary hormone secretion was impaired in the following sequence: ACTH, LH/FSH, GH, and TSH. TBI patients with abnormal stimulation tests had suffered from more severe TBI than patients with normal stimulation tests. In conclusion, our data confirm that hypopituitarism is a common complication of TBI and SAH. It is possible that patients with a higher likelihood of hypopituitarism were selected for endocrine stimulation tests. PMID- 21671798 TI - Common data elements for neuroimaging of traumatic brain injury: pediatric considerations. AB - As part of the Traumatic Brain Injury Common Data Elements project, a large-scale effort to define common data elements across a variety of domains, including neuroimaging, special considerations for pediatric patients were introduced. This article is an extension of that initial work, in which pediatric-specific pathoanatomical entities, technical considerations, interpretation paradigms, and safety considerations were reviewed. The goal of this review was to outline differences and specific information relevant to optimal performance and proper interpretation of neuroimaging in pediatric patients with traumatic brain injury. The long-range goal of this project is to facilitate data sharing as well as to provide critical infrastructure for potential clinical trials in this major public health area. PMID- 21671799 TI - Neuropathy-induced spinal GAP-43 expression is not a main player in the onset of mechanical pain hypersensitivity. AB - Structural plasticity within the spinal nociceptive network may be fundamental to the chronic nature of neuropathic pain. In the present study, the spatiotemporal expression of growth-associated protein-43 (GAP-43), a protein which has been traditionally implicated in nerve fiber growth and sprouting, was investigated in relation to mechanical pain hypersensitivity. An L5 spinal nerve transection model was validated by the presence of mechanical pain hypersensitivity and an increase in the early neuronal activation marker cFos within the superficial spinal dorsal horn upon innocuous hindpaw stimulation. Spinal GAP-43 was found to be upregulated in the superficial L5 dorsal horn from 5 up to 10 days after injury. GAP-43 was co-localized with calcitonin-gene related peptide (CGRP), but not vesicular glutamate transporter-1 (VGLUT-1), IB4, or protein kinase-gamma (PKC-gamma), suggesting the regulation of GAP-43 in peptidergic nociceptive afferents. These GAP-43/CGRP fibers may be indicative of sprouting peptidergic fibers. Fiber sprouting largely depends on growth factors, which are typically associated with neuro-inflammatory processes. The putative role of neuropathy induced GAP-43 expression in the development of mechanical pain hypersensitivity was investigated using the immune modulator propentofylline. Propentofylline treatment strongly attenuated the development of mechanical pain hypersensitivity and glial responses to nerve injury as measured by microglial and astroglial markers, but did not affect neuropathy-induced levels of spinal GAP-43 or GAP-43 regulation in CGRP fibers. We conclude that nerve injury induces structural plasticity in fibers expressing CGRP, which is regarded as a main player in central sensitization. Our data do not, however, support a major role of these structural changes in the onset of mechanical pain hypersensitivity. PMID- 21671800 TI - Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9. AB - Myocardial infarction (MI) results in loss of myofibers in the ischemic zone of the heart, followed by scar formation. These factors increase barriers to mobilization of mesenchymal stem cells (MSC), thereby impeding their effectiveness in cardiac repair. This study examined MSC overexpressing CXCR4 (MSC(CX4)) to determine penetration into infarcted myocardium by releasing collagen degrading enzyme, matrix metalloproteinase-9 (MMP-9). In vitro, mouse MSC were utilized, including MSC using adenoviral transduction, to express CXCR4/green fluorescent protein (GFP) (MSC(CX4)), Null/GFP (MSC(Null)), MSC treated with siRNA targeting CXCR4 (MSC(siR)), MSC treated with control siRNA(MSC(Con-siR)), MSC(CX4) treated with siRNA targeting MMP-9 (MSC(CX4 siRMP9)) and MMP-14 (MSC(CX4-siRMP14)), MSC derived from MMP-9 knockout mouse with adenoviral transduction for GFP (MSC(MP9-)), or MSC(MP9-) plus overexpressing CXCR4 (MSC(MP9-CX4)). The ability to cross the basement membrane was evaluated in all MSC using a trans-collagen gel invasion assay. The CXCR4 and MMP expression were analyzed by Western blot. In vivo, MSC with various treatments were infused into mice via tail vein injections 7 days after MI. Echocardiography was performed before harvesting hearts for analysis at 4 weeks after MSC injection. Both in vitro and in vivo studies demonstrated upregulation of MMP-9 induced by MSC(CX4), promoting increased GFP(+) cell migration into the infarcted area in comparison to control group. This enhanced response was associated with reduced left ventricular (LV) fibrosis, increased LV free wall thickness, angiogenesis, and improved LV function. Under hypoxic conditions, MMP 9 is upregulated in MSC(CX4), thus facilitating cross of the basement membrane, resulting in an improved remodeling of post-MI tissue. PMID- 21671801 TI - Long-term preservation of cones and improvement in visual function following gene therapy in a mouse model of leber congenital amaurosis caused by guanylate cyclase-1 deficiency. AB - Leber congenital amaurosis (LCA) is a severe retinal dystrophy manifesting from early infancy as poor vision or blindness. Loss-of-function mutations in GUCY2D cause LCA1 and are one of the most common causes of LCA, accounting for 20% of all cases. Human GUCY2D and mouse Gucy2e genes encode guanylate cyclase-1 (GC1), which is responsible for restoring the dark state in photoreceptors after light exposure. The Gucy2e(-/-) mouse shows partially diminished rod function, but an absence of cone function before degeneration. Although the cones appear morphologically normal, they exhibit mislocalization of proteins involved in phototransduction. In this study we tested the efficacy of an rAAV2/8 vector containing the human rhodopsin kinase promoter and the human GUCY2D gene. Following subretinal delivery of the vector in Gucy2e(-/-) mice, GC1 protein was detected in the rod and cone outer segments, and in transduced areas of retina cone transducin was appropriately localized to cone outer segments. Moreover, we observed a dose-dependent restoration of rod and cone function and an improvement in visual behavior of the treated mice. Most importantly, cone preservation was observed in transduced areas up to 6 months post injection. To date, this is the most effective rescue of the Gucy2e(-/-) mouse model of LCA and we propose that a vector, similar to the one used in this study, could be suitable for use in a clinical trial of gene therapy for LCA1. PMID- 21671802 TI - Gender disparity in susceptibility to oxidative stress and apoptosis induced by autoantibodies specific to RLIP76 in vascular cells. AB - AIM: Ral-binding protein 1 (RLIP76) is a cell surface protein that catalyzes the extrusion from the cell of reduced glutathione (GSH) conjugates. We recently demonstrated the presence of serum antibodies to RLIP76 (aaRLIP76) in patients with immune-mediated diseases characterized by vascular dysfunction. The aim of this work was to analyze the possible implication of gender in this issue, investigating the effects of aaRLIP76 in rat vascular smooth muscle cells and human endothelial cells from males and females. RESULTS: We observed that, after aaRLIP76 treatment, vascular cells from females showed a significantly higher susceptibility to the disturbance of intracellular redox balance, in terms of H(2)O(2) and O(2)(*) production, 4-hydroxy-t-2,3-nonenal and GSH levels, C-Jun NH2 kinase signaling activation, and apoptosis in comparison with cells from males. Interestingly, under mild oxidative stress (H(2)O(2) 30 MUm for 30 min), these sex-associated differences became significantly more pronounced. Experiments carried out in the presence of sex hormones in the culture medium clearly suggested that estrogens could significantly increase the susceptibility of cells from females to the effects of aaRLIP76, whereas cells from males appeared unaffected. INNOVATION: These results open a new perspective in the gender-dependent pathogenic mechanisms of autoimmune diseases characterized by vascular dysfunction. CONCLUSIONS: Altogether these results suggest that the impairment of RLIP76 by aaRLIP76 can play a role in the damage of vascular cells from females, contributing to the gender-associated pathogenesis of immune mediated vascular diseases. PMID- 21671803 TI - New serum biomarkers for detection of tuberculosis using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. AB - BACKGROUND: New technologies for the early detection of tuberculosis (TB) are urgently needed. Pathological changes within an organ might be reflected in proteomic patterns in serum. The aim of the present study was to screen for the potential protein biomarkers in serum for the diagnosis of TB using proteomic fingerprint technology. METHODS: Proteomic fingerprint technology combining protein chips with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to profile the serum proteins from 50 patients with TB, 25 patients with lung disease other than TB, and 25 healthy volunteers. The protein fingerprint expression of all the serum samples and the resulting profiles between TB and control groups were analyzed with the Biomarker Wizard system. RESULTS: A total of 30 discriminating m/z peaks were detected that were related to TB (p<0.01). The model of biomarkers constructed by the Biomarker Patterns Software based on the three biomarkers (2024, 8007, and 8598 Da) generated excellent separation between the TB and control groups. The sensitivity was 84.0% and the specificity was 86.0%. Blind test data indicated a sensitivity of 80.0% and a specificity of 84.2%. CONCLUSIONS: The data suggested a potential application of SELDI-TOF MS as an effective technology to profile serum proteome, and with pattern analysis, a diagnostic model comprising three potential biomarkers was indicated to differentiate people with TB and healthy controls rapidly and precisely. PMID- 21671804 TI - An investigation of the effect of sorafenib on tumour growth and recurrence after liver cancer resection in nude mice independent of phosphorylated extracellular signal-regulated kinase levels. AB - OBJECTIVE: The goal of this study is to investigate the effects of sorafenib on tumor growth, recurrence and metastasis after curative resection of liver cancer. RESEARCH METHODS: SMMC-7721 and HCCLM3 liver tumors, each with different metastatic potential and basal phosphorylated extracellular signal-regulated kinase (pERK) levels, were orthotopically implanted into 56 nude mice. Mice were divided into a treatment sub study and a prevention sub study. RESULTS: In the treatment sub study, tumor volumes in the high pERK-expressing HCCLM3 model were 2.58 ? 0.83 and 0.38 ? 0.09 cm(3) without and with sorafenib, respectively (p < 0.001). The corresponding volumes in the low pERK-expressing SMMC-7721 model were 1.36 ? 0.24 and 0.24 ? 0.14 cm(3) (p < 0.001), respectively. Sorafenib inhibited HCCLM3 cell proliferation and decreased tumor angiogenesis, but did not inhibit proliferation in the SMMC-7721 model. In the prevention sub study, intrahepatic recurrent tumor volumes were 1.96 ? 0.45 and 0.18 ? 0.24 cm(3) (p < 0.001); lung metastasis frequencies were 100 and 0% (p = 0.005); and lifespans were 36 ? 3 and 46 ? 5 days (p = 0.002) in the control and sorafenib subgroups, respectively. CONCLUSIONS: Sorafenib inhibits tumor growth and prevents metastatic recurrence after resection of hepatocellular carcinoma in nude mice. The effect of sorafenib does not exclusively depend on high levels of pERK in tumors. PMID- 21671806 TI - JAVMA News. Banfield reports on state of pet health. PMID- 21671807 TI - Ethical considerations raised by the provision of freebies to veterinary students. PMID- 21671808 TI - What is your diagnosis? Cervical vertebral compressive myelopathy at C6-7. PMID- 21671809 TI - Pathology in practice. Neutrophilic and histiocytic inflammation with intracellular bacteria (consistent with R equi). PMID- 21671810 TI - Pathology in practice. Thymic lymphoma with vertebral bone marrow involvement, spinal cord compression, and Wallerian degeneration. PMID- 21671811 TI - Assessment of avian influenza surveillance and reporting needs of stakeholders in Michigan, 2007. AB - OBJECTIVE: To identify stakeholders who should be included in a Michigan-based avian influenza surveillance system (AISS) and to describe their avian influenza (AI) surveillance and reporting needs. DESIGN: Cross-sectional survey involving a convenience sample of respondents. SAMPLE: 272 federal, state, and local governmental and regulatory agency professionals; veterinarians and laboratory professionals in academia; private practice veterinarians; and poultry industry members. PROCEDURES: A needs assessment survey that focused on stakeholder identification, current surveillance methods, information sharing, and desired AISS enhancements was administered by mail, and responses were summarized. RESULTS: Various AISS stakeholders were identified, among whom the requirements for surveillance information and methods of reporting (including via a World Wide Web-based database, e-mail, and a website) differed. Although 90% of all respondent types indicated that poultry industry representatives were key stakeholders, < 33% of poultry industry respondents indicated that private practice veterinarians and personnel in laboratories or public agencies should be considered stakeholders. The predominant concern (55.4% of respondents) regarding the current AISS was the effectiveness of communication among agencies, industry, and the public. The primary challenge identified by respondents was confidentiality (30.2% of respondents). CONCLUSIONS AND CLINICAL RELEVANCE: In Michigan-and potentially in other regions of the United States-integration of Internet-related data systems and stakeholder communication is likely to promote earlier identification of AI, achieve more effective responses to outbreaks, reduce morbidity among humans and other animals, and decrease outbreak-associated financial losses. Stakeholder education and technological safeguard assurances will be essential in AISS enhancement. PMID- 21671814 TI - Comparison of the effect of single-site and multiple-site disk fenestration on the rate of recurrence of thoracolumbar intervertebral disk herniation in dogs. AB - OBJECTIVE: To prospectively assess whether multiple-site disk fenestration decreases the incidence of recurrent thoracolumbar intervertebral disk herniation (IVDH), compared with single-site disk fenestration, in small-breed dogs treated for IVDH. DESIGN: Randomized controlled clinical trial. ANIMALS: 207 client-owned dogs. PROCEDURES: Dogs undergoing decompressive surgery of the spinal cord because of thoracolumbar IVDH between 2001 and 2004 were randomly assigned to receive single-site disk fenestration at the level of surgical decompression (n = 103) or multiple-site disk fenestration of all disks from T11 through L4 (104). Follow-up consisted of complete reevaluation of patients, telephone surveys, and further surgery if signs indicative of recurrence occurred. RESULTS: 189 dogs were available for long-term follow-up: 95 dogs in the single-site disk fenestration group and 94 in the multiple-site disk fenestration group. Twenty four dogs developed 28 confirmed episodes of recurrent thoracolumbar IVDH. The rate for first-time recurrence was 12.7% (24/189). First-time recurrence rates for single-and multiple-site disk fenestration groups were 17.89% (17/95) and 7.45% (7/94), respectively. Dogs undergoing single-site disk fenestration were significantly more likely to have recurrent thoracolumbar IVDH than were dogs undergoing multiple-site disk fenestration. Disk mineralization at the time of first surgery was associated with recurrence, and 87.5% (21/24) of recurrences occurred at a disk space adjacent to or 1 disk away from the initial lesion. Regardless of disk fenestration group, 22 of 24 (91.7%) recurrences occurred at a nonfenestrated disk space. CONCLUSIONS AND CLINICAL RELEVANCE: Multiple-site disk fenestration decreased the rate of recurrent IVDH in small-breed dogs, compared with the use of single-site disk fenestration. PMID- 21671815 TI - Intraobserver, interobserver, and intermethod agreement for results of myelography, computed tomography-myelography, and low-field magnetic resonance imaging in dogs with disk-associated wobbler syndrome. AB - OBJECTIVE: To determine intraobserver, interobserver, and intermethod agreement for results of myelography, computed tomography-myelography (CTM), and low-field magnetic resonance imaging (MRI) in dogs with disk-associated wobbler syndrome (DAWS). DESIGN: Prospective cross-sectional study. ANIMALS: 22 dogs with DAWS. PROCEDURES: All dogs underwent myelography, CTM, and low-field MRI. Each imaging study was interpreted twice by 4 observers who were blinded to signalment and clinical information of the patients. The following variables were assessed by all 3 techniques: number, site, and direction of spinal cord compressions; narrowed intervertebral disk spaces; vertebral body abnormalities; spondylosis deformans; and abnormal articular facets. Intervertebral foraminal stenosis was assessed on CTM and MRI images. Intraobserver, interobserver, and intermethod agreement were calculated by kappa and weighted kappa statistics. RESULTS: There was very good to good intraobserver agreement for most variables assessed by myelography and only moderate intraobserver agreement for most variables assessed by CTM and low-field MRI. There was moderate to fair interobserver and intermethod agreement for most variables assessed by the 3 diagnostic techniques. There was very good or good intraobserver, interobserver, or intermethod agreement for the site and direction of the worst spinal cord compression as assessed by all the imaging modalities; abnormal articular facets and intervertebral foraminal stenosis were the least reliably assessed variables, with poor interobserver agreement regardless of imaging modality used. CONCLUSIONS AND CLINICAL RELEVANCE: There was considerable variation in image interpretation among observers and between use of various imaging modalities; these imaging techniques should be considered complementary in assessment of dogs with DAWS. PMID- 21671816 TI - Analysis of solicitation of client concerns in companion animal practice. AB - OBJECTIVE: To examine veterinarian solicitation of client concerns in companion animal practice. DESIGN: Cross-sectional descriptive study. SAMPLE-20 veterinarians in companion animal practice in Eastern Ontario and 334 clients and their pets. PROCEDURES: Beginning segments of 334 appointments were coded for a veterinarian solicitation (open- or closed-ended question) used to elicit client concerns. Appointments including a solicitation were analyzed for completion of the client's response and its length. The association between veterinarian solicitations at the beginning and concerns arising at the closure of the interview was examined. RESULTS: 123 (37%) of the coded appointments contained a veterinarian solicitation, of which 93 (76%) were open-ended and 30 (24%) were closed-ended solicitations. Client responses to a solicitation were interrupted in 68 of 123 (55%) appointments. Main reasons for incomplete client responses were veterinarian interruptions in the form of closed-ended questioning (39/68) and noninterrogative statements (18/68). Median length of time clients spoke before interruption was 11 seconds (range, 1 to 139 seconds; mean, 15.3 seconds; SD, 12.1 seconds). The odds of a new concern arising during the closing segment of an appointment were 4 times as great when the appointment did not contain a veterinarian solicitation at the beginning of the interview. CONCLUSIONS AND CLINICAL RELEVANCE: Not soliciting client concerns at the beginning of an interview increased the odds of a concern arising during the final moments of the interaction. This required the veterinarian to choose among extending the appointment to address the concern, ignoring the concern at a possible cost to client satisfaction, or deferring the concern to another visit. PMID- 21671817 TI - Multiple endocrine diseases in dogs: 35 cases (1996-2009). AB - OBJECTIVE: To characterize a population of dogs from a tertiary care center with 2 or more endocrine disorders, including the specific disorders and time intervals between diagnosis of each disorder. DESIGN: Retrospective case series. ANIMALS: 35 dogs with 2 or more endocrine disorders. PROCEDURES: Medical records were reviewed, and the following was recorded: clinical signs, physical examination findings, and the results of CBC, serum biochemical analysis, urinalysis, aerobic bacterial culture of urine samples, endocrine testing, diagnostic imaging, and necropsy. RESULTS: 35 dogs with more than 1 endocrine disorder were identified. Seventy-seven percent (27/35) of the dogs were male, and the mean age at the time of diagnosis of the first endocrinopathy was 7.9 years. Miniature Schnauzer was the most common breed. Twenty-eight of 35 (80%) dogs had 2 disorders; 7 (20%) had 3 disorders. The most common combinations of disorders included diabetes mellitus and hyperadrenocorticism in 57.1 % (20/35) of dogs; hypoadrenocorticism and hypothyroidism in 22.9% (8/35) of dogs; and diabetes mellitus and hypothyroidism in 28.6% (10/35) of dogs. A mean of 14.5 months elapsed between diagnosis of the first and second endocrine disorders, whereas there was a mean of 31.1 months between diagnosis of the first and third endocrine disorders. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that the occurrence of multiple endocrine disorders was uncommon in dogs. The most common combinations of endocrine disorders in this population of dogs were diabetes mellitus and hyperadrenocorticism, followed by hypoadrenocorticism and hypothyroidism. PMID- 21671818 TI - Clinical factors associated with death before discharge and overall survival time in dogs with generalized megaesophagus. AB - OBJECTIVE: To investigate the association of 6 clinical features with outcome of dogs with generalized megaesophagus. DESIGN: Retrospective cohort study. ANIMALS: 71 client-owned dogs with radiographic evidence of generalized esophageal dilation. PROCEDURES: Medical records were reviewed for data on signalment, age at onset of clinical signs, body weight, evidence of undernutrition, and the administration of drugs to treat or prevent esophagitis. Radiographs were reviewed for evidence of aspiration pneumonia (AP) and to calculate the relative esophageal diameter. Details of outcome were collected from the medical records and by contacting owners and referring veterinarians. The association of 6 factors with death before discharge and overall survival time was assessed. RESULTS: Overall median survival time was 90 days. Nineteen (26.7%) patients died before discharge from the hospital. Radiographic evidence of AP was both positively associated with death before discharge and negatively associated with overall survival time. An age at onset of clinical signs of >13 months was negatively associated with overall survival time. No evidence of an association of the degree of esophageal dilation or the use of drugs to prevent or treat esophagitis with death before discharge or overall survival time was found. CONCLUSIONS AND CLINICAL RELEVANCE: Radiographic evidence of AP and the age at onset of clinical signs were the only variables found to be significantly associated with survival time in this study, and this should be considered when advising on prognosis in dogs with megaesophagus. PMID- 21671819 TI - Evaluation of sedation and analgesia in standing horses after administration of xylazine, butorphanol, and subanesthetic doses of ketamine. AB - OBJECTIVE: To evaluate the sedative and analgesic effects of subanesthetic doses of ketamine in horses sedated with xylazine, with or without butorphanol. DESIGN: Prospective, randomized, controlled study. ANIMALS: 10 adult horses. PROCEDURES: Each horse was sedated multiple times by administration of xylazine (treatment X), xylazine and butorphanol (treatment XB), xylazine with 1 of 2 dosages of ketamine (treatment XK1 or XK2), or xylazine and butorphanol with 1 of 2 dosages of ketamine (treatment XBK1 or XBK2). Head height and various behaviors, including responses to noise, insertion of a dental float, needle prick on the flank, algometer pressure on the scapula, and bilateral carpal arthrocenteses, were evaluated. RESULTS: No significant differences were detected among sedation treatments for head height, response to noise, or response to arthrocenteses. Insertion of a dental float was easiest with treatment XBK2 and most difficult with treatments XK1 and XK2. Response to a needle prick on the flank was lowest with treatment XB and highest with treatment XK2. Tolerance to algometer pressure over the scapula was highest with treatment XBK2 and lowest with treatment X. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of a subanesthetic dosage of ketamine with xylazine and butorphanol may facilitate certain procedures, such as insertion of a dental float, in horses and enhance tolerance to pressure stimulation, but it may worsen responses to acute pain, such as that caused by a needle prick. Further evaluation is needed to determine whether subanesthetic dosages of ketamine might be useful when performing certain clinical procedures in horses. PMID- 21671820 TI - Epiglottic abnormalities in mature nonracehorses: 23 cases (1990-2009). AB - OBJECTIVE: To identify history, clinical signs, endoscopic findings, treatment, and outcome of mature (> 8 years old) nonracehorses with epiglottic abnormalities. DESIGN: Retrospective case series. ANIMALS: 23 horses with an epiglottic abnormality. PROCEDURES: Medical records of horses examined between 1990 and 2009 because of an epiglottic abnormality were reviewed to obtain information on signalment, history, clinical signs, clinical examination findings, upper airway endoscopic findings, diagnosis, surgical procedure, clinical management, postoperative care, and outcome. RESULTS: Mean +/- SD age was 16 +/- 6 years (range, 9 to 30 years). Sixteen of the 23 (70%) horses had a primary complaint of a chronic cough. Thirteen (57%) horses had epiglottic entrapment, 7 (30%) had a subepiglottic granuloma, and 3 (13%) had a subepiglottic cyst. All 23 horses were treated surgically, with 1 (4%) requiring further surgical treatment. Follow-up examinations and conversations with owners indicated resolution of the primary complaint in 17 of the 23 (74%) horses, with 4 (24%) requiring prolonged medical treatment because of postoperative subepiglottic inflammation. Of the 6 horses without complete resolution, 4 (67%) had signs of recurrent airway obstruction and 2 (33%) developed persistent dorsal displacement of the soft palate following laryngotomy and subepiglottic membrane resection. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that coughing is a common complaint in mature nonracehorses with epiglottic abnormalities. Therefore, upper airway endoscopy is recommended in the evaluation of older horses with a cough. Surgical treatment can be beneficial in most horses, with some requiring further postoperative medical treatment. PMID- 21671821 TI - Advances in gastro retentive drug-delivery systems. AB - INTRODUCTION: In recent years, various technological improvements have been achieved and new concepts have been developed, in the area of controlled release solid oral dosage forms, especially for products where an extended time of release is associated with an extended gastric retention time. These Gastro Retentive Systems have been quite investigated because they can improve the in vivo performance of many drugs. AREAS COVERED: This paper summarizes current approaches in the research and development of gastro retentive dosage forms from recent literature. Apart from the numerous mechanisms of action involved, a short review of different key parameters is proposed, taking into account the stomach physiology. Most of the current technologies published, patented or marketed are presented. Promising drugs to develop in the near future are mentioned, and the importance of such systems in fixed Dose Combinations is also discussed. The importance of food effect is mentioned, and the impact of the multiple unit systems versus monolithic approach is discussed, especially regarding the dose intake. EXPERT OPINION: In conclusion, numerous mechanisms like floating, sinking, effervescence, swelling, bioadhesion, magnetic, etc. have been proposed over the years. While most of the proposed systems show promising dissolution profiles and in-vitro retention, only few of them have also shown success in vivo. Currently, the polymeric swelling monolithic systems are the most prominent marketed forms. The possibility to combine different mechanisms in order to ensure true gastric retention even in the fasted state should be further investigated. PMID- 21671822 TI - The correlation between zinc and insulin-like growth factor 1 (IGF-1), its binding protein (IGFBP-3) and prostate-specific antigen (PSA) in prostate cancer. AB - BACKGROUND: The objective of the present study is to explore the association between zinc concentrations and insulin-like growth factor 1 (IGF-1), its binding protein (IGFBP-3) and total prostate-specific antigen (tPSA) levels in the serum of patients with prostate cancer (PCa) and prostate intraepithelial neoplasia (PIN), a pre-cancer state matched for age. METHODS: The study was carried out in a group of 229 patients who had transurethral prostate biopsy performed. The patients were divided into three groups: control group (BPH), PIN group or PCa group. The patients had plasma zinc concentration determined by atomic absorption spectrometry; IGF-1, IGFBP-3 analyzed using the chemiluminescence method and tPSA detected in serum with DELFIA assay. RESULTS: The studies revealed that, in PCa and PIN patients aged under 65 years, mean zinc concentrations were significantly lower compared with the control group. IGF-1 level significantly increased with decreasing level of zinc in plasma, hence a significantly decreased Zn/IGF-1 ratio. The mean tPSA concentration was significantly increased only in PCa patients of both age groups, whereas the Zn/tPSA ratio significantly decreased with increasing severity of neoplastic lesions, particularly in patients aged under 65 years. Statistical significance was noted for IGF-1:tPSA and IGFBP 3:tPSA ratios, being almost two-fold lower in the PCa patients than in the control group. CONCLUSIONS: A significantly lowered Zn/tPSA ratio appears to be a sensitive marker of neoplastic lesions, PCa and PIN, regardless of age. In men under 65 years, the Zn/IGF-1 ratio was reduced, depending on the stage of neoplastic lesions (PIN>PCa). These finding can be useful in early diagnosis of prostate cancer. PMID- 21671823 TI - Application of autologous bone marrow mononuclear cells in six patients with advanced chronic critical limb ischemia as a result of diabetes: our experience. AB - BACKGROUND AIMS: Previous clinical studies have reported that the injection of bone marrow (BM)-derived mononuclear cells (MNC) results in improvement in symptoms and healing of ulcers in patients with critical limb ischemia (CLI) up to stage IV of Fontaine's classification. However, most patients with Fontaine stage IV CLI limbs had to undergo amputation even after stem cell therapy. We report on six patients, who had poorly controlled diabetes with extensive ulceration and gangrene of limbs because of Fontaine stage IV CLI and had been advised amputation elsewhere, who underwent injection of autologous BM MNC. METHODS: In all six patients, BM was aspirated and the isolated MNC from the BM were injected intralesionally at various sites of the ulcer and its surroundings after necessary debridement. The patients were followed up at regular intervals for at least 6 months. RESULTS: At the end of the 6-month follow-up, the lower limb pain and ulcers had improved significantly in all patients. The mean toe brachial index had increased from 0.26 to 0.36. One patient died a month after therapy because of causes unrelated to the procedure. Limb salvage was possible in the remaining five patients and they had a pain-free walking distance of 100 m within 6 months. CONCLUSIONS: Limb salvage was possible in all six diabetic patients with Fontaine stage IV CLI following autologous BM MNC injection. The procedure was safe without any adverse outcomes. PMID- 21671824 TI - Group B Streptococcus in a cohort of HIV-infected pregnant women: prevalence of colonization, identification and antimicrobial susceptibility profile. AB - Group B Streptococcus (GBS) is a leading cause of infectious morbidity in newborns. We describe the prevalence of GBS colonization and the serotypes and antibiotic susceptibility profiles of isolates obtained from a cohort of human immunodeficiency virus (HIV)-infected pregnant women. This was a cross-sectional study at a centre for the prevention of mother-to-child transmission of HIV. Vaginal and rectal swabs were collected at 35-37 weeks of gestation from 158 eligible women. GBS isolates were serotyped and antimicrobial susceptibility tests performed. Patient sociodemographic characteristics, CD4 counts and viral loads were abstracted from records. The overall anogenital prevalence of GBS colonization was 49/158 (31.0%): 40/158 (25.3%) for vagina, 19/158 (12.0%) for rectum and 10/158 (6.3%) for both. Predominant serotypes were Ib (34.9%) and Ia (25.6%). All were penicillin-susceptible. Two were resistant to erythromycin (4.0%) and one to clindamycin (2.0%). The colonization rate by GBS was high in this cohort. Serotype Ib was the most frequently identified. PMID- 21671825 TI - Linezolid in the treatment of methicillin-resistant staphylococcal post neurosurgical meningitis: a series of 17 cases. AB - BACKGROUND: Linezolid is a bacteriostatic antibiotic with good cerebrospinal fluid penetration. The aim of this study was to evaluate the efficacy of linezolid in methicillin-resistant staphylococcal (methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococcus (MRCoNS)) meningitis. METHODS: We extracted data and outcomes for all adult patients (age > 18 y) with culture-proven MRSA or MRCoNS meningitis treated with linezolid between January 2006 and September 2010 in our hospital. Demographic, clinical, and laboratory data and predisposing factors, as well as information on response to treatment and outcome were obtained by regular visits. RESULTS: A total of 17 cases (9 MRCoNS, 7 MRSA, and 1 MRCoNS and MRSA mixed) fulfilled the inclusion criteria. All patients had hospital-acquired meningitis and had undergone neurosurgery. Cumulative microbiological success on day 5 was 88%. There was 1 staphylococcal meningitis-related death. There were no severe adverse events. CONCLUSIONS: Our experience with linezolid suggests that it can be an alternative for the treatment of MRCoNS- and MRSA-related meningitis. PMID- 21671826 TI - Lower incidence of catheter-related bloodstream infection in cubital than in femoral artery access. AB - Data on catheter-related bloodstream infection (CRBSI) in cubital artery access are scarce. Thus, the objective of this study was to compare the incidence of CRBSI in a large series of patients with femoral or cubital artery catheters. We found 11 events of CRBSI in 1085 femoral artery catheters during 6497 days and none in 449 cubital artery catheters during 2709 days. Poisson regression analysis showed a higher incidence of CRBSI in femoral than in cubital artery site access (1.69 vs 0 CRBSI events per 1000 catheter-days; odds ratio 6.41, 95% confidence interval 1.05-infinite; p = 0.02). In conclusion, according to the results of our observational study, cubital artery access could have a lower risk of CRBSI than femoral artery access. However the development of randomized controlled trials is necessary before this conclusion can be definitively established. In addition, it is necessary to consider other potential mechanical complications when decision-making. PMID- 21671827 TI - AFCo1 as nasal adjuvant of capsular polysaccharide from Neisseria meningitidis serogroup C induces systemic and mucosal immune responses. AB - Increasing emphasis is being placed on the mucosal administration of vaccines in order to stimulate mucosal as well as systemic responses. Findings from our group suggest that proteoliposome-derived cochleate (AFCo1) acts as a potent mucosal adjuvant. As an alternative to chemical conjugation, the current study aimed to determine the benefit of using AFCo1 to improve the mucosal and systemic immune responses to capsular polysaccharide of Neisseria meningitidis serogroup C (PsC), a model of a thymus-independent (TI) antigen. Therefore, intranasal (i.n.) immunization of 3 doses 1 week apart with AFCo1 plus PsC in mice was conducted. Highly specific anti-PsC IgA responses and an anti-PsC IgG response were obtained. The subclass pattern induced against PsC was similar to that induced with the meningococcal vaccine. In summary, AFCo1 as nasal adjuvant was demonstrated to be capable of eliciting mucosal and systemic specific responses against a TI antigen. PMID- 21671828 TI - Driving and driving cessation after traumatic brain injury: processes and key times of need. AB - PURPOSE: The ability to drive safely is commonly affected by traumatic brain injury (TBI). Driving is a role and activity that is highly valued and also associated with successful community reintegration after TBI. Relatively little is understood about the processes of interruption to driving and potential return to driving that can be experienced by people with TBI and their family members (FMs). Exploring the way in which driving interruption, return to driving and permanent cessation of driving happen for people with TBI, their FMs and health professionals (HPs) who work with them can enable a fuller understanding of the experiences and needs and enhance the rehabilitation approaches in this situation. METHOD: A descriptive phenomenological approach was used to explore the experience with the aim of improving services for people with TBI. Semi structured interviews about driving and driving cessation were conducted with 15 people with TBI, 10 FMs and 10 HPs who had experience in driving and driving cessation issues. RESULTS: The findings reveal experiences of the process of driving and driving cessation contextualised within experiences of the accident and treatment process. Participants identified key times of need in relation to driving: being told about driving restrictions, understanding driving restrictions, the 'on hold' period, and returning to driving. CONCLUSIONS: The processes surrounding driving and driving cessation after TBI are complex. Informational, support and practical needs differ at the different times. There are key times where people may need further support to improve rehabilitation outcomes. Rehabilitation approaches may particularly need to provide clear, consistent information about driving restrictions, and the process required for returning to driving. While recovery time appears necessary for allowing a safe return to driving, active support for continued involvement in the community using alternative transport may reduce the frustration and disengagement experienced by people in the 'on hold' period. PMID- 21671829 TI - Voriconazole-associated severe hyponatremia. AB - Voriconazole is the drug of choice for invasive aspergillosis. We describe three patients who presented with severe hyponatremia after the initiation of voriconazole treatment. One patient expired while the other two patients recovered after a dose adjustment or discontinuation of the antifungal. The voriconazole trough levels were checked in all and two were elevated. These findings mandate monitoring electrolyte levels during voriconazole therapy. PMID- 21671830 TI - Adhesion and invasion of Candida albicans from periodontal pockets of patients with chronic periodontitis and diabetes to gingival human fibroblasts. AB - The objectives of this study were to evaluate clinical isolates of Candida albicans, particularly their adhesion to and invasion of gingival human fibroblasts in culture and to measure nitric oxide concentration (NO) produced by fibroblasts in the presence of these yeasts. Sixteen strains of C. albicans isolated from patients with chronic periodontitis and diabetes mellitus type II were divided on the basis of phenotypic tests into two groups, i.e., highly or weakly hydrophobic. Primary cultures of human fibroblasts were isolated from gingival biopsies and after subsequent subcultures, the cells were seeded into culture plates and incubated for 24 h. C. albicans strains were inoculated into these plates and maintained for 2 and 4 h to assess their adhesion and invasion, respectively. The number of adherent or invasive yeasts was evaluated by assessing colony-forming units (CFU). The production of NO by fibroblasts was also quantified. The results showed that strains with high hydrophobicity had a greater ability to adhere and invade fibroblasts (p < 0.05, ANOVA and Tukey). The production of NO was higher for the most hydrophobic strains, but did not reach statistical difference with the weakly hydrophobic isolates. These data indicated that the hydrophobicity may play a role in the adhesion and invasion of C. albicans in fibroblast cultures. PMID- 21671832 TI - Intergenerational and familial approaches to obesity and related conditions. PMID- 21671831 TI - Lindnera (Pichia) fabianii blood infection after mesenteric ischemia. AB - Lindnera (Pichia) fabianii (teleomorph of Candida fabianii) is a yeast species rarely involved in human infections. This report describes the first known human case of a Lindnera fabianii blood infection after mesenteric ischemia. The 53 year-old patient was hospitalized in the intensive care unit after a suicide attempt and was suffering from a mesenteric ischemia and acute renal failure. Lindnera fabianii was recovered from an oropharyngeal swab, then isolated from stool and urine samples before the diagnosis of the blood infection. Caspofungin intravenous treatment was associated with a successful outcome. Final unequivocal identification of the strain was done by sequencing the internal transcribed spacer (ITS) region, and regions of 18S rDNA gene and of the translation elongation factor-1alpha gene. Until our work, the genomic databases did not contain the complete ITS region of L. fabianii as a single nucleotide sequence (encompassing ITS1, the 5.8S rDNA and ITS2), and misidentification with other yeast species, e.g., Lindnera (Pichia) mississippiensis, could have occurred. Our work demonstrates that the usual DNA barcoding method based on sequencing of the ITS region may fail to provide the correct identification of some taxa, and that partial sequencing of the EF1alpha gene may be much more effective for the accurate delineation and molecular identification of new emerging opportunistic yeast pathogens. PMID- 21671833 TI - Experiences and needs for work participation in employees with rheumatoid arthritis treated with anti-tumour necrosis factor therapy. AB - PURPOSE: To investigate the experiences and needs with respect to work participation of employees with rheumatoid arthritis (RA) treated with anti tumour necrosis factor (TNF) therapy. METHOD: Face-to-face interviews in 14 employees with RA on anti-TNF therapy focused on experiences, offered support and needs with respect to work participation. RESULTS: Experiences regarding work participation varied and ranged from fatigue at work, having no job control, not being understood by the work environment or difficulty dealing with emotions as a result of interaction within the work environment. Support by health care professionals for work participation was considered important, especially concerning social or psychological issues. Advice in becoming aware of one's changes in abilities was highly appreciated, as was the availability of professional advice in times of an urgent work issue due to RA. Employees mentioned an increase in social support at work and job control as important facilitating factors for work participation. CONCLUSION: Although patients with RA report improvement in their work functioning after starting anti-TNF therapy, employees continue facing challenges in working life due to RA. For support concerning work participation, it is recommended that health care professionals are more aware of work-related problems in patients with RA treated with anti-TNF therapy. PMID- 21671834 TI - Parental and offspring adiposity associations: insights from the 1958 British birth cohort. AB - BACKGROUND/AIMS: Parent-offspring adiposity associations are well-established: offspring of obese parents have elevated risks of overweight/obesity. The aim of studies based on the 1958 British birth cohort has been to gain insights into explanations of these associations, such as whether parent-offspring BMI associations are due to offspring lifestyles or depend on socio-economic conditions. METHODS: All major studies on intergenerational adiposity associations in the three generations of the 1958 birth cohort were reviewed. In addition, BMI data for parents (G1) and the cohort (G2) were analysed stratified by social class. RESULTS: BMI of G1 and G2 were correlated both when offspring were children and in mid-adulthood: a 1 kg/m(2) higher parental BMI was associated with an average 0.24-0.35 kg/m(2) higher offspring (mothers/fathers vs sons/daughters) BMI at 45 years. Associations were little affected by adjustment for lifestyle and socio-economic factors, but varied by social class: average BMI gain in offspring relative to parents was greater in lower classes, e.g. for males vs fathers by 3.6 and 2.5 kg/m(2) in classes IV&V and I&II, respectively. Parent-offspring BMI associations were stronger for recent (G2 and G3) than older (G1 and G2) generations. CONCLUSIONS: Parent-offspring associations in BMI were not explained by offspring lifestyles, but varied over successive generations and by social class, suggesting that intergenerational transmission of adiposity at a population level is modifiable rather than immutable. PMID- 21671835 TI - Experience in the use of sunitinib given as a single agent in metastatic chemoresistant and castration-resistant prostate cancer patients. AB - OBJECTIVE: Vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) correlate with poor prognosis in castration-resistant prostate cancer (CRPC). Sunitinib has shown activity in CRPC and at the time of this analysis there was no standard therapy for docetaxel refractory CRPC. METHODS: We present a case series data collection of 19 patients with a median age of 73 years, CRPC and rising prostate-specific antigen (PSA). Patients received sunitinib 37.5 mg continuous daily dose. One cycle comprised a 4-week period. Patients were evaluated by CT scan every 8 weeks and PSA was monitored every 4 weeks. RESULTS: Median Eastern Cooperative Oncology Group (ECOG) performance status score was 2. Patients received a median of two previous treatment lines for the hormone-refractory setting. Baseline median PSA was 280 ng/ml. Patients received a median of 16 weeks of therapy (4 - 48+). One patient achieved a partial response (5%) and 12 (66.7%) achieved stable disease for at least 3 months according to RECIST criteria. Median progression-free survival was 4 months. PSA declined > 50% in 5/19 (26.3%) and stabilized in 7/19 (37%) patients. Frequent adverse events were grade 3 asthenia (21%), grade 3 diarrhea (10%) and grade 3 hand-foot syndrome (15.7%). CONCLUSIONS: Activity with sunitinib was observed in highly pretreated docetaxel-refractory CRPC with acceptable tolerability. Additional studies should confirm the role of antiangiogenic agents in this setting. PMID- 21671836 TI - Preparation and evaluation of zolmitriptan submicron emulsion for rapid and effective nasal absorption in beagle dogs. AB - Submicron emulsion was prepared for rapid and effective nasal absorption of zolmitriptan (ZT). The different charge inducers and pH values of the formulations were evaluated to optimize the formulations. Submicron emulsion prepared by using stearylamine as positive charge inducer with pH of 5.0 was stable and most of ZT was freely dispersed in the aqueous phase of the preparation. In vitro release study demonstrated that ZT from the submicron emulsion preparation could be released as fast as that from the solution preparation. The pharmacokinetics was studied after intranasal administration of the submicron emulsion and solution preparation of ZT to beagle dogs. ZT from the submicron emulsion was absorbed much more rapidly and the absolute availability of the submicron emulsion preparation was significantly higher compared with the solution preparation. The nasal ciliotoxicity of the preparations was evaluated by using in situ toad palate model, which indicated that the submicron emulsion of ZT did not exhibit any obvious nasal ciliotoxicity. These results demonstrated that the submicron emulsion preparation of ZT was a relatively safe dosage form for rapid and effective intranasal delivery of ZT. PMID- 21671837 TI - Ethyl acetate extracts of raw and steamed Codonopsis lanceolata protects against ischemic damage potentially by maintaining SOD1 and BDNF levels. AB - We observed the neuroprotective effects of ECLs treatment on ischemic damage in the gerbil hippocampal CA1 region four days after an ischemic insult. Among the 10 ECLs, EERCL and EESCL showed significant neuroprotection: the percentage of neurons remaining after treatment with EERCL and EESCL was 72.7% and 68.4% of that seen in the sham-ischemia group, respectively. The administration of EERCL and EESCL significantly decreased the reactive gliosis of microglia compared with that seen in the vehicle-treated ischemia group. In addition, SOD1 and BDNF immunoreactivity in the EERCL- and EESCL-ischemia groups were markedly increased compared with that in the vehicle-treated ischemia group. These results suggest that the administration of EERCL and EESCL can reduce ischemic neuronal loss potentially by maintaining SOD1 and BDNF immunoreactivity in the ischemic hippocampal CA1 region. PMID- 21671838 TI - Design and characterization of sustained release ketoprofen entrapped carnauba wax microparticles. AB - CONTEXT: Ketoprofen is a non-steroid anti-inflammatory drug (NSAID) used in the treatment of rheumatic diseases and in mild to moderate pain. Ketoprofen has a short biological half-life and the commercially available conventional release formulations require dosages to be administered at least 2-3 times a day. Due to these characteristics, ketoprofen is a good candidate for the preparation of controlled release formulations. OBJECTIVES: In this work, a multiparticulate sustained release dosage form containing ketoprofen in a carnauba wax matrix was developed. METHODS: Particles were prepared by an emulsion congealing technique. System variables were optimized using fractional factorial and response surface experimental design. Characterization of the particles included size and morphology, flow rate, drug loading and in vitro drug release. RESULTS: Spherical particles were obtained with high drug load and sustained drug release profile. The optimized particles had an average diameter of approximately 200 um, 50% (w/w) drug load, good flow properties and prolonged ketoprofen release for more than 24 h. CONCLUSIONS: Carnauba wax microspheres prepared in this work represent a new multiparticulate-sustained release system for the NSAID ketoprofen, exhibiting good potential for application in further pharmaceutical processes. PMID- 21671839 TI - Cannabinoid treatment renders neurons less vulnerable than oligodendrocytes in Experimental Autoimmune Encephalomyelitis. AB - Using the rat model Experimental Autoimmune Encephalomyelitis (EAE), we have investigated the cytokinetical and cellular events of axonal degeneration and demyelination following treatment with 5 mg/kg/24h R(+)WIN55,212-2 or 10 mg/kg/24h R(+)WIN55,212-2, which have immunosuppressive effects. EAE was induced using MOG(1-125) in Dark Agouti rats and treatment was initiated at symptom debut and continued until first relapse culminated. The central nervous system (CNS) cell death including caspase and calpain activation, axonal degeneration and demyelination as well as a wide range of immunological parameters were quantified. We found a significant reduction in axonal degeneration associated with reduced calpain 1 following treatment with 5 mg/kg/24h R(+)WIN55,212-2. Treatment with 10 mg/kg/24h resulted furthermore in an improved clinical performance and a reduction in inflammatory activity and demyelination. Furthermore, the cytokines IL-2, IL-6, IL-10, RANTES, and TGF-beta were significantly reduced as were the cellular infiltration with regulatory T cells. We suggest that cannabinoids in low doses are neuroprotective through a reduction in calpain 1 expression. Our study implies that long-term low-dose cannabinoid administration to multiple sclerosis (MS) patients could result in some degree of neuroprotection, and thereby slow down the atrophy associated with this disease. PMID- 21671840 TI - Determining the efficacy of rasagiline in reducing bradykinesia among Parkinson's disease patients: a review. AB - BACKGROUND: Bradykinesia has a significant impact on the lives of Parkinson's disease (PD) patients. Consequently, treating this symptom is of particular concern for patients and clinicians. A number of studies have documented the efficacy of rasagiline in reducing the severity of PD symptoms. OBJECTIVE: To summarize studies that specifically examined the impact of rasagiline on bradykinesia symptoms in PD patients across disease severity. METHODS: The EMBASE database was searched for relevant articles published between 2000 and November 2010. RESULTS: Three studies were identified that explicitly examined the effect of rasagiline on the bradykinesia subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. In each, 1 mg/day rasagiline significantly reduced bradykinesia scores in patients. CONCLUSION: As a monotherapy or an adjunctive therapy, rasagiline is an effective drug for reducing the severity of bradykinesia in PD patients. PMID- 21671841 TI - Retrospective chart review of duloxetine and pregabalin in the treatment of painful neuropathy. AB - The primary aims of our study were to compare pregabalin and duloxetine in a neuromuscular clinic for diabetic neuropathic pain (DPN) and to study the effect of these medications in cryptogenic sensory polyneuropathy. We performed a retrospective chart review of 143 patients who were started on pregabalin or duloxetine during a 10-month period in a tertiary neuromuscular outpatient center for neuropathic pain. Duloxetine and pregabalin were started in 103 and 91 patients, respectively. Ninety-two patients tried only one of the two medications while both medications were used at different time periods in 51 patients. Follow up was available for 87 patients on pregabalin and 89 patients on duloxetine. More patients with neuropathic pain reported an improvement with pregabalin (33%) than duloxetine (21%). Duloxetine (38%) had a higher frequency of side effects compared to pregabalin (30%). However, these differences between pregabalin and duloxetine were not statistically significant. Despite the study's limitations of retrospective design, these findings suggest that both pregabalin and duloxetine are probably effective for neuropathic pain, secondary to diabetes or cryptogenic sensory peripheral neuropathy in a tertiary care academic neuromuscular center. Prospective randomized controlled comparative effectiveness studies are required for both drugs in the treatment of neuropathic pain. PMID- 21671842 TI - Serum levels of lipoxin A(4) do not predict the development of subsequent asthma among young children with acute bronchiolitis. AB - BACKGROUND: Acute bronchiolitis frequently causes wheezing in infants and young children, although its relationship to asthma remains unclear. We hypothesized that serum lipoxin A(4) levels may be used as an early predictive biomarker of subsequent asthma in young children with acute bronchiolitis. METHODS: We recruited 69 children who were divided into 3 groups: 47 children younger than 24 months with acute bronchiolitis as an experimental group (Group 1); 11 children aged 2-24 months with viral acute gastroenteritis as a non-allergic control group (Group 2); and 11 children older than 24 months with physician-diagnosed asthma exacerbations as an asthma control group (Group 3). We determined white blood cell counts, eosinophil counts, and serum levels of C-reactive protein, interleukin-4, interleukin-5, prostaglandin E(2), tumor necrosis factor-alpha, and lipoxin A(4). RESULTS: The mean serum levels of lipoxin A(4) in the groups with acute bronchiolitis (1), acute gastroenteritis (2), and asthma (3) were 0.0430.028, 0.0540.015, and 0.0510.031 ng/ml, respectively. When compared by t tests, there were no significant differences between Groups 1 and 2, or Groups 1 and 3 (p0.05), despite a significant difference between Groups 2 and 3 (p=0.0392). In a final regression model, serum lipoxin A(4) levels were positively correlated with age, female gender, white blood cell counts, and interleukin-5 levels in all patients, while asthma patients had lower serum lipoxin A(4) levels compared to the other two groups. CONCLUSION: Serum levels of lipoxin A(4) cannot be used as an early predictive diagnostic marker for asthma in young children with acute bronchiolitis. PMID- 21671843 TI - Drug safety evaluation of adefovir in HBV infection. AB - INTRODUCTION: Several nucleos(t)ide analogs (NUC) are available for the management of patients with chronic hepatitis B (CHB). In most patients, NUC need to be administered on a long-term basis, thus increasing the risk of adverse effects. Adefovir dipivoxil (ADV), the first nucloeotide analog developed to treat CHB, may indeed cause nephrotoxicity. AREAS COVERED: The pharmacokinetic mechanism of action, potential mechanism of renal damage and long-term safety profile of ADV in CHB patients have been reported. The current monitoring modalities, together with dosage adjustments, treatment of patients with ADV related kidney impairment and the therapeutic algorithm in place at the authors' Liver Center are also summarized. Although, in short-term clinical trials, a daily dose of 10 mg of ADV was safe owing to a low rate of negligible nephrotoxic effects, the same dose may be associated with a usually reversible, proximal renal tubular toxicity as reflected by hypophosphatemia and elevated creatinine levels. Occasionally, Fanconi syndrome occurred in ADV-treated patients. EXPERT OPINION: Renal function at baseline and during treatment should be carefully assessed in all patients receiving ADV to adjust the dose according to creatinine clearance, aimed to prevent or minimize nephrotoxicity. PMID- 21671844 TI - Confirmatory factor analysis in neurophysiological and neuropsychological dimensions of schizophrenia. AB - This study applied confirmatory factor analysis (CFA) to examine the construct of smooth pursuit eye movements (SPEM) and the Wisconsin Card Sorting Test (WCST) in schizophrenia. Participants were assigned to two groups: Group 1 included 27 probands chosen from families with schizophrenia in first-degree relatives, and Group 2 included 54 schizophrenics who had no families with schizophrenia spectrum disorders. There were no differences in the eye tracking pursuit and the WCST between the sporadic and familial schizophrenics. Gender impacted the catch up saccades (CUS) and anticipatory saccades (AS) indices of the SPEM, and the conceptual level responses (CLR) index of the WCST. Education impacted the CLR and perseverative errors of the WCST. Although there were no correlation between the SPEM and the WCST, but the two instruments showed good content validity, which might be useful in the subtyping of schizophrenia. PMID- 21671845 TI - Treatment with calcimimetic (cinacalcet) alters epoetin dosage requirements in dialysis patients: preliminary report. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT), known complication of chronic renal failure, in addition to effects on bone and cardiovascular systems, is associated with reduced response to erythropoietin (EPO). Calcimimetics such as cinacalcet are the latest generation of drugs used in the treatment of SHPT. Few studies have evaluated the effect of cinacalcet on anemia associated with SHPT in dialysis patients, while no study has compared this cinacalcet effect with that of vitamin D analogs such as paricalcitol. PATIENTS AND METHODS: Using a retrospective chart-based review of dialysis patients' records to identify patients being treated with either cinacalcet or paricalcitol alone, matched for the same EPO treatment, which had been followed for 1 year, we have evaluated the effect of cinacalcet on anemia compared to that of paricalcitol. RESULTS: Ten patient records were found that fit the criteria, five treated with cinacalcet (Group 1) and five treated with paricalcitol (Group 2), all treated with the same dose of darbepoetin. Darbepoetin dosage was the only parameter that significantly changed between groups, decreasing in Group 1 (-33%, p = 0.009) while remaining unchanged in Group 2. PTH-level reduction, which was significant versus baseline in both groups, although not statistically different between groups, was higher with cinacalcet. CONCLUSION: The combination of lower EPO dose in cinacalcet treated patients compared with paricalcitol-treated patients, along with good SHPT control is a novel information and might have considerable benefits in dialysis patients not only preventing bone (fractures) and cardiovascular system (calcifications) damages but also in terms of cost savings via a reduction of EPO dosage. PMID- 21671846 TI - Epidemiology of multiple myeloma and the role of M-band detection on serum electrophoresis in a small developing country. A retrospective study. AB - OBJECTIVE: The objective of the study was to determine the role of M-band component on serum protein electrophoresis and bone marrow biopsy in the diagnosis. METHODS: Data was collected on 34 patients with MM diagnosed and/or treated. RESULTS: There were equal numbers of men 17 (50%) and women 17 (50%). All patients were first screened for the presence of M-Band using serum protein electrophoresis (SPE) followed by bone marrow biopsy as the confirmatory test. Only two patients screened negative by SPE. On the other hand six patients who tested positive by SPE were negative on biopsy. Thus the sensitivity of the SPE was 96% and specificity 71%. This means that 29 patients had an established diagnosis of MM. There was a slight male predominance when compared to females. CONCLUSION: The data showed that the SPE and bone biopsy are the important tools in the diagnosis of multiple myeloma in a small developing country. PMID- 21671847 TI - Invited manuscript poster on renal-related education American Society of Nephrology, Nov. 16-21, 2010. Nephrology teaching tool: anagrams. AB - At our institution we have developed unique ways of teaching nephrology and attracting medical students and residents to the field of nephrology. One of the ways we have achieved this is doing talks and sessions using puzzles. This teaching tool was designed to enhance resident learning and to complement resident's role as a teacher, while they were on their nephrology elective. Here we present a sample "anagram" and how it was used to teach the medical residents. PMID- 21671848 TI - Ask-Upmark kidney and tubulointerstitial nephritis in a woman with severe renal failure. AB - Ask-Upmark kidney is a rare diagnosis of segmental hypoplasia in pediatric population clinically characterized by severe hypertension potentially treatable with partial to total nephrectomy. Although originally was described only as a congenital anomaly, recent data suggest to be caused by vesicoureteral reflux, either in utero or in early childhood and pyelonephritis. The case we reported indicates that Ask-Upmark kidney should be considered as potential cause of hypertension and renal failure both in children and adults. The renal biopsy is necessary for early diagnosis and may consent to normalize blood pressure with nephrectomy; however, if renal damage is severe and progressive with tubulointerstitial nephritis, surgical management is excluded and renal transplant should be considered. PMID- 21671849 TI - Invited manuscript poster on renal-related education American Society of Nephrology, Nov. 16-21, 2010. Creative writing in nephrology education. AB - Creative writing has gained some interest in the medical profession in the last decade. There have been a fair amount of publications of using creative writing in the health-care setting as a teaching tool in humanism and doctoring of medicine. As an adjunctive effort, our institution has been experimenting with creative writing exercises to encourage reading in an entertaining way in nephrology. We present a description of two creative tools that we have used to teach renal medicine along with a small pilot study illustrating that the tools were useful in residency education. PMID- 21671850 TI - Acute kidney injury due to emphysematous pyelonephritis on a horseshoe kidney. PMID- 21671851 TI - The changing face of multiple sclerosis clinical trial populations. AB - BACKGROUND: Since the commercial introduction of disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS), there have been numerous randomized placebo-controlled and head-to-head clinical trials assessing the efficacy and safety of these agents in relapsing-remitting MS (RRMS). SCOPE: Recent trials in the past 10 years demonstrate that the characteristics and behavior of clinical trial populations in RRMS have changed. Here we review evidence from key published clinical trials of DMDs in RRMS that highlights the general shift in trial populations, and examine the implications of this shift for future trial design. FINDINGS: Populations in recent studies are characterized by lower clinical disease activity. This difference is apparent with regards to baseline patient characteristics and on-study behavior in terms of outcomes (e.g., relapse rates). The reasons for this shift are probably multifactorial and include study design, current treatment options, patient selection, and a possible change in the natural history of MS. CONCLUSIONS: The variation among study designs makes it difficult to draw more extensive conclusions about changes in clinical trial populations. However, these recent changes undoubtedly will affect interpretation of recent study results, some of which based clinical and statistical assumptions on earlier trials. Furthermore, the shift in populations has major implications for the design of future studies: (1) assumptions regarding effect size and statistical powering must be based on comparable patient populations; (2) larger trials of longer duration may be needed, possibly with stopping criteria based on the number of actual events rather than a preset, fixed time point for the end of study; (3) the use of biomarkers to facilitate identification of subpopulations may be considered; and (4) enhanced measures of disease activity (e.g., composite outcomes) may help to identify effects in multiple relevant MS outcomes. Furthermore, trial design may need to be modified to study the effects of a medication in patients who are representative of the anticipated patient population. To ensure that the clinical trial experience of a drug is reflected in its eventual clinical use, 'real-life' observation study programmers should be conducted to continuously monitor its effects in relevant populations and in comparison with available therapies. PMID- 21671853 TI - Asbestos fiber concentrations in the lungs of brake repair workers: commercial amphiboles levels are predictive of chrysotile levels. AB - OBJECTIVES: To investigate the impact of extreme data points in Finkelstein's 2009 findings of no association between lung levels of commercial and non commercial amphiboles (principally tremolite as a marker for chrysotile asbestos) in brake repair workers with mesothelioma. METHODS: We first identified potential outliers, high leverage points, and influential points among lung levels of commercial amphiboles and tremolite among 15 persons whose only known exposure to asbestos was through brake repair work. We used sensitivity analysis and quantile regression to account for extreme data points and model commercial amphibole levels as a predictor of tremolite levels. We also used quantile regression to evaluate whether case-reported duration of employment as a brake repair worker predicted lung levels of commercial amphiboles or tremolite. RESULTS: We found lung levels of commercial amphiboles are a statistically significant predictor of tremolite levels via sensitivity analysis (r = 0.82, slope estimate P-value = 0.001, R2 = 0.68) and quantile regression (slope estimate P-value <0.0001). Our data provide no evidence that duration of employment as a brake repair worker was a predictor of lung levels of tremolite or commercial amphiboles. CONCLUSIONS: Our findings suggest that elevated lung levels of tremolite in the lungs of brake repair workers with elevated levels of amphiboles arose from concurrent exposures to commercial amphibole and chrysotile asbestos in occupational settings other than brake repair work. These findings are supported by five new cases. The weight of the scientific evidence does not support a role for occupational exposure to brake dust and other friction products in the development of mesothelioma. PMID- 21671852 TI - Olanzapine effects on body composition, food preference, glucose metabolism and insulin sensitivity in the rat. AB - The atypical antipsychotic drug olanzapine induces weight gain and defects in glucose metabolism in patients. Using a rat model we investigated the effects of acute and long term olanzapine treatment on weight gain, food preference and glucose metabolism. Olanzapine treated rats fed a chow diet grew more slowly than vehicle controls but olanzapine treated animals fed a high fat/sugar diet grew faster than control animals on the same diet. These changes in weight were paralleled by changes in fat mass. Olanzapine also induced a strong preference for a high fat/high sugar diet. Acute exposure to olanzapine rapidly induced severe impairments of glucose tolerance and increased insulin secretion but did not impair insulin tolerance. These results indicate the defect in glucose metabolism induced by acute olanzapine treatment was most likely due to increased hepatic glucose output associated with a reduction in active GLP-1 levels and correspondingly high glucagon levels. PMID- 21671854 TI - Low lymphocyte count and cardiovascular diseases. AB - Inflammation plays a crucial pathophysiological role in the entire continuum of the atherosclerotic process, from its initiation, progression, and plaque destabilization leading ultimately to an acute coronary event. Furthermore, once the clinical event has occurred, inflammation also influences the left ventricular remodelling process. Under the same paradigm, there is evidence that lymphocytes play an important role in the modulation of the inflammatory response at every level of the atherosclerotic process. Low lymphocyte count (LLC) is a common finding during the systemic inflammatory response, and clinical and animal studies suggest that LCC plays a putative role in accelerated atherosclerosis. For instance, there is recent evidence that LLC is associated with worse outcomes in patients with heart failure, chronic ischemic heart disease and acute coronary syndromes. Further indirect evidence supports the pathologic role of LLC related to the fact that 1) lymphopenia--due to a decreased count of lymphocyte T cells- normally occurs as a part of the human ageing process, and 2) increased incidence of cardiovascular events has been reported in conditions where lymphopenia is common, such as renal transplant recipients, human immunodeficiency virus infection, survivors of nuclear disasters and autoimmune diseases. The aim of the present article is to review: a) the pathophysiological mechanisms that have been proposed for the observed association between LLC and cardiovascular diseases (CVD), b) the available evidence regarding the diagnostic and prognostic role attributable to LLC in patients with CVD, and; c) the potential therapeutic implications of these findings. PMID- 21671855 TI - Recent advances in sepsis research: novel biomarkers and therapeutic targets. AB - Sepsis remains a common cause of death in the intensive care units worldwide. However, in the last decade a significant development could be noticed in sepsis research regarding diagnostic markers that can help the physicians to recognize the disease in the early phase, which is the clue of the successful treatment of sepsis. This development provided the identification of new molecules and structures (i.e. cytokines, cell surface markers, receptors) that are potential biomarkers of sepsis in the clinical settings. Besides, the advance in the understanding of the pathophysiologic, immunologic and biochemical pathway of sepsis has made the way for assignment of new drug targets in the therapy of sepsis. This review aims to provide a summary about these novelties regarding our knowledge about sepsis published in the medical literature recently. We will describe the presumed pathophysiological role and diagnostic value of sepsis markers that are used even more widely in the clinical practice (i.e. procalcitonin, IL-6), summarize the data regarding the sepsis marker candidates that are investigated in some initial study (i.e. matrix metalloproteinases, microRNA fingerprints), and we will discuss substances that may be specific markers for certain organ failures related to sepsis (i.e. neutrophil gelatinase derived lipocalin in acute renal failure). Furthermore, we will review the mediators of the immuno-inflammatory cascade in sepsis concerning their potential applicability as therapeutic targets in the treatment of this often lethal disease. In addition, we present some insights into the identification of genetic markers of sepsis. PMID- 21671856 TI - Inhibition of tumor angiogenesis by antibodies, synthetic small molecules and natural products. AB - Cancer remains one of the major causes of death worldwide. The switch to pathological angiogenesis is a key process in the promotion of cancer and consequently provides several new and promising targets to anticancer therapy. Thus, antagonizing angiogenesis cuts off the tumor's oxygen and nutrition supply. This review focuses on angiogenesis inhibitors as option for cancer treatment. Modes of action, adverse effects, mechanisms of resistance as well as new developments are highlighted. One approach in angiogenesis inhibition is intermitting the further VEGF (vascular endothelial growth factor) signal pathway with monoclonal antibodies. Bevacizumab is a highly specific recombinant humanized monoclonal IgG antibody targeting VEGF-A. An efficient antitumor therapy demands more specific antibodies that affect other signal molecules besides VEGF-A, which is in the focus of current research. In addition to antagonizing VEGF, there are also small molecules that inhibit receptor tyrosine kinases (RTKs). Many RTK inhibitors have been described, which exhibit different specificity profiles. The question, whether highly specific antagonists are necessary remains open, because other affected RTKs may also represent growth factor receptors that are essential for tumor growth. Therefore their inhibition may also contribute to anticancer activity. Secondary plant metabolites represent templates for the development of new small molecules. The identification of new drugs from plants has a long and successful history. There is convincing evidence for the beneficial effect of phytochemicals on cancer-related pathways, particularly with regard to anti-angiogenesis. Plant phenolics are the most important category of phytochemicals, including flavanoids. Prominent phytochemicals affecting different pathways of angiogenesis are green tea polyphenols (epigallocatechin gallate) and soy bean isoflavones (genistein). PMID- 21671857 TI - Antioxidant properties and associated mechanisms of salicylates. AB - The pharmacological action of salicylates has been historically related to their ability to inhibit cyclooxygenases, thereby blocking the synthesis of prostaglandins and thromboxane A2. On the other hand, several studies have suggested that salicylates have a multitude of cyclooxygenase-independent actions specially related with their antioxidant properties, which might contribute to the overall salutary effects of these compounds. Although salicylates are well known antioxidants through their ability to scavenge hydroxyl radical, their antioxidant mechanisms of action have not been fully compiled and characterized. In this context, several mechanisms of action have been suggested, namely i) scavenging of hydroxyl radical and chelation of transition metals; ii) upregulation of nitric oxide; iii) increased synthesis of lipoxins; iv) inhibition of neutrophil oxidative burst; v) inhibition of NF-kappaB and AP-1 protein kinases; and vii) inhibiton of lectin-like oxidized LDL receptor-1. The newly discovered acetyl salicylic acid-triggered lipoxins probably play a key role in the maintenance of the oxidative stress balance. Furthermore, salicylates have shown to protect low-density lipoprotein from oxidation and elicit an inhibitory effect on the expression of lectin-like receptors on endothelial cells. This review aims to provide an overview of the various proposed antioxidant mechanisms of salicylates. PMID- 21671858 TI - Oxidative phosphorylation as a target to arrest malignant neoplasias. AB - Since Warburg proposed in 1956 that cancer cells exhibit increased glycolysis due to mitochondrial damage, numerous researchers have assumed that glycolysis is the predominant ATP supplier for cancer cell energy-dependent processes. However, chemotherapeutic strategies using glycolytic inhibitors have been unsuccessful in arresting tumor proliferation indicating that the Warburg hypothesis may not be applicable to all existing neoplasias. This review analyzes recent information on mitochondrial metabolism in several malignant neoplasias emphasizing that, although tumor cells maintain a high glycolytic rate, the principal ATP production may derive from active oxidative phosphorylation. Thus, anti mitochondrial drug therapy may be an adequate adjuvant strategy to arrest proliferation of oxidative phosphorylation-dependent neoplasias. PMID- 21671859 TI - Cancer therapeutic agents targeting hypoxia-inducible factor-1. AB - The discovery of hypoxia-inducible factor-1 has led to a rapidly increasing understanding of the molecular mechanism of tumor hypoxia in the past two decades. Today it is generally accepted that HIF-1 plays a pivotal role in the cellular response to tumor hypoxia which represents a major obstacle to the success of radiotherapy and chemotherapy. Meanwhile, many details involved in the expression, accumulation and transactivation of HIF-1 have been well elucidated. Targeting HIF-1 has become a novel and efficient strategy for cancer therapy and a number of agents have been developed aiming to suppress HIF-1. This review will concisely introduce the general knowledge on the molecular biology of HIF-1 and possible targets along the HIF-1 pathway. Moreover, a number of compounds reported with anti-HIF-1 activity are included and mainly classified as direct and indirect inhibitors based on their different modes of action. While direct HIF-1 inhibitors prevent HIF-1 from transactivation, DNA binding and subsequently initiating transcriptional activity, indirect HIF-1 inhibitors generally block the transcription or translation of HIF-1alpha or promote the degradation of HIF 1alpha protein. According to different structural features, direct HIF-1 inhibitors are divided into several groups: polyamides, quinols and naphthoquinone spiroketal analogues, shikonin derivatives, epidithiodiketopiperazines, and two representative drugs: echinomycin and bortezomib. In the same way, indirect inhibitors comprise the following classes: polyphenols, benzoazaheterocycles, rapamycins, camptothecins, geldanamycins, (aryloxyacetylamino)benzoic acid analogues, 2-methoxyestradiol and analogues, hydroxamic acid compounds and others. The rest with mechanism still not so clear would also be listed and introduced, with an emphasis on the marinederived natural products. The in vitro and/or in vivo activities of these compounds and their mechanisms of HIF-1 inhibition would be discussed and the SARs of unique structural types of HIF-1 inhibitors will be briefly concluded. PMID- 21671861 TI - Pharmacokinetic profiles of anticancer herbal medicines in humans and the clinical implications. AB - A number of herbal medicines are increasingly used by cancer patients worldwide, despite the fact that the clinical evidence that supports their use to fight cancer is weak or lacking. Pharmacokinetic studies have been integrated into modern drug development, but they are generally not needed for herbal remedies. To update our knowledge in this field, this paper highlights the pharmacokinetic properties of anticancer herbal medicines and the clinical relevance. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase ((all from inception to May 2011). An extensive literature search indicatesthat there are limited data on the pharmacokinetic properties of anticancer herbal medicines in humans. There are increasing pharmacokinetic studies of anticancer herbal remedies, but these studies are mainly focused on a small number of herbal medicines including curcumin, ginseng, ginkgo, ginger and milk thistle. For an anticancer herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and pharmacokinetic processes of active herbal components in the body determine their target-site concentrations and thus the anticancer effect. In this regard, a safe and optimal use of anticancer herbal medicines requires a full understanding of their pharmacokinetic profiles. To optimize the use of anticancer herbal remedies, further studies to explore their pharmacokinetic properties and the relevance to pharmacodynamics and toxicity in humans are certainly warranted. PMID- 21671860 TI - Phenylpropanoid sucrose esters: plant-derived natural products as potential leads for new therapeutics. AB - Natural products are regarded as vital key source of lead compounds for drug discovery due to their structural diversity and broad array of biological activities. Phenylpropanoid sucrose esters are naturally occurring compounds isolated from various plants and are structurally characterized by a sucrose core connected to one or more Ph-CH=CH-CO- moieties through an ester linkage. These compounds were extensively used in folk medicine and are found to possess many biological activities such as antitumor, antibacterial, antioxidant, antiviral, anti-inflammatory, neuro-protective and glycosidase inhibitory activities. This extensive review, which is the first of its kind on phenylpropanoid sucrose esters, aims to provide an up-to-date account of naturally occurring known phenylpropanoid sucrose esters with special focus on their sources, structures, biological and pharmacological activities. PMID- 21671862 TI - New insights into chemistry and anti-infective potential of triazole scaffold. AB - Research and development for novel substances possessing anti-infective activity have attracted considerable attention due to the escalating resistance towards conventional antibiotics. Therefore, the discovery and development of effective antimicrobial drugs with novel mechanism of action have become an insistent task for infectious diseases research programs. Triazole scaffold has been consistently rewarded as a promising versatile lead molecule with a pivotal position in modern medicinal chemistry. The literature reveals that this heterocyclic moiety has drawn attention of the chemists, pharmacologists, microbiologists and other researchers owing to its indomitable biological potential as anti-infective agents. The present communication is a cogent attempt to review the chemistry and antimicrobial activities of triazole derivatives reported in recent scientific literature. The biological profiles of these new triazole derivatives represent a fruitful matrix for further development as promising and superior anti-infective medicinal agents. PMID- 21671863 TI - Macromolecular prodrugs based on synthetic polyaminoacids: drug delivery and drug targeting in antitumor therapy. AB - In the last twenty years a depth study on potential pharmaceutical applications of synthetic polymers at proteinlike structure as carrier for macromolecular prodrug production has been performed in academia and in industry. In particular alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), alpha,beta polyaspartylhydrazide (PAHy), poly(glutamic acid) (PGA), poly(aspartic acid) (PAA) and polylysine (PLL) have been extensively studied in this field. In the present review, the use of PHEA, PAHy, PGA as starting materials to prepare macromolecular prodrugs is reported and drug delivery and targeting aspects have been considered. PMID- 21671864 TI - Anticancer prodrugs: an overview of major strategies and recent developments. AB - Research in anticancer chemotherapy has produced outstanding results, and mean survival rates have significantly improved over the last ten years. Nevertheless, all approved drugs are still characterized by narrow therapeutic windows that result mainly from their high systemic toxicity combined with their marked lack of tumor selectivity. Medicinal chemistry responds to the resulting demands with new analogues of a lead drug, or by developing prodrugs. Prodrugs are inactive compounds, which are metabolized in the body, either chemically or enzymatically, in a controlled or predictable manner, to the active parent drug. This review describes the results of strategies in prodrug development, subdivided into the principal categories of anticancer agents. The chemical implementation of prodrug approaches is illustrated through selected drug candidates. PMID- 21671865 TI - Rational design and development of colon-specific prodrugs. AB - Earlier colon was considered as a black-box, acting as a site for production and temporary storage of excreta and responsible for absorption of electrolytes and water. But, with the discovery of sulfasalazine as colon-specific prodrug, the promising and challenging issue of treating local pathologies was presented with colon as an organ of significance for target-specific delivery of drugs. The need and desirable attributes of colon-specific drug delivery systems have been well recognized, extensively explored and documented in the literature. The success of a colon-specific prodrug depends on its rational design and understanding the demands of the organ to be targeted and the delivery system to be developed. The present review mainly focuses on anatomy/physiology of colon, colonic microbiota, enzymatic set up of colon, pathophysiology of local diseases of colon, factors, obstacles and rationale for designing colon specific drug delivery system, various targets, potential drug candidates and novel colon-targeting carriers along with varied linkages that could be explored, merits and demerits of this design and recent trends in this field. Brief review of methodologies for characterization and in vitro/in vivo release studies is presented. The available animal models with quantifying parameters for evaluating colon-targeting potential and effectiveness of the colon-specific prodrugs for inflammatory bowel disease is also included in this review. PMID- 21671866 TI - Prodrug strategies for antihypertensives. AB - There is a great emphasis on research to discover methods aimed at enhancing the efficacy of drugs and reducing their toxicity and unwanted side effects. Prodrugs are biologically inactive compounds that are converted to actual drug molecule, through biotransformation, that combine with the receptors to produce the biological action. Prodrugs can thus be considered as drugs containing specialized nontoxic protective groups utilized in a transient manner to alter or eliminate the undesirable properties of the parent drug molecule. Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most of the drugs for cardiovascular diseases have low oral bioavailability, short duration of action, first pass metabolism and variable lipohilicities. Out of the need to overcome these limitations, various prodrugs have been designed for antihypertensive agents. This review extensively focuses on various strategies used for design and development of prodrugs for the various classes of antihypertensives, emphasizing on the details regarding the need for prodrug synthesis for each class, structure, type of modification and goal achieved. It also provides an insight into the major advances in the field of antihypertensive prodrug research. PMID- 21671867 TI - D-galactose as a vector for prodrug design. AB - D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization. PMID- 21671868 TI - Prodrugs - an efficient way to breach delivery and targeting barriers. AB - The study of prodrugs that are chemically modified bioreversible derivatives of active drug compounds to alter their undesired properties has been expanded widely during the last decades. Despite the commercial success the prodrugs have afforded, the concept is still quite unknown among many scientist. Furthermore, many scientists regard prodrugs as a pure interest of academic research groups and not as a feasible solution to improve the delivery or targeting properties of new chemical entities, drug candidates failed in clinical trials, or drugs withdrawn from the market. Although there are still unmet needs that require addressing, prodrugs should be seen as fine-tuning tools for the successful drug research and development. This review represents the potential of prodrugs to improve the drug delivery by enhanced aqueous solubility or permeability as well as describes several targeted prodrug strategies. PMID- 21671869 TI - Recent developments in prodrug design: drug targeting, pharmacological and pharmacokinetic improvements related to a reduction of adverse effects. PMID- 21671870 TI - Inhibition of the function of TRPV1-expressing nociceptive sensory neurons by somatostatin 4 receptor agonism: mechanism and therapeutical implications. AB - Release of somatostatin into the circulation from the activated TRPV1-expressing nociceptors revealed by antidromic stimulation of dorsal roots in the rat pinpointed to a novel potential drug target on these nociceptors. The review summarizes the functional, biochemical and pharmacological evidence for a novel somatostatin-mediated counter-regulatory antiinflammatory/antinociceptive "sensocrine" function in rats and guinea-pigs. To identify the somatostatin receptor subtype(s) responsible for this function, experiments were focused on actions of sstR4 receptor agonists as this subtype, similarly to sstR1, is not involved in endocrine regulation. Involvement of somatostatin and the sstR4 was revealed by using pretreatment with somatostatin antibody, depletion of somatostatin with cysteamine, measuring the plasma somatostatin-like immunoreactivity, release from nerves in vitro from isolated trachea, detection of sstR4 receptors in animal and human tissue specimens, using sstR4 gene-deleted mice and investigating in detail effects of a stable peptide analogue of somatostatin (TT-232) and of an ultrapotent non-peptide agonist of sstR4 receptors. Promising antinociceptive, antihyperalgesic effects of these sstR4 agonists were observed in various experimental models of inflammatory and neuropathic conditions which are mediated both by TRPV1-expressing nociceptors and non-neural cells involved in mediation of inflammation. In sstR4 receptor knockout mice an aggravation of inflammation and hyperalgesia was observed. PMID- 21671871 TI - TRPM8 biology and medicinal chemistry. AB - TRPM8 belongs to the TRPM Melastatin subfamily of Transient Receptor Potential (TRP) ion channels. Activated by cool temperatures and mimetic ligands, such as menthol and icilin, TRPM8 has been shown to play a role in thermoreception and is expressed in peripheral nerves. TRPM8 is also expressed in other tissues which are not exposed to temperature fluctuations, such as the prostate. The recent advancement of a TRPM8 agonist into the clinic for the treatment of prostate cancer suggests that the channel plays a role in some human pathologies. As more drug-like and selective agonists and antagonists of TRPM8 become available, in vivo pharmacology studies will complement already published knockout data to further our understanding of the role of TRPM8 in human disease. PMID- 21671872 TI - Transient receptor potential A1 modulators. AB - TRPA1 is a member of a superfamily of non-selective cation channels that is known to be involved in multiple physiological functions. TRPA1 is activated by a broad spectrum of chemical irritants and endogenous inflammatory compounds. An emerging role for TRPA1 in mediating pain and inflammation raises the possibility that compounds targeting TRPA1 might have significant therapeutic potential. This review discusses the broad classes of molecules that are known to act as agonists and antagonists of TRPA1 towards the aim of providing an overview of the structure and activity of TRPA1 modulators. PMID- 21671873 TI - TRPV4 agonists and antagonists. AB - TRPV4 belongs to the TRPV subfamily of Transient Receptor Potential (TRP) ion channels. This year marks the 10 year anniversary of the discovery of this polymodal ion channel which is activated by a variety of stimuli including warm temperatures, hypotonicity and endogenous lipids. Coupled with a widespread tissue distribution, this activation profile has resulted in a large number of disparate physiological functions for TRPV4. These range from temperature monitoring in skin keratinocytes to osmolarity sensing in kidneys, sheer stress detection in blood vessels and osteoclast differentiation control in bone. As knowledge of its physiological roles has expanded, interest in targeting TRPV4 modulation for therapeutic purposes has arisen and is now focused on several areas. First, as with related TRP channels TRPV1, TRPV3, TRPM8 and TRPA1, TRPV4 antagonism is being considered for inflammatory and neuropathic pain treatment. Recent work conducted using KO mice and agonists 4alphaPDD and GSK1016790A suggests bladder dysfunctions may also be targeted. Additionally, ventilator induced lung injury has emerged as another potential indication for TRPV4 antagonists. Herein we review the known small molecule modulators of TRPV4 and relate progress made in identifying potent, selective and bioavailable agonists and antagonists to interrogate this ion channel in vivo. PMID- 21671874 TI - Analgesic potential of TRPV3 antagonists. AB - The vanilloid subfamily of transient receptor potential (TRPV) ion channels serves critical functions in sensory signaling in specialized cells and intact organisms ranging from yeast to primates. As thermosensors, chemosensors, and/or mechanosensors, these channels monitor the local environment and integrate and respond to multiple stimuli distinctively. More than a decade of research on the founding member of the subclass, TRPV1, has led to advancement of multiple antagonists into the clinic for the treatment of chronic pain. In recent years the comprehensive knowledge accessed through these studies has been applied to enhance understanding of other TRPV isoforms and, in particular, to determine whether they, too, represent promising targets for drug discovery. This review focuses on emerging data that define a role for TRPV3 in transducing signals in pain pathways and identify antagonists that demonstrate efficacy in relevant preclinical behavioral models. PMID- 21671875 TI - Disease-related changes in TRPV1 expression and its implications for drug development. AB - The transient receptor potential vanilloid 1 (TRPV1) channel has been a topic of great interest, since its discovery in 1997. It is a homotetrameric non-selective cation channel predominantly expressed in a population of sensory neurons and its involvement in different modalities of pain has been extensively studied. However, TRPV1 has also been shown to be expressed in non-sensory neurons and non neuronal cells. TRPV1 is considered as a potential target for drug development, based on its tissue distribution and its role in physiological functions. Here, we summarize the evidences for disease-related alterations in TRPV1 expression and function and review the current perspectives for the therapeutic potential of TRPV1 agonists and antagonists in the treatment of a wide range of diseases. PMID- 21671876 TI - TRPV1 signaling: mechanistic understanding and therapeutic potential. AB - Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 is acting as an important signal integrator in sensory nociceptors under physiological and pathological conditions including inflammation and neuropathy. Because of its integrative signaling properties in response to inflammatory stimuli, TRPV1 agonists and antagonists are predicted to inhibit the sensation of ongoing or burning pain that is reported by patients suffering from chronic pain, therefore offering an unprecedented advantage in selectively inhibiting painful signaling from where it is initiated. In this article, we firstly summarize recent advances in the understanding of the role of TRPV1 in pain signaling, including a overview of clinical pharmacological trials using TRPV1 agonists and antagonists. Finally, we also present an update on the mechanistic understanding and controlling of hyperthermia caused by TRPU1 antagonists, and provide perspective for future study. PMID- 21671877 TI - The vanilloid agonist resiniferatoxin for interventional-based pain control. AB - The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1. PMID- 21671878 TI - Therapeutic targeting of TRPV1 by resiniferatoxin, from preclinical studies to clinical trials. AB - In primary sensory neurons, the capsaicin receptor TRPV1 functions as a molecular integrator for a broad range of seemingly unrelated chemical and physical noxious stimuli, including heat and altered pH. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and tissue injury as this response is impaired in TRPV1-deficient mice. Following the molecular cloning of TRPV1 in 1997, over a dozen companies embarked on efforts to find clinically useful TRPV1 antagonists, but side-effects and limited efficacy have thus far prevented any compounds from progressing beyond phase II. This has rekindled interest in desensitization of nociceptive neurons to TRPV1 agonists (e.g. capsaicin and its ultrapotent analog resiniferatoxin) as an alternative pharmacological approach to block pain in the periphery where it is generated. The clinical value of capsaicin is, however, limited by its unfavorable irritancy to desensitization ratio. In animal experiments, resiniferatoxin treatment is a powerful approach to achieve long-lasting analgesia. In patients with overactive bladder, intravesical resiniferatoxin improves bladder function (or even restores continence) without significant irritancy and/or toxicity. In this review, we argue that resiniferatoxin is an attractive alternative to capsaicin in that it achieves lasting desensitization without the side effects that complicate capsaicin therapy. PMID- 21671880 TI - TRP channel gating physiology. AB - Transient Receptor Potential (TRP) cation channels participate in several processes of vital importance in cell and organism physiology, and have been demonstrated to participate in the detection of sensory stimuli. The thermo TRP's reviewed: TRPV1 (vanilloid 1), TRPM8 (melastatin 8) and TRPA1 (ankyrin-like 1) are known to integrate different chemical and physical stimuli such as changes in temperature and sensing different irritant or pungent compounds. However, despite the physiological importance of these channels the mechanisms by which they detect incoming stimuli, how the sensing domains are coupled to channel gating and how these processes are connected to specific structural regions in the channel are not fully understood, but valuable information is available. Many sites involved in agonist detection have been characterized and gating models that describe many features of the channel's behavior have been put forward. In this review we will survey some of the key findings concerning the structural and molecular mechanisms of TRPV1, TRPA1 and TRPM8 activation. PMID- 21671879 TI - TRPV1 activation is not an all-or-none event: TRPV1 partial agonism/antagonism and its regulatory modulation. AB - TRPV1 has emerged as a promising therapeutic target for pain as well as a broad range of other conditions such as asthma or urge incontinence. The identification of resiniferatoxin as an ultrapotent ligand partially able to dissect the acute activation of TRPV1 from subsequent desensitization and the subsequent intense efforts in medicinal chemistry have revealed that TRPV1 affords a dramatic landscape of opportunities for pharmacological manipulation. While agonism and antagonism have represented the primary directions for drug development, the pharmacological complexity of TRPV1 affords additional opportunities. Partial agonism/partial antagonism, its modulation by signaling pathways, variable desensitization, and slow kinetics of action can all be exploited through drug design. PMID- 21671881 TI - Therapeutic targeting of TRP channels--the TR(i)P to pain relief. AB - Following the cloning and characterization of the transient receptor potential vanilloid 1 (TRPV1), a growing body of research has identified the important role of TRPV1 and related channels in diverse physiological functions including temperature transduction and pain signalling. As a result, there has been a great deal of interest by the pharmaceutical industry to develop small molecule modulators of the activity of these channels for potential therapeutic use. While most of the efforts have focused on examining the role of TRPV1 in nociception, more recent work has begun to assess the therapeutic utility of targeting other TRP channels. This manuscript is aimed at introducing the reader of this special issue to the promising new developments and findings as well as emerging challenges in the targeting of the thermoTRP family of receptors for clinical therapeutic use. This chapter will focus on current efforts from the pharmaceutical industry to develop highly potent and efficacious compounds that modulate TRP channel function. In particular, this chapter will highlight recent drug discovery activities around the transient receptor potential vanilloid family members TRPV1, TRPV3, and TRPV4, the transient receptor potential ankyrin family member TRPA1, and the transient receptor potential melastatin family member TRPM8. The majority of the work included in this chapter will focus on recent findings in the development of TRP modulators for pain indications; however, for certain targets where data exist, other indications will be discussed. The increasing number of small biotech and pharmaceutical companies pursuing targets in these families of ion channels highlights the perceived importance of these targets in the treatment of a variety of disease states including inflammatory and neuropathic pain, urinary incontinence, painful bladder syndrome, and even types of prostate cancer. PMID- 21671882 TI - New developments in the medicinal chemistry of vanilloid TRPV1 and related receptors. PMID- 21671883 TI - Detection of hepatitis B virus variants in HBV monoinfected and HBV/HIV coinfected Iranian patients under lamivudine treatment. AB - Chronic hepatitis B affects nearly 10% of HIV-infected patients. Hepatitis B virus (HBV) infection is a dynamic disease and coinfection with HIV impacts directly on the outcome of HBV infection, considerably complicating its natural history, diagnosis, and management. The aim of this study was to compare two cohorts of HBV monoinfected and HBV/HIV coinfected Iranian patients undergoing long-term lamivudine therapy from the clinical and virological aspects, as well as the frequency of detected mutations in HBV genome. To this end, HBV Pol/S regions from 72 patients were PCR-amplified and directly sequenced. Phylogenetic analysis indicated a 40-times higher risk of coinfection with ayw3 subtype of HBV genotype D rather than ayw2 subtype [P<0.001, odd: 40.66, CI: 95 % (4.69 352.23)]. While no resistance mutation was detected in HBV/HIV coinfected cohort, LAM-resistance mutations (rtM204I/V in YMDD and rtL180M in FLLA polymerase motifs) were identified in 30% (9 out of 30) and 16.66% (5 out of 30) of HBV monoinfected patients (P<0.05). Moreover, several mutations (sP105A, sI110S/L, sS136Y and sP127T/L) with significant differences in the frequency were identified in the S region of both cohorts. Finally, this study found strong correlation between the type of infection (mono or coinfection) and characteristics like patient gender, ALT levels, HBV-DNA levels and HBV subtypes. These results pointed to the importance of determination of HBV variants in the management of patients and suggested that in contrary to HBV monoinfections, LAM may be still an appropriate drug for the treatment of HBV in HBV/HIV coinfected patients; however, further studies to clarify the role of HIV in HBV LAM resistance mutations are required. PMID- 21671884 TI - Effects of tipranavir, darunavir, and ritonavir on platelet function, coagulation, and fibrinolysis in healthy volunteers. AB - The use of HIV protease inhibitors (PIs) as part of antiretroviral therapy in the treatment of HIV-1 infection may be associated with an increased risk of bleeding. This prospective, randomized, open-label trial in healthy volunteers compared the effects of tipranavir/ritonavir (TPV/r), darunavir/ ritonavir (DRV/r), and ritonavir (RTV) alone on platelet aggregation after a single dose and at steady-state concentrations. Subjects were selected on the basis of normal platelet aggregation and arachidonic acid (AA)-induced platelet aggregation inhibition after administration of a single 325-mg dose of aspirin. All 3 PI therapies were administered twice daily for 10 days. In some but not all subjects, TPV/r inhibited AA-induced platelet aggregation and prolonged PFA 100(r) closure time with collagen-epinephrine cartridge, which was of lesser magnitude and consistency compared with aspirin, but greater when compared to DRV/r and RTV. At least 2 subjects in each treatment arm showed complete inhibition of AA-induced platelet aggregation on treatment, and the magnitude of change in all platelet-function tests did not correlate with PI plasma concentrations. Effects of TPV/r on platelet aggregation were reversed 24 hours after the last TPV/r dose. None of the PI treatments tested were associated with increases in bleeding time, decreases in plasma coagulation factors, or increase in fibrinolysis. There was large inter-patient variability in antiplatelet effect for all PI treatments, ranging from no effect to complete inhibition of AA induced platelet aggregation. PMID- 21671885 TI - Evaluation of saliva as an alternative matrix for monitoring plasma Zidovudine, Lamivudine and nevirapine concentrations in Rwanda. AB - Saliva may provide interesting advantages as matrix for compliance measurements, pharmacokinetic studies and therapeutic drug monitoring in resource limited countries. We investigated the feasibility of using saliva for compliance monitoring of zidovudine (ZDV), lamivudine (3TC) and nevirapine (NVP) in 29 HIV-1 infected patients from Rwanda. ZDV, 3TC and NVP drug levels were quantified by an LC/MS-MS method in plasma and stimulated saliva samples and compared using Bland Altman analysis. Seven patients demonstrated undetectable saliva ZDV levels while five out of these seven also showed no 3TC salivary concentrations. For the other samples, we observed a good agreement between salivary and plasma concentrations of each antiretroviral drug. A significant relation between the difference in saliva and plasma ZDV concentrations and the average ZDV concentration in the two matrices was deduced as follow: y = -380.15 + 1.79 x. The log saliva and plasma concentration difference of both 3TC and NVP was consistent across the range of average log concentration. Overall, we showed large agreement limits suggesting a wide inter patient variability that may result to non-reliable plasma level predictions from saliva drug measurements. Therefore, our results indicate that saliva may serve as a valuable tool only for NVP compliance testing because of its high salivary concentration. PMID- 21671886 TI - Metabolic modulation induced by oestradiol and DHT in immature rat Sertoli cells cultured in vitro. AB - Sertoli cells actively metabolize glucose that is converted into lactate, which is used by developing germ cells for their energy metabolism. Androgens and oestrogens have general metabolic roles that reach far beyond reproductive processes. Hence, the main purpose of this study was to examine the effect of sex hormones on metabolite secretion/consumption in primary cultures of rat Sertoli cells. Sertoli cell-enriched cultures were maintained in a defined medium for 50 h. Glucose and pyruvate consumption, and lactate and alanine secretion were determined, by 1H-NMR (proton NMR) spectra analysis, in the presence or absence of 100 nM E2 (17beta-oestradiol) or 100 nM 5alpha-DHT (dihydrotestosterone). Cells cultured in the absence (control) or presence of E2 consumed the same amount of glucose (29+/-2 pmol/cell) at similar rates during the 50 h. After 25 h of treatment with DHT, glucose consumption and glucose consumption rate significantly increased. Control and E2-treated cells secreted similar amounts of lactate during the 50 h, while the amount of lactate secreted by DHT-treated cells was significantly lower. Such a decrease was concomitant with a significant decrease in LDH A [LDH (lactate dehydrogenase) chain A] and MCT4 [MCT (monocarboxylate transporter) isoform 4] mRNA levels after 50 h treatment in hormonally treated groups, being more pronounced in DHT-treated groups. Finally, alanine production was significantly increased in E2-treated cells after 25 h treatment, which indicated a lower redox/higher oxidative state for the cells in those conditions. Together, these results support the existence of a relation between sex hormones action and energy metabolism, providing an important assessment of androgens and oestrogens as metabolic modulators in rat Sertoli cells. PMID- 21671887 TI - Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries. AB - Statins can have beneficial cholesterol-independent effects on vascular contractility, which may involve increases in the bioavailability of NO (nitric oxide) as a result of phosphorylation of eNOS (endothelial NO synthase). Although this has been attributed to phosphorylation of Akt (also known as protein kinase B), studies in cultured cells have shown that statins can phosphorylate AMPK (AMP activated protein kinase); it is unknown whether this has functional effects in intact arteries. Thus we investigated the acute effects of simvastatin on resistance arterial contractile function, evaluating the involvement of NO, Akt and AMPK. Isolated rat mesenteric resistance arteries were mounted on a wire myograph. The effects of incubation (1 and 2 h) with simvastatin (0.1 or 1 MUM) on contractile responses were examined in the presence and absence of L-NNA (N nitro-L-arginine; 10 MUM) or mevalonate (1 mM). Effects on eNOS, phospho-eNOS (Ser1177), and total and phospho-Akt and -AMPK protein expression were investigated using Western blotting. The effect of AMPK inhibition (compound C, 10 MUM) on eNOS phosphorylation and contractile responses were also studied. Simvastatin (1 MUM, 2 h) significantly reduced constriction to U46619 and phenylephrine and enhanced dilations to ACh (acetylcholine) in depolarized, but not in U46619-pre-constricted arteries. These effects were completely and partially prevented by L-NNA and mevalonate respectively. Simvastatin increased eNOS and AMPKalpha phosphorylation, but had no effect on Akt protein expression and phosphorylation after 2 h incubation. Compound C prevented the effects of simvastatin on eNOS phosphorylation and contractility. Thus simvastain can acutely modulate resistance arterial contractile function via mechanisms that involve the AMPK/phospho-eNOS (Ser1177)/NO-dependent pathway. PMID- 21671888 TI - Interaction between bacterial outer membrane proteins and periplasmic quality control factors: a kinetic partitioning mechanism. AB - The OMPs (outer membrane proteins) of Gram-negative bacteria have to be translocated through the periplasmic space before reaching their final destination. The aqueous environment of the periplasmic space and high permeability of the outer membrane engender such a translocation process inevitably challenging. In Escherichia coli, although SurA, Skp and DegP have been identified to function in translocating OMPs across the periplasm, their precise roles and their relationship remain to be elucidated. In the present paper, by using fluorescence resonance energy transfer and single-molecule detection, we have studied the interaction between the OMP OmpC and these periplasmic quality control factors. The results of the present study reveal that the binding rate of OmpC to SurA or Skp is much faster than that to DegP, which may lead to sequential interaction between OMPs and different quality control factors. Such a kinetic partitioning mechanism for the chaperone-substrate interaction may be essential for the quality control of the biogenesis of OMPs. PMID- 21671889 TI - HLA-B*51:79 is a novel allele associated with a conserved haplotype. AB - The B*51:79 allele displays a conserved haplotype association with HLA-A*68:01, C*01:02, DRB1*14:01 and DQB1*05:03. PMID- 21671890 TI - Impact of type 1 diabetes and glycemic control on fetal aneuploidy biochemical markers. AB - OBJECTIVE: To determine the influence of type 1 diabetes mellitus (T1DM) on the first trimester serum markers of fetal aneuploidy; pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free beta-hCG) and to evaluate the influence of glycemic control on these parameters in the pregnant diabetic women. DESIGN: Retrospective study. SETTING: Data were extracted from electronic obstetric and laboratory databases at two Danish University Hospitals. POPULATION: Based on 36 415 pregnancies without T1DM (non T1DM) and 331 pregnancies with T1DM; beta-hCG and PAPP-A were obtained at 8+0 to 14+2 gestational weeks. METHODS: Medians for PAPP-A and free beta-hCG were generated and multiple of the normal gestation-specific median (MoM) values were calculated for each separate pregnancy. After adjustment for maternal weight, ethnicity and smoking status, MoM values were compared across the T1DM and non T1DM groups, respectively. Additionally, the relationship between PAPP-A MoM and HgbA1C was examined in 348 T1DM pregnancies by Spearman's rank correlation. MAIN OUTCOME MEASURES. Difference in biochemical marker levels between T1DM and non T1DM. RESULTS: PAPP-A was 0.86 MoM in T1DM pregnancies and 1.01 MoM in non-T1DM pregnancies, p < 0.0001. Conversely, free beta-hCG was not altered in T1DM pregnancies (T1DM 0.99 MoM, non-T1DM 0.98 MoM; p=0.14). There was a significant inverse correlation between HgbA1C and PAPP-A (rho=-0.12, p=0.02). CONCLUSIONS: In T1DM pregnancies, PAPP-A MoM values were lower than in non-T1DM pregnancies. This suggests that correction should be considered in first trimester biochemical screening for fetal aneuploidy in T1DM women. PMID- 21671891 TI - The correlation between cauda equina nerve root volume and sensory block height after spinal anaesthesia with glucose-free bupivacaine. AB - We examined the association between cauda equina nerve root volume and sensory block height in 15 patients undergoing spinal anaesthesia with 0.5% glucose-free bupivacaine. Magnetic resonance imaging and a separate image segmentation program were used to calculate the volume of the nerve roots. Nerve root volume was also correlated with lumbosacral cerebrospinal fluid volume and with patients' physical characteristics. Nerve root volume correlated negatively with sensory block height (Spearman rho -0.61 (95% CI -0.85 to -0.14)) and body mass index (Spearman rho -0.66 (95% CI -0.87 to -0.24)) but positively with cerebrospinal fluid volume (Spearman rho 0.76 (95% CI 0.43-0.91)). Factors that are thought to influence cerebrospinal fluid volume, such as body mass index, might similarly affect the volume of the nerve roots. The size of the nerve roots may influence the spread of spinal anaesthesia. PMID- 21671892 TI - Topical corticosteroid phobia in atopic dermatitis: a study of its nature, origins and frequency. AB - BACKGROUND: Topical corticosteroids remain the mainstay of atopic dermatitis therapy. Many atopic dermatitis therapeutic failures appear to be attributable to poor adherence to treatment due to topical corticosteroid phobia. OBJECTIVES: To assess the facets, origins and frequency of fear of topical corticosteroid use among patients with atopic dermatitis. METHODS: A questionnaire comprising 69 items, generated from information gathered during interviews with 21 patients and 15 health professionals, was given to consecutive patients consulting at the outpatient dermatology departments of five regional university hospitals or with 53 dermatologists in private practice. RESULTS: A total of 208 questionnaires were analysed (including 144 from parents and 87 from adult patients, 27 of whom were also parents); 80.7% of the respondents reported having fears about topical corticosteroids and 36% admitted nonadherence to treatment. A correlation was found between topical corticosteroid phobia and the need for reassurance, the belief that topical corticosteroids pass through the skin into the bloodstream, a prior adverse event, inconsistent information about the quantity of cream to apply, a desire to self-treat for the shortest time possible or poor treatment adherence. Topical corticosteroid phobia was not correlated with atopic dermatitis severity. CONCLUSION: Topical corticosteroid phobia is a genuine and complex phenomenon, common among French patients with atopic dermatitis, that has an important impact on treatment compliance. PMID- 21671893 TI - Site of venous thromboembolism and prothrombotic mutations according to body mass index. Results from the EDITH study. AB - This study evaluated the impact of body mass index (BMI) on venous thromboembolism (VTE) site and assessed a possible interaction between BMI and prothrombotic risk factors in patients included in the EDITH (Etude des Determinants et Interactions de le THrombose veineuse) study. A cross-sectional study was used to compare the site of unprovoked VTE according to BMI categories in 1077 patients and a matched case-control study (732 pairs) assessed the joint effect of BMI and prothrombotic mutations on VTE risk. The cross sectional analysis showed that the proportion of patients with pulmonary embolism was higher in overweight (63%) and obese (63.5%) patients than among patients with a BMI<25kg/m(2) (55%), P=0.02 and P=0.05 respectively. No interaction was found between F5 G1691A (factor V Leiden) and BMI for VTE risk (P=0.90). There was a significant interaction between F2 G20210A and BMI (P=0.02). The risk of VTE associated with BMI was 1.7 [95% confidence interval (CI): 0.8-3.7], 4.36 (95%CI: 1.49-12.78) and 12.03 (95%CI: 1.53-94.29) in patients with BMI<25kg/m(2) , 25<=BMI<30 and >=30kg/m(2) respectively after adjustment for age and oestrogen use. This study showed that BMI may play a role in determining the site of VTE and may interact with F2 G20210A but not with F5 G1691A for the risk of VTE. PMID- 21671894 TI - Guidelines on oral anticoagulation with warfarin - fourth edition. PMID- 21671895 TI - Prospective multicentre cohort study of heparin-induced thrombocytopenia in acute ischaemic stroke patients. AB - Acute ischaemic stroke patients sometimes receive heparin for treatment and/or prophylaxis of thromboembolic complications. This study was designed to elucidate the incidence and clinical features of heparin-induced thrombocytopenia (HIT) in acute stroke patients treated with heparin. We conducted a prospective multicentre cohort study of 267 patients who were admitted to three stroke centres within 7 d after stroke onset. We examined clinical data until discharge and collected blood samples on days 1 and 14 of hospitalization to test anti platelet factor 4/heparin antibodies (anti-PF4/H Abs) using an enzyme-linked immunosorbent assay (ELISA); platelet-activating antibodies were identified by serotonin-release assay (SRA). Patients with a 4Ts score >=4 points, positive ELISA, and positive-SRA were diagnosed as definite HIT. Heparin was administered to 172 patients (64.4%: heparin group). Anti-PF4/H Abs were detected by ELISA in 22 cases (12.8%) in the heparin group. Seven patients had 4Ts >= 4 points. Among them, three patients (1.7% overall) were also positive by both ELISA and SRA. National Institutes of Health Stroke Scale score on admission was high (range, 16 23) and in-hospital mortality was very high (66.7%) in definite HIT patients. In this study, the incidence of definite HIT in acute ischaemic stroke patients treated with heparin was 1.7% (95% confidence interval: 0.4-5.0). The clinical severity and outcome of definite HIT were unfavourable. PMID- 21671896 TI - High transfusion failure rates in Malawian children with severe anaemia following a standard blood transfusion regimen. PMID- 21671897 TI - Molecular basis of selective antagonism of the P2X1 receptor for ATP by NF449 and suramin: contribution of basic amino acids in the cysteine-rich loop. AB - BACKGROUND AND PURPOSE: The cysteine-rich head region, which is adjacent to the proposed ATP-binding pocket in the extracellular ligand-binding loop of P2X receptors for ATP, is absent in the antagonist-insensitive Dictyostelium receptors. In this study we have determined the contribution of the head region to the antagonist action of NF449 and suramin at the human P2X1 receptor. EXPERIMENTAL APPROACH: Chimeras and point mutations in the cysteine-rich head region were made between human P2X1 and P2X2 receptors. Mutant receptors were expressed in Xenopus oocytes and P2X receptor currents characterized using two electrode voltage clamp. KEY RESULTS: The chimera replacing the region between the third and fourth conserved cysteine residues of the P2X1 receptor with the corresponding part of P2X2 reduced NF449 sensitivity a thousand fold from an IC(50) of ~1 nM at the P2X1 receptor to that of the P2X2 receptor (IC(50) ~1 uM). A similar decrease in sensitivity resulted from mutation of four positively charged P2X1 receptor residues in this region that are absent from the P2X2 receptor. These chimeras and mutations were also involved in determining sensitivity to the antagonist suramin. Reciprocal chimeras and mutations in the P2X2 receptor produced modest increases in antagonist sensitivity. CONCLUSIONS AND IMPLICATIONS: These data indicate that a cluster of positively charged residues at the base of the cysteine-rich head region can account for the highly selective antagonism of the P2X1 receptor by the suramin derivative NF449. PMID- 21671900 TI - Rosiglitazone inhibits vascular KATP channels and coronary vasodilation produced by isoprenaline. AB - BACKGROUND AND PURPOSE: Rosiglitazone is an anti-diabetic drug improving insulin sensitivity and glucose uptake in skeletal muscle and adipose tissues. However, several recent clinical trials suggest that rosiglitazone can increase the risk of cardiovascular ischaemia, although other studies failed to show such risks. Therefore, the effects of rosiglitazone on the coronary circulation and any potential vascular targets need to be elucidated. Here, we show that the vascular isoform of the ATP-sensitive K(+) (K(ATP) ) channel is inhibited by rosiglitazone, impairing physiological regulation of the coronary circulation. EXPERIMENTAL APPROACH: The K(IR) 6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell and inside-out patch configurations. The Langendorff heart preparation was used to evaluate rosiglitazone in the coronary circulation of wild-type (WT) and K(IR) 6.1-null (Kcnj8(-/-) ) mice. KEY RESULTS: K(IR) 6.1/SUR2B channels in HEK cells were inhibited by rosiglitazone in a membrane delimited manner. This effect was markedly enhanced by sub-micromolar concentrations of glibenclamide and the IC(50) for rosiglitazone fell to 2uM, a therapeutically achievable concentration. In the Langendorff heart preparation rosiglitazone inhibited, concentration-dependently, the coronary vasodilation induced by isoprenaline, without affecting basal coronary tone. Effects of rosiglitazone on coronary perfusion were attenuated by more than 50% in the Kcnj8(-/-) mice, supporting the involvement of K(ATP) channels in this effect of rosiglitazone on the coronary circulation. CONCLUSIONS AND IMPLICATIONS: These results indicate that the vascular K(ATP) channel is one of the targets of rosiglitazone action, through which this drug may compromise coronary responses to circulating vasodilators and perhaps also to metabolic stress. PMID- 21671899 TI - From in vivo gene targeting of oestrogen receptors to optimization of their modulation in menopause. AB - The ancestral status of oestrogen receptor (ER) in the family of the steroid receptors has probably contributed to the pleiotropic actions of oestrogens, and in particular, that of 17beta-oestradiol (E2). Indeed, in addition to their well described role in sexual development and reproduction, they influence most of the physiological processes. The pathophysiological counterpart of these actions includes prevention of osteoporosis, atheroma and type 2 diabetes, and also the promotion of uterus and breast cancer growth. Thus, the major challenge consists in uncoupling some beneficial actions from other deleterious ones, that is, selective ER modulation. Tamoxifen and raloxifene are already used, as they prevent the recurrence of breast cancer and mimic oestrogen action mainly on bone. Both E2 and tamoxifen exhibit a proliferative and, thus, a protumoural action on the endometrium. Activation of ERalpha and ERbeta regulates target gene transcription (genomic action) through two independent activation functions, AF-1 and AF-2, but can also elicit rapid membrane-initiated steroid signals. In the present review, we attempted to summarize recent advances provided by the in vivo molecular 'dissection' of ERalpha, allowing the uncoupling of some of its actions and potentially paving the way to optimized selective ER modulators. PMID- 21671901 TI - Intermedin (adrenomedullin2) stabilizes the endothelial barrier and antagonizes thrombin-induced barrier failure in endothelial cell monolayers. AB - BACKGROUND AND PURPOSE: Intermedin is a member of the calcitonin gene-related peptide (CGRP) family expressed in endothelial cells and acts via calcitonin receptor-like receptors (CLRs). Here we have analysed the receptors for intermedin and its effect on the endothelial barrier in monolayers of human umbilical vein endothelial cells (HUVECs). EXPERIMENTAL APPROACH: We analysed the effect of intermedin on albumin permeability, contractile machinery, actin cytoskeleton and VE-cadherin in cultured HUVECs. KEY RESULTS: Intermedin concentration-dependently reduced basal endothelial permeability to albumin and antagonized thrombin-induced hyperpermeability. Intermedin was less potent (EC(50) 1.29 +/- 0.12 nM) than adrenomedullin (EC(50) 0.24 +/- 0.07 nM) in reducing endothelial permeability. These intermedin effects were inhibited by AM(22-52) and higher concentrations of alphaCGRP(8-37), with pA(2) values of alphaCGRP(8-37) of 6.4 for both intermedin and adrenomedullin. PCR data showed that HUVEC expressed only the CLR/RAMP2 receptor complex. Intermedin activated cAMP/PKA and cAMP/Epac signalling pathways. Intermedin's effect on permeability was blocked by inhibition of PKA but not of eNOS. Intermedin antagonized thrombin induced contractile activation, RhoA activation and stress fibre formation. It also induced Rac1 activation, enhanced cell-cell adhesion and antagonized thrombin-induced loss of cell-cell adhesion. Treatment with a specific inhibitor of Rac1 prevented intermedin-mediated barrier stabilization. CONCLUSION AND IMPLICATIONS: Intermedin stabilized endothelial barriers in HUVEC monolayers via CLR/RAMP2 receptors. These effects were mediated via cAMP-mediated inactivation of contractility and strengthening of cell-cell adhesion. These findings identify intermedin as a barrier stabilizing agent and suggest intermedin as a potential treatment for vascular leakage in inflammatory conditions. PMID- 21671898 TI - GLP-1R and amylin agonism in metabolic disease: complementary mechanisms and future opportunities. AB - The discoveries of the incretin hormone glucagon-like peptide-1 (GLP-1) and the beta-cell hormone amylin have translated into hormone-based therapies for diabetes. Both classes of molecules also exhibit weight-lowering effects and have been investigated for their anti-obesity potential. In the present review, we explore the mechanisms underlying the physiological and pharmacological actions of GLP-1 and amylin agonism. Despite their similarities (e.g. both molecular classes slow gastric emptying, decrease glucagon and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on glycaemia and energy balance. We suggest that understanding the similarities and differences between these molecules holds important implications for the development of novel, combination-based therapies, which are increasingly the norm for diabetes/metabolic disease. Finally, the future of GLP-1- and amylin agonist-based therapeutics is discussed. PMID- 21671902 TI - Br-DIF-1 accelerates dimethyl sulphoxide-induced differentiation of P19CL6 embryonic carcinoma cells into cardiomyocytes. AB - BACKGROUND AND PURPOSE: Stem cell transplantation therapy is a promising option for treatment of severe ischaemic heart disease. Dimethyl sulphoxide (DMSO) differentiates P19CL6 embryonic carcinoma cells into cardiomyocyte-like cells, but with low differentiation capacity. To improve the degree of this differentiation, we have assessed several derivatives of the differentiation inducing factor-1 (DIF-1), originally found in the cellular slime mould Dictyostelium discoideum, on P19CL6 cells. EXPERIMENTAL APPROACH: P19CL6 cells were cultured with each derivative and 1% DMSO for up to 16 days. Differentiation was assessed by measuring the number of beating and non-beating aggregates, and the expression of genes relevant to cardiac tissue. The mechanism of action was investigated using a T-type Ca(2+) channel blocker. KEY RESULTS: Of all the DIF-1 derivatives tested only Br-DIF-1 showed any effects on cardiomyocyte differentiation. In the presence of 1% DMSO, Br-DIF-1 (0.3-3 uM) significantly and dose-dependently increased the number of spontaneously beating aggregates compared with 1% DMSO alone, by day 16. Expression of mRNA for T-type calcium channels was significantly increased by Br-DIF-1 + 1% DMSO compared with 1% DMSO alone. Mibefradil (a T-type Ca(2+) channel blocker; 100 nM) and a small interfering RNA for the T-type Ca(2+) channel both significantly decreased the beating rate of aggregates induced by Br-DIF-1 + 1% DMSO. CONCLUSIONS AND IMPLICATIONS: Br-DIF-1 accelerated the differentiation, induced by 1% DMSO, of P19CL6 cells into spontaneously beating cardiomyocyte-like cells, partly by enhancing the expression of the T-type Ca(2+) channel gene. PMID- 21671903 TI - Cannabinoid CB2 receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice. AB - BACKGROUND AND PURPOSE: This study evaluated gene expression differences between two mouse strains, characterized by opposite impulsivity-like traits and the involvement of the cannabinoid CB(2) receptor in the modulation of impulsivity. EXPERIMENTAL APPROACH: Behavioural tests were conducted to compare motor activity, exploration and novelty seeking, attention and cognitive and motor impulsivity (delayed reinforcement task: session duration 30 min; timeout 30 s) between A/J and DBA/2 mice. Expression of genes for dopamine D(2) receptors, CB(1) and CB(2) receptors were measured in the cingulate cortex (CgCtx), caudate putamen (CPu), accumbens (Acc), amygdala (Amy) and hippocampus (Hipp). Involvement of CB(2) receptors in impulsivity was evaluated in DBA/2 mice with a CB(2) receptor agonist (JWH133) and an antagonist (AM630). KEY RESULTS: DBA/2 mice presented higher motor and exploratory activity, pre-pulse inhibition impairment and higher cognitive and motor impulsivity level than A/J mice. In addition, DBA/2 mice showed lower (CgCtx, Acc, CPu) D(2) receptor, lower (Amy) and higher (CgCtx, Acc, CPu, Hipp) CB(1) receptor and higher (CgCtx, Acc, Amy) and similar (CPu, Hipp) CB(2) receptor gene expressions. Treatment with JWH133 (0.5, 1, 3 mg.kg(-1), i.p.) reduced cognitive and motor impulsivity level, accompanied by CB(2) receptor down-regulation (CgCtx, Acc, Amy) but did not modify other behaviours. In contrast, AM630 (1, 2, 3 mg.kg(-1), i.p.) improved pre-pulse inhibition and reduced novelty seeking behaviour in DBA/2 mice. CONCLUSIONS AND IMPLICATIONS: CB(2) receptors might play an important role in regulating impulsive behaviours and should be considered a promising therapeutic target in the treatment of impulsivity-related disorders. PMID- 21671904 TI - Prostaglandin E2 induces spontaneous rhythmic activity in mouse urinary bladder independently of efferent nerves. AB - BACKGROUND AND PURPOSE: The acute effects of PGE(2) on bladder smooth muscle and nerves were examined to determine the origin of PGE(2)-induced spontaneous rhythmic contractions. EXPERIMENTAL APPROACH: Contraction studies, confocal Ca(2+) imaging and electrophysiological recordings in strips of mouse urinary bladder were used to differentiate the effects of PGE(2) on bladder smooth muscle and efferent nerves. KEY RESULTS: PGE(2) (50 uM) increased the tone and caused phasic contractions of detrusor smooth muscle strips. Confocal Ca(2+) imaging showed that PGE(2) increased the frequency of whole-cell Ca(2+) transients (WCTs) (72 +/- 5%) and intracellular recordings showed it increased the frequency of spontaneous depolarizations, from 0.31.s(-1) to 0.90.s(-1). Non-selective inhibition of EP receptors using SC-51322 and AH-6809 (10 uM), or the L-type Ca(2+) channel blocker nifedipine (1 uM), prevented these phasic contractions and WCTs, and reduced the tone (by 45 +/- 7% and 59 +/- 6%, respectively). Blocking P2X1 receptors with NF449 (10 uM) caused a small but significant reduction in the frequency of PGE(2)-induced phasic contractions (24 +/- 9%) and WCTs (28 +/- 17%) but had no significant effect on spontaneous depolarizations or tone. Inhibiting muscarinic receptors with cyclopentolate (1 uM) had no significant effect on these measures. Spontaneous WCTs became synchronous in PGE(2), implying enhanced functional coupling between neighbouring cells. However, the electrical input resistance was unchanged. CONCLUSIONS AND IMPLICATIONS: It was concluded that depolarization alone is sufficient to explain a functional increase in intercellular coupling and the ability of PGE(2) to increase detrusor spontaneous rhythmic activity does not require parasympathetic nerves. PMID- 21671905 TI - Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting kappa opioid receptor antagonism. AB - BACKGROUND AND PURPOSE: The kappa opioid receptor antagonists demonstrate potential for maintaining abstinence from psychostimulant abuse, but existing non peptide kappa-receptor selective antagonists show exceptionally long activity. We hypothesized that the L- and D-Trp isomers of CJ-15,208, a natural cyclic tetrapeptide reported to be a kappa-receptor antagonist in vitro, would demonstrate short-acting, dose-dependent antagonism in vivo, preventing reinstatement of cocaine-seeking behaviour. EXPERIMENTAL APPROACH: Affinity, selectivity and efficacy of the L-Trp and D-Trp isomers for opioid receptors were assessed in vitro in radioligand and GTPgammaS binding assays. Opioid receptor agonist and antagonist activities were characterized in vivo following i.c.v. administration with the 55 degrees C warm water tail-withdrawal assay. The D-Trp isomer, which demonstrated primarily kappa-receptor selective antagonist activity, was further evaluated for its prevention of stress- and drug-induced reinstatement of extinguished cocaine conditioned place preference (CPP). KEY RESULTS: The two isomers showed similar affinity and selectivity for kappa receptors (K(i) 30-35 nM) as well as kappa receptor antagonism in vitro. As expected, the D-Trp cyclic tetrapeptide exhibited minimal agonist activity and induced dose-dependent kappa-receptor selective antagonism lasting less than 18 h in vivo. Pretreatment with this peptide prevented stress-, but not cocaine induced, reinstatement of extinguished cocaine CPP. In contrast, the L-Trp cyclic tetrapeptide unexpectedly demonstrated mixed opioid agonist/antagonist activity. CONCLUSIONS AND IMPLICATIONS: The L-Trp and the D-Trp isomers of CJ-15,208 demonstrate stereospecific opioid activity in vivo. The relatively brief kappa opioid receptor antagonism, coupled with the prevention of stress-induced reinstatement of extinguished cocaine-seeking behaviour, suggests the D-Trp isomer could be used therapeutically to maintain abstinence from psychostimulant abuse. PMID- 21671908 TI - p16 immunohistochemistry of multiple primary melanomas as screening to identify Familial Melanoma Syndrome. PMID- 21671909 TI - Circumscribed palmar hypokeratosis. PMID- 21671906 TI - Antigen-specific T cell responses to BK polyomavirus antigens identify functional anti-viral immunity and may help to guide immunosuppression following renal transplantation. AB - Infection with the polyoma virus BK (BKV) is a major cause of morbidity following renal transplantation. Limited understanding of the anti-viral immune response has prevented the design of a strategy that balances treatment with the preservation of graft function. The proven utility of interferon-gamma enzyme linked immunospot (ELISPOT) assays to measure T cell responses in immunocompetent hosts was the basis for trying to develop a rational approach to the management of BKV following renal transplantation. In a sample of transplant recipients and healthy controls, comparisons were made between T cell responses to the complete panel of BKV antigens, the Epstein-Barr virus (EBV) antigens, BZLF1 and EBNA1, and the mitogen phytohaemagglutinin (PHA). Correlations between responses to individual antigens and immunosuppressive regimens were also analysed. Antigen specific T cell responses were a specific indicator of recent or ongoing recovery from BKV infection (P < 0.05), with responses to different BKV antigens being highly heterogeneous. Significant BKV immunity was undetectable in transplant patients with persistent viral replication or no history of BKV reactivation. Responses to EBV antigens and mitogen were reduced in patients with BKV reactivation, but these differences were not statistically significant. The T cell response to BKV antigens is a useful and specific guide to recovery from BKV reactivation in renal transplant recipients, provided that the full range of antigenic responses is measured. PMID- 21671907 TI - Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis? AB - The resolution of inflammation is central to the maintenance of good health and immune homeostasis. Recently, several intracellular stress proteins have been described as having extracellular properties that are anti-inflammatory or favour the resolution of inflammation. We propose that these molecules should be defined as resolution-associated molecular patterns (RAMPs). RAMPs are released at times of cellular stress and help to counterbalance the inflammatory effects of pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns. We propose that heat shock protein 10 (HSP10), alphaB-crystallin (alphaBC), HSP27 and binding immunoglobulin protein (BiP) should be considered founding members of the RAMP family. A greater understanding of RAMP biology may herald the development of novel immunotherapies. PMID- 21671910 TI - Scleromyxedema with monoclonal gammopathy and neurological involvement: recovery from coma after plasmapheresis? PMID- 21671911 TI - Novel stain-free lecithinized coal tar formulation for psoriasis. AB - BACKGROUND: Coal tar has been a very popular traditional treatment for various types of psoriasis for over a century. It is the first-line treatment for scalp, hand, and foot psoriasis. However, the application of coal tar on hair invariably causes staining, which results in a high degree of patient non-compliance, especially in patients with non-black hair. Thus, the treatment of scalp psoriasis with a topical coal tar formulation requires that special concern be paid to product esthetics. OBJECTIVE: This study aimed to evaluate the hair staining characteristics of a novel lecithinized coal tar (LCT) formulation on different types of mammalian hair. METHODS: Samples of hair from different mammals, including human, sheep, rabbit, and goat, were repeatedly exposed to the LCT formulation over 14 days. The color of hair samples treated with LCT was compared with that of untreated control hair samples. RESULTS: The study revealed the distinct non-staining potential of the LCT formulation. CONCLUSIONS: This LCT formulation lacks the propensity to stain hair and thus has excellent potential to be exploited in the treatment of scalp psoriasis. PMID- 21671912 TI - Novel population of embryonic secondary mesenchyme cells in the keyhole sand dollar Astriclypeus manni. AB - We have found a novel embryonic cell population in the keyhole sand dollar Astriclypeus manni, which we refer to as lucent fluorescent cells (LFCs). Live LFCs are transparent, but emit autofluorescence after formaldehyde fixation. LFCs become noticeable in the vegetal plate of early gastrulae immediately after the appearance of pigment cells. As development progresses, LFCs increase in number and migrate from the vegetal plate toward the animal pole in a manner similar to pigment cells. Notably, LFCs also migrate into the oral ectoderm, while pigment cells do not. In addition, we determined that there were nearly 300 LFCs per embryo, which greatly exceeds the number of pigment cells. Treatment with the Notch signaling inhibitor N-[(3,5-Difluorophenyl)acetyl]-l-alanyl-2 phenyl]glycine-1,1-dimethylethyl ester (DAPT) resulted in a marked decrease in pigment cell number, but only a modest decrease in LFCs. In DAPT-treated embryos, LFCs had a distribution pattern similar to pigment cells and were excluded from the oral ectoderm. Unlike other sea urchins, Nodal signaling was not involved in the specification of pigment cells and LFCs in these embryos. Pulse treatment and measurement of cell diameters revealed that LFCs underwent 13-15 cycles of cell division and were specified during the 11th cleavage, one cell cycle later than observed for pigment cells. At the pluteus stage, a cluster of LFCs was observed in the animal plate in addition to two rows of LFCs running along the ciliary band. In addition, dozens of LFCs aligned at the uppermost level of the stomodaeum. Therefore, though the two cell populations share some features, LFCs are considerably different from pigment cells. PMID- 21671913 TI - Spatiotemporal expression pattern of gonad-stimulating substance-like peptide of the sea cucumber, Apostichopus japonicus. AB - The spatiotemporal expression pattern of gonad-stimulating substance-like peptide containing polypeptide (GSSLP) in the sea cucumber Apostichopus japonicus was examined using immunochemistry. The GSSLP was detected in the gonads from shortly before the empirical breeding season (May and June) to July. On the basis of immunoblotting analysis, GSSLP showed considerable polymorphism among the organs examined in this study, particularly in the gonads, in which the polymorphism was associated with N-glycosylation and the formation of intra-molecular disulfide bonds. In the ovary, GSSLP was expressed from March to June and corresponded to two bands at 113 and 100 kDa under reducing conditions. In July, only the larger band weakly remained. In testis, GSSLP was detected first in April as two bands of 245 and 190 kDa under reducing conditions. The number of bands increased to five in June but decreased to three smeared bands in July. In the radial nerve and circumoral nerve ring, GSSLP corresponded to a single peptide of 170 kDa with little N-glycosylation and its expression level hardly changed throughout a year with no correlation with the breeding season. GSSLP was detected mainly in the morula cells in all the organs examined. In addition, GSSLP was detected in the follicle cells of the ovary and, for a brief period, in the jelly space, but never in the ooplasm. In testis, the morula cells were localized close to the invaginated inner epithelium, but never in the male gametes. In July animals, gonadal morula cells were rarely observed. PMID- 21671914 TI - Fat/Hippo pathway regulates the progress of neural differentiation signaling in the Drosophila optic lobe. AB - A large number of neural and glial cell species differentiate from neuronal precursor cells during nervous system development. Two types of Drosophila optic lobe neurons, lamina and medulla neurons, are derived from the neuroepithelial (NE) cells of the outer optic anlagen. During larval development, epidermal growth factor receptor (EGFR)/Ras signaling sweeps the NE field from the medial edge and drives medulla neuroblast (NB) formation. This signal drives the transient expression of a proneural gene, lethal of scute, and we refer to its signal array as the "proneural wave," as it is the marker of the EGFR/Ras signaling front. In this study, we show that the atypical cadherin Fat and the downstream Hippo pathways regulate the transduction of EGFR/Ras signaling along the NE field and, thus, ensure the progress of NB differentiation. Fat/Hippo pathway mutation also disrupts the pattern formation of the medulla structure, which is associated with the regulation of neurogenesis. A candidate for the Fat ligand, Dachsous is expressed in the posterior optic lobe, and its mutation was observed to cause a similar phenotype as fat mutation, although in a regionally restricted manner. We also show that Dachsous functions as the ligand in this pathway and genetically interacts with Fat in the optic lobe. These findings provide new insights into the function of the Fat/Hippo pathway, which regulates the ordered progression of neurogenesis in the complex nervous system. PMID- 21671915 TI - Robustness of the Dpp morphogen activity gradient depends on negative feedback regulation by the inhibitory Smad, Dad. AB - Developmental patterning relies on morphogen concentration gradients, which generally provide invariable positional information despite genetic fluctuations. Theoretical studies have predicted robust patterning; however, little experimental evidence exists to support this idea. In this report, we examine the robustness of the Decapentaplegic (Dpp) (a Drosophila homologue of bone morphogenetic protein [BMP]) activity gradient in the presence of fluctuations in Dpp receptor levels. Dpp activity can be measured by the degree of phosphorylation of Mothers against dpp (Mad), a major signal transducer. We determined that phosphorylated Mad (pMad) levels remain constant when an extra copy of thickveins (tkv), which encodes the receptor, is introduced into the wild type background. Higher Tkv levels, expressed under the control of an artificial promoter, result in constant pMad levels. This prompted us to study the mechanisms that underlie pMad level maintenance even when Tkv levels are increased. We focused on the inhibitory Smad, daughters against dpp (dad), which is induced by Dpp signaling and negatively regulates Dpp activity. In the absence of dad, pMad levels significantly increase when Tkv levels increase. These results suggest that Dpp activity gradient robustness when Tkv levels increase depends, at least in part, on negative feedback regulation by dad. PMID- 21671917 TI - Regulatory mechanisms of ecdysone-inducible Blimp-1 encoding a transcriptional repressor that is important for the prepupal development in Drosophila. AB - Blimp-1 is an ecdysone-inducible transcription factor that is expressed in the early stage of the prepupal period. The timing of its disappearance determines expression timing of the FTZ-F1 gene, whose temporally restricted expression is essential for the prepupal development. To elucidate the termination mechanism of Blimp-1 gene expression, we examined the regulation of the Blimp-1 gene using an organ culture system. The results showed that the Blimp-1 gene is transcribed in cultured organs taken from a low ecdysteroid period even after extended exposure to 20-hydroxyecdysone, while well-known early genes such as E75A are repressed under the same conditions. Similar selective transcription was observed in the cultured organs obtained from a high ecdysteroid period. We further showed that Blimp-1 transcripts quickly disappeared in the presence of actinomycin D. From these results, we concluded that the Blimp-1 gene is transcribed when the ecdysteroid titer is high, but the expressed mRNA degrades rapidly; these unique regulations limit its expression to the high ecdysteroid stage. PMID- 21671916 TI - Necessary role for intracellular Ca2+ transients in initiating the apical basolateral thinning of enveloping layer cells during the early blastula period of zebrafish development. AB - During the early blastula period of zebrafish embryos, the outermost blastomeres begin to undergo a significant thinning in the apical/basolateral dimension to form the first distinct cellular domain of the embryo, the enveloping layer (EVL). During this shape transformation, only the EVL-precursor cells generate a coincidental series of highly restricted Ca(2+) transients. To investigate the role of these localized Ca(2+) transients in this shape-change process, embryos were treated with a Ca(2+) chelator (5,5'-difluoro BAPTA AM; DFB), or the Ca(2+) ionophore (A23187), to downregulate and upregulate the transients, respectively, while the shape-change of the forming EVL cells was measured. DFB was shown to significantly slow, and A23187 to significantly facilitate the shape change of the forming EVL cells. In addition, to investigate the possible involvement of the phosphoinositide and Wnt/Ca(2+) signaling pathways in the Ca(2+) transient generation and/or shape-change processes, embryos were treated with antagonists (thapsigargin, 2-APB and U73122) or an agonist (Wnt-5A) of these pathways. Wnt-5A upregulated the EVL-restricted Ca(2+) transients and facilitated the change in shape of the EVL cells, while 2-APB downregulated the Ca(2+) transients and significantly slowed the cell shape-change process. Furthermore, thapsigargin and U73122 also both inhibited the EVL cell shape-change. We hypothesize, therefore, that the highly localized and coincidental Ca(2+) transients play a necessary role in initiating the shape-change of the EVL cells. PMID- 21671918 TI - Rho-kinase in sea urchin eggs and embryos. AB - The activation of sea urchin eggs at fertilization provides an ideal system for studying the molecular events involved in cellular activation. Rho GTPases, which are key signaling enzymes in eukaryotes, are involved in sustaining the activation of sea urchin eggs; however, their downstream effectors have not yet been characterized. In somatic cells, RhoA regulates a serine/threonine kinase known as Rho-kinase (ROCK). The activity of ROCK in early sea urchin development has been inferred, but not tested directly. A ROCK gene was identified in the sea urchin (Strongylocentrotus purpuratus) genome and the sequence of its cDNA determined. The sea urchin ROCK (SpROCK) sequence predicts a protein of 158 kDa with >72% and 45% identities with different protein orthologues of the kinase catalytic domain and the complete protein sequence, respectively. SpROCK mRNA levels are high in unfertilized eggs and decrease to 35% after 15 min postfertilization and remain low up to the 4 cell stage. Antibodies to the human ROCK-I kinase domain revealed SpROCK to be concentrated in the cortex of eggs and early embryos. Co-immunoprecipitation assays indicate that RhoA and SpROCK are physically associated. This association is destroyed by treatment with the C3 exoenzyme and with the ROCK antagonist H-1152. H-1152 also inhibited DNA synthesis in embryos. We conclude that the Rho-dependent signaling pathway, via SpROCK, is essential for early embryonic development. PMID- 21671919 TI - Embryogenic staging of fugu, Takifugu rubripes, and expression profiles of aldh1a2, aldh1a3 and cyp26a1. AB - Fugu (Takifugu rubripes) has contributed as an ideal model organism for understanding the structure and evolution of vertebrate genomes, but also has potential as a good model organism for developmental biology because of the availability of the genome information. However, there is no comprehensive report describing the developmental stages, which is fundamental data for developmental biology. Here we describe a series of stages of the embryonic development of fugu during the first 8 days after fertilization, i.e. from fertilization to hatching. We define seven periods of embryogenesis - the zygote, cleavage, blastula, gastrula, segmentation, pharyngula, and hatching periods. Stages subdividing these periods are defined based on morphological characteristics. In addition, as a model experiment of gene expression analysis using this staging series, we performed in situ hybridization of aldh1a2, aldh1a3 and cyp26a1 that play regulatory roles in retinoic acid (RA) metabolism essential for embryogenesis. This report provides fundamental information on fugu embryogenesis, which is anticipated to facilitate the use of fugu as a model organism for developmental studies. PMID- 21671920 TI - Differential expression of the ADAMs in developing chicken retina. AB - The expression patterns of the seven members of the ADAM (a disintegrin and metalloprotease) family, ADAM9, ADAM10, ADAM12, ADAM13, ADAM17, ADAM22, and ADAM23 were analyzed in the developing chicken retina by in situ hybridization and immunohistochemistry. Results show that each individual ADAM is expressed and regulated spatiotemporally in the developing retinal layers. ADAM9, ADAM10 and ADAM17 are widely expressed in the differential layers of the retina throughout the whole embryonic period, while ADAM12 and ADAM13 are mainly expressed in the ganglion cell layer at a later stage. ADAM22 and ADAM23 are restricted to the inner nuclear layer and the ganglion cell layer at a later stage. Furthermore, ADAM10 protein is co-expressed with the four members of the classic cadherins, N cadherin, R-cadherin, cadherin-6B and cadherin-7 in distinct retinal layers. Therefore, the differential expression of the investigated ADAMs in the developing retina suggests the contribution of them to the retina development. PMID- 21671921 TI - Development of the nervous system in hatchlings of Spadella cephaloptera (Chaetognatha), and implications for nervous system evolution in Bilateria. AB - Chaetognaths (arrow worms) play an important role as predators in planktonic food webs. Their phylogenetic position is unresolved, and among the numerous hypotheses, affinities to both protostomes and deuterostomes have been suggested. Many aspects of their life history, including ontogenesis, are poorly understood and, though some aspects of their embryonic and postembryonic development have been described, knowledge of early neural development is still limited. This study sets out to provide new insights into neurogenesis of newly hatched Spadella cephaloptera and their development during the following days, with attention to the two main nervous centers, the brain and the ventral nerve center. These were examined with immunohistological methods and confocal laser scan microscopic analysis, using antibodies against tubulin, FMRFamide, and synapsin to trace the emergence of neuropils and the establishment of specific peptidergic subsystems. At hatching, the neuronal architecture of the ventral nerve center is already well established, whereas the brain and the associated vestibular ganglia are still rudimentary. The development of the brain proceeds rapidly over the next 6 days to a state that resembles the adult pattern. These data are discussed in relation to the larval life style and behaviors such as feeding. In addition, we compare the larval chaetognath nervous system and that of other bilaterian taxa in order to extract information with phylogenetic value. We conclude that larval neurogenesis in chaetognaths does not suggest an especially close relationship to either deuterostomes or protostomes, but instead displays many apomorphic features. PMID- 21671922 TI - Medically refractory epilepsy in autism. AB - PURPOSE: Epilepsy and electroencephalographic abnormalities are frequent in idiopathic autism, but there is little information regarding treatment-resistant epilepsy (TRE) in this group. We sought to define the clinical and electrophysiologic characteristics and treatment outcomes in these patients. METHODS: We retrospectively reviewed clinical and laboratory data of patients with idiopathic autism evaluated at NYU Epilepsy Center during a 20-year period. KEY FINDINGS: One hundred twenty-seven patients had idiopathic autism and at least one epileptic seizure; 33.9% had TRE and 27.5% were seizure free. The remaining 38.6% of patients had infrequent seizures or insufficient data to categorize. Patients with TRE had a significantly earlier onset of seizures than seizure-free patients, and a trend for more developmental regression and motor and language delays. Three patients had surgical resection (two had limited improvement and one had no improvement) and one had an anterior callosotomy (no improvement). Vagus nerve stimulator (VNS) implantation provided limited improvement (2 patients) and no improvement (7). SIGNIFICANCE: This study found that TRE is common in idiopathic autism and more common with early age of seizure onset. Relatively few patients underwent surgical resection due to multifocal partial epilepsy, comorbid generalized epilepsy, or limited impact of ongoing partial seizures given other problems related to autism. Our small sample suggests that surgical and VNS outcomes in this group are less favorable than in other TRE populations. PMID- 21671923 TI - Changes preceding interictal epileptic EEG abnormalities: comparison between EEG/fMRI and intracerebral EEG. AB - PURPOSE: In simultaneous scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), blood oxygen level dependent (BOLD) changes occurring before the spike have been sometimes described but could not be explained. To characterize the origin of this prespike BOLD signal change, we looked for electrographic changes in stereo-EEG (SEEG) possibly preceding the scalp spike in patients that showed early BOLD response in EEG/fMRI. METHODS: We studied four patients with drug-resistant focal epilepsy who underwent EEG/fMRI, showed a prespike BOLD response, and were then studied with depth electrodes for presurgical localization of the epileptic generator. Early BOLD responses in the region of the spike field were analyzed using models with hemodynamic response functions (HRFs) peaking from -9 to +9 s around the spike. SEEG recordings in the period and location corresponding to the early HRF responses were analyzed to detect if electrographic changes were present in the SEEG before the scalp abnormality. KEY FINDINGS: One of the four patients presented a SEEG interictal discharge in the period corresponding to the early BOLD response. In the other three, no electrographic changes were detected in the SEEG in the period corresponding to early BOLD changes. SIGNIFICANCE: Although the early BOLD activity may sometimes be explained by a synchronized neural discharge detectable with SEEG but not visible on the scalp EEG, in most cases the early BOLD response reflects a metabolic phenomenon that does not appear to result from a synchronized neuronal discharge. Prespike metabolic responses can result from synchronized or nonsynchronized neuronal activity, or from nonneuronal mechanisms including glia. PMID- 21671924 TI - Continuous video-EEG monitoring in pediatric intensive care units. AB - PURPOSE: Several studies indicate a higher occurrence than might be expected of seizures in intensive care unit patients, many of which are not clinically apparent. Few of these studies are devoted exclusively to pediatric patients. The purpose of this study is to determine the occurrence of seizures in a cohort of pediatric and neonatal intensive care unit patients. METHODS: Long-term video electroencephalography (EEG) monitoring studies performed in the pediatric and neonatal intensive care units were reviewed. Age, gender, diagnosis, EEG background, epileptiform activity, time of onset and duration of seizures, presence of electroclinical or electrographic seizures, and survival were collected. KEY FINDINGS: One hundred thirty-eight recordings encompassing 122 patients were identified. Thirty-four percent of the sessions identified seizures in the first 24 h (38% of the cohort experienced a seizure at some time during monitoring, which ranged from 1-22 days): 17% captured only electroclinical seizures, 49% were electrographic only, and 34% had both electroclinical and electrographic seizures. Seventy percent of those patients experiencing seizures had their first seizure within the first hour of EEG recording. Younger age and epileptiform activity (including periodic) were associated with the occurrence of seizures. Diagnoses of head trauma and status epilepticus/recent prior seizure were more likely than other at-risk diagnoses to be associated with seizures; cardiac arrest managed with hypothermia was less likely to be associated with seizures. One-fourth of the recordings identified nonepileptic events. SIGNIFICANCE: Seizures occurred in one-third of critically ill pediatric patients at risk for seizures who underwent video-EEG monitoring, and many of these seizures did not have a clinical correlate. In those at risk for seizures in intensive care units, there should be a low threshold for obtaining long-term monitoring. PMID- 21671925 TI - Combined analysis of risk factors for SUDEP. AB - PURPOSE: To pool data from four published case-control studies of sudden unexpected death in epilepsy (SUDEP) with live controls, to increase the power to determine risk factors. METHODS: Case-control studies from the United States, Sweden, Scotland, and England were combined. SUDEP was defined as (1) a history of epilepsy (>1 epileptic seizure during a period of < 5 years); (2) death occurring suddenly; (3) death unexpected (i.e., no life-threatening illness); and (4) death remained unexplained after all investigative efforts, including autopsy. Definite SUDEP required all criteria. Logistic regression analyses adjusted for study. Further analysis simultaneously adjusted for study, age at death, gender, and duration of epilepsy. KEY FINDINGS: Of the risk factors that could be analyzed across some or all studies, those that were statistically significant were increased frequency of generalized tonic-clonic seizures (GTCS), use of polytherapy, duration of epilepsy, young age at onset, gender, symptomatic etiology, and lamotrigine therapy. Results persisted when epilepsy onset was younger than 16 years and when it was 16 years or older. In univariate analysis, lamotrigine therapy was associated with significantly increased risk for SUDEP among individuals with idiopathic generalized epilepsy. SIGNIFICANCE: This analysis refines the identification of people with epilepsy that are at particular risk of SUDEP. The emerging profile indicates that people with early onset refractory symptomatic epilepsy with frequent GTCS and antiepileptic drug (AED) polytherapy are at higher risk. The results suggest that reduction of the number of GTCS is a priority, of more importance than reducing the number of AEDs. The role of AEDs and other treatment should be analyzed further in future studies. PMID- 21671926 TI - SPECT findings during postictal psychoses: predominance of relative increase of perfusion in right temporal lobe. AB - To identify brain regions activated during episodes of postictal psychoses (PIP), we investigated single-photon emission computed tomography (SPECT) data obtained from five patients treated at our institutions and also reviewed four previous studies. Therefore, SPECT findings in a total of 19 cases were analyzed, including 16 patients with temporal lobe epilepsy (TLE). During nonpsychotic states, the laterality of epileptic foci was judged as left-sided in nine episodes, right-sided in six episodes, and nonlateralized in four episodes. In PIP states, 88% of the patients showed a relative increase of right temporal perfusion (increased right temporal or decreased left temporal perfusion). Regardless of whether right- or left-sided pathology was suspected during a nonpsychotic state, SPECT findings obtained during PIP episodes revealed a trend of right-sided temporal predominance. PMID- 21671927 TI - The etiologic classification of epilepsy. PMID- 21671928 TI - New classification proposals for epilepsy: a real advancement in the nosography of the disease? PMID- 21671929 TI - Networks and systems, conceptualizations, and research. PMID- 21671930 TI - In support of the ILAE Commission classification proposal. PMID- 21671931 TI - Epilepsy is both a symptom and a disease: a proposal for a two-tiered classification system. PMID- 21671932 TI - Classification of the epilepsies 2011. PMID- 21671933 TI - The evolving classification of seizures and epilepsies. PMID- 21671936 TI - Lessons learned from bacterial transport research at the South Oyster Site. AB - This paper provides a review of bacterial transport experiments conducted by a multiinvestigator, multiinstitution, multidisciplinary team of researchers under the auspices of the U.S. Department of Energy (DOE). The experiments were conducted during the time period 1999-2001 at a field site near the town of Oyster, Virginia known as the South Oyster Site, and included four major experimental campaigns aimed at understanding and quantifying bacterial transport in the subsurface environment. Several key elements of the research are discussed here: (1) quantification of bacterial transport in physically, chemically, and biologically heterogeneous aquifers, (2) evaluation of the efficacy of conventional colloid filtration theory, (3) scale effects in bacterial transport, (4) development of new methods for microbial enumeration and screening for low adhesion strains, (5) application of novel hydrogeophysical techniques for aquifer characterization, and (6) experiences regarding management of a large field research effort. Lessons learned are summarized in each of these areas. The body of literature resulting from South Oyster Site research has been widely cited and continues to influence research into the controls exerted by aquifer heterogeneity on reactive transport (including microbial transport). It also served as a model (and provided valuable experience) for subsequent and ongoing highly-instrumented field research efforts conducted by DOE-sponsored investigators. PMID- 21671937 TI - The unusual and large drawdown response of buried-valley aquifers to pumping. AB - The buried-valley aquifers that are common in the glacial deposits of the northern hemisphere are a typical case of the strip aquifers that occur in many parts of the world. Pumping from a narrow strip aquifer leads to much greater drawdown and much more distant drawdown effects then would occur in a sheet aquifer with a similar transmissivity and storage coefficient. Widely used theories for radial flow to wells, such as the Theis equation, are not appropriate for narrow strip aquifers. Previously published theory for flow to wells in semiconfined strip aquifers is reviewed and a practical format of the type curves for pumping-test analysis is described. The drawdown response of strip aquifers to pumping tests is distinctive, especially for observation wells near the pumped well. A case study is presented, based on extensive pumping test experience for the Estevan Valley Aquifer in southern Saskatchewan, Canada. Evaluation of groundwater resources in such buried-valley aquifers needs to take into account the unusually large drawdowns in response to pumping. PMID- 21671938 TI - Psychiatric comorbidity in gender dysphoric adolescents. AB - BACKGROUND: This study examined psychiatric comorbidity in adolescents with a gender identity disorder (GID). We focused on its relation to gender, type of GID diagnosis and eligibility for medical interventions (puberty suppression and cross-sex hormones). METHODS: To ascertain DSM-IV diagnoses, the Diagnostic Interview Schedule for Children (DISC) was administered to parents of 105 gender dysphoric adolescents. RESULTS: 67.6% had no concurrent psychiatric disorder. Anxiety disorders occurred in 21%, mood disorders in 12.4% and disruptive disorders in 11.4% of the adolescents. Compared with natal females (n = 52), natal males (n = 53) suffered more often from two or more comorbid diagnoses (22.6% vs. 7.7%, p = .03), mood disorders (20.8% vs. 3.8%, p = .008) and social anxiety disorder (15.1% vs. 3.8%, p = .049). Adolescents with GID considered to be 'delayed eligible' for medical treatment were older [15.6 years (SD = 1.6) vs. 14.1 years (SD = 2.2), p = .001], their intelligence was lower [91.6 (SD = 12.4) vs. 99.1 (SD = 12.8), p = .011] and a lower percentage was living with both parents (23% vs. 64%, p < .001). Although the two groups did not differ in the prevalence of psychiatric comorbidity, the respective odds ratios ('delayed eligible' adolescents vs. 'immediately eligible' adolescents) were >1.0 for all psychiatric diagnoses except specific phobia. CONCLUSIONS: Despite the suffering resulting from the incongruence between experienced and assigned gender at the start of puberty, the majority of gender dysphoric adolescents do not have co occurring psychiatric problems. Delayed eligibility for medical interventions is associated with psychiatric comorbidity although other factors are of importance as well. PMID- 21671939 TI - Commentary: I don't second that emotion: subjective experience of fear in adolescents with psychopathic traits - reflections on Marsh et al. (2011). PMID- 21671940 TI - Prevalence, comorbidity and course of trauma reactions in young burn-injured children. AB - BACKGROUND: Infants, toddlers and preschoolers are the highest risk group for burn injury. However, to date this population has been largely neglected. This study examined the prevalence, onset, comorbidity and recovery patterns of posttrauma reactions in young children with burns. METHODS: Parents of 130 unintentionally burned children (1-6 years) participated in the study. The Diagnostic Infant Preschool Assessment was conducted with parents at 1 and 6 months postinjury. RESULTS: The majority of children were resilient. However, 35% were diagnosed with at least one psychological disorder, there was a high rate of comorbidity with posttraumatic stress disorder, and 8% of children did not experience recovery in distress levels over the course of 6 months. CONCLUSIONS: These outcomes are likely to have serious repercussions for a young child's medical and psychosocial recovery as well as their normal developmental trajectories. It is recommended that screening, prevention and early intervention resources are incorporated into paediatric health care settings to optimise children's psychological adjustment following burn injury. PMID- 21671941 TI - Commentary: disengaging the infant mind: genetic dissociation of attention and cognitive skills in infants - reflections on Leppanen et al. (2011). PMID- 21671942 TI - Occurrence of systemic hypertension in dogs with acute kidney injury and treatment with amlodipine besylate. AB - OBJECTIVES: To describe the occurrence of systemic hypertension in dogs with acute kidney injury and the efficacy of amlodipine besylate for its treatment. METHODS: This retrospective study included 52 dogs with acute kidney injury (2007 to 2008) grouped based on the use of amlodipine in their treatment. Systemic blood pressure was measured with an oscillometric device at admission, before, during, and after amlodipine therapy. RESULTS: Occurrence of systolic systemic hypertension (>=160 mmHg) and severe systolic systemic hypertension (>=180 mmHg) was 37% and 15% at admission and increased with hospitalisation to 81% and 62%, respectively. Twenty-two dogs were treated with amlodipine, at a median daily dosage of 0.38 mg/kg (interquartile range 0.28 to 0.49) divided in one to two applications per day. Amlodipine therapy was associated with a decrease in systolic systemic blood pressure of 24 mmHg (12 to 34) and a correction of severe systemic hypertension in 10 of 11 dogs within 24 hours. Overall, 73% of the dogs survived with a significantly lower proportion of survivors in treated compared to non-treated dogs (59% versus 83%, respectively, P=0.05). CLINICAL SIGNIFICANCE: Results of this study reveal that systemic hypertension is common in canine acute kidney injury and that treatment with amlodipine is beneficial in reducing systemic hypertension. The potential effect of amlodipine on global outcome requires prospective assessment. PMID- 21671943 TI - Extrahepatic biliary tract obstruction in two ferrets (Mustela putorius furo). AB - This report describes extrahepatic bile duct obstruction in two ferrets, which were presented with anorexia, chronic weight loss and general weakness. Physical examination revealed lethargy, cachexia, dehydration, abdominal pain and icterus. Marked haematological, serum chemistry and urinalysis abnormalities included hyperbilirubinaemia (65.5 and 114.2 MUmol/L), high concentrations of alanine transaminase (1327.53 and 2578.88 IU/L) and biluribinuria. Abdominal ultrasonography revealed thickening of the bile duct together with the gall bladder wall. The common bile duct was obviously distended. Choledochotomy revealed inspissated bile with fragile green gelatinous plugs that was removed to allow the bile to flow into the duodenum. Cytology and culture of the biliary tract contents were negative for bacteria. Laboratory analyses of biliary plugs showed presence of only protein substances, without detectable mineral composition. Histopathological examination of the liver showed diffuse steatosis and non-specific cholangiohepatitis in both cases. PMID- 21671944 TI - Epidermal growth factor and active caspase-3 expression in the levator ani muscle of dogs with and without perineal hernia. AB - OBJECTIVES: To perform a histological and immunohistochemical study of epidermal growth factor, transforming growth factor-alpha and their receptor, as well as the apoptotic signal active caspase-3 in the levator ani muscle of dogs with and without perineal hernia. METHODS: Biopsy specimens of the levator ani muscle were obtained from 25 dogs with perineal hernia and 4 non-affected dogs and were processed for Masson and immunohistochemical staining. RESULTS: The affected dogs exhibited myopathological features, internalised nuclei, destruction and abnormal size of muscle fibres, which were replaced by collagen. The immunohistochemical study revealed active caspase-3, epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor in the levator ani. Compared to the healthy muscle, transforming growth factor-alpha staining intensity was lower in the affected muscle, whereas epidermal growth factor receptor and active caspase-3 staining were higher. CLINICAL SIGNIFICANCE: Pelvic diaphragm muscle weakening is the leading cause of perineal hernia in the dog. Survival and death signals expressed in these muscles may contribute to the pathogenesis of this disease. This study reports epidermal growth factor, transforming growth factor alpha and epidermal growth factor receptor immunohistochemical expression in the skeletal muscle and suggests that perineal hernia in the dog is accompanied by levator ani muscle atrophy, increased expression of epidermal growth factor receptor, caspase-3 activation, and decreased expression of transforming growth factor-alpha. PMID- 21671945 TI - Corticosteroid cross-reactivity: clinical and molecular modelling tools. AB - BACKGROUND: Corticosteroids have been classified into following four cross reacting groups in function of their contact-allergenic properties: A, B, C and D, the last subdivided into D1 and D2. Recent data indicate that C(16)-methylated and nonmethylated molecules need to be distinguished, the latter selectively binding with arginine to form stable cyclic adducts and producing considerably more positive reactions than the former. This study compares molecular modelling and patch-test results to determine cross-reactivity patterns. METHODS: The patch test results obtained with 66 corticosteroid molecules in 315 previously sensitized subjects were analysed and correlated with modelling and clustering in function of the electrostatic and steric fields of these molecules. RESULTS: The classification obtained after in silico hydrolysis of C(21) and C(17) esters was selected with an optimal cut into three clusters: the patients who reacted positively to cluster 2 (halogenated molecules from group B, with C(16)/C(17) cis ketal or diol structure) and cluster 3 (halogenated molecules from groups C and D1, C(16)-methylated) also reacted to cluster 1 (molecules mostly from groups A and D2, without C(16)-methyl substitution or halogenation and budesonide). The reverse, however, was not the case. CONCLUSION: Two patient profiles with probably different areas of immune recognition are identified as follows: the profile 1 patients were allergic to the frequently positively reacting cluster 1 only, for whom electrostatic fields (molecular charge) seem important; the profile 2 patients reacted to clusters 1 and 2 and/or 3, for whom steric fields (structure) are determinant and who probably presented a global recognition of the corticosteroid skeleton. A modified classification is thus proposed. PMID- 21671946 TI - Development of a physiologically based pharmacokinetic model to predict tulathromycin distribution in goats. AB - Physiologically based pharmacokinetic (PBPK) models, which incorporate species- and chemical-specific parameters, could be useful tools for extrapolating withdrawal times for drugs across species and doses. The objective of this research was to develop a PBPK model for goats to simulate the pharmacokinetics of tulathromycin, a macrolide antibiotic effective for treating respiratory infections. Model compartments included plasma, lung, liver, muscle, adipose tissue, kidney, and remaining poorly and richly perfused tissues. Tulathromycin was assumed to be 50% protein bound in plasma with first-order clearance. Literature values were compiled for physiological parameters, partition coefficients were estimated from tissue:plasma ratios of AUC, and the remaining model parameters were estimated by comparison against the experimental data. Three separate model structures were compared with plasma and tissue concentrations of tulathromycin in market age goats administered 2.5 mg/kg tulathromycin subcutaneously. The best simulation was achieved with a diffusion limited PBPK model and absorption from a two-compartment injection site, which allowed for low persistent concentrations at the injection site and slower depletion in the tissues than the plasma as observed with the experimental data. The model with age-appropriate physiological parameters also predicted plasma concentrations in juvenile goats administered tulathromycin subcutaneously. The developed model and compilation of physiological parameters for goats provide initial tools that can be used as a basis for predicting withdrawal times of drugs in this minor species. PMID- 21671947 TI - New tools for an old trade: a socio-technical appraisal of how electronic decision support is used by primary care practitioners. AB - This article explores Australian general practitioners' (GPs) views on a novel electronic decision support (EDS) tool being developed for cardiovascular disease management. We use Timmermans and Berg's technology-in-practice approach to examine how technologies influence and are influenced by the social networks in which they are placed. In all, 21 general practitioners who piloted the tool were interviewed. The tool occupied an ill-defined middle ground in a dialectical relationship between GPs' routine care and factors promoting best practice. Drawing on Lipsky's concept of 'street-level bureaucrats', the tool's ability to process workloads expeditiously was of greatest appeal to GPs. This feature of the tool gave it the potential to alter the structure, process and content of healthcare encounters. The credibility of EDS tools appears to be mediated by fluid notions of best practice, based on an expert scrutiny of the evidence, synthesis via authoritative guidelines and dissemination through trusted and often informal networks. Balanced against this is the importance of 'soft' forms of knowledge such as intuition and timing in everyday decision-making. This resonates with Aristotle's theory of phronesis (practical wisdom) and may render EDS tools inconsequential if they merely process biomedical data. While EDS tools show promise in improving health practitioner performance, the socio-technical dimensions of their implementation warrant careful consideration. PMID- 21671948 TI - Managing severe curvature of radix entomolaris: three-dimensional analysis with cone beam computed tomography. AB - AIM: To present a case of a mandibular first molar with an additional distolingual root [radix entomolaris (RE)] and to discuss the use of cone beam computed tomography (CBCT) for its identification and management during root canal treatment. SUMMARY: A 52-year-old Caucasian woman was referred for root canal treatment of the right mandibular first molar (tooth 46). After clinical and radiographic examination, a symptomatic irreversible pulpitis was diagnosed. Three periapical radiographs with different horizontal angulations revealed the presence of an additional distolingual root. This extra root, termed RE, has an incidence of <5% in the Caucasian population. A CBCT examination was also taken, which revealed a severe root canal curvature, especially in the middle third, of this supernumerary root. CBCT provided more accurate information in terms of RE inclination and root canal curvature before commencing root canal treatment. The conventional access opening was modified into a more trapezoidal cavity, and five root canals were found. All canals were instrumented with new nickel-titanium (NiTi) files to reduce the risk of fractured instruments. After preparation, the root canals were filled using thermoplastified techniques. The 1-year follow-up periapical radiographs and CBCT images revealed a continuous periodontal space with no signs of apical periodontitis. KEY LEARNING POINTS: * Cone beam computed tomography imaging is useful in identifying the root canal system and the surrounding structures. * An accurate detection of supernumerary roots, such as RE, can avoid complications during and after root canal treatment. * The analysis of root canal curvature is important because instrument fracture has been linked to angle and radius of curvature. * The use of new instruments can reduce the incidence of instrument fracture. PMID- 21671949 TI - Strategic use of preference confirmation in group decision making: the role of competition and dissent. AB - The present research investigates the moderating role of goal interdependence and dissent on individual preference confirmation in hidden-profile tasks. We propose that preference confirmation can be used strategically to deal with competition and dissent likely to arise in group decision making. In two studies, participants first received incomplete information about a car accident investigation, and then read a fictitious discussion with two other participants containing full information. The interaction with the fictitious participants was presented either as cooperative or competitive. We predicted and found preference confirmation to be higher in competition than cooperation, when initial preferences were dissenting (Studies 1 & 2), but to be higher in cooperation than in competition, when initial preferences were consensual (Study 2). Also, the increased versus decreased preference confirmation in competition with, respectively, dissent and no dissent were found to be predicted by self enhancement strategies (Study 2). These findings contribute to a better understanding of the boundary conditions of preference confirmation in hidden profiles and shed a new light on the role of motivated information processing in these tasks. PMID- 21671950 TI - Purkinje-related arrhythmias part ii: polymorphic ventricular tachycardia and ventricular fibrillation. AB - There has been growing evidence that the Purkinje network plays a pivotal role in both the initiation and perpetuation of ventricular fibrillation (VF). A triggering ventricular premature beat (VPB) with a short-coupling interval could arise from either the right or left Purkinje system in patients with polymorphic ventricular tachycardia (VT) or VF, and that can be suppressed by the catheter ablation of the trigger. A focal breakdown in the "gating mechanism" at the Purkinje system resulting in a short-circuiting of the transmission across the gate at the distal Purkinje network might predispose to reentrant circuits of polymorphic VT/VF. Many investigators also reported the successful ablation of Purkinje-related VF with an acute or remote myocardial infarction. The same approach with good short-term results has been reported in a small number of patients with other heart diseases (i.e., amyloidosis, chronic myocarditis, nonischemic cardiomyopathy). Catheter ablation of the triggering VPBs from the Purkinje system can be used as an electrical bailout therapy in patients with VF storm. PMID- 21671951 TI - Management of symptomatic inadvertently placed endocardial leads in the left ventricle. AB - BACKGROUND: There are limited data regarding the clinical care of inadvertently placed endocardial leads in the left ventricle (LV). We clarified the appropriate management within the context of our experience and published literature. METHODS: Hospital charts dating from October 2008 to December 2010 were reviewed at a high-volume cardiovascular tertiary referral center. Six patients were identified with inadvertently placed leads in the LV through an atrial septal defect. RESULTS: Six patients (four males, two females) underwent LV lead removal, four through open surgical intervention and two percutaneously. Three (50%) patients presented with severe mitral regurgitation; one (16%) with a thromboembolic transient ischemic attack and two (33%) were asymptomatic. The mean age was 68.5 +/- 8.48 years (55-78). Mean ejection fraction was 38.47 +/- 11.1% (25%-50%). Four patients (66%) had a pacemaker and two (33%) had implantable cardioverter defibrillators. Comorbidities consisted of diabetes mellitus (50%), chronic renal failure (16%), severe chronic pulmonary hypertension (16%), and congestive heart failure (33%). Hypertension and coronary arterial disease were present in all patients. All patients had complete extraction or repositioning without intraoperative complications or mortality within 30 days. At 6-month follow-up, the patient with severe pulmonary hypertension died of pneumonia and the other five were alive and well. CONCLUSION: The avoidance and early recognition of inadvertently placed endocardial leads in the LV is imperative in order to avoid potentially serious sequelae and invasive interventions. Treatment usually consists of surgical extraction, although anticoagulation and percutaneous simple traction techniques are an option in certain scenarios. PMID- 21671952 TI - Percutaneous lead and system extraction in patients with cardiac resynchronization therapy (CRT) devices and coronary sinus leads. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) device and coronary sinus (CS) lead extraction is required due to the occurrence of system infection, malfunction, or upgrade. Published series of CS lead extraction are limited by small sample sizes. We present a 10-year experience of CRT device and CS lead extraction. METHODS: All lead extractions between 2000 and 2010 were entered into a computer database. From these, a cohort of 71 cases involving a CRT device or CS lead was analyzed for procedural method, success, and complications. RESULTS: Sixty coronary sinus leads were extracted in 71 cases (median age 71 years; 90% male) by manual traction/locking stylets (n = 54) or using a laser sheath (n = 6). Procedural success was achieved in 98% of CS leads. A total of 143 non-CS leads were extracted, with laser required in 46% of cases. The mean duration of lead implantation was 35.8 months (range 1-116 months) and 2.86 +/- 1.07 leads were extracted per case. CRT extraction case load increased significantly over time. Minor complications occurred in four (5.6%) cases and major complications in one (1.4%) case. There were no intraprocedural deaths, but two deaths occurred within 30 days of extraction. CONCLUSIONS: Our 10-year experience confirms that percutaneous removal of CS leads can be achieved with high procedural success. Our recorded complication rates are no higher than those of non-CS lead extraction series, and should be taken in the context of the frail nature of CRT patients. Ongoing audit of procedure success and complications will be required to further guide best practice in CS lead extraction. PMID- 21671953 TI - Electrocardiographic changes in Takotsubo cardiomyopathy. AB - INTRODUCTION: Takotsubo cardiomyopathy (TC) is a unique transient nonischemic cardiomyopathy that mimics acute myocardial infarction (MI). The aim of our study was to evaluate electrocardiographic changes in patients with TC, including the frequency of ST elevation and other abnormalities. METHODS: Eleven patients were retrospectively identified from echocardiography database. All patients underwent coronary angiography and fulfilled the Mayo criteria for diagnosis of TC during the period November 2005 to September 2010. Standard 12-lead electrocardiograms recorded daily during the first week of hospitalization, after onset of symptoms were analyzed. RESULTS: Eight of 11 patients were found to have ST elevation, of which two patients had ST depression in reciprocal leads. No patient had ST elevation in lead V1, most likely reason being that wall-motion abnormalities in TC rarely extend to the region faced by lead V1. Pathological Q waves were found in five patients, of which two patients had transient Q waves, suggesting less myocardial damage. All 11 patients had T-wave inversion; eight of these patients had diffuse symmetric T-wave inversion, extending beyond the perfusion territory of any single coronary artery. QTc interval prolongation was found in 10 patients. All patients had left ventricular ejection fraction between 25% and 35% on presentation, which could not be predicted by the extent of electrocardiogram (ECG) changes. CONCLUSION: ECG changes in TC are distinctive and differ from those typically seen in acute anterior MI. The ECG abnormalities described may be important clues for the clinician to suspect diagnosis of TC in the right clinical setting. PMID- 21671954 TI - A 2:1 AV rhythm: an adverse effect of a long AV delay during DDI pacing and its prevention by the ventricular intrinsic preference algorithm in DDD mode. AB - A 91-year-old woman received a dual-chamber pacemaker for sick sinus syndrome and intermittently abnormal atrioventricular (AV) conduction. The pacemaker was set in DDI mode with a 350-ms AV delay to preserve intrinsic ventricular activity. She complained of palpitation during AV sequential pacing. The electrocardiogram showed a 2:1 AV rhythm from 1:1 ventriculoatrial (VA) conduction during ventricular pacing in DDI mode with a long AV interval. After reprogramming of the pacemaker in DDD mode with a 250-ms AV interval and additional 100-ms prolongation of the AV interval by the ventricular intrinsic preference function, VA conduction disappeared and the patient's symptom were alleviated without increasing unnecessary right ventricular pacing. PMID- 21671955 TI - Failure of the active-fixation mechanism during removal of active-fixation pacing leads. AB - BACKGROUND: Active-fixation pacing leads are being widely employed due to their theoretical advantages when compared with traditional passive-fixation leads: easy fixation and reposition, possible deployment in alternative pacing sites, lower rates of dislodgment, and chronic removability. However, the behavior of the active-fixation mechanism during lead removal has not been yet systematically studied and may have important clinical implications. OBJECTIVE: To evaluate if the active-fixation mechanism was still working properly in pacing leads that were removed due to different causes. METHODS: Thirty-one consecutive patients undergoing active-fixation lead removal (40 leads) were studied. Before lead removal, the helix was retracted using the appropriate tool, and fluoroscopy signs were evaluated. After removal, the helix status was examined, and the active-fixation mechanism was once again retested when possible. RESULTS: In nine of 40 leads (22.5%), the helix remained extended after lead removal in spite of having applied the number of rotations recommended by the manufacturer with the clip-on tool. There was no linear relationship between lead longevity and the presence of an extended helix after lead removal. However, failure of the active fixation mechanism was more frequent among leads implanted <1 year before versus >1 year before (OR 6.8, 95% CI 1.1-42.7, P = 0.043). In 38% of patients with failure of the active-fixation mechanism, a previous lead reposition had been attempted before lead removal due to significant pacing threshold rise. CONCLUSIONS: In our series, the active-fixation mechanism failed in up to 22.5% of explanted leads. This may have important clinical implications during active fixation lead removal and reposition. PMID- 21671956 TI - Profound sinus node dysfunction in anti-N-methyl-d-aspartate receptor limbic encephalitis. AB - A form of limbic encephalitis associated with antibodies against the N-methyl-D aspartate receptor (NMDAR) was discovered in 2007. It is often a multistage illness that progresses from psychosis, memory deficits, seizures into a state of unresponsiveness with catatonic features, abnormal movements, autonomic, and respiratory instability. We present two cases of anti-NMDAR encephalitis to highlight the cardiac complications and their management. PMID- 21671957 TI - False tendon-related polymorphic ventricular tachycardia. AB - A 39-year-old woman showed nonsustained polymorphic ventricular tachycardia (PVT) during light physical activity. Cardiac multidetector row computed tomography demonstrated false tendons, one of which proved to be the focus triggering premature ventricular contraction (PVC) in electrophysiological studies. The triggered PVC arose during the diastolic period, which might have caused tension in the false tendon. Radiofrequency catheter ablation targeting the triggered PVC by pace mapping was performed and proved partially effective against PVT. PMID- 21671958 TI - Effect of cardiac resynchronization therapy on cardiac sympathetic nervous dysfunction and serum C-reactive protein level. AB - BACKGROUND: Cardiac autonomic dysfunction is associated with a poor prognosis in patients with heart failure (HF). Systemic inflammation is elevated in patients with HF. We hypothesized that cardiac resynchronization therapy (CRT) improves cardiac sympathetic nervous dysfunction and systemic inflammation. To test our hypothesis, we evaluated cardiac sympathetic activity and serum levels of high sensitive C-reactive protein (hs-CRP) before and after CRT. METHODS: Twenty seven patients with chronic HF (19 men, eight women; mean age 67 +/- 10 years) with nonischemic cardiomyopathy who underwent CRT were evaluated. Each patient was evaluated before and 6 months after CRT. Responders were defined as patients showing >=15% absolute decrease in left ventricular end-systolic volume. Cardiac sympathetic activity was estimated with cardiac (123) I-metaiodobenzylguanidine (MIBG) scintigrams. RESULTS: Patients were categorized as responders (n = 19) and nonresponders (n = 8) according to echocardiographic findings. In responders, the mean heart-to-mediastinum (H/M) ratio at the delayed phase in cardiac (123) I MIBG scintigraphic findings was significantly increased (P<0.05) and serum levels of hs-CRP were decreased (P <0.01). Such improvements were not observed in nonresponders. Stepwise multiple regression analysis showed that the reduction in hs-CRP level was independently associated with the increase in the H/M ratio at delayed phase. CONCLUSIONS: Our results demonstrated that cardiac sympathetic nervous dysfunction and systemic inflammation were improved in responder HF patients to CRT. Furthermore, the reduction in systemic inflammation was associated with the improvement in cardiac sympathetic nervous dysfunction. PMID- 21671959 TI - Computer-assisted numerical analysis for oxygen and carbon dioxide mass transfer in blood oxygenators. AB - A two-dimensional numeric simulator is developed to predict the nonlinear, convective-reactive, oxygen mass exchange in a cross-flow hollow fiber blood oxygenator. The numeric simulator also calculates the carbon dioxide mass exchange, as hemoglobin affinity to oxygen is affected by the local pH value, which depends mostly on the local carbon dioxide content in blood. Blood pH calculation inside the oxygenator is made by the simultaneous solution of an equation that takes into account the blood buffering capacity and the classical Henderson-Hasselbach equation. The modeling of the mass transfer conductance in the blood comprises a global factor, which is a function of the Reynolds number, and a local factor, which takes into account the amount of oxygen reacted to hemoglobin. The simulator is calibrated against experimental data for an in-line fiber bundle. The results are: (i) the calibration process allows the precise determination of the mass transfer conductance for both oxygen and carbon dioxide; (ii) very alkaline pH values occur in the blood path at the gas inlet side of the fiber bundle; (iii) the parametric analysis of the effect of the blood base excess (BE) shows that (.)V(CO2) is similar in the case of blood metabolic alkalosis, metabolic acidosis, or normal BE, for a similar blood inlet P(CO2), although the condition of metabolic alkalosis is the worst case, as the pH in the vicinity of the gas inlet is the most alkaline; (iv) the parametric analysis of the effect of the gas flow to blood flow ratio (QG/QB) shows that (.)V(CO2) variation with the gas flow is almost linear up to QG/QB = 2.0. (.)V(O2) is not affected by the gas flow as it was observed that by increasing the gas flow up to eight times, the (.)V(O2) grows only 1%. The mass exchange of carbon dioxide uses the full length of the hollow-fiber only if Q(G) /Q(B)> 2.0, as it was observed that only in this condition does the local variation of pH and blood P(CO2) comprise the whole fiber bundle. PMID- 21671960 TI - Pulsatile culture of a poly(DL-lactic-co-glycolic acid) sandwiched cell/hydrogel construct fabricated using a step-by-step mold/extraction method. AB - To overcome the weak mechanical properties of cell/hydrogel composites, a poly(DL lactic-co-glycolic acid) sandwiched adipose-derived stem cell (ADSC)/fibrin construct was fabricated using a step-by-step mold/extraction method to generate the middle smooth muscle layer of natural blood vessels. A pulse bioreactor with an adjustable 0-0.2 MPa pressure, 0-7% pulse amplitude, and 0-80 times/min pulse frequency was developed to mimic the liquid movement in the natural blood vessels. This new type of pulse bioreactor is sterilizable and dismantles easily. A comparative study was conducted with static and dynamic in vitro cultures. Exogenous growth factors, such as hepatocyte growth factor, platelet-derived growth factor BB, transforming growth factor beta1, and basic fibroblast growth factor were used as additives in the culture medium for inducing the ADSCs into smooth muscle cells. The dynamic training, integrated with the growth factor, induced the transformation of ADSCs into smooth muscle-like cells with regular arrangement. This strategy shows promise of being widely used in tissue engineering and complex organ manufacturing. PMID- 21671961 TI - A survey of the cellular responses in Pseudomonas putida KT2440 growing in sterilized soil by microarray analysis. AB - Genome-wide scanning of gene expression by microarray techniques was successfully performed on RNA extracted from sterilized soil inoculated with Pseudomonas putida KT2440/pSL1, which contains a chloroaromatic degrading plasmid, in the presence or absence of 3-chlorobenzoic acid (3CB). The genes showing significant changes in their expression in both the triplicate-microarray analysis using amplified RNA and the single-microarray analysis using unamplified RNA were investigated. Pathway analysis revealed that the benzoate degradation pathway underwent the most significant changes following treatment with 3CB. Analysis based on categorization of differentially expressed genes against 3CB revealed new findings about the cellular responses of the bacteria to 3CB. Genes specifically involved in the transport of 3CB were upregulated, including a K(+)/H(+) antiporter complex, a universal stress protein, two cytochrome P450 proteins and an efflux transporter. The downregulated expression of several genes involved in carbon metabolism and the genes belonging to a prophage in the presence of 3CB was observed. This study demonstrated the applicability of the method of soil RNA extraction for microarray analysis of gene expression in bacteria growing in sterilized soil. PMID- 21671962 TI - Microbiome analysis of dairy cows fed pasture or total mixed ration diets. AB - Understanding rumen microbial ecology is essential for the development of feed systems designed to improve livestock productivity, health and for methane mitigation strategies from cattle. Although rumen microbial communities have been studied previously, few studies have applied next-generation sequencing technologies to that ecosystem. The aim of this study was to characterize changes in microbial community structure arising from feeding dairy cows two widely used diets: pasture and total mixed ration (TMR). Bacterial, archaeal and protozoal communities were characterized by terminal restriction fragment length polymorphism of the amplified SSU rRNA gene and statistical analysis showed that bacterial and archaeal communities were significantly affected by diet, whereas no effect was observed for the protozoal community. Deep amplicon sequencing of the 16S rRNA gene revealed significant differences in the bacterial communities between the diets and between rumen solid and liquid content. At the family level, some important groups of rumen bacteria were clearly associated with specific diets, including the higher abundance of the Fibrobacteraceae in TMR solid samples and members of the propionate-producing Veillonelaceae in pasture samples. This study will be relevant to the study of rumen microbial ecology and livestock feed management. PMID- 21671964 TI - Impact of luteolin on the production of alpha-toxin by Staphylococcus aureus. AB - AIMS: To investigate the influence of subinhibitory concentrations of luteolin on the production of alpha-toxin in Staphylococcus aureus. METHODS AND RESULTS: The minimal inhibitory concentrations (MICs) were determined using a broth microdilution method, and the MICs of luteolin against the tested Staph. aureus strains ranged from 16 to 64 MUg ml(-1). Haemolysis, Western blot and real-time reverse transcription (RT)-PCR assays were used to evaluate the effect of luteolin on Staph. aureusalpha-toxin secretion and on the level of gene expression, respectively. The data indicated that subinhibitory concentrations of luteolin dose dependently decreased the production of alpha-toxin in both meticillin-sensitive Staph. aureus (MSSA) and meticillin-resistant Staph. aureus (MRSA). Furthermore, the transcriptional levels of agr (accessory gene regulator) in Staph. aureus were also inhibited by luteolin. CONCLUSIONS: Luteolin decreases the production and/or secretion of alpha-toxin in Staph. aureus; the reduced production may be dependent, in part, upon the luteolin-induced inhibition of the agr locus. SIGNIFICANCE AND IMPACT OF THE STUDY: The findings indicate that luteolin may be used as a basis for the development of antimicrobial agents aimed at bacterial virulence factors. PMID- 21671963 TI - Ecology of microfungal communities in gardens of fungus-growing ants (Hymenoptera: Formicidae): a year-long survey of three species of attine ants in Central Texas. AB - We profiled the microfungal communities in gardens of fungus-growing ants to evaluate possible species-specific ant-microfungal associations and to assess the potential dependencies of microfungal diversity on ant foraging behavior. In a 1 year survey, we isolated microfungi from nests of Cyphomyrmex wheeleri, Trachymyrmex septentrionalis and Atta texana in Central Texas. Microfungal prevalence was higher in gardens of C. wheeleri (57%) than in the gardens of T. septentrionalis (46%) and A. texana (35%). Culture-dependent methods coupled with a polyphasic approach of species identification revealed diverse and changing microfungal communities in all the sampling periods. Diversity analyses showed no obvious correlations between the number of observed microfungal species, ant species, or the ants' changing foraging behavior across the seasons. However, both correspondence analysis and 5.8S-rRNA gene unifrac analyses suggested structuring of microfungal communities by ant host. These host-specific differences may reflect in part the three different environments where ants were collected. Most interestingly, the specialized fungal parasite Escovopsis was not isolated from any attine garden in this study near the northernmost limit of the range of attine ants, contrasting with previous studies that indicated a significant incidence of this parasite in ant gardens from Central and South America. The observed differences of microfungal communities in attine gardens suggest that the ants are continuously in contact with a diverse microfungal species assemblage. PMID- 21671965 TI - Extended-spectrum beta-lactamase-producing Escherichia coli in turkey meat production farms in the Czech Republic: national survey reveals widespread isolates with bla(SHV-12) genes on IncFII plasmids. AB - AIM: The occurrence and epidemiology of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli in the environment of turkey farms in the Czech Republic were studied. METHODS AND RESULTS: Extended-spectrum beta-lactamase producing E. coli isolates were found on 8 (20%) of 40 turkey farms surveyed. A total of 200 environmental smears were examined, and a total of 25 ESBL-producing E. coli were isolated. These isolates were analysed using XbaI pulsed-field gel electrophoresis and divided into nine pulsotypes. Most of the isolates harboured the gene bla(SHV-12) on a 40-kb plasmid of the IncFII group with an identical EcoRV restriction profile. Indistinguishable or clonally related SHV-12-producing isolates belonging to the same pulsotypes were found at some unrelated farms. CONCLUSIONS: Widespread occurrence of ESBL-producing E. coli isolates with bla(SHV-12) carried on IncFII plasmids in meat production flocks in the Czech Republic was demonstrated. SIGNIFICANCE AND IMPACT OF THE STUDY: Results indicate vertical transmission of ESBL-producing E. coli within the turkey production pyramid. The study shows the risk of multiresistant ESBL-producing bacteria and antibiotic-resistance genes being transmitted to humans via the food chain. PMID- 21671966 TI - Mesalazine (5-aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea-predominant irritable bowel syndrome. AB - BACKGROUND: Imbalances in gut luminal bacteria may contribute to the pathogenesis of irritable bowel syndrome (IBS). AIM: To explore select bacteriological and anti-inflammatory effects of mesalazine (mesalamine; 5-aminosalicylic acid or 5ASA) and their relation to potential therapeutic effects in IBS. METHODS: Prospective pilot study of 12 women with diarrhoea-predominant IBS. Patients received oral mesalazine (1.5 g b.d.) for 4 weeks followed by a 4-week washout phase. Molecular profiling of stool bacterial communities and IBS symptoms were assessed before, during and after mesalazine treatment. Colonic mucosal biopsies were assessed for proteolytic activity. Qualitative and quantitative effects of mesalazine on stool microbiota, mucosal proteolytic activity and IBS symptoms were assessed. RESULTS: Faecal bacteria decreased by 46% on mesalazine treatment (P = 0.014), but returned to baseline during washout. Firmicutes and Bacteroidetes represented 95% of identified phylotypes, with a trend towards an increase in the proportion of Firmicutes at week 4 in symptomatic responders [median (IQR) 14% (49) increase] compared with nonresponders [median 5% (11) decrease, P = 0.088]. Rectosigmoid mucosal proteolytic activity did not change between baseline and treatment [median 23.2 (17.9) vs. 19.5 (46.7) mU activity/mg tissue, P = 0.433]. Eight of 12 (67%) patients responded favourably to mesalazine based on a global relief questionnaire, with significant decreases in days with discomfort and increases in bowel movement satisfaction. CONCLUSIONS: Mesalazine treatment is associated with a decrease in faecal bacteria abundance and rebalancing of the major constituents of the microbiota. Further study of the bacteriological and anti-inflammatory properties of mesalazine in IBS is warranted. PMID- 21671967 TI - Predictors of relapse in chronic hepatitis B after discontinuation of anti-viral therapy. AB - BACKGROUND: Optimal duration of anti-viral therapy in chronic hepatitis B virus (HBV) infection remains unclear. AIM: To investigate factors that could predict relapse after stopping anti-viral agents. METHODS: Chronic hepatitis B patients who were treated with anti-viral agents (lamivudine, adefovir, entecavir) and have stopped the treatment were recruited. Anti-viral agents were stopped according to the recommendations of the Asian Pacific Association for the Study of the Liver. Virological relapse was defined as an increase in serum HBV DNA to >1000 copies/mL after discontinuation of treatment. RESULTS: Eighty-four (69 treatment naive and 15 lamivudine resistant) patients were eligible for this study. Thirty-seven patients developed virological relapse at 4.3 +/- 2.9 (range 1-11) months after discontinuation of therapy. The 1-year cumulative probability of virological relapse was 42% and 47% in HBeAg (hepatitis B e antigen)-positive (n = 41) and HBeAg (hepatitis B e antigen)-negative (n = 43) patients, respectively. On multivariate analysis by Cox proportional hazard model, pre existing lamivudine resistance, delayed suppression of HBV DNA to undetectable level during anti-viral therapy and to a higher HBsAg (hepatitis B surface antigen) level at the end of treatment were associated with virological relapse. Twelve of the 15 (80%) lamivudine resistant patients developed virological relapse. Among the 11 treatment naive patients who had HBsAg <= 2 log IU/mL at the end of treatment, 1 (9%) of them had virological relapse. CONCLUSIONS: Treatment cessation among lamivudine resistant patients is associated with high risk of virological relapse. Serum HBsAg level at the end of treatment and rate of HBV DNA suppression can provide supplementary information to guide the timing of stopping anti-viral drugs. PMID- 21671968 TI - Oesophageal motility and bolus transit abnormalities increase in parallel with the severity of gastro-oesophageal reflux disease. AB - BACKGROUND: Limited data are available regarding the frequency of oesophageal motility and bolus transit abnormalities in subgroups of patients with gastro oesophageal reflux disease (GERD). AIM: To assess oesophageal motility and bolus transit in endoscopically defined GERD subgroups. METHODS: Patients (N=755) with typical reflux symptoms underwent upper endoscopy, conventional or impedance oesophageal manometry and/or impedance-pH testing. They were divided into: erosive oesophagitis (EO; N=340), Barrett Oesophagus (BO; N=106), non-erosive reflux disease (NERD; endoscopy-, abnormal pH and/or SAP/SI+; N=239) and functional heartburn (FH; endoscopy-, normal pH and SAP/SI-; N=70). Manometric patterns and bolus transit were defined according to previously published criteria. RESULTS: Increasing GERD severity was associated with decreased lower oesophageal sphincter resting pressure (P< 0.05) and distal oesophageal amplitude (P<0.01), higher prevalence of hiatal hernia (P<0.01) and increased prevalence of ineffective oesophageal motility (P<0.01). Patients with EO and BO had a significantly lower percentage of complete bolus transit compared with NERD and FH (P<0.01). Overall, abnormal bolus transit (ABT) for liquid swallows was found in 12% of FH, 20% of NERD, 54% of EO and 56% of BO (P<0.01). Combined impedance manometry showed abnormal oesophageal function in 4% of FH, 4% of NERD, 22% of EO and 21% of BO patients with normal oesophageal manometry. CONCLUSIONS: Oesophageal motility abnormalities increase in parallel with the severity of GERD from NERD to EO and BO. Bolus transit abnormalities in severe reflux disease underscore the importance of impaired oesophageal function in the development of mucosal injury. PMID- 21671969 TI - Cholinesterase activity during embryonic development in the blood-feeding bug Triatoma patagonica. AB - Triatoma patagonica Del Ponte (Hemiptera: Reduviidae), a vector of Chagas' disease, is widely distributed in Argentina and is found in sylvatic and peridomiciliary ecotopes, as well as occasionally in human dwellings after the chemical control of Triatoma infestans. Anti-cholinesteratic products can be applied in peridomiciliary areas and thus knowledge of cholinesterase activity during embryonic development in this species might contribute further information relevant to effective chemical control. Cholinesterase activity was characterized by reactions to eserine 10(-5) m, to increasing concentrations of substrate and to varying centrifugal speeds. Acetylcholinesterase activity was detected on day 4 and was significant from day 5. A reduction in cholinesterase activity towards acetylthiocholine (ATC) was observed on days 9 and 10 of development. Cholinesterase activity towards ATC and butyrylthiocholine (BTC) in homogenates of eggs was inhibited by eserine 10(-5) m. The shape of the curve indicating levels of inhibition at different concentrations of ATC was typical of acetylcholinesterase. Activity towards BTC did not appear to be inhibited by excess substrate, which parallels the behaviour of butyrylcholinesterases. Cholinesterase activity towards ATC was reduced in supernatant centrifuged at 15 000 g compared with supernatant centrifuged at 1100 g. The cholinesterase system that hydrolyzes mainly ATC seems to belong to the nervous system, as indicated by its behaviour towards the substrates assayed, its greater insolubility and the fact that it evolves parallel to the development of the nervous system. Knowledge of biochemical changes associated with the development and maturation of the nervous system during embryonic development would contribute to the better understanding of anti-cholinesteratic compounds with ovicidal action that might be used in control campaigns against vectors of Chagas' disease. PMID- 21671970 TI - Prediction of Crohn's disease relapse with faecal calprotectin in infliximab responders: a prospective study. AB - BACKGROUND: Faecal calprotectin is a reliable tool for predicting Crohn's disease (CD) relapse in patients with sustained remission. Prediction of relapse with faecal calprotectin has been less studied in patients with severe CD treated with anti-TNF. AIM: To identify an association between faecal calprotectin concentration and CD clinical relapse in patients achieving remission with infliximab (IFX). METHODS: From February 2007 to October 2008, consecutive patients with refractory luminal CD were prospectively included when they received three IFX infusions (5mg/kg at weeks 0, 2 and 6) followed by maintenance with an immunomodulator alone. Faecal calprotectin and C-reactive protein (CRP) were measured at entry and at week 14 (w14). RESULTS: Sixty-five patients (43W; median age: 30.4years) were included, and 50 (77%) were in clinical remission off steroids at w14; twenty-three of fifty (46%) experienced CD clinical relapse during the first year of follow-up. Median faecal calprotectin level at w14 was similar in patients with and without CD clinical relapse (200 and 150MUg/g respectively). When considering two suggested faecal calprotectin cut-offs to predict CD relapse, sensitivities and specificities were 61% and 48% for 130MUg/g, respectively, and 43% and 57% for 250MUg/g. Neither faecal calprotectin nor CRP at baseline and at w14 could predict relapse even when CD location subgroup analysis was considered. CONCLUSION: In patients responding to an infliximab induction regimen, faecal calprotectin measurement at w14 cannot predict Crohn's disease clinical relapse at 1year. PMID- 21671971 TI - Biosecurity policy and the use of geospatial predictive tools to address invasive plants: updating the risk analysis toolbox. AB - International and national biosecurity policies consider risk assessment a critical component of overall plant health risk analysis. The Agreement on the Application of Sanitary and Phytosanitary Measures, the International Plant Protection Convention, and the Convention on Biological Diversity all provide guidelines and recommendations on how to use risk assessment. This article discusses how these instruments address risk assessment, and makes recommendations on how the risk assessment process needs to incorporate current geospatial predictive science and geographic information systems into the plant health biosecurity risk analysis toolbox. PMID- 21671972 TI - iNKT cell frequency in peripheral blood of Caucasian children and adolescent: the absolute iNKT cell count is stable from birth to adulthood. AB - Human invariant natural killer T cells (iNKT cells) are a unique population of T cells that express a semi-invariantly rearranged T cell receptor (TCR) and are involved in a variety of immunoregulatory processes. We assessed the frequency of peripheral blood iNKT cells in 64 healthy Caucasian children from 7 months to 18 years of age and five cord blood samples by flow cytometry. iNKT cells were measured as CD3(+) cells co-expressing TCRValpha24 and TCRVbeta11 and using the monoclonal antibody 6B11, which recognizes specifically their invariant TCR rearrangement. The absolute number of iNKT cells ranged from 86 to 10,499 (CD3(+) /TCRValpha24(+) / TCRVbeta11(+)) and 233 to 11,167 (CD3(+) /6B11(+)) iNKT cells per millilitre of blood. This range is stable from birth to adulthood. The relative iNKT cell count was found to be 0.003-0.71% (CD3(+) /TCRValpha24/TCRVbeta11) and 0.019-0.776% (CD3/6B11) of peripheral blood T cells and shows only a slight increase with age. PMID- 21671973 TI - Salivary chromogranin A, but not alpha-amylase, correlates with cardiovascular parameters during high-intensity exercise. AB - INTRODUCTION: Several studies have shown that activation of the sympathetic nervous system results in the increased secretion of alpha-amylase (sAA), an enzyme produced by salivary glands. Recently, chromogranin A (CgA), a soluble protein costored and coreleased with catecholamines from the adrenal medulla and sympathetic nerve endings, has been proposed as a marker of sympathoadrenal medullary system (SAM) activity. The aim of this study was to investigate the behaviour of salivary chromogranin A (sCgA) and sAA during high-intensity exercise and to analyse their possible correlation with cardiovascular and psychological parameters. METHODS: Before and during a standardized treadmill stress test, and at 5, 15 and 30 min during the recovery phase, sCgA and sAA were monitored in 21 healthy men. The double product (DP) of blood pressure and heart rate responses, and the product of the subjective ratings of perceived exertion recorded at the final step (RPE) and the exercise duration were used as indices of cardiovascular and exercise intensity, respectively. RESULTS: With respect to baseline, significant (P < 0.001) increases in peak sCgA (median 64%) and sAA (median 86%) were observed at the end of exercise. During the recovery phase, sAA levels fell abruptly, whereas sCgA remained elevated (P < 0.001). Significant correlations emerged only for sCgA with respect to %DP (r = 0.84; P < 0.001) and last step-RPE (r = 0.82; P = 0.024). CONCLUSIONS: These data suggest sCgA as a reliable marker of SAM activation. Furthermore, the relationship between sCgA and exercise intensity highlights the potential use of this noninvasive parameter in monitoring the adrenergic response during intense physical stress. PMID- 21671974 TI - Resistin is associated with breach of tolerance and anti-nuclear antibodies in patients with hepatobiliary inflammation. AB - Resistin is a cysteine-rich protein, which is abundantly expressed at the site of inflammation, and acts as a regulator of the NF-kB-dependent cytokine cascade. The aim of this study was to evaluate resistin levels in relation to inflammatory mediators, disease phenotype and autoantibody status in a spectrum of pathological conditions of the gastrointestinal tract. Resistin levels were measured with an ELISA in sera originated from 227 patients and 40 healthy controls (HC). Fifty patients diagnosed with non-alcoholic fatty liver disease (NAFLD), 53 ulcerative colitis (UC), 51 Crohn's disease (CD), 46 autoimmune hepatitis (AIH) and 27 primary sclerosing cholangitis (PSC) were included. The sera were analysed with respect to biochemical parameters of systemic inflammation and liver function and to the presence of antibodies to nuclear antigens (ANA), mitochondria (AMA) and smooth muscle (SMA). Compared with HC, resistin levels were raised in AIH (P = 0.017) and PSC (P = 0.03); compared with NAFLD, levels were elevated in CD (P = 0.041), AIH (P < 0.001) and PSC (P < 0.001). Patients with elevated levels of resistin were more often treated with corticosteroids, but no difference was found between active disease and clinical remission. Resistin levels were significantly higher in ANA-positive individuals compared with ANA-negative (P = 0.025). Resistin levels were directly correlated with IL-6 (r = 0.30, P = 0.02) and IL-8 (r = 0.51, P < 0.001). Elevated levels of resistin were prominent in patients with hepatobiliary inflammation and were associated with breach of self-tolerance, i.e. ANA positivity. Thus, we propose that resistin may be an important marker of disease severity in autoantibody mediated gastrointestinal inflammatory diseases. PMID- 21671975 TI - Somatic mosaicism caused by monoallelic reversion of a mutation in T cells of a patient with ADA-SCID and the effects of enzyme replacement therapy on the revertant phenotype. AB - Patients with adenosine deaminase (ADA) deficiency exhibit spontaneous and partial clinical remission associated with somatic reversion of inherited mutations. We report a child with severe combined immunodeficiency (T-B- SCID) due to ADA deficiency diagnosed at the age of 1 month, whose lymphocyte counts including CD4+ and CD8+ T and NK cells began to improve after several months with normalization of ADA activity in Peripheral blood lymphocytes (PBL), as a result of somatic mosaicism caused by monoallelic reversion of the causative mutation in the ADA gene. He was not eligible for haematopoietic stem cell transplantation (HSCT) or gene therapy (GT); therefore he was placed on enzyme replacement therapy (ERT) with bovine PEG-ADA. The follow-up of metabolic and immunologic responses to ERT included gradual improvement in ADA activity in erythrocytes and transient expansion of most lymphocyte subsets, followed by gradual stabilization of CD4+ and CD8+ T (with naive phenotype) and NK cells, and sustained expansion of TCRgammadelta+ T cells. This was accompanied by the disappearance of the revertant T cells as shown by DNA sequencing from PBL. Although the patient's clinical condition improved marginally, he later developed a germinal cell tumour and eventually died at the age of 67 months from sepsis. This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion. PMID- 21671976 TI - Nonmosaic 47,XYY syndrome presenting with male infertility: case series. AB - In this study, we describe nine patients with 47,XYY presenting with male infertility. All patients were subjected to history taking, clinical examination, duplex ultrasonographic examination of the scrotum, endocrinological investigations and cytogenetic analysis of peripheral lymphocytes. Two patients tried intracytoplasmic sperm injection (ICSI). Our results showed that seven patients were oligospermic and two patients were azoospermic. Bilateral varicocele was detected in seven patients. The hormonal levels in the majority of the patients were within normal range. Two patients showed improvement after varicocelectomy. The wife of one of the oligospermic patients became successfully pregnant after the first trial of ICSI. In conclusion, this report suggests that patients with XYY may present with primary infertility and may show oligospermia and nonobstructive azoospermia. Careful clinical, ultrasonographic, endocrinological and cytogenetic examinations should be a part of their diagnostic work-up for the proper management of these patients. In addition, ICSI may be a hope for some of these patients. PMID- 21671977 TI - Potential role of p38-mitogene-activated protein kinase and nuclear factor-kappa B expression in testicular dysfunction associated with varicocele: an experimental study. AB - The aim of this study was to investigate p38-mitogene-activated protein kinase (p38-MAPK), nuclear factor-kappa B (p65-NF-kB) and inducible nitric oxide synthase (iNOS) expression in an experimental model of varicocele in the rat testis. Male Wistar albino rats (n = 18) were divided into three equal groups: control group, sham operated group and left varicocele-induced group. Malondialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) levels were biochemically assessed, and the p38-MAPK and NF-kB activity, and iNOS expression were immunohistochemically studied in the right and left testicles of rats from each group. The GSH levels were significantly decreased, whereas the level of MDA and NO was significantly increased in the testicular tissues of rats in varicocele group compared with those of the control and sham groups. There was a marked staining for iNOS, p38-MAPK and p65-NF-kB expression in rats of varicocele group compared with the sham group. There was no positive staining in rats of control group. There were significant differences in biochemical, histological and immunohistochemical studies, but no significant differences were noted between other groups. p38-MAPK and p65-NF-kB activation, and iNOS expression have a significant role in varicocele-induced testicular dysfunction. PMID- 21671978 TI - Standardised water-soluble extract of Eurycoma longifolia, Tongkat ali, as testosterone booster for managing men with late-onset hypogonadism? AB - In most countries, millions of people are relying on herbal medicines as remedy for numerous ailments. In South-East Asia, Eurycoma longifolia Jack, also known as 'Malaysian ginseng' or Tongkat ali, is used to combat stress and disease and to improve physical strength. Moreover, the compounds of the roots of this plant are reported to have aphrodisiac and testosterone enhancing effects in the rat. Considering that human studies are not available, 76 of 320 patients suffering from late-onset hypogonadism (LOH) were given 200 mg of a standardised water soluble extract of Tongkat ali for 1 month. The Ageing Males' Symptoms (AMS) according to the standardised rating scale and the serum testosterone concentration were taken. Results show that treatment of LOH patients with this Tongkat ali extract significantly (P < 0.0001) improved the AMS score as well as the serum testosterone concentration. While before treatment only 10.5% of the patients did not show any complaint according to the AMS scale and 35.5% had normal testosterone levels, after the completed treatment 71.7% and 90.8% of the patients showed normal values, respectively. Thus, Tongkat ali extract appears to be useful as a supplement in overcoming the symptoms of LOH and for the management of hypogonadism. PMID- 21671979 TI - Studies on the viability and membrane integrity of human spermatozoa treated with essential oil of Trachyspermum ammi (L.) Sprague ex Turrill fruit. AB - The present study aimed at investigating the effects of essential oil of Trachyspermum ammi fruits, an oil-bearing plant of Apiaceae family, on human sperm viability and membrane integrity. Chemical compositions of the oil were analysed by GC-MS. Thirty compounds representing 91.39% of the total oil were identified. The viability and membrane integrity of human spermatozoa were assessed using minimum effective dose (MED) concentration (125 MUg ml(-1)) of the oil. Sperm treated with essential oil showed a significant decrease (P < 0.05) in viability assessed by eosin-nigrosin and fluorescence dual staining. Moreover, the treated sperm also showed a significant loss (P < 0.05) of functional mitochondria and antioxidant enzyme, catalase (EC 1.11.1.6, CAT), when compared to control. The cholesterol:phospholipid ratio was also increased (P < 0.05) in treated sperm when compared to control, which is an indicator of loss of binding ability of human spermatozoa to the zona pellucida. The scanning electron microscopic studies demonstrated the loss of membrane integrity in essential oil treated human spermatozoa, which showed vacuolation, swelling of acrosomal cap, detachment of head portion and tail coiling. Present observations indicate the spermicidal property of essential oil of T. ammi fruits, which could be helpful to develop medicinal preparations as a male contraceptive. PMID- 21671980 TI - Nurses' experiences of caring for children in pain. AB - AIM: To describe nurses' experiences when caring for children in pain. BACKGROUND: Earlier studies have shown that nurses are key actors in pain management and that there is a need to focus on the nurses' own experiences of caring for children in pain. METHOD: Semi-structured interviews were conducted with 21 nurses at one paediatric clinic. The data were analysed by means of content analysis. RESULTS: The interviews suggested that when a child's pain followed an expected pattern and they complied with treatment, the nurses trusted their knowledge and felt comfortable. On the other hand, in unpredictable situations the nurses felt fearful, powerless, abandoned and distrustful. CONCLUSION: The nurses were comfortable in predictable situations, but if a situation was unpredictable, they felt they had lost control over it. IMPLICATIONS FOR PAIN MANAGEMENT: To reduce feelings of abandonment, work shifts should be organized so that more experienced nurses can work side by side with those who are less experienced. Pain assessment tools and guidelines for pain management should be introduced into the daily work, and systematic reflection should be used for nurses' professional development. PMID- 21671981 TI - Improving quality of life of children with cerebral palsy: a systematic review of clinical trials. AB - OBJECTIVE: To systematically review the impact of different interventions on quality of life (QoL) for children with cerebral palsy. METHODS: English articles were sought from five major English databases from inceptions until March 2010. Keywords used consisted of four components (and their variants): (i) clinical condition: cerebral palsy; (ii) outcome measures: quality of life, well-being; (iii) study design: clinical trials; and (iv) target population: people aged 0 18. RESULTS: Eight studies satisfied the inclusion criteria, all of which are of good to excellent quality (a Jadad score of 4 or above). The Pediatric Evaluation of Disability Inventory, the Pediatric Quality of Life Inventory, the TNO-AZL Children's Health-Related Quality of Life and the Caregiver Priorities and Child Health Index of Life with Disabilities were used to measure QoL. Significant positive results were reported by two studies using medicinal interventions (diazepam and intrathecal baclofen therapy, effect sizes 5.9, 9.1 respectively) and two studies employing motor control approach training (strength training and exercise training, former effect size being 3.8). CONCLUSION: Current review suggests that positive effect was shown in medicinal and motor control interventions on QoL. However, no single interventional approach can demonstrate a consistent positive impact on QoL across different studies. Future studies are recommended to (i) provide a clear definition of QoL, and investigate the relationship between symptoms' severity and QoL; (ii) measure outcome at different time points to capture real effects of interventions; and (iii) make more use of valid outcome instruments, either self-report or parent/caregiver proxy reports. PMID- 21671982 TI - Quality of life in paediatric eosinophilic oesophagitis: what is important to patients? AB - BACKGROUND AND AIMS: Current research outcomes in paediatric eosinophilic oesophagitis (EoE) are directed towards histological improvement with no attention to health-related quality of life (HRQOL). The primary objective of this study was to identify key patient-reported and parent proxy outcome elements of EoE disease-specific HRQOL. METHODS: The research team comprised clinical allergists and gastroenterologists with expertise in paediatric EoE as well as two PhD psychologists with extensive experience in qualitative research. Focused interview techniques were adapted from the Pediatric Quality of Life Inventory 4.0TM methodology and the consolidated criteria for reporting qualitative research. A semi-structured interview guide of open-ended questions was developed, and extensive review of audio-taped transcripts was performed. RESULTS: A total of 42 focus interviews were conducted. Child self-reports were obtained for patients in the 5-7, 8-12 and 13-18 years of age groups, and parent proxy reports were obtained in the 2-4, 5-7, 8-12 and 13-18 years of age groups. We discovered that patients and parents often had different concerns, illustrating unique aspects of EoE-specific HRQOL that were not captured in generic HRQOL instruments. Specific themes that emerged from these interviews included, but are not limited to: feelings of being different than family and peers, diet and medication adherence, difficulties with eating food and worry about symptoms and illness. CONCLUSION: Paediatric EoE patient and parent proxy interviews revealed many EoE-specific aspects of HRQOL that are not captured in generic HRQOL instruments. Outcome measures that reflect patient- and parent proxy-reported HRQOL are a critical need in paediatric EoE. PMID- 21671983 TI - Parent proxy-reported quality of life for children with cerebral palsy: is it related to parental psychosocial distress? AB - BACKGROUND: Parent-proxy reports of quality of life (QOL) are often used to guide decisions about children with cerebral palsy (CP), although little is known about the factors that influence parent-proxy reports. The aim of this study was to examine (i) the relationship between parental psychosocial distress and parent proxy-reported QOL; and (ii) whether parental psychosocial distress mediates the relationship between child impairment and proxy-reported QOL. METHODS: A sample of 201 primary caregivers of children aged 4-12 years with CP completed the Cerebral Palsy Quality of Life Questionnaire for Children, a condition-specific QOL instrument, and a measure of psychosocial distress, the Kessler 10. The children, evenly distributed by gender (56% male) were sampled across Gross Motor Function Classification System levels (Level I = 18%, II = 28%, III = 14%, IV = 11%, V = 27%). RESULTS: Consistent with the hypotheses, parental distress was negatively correlated with all domains of parent proxy-reported QOL (r = -0.18 to r = -0.55). The relationship between impairment and proxy-reported QOL was mediated by parental distress for five of the seven domains of QOL (social well being and acceptance, feelings about functioning, participation and physical health, emotional well-being and self-esteem, and pain and impact of disability). Child impairment did not predict access to services or family health. CONCLUSION: This is the first study that assesses the relationship between parental distress and proxy-reported QOL for children with CP. Although the cross-sectional nature of the available data precludes any statements of causality, the results suggest that, when using parent proxy, the parents' psychological state should also be measured. This is particularly important when, as is often the case for child disability research, proxy-reported QOL are the only available data. PMID- 21671984 TI - Effect of weight loss on gelatinase levels in obese mice. AB - 1. Gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) might play a role in the development and structural organization of adipose tissue. Obese mice were subjected to caloric restriction (from 82 to 27 kJ/day) for 6 weeks, in order to investigate the effect of drastic weight loss on gelatinase mRNA, protein and activity levels. 2. Caloric restriction resulted in significantly lower bodyweight, as well as subcutaneous (SC) and gonadal (GON) fat mass (all P < 0.001). 3. The expression of MMP-2 mRNA was significantly upregulated in both SC (3.3-fold) and GON (2.2-fold) adipose tissues; however, without significant effect on total MMP-2 protein levels in fat tissues or in plasma. In contrast, MMP-9 mRNA expression in SC or GON fat was not affected by caloric restriction, whereas protein levels were reduced in SC and GON fat, but not in plasma. Zymography showed significantly elevated levels of active MMP-2 in both SC and GON adipose tissues, whereas active MMP-9 levels were reduced in GON fat. 4. These findings imply that the evaluation of the role of gelatinases in obesity and metabolic disorders requires the determination of both antigen and activity levels in plasma and fat tissues. PMID- 21671985 TI - Heart failure enhances arrhythmogenesis in pulmonary veins. AB - 1. Heart failure (HF) predisposes to atrial fibrillation (AF) as a result of substrate remodelling. The present study aimed to investigate the impact of HF on the electrical remodelling of the pulmonary veins (PV) and left atrium (LA). 2. The electrical activity was recorded in LA and PV from control rabbits and rabbits with rapid ventricular pacing-induced HF, using a multi-electrode array system and conventional microelectrodes. 3. Compared with the control-PV (n = 21), the HF-PV (n = 13) had a higher incidence and frequency of rapid pacing induced spontaneous activity (85 vs 29%, P = 0.005; 3.5 +/- 0.2 vs 1.7 +/- 0.1 Hz, P < 0.001) and high-frequency irregular electrical activity (92 vs 38%, P = 0.01; 23 +/- 1 vs 19 +/- 1 Hz, P = 0.003), greater depolarized resting membrane potential (-59 +/- 1 vs -70 +/- 2 mV, P < 0.001), higher incidence of early afterdepolarizations (EAD; 69 vs 6%, P = 0.001) and delayed afterdepolarizations (DAD; 92 vs 25%, P = 0.001), and slower conduction velocity (38 +/- 2 vs 63 +/- 2 cm/s, P < 0.05). In comparison to the HF-LA, the HF-PV had a higher incidence of spontaneous activity and high-frequency irregular electrical activity (85 vs 39%, P = 0.04; 92 vs 46%, P = 0.03), and higher incidence of EAD and DAD, and those differences were not found between the control-LA and control-PV. The control-PV with high-frequency irregular electrical activity had a higher incidence of DAD and spontaneous activity as compared with those without it. 4. HF contributed to an increased automaticity, triggered activity and conduction disturbance in the PV. The PV possessed more arrhythmogenic properties, which might play an important role in the genesis of AF in HF. PMID- 21671986 TI - Phenotype and differentiation of bone marrow-derived smooth muscle progenitor cells. AB - 1. Smooth muscle progenitor cells (SPC) are undifferentiated vascular smooth muscle cells implicated in many hyperplastic diseases of the blood vessels. However, few in vitro studies have investigated the characteristics of SPC. 2. In the present study, we constructed a recombinant plasmid with the enhanced green fluorescent protein (GFP) gene and a rat SM22alpha promoter, which was exclusively promoted in a smooth muscle cell lineage. Constructs were then transferred into adherent mononuclear cells derived from rat bone marrow. After 3 days, GFP-positive cells, which should be SPC, were isolated by flow cytometry. 3. Flow cytometric analysis and dual immunofluorescent staining showed that the GFP-positive cells expressed both alpha-smooth muscle actin (a specific marker for smooth muscle) and the chemokine receptor CXCR4 (abundant on precursor cells), but not calmodulin or CD31. After stimulation of SPC with 50 ng/mL platelet-derived growth factor-BB, CXCR4 levels decreased and calmodulin protein content increased, as determined by western blot analysis. 4. On the basis of these results, we conclude that SPC have dual characteristics of both precursor and smooth muscle cells, and might well differentiate into smooth muscle-like cells under certain conditions. PMID- 21671987 TI - Adult age and ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects. AB - AIM: To see if adult age correlates with ex vivo protein binding of lorazepam, oxazepam and temazepam in healthy subjects. METHODS: Sixty healthy drug free subjects were recruited in the age groups 18-39, 40-64 and >=65 years. Plasma albumin concentrations were determined. Ex vivo unbound fractions (f(u)) were assessed by spiking samples and measuring the free and total concentrations. RESULTS: No correlation of age with f(u) was seen. The study was powered to demonstrate a change in f(u) of >=7-10%. A decline in plasma albumin concentration of ~0.03 g l(-1) year(-1) was seen with increasing age (P= 0.032) and was associated with increased f(u) of lorazepam (P= 0.009) and oxazepam (P= 0.014). CONCLUSIONS: There was no association of adult age with ex vivo f(u) of lorazepam, oxazepam or temazepam in healthy subjects. PMID- 21671988 TI - What's new in skin cancer? An analysis of guidelines and systematic reviews published in 2008-2009. AB - This review summarizes clinically important findings from 17 systematic reviews and 2 guidelines on skin cancer indexed between April 2008 and April 2009. Melanoma primary-prevention measures, such as education, are more likely to be successful in younger children than adolescents, and general population screening for melanoma by whole-body examination is not currently supported by the evidence. A large systematic review of melanoma and pregnancy concluded that pregnancy does not affect prognosis. Two systematic reviews imply that sunburn later in life also increases the risk of melanoma, and that it is just as important as sunburn early in life. Three systematic reviews discussed the role of positron emission tomography and sentinel lymph-node biopsy for melanoma staging, but produced conflicting results. Superior diagnostic accuracy of dermatoscopy over naked-eye examination for melanoma was found in one review, while a second implied nonsignificantly higher sensitivity of computer-based diagnostic methods over dermatoscopy for melanoma but with reduced specificity. There were no identified randomized controlled trials of treatments for unresectable recurrent melanoma, and a review of immunotherapy with vaccines for melanoma failed to prove improved overall and disease-free survival. Guidelines for the management of basal cell carcinoma call for risk stratification, based on numerous factors including tumour size, site and histological subtype. Squamous cell carcinoma of the ear has been shown to spread to regional lymph nodes more commonly than to other sites, and may be predicted by depth of invasion, tumour size, cellular differentiation and completeness of excision. PMID- 21671990 TI - Postinflammatory hypopigmentation. AB - Postinflammatory hypopigmentation is a common cause of acquired hypopigmentary disorders. It can be a result of cutaneous inflammation, injury or dermatological treatment. There are also many specific conditions that present with hypopigmentation other than postinflammatory hypopigmentation. Most cases of postinflammatory hypopigmentation improve spontaneously within weeks or months if the primary cause is ceased; however, it can be permanent if there is complete destruction of melanocytes. This article reviews the aetiology, pathogenesis, clinical features, differential diagnosis and therapeutic options for postinflammatory hypopigmentation. PMID- 21671989 TI - Dosing equation for tacrolimus using genetic variants and clinical factors. AB - AIM: To develop a dosing equation for tacrolimus, using genetic and clinical factors from a large cohort of kidney transplant recipients. Clinical factors and six genetic variants were screened for importance towards tacrolimus clearance (CL/F). METHODS: Clinical data, tacrolimus troughs and corresponding doses were collected from 681 kidney transplant recipients in a multicentre observational study in the USA and Canada for the first 6 months post transplant. The patients were genotyped for 2,724 single nucleotide polymorphisms using a customized Affymetrix SNP chip. Clinical factors and the most important SNPs (rs776746, rs12114000, rs3734354, rs4926, rs3135506 and rs2608555) were analysed for their influence on tacrolimus CL/F. RESULTS: The CYP3A5*1 genotype, days post transplant, age, transplant at a steroid sparing centre and calcium channel blocker (CCB) use significantly influenced tacrolimus CL/F. The final model describing CL/F (l h(-1)) was: 38.4 *[(0.86, if days 6-10) or (0.71, if days 11 180)]*[(1.69, if CYP3A5*1/*3 genotype) or (2.00, if CYP3A5*1/*1 genotype)]* (0.70, if receiving a transplant at a steroid sparing centre) * ([age in years/50](-0.4)) * (0.94, if CCB is present). The dose to achieve the desired trough is then prospectively determined using the individuals CL/F estimate. CONCLUSIONS: The CYP3A5*1 genotype and four clinical factors were important for tacrolimus CL/F. An individualized dose is easily determined from the predicted CL/F. This study is important towards individualization of dosing in the clinical setting and may increase the number of patients achieving the target concentration. This equation requires validation in an independent cohort of kidney transplant recipients. PMID- 21671991 TI - The challenges of meeting nutritional requirements in children and adults with epidermolysis bullosa: proceedings of a multidisciplinary team study day. AB - This is a report of a study day held in London on 3 March 2010 to discuss measures with which to meet the nutritional requirements of patients with epidermolysis bullosa (EB). Members of national and international multidisciplinary teams (MDTs) caring for patients with EB attended this event. The study day focused on four challenging aspects of management intimately associated with nutritional status in EB, necessitating close cooperation between MDT members: iron-deficiency anaemia, gastrostomy placement and feeding, muscle mass and mobility, and dental health. The study day provided a unique forum for dietitians, doctors, nurses, physiotherapists, psychologists, psychotherapists, dentists, dental hygienists and occupational therapists to share knowledge and debate problems common to all who strive to promote best practice in this rare and complex group of conditions. PMID- 21671992 TI - Microscopy of the echidna sublingual glands. AB - The secretory units and duct system of the echidna sublingual glands exhibit subtle architectural modifications to accommodate the viscous secretion produced by these glands. The glands are compound tubular glands, the secretory units of which are elongate with open lumina and consist only of mucous cells. Closely packed spindle-shaped myoepithelial cells invest the secretory units, but are absent around the ducts. The branched secretory tubules open into an abbreviated duct system characterized by wide lumina. Striated ducts normally associated with the second portion of the intralobular duct system are absent. The duct system shows the most obvious modification of general salivary gland architecture presumably to accommodate the viscous secretion propelled from the secretory units by surrounding myoepithelial cells. PMID- 21671993 TI - Approach to reticulate hyperpigmentation. AB - Reticulate hyperpigmentation is a feature of a number of conditions, which differ in age of onset and distribution of the lesions. Associated clinical findings (e.g. hair, nail, teeth, systemic involvement), are used to differentiate between the conditions. Histopathological examination is useful in some disorders. Diagnosing the disorders is important, because the underlying causes may be treatable, and some of the disorders are associated with malignancies and life threatening systemic involvement. In this review, I present a concise, systematic approach to the treatment of the patient with reticulate hyperpigmentation. PMID- 21671994 TI - Structural and functional components of the feline enteric nervous system. AB - Neurohistological and immunohistochemical examinations of the feline enteric nervous system (ENS) were performed by using antibodies against neuron-specific enolase (NSE), phosphorylated neurofilaments (PN), non-phosphorylated neurofilaments (NPN) and vasoactive intestinal peptide (VIP), whereas glial cells were investigated by using antibodies against glial fibrillary acidic protein (GFAP). The study included full-thickness biopsies of the stomach, duodenum, jejunum, ileum and colon of 11 healthy cats. In this study, immunohistochemical staining of feline ENS with antibodies to NSE, PN and NPN revealed the presence of different ganglionated and aganglionated plexus. The two ganglionated plexus were arranged in a plexus submucosus internus & externus and a plexus myentericus. Furthermore, plexus mucosus and subserosal plexus represented two aganglionated plexus. GFAP-stained cellular elements were smaller than and in close contact to enteric neurons possibly resembling astrocytes of the central nervous system. VIP is one of the major neurotransmitters of enteric inhibitory neurons, and immunoreactivity was present in all layers of the gut, especially in ganglionated plexus. This is the first report, describing feline ENS by using immunohistochemical methods. PMID- 21671995 TI - Ultrastructure of the platypus and echidna mandibular glands. AB - The secretory units of the platypus and echidna mandibular glands consist of a single serous cell type. Secretory granules within the cells of the platypus mandibular gland stained intensely with the periodic acid-Schiff staining procedure but failed to stain with Alcian Blue, suggesting the granules contained neutral glycoproteins. Secretory granules within the mandibular glands of the echidna failed to stain with the methods used indicating little if any glycoprotein was associated with the secretory granules. Ultrastructurally, secretory granules of the platypus mandibular gland were electron dense with a central core of less electron-dense material and were membrane bound. In contrast, those of the echidna presented a lamellated appearance and also were limited by a membrane. These secretory granules appeared to form as a result of concentric layering of lamellae within cisternae of the Golgi membranes. The intralobular ductal system of the platypus was more extensively developed than that of the echidna. The striated ducts of both species were characterized by elaborate infoldings of the basolateral plasmalemma and an abundance of associated mitochondria. PMID- 21671996 TI - Developmental changes in cell proliferation and apoptosis in the normal duck thymus. AB - Cell proliferation and apoptosis in the normal duck thymus during embryonic and post-embryonic development were studied. The flow cytometry assay shows that the level of G(0)/G(1) thymic cell population and the proportion of apoptotic cells increased with age, while the levels of S phase, G(2) + M phase and the proliferating index decreased with age. Proliferation cell nuclear antigen (PCNA) was mainly detected in the nuclei of lymphocytes. The number of PCNA-positive cells in the cortex and medulla significantly decreased with age. Transferase mediated dUTP nick-end labelling (TUNEL) reaction stained apoptotic bodies in the cytoplasm of macrophages and free apoptotic bodies or nuclei with condensed chromatin in lymphocytes. The number of TUNEL-positive cells in the cortex and medulla markedly increased with age. The amount of proliferation and apoptotic cells in the thymic cortex was higher than that in the medulla. The balance between proliferation and apoptosis in the duck thymus may account for the process of thymic development and involution. PMID- 21671997 TI - The purL gene of Bacillus subtilis is associated with nematicidal activity. AB - Parasitic nematodes of plants are important plant pathogens that represent a significant financial burden on agriculture. This study evaluated the efficacy of Bacillus spp. as nematode biocontrol agents and identified Bacillus genes associated with nematicidal activity. Culture by products of Bacillus subtilis strains OKB105 and 69 and Bacillus amyloliquefaciens strains FZB42 and B3 were used to treat Aphelenchoides besseyi, Ditylenchus destructor, Bursaphelenchus xylophilus and Meloidogyne javanica, respectively. The highest mortality rates were observed at 12 h when combinations of either A. besseyi/B3, D. destructor/OKB105, B. xylophilus/69 or M. javanica/OKB105 resulted in 10.6%, 27.6%, 35.6% and 100% mortality rates, respectively. Supernatant analysis demonstrated that the nematicidal active ingredients of strain OKB105, with a molecular weight of <1000 Da, were nonproteinaceous, heat and cold resistant, highly polar and could be evaporated but not extracted by some organic solvents. To identify nematicidal-related genes, 2000 OKB105 mutants were generated using the TnYLB-1 transposon. Mutant M1 lost nematicidal activity by 72 h and inverse PCR results demonstrated disruption of the purL gene. Nematicidal activity was restored when M1 mutant was complemented with either plasmid pMA5-purL or pUC18 purL, demonstrating a role for purL in mediating nematicidal activity. PMID- 21671999 TI - A call for action in diabetes care for older people. PMID- 21672000 TI - Thiazolidinediones and fracture risk in patients with Type 2 diabetes. AB - Thiazolidinediones are widely used effective drugs for the management of hyperglycaemia in Type 2 diabetes and may provide additional metabolic benefits. Any advantages of these agents need to be considered in the context of any potential risk from adverse events. Recent evidence from several sources, including large-scale randomized controlled trials and observational studies, suggests that long-term use of thiazolidinediones is associated with bone loss and an increased risk of fractures in women with Type 2 diabetes. As patients with Type 2 diabetes are already at high risk for fractures, the clinical relevance of this reported association with thiazolidinedione therapy deserves careful consideration. Generally, the fracture risk with thiazolidinediones appears similar in magnitude to that associated with several other widely used drug classes, although there are unanswered questions regarding susceptibility factors, differential effects on bone sites and potential management approaches. This article provides a comprehensive overview of the evidence for an increase in fracture risk with thiazolidinediones and places it in the context of recent analyses of fracture risk with other commonly used drug classes. The potential clinical implications of any association are also discussed. PMID- 21672001 TI - Good clinical practice guidelines for care home residents with diabetes: an executive summary. AB - A Task and Finish Group of Diabetes UK was convened over 14 months to undertake a systematic review of the original 1999 British Diabetic Association guidance on care home diabetes, incorporate new research findings and produce a set of recommendations that are evidenced-based, practical and implementable within UK care home settings. The anticipation of Diabetes UK is that these guidelines will represent a national policy of good clinical practice for diabetes care within care homes. This executive summary demonstrates how the full guidelines should provide a framework of assessment of the quality of diabetes care within care homes, for use by regulatory bodies who have responsibility for this provision of diabetes care. This document is primarily based on recommendations for adults living within British care home environments and its focus, by virtue of the nature and characteristics of residents, is on older adults. Improvements in diabetes care within residential and nursing homes are likely to follow a sustained commitment by health and social care professionals to ensure that the well-being of residents with diabetes is paramount, that high-quality policies of diabetes care are implemented and monitored and effective diabetes education is a mandatory and integral part of care home staff training. PMID- 21672002 TI - People living with diabetes resident in nursing homes--assessing levels of disability and nursing needs. AB - AIMS: To describe the degree of disability and nursing need of people living with diabetes resident in nursing homes in one Primary Care Trust in the UK. METHODS: A retrospective case notes review of 75 people with known diabetes who were resident in the 11 nursing homes in Coventry Teaching Primary Care Trust. RESULTS: Very significant levels of disability and nursing need were documented in areas of continence, feeding, mobility and communication. Each individual had a mean of four co-morbidities (range 1-8), excluding diabetes. Using the definition of terminal illness based on a negative answer to the question 'would I be surprised if my patient were to die in the next 12 months' it is likely that the majority of individuals described in this study would be classified as being terminally ill. CONCLUSION: Using four practical clinical measures, this study has shown very significant levels of disability and nursing care need in this population of mainly elderly people resident in nursing homes in Coventry. In addition, it has demonstrated that a large proportion of nursing home residents with diabetes can be considered to be in the terminal phase of life, a period where many other factors interplay in how care should be delivered and what outcomes are appropriate. In fact, residents in this category may well be candidates for a considered withdrawal of treatments, but not of care. PMID- 21672003 TI - The association between anxiety and measures of glycaemia in a population-based diabetes screening programme. AB - AIM: To investigate associations between anxiety and measures of glycaemia in a White European and South Asian population attending community-based diabetes screening. METHODS: In total, 4688 White European and 1353 South Asian participants (aged 40-75 years) without a previous diagnosis of Type 2 diabetes underwent an oral glucose tolerance test and HbA(1c) measurement, detailed history, anthropometric measurements and completed the short-form Spielberger State Trait Anxiety Inventory. RESULTS: Anxiety was significantly higher in South Asian participants (mean 34.1; sd 0.37) compared with White European participants (mean 29.8; sd 0.13). Significant correlations were not identified between anxiety and fasting (r = -0.01, P = 0.75), 2-h glucose (r = -0.10, P = 0.24) or HbA(1c) (r = 0.01, P = 0.40). CONCLUSIONS: Anxiety levels at screening were greater among South Asian people. Fasting, 2-h plasma glucose and HbA(1c) are not affected by anxiety during screening tests for diabetes. Current and proposed screening methods for diagnosis of diabetes are not affected by anxiety at screening. PMID- 21672004 TI - The humoral immune response to the inactivated influenza A (H1N1) 2009 monovalent vaccine in patients with Type 2 diabetes mellitus in Korea. AB - AIMS: We evaluated the antibody response to a single-dose adjuvanted, inactivated, pandemic H1N1 influenza vaccination in patients with diabetes and assessed factors associated with the failure to induce antibody responses. METHODS: Eighty-two patients with Type 2 diabetes were vaccinated and antibody responses were determined with haemagglutination inhibition assay and anti haemagglutinin antibody ELISA. RESULTS: Among 70 antibody-negative patients at baseline, 34 (48.6%) achieved seroconversion; 28 (60.9%) in the young adults group and six (25%) in the elderly group acquired H1N1-specific antibodies. Patients in the older age range or with longer duration of diabetes had a lower seroconversion rate. CONCLUSIONS: Our data show low cross-reactive antibody carrying rate and low seroconversion rate in patients with diabetes. Until larger scale, case-controlled trials become available, older patients and patients with a longer duration of diabetes should be considered for the two-dose vaccination or have antibody titres measured after the first vaccination. PMID- 21672007 TI - Glycaemic control in patients with diabetes at the point of referral for a second opinion. PMID- 21672008 TI - The Pre-diabetes Risk Education and Physical Activity Recommendation and Encouragement (PREPARE) programme study: are improvements in glucose regulation sustained at 2 years? AB - OBJECTIVE: To determine whether improvements in glucose regulation following the PREPARE structured education programme were sustained at 24 months. PATIENTS AND METHODS: Ninety-eight overweight or obese individuals with impaired glucose tolerance were randomized to receive: (1) advice leaflet, (2) 3-h structured education programme aimed at promoting physical activity, (iii) 3-h structured education with personalized pedometer use. The primary outcome was change in 2-h post-challenge plasma glucose. RESULTS: Seventy-three (74%) individuals were included for analysis at 24 months; age 65 +/- 8 years, BMI 29.3 +/- 4.8 kg/m(2), South Asian ethnicity 21%. A statistically significant reduction in 2-h glucose of -1.6 mmol/l (-0.4 to -2.7) was seen in the education-with-pedometer group compared with the control group. There is no significant difference in the education-only group. CONCLUSION: Improvements in glucose regulation following a pragmatic group-based structured education with pedometer use were sustained at 24 months. PMID- 21672009 TI - Association of a polymorphism of BTN2A1 with type 2 diabetes mellitus in Japanese individuals. AB - AIMS: We previously showed that the C->T polymorphism (rs6929846) of BTN2A1 was significantly associated with myocardial infarction in Japanese individuals by a genome-wide association study. Given that diabetes mellitus is an important risk factor for myocardial infarction, the association of rs6929846 of BTN2A1 with myocardial infarction might be attributable, at least in part, to its effect on susceptibility to diabetes. The purpose of this study was to examine the relation of rs6929846 of BTN2A1 to Type 2 diabetes mellitus. METHODS: A total of 8650 Japanese individuals from two independent subject panels were examined: Panel A comprised 1141 individuals with Type 2 diabetes and 3161 control subjects and panel B comprised 1664 individuals with Type 2 diabetes and 2684 control subjects. RESULTS: The chi-square test revealed that rs6929846 of BTN2A1 was significantly related to the prevalence of Type 2 diabetes in subject panel A (P = 0.0002) and subject panel B (P=0.006). Multivariable logistic regression analysis with adjustment for age, sex, body mass index and smoking status revealed that rs6929846 was significantly associated with Type 2 diabetes (P = 0.0006; odds ratio 1.25) in all individuals, with the T allele representing a risk factor for this condition. Multiple regression analysis with adjustment for age, sex and body mass index revealed that rs6929846 was significantly (P=0.04) related to blood glycosylated haemoglobin content in control subjects. CONCLUSIONS: BTN2A1 may be a susceptibility gene for Type 2 diabetes in Japanese individuals. PMID- 21672011 TI - Inappropriate antidiuretic hormone secretion: long-term successful urea treatment. AB - Hyponatremia is the main complication of inappropriate antidiuretic hormone secretion (SIADH), sometimes fatal. Treatment strategy depends on the cause and the severity of the hyponatremia. Recent studies have shown the efficacy of urea in treating acute hyponatremia secondary to SIADH, by inducing an osmotic water drive. We describe an infant with chronic hyponatremia secondary to SIADH in which the long-term oral treatment with urea was successful and well tolerated. The aim of this paper is to highlight the potential benefits of urea treatment in case of chronic hyponatremia secondary to SIADH. CONCLUSION: Chronic oral urea treatment in children with SIADH allows an easy and safe water and sodium control and may permit a decrease in fluid restriction in this situation. PMID- 21672010 TI - Gestational diabetes mellitus is associated with TCF7L2 gene polymorphisms independent of HLA-DQB1*0602 genotypes and islet cell autoantibodies. AB - AIMS: To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth. METHODS: We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skane Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin. RESULTS: The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P < 0.0001). These associations remained statistically significant after adjusting for maternal age, number of pregnancies, family history of diabetes and HLA-DQ genotypes and were independent of the presence of islet cell autoantibodies. No interaction was observed between TCF7L2 and HLA-DQB1*0602, which was shown to be negatively associated with gestational diabetes in mothers born in Sweden (P = 0.010). CONCLUSIONS: The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden. PMID- 21672012 TI - Vitamin D deficiency and prevention: Turkish experience. AB - A nationwide 'vitamin D prophylaxis augmentation programme' initiated in 2005 in Turkey reduced the prevalence of rickets from 6% in 1998 to 0.1% in 2008 in children under 3 years of age. The programme included free distribution of vitamin D drops to all newborns and infants (0-12 months) visiting primary health stations throughout the country. Free disposal of vitamin D to infants is an effective strategy for preventing vitamin D-deficient rickets. PMID- 21672013 TI - Respiratory disease and early serum S100A12 changes in very premature infants. AB - AIM: The role of granulocyte-specific S100A12, a marker for inflammatory disorders, in newborn lung disease is unknown. We compared postnatal blood S100A12 concentrations against respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD). METHODS: Blood samples from 92 newborns were collected on admission, 12 h, day 1, day 3-4 and day 7, and analysed for S100A12. IL-8 and IL-6 were assayed in 52 infants. RESULTS: Infants with RDS were significantly more premature (median 27 vs. 34 weeks), more likely to receive antenatal corticosteroids (84% vs. 26%) and have lower neutrophil counts (median 2.4 vs. 3.8 * 10(9) /L) at admission. S100A12 levels peaked during the first day and were significantly lower in preterm infants with RDS compared to those without (median 250 vs. 616 ng/mL at 12 h, 281 vs. 828 ng/mL day 1, respectively). S100A12 levels were low among the 35 very preterm infants (24-29 week gestation) regardless of the presence of BPD (285 vs. 288 ng/mL on day 1). In comparison, IL-8 and IL-6 levels were not different between groups. CONCLUSION: Plasma S100A12 is low in infants with RDS, possibly because of gestationally related differences in neutrophil response or to the effects of antenatal corticosteroids. It is therefore not a useful marker of BPD development. PMID- 21672014 TI - Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3 year follow-up. AB - AIM: We present a 3-year follow-up of a boy with mucopolysaccharidosis type II (MPS II) who had idursulfase therapy initiated at the age of 3 months and compare his clinical course to his healthy twin brother. METHODS: Detailed anthropometric features, ultrasound studies of liver and spleen volumes, echocardiography and audiological examinations, psychological tests, joint range of motion (ROM) and skeletal radiographs were monitored. RESULTS: After 3 years of treatment, the patient has not developed any clinical manifestations of MPS II. He did not develop coarse facial features, joint disease, or organomegaly, and his cardiac function remained normal. There were no pronounced signs of dysostosis multiplex on radiographs. The only difference when compared with his healthy twin brother was lower IQ (Termann-Merrill 98 vs. 118) and mild deformity of one vertebrae. CONCLUSION: Our study suggests that early initiation of enzyme replacement therapy may significantly slow or prevent the development of irreversible disease manifestations and therefore modify the natural history of MPS II. PMID- 21672017 TI - Le plus ca change: why we need better biomarkers to predict outcomes in ulcerative colitis. PMID- 21672018 TI - Learning from the genetics of enteric tuberculosis. PMID- 21672019 TI - Education and imaging. Gastrointestinal: rectal cancer initial PET/CT staging with isolated synchronous adrenal metastasis. PMID- 21672020 TI - Education and imaging. Gastrointestinal: chronic cellcept-induced colitis. PMID- 21672021 TI - Education and imaging. Gastrointestinal: EUS-guided FNA for a mimicking esophageal submucosal tumor in an immunocompromised patient. PMID- 21672022 TI - Education and imaging. Hepatobiliary and pancreatic: Bouveret's syndrome. PMID- 21672023 TI - Education and imaging. Hepatobiliary and pancreatic: inflammatory pseudotumors of the liver. PMID- 21672024 TI - Taxonomic and geographic patterns of decline for threatened and endangered species in the United States. AB - Species listed under the U.S. Endangered Species Act (i.e., listed species) have declined to the point that the probability of their extinction is high. The decline of these species, however, may manifest itself in different ways, including reductions in geographic range, number of populations, or overall abundance. Understanding the pattern of decline can help managers assess extinction probability and define recovery objectives. Although quantitative data on changes in geographic range, number of populations, and abundance usually do not exist for listed species, more often qualitative data can be obtained. We used qualitative data in recovery plans for federally listed species to determine whether each listed species declined in range size, number of populations, or abundance relative to historical levels. We calculated the proportion of listed species in each state (or equivalent) that declined in each of those ways. Nearly all listed species declined in abundance, and range size or number of populations declined in approximately 80% of species for which those data were available. Patterns of decline, however, differed taxonomically and geographically. Declines in range were more common among vertebrates than plants, whereas population extirpations were more common among plants. Invertebrates had high incidence of range and population declines. Narrowly distributed plants and invertebrates may be subject to acute threats that may result in population extirpations, whereas vertebrates may be affected by chronic threats that reduce the extent and size of populations. Additionally, in the eastern United States and U.S. coastal areas, where the level of land conversion is high, a greater percentage of species' ranges declined and more populations were extirpated than in other areas. Species in the Southwest, especially plants, had fewer range and population declines than other areas. Such relations may help in the selection of species' recovery criteria. PMID- 21672025 TI - Improving anaphylaxis management in a pediatric emergency department. AB - BACKGROUND: The management of anaphylaxis in pediatric emergency units (PEU) is sometimes deficient in terms of diagnosis, treatment, and subsequent follow-up. The aims of this study were to assess the efficiency of an updated protocol to improve medical performance, and to describe the incidence of anaphylaxis and the safety of epinephrine use in a PEU in a tertiary hospital. METHODS: We performed a before-after comparative study with independent samples through review of the clinical histories of children aged <14 years old diagnosed with anaphylaxis in the PEU according to the criteria of the European Academy of Allergy and Clinical Immunology (EAACI). Two allergists and a pediatrician reviewed the discharge summaries codified according to the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) as urticaria, acute urticaria, angioedema, angioneurotic edema, unspecified allergy, and anaphylactic shock. Patients were divided into two groups according to the date of implantation of the protocol (2008): group A (2006-2007; the period before the introduction of the protocol) and group B (2008-2009; after the introduction of the protocol). We evaluated the incidence of anaphylaxis, epinephrine administration, prescription of self-injecting epinephrine (SIE), other drugs administered, the percentage of admissions and length of stay in the pediatric emergency observation area (PEOA), referrals to the allergy department, and the safety of epinephrine use. RESULTS: During the 4 years of the study, 133,591 children were attended in the PEU, 1673 discharge summaries were reviewed, and 64 cases of anaphylaxis were identified. The incidence of anaphylaxis was 4.8 per 10,000 cases/year. After the introduction of the protocol, significant increases were observed in epinephrine administration (27% in group A and 57.6% in group B) (p = 0.012), in prescription of SIE (6.7% in group A and 54.5% in group B) (p = 0.005) and in the number of admissions to the PEOA (p = 0.003) and their duration (p = 0.005). Reductions were observed in the use of corticosteroid monotherapy (29% in group A, 3% in group B) (p = 0.005), and in patients discharged without follow-up instructions (69% in group A, 22% in group B) (p = 0.001). Thirty-three epinephrine doses were administered. Precordial palpitations were observed in one patient. CONCLUSION: The application of the anaphylaxis protocol substantially improved the physicians' skills to manage this emergency in the PEU. Epinephrine administration showed no significant adverse effects. PMID- 21672026 TI - Effect of knee joint angle on neuromuscular activation of the vastus intermedius muscle during isometric contraction. AB - The purpose of this study was to compare the relationship between surface electromyography (EMG) and knee joint angle of the vastus intermedius muscle (VI) with the synergistic muscles in the quadriceps femoris (QF) muscle group. Fourteen healthy men performed maximal voluntary contractions during isometric knee extension at four knee joint angles from 90 degrees , 115 degrees , 140 degrees , and 165 degrees (180 degrees being full extension). During the contractions, surface EMG was recorded at four muscle components of the QF muscle group: the VI, vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) muscles. The root mean square of the surface EMG at each knee joint angle was calculated and normalized by that at a knee joint angle of 90 degrees for individual muscles. The normalized RMS of the VI muscle was significantly lower than those of the VL and RF muscles at the knee joint angles of 115 degrees and 165 degrees and those of the VL, VM, and RF muscles at the knee joint angle of 140 degrees (P<0.05). The present results suggest that the neuromuscular activation of the VI muscle is regulated in a manner different from the alteration of the knee joint angle compared with other muscle components of the QF muscle group. PMID- 21672027 TI - Acute effects of static stretching on peak torque and the hamstrings-to quadriceps conventional and functional ratios. AB - Recent evidence has shown acute static stretching may decrease hamstring-to quadriceps (H:Q) ratios. However, the effects of static stretching on the functional H:Q ratio, which uses eccentric hamstrings muscle actions, have not been investigated. This study examined the acute effects of hamstrings and quadriceps static stretching on leg extensor and flexor concentric peak torque (PT), leg flexor eccentric PT, and the conventional and functional H:Q ratios. Twenty-two women (mean +/- SD age=20.6 +/- 1.9 years; body mass=64.6 +/- 9.1 kg; height=164.5 +/- 6.4 cm) performed three maximal voluntary unilateral isokinetic leg extension, flexion, and eccentric hamstring muscle actions at the angular velocities of 60 and 180 degrees /s before and after a bout of hamstrings, quadriceps, and combined hamstrings and quadriceps static stretching, and a control condition. Two-way repeated measures ANOVAs (time * condition) were used to analyze the leg extension, flexion, and eccentric PT as well as the conventional and functional H:Q ratios. Results indicated that when collapsed across velocity, hamstrings-only stretching decreased the conventional ratios (P<0.05). Quadriceps-only and hamstrings and quadriceps stretching decreased the functional ratios (P<0.05). These findings suggested that stretching may adversely affect the conventional and functional H:Q ratios. PMID- 21672028 TI - Ergogenic effect of hyperoxic recovery in elite swimmers performing high intensity intervals. AB - This investigation tested the hypothesis that breathing oxygen-enriched air (F(i)O(2) =1.00) during recovery enhances peak (P(peak)) and mean power (P(mean)) output during repeated high-intensity exercise. Twelve elite male swimmers (21 +/ 3 years, 192.1 +/- 5.9 cm, 79.1 +/- 8.2 kg) inhaled either hyperoxic (HOX) or normoxic (NOX) air during 6-min recovery periods between five repetitions of high intensity bench swimming, each involving 40 maximal armstrokes. Oxygen partial pressure (pO(2)) and saturation (SO(2)), [H(+)], pH, base excess and blood lactate concentration were measured before and after all intervals. The production of the reactive oxygen species (ROS) hydrogen peroxide was measured before, directly after and 15 min after the test. P(peak) and P(mean) with HOX recovery were significantly higher than with NOX throughout the third, fourth and fifth intervals (P<0.001-0.04). With HOX, electromyography activity was lower during the third, fourth and fifth intervals than during the first (P=0.05 0.001), with no such changes in NOX (P=0.99). There were no differences in blood lactate, pH, [H(+)] or base excess and ROS production at any time point with either HOX or NOX recovery. These findings demonstrate that the P(peak) and P(mean) of elite swimmers performing high-intensity intervals can be improved by exposure to oxygen-enriched air during recovery. PMID- 21672029 TI - Fatigue is mediated by cholinoceptors within the ventromedial hypothalamus independent of changes in core temperature. AB - We investigated brain mechanisms modulating fatigue during prolonged physical exercise in cold environments. In a first set of studies, each rat was subjected to three running trials in different ambient temperatures (T(a)). At 8 degrees C and 15 degrees C, core body temperature (T(core)) decreased and increased, respectively, whereas at 12 degrees C, the T(core) did not change throughout the exercise. In another set of experiments, rats were randomly assigned to receive bilateral 0.2 MUL injections of 2.5 * 10(-2) M methylatropine or 0.15 M NaCl solution into the ventromedial hypothalamic nuclei (VMH). Immediately after the injections, treadmill exercise was started. Each animal was subjected to two experimental trials at one of the following T(a) : 5 degrees C, 12 degrees C or 15 degrees C. Muscarinic blockade of the VMH reduced the time to fatigue (TF) in cold environments by 35-37%. In all T(a) studied, methylatropine-treated rats did not present alterations in T(core) and tail skin temperature compared with controls. These results indicate that, below the zone of thermoneutrality, muscarinic blockade of the VMH decreases the TF, independent of changes in T(core). In conclusion, our data suggest that VMH muscarinic transmission modulates physical performance, even when the effects of thermoregulatory adjustments on fatigue are minimal. PMID- 21672030 TI - Upregulation and nuclear localization of TNF-like cytokine 1A (TL1A) and its receptors DR3 and DcR3 in psoriatic skin lesions. AB - TNF is critically involved in the pathogenesis of psoriasis. TL1A is a TNF-like cytokine, which, after binding to death domain receptor DR3, provides costimulatory signals to lymphocytes, amplifies Th1- and Th17-mediated immune responses and induces apoptotic cell death. These functions are inhibited when TL1A associates to decoy receptor DcR3. In the present study, we investigated the expression profiles for TL1A, DR3 and DcR3 in the normal skin and in psoriatic skin lesions. By use of immunohistochemistry, we were able to demonstrate constitutive cutaneous expression of DR3 and DcR3 but not of TL1A in healthy skin. On the other hand, in patients with active psoriasis, we observed abundant immunostaining for TL1A and significant upregulation of its receptors (P < 0.05 in comparison to healthy skin). TL1A, DR3 and DcR3 proteins, as well as mRNA transcripts reflecting in situ production of TL1A and DcR3, were also specifically increased in lesional as compared to non-lesional skin from patients with psoriasis (P < 0.05). These proteins were upregulated in cell populations that are critically involved in the pathogenesis of chronic skin inflammation, such as keratinocytes, macrophages in deep dermis and cells at the perivascular/endothelial area. Finally, we provide evidence for the existence of nuclear localization of TL1A in inflammatory cells from psoriatic lesions. This was also observed in inflamed synovia from patients with rheumatoid arthritis, but not in neoplastic TL1A-expressing cell lines. We conclude that interactions between TL1A and its two receptors may be involved in the pathogenesis of chronic skin inflammation that takes place in psoriasis. PMID- 21672031 TI - Ov-16 [4-(3,4-dihydroxybenzoyloxymethyl)phenyl-O-beta-D-glucopyranoside] inhibits melanin synthesis by regulating expressions of melanogenesis-regulated gene and protein. AB - Ov-16 (4-(3,4-dihydroxybenzoyloxymethyl)phenyl-O-beta-D-glucopyranoside), a polyphenolic glycoside that is isolated from oregano (Origanum vulgare L.), can scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals. This investigation is the first to study in detail the hypopigmentary properties of Ov-16. It demonstrates that 0-1000 MUg/ml Ov-16 inhibits the activity of mushroom tyrosinase (Tyr) in a concentration-dependent manner. The inhibitionary Tyr kinetics of Ov-16 towards the oxidation of L-DOPA was found to be uncompetitive. Following the treatment of human skin premalignant kerationcyte HaCaT cells, human skin fibroblast Hs68 cells and mice melanoma B16 cells with Ov-16 (0-100 MUg/ml), cell viability was >98%, suggesting that Ov-16 is non-toxic. Ov-16 can reduce cellular Tyr activity, DOPA oxidase activity and melanin synthesis in B16 cells that are stimulated by the alpha-melanocyte-stimulating hormone (alpha MSH). Moreover, Ov-16 inhibited the production of melanin in Streptomyces bikiniensis without affecting the growth of the microorganism. The treatment of B16 cells with Ov-16 considerably reduced the gene expressions of melanocortin-1 receptor (Mc1r), microphthalmia-associated transcription factor (Mitf), Tyr, tyrosinase-related proteins-2 (Trp-2) and Trp-1, as determined by RT-PCR. The expressions of Mc1r, Mift, Tyr, Trp-2 and TrpP-1 protein in Ov-16-treated B16 cells were also significantly reduced, as determined by western blotting and fluorescent staining analysis. These results suggest that Ov-16 exhibits hypopigmentary performance. PMID- 21672032 TI - No evidence of viral genomes in whole-transcriptome sequencing of three melanoma metastases. AB - Several viruses are known to cause cancer, such as human herpes virus 8 in Kaposi sarcoma and human papilloma viruses in cervical cancer. Recently, Merkel cell polyoma virus (MCPyV) has been described in 80% of Merkel cell carcinomas (MCC). Similarly to MCC and Kaposi sarcoma, melanoma incidence is increased in immunosuppressed patients. We asked whether infection by known or yet unknown viruses may play a role in melanoma development as well. To detect viral sequences expressed in melanoma cells, we analysed three melanoma metastases by whole-transcriptome sequencing and digital transcriptome subtraction. None of the samples investigated harboured viral sequences. In contrast, artificial viral sequences and MCPyV transcripts used as a positive control for the bioinformatics analysis were detected. This renders it less likely that viruses are frequently involved in melanoma induction. A larger number of melanoma transcriptome sequencings are required to rule out viruses as a relevant pathogen. PMID- 21672033 TI - Compartmentalization of the human stratum corneum by persistent tight junction like structures. AB - Several tight junction (TJ) proteins were detected in the living layers of adult human epidermis, and TJ-like membrane ridges were observed at the top of the stratum granulosum (SG) in freeze-fracture studies. We applied standard and immunoelectron microscopy to look for TJ-derived structures in the stratum corneum (SC) of human adult epidermis and in cornified envelopes purified from the plantar SC. Besides confirming claudin-1 labelling in the proximity of SG desmosomes, we also observed immunolocalization near corneodesmosomes in the lower SC. In addition, TJ proteins were consistently detected in the purified cornified envelopes. Lateral but not horizontal walls of the corneocytes showed frequent points of molecular fusion between lipid envelopes. These structural associations were very frequently localized at the top of the lateral corneocyte membranes, thus sealing the extremities of lateral intercorneocyte spaces. We propose that TJ-like structures persist in the SC and contribute to the reinforcement of lateral contacts and to the formation of membrane interdigitations between corneocytes. Their presence could contribute to subdivision of the extracellular spaces of SC into consecutive individualized compartments. Intercellular lipids, enzymes and other (glyco)protein content could thus evolve in the keratinized epidermal layer at different paces, as preprogrammed in the underlying living cells and influenced by the environment, e.g. humidity. Such situation might explain differences in the degradation rates between the 'peripheral' and the 'non-peripheral' corneodesmosomes observed during physiological desquamation, as previously suggested by us and others. PMID- 21672034 TI - Efficacy of excimer light therapy (308 nm) for palmoplantar pustulosis with the induction of circulating regulatory T cells. AB - In this open-label study, we investigated the efficacy of excimer light (308 nm) with a filter to cut off wavelengths below 297 nm for the treatment of palmoplantar pustulosis (PPP). Twenty patients with PPP were recruited and treated once a week for a total of 30 sessions. Patient response was assessed every 10 sessions based on the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score. Levels of Th17 cells and regulatory T cells (Treg) in the peripheral blood in patients with PPP were also evaluated. Mean PPPASI score was 19.5 at baseline, 13.2 at 10 treatments, 10.9 at 20 treatments and 9.5 at 30 treatments. Th17 levels after excimer therapy were not significantly different from those at baseline. In contrast, Treg levels after excimer therapy were significantly higher than those at baseline. PMID- 21672035 TI - p130Cas, E-cadherin and beta-catenin in human transitional cell carcinoma of the bladder: expression and clinicopathological significance. AB - OBJECTIVES: To investigate the effects of junction protein, p130 Crk-associated substance (p130Cas), and adhesion molecules, E-cadherin and beta-catenin, on the biological behavior of transitional cell carcinoma of the bladder. METHODS: In 72 paraffin embedded specimens of transitional cell carcinoma of the bladder and 20 normal controls, the expression of p130Cas, E-cadherin and beta-catenin was examined by quantum dot-based immunofluorescence histochemistry (QD-IHC) and conventional immunohistochemistry (IHC). RESULTS: QD-IHC was consistent with IHC in detecting the expression of the three molecules (P > 0.05 for all comparisons). The positive expression rate of p130Cas in bladder cancer tissues increased more significantly than that in normal bladder tissues (P < 0.001). Similarly, the aberrant expression rates of E-cadherin and beta-catenin in bladder cancer tissues were significantly higher than those in normal bladder tissues (P < 0.001 for both comparisons). The expression of each molecule was correlated with tumor pathological grade and clinical stage (P < 0.05 for all comparisons), but not with tumor number and size (P > 0.05 for all comparisons). Furthermore, negative correlations were found between the expression intensities of p130Cas and E-cadherin or beta-catenin in transitional cell carcinoma of the bladder (P < 0.05 for both comparisons). CONCLUSIONS: p130Cas, E-cadherin and beta-catenin might represent useful predictors of malignant degree of transitional cell carcinoma of the bladder. PMID- 21672036 TI - Assessing quality of life in patients with psoriasis and its improvement with treatment. PMID- 21672037 TI - Candida endocarditis associated with cardiac rhythm management devices: review with current treatment guidelines. AB - Coincident with an increased use of cardiac rhythm management devices (CRMD) has been an increase in the number of pacemaker and cardioverter-defibrillator infections. CRMD endocarditis accounts for about 10% of all device-related infections, and cardiac infection caused by Candida sp. is a rare event. To date, only sporadic reports of this unusual and life-threatening event have been reported. By describing a case of CRMD-related Candida endocarditis and conducting a literature review, we provide a detailed characterisation of this unusual clinical entity with an emphasis on diagnosis, management and treatment. A case of CRMD-related Candida endocarditis is presented and a computer search for confirmed cases of CRMD-Candida endocarditis was conducted. Current recommendations for management and treatment were documented. From 1969 to 2009, 15 patients with CRMD-Candida endocarditis (12 pacemaker and three implanted cardioverter-defibrillator) were documented. All were males, non-albicans Candida sp. were frequently recovered, a major fungal embolus occurred in 27% of patients and two of 10 patients who received defined antifungal therapy and device explantation expired. CRMD Candida endocarditis is a rare and serious clinical event; isolates can include Candida albicans and other Candida sp., and treatment involves both targeted antifungal therapy and device removal. PMID- 21672038 TI - Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul-Ehrlich-Society for Chemotherapy. AB - Invasive Candida infections are important causes of morbidity and mortality in immunocompromised and hospitalised patients. This article provides the joint recommendations of the German-speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMyKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG) for diagnosis and treatment of invasive and superficial Candida infections. The recommendations are based on published results of clinical trials, case series and expert opinion using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA). Key recommendations are summarised here: The cornerstone of diagnosis remains the detection of the organism by culture with identification of the isolate at the species level; in vitro susceptibility testing is mandatory for invasive isolates. Options for initial therapy of candidaemia and other invasive Candida infections in non-granulocytopenic patients include fluconazole or one of the three approved echinocandin compounds; liposomal amphotericin B and voriconazole are secondary alternatives because of their less favourable pharmacological properties. In granulocytopenic patients, an echinocandin or liposomal amphotericin B is recommended as initial therapy based on the fungicidal mode of action. Indwelling central venous catheters serve as a main source of infection independent of the pathogenesis of candidaemia in the individual patients and should be removed whenever feasible. Pre-existing immunosuppressive treatment, particularly by glucocorticosteroids, ought to be discontinued, if feasible, or reduced. The duration of treatment for uncomplicated candidaemia is 14 days following the first negative blood culture and resolution of all associated symptoms and findings. Ophthalmoscopy is recommended prior to the discontinuation of antifungal chemotherapy to rule out endophthalmitis or chorioretinitis. Beyond these key recommendations, this article provides detailed recommendations for specific disease entities, for antifungal treatment in paediatric patients as well as a comprehensive discussion of epidemiology, clinical presentation and emerging diagnostic options of invasive and superficial Candida infections. PMID- 21672039 TI - Clinical differences between invasive pulmonary infection by Scedosporium apiospermum and invasive pulmonary aspergillosis. AB - Invasive pulmonary infection by Scedosporium apiospermum (IPSA) and invasive pulmonary aspergillosis (IPA) are clinically similar. Our objective was to identify clinical parameters that may differentiate IPSA from IPA. Ours was a prospective cohort study that included patients with different degrees of immunosuppression and respiratory isolation of S. apiospermum (SCA). Episodes of invasive infection were classified according to the EORTC and MSG criteria. Clinical variables corresponding to patients with IPSA were compared with those collected from patients with a diagnosis of IPA during the same period. Twenty seven patients with positive culture for SCA from respiratory samples were evaluated. Of the 27 positive cultures, nine were classified as IPSA. When compared with the 89 patients with IPA, patients with IPSA were most likely to have received prophylaxis with either aerosolised (14.6% vs. 66.7%; P < 0.001) or intravenous amphotericin B (AMB; 4.5% vs. 44.4%; P = 0.002), to have prior episode of acute rejection (19% vs. 66.7%; P = 0.005), to have a later onset of infection after transplantation (251 days vs. 404 days; P = 0.009), and to have higher CD4(+) lymphocyte count (207.6 vs. 289.4; P = 0.005). Late-onset disease after transplantation and prophylaxis with AMB are more frequent in patients with IPSA compared with IPA. PMID- 21672040 TI - Probiotic sepsis due to Saccharomyces fungaemia in a critically ill burn patient. PMID- 21672041 TI - Successful treatment of central venous catheter infection due to Candida lipolytica by caspofungin-lock therapy. PMID- 21672042 TI - Photodynamic therapy for pathogenic fungi. AB - Photodynamic therapy (PDT) is a minimally invasive approach, in which a photosensitiser compound is activated by exposure to visible light. The activation of the sensitiser drug results in several chemical reactions, such as the production of oxygen reactive species and other reactive molecules, whose presence in the biological site leads to the damage of target cells. Although PDT has been primarily developed to combat cancerous lesions, this therapy can be employed for the treatment of several conditions, including infectious diseases. A wide range of microorganisms, including Gram positive and Gram negative bacteria, viruses, protozoa and fungi have demonstrated susceptibility to antimicrobial photodynamic therapy. This treatment might consist of an alternative to the management of fungal infections. Antifungal photodynamic therapy has been successfully employed against Candida albicans and other Candida species and also against dermatophytes. The strain-dependent antifungal effect and the influence of the biological medium are important issues to be considered. Besides, the choice of photosensitiser to be employed in PDT should consider the characteristics of the fungi and the medium to be treated, as well as the depth of penetration of light into the skin. In the present review, the state-of-the art of antifungal PDT is discussed and the photosensitiser characteristics are analysed. PMID- 21672043 TI - Potential role of probiotic bacteria in the treatment and prevention of localised candidosis. AB - The extensive use of immunosuppressive therapies in recent years has increased the number of patients prone to or actually suffering from localised candidosis. As Candida species gain increasing resistance towards common antifungal drugs, new strategies are needed to prevent and treat infections caused by these pathogens. Probiotic bacteria have been in vogue in the past two decades. More and more dairy products containing such organisms offer promising potential beneficial effects on human health and well-being. Because of the ability of probiotic bacteria to inhibit the growth of pathogens and to modulate human immune responses, these bacteria could provide new possibilities in antifungal therapy. We summarise the recent findings concerning the usefulness of probiotic treatment in localised candidosis, as well as discussing possible risks of probiotic treatment and highlighting the molecular mechanisms that are believed to contribute to probiotic effects. PMID- 21672044 TI - Occurrence of yeasts in faecal samples from Antarctic and South American seabirds. AB - During an expedition to the Southern Argentinean town of Ushuaia, the Antarctic Peninsula, Antarctic Islands and the Falkland Islands, we collected 94 faecal specimens from wild birds to screen for yeast within the different bird species. The yeast species were identified by morphological features and commercial characterisation kits. From 54% of the specimens, we isolated 122 strains representing 29 yeast species. Debaryomyces hansenii, Candida lambica and Candida krusei were the most frequently isolated species. We found a plethora of yeasts in birds living in proximity to humans, whereas birds living in more remote areas were colonised with a lower number of fungal species. PMID- 21672045 TI - Emerging moulds: epidemiological trends and antifungal resistance. AB - Invasive fungal infections (IFIs) are associated with high morbidity and mortality in immunocompromised patients. Although Aspergillus spp. remain an important cause of IFI, other moulds such as Fusarium spp., dematiaceous fungi and Mucorales have become increasingly prevalent among this patient population. Diagnosis and treatment of invasive mould infections remain a challenge. Because of the poor prognosis associated with IFIs, understanding the activity, efficacy and limitations of the available drugs is critical to select the appropriate antifungal agent on an individualised basis. PMID- 21672046 TI - Usefulness of serial determination of Aspergillus galactomannan in the diagnosis and management of invasive aspergillosis in an AIDS patient with non-Hodgkin lymphoma. PMID- 21672047 TI - Production of haemolytic factor by clinical isolates of Candida tropicalis. AB - Although haemolytic factor is known to be a putative virulence factor contributing to pathogenicity in Candida species, its production by Candida tropicalis is poorly understood. In this study, we analysed the culture conditions under which C. tropicalis can display haemolytic factor on plate assay and the secretion of haemolytic factor in liquid medium by clinical isolates obtained from different specimens. All the tested isolates exhibited an internal translucent ring, resembling beta-haemolysis, surrounding by a peripheral greenish-grey halo on sheep blood agar medium. Similar haemolytic pattern was observed on human blood enriched medium. Furthermore, incubation either under normal atmosphere or under increased CO(2) had no effect on haemolysis. Overall, no differences were observed on beta-haemolytic activities (P > 0.05) among tested isolates of C. tropicalis. In glucose-limited medium (RPMI 1640 with 0.2% glucose), none of the isolates induced haemolysis on red blood cells. Similarly to found on plate assays, there were no significant differences (P > 0.05) in the activity of secreted haemolytic factor in liquid medium among C. tropicalis isolates. However, after growth, the number of yeast cells varied among isolates revealing different efficiencies of haemolytic factor production. Haemolytic activity was neither inhibited by heat treatment (100 degrees C) nor by the addition of pepstatin A. The obtained results extend our knowledge about haemolytic factor production by Candida species. PMID- 21672048 TI - Efficacy of anidulafungin against biofilms of different Candida species in long term trials of continuous flow cultivation. AB - Long-term continuous flow culture allows the investigation of dynamic biofilms under microaerophilic or aerobic conditions. We studied the biofilm formation and changes of susceptibility in 30 blood culture isolates (48 experiments) of different Candida species exposed to anidulafungin in 0.16 ml or 7.7 ml flow chambers. The flow rate (F) was adjusted to a very low rate of 1.3 ml h(-1) resulting in an exchange rate of up to 180 and 6.25 times chamber volumes per 24 hours in the small and large chambers, respectively. The results of culture at a very low flow rate were markedly different from cultures in micro well plates. Low flow rates may better mimic the in vivo situation and thus may be of higher relevance for the clinical setting. Under these conditions, a general resistance of fungal biofilms against anidulafungin cannot be confirmed. Strains of C. albicans and C. glabrata showed very uniform results whereas the C. parapsilosis group and C. lusitaniae varied from high susceptibility to resistance. Species differentiation of the C. parapsilosis group appears to be appropriate in clinical microbiological diagnostics. For the majority of the tested Candida species, anidualafungin was more effective than voriconazole. For the species C. lusitaniae and C. guilliermondii susceptibility testing should be considered prior to clinical use of echinocandin antifungals. PMID- 21672049 TI - Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial. AB - The increased use of older and/or marginal donor organs in liver transplantation over the last decade calls for strategies to minimize ischaemic reperfusion (I/R) injury to prevent early graft failure. Tacrolimus, a very potent and effective calcineurin inhibitor, was selected because of its ability to ameliorate I/R injury. A randomized, blinded, controlled single-centre trial of 26 liver transplant recipients was performed between February 2008 and December 2009. Donor organs were randomized to be perfused intraportally during liver transplantation with 1.5 l 5% albumin infusion containing either 20 ng/ml tacrolimus or placebo. The primary end point was liver function as assessed by aspartate transaminase (AST) or alanine transaminase (ALT) levels 6 days after transplantation. Treatment effectiveness was tested by transcriptome-wide analysis of biopsies. There was no difference in the primary end point, i.e. AST (IU/l) and ALT (IU/l) at day 6 after transplantation between groups. Furthermore, choleastatic parameters as well as parameters of liver synthesis were not different between groups. However, tacrolimus treatment suppressed inflammation and immune response in the transplanted liver on a genome-wide basis. Intrahepatic administration of tacrolimus did not result in a reduction of AST and ALT within the first week after transplantation. PMID- 21672051 TI - Donor and recipient HLA/KIR genotypes do not predict liver transplantation outcome. AB - Whether or not Natural Killer (NK) cells affect the immune response to solid organ allografts is still controversial. Main determinants of NK-cell activation are specific HLA/killer-cell immunoglobulin-like receptors (KIR) interactions that, in transplantation, may induce NK-cell alloreactivity. So far, in liver transplantation (LTX) donor-versus-recipient alloreactivity has not been investigated; in addition, studies of predicted recipient-versus-donor NK-cell alloreactivity have led to contradicting results. We typed a cohort of LTX donors and recipients for HLA-C/Bw4 and KIRs. We estimated the effect of NK-cell alloreactivity, as predicted by classically used models, in the donor-versus recipient direction. The results indicate that HLA/KIR mismatches in the donor versus-recipient direction do not predict graft rejection nor graft or patient survival, suggesting that donor-derived NK cells do not play a major role in LTX outcome. In addition, when considering predicted NK-cell alloreactivity in the reverse direction (recipient-versus-donor), we first confirmed that donor HLA-C genotype was not associated with acute rejection, graft or patient survival and secondly we found that none of the models describing NK-cell alloreactivity could predict LTX outcome. Overall our observations suggest that, in contrast to what is shown in haematopoietic stem cell transplantation, donor-derived NK cells may not contribute in preventing liver graft rejection, and that recipient-versus donor NK-cell alloreactivity does not predict LTX outcome. PMID- 21672050 TI - Primary response against cytomegalovirus during antiviral prophylaxis with valganciclovir, in solid organ transplant recipients. AB - Antiviral prophylaxis has proved successful for prevention of cytomegalovirus (CMV) disease in solid organ transplant (SOT) patients; though emerging data suggest that antiviral agents interfere with immunity, and may inhibit immune priming. In this context, we investigated levels and phenotype of primary CMV specific immune responses that developed during antiviral prophylaxis in a cohort of CMV seronegative recipients (R(-) ) of a SOT from a seropositive donor (D(+) ). We longitudinally monitored CMV viral load, antibodies and levels of the negative immuno-modulator IL-10. PBMC were stimulated with CMV-specific peptide libraries to measure CD137 activation marker on CMV-specific T-cells and levels of PD-1 receptor, which is over expressed on exhausted T-cells. Unexpectedly, the majority (13/18) of D(+) R(-) patients who developed a primary CMV response showed early post-transplant CMV-specific responses, though levels of PD-1 on CMV specific T-cells remained elevated throughout prophylaxis. A strong inverse association was found between levels of plasma IL-10 and CMV-specific cellular immune responses. Our study suggests that during prophylaxis, subclinical CMV infection might have occurred in the D(+) R(-) patients, and primary CMV-specific responses were detected early post-transplant when levels of plasma IL-10 were low. Extended prophylaxis or antiviral treatment did not appear to suppress CMV specific antibodies or T-cells, which, however, showed exhaustion phenotypes. PMID- 21672052 TI - Dipeptidyl peptidase IV (DPP4) deficiency increases Th1-driven allergic contact dermatitis. AB - BACKGROUND: CD26 or dipeptidyl peptidase IV (DPP4) is known to be involved in several immunological processes and has recently been reported to play a crucial role in the allergic responses of the lungs. OBJECTIVES: To explore the impact of DPP4 on the allergic response of the skin. METHODS: Skin biopsies from patients suffering from atopic dermatitis (AD) and healthy controls were investigated for the expression of CD26/DPP4. Furthermore, the functional impact of CD26 was investigated in two models of contact hypersensitivity using CD26/DPP4-deficient and wild-type rats. Dinitrochlorobenzene (DNCB) was used to induce a T helper type 1 (Th1)-dominated inflammation and toluene-2,3-diisocyanate for a Th2 pronounced inflammation. The inflammatory responses were determined by histological quantification, flow cytometry [fluorescence-activated cell sorting (FACS)], and an enzyme-linked immunosorbant assay (ELISA). RESULTS: CD26/DPP4 expression was up-regulated in the lesional skin biopsies of patients compared with healthy controls as well as in both models of contact hypersensitivity. However, in the more Th2-driven model, a reduced inflammatory skin response was found in CD26/DPP4-deficient rats, analogous to the effects observed recently in a rat model of asthma. In partial contrast, there was an aggravation of local skin inflammation in CD26/DPP4-deficient rats under conditions of Th1-like skin inflammation. CONCLUSION AND CLINICAL RELEVANCE: The up-regulation of CD26 in atopic dermatitis represents a new finding, which has also been seen in other inflammatory skin diseases. However, tissue expression of CD26/DPP4 in immunological skin response can either be beneficial or aggravating, depending on a possible Th1/Th2 shift. This might have consequences for humans suffering from diabetes mellitus treated by DPP4 inhibitors, who have eczematous skin diseases as a co-morbidity. PMID- 21672053 TI - Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: a phase IIb study. AB - BACKGROUND: Allergic symptoms are generally caused by exposure to substances to which people have become sensitized. Associated with this is an 'unbalanced' Th1/Th2 immune response with T cell responses skewed towards the production of Th2 cytokines, IL-4, 5, and 13 and high levels of IgE antibodies. Current immune modulating therapies require the use of allergens, carrying the risk to induce potentially severe allergic reactions. OBJECTIVE: Goal of the present study was to assess the safety and efficacy of an allergen-free immune modulator in patients suffering from perennial allergy. METHODS: In order to be protected from immediate degradation upon injection, a toll-like receptor 9 (TLR9) agonist was packaged into virus-like particles. These nanoparticles loaded with TLR9 ligands (CYT003-QbG10) were injected six times, at weekly intervals, into patients with house dust mite allergy in an attempt to ameliorate allergic symptoms by modifying the immune response towards allergens. Two different doses were compared against placebo in this double-blind, randomized phase IIb study (n=299). Public trial registry: http://clinicaltrials.gov (NCT00800332). RESULTS: The treatment was safe and generally well tolerated. Rhinoconjunctivitis symptoms were significantly lower in patients treated with high dose of CYT003-QbG10 as compared with placebo (scores 0.31 vs. 0.52, P=0.04) based on a standardized average combined symptom and medication score. Furthermore, patients in the high dose group reported a significantly better quality of life score post-treatment than patients on placebo (scores 0.71 vs. 1.21, P=0.02). The conjunctival provocation test revealed a median 10-fold increase in allergen tolerance in the high dose group while in the placebo group it remained unchanged. CONCLUSION AND CLINICAL RELEVANCE: Treatment with high-dose CYT003-QbG10 improved disease symptoms and reduced medication use in allergic individuals thus providing first evidence for a new potential immunotherapeutic. PMID- 21672054 TI - Air pollution and children's respiratory health - gaps in the global evidence. AB - There is now convincing evidence that air pollution, especially the particulate matter (PM) fraction, adversely affects children's health. In general, the health effects of traffic-derived PM are well described in children living in high income countries. Conversely, studies into the health effects of PM from biomass and solid fuels are limited to children in lower-income countries. As PM from different combustion sources have components in common (e.g. elemental black carbon) - are we able to extrapolate from the research performed in different countries under different exposure conditions? Using lung function growth and vulnerability to infection as examples of health effects of global significance to children, this review addresses the question whether high-income-country research into air pollution can inform effects of pollution in low-income countries and vice versa. PMID- 21672055 TI - Bacillus-derived poly-gamma-glutamic acid attenuates allergic airway inflammation through a Toll-like receptor-4-dependent pathway in a murine model of asthma. AB - BACKGROUND: Asthma is an inflammatory disease of the airways that is mediated by Th2 responses. Poly-gamma-glutamic acid (gamma-PGA) is an extracellular polymeric compound that is synthesized by Bacillus cells. Previously, we found that gamma PGA promoted Th1 cell development in a manner dependent on antigen-presenting cells, but inhibited Th2 cell development. OBJECTIVE: To investigate the effect of gamma-PGA on dendritic cells (DCs), and its potential for treating Th2 mediated allergic asthma. METHODS: Wild-type, Toll-like receptor (TLR)-2 deficient, and TLR-4-defective mice were used. DCs derived from the bone marrow and extracted from the lung were stimulated with gamma-PGA and assayed for the expression of signalling molecules, costimulatory molecules, and cytokines. Mice were sensitized and challenged with ovalbumin (OVA) to induce asthma. They were repeatedly injected intranasally with gamma-PGA before and during the challenge period, and inflammation and structural remodelling of the airways were examined. RESULTS: gamma-PGA selectively signalled conventional DCs to activate NF-kappaB and mitogen-activated protein kinase, leading to the up-regulation of CD86, CD40, and IL-12, but not IL-10 and IL-6. These effects of gamma-PGA were dependent on TLR-4 and independent of TLR-2. Importantly, the intranasal administration of gamma-PGA to OVA-sensitized/challenged mice reduced the airway hyperresponsiveness and allergic inflammation such as leucocyte influx, goblet cell hyperplasia, eosinophilia, and Th2 cytokine production. In addition to lowered IgE titres, the treatment of mice with gamma-PGA significantly reduced the multiplication and Th2 polarization of mediastinal lymph node T cells upon allergen-specific restimulation. These anti-asthmatic effects of gamma-PGA were also abolished in TLR-4-defective mice. CONCLUSIONS AND CLINICAL RELEVANCE: Our data indicate that gamma-PGA activates DCs to favour Th1 cell induction through a TLR-4-dependent pathway and alleviates pathologic symptoms in a Th2-biased asthmatic model. These findings highlight the potential of gamma-PGA for the treatment of asthma and other allergic disease in which Th2 polarization plays an important role. PMID- 21672056 TI - Chronic rhinosinusitis, nasal polyposis and asthma: the united airways concept reconsidered? PMID- 21672057 TI - The role of thymic stromal lymphopoietin in the immunopathogenesis of atopic dermatitis. AB - Atopic dermatitis (AD), a skin disease characterized by pruritus and chronic inflammation, results from a complex interplay between environmental and genetic factors. Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is believed to propagate AD lesions through T helper 2 (Th2) polarization. This paper describes the immunologic mechanisms involving TSLP in the generation of allergic disease. Specifically in AD, TSLP has been shown to be an inducer of myeloid dendritic cells, Th2 responses, mast cells, and natural killer T cells, thereby leading to cytokine secretion and the development of AD. We hope that further understanding of the TSLP pathway and its role in the pathogenesis of AD will lead to improved clinical management of AD in the future. PMID- 21672058 TI - Iranian blood donors' motivations and their influencing factors. AB - AIM: One of the challenges faced by blood transfusion services is the motivation of blood donors. The purpose of this study was to define the motivations of Iranian donors. METHODOLOGY: A total of 16 955 volunteers were studied to evaluate their motivation for blood donation in 2003 and 2004. A questionnaire was designed covering socio-demographic characteristics, history of blood donation and a list of reasons for donating. The donor physician determined the donor's motivation after an interview. Motivation was classified as internal (altruistic and religious beliefs) and external motives. RESULTS: The main motivations were 6629 (39.1%) altruistic, 6552 (38.6%) good for one's health and 1931 (11.4%) religious beliefs. It was shown that 8560 volunteers (50.5%) had internal motivations and 8395 (49.5%) had external motivations. Internal motivations were significantly higher in women, regular and educated donors. CONCLUSION: This study showed that internal motives are the main reason for blood donation in Iranian donors, especially in female, regular and high-educated donors. Thus, altruistic and religious messages can be emphasized in recruiting and retaining donors, particularly in this group. Nearly half of the donors were motivated by external factors--mainly to improve their own health status, especially in older donors. This may be due to a psychological impact in which they feel improvement in their general health. As voluntary non-remunerated blood donation is defined without considering the motivational factor, one might consider a new term such as 'internal motivated voluntary blood donors' in accordance with their motivation and efforts could be centered about recruiting these specific donors. PMID- 21672059 TI - Abstracts of the 23rd Congress of the International Association of Paediatric Dentistry. June 15-18, 2011. Athens, Greece. PMID- 21672060 TI - Sensitivity, specificity and predictive value of Confidence in Managing Patient Aggression Scale on de-escalating behaviour. PMID- 21672061 TI - The anxiety of Taiwanese women with or without continuity treatment after previous in vitro fertilisation failure. AB - AIMS AND OBJECTIVES: To compare the anxiety levels of Taiwanese women who continued with in vitro fertilisation treatment and those who discontinued treatment post-in vitro fertilisation failure. BACKGROUND: In vitro fertilisation is perceived as the last resort of infertility treatment. The impact of unsuccessful in vitro fertilisation treatment on psychological function has been documented; however, research comparing the levels of anxiety of women who cease and those who continue in vitro fertilisation post-failure is scant. DESIGN: A cross-sectional comparative study design was used. METHOD: Fifty-eight women in whom in vitro fertilisation had failed within the previous year were recruited to this study from a medical centre in northern Taiwan; 34 women continued treatment and 24 discontinued treatment. The State-Trait Anxiety Inventory was used to assess their levels of anxiety. RESULTS: Women in the group who continued treatment exhibited higher state and trait anxiety (TA) than women in the group who discontinued treatment (p < 0.005). The number and frequency of in vitro fertilisation cycles were significantly higher in the group who continued treatment than in those who did not. A strong positive correlation between state and TA (r = 0.8, p < 0.01) existed in both groups. CONCLUSIONS: Both groups exhibited considerable levels of anxiety; however, the women who continued in vitro fertilisation treatment had higher levels of anxiety than those who discontinued treatment. RELEVANCE TO CLINICAL PRACTICE: The level of anxiety of women who decide to continue in vitro fertilisation treatment should be assessed as early as possible and counselling services provided to women who experience in vitro fertilisation failure should concentrate more on relieving psychological distress. One year after discontinuing treatment, some women still experience considerable anxiety; therefore, the care and assistance provided to these women need to be continually evaluated. PMID- 21672062 TI - Prevalence and correlates of self-induced vomiting as weight-control strategy among adolescents in Taiwan. AB - AIMS: This study was designed to assess the prevalence and correlates of self induced vomiting to control body weight among adolescents in Taiwan. BACKGROUND: Over the past decades, the rate of obesity among children in Taiwan has nearly tripled. Educational authorities have devoted considerable effort to prevent the increase in childhood obesity. DESIGN: An observational exploratory design to investigate the problem of using unhealthy weight-reduction strategy. METHODS: This study consists of a cross-sectional study aimed at collecting national representative data. We chose 120 representative schools using a three-stage stratified systematic sampling design with probability proportionate to the size of the population in Taiwan. Participants consisted of 8673 girls and 7043 boys, aged 10-18 old. RESULTS: Of the participants, 13% reported using self-induced vomiting, the prevalence being highest in participants aged 10-12 (15.9%) and lowest in participants aged 16-18 (7.5%). Several factors were significantly and positively associated with the use of self-induced vomiting as a weight-loss strategy, specifically subjects who (1) watched television, used computer, surfed the Internet or played video games for greater than or equal to two hours/day, (2) consumed fried food every day and (3) ate night-time snacks every day (odds ratio = 1.55, 2.10 and 1.51, respectively; p < 0.05). Eating breakfast every day and sleeping for more than eight hours a day were both protective factors against the use of self-induced vomiting to control body weight (odds ratio = 0.43 and 0.86, respectively; p < 0.05). CONCLUSIONS: Self-induced vomiting was prevalent among adolescents who had tried to lose weight; sedentary lifestyle, shorter sleep length and unhealthy eating habits may contribute significantly to this behaviour among these adolescents. RELEVANCE TO CLINICAL PRACTICE: School nurses who are helping adolescents lose weight should also pay attention to the possibility they are using self-induced vomiting as a weight-control strategy. PMID- 21672063 TI - Transcript analysis and comparative evaluation of shaker and slowmo gene homologues from the European corn borer, Ostrinia nubilalis. AB - The movement and dispersal of larval Lepidoptera impact their survival and distribution within the natural landscape. Homologues of the Drosophila behaviour linked genes shaker (shkr) and slowmo (slmo) were identified from Ostrinia nubilalis (Lepidoptera: Crambidae). Onshkr was isolated as a 1610-nucleotide (nt) constitutively expressed transcript encoding a membrane-localized 469-amino-acid (aa) protein with a conserved tetramerization domain and the six-domain architecture necessary for the molecule to fold into an active K(+) channel. Three expressed splice variants of 682, 970 and 1604 nt were identified for the Onslmo gene, and encode predicted 141 and 228 aa proteins with a conserved protein of relevant evolutionary and lymphoid interest (PRELI) domain that may function in mitochondrial protein sorting and perinuclear protein localization. Onshkr and Onslmo protein sequences aligned within monophyletic lepidopteran groups. PMID- 21672064 TI - Sympatric bromeliad species (Pitcairnia spp.) facilitate tests of mechanisms involved in species cohesion and reproductive isolation in Neotropical inselbergs. AB - The roles of intra- and interspecific gene flow in speciation and species evolution are topics of great current interest in molecular ecology and evolutionary biology. Recent modelling studies call for new empirical data to test hypotheses arising from the recent shift from a 'whole-genome reproductive isolation' view to a 'genic' view of species and speciation. Particularly scarce (and thus of particular interest) are molecular genetic data on recently radiated, naturally hybridizing species in strongly structured and species-rich environments. Here, we studied four sympatric plant species (Pitcairnia spp.; Bromeliaceae) adapted to Neotropical inselbergs (isolated outcrops resembling habitat 'islands' in tropical rainforests) using nuclear and plastid DNA. Patterns of plastid DNA haplotype sharing and nuclear genomic admixture suggest the presence of both, incomplete lineage sorting and interspecific gene flow over extended periods of time. Integrity and cohesion of inselberg species of Pitcairnia are maintained despite introgression and in the face of extremely low within-species migration rates (N(e)m < 1 migrant per generation). Cross evaluation of our genetic data against published pollination experiments indicate that species integrity is maintained by the simultaneous action of multiple prezygotic barriers, including flowering phenology, pollinator isolation and divergent mating systems. Postzygotic Bateson-Dobzhansky-Muller incompatibilities appear to contribute to isolation, as suggested by asymmetric introgression rates of single loci. Our results suggest that incomplete lineage sorting, hybridization and introgression form integral aspects of adaptive radiation in Neotropical inselberg 'archipelagos'. Inselbergs with multiple closely related co occurring species should be of special interest to students of speciation in mountain systems, and to ongoing conservation programmes in the Atlantic Rainforest biodiversity hotspot. PMID- 21672065 TI - Genetic differentiation and phylogeographical structure of the Brachionus calyciflorus complex in eastern China. AB - Spatio-temporal patterns and processes of genetic differentiation in passively dispersing zooplankton are drawing much attention from both ecologists and evolutionary biologists. Two opposite phylogeographical scenarios have already been demonstrated in rotifers, which consist of high levels of genetic differentiation among populations even on small geographical scales on the one hand and the traditionally known cosmopolitanism that is associated with high levels of gene flow and long-distance dispersal via diapausing stages on the other hand. Here, we analysed the population genetic structure and the phylogeography of the Brachionus calyciflorus species complex in eastern China. By screening a total of 318 individuals from ten locations along a 2320-km gradient and analysing samples from two growing seasons, we aimed at focusing on both small- and large-scale patterns. We identified eight cryptic species and verified species status of two of these by sexual reproduction tests. Samples in summer and winter yielded different cryptic species. The distribution patterns of these genetically distinct cryptic species were diverse across eastern China, from full cosmopolitanism to local endemism. The two most abundant cryptic species BcWIII and BcSW showed a pattern of strong genetic differentiation among populations and no significant isolation by distance. Long-distance colonization, secondary contact and recent range expansion are probably responsible for the indistinct pattern of isolation by distance. Our results suggest that geographical distance is more important than temporal segregation across seasons in explaining population differentiation and the occurrence of cryptic species. We explain the current phylogeographical structure in the B. calyciflorus species complex by a combination of recent population expansion, restricted gene flow, priority effects and long-distance colonization. PMID- 21672066 TI - Mass mortality in Pacific oysters is associated with a specific gene expression signature. AB - Mass mortality events occur in natural and cultured communities of bivalve molluscs. The Pacific oyster, Crassostrea gigas, is a dominant species in many intertidal locations as well as an important aquacultured bivalve species, and for the last 50 years, adult oysters have suffered frequent and extreme mass mortality events during summer months. To investigate the molecular changes that precede these mortality events, we employed a novel nonlethal sampling approach to collect haemolymph samples from individual oysters during the period that preceded a mortality event. Microarray-based gene expression screening of the collected haemolymph was used to identify a mortality gene expression signature that distinguished oysters that survived the mortality event from those individuals that died during the event. The signature was cross-validated by comparing two separate episodes of mortality. Here, we report that near-mortality oysters can be distinguished from longer-lived oysters by the elevated expression of genes associated with cell death, lysosomal proteolysis, and cellular assembly and organization. These results show the potential utility of nonlethal sampling approaches for investigating the environmental causes of mortality in natural populations in the field, and for predicting when such events could occur and which individuals will be affected. PMID- 21672067 TI - Recent vicariance and the origin of the rare, edaphically specialized Sandhills lily, Lilium pyrophilum (Liliaceae): evidence from phylogenetic and coalescent analyses. AB - Establishing the phylogenetic and demographic history of rare plants improves our understanding of mechanisms that have led to their origin and can lead to valuable insights that inform conservation decisions. The Atlantic coastal plain of eastern North America harbours many rare and endemic species, yet their evolution is poorly understood. We investigate the rare Sandhills lily (Lilium pyrophilum), which is endemic to seepage slopes in a restricted area of the Atlantic coastal plain of eastern North America. Using phylogenetic evidence from chloroplast, nuclear internal transcribed spacer and two low-copy nuclear genes, we establish a close relationship between L. pyrophilum and the widespread Turk's cap lily, L. superbum. Isolation-with-migration and coalescent simulation analyses suggest that (i) the divergence between these two species falls in the late Pleistocene or Holocene and almost certainly post-dates the establishment of the edaphic conditions to which L. pyrophilum is presently restricted, (ii) vicariance is responsible for the present range disjunction between the two species, and that subsequent gene flow has been asymmetrical and (iii) L. pyrophilum harbours substantial genetic diversity in spite of its present rarity. This system provides an example of the role of edaphic specialization and climate change in promoting diversification in the Atlantic coastal plain. PMID- 21672068 TI - Population differences in levels of linkage disequilibrium in the wild. AB - Information about the levels of linkage disequilibrium (LD) in wild animal populations is still limited, and this is true particularly with respect to possible interpopulation variation in the levels of LD. We compared the levels and extent of LD at the genome-wide scale in three Siberian jay (Perisoreus infaustus) populations, two of which (Kuusamo and Yllas) represented outbred populations within the main distribution area of the species, whereas the third (Suupohja) was a semi-isolated, partially inbred population at the margin of the species' distribution area. Although extensive long-range LD (>20 cM) was observed in all three populations, LD generally decayed to background levels at a distance of 1-5 cM or c. 200-600 kb. The degree and extent of LD differed markedly between populations but aligned closely with both observed levels of within-population genetic variation and expectations based on population history. The levels of LD were highest in the most inbred population with strong population substructure (Suupohja), compared with the two outbred populations. Furthermore, the decay of LD with increasing distance was slower in Suupohja, compared with the other two populations. By demonstrating that levels of LD can vary greatly over relatively short geographical distances within a species, these results suggest that prospects for association mapping differ from population to population. In this example, the prospects are best in the Suupohja population, given that minimized marker genotyping and a minimum marker spacing of 1-5 cM (c. 200-600 kb) would be sufficient for a whole genome scan for detecting QTL. PMID- 21672069 TI - Photoplethysmography as a single source for analysis of sleep-disordered breathing in patients with severe cardiovascular disease. AB - Sleep-disordered breathing and Cheyne-Stokes breathing are often not diagnosed, especially in cardiovascular patients. An automated system based on photoplethysmographic signals might provide a convenient screening and diagnostic solution for patient evaluation at home or in an ambulatory setting. We compared event detection and classification obtained by full polysomnography (the 'gold standard') and by an automated new algorithm system in 74 subjects. Each subject underwent overnight polysomnography, 60 in a hospital cardiology department and 14 while being tested for suspected sleep-disordered breathing in a sleep laboratory. The sleep-disordered breathing and Cheyne-Stokes breathing parameters measured by a new automated algorithm system correlated very well with the corresponding results obtained by full polysomnography. The sensitivity of the Cheyne-Stokes breathing detected from the system compared to full polysomnography was 92% [95% confidence interval (CI): 78.6-98.3%] and specificity 94% (95% CI: 81.3-99.3%). Comparison of the Apnea Hyponea Index with a cutoff level of 15 shows a sensitivity of 98% (95% CI: 87.1-99.6%) and specificity of 96% (95% CI: 79.8-99.3%). The detection of respiratory events showed agreement of approximately 80%. Regression and Bland-Altman plots revealed good agreement between the two methods. Relative to gold-standard polysomnography, the simply used automated system in this study yielded an acceptable analysis of sleep- and/or cardiac-related breathing disorders. Accordingly, and given the convenience and simplicity of its application, this system can be considered as a suitable platform for home and ambulatory screening and diagnosis of sleep disordered breathing in patients with cardiovascular disease. PMID- 21672070 TI - Chronic partial sleep deprivation reduces brain sensitivity to glutamate N-methyl D-aspartate receptor-mediated neurotoxicity. AB - It has been hypothesized that insufficient sleep may compromise neuronal function and contribute to neurodegenerative processes. While sleep loss by itself may not lead to cell death directly, it may affect the sensitivity to a subsequent neurodegenerative insult. Here we examined the effects of chronic sleep restriction (SR) on the vulnerability of the brain to N-methyl-d-aspartate (NMDA) induced excitotoxicity. Animals were kept awake 20 h per day and were only allowed to rest during the first 4 h of the light phase, i.e. their normal circadian resting phase. After 30 days of SR all rats received a unilateral injection with a neurotoxic dose of NMDA into the nucleus basalis magnocellularis (NBM). Brains were collected for assessment of damage. In the intact non-injected hemisphere, the number of cholinergic cells in the NBM and the density of their projections in the cortex were not affected by SR. In the injected hemisphere, NMDA caused a significant loss of cholinergic NBM cells and cortical fibres in all animals. However, the loss of cholinergic cells was attenuated in the SR group as compared with the controls. These data suggest that, if anything, SR reduces the sensitivity to a subsequent excitotoxic insult. Chronic SR may constitute a mild threat to the brain that does not lead to neurodegeneration by itself but prepares the brain for subsequent neurotoxic challenges. These results do not support the hypothesis that sleep loss increases the sensitivity to neurodegenerative processes. PMID- 21672071 TI - Alcohol use, heavy episodic drinking and subsequent problems among adolescents in 23 European countries: does the prevention paradox apply? AB - AIMS: According to the prevention paradox, a majority of alcohol-related problems in a population can be attributed to low to moderate drinkers simply because they are more numerous than heavy drinkers, who have a higher individual risk of adverse outcomes. We examined the prevention paradox in annual alcohol consumption, heavy episodic drinking (HED) and alcohol-related problems among adolescents in 23 European countries. DESIGN AND SETTING: Survey data from the 2007 European School Survey Project on Alcohol and Drugs (ESPAD) among 16-year old students were analysed. PARTICIPANTS: A total of 38,370 alcohol-consuming adolescents (19,936 boys and 18,434 girls) from 23 European countries were included. MEASUREMENTS: The upper 10% and the bottom 90% of drinkers by annual alcohol intake, with or without HED, and frequency of HED, were compared for the distribution of 10 different alcohol-related problems. FINDINGS: Although the mean levels of consumption and alcohol-related problems varied largely between genders and countries, in almost all countries the heavy episodic drinkers in the bottom 90% of consumers by volume accounted for most alcohol-related problems, irrespective of severity of problem. However, adolescents with three or more occasions of HED a month accounted for a majority of problems. CONCLUSIONS: The prevention paradox, based on measures of annual consumption and heavy episodic drinking, seems valid for adolescent European boys and girls. However, a minority with frequent heavy episodic drinking accounted for a large proportion of all problems, illustrating limitations of the concept. As heavy episodic drinking is common among adolescents, our results support general prevention initiatives combined with targeted interventions. PMID- 21672072 TI - 'Closet' quit attempts: prevalence, correlates and association with outcome. AB - AIMS: To examine the (i) prevalence, (ii) predictors and (iii) cessation outcomes of smokers who engage in undisclosed quit attempts. DESIGN: Online survey (n = 524), with balanced recruitment of current smokers (55%) and past-year quitters (45%). Participants were daily smokers (current or previous) who had at least one quit attempt in the past year. MEASUREMENTS: Respondents were grouped on whether they did versus did not make advanced disclosure to others of their most recent quit attempt. FINDINGS: Almost half (n = 234; 45%) reported that their most recent quit attempt was undisclosed to anyone in advance. Those who planned their quit attempt in advance [odds ratio (OR) = 0.10; 95% confidence interval (CI): 0.05-0.23] and those who used behavioral treatment (OR = 0.14; 95% CI: 0.05 0.43) were less likely to make 'closet quit attempts', while those who rated their attempt as being serious (OR = 2.52; 95% CI: 1.16-5.46) and those who deemed social support to be unhelpful (OR = 1.91; 95% CI: 1.24-2.95) were more likely to make such attempts. Closet quit attempters were more likely to achieve 30 days of abstinence than were those who made advanced disclosure (67% versus 58%; adjusted OR 1.8; 95% CI: 1.1-2.8), but there were no differences for achieving 6 months of abstinence (52% versus 49%; adjusted OR 1.2; 95% CI: 0.7 2.0). CONCLUSIONS: Attempting to quit smoking without telling anyone in advance is common, and does not appear to impede success. These findings do not support blanket advice to smokers to tell others about pending quit attempts. PMID- 21672073 TI - Pale neurites, premature alpha-synuclein aggregates with centripetal extension from axon collaterals. AB - Progressive aggregation of alpha-synuclein (alphaS) from pale bodies (PBs) and extension from Lewy neurites (LNs) are candidate mechanisms for Lewy body (LB) formation. To identify how aggregation of alphaS is related to its extension along neurites, 60-um-thick brainstem sections of Parkinson disease (PD) patients were prepared for three-dimensional (3D) reconstruction of alphaS-positive neurites with neurofilament (NF) and thiazin red (TR), a fluorochrome with an affinity to solid aggregates. This demonstrated 3D layering of alphaS surrounded by NF with the aggregates probed by TR in the center, corresponding to the eosinophilic core of mature LBs. This eosinophilic/TR-positive profile, characteristically absent in PBs, premature counterpart of LBs, was similarly absent in some LNs. We would like to refer these premature LNs as "pale neurites" (PNs). Their premature nature was evidenced by 3D fluoroprofiling with quantum dots (QDs) and subsequent electron microscopic identification (3D-oriented immunoelectron microscopy) as loosely packed alphaS (QDs)-positive filaments. Quantification of LNs, frequently extended around branching axons, demonstrated that LNs are initiated at axon collaterals to extend centripetally into proximal segments. This branching-oriented extension of alphaS is related to its selective predisposition to systems with highly divergent axons, preferentially affected in PD, which may explain barely somatotopic manifestations of PD. PMID- 21672075 TI - Catheter ablation in a patient with paroxysmal atrial fibrillation and partial anomalous pulmonary vein connection. PMID- 21672074 TI - Gain and loss of extracellular molecules in sporadic inclusion body myositis and polymyositis--a proteomics-based study. AB - Sporadic inclusion body myositis (sIBM) contains non-necrotic myofibers that are surrounded and/or invaded by inflammatory cells. In this study we aimed to identify selective molecules that are present at this site. Myofibers of four biopsies of sIBM that were surrounded and/or invaded by inflammatory cells were microdissected, pooled and profiled by proteomic studies using mass spectrometry. Normal skeletal muscle tissue served as control. Based on the table of proteins that were detected in sIBM only, we selected nine extracellular matrix molecules and validated the results performing immunofluorescence. Seven out of nine proteins that were detected in sIBM by mass spectrometry showed different immunohistochemical results in myositis and normal controls. Of these, the small leucine-rich repeat proteins proline arginine-rich end leucine-rich repeat protein (PRELP) and biglycan were deposited precisely at myofibers surrounded and/or invaded by inflammatory cells both in sIBM and polymyositis. The basement membrane (BM) molecules merosin, perlecan, nidogen-2 and collagen IV were variably destroyed or increased at these sites. P component, which ensheathed all myofibers in normal controls, was absent from invaded myofibers. Similar to BM remodeling, the specific deposition of PRELP and biglycan may represent a mechanism to defend against immune attack. Loss of P component may affect the anchorage of the myofiber in the endomysium. PMID- 21672076 TI - Change in coronary sinus activation following catheter ablation: what is the mechanism? PMID- 21672077 TI - Over-expression of sphingosine kinase-1 enhances a progenitor phenotype in human endothelial cells. AB - OBJECTIVES: The use of endothelial progenitor cells in vascular therapies has been limited due to their low numbers present in the bone marrow and peripheral blood. The aim of this study was to investigate the effect of sphingosine kinase on the de-differentiation of mature human endothelial cells toward a progenitor phenotype. METHODS: The lipid enzyme sphingosine kinase-1 was lentivirally over expressed in human umbilical vein endothelial cells and cells were analyzed for progenitor phenotype and function. RESULTS: Sphingosine kinase-1 mRNA expression was induced approximately 150-fold with a resultant 20-fold increase in sphingosine kinase-1 enzymatic activity. The mRNA expression of the progenitor cell markers CD34, CD133, and CD117 and transcription factor NANOG increased, while the endothelial cell markers analyzed were largely unchanged. The protein level of mature endothelial cell surface markers CD31, CD144, and von Willebrand factor significantly decreased compared to controls. In addition, functional assays provided further evidence for a de-differentiated phenotype with increased viability, reduced uptake of acetylated low-density lipoprotein and decreased tube formation in Matrigel in the cells over-expressing sphingosine kinase-1. CONCLUSIONS: These findings suggest that over-expression of sphingosine kinase-1 in human endothelial cells promotes, in part, their de-differentiation to a progenitor cell phenotype, and is thus a potential tool for the generation of a large population of vascular progenitor cells for therapeutic use. PMID- 21672078 TI - Lymphangioma in an elderly patient: an unusual cause of axillary mass. PMID- 21672079 TI - Toxicity of local anesthetic drugs: a pediatric perspective. AB - The main mechanism of action of local anesthetics (LA) is to block sodium channels, thereby interrupting the propagation of nerve impulses. However, this action not only is localized to the sodium channels of nerve tissues involved with pain transmission but will have its effect on any tissue containing sodium channels. Thus, if there is a rapid absorption into the systemic circulation of locally injected LA or if LA inadvertently is injected into a blood vessel, then significant blockade of sodium channels in other tissues may also be blocked and serious complications may ensue. The two most important tissues associated with systemic toxicity of LA are the central nervous and the cardiovascular systems, which may lead to seizures, tachyarrhythmias, and ultimately death from apnea and cardiovascular collapse. The aim of this communication is to elucidate some issues that are associated with toxicity of LA and its treatment in the pediatric population. PMID- 21672080 TI - Chorioamnionitis: from pathogenesis to treatment. AB - Chorioamnionitis refers to inflammation of the amniochorionic membrane, and is a significant cause of maternal and neonatal morbidity. Chorioamnionitis most often occurs as a result of ascending infection, and is commonly associated with premature rupture of the membranes. Chorioamnionitis is generally the result of a polymicrobial infection, with Ureaplasma urealyticum, Mycoplasma hominis and Gram negative anaerobes being frequent causative organisms. The mainstay of treatment includes antimicrobial agents, antipyretics, expedition of delivery and supportive care. Further research is required to identify mechanistic pathways and early biomarkers that accurately predict women at higher risk of adverse maternal and neonatal outcomes, and that can thus lead to the development of additional treatment and prevention strategies. PMID- 21672081 TI - Is there any rationale for treatment of Staphylococcus aureus infections with antimicrobials that are determined to be ineffective in vitro? AB - Antimicrobial drug resistance remains a leading problem in modern healthcare, impacting on treatment options, mortality, infection control and economic issues. The introduction of new antimicrobial drugs has consistently been followed by the emergence of resistant bacteria. This review aims to answer the question of whether clinical improvement is likely if treatment of Staphylococcus aureus infections is attempted with an antimicrobial drug against which resistance is expressed in vitro (RD). Over time, S. aureus has acquired a broad range of antimicrobial resistance mechanisms, and methicillin-resistant S. aureus (MRSA) strains have become the most common multidrug-resistant healthcare-related infection-causing bacteria in Europe. As intention-to-treat studies with an RD would be unethical, only observational studies to evaluate the impact of RD therapy have been performed. Most of these studies bolster the assumption that RD therapy offers no benefit to the patient, but some do not show a detrimental effect. Limited antimicrobial treatment options for severe, invasive infections caused by MRSA might tempt physicians to use antimicrobials to which in vitro resistance is reported by the microbiological laboratory. Reasons for this non evidence-based approach might include better pharmacokinetic/pharmacodynamic parameters, lower toxicity and better bioavailability in specific compartments, and/or the assumption of increased in vivo susceptibility of those microorganisms reported as resistant in vitro. In vitro resistance of a bacterium to a drug implies that exposing this bacterium to that drug should result in a worse clinical outcome than would be obtained with a drug to which resistance has not been observed (SD). As a counterpoint to in vitro resistance breakpoints, the concept of clinical breakpoints is therefore briefly revisited in this review. In a nutshell, no evidence has been published that S. aureus infections can be reliably treated with RDs, either as a single administration or in combination therapy. PMID- 21672082 TI - Xenotropic murine leukaemia virus-related virus is not found in peripheral blood cells from treatment-naive human immunodeficiency virus-positive patients. AB - The human pathogen xenotropic murine leukaemia virus-related virus (XMRV) has been tentatively associated with prostate cancer and chronic fatigue syndrome. Unfortunately, subsequent studies failed to identify the virus in various clinical settings. To determine whether XMRV circulates in humans and the relationship with its host, we searched for the virus in 124 human immunodeficiency virus-infected patients who might have been exposed to XMRV, might be prone to infection as a result of progressive immunodeficiency, and had not yet been treated with antiretroviral drugs. Using nested PCR and single-step TaqMan real-time PCR, both designed on the XMRV gag gene, we could not find any positive samples. These findings add to the growing amount of scepticism regarding XMRV. PMID- 21672083 TI - Neonatal group B streptococcal disease: from pathogenesis to preventive strategies. AB - Streptococcus agalactiae, or group B streptococcus (GBS), remains the leading cause of neonatal sepsis and meningitis, as early-onset or late-onset diseases (EOD, LOD). Where consensus guidelines to detect and treat intrapartum women with GBS colonization have been widely adopted, incidence of neonatal EOD has dramatically declined. In response to both successful impacts on the incidence of GBS-EOD and analyses of missed opportunities, the first American guidelines for prevention issued in the 1990s have since been adapted in several stages to improve their efficacy. In some countries in Europe, nationwide guidelines, whether screening-based or risk-based, for the prevention of neonatal GBS diseases have also been issued and adopted, with the expected impact on incidence of GBS-EOD. In spite of universal screening, in spite of the great progress that has been made, GBS-EOD continues to occur and the GBS burden remains a significant public health issue. Continuous efforts to improve screening for GBS status continue to be important and may be able to take advantage of new rapid diagnostic technologies. The current screening-based strategy for prevention is highly effective but imperfect. Given the challenges, limitations and potential complications of maternal intrapartum prophylaxis, a new approach is still needed. Maternal immunization against GBS is an attractive alternative for the prevention of not only neonatal diseases but also stillbirths and maternal diseases. Vaccines against GBS may become the most effective and sustainable long term preventive strategy. PMID- 21672084 TI - In vitro activity of several antimicrobial peptides against colistin-susceptible and colistin-resistant Acinetobacter baumannii. AB - At present, colistin is among the few antibiotics effective against Acinetobacter baumannii clinical isolates. However, in the last few years, colistin-resistant A. baumannii strains have been isolated. Therefore, antibiotics effective against these usually pan-resistant colistin-resistant A. baumannii strains are required. The main objective of this study was to analyse the activity of 15 peptides against colistin-susceptible and colistin-resistant A. baumannii. The MICs were determined by microdilution. Among these 15 antimicrobial peptides (AMPs), melittin, indolicidin and mastoparan showed good activity against both colistin susceptible and colistin-resistant A. baumannii. Further studies of mastoparan with time-killing curves showed bactericidal activity at MIC *8 for both colistin susceptible and colistin-resistant A. baumannii. In conclusion, mastoparan may be a potential alternative for the treatment of colistin-resistant A. baumannii infections. PMID- 21672085 TI - Intrapleural therapy. AB - Numerous intrapleural therapies have been adopted to treat a vast array of pleural diseases. The first intrapleural therapies proposed focused on the use of fibrinolytics and DNase to promote fluid drainage in empyema. Numerous case series and five randomized controlled trials have been published to determine the outcomes of fibrinolytics in empyema treatment. In the largest randomized trial, the use of streptokinase had no reduction in mortality, decortication rates or hospital days compared with placebo in the treatment of empyema. Criticism over study design and patient selection may have potentially affected the outcomes in this study. The development of dyspnoea is common in the setting of malignant pleural effusions. Pleural fluid evacuation followed by pleurodesis is often attempted. Numerous sclerosing agents have been studied, with talc emerging as the most effective agent. Small particle size of talc should be avoided because of increased systemic absorption potentiating toxicity, such as acute lung injury. Over the past several years, the use of chronic indwelling pleural catheters have emerged as the preferred modality in the treating a symptomatic malignant pleural effusion. For patients with malignant-related lung entrapment, pleurodesis often fails due to the presence of visceral pleural restriction; however, chronic indwelling pleural catheters are effective in palliation of dyspnoea. Finally, the use of staphylococcal superantigens has been proposed as a therapeutic model for the treatment of non-small lung cancer. Intrapleural instillation of staphylococcal superantigens increased median survival by 5 months in patients with non-small cell lung cancer with a malignant pleural effusion. PMID- 21672086 TI - Early weight changes after birth and serum high-molecular-weight adiponectin level in preterm infants. AB - BACKGROUND: Extra-uterine growth retardation (EUGR) is associated with an increased risk for cardiometabolic diseases later in life. The aim of the present study was to examine the relationship between early weight change after birth in preterm infants and adiponectin (adn) multimeric complexes. METHODS: Subjects included 28 preterm infants born between weeks 24 and 33 of gestation. Serum adn multimeric complexes and the anthropometric parameters were measured in preterm infants at birth and at corrected term. RESULTS: Bodyweight (BW) decreased during the first week of life, with birthweight restored at approximately 19 days after birth. Nineteen of the subjects had EUGR at corrected term. Total (T)-adn, high molecular-weight (H)-adn, and the ratio of H-adn to T-adn (H/T-adn) were significantly elevated at corrected term than at birth. Postmenstrual age, birthweight, birth length and lowest BW after birth were positively correlated with H-adn and H/T-adn. Weight reduction after birth was negatively correlated with H-adn. Age to restore birthweight was negatively correlated with T-adn, H adn and H/T-adn. Stepwise multiple regression analysis indicated age to restore birthweight as the major predictor of T-adn and H-adn. DISCUSSION: Early weight changes after birth may alter serum adn level in preterm infants at corrected term. The appropriate nutritional support in the early postnatal period could reduce the prevalence of EUGR and the future risk for cardiometabolic diseases. PMID- 21672088 TI - Normal prostate-derived stromal cells stimulate prostate cancer development. AB - Stromal cells play a decisive role in regulating tumor progression. In this study, we assessed the significance of normal prostate-derived stromal cells (PSCs) in prostate cancer development. An in vivo s.c. tumor model was established as follows: Group 1, DU145 cells alone; Group 2, DU145 + PSCs; Group 3, DU145 cells alone injected into pre-castrated mice; and Group 4, DU145 + PSCs injected into pre-castrated mice. Following injection, tumors were only detectable in the first two groups, with more aggressive growth in Group 2 than in Group 1 (P < 0.05). Immunohistochemical analysis revealed significantly higher proliferation (P < 0.05), but not apoptosis or altered expression of androgen receptor in Group 2, as compared with Group 1. In vitro, DU145 cells isolated from Group 1 tumors showed lower viability and migratory capability than those from Group 2. cDNA microarray on isolated DU145 cells from Groups 1 and 2 revealed the differential expression of genes regulating cell cycle progression and cell mobility, including GADD45A, RHOV, KLK11, and PCK1. Our results suggest that stromal cells derived from normal prostate potentiate the development of tumor growth in vivo, which is achieved at least in part through the regulation of cell-cycle- and migration-related gene expression within the tumor cells. PMID- 21672089 TI - Hemorrhagic complications after systemic thrombolysis in acute stroke patients with abnormal baseline coagulation. AB - BACKGROUND AND PURPOSE: As patients with abnormal baseline coagulation were excluded from the large randomized trials, the safety of intravenous thrombolysis after ischaemic stroke in this patient population remains controversial. METHODS: We assessed the risk of symptomatic intracerebral hemorrhage (SICH) after systemic thrombolysis in patients with elevated baseline international normalized ratios (INRs) (>=1.3) or activated partial thromboplastin times (aPTT) (>37 s) using a prospectively recorded database from 2006 to 2010. An intracerebral hemorrhage leading to a deterioration of >=4 points on the National Institutes of Health Stroke scale (NIHSS) was classified as symptomatic. RESULTS: Amongst 688 patients (mean age, 72 years; median NIHSS, 11, median onset-to-treatment time, 135 min), 36 patients (5%) had an abnormal baseline coagulation. Twenty-nine of these patients had taken oral anticoagulants leading to elevated baseline INRs (median INR: 1.5; IQR 1.4-1.9), whereas seven patients had elevated aPTTs because of heparin therapy (n = 2), a coagulation disorder (n = 2), or for unknown reasons (n = 3). The rate of SICH did not differ significantly between patients with abnormal and normal baseline coagulation (4.4% vs. 0%; P = 0.6). Moreover, the in-hospital mortality was not significantly different between both treatment groups (8.3% in patients with abnormal baseline coagulation vs. 8.7% in patients with normal baseline coagulation, P = 1.0). CONCLUSIONS: The risk of SICH following intravenous thrombolysis after ischaemic stroke does not appear to be increased in patients with abnormal baseline coagulation. PMID- 21672090 TI - Patients' and health care professionals' attitudes towards the PINK patient safety video. AB - RATIONALE, AIMS AND OBJECTIVES: Patients can play an important role in reducing health care harm. Finding strategies to encourage patients to take on an active role in issues related to the quality and safety of their care is therefore essential. The aim of this study was to examine patients' and health care professionals' attitudes towards a video aimed at promoting patient involvement in safety-related behaviours. METHOD: A within-subjects design was used where participants were required to complete a questionnaire pre and post screening of a patient safety video. Participants are 201 patients aged 19-103 years (mean 52) and 95 health care professionals aged 23-48 years (mean 32). Main outcome measures include (i) patients' willingness to participate and perceived importance in participating in safety-related behaviours; and (ii) health care professionals' willingness to support patient involvement. RESULTS: After watching the video patients elicited more positive attitudes towards asking doctors and nurses if they had washed their hands and notifying them about issues to do with personal hygiene. No significant effects were observed in relation to patients notifying staff if they have not received their medication or if they were in pain or feeling unwell. In relation to health care professionals, doctors and nurses were more willing to support patient involvement in asking about hand hygiene after they had watched the video. CONCLUSION: Video may be effective at changing patients' and health care professionals' attitudes towards patient involvement in some, but not all safety-related behaviours. Our findings suggest video may be most effective at encouraging involvement in behaviours patients are less inclined to participate in and health care professionals are less willing to support. PMID- 21672092 TI - Life science must go on: standing up after the 311 disaster. AB - Just 1 month has passed since the biggest earthquake ever recorded in Japan occurred in the Tohoku-Kanto area. The earthquake was followed soon afterwards by an unexpected huge tsunami that destroyed many villages and towns near the coast. Perhaps even more seriously, nuclear power plants in Fukushima were damaged, resulting in electricity interruptions and radioactive contamination. It is sad that nearly thirty thousand people died or are still missing as a result of this disaster. I wish to express my deepest sympathy to all the victims and for those that are still being affected by what happened. The 311 earthquake and the ensuing problems have shaken us to the bottom of our hearts, not only physically but also mentally. As one of the persons present in the area at the time of the earthquake, I would like to report how I experienced the 311 disaster in our laboratory in Tohoku University and how this experience has changed my outlook on many things. PMID- 21672091 TI - Transcriptional regulation of the CADM1 gene by retinoic acid during the neural differentiation of murine embryonal carcinoma P19 cells. AB - CADM1 is a multifunctional cell adhesion molecule expressed predominantly in the nerve system, testis and lung. The expression of the Cadm1 gene is induced during the neural differentiation of murine embryonal carcinoma P19 cells by treatment with retinoic acid (RA). Here, we show that the suppression of CADM1 expression using RNAi interfered with P19 cell aggregation and reduced cell populations expressing MAP2 after RA treatment. Nonaggregated P19 cells were not differentiated into neurons, suggesting that CADM1 participates in the aggregate formation and neuronal differentiation of P19 in vitro. A luciferase assay of a series of deletion mutants of the CADM1 promoter localized an RA-responsive cis acting element to an approximately 90-bp fragment upstream of the translational start site. This element contains a putative binding site for transcription factor Sp1, named Sp1-binding site-1 (Sp1BS-1). Sp1BS-1 and adjacent Sp1-binding sites (Sp1BS-2 and Sp1BS-3) showed enhanced transcriptional activity by RA. Moreover, a chromatin immunoprecipitation showed that RA receptor (RAR)alpha was associated with a DNA fragment containing Sp1BS-1, whereas suppression of RARalpha expression using siRNA reduced the responsiveness of the CADM1 promoter to RA. These results suggest that Sp1 plays a critical role in RA-induced CADM1 expression through possible interaction with RARalpha in the neural differentiation of P19. PMID- 21672093 TI - Drug use and HIV in West Africa: a neglected epidemic. AB - Injecting drug use is poorly documented in West Africa. HIV prevalence studies are still rare. Recent studies show that drug injection is on the rise. There is an urgent need to take this component of the HIV epidemic into account and to establish adapted intervention strategies. PMID- 21672094 TI - Antibacterial activity of naringin derivatives against pathogenic strains. AB - AIMS: To study the antimicrobial activity of naringin (NAR), a flavonoid extracted from citrus industry waste, and NAR derivatives [naringenin (NGE), prunin and alkyl prunin esters] against pathogenic bacteria such as L. monocytogenes, E. coli O157:H7 and S. aureus. The relationship between the structure of the chemical compounds and their antagonistic effect was also analysed. METHODS AND RESULTS: The agar dilution technique and direct contact assaying were applied. NGE, prunin and NAR showed no antimicrobial activity at a concentration of 0.25 mmol l(-1). Similarly, fatty acids with a chain length between C2 and C18 showed no antimicrobial activity at the same concentration. However, prunin-6"-O-acyl esters presented high antibacterial activity, mainly against Gram-positive strains. This activity increased with increasing chain length (up to 10-12 carbon atoms). Alkyl prunin esters with 10-12 carbon atoms diminished viability of L. monocytogenes by about 3 log orders and S. aureus by 6 log orders after 2 h of contact at 37 degrees C and at a concentration of 0.25 mmol l(-1). The compounds examined were not effective against any of the Gram negative strains assayed, even at the highest concentration. CONCLUSIONS: Addition of sugars to the aglycone did not enhance its antimicrobial activity. Attachment of a saturated aliphatic chain with 10-12 carbon atoms to the A ring of the flavonoid (or to sugars attached to this ring), seems to be the most promising modification. In conclusion, alkyl prunin esters with a chain length of C10-C12 have promising features as antimicrobial agents because of their high antilisterial and antistaphylococcal activity. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that it is possible to obtain NAR derivatives with important antimicrobial activity, especially against Gram-positive pathogenic bacteria. It also provides guidelines on the structural modifications in similar molecules to enhance the antimicrobial activity. PMID- 21672095 TI - Multiresistance, beta-lactamase-encoding genes and bacterial diversity in hospital wastewater in Rio de Janeiro, Brazil. AB - AIMS: To investigate the bacterial diversity, antimicrobial resistance patterns and types of beta-lactamase genes in Gram-negative bacteria isolated from a hospital sewage treatment plant. METHODS AND RESULTS: Between July and December 2008, we collected samples from influent, clarifier tank effluent and chlorine contact tank effluent from a sewage treatment plant service of a hospital located in the city of Rio de Janeiro, Brazil. Of the 221 isolates identified, 40% were characterized as extended-spectrum beta-lactamase (ESBL) producers. Nonpathogenic micro-organisms and some pathogenic genera were quantified. The most common ESBL producing isolates were Klebsiella pneumoniae, Enterobacter cloacae and Escherichia coli. The bla(TEM), bla(SHV) and bla(CTX-M) genes were detected in 82, 48 and 67% of bacterial isolates, respectively. CONCLUSIONS: Results showed that hospital wastewater treatment plant is not suitable systems for the removal of all antibiotic-resistant micro-organisms present in hospital wastewaters. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides evidence that bacteria resistant to multiple antibiotics and their resistance genes that are usually present in the hospital can reach the environment, even after the use of hospital wastewater treatment plants. PMID- 21672096 TI - Effects of prefermented cereal-derived substrates (ground barley and rye bran) enriched with fungal gamma-linolenic acid on rumen fermentation parameters and lipid metabolism in vitro. AB - AIMS: To increase rumen output of gamma-linolenic acid (GLA), we used two cereal derived substrates, ground barley (GB) and rye bran (RB), enriched with fungal GLA as components of feed rations. We examined their effects on rumen fermentation patterns, lipid metabolism and the ciliated protozoan population in an artificial rumen. METHODS AND RESULTS: Four diets consisting of meadow hay (MH) plus unfermented (GB or RB) or prefermented (GB - TE or RB - TE) cereal derived substrates were fermented in an artificial rumen with ovine rumen inoculum. The cereal-derived substrates were prefermented with the fungus Thamnidium elegans (TE) by fungal solid-state fermentation. The diets with TE increased the rumen input of dietary GLA (mg day(-1)) from 0 to 21 (GB - TE) or 26 (RB - TE). Both experimental diets increased the rumen output of GLA (P < 0.001). Adverse effects on the ciliate population were observed. Both diets also had an effect on the fatty acids profile. Fermentation patterns were also affected with MH + RB - TE. CONCLUSION: Cereal-derived substrates enriched with GLA effectively enhanced the output of GLA in artificial rumen. SIGNIFICANCE AND IMPACT OF THE STUDY: The ability of the fungal strain T. elegans to grow and utilize various agro-industrial substrates might be useful in developing potential new animal diets enriched in GLA. PMID- 21672097 TI - Lactic acid bacteria in the inhibition of Fusarium graminearum and deoxynivalenol detoxification. AB - AIMS: Considering the agronomic and industrial damage that is caused by the fungus Fusarium graminearum, as well as the serious health risks it poses to humans and animals exposed to F. graminearum-produced mycotoxin deoxynivalenol (DON), this study evaluated the ability of different lactic acid bacteria (LAB) strains to inhibit fungal development and remove DON in vitro. METHODS AND RESULTS: The antagonistic effects of strains and commercial cultures of LAB were evaluated against F. graminearum IAPAR 2218 by the agar diffusion method. Additionally, the influence of the culture media, pH and the presence of lactic and acetic acid on these effects was tested. The capacity to remove DON by viable cells and heat-inactivated cells was analysed in liquid media and quantified by high performance liquid chromatography (HPLC). All isolated strains and commercial cultures inhibited the fungus and removed DON. The pH and culture media concentration did not influence these abilities, but heat inactivation had a strong effect on the ability of bacteria to remove mycotoxin. CONCLUSIONS: The isolated bacteria are able to inhibit F. graminearum growth and remove DON in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests potential application of the isolated LAB strains in the inhibition of F. graminearum IAPAR 2218 and DON removal in vitro. PMID- 21672098 TI - Flow cytometry to assess biochemical pathways in heat-stressed Cronobacter spp. (formerly Enterobacter sakazakii). AB - AIMS: Using a flow cytometry (FC)-based approach in combination with four selected fluorescent probes, the biochemical pathway activated following the adaptation of Cronobacter spp. to lethal heat stress was investigated. This approach assessed the physiological changes induced in four strains of Cronobacter spp. METHODS AND RESULTS: Using the commercially available live/dead viability assessment fluorescence probes, live, injured or dead bacterial cells were studied. Cellular respiration and membrane potential were evaluated using the dye-labelled probe 3,3'-dihexylocarbocyanine iodide, metabolic activity was evaluated using a fluorescein diacetate (FDA) probe, intracellular pH changes were measured using a carboxy-fluorescein diacetate succinimidyl ester probe, and reactive oxygen species were measured using a hydroethidine fluorescent probe. Adaptation to lethal heat stress induced physiological changes that potentially improve the survival of Cronobacter spp. CONCLUSIONS: These data showed that in situ assessment of physiological behaviour of lethally stressed cells using multiparameter FC is a useful, rapid and sensitive tool to study and assess the viability and physiological state of Cronobacter cells. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that FC is a valuable tool in the study of physiological aspects of increased survival because of sublethal adaptation to heat. PMID- 21672099 TI - Molecular detection of enterotoxins E, G, H and I in Staphylococcus aureus and coagulase-negative staphylococci isolated from clinical samples of newborns in Brazil. AB - AIMS: The objective of this study was to investigate the detection of SEE, SEG, SEH and SEI in strains of Staphylococcus aureus and coagulase-negative staphylococci (CNS) using RT-PCR. METHODS AND RESULTS: In this study, 90 Staph. aureus strains and 90 CNS strains were analysed by PCR for the detection of genes encoding staphylococcal enterotoxins (SE) E, G, H and I. One or more genes were detected in 54 (60%) Staph. aureus isolates and in 29 (32.2%) CNS isolates. Staphylococcus epidermidis was the most frequently isolated CNS species (n = 64, 71.1%), followed by Staphylococcus warneri (n = 8, 8.9%) and other species (Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus lugdunensis, Staphylococcus simulans, Staphylococcus saprophyticus and Staphylococcus xylosus: n = 18, 20%). The genes studied were detected in Staph. epidermidis, Staph. warneri, Staph. haemolyticus, Staph. hominis, Staph. simulans and Staph. lugdunensis. The highest frequency of genes was observed in Staph. epidermidis and Staph. warneri, a finding indicating differences in the pathogenic potential between CNS species and highlighting the importance of the correct identification of these micro-organisms. RT-PCR used for the detection of mRNA revealed the expression of SEG, SEH and/or SEI in 32 (59.3%) of the 90 Staph. aureus isolates, whereas expression of some of these genes was observed in 10 (34.5%) of the 90 CNS isolates. CONCLUSIONS: Staphylococcus epidermidis was the most toxigenic CNS species. Among the other species, only Staph. warneri and Staph. lugdunensis presented a positive RT-PCR result. PCR was efficient in confirming the toxigenic capacity of Staph. aureus and CNS. SIGNIFICANCE AND IMPACT OF THE STUDY: This study permitted to confirm the toxigenic capacity of CNS to better characterize the pathogenic potential of this group of micro-organisms. In addition, it permitted the detection of SEG, SEH and SEI, enterotoxins that cannot be detected by commercially available immunological methods. PMID- 21672100 TI - Characterization of Streptococcus salivarius growth and maintenance in artificial saliva. AB - AIMS: To help gain a better understanding of factors influencing the establishment within the oral cavity of Streptococcus salivarius K12, a commensal oral bacterium, we characterized its behaviour in artificial saliva. METHODS AND RESULTS: Streptococcus salivarius K12 was grown in artificial saliva complemented with a representative meal, under oral pH and temperature conditions. Exponential growth phase was characterized by a high specific growth rate (2.8 h(-1)). During maintenance phase, an uncoupling between growth and lactic acid production occurred, which allowed maintaining viability (95%), intracellular pH (6.6) and membrane polarisation (95%), and thus proton motive force. However, in late stationary phase, viability (64%) and vitality were degraded as a result of lower synthesis of energetic and glycogen-related proteins as compared to a richer medium. CONCLUSIONS: Streptococcus salivarius was able to rapidly grow in complemented artificial saliva. Nevertheless, a degradation of its physiological state was observed in late-stationary phase. SIGNIFICANCE AND IMPACT OF THE STUDY: This work demonstrates, for the first time, that artificial saliva was a convenient medium that permitted Strep. salivarius to grow in oral conditions (physico-chemical environment, addition of meals) but not to maintain cellular viability and vitality in starvation conditions. PMID- 21672101 TI - Genome shuffling enhances biocontrol abilities of Streptomyces strains against two potato pathogens. AB - AIMS: To employ the genome shuffling technique for improving the phenotype of a biocontrol control agent of the genus Streptomyces. METHODS AND RESULTS: Two rounds of genome shuffling (GS) were carried out with Streptomyces melanosporofaciens EF-76, a geldanamycin producer. Six fusants that showed optimized in vitro antagonistic activity against Streptomyces scabies or Phytophthora infestans, two important pathogens of potato crops, were selected. All selected fusants retained the capacity to produce geldanamycin, but none overproduced this antibiotic. The higher antagonism ability appeared to result from a diversification of secreted metabolites. Seven or eight metabolites were detected in the HPLC profiles of parental strains, whereas 12-15 were detected in fusant strains. Biocontrol assays revealed that four of six fusants protected tubers more efficiently than parental strains. CONCLUSIONS: GS emerged as an elegant and rapid tool to optimize the antagonistic ability of Streptomyces strains. Optimization of the in vitro antagonistic activity against plant pathogens appears to be an effective approach to select for improved biocontrol agents. The enhanced phenotype did not depend on an overproduction of a specific antibiotic but rather on the secretion of a wider variety of secondary metabolites. SIGNIFICANCE AND IMPACT OF THE STUDY: Improved capacities of a biocontrol agent compensate for the lack of efficient chemical control of potato scab. PMID- 21672102 TI - In vitro analyses are not reliable predictors of the plant growth promotion capability of bacteria; a Pseudomonas fluorescens strain that promotes the growth and yield of wheat. AB - AIMS: In this study, we set out to identify bacteria that can be used to promote the growth of cereals, while concurrently investigating the merits of using a range of such tests to preselect bacteria for glasshouse studies. METHODS AND RESULTS: A panel of 15 strains isolated from the rhizosphere and phyllosphere of cereals was tested for the ability to improve the germination of wheat seeds and for production of a range of factors associated with plant growth promotion. In parallel, all bacteria were tested for their ability to improve biomass and grain yield when applied as a soil amendment in glasshouse trials. CONCLUSIONS: There was no significant correlation between growth promotion potential in the glasshouse and the results of either the phenotypic or the germination tests. Glasshouse tests identified that only one strain, Pseudomonas fluorescens strain MKB37, gave a significant increase in head weight and grain yield. SIGNIFICANCE AND IMPACT OF THE STUDY: While this study has identified a candidate for further field tests, it has also highlighted the fact that the modes of action for plant growth-promoting bacteria (PGPB) are still not fully understood, and that there is no efficient and effective screening method for identifying PGPB by laboratory tests. PMID- 21672103 TI - Recovery of graft steatosis and protein-losing enteropathy after biliary diversion in a PFIC 1 liver transplanted child. AB - PFIC 1 is a genetic disorder characterized by hepatic and gastrointestinal disease, often requiring LT during childhood. Extrahepatic symptoms, such as diarrhea and malabsorption, do not improve or may be aggravated after LT, as graft steatosis or steatohepatitis as consequences of the interaction between transplanted liver and native bowel. We describe a patient with PFIC 1 who presented with cholestasis in infancy, who developed intractable pruritus and liver fibrosis. The child underwent living donor LT at 3.6 yr of age, and he early developed severe refractory diarrhea, secondary malabsorption with protein losing enteropathy, and an early fatty liver disease trough graft steatohepatitis. As the response to cholestyramine was unsatisfactory, we decided to perform an EBD by using the jejunal loop used for the cholangiojejunostomy. Diarrhea resolved rapidly after surgery. He remained well after six months following biliary diversion, with normal stool output and no protein loss. We documented a dramatic improvement of graft steatosis at histology as well as normalization of liver function test. EBD can be considered a valuable treatment option to avoid organ disfunction and loss in PFIC 1 transplanted patients who develop graft steatohepatitis. PMID- 21672104 TI - Age-dependent changes of serum soluble CD30 concentration in children. AB - CD30 was originally described as a marker on Reed-Sternberg cells in Hodgkin lymphoma. The extracellular portion of CD30 is proteolytically cleaved from CD30+ cells, to produce a soluble form of the molecule (sCD30) detectable in serum. Measurement of sCD30 concentration in serum has been suggested to be a potential tool in monitoring of inflammatory status in variety of diseases. Several investigators reported the relevance for sCD30 as a predictive marker for allograft rejection following organ transplantation. The aim of the study was to verify whether sCD30 serum concentrations may be affected by an age in healthy children. Heparinized venous blood was taken from 78 healthy children. For the analysis of sCD30 levels, the commercially available sCD30 ELISA was used. The sCD30 was detected in all serum samples and concentrations ranged from 6.75 to 68.07ng/mL. The statistical analysis of all individuals showed that sCD30 concentration was significantly age depended (r=-0.618, p<0.0001). When sCD30 concentrations were analyzed in regard to gender, no significant differences were identified in age subgroups. PMID- 21672105 TI - Successful rescue of refractory acute antibody-mediated renal allograft rejection with splenectomy--a case report. AB - Highly sensitized patients receive fewer kidney transplants and have a high risk for severe rejection with increased rates of graft loss. We present a highly sensitized child who after desensitization protocol received a kidney transplant and developed refractory acute antibody-mediated rejection. He failed to respond to standard therapy and needed an urgent splenectomy as rescue therapy. Our patient, an 18-yr-old AA male with ESRD due to obstructive uropathy received a second DD transplant. The allograft functioned immediately with SCr 1.4 mg/dL on day #5. On day #8, he was re-admitted with fever, oligoanuria, and renal failure. He was started on methylprednisolone pulse, thymoglobulin, intravenous immunoglobulin, and PP. The transplant kidney biopsy revealed features suggestive of acute AMR. On day #14, the patient remained dialysis dependent with no response to therapy. He underwent an urgent splenectomy and a slow increase in urine output and GFR was noted. The SCr one month post-splenectomy was 1.1 mg/dL. At one yr post-txp, his GFR remained stable with SCr 0.9 mg/dL on tacrolimus, mycophenolate mofetil, and prednisone. Urgent splenectomy successfully reversed refractory acute AMR, in our highly sensitized patient with second renal transplant. PMID- 21672106 TI - Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type. AB - Congenital nephrotic syndrome (CNS) of the Finnish type due to mutation in the NPHS-1 gene results in massive proteinuria due to structural abnormality in the glomerular slit diaphragm, and is usually refractory to immunosuppressive therapy. Patients eventually require bilateral nephrectomy and renal replacement therapy, with transplantation being the ultimate goal. Post-transplant recurrence of nephrotic syndrome occurs in about 25% of children and is thought to be immune mediated secondary to antibodies formed against the nephrin protein in renal allograft. Conventional therapy with calcineurin inhibitors (CNI), cyclophosphamide and corticosteroids with or without plasmapheresis often fails to achieve remission resulting in graft loss in 12-16%. There is limited experience with use of rituximab (RTX) in pediatric organ transplant recipients. We report the first case of post-transplant recurrence of nephrotic syndrome in a 4-yr-old child with CNS due to NPHS-1 mutation in whom CNI, corticosteroid and cyclophosphamide therapy was unsuccessful, but who achieved remission after depletion of B cells with RTX, associated with a decrease in the level of anti nephrin antibodies. The child remains in remission 5 yr following treatment. Our experience suggests that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation in children with CNS. PMID- 21672107 TI - Diet, physical, and biochemical characteristics of children and adolescents with type 1 diabetes: relationship between dietary fat and glucose control. AB - BACKGROUND: Nutritional habits may significantly influence glycemic control and cardiovascular risk factors in youth with type 1 diabetes (T1D). AIMS: To assess dietary intake, cardiovascular risk factors, and the association between diet composition and glycemic control in Italian youth with T1D. METHODS: Subjects included 114 youth aged 6-16 yr with T1D receiving a routine treatment program with nutrition counseling and 448 controls. Cross-sectional measures included dietary intake, anthropometry, blood pressure, lipid profile, and, in children with diabetes, HbA1c. RESULTS: In prepubertal children, BMI, subcutaneous skinfolds, the prevalence of overweight/obesity, and LDL cholesterol (LDL-CH) were significantly lower in patients than in controls, whereas HDL cholesterol (HDL-CH) was higher. Pubertal boys with T1D did not differ significantly from controls in either anthropometry or lipid profile. Pubertal girls with T1D had a higher BMI and higher triceps skinfolds than controls but not significantly different prevalence of overweight/obesity or lipid profile. Compared to controls, participants with T1D had a lower intake of lipids and simple carbohydrates, a higher ratio of unsaturated/saturated fats and fibre, and a dietary intake closer to the National Reference Dietary Intakes (RDIs). The odds of having an HbA1c higher than 7.5, adjusted for BMI, lipid, and fibre intake, increases by 53% for every 1% increase of energy intake from saturated fat in the diet and by 30% for every year of duration of diabetes. CONCLUSIONS: Youth with T1D having regular nutritional counseling had a diet closer to RDIs than controls and not different cardiovascular risk factors. High saturated fatty acid intake was associated with poor blood glucose control. PMID- 21672108 TI - Quality of life in children with diabetes and celiac disease: minimal impact of the 'double diagnosis'. AB - BACKGROUND: Despite the advent of sensitive testing to detect celiac disease (CD), screening in type 1 diabetes (T1D) remains controversial. Many diabetes clinics are apprehensive about the prospect of introducing a second illness requiring intensive lifestyle changes in patients and families already managing a chronic condition, especially in asymptomatic patients. OBJECTIVE: To determine the impact of managing CD + T1D on quality of life in families, with attention to the effect of adherence with a gluten-free diet (GFD) and metabolic control. PATIENTS AND METHODS: Cross-sectional assessment using a validated self-reported quality of life measure: 28 children with biopsy-proven CD + T1D were compared with 40 subjects with T1D aged 8-18 yr. Parental and child reports were assessed as well as symptoms at the time of CD diagnosis and adherence with a GFD at the quality of life assessment. RESULTS: No significant differences in quality of life were observed between subjects with established CD + T1D and subjects with T1D alone. Parents of children with CD + T1D reported lower social functioning scores than parents of children with T1D (p = 0.03). In the CD + T1D group no differences in quality of life were observed with regard to age at CD diagnosis, CD duration, or on the basis of adherence with a GFD. CONCLUSIONS: The additional diagnosis of CD has minimal impact on quality of life in children with T1D; however, parents of CD + T1D children did express greater concern about their child's social functioning. PMID- 21672109 TI - . . . of beancounters and men . . . PMID- 21672110 TI - Research and evaluation priorities: the report of the Productivity Commission on Care of Older People. PMID- 21672111 TI - Productivity commission draft report 'caring for older Australians': what could a new system look like? PMID- 21672112 TI - Draft report of the productivity commission inquiry into caring for older Australians. PMID- 21672113 TI - Sarcopenia and sarcopenic obesity: is it time the health system accepted fitness of older people as a health responsibility? PMID- 21672114 TI - Clinical outcomes in residential care: setting benchmarks for quality. AB - AIM: Australian residential aged care does not have a system of quality assessment related to clinical outcomes, or comprehensive quality benchmarking. The Residential Care Quality Assessment was developed to fill this gap; and this paper discusses the process by which preliminary benchmarks representing high and low quality were developed for it. METHODS: Data were collected from all residents (n = 498) of nine facilities. Numerator-denominator analysis of clinical outcomes occurred at a facility-level, with rank-ordered results circulated to an expert panel. The panel identified threshold scores to indicate excellent and questionable care quality, and refined these through Delphi process. RESULTS: Clinical outcomes varied both within and between facilities; agreed thresholds for excellent and poor outcomes were finalised after three Delphi rounds. CONCLUSION: Use of the Residential Care Quality Assessment provides a concrete means of monitoring care quality and allows benchmarking across facilities; its regular use could contribute to improved care outcomes within residential aged care in Australia. PMID- 21672115 TI - The association between demographic and oral health-related quality of life factors and dental care attendance among underprivileged older people. AB - AIM: In order to identify whether demographic and oral health-related quality of life factors are associated with dental care attendance among an underprivileged older population, a comparison was performed between people who have and have not attended dental care. METHODS: A cross-sectional purposive sample of 344 older underprivileged people comprised the study population. The dependent variable was dental care attendance. The 14-item version of the Oral Health Impact Profile index (OHIP-14) was used as the independent variable, together with other social and general variables, using a structured interview. RESULTS: The variables that were significantly associated with dental care attendance were family status (not married, the highest attendance), dwelling location (living at home, the highest attendance), caregiver (family member, the highest attendance), place of birth (Western countries, the highest attendance) and income (pension, the highest attendance). Sex, welfare support, functional ability, education, age and OHIP-14 were not associated with dental care attendance. CONCLUSIONS: Attending dental care was not associated with oral health-related quality of life measured by OHIP 14. Several socioeconomic variables were strongly associated. PMID- 21672116 TI - Approving for a community aged care package: experiences and perceptions of six metropolitan aged care assessment service teams. AB - AIM: To establish whether the experiences and perceptions of different metropolitan Aged Care Assessment Service (ACAS) teams when approving people for Community Aged Care Packages (CACPs) were similar. METHODS: Six semi-structured 30-minute group interviews were completed. RESULTS: ACAS team approval processes for CACPs were similar. The primary criterion for approval was need for case management. Many factors, however, impinged on the approval process. Barriers to making approvals included long waiting times, a lack of confidence in the priority rating system, and consideration of whether a person was better off with Home and Community Care services because of the impact of the Australian Government's Cost Recovery policy. CONCLUSION: ACAS teams have competing considerations when approving a person for a CACP. In particular, structural barriers, such as cost recovery policies, can have a significant negative impact on approval decisions. PMID- 21672117 TI - Spirituality, religion, social support and health among older Australian adults. AB - AIM: To examine the impact of perceived importance of spirituality or religion (ISR) and religious service attendance (RSA) on health and well-being in older Australians. METHODS: A cross-sectional survey of 752 community-dwelling men and women aged 55-85 years from the Hunter Region, New South Wales. RESULTS: Overall, 51% of participants felt spirituality or religion was important in their lives and 24% attended religious services at least 2-3 times a month. In univariate regression analyses, ISR and RSA were associated with increased levels of social support (P < 0.001). However, ISR was also associated with more comorbidities (incidence-rate ratio= 1.2, 95% confidence interval 1.08-1.33). There were no statistically significant associations between ISR or RSA and other measures such as mental and physical health. CONCLUSION: Spirituality and religious involvement have a beneficial impact on older Australians' perceptions of social support, and may enable individuals to better cope with the presence of multiple comorbidities later in life. PMID- 21672118 TI - Association between sarcopenia and mortality in healthy older people. AB - AIM: To evaluate the association between loss of fat-free mass and mortality among older people. METHODS: Information of healthy Chilean older people evaluated by dual energy X-ray absorptiometry was used, identifying those who died in a period of 12 years. A Cox proportional hazards model was used to identify mortality predictors. Life tables were constructed calculating survival using predictive variables. RESULTS: Information from 1413 participants aged 74.3 +/- 5.6 years (1001 women), was obtained. During the follow-up (median 1594 days), 221 participants died. The Cox model identified age and appendicular fat free mass as predictors of death (hazard ratios 1.08 and 0.85, respectively). According to life tables, participants in the lower sex-specific quartile for appendicular fat-free mass/height had significantly higher mortality. This association was significant among participants aged over 73 years. CONCLUSION: A low fat-free mass was predictive of mortality in older people. PMID- 21672119 TI - Lichtenstein hernia repair under different anaesthetic techniques with special emphasis on outcomes in older people. AB - BACKGROUND: This study compared local (LA) and general anaesthesia (GA) for elective inguinal hernia repair with specific reference to older people (>=70 years). METHODS: A total of 470 inguinal hernia repairs were compared for demographics, operating time, day case rates and complications. Subgroup analysis was performed to evaluate outcomes in <70 and >70 years. RESULTS: A total of 288 LA and 182 GA repairs were performed. One hundred and forty-four (30.6%) patients were older than 70 years of which 80 (55%) were ASA (American Society of Anaesthesiologists) grades 3 and 4. Older (>=70 years) ASA grade 3 and 4 patients are more likely to undergo surgery under LA than GA (63% LA, 35% GA, P = 0.005) with higher day case rates of 81% LA, 33% GA, P = 0.0001). No significant difference in early complications, satisfaction rate and long-term recurrence rates were noted between the two groups. CONCLUSIONS: LA inguinal hernia repair has significant short-term advantages and facilitates day surgery in older patients. LA should be the preferred option in the older patients. PMID- 21672120 TI - Australian and New Zealand Society for Geriatric Medicine. Position statement - dysphagia and aspiration in older people*. PMID- 21672121 TI - Phylogenetic limiting similarity and competitive exclusion. AB - One of the oldest ecological hypotheses, proposed by Darwin, suggests that the struggle for existence is stronger between more closely related species. Despite its long history, the validity of this phylogenetic limiting similarity hypothesis has rarely been examined. Here we provided a formal experimental test of the hypothesis using pairs of bacterivorous protist species in a multigenerational experiment. Consistent with the hypothesis, both the frequency and tempo of competitive exclusion, and the reduction in the abundance of inferior competitors, increased with increasing phylogenetic relatedness of the competing species. These results were linked to protist mouth size, a trait potentially related to resource use, exhibiting a significant phylogenetic signal. The likelihood of coexistence, however, was better predicted by phylogenetic relatedness than trait similarity of the competing species. Our results support phylogenetic relatedness as a useful predictor of the outcomes of competitive interactions in ecological communities. PMID- 21672122 TI - The oxidative and nitrosative stress defence network of Wolinella succinogenes: cytochrome c nitrite reductase mediates the stress response to nitrite, nitric oxide, hydroxylamine and hydrogen peroxide. AB - Microorganisms employ diverse mechanisms to withstand physiological stress conditions exerted by reactive or toxic oxygen and nitrogen species such as hydrogen peroxide, organic hydroperoxides, superoxide anions, nitrite, hydroxylamine, nitric oxide or NO-generating compounds. This study identified components of the oxidative and nitrosative stress defence network of Wolinella succinogenes, an exceptional Epsilonproteobacterium that lacks both catalase and haemoglobins. Various gene deletion-insertion mutants were constructed, grown by either fumarate respiration or respiratory nitrate ammonification and subjected to disc diffusion, growth and viability assays under stress conditions. It was demonstrated that mainly two periplasmic multihaem c-type cytochromes, namely cytochrome c peroxidase and cytochrome c nitrite reductase (NrfA), mediated resistance to hydrogen peroxide. Two AhpC-type peroxiredoxin isoenzymes were shown to be involved in protection against different organic hydroperoxides. The phenotypes of two superoxide dismutase mutants lacking either SodB or SodB2 implied that both isoenzymes play important roles in oxygen and superoxide stress defence although they are predicted to reside in the cytoplasm and periplasm respectively. NrfA and a cytoplasmic flavodiiron protein (Fdp) were identified as key components of nitric oxide detoxification. In addition, NrfA (but not the hybrid cluster protein Hcp) was found to mediate resistance to hydroxylamine stress. The results indicate the presence of a robust oxidative and nitrosative stress defence network and identify NrfA as a multifunctional cytochrome c involved in both anaerobic respiration and stress protection. PMID- 21672123 TI - Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo controlled trial. AB - AIMS: Progressive deterioration of glycaemic control in type 2 diabetes mellitus (T2DM) often requires treatment intensification. Dapagliflozin increases urinary glucose excretion by selective inhibition of renal sodium-glucose cotransporter 2 (SGLT2). We assessed the efficacy, safety and tolerability of dapagliflozin added to glimepiride in patients with uncontrolled T2DM. METHODS: This 24-week, randomized, double-blind, placebo-controlled, parallel-group, international, multicentre trial (ClinicalTrials.gov NCT00680745) enrolled patients with uncontrolled T2DM [haemoglobin A1c (HbA1c) 7-10%] receiving sulphonylurea monotherapy. Adult patients (n = 597) were randomly assigned to placebo or dapagliflozin (2.5, 5 or 10 mg/day) added to open-label glimepiride 4 mg/day for 24 weeks. Primary endpoint was HbA1c mean change from baseline at 24 weeks. Secondary endpoints included change in body weight and other glycaemic parameters. RESULTS: At 24 weeks, HbA1c adjusted mean changes from baseline for placebo versus dapagliflozin 2.5/5/10 mg groups were -0.13 versus -0.58, -0.63, 0.82%, respectively (all p < 0.0001 vs. placebo by Dunnett's procedure). Corresponding body weight and fasting plasma glucose values were -0.72, -1.18, 1.56, -2.26 kg and -0.11, -0.93, -1.18, -1.58 mmol/l, respectively. In placebo versus dapagliflozin groups, serious adverse events were 4.8 versus 6.0-7.1%; hypoglycaemic events 4.8 versus 7.1-7.9%; events suggestive of genital infection 0.7 versus 3.9-6.6%; and events suggestive of urinary tract infection 6.2 versus 3.9-6.9%. No kidney infections were reported. CONCLUSIONS: Dapagliflozin added to glimepiride in patients with T2DM uncontrolled on sulphonylurea monotherapy significantly improved HbA1c, reduced weight and was generally well tolerated, although events suggestive of genital infections were reported more often in patients receiving dapagliflozin. PMID- 21672124 TI - Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*). AB - AIM: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily non-renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM). METHODS: Linagliptin pharmacokinetics was studied under single-dose and steady-state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end-stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM). RESULTS: Renal excretion of unchanged linagliptin was <7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration-time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20-60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and C(max) values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from 14-15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r(2) = 0.18) was seen between creatinine clearance and steady-state exposure. CONCLUSIONS: Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM. PMID- 21672125 TI - Antagonistic effect of atipamezole, flumazenil and naloxone following anaesthesia with xylazine, tramadol and tiletamine/zolazepam combinations in pigs. AB - OBJECTIVE: To evaluate the antagonistic effects of atipamezole (ATI), flumazenil (FLU) and naloxone (NAL) alone and in various combinations following administration of tiletamine-zolazepam-xylazine-tramadol. STUDY DESIGN: Prospective, experimental, randomized cross-over study. ANIMALS: Eight Chinese miniature pigs (three females and five males) mean age 8 (range 7-10) months and bodyweight 57.5 (52.4-62.1) kg. METHODS: All animals were anaesthetized with tiletamine/zolazepam (3.0 mg kg(-1)), xylazine (1.2 mg kg(-1)) and tramadol (1.6 mg kg(-1)) given intramuscularly (IM). Thirty minutes later, one of eight treatments was administered IM: saline control, ATI (0.12 mg kg(-1)), FLU (0.1 mg kg(-1)), NAL (0.03 mg kg(-1)), ATI-FLU, FLU-NAL, ATI-NAL or ATI-FLU-NAL. After injection of antagonists the following times were recorded: to recovery of the palpebral, pedal and tail clamp reflexes, to head movement, sternal recumbency, standing and walking. Posture, sedation, analgesia, jaw relaxation and auditory response were scored at set times until 120 minutes after injection of antagonists. Heart rates, respiratory rates and rectal temperature were measured at those times. Data were analyzed by anova for repeated measures, followed by the Tukey's test to compare differences between means, or by Kruskal-Wallis test as appropriate. RESULTS: FLU, NAL alone, or FLU-NAL did not effectively antagonize anaesthesia induced by tiletamine/zolazepam-xylazine-tramadol. ATI, ATI-FLU, ATI-NAL and ATI-FLU-NAL produced an immediate and effective recovery from anaesthesia. The combination of ATI-FLU-NAL was the most effective combination in antagonizing the anaesthetic effect. Adverse effects such as tachycardia, tachypnoea, excitement and muscle tremors were not observed during this study. CONCLUSION AND CLINICAL RELEVANCE: ATI-FLU-NAL is the most effective combination for antagonizing tiletamine/zolazepam-xylazine-tramadol anaesthesia in pigs. However, ATI alone or in various combinations also provides effective antagonism. PMID- 21672126 TI - Effect of fentanyl target-controlled infusions on isoflurane minimum anaesthetic concentration and cardiovascular function in red-tailed hawks (Buteo jamaicensis). AB - OBJECTIVE: To determine the impact of three different target plasma concentrations of fentanyl on the minimum anaesthetic concentration (MAC) for isoflurane in the red-tailed hawk and the effects on the haemodynamic profile. STUDY DESIGN: Experimental study. ANIMAL POPULATION: Six healthy adult red-tailed hawks (Buteo jamaicensis) of unknown sex with body weights (mean +/- SD) of 1.21 +/- 0.15 kg. METHODS: This study was undertaken in two phases. In the first phase anaesthesia was induced with isoflurane in oxygen via facemask and maintained with isoflurane delivered in oxygen via a Bain circuit. Following instrumentation baseline determination of the MAC for isoflurane was made for each animal using the bracketing method and a supramaximal electrical stimulus. End-tidal isoflurane concentration (E'Iso) was then set at 0.75 * MAC and after an appropriate equilibration period a bolus of fentanyl (20 MUg kg(-1)) was administered intravenously (IV) in order to determine the pharmacokinetics of fentanyl in the isoflurane-anaesthetized red-tailed hawk. During the second phase anaesthesia was induced in a similar manner and E'Iso was set at 0.75 * MAC for each individual. Fentanyl was infused IV to achieve target plasma concentrations between 8 and 32 ng mL(-1). At each fentanyl plasma concentration, the MAC for isoflurane and cardiovascular variables were determined. Data were analyzed by use of repeated-measures anova. RESULTS: Mean +/- SD fentanyl plasma concentrations and isoflurane MACs were 0 +/- 0, 8.51 +/- 4, 14.85 +/- 4.82 and 29.25 +/- 11.52 ng mL(-1), and 2.05 +/- 0.45%, 1.42 +/- 0.53%, 1.14 +/- 0.31% and 0.93 +/- 0.32% for the target concentrations of 0, 8, 16 and 32 ng mL(-1), respectively. At these concentrations fentanyl significantly (p = 0.0016) decreased isoflurane MAC by 31%, 44% and 55%, respectively. Dose had no significant effect on heart rate, systolic, diastolic or mean arterial blood pressure. CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl produced a dose-related decrease of isoflurane MAC with minimal effects on measured cardiovascular parameters in red-tailed hawks. PMID- 21672127 TI - Quantitative and qualitative comparison of three scoring systems for assessing recovery quality after general anaesthesia in horses. AB - OBJECTIVE: To assess the reproducibility and repeatability of two commonly used recovery quality scoring systems and compare them with those of a novel system based on a greater number of objective criteria. ANIMALS: The video-recorded recoveries of ten client-owned horses selected from all recovery recordings taken between September 2005 and March 2006 at the Royal (Dick) School of Veterinary Studies. MATERIALS AND METHODS: A digital versatile disc (DVD) was produced using edited video recordings of ten horses recovering from general anaesthesia. Twelve experienced equine anaesthetists (raters) studied the DVD on three occasions, and scored the recovery quality of each horse using one of three scoring systems (P, D or E) on each occasion. The process was repeated 6 months later (t = 6) to measure intra-observer reliability (repeatability). At first use (t = 0) raters were asked to comment on the advantages and disadvantages of each system. RESULTS: Inter-rater variability was limited for each system: at each observation period raters accounted for 0.3-4.4% variation. System P was insensitive to differences between recoveries. In system D, score variability increased as recovery quality deteriorated. Intra-rater variability varied with system: using system P, raters provided consistent scores between the observation periods for some, but not all horses ('horse' and 'rater' accounted for 9.7% and 1.9% of variation respectively). Raters were less consistent between t = 0 and t = 6 using system D, but each horse was scored with similar consistency. System E produced little variation at the level of horse (1.0%) and rater (1.9%). Raters broadly agreed on the principle advantages and disadvantages of the three systems. CONCLUSIONS AND CLINICAL RELEVANCE: The systems examined showed reliability and reproducibility but practicality and simplicity of use appeared to be inextricably linked with imprecision. Further work is required to produce a suitable recovery quality scoring system. PMID- 21672128 TI - Dose range finding study for the efficacy of meloxicam administered prior to sodium urate-induced synovitis in cats. AB - OBJECTIVE: To determine the lowest efficacious dose of oral meloxicam for relieving pain in cats with a sodium urate (SU)-induced acute inflammatory synovitis. STUDY DESIGN: Randomized, blinded, controlled, and four-way crossover study. ANIMALS: Eight surgically neutered cats (four males, four females) paired according to sex. METHODS: Each pair of cats was treated with 0 (placebo), 0.025, 0.05, or 0.075 mg kg(-1) oral meloxicam once daily for 4 days prior to injection, into alternating stifles, of 1 mL of 20 mg mL(-1) SU crystals, beginning with the right stifle. Each cat received each of the four treatments, separated by at least 21 days. Analgesic efficacy was evaluated based on objective (e.g., pressure mat data total force, contact pressure, and contact area) and subjective (e.g., scores for Analgesia Scale [AS], Lameness Scale [LS], and Visual Analog Scale [VAS]) outcome measures for pain assessment. All outcome measures were recorded before and during 30 hours after SU injection. The pre-defined primary outcome measure was the area under the response-time curve (AUC(0-30) hours) of the total force of the injected limb. Data were analyzed by analysis of variance. A sequential test procedure was applied and the test sequence stopped in case of a nonsignificant result. RESULTS: Meloxicam at doses of 0.05 and 0.075 mg kg(-1) day(-1) PO was significantly different from placebo for the pre-defined primary outcome measure (i.e., AUC(0-30) hours of total force). All tested meloxicam doses were lower than placebo for the subjective outcome measures (i.e., AUC(0 30) hours of AS, LS, and VAS). CONCLUSIONS AND CLINICAL RELEVANCE: The lowest efficacious dose of meloxicam for relieving pain in cats with an SU-induced synovitis was 0.05 mg kg(-1) day(-1) PO according to the pre-defined primary outcome measure. However, lower doses may also be effective as seen in the subjective outcome measures. PMID- 21672129 TI - Evaluation of transdermal fentanyl patch attachment in dogs and analysis of residual fentanyl content following removal. AB - OBJECTIVE: To investigate whether the method used to attach matrix-type fentanyl patches influences the degree of skin attachment and the amount of active drug remaining in patches after use. STUDY DESIGN: Prospective, randomised clinical study. STUDY POPULATION: Fifteen adult dogs of mixed breeds. METHODS: Two equally sized matrix-type fentanyl patches were attached to the dorsal third of the lateral thorax of fifteen dogs for 72 hours. The two patches were attached using different techniques: Method AD used an adhesive dressing in combination with a transparent film. Method TG used tissue adhesive applied to the edges of the patch. After 72 hours the patches were removed and the proportion of the patch attached at this time calculated. The residual content of the patches was analysed using a validated gas chromatography-mass spectrometery (GC-MS) analysis technique. RESULTS: After 72 hours of continuous attachment, the mean proportion of drug uptake for method AD was 17.2 (SD +/- 11.1)% and for method TG this was 16.9 (SD +/- 7.3)%. The median proportion of attachment for method AD was 100% and for method TG was 95.6%. CONCLUSIONS: The method of attachment did not significantly influence the uptake of fentanyl from matrix-type patches. The method of attachment resulted in a significant difference in the proportion of the patch attached 72 hours after placement, with method AD resulting in a greater median proportion of attachment than TG. CLINICAL RELEVANCE: The method used to attach matrix-type fentanyl patches to dogs should not interfere with drug uptake. The residual fentanyl content remaining in these patches after 72 hours of continuous application is significant and could lead to intoxication if ingested by humans. PMID- 21672130 TI - Cutaneous reaction after intravenous administration of medetomidine? PMID- 21672131 TI - Anatomical sector analysis of load-bearing tibial bone structure during 90-day bed rest and 1-year recovery. AB - The aim of this study was to investigate whether the bone response to long bed rest-related immobility and during subsequent recovery differed at anatomically different sectors of tibial epiphysis and diaphysis. For this study, peripheral quantitative tomographic (pQCT) scans obtained from a previous 90-day 'Long Term Bed Rest' intervention were preprocessed with a new method based on statistical approach and re-analysed sector-wise. The pQCT was performed on 25 young healthy males twice before the bed rest, after the bed rest and after 1-year follow-up. All men underwent a strict bed rest intervention, and in addition, seven of them received pamidronate treatment and nine did flywheel exercises as countermeasures against disuse-related bone loss. Clearly, 3-9% sector-specific losses in trabecular density were observed at the tibial epiphysis on average. Similarly, cortical density decreased in a sector-specific way being the largest at the anterior sector of tibial diaphysis. During recovery, the bed rest-induced bone losses were practically restored and no consistent sector-specific modulation was observed in any subgroup. It is concluded that the sector-specific analysis of bone cross-sections has potential to reveal skeletal responses to various interventions that cannot be inferred from the average analysis of the whole bone cross-section. This approach is considered also useful for evaluating the bone responses from the biomechanical point of view. PMID- 21672132 TI - Influence of long-term oxygen therapy on cardiac acceleration and deceleration capacity in hypoxic patients with chronic obstructive pulmonary disease. AB - BACKGROUND: There is increasing interest in cardiovascular co-morbidities of chronic obstructive pulmonary disease (COPD). Heart rate turbulence (HRT) and phase-rectified signal averaging (PRSA) techniques quantify the heart's acceleration/deceleration capacities. We postulated that these methods can help assess the integrity of cardiac control in hypoxic COPD. METHODS: Eight hypoxic stable COPD patients, nine healthy age-matched older adults and eight healthy young adults underwent ECG monitoring for 24 h. Patients with COPD were also monitored following 4 weeks of standardized oxygen therapy. HRT measures [turbulence onset (TO), turbulence slope (TS)] and PRSA-derived acceleration/deceleration (AC, DC) indices were quantified within 6-h blocks to assess circadian variation. RESULTS: There were between-group differences for variables TS, DC and AC (P<0.0005, eta(2) = 0.54-0.65), attributable solely to differences between healthy young and COPD subjects. Only HR (P<0.0005) and DC index (P = 0.008) showed circadian variation. A significant interaction 'trend' effect for HR (F(9,87) = 2.52, P = 0.015, eta(2) = 0.21) reflected the strong influence of COPD on HR circadian variation (afternoon and night values being different to those in healthy subjects). CONCLUSIONS: As expected, heart rate dynamics were substantially diminished in older (healthy and COPD) groups compared with healthy young controls. Patients with COPD showed similar heart rate dynamics compared with age-matched controls, both before and after hypoxia correction. However, there was a suggestion of diminished DC in COPD compared with age-matched controls (P = 0.059) that was absent following oxygen therapy. TS, DC and AC indices were altered by similar degrees in older subjects, apparently indicating equivalent tonic dysfunction of sympathetic/parasympathetic systems with ageing. PMID- 21672133 TI - Estimating oxygen consumption from heart rate and heart rate variability without individual calibration. AB - Heart rate (HR) as an estimator of oxygen consumption (VO(2) ) usually requires HR to be individually calibrated in a separate test. This study examined the validity of a new HR - and HR variability-based method (Firstbeat PRO heartbeat analysis software) in the estimation of VO(2) in real-life tasks. The method takes into account the respiration rate determined from HR variability and the differences in the on/off dynamics of HR and VO(2) , and no calibration tests are needed. Ten men and nine women performed 25 tasks representing different types of daily activities. Portable devices were used to measure R-to-R intervals (ECG), VO(2) and respiration rate. In pooled regression analysis, the estimated VO(2) accounted for 87% of the variability in the actual VO(2) , SEE 3.5 ml min(-1) kg( 1) (1 MET). At group level, the method underestimated slightly the measured VO(2) (mean difference - 1.5 ml min(-1) kg(-1) or - 0.4 METs). Some of the values at low exercise intensities were markedly underestimated, but the agreement was better during light and heavy activities. The limits of agreement for the data were from -8.4 to 5.4 ml min(-1) kg(-1) or from -2.4 to 1.5 METs. At individual level, the average deviations of the predicted VO(2) ranged from -1.0 to 0.6 METs and R(2) from 0.77 to 0.94, respectively. The present data indicate that the prediction method may be considered sufficiently accurate to determine the average VO(2) in field use, but it does not allow precise estimation of VO(2) . PMID- 21672134 TI - Sympatho-vagal interaction in the recovery phase of exercise. AB - Reciprocal autonomic regulation occurs during incremental exercise. We hypothesized that sympatho-vagal interplay may become altered after exercise because of the differences in recovery patterns of autonomic arms. The cardiac vagal activity was assessed by measurement of beat-to-beat R-R interval oscillations using a Poincare plot method (SD1), and muscle sympathetic nervous activity (MSNA) was measured from peroneus nerve by a microneurography technique during and after exercise in 16 healthy subjects. Autonomic regulation was compared between the rest and after exercise (3.5 +/- 1.0 min after exercise) at equal heart rates (HR). SD1 was at the equal level at the recovery phase (40 +/- 21 ms) compared to the resting condition (38 +/- 16 ms, P = ns) at comparable HR (57 +/- 10 for both). MSNA was higher at the recovery phase (40 +/- 19 burst per 100 heartbeats) than at rest (25 +/- 13 burst per 100 heartbeats, P<0.0001). The difference of MSNA activity between rest and late recovery phase had a strong positive correlation with the difference in SD1 (r = 0.78, P<0.001) at equal HRs. Subjects who have a higher sympathetic activity in the recovery phase of exercise have a more augmented cardiac vagal activity resulting in an accentuated sympatho vagal outflow. The altered autonomic interaction observed here may partly explain the clustering of various cardiovascular events to the recovery phase of exercise. PMID- 21672135 TI - Prolonged mean reaction time in posterior cerebral artery during visual stimulation in patients with severe carotid stenosis. AB - While the mean increase in flow velocities in posterior cerebral artery (PCA) as a response to visual stimuli is well documented, the data on the reaction time as a measurement of the vasomotor response of the posterior part of the circle of Willis are still sparse. The aim was to assess the visual evoked response in PCA during white light stimulation by means of functional transcranial doppler in patients with severe internal carotid artery (ICA) stenosis, to introduce a real time haemodynamic changes as a measurement of the effect of severe carotid disease on the posterior circulation. The measurements were taken in 49 right handed patients with severe ICA stenosis or occlusion and 30 healthy volunteers, simultaneously in left and right PCA using 2-MHz probes, successively in the dark and during the white light stimulation, during three consecutive repetitive periods of 1 min each. Mean values of mean blood flow velocities (MBFV) and mean reaction time (MRT) with and without visual stimuli were analysed. Linear regression analysis showed no statistically significant correlation between the age, MBFV and a degree of left and right carotid stenosis, and MRT in left and right PCA either in the group of healthy subjects or in the group of patients with severe carotid stenosis, in both test conditions. MRT could be an indicator of compromised cerebral circulation in the presence of haemodynamic significant carotid stenosis as well as an additional and independent haemodynamic parameter of the cerebral visual evoked response. PMID- 21672136 TI - Axillary sentinel node identification in breast cancer patients: degree of radioactivity present at biopsy is critical. AB - BACKGROUND: The radioactivity present in the patient (Act(rem) ) at sentinel node (SN) biopsy will depend on injected activity amount as well as on the time interval from tracer injection to biopsy, which both show great variations in the literature. The purpose of this study was to analyse the influence of varying Act(rem) levels on the outcome of axillary SN biopsy in patients with breast cancer (BC). MATERIAL AND METHODS: Eight hundred and fifty-eight patients with BC were consecutively referred to SN biopsy, 21% for a same-day and 79% of the patients for a 2-day procedure. Four hundred and nineteen patients underwent scintigraphy and 439 did not. For same-day procedures, 50 MBq (99m) Tc nanocolloid (Nanocoll((r)) ) was injected, and for 2-day procedures 110 MBq. For the analysis of SN biopsy outcome, the patients were divided into three Act(rem) groups: <10 (56% of the patients), 10-20 (23%), and >20 MBq (21%). During surgery, SNs were located using a hand-held gamma probe supported by image information when available and blue dye injection. Pathology included haematoxylin-eosin staining followed by immunohistochemistry. RESULTS: The number of SNs removed (mean value 1.87 versus 2.14, P = 0.0003) and the probability of finding a malignant SN (P = 0.034) were lower in the <10 MBq group of patients compared with higher Act(rem) >20 MBq. Of the 25 patients with SN non-detection, 20 patients had an Act(rem) <10 MBq. Imaging had no significant influence on the number of patients with a malignant SN (P = 0.48). CONCLUSION: Act(rem) above 10 MBq for nanocolloid tracer appears important for appropriate identification of SNs in patients with BC. PMID- 21672137 TI - Added value with extended NO analysis in atopy and asthma. AB - INTRODUCTION: Assessments of the usefulness of exhaled nitric oxide (NO) in the treatment of asthma have given conflicting results. It is not always obvious if atopic status has been tested in these evaluations. OBJECTIVES: The aim of the study is to use extended NO analysis to characterize subjects from a random sample populations with focus on rhinitis and asthma. METHODS: Data were extracted from the European Community Respiratory Health Survey II. A subgroup from the Uppsala site that had had their NO measured at multiple flow rates was included (n = 284). The nonlinear model for NO parameters was used. Atopy was defined as having a titre against at least one of the tested allergens >=0.35 kU l(-1) . Bronchial responsiveness was assessed by methacholine challenge. RESULTS: Subjects with non-atopic rhinitis or non-atopic asthma could not be separated from healthy subjects regarding NO parameters. There was a gradual increase with atopy in airway diffusion rate (D(aw) NO); healthy subject 8.0 (7.3, 8.8), healthy atopic 8.8 (6.7, 11.5), atopic rhinitis 10.6 (9.0, 12.4) and atopic asthma 11.2 (9.9, 28.3) ml s(-1) [geometrical mean (CI(95%) )]. There was a correlation between bronchial responsiveness and D(aw) NO in atopic rhinitis (r = -0.41, P<0.01), and bronchial responsiveness and airway wall content of NO (C(aw) NO) in atopic asthma (r = -0.56, P<0.001). CONCLUSION: It is of importance to characterize atopic status when evaluating the association between NO and asthma. Our results indicate that the use of extended NO analysis, with particular attention to D(aw) NO and C(aw) NO, may be useful in monitoring treatment for rhinitis and asthma. PMID- 21672138 TI - Diameter and compliance of the greater saphenous vein - effect of age and nitroglycerine. AB - OBJECTIVES: The greater saphenous vein (GSV) is commonly used in autologous vein graft surgery. GSV diameter has proven to influence graft patency, and furthermore venous compliance might be of importance. The purpose of the study was to evaluate the effect of age on GSV diameter and compliance, and to evaluate the effect of nitroglycerine (NTG). METHODS: The diameter and compliance of the GSV, with and without NTG, were examined with B-mode ultrasound in 12 elderly (70.3 +/- 1.2 year) and 15 young (25.1 +/- 0.6 year) men. The GSV diameter at the thigh and calf level was measured at rest, after 6 min of venous stasis (60 mmHg) and after NTG administration. Pressure-area curves during a linear venous pressure decrease were produced. Venous compliance was calculated using the quadratic regression equation (area) = beta(0) + beta(1) (cuff pressure) + beta(2) (cuff pressure)(2) . RESULTS: GVS diameter between the groups showed significant lower diameter in elderly compared to young men (P<0.05). Venous occlusion increased GSV diameter in elderly men (P<0.01) as well as young men (P<0.001). NTG increased GSV diameter in elderly men (P<0.01) with an equal trend in young men. During venous occlusion, after administration of NTG, GSV diameter increased further in both elderly (P<0.01) and young men (P<0.001). GSV compliance was decreased in elderly (beta(1) , 0.037 +/- 0019, beta(2,) -0.000064 +/- 00017) versus young men (beta(1) , 0.128 +/- 0.013, beta(2) , -0.00010 +/- 000018) [P<0.001 (beta(1) ), P<0.02 (beta(2) )]. CONCLUSIONS: Baseline GSV diameter as well as GSV compliance is decreased in elderly men compared to the young subjects. As reduced GSV diameter as well as reduced compliance is related to decreased graft patency, these findings might be of importance for the uses of GSV as graft material in cardiovascular bypass surgery. The clinical value has to be clarified in future studies. PMID- 21672139 TI - Measurements of skin temperature responses to cold exposure of foot and face in healthy individuals: variability and influencing factors. AB - Skin vasomotor responses to cold exposure (CE) have been measured widely and shown to be abnormal in some clinical conditions. Among other methods, monitoring of skin temperature (Tsk) changes has been applied for those purposes. We investigated such changes simultaneously in different skin areas of healthy young men during foot and facial CE. Tsk was measured using infrared thermography in the big toe and dorsum of the left foot and with a contact thermode in the fingertip. The relationship of Tsk responses within individuals and factors influencing them were examined using mixed model analysis. Tsk changes varied greatly between sessions, measured areas and individuals. Foot CE that was painful produced both stronger central circulatory and Tsk responses than facial CE. Tsk changes were prominent in the fingertip, moderate in the toe and weak or absent in the dorsal foot. The Tsk changes were related to the baseline levels and changes of blood pressure, heart rate, the baseline Tsk values and stimulus intensity. However, despite the different cold stimuli and measurement techniques, an intra-individual correlation of the Tsk responses was good. In the foot, the big toe area is applicable for studies of Tsk reactions when warm, and the modified Tsk gradient helps to evaluate the level of peripheral vasoconstriction. The cold-induced Tsk changes may be informative in the studies of the cutaneous vasoregulation but the individual character of the cold stress reactivity and numerous confusing factors should be considered when drawing conclusions on the basis of the recorded results. PMID- 21672140 TI - Evaluation of intima-media thickness and vascular elasticity of the common carotid artery in patients with isolated systolic hypertension using ultrasound radiofrequency-data technology. AB - BACKGROUND: Radiofrequency (RF) data technology is a newly developed method to evaluate vascular disease, especially subclinical atherosclerotic change. Data regarding predictors of intima-media thickness (IMT) and vascular elasticity of the common carotid artery (CCA) in subjects with isolated systolic hypertension (ISH) using ultrasound RF-data technology are scarce. AIMS: We evaluated the change in IMT and vascular elasticity of the CCA in patients with ISH at an early phase using US RF-data technology. METHODS: Thirty-nine patients with ISH and 41 age-matched control subjects were the study population. The common carotid arterial systolic diameter (Ds), diastolic diameter (Dd), IMT, carotid distensibility (CD), local pulse wave velocity (PWVbeta) and stiffness (beta) were compared between the two groups, as were correlations between pulse pressure (PP) and parameters of vascular stiffness. RESULTS: Common carotid arterial Ds, Dd, IMT, PWVbeta and beta increased whereas CD decreased more significantly in the ISH group than in age-matched controls. The level of PP in the ISH group had significant positive correlations with PWVbeta (r = 0.298, P<0.05) and beta (r = 0.291, P<0.05), whereas significant correlations with CD were not observed. CONCLUSIONS: US RF-data technology could be used to accurately and quantitatively evaluate increased IMT and decreased arterial elasticity of the CCA in patients with ISH compared with normal subjects. PMID- 21672141 TI - Comparison of ultrasound-measured age-related, site-specific muscle loss between healthy Japanese and German men. AB - The purpose of this study was to compare the age-related muscle loss in both the appendicular and trunk regions in 207 Japanese and 111 German men aged 20-62 years. Ultrasound-measured muscle thickness (MTH) was taken at eight sites from the anterior and posterior aspects of the body, and the MTH was expressed in terms relative to limb length (MTH/L) or standing height (MTH/Ht). In both the Japanese and Germans, age was correlated with quadriceps MTH (Japanese, r = 0.347; Germans, r = -0.292; both P<0.01) and abdomen MTH (Japanese, r = -0.300, P<0.01; Germans, r = -0.232; P<0.05). On the other hand, hamstring MTH was correlated with age in the Japanese (r = -0.188, P<0.01), but not in the Germans (r = 0.100). There were no significant correlations between age and other limb (i.e. triceps surae MTH/L, Japanese, r = 0.04; Germans, r = 0.05) and trunk sites (subscapula MTH/Ht, Japanese, r = -0.09; Germans, r = -0.02). In conclusion, age related skeletal muscle loss was strongly observed in the quadriceps and abdominal sites in both the Japanese and German men, although the rate of regular physical activity was different between the two groups. PMID- 21672142 TI - Comparison study of treadmill versus arm ergometry. AB - The Bruce treadmill test is used worldwide to assess cardiovascular disease. However, because of the high increments of intensity between the stages of this test, it is not best suited to a number of populations. Therefore, the aim of the study was to determine the difference between physiological outcomes of the arm crank test and Bruce treadmill test and to provide a regression equation to account for this. Thirty subjects (16 men and 14 women) performed both an arm crank test and the Bruce treadmill test, on two separate days, in a random order. Peak values of oxygen uptake (VO(2) ), respiratory exchange ratio (RER), ventilation rate (V(E) ), heart rate (HR) and ratings of perceived exertion (RPE) were recorded. Arm crank VO(2peak) and peak V(E) were significantly lower compared with treadmill VO(2peak) and peak VE, in both men and women (P<0.001). Arm crank HR(peak) was significantly lower than treadmill HR(peak) in men (P<0.001). The following is the regression equation to estimate treadmill: VO(2peak) = 0.8*arm crank VO(2peak) + 0.019*body weight + 2.025*gender 0.038*gender*body weight + 0.852, with gender being '0' for males and '1' for females. This model has a r(2) of 0.832 (SEE = 0.471). This strong correlation indicates that an accurate prediction of treadmill VO(2peak) can be made by arm crank VO(2peak) , which is a good estimate of a person's maximal oxygen uptake (VO(2max) ). Therefore, the arm crank test can be of great importance for evaluation of cardiovascular disease in many people. PMID- 21672143 TI - Massive clonidine overdose during refill of an implanted drug delivery device for intrathecal analgesia: a review of inadvertent soft-tissue injection during implantable drug delivery device refills and its management. AB - OBJECTIVES: The study aims to highlight the potentially serious consequences of inadvertent soft-tissue injection of intrathecal drugs such as clonidine, during refills of implanted drug delivery devices, and to suggest strategies to reduce this complication. DESIGN: Case report and literature review were used. RESULTS: We report the case of a 51-year-old female with chronic arm pain who sustained a massive clonidine overdose (18,000 mcg) due to inadvertent soft-tissue injection during a refill of an implanted drug delivery device, resulting in rapid loss of consciousness and significant cardiovascular instability requiring urgent resuscitation, subsequent myocardial infarction, cardiac failure, and other significant complications. The risks of inadvertent soft-tissue injection of intrathecal drugs during implanted drug delivery device refills and management of such events is poorly documented in the literature. CONCLUSION: Inadvertent soft tissue injection is possibly an underappreciated and underreported complication of intrathecal analgesia via an implanted drug delivery device. Under some circumstances, large doses of other intrathecal drugs such as bupivacaine, opioids, ziconotide, and baclofen may also be delivered by inadvertent soft tissue injection with potentially life-threatening consequences. We recommend that practitioners, institutions, and professional bodies who manage patients with intrathecal analgesia via intrathecal drug delivery devices highlight and audit this complication and develop systems to manage it. PMID- 21672144 TI - Using qualitative methodologies to evaluate randomized controlled trials: an ontological and epistemological paradox or a pragmatic recognition that context matters? PMID- 21672145 TI - When disaster strikes: donor deaths are treated with intense scrutiny, but broader sharing of information to benefit all living donors should be implemented. PMID- 21672146 TI - Major challenges limiting liver transplantation in the United States. AB - Liver transplantation is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin in the setting of liver dysfunction. From 1988 to 2009, liver transplantation in the United States grew 3.7-fold from 1713 to 6320 transplants annually. The expansion of liver transplantation is chiefly driven by scientific breakthroughs that have extended patient and graft survival well beyond those expected 50 years ago. The success of liver transplantation is now its primary obstacle, as the pool of donor livers fails to keep pace with the growing number of patients added to the national liver transplant waiting list. This review focuses on three major challenges facing liver transplantation in the United States and discusses new areas of investigation that address each issue: (1) the need for an expanded number of useable donor organs, (2) the need for improved therapies to treat recurrent hepatitis C after transplantation and (3) the need for improved detection, risk stratification based upon tumor biology and molecular inhibitors to combat hepatocellular carcinoma. PMID- 21672148 TI - Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression. AB - Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in animal models. Because Klotho is an aging suppressor gene controlling phosphate metabolism and insulin sensitivity, we investigated the influence of rapamycin on Klotho expression. A total of 100 kidney transplant recipients, 50 chronically treated with rapamycin and 50 with calcineurin inhibitors, were enrolled; 20 healthy subjects were employed as control. In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption. In addition, rapamycin increased insulin resistance as shown by HOMA index. Rapamycin treatment of an immortalized proximal tubular cell line induced the expression of Klotho, the phosphorylation of AKT in Ser473, downstream target of mTORC2 and the expression of RICTOR, mTORC2 main component. AKT inhibition reduced the rapamycin-induced expression of Klotho. In vivo rapamycin treatment induced higher degree of RICTOR and AKT Ser(473) expression directly correlating with long-term rapamycin exposure, FE(PO4) and HOMA index. In conclusion, our data would suggest that rapamycin may influence phosphate homeostasis and insulin resistance modulating Klotho expression through mTORC2 activation. PMID- 21672149 TI - Less maintenance immunosuppression in lung transplantation following hematopoietic stem cell transplantation from the same living donor. AB - Living-donor lobar lung transplantation (LDLLT) is one of the final options for saving patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). We retrospectively investigated 19 patients who had undergone LDLLT after HSCT in Japan. Eight patients underwent LDLLT after HSCT in which one of the donors was the same living donor as in HSCT (SD group), while 11 received LDLLT from relatives who were not the HSCT donors (non-SD group). In the SD group, three patients underwent single LDLLT. The 5-year survival rate was 100% and 58% in the SD and non-SD groups, respectively. In the SD group, postoperative immunosuppression was significantly lower than in the non-SD group. Two patients died of infection and one died of post-transplant lymphoproliferative disease (PTLD) in the non-SD group, while only one patient died of PTLD 7 years after LDLLT in the SD group. Hematologic malignancy relapsed in two patients in the non-SD group. For the three single LDLLTs in the SD group, immunosuppression was carefully tapered. In our study, LDLLT involving the same donor as for HSCT appeared to have advantages related to lower immunosuppression compared to LDLLT from relatives who were not the HSCT donors. PMID- 21672150 TI - Patients' willingness to accept expanded criteria donor liver transplantation. AB - Utilization of livers from expanded criteria donors (ECD) is one strategy to overcome the severe organ shortage. The decision to utilize an ECD liver is complex and fraught with uncertainty for both providers and patients. We assessed patients' willingness to accept ECD liver transplantation (LTx) and acceptable 1 year mortality risk. One hundred eight patients listed for LTx were asked to rate their willingness to accept ECD LTx and the associated 1-year mortality risk they were willing to accept. Also, patients completed the SF-36v2 and sociodemographic and health information was gathered from their medical records. Patients reported significantly higher willingness to accept standard criteria donor (SCD) versus ECD LTx (t = 13.8, p < 0.001), with more than one-third of patients reporting low willingness to accept ECD LTx. Relative to our center's 10% SCD LTx 1-year mortality rate, most patients (71%) were willing to accept moderately or substantially higher 1-year mortality risk for ECD LTx. In multivariable analyses, higher lab MELD score and white race were significant independent predictors of both ECD willingness and ECD increased mortality risk acceptability. Findings highlight the importance of assessing patients' willingness to pursue ECD LTx and the relative mortality risks they are willing to accept. PMID- 21672151 TI - High mean fluorescence intensity donor-specific anti-HLA antibodies associated with chronic rejection Postliver transplant. AB - In contrast to kidney transplantation where donor-specific anti-HLA antibodies (DSA) negatively impact graft survival, correlation of DSA with clinical outcomes in patients after orthotopic liver transplantation (OLT) has not been clearly established. We hypothesized that DSA are present in patients who develop chronic rejection after OLT. Prospectively collected serial serum samples on 39 primary OLT patients with biopsy-proven chronic rejection and 39 comparator patients were blinded and analyzed for DSA using LABScreen((r)) single antigen beads test, where a 1000 mean fluorescence value was considered positive. In study patients, the median graft survival was 15 months, 74% received >= one retransplant, 20% remain alive and 87% had >= one episode of acute rejection. This is in contrast to comparator patients where 69% remain alive, and no patient needed retransplant or experienced rejection. Thirty-six chronic rejection patients (92%) and 24 (61%) comparator patients had DSA (p = 0.003). Chronic rejection versus comparator patients had higher mean fluorescence intensity (MFI) DSA. Although a further study with larger numbers of patients is needed to identify clinically significant thresholds, there is an association of high-MFI DSA with chronic rejection after OLT. PMID- 21672152 TI - Interstitial fibrosis evolution on early sequential screening renal allograft biopsies using quantitative image analysis. AB - Screening renal biopsies (RB) may assess early changes of interstitial fibrosis (IF) after transplantation. The aim of this study was to quantify IF by automatic color image analysis on sequential RB. We analyzed RB performed at day (D) 0, month (M) 3 and M12 from 140 renal transplant recipients with a program of color segmentation imaging. The mean IF score was 19 +/- 9% at D0, 27 +/- 11% at M3 and 32 +/- 11% at M12 with a 8% progression during the first 3 months and 5% between M3 and M12. IF at M3 was correlated with estimated glomerular rate (eGFR) at M3, 12 and 24 (p < 0.02) and IF at M12 with eGFR at M12 and 48 (p < 0.05). Furthermore, IF evolution between D0 and M3 (DeltaIFM3-D0) was correlated with eGFR at M24, 36 and 48 (p < 0.03). IF at M12 was significantly associated with male donor gender and tacrolimus dose (p = 0.03). DeltaIFM3-D0 was significantly associated with male donor gender, acute rejection episodes (p = 0.04) and diabetes mellitus (p = 0.02). Thus, significant IF is already present before transplantation. IF evolution is more important during the first 3 months and has some predictive ability for change in GFR. Intervention to decrease IF should be applied early, i.e. before 3 months, after transplantation. PMID- 21672153 TI - Antibody-associated rejection in liver transplantation: keep on knocking, and the door will be opened to you. PMID- 21672154 TI - Evolution of the role of the transplant pharmacist on the multidisciplinary transplant team. AB - Transplant pharmacists have been recognized as an essential part of the transplant team by their colleagues along with several governing and professional organizations. The specific education, training and responsibilities of the transplant pharmacist have not been clearly delineated in the literature. Various pharmacists across the country have been called upon to serve on the transplant team necessitating standardization of their fundamental and desirable activities. Therefore, the purpose of this manuscript is to describe the training and role of a transplant pharmacist on the patient care team and provide a roadmap to implementation of novel transplant pharmacy services. PMID- 21672156 TI - Delineating the picture of renal graft injury in 2011. PMID- 21672157 TI - De novo anti-HLA antibody after pandemic H1N1 and seasonal influenza immunization in kidney transplant recipients. AB - In solid organ transplanted patients, annual influenza immunization is strongly recommended because of morbidity and mortality of influenza infections. In 2009, the rapid spread of a novel H1N1 influenza A virus led to the accelerated development of novel pandemic influenza vaccines. In Switzerland, the recipients received one dose of seasonal influenza and two doses of AS03-adjuvanted H1N1 vaccines. This situation provided a unique opportunity to analyze the influence of novel adjuvanted influenza vaccines on the production of de novo anti-HLA antibodies. We prospectively followed two independent cohorts including 92 and 59 kidney-transplanted patients, assessing their anti-HLA antibodies before, 6 weeks and 6 months after vaccination. Sixteen of 92 (17.3%) and 7 of 59 (11.9%) patients developed anti-HLA antibodies. These antibodies, detected using the single antigen beads technology, were mostly at low levels and included both donor-specific and non-donor-specific antibodies. In 2 of the 20 patients who were followed at 6 months, clinical events possibly related to de novo anti-HLA antibodies were observed. In conclusion, multiple doses of influenza vaccine may lead to the production of anti-HLA antibodies in a significant proportion of kidney transplant recipients. The long-term clinical significance of these results remains to be addressed. PMID- 21672158 TI - Immunization against influenza: a balancing act. PMID- 21672159 TI - Transplanting kidneys without points for HLA-B matching: consequences of the policy change. AB - In 2003, the US kidney allocation system was changed to eliminate priority for HLA-B similarity. We report outcomes from before and after this change using data from the Scientific Registry of Transplant Recipients (SRTR). Analyses were based on 108 701 solitary deceased donor kidney recipients during the 6 years before and after the policy change. Racial/ethnic distributions of recipients in the two periods were compared (chi-square); graft failures were analyzed using Cox models. In the 6 years before and after the policy change, the overall number of deceased donor transplants rose 23%, with a larger increase for minorities (40%) and a smaller increase for non-Hispanic whites (whites) (8%). The increase in the proportion of transplants for non-whites versus whites was highly significant (p < 0.0001). Two-year graft survival improved for all racial/ethnic groups after implementation of this new policy. Findings confirmed prior SRTR predictions. Following elimination of allocation priority for HLA-B similarity, the deficit in transplantation rates among minorities compared with that for whites was reduced but not eliminated; furthermore, there was no adverse effect on graft survival. PMID- 21672160 TI - Ethnic and gender related differences in the risk of end-stage renal disease after living kidney donation. AB - There is limited data pertaining to the risk of End Stage Renal Disease (ESRD) after living kidney donation. The Organ Procurement and Transplantation Network and the Center for Medicare and Medicaid Services databases were used to identify living kidney donors (LKDs) who subsequently developed ESRD and to calculate LKD ESRD rates. We found 126 cases of ESRD among 56 458 LKDs (0.22%) who donated during October 1, 1987-March 31, 2003. The overall LKD ESRD rate was 0.134 per 1000 years at risk, with an average duration of follow-up of 9.8 years. ESRD rates for LKDs overall and for Black, White, male and female donors compared favorably to the ESRD incidence in the general population. The LKD ESRD rate was nearly five times higher for Blacks than for Whites and two times higher for males than females. However, these ethnic and gender-related differences were similar to those previously reported for ESRD in the general population. Our findings do not show an increase in the risk of ESRD for LKDs and support the current practice of living kidney donation. Further research is needed to determine if improved donor screening or follow-up will reduce the risk of postdonation ESRD. PMID- 21672161 TI - Defining living kidney donor ESRD risk-looking beyond race and gender. PMID- 21672162 TI - Periodontal dressing may influence the clinical outcome of non-surgical periodontal treatment: a split-mouth study. AB - INTRODUCTION: After scaling and root planning (SRP), healing induces the formation of a junctional long epithelium rather than a new connective attachment. We hypothesize that the placement of a periodontal dressing will be able to prevent detachment of coagulum inducing proper healing and improving periodontal parameters. MATERIALS AND METHODS: This split-mouth study included 30 patients with periodontitis with ages ranging from 35 to 70 years. Probing pocket depth (PD), probing attachment level (PAL), bleeding on probing index (BoP) and plaque index (PI) were assessed before and after therapy. The group of patients received SRP in a span of 24 h. Then, a periodontal dressing was applied on the test side and it was removed after 1 week. RESULTS: CONTROL GROUP: The difference between PD values at baseline and after therapy was 1.6 +/- 0.6 mm. The difference in PAL (DeltaPAL) measurement was 1.4 +/- 0.4. Test group: there was a greater PD reduction, this being 2.4 +/- 0.6 mm on average. The difference in PAL was 2.5 +/- 0.4 mm. CONCLUSIONS: Our results clearly suggest that the use of a periodontal dressing improves the periodontal parameters after an SRP procedure. This is probably due to clot stabilization and prevention of bacterial colonization during wound healing. PMID- 21672163 TI - Effect of baby swimming and baby lotion on the skin barrier of infants aged 3-6 months. AB - BACKGROUND: Skin care is important especially in infancy as the skin barrier matures during the first year of life. We studied the effects of baby swimming and baby lotion on the skin barrier function of infants. SUBJECTS AND METHODS: 44 infants aged 3-6 months were included in this mono-center prospective study. The healthy infants swam four times and were randomized to group(L) : baby lotion was applied after swimming all over the body and to group(WL) : no lotion was used. Transepidermal water loss, stratum corneum hydration, skin-pH and sebum were measured on four body regions using non-invasive methods. RESULTS: In group(L), sebum and pH remained stable. In group(WL), significant decrease in sebum was noted on forehead and thigh, and for pH on thigh and buttock. Group(L) had fewer infants with at least one adverse event compared to group(WL). Location-dependent gender differences in skin barrier function were observed. CONCLUSIONS: Reaction of skin barrier function to baby swimming and skin care regimens showed typical regional variability between body areas. Influence of baby lotion on skin barrier and gender differences in skin functional parameters were demonstrated for the first time in healthy infants participating in baby swimming. PMID- 21672164 TI - Treatment of ocular rosacea with 40 mg doxycycline in a slow release form. AB - BACKGROUND: About 30-50 % of rosacea patients have ocular involvement. The symptoms range from a foreign-body sensation to conjunctivitis or blepharitis and may even include severe corneal ulcerations. Systemic treatment is generally with tetracycline. Side effects can occur with the usual antimicrobial dose. PATIENTS AND METHODS: In a retrospective study, seven patients were evaluated who had been treated for ocular rosacea with a sub-antimicrobial dose of doxycycline 40 mg in a slow-release form (Oraycea). The responses were evaluated on the basis of clinical findings. RESULTS: Seven patients with an average age of 63 took slow release doxycycline 40 mg every day for at least two months. In five patients, other systemic drugs had already failed. All patients experienced a clear improvement in their ocular rosacea after an average of 2.29 months of treatment. One patient had complete clearance and another had almost complete clearance. None of the patients experienced side effects. CONCLUSIONS: A sub-antimicrobial dose of slow release doxycycline 40 mg daily is an effective long-term therapy for ocular rosacea. It is not associated with the side effects of long-term antibiotic therapy or the risk of resistance. PMID- 21672165 TI - CoMFA, CoMSIA, and docking studies on thiolactone-class of potent anti-malarials: identification of essential structural features modulating anti-malarial activity. AB - The integrated ligand- and structure-based drug design techniques have been applied on a homogeneous dataset of thiolactone-class of potent anti-malarials, to explore the essential structural features for the inhibition of Plasmodium falciparum. Developed CoMFA (q(2) = 0.716) and CoMSIA (q(2) = 0.632) models well explained structure-activity variation in both the training (CoMFA R(2) = 0.948 & CoMSIA R(2) = 0.849) and test set (CoMFA R(2) (pred) = 0.789 & CoMSIA R(2) (pred) = 0.733) compounds. The docking and scoring of the most active compound 10 into the active site of high-resolution (2.35 A) structure of FabB-TLM binary complex (PDB-ID: 1FJ4) indicated that thiolactone core of this compound forms bifurcated H-bonding with two catalytic residues His298 and His333, and its saturated decyl side group is stabilized by hydrophobic interactions with the residues of a small hydrophobic groove, illustrating that the active site architecture, including two catalytic histidines and a small hydrophobic groove, is vital for protein-ligand interaction. In particular, the length and flexibility of the side group attached to the position 5 of thiolactone have been observed to play a significant role in the interaction with FabB enzyme. These results present scope for rational design of thiolactone-class of compounds that could furnish improved anti-malarial activity. PMID- 21672166 TI - Maternal outcomes among pregnant women receiving live attenuated influenza vaccine. AB - BACKGROUND: Although the live attenuated influenza vaccine (LAIV) prescribing information contains warnings/precautions against use during pregnancy, administration of LAIV to pregnant women does occur. Data regarding maternal outcomes after LAIV administration during pregnancy are limited. OBJECTIVES: Maternal outcomes after LAIV vaccination during pregnancy were examined. METHODS: Data from a health insurance claims database that covers approximately 50 million individuals were analyzed for the six influenza seasons from 2003-2004 through 2008-2009. Emergency department (ED) visits and hospitalizations occurring within 42 days of vaccination were analyzed by primary diagnosis; outcomes were categorized as cardiopulmonary, obstetric, and other. Cohort characteristics were analyzed using descriptive statistics. RESULTS: Of 834,999 pregnancies identified, 138 (0.017%) were among women who received LAIV vaccinations. Of the 138 pregnant women, 13% were <=19 years, 67% were 20-34 years, and 20% were >=35 years of age. Eight events occurred within 42 days of vaccination: one ED visit for bronchitis, two hospitalizations for hyperemesis gravidarum and premature labor, and five ED visits/hospitalizations for common medical conditions. All outcomes identified after LAIV exposure occurred at rates similar to rates in unvaccinated pregnant women reported in the medical literature. CONCLUSIONS: Administration of LAIV to pregnant women is rare; the rate has remained constant since 2004-2005. In this cohort, there was no evidence of significant maternal adverse outcomes after receipt of LAIV. These data may offer some reassurance to providers and pregnant women in the event of inadvertent LAIV administration, but do not support the routine use of LAIV in pregnant women. PMID- 21672168 TI - Not just another annual exam: thoughts on the nurse-patient relationship. PMID- 21672170 TI - Text4Baby: using text messaging to improve maternal and newborn health. PMID- 21672171 TI - Establishing a mentoring program: transforming organizational culture and improving nurse retention. PMID- 21672172 TI - Bariatric surgery and its impact on childbearing. PMID- 21672173 TI - Roadmapping health for the woman at 30. PMID- 21672174 TI - Do women in abusive relationships have contraceptive control? PMID- 21672175 TI - Insulin revisited: safety in the maternity setting. PMID- 21672176 TI - Denosumab: new horizons in the treatment of osteoporosis. PMID- 21672177 TI - Products for sexual lubrication: understanding and addressing options with your patients. PMID- 21672180 TI - The dreaded orange. PMID- 21672181 TI - Meeting report from the 2011 International Expert Meeting on Large Congenital Melanocytic Nevi and Neurocutaneous Melanocytosis, Tubingen. PMID- 21672182 TI - Contribution of susceptibility gene variants to melanoma risk in families from the Veneto region of Italy. PMID- 21672183 TI - Assessment of macular pigment optical density (MPOD) in patients with unilateral wet age-related macular degeneration (AMD). AB - PURPOSE: To compare the macular pigment optical density (MPOD) of patients with unilateral wet age-related macular degeneration (AMD) with the MPOD of bilateral dry AMD patients and healthy elderly individuals. METHODS: The MPOD of 34 patients with unilateral wet AMD was measured in their fellow eye that had the dry form of the disease (study group). The MPOD of the study group was compared with the MPOD of 33 patients with bilateral dry AMD (patients' control group) and 35 elderly subjects without any signs of retinal disease (control group). None of the subjects was under carotenoid supplementation. The MPOD was measured with Heterochromatic Flicker Photometry [QuantifEYETM- MPS 9000 (ZeaVision((c)))]. The statistical package SPSS v 17.0 was used for the analysis. RESULTS: The overall mean MPOD was 0.52 (SD 0.15). Patients with unilateral wet AMD have significantly higher levels of MPOD in their fellow eye compared with patients with bilateral dry AMD (0.58 versus 0.48, p = 0.026). Mean MPOD of patients with bilateral dry AMD does not differ significantly from that of healthy elderly subjects (0.48 versus 0.50, p = 0.865). In this population sample, no correlation with age was observed, while women have slightly but significantly higher levels of MPOD (0.55 versus 0.49, p = 0.029). CONCLUSION: In the present study, the mean MPOD at the fellow eye of patients with unilateral wet AMD was found to be significantly higher than that of patients with bilateral dry AMD, while no other significant difference emerged between groups. Further investigation is demanded to clarify the role of macular pigment in AMD progression. PMID- 21672184 TI - The pathogenesis of foot-and-mouth disease II: viral pathways in swine, small ruminants, and wildlife; myotropism, chronic syndromes, and molecular virus-host interactions. AB - Investigation into the pathogenesis of foot-and-mouth disease (FMD) has focused on the study of the disease in cattle with less emphasis on pigs, small ruminants and wildlife. 'Atypical' FMD-associated syndromes such as myocarditis, reproductive losses and chronic heat intolerance have also received little attention. Yet, all of these manifestations of FMD are reflections of distinct pathogenesis events. For example, naturally occurring porcinophilic strains and unique virus-host combinations that result in high-mortality outbreaks surely have their basis in molecular-, cellular- and tissue-level interactions between host and virus (i.e. pathogenesis). The goal of this review is to emphasize how the less commonly studied FMD syndromes and host species contribute to the overall understanding of pathogenesis and how extensive in vitro studies have contributed to our understanding of disease processes in live animals. PMID- 21672185 TI - Efficient alignment of pyrosequencing reads for re-sequencing applications. AB - BACKGROUND: Over the past few years, new massively parallel DNA sequencing technologies have emerged. These platforms generate massive amounts of data per run, greatly reducing the cost of DNA sequencing. However, these techniques also raise important computational difficulties mostly due to the huge volume of data produced, but also because of some of their specific characteristics such as read length and sequencing errors. Among the most critical problems is that of efficiently and accurately mapping reads to a reference genome in the context of re-sequencing projects. RESULTS: We present an efficient method for the local alignment of pyrosequencing reads produced by the GS FLX (454) system against a reference sequence. Our approach explores the characteristics of the data in these re-sequencing applications and uses state of the art indexing techniques combined with a flexible seed-based approach, leading to a fast and accurate algorithm which needs very little user parameterization. An evaluation performed using real and simulated data shows that our proposed method outperforms a number of mainstream tools on the quantity and quality of successful alignments, as well as on the execution time. CONCLUSIONS: The proposed methodology was implemented in a software tool called TAPyR--Tool for the Alignment of Pyrosequencing Reads- which is publicly available from http://www.tapyr.net. PMID- 21672186 TI - Contribution of midgut bacteria to blood digestion and egg production in aedes aegypti (diptera: culicidae) (L.). AB - BACKGROUND: The insect gut harbors a variety of microorganisms that probably exceed the number of cells in insects themselves. These microorganisms can live and multiply in the insect, contributing to digestion, nutrition, and development of their host.Recent studies have shown that midgut bacteria appear to strengthen the mosquito's immune system and indirectly enhance protection from invading pathogens. Nevertheless, the physiological significance of these bacteria for mosquitoes has not been established to date. In this study, oral administration of antibiotics was employed in order to examine the contribution of gut bacteria to blood digestion and fecundity in Aedes aegypti. RESULTS: The antibiotics carbenicillin, tetracycline, spectinomycin, gentamycin and kanamycin, were individually offered to female mosquitoes. Treatment of female mosquitoes with antibiotics affected the lysis of red blood cells (RBCs), retarded the digestion of blood proteins and reduced egg production. In addition, antibiotics did not affect the survival of mosquitoes. Mosquito fertility was restored in the second gonotrophic cycle after suspension of the antibiotic treatment, showing that the negative effects of antibiotics in blood digestion and egg production in the first gonotrophic cycle were reversible. CONCLUSIONS: The reduction of bacteria affected RBC lysis, subsequently retarded protein digestion, deprived mosquito from essential nutrients and, finally, oocyte maturation was affected, resulting in the production of fewer viable eggs. These results indicate that Ae. aegypti and its midgut bacteria work in synergism to digest a blood meal.Our findings open new possibilities to investigate Ae. aegypti-associated bacteria as targets for mosquito control strategies. PMID- 21672187 TI - Long term results of arthroscopic Bankart repair for traumatic anterior shoulder instability. AB - BACKGROUND: The arthroscopic method offers a less invasive technique of Bankart repair for traumatic anterior shoulder instability. We would like to report the 2 year clinical outcomes of bio-absorbable suture anchors used in traumatic anterior dislocations of the shoulder. METHODS: Data from 79 shoulders in 74 patients were collected over 4 years (2004-2008). Each patient was followed-up over a period of 2 years. The patients underwent arthroscopic Bankart repair using bio-absorbable suture anchors for their shoulder instability. These surgeries were performed at a single institution by a single surgeon over the time period. The patients were assessed with two different outcome measurement tools. The University of California at Los Angeles (UCLA) shoulder rating scale and the Simple Shoulder Test (SST) score. The scores were calculated before surgery and at the 2-year follow-up. The recurrence rates, range of motion as well post-operative function and return to sporting activities were evaluated. RESULTS: SST results from the 12 domains showed a significant improvement from a mean of 6.1 +/- 3.1 to 11.1 +/- 1.8 taken at the 2-year follow-up (p < 0.0001). Data from the UCLA scale showed a Pre and Post Operative Mean of 20.2 +/- 5.0 and 32.4 +/- 4.6 respectively (p < 0.0001). 34 had excellent post-operative scores, 35 had good scores, 1 had fair score and 3 had poor scores. 75% of the patients returned to sports while 7.6% developed a recurrence of shoulder dislocation or subluxation. CONCLUSION: Arthroscopic Bankart repair with the use of suture anchors is a reliable treatment method, with good clinical outcomes, excellent post-operative shoulder motion and low recurrence rates. PMID- 21672188 TI - Analysis of BAC-end sequences in rainbow trout: content characterization and assessment of synteny between trout and other fish genomes. AB - BACKGROUND: Rainbow trout (Oncorhynchus mykiss) are cultivated worldwide for aquaculture production and are widely used as a model species to gain knowledge of many aspects of fish biology. The common ancestor of the salmonids experienced a whole genome duplication event, making extant salmonids such as the rainbow trout an excellent model for studying the evolution of tetraploidization and re diploidization in vertebrates. However, the lack of a reference genome sequence hampers research progress for both academic and applied purposes. In order to enrich the genomic tools already available in this species and provide further insight on the complexity of its genome, we sequenced a large number of rainbow trout BAC-end sequences (BES) and characterized their contents. RESULTS: A total of 176,485 high quality BES, were generated, representing approximately 4% of the trout genome. BES analyses identified 6,848 simple sequence repeats (SSRs), of which 3,854 had high quality flanking sequences for PCR primers design. The first rainbow trout repeat elements database (INRA RT rep1.0) containing 735 putative repeat elements was developed, and identified almost 59.5% of the BES database in base-pairs as repetitive sequence. Approximately 55% of the BES reads (97,846) had more than 100 base pairs of contiguous non-repetitive sequences. The fractions of the 97,846 non-repetitive trout BES reads that had significant BLASTN hits against the zebrafish, medaka and stickleback genome databases were 15%, 16.2% and 17.9%, respectively, while the fractions of the non-repetitive BES reads that had significant BLASTX hits against the zebrafish, medaka, and stickleback protein databases were 10.7%, 9.5% and 9.5%, respectively. Comparative genomics using paired BAC-ends revealed several regions of conserved synteny across all the fish species analyzed in this study. CONCLUSIONS: The characterization of BES provided insights on the rainbow trout genome. The discovery of specific repeat elements will facilitate analyses of sequence content (e.g. for SNPs discovery and for transcriptome characterization) and future genome sequence assemblies. The numerous microsatellites will facilitate integration of the linkage and physical maps and serve as valuable resource for fine mapping QTL and positional cloning of genes affecting aquaculture production traits. Furthermore, comparative genomics through BES can be used for identifying positional candidate genes from QTL mapping studies, aid in future assembly of a reference genome sequence and elucidating sequence content and complexity in the rainbow trout genome. PMID- 21672189 TI - Increased cerebral (R)-[(11)C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study. AB - BACKGROUND: The aim of the present study was to investigate microglia activation over time following traumatic brain injury (TBI) and to relate these findings to glutamate release. PROCEDURES: Sequential dynamic (R)-[(11)C]PK11195 PET scans were performed in rats 24 hours before (baseline), and one and ten days after TBI using controlled cortical impact, or a sham procedure. Extracellular fluid (ECF) glutamate concentrations were measured using cerebral microdialysis. Brains were processed for histopathology and (immuno)-histochemistry. RESULTS: Ten days after TBI, (R)-[(11)C]PK11195 binding was significantly increased in TBI rats compared with both baseline values and sham controls (p < 0.05). ECF glutamate values were increased immediately after TBI (27.6 +/- 14.0 MUmol.L(-1)) as compared with the sham procedure (6.4 +/- 3.6 MUmol.L(-1)). Significant differences were found between TBI and sham for ED-1, OX-6, GFAP, Perl's, and Fluoro-Jade B. CONCLUSIONS: Increased cerebral uptake of (R)-[(11)C]PK11195 ten days after TBI points to prolonged and ongoing activation of microglia. This activation followed a significant acute posttraumatic increase in ECF glutamate levels. PMID- 21672190 TI - Circulating angiopoietins-1 and -2, angiopoietin receptor Tie-2 and vascular endothelial growth factor-A as biomarkers of acute myocardial infarction: a prospective nested case-control study. AB - BACKGROUND: Angiogenesis is up-regulated in myocardial ischemia. However, limited data exist assessing the value of circulating angiogenic biomarkers in predicting future incidence of acute myocardial infarction (AMI). Our aim was to examine the association between circulating levels of markers of angiogenesis with risk of incident acute myocardial infarction (AMI) in men and women. METHODS: We performed a case-control study (nested within a large cohort of persons receiving care within Kaiser Permanente of Northern California) including 695 AMI cases and 690 controls individually matched on age, gender and race/ethnicity. RESULTS: Median [inter-quartile range] serum concentrations of vascular endothelial growth factor-A (VEGF-A; 260 [252] vs. 235 [224] pg/mL; p = 0.01) and angiopoietin-2 (Ang-2; 1.18 [0.66] vs. 1.05 [0.58] ng/mL; p < 0.0001) were significantly higher in AMI cases than in controls. By contrast, endothelium-specific receptor tyrosine kinase (Tie-2; 14.2 [3.7] vs. 14.0 [3.1] ng/mL; p = 0.07) and angiopoietin-1 levels (Ang-1; 33.1 [13.6] vs. 32.5 [12.7] ng/mL; p = 0.52) did not differ significantly by case-control status. After adjustment for educational attainment, hypertension, diabetes, smoking, alcohol consumption, body mass index, LDL-C, HDL-C, triglycerides and C-reactive protein, each increment of 1 unit of Ang-2 as a Z score was associated with 1.17-fold (95 percent confidence interval, 1.02 to 1.35) increased odds of AMI, and the upper quartile of Ang-2, relative to the lowest quartile, was associated with 1.63-fold (95 percent confidence interval, 1.09 to 2.45) increased odds of AMI. CONCLUSIONS: Our data support a role of Ang-2 as a biomarker of incident AMI independent of traditional risk factors. PMID- 21672191 TI - A species independent universal bio-detection microarray for pathogen forensics and phylogenetic classification of unknown microorganisms. AB - BACKGROUND: The ability to differentiate a bioterrorist attack or an accidental release of a research pathogen from a naturally occurring pandemic or disease event is crucial to the safety and security of this nation by enabling an appropriate and rapid response. It is critical in samples from an infected patient, the environment, or a laboratory to quickly and accurately identify the precise pathogen including natural or engineered variants and to classify new pathogens in relation to those that are known. Current approaches for pathogen detection rely on prior genomic sequence information. Given the enormous spectrum of genetic possibilities, a field deployable, robust technology, such as a universal (any species) microarray has near-term potential to address these needs. RESULTS: A new and comprehensive sequence-independent array (Universal Bio Signature Detection Array) was designed with approximately 373,000 probes. The main feature of this array is that the probes are computationally derived and sequence independent. There is one probe for each possible 9-mer sequence, thus 49 (262,144) probes. Each genome hybridized on this array has a unique pattern of signal intensities corresponding to each of these probes. These signal intensities were used to generate an un-biased cluster analysis of signal intensity hybridization patterns that can easily distinguish species into accepted and known phylogenomic relationships. Within limits, the array is highly sensitive and is able to detect synthetically mixed pathogens. Examples of unique hybridization signal intensity patterns are presented for different Brucella species as well as relevant host species and other pathogens. These results demonstrate the utility of the UBDA array as a diagnostic tool in pathogen forensics. CONCLUSIONS: This pathogen detection system is fast, accurate and can be applied to any species. Hybridization patterns are unique to a specific genome and these can be used to decipher the identity of a mixed pathogen sample and can separate hosts and pathogens into their respective phylogenomic relationships. This technology can also differentiate between different species and classify genomes into their known clades. The development of this technology will result in the creation of an integrated biomarker-specific bio-signature, multiple select agent specific detection system. PMID- 21672192 TI - Angiographically borderline left main coronary artery lesions: correlation of transthoracic doppler echocardiography and intravascular ultrasound: a pilot study. AB - BACKGROUND: the clinical decision making could be difficult in patients with borderline lesions (visually assessed stenosis severity of 30 to 50%) of the left main coronary artery (LM). The aim of the study was to evaluate the relationship between transthoracic Doppler (TTDE) peak diastolic flow velocity (PDV) and intravascular ultrasound (IVUS) measurements in the assessment of angiographically borderline LM lesions. METHODS: 27 patients (mean age 64 +/- 8 years, 21 males) with borderline LM stenosis referred for IVUS examination were included in the study. We performed standard IVUS with minimal lumen area (MLA) and plaque burden (PB) measurement and routine quantitative coronary angiography (QCA) with diameter stenosis (%DS) and area stenosis (%AS) assessment in all. During TTDE, resting PDV was measured in the LM. RESULTS: interpretable Doppler signal could be obtained in 24 patients (88% feasibility); therefore these patients entered the final analysis. MLA was 7.1 +/- 2.7 mm2. TTDE measured PDV correlated significantly with IVUS-derived MLA (r = -0.46, p < 0.05) and plaque burden (r = 0.51, p < 0.05). Using a velocity cut-off of 112 cm/sec TTDE showed a 92% sensitivity and 62% specificity to identify IVUS-significant (MLA < 6 mm2) LM stenosis. CONCLUSION: In angiographically borderline LM disease, resting PDV from transthoracic echocardiography is increased in presence of increased plaque burden by IVUS. TTDE evaluation might be a useful adjunct to other invasive and non-invasive methods in the assessment of borderline LM lesions. Further, large scale studies are needed to establish the exact cut-off value of PDV for routine clinical application. PMID- 21672194 TI - Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors (NET) have diverse clinical presentations. Patients with symptoms of hormone secretion may require specific medical interventions to control those symptoms prior to antitumor intervention. In some patients, tumors in the pancreas may be occult and specialized diagnostic imaging or surgery may be required for diagnosis. Other patients may present with more advanced disease, presenting with symptoms of tumor bulk rather than hormone secretion. Treatment options for patients with advanced pancreatic neuroendocrine tumors include surgical resection and hepatic directed therapies, including partial hepatectomy, hepatic artery embolization, or other ablative techniques. Streptozocin or temozolomide-based chemotherapy regimens are active against pancreatic NET, and can also play an important role in the palliation of patients with advanced disease. A number of biologically targeted agents targeting the VEGF and mTOR signaling pathways have recently shown promise, with recent trials showing treatment with the VEGFR tyrosine kinase inhibitor sunitinib or the mTOR inhibitor everolimus improves progression-free survival in patients with advanced NET. PMID- 21672195 TI - Human defensins 5 and 6 enhance HIV-1 infectivity through promoting HIV attachment. AB - BACKGROUND: Concurrent sexually transmitted infections (STIs) increase the likelihood of HIV transmission. The levels of defensins are frequently elevated in genital fluids from individuals with STIs. We have previously shown that human defensins 5 and 6 (HD5 and HD6) promote HIV entry and contribute to Neisseria gonorrhoeae-mediated enhancement of HIV infectivity in vitro. In this study, we dissect the molecular mechanism of the HIV enhancing effect of defensins. RESULTS: HD5 and HD6 primarily acted on the virion to promote HIV infection. Both HD5 and HD6 antagonized the anti-HIV activities of inhibitors of HIV entry (TAK 779) and fusion (T-20) when the inhibitors were present only during viral attachment; however, when these inhibitors were added back during viral infection they overrode the HIV enhancing effect of defensins. HD5 and HD6 enhanced HIV infectivity by promoting HIV attachment to target cells. Studies using fluorescent HIV containing Vpr-GFP indicated that these defensins enhanced HIV attachment by concentrating virus particles on the target cells. HD5 and HD6 blocked anti-HIV activities of soluble glycosaminoglycans including heparin, chondroitin sulfate, and dextran sulfate. However, heparin, at a high concentration, diminished the HIV enhancing effect of HD5, but not HD6. Additionally, the degree of the HIV enhancing effect of HD5, but not HD6, was increased in heparinase-treated cells. These results suggest that HD5 and haparin/heparan sulfate compete for binding to HIV. CONCLUSIONS: HD5 and HD6 increased HIV infectivity by concentrating virus on the target cells. These defensins may have a negative effect on the efficacy of microbicides, especially in the setting of STIs. PMID- 21672196 TI - Alcohol use disorders in the emergency ward: choice of the best mode of assessment and identification of at-risk situations. AB - BACKGROUND: This study aims to identify the prevalence and at-risk situations of alcohol use disorders among patients examined in the emergency department and to compare the scales commonly used to identify alcohol use disorders. METHODS: We used the CAGE and AUDIT questionnaires and a structured interview, the MINI. FINDINGS: Of the presenting patients, 9.5% met the DSM-IV criteria for alcohol use disorders. The CAGE questionnaire was less sensitive (75%) and more specific (92%) than the AUDIT (87 and 80%, respectively). The typical alcohol-dependent patient is a young man who is unemployed and brought to the emergency department by the police. During the past 24 h, he has consumed alcohol, nicotine, cocaine, sedatives or cannabis. CONCLUSION: Of the patients, 9.5% examined in the emergency department present with alcohol abuse or dependence without asking spontaneously for treatment for their addiction. These results support the importance of systematically identifying alcohol use disorders with a simple and rapid questionnaire such as the CAGE questionnaire. PMID- 21672197 TI - Adverse events analysis as an educational tool to improve patient safety culture in primary care: a randomized trial. AB - BACKGROUND: Patient safety is a leading item on the policy agenda of both major international health organizations and advanced countries generally. The quantitative description of the phenomena has given rise to intense concern with the issue in institutions and organizations, leading to a number of initiatives and research projects and the promotion of patient safety culture, with training becoming a priority both in Spain and internationally. To date, most studies have been conducted in a hospital setting, even though primary care is the type most commonly used by the public, in our experience. Our study aims to achieve the following:--Assess the registry of adverse events as an education tool to improve patient safety culture in the Family and Community Teaching Units of Galicia.- Find and analyze educational tools to improve patient safety culture in primary care.--Evaluate the applicability of the Hospital Survey on Patient Safety Culture by the Agency for Healthcare Research and Quality, Spanish version, in the context of primary health care. DESIGN AND METHODS: DESIGN: Experimental unifactorial study of two groups, control and intervention. STUDY POPULATION: Tutors and residents in Family and Community Medicine in last year of studies in Galicia, Spain. SAMPLE: From the population universe through voluntary participation. Twenty-seven tutor-resident units in each group required, randomly assigned. INTERVENTION: Residents and their respective tutor (tutor-resident pair) in teaching units on Family and Community Medicine from throughout Galicia will be invited to participate. Tutor-resident pair that agrees to participate will be sent the Hospital Survey on Patient Safety Culture. Then, tutor-resident pair will be assigned to each group--either intervention or control--through simple random sampling. The intervention group will receive specific training to record the adverse effects found in patients under their care, with subsequent feedback, after receiving instruction on the process. No action will be taken in the control group. After the intervention has ended, the survey will once again be provided to all participants. OUTCOME MEASURES: Change in safety culture as measured by Hospital Survey on Patient Safety CultureCONSORT Extension for Non Pharmacologic Treatments 2008 was applied. DISCUSSION: The most significant limitations on the project are related to selecting a tool to measure the safety environment, the training calendar of residents in Family and Community Medicine in last year of studies and the no-answer bias inherent to research conducted through self-administered surveys.The development and application of a safety culture in the health sector, specifically in primary care, is as yet limited. Thus, identifying the strengths and weaknesses in the safety environment may assist in designing strategies for improvement in the primary care health centers of our region. TRIAL REGISTRATION: ISRCTN: ISRCTN41911128. PMID- 21672199 TI - Effects on duration of post-operative ischemia and patterns of blood flow recovery in different conditions of mouse hind limb ischemia. AB - BACKGROUND: Current limitations to the experimentation on patients with peripheral arterial disease push the development of different preclinical strategies. We investigated both duration of ischemia and blood flow recovery in mouse models of partial femoral artery ligation. METHODS: Male BALB/c mice were used. The ligation over needle method involved placing a suture needle over the femoral artery, ligating over it and then removing the needle. The transfixation method involved transfixing the approximate center of the femoral artery and then tying the suture. Laser Doppler Perfusion Imaging was used to assess perfusion every 3rd day until 42 days after the procedure. RESULTS: Ligation over needle method: Immediately post procedure, mean perfusion was -71.87% +/- 4.43. Then mean difference in perfusion remained below the base line reading on days 3, 6, 9, and 12. From day 15 on wards mean perfusion progressively improved remaining near base line. Transfixation Method: Immediately post procedure mean perfusion was -70.82% +/- 4.73. Mean perfusion improved following the procedure on days 3 and 6; a plateau followed this on days 9, 12 and 15. From day 15 onwards perfusion progressively improved remaining well below base line until crossing it on day 36. CONCLUSION: The currently described models do not pose major improvements over previously described methods. PMID- 21672193 TI - Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema. AB - BACKGROUND: Smoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists. We summarize evidence for various smoking indices. METHODS: Based on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking. Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded. Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment. For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics. RESULTS: Of 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema. RR estimates are markedly heterogeneous. Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11 2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94). For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition. Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated. For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function. For all outcomes, risk increases with amount smoked and pack-years. Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD. No clear relationship is seen with duration of smoking. CONCLUSIONS: The results confirm and quantify the causal relationships with smoking. PMID- 21672198 TI - Frequency of symptoms, determinants of severe symptoms, validity of and cut-off score for Menopause Rating Scale (MRS) as a screening tool: a cross-sectional survey among midlife Nepalese women. AB - BACKGROUND: Majority of Nepalese women live in remote rural areas, where health services are not easily accessible. We determined the validity of Menopause Rating Scale (MRS) as a screening tool for identification of women with severe menopausal symptoms and cut-off MRS score for referral. METHODS: A cross sectional survey was carried out between February and August, 2008. Trained health workers administered MRS and a questionnaire to 729 women (40 to 65 years) attending health screening camps in Kaski district of Western Development Region of Nepal. Information about demographics, menopausal status, and use of hormone replacement therapy (HRT), chronic disease, self-perceived general health and reproductive history was also collected. Menopausal status was classified according to the Staging of Reproductive Ageing Workshop (STRAW). We calculated rates of menopausal symptoms, sensitivity, and specificity and likelihood ratios of MRS scores for referral to a gynaecologist. We also carried out multivariate analyses to identify the predictors for referral to a gynaecologist for severe symptoms. RESULTS: A total 729 women were interviewed. Mean age at menopause was 49.9 years (SD 5.6). Most frequently reported symptoms were, sleeping problems (574, 78.7%), physical and mental exhaustion (73.5%), hot flushes (508, 69.7%), joint and muscular discomfort (500, 68.6%) and dryness of vagina (449, 61.6%). Postmenopausal women (247, 33.9%) and perimenopausal (215, 29.5%) women together experienced significantly higher prevalence of all symptoms than the premenopausal (267, 36.6%) women. MRS score of >=16 had highest ratio for (sensitivity + specificity)/2. Women who reported urogenital symptoms [OR 5.29, 95% CI 2.59, 10.78], and self perceived general health as poor [OR 1.29, 95% CI 1.11, 1.53] were more likely to be referred to a gynaecologist for severe menopausal symptoms. While women reporting somatic [OR 0.72, 95% CI 0.63, 0.82] and psychological [OR 0.86, 95% CI 0.74, 0.99] symptoms were less likely to be referred. CONCLUSION: MRS may be used as a screening tool at a cut-off score of >=16 with least misclassification rate. However, its utility may be limited by woman's general health status and occurrence of urogenital symptoms. PMID- 21672200 TI - The role of age in predicting the outcome of caustic ingestion in adults: a retrospective analysis. AB - BACKGROUND: Although the outcomes of caustic ingestion differ between children and adults, it is unclear whether such outcomes differ among adults as a function of their age. This retrospective study was performed to ascertain whether the clinical outcomes of caustic ingestion differ significantly between elderly and non-elderly adults. METHODS: Medical records of patients hospitalized for caustic ingestion between June 1999 and July 2009 were reviewed retrospectively. Three hundred eighty nine patients between the ages of 17 and 107 years were divided into two groups: non-elderly (< 65 years) and elderly (>= 65 years). Mucosal damage was graded using esophagogastroduodenoscopy (EGD). Parameters examined in this study included gender, intent of ingestion, substance ingested, systemic and gastrointestinal complications, psychological and systemic comorbidities, severity of mucosal injury, and time to expiration. RESULTS: The incidence of psychological comorbidities was higher for the non-elderly group. By contrast, the incidence of systemic comorbidities, the grade of severity of mucosal damage, and the incidence of systemic complications were higher for the elderly group. The percentages of ICU admissions and deaths in the ICU were higher and the cumulative survival rate was lower for the elderly group. Elderly subjects, those with systemic complications had the greatest mortality risk due to caustic ingestion. CONCLUSIONS: Caustic ingestion by subjects >=65 years of age is associated with poorer clinical outcomes as compared to subjects < 65 years of age; elderly subjects with systemic complications have the poorest clinical outcomes. The severity of gastrointestinal tract injury appears to have no impact on the survival of elderly subjects. PMID- 21672201 TI - Cor triatriatum presenting as heart failure with reduced ejection fraction: a case report. AB - Cor triatriatum is a rare congenital cardiac malformation and it usually refers to the left atrium. We report an unusual case of cor triatriatum in a 33 - year old woman presented with congestive heart failure caused by left ventricular systolic dysfunction. PMID- 21672202 TI - Dynamics of HPV vaccination initiation in Flanders (Belgium) 2007-2009: a Cox regression model. AB - BACKGROUND: We investigated dynamic patterns and predictors of HPV vaccination initiation in Flanders (Belgium) by girls aged 12 to 18, between 2007 and 2009, the period immediately after the introduction of the HPV vaccines on the Belgian market. During this period the initiative for vaccination was taken by the girl, her family or the general practitioner/pediatrician/gynecologist. METHODS: We used a Cox regression model with time constant and time varying predictors to model hazard rates of HPV vaccination initiation. The sample existed of 117,151 female members of the National Alliance of Christian Mutualities, the largest sickness fund in Flanders. RESULTS: The study showed that the hazard of HPV vaccination initiation was higher (1) for older girls, (2) for girls with a more favorable socio-economic background, (3) under more generous reimbursement regimes (with this effect being more pronounced for girls with weak socioeconomic backgrounds), (4) for girls that were informed personally about the reimbursement rules. CONCLUSIONS: When the initiative for HPV vaccination lies with the girls, their families or the physicians (no organized setting) the uptake of the vaccines is affected by both individual and organizational factors. PMID- 21672203 TI - Baseline characteristics and patient reported outcome data of patients prescribed etanercept: web-based and telephone evaluation. AB - BACKGROUND: The anti-TNF inhibitor, etanercept is administered as a once or twice weekly subcutaneous injection for the treatment of rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis (JIA). Limited data from the patients' perspective are available on the use of biologics in the treatment of these chronic conditions and this evaluation was designed to collect data from patients who had been prescribed etanercept for the first time. This manuscript describes the self-reported baseline characteristics and health-related quality of life of patients prior to treatment. Follow-up data will be reported separately. METHODS: Patients throughout the United Kingdom prescribed etanercept were invited to participate in an evaluation of their condition and treatment using a data collection tool consisting of a web-based system supplemented by telephone reporting (PROBE). Outcome measures reported at baseline included demographic data, the condition being treated, previous treatment with biologic agents and current and previous medications. Questions modified from standard, validated quality of life questionnaires such as EQ-5D were incorporated and patients made a global assessment of the severity of their own illness using the CGI-S scale. RESULTS: A total of 344 patients/carers/parents participated in the evaluation at baseline, 290 (84%) by online questionnaire and 54 (16%) by telephone. Overall, the study population had a mean age of 53 years, was predominantly female (62%) and 20% had been previously treated with a biologic agent. A total of 191 (56%) patients were receiving treatment with etanercept for rheumatoid arthritis, 44 (13%) for psoriatic arthritis, 43 (13%) for ankylosing spondylitis, 35 (10%) for psoriasis, 9 (3%) for known juvenile idiopathic arthritis (JIA) and 22 (6%) for another condition/patient unsure/missing response. All patients were prescribed the 50 mg weekly dose of etanercept except for 1 patient with JIA (40 mg) dose and 2 patients with psoriasis (100 mg). Thirty-eight percent of patients with rheumatoid arthritis were not receiving treatment with methotrexate. CONCLUSIONS: The baseline characteristics and health-related quality of life of first time users of etanercept can be adequately described using self-reported patient data collected using an online questionnaire with a telephone option (PROBE). PMID- 21672204 TI - A post-trial survey to assess the impact of dissemination of results and unmasking on participants in a 13-year randomised controlled trial on age-related cataract. AB - BACKGROUND: The Italian-American Clinical Trial of Nutritional Supplements and Age-Related Cataract was designed to assess the impact of a multivitamin-mineral supplement on age-related cataract. Trial results showed evidence of a beneficial effect of the supplement on all types of cataract combined, opposite effects on two of the three types of cataract (beneficial for nuclear opacities and harmful for posterior sub-capsular opacities) and no statistically significant effect on cortical opacities. No treatment recommendations were made. A post-trial survey was conducted on 817 surviving elderly participants to assess their satisfaction, their understanding of treatment assignment to supplement or placebo and the success of masking. METHODS: Trial results were communicated by letter and the level of satisfaction and of understanding of the results was assessed by a questionnaire. Participants were offered the option of being unmasked: a second questionnaire was administered to this subset to assess their understanding of the randomisation process and the success of masking. RESULTS: 610 participants (74.7%) responded to the survey:94.6% thought the description of the results was "very clear" or "quite clear", 5.4% "not clear" or "do not know"; 89.8% considered the results "very interesting" or "quite interesting", 10.2% "not interesting" or "do not know"; 60.3% expressed "satisfaction", 17.2% "both satisfaction and concern", 2.6% "concern", 19.9% "indifference" or "do not know".480 participants (78.7%) accepted the offer to be unmasked to their treatment assignment: 395 (82.3%) recalled/understood the possibility of assignment to vitamins or placebo, 85 (17.7%) did not. 68 participants (17.2%) thought they had taken vitamins (79.4% were correct; p = 0.0006), 47 (11.9%) thought they had taken placebo (59.6% were correct; p = 0.46) and 280 (70.9%) declared they did not know. CONCLUSIONS: The results were made difficult to explain to study participants by the qualitatively different effect of treatment on the two most visually significant types of cataract. Although the study did not lead to a recommendation to use the dietary supplement, the vast majority of participants reported satisfaction after they received the results but almost 20% of the participants expressed some concern. Masking to treatment assignment was successful in the majority of participants. PMID- 21672205 TI - CHAMP: Cognitive behaviour therapy for health anxiety in medical patients, a randomised controlled trial. AB - BACKGROUND: Abnormal health anxiety, also called hypochondriasis, has been successfully treated by cognitive behaviour therapy (CBT) in patients recruited from primary care, but only one pilot trial has been carried out among those attending secondary medical clinics where health anxiety is likely to be more common and have a greater impact on services. The CHAMP study extends this work to examine both the clinical and cost effectiveness of CBT in this population. METHOD/DESIGN: The study is a randomized controlled trial with two parallel arms and equal randomization of 466 eligible patients (assuming a 20% drop-out) to an active treatment group of 5-10 sessions of cognitive behaviour therapy and to a control group. The aim at baseline, after completion of all assessments but before randomization, was to give a standard simple explanation of the nature of health anxiety for all participants. Subsequently the control group was to receive whatever care might usually be available in the clinics, which is normally a combination of clinical assessment, appropriate tests and reassurance. Those allocated to the active treatment group were planned to receive between 5 and 10 sessions of an adapted form of cognitive behaviour therapy based on the Salkovskis/Warwick model, in which a set of treatment strategies are chosen aimed at helping patients understand the factors that drive and maintain health anxiety. The therapy was planned to be given by graduate research workers, nurses or other health professionals trained for this intervention whom would also have their competence assessed independently during the course of treatment. The primary outcome is reduction in health anxiety symptoms after one year and the main secondary outcome is the cost of care after two years. DISCUSSION: This represents the first trial of adapted cognitive behaviour therapy in health anxiety that is large enough to test not only the clinical benefits of treatment but also whether the cost of treatment is offset by savings from reduced use of other health services in comparison to the control group.Cognitive behaviour therapy for Health Anxiety in Medical Patients (CHAMP) TRIAL REGISTRATION: Current Controlled Trials ISRCTN14565822. PMID- 21672206 TI - Structure and epitope distribution of heparan sulfate is disrupted in experimental lung hypoplasia: a glycobiological epigenetic cause for malformation? AB - BACKGROUND: Heparan sulfate (HS) is present on the surface of virtually all mammalian cells and is a major component of the extracellular matrix (ECM), where it plays a pivotal role in cell-cell and cell-matrix cross-talk through its large interactome. Disruption of HS biosynthesis in mice results in neonatal death as a consequence of malformed lungs, indicating that HS is crucial for airway morphogenesis. Neonatal mortality (~50%) in newborns with congenital diaphragmatic hernia (CDH) is principally associated with lung hypoplasia and pulmonary hypertension. Given the importance of HS for lung morphogenesis, we investigated developmental changes in HS structure in normal and hypoplastic lungs using the nitrofen rat model of CDH and semi-synthetic bacteriophage ('phage) display antibodies, which identify distinct HS structures. RESULTS: The pulmonary pattern of elaborated HS structures is developmentally regulated. For example, the HS4E4V epitope is highly expressed in sub-epithelial mesenchyme of E15.5 - E17.5 lungs and at a lower level in more distal mesenchyme. However, by E19.5, this epitope is expressed similarly throughout the lung mesenchyme.We also reveal abnormalities in HS fine structure and spatiotemporal distribution of HS epitopes in hypoplastic CDH lungs. These changes involve structures recognised by key growth factors, FGF2 and FGF9. For example, the EV3C3V epitope, which was abnormally distributed in the mesenchyme of hypoplastic lungs, is recognised by FGF2. CONCLUSIONS: The observed spatiotemporal changes in HS structure during normal lung development will likely reflect altered activities of many HS-binding proteins regulating lung morphogenesis. Abnormalities in HS structure and distribution in hypoplastic lungs can be expected to perturb HS:protein interactions, ECM microenvironments and crucial epithelial-mesenchyme communication, which may contribute to lung dysmorphogenesis. Indeed, a number of epitopes correlate with structures recognised by FGFs, suggesting a functional consequence of the observed changes in HS in these lungs. These results identify a novel, significant molecular defect in hypoplastic lungs and reveals HS as a potential contributor to hypoplastic lung development in CDH. Finally, these results afford the prospect that HS-mimetic therapeutics could repair defective signalling in hypoplastic lungs, improve lung growth, and reduce CDH mortality. PMID- 21672207 TI - Stanniocalcin-1 promotes tumor angiogenesis through up-regulation of VEGF in gastric cancer cells. AB - BACKGROUND: Stanniocalcin-1(STC-1) is up-regulated in several cancers including gastric cancer. Evidences suggest that STC-1 is associated with carcinogenesis and angiogenic process. However, it is unclear on the exact role for STC-1 in inducing angiogenesis and tumorigeneisis. METHOD: BGC/STC cells (high-expression of STC-1) and BGC/shSTC cells (low- expression of STC-1) were constructed to investigate the effect of STC-1 on the xenograft tumor growth and angiogenesis in vitro and in vivo. ELISA assay was used to detect the expression of vascular endothelial growth factor (VEGF) in the supernatants. Neutralizing antibody was used to inhibit VEGF expression in supernatants. The expression of phosphorylated -PKCbetaII, phosphorylated -ERK1/2 and phosphorylated -P38 in the BGC treated with STC-1protein was detected by western blot. RESULTS: STC-1 could promote angiogenesis in vitro and in vivo, and the angiogenesis was consistent with VEGF expression in vitro. Inhibition of VEGF expression in supernatants with neutralizing antibody markedly abolished angiogenesis induced by STC-1 in vitro. The process of STC-1-regulated VEGF expression was mediated via PKCbetaII and ERK1/2. CONCLUSIONS: STC-1 promotes the expression of VEGF depended on the activation of PKCbetaII and ERK1/2 pathways. VEGF subsequently enhances tumor angiogenesis which in turn promotes the gastric tumor growth. PMID- 21672208 TI - ATRX has a critical and conserved role in mammalian sexual differentiation. AB - BACKGROUND: X-linked alpha thalassemia, mental retardation syndrome in humans is a rare recessive disorder caused by mutations in the ATRX gene. The disease is characterised by severe mental retardation, mild alpha-thalassemia, microcephaly, short stature, facial, skeletal, genital and gonadal abnormalities. RESULTS: We examined the expression of ATRX and ATRY during early development and gonadogenesis in two distantly related mammals: the tammar wallaby (a marsupial) and the mouse (a eutherian). This is the first examination of ATRX and ATRY in the developing mammalian gonad and fetus. ATRX and ATRY were strongly expressed in the developing male and female gonad respectively, of both species. In testes, ATRY expression was detected in the Sertoli cells, germ cells and some interstitial cells. In the developing ovaries, ATRX was initially restricted to the germ cells, but was present in the granulosa cells of mature ovaries from the primary follicle stage onwards and in the corpus luteum. ATRX mRNA expression was also examined outside the gonad in both mouse and tammar wallaby whole embryos. ATRX was detected in the developing limbs, craniofacial elements, neural tissues, tail and phallus. These sites correspond with developmental deficiencies displayed by ATR-X patients. CONCLUSIONS: There is a complex expression pattern throughout development in both mammals, consistent with many of the observed ATR X syndrome phenotypes in humans. The distribution of ATRX mRNA and protein in the gonads was highly conserved between the tammar and the mouse. The expression profile within the germ cells and somatic cells strikingly overlaps with that of DMRT1, suggesting a possible link between these two genes in gonadal development. Taken together, these data suggest that ATRX has a critical and conserved role in normal development of the testis and ovary in both the somatic and germ cells, and that its broad roles in early mammalian development and gonadal function have remained unchanged for over 148 million years of mammalian evolution. PMID- 21672209 TI - The embryonic development of the central American wandering spider Cupiennius salei. AB - BACKGROUND: The spider Cupiennius salei (Keyserling 1877) has become an important study organism in evolutionary and developmental biology. However, the available staging system for its embryonic development is difficult to apply to modern studies, with strong bias towards the earliest developmental stages. Furthermore, important embryonic events are poorly understood. We address these problems, providing a new description of the embryonic development of C. salei. The paper also discusses various observations that will improve our understanding of spider development. RESULTS: Conspicuous developmental events were used to define numbered stages 1 to 21. Stages 1 to 9 follow the existing staging system for the spider Achaearanea tepidariorum, and stages 10 to 21 provide a high-resolution description of later development. Live-embryo imaging shows cell movements during the earliest formation of embryonic tissue in C. salei. The imaging procedure also elucidates the encircling border between the cell-dense embryo hemisphere and the hemisphere with much lower cell density (a structure termed 'equator' in earlier studies). This border results from subsurface migration of primordial mesendodermal cells from their invagination site at the blastopore. Furthermore, our detailed successive sequence shows: 1) early differentiation of the precheliceral neuroectoderm; 2) the morphogenetic process of inversion and 3) initial invaginations of the opisthosomal epithelium for the respiratory system. CONCLUSIONS: Our improved staging system of development in C. salei development should be of considerable value to future comparative studies of animal development. A dense germ disc is not evident during development in C. salei, but we show that the gastrulation process is similar to that in spider species that do have a dense germ disc. In the opisthosoma, the order of appearance of precursor epithelial invaginations provides evidence for the non-homology of the tracheal and book lung respiratory systems. PMID- 21672210 TI - Personal genome testing: test characteristics to clarify the discourse on ethical, legal and societal issues. AB - BACKGROUND: As genetics technology proceeds, practices of genetic testing have become more heterogeneous: many different types of tests are finding their way to the public in different settings and for a variety of purposes. This diversification is relevant to the discourse on ethical, legal and societal issues (ELSI) surrounding genetic testing, which must evolve to encompass these differences. One important development is the rise of personal genome testing on the basis of genetic profiling: the testing of multiple genetic variants simultaneously for the prediction of common multifactorial diseases. Currently, an increasing number of companies are offering personal genome tests directly to consumers and are spurring ELSI-discussions, which stand in need of clarification. This paper presents a systematic approach to the ELSI-evaluation of personal genome testing for multifactorial diseases along the lines of its test characteristics. DISCUSSION: This paper addresses four test characteristics of personal genome testing: its being a non-targeted type of testing, its high analytical validity, low clinical validity and problematic clinical utility. These characteristics raise their own specific ELSI, for example: non-targeted genetic profiling poses serious problems for information provision and informed consent. Questions about the quantity and quality of the necessary information, as well as about moral responsibilities with regard to the provision of information are therefore becoming central themes within ELSI-discussions of personal genome testing. Further, the current low level of clinical validity of genetic profiles raises questions concerning societal risks and regulatory requirements, whereas simultaneously it causes traditional ELSI-issues of clinical genetics, such as psychological and health risks, discrimination, and stigmatization, to lose part of their relevance. Also, classic notions of clinical utility are challenged by the newer notion of 'personal utility.' SUMMARY: Consideration of test characteristics is essential to any valuable discourse on the ELSI of personal genome testing for multifactorial diseases. Four key characteristics of the test - targeted/non-targeted testing, analytical validity, clinical validity and clinical utility - together determine the applicability and the relevance of ELSI to specific tests. The paper identifies and discusses four areas of interest for the ELSI-debate on personal genome testing: informational problems, risks, regulatory issues, and the notion of personal utility. PMID- 21672211 TI - Effects of aerobic exercise therapy and cognitive behavioural therapy on functioning and quality of life in amyotrophic lateral sclerosis: protocol of the FACTS-2-ALS trial. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting motor neurons in the spinal cord, brainstem and motor cortex, leading to muscle weakness. Muscle weakness may result in the avoidance of physical activity, which exacerbates disuse weakness and cardiovascular deconditioning. The impact of the grave prognosis may result in depressive symptoms and hopelessness. Since there is no cure for ALS, optimal treatment is based on symptom management and preservation of quality of life (QoL), provided in a multidisciplinary setting. Two distinctly different therapeutic interventions may be effective to improve or preserve daily functioning and QoL at the highest achievable level: aerobic exercise therapy (AET) to maintain or enhance functional capacity and cognitive behavioural therapy (CBT) to improve coping style and cognitions in patients with ALS. However, evidence to support either approach is still insufficient, and the underlying mechanisms of the approaches remain poorly understood. The primary aim of the FACTS-2-ALS trial is to study the effects of AET and CBT, in addition to usual care, compared to usual care alone, on functioning and QoL in patients with ALS. METHODS/DESIGN: A multicentre, single-blinded, randomized controlled trial with a postponed information model will be conducted. A sample of 120 patients with ALS (1 month post diagnosis) will be recruited from 3 university hospitals and 1 rehabilitation centre. Patients will be randomized to one of three groups i.e. (1) AET + usual care, (2) CBT + usual care, (3) Usual care. AET consists of a 16-week aerobic exercise programme, on 3 days a week. CBT consists of individual psychological support of patients in 5 to 10 sessions over a 16-week period. QoL, functioning and secondary outcome measures will be assessed at baseline, immediately post intervention and at 3- and 6-months follow-up. DISCUSSION: The FACTS-2-ALS study is the first theory-based randomized controlled trial to evaluate the effects, and the maintenance of effects, of AET and CBT on functioning and QoL in patients with ALS. The results of this study are expected to generate new evidence for the effect of multidisciplinary care of persons with ALS. TRIAL REGISTRATION: Dutch Trial Register NTR1616. PMID- 21672212 TI - Low visual information-processing speed and attention are predictors of fatigue in elementary and junior high school students. AB - BACKGROUND: Fatigue is a common complaint among elementary and junior high school students, and is known to be associated with reduced academic performance. Recently, we demonstrated that fatigue was correlated with decreased cognitive function in these students. However, no studies have identified cognitive predictors of fatigue. Therefore, we attempted to determine independent cognitive predictors of fatigue in these students. METHODS: We performed a prospective cohort study. One hundred and forty-two elementary and junior high school students without fatigue participated. They completed a variety of paper-and pencil tests, including list learning and list recall tests, kana pick-out test, semantic fluency test, figure copying test, digit span forward test, and symbol digit modalities test. The participants also completed computerized cognitive tests (tasks A to E on the modified advanced trail making test). These cognitive tests were used to evaluate motor- and information-processing speed, immediate and delayed memory function, auditory and visual attention, divided and switching attention, retrieval of learned material, and spatial construction. One year after the tests, a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) was administered to all the participants. RESULTS: After the follow-up period, we confirmed 40 cases of fatigue among 118 students. In multivariate logistic regression analyses adjusted for grades and gender, poorer performance on visual information-processing speed and attention tasks was associated with increased risk of fatigue. CONCLUSIONS: Reduced visual information-processing speed and poor attention are independent predictors of fatigue in elementary and junior high school students. PMID- 21672213 TI - Immediate vs. delayed insertion of intrauterine contraception after second trimester abortion: study protocol for a randomized controlled trial. AB - BACKGROUND: We describe the rationale and protocol for a randomized controlled trial (RCT) to assess whether intrauterine contraception placed immediately after a second trimester abortion will result in fewer pregnancies than current recommended practice of intended placement at 4 weeks post-abortion. Decision analysis suggests the novel strategy could substantially reduce subsequent unintended pregnancies and abortions. This paper highlights considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion. METHODS/DESIGN: Consenting women choosing to use intrauterine contraception after abortion for a pregnancy of 12 to 24 weeks will be randomized to insertion timing groups either immediately (experimental intervention) or four weeks (recommended care) post abortion. Primary outcome measure is pregnancy rate at one year. Secondary outcomes include: cumulative pregnancy rates over five year follow-up period, comprehensive health economic analyses comparing immediate and delayed insertion groups, and device retention rates, complication rates (infection, expulsion) and, contraceptive method satisfaction. Web-based Contraception Satisfaction Questionnaires, clinical records and British Columbia linked health databases will be used to assess primary and secondary outcomes. Enrolment at all clinics in the province performing second trimester abortions began in May 2010 and is expected to complete in late 2011. Data on one year outcomes will be available for analysis in 2014. DISCUSSION: The RCT design combined with access to clinical records at all provincial abortion clinics, and to information in provincial single-payer linked administrative health databases, birth registry and hospital records, offers a unique opportunity to evaluate such an approach by determining pregnancy rate at one through five years among enrolled women. We highlight considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion. PMID- 21672214 TI - Unraveling the rapid radiation of crested newts (Triturus cristatus superspecies) using complete mitogenomic sequences. AB - BACKGROUND: The rapid radiation of crested newts (Triturus cristatus superspecies) comprises four morphotypes: 1) the T. karelinii group, 2) T. carnifex - T. macedonicus, 3) T. cristatus and 4) T. dobrogicus. These vary in body build and the number of rib-bearing pre-sacral vertebrae (NRBV). The phylogenetic relationships of the morphotypes have not yet been settled, despite several previous attempts, employing a variety of molecular markers. We here resolve the crested newt phylogeny by using complete mitochondrial genome sequences. RESULTS: Bayesian inference based on the mitogenomic data yields a fully bifurcating, significantly supported tree, though Maximum Likelihood inference yields low support values. The internal branches connecting the morphotypes are short relative to the terminal branches. Seen from the root of Triturus (NRBV = 13), a basal dichotomy separates the T. karelinii group (NRBV = 13) from the remaining crested newts. The next split divides the latter assortment into T. carnifex - T. macedonicus (NRBV = 14) versus T. cristatus (NRBV = 15) and T. dobrogicus (NRBV = 16 or 17). CONCLUSIONS: We argue that the Bayesian full mitochondrial DNA phylogeny is superior to previous attempts aiming to recover the crested newt species tree. Furthermore, our new phylogeny involves a maximally parsimonious interpretation of NRBV evolution. Calibrating the phylogeny allows us to evaluate potential drivers for crested newt cladogenesis. The split between the T. karelinii group and the three other morphotypes, at ca. 10.4 Ma, is associated with the separation of the Balkan and Anatolian landmasses (12-9 Ma). No currently known vicariant events can be ascribed to the other two splits, first at ca. 9.3 Ma, separating T. carnifex - T. macedonicus, and second at ca. 8.8 Ma, splitting T. cristatus and T. dobrogicus. The crested newt morphotypes differ in the duration of their annual aquatic period. We speculate on the role that this ecological differentiation could have played during speciation. PMID- 21672215 TI - Immunohistochemical analysis of ezrin-radixin-moesin-binding phosphoprotein 50 in prostatic adenocarcinoma. AB - BACKGROUND: Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is an adapter protein which has been shown to play an active role in a wide variety of cellular processes, including interactions with proteins related to both tumor suppression and oncogenesis. Here we use immunohistochemistry to evaluate EBP50's expression in normal donor prostate (NDP), benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets). METHODS: Tissue microarrays were immunohistochemically stained for EBP50, with the staining intensities quantified using automated image analysis software. The data were statistically analyzed using one-way ANOVA with subsequent Tukey tests for multiple comparisons. Eleven cases of NDP, 37 cases of NAC, 15 cases of BPH, 35 cases of HGPIN, 103 cases of PCa, and 36 cases of Mets were analyzed in the microarrays. RESULTS: Specimens of PCa and Mets had the lowest absolute staining for EBP50. Mets staining was significantly lower than NDP (p = 0.027), BPH (p = 0.012), NAC (p < 0.001), HGPIN (p < 0.001), and PCa (p = 0.006). Additionally, HGPIN staining was significantly higher than NAC (p < 0.009) and PCa (p < 0.001). CONCLUSIONS: To our knowledge, this represents the first study comparing the immunohistochemical profiles of EBP50 in PCa and Mets to specimens of HGPIN, BPH, NDP, and NAC and suggests that EBP50 expression is decreased in Mets. Given that PCa also had significantly higher expression than Mets, future studies are warranted to assess EBP50's potential as a prognostic biomarker for prostate cancer. PMID- 21672216 TI - Zoonoses and marginalised infectious diseases of poverty: where do we stand? AB - Despite growing awareness of the importance of controlling neglected tropical diseases as a contribution to poverty alleviation and achieving the Millennium Development Goals, there is a need to up-scale programmes to achieve wider public health benefits. This implementation deficit is attributable to several factors but one often overlooked is the specific difficulty in tackling diseases that involve both people and animals - the zoonoses. A Disease Reference Group on Zoonoses and Marginalised Infectious Diseases (DRG6) was convened by the Special Programme for Research and Training in Tropical Diseases (TDR), a programme executed by the World Health Organization and co-sponsored by UNICEF, UNDP, the World Bank and WHO. The key considerations included: (a) the general lack of reliable quantitative data on their public health burden; (b) the need to evaluate livestock production losses and their additional impacts on health and poverty; (c) the relevance of cross-sectoral issues essential to designing and implementing public health interventions for zoonotic diseases; and (d) identifying priority areas for research and interventions to harness resources most effectively. Beyond disease specific research issues, a set of common macro priorities and interventions were identified which, if implemented through a more integrated approach by countries, would have a significant impact on human health of the most marginalised populations characteristically dependent on livestock. PMID- 21672217 TI - Effectiveness, relapse prevention and mechanisms of change of cognitive therapy vs. interpersonal therapy for depression: Study protocol for a randomised controlled trial. AB - BACKGROUND: Major depression is a common mental disorder that substantially impairs quality of life and has high societal costs. Although psychotherapies have proven to be effective antidepressant treatments, initial response rates are insufficient and the risk of relapse and recurrence is high. Improvement of treatments is badly needed. Studying the mechanisms of change in treatment might be a good investment for improving everyday mental health care. However, the mechanisms underlying therapeutic change remain largely unknown. The objective of the current study is to assess both the effectiveness of two commonly used psychotherapies for depression in terms of reduction of symptoms and prevention of relapse on short and long term, as well as identifying underlying mechanisms of change. METHODS: In a randomised trial we will compare (a) Cognitive Therapy (CT) with (b) Interpersonal therapy (IPT), and (c) an 8-week waiting list condition followed by treatment of choice. One hundred eighty depressed patients (aged 18-65) will be recruited in a mental health care centre in Maastricht (the Netherlands). Eligible patients will be randomly allocated to one of the three intervention groups. The primary outcome measure of the clinical evaluation is depression severity measured by the Beck Depression Intenvory-II (BDI-II). Other outcomes include process variables such as dysfunctional beliefs, negative attributions, and interpersonal problems. All self-report outcome assessments will take place on the internet at baseline, three, seven, eight, nine, ten, eleven, twelve and twenty-four months. At 24 months a retrospective telephone interview will be administered. Furthermore, a rudimentary analysis of the cost effectiveness will be embedded. The study has been ethically approved and registered. DISCUSSION: By comparing CT and IPT head-to-head and by investigating multiple potential mediators and outcomes at multiple time points during and after therapy, we hope to provide new insights in the effectiveness and mechanisms of change of CT and IPT for depression, and contribute to the improvement of mental health care for adults suffering from depression. TRIAL REGISTRATION: The study has been registered at the Netherlands Trial Register, part of the Dutch Cochrane Centre (ISRCTN67561918). PMID- 21672218 TI - Prevalence, distribution and evolutionary significance of the IS629 insertion element in the stepwise emergence of Escherichia coli O157:H7. AB - BACKGROUND: Insertion elements (IS) are known to play an important role in the evolution and genomic diversification of Escherichia coli O157:H7 lineages. In particular, IS629 has been found in multiple copies in the E. coli O157:H7 genome and is one of the most prevalent IS in this serotype. It was recently shown that the lack of O157 antigen expression in two O rough E. coli O157:H7 strains was due to IS629 insertions at 2 different locations in the gne gene that is essential for the O antigen biosynthesis. RESULTS: The comparison of 4 E. coli O157:H7 genome and plasmid sequences showed numerous IS629 insertion sites, although not uniformly distributed among strains. Comparison of IS629s found in O157:H7 and O55:H7 showed the presence of at least three different IS629 sub types. O157:H7 strains carry IS629 elements sub-type I and III whereby the ancestral O55:H7 carries sub-type II. Analysis of strains selected from various clonal groups defined on the E. coli O157:H7 stepwise evolution model showed that IS629 was not observed in sorbitol fermenting O157 (SFO157) clones that are on a divergent pathway in the emergence of O157:H7. This suggests that the absence of IS629 in SFO157 strains probably occurred during the divergence of this lineage, albeit it remains uncertain if it contributed, in part, to their divergence from other closely related strains. CONCLUSIONS: The highly variable genomic locations of IS629 in O157:H7 strains of the A6 clonal complex indicates that this insertion element probably played an important role in genome plasticity and in the divergence of O157:H7 lineages. PMID- 21672219 TI - SIDECACHE: Information access, management and dissemination framework for web services. AB - BACKGROUND: Many bioinformatics algorithms and data sets are deployed using web services so that the results can be explored via the Internet and easily integrated into other tools and services. These services often include data from other sites that is accessed either dynamically or through file downloads. Developers of these services face several problems because of the dynamic nature of the information from the upstream services. Many publicly available repositories of bioinformatics data frequently update their information. When such an update occurs, the developers of the downstream service may also need to update. For file downloads, this process is typically performed manually followed by web service restart. Requests for information obtained by dynamic access of upstream sources is sometimes subject to rate restrictions. FINDINGS: SideCache provides a framework for deploying web services that integrate information extracted from other databases and from web sources that are periodically updated. This situation occurs frequently in biotechnology where new information is being continuously generated and the latest information is important. SideCache provides several types of services including proxy access and rate control, local caching, and automatic web service updating. CONCLUSIONS: We have used the SideCache framework to automate the deployment and updating of a number of bioinformatics web services and tools that extract information from remote primary sources such as NCBI, NCIBI, and Ensembl. The SideCache framework also has been used to share research results through the use of a SideCache derived web service. PMID- 21672220 TI - Genotyping of black grouse MHC class II B using reference Strand-Mediated Conformational Analysis (RSCA). AB - BACKGROUND: The Major Histocompatibility Complex (MHC) is a cluster of genes involved in the vertebrate immune system and includes loci with an extraordinary number of alleles. Due to the complex evolution of MHC genes, alleles from different loci within the same MHC class can be very similar and therefore difficult to assign to separate loci. Consequently, single locus amplification of MHC genes is hard to carry out in species with recently duplicated genes in the same MHC class, and multiple MHC loci have to be genotyped simultaneously. Since amplified alleles have the same length, accurate genotyping is difficult. Reference Strand-Mediated Conformational Analysis (RSCA), which is increasingly used in studies of natural populations with multiple MHC genes, is a genotyping method capable to provide high resolution and accuracy in such cases. FINDINGS: We adapted the RSCA method to genotype multiple MHC class II B (BLB) genes in black grouse (Tetrao tetrix), a non-model galliform bird species, using a 96 Capillary Array Electrophoresis, the MegaBACETM 1000 DNA Analysing System (GE Healthcare). In this study we used fluorescently labelled reference strands from both black grouse and hazel grouse and observed good agreement between RSCA and cloning/sequencing since 71 alleles were observed by cloning/sequencing and 76 alleles by RSCA among the 24 individuals included in the comparison. At the individual level however, there was a trend towards more alleles scored with RSCA (1-6 per individual) than cloning/sequencing (1-4 per individual). In 63% of the pair-wise comparison, the identical allele was scored in RSCA as in cloning/sequencing. Nine out of 24 individuals had the same number of alleles in RSCA as in cloning/sequencing. Our RSCA protocol allows a faster RSCA genotyping than presented in many other RSCA studies. CONCLUSIONS: In this study, we have developed the RSCA typing method further to work on a 96-Capillary Array Electrophoresis (MegaBACETM 1000). Our RSCA protocol can be applied to fast and reliable screening of MHC class II B diversity of black grouse populations. This will facilitate future large-scale population studies of black grouse and other galliformes species with multiple inseparable MHC loci. PMID- 21672221 TI - A STAT-1 knockout mouse model for Machupo virus pathogenesis. AB - BACKGROUND: Machupo virus (MACV), a member of the Arenaviridae, causes Bolivian hemorrhagic fever, with ~20% lethality in humans. The pathogenesis of MACV infection is poorly understood, and there are no clinically proven treatments for disease. This is due, in part, to a paucity of small animal models for MACV infection in which to discover and explore candidate therapeutics. METHODS: Mice lacking signal transducer and activator of transcription 1 (STAT-1) were infected with MACV. Lethality, viral replication, metabolic changes, hematology, histopathology, and systemic cytokine expression were analyzed throughout the course of infection. RESULTS: We report here that STAT-1 knockout mice succumbed to MACV infection within 7-8 days, and presented some relevant clinical and histopathological manifestations of disease. Furthermore, the model was used to validate the efficacy of ribavirin in protection against infection. CONCLUSIONS: The STAT-1 knockout mouse model can be a useful small animal model for drug testing and preliminary immunological analysis of lethal MACV infection. PMID- 21672222 TI - The novel chemokine receptor CXCR7 regulates trans-endothelial migration of cancer cells. AB - BACKGROUND: Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects. METHODS: The human Burkitt's lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM behavior by various concentrations of the various cognate chemokines for the above-mentioned receptors, placed in either the source or target wells of modified Boyden chamber migration plates, was assessed by quantifying the number of cells migrated under each experimental condition. RESULTS: Exposure of CXCR4+CXCR7+ cancer cells to CXCL12 greatly potentiated their TEM towards the chemokines CCL19 and CXCL13. This CXCL12-potentiated TEM was inhibited by the second CXCR7 chemokine ligand, CXCL11, as well as CXCR7-specific small molecule antagonists and antibodies. In contrast, the CXCR4 antagonist AMD3100 was less effective at inhibiting CXCL12-potentiated TEM. Thus, CXCR7 antagonists may be effective therapeutic agents for blocking CXCL12-mediated migration of CXCR4+CXCR7+ tumor cells into lymph nodes, regardless of whether the cancer cells follow a CXCL12 gradient or whether serum CXCL12 stimulates their migration towards CCR7 and CXCR5 chemokines in the lymph nodes. PMID- 21672223 TI - Intracluster correlation coefficients and coefficients of variation for perinatal outcomes from five cluster-randomised controlled trials in low and middle-income countries: results and methodological implications. AB - BACKGROUND: Public health interventions are increasingly evaluated using cluster randomised trials in which groups rather than individuals are allocated randomly to treatment and control arms. Outcomes for individuals within the same cluster are often more correlated than outcomes for individuals in different clusters. This needs to be taken into account in sample size estimations for planned trials, but most estimates of intracluster correlation for perinatal health outcomes come from hospital-based studies and may therefore not reflect outcomes in the community. In this study we report estimates for perinatal health outcomes from community-based trials to help researchers plan future evaluations. METHODS: We estimated the intracluster correlation and the coefficient of variation for a range of outcomes using data from five community-based cluster randomised controlled trials in three low-income countries: India, Bangladesh and Malawi. We also performed a simulation exercise to investigate the impact of cluster size and number of clusters on the reliability of estimates of the coefficient of variation for rare outcomes. RESULTS: Estimates of intracluster correlation for mortality outcomes were lower than those for process outcomes, with narrower confidence intervals throughout for trials with larger numbers of clusters. Estimates of intracluster correlation for maternal mortality were particularly variable with large confidence intervals. Stratified randomisation had the effect of reducing estimates of intracluster correlation. The simulation exercise showed that estimates of intracluster correlation are much less reliable for rare outcomes such as maternal mortality. The size of the cluster had a greater impact than the number of clusters on the reliability of estimates for rare outcomes. CONCLUSIONS: The breadth of intracluster correlation estimates reported here in terms of outcomes and contexts will help researchers plan future community-based public health interventions around maternal and newborn health. Our study confirms previous work finding that estimates of intracluster correlation are associated with the prevalence of the outcome of interest, the nature of the outcome of interest (mortality or behavioural) and the size and number of clusters. Estimates of intracluster correlation for maternal mortality need to be treated with caution and a range of estimates should be used in planning future trials. PMID- 21672224 TI - Needlestick and sharps injuries among health care workers at public tertiary hospitals in an urban community in Mongolia. AB - BACKGROUND: Needlestick and sharps injuries (NSSIs) are one of the major risk factors for blood-borne infections at healthcare facilities. This study examines the current situation of NSSIs among health care workers at public tertiary hospitals in an urban community in Mongolia and explores strategies for the prevention of these injuries. FINDINGS: A survey of 621 health care workers was undertaken in two public tertiary hospitals in Ulaanbaatar, Mongolia, in July 2006. A semi-structured and self-administered questionnaire was distributed to study injection practices and the occurrence of NSSIs. A multiple logistic regression analysis was performed to investigate factors associated with experiencing NSSIs. Among the 435 healthcare workers who returned a completed questionnaire, the incidence of NSSIs during the previous 3 months was 38.4%. Health care workers were more likely to report NSSIs if they worked longer than 35 hours per week (odds ratio, OR: 2.47; 95% confidence interval, CI: 1.31-4.66) and administered more than 10 injections per day (OR: 4.76; 95% CI: 1.97-11.49). The likelihood of self-reporting NSSIs significantly decreased if health care workers adhered to universal precautions (OR: 0.34; 95% CI: 0.17-0.68). CONCLUSIONS: NSSIs are a common public health problem at public tertiary hospitals in Mongolia. The promotion of adequate working conditions, elimination of excessive injection use, and adherence to universal precautions will be important for the future control of potential infections with blood-borne pathogens due to occupational exposures to sharps in this setting. PMID- 21672225 TI - Transcriptomic analysis of Clostridium thermocellum ATCC 27405 cellulose fermentation. AB - BACKGROUND: The ability of Clostridium thermocellum ATCC 27405 wild-type strain to hydrolyze cellulose and ferment the degradation products directly to ethanol and other metabolic byproducts makes it an attractive candidate for consolidated bioprocessing of cellulosic biomass to biofuels. In this study, whole-genome microarrays were used to investigate the expression of C. thermocellum mRNA during growth on crystalline cellulose in controlled replicate batch fermentations. RESULTS: A time-series analysis of gene expression revealed changes in transcript levels of ~40% of genes (~1300 out of 3198 ORFs encoded in the genome) during transition from early-exponential to late-stationary phase. K means clustering of genes with statistically significant changes in transcript levels identified six distinct clusters of temporal expression. Broadly, genes involved in energy production, translation, glycolysis and amino acid, nucleotide and coenzyme metabolism displayed a decreasing trend in gene expression as cells entered stationary phase. In comparison, genes involved in cell structure and motility, chemotaxis, signal transduction and transcription showed an increasing trend in gene expression. Hierarchical clustering of cellulosome-related genes highlighted temporal changes in composition of this multi-enzyme complex during batch growth on crystalline cellulose, with increased expression of several genes encoding hydrolytic enzymes involved in degradation of non-cellulosic substrates in stationary phase. CONCLUSIONS: Overall, the results suggest that under low substrate availability, growth slows due to decreased metabolic potential and C. thermocellum alters its gene expression to (i) modulate the composition of cellulosomes that are released into the environment with an increased proportion of enzymes than can efficiently degrade plant polysaccharides other than cellulose, (ii) enhance signal transduction and chemotaxis mechanisms perhaps to sense the oligosaccharide hydrolysis products, and nutrient gradients generated through the action of cell-free cellulosomes and, (iii) increase cellular motility for potentially orienting the cells' movement towards positive environmental signals leading to nutrient sources. Such a coordinated cellular strategy would increase its chances of survival in natural ecosystems where feast and famine conditions are frequently encountered. PMID- 21672226 TI - A new, fast algorithm for detecting protein coevolution using maximum compatible cliques. AB - BACKGROUND: The MatrixMatchMaker algorithm was recently introduced to detect the similarity between phylogenetic trees and thus the coevolution between proteins. MMM finds the largest common submatrices between pairs of phylogenetic distance matrices, and has numerous advantages over existing methods of coevolution detection. However, these advantages came at the cost of a very long execution time. RESULTS: In this paper, we show that the problem of finding the maximum submatrix reduces to a multiple maximum clique subproblem on a graph of protein pairs. This allowed us to develop a new algorithm and program implementation, MMMvII, which achieved more than 600* speedup with comparable accuracy to the original MMM. CONCLUSIONS: MMMvII will thus allow for more more extensive and intricate analyses of coevolution. AVAILABILITY: An implementation of the MMMvII algorithm is available at: http://www.uhnresearch.ca/labs/tillier/MMMWEBvII/MMMWEBvII.php. PMID- 21672227 TI - Microcirculatory changes during open label magnesium sulphate infusion in patients with severe sepsis and septic shock. AB - BACKGROUND: Microcirculatory alterations play a pivotal role in sepsis and persist despite correction of systemic hemodynamic parameters. Therefore it seems tempting to test specific pro-microcirculatory strategies, including vasodilators, to attenuate impaired organ perfusion. As opposed to nitric oxide donors, magnesium has both endothelium-dependent and non-endothelium-dependent vasodilatory pathways. METHODS: In a single-center open label study we evaluated the effects of magnesium sulphate (MgS) infusion on the sublingual microcirculation perfusion in fluid resuscitated patients with severe sepsis and septic shock within the first 48 hours after ICU admission. Directly prior to and after 1 hour of magnesium sulphate (MgS) infusion (2 gram) systemic hemodynamic variables, sublingual SDF images and standard laboratory tests, were obtained. RESULTS: Fourteen patients (12 septic shock, 2 severe sepsis) with a median APACHE II score of 20 were enrolled. No significant difference of the systemic hemodynamic variables was found between baseline and after MgS infusion. We did not observe any significant difference pre and post MgS infusion in the primary endpoint microvascular flow index (MFI) of small vessels: 2.25(1.98-2.69) vs. 2.33(1.96-2.62), p = 0.65. Other variables of microcirculatory perfusion were also unaltered. In the overall unchanged microvascular perfusion there was a non significant trend to an inverse linear relationship between the changes of MFI and its baseline value (y = -0.7260 * + 1.629, r2 = 0.270, p = 0.057). The correlation between baseline Mg concentrations and the change in MFI pre- and post MgS infusion was non-significant (rs = -0.165, p = 0.67). CONCLUSIONS: In the setting of severe sepsis and septic shock sublingual microcirculatory alterations were observed despite fulfillment of sepsis resuscitation guidelines. After infusion of a limited and fixed dose of MgS, microcirculatory perfusion did not improve over time. TRIAL REGISTRATION: ClinicalTrials.gov NTC01332734. PMID- 21672229 TI - Palaeoclimatic events, dispersal and migratory losses along the Afro-European axis as drivers of biogeographic distribution in Sylvia warblers. AB - BACKGROUND: The Old World warbler genus Sylvia has been used extensively as a model system in a variety of ecological, genetic, and morphological studies. The genus is comprised of about 25 species, and 70% of these species have distributions at or near the Mediterranean Sea. This distribution pattern suggests a possible role for the Messinian Salinity Crisis (from 5.96-5.33 Ma) as a driving force in lineage diversification. Other species distributions suggest that Late Miocene to Pliocene Afro-tropical forest dynamics have also been important in the evolution of Sylvia lineages. Using a molecular phylogenetic hypothesis and other methods, we seek to develop a biogeographic hypothesis for Sylvia and to explicitly assess the roles of these climate-driven events. RESULTS: We present the first strongly supported molecular phylogeny for Sylvia. With one exception, species fall into one of three strongly supported clades: one small clade of species distributed mainly in Africa and Europe, one large clade of species distributed mainly in Africa and Asia, and another large clade with primarily a circum-Mediterranean distribution. Asia is reconstructed as the ancestral area for Sylvia. Long-distance migration is reconstructed as the ancestral character state for the genus, and sedentary behavior subsequently evolved seven times. CONCLUSION: Molecular clock calibration suggests that Sylvia arose in the early Miocene and diverged into three main clades by 12.6 Ma. Divergence estimates indicate that the Messinian Salinity Crisis had a minor impact on Sylvia. Instead, over-water dispersals, repeated loss of long-distance migration, and palaeo-climatic events in Africa played primary roles in Sylvia divergence and distribution. PMID- 21672228 TI - SOX10 directly modulates ERBB3 transcription via an intronic neural crest enhancer. AB - BACKGROUND: The ERBB3 gene is essential for the proper development of the neural crest (NC) and its derivative populations such as Schwann cells. As with all cell fate decisions, transcriptional regulatory control plays a significant role in the progressive restriction and specification of NC derived lineages during development. However, little is known about the sequences mediating transcriptional regulation of ERBB3 or the factors that bind them. RESULTS: In this study we identified three transcriptional enhancers at the ERBB3 locus and evaluated their regulatory potential in vitro in NC-derived cell types and in vivo in transgenic zebrafish. One enhancer, termed ERBB3_MCS6, which lies within the first intron of ERBB3, directs the highest reporter expression in vitro and also demonstrates epigenetic marks consistent with enhancer activity. We identify a consensus SOX10 binding site within ERBB3_MCS6 and demonstrate, in vitro, its necessity and sufficiency for the activity of this enhancer. Additionally, we demonstrate that transcription from the endogenous Erbb3 locus is dependent on Sox10. Further we demonstrate in vitro that Sox10 physically interacts with that ERBB3_MCS6. Consistent with its in vitro activity, we also show that ERBB3_MCS6 drives reporter expression in NC cells and a subset of its derivative lineages in vivo in zebrafish in a manner consistent with erbb3b expression. We also demonstrate, using morpholino analysis, that Sox10 is necessary for ERBB3_MCS6 expression in vivo in zebrafish. CONCLUSIONS: Taken collectively, our data suggest that ERBB3 may be directly regulated by SOX10, and that this control may in part be facilitated by ERBB3_MCS6. PMID- 21672230 TI - Magnesium concentration in amniotic fluid in the early weeks of the second trimester of pregnancy. AB - BACKGROUND: We analyse magnesium levels in amniotic fluid to establish normal values for the 14th to 18th week of pregnancy and establish critical values that could be useful diagnostic and therapeutic guidelines for possible complications. FINDINGS: Ninety-two samples of amniotic fluid obtained by amniocentesis as well as the corresponding serum samples of pregnant women were analysed. The gestational age (mean +/- SD) at which the amniotic fluid sample was obtained was 16.13 +/- 1.87 weeks. Magnesium levels were determined by colorimetric assay with chlorophosphonazo-III using the the Cobas c 501 analyser (Roche Diagnostics). Statistical treatment of data was performed using the SPSS program, version 15.0.Results revealed a mean magnesium value of 1.65 +/- 0.16 mg/dL in amniotic fluid and 1.97 +/- 0.23 mg/dL in serum. CONCLUSIONS: It would be interesting to extend the study to a larger number of pregnant women to determine variations in normal magnesium values in the three trimesters of pregnancy. PMID- 21672231 TI - The effects on population health status of using dedicated property taxes to fund local public health agencies. AB - BACKGROUND: In the United States, a dedicated property tax describes the legal authority given to a local jurisdiction to levy and collect a tax for a specific purpose. We investigated for an association of locally dedicated property taxes to fund local public health agencies and improved health status in the eight states designated as the Mississippi Delta Region. METHODS: We analyzed the difference in health outcomes of counties with and without a dedicated public health tax after adjusting for a set of control variables using regression models for county level data from 720 counties of the Mississippi Delta Region. RESULTS: Levying a dedicated public health tax for counties with per capita income above $28,000 is associated with improved health outcomes of those counties when compared to counties without a dedicated property tax for public health. Alternatively, levying a dedicated property tax in counties with lower per capita income is associated with poor health outcomes. CONCLUSIONS: There are both positive and negative consequences of using dedicated property taxes to fund public health. Policymakers should carefully examine both the positive association of improved health outcomes and negative impact of taxation on poor populations before authorizing the use of dedicated local property tax levies to fund public health agencies. PMID- 21672232 TI - A retrospective evaluation of the impact of a dedicated obstetric and neonatal transport service on transport times within an urban setting. AB - OBJECTIVE: To determine whether the establishment of a dedicated obstetric and neonatal flying squad resulted in improved performance within the setting of a major metropolitan area. DESIGN AND SETTING: The Cape Town metropolitan service of the Emergency Medical Services was selected for a retrospective review of the transit times for the newly implemented Flying Squad programme. Data were imported from the Computer Aided Dispatch programme. Dispatch, Response, Mean Transit and Total Pre-hospital times relating to the obstetric and neonatal incidents was analysed for 2005 and 2008. RESULTS: There was a significant improvement between 2005 and 2008 in all incidents evaluated. Flying Squad dispatch performance improved from 11.7% to 46.6% of all incidents dispatched within 4 min (p < 0.0001). Response time performance at the 15-min threshold did not demonstrate a statistically significant improvement (p = 0.4), although the improvement in the 30-min performance category was statistically significant in both maternity and neonatal incidents. Maternity incidents displayed the greatest improvement with the 30-min performance increasing from 30.3% to 72.9%. The analysis of the mean transit times demonstrated that neonatal transfers displayed the longest status time in all but one of the categories. Even so, the introduction of the Flying Squad programme resulted in a reduction in a total pre hospital time from 177 to 128 min. CONCLUSION: The introduction of the Flying Squad programme has resulted in significant improvement in the transit times of both neonatal and obstetric patients. In spite of the severe resource constraints facing developing nations, the model employed offers significant gains. PMID- 21672233 TI - Convergent and parallel evolution in life habit of the scallops (Bivalvia: Pectinidae). AB - BACKGROUND: We employed a phylogenetic framework to identify patterns of life habit evolution in the marine bivalve family Pectinidae. Specifically, we examined the number of independent origins of each life habit and distinguished between convergent and parallel trajectories of life habit evolution using ancestral state estimation. We also investigated whether ancestral character states influence the frequency or type of evolutionary trajectories. RESULTS: We determined that temporary attachment to substrata by byssal threads is the most likely ancestral condition for the Pectinidae, with subsequent transitions to the five remaining habit types. Nearly all transitions between life habit classes were repeated in our phylogeny and the majority of these transitions were the result of parallel evolution from byssate ancestors. Convergent evolution also occurred within the Pectinidae and produced two additional gliding clades and two recessing lineages. Furthermore, our analysis indicates that byssal attaching gave rise to significantly more of the transitions than any other life habit and that the cementing and nestling classes are only represented as evolutionary outcomes in our phylogeny, never as progenitor states. CONCLUSIONS: Collectively, our results illustrate that both convergence and parallelism generated repeated life habit states in the scallops. Bias in the types of habit transitions observed may indicate constraints due to physical or ontogenetic limitations of particular phenotypes. PMID- 21672234 TI - Transcript analysis of the extended hyp-operon in the cyanobacteria Nostoc sp. strain PCC 7120 and Nostoc punctiforme ATCC 29133. AB - BACKGROUND: Cyanobacteria harbor two [NiFe]-type hydrogenases consisting of a large and a small subunit, the Hup- and Hox-hydrogenase, respectively. Insertion of ligands and correct folding of nickel-iron hydrogenases require assistance of accessory maturation proteins (encoded by the hyp-genes). The intergenic region between the structural genes encoding the uptake hydrogenase (hupSL) and the accessory maturation proteins (hyp genes) in the cyanobacteria Nostoc PCC 7120 and N. punctiforme were analysed using molecular methods. FINDINGS: The five ORFs, located in between the uptake hydrogenase structural genes and the hyp genes, can form a transcript with the hyp-genes. An identical genomic localization of these ORFs are found in other filamentous, N2-fixing cyanobacterial strains. In N. punctiforme and Nostoc PCC 7120 the ORFs upstream of the hyp-genes showed similar transcript level profiles as hupS (hydrogenase structural gene), nifD (nitrogenase structural gene), hypC and hypF (accessory hydrogenase maturation genes) after nitrogen depletion. In silico analyzes showed that these ORFs in N. punctiforme harbor the same conserved regions as their homologues in Nostoc PCC 7120 and that they, like their homologues in Nostoc PCC 7120, can be transcribed together with the hyp-genes forming a larger extended hyp-operon. DNA binding studies showed interactions of the transcriptional regulators CalA and CalB to the promoter regions of the extended hyp-operon in N. punctiforme and Nostoc PCC 7120. CONCLUSIONS: The five ORFs upstream of the hyp genes in several filamentous N2-fixing cyanobacteria have an identical genomic localization, in between the genes encoding the uptake hydrogenase and the maturation protein genes. In N. punctiforme and Nostoc PCC 7120 they are transcribed as one operon and may form transcripts together with the hyp-genes. The expression pattern of the five ORFs within the extended hyp-operon in both Nostoc punctiforme and Nostoc PCC 7120 is similar to the expression patterns of hupS, nifD, hypF and hypC. CalA, a known transcription factor, interacts with the promoter region between hupSL and the five ORFs in the extended hyp-operon in both Nostoc strains. PMID- 21672235 TI - The Drosophila Netrin receptor frazzled/DCC functions as an invasive tumor suppressor. AB - BACKGROUND: Loss of heterozygosity at 18q, which includes the Deleted in Colorectal Cancer (DCC) gene, has been linked to many human cancers. However, it is unclear if loss of DCC is the specific underlying cause of these cancers. The Drosophila imaginal discs are excellent systems in which to study DCC function, as it is possible to model human tumors through the generation of somatic clones of cells bearing multiple genetic lesions. Here, these attributes of the fly system were utilized to investigate the potential tumor suppressing functions of the Drosophila DCC homologue frazzled (fra) during eye-antennal disc development. RESULTS: Most fra loss of function clones are eliminated during development. However, when mutant clone cells generated in the developing eye were rescued from death, partially differentiated eye cells were found outside of the normal eye field, and in extreme cases distant sites of the body. Characterization of these cells during development indicates that fra mutant cells display characteristics of invasive tumor cells, including increased levels of phospho ERK, phospho-JNK, and Mmp-1, changes in cadherin expression, remodeling of the actin cytoskeleton, and loss of polarity. Mutation of fra promotes basement membrane degradation and invasion which are repressed by inhibition of Rho1 signaling. Although inhibition of JNK signaling blocks invasive phenotypes in some metastatic cancer models in flies, blocking JNK signaling inhibits fra mutant cell death, thereby enhancing the fra mutant phenotype. CONCLUSIONS: The results of this investigation provide the first direct link between point mutations in fra/DCC and metastatic phenotypes in an animal model and suggest that Fra functions as an invasive tumor suppressor during Drosophila development. PMID- 21672236 TI - The effects of publishing emergency department wait time on patient utilization patterns in a community with two emergency department sites: a retrospective, quasi-experiment design. AB - BACKGROUND: Providing emergency department (ED) wait time information to the public has been suggested as a mechanism to reduce lengthy ED wait times (by enabling patients to select the ED site with shorter wait time), but the effects of such a program have not been evaluated. We evaluated the effects of such a program in a community with two ED sites. METHODS: Descriptive statistics for wait times of the two sites before and after the publication of wait time information were used to evaluate the effects of the publication of wait time information on wait times. Multivariate logistical regression was used to test whether or not individual patients used published wait time to decide which site to visit. RESULTS: We found that the rates of wait times exceeding 4 h, and the 95th percentile of wait times in the two sites decreased after the publication of wait time information, even though the average wait times experienced a slight increase. We also found that after controlling for other factors, the site with shorter wait time had a higher likelihood of being selected after the publication of wait time information, but there was no such relationship before the publication. CONCLUSIONS: These findings were consistent with the hypothesis that the publication of wait time information leads to patients selecting the site with shorter wait time. While publishing ED wait time information did not improve average wait time, it reduced the rates of lengthy wait times. PMID- 21672237 TI - The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients. AB - INTRODUCTION: The detection of circulating tumour cells (CTCs) in the peripheral blood and disseminated tumour cells (DTCs) in the bone marrow are promising prognostic tools for risk stratification in early breast cancer. There is, however, a need for further validation of these techniques in larger patient cohorts with adequate follow-up periods. METHODS: We assayed CTCs and DTCs at primary surgery in 733 stage I or II breast cancer patients with a median follow up time of 7.6 years. CTCs were detected in samples of peripheral blood mononuclear cells previously stored in liquid-nitrogen using a previously developed multi-marker quantitative PCR (QPCR)-based assay. DTCs were detected in bone marrow samples by immunocytochemical analysis using anti-cytokeratin antibodies. RESULTS: CTCs were detected in 7.9% of patients, while DTCs were found in 11.7%. Both CTC and DTC positivity predicted poor metastasis-free survival (MFS) and breast cancer-specific survival (BCSS); MFS hazard ratio (HR) = 2.4 (P < 0.001)/1.9 (P = 0.006), and BCSS HR = 2.5 (P < 0.001)/2.3 (P = 0.01), for CTC/DTC status, respectively). Multivariate analyses demonstrated that CTC status was an independent prognostic variable for both MFS and BCSS. CTC status also identified a subset of patients with significantly poorer outcome among low risk node negative patients that did not receive adjuvant systemic therapy (MFS HR 2.3 (P = 0.039), BCSS HR 2.9 (P = 0.017)). Using both tests provided increased prognostic information and indicated different relevance within biologically dissimilar breast cancer subtypes. CONCLUSIONS: These results support the use of CTC analysis in early breast cancer to generate clinically useful prognostic information. PMID- 21672238 TI - Detection of changes in gene regulatory patterns, elicited by perturbations of the Hsp90 molecular chaperone complex, by visualizing multiple experiments with an animation. AB - BACKGROUND: To make sense out of gene expression profiles, such analyses must be pushed beyond the mere listing of affected genes. For example, if a group of genes persistently display similar changes in expression levels under particular experimental conditions, and the proteins encoded by these genes interact and function in the same cellular compartments, this could be taken as very strong indicators for co-regulated protein complexes. One of the key requirements is having appropriate tools to detect such regulatory patterns. RESULTS: We have analyzed the global adaptations in gene expression patterns in the budding yeast when the Hsp90 molecular chaperone complex is perturbed either pharmacologically or genetically. We integrated these results with publicly accessible expression, protein-protein interaction and intracellular localization data. But most importantly, all experimental conditions were simultaneously and dynamically visualized with an animation. This critically facilitated the detection of patterns of gene expression changes that suggested underlying regulatory networks that a standard analysis by pairwise comparison and clustering could not have revealed. CONCLUSIONS: The results of the animation-assisted detection of changes in gene regulatory patterns make predictions about the potential roles of Hsp90 and its co-chaperone p23 in regulating whole sets of genes. The simultaneous dynamic visualization of microarray experiments, represented in networks built by integrating one's own experimental with publicly accessible data, represents a powerful discovery tool that allows the generation of new interpretations and hypotheses. PMID- 21672239 TI - Neonatal outcomes among multiple births <= 32 weeks gestational age: does mode of conception have an impact? A cohort study. AB - BACKGROUND: Studies comparing perinatal outcomes in multiples conceived following the use of artificial reproductive technologies (ART) vs. spontaneous conception (SC) have reported conflicting results in terms of mortality and morbidity. Therefore, the objective of our study was to compare composite outcome of mortality and severe neonatal morbidities amongst preterm multiple births <= 32 weeks gestation infant born following ART vs. SC. METHODS: We conducted a single center cohort study at Mount Sinai Hospital, Toronto, Ontario, Canada. Data on all preterm multiple births (<= 32 weeks GA) discharged between July 2005 and June 2008 were retrospectively collected from a prospective database at our centre. Details regarding mode of conception were collected retrospectively from maternal health records. Preterm multiple births were categorized into those born following ART vs. SC. Composite outcome was defined as combination of death or any of the three neonatal morbidities (grade 3/4 intraventricular hemorrhage or periventricular leukomalacia; retinopathy of prematurity > stage 2 or chronic lung disease). Univariate and multivariate regression analysis were preformed after adjustment of confounders (maternal age, parity, triplets, gestational age, sex, and small for gestational age). RESULTS: One hundred and thirty seven neonates were born following use of ART and 233 following SC. The unadjusted composite outcome rate was significantly higher in preterm multiples born following ART vs. SC [43.1% vs. 26.6%, p = 0.001; OR 1.98 (95% CI 1.13, 3.45)]; however, when adjusted for confounders the difference between groups was not statistically significant [OR 1.39, 95% CI 0.67, 2.89]. CONCLUSION: In our population of preterm multiple births, the mode of conception had no detectable effect on the adjusted composite neonatal outcome of mortality and/or three neonatal morbidities. PMID- 21672240 TI - Incidence of new coding for dry eye and ocular infection in open-angle glaucoma and ocular hypertension patients treated with prostaglandin analogs: retrospective analysis of three medical/pharmacy claims databases. AB - BACKGROUND: To investigate the clinical relevance of two different preservative formulations, we compared 1-year incidence rates of additional coding of dry eye, ocular infection, or ocular surface disease (either dry eye or ocular infection) in open-angle glaucoma and ocular hypertension patients newly treated with latanoprost with benzalkonium chloride (BAK) or with travoprost-Z with SofZia(r). METHODS: This was a retrospective study of three U.S.-based patient-centric medical/pharmacy claims databases (MedStat, PharMetrics, i3-Ingenix). Patients were eligible if they filled a prescription for latanoprost or travoprost-Z between October 2006 and Q2 2008 (prescription date = index date) AND were continuously enrolled 6 months prior through 12 months after the index date AND had any open-angle glaucoma or ocular hypertension diagnosis within 90 days prior to the index date AND did not have an ocular surface disease diagnosis during the 180 days prior to the index date AND if they had not had a prescription for the index agent in the 180 days prior to the index date. Time to incidence of new coding for ocular surface disease in the first year post-index was estimated with a composite endpoint: diagnosis of dry eye or ocular infection by ICD-9-CM or Current Procedural Terminology code OR by prescription for cyclosporine ophthalmic emulsion or ocular antibiotics. RESULTS: In all, 15,933 patients were treated with latanoprost and 7670 with travoprost-Z. Over 1 year, 4.3% of latanoprost and 4.5% of travoprost-Z patients were identified with dry eye (p = 0.28), and 10.9% and 11.1%, respectively, were identified with an ocular infection (p = 0.79). The 1-year incidence of new coding for ocular surface disease also was similar across treatments (13.9% vs 14.3%, respectively; p = 0.48). CONCLUSIONS: The retrospective analysis of three large prescription databases revealed that open-angle glaucoma and ocular hypertension patients newly treated with latanoprost preserved with BAK or travoprost-Z preserved with SofZia did not differ statistically in rates of dry eye, ocular infection, or ocular surface disease (either dry eye or ocular infection) during the first year post-index. Claims-based analyses are limited by nonrandomization and the inability to account for over-the-counter use or samples. PMID- 21672241 TI - Ancient feeding ecology inferred from stable isotopic evidence from fossil horses in South America over the past 3 Ma. AB - BACKGROUND: Stable isotope ratios (13C/12C and 18O/16O) in fossil teeth and bone provide key archives for understanding the ecology of extinct horses during the Plio-Pleistocene in South America; however, what happened in areas of sympatry between Equus (Amerhippus) and Hippidion is less understood. RESULTS: Here, we use stable carbon and oxygen isotopes preserved in 67 fossil tooth and bone samples for seven species of horses from 25 different localities to document the magnitude of the dietary shifts of horses and ancient floral change during the Plio-Pleistocene. Dietary reconstructions inferred from stable isotopes of both genera of horses present in South America document dietary separation and environmental changes in ancient ecosystems, including C3/C4 transitions. Stable isotope data demonstrate changes in C4 grass consumption, inter-species dietary partitioning and variation in isotopic niche breadth of mixed feeders with latitudinal gradient. CONCLUSIONS: The data for Hippidion indicate a preference varying from C3 plants to mixed C3-C4 plants in their diet. Equus (Amerhippus) shows three different patterns of dietary partitioning Equus (A.) neogeus from the province of Buenos Aires indicate a preference for C3 plants in the diet. Equus (A.) andium from Ecuador and Equus (A.) insulatus from Bolivia show a preference for to a diet of mixed C3-C4 plants, while Equus (A.) santaeelenae from La Carolina (sea level of Ecuador) and Brazil are mostly C4 feeders. These results confirm that ancient feeding ecology cannot always be inferred from dental morphology. While the carbon isotope composition of horses skeletal material decreased as latitude increased, we found evidence of boundary between a mixed C3/C4 diet signal and a pure C4 signal around 32 degrees S and a change from a mixed diet signal to an exclusively C3 signal around 35 degrees S.We found that the horses living at high altitudes and at low to middle latitude still have a C4 component in their diet, except the specimens from 4000 m, which have a pure C3 diet. The change in altitudinal vegetation gradients during the Pleistocene is one of several possibilities to explain the C4 dietary component in horses living at high altitudes. Other alternative explanations imply that the horses fed partially at lower altitudes. PMID- 21672242 TI - Perceived usefulness of a distributed community-based syndromic surveillance system: a pilot qualitative evaluation study. AB - BACKGROUND: We conducted a pilot utility evaluation and information needs assessment of the Distribute Project at the 2010 Washington State Public Health Association (WSPHA) Joint Conference. Distribute is a distributed community-based syndromic surveillance system and network for detection of influenza-like illness (ILI). Using qualitative methods, we assessed the perceived usefulness of the Distribute system and explored areas for improvement. Nine state and local public health professionals participated in a focus group (n = 6) and in semi-structured interviews (n = 3). Field notes were taken, summarized and analyzed. FINDINGS: Several emergent themes that contribute to the perceived usefulness of system data and the Distribute system were identified: 1) Standardization: a common ILI syndrome definition; 2) Regional Comparability: views that support county-by county comparisons of syndromic surveillance data; 3) Completeness: complete data for all expected data at a given time; 4) Coverage: data coverage of all jurisdictions in WA state; 5) CONTEXT: metadata incorporated into the views to provide context for graphed data; 6) Trusted Data: verification that information is valid and timely; and 7) Customization: the ability to customize views as necessary. As a result of the focus group, a new county level health jurisdiction expressed interest in contributing data to the Distribute system. CONCLUSION: The resulting themes from this study can be used to guide future information design efforts for the Distribute system and other syndromic surveillance systems. In addition, this study demonstrates the benefits of conducting a low cost, qualitative evaluation at a professional conference. PMID- 21672243 TI - Gastronet survey on the use of one- or two-person technique for colonoscopy insertion. AB - BACKGROUND: Usually, colonoscopy insertion is performed by the colonoscopist (one person technique). Quite common in the early days of endoscopy, the assisting nurse is now only rarely doing the insertion (two-person technique). Using the Norwegian national endoscopy quality assurance (QA) programme, Gastronet, we wanted to explore the extent of two-person technique practice and look into possible differences in performance and QA output measures. METHODS: 100 colonoscopists in 18 colonoscopy centres having reported their colonoscopies to Gastronet between January and December 2009 were asked if they practiced one- or two-person technique during insertion of the colonoscope. They were categorized accordingly for comparative analyses of QA indicators. RESULTS: 75 endoscopists responded to the survey (representing 9368 colonoscopies) - 62 of them (83%) applied one-person technique and 13 (17%) two-person technique. Patients age and sex distributions and indications for colonoscopy were also similar in the two groups. Caecal intubation was 96% in the two-person group compared to 92% in the one-person group (p < 0.001). Pain reports were similar in the groups, but time to the caecum was shorter and the use of sedation less in the two-person group. CONCLUSION: Two-person technique for colonoscope insertion was practiced by a considerable minority of endoscopists (17%). QA indicators were either similar to or better than one-person technique. This suggests that there may be some beneficial elements to this technique worth exploring and try to import into the much preferred one-person insertion technique. PMID- 21672244 TI - Extensin network formation in Vitis vinifera callus cells is an essential and causal event in rapid and H(2)O(2)-induced reduction in primary cell wall hydration. AB - BACKGROUND: Extensin deposition is considered important for the correct assembly and biophysical properties of primary cell walls, with consequences to plant resistance to pathogens, tissue morphology, cell adhesion and extension growth. However, evidence for a direct and causal role for the extensin network formation in changes to cell wall properties has been lacking. RESULTS: Hydrogen peroxide treatment of grapevine (Vitis vinifera cv. Touriga) callus cell walls was seen to induce a marked reduction in their hydration and thickness. An analysis of matrix proteins demonstrated this occurs with the insolubilisation of an abundant protein, GvP1, which displays a primary structure and post-translational modifications typical of dicotyledon extensins. The hydration of callus cell walls free from saline-soluble proteins did not change in response to H(2)O(2), but fully regained this capacity after addition of extensin-rich saline extracts. To assay the specific contribution of GvP1 cross-linking and other wall matrix proteins to the reduction in hydration, GvP1 levels in cell walls were manipulated in vitro by binding selected fractions of extracellular proteins and their effect on wall hydration during H(2)O(2) incubation assayed. CONCLUSIONS: This approach allowed us to conclude that a peroxidase-mediated formation of a covalently linked network of GvP1 is essential and causal in the reduction of grapevine callus wall hydration in response to H(2)O(2). Importantly, this approach also indicated that extensin network effects on hydration was only partially irreversible and remained sensitive to changes in matrix charge. We discuss this mechanism and the importance of these changes to primary wall properties in the light of extensin distribution in dicotyledons. PMID- 21672245 TI - Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes. AB - INTRODUCTION: Breast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity. METHODS: We report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies. RESULTS: Through the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2 related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1alpha compared to luminal types and silencing of HIF-1alpha results in decreased expression of hypoxia induced genes. CONCLUSIONS: This study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity. PMID- 21672247 TI - In situ lignocellulosic unlocking mechanism for carbohydrate hydrolysis in termites: crucial lignin modification. AB - BACKGROUND: Termites are highly effective at degrading lignocelluloses, and thus can be used as a model for studying plant cell-wall degradation in biological systems. However, the process of lignin deconstruction and/or degradation in termites is still not well understood. METHODS: We investigated the associated structural modification caused by termites in the lignin biomolecular assembly in softwood tissues crucial for cell-wall degradation. We conducted comparative studies on the termite-digested (i.e. termite feces) and native (control) softwood tissues with the aid of advanced analytical techniques: 13C crosspolarization magic angle spinning and nuclear magnetic resonance (CP-MAS NMR) spectroscopy, flash pyrolysis with gas chromatography mass spectrometry (Py GC/MS), and Py-GC-MS in the presence of tetramethylammonium hydroxide (Py-TMAH) GC/MS. RESULTS: The 13C CP/MAS NMR spectroscopic analysis revealed an increased level of guaiacyl-derived (G unit) polymeric framework in the termite-digested softwood (feces), while providing specific evidence of cellulose degradation. The Py-GC/MS data were in agreement with the 13C CP/MAS NMR spectroscopic studies, thus indicating dehydroxylation and modification of selective intermonomer side chain linkages in the lignin in the termite feces. Moreover, Py-TMAH-GC/MS analysis showed significant differences in the product distribution between control and termite feces. This strongly suggests that the structural modification in lignin could be associated with the formation of additional condensed interunit linkages. CONCLUSION: Collectively, these data further establish: 1) that the major beta-O-4' (beta-aryl ether) was conserved, albeit with substructure degeneracy, and 2) that the nature of the resulting polymer in termite feces retained most of its original aromatic moieties (G unit-derived). Overall, these results provide insight into lignin-unlocking mechanisms for understanding plant cell-wall deconstruction, which could be useful in development of new enzymatic pretreatment processes mimicking the termite system for biochemical conversion of lignocellulosic biomass to fuels and chemicals. PMID- 21672246 TI - Expression of IL-23/Th17 pathway in a murine model of Coxsackie virus B3-induced viral myocarditis. AB - BACKGROUND: The IL-23/Th17 pathway is implicated in the pathogenesis of a number of chronic inflammatory and autoimmune diseases. Whether it regulates the viral myocarditis (VMC) is unknown. RESULTS: To examine the pathogenesis role of IL 23/Th17 axis in VMC, we used male BALB/c mice to induced VMC by Coxsackie virus B3 (CVB3) peritoneal injection. IL-23, IL-17, and signal transducer and activator of transcription 3 (STAT3) mRNA in the myocardium of VMC mice were assessed by semi-quantitative RT-PCR. IL-23 and IL-17 protein from blood serum were evaluated by ELISA. Phosphorylated-STAT3 (p-STAT3) protein expression in the myocardium was evaluated by immunohistochemical staining. Flow cytometric analysis was used to evaluate the frequencies of Th17 subsets. Isolated CD4+ T cells from VMC mice were cultured with recombinant IL-23(rIL-23) in vitro. In addition, a STAT3 specific inhibitor (S3I-201) was used to test whether regulation of STAT3 could be partly responsible for Th17 diminution. Results showed that expression of IL 23, IL-17, STAT3 mRNA and protein increased in VMC mice. When purified CD4+ T cells derived from VMC mice were cultured in vitro with rIL-23, the frequency of Th17 cells was dramatically increased, accompanied by significantly enhanced production of IL-17 in the supernatants of cultured CD4+ T cells. S3I-201 significantly restrained Th17 cell proliferation. CONCLUSIONS: The IL-23/Th17 pathway axis is strongly expressed in murine VMC, identifying a novel pathway of potential significance in viral myocarditis. PMID- 21672249 TI - Health aspects, nutrition and physical characteristics in matched samples of institutionalized vegetarian and non-vegetarian elderly (> 65yrs). AB - BACKGROUND: Epidemiological studies indicate that a well balanced vegetarian diet offers several health benefits including a lower prevalence of prosperity diseases in vegetarians compared to omnivores. It was the purpose of the present study to compare nutritional and physical characteristics in matched samples of institutionalized vegetarian (V) and non-vegetarian (NV) elderly. METHODS: Twenty two female and 7 male V (females: 84.1 +/- 5.1yrs, males: 80.5 +/- 7.5yrs) and 23 female and 7 male NV (females: 84.3 +/- 5.0yrs, males: 80.6 +/- 7.3yrs) participated. All subjects were over 65 years of age, and free of major disease or physical handicap. Dietary intake, blood profile, anthropometrics, and handgrip strength were determined. RESULTS: Mean daily energy intake was 6.8 +/- 2.0MJ in V females, and 8.0 +/- 1.4MJ in the NV females, only the V did not reach the recommended value of 7.8 MJ. Male V and NV had a mean daily energy intake of 8.7 +/- 1.6MJ and 8.7 +/- 1.2MJ respectively (RDI: 8.8 MJ). Mean carbohydrate intake was significantly below the RDI in NV only (female V: 47.8 +/- 7.5E%, female NV: 43.3 +/- 4.6E%, male V: 48.1 +/- 6.4E%, male NV: 42.3 +/- 3.6E%), while protein (female V: 17.3 +/- 3.4E%, female NV: 19.5 +/- 3.5E%, male V: 17.8 +/- 3.4E%, male NV: 21.0 +/- 2.0E%), and saturated fat intake (female V: 25.4 +/- 8.2 g/day, female NV: 32.2 +/- 6.9 g/day, male V: 31.4 +/- 12.9 g/day, male NV: 33.4 +/- 4.7 g/day) were too high in both V and NV. Mean micronutrient intakes met the RDI's in all 4 groups. Mean blood concentrations for vitamin B12, folic acid, iron, and calcium were normal in all 4 groups. Mean zinc blood serum was below the reference value in all groups, whereas estimated zinc intake was in agreement with the RDI. The mean blood cholesterol concentration was above the 200 mg/dl upper limit in the V group (213 +/- 40 mg/dl) and below that limit in the NV (188 +/- 33 mg/dl) group. Mean BMI was 26.1 +/- 4.7 kg/m2 in the female V, 26.8 +/- 3.7 kg/m2 in the female NV, 23.5 +/- 3.7 kg/m2 in the male V, and 25.2 +/- 4.2 kg/m2 in the male NV. V and NV scored below the reference values for the handgrip strength test. CONCLUSIONS: Generally, our results show a similar profile for V and NV concerning dietary intake, blood values, and physical characteristics. Attention should be paid to the intake of mono- and disaccharides and saturated fats in the diet of both V and NV. This study indicates that a vegetarian lifestyle has no negative impact on the health status at older age. PMID- 21672248 TI - A prognostic model for estimating the time to virologic failure in HIV-1 infected patients undergoing a new combination antiretroviral therapy regimen. AB - BACKGROUND: HIV-1 genotypic susceptibility scores (GSSs) were proven to be significant prognostic factors of fixed time-point virologic outcomes after combination antiretroviral therapy (cART) switch/initiation. However, their relative-hazard for the time to virologic failure has not been thoroughly investigated, and an expert system that is able to predict how long a new cART regimen will remain effective has never been designed. METHODS: We analyzed patients of the Italian ARCA cohort starting a new cART from 1999 onwards either after virologic failure or as treatment-naive. The time to virologic failure was the endpoint, from the 90th day after treatment start, defined as the first HIV-1 RNA > 400 copies/ml, censoring at last available HIV-1 RNA before treatment discontinuation. We assessed the relative hazard/importance of GSSs according to distinct interpretation systems (Rega, ANRS and HIVdb) and other covariates by means of Cox regression and random survival forests (RSF). Prediction models were validated via the bootstrap and c-index measure. RESULTS: The dataset included 2337 regimens from 2182 patients, of which 733 were previously treatment-naive. We observed 1067 virologic failures over 2820 persons-years. Multivariable analysis revealed that low GSSs of cART were independently associated with the hazard of a virologic failure, along with several other covariates. Evaluation of predictive performance yielded a modest ability of the Cox regression to predict the virologic endpoint (c-index~0.70), while RSF showed a better performance (c index~0.73, p < 0.0001 vs. Cox regression). Variable importance according to RSF was concordant with the Cox hazards. CONCLUSIONS: GSSs of cART and several other covariates were investigated using linear and non-linear survival analysis. RSF models are a promising approach for the development of a reliable system that predicts time to virologic failure better than Cox regression. Such models might represent a significant improvement over the current methods for monitoring and optimization of cART. PMID- 21672250 TI - Investigation of fMRI activation in the internal capsule. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) in white matter has long been considered controversial. Recently, this viewpoint has been challenged by an emerging body of evidence demonstrating white matter activation in the corpus callosum. The current study aimed to determine whether white matter activation could be detected outside of the corpus callosum, in the internal capsule. Data were acquired from a 4 T MRI using a specialized asymmetric spin echo spiral sequence. A motor task was selected to elicit activation in the posterior limb of the internal capsule. RESULTS: White matter fMRI activation was examined at the individual and group levels. Analyses revealed that activation was present in the posterior limb of the internal capsule in 80% of participants. These results provide further support for white matter fMRI activation. CONCLUSIONS: The ability to visualize functionally active tracts has strong implications for the basic scientific study of connectivity and the clinical assessment of white matter disease. PMID- 21672251 TI - Primary testicular necrotizing vasculitis clinically presented as neoplasm of the testicle: a case report. AB - We present a case of necrotizing vasculitis with the testicle as the isolated affected organ. A 25-year-old man, pretreated for epididymo-orchitis, presented with a presumed testicular neoplasm. Radical orchiectomy was performed and diagnosis of necrotizing vasculitis was established. In the absence of any other sign of systemic disease, the diagnosis of isolated necrotizing vasculitis of the testis was confirmed. Two years after the operation, the patient showed no symptoms of systemic disease. PMID- 21672253 TI - A validated stability-indicating HPLC method for determination of varenicline in its bulk and tablets. AB - A simple, sensitive and accurate stability-indicating HPLC method has been developed and validated for determination of varenicline (VRC) in its bulk form and pharmaceutical tablets. Chromatographic separation was achieved on a Zorbax Eclipse XDB-C8 column (150 mm * 4.6 mm i.d., particle size 5 MUm, maintained at ambient temperature) by a mobile phase consisted of acetonitrile and 50 mM potassium dihydrogen phosphate buffer (10:90, v/v) with apparent pH of 3.5 +/- 0.1 and a flow rate of 1.0 ml/min. The detection wavelength was set at 235 nm. VRC was subjected to different accelerated stress conditions. The degradation products, when any, were well resolved from the pure drug with significantly different retention time values. The method was linear (r = 0.9998) at a concentration range of 2 - 14 MUg/ml. The limit of detection and limit of quantitation were 0.38 and 1.11 MUg/ml, respectively. The intra- and inter-assay precisions were satisfactory; the relative standard deviations did not exceed 2%. The accuracy of the method was proved; the mean recovery of VRC was 100.10 +/- 1.08%. The proposed method has high throughput as the analysis involved short run time (~ 6 min). The method met the ICH/FDA regulatory requirements. The proposed method was successfully applied for the determination of VRC in bulk and tablets with acceptable accuracy and precisions; the label claim percentages were 99.65 +/- 0.32%. The results demonstrated that the method would have a great value when applied in quality control and stability studies for VRC. PMID- 21672252 TI - Improving glycaemic control and life skills in adolescents with type 1 diabetes: a randomised, controlled intervention study using the Guided Self-Determination Young method in triads of adolescents, parents and health care providers integrated into routine paediatric outpatient clinics. AB - BACKGROUND: Adolescents with type 1 diabetes face demanding challenges due to conflicting priorities between psychosocial needs and diabetes management. This conflict often results in poor glycaemic control and discord between adolescents and parents. Adolescent-parent conflicts are thus a barrier for health care providers (HCPs) to overcome in their attempts to involve both adolescents and parents in improvement of glycaemic control. Evidence-based interventions that involve all three parties (i.e., adolescents, parents and HCPs) and are integrated into routine outpatient clinic visits are lacking. The Guided Self Determination method is proven effective in adult care and has been adapted to adolescents and parents (Guided Self-Determination-Young (GSD-Y)) for use in paediatric diabetes outpatient clinics. Our objective is to test whether GSD-Y used in routine paediatric outpatient clinic visits will reduce haemoglobin A1c (HbA1c) concentrations and improve adolescents' life skills compared with a control group. METHODS/DESIGN: Using a mixed methods design comprising a randomised controlled trial and a nested qualitative evaluation, we will recruit 68 adolescents age 13-18 years with type 1 diabetes (HbA1c > 8.0%) and their parents from 2 Danish hospitals and randomise into GSD-Y or control groups. During an 8-12 month period, the GSD-Y group will complete 8 outpatient GSD-Y visits, and the control group will completes an equal number of standard visits. The primary outcome is HbA1c. Secondary outcomes include the following: number of self-monitored blood glucose values and levels of autonomous motivation, involvement and autonomy support from parents, autonomy support from HCPs, perceived competence in managing diabetes, well-being, and diabetes-related problems. Primary and secondary outcomes will be evaluated within and between groups by comparing data from baseline, after completion of the visits, and again after a 6-month follow-up. To illustrate how GSD-Y influences glycaemic control and the development of life skills, 10-12 GSD-Y visits will be recorded during the intervention and analysed qualitatively together with individual interviews carried out after follow-up. DISCUSSION: This study will provide evidence of the effectiveness of using a GSD-Y intervention with three parties on HbA1c and life skills and the feasibility of integrating the intervention into routine outpatient clinic visits. Danish Data Association ref nr. 2008-41-2322. TRIAL REGISTRATION: ISRCTN54243636. PMID- 21672254 TI - Health-related quality of life changes of children and adolescents with chronic disease after participation in therapeutic recreation camping program. AB - BACKGROUND: The principals of therapeutic recreation underpin a camping program for children and adolescents living with chronic disease. This study aimed to evaluate the campers' health-related quality of life (HRQoL) before and after the program. METHOD: We used the Hungarian version of Kidscreen-52 questionnaire to assess HRQoL. The study sample (n = 115) consisted of children and adolescents aged 10-18 (Mean Age: 13,34; SD: 2,20) collected two months before and two months after camp with the following illnesses: oncology patients (n = 32), diabetes (n = 55) and juvenile immune arthritis (JIA) (n = 28). Repeated measures of multivariate analysis of variance (MANOVA) evaluated pre and post camp changes. We used the Reliable Change Index (RCI) to calculate all the 10 subscales of clinically significant changes. RESULTS: The Self-perception subscale showed significant positive change from pre camp to post camp with small effect size. Autonomy scores showed time related decline as well as significant time and age group interaction: children under 14 years of age showed a significant moderate effect size decrease on the Autonomy subscale. 32 children (27.8%) showed clinically significant improvement (RCI > 1.96) at least on one subscale. All positive changes were independent of the type of disease, age, gender, and previous camp experience. CONCLUSION: The therapeutic recreation camping program had a positive impact on HRQoL of children and adolescents living with cancer, diabetes mellitus and JIA. The experience enhanced their self-perception in all age groups and reduced the autonomy of children under 14 years of age. This study is an innovative use of the KIDSCREEN-52 questionnaire to measure the outcome effectiveness of a psychosocial rehabilitation program and to assess and compare HRQoL of children living with different chronic diseases. PMID- 21672255 TI - Multi-susceptibility genes associated with the risk of the development stages of esophageal squamous cell cancer in Feicheng County. AB - BACKGROUND: The purpose of this study was to evaluate the association of multi genotype polymorphisms with the stepwise progression of esophageal squamous cell cancer (ESCC) and the possibility of predicting those at higher risk. METHODS: A total of 1,004 subjects were recruited from Feicheng County, China, between Jan. 2004 and Dec. 2007 and examined by endoscopy for esophageal lesions. These subjects included 270 patients with basal cell hyperplasia (BCH), 262 patients with esophageal squamous cell dysplasia (ESCD), 226 patients with ESCC, and 246 controls with Lugol-voiding area but diagnosed as having normal esophageal squamous epithelial cells by histopathology. The genotypes for CYP2E1 G1259C, hOGG1 C326G, MTHFR C677T, MPO G463A, and ALDH2 allele genes were identified in blood samples collected from all participants. RESULTS: The alleles ALDH2 and MTHFR C677T were critical for determining individual susceptibility to esophageal cancer. Compared to the ALDH 1*1 genotype, the ALDH 2*2 genotype was significantly associated with increased risks of BCH, ESCD, and ESCC. However, the TT genotype of MTHFR C677T only increased the risk of ESCC. Further analysis revealed that the combination of the high-risk genotypes 2*2/1*2 of ALDH 2 and TT/TC of MTHFR C677T increased the risk of BCH by 4.0 fold, of ESCD by 3.7 fold, and ESSC by 8.72 fold. The generalized odds ratio (ORG) of the two combined genotypes was 1.83 (95%CI: 1.55-2.16), indicating a strong genetic association with the risk of carcinogenic progression in the esophagus. CONCLUSIONS: The study demonstrated that the genotypes ALDH2*2 and MTHFR 677TT conferred elevated risk for developing esophageal carcinoma and that the two susceptibility genotypes combined to synergistically increase the risk. PMID- 21672256 TI - Immunolocalization of the short neuropeptide F receptor in queen brains and ovaries of the red imported fire ant (Solenopsis invicta Buren). AB - BACKGROUND: Insect neuropeptides are involved in diverse physiological functions and can be released as neurotransmitters or neuromodulators acting within the central nervous system, and as circulating neurohormones in insect hemolymph. The insect short neuropeptide F (sNPF) peptides, related to the vertebrate neuropeptide Y (NPY) peptides, have been implicated in the regulation of food intake and body size, and play a gonadotropic role in the ovaries of some insect species. Recently the sNPF peptides were localized in the brain of larval and adult Drosophila. However, the location of the sNPF receptor, a G protein-coupled receptor (GPCR), has not yet been investigated in brains of any adult insect. To elucidate the sites of action of the sNPF peptide(s), the sNPF receptor tissue expression and cellular localization were analyzed in queens of the red imported fire ant, Solenopsis invicta Buren (Hymenoptera), an invasive social insect. RESULTS: In the queen brains and subesophageal ganglion about 164 cells distributed in distinctive cell clusters (C1-C9 and C12) or as individual cells (C10, C11) were immuno-positive for the sNPF receptor. Most of these neurons are located in or near important sensory neuropils including the mushroom bodies, the antennal lobes, the central complex, and in different parts of the protocerebrum, as well as in the subesophageal ganglion. The localization of the sNPF receptor broadly links the receptor signaling pathway with circuits regulating learning and feeding behaviors. In ovaries from mated queens, the detection of sNPF receptor signal at the posterior end of oocytes in mid-oogenesis stage suggests that the sNPF signaling pathway may regulate processes at the oocyte pole. CONCLUSIONS: The analysis of sNPF receptor immunolocalization shows that the sNPF signaling cascade may be involved in diverse functions, and the sNPF peptide(s) may act in the brain as neurotransmitter(s) or neuromodulator(s), and in the ovaries as neurohormone(s). To our knowledge, this is the first report of the cellular localization of a sNPF receptor on the brain and ovaries of adult insects. PMID- 21672258 TI - Menopausal symptoms assessment among middle age women in Kushtia, Bangladesh. AB - BACKGROUND: There are few menopausal study data available in South East Asia especially in Bangladesh. This study was conducted in a well populated town named Kushtia, which is located in the western part of Bangladesh. OBJECTIVES: This study was aimed to document the menopausal-related symptoms among middle age women of Kushtia region of Bangladesh. METHODS: By using modified MRS (Menopause Rating Scale) questionnaire, 509 women aged 40-70 years were interviewed to document symptoms commonly associated with menopause. FINDINGS: The mean age of menopause was 51.14 years. The most prevalent symptoms reported include, feeling tired (92.90%); headache (88.80%); joint and muscular discomfort (76.20%); physical and mental exhaustion (60.90%) and sleeplessness (54.40%) which are followed by depressive mood (37.30%); irritability (36%); dryness of vagina (36%); hot flushes and sweating (35.80%); anxiety (34.20%). However, noted less frequent symptoms were sexual problem (31.20%); cardiac discomfort (19.10%) and bladder problem (12.80%). CONCLUSIONS: The prevalence of menopausal symptoms found in this study correspond to other studies on Asian women however the prevalence of classical menopausal symptoms of hot flushes and sweating were lower compared to studies on Caucasian women. PMID- 21672257 TI - A model for the Escherichia coli FtsB/FtsL/FtsQ cell division complex. AB - BACKGROUND: Bacterial division is produced by the formation of a macromolecular complex in the middle of the cell, called the divisome, formed by more than 10 proteins. This process can be divided into two steps, in which the first is the polymerization of FtsZ to form the Z ring in the cytoplasm, and then the sequential addition of FtsA/ZipA to anchor the ring at the cytoplasmic membrane, a stage completed by FtsEX and FtsK. In the second step, the formation of the peptidoglycan synthesis machinery in the periplasm takes place, followed by cell division. The proteins involved in connecting both steps in cell division are FtsQ, FtsB and FtsL, and their interaction is a crucial and conserved event in the division of different bacteria. These components are small bitopic membrane proteins, and their specific function seems to be mainly structural. The purpose of this study was to obtain a structural model of the periplasmic part of the FtsB/FtsL/FtsQ complex, using bioinformatics tools and experimental data reported in the literature. RESULTS: Two oligomeric models for the periplasmic region of the FtsB/FtsL/FtsQ E. coli complex were obtained from bioinformatics analysis. The FtsB/FtsL subcomplex was modelled as a coiled-coil based on sequence information and several stoichiometric possibilities. The crystallographic structure of FtsQ was added to this complex, through protein-protein docking. Two final structurally-stable models, one trimeric and one hexameric, were obtained. The nature of the protein-protein contacts was energetically favourable in both models and the overall structures were in agreement with the experimental evidence reported. CONCLUSIONS: The two models obtained for the FtsB/FtsL/FtsQ complex were stable and thus compatible with the in vivo periplasmic complex structure. Although the hexameric model 2:2:2 has features that indicate that this is the most plausible structure, the ternary complex 1:1:1 cannot be discarded. Both models could be further stabilized by the binding of the other proteins of the divisome. The bioinformatics modelling of this kind of protein complex, whose function is mainly structural, provide useful information. Experimental results should confirm or reject these models and provide new data for future bioinformatics studies to refine the models. PMID- 21672259 TI - The characterisation of piRNA-related 19mers in the mouse. AB - BACKGROUND: Piwi interacting RNA, or piRNA, is a class of small RNA almost exclusively expressed in the germline where they serve essential roles in retrotransposon silencing. There are two types, primary and secondary piRNA, and the latter is a product of enzymatic cleavage of retrotransposons' transcripts directed by the former. Recently, a new class of 19nt long RNA was discovered that is specific to testis and appears to be linked to secondary piRNA biogenesis. RESULTS: We locate clusters of the testis-specific 19mers, which we call piRNA-related 19mers (pr19RNA), and characterise the transcripts from which they are derived. Most pr19RNA clusters were associated with retrotransposons and unannotated antisense transcripts overlapping piRNA clusters. At these loci the abundance of 19mers was found to be greater than that of secondary piRNAs. CONCLUSION: We find that pr19RNAs are distinguished from other RNA populations by their length and flanking sequence, allowing their identification without requiring overlapping piRNAs. Using such sequence features allows identification of the source transcripts, and we suggest that these likely represent the substrates of primary piRNA-guided RNA cleavage events. While pr19RNAs appear not to bind directly to Miwi or Mili, their abundance relative to secondary piRNAs, in combination with their precise length, suggests they may be more than by products of secondary piRNA biogenesis. PMID- 21672260 TI - Multi-locus sequence typing of Salmonella enterica subsp. enterica serovar Enteritidis strains in Japan between 1973 and 2004. AB - Salmonella enterica subsp. enterica serovar Enteritidis (S. Enteritidis) was responsible for a worldwide pandemic during the 1980s and 1990s; however, changes in the dominant lineage before and after this event remain unknown. This study determined S. Enteritidis lineages before and after this pandemic event in Japan using multilocus sequence typing (MLST). Thirty S. Enteritidis strains were collected in Japan between 1973 and 2004, consisting of 27 human strains from individual episodes, a bovine strain, a liquid egg strain and an eggshell strain. Strains showed nine phage types and 17 pulsed-field profiles with pulsed-field gel electrophoresis. All strains had homologous type 11 sequences without any nucleotide differences in seven housekeeping genes. These MLST results suggest that S. Enteritidis with the diversities revealed by phage typing and pulsed field profiling has a highly clonal population. Although type 11 S. Enteritidis may exhibit both pleiotropic surface structure and pulsed-field type variation, it is likely to be a stable lineage derived from an ancestor before the 1980s and/or 1990s pandemic in Japan. PMID- 21672261 TI - A large scale comparative genomic analysis reveals insertion sites for newly acquired genomic islands in bacterial genomes. AB - BACKGROUND: Bacterial virulence enhancement and drug resistance are major threats to public health worldwide. Interestingly, newly acquired genomic islands (GIs) from horizontal transfer between different bacteria strains were found in Vibrio cholerae, Streptococcus suis, and Mycobacterium tuberculosis, which caused outbreak of epidemic diseases in recently years. RESULTS: Using a large-scale comparative genomic analysis of 1088 complete genomes from all available bacteria (1009) and Archaea (79), we found that newly acquired GIs are often anchored around switch sites of GC-skew (sGCS). After calculating correlations between relative genomic distances of genomic islands to sGCSs and the evolutionary distances of the genomic islands themselves, we found that newly acquired genomic islands are closer to sGCSs than the old ones, indicating that regions around sGCSs are hotspots for genomic island insertion. CONCLUSIONS: Based on our results, we believe that genomic regions near sGCSs are hotspots for horizontal transfer of genomic islands, which may significantly affect key properties of epidemic disease-causing pathogens, such as virulence and adaption to new environments. PMID- 21672262 TI - PI: an open-source software package for validation of the SEQUEST result and visualization of mass spectrum. AB - BACKGROUND: Tandem mass spectrometry (MS/MS) has emerged as the leading method for high- throughput protein identification in proteomics. Recent technological breakthroughs have dramatically increased the efficiency of MS/MS data generation. Meanwhile, sophisticated algorithms have been developed for identifying proteins from peptide MS/MS data by searching available protein sequence databases for the peptide that is most likely to have produced the observed spectrum. The popular SEQUEST algorithm relies on the cross-correlation between the experimental mass spectrum and the theoretical spectrum of a peptide. It utilizes a simplified fragmentation model that assigns a fixed and identical intensity for all major ions and fixed and lower intensity for their neutral losses. In this way, the common issues involved in predicting theoretical spectra are circumvented. In practice, however, an experimental spectrum is usually not similar to its SEQUEST -predicted theoretical one, and as a result, incorrect identifications are often generated. RESULTS: Better understanding of peptide fragmentation is required to produce more accurate and sensitive peptide sequencing algorithms. Here, we designed the software PI of novel and exquisite algorithms that make a good use of intensity property of a spectrum. CONCLUSIONS: We designed the software PI with the novel and effective algorithms which made a good use of intensity property of the spectrum. Experiments have shown that PI was able to validate and improve the results of SEQUEST to a more satisfactory degree. PMID- 21672263 TI - Immunogenicity in mice and rhesus monkeys vaccinated with recombinant vaccinia virus expressing bivalent E7E6 fusion proteins from human papillomavirus types 16 and 18. AB - BACKGROUND: Persistent infection with high-risk human papillomavirus (HPV) is a predominant cause of cervical cancer, and HPV16 and HPV18 occur in 50% and 20% of cervical cancer cases, respectively. The viral oncogenes E6 and E7 are constitutively expressed by HPV-associated tumour cells and can therefore be used as target antigens for immunotherapy. In this study, we constructed a recombinant vaccinia virus co-expressing the HPV16/18 E7E6 fusion proteins (rVVJ16/18E7E6) for use as a therapeutic vaccine for the treatment of HPV16+ and HPV18+ cancers. METHODS: We constructed a bivalent recombinant vaccinia virus expressing modified E7E6 fusion proteins of HPV type 16 and 18 (rVVJ16/18E7E6) based on the vaccinia virus Tiantan strain. We then defined the cellular immune responses to the virus in mice and rhesus monkeys and assessed antitumour efficacy of these responses in mice using the TC-1 tumour challenge model. RESULTS: Our data demonstrated that rVVJ16/18E7E6 was able to elicit varying levels of CD8+ T cell immune responses and lysis of target cells in mice in response to peptides HPV16E749-57 and HPV18E667-75. Furthermore, the virus was also able to induce anti-tumour responses in the HPV16+ TC-1 tumour challenge model, including partial protection (30-40%) and delayed tumour appearance. In addition, the virus was able to induce immune responses in rhesus monkeys. CONCLUSIONS: The recombinant vaccinia virus rVVJ16/18E7E6 can generate clear and significant cellular immunity in both mice and rhesus monkeys. These data provide a basis for the use of this recombinant virus as a potential vaccine candidate for further study. PMID- 21672264 TI - Parallel mutual information estimation for inferring gene regulatory networks on GPUs. AB - BACKGROUND: Mutual information is a measure of similarity between two variables. It has been widely used in various application domains including computational biology, machine learning, statistics, image processing, and financial computing. Previously used simple histogram based mutual information estimators lack the precision in quality compared to kernel based methods. The recently introduced B spline function based mutual information estimation method is competitive to the kernel based methods in terms of quality but at a lower computational complexity. RESULTS: We present a new approach to accelerate the B-spline function based mutual information estimation algorithm with commodity graphics hardware. To derive an efficient mapping onto this type of architecture, we have used the Compute Unified Device Architecture (CUDA) programming model to design and implement a new parallel algorithm. Our implementation, called CUDA-MI, can achieve speedups of up to 82 using double precision on a single GPU compared to a multi-threaded implementation on a quad-core CPU for large microarray datasets. We have used the results obtained by CUDA-MI to infer gene regulatory networks (GRNs) from microarray data. The comparisons to existing methods including ARACNE and TINGe show that CUDA-MI produces GRNs of higher quality in less time. CONCLUSIONS: CUDA-MI is publicly available open-source software, written in CUDA and C++ programming languages. It obtains significant speedup over sequential multi-threaded implementation by fully exploiting the compute capability of commonly used CUDA-enabled low-cost GPUs. PMID- 21672266 TI - The high Andes, gene flow and a stable hybrid zone shape the genetic structure of a wide-ranging South American parrot. AB - BACKGROUND: While the gene flow in some organisms is strongly affected by physical barriers and geographical distance, other highly mobile species are able to overcome such constraints. In southern South America, the Andes (here up to 6,900 m) may constitute a formidable barrier to dispersal. In addition, this region was affected by cycles of intercalating arid/moist periods during the Upper/Late Pleistocene and Holocene. These factors may have been crucial in driving the phylogeographic structure of the vertebrate fauna of the region. Here we test these hypotheses in the burrowing parrot Cyanoliseus patagonus (Aves, Psittaciformes) across its wide distributional range in Chile and Argentina. RESULTS: Our data show a Chilean origin for this species, with a single migration event across the Andes during the Upper/Late Pleistocene, which gave rise to all extant Argentinean mitochondrial lineages. Analyses suggest a complex population structure for burrowing parrots in Argentina, which includes a hybrid zone that has remained stable for several thousand years. Within this zone, introgression by expanding haplotypes has resulted in the evolution of an intermediate phenotype. Multivariate regressions show that present day climatic variables have a strong influence on the distribution of genetic heterogeneity, accounting for almost half of the variation in the data. CONCLUSIONS: Here we show how huge barriers like the Andes and the regional environmental conditions imposed constraints on the ability of a parrot species to colonise new habitats, affecting the way in which populations diverged and thus, genetic structure. When contact between divergent populations was re-established, a stable hybrid zone was formed, functioning as a channel for genetic exchange between populations. PMID- 21672265 TI - Genetic structure of the Mon-Khmer speaking groups and their affinity to the neighbouring Tai populations in Northern Thailand. AB - BACKGROUND: The Mon-Khmer speaking peoples inhabited northern Thailand before the arrival of the Tai speaking people from southern China in the thirteenth century A.D. Historical and anthropological evidence suggests a close relationship between the Mon-Khmer groups and the present day majority northern Thai groups. In this study, mitochondrial and Y-chromosomal DNA polymorphisms in more than 800 volunteers from eight Mon-Khmer and ten Tai speaking populations were investigated to estimate the degree of genetic divergence between these major linguistic groups and their internal structure. RESULTS: A large fraction of genetic variation is observed within populations (about 80% and 90% for mtDNA and the Y-chromosome, respectively). The genetic divergence between populations is much higher in Mon-Khmer than in Tai speaking groups, especially at the paternally inherited markers. The two major linguistic groups are genetically distinct, but only for a marginal fraction (1 to 2%) of the total genetic variation. Genetic distances between populations correlate with their linguistic differences, whereas the geographic distance does not explain the genetic divergence pattern. CONCLUSIONS: The Mon-Khmer speaking populations in northern Thailand exhibited the genetic divergence among each other and also when compared to Tai speaking peoples. The different drift effects and the post-marital residence patterns between the two linguistic groups are the explanation for a small but significant fraction of the genetic variation pattern within and between them. PMID- 21672267 TI - Reliability of the Cerebral Performance Category to classify neurological status among survivors of ventricular fibrillation arrest: a cohort study. AB - BACKGROUND: The Cerebral Performance Category (CPC) score is widely used in research and quality assurance to assess neurologic outcome following cardiac arrest. However, little is known about the inter- and intra-reviewer reliability of the CPC. METHODS: We undertook an investigation to assess the inter-reviewer and source document reliability of the CPC among a cohort of survivors from out of-hospital ventricular fibrillation cardiac arrest (n = 131) in a large metropolitan area between November 1, 2003 and December 31, 2005. Subjects with a CPC of 1 or 2 were classified as favorable outcome and those with CPC 3 or greater were classified as unfavorable outcome. One abstractor first used the discharge summary alone to determine the CPC. All 3 abstractors independently reviewed the entire hospital record. Reliability was assessed by determining the proportion of determinations that agreed between abstractors and the respective kappa statistics. We also evaluated the implications for determining survival with favorable neurological outcome when survival to hospital discharge was 20% and 30%. RESULTS: When the entire hospital record was used to determine CPC, favorable neurologic outcome (CPC 1 or 2) was recorded in 92% by abstractor 1, 89% by abstractor 2, and 74% by abstractor 3. Agreement was 96% (kappa = 0.78) between abstractors 1 and 2, 84% (kappa = 0.49) between abstractors 2 and 3, 82% (kappa = 0.38) between abstractors 1 and 3. The 3-way kappa was 0.50. Agreement was 90% (kappa = 0.71) between the discharge summary alone and the entire hospital record. If the results from review of the entire record are applied to a circumstance where survival to discharge is 20%, favorable neurologic status would occur in 18.4% for abstractor 1, 17.8% for abstractor 2, and 14.8% for abstractor 3. For survival to hospital discharge of 30%, favorable neurologic status would occur in 27.6% for abstractor 1, 26.7% for abstractor 2, and 22.2% for abstractor 3. CONCLUSIONS: In this cohort study of survivors of out-of hospital ventricular fibrillation cardiac arrest, the use of the CPC to classify favorable versus unfavorable neurological status at hospital discharge produced variable inter- and intra-reviewer agreement. The findings provide useful context to interpret outcome evaluations that report CPC. PMID- 21672268 TI - A nosocomial transmission of crimean-congo hemorrhagic fever to an attending physician in North Kordufan, Sudan. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF), a tick-borne disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is a member of the genus Nairovirus in the family Bunyaviridae. Recently, CCHFV has been reported as an important emerging infectious viral pathogen in Sudan. Sporadic cases and multiple CCHF outbreaks, associated with nosocomial chain of transmission, have been reported in the Kordufan region of Sudan. AIMS: To confirm CCHF in an index patient and attending physician in North Kordufan region, Sudan, and to provide some information on virus genetic lineages. METHODS: Antibody captured ELISA, reverse transcription PCR, partial S segment sequences of the virus and subsequent phylogenetic analysis were used to confirm the CCHFV infection and to determine the virus genetic lineages. RESULTS: CCHF was confirmed by monitoring specific IgM antibody and by detection of the viral genome using RT-PCR. Treatment with oral ribavirin, replacement with fluid therapy, blood transfusion and administration of platelets concentrate resulted in rapid improvement of the health condition of the female physician. Phylogenetic analysis of the partial S segment sequences of the 2 CCHFV indicates that both strains are identical and belong to Group III virus lineage, which includes viruses from Africa including, Sudan, Mauritania, South Africa and Nigeria. CONCLUSION: Further epidemiologic studies including, CCHFV complete genome analysis and implementation of improved surveillance are urgently needed to better predict and respond to CCHF outbreaks in the Kordufan region, Sudan. PMID- 21672269 TI - Falling behind: life expectancy in US counties from 2000 to 2007 in an international context. AB - BACKGROUND: The United States health care debate has focused on the nation's uniquely high rates of lack of insurance and poor health outcomes relative to other high-income countries. Large disparities in health outcomes are well documented in the US, but the most recent assessment of county disparities in mortality is from 1999. It is critical to tracking progress of health reform legislation to have an up-to-date assessment of disparities in life expectancy across counties. US disparities can be seen more clearly in the context of how progress in each county compares to international trends. METHODS: We use newly released mortality data by age, sex, and county for the US from 2000 to 2007 to compute life tables separately for each sex, for all races combined, for whites, and for blacks. We propose, validate, and apply novel methods to estimate recent life tables for small areas to generate up-to-date estimates. Life expectancy rates and changes in life expectancy for counties are compared to the life expectancies across nations in 2000 and 2007. We calculate the number of calendar years behind each county is in 2000 and 2007 compared to an international life expectancy time series. RESULTS: Across US counties, life expectancy in 2007 ranged from 65.9 to 81.1 years for men and 73.5 to 86.0 years for women. When compared against a time series of life expectancy in the 10 nations with the lowest mortality, US counties range from being 15 calendar years ahead to over 50 calendar years behind for men and 16 calendar years ahead to over 50 calendar years behind for women. County life expectancy for black men ranges from 59.4 to 77.2 years, with counties ranging from seven to over 50 calendar years behind the international frontier; for black women, the range is 69.6 to 82.6 years, with counties ranging from eight to over 50 calendar years behind. Between 2000 and 2007, 80% (men) and 91% (women) of American counties fell in standing against this international life expectancy standard. CONCLUSIONS: The US has extremely large geographic and racial disparities, with some communities having life expectancies already well behind those of the best-performing nations. At the same time, relative performance for most communities continues to drop. Efforts to address these issues will need to tackle the leading preventable causes of death. PMID- 21672270 TI - Brain-computer interfacing using modulations of alpha activity induced by covert shifts of attention. AB - BACKGROUND: Visual brain-computer interfaces (BCIs) often yield high performance only when targets are fixated with the eyes. Furthermore, many paradigms use intense visual stimulation, which can be irritating especially in long BCI sessions. However, BCIs can more directly directly tap the neural processes underlying visual attention. Covert shifts of visual attention induce changes in oscillatory alpha activity in posterior cortex, even in the absence of visual stimulation. The aim was to investigate whether different pairs of directions of attention shifts can be reliably differentiated based on the electroencephalogram. To this end, healthy participants (N = 8) had to strictly fixate a central dot and covertly shift visual attention to one out of six cued directions. RESULTS: Covert attention shifts induced a prolonged alpha synchronization over posterior electrode sites (PO and O electrodes). Spectral changes had specific topographies so that different pairs of directions could be differentiated. There was substantial variation across participants with respect to the direction pairs that could be reliably classified. Mean accuracy for the best-classifiable pair amounted to 74.6%. Furthermore, an alpha power index obtained during a relaxation measurement showed to be predictive of peak BCI performance (r = .66). CONCLUSIONS: Results confirm posterior alpha power modulations as a viable input modality for gaze-independent EEG-based BCIs. The pair of directions yielding optimal performance varies across participants. Consequently, participants with low control for standard directions such as left right might resort to other pairs of directions including top and bottom. Additionally, a simple alpha index was shown to predict prospective BCI performance. PMID- 21672271 TI - Notch signaling as a therapeutic target for breast cancer treatment? AB - Aberrant Notch signaling can induce mammary gland carcinoma in transgenic mice, and high expressions of Notch receptors and ligands have been linked to poor clinical outcomes in human patients with breast cancer. This suggests that inhibition of Notch signaling may be beneficial for breast cancer treatment. In this review, we critically evaluate the evidence that supports or challenges the hypothesis that inhibition of Notch signaling would be advantageous in breast cancer management. We find that there are many remaining uncertainties that must be addressed experimentally if we are to exploit inhibition of Notch signaling as a treatment approach in breast cancer. Nonetheless, Notch inhibition, in combination with other therapies, is a promising avenue for future management of breast cancer. Furthermore, since aberrant Notch4 activity can induce mammary gland carcinoma in the absence of RBPjkappa, a better understanding of the components of RBPjkappa-independent oncogenic Notch signaling pathways and their contribution to Notch-induced tumorigenesis would facilitate the deployment of Notch inhibition strategies for effective treatment of breast cancer. PMID- 21672272 TI - Waking up dormant tumors. AB - As appreciation grows for the contribution of the tumor microenvironment to the progression of cancer, new evidence accumulates to support that the participation of stromal cells can extend beyond the local environment. Recently, Elkabets and colleagues demonstrated a systemic interaction between cancer cells and distant bone marrow cells to support the growth of otherwise indolent tumor cells at a secondary site, raising thought-provoking questions regarding the involvement of stromal cells in maintaining metastatic dormancy. PMID- 21672273 TI - Is faster still better in therapeutic hypothermia? AB - The rapid institution of therapeutic hypothermia after cardiac arrest has become an accepted practice. In the previous issue of Critical Care, Haugk and colleagues present a retrospective analysis of 13 years of experience with therapeutic hypothermia at their center that suggests an association between rate of cooling and less favorable neurological outcomes. The association most likely reflects easier cooling in patients more severely brain injured by their initial cardiac arrest, and should not lead clinicians to abandon or slow their efforts to achieve post-resuscitative cooling. PMID- 21672274 TI - Cardiac-related impedance changes obtained by electrical impedance tomography: an acceptable parameter for assessment of pulmonary perfusion? PMID- 21672275 TI - Postoperative left ventricular thrombosis and transthoracic echocardiography: is it enough? PMID- 21672276 TI - Clinical review: fever in septic ICU patients--friend or foe? AB - In recent years, fever control in critically ill patients by medications and/or external cooling has gained widespread use, notably in patients suffering from neurological injuries. Nevertheless, such a strategy in septic patients is not supported by relevant data. Indeed, in response to sepsis, experimental and clinical studies argue that fever plays a key role in increasing the clearance of microorganisms, the immune response and the heat shock response. Moreover, fever is a cornerstone diagnostic sign in clinical practice, which aids in early and appropriate therapy, and allows physicians to follow the infection course. After discussing the physiological aspects of fever production, the present review aims to delineate the advantages and drawbacks of fever in septic patients. Finally, the treatment of fever by pharmacological and/or physical means is discussed with regards to their drawbacks, which argues for their careful use in septic patients in the absence of clinical relevance. PMID- 21672277 TI - Are we sedating more than just the brain? AB - Heavy sedation in the ICU is associated with coma, delirium, and prolonged stays, but links between sedatives and non-brain organ failure have rarely been described. In a post hoc analysis, Strom and colleagues explored associations between sedation and acute kidney injury among ICU patients randomly assigned to one of two sedation strategies. The 'no sedation' protocol was associated with less kidney injury, but methodologic limitations preclude firm conclusions regarding mechanisms underlying this association. This hypothesis-generating study warns that sedation may harm organs other than the brain during critical illness, a possibility that warrants careful study in the future. PMID- 21672278 TI - Totem and taboo: fluids in sepsis. AB - The need for early, rapid, and substantial fluid resuscitation in septic patients has long been an article of faith in the intensive care community, a tribal totem that is taboo to question. The results of a recent multicenter trial in septic children in Africa, published in The New England Journal of Medicine, powerfully challenge the fluid paradigm. The salient aspects of the trial need to be understood and reflected upon. In this commentary, we discuss the background to and findings of the trial and explain why they will likely trigger a re evaluation of our thinking about fluids in sepsis, a re-evaluation that is already happening in the treatment of acute respiratory distress syndrome and acute kidney injury and in postoperative care. PMID- 21672281 TI - Ability of respiratory pulse pressure variation to predict fluid responsiveness in ARDS: still an unanswered question? PMID- 21672279 TI - Clinical review: timing of renal replacement therapy. AB - Acute kidney injury is common in intensive care patients and continuous renal replacement therapy is the preferred treatment for this in most centres. Although these techniques have been adopted internationally, there remains significant variation with regard to their clinical application. This is particularly pertinent when one considers that the fundamental questions regarding any treatment, such as initiation, dose and length of treatment, remain a source of debate and have not as yet all been fully answered. In this narrative review we consider the timing of renal replacement therapy, highlighting the relative paucity of high quality data regarding this fundamental question. We examine the role of the usual biochemical criteria as well as conventional clinical indications for commencing renal replacement therapy together with the application of recent classification systems, namely RIFLE and AKIN. We discuss the potential role of biomarkers for acute kidney injury as predictors for the need for renal support and discuss commencing therapy for indications other than acute kidney injury. PMID- 21672282 TI - Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition. AB - Induction of epithelial-to-mesenchymal transition (EMT) in cancer stem cells (CSCs) can occur as the result of embryonic pathway signaling. Activation of Hedgehog (Hh), Wnt, Notch, or transforming growth factor-beta leads to the upregulation of a group of transcriptional factors that drive EMT. This process leads to the transformation of adhesive, non-mobile, epithelial-like tumor cells into cells with a mobile, invasive phenotype. CSCs and the EMT process are currently being investigated for the role they play in driving metastatic tumor formation in breast cancer. Both are very closely associated with embryonic signaling pathways that stimulate self-renewal properties of CSCs and EMT inducing transcription factors. Understanding these mechanisms and embryonic signaling pathways may lead to new opportunities for developing therapeutic agents to help prevent metastasis in breast cancer. In this review, we examine embryonic signaling pathways, CSCs, and factors affecting EMT. PMID- 21672283 TI - Which is the most effective strategy: early detection of coagulopathy with thromboelastometry or use of hemostatic factors or both? PMID- 21672285 TI - EZH2-mediated epigenetic repression of DNA repair in promoting breast tumor initiating cells. AB - Members of the Polycomb-group (PcG) family of proteins, including EZH2 (enhancer of zeste homolog 2), are involved in establishing epigenetic silencing of developmental genes in adult and embryonic stem cells, and their deregulation has been implicated in cancer. In a recent report, EZH2-mediated epigenetic repression of DNA damage repair in breast tumor initiating cells (BTICs) was identified as a mechanism that could promote expansion of BTICs, and may contribute to cancer progression. PMID- 21672286 TI - [A man with thoracic pain]. AB - A 46-year-old man had pain between the shoulders and at the sternum. Two and a half months earlier he had fallen when cycling. It appeared the pain was caused by fractures of thoracic vertebrae V and VI and a dislocation of the manubrium and body of the sternum. PMID- 21672284 TI - Sjogren's syndrome: studying the disease in mice. AB - Sjogren's syndrome (SS), a systemic autoimmune disease, is characterized by inflammation of exocrine tissues accompanied by a significant loss of their secretory function. Clinical symptoms develop late and there are no diagnostic tests enabling early diagnosis of SS. Thus, particularly to study these covert stages, researchers turn to studying animal models where mice provide great freedom for genetic manipulation and testing the effect of experimental intervention. The present review summarizes current literature pertaining to both spontaneous and extrinsic-factor induced SS-like diseases in mouse models, discussing advantages and disadvantages related to the use of murine models in SS research. PMID- 21672287 TI - [Pyelonephritis with renal abscess in a child]. AB - BACKGROUND: Pyelonephritis is a rare condition. It can sometimes be complicated by a renal abscess. CASE DESCRIPTION: A 7-year-old girl had a complicated course of a pyelonephritis. She was being administered intravenous antimicrobial agents and developed a fever with cold chills during treatment. Ultrasound and MRI revealed that the cause of the deterioration was a renal abscess. The patient was treated with ceftriaxone en gentamicin. Escherichia coli was isolated from the abscess. After two weeks of treatment, an MRI showed that the renal abscess had almost disappeared; this was confirmed by an additional ultrasound one week after the treatment had been discontinued. CONCLUSION: The symptoms of a renal abscess are high fever, cold chills, stomach pain, groin pain, weight loss, total malaise, and clinical deterioration whilst under treatment. Quick recognition of the condition is important. An abscess of less than 5 cm in diameter may be treated with antibiotics alone. PMID- 21672288 TI - [Outcomes after hand injuries]. AB - A 25-year-old male and a 41-year-old male presented at the Emergency Department with a hand injury. Although both patients received immediate surgical care and specialized rehabilitation care, outcomes were better in the first patient, who had sustained the more severe hand injury. Outcomes were influenced not only by injury severity, but also by personal and external factors. Personal factors, such as age, motivation and compliance, were more favourable in the first patient. External factors, such as complications, delayed care, language problems and social problems, mainly affected the second patient, who was less severely injured. As a result, outcomes on all functional levels of the WHO's International Classification of Functioning, Disability and Health (body functions and structure, and activity and participation) were better in the patient with the more severe injury. Specialized hand care is required in hand injuries, but professionals should also be aware that personal and external factors have a substantial influence on outcomes after hand injuries. PMID- 21672289 TI - [Lung volume recruitment in impending respiratory failure]. AB - Lung volume recruitment can improve peak cough flows and respiratory compliance in patients who either do or do not require mechanical ventilation. There are several lung volume recruitment techniques: air stacking, glossopharyngeal breathing and mechanical insufflation-exsufflation with cough assist devices. The principle of lung volume recruitment is based on the insufflation of air in the lungs after maximal inspiration. In air stacking, a manual resuscitation bag is used for insufflation. Glossopharyngeal breathing requires the use of oropharyngeal and laryngeal muscles by the patient. The mechanical cough assist device exsufflates the air after insufflation. These techniques may prevent pulmonary complications, hospital admission and tracheotomy in patients with a reduced ability to cough, a proclivity towards atelectasis and recurrent airway infections. The combination of long-term mechanical ventilation with lung volume recruitment has led to further improvement in the prognosis of chronic respiratory failure. More patients may potentially benefit from lung volume recruitment than only those being converted from short-term to long-term mechanical ventilation. PMID- 21672290 TI - [Communication with the relatives of a patient presumed brain dead]. AB - BACKGROUND: The choice of wording in cases of suspected brain death is important. If brain death has not been proven by electrocerebral silence and by absence of spontaneous breathing in an apnoea test in a patient in intensive care, then words like 'brain dead', 'has died' and 'clinical brain death' should be avoided in conversations with the relatives of the patient. This is illustrated by three cases. CASES: The first patient was a 46-year-old woman, with thrombosis of the basilar artery; the second was a 26-year-old man who was resuscitated after a bilateral pneumothorax, but developed severe postanoxic encephalopathy; and the third patient was a 64-year-old man with a large intracerebral haemorrhage. The relatives were informed that the patient was 'brain dead' or 'deceased' based on loss of consciousness (Glasgow Coma score of 3) and absence of brain stem reflexes, but prior to the completion of the brain death protocol by electroencephalography and apnoea testing. In the first and third cases, brain death could not be proven, and the pronouncement that the patient was deceased had to be reversed. The emotional relatives refused organ donation. In the second case, death was pronounced upon loss of consciousness and absence of brain stem reflexes. The relatives refused organ donation, after which mechanical ventilation was withdrawn and the patient was declared dead for a second time based on circulatory arrest. CONCLUSION: A patient is dead after complete brain death determination or after circulatory arrest. Loss of consciousness (Glasgow Coma score of 3) and absence of brain stem reflexes lead to a state of catastrophic cerebral damage, but not to brain death. In such a situation, wording such as 'brain death', 'deceased' and 'clinical brain death' should be avoided in conversations with the relatives. PMID- 21672291 TI - [New Dutch practice guideline for administration of vitamin K to full-term newborns]. AB - Vitamin K-deficiency can cause haemorrhage in newborns and infants from the first hours up to several months after birth. These 'vitamin K deficiency bleedings' (VKDB) can be divided into 3 forms: early (occur in the first hours after birth), classic (first week after birth) and late (between the 2nd and the 12th week of life). The current Dutch vitamin K practice guideline consists of prophylactic administration of 1 mg vitamin K orally directly after birth and a daily dose of 25 MUg from day 8 onwards. The current prophylactic treatment provides good protection against VKDB for healthy, breastfed infants. However, the current prophylactic treatment provides insufficient protection for a specific group of infants, namely breastfed infants with defective fat absorption (in cholestasis), leading to less efficient absorption of vitamin K by the body. Anually approximately 5 infants from this group suffer serious haemorrhage. After evaluation of current literature and advice from The Health Council of the Netherlands, vitamin K dosage was adapted for all breastfed infants from day 8 to 3 months (12th week of life) following birth: the daily dose was raised from 25 ug to 150 ug per day. PMID- 21672292 TI - Recommendations from the Association for European Paediatric Cardiology for training in paediatric cardiac intensive care. AB - The following document provides a summary of the guidelines and recommendations for paediatric cardiac intensive care training as a requirement for recognition as a European paediatric cardiologist. It is therefore primarily targeting paediatric cardiology trainees in Europe, including those doctors who might wish to become experts in cardiac intensive care. These recommendations represent a frame for consistency, will evolve, and may be adapted to specific institutional requirements. They will be complemented by a learning module to be provided by our Association in the near future. PMID- 21672293 TI - Trichogramma pretiosum parasitism and dispersal capacity: a basis for developing biological control programs for soybean caterpillars. AB - In order to succeed in biological control programs, not only is it crucial to understand the number of natural enemies to be released but also on how many sites per area this releasing must be performed. These variables might differ deeply among egg parasitoid species and crops worked. Therefore, these trials were carried out to evaluate the parasitism (%) in eggs of Anticarsia gemmatalis and Pseudoplusia includens after the release of different densities of the egg parasitoid Trichogramma pretiosum. Field dispersal was also studied, in order to determine appropriate recommendations for the release of this parasitoid in soybean fields. The regression analysis between parasitism (%) and densities of the parasitoid indicated a quadratic effect for both A. gemmatalis and P. includens. The maximum parasitism within 24 h after the release was reached with densities of 25.6 and 51.2 parasitoids per host egg, respectively, for the two pests. Parasitism of T. pretiosum in eggs of P. includens decreased linearly as the distance of the pest eggs from the parasitoid release sites increased. For P. includens, the mean radius of T. pretiosum action and the area of parasitoid dispersal in the soybean crop were 8.01 m and 85.18 m2, respectively. We conclude that for a successful biological control program of lepidopteran pests using T. pretiosum in soybean fields, a density of 25.6 parasitoids per host egg, divided into 117 sites per hectare, should be used. PMID- 21672294 TI - Effect of temperature and relative humidity on the development and fecundity of Chilo partellus (Swinhoe) (Lepidoptera: Crambidae). AB - The spotted stemborer, Chilo partellus (Swinhoe) (Lepidoptera: Crambidae), is one of the most important insect pests attacking maize and sorghum in Ethiopia. Recent studies have indicated that the pest is spreading to new locations where it was not reported before. In the current study, laboratory investigations were carried out to determine the combined effect of different levels of relative humidity and temperature regimes on the development and fecundity of C. partellus, as these physical factors are known to play an important role in the life cycle of insects and adaptability to local climate. Developmental time, longevity, potential fecundity and realized fecundity of C. partellus were measured under controlled conditions. Three temperature regimes (22 degrees C, 26 degrees C and 30 degrees C) and three relative humidity levels (40%, 60% and 80%) were tested. It was found that temperature, relative humidity (RH) and their interaction significantly affected the developmental time, adult longevity, potential fecundity and realized fecundity of the pest. Developmental time was inversely related to temperature. Mean duration of C. partellus life cycle was 70.2 days at 22 degrees C and 80% RH, whereas it took only 26.5 days to complete its life cycle at 30 degrees C and 40% RH. Male and female longevity were similar in most cases. The adult life span ranged between 6.9-11.1 days at 22 degrees C and 3.1-7.2 days at 30 degrees C for different levels of relative humidity. The most suitable conditions for C. partellus development and fecundity were 26-30 degrees C temperatures regimes and 60-80% RH levels. PMID- 21672295 TI - Prevalence and risk factors for hepatitis C virus infection in Kech District, Balochistan, Pakistan: most infections remain unexplained. A cross-sectional study. AB - We studied a cross-sectional sample of the population of Kech, a small rural town in Pakistan to determine the prevalence and risk factors for hepatitis C infection. The prevalence of hepatitis C was 110 out of 2000 persons (5.5%, 95% confidence interval 4.5-6.5). Higher rates were identified in males. Independent risk factors identified were age >=75 years, being a healthcare worker, and injecting drug use. There was a high prevalence of many potential routes of transmission of bloodborne viruses and most people reported at least one potential risk factor. PMID- 21672296 TI - Risk factors prospectively associated with adult obsessive-compulsive symptom dimensions and obsessive-compulsive disorder. AB - BACKGROUND: Very few longitudinal studies have evaluated prospective neurodevelopmental and psychosocial risk factors for obsessive-compulsive disorder (OCD). Furthermore, despite the heterogeneous nature of OCD, no research has examined risk factors for its primary symptom dimensions, such as contamination/washing. METHOD: Potential risk factors for symptoms or diagnosis of OCD in adulthood and for specific adult obsessive-compulsive (OC) symptom dimensions were examined in the Dunedin Study birth cohort. The presence of obsessions and compulsions and psychological disorders was assessed using the Diagnostic Interview Schedule (DIS) at ages 26 and 32 years. Individuals with a diagnosis of OCD at either age (n=36) were compared to both a healthy control group (n=613) and an anxious control group (n=310) to determine whether associations between a risk factor and an OCD diagnosis were specific. RESULTS: Childhood neurodevelopmental, behavioral, personality and environmental risk factors were associated with a diagnosis of OCD and with OC symptoms at ages 26 and 32. Social isolation, retrospectively reported physical abuse and negative emotionality were specific predictors of an adult OCD diagnosis. Of note, most risk factors were associated with OC symptoms in adulthood and several risk factors predicted specific OCD dimensions. Perinatal insults were linked to increased risk for symmetry/ordering and shameful thoughts dimensions, whereas poor childhood motor skills predicted the harm/checking dimension. Difficult temperament, internalizing symptoms and conduct problems in childhood also predicted specific symptom dimensions and lower IQ non-specifically predicted increased risk for most dimensions. CONCLUSIONS: The current findings underscore the need for a dimensional approach in evaluating childhood risk factors for obsessions and compulsions. PMID- 21672297 TI - The clinical effectiveness of CBT-based guided self-help interventions for anxiety and depressive disorders: a systematic review. AB - BACKGROUND: Cognitive-behavioural therapy (CBT)-based guided self-help (GSH) has been suggested to be an effective intervention for mild to moderate anxiety and depression, yet the evidence seems inconclusive, with some studies reporting that GSH is effective and others finding that GSH is ineffective. GSH differs in important respects from other levels of self-help, yet the literature regarding exclusively guided self-help interventions for anxiety and depression has not been reviewed systematically. METHOD: A literature search for randomized controlled trials (RCTs) examining CBT-based GSH interventions for anxiety and depressive disorders was conducted. Multiple electronic databases were searched; several journals spanning key disciplines were hand-searched; reference lists of included review articles were scanned and relevant first authors were contacted. RESULTS: Thirteen studies met the inclusion criteria. Meta-analysis indicated the effectiveness of GSH at post-treatment, although GSH was found to have limited effectiveness at follow-up or among more clinically representative samples. Studies that reported greater effectiveness of GSH tended to be of lower methodological quality and generally involved participants who were self-selected rather than recruited through clinical referrals. CONCLUSIONS: Although there is support for the effectiveness of CBT-based GSH among media-recruited individuals, the finding that the reviewed RCTs had limited effectiveness within routine clinical practice demonstrates that the evidence is not conclusive. Further rigorous evidence based on clinical populations that examines longer-term outcomes is required before CBT-based GSH interventions can be deemed effective for adults accessing primary care services for treatment of anxiety and depression. PMID- 21672299 TI - Self-rating scales assessing subjective well-being and distress correlate with rCBF in PTSD-sensitive regions. AB - BACKGROUND: The aim of this study was to investigate the distribution of the regional cerebral blood flow (rCBF) in occupational-related post-traumatic stress disorder (PTSD) subjects and to seek possible correlations between brain perfusion and self-rating scales (SRS) in order to cross-check their diagnostic value and to look for their neural correlates. METHOD: A total of 13 traumatized underground and long-distance train drivers developing (S) and 17 not developing (NS) PTSD who had experienced a 'person under train' accident or who had been assaulted at work underwent clinical assessment and 99mTc-HMPAO SPECT imaging during autobiographical trauma scripts. Statistical parametric mapping was applied to analyse rCBF changes in S as compared with NS and to search for correlations between rCBF and the administered SRS scores, modelling age, months to SPECT and the ratio 'grey matter/intra-cranial volume' as nuisance variables. RESULTS: Significantly higher activity was observed during trauma script in left posterior and anterior insula, posterior cingulate, inferior parietal lobule, precuneus, caudate and putamen in PTSD subjects as compared with the trauma exposed control group. Impact of Event Scale and World Health Organisation (10) Well-Being Index scores highly correlated with tracer uptake to a great extent in the same regions in which rCBF differences between S and NS were found. CONCLUSIONS: These findings support the involvement of insular, cingulate and parietal cortices (as well as the basal ganglia) in the pathogenesis of PTSD and in the processing of related subjective well-being and distress. PMID- 21672298 TI - Heart rate after trauma and the specificity of fear circuitry disorders. AB - BACKGROUND: Fear circuitry disorders purportedly include post-traumatic stress disorder (PTSD), panic disorder, agoraphobia, social phobia and specific phobia. It is proposed that these disorders represent a cluster of anxiety disorders triggered by stressful events and lead to fear conditioning. Elevated heart rate (HR) at the time of an aversive event may reflect strength of the unconditioned response, which may contribute to fear circuitry disorders. METHOD: This prospective cohort study assessed HR within 48 h of hospital admission in 602 traumatically injured patients, who were assessed during hospital admission and within 1 month of trauma exposure for lifetime psychiatric diagnosis. At 3 months after the initial assessment, 526 patients (87%) were reassessed for PTSD, major depressive disorder, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and generalized anxiety disorder. RESULTS: At the 3-month assessment there were 77 (15%) new cases of fear circuitry disorder and 87 new cases of non-fear circuitry disorder (17%). After controlling for gender, age, type of injury and injury severity, patients with elevated HR (defined as >=96 beats per min) at the time of injury were more likely to develop PTSD [odds ratio (OR) 5.78, 95% confidence interval (CI) 2.32-14.43], panic disorder (OR 3.46, 95% CI 1.16-10.34), agoraphobia (OR 3.90, 95% CI 1.76-8.61) and social phobia (OR 3.98, 95% CI 1.42-11.14). Elevated HR also predicted new fear circuitry disorders that were not co-morbid with a non-fear circuitry disorder (OR 7.28, 95% CI 2.14 24.79). CONCLUSIONS: These data provide tentative evidence of a common mechanism underpinning the onset of fear circuitry disorders. PMID- 21672300 TI - Which cognitions and behaviours mediate the positive effect of cognitive behavioural therapy on fatigue in patients with multiple sclerosis? AB - BACKGROUND: Chronic fatigue is a common symptom of multiple sclerosis (MS). A randomized controlled trial (RCT) showed that cognitive behavioural therapy (CBT) was more effective in reducing MS fatigue than relaxation training (RT). The aim of the current study was to analyse additional data from this trial to determine whether (1) CBT compared to RT leads to significantly greater changes in cognitions and behaviours hypothesized to perpetuate MS fatigue; (2) changes in these variables mediate the effect of CBT on MS fatigue; and (3) these mediation effects are independent of changes in mood. METHOD: Seventy patients (CBT, n=35; RT, n=35) completed the Cognitive and Behavioural Responses to Symptoms Questionnaire (CBSQ), the Brief Illness Perception Questionnaire (B-IPQ) modified to measure negative representations of fatigue, the Hospital Anxiety and Depression Scale (HADS), and the Chalder Fatigue Questionnaire (CFQ), pre- and post-therapy. Multiple mediation analysis was used to determine which variables mediated the change in fatigue. RESULTS: Avoidance behaviour and three cognitive variables (symptom focusing, believing symptoms are a sign of damage and a negative representation of fatigue) improved significantly more in the CBT than the RT group. Mediation analysis showed that changing negative representations of fatigue mediated the decrease in severity of fatigue. Change in anxiety covaried with reduction in fatigue but the mediation effect for negative representations of fatigue remained when controlling for improvements in mood. CONCLUSIONS: Change in beliefs about fatigue play a crucial role in CBT for MS fatigue. These beliefs and the role of anxiety deserve more attention in the further development of this intervention. PMID- 21672301 TI - How psychotic-like are unusual subjective experiences? PMID- 21672302 TI - MicroRNA in osteoarthritis. AB - Osteoarthritis (OA) is the most prevalent degenerative joint disease and is accompanied by pain and joint dysfunction. Its clinical treatment tends to be unsatisfactory. Novel targets in OA include genes that are involved in OA pathophysiology and have been discovered using gene network, epigenetic and microRNA (miRNA) approaches. miRNA has been implicated in important cellular processes such as lipid metabolism, apoptosis, differentiation and organ development. The importance of miRNA regulation in cellular function is becoming increasingly clear as new miRNA targets are revealed. The present review summarizes the current evidence of the important role played by miRNA in determining the complex gene expression patterns of OA chondrocytes and their role in the regulation of transcription, and possible demethylation mechanisms that might be applicable in OA. In summary, miRNA may have important diagnostic and therapeutic potential, and might provide a novel means of treating OA. PMID- 21672303 TI - Meta-analysis of the efficacy and safety of bronchial thermoplasty in patients with moderate-to-severe persistent asthma. AB - This meta-analysis assessed the efficacy and safety of a novel intervention for asthma, bronchial thermoplasty (BT), in patients with moderate-to-severe persistent asthma. An electronic literature search identified three randomized controlled trials (RCT) of BT that recruited 421 patients in total. Outcomes of interest were the Asthma Quality of Life Questionnaire (AQLQ) score, morning peak expiratory flow (PEF), tolerability and safety. Compared with standard medications and sham BT treatment, BT significantly improved AQLQ scores and PEF from baseline to the end of the trials. There were more respiratory adverse events and hospitalizations for adverse respiratory events with BT than with medications or sham treatment during the treatment period, but most events resolved, on average, within a week. This effect of BT treatment was not seen during the posttreatment period. Additional long-term RCT are required to confirm whether BT provides benefit to patients with moderate-to-severe persistent asthma. PMID- 21672304 TI - Increase in body mass index, waist circumference and waist-to-height ratio is associated with high blood pressure in children and adolescents in China. AB - This study compared the association between blood pressure (BP) and obesity in 1145 Chinese children and adolescents (608 males, 537 females) using data from the 2006 China Health and Nutrition Survey. Obesity was diagnosed by body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR). Analysis of variance was used to analyse the difference in BP among different subgroups. Odds ratios (OR) were calculated and multivariate logistic regression analysis was carried out. The prevalence of high systolic and diastolic BP increased directly with corresponding increments in BMI, WC and WHtR, although the prevalence and OR of high BP were higher when increased BMI was combined with WC (OR 3.39; 95% confidence interval [CI] 1.79, 6.41) or WHtR (OR 3.28; 95% CI 1.71, 6.30). In conclusion, increased BMI, WC and WHtR were directly associated with high BP in Chinese children and adolescents. PMID- 21672305 TI - Ureaplasma urealyticum in male infertility in Jilin Province, North-east China, and its relationship with sperm morphology. AB - This study investigated the effects of Ureaplasma urealyticum infection and raised seminal leucocyte levels on sperm morphology in 967 infertile males and 201 fertile healthy volunteers. U. urealyticum infection led to a significant decrease in the percentage of morphologically normal sperm in infertile males. There was a clear correlation between U. urealyticum infection, raised seminal leucocytes and abnormal sperm morphology. The percentage of morphologically normal sperm was significantly lower in U. urealyticum-positive than U. urealyticum-negative infertile males or fertile controls. The percentage of morphologically normal sperm was lowest in U. urealyticum-positive males with raised seminal leucocytes. Previous studies have found raised seminal leucocyte levels to be associated with reactive oxygen species. The authors suggest that oxidative stress contributes to the effects of U. urealyticum on sperm morphology. In conclusion, U. urealyticum infection can negatively affect sperm morphology and this study provided two possible mechanistic explanations. PMID- 21672306 TI - The Bowel Function Index for evaluating constipation in pain patients: definition of a reference range for a non-constipated population of pain patients. AB - Opioid-induced constipation (OIC) is a severe, persisting side-effect of opioid therapy. The Bowel Function Index (BFI(a), numerical analogue scale 0 - 100), calculated as the mean of three variables (ease of defaecation, feeling of incomplete bowel evacuation, and personal judgement of constipation) was developed to evaluate bowel function in opioid-treated patients with pain. This clinician-administered tool allows easy measurement of OIC from the patient's perspective. The purpose of this investigation was to define a reference range reflecting BFI values in non-constipated chronic pain patients who were recruited into a cross-sectional survey and asked for their perceptions of constipation. The BFI scores were assessed and compared with those of patients with confirmed OIC obtained from two previously published trials. Results were analysed and a reference range of BFI values of 0 - 28.8, into which 95% of non-constipated chronic pain patients fell, was defined. This permits discrimination between chronic pain patients with, or without, constipation. PMID- 21672307 TI - QT dispersion measured by automatic computerized 12-lead electrocardiography contributes significantly to detection of left ventricular hypertrophy in Japanese patients. AB - This study assessed the diagnostic value of QT dispersion for left ventricular hypertrophy (LVH) as determined by echocardiography. The QT and QRS interval parameters were determined automatically using computerized 12-lead electrocardiography in 153 Japanese out-patients. Corrected QT dispersion (QTcD) and maximal QRS duration (MaxQRS) were significantly correlated with left ventricular mass index. The sum of QTcD and MaxQRS showed the highest correlation with left ventricular mass index among QT and QRS interval parameters and their combinations. The cut-off points for LVH discrimination in this study were different to those reported in Western, mainly Caucasian, populations, suggesting the need for ethnicity-specific LVH detection criteria. A scoring system derived from multiple logistic regression analysis, employing a combination of QTcD, QRS time-voltage product and ST-T change, showed a specificity of 86.3%. It was concluded that QTcD, in addition to QRS time-voltage product and ST-T change, improved the detection of LVH. PMID- 21672308 TI - Aortic root dilatation as a marker of subclinical left ventricular diastolic dysfunction in patients with cardiovascular risk factors. AB - Consensus is lacking about the clinical importance of aortic root dilatation in assessment of the risk of cardiovascular disease. In this study, correlations between aortic root diameter and echocardiographic features of left ventricular (LV) diastolic function were investigated in 333 patients with at least one cardiovascular risk factor (hypertension, diabetes or dyslipidaemia) and preserved LV systolic function. Aortic root diameter was measured by M-mode echocardiography, and LV diastolic function was evaluated by measuring the peak velocity of early (E) and late (A) diastolic transmitral blood flow and peak early diastolic mitral annular velocity (E') by Doppler echocardiography. Linear regression analysis showed that, in men, age was not related to aortic root diameter but hypertension and LV hypertrophy were, whereas the converse was true in women. The parameters E, E/A ratio and E', were related to aortic root diameter in both sexes. Stepwise multiple regression analysis confirmed that E in women and E' in men were independently associated with aortic root diameter. It is concluded that aortic root dilatation might be a useful marker of subclinical LV diastolic dysfunction. Patients with preserved systolic function showing aortic root dilatation should, therefore, be given preventative therapy against LV diastolic heart failure. PMID- 21672309 TI - Pathological features and prognosis in chronic hepatitis B virus carriers. AB - This retrospective study examined 220 Chinese chronic hepatitis B virus carriers over 5 years. After initial liver biopsy, liver function tests and serological analysis, patients underwent further tests of liver function and hepatitis B seromarkers at 6-month intervals. Second and third liver biopsies were performed in 56 and 23 patients, respectively. Liver pathology was classified according to inflammatory activity (G(0) - G(4)) and degree of fibrosis (S(0) - S(4)). A significantly greater proportion of hepatitis B e antigen antibody-positive patients had a more severe level of inflammation and fibrosis than patients who were hepatitis B e antigen (HBeAg)-positive. Abnormal inflammation (>= G(2)) occurred in 122 (55.5%) patients. Hepatitis B reactivation occurred in 35 (15.9%) patients: 33 had obvious liver inflammation at the initial biopsy (>= G(2)) and only two had a low level of liver inflammation (G(0) - G(1)). The hepatitis B reactivation rate was significantly related to age but not to gender. Hepatitis B surface antigen clearance was 1.55% per year and HBeAg seroconversion was 5.36% per year. In conclusion, hepatitis B reactivation was closely correlated with age and the level of liver inflammation. PMID- 21672311 TI - Correlation between B lymphocyte abnormality and disease activity in patients with idiopathic membranous nephropathy. AB - This study investigated the relationship between peripheral blood B lymphocytes, regulatory T-cells and T lymphocyte subsets, the distribution of B lymphocytes in the kidney, and the pathogenesis of idiopathic membranous nephropathy (IMN). Lymphocyte subsets were measured using flow cytometry in 66 patients with clinically-confirmed IMN and in 40 healthy control subjects. Compared with healthy subjects, the number of peripheral blood B lymphocytes was significantly increased in IMN patients and that of regulatory T-cells was significantly decreased, accompanied by an increased CD4(+)/CD8(+) T-cell ratio. There was no relationship between the number of peripheral blood B lymphocytes and markers of kidney function. Although the number of infiltrating B lymphocytes in the kidney of IMN patients was higher, there was no relationship with the number of peripheral blood B lymphocytes. In conclusion, there was no relationship between peripheral blood B lymphocytes and disease activity, suggesting that peripheral blood B lymphocytes are not a biomarker of disease activity and therapeutic efficacy in IMN. PMID- 21672310 TI - AKR1B10 is associated with smoking and smoking-related non-small-cell lung cancer. AB - This prospective study explored the relationship between expression of AKR1B10 mRNA and various clinical parameters in non-small-cell lung cancer (NSCLC) in terms of its validation as a marker for NSCLC. Tumour tissue samples were collected from 229 patients with NSCLC. Tissue samples from adjacent non malignant lung tissue (> 5 cm from the tumour) of 89 of these patients and samples from 20 patients with benign lung disease were used as controls. Quantitative reverse transcription- polymerase chain reaction showed significantly higher levels of AKR1B10 mRNA expression in NSCLC tumour tissue than in adjacent non-malignant lung tissue and benign lung tissue. Statistically significant factors for AKR1B10 mRNA over-expression were found to be male gender, smoking, squamous cell carcinoma and moderate or poor cell differentiation. It is concluded that AKR1B10 seems to have potential as a prognostic marker for NSCLC and warrants further investigation. PMID- 21672312 TI - A modification of the trans-oesophageal echocardiography protocol can reduce post operative dysphagia following cardiac surgery. AB - Use of intra-operative trans-oesophageal echocardiography (TEE) is an independent risk factor for post-operative dysphagia. This study investigated whether modifying the TEE probe-placement protocol could reduce the incidence of post operative dysphagia. In group I (n = 100), the TEE probe was inserted after anaesthetic induction and remained in place until the completion of surgery. In group II (n = 100), the TEE probe was inserted after anaesthetic induction, the heart was examined, then the probe was removed. The probe was inserted again before weaning from cardiopulmonary bypass and then immediately removed after examination. The incidence of dysphagia was significantly higher in group I than in group II patients (51.1% versus 28.6%). Multivariate regression analysis showed that the length of time that the TEE probe was in the oesophagus was an independent predictor of dysphagia. Modification of the TEE protocol in this way can reduce the incidence of post-operative dysphagia in cardiac surgery patients. PMID- 21672313 TI - Significant increase in natural-killer T cells in patients with tuberculosis complicated by type 2 diabetes mellitus. AB - This study examined the frequency of Valpha24(+)/Vbeta11(+) natural-killer T (NKT) cells from peripheral blood and bronchoalveolar lavage fluid in pulmonary tuberculosis (TB) patients with or without diabetes mellitus (DM). The clinical grade of TB was significantly higher among diabetic patients. NKT cells from both peripheral blood and bronchoalveolar lavage were significantly increased in diabetic TB patients compared with non-diabetic TB patients. This may be due to the generally higher bacillary burden in diabetic TB patients. NKT cells from peripheral blood mononuclear cells in TB patients with or without DM were significantly increased, compared with levels in non-TB diabetic patients and healthy controls. The measurement of NKT cells from peripheral blood has the potential to be a reliable, non-invasive, practical diagnostic marker for active TB. PMID- 21672314 TI - Effects of dicalcium silicate coating ionic dissolution products on human mesenchymal stem-cell proliferation and osteogenic differentiation. AB - This study investigated the effects of ionic dissolution products released from dicalcium silicate (DS) coatings on human mesenchymal stem cells (hMSC), cultured in the presence or absence of the dissolution products, with or without osteogenic supplements (OS). DS(+) medium promoted cell proliferation during the first 4 days, but then inhibited proliferation. DS(+)OS(-) medium increased alkaline phosphatase (ALP) activity on day 14, and upregulated runt-related transcription factor 2 and osteonectin mRNA on days 7 and 14, respectively. The addition of osteogenic supplements (DS(+)OS(+)) led to a significant increase in ALP activity from days 7 to 21, upregulation of osteogenic markers on day 14, and formation of more mineralized nodules on day 28. The results demonstrated that the ionic dissolution products from DS coating alone can partly induce osteogenic differentiation of hMSC, and that the addition of osteogenic supplements further enhances osteoblast-specific gene expression and mineralization in hMSC. PMID- 21672315 TI - A randomized crossover study comparing patient preference for tamsulosin and silodosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia. AB - Patient preference for benign prostatic hyperplasia (BPH) treatment with the alpha(1)-blockers, tamsulosin or silodosin, was compared using patient-reported outcomes. Japanese patients with lower urinary tract symptoms associated with BPH were randomly allocated to either the T-S group (tamsulosin 0.2 mg orally once daily for 4 weeks then silodosin 4 mg orally twice daily for 4 weeks) or the S-T group (silodosin 4 mg orally twice daily for 4 weeks then tamsulosin 0.2 mg orally once daily for 4 weeks). The primary endpoint was the preferred drug for treatment continuation at 8 weeks, determined by a patient-reported questionnaire. In total, 102 patients (mean age 70.3 years) were enrolled and 84 (n = 42 per group) completed the study. A significant difference was observed between the proportion of patients who preferred tamsulosin (59/84 patients; 70.2%) and those who preferred silodosin (18/84 patients; 21.4%). A major reason for preference of either drug was 'good efficacy'. Incidence of adverse effects was significantly lower with tamsulosin (3/91 patients; 3.3%) than with silodosin (25/88 patients; 28.4%). These findings indicate that tamsulosin is very effective for BPH, has few adverse effects and that patients want to continue to use it. PMID- 21672316 TI - The effects of colloid pre-loading on thromboelastography prior to caesarean delivery: hydroxyethyl starch 130/0.4 versus succinylated gelatine. AB - This prospective, randomized, double-blind study compared the effects on thromboelastography (TEG) of pre-loading with two different colloid fluids prior to spinal anaesthesia for caesarean section. Healthy full-term parturients received either 500 ml 6% hydroxyethyl starch 130/0.4 (HES, n = 25) or 500 ml 4% succinylated gelatine (GEL, n = 25) prior to spinal anaesthesia. TEG parameters including reaction time (r-time), clot formation time (k-time), clot formation rate (alpha-angle) and maximum amplitude (MA) were measured immediately before and after pre-loading. Both groups had significantly shorter r-time and lower MA after pre-loading. The alpha-angle was significantly decreased after pre-loading with HES but not with GEL. No significant differences in k-time were induced pre loading. In conclusion, pre-loading with HES or GEL was associated with a mild hypocoagulable effect in healthy parturients presenting for elective caesarean section; however, all TEG parameters in both groups remained within or very close to the normal range after pre-loading. PMID- 21672317 TI - Relationship between cellular apoptosis and the expression of p75 neurotrophin receptor and tyrosine kinase A receptor in tissue surrounding haematoma in intracerebral haemorrhage. AB - Cellular apoptosis and the expression of p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase A receptor (TrkA) were investigated in the tissues surrounding haematoma in patients with intracerebral haemorrhage. Specimens of tissue from near the haematoma (haemorrhagic samples) and tissue from a distant site (control samples) were collected from 14 patients with basal ganglia haemorrhage undergoing surgical intervention. Cellular apoptosis was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL), and p75(NTR) and TrkA location, protein and gene expression were studied using immunohistochemistry, Western blot and real-time polymerase chain reaction, respectively. The percentage of apoptotic cells and expression of p75(NTR), but not of TrkA, were significantly higher in the haemorrhagic samples than in the control samples. There was a positive correlation between the percentage of TUNEL-positive cells and the percentage of p75(NTR)-positive cells. These results suggest that the p75(NTR)-dependent signal transduction pathway plays an important role in apoptosis after intracerebral haemorrhage. PMID- 21672318 TI - A method of utrophin up-regulation through RNAi-mediated knockdown of the transcription factor EN1. AB - The aim of this study was to induce up-regulation of the dystrophin-related gene UTRN that encodes the protein utrophin, to determine whether this could compensate for the lack of dystrophin function in Duchenne muscular dystrophy. The human UTRN promoter, which contains two putative binding sites for homeobox protein engrailed-1 (EN1), was analysed. It was found that EN1 binding site 2 in the UTRN gene promoter directly interacted with transcription factor EN1 in vitro. Chromatin immunoprecipitation assays of the EN1-UTRN promoter complex from rhabdomyosarcoma and HeLa cell lines confirmed that endogenous EN1 interacted with this region in vivo. The findings suggest that EN1 directly interacts with the UTRN promoter. Small interfering RNA was used to inhibit EN1 gene expression. Higher utrophin mRNA levels were observed in EN1-inhibited cells compared with controls. The increase in utrophin mRNA in rhabdomyosarcoma cells and HeLa cells may have resulted from inhibition of EN1 expression. PMID- 21672319 TI - Gasless laparoscopy versus conventional laparoscopy in uterine myomectomy: a single-centre randomized trial. AB - In a single-centre, randomized trial, gasless laparoscopic myomectomy was compared with conventional laparoscopic myomectomy. The study examined feasibility, safety, reliability and post-operative outcomes. Estimated blood loss, duration of surgery, early post-operative outcomes and length of hospital stay were recorded. Compared with conventional laparoscopic myomectomy, gasless laparoscopy resulted in significantly lower intra-operative blood loss (median 100 ml vs 80 ml, respectively) and duration of surgery (median 94 min vs 71 min, respectively). Post-operative abdominal drainage volume was significantly lower after gasless laparoscopy than after conventional laparoscopy (median 100 ml vs 240 ml). There was no significant difference between duration of post-operative fever, post-operative time to flatus or length of hospital stay. Both forms of laparoscopy are suitable for uterine myomectomy, and comparison of these methods showed that gasless laparoscopy had potential advantages over conventional laparoscopy. PMID- 21672320 TI - Clinical significance of CDH13 promoter methylation in serum samples from patients with bladder transitional cell carcinoma. AB - H-cadherin (CDH13; also known as T-cadherin), which functions as a tumour suppressor, is frequently silenced by promoter methylation in human cancers including bladder transitional cell carcinoma (TCC). This study investigated the clinical significance of methylation of the CDH13 gene promoter in serum from patients with bladder TCC. Methylation status of CDH13 in serum samples from 127 patients with primary bladder TCC and 41 healthy volunteers (controls) was examined by methylation-specific polymerase chain reaction. CDH13 methylation was found in 39 patients with bladder TCC (30.7%) but in no controls. CDH13 methylation was significantly associated with advanced tumour stage, high-grade tumour, large tumour size, tumour recurrence and poor prognosis. The results suggested that CDH13 methylation in serum may be a potential predictive biomarker for malignancy in bladder TCC, and an independent pretherapeutic predictor of outcome. Demonstration of CDH13 methylation in serum may facilitate in the prediction of which patients require more aggressive additional post-operative systemic therapy. PMID- 21672321 TI - Emu model of full-range femoral head osteonecrosis induced focally by an alternating freezing and heating insult. AB - The emu, a large bipedal bird with hip joint biomechanics similar to humans, was used to establish an experimental model of femoral head osteonecrosis and subsequent femoral head collapse. Focal lesions were induced in 20 adult male emus using an alternating liquid nitrogen freezing and radiofrequency heating insult. At 2, 4, 8, 12 and 16 weeks post-surgery, hip magnetic resonance imaging (MRI) was performed. Before the emus were sacrificed, barium sulphate was infused to the lower extremity to study blood vessel distribution patterns. Femoral samples were scanned by micro-computed tomography (micro-CT) and evaluated histologically. Hip MRI showed changes from broad oedema to femoral head collapse. Emus developed a crippled gait from post-operative week 6. Micro-CT scans and histology showed human-like osteonecrotic changes with an impaired local blood supply. The protocol resulted in consistent full-range osteonecrosis of the femoral head that may serve as a model for testing potential treatments. PMID- 21672322 TI - Haemodynamic brain response to visual sexual stimuli is different between homosexual and heterosexual men. AB - The underlying neurobiological factors involved in sexual orientation are largely unknown. This study investigated whether neural circuits or different cognitive processes accounted for differences in brain activation in 14 heterosexual and 14 homosexual males. Brain scans were undertaken in each subject using functional magnetic resonance imaging while they viewed different sexual stimuli, i.e. heterosexual couple stimuli (HCS), gay couple stimuli (GCS), lesbian couple stimuli (LCS) and neutral stimuli (NS). Ratings of sexual attractiveness of the stimuli were assessed. Subjective sexual arousal was induced by HCS and GCS in heterosexual and homosexual men, respectively. Sexual disgust was induced by GCS and LCS in heterosexual and homosexual men, respectively. Compared with viewing NS, viewing sexual stimuli induced significantly different brain activations, most of which had the characteristics of cognitive processes. These observations suggest that different cognitive patterns may be the major cause of different subjective responses to sexual stimuli between heterosexual and homosexual men. PMID- 21672323 TI - Increased tenderness in the left third intercostal space in adult patients with myalgic encephalomyelitis: a controlled study. AB - A clinical sign has not thus far been associated with myalgic encephalo myelitis (ME). The present study involved systematic clinical examination that included inspection, palpation, percussion and auscultation of the thorax of 42 ME patients and 20 age-matched healthy controls while sitting. Left lateral third intercostal space tenderness was noted in 34 (81%) of the patients and in none of the controls, a difference that was highly statistically significant. This finding may be related to changes in lymphatic function and to the descending course of the thoracic duct. Further studies, preferably blinded and combined with appropriate imaging, are required. PMID- 21672324 TI - Response to air insufflation in patients with non-erosive gastro-oesophageal reflux disease (NERD). AB - This study compared changes in intragastric pressure (IGP) in response to a gastric distension stimulus caused by air insufflation in 25 patients with non erosive gastro-oesophageal reflux disease (NERD) and 34 healthy volunteers (controls). In four NERD patients, IGP responses were also measured before and after oral treatment with 10 mg rabeprazole daily for 2 weeks. The rate of increase in IGP at the start of insufflation was significantly higher in NERD patients than in controls. The time to appearance of symptoms (i.e. time to threshold) was significantly shorter in NERD patients than in controls. Direct measurement of IGP showed that visceral hypersensitivity and impaired fundal relaxation are both characteristic of NERD. Administration of rabeprazole led to a marked prolonging of time to threshold, indicating that treatment could alleviate this hypersensitivity. PMID- 21672325 TI - Features of Hirayama disease on fully flexed position cervical MRI. AB - This study reports on cervical magnetic resonance imaging (MRI) performed in the fully flexed position in 13 male patients with Hirayama disease and 12 normal controls (males). The anterior-posterior diameter of the cervical cord at the superior margin of the C6 vertebral body was measured, as well as the angle between adjacent cervical bodies. Localized lower cervical-cord atrophy, cord flattening and abnormal signals in the posterior epidural space were studied. Patients demonstrated an increased angle between C5 and C6, and C6 cord lesions. There were significant differences between patients and controls in localized lower cervical-cord atrophy and cord flattening. Many patients were found to have a crescent-shaped high-intensity mass on T2WI MRI and a low-intensity mass on T1WI MRI in the posterior epidural space. In patients, there were specific imaging features of Hirayama disease on fully flexed MRI. Cervical MRI in the fully flexed position has significant value in the clinical diagnosis of Hirayama disease. PMID- 21672326 TI - Immunohistochemical detection of Raf kinase inhibitor protein in normal cervical tissue and cervical cancer tissue. AB - Raf kinase inhibitor protein (RKIP) may be a suppressor of metastasis: RKIP levels are high in normal tissues, low in primary cancers and lowest or absent in metastatic cancers. This immunohisto chemistry study investigated RKIP protein levels in 250 clinical specimens of human cervical tissue and lymph node metastases (LNM) from 210 patients with normal cervical tissue, cervical intra epithelial neoplasia (CIN), or cervical cancer with/without LNM. Thirty-nine (86.7%) of the 45 normal-tissue samples were RKIP-positive, six (13.3%) were RKIP negative; 48/60 (80.0%) CIN samples were positive, 12 (20.0%) were negative; 47/105 (44.8%) cervical cancer tissue samples were positive, 58 (55.2%) were negative; only 7/40 (17.5%) LNM tissue samples were positive, 33 (82.5%) were negative. There was no significant correlation between RKIP positivity and clinical stage, microscopic subtype or pathological differentiation grade. RKIP positivity correlated inversely with LNM. RKIP may play a role in cervical-cancer genesis and metastasis; RKIP down-regulation was associated with metastatic disease in human cervical cancer. PMID- 21672327 TI - Alterations of serum lipid and inflammatory cytokine profiles in patients with coronary heart disease and chronic periodontitis: a pilot study. AB - Serum lipid and inflammatory cytokine profiles were assessed in 124 in-patients with coronary heart disease (CHD) (CHD group) and 43 inpatients with no evidence of CHD (control group). In all patients, research questionnaires and examinations of periodontal health were conducted and venous blood samples were analysed. Both groups were divided into two subgroups according to the presence or absence of chronic periodontitis in individual patients. The prevalence of chronic periodontitis was higher in patients from the CHD group than in the control group. Levels of total cholesterol, triglycerides, low-density lipoprotein, oxidized low-density lipoprotein, high-sensitivity C-reactive protein, interleukin-6 and tumour necrosis factor-alpha were significantly higher in CHD patients with chronic periodontitis than in those without periodontitis. In conclusion, chronic periodontitis may be associated with CHD. PMID- 21672328 TI - Renal haemodynamics in patients with liver cirrhosis assessed by colour ultrasonography. AB - Colour Doppler flow imaging was used in this prospective, cross-sectional study to analyse renal haemodynamics in 50 cirrhotic patients and 15 healthy controls. Mean renal arterial resistive index (RI) was higher in cirrhotic patients than in healthy controls. Mean RI was also higher in cirrhotic patients with non refractory ascites than in those without ascites, suggesting that the degree of renal vasoconstriction varies with the severity of ascites. A gradient of RI values across the main renal artery, interlobar artery and interlobular renal artery was retained in cirrhotic patients even in the decompensatory stage with non-refractory ascites but was not present in the decompensatory stage with refractory ascites. The disappearance of this gradient may be an important prognostic factor in the development of hepatorenal syndrome (HRS). An inverse correlation between creatinine clearance and interlobular arterial RI was shown for all cirrhotic patients suggesting that even patients with refractory ascites are in a prophase of HRS. PMID- 21672329 TI - Evaluation of diffusion-weighted magnetic resonance imaging and contrast-enhanced harmonic ultrasonography in detection and location of prostate transition-zone cancer. AB - This retrospective study was designed to evaluate the value of contrast-enhanced harmonic ultrasonography (CEHU), diffusion-weighted magnetic resonance imaging (DW-MRI) and CEHU plus DW-MRI for the diagnosis of prostate transition-zone (TZ) cancer. In total, 31 TZ cancers in 28 patients and 25 peripheral zone (PZ) cancers in 21 patients without a TZ cancer were evaluated. All patients underwent DW-MRI and CEHU followed by radical prostatectomy. Predictors for the diagnosis of prostate cancer were evaluated in three protocols (CEHU, DW-MRI, CEHU plus DW MRI). Statistical analysis of the differences between these protocols and receiver operating characteristic (ROC) curve analysis were carried out. CEHU plus DW-MRI had a significantly higher sensitivity, accuracy and negative predictive value (90.3%, 73.2% and 81.3%, respectively) for TZ cancer than either method alone. The area under the ROC curve values were 0.659, 0.679 and 0.712 for CEHU, DW-MRI, and CEHU plus DW-MRI, respectively. In conclusion, CEHU plus DW-MRI might be a useful protocol for the detection and location of TZ cancer. PMID- 21672330 TI - Adherence to guideline-based standard operating procedures in pre-hospital emergency patients with chronic obstructive pulmonary disease. AB - This study investigated improvements in pre-hospital care for patients with acute exacerbated chronic obstructive pulmonary disease (aeCOPD) achieved by using a standard operating procedure (SOP). An SOP for pre-hospital treatment of patients with aeCOPD was designed based on valid national guidelines. A total of 1000 Emergency Medical Service patient care reports were analysed prospectively: 500 before and 500 after introduction of the SOP. Overall guideline adherence was 34.6% before and 53.8% after introduction of the SOP; this increase was not statistically significant. After SOP introduction, the administration of beta(2) mimetics by inhalative, intravenous and subcutaneous routes increased significantly. The level of knowledge of the national guidelines was rated at 67% by emergency physicians during self-assessment, but was only 33% when physicians were asked specific questions during interview. Introducing the SOP for patients with aeCOPD did not significantly improve adherence to valid national guidelines, but did help to improve specific elements of therapy. PMID- 21672331 TI - Pre-operative trans-thoracic doppler ultrasonography evaluation and intraoperative manual evaluation of the left internal thoracic artery in patients with type 2 diabetes with coronary artery disease. AB - Patients with coronary artery disease, with (n = 25) and without (n = 59) type 2 diabetes, who were scheduled to undergo coronary artery bypass grafting were enrolled in this prospective study. The left internal thoracic artery (LITA) was assessed for graft suitability before surgery by trans-thoracic Doppler ultra sonography and during surgery by manual measurement. Significant differences were seen between preoperative and intra-operative LITA blood flow rates and LITA diameters, and the values of each at the two time points showed significant correlation, suggesting that pre-operative measurements largely related to intra operative conditions. The pre-operative and intra-operative LITA blood flow rates and LITA diameters were not significantly different between patients with and without type 2 diabetes. Pre-operative LITA blood flow was monophasic in three patients without diabetes and the LITA grafts of these patients were deemed unsuitable for implantation during surgery. It is concluded that type 2 diabetes does not seem to have a negative effect on the suitability of LITA grafts. In addition, trans-thoracic Doppler ultrasonography is an easy, cost-effective, reproducible and non-invasive examination method, which may help in the evaluation of LIMA function and contribute to graft selection. PMID- 21672332 TI - Diagnosis of small-bowel disease: comparison of magnetic resonance enteroclysis and conventional enteroclysis. AB - In this prospective study, 32 patients with symptoms suggestive of small-bowel disease underwent conventional enteroclysis and magnetic resonance (MR) enteroclysis. Image quality, luminal distension, wall thickening, homogeneity of luminal opacification, the presence of artefacts and extraluminal changes were assessed. Small-bowel pathologies were subsequently proved surgically and by follow-up examinations in 19 (59.4%) of the patients. Abnormal findings were detected by MR enteroclysis in 11 of these 19 patients (57.9%). Normal findings on MR enteroclysis were found in eight of the 19 patients (42.1%) whereas conventional enteroclysis detected abnormal findings in these patients. Abdominal lesions outside the small bowel, comprised renal cysts, cholelithiasis, ovarian cysts and horseshoe kidney, and were detected by MR enteroclysis in two, one, four and one, respectively, of these normal patients but not by conventional enteroclysis. Excluding lesions outside of the small bowel, a higher rate of false-negative results and the missing of superficial lesions occurred with MR enteroclysis. It is, therefore, suggested that MR enteroclysis should not be used as a primary way of evaluating small-bowel disease and its use should be restricted to follow-up examinations of known disease. PMID- 21672333 TI - Clinicopathological characteristics and computed tomography features of mucinous gastric carcinoma. AB - This study investigated the clinicopathological characteristics of mucinous gastric carcinoma (MGC) and assessed whether multidetector-row computed tomography (MDCT) could differentiate MGC from non-mucinous gastric carcinoma (NGC). Clinicopathological data from 542 patients with gastric carcinoma (23 MGC, 519 NGC), who underwent pre-operative MDCT examination and curative or palliative gastrectomy, were analysed. Only seven of the 23 patients with MGC were correctly diagnosed pre-operatively by endoscopic biopsy. The MGC patients had larger tumours, a higher frequency of lymph node metastases, were more likely to have tumours of tumour, node, metastasis stages III and IV, and were less likely to have a curative resection than NGC patients. In addition, five MGC patients had calcifications in the thickened gastric wall. In conclusion, MGC is rare and is detected mostly at an advanced stage. The diagnostic sensitivity of MGC by endoscopic biopsy was relatively low, whereas MDCT was helpful in distinguishing MGC from NGC. PMID- 21672334 TI - The safety and efficacy of early-stage bi-weekly alendronate to improve bone mineral density and bone turnover in chinese post-menopausal women at risk of osteoporosis. AB - The efficacy and safety of early, low frequency antiresorptive drug intervention for osteopaenia on bone mineral density (BMD) and bone turnover in Chinese post menopausal women at risk of developing osteoporosis were investigated. A total of 180 women aged 40 - 70 years were enrolled and equally randomized to receive either 70 mg alendronate once every 2 weeks plus 0.5 MUg alfacalcidol daily (treatment group) or alfacalcidol 0.5 MUg daily alone (control group) for 12 months. In the treatment group, lumbar spine and total hip BMD at 12 months had increased significantly from baseline and compared with the control group. There were also significant reductions in serum levels of the bone turnover biomarkers, bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen, compared with the control. No serious adverse events were observed in either group and safety profiles were similar. It was concluded that early intervention with 70 mg alendronate once every 2 weeks was safe, well tolerated and more effective than alfacalcidol alone (control) in increasing BMD and reducing bone turnover, and might prevent serious outcomes, such as fragility fractures, reduce rates of adverse effects and improve patient compliance. PMID- 21672335 TI - Differential diagnosis of inflammatory myofibroblastic tumour and low-grade myofibroblastic sarcoma: two case reports with a literature review. AB - Inflammatory myofibroblastic tumour (IMT) and low-grade myofibroblastic sarcoma (LGMS) have similar morpho logical and immunophenotypic features, but LGMS is more malignant than IMT and the treatment requires a wider surgical margin plus post-operative chemotherapy or radiotherapy. To date, only 28 cases of IMT and two cases of LGMS have been reported in the laryngopharynx. Recent studies have suggested that anaplastic lymphoma kinase (ALK) and cytokeratin are important markers for differentiating between the two tumours. Here, two cases involving different myofibroblastic tumours of the larynx are reported. Based on the histological and immunohistochemical results, case 1 was diagnosed as IMT involving the right arytenoepiglottic fold, while case 2 was diagnosed as LGMS involving the epiglottic-glossal surface. There was no recurrence or metastasis in either case after post-operative follow-up (12 and 14 months, respectively). It is difficult to distinguish IMT from LGMS; both morphological and immunohistological analyses are required. PMID- 21672336 TI - Tuberculous sacroiliitis: a study of the diagnosis, therapy and medium-term results of 15 cases. AB - This report reviews the diagnosis, treatment and follow-up of 15 Chinese patients with tuberculous sacroiliitis (TBS) from 1997 to 2007. Buttock pain and lower back pain were the main complaints. All patients received antituberculosis chemotherapy treatment for at least 18 months; 10 also underwent surgery, with seven undergoing modified Smith-Petersen arthrodesis (evaluated using a visual analogue scale [VAS] for pain and the Oswestry Disability Index [ODI]). No simplex tuberculous synovitis existed at diagnosis. Bone-marrow oedema, cold abscess and soft-tissue oedema responded to antituberculosis treatment. Thirteen patients (86.7%) had satisfactory outcomes. There were also significant improvements in VAS and ODI scores post-operatively. In the chemotherapy plus surgery group, eight patients had solid bony fusions at 24 months post operatively, while the five on chemotherapy alone presented with fibrous ankylosis at 24 months. Chemotherapy is the main treatment for TBS and modified arthrodesis is a feasible and effective method for treating severe joint destruction. PMID- 21672337 TI - Dasatinib treatment for imatinib resistant or intolerant patients with chronic myeloid leukaemia. AB - Chronic myeloid leukaemia (CML) is a genetically associated malignancy of haematopoietic stem cells, characterized by a t(9;22) translocation that forms the Philadelphia chromosome and creates a novel fusion gene, BCR-ABL. Treatment with molecular-targeted therapy is usually initiated with imatinib, an inhibitor of BCR-ABL tyrosine kinase. Imatinib resistance is, however, observed in some CML patients, especially in those with advanced disease. Through computerized literature searches, a systematic analysis was conducted to examine the efficacy and benefits of dasatinib therapy for imatinib resistant or intolerant CML patients in the chronic phase (CP), accelerated phase (AP) and fatal blast crisis phase (BC). In terms of major haematological and cytogenetic responses, this meta analysis showed no significant differences in dasatinib treatment between myeloid BC-CML and lymphoid BC-CML patients with imatinib resistance or intolerance. Dasatinib therapy was, however, significantly more effective in improving major haematological and cytogenetic responses for CP-CML patients than for AP-CML patients with imatinib resistance or intolerance. PMID- 21672338 TI - Expression of the stem cell marker nestin in pre/hypertrophic chondrocytes in osteochondroma. AB - The pathogenesis of osteochondroma, the most common benign bone tumour, is not fully known. To date, regulation of nestin protein levels in osteochondromas and normal growth plates has not been reported. This study used immunohistochemical analysis to detect nestin protein levels in 48 osteochondromas and 13 normal growth plates (eight fetal and five postnatal). Nestin protein was mainly restricted to prehypertrophic and hypertrophic chondrocytes in osteochondroma. Nestin levels were significantly higher in osteochondromas in adolescents (age range 4 - 18 years, n = 32) than in osteochondromas in young adults (age range 20 - 28 years, n = 11), and significantly higher in osteochondromas in young adults than in those in older adults (age range 40 - 77 years; n = 5). Nestin protein was not present in normal growth plates. The presence of nestin protein parallels the biological behaviour of osteochondromas and is restricted to prehypertrophic and hypertrophic chondrocytes, indicating that these nestin-positive cells may be central to osteochondroma development. PMID- 21672339 TI - Effects of metformin and rosiglitazone on peripheral insulin resistance and beta cell function in obesity: a double-blind, randomized, controlled study. AB - Metformin and rosiglitazone combination therapy is known to improve insulin resistance and postpone diabetes mellitus development in subjects with impaired glucose tolerance. This double-blind, randomized, controlled study assessed this combination therapy for preventing type 2 diabetes in obese subjects with hyperinsulinaemia. Subjects received metformin (500 mg three times daily, orally) plus either rosiglitazone (4 mg once daily, orally; n = 94) or placebo (n = 95) and were followed for 6 months. Blood pressure, body fat, body mass index (BMI), lipid and insulin levels were recorded pre- and post-treatment. Metformin plus rosiglitazone significantly decreased blood pressure, lipids, BMI, and fasting and postmeal insulin levels. Metformin plus placebo led to a significant decrease in blood pressure, BMI and lipid levels, but fasting and postmeal insulin levels were unchanged. Adverse events were similar between the two groups. The metformin and rosiglitazone combination increased insulin sensitivity and beta-cell function recovered. This approach may represent a therapeutic option for preventing development of type 2 diabetes in obese subjects with hyperinsulinaemia. PMID- 21672340 TI - Prevalence of painful diabetic peripheral neuropathy among patients with diabetes mellitus in the Middle East region. AB - The prevalence of painful diabetic peripheral neuropathy (DPN) was evaluated in type 1 or type 2 diabetes mellitus patients (n = 4097) attending outpatient clinics across the Middle East. Overall, 53.7% of 3989 patients with DN4 data met the criteria for painful DPN (Douleur Neuropathique-4 [DN4] scores >= 4). Significant predictors of painful DPN included long history (>= 10 years) of diabetes (odds ratio [OR] 2.43), age >= 65 years (OR 2.13), age 50 - 64 years (OR 1.75), presence of type 1 versus type 2 diabetes (OR 1.59), body mass index > 30 kg/m(2) (OR 1.35) and female gender (OR 1.27). Living in one of the Gulf States was associated with the lowest odds of having painful DPN (OR 0.44). The odds of painful DPN were highest among patients with peripheral vascular disease (OR 4.98), diabetic retinopathy (OR 3.90) and diabetic nephropathy (OR 3.23). Because of the high prevalence and associated suffering, disability and economic burden of painful DPN, it is important that diabetic patients are periodically screened, using a simple instrument such as the DN4, and receive appropriate treatment if symptoms develop. PMID- 21672341 TI - The study of myogenin expression in denervated human skeletal muscles. AB - Skeletal muscle denervation eventually causes atrophy as a result of interrupted nerve conduction and the lack of nutritional factors. Myogenin is a myogenic regulatory factor that plays a key role in myoblast differentiation. Changes in myogenin expression in denervated rat skeletal muscle have been demonstrated, but myogenin expression in denervated human skeletal muscle has not been reported. Human muscle samples were analysed at different time-points post-denervation to evaluate changes in myogenin expression and their relationship with skeletal muscle atrophy. Post-denervation, myogenin mRNA levels peaked at 7 months and were 37.5 times the normal level. Expression levels then declined to 21 and 11 times the normal level at 12 and 26 months post-denervation, respectively. Prolonged denervation resulted in pathological changes characterized by decreased numbers of intact muscle fibres. PMID- 21672342 TI - Interleukin-18 and IL18 -607A/C and -137G/C gene polymorphisms in patients with penicillin allergy. AB - This study investigated the association between polymorphisms (-607A/C and 137G/C) in the promoter region of the IL18 gene (which encodes interleukin [IL] 18) and serum levels of IL-18, using standard genotyping techniques (sequence specific primer-polymerase chain reaction) and an enzyme-linked immunosorbent assay, respectively, in patients allergic to penicillin. A higher frequency of A alleles and the AA genotype was found at position -607A/C in patients allergic to penicillin than in control subjects. For the -137G/C position, the C allele was more frequent in patients allergic to penicillin than in control subjects. Haplotype analysis showed that the -607A/-137C haplotype was more frequent in patients allergic to penicillin than in control subjects. The patients had a significantly higher serum IL-18 level than the control subjects. In conclusion, IL18 -607A/C and -137G/C promoter polymorphisms are associated with susceptibility to penicillin allergy. In particular, the -137G/C position appears to play an important role in IL18 expression. PMID- 21672343 TI - A randomized, double-blind trial of palonosetron compared with ondansetron in preventing postoperative nausea and vomiting after gynaecological laparoscopic surgery. AB - This randomized, double-blind study evaluated the relative efficacy of palonosetron (a new, selective 5-hydroxytryptamine type 3 [5-HT(3)] receptor antagonist) and ondansetron in preventing postoperative nausea and vomiting (PONV) in patients undergoing gynaecological laparoscopic surgery. Patients received either palonosetron 0.075 mg (n = 45) or ondansetron 8 mg (n = 45), intravenously, immediately before induction of general anaesthesia. The occurrence of nausea and vomiting and the severity of nausea according to a visual analogue scale were monitored immediately after the end of surgery and during the following 24 h. The incidence of PONV was significantly lower in the palonosetron group compared with the ondansetron group (42.2% vs 66.7%, respectively). There were no significant statistical differences in the visual analogue scale for nausea. In conclusion, palonosetron 0.075 mg was more effective than ondansetron 8 mg in preventing PONV. PMID- 21672344 TI - Topiramate as an adjunctive treatment for refractory partial epilepsy in the elderly. AB - This double-blind, placebo-controlled study investigated the efficacy and tolerability of adjunctive topiramate in 86 elderly Chinese patients with refractory partial epilepsy. Patients who had at least four seizures per 4 weeks during an 8-week baseline period, despite medication with up to three standard antiepileptic drugs (AEDs), were randomly assigned to receive topiramate (n = 46) or placebo (n = 40). Topiramate dosages were titrated (target dose 200 mg/day orally) for 8 weeks and maintained at stable levels for another 12 weeks; concomitant AEDs continued at original dosages. All patients completed the study: 47.8% in the topiramate group and 7.5% on placebo reached >= 50% reduction in complex partial seizures. In the topiramate group, the most common adverse events were dizziness, somnolence, fatigue, headache and difficulty with memory; most events were transient and mild or moderate in severity. It was concluded that 200 mg/day topiramate was effective and well-tolerated in elderly patients with refractory partial epilepsy. PMID- 21672346 TI - Evaluation of the clinical significance of classification of traumatic anterior shoulder instability using double-contrast computed tomography arthrography. AB - This study evaluated the clinical significance of traumatic anterior shoulder instability (TASI) classification using double-contrast computed tomography (CT) arthrography. Patient were randomly assigned to two groups: group 1 (n = 62); and group 2 (n = 63). TASI symptom severity in group 1 was assessed using physical signs of shoulder trauma and conventional X-ray, CT and magnetic resonance imaging; these patients received either conservative management (with physical rehabilitation) or standard surgery. Group 2 underwent double-contrast CT arthrography to classify TASI; its findings formed the basis of subsequent management. At 24 months post-therapy, significant improvements in clinical outcomes were observed in group 2: Constant scores were higher and Western Ontario Shoulder Instability Index scores were lower. At 24 months, recurrence rates were 21.0% (13/62) in group 1 and 7.9% (5/63) in group 2. Findings suggested that TASI classification using double-contrast CT arthrography provided meaningful information thereby improving treatment efficacy. PMID- 21672345 TI - Lack of keratinocyte growth factor retards angiogenesis in cutaneous wounds. AB - This study investigated the effects of keratinocyte growth factor (KGF) on wound healing. Full-thickness excisional dorsal wounds were created on KGF knockout mice (KGF KO, n = 12) and wild-type C57BL/6 mice (WT, n = 12), and wound closure rates were measured. Immunohistochemical staining was used to investigate cell proliferation and blood vessel density by assessing Ki67 and CD31 protein levels, respectively, and real-time reverse transcription-polymerase chain reaction was used to measure vascular endothelial growth factor (VEGF) mRNA levels. No differences in the rate of wound closure were found between KGF KO and WT mice, however the KGF KO mice showed decreased proliferation of keratinocytes, angiogenesis and VEGF mRNA levels in vivo. These results suggest that KGF may play an important role in the regulation of VEGF gene expression and angiogenesis during wound healing. PMID- 21672347 TI - Intravenous lidocaine for effective pain relief after inguinal herniorrhaphy: a prospective, randomized, double-blind, placebo-controlled study. AB - This prospective, randomized, double-blind, placebo-controlled study evaluated the effectiveness of intravenous lidocaine to reduce post-operative pain in 64 inguinal herniorrhaphy patients. Intravenous bolus injection of 1.5 mg/kg lidocaine followed by a continuous lidocaine infusion of 2 mg/kg per h was randomly assigned to 32 patients (lidocaine group) and intravenous normal saline bolus injection followed by infusion of normal saline was assigned to 32 other patients (control group). Visual analogue scale pain scores, fentanyl consumption and the frequency at which analgesia was administered from a patient-controlled analgesia device (measured by number of button pushes) were significantly lower in the lidocaine group than in the control group until 12 h after surgery. Total fentanyl consumption (patient-controlled plus investigator-controlled rescue administration) and the total number of button pushes were significantly lower in the lidocaine group than in the control group. It is concluded that intravenous lidocaine injection reduced post-operative pain after inguinal herniorrhaphy, is easy to administer and may have potential to become routine practice for this type of surgery. PMID- 21672348 TI - Transgenic expression of human IGF1 in intervertebral degenerative discs. AB - This study investigated the role of human insulin-like growth factor-1 (hIGF-1; encoded by the hIGF1 gene) on intervertebral disc degeneration. A total of 24 male New Zealand rabbits of an intervertebral disc degeneration (IVDD) model were randomly divided into three groups where the following were injected into the lumbar 4 - 5 and 5 - 6 discs: second generation adenovirus containing cytomegalovirus hIGF1 (Ad/CMV-hIGF1); 100 MUg/l hIGF-1 protein; or phosphate buffered saline. At 1, 2, 4 and 8 weeks post-injection, intervertebral disc samples were harvested. Human IGF-1 protein was detected using Western blot analysis, and aggrecan and collagen type II gene fragments were quantified using reverse transcription-polymerase chain reaction. At week 1 post-injection, hIGF-1 protein levels were similar in the Ad/CMV-hIGF1 and hIGF-1 groups. By week 2 the level had decreased substantially in the hIGF-1 group. At week 4 it was still present in the Ad/CMV-hIGF1 group and, by week 8, no protein was detected in any of the three groups. Aggrecan and collagen type II mRNA levels increased in the Ad/CMV-hIGF1 group 1 - 4 weeks post-injection, but declined by week 8, while both decreased steadily over 8 weeks in the other two groups. In conclusion, hIGF1 gene expression lasted for 4 weeks and stimulated the synthesis of aggrecan and collagen type II in the Ad/CMV-hIGF1 group. PMID- 21672349 TI - Osteogenic growth peptide accelerates bone healing during distraction osteogenesis in rabbit tibia. AB - Distraction osteogenesis is a valuable treatment method that allows limb lengthening or reconstruction of large bone defects. However, its major disadvantage is the long period required for the consolidation of a distraction callus. Osteogenic growth peptide (OGP) stimulates endochondral bone formation in fracture callus, but its capacity to promote regenerate ossification during distraction osteogenesis has not been evaluated. This study investigated whether intravenously administered OGP accelerated bone healing during distraction osteogenesis in 36 male New Zealand White rabbits, randomized into two groups. The treatment group received OGP (200 ng/kg body weight) in phosphate-buffered saline (PBS), intravenously, each day; the control group received PBS alone. A 15 mm lengthening of the right lower leg was performed using the method of Ilizarov. Evidence from biomechanical, histological and radiographic evaluations demonstrated that systemic OGP treatment promoted optimal new bone formation during distraction osteogenesis in this rabbit model. PMID- 21672350 TI - Expression of aquaporin 4 and Kir4.1 in diabetic rat retina: treatment with minocycline. AB - This study examined aquaporin 4 (AQP4) and Kir4.1 (a potassium channel subunit) in normal and diabetic adult Sprague-Dawley rats, and determined the effect of minocycline treatment. Retinal expression of the AQP4 and Kir4.1 genes was examined using double immuno fluorescence, Western blot analysis, and real-time reverse transcription-polymerase chain reaction. Retinal levels of vascular endothelial growth factor (VEGF), ionized calcium-binding adaptor molecule (Iba) 1 and interleukin (IL)-1beta were also ascertained. The blood-retinal barrier (BRB) and retinal oedema were assessed using rhodamine isothiocyanate. AQP4, VEGF, Iba-1, and IL-1beta mRNA and protein levels increased, and Kir4.1 mRNA and protein levels decreased, in diabetic rat retinas. Both BRB disruption and retinal oedema were also observed in these retinas. In diabetic rats, minocycline treatment decreased AQP4, VEGF, Iba-1 and IL-1beta levels and retinal oedema, and increased Kir4.1 levels. These findings suggest that minocycline might be beneficial for retinal fluid clearance and reduction of retinal oedema in diabetic retinopathy. PMID- 21672351 TI - Acute rejection correlates with expression of major histocompatibility complex class I antigens on peripheral blood CD3(+)CD8(+) T-lymphocytes following skin transplantation in mice. AB - This study investigated major histocompatibility complex class I (MHC-I) antigen expression on peripheral blood T-cells after transplantation to assess its potential as an early marker of acute graft rejection (AGR). Using a mouse model with or without immunosuppressive treatment, the expression of MHC-I antigens on CD3(+)CD8(+) T-lymphocytes was assessed by flow cytometry following syngeneic graft (n = 138) or allograft (n = 138) skin transplantation. The occurrence of AGR was assessed by examining the degree of lymphocyte and monocyte infiltration in transplant biopsies. During AGR, expression of MHC-I antigens increased significantly compared with pre-transplant levels in the allograft group, even with immunosuppressive treatment. The highest expression of MHC-I antigens occurred 5 - 6 days before macroscopic rejection. These results suggest that expression of MHC-I antigens on peripheral blood CD3(+)CD8(+) T-lymphocytes could be used as an early marker for predicting AGR. PMID- 21672352 TI - Functional recovery after transplantation of neural stem cells modified by brain derived neurotrophic factor in rats with cerebral ischaemia. AB - Functional recovery after transplantation of brain-derived neurotrophic factor (BDNF)-modified neural stem cells (NSCs) was evaluated in a rat model of cerebral ischaemia damage induced by temporary middle cerebral artery occlusion (tMCAO). Western blotting and enzyme-linked immunosorbent assay demonstrated upregulated BDNF protein expression by rat embryonic NSCs transfected with the human BDNF gene (BDNF-NSCs). BDNF-NSCs stimulated neurite outgrowth in cocultured dorsal root ganglion neurons, suggesting that BDNF increased neurogenesis in vitro. In vivo, BDNF promoted recovery of tMCAO. Phosphate-buffered saline, untransformed NSCs or BDNF-NSCs were introduced into the penumbra zone of the right striatum of tMCAO rats and neurological function deficit was assessed for up to 12 weeks using the neurological severity score (NSS). The NSS was significantly lower in the BDNF-NSC transfected transplant group than in all the other groups from week 10. BDNF-NSCs recovered 1 week after transplantation expressed BDNF protein. Transplanted NSCs had differentiated into mature neurons 12 weeks after transplantation. Transgenic NSCs have potential as a therapeutic agent for brain ischaemia. PMID- 21672353 TI - Heat shock proteins and myocardial protection during cardiopulmonary bypass. AB - This prospective randomized study investigated the effects of two different cardioplegia techniques on myocardial heat shock protein 70 (HSP70) mRNA levels. Patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass (CPB) were divided into two equal groups. All patients received the same anaesthesia. Myocardial preservation was achieved by delivering intermittent antegrade isothermic blood cardioplegia in one group and antegrade plus continuous retrograde isothermic blood cardioplegia in the other. Biopsies for measurement of HSP70 mRNA levels were taken from the right atria before surgical manipulation of the heart, and later from the same place following CPB. HSP70 mRNA levels were evaluated using quantitative real-time reverse transcription polymerase chain reaction. Crossing-point values for HSP70 and beta-actin were used to evaluate up-regulation. There was a significant increase in HSP70 mRNA levels in response to CPB in both groups, but no significant between-group difference in HSP70 up-regulation. Further investigation is required to evaluate the correlation between the level of HSP induction and the degree of myocardial protection in more heterogeneous groups of patients. PMID- 21672354 TI - The amount of surface HLA-I on T lymphocytes decreases in breast infiltrating ductal carcinoma patients. AB - Human leucocyte antigen class I (HLA-I), which includes HLA-A, -B and -C, is an essential immune factor participating in the antitumour immune response. The changes in HLA-I expression in peripheral blood T lymphocytes in cancer patients have yet to be defined. This study examined the expression of HLA-I on CD4(+) and CD8(+) T lymphocytes in female patients with stage I - IV breast infiltrating ductal carcinoma, benign breast tumour diseases (mammary intraductal papilloma or breast fibroadenoma), and in healthy controls. HLA-I was down-regulated on CD4(+) T lymphocytes from patients with stage III and IV cancer, and on CD8(+) T lymphocytes in patients with stage I - IV cancer compared with healthy controls. HLA-I expression in T lymphocytes may contribute towards immune-balance disorders in tumour patients. PMID- 21672356 TI - Expression profiling of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. AB - Ephrin B1 and its cognate receptor, Eph receptor B2, key regulators of embryogenesis, are expressed in human atherosclerotic plaque and inhibit adult human monocyte chemotaxis. Few data exist, however, regarding the gene expression profiles of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. Gene expression profiles were determined of all 21 members of this gene family in atherosclerosis-related cells by reverse transcription-polymerase chain reaction analysis. The following 17 members were detected in adult human peripheral blood monocytes: EFNA1 and EFNA3 - EFNA5 (coding for ephrins A1 and A3 - A5); EPHA1, EPHA2, EPHA4 - EPHA6 and EPHA8 (coding for Eph receptors A1, A2, A4 - A6 and A8); EFNB1 and EFNB2 (coding for ephrins B1 and B2); and EPHB1 - EPHB4 and EPHB6 (coding for Eph receptors B1 - B4 and B6). THP-1 monocytic cells, Jurkat T cells and adult arterial endothelial cells also expressed multiple EFN and EPH genes. These results indicate that a wide variety of ephrins and Eph receptors might affect monocyte chemotaxis, contributing to the development of atherosclerosis. Their pathological significance requires further study. PMID- 21672355 TI - Humoural immune responses to a recombinant 16-kDa-38-kDa-ESAT-6 mycobacterial antigen in tuberculosis. AB - The present study investigated the diagnostic value of a recombinant 38-kDa-16 kDa-early secreted antigenic target of 6 kDa (ESAT-6) Mycobacterium tuberculosis (MTB) fusion antigen in 105 patients with tuberculosis (TB), 25 non-TB pulmonary disease patients and 20 healthy individuals. Its diagnostic value was compared with the commercially available enzyme-linked immunosorbent assay kit, the TB directly observed therapy (DOT) kit. In the controls, the rate of positive antibody response to the TB-DOT kit was significantly higher than that of the recombinant antigen. The area under the receiver operating characteristic curve was 0.751, and the optimum sensitivity and specificity for detecting antibody responses to the recombinant antigen were 65.4% and 84.8%, respectively. The recombinant 38-kDa-16-kDa-ESAT-6 MTB antigen was more effective than the TB-DOT kit in distinguishing between TB patients and controls, and may be an optimal combination of antigens to provide a useful tool for the sensitive and specific diagnosis of patients with TB. PMID- 21672357 TI - The association between circulating secreted protein acidic and rich in cysteine (SPARC) and glycosylated haemoglobin (HbA(1c)) during lifestyle-modified weight reduction intervention in obese male subjects. AB - The physiological role and clinical relevance of circulating secreted protein acidic and rich in cysteine (SPARC, or osteonectin) is still poorly understood. This study investigated the correlation between circulating SPARC and metabolic variables, including glucose and glycosylated haemoglobin (HbA(1c)), during a diet and exercise modified weight reduction intervention programme. Changes in plasma SPARC levels and several metabolic variables were analysed in asymptomatically obese, nondiabetic, male subjects before and after weight reduction intervention. Body mass index and blood pressure, serum cholesterol and HbA(1c) levels were all significantly reduced after weight reduction intervention. Multiple regression analysis demonstrated that changes in SPARC levels were significantly and positively correlated with HbA(1c). The relationship between SPARC and HbA(1c) may merit further investigation with regard to its association with postprandial or long-term glucose variation in obese male subjects. PMID- 21672358 TI - Cyclin-dependent kinase-associated protein Cks2 is associated with bladder cancer progression. AB - In this observational retrospective study, expression of possible cancer-related genes was measured in patients with a pathological diagnosis of superficial bladder cancer. Further measurements were made in those who subsequently developed muscle-invasive cancer. Seven of the 45 patients with superficial bladder cancer progressed to muscle-invasive cancer. Expression of fatty acid binding protein 5 (FABP5), poly(A) binding protein cytoplasmic 1 (PABPC1), DEAD box polypeptide 5 (DDX5), splicing factor 3b subunit 1 (SF3B1), murine mammary tumour integration site 6 (EIF3S6), tropomyosin 2beta (TPM2), transgelin (TAGLN) and cyclin-dependent kinase-associated protein (Cks2) genes was measured in bladder samples using real-time reverse transcription-polymerase chain reaction. FABP5, PABPC1, DDX5, SF3B1, EIF3S6 and Cks2 expression levels were significantly increased, and TPM2 and TAGLN were significantly decreased, in superficial bladder cancer compared with normal bladder tissue. In patients who developed muscle-invasive cancer, the Cks2 gene showed significantly increased expression after, compared with before, invasion. The Cks2 gene may have potential as a biomarker for predicting superficial bladder cancer progression to muscle invasive cancer. PMID- 21672359 TI - Functional effect of platelet membrane glycoprotein ia gene polymorphism in the pathogenesis of unstable angina pectoris. AB - The functional effect of platelet membrane glycoprotein Ia (GPIa) gene 807C/T polymorphism in unstable angina pectoris (UAP) pathogenesis was investigated in Chinese Han individuals. Collagen type I-induced platelet aggregation was measured in 33 healthy subjects. Plasma levels of alpha-granule membrane protein (GMP-140) were measured in 33 healthy subjects and in 35 patients with recent onset angina at rest within 24 h of hospitalization. Platelet membrane GPIa gene 807C/T polymorphism was determined in all subjects. Lag-time before 30% platelet aggregation was significantly longer in CC genotype than in TC genotype healthy subjects, although there was no significant difference in maximal platelet aggregation between healthy subjects with either genotype. Plasma GMP-140 levels were significantly higher in TC genotype patients compared with CC genotype patients or healthy subjects; a significant difference was also observed between the latter two groups. It was concluded that rapid initiation of collagen-induced platelet aggregation may be associated with the platelet membrane GPIa T807 allele, which may be important in UAP pathogenesis. PMID- 21672360 TI - Impact of severe coronary disease associated or not associated with diabetes mellitus on outcome of interventional treatment using stents: results from HERZ (Heart Research Group of Kanazawa) analyses. AB - Percutaneous coronary intervention (PCI) using a drug-eluting stent (DES) leads to less re-stenosis than PCI using a bare metal stent (BMS), however there is still controversy whether use of a DES for severe coronary disease leads to an acceptable outcome in patients with diabetes mellitus (DM). In this study 8159 lesions were treated in 6739 patients (mean age 68.9 years) with coronary artery disease. Use of a DES significantly decreased the re-stenosis rate compared with BMS in both DM (9.6% versus 21.3%) and non-DM (9.5% versus 17.1%) patients. The re-stenosis rate was significantly higher in DM than in non-DM patients in the BMS group but not in the DES group. There was no statistically significant difference in event-free survival after stenting of patients with left main coronary artery (LMCA) disease between the BMS and DES groups. It was concluded that, compared with BMS, DES reduced re-stenosis in patients with DM, however, we advise careful treatment after using DES for severe coronary disease, including LMCA lesions, in patients with DM. PMID- 21672361 TI - Sildenafil for erectile dysfunction in the Middle East: observational analysis of patients with diabetes and/or hypertension treated in the clinical practice setting. AB - The effectiveness and tolerability of 12 weeks of open-label treatment with sildenafil citrate for erectile dysfunction (ED) associated with a diagnosis of diabetes mellitus and/or hypertension were assessed in clinical practice in three Middle Eastern countries. The dose was initially 50 mg and was adjusted by the physician as needed (permissible dose range 25 - 100 mg). Total mean +/- SD score on the five-item version of the International Index of Erectile Function (severe ED, score 0 - 7; no ED, score 22 - 25) was 13.6 +/- 5.7 at baseline (4556 patients) and increased significantly to 21.7 +/- 4.1 at week 12. Global effectiveness was rated as good or very good by 91.4% of patients, 93.9% rating their sexual activity as spontaneous and 91.4% as natural. Discontinuation of sildenafil due to adverse events was infrequent (0.5%). Tolerability was rated as good or very good by 95.7% of patients. It is concluded that sildenafil was a well-tolerated and highly effective treatment of ED in outpatients with diabetes and/or hypertension from the three Middle Eastern countries studied. PMID- 21672362 TI - Intervertebral disc changes after 1 h of running: a study on athletes. AB - The lumbar spines of 25 long-distance runners were examined using an upright magnetic resonance imaging scanner. All volunteer runners were scanned before and after running for 1 h. Scanning was performed with the runners seated upright (neutral), leaning forwards (flexion) and leaning backwards (extension). All measured discs showed a reduction in disc height after 1 h of running. A significant reduction in disc height was observed in all three body positions (neutral, flexion and extension) after 1 h of running. The results showed that, in flexion, extension and neutral positions, intervertebral discs undergo significant strain after 1 h of running. The lowest disc-height reduction was found at the L5 - S1 space in the neutral position; the same space had the highest percentage of disc degeneration. PMID- 21672363 TI - Pre-operative versus post-operative gait variability in patients with acute anterior cruciate ligament deficiency. AB - Change in gait variability at least 6 months after surgical reconstruction of the anterior cruciate ligament (ACL) was assessed in 20 male patients with acute ACL deficiency and compared with pre-operative data and that from 20 healthy male controls. Gait was measured using a triaxial accelerometer and data were analysed by the Gait Evaluation Differential Entropy Method (GEDEM) to determine gait variability. Pain was assessed with a visual analogue scale and functional ability with the Oswestry Disability Index and the International Knee Documentation Committee score. Mean gait variability was significantly lower after than before surgery, with values for the anterior-posterior axis being in the normal range of controls after 6 months, whereas in the mediolateral axis mean gait variability remained significantly higher, indicating that some rotational instability remained in the time-frame of the study. Pain and functional ability scores improved after surgery compared with before surgery. The combination of accelerometry and GEDEM may be a useful orthopaedic tool for the post-operative evaluation of patients who have undergone ACL reconstruction. PMID- 21672364 TI - Epidemiological findings and clinical and magnetic resonance presentations in subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis (SSPE) is a rare, progressive, inflammatory neurodegenerative disease. This study investigated the relationships of clinical stage with epidemiological and magnetic resonance imaging (MRI) findings in SSPE by retrospective review of 76 cases (57 male) diagnosed by typical periodic electroencephalographic features, clinical symptoms and elevated measles antibody titre in cerebrospinal fluid. Clinical stage at diagnosis was I or II in 48 patients, III in 25 and IV in three. Prominent findings at presentation were atonic/myoclonic seizures (57.9%) and mental deterioration with behaviour alteration (30.3%). Frequent MRI findings (13 - 32 patients) were subcortical, periventricular and cortical involvement and brain atrophy; the corpus callosum, basal ganglia, cerebellum and brainstem were less frequently involved. Five patients had pseudotumour cerebri. Cranial MRI at initial diagnosis was normal in 21 patients (19 stage I/II, two stage III/IV). Abnormal MRI findings were significantly more frequent in the later stages, thus a normal initial cranial MRI does not exclude SSPE, which should, therefore, be kept in mind in childhood demyelinating diseases even when the presentation is unusual. PMID- 21672365 TI - The necessity of voiding cystourethrography in children with prenatally diagnosed hydronephrosis. AB - The postnatal persistence of fetal hydronephrosis requires further evaluation to establish whether pathological abnormalities are present. This study determined the necessity for voiding cystourethrography (VCUG) to identify vesicoureteral reflux (VUR) in children (n = 195) with prenatally diagnosed hydronephrosis. Among the study population, the prevalence of VUR was 17.4% (24 males, 10 females). There was a poor correlation between the severity of hydronephrosis, ureteral dilatation, presence of bilateral hydronephrosis and presence of VUR. Except for the frequency of urinary tract infections and the presence of renal damage on (99m)Tc-dimercaptosuccinic acid scans, VCUG was the only reliable method for confirming VUR in this study. The diagnosis of VUR is important for the early detection of renal damage. Further information is needed to develop the optimal approach to the evaluation of prenatal hydronephrosis, with reliable parameters that avoid invasive procedures such as VCUG. PMID- 21672366 TI - Preoperative diagnostic role of hyperbilirubinaemia as a marker of appendix perforation. AB - This retrospective study investigated preoperative markers of appendix perforation in 351 acute appendicitis cases: group 1, appendicitis not histologically confirmed; group 2, appendicitis without perforation or gangrenous changes; and group 3, histologically confirmed perforated appendicitis with gangrenous changes. In group 3, symptom duration was significantly longer, and white blood cell (WBC) and bilirubin values significantly higher, than for the other groups. Symptom duration, gender, bilirubin and elevated WBC were significantly associated with early diagnosis of acute appendicitis in univariate analysis. Multivariate analysis identified increased WBC counts and male gender as independent variables for the early diagnosis of acute suppurative appendicitis, and symptom duration, total bilirubin and elevated WBC as independent variables for identifying appendix perforation amongst acute suppurative appendicitis patients. Receiver operating characteristic curve analysis showed good discrimination of bilirubin and moderate discrimination of WBC as markers of appendix perforation. It is concluded that assessment of preoperative total bilirubin is useful for the differential diagnosis of perforated versus acute suppurative appendicitis, whereas WBC assessment is effective for diagnosing the presence versus absence of appendicitis. Symptom duration, WBC and total bilirubin should be used as independent parameters in the early diagnosis of appendix perforation. PMID- 21672367 TI - Household transmission of influenza (H1N1-2009) in Japan: age-specificity and reduction of household transmission risk by zanamivir treatment. AB - This study investigated household transmission data for influenza (H1N1-2009) in Japan in order to quantify the age-specific risk of infection and estimate the impact of antiviral treatment on the risk of household transmission. Among a total of 1547 households, involving 4609 household contacts, the secondary attack ratio (SAR) was estimated to be 11.4%. School children aged 5 - 18 years dominated the index cases. Age-specific infectiousness and susceptibility were highest among 0 - 4-year olds, with SAR estimated at 19.4% and 29.6%, respectively. Zanamivir treatment within 24 and 24 - 48 h of illness onset in index cases, respectively, reduced the risk of household transmission to 0.57 (95% CI 0.44, 0.73) and 0.58 (95% CI 0.38, 0.86) times that among those receiving the same treatment at > 48 h and those not receiving treatment. The preventive performance of antiviral treatment and prophylaxis should be further examined in randomized controlled trials. PMID- 21672368 TI - A 24-h work shift in intensive care personnel: biological pathways between work stress and ill health. AB - This study evaluated inflammatory, coagulation and microvascular responses to a continuous 24-h work day in 13 healthy intensive care physicians. Inflammatory markers (interleukin [IL]-2, IL-6, IL-10, tumour necrosis factor-alpha, matrix metalloproteinase [MMP]-9 and adiponectin), adhesion molecules (vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1 [ICAM-1]), coagulation parameters (thrombin-anti thrombin, von Willebrand factor and tissue factor) and sublingual micro circulation were assessed before and after a 24-h work shift. The 24-h work shift had no effect on inflammatory markers and ICAM-1. Direct visualization of micro-circulation did not reveal stress-related perfusion abnormalities. A 24-h work shift in the intensive care unit was associated with significantly increased plasma levels of tissue factor - a potentially important mechanism linking acute job strain, haemostasis and atherosclerosis. The long term consequences warrant further evaluation. PMID- 21672369 TI - Using an abnormal increase in postexercise systolic blood pressure to diagnose coronary artery disease in gerontal patients. AB - Data from 66 patients >= 60 years old with suspected coronary artery disease (CAD) were studied to determine the diagnostic value of an abnormal increase in postexercise systolic blood pressure (SBP) for detecting CAD in gerontal patients. Treadmill exercise testing (TET) and selective coronary angiography (CAG) were carried out and SBP was measured pre-TET and at each minute during a 6 min post-TET recovery phase. Abnormal increase in postexercise SBP was defined as a higher SBP compared with that measured earlier during the 6-min post-TET period. An abnormal increase of >= 7 mmHg in postexercise SBP had a statistically significantly better specificity, and also showed higher sensitivity and accuracy, than ST-segment depression >= 1 mV in identifying gerontal patients with CAD. The combination of ST-segment depression and abnormal SBP resulted in further improvement of the specificity for detecting CAD. It is concluded that measurement of abnormal increase in postexercise SBP may be a sensitive indicator of gerontal CAD. PMID- 21672370 TI - Assessment of urinary N-acetyl-beta-glucosaminidase as an early marker of contrast-induced nephropathy. AB - Early detection and timely intervention are important for improving contrast induced nephropathy (CIN) prognosis. Whether urinary N-acetyl-beta glucosaminidase (NAG) is a useful marker for early detection of CIN was investigated in 590 patients undergoing diagnostic coronary angiography (CA) and/or therapeutic percutaneous coronary intervention (PCI) for acute coronary syndromes or stable angina, and who received low-osmolality nonionic contrast agent. Urinary NAG, osmolality and serum creatinine were measured before and 1, 2 and 6 days after contrast agent exposure. CIN occurred in 33 patients; its incidence in high-risk patients (pre-existing renal dysfunction with/without diabetes mellitus) was significantly higher than in others. In patients with CIN, urinary NAG and serum creatinine levels on days 1 and 2 were significantly higher than at baseline and compared with patients without CIN; mean levels were gradually returning to baseline by day 6. Compared with serum creatinine, urinary NAG levels peaked earlier in CIN patients and increased much more. The results suggest that, following CA and/or PCI, CIN occurs to a certain degree and that NAG may be a useful early CIN marker as it is noninvasive, simple, inexpensive and sensitive. PMID- 21672371 TI - Effects of transcatheter closure of atrial septal defects on heart rate variability. AB - This study evaluated heart rate variability and its changes in 30 patients before and after transcatheter closure of secundum atrial septal defects. Heart rate variability data from 30 healthy volunteers with normal echocardiographic parameters and no history of atrial septal defects were included as controls. Values for the SD of all the normal RR intervals (SDNN), the SD of the means of all the 5-min segment normal RR intervals (SDANN), and the mean of all the 5-min SDs of normal RR intervals during the 24-h period (SDNN index) in patients with atrial septal defects before transcatheter closure were statistically significantly different from controls. At 6 months after closure of the defects these values were not statistically different from controls. It is concluded that transcatheter closure of secundum atrial septal defects had positive effects on heart rate variability and, consequently, may contribute to less mortality and morbidity. PMID- 21672372 TI - The effect of posterior scleral reinforcement for high myopia macular splitting. AB - This study investigated the effect of posterior scleral reinforcement for high myopia macular splitting in 15 patients with high myopia and macular splitting (20 eyes), including three eyes with shallow retinal detachment. Main outcome measures included best-corrected visual acuity, refractive error, axial length, optical coherence tomography (OCT) findings and post-surgical complications. Best corrected visual acuity, myopial dioptres and axial length reduced significantly post-surgery. The OCT findings showed different degrees of reduction in the split cavity between inner and outer retinal layers, and that retinal thickness declined significantly post-operatively. No serious complications were observed. Posterior scleral reinforcement was effective, with a good safety profile, for patients with high myopia macular splitting with or without retinal detachment. PMID- 21672373 TI - Multiple primary malignant neoplasms from the black sea region of Turkey. AB - Long-term cancer survival is increasing and, as a consequence, so is the prevalence of secondary malignancies. This study evaluated the patient and tumour characteristics of 117 patients with multiple primary malignant neoplasms (MPMN). The incidence of MPMN in children and adults was 0.28% and 1.23%, respectively. The male : female ratio was 1.7 : 1. The mean +/- SE age at tumour diagnosis was 60.56 +/- 1.18 years. Overall, the top three tumour sites were the larynx, bladder and breast. Among secondary tumours, lung cancer was the most frequent, followed by breast and colon cancer. Among males, the leading primary and secondary tumour sites were the larynx (30.1%) and lung (50.7%), respectively. Among females, the breasts were both the leading primary (32.6%) and secondary (37.2%) cancer site. The mean +/- SE overall survival was 97.2 +/- 15.0 months. During follow-up, the brain was the most commonly observed site of metastasis. The occurrence and characteristics of MPMN reported in the literature are also reviewed. The present study contributes towards increasing understanding and treatment of MPMN in a different population group. PMID- 21672374 TI - Solitary intracerebral chondroma without meningeal attachment: a case report with review of the literature. AB - Intracranial chondromas are rare, benign cartilaginous tumours that account for < 0.3% of primary intracranial tumours. They usually originate from the basal synchondrosis and are extradural though, extremely rarely, they can be intracerebral. Here the case of a 45-year old female is presented with a solitary intracerebral chondroma located in the right frontal lobe with no meningeal attachment. The epidemiology, aetiology, clinical behaviour, radiological features, histological features and treatment of the case are discussed with a review of previous cases reported in the literature. PMID- 21672375 TI - Aggressive fibromatosis of the larynx: case report and brief review. AB - Aggressive fibromatosis is a rare, benign, fibroblastic neoplasm, characterized by local invasion and a relatively high rate of recurrence. Here a case of laryngeal aggressive fibromatosis in a 47-year old man is reported. The patient presented with worsening dyspnoea and hoarseness and was hospitalized for treatment with partial laryngectomy. Final pathological evaluation of the tumour confirmed a diagnosis of aggressive fibromatosis. The patient has remained disease-free without further treatment for 5 years. This study demonstrated that aggressive fibromatosis may occur around the larynx and can be managed by partial laryngectomy alone. It is, therefore, important to include this rare disease entity in the routine differential diagnosis of laryngeal masses. PMID- 21672376 TI - [The balance between macrocirculation and microcirculation in cardiopulmonary resuscitation]. PMID- 21672377 TI - [The role of diabetes mellitus as a risk factor of acute myocardial infarction]. AB - OBJECTIVE: To determine the impact of elevated in-hospital glucose level on outcome of patients with acute myocardial infarction (AMI), and evaluate the role of diabetes mellitus as a risk factor of AMI. METHODS: The study included a retrospective analysis of AMI patients who were admitted to No. 81 Hospital of PLA from January 2000 to May 2010. In patients without a history of diabetes, and those with fasting blood glucose (FBG)>=7.0 mmol/L at admission but returned to normal range soon after admission were defined as stress hyperglycemia of non diabetic AMI patients. Both diabetic patients and non-diabetic patients were stratified into four mutually exclusive groups according to FBG levels: <7.0, 7.0 7.9, 8.0-11.0 and >=11.1 mmol/L. The in-hospital mortality, incidence of complications, and treatment to lower glucose level were analyzed. Logistic regression analysis was conducted on risk factors of outcome of AMI patients. RESULTS: One hundred and fifty-two AMI patients were enrolled with 45 diabetic patients and 107 patients without previous diabetes. In diabetic group patients with FBG>=8.0 mmol/L and those with FBG>=11.1 mmol/L accounted for 73.3% (33 cases) and 46.7% (21 cases), respectively. In non-diabetic group patients with stress hyperglycemia accounted for 43.9% (47 cases), among which patients with FBG levels of 7.011.0 mmol/L accounted for 91.5% (43 cases). Compared with the non-diabetic group, the in-hospital mortality was significantly higher in diabetic group (35.6% vs. 15.9%, P=0.007). In both groups, the in-hospital mortality presented an elevating tendency with an increasing FBG level. Multivariate Logistic regression analysis demonstrated that in diabetic group patients with FBG>=8.0 mmol/L had 12.28-fold higher risk of death than patients with FBG<8.0 mmol/L, and that in non-diabetic group patients with FBG>=7.0 mmol/L had 4.81-fold higher risk of death than patients with FBG<7.0 mmol/L. FBG was an independent risk factor of death with relative odds ratio (OR) 1.03, with 95% confidence interval (95%CI) 1.01-1.16, P=0.012, and OR 1.56, 95%CI 1.09-2.23, P=0.015 in diabetic group and non-diabetic group, respectively. The incidence of congestive heart failure in diabetic group was significantly higher than that in non-diabetic group (40.0% vs. 22.4%, P=0.027). In non-diabetic group, the incidence of lung infection, congestive heart failure, serious arrhythmias and acute cerebrovascular events (51.1%, 34.0%, 27.7%, 14.9%, respectively) was increased significantly in patients with FBG>=7.0 mmol/L than that in patients with FBG<7.0 mmol/L (18.3%, 13.3%, 10.0%, 0, respectively, P<0.05 or P<0.01). This association was not seen in diabetic group. 80.0% of patients (36 cases) in diabetic group received anti-hyperglycemia treatments in which insulin therapy accounted for 63.9% (23 cases), while there was not even 1 patient who needed insulin therapy in non-diabetic patients with stress hyperglycemia. CONCLUSION: In-hospital mortality and complications were significantly increased in diabetic AMI patients and in non-diabetic AMI patients with stress hyperglycemia. Both a history of diabetes mellitus and stress hyperglycemia have strong influence on AMI prognosis. It seems to be more plausible to collaborate blood glucose level with history of diabetes in considering risk factors in AMI patients. PMID- 21672378 TI - [A study of traditional Chinese medicine syndromes correlated to neurologic function or to coagulation function in patients with acute cerebral infarction]. AB - OBJECTIVE: To investigate the correlations between traditional Chinese medicine (TCM) syndrome elements and neurologic function and between them and coagulation function in patients with acute cerebral infarction (ACI). METHODS: Two hundred and twenty-three patients with ACI were enrolled. The syndromes of this disease were scored according to Stroke Diagnostic Criteria for Differentiation of Syndromes. Neurologic function deficit score (NDS) was scored according to stroke scale of the National Institutes of Health (NIHSS). The prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (FIB) contents were detected. The correlations between TCM syndrome elements and NDS and between them and coagulation function were investigated. RESULTS: Two hundred and twenty-three patients with ACI were divided into six syndromes: wind syndrome (n=147, 65.92%), fire syndrome ( n=100, 44.84%), tan syndrome (n=123, 55.16%), blood stasis syndrome (n=78, 34.98%), deficiency of qi syndrome (n=31, 13.90%), and yin deficiency causing hyperactivity of yang syndrome (n=25, 11.21%). The wind, tan and fire syndromes were the main syndrome elements related to ACI. The scores of wind, fire, tan and deficiency of qi syndromes were positively related to NDS (r1=0.207, P1=0.002; r2=0.284, P2=0.000; r3=0.245, P3=0.000; r4=0.152, P4=0.023). The score of deficiency of qi syndrome was negatively correlated with PT (r= 0.170, P=0.011); and the scores of tan, blood stasis, and deficiency of qi syndromes were negatively correlated with APTT (r1=-0.182, P1=0.006; r2=-0.148, P2=0.027; r3=-0.211, P3=0.001).Other syndromes were not correlated to NDS or coagulation factors. CONCLUSION: The neurologic function deficiency due to ACI is more likely influenced by wind, tan, and fire syndromes; deficiency of qi syndrome also has some effects. The syndromes of tan, blood stasis, and deficiency of qi are closely correlated with coagulation function, and their scores may reflect the clotting function in patients with ACI. PMID- 21672379 TI - [Influence of granulocyte colony stimulating factor on distribution of bone marrow stem cells and its role in protecting brain in rats with cerebral ischemia]. AB - OBJECTIVE: To explore the influence of recombination granulocyte colony stimulating factor (rG-CSF) on mobilization and distribution of bone marrow stem cells (BMSCs) in blood and brain tissue, and its role in protecting brain in rats with cerebral ischemia. METHODS: One hundred and six Sprague-Dawley (SD) rats were divided into sham-operated group (n=10),model group (n=48), rG-CSF group (n=48) according to the method of random digital table, and rats in model and rG CSF groups were divided into four subgroups: i.e. 2, 3, 7 and 14 days subgroups, with 12 rats in each subgroup. Middle cerebral artery occlusion (MCAO) model was reproduced with nylon thread. In rats of rG-CSF group rG-CSF (10 MUg/kg) was administered by subcutaneous injection 3 days before and 2 days after operation respectively, once a day. Rats in sham-operated and model groups were administered with normal saline in the same volume, once a day. At the corresponding time after operation, general neural function score (GNFS) of rats was measured. Blood was collected through abdominal aorta, then white blood cell (WBC) and CD34+ cells in peripheral blood were counted. Brain pathologic changes were observed, and expression of CD34+ cells in rats brain tissue was determined by using immunohistochemical method. RESULTS: (1) GNFS was lower obviously in 2 day model group compared with that in sham-operated group, and then increased gradually. At 7 days and 14 days after operation, GNFS in rG-CSF group was higher significantly than that in model group (7 days: 11.86+/-0.69 vs. 10.53+/-0.76, 14 days: 13.38+/-0.52 vs. 12.38+/-0.52, both P<0.01). (2) WBC and CD34+ cells in peripheral blood in model group increased obviously, with the highest level appeared at 3 days and lowered at 7 days and 14 days. Increase of WBC and CD34+ cells in rats of rG-CSF group was more obvious than that of model group at each time point except CD34+ in 14 days group [WBC (*10(9)/L) 2 days: 11.75+/-1.76 vs. 8.07+/-1.27, 3 days: 13.07+/-1.70 vs. 10.88+/-1.78, 7 days: 8.63+/-1.36 vs. 5.58+/-1.57, 14 days: 6.98+/-0.98 vs. 4.87+/-0.92; CD34+ (cells/MUl) 2 days: 8.83+/-2.14 vs. 3.17+/-0.75, 3 days: 13.50+/-1.87 vs. 5.00+/-1.55, 7 days: 5.33+/ 1.21 vs. 2.33+/-1.21, P<0.05 or P<0.01]. (3) Expression of CD34+ cells in the brain of rats in 2-day model group increased significantly, and the highest level appeared at 7 days and decreased at 14 days. Absorbance (A) value of CD34+ cells expression in rat brains of each rG-CSF group was more significant than that in model group (2 days: 43.21+/-4.41 vs. 22.04+/-2.95, 3 days: 45.79+/-1.76 vs. 25.69+/-2.44, 7 days: 52.09+/-2.86 vs. 33.04+/-2.62, 14 days: 29.73+/-1.99 vs. 16.91+/-2.95, all P<0.01). (4) The signs of injury to brain in pathological examination were less obvious in 14 days rG-CSF group. CONCLUSION: BMSCs could be induced to enter peripheral blood and "home" to brain tissue after cerebral ischemia. It was showed that BMSCs increased in number at first and then decreased in peripheral blood and brain, the peak number was found on 3rd day in peripheral blood and 7th day in brain. Mobilization with rG-CSF could increase the number of BMSCs in peripheral blood and brain tissue. The effect of mobilization of BMSCs on protecting brain was significant after cerebral ischemia, and effect appeared to be more pronounced with prolongation of mobilization. PMID- 21672380 TI - [Effects of scutellarin benzyl ester on the expressions of Bcl-2 and Bax in cardiomyocytes injured by acute hypoxia]. AB - OBJECTIVE: To investigate the effects of scutellarin benzyl ester on the expressions of Bcl-2 and Bax in cardiomyocytes after acute injury of hypoxia. METHODS: Cardiomyocytes harvested from neonatal Sprague-Dawley (SD) rats were cultured for 4 days. The cells of the primary culture were assigned randomly to five groups: control group, hypoxia model group (acute hypoxic injury was induced by exposing cells to anoxic condition with 95%N2 and 5%CO2) and high, moderate and low dose of scutellarin benzyl ester groups (pretreated with 100, 50 and 25 MUmol/L scutellarin benzyl ester before hypoxia) with 6 wells in each group. After hypoxic injury for 6 hours, the activity of lactate dehydrogenase (LDH) and content of nitric oxide (NO) in media were measured by biochemical methods. The mRNA and protein expressions of Bcl-2 and Bax were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. RESULTS: After hypoxic injury, comparing with those in control group, the leakage of LDH (U/L) in hypoxia model group increased (288.10 +/- 30.69 vs. 78.75 +/- 12.85) and the release of NO (MUmol/L) decreased (9.02 +/- 1.55 vs. 24.11 +/- 2.04, both P<0.01). However, high, moderate and low dose of scutellarin benzyl ester could significantly reduce the LDH leakage (64.19 +/- 22.90, 101.35 +/- 22.71, 141.34 +/- 23.08) and high and moderate dose of scutellarin benzyl ester could increase the NO release (14.45 +/- 3.57, 12.38 +/- 1.57), with remarkably significant statistical difference (all P<0.01). After hypoxic injury, comparing with those in control group, the mRNA and protein expressions of Bcl-2 in hypoxia model group decreased (Bcl-2 mRNA: 0.544 +/- 0.108 vs. 0.837 +/- 0.213, Bcl-2 protein: 0.813 +/- 0.041 vs. 0.917 +/- 0.046), and the mRNA and protein expressions of Bax in hypoxia model group increased (Bax mRNA: 0.918 +/- 0.228 vs. 0.493 +/- 0.123, Bax protein: 0.623 +/- 0.031 vs. 0.490 +/- 0.025, all P<0.01). Comparing with those in hypoxia model group, high and moderate dose of scutellarin benzyl ester could up-regulate the mRNA and protein expressions of Bcl-2 (Bcl-2 mRNA: 0.708 +/- 0.123, 0.604 +/- 0.116 vs. 0.544 +/- 0.108, Bcl-2 protein: 0.887 +/- 0.044, 0.850 +/- 0.043 vs. 0.813 +/- 0.041) and down-regulate the mRNA and protein expressions of Bax (Bax mRNA: 0.614 +/- 0.136, 0.728 +/- 0.152 vs. 0.918 +/-0.228, Bax protein: 0.518 +/- 0.026, 0.547 +/- 0.027 vs. 0.623 +/- 0.031, all P<0.01). However, there was no statistical difference in the mRNA and protein expressions of Bcl-2 and Bax between hypoxia model group and low dose of scutellarin benzyl ester group (Bcl-2 mRNA 0.551 +/- 0.112, Bcl-2 protein 0.823 +/- 0.041; Bax mRNA 0.857 +/- 0.218, Bax protein 0.617 +/- 0.031). CONCLUSION: Scutellarin benzyl ester has a protective effect on acute myocardial hypoxic injury, and the mechanism is probably related to the regulation of the expressions of Bcl-2 and Bax. PMID- 21672381 TI - [The influence of different asphyxia time on the reproduction of multiply organ dysfunction model after cardiopulmonary resuscitation following cardiac arrest in rabbit]. AB - OBJECTIVE: To explore the effects of different asphyxia time on the reproduction of multiply organ dysfunction syndrome in rabbit after cardiopulmonary resuscitation (CPR-MODS) for cardiac arrest, in order to provide a method to reproduce an animal model of CPR-MODS for further research of cardiopulmonary resuscitation (CPR). METHODS: The rabbit cardiac arrest was caused by asphyxia as a result of clamping the trachea. Thirty rabbits were divided into 7-minute asphyxia group and 8-minute asphyxia group by means of random number table with 15 rabbits in each group. The rate of resumption of spontaneous circulation (ROSC), the mortality at different time points and the occurrence incidence of systemic inflammatory response syndrome (SIRS) of two groups were observed after CPR and the ROSC. The levels of serum tumor necrosis factor-alpha (TNF-alpha), myocardial MB-isoenzyme of creatine kinase (CK-MB), alanine aminotransferase (ALT), creatinine (Cr), glucose (Glu) and arterial partial pressure of oxygen (PaO2) before resuscitation and 12, 24 and 48 hours after ROSC were measured simultaneously in the two groups. The incidence of CPR-MODS was calculated. RESULTS: The CPR time (seconds) in 7-minute asphyxia group was significantly shorter than that in 8-minute asphyxia group (147.60+/-22.09 vs. 193.08+/-23.07, P<0.01). The ROSC rate of 7-minute asphyxia group and 8-minute asphyxia group was 100.00% and 86.67%, respectively, and there was no significant difference. The incidence of MODS in the rabbits surviving more than 24 hours after ROSC was 100% in both groups. The mortality at 6 hours after ROSC in 7-minute asphyxia group was remarkably lower than that of 8-minute asphyxia group (6.67% vs. 46.67%, P<0.05). All the rabbits in 8-minute asphyxia group died at 48 hours. The incidence of SIRS after ROSC was 100% in both groups. Compared with that before asphyxiation, the level of serum TNF-alpha (ng/L) as well as CK-MB (U/L) increased significantly at 12 hours after ROSC in both groups (TNF-alpha in 7 minute asphyxia group: 100.71+/-20.43 vs. 49.13+/-8.64, in 8-minute asphyxia group: 118.09+/-21.90 vs. 48.48+/-6.70; CK-MB in 7-minute asphyxia group: 786.88+/-211.84 vs. 468.20+/-149.45, in 8-minute asphyxia group: 894.88+/-248.80 vs. 462.11+/-115.15, all P<0.05). There was a significant elevation of ALT (U/L) and Glu (mmol/L) at 24 hours after ROSC (ALT in 7-minute asphyxia group: 174.25+/ 36.28 vs. 50.27+/-9.37, in 8-minute asphyxia group: 205.50+/-10.61 vs. 51.13+/ 10.37; Glu in 7-minute asphyxia group: 11.21+/-1.14 vs. 5.59+/-1.10, in 8-minute asphyxia group: 11.55+/-0.35 vs. 6.41+/-1.23, all P<0.05). Cr (MUmol/L) was significantly higher at 12 hours after ROSC in 8-minute asphyxia group (98.83+/ 16.70 vs. 65.93+/-13.81), while it was elevated at 24 hours in 7-minute asphyxia group (144.25+/-41.64 vs. 67.71+/-16.47, both P<0.05). PaO2 in both groups was significantly higher at 12 hours after ROSC and significantly decreased at 24 hours. CONCLUSION: The model of cardiac arrest caused by 7 minutes asphyxia provided more possibility and feasibility for the subsequent study of reproducing CPR-MODS model. PMID- 21672383 TI - [A study on expression of Wnt signal pathway gene in familial aggregated hypertension]. AB - OBJECTIVE: To determine the role of gene expression of Wnt signal pathway in the pathogenesis of familial aggregated hypertension. METHODS: The patients having directly related family members for more than three generations suffering from hypertension were enlisted in the hypertension group, and healthy individuals served as control group. The real-time polymerase chain reaction (PCR) gene array was used to detect the expression of functional classification genes of Wnt signal pathway in peripheral blood, with standard value deviated>2.0 from hypertension group/control group as differential genes. RESULTS: When hypertension group was compared with the control group, there were 6 differentially expressed genes, with 5 genes up-regulated, including Bcl-9, microphthalmia associated transcription factor (Mitf), secreted frizzled-related protein-1 (Sfrp-1), Wnt inhibiting factor-1 (Wif-1) and ribosomal protein-l13a (Rp-l13a). There was 1 gene down-regulated, i.e. dickkopf homolog-3 (Dkk-3). CONCLUSION: The result of this study suggested that the Wnt signal pathway may be related to the occurrence and development of the familial aggregated hypertension. PMID- 21672382 TI - [The role of Leptin on neuron apoptosis in mice with cerebral ischemia/reperfusion injury]. AB - OBJECTIVE: To study the effect of Leptin on neuron apoptosis in mice with cerebral ischemia injury and its mechanism. METHODS: Seventy-five mice were randomly divided into three groups. Focal cerebral ischemia/reperfusion injury model in mice was reproduced by middle cerebral artery occlusion for 2 hours followed by reperfusion. In Leptin intervention group mice were given Leptin 1 MUg/g during cerebral ischemia by intraperitoneal injection. Mice in the model group were given equal amount of phosphate buffer saline. After reperfusion for 24 hours, the neuron apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. The mRNA and protein expression of apoptosis relative gene caspase-3 and bcl-2 were determined by reverse transcription-polymerase chain reaction (RT-PCR) and immuno histochemistry. RESULTS: Most of neuron necrosis was observed in cerebral ischemia center in model group. Compared with sham-operation group, neuron apoptosis rate, mRNA and protein expression of caspase-3 and bcl-2 in model group increased significantly [apoptosis rate: (68.65 +/- 0.79)% vs. (4.40 +/- 0.00)%, caspase-3 mRNA: 2.563 +/- 0.250 vs. 0.153 +/- 0.020, bcl-2 mRNA: 0.337 +/- 0.100 vs. 0.125 +/- 0.030, caspase-3 protein (absorbance value, A value): 0.57 +/- 0.05 vs. 0.37 +/- 0.03, bcl-2 protein (A value): 0.51 +/- 0.04 vs. 0.35 +/- 0.01, all P<0.01]. The apoptosis rate of penumbra neurons was reduced in Leptin intervention group significantly compared with model group [(42.30 +/- 8.45)% vs. (68.65 +/- 0.79)%, P<0.01]. Compared with model group, the mRNA and protein expression of caspase-3 in Leptin intervention group were reduced significantly [caspase-3 mRNA: 2.267 +/- 0.040 vs. 2.563 +/- 0.250, caspase-3 protein (A value): 0.45 +/- 0.04 vs. 0.57 +/- 0.05, P>0.05 and P<0.01], and the mRNA and protein expression of bcl-2 in Leptin intervention group upregulated significantly [bcl-2 mRNA: 0.662 +/- 0.040 vs. 0.337 +/- 0.100, bcl-2 protein (A value): 0.76 +/- 0.09 vs. 0.51 +/- 0.04, both P<0.01]. CONCLUSION: Leptin could reduce apoptosis of neurons through down-regulation of the expression of caspase 3 and up-regulation of the expression of bcl-2. The results suggest that Leptin plays a neuroprotective role in cerebral ischemia injury. PMID- 21672384 TI - [Evaluation of continuous monitoring of bispectral index in prognosis in patients with acute brain injury]. AB - OBJECTIVE: To discuss the effect of continuous monitoring of bispectral index (BIS) on the prognosis of patients with acute brain injury. METHODS: A retrospective study was carried out, 61 patients with acute brain injury admitted to the intensive care unit (ICU) from March 2009 to July 2010 were divided into survival group (n=25) and death group (n=36). The BIS was continuously monitored for 12 hours within the first 3 days or 24 hours after stoppage of sedative after admission to ICU. The mean value of BIS (BISmean), the maximal value of BIS (BISmax), and the minimal value of BIS (BISmin) were evaluated. At the same time, the acute physiology and chronic health evaluationII (APACHEII) score, probability of survival (PS) and Glasgow coma score (GCS) were evaluated. The values of serum S100 protein and neuron-specific enolase (NSE) were determined. The relationship between BISmean and GCS, S100 protein and NSE were respectively analyzed. RESULTS: (1)There was no significant difference in the sex, age, or duration of mechanical ventilation between two groups. APACHEII score in death group was significantly higher than the survival group (27.36+/-5.99 vs. 23.28+/ 6.69), PS was significantly lower than the survival group (0.31+/-0.17 vs. 0.49+/ 0.19), and length of stay in ICU (days) was significantly lower than that of the survival group (6.33+/-4.48 vs. 27.88+/-54.46), P<0.05 or P<0.01. (2) BISmean, BISmax, BISmin, GCS in death group were significantly lower than those in the survival group (BISmean: 35.45+/-28.31 vs. 55.91+/-17.53, BISmax: 51.92+/-34.24 vs. 74.84+/-16.58, BISmin: 22.39+/-24.83 vs. 39.68+/-15.72, GCS score: 3.64+/ 1.19 vs. 5.60+/-2.22), P<0.05 or P<0.01, while serum S100 protein and NSE levels were significantly higher than the survival group [S100 protein (MUg/L): 7.54+/ 10.49 vs. 1.18+/-1.57, NSE (MUg/L): 120.74+/-109.01 vs. 49.83+/-54.94], both P<0.01. (3) By bivariate analysis, BISmean was positively correlated with GCS (r=0.379, P=0.003), whereas it was found to be negatively correlated with S100 protein and NSE levels (r1=-0.418, P1=0.001; r2=-0.290, P2=0.023). CONCLUSION: BIS monitoring can be applied as an early objective indicator to evaluate the prognosis of the acute brain injured patients with the characteristics of being noninvasive, intuitive, easy-to-manipulate, and non-stop monitoring. PMID- 21672385 TI - [The role of Notch signaling during the differentiation of rat bone marrow mesenchymal stem cells into endothelial cells]. AB - OBJECTIVE: To research the role of Notch signaling during the differentiation of bone marrow mesenchymal stem cells (MSCs) into endothelial cells and its effect on the functions of the differentiated cells. METHODS: Rat bone marrow MSCs were isolated and cultured in vitro, then the cells were treated with vascular endothelial growth factor (VEGF165) and basic fibroblast growth factor (bFGF) for 2 weeks to induce it to differentiate into endothelial cells. The differentiated cells were identified by fluorescence immunoassay. The receptors and ligands of the Notch signaling were detected by reverse transcription-polymerase chain reaction (RT-PCR) before and after the differentiation. gamma-secretase inhibitor was used to block Notch pathway. Migration ability of cells were assessed by scarification test. Cells were inoculated on semisolid gel to study their ability of forming the capillary-like structure. RESULTS: After inducing MSCs to differentiate into endothelial cells by VEGF165 and bFGF, MSCs gained the characteristics of the endothelial cells with expression of CD31 and Flk1. There were Notch1 mRNA and Jagged1 mRNA expressions in rat bone marrow MSCs. The expression changes in the receptor Notch1 were not statistically significant on the differentiated cells (0.59+/-0.01 vs. 0.59+/-0.01, P>0.05), but there was a trend towards an increase of Jagged1 mRNA (1.01+/-0.02 vs. 0.99+/-0.03, P>0.05). When Notch pathway was blocked, the differentiated cells' migration ability was increased (number of cells on the scratched area: 44.61+/-4.34 vs. 40.06+/-2.43, P<0.05), and the ability of forming capillary-like structure was also increased (cells classification: 3.67+/-0.82 vs. 2.00+/-0.89, P<0.01). CONCLUSION: Notch signaling may have an important role during the differentiation of MSCs into endothelial cells. The function of differentiated cells were strengthened when Notch pathway was blocked. PMID- 21672386 TI - [The value of aggressive diuretic therapy in acute decompensated stage of chronic heart failure]. AB - OBJECTIVE: To evaluate both the efficacy, safety, length of stay in hospital and expenses of aggressive diuretic therapy in patients with acute decompensation of chronic heart failure (CHF). METHODS: The retrospective analysis was conducted in the patients with acute decompensation CHF New York Heart Association (NYHA) class III or IV in department of cardiology of Fujian Medical University Union Hospital from January 1st 2006 to September 1st 2007. The 24-hour urine volume on the 2nd day was equivalent or over 2 400 ml was defined as aggressive diuretic therapy group, and those with less than 2 400 ml of urine as non-aggressive diuretic therapy group. The biochemical parameters and vital signs were compared before and after aggressive diuretic therapy, and the mortality, the length of stay and expenses were also compared between the two groups. RESULTS: One hundred and ninety-five patients were enrolled in the study, there were 73 and 122 patients in aggressive diuretic therapy group and in non-aggressive diuretic therapy group respectively. The mortality in aggressive diuretic therapy group was lower than that in non-aggressive diuretic therapy group (1.4% vs. 9.8%, P<0.05). The length of stay, total expenses and average cost in aggressive diuretic therapy group were lower than those in non-aggressive diuretic therapy group respectively [the length of stay: 11 days vs. 16 days; total expenses: 8 483 yuan vs. 12 182 yuan; average expenseI: 721.1 yuan/d vs. 854.4 yuan/d; average expenseII (except for examination expenses): 580.0 yuan/d vs. 698.2 yuan/d, P<0.05 or P<0.01]. There were no significant changes in biochemical parameters and heart rate before and after aggressive diuretic therapy. The systolic pressure (SBP) and diastolic pressure (DBP) were reduced significantly after aggressive diuretic therapy [SBP: (118.2+/-16.9) mm Hg vs. (127.0+/-24.9) mm Hg; DBP: (67.2+/-4.5) mm Hg vs. (75.2+/-4.9) mm Hg, 1 mm Hg=0.133 kPa, P<0.05 and P<0.01]. No hypotension symptoms such as dizziness and chest distress were found in all patients. CONCLUSION: Aggressive diuretic therapy in patients with acute decompensation CHF is a safe, effective mode of therapy. It can reduce the length of stay in hospital, expenses and the mortality during hospitalization. PMID- 21672387 TI - [Diagnostic significance of creatine kinase mass in children with myocardial injury]. PMID- 21672388 TI - [The protective effect of heat shock protein 70 gene transfection on rats with cerebral hypoxia-ischemia]. PMID- 21672389 TI - [Effect of abdominal lifting and compression maneuver for cardiopulmonary resuscitation on ventilation in pigs with respiratory arrest]. PMID- 21672390 TI - [Prognostic value of heart-fatty acid-binding protein for myocardial infarction in early post operative period after off-pump coronary artery bypass grafting]. PMID- 21672391 TI - [Expression of tissue factor in monocytes and plasma during acute phase and recovery stage of patients with myocardial infarction]. PMID- 21672392 TI - [Treatment for a burn patient complicated by diabetes insipidus]. PMID- 21672393 TI - [Wernicke encephalopathy induced by malnutrition in intensive care unit: a report of 1 case]. PMID- 21672394 TI - [Advance in the study of mitochondrial permeability transition pore and a strategy of protection of myocardium against injury]. PMID- 21672395 TI - Fast-food consumption and obesity among Michigan adults. AB - INTRODUCTION: Consumption of meals eaten away from home, especially from fast food restaurants, has increased in the United States since the 1970s. The main objective of this study was to examine the frequency and characteristics of fast food consumption among adults in Michigan and obesity prevalence. METHODS: We analyzed data from 12 questions about fast-food consumption that were included on the 2005 Michigan Behavioral Risk Factor Survey, a population-based telephone survey of Michigan adults, using univariate and bivariate analyses and multivariate logistic regression, and compared these data with data on Michigan obesity prevalence. RESULTS: Approximately 80% of Michigan adults went to fast food restaurants at least once per month and 28% went regularly (>=2 times/wk). Regular fast-food consumption was higher among younger adults (mostly men) but was not significantly associated with household income, education, race, or urbanicity (in a multivariate framework). The prevalence of obesity increased consistently with frequenting fast-food restaurants, from 24% of those going less than once a week to 33% of those going 3 or more times per week. The predominant reason for choosing fast food was convenience. Although hypothetically 68% of adults who go to fast-food restaurants would choose healthier fast-food items when available, only 16% said they ever use nutritional information when ordering. CONCLUSION: The prevalence of fast-food consumption is high in Michigan across education, income, and racial groups and is strongly associated with obesity. Making nutritional information at fast-food restaurants more readily available and easier to use may help consumers to order more healthful or lower calorie items. PMID- 21672396 TI - Playground renovations and quality at public parks in Boston,Massachusetts, 1996 2007. AB - INTRODUCTION: Recreational and transportation infrastructure can promote physical activity among children and adolescents. The Play Across Boston community-based research project sought to estimate and compare playground renovation rates across Boston areas before and after a playground quality assessment, to describe changes in playground quality among a subset of parks, and to document features of local transportation infrastructure around parks. METHODS: We used an observational pretest-posttest design to estimate playground renovation rates among 103 city-operated parks. Renovation rates were calculated on the basis of annual city Parks Department capital budgets from fiscal years 1996 through 2007. We used the same design to describe changes between a 2000 to 2001 baseline assessment of playground quality and a 2007 follow-up measured via observation of a subsample of 18 low-scoring parks in disadvantaged areas. We used chi(2 ) analysis to compare percentages of playgrounds renovated across city areas before and after baseline assessment, logistic regression analysis to calculate odds ratios comparing renovation rates after baseline by city area, and paired t tests to compare playground quality at baseline and follow-up. RESULTS: Overall playground renovation rates before (29%) and after (34%) baseline assessment were similar. Parks scoring low on playground quality at baseline were renovated after baseline at a higher rate than high-scoring playgrounds. After accounting for baseline playground quality, parks in disadvantaged areas were renovated at a rate similar to those in other areas. Playground quality scores improved between baseline (mean, 38.3; 95% confidence interval, 35.3-41.3) and 2007 in a subsample of previously low-scoring parks in disadvantaged areas. CONCLUSION: The findings of the 2007 follow-up assessment indicate an equitable rate of playground renovation across city areas according to need. PMID- 21672397 TI - Awareness of racial and socioeconomic health disparities in the United States: the national opinion survey on health and health disparities, 2008-2009. AB - INTRODUCTION: Recent initiatives aim to improve public awareness of health disparities. However, little research has actually documented the US public's awareness of racial/ethnic and socioeconomic health disparities. We sought to determine 1) whether the US public is aware of racial, educational, and income disparities in health, 2) whether awareness differs across these disparity domains, and 3) what respondent characteristics are associated with awareness of racial, educational, and income disparities in health. METHODS: We conducted the National Opinion Survey on Health and Health Disparities with 2,791 US adults. We asked respondents to answer questions about disparities in health between 1 of several pairs of population subgroups: African Americans versus whites, non-high school graduates versus high school graduates, high school graduates versus college graduates, the poor versus the middle class, or the middle class versus the rich. We used chi(2) tests and logistic regression to compare correlates of respondents' awareness of disparities across the different pairs of population subgroups. RESULTS: Most respondents were aware of health disparities between the poor and middle class (73%); fewer were aware of health disparities between African Americans and whites (46%). Although respondents recognized that education is associated with many positive life outcomes, they were less aware of the link between education and health. Respondents who were younger, less educated, lower-income, healthier, or politically conservative were less likely to be aware of health disparities. CONCLUSION: Public awareness of disparities in health differs depending on both the type of disparity and the characteristics of the individual respondent. PMID- 21672398 TI - Effect of school district policy change on consumption of sugar-sweetened beverages among high school students, Boston, Massachusetts, 2004-2006. AB - INTRODUCTION: Consumption of sugar-sweetened beverages has increased among youth in recent decades, accounting for approximately 13% of total calories consumed. The Boston Public Schools passed a policy restricting sale of sugar-sweetened beverages in Boston schools in June 2004. The objective of this study was to determine whether high school students' consumption of sugar-sweetened beverages declined after this new policy was implemented. METHODS: We conducted a quasi experimental evaluation by using data on consumption of sugar-sweetened beverages by public high school students who participated in the Boston Youth Survey during February through April 2004 and February through April 2006 (N = 2,033). We compared the observed change with national trends by using data from the 2003 2004 and 2005-2006 National Health and Nutrition Examination Survey (NHANES). Regression methods were adjusted for student demographics. RESULTS: On average, Boston's public high school students reported daily consumption of 1.71 servings of sugar-sweetened beverages in 2004 and 1.38 servings in 2006. Regression analyses showed significant declines in consumption of soda (-0.16 servings), other sugar-sweetened beverages (-0.14 servings), and total sugar-sweetened beverages (-0.30 servings) between 2004 and 2006 (P < .001 for all). NHANES indicated no significant nationwide change in adolescents' consumption of sugar sweetened beverages between 2003-2004 and 2005-2006. DISCUSSION: Data from Boston youth indicated significant reductions in consumption of sugar-sweetened beverages, which coincided with a policy change restricting sale of sugar sweetened beverages in schools. Nationally, no evidence was found for change in consumption of sugar-sweetened beverages among same-aged youth, indicating that implementing policies that restrict the sale of sugar-sweetened beverages in schools may be a promising strategy to reduce adolescents' intake of unnecessary calories. PMID- 21672399 TI - A qualitative examination of the role of small, rural worksites in obesity prevention. AB - INTRODUCTION: The prevalence of overweight and obesity in the United States is highest in rural counties. We explored social support, policies, and programmatic resources that encourage more healthful diets and participation in physical activity among employees of small, rural worksites. METHODS: We conducted in depth interviews with 33 employed adults aged 50 years or older in rural Georgia about access to healthful foods and opportunities for physical activity at work; conversations about exercise, weight loss, and eating healthfully in general; and worksite nutrition and physical activity programs; and we asked for suggestions for making the worksite more healthful. The research team developed a codebook, and 2 coders coded each transcript. Data were analyzed and reports were generated for thematic analyses. RESULTS: Participants from rural worksites, most with fewer than 50 employees, cited lack of vending machines and cafeterias, health promotion programs to address healthful eating and exercise, and facilities for physical activity as barriers to eating healthfully and engaging in physical activity at work. Many participants reported conversations with coworkers about how to eat more healthfully by making more nutritious choices or preparing food more healthfully. Participants also discussed the importance of engaging in physical activity on their own and gave suggestions on ways to incorporate exercise into their routines. Participants' access to healthful foods at work varied, but barriers such as being too busy, worksite location, and no worksite cafeteria were noted. Some workers reported engaging in physical activity at work, and others reported a heavy workload and lack of time as barriers. CONCLUSION: Building on the social environment and implementing policies for healthful eating and participation in physical activity may help address obesity prevention in rural workplaces. PMID- 21672400 TI - Risks to health among American Indian/Alaska Native high school students in the United States. AB - INTRODUCTION: According to the World Health Organization, the 10 leading risk factor causes of death in high-income countries are tobacco use, high blood pressure, overweight and obesity, physical inactivity, high blood glucose, high cholesterol, low fruit and vegetable intake, urban air pollution, alcohol use, and occupational risks. We examined the prevalence of some of the leading risks to health among nationally representative samples of American Indian/Alaska Native (AI/AN) high school students and compared rates across racial/ethnic groups. METHODS: We combined data from the 2001, 2003, 2005, 2007, and 2009 national Youth Risk Behavior Survey. The survey is a biennial, self-administered, school-based survey of 9th- through 12th-grade students in the United States. Overall response rates for the surveys ranged from 63% to 72%. Of 73,183 participants, 952 were AI/AN students. RESULTS: For 7 of the 16 variables examined in this study, the prevalence among AI/AN high school students was higher than the prevalence among white high school students. For 1 variable (ate fruit and vegetables <5 times per day), the prevalence among AI/AN students was significantly lower than that among white students. The prevalence for the remaining 8 variables was similar among AI/AN students and white students. These findings also show differences in the prevalence of some behaviors among AI/AN, black, and Hispanic students. CONCLUSION: These findings show the prevalence of some health risk behaviors was significantly higher among AI/AN high school students than among high school students in other racial/ethnic groups. PMID- 21672401 TI - Clean indoor air regulation and incidence of hospital admissions for acute coronary syndrome in Kanawha County, West Virginia. AB - INTRODUCTION: Secondhand smoke is a risk factor for coronary heart disease. Laws and regulations prohibiting smoking in public areas and workplaces can reduce rates of acute myocardial infarction. Our objective was to describe hospital admission rates for acute coronary events, based on smoking status, diabetes status, and sex, in the presence of a long-standing (2000-2008) county clean indoor air regulation (CIAR). We also examined the effect of making restaurants completely smoke-free. METHODS: We obtained hospital admission data for acute coronary syndrome (ACS) and acute myocardial infarction from all acute care hospitals serving Kanawha County, West Virginia, for 2000 through 2008. A CIAR was enacted in 1995 and revised in 2000 and 2003. We performed descriptive analyses on hospital admission rates of ACS over time and present these data by sex, age group, smoking status, and medical history of diabetes. RESULTS: The incidence of hospital admissions for ACS consistently declined during the period studied. This change was most pronounced among nonsmokers, people without diabetes, and women, compared with their respective counterparts. Similar benefits occurred for male smokers when the CIAR was revised to make restaurants completely smoke-free in 2004. CONCLUSION: In the presence of a CIAR, a consistent decline in incidence of hospital admissions for ACS can be demonstrated. However, the benefits derived may be disproportionately affected by smoking status, diabetes status, and sex. PMID- 21672402 TI - Racial/ethnic and socioeconomic disparities in health-related quality of life among people with coronary heart disease, 2007. AB - INTRODUCTION: Health-related quality of life (HRQOL) refers to a person's or group's perceived physical and mental health over time. Coronary heart disease (CHD) affects HRQOL and likely varies among groups. This study examined disparities in HRQOL among adults with self-reported CHD. METHODS: We examined disparities in HRQOL by using the unhealthy days measurements among adults who self-reported CHD in the 2007 Behavioral Risk Factor Surveillance System state based telephone survey. CHD was based on self-reported medical history of heart attack, angina, or coronary heart disease. We assessed differences in fair/poor health status, 14 or more physically unhealthy days, 14 or more mentally unhealthy days, 14 or more total unhealthy days (total of physically and mentally unhealthy days), and 14 or more activity-limited days. Multivariate logistic regression models included age, race/ethnicity, sex, education, annual household income, household size, and health insurance coverage. RESULTS: Of the population surveyed, 35,378 (6.1%) self-reported CHD. Compared with non-Hispanic whites, Native Americans were more likely to report fair/poor health status (adjusted odds ratio [AOR], 1.7), 14 or more total unhealthy days (AOR, 1.6), 14 or more physically unhealthy days (AOR, 1.7), and 14 or more activity-limited days (AOR, 1.9). Hispanics were more likely than non-Hispanic whites to report fair/poor health status (AOR, 1.5) and less likely to report 14 or more activity-limited days (AOR, 0.5), and Asians were less likely to report 14 or more activity limited days (AOR, 0.2). Non-Hispanic blacks did not differ in unhealthy days measurements from non-Hispanic whites. The proportion reporting 14 or more total unhealthy days increased with increasing age, was higher among women than men, and was lower with increasing levels of education and income. CONCLUSION: There are sex, racial/ethnic, and socioeconomic disparities in HRQOL among people with CHD. Tailoring interventions to people who have both with CHD and poor HRQOL may assist in the overall management of CHD. PMID- 21672403 TI - Geographic and sociodemographic disparities in drive times to Joint Commission certified primary stroke centers in North Carolina, South Carolina, and Georgia. AB - INTRODUCTION: Timely access to facilities that provide acute stroke care is necessary to reduce disabilities and death from stroke. We examined geographic and sociodemographic disparities in drive times to Joint Commission-certified primary stroke centers (JCPSCs) and other hospitals with stroke care quality improvement initiatives in North Carolina, South Carolina, and Georgia. METHODS: We defined boundaries for 30- and 60-minute drive-time areas to JCPSCs and other hospitals by using geographic information systems (GIS) mapping technology and calculated the proportions of the population living in these drive-time areas by sociodemographic characteristics. Age-adjusted county-level stroke death rates were overlaid onto the drive-time areas. RESULTS: Approximately 55% of the population lived within a 30-minute drive time to a JCPSC; 77% lived within a 60 minute drive time. Disparities in percentage of the population within 30-minute drive times were found by race/ethnicity, education, income, and urban/rural status; the disparity was largest between urban areas (70% lived within 30-minute drive time) and rural areas (26%). The rural coastal plains had the largest concentration of counties with high stroke death rates and the fewest JCPSCs. CONCLUSION: Many areas in this tri-state region lack timely access to JCPSCs. Alternative strategies are needed to expand provision of quality acute stroke care in this region. GIS modeling is valuable for examining and strategically planning the distribution of hospitals providing acute stroke care. PMID- 21672404 TI - Forecasting diabetes prevalence in California: a microsimulation. AB - INTRODUCTION: Setting a goal for controlling type 2 diabetes is important for planning health interventions. The purpose of this study was to explore what may be a feasible goal for type 2 diabetes prevention in California. METHODS: We used the UCLA Health Forecasting Tool, a microsimulation model that simulates individual life courses in the population, to forecast the prevalence of type 2 diabetes in California's adult population in 2020. The first scenario assumes no further increases in average body mass index (BMI) for cohorts entering adolescence after 2003. The second scenario assumes a gradual BMI decrease for children entering adolescence after 2010. The third scenario builds on the second by extending the same BMI decrease to people aged 12 to 65 years. The fourth scenario builds on the third by eliminating racial/ethnic disparities in physical activity. RESULTS: We found the predicted diabetes prevalence of the first, second, third, and fourth scenarios in 2020 to be 9.93%, 9.91%, 9.76%, and 9.77%, respectively. We found obesity prevalence for type 2 diabetes patients in 2020 to be 34.2%, 34.0%, 25.7%, and 25.6% for the 4 scenarios. Life expectancy in the third (80.56 y) and fourth (80.94 y) scenarios compared favorably with that of the first (80.32 y) and second (80.32 y) scenarios. CONCLUSION: For the next 10 years, behavioral risk factor modifications are more likely to affect obesity prevalence and life expectancy in the general population and obesity prevalence among diabetic patients than to alter type 2 diabetes prevalence in the general population. We suggest setting more specific goals for reducing the prevalence of diabetes, such as reducing obesity-related diabetes complications, which may be more feasible and easier to evaluate than the omnibus goal of lowering overall type 2 diabetes prevalence by 2020. PMID- 21672405 TI - Effects of a behavior-based weight management program delivered through a state cooperative extension and local public health department network, North Carolina, 2008-2009. AB - INTRODUCTION: Eat Smart, Move More, Weigh Less (ESMMWL) is an adult weight management program developed in response to North Carolina Obesity Plan recommendations to make weight management interventions accessible to underserved populations. ESMMWL was designed to be delivered through the North Carolina Cooperative Extension and North Carolina Division of Public Health. Program coursework included content on evidence-based eating and physical activity behaviors and incorporated mindful eating concepts. The objectives of this study were to describe participant changes in weight and behaviors and to document the effectiveness of the program. METHODS: In this prospective pilot study, courses were delivered and data collected from January 2008 through June 2009. Instructors provided feedback about implementation. For participants, height, weight, and waist circumference were measured at baseline and completion. Participants completed a questionnaire about changes in their eating and physical activity behaviors, changes in their confidence to engage in weight management behaviors, and their satisfaction with the course. RESULTS: Seventy-nine instructors delivered 101 ESMMWL courses in 48 North Carolina counties. Most of the 1,162 completers were white women. Approximately 83% reported moving toward or attaining their goal. The average weight loss was 8.4 lb. Approximately 92% reported an increase in confidence to eat healthfully, and 82% reported an increase in confidence to be physically active. Instructors made suggestions for program standardization. CONCLUSION: This study demonstrated the effectiveness, diffusion, and implementation of a theoretically based weight management program through a state extension and local public health department network. Study of the sustainability of changes in eating and physical activity behaviors is needed. PMID- 21672406 TI - Associations between colorectal cancer screening and glycemic control in people with diabetes, Boston, Massachusetts, 2005-2010. AB - INTRODUCTION: Recent studies indicate an increased risk of colorectal cancer in people with diabetes. However, people with diabetes may have lower colorectal cancer screening rates than people without diabetes. Few data are available regarding factors associated with lack of screening for people with diabetes. Our objective was to describe factors associated with lack of timely colorectal cancer screening in people with diabetes. METHODS: We examined an electronic medical record database with more than 6,000 patients aged 50 years or older who had diabetes and were seen in a large hospital system in Boston, Massachusetts. We compared patients who had received timely colorectal cancer screening with those who had not on several variables, including glycemic control, expressed as average hemoglobin A1c (HbA1c). Bivariate analyses were performed using chi(2) and t tests for means when applicable. Logistic regression was used to determine the independent association of variables with lack of screening. RESULTS: Patients with poor glycemic control (average HbA1c >8.5%) were more likely not to have been screened for colorectal cancer than those with good glycemic control, even after adjusting for the number of primary care visits. Patients with fewer than 20 primary care visits in 5 years were more likely not to have been screened than those with more visits. CONCLUSION: Glycemic control appears to be independently associated with the likelihood of colorectal cancer screening. People with poorly controlled diabetes should be targeted in future research and individual patient care. PMID- 21672407 TI - An observational study of the secondary effects of a local smoke-free ordinance. AB - INTRODUCTION: The secondary, sometimes unintended effects of smoke-free ordinances have not been thoroughly evaluated. In this observational study, we evaluated the association of a local ordinance implemented in Madison, Wisconsin, with changes in public disturbances; smoking, drinking, and bar-going behaviors in the general population; and smoking and drinking behaviors among university students. METHODS: We obtained data from 4 sources: police records, key informant interviews, a community survey, and an undergraduate survey. Except for interviews, which we conducted postenactment only, we compared measures before and after the ordinance was put into effect. RESULTS: We found no evidence of association of the ordinance with public disturbances. We found that the ordinance was not associated with changes in smoking rates, drinking rates, or bar-going in the general population, although bar-going decreased among the 16% of the general adult population who smokes (from 84% in 2005 to 70% in 2007, P < .001). Student smoking rates also decreased (from 23% in 2005 to 16% in 2007, P < .001), but student binge drinking did not change. CONCLUSION: The study adds unique information to the evidence base on the effect of smoke-free policies, finding little evidence of their secondary, unintended effects. With the addition of these results to existing evidence, we conclude that the potential health benefits of smoke-free ordinances outweigh the potential harms from unintended effects. PMID- 21672408 TI - Smoking and visual impairment among older adults with age-related eye diseases. AB - INTRODUCTION: Tobacco use is the leading preventable cause of death in the United States. Visual impairment, a common cause of disability in the United States, is associated with shorter life expectancy and lower quality of life. The relationship between smoking and visual impairment is not clearly understood. We assessed the association between smoking and visual impairment among older adults with age-related eye diseases. METHODS: We analyzed Behavioral Risk Factor Surveillance System data from 2005 through 2008 on older adults with age-related eye diseases (cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy; age >=50 y, N = 36,522). Visual impairment was defined by self reported difficulty in recognizing a friend across the street or difficulty in reading print or numbers. Current smokers were respondents who reported having smoked at least 100 cigarettes ever and still smoked at the time of interview. Former smokers were respondents who reported having ever smoked at least 100 cigarettes but currently did not smoke. We used multivariate logistic regressions to examine the association and to adjust for potential confounders. RESULTS: Among respondents with age-related eye diseases, the estimated prevalence of visual impairment was higher among current smokers (48%) than among former smokers (41%, P < .05) and respondents who had never smoked (42%, P < .05). After adjustment for age, sex, race/ethnicity, education, and general health status, current smokers with age-related eye diseases were more likely to have visual impairment than respondents with age-related eye diseases who had never smoked (odds ratio, 1.16, P < .05). Furthermore, respondents with cataract who were current smokers were more likely to have visual impairment than respondents with cataract who had never smoked (predictive margin, 44% vs 40%, P = .03), and the same was true for respondents with age-related macular degeneration (65% of current smokers vs 57% of never smokers, P = .02). This association did not hold true among respondents with glaucoma or diabetic retinopathy. CONCLUSION: Smoking is linked to self-reported visual impairment among older adults with age-related eye diseases, particularly cataract and age-related macular degeneration. Longitudinal evaluation is needed to assess smoking cessation's effect on vision preservation. PMID- 21672409 TI - Using small-area estimation method to calculate county-level prevalence of obesity in Mississippi, 2007-2009. AB - INTRODUCTION: Obesity is one of Mississippi's pressing public health problems. Since 2005, the state has ranked first in the nation in adult obesity prevalence. For authorities to take targeted action against the obesity epidemic, counties, regions, and subpopulations that are most affected by obesity need to be identified. The objective of this study was to assess the scope, socioeconomic and geographic characteristics, and temporal trends of the obesity epidemic in Mississippi. METHODS: Using 2007-2009 Mississippi Behavioral Risk Factor Surveillance System data and auxiliary data, we applied a small-area estimation method to estimate county-level obesity prevalence in 2007 through 2009, to assess the association between obesity and socioeconomic factors and to evaluate temporal trends. We determined geographic patterns by mapping obesity prevalence. We appraised the precision of estimates by the width of 95% confidence intervals, and we validated our small-area estimates by comparing them with direct estimates. RESULTS: In 2009, the county prevalence of obesity ranged from 30.5% to 44.2%. Counties with the highest prevalence of obesity were in the Delta region and along the Mississippi River. The obesity prevalence increased from 2007 through 2009. Age, sex, race, education, and employment status were associated with obesity. CONCLUSION: The 2009 obesity prevalence in all Mississippi counties was substantially higher than the national average and differed by geography and race. Although urgent intervention measures are needed in the entire state, policies and programs giving higher priority to higher-risk areas and subpopulations identified by this study may be better strategies. PMID- 21672410 TI - Chronic disease surveillance systems within the US Associated Pacific Island jurisdictions. AB - In recent years, illness and death due to chronic disease in the US Associated Pacific Islands (USAPI) jurisdictions have dramatically increased. Effective chronic disease surveillance can help monitor disease trends, evaluate public policy, prioritize resource allocation, and guide program planning, evaluation, and research. Although chronic disease surveillance is being conducted in the USAPI, no recently published capacity assessments for chronic disease surveillance are available. The objective of this study was to assess the quality of existing USAPI chronic disease data sources and identify jurisdictional capacity for chronic disease surveillance. The assessment included a chronic disease data source inventory, literature review, and review of surveillance documentation available from the web or through individual jurisdictions. We used the World Health Organization's Health Metric Network Framework to assess data source quality and to identify jurisdictional capacity. Results showed that USAPI data sources are generally aligned with widely accepted chronic disease surveillance indicators and use standardized data collection methodology to measure chronic disease behavioral risks, preventive practices, illness, and death. However, all jurisdictions need to strengthen chronic disease surveillance through continued assessment and expanded support for valid and reliable data collection, analysis and reporting, dissemination, and integration among population-based and institution-based data sources. For sustained improvement, we recommend investment and technical assistance in support of a chronic disease surveillance system that integrates population-based and institution-based data sources. An integrated strategy that bridges and links USAPI data sources can support evidence-based policy and population health interventions. PMID- 21672411 TI - The role of state health departments in supporting community-based obesity prevention. AB - BACKGROUND: Recent national attention to obesity prevention has highlighted the importance of community-based initiatives. State health departments are in a unique position to offer resources and support for local obesity prevention efforts. COMMUNITY CONTEXT: In North Carolina, one-third of children are overweight or obese. North Carolina's Division of Public Health supports community-based obesity prevention by awarding annual grants to local health departments, providing ongoing training and technical assistance, and engaging state-level partners and resources to support local efforts. METHODS: The North Carolina Division of Public Health administered grants to 5 counties to implement the Childhood Obesity Prevention Demonstration Project; counties simultaneously carried out interventions in the community, health care organizations, worksites, schools, child care centers, and faith communities. OUTCOME: The North Carolina Division of Public Health worked with 5 local health departments to implement community-wide policy and environmental changes that support healthful eating and physical activity. The state health department supported this effort by working with state partners to provide technical assistance, additional funding, and evaluation. INTERPRETATION: State health departments are well positioned to coordinate technical assistance and leverage additional support to increase the strength of community-based obesity prevention efforts. PMID- 21672412 TI - Warning signs observed in tanning salons in New York City: implications for skin cancer prevention. AB - Use of artificial tanning may be contributing to the increased incidence of skin cancer. Federal law requires warning signs to inform consumers about health risks. All of the tanning facilities in New York City were assessed for compliance with this law during April and May 2010. More than one-third of the 224 tanning machines observed in 47 of the 85 facilities visited did not have any warning signs posted, and signs were difficult to see in many others. PMID- 21672413 TI - The minigrant model: a strategy to promote local implementation of state cancer plans in Appalachian communities. AB - East Tennessee State University (ETSU) was awarded a grant through an interagency agreement between the Centers for Disease Control and Prevention and the Appalachian Regional Commission to promote cancer control activities between state comprehensive cancer control (CCC) coalitions and local Appalachian communities. We invited representatives from CCC coalitions and Appalachian communities to a forum to develop a plan of action. The attendees recommended a minigrant model that uses a request for proposals (RFP) strategy to encourage CCC coalitions and Appalachian communities to collaboratively conduct forums and roundtables locally. They set criteria to guide the development of the RFPs and the agendas for the roundtables and forums that ensured new communication and collaboration between the CCC coalitions and the Appalachian communities. We established the roundtable agenda to focus on the presentation and discussion of state and local Appalachian community cancer risk, incidence, and death rates and introduction of state cancer plans. The forums had a more extensive agenda to present cancer data, describe state cancer plans, and describe successful cancer control programs in local Appalachian communities. This article describes the ETSU minigrant model that supports forums and roundtables and reports how this strategy improves cooperative partnerships between CCC coalitions and Appalachian communities in the local implementation of state cancer plans in Appalachia. PMID- 21672414 TI - Getting serious about the prevention of chronic diseases. PMID- 21672415 TI - [Relationship between plasma levels of vasoactive intestinal peptide and feeding intolerance in preterm infants]. AB - OBJECTIVE: To study the changes of plasma vasoactive intestinal peptide (VIP) levels and the relationship of plasma VIP levels with feeding intolerance (FI) in preterm infants. METHODS: Plasma VIP concentrations were measured using radioimmunoassay in 53 preterm infants with FI 1, 4, 7 and 14 days after birth. Fifty-nine preterm infants without FI served as the control group. RESULTS: The fasting plasma concentrations of VIP in the FI group 1, 4 and 7 days after birth (129 +/- 46, 144 +/- 32 and 166 +/- 31 pg/mL respectively) were significantly lower than those in the control group (195 +/- 63, 197 +/- 31 and 205 +/- 34 pg/mL respectively) (P<0.05). The increased plasma VIP concentrations were associated with the increased gestational age, age in days and enteral feeding volume in the FI group. By 14 days, the plasma concentrations of VIP in the FI group (198 +/- 41 pg/mL) were similar to those in the control group (202 +/- 48 pg/mL) (P>0.05). The younger the infant's gestational age, the more prolonged the FI. Plasma levels of VIP on day 1 of life in the FI group were negatively correlated with the duration of FI (r=-0.799, P<0.05). CONCLUSIONS: Plasma levels of VIP might be related to the development of FI in preterm infants and might serve as a predictor of FI. PMID- 21672416 TI - [Causes of hematochezia in exclusively breast fed infants]. AB - OBJECTIVE: To investigate the causes of haematochezia in exclusively breast fed infants. METHODS: Seventy-five babies presenting with haematochezia were enrolled. These babies were exclusively breast fed. The age of haematochezia occurrence, concomitant symptoms and laboratory findings (including routine blood test, routine stool test, liver function, stool culture, colonoscopy and histological examination) were recorded. The mothers of the 75 babies were given a diet without animal and floristic proteins for four weeks. The symptoms of haematochzia in the babies were observed after maternal protein-free diets. RESULTS: Haematochezia occurred at an average age of 7.4 weeks. Diarrhea was the most common concomitant symptom (71%). The laboratory testing showed that mild anaemia was the most common (60%). Red cells and white cells were found in the routine stool test. Stool culture was negative. Colonitis was proved through colonoscopy. Twenty babies underwent histological examinations and eosinophilia was noted. Gross hematochezia disappeared 72-96 hrs after maternal protein-free diets. CONCLUSIONS: Exclusively breast fed infants may be sensitive to protein taken by their mothers and may appear with haematochazia. PMID- 21672417 TI - [An epidemiologic investigation of newborns from obstetric departments in the central south region of China]. AB - OBJECTIVE: To investigate the birth information of newborn infants from obstetric departments in the Central South Region of China. METHODS: A retrospective investigation was carried out in 15582 newborns from obstetric departments of 23 hospitals in the Central South Region of China between January 1 and December 31 of 2005. RESULTS: The sex ratio (male/female) of neonates was 1.16?1. The proportion of preterm infants was 8.11%. The very low birth weight infants accounted for 0.73%. The neonates born by spontaneous labor accounted for 57.52%. Cesarean sections accounted for 40.82% (social factor of cesarean section: 29.91%). The incidence of neonatal asphyxia was 3.78%, in which 0.75% of the cases were severe asphyxia. The mortality of newborn infants was 0.55%, in which the mortality of preterm infants was 5.56%. CONCLUSIONS: The proportion of preterm infants and the incidence of neonatal asphyxia is high in the Central South Region of China. The proportion of births delivered by cesarean section is high, and social factors are probably responsible for the high rate. PMID- 21672418 TI - [Prevalence of astigmatism in 2023 children with amblyopia]. AB - OBJECTIVE: To investigate the prevalence, type and distribution of astigmatism in children with amblyopia. METHODS: A total of 2023 children with amblyopia (aged 4 11 years, 3657 eyes) were recruited. The prevalence of astigmatism was investigated. RESULTS: Of the 3657 amblyopic eyes, 91.9% presented astigmatism (>=0.5 D). The proportion of eyes with astigmatism decreased with the increasing age. Compound hyperopic astigmatism was the most common type of astigmatism (38.8%) and its prevalence increased with the increasing age in children with amblyopia. Astigmatism with the rule was the most common (90.1%) in the axial distribution test. There were statistical significances in the axial distribution of astigmatism in different age groups. Statistical significances were also found in the degree, type and axis of astigmatism among the children with mild, moderate and severe amblyopia (P<0.05). CONCLUSIONS: The prevalence of astigmatism in children with amblyopia is high but is reduced with age. The age and the degree of amblyopia might be influential factors in the distribution of astigmatism. PMID- 21672419 TI - [Correlation between blood T-cell receptor rearrangement excision circles levels and severe infection in children with acute lymphoblastic leukemia]. AB - OBJECTIVE: This study quantitatively examined signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels in peripheral blood of children with acute lymphoblastic leukemia (ALL) at different stages in order to evaluate the role of sjTRECs in predicting severe infection postchemotherapy. METHODS: sjTRECs levels in peripheral blood were measured by fluorescent quantitation polymerase chain reaction in 30 children with newly diagnosed ALL, 36 children with ALL who accepted chemotherapy but were not infected, 30 children with ALL who had severe infection after chemotherapy, and 50 normal children. RESULTS: Blood sjTRECs levels in the normal group (394 +/- 270 copies/103 MNC) were significantly higher than those in the other three groups (P<0.05). Blood sjTRECs levels in the chemotherapy group without infection (96 +/- 78 copies/103 MNC) were significantly lower than those in the newly diagnosed ALL group (210 +/- 219 copies/103 MNC) (P<0.05). The chemotherapy group with severe infection showed the lowest blood sjTRECs levels (48 +/- 40 copies/103 MNC) in the four groups. CONCLUSIONS: The measurement of blood sjTRECs levels might be helpful for predicting the occurrence of severe infection postchemotherapy in children with ALL. PMID- 21672420 TI - [Mobilization and collection of autologous peripheral blood stem cells by CIE or IEV protocol in children with malignant solid tumors]. AB - OBJECTIVE: Autologous peripheral blood stem cell transplantation (APBSCT) is an important method for treatment of malignant solid tumors in children. The mobilization and collection of blood stem cells is crucial for APBSCT. This study aimed to evaluate the clinical efficacy of mobilization and collection of blood stem cells by CIE or IEV chemotherapy protocol in APBSCT in children with neuroblastoma (NB) or rhabdomyosarcoma. METHODS: The protocols of CIE (cisplatin, etoposide) and IEV (vincristine, dosfamide, etoposide) were used as mobilization chemotherapy in 8 cases of NB with stage IV and 3 cases of rhabdomysacoma with stage III, respectively. The results of the mobilization of blood stem cells were observed. RESULTS: Of the 11 cases, mononuclear cells (MNC) and CD34+ cells were successfully collected and the volume of MNC and CD34 averaged (5.55 +/- 1.43)* 10(8)/kg and (4.88 +/- 2.48) * 10(6)/kg, respectively. No severe complications were observed during the mobilization and collection. A rapid hemopoietic reconstitution was observed in 10 children after APBSCT. One with NB out of the 10 children died of left heart failure 32 days after APBSCT. Others (9 cases) showed a nearly normal result of routine peripheral blood test 60 days after APBSCT. CONCLUSIONS: CIE or IEV protocol is effective and safe for the mobilization and collection of peripheral blood stem cells in children with NB or rhabdomysacoma. PMID- 21672421 TI - [Correlation between the ratio of serum vascular endothelial growth factor/endostatin and childhood acute leukemia]. AB - OBJECTIVE: To investigate the correlation between the ratio of serum vascular endothelial growth factor (VEGF)/endostatin (ES) and childhood acute leukemia(AL). METHODS: Serum levels of VEGF and ES were measured using ELISA in 35 children with acute AL before and after chemotherapy. The ratio of VEGF/ES was calculated. Thirty healthy children served as the control group. RESULTS: The serum levels of VEGF (196 +/- 66 pg/mL vs 29 +/- 10 pg/mL) and ES (35 +/- 7 ng/mL vs 19 +/- 4 ng/mL) in the AL group before chemotherapy were significantly higher than those in the control group (P<0.01). The ratio of VEGF/ES in the AL group before chemotherapy was significantly higher than that in the control group (6.7 +/- 3.0 vs 1.6 +/- 0.7; P<0.01). In 20 children with AL who achieved complete remission, the serum levels of VEGF and ES and the VEGF/ES ratio were reduced after chemotherapy (83 +/- 35 pg/mL, 27 +/- 5 ng/mL, 3.1 +/- 1.3, respectively; P<0.01), although the serum levels of VEGF and ES were still higher than those in the control group (P<0.01). The VEGF/ES ratio in CR patients was not significantly different from that in the control group. The serum levels of VEGF (r=0.301, P=0.045) and the VEGF/ES ratio (r=0.411, P=0.015) were positively correlated with the count of blast cells in juvenile bone marrow in 35 children with AL before chemotherapy. CONCLUSIONS: Serum VEGF and ES levels are associated with the development of childhood AL. The VEGF/ES ratio can be used to evaluate the disease progression in children with AL. PMID- 21672422 TI - [Expression of COL9A1 gene and its polymorphism in children with idiopathic congenital talipes equinovarus]. AB - OBJECTIVE: COL9A1 gene is located in the susceptibility region of idiopathic congenital talipes equinovarus (ICTEV) (6q12-13). This study aimed to investigate the expression of the COL9A1 gene and the distribution of single nucleotide polymorphism (SNP) of COL9A1 gene in patients with ICTEV and normal controls. METHODS: Immunohistochemistry was used to detect the expression of COL9A1 in 25 children with ICTEV and 5 normal controls. The frequencies of genotypes and allele of two SNPs in COL9A1 gene rs35470562 and rs1135056 were investigated by PCR-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing in 118 patients with ICTEV and 100 normal controls. RESULTS: The COL9A1 protein expression was significantly higher in 22 (88%) out of 25 children with ICTEV than normal controls. There were significant differences in the frequencies of genotypes and allele of rs1135056 in COL9A1 gene between the ICTEV and the control groups: the G allele frequency was higher, the frequency of AA genotype was lower, and the frequencies of AG and GG genotypes were higher in ICTEV patients than those in healthy controls (P<0.05). CONCLUSIONS: COL9A1 protein is highly expressed in patients with ICTEV and rs1135056, which is located in the coding region of COL9A1 gene, may be associated with the pathogenesis of ICTEV. PMID- 21672423 TI - [Changes of regulatory T cells and T helper cells in peripheral blood and their roles in the severity evaluation in children with asthma]. AB - OBJECTIVE: To investigate the changes of CD4+CD25+Foxp3+ regulatory T cells (Treg) and T helper cells (Th1/Th2) in peripheral blood and their roles in the severity evaluation in children with asthma. METHODS: One hundred and fifty children with asthma were classified into acute attack (94 cases) and remission (56 cases) groups according to their clinical features, and the acute attack children were subdivided into mild asthma (54 cases) and severe asthma (40 cases) groups. Fifty healthy children were enrolled as a control group. The levels of CD4+CD25+Foxp3+ Treg, CD4+IFN-gamma+ Th1 and CD4+IL-4+ Th2 in peripheral blood were measured by flow cytometer. RESULTS: The mean levels of CD4+CD25+Foxp3+ Treg and the ratio of Th1/Th2 in asthmatic children were lower than those in the control group (P<0.01). The Treg levels and the ratio of Th1/Th2 in the acute attack group were lower than those in the remission group and in the control group (P<0.01). The Treg levels in the severe asthma group were lower than those in the mild asthma group (P<0.01). There was a remarkably negative correlation between Treg levels and the asthma severity (r=-0.737, P<0.01), and the Th1/Th2 ratio was also negatively correlated with the asthma severity (r=-0.615, P<0.01). The Treg levels were positively correlated with the Th1/Th2 ratio (r=0.856, P<0.01). CONCLUSIONS: The Treg levels decrease remarkably and Th subsets imbalance occurs in children with asthma. This suggests that Treg and Th immunity play important roles in the pathogenesis of asthma. The Treg levels and the ratio of Th1/Th2 in peripheral blood may be useful in the evaluation of severity in children with asthma. PMID- 21672424 TI - [Correlation between pneumonia and meteorological factors in children from Hohhot]. AB - OBJECTIVE: To study the correlation between the morbidity of pneumonia and meteorological factors in children from Huhhot, in order to provide a basis to prevent and decrease the morbidity of childhood pneumonia. METHODS: A total of 5087 hospitalized children with pneumonia from Huhhot between January 2004 and December 2009 were enrolled. The Circular Distribution method was applied to analyze the seasonal characteristics of the morbidity of pneumonia. The Linear Stepwise Regression Analysis was applied to investigate the relationship between the morbidity of childhood pneumonia and meteorological factors. RESULTS: The morbidity of childhood pneumonia displayed an obvious seasonal trend. Childhood pneumonia was common in winter and spring and its peak morbidity was noted in March. The higher morbidity of pneumonia was related to low air temperature, high air pressure, low precipitation, low humidity and high wind velocity. CONCLUSIONS: Meteorological factors affect the morbidity of childhood pneumonia in Hohhot, and should be considered in the prevention of the disease. PMID- 21672425 TI - [Evaluation of early monitoring of cardiotoxicity induced by anthracyclines]. AB - OBJECTIVE: Anthracyclines (ANT) are effective for leukemia and solid tumors. However the long-term life quality of patients is seriously affected by ANT related cardiotoxicity. The aim of this study was to evaluate the value of two dimension echocardiography (2DE) and serum biochemical indicators in monitoring ANT-related cardiotoxicity. METHODS: Seventy children who received ANT chemotherapy (ANT dose: 124 +/- 73 mg/m2) and were followed up for 22 +/- 13 months were enrolled. 2DE with aspects of conventional indexes (left ventricular diameter and wall thickness, ejection fraction, E/A), myocardial performance index (MPI) and tissue Doppler imaging (TDI) were performed. Serum levels of troponin (CTnI) and brain natriuretic peptide (BNP) were measured. Thirty-seven healthy children served as the control group. RESULTS: There were no significant differences in conventional indexes of 2DE between the ANT and the control groups. The MPI of left and right ventricular in the ANT group increased significantly compared with that in the control group (0.237 +/- 0.06 vs 0.203 +/ 0.06, 0.171 +/- 0.05 vs 0.140 +/- 0.04 respectively; P<0.01). TDI showed the late diastolic peak velocity in the basal and middle sections of left ventricular, interventricular septum and right ventricular in the ANT group were significantly higher than the controls. There were significant differences in the ratio of early to late diastolic peak velocity of the middle section of left ventricular and the basal and middle sections of the interventricular septum between the two groups (P<0.05). The changes of MPI and TDI became more obvious with the increased dose of ANT. There were no significant differences in serum CtnI and BNP levels between the two groups. CONCLUSIONS: The heart function of patients who received ANT chemotherapy needs to be monitored for a long term. MPI and TDI can be used as early indexes for monitoring the heart function. PMID- 21672426 TI - [Expression of Wnt5a in the terminal rectum of children with anorectal malformation]. AB - OBJECTIVE: To study the expression of Wnt5a protein in the terminal rectum of children with anorectal malformation (ARM) and the possible association between Wnt5a and ARM. METHODS: Specimens were obtained from 20 children with ARM, 7 children with acquired rectovestibular fistula and 6 children with non gastrointestinal tract disease (control group). The expression of Wnt5a protein in the terminal rectum was determined by immunohistochemistry and Western blot. RESULTS: Wnt5a was mainly expressed in the rectum of the myenteric nerve plexus, mucosal layer and submucosa in the control group. Compared with the control group, Wnt5a expression in the terminal rectum decreased significantly in the ARM group, and decreased more significantly in children with high ARM. The results of Western blot showed the expression of Wnt5a protein in the high, intermediate and low ARM groups were significantly lower than that in the acquired rectovestibular fistula and the control groups (P<0.01). The expression of Wnt5a protein in the high and the intermediate ARM groups were also lower than that in the low ARM group (P<0.01). There was no significant difference in the Wnt5a protein expression between the acquired rectovestibular fistula and the control groups. CONCLUSIONS: The expression of Wnt5a in the termina1 rectum decreases in children with ARM, suggesting Wnt5a may play an important role in the development of ARM. PMID- 21672427 TI - [Congenital myopathy with type 1 fiber predominance in two children]. AB - Non-progressive congenital myopathy is a group of muscle diseases occurring at birth or during teenage years. A number of new reports of congenital myopathy, such as homogeneous bodies myopathy, muscle quality control myopathy and type 1 fiber predominance have recently been reported, but they lack of sufficient quantity and constant clinico-pathologic manifestations. This paper reports two cases of congenital myopathy with type 1 fiber predominance confirmed by muscle biopsy. The clinical manifestations of the two children (a 4.5-year-old girl and an 11-year-old boy) included non-progressive symptoms of muscle weakness, skeletal deformities and other clinical features of congenital myopathy. The physical examinations showed a long face or figure and funnel chest or kyphosis/scoliosis, high palatal arch and wing-like shoulder. Serum levels of creatine kinase were normal but slightly elevated serum lactate dehydrogenase levels were noted in the two children. The skeletal muscle biopsy by ATPase staining showed that type 1 fibers accounted for more than 90% of the total number of muscle fibers. No other abnormal pathological changes, such as central cores, muscle tube and central nuclei, were found in the two children. PMID- 21672428 TI - [Effect of inhibition of Notch signal on pulmonary vascular remodeling induced by angiotensin II]. AB - OBJECTIVE: It is known that Notch signal is very important to vascular remodeling during the process of embryonic development, vessel repair and tumor growth, but there are few studies about pulmonary vascular remodeling in pulmonary hypertension. This study was to explore the effect of inhibiting Notch signal on pulmonary vascular remodeling induced by angiotensin II. METHODS: Vessel strips taken from healthy Wistar rats were co-cultured with extrogenous angiotensin II and the potent smooth muscle cell proliferation stimulators for 7 days. Vascular wall thickness, proliferating cell nuclear antigen (PCNA) positive cell rate and caspase-3 positive cell rate were examined in vessel strips. Then some vessel strips were cultured with angiotensin II and gamma-secretase inhibitor DAPT, a Notch signaling inhibitor for 7 days. The levels of Notch 1 to 4 receptor and HERP1/2 mRNA were ascertained by FQ-PCR. RESULTS: Angiotensin II stimulation in the cultured normal pulmonary arteries resulted in an increase in the vascular medial thickness by nearly 50%, and a significant increase in the PCNA positive cell rate and a decrease in the caspase-3 positive cell rate. DAPT treatment did not result in the alterations of Notch 1 to 4 receptor levels, but decreased remarkably HERP1 and HERP2 mRNA expression. DAPT treatment also decreased angiotensin II-induced vascular medial thickness and PCNA positive cell rate and increased caspase-3 positive cell rate. CONCLUSIONS: Inhibiting Notch signal by gamma-secretase inhibitor may lead to the suppression of pulmonary vascular remodeling induced by angiotensin II, suggesting that the inhibition of Notch signal pathway might be a novel strategy for the treatment of pulmonary hypertension. PMID- 21672429 TI - [Effects of bicyclol on renal PAI-1 expression in rats with uniliteral ureteral obstruction]. AB - OBJECTIVE: To explore the protective effects of bicyclol against renal interstitial fibrosis and possible mechanisms of the protection. METHODS: Eighty one Sprague-Dawley (SD) rats were randomly assigned to a sham-operated group and UUO groups with and without bicyclol treatment. A rat model of renal interstitial fibrosis was prepared by unilateral ureteral obstruction (UUO). Renal tissues were examined by hematoxylin & eosin and Masson staining on 7, 14 and 21 days. Immunhistochemistry was used for determining plasminogen activator inhibitor 1(PAI-1) expression in the renal interstitium. PAI-1 mRNA expression in renal tissues was semi-quantitatively determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The relative areas of renal interstitial fibrosis in the bicyclol-treated UUO group 7, 14 and 21 days after operation were (9.6 +/- 0.6)%, (16.8 +/- 0.8)% and (33.6 +/- 1.6)% respectively, which were significantly lower than those in the untreated UUO group [13.0 +/- 0.7)%, (25.8 +/- 1.5)% and (53.2 +/- 2.5)% respectively] (P<0.05). The levels of protein and mRNA expression of PAI-1 in the bicyclol-treated UUO group decreased significantly compared with those in the untreated UUO group 7, 14 and 21 days after operation (P<0.05). CONCLUSIONS: Bicyclol can alleviate renal interstitial injury and renal interstitial fibrosis caused by UUO in rats, possibly through a down?regulation of renal PAI-1 expression. PMID- 21672430 TI - [Protective effects of mitochondrial ATP-sensitive potassium channel on A549 cell apoptosis induced by hyperoxia]. AB - OBJECTIVE: To explore the protective effects of mitochondrial ATP-sensitive potassium channel opener diazoxide on hyperoxia-induced apoptosis of type II alveolar epithelial cells (A549 cells) and possible mechanisms. METHODS: A549 cells were cultured in vitro and divided randomly into control, hyperoxia and diazoxide group. The hyperoxia group was exposed to a mixture of O2 (900 mL/L) and CO2 (50 mL/L) for 10 minutes, then cultured in a closed environment. The diazoxide group was pretreated with diazoxide of 100 MUmol/L for 24 hrs before hyperxia induction. The cells were collected 12, 24 and 48 hrs after culture. The morphologic changes of A549 cells were observed under an inverted microscope. A549 cell apoptosis was detected by flow cytometry. The expression of Omi/HtrA2 in the endochylema of A549 cells was determined by immunohistochemistry. RESULTS: A549 cells were damaged and the changes in morphology of the cells were serious in the hyperoxia group. The apoptosis rate of A549 cells and the expression of Omi/HtrA2 in the endochylema increased in the hyperoxia group compared with the control group (P<0.05). The growth and the morphology of A549 cells were greatly improved and the cell injuries were obviously alleviated in the diazoxide group. The expression of Omi/HtrA2 in the endochylema and the apoptosis rate of A549 cells were significantly reduced in the diazoxide group compared with the hyperoxia group (P<0.05). CONCLUSIONS: Diazoxide as an opener of mitoKATP channel can reduce the expression of Omi/HtrA2 and the apoptosis rate of A549 cells, thus relieves the injury of A549 cells induced by hyperoxia. PMID- 21672431 TI - [Childhood Henoch-Schonlein purpura complicated by pancreas involvement: clinical analysis of 7 cases]. PMID- 21672432 TI - [Treatment of nephritic edema by torasemide in children]. PMID- 21672433 TI - [A case report of recurrent right-sided oculomotor palsy]. PMID- 21672434 TI - [A case report of general Takayasu syndrome complicated by Moyamoya disease]. PMID- 21672435 TI - [Present status and prospects of fetal cardiac intervention]. PMID- 21672436 TI - [The predictive and monitoring value of serum HER2/NEU in breast cancer under trastuzumab therapy]. AB - INTRODUCTION: In breast cancer, the Human Epidermal growth factor Receptor 2 (HER2) is associated with worst prognosis in all stages of the disease, and it is specifically targeted by a monoclonal antibody (trastuzumab). Nevertheless, the different response rates observed have increased the search for better predictive markers. Elevated levels of the extracellular domain of HER2/neu in the serum have been associated with the clinical outcome of breast cancer patients. MATERIAL AND METHODS: The authors proposed to analyze serum HER2/neu in breast cancer patients, under treatment with trastuzumab, in monotherapy or associated with another systemic therapy, either in adjuvant or metastatic setting, in order to evaluate its role as prognostic, predictive and monitoring factor. From March 2007 to May 2008, 173 serum samples from 43 patients were analysed, corresponding to the beginning of the treatment of trastuzumab and 3/3 months afterwards. Serum HER2/neu levels were measured with ADVIA Centaur((r)) immunoassay and levels > 15 ng/mL were defined as elevated, according to previous reports. RESULTS: Elevated baseline serum levels were found to be associated with a worst overall survival (p = 0,003). In the metastatic setting, baseline HER2/neu serum levels were not associated with response rate to trastuzumab. However, when we analyzed the variations in HER2/neu serum levels between the response evaluation date and the first measurement, we observed that patients whose serum levels declined showed significantly higher objective response compared with patients with stable or elevated serum values (p = 0,001). Moreover, monitoring early changes in serum levels (three months) could also predict the probability of response to trastuzumab-based treatment (p = 0,007). CONCLUSION: The use of this predictive potential could not only focus and tailor treatment individually but also adapt to economic needs. PMID- 21672437 TI - [Medication adherence rating scale]. AB - Medication compliance is one of the foremost problems affecting neuroleptic efficacy in psychiatric patients. It is a crucial point to dispone of useful instruments that allow us a fiable assessment of patients' medication adherence in order to plan more appropriate therapeutical interventions. The aim of our study was to validade the Portuguese version of the Medication Adherence Rating Scale (MARS), a concise instrument for assessment of medication compliance in psychosis. METHODS: A translation-backtranslation of the original scale was elaborated. The sample consisted of 77 psychotic patients according to the DSM-IV criteria. Feasibility and reliability were calculated. RESULTS: The results demonstrated that the MARS has a good internal consistence (Cronbach alpha = 0,73) and reliability (Pearson's r = 0,76; p < 0,05). DISCUSSION: These coefficients were similar to those found by the researchers who developed this scale. The MARS scale has proven to be easily applied and may be deemed a valid and reliable measure of compliancy for psychoactive medications. PMID- 21672438 TI - [Cerebral venous thrombosis: retrospective analysis of 49 cases]. AB - INTRODUCTION: Cerebral Venous Thrombosis (CVT) is a rare and potentially life threatening disease, accounting for about 0.5% of stroke cases. However, it is believed to be an underdiagnosed condition. Early diagnosis requires a high degree of suspicion and appropriate use of imaging modalities. OBJECTIVES: Imagiological and clinical characterization of CVT cases diagnosed at our hospital from 2004 to 2007. METHODS: This study was a retrospective, cross sectional analysis from 2004 to 2007, using our institution database. We reviewed hospital discharge data to assess the incidence of CVT. The study population consisted of 49 patients. Retrospective review of the clinical data and imaging studies of these patients was then performed. RESULTS: Of the 49 patients with confirmed CVT, 38 were female. Patient age varied between 16 and 75 years, with an average of 42.6 years. Thrombotic risk factors were found in 43 patients; the most frequent was dyslipidemia (n = 22) followed by oral contraceptive use (n = 18). Initial head Computerized Tomography (CT) was normal in six cases. Diagnosis was made by Magnetic Resonance (MR) in 38 cases, Cerebral CT-Venography in 10 cases and Digital Subtraction Angiography in one case. Average time from onset of symptoms to diagnosis was nine days; this was not significantly different when comparing the group diagnosed by MR with the group diagnosed by CT-Venography. Right transverse sinus was the most frequent location of thrombosis (n = 36). Only in four cases thrombosis did not involve the lateral sinuses. CONCLUSIONS: Lateral sinus thrombosis is a frequent variety of CVT, accounting for 91.8% of our cases. A negative Head CT scan does not exclude the presence of cerebral venous thrombosis; therefore appropriate imaging study should be performed whenever there's a high degree of clinical suspicion. Cerebral CT-Venography seems to be a good alternative to MR for the diagnosis of CVT. PMID- 21672439 TI - [Transcatheter arterial chemoembolization with doxorubicin eluting beads in the treatment of hepatocellular carcinoma]. AB - Retrospective study to evaluate local tumor control and survival data after transcatheter arterial chemoembolization with doxorubicin eluting beads in the treatment of hepatocellular carcinoma. Between April 2007 and November 2008, a total of 47 patients (mean age 61,7 years; range 42-84 years) with hepatocellular carcinoma were treated with transcatheter arterial chemoembolization. In total 73 chemoembolization procedures were performed in superselective manner with microcatheter (mean 1,57 procedures per patient). The local chemoembolization protocol consisted of doxorubicin eluting beads mainly 300-500 micra but also 500 700 micra and 700-900 micra, to a maximum dose per session of 150 mg doxorubicin. Tumor response was evaluated with CT imaging. Change in tumor size was calculated and response was evaluated according to the European Association for the Study of the Liver (EASL) criteria. Survival from first chemoembolization was calculated in the subgroup treated between April 2007 and January 2008 (24 patients). Follow up imaging was performed until January 2009 or patient death. Evaluation of tumor response resulted in complete response in 13 patients (27,7%), partial response in 15 patients (31,9%), stable disease in 9 patients (19,1%) and progressive disease in 10 patients (21,3%). The one year survival rate after chemoembolization in the 24-patient subgroup was 54%. Chemoembolization with doxorubicin eluting beads is a minimally invasive, safe and effective therapy option for palliative treatment of hepatocellular carcinoma. PMID- 21672440 TI - [Periodic fever with aphthous stomatitis, pharyngitis and adenitis: report of 21 cases]. AB - INTRODUCTION: PFAPA syndrome (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis) is a benign sporadic syndrome of unknown cause and an important diagnosis to consider in the child with recurrent fever and tonsillitis. OBJECTIVES: To describe the presentation, age of onset, time until diagnosed, episode duration, frequency of typical and atypical symptoms, clinical course after diagnosis and response to treatment in a case series of children with PFAPA. METHODS: Case series of children with PFAPA referred to our consult over an eight-year period (from May 2001 to May 2009). Data were collected from medical records and telephone calls. RESULTS: We included 21 patients with PFAPA, with age of onset between 6 months and 5 years (median 24 months). Diagnosis was established 4 months to 3 years after onset of crises (median 24 months). Episodes recurred every 2 to 6 weeks (median 30 days), and consisted in 3 to 10 days (median 4,5 days) of fever (21/21), pharyngitis (21/21), cervical adenitis (19/21), and aphthous stomatitis (16/21). Atypical symptoms were reported sporadically and without clinical severity: abdominal pain (8 patients), nauseas/vomits (3 patients), arthralgia (3 patients), hepatosplenomegaly (1 patient), lactose intolerance (1 patient). Eighteen patients received treatment with one dose of prednisolone with rapid symptomatic relief. In two patients subsequent crises became more frequent for a short period of time and then returned to monthly periodicity. Seven treated patients experienced less frequent episodes and in four of them this occurred after diagnosis but before first dose of prednisolone. In the three untreated patients the crises became rare and treatment was not prescribed. Tonsillectomy was performed in two patients and in one the monthly episodes reappeared five months after the procedure. DISCUSSION: In spite including a small number of patients, our case series is similar to others in the literature regarding most clinical aspects. PFAPA syndrome should be considered even in the absence of all clinical criteria. Correct and timely diagnosis does not require and obviates unnecessary diagnostic tests. The outcome after symptomatic therapy with corticosteroids and family reassurance was generally good and we do not recommend tonsillectomy as a first line treatment in this syndrome. PMID- 21672441 TI - In vitro and in vivo chitosan membranes testing for peripheral nerve reconstruction. AB - Tissue regeneration over a large defect with a subsequent satisfactory functional recovery still stands as a major problem in areas such as nerve regeneration or bone healing. The routine technique for the reconstruction of a nerve gap is the use of autologous nerve grafting, but still with severe complications. Over the last decades several attempts have been made to overcome this problem by using biomaterials as scaffolds for guided tissue regeneration. Despite the wide range of biomaterials available, functional recovery after a serious nerve injury is still far from acceptable. Prior to the use of a new biomaterial on healing tissues, an evaluation of the host's inflammatory response is mandatory. In this study, three chitosan membranes were tested in vitro and in vivo for later use as nerve guides for the reconstruction of peripheral nerves submitted to axonotmesis or neurotmesis lesions. Chitosan membranes, with different compositions, were tested in vitro, with a nerve growth factor cellular producing system, N1E-115 cell line, cultured over each of the three membranes and differentiated for 48h in the presence of 1.5% of DMSO. The intracellular calcium concentrations of the non-differentiated and of the 48h-differentiated cells cultured on the three types of the chitosan membranes were measured to determine the cell culture viability. In vivo, the chitosan membranes were implanted subcutaneously in a rat model, and histological evaluations were performed from material retrieved on weeks 1, 2, 4 and 8 after implantation. The three types of chitosan membranes were a viable substrate for the N1E-115 cell multiplication, survival and differentiation. Furthermore, the in vivo studies suggested that these chitosan membranes are promising candidates as a supporting material for tissue engineering applications on the peripheral nerve, possibly owing to their porous structure, their chemical modifications and high affinity to cellular systems. PMID- 21672443 TI - [Stevens-Johnson syndrome and toxic epidermal necrolysis: a 15-year retrospective study]. AB - Stevens-Johnson Syndrome (SJS), Overlap Syndrome (OS) and Toxic Epidermal Necrosis (TEN) are rare medical emergencies associated with a high morbidity and mortality. The literature on the characteristics of these diseases in Portugal is scarce. A retrospective study was conducted based on the clinical notes of the 20 patients admitted to Sao Jose Burn Unit in the previous 15 years with the diagnosis of SJS, OS or TEN. Most patients had TEN (65%), followed by OS (25%) and SJS (10%). Average age was 57,1 +/- 19,0 years. The mean duration of stay in the Burn Unit was 12,6 +/- 7,8 days. Mortality was 50%, being significantly higher than the 16,4% overall mortality in the general Burn Unit population in the same period (p < 0,01). The mean surface area involved was 43,9 +/- 28,6 %. Allopurinol was the causal agent most frequently implicated (35%) followed by UV light exposure (15%). Fourteen patients (70%) were treated with steroids in the first days, whereas six patients were treated conservatively (30%). Mortality was inferior in the patients treated with steroids (42,8 vs. 66,7%), even though this difference did not reach statistical significance. Infection rates were not significantly different between the two groups. SCORTEN score proved to be a good predictor of mortality. Further studies are needed to reduce mortality in these diseases. PMID- 21672442 TI - [Analgesic prescription habits in a population of patients with chronic rheumatic disease]. AB - OBJECTIVES: The aim of this study was to record the analgesic prescription commonly performed by Portuguese Rheumatologists in patients with chronic Rheumatologic disease, using the guidelines provided by the World Health Organization for treatment of chronic pain as comparative. MATERIAL AND METHODS: We randomly selected the clinical records of 203 patients with complete clinical record. We excluded patients with less than a year of follow-up, last consultations over a year ago, age under 16 years, patients with no rheumatologic diagnose, being the final sample of 94 patients. The items collected were gender, age, primary diagnosis, prescribed drugs (paracetamol, nonsteroidal anti inflammatory steroids, glucocorticoids, tricyclic antidepressants, selective serotonin reuptake inhibitors - paroxetine and fluoxetine, anticonvulsants - gabapentin and pregabalin, colchicine and muscle relaxers with pain modulator effects of, weak and strong opioids), degree of pain (0-10). RESULTS: 84.94% of patients were female and 15.06% male. The average age was 51.5 years, men's average was 54.0 years and women 51.1 years. Overall prescription of paracetamol was 23.4% and 8.5% for tramadol (always associated with paracetamol). In 17% of patients paracetamol was added successfully. The use of various antiinflammatory agents reached a prevalence of 80.9%. Other agents were also used either Glucocorticoids - Deflazacort and prednisolone - (36.2%), tricyclic antidepressants with expressed antalgic intention (6.4%). CONCLUSIONS: There was a discrepancy between the prescription and the current indications of WHO for the control of chronic pain. This discrepancy raises the possibility of failure of some pharmacological agents in this type of pain and/or lack of systematization of analgesic therapy. We recommend further studies to prove the hypothesis. PMID- 21672444 TI - [Leg ulcer: conservative treatment]. AB - During 16 years 202 patients with leg ulcer have been studied prospectively. Whenever possible, cure has been obtained in ambulatory, which was the main objective. Surgery was preferentially made after the cure of the ulcer. From the 202 patients, 166 have made a prolonged follow-up. Cure in ambulatory has been obtained in 91% of the patients. We stress the importance of the direct control of all the treatment by the responsible doctor. PMID- 21672445 TI - [Does rurality affect the outcome of trauma patients?]. AB - OBJECTIVES: To determine the impact of rurality in epidemiology, injury severity, health care facilities, length of stay, mortality, functional outcome and quality of life in severe trauma patients. METHODS: All trauma patients admitted in our Emergency Room between 2001 and 2007. Data was collected from the prospective Trauma Registry and Follow-Up Registry 6 months after the accident. Patients were divided in three groups according to residence area: R (rural), SU (semi-urban) and U (urban). Sex, age, type of injury, length of stay in hospital and intensive care, anatomic severity (AIS), politrauma severity (ISS), physiologic severity (RTS), surveillance probability (TRISS index), pre-hospital care, previous admission in other hospital, intensive care admission, Euroqol and Extended Glasgow Outcome scale and mortality were studied in order to find a relation with rurality. RESULTS: 1150 patients were analyzed (214 rural, 219 semi-urban, 717 urban). We found a statistical significant relation between rurality and pre hospital care with rural patients having less medical approach in pre-hospital (R group: 12,2%; SU group: 17,7%; U group: 70,1%, p < 0,001), previous admission in other hospital with rural patients being more often admitted in another hospital before transfer to the trauma centre (R group: 89,2%; SU group: 85,8%; U group: 61,9%, p < 0,001) and intensive care admission (R group: 82,2%; SU group: 78,5%; U group: 72,4%, com p < 0,006). We did not find any significant relation between other variables studied namely severity and early or late outcome. CONCLUSIONS: Living in rural areas does not seam to give more burden of disease to severe trauma patients. Rural patients are similar to those that live in urban areas concerning epidemiology, injury severity and outcome. Despite lack of medical pre hospital care and higher previous admission in other hospital in rural patients, mortality between groups didn't differ in our trauma centre. PMID- 21672446 TI - [Antidepressant drugs]. AB - Depression is a disorder of mood that causes strong impact on the patient and his family's quality of life. The increasing number of cases and its social consequences have made depression a great public health problem. Some depressant patients develop suicide thoughts and may try suicide later. The disease occurs in all ages and its prevalence is of 7.4%. Women aged 15 to 29 are more likely to be affected, whereas people aged 50 or older are less affected. The presence of depression worsens the prognostic of other clinical conditions when compared to not depressant patients. This paper describes the main drugs used in the treatment of depression and correlates the drug with the neurobiology of the disease. Aiming the study of the pharmacologic and therapeutic characteristics of antidepressant drugs, a literature review was performed using electronic databases (Pubmed and Lilacs), papers and books related to the theme. The main antidepressant drugs are classified according to their chemical structure or their action on neurotransmitters. An important point in the therapy is the understanding of the pharmacokinetics of the drugs. The choice of the drug must consider the symptoms, the patient's age, other drugs in use, the history of pharmacological treatments and so forth. No drug is significantly better than the other in the treatment of depression. The important thing in choosing a drug is to have the best therapeutic response, the reduction of symptoms, a good adherence to therapy, few side effects and secure drug interaction. By understanding the use of these drugs, it will be possible to give the patient and his family a better quality of life. PMID- 21672447 TI - [Late onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency: revision of literature and preconception genetic study of five couples]. AB - The deficiency of the enzyme 21-hydroxylase (21-HO) is responsible for about 90% to 95% of all cases of congenital adrenal hyperplasia (HCSR). This disorder is one of the most frequent hereditary illnesses of autosomal recessive trait. The illness can be presented in two clinical forms: 1 - classic, subdivided in saltwasting form and simple virilizing form; 2 - nonclassic or late-onset. The severity of the illness is correlated with the degree of enzymatic activity of 21 HO, which depends on the type of mutation that occurs in gene CYP21A2. The late onset congenital adrenal hyperplasia is that one where the enzymatic blockade is less intense. The clinical is variable: precocious pubarche, polycystic ovaries, hirsutism, oligoamenorrhea, acne and infertility. Gold standard for the diagnosis of late onset congenital adrenal hyperplasia consists on the test of the tetracosactide, considering itself diagnostic positive when 17 hidroxiprogesterona (17-OHP) is higher of 10-15 ng per mL. Many patients don't need treatment; however, if necessary, such a treatment essentially consists on the Administration of glucocorticoids and antiandrogens. Considering that affected individuals and the carriers may have a severe mutation in CYP21A2, they can have descendents with the classic form (if their partner is also a carrier of a severe mutation), it is mandatory the genetic study of the couple. The authors illustrate the importance of this genetic study through five clinical cases, whose common link is the desire to have children, as well as the presence on the feminine element of late onset congenital adrenal hyperplasia. The genetic study of the couple allows adequate pre-conception counseling and also prevents the use of corticoids throughout the pregnancy (if there's no risk of descendents being affected with the classic form). This aspect must be had in account in programming the pregnancy, in order to prevent therapeutics and unnecessary distrusts. PMID- 21672448 TI - [Bariatric surgery: epidemic of the XXI century]. AB - Obesity is a chronic and endemic disease in developed countries, there is an inverse relationship between the socio-economic level and the prevalence of this disease. Their costs are responsible from 2 to 7% of the total health costs. The prevalence of obesity in the world is so high that the World Health Organization considered this disease as the global epidemic of the XXI century. In Portugal it's estimated that around 16.5% of the population aged over 18 years, has obesity, and due to the morbidity and mortality associated with this pathology, this constitutes a serious public health issue. There are several ancient references to obesity and its consequences, with descriptions of different therapeutic attitudes. But only in 1965 the term bariatric was introduced and consequently the term bariatric surgery. Mason, the father of bariatric surgery, started its history in 1966. Several surgical techniques were subsequently developed, but currently the most used are the gastric bandoplastia, a restrictive surgery, and the gastric bypass, a combined surgery. Today, the bariatric surgery is not limited to the treatment of obesity, but the treatment of a syndrome associated with obesity, allowing a significant improvement in Quality of life of these patients. Thus, it's licit to think that the surgery that allows addressing the epidemic of the XXI century is the surgery of the century, with curative rates, of obesity and their comorbidities, which were never achieved by any other pharmacological treatment. PMID- 21672449 TI - [Early intervention in psychosis: first-episode psychosis and critical period]. AB - Besides intervention in prepsychotic period, early intervention in psychosis includes interventions done after the onset of the first-episode psychosis, namely psychopharmacological and psychosocial phase-specific intervention. The main aim is to reduce the duration of untreated psychosis (DUP) and to ensure that besides remission of the symptoms there is also a psychosocial recovery. Many centers set up an assertive and integrated early intervention program, involving an active search of patients with a treatment that includes antipsychotic medication, cognitive behavioral therapy, psychoeducation, family and vocational interventions. The authors of this review explain the concepts and main studies that support this kind of treatment in early psychosis. The results of published data show that is possible to reduce the DUP and improve the clinical and functional outcomes with this intervention. Critical period hypothesis proposes that deterioration occurs aggressively in the first 2 to 5 years of early psychosis, so it is crucial to intervene in this period to ensure a functional recovery. Cost-benefit ratio seems to be favorable to early intervention model, with reduction of in-stay period, which is an important component of the direct costs of psychotic illness. Early intervention service model organization is also reviewed by the authors of this research. The results of many studies show favorable outcomes for the integrative early intervention and so many countries included it in their political mental health directives and attributed funds for early intervention in psychosis. PMID- 21672450 TI - Is there a biological plausability for p53 codon 72 polymorphism influence on cervical cancer development? AB - The interaction between HPV E6 and p53 protein is known as the most important event in HPV-associated carcinogenesis. Some in vitro studies suggested that p53 genetic variants are targeted for ubiquitin-proteasome degradation induced by E6 with different abilities. A common p53 variant at position 72 (R72P) has leaded to the development of several studies regarding its role on cervical cancer development. However, only few reports have shown an association between the Arginine (R) variant at position 52 of p53 and increased susceptibility to HPV E6 mediated degradation and thus to increased cancer susceptibility. We revised the literature in order to obtain plausible data to discuss about these evidences for cervical cancer susceptibility. The more recent studies, including meta-analysis reviews, point out that there is no association of this p53 variant and cervical cancer development. This variant seems to be differently segregated in different ethnic/geographical locations; therefore, there might be a possible role of this genetic variant associated with a certain genetic background, which can explain why some studies reveal increased risk of cervical cancer development associated with Arginine p53 variant. PMID- 21672451 TI - [Management of adult secondary insomnia in primary health care]. AB - INTRODUCTION: Insomnia is the most common sleep disorder in adults, with secondary insomnia being the most prevalent. This sleep disorder is associated with important medical and social consequences. The General Practitioner (GP) plays a key role in the diagnosis of insomnia, which may affect about 69% of their patients in the PHC (Primary Health Care). OBJECTIVES: Recognize the differential diagnosis of secondary insomnia in adults, evaluate and manage these patients in the PHC, appropriately use the treatments available and meet the criteria for referral. METHODS: Bibliographic search in MEDLINE databases, and evidence based review databases, using the MeSH terms: Primary Health Care, Sleep Disorders, Insomnia, for articles published since January 2000 until July 2009, in English, Portuguese, French and Spanish. Index de Revistas Medicas Portuguesas and scientific societies dedicated to sleep disorders were searched. RESULTS: Mood and anxiety disorders are the main co-morbidities associated with secondary insomnia, being present in 30% to 50% of patients with insomnia. The medical pathology and substance abuse are present respectively in 10% of patients. It is essential a proper clinical history, with a history of sleep, sleep diary and the partner information. There is evidence that the combination of specific pharmacological treatments (benzodiazepines and the benzodiazepine receptor agonists) with the nonpharmacological (cognitive-behavioral therapy) may be useful in secondary insomnia, as co-adjuvant treatment of the underlying disease. There are several treatment options with their indications and adverse effects. The criteria for referral should be defined according to the availability of human resources. CONCLUSION: Due to the high prevalence and the serious consequences of secondary insomnia in adults, it must be systematically managed by the GP. It is important to know and to use non-pharmacological therapy in GP consultation, because this therapy was shown to be important in treating this type of insomnia. The GP must know the precise indications for pharmacological treatment and criteria for referral. PMID- 21672453 TI - [The new face of Portuguese medicine: the generation of 1911 and the research school of Marck Athias]. AB - This paper aims to demonstrate that with Marck Athias, the Portuguese medicine inaugurated a new chapter in its history, in the Republic period, characterized by the experimental training at the laboratory. Thus, book-based knowledge gave way to a more clinically based approach favouring laboratory practice and basic research within several scientific domains. This new perspective operated important changes in the Portuguese medical community in the first half of century XX. Marck Athias (1857-1946), a Portuguese, was a physician trained at the University of Paris under Mathias Duval (a former student of Santiago Ramon y Cajal). It was in his laboratory that Athias began his career as researcher. Returning to Portugal, Athias founded a research school in physiology and histology which stressed a new approach in medicine based on experimental research. At the beginning of the twentieth century, scientific research in Portugal was virtually devoid of any of the practical clinic aspects. It is in fact Athias who introduced a new scientific perspective in Portuguese scientific community as well as influenced generations of graduate students in several national higher education and scientific research centres associated with Medicine. His influence and impact was due in great part to the underlying ideology of a positivist nature which succeeded in attracting several generations of followers, promoting a new step for the modernization of Portuguese medicine. PMID- 21672452 TI - [Diagnostic tools in tuberculosis]. AB - Early diagnosis and treatment are critical to minimize the spread and to reduce morbidity and mortality from tuberculosis. Clinical diagnosis is most time difficult resulting from non-specific and frequently indolent symptoms. Radiological presentation may be very diverse. Currently TB diagnosis still depends on microbiological exams which require a very careful and quick specimen handling. A positive acid-fast bacilli smear makes a rapid presumptive diagnosis. Nevertheless the gold-standard for diagnosis still is cultural-isolation of the Mycobacterium tuberculosis, which may take several weeks to attain. Biochemical (adenosine deaminase) and molecular techniques (nucleic acid amplification tests) are already approved for tuberculosis diagnosis and can provide rapid diagnostic information to the clinician. Numerous alternative diagnostic methods are still under experimentation but none of them has a recognized role. In most cases diagnosis of tuberculosis lays on an adequate combination of different diagnostic methods which is time-consuming. Even though in some cases laboratory confirmation is never obtained and diagnosis and treatment is established on suspicious basis. The purpose of this paper is to discuss the utility of the several diagnostic methods currently available and to point out most common difficulties found by the clinicians to the correct and timely diagnosis. PMID- 21672454 TI - [System of biometric identification: by the way of control]. AB - The ethics and morals make the line between lawful to unlawful, the right and wrong, acceptable from the unacceptable. Furthermore the purpose of ethics in the field of profesional practice is, in particular the application of moral standards based on honesty, courtesy and honour. But they are not the only ones. Confidentiality should be the first of duties the professional has no right to disclose information that was only reported in their work and because it was necessary to run it. This requirement aims to protect the recipient of the service and avoid damage to society. The professional should also encourage members of his team, because solidarity is a very effective way to improve the intellectual and moral qualities of work partners and ensure their involvement. When you have an honest professional conduct within and outside of professional practice, you attract confidence and prestige, which is an incentive to drive, with safety, the proper course of his career. The purpose of the biometric control based on the need to expedite the fulfilment of a goal whose integration is recognized by law under the control of the employer's: the setting of working hours, monitoring the attendance and registration of working time. This record is also the accounting and control of additional work. To consider the biometric control as an appropriate mean to ensure a "legitimate purpose", the Law 67/98 requires the National Commission for Data Protection, in each case, to ascertain whether the prevailing interests the rights and freedoms guarantees data subjects on the interest for the treatment of data relied upon by the employer. This procedure seems to be the best fit to the principle of proportionality and therefore the processing of data should be refused where it appears unjustified, inappropriate and excessive, or when, by their lack of reliability, it undermines the purpose of determining it. PMID- 21672455 TI - [Adverse events and near misses in medical imaging]. AB - In 2000, the Institute of Medicine's report, To Err Is Human: Building a Safer Health System, caught the public attention documenting the magnitude of the medical error problem and the inherent patient safety: medical errors cause between 44,000 and 98,000 deaths annually in the United States. Currently, there is a growing interest in risk management on the medical field, particularly in the management of adverse events. It has been mainly due to the commitment of the World Health Organization, that this field of research has gained increasing the attention it deserves. Medical imaging is one of the high risk fields for the occurrence of errors, especially due to the multiplicity of techniques, the several stakeholders and the complexity of the whole circuit that involves the conduct of studies. Many of the methods used to analyze patient safety were adapted from risk-management techniques in high-risk industries (e.g. chemical, nuclear power and aviation industry). It is recognized that we can learn more from our mistakes than from our successes and the reporting systems in these industries have provided a valuable contribution to error prevention and risk management techniques. At a minimum, adverse events reporting systems can help to identify hazards and risks, providing important information on the system aspects that should be improved. However, the accumulation of potentially relevant data contributes little to healthcare services improvement. It is crucial to apply models to identify the underlying system failures, the root causes, and enhance the sharing of knowledge and experience. In this paper, it is suggested a solution to reduce adverse events, by identifying and eliminating the root causes that are in their source. How the Eindhoven Classification Model was adapted and extended specifically for the Medical Imaging field is also presented. The proposed approach includes the root causes analysis and introduces incomplete information concepts through the use of logical-mathematical operators formally sustained. This model is the basis of the adverse event and near misses reporting and learning system that was developed for Medical Imaging and is implemented in two Portuguese healthcare institutions. The objectives, characteristics and function of this system are presented throughout this article. PMID- 21672456 TI - [Small bowel metastatic of malignant melanoma: a rare cause of lower gastrointestinal bleeding]. AB - The malignant melanoma is the most common cause of metastatic lesion in the gastrointestinal tract, representing about 33% of all the metastatic malignant tumors of the digestive tract. In 35% of patients the small bowel is impaired, and lower gastrointestinal bleeding is a rare form of presentation. The authors report a case of a 81-year-old male with a history of malignant skin melanoma excised in 1994. Underwent middle lobectomy due right pulmonary metastasis of melanoma in 2002. In 2005, in the context of gastrointestinal bleeding is diagnosed metastases of malignant melanoma in the small bowel, and underwent a segmentary enterectomy. At present the follow-up is without symptoms. PMID- 21672457 TI - [New insights in adult Still disease's knowledge]. AB - INTRODUCTION: Adult Still's Disease has systemic consequences, an inflammatory origin and unknown etiology. Knowledge about this disease is still limited, but some evolution has occurred in the last few years. AIMS: Using a clinical case as example, the purpose of this paper is to review actual knowledge about Adult Still's Disease, giving special relevance to the most recent findings. METHODS: Search in Pubmed and Cochrane database (1970-2009) for the terms Adultonset Still's Disease for all available papers. Those considered clinically and historically relevant were selected. An additional search was done in scientific journals and textbooks and other web sites. The information was analysed, using a clinical case in an atypical age as illustration. RESULTS: Adult Still's Disease as multiple manifestations, being fever, evanescent skin rash and arthralgia the most typical. Laboratorial parameters are inespecific, but high glycosilated ferritin is highly suggestive. Non-steroid anti-inflammatory, corticoids, immunosuppressors, and recent biological agents are used in treatment. CONCLUSION: Being uncommon, actual knowledge about this disease is based in isolated descriptions or very short series. There are no specific guidelines, but diagnostic criteria have been improved in recent years, as have the insights in pathophysiology and therapeutic resources. PMID- 21672458 TI - [Cerebral venous thrombosis imagiologic features in a pregnant woman]. AB - Cerebral venous thrombosis (CVT) is a relatively rare but serious condition potentially reversible upon accurate diagnosis and adequate therapy. The peri partum state and pregnancy are predisposing factors and TVC accounts for about 6% of maternal deaths. Its clinical symptoms depend on the the thrombus site and extension, and also on the existing collateral vessels network. We present the case of a 33 year-old woman, 13 weeks pregnant, that complained of headaches and whose cranial magnetic resonance imaging revealed a subtotal oclusion of the superior sagittal sinus. We discuss the imaging features of dural venous thrombosis in the acute phase. PMID- 21672459 TI - [Treatment of HBV HCV co-infection: exceeded response]. AB - Hepatitis B (HBV) and hepatitis C (HCV) are the most common causes of chronic liver disease. Due to shared routes of transmission, co-infection with HBV and HCV is not uncommon. Higher rates of cirrhosis and hepatocelular carcinoma have been demonstrated in HBV/HCV co-infected patients. No treatment standard has been established for HBV/HCV co-infected patients. Treatment decisions must be made based upon identification of the dominant virus, usually HCV, thus patients should receive pegylated interferon alpha with ribavirin as for HCV monoinfection. Sustained virological response rates for HCV are broadly comparable with HCV monoinfected patients. There is limited information regarding the benefit of combination with nucleos(t)ide analogues. Treatment decisions may modify the complex interaction between HBV and HCV, as flares of the untreated virus may occur, namely with reactivation of HBV. The authors report a case of HBV/HCV co-infection, without a dominant profile, in which the treatment response exceeded expectations regarding the available evidence. PMID- 21672460 TI - [General practitioner's advice to depressed pregnant women]. PMID- 21672461 TI - [Use of antidepressants during pregnancy]. AB - Pharmacological treatment of depression during pregnancy must balance the potential fetal risks of the medication with the risks of an undertreated or untreated depression. The choice of treatment is difficult and an increasing number of pregnant women and their doctors face the dilemma. There are non pharmacological options for treatment but they may not be sufficient or available. The paper summarises the potential fetal effects of antidepressant use during pregnancy and attempts to put these effects in a clinical context. PMID- 21672462 TI - [Isovaleric acidaemia--a rare and serious defect in the metabolism of leucine]. AB - Isovaleric acidaemia (IVA) is an organic acidemia caused by deficient metabolism of the essential amino acid leucine. We describe the biochemistry, diagnostics, and treatment of IVA, and present the known Danish patients. PMID- 21672463 TI - [Preoperative full-body magnetic resonance imaging is indicated on suspicion of multifocal infection in children]. AB - Musculoskeletal infections in children present a challenge regarding diagnosis and treatment. Conventional radiographs guide the initial radiographic assessment. Additional imaging is often performed to improve the diagnosis of the abnormality. The modalities used are ultrasound, bone-scan, computed tomography or magnetic resonance imaging (MRI). On suspicion of multifocal musculoskeletal infections (MMI), MRI may save time and improve preoperative planning. We highly recommend the use of MRI for the preoperative assessment of children with MMI. PMID- 21672464 TI - [Preoperative magnetic resonance imaging of children with multifocal musculoskeletal infections]. AB - We describe the case of a three-week-old female, who presented with fever and swelling of the left thigh. Initial examination revealed signs of infection in both hips, which was confirmed at surgery. However, as the child did not recover despite relevant antibiotics, a full body MRI was performed, revealing multiple abscesses, some of which had to be managed surgically. We emphasize the benefit of MRI as part of the preoperative assessment of multifocal musculoskeletal infections in children. PMID- 21672465 TI - [Side annotations on X-rays are not always correct]. AB - R and L annotations on X-rays are important! Is it done? A quality assurance project from an X-ray department in Gentofte Hospital, Copenhagen, focuses on right and left annotations on conventional, digital X-rays. Included images were those of greater joints and extremities pre and post surgery, and controls after minor emergency injuries. The sum of included images was 2499, and the error level was 1.8%. Annotations are the radiographer's obligation and can be forgotten. Factors like stress, interruptions, different equipment or amnesic patients play a role. No available, comparable studies have been found. PMID- 21672466 TI - [The optimal timing for gastroscopy in severe ulcer bleeding is not determined]. AB - This review presents the current evidence concerning timing of upper endoscopy in patients with suspected peptic ulcer bleeding. These patients should receive endoscopy within 24 hours after hospitalization in order to decrease the need of surgical haemostasis, risk of rebleeding and duration of hospital stay. In case of suspected serious bleeding and bloody nasogastric aspirate therapeutic endoscopy within 12 hours is beneficial in further reduction of length of hospital stay and need for blood transfusion. Early intensive resuscitation is presumably more important than early endoscopy in most patients. PMID- 21672467 TI - [Survival following lightning strike and treatment of sequelae]. AB - Lightning strike is an unpredictable weather phenomenon which can cause a variety of injuries to the human body. We present a case report with a 24-year-old male football player, who survived prolonged cardiac arrest after a lighting strike and then presented with multiple organ dysfunction due to cellular swelling, extreme rhabdomyolysis and global hypoperfusion. We describe the clinical observations, therapy and injuries which may be expected. Furthermore, the pathophysiology and factors influencing the survival of this patient are discussed. PMID- 21672468 TI - [Contrast enhanced ultrasound improves detection and quantification of intra abdominal bleeding]. AB - A 71-year-old man had a coarse needle biopsy performed. After the biopsy symptoms of abdominal bleeding were deteced. An acute ultrasound examination was performed as Focussed Assessment with Sonography in Trauma (FAST). The findings were inconclusive and a Contrast Enhanced Ultrasound (CEUS) was carried out. CEUS immediately demonstrated as well a rim around the liver with clear borders as a large amount of abdominal fluid. Upon these findings immediate surgery was performed. CEUS improves the contrast between areas with and without perfusion, which enhance the presence of haemorrhagic fluid, independently of the fluid's echo-pattern. CEUS seems to be a fast and valuable extension to FAST. PMID- 21672469 TI - [Dilated cardiomyopathy in an amphetamine user]. AB - The patient presented himself at the primary practitioner with dyspnoea and chest pain, and was initially misdiagnosed as having pneumonia. Two weeks later the patient developed universal oedema and was hospitalized. Echocardiography showed dilated cardiomyopathy. The initial diagnosis was delayed because the patient was not asked about his possible drug abuse. Remember to ask about drug abuse in younger patients with dyspnoea and uncharacteristic chest pains. PMID- 21672470 TI - "We got it all". PMID- 21672471 TI - " Nous avons tout enleve ". PMID- 21672472 TI - CUA growth: the fruits of teamwork. PMID- 21672473 TI - La croissance de l'AUC : Les fruits du travail d'equipe. PMID- 21672474 TI - Bloodletting and the management of localized prostate cancer. PMID- 21672475 TI - Surgical margin status among men with organ-confined (pT2) prostate cancer: a population-based study. AB - BACKGROUND: : Following prostate cancer surgery, positive surgical margin (PSM) status varies among institutions and there is evidence that high-volume surgeons and centres obtain better oncological results. However, larger studies recording PSM for radical prostatectomy (RP) are from large "centres of excellence" and not population-based. Cancer Care Ontario undertook an audit of pathology reports to determine the province-wide PSM rate for pathological stage T2 (pT2) disease prostate cancer and to assess the overall and regional-based PSM rates based on surgical volume to understand gaps in quality of care prior to undertaking quality improvement initiatives. METHODS: : Data were extracted as part of the Pathology Project Audit data output (2005, 2006). Pathology reports were submitted to Cancer Care Ontario by Ontario hospitals electronically via the Pathology Information Management System. An experienced cancer pathology coder extracted the PSM data from eligible RP cancer specimen pathology reports. Only reports that provided a pathological stage were included in the analysis. Biopsy and transurethral resection of the prostate reports were excluded. A convenience sample of 1346 reports from 2006 and 728 from 2005 were analyzed. Regression analysis was performed to assess volume-margin associations. RESULTS: : The median province-wide surgical PSM rate for pT2 disease was 33%, ranging 0-100% among 43 hospitals where RP volumes ranged 12-625. There was no significant correlation (p > 0.05) between volume and PSM by logistic regression with variable odds ratios (95% confidence interval [CI]) for PSM by quartile (1(st) = 1.66 [0.93-2.96]; 2(nd) = 0.97 [0.58-1.62]; 3(rd) = 1.44[0.91-2.29]) compared to the highest volume last quartile. Mean PSM rates between community and teaching hospitals were not significantly different. CONCLUSIONS: : The province-wide PSM rate for pT2 disease prostate cancer undergoing RP is higher than those published from "centres of excellence." Results from larger volume centres were not statistically significantly better, which contradicts previously published data. Factors, such as individual surgeon, patient selection, pathological processing and interpretation, may explain the differences. PMID- 21672476 TI - Variation spatiotemporelle de la cryptorchidie et de l'hypospadias au Quebec : Une etude exploratoire. AB - ReSUMe: OBJECTIFS: : La majorite des etudes effectuees au cours des dernieres decennies ont mis en evidence une augmentation du nombre de cas de cryptorchidie et d'hypospadias entre 1970 et 1990. De plus, l'importante variabilite geographique de ces anomalies est bien decrite. Cette etude vise a mesurer la prevalence a la naissance de la cryptorchidie et de l'hypospadias au Quebec, a verifier si ces anomalies sont en augmentation et a en evaluer la repartition interregionale. MeTHODE :: Une etude epidemiologique descriptive a ete realisee a partir du nombre de garcons de cinq ans et moins hospitalises pour une cryptorchidie ou un hypospadias au Quebec de 1989 a 2004 selon les donnees du fichier administratif d'hospitalisation MED-ECHO. Les donnees sur les naissances provenaient de l'Institut de la statistique du Quebec. ReSULTATS :: La prevalence annuelle moyenne pour 1000 naissances vivantes de sexe masculin est de 19,1 (IC a 95 % : 18,8-19,4) pour la cryptorchidie et 11,4 (IC a 95 % 11,1-11,6) pour l'hypospadias au Quebec. Au cours de la periode etudiee, la prevalence de cryptorchidie a legerement diminue, alors que celle de l'hypospadias est demeuree stable. Comparativement a la province du Quebec, des regions presentent une prevalence significativement differente de cryptorchidie et/ou d'hypospadias. . CONCLUSION: : Au Quebec, la prevalence de cryptorchidie est en legere diminution alors que celle de l'hypospadias est stable. Des variations regionales significatives sont observables. D'autres etudes sont necessaires afin d'evaluer l'hypothese d'un lien avec les contaminants environnementaux en emergence. L'implantation d'un systeme de surveillance des anomalies congenitales permettrait une representation plus valide de la situation. PMID- 21672477 TI - Documenting the prevalence of cryptorchidism and hypospadias. PMID- 21672478 TI - Randomized study evaluating testosterone recovery using short-versus long-acting luteinizing hormone releasing hormone agonists. AB - INTRODUCTION: : We sought to compare the rate of return of testosterone levels and sexual function in men with prostate cancer receiving longer acting, 3-month preparation of luteinizing hormone-releasing hormone agonist (L-LHRH-A) versus shorter acting, 1-month preparation of luteinizing hormone-releasing hormone agonist (S-LHRH-A). METHODS AND MATERIALS: : Men with low to intermediate risk localized prostate cancer were randomized to either L-LHRH-A (2-3 month duration LHRH-A) or S-LHRH-A (6-1 month duration LHRH-A) of androgen suppression therapy (AST) and prostate brachytherapy using iodine-125 radioisotopes. Serum total testosterone levels and PSA were recorded every 2 months for 2 years. RESULTS: : A planned target sample size of 100 was not achieved due to insufficient accrual. A total of 55 patients were randomized and 46 were used for analysis. The median time to recovery of testosterone to baseline levels (calculated from end of AST) was 8 and 4 months in the L-LHRH-A and S-LHRH-A arms, respectively (p = 0.268). The median time to testosterone recovery to lower limit of reference range was 4 and 2 months respectively (p = 0.087). INTERPRETATION: : This randomized study, which failed to reach accrual target, showed a trend towards more rapid recovery of testosterone levels using shorter acting LHRH-A. Another randomized study would be required to validate these findings. Currently, there is insufficient evidence to recommend the use of shorter acting LHRH-A as a means of providing more rapid recovery of testosterone levels. PMID- 21672479 TI - A new dawn in prostate cancer management: Do we have the trials to support it? PMID- 21672480 TI - The surgical personality: comparisons between urologists, non-urologists and non surgeons. AB - BACKGROUND: : Our objective was to compare personality traits between urologists and other surgeons, as well as between surgeons and non-surgeons. METHODS: : Eighty-six surgeons (57 faculty, 29 residents) completed the Revised NEO Personality Inventory (NEO PI-R), a validated measure of normal personality traits. Subjects agree or disagree with 240 statements to generate a score in each of the 5 major character traits: extraversion (E), openness (O), conscientiousness (C), agreeableness (A) and neuroticism (N). Each factor is subdivided into 6 component facets. Scores for urology faculty and residents were compared to the other surgical groups and 21 pediatricians. RESULTS: : The 3 groups differed significantly on extraversion (p < 0.001). Post-hoc analyses indicated that urologists obtained significantly higher extraversion scores than other surgeons (p < 0.05) and non-surgeons (p < 0.001) Other surgeons also scored significantly higher than non-surgeons on the extraversion factor (p < 0.05). No significant differences emerged on openness, conscientiousness, agreeableness or neuroticism. Of the 6 extraversion facets, urologists obtained significantly higher scores on gregariousness and excitement-seeking (p < 0.05) than non urologist surgeons, and significantly higher scores on gregariousness (p < 0.05), activity (p < 0.01), excitement seeking (p < 0.001), and positive emotions (p < 0.05) than non-surgeons. Non-urologist surgeons obtained significantly higher scores than non-surgeons on Activity and Excitement-seeking (p < 0.01).There were no significant differences in the facets of warmth or assertiveness. INTERPRETATION: : Urologists appear to be more extraverted compared to other surgeons. Both groups of surgeons were more extraverted than non-surgeons. If these findings can be confirmed on a wider basis, the data may be helpful in resident selection, mentoring, evaluation and career counselling. PMID- 21672481 TI - The urologist: the life of the party. PMID- 21672482 TI - Novel method of knotless vesicourethral anastomosis during robot-assisted radical prostatectomy: feasibility study and early outcomes in 30 patients using the interlocked barbed unidirectional V-LOC180 suture. AB - PURPOSE: : Our purpose was to describe the safety and feasibility of a running posterior reconstruction (PR) integrated with continuous vesicourethral anastomosis (VUA) using a novel self-cinching unidirectional barbed suture in robot-assisted radical prostatectomy (RARP). METHODS: : Between March and October 2010, 30 consecutive patients with organ-confined prostate cancer underwent RARP by an experienced single surgeon (KCZ). Upon completion of radical prostatectomy, urinary reconstruction was carried out using 2 knotless, interlocked 6-inches 3-0 V-Loc-180 suture. The left tail of the suture was initially used for PR (starting at 5-o'clock and ran to re-approximate the retrotrigonal layer to the rectourethralis) followed by left-sided VUA (from 6- to 12-o'clock), while the right-sided suture completed the right-sided VUA. Assurance of watertight closure with an intraoperative 300 cc saline visual cystogram was performed in all cases prior to case completion. Perioperative outcomes and 30-day complications were recorded. RESULTS: : All anastamoses were performed without assistance and without knot tying. Median time for nurse setup and urinary reconstruction was 40 seconds (interquartile range [IQR] 25-60) and 14.6 min (IQR 10-18), respectively. The need to readjust suture tension or place Lapra-Ty clips (Ethicon Endo Surgery, Cincinnati, OH) to establish watertight closure was observed in 2 cases (7%). No patient had clinical urinary leak and there was no urinary retention after catheter removal on mean postoperative day 5 (IQR 4-6). CONCLUSIONS: : Our clinical experience with a novel technique using the interlocked V-Loc suture during RARP for both PR and anastomosis appears to be safe and efficient. Using the barbed suture prevents slippage and eliminates the need for bedside assistance to maintain suture tension or knot tying, thus assuring watertight tissue closure. PMID- 21672483 TI - Recent developments in kidney cancer. AB - Renal cell carcinoma (RCC) diagnosis and management have undergone significant shifts in the recent past. The increasing rate of diagnosis of small renal masses, often in patients at high risk of morbidity with operative treatment, has led to studies, trials and discoveries in renal mass biopsy, active surveillance and minimally invasive thermal ablation. At the other end of the disease spectrum, targeted systemic therapies for metastatic RCC have supplanted cytokine based treatment, with significant benefits to progression and survival. Recent reviews and trials have also cemented the role of partial nephrectomy as standard surgical management for most low-stage masses, and the roles of regional lymphadenectomy and adrenalectomy concomitant with nephrectomy have been clarified. This review aims to highlight recent evidence that has emerged in the management of this complicated oncologic issue. PMID- 21672484 TI - Botulinum toxin A should not be first-line therapy for overactive bladder. PMID- 21672485 TI - Moving beyond ineffective medication for OAB. PMID- 21672486 TI - Botulinum toxin A: First-line therapy for idiopathic detrusor overactivity. PMID- 21672487 TI - More data are needed to use BTX A as first-line treatment. PMID- 21672489 TI - In memoriam. PMID- 21672488 TI - Cryptorchidism and its impact on male fertility: a state of art review of current literature. AB - Cryptorchidism is associated with impairment of germ cell maturation and subsequent infertility in adulthood. The present report details common scenarios of referral of men with prior history of cryptorchidism and orchidopexy seeking advice for infertility, and examines the association between cyrptorchidism and male infertility. The increase in the understanding of the hormonal profiles and patho-physiological changes in germ cell maturation in cryptorchid boys may potentially change our approach and management strategies. Improvement in sperm retrieval techniques and micromanipulation techniques, such as intracytoplasmic sperm injection, has led to excellent fertilization and pregnancy outcomes of treatment cycles. PMID- 21672490 TI - Carcinome epidermoide de l'uretre masculin revele par une rupture spontanee de l'uretre. AB - ReSUMe: Le carcinome epidermoide de l'uretre masculin est une tumeur rare, les tumeurs de l'uretre tous types confondus representant moins de 1 % des tumeurs de l'appareil urinaire. Le pronostic reste defavorable malgre un traitement chirurgical energique. La radiochimiotherapie semble etre un traitement prometteur, mais son role doit etre defini par d'autres etudes.Nous rapportons un cas rare de carcinome epidermoide de l'uretre bulbo-membraneux decouvert a un stade localement avance apres observation d'une rupture uretrale transtumorale chez un homme age de 70 ans. Le patient a ete traite, apres drainage vesical, par une irradiation externe associee a une chimiotherapie par cisplatine, et est decede apres progression de la maladie sur un an.La rupture spontanee de l'uretre transtumorale est un mode de decouverte exceptionnel temoignant d'une evolution locale defavorable, ce qui rend ces tumeurs difficilement operables. Cependant, l'espoir actuel reside dans des protocoles therapeutiques associant radiotherapie et chimiotherapie. PMID- 21672491 TI - The deep vein thrombosis caused by lymphocele after endoscopic extraperitoneal radical prostatectomy and pelvic lymph node dissection. AB - Pelvic lymphocele is a postoperative complications than can result after endoscopic extraperitoneal radical prostatectomy and pelvic lymph node dissection. Radical prostatectomy have many risk factors of deep vein thrombosis including location of target organ, malignancy, old age, Trendelenburg position, pelvic lymph node dissection, and long procedure time. A 57-year-old man with a localized prostate cancer was treated with endoscopic extraperitoneal radical prostatectomy and pelvic lymph node dissection. Deep vein thrombosis was detected as a first sign of pelvic lymphocele. Lymphocele was managed with a percutaneous drainage without sclerosant. We report a case of deep vein thrombosis due to pelvic lymphocele after endoscopic extraperitoneal radical prostatectomy. PMID- 21672492 TI - Ureteral erosion of a transvaginal tape. AB - The transvaginal tape (TVT) has gained acceptance as an effective surgical treatment of female stress incontinence. The popularity of this procedure is due to its relatively high success rate, short operative time and low incidence of complications. However, this procedure is not without potential for complications; the erosion of synthetic tape materials into adjacent pelvic structures has been reported. This report represents the first published case of ureteral erosion of TVT. PMID- 21672493 TI - Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To assess efficacy and safety of adjunctive ziprasidone in subjects with bipolar depression treated with lithium, lamotrigine, or valproate. METHOD: 298 adult outpatients with bipolar I disorder (DSM-IV criteria) were randomized to receive ziprasidone, 20-80 mg twice a day, or placebo twice a day for 6 weeks plus their preexisting mood stabilizer. The primary efficacy variable was change in Montgomery-Asberg Depression Rating Scale (MADRS) total scores from baseline to 6 weeks. The key secondary efficacy endpoint was change from baseline to week 6 in Clinical Global Impressions-Severity (CGI-S) scores. Computer-administered assessments for diagnostic confidence were included for quality control and to evaluate study performance. The study was conducted between October 2007 and December 2008. RESULTS: The mean +/- SD daily dose of ziprasidone was 89.8 +/- 29.1 mg. Least squares mean +/- standard error changes from baseline to week 6 on MADRS total score for ziprasidone and placebo treatment groups were -13.2 +/- 1.2 and -12.9 +/- 1.1, respectively, with a 2-sided P value of .792. There was no significant difference on the key secondary variable (CGI-S). Adjunctive ziprasidone was well tolerated. Poor quality ratings at baseline were associated with a trend for better improvement on placebo than ziprasidone. Among 43 placebo treated subjects with poor baseline quality ratings, 29 (67.4%) had baseline MADRS scores > 10 points higher on the computer-administered assessment than the MADRS administered by the site-based rater. The response favoring placebo over ziprasidone observed in this subgroup suggests that poor signal detection in some clinical trials can be a consequence of "subject inflation" as well as "rater inflation." CONCLUSIONS: Adjunctive ziprasidone treatment failed to separate from mood stabilizer alone on primary and secondary endpoints. Possible contributions to this result include enrollment of a substantial number of subjects with low diagnostic confidence, low quality ratings on the MADRS, and overzealous reporting of symptoms by subjects. TRIAL REGISTRATION: clinical trials.gov Identifier: NCT00483548. PMID- 21672494 TI - Concerns regarding the inclusion of temper dysregulation disorder with dysphoria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. PMID- 21672495 TI - Acupuncture for the treatment of major depressive disorder: a randomized controlled trial. AB - BACKGROUND: Over 50% of patients with major depressive disorder (MDD) either do not tolerate or do not respond to antidepressant medications. Several preliminary studies have shown the benefits of acupuncture in the treatment of depression. We sought to determine whether a 2-point electroacupuncture protocol (verum acupuncture) would be beneficial for MDD, in comparison to needling at nonchannel scalp points with sham electrostimulation (control acupuncture). METHOD: Fifty three subjects aged 18-80 years, recruited via advertisement or referral, were included in the primary analysis of our randomized controlled trial, which was conducted from March 2004 through May 2007 at UPMC Shadyside, Center for Complementary Medicine, in Pittsburgh, Pennsylvania. Inclusion criteria were mild or moderate MDD (according to the Structured Clinical Interview for DSM-IV Axis I Disorders) and a score of 14 or higher on the Hamilton Depression Rating Scale (HDRS). Exclusion criteria included severe MDD, seizure disorder or risk for seizure disorder, psychosis, bipolar disorder, chronic MDD, treatment-resistent MDD, and history of substance abuse in the prior 6 months. Patients were randomized to receive twelve 30-minute sessions of verum versus control acupuncture over 6 to 8 weeks. The HDRS was the primary outcome measure. The UKU Side Effect Rating Scale was used to assess for adverse effects. RESULTS: Twenty eight subjects were randomized to verum electroacupuncture and 25 to control acupuncture. The 2 groups did not differ with regard to gender, age, or baseline severity of depression. Both groups improved, with mean (SD) absolute HDRS score decreases of -6.6 (5.9) in the verum group and -7.6 (6.6) in the control group, corresponding to 37.5% and 41.3% relative decreases from baseline. There were no serious adverse events associated with either intervention, and endorsement of adverse effects was similar in the 2 groups. CONCLUSIONS: We were unable to demonstrate a specific effect of electroacupuncture. Electroacupuncture and control acupuncture were equally well tolerated, and both resulted in similar absolute and relative improvement in depressive symptoms as measured by the HDRS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00071110. PMID- 21672496 TI - Sudden deaths in psychiatric patients. AB - BACKGROUND: Studies using death certificates have indicated an excess of sudden cardiac deaths among users of antipsychotic drugs compared to the general population, but they may have underestimated the presence of other known causes of sudden and unexpected death. OBJECTIVE: To assess the causes and risk factors for sudden death discovered by contemporaneous investigation of all deaths occurring over a 26-year period (1984-2009) in adults (119,500 patient-years) receiving care in one large psychiatric hospital in New York. METHOD: Circumstances of death, psychiatric diagnoses, psychotropic drugs, and past medical history were extracted from the root cause analyses of sudden, unexpected deaths. After cases involving suicide, homicide, and drug overdoses were excluded, the remaining explained and unexplained cases of sudden death were compared regarding clinical variables and the utilization of antipsychotics. RESULTS: One hundred cases of sudden death were identified. The death remained unexplained in 52 cases. The incidence of unexplained sudden death per 100,000 patient-years increased from 7 (95% CI, 3.7-19.4) in 1984-1998 to 125 (95% CI, 88.9-175.1) in 2005-2009. Explained and unexplained cases were similar regarding psychiatric diagnoses and use of all psychotropic classes, including first- and second-generation antipsychotics. Dyslipidemia (P = .012), diabetes (P = .054), and comorbid dyslipidemia and diabetes (P = .006) were more common in the unexplained group. CONCLUSIONS: In a consecutive cohort of psychiatric patients, the unexplained sudden deaths were not associated with higher utilization of first- or second-generation antipsychotics. The role of diabetes and dyslipidemia as risk factors for sudden death in psychiatric patients requires careful longitudinal studies. PMID- 21672497 TI - Assessment of treatment algorithms including amantadine, metformin, and zonisamide for the prevention of weight gain with olanzapine: a randomized controlled open-label study. AB - OBJECTIVE: This 22-week, open-label study, conducted between November 2006 and September 2008 in a community setting, was designed to determine if weight gain during olanzapine treatment can be prevented or mitigated with adjunctive treatment algorithms that include amantadine, metformin, and zonisamide. METHOD: Outpatients with schizophrenia or schizoaffective disorder (DSM-IV-TR criteria) were randomly assigned to olanzapine alone (n = 50), olanzapine plus algorithm A (olanzapine + A [amantadine 200 mg/d with possible switches to metformin 1,000 1,500 mg/d and then to zonisamide 100-400 mg/d; n = 76]), or olanzapine plus algorithm B (olanzapine + B [metformin 1,000-1,500 mg/d with possible switches to amantadine 200 mg/d and then to zonisamide 100-400 mg/d; n = 73]). Brief weight management education was provided at baseline. The primary outcome measure was comparison of mean weight gain between olanzapine and pooled olanzapine + A and olanzapine + B results. RESULTS: Least squares mean +/- SE weight gain was 2.76 +/- 0.75 kg for olanzapine, 2.40 +/- 0.65 kg for olanzapine + A, and 0.65 +/- 0.63 kg for olanzapine + B. Mean weight gain during olanzapine treatment did not differ significantly from pooled results for olanzapine + A and olanzapine + B (P = .065). Participants treated with olanzapine + B experienced significantly less mean weight gain than olanzapine-treated participants (P = .036). CONCLUSIONS: Pooled treatment algorithm results were not significantly different from olanzapine monotherapy in mitigating weight gain. However, participants who received treatment with metformin with possible progression to amantadine and then zonisamide had significantly less mean weight gain than participants treated with olanzapine alone. Progression of some participants through the algorithm indicated that a single therapy solution may not be adequate for every patient. Patients treated with olanzapine should receive regular weight monitoring. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00401973. PMID- 21672498 TI - A prospective, naturalistic, blinded study of early neurobehavioral outcomes for infants following prenatal antidepressant exposure. AB - OBJECTIVE: This study examined the potential effects of antidepressant exposure in pregnancy on early infant neurobehavioral outcomes. METHOD: In this prospective, naturalistic study, neurobehavioral assessments using the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) were completed by blinded raters between March 2001 and August 2005 on 64 infants who were born to mothers in 1 of 3 categories: (1) women with a history of DSM-IV-diagnosed major depressive disorder (MDD) who were treated with antidepressants during pregnancy, (2) women with a history of DSM-IV-diagnosed MDD who discontinued or chose not to be treated with antidepressants during pregnancy, and (3) a nonpsychiatric control group. Summary scores for the BNBAS were obtained within the first week of life and at 6 to 8 weeks of age. RESULTS: No significant differences were observed between groups at either the first week after delivery or at 6 to 8 weeks of age on any of the summary scores for the 7 major clusters of the BNBAS. CONCLUSIONS: Antidepressant exposure during pregnancy does not appear to have major adverse effects on indices of early infant neurobehavioral development during the first 2 months of life as assessed by the BNBAS. While this finding is encouraging, further studies with larger samples and longer follow-up are needed. PMID- 21672500 TI - The impact of changing diagnostic criteria in posttraumatic stress disorder in a Canadian epidemiologic sample. AB - BACKGROUND: Since its inclusion in DSM-III, posttraumatic stress disorder (PTSD) has undergone a number of changes in its diagnostic criteria, including the expansion of Criterion A (traumatic stressor), the addition of symptom duration (none specified in DSM-III), and the requirement for impairment or distress (Criterion F, DSM-IV only). METHOD: This study examined the impact of changes in PTSD diagnostic criteria using a Canadian PTSD epidemiologic sample. The rates of PTSD and its correlates were evaluated in a nationally representative random sample of 3,006 adults. DSM-III, DSM-III-R, DSM-IV, and ICD-10 criteria were employed. DSM-III, DSM-III-R, and ICD-10 rates were re-evaluated, substituting specific DSM-IV criteria (A-F). RESULTS: The prevalence rates of lifetime PTSD ranged from 13.4% (DSM-III) to 13.0% (ICD-10) to 12.2% (DSM-III-R) to 9.2% (DSM IV); all rates differed significantly from each other (P < .001). Regardless of diagnostic criteria, most people reported more than 1-year duration of symptoms, although rates were significantly higher in those with DSM-IV PTSD (68.2%, P < .0001). Rates of comorbid major depressive disorder and alcohol and substance abuse and dependence were also significantly higher (P < .05) using the DSM-IV PTSD criteria, and those with DSM-IV PTSD reported significantly higher rates of help-seeking (P < .001). When Criterion F was added to earlier versions, lifetime PTSD rates became much closer to those obtained using DSM-IV criteria: 10.6% (DSM III), 10.2% (DSM-III-R), and 9.9% (ICD-10); however, rates fluctuated when operational definitions of Criterion F were modified. DSM-III PTSD was also substantially affected by DSM-IV Criteria A and C. CONCLUSIONS: DSM-IV PTSD may identify a more severe disorder. The addition of the clinical significance criterion (F) appeared to affect the greatest change in prevalence rates. Defining Criterion F as having both clinically significant psychological distress and functional impairment lowered the diagnostic threshold to a greater degree than did either distress or impairment alone. This information may be useful for future revisions of PTSD diagnostic criteria. PMID- 21672499 TI - Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume. AB - BACKGROUND: Reduced brain-derived neurotrophic factor (BDNF) levels have been reported in the serum and plasma of patients with psychosis. The aim of this cross-sectional case-control study was to investigate potential causes and consequences of reduced BDNF expression in these patients by examining the association between BDNF levels and measures of stress, inflammation, and hippocampal volume in first-episode psychosis. METHOD: Brain-derived neurotrophic factor, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha messenger RNA levels were measured in the leukocytes of 49 first-episode psychosis patients (DSM-IV criteria) and 30 healthy controls, all aged 18 to 65 years, recruited between January 2006 and December 2008. Patients were recruited from inpatient and outpatient units of the South London and Maudsley National Health Service Foundation Trust in London, United Kingdom, and the healthy controls were recruited from the same catchment area via advertisement and volunteer databases. In these same subjects, we measured salivary cortisol levels and collected information about psychosocial stressors (number of childhood traumas, number of recent stressors, and perceived stress). Finally, hippocampal volume was measured using brain magnetic resonance imaging in a subsample of 19 patients. RESULTS: Patients had reduced BDNF (effect size, d = 1.3; P < .001) and increased IL-6 (effect size, d = 1.1; P < .001) and TNF-alpha (effect size, d = 1.7; P < .001) gene expression levels when compared with controls, as well as higher levels of psychosocial stressors. A linear regression analysis in patients showed that a history of childhood trauma and high levels of recent stressors predicted lower BDNF expression through an inflammation-mediated pathway (adjusted R(2) = 0.23, P = .009). In turn, lower BDNF expression, increased IL-6 expression, and increased cortisol levels all significantly and independently predicted a smaller left hippocampal volume (adjusted R(2) = 0.71, P < .001). CONCLUSIONS: Biological changes activated by stress represent a significant factor influencing brain structure and function in first-episode psychosis through an effect on BDNF. PMID- 21672501 TI - Meta-analysis of epidemiologic studies of pediatric bipolar disorder. AB - OBJECTIVE: Meta-analyze all published epidemiologic studies reporting pediatric mania or bipolar disorder to investigate whether pediatric bipolar disorder is becoming more prevalent and whether rates vary significantly by country. DATA SOURCES: Searches of PubMed and PsycInfo were conducted through the spring of 2010 using the following search terms: child, pediatric, young, adolescent, epidemiology, prevalence, bipolar, mania, suicide, and psychiatric. We also manually reviewed references in recent reviews of epidemiology of bipolar disorder. STUDY SELECTION: All studies reporting rates for mania or hypomania in community epidemiologic samples with participants up to 21 years of age. DATA EXTRACTION: All articles were coded to extract relevant variables. Prevalence rates were calculated from reported number of cases with bipolar disorders, then logit transformed. Twelve studies were included, enrolling 16,222 youths between the ages of 7 and 21 years during a period from 1985 to 2007. Six samples were from the United States; 6 were from other countries (the Netherlands, the United Kingdom, Spain, Mexico, Ireland, and New Zealand). RESULTS: The overall rate of bipolar disorder was 1.8% (95% CI, 1.1%-3.0%). There was no significant difference in the mean rates between US and non-US studies, but the US studies had a wider range of rates. The highest estimates came from studies that used broad definitions and included bipolar disorder not otherwise specified. Year of enrollment was negatively correlated with prevalence (r = -0.04) and remained nonsignificant when controlling for study methodological differences. CONCLUSIONS: Mean rates of bipolar disorder were higher than commonly acknowledged and not significantly different in US compared to non-US samples, nor was there evidence of an increase in rates of bipolar disorder in the community over time. Differences in diagnostic criteria were a main driver of different rates across studies. PMID- 21672502 TI - Response rates to fluoxetine in subjects who initially show no improvement. AB - OBJECTIVE: This study sought to investigate the likelihood that subjects will respond to continued antidepressant therapy when little or no benefit has yet been observed. METHOD: Six hundred twenty-seven subjects diagnosed with DSM-IV major depressive disorder were recruited in a 12-week open-label trial with fluoxetine, which was designed as a preliminary phase to a subsequent 52-week continuation trial, which was conducted in 1997-2003. For each week of the study, a calculation was made for all subjects who had heretofore demonstrated little or no improvement as to the likelihood of converting to a positive response in subsequent weeks as measured by the Clinical Global Impressions scale, the primary outcome measure. In order to compare our findings with prior research, we focused primarily on outcomes at weeks 6, 8, and 12. RESULTS: The likelihood of converting to a positive response decreased the longer subjects remained unimproved. When week 6 was used as the end point, the likelihood of converting to a positive response for unimproved subjects at week 1 was 36% (n = 302); the respective conversion rates for weeks 2-5 were 29% (n = 208) at week 2, 18% (n = 151) at week 3, 17% (n = 120) at week 4, and 9% (n = 91) at week 5. When week 8 was used as the end point, the likelihood of converting to a positive response for unimproved subjects at week 4 was 23% (n = 118) and, at week 6, was 10% (n = 61). Finally, when week 12 was used as the end point, the likelihood of unimproved subjects at weeks 4, 6, and 8 converting to a positive response at week 12 was 50% (n = 117), 33% (n = 60), and 30% (n = 46), respectively. CONCLUSIONS: The study adds to a small, but growing literature that gives clinicians some guidelines to help decide whether to continue an antidepressant trial when little or no benefit has yet been observed. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00427128. PMID- 21672503 TI - [The 25th anniversary of the journal "Neuropsychiatrie"]. PMID- 21672504 TI - [ADHD in adults: identifying, experiencing, comprehending]. AB - In former times ADHD was seen as a children's disease, nowadays it is assured, that 4 % of adults suffer from ADHD. By today's state of research there are a lot of factors of influence according to the biopsychosocial model. For the development of mentalization and ability of reflexion, difficult early relationships, mistreatment or other traumatisations are characteristically relevant. In this paper the authors want to point to the interaction and the correlation of neurobiological, psychodynamic and psychosocial influences and to discuss the multifactorial development of this disease pattern. By the use of a multidimensional approach there could be additional therapeutic possibilities considering the patient individually and integrated. PMID- 21672505 TI - [Psychiatric hospitalisation across the life span]. AB - OBJECTIVE: The study addresses changes in the use of inpatient psychiatric treatment during the life course in various mental disorders. METHODS: We analysed inpatient admissions from a defined catchment area (1.3 mill. people) over a 1-year period by means of register data. All patients aged 15-80 referred to a psychiatric hospital in the Canton of Zurich were included in the study (9'637 inpatient admissions). To model effects of age, gender and diagnostic group we used Poisson regression analysis. RESULTS: In terms of the absolute number of psychiatric admissions, results suggest a peak in middle aged people (30-40 years). Nevertheless, the risk of inpatient psychiatric admission in terms of treatment prevalence (1.6 per 10'000 population) remains rather stable over the life course in both genders. On the level of specific mental disorders (ICD 10 main categories), treatment prevalence varies significantly over the life course in all diagnostic groups and, except for organic mental disorders, between both genders. From a life course perspective, data strongly suggest specific profiles of inpatient use in any mental disorder whatsoever, not only in disorders of childhood and adolescence or of ageing. In males with psychotic disorder for instance, use of inpatient treatment decreases significantly (from 6.1 to 1.0 per 10'000) after the age of 30. Only in psychotic disorders there was a significant age-by-gender interaction effect regarding the use of inpatient psychiatric treatment. CONCLUSIONS: Neither the specific profiles of inpatient use across the life span nor the gender differences can be traced back to the morbidity rates of corresponding disorders at the respective ages, not even in serious chronic mental disorders. The findings there fore bear important implications for both clinical practice and health policy. They accentuate the need for efforts to ensure adequate treatment and continuity of care particularly for those patients at the more severe end of the spectrum of mental disorders. PMID- 21672506 TI - [Psychopharmocotherapy of schizophrenia in forensic and general psychiatry]. AB - OBJECTIVE: In general psychiatry, the treatment of schizophrenic psychoses is focused on the reduction of symptoms, the improvement of quality of life and the recovery of the capacity to work. In forensic psychiatry, a further major targets is the reduction of aggressive behavior - not least by the establishment of a stable adherence to medication. It is unclear until now, whether this leads to different psychopharmacological treatment strategies. METHOD: The study includes 91 patients from the Psychiatric University Clinic Vienna (PUC) and 116 patients from the Justizanstalt Gollersdorf (JAGO), Austrian's central institution for the treatment of mentally disordered offenders not guilty by reason of insanity. We compared dosage, way of administration (oral, depot) and additional other medication. For both groups the chlorpromazine-equivalents were calculated. Additionally, combinations of different antipsychotic drugs and those of antipsychotics with medication of other substance classes (antidepressants, mood stabilizers, benzodiazepines, anticholinergics) were compared. RESULTS: Forensic patients were statistically significantly more often treated with intramuscular long-acting antipsychotics (LAI). Surprisingly, the total chlorpromazine equivalents did not differ between the groups. Combinations of two or more antipsychotics were common in both groups, in the JAGO frequently as a combination of a first generation depot antipsychotic drug (FGA) with oral second genera tion antipsychotics (SGA), in the PUC more as often a combination of two or more oral SGA. Antidepressants and benzodiazepines were more frequently prescribed in the PUC, anticholinergics in the JAGO. CONCLUSION: Patients suffering from schizophrenia are often non-compliant to medication. As nonadherence is a strong predictor for criminal offences, LAI-formulations are an important treatment tool in forensic psychiatry. This does not result in higher dosages. The high rates of polypharmacy in both groups emphasizes the well known problem that therapeutic guidelines based on studies in highly selected samples are often not transferable into everyday clinical practice. PMID- 21672507 TI - [Computer assisted cognitive training advances mood and psychological wellbeing - a comparison to paper pencil training relating to neuropsychological parameters, mood and cognitions]. AB - AIM: In this study a computer-assisted cognitive training programme (CAT) was compared to a paper-pencil-cognitive training and evaluated in psychiatric patients for its effects on neuropsychological parameters, mood and dysfunctional cognitions. METHODS: A total of 29 subjects were randomized either to the computer group or the paper-pencil group. Both groups underwent 20 sessions cognitive training. At the beginning and at the end of the training, both groups were given neuropsychological tests (memory, attention, concentration and information processing speed) and also questionnaires to assess depressive mood, thoughts, negative self communication and locus of control. RESULTS: At the start of the study, both the groups were comparable in demographic, diagnostic, neuropsychological and almost cognitive parameters. Compared to the baseline values, only the computer group improves significantly in mood and increases its positive self-verbalisation. In both groups no remarkable changes were found in the neuropsychological parameters. CONCLUSION: According to these results a computer-assisted cognitive training programme might primarily have a positive influence on mood than in parameters of performance and thus could be a very interesting therapeutic tool in the treatment of psychiatric patients. PMID- 21672508 TI - [Suicide in ethnic and cultural minorities - a research on literature]. AB - Suicide plays an important role in the history of civilization. For health, moral, cultural, social and psychological reasons it exhibits an impressive phenomenon all over the world. From a sociological point of wiev globalization leads to migration and enlarges ethnic minorities. Thus it influences the suicide risk of ethnicities - usually in different terms for both genders. Our review is based on data from a few countries. Found protective or risk factors refer to specific minorities and cannot implicitly be generalized. Poor methodological preciseness regards varying definitions of minority, ethnicitiy and immigrant as well as the heterogeneous description of interactions between minority and host country, of social inclusion and cultural peculiarities. On the other hand ethnic aspects involved in suicide are so relevant that they have to be explored as exactly as possible. PMID- 21672509 TI - [Family planning in women with schizophrenia - case report on a schizophrenic patient with multiple pregnancy resulting from in vitro fertilization]. AB - Case report on a 31-year old woman with chronic schizophrenia turning to a gynaecological university outpatient clinic with her husband and asking for an in vitro fertilization. After referral to the psychiatric consultation service the patient's psychiatric and psychosocial history was taken. The issue of indication was settled by considering medicoethical aspects, general risks in respect of the course of illness in pregnancy, postpartum period, and parenthood, and the special psychological burden due to in vitro fertilization with the issues of multiple pregnancy and the dilemma of fetal reduction. The patient's course during a triple pregnancy, postpartum period and early parenthood is described. PMID- 21672510 TI - Influence of the quality and quantity of blood ingested on reproductive parameters and life-span in Triatoma infestans (Klug). AB - In Triatominae, female fecundity and fertility may be affected by age, adult nutritional status (i.e., blood meal source and amount of blood ingested) and number of matings. Triatoma infestans (Klug) is the main vector of Chagas disease in southern South America and considering that reproductive success is intimately associated with the potential for colonizing or re-colonizing new ecotopes in endemic areas, we studied whether the blood meal source and the amount of blood ingested have influence on reproductive parameters. We constitute two groups: couples feeding regularly on guinea pigs and couples feeding regularly on pigeons. We registered quantity of blood ingested, fecundity, fertility, number of matings, days between the first feeding and mating, copula initiation, oviposition initiation and adult life-span. Results showed that females that fed on guinea pigs exhibited high fecundity and fertility, higher number of matings and they needed a lower amount of blood to form an egg. The number of matings and fecundity increased linearly and significantly with the quantity of blood ingested for both meal sources. Results from lineal regression between life-span and fecundity showed a positive and significant relation for both meal sources. The number of matings showed a positive relation with fecundity for both meal sources but significant only for guinea pigs. In T. infestans, the quantity of blood ingested could be a determinant of their reproductive efficiency. This species is mainly adapted to human dwelling and peridomestic structures where there is low host diversity. Considering that this species is in contact with mammals over other food sources, a greater reproductive success may result from an adaptation to this environment. PMID- 21672511 TI - Use of isotope differential derivatization for simultaneous determination of thiols and oxidized thiols by liquid chromatography tandem mass spectrometry. AB - Here we report a new isotopic pair of derivatization reagents, omega bromoacetonylquinolinium bromide (BQB) and d(7)-omega-bromoacetonylquinolinium bromide (d(7)-BQB). BQB and d(7)-BQB both rapidly and selectively reacted with thiols in acidic medium within 3min with the aid of a microwave. Reduced thiols and total thiols in urine were labeled with BQB and d(7)-BQB, respectively. The BQB- and d(7)-BQB-labeled urine samples were then mixed and separated on a HILIC (hydrophilic interaction chromatography) column followed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection. The new strategy, which we have named isotope differential derivatization, allows us to simultaneously determine thiols and oxidized thiols in a single run. Compared with positive mode ESI detection of unlabeled thiols, the positive mode ESI-MS signal intensities of BQB-labeled thiols were found to increase by 10-, 20-, and 40-fold for cysteine (Cys), homocysteine (HCys), and glutathione (GSH), respectively (unlabeled N-acetylcysteine (Nac) is difficult to detect by ESI-MS in positive mode due to its low ionization efficiency). The detection limits calculated at a signal-to-noise ratio of 3 were found to be 8.02, 1.56, 0.833, and 3.27nmol/L for Cys, HCys, Nac, and GSH, respectively. Recoveries of thiols and disulfides from spiked urine samples were between 80% and 105%. The method was successfully used to determine thiols and oxidized thiols in urine samples of 25 healthy volunteers. PMID- 21672512 TI - A tetrameric structure is not essential for activity in dihydrodipicolinate synthase (DHDPS) from Mycobacterium tuberculosis. AB - Dihydrodipicolinate synthase (DHDPS) is a validated antibiotic target for which a new approach to inhibitor design has been proposed: disrupting native tetramer formation by targeting the dimer-dimer interface. In this study, rational design afforded a variant of Mycobacterium tuberculosis, Mtb-DHDPS-A204R, with disrupted quaternary structure. X-ray crystallography (at a resolution of 2.1A) revealed a dimeric protein with an identical fold and active-site structure to the tetrameric wild-type enzyme. Analytical ultracentrifugation confirmed the dimeric structure in solution, yet the dimeric mutant has similar activity to the wild type enzyme. Although the affinity for both substrates was somewhat decreased, the high catalytic competency of the enzyme was surprising in the light of previous results showing that dimeric variants of the Escherichia coli and Bacillus anthracis DHDPS enzymes have dramatically reduced activity compared to their wild-type tetrameric counterparts. These results suggest that Mtb-DHDPS A204R is similar to the natively dimeric enzyme from Staphylococcus aureus, and highlight our incomplete understanding of the role played by oligomerisation in relating protein structure and function. PMID- 21672513 TI - Molecular, kinetic, thermodynamic, and structural analyses of Mycobacterium tuberculosis hisD-encoded metal-dependent dimeric histidinol dehydrogenase (EC 1.1.1.23). AB - The emergence of drug-resistant strains of Mycobacterium tuberculosis, the major causative agent of tuberculosis (TB), and the deadly HIV-TB co-infection have led to an urgent need for the development of new anti-TB drugs. The histidine biosynthetic pathway is present in bacteria, archaebacteria, lower eukaryotes and plants, but is absent in mammals. Disruption of the hisD gene has been shown to be essential for M. tuberculosis survival. Here we present cloning, expression and purification of recombinant hisD-encoded histidinol dehydrogenase (MtHisD). N terminal amino acid sequencing and electrospray ionization mass spectrometry analyses confirmed the identity of homogeneous MtHisD. Analytical gel filtration, metal requirement analysis, steady-state kinetics and isothermal titration calorimetry data showed that homodimeric MtHisD is a metalloprotein that follows a Bi Uni Uni Bi Ping-Pong mechanism. pH-rate profiles and a three-dimensional model of MtHisD allowed proposal of amino acid residues involved in either catalysis or substrate(s) binding. PMID- 21672514 TI - Effect of E1(64-81) hepatitis G peptide on the in vitro interaction of HIV-1 fusion peptide with membrane models. AB - One way to gain information about the fusogenic potential of virus-derived synthetic peptides is to examine their interfacial properties and subsequently to study them in monolayers and bilayers. Here, we characterize the physicochemical surface properties of the peptide E1(64-81), whose sequence is AQLVGELGSLYGPLSVSA. This peptide is derived from the E1 structural protein of GBV C/HGV which was previously shown to inhibit leakage of vesicular contents caused by the HIV-1 fusion peptide (HIV-1 FP). Mixed isotherms of E1(64-81) and HIV-1 FP were obtained and their Brewster angle microscopy (BAM) and atomic force microscopy (AFM) images showed that the peptide mixture forms a different structure that is not present in the pure peptide images. Studies with lipid monolayers (1,2-dimyristoyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (DMPG) and 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG)) show that both peptides interact with all the lipids assayed but the effect that HIV-1 FP has on the monolayers is reduced in the presence of E1(64-81). Moreover, differential scanning calorimetry (DSC) experiments show the capacity of HIV-1 FP to modify the properties of the bilayer structure and the capacity of E1(64-81) to inhibit these modifications. Our results indicate that E1(64-81) interacts with HIV-1 FP to form a new structure, and that this may be the cause of the previously observed inhibition of the activity of HIV-1 FP by E1(64-81). PMID- 21672515 TI - Reducing blood glucose level in TIDM mice by orally administering the silk glands of transgenic hIGF-I silkworms. AB - To realize the secretory expression of human insulin-like growth factor-I (hIGF I) in the posterior silk glands (PSGs) of transgenic silkworms, the piggyBac transposon vector pigA3GFP-fibHS-hIGF-i.e.-neo containing a neomycin-resistance gene (neo), green fluorescent protein gene (gfp) and human insulin-like growth factor I (hIGF-I) gene controlled by the Bombyxmori fibroin heavy chain gene (fib H) promoter with its downstream signal peptide sequence, and a helper plasmid containing the piggyBac transposase sequence under the control of the B. mori actin 3 gene (A3) promoter were transferred into silkworm eggs by sperm-mediated gene transfer. Transformed silkworms were obtained after being screened for green fluorescence and by the antibiotic G418. In the PSGs of the transformed silkworms, a specific band representing hIGF-I could be detected by Western blotting, and the content of the hIGF-I estimated by ELISA was approximately 1.84 MUg/gram of cocoon and 19.18 MUg/gram of freeze-dried PSG powder. To further estimate the biological activity of the expressed hIGF-I, streptozotocin-induced TIDM mice were orally administered with the PSG powder of the transgenic silkworms, the results showed the blood glucose levels of mice were significantly reduced, suggesting that the the PSGs powder of transgenic hIGF-I silkworms could possibly be used as a perorally administered medicine. PMID- 21672516 TI - Podocan-like protein: a novel small leucine-rich repeat matrix protein in bone. AB - Recently, significant attention has been drawn to the biology of small leucine rich repeat proteoglycans (SLRPs) due to their multiple functionalities in various cell types and tissues. Here, we characterize a novel SLRP member, "Podocan-like (Podnl) protein" identified by a bioinformatics approach. The Podnl protein has a signal peptide, a unique cysteine-rich N-terminal cluster, 21 leucine-rich repeat (LRR) motifs, and one putative N-glycosylation site. This protein is structurally similar to podocan in SLRPs. The gene was highly expressed in mineralized tissues and in osteoblastic cells and the high expression level was observed at and after matrix mineralization in vitro. Podnl was enriched in newly formed bones based on immunohistochemical analysis. When Podnl was transfected into osteoblastic cells, the protein with N-glycosylation was detected mainly in the cultured medium, indicating that Podnl is a secreted N glycosylated protein. The endogenous Podnl protein was also present in bone matrix. These data provide a new insight into our understanding of the emerging SLRP functions in bone formation. PMID- 21672517 TI - Atrial natriuretic peptide regulates lipid mobilization and oxygen consumption in human adipocytes by activating AMPK. AB - Atrial natriuretic peptide (ANP) has been shown to regulate lipid and carbohydrate metabolism providing a possible link between cardiovascular function and metabolism by mediating the switch from carbohydrate to lipid mobilization and oxidation. ANP exerts a potent lipolytic effect via cGMP-dependent protein kinase (cGK)-I mediated-stimulation of AMP-activated protein kinase (AMPK). Activation of the ANP/cGK signaling cascade also promotes muscle mitochondrial biogenesis and fat oxidation. Here we demonstrate that ANP regulates lipid metabolism and oxygen utilization in differentiated human adipocytes by activating the alpha2 subunit of AMPK. ANP treatment increased lipolysis by seven fold and oxygen consumption by two fold, both of which were attenuated by inhibition of AMPK activity. ANP-induced lipolysis was shown to be mediated by the alpha2 subunit of AMPK as introduction of dominant-negative alpha2 subunit of AMPK attenuated ANP effects on lipolysis. ANP-induced activation of AMPK enhanced mitochondrial oxidative capacity as evidenced by a two fold increase in oxygen consumption and induction of mitochondrial genes, including carnitine palmitoyltransferase 1A (CPT1a) by 1.4-fold, cytochrome C (CytC) by 1.3-fold, and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) by 1.4-fold. Treatment of human adipocytes with fatty acids and tumor necrosis factor alpha (TNFalpha) induced insulin resistance and down-regulation of mitochondrial genes, which was restored by ANP treatment. These results show that ANP regulates lipid catabolism and enhances energy dissipation through AMPK activation in human adipocytes. PMID- 21672518 TI - Acupuncture ameliorated skeletal muscle atrophy induced by hindlimb suspension in mice. AB - Preventing skeletal muscle atrophy is critical for maintaining quality of life, but it is often a challenging goal for the elderly and patients with severe conditions. We hypothesized that acupuncture in place of exercise training is an alternative non-pharmacological intervention that can help to prevent muscle atrophy. To elucidate the effects of acupuncture on skeletal muscle atrophy caused by hindlimb suspension (HS), we performed acupuncture on mice according to two different methods: acupuncture with electrical stimulation (EA: electroacupuncture) and without electrical stimulation (MA: manual acupuncture). A needle was retained in the gastrocnemius muscle for 30 min every day for 2 weeks in the EA and MA groups. In the EA group, 30 min of repetitive electrical stimulation (1 Hz, 1 ms pulse width, 6.5 mA intensity) was also applied. HS significantly reduced muscle mass and the cross-sectional area of the soleus muscles. This HS-induced reduction was significantly improved in the EA group, although the level of improvement remained insufficient when compared with the control group. We found that the mRNA expression levels of atrogin-1 and MuRF1, which play a principal role in muscle-specific degradation as E3 ubiquitin ligases, were significantly increased in the HS group compared to the control group. EA and MA reduced the HS-induced upregulation of atrogin-1 (p<0.01 in EA and MA) and MuRF1 (p<0.01 in EA) mRNAs. We also found that the expression levels of PI3K, Akt1, TRPV4, adenosine A1 receptor, myostatin, and SIRT1 mRNAs tended to be increased by HS. EA and MA further increased the HS-induced upregulation of Akt1 (p<0.05 in MA) and TRPV4 (p<0.05 in MA) mRNAs. We concluded that acupuncture partially prevented skeletal muscle atrophy. This effect might be due to an increase in protein synthesis and a decrease in protein degradation. PMID- 21672519 TI - Electrostatic potential as a tool to understand interactions between malaria vaccine candidate peptides and MHC II molecules. AB - One of the most important problems in vaccine development consists in understanding receptor-ligand interactions between Class II Major Histocompatibility Complex molecules (MHC II) and antigenic peptides involved in inducing an appropriate immune response. In this study, we used X-ray crystallography structural data provided by the HLA-DRbeta1*0301-CLIP peptide interaction to compare native non-immunogenic and specifically-modified immunogenic peptides derived from the malarial SALSA protein, by analyzing molecular electrostatic potential surfaces on the most important regions of the peptide binding groove (Pockets 1, 4, 6 and 9). Important differences were found on the electrostatic potential induced by these peptides, particularly in MHC II conserved residues: Qalpha9, Salpha53, Nalpha62, Nalpha69, Ybeta30, Ybeta60, Wbeta61, Qbeta70, Kbeta71 and Vbeta86, the same ones involved in establishing hydrogen bonds between Class II molecule-peptide and the recognition by T cell receptor, it correlating well with the change in their immunological properties. The results clearly suggest that modifications done on the electrostatic potential of these amino acids could favor the induction of different immune responses and therefore, their identification could allow modifying peptides a priori and in silico, so as to render them into immunogenic and protection inducers and hence suitable components of a chemically-synthesized, multi antigenic, minimal subunit based vaccine. PMID- 21672520 TI - Crystal structure of the sweet-tasting protein thaumatin II at 1.27A. AB - Thaumatin, an intensely sweet-tasting protein, elicits a sweet taste sensation at 50 nM. Here the X-ray crystallographic structure of one of its variants, thaumatin II, was determined at a resolution of 1.27 A. Overall structure of thaumatin II is similar to thaumatin I, but a slight shift of the Calpha atom of G96 in thaumatin II was observed. Furthermore, the side chain of residue 67 in thaumatin II is highly disordered. Since residue 67 is one of two residues critical to the sweetness of thaumatin, the present results suggested that the critical positive charges at positions 67 and 82 are disordered and the flexibility and fluctuation of these side chains would be suitable for interaction of thaumatin molecules with sweet receptors. PMID- 21672521 TI - Lovastatin and valproic acid additively attenuate cell invasion in ACC-MESO-1 cells. AB - Malignant pleural mesothelioma is known to be widely resistant to therapy and new treatment strategies are needed. Both statins and valproic acid are known to suppress the growth of multiple cancer lines, but the effects on mesothelioma cells are not well defined. In the present study we examined the effects of lovastatin and valproic acid on ACC-MESO-1, which is a human derived mesothelioma cell line. We found that lovastatin (2 MUM) and/or valproic acid (5 mM) did not reduce cell viability nor induce apoptosis, but reduced cell invasion. The effect was additive when combined. Furthermore it was speculated that induction of autophagic changes was at least in part involved in this process. PMID- 21672522 TI - Apical localization of PMCA2w/b is enhanced in terminally polarized MDCK cells. AB - The "w" splice forms of PMCA2 localize to distinct membrane compartments such as the apical membrane of the lactating mammary epithelium, the stereocilia of inner ear hair cells or the post-synaptic density of hippocampal neurons. Previous studies indicated that PMCA2w/b was not fully targeted to the apical domain of MDCK cells but distributed more evenly to the lateral and apical membrane compartments. Overexpression of the apical scaffold protein NHERF2, however, greatly increased the amount of the pump in the apical membrane of these epithelial cells. We generated a stable MDCK cell line expressing non-tagged, full-length PMCA2w/b to further study the localization and function of this protein. Here we demonstrate that PMCA2w/b is highly active and shows enhanced apical localization in terminally polarized MDCK cells grown on semi-permeable filters. Reversible surface biotinylation combined with confocal microscopy of fully polarized cells show that the pump is stabilized in the apical membrane via the apical membrane cytoskeleton with the help of endogenous NHERF2 and ezrin. Disruption of the actin cytoskeleton removed the pump from the apical actin patches without provoking its internalization. Our data suggest that full polarization is a prerequisite for proper positioning of the PMCA2w variants in the apical membrane domain of polarized cells. PMID- 21672523 TI - The disordered C-terminus of the RNA polymerase II phosphatase FCP1 is partially helical in the unbound state. AB - Intrinsically disordered proteins (IDPs) lack unique 3D structures under native conditions and yet retain critical functions. Recycling of RNA Polymerase II after transcription is promoted by an interaction between the winged helix domain of RAP74, a component of the general transcription factor IIF (TFIIF), and the C terminus of the TFIIF-associating CTD phosphatase (FCP1). Sixteen residues from the C-terminus of FCP1 form an alpha-helix in the complex, but the protein is otherwise agreed in the literature to be intrinsically disordered. Here we show through CD and recently developed carbon-detected NMR that, although FCP1 is intrinsically disordered, the above 16 residues composing the RAP74 binding surface form nascent alpha-helical structure in the unbound state. We further show retention of general FCP1 disorder and the nascent helical content in HeLa extract, establishing cellular relevance. The conformational bias observed leads to a mechanistic proposal for FCP1's transition from a disordered ensemble to an ordered conformation upon binding. PMID- 21672524 TI - Heparin-binding hemagglutinin HBHA from Mycobacterium tuberculosis affects actin polymerisation. AB - HBHA is a mycobacterial cell surface protein that mediates adhesion to epithelial cells and that has been implicated in the dissemination of Mycobacterium tuberculosis (Mtb) from the site of primary infection. In this work, we demonstrate that HBHA is able to bind G-actin whereas its shorter form, deprived of the lysine-rich C-terminal region (HBHADeltaC), does not bind. Consistently, interaction of actin with HBHA is competitive with heparin binding. Notably, we also observe that HBHA, but not HBHADeltaC, clearly hampers G-actin polymerisation into F-actin filaments. Since Mtb escapes from the phagosome into the cytosol of host cells, where it can persist and replicate, HBHA is properly localised on the bacterial surface to regulate the dynamic process of cytoskeleton formation driven by actin polymerisation and depolymerisation. PMID- 21672525 TI - MiR-192 inhibits nucleotide excision repair by targeting ERCC3 and ERCC4 in HepG2.2.15 cells. AB - Deficient DNA repair capacity is associated with genetic lesions accumulation and susceptibility to carcinogenesis. MicroRNAs (miRNAs) are small non-coding RNAs that regulate various cellular pathways including DNA repair. Here we hypothesized that the existence of HBV products may interfere with cellular nucleotide excision repair (NER) through microRNA-mediated gene regulation. We found that NER was impaired in HepG2.2.15 cells, a stable HBV-expressing cell line, compared with its parental cell line HepG2. Altered miRNA expression profile, in particular the significant upregulation of miR-192, was observed in HepG2.2.15 cells. Additionally, ERCC3 and ERCC4, two key factors implicated in NER, were identified as targets of miR-192 and over-expressing miR-192 significantly inhibited cellular NER. These results indicated that persistent HBV infection might trigger NER impairment in part through upregulation of miR-192, which suppressed the levels of ERCC3 and ERCC4. It provides new insight into the effect of chronic HBV infection on NER and genetic instability in cancer. PMID- 21672526 TI - Identification and clarification of the role of key active site residues in bacterial glutathione S-transferase zeta/maleylpyruvate isomerase. AB - The maleylpyruvate isomerase NagL from Ralstonia sp. strain U2, which has been structurally characterized previously, catalyzes the isomerization of maleylpyruvate to fumarylpyruvate. It belongs to the class zeta glutathione S transferases (GSTZs), part of the cytosolic GST family (cGSTs). In this study, site-directed mutagenesis was conducted to probe the functions of 13 putative active site residues. Steady-state kinetic information for mutants in the reduced glutathione (GSH) binding site, suggested that (a) Gln64 and Asp102 interact directly with the glutamyl moiety of glutathione, (b) Gln49 and Gln64 are involved in a potential electron-sharing network that influences the ionization of the GSH thiol. The information also suggests that (c) His38, Asn108 and Arg109 interact with the GSH glycine moiety, (d) His104 has a role in the ionization of the GSH sulfur and the stabilization of the maleyl terminal carboxyl group in the reaction intermediate and (e) Arg110 influences the electron distribution in the active site and therefore the ionization of the GSH thiolate. Kinetic data for mutants altered in the substrate-binding site imply that (a) Arg8 and Arg176 are critical for maleylpyruvate orientation and enolization, and (b) Arg109 (exclusive to NagL) participates in k(cat) regulation. Surprisingly, the T11A mutant had a decreased GSH K(m) value, whereas little impact on maleylpyruvate kinetics was observed, suggesting that this residue plays an important role in GSH binding. An evolutionary trend in this residue appears to have developed not only in prokaryotic and eukaryotic GSTZs, but also among the wider class of cGSTs. PMID- 21672527 TI - Exploration of target molecules for molecular imaging of inflammatory bowel disease. AB - Molecular imaging technology is a powerful tool for the diagnosis of inflammatory bowel disease (IBD) and the efficacy evaluation of various drug therapies for it. However, it is difficult to elucidate directly the relationships between the responsible molecules and IBD using existing probes. Therefore, the development of an alternative probe that is able to elucidate the pathogenic mechanism and provide information on the appropriate guidelines for treatment is earnestly awaited. In this study, we investigated pathognomonic molecules in the intestines of model mice. The accumulation of fluorine-18 fluorodeoxyglucose ((18)F-FDG) in the inflamed area of the intestines of dextran sulfate sodium (DSS)- or indomethacin (IND)-induced IBD model mice was measured by positron emission tomography (PET) and autoradiography to confirm the inflamed area. The results suggested that the inflammation was selectively induced in the colons of mice by the administration of DSS, whereas it was induced mainly in the ilea and the proximal colons of mice by the administration of IND. To explore attractive target molecules for the molecular imaging of IBD, we evaluated the gene expression levels of cytokines and cytokine receptors in the inflamed area of the intestines of both model mice. We found that the expression levels of cytokines and cytokine receptors were significantly increased during the progression of IBD, whereas the expression levels were decreased as the mucosa began to heal. In particular, the expression levels of these molecules had already changed before the symptoms of IBD appeared. In addition, the alterations of cytokine and cytokine receptor expression levels indicated differences in the expression pattern depending on the pathogenic mechanism or the region of inflammation (e.g., TNF-alpha). Our results suggest that these cytokines or cytokine receptors participate in the pathogenesis of IBD and are valuable biomarkers for the detection of the different circumstances underlying inflammation by the molecular imaging method. Finally, the development of an imaging probe for our target molecules is expected to improve our understanding of the inflammatory conditions of IBD. PMID- 21672528 TI - Helix stabilization of amphipathic peptides by hydrocarbon stapling increases cholesterol efflux by the ABCA1 transporter. AB - Apolipoprotein mimetic peptides are short amphipathic peptides that efflux cholesterol from cells by the ABCA1 transporter and are being investigated as therapeutic agents for cardiovascular disease. We examined the role of helix stabilization of these peptides in cholesterol efflux. A 23-amino acid long peptide (Ac-VLEDSFKVSFLSALEEYTKKLNTQ-NH2) based on the last helix of apoA-I (A10) was synthesized, as well as two variants, S1A10 and S2A10, in which the third and fourth and third and fifth turn of each peptide, respectively, were covalently joined by hydrocarbon staples. By CD spectroscopy, the stapled variants at 24 degrees C were more helical in aqueous buffer than A10 (A10 17%, S1A10 62%, S2A10 97%). S1A10 and S2A10 unlike A10 were resistant to proteolysis by pepsin and chymotrypsin. S1A10 and S2A10 showed more than a 10-fold increase in cholesterol efflux by the ABCA1 transporter compared to A10. In summary, hydrocarbon stapling of amphipathic peptides increases their helicity, makes them resistant to proteolysis and enhances their ability to promote cholesterol efflux by the ABCA1 transporter, indicating that this peptide modification may be useful in the development of apolipoprotein mimetic peptides. PMID- 21672529 TI - Mutated C-terminal fragments of Clostridium perfringens enterotoxin have increased affinity to claudin-4 and reversibly modulate tight junctions in vitro. AB - Passage across epithelial cell sheets is the first step in drug absorption. Tight junctions (TJs) are located between adjacent epithelial cells and seal the intercellular space preventing leakage of solutes. Claudin, a tetra-transmembrane protein family, is a pivotal functional and structural component of the TJ barrier. Modulation of the claudin-based TJ seal is a strategy for mucosal drug absorption. We previously found that a claudin-4 binder, a C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE194), was a modulator of the TJ seal and a potent mucosal absorption enhancer. In the present study, we attempted to improve claudin-4 binders by modification of C-CPE194. Substitution of Asn at position 309 and Ser at position 313 with Ala increased the affinity to claudin-4 by 9.9-fold as compared to C-CPE194. Deletion of 10 amino acids in the N-terminal domain of the double-alanine-substituted mutant increased affinity to claudin-4 by 23.9-fold as compared to C-CPE194. These C-CPE194 mutants reversibly modulated the TJ seal in human intestinal epithelial cell sheets. The N-terminal-truncated mutant was the most potent modulator of the TJ seal. These findings indicate that the C-CPE mutant may be a promising lead for the development of a clinical TJ modulator. PMID- 21672531 TI - CBI Editorial 2011. PMID- 21672530 TI - Enzymatic and non-enzymatic activities of SHIP-1 in signal transduction and cancer. AB - PI3K cascade is a central signaling pathway regulating cell proliferation, growth, differentiation, and survival. Tight regulation of the PI3K signaling pathway is necessary to avoid aberrant cell proliferation and cancer development. Together with SHIP-1, the inositol phosphatases PTEN and SHIP-2 are the gatekeepers of this pathway. In this review, we will focus on SHIP-1 functions. Negative regulation of immune cell activation by SHIP-1 is well characterized. Besides its catalytic activity, SHIP-1 also displays non-enzymatic activity playing role in several immune pathways. Indeed, SHIP-1 exhibits several domains that mediate protein-protein interaction. This review emphasizes the negative regulation of immune cell activation by SHIP-1 that is mediated by its protein protein interaction. PMID- 21672532 TI - Lipoprotein(a)-cholesterol: a significant component of serum cholesterol. AB - BACKGROUND: Lipoprotein(a) [Lp(a)] is known to be a cholesterol-rich lipoprotein, however, the contribution of Lp(a)-cholesterol [Lp(a)-C] to the serum cholesterol and LDL-C levels has not yet been fully evaluated. METHODS: We determined the serum Lp(a)-C in 55 subjects with serum Lp(a) concentrations ranging from 9 to 129 mg/dl. To measure the serum Lp(a)-C concentrations, we developed an immunoaffinity gel assay; serum was incubated with Sepharose 4B gel coupled with immunoglobulin G (IgG) prepared from a polyclonal anti-Lp(a) goat antiserum. After separating Lp(a) from other lipoproteins, we determined the serum Lp(a)-C concentrations. Validation of the assay showed satisfactory results in terms of the specificity and reproducibility. RESULTS: The mean cholesterol content of Lp(a), determined as Lp(a)-C/Lp(a), was 29.5+/-10.4%. The serum Lp(a)-C values were found to be highly correlated with the serum Lp(a) mass (r=0.923, p<0.001). At serum Lp(a) levels of over 50mg/dl, the contribution of Lp(a)-C to the serum total cholesterol was 10.2%. Further, the Friedewald formula overestimated the serum LDL-C by 20.4%. CONCLUSIONS: Lp(a) contains approximately 30% cholesterol in each molecule. In subjects with markedly elevated serum Lp(a) concentrations, the Lp(a)-C values should be taken into account when evaluating the serum LDL-C. PMID- 21672533 TI - Cardiovascular diseases and genome-wide association studies. AB - Genome-Wide Association Studies (GWAS) on cardiovascular diseases and related quantitative traits revealed numerous genetic variants, which however have been partially replicated, probably due to the heterogeneity of the clinical phenotypes and the populations studied. Even if novel biological pathways have been identified through these studies, there is still a long way until the validation of causal variants and their use in clinical practice as factors for prevention, risk assessment and as targets for the development of new medications. GWAS methodologies should, in the following years, integrate gene gene and gene-environment interaction analyses in a global research strategy and also involve subsequent transcriptomic and proteomic investigations. The GWAS era is very promising but it is just at the beginning. PMID- 21672534 TI - Reference intervals for serum creatinine with enzymatic assay and evaluation of four equations to estimate glomerular filtration rate in a healthy Chinese adult population. AB - BACKGROUND: With the wide usage of enzymatic assays to determine serum creatinine (Scr) in China, reference interval (RI) needs to be established. At the same time, the performance of Scr based equations to calculate estimated glomerular filtration rate (eGFR) in healthy Chinese adults has not been extensively investigated. METHODS: This study has strictly followed the International Federation of Clinical Chemistry (IFCC) recommendations and the Clinical Laboratory Standards Institute (CLSI) C28-A2 document. A total number of 778 healthy Chinese adults (male 433, female 345) were enrolled in this study. RESULTS: By nonparametric method, RIs for males were: <60 years, 58-93 MUmol/l and >60 years, 54-109 MUmol/l; RIs for females were: <60 years, 42-69 MUmol/l and >60 years, 43-83 MUmol/l. Modification of Diet in Renal Disease (MDRD) equation and MDRD for Japanese made the percentage of eGFR >90 ml/min/1.73 m(2) 31.7% and 4.9%; percentage of eGFR 60-89 ml/min/1.73 m(2) 65.2% and 64.0%, respectively. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and CKD-EPI for Asian made the percentage of eGFR >90 ml/min/1.73 m(2) 89.2% and 94.0%; percentage of eGFR 60-89 ml/min/1.73 m(2) 10.3% and 5.7%, respectively. CONCLUSION: Scr RIs of healthy Chinese adults were found to be lower than those of Caucasians. Two MDRD equations underestimated GFR, while two CKD-EPI equations seemed to estimate a reasonable distribution of eGFR in healthy Chinese adult populations. PMID- 21672535 TI - Involvement of multimeric protein complexes in mediating the capacitation dependent binding of human spermatozoa to homologous zonae pellucidae. AB - The recognition and binding of a free-swimming spermatozoon to an ovulated oocyte is one of the most important cellular interactions in biology. While traditionally viewed as a simple lock and key mechanism, emerging evidence suggests that this event may require the concerted action of several sperm proteins. In this study we examine the hypothesis that the activity of such proteins may be coordinated by their assembly into multimeric recognition complexes on the sperm surface. Through the novel application of blue native polyacrylamide gel electrophoresis (BN-PAGE), we tender the first direct evidence that human spermatozoa do indeed express a number of high molecular weight protein complexes on their surface. Furthermore, we demonstrate that a subset of these complexes displays affinity for homologous zonae pellucidae. Proteomic analysis of two such complexes using electrospray ionization mass spectrometry identified several of the components of the multimeric 20S proteasome and chaperonin-containing TCP-1 (CCT) complexes. The latter complex was also shown to harbor at least one putative zona pellucida binding protein, ZPBP2. Consistent with a role in the mediation of sperm-zona pellucida interaction we demonstrated that antibodies directed against individual subunits of these complexes were able to inhibit sperm binding to zona-intact oocytes. Similarly, these results were able to be recapitulated using native sperm lysates, the zona affinity of which was dramatically reduced by antibody labeling of the complex receptors, or in the case of the 20S proteasome the ubiquitinated zonae ligands. Overall, the strategies employed in this study have provided novel, causal insights into the molecular mechanisms that govern sperm-egg interaction. PMID- 21672536 TI - Personality, a key factor in personalized medicine? AB - The incidence of health problems resulting from obesity is growing and obesity and its related diseases has become one of the main causes in death in industrialized societies. Environmental influences are crucial for the interactions between genetic, neurohormonal and metabolic factors that may be important in understanding individual differences in the development of obesity and metabolic diseases like type 2 diabetes. In particular the interactions between the personality of an individual and the environment play a key role in predicting the chance for successful treatment. Our experimental data clearly point out that the success of interventions designed to prevent or treat metabolic diseases could be considerably improved by adjusting the intervention to the personality of the individual. Furthermore, certain physiological and neuroendocrine characteristics of a personality are strong indicators for pathology development, both in experimental animals and humans. Future research should focus on the identification of easily measurable physiological and neuroendocrine markers indicative of the coping style or personality in humans. PMID- 21672538 TI - IGF2 derived from SH-SY5Y neuroblastoma cells induces the osteoclastogenesis of human monocytic precursors. AB - The insulin-like growth factors 2 (IGF2) is a peptide hormone that binds to the insulin-like growth factor 1 receptor (IGF1R) and is abundantly stored in bone. IGF1R is deeply involved in the pathogenesis of many cancers that growth within bone and is also involved in osteoclast biology. Among different cell lines representative of osteolytic tumors, we found a very high expression of IGF2 in SH-SY5Y cells derived from neuroblastoma (NB). We previously showed that NB cells induce an osteolytic process through the Osteoprotegerin/RANKL/RANK and the canonical Wnt pathway system. Here, we hypothesized that NB promotes osteoclastogenesis also via IGF2. First, we demonstrated the presence of IGF1R on the osteoclast basolateral membrane, and we observed a cyclic IGF1R activation along with the differentiation process, also when induced by SH-SY5Y. Moreover, we found that IGF2 mRNA expression in SH-SY5Y cells was further increased when co cultured with mesenchymal stromal cells, suggesting that IGF2 is important for NB interaction with the bone microenvironment. Finally, the treatment of SH-SY5Y cells with an anti-IGF2 siRNA or the addition of anti-IGF1R molecules impaired NB induced osteoclastogenesis, even though the chemoattraction of monocytes by NB cells was unaffected. Our findings suggest that in IGF2-producing osteolytic tumors IGF1R is a good candidate for targeted therapies in combination with conventional drugs. PMID- 21672539 TI - Identification and characterization of protein interactions in the mammalian mRNA processing body using a novel two-hybrid assay. AB - Components of the mRNA processing body (P-body) regulate critical steps in mRNA storage, transport, translation and degradation. At the core of the P-body is the decapping complex, which removes the 5' cap from de-adenylated mRNAs and mediates an irreversible step in mRNA degradation. The assembly of P-bodies in Saccharomyces cerevisiae, Arabidopsis thaliana and Drosophila melanogaster has been previously described. Less is known about the assembly of mammalian P bodies. To investigate the interactions that occur between components of mammalian P-bodies, we developed a fluorescence-based, two-hybrid assay system. The assay depends on the ability of one P-body component, fused to an exogenous nuclear localization sequence (NLS), to recruit other P-body components to the nucleus. The assay was used to investigate interactions between P-body components Ge-1, DCP2, DCP1, EDC3, RAP55, and RCK. The results of this study show that the modified two-hybrid assay can be used to identify protein interactions that occur in a macromolecular complex. The assay can also be used to efficiently detect protein interaction domains. The results provide important insights into mammalian P-body assembly and demonstrate similarities, and critical differences, between P-body assembly in mammalian cells compared with that of other species. PMID- 21672537 TI - Structural changes in the skin of hairless mice following exposure to sulfur mustard correlate with inflammation and DNA damage. AB - Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1-14 days later. After 1 day, SM caused epidermal thinning, stratum corneum shedding, basal cell karyolysis, hemorrhage and macrophage and neutrophil accumulation in the dermis. Cleaved caspase-3 and phosphorylated histone 2A.X (phospho-H2A.X), markers of apoptosis and DNA damage, respectively, were increased whereas proliferating cell nuclear antigen (PCNA) was down-regulated after SM exposure. By 3 days, epithelial cell hypertrophy, edema, parakeratosis and loss of epidermal structures were noted. Enzymes generating pro-inflammatory mediators including myeloperoxidase and cyclooxygenase-2 were upregulated. After 7 days, keratin-10, a differentiation marker, was evident in the stratum corneum. This was associated with an underlying eschar, as neoepidermis began to migrate at the wound edges. Trichrome staining revealed increased collagen deposition in the dermis. PCNA expression in the epidermis was correlated with hyperplasia, hyperkeratosis, and parakeratosis. By 14 days, there was epidermal regeneration with extensive hyperplasia, and reduced expression of cleaved caspase-3, cyclooxygenase-2 and phospho-H2A.X. These findings are consistent with the pathophysiology of SM-induced skin injury in humans suggesting that the hairless mouse can be used to investigate the dermatoxicity of vesicants and the potential efficacy of countermeasures. PMID- 21672540 TI - Annexin VI is a mannose-6-phosphate-independent endocytic receptor for bovine beta-glucuronidase. AB - Endocytosis and transport of bovine liver beta-glucuronidase to lysosomes in human fibroblasts are mediated by two receptors: the well-characterized cation independent mannose 6-phosphate receptor (IGF-II/Man6PR) and an IGF-II/Man6PR independent receptor, which recognizes a Ser-Trp*-Ser sequence present on the ligand. The latter receptor was detergent extracted from bovine liver membranes and purified. LC/ESI-MS/MS analysis revealed that this endocytic receptor was annexin VI (AnxA6). Several approaches were used to confirm this finding. First, the binding of bovine beta-glucuronidase to the purified receptor from bovine liver membranes and His-tagged recombinant human AnxA6 protein was confirmed using ligand-blotting assays. Second, western blot analysis using antibodies raised against IGF-II/Man6PR-independent receptor as well as commercial antibodies against AnxA6 confirmed that the receptor and AnxA6 were indeed the same protein. Third, double immunofluorescence experiments in human fibroblasts confirmed a complete colocalization of the bovine beta-glucuronidase and the AnxA6 receptor on the plasma membrane. Lastly, two cell lines were stably transfected with a plasmid containing the cDNA for human AnxA6. In both transfected cell lines, an increase in cell surface AnxA6 and in mannose 6 phosphate-independent endocytosis of bovine beta-glucuronidase was detected. These results indicate that AnxA6 is a novel receptor that mediates the endocytosis of the bovine beta-glucuronidase. PMID- 21672541 TI - Genomic imprinting as an adaptative model of developmental plasticity. AB - Developmental plasticity can be defined as the ability of one genotype to produce a range of phenotypes in response to environmental conditions. Such plasticity can be manifest at the level of individual cells, an organ, or a whole organism. Imprinted genes are a group of approximately 100 genes with functionally monoallelic, parental-origin specific expression. As imprinted genes are critical for prenatal growth and metabolic axis development and function, modulation of imprinted gene dosage has been proposed to play a key role in the plastic development of the unborn foetus in response to environmental conditions. Evidence is accumulating that imprinted dosage may also be involved in controlling the plastic potential of individual cells or stem cell populations. Imprinted gene dosage can be modulated through canonical, transcription factor mediated mechanisms, or through the relaxation of imprinting itself, reactivating the normally silent allele. PMID- 21672542 TI - Serum hepatitis B surface antigen levels predict surface antigen loss in hepatitis B e antigen seroconverters. AB - BACKGROUND & AIMS: Loss of hepatitis B surface antigen (HBsAg) usually indicates that hepatitis B virus (HBV) infection has been cured. However, little is known about factors predicting HBsAg loss in patients who spontaneously clear hepatitis B e antigen (HBeAg). METHODS: We studied 390 Taiwanese HBeAg-positive patients with chronic hepatitis who had spontaneously cleared HBeAg (seroconversion) during follow-up. Serum levels of HBV DNA and HBsAg were determined 1 year after HBeAg seroconversion, and their relationships with subsequent HBsAg loss were investigated. RESULTS: In a mean follow-up of 7.4 years, the average annual rate of HBsAg loss was 0.62%. Serum levels of HBsAg and HBV DNA were inversely associated with HBsAg loss in a dose-response manner. Compared with patients with HBsAg levels >=1000 IU/mL, the HBsAg loss rate was higher for those with HBsAg levels of 100 to 999 and <100 IU/mL, with hazard ratios of 4.4 (95% confidence interval, 1.1-17.0) and 24.3 (8.7-67.5), respectively. Among those who underwent HBsAg loss within 6 years of follow-up, serum HBsAg levels were a better predictor than HBV DNA levels by receiver operating characteristic curve analysis (area under the receiver operating characteristic curve, 0.90 vs 0.69; P = .012); an HBsAg level <100 IU/mL predicted HBsAg loss within 6 years with a diagnostic accuracy of 91.5%, sensitivity of 83.3%, specificity of 92.1%, positive predictive value of 45.5%, and negative predictive value of 98.6% in patients with an HBV DNA level <200 IU/mL. CONCLUSIONS: Low serum levels of HBsAg, alone or in combination with HBV DNA levels, 1 year after HBeAg seroconversion can predict HBsAg loss in patients with HBV genotype B or C infection. PMID- 21672543 TI - Cues to sex- and stress-hormones in the human male face: functions of glucocorticoids in the immunocompetence handicap hypothesis. AB - The stress-linked version of the immunocompetence handicap hypothesis has been proposed to account for inconsistencies in relationships between testosterone and immune response. The model has received some support from studies demonstrating roles of stress hormones in relationships between testosterone, immune function and secondary sexual ornamentation. Such work, however, has relied on artificial elevation of testosterone so may not reflect relationships in natural populations. We created human male facial stimuli on the basis of naturally co occurring levels of salivary testosterone and the stress hormone cortisol. In Study 1 we tested female preferences for male faces with cues to combinations of the hormones across the menstrual cycle, and in Study 2 we tested perceptions of health and dominance in a novel set of facial stimuli. Females preferred cues to low cortisol, a preference that was strongest during the fertile phase of the menstrual cycle. The effects of cortisol on attractiveness and perceived health and dominance were contingent upon level of testosterone: the effects of the stress hormone were reduced when testosterone was high. We propose explanations for our results, including low cortisol as a cue to a heritable component of health, attractiveness as a predictor of low social-evaluative threat (and, therefore, low baseline cortisol) and testosterone as a proxy of male ability to cope efficiently with stressors. PMID- 21672544 TI - The intra-molecular activation mechanisms of the dimeric metabotropic glutamate receptor 1 differ depending on the type of G proteins. AB - Metabotropic glutamate receptor 1 (mGlu1) functions as a homodimer and activates not only the Gq but also the Gi/o and Gs pathways. Because of the dimeric configuration, different pathways could be activated either through the glutamate bound subunit (cis-activation) and/or the other one (trans-activation). We here examined whether the intra-molecular activation mechanisms in the mGlu1 differ depending on the type of coupling G proteins, using various combinations of mGlu1 constructs that lack glutamate binding and/or G-protein coupling. The cis- or trans-activation alone was confirmed to trigger the Gq-coupled intracellular Ca(2+) transient. In contrast, the Gi/o-coupled G protein-dependent inward rectifying potassium (GIRK) channels were not activated either through the cis- or trans-activation alone. When one subunit of dimeric mGlu1 lacked the G-protein coupling, a significant decrease in the glutamate-induced GIRK current density was also observed. As the G protein-coupling-deficient subunit did not decrease the cell surface expression of mGlu1 and the Gq-coupled Ca(2+) transient, it was suggested that the coupling deficiency in one subunit of mGlu1 attenuates the Gi/o but not Gq coupling. In conclusion, multiple G-protein signaling was differentially activated by different intra-molecular activation mechanisms of the dimeric mGlu1. PMID- 21672545 TI - Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice. AB - Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (-/-) mice. Mice of both genotypes (n=5-6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82-95% at 48h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 MUM) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20-23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. PMID- 21672546 TI - Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes. AB - 2'-3-dimethyl-4-aminoazobenzene (ortho-aminoazotoluene, OAT) is an azo dye and a rodent carcinogen that has been evaluated by the International Agency for Research on Cancer (IARC) as a possible (class 2B) human carcinogen. Its mechanism of action remains unclear. We examined the role of the xenobiotic receptor Constitutive Androstane Receptor (CAR, NR1I3) as a mediator of the effects of OAT. We found that OAT increases mouse CAR (mCAR) transactivation in a dose-dependent manner. This effect is specific because another closely related azo dye, 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB), did not activate mCAR. Real-time Q-PCR analysis in wild-type C57BL/6 mice revealed that OAT induces the hepatic mRNA expression of the following CAR target genes: Cyp2b10, Cyp2c29, Cyp3a11, Ugt1a1, Mrp4, Mrp2 and c-Myc. CAR-null (Car(-/-)) mice showed no increased expression of these genes following OAT treatment, demonstrating that CAR is required for their OAT dependent induction. The OAT-induced CAR-dependent increase of Cyp2b10 and c-Myc expression was confirmed by Western blotting. Immunohistochemistry analysis of wild-type and Car(-/-) livers showed that OAT did not acutely induce hepatocyte proliferation, but at much later time points showed an unexpected CAR-dependent proliferative response. These studies demonstrate that mCAR is an OAT xenosensor, and indicate that at least some of the biological effects of this compound are mediated by this nuclear receptor. PMID- 21672548 TI - Sex differences in the burying behavior test in middle-aged rats: effects of diazepam. AB - The full behavioral profile displayed during the burying behavior test was studied in middle aged (11-14 months) males, females with irregular estrous cycles, and females in persistent diestrus, with and without diazepam (0.5 2.0mg/kg). Ambulation and motor coordination were also tested to discern behavioral changes from general motor alterations. Without diazepam treatment, middle-aged males showed longer burying behavior latencies, more prod explorations and less freezing than both groups of females. Untreated middle aged males also showed less cumulative burying and more immobility compared to females with irregular cycles. None of the parameters showed any difference between the female groups. Diazepam (0.5 and 1.0mg/kg) increased burying behavior latency in females, but had no effect on any parameter in middle aged males. However, a higher dose (2.0mg/kg) of diazepam increased immobility, freezing and the number of prod shocks and decreased prod explorations and groomings, but impaired motor coordination in males. In contrast with young males and females, diazepam at any dose reduced cumulative burying. Data are discussed on the bases of (1) sex and age differences in burying behavior and on (2) the anxiolytic-like action of diazepam and its side effects. PMID- 21672547 TI - Rabbit-specific ventricular model of cardiac electrophysiological function including specialized conduction system. AB - The function of the ventricular specialized conduction system in the heart is to ensure the coordinated electrical activation of the ventricles. It is therefore critical to the overall function of the heart, and has also been implicated as an important player in various diseases, including lethal ventricular arrhythmias such as ventricular fibrillation and drug-induced torsades de pointes. However, current ventricular models of electrophysiology usually ignore, or include highly simplified representations of the specialized conduction system. Here, we describe the development of an image-based, species-consistent, anatomically detailed model of rabbit ventricular electrophysiology that incorporates a detailed description of the free-running part of the specialized conduction system. Techniques used for the construction of the geometrical model of the specialized conduction system from a magnetic resonance dataset and integration of the system model into a ventricular anatomical model, developed from the same dataset, are described. Computer simulations of rabbit ventricular electrophysiology are conducted using the novel anatomical model and rabbit specific membrane kinetics to investigate the importance of the components and properties of the conduction system in determining ventricular function under physiological conditions. Simulation results are compared to panoramic optical mapping experiments for model validation and results interpretation. Full access is provided to the anatomical models developed in this study. PMID- 21672549 TI - Meta-analysis: Serum vitamin D and colorectal adenoma risk. AB - OBJECTIVE: To perform a systematic review and meta-analysis of human studies on the association between serum 25 hydroxyvitamin D (25(OH)D) and incident, sporadic colorectal adenoma (CRA) and CRA recurrence. METHODS: Relevant studies among humans were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases and by cross-referencing. Due to the heterogeneity across studies in categorizing serum vitamin D levels, all results were recalculated for an increase of serum 25(OH)D by 20 ng/ml. Summary odds ratios (ORs) were calculated using meta-analysis methods. RESULTS: Overall, 10 original studies were included. Specific results for incident CRA according to serum 25(OH)D were reported in 8 studies, and for CRA recurrence in 2 studies, respectively. In meta-analyses, summary ORs (95% confidence intervals) regarding incident and recurrent CRA, and both outcomes combined were 0.82 (0.69-0.97), 0.87 (0.56-1.35), and 0.84 (0.72-0.97), respectively, for an increase of 25(OH)D by 20 ng/ml. No publication bias was found. CONCLUSION: Our results support suggestions that serum 25(OH)D levels are inversely associated with CRA risk. PMID- 21672550 TI - Rodent empathy and affective neuroscience. AB - In the past few years, several experimental studies have suggested that empathy occurs in the social lives of rodents. Thus, rodent behavioral models can now be developed to elucidate the mechanistic substrates of empathy at levels that have heretofore been unavailable. For example, the finding that mice from certain inbred strains express behavioral and physiological responses to conspecific distress, while others do not, underscores that the genetic underpinnings of empathy are specifiable and that they could be harnessed to develop new therapies for human psychosocial impairments. However, the advent of rodent models of empathy is met at the outset with a number of theoretical and semantic problems that are similar to those previously confronted by studies of empathy in humans. The distinct underlying components of empathy must be differentiated from one another and from lay usage of the term. The primary goal of this paper is to review a set of seminal studies that are directly relevant to developing a concept of empathy in rodents. We first consider some of the psychological phenomena that have been associated with empathy, and within this context, we consider the component processes, or endophenotypes of rodent empathy. We then review a series of recent experimental studies that demonstrate the capability of rodents to detect and respond to the affective state of their social partners. We focus primarily on experiments that examine how rodents share affective experiences of fear, but we also highlight how similar types of experimental paradigms can be utilized to evaluate the possibility that rodents share positive affective experiences. Taken together, these studies were inspired by Jaak Panksepp's theory that all mammals are capable of felt affective experiences. PMID- 21672551 TI - Region and state specific glutamate downregulation in major depressive disorder: a meta-analysis of (1)H-MRS findings. AB - For major depressive disorder (MDD), magnetic resonance spectroscopy ((1)H-MRS) studies of glutamate, glutamine and Glx (the composite measure of mainly glutamate and glutamine) have yielded inconclusive or seemingly inconsistent results. We therefore systematically reviewed whether in vivo concentrations of glutamate, glutamine and Glx measured with (1)H-MRS differ between MDD patients and controls. Meta-analysis including meta-regression, sensitivity, statistical heterogeneity, and publication bias analyses were conducted. Glutamate and Glx concentrations were found to be lower in the anterior cingulate cortex (ACC) in patients compared to controls (standardized mean difference (SMD) for glutamate with 95% CIs: -0.86, -1.55 to -0.17; and for Glx: -1.15, -1.86 to -0.44). In addition, Glx was decreased in all brain regions together in current episode patients (SMD: -0.62, -1.17 to -0.07). We conclude that in MDD, glutamate and possibly glutamine are downregulated primarily in the ACC and during depressive states. These results fit the central role of the ACC in depressive symptomatology and suggest that in MDD changes in glutamatergic neurotransmission are state-dependent. PMID- 21672552 TI - Bacteremia related with arterial catheter in critically ill patients. AB - OBJECTIVE: Catheter-related bloodstream infections (CR-BSI) are an increasing problem in the management of critically ill patients. Our objective was to analyze the incidence and epidemiology of CR-BSI in arterial catheters (AC) in a population of critically ill patients. METHODS: We conducted a two-year, prospective, non-randomized study of patients admitted for > 24 h in a 24-bed medical-surgical major teaching ICU. We analyzed the arterial catheters and differentiated between femoral and radial locations. Difference testing between groups was performed using the two-tailed t-test and chi-square test as appropriate. Multivariate logistic regression analyses were conducted to identify independent predictors of CR-BSI occurrence and type of micro-organism responsible. RESULTS: The study included 1456 patients requiring AC placement for >= 24 h. A total of 1543 AC were inserted for 14,437 catheter days. The incidence of AC-related bloodstream infections (ACR-BSI) was 3.53 episodes per 1000 catheter days. In the same period the incidence of central venous catheter (CVC) related bloodstream infections was 4.98 episodes per 1000 catheter days. Logistic regression analysis showed that days of insertion (OR: 1.118 95% confidence interval (CI) 1.026-1.219) and length of ICU stay (OR: 1.052 95% CI: 1.025-1.079) were associated with a higher risk of ACR-BSI. Comparing 705 arterial catheters in femoral location with 838 in radial location, no significant differences in infection rates were found, although there was a trend toward a higher rate among femoral catheters (4.13 vs. 3.36 episodes per 1000 catheter days) (p = 0.72). Among patients with ACR-BSI, Gram-negative bacteria were isolated in 16 episodes (61.5%) in the femoral location and seven (28%) in radial location (OR: 2.586; 95% CI: 1.051-6.363). CONCLUSIONS: We concluded that as has been reported for venous catheters ACR-BSI plays an important role in critically ill patients. Days of insertion and length of ICU stay increase the risk of ACR-BSI. The femoral site increases the risk for Gram-negative infection. PMID- 21672553 TI - Pulmonary capillary leak syndrome following influenza A (H1N1) virus infection in pregnant and postpartum women. PMID- 21672554 TI - An embryonic culture system for the investigation of striatal medium spiny neuron dendritic spine development and plasticity. AB - Dendritic spines of striatal Medium Spiny Neurons (MSNs) receive converging dopaminergic and glutamatergic inputs. These spines undergo experience-dependent structural plasticity following repeated drug administration and during disease states like Huntington's and Parkinson's. Thus, understanding the molecular mechanisms leading to structural plasticity is an important step toward establishing a clear relationship between spine structure and function, and will ultimately contribute to understanding how changes in dendritic spine structure relate to behaviors or diseases. One major difficulty faced when studying MSN development is the lack of a detailed, standardized in vitro model system that produces MSNs with in vivo-like morphologies. For example, unlike cultured pyramidal neurons, MSNs grown in mono-cultures display stunted dendritic arborization and fail to develop a full cohort of mature dendritic spines. Here we report the generation of an embryonic mouse cortical-striatal co-culture that generates high cell yields from a single embryo. Unlike MSNs in striatal mono culture, MSNs in co-culture develop in vivo-like morphologies and high densities of dendritic spines. Morphological identification of co-cultured MSNs expressing a soluble fluorescent protein can be confirmed by immunochemical detection of DARPP-32 (Dopamine and cyclic AMP regulated phosphoprotein of 32kDa). Additionally, co-cultured MSN spines contain PSD-95 puncta and are apposed to SV2 puncta, indicating the spines express synaptic machinery. Finally, whole-cell recordings of co-cultured MSNs exhibit higher mEPSC frequency compared to mono cultured MSNs, suggesting that the spines are functionally mature. These studies establish that this co-culture system is suitable for studying the morphological and physiological development and function of MSN dendritic spines. PMID- 21672555 TI - Normalization of gene expression using SYBR green qPCR: a case for paraoxonase 1 and 2 in Alzheimer's disease brains. AB - Validating the expression stability of reference genes is crucial for reliable normalization of real-time quantitative PCR (qPCR) data, but relatively few studies have investigated this issue in brain human tissues. The present study thus aimed at identifying in human post-mortem brain tissues a set of suitable endogenous reference genes (ERG) for the expression analysis of potential candidate genes associated with Alzheimer's disease (AD). The mRNA levels of ten common ERGs (ACTB, GAPDH, GPS1, GUSB, M-RIP, PGK1, POL2RF, PPIA, UBE2D2, and YES1) were determined in the frontal cortex of autopsy-confirmed AD and non demented control cases (n=20) using SYBR Green technology. Then, these levels were ranked according to their expression stability using three software applications: geNorm, NormFinder and BestKeeper. Whereas PPIA and UBE2D2 were among the ERGs with the most reliable expression, ACTB was the worst. Subsequently, using PPIA and UBE2D2 as ERGs for normalization, the mRNA levels of paraoxonase 1 (PON1) and paraoxonase 2 (PON2) were quantified in the frontal cortex of AD and control cases (n=80) and analyzed using the REST 2009 program. Our results indicate that both paraoxonases are expressed in the human frontal cortex and that PON2 but not PON1 mRNA levels are up-regulated in AD relative to non-demented controls. However, re-analysis of the results by ANCOVA indicated that the significance of the difference between AD and control groups depended upon the ERG used for normalization. The use of a computational method allowing the inclusion of possible confounding factors is thus recommended for the analysis of data. PMID- 21672556 TI - An acoustic startle-based method of assessing frequency discrimination in mice. AB - The acoustic startle response (ASR) is a reflexive contraction of skeletal muscles in response to a loud, abrupt acoustic stimulus. ASR magnitude is reduced if the startle stimulus is preceded by a weaker acoustic or non-acoustic stimulus, a phenomenon known as prepulse inhibition (PPI). PPI has been used to test various aspects of sensory discrimination in both animals and humans. Here we show that PPI of the ASR is an advantageous method of assessing frequency discrimination. We describe the apparatus and its performance testing frequency discrimination in young CD1 mice. Compared to classical conditioning paradigms, PPI of the ASR is less time consuming, produces robust results, and can be used without training even in young animals. This approach can be used to investigate the neuronal mechanisms underlying frequency discrimination, its maturation during development, and its relationship to tonotopic organization. PMID- 21672557 TI - Repeated administration of the nitric oxide synthase inhibitor l-NAME differentially affects rats' recognition memory. AB - Nitric oxide (NO) is sought to be an intracellular messenger in the central nervous system and its implication in learning and memory is well documented. Compounds that inhibit nitric oxide synthase (NOS), the key synthesizing enzyme, block cognition, though discrepant findings, in this context, have also been reported. The present study was designed to investigate in the rat (a) the effects of repeated treatment with the NOS inhibitor l-NAME (1, 3 and 10mg/kg, i.p., for 5 consecutive days) on rats' recognition memory and (b) whether or not at this treatment condition, l-NAME (1, 3 and 10mg/kg, i.p., for 5 consecutive days), was able to counteract delay-dependent recognition memory deficits. For this aim, the novel object recognition task was selected. l-NAME (3, but not 1 or 10mg/kg) disrupted rats' performance in this recognition memory paradigm as compared to that expressed by their vehicle-treated cohorts. Subsequently, l-NAME (1 and 10, but not 3mg/kg)-treated rats were capable to antagonize delay dependent deficits, which instead were present in the vehicle-treated animals. These results indicate that repeated administration of this NOS inhibitor exerts a dual effect on rats' recognition memory abilities suggesting a complex involvement of l-NAME in cognition. PMID- 21672558 TI - Effects of the growth hormone-releasing hormone (GH-RH) antagonist on brain functions in mice. AB - The growth hormone-releasing hormone (GH-RH) antagonist MZ-4-71 has been shown to suppress secretion of GH and insulin-like growth factor-1 (IGF-1) secretion. These findings suggested that GH-RH antagonists could be used for the therapy of disorders characterized by excessive GH secretion. A number of GH-RH antagonists has been synthesized, and shown to suppress the growth of various tumors. However, little is known about the possible action of GR-RH antagonists on brain functions. In the present work, the influence of MZ-4-71 on different aspects of brain function was studied in mice, following its administration into the lateral brain ventricle. The effects tested included the action of MZ-4-71 on passive avoidance learning and on the impairment of the consolidation of a passive avoidance reflex caused by beta-amyloid 25-35, antidepressive action in a forced swimming test, and anxiolytic action on plus-maze and open-field behavior. MZ-4 71 facilitated the consolidation of passive avoidance learning. Beta-amyloid 25 35 administered immediately after the learning trial impaired the consolidation of passive avoidance learning. MZ-4-71 fully blocked this impairment when given simultaneously with or 30min following beta-amyloid 25-35 administration icv. In the forced swimming tests, MZ-47-1 demonstrated antidepressive-like action and in the plus-maze, depending on the dose used it elicited mild anxiolytic action, however, in open-field behavior tests, it displayed no action on locomotion, rearing or grooming. The results demonstrate that MZ-4-71 affects the brain functions: by improving memory consolidation in passive avoidance learning and correcting the impairment of the memory consolidation caused by beta-amyloid 25 35. MZ-4-71 also elicits anxiolytic and antidepressive effects, but it does not influence the open-field activity. Further experimental work with MZ-4-71 is necessary, to determine the possible mechanism of action. The results imply a possible merit of a clinical trial with MZ-4-71 in patients with anxiety, depression and cognitive impairment, as observed in Alzheimer's disease. PMID- 21672559 TI - Subthreshold corticospinal control of anticipatory actions in humans. AB - Previous findings suggest that, by influencing the subthreshold state of motoneurons, the corticospinal pathways can set and reset the threshold position at which wrist muscle recruitment begins. Here we assumed that the corticospinal system can change the threshold position in a similar way before anticipated perturbation to pre-determine an appropriate emerging response to it. We first analyzed motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) applied to the wrist area of motor cortex before unloading of preloaded wrist flexors, i.e. before the subsequent involuntary wrist motion to another position (natural unloading). Subjects then learned to diminish the post unloading movement extent without activating antagonist (extensor) muscles before unloading or making intentional movement corrections after unloading (adjusted unloading). Although activity levels of wrist muscles before unloading were similar, MEPs of extensor but not pre-loaded flexor muscles were higher before adjusted unloading. We also applied TMS in combination with a torque pulse that shortened extensor muscles such that the MEP occurred when the motoneuronal excitability was minimized. Although diminished following muscle shortening, MEPs before adjusted unloading were still higher than before natural unloading. Results suggest that the corticospinal system, possibly together with other descending systems participated in the tonic subthreshold facilitation of antagonist motoneurons before adjusted unloading, which appears sufficient in modifying motor commands and motion leading to adjusted unloading. This study reinforces previous findings that descending systems, in particular, the corticospinal system can employ threshold position control during and after learning a novel action. PMID- 21672560 TI - A role for the head-direction system in geometric learning. AB - Several recent models of episodic memory have highlighted a potential contribution from the head-direction system; there is, however, surprisingly little known about the behavioural effects of selective lesions within the head direction system. To address this issue, and determine what aspects of spatial memory are dependent on the head-direction system, rats with selective lateral mammillary body lesions were tested on tasks that required the use of specific spatial cues, including direction, visual allocentric, and geometric cues. Animals were first tested on a modified version of the T-maze alternation task that enabled the systematic removal of intramaze and visual allocentric cues. Rats were next tested on a geometric task that required the use of the shape of the environment to locate a hidden platform in the water-maze. The lesion rats were impaired on one stage of the T-maze alternation task and on the acquisition of the geometric task; these results are consistent with the head-direction system contributing to the processing of, and/or subsequent use, of visual allocentric and geometric cues. From the pattern of impairments it also appears that, with training, rats with lateral mammillary body lesions are able to recruit other navigational systems or that there is some degree of redundancy within the head-direction system. PMID- 21672561 TI - A novel multiplex PCR method for detecting the major clonal complexes of MRSA in nasal isolates from a Pennsylvania hospital. AB - A novel multiplex PCR was developed which targeted virulence genes associated with the major clonal complexes (CCs) of healthcare- and community-associated methicillin-resistant Staphylococcus aureus (MRSA) in the USA. Most isolates (40/66) were identified as CC 5, while remaining isolates represented CCs 1, 8, 30, 45, 59, 133, and five isolates were not S. aureus. PMID- 21672562 TI - Puumala virus infection in Syrian hamsters (Mesocricetus auratus) resembling hantavirus infection in natural rodent hosts. AB - The mechanism of hantavirus persistent infection in natural hosts is poorly understood due to a lack of laboratory animal models. Herein, we report that Syrian hamsters (Mesocricetus auratus) infected with Puumala virus (PUUV) at 4 weeks old show persistent infection without clinical symptoms for more than 2 months. IgG and IgM antibodies against the viral nucleocapsid protein and neutralizing antibody were first detectable at 14 days postinoculation (dpi) and maintained through 70 dpi. Viral RNA was first detected from 3 dpi in lungs and blood clots, and was detected in all tissues tested at 7 dpi. The viral RNA persisted for at least 70 days in the lungs, kidney, spleen, heart, and brain. The highest level of RNA copies was observed at 14 dpi in the lungs. Slight inflammatory reactions were observed in the lungs, adrenal glands, and brain. Immunohistochemical analysis revealed that PUUV antigen persisted until 56 dpi in the kidneys and adrenal glands. Infected hamsters showed no body weight loss or clinical signs. These results indicate that PUUV infection in hamsters is quite similar to the hantavirus infection of natural host rodents. PMID- 21672563 TI - Unraveling the penetration: model giant plasma membrane vesicles for study of cell-penetrating peptides. PMID- 21672564 TI - New insights on the pathogenesis of biliary cirrhosis provided by studies in FXR knockout mice. AB - The nuclear bile acid receptor, farnesoid X receptor (FXR), may play a pivotal role in liver fibrosis. We tested the impact of genetic FXR ablation in four different mouse models. Hepatic fibrosis was induced in wild-type and FXR knock out mice (FXR((-/-))) by CCl(4) intoxication, 3,5-diethoxycarbonyl-1,4 dihydrocollidine feeding, common bile duct ligation, or Schistosoma mansoni (S.m.)-infection. In addition, we determined nuclear receptor expression levels (FXR, pregnane X receptor (PXR), vitamin D receptor, constitutive androstane receptor (CAR), small heterodimer partner (SHP)) in mouse hepatic stellate cells (HSCs), portal myofibroblasts (MFBs), and human HSCs. Cell type-specific FXR protein expression was determined by immunohistochemistry in five mouse models and prototypic human fibrotic liver diseases. Expression of nuclear receptors was much lower in mouse and human HSCs/MFBs compared with total liver expression with the exception of vitamin D receptor. FXR protein was undetectable in mouse and human HSCs and MFBs. FXR loss had no effect in CCl(4)-intoxicated and S.m. infected mice, but significantly decreased liver fibrosis of the biliary type (common bile duct ligation, 3,5-diethoxycarbonyl-1,4-dihydrocollidine). These data suggest that FXR loss significantly reduces fibrosis of the biliary type, but has no impact on non-cholestatic liver fibrosis. Since there is no FXR expression in HSCs and MFBs in liver fibrosis, our data indicate that these cells may not represent direct therapeutic targets for FXR ligands. PMID- 21672566 TI - Development and factor structure of the Baby Eating Behaviour Questionnaire in the Gemini birth cohort. AB - The objective of this study was to develop a parent-report psychometric measure of infant appetite during the period of exclusive milk-feeding. Constructs and items for the Baby Eating Behaviour Questionnaire (BEBQ) were derived from an existing psychometric measure validated for older ages, the Children's Eating Behaviour Questionnaire, supplemented by a review of the literature on milk feeding behaviours. Cognitive interviewing with a sample of mothers (n=10) was used to refine the questions. The factor structure of the 18-item BEBQ was assessed in infants (one per family) from the Gemini twin birth cohort (n=2402 families). Principal Component Analysis identified four distinct appetitive constructs, all of which had good internal reliability: 'enjoyment of food' (Cronbach's alpha=0.81), 'food responsiveness' (alpha=0.79), 'slowness in eating' (alpha=0.76), and 'satiety responsiveness' (alpha=0.73). A single item assessing 'general appetite' correlated with all of the constructs. The BEBQ is the first standardised measure of infant appetite designed to characterise appetitive traits that might confer susceptibility to excess weight gain. PMID- 21672565 TI - Dopamine polymorphisms and depressive symptoms predict foods intake. Results from a nationally representative sample. AB - Depression and variation in dopamine related genes have both independently been associated with food consumption. Depressive symptoms could synergistically interact with genetic variation to influence food intake. We examined the interaction between high depressive symptoms and functional polymorphisms of dopamine transporter (SLC6A3), monoamine oxidase A (MAOA), dopamine receptor D2 (DRD2) and dopamine receptor D4 (DRD4) on intake of high-calorie sweet, high calorie non-sweet, and low-calorie foods in the National Longitudinal Study of Adolescent Health (Add Health). Multivariate linear regression analyses were used to examine main effects of gene and depression symptoms and their interaction (genotype-by-high depression symptoms) on food categories. Applying a false discovery rate criterion for multiple comparisons indicated a statistically significant interaction for females with high depressive symptoms and the SLC6A3 gene, such that those with the SLC6A3 10/10 allele reported greater intake of high-calorie sweet foods than their counterparts high in depressive symptoms with the SLC6A3 any 9 allele (LS mean 10/10 allele=2.5, SE=.13; LS mean any 9 allele=1.8, SE=.13, p<.05). These findings highlight that the relationship between depression and food intake may vary as a function of genetic polymorphism. Further research is needed to confirm these findings. PMID- 21672567 TI - Ghrelin, appetite and gastric electrical stimulation. AB - Ghrelin is a peptide hormone produced mainly by the stomach and has widespread physiological functions including increase in appetite. The stimulation of the ghrelin system represents a potential therapeutic approach in various disorders characterized by deficient ghrelin signaling or by low appetite. This stimulation may be achieved via pharmacological targeting of the ghrelin receptor with synthetic ghrelin or ghrelin mimetics or via increased endogenous ghrelin production. Recently, it was demonstrated that gastric electrical stimulation (GES) with Enterra parameters results in increased ghrelin production in rats. Furthermore, recent data revealed putative role of ghrelin-reactive immunoglobulins in the modulation of the ghrelin signaling which can be also stimulated by GES. Here, we review the links between GES and ghrelin in existing GES experimental and clinical applications for treatment of gastroparesis, functional dyspepsia or obesity and discuss if GES can be proposed as a non pharmacological approach to improve ghrelin secretion in several pathological conditions characterized by low appetite, such as anorexia nervosa or anorexia cachexia syndrome. PMID- 21672568 TI - Antinociceptive effects of spinally administered nociceptin/orphanin FQ and its N terminal fragments on capsaicin-induced nociception. AB - Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for the N/OFQ peptide (NOP) receptors, has been shown to be metabolized into some fragments. We examined to determine whether intrathecal (i.t.) N/OFQ (1-13), (1-11) and (1-7) have antinociceptive activity in the pain-related behavior after intraplantar injection of capsaicin. The i.t. administration of N/OFQ (0.3-1.2 nmol) produced an appreciable and dose-dependent inhibition of capsaicin-induced paw licking/biting response. The N-terminal fragments of N/OFQ, (1-13) and (1-11), were antinociceptive with a potency lower than N/OFQ. Calculated ID50 values (nmol, i.t.) were 0.83 for N/OFQ, 2.5 for N/OFQ (1-13) and 4.75 for N/OFQ (1-11), respectively. The time-course effect revealed that the antinociceptive effects of these N-terminal fragments lasted longer than those of N/OFQ. Removal of amino acids down to N/OFQ (1-7) led to be less potent than N/OFQ and its fragments, (1 13) and (1-11). Antinociception induced by N/OFQ or N/OFQ (1-13) was reversed significantly by i.t. co-injection of [Nphe1]N/OFQ (1-13)NH2, a peptidergic antagonist for NOP receptors, whereas i.t. injection of the antagonist did not interfere with the action of N/OFQ (1-11) and (1-7). Pretreatment with the opioid receptor antagonist naloxone hydrochloride did not affect the antinociception induced by N/OFQ and its N-terminal fragments. These results suggest that N terminal fragments of N/OFQ are active metabolites and may modulate the antinociceptive effect of N/OFQ in the spinal cord. The results also indicate that N/OFQ (1-13) still possess antinociceptive activity through NOP receptors. PMID- 21672569 TI - BDNF concentrations are decreased in serum and parietal cortex in immunotoxin 192 IgG-Saporin rat model of cholinergic degeneration. AB - The neurotrophin brain-derived neurotrophic factor (BDNF) has been extensively studied because of its role in survival, differentiation and function of neurons undergoing degeneration in pathological conditions such as cholinergic neurons in Alzheimer's disease (AD). However, despite these evidences, the role of BDNF in these events is still matter of debate because central and peripheral BDNF levels are often found in opposite direction. Another puzzling factor is represented by pharmacological treatments known to cause alterations of BDNF peripheral levels. Thus, a pivotal issue would be to verify whether brain and serum BDNF changes are interconnected as well as the possibility that different stages of cholinergic degeneration are characterized by different changes in BDNF brain and serum levels. With this in mind in this study we used a rat model of cholinergic degeneration based on intracerebroventricular (i.c.v.) injections of 192 IgG Saporin and measured brain and serum BDNF concentrations by enzyme-linked immunosorbent assay (ELISA) at 3, 7 and 15days from immunotoxin injection. We found that BDNF levels were reduced in parietal cortex and serum of Saporin treated rats at 15days from lesion. Moreover, a positive correlation between serum and parietal cortex was observed at 15days from lesion. These alterations were not present at the earlier post-operative time points. In conclusion, this study shows that BDNF levels are reduced in a rat model of cholinergic degeneration and suggests that these alterations may occur at later stages. In addition, a positive correlation between serum and parietal cortex changes is observed. Even if the cause for the relationship between BDNF in serum and this brain region is unknown, these data may help to elucidate the significance of peripheral and central BDNF changes in brain pathological conditions. PMID- 21672570 TI - Changes in iron-regulatory gene expression occur in human cell culture models of Parkinson's disease. AB - BACKGROUND: Neuronal iron accumulation is thought to be relevant to the pathogenesis of Parkinson's disease (PD), although the mechanism remains elusive. We hypothesized that neuronal iron uptake may be stimulated by functional mitochondrial iron deficiency. OBJECTIVE: To determine firstly whether the mitochondrial toxin, 1-methyl-4-phenylpyridinium iodide (MPP(+)), results in upregulation of iron-import proteins and transporters of iron into the mitochondria, and secondly whether similar changes in expression are induced by toxins with different mechanisms of action. METHODS: We used quantitative PCR and Western blotting to investigate expression of the iron importers, divalent metal transporter, transferrin receptor 1 and 2 (TfR1 and TfR2) and mitoferrin-2 and the iron exporter ferroportin in differentiated SH-SY5Y cells exposed to three different toxins relevant to PD, MPP(+), paraquat (a free radical generator) and lactacystin (an inhibitor of the ubiquitin-proteasome system (UPS)). RESULTS: MPP(+) resulted in increased mRNA and protein levels of genes involved in cellular iron import and transport into the mitochondria. Similar changes occurred following exposure to paraquat, another inducer of oxidative stress. Lactacystin also resulted in increased TfR1 mRNA levels, although the other changes were not found. CONCLUSION: Our results support the hypothesis of a functional mitochondrial iron deficit driving neuronal iron uptake but also suggest that differences exist in neuronal iron handling induced by different toxins. PMID- 21672571 TI - Presynaptic malfunction: the neurotoxic effects of cadmium and lead on the proton gradient of synaptic vesicles and glutamate transport. AB - Exposure to Cd(2+) and Pb(2+) has neurotoxic consequences for human health and may cause neurodegeneration. The study focused on the analysis of the presynaptic mechanisms underlying the neurotoxic effects of non-essential heavy metals Cd(2+) and Pb(2+). It was shown that the preincubation of rat brain nerve terminals with Cd(2+) (200 MUM) or Pb(2+) (200 MUM) resulted in the attenuation of synaptic vesicles acidification, which was assessed by the steady state level of the fluorescence of pH-sensitive dye acridine orange. A decrease in L [(14)C]glutamate accumulation in digitonin-permeabilized synaptosomes after the addition of the metals, which reflected lowered L-[(14)C]glutamate accumulation by synaptic vesicles inside of synaptosomes, may be considered in the support of the above data. Using isolated rat brain synaptic vesicles, it was found that 50 MUM Cd(2+) or Pb(2+) caused dissipation of their proton gradient, whereas the application of essential heavy metal Mn(2+) did not do it within the range of the concentration of 50-500 MUM. Thus, synaptic malfunction associated with the influence of Cd(2+) and Pb(2+) may result from partial dissipation of the synaptic vesicle proton gradient that leads to: (1) a decrease in stimulated exocytosis, which is associated not only with the blockage of voltage-gated Ca(2+) channels, but also with incomplete filling of synaptic vesicles; (2) an attenuation of Na(+)-dependent glutamate uptake. PMID- 21672572 TI - Chemical neuroprotection in the cochlea: the modulation of dopamine release from lateral olivocochlear efferents. AB - The prevalence of sensorineural hearing loss is increasing worldwide, mainly due to ageing, increased noise exposure and cardiovascular risk factors. Several papers dealt with the mechanisms underlying the primary causes of impaired hearing and eventual deafness, including the damage and loss of auditory hair cells; however, very little is known about the protective mechanisms that exist for hearing. Several recent investigations have implicated dopamine (DA) in a neuroprotective circuit for the cochlea. The lateral olivocochlear (LOC) efferents provide axonal innervation of the inner hair cell afferent synapses and release DA and other substances in response to different stimuli. Under ischemic conditions or during noise exposure, DA has been proven to play a neuroprotective role against glutamate excitotoxicity. This review summarises what is currently known about the modulation of DA release in the cochlea, using primarily in vitro experimental data. Based on recent knowledge, there could be two functional subgroups within the LOC fibres, i.e., the DA- and GABA-containing projections. In this review, we attempt to show the neurochemical interactions between these two subsystems. Other aspects of cochlear neurotransmission are also discussed to provide a complete picture of cochlear dopaminergic function in physiological and pathophysiological cases with particular reference to excitotoxicity. PMID- 21672573 TI - Thymus-expressed chemokine promotes survival of PC12 cells via PI3K pathway. AB - We reported previously that CCR9 was neuroprotective in the mouse hippocampal neurons. This study was aimed to investigate if thymus-expressed chemokine (TECK)/CCL25 could promote survival of PC12 cells though its receptor CCR9. pEGFP N1/CCR9 recombinant was constructed and transfected into PC12 cells. Along with this, 50 nM NGF was used to induce PC12 cells to differentiate into sympathetic like neurons. We show here that under serum-free conditions and within a concentration range (50-200 nM), TECK rescued pEGFP-N1/CCR9 transfected PC12 cells from undergoing apoptosis in serum-free medium; however, it did not exert a similar effect on the cells in the control. On the other hand, the PC12 cells succumbed to a higher concentration of TECK (>= 300 nM). Bim expression was up regulated in PC12 cells cultured in serum-free medium in the absence of factors or with anti-TECK+TECK; however, it was not up-regulated in TECK-treated PC12 cells. p-Akt was detected at 15 min which lasted for at least 60 min when PC12 cells were cultured in serum-free medium with TECK. Additionally, it was shown that such an effect was effectively blocked by PI3K inhibitor, Wortmannin. These data suggest that TECK promotes survival of serum-deprived PC12 cells through its receptor, CCR9, most likely via the PI3K/Akt signaling pathway. PMID- 21672574 TI - Hypoxic preconditioning induces neuroprotection against transient global ischemia in adult rats via preserving the activity of Na(+)/K(+)-ATPase. AB - We demonstrated previously that 30min of hypoxic preconditioning (HPC) applied 1day before 10min of transient global cerebral ischemia (tGCI) reduced neuronal loss in the hippocampal CA1 subregion in adult rats. The aim of the present study was to investigate the role of Na(+)/K(+)-ATPase and protein kinase Mzeta (PKMzeta) in the protective effect of HPC against tGCI in adult rats. We found that the activity of Na(+)/K(+)-ATPase decreased in the hippocampal CA1 subregion after 10min of tGCI. This effect was not seen after 30min of HPC in adult rats. Corresponding to the changes in Na(+)/K(+)-ATPase activity, the surface expression of Na(+)/K(+)-ATPase alpha1 subunit increased after HPC. Furthermore, HPC dramatically reduced the number of terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL)-positive cells in the hippocampal CA1 subregion after tGCI. However, neither PKMzeta nor phosphorylation of PKMzeta was changed after tGCI or HPC. The results of the present study are consistent with the hypothesis that both enhanced recovery of Na(+)/K(+)-ATPase activity due to preserved the protein levels of Na(+)/K(+)-ATPase alpha1 subunit and reduced DNA fragmentation after tGCI contribute to the protection afforded by HPC. However, PKMzeta activation does not appear to play a role in this neuroprotection. PMID- 21672575 TI - Evidence for a pathway that facilitates nitric oxide diffusion in the brain. AB - Nitric oxide (()NO) is a diffusible messenger that conveys information based on its concentration dynamics, which is dictated by the interplay between its synthesis, inactivation and diffusion. Here, we characterized ()NO diffusion in the rat brain in vivo. By direct sub-second measurement of ()NO, we determined the diffusion coefficient of ()NO in the rat brain cortex. The value of 2.2*10( 5)cm(2)/s obtained in vivo was only 14% lower than that obtained in agarose gel (used to evaluate ()NO free diffusion). These results reinforce the view of ()NO as a fast diffusing messenger but, noticeably, the data indicates that neither ()NO diffusion through the brain extracellular space nor homogeneous diffusion in the tissue through brain cells can account for the similarity between ()NO free diffusion coefficient and that obtained in the brain. Overall, the results support that ()NO diffusion in brain tissue is heterogeneous, pointing to the existence of a pathway that facilitates ()NO diffusion, such as cell membranes and other hydrophobic structures. PMID- 21672576 TI - The effect of Ndrg2 expression on astroglial activation. AB - N-myc downstream-regulated gene 2 (Ndrg2) is a differentiation- and stress associated molecule predominantly expressed in astrocytes in the central nervous system (CNS). To study the expression and possible role of Ndrg2 in quiescent and activated astrocytes, mice were administrated with 1-methyl-4-phenyl-1,2,3,6 tetrahydropypridine (MPTP), a Parkinson disease (PD)-related neurotoxin which causes both neurodegeneration and glial activation. Immunohistological analysis revealed that Ndrg2 was highly expressed in both types of astrocytes, but less so in astrocytes during the early process of activation. Ndrg2 was also expressed in astrocyte-like cells, but not in neurons, in human brains from PD and Cortico basal degeneration (CBD) patients. In cultured astrocytes, gene silencing of Ndrg2 significantly enhanced the numbers of 5-bromo-2'-deoxy-uridine (BrdU) incorporated and proliferating cell nuclear antigen (PCNA)-positive cells, and reduced the length of cell processes and the amount of F-actin. In contrast, adenovirus-mediated overexpression of Ndrg2 significantly reduced the numbers of BrdU-incorporated and PCNA-positive cells, and enhanced the amount of F-actin. Fractionation and immunocytochemical analysis further revealed that Ndrg2 was located in different cellular fractions including the cytosol and cell surface membranes. These results suggest that Ndrg2 may regulate astroglial activation through the suppression of cell proliferation and stabilization of cell morphology. PMID- 21672577 TI - Tau phosphorylation and neuronal apoptosis induced by the blockade of PP2A preferentially involve GSK3beta. AB - Overactivation of GSK3beta (glycogen synthase kinase-3beta) and downregulation of PP2A (protein phosphatase-2A) have been proposed to be involved in the abnormal tau phosphorylation and aggregation in Alzheimer's disease (AD). GSK3beta and PP2A signaling pathways were reported to be interconnected. Targeting tau kinases was suggested to represent a therapeutic strategy for AD. Here, tau phosphorylation and neuronal apoptosis were induced in cortical cultured neurons by the inhibition of PP2A by okadaic acid (OKA). In this in vitro model of 'tau pathology' and neurodegeneration, we tested whether GSK3beta and other tau kinases including DYRK1A and CDK5 were implicated. Our results show that the inhibitors of GSK3beta, lithium and 6-BIO (6-bromoindirubin-3'-oxime), prevented OKA-induced tau phosphorylation and neuronal apoptosis. The implication of GSK3beta in these OKA-induced effects was confirmed by its silencing by hairpin siRNA. By contrast, inhibition of DYRK1A (dual-specificity tyrosine phosphorylation regulated kinase-1A) and CDK5 (cyclin-dependent kinase-5) reversed OKA-induced tau phosphorylation at certain sites but failed to prevent neuronal apoptosis. These results indicate that OKA-induced effects, especially neuronal apoptosis, are preferentially mediated by GSK3beta. Furthermore, since chronic exposure to lithium and 6-BIO might be deleterious for neurons, we tested the effect of a new 6-BIO derivative, 6-BIBEO (6-bromoindirubin-3'-(2-bromoethyl) oxime), which is much less cytotoxic and more selectively inhibits GSK3beta compared to lithium and 6-BIO. We show that 6-BIBEO efficiently reversed OKA induced tau phosphorylation and neuronal apoptosis. It will be interesting to test neuroprotection by 6-BIBEO in an in vivo model of tau pathology and neurodegeneration. PMID- 21672579 TI - Presynaptic kainate and NMDA receptors are implicated in the modulation of GABA release from cortical and hippocampal nerve terminals. AB - One of the pathways implicated in a fine-tuning control of synaptic transmission is activation of the receptors located at the presynaptic terminal. Here we investigated the intracellular events in rat brain cortical and hippocampal nerve terminals occurring under the activation of presynaptic glutamate receptors by exogenous glutamate and specific agonists of ionotropic receptors, NMDA and kainate. Involvement of synaptic vesicles in exocytotic process was assessed using [(3)H]GABA and pH-sensitive fluorescent dye acridine orange (AO). Glutamate as well as NMDA and kainate were revealed to induce [(3)H]GABA release that was not blocked by NO-711, a selective blocker of GABA transporters. AO-loaded nerve terminals responded to glutamate application by the development of a two-phase process. The first phase, a fluorescence transient completed in ~1min, was similar to the response to high K(+). It was highly sensitive to extracellular Ca(2+) and was decreased in the presence of the NMDA receptor antagonist, MK-801. The second phase, a long-lasting process, was absolutely dependent on extracellular Na(+) and attenuated in the presence of CNQX, the kainate receptor antagonist. NMDA as well as kainate per se caused a rapid and abrupt neurosecretory process confirming that both glutamate receptors, NMDA and kainate, are involved in the control of neurotransmitter release. It could be suggested that at least two types ionotropic receptor are attributed to glutamate induced two-phase process, which appears to reflect a rapid synchronous and a more prolonged asynchronous vesicle fusion. PMID- 21672580 TI - Carotenoids and Alzheimer's disease: an insight into therapeutic role of retinoids in animal models. AB - Carotenoids play a pivotal role in prevention of many degenerative diseases mediated by oxidative stress including neurodegenerative diseases like Alzheimer's Disease (AD). The involvement of retinoids in physiology, AD pathology and their therapeutic role in vitro and in vivo has been extensively studied. This review focuses on the role of carotenoids like retinoic acid (RA), all trans retinoic acid (ATRA), lycopene and beta-carotene in prevention of AD symptoms primarily through inhibition of amyloid beta (Abeta) formation, deposition and fibril formation either by reducing the levels of p35 or inhibiting corresponding enzymes. The role of antioxidant micronutrients in prevention or delaying of AD symptoms has been included. This study emphasizes the dietary supplementation of carotenoids to combat AD and warrants further studies on animal models to unravel their mechanism of neuroprotection. PMID- 21672578 TI - Role of oxidative stress in epileptic seizures. AB - Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetic rat models, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment. PMID- 21672581 TI - Oxygen-glucose deprivation increases the enzymatic activity and the microvesicle mediated release of ectonucleotidases in the cells composing the blood-brain barrier. AB - The blood-brain barrier (BBB), the dynamic interface between the nervous tissue and the blood, is composed by endothelial cells, pericytes and astrocytes. Extracellular nucleotides and nucleosides and their receptors (the purinergic system) constitute a widely diffused signaling system involved in many pathophysiological processes. However, the role of this system in controlling BBB functions is still largely unknown. By using cultures of these three cell types grown separately and a BBB in vitro model consisting of triple co-cultures, we studied for the first time the expression and distribution of the ecto-enzymes nucleoside triphosphate diphosphohydrolases (NTPDases, the enzymes which hydrolyze extracellular nucleotides) under control and ischemic (oxygen-glucose deprivation in vitro; OGD) conditions. NTPDase1 was detected in all three cell types, whereas NTPDase2 was expressed by astrocytes and pericytes and, to a lesser extent, by endothelial cells. Endothelial cells were extremely susceptible to cell death when OGD was applied to mimic in vitro the cytotoxicity induced by ischemia, whereas astrocytes and pericytes were more resistant. A semi quantitative assay highlighted markedly increased e-ATPase activity following exposure to OGD in all three cell types, either when grown separately or when co cultured together to resemble the composition of the BBB. Moreover, electron microscopy analysis showed that both endothelial cells and astrocytes shed microvesicles containing NTPDases from their membrane, which may suggest a novel mechanism to increase the breakdown of ATP released to toxic levels by damaged BBB cells. We hypothesize that this phenomenon could have a protective and/or modulatory effect for brain parenchymal cells. This in vitro model is therefore useful to study the role of extracellular nucleotides in modulating BBB responses to ischemic events, and to develop new effective purinergic-based approaches for brain ischemia. PMID- 21672582 TI - An ouabain-like factor is secreted from immortalized hypothalamic cells in an aldosterone-dependent manner. AB - Ouabain-like factor (OLF) modulates blood pressure via sodium pump inhibition in the central nervous system and in the peripheral circulation. Ouabain-like factor (OLF) is thought to be produced in the adrenal gland and hypothalamus, and it may relate locally to the renin-angiotensin-aldosterone system. However, the evidence for the latter was obtained from in vivo experiments using animals. In the present study, we investigated ouabain production in the immortalized hypothalamic cell line N1. First, cell culture supernatant was collected from the immortalized hypothalamic cell line N1 at 0.5, 4, 8, and 24 h. A newly developed enzyme-linked immunosorbent assay (ELISA) that used anti-ouabain antibody showed that immunoreactivity in the supernatant was increased significantly at 24 vs. 0.5 h (0.01+/-0.004 vs. 0.16+/-0.033 pmol/mg protein, p<0.01). A combination of HPLC and ELISA was used to characterize N1 cell-derived OLI, showing that the highest peak of OLI had the same retention time as authentic ouabain. Thereafter, N1 cells were cultured with (1-10 MUM) aldosterone, and supernatant was collected after 24 h of culture. In addition, N1 cells were cultured with 5 MUM eplerenone, a mineralocorticoid receptor blocker, plus aldosterone. OLI was significantly increased in the supernatant of the cells cultured with 10 MUM aldosterone (0.40+/-0.078 pmol/mg protein), and this increase was abolished by the addition of the aldosterone antagonist eplerenone (0.12+/-0.030 pmol/mg protein). These data suggest that the immortalized hypothalamic N1 cells secrete OLF and that aldosterone stimulates its secretion via mineralocorticoid receptors. PMID- 21672583 TI - The specific Na(+)/Ca(2+) exchange inhibitor SEA0400 prevents nitric oxide induced cytotoxicity in SH-SY5Y cells. AB - The Na(+)/Ca(2+) exchanger (NCX) plays a role in the regulation of intracellular Ca(2+) levels, and nitric oxide (NO) is involved in many pathological conditions including neurodegenerative disorders. We have previously found that sodium nitroprusside (SNP), an NO donor, causes apoptotic-like cell death in cultured glial cells via NCX-mediated pathways and the mechanism for NO-induced cytotoxicity is cell type-dependent. The present study examined using the specific NCX inhibitor 2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline (SEA0400) whether NCX is involved in NO-induced injury in cultured neuronal cells. The treatment of neuroblastoma SH-SY5Y cells with SNP resulted in apoptosis and the cytotoxicity was blocked by the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126 and the p38 MAP kinase (MAPK) inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP60012. SNP increased Ca(2+) influx and intracellular Ca(2+) levels. In addition, SNP increased ERK and p38 MAPK phosphorylation, and production of reactive oxygen species (ROS) in an extracellular Ca(2+)-dependent manner. These effects of SNP were prevented by SEA0400. SNP-induced cytotoxicity was not affected by inhibitors of the Ca(2+), Na(+) and store operated/capacitative channels. Moreover, SNP-induced increase in intracellular Ca(2+) levels, ROS production and decrease in cell viability were blocked by a cGMP-dependent protein kinase (PKG) inhibitor. These results suggest that Ca(2+) influx via the reverse of NCX is involved in the cascade of NO-induced neuronal apoptosis and NO activates the NCX through guanylate cyclase/PKG pathway. PMID- 21672584 TI - Tissue concentration changes of amino acids and biogenic amines in the central nervous system of mice with experimental autoimmune encephalomyelitis (EAE). AB - We have characterized the changes in tissue concentrations of amino acids and biogenic amines in the central nervous system (CNS) of mice with MOG(35-55) induced experimental autoimmune encephalomyelitis (EAE), an animal model commonly used to study multiple sclerosis (MS). High performance liquid chromatography was used to analyse tissue samples from five regions of the CNS at the onset, peak and chronic phase of MOG(35-55) EAE. Our analysis includes the evaluation of several newly examined amino acids including d-serine, and the inter-relations between the intraspinal concentration changes of different amino acids and biogenic amines during EAE. Our results confirm many of the findings from similar studies using different variants of the EAE model as well as those examining changes in amino acid and biogenic amine levels in the cerebrospinal fluid (CSF) of MS patients. However, several notable differences were observed between mice with MOG(35-55)-induced EAE with findings from human studies and other EAE models. In addition, our analysis has identified strong correlations between different amino acids and biogenic amines that appear to change in two distinct groups during EAE. Group I analyte concentrations are increased at EAE onset and peak but then decrease in the chronic phase with a large degree of variability. Group II is composed of amino acids and biogenic amines that change in a progressive manner during EAE. The altered levels of these amino acids and biogenic amines in the disease may represent a critical pathway leading to neurodegenerative processes that are now recognized to occur in EAE and MS. PMID- 21672586 TI - A comprehensive study on the putative delta-opioid receptor (sub)types using the highly selective delta-antagonist, Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH. AB - The goal of our work was a throughout characterization of the pharmacology of the TIPP-analog, Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH and see if putative delta-opioid receptor subtypes can be distinguished. Analgesic latencies were assessed in mouse tail-flick assays after intrathecal administration. In vitro receptor autoradiography, binding and ligand-stimulated [(35)S]GTPgammaS functional assays were performed in the presence of putative delta(1)-(DPDPE: agonist, BNTX: antagonist), delta(2)-(agonist: deltorphin II, Ile(5,6)-deltorphin II, antagonist: naltriben) and MU-(DAMGO: agonist) opioid ligands. The examined antagonist inhibited the effect of DPDPE by 60%, but did not antagonize delta(2)- and MU-agonist induced analgesia. The radiolabeled form identified binding sites with K(D)=0.18 nM and receptor densities of 102.7 fmol/mg protein in mouse brain membranes. The binding site distribution of the [(3)H]Tyr-Tic-(2S,3R)-beta-MePhe Phe-OH agreed well with that of [(3)H]Ile(5,6)-deltorphin II as revealed by receptor autoradiography. Tyr-Tic-(2S,3R)-beta-MePhe-Phe-OH displayed 2.49+/-0.06 and 0.30+/-0.01 nM potency against DPDPE and deltorphin II in the [(35)S]GTPgammaS functional assay, respectively. The rank order of potency of putative delta(1)- and delta(2)-antagonists against DPDPE and deltorphin was similar in brain and CHO cells expressing human delta-opioid receptors. Deletion of the DOR-1 gene resulted in no residual binding of the radioligand and no significant DPDPE effect on G-protein activation. Tyr-Tic-(2S,3R)-beta-MePhe-Phe OH is a highly potent and delta-opioid specific antagonist both in vivo and in vitro. However, the putative delta(1)- and delta(2)-opioid receptors could not be unequivocally distinguished in vitro. PMID- 21672587 TI - WITHDRAWN: Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21672585 TI - PKCdelta inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment. AB - The present study was designed to evaluate the specific role of protein kinase C (PKC) delta in methamphetamine (MA)-induced dopaminergic toxicity. A multiple dose administration regimen of MA significantly increases PKCdelta expression, while rottlerin, a PKCdelta inhibitor, significantly attenuates MA-induced hyperthermia and behavioral deficits. These behavioral effects were not significantly observed in PKCdelta antisense oligonucleotide (ASO)-treated- or PKCdelta knockout (-/-)-mice. There were no MA-induced significant decreases of dopamine (DA) content or tyrosine hydroxylase (TH) expression in the striatum in rottlerin-treated-, ASO-treated- or PKCdelta (-/-)-mice. The administration of MA also results in a significant decrease of TH phosphorylation at ser 40, but not ser 31, while the inhibition of PKCdelta consistently and significantly attenuates MA-induced reduction in the phosphorylation of TH at ser 40. Therefore, these results suggest that the MA-induced enhancement of PKCdelta expression is a critical factor in the impairment of TH phosphorylation at ser 40 and that pharmacological or genetic inhibition of PKCdelta may be protective against MA-induced dopaminergic neurotoxicity in vivo. PMID- 21672588 TI - Antidepressant-like effect of a Ginkgo biloba extract (EGb761) in the mouse forced swimming test: role of oxidative stress. AB - EGb761 is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves. This extract is used clinically due to its neuroprotective effects, exerted probably via its potent antioxidant or free radical scavenger action. Previous studies suggest that oxidative stress, via free radical production, may play an important role in depression and animal models for depression-like behavior. Preclinical studies have suggested that antioxidants may have antidepressants properties. The aim of this study was to investigate the antidepressant-like of EGb761 due to its antioxidant role against oxidative stress induced in the forced swimming test, the most widely used preclinical model for assessing antidepressant-like behavior. Male BALB/c mice were pretreated with EGb761 (10mg/kg, ip) daily for 17 days followed by the forced swimming test and spontaneous locomotor activity. Animals were sacrificed to evaluate lipid peroxidation, different antioxidant enzyme activities, serotonin and dopamine content in midbrain, hippocampus and prefrontal cortex. EGb761 significantly decreased the immobility time (39%) in the forced swimming test. This antidepressant-like effect of EGb761 was associated with a reduction in lipid peroxidation and superoxide radical production (indicated by a downregulation of Mn-superoxide dismutase activity), both of which are indicators of oxidative stress. The protective effect of EGb761 is not related to excitatory or inhibitory effects in locomotor activity, and was also associated with the modulation of serotonergic and dopaminergic neurotransmission. It is suggested that EGb761 produces an antidepressant-like effect, and that an antioxidant effect against oxidative stress may be partly responsible for its observed neuroprotective effects. PMID- 21672590 TI - Tolerated nitrite therapy in experimental intracerebral hemorrhage: Rationale of nitrite therapy in a broad range of hyperacute strokes. AB - Nitrite therapy is more effective in cerebral ischemia when administered earlier. It would be beneficial during the hyperacute stages of stroke if the nitrite effect is demonstrated in intracerebral hemorrhage (ICH). When nitrite is injected intravenously 3h after ICH induction in rats, most doses of nitrite provided no beneficial effects on behavioral deficits, brain edema and hematoma volumes. A high dose of nitrite, however, decreased hematoma volume, but not brain edema. Peri-hematomal apoptosis and inflammation were similar between the control and nitrite groups. Nitrite therapy may be considered a therapeutic option in hyperacute stroke because nitrite therapy is tolerated in ICH as well. PMID- 21672589 TI - Loss of PINK1 function decreases PP2A activity and promotes autophagy in dopaminergic cells and a murine model. AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of recessive PD. Autophagy, a pathway for clearance of protein aggregates or impaired organelles, is a newly identified mechanism for PD development. However, it is still unclear what molecules regulate autophagy in PINK1-silenced cells. Here we report that autophagosome formation is promoted in the early phase in response to PINK1 gene silencing by lentivirus transfer vectors expressed in mouse striatum. Reduced PP2A activity and increased phosphorylation of PP2A at Y307 (inactive form of PP2A) were observed in PINK1-knockdown dopaminergic cells and striatum tissues. Treatment with C2-ceramide (an agonist of PP2A) reduced autophagy levels in PINK1 silenced MN9D cells, which suggests that PP2A plays an important role in the PINK1-knockdown-induced autophagic pathway. Furthermore, phosphorylation of Bcl-2 at S87 increased in PINK1-silenced cells and was negatively regulated by additional treatment with C2-ceramide, which indicates that Bcl-2 may be downstream of PP2A inactivation in response to PINK1 dysfunction. Immunoprecipitation also revealed dissociation of the Bcl-2/Beclin1 complex in PINK1-silenced cells, which was reversed by additional treatment with C2 ceramide, and correlated with changes in level of autophagy and S87 phosphorylation of Bcl-2. Finally, Western blots for cleaved caspase-9 and flow cytometry results for active caspase-3 revealed that PP2A inactivation is involved in the protective effect of autophagy on PINK1-silenced cells. Our findings show that downregulation of PP2A activity in PINK1-silenced cells promotes the protective effect of autophagy through phosphorylation of Bcl-2 at S87 and blockage of the caspase pathway. These results may have implications for identifying the mechanism of PD. PMID- 21672591 TI - Calpain regulates N-terminal interaction of GSK-3beta with 14-3-3zeta, p53 and PKB but not with axin. AB - Calpain produces a truncation of GSK3beta that removes the N-terminal inhibitory domain. Here we analyze the effect of that truncation on protein-protein interaction. We pulled down GST-tagged proteins in the presence of full length GSK-3beta and calpain-cleaved GSK-3beta. Commercial GSK-3beta was first incubated with calpain for 2.5 min in vitro, and then with GST-tagged proteins in the presence of calpeptin, a synthetic calpain inhibitor. Western blot analyses were performed to determine if there is an interaction between these GST-tagged proteins and truncated GSK-3beta. Using axin GST-tagged, we pulled down the protein in the presence of full length GSK-3beta and calpain-cleaved GSK-3beta. Western blot analyses showed full length GSK-3beta in the pellet as well GSK 3beta cleaved by calpain. Thus axin was able to bind GSK-3beta without the N terminal end. When the same experiment was carried out with GST-tagged 14-3 3zeta, p53 and PKB, full length GSK-3beta was observed in the pellet, but GSK 3beta truncated by calpain was not pulled down demonstrating that GSK-3beta N terminal end is necessary to interact with these three proteins. Our data demonstrate that N-terminal end is necessary for 14-3-3zeta, p53 and PKB interaction. However, the interaction of GSK3beta with axin is not altered by calpain. These data support a physiological role for GSK3beta truncation mediated by calpain. PMID- 21672592 TI - Acetyl-CoA metabolism in amprolium-evoked thiamine pyrophosphate deficits in cholinergic SN56 neuroblastoma cells. AB - Inhibition of pyruvate (PDHC) and ketoglutarate (KDHC) dehydrogenase complexes induced by thiamine pyrophosphate deficits is known cause of disturbances of cholinergic transmission in the brain, yielding clinical symptoms of cognitive, vegetative and motor deficits. However, particular alterations in distribution of key acetylcholine precursor, acetyl-CoA, in the cholinergic neuron compartment of thiamine pyrophosphate-deficient brain remain unknown. Therefore, the aim of our work was to find out how amprolium-induced thiamine pyrophosphate deficits (TD) affect distribution of acetyl-CoA in the compartment of pure cholinergic neuroblastoma SN56 cells originating from murine septum. Amprolium caused similar concentration-dependent decreases in thiamine pyrophosphate levels in nondifferentiated (NC) and differentiated (DC) cells cultured in low thiamine medium. In such conditions DC displayed significantly greater loss of viability than the NC ones, despite of lesser suppressions of PDHC activities and tetrazolium salt reduction rates in the former. On the other hand, intramitochondrial acetyl-CoA levels in DC were 73% lower than in NC, which explains their greater susceptibility to TD. Choline acetyltransferase activity and acetylcholine content in DC were two times higher than in NC. TD caused 50% decrease of cytoplasmic acetyl-CoA levels that correlated with losses of acetylcholine pool in DC but not in NC. These data indicate that particular sensitivity of DC to TD may result from relative shortage of acetyl-CoA due to its higher utilization in acetylcholine synthesis. PMID- 21672593 TI - The effects of the perinatal treatment with 5-hydroxytryptophan or tranylcypromine on the peripheral and central serotonin homeostasis in adult rats. AB - Serotonin (5HT) is a biologically active amine present in mammals in the brain and the peripheral tissues. Autism is a neurodevelopmental disorder in which 5HT homeostasis is disturbed both centrally and peripherally, but the relationship between the 5HT disturbances in the two compartments is not understood. In an attempt to explore the relationship between the disturbed peripheral 5HT homeostasis and central 5HT functioning, we exposed the developing rat brain to increased 5HT concentrations, by treatment of rats with subcutaneous injections of the immediate 5HT precursor 5-hydroxy-L-tryptophan (5HTP, 25 mg/kg), or the non-selective MAO inhibitor tranylcypromine (TCP, 2 mg/kg), during the period of the most intensive development of 5HT neurons--from gestational day 13 to post natal day 21. The effects of the mentioned treatments on peripheral and central 5HT levels were then studied in adult rats. Platelet and plasma 5HT concentrations (measured by ELISA), as well as cortical and midbrain 5HT, tryptophan and 5-hydroxyindoleacetic acid levels (measured by HPLC) were determined in twelve 5HTP treated and eight TCP treated rats, and compared with the values measured in 10 control, saline treated rats. Treatment with 5HTP significantly raised peripheral but not central 5HT concentrations. At adult age, peripheral 5HT homeostasis was re-established, while modest decrease in 5HT concentration was observed in frontal cortex, presumably due to hyperserotonemia induced loss of 5HT terminals during brain development. Treatment with TCP induced significant 5HT elevations in both compartments. At adult age, permanent changes in 5HT homeostasis were observed, both peripherally (as hyperserotonemia) and centrally (as altered 5HT metabolism with decreased 5HT concentrations). Further studies are planned in order to explore the nature of the different disturbances of 5HT homeostasis induced by the two compounds, and their results are expected to shed some light on the role of hyperserotonemia in autism. PMID- 21672594 TI - Neuroprotective effects of genistein in VSC4.1 motoneurons exposed to activated microglial cytokines. AB - Pro-inflammatory cytokines released from activated microglia may be responsible for neuronal damage and resulting motor deficits associated with CNS disorders such as spinal cord injury, Parkinson's disease, and multiple sclerosis. Estrogen (17beta-estradiol) is capable of ameliorating motoneuron death following spinal cord injury, but has a number of deleterious side effects. Genistein (GEN), an estrogen receptor beta agonist and potent antioxidant, may represent an alternative to estrogen in treating neurodegenerative disorders. However, little is known about the neuroprotective effects of GEN. We therefore tested whether GEN would prevent apoptosis in cultured motoneurons following exposure to pro inflammatory cytokines released from IFN-gamma activated microglia. Exposure of ventral spinal cord 4.1 motoneurons to microglial cytokine supernatant in vitro caused significant apoptosis and reduced mitochondrial membrane potential. An increase in reactive oxygen species, intracellular Ca(2+), calpain, caspases, cytochrome c, and the bax:bcl-2 ratio were also noted. GEN treatment reversed apoptotic death and cellular changes following cytokine exposure and was associated with increased expression of estrogen receptor beta suggesting that GEN may promote neuroprotection via receptor-mediated pathways. The addition of ICI 182, 780, an estrogen receptor antagonist following GEN treatment attenuated neuroprotection, suggesting that GEN may act mainly via estrogen receptor beta to protect VSC4.1 motoneurons. We conclude that GEN protects cultured ventral spinal cord 4.1 cells from inflammatory insult and thus may represent a potential beneficial therapy in the treatment of neurodegenerative disorders. PMID- 21672595 TI - Single nucleotide polymorphisms in interleukin-1gene cluster and subgingival colonization with Aggregatibacter actinomycetemcomitans in patients with aggressive periodontitis. AB - Periodontitis is initiated by the subgingival occurrence of periodontopathogens. It is triggered by a specific host-dependent immune response that is influenced by genetic predisposition. Polymorphisms in the interleukin-1 (IL-1) gene cluster have been suggested to influence the pathogenesis of periodontitis. A total of 159 periodontitis patients (chronic disease: n = 73, aggressive disease: n = 86) and 89 periodontitis-free controls were included in the study. Polymorphisms IL 1alpha (rs1800587), IL-1beta (rs16944, rs1143634), IL-1 receptor (rs2234650), and IL-1 receptor antagonist (rs315952) were determined by polymerase chain reaction with sequence-specific primers (PCR-SSP). Subgingival bacterial colonization was assessed using a polymerase chain reaction/DNA probe test (micro-Ident). Haplotype block structure was determined using Haploview 4.2. Statistical analyses were performed applying SPSS 17.0 considering dominant, recessive, and codominant genetic models. In this case-control study, no association between genomic variants of the IL-1 gene cluster and the incidence of severe periodontitis could be shown. Carriers of the rare genotypes of rs1800587 (p(corr) = 0.009), rs1143634 (p(corr) = 0.009) and composite genotype (rs1800587+rs1143634) (p(corr) = 0.031) had a twofold higher risk for subgingival occurrence of Aggregatibacter actinomycetemcomitans. In forward stepwise binary logistic regression analyses considering age, gender, smoking, and approximal plaque index as potential confounders these significant associations were demonstrated. Despite the genetic background of IL-1 gene cluster could be shown to be associated with subgingival colonization of A actinomycetemcomitans, there is no evidence that it is an independent risk indicator for periodontitis. PMID- 21672596 TI - Toxicological studies on a novel phytase expressed from synthetic genes in Aspergillus oryzae. AB - Phytases are widely used as feed additives for monogastric animals, which cannot easily utilise the phosphorus bound in phytate (myo-inositol hexakisphosphate). The current study presents a safety evaluation of a 6-phytase produced by an Aspergillus oryzae strain expressing two synthetic genes, both mimicking a phytase gene from a Citrobacter braakii strain. Oral administration of the phytase preparation to rats at a dose level of 0.86 g total organic solids/kg body weight/day for 13 weeks did not cause any adverse effect. The phytase preparation did not exhibit irritative potential when applied locally to the eyes of rabbits or when applied to the skin using the in vitro three-dimensional epidermis model of adult human-derived epidermal keratinocytes. Furthermore, the phytase preparation was found not to represent mutagenic or clastogenic potential in the bacterial reverse mutation assay and in the in vitro micronucleus assays. Based on the toxicological data, the large safety factors calculated under common recommended dose assumptions for broiler chickens and weaned piglets, and the fact that Aspergillus oryzae is considered a safe strain lineage, it is concluded that there are no reasons for safety concerns when using this phytase as a feed additive. PMID- 21672597 TI - A study to evaluate the effect on Mouth Level Exposure and biomarkers of exposure estimates of cigarette smoke exposure following a forced switch to a lower ISO tar yield cigarette. AB - A forced switch to a lower ISO tar yield cigarette was used in a clinical study, conducted in Germany, that compared two methods of estimating exposure to cigarette smoke. Pre- and post-switch estimates of Mouth Level Exposure (MLE) to nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), pyrene and acrolein were obtained by chemical analysis of spent cigarette filters for nicotine content. Similarly, pre- and post-switch estimates of uptake of these smoke constituents were achieved by analysis of corresponding urinary biomarkers of exposure (BoE): total nicotine equivalents; total 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanol (NNAL); total 1-hydroxypyrene (1-OHP), and 3-hydroxypropyl mercapturic acid (3-HPMA), plus the nicotine metabolite cotinine, in plasma and saliva. Three hundred healthy volunteers were recruited comprising 100 smokers of each of 9-10 and 4-6 mg ISO tar yield cigarettes and 50 smokers of 1-2mg ISO tar yield cigarettes and 50 non-smokers. Fifty smokers of each of the 9-10 and 4-6 mg ISO tar yield cigarettes took part in the switching aspects of this study whilst the remaining smokers formed non-switching control groups who smoked their usual ISO tar yield cigarette throughout the study. After 5 days, all subjects were admitted into a clinic where baseline measures of MLE and BoE were obtained. The 10mg switching group was then switched to the 4 mg ISO tar yield cigarette and the 4 mg ISO tar yield switching group switched to the 1mg cigarette. Subjects returned home for 12 days, continuing to smoke the supplied cigarettes before being readmitted into the clinic where samples were collected for MLE and BoE analysis. Changes in daily exposure estimates were determined on a group and individual basis for both methods. The pre- to post-switch directional changes in MLEs and their corresponding BoEs were generally consistent and the MLE/BoE relationship maintained. Switching to a lower yield cigarette generally resulted in reductions in exposure with the resultant exposure level being similar to that seen in regular smokers of the lower yield cigarette. PMID- 21672598 TI - Lead acetate does not inhibit dimethylnitrosamine activation and interacts with phenobarbital which is genotoxic in the ST cross of the Drosophila wing spot test. AB - Lead acetate (PbAc) is known to inhibit the synthesis of the heme group, needed for hemeproteins like Cytochromes P450 (CYP450s). Dimethylnitrosamine (DMN) requires metabolic activation by CYP450s. The Drosophila wing spot test was performed to establish whether PbAc inhibits DMN activation in the standard (ST) and high bioactivation (HB) crosses, with different levels of CYP450s. Phenobarbital (PH) was used as an antagonist for its ability to induce CYP450s synthesis. PbAc (0.01, 0.1, 1.0mM) produced significant small spots frequencies in the ST cross, indicating a possible genotoxic activity, however, the total spots frequency was negative at all concentrations. DMN (0.076 mM) was genotoxic in both crosses; surprisingly, PH (12 mM) was genotoxic and the PH-DMN treatment resulted synergic in the ST cross. Interestingly, the PbAc-PH pre-co-treatments showed a possible interaction in the ST cross. The GC-MS analysis showed a drop in the PH content as the PbAc concentration increased. PbAc also seemed to inhibit the genotoxic activity of PH, except at 0.01 mM. It is concluded that PbAc does not inhibit DMN activation by CYP450s in both crosses since it exerted a clear genotoxicity and that PH is genotoxic and interacts with PbAc in the ST but not the HB cross. PMID- 21672599 TI - Transcellular transport of domoic acid across intestinal Caco-2 cell monolayers. AB - The intestinal absorption mechanism of domoic acid (DA) was investigated using Caco-2 cells. DA is a tricarboxylic amino acid that contains a glutamic acid moiety, and causes deficits in short-term memory by binding to glutamate receptors as an agonist of glutamic acid. Caco-2 cell monolayers cultured on permeable membranes were incubated with 100 MUM DA on either the apical or basolateral side, and the transcellular transport of DA was measured. The transcellular transport of DA from the apical to basolateral side was about twofold that in the opposite direction. The transcellular transport of DA from the apical side was optimal at a neutral pH, and was temperature- and Cl(-) dependent, but was Na(+)-independent. Coincubation of DA with 4,4' diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an anion exchange inhibitor, significantly decreased the apical-to-basolateral transport of DA by 48%, and coincubation with probenecid (a non-specific anion transport inhibitor) significantly decreased the transport of DA by 31%. In contrast, coincubation with glutamic acid, succinic acid (a dicarboxylic acid), or citric acid (a tricarboxylic acid) did not decrease the transport of DA. These results suggest that the apical-to-basolateral transport of DA across the Caco-2 cell monolayers is mediated by DIDS-sensitive anion transporters. PMID- 21672600 TI - Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine. AB - Gender is a factor that influences susceptibility of individuals to drug-induced liver injury in experimental animals and humans. In this study, we investigated the mechanisms underlying resistance of female mice to acetaminophen (APAP) induced hepatotoxicity. Overnight-fasted male and female CD-1 mice were administered APAP intraperitoneally. A minor increase in serum alanine aminotransferase levels was observed in female mice after APAP administration at a dose that causes severe hepatotoxicity in males. Hepatic glutathione (GSH) depleted rapidly in the both genders prior to development of hepatotoxicity, whereas its recovery was more rapid in female than in male mice. This was consistent with higher induction of hepatic glutamate-cysteine ligase (GCL) in females. Pretreatment of mice with L-buthionine sulfoximine (BSO), an inhibitor of GCL, exaggerated APAP hepatotoxicity only in female mice, resulting in much higher hepatotoxicity in female than in male mice. In addition, hepatic GSH was markedly depleted in BSO-pretreated female mice compared with male mice, which supports severe hepatotoxicity in BSO-pretreated females. APAP treatment highly induced multidrug resistance-associated protein 4 (Mrp4) only in female mice. The resulting high Mrp4 expression could thus contribute to decreased hepatic GSH levels via sinusoidal efflux when GCL is inhibited. In conclusion, resistance to APAP hepatotoxicity in female mice and its reversal by pretreatment with BSO could be attributed to sex differences in disposition of hepatic GSH, which may generally determine susceptibility to drug-induced liver injury. PMID- 21672601 TI - Protease inhibitors clitocypin and macrocypin are differentially expressed within basidiomycete fruiting bodies. AB - Clitocypin and macrocypin are cysteine protease inhibitors of the mycocypin family which is unique to basidiomycetes. We have established that Clitocybe nebularis and Macrolepiota procera each contain genes for both macrocypin and clitocypin. Both are expressed in M. procera but only clitocypin in C. nebularis. Further analysis of mycocypin expression at the mRNA and protein levels in mature fruiting bodies of M. procera revealed that clitocypin is expressed evenly throughout the fruiting body, while the level of expression of macrocypins varies, and, at the protein level, is much higher in the veil fragments and the ring. The expression patterns of various mycocypins were determined in Coprinopsis cinerea, using promoters linked to a reporter gene. The expression profile of the clitocypin promoter was similar to that of the constitutive promoter gpdII from Agaricus bisporus, while that of the macrocypin 4 promoter was limited to the outer edges of the fruiting body throughout development. In addition, the activity of the macrocypin 3 promoter was different, indicating different regulation of expression for different macrocypin genes. The complex, tissue specific expression patterns for mycocypin genes suggest different biological roles for the products, either in regulation of endogenous proteases or in defense against pathogens or predators. PMID- 21672602 TI - A new chitooligosaccharide specific lectin from snake gourd (Trichosanthes anguina) phloem exudate. Purification, physico-chemical characterization and thermodynamics of saccharide binding. AB - A new lectin has been purified to homogeneity from the phloem exudate of snake gourd (Trichosanthes anguina) by affinity chromatography on chitin. The snake gourd phloem lectin (SGPL) specifically binds chitooligosaccharides and their inhibitory potency increased with increase in size. PAGE and SDS-PAGE studies indicate that SGPL is a heterodimer, in which the two subunits (48 and 53kDa) are joined by disulfide bonds. Consistent with this, electrospray-ionization mass spectrum yielded the exact mass of the protein as 104,621.8 Daltons. CD studies showed that SGPL contains about 9% alpha-helix, 39% beta-sheet, 20% beta-turns and 32% unordered structures and that saccharide binding does not significantly affect its secondary and tertiary structures. Titration calorimetric studies indicate that the dimeric lectin binds two ligand molecules [(GlcNAc)(3-6)] with association constants determined at 25 degrees C being 1.7*10(5) and 3.6*10(5)M( 1), for chitotriose and chitohexaose, respectively. Binding of all the chitooligosaccharides is governed by enthalpic forces, whereas the contribution from binding entropies was unfavorable. These results suggest that the SGPL saccharide interaction is stabilized by hydrogen bonding and van der Waals' interactions. Enthalpy-entropy compensation was observed for the SGPL chitooligosaccharide interaction, suggesting that water molecules play a key role in the binding process. PMID- 21672603 TI - Validation of the catalytic mechanism of Escherichia coli purine nucleoside phosphorylase by structural and kinetic studies. AB - The catalytic mechanism of Escherichia coli purine nucleoside phosphorylase (PNP) is revised using site-directed mutagenesis, kinetic studies and structure determinations. The experimental evidence on the role of the particular catalytic amino acid during catalysis has not been available. Therefore, the active site mutants Arg24Ala, Asp204Ala, Asp204Asn, Arg217Ala and Asp204Ala/Arg217Ala were prepared and their kinetics and thermodynamic studies were carried out. The activity tests with natural substrates and 7-methylguanosine confirmed the earlier hypothesis, that catalysis involves protonation of the purine base at position N7 by Asp204, which is triggered by Arg217. The crystal structures of the wild type in complexes with phosphate and sulphate, respectively, and of the Arg24Ala mutant in complex with phosphate/sulphate were determined. The structural data show that previously observed conformational change is a result of the phosphate binding and its interaction with Arg24. As E. coli PNP is a promising candidate for the tumour-directed gene therapy, our results may also help to design efficient mutants useful in gene therapy. PMID- 21672604 TI - N-phenyl-carbazole-based two-photon fluorescent probes: strong sequence dependence of the duplex vs quadruplex selectivity. AB - Herein we report on the synthesis and DNA recognition properties of a series of three N-phenyl carbazole-based light-up probes initially designed for two-photon absorption. The vinylic derivatives (Cbz-2Py, Cbz-3Py) display strong fluorescence enhancement when bound to various duplex- and quadruplex-forming oligonucleotides whereas the oxazole derivative is not fluorescent in DNA. Determination of affinity constants by fluorimetric titrations evidenced that Cbz 2Py has a clear preference for AT-rich duplex structures. Circular Dichroism (CD) measurements confirmed the sequence-dependent binding of this compound and suggest insertion in the minor groove as shown by a strong induced CD (ICD) signal and further supported by molecular modeling. Altogether the data indicate that duplex vs quadruplex selectivity of the dyes is strongly dependent on the sequence of the duplex. Finally, the dyes exhibit high two-photon absorption cross-sections (up to 540GM in glycerol) and allow a fine and bright staining of nuclear DNA with low background fluorescence as shown by one and two-photon confocal microscopy imaging of fixed cells. PMID- 21672605 TI - Genetic algorithm with alternating selection pressure for protein side-chain packing and pK(a) prediction. AB - The prediction of protein side-chain conformation is central for understanding protein functions. Side-chain packing is a sub-problem of protein folding and its computational complexity has been shown to be NP-hard. We investigated the capabilities of a hybrid (genetic algorithm/simulated annealing) technique for side-chain packing and for the generation of an ensemble of low energy side-chain conformations. Our method first relies on obtaining a near-optimal low energy protein conformation by optimizing its amino-acid side-chains. Upon convergence, the genetic algorithm is allowed to undergo forward and "backward" evolution by alternating selection pressures between minimal and higher energy setpoints. We show that this technique is very efficient for obtaining distributions of solutions centered at any desired energy from the minimum. We outline the general concepts of our evolutionary sampling methodology using three different alternating selective pressure schemes. Quality of the method was assessed by using it for protein pK(a) prediction. PMID- 21672606 TI - The effect of predation on the prevalence and aggregation of pathogens in prey. AB - Although pathogens and predators have been widely used as bio-control agents against problematic prey species, little has been done to examine the prevalence and aggregation of pathogens in spatially structured eco-epidemiological systems. Here, we present a spatial model of a predator-prey/host-parasite system based on pair approximation and spatially stochastic simulations, with the predation pressure indicated by predator abundance and predation rates. Susceptible prey can not only be infected by contacting adjacent infected individuals but also by the global transmission of pathogens. The disease prevalence was found to follow a hump-shaped function in response to predation pressure. Moreover, predation pressure was not always negatively correlated with pathogen aggregation as proposed from empirical studies, but depending on the level of predation pressure. Highly connected site network facilitated the parasites infection, especially under high predation pressure. However, the connectivity of site network had no effect on the prevalence and aggregation of pathogens that can infect health prey through global transmission. It is thus possible to better design biological control strategies for target species by manipulating predation pressure and the range of pathogen transmission. PMID- 21672607 TI - Hypogonadotropic hypogonadism in subjects with DAX1 mutations. AB - DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; also known as NROB1, nuclear receptor subfamily 0, group B, member 1) encodes a nuclear receptor that is expressed in embryonic stem (ES) cells, steroidogenic tissues (gonads, adrenals), the ventromedial hypothalamus (VMH), and pituitary gonadotropes. Humans with DAX1 mutations develop an X-linked syndrome referred to as adrenal hypoplasia congenita (AHC). These boys typically present in infancy with adrenal failure but later fail to undergo puberty because of hypogonadotropic hypogonadism (HHG). The adrenal failure reflects a developmental abnormality in the transition of the fetal to adult zone, resulting in glucocorticoid and mineralocorticoid deficiency. The etiology of HHG involves a combined and variable deficiency of hypothalamic GnRH secretion and/or pituitary responsiveness to GnRH resulting in low LH, FSH and testosterone. Treatment with exogenous gonadotropins generally does not induce spermatogenesis. Animal models indicate that DAX1 also plays a critical role in testis development and function. As a nuclear receptor, DAX1 has been shown to function as a transcriptional repressor, particularly of pathways regulated by other nuclear receptors, such as steroidogenic factor 1 (SF1). In addition to reproductive tissues, DAX1 is also expressed at high levels in ES cells and plays a role in the maintenance of pluripotentiality. Here we review the clinical manifestations associated with DAX1 mutations as well as the evolving information about its function based on animal models and in vitro studies. PMID- 21672609 TI - Transcriptional regulation of the human KiSS1 gene. AB - Kisspeptin, the product of the KiSS1 gene, has emerged as a key component of the mechanism by which the hypothalamus controls puberty and reproductive development. It does so by stimulating the secretion of gonadotropin releasing hormone (GnRH). Little is known about the transcriptional control of the KiSS1 gene. Here we show that a set of proteins postulated to be upstream components of a hypothalamic network involved in controlling female puberty regulates KiSS1 transcriptional activity. Using RACE-PCR we determined that transcription of KiSS1 mRNA is initiated at a single transcription start site (TSS) located 153 156bp upstream of the ATG translation initiation codon. Promoter assays performed using 293 MSR cells showed that the KiSS1 promoter is activated by TTF1 and CUX1 p200, and repressed by EAP1, YY1, and CUX1-p110. EAP1 and CUX-110 were also repressive in GT1-7 cells. All four TFs are recruited in vivo to the KiSS1 promoter and are expressed in kisspeptin neurons. These results suggest that expression of the KiSS1 gene is regulated by trans-activators and repressors involved in the system-wide control of mammalian puberty. PMID- 21672610 TI - Cognitive alteration after carotid revascularization is correlated with cortical GABA(B)-ergic modulations. AB - The present study evaluates the hypotheses that a GABAergic mechanism underlies neurobehavioral sequelae of carotid stenosis and that it can be reversed by carotid revascularization. We used the Rivermead Behavioural Memory Test (RBMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), long interval intracortical inhibition (LICI), and cortical silent period (CSP) to evaluate cognitive function and cerebral cortical excitability in 16 carotid artery stenosis patients with cognitive impairment before carotid arterial stenting (CAS) and 1 month later. We compared the pre- and post-CAS results and those of 16 healthy controls. CSP was prolonged in patients compared with controls (195.8+/-18ms vs. 157.8+/-13.9ms; p<0.0001, unpaired t-test). Patients tended to a have high resting motor threshold and less pronounced SICI and ICF than controls, but differences were not significant. Decreased RBMT score was correlated with hyperperfusion and CSP increase after CAS. RBMT score increase was correlated with CSP normalization. LICI showed positive correlation with CSP. CSP may provide a means of probing the integrity of GABA(B)-ergic networks in an ischemic human brain. CSP and LICI are potential tools to explore neuronal function for improvement as well as impairment after carotid revascularization. PMID- 21672608 TI - The role of progesterone signaling in the pathogenesis of uterine leiomyoma. AB - Uterine leiomyomas are benign tumors that originate from the myometrium. Evidence points to ovarian steroid hormones, in particular, progesterone as major promoters of leiomyoma development and growth. While progesterone action in leiomyomas involves the classical nuclear receptor effects on gene regulation, there is growing evidence that signaling pathways are directly activated by the progesterone receptor (PR) and that PR can interact with growth factor signaling systems to promote proliferation and survival of leiomyomas. Studies investigating the genomic and non-genomic actions of PR and its role in leiomyoma growth are summarized here. Studies testing various selective progesterone receptor modulators for the treatment of leiomyomas are also highlighted. An increased understanding of the mechanisms associated with progesterone-driven growth of leiomyomas is critical in order to develop more efficient and targeted therapies for this prevalent disease. PMID- 21672611 TI - Ion channels and ionotropic receptors in human embryonic stem cell derived neural progenitors. AB - Human neural progenitor cells differentiated from human embryonic stem cells offer a potential cell source for studying neurodegenerative diseases and for drug screening assays. Previously, we demonstrated that human neural progenitors could be maintained in a proliferative state with the addition of leukemia inhibitory factor and basic fibroblast growth factor. Here we demonstrate that 96 h after removal of basic fibroblast growth factor the neural progenitor cell culture was significantly altered and cell replication halted. Fourteen days after the removal of basic fibroblast growth factor, most cells expressed microtubule-associated protein 2 and TUJ1, markers characterizing a post-mitotic neuronal phenotype as well as neural developmental markers Cdh2 and Gbx2. Real time PCR was performed to determine the ionotropic receptor subunit expression profile. Differentiated neural progenitors express subunits of glutamatergic, GABAergic, nicotinic, purinergic and transient receptor potential receptors. In addition, sodium and calcium channel subunits were also expressed. Functionally, virtually all the hNP cells tested under whole-cell voltage clamp exhibited delayed rectifier potassium channel currents and some differentiated cells exhibited tetrodotoxin-sensitive, voltage-dependent sodium channel current. Action potentials could also be elicited by currents injection under whole-cell current clamp in a minority of cells. These results indicate that removing basic fibroblast growth factor from the neural progenitor cell cultures leads to a post mitotic state, and has the capability to produce excitable cells that can generate action potentials, a landmark characteristic of a neuronal phenotype. This is the first report of an efficient and simple means of generating human neuronal cells for ionotropic receptor assays and ultimately for electrically active human neural cell assays for drug discovery. PMID- 21672612 TI - Galanin receptor 2 overexpressing mice display an antidepressive-like phenotype: possible involvement of the subiculum. AB - The behavioral phenotype of a transgenic mouse overexpressing a galanin receptor 2 (GalR2)-enhanced, green fluorescent protein (EGFP)-construct under the platelet derived growth factor-B promoter, and of controls, was assessed in various behavioral tests, such as the Porsolt forced swim test, as well as the open field, elevated plus maze and passive avoidance tests. In addition, the distribution of GalR2-EGFP expressing cell bodies and processes was studied in the brain of these mice using histochemical methods. Three age groups of the transgenic mice demonstrated decreased levels of immobility in the forced swim test, indicative of antidepressive-like behavior and/or increased stress resistance. Anxiety-like behaviors, measured in two different tests, did not differ between the GalR2-overexpressing and the wild-type mice, nor did motor activity levels, emotional learning or memory behaviors. High levels of GalR2 mRNA and protein expression were observed in the presubiculum, subiculum, cingulate cortex, retrosplenial granular and agranular cortices, subregions of prefrontal cortex, and the olfactory bulb, regions which are directly or indirectly implicated in depression-like behavior. These results may contribute to the understanding of the pathophysiology of major depressive disorder and the role of GalR2 in the regulation of mood, and suggest a potential therapeutic effect by targeting the GalR2 for treatment of depressive disorders. PMID- 21672613 TI - Genome structure analysis of molluscs revealed whole genome duplication and lineage specific repeat variation. AB - Comparative genome structure analysis allows us to identify novel genes, repetitive sequences and gene duplications. To explore lineage-specific genomic changes of the molluscs that is good model for development of nervous system in invertebrate, we conducted comparative genome structure analyses of three molluscs, pygmy squid, nautilus and scallops using partial genome shotgun sequencing. Most effective elements on the genome structural changes are repetitive elements (REs) causing expansion of genome size and whole genome duplication producing large amount of novel functional genes. Therefore, we investigated variation and proportion of REs and whole genome duplication. We, first, identified variations of REs in the three molluscan genomes by homology based and de novo RE detection. Proportion of REs were 9.2%, 4.0%, and 3.8% in the pygmy squid, nautilus and scallop, respectively. We, then, estimated genome size of the species as 2.1, 4.2 and 1.8 Gb, respectively, with 2* coverage frequency and DNA sequencing theory. We also performed a gene duplication assay based on coding genes, and found that large-scale duplication events occurred after divergence from the limpet Lottia, an out-group of the three molluscan species. Comparison of all the results suggested that RE expansion did not relate to the increase in genome size of nautilus. Despite close relationships to nautilus, the squid has the largest portion of REs and smaller genome size than nautilus. We also identified lineage-specific RE and gene-family expansions, possibly relate to acquisition of the most complicated eye and brain systems in the three species. PMID- 21672614 TI - Two GH3 genes from longan are differentially regulated during fruit growth and development. AB - In the present work, two full length cDNAs of GH3 genes, named DlGH3.1 and DlGH3.2 were cloned from pericarp and aril tissues of the longan fruit, respectively. Three conserved motifs, SSGTSAGERK, YASSE and YRVGD, as a characteristic of the acyladenylate/thioester forming enzyme superfamily were observed in DlGH3.1 and DlGH3.2 proteins. DlGH3.1 mainly expressed in pericarp tissues while DlGH3.2 accumulated in both the pericarp and aril tissues during fruit growth and development. In addition, NAA treatment induced the expression of DlGH3.1 and DlGH3.2 in the pericarp tissues at 21 and 77days after anthesis (DAA), while only DlGH3.2 in the aril tissues could be induced by NAA at 77DAA. More importantly, ABA and ethrel treatments suppressed the accumulations of DlGH3.1 and DlGH3.2 in the pericarp tissues of longan fruit at 21DAA (a rapid growth stage of pericarp), but enhanced DlGH3.2 expression in the aril tissues at 77DAA (a fruit ripening stage). Furthermore, the expression patterns of DlGH3.1 and DlGH3.2 showed different tissue specificity. Thus, our results suggest that DlGH3.1 gene expression might be associated with pericarp growth, while DlGH3.2 accumulation is likely to be related to both pericarp growth and fruit ripening, and the responses of DlGH3s to plant growth hormones are different and dependent on fruit development stage and fruit tissue. PMID- 21672615 TI - Relationship between TP73 polymorphism (G4C14-A4T14) and cancer risk: a meta analysis based on literatures. AB - The tumor protein p73 (TP73) gene belongs to the TP53 gene family and functions in the induction of apoptosis or cell-cycle arrest. The TP73 polymorphism (G4C14 A4T14) has been reported and many studies have focused on the role of this polymorphism in various cancers. However, the data reported for most individual cancer types were limited and not able to support a convincible conclusion. Hence, in this study, we explored the relationship between TP73 polymorphism (G4C14-A4T14) and cancer risk by carrying out a comprehensive meta-analysis. Performing both the overall and subgroup meta-analyses with a total of 23 eligible studies (6635 cases and 7378 controls in all), we detected significant cancer risk variations in the overall analysis, as well as the subgroup analysis based on ethnicity for both Asians and Caucasians. In the subgroup analysis based on source of controls, significant associations were also observed in the hospital-based controls' subgroup yet not in the population-based controls' subgroup. Furthermore, in the subgroup analysis based on cancer types, significant associations were found in colorectal cancer's subgroup but not in other cancer types' subgroups. In summary, according to the results of our meta analysis, the TP73 polymorphism (G4C14-A4T14) probably associates with cancer risk. PMID- 21672616 TI - Inhibition effect of Gynura procumbens extract on UV-B-induced matrix metalloproteinase expression in human dermal fibroblasts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gynura procumbens Merr. (Asteraceae) has been used as a traditional remedy for various skin diseases in certain areas of Southeast Asia. AIM OF THE STUDY: In order to evaluate the protective activity of Gynura procumbens extract on skin photoaging and elucidate its mode of action. MATERIALS AND METHODS: Matrix-metalloproteinase (MMP)-1 and -9 expressions were induced by UV-B irradiation in human primary dermal fibroblasts. MMP-1 expression level was measured by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Zymography was employed for evaluating the enzymatic activity of MMP-9. Anti-inflammatory activity and anti-oxidative capacity of the extract were evaluated by ELISA and dichlorodihydrofluorescein diacetate (DCF-DA) assay. RESULTS: The ethanolic extract of Gynura procumbens inhibited MMP-1 expression up to 70% compare to negative control group. The enzymatic activity of MMP-9 was inhibited around 73% by the treatment of 20MUg/mL of the extract. The extract markedly reduced the production of reactive oxygen species (ROS). Gynura procumbens extract showed an inhibitory effect on releasing pro-inflammatory cytokines (IL-6 and IL-8) in human HaCat keratinocyte. CONCLUSION: The ethanolic extract of Gynura procumbens inhibited MMP-1 and MMP-9 expressions induced by UV B irradiation via inhibition of pro-inflammatory cytokine mediator release and ROS production. PMID- 21672617 TI - Algal chemodiversity and bioactivity: sources of natural variability and implications for commercial application. AB - There has been significant recent interest in the commercial utilisation of algae based on their valuable chemical constituents many of which exhibit multiple bioactivities with applications in the food, cosmetic, agri- and horticultural sectors and in human health. Compounds of particular commercial interest include pigments, lipids and fatty acids, proteins, polysaccharides and phenolics which all display considerable diversity between and within taxa. The chemical composition of natural algal populations is further influenced by spatial and temporal changes in environmental parameters including light, temperature, nutrients and salinity, as well as biotic interactions. As reported bioactivities are closely linked to specific compounds it is important to understand, and be able to quantify, existing chemical diversity and variability. This review outlines the taxonomic, ecological and chemical diversity between, and within, different algal groups and the implications for commercial utilisation of algae from natural populations. The biochemical diversity and complexity of commercially important types of compounds and their environmental and developmental control are addressed. Such knowledge is likely to help achieve higher and more consistent levels of bioactivity in natural samples and may allow selective harvesting according to algal species and local environmental conditions for different groups of compounds. PMID- 21672618 TI - Substrate channeling and enzyme complexes for biotechnological applications. AB - Substrate channeling is a process of transferring the product of one enzyme to an adjacent cascade enzyme or cell without complete mixing with the bulk phase. Such phenomena can occur in vivo, in vitro, or ex vivo. Enzyme-enzyme or enzyme-cell complexes may be static or transient. In addition to enhanced reaction rates through substrate channeling in complexes, numerous potential benefits of such complexes are protection of unstable substrates, circumvention of unfavorable equilibrium and kinetics imposed, forestallment of substrate competition among different pathways, regulation of metabolic fluxes, mitigation of toxic metabolite inhibition, and so on. Here we review numerous examples of natural and synthetic complexes featuring substrate channeling. Constructing synthetic in vivo, in vitro or ex vivo complexes for substrate channeling would have great biotechnological potentials in metabolic engineering, multi-enzyme-mediated biocatalysis, and cell-free synthetic pathway biotransformation (SyPaB). PMID- 21672619 TI - Suitability of non-lethal marker and marker-free systems for development of transgenic crop plants: present status and future prospects. AB - Genetically modified crops are one of the prudent options for enhancing the production and productivity of crop plants by safeguarding from the losses due to biotic and abiotic stresses. Agrobacterium-mediated and biolistic transformation methods are used to develop transgenic crop plants in which selectable marker genes (SMG) are generally deployed to identify 'true' transformants. The commonly used SMG obtained from prokaryotic sources when employed in transgenic plants pose risks due to their lethal nature during selection process. In the recent past, some non-lethal SMGs have been identified and used for selection of transformants with increased precision and high selection efficiency. Considering the concerns related to bio-safety of the environment, it is desirable to remove the SMG in order to maximize the commercial success through wide adoption and public acceptance of genetically modified (GM) food crops. In this review, we examine the availability, and the suitability of wide range of non-lethal selection markers and elimination of SMG methods to develop marker-free transgenics for achieving global food security. As the strategies for marker-free plants are still in proof-of-concept stage, adaptation of new genomics tools for identification of novel non-lethal marker systems and its application for developing marker-free transgenics would further strengthen the crop improvement program. PMID- 21672620 TI - Hippocampal cell loss after an anterior and posterior anastomotic vein occlusion model in rats. AB - Estimation of the cell number after cortical venous ischemia/infarction induced by anterior and posterior anastomotic veins occlusion in a rat model is very important. Twenty male Sprague-Dawley rats were used in this experiment. Small burr-holes were made over the anterior (the crossing point of the line drawn from the posterior border of the orbital rim and the line drawn along the para-midline to the superior sagittal suture) and posterior (just inferior point of the posterior ending of the zygomatic arch) anastomotic veins. Bipolar coagulation technique and micro-scissor were used to sacrifice the venous vessels after final inspection and description. Specimens were evaluated by histopathological and unbiased stereological methods for microscopic evaluation and volumetric analysis, respectively. Significant cell loss was seen in the pyramidal and granule cells of the cornu ammonis and dentate gyrus of the hippocampus after venous ischemia. Cell loss was also pronounced when seen in the histological examination. The present results suggest that the sacrifice of anterior and posterior anastomotic veins can be used as an experimental rat model in the evaluation of pyramidal and granule cell loss in the hippocampus that often assesses the neural damage inflicted by this intervention. PMID- 21672621 TI - Different sensitivity of BALB/c 3T3 cell clones in the response to carcinogens. AB - Cell transformation assays (CTAs) are currently regarded as the only possible in vitro alternative to animal testing for carcinogenesis studies. CTAs have been proposed as screening tests for the carcinogenic potential of compounds that have no evidence of genotoxicity but present structural alerts for carcinogenicity. We have extensively used the BALB/c 3T3 model based on the A31 cell clone to test single chemicals, complex mixtures and environmental pollutants. In the prevalidation study carried out by ECVAM, the improved protocol is based on BALB/c 3T3 A31-1-1 cells, a clone derived by A31 cells, that is very sensitive to PAH-induced transformation. The present study was performed in the aim to compare the results obtained with the two different clones exposed to different classes of carcinogens. Cells were treated with PAHs (3-methylcholanthrene, benzo(a)pyrene), alkylating agents (melphalan) and aloethanes (1,2 dibromoethane). The induction of cytotoxicity and the onset of chemically transformed foci were evaluated by two experimental protocols, differing for cell seeding density and chemical treatment duration. The A31-1-1 cells showed higher inherent transformation rate after PAHs treatment, but they were insensitive to 1,2-dibromoethane at concentrations that usually induced transformation in A31 cells. As 1,2-dibromoethane is bioactivated to reactive forms able to bind DNA mainly through the conjugation with intracellular glutathione, these results suggested a reduced activity of phase-2 enzymes involved in glutathione conjugation in A31-1-1 cells. Our results give evidence that inherent metabolic capacity of cells may play a critical role in in vitro cell transformation, cautioning against possible misclassification of chemicals. PMID- 21672622 TI - Wavelet analysis of human DNA. AB - This paper studies the human DNA in the perspective of signal processing. Six wavelets are tested for analyzing the information content of the human DNA. By adopting real Shannon wavelet several fundamental properties of the code are revealed. A quantitative comparison of the chromosomes and visualization through multidimensional and dendograms is developed. PMID- 21672623 TI - A functional in vivo screen for regulators of tumor progression identifies HOXB2 as a regulator of tumor growth in breast cancer. AB - Microarray profiling in breast cancer patients has identified genes correlated with prognosis whose functions are unknown. The purpose of this study was to develop an in vivo assay for functionally screening regulators of tumor progression using a mouse model. Transductant shRNA cell lines were made in the MDA-MB-231 breast cancer line. A pooled population of 25 transductants was injected into the mammary fat pads and tail veins of mice to evaluate tumor growth, and experimental metastasis. The proportions of transductants were evaluated in the tumor and metastases using barcodes specific to each shRNA transductant. We characterized the homeobox 2 transcription factor as a negative regulator, decreasing tumor growth in MDA-MB-231, T47D, and MTLn3 mammary adenocarcinoma cell lines. Homeobox genes have been correlated with cancer patient prognosis and tumorigenesis. Here we use a novel in vivo shRNA screen to identify a new role for a homeobox gene in human mammary adenocarcinoma. PMID- 21672624 TI - Early childhood socioeconomic status is associated with circulating interleukin-6 among mid-life adults. AB - It is proposed that socioeconomic conditions in early childhood effect immune programming, with poorer conditions resulting in adult phenotypes that are prone to inflammation. Recent evidence supports this possibility, showing an inverse association of childhood SES with adult markers of systemic inflammation. In this study, we further investigate this association, extending prior studies to include an examination of multiple indices of SES across distinct periods of childhood. Subjects were 112 men and women, 40-60 years of age (88.6% Caucasian). Childhood SES was indexed by a composite of three indicators of parental wealth (parental home and vehicle ownership, and number of bedrooms per child in the family home) averaged across 2 year periods of childhood between 1 and 18 years old. Higher adult serum concentrations of interleukin (IL)-6 were associated with lower SES in early childhood (years 1-2) (beta=-.05, p<.05), associations that were independent of adult age, personal income, educational attainment, gender, race, body mass index, and physical activity. These associations support recent suggestions that the early environment may program immune phenotypes that contribute to disease risk. PMID- 21672625 TI - Genome-wide DNA methylation patterns in IVF-conceived mice and their progeny: a putative model for ART-conceived humans. AB - The aim of this study was to use a mouse model to gain an understanding of the safety of reproduction between humans conceived through assisted reproductive technology (ART). Mice derived from in vitro fertilization and embryo transfer (IVF-ET) were crossed. Their behavior, morphology, histology and genome-wide DNA methylation status in the brain were examined by the Morris water maze, H&E staining and methylated DNA immunoprecipitation coupled with DNA methylation microarrays. Although no significant differences in behavior or morphology were observed, we did find small clusters of CpG islands and promoters that were aberrantly methylated. Hypermethylation was more common than hypomethylation in each of the two generations. Some of the aberrant methylated promoters were validated by bisulfite sequencing. Our results show that IVF may slightly modify the somatic methylation pattern and that some of this aberrant methylation might be inherited by the following generation. PMID- 21672626 TI - Measurement of in vivo nitric oxide synthesis in humans using stable isotopic methods: a systematic review. AB - Stable isotopic methods are considered the "gold standard" for the measurement of rates of in vivo NO production. However, values reported for healthy human individuals differ by more than 1 order of magnitude. The reason for the apparent variability in NO production is unclear. The primary aim of this review was to evaluate and compare the rates of in vivo NO production in health and disease using stable isotope methods. Articles were retrieved using the PubMed electronic database. Information on concentrations, isotopic enrichments of fluxes, and conversion rates of molecules involved in the NO metabolic pathway was extracted from selected articles; 35 articles were included in the final analysis. Three protocols were identified, including the arginine-citrulline, the arginine nitrate, and the oxygen-nitrate protocols. The arginine-citrulline protocol showed a wider variability compared to the arginine-nitrate and oxygen-nitrate protocols. The direction of the association between disease state and rate of NO production was essentially determined by the etiopathogenesis of the disorder (inflammatory, metabolic, vascular). Considerable variation in methodologies used to assess whole-body NO synthesis in humans exists. The precision of several aspects of the techniques and the validity of some assumptions made remain unknown, and there is a paucity of information about physiological rates of NO production from childhood over adolescence to old age. PMID- 21672627 TI - Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. AB - Two popular complementary, alternative, and integrative medicine therapies, high dose intravenous ascorbic acid (AA) and intravenous glutathione (GSH), are often coadministered to cancer patients with unclear efficacy and drug-drug interaction. In this study we provide the first survey evidence for clinical use of iv GSH with iv AA. To address questions of efficacy and drug-drug interaction, we tested 10 cancer cell lines with AA, GSH, and their combination. The results showed that pharmacologic AA induced cytotoxicity in all tested cancer cells, with IC(50) less than 4 mM, a concentration easily achievable in humans. GSH reduced cytotoxicity by 10-95% by attenuating AA-induced H(2)O(2) production. Treatment in mouse pancreatic cancer xenografts showed that intraperitoneal AA at 4 g/kg daily reduced tumor volume by 42%. Addition of intraperitoneal GSH inhibited the AA-induced tumor volume reduction. Although all treatments (AA, GSH, and AA+GSH) improved survival rate, AA+GSH inhibited the cytotoxic effect of AA alone and failed to provide further survival benefit. These data confirm the pro-oxidative anti-cancer mechanism of pharmacologic AA and suggest that AA and GSH administered together provide no additional benefit compared with AA alone. There is an antagonism between ascorbate and glutathione in treating cancer, and therefore iv AA and iv GSH should not be coadministered to cancer patients on the same day. PMID- 21672628 TI - Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells. AB - Superoxide (O(2)(*-)) is implicated in inflammatory states including arteriosclerosis and ischemia-reperfusion injury. Cobalamin (Cbl) supplementation is beneficial for treating many inflammatory diseases and also provides protection in oxidative-stress-associated pathologies. Reduced Cbl reacts with O(2)(*-) at rates approaching that of superoxide dismutase (SOD), suggesting a plausible mechanism for its anti-inflammatory properties. Elevated homocysteine (Hcy) is an independent risk factor for cardiovascular disease and endothelial dysfunction. Hcy increases O(2)(*-) levels in human aortic endothelial cells (HAEC). Here, we explore the protective effects of Cbl in HAEC exposed to various O(2)(*-) sources, including increased Hcy levels. Hcy increased O(2)(*-) levels (1.6-fold) in HAEC, concomitant with a 20% reduction in cell viability and a 1.5 fold increase in apoptotic death. Pretreatment of HAEC with physiologically relevant concentrations of cyanocobalamin (CNCbl) (10-50nM) prevented Hcy-induced increases in O(2)(*-) and cell death. CNCbl inhibited both Hcy and rotenone induced mitochondrial O(2)(*-) production. Similarly, HAEC challenged with paraquat showed a 1.5-fold increase in O(2)(*-) levels and a 30% decrease in cell viability, both of which were prevented with CNCbl pretreatment. CNCbl also attenuated elevated O(2)(*-) levels after exposure of cells to a Cu/Zn-SOD inhibitor. Our data suggest that Cbl acts as an efficient intracellular O(2)(*-) scavenger. PMID- 21672629 TI - Apical membrane segregation of phosphatidylinositol-4,5-bisphosphate influences parathyroid hormone 1 receptor compartmental signaling and localization via direct regulation of ezrin in LLC-PK1 cells. AB - The parathyroid hormone 1 receptor (PTH1R), a primary regulator of mineral ion homeostasis, is expressed on both the apical and basolateral membranes of kidney proximal tubules and in the LLC-PK1 kidney cell line. In LLC-PK1 cells, apical PTH1R subpopulations are far more effective at signaling via phospholipase (PLC) than basolateral counterparts, revealing the presence of compartmental signaling. Apical PTH1R localization is dependent upon direct interactions with ezrin, an actin-membrane cross-linking scaffold protein. Ezrin undergoes an activation process that is dependent upon phosphorylation and binding to phosphatidylinositol-4,5-bisphosphate (PIP2), a lipid that is selectively concentrated to apical surfaces of polarized epithelia. Consistently, the intracellular probe for PIP2, GFP-PLCdelta1-PH, localizes to the apical membranes of LLC-PK1 cells, directly overlapping ezrin and PTH1R expression. Activation of the apical PTH1R shifts the GFP-PLCdelta1-PH probe from the apical membrane to the cytosol and basolateral membranes, reflecting domain-specific activation of PLC and hydrolysis of PIP2. This compartmental signaling is likely due to the polarized localization of PIP2, the substrate for PLC. PIP2 degradation using a membrane-directed phosphatase shifts ezrin localization to the cytosol and induces ezrin de-phosphorylation, processes consistent with inactivation. PIP2 degradation also shifts PTH1R expression from brush border microvilli to basolateral membranes and markedly blunts PTH-elicited activation of the MAPK pathway. Transient expression of ezrin in HEK293 cells shifts PTH1R expression from the plasma membrane to microvilli-like surface projections that also contain PIP2. As a result, ezrin enhances PTH mediated activation of the PLC pathway in this cell model with increasing total receptor surface expression. Collectively, these findings demonstrate that the apical segregation of PIP2 to the apical domains not only promotes the activation of ezrin and the subsequent formation of the PTH1R containing scaffold, but also ensures the presence of ample substrate for propagating the PLC pathway. PMID- 21672630 TI - Transient receptor potential vanilloid 1 channels modulate the synaptic effects of TNF-alpha and of IL-1beta in experimental autoimmune encephalomyelitis. AB - Transient receptor potential vanilloid 1 (TRPV1) channels are involved in several inflammatory diseases. However, their action is still controversial, and both pro inflammatory and anti-inflammatory roles have been described. We used a strain of TRPV1-KO mice to characterize the role of these channels in experimental autoimmune encephalomyelitis (EAE), which models multiple sclerosis (MS) in mice. EAE mice showed higher lethality in the peak phase of the disease and a better recovery of the surviving animals in the chronic stages, compared to their wild type (WT) counterparts. By means of whole-cell patch clamp experiments in corticostriatal brain slices, we found that the absence of TRPV1 channels exacerbated the defect of glutamate transmission occurring in the peak phase of EAE, and attenuated the alterations of GABA synapses in the chronic phase of EAE, thus paralleling the dual effects of TRPV1-KO on the motor deficits of EAE mice. Furthermore, in slices from non-EAE mice, we found that genetic or pharmacological blockade of TRPV1 channels enhanced the synaptic effects of tumor necrosis factor alpha (TNF-alpha) on glutamate-mediated excitatory postsynaptic currents, and prevented the action of interleukin 1beta (IL-1beta) on GABAergic inhibitory postsynaptic currents. Together, our results suggest that TRPV1 channels contrast TNF-alpha-mediated synaptic deficits in the peak phase of EAE and, in the chronic stages, enhance IL-1beta-induced GABAergic defects. The opposing interplay with the synaptic actions of the two major pro-inflammatory cytokines might explain the bimodal effects of TRPV1 ablation on the motor deficits of EAE, and suggests that the inflammatory milieu determines whether TRPV1 channels exert preferentially aversive or protective effects on neurons during neuroinflammatory diseases. PMID- 21672631 TI - Flow cytometry assays of respiratory burst in Atlantic salmon (Salmo salar L.) and in Atlantic cod (Gadus morhua L.) leucocytes. AB - The oxidation of dihydrorhodamine 123 (DHR) to the fluorescent rhodamine 123 (RHO) was detected using flow cytometry. This assay for detection of respiratory burst activity was established in peripheral blood leucocytes (PBL) and head kidney leucocytes (HKL) of Atlantic salmon and Atlantic cod. The leucocytes were stimulated by phorbol 12-myristate 13-acetate (PMA). For cod cells 10 times lower concentration of PMA had to be used compared to salmon cells, as higher concentrations were toxic and resulted in considerable cell death. The cells found to be RHO-positive were monocytes/macrophages and neutrophils based on the scatter dot plots, but for salmon also some small cells were found to have high fluorescence intensity both in the flow cytometry analyses and by fluorescence microscopy of cytospin preparations. The nature of these cells is not known. For cod leucocytes, such cells were not obvious. The instrument settings are a bit more demanding for cod, as cod cells die more easily compared to salmon cells. In both assays the limit between negative and positive cells has to be carefully considered. The presented flow cytometry protocols for measurements of respiratory burst in salmon and cod leucocytes can be applied in various studies where respiratory burst functions are involved, such as to verify if it is activated or suppressed in connection with infections and immunostimulation. PMID- 21672632 TI - Effects of dietary beta-glucan, mannan oligosaccharide and their combinations on growth performance, immunity and resistance against Vibrio splendidus of sea cucumber, Apostichopus japonicus. AB - A 4-week feeding trial was conducted to investigate the effects of dietary beta glucan, mannan oligosaccharide (MOS) and their combinations on growth performance, immunity and disease resistance of sea cucumber Apostichopus japonicus. Sea cucumbers (1215 individuals with initial weight of 3.8 +/- 0.2 g) were fed nine practical diets according to a 3 * 3 factorial design: the basal diet as the control supplemented with three levels of beta-glucan (0, 0.075, 0.15% w/w), crossed with 0, 0.1% (w/w) or 0.2% (w/w) MOS. Immune indices including total coelomocytes count (TCC), phagocytosis, superoxide anion production, superoxide dismutase (SOD) activity and total nitric oxide synthase activity (T-NOS) were measured at days 7, 11, 15, 18, 22, 25 and 29. At the end of the feeding trial, all the sea cucumbers left were weighted to monitor growth, and then were challenged by Vibrio splendidus. The results showed that dietary beta-glucan, MOS and their combinations significantly increased TCC, phagocytosis, superoxide anion production and SOD activity of sea cucumbers (P < 0.05). Only 0.15% beta-glucan and the combinations of beta-glucan and MOS significantly increased the T-NOS activity (P < 0.05). A synergistic effect was found between dietary beta-glucan and MOS. Moreover, combinations of beta-glucan and MOS prolonged the high levels of immune indices compared with beta-glucan or MOS supplementation alone. Except the 0.15% beta-glucan group, all the other treatments showed significantly lower cumulative mortality compared with control (P < 0.05). Furthermore, combination of 0.15% beta-glucan and 0.1% MOS had the best effects on enhancing disease resistance of sea cucumber. All treatments showed significantly higher specific growth rate (SGR) compared with control (P < 0.05), and the combination of 0.15% beta-glucan and 0.1% MOS was significantly higher than other treatments (P < 0.05). In conclusion, our results confirm the potential of beta-glucan and MOS as dietary immunostimulants and the synergistic effects of beta-glucan and MOS on A. japonicus. PMID- 21672633 TI - Long-term effects of motor training on resting-state networks and underlying brain structure. AB - Acquired motor skills are coded in fronto-parietal brain networks, but how these networks evolve through motor training is unclear. On the one hand, increased functional connectivity has been shown immediately after a training session; on the other hand, training-induced structural changes are visible only after several weeks. Based on known associations between functional and structural network development during human ontogeny, we hypothesised that learning a challenging motor task leads to long-lasting changes in functional resting-state networks and the corresponding cortical and sub-cortical brain structures. Using longitudinal functional and structural MRI at multiple time points, we demonstrate increased fronto-parietal network connectivity one week after two brief motor training sessions in a dynamic balancing task, although subjects were engaged in their regular daily activities during the week. Repeated training sessions over six consecutive weeks progressively modulate these changes in accordance with individual performance improvements. Multimodal correlation analyses showed an association between structural grey matter alterations and functional connectivity changes in prefrontal and supplementary-motor areas. These coincident changes were most prominent in the first three weeks of training. In contrast, changes in fronto-parietal functional connectivity and the underlying white matter fibre structure developed gradually during the six weeks. Our results demonstrate a tight correlation between training-induced functional and structural brain plasticity on the systems level and suggest a functional relevance of intrinsic brain activity for morphological adaptation in the human brain. PMID- 21672634 TI - Localization of cortico-peripheral coherence with electroencephalography. AB - BACKGROUND: The analysis of coherent networks from continuous recordings of neural activity with functional MRI or magnetoencephalography has provided important new insights into brain physiology and pathology. Here we assess whether valid localizations of coherent cortical networks can also be obtained from high-resolution electroencephalography (EEG) recordings. METHODS: EEG was recorded from healthy subjects and from patients with ischemic brain lesions during a tonic hand muscle contraction task and during continuous visual stimulation with an alternating checkerboard. These tasks induce oscillations in the primary hand motor area or in the primary visual cortex, respectively, which are coherent with extracerebral signals (hand muscle electromyogram or visual stimulation frequency). Cortical oscillations were reconstructed with different inverse solutions and the coherence between oscillations at each cortical voxel and the extracerebral signals was calculated. Moreover, simulations of coherent point sources were performed. RESULTS: Cortico-muscular coherence was correctly localized to the primary hand motor area and the steady-state visual evoked potentials to the primary visual cortex in all subjects and patients. Sophisticated head models tended to yield better localization accuracy than a single sphere model. A Minimum Variance Beamformer (MVBF) provided more accurate and focal localizations of simulated point sources than an L2 Minimum Norm (MN) inverse solution. In the real datasets, the MN maps had less localization error but were less focal than MVBF maps. CONCLUSIONS: EEG can localize coherent cortical networks with sufficient accuracy. PMID- 21672635 TI - Phylogeny of the gudgeons (Teleostei: Cyprinidae: Gobioninae). AB - The members of the cyprinid subfamily Gobioninae, commonly called gudgeons, form one of the most well-established assemblages in the family Cyprinidae. The subfamily is a species-rich group of fishes, these fishes display diverse life histories, appearances, and behavior. The phylogenetic relationships of Gobioninae are examined using sequence data from four loci: cytochrome b, cytochrome c oxidase I, opsin, and recombination activating gene 1. This investigation produced a data matrix of 4114 bp for 162 taxa that was analyzed using parsimony, maximum likelihood, and Bayesian inference methods. The phylogenies our analyses recovered corroborate recent studies on the group. The subfamily Gobioninae is monophyletic and composed of three major lineages. We find evidence for a Hemibarbus-Squalidus group, and the tribes Gobionini and Sarcocheilichthyini, with the Hemibarbus-Squalidus group sister to a clade of Gobionini-Sarcocheilichthyini. The Hemibarbus-Squalidus group includes those two genera; the tribe Sarcocheilichthyini includes Coreius, Coreoleuciscus, Gnathopogon, Gobiocypris, Ladislavia, Paracanthobrama, Pseudorasbora, Pseudopungtungia, Pungtungia, Rhinogobio, and Sarcocheilichthys; the tribe Gobionini includes Abbottina, Biwia, Gobio, Gobiobotia, Huigobio, Microphysogobio, Platysmacheilus, Pseudogobio, Romanogobio, Saurogobio, and Xenophysogobio. The monotypic Acanthogobio is placed into the synonymy of Gobio. We tentatively assign Belligobio to the Hemibarbus-Squalidus group and Mesogobio to Gobionini; Paraleucogobio and Parasqualidus remain incertae sedis. Based on the topologies presented, the evolution of swim bladder specializations, a distinctive feature among cyprinids, has occurred more than once within the subfamily. PMID- 21672636 TI - Burden of emerging anaerobes in the MALDI-TOF and 16S rRNA gene sequencing era. AB - The isolation of anaerobes from patients has declined in recent years, whereas their detection by molecular techniques has increased. In the present work, we analyzed the application of matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing to routine identification of anaerobes in clinical microbiology laboratory. We identified 544 isolates of 79 species by routine culture from deep samples in our hospital. MALDI-TOF MS allowed identification of 332 isolates (61%). The remaining 212 (39%) were identified by 16S rRNA gene sequencing, allowing identification of 202 at the species level. The most common anaerobes were Propionibacterium spp. (12%), Finegoldia magna (4%), Fusobacterium spp. (6%) and Bacteroides spp. (6%). However, among the 79 identified species, seven were new species or genera, including two Prevotella conceptionensis, a species previously detected by our team by amplification and sequencing, five Anaerococcus sp. and one Prevotella sp. Beyond the identification of these new species, we also identified several uncommon or previously not described associations between species and specific pathologic conditions. MALDI-TOF MS-based identification, which will become more effective with future spectra database improvement, will be likely responsible of a burden of emerging anaerobes in clinical microbiology. PMID- 21672637 TI - Proteomic analyses of the Xiphophorus Gordon-Kosswig melanoma model. AB - Interspecies hybridization between the platyfish X. maculatus Jp 163 A, and the swordtail X. helleri (Sarabia), generates F(1) hybrids with pronounced melanin pigmentation. Backcrossing of F(1) hybrids with the X. helleri parent results in 25% of progeny that will spontaneously develop melanoma. We have applied proteomic methods to this Gordon-Kosswig (G-K) melanoma model to identify candidate proteins that exhibit modulated expression in fin tissue due to interspecies hybridization and progression of hybrid tissues to spontaneous melanoma. Difference Gel Electrophoresis (DIGE) was used to minimize the variability commonly observed in quantitative analyses of comparative protein samples. Following identification of up- or down-regulated protein expression by DIGE, candidate protein spots were identified by mass spectrometric sequencing. Several protein expression differences displayed in interspecies hybrids were identified and compared to distinct differences that occur upon backcrossing and progression to melanoma. These studies are important for the identification of distinct biochemical pathways involved in the variety of Xiphophorus interspecies hybrid tumor models. PMID- 21672638 TI - Novel fungal phenylpyruvate reductase belongs to d-isomer-specific 2-hydroxyacid dehydrogenase family. AB - We discovered the phenyllactate (PLA)-producing fungal strain Wickerhamia fluorescens TK1 and purified phenylpyruvate reductase (PPR) from fungal cell-free extracts. The PPR used both NADPH and NADH as cofactors with more preference for the former. The enzyme reaction as well as the fungal culture produced optically active d-PLA. The gene for the PPR (pprA) was cloned and expressed in Escherichia coli cells. Purified preparations of both native and recombinant PPR used hydroxyphenylpyruvate, glyoxylate and hydroxypyruvate as substrates but not pyruvate, oxaloacetate or benzoylformate. The predicted PPR protein had sequence similarity to proteins in the d-isomer-specific 2-hydroxyacid dehydrogenase family. Phylogenetic analyses indicated that the predicted PPR protein together with fungal predicted proteins constitutes a novel group of glyoxylate/hydroxypyruvate reductases. The fungus efficiently converted phenylalanine and phenylpyruvate to d-PLA. These compounds up-regulated the transcription of pprA, suggesting that it plays a role in fungal phenylalanine metabolism. PMID- 21672639 TI - The reducing component BoxA of benzoyl-coenzyme A epoxidase from Azoarcus evansii is a [4Fe-4S] protein. AB - BoxA is the reductase component of the benzoyl-coenzyme A (CoA) oxidizing epoxidase enzyme system BoxAB. The enzyme catalyzes the key step of an hitherto unknown aerobic, CoA-dependent pathway of benzoate metabolism, which is the epoxidation of benzoyl-CoA to the non-aromatic 2,3-epoxybenzoyl-CoA. The function of BoxA is the transfer of two electrons from NADPH to the epoxidase component BoxB. We could show recently that BoxB is a diiron enzyme, whereas here we demonstrate that BoxA harbors an FAD and two [4Fe-4S] clusters per protein monomer. The characterization of BoxA was hampered by severe oxygen sensitivity; the cubane [4Fe-4S] clusters degrade already with traces of oxygen. Interestingly, the adventitiously formed [3Fe-4S] centers could be reconstituted in vitro by adding Fe(II) and sulfide to retrieve the native cubane centers. BoxA is the first example of a reductase of this type that has an FAD and two bacterial ferredoxin-type [4Fe-4S] clusters. In other cases within the catalytically versatile family of diiron enzymes, the related reductases have plant-type ferredoxin or Rieske-type [2Fe-2S] centers only. PMID- 21672640 TI - Substitutions of cerium, gallium and zinc in ordered mesoporous bioactive glasses. AB - Ordered mesoporous glasses based on the 80% SiO(2)-15% CaO-5% P(2)O(5) system including up to 3.5% Ce(2)O(3), 3.5% Ga(2)O(3) or 7.0% ZnO (in mol.%) were synthesized by the evaporation-induced self-assembly process using Pluronic(r) 123 as a surfactant. An ordered hexagonal mesophase was observed in both the unsubstituted glass (denoted in this paper as B: blank) and glasses containing <0.4% of substituent by X-ray diffraction, transmission electron microscopy and electron diffraction. The increase in the amount of substituent led to a decrease in the mesopore order. B glass exhibited good textural properties: S(BET)=515m(2)g(-1), D(P)=4.7nm and V(P)=0.58cm(3)g(-1). With the inclusion of cerium, gallium and zinc oxides the textural properties decreased, but remained in amounts useful for clinical applications. Zinc-containing samples showed the highest decrement in the textural properties. Substituted glasses exhibited a quick in vitro bioactive response except when the ZnO content was over 0.4%. Taking into account the ordered mesoporosity, the quick in vitro bioactive response and the added values of the substituents, this new family of glasses are promising candidates for applications in bone tissue engineering. PMID- 21672641 TI - Characterization of the thermo- and pH-responsive assembly of triblock copolymers based on poly(ethylene glycol) and functionalized poly(epsilon-caprolactone). AB - A series of novel triblock copolymers composed of poly(ethylene glycol) (PEG) and poly(epsilon-caprolactone)-bearing benzyl carboxylate on the alpha-carbon of epsilon-caprolatone were synthesized through ring opening polymerization of alpha benzyl carboxylate-epsilon-caprolactone by dihydroxylated PEG. The debenzylation of the synthesized copolymer, i.e., poly(alpha-benzyl carboxylate-epsilon caprolactone)-b-PEG-b-poly(alpha-benzyl-carboxylate-epsilon-caprolactone) (PBCL-b PEG-b-PBCL), in the presence of hydrogen gas using different levels of catalyst, was carried out to achieve copolymers with various degrees of free alpha-carboxyl to alpha-benzyl-epsilon-carboxylate groups on the hydrophobic block. Incomplete reduction of PBCL led to the formation of poly(alpha-carboxyl-co-benzyl caboxylate-epsilon-caprolactone) PCBCL in the lateral blocks at 27%, 50% and 75% carboxyl group substitution. The molecular weight and polydispersity of the resultant copolymers were estimated by (1)H NMR and MALDI-TOF. Synthesized triblock copolymers formed stable micelles at low concentrations (critical micellar concentrations (CMC) of 0.34-12.5 MUg ml(-1)). Polymers containing carboxyl groups in their structure showed a pH-dependent increase in CMC. As the pH was raised from 4.0 to 9.0, CMC increased from 0.76 to 1.06 MUg ml(-1), for 27% debenzylated polymer, and from 1.30 to 2.20 MUg ml(-1), for 50% debenzylated polymers. In contrast, the CMC in polymers without carboxyl group was independent of pH (0.55 MUg ml(-1)). Different changes in micellar size as a function of temperature was observed depending on the degree of debenzylation on the PCBCL block: polymers with 27% degree of debenzylation illustrated a rise in micelle size from ~38 to 55 nm as the temperature increased above 29 degrees C, while polymers with 50% debenzylation showed a decrease in micelle size, from ~52 to 38 nm, with increase in temperature. A similar trend was observed at pH 4.5, 7.0 and 9.0 for polymers containing carboxyl groups on their hydrophobic block. The temperature for the onset of size change and/or the extent of aggregate size change was found to be dependent on the pH of the medium and the polymer concentration. The results point to a potential for the formation of thermo- and pH-responsive micelles from triblock copolymers of PEG and carboxyl substituted caprolactone. The results also imply a potential for the 27% debenzylated PCBCL-b PEG-b-PCBCL copolymers to form a biodegradable thermoreversible gel with a transition temperature a few degrees below 37 degrees C. PMID- 21672642 TI - Rat liver mitochondrial proteome: changes associated with aging and acetyl-L carnitine treatment. AB - Oxidative stress has a central role in aging and in several age-linked diseases such as neurodegenerative diseases, diabetes and cancer. Mitochondria, as the main cellular source and target of reactive oxygen species (ROS) in aging, are recognized as very important players in the above reported diseases. Impaired mitochondrial oxidative phosphorylation has been reported in several aging tissues. Defective mitochondria are not only responsible of bioenergetically less efficient cells but also increase ROS production further contributing to tissues oxidative stress. Acetyl-L-carnitine (ALCAR) is a biomolecule able to limit age linked mitochondrial decay in brain, liver, heart and skeletal muscles by increasing mitochondrial efficiency. Here the global changes induced by aging and by ALCAR supplementation to old rat on the mitochondrial proteome of rat liver has been analyzed by means of the two-dimensional polyacrylamide gel electrophoresis. Mass spectrometry has been used to identify the differentially expressed proteins. A significant age-related change occurred in 31 proteins involved in several metabolisms. ALCAR supplementation altered the levels of 26 proteins. In particular, ALCAR reversed the age-related alterations of 10 mitochondrial proteins relative to mitochondrial cristae morphology, to the oxidative phosphorylation and antioxidant systems, to urea cycle, to purine biosynthesis. PMID- 21672643 TI - The oxidized thiol proteome in fission yeast--optimization of an ICAT-based method to identify H2O2-oxidized proteins. AB - Major intracellular disulfide formation is prevented in the cytosol by potent reducing systems. However, protein thiols can be oxidized as a consequence of redox-mediated physiological reactions or due to the unwanted toxicity of reactive oxygen species. In addition, the reactivity of cysteine residues towards peroxides is used by H(2)O(2) sensors in signal transduction pathways in a gain of-function process to induce transcriptional antioxidant responses. Thus, the Schizosaccharomyces pombe peroxiredoxin Tpx1 and the transcription factor Pap1 are sensors of H(2)O(2) meant to promote cell survival. In an attempt to compare signaling events versus global thiol oxidation, we have optimized thiol-labeling approaches to characterize the disulfide proteome of fission yeast in response to added H(2)O(2). We propose a method based on (i) freezing the redox state of thiols with strong acids prior to cell lysis; (ii) blocking thiol groups with iodoacetamide, and reversibly oxidized thiols with heavy and light isotope-coded affinity tags (ICAT) reagents; and (iii) quantifying individual relative protein concentrations with stable-isotope dimethyl labeling. We have applied this highly sensitive strategy to provide a map of H(2)O(2)-dependent oxidized thiols in fission yeast, and found Tpx1 and Pap1 as some of the major targets. PMID- 21672644 TI - Vertebral morphometry by X-ray absorptiometry: which reference data for vertebral heights? AB - INTRODUCTION: The recent improvement in the resolution of dual-energy X-ray absorptiometry (DXA) images enables most vertebral levels to be seen adequately and thus DXA may be a worthwhile alternative to radiologic morphometry for the identification of vertebral fractures (VF). In this multicenter study, we have derived reference data for vertebral heights and their ratios in Italian women using morphometric X-ray absorptiometry (MXA). METHODS: DXA scans were acquired in 1254 consecutive pre- and postmenopausal women, (mean age 63.7 +/- 11.3, range 26-88 yrs), referred to six osteoporosis centers. MXA analysis of these images was performed by the same operator measuring vertebral heights and height ratios from L4 to T4. We calculated measures of central tendency and dispersion of vertebral heights and vertebral ratios using different approaches (mean and standard deviation as well as median and interquartile range of raw data, mean and standard deviation of trimmed data using an iterative algorithm, and mean and standard deviation of not fractured vertebrae). RESULTS: Independently of the approach that we used, all the measures of central tendency were similar, while significant differences were found when compared with reference ranges in other populations. The vertebral heights of our sample at every vertebral level were significantly smaller than both Rea population and the Lunar reference values, even after normalization. Splitting data according to age groups, there was a decrease in the vertebral heights and ratios between the younger and older women. CONCLUSIONS: This study demonstrates that reference data for MXA should be population specific and age matched. PMID- 21672645 TI - Consumption of different sources of omega-3 polyunsaturated fatty acids by growing female rats affects long bone mass and microarchitecture. AB - Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) consumption has been reported to improve bone health. However, sources of omega-3 PUFAs differ in the type of fatty acids and structural form. The study objective was to determine the effect of various omega-3 PUFAs sources on bone during growth. Young (age 28d) female Sprague-Dawley rats were randomly assigned (n=10/group) to a high fat 12% (wt) diet consisting of either corn oil (CO) or omega-3 PUFA rich, flaxseed (FO), krill (KO), menhaden (MO), salmon (SO) or tuna (TO) for 8 weeks. Bone mass was assessed by dual-energy X-ray absorptiometry (DXA) and bone microarchitecture by micro-computed tomography (MUCT). Bone turnover markers were measured by enzyme immunoassay. Lipid peroxidation was measured by calorimetric assays. Results showed that rats fed TO, rich in docosahexaenoic acid (DHA, 22:6omega-3) had higher (P<0.009) tibial bone mineral density (BMD) and bone mineral content (BMC) and lower (P=0.05) lipid peroxidation compared to the CO-fed rats. Reduced lipid peroxidation was associated with increased tibial BMD (r2=0.08, P=0.02) and BMC (r2=0.71, P=0.01). On the other hand, rats fed FO or MO, rich in alpha-linolenic acid (ALA, 18:3omega-3), improved bone microarchitecture compared to rats fed CO or SO. Serum osteocalcin was higher (P=0.03) in rats fed FO compared to rats fed SO. Serum osteocalcin was associated with improved trabecular bone microarchitecture. The animal study results suggest consuming a variety of omega 3 PUFA sources to promote bone health during the growth stage. PMID- 21672646 TI - Development of mesenchymal stem cell-implant complexes by cultured cells sheet enhances osseointegration in type 2 diabetic rat model. AB - This study investigated the hypothesis that a mesenchymal stem cells (MSC) implant complex could be used in type 2 diabetic rats. Diabetes was modeled with type 2 diabetic rats induced by high fat diet with low dose streptozotocin (STZ) injected intraperitoneally. MSC sheets were harvested from culture flasks, wrapped around implants to construct the complexes, and then cultured in an osteogenic medium. The layered cell sheets integrated well with the implants and remained viable, with small mineralized nodules visible on the implant surfaces after culturing. The MSC-implant complexes were inserted into the right tibiae of the diabetic rats. Titanium implants served as controls. After four and eight weeks of healing, the tibiae were observed via MicroCT and harvested for histological examination. For the MSC-implant complexes, MicroCT analysis showed that bone volume ratio and trabecular thickness increased significantly (p<0.05), and trabecular separation decreased significantly (p<0.05) compared to the titanium implants in diabetic rats. Histological examination revealed a greater amount of new bone tissue forming around the MSC-implant complexes and a higher bone implant contact (BIC) rate than the titanium implants. These findings demonstrate that MSC-implant complexes possess osteogenic abilities and can be used in diabetic rats to improve the BIC rate. Thus, MSC-implant complexes provide a novel tissue engineering approach that promotes osseous healing and may potentially be useful in the treatment of diabetic patients. PMID- 21672648 TI - Standardization, integration, and sharing-leveraging research investments. PMID- 21672649 TI - "Resistance is useless!" ... or should that be "Resistance is futile"? PMID- 21672650 TI - The chemotherapy of osteo-articular tuberculosis with recommendations for treatment of children. AB - OBJECTIVE: To review literature regarding osteo-articular tuberculosis (OATB) and make recommendations made for the chemotherapy of children. METHODS: Key words bone tuberculosis, joint tuberculosis, tuberculosis of the spine, tuberculous osteomyelitis were used to search Pubmed and further references obtained by cross referencing and searching the indices of known papers. Results were tabulated regarding regimens, treatment duration, treatment failure, death and relapse. RESULTS: Twenty one papers described treatment of OATB with isoniazid (INH), streptomycin and para-aminosalicylic acid in 2466 patients; 2.1% failed treatment, 1.3% died due to tuberculosis (TB), 2.2% relapsed. Seventy seven papers provide details of 2950 patients receiving INH, rifampicin (RMP) and pyrazinamide (PZA) based regimens. Fifteen described six months treatment which failed in 2.5%, no patients died and 1.3% of patients followed up relapsed. Sixteen papers described 6-11 months treatment which failed in 4.3% of patients, 0.86% died due to TB and 0.86% relapsed. Forty six papers described treatment for >=12 months; treatment failed in 0.74% of patients and death due to TB occurred in 0.84% and 0.51% relapsed. CONCLUSIONS: The majority of OATB cases in children (and adults) can be satisfactorily treated for 6 months with RMP and PZA based regimens; in spinal TB well documented cases of relapse and persistent signs of acute inflammatory response in some patients argue for caution with 6 month regimens at present. Dosages of INH (5-15 mg/kg), RMP (10-20 mg/kg), PZA (30-40 mg/kg), EMB (15-25 mg/kg) and SM (12-18 mg/kg) are recommended for treatment of children. Daily regimens are preferred. PMID- 21672651 TI - General paediatric surgery or adult urology? PMID- 21672652 TI - Presence of dextranomer-hyaluronic acid (DxHA) mound on postoperative ultrasound does not predict resolution of vesicoureteral reflux. AB - OBJECTIVE: Dextranomer-hyaluronic acid (DxHA) injection is an accepted treatment for vesicoureteral reflux (VUR), with success rates as high as 85-90% in selected patients. The DxHA mound can often be seen on postoperative ultrasound. We sought to determine whether the presence or absence of this mound on ultrasound can predict resolution of VUR on voiding cystourethrogram (VCUG). MATERIALS AND METHODS: A retrospective study evaluating patients who underwent cystoscopy and injection of DxHA from 2003 to the present was performed. Demographic variables, laterality and grade of VUR, postoperative ultrasound findings, and presence of VUR on postoperative VCUG were recorded. RESULTS: Fifty-one patients (95 ureters) underwent DxHA injection and had a postoperative ultrasound and VCUG for review. Five patients with persistent voiding dysfunction were excluded, leaving 46 patients and 86 ureters for review. The mean age at time of injection was 5.2 years (range 0.75-11 years) and mean grade of VUR was 2.5 (range 1-5). After DxHA injection, 75% of the ureters showed resolution of VUR, while 25% demonstrated persistent VUR. No correlation was made between the presence of DxHA mound and resolution of VUR on VCUG. CONCLUSION: In this series, the presence of a DxHA mound on initial postoperative ultrasound does not predict resolution of VUR. A larger prospective study is needed to evaluate additional parameters. PMID- 21672653 TI - Commentary to "Evaluation in the United States pediatric urology workforce and fellowships: a series of surveys during 2006-2010". PMID- 21672654 TI - Commentary to "Evaluation of the United States pediatric urology workforce and fellowships: a series of surveys performed in 2006-2010". PMID- 21672655 TI - Improving patient flow: the impact of consultant work pattern on trauma ward efficiency. AB - OBJECTIVE: To determine the effect on trauma ward efficiency of altering consultant shift patterns. DESIGN: Outcome measures were compared for neck of femur fracture patients before and after the consultant rota changed (Feb 2007) from a single day on-call to a full week on-call. SETTING: Patients admitted to Stirling Royal Infirmary with neck of femur fractures. PARTICIPANTS: 359 patients were identified from the Scottish Hip Fracture Audit database for the year preceding the rota change and 379 after. MAIN OUTCOME MEASURES: Time to surgery for medically fit patients and overall length of stay on the acute trauma ward. RESULTS: Patients were operated on quicker after the rota change (Mann-Whitney U test, before v after: z=2.67, p=0.008), with a greater percentage being operated within the first 24h (60% before v 78% after; Chi-square test, before v after: chi(1)(2)=19.9, p<0.001). Overall, the length of stay on the acute trauma ward was reduced (Chi-square test, before v after by intervals: chi(3)(2)=21.1, p<0.001). The proportion of patients discharged from the ward within one week increased from 47% before the rota change to 63% after. CONCLUSION: By applying the industry-based methods of 'process management', we have shown that a simple intervention (alteration of consultant shift patterns) has had a significant impact in reducing time to theatre for neck of femur trauma patients and reducing the length of stay on the acute trauma ward. Thus, the 'patient flow' has been made more efficient making more acute trauma beds available for new admissions. PMID- 21672657 TI - Evidence based surgery--do we practice what we preach? AB - BACKGROUND: Good surgical practice assumes knowledge of the current literature. However, we suspect that published clinical recommendations are not always followed by the department producing the research. We sought to assess whether clinical recommendations made by surgical units are followed within their own department. We carried out a prospective study of the British Journal of Surgery and contacted individual departments to assess whether recommendations made by the senior author were being followed. METHODS: Journal articles between January 2005 and December 2006 were reviewed with respect to any recommendations made from research findings. Individual departments were contacted by telephone and an appropriate individual was asked whether the recommendations were being followed by the lead author. RESULTS: Sixty-six units were successfully contacted and 49 (74%) followed their own recommendations, leaving 17 (26%) who did not. CONCLUSION: Most surgical units who publish recommendations in the British Journal of Surgery implement changes within department. However, there is significant proportion who don't practice what they preach. PMID- 21672656 TI - The management of rectal cancer in Ireland in 2007--room for improvement? AB - INTRODUCTION: Effective management of rectal cancer relies on accurate pre operative assessment, surgical technical excellence and integrated neoadjuvant and adjuvant chemo and/or radiotherapy. The aim of this study was to examine the management of rectal cancer in Ireland. METHODS: This was a retrospective chart review. All cases of rectal cancer (15 cm or less from the anal verge) diagnosed in Ireland in the year 2007 were included in the audit. RESULTS: In total data for 585 patients were included, under the care of 87 consultant surgeons operating in 48 hospitals. Only data recorded in medical charts were included. Pre-operative investigations were less utilised than recommended by current guidelines and consequently many cancers were inadequately staged. In total 52.5% of cases were discussed at a multi-disciplinary meeting. Overall, 88% of the patients had surgery, and the 30-day mortality rate was 1.7%. The quality of post operative pathology reporting was variable, with adequacy of total mesorectal excision status unclear or unknown in 74% of cases. Cases were managed in a large number of centres, and in lower volume centres (<5 cases per annum) patients appeared to be less adequately investigated. CONCLUSION: This study gives a snapshot of recent practice in the management of rectal cancer in Ireland but is of necessity limited as the audit was retrospective and long term outcomes have not been assessed. In 2007 rectal cancer was managed in a large number of centres and best practice was frequently not adhered to. The impending centralisation of cancer services is likely to impact on the management of rectal cancer in Ireland. PMID- 21672658 TI - A study of the factors influencing school-going students considering medical careers. AB - INTRODUCTION: Obtaining a place in an Irish medical school is extremely competitive, a situation mirrored in many other countries. We aimed to determine the factors influencing school students in deciding to study medicine in university. We further determined what level of interest exists in pursuing a surgical career after completion of medical school. METHODS: The Royal College of Surgeons in Ireland hosts an annual "Introduction to Medicine" programme for senior school children. Attendees were surveyed using a Likert scale to examine the factors influencing the group in choosing to study medicine, and pursue surgery as their ultimate career choice. RESULTS: A total of 128 completed the survey, giving a response rate of 100%. The opportunity to help others was most the most influential factors cited by students (97%). Males were significantly more likely to have an interest in a career in surgery rather than medicine (p = 0.003), and ranked "financial reward" (p = 0.036) as a more significant factors in influencing career choice than did females. CONCLUSIONS: A clear understanding of these factors influencing our students in their career choices and a strategy of recruitment based on these is imperative in order to optimize recruitment of students most suited to working as doctors. PMID- 21672659 TI - Colonoscopy in the octogenarian population: diagnostic and survival outcomes from a large series of patients. AB - OBJECTIVE: Our aim was to audit the diagnostic and survival outcomes of colonoscopy in octogenarians and to determine if it confers any survival benefit. METHODS: A review of a prospectively maintained database over a two year period between October 2005 and September 2007 was undertaken. Data on numerous outcome variables and survival were collected and analysed. Categorical variables were compared using the Chi-square test. Kaplan-Meier survival curves were constructed and log rank test were used to compare survival curves. RESULTS: There were 1905 patients, of which 289 (15%) were over the age of 80 years. Caecal intubation was significantly lower in octogenarians when compared with young patients (239/289, (82%) vs. 1411/1616 (88%), p = 0.025). The most common reason for failure to intubate the caecum was presence of stenosing pathology in distal bowel (octogenarians 46% (23 out of 50 failed intubations) vs. young 23% (49 out of 205 failed intubations), p = 0.002). A greater proportion of octogenarians had poor bowel preparation when compared with the young (20% vs. 13%, p = 0.001). Significantly more pathology was detected in octogenarians (72% vs. 59%, p = 0.001). Forty-four (15.2%) octogenarians were found to have malignancy. Of these, only 23 (52%) underwent subsequent surgery. Median survival of octogenarians who had surgery was not statistically better (31 (IQR 12-38) months vs. 16 (IQR 5-31) months, p = 0.10) than those who did not. CONCLUSION: Colonoscopy is safe in octogenarians and provides a high yield. Our results suggest that it does not appear to result in any survival benefit. However, to establish this, further research with larger cohorts and longer follow-up periods would be required. PMID- 21672660 TI - The molecular biology of colorectal carcinoma and its implications: a review. AB - Colorectal carcinoma is one of the most common cancers encountered in the western world and increasingly in the developing world as well. This conditions results in considerable morbidity and mortality. As a result of the impact colorectal carcinoma has on society, a considerable amount of research has gone into elucidating the molecular mechanisms of this disease. This has led to a proliferation in the understanding of the molecular aetiology of the disease. Such research has revealed the underlying mechanisms to be complex and diverse, with no single molecular cause for the development of colorectal cancer. In this review, we look at the basic underlying molecular mechanisms of colorectal cancer and also briefly explore its implications with regards to clinical applications. We look at how this information relates to the prognosis and also its potential use in screening. A medline and pubmed search was conducted using the keywords colorectal carcinoma, molecular biology of colorectal carcinoma, mutations, and the relevant articles were used for this review. Bibliographies of these articles were also searched for relevant articles. There is considerable information available on the pathogenesis of colorectal carcinoma and such knowledge is beginning to impact on clinical practice. PMID- 21672661 TI - Postoperative pancreatic fistula. AB - Postoperative pancreatic fistula is an important complication after pancreatic resection. The frequency of its incidence varies between 3% after pancreatic head resections and up to 30% following distal pancreatectomy. In recent years, the international definition of pancreatic fistula has been standardised according to the approach of the International Study Group on Pancreatic Fistula (ISGPF). Consequently, results from different studies have become comparable and the historically reported fistula rates can be evaluated more critically. The present review summarises the currently available data on incidence, risk factors, fistula-associated complications and management of postoperative pancreatic fistula. PMID- 21672662 TI - A systematic review of laparoscopic port site hernias in gastrointestinal surgery. AB - INTRODUCTION: Port site hernia is an important yet under-recognised complication of laparoscopic surgery, which carries a high risk of strangulation due to the small size of the defect involved. The purpose of this study was to examine the incidence, classification, and pathogenesis of this complication, and to evaluate strategies to prevent and treat it. METHODS: Medline was searched using the words "port site hernia", "laparoscopic port hernia" "laparoscopic complications" and "trocar site hernias". The search was limited to articles on cholecystectomy, colorectal, bariatric or anti-reflux surgery published in English. A total of 42 articles were analysed and of these 35 were deemed eligible for review. Inclusion criteria were laparoscopic gastrointestinal surgery in English only with reported incidence of port site herniation. Studies were excluded if insufficient data was provided. Eligible studies were also cross-referenced. RESULTS: Analysis of 11,699 patients undergoing laparoscopic gastrointestinal procedures demonstrated an incidence of port site hernias of 0.74% with a mean follow-up of 23.9 months. The lowest incidence of port site herniation was for bariatric surgery with 0.57% in 2644 patients with a mean follow-up of 67.4 months while the highest incidence was for laparoscopic colorectal surgery with an incidence of 1.47% in 477 patients with a mean follow-up of 71.5 months. CONCLUSION: All fascial defects larger than or equal to 10mm should be closed with peritoneum, while smaller defects may require closure in certain circumstances to prevent herniation. Laparoscopic port site herniation is a completely preventable cause of morbidity that requires a second surgical procedure to repair. PMID- 21672663 TI - The effects of tobacco smoking on the incidence and risk of intraoperative and postoperative complications in adults. AB - INTRODUCTION: Despite the warnings of health hazards of cigarette smoking, still one third of the population in industrial countries smoke. This review was conducted with the aim of exploring the effects of preoperative tobacco smoking on the risk of intra- and postoperative complications and to identify the value of preoperative smoking cessation. METHODS: The databases that were searched included The Cochrane Library Database, Medline, and EMBASE. Articles were also identified through a general internet search using the Google search engine. The incidence or risk of different types of intra- and postoperative complications were used as outcome measures. RESULTS: Tobacco smoking has a negative effect on surgical outcome, as has been found to be a risk factor for the development of complications during and after many types of surgery, even in the absence of chronic lung disease. Furthermore, the long-term health hazards of smoking reduce health-related quality of life and premature death. CONCLUSION: It is widely documented that stopping smoking before surgery has substantial health benefits in the longer term and should be recommended to every smoker in order for them to gain maximum benefit from their treatment. However, identification of the optimal period of preoperative smoking cessation on postoperative complications cannot be determined. PMID- 21672664 TI - Infected circumcision ring: a trend of self-circumcision practice? PMID- 21672666 TI - Mechanisms of neuropathic pain. AB - Neuropathic pain is a disease of global burden. Its symptoms include spontaneous and stimulus-evoked painful sensations. Several maladaptive mechanisms underlying these symptoms have been elucidated in recent years: peripheral sensitization of nociception, abnormal excitability of afferent neurons, central sensitization comprising pronociceptive facilitation, disinhibition of nociception and central reorganization processes, and sympathetically maintained pain. This review aims to illustrate these pathophysiological principles, focussing on molecular and neurophysiological findings. Finally therapeutic options based on these findings are discussed. PMID- 21672665 TI - Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with L-arginine decreases contusion size but not behavioral deficits after traumatic brain injury. AB - Our laboratory has previously demonstrated that viral administration of glial cell line-derived neurotrophic factor (AdGDNF), one week prior to a controlled cortical impact (CCI) over the forelimb sensorimotor cortex of the rat (FL-SMC) is neuroprotective, but does not significantly enhance recovery of sensorimotor function. One possible explanation for this discrepancy is that although protected, neurons may not have been functional due to enduring metabolic deficiencies. Additionally, metabolic events following TBI may interfere with expression of therapeutic proteins administered to the injured brain via gene therapy. The current study focused on enhancing the metabolic function of the brain by increasing cerebral blood flow (CBF) with l-arginine in conjunction with administration of AdGDNF immediately following CCI. An adenoviral vector harboring human GDNF was injected unilaterally into FL-SMC of the rat immediately following a unilateral CCI over the FL-SMC. Within 30min of the CCI and AdGDNF injections, some animals were injected with l-arginine (i.v.). Tests of forelimb function and asymmetry were administered for 4weeks post-injury. Animals were sacrificed and contusion size and GDNF protein expression measured. This study demonstrated that rats treated with AdGDNF and l-arginine post-CCI had a significantly smaller contusion than injured rats who did not receive any treatment, or injured rats treated with either AdGDNF or l-arginine alone. Nevertheless, no amelioration of behavioral deficits was seen. These findings suggest that AdGDNF alone following a CCI was not therapeutic and although combining it with l-arginine decreased contusion size, it did not enhance behavioral recovery. PMID- 21672667 TI - Palaeogenomics of Mycobacterium tuberculosis: epidemic bursts with a degrading genome. AB - Genome-scale analysis suggests that the last common ancestor of the Mycobacterium tuberculosis complex and Mycobacterium leprae diverged 36 million years ago, and members of the Mycobacterium tuberculosis complex differentiated 40,000 years ago. Analysis of palaeomicrobiological data from a 17,000-year-old sample from a bison and a 9000-year-old sample from a human being suggested that M tuberculosis preceded Mycobacterium bovis and related species. Whole-genome comparisons show that members of the M tuberculosis complex form a unique bacterial species with distinct ecotypes that are transmissible from any infected mammalian species to several others. Genomic deletions identified several M tuberculosis lineages that could be placed on a phylogeographical map, suggesting adaptation to local host populations. The degrees of transmissibility and virulence vary between M tuberculosis clones, with increased virulence mainly linked to gene loss in regulatory pathways. Such data suggest that most M tuberculosis clones have a restricted spreading capacity between the host population, allowing unpredictable bursts of highly transmissible, virulent, and successful clones, such as the east Asian (Beijing) clone. Advances in genomics have helped the development of molecular techniques for accurate identification of species and clones in the M tuberculosis complex, which is essential for tracing the source of infections. PMID- 21672668 TI - Minimizing hot spot temperature in asymmetric gradient coil design. AB - Heating caused by gradient coils is a considerable concern in the operation of magnetic resonance imaging (MRI) scanners. Hot spots can occur in regions where the gradient coil windings are closely spaced. These problem areas are particularly common in the design of gradient coils with asymmetrically located target regions. In this paper, an extension of an existing coil design method is described, to enable the design of asymmetric gradient coils with reduced hot spot temperatures. An improved model is presented for predicting steady-state spatial temperature distributions for gradient coils. A great amount of flexibility is afforded by this model to consider a wide range of geometries and system material properties. A feature of the temperature distribution related to the temperature gradient is used in a relaxed fixed point iteration routine for successively altering coil windings to have a lower hot spot temperature. Results show that significant reductions in peak temperature are possible at little or no cost to coil performance when compared to minimum power coils of equivalent field error. PMID- 21672669 TI - Numerical model of heat transfer in the rabbit eye exposed to 60-GHz millimeter wave radiation. AB - A numerical model of the anterior chamber of the rabbit eye is presented. The model takes into account both the fluid dynamics of the aqueous humor and the realistic boundary conditions at the interface of the cornea with the environment. The model is used to determine the temperature distribution and velocity field under 60-GHz millimeter wave radiation. The maximum predicted temperature (45.8 ( degrees ) C for an incident power density of 475 mW/cm(2)) is in good agreement with experimental results. Moreover, the model shows that there is a value for the incident power density (about 100 mW/cm(2)) for which the direction of aqueous humor flow due to buoyancy is inverted, because of the inversion of the temperature gradient in the anterior chamber of the eye. This phenomenon has already been reported from experimental observations and can be numerically studied, if aqueous humor fluid dynamics are taken into account in the heat-transfer model. PMID- 21672670 TI - fMRI-based hierarchical SVM model for the classification and grading of liver fibrosis. AB - We present a novel method for the automatic classification and grading of liver fibrosis based on hepatic hemodynamic changes measured noninvasively from functional MRI (fMRI) scans combined with hypercapnia and hyperoxia. The supervised learning method automatically creates a classification and grading model for liver fibrosis grade from training datasets. It constructs a statistical model of liver fibrosis by evaluating the signal intensity time course and local variance in T2(*)-W fMRI scans acquired during the breathing of air, air-carbon dioxide, and carbogen with a hierarchical multiclass binary-based support vector machine (SVM) classifier. Two experimental studies on 162 slices from 34 mice with the hierarchical multiclass binary-based SVM classifier yield 96.9% separation accuracy between healthy and histological-based fibrosis graded subjects, and an overall accuracy of 75.3% for healthy, fibrotic, and cirrhotic subjects. These results outperform existing image-based methods that can discriminate between healthy and mild-grade fibrosis subjects. PMID- 21672671 TI - Automated prescription of an optimal imaging plane for measurement of cerebral blood flow by phase contrast magnetic resonance imaging. AB - This study describes and evaluates a semiautomated method for prescribing an optimal imaging plane that is located as close as possible to the skull base, and is simultaneously nearly perpendicular to the four arteries leading blood to the brain [internal carotid arteries (ICAs) and vertebral arteries (VAs)]. Such a method will streamline and improve reliability of the measurement of total cerebral blood flow and intracranial pressure by velocity encoding phase-contrast magnetic resonance imaging. The method first extracts the vessels' centerline from a 2-D time-of-flight magnetic resonance angiogram of the neck by performing distance transformations. An anatomical marker, the V2 segment of the VAs, is then identified to guide the imaging plane to be as close and below the skull base. An imaging plane that is nearly perpendicular to the ICAs and V2 segment of VAs is then identified by minimizing a misalignment value, estimated by a weighted mean of the angles between the plane's normal and the vessel axes at the vessel-plane intersections. The performance of the semiautomated method was evaluated by comparing manually selected planes to those found semiautomatically in nine magnetic resonance angiogram datasets. The semiautomated method consistently outperformed manual prescription with a significantly smaller misalignment value, 8.6 degrees versus 20.7 degrees (P < 0.001), respectively, and significantly improved reproducibility. PMID- 21672672 TI - In vivo fluorescence spectra unmixing and autofluorescence removal by sparse nonnegative matrix factorization. AB - Fluorescence imaging locates fluorescent markers that specifically bind to targets; like tumors, markers are injected to a patient, optimally excited with near-infrared light, and located thanks to backward-emitted fluorescence analysis. To investigate thick and diffusive media, as the fluorescence signal decreases exponentially with the light travel distance, the autofluorescence of biological tissues comes to be a limiting factor. To remove autofluorescence and isolate specific fluorescence, a spectroscopic approach, based on nonnegative matrix factorization (NMF), is explored. To improve results on spatially sparse markers detection, we suggest a new constrained NMF algorithm that takes sparsity constraints into account. A comparative study between both algorithms is proposed on simulated and in vivo data. PMID- 21672673 TI - In silico investigation of electrically silent acute cardiac ischemia in the human ventricles. AB - Acute cardiac ischemia, which is caused by the occlusion of a coronary artery, often leads to lethal ventricular arrhythmias or heart failure. The early diagnosis of this pathology is based on changes of the electrocardiogram (ECG), i.e., mainly shifts of the ST segment. However, the underlying mechanisms responsible for these shifts are not completely understood. Furthermore, clinical observations indicate that some acute ischemia cases can hardly be detected using standard 12-lead ECG only. Therefore, multiscale computer simulations of cardiac ischemia using realistic models of human ventricles were carried out in this work. For this purpose, the transmembrane voltage distributions in the heart and the corresponding body surface potentials were computed with varying transmural extent of the ischemic region at different ischemia stages. Some of the simulated ischemia cases were " electrically silent," i.e., they could hardly be identified in the 12-lead ECG. PMID- 21672676 TI - A uniform grid structure to speed up example-based photometric stereo. AB - In this paper, we describe a data structure and an algorithm to accelerate the table lookup step in example-based multiimage photometric stereo. In that step, one must find a pixel of a reference object, of known shape and color, whose appearance under m different illumination fields is similar to that of a given scene pixel. This search reduces to finding the closest match to a given m-vector in a table with a thousand or more m-vectors. Our method is faster than previously known solutions for this problem but, unlike some of them, is exact, i.e., always yields the best matching entry in the table, and does not assume point-like sources. Our solution exploits the fact that the table is in fact a fairly flat 2-D manifold in m-dimensional space so that the search can be efficiently solved with a uniform 2-D grid structure. PMID- 21672674 TI - Analysis of EMG and acceleration signals for quantifying the effects of deep brain stimulation in Parkinson's disease. AB - Deep brain stimulation (DBS) is effective in reducing motor symptoms in Parkinson's disease (PD). However, objective methods for quantifying its efficacy are lacking. We present a principal component (PC)-based tracking method for quantifying the effects of DBS in PD by using electromyography (EMG) and acceleration measurements. Ten parameters capturing PD characteristic signal features were initially extracted from isometric EMG and acceleration recordings. Using a PC approach, the original parameters were transformed into a smaller number of PCs. Finally, the effects of DBS were quantified by examining the PCs in a low-dimensional feature space. The EMG and acceleration data from 13 PD patients with DBS ON and OFF, and 13 healthy age-matched controls were used for analysis. Clinical evaluation of patients showed that their motor symptoms were effectively reduced with DBS. The analysis results showed that the signal characteristics of 12 patients were more similar to those of the healthy controls with DBS ON than with DBS OFF. These observations indicate that the PC-based tracking method can be used to objectively quantify the effects of DBS on the neuromuscular function of PD patients. Further studies are suggested to estimate the clinical sensitivity of the method to different types of PD. PMID- 21672675 TI - Power-constrained contrast enhancement for emissive displays based on histogram equalization. AB - A power-constrained contrast-enhancement algorithm for emissive displays based on histogram equalization (HE) is proposed in this paper. We first propose a log based histogram modification scheme to reduce overstretching artifacts of the conventional HE technique. Then, we develop a power-consumption model for emissive displays and formulate an objective function that consists of the histogram-equalizing term and the power term. By minimizing the objective function based on the convex optimization theory, the proposed algorithm achieves contrast enhancement and power saving simultaneously. Moreover, we extend the proposed algorithm to enhance video sequences, as well as still images. Simulation results demonstrate that the proposed algorithm can reduce power consumption significantly while improving image contrast and perceptual quality. PMID- 21672677 TI - An efficient selective perceptual-based super-resolution estimator. AB - In this paper, a selective perceptual-based (SELP) framework is presented to reduce the complexity of popular super-resolution (SR) algorithms while maintaining the desired quality of the enhanced images/video. A perceptual human visual system model is proposed to compute local contrast sensitivity thresholds. The obtained thresholds are used to select which pixels are super-resolved based on the perceived visibility of local edges. Processing only a set of perceptually significant pixels reduces significantly the computational complexity of SR algorithms without losing the achievable visual quality. The proposed SELP framework is integrated into a maximum-a posteriori-based SR algorithm as well as a fast two-stage fusion-restoration SR estimator. Simulation results show a significant reduction on average in computational complexity with comparable signal-to-noise ratio gains and visual quality. PMID- 21672678 TI - Automated delineation of lung tumors in PET images based on monotonicity and a tumor-customized criterion. AB - Reliable automated or semiautomated lung tumor delineation methods in positron emission tomography should provide accurate tumor boundary definition and separation of the lung tumor from surrounding tissue or "hot spots" that have similar intensities to the lung tumor. We propose a tumor-customized downhill (TCD) method to achieve these objectives. Our approach includes: 1) automatic formulation of a tumor-customized criterion to improve tumor boundary definition, 2) a monotonic property of the standardized uptake value (SUV) of tumors to separate the tumor from adjacent regions of increased metabolism ("hot spot"), and 3) accounts for tumor heterogeneity. Three simulated lesions and 30 PET-CT studies, grouped into "simple" and "complex" groups, were used for evaluation. Our main findings are that TCD, when compared to the threshold based on 40% and 50% maximum SUV, adaptive threshold, Fuzzy c-means, and watershed techniques achieved the highest Dice's similarity coefficient average for simulation data (0.73) and "complex" group (0.71); the least volumetric error in the "simple" (1.76 mL) and the "complex" group (14.59 mL); and TCD solves the problem of leakage into adjacent tissues when many other techniques fail. PMID- 21672680 TI - [Surgical infections as patient safety problems]. AB - Surgical infections are severe complications of surgical interventions and one of the most important patient safety issues. These are associated with increased morbidity, mortality, costs and decreased quality of life. Prevention of infections is essential, while one has to consider pre-, intra- and postoperative factors and procedures in the clinical practice. In this article we summarize the latest recommendations for clinicians based on the relevant published literature. PMID- 21672679 TI - Traffic-related air pollution and acute changes in heart rate variability and respiratory function in urban cyclists. AB - BACKGROUND: Few studies have examined the acute health effects of air pollution exposures experienced while cycling in traffic. OBJECTIVES: We conducted a crossover study to examine the relationship between traffic pollution and acute changes in heart rate variability. We also collected spirometry and exhaled nitric oxide measures. METHODS: Forty-two healthy adults cycled for 1 hr on high- and low-traffic routes as well as indoors. Health measures were collected before cycling and 1-4 hr after the start of cycling. Ultrafine particles (UFPs; <= 0.1 MUm in aerodynamic diameter), particulate matter <= 2.5 MUm in aerodynamic diameter (PM2.5), black carbon, and volatile organic compounds were measured along each cycling route, and ambient nitrogen dioxide (NO2) and ozone (O3) levels were recorded from a fixed-site monitor. Mixed-effects models were used to estimate associations between air pollutants and changes in health outcome measures relative to precycling baseline values. RESULTS: An interquartile range increase in UFP levels (18,200/cm3) was associated with a significant decrease in high-frequency power 4 hr after the start of cycling [beta = -224 msec2; 95% confidence interval (CI), -386 to -63 msec2]. Ambient NO2 levels were inversely associated with the standard deviation of normal-to-normal (NN) intervals (beta = -10 msec; 95% CI, -20 to -0.34 msec) and positively associated with the ratio of low-frequency to high-frequency power (beta = 1.4; 95% CI, 0.35 to 2.5) 2 hr after the start of cycling. We also observed significant inverse associations between ambient O3 levels and the root mean square of successive differences in adjacent NN intervals 3 hr after the start of cycling. CONCLUSIONS: Short-term exposures to traffic pollution may contribute to altered autonomic modulation of the heart in the hours immediately after cycling. PMID- 21672681 TI - [Prevalence of male breast cancer in our department during a 5-year period]. AB - Male breast cancer is a rare entity. Statistics suggest the female:male ratio is100:1. Male breast cancer is most frequent in elderly patients, but it can occur at any age. The mean age of the onset of the disease is 10 years later in males compared to female patients. Here, the authors review the predisposing factors, main types of male breast cancer, diagnosis and treatment principals. Furthermore, they summarise data of five patients from their practice as regards diagnostic work-up, surgical and adjuvant treatments. PMID- 21672682 TI - [Computerized modelling of operation (CMO) before thoracoplasty]. AB - INTRODUCTION: Thoraco-myoplasty (TMP) has proven to be the only successful method of treatment for severe cases of chronic pyothorax (CPT). Great loss of muscle tissue and permanent bone-structure defects with severe functional damage can be caused by this method. The aim of the applied CMO was to prevent additional loss of muscle function. Preoperative evaluation of spiral CT scan 3-dimensional imaging provided a significant aid in decreasing adverse effects of the TMP. MATERIALS AND METHOD: Between 1990 and 2010, TMP was applied in 85 patients, whose CPT came from several different origins. CLINICAL DATA: average age: 62.7; mortality: 4.8%. Tissue and function preserving TMP was achieved following open treatment after thoracic fenestration in 76 cases, and drainage with continuous suction was performed in 9 patients prior to this. In our department TMP with computerized modeling was introduced as the definitive treatment of CPT in 2006, since then it has been applied in 8 patients. RESULTS: The number and length of the ribs to be resected can be anticipated applying spiral CT imaging. Furthermore, accurate volume measurement of the empyema cavity and rotatable muscles (pectoral major and latissimus dorsal) faciliatates elimination of the primary defect during surgery. CONCLUSION: Therefore, we believe that CMO can provide significant aid for surgeons to reduce the negative effects caused by muscle trauma and the structural changes in the thoracic wall. PMID- 21672683 TI - [Isolated bronchial resection for tumor]. AB - Tumors that are confined to specific areas of the airway (e.g. left main stem bronchus or the bronchus intermedius) can be removed with resections of the bronchus only and preservation of the parenchyma. During the period of January 2004 to February 2009 five patients underwent isolated bronchial resection for lung tumor with curative intent. In this study we analyzed the data of five men with a median age of 47.6 years (range 29-68 years). In four cases resection of the intermediate bronchus was performed, and in one case left main bronchus was removed. Intraoperative frozen section revealed negative bronchial resection margins in all cases. Four patients had carcinoid tumors, while one was diagnosed with chemodectoma. Minor postoperative complications were observed in two patients only. Isolated bronchial resection for lung tumor is associated with low morbidity and mortality. Lung sparing procedures are preferable in the above cases but sufficient experience and conditions are mandatory to achieve adequate results. PMID- 21672684 TI - [Combined transplantation of a free skin island flap supplied by a septo cutaneous perforator of the posterior tibial artery and the underlying fibula for the full reconstruction of the mandible and the mouth floor]. AB - Microsurgical transplantation of the osteo-cutaneous fibula as a free flap to reconstruct the defect following radical resection of a mouth floor's tumor is a well-known and often applied procedure. Anatomy of the vessels supplying this flap is recognized but it may have some rare and unexpected variations. In this case report we discuss the reconstruction of the middle and lateral parts of the mandible which was resected due to a T4 gingival tumor. Interestingly, the aforementioned segment of the fibula and the overlying skin island were supplied by different pedicles, both emerging from the posterior tibial vessels. Both flaps were transplanted using autologous arterial and venous grafts of the peroneal artery and vein in case of the fibula. We believe this case is worth publishing due to its relative rarity in the literature and the applied surgical method. PMID- 21672685 TI - [About the so-called residents]. PMID- 21672686 TI - [Letter to the editor: Parasternal fenestration for malignant pericardial effusion]. PMID- 21672689 TI - Risk assessment, primary prevention, and the chronic care model. PMID- 21672690 TI - Clinical neurology training of foreign nationals in Canada--the current situation. PMID- 21672691 TI - Decompressive craniectomy for traumatic brain injury. PMID- 21672692 TI - Inflammation complicates an 'age-related' cerebral microangiopathy. PMID- 21672693 TI - Monoclonal antibody therapy and progressive multifocal leukoencephalopathy. PMID- 21672694 TI - Tauopathies: one disease or many? AB - Tauopathies are a group of disorders that have in common abnormal accumulation of tau protein in the brain. Although the different tauopathies have long been considered to be separate diseases, it is now clear that progressive supranuclear palsy, corticobasal degeneration and some forms of tau-positive frontotemporal lobar degeneration share clinical, pathological and genetic features. The important overlap between these disorders suggest they may represent different phenotypes of a single disease process, the clinical result depending on the topography of pathological lesions as well as other unknown factors. PMID- 21672695 TI - Gastrointestinal symptoms in Parkinson disease: clinical aspects and management. AB - Although it is now generally recognized that the clinical spectrum of Parkinson disease (PD) is broader than its defining motor aspects, its various non-motor symptoms are often not routinely assessed in the clinical setting. As most of these symptoms are amenable to treatment, improved recognition would lead to more comprehensive management of the disease, and ultimately improve the quality of life for PD patients. In an attempt to increase the general awareness of physicians caring for these patients, this article focuses on the clinical manifestations and treatment of the gastrointestinal symptoms most commonly experienced by PD patients, as well as on the gastrointestinal side effects of antiparkinsonian treatments. PMID- 21672696 TI - Monoclonal antibodies and progressive multifocal leukoencephalopathy. AB - Monoclonal antibodies have become an important treatment option for a number of serious conditions. Concerns have arisen about the potential association of these products with progressive multifocal leukoencephalopathy (PML). A list of monoclonal antibodies authorized for sale was derived from the Health Canada Drug Product Database. Case reports of PML after exposure to a monoclonal antibody authorized for use in Canada were retrieved by searching Canada Vigilance and WHO adverse event databases and through a Pub MED/Medline literature search. 182 adverse event case reports were retrieved (adalimumab -1 case, alemtuzumab-14, bevacizumab -3, cetuximab -1, efalizumab - 8, ibritumomab tiuxetan-5, infliximab 4, natalizumab-32, and rituximab-114). The Canadian Product Monographs for natalizumab and ritiximab contain box warnings for PML. A natalizumab registry has been established. PMID- 21672697 TI - A canadian perspective on ethics review and neuroimaging: tensions and solutions. AB - Neuroimaging research has raised ethical concerns such as the management of unexpected findings and the classification and assessment of risks. Research ethics boards (REBs) bear responsibility for the oversight of these challenges but neuroimagers struggle with the practical aspects of ethics review and report that administrative load and inconsistency contribute to eroding confidence and trust in ethics review. Our goal was to discuss and propose strategies for institutional and educational change to improve ethics review. We used an iterative and deliberative workshop-based writing process involving multiple disciplines. We propose recommendations in three tension areas: (1) communication between researchers and REBs; (2) collaboration and sharing of expertise between REBs; and (3) practical considerations and the needs of neuroimagers engaged in the ethics review process. Our recommendations are intended as openings rather than endpoints. Researchers and research ethics governance communities should decide on the future uptake of these recommendations. PMID- 21672698 TI - Risk profiles of Alzheimer disease. AB - Alzheimer disease (AD) is a dementing, neurodegenerative disorder that affects approximately 500,000 Canadians and its prevalence is expected to double over the next 30 years. Although several medications may temporarily augment cognitive abilities in AD, there presently exists no proven method to avoid the inevitable clinical deterioration in this devastating condition. The delineation of risk factors for the development of AD offers hope for the advent of effective prevention or interventions that might retard the onset of symptoms. In this article, we provide a comprehensive review of midlife risk factors implicated in the etiopathogenesis of sporadic AD. Although some risk factors are heritable and largely beyond our control, others are determined by lifestyle or environment and are potentially modifiable. In a companion paper, we introduce the concept of an Alzheimer Risk Assessment Clinic for ascertainment and mitigation of these and other putative dementia risk factors in middle-aged adults. PMID- 21672699 TI - Angioplasty as an adjuvant therapy for the treatment of acute ischemic stroke. AB - BACKGROUND: Different endovascular techniques can be employed to achieve vessel recanalization in acute stroke. We assessed whether an endovascular strategy that included angioplasty was safe and effectively recanalized acutely occluded intracranial vessels. METHODS: We retrospectively reviewed 70 patients that received intra-arterial therapy for acute stroke. Patients were divided into two groups depending on whether they had received angioplasty as part of their endovascular treatment. RESULTS: Angioplasty was used in the treatment of 35/70 patients (50%). Median baseline NIHSS was 15. The site of occlusion was at the M1 in 11 patients, M1/M2 in 3, ICA/M1 in 13 and vertebrobasilar in 8 patients. Intravenous thrombolysis was administered to 16/35 patients (46%). Angioplasty was used alone in 4 patients, in combination with intra-arterial thrombolysis in 27 and with a mechanical retrieval device or stent in 13 patients. Recanalization (TICI 2-3) was achieved in 23/35 patients (66%). Median time from symptom onset to recanalization was six hours. In patients where angioplasty was employed, symptomatic intracranial hemorrhage occurred in 2/35 (6%), which was similar to patients that were not treated with angioplasty. A favorable functional outcome (mRS=2) was achieved in 20% (7/35) at 24 hour and 34% (12/35) at one month. All patients that had a favorable outcome had recanalized. CONCLUSION: In this small cohort, an endovascular treatment strategy that employed angioplasty was safe and effectively recanalized acutely occluded intracranial vessels. Angioplasty should be considered as a potential treatment option in interventional acute stroke trials. PMID- 21672700 TI - ARAC--The Montreal Jewish General Hospital Alzheimer Risk Assessment Clinic. AB - INTRODUCTION: In parallel with robust efforts world-wide to develop effective neuroprotection for established disease, resources are being mobilized to delineate risk factors and implement preventive measures in a concerted effort to forestall the anticipated Alzheimer disease (AD) epidemic. A review of heritable and 'acquired' dementia risk factors, many operating at midlife, is presented in a companion paper. OBJECTIVES: In 2009, an Alzheimer Risk Assessment Clinic (ARAC) was established at the Jewish General Hospital (Montreal) to address the concerns increasingly being voiced by active middle-aged individuals at risk for AD. A positive family history of AD and/or perceived changes in personal cognitive function (predominantly short-term memory) are main reasons for referral. The primary objectives of ARAC are to (i) ascertain, inform and mitigate the risks of developing AD in cognitively-healthy persons aged 40-65 based on best available medical and epidemiological evidence, (ii) conduct scientific research on midlife dementia risk and prevention in this population and (iii) provide instruction in dementia risk assessment and management to health professionals, clinical/research fellows, medical residents and students. ARAC infrastructure, evaluation protocol, risk profile classification scheme, interventions, knowledge dissemination program, case vignettes, and seminal research projects are described. CONCLUSIONS: It is hoped that ARAC and similar initiatives will help prevent or delay dementia by innovating effective interventions based on increasingly nuanced estimation of modifiable AD risk in presymptomatic persons. PMID- 21672701 TI - Primary or secondary decompressive craniectomy: different indication and outcome. AB - BACKGROUND: Intracranial hypertension can cause secondary damage after a traumatic brain injury. Aggressive medical management might not be sufficient to alleviate the increasing intracranial pressure (ICP), and decompressive craniectomy (DC) can be considered. Decompressive craniectomy can be divided into categories, according to the timing and rationale for performing the procedure: primary (done at the time of mass lesion evacuation) and secondary craniectomy (done to treat refractory ICP). Most studies analyze primary and secondary DC together. Our hypothesis is that these two groups are distinct and the aim of this retrospective study is to evaluate the differences in order to better predict outcome after DC. METHODS: Seventy patients had DC over a period of four years at our center. They were divided into two groups based on the timing of the DC. Primary DC (44 patients) was done within 24 hours of the injury for mass lesion evacuation. Secondary DC (26 patients) was done after 24 hours and purely for the treatment of refractory ICP. Pre-op characteristics and post-op outcomes were compared between the two groups. RESULTS: There was a significant difference in the mechanism of injury, the pupil abnormalities and Marshall grade between primary and secondary DC. There was also a significant difference in outcome with primary DC showing 45.5% good outcome and 40.9% mortality and secondary DC showing 73.1% good outcome and 15.4% mortality. CONCLUSIONS: Primary and secondary DC have different indications and patients characteristics. Outcome prediction following DC should be adjusted according to the surgical indication. PMID- 21672702 TI - Glioblastoma: patterns of recurrence and efficacy of salvage treatments. AB - BACKGROUND: It is controversial if distant recurrence of glioblastoma is more common after temozolomide (TMZ) concurrent with radiotherapy (RT). Optimal therapy for patients with recurrent disease after RT/TMZ is unclear. Our purpose was to evaluate recurrence patterns in glioblastoma and the effect of treatment at recurrence upon survival. METHODS: We performed a retrospective review of 67 patients with newly diagnosed glioblastoma treated with RT/TMZ between 2003-2007. Statistical analyses included Kaplan-Meier method for survival, and multivariate Cox proportional hazards model for the effect of salvage treatment on survival. RESULTS: 58 patients (86.6%) recurred locally; 9 patients (13.4%) had a distant non-contiguous focus of new disease. Median survival(MS) was 17 months; median time-to-progression(TTP) 6.8 months. The local and distant groups had comparable prognostic factors. There was no difference in MS(p=0.35) or TTP(p=0.95) by location of recurrence. At relapse, 26 patients(38.8%) received continuous, dose intense TMZ, 24(35.8%) other therapy(4.5% RT; 20.9% lomustine+/-procarbazine; 4.5% etoposide; 1.5% conventional TMZ; 4.5% TMZ then lomustine), and 17(25.4%) were untreated. Dose-intense TMZ was associated with prolonged MS compared to all other patients(21.5 months vs. 12.4 months, p=0.019, HR=3.86, 95%CI: 1.81-8.22) and similar to MS with other chemotherapy regimens(18.8 months, p=0.40, HR=1.30, 95% CI: 0.65-2.61). CONCLUSION: The pattern of recurrence of glioblastoma treated with RT/TMZ was predominantly local. Second-line treatment with continuous dose intense TMZ may prolong survival in patients with recurrent glioblastoma. Overall survival is similar to other conventional salvage regimens; however TMZ may be better tolerated. This study is limited by its retrospective nature and potential selection bias. Prospective controlled studies are needed. PMID- 21672703 TI - Amyloid beta-related angiitis of the central nervous system: report of 3 cases. AB - OBJECTIVE: Amyloid-beta (Abeta) related angiitis (ABRA) is a recently described clinicopathological entity characterized by cerebrovascular Abeta deposition and arteritis. Cerebral Abeta deposition is commonly present in cerebal amyloid angiopathy (CAA) and Alzheimer's disease (AD) but is rarely associated with inflammatory infiltration of vessel walls. Our objective is to help clarify the clinical spectrum, radiographic findings, response to treatment, and outcomes of ABRA. The neuropathological relationship between ABRA, cerebral amyloid angiopathy, and Alzheimer's disease is discussed. METHODS: We present three cases of ABRA managed at a tertiary care centre. RESULTS: All three patients presented with seizures and cognitive dysfunction; one had multifocal neurologic findings. Brain biopsies revealed inflammatory arteritis with Abeta deposits in the vessel walls. All were treated with steroids and cyclophosphamide. Two had favorable outcomes and one stabilized but with severe residual neurologic disability. CONCLUSIONS: ABRA is an unusual but likely under-recognized and potentially treatable disorder. As in other reported cases, our findings suggest that many patients respond favorably to immunosuppressive therapy. We believe that all biopsy specimens consistent with primary angiitis of the central nervous system (CNS) should be further examined for vascular Abeta deposition. PMID- 21672704 TI - 2-methoxyestradiol attenuates autophagy activation after global ischemia. AB - BACKGROUND: Hypoxia inducible factor 1 (HIF-1) is a key transcriptional factor activated during cerebral ischemia, which regulates a great number of downstream genes, including those associated with cell death. In the present study, we aimed to test the hypothesis that post-ischemic HIF-1alpha up-regulation might promote autophagy activation; thereby, HIF-1alpha inhibitor 2ME2 might prevent neurons from ischemic injury through inhibiting autophagy. METHODS: Global ischemia was induced using the four-vessel occlusion model (4-VO) in Sprague-Dawley rats (male, 250-280g). 2-Methoxyestradiol (2ME2, 5mg/kg, i.p.) was administrated to down-regulate HIF-1alpha expression. Post-ischemic beclin-1 and LC3 protein expression was determined at different time points through Western blot assay. Neuronal injury was determined by cresyl violet staining and TUNEL staining in coronal histological sections. RESULTS: The expression of beclin-1 and the ratio of LC3-II/LC3-I increased significantly at 12 and 24 h after ischemia. 2ME2 could remarkably inhibit the up-regulation of beclin-1 and the increase of LC3-II/LC3-I ratio during reperfusion. Moreover, 2ME2 and 3-MA exhibited powerful protective effects against ischemic/reperfusion induced neuronal injury. CONCLUSIONS: This study confirmed that autophagy participated in post-ischemic neuronal injury. 2ME2, a HIF-1alpha inhibitor, might significantly decrease autophagy activation after cerebral ischemia and relieve post-ischemic neuronal injury. Our findings demonstrate that autophagy could be a potential target for neuronal protection after cerebral ischemia. PMID- 21672706 TI - Low-energy penetrating nail injury through the petrous segment of the ICA. PMID- 21672705 TI - ERK5: a novel IKKalpha-kinase in rat hippocampal neurons. AB - BACKGROUND: Alzheimer's Disease (AD) is characterized in part by the increased presence of neurofibrillary tangles and amyloid beta (Abeta) plaques. Alzheimer's Disease is considered an inflammatory disease and, as such, nuclear factor-kappaB (NFkappaB) plays an important role in the pathophysiology of AD. Insulin acts as a neurotrophic factor. Yet, in the context of insulin resistance, concomitant hyperinsulinemia may contribute to the pathogenesis of AD. METHODS: Rat Primmary Hippocampal Neurons (RPHN) were treated with insulin in the absence and presence of Wortmannin and ERK5 small inhibitory RNA and assayed for downstream effectors of activated ERK5. RESULTS: Here we demonstrate that genetic inhibition of ERK5 blocks insulin stimulated (1) activation and translocation of ERK5 and NFkappaB, (2) phosphorylation of IKKalpha via association with ERK5, (3) increases in Abeta1-40 and Abeta1-42 soluble proteins 3-fold and 2.2-fold, respectively, and (4) increases in tau phosphorylation in RPHN. CONCLUSIONS: ERK5 plays an active role in insulin signaling in neurons and may be a potential therapeutic target for neurodegenerative diseases. PMID- 21672707 TI - A Case Report and Review of Hyperprolactinemia that is not Prolactinoma. PMID- 21672708 TI - Neuroimaging findings in acute intermittent porphyria. PMID- 21672709 TI - Variant Alzheimer disease with spastic paraparesis: a rare presenilin-1 mutation. PMID- 21672712 TI - Erratum. PMID- 21672711 TI - Recurrence of hyperglycemic-induced chorea-ballismus after haloperidol withdrawal. PMID- 21672714 TI - Erratum. PMID- 21672713 TI - Erratum. PMID- 21672715 TI - Erratum. PMID- 21672716 TI - Erratum. PMID- 21672717 TI - Adaptations to life at high elevation: An introduction to the symposium. PMID- 21672718 TI - Are mountain passes higher in the tropics? Janzen's hypothesis revisited. AB - Synopsis In 1967 Daniel Janzen published an influential paper titled "Why Mountain Passes Are Higher in the Tropics." Janzen derived a simple climatic physiological model predicting that tropical mountain passes would be more effective barriers to organismal dispersal than would temperate-zone passes of equivalent altitude. This prediction derived from a recognition that the annual variation in ambient temperature at any site is relatively low in the tropics. Such low variation within sites not only reduces the seasonal overlap in thermal regimes between low- and high-altitude sites, but should also select for organisms with narrow physiological tolerances to temperature. As a result, Janzen predicted that tropical lowland organisms are more likely to encounter a mountain pass as a physiological barrier to dispersal (hence "higher"), which should in turn favor smaller distributions and an increase in species turnover along altitudinal gradients. This synthetic hypothesis has long been at the center of discussions of latitudinal patterns of physiological adaptation and of species diversity. Here we review some of the key assumptions and predictions of Janzen's hypothesis. We find general support for many assumptions and predictions, but call attention to several issues that somewhat ameliorate the generality of Janzen's classic hypothesis. PMID- 21672719 TI - Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. AB - Research on humans at high-altitudes contributes to understanding the processes of human adaptation to the environment and evolution. The unique stress at high altitude is hypobaric hypoxia caused by the fall in barometric pressure with increasing altitude and the consequently fewer oxygen molecules in a breath of air, as compared with sea level. The natural experiment of human colonization of high-altitude plateaus on three continents has resulted in two-perhaps three quantitatively different arterial-oxygen-content phenotypes among indigenous Andean, Tibetan and Ethiopian high-altitude populations. This paper illustrates these contrasting phenotypes by presenting evidence for higher hemoglobin concentration and percent of oxygen saturation of hemoglobin among Andean highlanders as compared with Tibetans at the same altitude and evidence that Ethiopian highlanders do not differ from sea-level in these two traits. Evolutionary processes may have acted differently on the colonizing populations to cause the different patterns of adaptation. Hemoglobin concentration has significant heritability in Andean and Tibetan samples. Oxygen saturation has no heritability in the Andean sample, but does among Tibetans where an autosomal dominant major gene for higher oxygen saturation has been detected. Women estimated with high probability to have high oxygen saturation genotypes have more surviving children than women estimated with high probability to have the low oxygen saturation genotype. These findings suggest the hypothesis that ongoing natural selection is increasing the frequency of the high saturation allele at this major gene locus. PMID- 21672720 TI - Human responses to extreme altitudes. AB - It is a strange coincidence that the highest point on Earth is very close to the limit of human tolerance to hypoxia. The physiological changes that allow humans to reach these extreme altitudes involve enormous alterations of their normal state. It is useful to contrast this response with two others to high altitude. One is acclimatization that allows lowlanders to ascend to altitudes of up to 5000 m and remain there for an indefinite period. The other is evolutionary adaptation which allows highlanders to live continuously over generations at altitudes up to 5000 m. These two responses enable humans to survive for an indefinite period at high altitude. By contrast, the changes that allow ascent to extreme altitudes are not compatible with an extended stay because of a poorly understood process called high-altitude deterioration. The most important physiological response to extreme altitude is extreme hyperventilation which, on the summit of Mt. Everest, drives the alveolar P(CO(2)) down to 7-8 mmHg. This is associated with a marked respiratory alkalosis with an arterial pH exceeding 7.7. Interestingly this alkalosis increases the oxygen affinity of hemoglobin, a response which the successful climber shares with many other animals in oxygen deprived environments. The arterial P(O(2)) on the Everest summit is only about 30 mmHg and falls on exercise because of diffusion limitation of oxygen across the blood-gas barrier. Maximal oxygen consumption on the summit is just over 1 liter.min(-1). Anaerobic metabolism as measured by blood lactate levels is paradoxically reduced at extreme altitudes. PMID- 21672721 TI - Nitrogen and carbon storage in alpine plants. AB - Alpine plants offer unique opportunities to study the processes and economics of nutrient storage. The short alpine growing season forces rapid completion of plant growth cycles, which in turn causes competition between vegetative and reproductive growth sinks during the early part of the growing season. Mobilization of stored nitrogen and carbon reserves facilitates competing sinks and permits successful completion of reproduction before the onset of winter stress. We discuss the theoretical framework for assessing the costs and benefits of nutrient storage in alpine plants in order to lay the foundation for interpretation of observations. A principal point that has emerged from past theoretical treatments is the distinction between reserve storage, defined as storage that occurs with a cost to growth, and resource accumulation, defined as storage that occurs when resource supply exceeds demand, and thus when there is no cost to growth. We then discuss two case studies, one already published and one not yet published, pertaining to the storage and utilization of nitrogen and carbon compounds in alpine plants from Niwot Ridge, Colorado. In the first case, we tested the hypothesis that the seasonal accumulation of amino acids in the rhizome of N-fertilized plants of Bistorta bistortoides provides an advantage to the plant by not imposing a cost to growth at the time of accumulation, but providing a benefit to growth when the accumulated N is remobilized. We show that, as predicted, there is no cost during N accumulation but, not as predicted, there is no benefit to future growth. In the presence of N accumulation, reliance on stored N for growth increases, but reliance on current-season, soil-derived N decreases; thus the utilization of available N in this species is a 'zero sum' process. Inherent meristematic constraints to growth cause negative feedback that limits the utilization of accumulated N and precludes long-term advantages to this form of storage. In the second case study, we discuss new results showing high concentrations of cyclic polyol (cyclitol) compounds in the leaves of many alpine species dominant in the dry fellfield habitat. In Artemisia scopulorum, cyclitols were induced as the growing season progressed, and reached highest concentrations during the dry, late-summer months. Leaf cyclitol concentrations were high in all four species of the Caryophyllaceae that we examined and appeared to be constitutive components of the leaf carbohydrate pool as concentrations were high through the entire growing season. We observed correlations among seedling abundance, seeding survivorship and the presence of high leaf cyclitol concentrations. We propose that the primary function of cyclitols in the leaves of alpine, fellfield herbs is to promote drought tolerance through osmotic protection, and enhance fitness by improving seedling survival. We considered the possibility that cyclitols also function as carbon storage compounds that are remobilized at the end of the growing season and used to support growth the following year. Our observations do not support this hypothesis in the Caryophyllaceae because the requirement for high constitutive concentrations year-after-year prevents long-term advantages of storage and remobilization. However, in A. scopulorum, remobilization of cyclitols following the end of the growing season may provide storage substrates that can be used for growth the following season. From our analysis we conclude that it is difficult to use current theory that is embedded in the economic concept of costs and benefits to interpret observed dynamics in nitrogen and carbon allocation. Future theoretical developments that move away from an abstract foundation embedded in cost-benefit tradeoffs and toward phenotypic integration of source-sink relationships will improve our ability to merge observations and theory. PMID- 21672722 TI - Into thin air: Physiology and evolution of alpine insects. AB - Numerous physical parameters that influence insect physiology vary substantially with altitude, including temperature, air density, and oxygen partial pressure. Here, we review existing literature and present new empirical data to better characterize the high-altitude environment, and then consider how this environment affects the physiology and evolution of insects. Using weather balloon data from fifty-three sites across the globe, we estimate a mean altitudinal temperature lapse rate of 6.0 degrees C/km. We also present empirically determined lapse rates for P(o(2)) and air density. The temperature decline with elevation may substantially compromise insect thermoregulation at high altitude. However, heat-transfer models predict that lower air density at elevation reduces convective heat loss of insects by to a surprisingly large degree. This effect combined with behavioral thermoregulation and the availability of buffered microhabitats make the net thermal consequences of high altitude residence strongly context-specific. The decline in P(o(2)) with elevation may compromise insect development and physiology, but its effects are difficult to predict without simultaneously considering temperature and air density. Flying insects compensate for low air densities with both short-term responses, such as increased stroke amplitude (but not wingbeat frequency), and with long-term developmental and/or evolutionary increases in wing size relative to body size. Finally, in contrast to predictions based on Bergmann's Rule, a literature survey of thirty-six insect species suggests that those living in colder, higher altitudes do not tend to have larger body sizes. PMID- 21672723 TI - The physiology and biomechanics of avian flight at high altitude. AB - Many birds fly at high altitude, either during long-distance flights or by virtue of residence in high-elevation habitats. Among the many environmental features that vary systematically with altitude, five have significant consequences for avian flight performance: ambient wind speeds, air temperature, humidity, oxygen availability, and air density. During migratory flights, birds select flight altitudes that minimize energy expenditure via selection of advantageous tail- and cross-winds. Oxygen partial pressure decreases substantially to as little as 26% of sea-level values for the highest altitudes at which birds migrate, whereas many taxa reside above 3000 meters in hypoxic air. Birds exhibit numerous adaptations in pulmonary, cardiovascular, and muscular systems to alleviate such hypoxia. The systematic decrease in air density with altitude can lead to a benefit for forward flight through reduced drag but imposes an increased aerodynamic demand for hovering by degrading lift production and simultaneously elevating the induced power requirements of flight. This effect has been well studied in the hovering flight of hummingbirds, which occur throughout high elevation habitats in the western hemisphere. Phylogenetically controlled studies have shown that hummingbirds compensate morphologically for such hypodense air through relative increases in wing size, and kinematically via increased stroke amplitude during the wingbeat. Such compensatory mechanisms result in fairly constant power requirements for hovering at different elevations, but decrease the margin of excess power available for other flight behaviors. PMID- 21672724 TI - Diversification of tanagers, a species rich bird group, from lowlands to montane regions of South America. AB - Synopsis The process of diversification since the late Tertiary was studied by linking together well-resolved phylogenies and species distributions for tanagers (Aves, Thraupini). Species richness patterns reveal very high densities of range restricted species in the Andes, and to a lesser extent in the Atlantic forests of south-eastern Brazil, and moderate densities of widespread species in the tropical lowlands. Contemporary climate explains well the variation in species richness for the 25% most widespread species; for the remaining 75% of species with more restricted distributions, variation can only be explained well from topography and landscape complexity. Phylogenetically old species are mainly found along the Andes and along the Rio coast of Brazil. Most other areas outside the Andes probably had very moderate rates of later diversification. In contrast, the humid tropical Andes region was a centre of intensive speciation throughout the evolutionary history of the group, and species richness patterns here seem largely to be driven by the rate of speciation, with further diversification from the highlands into adjacent lowlands. The diversification process in montane areas may be related to high persistence of lineages in specific areas, something that may be related to how climatic changes are moderated by local topography. PMID- 21672725 TI - Patterns of distribution of anurans in high Andean tropical elevations: Insights from integrating biogeography and evolutionary physiology. AB - Among ectothermic tetrapods, amphibians are by far the most diverse group at high elevations in the tropical Andes. This article asks whether this pattern reflects intrinsic aspects of amphibian natural history. An interdisciplinary analysis suggests that amphibians have a long evolutionary history at moderate Andean elevations and that adaptation for activity at low temperature occurred frequently and independently in different taxa. One conclusion is that temperature is unlikely to be the only or the main factor constraining some unrepresented anuran taxa that do not reach high elevations. Other physical variables (e.g. the effects of ultraviolet radiation on egg development) could better explain anuran diversity along tropical altitudinal gradients. In contrast, heliothermic taxa, such as lizards, might indeed be constrained by the low and variable temperatures that characterize high tropical elevations. Ecological gradients, therefore, might not affect ectothermic tetrapods in a similar manner, and differential susceptibility to biotic and abiotic factors that change with elevation might help to explain current patterns of distribution and diversity. PMID- 21672726 TI - Challenging received wisdoms: Some contributions of the new microscopy to the new animal phylogeny. AB - Inspired by the emerging new view of animal phylogeny, recent comparative morphological studies have applied the range of available new and established microscopical techniques to shed new light on many received wisdoms about animal evolution. Here I review some illustrative recent work of the participants in the symposium "The New Microscopy: Toward a Phylogenetic Synthesis" held at the annual Society for Integrative and Comparative Biology meeting in San Diego in January 2005. I will discuss 6 case studies. Of these, 3 have generated new morphological insights that are significantly at odds with received wisdom about high-level animal phylogeny but congruent with emerging molecular phylogenies. These examples examine the value of characteristics of arthropod neurogenesis in supporting a controversial new hypothesis of high-level arthropod phylogeny, the insights into annelid phylogeny provided by studies on central nervous system development in clitellates, and how new data on the source of mesoderm in phoronids corroborates their placement in the Lophotrochozoa. The remaining 3 case studies shed new light particularly on the evolution of important innovations that are at the base of successful clades. The examples deal with the evolution of torsion as a major synapomorphy of the gastropods, illustrate how the origin of gastrulation could be studied in sponges, and show that trochophore larvae may characterize a larger clade of spiralians than hitherto suspected. PMID- 21672727 TI - Embryogenesis in the glass sponge Oopsacas minuta: Formation of syncytia by fusion of blastomeres. AB - Sponges (Porifera) are unusual animals whose body plans make interpreting phylogenetic relationships within the group and with other basal metazoan taxa a difficult task. Although molecular approaches have offered new insights, some questions require a morphological approach using detailed ultrastructural or light microscopical studies of developing embryos and larvae. Glass sponges (Hexactinellida) have perhaps the most unusual body plan within the Metazoa because the majority of the tissue of the adult consists of a single giant multinucleated syncytium that forms the inner and outer layers of the sponge and is joined by cytoplasmic bridges to uninucleate cellular regions. Here we have used serial section transmission and high-resolution scanning electron microscopy to examine when syncytia first form in the cave-dwelling glass sponge Oopsacas minuta. We confirm that in O. minuta blastomeres are separate until the 32-cell stage; cleavage is equal but asynchronous until a hollow blastula is formed. The sixth division yields a collection of variously sized micromeres at the surface of the embryo and large yolk- and lipid-filled macromeres lining the blastocoel. Syncytia then form by the fusion of micromeres to form cytoplasmic bridges with each other and the fusion of macromeres to form the future multinucleated trabecular tissue of the larva and adult sponge. The multinucleated trabecular tissue envelops and forms cytoplasmic bridges with all uninucleate cells, covering the developing larva with a continuous syncytial epithelium. Differentiation of tissues occurs very early during embryogenesis with the separation of uninucleate and multinucleate lineages, but all cells and syncytia are joined by cytoplasmic bridges such that there is cytoplasmic continuity throughout the entire larva. Although glass sponges begin life as a cellular embryo, the unusual mechanism of syncytia formation at such an early stage in development distinguishes this group of animals from their closest multicellular relatives, the Demospongiae. Most important, however, these data lend support to the hypothesis that the original metazoans were cellular, not syncytial. PMID- 21672728 TI - Concordance of molecular and morphological data: The example of the Acoela. AB - Morphological features of the Acoela appear to be quite plastic, including those of the copulatory organs, which provide the principle characteristics used for the systematics of this group. Consequently, classification schemes of the Acoela comprise numerous polyphyletic groupings. In this review, we detail recent revisions of acoel systematics using molecular sequence data and new and reevaluated morphological characteristics. Gene trees are discordant with traditional systematic schemes but strongly concordant with new morphological characteristics obtained through the use of transmission electron microscopy and confocal laser scanning microscopy, namely, characteristics of body-wall and copulatory organ musculature, sperm, sperm ducts, sagittocysts, and immunocytochemistry of the nervous system. This merger of molecular and morphological data has led to significant changes in acoel classification, including a major emendation of the largest family of the Acoela, the Convolutidae, whereby half of its members were transferred to a newly created family, the Isodiametridae. PMID- 21672729 TI - Polychaete nervous systems: Ground pattern and variations--cLS microscopy and the importance of novel characteristics in phylogenetic analysis. AB - In Annelida, as well as in other invertebrate taxa, the nervous system is considered to be a very conservative organ system. Immunohistochemical investigations [use of anti-5-HT (serotonin), FMRFamide, and acetylated alpha tubulin antibodies] in combination with laser scanning microscopy enable more detailed reanalyses of known structures and detection of new characteristics that are useful for phylogenetic analyses. One hypothesis enabled by such studies is outlined for the evolution of arrangements of the dorsal circumesophageal roots in polychaetes and oligochaetes. These roots are not a unique feature of polychaetes; they also occur in oligochaetes. According to the Articulata hypothesis of metazoan relationships, the specific structure of the rope-ladder like nervous system is, among others, an autapomorphic characteristic that unifies Annelida and Arthropoda. Recent studies applying the techniques mentioned here, however, demonstrate that the annelidan bauchmark (central nervous system of the trunk), in contrast to the arthropod pattern, is highly variable in terms of the number and position of connectives and the number of commissures per segment. The variability of the neuronal architecture as well as a hypothesis on how it evolved will be introduced with the aid of regeneration and developmental studies. Furthermore, it is shown that hitherto unknown nerves are present in the peripheral nervous system. PMID- 21672730 TI - Modern insights on gastropod development: Reevaluation of the evolution of a novel body plan. AB - More than a century of speculation about the evolutionary origin of the contorted gastropod body plan has been inspired by adult anatomy and by long-standing developmental observations. The result has been a concept of gastropod torsion that I call the "rotation hypothesis." Under the rotation hypothesis, gastropods originated when all components of the visceropallium (shell, mantle, mantle cavity with contained structures, and viscera) rotated by 180 degrees relative to the head and foot. This evolutionary rotation is echoed during early development of patellogastropods and vetigastropods and occurs to some extent during development of more derived clades. However, comparative developmental data on ontogenetic torsion are minimal and I argue that the rotation hypothesis is a tautological argument. More recent studies on representatives from 3 major clades of gastropods suggest that the highly conserved aspect of gastropod development is not synchronous rotation of all components of the visceropallium relative to the head and foot but rather a state of anatomical organization in which the developing mantle cavity is on the right but the shell coil is posterior (endogastric orientation). This conserved state of developmental anatomy has inspired an alternative hypothesis for the evolutionary origin of the gastropod body plan, the "asymmetry hypothesis." Under the asymmetry hypothesis, the gastropod mantle cavity originated from 1 side only of a bilateral set of mantle cavities. The asymmetry hypothesis does not require a saltation event to explain the origin of gastropods, nor does it require that the ancient molluscan precursor of gastropods carried the shell coil over the head (exogastric orientation). PMID- 21672731 TI - Postembryonic development of dorsoventral and longitudinal musculature in Pycnophyes kielensis (Kinorhyncha, Homalorhagida). AB - We investigated the development of dorsoventral and longitudinal musculature in all postembryonic stages of the kinorhynch Pycnophyes kielensis. Although the earliest stages have only 8 externally separated trunk segments, they already possess dorsoventral muscles for 10 (prospective) trunk segments. The last, 11th, pair is added in the third juvenile stage. Longitudinal musculature, in contrast, is slower to develop and reaches its full length only in the adult. In several juvenile individuals, single fibers project from the longitudinal musculature into the following segments. In all juvenile stages, longitudinal muscles are continuous between segments, whereas in adults they are segmentally separated from each other. Such late occurrence of a segmental pattern in the longitudinal musculature is in contrast to patterns of muscle development in arthropods and annelids. PMID- 21672732 TI - What a couple of dimensions can do for you: Comparative developmental studies using 4D microscopy--examples from tardigrade development. AB - The development of an organism consists of processes occurring in space and time. To analyze this 4-dimensional development in embryogenesis, an appropriate method should be chosen. We present here a sophisticated method, 4D microscopy (3D time lapse microscopy), initially developed to analyze the cell lineage of wild-type and mutant embryos of the nematode Caenorhabditis elegans. Our method records the entire development of an embryo and allows detailed analyses of events such as cleavage, cell migration, cell death (apoptosis), and cell differentiation during development. The 4D microscopy system has 3 main parts: a motorized microscope, trigger software, and a database that facilitates the analysis of recordings. Adopting the 4D microscopy technique for uses beyond the analysis of C. elegans makes it possible to discern the cell lineage of other small embryos. Our method fills a gap in the study of the development of diverse organisms that are impossible to observe with fluorescent labeling techniques using single blastomeres. The use of this technique to investigate the development of organisms such as tardigrades, acoelomorphs, rotifers, and gastrotrichs provides fresh insight into the evolution of developmental processes and the phylogenetic relationships between such taxa. Using tardigrade development as an example, we demonstrate that the use of 4D microscopy can reveal new characters and corroborate or disapprove old characters. We discuss the results in the light of recent phylogenetic hypotheses regarding the Arthropoda and their probable sister group, the Cycloneuralia, which together form the Ecdysozoa. PMID- 21672733 TI - Neurophylogeny: Architecture of the nervous system and a fresh view on arthropod phyologeny. AB - The phylogenetic relationships within the Arthropoda have been controversial for more than a century. Today, comparative studies on the structure and development of the nervous system contribute important arguments to this discussion, so that the term "neurophylogeny" was coined for this discipline. The large number of recent studies on the nervous system in various nonmodel arthropods indicates that we are far advanced in the process of analyzing the cellular architecture of the arthropod nervous system in a depth that will ultimately provide characters at a level of resolution equal or even superior to that of characters traditionally used in morphological phylogenetic studies. This article sets out to summarize the current state of the discussion on arthropod phylogeny and briefly evaluates the morphological characters that have been used as arguments in favor of the traditional Tracheata hypothesis. Then, a thorough overview is given of characters derived from structure and development of the arthropod brain and the ventral nerve cord from the cellular level to the level of larger neuropil systems. These characters support the new Tetraconata hypothesis suggested by Dohle and provide evidence for a clade that unites malacostracan and remipede crustaceans with the Hexapoda. PMID- 21672734 TI - Neurogenesis in myriapods and chelicerates and its importance for understanding arthropod relationships. AB - Several alternative hypotheses on the relationships between the major arthropod groups are still being discussed. We reexamine here the chelicerate/myriapod relationship by comparing previously published morphological data on neurogenesis in the euarthropod groups and presenting data on an additional myriapod (Strigamia maritima). Although there are differences in the formation of neural precursors, most euarthropod species analyzed generate about 30 single neural precursors (insects/crustaceans) or precursor groups (chelicerates/myriapods) per hemisegment that are arranged in a regular pattern. The genetic network involved in recruitment and specification of neural precursors seems to be conserved among euarthropods. Furthermore, we show here that neural precursor identity seems to be achieved in a similar way. Besides these conserved features we found 2 characters that distinguish insects/crustaceans from myriapods/chelicerates. First, in insects and crustaceans the neuroectoderm gives rise to epidermal and neural cells, whereas in chelicerates and myriapods the central area of the neuroectoderm exclusively generates neural cells. Second, neural cells arise by stem-cell-like divisions of neuroblasts in insects and crustaceans, whereas groups of mainly postmitotic neural precursors are recruited for the neural fate in chelicerates and myriapods. We discuss whether these characteristics represent a sympleisiomorphy of myriapods and chelicerates that has been lost in the more derived Pancrustacea or whether these characteristics are a synapomorphy of myriapods and chelicerates, providing the first morphological support for the Myriochelata group. PMID- 21672735 TI - Novel methodology utilizing confocal laser scanning microscopy for systematic analysis in arthropods (Insecta). AB - The use of confocal laser scanning microscopy (CLSM) for imaging arthropod structures has the potential to profoundly impact the systematics of this group. Three-dimensional visualization of CLSM data provides high-fidelity, detailed images of minuscule structures unobtainable by traditional methods (for example, hand illustration, bright-field light microscopy, scanning electron microscopy). A CLSM data set consists of a stack of 2-D images ("optical slices") collected from a transparent, fluorescent specimen of suitable thickness. Small arthropod structures are particularly well suited for CLSM imaging owing to the autofluorescent nature of their tissues. Here, we document the practical aspects of a methodology developed for obtaining image stacks via CLSM from autofluorescent insect cuticular structures. PMID- 21672736 TI - Legacies in life histories. AB - Complex life-histories are common in nature, have many important biological consequences, and are an important focal area for integrative biology. For organisms with complex life-histories, a legacy is something handed down from an ancestor or previous stage, and can be genetic, nutritional/provisional, experiential, as well as the result of random chance and natural variation in the environment. As we learn more about complex life-histories, it becomes clear that legacies are inexorably linked in the short- and long-term through ecology and evolution. Understanding the consequences and drivers of life-history patterns can therefore only be understood by considering all types of legacies and integrating legacies across the entire life cycle. Larry McEdward was a leader in the field of ecological physiology, and evolutionary ecology of marine invertebrate larvae with complex life-histories. Through his scientific work and publications, devotion to students, colleagues, family, and friends, Larry has left a lasting legacy that will impact the future development of the field of larval ecology and complex life-histories. PMID- 21672737 TI - Estimation and interpretation of egg provisioning in marine invertebrates. AB - Per-offspring maternal investment is an integral part of life-history theory. To understand the evolution of per-offspring maternal investment in marine invertebrates, a number of mathematical models have been developed. These models examine how selection affects the proportion of maternally derived egg energy used to produce a newly metamorphosed juvenile (s) and make predictions about the distribution of s in nature. However, there are very few published values of s and therefore it is difficult to evaluate how well these models match nature. We present several equations to empirically estimate values of s for any group of marine invertebrate, and use data from echinoderms to compare the different equations. The calculations that directly estimate s require information on the amount of egg energy, juvenile energy, and energy metabolized during development. Currently, there are few data available for directly estimating s, and thus generating distributions of s derived from direct estimates is not possible. Furthermore, the direct estimations of s are informative for planktotrophy but not for lecithotrophy. We have developed an equation that can be used to directly estimate s for lecithotrophs. The calculations to indirectly estimate s only require egg energy or egg size for the species in question and the value of s and egg energy or size for a reference species. This reference species replaces the need to measure juvenile energy and energy metabolized during larval development. Because egg energy or size is currently available for many species, the indirect estimates will be useful for generating distributions of s, and will allow comparisons with models. Although these indirect methods are good for generating distributions of s, they do not provide reliable estimates of s for any particular species. Estimating values of s to compare models is a critical gap in our current evaluations of marine invertebrate life-history models. PMID- 21672738 TI - The evolution of embryonic gene expression in sea urchins. AB - Many evolutionary modifications in development and life history derive from changes in embryonic gene expression. However, the genetic variation affecting gene expression in natural populations is not well understood, nor are the evolutionary mechanisms that operate on that variation. The early embryonic gene network of the purple sea urchin (Strongylocentrotus purpuratus) has been studied in considerable detail, providing an informative basis for analyzing the developmental and evolutionary mechanisms that alter gene expression. Comparative functional analyses have been carried out for several genes. These case studies indicate a complex relationship between sequence divergence and gene expression: in some cases, gene expression is conserved despite extensive divergence in cis regulatory sequences, while in others the basis for a change in gene expression does not reside locally but rather in the expression or activity of transcription factors that regulate its expression. Diverse evolutionary mechanisms apparently operate on cis-regulatory regions, including negative, balancing, and stabilizing selection. PMID- 21672739 TI - Life history diversity and evolution in the Asterinidae. AB - Asterinid sea stars have the greatest range of life histories known for the Asteroidea. Larval form in these sea stars has been modified in association with selection for planktonic, benthic, or intergonadal developmental habitats. Life history data are available for 31 species and molecular data for 28 of these. These data were used to assess life history evolution and relationships among asterinid clades. Lecithotrophy is prevalent in Asterinidae, with at least 6 independent origins of this developmental mode. Morphological differences in the attachment complex of brachiolaria larvae were evident among species with planktonic lecithotrophy. Some features are clade specific while others are variable within clades. Benthic brachiolariae are similar in Aquilonastra and Parvulastra with tripod-shaped larvae, while the bilobed sole-shaped larvae of Asterina species appear unique to this genus. Multiple transitions and pathways have been involved in the evolution of lecithotropy in the Asterinidae. Although several genera have a species with a planktonic feeding larva in a basal phylogenetic position, relative to species with planktonic or benthic lecithotrophy, there is little evidence for the expected life history transformation series from planktonic feeding, to planktonic non-feeding, to benthic non-feeding development. Intragonadal development, a life history pattern unique to the Asterinidae, arose three times through ancestors with benthic or pelagic lecithotrophy. Evolution of lecithotrophy appears more prevalent in the Asterinidae than other asteroid families. As diverse modes of development are discerned in cryptic species complexes, new insights into life history evolution in the Asterinidae are being generated. PMID- 21672740 TI - Coloniality has evolved once in Stolidobranch Ascidians. AB - Ascidians exhibit a rich array of body plans and life history strategies. Colonial species typically consist of zooids embedded in a common test and brood large, fully developed larvae, while solitary species live singly and usually free-spawn eggs that develop into small, undifferentiated larvae. Ascidians in the order Stolidobranchia include both colonial and solitary species, as well as several species with intermediate morphologies. These include social species, which are colonial but do not live completely embedded in a common test, and a few solitary species that brood embryos and larvae until they are competent to metamorphose. We examined how many times coloniality has evolved within the Stolidobranchia, with phylogenetic analyses using full-length 18S rDNA and partial cytochrome oxidase B sequences for taxa in the families Molgulidae, Styelidae, and Pyuridae. Tunicata orders Phlebobranchia and Stolidobranchia are sister groups, and the family Molgulidae is a monophyletic group and should be raised to the subordinal level, as shown previously by analyses from this lab with partial 18S sequences. In contrast to previous studies, styelids and pyurids are separated into monophyletic groups by ML and Bayesian analyses. We show a single clade within the family Styelidae that contains two colonial (compound) botryllid species, a Symplegma (colonial compound), a colonial (social) species Metandrocarpa taylori, as well as four solitary species, thus confirming that the botryllids are a subfamily of the Styelidae. These results suggest that the ancestor of the Stolidobranchia was solitary and that coloniality has evolved only once within this clade of ascidians. Further phylogenetic analyses of aplousobranch and phlebobranch ascidians will be necessary to understand the number of times that coloniality has evolved within the class Ascidiacea. PMID- 21672741 TI - Dispersal and divergence across the greatest ocean region: Do larvae matter? AB - For marine, benthic animals, duration of planktonic larval stages is expected to correlate with dispersal ability, and thus species ranges, at least where planktonic dispersal is necessary to reach habitats. Yet past analyses of larval duration and species ranges across the insular Pacific show at most a weak correlation. So, do larvae matter in determining species ranges in such an island setting? We analyze an extensive dataset on cowries and find, again, that estimated larval duration does not correlate with species ranges. Several factors can obscure a real correlation, however, including estimation error, intraspecific variation, other factors affecting dispersal, poor taxonomy, and remote endemics. We show that taking these into consideration greatly improves correlation. Further evidence for the importance of larval duration comes from diversity and speciation patterns. Diversity of poor dispersers drops more rapidly eastward across the Pacific and leads to taxonomic differences in community composition across the basin. Geographic scale of differentiation is strongly influenced by larval duration and leads to the most rapid diversification at intermediate dispersal capacities. A major lesson from the phylogenetically corrected cowrie dataset is that without accurate and appropriate taxonomy, clear and important distributional and diversity patterns can become obscured. Inappropriate taxonomic scale can also obscure macroecological patterns: cowrie tribes/subfamilies show substantial variation in the steepness of their diversity cline across the Pacific and in their proportional local abundance, showing the importance of ecological traits in controlling distributions. In contrast such variation was not evident in a study focused at the family level in corals and fishes. PMID- 21672742 TI - Recent progress in understanding larval dispersal: new directions and digressions. AB - Larvae have been difficult to study because their small size limits our ability to understand their behavior and the conditions they experience. Questions about larval transport focus largely on (a) where they go [dispersal] and (b) where they come from [connectivity]. Mechanisms of transport have been intensively studied in recent decades. As our ability to identify larval sources develops, the consequences of connectivity are garnering more consideration. Attention to transport and connectivity issues has increased dramatically in the past decade, fueled by changing motivations that now include management of fisheries resources, understanding of the spread of invasive species, conservation through the design of marine reserves, and prediction of climate-change effects. Current progress involves both technological advances and the integration of disciplines and approaches. This review focuses on insights gained from physical modeling, chemical tracking, and genetic approaches. I consider how new findings are motivating paradigm shifts concerning (1) life-history consequences; (2) the openness of marine populations, self-recruitment, and population connectivity; (3) the role of behavior; and (4) the significance of variability in space and time. A challenge for the future will be to integrate methods that address dispersal on short (intragenerational) timescales such as elemental fingerprinting and numerical simulations with those that reflect longer timescales such as gene flow estimates and demographic modeling. Recognition and treatment of the continuum between ecological and evolutionary timescales will be necessary to advance the mechanistic understanding of larval and population dynamics. PMID- 21672743 TI - The relationship between egg size and fertilization success in broadcast-spawning marine invertebrates. AB - Egg size is a critical life-history trait because it can profoundly influence offspring fitness and the number of offspring that can be produced. Recently, interest has grown in how egg size influences fertilization rate and in turn how sperm availability might influence the evolution of egg size among broadcast spawning marine invertebrates. In this article I review the empirical evidence on the ways in which egg size and egg accessory structures influence fertilization and theoretical models of the ways sperm availability might influence the evolution of egg size. Evidence suggests that egg size does influence the collision frequency with sperm, and models suggest that sperm availability can influence selection on egg size. Sperm availability appears to be one of the several factors that influence optimal egg size in broadcast-spawning marine invertebrates. PMID- 21672744 TI - Good eaters, poor swimmers: compromises in larval form. AB - Compromises between swimming and feeding affect larval form and behavior. Two hypotheses, with supporting examples, illustrate these feeding-swimming trade offs. (1) Extension of ciliated bands into long loops increases maximum clearance rates in feeding but can decrease stability of swimming in shear flows. A hydromechanical model of swimming by ciliated bands on arms indicates that morphologies with high performance in swimming speed and weight-carrying ability in still water differ from morphologies conferring high stability to external disturbances such as shear flows. Instability includes movement across flow lines from upwelling to downwelling water in vertical shear. Thus a hypothesis for the high arm elevation angles of sea urchin larvae, which reduce speed in still water, is that they reduce a downward bias imposed by the vertical shear in turbulence. Observations of sea urchin larvae in vertical shear and comparisons among brittle star larvae are consistent with the performance trade-offs predicted by the model. (2) Structures and behaviors that reduce swimming speed can enhance filtering for feeding. In the opposed-band feeding mechanisms of veligers and many trochophores, cilia push water to swim but movement of cilia relative to the water occurs when cilia overtake and capture particles. Features that may increase clearance rates at the expense of speed and weight capacity include structures that increase drag or body weight and a ciliary band that beats in opposition to the feeding-swimming current. Larval feeding mechanisms inherited from distant ancestors result in different swimming-feeding trade-offs. The different trade-offs further diversify larval form and behavior. PMID- 21672745 TI - Larval experience and latent effects--metamorphosis is not a new beginning. AB - For many years ecologists have documented the remarkable within-species variation inherent in natural systems-for example, variability in juvenile growth rates, mortality rates, fecundities, time to reproductive maturity, the outcomes of competitive interactions, and tolerance to pollutants. Over the past 20 years, it has become increasingly apparent that at least some of this variation may reflect differences in embryonic or larval experiences. Such experiences may include delayed metamorphosis, short term starvation, short term salinity stress, or exposure to sublethal concentrations of pollutants or sublethal levels of ultra violet irradiation. Latent effects-effects that have their origins in early development but that are first exhibited in juveniles or adults-have now been documented among gastropods, bivalves, echinoderms, polychaetes, crustaceans, bryozoans, urochordates, and vertebrates. The extent to which latent effects alter ecological outcomes in natural populations in the field, and the mechanisms through which they are mediated are largely unexplored. PMID- 21672746 TI - Linking stages of life history: How larval quality translates into juvenile performance for an intertidal barnacle (Balanus glandula). AB - Many marine invertebrates with complex life cycles produce planktonic larvae that experience environmental conditions different from those encountered by adults. Factors such as temperature and food, known to impact the larval period, can also affect larval size and consequently the size of newly settled juveniles. After documenting natural variation in the size of cyprids (the final larval stage) of the barnacle Balanus glandula, we experimentally manipulated temperature and food given to larvae to produce cyprids of differing sizes but within the size range of cyprids found in the field. In a set of trials in which larvae of B. glandula were raised on full or reduced rations in the laboratory and subsequently outplanted into the field as newly metamorphosed juveniles, we explored the effects of larval nutrition and size on juvenile performance. Larvae that received full rations throughout their feeding period produced larger cyprids (with more lipid and protein). These larger cyprids grew faster as juveniles and sometimes survived better in the field than juveniles from larvae that had their food ration reduced in the last feeding instar. For naturally settling barnacles brought into the laboratory within 2 days of settlement and fed, we found that initial juvenile size was a good predictor of juvenile size even after 2 weeks of growth. By manipulating food given to juveniles that were derived from larvae fed either full or reduced rations, we found that larval nutritional effects persisted in juveniles for 2-3 times the period that larvae experienced altered food rations. PMID- 21672747 TI - Sexual selection: lessons from hermaphrodite mating systems. AB - Over the last 130 years, research has established that (a) sexual selection exists and is widespread in the plant and animal kingdoms; (b) it does not necessarily entail sexual dimorphism; even hermaphrodites have it; (c) it does not require intelligence or a sophisticated sense of esthetics; even tapeworms and plants choose mates; and (d) it does not require brawn or even mobility for competition; plants may compete for pollinators, and broadcast spawning invertebrates may also compete for matings. Although discussions of sexual selection often focus on sexual dimorphism, several phenomena that are commonly associated with sexual selection are widespread and highly developed in hermaphrodites. These phenomena include (a) bizarre and expensive courtship and copulatory behavior, (b) multiple mating and sperm competition, (c) rapid evolution of genitalia, (d) special structures associated with courtship, and (e) sexual polymorphism. The skewed breeding sex ratios associated with sequential hermaphroditism have long been recognized as contributory to sexual selection. In many simultaneous hermaphrodites, although the sex ratio at mating may be one to one, the actual reproductive sex ratio may also be skewed, creating a high potential for sexual selection. Reproductive biology in hermaphroditic taxa also involves a lot of complexity unknown in dioecious taxa, such as sex change, facultative sex allocation and conditional reciprocity that offers opportunities to enrich our understanding of sexual selection and to test the assumptions and predictions of theory. PMID- 21672748 TI - Sexual selection in hermaphrodites: where did our ideas come from? AB - Interpretations of hermaphroditism have been influenced by the old idea that organisms can be arranged in a series from lower to higher, with human beings at the top, leading toward the angels and God (the scala naturae). The consequent notion that hermaphroditism is a primitive condition is still with us. Such issues need to be addressed empirically, in a phylogenetic context. Darwin's theory of sexual selection provided the key to understanding sex switches, but it was not invoked until 1969 when it was conjoined with ideas about relative size influenced by the work of Bernhard Rensch. In principle the problem could have been solved a century earlier, and genetics was misleading rather than helpful. What really helped was an appreciation of Darwin's nonteleological way of thinking. PMID- 21672749 TI - Fitness consequences of selfing and outcrossing in the cestode Schistocephalus solidus. AB - Mixed-mating, that is reproduction by both self-fertilization and cross fertilization is common in hermaphroditic parasites. Its maintenance poses, however, a problem for evolutionary biology. The tapeworm Schistocephalus solidus Muller 1776, served as a model to study experimentally the consequences of selfing and outcrossing in its 2 consecutive intermediate hosts, a copepod (Macrocyclops albidus Jurine) and the three-spined stickleback fish (Gasterosteus aculeatus). Size-matched tapeworms were allowed to reproduce either alone or in pairs in an in vitro system that replaced the definitive bird host's gut. Selfed eggs from singletons had a 4 times lower hatching success than outcrossed eggs from pairs. Outcrossed offspring achieved both a higher infection success and a higher weight in the copepod, and a higher number of parasites per host in both intermediate hosts, but only under competition. Outcrossed offspring were generally more successful. If a S. solidus plerocercoid has a partner in the bird's gut, they should outcross unless they differ in size and thus cannot solve the Hermaphrodite's Dilemma cooperatively. Using microsatellite markers, the proportion of selfed offspring and the total reproductive output of each worm within pairs varying in mean weight and in weight difference was measured. Worms produced more selfed offspring not only with increasing weight difference as expected but also with decreasing total weight of the pair. If small worms were selfed, they have already purged deleterious mutations and would thus be better selfers in a year with low parasite density when worms cannot find partners. To maintain this advantage they should self a higher proportion of their eggs even with a partner. Here I review recent exprimental evidence. PMID- 21672750 TI - Life history and sex allocation in the simultaneously hermaphroditic polychaete worm Ophryotrocha diadema: the role of sperm competition. AB - Sex allocation theory predicts that, in hermaphroditic organisms, individuals allocate a fixed amount of resources divided among male and female functions to reproduction and that the proportion devoted to each sex depends on the mating group size. As the mating group size increases, hermaphrodites are predicted to allocate proportionally more resources to the male and less resources to the female function (approaching equal allocation to both sexes) to face increased sperm competition. Up to now little experimental evidence has been provided to support the theory in hermaphroditic animals. Facultative shift between male and female allocation in response to variation in local group size does occur in several taxa but not always in the expected direction and not with similar patterns. In the protandric and then simultaneously hermaphroditic polychaete worm Ophryotrocha diadema reproductive resources are flexibly allocated in the protandrous and the hermaphroditic phase. The cost of male reproduction during adolescence is spread over the whole energy budget of the animal as shown by the shortening of lifespan and the lowering of growth rate in individuals with enhanced male expenditure during the protandrous phase. Moreover, in this species, short term sex allocation adjustments differ from those described in other taxa. Individuals regulate their reproductive output so that where reproductive competitors are present, the number of female gametes is strongly reduced but the number of male gametes (although it changes) is not significantly increased. Resources subtracted from the female function are not directly allocated to sperm production, but to expensive male behaviors that are likely to enhance male reproductive success. These results are discussed in the light of the relevance of sexual selection in large populations of hermaphrodites. PMID- 21672751 TI - Tactics for male reproductive success in plants: contrasting insights of sex allocation theory and pollen presentation theory. AB - The basic tenet of sex allocation theory is that an organism's reproductive success, through either male or female function, can be represented as a sex specific, monotonic, increasing function of the organism's investment of resources in that function. The shapes of these curves determine what patterns of resource allocation can be evolutionarily stable. Although SA theory has stimulated creative thinking about plant sexual tactics, quantifying the shapes of male and female gain curves has proven so difficult that other approaches must be considered. I contrast sex allocation theory to a different, emerging viewpoint, pollen presentation theory (PPT), which attempts to address variation in reproductive success by measuring and modeling the quantitative fates of pollen grains. Models suggest that RS through male function depends heavily on the packaging and gradual dispensing of pollen to pollinators, even with the amount of investment held constant. Many plants do deploy pollen gradually, through morphological and "behavioral" mechanisms that range from obvious to subtle. They may thereby influence many aspects of the evolution of sexual modes in plants, including transitions between dioecy and cosexuality. After reviewing the main implications of the models, I discuss recent work aimed at testing some key assumptions and predictions by functional and comparative studies in the genus Penstemon. Species of Penstemon conform to PPT predictions that bee-adapted flowers will restrict per-visit pollen availability more than hummingbird-adapted flowers. PMID- 21672752 TI - The third way: spermcast mating in sessile marine invertebrates. AB - Marine invertebrates belonging to a broad range of taxa disperse aquatic spermatozoa to fertilize eggs that are retained rather than spawned. We outline the occurrence of this mechanism, which we refer to as spermcast mating, and identify tentative generalizations relating to it. Contrasts are drawn where appropriate with broadcast spawning of both eggs and sperm for external fertilization, and with copulation or pseudocopulation. Spermcast mating may involve the gradual accumulation of long-lived spermatozoa from dilute suspension, probably during suspension feeding, and the subsequent storage of spermatozoa by the recipient (acting female) prior to fertilization. This process may involve extensive contact between spermatozoa and recipient (maternal) tissue. Mating may be influenced by compatibility systems, and receipt of compatible allosperm may trigger female investment, giving apparent scope for sexual conflict over levels of maternal investment. External fertilization of cohesive egg masses remaining close to the acting female may appear somewhat intermediate between spermcast mating and broadcast spawning but, while it may be possible to envisage a continuum between the 2 modes, the end points are distinct, commonplace, and involve contrasting reproductive characteristics. Three variants of the typical pattern of spermcast mating are briefly discussed: the spawning of zygotes (rather than the more usual brooding of progeny), polyembryony, and the dispersal of spermatophores rather than individual spermatozoa. PMID- 21672753 TI - Mate choice, frequency dependence, and the maintenance of resistance to parasitism in a simultaneous hermaphrodite. AB - Biomphalaria glabrata are simultaneous hermaphroditic freshwater snails that act as intermediate hosts for the macroparasitic trematode Schistosoma mansoni, a causative agent of schistosomiasis. Heritability and strain-specificity of both snail resistance and susceptibility to schistosome infection have been demonstrated, genetic variability for which is maintained, in part, through trade offs between high fitness costs associated with infection and those associated with resistance. However, despite such a high cost of resistance and a low prevalence of infection in natural snail populations, genes for resistance are maintained within snail populations over successive generations, including in the complete absence of parasite pressure in laboratory populations. This may be indicative of alternative benefits of resistance genes, in addition to parasite defense, such as differential mating success between genotypes. Here we examined the mate and gender choice of snails across a multi-factorial range of potential partner combinations. These included host-resistance or susceptibility genotype, host genotype frequency within the population, current parasite infection status, and parasite genotype. We demonstrate recognition and discrimination by host snails depending on host and/or parasite genotype for each of these factors. In particular, our results suggest that a rare mating advantage to resistant genotypes may be a potential explanation for the maintenance of highly costly resistance genes within intermediate host populations under conditions of low or zero parasite pressure. PMID- 21672754 TI - Tales of two snails: sexual selection and sexual conflict in Lymnaea stagnalis and Helix aspersa. AB - Sexual selection and sexual conflict have been shown to play key roles in the evolution of species with separate sexes. Experimental evidence is accumulating that this is also true for simultaneous hermaphrodites. For example, many species of land snails forcefully stab their mating partners with love darts. In the brown garden snail (Helix aspersa, now called Cantareus asperses), this dart increases sperm storage and paternity, probably via the transfer of an allohormone that inhibits sperm digestion. A recent interspecies comparison of dart-possessing land snails revealed coevolution between darts and spermatophore receiving organs that is consistent with counteradaptation against an allohormonal manipulation. The great pond snail (Lymnaea stagnalis) seems to use a seminal product to manipulate its partner and mates in the male role when enough seminal fluid is available in the prostate gland. Receipt of semen not only initiates egg laying in virgin animals, but also feminizes the mating partner later in life. These increases in the female function have been shown to go at the expense of growth and seminal fluid production of the sperm recipient. Although in Helix, and probably also Lymnaea, the sperm donor benefits from the induced changes through increased fertilization success, the sperm recipient may experience injury, imposed reallocation of resources, and altered sperm storage. These findings support the existence of sexual conflict in simultaneously hermaphroditic snails, and its importance for the evolution of mating behaviors and reproductive morphologies is discussed. PMID- 21672755 TI - Same sexual system but variable sociobiology: evolution of protandric simultaneous hermaphroditism in Lysmata shrimps. AB - The sexual system of the decapod (caridean) shrimp Lysmata is protandric simultaneous hermaphroditism (PSH). Individuals first mature as males (male phase = MP) and then when older (larger) change to the external phenotype of female carideans (female phase = FP). However, unlike purely protandric carideans, Lysmata FPs retain reduced male gonadal tissues and ducts, and are able to mate nonreciprocally as males as well as to reproduce as females. Thus, FPs of Lysmata species are functional simultaneous hermaphrodites although most reproductive effort is devoted to embryo production and incubation. The question explored here is, given the propensity of carideans to protandry, the apparent low cost, and high reproductive advantage of PSH, why has not PSH evolved more frequently? The mating systems and sexual selection of caridean shrimps, the original sex of protandric individuals, the cost of maleness, and sex allocation theory are discussed in relation to protandry and PSH. None of these factors adequately explains the evolution of PSH of Lysmata species. Lysmata has at least 2 species groups with very different sociobiologies; these groups do not appear to share current selective pressures that would explain PSH in both. A historical contingency hypothesis, testable in part with a phylogenetic analysis, may explain the evolution of PSH in Lysmata. PMID- 21672756 TI - Sexual selection and reproductive success in hermaphroditic seabasses. AB - Mating behavior in simultaneously hermaphroditic seabasses has been often cited as an example of cooperation among unrelated conspecifics. The predominant mating behavior in this group involves egg trading, where individuals reciprocally fertilize parcels of eggs from a partner. Egg trading has been suggested as a good example of a tit-for-tat cooperative mating strategy. Although simultaneous hermaphroditic fishes are often held up as strong examples of cooperation in mating behavior, a closer examination reveals significant sexual selection and sexual conflict between male and female roles among individuals. In the 7 species where data exist, there is a significant increase in male reproductive success with individual size, and in all but 1 species success through male function increases faster than reproductive success through female function. Despite this male-size advantage in simultaneous hermaphrodites, most species maintain their hermaphroditism for their entire life, and the increased male allocation while engaging in biased forms of reciprocation appear to increase the evolutionary stability of hermaphroditism in these species. Thus, egg-trading behavior is probably more complicated than was initially recognized, with individuals releasing different numbers of eggs in spawns, spawning at different rates as males and females, and partitioning male effort between pair and alternative mating tactics. The departures from equal reciprocity can probably be best understood by including aspects of traditional mating-system theory, with individuals increasing male mating success through a variety of behavioral tactics. PMID- 21672757 TI - When males and hermaphrodites coexist: a review of androdioecy in animals. AB - Androdioecy (populations consisting of males and hermaphrodites) is a rare mating system in plants and animals: up to 50 plants and only 36 animals have been described as being androdioecious, with most of the latter being crustaceans. To date, a thorough comparative analysis of androdioecy in animals has not been undertaken. Herein we present such an analysis. Androdioecy has only been extensively surveyed in 2 animal taxa: the nematode Caenorhabditis and the clam shrimp Eulimnadia. The other major taxon having androdioecious species is the Cirripedia (barnacles), but there are only limited studies on androdioecy in this group. In animals, androdioecy is found either in species that have morphologically and ecologically distinct sexes (that is, hermaphrodites and small, "complemental" males) that are derived from hermaphroditic ancestors (that is, the barnacles) or in species that have similarly-sized males and hermaphrodites that have been derived from dioecious ancestors (the remaining androdioecious species). We suggest that the barnacles have evolved a sexual specialization in the form of these complemental males that can more efficiently use the constrained habitats that these barnacles often experience. For the remaining species, we suggest that androdioecy has evolved as a response to reproductive assurance in species that experience episodic low densities. Additionally, we hypothesize that the development of mechanisms allowing reproductive assurance in species with a number of sexually differentiated traits is most likely to result in androdioecy rather than gynodioecy (mixtures of females and hermaphrodites), and that these species may be developmentally constrained to stay androdioecious rather than being capable of evolving into populations solely consisting of efficient, self-compatible hermaphrodites. We conclude by suggesting several areas in need of further study to understand more completely the evolution and distribution of this interesting mating system in animals. PMID- 21672758 TI - Trait selection in flowering plants: how does sexual selection contribute? AB - By highlighting and merging the frameworks of sexual selection envisioned by Arnold (1994) and Murphy (1998), we discuss how sexual selection can occur in plants even though individuals do not directly interact. We review studies on traits that influence pollen export and receipt in a variety of hermaphroditic and gynodioecious plants with the underlying premise that pollination dynamics influences mate acquisition. Most of the studies reviewed found that phenotypes that enhance pollen export are in harmony with those that enhance pollen receipt suggesting that in many cases pollinator visitation rates limit both male and female function. In contrast, fewer traits were under opposing selection; but when they were, the traits most often were associated with enhancing the specific aspects of a given sex function. Our review helps clarify and illustrate why sexual selection can be a component of trait evolution in hermaphrodite plants. PMID- 21672759 TI - Sexual selection favors harmful mating in hermaphrodites more than in gonochorists. AB - Hermaphroditic animals often exhibit mating mechanisms that seem more damaging than those in species with separate sexes. Our analyses indicate that this difference is real. While females only remate when the benefit is positive, hermaphrodites remate even when this implies losing female fitness. This occurs because hermaphrodites can outweigh losses in the female function by gaining paternity. In an extended model we ask whether this favors the evolution of more male harm in hermaphrodites. When male harm only suppresses remating in the receiver it neither evolves in hermaphrodites nor in gonochorists. However, when male harm is coupled to a fertilization advantage, it evolves in both forms of gender expression with the highest levels in hermaphrodites. Hence, hermaphrodites are more prone to be caught in costly escalations than gonochorists. We discuss the implications for the evolution of gender expression in animals and plants. PMID- 21672760 TI - Polychaete chaetae: Function, fossils, and phylogeny. AB - In this article we review the phylogenetic distribution of major chaetal types within the Polychaeta, discuss what has been demonstrated about chaetal function in modern worms, and examine what is known about the evolution of chaete through the fossil record. We conclude with specific cautions about how chaetae are treated in phylogenetic analyses and make suggestions about how they could be used to provide a stronger phylogenetic signal. PMID- 21672761 TI - Evolution of body wall musculature. AB - A body wall musculature comprising an outer layer of circular fibers and an inner layer of longitudinal fibers is generally seen as the basic plan in Annelida. Additional muscles may be present such as oblique, parapodial, chaetal, and dorsoventral muscles. The longitudinal muscle fibers do not form a continuous layer but are arranged in distinct bands in polychaetes. Mostly there are four to six bands, usually including prominent ventral and dorsal bands. However, other patterns of muscle band arrangement also exist. The ventral nerve cord lies between the two ventral bands in certain polychaetes, and is covered by an additional longitudinal muscle band of comparatively small size. In many polychaetes with reduced parapodia and in Clitellata a more or less continuous layer of longitudinal fibers is formed. Clitellata is the only group with a complete layer of longitudinal musculature. Circular fibers are usually less developed than the longitudinal muscles. However, recent investigations employing phalloidin staining in combination with confocal laser scanning microscopy revealed that absence of circular muscles is much more widely distributed within the polychaetes than was previously known. This necessitates thorough reinvestigations of polychaete muscle systems, and this feature has to be taken into account in further discussions of the phylogeny and evolution of Annelida. PMID- 21672762 TI - Distribution of segment regeneration ability in the Annelida. AB - The annelids are an excellent group in which to investigate the evolution of regeneration abilities. They exhibit qualitative and quantitative variation in regeneration ability, including among closely related species, and their segmental body organization makes comparing results among species relatively straightforward. Here, I compile information on the presence/absence of segment regeneration ability across the annelids. The ability to regenerate posteriorly appears to be nearly universal in the annelids. It is almost certainly ancestral for the phylum and may have been lost only a few times. The ability to regenerate anteriorly is common but less widespread. It is absent in about a dozen groups, almost surely representing multiple independent losses of this ability. Several non-regenerating species are closely related to regenerating species, indicating very recent losses (or gains). Despite the fact that lack of this ability is unusual, there is a publication bias against reporting the lack of regeneration ability, and in many cases the judgment that a particular species is unable to regenerate is based on incomplete or unpublished data. Thus, in order to build rigorous frameworks for future comparative studies of annelid regeneration, there is a need for published studies clearly documenting the lack of regeneration abilities in annelid species. The review of regeneration data presented here is especially useful in highlighting annelid groups that possess both regenerating and non-regenerating representatives. Investigations of these groups may be particularly useful for elucidating the mechanisms leading to the loss (or perhaps gain) of segment regeneration ability. PMID- 21672763 TI - The divergent roles of the segmentation gene hunchback. AB - The hunchback (hb) gene is a member of the gap class of segmentation genes first identified in the dipteran insect Drosophila melanogastor. The hb gene encodes a C(2)H(2) zinc finger transcription factor whose primary function is to regulate the expression of its target genes along the anteroposterior (AP) axis based on its distribution in the blastoderm embryo. The loss of zygotic hb in Drosophila results in a "gap" in anterior pattern elements that include the loss of labial and thoracic segments in addition to the fusion of the abdominal segments 7 and 8. The hunchback protein is also expressed in the extraembryonic epithelial tissues and the developing nervous system in the zygote. Although the role of hunchback in AP patterning is likely to be an ancestral trait to the insect clade, higher order comparisons of hunchback orthologs suggest that it is a derived trait specific to the arthropod and/or insect lineage. This view is supported by a combination of comparative gene expression data, phylogenetic analyses, and an examination of the evolution of structural domains in the hb protein isolated from annelids, nematodes, and insects. The 3 independent lines of comparative data strongly support the idea that the anterior organizing function of hb originated in the arthropod and/or insect lineage and that its roles in epithelial and CNS patterning are likely to be broadly conserved within protostomes. PMID- 21672764 TI - A review of molecular markers used for Annelid phylogenetics. AB - Annelida, one of the most successful animal phyla, exhibits an amazing variety of morphological forms. Disparity between some of the forms is so great that until molecular tools were used, some annelid lineages (for example, echiurids and pogonophorans) were not commonly recognized as belonging to the group. Although it is easy to assign annelids to a given family, understanding the deeper relationships within the group has been difficult. The main working hypothesis for annelid phylogeny is based on morphological cladistic analysis. However, the recent work using molecular tools has caused a revision of our view of annelid evolutionary history. For example, Scolecida and Palpata appear not to be natural groups, and the phylogenetic positions of some aberrant taxa (for example, Siboglinidae, Poeobius, Pisione) have been determined. Herein, we discuss some of the main molecular markers that have been used to elucidate annelid phylogeny and the contribution that such work is making to our understanding. A table highlighting the molecular literature and the genes used is included. PMID- 21672765 TI - Lophotrochozoan mitochondrial genomes. AB - Progress in both molecular techniques and phylogenetic methods has challenged many of the interpretations of traditional taxonomy. One example is in the recognition of the animal superphylum Lophotrochozoa (annelids, mollusks, echiurans, platyhelminthes, brachiopods, and other phyla), although the relationships within this group and the inclusion of some phyla remain uncertain. While much of this progress in phylogenetic reconstruction has been based on comparing single gene sequences, there are also higher order features of genomes, such as the relative order of genes, that have contributed, and this seems likely to be even more fruitful in the future. Even though tremendous progress is being made on the sequence determination of whole nuclear genomes, the dataset of choice for genome-level characters for many animals across a broad taxonomic range remains mitochondrial genomes. We review here what is known about mitochondrial genomes of the lophotrochozoans and how comparisons of some of these features may be useful in discerning the phylogeny of this group. PMID- 21672766 TI - Progenetic species in polychaetes (Annelida) and problems assessing their phylogenetic affiliation. AB - Progenesis is defined as the retention of ancestral juvenile characters by adult stages of descendants due to an acceleration of the sexual maturation and thus is often regarded as a fast evolutionary process. Several small, meiofaunal polychaetes, such as Dinophilidae, some "Dorvilleidae" (for example, Parapodrilus), and Protodrilida, exhibit morphological simplicity in that they lack features typical of larger polychaetes, for example, parapodia and/or head appendages. Due to the general resemblance of adult meiofaunal polychaetes to juveniles of larger forms, progenesis has been invoked to explain evolutionary origins of many smaller taxa with increasing frequency over the past 4 decades. In this review, I summarize the interstitial species of polychaetes for which progenetic origin has been suggested on the basis of morphology. However, critical examination of morphological data that includes larval features reveals that autapomorphic characters uniting supposed progenetic taxa to specific annelid lineages are often missing. Typically larval and juvenile characters, which are argued to support hypotheses of progenetic origin, are often widely dispersed, homoplastic features. Because of this situation, molecular data seem to be the most reliable source for phylogenetic inference. However, other biological data, for example, from life history and morphology, are necessities to substantiate the progenetic evolution of these species. PMID- 21672767 TI - Zebrafish in comparative context: A symposium. AB - The Symposium "Zebrafish in Comparative Context" was organized to bring together two largely separate but highly complementary research traditions in order to make developmental and genetic information about a model species (Danio rerio, the zebrafish) more accessible to the comparative biology community. The meeting focused on the relationship of this model organism to other vertebrates (particularly other fishes) using a comparative and evolutionary approach. Topics included the phylogeny of cypriniform fishes, genome evolution, the evolution of gastrulation, dentition, pigmentation, craniofacial development, and nervous system structure and function. Participants also met informally to discuss ways to facilitate collaborative projects in areas of common interest and determine priorities for the development of shared resources. Continuing interactions between comparative biologists, with their extensive body of knowledge of morphological variation among fish species, and developmental biologists and geneticists working with model species such as the zebrafish will facilitate our understanding of the evolution of developmental patterns and processes in vertebrates. PMID- 21672768 TI - Integrating function across marine life cycles. AB - Complex life cycles involve a set of discrete stages that can differ dramatically in form and function. Transitions between different stages vary in nature and magnitude; likewise, the degree of autonomy among stages enabled by these transitions can vary as well. Because the selective value of traits is likely to shift over ontogeny, the degree of autonomy among stages is important for understanding how processes at one life-history stage alter the conditions for performance and selection at others. We pose 3 questions that help to define a research focus on processes that integrate function across life cycles. First, to what extent do particular transitions between life-history stages allow those stages to function as autonomous units? We identify the roles that stages play in the life history, types of transitions between stages, and 3 forces (structural, genetic/epigenetic, and experiential) that can contribute to integration among stages. Second, what are the potential implications of integration across life cycles for assumptions and predictions of life-history theory? We provide 3 examples where theory has traditionally focused on processes acting within stages in isolation from others. Third, what are the long-term consequences of carryover of experience from one life cycle stage to the next? We distinguish 3 scenarios: persistence (effects of prior experience persist through subsequent stages), amplification (effects persist and are magnified at subsequent stages), and compensation (effects are compensated for and diminish at subsequent stages). We use these scenarios to differentiate between effects of a carryover of state and carryover into subsequent processes. The symposium introduced by our discussion is meant to highlight how discrete stages can be functionally coupled, such that life cycle evolution becomes a more highly integrated response to selection than can be deduced from the study of individual stages. PMID- 21672769 TI - Revisiting synchronous gamete release by fucoid algae in the intertidal zone: fertilization success and beyond? AB - In the marine environment, both external fertilization and settlement are critical processes linking adult and early juvenile life-history phases. The success of both processes can be tightly linked in organisms lacking a larval dispersive phase. This review focuses on synchronous gamete release (= spawning) in fucoid algae. These brown macroalgae are important components of temperate intertidal ecosystems in many parts of the world, and achieve synchronous gamete release by integrating various environmental signals. Photosynthesis-dependent sensing of boundary-layer inorganic carbon fluxes, as well as blue light and green light signals, possibly perceived via a chloroplast-located photoreceptor(s), are integrated into pathways that restrict gamete release to periods of low water motion. Avoidance of turbulent and/or high flow conditions in the intertidal zone allows high levels of fertilization success in this group. Temporal patterns and synchrony of spawning in natural populations are reviewed. Most species/populations have a more or less semilunar periodicity, although phase differences occur both between and within species at different geographical locations, raising the possibility that tidal and diurnal cues are more important than semilunar cues in entraining the response. The ecological and evolutionary role(s) of synchronous spawning in the intertidal zone are considered, particularly with regard to hybridization/reproductive isolation in species complexes, and reproductive versus recruitment assurance in the intertidal zone, where synchronous spawning during calm periods may be important for recruitment assurance in addition to fertilization success. Ways in which the roles of spawning synchrony could be tested in closely related species with contrasting mating systems (outcrossing versus selfing) are discussed. PMID- 21672770 TI - Natural variability in size and condition at settlement of 3 species of marine invertebrates. AB - Experimental studies have demonstrated that for many marine invertebrate species, variability in larval condition or quality at settlement may have important effects on post-settlement, early juvenile performance. Relatively few studies, however, explicitly examine natural variability in larval condition at settlement. This study examines natural variability in larval attributes (size and lipid index) at settlement for terminal-stage larvae of intertidal mussels (Mytilus sp.) and barnacles (Pollicipes polymerus and Chthamalus dalli) from southern California. Despite significant differences among cohorts in larval attributes, for all 3 species a greater percentage of the variance in larval length (80-100%) and lipids (58-83%) occurred among individuals within a cohort, rather than among cohorts. For all 3 species, coefficients of variation within a cohort for length were much smaller (3-8%) than those for lipid index (30-93%), suggesting that lipid storage is a much more plastic attribute than size for larvae. For mussels, settlement intensity and larval attributes were decoupled, such that average larval condition of a cohort was not related to the number of larvae that settled. At the cohort level, Mytilus and Pollicipes settling together across 3 dates showed similar trends of decreasing lipid index over time, suggesting that environmental conditions may influence co-occurring planktonic larvae similarly across species. This work highlights the need for further experiments in the field on the effects of larval history on recruitment success in natural populations, and further studies to determine what factors influence larval attributes for planktonic larvae in the field. PMID- 21672771 TI - Functional properties of the isomorphic biphasic algal life cycle. AB - Many species of marine algae have life cycles that involve multiple separate, free-living phases that frequently differ in ploidy levels. These complex life cycles have received increasing scientific attention over the past few decades, due to their usefulness for both ecological and evolutionary studies. I present a synthesis of our current knowledge of the ecological functioning and evolutionary implications of the isomorphic, biphasic life cycles commonly found in many species of marine algae. There are both costs and benefits to life cycles with 2 morphologically similar but separate, free-living phases that differ in ploidy levels (haploids and diploids). Evolutionary theory predicts that the existence of subtle yet important differences between the phases may be what allows these life cycles to be maintained. Different phases of the same species can vary in abundance, in demographic parameters such as mortality and fecundity, in their physiology, and in their resistance to herbivory. Some taxonomic groups within the red algae have received significant attention toward these issues, while our knowledge of these properties for brown and green algae remains limited. PMID- 21672772 TI - Phenotypic links in complex life cycles: conclusions from studies with decapod crustaceans. AB - I review studies on decapod crustaceans to draw conclusions about the importance of effects of past environmental conditions on development, phenotype, performance, and survival in animals. I consider 3 critical points of the life cycle: the allocation of reserves into eggs, the hatching of larvae, and metamorphosis from the larval to the juvenile phase. Biomass allocated to eggs varies among females as a response to changes in environmental conditions. These variations are propagated to the larval stages, influencing the biomass at hatching, subsequent larval developmental pathways, and survival during periods of limited starvation. Suboptimal conditions experienced by embryos increase the loss of mass during embryogenesis; size or biomass of the juvenile is either positively or negatively correlated with initial biomass. Positive correlations may be the normal pattern; negative correlations occur when individuals hatched with low initial biomass follow developmental pathways that lead to increased biomass at metamorphosis. In estuarine crabs, salinity experienced by embryos leads to salinity acclimation in early larval stages. Phenotypic links originate as transgenerational effects that propagate to the juvenile stages. There are least 3 types of effects: disruption of physiological processes; direct adaptive responses; and indirect consequences of adaptive mechanisms. All types appear within a species; they are produced as a response to a single environmental factor. Variability in phenotype remains latent and is expressed in terms of survival according to the environmental conditions experienced by a particular stage. The fate of individuals is thus affected by interactions between their immediate developmental processes and their environmental history. PMID- 21672773 TI - Environmental variability, early life-history traits, and survival of new coral reef fish recruits. AB - For benthic marine organisms with complex life cycles, conditions experienced by pelagic larvae can influence juvenile survival. Trait-specific selective mortality has been documented in the laboratory and field, yet our knowledge of the factors contributing to the existence, strength, and consistency of natural selective mortality is limited. We compiled previously published and unpublished data on the common Caribbean coral reef fish, Thalassoma bifasciatum, recruiting to Barbados, West Indies, and the upper Florida Keys to examine how environmental variability during pelagic larval life influences the distribution of early life history traits exhibited by new recruits. We explored how the scope of variability in otolith-derived traits such as larval growth, pelagic larval duration (PLD), size and condition at settlement, and early juvenile growth influences the degree to which mortality of juveniles is selective. At both locations, contrasting oceanographic conditions (periodic passage of large low salinity North Brazil Current [NBC] rings near Barbados and seasonal variation in water temperature at Florida) led to significant differences in the early life history traits of recruits. Mortality was most frequently selective for the two most variable traits, condition at settlement and early juvenile growth. Environmental variability (including variation in predation pressure and stress inducing conditions) also likely influences juvenile mortality and consequently the degree to which selective loss of particular traits occurs. As we begin to better understand the spatial, temporal, and species-specific circumstances in which events occurring during larval life influence juvenile performance, studies must also be extended to examine how these processes are translated into adult fitness. PMID- 21672774 TI - Using latent effects to determine the ecological importance of dissolved organic matter to marine invertebrates. AB - The uptake and utilization of dissolved organic matter (DOM) by marine invertebrates is a field that has received significant attention over the past 100 years. Although it is well established that DOM is taken up by marine invertebrates, the extent to which it contributes to an animal's survival, growth, and reproduction (that is, the ecological benefits) remains largely unknown. Previous work seeking to demonstrate the putative ecological benefits of DOM uptake have examined them within a single life stage of an animal. Moreover, most of the benefits are demonstrated through indirect approaches by examining (1) mass balance, or (2) making comparisons of oxyenthalpic conversions of transport rates to metabolic rate as judged by oxygen consumption. We suggest that directly examining delayed metamorphosis or the latent effects associated with nutritional stress of larvae is a better model for investigating the ecological importance of DOM to marine invertebrates. We also provide direct evidence that availability of DOM enhances survival and growth of the bryozoan Bugula neritina. That DOM offsets latent effects in B. neritina suggests that the underlying mechanisms are at least in part energetic. PMID- 21672775 TI - Complex life cycles and offspring provisioning in marine invertebrates. AB - Offspring size can have pervasive effects throughout an organism's life history. Mothers can make either a few large or many small offspring, and the balance between these extremes is determined by the relationship between offspring size and performance. This relationship in turn is thought to be determined by the offspring's environment. Recently, it has become clear that events in one life history stage can strongly affect performance in another. Given these strong carryover effects, we asked whether events in the larval phase can change the relationship between offspring size and performance in the adult phase. We manipulated the length of the larval period in the bryozoan Bugula neritina and then examined the relationship between offspring size and various parameters of adult performance under field conditions. We found that despite the adult stage being outplanted into identical conditions, different offspring sizes were predicted to be optimal, depending on the experience of those adults as larvae. This work highlights the fact that the strong phenotypic links between life history stages may result in optimal offspring size being highly unpredictable for organisms with complex life cycles. PMID- 21672776 TI - What is metamorphosis? AB - Metamorphosis (Gr. meta- "change" + morphe "form") as a biological process is generally attributed to a subset of animals: most famously insects and amphibians, but some fish and many marine invertebrates as well. We held a symposium at the 2006 Society for Integrative and Comparative Biology (SICB) annual meeting in Orlando, FL (USA) to discuss metamorphosis in a comparative context. Specifically, we considered the possibility that the term "metamorphosis" could be rightly applied to non-animals as well, including fungi, flowering plants, and some marine algae. Clearly, the answer depends upon how metamorphosis is defined. As we participants differed (sometimes quite substantially) in how we defined the term, we decided to present each of our conceptions of metamorphosis in 1 place, rather than attempting to agree on a single consensus definition. Herein we have gathered together our various definitions of metamorphosis, and offer an analysis that highlights some of the main similarities and differences among them. We present this article not only as an introduction to this symposium volume, but also as a reference tool that can be used by others interested in metamorphosis. Ultimately, we hope that this article-and the volume as a whole-will represent a springboard for further investigations into the surprisingly deep mechanistic similarities among independently evolved life cycle transitions across kingdoms. PMID- 21672777 TI - Interspecific variation in metamorphic competence in marine invertebrates: the significance for comparative investigations into the timing of metamorphosis. AB - Metamorphosis in marine invertebrate larvae is a dynamic, environmentally dependent process that integrates ontogeny with habitat selection. The capacity of many marine invertebrate larvae to survive and maintain metamorphic competence in the absence of environmental cues has been hypothesized to be an adaptive convergence (Hadfield and others 2001). A survey of the literature reveals that a single generalized hypothesis about metamorphic competence as an adaptive convergence is not sufficient to account for interspecific variation in this character. In an attempt to capture this variation, we discuss the "desperate larva hypothesis" and propose two additional hypotheses called the "variable retention hypothesis" and the "death before dishonor hypothesis." To validate these additional hypotheses we collected data on taxa from the published literature and performed a contingency analysis to detect correlations between spontaneous metamorphosis, habitat specificity and/or larval life-history mode, three characters relevant to environmentally induced settlement and metamorphosis. In order to account for phylogenetic bias in these correlations, we also constructed a phylogeny of these taxa and again performed a character correlation analysis. Both these tests suggest that juvenile habitat specificity is correlated to the capacity of individuals to retain the competent larval state in the absence of substrate cues and therefore validate the existence of more than one hypothesis about metamorphic competence. We provide new data from the sea urchin Lytechinus pictus that suggest that nitric oxide (NO) and thyroxine hormone signaling interact to determine the probability of settlement in response to a settlement cue. Similarly, we provide evidence that thyroxine signaling in the sand dollar Dendraster excentricus increases spontaneous metamorphosis in the absence of cues from adult conspecifics in a manner that is independent of larval age. PMID- 21672778 TI - The origin of the pelagobenthic metazoan life cycle: what's sex got to do with it? AB - The biphasic (pelagobenthic) life cycle is found throughout the animal kingdom, and includes gametogenesis, embryogenesis, and metamorphosis. From a tangled web of hypotheses on the origin and evolution of the metazoan pelagobenthic life cycle, current opinion appears to favor a simple, larval-like holopelagic ancestor that independently settled multiple times to incorporate a benthic phase into the life cycle. This hypothesis derives originally from Haeckel's (1874) Gastraea theory of ontogeny recapitulating phylogeny, in which the gastrula is viewed as the recapitulation of a gastraean ancestor that evolved via selection on a simple, planktonic hollow ball of cells to develop the capacity to feed. Here, we propose an equally plausible hypothesis that the origin of the metazoan pelagobenthic life cycle was a direct consequence of sexual reproduction in a likely holobenthic ancestor. In doing so, we take into account new insights from poriferan development and from molecular phylogenies. In this scenario, the gastrula does not represent a recapitulation, but simply an embryological stage that is an outcome of sexual reproduction. The embryo can itself be considered as the precursor to a biphasic lifestyle, with the embryo representing one phase and the adult another phase. This hypothesis is more parsimonious because it precludes the need for multiple, independent origins of the benthic form. It is then reasonable to consider that multilayered, ciliated embryos ultimately released into the water column are subject to natural selection for dispersal/longevity/feeding that sets them on the evolutionary trajectory towards the crown metazoan planktonic larvae. These new insights from poriferan development thus clearly support the intercalation hypothesis of bilaterian larval evolution, which we now believe should be extended to discussions of the origin of biphasy in the metazoan last common ancestor. PMID- 21672779 TI - Sclerotial metamorphosis in filamentous fungi is induced by oxidative stress. AB - Sclerotium-forming filamentous fungi are of great agricultural and biological interest because they can be viewed as models of simple metamorphosis. They differentiate by asexually producing sclerotia but the processes involved in sclerotial metamorphosis were poorly understood. In 1997, it was shown for the first time that the sclerotial differentiation state in Sclerotium rolfsii concurred with increasing levels of lipid peroxides. This finding prompted the development of a theory supporting that sclerotial metamorphosis is induced by oxidative stress. Growth factors that reduce or increase oxidative stress are expected to inhibit or promote sclerotium metamorphosis, respectively. This theory has been verified by a series of published data on the effect of certain hydroxyl radical scavengers on sclerotial metamorphosis, on the identification and quantification of certain endogenous antioxidants (such as ascorbic acid, beta-carotene) in relation to the fungal undifferentiated and differentiated states, and on their inhibiting effect on sclerotial metamorphosis as growth nutrients. In 2004-2005, we developed assays for the measurement of certain redox markers of oxidative stress, such as the thiol redox state, the small-sized fragmented DNA, and the superoxide radical. These new advances allowed us to initiate studies on the exact role of glutathione, hydrogen peroxide, and superoxide radical on sclerotial metamorphosis. The emerging data, combined with similar data from other better-studied fungi, allowed us to make some preliminary postulations on the ROS-dependent biochemical signal transduction pathways in sclerotiogenic filamentous fungi. PMID- 21672780 TI - Applying the concept of metamorphosis to the crustose-to-erect thallus transition of macroalgae. AB - Metamorphosis is broadly defined as a more or less radical morphological change between 2 multicellular life stages within an organism's life phase, often marking the transition from pre-reproductive to reproductive stages. It involves structural reorganization and major physiological changes, generally under the control of endogenous and exogenous factors and often resulting in changes in habitat use. This concept has been applied to the crustose-to-erect thallus transition of some red algae and the present study evaluates the validity of such hypotheses. Available literature suggests that the crustose-to-erect thallus transition involves significant morphological and habitat changes, separating pre reproductive and reproductive stages. The onset of the morphological changes (for example axis differentiation) appears regulated by endogenous signals (growth factors) and growth is modified by environmental factors. The algae do not exhibit structural reorganization, however, probably due to their simple morphological structure and the lack of several cell and tissue mechanisms involving cell motility. The presence of cell walls in the algae impairs cell motility and maintains the cell in a fixed position within the plant. These are important differences restricting the extension of the definition of metamorphosis to the crust-to-erect thallus transition. The above restrictions also seem to apply to other macroalgae, fungi, and terrestrial plants. PMID- 21672781 TI - Expanding networks: Signaling components in and a hypothesis for the evolution of metamorphosis. AB - Metamorphosis is a substantial morphological transition between 2 multicellular phases in an organism's life cycle, often marking the passage from a prereproductive to a reproductive life stage. It generally involves major physiological changes and a shift in habitat and feeding mode, and can be subdivided into an extended phase of substantial morphological change and/or remodeling, and a shorter-term phase (for example, marine invertebrate "settlement," insect "adult eclosion," mushroom fruiting body emergence) where the actual habitat shift occurs. Disparate metamorphic taxa differ substantially with respect to when the habitat shift occurs relative to the timing of the major events of morphogenetic change. I will present comparative evidence across a broad taxonomic scope suggesting that longer-term processes (morphogenetic changes) are generally hormonally regulated, whereas nitric oxide (NO) repressive signaling often controls the habitat shift itself. Furthermore, new evidence from echinoids (sea urchins, sand dollars) indicates a direct connection between hormonal and NO signaling during metamorphosis. I incorporate 2 hypotheses for the evolution of metamorphosis-one involving heterochrony, the other involving phenotypic integration and evolutionarily stable configurations (ESCs)-into a network model for metamorphosis in echinoderms (sea urchins, starfish, and their kin). Early indications are that this core regulatory network can be acted upon by natural selection to suit the diverse ecological needs of disparate metamorphic organisms, resulting in evolutionary expansions and contractions in the core network. I briefly speculate on the ways that exposure to xenobiotic pollutants and other compounds might influence successful settlement of juveniles in the wild. Indeed, environmentally regulated life history transitions-such as settlement, metamorphosis, and reproductive maturation-may be developmental periods that are especially sensitive to such pollutants. PMID- 21672782 TI - Signaling mechanisms underlying metamorphic transitions in animals. AB - Metamorphosis in many animal groups involves a radical transition from a larval to a juvenile/adult body plan and the challenge of orchestrating 2 overlapping developmental programs simultaneously, that is, larval development and juvenile development. Metamorphic competence directly precedes this radical change in morphology and can be best described as the developmental potential of a larva to undergo the radical transition in response to internal or external signals. Several studies have employed genomic approaches (for example, microarrays or subtractive hybridization methods) to gain insights into the complexity of changes in gene expression associated with metamorphic transitions. Availability of this technology for an increasing number of organisms from diverse taxonomic groups expands the scope of species for which we can gain detailed understanding of the genetic and epigenetic architecture underlying metamorphosis. Here, we review metamorphosis in insects, amphibians, and several marine invertebrate species including the sea hare Aplysia californica and summarize mechanisms underlying the transition. We conclude that all metamorphoses share at least 4 components: (1) the differentiation of juvenile/adult structures, (2) the degeneration of larval structures, (3) metamorphic competence, and (4) change in habitat. While transcription levels detected by microarray or other molecular methods can vary significantly, some similarities can be observed. For example, transcripts related to stress response, immunity, and apoptosis are associated with metamorphosis in all investigated phyla. It also appears that signaling mediated by hormones and by nitric oxide can contribute to these stress-related responses and that these molecules can act as regulators of metamorphic transitions. This might indicate either that all of these distantly related organisms inherited the same basic regulatory machinery that was employed by their most recent common ancestor (RCA) in orchestrating life history transitions. Alternatively, these regulatory modules may have been used by the RCA for other purposes and have been independently co-opted to regulate metamorphic transitions in a variety of distantly related animals. We propose that such instances of independent origin or homoplasy in the evolution of metamorphosis might have resulted from specific constraints in signal transduction pathways. Modern genomic tools can help to further explore homoplastic signaling modules when used in a comparative context. PMID- 21672784 TI - Comparing thyroid and insect hormone signaling. AB - Transitions between different states of development, physiology, and life history are typically mediated by hormones. In insects, metamorphosis and reproductive maturation are regulated by an interaction between the sesquiterpenoid juvenile hormone (JH) and the steroid 20-hydroxy-ecdysone (20E). In vertebrates and some marine invertebrates, the lipophilic thyroid hormones (THs) affect metamorphosis and other life history transitions. Interestingly, when applied to insects, THs can physiologically mimic many facets of JH action, suggesting that the molecular actions of THs and JH/20E might be similar. Here we discuss functional parallels between TH and JH/20E signaling in insects, with a particular focus on the fruit fly, Drosophila melanogaster, a genetically and physiologically tractable model system. Comparing the effects of THs with the well defined physiological roles of insect hormones such as JH and 20E in Drosophila might provide important insights into hormone function and the evolution of endocrine signaling. PMID- 21672783 TI - The effect of larval age on morphology and gene expression during ascidian metamorphosis. AB - Metamorphosis is both an ecological and a developmental genetic transition that an organism undergoes as a normal part of ontogeny. Many organisms have the ability to delay metamorphosis when conditions are unsuitable. This strategy carries obvious benefits, but may also result in severe consequences for older larvae that run low on energy. In the marine environment, some lecithotrophic larvae that have prolonged periods in the plankton may begin forming postlarval and juvenile structures that normally do not appear until after settlement and the initiation of metamorphosis. This precocious activation of the postlarval developmental program may reflect an adaptation to increase the survival of older, energy-depleted larvae by allowing them to metamorphose more quickly. In the present study, we investigate morphological and genetic consequences of delay of metamorphosis in larvae of Herdmania momus (a solitary stolidobranch ascidian). We observe significant morphological and genetic changes during prolonged larval life, with older larvae displaying significant changes in RNA levels, precocious migration of mesenchyme cells, and changes in larval shape including shortening of the tail. While these observations suggest that the older H. momus larvae are functionally different from younger larvae and possibly becoming more predisposed to undergo metamorphosis, we did not find any significant differences in gene expression levels between postlarvae arising from larvae that metamorphosed as soon as they were competent and postlarvae developing from larvae that postponed metamorphosis. This recalibration, or convergence, of transcript levels in the early postlarva suggests that changes that occur during prolonged larval life of H. momus are not necessarily associated with early activation of adult organ differentiation. Instead, it suggests that an autonomous developmental program is activated in H. momus upon the induction of metamorphosis regardless of the history of the larva. PMID- 21672785 TI - Imperfect eggs and oviform nymphs: a history of ideas about the origins of insect metamorphosis. AB - The problem of insect metamorphosis has inspired naturalists for centuries. One question that often arises is why some insects, such as butterflies and bees, undergo a fairly radical metamorphosis while others, such as crickets and lice, do not. Even before the concept of homology emerged scientists speculated which stage found in more direct-developing insects would correspond with the pupal stage of metamorphosing insects. William Harvey (1651) considered the pupal stage to be a continuation of embryonic events, calling it a "second egg." Since then variations of this idea have emerged over the centuries of scientific research and have been supported by a wide variety of methods and rationales. This review will follow those ideas and the ideas that emerged in opposition to them to the present state of the field. PMID- 21672786 TI - Evolution of metamorphosis: role of environment on expression of mutant nuclear receptors and other signal-transduction proteins. AB - Various lipophilic signals, including ecdysone, retinoic acid, estradiol, cortisol, testosterone, and progesterone, act through nuclear receptors, a large group of transcription factors that regulate differentiation and development, which are central to metamorphosis. Here, we focus on environmental factors (for example climate and chemicals) in the evolution of nuclear receptors and other signal-transduction proteins that interact with heat-shock protein 90 (Hsp90), a chaperone that promotes the proper folding and trafficking in cells of proteins. Hsp90 also promotes functional folding of some mutant signal proteins, which would be otherwise destabilized. Stress diverts Hsp90 from stabilizing mutant signal-transduction proteins and toward promoting proper folding of stress damaged proteins and preventing the aggregation of denatured proteins. Reduced Hsp90 levels allow expression of cryptic mutations in signal-transduction proteins and new developmental patterns. Thus, environmental stress in the form of extreme climate can influence the evolution of metamorphosis. We discuss how extreme cooling called "Snowball Earth," which occurred in the late Proterozoic, diverted Hsp90 from chaperoning signal-transduction proteins. As a result, pre existing mutant signal-transduction proteins were expressed in animals. Some mutations were selectively advantageous in animals that are seen in the Cambrian, when diverse pathways for metamorphosis in metazoans first appear in the fossil record. Other environmental factors, such as biological chemicals (for example the antibiotic geldanamycin) can reduce the levels of active Hsp90 providing another mechanism for the emergence of mutant signaling pathways. PMID- 21672787 TI - Evolution of the thyroid hormone, retinoic acid, ecdysone and liver X receptors. AB - Ecdysone and thyroid hormone are 2 ligands that have important roles in regulating metamorphosis in animals. Ecdysone is a steroid that regulates molting in insects. Thyroid hormone regulates differentiation and development in fish and amphibia. Although ecdysone and thyroid hormone have different chemical structures, both hormones act by binding to transcription factors that belong to the nuclear receptor family. We investigated the evolution of structure and function in the ecdysone receptor (EcR) and thyroid hormone receptor (TR), and liver X receptor (LXR) and retinoic acid receptor (RAR), which cluster with EcR and TR, respectively (Bertrand S, Brunet FG, Escriva H, Parmentier G, Laudet V, Robinson-Rechavi M. 2004. Mol Biol Evol 21:1923-37), by constructing a multiple alignment of their sequences and calculating ancestral sequences for TR, RAR, EcR, and LXR. These alignments were mapped onto the 3D structures of TR, RAR, EcR, and LXR in the Protein Data Bank to examine the evolution of amino acids involved in the binding of ligands to TR, RAR, EcR, and LXR. PMID- 21672788 TI - Qualitative shift to indirect development in the parasitic sea anemone Edwardsiella lineata. AB - Direct development lies at 1 end of a continuum that encompasses various degrees of indirect development. Indirect development exists where a larval stage is interposed between the embryo and the adult and undergoes metamorphosis, though the ecological and morphological distinctiveness of the larval stage relative to the adult stage can vary tremendously. There are numerous empirical examples where direct development has evolved from indirect development, but little empirical evidence describing a recent transition from direct to indirect development. Here, we suggest 4 criteria for defining indirect, and therefore metamorphic, life histories. We then apply these criteria to address the planula polyp transition in cnidarians, focusing on 2 species in the anthozoan family Edwardsiidae. The lined sea anemone, Edwardsiella lineata, has made a qualitative shift towards indirect development that coincides with, and was potentially facilitated by, the evolution of endoparasitism. We compare E. lineata's development with that of a closely related sea anemone, Nematostella vectensis, where the nonfeeding planula gradually develops the morphology of the adult polyp. In E. lineata, a novel parasitic life history stage is interposed between the planula and the polyp. We discuss how the evolution of endoparasitism could facilitate the evolution metamorphic life histories. PMID- 21672789 TI - Evolution and function in serotonergic systems. AB - Serotonergic systems of invertebrate and vertebrate central nervous systems (CNS) are functionally similar in multiple characters. Serotonin (5-HT) neurons dispersed throughout the CNS of lophotrochozoan invertebrates (molluscs and leeches) are analogous to vertebrate 5-HT neurons concentrated in the raphe nuclei of mid- and hindbrain: they innervate specific central pattern generators and other circuits of the CNS, receive feedback from them, and support general behavioral arousal. In both groups 5-HT regulates excitatory gain of CNS circuitry and uses similarly diverse 5-HT receptors. Marked contrast, however, exists for roles of 5-HT in regulation of appetite. Where invertebrate 5-HT neurons promote an appetitive state, this role is supplanted in the vertebrates by a peptidergic network centered around orexins/hypocretins, to which the role of 5-HT in arousal is subordinate. In the vertebrates, 5-HT has appetite suppressant properties. This is paralleled by differing complexities of mechanisms that bring about satiety. Lophotrozoans appear to rely on simple stretching of the gut, with no obvious feedback from true nutrient stores. In contrast, vertebrate appetite is regulated by hypothalamic sensitivity to hormonal signals reporting separately on the status of fat cells and digestive activity, and to blood glucose, in addition to gut stretch. The simple satiety mechanism of a mollusc can be used in value-based foraging decisions that integrate hunger state, taste, and experience (Gillette and others 2000). For vertebrates, where appetite and arousal are regulated by signals from long-lived nutrient stores, decisions can be based on resource need going far beyond simple gut content, enabling value estimation and risk assessment in the longer-term. Thus, connection of nutrient storage depots to CNS circuitry mediating appetite may supply critical substrate for evolving complexity in brain and behavior. This hypothesis may be tested in expanded comparative studies of 5-HT and peptidergic functions in appetite and arousal. PMID- 21672791 TI - Advances in the neural bases of orientation and navigation. AB - The ability to locomote in one direction (oriented movement), and the ability to navigate toward a distant goal are related behaviors that are phylogenetically widespread. Orientation behaviors include finding the source of an odor or acoustic signal, using a sun-compass for guidance, and moving relative to fluid dynamic cues. Such abilities might require little more than directionally selective sensors coupled to a turning mechanism. This type of behavior, therefore, can be implemented by relatively simple circuits. In contrast, navigation involves both the ability to detect direction, as well as a map-sense that provides position. Navigation is less common and arguably requires greater brain computation than does simple orientation, but may be present in arthropods as well as in vertebrates. Great progress has been made in exploring the biophysical and sensory bases for these behaviors, and in recent years the locations and the identity of the cellular transducers of the sensory stimuli (for example, geomagnetic fields) have been narrowed in some taxa. Similarly, neurons within the central nervous that most likely function in higher order computational processes have been identified. For example, direction-selective and position-responsive brain cells have been located in the brains of mammals and birds, and these cells might contribute to a cognitive map that can enable navigation. One model organism in which orientation and navigation has been extensively studied is the sea slug Tritonia diomedea. This animal orients its crawling to chemical, hydrodynamic, and geomagnetic cues. The brain of Tritonia has ~7000 relatively large neurons that facilitate circuit analysis. Recent work has characterized both peripheral and central neural correlates of orientation signals, as well as the control of thrust and turning, and studies of their field behavior have suggested how these disparate orientation systems may be integrated. These findings provide the basis for future studies to determine how the nervous system combines multiple sensory cues into a complex hierarchy of signals that can direct motor output and therefore guide navigational tasks. PMID- 21672790 TI - The largest growth cones in the animal kingdom: an illustrated guide to the dynamics of Aplysia neuronal growth in cell culture. AB - The marine mollusc, Aplysia californica is a powerful experimental model in cellular and systems neuroscience. Aplysia neurons are large, colored, and located at the ganglionic surface. Because of this, many neurons can be easily identified in terms of their physiological properties, synaptic connections, and behavioral roles. Simple networks can be reconstructed in cell culture and have been widely useful for cellular and molecular biological studies of neuronal growth, synaptogenesis, and learning and memory mechanisms. Here, we show that Aplysia neurons can form truly gigantic growth cones reaching up to 630 MUm in diameter making them the largest growth cones ever reported in the animal kingdom. Second, using time-lapse video microscopy we have characterized the dynamics of neuronal outgrowth for 3 identified cell types (mechanosensory neurons, L7 motoneurons, and modulatory MCC neurons) representing 3 major functional classes of neurons. We show both cell-specific and neurite-specific growth characteristics and an irregular oscillatory rate of outgrowth ranging from 20 to 100 MUm/h. Third, we characterized the dynamics of axotomy-induced neurite outgrowth as well as extrasomatic localization of beta-tubulin mRNA in restricted regions of neuronal processes including growth cones and varicosities. The extrasomatically located mRNAs can be an important pool of neuronal transcripts supporting semiautonomous behavior of growth cones and localized synthesis of proteins in distinct and distant neuronal compartments. The reported data are compared with the existing literature from Lymnaea and Helisoma neurons as well as vertebrate preparations. Finally, our observations can provide an illustrated guide to complex behavior of neurons and glia in cell culture as well as their dependence upon various trophic factors and responses to neuronal injury. PMID- 21672792 TI - Neural regulation of a complex behavior: body patterning in cephalopod molluscs. AB - Unshelled cephalopods have a remarkable ability to alter their appearance, using textural, postural, and chromatic elements to generate a myriad of body patterns. Of the unshelled cephalopods, it is generally acknowledged that cuttlefish express the most detailed and widest range of body patterns, including static and dynamic patterns. In this paper we present data on the neuronal mechanisms underlying this amazing behavior, focusing on the neuroregulation of the chromatic elements, the chromatophore organs, in the European cuttlefish Sepia officinalis. Cephalopod chromatophore organs, including those in Sepia, are unlike those in any other animal taxa; each consists of a pigment-containing chromatophore cell that expands in response to the coordinated activation of a set of radial muscles which are directly attached to the chromatophore cell. We show that the chromatophore muscles are regulated by 2 different excitatory transmitters, glutamate and the family of FMRFamide-related peptides (FaRPs). Glutamate mediates rapid and transient chromatophore cell expansion whereas the FaRPs are responsible for slower, more sustained responses. Using retrograde dye filling, immunocytochemical and in situ hybridization techniques, we demonstrate that the cell bodies of the glutamatergic and FaRPs-containing motoneurons innervating the fin chromatophore muscles are primarily localized to the posterior chromatophore and fin lobes in the posterior subesophageal mass of the Sepia brain. Data are also presented showing that some fin chromatophore motoneurons have multiple axons in different nerve branches, which accounts for overlapping chromatophore motor fields by adjacent peripheral nerves. PMID- 21672793 TI - Hox gene expression in the hemichordate Saccoglossus kowalevskii and the evolution of deuterostome nervous systems. AB - The evolutionary origins of the chordate central nervous system remain uncertain. Conclusions drawn from classical morphological comparisons and from a broad range of metazoan phyla conflict with the new molecular genetic information from developmental model systems characterized by central nervous systems. This has led to debate as to the nature of the ancestral deuterostome nervous system. Hemichordates as basal deuterostomes occupy a phylogenetically critical position for addressing hypotheses on the evolution of the chordate nervous system. Characterizing the molecular basis of the development of their diffuse nervous system offers insights into the role of conserved body patterning genes in the evolution of specific neural anatomies. We present a description of hox gene expression during the development of the direct-developing hemichordate Saccoglossus kowalevskii. The nested ectodermal expression of these genes in a hemichordate suggest that they play a general patterning role in the anterior/posterior regionalization of the ectoderm of bilaterians rather than being uniquely associated with the development and evolution of central nervous systems. PMID- 21672794 TI - EcoGenomics: analysis of complex systems via fractal geometry. AB - Ecogenomics is a convenient descriptor for the application of advanced molecular technologies to studies of organismal responses to environmental challenges in their natural settings. The development of molecular tools to survey changes in the transcript profile of thousands of genes has presented scientists with enormous analytical challenges. In the main, these center about the reduction of massively paralleled data to statistics or indices comprehensible to the human mind. Historically, scientists have used linear statistics such as ANOVA to accomplish this task, but the sheer volume of information available from microarrays severely limits this approach. In addition, important information in microarrays may not reside solely in the up or down regulation of individual genes, but rather in their dynamic, and probably nonlinear, interactions. In this presentation, we will explore alternative approaches to extracting of these signals using artificial neural networks and fractal geometry. The goal is to produce predictive models of gene dynamics in individuals and populations under environmental stress and reduce the number of genes that must be surveyed in order to recover transcript profile patterns of environmental challenges. PMID- 21672795 TI - Gene discovery in Carcinus maenas and Homarus americanus via expressed sequence tags. AB - Expressed sequence tags (ESTs) were produced for normalized cDNA libraries prepared from several tissues of 2 marine crustaceans, the green shore crab Carcinus maenas and the American lobster Homarus americanus. Tissues represented in the Carcinus library were anterior and posterior gills, hypodermis, heart, hepatopancreas, antennal gland, brain, testis, and skeletal muscle, obtained from animals acclimated to 35 and 100/00 salinity. Tissues represented in the Homarus library were gill, epipodite, branchiostegite, heart, ovary, testis, antennal gland, skeletal muscle, hepatopancreas, and brain, obtained from intermolt and post-molt animals. Directional libraries from oligo-dT-primed cDNA were constructed in the pCMVsport6.1 vector and normalized by self-subtraction at 2 different Cot values. Randomly picked clones were single-pass sequenced from the 5' end. Raw sequence data were trimmed and prepared for submission to dbEST using phred, cross-match, and blastx protocols embedded within trace2dbest software. A total of 4604 Homarus and 12 401 Carcinus ESTs produced 540 and 2651 clusters, respectively, as determined by TIGR Gene Index Clustering software. Gene Ontology analysis with reference to a Drosophila melanogaster database using GOblet revealed 187 positive hits (35%) with the Homarus clusters and 1037 positive hits (39%) with the Carcinus clusters. Combining the number of assembled sequences with the number of singlets obtained after cluster analysis suggested that transcripts representing as much as 25% of the total number of genes in Carcinus have been isolated. PMID- 21672796 TI - Construction and characterization of EST libraries from the porcelain crab, Petrolisthes cinctipes. AB - The thermal phenotype of an organism (heat and cold tolerance, thermal range, and thermal plasticity) is an essential feature of how the organism performs across thermal environments and in response to thermal stress. Porcelain crabs are of interest in addressing questions of thermal phenotype because of their high species diversity and the large variation in thermal phenotype among species, as well as the biogeographic patterning of these crabs along environmental stress gradients. We are studying the cellular bases of thermal phenotype and physiological responses to environmental stress using a functional genomics cDNA microarray approach. To do this, we have isolated total RNA from a range of tissues from 1 species of porcelain crab (Petrolisthes cinctipes) exposed to a suite of thermal conditions, and have used this RNA to construct a 13 824-clone EST library. Here, we describe construction, EST sequencing, assembly and clustering, and results of BLASTx homology search for our initial 13 824-clone library. From 12 060 usable ESTs, 6717 consensus sequences were identified, and roughly 50% of these have homology to known proteins. At present, an additional 50 000-75 000-clone library of P. cinctipes ESTs is being generated, with the aim of developing a library with near-complete coverage of the transcriptome. The libraries and sequence information that will be generated as a result of this project should be of value for crustacean biologists working across a broad range of scientific disciplines (for example, physiology, developmental biology, biological rhythms, ecology, fisheries biology), as well as in studies of molecular evolution and phylogeography. PMID- 21672797 TI - Analysis of multiple tissue-specific cDNA libraries from the Pacific whiteleg shrimp, Litopenaeus vannamei. AB - Multiple small-scale transcriptome studies have been undertaken for various members of the Penaeidae. Penaeid shrimp are important both as members of diverse ecosystems around the world and for their importance as commercial commodities. Of the many shrimps, the most important from this family is the Pacific whiteleg shrimp, Litopenaeus vannamei, as it is the primary shrimp used in worldwide aquaculture. The sequencing and analysis of 13 656 expressed sequence tags (ESTs) from this species is presented. ESTs were derived from multiple tissue-specific cDNA libraries with an emphasis being placed on those tissues with predicted immune function. Assembly of the sequences into non-overlapping clusters yielded 7466 putative unigenes (1981 contigs and 5485 singletons). Multiple approaches were taken to assign putative function to each transcript; sequence homology searches using BLASTX (Basic Local Alignment Search Tool: Translated query versus protein database) of the National Center for Biotechnology Information's (NCBI) GenBank Database and Gene Ontology annotation, and still a significant portion of the shrimp ESTs (62%) had no homology with known proteins in the public databases. The sequence and complete annotation of all ESTs is available at www.marinegenomics.org, a publicly accessible database. In addition to providing the basic resources for microarray construction, transcript profiling, and novel gene discovery, this study constitutes the largest combined analysis of ESTs from any shrimp species and is a prelude to an even larger effort aimed at identifying and depleting highly redundant genes from shrimp cDNA libraries toward the goal of sequencing 100 000 shrimp ESTs. PMID- 21672798 TI - Lobster olfactory genomics. AB - Lobsters have numerous adaptive specializations of the olfactory system that make them especially suitable model organisms for the study of olfaction. Recent work using genomics and physiological genomics to study the lobster olfactory organ extends the advantages of their use further. A subtracted cDNA library from the mature zone of the olfactory organ and 3 physiological genomics experiments have helped identify numerous functionally interesting genes. These include specific markers of 3 cell types that previously could be discriminated only in anatomical sections, plus a marker of reactive epithelial cells at sites of cellular proliferation for both the normal ongoing replacement of olfactory tissue and the regeneration of damaged olfactory tissue. The approaches were instrumental in the discovery of a new exocrine gland, the aesthetasc tegumental gland, which is linked to grooming and the prevention of fouling of the olfactory aesthetasc setae. They also suggest a previously unknown endocrine or paracrine function performed by auxiliary cells of the olfactory aesthetasc sensory units. Other discoveries include candidates for gene products involved in olfactory transduction, presynaptic modulation of olfactory neuron axons by ionotropic receptors, and neuromodulation of both the olfactory sensory neurons and the interneurons in the olfactory lobe of the brain. PMID- 21672799 TI - EST library sequencing of genes expressed during early limb regeneration in the fiddler crab and transcriptional responses to ecdysteroid exposure in limb bud explants. AB - We have constructed directional and randomly primed cDNA libraries from mRNAs isolated during progressive stages of fiddler crab (Uca pugilator) limb regeneration. Data from these libraries are being assembled into an on-line database (http://www.genome.ou.edu/crab.html) that is both BLAST and keyword searchable; the data set is also available through GenBank. The first characterized library was made from mRNA isolated 4 days post-autotomy, when the first sign of morphological differentiation, cuticle secretion, is observed. Analysis of 1698 cDNA clones led to assignment of 473 contigs and 417 singlets, for a total of 890 sequences. Of these, ~86% showed no assignments to characterized genes on database searching, while 14% could be assigned to a known ortholog in the COG (Clusters of Orthologous Groups) database. BLAST searches to specific protein domains in the Gene Ontology database led to assignments for ~40% of the assembled sequences. Sequence similarity searches of other crustacean EST databases produced hits to 13-30% of the Uca query sequences. The ESTs include several genes that may be potentially ecdysteroid-responsive, such as homologs to chaperone proteins and cuticle protein genes, as well as homologs to arthropod proteins involved in retinoid/terpenoid metabolism. We have tested 3 potential candidate genes for their ability to be induced by ecdysteroid in limb bud explants; an arthropodial cuticle protein gene, and the nuclear receptor genes EcR and RXR. A subset of early blastemal limb buds (8 days post autotomy) show a positive response to ecdysteroid by 1-1.5 h, followed by a decrease in transcript abundance at longer periods of sustained incubation. Later stage buds (12 days post autotomy-late premolt) show decreases in steady-state mRNA levels by 1.5 h, or are completely refractory to ecdysteroid exposure. PMID- 21672800 TI - Proteomics and signal transduction in the crustacean molting gland. AB - Regulation of the molting cycle in decapod crustaceans involves 2 endocrine organs: the X-organ/sinus gland (XO/SG) complex located in the eyestalk ganglia and the Y-organ (YO) located in the cephalothorax. Two neuropeptides [molt inhibiting hormone (MIH) and crustacean hyperglycemic hormone (CHH)] are produced in the XO/SG complex and inhibit ecdysteroidogenesis in the YO. Thus, YO activation is induced by eyestalk ablation (ESA), which removes the primary source of MIH and CHH. Cyclic nucleotides (cAMP and cGMP) and nitric oxide (NO) appear to mediate neuropeptide suppression of the YO. Proteomics was used to identify potential components of signal transduction pathways ("targeted" or cell map proteomics) as well as assess the magnitude of protein changes in response to activation ("global" or expression proteomics) in the tropical land crab, Gecarcinus lateralis. Total proteins in YOs from intact and ES-ablated animals were separated by two-dimensional gel electrophoresis and expression profiles were assessed by image analysis and gene clustering software. ESA caused a >3 fold increase in the levels of 170 proteins and >3-fold decrease in the levels of 89 proteins; a total of 543 proteins were quantified in total YO extracts. ESA induced significant changes in the levels of 3 groups of proteins eluting from a phosphoprotein column and detected with phosphoprotein staining of two dimensional gels; ~17 kDa and ~150 kDa phosphoproteins increased in activated YOs, while ~12 kDa phosphoproteins decreased. A ~150 kDa phosphoprotein, which was isolated only from activated YO, was identified as NO synthase by western blotting and mass spectrometry of trypsin peptides. These data show that phosphorylation of NO synthase is associated with activation of the YO. A neuropeptide signaling pathway involving NO synthase and NO-sensitive guanylyl cyclase is proposed. PMID- 21672801 TI - Identifying exoskeleton proteins in the blue crab from an expressed sequence tag (EST) library. AB - A blue crab (Callinectes sapidus) expressed sequence tag project was designed for multiple purposes including discovery of genes for cuticular (exoskeletal) proteins, some of which may regulate mineralization. One of the expression libraries sequenced was from the hypodermis (the epithelium depositing the cuticle). RNAs used for cDNA synthesis were pooled from arthrodial and mid-dorsal hypodermis at both pre-ecdysis and post-ecdysis. This ensured representation from both calcifying and non-calcifying regions and from layers of cuticle deposited both before and after ecdysis. The EST database was mined for cuticular protein sequences in three ways. First, we searched for sequences coding for known cuticle-specific motifs like the Rebers-Riddiford chitin-binding sequence and a motif known only from proteins extracted from mineralized exoskeletons of other decapods. Second, we checked the associated annotations in the EST project for similarity to known cuticular proteins, often from insects. Third, BLAST was used to search the EST data for significant homology to published cuticular protein sequences from other crustaceans. In all, the database contains at least 73 contigs or singlets representing transcripts of cuticular proteins. Forty-five of these distribute among ten clusters of very similar transcripts, possibly representing alternative splicing or recent gene duplications. The rest share less similarity. We have obtained complete sequences for 25 of the transcripts, have produced phylogenetics trees comparing them with similar proteins from insects and other crustaceans, and have determined expression patterns across the molt in calcifying versus non-calcifying cuticle. The combination of homology analysis and gene expression analysis allows us to infer putative functions in cuticle synthesis and calcification. PMID- 21672802 TI - Crustacean hemocyanin gene family and microarray studies of expression change during eco-physiological stress. AB - Proteins in the arthropod hemocyanin gene family are involved in major physiological processes, including aerobic respiration, the innate immune response, and molting. Members of this family, hemocyanin, cryptocyanin, and phenoloxidase, are multisubunit molecules that assemble into hexamers and higher aggregates. The hemocyanin hexamers show species-specific subunit heterogeneity. It is hypothesized that this subunit diversity is maintained as a mechanism of selection for functional diversity under changing developmental and environmental conditions. There is good evidence for a strong relationship between subunit composition and functional diversity in the hemocyanins. We have amplified, cloned, and sequenced the complete cDNAs of the 6 hemocyanin genes, 2 cryptocyanins, and 1 phenoloxidase of Cancer magister. Alignment of the amino acid sequences provides the first opportunity to assess in 1 species of brachyuran crustacean the similarities and differences among all the hemocyanin subunits and compare them with cryptocyanin and phenoloxidase. A phylogeny of sequences of crustacean members of the arthropod hemocyanin gene family is described. Construction of a cDNA library for C. magister microarray studies is in progress. The microarrays will be queried using transcriptional profiles from crabs sampled during developmental, molting, and physiological perturbations. The combination of genomics, proteomics, and gene-by-gene analyses will help us dissect how much a gene sequence in this hemocyanin family can vary while conserving function and which aspects of preservation of shape and structural flexibility are essential for functional stability. Integrating focused gene studies with global-expression profiling can eventually lead to the identification of functional networks at the level of the gene, the multisubunit molecule, and the whole organism. PMID- 21672803 TI - Linking immune defenses and life history at the levels of the individual and the species. AB - Immune defenses have been suggested to play an important role in mediating life history trade-offs. Detecting and understanding such trade-offs, however, is complicated by the complexity of the immune system. The measurement of multiple immune indices in studies of "eco-immunology" has only recently become more common, but has great potential for furthering an understanding of the ecological and evolutionary forces driving immunological variation. Building on previous proposals, I create a framework integrating immunological and life history axes that can be used to formulate predictions and interpret variation in multiple types of immune defense at both the individual and species levels in vertebrates. In particular, this framework predicts that "fast-living" species (those with high reproductive and low survival rates) should rely more heavily on nonspecific and inflammatory immune defenses, while "slow-living" species should exhibit stronger specific and especially antibody-mediated immunity. At the level of individuals within species, nonspecific and inflammatory responses should be downregulated, and specific defenses upregulated (1) in individuals experiencing the greatest demands on their resources (for example, undertaking large reproductive efforts); (2) in the sex investing more in a particular activity (for example, females during reproduction); and (3) during the most demanding periods of the year (for example, the breeding season). A review of the literature reveals that incorporating multiple facets of the immune system into a model of the relationship between immune defense and life histories brings disparate questions and systems into a common context, and helps explain empirical results that are sometimes counterintuitive. PMID- 21672804 TI - Functional implications of Major Histocompatibility (MH) variation using estuarine fish populations. AB - Recently, there has been a dramatic expansion of studies of major histocompatibility complex (MHC) variation aimed at discovering functional differences in immunity across wild populations of diverse vertebrate species. Some species with relatively low genetic diversity or under strong directional selection by pathogens have revealed fascinating cases of MHC allelic disease linkage. More generally in genetically diverse species, however, these linkages may be hard to find. In this paper, we review approaches for assessing functional variation in MHC and discuss their potential use for discovering smaller-scale intraspecific spatial and temporal patterns of MHC variation. Then, we describe and illustrate an approach using the structural model to produce a population composite of variation in antigen-binding regions by mapping population-specific substitutions onto functional regions of the molecule. We are producing models of variation in major histocompatibility (MH) loci for populations of non-migratory fish (killifish, Fundulus heteroclitus) resident at sites that vary dramatically in environmental quality. We discuss the goal of relating MH population variation to functional differences in disease susceptibility such as those inferred by observations of parasitic infection and direct measurement of bacterial challenges in the laboratory. Our study has focused on relatively well-studied killifish populations, including those resident in a highly disturbed, chemically contaminated estuary and nearby less contaminated sites. Population-specific genetic changes at MHC antigen-binding loci are described, and evidence relevant to functional implications of these changes is reviewed. Population-specific patterns of variation in antigen-binding regions in combination with a range of assessments of immune function will provide a powerful new approach to reveal functional changes in MHC. PMID- 21672805 TI - Refining approaches and diversifying directions in ecoimmunology. AB - Ecoimmunologists have made many important discoveries about the immune systems of wild animals including (1) immune activity is usually costly, (2) counter intuitive decrements in immune activity are often due to trade-offs with other physiological activities or behaviors, and (3) immune activity is a currency by which sexually selected traits are indices of individual quality. The use of single assays to characterize "immunocompetence," however, as was, and is, the common practice in ecoimmunology, ignores the inherent complexity of the immune system and may have led to inappropriate conclusions or even positive publication bias. Recently, some have suggested that ecoimmunologists measure disease resistance or the fitness consequences of immunological insults instead of the immune system itself. We propose that researchers continue to use the techniques that have already been fruitful in ecoimmunology, but better incorporate the underlying immunophysiology of such techniques into their study designs and interpretation. We review the benefits and some recent successes of such an approach. Then, we discuss several under-explored but potentially rewarding areas of ecoimmunology, including development of the immune system, immunosenescence, and immunoredistribution. All three areas are well studied in biomedicine and are likely to be relevant in ecological contexts. For instance, because of the inherent costliness of immune defense and reproduction, variation in rates of development and senescence of the immune system likely impacts the ways in which individuals of different species mature and/or breed. Likewise, differential capacity to redistribute immune resources in response to changes within the endocrine system may explain some of the inconsistencies regarding the immunocompetence handicap hypothesis of sexual selection. PMID- 21672806 TI - Arsenic ecotoxicology and innate immunity. AB - Understanding the ecotoxicological effects of arsenic in the environment is paramount to mitigating its deleterious effects on ecological and human health, particularly on the immune response. Toxicological and long-term health effects of arsenic exposure have been well studied. Its specific effects on immune function, however, are less well understood. Eukaryotic immune function often includes both general (innate) as well as specific (adaptive) responses to pathogens. Innate immunity is thought to be the primary defense during early embryonic development, subsequently potentiating adaptive immunity in jawed vertebrates, whereas all other eukaryotes must rely solely on the innate immune response throughout their life cycle. Here, we review the known ecotoxicological effects of arsenic on general health, including immune function, and propose the adoption of zebrafish as a vertebrate model for studying such effects on innate immunity. PMID- 21672807 TI - Immune cell-endothelial cell interactions in the bovine corpus luteum. AB - Early embryonic mortality accounts for a substantial portion of reproductive failure in agriculturally important livestock, including the dairy cow. The maintenance of early pregnancy requires a fully functional corpus luteum (CL) that is not susceptible to regression following fertilization, yet the cellular mechanisms of luteal regression are not clearly understood. Immune-cell accumulation within the CL at the time of regression is a well-documented phenomenon in a variety of species. In the dairy cow, immune-cell accumulation precedes luteal regression by several days and coincides with an increase in expression of the chemokine monocyte chemoattractant protein 1 (CCL2), suggesting that immune-mediated events promote tissue destruction. Recent studies indicate that endothelial cells comprising the CL are a primary source of CCL2 secretion. Moreover, although uterine-derived prostaglandin F(2alpha) (PGF) initiates luteal regression in the cow, PGF does not directly provoke CCL2 secretion by luteal endothelial cells. Instead, PGF-induced luteal regression is thought to require cooperative interaction among immune cells, endothelial cells, and steroidogenic cells of the CL to further promote CCL2 secretion, enhance immune-cell recruitment, and eliminate luteal tissue. This brief review focuses on putative interactions between immune cells and endothelial cells derived from the bovine CL that result in enhanced CCL2 expression and the elaboration of other inflammatory mediators (for example, cytokines), which perpetuate luteal regression. Fundamental knowledge of immune-endocrine interactions within the reproductive system of cows has relevance to other CL-bearing mammals, including humans and endangered animals, particularly in the development of methods to control and/or improve fertility. Thus, it is a timely topic for this symposium concerning ecological immunology and public health. PMID- 21672808 TI - Evolution of reproductive-immune interactions. AB - The comparative approach in biological sciences has provided valuable insights into the role of different organ systems in adaptation and evolution, and seeks to establish unifying themes. This approach also plays a key role in identifying model species and systems for the study of specific questions and problems. Further, by applying the concept of homology, information about nonmammalian species may be used either to directly understand mammalian/human regulatory processes, or to formulate hypotheses for direct testing. Individual physiological systems function in a milieu provided by the integrated activities of all of the systems to adapt, adjust and sustain the organism in its environment. The overlapping interfaces between the different physiological systems provide fertile ground for new insights and to enhance our knowledge. These interdisciplinary areas are of great importance if we are to understand the full complexity of organismal function. Of particular interest are the interactions between the reproductive system and the immune system. The reproductive system is unique in that its primary role is to assure the continuity of the species, while the immune system provides internal protection and thus facilitates continued health and survival. The modus operandi of these 2 morphologically diffuse systems involves widely distributed chemical signals in response to environmental input, and both systems must interact for the normal functioning of each. While the major focus of reproductive-immune research has historically been with mammals, and has provided substantial insight into the interactions between these physiological systems, comparative studies offer unique perspectives. Further, dysregulation of normal physiological interactions between the reproductive and immune systems can lead to disorders and diseases effecting one system or the other. Thus, comparative studies of these interactions may shed some light upon the evolutionary mechanisms involved in such cases. PMID- 21672809 TI - Sex hormone modulation of human uterine epithelial cell immune responses. AB - Sexually transmitted infections are a major worldwide public health problem affecting millions of people. A number of bacteria, fungi, viruses, and protozoa can infect reproductive tissues, resulting in varying degrees of pathology ranging from little discomfort to death. The female reproductive tract has evolved innate and adaptive immune mechanisms that protect from microbial infection, thereby reducing infection and disease. Central to this protection are the epithelial cells that line the female reproductive tract. In the uterus, columnar epithelial cells provide a physical barrier to microbial infection, possess toll-like receptors that detect pathogens and secrete a number of constitutive and induced factors that directly or indirectly hinder infection. For example, uterine epithelial cells secrete peptides that destroy pathogenic microbes. In addition, epithelial cells produce chemokines and cytokines that attract and activate innate immune cells and serve as a link to the adaptive immune system. Further, uterine epithelial cells serve as a conduit for secretory antibodies to enter the lumen and can present antigen to T cells. These protective mechanisms contribute to an environment in the uterus that is generally considered sterile, unlike the environment in the lower female reproductive tract. The uterine environment is in constant flux due to the concentration changes in sex hormones that occur in preparation for reproduction. The sex hormones estrogen and progesterone alter the local immune system to prepare for conception, influence how well the immune system will tolerate antigenic sperm and a semi-allogeneic fetus and yet provide a network of protective immune mechanisms against microbial pathogens. Understanding how sex hormones influence uterine epithelial cell function will provide a basis for immune protection in the uterus. PMID- 21672810 TI - Ecophysiology and conservation: The contribution of energetics--introduction to the symposium. AB - Animal physiologists have begun making contributions to conservation biology based on their knowledge of endocrinology, immunology, and sensory biology. Contributions to this symposium use the perspective of energy and mass balance to examine questions about habitat usage, activity times, competition, foraging, reproduction, and body condition. Physiological constraints or requirements sculpt the behavioral and life history choices of individuals and provide mechanistic linkages with population processes and conservation policies. PMID- 21672811 TI - Linking physiological effects on activity and resource use to population level phenomena. AB - We present an approach to delineating physiological effects on population level processes by modeling the activity and resource budgets of animals. Physiology and its environmental forcing functions are assumed to affect both the total time available for activity and foraging and the resource budgets by affecting resource acquisition, costs, and handling. We extend the earlier model of Dunham and others (1989) and translate it into a computational algorithm. To satisfy conservation needs for accuracy, wide applicability, and rapid deployment, the model is relatively simple, uses as much data on the focal organism as possible, is mechanistically driven, and can be adapted to new organisms by using data for the new species, or the best available approximations to those data. We present 2 applications of the modeling approach. First, we consider a system with substantial information available, canyon lizards (Sceloporus merriami) studied by Dunham and colleagues in west Texas. In this case the focus is on integration of numerous inputs and the ability of the model to produce predictions that approximate counterintuitive empirical patterns. By using the wealth of specific data available, the model outperforms previous attempts at explanation of those patterns. Next, we consider a system with much less available information (forest dwelling semi-fossorial frogs). The question here is how hydric conditions can become limiting. A model of evaporation from frogs buried in leaf litter was incorporated and it demonstrates how rainfall patterns can both supply water and put the frogs at risk of critical dehydration. PMID- 21672812 TI - Environmental physiology of the invasion of the Americas by Africanized honeybees. AB - The expansion of Africanized honeybees (AHB) through the Americas has been one of the most spectacular and best-studied invasions by a biotype. African and European honeybees (EHB) hybridize, but with time, tropical and subtropical American environments have become dominated by AHB that exhibit only 20-35% genetic contribution from western European bees, and a predominance of African behavioral and physiological traits. EHB persist in temperate environments. Clines between AHB and EHB exist in ecotones of South and Central America, and are forming in North America. What individual-level genetic, behavioral and physiological traits determine the relative success of the AHB as an invader in the neotropics, and of the EHB in temperate areas? Preference for pollen versus nectar may be an important trait mediating these ecological trade-offs, as preference for pollen enhances nutrient intake and brood production for the AHB in the tropics, while a relative preference for nectar enhances honey stores and winter survival for EHB. AHB exhibit morphological (higher thorax-to-body mass ratios) and physiological (higher thorax-specific metabolic rates) traits that may improve flight capacity, dispersal, mating success and foraging intake. Enhanced winter longevity, linked with higher hemolymph vitellogenin levels, may be a key factor improving winter survival of EHB. Data from South America and distributions of AHB in the southwestern United States suggest that AHB-EHB hybrids will extend 200 km north of regions with a January maximal temperatures of 15-16 degrees C. The formation of biotypic clines between AHB and EHB represents a unique opportunity to examine mechanisms responsible for the range limit of invaders. PMID- 21672813 TI - Fueling the fall migration of the monarch butterfly. AB - Monarch butterflies in eastern North America accumulate lipids during their fall migration to central Mexico, and use them as their energy source during a 5 month overwintering period. When and where along their migratory journey the butterflies accumulate these lipids has implications for the importance of fall nectar sources in North America. We analyzed the lipid content of 765 summer breeding and fall migrant monarch butterflies collected at 1 nectaring site in central Virginia over 4 years (1998-2001), and compared them with 16 additional published and unpublished datasets from other sites, dating back to 1941. Virginia migrants store significantly more lipid than summer butterflies, and show significant intraseason and between-year variation. None of the Virginia samples, and none of the historical samples, with one exception, had lipid levels comparable with those found in migrants that had reached Texas and northern Mexico. This evidence suggests that upon reaching Texas, the butterflies undergo a behavioral shift and spend more time nectaring. The one exceptional sample led us to the discovery that monarchs that form roosts along their migratory routes have higher lipid contents than monarchs collected while nectaring at flowers. We propose that for much of their journey monarchs are opportunistic migrants, and the variation within and between samples reflects butterflies' individual experiences. The stored lipids appear to be of less importance as fuel for the butterflies' migration than for their survival during their overwintering period, in part because soaring on favorable winds reduces the energetic cost of flying. The conservation of nectar plants in Texas and northern Mexico is crucial to sustaining the monarch's migratory spectacle, and nectar abundance throughout eastern North America is also important. As generalists in their selection of nectar sources and nectaring habitats, monarchs are unlikely to be affected by small changes in plant communities. Agricultural transformations of natural communities in the eastern United States and Great Plains, however, and especially the extensive planting of genetically modified herbicide-resistant soybeans and corn, may be changing the availability of nectar for monarchs and other pollinators. This new technology is eliminating virtually all forbs in and surrounding agricultural fields, including the monarch's larval hostplants (milkweeds) and native and nonnative nectar sources. To evaluate whether changes in nectar availability are altering the butterflies' ability to accumulate energy, we recommend that monarchs' lipid contents be assayed annually at sites throughout eastern North America. PMID- 21672814 TI - Po'ouli landscape bioinformatics models predict energetics, behavior, diets, and distribution on Maui. AB - This study uses a spatially explicit microclimate/biophysical approach to examine the potential distribution of the Po'ouli on Maui to find either new habitats to search for existence or refine search efforts in previously occupied areas. We used specific physiological and behavioral ecology bird data, and Po'ouli morphological and spectral data obtained from museum specimens to address ecological and conservation-related questions about the Po'ouli that are otherwise very difficult to quantify. Laboratory and field tested microclimate and biophysical-behavioral animal computer models were integrated with remote sensing technologies. To show that the generic microclimate and endotherm models can predict metabolic and water loss requirements of Hawaiian Honeycreepers, we used the 2 species with known physiological properties, the Hawaiian Amakihi, Hemignathus virens, and the Hawaiian Anianiau, Hemignathus parvus. Predictions were within experimental measurement error of the laboratory measurements. Then using field rather than laboratory conditions as input data, we predict the field distribution of the Amakihi on Maui as the first spatial test of the models applied to birds. Results are consistent with Amakihi field distribution data. Fossils show that the Po'ouli once lived on Maui at low elevations in dry/mesic habitats on a likely diet of native tree snails and insects. The arrival of lethal mosquito-borne avian malaria in Hawaii exterminated low elevation Po'ouli forcing a population shift to mountain rainforests and possibly a snail diet instead of insects. To explore the maximum consequences of such a diet shift we assumed exclusive diets of snails versus insects at both low and high elevations. Snail diets require ~4 times higher foraging rates than do insect diets, making a predominantly snail diet an unlikely prospect for the Po'ouli. Landscape scale simulations suggest that a snail diet would force a Po'ouli distribution inconsistent with observations. A predominantly insect diet is consistent with distribution observations. We show that as local environmental conditions change across the landscape in space and diurnal/seasonal time it is possible to quantify animal physiological and behavioral consequences of those variations in their local environment. This enables quantification of the requisite spatial and temporal distribution and amount or availability of resources that may affect species' potential for survival, growth, reproduction and distribution. PMID- 21672815 TI - The energetics of reproduction in endotherms and its implication for their conservation. AB - The energy expenditure of endotherms, through its impact on the rate of reproduction, affects their ability to withstand competition, to tolerate environmental disturbances, and to endure predation. The fecundity of eutherian mammals increases with rate of metabolism because the post-natal growth rate increases and the gestation and conception-to-weaning periods decrease with a mass-independent increase in basal rate of metabolism. These correlations account for the observation that species that have large population fluctuations have high rates of metabolism and reproduction. Species with high rates of metabolism out-compete species with low rates when using resources that permit consumers to have high rates of metabolism, which explains why eutherian carnivores replace marsupial carnivores, none of which have high basal rates as a result of their form of reproduction. Fecundity in birds also appears to correlate with energy expenditure, which may account for the huge die-off of birds endemic to oceanic islands after the invasion of humans: island endemics, many of which have low rates of metabolism, are unable to increase fecundity in response to a human based increase in mortality. The long-term protection for endotherms characterized by low rates of energy expenditure requires their isolation from high levels of predation and competition, conditions that are likely to occur only on islands free from eutherian predators and with low species diversity. Such endotherms may survive on continents if they are ecologically isolated from the general fauna. PMID- 21672816 TI - Condition indices for conservation: new uses for evolving tools. AB - Biologists have developed a wide range of morphological, biochemical and physiological metrics to assess the health and, in particular, the energetic status of individual animals. These metrics originated to quantify aspects of human health, but have also proven useful to address questions in life history, ecology and resource management of game and commercial animals. We review the application of condition indices (CI) for conservation studies and focus on measures that quantify fat reserves, known to be critical for energetically challenging activities such as migration, reproduction and survival during periods of scarcity. Standard methods score fat content, or rely on a ratio of body mass rationalized by some measure of size, usually a linear dimension such as wing length or total body length. Higher numerical values of these indices are interpreted to mean an animal has greater energy reserves. Such CIs can provide predictive information about habitat quality and reproductive output, which in turn can help managers with conservation assessments and policies. We review the issues about the methods and metrics of measurement and describe the linkage of CIs to measures of body shape. Debates in the literature about the best statistical methods to use in computing and comparing CIs remain unresolved. Next, we comment on the diversity of methods used to measure body composition and the diversity of physiological models that compute body composition and CIs. The underlying physiological regulatory systems that govern the allocation of energy and nutrients among compartments and processes within the body are poorly understood, especially for field situations, and await basic data from additional laboratory studies and advanced measurement systems including telemetry. For now, standard physiological CIs can provide supporting evidence and mechanistic linkages for population studies that have traditionally been the focus of conservation biology. Physiologists can provide guidance for the field application of conditions indices with validation studies and development of new instruments. PMID- 21672817 TI - The importance of physiological ecology in conservation biology. AB - Many of the threats to the persistence of populations of sensitive species have physiological or pathological mechanisms, and those mechanisms are best understood through the inherently integrative discipline of physiological ecology. The desert tortoise was listed under the Endangered Species Act largely due to a newly recognized upper respiratory disease thought to cause mortality in individuals and severe declines in populations. Numerous hypotheses about the threats to the persistence of desert tortoise populations involve acquisition of nutrients, and its connection to stress and disease. The nutritional wisdom hypothesis posits that animals should forage not for particular food items, but instead, for particular nutrients such as calcium and phosphorus used in building bones. The optimal foraging hypothesis suggests that, in circumstances of resource abundance, tortoises should forage as dietary specialists as a means of maximizing intake of resources. The optimal digestion hypothesis suggests that tortoises should process ingesta in ways that regulate assimilation rate. Finally, the cost-of-switching hypothesis suggests that herbivores, like the desert tortoise, should avoid switching food types to avoid negatively affecting the microbe community responsible for fermenting plants into energy and nutrients. Combining hypotheses into a resource acquisition theory leads to novel predictions that are generally supported by data presented here. Testing hypotheses, and synthesizing test results into a theory, provides a robust scientific alternative to the popular use of untested hypotheses and unanalyzed data to assert the needs of species. The scientific approach should focus on hypotheses concerning anthropogenic modifications of the environment that impact physiological processes ultimately important to population phenomena. We show how measurements of such impacts as nutrient starvation, can cause physiological stress, and that the endocrine mechanisms involved with stress can result in disease. Finally, our new syntheses evince a new hypothesis. Free molecules of the stress hormone corticosterone can inhibit immunity, and the abundance of "free corticosterone" in the blood (thought to be the active form of the hormone) is regulated when the corticosterone molecules combine with binding globulins. The sex hormone, testosterone, combines with the same binding globulin. High levels of testosterone, naturally occurring in the breeding season, may be further enhanced in populations at high densities, and the resulting excess testosterone may compete with binding globulins, thereby releasing corticosterone and reducing immunity to disease. This sequence could result in physiological and pathological phenomena leading to population cycles with a period that would be essentially impossible to observe in desert tortoise. Such cycles could obscure population fluctuations of anthropogenic origin. PMID- 21672818 TI - The emergence of comparative biomechanics. AB - In recent years, comparative biomechanics, while anything but a new subject, has by an odd concatenation of circumstances emerged from obscurity to become a widely recognized and active area of biology-remarkably diverse in questions asked and techniques employed but with clear intellectual coherence. In North America the Society for Integrative and Comparative Biology currently represents the center of gravity in this field. PMID- 21672820 TI - Evolution and ecology of feeding in elasmobranchs. AB - Paleozoic chondrichthyans had a large gape, numerous spike-like teeth, limited cranial kinesis, and a non-suspensory hyoid, suggesting a feeding mechanism dominated by bite and ram. Modern sharks are characterized by a mobile upper jaw braced by a suspensory hyoid arch that is highly kinetic. In batoids, the upper jaw is dissociated from the cranium permitting extensive protrusion of the jaws. Similar to actinopterygians, the evolution of highly mobile mandibular and hyoid elements has been correlated with extensive radiation of feeding modes in elasmobranchs, particularly that of suction. Modern elasmobranchs possess a remarkable variety of feeding modes for a group containing so few species. Biting, suction or filter-feeding may be used in conjunction with ram to capture prey, with most species able to use a combination of behaviors during a strike. Suction-feeding has repeatedly arisen within all recent major elasmobranch clades and is associated with a suite of morphological and behavioral specializations. Prey capture in a diverse assemblage of purported suction-feeding elasmobranchs is investigated in this study. Drop in water pressure measured in the mouth and at the location of the prey shows that suction inflow drops off rapidly with distance from the predator's mouth. Elasmobranchs specializing in suction-feeding may be limited to bottom associated prey and because of their small gape may have a diet restricted to relatively small prey. Behavior can affect performance and overcome constraints imposed by the fluid medium. Suction performance can be enhanced by proximity to a substrate or by decreasing distance from predator to prey using various morphological and/or behavioral characteristics. Benthic suction-feeders benefit by the increased strike radius due to deflection of water flow when feeding close to a substrate, and perhaps require less accuracy when capturing prey. Suction and ram-suction-feeding elasmobranchs can also use suction inflow to draw prey to them from a short distance, while ram-feeding sharks must accelerate and overtake the prey. The relationship between feeding strategy and ecology may depend in part on ecological, mechanistic or evolutionary specialization. Mechanistic suction-feeding specialist elasmobranchs are primarily benthic, while most epibenthic and pelagic elasmobranchs are generalists and use ram, suction, and biting to catch a diversity of prey in various habitats. Some shark species are considered to be ecological specialists in choosing certain kinds of prey over others. Batoids are evolutionary specialists in having a flattened morphology and most are generalist feeders. Filter-feeding elasmobranchs are ecological, mechanistic, and evolutionary specialists. PMID- 21672819 TI - Neuromechanics: an integrative approach for understanding motor control. AB - Neuromechanics seeks to understand how muscles, sense organs, motor pattern generators, and brain interact to produce coordinated movement, not only in complex terrain but also when confronted with unexpected perturbations. Applications of neuromechanics include ameliorating human health problems (including prosthesis design and restoration of movement following brain or spinal cord injury), as well as the design, actuation and control of mobile robots. In animals, coordinated movement emerges from the interplay among descending output from the central nervous system, sensory input from body and environment, muscle dynamics, and the emergent dynamics of the whole animal. The inevitable coupling between neural information processing and the emergent mechanical behavior of animals is a central theme of neuromechanics. Fundamentally, motor control involves a series of transformations of information, from brain and spinal cord to muscles to body, and back to brain. The control problem revolves around the specific transfer functions that describe each transformation. The transfer functions depend on the rules of organization and operation that determine the dynamic behavior of each subsystem (i.e., central processing, force generation, emergent dynamics, and sensory processing). In this review, we (1) consider the contributions of muscles, (2) sensory processing, and (3) central networks to motor control, (4) provide examples to illustrate the interplay among brain, muscles, sense organs and the environment in the control of movement, and (5) describe advances in both robotics and neuromechanics that have emerged from application of biological principles in robotic design. Taken together, these studies demonstrate that (1) intrinsic properties of muscle contribute to dynamic stability and control of movement, particularly immediately after perturbations; (2) proprioceptive feedback reinforces these intrinsic self stabilizing properties of muscle; (3) control systems must contend with inevitable time delays that can simplify or complicate control; and (4) like most animals under a variety of circumstances, some robots use a trial and error process to tune central feedforward control to emergent body dynamics. PMID- 21672821 TI - The evolution of cranial design, diet, and feeding mechanisms in batoid fishes. AB - The batoid fishes (electric rays, sawfishes, skates, guitarfishes, and stingrays) are a trophically and morphologically diverse clade in which the observed range of diets is a product of a feeding mechanism with few parts and therefore a limited number of functional interactions. This system allows an intriguing comparison to the complex network of associations in the feeding apparatus of bony fishes and an anatomically simple framework for investigations of the mechanisms underlying the evolution of functional and phenotypic diversity. We quantified morphology from reconstructed CT scans of 40 batoid species, representing more than half of the extant genera. We used pairwise comparisons to evaluate the extent of coevolution among components of the feeding apparatus and among morphologies and diets. These relationships were then used to predict diets in poorly studied taxa and in a reconstruction of the batoid ancestor. Although functionally there are fewer examples of convergence in the batoid feeding mechanism than in bony fishes, our data show multiple evolutions of similar dietary compositions underlain by a broad morphological diversity. Elements of the feeding apparatus evolved independently of one another, suggesting that decoupling components of the head skeleton created separate but interacting evolutionary modules that allowed trophic diversification. Our data imply that food habits exhibit strong independent and convergent evolution and that suites of morphologies are associated with certain diets; however, lack of behavioral data for this clade, and one example of divergent diets underlain by convergent morphology, caution against the assumption of simplistic relationships between form and function. We therefore urge future work to ground truth our study by testing the functional, dietary and evolutionary hypotheses suggested by our data. PMID- 21672822 TI - The integration of locomotion and prey capture in vertebrates: Morphology, behavior, and performance. AB - For most vertebrates, locomotion is a fundamental component of prey capture. Despite this ubiquitous link, few studies have quantified the integration of these complex systems. Several variables related to locomotor performance, including maximum speed, acceleration, deceleration, maneuverability, accuracy, and approach stability, likely influence feeding performance in vertebrates. The relative importance of these measures of performance, however, depends on the ecology of the predator. While factors such as morphology and physiology likely define the limits of these variables, other factors such as motivation of the predator, prey type, and habitat structure can also influence performance. Understanding how these variables relate to feeding under a given suite of ecological conditions is central to understanding predator-prey interactions, and ultimately how locomotion and feeding have co-evolved. The goals of this article are to discuss several variables of locomotor performance related to prey capture, present new data on the relationship between locomotor and feeding morphology in fishes, discuss the evolution of prey capture in cichlid fishes, and outline some future directions for research. While suction feeding is a primary mechanism of prey capture in fishes, swimming is vital for accurately positioning the mouth relative to the prey item. Many fishes decelerate during prey capture using their body and fins, but the pectoral fins have a dominant role in maintaining approach stability. This suggests that fishes employing high performance suction feeding (relatively small mouth) will have larger pectoral fins to facilitate accurate and stable feeding. I provide new data on the relationship between pectoral fin morphology and maximum gape in centrarchid fishes. For seven species, pectoral fin area was significantly, and negatively, correlated with maximum gape. This example illustrates that the demands from one complex system (feeding) can influence another complex system (locomotion). Future studies that examine the morphological, physiological, and functional evolution of locomotion involved in prey capture by aquatic and terrestrial vertebrates will provide insight into the origin and consequences of diversity. PMID- 21672823 TI - Suction feeding mechanics, performance, and diversity in fishes. AB - Despite almost 50 years of research on the functional morphology and biomechanics of suction feeding, no consensus has emerged on how to characterize suction feeding performance, or its morphological basis. We argue that this lack of unity in the literature is due to an unusually indirect and complex linkage between the muscle contractions that power suction feeding, the skeletal movements that underlie buccal expansion, the sharp drop in buccal suction pressure that occurs during expansion, the flow of water that enters the mouth to eliminate the pressure gradient, and the forces that are ultimately exerted on the prey by this flow. This complexity has led various researchers to focus individually on suction pressure, flow velocity, or the distance the prey moves as metrics of suction-feeding performance. We attempt to integrate a mechanistic view of the ability of fish to perform these components of suction feeding. We first discuss a model that successfully relates aspects of cranial morphology to the capacity to generate suction pressure in the buccal cavity. This model is a particularly valuable tool for studying the evolution of the feeding mechanism. Second, we illustrate the multidimensional nature of suction-feeding performance in a comparison of bluegill, Lepomis macrochirus, and largemouth bass, Micropterus salmoides, two species that represent opposite ends of the spectrum of performance in suction feeding. As anticipated, bluegills had greater accuracy, lower peak flux into the mouth, and higher flow velocity and acceleration of flow than did bass. While the differences between species in accuracy of strike and peak water flux were substantial, peak suction velocity and acceleration were only about 50% higher in bluegill, a relatively modest difference. However, a hydrodynamic model of the forces that suction feeders exert on their prey shows that this difference in velocity is amplified by a positive effect of the smaller mouth aperture of bluegill on force exerted on the prey. Our model indicates that the pressure gradient in front of a fish that is feeding by suction, associated with the gradient in water velocity, results in a force on the prey that is larger than drag or acceleration reaction. A smaller mouth aperture results in a steeper pressure gradient that exerts a greater force on the prey, even when other features of the suction flow are held constant. Our work shows that some aspects of suction-feeding performance can be determined from morphology, but that the complexity of the behavior requires a diversity of perspectives to be used in order to adequately characterize performance. PMID- 21672824 TI - The evolution of cranial design and performance in squamates: Consequences of skull-bone reduction on feeding behavior. AB - The evolution of cranial design in lepidosaurians is characterized by a general trend toward the loss of cranial elements. The evolution of relatively lighter skulls in squamates appears tightly coupled to a reduction in relative mass of the jaw adductor, implying functional consequences for bite force and feeding behavior. Interestingly, among squamates the postorbital bar was reduced or lost at least twice independently and taxa characterized by the loss of these cranial elements (e.g., geckos and varanids) are generally reported as having a mobile skull. In Gekkotans, the loss of the postorbital bar was accompanied by a reduction of the supratemporal bar, resulting in a pronounced cranial kinesis. Our data show that having a kinetic skull has functional consequences and results in a reduction in bite force. The lower bite force may in turn be responsible for the decreased feeding efficiency as reflected in the longer duration of intra oral transport cycles. Gekkotans, however, appear to exploit their intracranial mobility in ways that increases the velocity of jaw movement during opening and closing, which may allow them to capture more elusive prey. The morphological changes observed in the evolution of the cranial system in squamates appear tightly linked to functional and constructional demands on the skull, making squamate skull evolution a model system to investigate the consequences of morphological changes in a complex integrated system of performance, behavior, and ecology. PMID- 21672825 TI - Modulation of intra-oral processing in mammals and lepidosaurs. AB - The mammalian masticatory apparatus is distinguished from the intra-oral processing systems of other amniotes by a number of morphological and functional features, including transverse movements of the teeth during the power stroke, precise occlusion, suspension of the teeth in the socket by a periodontal ligament, diphyodonty (reduction to two generations of teeth), a hard palate, and the presence of a single bone (the dentary) in the lower jaw which articulates with the skull at the temporomandibular jaw joint. The evolution of these features is commonly argued to have improved the efficiency of food processing in the oral cavity. The present aricle highlights the existence in mammals of the fusimotor system and afferent fibers from the periodontal ligament through which the CNS modulates the responses by the muscle spindles. Published data suggest that the fusimotor system and the periodontal afferents are important components in feed-forward (or anticipatory) control of chewing behavior. We hypothesize that this feed-forward control is used to maintain relatively constant cycle lengths in mammals in the face of intra-sequence and inter-sequence variation in material properties of the food, and that this enables them to maintain a higher average chewing frequency than that of lizards. These predictions were evaluated using data on mean cycle length and its variance from the literature and from our own files. On average, mammals have less variable cycle lengths than do lizards and shorter cycle lengths than do lizards of similar size. We hypothesize that by decreasing variance in cycle length, presumably close to the natural frequency of their feeding systems, mammals minimize energy expenditure during chewing, allowing them to chew for longer, thereby maintaining the high rates of food intake required for their high metabolic rates. PMID- 21672826 TI - Feeding mechanisms in bats: variation within the constraints of flight. AB - By any standard, bats are a successful group of mammals and the evolution of flight and echolocation were certainly key innovations behind their success. That is only part of the story, however. Bats have diversified into trophic niches that range from insectivory to feeding on blood, fruit, or nectar. While flight places fundamental constraints on the shape of the postcranial skeleton, skull shape in bats is remarkably diverse. Morphological studies of individual families and sympatric assemblages demonstrate that variation in skull shape is clearly associated with trophic specialization. Field experiments demonstrate that species-specific biting behaviors during feeding are common and analyses indicate that the evolution of cranial morphology and feeding behavior are correlated. Modeling experiments further suggest that feeding (loading) behaviors and skull shape are functionally linked. If the skulls of bats are under selective pressure for minimal mass because of the energetic demands of flight, then they may be more "optimized" to meet mechanical demands than are the skulls of other mammals. This would make bats a unique model system for studying the evolution of diversity in skull shape and its functional implications for the evolution of feeding strategies in mammals. PMID- 21672827 TI - Deja vu: the evolution of feeding morphologies in the Carnivora. AB - The fossil record of the order Carnivora extends back at least 60 million years and documents a remarkable history of adaptive radiation characterized by the repeated, independent evolution of similar feeding morphologies in distinct clades. Within the order, convergence is apparent in the iterative appearance of a variety of ecomorphs, including cat-like, hyena-like, and wolf-like hypercarnivores, as well as a variety of less carnivorous forms, such as foxes, raccoons, and ursids. The iteration of similar forms has multiple causes. First, there are a limited number of ways to ecologically partition the carnivore niche, and second, the material properties of animal tissues (muscle, skin, bone) have not changed over the Cenozoic. Consequently, similar craniodental adaptations for feeding on different proportions of animal versus plant tissues evolve repeatedly. The extent of convergence in craniodental form can be striking, affecting skull proportions and overall shape, as well as dental morphology. The tendency to evolve highly convergent ecomorphs is most apparent among feeding extremes, such as sabertooths and bone-crackers where performance requirements tend to be more acute. A survey of the fossil record indicates that large hypercarnivores evolve frequently, often in response to ecological opportunity afforded by the decline or extinction of previously dominant hypercarnivorous taxa. While the evolution of large size and carnivory may be favored at the individual level, it can lead to a macroevolutionary ratchet, wherein dietary specialization and reduced population densities result in a greater vulnerability to extinction. As a result of these opposing forces, the fossil record of Carnivora is dominated by successive clades of hypercarnivores that diversify and decline, only to be replaced by new hypercarnivorous clades. This has produced a marvelous set of natural experiments in the evolution of similar ecomorphs, each of which start from phylogenetically and morphologically unique positions. PMID- 21672828 TI - Ecological dimorphisms: An introduction to the symposium. AB - A growing body of literature is devoted to understanding differences between males and females in numerous behavioral, morphological, and physiological variables that do not appear to play a role in sexual or fecundity selection. Despite the increasing attention paid to such ecological dimorphisms, there has thus far been no attempt to consolidate or review studies in this area. This symposium comprises a series of papers that examine ecological dimorphisms from several diverse perspectives, spanning a range of ecological fields from functional morphology to behavior and evolution of life-history. These studies show that gender exerts considerable effects on individual ecology, even outside of the context of reproduction. PMID- 21672829 TI - Functional and ecological correlates of ecologically-based dimorphisms in squamate reptiles. AB - Sexual dimorphism in phenotypic traits associated with the use of resources is a widespread phenomenon throughout the animal kingdom. While ecological dimorphisms are often initially generated by sexual selection operating on an animal's size, natural selection is believed to maintain, or even amplify, these dimorphisms in certain ecological settings. The trophic apparatus of snakes has proven to be a model system for testing the adaptive nature of ecological dimorphisms because head size is rarely under sexual selection and it limits the maximum ingestible size of prey in these gape-limited predators. Significantly less attention has been paid to the evolution of ecological dimorphisms in lizards, however, which may be due to the fact that lizards' feeding apparatus can be under both sexual and natural selection simultaneously, making it difficult to formulate clear-cut hypotheses to distinguish between the influences of natural and sexual selection. In order to tease apart the respective influences of natural selection and sexual selection on the feeding apparatus of squamates, we take an integrative approach to formulate two hypotheses for snakes and lizards, respectively: (1) For gape limited snakes, we predict that natural selection will act to generate differences in maximum gape, which will translate into differences in maximum ingestible prey size between the sexes. (2) For lizards which mechanically reduce their prey, we predict that the degree of dimorphism in head size should be positively correlated to the degree of dimorphism in bite force which, in turn, should be correlated to dimorphism in aspects of size or hardness of prey. Finally, we predict that functional differences in the feeding apparatus of these animals will also be linked with differences in sex-based feeding behavior and with selection of prey. PMID- 21672830 TI - Interactive effects of sex and temperature on locomotion in reptiles. AB - Males and females from several animal taxa differ in locomotor performance traits such as sprinting and jumping. These performance dimorphisms may be explained at least partially by sexual differences in physiology or morphology. In ectotherms such as reptiles, however, thermal ecology places an additional constraint on realized locomotor performance. I review recent studies on reptiles examining sexual differences in locomotor capacity and related thermoregulatory behavior, and discuss potential causes, constraints, and selective pressures that might drive intersexual divergence in capacity for locomotor performance in reptiles. In several cases where such differences occur, sexual dimorphisms in body size do not account for all the observed variation in performance. However, while sex specific locomotor capacities might be evident in the laboratory, ecological performance in nature is likely the result of complex interactions among sex, thermal sensitivity, habitat type, and behavioral locomotor compensation. Results from laboratory studies of dimorphisms in maximum locomotor capacity are therefore likely to be poor predictors of realized ecological differences in performance. Nonetheless, sex differences in performance are potentially important modifiers of male and female behavioral strategies and overall fitness, and consequently are deserving of more attention than they have thus far received. PMID- 21672831 TI - Determinants of sexual differences in escape behavior in lizards of the genus Anolis: a comparative approach. AB - Males and females are known to differ in a whole suite of characteristics, such as morphology, physiology, ecology, and behavior. Intersexual differences are generally believed to arise because of differences in selective pressures on either sex. In this study, we investigated whether intersexual differences in escape behavior exist in lizards of the genus Anolis, and whether these could be explained by intersexual differences in body size and/or microhabitat use. To do so, we compared the behavioral response to an approaching human predator in the field in males and females of 12 Anolis species. We found that ecomorphs and sexes differ greatly with respect to escape behavior. Twig anoles have the shortest approach distance (i.e., distance between the observer and the lizard when it starts fleeing) and final distance (i.e., distance between the observer and the lizard when it stops moving), compared with the other ecomorphs. The distance fled, on the contrary, is greatest in twig anoles. Also, females flee less soon and run over shorter distances than do males. Since twig anoles are considered the most cryptic anoles, and females may be less conspicuous than males, these results corroborate the idea that well camouflaged animals allow predators to come closer. The interspecific variation in sexual dimorphism in escape behavior, however, cannot be explained by the interspecific variation in sexual size dimorphism or sexual dimorphism in microhabitat use. Thus, escape behavior appears determined by different factors in males and females. PMID- 21672832 TI - Morphology, performance, behavior and ecology of three color morphs in males of the lizard Podarcis melisellensis. AB - Males of a Croatian population of the lacertid lizard Podarcis melisellensis exhibit a striking polymorphism, with coloration of the throat and abdomen ranging from completely white, to yellow or orange. In a first attempt to explore the potential ecological and evolutionary significance of this polymorphism, we compared the three forms of males in aspects of their morphology, whole-animal performance, behavior, and ecology. Orange males are, on average, larger in snout vent length and have disproportionately larger heads than either white or yellow males. This is reflected in orange males having higher bite force capacity and theoretically an increased access to harder prey. Residual limb length, maximal sprint speed and maximal exertion do not differ among color morphs. Body temperatures in the field are similar in the three morphs, but yellow males are caught at sites with slightly higher air temperatures than are orange and white males. Behavioral observations show no differences in time budgets or in the timing of activities among morphs. Microhabitat use is also similar in the three color morphs, but orange males were more often initially seen on rocky substrates. Our findings suggest that the observed polymorphism likely does not originate from a divergence in niche or use of resources, but possibly reflects an underlying polymorphism in mating tactics. PMID- 21672833 TI - Developmental evolution of sexual ornamentation: model and a test of feather growth and pigmentation. AB - A tremendous diversity of avian color displays has stimulated numerous studies of natural and sexual selection. Yet, the developmental mechanisms that produce such diversification, and thus the proximate targets of selection pressures, are rarely addressed and poorly understood. In particular, because feathers are colored during growth, the dynamics of feather growth play a deterministic role in the variation in ornamentation. No study to date, however, has addressed the contribution of feather growth to the expression of carotenoid-based ornamentation. Here, we examine the developmental basis of variation in ornamental feather shapes in male house finches (Carpodacus mexicanus)-a species in which carotenoid displays are under strong natural and sexual selection. First, we use geometric morphometrics to partition the observed shape variation in fully grown feathers among populations, ages, degrees of elaboration, ornamental body parts, and individuals. Second, we use a biologically informed mathematical model of feather growth to predict variation in shape of ornamental feathers due to simulated growth rate, angle of helical growth of feather barbs, initial number of barb ridges, rate of addition of new barbs, barb diameter, and ramus-expansion angle. We find close concordance between among-individual variation in feather shape and hue of entire ornament, and show that this concordance can be attributed to a shared mechanism-growth rate of feather barbs. Predicted differences in feather shape due to rate of addition of barbs and helical angle of feather growth explained observed variation in ornamental area both among individuals and between populations, whereas differences in helical angle of growth and the number of barbs in the feather follicle explained differences in feather shape between ornamental parts and among males of different ages. The findings of a close association of feather growth dynamics and overall ornamentation identify the proximate targets of selection for elaboration of sexual displays. Moreover, the close association of feather growth and pigmentation not only can reinforce condition-dependence in color displays, but can also enable phenotypic and genetic accommodation of novel pigments into plumage displays providing a mechanism for the observed concordance of within population developmental processes and between-population diversification of color displays. PMID- 21672834 TI - Evolution of ontogeny: linking epigenetic remodeling and genetic adaptation in skeletal structures. AB - Evolutionary diversifications are commonly attributed to the continued modifications of a conserved genetic toolkit of developmental pathways, such that complexity and convergence in organismal forms are assumed to be due to similarity in genetic mechanisms or environmental conditions. This approach, however, confounds the causes of organismal development with the causes of organismal differences and, as such, has only limited utility for addressing the cause of evolutionary change. Molecular mechanisms that are closely involved in both developmental response to environmental signals and major evolutionary innovations and diversifications are uniquely suited to bridge this gap by connecting explicitly the causes of within-generation variation with the causes of divergence of taxa. Developmental pathways of bone formation and a common role for bone morphogenetic proteins (BMPs) in both epigenetic bone remodeling and the evolution of major adaptive diversifications provide such opportunity. We show that variation in timing of ossification can result in similar phenotypic patterns through epigenetically induced changes in gene expression and propose that both genetic accommodation of environmentally induced developmental pathways and flexibility in development across environments evolve through heterochronic shifts in bone maturation relative to exposure to unpredictable environments. We suggest that such heterochronic shifts in ossification can not only buffer development under fluctuating environments while maintaining epigenetic sensitivity critical for normal skeletal formation, but also enable epigenetically induced gene expression to generate specialized morphological adaptations. We review studies of environmental sensitivity of BMP pathways and their regulation of formation, remodeling, and repair of cartilage and bone to examine the hypothesis that BMP-mediated skeletal adaptations are facilitated by evolved reactivity of BMPs to external signals. Surprisingly, no empirical study to date has identified the molecular mechanism behind developmental plasticity in skeletal traits. We outline a conceptual framework for future studies that focus on mediation of phenotypic plasticity in skeletal development by the patterns of BMP expression. PMID- 21672835 TI - Sexual segregation in vertebrates: proximate and ultimate causes. AB - Sexual segregation is very common in vertebrates that live in groups. In this article, I will review proximate and ultimate causes of sexual segregation in social species and in particular in ungulates in which the bulk of research on the topic has been carried out. In most social ungulate species, males and females live in separate groups outside the breeding season, sometimes using different home ranges and types of habitat. In most of these species, males are larger than females. Dimorphism in body size can lead to sexual differences in ecology and behavior making it difficult for the two sexes to stay in the same group. It is important for our better understanding of the evolution of sociality, sexual dimorphism and different mating systems to determine why sexual segregation is so widespread not only in ungulates but also in other vertebrates. In this article, I discuss the ecology of the two sexes by reviewing proximate and ultimate causes of sexual segregation. To do this, I compare a range of studies of ruminants and include explanations for social segregation as well as for habitat segregation by gender. This leads into a review and updates current knowledge of the phenomenon. Although I present a number of different hypotheses, I focus in particular on predation risk, forage selection and activity budget and discuss the social-factors hypothesis. I stress that the key in solving the enigma of sexual segregation lies in clearly separating hypotheses that try to explain social segregation and habitat segregation, as well as in including experiments or model systems. To that end, I present a preliminary study on a test of the activity-budget hypothesis in three-spine sticklebacks and explain why I believe that shoaling fish are useful for analysing the underlying processes and mechanisms that lead to sexual segregation in animals. Lastly, I argue that it is unlikely that a single factor can explain social segregation or habitat segregation but that a model integrating different factors and different levels of segregation might succeed in describing proximate and ultimate causes of sexual segregation. PMID- 21672836 TI - Proximate developmental mediators of sexual dimorphism in size: case studies from squamate reptiles. AB - Sexual dimorphism in size (sexual size dimorphism; SSD) is nearly ubiquitous, but the relative importance of genetic versus environmental control of SSD is not known for most species. We investigated proximate determinants of SSD in several species of squamate reptiles, including three species of Sceloporus lizards and the diamond-backed rattlesnake (Crotalus atrox). In natural populations of these species, SSD is caused by sexual differences in age-specific growth. Males and females, however, may often share similar potentials for growth: growth is strongly responsive to the availability of food, and sexual differences in growth can be greatly suppressed or completely absent under common environmental conditions in the laboratory. Sexually divergent growth is expressed in natural environments because of inherent ecological differences between males and females and because of potential epigenetic effects of sex-specific growth regulators. In field-active Sceloporus, sexual differences in growth rate are associated with sexual divergence in plasma testosterone. Experiments confirm that testosterone inhibits growth in species in which females are larger (for example, S. undulatus and S. virgatus) and stimulates growth in those in which males are larger (for example, S. jarrovii). Interestingly, however, sexual divergence in plasma testosterone is not accompanied by divergence in growth in S. jarrovii or in male larger C. atrox in the laboratory. Furthermore, experimental effects of castration and testosterone replacement on growth are not evident in captive S. jarrovii, possibly because growth effects of testosterone are superseded by an abundant, high-quality diet. In female-larger S. undulatus, growth may be traded off against testosterone-induced reproductive costs of activity. In male-larger species, costs of reproduction in terms of growth are suggested by supplemental feeding of reproductive female C. atrox in their natural environment and by experimental manipulation of reproductive cost in female S. jarrovii. Growth costs of reproduction, however, do not contribute substantially to the development of SSD in male-larger S. jarrovii. We conclude that the energetic costs of testosterone-induced, male reproductive behavior may contribute substantially to the development of SSD in some female-larger species. However, despite strong evidence that reproductive investment exacts a substantial cost in growth, we do not support the reproductive cost hypothesis as a general explanation of SSD in male-larger species. PMID- 21672837 TI - Vive le difference! Sexual dimorphism and adaptive patterns in lizards of the genus Anolis. AB - The repeated, convergent evolution of body shape and microhabitat use in Greater Antillean lizards of the genus Anolis (anoles) provides compelling evidence of the importance of microhabitat specialization in shaping morphology. Interestingly, sexual dimorphism is also extensive, with males and females differing in body size as well as in shape. It is important to note that the components of shape analyzed in these studies is related to locomotion and are size-adjusted, including: relative limb and body lengths and mass of the body. Numbers of lamellae were also used and these do not vary with size. Furthermore, dimorphism in both size and shape differs by habitat type. Thus, does functionally-relevant sexual dimorphism imply that one sex is the "ecological" sex, with the other being maladapted to it's environment? Alternatively, sexual dimorphism may interact with adaptive diversification. Different classes of individuals within a species may act as separate ecological units if they play ecologically different roles. Here, I reanalyze a data set of morphological data for 15 species of Puerto Rican and Jamaican Anolis, which represent two largely independent adaptive radiations of lizards. I test for concordance between size and shape dimorphism and microhabitat (ecomorph) type, and for "parallel" patterns of sexual dimorphism among species. I integrate these results and, in the light of previous research, evaluate the relative influence that larger-scale ecological patterns have on sexual dimorphism, as well as the influence of sexual dimorphism on community structuring. I conclude that the presence of ecologically relevant dimorphism may in fact increase the adaptive diversity present within a community. PMID- 21672838 TI - Are powerful females powerful enough? Acceleration in gravid green iguanas (Iguana iguana). AB - One demand placed exclusively on the musculoskeletal system of females is maintaining locomotor performance with an increasing load over the reproductive cycle. Here, we examine whether gravid (i.e., "pregnant") iguanas can increase their force and power production to support, stabilize, and accelerate the additional mass of a clutch of eggs. At any acceleration, gravid iguanas produced very high mechanical power (average total power = 673 w/kg; total peak power = 1175 w/kg). While the increase in total power was partly a result of greater propulsive power (average propulsive power = 25% higher, peak propulsive power = 38% higher), increased vertical power (roughly 200% increase) was the main contributor. Gravid iguanas were also able to increase peak forces (propulsive = 23%, mediolateral = 44%, vertical = 42%), and step duration (44%) resulting in greater impulses (i.e., the sum of force produced during a step) to accelerate, balance, and support their increased mass. The increase in step duration and smaller increase in peak propulsive force suggests that gravid iguanas may be force-limited in the direction of motion. We discuss how biomechanical constraints due to females' reproductive role may influence the evolution of the female musculoskeletal systems and contribute to the evolution and maintenance of ecological dimorphism in lizards. PMID- 21672839 TI - Parasitic castration: a perspective from a model of dynamic energy budgets. AB - Models of the evolution of virulence have typically focused on increased mortality, one of two negative effects that parasites can inflict on their host. Those that consider the other effect, fecundity reduction, can predict that parasites should completely sterilize their hosts. Although this prediction seems extreme, sterilization features prominently in a fascinating strategy, parasitic castration. Such castration can be accompanied by gigantism (unusually large growth of infected hosts), long infectious periods, and fecundity compensation (where, before heavy parasite burdens ensue, newly infected hosts reproduce earlier/more than they would if not infected). Using a model of dynamic energy budgets (DEB), we show how these results readily emerge, assuming that parasites consume energy reserves of the host. The simple, but mechanistic, DEB model follows energy flow though hosts and parasites, starting with ingestion, and continuing with storage of assimilated energy, and use of those reserves for growth and reproduction, as allocated by the host according to the "kappa-rule". Using this model, we compare and contrast two strategies for parasites. "Consumers" only steal energy from their hosts, thereby indirectly altering allocation of energy to growth and reproduction, reducing fecundity, and enhancing mortality. "Castrators" steal energy but also directly modify the scheme by which hosts allocate reserve energy, shunting resources from reproduction to growth. Not surprisingly, the model predicts that this strategy should promote gigantism, but it also forecasts longer infectious periods and fecundity compensation. Thus, commonly observed characteristics of parasitic castration readily emerge from a mechanistic model of energy flow using a minimal number of assumptions. Finally, the DEB model for both "consumers" and "castrators" highlight that variation in resources supplied to hosts promotes variation in virulence in a given host-parasite system, holding all else equal. Such predictions highlight the potential importance of resource ecology for virulence in disease systems. PMID- 21672840 TI - Host resource supplies influence the dynamics and outcome of infectious disease. AB - Pathogens and their host organisms share a wide range of resource needs that are required to support normal metabolism and growth. Because the development of infectious disease on or within the host involves the processes of invasion and resource consumption, competition for growth-limiting resources potentially may occur between pathogens and cellular or sub-cellular components of the host ecosystem. Examples from the plant, animal, and microbiological literature provide unambiguous evidence that external resource supplies to the host organism can have profound effects on the outcome of infection by a broad diversity of bacterial, fungal, metazoan, protozoan, and viral pathogens. PMID- 21672841 TI - Why don't all whales have cancer? A novel hypothesis resolving Peto's paradox. AB - Larger organisms have more potentially carcinogenic cells, tend to live longer and require more ontogenic cell divisions. Therefore, intuitively one might expect cancer incidence to scale with body size. Evidence from mammals, however, suggests that the cancer risk does not correlate with body size. This observation defines "Peto's paradox." Here, we propose a novel hypothesis to resolve Peto's paradox. We suggest that malignant tumors are disadvantaged in larger hosts. In particular, we hypothesize that natural selection acting on competing phenotypes among the cancer cell population will tend to favor aggressive "cheaters" that then grow as a tumor on their parent tumor, creating a hypertumor that damages or destroys the original neoplasm. In larger organisms, tumors need more time to reach lethal size, so hypertumors have more time to evolve. So, in large organisms, cancer may be more common and less lethal. We illustrate this hypothesis in silico using a previously published hypertumor model. Results from the model predict that malignant neoplasms in larger organisms should be disproportionately necrotic, aggressive, and vascularized than deadly tumors in small mammals. These predictions may serve as the basis on which to test the hypothesis, but to our knowledge, no one has yet performed a systematic investigation of comparative necrosis, histopathology, or vascularization among mammalian cancers. PMID- 21672842 TI - Cyclostome embryology and early evolutionary history of vertebrates. AB - Modern agnathans include only two groups, the lampreys and the hagfish, that collectively comprise the group Cyclostomata. Although accumulating molecular data support the cyclostomes as a monophyletic group, there remain some unsettled questions regarding the evolutionary relationships of these animals in that they differ greatly in anatomical and developmental patterns and in their life histories. In this review, we summarize recent developmental data on the lamprey and discuss some questions related to vertebrate evolutionary development raised by the limited information available on hagfish embryos. Comparison of the lamprey and gnathostome developmental patterns suggests some plesiomorphic traits of vertebrates that would have already been established in the most recent common ancestor of the vertebrates. Understanding hagfish development will further clarify the, as yet, unrecognized ancestral characters that either the lampreys or hagfishes may have lost. We stress the immediate importance of hagfish embryology in the determination of the most plausible scenario for the early history of vertebrate evolution, by addressing questions about the origins of the neural crest, thyroid, and adenohypophysis as examples. PMID- 21672843 TI - The origins of species-specific facial morphology: the proof is in the pigeon. AB - One of the principal objectives of developmental research is to understand morphogenesis and in doing so, gain insights into the genetic basis of variation observed throughout the Animal Kingdom. In this review we take an approach, first popularized by Darwin, to understanding how diversity is created by using the domesticated pigeon as a model organism. Nearly 3000 years of selective breeding has produced an astonishing array of feather patterns, behaviors, skeletal shapes, and body sizes. Cumulatively, these features make the pigeon an exemplar of morphological variation. Our research interests center around exploiting the unique properties of domesticated pigeons to gain critical insights into the molecular and cellular basis for craniofacial variation. PMID- 21672844 TI - How old genes make a new head: redeployment of Six and Eya genes during the evolution of vertebrate cranial placodes. AB - Cranial placodes give rise to many evolutionary novelties of the vertebrate head, such as its specialized paired sense organs and cranial ganglia. There is an increasing evidence that all placodes originate from a common primordium located around the anterior neural plate and defined by the expression of transcription factors of the Six1/2, Six4/5, and Eya families. These transcription factors continue to be expressed in the different placodes and appear to control similar developmental processes (e.g., proliferation, cell shape changes, and neurogenesis) in the different placodes suggesting that they play a central role for generic placodal development. Elucidating the central role of Six and Eya genes for placodal development requires an understanding of (1) how these genes are induced in the pre-placodal ectoderm at the right place and time and (2) how they subsequently affect and promote placodal development. The first part of this review gives a brief overview of what is currently known about these upstream and downstream regulatory linkages of Six and Eya genes. The second part of the review then discusses the distribution and function of Six and Eya genes in other deuterostomes in order to infer changes of upstream and downstream linkages in the course of deuterostome evolution by which Six and Eya genes adopted their new role in vertebrate placode development. It is argued that these genes were probably recruited to the neural plate border in the ancestor of urochordates and vertebrates, and adopted novel roles in the regulation of neuronal differentiation and possibly other pathways of cytodifferentiation as well in the vertebrate lineage. PMID- 21672845 TI - A revised fate map for amphioxus and the evolution of axial patterning in chordates. AB - The chordates include vertebrates plus two groups of invertebrates (the cephalochordates and tunicates). Previous embryonic fate maps of the cephalochordate amphioxus (Branchiostoma) were influenced by preconceptions that early development in amphioxus and ascidian tunicates should be fundamentally the same and that the early amphioxus embryo, like that of amphibians, should have ventral mesoderm. Although detailed cell lineage tracing in amphioxus has not been done because of limited availability of the embryos and because cleavage is radial and holoblastic with the blastomeres nearly equal in size and not tightly adherent until the mid-blastula stage, a compilation of data from gene expression and function, blastomere isolation and dye labeling allows a more realistic fate map to be drawn. The revised fate map is substantially different from that of ascidians. It shows (1) that the anterior pole of the amphioxus embryo is offset dorsally from the animal pole only by about 20 degrees , (2) that the ectoderm/mesendoderm boundary (the future rim of the blastopore) is at the equator of the blastula, which approximately coincides with the 3rd cleavage plane, and (3) that there is no ventral mesoderm during the gastrula stage. Involution or ingression of cells over the blastopore lip is negligible, and the blastopore, which is posterior, closes centripetally as if by a purse string. During the gastrula stage, the animal pole shifts ventrally, coming to lie about 20 degrees ventral to the anterior tip of the late gastrula/early neurula. Comparisons of the embryos of amphioxus and vertebrates indicate that in spite of large differences in the mechanics of cleavage and gastrulation, anterior/posterior and dorsal/ventral patterning occur by homologous genetic mechanisms. Therefore, the small, nonyolky embryo of amphioxus is probably a reasonable approximation of the basal chordate embryo before the evolution of determinate cleavage in the tunicates and the evolution large amounts of yolk in basal vertebrates. PMID- 21672846 TI - Watch-ing out for chick limb development. AB - Time control is a crucial issue during embryonic development. Nevertheless, little is known about how embryonic cells measure time. Until recently, the only molecular clock known to operate during vertebrate embryonic development was the somitogenesis clock, exclusively functioning in coordinating the precise timing of each new pair of somites formed from the presomitic mesoderm. We have recently evidenced that a similar molecular clock also underlies the timing at which autopod chondrogenic precursors are laid down to form a skeletal limb element. In addition, we herein suggest that the molecular clock is not the only parallelism that can be established between somitogenesis and limb-bud development. In an evolutionary perspective, we support the previously proposed idea that the molecular mechanisms involved in the segmentation of the body axis may have been partially reused in the mesoderm of the lateral plate, thereby allowing the emergence of paired appendages. PMID- 21672847 TI - On the origins of morphological variation, canalization, robustness, and evolvability. AB - Canalization is a concept, introduced by Waddington that describes the reduced sensitivity of a phenotype to genetic and environmental perturbations. Some research in canalization assumes that lack of variation in a trait in one genotype with respect to another genotype in a population, is due to the existence of buffering mechanisms against environmental and/or genetic variation. This article criticizes this assumption and out points out other possible problems with the concepts of canalization, robustness, and evolvability. These involve: the neglect of alternative explanations for the lack of variation in a trait, the incompatibility with current understanding of development, the way the mutivariate nature of morphological variation is considered. In addition, this article tries to explain that these concepts implicitly assume, although not generally acknowledged, that without buffering any genetic or environmental variation should give rise to a distinct phenotypic outcome. This can be avoided by restricting the use of canalization to cases in which, as in hsp90, there is direct evidence of buffering. For the other cases it would be clearer to talk about variational properties or simply type of variation. The concept of evolvability is also biased towards univariate comparisons and is dependent on selective pressures. It is suggested that this can be replaced by "type of phenotypic variation" from a genotype or variational properties. Overall, this article proposes that the concepts of canalization and evolvability involve some assumptions that, in most situations, unnecessarily complicate the study of evolution and development. PMID- 21672848 TI - The contribution of neural crest cells to the nuchal bone and plastron of the turtle shell. AB - The origin of the turtle plastron is not well understood, and these nine bones have been homologized to the exoskeletal components of the clavicles, the interclavicular bone, and gastralia. Earlier data from our laboratory showed that the plastral bone-forming cells stained positively for HNK-1 and PDGFRalpha, two markers of skeletogenic neural crest cells. We have now shown that the HNK-1(+) cells are also positive for p75 and FoxD3, affirming their neural crest identity. These cells originate from the dorsal neural tube of stage-17 turtle embryos, several days after the original wave of neural crest cells have migrated and differentiated. Moreover, we have demonstrated the existence of a staging area, above the neural tube and vertebrae, where these late-emigrating neural crest cells collect. After residing in the carapacial staging area, these cells migrate to form the plastral bones. We also demonstrate that one bone of the carapace, the nuchal bone, also stains with HNK-1 and with antibodies to PDGFRalpha. The nuchal bone shares several other properties with the plastral bones, suggesting that it, too, is derived from neural crest cells. Alligator gastralia stain for HNK-1, while their ribs do not, thus suggesting that the gastralial precursor may also be derived from neural crest cells. PMID- 21672849 TI - Evolutionary novelties: the making and breaking of pleiotropic constraints. AB - Body plans are remarkably well conserved, but on (very) rare occasions important novelties evolve. Such novelties involve changes at the genotypic and phenotypic level affecting both developmental and adult traits. At all levels, duplications play an important role in the evolution of novelties. Mutations for duplications, including mutations for duplications of body parts, as well as mutations for other changes in the body plan, in particular homeotic ones, occur surprisingly frequently. Hence the limitation of mutations appears to be relatively unimportant for the conservation of body plans. However, mutations for duplications of body parts and homeotic changes rarely persist in populations. We argue that the root cause of the conservation of body plans is the strong interactivity during the patterning of the embryonic axes, including the interactivity between patterning and proliferation processes. Due to this interactivity, mutations cause many negative pleiotropic effects (malformations and cancers) that dramatically lower fitness. As an example, we have shown that in humans there is extreme selection against negative pleiotropic effects of the, surprisingly frequent, mutations affecting the number of cervical vertebrae. Moreover, we argue for the relevance of relaxed selection, which temporarily allows just-arisen novelties to persist, for the effective breaking of pleiotropic constraints. We illustrate this with two empirical examples. PMID- 21672850 TI - Gray anatomy: phylogenetic patterns of somatic gonad structures and reproductive strategies across the Bilateria. AB - The last common ancestor of extant bilaterian animals is often referred to as "Urbilateria". Comparative studies of development in a variety of laboratory animals, both traditional model systems and newer "emerging" models, have resulted in many proposals as to the morphological and developmental genetic characteristics of Urbilateria. Most of these proposals are concerned with the development and emergence of external morphology, such as appendages, eyes, and ectodermal segmentation. Less attention has been paid to the evolutionary developmental biology of organogenesis. Arguably, one of the most important aspects of urbilaterian organogenesis would have been gonadogenesis, since Urbilateria must have successfully generated gametes and developed a strategy for extrusion and fertilization, in order to be the ancestor of all living Bilateria. This article considers what is known about gonadogenesis and reproductive strategies in extant metazoans, and searches for phylogenetic patterns that suggest what shared characteristics of these processes Urbilateria might have displayed. I conclude that the data presently available cannot suggest homologies of the somatic components of metazoan gonads, and that convergent evolution has resulted in many different morphological, and possibly molecular genetic, solutions to the various problems posed by sexual reproduction. PMID- 21672851 TI - Seminal influences: Drosophila Acps and the molecular interplay between males and females during reproduction. AB - Successful reproduction requires contributions from both the male and the female. In Drosophila, contributions from the male include accessory gland proteins (Acps) that are components of the seminal fluid. Upon their transfer to the female, Acps affect the female's physiology and behavior. Although primary sequences of Acp genes exhibit variation among species and genera, the conservation of protein biochemical classes in the seminal fluid suggests a conservation of functions. Bioinformatics coupled with molecular and genetic tools available for Drosophila melanogaster has expanded the functional analysis of Acps in recent years to the genomic/proteomic scale. Molecular interplay between Acps and the female enhances her egg production, reduces her receptivity to remating, alters her immune response and feeding behavior, facilitates storage and utilization of sperm in the female and affects her longevity. Here, we provide an overview of the D. melanogaster Acps and integrate the results from several studies that bring the current number of known D. melanogaster Acps to 112. We then discuss several examples of how the female's physiological processes and behaviors are mediated by interactions between Acps and the female. Understanding how Acps elicit particular female responses will provide insights into reproductive biology and chemical communication, tools for analyzing models of sexual cooperation and/or sexual conflict, and information potentially useful for strategies for managing insect pests. PMID- 21672852 TI - Recent developments in neurobiology: introduction to the symposium to honor Professor Douglas G. Stuart. PMID- 21672853 TI - The role of postinhibitory rebound in the locomotor central-pattern generator of Clione limacina. AB - In animals, networks of central neurons, called central-pattern generators (CPGs), produce a variety of locomotory behaviors including walking, swimming, and flying. CPGs from diverse animals share many common characteristics that function at the system level, circuit level, and cellular level. However, the relative roles of common CPG characteristics are variable among different animal species, in ways that suit different forms of locomotion in different environmental contexts. Here, we examine some of these common features within the locomotor CPG in a model system used to investigate changes in locomotory speed the swim system of the pteropod mollusk, Clione limacina. In particular, we discuss the role of one cellular characteristic that is essential for locomotor pattern generation in Clione, postinhibitory rebound. PMID- 21672854 TI - Contextual learning and obstacle memory in the walking cat. AB - Animals in their natural environments display a remarkably diverse variety of walking patterns. Although some of this diversity is generated by alterations in feedback from the moving limbs, animals can modify their walking in many ways that cannot be directly attributed to this sensory feedback. For example, animals and humans can learn to associate a particular environment with disturbances that were experienced there earlier, and alter their stepping accordingly even after the disturbance has ceased. Another relevant example is that walking animals are aware of the locations of obstacles around them, and use this awareness to alter their stepping patterns even when there is no visual information available about the location of the obstacles relative to the body. In this article, we discuss recent work from our laboratory that addresses these two topics. First, we report that perturbing walking cats in a consistent manner evokes long-lasting changes to the walking pattern that are expressed only in the context in which walking was disturbed. Secondly, we show that cats that have stepped over an obstacle remember the location of that obstacle relative to the body during long delays, and can use that memory to guide stepping. The general theme of this research is that sensory inputs that signal context-the visual and auditory environment that surrounds an animal-play an important role in shaping the basic pattern of locomotion. PMID- 21672855 TI - The neurobiology of muscle fatigue: 15 years later. AB - This brief review summarizes progress that has been made in the study of muscle fatigue since a review published 15 years ago (Enoka RM, Stuart DG. 1992. Neurobiology of muscle fatigue. J Appl Physiol 72:1631-48.). The present review first discusses progress on the four themes identified in the 1992 review and then describes a new approach that can be used to identify the functionally significant physiological adjustments that occur during fatiguing contractions. As described in the previous review, it is currently not possible to develop a comprehensive model of muscle fatigue because the prevailing mechanism that impairs performance varies with the characteristics of the task that is being performed. An alternative approach is to focus on the mechanisms that cause failure to complete the task. This task-failure approach involves comparing two performances and identifying the adjustments that limit the rate for the more difficult condition. With this approach, initial studies have demonstrated that the time to failure of a sustained contraction can be influenced by such variables as the type of load supported by the limb, the posture of the limb, and the group of muscles involved in the task. The challenge is to identify the mechanisms that enable these different variables influence the time to task failure. PMID- 21672856 TI - Predictive and reactive tuning of the locomotor CPG. AB - The neural control of locomotion involves a constant interplay between the actions of a central pattern generator (CPG) and sensory input elicited by bodily movement. With respect to the CPG, recent analysis of fictive locomotion has shown that durations of flexion and extension tend to covary along specific lines in plots of phase duration versus cycle duration. The slopes of these lines evidently depend on internal states that vary among preparations, but, within a preparation, remain rather steady from one sequence to the next. These relationships can be reproduced in a simple oscillator model having two pairs of preset parameters, suggesting that steady internal drives to flexor and extensor half-centers determine how phase durations covary. Regarding the role of sensory inputs, previous experiments have revealed state-dependent rules that govern phase-switching independently of the CPG rhythm. In addition, sensory input is known to modulate motoneuronal activation through stretch reflexes. To explore how sensory input combines with the locomotor CPG, we used a neuromechanical model with muscle actuators, proprioceptive feedback, sensory phase-switching rules, and a CPG. Interestingly, sequences of stable locomotion were always associated with phase durations that conformed to an extensor-dominated phase duration characteristic (where extension durations vary more than flexion durations). This is the characteristic seen in normal animals, but not necessarily in fictive locomotion, where movement and associated sensory input are absent. This suggests that to produce the biomechanical events required for stability, an extensor-dominated phase-duration characteristic is required. In the model, when the preset CPG phase durations were well matched to coincide the biomechanical requirements, CPG-mediated phase switching produced stable cycles. When CPG phase durations were too short, phases switched prematurely and the model soon fell. When CPG phase durations were too long, sensory rules fired and overrode the CPG, maintaining stability. We posit that under normal circumstances, descending input from higher centers continually adjusts the operating point of the CPG on the preset phase-duration characteristic according to anticipated biomechanical requirements. When the predictions are good, CPG generated phase durations closely match those required by the kinetics and kinematics, and little or no sensory adjustment occurs. We propose the term "neuromechanical tuning" to describe this process of matching the CPG to the biomechanical requirements. PMID- 21672857 TI - Reflections on integrative and comparative movement neuroscience. AB - Integrative movement neuroscience involves blending "inside-out" and "outside-in" approaches in the study of posture and movement. The former is characterized by determining the properties of single cells within the central nervous system (CNS) and then ascertaining how these properties influence the operation of CNS microcircuits, single reflexes, groups of reflexes, and generators of central pattern. This information is then used to theorize about CNS control of overt motor behavior. In contrast, the outside-in approach begins with analysis of the biomechanics of posture and movement and then uses this information to theorize how the mechanics are solved by the CNS and its pathways, circuitry, and even single cells. Studies conducted in the 1960s on CNS circuitry generating locomotor patterns in several invertebrate and vertebrate species, together with work on the treadmill locomotion of brain-stimulated decerebrate cats, led to a subsequent convergence of inside-out and outside-in understanding of the neural control of locomotion in invertebrates, nonmammalian vertebrates, and mammalian vertebrates, even including humans. This convergence of integrative and comparative approaches has been facilitated by modeling and simulation studies. These developments have important implications for doctoral and postdoctoral training programs in movement neuroscience. They can profit greatly by use of a multidisciplinary university-wide faculty who place a strong emphasis on integrative and comparative biology. Furthermore, the next generation of movement neuroscientists will require more familiarity with modeling and simulation than are being provided in most current training programs. To achieve the above, it will be advantageous if university culture and structure truly champion university-wide interdisciplinary research. PMID- 21672858 TI - Introduction to special section on respiratory biology. PMID- 21672859 TI - Why respiratory biology? The meaning and significance of respiration and its integrative study. AB - Traditionally the process of respiration is divided into three phases: (1) cellular respiration, (2) transport of respiratory gases and (3) ventilation of the gas exchange organs (breathing). Thereby organisms assimilate chemical energy from the environment, and within their cells transfer it from molecule to molecule in a stepwise fashion. Although studied separately, these phases represent a continuum and cellular respiration in all life forms has much in common. Ironically, these respiratory foci have been artificially delineated by their own practitioners, who tend to publish in their own journals, and attend their own conferences. The goal of modern respiratory biology should be to understand biological connectivity and complexity by viewing an organism as a series of interconnecting systems from molecule to ecosystem. The future of science in general, and biology in particular, lies in disciplinary networking: combining the results of traditional disciplines to better understand the whole. Because of its universality, Respiratory Biology can best provide this bridge and improve interdisciplinary studies in biology generally. To this end, the First International Congress of Respiratory Biology was held from August 14 to 16, 2006, at Bonn, Germany. As evident from the success of this inaugural meeting, these are exciting times for Respiratory Biology. The explosion of "X-omics" and systems biology, the powerful genetic approaches to disease treatment, and the long-standing and newly emerging questions in evolutionary biology and ecology; all portend a continuing role of respiratory biology as a key integrative discipline. PMID- 21672860 TI - Devonian climate change, breathing, and the origin of the tetrapod stem group. AB - The diversification of the tetrapod stem group occurred during the late Middle through the Late Devonian, that is from the Givetian to Famennian stages about 385-365 million years ago. The relationships between the known taxa representing this radiation have currently reached a reasonable consensus so that interpretations of the order of appearance of tetrapod characters is possible. The immediate fish relatives of the earliest limbed tetrapods show what is interpreted as a progressive increase in the spiracular chamber and its opening to the outside. Here, this is inferred to be associated with an increased capacity for air-breathing. Lungs are thought to have been present in most early bony fishes, and were most likely ventilated by air-gulping. This could have brought about a facultative capacity for air-breathing, which the tetrapod stem group exploited to the greatest degree. These adaptations are shown not only in freshwater forms but also in estuarine and marginal marine forms. Estimates of oxygen levels during this period suggest that they were unprecedentedly low during the Givetian and Frasnian periods. At the same time, plant diversification was at its most rapid, changing the character of the landscape and contributing, via soils, soluble nutrients, and decaying plant matter, to anoxia in all water systems. The co-occurrence of these global events may explain the evolution of air-breathing adaptations in at least two lobe-finned groups, contributing directly to the rise of the tetrapod stem group. In contrast to recent studies, low atmospheric oxygen is not considered to be a causal factor in the lack of fossils documenting the evolution of Early Carboniferous tetrapods. PMID- 21672861 TI - Coping with cyclic oxygen availability: evolutionary aspects. AB - Both the gradual rise in atmospheric oxygen over the Proterozoic Eon as well as episodic fluctuations in oxygen over several million-year time spans during the Phanerozoic Era, have arguably exerted strong selective forces on cellular and organismic respiratory specialization and evolution. The rise in atmospheric oxygen, some 2 billion years after the origin of life, dramatically altered cell biology and set the stage for the appearance of multicelluar life forms in the Vendian (Ediacaran) Period of the Neoproterozoic Era. Over much of the Paleozoic, the level of oxygen in the atmosphere was near the present atmospheric level (21%). In the Late Paleozoic, however, there were extended times during which the level of atmospheric oxygen was either markedly lower or markedly higher than 21%. That these Paleozoic shifts in atmospheric oxygen affected the biota is suggested by the correlations between: (1) Reduced oxygen and the occurrences of extinctions, a lowered biodiversity and shifts in phyletic succession, and (2) During hyperoxia, the corresponding occurrence of phenomena such as arthropod gigantism, the origin of insect flight, and the evolution of vertebrate terrestriality. Basic similarities in features of adaptation to hyopoxia, manifest in living organisms at levels ranging from genetic and cellular to physiological and behavioral, suggest the common and early origin of a suite of adaptive mechanisms responsive to fluctuations in ambient oxygen. Comparative integrative approaches addressing the molecular bases of phenotypic adjustments to cyclic oxygen fluctuation provide broad insight into the incremental steps leading to the early evolution of homeostatic respiratory mechanisms and to the specialization of organismic respiratory function. PMID- 21672862 TI - Respiratory plasticity in response to changes in oxygen supply and demand. AB - Aerobic organisms maintain O(2) homeostasis by responding to changes in O(2) supply and demand in both short and long time domains. In this review, we introduce several specific examples of respiratory plasticity induced by chronic changes in O(2) supply (environmental hypoxia or hyperoxia) and demand (exercise induced and temperature-induced changes in aerobic metabolism). These studies reveal that plasticity occurs throughout the respiratory system, including modifications to the gas exchanger, respiratory pigments, respiratory muscles, and the neural control systems responsible for ventilating the gas exchanger. While some of these responses appear appropriate (e.g., increases in lung surface area, blood O(2) capacity, and pulmonary ventilation in hypoxia), other responses are potentially harmful (e.g., increased muscle fatigability). Thus, it may be difficult to predict whole-animal performance based on the plasticity of a single system. Moreover, plastic responses may differ quantitatively and qualitatively at different developmental stages. Much of the current research in this field is focused on identifying the cellular and molecular mechanisms underlying respiratory plasticity. These studies suggest that a few key molecules, such as hypoxia inducible factor (HIF) and erythropoietin, may be involved in the expression of diverse forms of plasticity within and across species. Studying the various ways in which animals respond to respiratory challenges will enable a better understanding of the integrative response to chronic changes in O(2) supply and demand. PMID- 21672863 TI - From critters to cancers: bridging comparative and clinical research on oxygen sensing, HIF signaling, and adaptations towards hypoxia. AB - The objective of this symposium at the First International Congress of Respiratory Biology (ICRB) was to enhance communication between comparative biologists and cancer researchers working on O(2) sensing via the HIF pathway. Representatives from both camps came together on August 13-16, 2006, in Bonn, Germany, to discuss molecular adaptations that occur after cells have been challenged by a reduced (hypoxia) or completely absent (anoxia) supply of oxygen. This brief "critters-to-cancer" survey discusses current projects and new directions aimed at improving understanding of hypoxic signaling and developing therapeutic interventions. PMID- 21672864 TI - Implications of dealing with airborne substances and reactive oxygen species: what mammalian lungs, animals, and plants have to say? AB - A gas-exchange structure interacts with the environment and is constantly challenged by contaminants that may elicit defense responses, thus compromising its primary function. It is also exposed to high concentrations of O(2) that can generate reactive oxygen species (ROS). Revisiting the lung of mammals, an integrative picture emerges, indicating that this bronchi-alveolar structure deals with inflammation in a special way, which minimizes compromising the gas exchange role. Depending on the challenge, pro-inflammatory or antiinflammatory responses are elicited by conserved molecules, such as surfactant proteins A and D. An even broader picture points to the participation of airway sensors, responsive to inflammatory mediators, in a loop linking the immunological and nervous systems and expanding the role played by respiratory organs in functions other than gas-exchange. A byproduct of exposure to high concentration of O(2) is the formation of superoxide ( ), hydrogen peroxide (H(2)O(2)), hydroxyl radical (HO(*)), and other ROS, which are known to be toxic to different types of cells, including the lung epithelium. A balance between antioxidants and oxidants exists; in pulmonary epithelial cells high intracellular and extracellular levels of antioxidants are found. Antioxidant adaptations related to plant and animal life-styles involve a broad range of overlapping strategies based on well conserved molecules. Glutathione (GSH) is an abundant and ubiquitous thiol tripeptide antioxidant, also present in lungs, whose role in providing information on the intracellular redox state of animals and plants is well established. In these organisms, GSH influences gene expression associated with stress, maximizing defense responses. Several enzymatic antioxidants, such as glutathione peroxidase (GPx), glutathione reductase, glutathione S-transferase, and glucose 6-phosphate dehydrogenase participate in the redox system; in animals that are stress-tolerant GPx is a key element against oxidative assaults. Most importantly, alternative roles of ROS as signaling molecules have been found in all plants and animals. For example, alveolar macrophages produce that act as second messengers, in addition to having a bactericidal role. The nonradical ROS H(2)O(2) signals inflammation in mammalian lungs, apoptosis in different animal tissues, and is also involved in stomatal closure, root development, gene expression, and defense responses of plants. Antioxidant adaptations in some water-breathing animals involve the excretion of H(2)O(2) by diffusion through gas-exchange structures. The fine balance among a multitude of factors and cells makes the difference between damage and protection in animals and plants. Knowledge about the mechanisms and consequences of these molecular interactions is now starting to be integrated. PMID- 21672865 TI - Respiratory chemoreceptor function in vertebrates comparative and evolutionary aspects. AB - The sensing of blood gas tensions and/or pH is an evolutionarily conserved, homeostatic mechanism, observable in almost all species studied from invertebrates to man. In vertebrates, a shift from the peripheral O(2)-oriented sensing in fish, to the central CO(2)/pH sensing in most tetrapods reflects the specific behavioral requirements of these two groups whereby, in teleost fish, a highly O(2)-oriented control of breathing matches the ever-changing and low oxygen levels in water, whilst the transition to air-breathing increased the importance of acid-base regulation and O(2)-related drive, although retained, became relatively less important. The South American lungfish and tetrapods are probably sister groups, a conclusion backed up by many similar features of respiratory control. For example, the relative roles of peripheral and central chemoreceptors are present both in the lungfish and in land vertebrates. In both groups, the central CO(2)/pH receptors dominate the ventilatory response to hypercarbia (60-80%), while the peripheral CO(2)/pH receptors account for 20-30%. Some basic components of respiratory control have changed little during evolution. This review presents studies that reflect the current trends in the field of chemoreceptor function, and several laboratories are involved. An exhaustive review on the previous literature, however, is beyond the intended scope of the article. Rather, we present examples of current trends in respiratory function in vertebrates, ranging from fish to humans, and focus on both O(2) sensing and CO(2) sensing. As well, we consider the impact of chronic levels of hypoxia-a physiological condition in fish and in land vertebrates resident at high elevations or suffering from one of the many cardiorespiratory disease states that predispose an animal to impaired ventilation or cardiac output. This provides a basis for a comparative physiology that is informative about the evolution of respiratory functions in vertebrates and about human disease. Currently, most detail is known for mammals, for which molecular biology and respiratory physiology have combined in the discovery of the mechanisms underlying the responses of respiratory chemoreceptors. Our review includes new data on nonmammalian vertebrates, which stresses that some chemoreceptor sites are of ancient origin. PMID- 21672867 TI - The integrative and evolutionary biology of gas-binding copper proteins: an introduction. AB - This article summarizes the contributions given at the symposium "The Benefits of Gas-binding Proteins. Integrative and Evolutionary Physiology of Copper Proteins: Molecules to Organisms and their Environment," presented at the First International Congress of Respiratory Biology, August 14-16, at Bad Honnef/Bonn, Germany. PMID- 21672866 TI - The anatomy, physics, and physiology of gas exchange surfaces: is there a universal function for pulmonary surfactant in animal respiratory structures? AB - (Orgeig and Daniels) This surfactant symposium reflects the integrative and multidisciplinary aims of the 1st ICRB, by encompassing in vitro and in vivo research, studies of vertebrates and invertebrates, and research across multiple disciplines. We explore the physical and structural challenges that face gas exchange surfaces in vertebrates and insects, by focusing on the role of the surfactant system. Pulmonary surfactant is a complex mixture of lipids and proteins that lines the air-liquid interface of the lungs of all air-breathing vertebrates, where it functions to vary surface tension with changing lung volume. We begin with a discussion of the extraordinary conservation of the blood gas barrier among vertebrate respiratory organs, which has evolved to be extremely thin, thereby maximizing gas exchange, but simultaneously strong enough to withstand significant distension forces. The principal components of pulmonary surfactant are highly conserved, with a mixed phospholipid and neutral lipid interfacial film that is established, maintained and dynamically regulated by surfactant proteins (SP). A wide variation in the concentrations of individual components exists, however, and highlights lipidomic as well as proteomic adaptations to different physiological needs. As SP-B deficiency in mammals is lethal, oxidative stress to SP-B is detrimental to the biophysical function of pulmonary surfactant and SP-B is evolutionarily conserved across the vertebrates. It is likely that SP-B was essential for the evolutionary origin of pulmonary surfactant. We discuss three specific issues of the surfactant system to illustrate the diversity of function in animal respiratory structures. (1) Temperature: In vitro analyses of the behavior of different model surfactant films under dynamic conditions of surface tension and temperature suggest that, contrary to previous beliefs, the alveolar film may not have to be substantially enriched in the disaturated phospholipid, dipalmitoylphosphatidylcholine (DPPC), but that similar properties of rate of film formation can be achieved with more fluid films. Using an in vivo model of temperature change, a mammal that enters torpor, we show that film structure and function varies between surfactants isolated from torpid and active animals. (2) Spheres versus tubes: Surfactant is essential for lung stabilization in vertebrates, but its function is not restricted to the spherical alveolus. Instead, surfactant is also important in narrow tubular respiratory structures such as the terminal airways of mammals and the air capillaries of birds. (3). Insect tracheoles: We investigate the structure and function of the insect tracheal system and ask whether pulmonary surfactant also has a role in stabilizing these minute tubules. Our theoretical analysis suggests that a surfactant system may be required, in order to cope with surface tension during processes, such as molting, when the tracheae collapse and fill with water. Hence, despite observations by Wigglesworth in the 1930s of fluid-filled tracheoles, the challenge persists into the 21st century to determine whether this fluid is associated with a pulmonary-type surfactant system. Finally, we summarize the current status of the field and provide ideas for future research. PMID- 21672868 TI - Minireview: Recent progress in hemocyanin research. AB - This review summarizes recent highlights of our joint work on the structure, evolution, and function of a family of highly complex proteins, the hemocyanins. They are blue-pigmented oxygen carriers, occurring freely dissolved in the hemolymph of many arthropods and molluscs. They are copper type-3 proteins and bind one dioxygen molecule between two copper atoms in a side-on coordination. They possess between 6 and 160 oxygen-binding sites, and some of them display the highest molecular cooperativity observed in nature. The functional properties of hemocyanins can be convincingly described by either the Monod-Wyman-Changeux (MWC) model or its hierarchical extension, the Nested MWC model; the latter takes into account the structural hierarchies in the oligomeric architecture. Recently, we applied these models to interpret the influence of allosteric effectors in detailed terms. Effectors shift the allosteric equilibria but have no influence on the oxygen affinities characterizing the various conformational states. We have shown that hemocyanins from species living at different environmental temperatures have a cooperativity optimum at the typical temperature of their natural habitat. Besides being oxygen carriers, some hemocyanins function as a phenoloxidase (tyrosinase/catecholoxidase) which, however, requires activation. Chelicerates such as spiders and scorpions lack a specific phenoloxidase, and in these animals activated hemocyanin might catalyse melanin synthesis in vivo. We propose a similar activation mechanism for arthropod hemocyanins, molluscan hemocyanins and tyrosinases: amino acid(s) that sterically block the access of phenolic compounds to the active site have to be removed. The catalysis mechanism itself can now be explained on the basis of the recently published crystal structure of a tyrosinase. In a series of recent publications, we presented the complete gene and primary structure of various hemocyanins from different molluscan classes. From these data, we deduced that the molluscan hemocyanin molecule evolved ca. 740 million years ago, prior to the separation of the extant molluscan classes. Our recent advances in the 3D cryo-electron microscopy of hemocyanins also allow considerable insight into the oligomeric architecture of these proteins of high molecular mass. In the case of molluscan hemocyanin, the structure of the wall and collar of the basic decamers is now rapidly becoming known in greater detail. In the case of arthropod hemocyanin, a 10-A structure and molecular model of the Limulus 8 * 6mer shows the amino acids at the various interfaces between the eight hexamers, and reveals histidine-rich residue clusters that might be involved in transferring the conformational signals establishing cooperative oxygen binding. PMID- 21672869 TI - Role of blood-oxygen transport in thermal tolerance of the cuttlefish, Sepia officinalis. AB - Mechanisms that affect thermal tolerance of ectothermic organisms have recently received much interest, mainly due to global warming and climate-change debates in both the public and in the scientific community. In physiological terms, thermal tolerance of several marine ectothermic taxa can be linked to oxygen availability, with capacity limitations in ventilatory and circulatory systems contributing to oxygen limitation at extreme temperatures. The present review briefly summarizes the processes that define thermal tolerance in a model cephalopod organism, the cuttlefish Sepia officinalis, with a focus on the contribution of the cephalopod oxygen-carrying blood pigment, hemocyanin. When acutely exposed to either extremely high or low temperatures, cuttlefish display a gradual transition to an anaerobic mode of energy production in key muscle tissues once critical temperatures (T(crit)) are reached. At high temperatures, stagnating metabolic rates and a developing hypoxemia can be correlated with a progressive failure of the circulatory system, well before T(crit) is reached. However, at low temperatures, declining metabolic rates cannot be related to ventilatory or circulatory failure. Rather, we propose a role for hemocyanin functional characteristics as a major limiting factor preventing proper tissue oxygenation. Using information on the oxygen binding characteristics of cephalopod hemocyanins, we argue that high oxygen affinities (= low P(50) values), as found at low temperatures, allow efficient oxygen shuttling only at very low venous oxygen partial pressures. Low venous PO(2)s limit rates of oxygen diffusion into cells, thus eventually causing the observed transition to anaerobic metabolism. On the basis of existing blood physiological, molecular, and crystallographical data, the potential to resolve the role of hemocyanin isoforms in thermal adaptation by an integrated molecular physiological approach is discussed. PMID- 21672870 TI - Negative cooperativity in Root-effect hemoglobins: role of heterogeneity. AB - In some animals, the oxygen transport capacity of blood decreases when pH is lowered, yielding oxygen binding curves with Hill-coefficients smaller than unity. This so-called Root effect is observed in several fishes and is important for creating large oxygen partial pressures locally, for example in the swim bladder. While there is general agreement on the physiological advantages of this effect, its molecular basis remains ambiguous. Various studies show that isoforms of hemoglobins usually are present in the hemolymph, when the Root effect is observed. Here, we show that in such a case the mixture of these isoforms can exhibit apparent negative cooperativity, although each component taken separately can be described by the MWC model. In other cases, isolated isoforms exhibit true negative cooperativity. The well established MWC model describes many cooperative phenomena of enzymes and respiratory proteins but is not capable of describing negative cooperativity. In order to model negative cooperativity within a single molecular species a decoupling model might be employed, as pointed out previously. However, simulations show that it is not mandatory to have species with negative cooperativity, in order to obtain the binding curves typically seen for whole blood. These two aspects of the Root effect will be discussed on the basis of data from the literature. PMID- 21672871 TI - Hemocyanins and the immune response: defense against the dark arts. AB - The innate immune response is a conserved trait shared by invertebrates and vertebrates. In crustaceans, circulating hemocytes play significant roles in the immune response, including the release of prophenoloxidases. Activated phenoloxidase (tyrosinase) participates in encapsulation and melanization of foreign organisms as well as sclerotization of the new exoskeleton after wound repair or molting. Hemocyanin functions as a phenoloxidase under certain conditions and thus also participates in the immune response and molting. The relative contributions of hemocyte phenoloxidase and hemocyanin in the physiological ratio at which they occur in hemolymph have been investigated in the crab Cancer magister. Differences in activity, substrate affinity, and catalytic ability between the two enzymes indicate that hemocytes are the predominant source of phenoloxidase activity in crabs. In contrast, hemocyanin is the primary source of phenoloxidase activity in isopods and chelicerates whose hemocytes show no phenoloxidase activity. Quantitative PCR studies on the distribution of prophenoloxidase mRNA in the tissues of Carcinus maenas showed little effect relative to salinity stress. Phylogenetic analysis of hemocyanin, phenoloxidase, and other members of this arthropod gene family are consistent with the possibility that a common ancestral molecule had both phenoloxidase and oxygen-binding capabilities. PMID- 21672872 TI - Issues of body weight and eating behavior in psychiatric and mental health nursing practice. PMID- 21672873 TI - Bipolar disorder and weight gain: a multifactorial assessment. AB - Obesity is highly prevalent in persons with bipolar disorder. This results in increased physical morbidity and poorer psychiatric outcomes. Multiple variables have been identified as potentially responsible for the weight gain in these individuals. Efforts to use successful treatment strategies require an understanding of these variables and methods that clinicians and their clients can use to reduce or minimize these risk factors. This article will review the emerging findings related to primary and secondary weight gain in bipolar disorder. The sequelae of weight gain on psychiatric and medical morbidity will be discussed. Lastly, a model for nursing assessment will propose methods for modifying risk factors and encouraging healthy lifestyle changes. The goal is to improve this component of quality of life for persons with bipolar disorder. J Am Psychiatr Nurses Assoc, 2008; 13(6), 345-352. DOI: 10.1177/1078390307310145. PMID- 21672874 TI - Pilot study of a cognitive behavioral group intervention to prevent further weight gain in Hispanic individuals with schizophrenia. AB - BACKGROUND: Obesity and type 2 diabetes are increasing significantly in the Hispanic population and in the Hispanic population with schizophrenia. In the Diabetes Prevention Project (DPP), cognitive-behavioral (CB) interventions were more effective in reducing weight and preventing diabetes. OBJECTIVE: To test a CB group intervention based on the DPP model among Hispanic individuals with schizophrenia on weight, body mass index (BMI), and waist-hip circumference (WH). STUDY DESIGN: Pilot study using a pre-post quasi-experimental design and convenience sample of 8 subjects from a public mental health clinic who met for 8 weekly group meetings. RESULTS: No significant differences in BMI, weight, or WH scores based on t-test results; the subjects' weight remained stable, there was a trend toward weight loss, and no one gained weight during the trial. CONCLUSIONS: No further weight gain is a finding that merits further research using a larger sample size and a randomized controlled design. J Am Psychiatr Nurses Assoc, 2008; 13(6), 353-359. PMID- 21672875 TI - Eating Behavior in Persons With Moderate to Late-stage Dementia: Assessment and Interventions. AB - Persons with various forms of dementia suffer from a progressive disease in which memory and the ability to function independently are lost. During moderate to late-stage dementia, individuals experience increased difficulty with eating and require more feeding assistance. Clinicians working with this population must acknowledge the multifactorial aspects of eating behavioral issues, use a team approach, and make careful assessments using appropriate instruments. Interventions should include attention to cognitive impairment, nutritional intake, training of caregivers, modification of the environment, and the quality of the interaction. Planning for care should include promoting the highest quality of life for these individuals and their caregivers. J Am Psychiatr Nurses Assoc, 2008; 13(6), 360-367. PMID- 21672876 TI - The Individual Within a Condition: A Qualitative Study of Young People's Reflections on Being Treated for Anorexia Nervosa. AB - BACKGROUND: Anorexia nervosa is a mental health problem that can seriously impede the physical, social, and psychological functioning of those who develop it. Unfortunately, outcome for this patient group, even after treatment, is not necessarily promising. OBJECTIVE: To explore the views of young people about being treated for anorexia. STUDY: DESIGN: Qualitative interviews were conducted with 10 adolescents. All interviews were recorded with participants' written consent and transcribed verbatim. A thematic analysis was applied to these data. RESULTS: Five themes were derived from the analysis: a) accessing appropriate care, b) balancing the physical and psychological, c) qualities required in professionals, d) help from nonprofessional routes, and e) perceived progress. CONCLUSIONS: Participants were clear about needing to be motivated to change. Practitioners can help by challenging patients in a nonconfrontational manner, treating them as individuals rather than cases of anorexia, and considering their psychosocial and physical functioning. J Am Psychiatr Nurses Assoc, 2008; 13(6), 368.-375. DOI: 10.1177/1078390307309215. PMID- 21672877 TI - Weight-related concerns and behaviors in children and adolescents with type 1 diabetes. AB - Children and adolescents with type 1 diabetes are at risk for disordered eating and unhealthy weight-control practices. This study describes (a) participants' weight perception and weight satisfaction, (b) participants' scores on the Diabetes Eating Problem Survey (DEPS), (c) prevalence of weight-control behaviors, and (d) association of DEPS and weight-control behaviors with race, gender, age, body mass index (BMI), hemoglobin A1c (HbA1c), weight satisfaction, and weight perception. TheAHEAD survey was completed by 295 participants to determine weight satisfaction, weight perception, and weight-control behaviors. Height, weight, and HbA1c were obtained from clinic charts. Older females with higher BMI and elevated HbA1c used significantly more weight-control behaviors. Weight dissatisfaction and heavy weight perception were associated with significantly more unhealthy weight-control practices. Prevention programs should be directed toward the preteen female. Older female teens presenting with higher BMI, elevated HbA1c, weight dissatisfaction, and heavy weight perception should be formally assessed for unhealthy weight-control behaviors. J Am Psychiatr Nurses Assoc, 2008; 13(6), 376-385. DOI: 10.1177/1078390307310154. PMID- 21672878 TI - Readership survey results. PMID- 21672879 TI - Psychiatric nursing education at a distance. AB - Accessibility is a major impediment to nursing education, whether you live in densely populated southern California or rural upstate New York. During the past 10 years, there have been scientific advances, technological breakthroughs, new reimbursement mechanisms and regulatory practices, and shifts in society's priorities. Consequently, the focus of master's programs and the role of graduates has adapted to the needs of the mental health care delivery system. What has not changed much is the way we offer psychiatric nursing education. There is still a strong emphasis on traditional classroom teaching, on campus based activities and face-to-face supervision. One solution that might increase access to psychiatric nursing programs is to develop educational programs with quality distance education standards and practices as a primary means for educating future psychiatric nurses. Psychiatric nursing faculties need to design creative scenarios and interactive activities to engage students in online learning about psychiatric and mental health nursing. J Am Psychiatr Nurses Assoc, 2008; 14(1), 36-38. DOI: 10.1177/1078390307307451. PMID- 21672880 TI - Dementia-specific assisted living: clinical factors and psychotropic medication use. AB - BACKGROUND: Assisted living (AL) is an increasingly popular long-term care alternative for older adults with dementia, making this setting an important focus for both clinical practice and research among psychiatric nurses. OBJECTIVES: This article describes results from a pilot study focusing on residents' cognitive and emotional status as well as psychotropic drug use. Findings are compared to reports from larger studies in the literature. STUDY DESIGN: A descriptive, correlational design was used to collect data from 17 residents in two dementia-specific AL facilities. RESULTS: Thirty-one psychiatric diagnoses were identified for 17 participants. Anxiety and depression symptoms were endorsed by more than 50% of participants, and 88% were prescribed psychotropic medications. CONCLUSIONS: AL residents may experience problems with cognition and emotional symptoms such as anxiety and depression, creating important roles for psychiatric nurses in staff education, promotion of nonpharmacologic interventions, and monitoring of psychotropic medication use in this growing population. J Am Psychiatr Nurses Assoc, 2008; 14(1), 39-49. DOI: 10.1177/1078390307310692. PMID- 21672881 TI - Parent--Adolescent Communication About Sexual Pressure, Maternal Norms About Relationship Power, and STI/HIV Protective Behaviors of Minority Urban Girls. AB - Racial/ethnic minority adolescent girls bear a disproportionate risk for HIV and face barriers to autonomous sexual decision making, but parental messages may help protect against sexual risk taking. The authors examined African American and Hispanic girls' sexually transmitted infection (STI) and HIV prevention practices, parent-adolescent communication about sexual pressure, and maternal gender norms (N = 118). Teens were more likely to practice consistent STI/HIV prevention when mothers talked about partner sexual pressure (p = .017) and fathers talked about resisting partner sexual pressure (p = .034). Sexually active girls who perceived that their mothers held egalitarian beliefs about partner decision making had more consistent condom use (p = .029). Given the context of increased STI/HIV risk, it is critical that parents discuss partner dynamics with daughters. Nurses play a unique role in facilitating these conversations; they provide parents with age-appropriate resources and assist in normalizing fears, which can help increase parent-child sexual-risk communication. J Am Psychiatr Nurses Assoc, 2008; 14(1), 50-60. DOI : 10.1177/1078390307311770. PMID- 21672882 TI - Are you including genomics in nursing practice? AB - A national consensus panel representing 48 nursing organizations, including the American Psychiatric Nurses Association, identified and endorsed essential genetic and genomic competencies for all registered nurses regardless of academic preparation, role, or clinical specialty. The competencies were designed to guide academic curricula, continuing education, and specialty certification. A 5-year implementation plan for these competencies includes components applicable to practicing psychiatric nurses, regulatory and quality control issues, and academics. This article will describe the implementation strategies identified, some examples of genetics and genomics nursing activities in the psychiatric specialty, and recommendations that support the national implementation plan. J Am Psychiatr Nurses Assoc, 2008; 14(1), 63-68. DOI: 10.1177/1078390307311974. PMID- 21672884 TI - Erratum. PMID- 21672883 TI - Comment on lessons learned column. PMID- 21672885 TI - Combination loxapine and aripiprazole for refractory hallucinations in schizophrenia. AB - OBJECTIVE: To document the effects of combining loxapine with aripiprazole for refractory hallucinations in 2 patients with chronic schizophrenia. CASE SUMMARY: Two patients with schizophrenia and auditory hallucinations that were unresponsive to what was considered adequate treatment with multiple typical and atypical antipsychotic medications given over several years were prescribed a combination of aripiprazole 20-30 mg and high-dose loxapine (100-300 mg/day). Both patients had refused clozapine and depot antipsychotics. Aripiprazole/loxapine therapy resolved hallucinations in both patients, and discontinuation of either medication resulted in a return of persecutory voices. Breakthrough hallucinations in both individuals responded to increasing the loxapine dosage. Adverse effects included hypersalivation and tremor, which were treated with benztropine and propranolol. The patients also reported mild sedation, which resolved after several weeks of treatment. Both patients continued to do well during 2 years after starting this combination of medications. DISCUSSION: Recent research has indicated serotonergic and dopaminergic abnormalities in the superior temporal gyrus of patients with a history of chronic auditory hallucinations. Both loxapine and aripiprazole have effects on dopaminergic and postsynaptic serotonergic (5-HT2A) receptor systems, which could account for synergistic effects in treating refractory hallucinations. The combination appears safe, even when loxapine is given in high dosages. Patients should be monitored for the development of parkinsonian tremors. CONCLUSIONS: The combination of aripiprazole and high-dose loxapine should be considered in patients with schizophrenia who develop treatment refractory hallucinations, particularly those who are unwilling to accept treatment with either depot antipsychotics or clozapine. PMID- 21672886 TI - Thioctic acid-induced acute cholestatic hepatitis. AB - OBJECTIVE: To report a case of severe cholestatic hepatitis caused by thioctic acid in a patient with diabetic peripheral polyneuropathy and mild chronic renal failure. CASE SUMMARY: A 63-year-old man with type 2 diabetes, hypertension, hypothyroidism, and stage 2 chronic renal failure was referred to the outpatient liver clinic with fever, asthenia, nausea, and pruritus. Because of the presence of symptomatic diabetic neuropathy, he began treatment with thioctic acid 600 mg/day. Serum transaminase levels were measured before starting thioctic acid treatment and values were within the normal range. Symptoms progressively worsened and the patient developed a low-grade fever and evidence of increased serum liver enzyme levels 45 days after starting thioctic acid treatment: aspartate aminotransferase (AST) (114 IU/L [reference range <40]), alanine aminotransferase (ALT) (191 IU/L [<35]), alkaline phosphatase (ALP) (562 IU/L [<130]), and gamma-glutamyltransferase (GGT) (592 IU/L [<50]). Thioctic acid treatment was discontinued 2 days after admission. Four months after the initial presentation, his AST, ALT, and ALP levels normalized and GGT level had decreased (88 IU/L). As the patient's neuropathic symptoms worsened, thioctic acid therapy was restarted. Two months after restarting therapy, pruritus, nausea, and asthenia reappeared and the patient's liver enzyme levels became clearly abnormal again (AST 100 IU/L, ALT 129 IU/L, ALP 161 IU/L, GGT 180 IU/L). Thioctic acid was stopped, and the patient's liver enzyme levels returned to normal 2 months later. DISCUSSION: Alpha-lipoic acid, also known as thioctic acid, improves metabolic glucose control and peripheral neuropathies associated with diabetes mellitus. Its administration appears to be safe and, as far as we know, there are no reports of liver toxicity associated with its use. Our patient developed acute cholestatic hepatitis after beginning treatment with thioctic acid. Use of the Roussel Uclaf causality assessment scale indicated that the association between thioctic acid treatment and our patient's drug-induced liver injury was highly probable; use of the Maria and Victorino scale indicated that the association was probable. CONCLUSIONS: To our knowledge, this is the first report of probable liver toxicity due to thioctic acid, a proposed "hepatoprotectant." PMID- 21672887 TI - Dipyridamole-associated shock and pulmonary edema. AB - OBJECTIVE: To report a case of fulminant shock and noncardiogenic pulmonary edema induced by intravenously administered dipyridamole. CASE SUMMARY: A 73-year-old woman presented to the office of her cardiologist for dipyridamole myocardial scintigraphy. Several minutes after administration of intravenous dipyridamole 0.57 mg/kg over 4 minutes she developed wheezing, followed by cardiovascular collapse and pulmonary edema requiring 100% oxygen and endotracheal intubation. She had never received dipyridamole before this, and no other medications or exposures were documented proximate to the collapse. On transfer to the hospital, she developed shock refractory to multiple vasopressors, which responded to continuous infusions of epinephrine. She also had severe pulmonary edema requiring invasive ventilation, 100% inspired oxygen, and 24 cm H2O positive end expiratory pressure. An echocardiogram did not show new left-ventricular dysfunction and there were signs of right-heart underfilling, supporting a diagnosis of noncardiogenic pulmonary edema. Both shock and pulmonary edema resolved within 12 hours. DISCUSSION: Dipyridamole-associated hypotension has been reported in a number of case series and registries. Detailed case descriptions, however, are not available in the literature to permit understanding of the mechanism of shock following hypotension resulting from dipyridamole myocardial scintigraphy. Our case is exceptional in that echocardiography results support a diagnosis of hypovolemic (rather than cardiogenic) shock. To our knowledge, this is the first case of severe (most likely noncardiogenic) pulmonary edema associated with intravenous infusion of dipyridamole. An objective causality assessment suggested that this patient's cardiopulmonary collapse was probably related to dipyridamole. CONCLUSIONS: While hypotension has been previously associated with intravenous use of dipyridamole, ours is the first report to suggest a noncardiogenic mechanism for shock. To our knowledge, this is the first reported case of noncardiogenic pulmonary edema following dipyridamole infusion. PMID- 21672888 TI - Vilazodone for the treatment of depression. AB - OBJECTIVE: To evaluate the clinical literature on and potential clinical role of vilazodone for the treatment of major depressive disorder. DATA SOURCES: Searches were conducted on MEDLINE (1948-February 2011), Iowa Drug Information Service (1988-February 2011), EBSCO Academic Search Premier (1975-February 2011), Google Scholar (1992-February 2011), PsycINFO (1980-February 2011), and PsycARTICLES (1985-February 2011), and on general Internet search engines including Google and Bing (no lower limit-February 2011). Search terms were vilazodone, EMD 68843, depression, and major depressive disorder. Potential prior marketers of vilazodone, including Merck KGaA in Germany and Genaissance Pharmaceuticals, were contacted for any available unpublished Phase 1, Phase 2, Phase 3 studies, or preclinical information. STUDY SELECTION AND DATA EXTRACTION: All applicable full text English-language articles, abstracts, and professional poster presentations found were evaluated and included in the review, as well as marketing and Securities and Exchange Commission filings available from the patent holders. DATA SYNTHESIS: Vilazodone is an antidepressant recently approved by the Food and Drug Administration (FDA) that is first in a new class regarding mechanism of action. It has demonstrated efficacy in the primary outcome of the Montgomery Asberg Depression Rating Scale (MADRS) response in an 8-week pivotal Phase 3 trial. Phase 2 trials did not demonstrate efficacy for primary outcomes of the 17 item Hamilton Rating Scale for Depression but showed statistically significant improvements in select secondary outcomes such as Clinical Global Impressions severity and MADRS. Long-term efficacy data are still forthcoming. An emerging aspect to vilazodone's development has been the identification and assessment of potential genetic biomarkers associated with both therapeutic response and more serious adverse effects. Initial studies into biomarkers have been inconclusive. CONCLUSIONS: Vilazodone is a new agent recently approved by the FDA for treating major depressive disorder. Response rates seen with vilazodone are similar to those of currently available antidepressants. PMID- 21672889 TI - An NCI perspective on creating sustainable biospecimen resources. AB - High-quality biospecimens with appropriate clinical annotation are critical in the era of personalized medicine. It is now widely recognized that biospecimen resources need to be developed and operated under established scientific, technical, business, and ethical/legal standards. To date, such standards have not been widely practiced, resulting in variable biospecimen quality that may compromise research efforts. The National Cancer Institute (NCI) Office of Biorepositories and Biospecimen Research (OBBR) was established in 2005 to coordinate NCI's biospecimen resource activities and address those issues that affect access to the high-quality specimens and data necessary for its research enterprises as well as the broader translational research field. OBBR and the NCI Biorepository Coordinating Committee developed NCI's "Best Practices for Biospecimen Resources" after consultation with a broad array of experts. A Biospecimen Research Network was established to fund research to develop additional evidence-based practices. Although these initiatives will improve the overall availability of high-quality specimens and data for cancer research, OBBR has been authorized to implement a national biobanking effort, cancer HUman Biobank (caHUB). caHUB will address systematically the gaps in knowledge needed to improve the state-of-the-science and strengthen the standards for human biobanking. This commentary outlines the progressive efforts by NCI in technical, governance, and economic considerations that will be important as the new caHUB enterprise is undertaken. PMID- 21672890 TI - Assessing the need for a standardized cancer HUman Biobank (caHUB): findings from a national survey with cancer researchers. AB - BACKGROUND: Before developing a national standardized cancer HUman Biobank (caHUB), the National Cancer Institute sought feedback from the cancer research community. METHODS: NCI conducted an online survey (N = 727) about current biospecimen needs and reactions to creating a national resource cancer researchers and others. RESULTS: Most (56%) participants obtained biospecimens within their own institutions, and 63% wanted more information about their biospecimens. Large proportions reported difficulty obtaining biospecimens of adequate numbers (39%) and quality (47%). Low-quality biospecimens resulted in 60% questioning their findings and 81% limiting the scope of their work. Nine in every 10 (91.3%) respondents reacted positively to the idea of a national biospecimen resource, with 62% reporting that they would obtain biospecimens from it and 53% reporting that they would be willing to contribute biospecimens to it. CONCLUSIONS: Initial reactions to caHUB were positive and seen as a feasible option to addressing respondents' research challenges. National Cancer Institute will need to address several concerns to assure its adoption, including standardization and sustainability. PMID- 21672891 TI - Stakeholder research on biospecimen needs and reactions to the development of a national cancer human biobank by the National Cancer Institute. AB - An initial survey conducted by the National Cancer Institute (NCI) in October 2008 with cancer researchers around the country revealed both a need and support for the development of a national cancer HUman Biobank (caHUB). NCI sought additional feedback from decision makers whose organizations are potential users of a caHUB and who would have a direct influence on whether or not their organizations would participate in a caHUB. NCI commissioned online discussion groups with executive-level decision makers at academic institutions with cancer research programs and pharmaceutical/biotechnology organizations. Across both groups, a clear need for a national caHUB was uniformly expressed. While having a broad range of biospecimens--especially those hard to obtain--in one location was important, stakeholders agreed that the level of standardization the caHUB could offer was the most important benefit. Stakeholders believed the development of standard operating procedures around collection, storage, and quality assessment of biospecimens would be the greatest contribution of the caHUB, allowing more collaboration and higher confidence in research results. Barriers to contribution and/or use of the caHUB focused on funding and resources required of participants, concerns over standard operating procedures, and impositions on their organizations' intellectual property. Findings from the qualitative research are consistent with previous research and point to an overwhelming need for a solution that will address growing concerns about access and availability of quality biospecimens to conduct cancer research and ultimately expedite future discoveries to treat and cure cancer. PMID- 21672892 TI - Biobankonomics: developing a sustainable business model approach for the formation of a human tissue biobank. AB - The preservation of high-quality biospecimens and associated data for research purposes is being performed in variety of academic, government, and industrial settings. Often these are multimillion dollar operations, yet despite these sizable investments, the economics of biobanking initiatives is not well understood. Fundamental business principles must be applied to the development and operation of such resources to ensure their long-term sustainability and maximize their impact. The true costs of developing and maintaining operations, which may have a variety of funding sources, must be better understood. Among the issues that must be considered when building a biobank economic model are: understanding the market need for the particular type of biobank under consideration and understanding and efficiently managing the biobank's "value chain," which includes costs for case collection, tissue processing, storage management, sample distribution, and infrastructure and administration. By using these value chain factors, a Total Life Cycle Cost of Ownership (TLCO) model may be developed to estimate all costs arising from owning, operating, and maintaining a large centralized biobank. The TLCO approach allows for a better delineation of a biobank's variable and fixed costs, data that will be needed to implement any cost recovery program. This article represents an overview of the efforts made recently by the National Cancer Institute's Office of Biorepositories and Biospecimen Research as part of its effort to develop an appropriate cost model and cost recovery program for the cancer HUman Biobank (caHUB) initiative. All of these economic factors are discussed in terms of maximizing caHUB's potential for long-term sustainability but have broad applicability to the wide range of biobanking initiatives that currently exist. PMID- 21672893 TI - Biobankonomics: a taxonomy for evaluating the economic benefits of standardized centralized human biobanking for translational research. AB - Investments in medical research and development enable the scientific progress that influences our society's body of knowledge about disease, the quality of health care, and our quality of life. Critical components of these investments include the technological and human capital factors rooted in human specimen biobanking, which can be considered foundational to driving post genomic scientific and medical research. Their importance to cancer research, information based medicine, and quality of health care are becoming increasingly recognized by pharmaceutical companies, non profit foundations, academic researchers, and government research agencies. However, the failure to standardize tissue collection, handling, processing, and preservation so that data can be directly compared between specimen sets, as well as insufficient leveraging of the highest quality tissue samples and associated data across an array of research needs, have strained economies of scale for the biobanking field. Although existing biobanks for private research contribute economic benefits to stakeholders that can be easily substantiated, little has been published to demonstrate the positive outcomes generated from the use, application, and dissemination of their resources more broadly. Through the use of analogous examples, this article presents a rationale for how standardization and consolidation of biobanking resources would contribute to the realization of budget savings, cost avoidances, process efficiencies, and other financial impacts to both the research community and the public. A number of areas are examined, including laboratory analysis efficiencies, data modeling accuracy, infrastructure cost savings, reduced clinical trials evaluation costs, improvements in patient diagnosis, and the potential impact on industry professionalization and job creation. Areas for further study are also outlined. PMID- 21672894 TI - Reexamining our routines of handing surgical tissue in the operating room. PMID- 21672895 TI - Biospecimens and people: a fundamental connection. AB - This commentary includes the public- and patient-oriented perspective on research biospecimens and the National Cancer Institute's cancer HUman Biobank (caHUB) project. Definitions of biospecimens and the importance to the research community and the public are included, as are conditions that caused the impetus of the caHUB. PMID- 21672896 TI - Breast cancer predictive factor testing: the challenges and importance of standardizing tissue handling. AB - The introduction of breast biomarkers into clinical practice and their critically important role in adjuvant treatment decisions has created new challenges for the surgical pathology laboratory. In most institutions, the current standards for collection and preservation of clinical samples have been in place for decades and have focused on tissue preservation for morphologic examination, with little if any attention paid to preserving the quality of macromolecules that may be in the tissue. Because of the importance of these markers for determining the most appropriate treatments available for each patient, there is a need for standardizing pre-analytic variables, with the goal of developing standardized methods of tissue procurement and processing, and documenting how these variables affect the quality of tissue for biomarker testing and molecular analysis. By better defining specimen handling requirements and approaching diagnostic tissue samples as analytes, we can improve the quality of routine diagnostic samples, which in turn will enhance adjuvant treatment decisions when dealing with breast cancer and other solid tumor malignancies. The quality of archival tissue samples for future biomarker research will also benefit. PMID- 21672897 TI - The value of banked samples for oncology drug discovery and development. AB - To gain insights into human biology and pathobiology, ready access to banked human tissue samples that encompass a representative cross section of the population is required. For optimal use, the banked human tissue needs to be appropriately consented, collected, annotated, and stored. If any of these elements are missing, the studies using these samples are compromised. These elements are critical whether the research is for academic or pharmaceutical industry purposes. An additional temporal element that adds enormous value to such banked samples is treatment and outcome information from the people who donated the tissue. To achieve these aims, many different groups have to work effectively together, not least of which are the individuals who donate their tissue with appropriate consent. Such research is unlikely to benefit the donors but others who succumb to the same disease. The development of a large accessible human tissue bank resource (National Cancer Institute's Cancer HUman Biobank [caHUB]) that provides an ongoing supply of human tissue for all working toward the common goal of understanding human health and disease has a number of advantages. These include, but are not limited to, access to a broad cross section of healthy and diseased populations beyond what individual collections may achieve for understanding disease pathobiology, therapeutic target discovery, as well as a source of material for diagnostic assay validation. Models will need to be developed to enable fair access to caHUB under terms that enable appropriate intellectual property protection and ultimate data sharing to ensure that the biobank successfully distributes samples to a broad range of researchers. PMID- 21672898 TI - Biobanking in a fast moving world: an international perspective. AB - Diseases including the main chronic "killer" diseases have a global dimension and so has biobanking, the main cornerstone for biomarker discovery, validation and implementation in prevention, diagnosis, or therapy. Interconnecting biobanks associated with cohort studies or collections of diseased tissues raises many issues in terms of ethics, governance, regulations, technical standardization, quality control, and sharing of specimens and data. In this perspective article, we briefly address the importance of international networks of biobanks, identify the main challenges, and discuss different models of such networks, balancing the needs for centralization of specimens and resources with the reality of delocalized collection activities, in particular in a clinical context. PMID- 21672899 TI - Identifying aspects of pharmacists' attitudes and barriers toward health literacy: a factor analytic study. AB - BACKGROUND: Health literacy has gained prominence since the Institute of Medicine Report publicized the widespread prevalence of low health literacy. Pharmacists play an important role in enhancing health literacy as a result of their proximity to patients. Literature about pharmacists' perceptions and barriers in incorporating health literacy interventions is lacking. OBJECTIVE: To develop an instrument to measure pharmacists' attitudes and barriers toward health literacy. METHODS: A survey instrument assessing attitudes and barriers was designed based on a pharmacist focus group. The instrument was pretested among a sample of pharmacists from Illinois. The final instrument was administered to a systematic sample of 1500 pharmacists who were members of the Illinois Pharmacists Association. Dillman's 5-step total design method was followed to maximize survey responses. Exploratory principal components analysis with varimax rotation was performed on attitudes and barriers items to identify underlying components. Internal consistency of the components was determined using the Cronbach alpha and corrected item-total correlations. RESULTS: Overall, usable responses were received from 701 respondents, yielding a 48.1% response rate. Exploratory principal components analysis of the attitudes subscale produced a 5-factor solution that explained 55.87% of the variance. The 5 components included (1) low health literacy (LHL) situations, (2) LHL reasons, (3) LHL patient characteristics, (4) medication-related factors, and (5) LHL patient-interaction factors. The barriers subscale produced 3 components: (1) practice-related barriers, (2) knowledge and interaction-related barriers, and (3) process barriers, all of which explained 53.74% of the variance. Cronbach alpha values for the 5 attitudes subscales ranged from 0.33 to 0.78 and, for the 3 barriers, subscale values ranged from 0.56 to 0.71, offering evidence of internal consistency. CONCLUSIONS: Identification of components of pharmacists' attitudes and barriers toward health literacy will be useful to managers interested in incorporating health literacy interventions in their practice. PMID- 21672900 TI - Use of tyrosine kinase inhibitors for chronic myeloid leukemia: management of patients and practical applications for pharmacy practitioners. AB - OBJECTIVE: To summarize the use of tyrosine kinase inhibitors (TKIs) for treatment of patients with chronic myeloid leukemia (CML) and provide practical information for patient management. DATA SOURCES: Literature was retrieved from PubMed (2000-January 2011), using the search terms chronic myeloid leukemia and tyrosine kinase inhibitor. Abstracts presented at the 2008-2010 annual meetings of the American Society of Hematology and the American Society of Clinical Oncology, reference citations from identified publications, as well as the manufacturers' full prescribing information for cited drugs, also were reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles evaluating the efficacy and safety of the TKIs imatinib, nilotinib, and dasatinib were evaluated. Focus was placed on publications supporting management of patients with CML in the chronic phase. Reports presenting clinical trial information of TKIs in development also were included. DATA SYNTHESIS: The discovery of targeted tyrosine kinase inhibition of BCR-ABL kinase dramatically changed the treatment of CML. Imatinib, the first TKI approved for treatment of patients with Philadelphia chromosome--positive CML, demonstrated significant superiority over the previous standard of care: interferon plus cytarabine. The newer, more potent TKIs, nilotinib and dasatinib, have demonstrated improved efficacy over imatinib as first-line therapy and provide an effective option for patients with resistance or intolerance to imatinib. CONCLUSIONS: To maximize efficacy of TKI therapy, close patient management, involving frequent monitoring of patient response, is essential. Given the importance of continuing TKI therapy, early recognition and management of adverse events are critical to optimizing outcomes in patients with CML. In addition to the safety profile and considerations of comorbidities, additional factors can affect therapeutic selection, including drug-drug and drug-food interactions. Research investigating new therapies, particularly for patients harboring the T315I mutation-which remains refractory to current TKIs-continues in the quest to improve outcomes in patients with CML. PMID- 21672901 TI - Comment: evaluation of contraindicated drug-drug interaction alerts in a hospital setting. PMID- 21672902 TI - Endometrial alterations in endometriosis: a systematic review of putative biomarkers. AB - BACKGROUND: Endometriosis is usually diagnosed by an invasive procedure such as a laparoscopy. Great interest therefore lies in the potential to identify biomarkers which may be surrogates of disease presence or activity, especially relating to the effects of therapy. We have reviewed the existing literature on endometrial differences in women with endometriosis, and assess their potential use as disease biomarkers. METHODS: We used QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria to conduct a systematic review of published papers over the past 25 years on the subject of endometrial differences in endometriosis. We searched for all studies assessing differences between eutopic endometrium of women with and without endometriosis. RESULTS: We identified 182 relevant articles that are summarized in the review. These studies assess over 200 potential biomarkers, including hormones and their receptors (n = 29), cytokines (n = 25), factors identified using proteomics (n = 8) and histological analysis (n = 10) of endometrial tissue. Sensitivity and specificity were reported or could be calculated for only 32 articles, and ranged from 0 to 100%. Of the nine highest quality studies, six identified putative biomarkers related to nerve fibre growth or cell cycle control, highlighting these areas as promising candidates for future biomarker research. CONCLUSIONS: This systematic review identified several reports of endometrial differences which have the potential to be biomarkers of endometriosis. However, larger studies in well defined populations are clearly required to determine their true usefulness. PMID- 21672903 TI - Biomedical informatics: how we got here and where we are headed. PMID- 21672904 TI - Computationally translating molecular discoveries into tools for medicine: translational bioinformatics articles now featured in JAMIA. PMID- 21672905 TI - 2010 translational bioinformatics year in review. AB - A review of 2010 research in translational bioinformatics provides much to marvel at. We have seen notable advances in personal genomics, pharmacogenetics, and sequencing. At the same time, the infrastructure for the field has burgeoned. While acknowledging that, according to researchers, the members of this field tend to be overly optimistic, the authors predict a bright future. PMID- 21672907 TI - The application of naive Bayes model averaging to predict Alzheimer's disease from genome-wide data. AB - OBJECTIVE: Predicting patient outcomes from genome-wide measurements holds significant promise for improving clinical care. The large number of measurements (eg, single nucleotide polymorphisms (SNPs)), however, makes this task computationally challenging. This paper evaluates the performance of an algorithm that predicts patient outcomes from genome-wide data by efficiently model averaging over an exponential number of naive Bayes (NB) models. DESIGN: This model-averaged naive Bayes (MANB) method was applied to predict late onset Alzheimer's disease in 1411 individuals who each had 312,318 SNP measurements available as genome-wide predictive features. Its performance was compared to that of a naive Bayes algorithm without feature selection (NB) and with feature selection (FSNB). MEASUREMENT: Performance of each algorithm was measured in terms of area under the ROC curve (AUC), calibration, and run time. RESULTS: The training time of MANB (16.1 s) was fast like NB (15.6 s), while FSNB (1684.2 s) was considerably slower. Each of the three algorithms required less than 0.1 s to predict the outcome of a test case. MANB had an AUC of 0.72, which is significantly better than the AUC of 0.59 by NB (p<0.00001), but not significantly different from the AUC of 0.71 by FSNB. MANB was better calibrated than NB, and FSNB was even better in calibration. A limitation was that only one dataset and two comparison algorithms were included in this study. CONCLUSION: MANB performed comparatively well in predicting a clinical outcome from a high dimensional genome-wide dataset. These results provide support for including MANB in the methods used to predict outcomes from large, genome-wide datasets. PMID- 21672908 TI - Facilitating pharmacogenetic studies using electronic health records and natural language processing: a case study of warfarin. AB - OBJECTIVE: DNA biobanks linked to comprehensive electronic health records systems are potentially powerful resources for pharmacogenetic studies. This study sought to develop natural-language-processing algorithms to extract drug-dose information from clinical text, and to assess the capabilities of such tools to automate the data-extraction process for pharmacogenetic studies. MATERIALS AND METHODS: A manually validated warfarin pharmacogenetic study identified a cohort of 1125 patients with a stable warfarin dose, in which 776 patients were managed by Coumadin Clinic physicians, and the remaining 349 patients were managed by their providers. The authors developed two algorithms to extract weekly warfarin doses from both data sets: a regular expression-based program for semistructured Coumadin Clinic notes; and an advanced weekly dose calculator based on an existing medication information extraction system (MedEx) for narrative providers' notes. The authors then conducted an association analysis between an automatically extracted stable weekly dose of warfarin and four genetic variants of VKORC1 and CYP2C9 genes. The performance of the weekly dose-extraction program was evaluated by comparing it with a gold standard containing manually curated weekly doses. Precision, recall, F-measure, and overall accuracy were reported. Associations between known variants in VKORC1 and CYP2C9 and warfarin stable weekly dose were performed with linear regression adjusted for age, gender, and body mass index. RESULTS: The authors' evaluation showed that the MedEx-based system could determine patients' warfarin weekly doses with 99.7% recall, 90.8% precision, and 93.8% accuracy. Using the automatically extracted weekly doses of warfarin, the authors successfully replicated the previous known associations between warfarin stable dose and genetic variants in VKORC1 and CYP2C9. PMID- 21672909 TI - Protein-network modeling of prostate cancer gene signatures reveals essential pathways in disease recurrence. AB - OBJECTIVE: Uncovering the dominant molecular deregulation among the multitude of pathways implicated in aggressive prostate cancer is essential to intelligently developing targeted therapies. Paradoxically, published prostate cancer gene expression signatures of poor prognosis share little overlap and thus do not reveal shared mechanisms. The authors hypothesize that, by analyzing gene signatures with quantitative models of protein-protein interactions, key pathways will be elucidated and shown to be shared. DESIGN: The authors statistically prioritized common interactors between established cancer genes and genes from each prostate cancer signature of poor prognosis independently via a previously validated single protein analysis of network (SPAN) methodology. Additionally, they computationally identified pathways among the aggregated interactors across signatures and validated them using a similarity metric and patient survival. MEASUREMENT: Using an information-theoretic metric, the authors assessed the mechanistic similarity of the interactor signature. Its prognostic ability was assessed in an independent cohort of 198 patients with high-Gleason prostate cancer using Kaplan-Meier analysis. RESULTS: Of the 13 prostate cancer signatures that were evaluated, eight interacted significantly with established cancer genes (false discovery rate <5%) and generated a 42-gene interactor signature that showed the highest mechanistic similarity (p<0.0001). Via parameter-free unsupervised classification, the interactor signature dichotomized the independent prostate cancer cohort with a significant survival difference (p=0.009). Interpretation of the network not only recapitulated phosphatidylinositol-3 kinase/NF-kappaB signaling, but also highlighted less well established relevant pathways such as the Janus kinase 2 cascade. CONCLUSIONS: SPAN methodology provides a robust means of abstracting disparate prostate cancer gene expression signatures into clinically useful, prioritized pathways as well as useful mechanistic pathways. PMID- 21672910 TI - Targeted screening for pediatric conditions with the CHICA system. AB - OBJECTIVE: The Child Health Improvement through Computer Automation (CHICA) system is a decision-support and electronic-medical-record system for pediatric health maintenance and disease management. The purpose of this study was to explore CHICA's ability to screen patients for disorders that have validated screening criteria--specifically tuberculosis (TB) and iron-deficiency anemia. DESIGN: Children between 0 and 11 years were randomized by the CHICA system. In the intervention group, parents were asked about TB and iron-deficiency risk, and physicians received a tailored prompt. In the control group, no screens were performed, and the physician received a generic prompt about these disorders. RESULTS: 1123 participants were randomized to the control group and 1116 participants to the intervention group. Significantly more people reported positive risk factors for iron-deficiency anemia in the intervention group (17.5% vs 3.1%, OR 6.6, 95% CI 4.5 to 9.5). In general, far fewer parents reported risk factors for TB than for iron-deficiency anemia. Again, there were significantly higher detection rates of positive risk factors in the intervention group (1.8% vs 0.8%, OR 2.3, 95% CI 1.0 to 5.0). LIMITATIONS: It is possible that there may be more positive screens without improving outcomes. However, the guidelines are based on studies that have evaluated the questions the authors used as sensitive and specific, and there is no reason to believe that parents misunderstood them. CONCLUSIONS: Many screening tests are risk-based, not universal, leaving physicians to determine who should have a further workup. This can be a time consuming process. The authors demonstrated that the CHICA system performs well in assessing risk automatically for TB and iron-deficiency anemia. PMID- 21672911 TI - Comparison of computerized surveillance and manual chart review for adverse events. AB - OBJECTIVE: To understand how the source of information affects different adverse event (AE) surveillance methods. DESIGN: Retrospective analysis of inpatient adverse drug events (ADEs) and hospital-associated infections (HAIs) detected by either a computerized surveillance system (CSS) or manual chart review (MCR). MEASUREMENT: Descriptive analysis of events detected using the two methods by type of AE, type of information about the AE, and sources of the information. RESULTS: CSS detected more HAIs than MCR (92% vs 34%); however, a similar number of ADEs was detected by both systems (52% vs 51%). The agreement between systems was greater for HAIs than ADEs (26% vs 3%). The CSS missed events that did not have information in coded format or that were described only in physician narratives. The MCR detected events missed by CSS using information in physician narratives. Discharge summaries were more likely to contain information about AEs than any other type of physician narrative, followed by emergency department reports for HAIs and general consult notes for ADEs. Some ADEs found by MCR were detected by CSS but not verified by a clinician. LIMITATIONS: Inability to distinguish between CSS false positives and suspected AEs for cases in which the clinician did not document their assessment in the CSS. CONCLUSION: The effect that information source has on different surveillance methods depends on the type of AE. Integrating information from physician narratives with CSS using natural language processing would improve the detection of ADEs more than HAIs. PMID- 21672912 TI - Using statistical and machine learning to help institutions detect suspicious access to electronic health records. AB - OBJECTIVE: To determine whether statistical and machine-learning methods, when applied to electronic health record (EHR) access data, could help identify suspicious (ie, potentially inappropriate) access to EHRs. METHODS: From EHR access logs and other organizational data collected over a 2-month period, the authors extracted 26 features likely to be useful in detecting suspicious accesses. Selected events were marked as either suspicious or appropriate by privacy officers, and served as the gold standard set for model evaluation. The authors trained logistic regression (LR) and support vector machine (SVM) models on 10-fold cross-validation sets of 1291 labeled events. The authors evaluated the sensitivity of final models on an external set of 58 events that were identified as truly inappropriate and investigated independently from this study using standard operating procedures. RESULTS: The area under the receiver operating characteristic curve of the models on the whole data set of 1291 events was 0.91 for LR, and 0.95 for SVM. The sensitivity of the baseline model on this set was 0.8. When the final models were evaluated on the set of 58 investigated events, all of which were determined as truly inappropriate, the sensitivity was 0 for the baseline method, 0.76 for LR, and 0.79 for SVM. LIMITATIONS: The LR and SVM models may not generalize because of interinstitutional differences in organizational structures, applications, and workflows. Nevertheless, our approach for constructing the models using statistical and machine-learning techniques can be generalized. An important limitation is the relatively small sample used for the training set due to the effort required for its construction. CONCLUSION: The results suggest that statistical and machine-learning methods can play an important role in helping privacy officers detect suspicious accesses to EHRs. PMID- 21672913 TI - Bridging the integration gap between imaging and information systems: a uniform data concept for content-based image retrieval in computer-aided diagnosis. AB - It is widely accepted that content-based image retrieval (CBIR) can be extremely useful for computer-aided diagnosis (CAD). However, CBIR has not been established in clinical practice yet. As a widely unattended gap of integration, a unified data concept for CBIR-based CAD results and reporting is lacking. Picture archiving and communication systems and the workflow of radiologists must be considered for successful data integration to be achieved. We suggest that CBIR systems applied to CAD should integrate their results in a picture archiving and communication systems environment such as Digital Imaging and Communications in Medicine (DICOM) structured reporting documents. A sample DICOM structured reporting template adaptable to CBIR and an appropriate integration scheme is presented. The proposed CBIR data concept may foster the promulgation of CBIR systems in clinical environments and, thereby, improve the diagnostic process. PMID- 21672917 TI - AMIA president's column: AMIA and HIT policy activities. PMID- 21672914 TI - Personal health records: a scoping review. AB - Electronic personal health record systems (PHRs) support patient centered healthcare by making medical records and other relevant information accessible to patients, thus assisting patients in health self-management. We reviewed the literature on PHRs including design, functionality, implementation, applications, outcomes, and benefits. We found that, because primary care physicians play a key role in patient health, PHRs are likely to be linked to physician electronic medical record systems, so PHR adoption is dependent on growth in electronic medical record adoption. Many PHR systems are physician-oriented, and do not include patient-oriented functionalities. These must be provided to support self management and disease prevention if improvements in health outcomes are to be expected. Differences in patient motivation to use PHRs exist, but an overall low adoption rate is to be expected, except for the disabled, chronically ill, or caregivers for the elderly. Finally, trials of PHR effectiveness and sustainability for patient self-management are needed. PMID- 21672918 TI - Protease inhibitor monotherapy and the CNS: peace of mind? AB - Boosted protease inhibitor (bPI) monotherapy has demonstrated high efficacy for maintaining viral suppression in the blood. bPI monotherapy has the theoretical advantage of avoiding the long-term toxicity associated with the use of nucleoside reverse transcriptase inhibitors. Concern about the efficacy of bPI monotherapy in preventing HIV replication in the CNS is one reason that has precluded the widespread use of this therapeutic strategy. In several studies, a low CNS penetration-effectiveness (CPE) score has been associated with a higher risk of virological failure in the CNS and with neurocognitive impairment. Since the CPE score is substantially lower for bPI monotherapy than for triple-drug highly active antiretroviral therapy (HAART), it has been postulated that bPI monotherapy might have a higher risk for CNS virological failure and neurocognitive impairment. However, the available evidence, although limited, does no support this notion. Lopinavir and darunavir achieve CSF drug levels that are sufficient to fully suppress HIV replication. In clinical trials, when compared with triple-drug HAART, patients receiving bPI monotherapy with lopinavir and darunavir who maintain full virological suppression in plasma do not appear to be at a higher risk of discordant HIV replication in the CSF or of neuropsychiatric adverse events. It should be noted that several studies have suggested that nucleoside reverse transcriptase inhibitors might have neurotoxic effects and, consequently, bPI monotherapy might be able to avoid the CNS toxicity induced by nucleosides. It is clear that more studies including detailed neurocognitive testing are needed to completely establish the risk/benefit ratio of bPI monotherapy or triple-drug HAART for preserving neurocognitive function in HIV-infected patients. PMID- 21672920 TI - Genomic, genetic and functional dissection of bitter taste responses to artificial sweeteners. AB - Bitter taste perception is initiated by TAS2R receptors, which respond to agonists by triggering depolarization of taste bud cells. Mutations in TAS2Rs are known to affect taste phenotypes by altering receptor function. Evidence that TAS2Rs overlap in ligand specificity suggests that they may also contribute joint effects. To explore this aspect of gustation, we examined bitter perception of saccharin and acesulfame K, widely used artificial sweeteners with aversive aftertastes. Both substances are agonists of TAS2R31 and -43, which belong to a five-member subfamily (TAS2R30-46) responsive to a diverse constellation of compounds. We analyzed sequence variation and linkage structure in the ~140 kb genomic region encoding TAS2R30-46, taste responses to the two sweeteners in subjects, and functional characteristics of receptor alleles. Whole-gene sequences from TAS2R30-46 in 60 Caucasian subjects revealed extensive diversity including 34 missense mutations, two nonsense mutations and high-frequency copy number variants. Thirty markers, including non-synonymous variants in all five genes, were associated (P< 0.001) with responses to saccharin and acesulfame K. However, linkage disequilibrium (LD) in the region was high (D', r(2) > 0.95). Haplotype analyses revealed that most associations were spurious, arising from LD with variants in TAS2R31. In vitro assays confirmed the functional importance of four TAS2R31 mutations, which had independent effects on receptor response. The existence of high LD spanning functionally distinct TAS2R loci predicts that bitter taste responses to many compounds will be strongly correlated even when they are mediated by different genes. Integrative approaches combining phenotypic, genetic and functional analysis will be essential in dissecting these complex relationships. PMID- 21672919 TI - Temporal requirement for high SMN expression in SMA mice. AB - Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron 1 gene (SMN1) and retention of the SMN2 gene, resulting in reduced SMN. SMA mice can be rescued with high expression of SMN in neurons, but when is this high expression required? We have developed a SMA mouse with inducible expression of SMN to address the temporal requirement for high SMN expression. Both embryonic and early postnatal induction of SMN resulted in a dramatic increase in survival with some mice living greater than 200 days. The mice had no marked motor deficits and neuromuscular junction (NMJ) function was near normal thus it appears that induction of SMN in postnatal SMA mice rescues motor function. Early postnatal SMN induction, followed by a 1-month removal of induction at 28 days of age, resulted in no morphological or electrophysiological abnormalities at the NMJ and no overt motor phenotype. Upon removal of SMN induction, five mice survived for just over 1 month and two female mice have survived past 8 months of age. We suggest that there is a postnatal period of time when high SMN levels are required. Furthermore, two copies of SMN2 provide the minimal amount of SMN necessary to maintain survival during adulthood. Finally, in the course of SMA, early induction of SMN is most efficacious. PMID- 21672922 TI - Criterion-based clinical audit to assess quality of obstetrical care in low- and middle-income countries: a systematic review. AB - PURPOSE: Low-quality obstetric care in low- and middle-income countries contributes to high in-hospital maternal mortality. Criterion-based clinical audits are increasingly used to measure and improve obstetric care in these settings. This article systematically reviews peer-reviewed literature to determine if these audits are feasible, valid and reliable measurement tools for assessing the quality of obstetric care. DATA SOURCES: PUBMED, Google Scholar and Web of Science databases were searched for peer-reviewed articles published between 1995 and 2009 and which used criterion-based clinical audits to measure the quality of obstetric care in low- and middle-income countries. STUDY SELECTION: Sixty-nine studies were identified by key terms and subsequently reviewed. Ten were retained based on inclusion/exclusion criteria. DATA EXTRACTION: (i) General characteristics of the study; (ii) compliance with expected standards of care and on maternal/child health outcomes; (iii) selection of the study population and sampling methods; and (iv) quality control and reliability. RESULTS OF DATA SYNTHESIS: Criterion-based clinical audit is increasingly used in low- and middle-income countries. Most audits were conducted in sub-Saharan Africa. Studies had cross-sectional study or before-and-after designs. Sampling methods were poorly reported and selection bias was a concern. No studies compared audit against other measures of quality of care or against patient outcomes. METHODS: for quality control and assurance were generally not documented and reliability was mostly unaddressed. CONCLUSIONS: Criterion-based clinical audit appears feasible. No studies have rigorously evaluated its measurement properties in low- and middle-income countries. Without such evaluation, measurement properties of the audit remain under question. PMID- 21672921 TI - A natural antisense transcript at the Huntington's disease repeat locus regulates HTT expression. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of huntingtin (HTT). Relatively little attention has been directed to the genomic features of the antisense strand at the HD locus, though the presence of a transcript from this strand has been suggested by a survey of the entire transcriptome and the existence of several EST tags. In this study, we identified huntingtin antisense (HTTAS), a natural antisense transcript at the HD repeat locus that contain the repeat tract. HTTAS is 5' capped, poly (A) tailed and contains three exons, alternatively spliced into HTTAS_v1 (exons 1 and 3) and HTTAS_v2 (exons 2 and 3). Exon 1 includes the repeat. HTTAS_v1 has a weak promoter, and is expressed at low levels in multiple tissue types and throughout the brain. Reporter assays indicate that while efficient promoter activity requires a short repeat, repeat expansion reduces promoter efficiency. Consistent with the reporter assays, levels of HTTAS_v1 are reduced in human HD frontal cortex. In cell systems, overexpression of HTTAS_v1 specifically reduces endogenous HTT transcript levels, while siRNA knockdown of HTTAS_v1 increases HTT transcript levels. Minigene constructs of the HD locus confirm the regulatory effect of HTTAS_v1 on HTT, and demonstrate that the effect is dependent on repeat length and is at least partially Dicer dependent. Together, these findings provide strong evidence for the existence of a gene antisense to HTT, with properties that include regulation of HTT expression. PMID- 21672923 TI - Do doctors under-provide, over-provide or do both? Exploring the quality of medical treatment in the Philippines. AB - OBJECTIVE: To assess the quality of medical treatment by disaggregating quality into components that distinguish between insufficient and unnecessary care. DESIGN: Randomly selected doctors were asked how they would treat a sick child. Their responses were disaggregated into how much of an evidence-based essential treatment plan was completed and the number of additional non-essential treatments that were given. Key variables included the expected cost, the health consequences of insufficient and unnecessary care and comparisons between public and private physicians. Responses to 160 clinical performance vignettes (CPVs) were analysed. SETTING: Philippines. PARTICIPANTS: One hundred and forty-three public and private physicians in the Philippines, collected in November 2003 December 2004 and September 2006-June 2007. INTERVENTIONS: CPVs administered to physicians. MAIN OUTCOME MEASURES: Process quality measures (accounting for the possibility of both over-treatment and under-treatment). RESULTS: Based on CPVs, doctors gave both insufficient and unnecessary treatment to under-five children in 69% of cases. Doctors who provided the least sufficient care were also the most likely to give costly or harmful unnecessary care. Insufficient care typically had potentially worse health consequences for the patient than unnecessary care, though unnecessary care remains a concern because of overuse of antibiotics (47%) and unnecessary hospitalization (34%). CONCLUSIONS: Quality of care is complex, but over- and under-treatment coexist and, in our analysis physicians that were more likely to under-treat a sick child were also those more likely to over-treat. PMID- 21672924 TI - Efficacy and safety of a levonorgestrel enteric-coated tablet as an over-the counter drug for emergency contraception: a Phase IV clinical trial. AB - BACKGROUND: An enteric-coated levonorgestrel emergency contraceptive pill (E-LNG ECP) is an improved formulation, in terms of side effects, which both dissolves and is absorbed in the intestine. Our aim was to evaluate the efficacy and safety of E-LNG-ECP as an over-the-counter (OTC) drug for emergency contraception (EC) in Chinese women. METHODS: A Phase IV clinical trial was conducted in five family planning clinics in China. Women seeking EC within 72 h after unprotected sexual intercourse or contraceptive failure who met the inclusion criteria were recruited. The efficacy of contraception (primary end-point was pregnancy rate), side effects (i.e. safety) and the value of E-LNG-ECP for EC were investigated. RESULTS: Of 2445 women (aged 15-48 years) who took E-LNG-ECP with follow-up to determine pregnancy, only five pregnancies (0.2%) occurred. The efficacy of contraception was 95.3%. In total, 6.5% of women reported at least one adverse event after taking E-LNG-ECP, and no serious adverse events were reported. Only four subjects (0.16%) reported vomiting. The incidence of menstrual cycle disturbance was 20.1% after taking E-LNG-ECP. Subjects who had previously taken ECPs (54.4% of these women) rated the acceptability of E-LNG-ECP at 9.36 (on a 10 point scale) higher (P<0.05) than the rating of other LNG-EC pills taken previously. CONCLUSIONS: The study found that E-LNG-ECP was effective, safe and well tolerated as an OTC drug. However, an randomized controlled trial should be performed to compare standard LNG tablets with E-LNG-ECP. PMID- 21672925 TI - Discouraging trends in reproductive health service use among adolescent and young adult women in the USA, 2002-2008. AB - BACKGROUND: To investigate reproductive health service use by young women in the USA between 2002 and 2008. METHODS: Using data from two waves of The National Survey of Family Growth, we investigated reproductive health service utilization among women aged 15-24 years (2002 n=2157; 2006-2008 n=2264). Descriptive and univariate statistics and multivariate regression models were employed to describe types of reproductive health services used and compare service use across years. Analyses focused on questions regarding specific recent use of reproductive health services (within the previous 12 months). RESULTS: Over half the pooled sample (n=4421) reported lifetime family planning clinic (58%) and recent reproductive health service (59%) use, including contraceptive (48%), gynecological exam (47%) and counseling (37%) services. Lifetime family planning service use declined by 15% from 2002 to 2008 (P<0.001) and recent reproductive health service use by 8% (P=0.01), including gynecological exam (8%, P= 0.03) and contraceptive (6%, P= 0.02) services. By 2006-2008, women were less likely to use reproductive health and contraceptive services than in 2002 [odds ratio (OR) 0.6, confidence interval (CI) 0.5, 0.8, P< 0.001 and OR 0.7, CI 0.6, 0.9, P= 0.005, respectively]. Trends were similar but smaller in magnitude among the sexually experienced women, with a 5% decline in both reproductive health (OR 0.7, CI 0.6, 1.0, P= 0.02) and contraceptive (OR 0.8, CI 0.6, 1.0, P= 0.03) service use. CONCLUSIONS: Reproductive health service use among young women in the USA has declined over the past decade. Public health and policy strategies are needed to promote service use, ultimately to improve reproductive health outcomes. PMID- 21672926 TI - Women's perspectives regarding subcutaneous injections, costs and live birth rates in IVF. AB - BACKGROUND: The addition of recombinant LH (rLH) to controlled ovarian hyperstimulation (COH) shows a beneficial effect on ongoing pregnancy rates in poor responder women, with an increase of ongoing pregnancy rate. Next to this possible beneficial effect, there are two potential drawbacks of adding rLH to COH; women have to administer extra injections, and daily rLH injections generate additional costs. We therefore investigated women's perspectives on an additional injection of rLH with respect to live birth rates (LBR) and out-of-pocket costs in a discrete choice experiment. METHODS: Women eligible for IVF were asked to choose between treatments that differed in LBR after one IVF cycle, the amount of self-administered injections and out-of-pocket costs or reimbursement. The relative weights that women place on these attributes were estimated with a logistic regression model. To test for heterogeneity of preferences among women, patient characteristics were included in the model. RESULTS: Two-hundred and thirty-four women were asked to participate in the study. In total, 223 women responded (response rate 95%) and 206 questionnaires were analysed. An increase of one daily injection did not alter women's treatment preference. LBR and costs did have a significant (P < 0.001) impact on women's choice of IVF treatment. Patient characteristics significantly influenced the effect of costs on women's preferences. CONCLUSIONS: One extra daily injection will not cause a woman to refrain from a certain IVF treatment. However, to compensate for the out-of pocket costs of this extra daily injection, the expected LBR should at least be 6%. PMID- 21672927 TI - Suicide in Danish women evaluated for fertility problems. AB - BACKGROUND: Women with fertility problems often experience higher levels of stress, anxiety and depressive symptoms associated with both the infertility diagnosis and eventual fertility treatment. The authors investigated whether women who do not succeed in having a child after an infertility evaluation are at a higher risk of suicide than women who succeed in having a child after an infertility evaluation. METHODS: A cohort of 51 221 Danish women with primary or secondary infertility and referred to hospitals or private fertility clinics in Denmark during 1973-1998 was established. The cohort was linked to four Danish administrative population-based registries. Each woman was followed from the date of her initial fertility evaluation at the clinic or hospital until 2006. Cox proportional hazards regression analyses was used to calculate hazard ratios (HRs) for suicide and their corresponding 95% confidence intervals (CIs) adjusted for potential confounders. RESULTS: Women who did not have a child after an initial fertility evaluation had a >2-fold (HR: 2.43; 95% CI: 1.38-3.71) greater risk of suicide than women who had at least one child after a fertility evaluation. Women with secondary infertility, i.e. women who had a child before a fertility evaluation but did not succeed in having one after, also had an increased risk for suicide (HR: 1.68; 95% CI, 0.82-3.41) compared with women who succeeded in having another child, although the risk estimate failed to reach significance. CONCLUSIONS: Health-care personnel treating women with fertility problems should be aware of the emotional response of their patients in order to recognize and treat possible psychiatric morbidity after fertility problems. PMID- 21672928 TI - Anti-Mullerian hormone-tailored stimulation protocols improve outcomes whilst reducing adverse effects and costs of IVF. AB - BACKGROUND: Anti-Mullerian hormone (AMH) is increasingly used to quantify ovarian reserve, but it has not yet realized its full clinical potential in assisted reproduction technology. We investigated the possible benefits of using novel, stratified ovarian hyperstimulation protocols, tailored to individual AMH levels, compared with conventional stimulation. METHODS: Retrospective data were collected from 769 women (first cycle of IVF, using fresh embryos), in a UK tertiary care unit: 346 women using conventional stimulation protocols; 423 women treated under new AMH-tailored protocols. RESULTS: Embryo transfer rates increased significantly (79-87%: P= 0.002) after the introduction of AMH-tailored stimulation protocols. Pregnancy rate per cycle started and live birth rate also increased significantly compared with conventionally treated women (17.9-27.7%, P= 0.002 and 15.9-23.9%, P = 0.007, respectively). Moreover, in the AMH group, the incidence of the ovarian hyperstimulation syndrome (OHSS) fell significantly (6.9-2.3%, P = 0.002) and failed fertilization fell from 7.8 to 4.5%. The cost of fertility drug treatment fell by 29% per patient and the overall cost of clinical management of OHSS fell by 43% in the AMH group. GnRH antagonist protocols, introduced as part of AMH-tailored treatment, may have contributed to the observed improvements: however, within the AMH-tailored group, the live birth rate was not significantly different between agonist and antagonist-treated groups. CONCLUSIONS: Although large, prospective, multicentre studies are indicated, we have clearly demonstrated that individualized, AMH-guided, controlled ovarian hyperstimulation protocols significantly improved positive clinical outcomes, reduced the incidence of complications and reduced the financial burden associated with assisted reproduction. PMID- 21672929 TI - Sam68 mediates leptin-stimulated growth by modulating leptin receptor signaling in human trophoblastic JEG-3 cells. AB - BACKGROUND: Sam68, a member of the signal transduction and activation of RNA metabolism (STAR) family of RNA-binding proteins, has been previously implicated as an adaptor molecule in different signaling systems, including leptin receptor (LEPR) signaling. LEPR activation is known to stimulate JAK-STAT, MAPK and PI3K signaling pathways, thus mediating the biological effects of leptin in different cell types, including trophoblastic cells. We have recently found that leptin stimulation also promotes the overexpression and tyrosine phosphorylation of Sam68 in human trophoblastic JEG-3 cells, suggesting a role for Sam68 in leptin signaling and action in these cells. In the present work, we have studied the participation of Sam68 in the main signaling pathways activated by LEPR to increase growth and proliferation in trophoblastic JEG-3 cells. METHODS: We used an antisense strategy to down-regulate Sam68 expression in these cells, and we studied LEPR signaling by immunoprecipitation and poly-U affinity precipitation and by analyzing phosphorylation levels of signaling proteins by immunoblot. The effect of leptin on protein synthesis and proliferation was studied by 3[H] leucine and 3[H]-thymidine incorporation. RESULTS: Sam68 knockdown impaired leptin activation of JAK-STAT, PI3K and MAPK signaling pathways in JEG-3 cells. We have also found that leptin-stimulated Sam68 tyrosine phosphorylation is dependent on JAK-2 activity, since the pharmacological inhibitor AG490 prevents the phosphorylation of Sam68 in JEG-3 cells. Finally, the trophic and proliferative effect of leptin in trophoblastic cells is dependent on Sam68 expression, since its down-regulation impaired the leptin-stimulated DNA and protein synthesis. CONCLUSIONS: These data demonstrate that Sam68 participates in the main signaling pathways of LEPR to mediate the trophic and proliferative effect of leptin in human trophoblastic cells. PMID- 21672930 TI - A key role of TRPC channels in the regulation of electromechanical activity of the developing heart. AB - AIMS: It is well established that dysfunction of voltage-dependent ion channels results in arrhythmias and conduction disturbances in the foetal and adult heart. However, the involvement of voltage-insensitive cationic TRPC (transient receptor potential canonical) channels remains unclear. We assessed the hypothesis that TRPC channels play a crucial role in the spontaneous activity of the developing heart. METHODS AND RESULTS: TRPC isoforms were investigated in isolated hearts obtained from 4-day-old chick embryos. Using RT-PCR, western blotting and co immunoprecipitation, we report for the first time that TRPC1, 3, 4, 5, 6, and 7 isoforms are expressed at the mRNA and protein levels and that they can form a macromolecular complex with the alpha1C subunit of the L-type voltage-gated calcium channel (Cav1.2) in atria and ventricle. Using ex vivo electrocardiograms, electrograms of isolated atria and ventricle and ventricular mechanograms, we found that inhibition of TRPC channels by SKF-96365 leads to negative chrono-, dromo-, and inotropic effects, prolongs the QT interval, and provokes first- and second-degree atrioventricular blocks. Pyr3, a specific antagonist of TRPC3, affected essentially atrioventricular conduction. On the other hand, specific blockade of the L-type calcium channel with nifedipine rapidly stopped ventricular contractile activity without affecting rhythmic electrical activity. CONCLUSIONS: These results give new insights into the key role that TRPC channels, via interaction with the Cav1.2 channel, play in regulation of cardiac pacemaking, conduction, ventricular activity, and contractility during cardiogenesis. PMID- 21672931 TI - Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model. AB - AIMS: Increasing evidence indicates that congenital long QT syndromes (LQTSs) promote atrial fibrillation. The atrial action potential (AP) has a short plateau, and whether LQTS atrial cardiomyocytes generate triggered activity via early afterdepolarizations (EADs) is unclear. Atrial cellular arrhythmia mechanisms have not been defined in congenital LQTS. Therefore, we studied atrial cardiomyocyte electrophysiology in mice with an LQTS3 SCN5A inactivation impairing mutation (DeltaKPQ heterozygotes). METHODS AND RESULTS: Peak and late Na(+) current (I(NaP) and I(NaL)) were measured with whole-cell patch clamp in left atrial (LA) cardiomyocytes. APs were recorded in multicellular LA preparations with floating microelectrodes. I(NaL) was increased by 110% in LA cardiomyocytes of DeltaKPQ mice, whereas I(NaP) was unchanged. AP duration (APD) was prolonged over all frequencies in DeltaKPQ mice, but particularly at lower frequencies [e.g. APD(90) at 0.5 Hz: 197 +/- 8 ms vs. wild-type (WT) 82 +/- 2 ms, P< 0.001]. EADs occurred at 0.5 Hz in 10/18 DeltaKPQ (56%) vs. 1/10 WT (10%) atria (P< 0.05). EADs immediately preceded premature APs in other LA regions, suggesting triggered activity. Ranolazine preferentially inhibited I(NaL) (50% inhibitory concentration: 12.5 vs. 151.8 uM for I(NaP)) in DeltaKPQ myocytes. At 10 uM, ranolazine shortened APD (e.g. APD(90) at 0.5 Hz to 122 +/- 4 ms, P= 0.01) without changing APD in WT and suppressed EAD occurrence and triggered activity (from 10/18 to 1/9 preparations, 11%, P< 0.05). CONCLUSION: This study implicates increased I(NaL) in excessive atrial APD prolongation and arrhythmic EAD occurrence in a congenital LQTS3 mouse model. Our observations provide the first direct demonstration of atrial EADs and triggered activity in a genetically defined animal model of human LQTS and have potential clinically-relevant mechanistic and therapeutic implications. PMID- 21672932 TI - Consensus document regarding cardiovascular safety at sports arenas: position stand from the European Association of Cardiovascular Prevention and Rehabilitation (EACPR), section of Sports Cardiology. AB - Mass gathering events in sports arenas create challenges regarding the cardiovascular safety of both athletes and spectators. A comprehensive medical action plan, to ensure properly applied cardiopulmonary resuscitation, and wide availability and use of automated external defibrillators (AEDs), is essential to improving survival from sudden cardiac arrest at sporting events. This paper outlines minimum standards for cardiovascular care to assist in the planning of mass gathering sports events across Europe with the intention of local adaptation at individual sports arenas, to ensure the full implementation of the chain of survival. PMID- 21672933 TI - Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. AB - Acute heart failure syndromes (AHFS) are a heterogeneous group of commonly encountered and difficult to manage clinical syndromes associated with high morbidity and mortality. Dyspnoea, pulmonary, and systemic congestion often characterize AHFS due to acutely elevated intracardiac filling pressures and fluid overload. Diuresis, respiratory support, vasodilator therapy, and gradual attenuation of the activation of renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are the keystones of AHFS management. Despite available therapies, post-discharge mortality and re-hospitalization rates remain unacceptably high in AHFS. Neurohumoral-mediated cardiorenal dysfunction and congestion may contribute to these high event rates. Mineralocorticoid receptor antagonists (MRAs) serve a dual therapeutic role by enhancing diuresis and attenuating the pathological effects of RAAS and SNS activation. Although these agents are indicated in patients with chronic, severe heart failure with reduced ejection fraction (HF/REF) and in patients with HF/REF post-myocardial infarction (MI), they have not been systematically studied in patients with AHFS. The purpose of this review is to explore the potential efficacy and safety of MRAs in AHFS. PMID- 21672934 TI - The new European Society of Cardiology declaration of interest procedure: a step towards improved transparency in relations between professionals and industry partners. AB - The ESC has launched a new declaration of interest form and review process to increase transparency. Prof Michel Komajda, ESC President, speaks to Helen Jaques about the new process. PMID- 21672935 TI - Shielding of proton accelerators. AB - This paper discusses some of the methods that can be employed for calculating shielding of proton accelerators, showing that a simple analytical model is often useful for a first estimate before going into complex Monte Carlo simulations. In particular what we call the Monte Carlo 'hybrid' approach, which employs source terms and attenuation length data calculated by Monte Carlo simulations under generic geometrical conditions, with a point-source line-of-sight model is discussed. Examples are given of the application of this method to the shielding calculations of two versions of the CERN SPL (2- and 3.5-GeV energy), comparing its results with Monte Carlo simulations of the full geometry. PMID- 21672936 TI - Comparison of the Repeatable Battery for the Assessment of Neuropsychological Status Effort Index and stand-alone symptom validity tests in a military sample. AB - The current study sought to report the base rates of Symptom Validity Test (SVT) failure in an active duty military sample as well as to compare the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Effort Index (EI) to stand-alone measures of symptom validity. SVT failure varied from previous studies and even among different subgroups in the current sample, ranging from 8% to 30%. The RBANS EI demonstrated modest sensitivity in the detection of suboptimal effort when compared with stand-alone SVTs. Although the index appears to add some utility to the detection of suboptimal effort, sole use of the EI as a measure of symptom validity could conceivably result in an unnecessarily high rate of false negatives. PMID- 21672937 TI - The ethics of disclosing genetic diagnosis for Alzheimer's disease: do we need a new paradigm? AB - INTRODUCTION OR BACKGROUND: Genetic testing for rare Mendelian disorders represents the dominant ethical paradigm in clinical and professional practice. Predictive testing for Huntington's disease is the model against which other kinds of genetic testing are evaluated, including testing for Alzheimer's disease. SOURCES OF DATA: This paper retraces the historical development of ethical reasoning in relation to predictive genetic testing and reviews a range of ethical, sociological and psychological literature from the 1970s to the present. AREAS OF AGREEMENT: In the past, ethical reasoning has embodied a distinct style whereby normative principles are developed from a dominant disease exemplar. AREAS OF CONTROVERSY: This reductionist approach to formulating ethical frameworks breaks down in the case of disease susceptibility. GROWING POINTS: Recent developments in the genetics of Alzheimer's disease present a significant case for reconsidering the ethics of disclosing risk for common complex diseases. Disclosing the results of susceptibility testing for Alzheimer's disease has different social, psychological and behavioural consequences. Furthermore, what genetic susceptibility means to individuals and their families is diffuse and often mitigated by other factors and concerns. AREAS TIMELY FOR DEVELOPING RESEARCH: The ethics of disclosing a genetic diagnosis of susceptibility is contingent on whether professionals accept that probabilistic risk information is in fact 'diagnostic' and it will rely substantially on empirical evidence of how people actually perceive, recall and communicate complex risk information. PMID- 21672938 TI - Trypsinogen activation in acute and chronic pancreatitis: is it a prerequisite? PMID- 21672939 TI - Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease. AB - BACKGROUND AND AIMS: To identify the associations of genetic and epigenetic variations in IL-23R and IL-17A with inflammatory bowel diseases (IBD). METHODS: The promoter and exon regions of IL-23R and IL-17A were analysed in 727 subjects (201 Crohn's disease, 268 ulcerative colitis and 258 healthy controls) using DNA sequencing and denaturing high performance liquid chromatography. Transcription factor binding affinity, IL-17A mRNA expression and methylation of the IL-17A promoter were evaluated in peripheral blood mononuclear cells (PBMC) and Jurkat cells. RESULTS: A case-control analysis showed that development of Crohn's disease is associated with the IL-23R variant G149R (OR 0.32, 95% CI 0.15 to 0.68) and IL-17A variant IVS1+18G>C (OR 10.65, 95% CI 1.32 to 85.89). Ulcerative colitis patients showed an association with IL-23R variants G149R (OR 0.41, 95% CI 0.21 to 0.76), IVS4+17C>T (OR 2.89, 95% CI 1.20 to 6.96) and Q3H (OR 0.61, 95% CI 0.38 to 0.99), and IL-17A variants -737C>T (OR 1.50, 95% CI 1.06 to 2.13), 197G>A (OR 0.63, 95% CI 0.40 to 0.97) and IVS1+18 G>C (OR 8.93, 95% CI 1.12 to 70.99). The -877G, -737T and -444A risk alleles of IL-17A displayed higher binding affinities with the transcription factor complex and higher expression levels of IL-17A transcripts. DNA hypomethylation of the IL-17A promoter was observed in PBMC from IBD patients with a significant inverse correlation between methylation extent of IVS1+17 and IL-17A mRNA level. Finally, Jurkat cells recovered IL-17A mRNA expression after exposure to demethylating agent. CONCLUSIONS: The results provide insights into the genetic and epigenetic interactions in the IL-23R/IL-17 axis that are associated with elevated expression of IL-17 and IBD pathogenesis. PMID- 21672940 TI - The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. AB - BACKGROUND: Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-124) in hepatocellular carcinoma (HCC). OBJECTIVE: To determine the status of miR-124 expression and its underlying mechanisms in the pathogenesis of HCC. METHODS: The expression levels of miR-124 were first examined in HCC cell lines and tumour tissues by real-time PCR. The in vitro and in vivo functional effect of miR-124 was examined further. A luciferase reporter assay was conducted to confirm target associations. RESULTS: The expression levels of miR-124 were frequently reduced in HCC cells and tissues, and low-level expression of miR-124 was significantly associated with a more aggressive and/or poor prognostic phenotype of patients with HCC (p<0.05). In HCC cell lines, stable overexpression of miR-124 was sufficient to inhibit cell motility and invasion in vitro, and suppress intrahepatic and pulmonary metastasis in vivo. In addition, ectopic overexpression of miR-124 in HCC cells inhibited epithelial mesenchymal cell transition, formation of stress fibres, filopodia and lamellipodia. Further studies showed that miR-124 could directly target the 3' untranslated region (3'-UTR) of both ROCK2 and EZH2 mRNAs, and suppress their mRNA and protein expressions. These findings suggest that miR-124 plays a critical role in regulating cytoskeletal events and epithelial-mesenchymal cell transition and, ultimately, inhibits the invasive and/or metastatic potential of HCC, probably by its direct target on ROCK2 and EZH2 genes. These results provide functional and mechanistic links between the tumour suppressor miRNA-124 and the two oncogenes ROCK2 and EZH2 on the aggressive nature of HCC. CONCLUSION: These data highlight an important role for miR-124 in the regulation of invasion and metastasis in the molecular aetiology of HCC, and suggest a potential application of miR-124 in prognosis prediction and cancer treatment. PMID- 21672941 TI - Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/beta-catenin signalling pathway. AB - OBJECTIVES: Interaction between neoplastic and stromal cells plays an important role in tumour progression. It was recently found that WNT2 was frequently overexpressed in fibroblasts isolated from tumour tissue tumour fibroblasts (TF) compared with fibroblasts from non-tumour tissue normal fibroblasts in oesophageal squamous cell carcinoma (OSCC). This study aimed to investigate the effect of TF-secreted Wnt2 in OSCC development via the tumour-stroma interaction. METHODS: Quantitative PCR, western blotting, immunohistochemistry and immunofluorescence were used to study the expression pattern of Wnt2 and its effect on the Wnt/beta-catenin pathway. A Wnt2-secreting system was established in Chinese hamster ovary cells and its conditioned medium was used to study the role of Wnt2 in cell proliferation and invasion. RESULTS: Expression of Wnt2 could only be detected in TF but not in OSCC cancer cell lines. In OSCC tissues, Wnt2(+) cells were mainly detected in the boundary between stroma and tumour tissue or scattered within tumour tissue. In this study, Wnt2-positive OSCC was defined when five or more Wnt2(+) cells were observed in 200* microscopy field. Interestingly, Wnt2-positive OSCC (22/51 cases) was significantly associated with lymph node metastases (p=0.001), advanced TNM stage (p=0.001) and disease specific survival (p<0.0001). Functional study demonstrated that secreted Wnt2 could promote oesophageal cancer cell growth by activating the Wnt/beta-catenin signalling pathway and subsequently upregulated cyclin D1 and c-myc expression. Further study found that Wnt2 could enhance cell motility and invasiveness by inducing epithelial-mesenchymal transition. CONCLUSIONS: TF-secreted Wnt2 acts as a growth and invasion-promoting factor through activating the canonical Wnt/beta catenin signalling pathway in oesophageal cancer cells. PMID- 21672942 TI - Apical right ventricular dysfunction in patients with pulmonary hypertension demonstrated with magnetic resonance. AB - OBJECTIVE: To evaluate segmental right ventricular (RV) dysfunction in pulmonary hypertension (PH) using cardiac magnetic resonance (CMR). DESIGN: Cross-sectional analysis in a retrospective cohort of consecutive adult patients. SETTING: Mount Sinai Hospital in New York. PATIENTS: 192 patients with known or suspected PH undergoing right heart catheterisation and CMR. PH was defined as mean pulmonary artery pressure >= 25 mm Hg. Abnormal RV ejection fraction (RVEF) was defined as <50%. Patients were classified into: group 1 (no PH, normal RVEF; n = 40), group 2 (PH, normal RVEF; n = 41) or group 3 (PH, abnormal RVEF; n=111). INTERVENTIONS: CMR and right heart catheterisation within a 2-week interval. Main outcome measures On cine CMR images, the stack of RV short-axis views was divided into two equal halves. Basal and apical RVEF were calculated using Simpson's method, and a ratio of basal-to-apical RVEF (RVEF(ratio)) was derived. RESULTS: Basal RVEF did not differ between groups 1 and 2 (63 +/- 8% vs 64 +/- 8%; p = 1); however, patients in group 2 had significantly lower apical RVEF (46 +/- 13% vs 58 +/- 10%; p<0.01) and higher RVEF(ratio) (median 1.4 vs 1.1; p<0.01). Both apical and basal RVEF were reduced in group 3 compared with groups 1 and 2 (p<0.01), and the RVEF(ratio) increased with increasing PH severity (p<0.01 for trend). An apical RVEF <50% was more sensitive than global RV dysfunction for the detection of PH. CONCLUSIONS: Apical dysfunction appears to occur before global RVEF decreases in chronic PH, potentially constituting an early and sensitive marker of RV dysfunction in this setting. PMID- 21672943 TI - Influenza A (H1N1) and myocarditis. PMID- 21672944 TI - CT coronary angiography: a new unique prognosticator? PMID- 21672945 TI - Current knowledge on contralateral prophylactic mastectomy among women with sporadic breast cancer. AB - The use of contralateral prophylactic mastectomy (CPM) in the U.S. among patients with unilateral invasive breast cancer increased by 150% from 1993 to 2003. Although CPM has been shown to reduce the risk for developing contralateral breast cancer, there is conflicting evidence on whether or not it reduces breast cancer mortality or overall death. The increase in the CPM rate is especially concerning among women with early-stage sporadic breast cancer who have a minimal annual risk for developing contralateral breast cancer, and for many of these women the risk for distant metastatic disease outweighs the risk for contralateral breast cancer. The lack of information about the clinical value of CPM in women with sporadic breast cancer is an important public health problem. This review evaluates current data on the clinical indications for CPM and long term patient satisfaction and psychosocial outcomes. Gaps in knowledge about the clinical value of CPM, including patient- and physician-related psychosocial factors that influence the decision-making process of CPM among women with sporadic breast cancer, are highlighted. PMID- 21672946 TI - Severe occult upper gastrointestinal haemorrhage. PMID- 21672947 TI - Male circumcision and sexual function in men and women: a survey-based, cross sectional study in Denmark. AB - BACKGROUND: One-third of the world's men are circumcised, but little is known about possible sexual consequences of male circumcision. In Denmark (~5% circumcised), we examined associations of male circumcision with a range of sexual measures in both sexes. METHODS: Participants in a national health survey (n = 5552) provided information about their own (men) or their spouse's (women) circumcision status and details about their sex lives. Logistic regression derived odds ratios (ORs) measured associations of circumcision status with sexual experiences and current difficulties with sexual desire, sexual needs fulfilment and sexual functioning. RESULTS: Age at first intercourse, perceived importance of a good sex life and current sexual activity differed little between circumcised and uncircumcised men or between women with circumcised and uncircumcised spouses. However, circumcised men reported more partners and were more likely to report frequent orgasm difficulties after adjustment for potential confounding factors [11 vs 4%, OR(adj) = 3.26; 95% confidence interval (CI) 1.42 7.47], and women with circumcised spouses more often reported incomplete sexual needs fulfilment (38 vs 28%, OR(adj) = 2.09; 95% CI 1.05-4.16) and frequent sexual function difficulties overall (31 vs 22%, OR(adj) = 3.26; 95% CI 1.15 9.27), notably orgasm difficulties (19 vs 14%, OR(adj) = 2.66; 95% CI 1.07-6.66) and dyspareunia (12 vs 3%, OR(adj) = 8.45; 95% CI 3.01-23.74). Findings were stable in several robustness analyses, including one restricted to non-Jews and non-Moslems. CONCLUSIONS: Circumcision was associated with frequent orgasm difficulties in Danish men and with a range of frequent sexual difficulties in women, notably orgasm difficulties, dyspareunia and a sense of incomplete sexual needs fulfilment. Thorough examination of these matters in areas where male circumcision is more common is warranted. PMID- 21672948 TI - Neural correlates of perceived risk: the case of HIV. AB - Research indicates that many people do not use condoms consistently but rather rely on illusory control strategies for avoiding an infection with HIV. Preliminary evidence suggests that people form impressions of a partner's HIV risk based on his or her physical appearance. To examine the neural correlates of such appearance-based HIV risk impressions, event-related potentials were recorded while participants viewed portraits of unacquainted persons. Participants' explicit HIV risk ratings for each of the presented unacquainted persons were used to form categories of low and high HIV risk persons. Results showed that risky, compared to safe persons elicited distinct event-related potential (ERP) modulations. Viewing risky persons was associated with an increased positivity over right frontal regions between 180 and 240 ms. This suggests that impressions related to HIV risk occur rapidly, presumably reflecting automatic person evaluations eluding introspection. In a time window between 450 and 600 ms, risky persons elicited an increased late positive potential. Consistent with previous findings reporting augmented late positive potentials (LPP) amplitudes to affectively significant stimuli, the results support the assumption that risky faces draw more attention resources. These findings are in accordance with the 'risk as feeling' notion. PMID- 21672949 TI - Spinal cord injury during recovery from anaesthesia in a giraffe. PMID- 21672950 TI - Limitations of sandwich ELISAs for bluetongue virus antibody detection. PMID- 21672951 TI - Renal function of dairy cows with subclinical ketosis. PMID- 21672952 TI - Impact of pelleted diets with different mineral compositions on the crown size of mandibular cheek teeth and mandibular relative density in degus (Octodon degus). AB - The impact of pelleted diets with different mineral compositions on the crown size of the mandibular cheek teeth, as well as the mandibular bone and cheek teeth density, in degus (Octodon degus) was investigated. A total of 28 animals were randomly divided into four groups and fed different calcium or phosphorous dietary content, in the presence or absence of UV light, for 14 months. Dental radiographs and CT images of the head were taken, and the crown size of premolar and molar teeth was recorded. Apical and coronal crown elongation of all cheek teeth and significantly smaller relative cheek teeth and mandibular densities were recorded in degus fed a high-phosphorus diet with an improper calcium:phosphorus ratio. A diet with a calcium:phosphorus ratio of 1:1 was also responsible for the rapid development of dental disease with subsequent severe health impairment. PMID- 21672953 TI - Molecular epidemiology of strangles outbreaks in the UK during 2010. AB - The sequence of the Streptococcus equi subspecies equi (S equi) M-like protein (SeM) gene was determined for 105 isolates of S equi from strangles outbreaks in the UK during 2010 and compared with previous data from 2007 to 2008. Twenty three distinct alleles were identified, including 11 novel alleles. One allele giving rise to a putative truncated M protein was identified from the guttural pouch of an asymptomatic carrier. Allele 9 was the most prevalent, comprising 57.7 per cent of isolates, followed by allele 6 (10.3 per cent). Significant changes in allele prevalence were found between 2007, 2008 and 2010, with an increasing prevalence in SeM-9-related alleles and a corresponding decreasing prevalence in SeM-6-related alleles observed over the period (P<0.001). Geographical proximity of outbreaks caused by some uncommon alleles was apparent between 2007, 2008 and 2010. PMID- 21672954 TI - Prevalence of asymptomatic syringomyelia in Cavalier King Charles spaniels. AB - The prevalence of syringomyelia was investigated in a sample population of 555 Cavalier King Charles spaniels. All dogs, which were declared by their owners to be showing no clinical signs of syringomyelia, underwent MRI to determine the presence or absence of the condition. Data were analysed by logistic regression to determine the effects of sex and age on the prevalence of syringomyelia. Only increased age was found to have a significant effect. The prevalence of syringomyelia was 25 per cent in dogs aged 12 months, increasing to a peak of 70 per cent in dogs aged 72 months or more. PMID- 21672955 TI - PHAST: a fast phage search tool. AB - PHAge Search Tool (PHAST) is a web server designed to rapidly and accurately identify, annotate and graphically display prophage sequences within bacterial genomes or plasmids. It accepts either raw DNA sequence data or partially annotated GenBank formatted data and rapidly performs a number of database comparisons as well as phage 'cornerstone' feature identification steps to locate, annotate and display prophage sequences and prophage features. Relative to other prophage identification tools, PHAST is up to 40 times faster and up to 15% more sensitive. It is also able to process and annotate both raw DNA sequence data and Genbank files, provide richly annotated tables on prophage features and prophage 'quality' and distinguish between intact and incomplete prophage. PHAST also generates downloadable, high quality, interactive graphics that display all identified prophage components in both circular and linear genomic views. PHAST is available at (http://phast.wishartlab.com). PMID- 21672956 TI - BioPortal: enhanced functionality via new Web services from the National Center for Biomedical Ontology to access and use ontologies in software applications. AB - The National Center for Biomedical Ontology (NCBO) is one of the National Centers for Biomedical Computing funded under the NIH Roadmap Initiative. Contributing to the national computing infrastructure, NCBO has developed BioPortal, a web portal that provides access to a library of biomedical ontologies and terminologies (http://bioportal.bioontology.org) via the NCBO Web services. BioPortal enables community participation in the evaluation and evolution of ontology content by providing features to add mappings between terms, to add comments linked to specific ontology terms and to provide ontology reviews. The NCBO Web services (http://www.bioontology.org/wiki/index.php/NCBO_REST_services) enable this functionality and provide a uniform mechanism to access ontologies from a variety of knowledge representation formats, such as Web Ontology Language (OWL) and Open Biological and Biomedical Ontologies (OBO) format. The Web services provide multi layered access to the ontology content, from getting all terms in an ontology to retrieving metadata about a term. Users can easily incorporate the NCBO Web services into software applications to generate semantically aware applications and to facilitate structured data collection. PMID- 21672957 TI - A PLAC8-containing protein from an endomycorrhizal fungus confers cadmium resistance to yeast cells by interacting with Mlh3p. AB - Cadmium is a genotoxic pollutant known to target proteins that are involved in DNA repair and in antioxidant defence, altering their functions and ultimately causing mutagenic and carcinogenic effects. We have identified a PLAC8 domain containing protein, named OmFCR, by a yeast functional screen aimed at identifying genes involved in cadmium resistance in the endomycorrhizal fungus Oidiodendron maius. OmFCR shows a remarkable specificity in mediating cadmium resistance. Both its function and its nuclear localization in yeast strictly depend on the interaction with Mlh3p, a subunit of the mismatch repair (MMR) system. Although proteins belonging to the PLAC8 family are widespread in eukaryotes, they are poorly characterized and their biological role still remains elusive. Our work represents the first report about the potential role of a PLAC8 protein in physically coupling DNA lesion recognition by the MMR system to appropriate effectors that affect cell cycle checkpoint pathways. On the basis of cell survival assays and yeast growth curves, we hypothesize that, upon cadmium exposure, OmFCR might promote a higher rate of cell division as compared to control cells. PMID- 21672958 TI - antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. AB - Bacterial and fungal secondary metabolism is a rich source of novel bioactive compounds with potential pharmaceutical applications as antibiotics, anti-tumor drugs or cholesterol-lowering drugs. To find new drug candidates, microbiologists are increasingly relying on sequencing genomes of a wide variety of microbes. However, rapidly and reliably pinpointing all the potential gene clusters for secondary metabolites in dozens of newly sequenced genomes has been extremely challenging, due to their biochemical heterogeneity, the presence of unknown enzymes and the dispersed nature of the necessary specialized bioinformatics tools and resources. Here, we present antiSMASH (antibiotics & Secondary Metabolite Analysis Shell), the first comprehensive pipeline capable of identifying biosynthetic loci covering the whole range of known secondary metabolite compound classes (polyketides, non-ribosomal peptides, terpenes, aminoglycosides, aminocoumarins, indolocarbazoles, lantibiotics, bacteriocins, nucleosides, beta-lactams, butyrolactones, siderophores, melanins and others). It aligns the identified regions at the gene cluster level to their nearest relatives from a database containing all other known gene clusters, and integrates or cross-links all previously available secondary-metabolite specific gene analysis methods in one interactive view. antiSMASH is available at http://antismash.secondarymetabolites.org. PMID- 21672959 TI - firestar--advances in the prediction of functionally important residues. AB - firestar is a server for predicting catalytic and ligand-binding residues in protein sequences. Here, we present the important developments since the first release of firestar. Previous versions of the server required human interpretation of the results; the server is now fully automatized. firestar has been implemented as a web service and can now be run in high-throughput mode. Prediction coverage has been greatly improved with the extension of the FireDB database and the addition of alignments generated by HHsearch. Ligands in FireDB are now classified for biological relevance. Many of the changes have been motivated by the critical assessment of techniques for protein structure prediction (CASP) ligand-binding prediction experiment, which provided us with a framework to test the performance of firestar. URL: http://firedb.bioinfo.cnio.es/Php/FireStar.php. PMID- 21672960 TI - RNApredator: fast accessibility-based prediction of sRNA targets. AB - Bacterial genomes encode a plethora of small RNAs (sRNAs), which are heterogeneous in size, structure and function. Most sRNAs act as post transcriptional regulators by means of specific base pairing interactions with the 5'-untranslated region of mRNA transcripts, thereby modifying the stability of the target transcript and/or its ability to be translated. Here, we present RNApredator, a web server for the prediction of sRNA targets. The user can choose from a set of over 2155 genomes and plasmids from 1183 bacterial species. RNApredator then uses a dynamic programming approach, RNAplex, to compute putative targets. Compared to web servers with a similar task, RNApredator takes the accessibility of the target during the target search into account, improving the specificity of the predictions. Furthermore, enrichment in Gene Ontology terms, cellular pathways as well as changes in accessibilities along the target sequence can be done in fully automated post-processing steps. The predictive performance of the underlying dynamic programming approach RNAplex is similar to that of more complex methods, but needs at least three orders of magnitude less time to complete. RNApredator is available at http://rna.tbi.univie.ac.at/RNApredator. PMID- 21672961 TI - MarkUs: a server to navigate sequence-structure-function space. AB - We describe MarkUs, a web server for analysis and comparison of the structural and functional properties of proteins. In contrast to a 'structure in/function out' approach to protein function annotation, the server is designed to be highly interactive and to allow flexibility in the examination of possible functions, suggested either automatically by various similarity measures or specified by a user directly. This is combined with tools that allow a user to assess independently whether or not a suggested function is consistent with the bioinformatic and biophysical properties of a given query structure, further allowing the user to generate testable hypotheses. The server is available at http://wiki.c2b2.columbia.edu/honiglab_public/index.php/Software:Mark-Us. PMID- 21672963 TI - 'I did it for him, not for me': an exploratory study of factors influencing sexual debut among female university students in Durban, South Africa. AB - We used qualitative interviews to explore the influences on first sexual intercourse among 10 young women who had sexual debut within a year of enrolling in the university. University culture of sexual permissiveness and pressure from sexually experienced friends and male partners were the main factors influencing sexual debut. Ambivalence and a range of coercive behaviours characterized first sex. Participants were unprepared for sex and lacked power in deciding the timing and circumstances of first sex resulting in physical and emotional pain and regret. Interventions should address the risks of first sex among students in institutions of higher learning. PMID- 21672962 TI - Telomere shortening reduces Alzheimer's disease amyloid pathology in mice. AB - Alzheimer's disease is a neurodegenerative disorder of the elderly and advancing age is the major risk factor for Alzheimer's disease development. Telomere shortening represents one of the molecular causes of ageing that limits the proliferative capacity of cells, including neural stem cells. Studies on telomere lengths in patients with Alzheimer's disease have revealed contrary results and the functional role of telomere shortening on brain ageing and Alzheimer's disease is not known. Here, we have investigated the effects of telomere shortening on adult neurogenesis and Alzheimer's disease progression in mice. The study shows that aged telomerase knockout mice with short telomeres (G3Terc-/-) exhibit reduced dentate gyrus neurogenesis and loss of neurons in hippocampus and frontal cortex, associated with short-term memory deficit in comparison to mice with long telomere reserves (Terc+/+). In contrast, telomere shortening improved the spatial learning ability of ageing APP23 transgenic mice, a mouse model for Alzheimer's disease. Telomere shortening was also associated with an activation of microglia in ageing amyloid-free brain. However, in APP23 transgenic mice, telomere shortening reduced both amyloid plaque pathology and reactive microgliosis. Together, these results provide the first experimental evidence that telomere shortening, despite impairing adult neurogenesis and maintenance of post-mitotic neurons, can slow down the progression of amyloid plaque pathology in Alzheimer's disease, possibly involving telomere-dependent effects on microglia activation. PMID- 21672964 TI - Mothers' perceptions of introducing solids to their infant at six months of age: identifying critical belief-based targets to promote adherence to current infant feeding guidelines. AB - We investigated critical belief-based targets for promoting the introduction of solid foods to infants at six months. First-time mothers (N = 375) completed a Theory of Planned Behaviour belief-based questionnaire and follow-up questionnaire assessing the age the infant was first introduced to solids. Normative beliefs about partner/spouse (beta = 0.16) and doctor (beta = 0.22), and control beliefs about commercial baby foods available for infants before six months (beta = -0.20), predicted introduction of solids at six months. Intervention programs should target these critical beliefs to promote mothers' adherence to current infant feeding guidelines to introduce solids at around six months. PMID- 21672965 TI - Therapeutic effects of propolis essential oil on anxiety of restraint-stressed mice. AB - Propolis has a broad spectrum of biological activities; however, whether its essential oils have neuroprotective effects is unknown. In this study, we found that propolis essential oil (PEO) could significantly reverse the anxiety-like behavior of restraint-stressed mice, and has no effect on locomotor activity. Furthermore, PEO significantly decreased the plasma levels of cortisol (CORT), adrenocorticotropic hormone (ACTH) and malondialdehyde (MDA), whereas it increased the activity of superoxide dismutase (SOD) in restraint-stressed mice. These results strongly suggest that PEO has therapeutic effects on anxiety through antagonizing the hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis and improving the ability of antioxidation in brain tissue. PMID- 21672966 TI - Ain't misbehavin': is it possible to criticize maintenance of certification (MOC)? PMID- 21672967 TI - Comment on: Low TNF-induced NF-kappaB and p38 phosphorylation levels in leucocytes in tumour necrosis factor receptor-associated periodic syndrome. PMID- 21672968 TI - Reflections in the assessment of secondary Sjogren's syndrome. PMID- 21672969 TI - Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years--early clinical response predicts long-term outcome. AB - OBJECTIVES: To report for the first time on the efficacy and safety of anti-TNF therapy after 8 years of follow-up in patients with active AS, and analyse possible short-term predictors for long-term clinical outcomes. METHODS: In this open-label extension of a randomized controlled trial, proportions of the initially included 69 patients with active AS were treated with infliximab 5 mg/kg i.v./6 weeks for 8 years. The last report was published after 5 years. All analyses were based on completers. RESULTS: Overall, 33 (48%) patients completed 8 years. Their mean (s.d.) BASDAI [2.6 (1.9)], BASFI [3.3 (2.6)] and BASMI [2.7 (2.4)] remained low at Year 8. At the end of Year 8, most patients were either in partial remission (n = 8, 24%) or had low disease activity (BASDAI < 3; n = 21, 64%). No new serious adverse events occurred within the past 3 years. Adverse events were the most frequent reason for dropout (56%). There were no differences between completers and dropouts at baseline, but the latter had higher BASFI values at dropout. No baseline parameter was associated with good long-term response to infliximab, but lower BASDAI levels after 12 weeks were predictive of a higher probability of partial remission [odds ratio (OR) 2.9, 95% CI 1.3, 6.3, P = 0.007], low disease activity (OR 1.7, 95% CI 1.2, 2.3, P = 0.005) or remaining on treatment (OR 0.79, 95% CI 0.61, 1.01, P = 0.06) after 8 years. CONCLUSION: Almost half of the initially treated patients remained on anti-TNF therapy for 8 years, and almost 90% were in partial remission or had low disease activity. Short-term response (low BASDAI at 3 months) is predictive of outcome after 8 years. Infliximab therapy was safe over 8 years. PMID- 21672971 TI - Question answering systems in biology and medicine--the time is now. PMID- 21672972 TI - New management of gonorrhoea. Impact of antibiotic resistance. PMID- 21672973 TI - NICE v world on endocarditis prophylaxis. PMID- 21672974 TI - Always take a travel history in eosinophilia. PMID- 21672976 TI - What's in a name? PMID- 21672975 TI - The BMJ and the Big Society. PMID- 21672977 TI - Local authorities should be responsible for public health. PMID- 21672978 TI - Study raises five questions. PMID- 21672979 TI - Evidence of overdiagnosis. PMID- 21672980 TI - What is mortality denominator? PMID- 21672981 TI - Report bias favours screening. PMID- 21672982 TI - Study has major shortcomings. PMID- 21672983 TI - Underscreened and undertreated. PMID- 21672984 TI - Economic benefits of vaccination need to be seen in wider context. PMID- 21672985 TI - More than half of child labourers work in hazardous conditions. PMID- 21672986 TI - Research into treatments for mental illness is under threat. PMID- 21672987 TI - Bahraini doctors deny anti-state activities. PMID- 21672988 TI - Winning hearts. PMID- 21672989 TI - London vaccination summit is "milestone in global health". PMID- 21672990 TI - The Future Forum proposes major changes to the government's plans for NHS reform. PMID- 21672991 TI - UK government spells out new plan for NHS in England. PMID- 21672993 TI - H1N1 influenza in pregnant women. PMID- 21672994 TI - Clinical trials: can technology solve the problem of low recruitment? PMID- 21672992 TI - Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. AB - OBJECTIVES: To follow up a UK national cohort of women admitted to hospital with confirmed 2009/H1N1 influenza in pregnancy in order to obtain a complete picture of pregnancy outcomes and estimate the risks of adverse fetal and infant outcomes. DESIGN: National cohort study. SETTING: 221 hospitals with obstetrician led maternity units in the UK. PARTICIPANTS: 256 women admitted to hospital with confirmed 2009/H1N1 in pregnancy during the second wave of pandemic infection between September 2009 and January 2010; 1220 pregnant women for comparison. MAIN OUTCOME MEASURES: Rates of stillbirth, perinatal mortality, and neonatal mortality; odds ratios for infected versus comparison women. RESULTS: Perinatal mortality was higher in infants born to infected women (10 deaths among 256 infants; rate 39 (95% confidence interval 19 to 71) per 1000 total births) than in infants of uninfected women (9 deaths among 1233 infants; rate 7 (3 to 13) per 1000 total births) (P < 0.001). This was principally explained by an increase in the rate of stillbirth (27 per 1000 total births v 6 per 1000 total births; P = 0.001). Infants of infected women were also more likely to be born prematurely than were infants of comparison women (adjusted odds ratio 4.0, 95% confidence interval 2.7 to 5.9). Infected women who delivered preterm were more likely to be infected in their third trimester (P = 0.046), to have been admitted to an intensive care unit (P < 0.001), and to have a secondary pneumonia (P = 0.001) than were those who delivered at term. CONCLUSIONS: This study suggests an increase in the risk of poor outcomes of pregnancy in women infected with 2009/H1N1, which reinforces the message from studies of maternal risk alone. The health of pregnant women is an important public health priority in future waves of this and other influenza pandemics. PMID- 21672995 TI - Pfizer launches virtual clinical trial. PMID- 21672997 TI - Germany legislates to boost organ transplant numbers. PMID- 21672996 TI - Bean sprouts are identified as cause of E coli outbreak. PMID- 21672998 TI - Safety of tiotropium. PMID- 21672999 TI - Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease. DATA SOURCES: Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010. STUDY SELECTION: Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I(2) statistic. RESULTS: Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P = 0.02; I(2) = 0%). Both 10 ug (2.15, 1.03 to 4.51; P = 0.04; I(2) = 9%) and 5 ug (1.46, 1.01 to 2.10; P = 0.04; I(2) = 0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P = 0.04), limiting the analysis to three trials of one year's duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 ug dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials. CONCLUSIONS: This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease. PMID- 21673000 TI - Are traditional birth attendants good for improving maternal and perinatal health? No. PMID- 21673001 TI - Are traditional birth attendants good for improving maternal and perinatal health? Yes. PMID- 21673002 TI - Association between maternal sleep practices and risk of late stillbirth: a case control study. AB - OBJECTIVES: To determine whether snoring, sleep position, and other sleep practices in pregnant women are associated with risk of late stillbirth. DESIGN: Prospective population based case-control study. SETTING: Auckland, New Zealand PARTICIPANTS: CASES: 155 women with a singleton late stillbirth (>= 28 weeks' gestation) without congenital abnormality born between July 2006 and June 2009 and booked to deliver in Auckland. CONTROLS: 310 women with single ongoing pregnancies and gestation matched to that at which the stillbirth occurred. Multivariable logistic regression adjusted for known confounding factors. MAIN OUTCOME MEASURE: Maternal snoring, daytime sleepiness (measured with the Epworth sleepiness scale), and sleep position at the time of going to sleep and on waking (left side, right side, back, and other). RESULTS: The prevalence of late stillbirth in this study was 3.09/1000 births. No relation was found between snoring or daytime sleepiness and risk of late stillbirth. However, women who slept on their back or on their right side on the previous night (before stillbirth or interview) were more likely to experience a late stillbirth compared with women who slept on their left side (adjusted odds ratio for back sleeping 2.54 (95% CI 1.04 to 6.18), and for right side sleeping 1.74 (0.98 to 3.01)). The absolute risk of late stillbirth for women who went to sleep on their left was 1.96/1000 and was 3.93/1000 for women who did not go to sleep on their left. Women who got up to go to the toilet once or less on the last night were more likely to experience a late stillbirth compared with women who got up more frequently (adjusted odds ratio 2.28 (1.40 to 3.71)). Women who regularly slept during the day in the previous month were also more likely to experience a late stillbirth than those who did not (2.04 (1.26 to 3.27)). CONCLUSIONS: This is the first study to report maternal sleep related practices as risk factors for stillbirth, and these findings require urgent confirmation in further studies. PMID- 21673003 TI - Should pregnant women sleep on their left? PMID- 21673004 TI - Diagnostic challenges in RCVS, PACNS, and other cerebral arteriopathies. PMID- 21673008 TI - Cephalalgia is 30 years old. PMID- 21673005 TI - Migraine and cardiovascular disease in women and the role of aspirin: subgroup analyses in the Women's Health Study. AB - BACKGROUND: Migraine with aura (MA) has been associated with increased risk of cardiovascular disease (CVD). The role of aspirin on this association remains unclear. METHODS: Post-hoc subgroup analyses of the Women's Health Study, a randomized trial testing 100 mg aspirin on alternate days in primary prevention of CVD among 39,876 women aged >= 45. RESULTS: During 10 years, 998 major CVD events were confirmed in 39,757 women with complete migraine information. Aspirin reduced risk of ischaemic stroke (relative risk, RR, 0.76, 95% CI 0.63-0.93) but not other CVD. Migraine or MA did not modify the effect of aspirin on CVD except for myocardial infarction (MI) (p for interaction = 0.01). Women with MA on aspirin had increased risk of MI (RR 3.72, 95% CI 1.39-9.95). Further exploratory analyses indicate that this increased risk is only apparent among women with MA on aspirin who ever smoked or had history of hypertension (p for interaction<0.01). CONCLUSIONS: In post-hoc subgroup analyses, aspirin had similar protective effects on ischaemic stroke for women with or without migraine. By contrast, our data suggest that women with MA on aspirin had increased risk of MI. The small number of outcome events in subgroups, the exploratory nature of our analyses, and lack of plausible mechanisms raise the possibility of a chance finding, which must caution the interpretation. PMID- 21673009 TI - The four Arabidopsis reduced wall acetylation genes are expressed in secondary wall-containing cells and required for the acetylation of xylan. AB - Xylan is one of the major polysaccharides in cellulosic biomass, and understanding the mechanisms underlying xylan biosynthesis will potentially help us design strategies to produce cellulosic biomass better suited for biofuel production. Although a number of genes have been shown to be essential for xylan biosynthesis, genes involved in the acetylation of xylan have not yet been identified. Here, we report the comprehensive genetic and functional studies of four Arabidopsis REDUCED WALL ACETYLATION (RWA) genes and demonstrate their involvement in the acetylation of xylan during secondary wall biosynthesis. It was found that the RWA genes were expressed in cells undergoing secondary wall thickening and their expression was regulated by SND1, a transcriptional master switch of secondary wall biosynthesis. The RWA proteins were shown to be localized in the Golgi, where xylan biosynthesis occurs. Analyses of a suite of single, double, triple and quadruple rwa mutants revealed a significant reduction in the secondary wall thickening and the stem mechanical strength in the quadruple rwa1/2/3/4 mutant but not in other mutants. Further chemical and structural analyses of xylan demonstrated that the rwa1/2/3/4 mutations resulted in a reduction in the amount of acetyl groups on xylan. In addition, the ratio of non-methylated to methylated glucuronic acid side chains was altered in the rwa1/2/3/4 mutant. Together, our results demonstrate that the four Arabidopsis RWA genes function redundantly in the acetylation of xylan during secondary wall biosynthesis. PMID- 21673010 TI - N-Glycan synthesis in the apical and basolateral secretory pathway of epithelial MDCK cells and the influence of a glycosaminoglycan domain. AB - Different classes of glycans are implicated as mediators of apical protein sorting in the secretory pathway of epithelial cells, but recent research indicates that sorting to the apical and basolateral surfaces may occur before completion of glycan synthesis. We have previously shown that a proteoglycan (PG) core protein can obtain different glycosaminoglycan (GAG) structures in the apical and basolateral secretory routes (Tveit H, Dick G, Skibeli V, Prydz K. 2005. A proteoglycan undergoes different modifications en route to the apical and basolateral surfaces of Madin-Darby canine kidney cells. J Biol Chem. 280:29596 29603) of epithelial Madin-Darby canine kidney (MDCK) cells. We have now also determined the detailed N-glycan structures acquired by a single glycoprotein species in the same apical and basolateral secretory pathways. For this purpose, rat growth hormone (rGH) with two N-glycan sites (rGH-2N) inserted into the rGH portion (NAS and NFT) was fused to green fluorescent protein (GFP) and expressed in MDCK cells. Immunoisolated rGH variants were analyzed for site occupancy and N glycan structure by mass spectrometry. The extent of NAS and NFT site occupancy was different, but comparable for rGH-2N secreted apically and basolaterally. Microheterogeneity existed for the glycans attached to each N-glycan site, but no major differences were observed in the apical and basolateral pathways. Transfer of the GAG modification domain from the PG serglycin to the fusion site of rGH-2N and GFP allowed polymerization of GAG chains onto the novel protein variant and influenced the microheterogeneity of the N-glycans toward more acidic glycans, but did not alter the relative site occupancy. In conclusion, no major differences were observed for N-glycan structures obtained by the expressed model proteins in the apical and basolateral secretory pathways of epithelial MDCK cells, but insertion of a GAG attachment domain shifted the N-glycans to more acidic structures. PMID- 21673011 TI - Osteopontin stimulates preneoplastic cellular proliferation through activation of the MAPK pathway. AB - Alterations in the microenvironment collaborate with cell autonomous mutations during the transformation process. Indeed, cancer-associated fibroblasts and senescent fibroblasts stimulate tumorigenesis in xenograft models. Because senescent fibroblasts accumulate with age, these findings suggest that they contribute to age-related increases in tumorigenesis. Previously we showed that senescence-associated stromal-derived osteopontin contributes to preneoplastic cell growth in vitro and in xenografts, suggesting that it impacts neoplastic progression. Analysis of fibroblasts within premalignant and malignant skin lesions ranging from solar/actinic keratosis to squamous cell carcinoma revealed they express osteopontin. Given the stromal expression of osteopontin, we investigated how osteopontin impacts preneoplastic cell growth. We show that osteopontin promotes preneoplastic keratinocyte cellular proliferation and cell survival through the CD44 cell receptor and activation of the MAPK pathway. These data suggest that stromal-derived osteopontin impacts tumorigenesis by stimulating preneoplastic cell proliferation thus allowing expansion of initiated cells in early lesions. PMID- 21673012 TI - KIAA0101 interacts with BRCA1 and regulates centrosome number. AB - To find genes and proteins that collaborate with BRCA1 or BRCA2 in the pathogenesis of breast cancer, we used an informatics approach and found a candidate BRCA interactor, KIAA0101, to function like BRCA1 in exerting a powerful control over centrosome number. The effect of KIAA0101 on centrosomes is likely direct, as its depletion does not affect the cell cycle, KIAA0101 localizes to regions coincident with the centrosomes, and KIAA0101 binds to BRCA1. We analyzed whether KIAA0101 protein is overexpressed in breast cancer tumor samples in tissue microarrays, and we found that overexpression of KIAA0101 correlated with positive Ki67 staining, a biomarker associated with increased disease severity. Furthermore, overexpression of the KIAA0101 gene in breast tumors was found to be associated with significantly decreased survival time. This study identifies KIAA0101 as a protein important for breast tumorigenesis, and as this factor has been reported as a UV repair factor, it may link the UV damage response to centrosome control. PMID- 21673013 TI - Effects of myofascial release techniques on pain, physical function, and postural stability in patients with fibromyalgia: a randomized controlled trial. AB - OBJECTIVE: To determine the effect of myofascial release techniques on pain symptoms, postural stability and physical function in fibromyalgia syndrome. DESIGN: A randomized, placebo-controlled trial was undertaken. SUBJECTS: Eighty six patients with fibromyalgia syndrome were randomly assigned to an experimental group and a placebo group. INTERVENTIONS: Patients received treatments for 20 weeks. The experimental group underwent 10 myofascial release modalities and the placebo group received sham short-wave and ultrasound electrotherapy. MAIN MEASURES: Outcome variables were number of tender points, pain, postural stability, physical function, clinical severity and global clinical assessment of improvement. Outcome measures were assessed before and immediately after, at six months and one year after the last session of the corresponding intervention. RESULTS: After 20 weeks of myofascial therapy, the experimental group showed a significant improvement (P < 0.05) in painful tender points, McGill Pain Score (20.6 +/- 6.3, P < 0.032), physical function (56.10 +/- 17.3, P < 0.029), and clinical severity (5.08 +/- 1.03, P < 0.039). At six months post intervention, the experimental group had a significantly lower mean number of painful points, pain score (8.25 +/- 1.13, P < 0.048), physical function (58.60 +/- 16.30, P < 0.049) and clinical severity (5.28 +/- 0.97, P < 0.043). At one year post intervention, the only significant improvements were in painful points at second left rib and left gluteal muscle, affective dimension, number of days feeling good and clinical severity. CONCLUSION: The results suggest that myofascial release techniques can be a complementary therapy for pain symptoms, physical function and clinical severity but do not improve postural stability in patients with fibromyalgia syndrome. PMID- 21673014 TI - Efficacy of systemic propranolol for severe infantile haemangioma of the orbit and eyelid: a case study of eight patients. AB - AIM: To assess the efficacy of systemic propranolol for severe capillary haemangiomas involving eyelid and orbit. METHOD: This was a longitudinal retrospective study that began in November 2007, involving eight children with disfiguring orbit and eyelid capillary haemangioma who received oral propranolol therapy. Three patients with life-threatening haemangiomas spreading to the orbit were first treated with systemic corticosteroids and beta-adrenergenic blocking agents. The remaining five patients with functional visual impairment received propranolol only. All children were given propranolol at a dose of 2 mg/kg body weight per day. The treatment was initiated between 2 and 36 months of age, with a follow-up period ranging from 6 to 30 months. Beta-blocking agents were used for 3-10 months. RESULTS: We observed a successful 100% regression: that is, clinical regression by flattening 24 h after the start of treatment, regression on colour Doppler ultrasound imaging with an increase in resistance index of blood vessels, or regression seen on MRI. No re-growth was observed after the trial ended. CONCLUSION: Despite their self-limiting course, infantile orbital and eyelid haemangiomas can cause visual impairment or disfigurement. Corticosteroids are used as first-line therapeutic agents for problematic infantile haemangiomas. Other options include interferon-alpha and vincristine, which present problematic side effects. In our series, propranolol was shown to inhibit haemangioma tumour growth with a better benefit/risk ratio. In the absence of any randomised study comparing the effects of systemic corticosteroids and propranolol, we propose that beta-blockers could be used as first-line therapy for severe periocular haemangiomas. PMID- 21673015 TI - Did not wait patient management strategy (DNW PMS) study. AB - OBJECTIVES: This study was undertaken to assess the usefulness of senior emergency medicine specialists' review of all 'did not wait' (DNW) patients' triage notes and the recall of at-risk patients. METHODS; A prospective study of all DNW patients was performed from 1 January to 31 December 2008. Following a daily review of charts of those who failed to wait to be seen, those patients considered to be at risk of adverse outcome were contacted by the liaison team and advised to return. Data were gathered on all DNW patients on the Oracle database and interrogated using the Diver solution. RESULTS: 2872 (6.3%) of 45,959 patients did not wait to be seen. 107 (3.7%) were recalled on the basis of senior emergency medicine doctor review of the patients' triage notes. Variables found to be associated with increased likelihood of being recalled included triage category (p<0.001), male sex (p<0.004) and certain clinical presentations. The presenting complaints associated with being recalled were chest pain (p<0.001) and alcohol/drug overdose (p=0.001). 9.4% of DNW patients required admission following recall. CONCLUSION: The systematic senior doctor review of triage notes led to 3.7% of patients who failed to wait being recalled. 9.4% of those recalled required acute admission. The daily review of DNW patients' triage notes and the recalling of at-risk patients is a valuable addition to our risk management strategy. PMID- 21673016 TI - Body-conscious Shakespeare: sensory disturbances in troubled characters. AB - It is widely accepted that Shakespeare was unique in the range of his insights into the human mind, but the way his characters reveal their mental states through bodily sensations has not been systematically explored. The author has searched for these phenomena in the 42 major works of Shakespeare and in 46 genre matched works by his contemporaries, and in this paper the author focuses on sensory changes other than those involving vision, taste, the heart and the alimentary tract (all considered in other papers). Vertigo is experienced by five distressed Shakespearean characters, all men, but not at all by the other writers' characters. Breathlessness, probably representing hyperventilation, occurs eleven times in Shakespeare's works but only twice in the other writers' works. Fatigue, expressing grief, is articulated by several Shakespearean characters including Hamlet. It features less often in the others' works. Deafness at a time of high emotion is mentioned by Shakespeare several times but usually by a character 'turning a deaf ear', consciously or unconsciously. To the other writers, ears show emotion only by burning or itching. Blunting of touch and pain and their opposites of hypersensitivity to touch and pain are all to be found in Shakespeare's works when a character is distressed or excited, but not so with his contemporaries' works. Faint feelings and cold feelings are also more common in the works of Shakespeare. Overall, therefore, Shakespeare was exceptional in his use of sensory disturbances to express emotional upset. This may be a conscious literary device or a sign of exceptional awareness of bodily sensations. PMID- 21673017 TI - Research, engagement and public bioethics: promoting socially robust science. AB - Citizens today are increasingly expected to be knowledgeable about and prepared to engage with biomedical knowledge. In this article, I wish to reframe this 'public understanding of science' project, and place fresh emphasis on public understandings of research: an engagement with the everyday laboratory practices of biomedicine and its associated ethics, rather than with specific scientific facts. This is not based on an assumption that non-scientists are 'ignorant' and are thus unable to 'appropriately' use or debate science; rather, it is underpinned by an empirically-grounded observation that some individuals may be unfamiliar with certain specificities of particular modes of research and ethical frameworks, and, as a consequence, have their autonomy compromised when invited to participate in biomedical investigations. Drawing on the perspectives of participants in my own sociological research on the social and ethical dimensions of neuroscience, I argue that public understanding of biomedical research and its ethics should be developed both at the community level and within the research moment itself in order to enhance autonomy and promote more socially robust science. Public bioethics will have to play a key role in such an endeavour, and indeed will contribute in important ways to the opening up of new spaces of symmetrical engagement between bioethicists, scientists and wider publics-and hence to the democratisation of the bioethical enterprise. PMID- 21673018 TI - Surgical ablation of refractory ventricular tachycardia in patients with nonischemic cardiomyopathy. AB - BACKGROUND: The surgical approach for the treatment of ventricular tachycardia (VT) has been largely replaced by percutaneous, catheter-based techniques. However, some VT circuits, particularly in patients with nonischemic cardiomyopathy, remain inaccessible to percutaneous ablation. Surgical therapy of these VTs is an alternative approach; however, its methodology has not been well defined. The purpose of this study was to evaluate the efficacy of preoperative electroanatomic and electrophysiological characterization of the VT substrate and circuit to guide surgical ablation. METHODS AND RESULTS: Eight patients with recurrent sustained VT refractory to antiarrhythmic drugs underwent endocardial and/or epicardial ablation procedures. Electroanatomic mapping was performed, and the VT substrate and circuit(s) were defined using voltage, activation, entrainment, and pace mapping. All 8 patients underwent detailed endocardial mapping; 6 patients also underwent epicardial mapping. Radiofrequency ablation was performed with the use of an open-irrigation catheter. After the unsuccessful percutaneous approach, surgical cryoablation was applied to the sites previously identified and targeted during the percutaneous procedure. There were no significant perioperative complications. During a mean follow-up period of 23 +/- 6 months (range, 15 to 34 months), 6 patients had significant reduction in VT burden as evident by a reduced number of implantable cardioverter-defibrillator shocks after ablation (6.6 to 0.6 shocks per patient; P = 0.026). Two patients died, one of progressive heart failure and one of sepsis. CONCLUSIONS: VT circuits inaccessible to percutaneous ablation techniques are rare but can be encountered in patients with nonischemic cardiomyopathy. These VTs can be successfully targeted by surgical cryoablation guided by preoperative electroanatomic and electrophysiological mapping. PMID- 21673019 TI - Shock lead impedance alert: replace or reconsider? PMID- 21673020 TI - Restoration of sinus rhythm by incarceration, not elimination, of focal atrial tachycardia in left atrial substrate post atrial fibrillation ablation. PMID- 21673021 TI - Teaching points with 3-dimensional mapping of cardiac arrhythmias: taking points: activation mapping. PMID- 21673022 TI - Thoracoscopic surgical treatment of atrial fibrillation with electrophysiologic end points. PMID- 21673023 TI - Exposing gaps in linear radiofrequency lesions: form before function. PMID- 21673024 TI - When should high-grade heart block trigger a search for a treatable cardiomyopathy? PMID- 21673025 TI - Device-based left atrial appendage closure. PMID- 21673027 TI - The nonspecific effects of vaccines and the expanded program on immunization. PMID- 21673026 TI - The skeleton: a multi-functional complex organ: new insights into osteoblasts and their role in bone formation: the central role of PI3Kinase. AB - Studies on bone development, formation and turnover have grown exponentially over the last decade in part because of the utility of genetic models. One area that has received considerable attention has been the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which has emerged as a major survival network for osteoblasts. Genetic engineering has enabled investigators to study downstream effectors of PI3K by directly overexpressing activated forms of AKT in cells of the skeletal lineage or deleting Pten that leads to a constitutively active AKT. The results from these studies have provided novel insights into bone development and remodeling, critical processes in the lifelong maintenance of skeletal health. This paper reviews those data in relation to recent advances in osteoblast biology and their potential relevance to chronic disorders of the skeleton and their treatment. PMID- 21673029 TI - Transocular entry of seasonal influenza-attenuated virus aerosols and the efficacy of n95 respirators, surgical masks, and eye protection in humans. AB - BACKGROUND: The efficacy of barrier precautions to prevent influenza transmission is unknown. METHODS: Twenty-eight participants were exposed to monodispersed live attenuated influenza vaccine (LAIV) particles (4.9 MUm) in 6 groups: group 1, no precautions; group 2, ocular exposure only; group 3, surgical mask without eye protection; group 4, surgical mask with eye protection; group 5, fit-tested N95 respirator without eye protection; and group 6, fit-tested N95 respirator with eye protection. Influenza was detected by reverse-transcription polymerase chain reaction (RT-PCR) and culture in nasal washes. Exact 95% confidence intervals (CIs) were calculated. RESULTS: Influenza was detected in 4 of 4 participants in group 1 (95% CI, 0-.60), 3 of 4 in group 2 (95% CI, .006-.806]), 5 of 5 in group 3 (95% CI, 0-.522), 5 of 5 in group 4, (95% CI, 0-.522), 3 of 5 in group 5 (95% CI, .053-.853), and 1 of 5 in group 6 (95% CI, .05-.72). RT-PCR revealed significant differences between group 1 and all other groups except group 3. CONCLUSIONS: Transocular transmission of LAIV occured in most participants suggesting the necessity of eye protection. An N95 respirator provided the best guard further enhanced by eye protection. PMID- 21673031 TI - Human papillomavirus infection and bladder cancer risk: a meta-analysis. AB - BACKGROUND: Despite an increase in the number of molecular epidemiological studies conducted in recent years to evaluate the association between human papillomavirus (HPV) infection and risk of bladder cancer, the studies remain inconclusive. METHODS: The prevalence of HPV in bladder cancer was estimated by pooling data from 52 studies, taking into consideration the heterogeneity from major related parameters including study region, histological type, HPV DNA specimen, publication calendar period, and detection method. Moreover, the association of HPV infection with bladder cancer was tested by a meta-analysis with 19 case-control studies. RESULTS: An HPV prevalence of 16.88% (95% confidence interval [CI], 15.53%-18.31%) among the bladder cancer cases was revealed, most of whom were high-risk HPV types (15.82% [95% CI, 14.37%-17.36%]). The prevalence varied by region, types of HPV DNA specimen, and polymerase chain reaction primers used. A significantly increased risk of bladder cancer was shown for the positivity of overall HPV (odds ratio, 2.84 [95% CI, 1.39-5.80]), which was also infuenced by HPV type, study region, HPV DNA specimen, and detection method. CONCLUSIONS: Infection of high-risk HPV types, especially HPV16, may play a role in bladder carcinogenesis. PMID- 21673030 TI - Serum antibody response following genital {alpha}9 human papillomavirus infection in young men. AB - Background. Although the prevalence of human papillomavirus (HPV) genital infection is similarly high in males and females, seroprevalence is lower in males. This study assessed rates and determinants of seroconversion after detection of genital HPV infection in young men. Methods. We investigated HPV type-specific seroconversion in a cohort of heterosexual male university students who had an alpha9 HPV type (HPV-16, -31, -33, -35, -52, -58, or -67) detected in the genital tract (n = 156). HPV DNA and antibodies were detected and typed using liquid bead-based multiplex assays. We calculated seroconversion using Kaplan Meier survival analysis. Cox proportional hazards models with generalized estimating equations were used to examine associations with seroconversion. Results. Within 24 months of detecting genital HPV infection, type-specific seroconversion ranged from 4% for HPV-52 to 36% for HPV-31. HPV-16 seroconversion at 24 months was 13% (95% confidence interval [CI], 7%-25%). Among incident HPV infections, ever cigarette smoking and infection site(s) (shaft/scrotum and glans/urine vs shaft/scrotum or glans/urine only) were positively associated with type-specific seroconversion. Conclusions. For each of the alpha9 HPV types, type specific seroconversion within 24 months was observed in 36% or less of infected men. Seroconversion might be related to cigarette smoking and genital site(s) infected. PMID- 21673032 TI - Effects of hepatitis B virus infection on the interferon response in immunodeficient human hepatocyte chimeric mice. AB - Complementary DNA microarray analysis of human livers cannot exclude the influence of the immunological response. In this study, complementary DNA microarray analysis was performed under immunodeficient conditions with human hepatocyte chimeric mice, and gene expression profiles were analyzed by hepatitis B virus (HBV) infection and/or interferon treatment. The expression levels of 183 of 525 genes upregulated by interferon treatment were significantly suppressed in response to HBV infection. Suppressed genes were statistically significantly associated with the interferon signaling pathway and pattern recognition receptors in the bacteria/virus recognition pathway (P = 1.0 * 10(-8) and P = 1.2 * 10(-8), respectively). HBV infection attenuated virus recognition and interferon response in hepatocytes, which facilitated HBV escape from innate immunity. PMID- 21673033 TI - Protection of MP-12-vaccinated rhesus macaques against parenteral and aerosol challenge with virulent rift valley fever virus. AB - To test safety and efficacy of the Rift Valley fever MP-12 (RVF MP-12) vaccine, 9 healthy adult Rhesus macaques, weighing 5-10 kg, were inoculated intramuscularly with 6 * 10(3) plaque forming units (PFUs) of MP-12 vaccine. The monkeys developed neutralizing antibody responses with no adverse effects other than a transient, low-titer viremia in 3 monkeys. Four vaccinated animals challenged intravenously with 3 * 10(6) PFUs of virulent Rift Valley fever virus strain ZH 501 (RVFV ZH-501) at 126 days after vaccination were protected against infection. The remaining 5 vaccinated monkeys along with 2 monkeys that had been vaccinated 6 years prior were completely protected against a small particle aerosol challenge of 5 * 10(5) PFUs of RVFV ZH-501. The mutagen-attenuated RVF MP-12 vaccine was determined to be protective against intravenous and aerosol challenge with virulent RVFV in these macaques, which suggests further development as a vaccine for humans is warranted. PMID- 21673034 TI - Sequencing and analysis of JC virus DNA from natalizumab-treated PML patients. AB - BACKGROUND: Progressive multifocal leukoencephalopathy (PML) in natalizumab treated MS patients is linked to JC virus (JCV) infection. JCV sequence variation and rearrangements influence viral pathogenicity and tropism. To better understand PML development, we analyzed viral DNA sequences in blood, CSF and/or urine of natalizumab-treated PML patients. METHODS: Using biofluid samples from 17 natalizumab-treated PML patients, we sequenced multiple isolates of the JCV noncoding control region (NCCR), VP1 capsid coding region, and the entire 5 kb viral genome. RESULTS: Analysis of JCV from multiple biofluids revealed that individuals were infected with a single genotype. Across our patient cohort, multiple PML-associated NCCR rearrangements and VP1 mutations were present in CSF and blood, but absent from urine-derived virus. NCCR rearrangements occurred in CSF of 100% of our cohort. VP1 mutations were observed in blood or CSF in 81% of patients. Sequencing of complete JCV genomes demonstrated that NCCR rearrangements could occur without VP1 mutations, but VP1 mutations were not observed without NCCR rearrangement. CONCLUSIONS: These data confirm that JCV in natalizumab-PML patients is similar to that observed in other PML patient groups, multiple genotypes are associated with PML, individual patients appear to be infected with a single genotype, and PML-associated mutations arise in patients during PML development. PMID- 21673036 TI - A modulatory interleukin-10 response to staphylococcal peptidoglycan prevents Th1/Th17 adaptive immunity to Staphylococcus aureus. AB - Toll-like receptor (TLR) 2 on antigen-presenting cells (APCs) enables these cells to recognize peptidoglycan-embedded lipopeptides and glycopolymers in the Staphylococcus aureus cell wall and mount an inflammatory response to this microbe. TLR2 signalling can also modulate immunity to S. aureus by inducing an interleukin (IL)-10 response in APCs. What determines the balance between proinflammatory and modulatory responses to S. aureus is unknown. We show that the modulatory IL-10 response preferentially occurs upon CD14- and CD36 independent TLR2 signaling, triggering PI3K activation, and is restricted to monocytes and monocyte-derived macrophages (MPhis). In contrast, monocyte-derived dendritic cells (DCs) produce mostly IL-12 and IL-23. The differential APC polarization induced by staphylococcal peptidoglycan translates into differential T helper responses: MPhis primarily trigger IL-10 and weak IL-17 responses, whereas DCs trigger a robust Th1/Th17 response. Exploitation of TLR2 signalling plasticity by S. aureus may explain the wide range of outcomes of human encounters with this microbe. PMID- 21673035 TI - Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? AB - BACKGROUND: Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. METHODS: In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. RESULTS: Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria tetanus-pertussis vaccinations. CONCLUSIONS: Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries. PMID- 21673037 TI - Deaths associated with bacterial pathogens transmitted commonly through food: foodborne diseases active surveillance network (FoodNet), 1996-2005. AB - BACKGROUND: Foodborne diseases are typically mild and self-limiting but can cause severe illness and death. We describe the epidemiology of deaths associated with bacterial pathogens using data from the Foodborne Diseases Active Surveillance Network (FoodNet) in the United States. METHODS: We analyzed FoodNet data from 1996-2005 to determine the numbers and rates of deaths occurring within 7-days of laboratory-confirmation. RESULTS: During 1996-2005, FoodNet ascertained 121,536 cases of laboratory-confirmed bacterial infections, including 552 (.5%) deaths, of which 215 (39%) and 168 (30%) were among persons infected with Salmonella and Listeria, respectively. The highest age-specific average annual population mortality rates were in older adults (>=65 years) for all pathogens except Shigella, for which the highest age-specific average annual population mortality rate was in children <5 years (.2/1 million population). Overall, most deaths (58%; 318) occurred in persons >=65 years old. Listeria had the highest case fatality rate overall (16.9%), followed by Vibrio (5.8%), Shiga toxin-producing Escherichia coli O157 (0.8%), Salmonella (0.5%), Campylobacter (0.1%), and Shigella (0.1%). CONCLUSIONS: Salmonella and Listeria remain the leading causes of death in the United States due to bacterial pathogens transmitted commonly through food. Most such deaths occurred in persons >=65 years old, indicating that this age group could benefit from effective food safety interventions. PMID- 21673038 TI - Number of years of annual mass treatment with azithromycin needed to control trachoma in hyper-endemic communities in Tanzania. AB - BACKGROUND: The World Health Organization recommends mass treatment as part of a trachoma control strategy. However, scant empirical data from hyperendemic communities exist on the number of rounds of treatment needed to reach a goal of <5% prevalence in children. We determined the prevalence of trachoma and infection with Chlamydia trachomatis in communities after 3-7 years of annual mass treatment in Tanzania. METHODS: Seventy-one communities with trachoma and annual azithromycin coverage data were enrolled. A cross-sectional survey of >=100 randomly selected children aged <5 years in each community was performed. Children were examined for clinical trachoma, and swab samples were taken for determination of ocular C. trachomatis infection. RESULTS: After 3 years of mass treatment, the prevalence of trachoma decreased in a linear fashion with number of years of mass treatment, whereas decreased prevalences of C. trachomatis infection were related to the extent of the previous year's azithromycin coverage. Our model suggests that, for communities with baseline trachoma prevalence of 50% and annual treatment coverage of 75%, >7 years of annual mass treatment will be needed to reach a prevalence of trachoma of <5%. CONCLUSIONS: Country programs in trachoma-endemic regions must realistically expect that several years of annual mass treatment may be necessary to eliminate trachoma. PMID- 21673039 TI - Role of a type IV-like secretion system of Streptococcus suis 2 in the development of streptococcal toxic shock syndrome. AB - Streptococcus suis serotype 2 (S. suis 2) has evolved into a highly invasive pathogen that was found to be the cause of 2 large-scale outbreaks of streptococcus toxic shock syndrome (STSS) in China. However, the mechanism of action of this non-group A streptococcal (GAS) S. suis-caused STSS is still unknown. Previously, we identified a unique pathogenicity island (PAI) designated 89K that is specific to the STSS-causing epidemic strains of S. suis 2. In this study, we further report a functional type IV-like secretion system (T4SS-like system) harbored in the 89K PAI that contributes to the development of STSS. Knockout of the 2 key components (VirD4-89K and VirB4-89K) of the T4SS-like system eliminated the lethality of the highly virulent strain and impaired its ability to trigger host immune response in experimental infection of mice. Our findings provide a new insight into the pathogenesis of STSS caused by the highly pathogenic S. suis 2 isolates. PMID- 21673040 TI - Nutritional status and mortality among HIV-infected patients receiving antiretroviral therapy in Tanzania. AB - BACKGROUND: Poor nutritional status is associated with immunologic impairment and adverse health outcomes among adults infected with human immunodeficiency virus (HIV). METHODS: We investigated body mass index (BMI), middle upper arm circumference (MUAC), and hemoglobin (Hgb) concentrations at initiation of antiretroviral therapy (ART) in 18,271 HIV-infected Tanzanian adults and their changes in the first 3 months of ART, in relation to the subsequent risk of death. RESULTS: Lower BMI, MUAC, and Hgb concentrations at ART initiation were strongly associated with a higher risk of death within 3 months. Among patients who survived >3 months after ART initiation, those with a decrease in weight, MUAC, or Hgb concentrations by 3 months had a higher risk of death during the first year. After 1 year, only a decrease in MUAC by 3 months after ART initiation was associated with a higher risk of death. Weight loss was associated with a higher risk of death across all levels of baseline BMI, with the highest risk observed among patients with BMI <17 kg/m(2) (relative risk, 7.9; 95% confidence interval, 4.4-14.4). CONCLUSIONS: Poor nutritional status at ART initiation and decreased nutritional status in the first 3 months of ART were strong independent predictors of mortality. The role of nutritional interventions as adjunct therapies to ART merits further investigation. PMID- 21673041 TI - Chemokine (C-C motif) receptor 5 -2459 genotype in patients receiving highly active antiretroviral therapy: race-specific influence on virologic success. AB - BACKGROUND: In patients receiving highly active antiretroviral therapy (HAART), antiretroviral drug-metabolizing enzyme and transporter gene polymorphisms, as well as chemokine receptor gene polymorphisms, may influence response to treatment. METHODS: In a North American, treated, adherent human immunodeficiency virus (HIV)-positive cohort (self-identified whites, n = 175; blacks, n = 218), we investigated whether CYP2B6 (516G>T, 983T>C), UGT2B7 (IVS1+985A>G, 802C>T), MDR1 3435C>T, chemokine (C-C motif) receptor 2 (CCR2) 190G>A, and CCR5 (-2459G>A, Delta32) polymorphisms influenced the time to achieve virologic success (TVLS). RESULTS: No difference in TVLS was observed between races. In Kaplan-Meier analyses, only 516G>T (log-rank P = .045 for comparison of GG, GT, and TT and P = .02 GG + GT vs TT) and -2459G>A (log-rank P = .04 for GG, GA, and AA and P = .02 for GG + GA vs AA) genotypes were significantly associated with TVLS in black patients but not in white patients. However, in the Cox proportional hazards model that included age, sex, baseline CD4(+) T cell count, and baseline viral load, no significant association was observed between 516G>T and TVLS, whereas the association between -2459G>A and TVLS remained significant even after including CCR2 190G>A as well as all the drug-metabolizing enzyme and transporter genotypes. CONCLUSIONS: These findings suggest that CCR5 -2459G>A genotype had a strong, race-specific influence on TVLS in this cohort. Understanding the possible mechanisms underlying this influence requires further studies. PMID- 21673042 TI - Endometrial epithelial cell responses to coinfecting viral and bacterial pathogens in the genital tract can activate the HIV-1 LTR in an NF{kappa}B-and AP 1-dependent manner. AB - BACKGROUND: Sexually transmitted infections (STIs) are associated with increased human immunodeficiency virus type 1 (HIV-1) susceptibility and viral shedding in the genital tract, but the mechanisms underlying this association are poorly understood. METHODS: Direct activation of HIV long terminal repeats (LTRs), a proxy measure for HIV-1 replication, was measured after treatment of 1G5 T cells with Toll-like receptor (TLR) ligands, herpes simplex virus type 1 or 2 (HSV 1/2), or Neisseria gonorrhoeae. For indirect activation, 1G5 T cells were incubated with supernatants from female primary genital epithelial cells (GECs) previously exposed to these agents. Proinflammatory cytokines and chemokines were measured in GEC supernatants. Proinflammatory pathways were blocked to determine the mechanisms of direct and indirect HIV-LTR activation. RESULTS: HSV-1/2, N. gonorrhoeae, and TLR ligands FimH (TLR-4), flagellin (TLR-5), and Poly (I:C) (TLR 3) directly induced HIV-LTR activation in 1G5 T cells. Supernatants collected from GECs incubated with these agents indirectly induced HIV-LTR activation. Production of tumor necrosis factor alpha, interleukin 6, interleukin 8, and monocyte chemoattractant protein-1 was elevated in GECs exposed to copathogens. Inhibition of nuclear factor kappaB and activator protein-1 (AP-1) signaling pathways in 1G5 T cells abrogated both direct and indirect HIV-LTR activation. CONCLUSIONS: STIs may increase HIV-1 replication in the female genital tract via proinflammatory signaling pathways directly and indirectly via their effects on GECs. This increased HIV-1 replication may enhance sexual and vertical HIV transmission. PMID- 21673044 TI - Human lymphatic filariasis: genetic polymorphism of endothelin-1 and tumor necrosis factor receptor II correlates with development of chronic disease. AB - BACKGROUND: Hydrocele and elephantiasis are 2 clinically very diverse and often mutually exclusive chronic manifestations of human bancroftian filariasis. Plasma levels of endothelin-1 (ET-1), a major angiogenic factor, and tumor necrosis factor receptors (TNFRs) that regulate host inflammation have been associated with development of chronic filariasis, although their genetic basis are not known. METHODS: We studied polymorphisms of ET-1 (Ala288Ser) and TNFR-II (Met196Arg) genes by means of the polymerase chain reaction confronting 2 pairs primers method and restriction fragment length polymorphism, respectively. Plasma ET-1 level was measured by enzyme-linked immunosorbent assay. RESULTS: Met196Arg genotype frequency of TNFR-II polymorphism was significantly greater in hydrocele patients, compared with elephantiasis patients (OR, 4.34 [95% CI, 2.04-9.20]). Conversely, a significantly high prevalence of the Ala288Ser mutation of ET-1 was observed in elephantiasis patients, compared with hydrocele cases (OR, 2.15 [95% CI, 1.13-4.10]). Decreased plasma ET-1 levels associated significantly with Ala288Ser mutation in the study population. A combined analysis indicated a 23 fold higher risk for developing elephantiasis in individuals with TNFR-II (Met196Met) and ET-1 mutants (Ala288Ser + Ser288Ser). CONCLUSIONS: ET-1 (Ala288Ser) and TNFR-II (Met196Arg) polymorphisms are associated with development of one or the other form of chronic disease in bancroftian filariasis. PMID- 21673046 TI - Mycobacterium tuberculosis-Induced Reduction of Interferon {gamma}-Producing CD4 T cells in active tuberculosis. PMID- 21673045 TI - Establishing and sustaining a healthy vaginal environment: analysis of data from a randomized trial of periodic presumptive treatment for vaginal infections. AB - Data from a randomized trial of oral periodic presumptive treatment (PPT) to reduce vaginal infections were analyzed to assess the effect of the intervention on a healthy vaginal environment (normal flora confirmed by Gram stain with no candidiasis or trichomoniasis). The incidence of a healthy vaginal environment was 608 cases per 100 person-years in the intervention arm and 454 cases per 100 person-years in the placebo arm (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.17-1.58). Sustained vaginal health (healthy vaginal environment for >=3 consecutive visits) was also more frequent in the intervention arm (HR, 1.69; 95% CI, 1.23-2.33). PPT is effective at establishing and sustaining a healthy vaginal environment. PMID- 21673048 TI - Sex-dependent hepatic transcripts and metabolites in the development of glucose intolerance and insulin resistance in Zucker diabetic fatty rats. AB - Male Zucker diabetic fatty (mZDF) rats spontaneously develop type 2 diabetes, whereas females only become diabetic when fed a diabetogenic high-fat diet (high fat-fed female ZDF rat, HF-fZDF). The aim of this study was to investigate if differences in liver functions could provide clues to this sex difference. Non diabetic obese fZDF rats were compared with either mZDF or HF-fZDF regarding hepatic molecular profiles, to single out those components that might be protective in the females. High-fat feeding in fZDF led to enhanced weight gain, increased blood glucose and insulin levels, reduced insulin sensitivity and a trend towards reduced glucose tolerance, indicative of a prediabetic state. mZDF rats were diabetic, with low levels of insulin, high levels of glucose, reduced insulin sensitivity and impaired glucose tolerance. Transcript profiling and capillary electrophoresis time-of-flight mass spectrometry were used to indentify hepatic transcripts and metabolites that might be related to this. Many diet induced alterations in transcript and metabolite levels in female rats were towards a 'male-like' phenotype, including reduced lipogenesis, increased fatty acid (FA) oxidation and increased oxidative stress responses. Alterations detected at the level of hepatic metabolites, indicated lower capacity for glutathione (GSH) production in male rats, and higher GSH turnover in females. Taken together, this could be interpreted as if anabolic pathways involving lipogenesis and lipid output might limit the degree of FA oxidation and oxidative stress in female rats. Together with a greater capacity to produce GSH, these hepatic sex differences might contribute to the sex-different development of diabetes in ZDF rats. PMID- 21673043 TI - Lack of compartmentalization of HIV-1 quasispecies between the gut and peripheral blood compartments. AB - Compartmental differences in human immunodeficiency virus type 1 (HIV-1) between the gut and peripheral blood and within the gut were examined. Biopsy specimens from the colon and ileum and peripheral blood samples were collected from chronically HIV-1-infected individuals. HIV-1 envelope sequences were examined from cell-associated DNA and RNA and virion RNA. Phylogenetic analysis revealed no evidence of compartmentalization of HIV-1 between the gut and peripheral blood and within the gut (colon and ileum). HIV-1 sequences detected in the gut were transcriptionally active and were also found in peripheral blood from matching time points, providing evidence of ongoing virus production in the gut and equilibrium of HIV-1 between the gut and peripheral blood compartments. PMID- 21673049 TI - Retinoid X receptor alpha and retinoids are key regulators in apoptosis of trophoblasts of patients with recurrent miscarriages. AB - The retinoid X receptor alpha (RXRalpha) is a nuclear hormone receptor that is able to bind other nuclear receptors in a heterodimeric complex, thereby activating gene transcription. Recently, we identified enhanced expression of RXRalpha in extravillous trophoblasts (EVT) and villous trophoblasts (VT) of miscarried placentas. In addition, an increased number of apoptotic EVT was present in miscarried placentas. In this study, on the basis of immunocytochemical analysis, western blots, and quantitative real-time reverse transcription PCR, we could demonstrate a reduced expression of RXRalpha in choriocarcinoma cell lines and in human VTs after stimulation with the retinoids 9-cis-retinoic acid and all-trans-retinoic acid and the prostaglandin 15-deoxy Delta(12,14)-prostaglandin J(2). Furthermore, a simultaneous expression of RXRalpha and the apoptotic marker M30 CytoDEATH in EVT of miscarried placentas from the first trimester was shown. In EVT of control placentas from legal termination of pregnancies, no co-expression of RXRalpha and M30 could be detected. A likely conclusion is that RXRalpha plays an important role in the induction of apoptosis. Downregulation of RXRalpha, as observed in the tested choriocarcinoma cells and trophoblasts, might serve as a protection against apoptosis and miscarriage. In conclusion, RXRalpha represents a potential target in the treatment of recurrent miscarriages. PMID- 21673051 TI - Of global space or perceived place? Comment on Kelly et al. PMID- 21673050 TI - Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism. AB - Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors long-range enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dose-dependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease. PMID- 21673052 TI - Combining betulinic acid and mithramycin a effectively suppresses pancreatic cancer by inhibiting proliferation, invasion, and angiogenesis. AB - Both betulinic acid (BA) and mithramycin A (MIT) exhibit potent antitumor activity through distinct mechanisms of Sp1 inhibition. However, it is unknown whether a combination of these two compounds results in a synergistic inhibitory effect on pancreatic cancer growth and/or has a therapeutic advantage over gemcitabine. In xenograft mouse models of human pancreatic cancer, treatment with either BA or MIT alone showed dose-dependent antitumor activity but led to systemic side effects as measured by overall weight loss. Treatment with a nontoxic dose of either compound alone had only marginal antitumor effects. Importantly, combination treatment with nontoxic doses of BA and MIT produced synergistic antitumor activity, including inhibitory effects on cell proliferation, invasion, and angiogenesis. The treatment combination also produced less discernible side effects than therapeutic doses of gemcitabine. Moreover, combined treatment of BA and MIT resulted in drastic inhibition of Sp1 recruitment onto Sp1 and VEGF promoters, leading to transcriptional inhibition of both Sp1 and VEGF and downregulation of Sp1 and VEGF protein expression. Ectopic overexpression of Sp1 rendered tumor cells resistant to BA, MIT, and the combination of the two. Overall, our findings argue that Sp1 is an important target of BA and MIT and that their combination can produce an enhanced therapeutic response in human pancreatic cancer. PMID- 21673053 TI - A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. AB - Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression. PMID- 21673056 TI - Supreme Court rules expert witnesses may now be sued for negligence. PMID- 21673057 TI - Prison psychiatry. PMID- 21673058 TI - Some curare murders? PMID- 21673059 TI - Experts, laymen, and the identification of Cora Crippen: an exercise in medicolegal cooperation. PMID- 21673060 TI - Psychiatric injury. the lawyer's view. PMID- 21673061 TI - Detection of doping in sport: detecting anabolic-androgenic steroids in human fingernail clippings. PMID- 21673062 TI - The Medico-Legal Society's sponsorship of the HealthWatch student prize. PMID- 21673063 TI - Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1alpha in advanced solid tumors. AB - PURPOSE: Hypoxia-inducible factor 1 (HIF-1) alpha is frequently overexpressed in human tumors and is associated with angiogenesis and metastasis. Topotecan, a topoisomerase I inhibitor, has been shown to inhibit HIF-1alpha expression in preclinical models. We designed a pilot trial to measure HIF-1alpha inhibition in tumor biopsies from patients with advanced solid tumors overexpressing HIF 1alpha, after treatment with oral topotecan. EXPERIMENTAL DESIGN: Topotecan was administered orally at 1.6 mg/m(2) once daily for 5 days/week for 2 weeks, in 28 day cycles. Objectives were to determine inhibition of expression of HIF-1alpha and HIF-1 target genes in tumor; to assess tumor blood flow by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI); and to measure pharmacokinetics. Tumor biopsies were collected at baseline and during the second cycle of treatment. RESULTS: Sixteen patients were enrolled. The dose of topotecan was reduced to 1.2 mg/m(2)/day due to myelosuppression. Seven patients had paired tumor biopsies. In 4 patients, HIF-1alpha nuclear staining became undetectable after treatment (7.5%-50% staining at baseline). Decreased levels of VEGF and GLUT-1 mRNA were measured in 4 patients; the changes were concordant with reduction in HIF-1alpha in 3 patients. Decreased tumor blood flow and permeability were observed by DCE-MRI in 7 of 10 patients after 1 cycle. One patient had a partial response accompanied by inhibition of HIF-1alpha in tumor and reduction in tumor blood flow on DCE-MRI. CONCLUSIONS: This multihistology, target assessment trial of a small molecule inhibitor of HIF-1alpha showed that topotecan could decrease HIF-1alpha expression in advanced solid tumors. PMID- 21673064 TI - Fibroblast growth factor receptors are components of autocrine signaling networks in head and neck squamous cell carcinoma cells. AB - PURPOSE: We previously reported that a fibroblast growth factor (FGF) receptor (FGFR) signaling pathway drives growth of lung cancer cell lines of squamous and large cell histologies. Herein, we explored FGFR dependency in cell lines derived from the tobacco-related malignancy, head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: FGF and FGFR mRNA and protein expression was assessed in nine HNSCC cell lines. Dependence on secreted FGF2 for cell growth was tested with FP-1039, an FGFR1-Fc fusion protein. FGFR and epidermal growth factor receptor (EGFR) dependence was defined by sensitivity to multiple inhibitors selective for FGFRs or EGFR. RESULTS: FGF2 was expressed in eight of the nine HNSCC cell lines examined. Also, FGFR2 and FGFR3 were frequently expressed, whereas only two lines expressed FGFR1. FP-1039 inhibited growth of HNSCC cell lines expressing FGF2, identifying FGF2 as an autocrine growth factor. FGFR inhibitors selectively reduced in vitro growth and extracellular signal regulated kinase signaling in three HNSCC cell lines, whereas three distinct lines exhibited responsiveness to both EGFR and FGFR inhibitors. Combinations of these drugs yielded additive growth inhibition. Finally, three cell lines were highly sensitive to EGFR tyrosine kinase inhibitors (TKI) with no contribution from FGFR pathways. CONCLUSIONS: FGFR signaling was dominant or codominant with EGFR in six HNSCC lines, whereas three lines exhibited little or no role for FGFRs and were highly EGFR dependent. Thus, the HNSCC cell lines can be divided into subsets defined by sensitivity to EGFR and FGFR-specific TKIs. FGFR inhibitors may represent novel therapeutics to deploy alone or in combination with EGFR inhibitors in HNSCC. PMID- 21673065 TI - To DNA or not to DNA? That is the question, when it comes to molecular subtyping for the clinic! AB - Genome-wide RNA expression profiling has yielded tumor subtypes with strong predictive or prognostic value for a wide variety of cancers. Recently, for breast cancer two RNA expression classifiers have been adopted by the World Health Organization (WHO) and approved by the Food and Drug Administration (FDA). Also on the basis of DNA copy number profiles, tumor subtypes with different prognosis have been described, but have not yet led to clinical implementation. The genomic revolution caused by next generation sequencing of DNA samples presents additional mutation, balanced translocations, single-nucleotide polymorphisms (SNP), and copy neutral loss of heterozygosity data simultaneously. We foresee a further boost of the potential of DNA profiling in the clinic when these multidimensional DNA factors will be implemented. Here we evaluate the current stratification power with DNA copy numbers. In a training and validation approach using data of 400 published breast cancer samples, we show that a DNA copy number classifier accurately classifies RNA expression subtypes. We consider this an important step forward for clinical implementation of genomic subtyping using DNA and discuss the extra dimensions upcoming techniques will bring to the DNA palette. PMID- 21673066 TI - Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma. AB - PURPOSE: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM. EXPERIMENTAL DESIGN: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle. RESULTS: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2' deoxycytidine treatment. Because epigenetic silencing was the major event in miR 34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells. CONCLUSIONS: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM. PMID- 21673067 TI - FDG-PET as a potential tool for selecting patients with advanced non-small cell lung cancer who may be spared maintenance therapy after first-line chemotherapy. AB - PURPOSE: To investigate whether 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) may be a potential tool to select a subgroup of patients who might be spared maintenance treatment, if the metabolic response after first-line chemotherapy could predict time-to-progression (TTP). EXPERIMENTAL DESIGN: A total of 43 patients who underwent baseline FDG-PET scan and did not show disease progression (DP) after 4 cycles of first-line chemotherapy were enrolled and underwent second FDG-PET 3 weeks after completion of the first-line chemotherapy. The primary endpoint was to compare percent decrease in maximum standard uptake value (SUVmax) between early (TTP after second PET examination <8 weeks) and late (TTP >=8 weeks) DP subgroups. Secondary endpoints were to determine whether fractional decrease in SUVmax could predict TTP and overall survival (OS), both calculated from the date of the second FDG-PET. RESULTS: Percent decreases in SUVmax in late DP subgroup were greater than those in early DP subgroup (mean reduction, 54.7% +/- 27.2% vs. 27.8% +/- 46.8%, P = 0.021). Receiver operating characteristic curves identified a 50.0% decrease in SUVmax as the optimal threshold to distinguish these subgroups. Using this value as the cutoff resulted in a positive predictive value of 82.6% and negative predictive value of 60.0% in predicting TTP >=8 weeks. Patients with SUVmax decrease <50% had significantly longer median TTP (3.0 vs. 1.5 months, P = 0.001) and OS (not reached vs. 14.2 months, P = 0.003). CONCLUSIONS: Fractional decrease in SUVmax of the main lesion after completion of 4 cycles of chemotherapy may discriminate patients with TTP >=8 weeks and predict TTP and OS in patients with advanced NSCLC. PMID- 21673070 TI - Involvement of cannabinoid CB1 receptor in associative learning and in hippocampal CA3-CA1 synaptic plasticity. AB - We studied, in behaving mice, the contribution of CB1 receptors to the activity dependent changes induced at the hippocampal CA3-CA1 synapse by associative learning and following experimentally evoked long-term potentiation (LTP). Mice were classically conditioned to evoke eyelid responses with a trace paradigm using a tone as conditioned stimulus (CS) and an electric shock as unconditioned stimulus (US). Field excitatory postsynaptic potentials (fEPSPs) were evoked at the CA3-CA1 synapse during the CS-US interval across training. Conditioning was performed in presence of an agonist (WIN55,212-2) alone or with an antagonist (AM251) of the CB1 receptor, injected either systemically or locally. Conditioned responses (CRs) and fEPSP potentiation were depressed by WIN55,212-2. LTP was evoked by high-frequency stimulation of Schaffer collaterals after systemic or local WIN55,212-2 and AM251 injections. WIN55,212-2 affected the induction phase of LTP, mainly when injected locally. The addition of AM251 canceled out the effects of WIN55,212-2. Similar experiments were carried out in animals lacking the CB1 receptor (CB1(-/-) mice) and following silencing of hippocampal CB1 receptors (CB1R-siRNA-injected animals). In this case, CRs (CB1(-/-) mice) and LTP (CB1(-/-) and CB1R-siRNA-injected mice) reached lower values than their respective controls. Results offer new insights for understanding CB1 receptor contribution to associative learning and to CA3-CA1 synaptic plasticity. PMID- 21673069 TI - EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients. AB - BACKGROUND: Cetuximab has shown significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in epidermal growth factor receptor pathway, angiogenesis, antibody dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation. METHODS: 130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was done by using PCR-RFLP assays. Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade III vs. grade IV: complete response). RESULTS: Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P < 0.001). In addition, this association between EGF 61 G allele and pCR remained significant (P = 0.019) in the 59 patients with wild-type KRAS. CONCLUSION: This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer. PMID- 21673068 TI - ERK1/2 and p38alpha/beta signaling in tumor cell quiescence: opportunities to control dormant residual disease. AB - Systemic minimal residual disease after primary tumor treatment can remain asymptomatic for decades. This is thought to be due to the presence of dormant disseminated tumor cells (DTC) or micrometastases in different organs. DTCs lodged in brain, lungs, livers, and/or bone are a major clinical problem because they are the founders of metastasis, which ultimately kill cancer patients. The problem is further aggravated by our lack of understanding of DTC biology. In consequence, there are almost no rational therapies to prevent dormant DTCs from surviving and expanding. Several cancers, including melanoma as well as breast, prostate, and colorectal carcinomas, undergo dormant periods before metastatic recurrences develop. Here we review our experience in studying the cross-talk between ERK1/2 and p38alpha/beta signaling in models of early cancer progression, dissemination, and DTC dormancy. We also provide some potential translational and clinical applications of these findings and describe how some currently used therapies might be useful to control dormant disease. Finally, we draw caution on the use of p38 inhibitors currently in clinical trials for different diseases as these may accelerate metastasis development. PMID- 21673071 TI - Combining small interfering RNAs targeting thymidylate synthase and thymidine kinase 1 or 2 sensitizes human tumor cells to 5-fluorodeoxyuridine and pemetrexed. AB - Thymidylate synthase (TS) is the only de novo source of thymidylate (dTMP) for DNA synthesis and repair. Drugs targeting TS protein are a mainstay in cancer treatment, but off-target effects and toxicity limit their use. Cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2) contribute to an alternative dTMP-producing pathway, by salvaging thymidine from the tumor milieu, and may modulate resistance to TS-targeting drugs. Combined down-regulation of these enzymes is an attractive strategy to enhance cancer therapy. We have shown previously that antisense-targeting TS enhanced tumor cell sensitivity to TS targeting drugs in vitro and in vivo. Because both TS and TKs contribute to increased cellular dTMP, we hypothesized that TKs mediate resistance to the capacity of TS small interfering RNA (siRNA) to sensitize tumor cells to TS targeting anticancer drugs. We assessed the effects of targeting TK1 or TK2 with siRNA alone and in combination with siRNA targeting TS and/or TS-protein targeting drugs on tumor cell proliferation. Down-regulation of TK with siRNA enhanced the capacity of TS siRNA to sensitize tumor cells to traditional TS protein-targeting drugs [5-fluorodeoxyuridine (5FUdR) and pemetrexed]. The sensitization was greater than that observed in response to any siRNA used alone and was specific to drugs targeting TS. Up-regulation of TK1 in response to combined 5FUdR and TS siRNA suggests that TK knockdown may be therapeutically useful in combination with these agents. TKs may be useful targets for cancer therapy when combined with molecules targeting TS mRNA and TS protein. PMID- 21673072 TI - Targeting cannabinoid receptors as a novel approach in the treatment of graft versus-host disease: evidence from an experimental murine model. AB - Allogeneic hematopoietic cell transplantation (HCT) is widely used to treat patients with life-threatening malignant and nonmalignant hematological diseases. However, allogeneic HCT often is accompanied by severe and lethal complications from graft-versus-host disease (GVHD), in which activated donor T cells recognize histocompatibility antigenic mismatches and cause significant toxicity in the recipient. In the current study, we tested the hypothesis that activation of cannabinoid receptors on donor-derived T cells may prevent GVHD. We tested the effect of Delta(9)-tetrahydrocannabinol (THC) in an acute model of GVHD that was induced by transferring parental C57BL/6 (B6) spleen cells into (C57BL/6 * DBA/2) F(1)(BDF1) mice. Transfer of B6 cells into BDF1 mice produced severe acute GVHD in the recipient, characterized by lymphoid hyperplasia, weight loss, T helper l cytokine production and mortality. THC administration led to early recovery from body weight loss, reduced tissue injury in the liver and intestine, as well as complete survival. THC treatment reduced the expansion of donor-derived effector T cells and blocked the killing of host-derived immune cells while promoting Foxp3(+) regulatory T cells. Impaired hematopoiesis seen during GVHD was rescued by treatment with THC. The ability of THC to reduce the clinical GVHD was reversed, at least in part, by administration of cannabinoid receptor (CB) 1 and CB2 antagonists, thereby demonstrating that THC-mediated amelioration of GVHD was cannabinoid receptor-dependent. Our results demonstrate for the first time that targeting cannabinoid receptors may constitute a novel treatment modality against acute GVHD. PMID- 21673073 TI - Maybe repressed mRNAs are not stored in the chromatoid body in mammalian spermatids. AB - The chromatoid body is a dynamic organelle that is thought to coordinate the cytoplasmic regulation of mRNA translation and degradation in mammalian spermatids. The chromatoid body is also postulated to function in repression of mRNA translation by sequestering dormant mRNAs where they are inaccessible to the translational apparatus. This review finds no convincing evidence that dormant mRNAs are localized exclusively in the chromatoid body. This discrepancy can be explained by two hypotheses. First, experimental artifacts, possibly related to peculiarities of the structure and function of the chromatoid body, preclude obtaining an accurate indication of mRNA localization. Second, mRNA is not stored in the chromatoid body, because, like perinuclear P granules in Caenorhabditis elegans, the chromatoid body functions as a center for mRNP remodeling and export to other cytoplasmic sites. PMID- 21673074 TI - Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes. AB - Physical exercise induces adaptive changes leading to a muscle phenotype with enhanced performance. We first investigated whether genetic polymorphisms altering enzymes involved in DNA methylation, probably responsible of DNA methylation deficiency, are present in athletes' DNA. We determined the polymorphic variants C667T/A1298C of 5,10-methylenetetrahydrofolate reductase (MTHFR), A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR), G742A of betaine:homocysteine methyltransferase (BHMT), and 68 bp ins of cystathionine beta-synthase (CBS) genes in 77 athletes and 54 control subjects. The frequency of MTHFR (AC), MTR (AG), and MTRR (AG) heterozygous genotypes was found statistically different in the athletes compared with the control group (P=0.0001, P=0.018, and P=0.0001), suggesting a reduced DNA methylating capacity. We therefore assessed whether DNA hypomethylation might increase the expression of myogenic proteins expressed during early (Myf-5 and MyoD), intermediate (Myf-6), and late-phase (MHC) of myogenesis in a cellular model of hypomethylated or unhypomethylated C2C12 myoblasts. Myogenic proteins are largely induced in hypomethylated cells [fold change (FC)=Myf-5: 1.21, 1.35; MyoD: 0.9, 1.47; Myf-6: 1.39, 1.66; MHC: 1.35, 3.10 in GMA, DMA, respectively] compared with the control groups (FC=Myf-5: 1.0, 1.38; MyoD: 1.0, 1.14; Myf-6: 1.0, 1.44; MHC: 1.0, 2.20 in GM, DM, respectively). Diameters and length of hypomethylated myotubes were greater then their respective controls. Our findings suggest that DNA hypomethylation due to lesser efficiency of polymorphic MTHFR, MS, and MSR enzymes induces the activation of factors determining proliferation and differentiation of myoblasts promoting muscle growth and increase of muscle mass. PMID- 21673076 TI - Glycemic index differences of high-fat diets modulate primarily lipid metabolism in murine adipose tissue. AB - A low vs. high glycemic index of a high-fat (HF) diet (LGI and HGI, respectively) significantly retarded adverse health effects in adult male C57BL/6J mice, as shown recently (Van Schothorst EM, Bunschoten A, Schrauwen P, Mensink RP, Keijer J. FASEB J 23: 1092-1101, 2009). The LGI diet enhanced whole body insulin sensitivity and repressed HF diet-induced body and white adipose tissue (WAT) weight gain, resulting in significantly reduced serum leptin and resistin levels and increased adiponectin levels. We questioned how WAT is modulated and characterized the molecular mechanisms underlying the glycemic index-mediated effects using whole genome microarrays. This showed that the LGI diet mainly exerts its beneficial effects via substrate metabolism, especially fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression, in line with lower WAT mass. An important transcription factor showing enhanced expression is PPAR-gamma. Furthermore, serum levels of triglycerides, total cholesterol, and HDL- and LDL-cholesterol were all significantly reduced by LGI diet, and simultaneously muscle insulin sensitivity was significantly increased as analyzed by protein kinase B/Akt phosphorylation. Cumulatively, even though these mice were fed an HF diet, the LGI diet induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones to treat insulin resistance and statins for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans. PMID- 21673075 TI - Modeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia. AB - Heart rate variability (HRV), the quantification of beat-to-beat variability, has been studied as a potential prognostic marker in inflammatory diseases such as sepsis. HRV normally reflects significant levels of variability in homeostasis, which can be lost under stress. Much effort has been placed in interpreting HRV from the perspective of quantitatively understanding how stressors alter HRV dynamics, but the molecular and cellular mechanisms that give rise to both homeostatic HRV and changes in HRV have received less focus. Here, we develop a mathematical model of human endotoxemia that incorporates the oscillatory signals giving rise to HRV and their signal transduction to the heart. Connections between processes at the cellular, molecular, and neural levels are quantitatively linked to HRV. Rhythmic signals representing autonomic oscillations and circadian rhythms converge to modulate the pattern of heartbeats, and the effects of these oscillators are diminished in the acute endotoxemia response. Based on the semimechanistic model developed herein, homeostatic and acute stress responses of HRV are studied in terms of these oscillatory signals. Understanding the loss of HRV in endotoxemia serves as a step toward understanding changes in HRV observed clinically through translational applications of systems biology based on the relationship between biological processes and clinical outcomes. PMID- 21673077 TI - Recurrent tubulointerstitial nephritis and uveitis syndrome in a renal transplant recipient. AB - We report for the time a patient with recurrence of tubulointerstitial nephritis and uveitis (TINU) following renal transplantation. Our patient was diagnosed at the age of 8 years and, despite treatment with systemic steroids, developed established renal failure. At the age of 17 years, he underwent a live-related donor renal transplant. Immunosuppression included tacrolimus, mycophenolate mofetil and prednisolone. Having had normal renal function for 3 years after transplantation, he developed uveitis and decline in the graft function. A biopsy of the allograft demonstrated recurrent granulomatous interstitial nephritis. The recurrence of TINU following transplantation suggests a role for circulating autoantibodies in the disease pathology. PMID- 21673078 TI - The Arabidopsis NAC transcription factor VNI2 integrates abscisic acid signals into leaf senescence via the COR/RD genes. AB - Leaf aging is a highly regulated developmental process, which is also influenced profoundly by diverse environmental conditions. Accumulating evidence in recent years supports that plant responsiveness to abiotic stress is intimately related with leaf longevity. However, molecular mechanisms underlying the signaling crosstalks and regulatory schemes are yet unknown. In this work, we demonstrate that an abscisic acid (ABA)-responsive NAC transcription factor VND-INTERACTING2 (VNI2) integrates ABA-mediated abiotic stress signals into leaf aging by regulating a subset of COLD-REGULATED (COR) and RESPONSIVE TO DEHYDRATION (RD) genes. The VNI2 gene was induced by high salinity in an ABA-dependent manner. In addition, spatial and temporal expression patterns of the VNI2 gene are correlated with leaf aging and senescence. Accordingly, leaf aging was delayed in transgenic plants overexpressing the VNI2 gene but significantly accelerated in a VNI2-deficient mutant. The VNI2 transcription factor regulates the COR and RD genes by binding directly to their promoters. Notably, transgenic plants overexpressing the COR or RD genes exhibited prolonged leaf longevity. These observations indicate that the VNI2 transcription factor serves as a molecular link that integrates plant responses to environmental stresses into modulation of leaf longevity. PMID- 21673082 TI - Are clinical protocols for osteopathic manipulative procedures truly "osteopathic"? PMID- 21673079 TI - The MYB80 transcription factor is required for pollen development and the regulation of tapetal programmed cell death in Arabidopsis thaliana. AB - Arabidopsis thaliana MYB80 (formerly MYB103) is expressed in the tapetum and microspores between anther developmental stages 6 and 10. MYB80 encodes a MYB transcription factor that is essential for tapetal and pollen development. Using microarray analysis of anther mRNA, we identified 404 genes differentially expressed in the myb80 mutant. Employing the glucocorticoid receptor system, the expression of 79 genes was changed when MYB80 function was restored in the myb80 mutant following induction by dexamethasone. Thirty-two genes were analyzed using chromatin immunoprecipitation, and three were identified as direct targets of MYB80. The genes encode a glyoxal oxidase (GLOX1), a pectin methylesterase (VANGUARD1), and an A1 aspartic protease (UNDEAD). All three genes are expressed in the tapetum and microspores. Electrophoretic mobility shift assays confirmed that MYB80 binds to all three target promoters, with the preferential binding site containing the CCAACC motif. TUNEL assays showed that when UNDEAD expression was silenced using small interfering RNA, premature tapetal and pollen programmed cell death occurred, resembling the myb80 mutant phenotype. UNDEAD possesses a mitochondrial targeting signal and may hydrolyze an apoptosis-inducing protein(s) in mitochondria. The timing of tapetal programmed cell death is critical for pollen development, and the MYB80/UNDEAD system may regulate that timing. PMID- 21673083 TI - Can laypersons be trained to effectively deliver osteopathic manual therapy to patients with HIV?: a pilot study. AB - CONTEXT: Osteopathic manipulative treatment (OMT) may provide added benefits to standard human immunodeficiency virus (HIV) and AIDS treatments. However, lack of access to trained OMT providers is a potential barrier to the widespread use of OMT in the management of HIV and AIDS. OBJECTIVES: To determine the best time to measure the short-term impact of a brief OMT protocol on white blood cell counts in individuals with HIV and AIDS. Also, to explore recruiting and training laypersons to administer select osteopathic manual techniques. METHODS: Participants were HIV-positive men aged between 18 and 65 years who had not undergone antiretroviral therapy in the past 12 months, had CD4(+) lymphocyte counts of 200 to 700 cells/mm(3), and had viral load levels of less than 100,000 copies/mL. Participants were randomly assigned to an OMT group or a control group; those in the OMT group recruited a layperson for training in osteopathic manual therapy. Participants in the OMT group received a 15-minute OMT protocol consisting of myofascial release of the thoracic inlet, pectoral traction, rib raising, thoracic pump, and abdominal pump. Participants in the control group engaged in conversation with the researcher for 15 minutes. Between-group differences for each white blood cell type were examined at varying time intervals after the protocols. Laypersons were trained to administer thoracic and abdominal pump techniques. They were tested by multiple choice examinations and by an independent rater for fidelity of administration. RESULTS: Twenty-one participants met the eligibility criteria. Of those, 18 returned for their study visit (OMT group, n=9; control group, n=9). An optimal time interval for measurement of white blood cell changes across the 5 cell types was not determined. However, P values for the 30-minute interval were consistently below 0.18 for neutrophils, eosinophils, and monocytes. Nine laypersons were trained in osteopathic manual therapy, 5 of whom scored 100% on initial completion of the multiple-choice examination; the remaining 4 laypersons scored 80% on the first try and 100% on the second try. All laypersons appropriately administered the manual therapy protocol. CONCLUSION: It is feasible to recruit and train laypersons to administer selected osteopathic manual therapy techniques with fidelity. Longitudinal studies on this concept are needed to examine patient outcomes and to evaluate the retention and fidelity of laypersons over time. PMID- 21673084 TI - Pain management and osteopathic manipulative medicine in the Army: new opportunities for the osteopathic medical profession. AB - Osteopathic manipulative medicine (OMM) is the most visible distinction between osteopathic physicians and allopathic physicians, and the osteopathic medical profession recognizes the proven clinical efficacy and value of OMM. The recently published report by the US Army Surgeon General's Pain Management Task Force provides a strong endorsement for the Army to increase the practice of OMM, to create OMM continuing medical education opportunities, and to improve research in OMM's role in pain management. This comprehensive restructuring of the Army's approach to pain management provides a unique opportunity for the civilian osteopathic medical profession-the true OMM experts-to collaborate with Army osteopathic physicians in OMM training, teaching, and research. PMID- 21673085 TI - Dermatology: a specialty that exemplifies the osteopathic medical profession. AB - Even though the tradition of osteopathic medicine is based in primary care, more osteopathic graduates than in the past are pursuing subspecialties within medicine. Some claim that medical specialties, such as dermatology, compromise osteopathic principles and philosophy. However, the authors contend that dermatology exemplifies the ideals expressed by Andrew Taylor Still, MD, DO, and explain how osteopathic manipulative treatment and the principles of osteopathic medicine can be applied to dermatologic disease and patient care. PMID- 21673086 TI - "Whatever you are, be a good one": osteopathic identity, equality, and the california merger. AB - In the early 1960s, Dorothy Marsh, DO, then president of the California Osteopathic Association, ardently promoted an amalgamation with the California Medical Association that would eliminate the doctorate of osteopathy (ie, DO) degree and grant medical doctor (MD) degrees to DO holders. Marsh traveled extensively throughout California in an effort to gain support for the merger, which passed in spring 1961. The osteopathic medical community tends to view the California merger as a dark period in history of the profession, a devastating loss of members and facilities. Yet, on the day it was signed, Marsh called the event a "historic achievement in the field of osteopathy." Using primary documents from the Dorothy Marsh Collection at the University of California, Los Angeles, the author attempts to understand the reasons why an osteopathic physician would fight so passionately to abandon her own professional identity. These documents shed light on Marsh's motivations and the perspectives of merger supporters and opponents during this period. PMID- 21673087 TI - Non-anion gap metabolic acidosis in a patient with a pancreaticopleural fistula. AB - While acid-base disturbances are known to occur with chronic pancreatitis, few cases have been reported in which non-anion gap metabolic acidosis is caused by pancreaticopleural fistula, a known complication of chronic pancreatitis. The current report describes the case of a 49-year-old African American woman who presented with severe pleuritic chest pain and dyspnea at rest. The patient had a history of alcohol-induced chronic pancreatitis. Her chest radiograph was positive for a large left-sided pleural effusion. Magnetic resonance cholangiopancreatography revealed a small connection between the pancreas and the thoracic cavity. Arterial blood gas analysis revealed non-anion gap metabolic acidosis in the absence of substantial urinary or diarrheal bicarbonate losses. The patient was diagnosed as having non-anion gap metabolic acidosis as a result of a pancreaticopleural fistula and was successfully treated with pancreatic ductal stent placement by means of endoscopic retrograde cholangiopancreatography. PMID- 21673088 TI - Dos should endorse an evidence-based national healthcare policy. PMID- 21673089 TI - One osteopathic physician's path through an ACGME-Accredited Residency. PMID- 21673090 TI - Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors. AB - ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs. PMID- 21673091 TI - Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. AB - The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC(50) values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Kalpha, PI3Kbeta, PI3Kgamma, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling. OSI-027 shows concentration dependent pharmacodynamic effects on phosphorylation of 4E-BP1 and AKT in tumor tissue with resulting tumor growth inhibition. OSI-027 shows robust antitumor activity in several different human xenograft models representing various histologies. Furthermore, in COLO 205 and GEO colon cancer xenograft models, OSI 027 shows superior efficacy compared with rapamycin. Our results further support the important role of mTOR as a driver of tumor growth and establish OSI-027 as a potent anticancer agent. OSI-027 is currently in phase I clinical trials in cancer patients. PMID- 21673092 TI - A pilot clinical study of treatment guided by personalized tumorgrafts in patients with advanced cancer. AB - Patients with many advanced solid cancers have very poor prognosis, and improvements in life expectancy are measured only in months. We have recently reported the remarkable clinical outcome of a patient with advanced, gemcitabine resistant, pancreatic cancer who was later treated with DNA-damaging agents, on the basis of the observation of significant activity of this class of drugs against a personalized tumorgraft generated from the patient's surgically resected tumor. Here, we extend the approach to patients with other advanced cancers. Tumors resected from 14 patients with refractory advanced cancers were propagated in immunodeficient mice and treated with 63 drugs in 232 treatment regimens. An effective treatment regimen in the xenograft model was identified for 12 patients. One patient died before receiving treatment, and the remaining 11 patients received 17 prospectively guided treatments. Fifteen of these treatments resulted in durable partial remissions. In 2 subjects, no effective treatments were found. Overall, there was a remarkable correlation between drug activity in the model and clinical outcome, both in terms of resistance and sensitivity. The data support the use of the personalized tumorgraft model as a powerful investigational platform for therapeutic decision making and to efficiently guide cancer treatment in the clinic. PMID- 21673093 TI - BnHO1, a haem oxygenase-1 gene from Brassica napus, is required for salinity and osmotic stress-induced lateral root formation. AB - In this report, a rapeseed (Brassica napus) haem oxygenase-1 gene BnHO1 was cloned and sequenced. It shared high homology with Arabidopsis HY1 proteins, and encodes a 32.6 kDa protein with a 54-amino-acid transit peptide, predicting the mature protein of 25.1 kDa. The mature BnHO1 expressed in Escherichia coli exhibits haem oxygenase (HO) activity. Furthermore, the application of lower doses of NaCl (10 mM) and polyethylene glycol (PEG) (2%) mimicked the inducible effects of naphthylacetic acid and the HO-1 inducer haemin on the up-regulation of BnHO1 and subsequent lateral root (LR) formation. Contrasting effects were observed when a higher dose of NaCl or PEG was applied. The above inducible and inhibitory responses were blocked significantly when the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX) or haemin was applied, both of which were reversed by the application of carbon monoxide or ZnPPIX, respectively. Moreover, the addition of ZnPPIX at different time points during LR formation indicated that BnHO1 might be involved in the early stages of LR formation. The auxin response factor transcripts and the auxin content in seedling roots were clearly induced by lower doses of salinity or osmotic stress. However, treatment with the inhibitor of polar auxin transport N-1-naphthylphthalamic acid prevented the above inducible responses conferred by lower doses of NaCl and PEG, which were further rescued when the treatments were combined with haemin. Taken together, these results suggested a novel role of the rapeseed HO-1 gene in salinity and osmotic stress-induced LR formation, with a possible interaction with auxin signalling. PMID- 21673095 TI - Functional diversification of the twin-arginine translocation pathway mediates the emergence of novel ecological adaptations. AB - Microorganisms occupy a myriad of ecological niches that show an astonishing diversity. The molecular mechanisms underlying microbes' ecological diversity remain a fundamental conundrum in evolutionary biology. Evidence points to that the secretion of a particular set of proteins mediates microbes' interaction with the environment. Several systems are involved in this secretion, including the Sec secretion system and the Tat pathway. Shifts in the functions of proteins from the secretion systems may condition the set of secreted proteins and can, therefore, mediate adaptations to new ecological niches. In this manuscript, we have investigated processes of functional divergence (FD)-a term used here to refer to the emergence of novel functions by the modification of ancestral ones of Tat pathway proteins using a large set of microbes with different lifestyles. The application of a novel approach to identify FD allowed us to distinguish molecular changes in the three Tat proteins among different groups of archaea and bacteria. We found these changes as well as the composition of secreted proteins to be correlated with differences in microbe's lifestyles. We identified major signatures of FD in halophilic and thermophilic archaea as well as in pathogenic bacteria. The location of amino acids affected by FD in functionally important domains of Tat proteins made it possible to find the link between the molecular changes in Tat, the set of secreted proteins and the environmental features of the microbes. We present evidence that links specific molecular changes in secretion mediating proteins of microbes to their ecological adaptations. PMID- 21673094 TI - A pilot study of bacterial genes with disrupted ORFs reveals a surprising profusion of protein sequence recoding mediated by ribosomal frameshifting and transcriptional realignment. AB - Bacterial genome annotations contain a number of coding sequences (CDSs) that, in spite of reading frame disruptions, encode a single continuous polypeptide. Such disruptions have different origins: sequencing errors, frameshift, or stop codon mutations, as well as instances of utilization of nontriplet decoding. We have extracted over 1,000 CDSs with annotated disruptions and found that about 75% of them can be clustered into 64 groups based on sequence similarity. Analysis of the clusters revealed deep phylogenetic conservation of open reading frame organization as well as the presence of conserved sequence patterns that indicate likely utilization of the nonstandard decoding mechanisms: programmed ribosomal frameshifting (PRF) and programmed transcriptional realignment (PTR). Further enrichment of these clusters with additional homologous nucleotide sequences revealed over 6,000 candidate genes utilizing PRF or PTR. Analysis of the patterns of conservation apparently associated with nontriplet decoding revealed the presence of both previously characterized frameshift-prone sequences and a few novel ones. Since the starting point of our analysis was a set of genes with already annotated disruptions, it is highly plausible that in this study, we have identified only a fraction of all bacterial genes that utilize PRF or PTR. In addition to the identification of a large number of recoded genes, a surprising observation is that nearly half of them are expressed via PTR-a mechanism that, in contrast to PRF, has not yet received substantial attention. PMID- 21673096 TI - Use of sleep care guidelines in a surgical intensive care unit reduces noise levels and improves patient-reported sleep quality. PMID- 21673097 TI - Mechanisms of estradiol-induced insulin secretion by the G protein-coupled estrogen receptor GPR30/GPER in pancreatic beta-cells. AB - Sexual dimorphism and supplementation studies suggest an important role for estrogens in the amelioration of glucose intolerance and diabetes. Because little is known regarding the signaling mechanisms involved in estradiol-mediated insulin secretion, we investigated the role of the G protein-coupled receptor 30, now designated G protein-coupled estrogen receptor (GPER), in activating signal transduction cascades in beta-cells, leading to secretion of insulin. GPER function in estradiol-induced signaling in the pancreatic beta-cell line MIN6 was assessed using small interfering RNA and GPER-selective ligands (G-1 and G15) and in islets isolated from wild-type and GPER knockout mice. GPER is expressed in MIN6 cells, where estradiol and the GPER-selective agonist G-1 mediate calcium mobilization and activation of ERK and phosphatidylinositol 3-kinase. Both estradiol and G-1 induced insulin secretion under low- and high-glucose conditions, which was inhibited by pretreatment with GPER antagonist G15 as well as depletion of GPER by small interfering RNA. Insulin secretion in response to estradiol and G-1 was dependent on epidermal growth factor receptor and ERK activation and further modulated by phosphatidylinositol 3-kinase activity. In islets isolated from wild-type mice, the GPER antagonist G15 inhibited insulin secretion induced by estradiol and G-1, both of which failed to induce insulin secretion in islets obtained from GPER knockout mice. Our results indicate that GPER activation of the epidermal growth factor receptor and ERK in response to estradiol treatment plays a critical role in the secretion of insulin from beta cells. The results of this study suggest that the activation of downstream signaling pathways by the GPER-selective ligand G-1 could represent a novel therapeutic strategy in the treatment of diabetes. PMID- 21673098 TI - Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. AB - Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis. PMID- 21673099 TI - 1,25(OH)2vitamin D3 stimulates myogenic differentiation by inhibiting cell proliferation and modulating the expression of promyogenic growth factors and myostatin in C2C12 skeletal muscle cells. AB - Skeletal muscle wasting is an important public health problem associated with aging, chronic disease, cancer, kidney dialysis, and HIV/AIDS. 1,25 Dihydroxyvitamin D (1,25-D3), the active form of vitamin D, is widely recognized for its regulation of calcium and phosphate homeostasis in relation to bone development and maintenance and for its calcemic effects on target organs, such as intestine, kidney, and parathyroid glands. Emerging evidence has shown that vitamin D administration improves muscle performance and reduces falls in vitamin D-deficient older adults. However, little is known of the underlying mechanism or the role 1,25-D3 plays in promoting myogenic differentiation at the cellular and/or molecular level. In this study, we examined the effect of 1,25-D3 on myoblast cell proliferation, progression, and differentiation into myotubes. C(2)C(12) myoblasts were treated with 1,25-D3 or placebo for 1, 3, 4, 7, and 10 d. Vitamin D receptor expression was analyzed by quantitative RT-PCR, Western blottings and immunofluorescence. Expression of muscle lineage, pro- and antimyogenic, and proliferation markers was assessed by immunocytochemistry, PCR arrays, quantitative RT-PCR, and Western blottings. Addition of 1,25-D3 to C(2)C(12) myoblasts 1) increased expression and nuclear translocation of the vitamin D receptor, 2) decreased cell proliferation, 3) decreased IGF-I expression, and 4) promoted myogenic differentiation by increasing IGF-II and follistatin expression and decreasing the expression of myostatin, the only known negative regulator of muscle mass, without changing growth differentiation factor 11 expression. This study identifies key vitamin D-related molecular pathways for muscle regulation and supports the rationale for vitamin D intervention studies in select muscle disorder conditions. PMID- 21673100 TI - Suppression of AMPK activation via S485 phosphorylation by IGF-I during hyperglycemia is mediated by AKT activation in vascular smooth muscle cells. AB - As a metabolic sensor, the serine/threonine protein kinase AMP-activated protein kinase (AMPK) promotes the adaptation of cells to signals arising from nutrients, hormones, and growth factors. The ability of IGF-I to stimulate protein synthesis is suppressed by AMPK, therefore, these studies were undertaken to determine whether IGF-I modulates AMPK activity. IGF-I dose-dependently suppressed phosphorylation of AMPK T172, and it stimulated AMPK S485 phosphorylation in vascular smooth muscle cells (VSMC). To determine whether stimulation of AMPK S485 phosphorylation was mediating this response, VSMC were transduced with a mutant AMPKalpha (AMPK S485A). Expression of this altered form inhibited the ability of IGF-I to suppress AMPK T172 activation, which resulted in inhibition of IGF-I-stimulated phosphorylation of P70S6 kinase. In contrast, expression of an AMPK S485D mutant resulted in constitutive suppression of AMPK activity and was associated with increased IGF-I-stimulated P70S6K phosphorylation and protein synthesis. The addition of a specific AKT inhibitor or expression of an AKT1 short hairpin RNA inhibited AMPK S485 phosphorylation, and it attenuated the IGF I-induced decrease in AMPK T172 phosphorylation. Exposure to high glucose concentrations suppressed AMPK activity and stimulated S485 phosphorylation, and IGF-I stimulated a further increase in S485 phosphorylation and AMPK T172 suppression. We conclude that AMPK S485 phosphorylation negatively regulates AMPK activity by modulating the T172 phosphorylation response to high glucose and IGF I. IGF-I stimulates S485 phosphorylation through AKT1. The results suggest that AMPK plays an inhibitory role in modulating IGF-I-stimulated protein synthesis and that IGF-I must down-regulate AMPK activity to induce an optimal anabolic response. PMID- 21673101 TI - Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice. AB - The pattern of fetal growth is a major determinant of the subsequent health of the infant. We recently showed in undernourished (UN) mice that fetal growth is maintained until late pregnancy, despite reduced placental weight, through adaptive up-regulation of placental nutrient transfer. Here, we determine the role of the placental-specific transcript of IGF-II (Igf2P0), a major regulator of placental transport capacity in mice, in adapting placental phenotype to UN. We compared the morphological and functional responses of the wild-type (WT) and Igf2P0-deficient placenta in WT mice fed ad libitium or 80% of the ad libitium intake. We observed that deletion of Igf2P0 prevented up-regulation of amino acid transfer normally seen in UN WT placenta. This was associated with a reduction in the proportion of the placenta dedicated to nutrient transport, the labyrinthine zone, and its constituent volume of trophoblast in Igf2P0-deficient placentas exposed to UN on d 16 of pregnancy. Additionally, Igf2P0-deficient placentas failed to up-regulate their expression of the amino acid transporter gene, Slc38a2, and down-regulate phosphoinositide 3-kinase-protein kinase B signaling in response to nutrient restriction on d 19. Furthermore, deleting Igf2P0 altered maternal concentrations of hormones (insulin and corticosterone) and metabolites (glucose) in both nutritional states. Therefore, Igf2P0 plays important roles in adapting placental nutrient transfer capacity during UN, via actions directly on the placenta and/or indirectly through the mother. PMID- 21673102 TI - PWD/PhJ and WSB/EiJ mice are resistant to diet-induced obesity but have abnormal insulin secretion. AB - Recently, novel inbred mouse strains that are genetically distinct from the commonly used models have been developed from wild-caught mice. These wild derived inbred strains have been included in many of the large-scale genomic projects, but their potential as models of altered obesity and diabetes susceptibility has not been assessed. We examined obesity and diabetes-related traits in response to high-fat feeding in two of these strains, PWD/PhJ (PWD) and WSB/EiJ (WSB), in comparison with C57BL/6J (B6). Young PWD mice displayed high fasting insulin levels, although they had normal insulin sensitivity. PWD mice subsequently developed a much milder and delayed-onset obesity compared with B6 mice but became as insulin resistant. PWD mice had a robust first-phase and increased second-phase glucose-stimulated insulin secretion in vivo, rendering them more glucose tolerant. WSB mice were remarkably resistant to diet-induced obesity and maintained very low fasting insulin throughout the study. WSB mice exhibited more rapid glucose clearance in response to an insulin challenge compared with B6 mice, consistent with their low percent body fat. Interestingly, in the absence of a measurable in vivo insulin secretion, glucose tolerance of WSB mice was better than B6 mice, likely due to their enhanced insulin sensitivity. Thus PWD and WSB are two obesity-resistant strains with unique insulin secretion phenotypes. PWD mice are an interesting model that dissociates hyperinsulinemia from obesity and insulin resistance, whereas WSB mice are a model of extraordinary resistance to a high-fat diet. PMID- 21673103 TI - Visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes. AB - Psoriasis patients are frequently associated with metabolic syndromes. Such associations are possibly mediated by adipokines. We investigated the in vitro effects of visfatin (an adipokine) on chemokine expression in human keratinocytes. Normal human keratinocytes were incubated with visfatin, and their chemokine production was analyzed by ELISA and RT-PCR. Visfatin enhanced TNF alpha-induced CXC chemokine ligand (CXCL) 8, CXCL10, and CC chemokine ligand (CCL) 20 secretion and mRNA expression in keratinocytes, although visfatin alone was ineffective. A small interfering RNA against nuclear factor-kappaB (NF kappaB) p65 suppressed the visfatin-induced production of CXCL8, CXCL10, and CCL20 whereas a small interfering RNA against signal transducer and activator of transcription (STAT) 3 suppressed CXCL8 induction. This indicates the involvement of NF-kappaB in CXCL8, CXCL10, and CCL20 induction by visfatin and the involvement of STAT3 in CXCL8 induction. Visfatin alone increased the transcriptional activity and tyrosine phosphorylation of STAT3, which was suppressed by Janus kinase (JAK) 2 inhibitor. Visfatin enhanced basal and TNF alpha-induced NF-kappaB activity and inhibitory kappaB (IkappaB) alpha phosphorylation, which was suppressed by IkappaB kinase inhibitor. Visfatin induced the tyrosine and serine phosphorylation of JAK2 and IkappaB kinase alpha/beta, respectively. Intraperitoneal injection of visfatin elevated mRNA and protein levels of CXCL1, CXCL10, and CCL20 in murine skin. These results suggest that visfatin enhances CXCL8, CXCL10, and CCL20 production in human keratinocytes and homologous chemokine production in murine skin. Visfatin may induce the infiltration of type 1 or type 17 helper T cells or neutrophils to the skin via chemokine induction and thus link metabolic syndromes to psoriasis. PMID- 21673105 TI - Intron cleavage affects processing of alternatively spliced transcripts. AB - We previously showed that the insertion of a hammerhead ribozyme (Rz) in a critical intronic position between the EDA exon and a downstream regulatory element affects alternative splicing. Here we evaluate the effect of other intronic cotranscriptional cleavage events on alternative pre-mRNA processing using different ribozymes (Rz) and Microprocessor target sequences (MTSs). In the context of the fibronectin EDA minigene, intronic MTSs were cleaved very inefficiently and did not affect alternative splicing or the level of mature transcripts. On the contrary, all hammerhead Rz derivatives and hepatitis delta Rz were completely cleaved before a splicing decision and able to affect alternative splicing. Despite the very efficient Rz-mediated cleavage, the levels of mature mRNA were only reduced to ~40%. We show that this effect on mature transcripts occurs regardless of the type and intronic position of Rzs, or changes in alternative splicing and exon definition. Thus, we suggest that intron integrity is not strictly required for splicing but is necessary for efficient pre-mRNA biosynthesis. PMID- 21673104 TI - Minireview: Vitamin D: is there a role in extraskeletal health? AB - In recent years, vitamin D has received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries together with the identification of extraskeletal vitamin D receptor-mediated actions, suggesting unexpected benefits of vitamin D in health and diseases. Although there is increased awareness of the importance of vitamin D, the role of vitamin D in extraskeletal health has been a matter of debate. In this review, we will summarize what is known and indicate the questions that remain and need to be addressed. PMID- 21673106 TI - down-regulation of Kruppel-like factor-4 (KLF4) by microRNA-143/145 is critical for modulation of vascular smooth muscle cell phenotype by transforming growth factor-beta and bone morphogenetic protein 4. AB - In the postnatal vasculature, fully differentiated and quiescent vascular smooth muscle cells (VSMCs) in a "contractile" phenotype are required for the normal regulation of vascular tone. The transforming growth factor-beta (TGF-beta) superfamily of growth factors (TGF-betas and bone morphogenetic proteins (BMPs)) are potent inducers of contractile phenotype and mediate (i) induction of contractile genes, and (ii) inhibition of VSMC growth and migration. Transcription of contractile genes is positively regulated by a regulatory DNA element called a CArG box. The CArG box is activated by the binding of serum response factor and its coactivators, myocardin (Myocd) or Myocd-related transcription factors (MRTFs). Kruppel-like factor-4 (KLF4) is known to inhibit activation of the CArG box. However, the potential role of KLF4 in the contractile activities of TGF-beta or BMP has not been explored. Here, we demonstrate that TGF-beta and BMP4 rapidly down-regulate KLF4 through induction of microRNA-143 (miR-143) and miR-145, which leads to a reduction of KLF4 transcripts and decreased KLF4 protein expression. Inhibition of miR-145 prevents down-regulation of KLF4 and activation of contractile genes by TGF-beta or BMP4, suggesting that modulation of KLF4 is a prerequisite for induction of contractile genes by TGF-beta and BMP4. Interestingly, both TGF-beta and BMP4 activate transcription of the miR-143/145 gene cluster through the CArG box, however, TGF beta mediates this effect through induction of Myocd expression, whereas BMP4 utilizes nuclear translocation of MRTF-A. Thus, this study sheds light on both the similarities and the differences of TGF-beta and BMP4 signaling in the regulation of KLF4 and contractile genes. PMID- 21673107 TI - Alboserpin, a factor Xa inhibitor from the mosquito vector of yellow fever, binds heparin and membrane phospholipids and exhibits antithrombotic activity. AB - The molecular mechanism of factor Xa (FXa) inhibition by Alboserpin, the major salivary gland anticoagulant from the mosquito and yellow fever vector Aedes albopictus, has been characterized. cDNA of Alboserpin predicts a 45-kDa protein that belongs to the serpin family of protease inhibitors. Recombinant Alboserpin displays stoichiometric, competitive, reversible and tight binding to FXa (picomolar range). Binding is highly specific and is not detectable for FX, catalytic site-blocked FXa, thrombin, and 12 other enzymes. Alboserpin displays high affinity binding to heparin (K(D) ~ 20 nM), but no change in FXa inhibition was observed in the presence of the cofactor, implying that bridging mechanisms did not take place. Notably, Alboserpin was also found to interact with phosphatidylcholine and phosphatidylethanolamine but not with phosphatidylserine. Further, annexin V (in the absence of Ca(2+)) or heparin outcompetes Alboserpin for binding to phospholipid vesicles, suggesting a common binding site. Consistent with its activity, Alboserpin blocks prothrombinase activity and increases both prothrombin time and activated partial thromboplastin time in vitro or ex vivo. Furthermore, Alboserpin prevents thrombus formation provoked by ferric chloride injury of the carotid artery and increases bleeding in a dose dependent manner. Alboserpin emerges as an atypical serpin that targets FXa and displays unique phospholipid specificity. It conceivably uses heparin and phosphatidylcholine/phosphatidylethanolamine as anchors to increase protein localization and effective concentration at sites of injury, cell activation, or inflammation. PMID- 21673108 TI - Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist. AB - The Epstein-Barr virus-induced receptor 2 (EBI2) is a constitutively active seven transmembrane receptor, which was recently shown to orchestrate the positioning of B cells in the follicle. To date, no ligands, endogenously or synthetic, have been identified that modulate EBI2 activity. Here we describe an inverse agonist, GSK682753A, which selectively inhibited the constitutive activity of EBI2 with high potency and efficacy. In cAMP-response element-binding protein-based reporter and guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding assays, the potency of this compound was 2.6-53.6 nm, and its inhibitory efficacy was 75%. In addition, we show that EBI2 constitutively activated extracellular signal regulated kinase (ERK) in a pertussis toxin-insensitive manner. Intriguingly, GSK682753A inhibited ERK phosphorylation, GTPgammaS binding, and cAMP-response element-binding protein activation with similar potency. Overexpression of EBI2 profoundly potentiated antibody-stimulated ex vivo proliferation of murine B cells compared with WT cells, whereas this was equivalently reduced for EBI2 deficient B cells. Inhibition of EBI2 constitutive activity suppressed the proliferation in all cases. Importantly, the suppression was of much higher potency (32-fold) in WT or EBI2-overexpressing B cells compared with EBI2 deficient counterparts. Finally, we screened GSK682753A against an EBI2 mutant library to determine putative molecular binding determinants in EBI2. We identified Phe(111) at position III:08/3.32 as being crucial for GSK682753A inverse agonism because Ala substitution resulted in a >500-fold decrease in IC(50). In conclusion, we present the first ligand targeting EBI2. In turn, this molecule provides a useful tool for further characterization of EBI2 as well as serving as a potent lead compound. PMID- 21673109 TI - BCL-2 modifying factor (BMF) is a central regulator of anoikis in human intestinal epithelial cells. AB - BCL-2 modifying factor (BMF) is a sentinel considered to register damage at the cytoskeleton and to convey a death signal to B-cell lymphoma 2. B-cell lymphoma 2 is neutralized by BMF and thereby facilitates cytochrome C release from mitochondria. We investigated the role of BMF for intestinal epithelial cell (IEC) homeostasis. Acute colitis was induced in Bmf-deficient mice (Bmf(-/-)) with dextran sulfate sodium. Colonic crypt length in Bmf(-/-) mice was significantly increased as compared with WT mice. Dextran sulfate sodium induced less signs of colitis in Bmf(-/-) mice, as weight loss was reduced compared with the WT. Primary human IEC exhibited increased BMF in the extrusion zone. Quantitative PCR showed a significant up-regulation of BMF expression after initiation of anoikis in primary human IEC. BMF was found on mitochondria during anoikis, as demonstrated by Western blot analysis. RNAi mediated knockdown of BMF reduced the number of apoptotic cells and led to reduced caspase 3 activity. A significant increase in phospho-AKT was determined after RNAi treatment. BMF knockdown supports survival of IEC. BMF is induced in human IEC by the loss of cell attachment and is likely to play an important role in the regulation of IEC survival. PMID- 21673110 TI - Rrn7 protein, an RNA polymerase I transcription factor, is required for RNA polymerase II-dependent transcription directed by core promoters with a HomolD box sequence. AB - The region in promoters that specifies the transcription machinery is called the core promoter, displaying core promoter elements (CPE) necessary for establishment of a preinitiation complex and the initiation of transcription. A classical CPE is the TATA box. In fission yeast, Schizosaccharomyces pombe, a new CPE, called HomolD box, was discovered. Collectively, 141 ribosomal protein genes encoding the full set of 79 different ribosomal proteins and more than 60 other housekeeping genes display a HomolD box in the core promoter. Here, we show that transcription directed by the HomolD box requires the RNA polymerase II machinery, including the general transcription factors. Most intriguingly, however, we identify, by DNA affinity purification, Rrn7 as the protein binding to the HomolD box. Rrn7 is an evolutionary conserved member of the RNA polymerase I machinery involved in transcription initiation of core ribosomal DNA promoters. ChIP shows that Rrn7 cross-links to a ribosomal protein gene promoter containing the HomolD box but not to a promoter containing a TATA box. Taken together, our results suggest that Rrn7 is an excellent candidate to be involved in the coordination of ribosomal DNA and ribosomal gene transcription during ribosome synthesis and, therefore, offer a new perspective to study conservation and evolvability of regulatory networks in eukaryotes. PMID- 21673111 TI - N-terminal residues of the Vibrio cholerae virulence regulatory protein ToxT involved in dimerization and modulation by fatty acids. AB - The regulatory protein ToxT is an AraC family protein that is responsible for activating transcription of the genes encoding cholera toxin and toxin coregulated pilus, which are required for virulence by the human pathogen Vibrio cholerae. The N terminus of ToxT contains dimerization and regulatory elements, whereas the C terminus contains the DNA binding domain. Bile and long chain fatty acids negatively regulate ToxT activity. Utilizing a comprehensive alanine substitution mutant library of ToxT, 19 N-terminal residues were found to be critical for dimerization and transcriptional activation. One of these mutant proteins (F151A) was confirmed to be monomeric via centrifugation and exhibited a weakened ability to bind to the tcpA promoter in a gel mobility shift assay. Moreover, a V. cholerae toxTF151A mutant failed to colonize the infant mouse intestine, emphasizing the importance of ToxT N-terminal dimerization to cholera pathogenesis. Six N-terminal alanine substitutions allowed ToxT transcriptional activity in the presence of inhibitory concentrations of bile, palmitoleic acid, and the small molecule inhibitor virstatin. Two of these mutations (N106A and L114A) enhance N-terminal dimerization in a bacterial two-hybrid system reconstituted in V. cholerae, which is otherwise disrupted by bile, palmitoleic acid, and virstatin. We demonstrate that V. cholerae toxTN106A and toxTL114A strains colonize the infant mouse intestine at significantly higher levels than the wild type strain. Our results demonstrate that ToxT N-terminal dimerization is required for transcriptional activation and cholera pathogenesis and that fatty acids modulate ToxT activity via modulation of dimerization. PMID- 21673112 TI - Homologous elements hs3a and hs3b in the 3' regulatory region of the murine immunoglobulin heavy chain (Igh) locus are both dispensable for class-switch recombination. AB - Immunoglobulin heavy chain (IgH) genes are formed, tested, and modified to yield diverse, specific, and high affinity antibody responses to antigen. The processes involved must be regulated, however, to avoid unintended damage to chromosomes. The 3' regulatory region of the Igh locus plays a major role in regulating class switch recombination (CSR), the process by which antibody effector functions are modified during an immune response. Loss of all known enhancer-like elements in this region dramatically impairs CSR, but individual element deletions have no effect on this process. In the present study, we explored the hypothesis that an underlying functional redundancy in the homologous elements hs3a and hs3b was masking the importance of either element to CSR. Several transgenic mouse lines were generated, each carrying a bacterial artificial chromosome transgene that mimicked Igh locus structure but in which hs3a was missing and hs3b was flanked by loxP sites. Matings to Cyclization Recombination Enzyme-expressing mice established "pairs" of lines that differed only in the presence or absence of hs3b. Remarkably, CSR remained robust in the absence of both hs3a and hs3b, suggesting that the remaining two elements of the 3' regulatory region, hs1.2 and hs4, although individually dispensable for CSR, are, together, sufficient to support CSR. PMID- 21673113 TI - Deciphering the role of histidine 252 in mycobacterial adenosine 5' phosphosulfate (APS) reductase catalysis. AB - Mycobacterium tuberculosis adenosine 5'-phosphosulfate reductase (APR) catalyzes the first committed step in sulfate reduction for the biosynthesis of cysteine and is essential for survival in the latent phase of tuberculosis infection. The reaction catalyzed by APR involves the nucleophilic attack by conserved Cys-249 on adenosine 5'-phosphosulfate, resulting in a covalent S-sulfocysteine intermediate that is reduced in subsequent steps by thioredoxin to yield the sulfite product. Cys-249 resides on a mobile active site lid at the C terminus, within a K(R/T)ECG(L/I)H motif. Owing to its strict conservation among sulfonucleotide reductases and its proximity to the active site cysteine, it has been suggested that His-252 plays a key role in APR catalysis, specifically as a general base to deprotonate Cys-249. Using site-directed mutagenesis, we have changed His-252 to an alanine residue and analyzed the effect of this mutation on the kinetic parameters, pH rate profile, and ionization of Cys-249 of APR. Interestingly, our data demonstrate that His-252 does not perturb the pK(a) of Cys-249 or play a direct role in rate-limiting chemical steps of the reaction. Rather, we show that His-252 enhances substrate affinity via interaction with the alpha-phosphate and the endocyclic ribose oxygen. These findings were further supported by isothermal titration calorimetry to provide a thermodynamic profile of ligand-protein interactions. From an applied standpoint, our study suggests that small-molecules targeting residues in the dynamic C-terminal segment, particularly His-252, may lead to inhibitors with improved binding affinity. PMID- 21673114 TI - Combinatorial regulation of photoreceptor differentiation factor, neural retina leucine zipper gene NRL, revealed by in vivo promoter analysis. AB - Development and homeostasis require stringent spatiotemporal control of gene expression patterns that are established, to a large extent, by combinatorial action of transcription regulatory proteins. The bZIP transcription factor NRL (neural retina leucine zipper) is critical for rod versus cone photoreceptor cell fate choice during retinal development and acts as a molecular switch to produce rods from postmitotic precursors. Loss of Nrl in mouse leads to a cone-only retina, whereas ectopic expression of Nrl in photoreceptor precursors generates rods. To decipher the transcriptional regulatory mechanisms upstream of Nrl, we identified putative cis-control elements in the Nrl promoter/enhancer region by examining cross-species sequence conservation. Using in vivo transfection of promoter-reporter constructs into the mouse retina, we show that a 0.9-kb sequence upstream of the Nrl transcription initiation site is sufficient to drive reporter gene expression in photoreceptors. We further define a 0.3-kb sequence including a proximal promoter (cluster A1) and an enhancer (cluster B) that can direct rod-specific expression in vivo. Electrophoretic mobility shift assays using mouse retinal nuclear extracts, in combination with specific antibodies, demonstrate the binding of retinoid-related orphan nuclear receptor beta (RORbeta), cone rod homeobox, orthodenticle homolog 2, and cyclic AMP response element-binding protein to predicted consensus elements within clusters A and B. Our studies demonstrate Nrl as a direct transcriptional target of RORbeta and suggest that combinatorial action of multiple regulatory factors modulates the expression of Nrl in developing and mature retina. PMID- 21673115 TI - Shaping strategic change: making change in large organizations. PMID- 21673116 TI - Assuring the safety and effectiveness of new drugs: rigorous phase IV trials randomizing general practices to delayed access to new drugs. AB - Randomized trials are crucial for establishing the effectiveness of new drugs and procedures. However, they are less effective at detecting uncommon but clinically significant side effects. We propose a solution. All UK general practices could be randomized to be allowed to prescribe new licenced drugs earlier or later. This would produce a large pragmatic cluster trial which could enable rare, but harmful, effects to be demonstrated more quickly than the current usual practice of looking for harmful events in observational datasets. Given current computerization of practice records such an approach is feasible and likely to be cost-effective. PMID- 21673117 TI - Moving (realistically) from volume-based to value-based health care payment in the USA: starting with medicare payment policy. AB - Employers and policy-makers in the USA are desperate to slow the rate at which health expenditures grow. Changing how most health care providers are reimbursed will be necessary to achieve this. Although both politically and practically daunting, massive restructuring or replacement of fee-for-service (FFS) reimbursement is what is most required. As the dominant reimbursement model in the USA, FFS payment to individual providers strongly encourages and financially rewards the quantity of care provided, regardless of its quality or necessity. Providing high quality, lower cost care with fewer complications and hospital re admissions can even financial penalize providers. Unfortunately, physicians and other health providers respond rationally to existing financial incentives (translation: they do what they get paid to do and generally try to, or have to, minimize those activities and services for which they are not paid). Altering this reality and fostering the expansion of exemplary delivery models-such as the Mayo Clinic or Geisinger Health System-requires change in how providers behave. And changing behavior often starts with adjusting how providers are paid. Medicare is the programme and payer most capable of using payment reform to catalyze delivery system reform. PMID- 21673118 TI - Ethical decision-making in nursing homes: influence of organizational factors. AB - In this article we report findings from a qualitative study that explored how doctors and nurses in nursing homes describe professional collaboration around dying patients. The study also examined the consequences this can have for the life-prolonging treatment of patients and the care of them and their relatives. Nine doctors and 10 nurses from 10 Norwegian nursing homes were interviewed about their experience of decision-making processes on life-prolonging treatment and care. The findings reveal that the frameworks for the professional collaboration and organization of physicians and nurses prevent patient treatment and care complying with ethical considerations and the law. These conditions have a challenging impact on the care of dying patients and their relatives. PMID- 21673119 TI - Accession to the European Union 2001-2010: a reflection on some of the ethical issues for nursing. AB - Since 2001, the Commission of the European Union has instigated Peer Reviews to help countries preparing to accede to the European Union. Added to this has been the provision of workshops and individual expert inputs. This article recounts the experiences of the author in this process. It focuses on how a single directive has revealed major ethical challenges for nurses, their national associations and state governments as they seek to implement the changes required. In particular a sub-agenda has emerged relating to general education, access to higher education and the position of women in these countries. The ethical challenges include freedom to practice and creation of competent authorities to provide proper oversight of the health care professions. In 2011, the directive is being reviewed and this article offers arguments for its continuation, even in an unreformed state. PMID- 21673120 TI - A critical lens on culture in nursing practice. AB - Increasing evidence demonstrates that the Aboriginal population experience greater health disparities and receive a lower quality of health care services. The Canadian Nurses Association (CNA) code of ethics states that nurses are required to incorporate culture into all domains of their nursing practice and ethical care. The aim of this article is to examine the concepts of cultural competency and cultural safety by way of relational ethics. To address these disparities in health care, cultural competency training programs are being widely advised. Recent research into cultural safety has not only recognized the importance of culture in nursing practice and organizational structures, but also extended the concepts to the culture of the client. In recognizing this diversity, nurses must pay close attention to their relationships with their clients. It is argued that the answers lie in relational ethics, which honors indigenous people's connection to self, others, the environment, and the universe. PMID- 21673121 TI - Case study: Baby John--nursing reflections on moral angst. PMID- 21673122 TI - Optimal cutoff values for high-risk waist circumference in older adults based on related health outcomes. AB - The authors aimed to explore optimal cutoffs for high-risk waist circumference (WC) in older adults to assess the health risks of obesity. Prospective data from 4,996 measurements in 2,232 participants aged >=70 years were collected during 5 triennial measurement cycles (1992/1993-2005/2006) of a population-based cohort study, the Longitudinal Aging Study Amsterdam (Amsterdam, the Netherlands). Cross sectional associations of WC with pain, mobility limitations, incontinence, knee osteoarthritis, cardiovascular disease, and diabetes were studied. Generalized estimating equations models were fitted with restricted cubic spline functions in order to carefully study the shapes of the associations. Model fits for applying different cutoffs to categorize WC in the association with all outcomes were tested using the quasi-likelihood under the Independence Criterion (QIC). On the basis of the spline regression curves, potential WC cutoffs of approximately 109 cm in men and 98 cm in women were proposed. Based on the model fit, cutoffs between 100 cm and 106 cm were equally applicable in men but should not be higher. In women, the QIC confirmed an optimal cutoff of 99 cm. PMID- 21673124 TI - Evaluating the incremental value of new biomarkers with integrated discrimination improvement. AB - The integrated discrimination improvement (IDI) index is a popular tool for evaluating the capacity of a marker to predict a binary outcome of interest. Recent reports have proposed that the IDI is more sensitive than other metrics for identifying useful predictive markers. In this article, the authors use simulated data sets and theoretical analysis to investigate the statistical properties of the IDI. The authors consider the common situation in which a risk model is fitted to a data set with and without the new, candidate predictor(s). Results demonstrate that the published method of estimating the standard error of an IDI estimate tends to underestimate the error. The z test proposed in the literature for IDI-based testing of a new biomarker is not valid, because the null distribution of the test statistic is not standard normal, even in large samples. If a test for the incremental value of a marker is desired, the authors recommend the test based on the model. For investigators who find the IDI to be a useful measure, bootstrap methods may offer a reasonable option for inference when evaluating new predictors, as long as the added predictive capacity is large. PMID- 21673125 TI - Tension pneumomediastinum with subcutaneous emphysema. PMID- 21673123 TI - Aspirin use, body mass index, physical activity, plasma C-peptide, and colon cancer risk in US health professionals. AB - Aspirin use decreases colon cancer risk, but this association may vary among population subgroups. The aspirin-colon cancer association was evaluated according to body mass index and physical activity in 1,701 incident colon cancer cases diagnosed during follow-up of 139,310 participants for up to 26 years in 2 US prospective cohort studies that began in 1980 and 1992, respectively. Whether plasma C-peptide levels modified the association was examined by using a nested case-control design (n = 384 cases, 749 controls). Multiplicative and additive interactions were tested. Body mass index did not modify the association; pooled multivariable relative risks for regular aspirin use versus nonuse ranged from 0.74 to 0.75 in the normal weight and obese groups (test for multiplicative interaction, P = 0.75; test for additive interaction, P = 0.66). Pooled multivariable relative risks for regular aspirin use were 0.86 (95% confidence interval (CI): 0.66, 1.11) in the low and 0.67 (95% CI: 0.58, 0.77) in the high physical activity groups with no interaction evident on either the multiplicative or additive scale (P > 0.10). Plasma C-peptide levels also did not modify the aspirin-colon cancer association, with multivariable relative risks of 0.74 (95% CI: 0.50, 1.10) for the low and 0.65 (95% CI: 0.46, 0.92) for the high group. Reductions in colon cancer risk associated with aspirin use were not significantly modified by body mass index, physical activity, or plasma C-peptide level in this study. PMID- 21673126 TI - Exposure to pesticides and metal contaminants of fertilizer among tree planters. AB - In British Columbia, Canada, harvested forests are manually replanted by seasonal workers. The work is known to be physically demanding and ergonomically difficult, and recently, there have been concerns over chemical exposures due to pesticide residues on seedlings, fertilizers (often applied alongside seedlings), and potential metal contamination of these fertilizers. This study aimed to characterize metal and pesticide exposure among a sample of British Columbia tree planters. Between May 2006 and April 2007, exposure measurements were taken from 54 tree planters at five geographically disperse worksites throughout British Columbia. Four worksites were using fertilizer and one was not. Metal concentrations were measured by inductively coupled plasma mass spectrometry on post-shift hand wipes, full-shift personal air sample, bulk soil, seedling root balls, and fertilizer samples. Pesticides were measured on post-shift hand wipes and on bulk seedling samples. Seedling nursery pesticide application records were used to focus pesticide analyses on pesticides known to have been applied to the seedlings used at the study sites. Carbamate pesticides were analyzed by high performance liquid chromatography/mass spectroscopy and all other pesticides by gas chromatography mass spectrometry. No evidence was found that tree planters who worked with fertilizer were at an elevated risk of exposure to arsenic, lead, cadmium, chromium, and nickel relative to tree planters who did not. Pesticide residues were found on seedlings taken from work sites early in the tree planting season in April 2007. At these worksites, the fungicides chlorothalonil and iprodione were found on the skin of workers at low levels (range 0.37-106.3 ng cm(-2) and 0.48-15.9 ng cm(-2), respectively), providing evidence for exposure potential. Very poor hygiene conditions were observed at all tree planting work sites. Hand washing facilities were not available at work sites and only 5.6% of subjects reported hand washing during the work day, including prior to eating or smoking. Gloves were worn by all subjects but no personal protective equipment programs existed to train workers in the correct use or selection of gloves, and consequentially, many glove choices were inappropriate. The lack of hand washing facilities combined with incorrect glove use could increase the duration of dermal exposure and increase the risk of hand-to-mouth ingestion exposure. PMID- 21673127 TI - A novel biotransformation of alkyl aminopyrrolidine to aminopiperidine ring by human CYP3A. AB - The novel biotransformation of an aminopyrrolidine to an aminopiperidine during the metabolism of 5-(4-chlorophenyl)-3-methyl-2-((2R)-2-(((1 methylethyl)amino)methyl)-1-pyrrolidinyl)-6-(4-pyridinyl)-4(3H)-pyrimidinone (AMG657417) was investigated using the NADPH-fortified S9 fraction from human liver. The major metabolite (M18) had a protonated molecule (MH(+) m/z 438) identical to that of AMG657417 except that it eluted earlier on a reverse-phase high-performance liquid chromatography. The structure of M18 had been identified as 5-(4-chlorophenyl)-3-methyl-2-((1-(1-methylethyl)-3-piperidinyl)amino)-6-(4 pyridinyl)-4(3H)-pyrimidinone (I) by liquid chromatography-mass spectrometry and proton NMR. M18 was not observed when AMG657417 was incubated with either microsomal or cytosolic fraction from human liver, suggesting the involvement of both microsomal and cytosolic enzymes in the biotransformation. The reaction mechanisms have been elucidated by trapping the intermediates formed during the biotransformation. An aldehyde intermediate was initially produced by hydroxylation and opening of the pyrrolidine ring of the parent molecule, followed by intramolecular Schiff-base formation between the exocyclic isopropylamine nitrogen and the aldehyde carbonyl to form a piperidinyl iminium ion. The iminium ion was then reduced to the piperidine product. The presence of the aldehyde intermediate was verified by the formation of semicarbazide conjugates in human liver microsomal, S9, and recombinant CYP3A4 incubations of AMG657417. The presence of the piperidinyl iminium ion intermediate was confirmed by the formation of cyanide conjugates in the incubations in human liver S9. Two cyanide conjugates with identical protonated molecule and product ion mass spectra were observed, indicating the likelihood of diastereomer formation. A chemical inhibition study in NADPH-fortified S9 fraction indicated that the oxidation of AMG657417 was catalyzed almost exclusively by CYP3A. PMID- 21673128 TI - Culture period-dependent changes in the uptake of transporter substrates in sandwich-cultured rat and human hepatocytes. AB - Sandwich-cultured hepatocytes (SCH) are a useful tool for evaluating hepatobiliary drug transport in vitro. Some studies have investigated the in vitro-in vivo correlations of the biliary clearance of drugs using SCH. In most cases, the biliary clearance observed in vivo correlated well with the predicted clearance, but the predicted absolute values were underestimated when based on in vitro experiments with SCH. We hypothesized that the down-regulated function of uptake transporters is one of the causes of this underestimation. Therefore, the uptake of taurocholate, digoxin, pravastatin, and rosuvastatin was investigated in sandwich-cultured rat hepatocytes (SCRH) cultured for 5, 24, 48, and 96 h, and the predicted hepatic clearance from in vitro uptake clearance (CL(H, vitro)) was calculated with a dispersion model. In SCRH cultured for 96 h, the saturable uptake of taurocholate, digoxin, pravastatin, and rosuvastatin decreased to 7.5, 3.3, 64, and 23%, respectively, of their uptake in hepatocytes cultured for 5 h, and a better prediction of in vivo hepatic clearance (CL(H, vivo)) was achieved when based on CL(H, vitro) of 5-h-cultured hepatocytes. These results suggest that the uptake activity is considerably reduced in cell culture, even in a sandwich-culture format. In a similar study, we also examined taurocholate and rosuvastatin in sandwich-cultured human hepatocytes (SCHH). Unlike in SCRH, the saturable uptake of these compounds did not differ markedly in SCHH cultured for 5 or 96 h. Thus, the uptake activity in SCHH was maintained relatively well compared with that in SCRH. PMID- 21673129 TI - Ocular pharmacokinetics of dorzolamide and brinzolamide after single and multiple topical dosing: implications for effects on ocular blood flow. AB - Ophthalmic carbonic anhydrase inhibitors have been shown to improve retinal and optic nerve blood flow. However, the relative tissue distributions of commercially available carbonic anhydrase inhibitors to the optic nerve are not known. The objective of this study was to compare the ocular pharmacokinetics and tissue distribution profiles of dorzolamide and brinzolamide after single and multiple topical applications. Pigmented rabbits were treated with single or multiple topical administrations of 30 MUl of Trusopt (dorzolamide hydrochloride ophthalmic solution, 2%) to one eye and 30 MUl of Azopt (brinzolamide ophthalmic suspension, 1%) to the other eye. Rabbits were euthanized at 10 predetermined time intervals over a period of 24 h, and ocular tissues and plasma samples were collected. For multiple dosing, rabbits were dosed twice per day with an 8-h interval between two doses, groups of rabbits were euthanized at 7, 14, and 21 days at 1 h after the last dose, and ocular tissues and plasma samples were collected. Drug levels in tissue samples were measured using liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters (C(max), T(max), and AUC(0-24)) were estimated by noncompartmental analysis. After a single dose, dorzolamide delivery (AUC(0-24)) to the aqueous humor, anterior sclera, posterior sclera, anterior retina, posterior retina, anterior vitreous, and optic nerve was 2-, 7-, 2.6-, 1.4-, 1.9-, 1.2-, and 9-fold higher than those of brinzolamide. C(max) was 2- to 5-fold higher for dorzolamide than that of brinzolamide in all of the ocular tissue. After multiple dosing, dorzolamide levels in the aqueous humor, sclera, retina, vitreous humor, and optic nerve were higher than those of brinzolamide, but statistical significance was achieved only with aqueous humor, vitreous humor, and optic nerve. Dorzolamide levels in the aqueous humor, anterior vitreous, posterior vitreous, and optic nerve were 1.4- to 3.2-, 2.4- to 2.7-, 2.2- to 4.5-, and 2.4- to 5.2-fold higher than those of brinzolamide. Upon multiple dosing, both drugs accumulated in all of the tissues except the conjunctiva, where the drug levels were lower than those observed with single dosing. No significant differences were found in the AUC values of these two drugs in the cornea and conjunctiva after single and multiple dosing. Drug levels were significantly higher in anterior regions than posterior regions in the sclera, retina, and vitreous for both drugs. PMID- 21673130 TI - Hepatic UDP-glucuronosyltransferase is responsible for eslicarbazepine glucuronidation. AB - Eslicarbazepine acetate (ESL) is a once-daily novel antiepileptic drug approved in Europe for use as adjunctive therapy for refractory partial-onset seizures with or without secondary generalization. Metabolism of ESL consists primarily of hydrolysis to eslicarbazepine, which is then subject to glucuronidation followed by renal excretion. In this study, we have identified that human liver microsomes (HLM) enriched with uridine 5'-diphosphoglucuronic acid give origin to a single Escherichia coli beta-glucuronidase-sensitive eslicarbazepine glucuronide (most likely the O-glucuronide). The kinetics of eslicarbazepine glucuronidation in HLM was investigated in the presence and absence of bovine serum albumin (BSA). The apparent K(m) were 412.2 +/- 63.8 and 349.7 +/- 74.3 MUM in the presence and absence of BSA, respectively. Incubations with recombinant human UDP glucuronosyltransferases (UGTs) indicated that UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17 appear to be involved in eslicarbazepine conjugation. The UGT with the highest affinity for conjugation was UGT2B4 (K(m) = 157.0 +/- 31.2 and 28.7 +/- 10.1 MUM, in the absence and presence of BSA, respectively). There was a significant correlation between eslicarbazepine glucuronidation and trifluoperazine glucuronidation, a typical UGT1A4 substrate; however, no correlation was found with typical substrates for UGT1A1 and UGT1A9. Diclofenac inhibited eslicarbazepine glucuronidation in HLM with an IC(50) value of 17 MUM. In conclusion, glucuronidation of eslicarbazepine results from the contribution of UGT1A4, UGT1A9, UGT2B4, UGT2B7, and UGT2B17, but the high-affinity component of the UGT2B4 isozyme may play a major role at therapeutic plasma concentrations of unbound eslicarbazepine. PMID- 21673131 TI - In vitro characterization of the metabolic pathways and cytochrome P450 inhibition and induction potential of BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor. AB - (3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5 yl)methyl)-3-piperidinol (BMS-690514) is a potent inhibitor of ErbB human epidermal growth factor receptors (HER1, 2, and 4) and vascular endothelial growth factor receptors 1 to 3 that has been under clinical development for solid tumor malignancies. BMS-690514 is primarily cleared by metabolism with the primary metabolic pathways being direct glucuronidation (M6), hydroxylation (M1, M2, and M37), and O-demethylation (M3). In the current investigation, the metabolic drug-drug interaction potential of BMS-690514 was evaluated in a series of in vitro studies. Reaction phenotyping experiments with cDNA-expressed human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes and human liver microsomes (HLM) in the presence of P450 or UGT inhibitors suggested that CYP3A4, CYP2D6, and CYP2C9 were the major enzymes responsible for the oxidative metabolism of BMS-690514, whereas both UGT2B4 and UGT2B7 were responsible for the formation of M6. BMS-690514 did not cause direct or time-dependent inhibition of P450 enzymes (IC(50) values >=40 MUM) in incubations with HLM and probe substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. The compound also did not substantially induce CYP1A1, CYP1A2, CYP2B6, CYP3A4, or UGT1A1 at concentrations up to 10 MUM in cultured human hepatocytes. Considering the submicromolar plasma C(max) concentration at the anticipated clinical dose of 200 mg, BMS-690514 is unlikely to cause clinically relevant drug-drug interactions when coadministered with other medications. In addition, because multiple enzymatic clearance pathways are available for the compound, inhibition of an individual metabolic pathway either via coadministered drugs or gene polymorphisms is not expected to cause pronounced (>2-fold) increases in BMS 690514 exposure. PMID- 21673132 TI - Efficient screening of cytochrome P450 BM3 mutants for their metabolic activity and diversity toward a wide set of drug-like molecules in chemical space. AB - In the present study, the diversity of a library of drug-metabolizing bacterial cytochrome P450 (P450) BM3 mutants was evaluated by a liquid chromatography-mass spectrometry (LC-MS)-based screening method. A strategy was designed to identify a minimal set of BM3 mutants that displays differences in regio- and stereoselectivities and is suitable to metabolize a large fraction of drug chemistry space. We first screened the activities of six structurally diverse BM3 mutants toward a library of 43 marketed drugs (encompassing a wide range of human P450 phenotypes, cLogP values, charges, and molecular weights) using a rapid LC MS method with an automated method development and data-processing system. Significant differences in metabolic activity were found for the mutants tested and based on this drug library screen; nine structurally diverse probe drugs were selected that were subsequently used to study the metabolism of a library of 14 BM3 mutants in more detail. Using this alternative screening strategy, we were able to select a minimal set of BM3 mutants with high metabolic activities and diversity with respect to substrate specificity and regiospecificity that could produce both human relevant and BM3 unique drug metabolites. This panel of four mutants (M02, MT35, MT38, and MT43) was capable of producing P450-mediated metabolites for 41 of the 43 drugs tested while metabolizing 77% of the drugs by more than 20%. We observed this as the first step in our approach to use of bacterial P450 enzymes as general reagents for lead diversification in the drug development process and the biosynthesis of drug(-like) metabolites. PMID- 21673133 TI - Increase in tomato locule number is controlled by two single-nucleotide polymorphisms located near WUSCHEL. AB - In tomato (Solanum lycopersicum) fruit, the number of locules (cavities containing seeds that are derived from carpels) varies from two to up to 10 or more. Locule number affects fruit shape and size and is controlled by several quantitative trait loci (QTLs). The large majority of the phenotypic variation is explained by two of these QTLs, fasciated (fas) and locule number (lc), that interact epistatically with one another. FAS has been cloned, and mutations in the gene are described as key factors leading to the increase in fruit size in modern varieties. Here, we report the map-based cloning of lc. The lc QTL includes a 1,600-bp region that is located 1,080 bp from the 3' end of WUSCHEL, which encodes a homeodomain protein that regulates stem cell fate in plants. The molecular evolution of lc showed a reduction of diversity in cultivated accessions with the exception of two single-nucleotide polymorphisms. These two single-nucleotide polymorphisms were shown to be responsible for the increase in locule number. An evolutionary model of locule number is proposed herein, suggesting that the fas mutation appeared after the mutation in the lc locus to confer the extreme high-locule-number phenotype. PMID- 21673135 TI - Acute non-invasive ventilation in older patients: medical evolution and improvement in survival of the un-fittest. PMID- 21673136 TI - Occurrence of medical co-morbidity in mild cognitive impairment: implications for generalisation of MCI research. AB - BACKGROUND: diagnosis of mild cognitive impairment (MCI) typically excludes individuals with medical co-morbidity. Interest in MCI screening raises the questions of what are the best criteria to identify a representative sample and what factors are associated with MCI progression to dementia. OBJECTIVES: to compare the pattern of disease co-morbidity across different cognitive groups and to examine the role of health co-morbidity as a risk factor for dementia progression from MCI. METHODS: individuals from the MRC Cognitive Function and Ageing Study were classified as having no cognitive impairment (NCI), MCI, other cognitive impairment no dementia (OCIND) or dementia. At 2 years dementia status was assessed. FINDINGS: over 50% of individuals in each group reported one or more medical condition. The pattern of disease prevalence was similar in the NCI, MCI and OCIND groups. Anaemia was the only health factor associated with an increased risk of dementia progression from MCI. CONCLUSION: classification of MCI using medical exclusions would exclude the majority of the population from a MCI diagnosis. This has implications for treatment decisions and clinical trial recruitment. This could not only make recruitment more difficult but also limit the generalisability of trial results. Medical co-morbidity does not help to distinguish progressive from non-progressive MCI. PMID- 21673137 TI - Pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue, is well tolerated when administered as a continuous 7-day subcutaneous infusion in healthy male volunteers. AB - Pasireotide is a novel multireceptor-targeted somatostatin analogue that has shown efficacy in patients with acromegaly and Cushing's disease when administered by subcutaneous (SC) injection. This study assessed the safety, tolerability, and pharmacokinetics (PK) of a continuous infusion of pasireotide in healthy volunteers. In this single-center, open-label, dose escalation study, healthy male volunteers received a 7-day continuous SC infusion of pasireotide in sequential ascending-dose cohorts. Single and/or 8-hour blood samples were taken on days 1 to 10 to assess PK and on days 1, 2, and 7 and a control day to assess glucose metabolism. Adverse events were evaluated throughout. Forty-four participants were enrolled into 8 cohorts: pasireotide 450, 900, 1350, 1800 (3 cohorts were enrolled at this dose level), 2250, and 2025 ug/d. Doses were well tolerated up to 2025 ug/d. Adverse events were generally mild and gastrointestinal. Pasireotide steady-state clearance was reduced at high doses, and plasma concentrations increased disproportionately with increasing dose. Blood glucose levels increased after initiation of pasireotide infusion with attenuation by day 7. Insulin and glucagon levels decreased after pasireotide infusion, with insulin levels exhibiting a greater degree of suppression. Pasireotide has the potential to be administered as a long-acting release formulation, and future studies are warranted. PMID- 21673138 TI - Uterine selection for immunocompetent offspring. PMID- 21673139 TI - Circadian function in cancer: regulating the DNA damage response. PMID- 21673140 TI - Structural basis for recognition of AT-rich DNA by unrelated xenogeneic silencing proteins. AB - H-NS and Lsr2 are nucleoid-associated proteins from Gram-negative bacteria and Mycobacteria, respectively, that play an important role in the silencing of horizontally acquired foreign DNA that is more AT-rich than the resident genome. Despite the fact that Lsr2 and H-NS proteins are dissimilar in sequence and structure, they serve apparently similar functions and can functionally complement one another. The mechanism by which these xenogeneic silencers selectively target AT-rich DNA has been enigmatic. We performed high-resolution protein binding microarray analysis to simultaneously assess the binding preference of H-NS and Lsr2 for all possible 8-base sequences. Concurrently, we performed a detailed structure-function relationship analysis of their C-terminal DNA binding domains by NMR. Unexpectedly, we found that H-NS and Lsr2 use a common DNA binding mechanism where a short loop containing a "Q/RGR" motif selectively interacts with the DNA minor groove, where the highest affinity is for AT-rich sequences that lack A-tracts. Mutations of the Q/RGR motif abolished DNA binding activity. Netropsin, a DNA minor groove-binding molecule effectively outcompeted H-NS and Lsr2 for binding to AT-rich sequences. These results provide a unified molecular mechanism to explain findings related to xenogeneic silencing proteins, including their lack of apparent sequence specificity but preference for AT-rich sequences. Our findings also suggest that structural information contained within the DNA minor groove is deciphered by xenogeneic silencing proteins to distinguish genetic material that is self from nonself. PMID- 21673141 TI - Site-specific acetylation mark on an essential chromatin-remodeling complex promotes resistance to replication stress. AB - Recent work has identified several posttranslational modifications (PTMs) on chromatin-remodeling complexes. Compared with our understanding of histone PTMs, significantly less is known about the functions of PTMs on remodeling complexes, because identification of their specific roles often is hindered by the presence of redundant pathways. Remodels the Structure of Chromatin (RSC) is an essential, multifunctional ATP-dependent chromatin-remodeling enzyme of Saccharomyces cerevisiae that preferentially binds acetylated nucleosomes. RSC is itself acetylated by Gcn5 on lysine 25 (K25) of its Rsc4 subunit, adjacent to two tandem bromodomains. It has been shown that an intramolecular interaction between the acetylation mark and the proximal bromodomain inhibits binding of the second bromodomain to acetylated histone H3 tails. We report here that acetylation does not significantly alter the catalytic activity of RSC or its ability to recognize histone H3-acetylated nucleosomes preferentially in vitro. However, we find that Rsc4 acetylation is crucial for resistance to DNA damage in vivo. Epistatic miniarray profiling of the rsc4-K25R mutant reveals an interaction with mutants in the INO80 complex, a mediator of DNA damage and replication stress tolerance. In the absence of a core INO80 subunit, rsc4-K25R mutants display sensitivity to hydroxyurea and delayed S-phase progression under DNA damage. Thus, Rsc4 helps promote resistance to replication stress, and its single acetylation mark regulates this function. These studies offer an example of acetylation of a chromatin-remodeling enzyme controlling a biological output of the system rather than regulating its core enzymatic properties. PMID- 21673144 TI - Policy brief. PMID- 21673143 TI - Mechanisms linking social ties and support to physical and mental health. AB - Over the past 30 years investigators have called repeatedly for research on the mechanisms through which social relationships and social support improve physical and psychological well-being, both directly and as stress buffers. I describe seven possible mechanisms: social influence/social comparison, social control, role-based purpose and meaning (mattering), self-esteem, sense of control, belonging and companionship, and perceived support availability. Stress-buffering processes also involve these mechanisms. I argue that there are two broad types of support, emotional sustenance and active coping assistance, and two broad categories of supporters, significant others and experientially similar others, who specialize in supplying different types of support to distressed individuals. Emotionally sustaining behaviors and instrumental aid from significant others and empathy, active coping assistance, and role modeling from similar others should be most efficacious in alleviating the physical and emotional impacts of stressors. PMID- 21673145 TI - The urban neighborhood and cognitive functioning in late middle age. AB - This study examines the association of cognitive functioning with urban neighborhood socioeconomic disadvantage and racial/ethnic segregation for a U.S. national sample of persons in late middle age, a time in the life course when cognitive deficits begin to emerge. The key hypothesis is that effects of neighborhood on cognitive functioning are not uniform but are most pronounced among subgroups of the population defined by socioeconomic status and race/ethnicity. Data are from the third wave of the Health and Retirement Survey for the birth cohort of 1931 to 1941, which was 55 to 65 years of age in 1996 (analytic N = 4,525), and the 1990 U.S. Census. Neighborhood socioeconomic disadvantage has an especially large negative impact on cognitive functioning among persons who are themselves poor, an instance of compound disadvantage. These findings have policy implications supporting "upstream" interventions to enhance cognitive functioning, especially among those most adversely affected by neighborhood socioeconomic disadvantage. PMID- 21673146 TI - Disentangling the exposure experience: the roles of community context and report back of environmental exposure data. AB - This article examines participants' responses to receiving their results in a study of household exposure to endocrine disrupting compounds and other pollutants. The authors study how the "exposure experience"-the embodied, personal experience and understanding of chronic exposure to environmental pollutants-is shaped by community context and the report-back process itself. In addition, the authors investigate an activist, collective form of exposure experience. The authors analyze themes of expectations and learning, trust, and action. The findings reveal that while participants interpret scientific results to affirm lay knowledge of urban industrial toxics, they also absorb new information regarding other pollutant sources. By linking the public understanding of science literature to the illness and exposure experience concepts, this study unravels the complex relationship between lay experience and lay understanding of science. It also shows that to support policy development and/or social change, community-based participatory research efforts must attend to participants' understanding of science. PMID- 21673147 TI - Education and racial-ethnic differences in types of exercise in the United States. AB - Epidemiological research typically focuses on the intensity, frequency, or duration of physical activity, without consideration of the socially meaningful dimensions of exercise. The authors use data from the 1998 National Health Interview Survey (N = 17,455) and information on participation in 15 exercise behaviors to examine educational differences in exercise among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. Factor analysis identifies three types of exercise: team sports (e.g., basketball, football), fitness activities (e.g., running, weight lifting), and activities that require the use of specialized facilities (e.g., golf, tennis). Cultural capital and human capital perspectives offer insight into different dimensions of the relationship between education and exercise. Whites disproportionately undertake facility based exercise, blacks tend toward team and fitness activities, and Mexican Americans gravitate toward team sports. Our findings offer insight into the social stratification of health and can aid the design of public health interventions. PMID- 21673148 TI - Using anchoring vignettes to assess group differences in general self-rated health. AB - This article addresses a potentially serious problem with the widely used self rated health (SRH) survey item: that different groups have systematically different ways of using the item's response categories. Analyses based on unadjusted SRH may thus yield misleading results. The authors evaluate anchoring vignettes as a possible solution to this problem. Using vignettes specifically designed to calibrate the SRH item and data from the Wisconsin Longitudinal Study (WLS; N = 2,625), the authors show how demographic and health-related factors, including sex and education, predict differences in rating styles. Such differences, when not adjusted for statistically, may be sufficiently large to lead to mistakes in rank orderings of groups. In the present sample, unadjusted models show that women have better SRH than men, but this difference disappears in models adjusting for women's greater health-optimism. Anchoring vignettes appear a promising tool for improving intergroup comparability of SRH. PMID- 21673149 TI - A disservice to advances in newborn genetic screening: comment on Timmermans and Buchbinder. PMID- 21673151 TI - Sociology's contribution to understanding the consequences of medical innovations. PMID- 21673152 TI - Avian necrotic enteritis: experimental models, host immunity, pathogenesis, risk factors, and vaccine development. AB - The increasing trends of legislative restrictions and voluntary removal of antibiotic growth promoters worldwide has already affected, and will continue to affect, poultry production and animal health. Necrotic enteritis (NE) is being considered among the most important infectious diseases in the current poultry production system globally, with an estimated annual economic loss of more than $2 billion, largely attributable to medical treatments and impaired growth performance. Thus, there is an urgent need to develop rational, alternative, and integrated management strategies not only to control NE, but also to prevent it. In both humans and many warm-blooded animals and birds, NE is caused by Clostridium perfringens, a gram-positive, anaerobic, spore-forming bacterium. To accomplish these goals, better understanding of host- and environmentally related factors on the development of NE and potential vaccination strategies against C. perfringens infection will be necessary. Furthermore, a reliable and reproducible NE disease model is needed for characterization of C. perfringens pathogenesis and host protective immunity. This review summarizes recent developments in NE disease models, pathogenesis, host immunity, risk factors, and vaccine development for C. perfringens-associated NE in poultry. PMID- 21673153 TI - Horizontal transmission of Salmonella enteritidis in groups of experimentally infected laying hens housed in different housing systems. AB - Concerns regarding the welfare of laying hens have led to the ban of conventional battery cages in Europe from 2012 onward and to the development of alternative housing systems that allow hens to perform a broader range of natural behaviors. Limited information is available about the consequences of alternative housing systems on transmission of zoonotic pathogens such as Salmonella Enteritidis. However, Salmonella enterica serovar Enteritidis continues to be one of the leading causes of bacterial foodborne disease worldwide and this is mainly attributed to the consumption of contaminated eggs. A transmission experiment was performed to quantify the effect of the housing system on the spread of a Salmonella Enteritidis infection within a group of layers and on internal egg contamination. At the age of 16 wk, 126 birds housed on the floor were inoculated with Salmonella Enteritidis. Three weeks later, the inoculated hens were housed together with equal numbers of susceptible contact animals in 4 different housing systems: a conventional cage system, a furnished cage, an aviary, and a floor system. Transmission and egg contamination were followed during a 4-wk period. A trend toward increased bird-to-bird transmission was detected in the aviary and floor system compared with the cage systems. Also, significantly more contaminated eggs were found in the aviary compared with the cage systems and the floor system. These results suggest that there is a clear need to optimize and maintain Salmonella surveillance programs when laying hens will be moved from conventional cage systems to alternative housing systems. PMID- 21673154 TI - High litter moisture content suppresses litter ammonia volatilization. AB - With global food demand expected to increase by 100% in the next 50 yr, urgency to combine comprehensive strategies for sustainable, efficacious, and environmentally sensible agronomic practices has never been greater. One effort for US meat bird management is to reduce NH(3) volatilization from litter to create a better growing environment for the birds, improve production efficiency, retain N in litter for fertilizer value, and negate the detrimental environmental impacts of NH(3) loss to the air. To derive the fundamental effects of temperature and moisture on litter NH(3) volatilization over the range of conditions found in commercial houses, experiments were conducted using commercial broiler litter that had moisture contents of approximately 20 to 55% while controlling temperatures ranging from 18.3 to 40.6 degrees C. Litter samples (100 g) were placed in 1-L containers that received humidified air at approximately 113 mL/min. Volatilized NH(3) in exhaust air was captured in H(3)BO(3) traps. Ammonia loss (log(10) transformation) was modeled via an equation using linear coefficients for temperature and moisture, an interaction term for temperature * moisture, and a quadratic term for moisture. The surface responses resembled parabolic cylinders, indicating a critical moisture level at which NH(3) no longer increases but is diminished as moisture continues to increase. The critical moisture level lies between 37.4 and 51.1% litter moisture, depending on the temperature. An increase in temperature consistently increased NH(3) generation. When the temperature extremes were compared, the maximum NH(3) was up to 7 times greater at 40.6 vs. 18.3 degrees C. The upper moisture limit at which NH(3) release is maximized and subsequently arrested as moisture continues to increase had not been defined previously for commercial broiler litter. The poultry industry and researchers can use these results as a decision tool to enable management strategies that limit NH(3) production. PMID- 21673155 TI - Stocking density affects the growth performance of broilers in a sex-dependent fashion. AB - The effects of stocking density, sex, and dietary ME concentration on live performance, footpad burns, and leg weakness of broilers were investigated. A total of 876 male and 1,020 female 1-d-old chicks were placed in 24 pens to simulate final stocking density treatments of 26 kg (LSD; 10 males or 12 females/m(2)) and 42 kg (HSD; 16 males or 18 females/m(2)) of BW/m(2) floor space. Two series of experimental diets with a 150 kcal/kg difference in ME concentration (2,800, 2,900, and 3,000 or 2,950, 3,050, and 3,150 kcal of ME/kg) were compared in a 3-phase feeding program. The HSD treatment significantly decreased BW gain and feed conversion ratio (FCR). The HSD chickens consumed less feed by 35 d of age; thereafter, the reverse was true. Male chickens had significantly higher feed intake (FI), BW gain, and FCR compared with females. A significant interaction was found of stocking density and age for FI, BW gain, and FCR. Compared with LSD treatment, HSD broilers had a higher FI and a lower FCR from 36 to 42 d of age. Stocking density, sex, and age had a significant interaction for BW gain and FCR. Female broilers had worse BW gain and FCR when stocked at high density from 36 to 42 d of age. Stocking density had no significant influence on breast, thigh, or abdominal fat yield. Female broilers had significantly higher breast yield and abdominal fat. Male broilers and HSD treatment had high footpad burn and gait scores. A low ME diet increased footpad burn score but had no effect on gait score. The result indicated that stocking density had a more severe effect on the growth of male broilers before 35 d of age. Female broilers need more space than males at similar BW per square meter near marketing age. The incidence and severity of leg weakness are associated with sex, diet, and stocking density. This result suggests that the deteriorated effect of high stocking density is sex and age dependent. PMID- 21673156 TI - Effect of diatomaceous earth on parasite load, egg production, and egg quality of free-range organic laying hens. AB - The effectiveness of diatomaceous earth (DE) as a treatment against parasites and to increase feed efficiency and egg production of organically raised free-range layer hens was evaluated in 2 breeds of commercial egg layers [Bovan Brown (BB) and Lowmann Brown (LB)] that differ in their resistance to internal parasitic infections. Half the hens of each breed were fed diets supplemented with DE (2%). Their internal parasite loads were assessed by biweekly fecal egg counts (FEC) and by postmortem examination of the gastrointestinal tract. Supplementing DE in diets of LB hens, the more parasite-resistant breed, did not significantly affect their FEC and adult parasite load. However, BB hens treated with dietary DE had significantly lower Capillaria FEC, slightly lower Eimeria FEC, fewer birds infected with Heterakis, and significantly lower Heterakis worm burden than control BB hens. Both BB and LB hens fed the diet containing DE were significantly heavier, laid more eggs, and consumed more feed than hens fed the control diet, but feed efficiency did not differ between the 2 dietary treatments. Additionally, BB hens consuming the DE diet laid larger eggs containing more albumen and yolk than hens consuming the control diet. In a subsequent experiment, the effectiveness of DE to treat a Northern fowl mite (Ornithonyssus sylviarum) infestation was tested. Relative to controls, both breeds of hens that were dusted with DE had reduced number of mites. The results of this study indicate the DE has the potential to be an effective treatment to help control parasites and improve production of organically raised, free-range layer hens. PMID- 21673157 TI - Neonatal feed restriction modulates circulating levels of corticosterone and expression of glucocorticoid receptor and heat shock protein 70 in aged Japanese quail exposed to acute heat stress. AB - This study aimed to determine the effect of neonatal feed restriction on plasma corticosterone concentration (CORT), hippocampal glucocorticoid receptor (GR) expression, and heat shock protein (Hsp) 70 expression in aged male Japanese quail subjected to acute heat stress. Equal numbers of chicks were subjected to either ad libitum feeding (AL) or 60% feed restriction on d 4, 5, and 6 (FR). At 21 (young) and 270 (aged) d of age, birds were exposed to 43 +/- 1 degrees C for 1 h. Blood and hippocampus samples were collected to determine CORT and Hsp 70 and GR expressions before heat stress and following 1 h of heat stress, 1 h of post-heat stress recovery, and 2 h of post-heat stress recovery. With the use of real-time PCR and enzyme immunoassay, we examined the hippocampal expression of GR and Hsp 70 and CORT. The GR expression of the young birds increased following heat stress and remained consistent throughout the period of recovery. Conversely, no significant changes were noted on GR expression of aged birds. Although both young and aged birds had similar CORT before and during heat stress, the latter exhibited greater values following 1 and 2 h of recovery. Within the young group, feeding regimens had no significant effect on Hsp 70 expression. However, neonatal feed restriction improved Hsp 70 expression in aged birds. Neonatal feed restriction, compared with the AL group, resulted in higher CORT on d 21 but the converse was noted on d 270. Neonatal feed restriction appears to set a robust reactive hypothalamo-pituitary-adrenal response allowing the development of adaptive, healthy, and resilient phenotypes in aged quail as measured by a higher hippocampal Hsp 70 expression along with lower CORT. PMID- 21673158 TI - Physiological responses of 3 chicken breeds to acute heat stress. AB - Domestic animals have been modified by selecting individuals exhibiting desirable traits and culling the others. To investigate the alterations introduced by domestication and selective breeding in heat stress response, 2 experiments were conducted using Red Jungle Fowl (RJF), village fowl (VF), and commercial broilers (CB). In experiment 1, RJF, VF, and CB of a common chronological age (30 d old) were exposed to 36 +/- 1 degrees C for 3 h. In experiment 2, RJF, VF, and CB of common BW (930 +/- 15 g) were subjected to similar procedures as in experiment 1. Heat treatment significantly increased body temperature, heterophil:lymphocyte ratio, and plasma corticosterone concentration in CB but not in VF and RJF. In both experiments and irrespective of stage of heat treatment, RJF showed lower heterophil:lymphocyte ratio, higher plasma corticosterone concentration, and higher heat shock protein 70 expression than VF and CB. It can be concluded that selective breeding for phenotypic traits in the domestication process has resulted in alterations in the physiology of CB and concomitantly the ability to withstand high ambient temperature compared with RJF and VF. In other words, domestication and selective breeding are leading to individuals that are more susceptible to stress rather than resistant. It is also apparent that genetic differences in body size and age per se may not determine breed or strain variations in response to heat stress. PMID- 21673159 TI - Sodium alginate oligosaccharides from brown algae inhibit Salmonella Enteritidis colonization in broiler chickens. AB - The effects of sodium alginate oligosaccharides (sAO) on growth performance, cecal microbiota, Salmonella translocation to internal organs, and mucosal immune responses to challenge with Salmonella enterica serovar Enteritidis in broiler chickens were investigated. We designed an experiment with a 2 * 3 factorial arrangement, in which 3 feed treatments with supplementation of sAO at 0 (controls), 0.04, or 0.2% were provided in the diet for birds not challenged or challenged with Salmonella Enteritidis. There were 5 randomly placed replicate pens for each treatment. At 8 to 12 d of age, one-half the poults were orally gavaged with 10(8) cfu of Salmonella Enteritidis and the nonchallenged groups were inoculated with sterile PBS. Body weight loss and mortality resulting from Salmonella infection were mitigated by the addition of sAO. Supplementation of sAO at 0.2% was the most effective concentration for reducing Salmonella colonization and increasing the number of lactic acid bacteria in the cecum of chickens challenged with Salmonella Enteritidis. Cecal Salmonella Enteritidis specific IgA production was significantly increased by sAO at 0.2% at 5 d postchallenge compared with the other treatments and was maintained at higher levels at the 2 dosages of sAO at 10 d postchallenge. With Salmonella Enteritidis challenge, sAO at 0.04% showed an anti-inflammatory effect through upregulation of interleukin (IL)-10 expression in the cecal tonsils. The supplementation level of 0.2% showed dramatic immunostimulatory activity by inducing interferon-gamma, IL-10, and IL-1beta mRNA expression in cecal tonsils of nonchallenged birds. However, the high level of sAO induced a robust mucosal immune response in the absence of a challenge, and this may have led to a decline in BW. These findings suggest that dietary sAO can decrease Salmonella colonization and improve intestinal barrier function and performance of chickens. PMID- 21673160 TI - Characterization of the low-pathogenic H5N1 avian influenza virus in South Korea. AB - The low-pathogenic avian influenza (LPAI) virus can serve as a progenitor of the highly pathogenic avian influenza virus, so it is important to monitor the LPAI virus as well as the highly pathogenic avian influenza virus. The Korean LPAI H5N1 virus, A/wild duck/Kr/CSM4-12/09 (H5N1) [Wd/CSM4-12/09], was first isolated from feces of the wild duck in South Korea. Genetic analysis showed that 7 genes of Wd/CSM 4-12/09 clustered in eastern Asia and that the neuraminidase (NA) gene of this isolate was closely related to European LPAI viruses. The Korean LPAI H5N1 virus has the highest similarity with the Japanese LPAI H5N1 virus, A/mallard/Hokkaido/24/09 (H5N1), in 6 genes [polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), polymerase acidic protein (PA), hemagglutinin (HA), NA, and nonstructural (NS) genes]. The Korean LPAI H5N1 virus did not replicate in experimentally infected chickens, whereas it replicated in ducks and mice without preadaptation. This study shows that the first Korean LPAI H5N1 reassortment, which occurred between influenza viruses from wild migratory birds in Eurasia, has contributed to the increased diversity of the viral gene pool in eastern Asia; this has the potential to change the host range and to allow the virus to evolve into forms with increased pathogenicity. PMID- 21673161 TI - Influence of different rearing systems on natural immune parameters in broiler turkeys. AB - The aim of this study was to determine serological values of lysozyme, hemolytic complement levels (alternative pathway), and bactericidal activity of serum in turkeys kept in different rearing systems (industrial, backyard, and experimental). Results showed that the values for serum bactericidal activity and hemolytic complement levels increased with age, and their values were higher in experimental and in industrial turkeys than in turkeys reared in backyard. Lysozyme concentration showed a similar pattern; its value was higher in the industrial and experimental groups than in the backyard group. Data obtained suggest that rearing system can have an influence on the natural immune parameters considered; experimental and industrial groups showed a similar trend, differentiated from that observed in the backyard group. In the backyard group, the values observed may suggest that hybrid turkeys, selected for high production, have difficulty with being reared outside where predators (foxes and weasels) and weather conditions could be responsible for a stress situation. PMID- 21673162 TI - Effect of in ovo feeding and its interaction with timing of first feed on glycogen reserves, muscle growth, and body weight. AB - Chicks are commonly fasted for the first 36 to 72 h posthatch because of the logistics of commercial production. Fasting for 48 to 72 h posthatch results in retarded BW, delayed intestinal development, and lower pectoral muscle weight. This study is focused on the first 36 h of fasting and its interaction with feeding before hatch. Four treatment groups, differing in time of first feed, 6 h [early feeding (EF)] or 36 h [standard feeding procedure (SP)] posthatch, with or without in ovo feeding (IOF) with dextrin and beta-hydroxy-beta-methylbutyrate calcium salt in a saline solution, were examined for glycogen status in the liver and pectoral muscle, myogenic cell proliferation, and myofiber diameter in embryos and chickens on various days posthatch. In addition, chicken BW, ADG, pectoral muscle weight, and pectoral muscle percentage of BW until 35 d of age were recorded. Results showed that delaying the first feed for 36 h posthatch (SP group) led to an irreversibly reduced growth rate compared with the EF group. However, IOF affected the growth of chickens in the SP group, whereas the control embryos had depleted glycogen reserves in the liver; IOF-treated embryos had elevated hepatic glycogen contents on embryonic day (E) 19, E20, and the day of hatch. In addition, on d 2 posthatch, although hatchlings in the SP group showed the predicted low levels of glycogen in their livers, birds in the EF group exhibited more than 30-fold and 3-fold increases in liver and muscle glycogen, respectively. In ovo-fed birds in the SP group also exhibited higher glycogen reserves, BW, pectoral muscle weight, and BW gain than control birds in the SP group. In ovo feeding had an immediate effect on promoting myoblast proliferation on E19, whereas on d 3 posthatch, the effect was pronounced only in the EF groups. On d 5, although myoblast proliferation in all groups declined, it remained higher in both IOF groups. These effects were expressed on d 3 and 35 by myofiber diameter. Together, IOF had a long-term supportive effect on BW and posthatch muscle growth when first feed was delayed by 36 h. PMID- 21673163 TI - Evaluation of different vitamin E recommendations and bioactivity of alpha tocopherol isomers in broiler nutrition by measuring oxidative stress in vivo and the oxidative stability of meat. AB - The aim of this study was to compare recommendations for vitamin E supplementation regarding high polyunsaturated fatty acid intake and to compare the bioactivity of RRR- and all-rac-alpha-tocopherol with respect to oxidative stress in vivo and the oxidative stability of broiler meat. Fifty male broilers were divided into 5 groups. All groups received diets with a high inclusion of fat (7.5%), one with palm fat and the others with linseed oil, which were either unsupplemented or supplemented with vitamin E to contain in total 85 or 200 IU of vitamin E as all-rac-alpha-tocopherol and 85 IU as RRR-alpha-tocopherol. Oxidative stress in vivo was studied by measuring the DNA damage; measuring malondialdehyde (MDA) in plasma, liver, and breast muscle; and analyzing the antioxidant capacity of the lipid-soluble compounds, total antioxidant status of plasma, and antioxidant enzyme assays. The tocopherols in plasma, liver, and breast muscle were also analyzed. In vitro oxidative stability was studied by measuring MDA in fresh, stored, and heat-treated breast meat. Linseed oil, as opposed to palm fat, induced DNA fragmentation and MDA formation. Both forms and concentrations of vitamin E reduced DNA damage and breast muscle MDA. The groups receiving 200 IU of all-rac-alpha-tocopherol and 85 IU of RRR-alpha-tocopherol had much higher values for antioxidant capacity of lipid-soluble compounds than did the controls. No differences were observed in the values of antioxidant enzymes. The alpha-tocopherol levels in tissues and plasma were significantly influenced by the level of alpha-tocopherol supplementation. Malondialdehyde formation in meat from the vitamin E-supplemented groups was decreased in comparison with that from the control linseed oil group. We conclude that both vitamin E concentrations were insufficient to prevent all harmful effects of lipid oxidation in vivo and that both were equally effective. On the contrary, to ensure good stability of meat lipids, higher vitamin E supplementation is needed, especially after heat treatment. The results of in vivo oxidative stress and meat lipid oxidation confirmed the currently accepted bioactivity of the RRR-alpha- to all-rac-alpha-tocopherol ratio of 1.39 in in vivo and in vitro systems. PMID- 21673164 TI - Structural and functional analyses of chicken liver ferritin. AB - Characterization of ferritins from different species has provided insight into iron regulation mechanisms and evolutionary relationships. Here, we examined chicken liver ferritin, which comprises only H subunit and has 14.8 ug of Fe/100 ug of protein. The chicken H subunit apo homopolymer showed the same iron uptake rate as bovine H subunit homopolymer expressed with a baculovirus expression system (0.31 and 0.28 mmol of Fe/min per micromole of protein for chicken and bovine H subunit, respectively). Chicken H subunit apo homopolymer showed a significantly higher biotinylated hemin-binding activity than liver holoferritin. Although bovine spleen apoferritin, which has an L (liver or light):H (heart or heavy) subunit ratio of 1:1, also shows a significantly higher biotinylated hemin binding activity than its holoferritin, these biotinylated hemin-binding activities were markedly lower than those of both chicken holo- and apoferritins. Binding of chicken holo- and apoferritin with biotinylated hemin was strongly inhibited by hemin but not iron-free hemin, protoporphyrin IX, or Zn protoporphyrin. These findings demonstrate that chicken ferritin comprises only an H subunit, possesses ferroxidase activity as in mammalian ferritin H subunits, and binds heme more strongly than mammalian ferritins. PMID- 21673165 TI - Estimating digestible methionine requirements for laying hens using multivariate nonlinear mixed effect models. AB - The purpose of this paper was to develop a unified framework for analyzing dose response data in farm animals and apply it to meta-analysis of digestible Met requirement studies in laying hens. A database containing Met dose-response data from 23 trials originating from 15 peer-reviewed publications was constructed. A multivariate nonlinear mixed effects model was chosen as the statistical framework to model egg mass (g/d) and feed utilization (%) responses simultaneously. The framework accounted for responses being correlated in both the random effects and the errors, which provided a superior fit to data compared with modeling these separately. The framework was implemented in the NLMIXED procedure in SAS and could accommodate different dose-response functions per response. Three different dose-response functions-the linear broken line, quadratic plateau, and monomolecular functions-were used to identify the best performing function. The statistical model, which used the quadratic plateau as the functional base for both responses, provided the best fit to data; hence, it was used for biological inference. Effects of secondary covariates of nutritional, genetic, and experimental design origin were investigated, and a systematic trend across studies was detected. The BW of the hens accounted for the majority of the between-study variability by allowing the asymptotic responses to be dependent on the BW. The final estimate of the Met requirement for maximizing egg mass was 356 (SE = 6.1) mg/d, whereas the corresponding Met requirement for maximizing feed utilization was significantly higher (P < 0.001), at 390 (SE = 11) mg/d. Thus, it can be concluded that the biological requirement for digestible Met is at least 356 mg/d. When multiple responses are collected in dose-response studies, these should preferably be analyzed simultaneously because the requirements are established within the same statistical model that accounts for correlation among the errors and among the random effects associated with distinct responses in the model. PMID- 21673166 TI - Protein utilization and amino acid digestibility of canola meal in response to phytase in broiler chickens. AB - The regression method was used in a 14-d broiler chicken study to determine the true ileal digestibility of amino acid (AA) and protein utilization in canola meal (CM, 388 g of CP/kg) without or with added phytase. Experimental treatments consisted of 2 factors, phytase at 2 levels (0 or 1,500 phytase units/kg) and CM at 3 levels (125, 250, or 375 g/kg). Birds received a standard starter diet from d 1 to 8 and the assay diets from d 8 to 22 posthatch. On d 8, a total of 384 birds were allocated to 6 dietary treatments in a randomized complete block design; excreta were collected from d 12 to 14 and d 19 to 21, and ileal digesta were collected on d 22 posthatch. True ileal indispensable AA digestibility of CM were derived from the regression of AA flow (mg/kg of DM intake) at the terminal ileum against the intake of AA (mg/kg of dietary DM) of birds fed diets without or with phytase. Body weight gain (BWG), protein gain, and protein intake increased linearly (P < 0.001) with increasing CM level, regardless of phytase supplementation. Effects of phytase (P < 0.05) were observed on BWG and the protein efficiency ratio from d 8 to 15, whereas effects of phytase (P < 0.05) were observed on BWG and protein gain from d 15 to 22. There was no effect of phytase on protein intake and net protein utilization from d 8 to 22. Phytase supplementation at 1,500 phytase units/kg did not affect true ileal digestibility of any AA in CM. In conclusion, the results of this study indicated that phytase supplementation improved the protein efficiency ratio of birds fed diets containing CM as the sole protein source from d 8 to 15 posthatch but did not affect the true ileal digestibility of AA in CM as determined by the regression method. PMID- 21673168 TI - Content and uptake of minerals in the yolk of broiler embryos during incubation and effect of nutrient enrichment. AB - Although embryo and chicken growth and development rely on mineral nutrition, information on mineral levels in the egg compartments during incubation is limited. Accordingly, we examined P, Ca, Fe, Zn, Cu, and Mn levels in the yolk of breeder eggs during incubation and the effect of embryonic mineral (with specific nutrients) enrichment on yolk mineral levels and consumption. First, fertile eggs were examined on day of setting (DOS), embryonic day (E) 11, E13, E15, E17, E19, E20, and day of hatch (DOH) for the mineral content in the yolk (and albumen on DOS) by inductively coupled plasma atomic emission spectroscopy. Results showed that on DOS, the yolk is the major origin for Mn, P, Fe, Ca, Cu, and Zn. Interestingly, P, Fe, Zn, Cu, and Mn were mostly consumed from the yolk until E17, after which their consumption was very low. Consumption of P was constant until E17 and then decreased until E20. Consumption of Fe, Zn, Cu, and Mn was medium to mild until E11, increased between E11 and E17, and minimal between E17 and DOH. Enrichment treatment, where fertile eggs were divided into 2 groups [nonenriched (control) and enriched (with minerals, vitamins, and carbohydrates on E17 using the in ovo feeding method)] showed that the enriched group had higher Fe, Zn, Cu, and Mn levels than the nonenriched group and exhibited higher consumption of Fe, Zn, and Mn between E20 and DOH. Analysis of the shell mineral composition along incubation showed that the shell released low amounts of P, Fe, and Mn in comparison with the yolk mineral content. Therefore, we concluded that the shell is a minor source of these minerals. Studying the mineral resources and consumption of embryos can lead to a better understanding of the mineral limitations of embryos during incubation. Additionally, because minerals are important for the development of the embryo, the higher mineral levels and consumption observed in the enriched group may affect the development of critical organs, such as the skeletal system. PMID- 21673167 TI - Influence of canthaxanthin on broiler breeder reproduction, chick quality, and performance. AB - To investigate the effect of canthaxanthin supplied via a maternal route on the production of both breeder hens and chickens, 270 Chinese Three-Yellow breeder hens were randomly divided into 2 groups consisting of 135 birds each (5 replicates of 27) for study. The breeder hens were fed either a basal diet or the basal diet supplemented with 6 mg of canthaxanthin/kg for 24 wk. At the end of the 24-wk breeder experiment, all hatching eggs laid in 5 consecutive days of each group were collected and incubated. For each breeder group, 100 newly hatched chicks (5 replicates of 20) were reared under environmentally controlled conditions for 21 d. Canthaxanthin supplementation resulted in the following outcomes: an enhancement of the serum total antioxidant capacity (TAC) of breeder hens (P = 0.029), a significant increase in the yolk colorimetric score of Roche Yolk Color Fan (RYCF; P < 0.001), and a significant improvement of the antioxidant status of the egg yolk (P < 0.05). The chicks that hatched from eggs laid by breeder hens fed the canthaxanthin supplementation diet demonstrated a higher pigmentation colorimetric score of RYCF for their shank skin (P < 0.05), and the antioxidant capacity of the newly hatched chicks was significantly increased (P < 0.05). Both of these positive effects on shank skin pigmentation colorimetric score of RYCF and antioxidant capacity were observed for at least 7 d posthatching, and the chicks that hatched from canthaxanthin-enriched eggs showed a lower mortality (0 vs. 4%) during the first 21 d posthatching. These findings support the hypothesis that canthaxanthin supplementation of the maternal diet enhances the protective capacity of tissues against oxidative stress in vivo, which might be beneficial for poultry producers. PMID- 21673169 TI - Effect of the antibiotic avilamycin on the structure of the microbial community in the jejunal intestinal tract of broiler chickens. AB - This study was conducted to determine whether avilamycin, which is used as a growth promoter in broiler chickens, would affect the structure of the bacterial community within the jejunal intestinal tract. Sixty chickens were assigned to 2 groups: a control group and an avilamycin-treated group. The jejunal tissue from 4 chicks randomly sampled on d 1, 3, 7, 21, and 42 from each treatment group were investigated for changes in villus height, total mesophilic bacteria, lactic acid bacteria, and the structure of the microbial community using PCR-denaturant gradient gel electrophoresis. Supplementation with avilamycin had no effect on villus height and total bacterial count in either the mesophile or lactic acid bacteria. Based on PCR-denaturant gradient gel electrophoresis analysis, 3 bacterial groups were identified in both groups of chicks: gram-positive bacteria having low contents of guanine and cytosine, gamma proteobacteria, and actinobacteria. The abundance of Weisella, Enterococcus faecium, and Pediococcus acidophilus found only in the control group indicated that avilamycin did affect their growth and led to low microbial diversity among the low guanine and cytosine group compared with the control group. In contrast, however, avilamycin treatment was associated with higher microbial diversity among the gamma proteobacteria group in respect of the various Pseudomonas species. This finding should increase awareness of the potential effects of antibiotic use and particularly avilamycin in commercial poultry production in tropical areas. PMID- 21673170 TI - Oviductal expression of avidin, avidin-related protein-2, and progesterone receptor in turkey hens in relation to sperm storage: effects of oviduct tissue type, sperm presence, and turkey line. AB - The sperm storage tubules (SST) of the turkey hen, which are located in the uterovaginal junction (UVJ) of the oviduct, maintain viable sperm for up to 10 wk after a single insemination. The mechanisms of this in vivo sperm storage are poorly understood. Our objective was to evaluate mRNA and protein expression of avidin and 2 avidin-associated factors, avidin-related protein-2 (AVR2) and progesterone receptor, in the oviducts of 2 different lines to determine the extent to which they were sperm responsive and tissue specific. At 38 wk of age, Hybrid Grade Maker and Converter turkey hens were artificially inseminated with diluted semen (AI) or were sham-inseminated with extender alone (SI). Forty-eight hours after insemination, total RNA was extracted from the UVJ epithelium (containing SST) and vaginal epithelium (VGE) of SI and AI hens. Real time polymerase chain reaction data showed a clear tissue region-specific effect on gene expression in the turkey hen oviduct, with much greater (P < 0.0001) expression in the UVJ compared with VGE region for avidin and AVR2 mRNA in both lines and for progesterone receptor mRNA in the Converter line. In contrast to real-time PCR data, in situ hybridization of SI and AI tissues showed that the presence of sperm increased avidin mRNA in the SST and UVJ surface epithelium in the Converter hens. Immunohistochemistry confirmed the presence of avidin protein in the epithelium of the UVJ in both lines; however, whereas avidin protein was localized in the SST of SI-Grade Maker hens, this protein was not detected in the SST of Converter hens. The upregulation of avidin and AVR2 mRNA within the sperm storage region indicates the involvement of avidin, and perhaps avidin analogs, in the sustained storage of sperm in the SST, possibly through the binding of biotin to avidin. The absence of avidin protein in the SST and VGE of Converter hens in the presence of increased mRNA may indicate a rapid turnover of protein. PMID- 21673171 TI - Complementary deoxyribonucleic acid cloning of avian G0/G1 switch gene 2, and its expression and association with production traits in chicken. AB - As a member of the G0/G1 switch genes, G0/G1 switch gene 2 (G0S2) is related to many regulatory processes in the human and mouse. For example, it interacts directly with adipose triglyceride lipase to active its triglyceride hydrolysis activities. In this study, G0S2 gene cDNA of the chicken (522 bp), zebra finch (420 bp), sparrow (417 bp), pigeon (417 bp), and Bengalese finch (416 bp) were cloned, and each of them was encoded as a protein of 99 amino acids. The expression of G0S2 mRNA was determined by real-time reverse-transcription PCR analysis in 20 tested tissues of 21- and 91-d-old chickens. The highest mRNA level was found in abdominal fat and subcutaneous fat in both stages. Considerable G0S2 mRNA was also observed in chicken heart and muscle tissues. Expression of the chicken G0S2 gene varied at different stages and sexes. The abundance of G0S2 mRNA on d 21 was far higher than that on d 91. The abundance in female chickens was higher than that in males at both stages. In the coding region, we found 4 SNP, among which only G197A led to a change in the amino acids (Arg66Gln); the rest were synonymous substitutions. Association analysis showed that both G102A and G255A were significantly associated with head width (P < 0.05) and were highly significantly associated with leg muscle color (P < 0.01). The G102A was significantly associated with shank diameter at 63 d (P < 0.05). The SNP G197A was significantly associated with shank diameter at 49 d; CP content of leg muscle; total weights of the heart, liver, gizzard, and glandular stomach; and small intestine length (P < 0.05). In conclusion, much higher G0S2 mRNA was detected in both male and female chickens at 21 d of age than at 91 d of age, and 3 SNP (G102A, G197, and G255A) were associated with chicken production traits. PMID- 21673172 TI - Effects of cold stress on nitric oxide in duodenum of chicks. AB - Animals may suffer from a variety of environmental stressors every day, among which is cold stress, which commonly exists in cold regions. The aim of this study was to investigate changes in antioxidative function and inducible nitric oxide synthase-nitric oxide (iNOS-NO) system activity in the duodenum of chicks as a reaction to cold stress. A total of 84 male chicks (15 d old) were randomly allocated to 12 groups (7 chickens/group). There were 1 control group and 5 treatment groups for acute cold stress and 3 control groups and 3 treatment groups for chronic cold stress. Antioxidative function was examined by superoxide dismutase (SOD), and oxidative damage was examined by malondialdehyde (MDA) detection. The iNOS-NO system activity was identified by NO content and NOS activity assay, and the transcription of iNOS mRNA was tested by fluorescence quantitative PCR. The results showed that under acute cold stress MDA level increased, the activity of NO in the duodenum fluctuated, and the activity of SOD and iNOS in the duodenum first increased and then decreased, whereas the expression of iNOS mRNA decreased. Under chronic cold stress the activity of SOD, NO, and NOS first decreased and then increased, whereas the MDA level and the expression of iNOS mRNA increased. The results indicated that both acute and chronic cold stress could cause duodenum oxidative stress and change in iNOS, which was related to the intestinal damage process. PMID- 21673173 TI - Exposure assessment and process sensitivity analysis of the contamination of Campylobacter in poultry products. AB - Studies were conducted in a Thai poultry plant to identify the factors that affected numbers of Campylobacter jejuni in chicken carcasses. The concentrations of Campylobacter were determined using the SimPlate most probable number and modified charcoal cefoperazone deoxycholate plating methods. Results indicated that the mean concentrations of C. jejuni in carcasses after scalding, plucking, and chilling were 2.93 +/- 0.31, 2.98 +/- 0.38, 2.88 +/- 0.31, and 0.85 +/- 0.95 log cfu, whereas the concentrations of C. jejuni in the scalding tank water, plucked feathers, and chicken breast portion were 1.39 +/- 0.70, 3.28 +/- 0.52, and 0.50 +/- 1.22 log cfu, respectively. Sensitivity analysis using tornado order correlation analysis showed that risk parameters affecting the contamination of C. jejuni in the chicken slaughter and processing plant could be ranked as chilling water pH, number of pathogens in the scald tank water, scalding water temperature, number of C. jejuni on plucked feathers, and residual chlorine in the chill water, respectively. The exposure assessment and analysis of process parameters indicated that some of the current critical control points were not effective. The suggested interventions included preventing fecal contamination during transportation; increasing the scalding temperature, giving the scalding water a higher countercurrent flow rate; reducing contamination of feathers in the scalding tank to decrease C. jejuni in the scalding water; spraying water to reduce contamination at the plucking step; monitoring and maintaining the chill water pH at 6.0 to 6.5; and increasing the residual chlorine in the chill water. These interventions were recommended for inclusion in the hazard analysis and critical control point plan of the plant. PMID- 21673174 TI - Evaluation of Bacillus species as potential candidates for direct-fed microbials in commercial poultry. AB - Increasing sociopolitical concerns with antibiotic use have led to investigations of potential alternatives for food safety and growth promotion. Direct-fed microbials (DFM) including spore-based probiotics are amenable to feed inclusion and are extremely stable. We isolated several Bacillus spp. from environmental and poultry sources and tested them for their ability to reduce Salmonella in vitro. In a preliminary in vivo trial, day-of-hatch chicks and poults were randomly assigned to the following treatments (24 birds/treatment): control and one of 8 DFM candidates at 10(6) spores/g of feed. Chicks and poults were tagged, weighed, and orally challenged with Salmonella Typhimurium (ST). Body weight gain and ST recovery were measured 11 d posthatch. Total percentages of ST-positive crop and ceca were significantly lower (P < 0.05) in at least 3 DFM candidates compared with control. Additionally, beneficial effects on BW gain were observed in at least 5 DFM candidates (P < 0.05) compared with control. In a second study, birds treated with NP122 (identified as Bacillus subtilis) had significantly lower (P < 0.05) cecal ST than control and benefitted BW gain irrespective of the presence or absence of a Salmonella challenge. In conclusion, NP122 markedly reduced ST recovery and increased BW gain in both chicks and poults. This provides preliminary evidence that this isolate may have potential use as a DFM in poultry. PMID- 21673175 TI - Assessment of Salmonella spp. in feces, cloacal swabs, and eggs (eggshell and content separately) from a laying hen farm. AB - Microbial pathogens of the genus Salmonella are among the leading causes of foodborne illness in the world. The present study was done on a laying hen farm with a Salmonella enterica serovar Enteritidis-positive result according to the testing specified by European regulation 2160/2003. The aim of this study was to compare the Salmonella contamination on a laying hen farm with the Salmonella presence in the hen eggs. The strains were isolated by ISO method 6579:2002 (standard method for the detection of Salmonella spp. in the European regulation for food and animal feeding stuffs, animal feces, and environmental samples from the primary production stage, including poultry farms) and were confirmed as Salmonella Enteritidis by the Kauffmann-White method. In addition, strains were compared with genomic macrorestriction followed by pulsed-field gel electrophoresis. Four types of samples, namely, feces (n = 50), cloacal swabs (n = 150), eggshells (n = 50), and egg contents (n = 50), were taken from each of 50 randomly selected battery cages. Results demonstrated that feces (92%) were the most positive sample, followed by eggshells (34%) and cloacal swabs (4%). No Salmonella spp. were detected in the egg contents. Our results show that a Salmonella Enteritidis-positive result on a laying hen farm, according to the testing specified by European regulation 2160/2003, did not imply the presence of the pathogen in the egg contents. Additionally, XbaI-digested genomic DNA of Salmonella Enteritidis strains isolated from several samples resulted in the same pattern, so were probably of the same origin. PMID- 21673176 TI - Comparison of shell bacteria from unwashed and washed table eggs harvested from caged laying hens and cage-free floor-housed laying hens. AB - These studies evaluated the bacterial level of unwashed and washed shell eggs from caged and cage-free laying hens. Hy-Line W-36 White and Hy-Line Brown laying hens were housed on all wire slats or all shavings floor systems. On the sampling days for experiments 1, 2, and 3, 20 eggs were collected from each pen for bacterial analyses. Ten of the eggs collected from each pen were washed for 1 min with a commercial egg-washing solution, whereas the remaining 10 eggs were unwashed before sampling the eggshell and shell membranes for aerobic bacteria and coliforms (experiment 1 only). In experiment 1, the aerobic plate counts (APC) of unwashed eggs produced in the shavings, slats, and caged-housing systems were 4.0, 3.6, and 3.1 log(10) cfu/mL of rinsate, respectively. Washing eggs significantly (P < 0.05) reduced APC by 1.6 log(10) cfu/mL and reduced the prevalence of coliforms by 12%. In experiment 2, unwashed eggs produced by hens in triple-deck cages from 57 to 62 wk (previously housed on shavings, slats, and cages) did not differ, with APC ranging from 0.6 to 0.8 log(10) cfu/mL. Washing eggs continued to significantly reduce APC to below 0.2 log(10) cfu/mL. In experiment 3, the APC for unwashed eggs were within 0.4 log below the APC attained for unwashed eggs in experiment 1, although hen density was 28% of that used in experiment 1. Washing eggs further lowered the APC to 0.4 to 0.7 log(10) cfu/mL, a 2.7-log reduction. These results indicate that shell bacterial levels are similar after washing for eggs from hens housed in these caged and cage-free environments. However, housing hens in cages with manure removal belts resulted in lower APC for both unwashed and washed eggs (compared with eggs from hens housed in a room with shavings, slats, and cages). PMID- 21673177 TI - Feasibility of the direct application of near-infrared reflectance spectroscopy on intact chicken breasts to predict meat color and physical traits. AB - Physical and color characteristics of chicken meat were investigated on 193 animals by directly applying a fiberoptic probe to the breast muscle and using the visible-near-infrared (NIR) spectral range from 350 to 1,800 nm. Data on pH was recorded 48 h postmortem (pH); lightness (L*), redness (a*), and yellowness (b*) 48 h postmortem; thawing and cooking losses and shear force after freezing. Partial least squares regressions were performed using untreated data, raw absorbance data (log(1/R)), and multiplicative scatter correction plus first or second derivative spectra. Models were validated using full cross-validation, and their predictive ability was determined by root mean square error of cross validation (RMSE(CV)) and correlation coefficient of cross-validation (r(cv)). Means (+/-SD) of pH, L*, a*, b*, thawing loss, cooking loss, and shear force were 5.83 +/- 0.13, 44.54 +/- 2.42, -1.90 +/- 0.62, 3.21 +/- 3.28, 4.84 +/- 2.44%, 19.39 +/- 2.95%, and 16.08 +/- 3.83 N, respectively. The best prediction models were developed using log(1/R) spectra for b* (r(cv) = 0.93; RMSE(CV) = 1.16) and a* (r(cv) = 0.88; RMSE(CV) = 0.29), while a medium predictive ability of NIR was obtained for pH, L*, and thawing and cooking losses (r(cv) from 0.69 to 0.76; RMSE(CV) from 0.01 to 1.73). Finally, predicted model for shear force (r(cv) = 0.41; RMSE(CV) = 3.18) was unsatisfactory. Results suggest that NIR is a feasible technique for the assessment of several quality traits of intact breast muscle. PMID- 21673178 TI - Comparison of fatty acid, cholesterol, and vitamin A and E composition in eggs from hens housed in conventional cage and range production facilities. AB - The public perceives that the nutritional quality of eggs produced as free range is superior to that of eggs produced in cages. Therefore, this study compared the nutrient content of free-range vs. cage-produced shell eggs by examining the effects of the laboratory, production environment, and hen age. A flock of 500 Hy Line Brown layers were hatched simultaneously and received the same care (i.e., vaccination, lighting, and feeding regimen), with the only difference being access to the range. The nutrient content of the eggs was analyzed for cholesterol, n-3 fatty acids, saturated fat, monounsaturated fat, polyunsaturated fat, beta-carotene, vitamin A, and vitamin E. The same egg pool was divided and sent to 4 different laboratories for analysis. The laboratory was found to have a significant effect on the content of all nutrients in the analysis except for cholesterol. Total fat content in the samples varied (P < 0.001) from a high of 8.88% to a low of 6.76% in laboratories D and C, respectively. Eggs from the range production environment had more total fat (P < 0.05), monounsaturated fat (P < 0.05), and polyunsaturated fat (P < 0.001) than eggs produced by caged hens. Levels of n-3 fatty acids were also higher (P < 0.05), at 0.17% in range eggs vs. 0.14% in cage eggs. The range environment had no effect on cholesterol (163.42 and 165.38 mg/50 g in eggs from caged and range hens, respectively). Vitamin A and E levels were not affected by the husbandry to which the hens were exposed but were lowest at 62 wk of age. The age of the hens did not influence the fat levels in the egg, but cholesterol levels were highest (P < 0.001) at 62 wk of age (172.54 mg/50 g). Although range production did not influence the cholesterol level in the egg, there was an increase in fat levels in eggs produced on the range. PMID- 21673179 TI - Comparison between rinse and crush-and-rub sampling for aerobic bacteria recovery from broiler hatching eggs after sanitization. AB - This study compared surface and deep eggshell aerobic bacteria recovered by the rinse and crush-and-rub sampling methods for commercial hatching eggs after treatment with sanitizers. Eggs were arranged into 5 treatments consisting of no treatment, water, and 3 sanitizers. The sanitizers were H(2)O(2), phenol, and Q(4)B (a compound chemical containing 4 quaternary ammoniums and 1 biguanide moiety). Eggs were sprayed according to treatment and allowed to dry for 1 h before sampling. To collect samples for the eggshell rinse, each egg was massaged in a plastic bag with 20 mL of saline. Eggshells were then aseptically opened and their contents were discarded before being individually crushed into 50-mL centrifuge tubes containing 20 mL of saline. Aerobic bacteria were enumerated on Petrifilm after 48 h of incubation at 37 degrees C. Aerobic bacteria recovered (log(10) cfu/mL) from the eggshell rinse were highest and similar for the no treatment (4.0) and water (3.7) groups, lower for the phenol (3.2) and H(2)O(2) (3.1) groups, and lowest for the Q(4)B (2.4) group. Aerobic bacteria levels with the crush-and-rub method were similar for the no-treatment (2.5) and water (2.3) groups, lower for the phenol (1.6) group, intermediate for the H(2)O(2) (1.2) group, and lowest for the Q(4)B (0.9) group. The overall correlation between the rinse and crush-and-rub sampling methods for individual egg aerobic bacteria counts was r = 0.71. The correlation within each treatment revealed the following r values: no treatment, 0.55; water, 0.72; H(2)O(2), 0.67; phenol, 0.73; and Q(4)B, 0.38. A second experiment was designed to further examine the lower aerobic bacterial levels recovered by the crush-and-rub method (for previously rinsed eggs) than the levels recovered in the initial eggshell rinse sample. Eggs were either rinsed and then crushed and rubbed, or they were only crushed and rubbed without a prior rinse. Results confirmed a significant decrease (1.5 log(10) cfu/mL) in bacteria levels between the initial rinse (4.4) and the subsequent crush and rub (2.9) for the same eggshell. For the crush-and-rub eggs with no previous rinsing, the bacteria recovery level (3.9) was not significantly different from levels for the rinse method. Therefore, either the rinse or crush and-rub sampling methods can be used to recover similar levels of eggshell aerobic bacteria. PMID- 21673180 TI - Salmonella contamination in shell eggs exposed to modified-pressure imaging for microcrack detection. AB - Microcracks in egg shells are a food safety risk and are difficult for professional human graders to detect. Modified-pressure imaging technology with 99.6% accuracy has been developed to detect microcracks. This study was conducted to determine whether the microcrack detection system would increase penetration of Salmonella into egg contents or lead to cross-contamination within the system. Thirty dozen grade A large white retail eggs were used for each of 3 replicates. Cracked eggs were removed and 72 eggs/replicate were dip inoculated in buffered peptone water containing 10(5) cfu/mL of nalidixic acid-resistant Salmonella Typhimurium (ST), whereas 144 eggs were dipped in sterile buffered peptone water. All eggs were incubated overnight at 25 degrees C before imaging. Forty-five eggs of each treatment were imaged in the following order: control, inoculated, control. Imaged and nonimaged eggs from each treatment were used for cultural analysis of a shell rinse, shell emulsion, and contents sample for each egg. The ST levels were monitored on brilliant green sulfa agar with 200 mg/L of nalidixic acid. Egg contents were also enriched to determine the prevalence of ST in low levels. Salmonella Typhimurium was not detected on or in any of the control eggs, including the eggs imaged after the inoculated eggs. The highest level of ST was detected in inoculated shell emulsions (4.79 log cfu/mL). No differences in ST levels were found for any sample location between imaged and nonimaged inoculated eggs. Therefore, the modified-pressure imaging system for microcrack detection did not result in microbial cross-contamination or increase the level of microbial penetration in inoculated eggs. The imaging system can be used to assess eggs for cracks without negative food safety implications. PMID- 21673181 TI - Cholesterol content and intramuscular collagen properties of pectoralis superficialis muscle of quail from different genetic groups. AB - To study growth performance and meat quality traits (cholesterol content and intramuscular collagen properties) of quail, 3 trials were carried out. Trial 1 used males of generation 19 of the egg type Japanese quail (Coturnix japonica) selected previously (until generation 17) for low (n = 8) or high (n = 7) yolk cholesterol content as well as an unselected control (n = 11). Trial 2 used males of meat Pharaoh quail selected earlier (generations 1 to 6 and 9 to 11) on the basis of BW decrease after periodic deprivation of food (high decrease of weight, n = 10; low decrease of weight, n = 8) and unselected control (n = 10). Trial 3 compared males of English White quail, Manchurian Golden quail, and British Range quail. The birds were raised to 35 d of age. Quail were fed ad libitum commercial diets according to age and had free access to water. At slaughter, all birds were individually weighed (after a fasting period of 12 h), stunned, and decapitated. After the refrigeration period (24 h at 4 degrees C), the left pectoralis superficialis muscle was removed from the carcasses, weighed, vacuum packaged, and stored frozen (-40 degrees C) for analyses of cholesterol and intramuscular collagen (IMC; collagen and crosslink concentration). In trial 1, divergent selection for yolk cholesterol content did not significantly influence pectoralis superficialis muscle weight and IMC crosslinking of Japanese quail, whereas it significantly reduced growth and IMC amount. In addition, it had greater effect on the amount of cholesterol in meat; in fact, the meat of quail with low yolk cholesterol content contained lower cholesterol (-36.6%) than that of birds with high yolk cholesterol content. In trial 2, divergent selection on the basis of Pharaoh quail BW decrease altered IMC crosslinking, leading to variability in meat tenderness of Pharaoh quail. In trial 3, English White quail were significantly heavier than the other breeds. PMID- 21673183 TI - Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial. AB - OBJECTIVE: The preservation of nutritional status and growth is an important aim in critically ill infants, but difficult to achieve due to the metabolic stress response and inadequate nutritional intake, leading to negative protein balance. This study investigated whether increasing protein and energy intakes can promote anabolism. The primary outcome was whole body protein balance, and the secondary outcome was first pass splanchnic phenylalanine extraction (SPE(Phe)). DESIGN: This was a double-blind randomised controlled trial. Infants (n=18) admitted to the paediatric intensive care unit with respiratory failure due to viral bronchiolitis were randomised to continuous enteral feeding with protein and energy enriched formula (PE-formula) (n=8; 3.1 +/- 0.3 g protein/kg/24 h, 119 +/- 25 kcal/kg/24 h) or standard formula (S-formula) (n=10; 1.7 +/- 0.2 g protein/kg/24 h, 84 +/- 15 kcal/kg/24 h; equivalent to recommended intakes for healthy infants <6 months). A combined intravenous-enteral phenylalanine stable isotope protocol was used on day 5 after admission to determine whole body protein metabolism and SPE(Phe). RESULTS: Protein balance was significantly higher with PE-formula than with S-formula (PE-formula: 0.73 +/- 0.5 vs S formula: 0.02 +/- 0.6 g/kg/24 h) resulting from significantly increased protein synthesis (PE-formula: 9.6 +/- 4.4, S-formula: 5.2 +/- 2.3 g/kg/24 h), despite significantly increased protein breakdown (PE-formula: 8.9 +/- 4.3, S-formula: 5.2 +/- 2.6 g/kg/24 h). SPE(Phe) was not statistically different between the two groups (PE-formula: 39.8 +/- 18.3%, S-formula: 52.4 +/- 13.6%). CONCLUSIONS: Increasing protein and energy intakes promotes protein anabolism in critically ill infants in the first days after admission. Since this is an important target of nutritional support, increased protein and energy intakes should be preferred above standard intakes in these infants. Dutch Trial Register number: NTR 515. PMID- 21673184 TI - Genital herpes in children under 11 years and investigations for sexual abuse. AB - OBJECTIVE: The implications for sexual abuse investigation of genital herpes in a child are uncertain because of a lack of good quality research evidence. The incidence, presenting features, history of exposure, indicators of child maltreatment and outcomes of child protection investigations in children with genital herpes are described. PATIENTS AND METHODS: Ascertainment of all cases of genital herpes in children <11 years of age first presenting to paediatricians in the UK and Ireland from April 2007 to April 2009 conducted through the British Paediatric Surveillance Unit. RESULTS: 23 cases were notified. The incidence of confirmed and all reported cases was 0.091 and 0.13 per 100,000 children per year, respectively. Of the 16 virologically confirmed cases, 12 were female, 11 were <5 years of age, 14 had herpes simplex type 1, eight were tested for other sexually transmitted infections (STIs), and only one had a full STI screen. Three cases had other clinical features suggestive of sexual abuse. Six cases were referred for child protection investigation, but no sexual abuse was substantiated. CONCLUSIONS: Genital herpes in children under 11 years is rare. Almost a third of children diagnosed with genital herpes did not have appropriate virological investigation and few were screened for other STIs. Around a quarter of cases were referred to child protection agencies for further investigation, which limits any inferences in this study about mode of transmission in children. Sexual abuse guidance should emphasise the need for thorough assessment and investigation in cases of genital herpes in children. PMID- 21673185 TI - Small supernumerary marker chromosomes and uniparental disomy have a story to tell. AB - Small supernumerary maker chromosomes (sSMC) and uniparental disomy (UPD) are rare, and a combination of both is rarely encountered. Accordingly, only 46 sSMC cases UPD have been reported. Despite of its rareness, UPD has to be considered, especially in prenatal cases with sSMC. Here, the authors reviewed all sSMC cases with UPD (sSMC(U+)) and compared them to sSMC without UPD (sSMC(U-)), which resulted in the following correlations: 1) every sSMC, irrespective of its chromosomal origin, may be principally connected with UPD; 2) mixed hetero- and iso-UPD (hUPD/iUPD) can be observed most often in sSMC(U+) cases followed by complete iUPD, complete hUPD, and segmental iUPD; 3) UPD of chromosomes 6, 7, 14, 15, 16, and 20 is most often reported in sSMC(U+); 4) maternal UPD was approximately nine times more frequent than paternal UPD; 5) if mosaic with a normal cell line, acrocentric-derived sSMC had a three times higher chance of occurrence than the corresponding nonmosaic sSMC cases; 6) UPD in connection with a parentally inherited sSMC is, if existent at all, a rare event; and 7) the gender type and shape of sSMC had no effect on UPD formation. Overall, sSMC(U+) cases may have a story to tell about chromosome number control mechanisms in early embryogenesis. PMID- 21673186 TI - A systematic comparison of microsimulation models of colorectal cancer: the role of assumptions about adenoma progression. AB - BACKGROUND: As the complexity of microsimulation models increases, concerns about model transparency are heightened. METHODS: The authors conducted model "experiments" to explore the impact of variations in "deep" model parameters using 3 colorectal cancer (CRC) models. All natural history models were calibrated to match observed data on adenoma prevalence and cancer incidence but varied in their underlying specification of the adenocarcinoma process. The authors projected CRC incidence among individuals with an underlying adenoma or preclinical cancer v. those without any underlying condition and examined the impact of removing adenomas. They calculated the percentage of simulated CRC cases arising from adenomas that developed within 10 or 20 years prior to cancer diagnosis and estimated dwell time-defined as the time from the development of an adenoma to symptom-detected cancer in the absence of screening among individuals with a CRC diagnosis. RESULTS: The 20-year CRC incidence among 55-year-old individuals with an adenoma or preclinical cancer was 7 to 75 times greater than in the condition-free group. The removal of all adenomas among the subgroup with an underlying adenoma or cancer resulted in a reduction of 30% to 89% in cumulative incidence. Among CRCs diagnosed at age 65 years, the proportion arising from adenomas formed within 10 years ranged between 4% and 67%. The mean dwell time varied from 10.6 to 25.8 years. CONCLUSIONS: Models that all match observed data on adenoma prevalence and cancer incidence can produce quite different dwell times and very different answers with respect to the effectiveness of interventions. When conducting applied analyses to inform policy, using multiple models provides a sensitivity analysis on key (unobserved) "deep" model parameters and can provide guidance about specific areas in need of additional research and validation. PMID- 21673187 TI - Clarifying differences in natural history between models of screening: the case of colorectal cancer. AB - BACKGROUND: Microsimulation models are important decision support tools for screening. However, their complexity makes them difficult to understand and limits realization of their full potential. Therefore, it is important to develop documentation that clarifies their structure and assumptions. The authors demonstrate this problem and explore a solution for natural history using 3 independently developed colorectal cancer screening models. METHODS: The authors first project effectiveness and cost-effectiveness of colonoscopy screening for the 3 models (CRC-SPIN, SimCRC, and MISCAN). Next, they provide a conventional presentation of each model, including information on structure and parameter values. Finally, they report the simulated reduction in clinical cancer incidence following a one-time complete removal of adenomas and preclinical cancers for each model. They call this new measure the maximum clinical incidence reduction (MCLIR). RESULTS: Projected effectiveness varies widely across models. For example, estimated mortality reduction for colonoscopy screening every 10 years from age 50 to 80 years, with surveillance in adenoma patients, ranges from 65% to 92%. Given only conventional information, it is difficult to explain these differences, largely because differences in structure make parameter values incomparable. In contrast, the MCLIR clearly shows the impact of model differences on the key feature of natural history, the dwell time of preclinical disease. Dwell times vary from 8 to 25 years across models and help explain differences in projected screening effectiveness. CONCLUSIONS: The authors propose a new measure, the MCLIR, which summarizes the implications for predicted screening effectiveness of differences in natural history assumptions. Including the MCLIR in the standard description of a screening model would improve the transparency of these models. PMID- 21673189 TI - Type III secretion is essential for the rapidly fatal diarrheal disease caused by non-O1, non-O139 Vibrio cholerae. AB - Cholera is a severe diarrheal disease typically caused by O1 serogroup strains of Vibrio cholerae. The pathogenicity of all pandemic V. cholerae O1 strains relies on two critical virulence factors: cholera toxin, a potent enterotoxin, and toxin coregulated pilus (TCP), an intestinal colonization factor. However, certain non O1, non-O139 V. cholerae strains, such as AM-19226, do not produce cholera toxin or TCP, yet they still cause severe diarrhea. The molecular basis for the pathogenicity of non-O1, non-O139 V. cholerae has not been extensively characterized, but many of these strains encode related type III secretion systems (TTSSs). Here, we used infant rabbits to assess the contribution of the TTSS to non-O1, non-O139 V. cholerae pathogenicity. We found that all animals infected with wild-type AM-19226 developed severe diarrhea even more rapidly than rabbits infected with V. cholerae O1. Unlike V. cholerae O1 strains, which do not damage the intestinal epithelium in rabbits or humans, AM-19226 caused marked disruptions of the epithelial surface in the rabbit small intestine. TTSS proved to be essential for AM-19226 virulence in infant rabbits; an AM-19226 derivative deficient for TTSS did not elicit diarrhea, colonize the intestine, or induce pathological changes in the intestine. Deletion of either one of the two previously identified or two newly identified AM-19226 TTSS effectors reduced but did not eliminate AM-19226 pathogenicity, suggesting that at least four effectors contribute to this strain's virulence. In aggregate, our results suggest that the TTSS-dependent virulence in non-O1, non-O139 V. cholerae represents a new type of diarrheagenic mechanism. PMID- 21673190 TI - BiP and multiple DNAJ molecular chaperones in the endoplasmic reticulum are required for efficient simian virus 40 infection. AB - Simian virus 40 (SV40) is a nonenveloped DNA virus that traffics through the endoplasmic reticulum (ER) en route to the nucleus, but the mechanisms of capsid disassembly and ER exit are poorly understood. We conducted an unbiased RNA interference screen to identify cellular genes required for SV40 infection. SV40 infection was specifically inhibited by up to 50-fold by knockdown of four different DNAJ molecular cochaperones or by inhibition of BiP, the Hsp70 partner of DNAJB11. These proteins were not required for the initiation of capsid disassembly, but knockdown markedly inhibited SV40 exit from the ER. In addition, BiP formed a complex with SV40 capsids in the ER in a DNAJB11-dependent fashion. These experiments identify five new cellular proteins required for SV40 infection and suggest that the binding of BiP to the capsid is required for ER exit. Further studies of these proteins will provide insight into the molecular mechanisms of polyomavirus infection and ER function. PMID- 21673191 TI - Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. AB - Tuberculosis continues to be a major public health problem in many parts of the world. Significant obstacles in controlling the epidemic are the length of treatment and the large reservoir of latently infected people. Bacteria form dormant, drug-tolerant persister cells, which may be responsible for the difficulty in treating both acute and latent infections. We find that in Mycobacterium tuberculosis, low numbers of drug-tolerant persisters are present in lag and early exponential phases, increasing sharply at late exponential and stationary phases to make up ~1% of the population. This suggests that persister formation is governed by both stochastic and deterministic mechanisms. In order to isolate persisters, an exponentially growing population was treated with d cycloserine, and cells surviving lysis were collected by centrifugation. A transcriptome of persisters was obtained by using hybridization to an Affymetrix array. The transcriptome shows downregulation of metabolic and biosynthetic pathways, consistent with a certain degree of dormancy. A set of genes was upregulated in persisters, and these are likely involved in persister formation and maintenance. A comparison of the persister transcriptome with transcriptomes obtained for several in vitro dormancy models identified a small number of genes upregulated in all cases, which may represent a core dormancy response. PMID- 21673193 TI - Impact of change in serum sodium concentration on mortality in patients hospitalized with heart failure and hyponatremia. AB - BACKGROUND: Hyponatremia is a common electrolyte abnormality among patients hospitalized with heart failure and it is a marker for increased short-term and long-term mortality. However, little is known about the time course of hyponatremia and whether changes in serum sodium levels affect clinical outcomes. METHODS AND RESULTS: Patients (n=322) hospitalized with decompensated heart failure and serum sodium <135 mmol/L were evaluated. After hospital discharge, the first sodium value obtained within a 60- to 270-day period was recorded, and patients were classified into 3 groups, based on whether the serum sodium value increased (>=2 mmol/L), decreased (<=2 mmol/L), or remained unchanged (+/-1 mmol/L) relative to the baseline value. Kaplan-Meier survival curves were constructed to illustrate mortality as a function of change in sodium concentration over time, and a Cox-proportional hazards model was constructed to determine if change in serum sodium concentration predicted mortality after adjusting for relevant covariates. The mean age of the population was 66 years, 45% were women, and 55% were white. The mean baseline sodium level was 131 mmol/L and the mean ejection fraction was 32.5%. Two hundred twenty-two patients (68.9%) exhibited an increase in sodium during follow-up; in 57 patients (17.7%) the level was unchanged and in 43 patients (13.4%) there was a decrease in sodium level. During a median follow-up of 610 days, there was a strong positive association between change in sodium level and survival (P for trend <0.001); that is, increased sodium was associated with decreased mortality. In multivariable analysis, change in sodium concentration and higher blood urea nitrogen were the strongest predictors of mortality (both P<0.0001). CONCLUSIONS: Among patients hospitalized with heart failure and hyponatremia, change in serum sodium concentration over time is a strong predictor of long-term survival. PMID- 21673192 TI - An insect nidovirus emerging from a primary tropical rainforest. AB - Tropical rainforests show the highest level of terrestrial biodiversity and may be an important contributor to microbial diversity. Exploitation of these ecosystems may foster the emergence of novel pathogens. We report the discovery of the first insect-associated nidovirus, tentatively named Cavally virus (CAVV). CAVV was found with a prevalence of 9.3% during a survey of mosquito-associated viruses along an anthropogenic disturbance gradient in Cote d'Ivoire. Analysis of habitat-specific virus diversity and ancestral state reconstruction demonstrated an origin of CAVV in a pristine rainforest with subsequent spread into agriculture and human settlements. Virus extension from the forest was associated with a decrease in virus diversity (P<0.01) and an increase in virus prevalence (P<0.00001). CAVV is an enveloped virus with large surface projections. The RNA genome comprises 20,108 nucleotides with seven major open reading frames (ORFs). ORF1a and -1b encode two large proteins that share essential features with phylogenetically higher representatives of the order Nidovirales, including the families Coronavirinae and Torovirinae, but also with families in a basal phylogenetic relationship, including the families Roniviridae and Arteriviridae. Genetic markers uniquely conserved in nidoviruses, such as an endoribonuclease- and helicase-associated zinc-binding domain, are conserved in CAVV. ORF2a and -2b are predicted to code for structural proteins S and N, respectively, while ORF3a and -3b encode proteins with membrane-spanning regions. CAVV produces three subgenomic mRNAs with 5' leader sequences (of different lengths) derived from the 5' end of the genome. This novel cluster of mosquito-associated nidoviruses is likely to represent a novel family within the order Nidovirales. PMID- 21673194 TI - Who benefits from chatting, and why? The roles of extraversion and supportiveness in online chatting and emotional adjustment. AB - The current study aimed to provide more insight into the role of online chatting in young adults' emotional adjustment. A model was tested that takes into account (a) extraversion of individuals who communicate online, (b) the kind of peers these individuals communicate with online (i.e., online-exclusive peers vs. friends), and (c) the extent to which effects of online chatting on emotional adjustment are mediated by individuals' ability to provide support to others. Young adults (age M = 18.9) filled out questionnaires about themselves and their fellow students at three measurements with a 4-month interval. Results showed that only for less extraverted individuals, chatting with peers found exclusively online directly predicted higher self-esteem and indirectly predicted less depressive symptoms through increases in supportiveness. Thus, results supported a model of social compensation where effects of online chatting with online exclusive peers improved young adults' emotional adjustment. PMID- 21673195 TI - Mortality and treatment failure among HIV-infected adults in Dar Es Salaam, Tanzania. AB - OBJECTIVES: Monitoring antiretroviral treatment (ART) outcomes is essential for assessing the success of HIV care and treatment programs in resource-limited settings (RLS). METHODS: Longitudinal analyses of clinical and immunologic parameters in HIV-infected adults initiated on ART between November 2004 and June 2008 at Management and Development for Health (MDH)-Presidents Emergency Plan For AIDS Relief PEPFAR supported HIV care and treatment clinics in Tanzania. RESULTS: A total of 12 842 patients were analyzed (65.9% female, median baseline CD4 count, 106 cells/mm(3)). Significant improvements in immunologic status were observed with an increase in CD4 count to 298 (interquartile range [IQR] 199 416), 372 (256-490) and 427 (314-580) cells/mm(3), at 1, 2, and 3 years, respectively. Overall mortality was 13.1% (1682 of 12 842). Male sex, World Health Organization (WHO) stage III/IV, CD4 <200 cells/mm(3), hemoglobin (Hgb) <8.5 g/dL, and stavudine (d4T)-containing regimens were independently associated with early and overall mortality. CONCLUSIONS: Closer monitoring of males and patients with advanced HIV disease following ART initiation may improve clinical and immunologic outcomes in these individuals. PMID- 21673196 TI - Development of the Champlain primary care cardiovascular disease prevention and management guideline: tailoring evidence to community practice. AB - PROBLEM ADDRESSED: A well documented gap remains between evidence and practice for clinical practice guidelines in cardiovascular disease (CVD) care. OBJECTIVE OF PROGRAM: As part of the Champlain CVD Prevention Strategy, practitioners in the Champlain District of Ontario launched a large quality-improvement initiative that focused on increasing the uptake in primary care practice settings of clinical guidelines for heart disease, stroke, diabetes, and CVD risk factors. PROGRAM DESCRIPTION: The Champlain Primary Care CVD Prevention and Management Guideline is a desktop resource for primary care clinicians working in the Champlain District. The guideline was developed by more than 45 local experts to summarize the latest evidence-based strategies for CVD prevention and management, as well as to increase awareness of local community-based programs and services. CONCLUSION: Evidence suggests that tailored strategies are important when implementing specific practice guidelines. This article describes the process of creating an integrated clinical guideline for improvement in the delivery of cardiovascular care. PMID- 21673197 TI - FLOW (finding lasting options for women): multicentre randomized controlled trial comparing tampons with menstrual cups. AB - OBJECTIVE: To determine whether menstrual cups are a viable alternative to tampons. DESIGN: Randomized controlled trial. SETTING: Prince George, Victoria, and Vancouver, BC. PARTICIPANTS: A total of 110 women aged 19 to 40 years who had previously used tampons as their main method of menstrual management. INTERVENTION: Participants were randomized into 2 groups, a tampon group and a menstrual cup group. Using online diaries, participants tracked 1 menstrual cycle using their regular method and 3 menstrual cycles using the method of their allocated group. MAIN OUTCOME MEASURES: Overall satisfaction; secondary outcomes included discomfort, urovaginal infection, cost, and waste. RESULTS: Forty-seven women in each group completed the final survey, 5 of whom were subsequently excluded from analysis (3 from the tampon group and 2 from the menstrual cup group). Overall satisfaction on a 7-point Likert scale was higher for the menstrual cup group than for the tampon group (mean [standard deviation] score 5.4 [1.5] vs 5.0 [1.0], respectively; P=.04). Approximately 91% of women in the menstrual cup group said they would continue to use the cup and recommend it to others. Women used a median of 13 menstrual products per cycle, or 169 products per year, which corresponds to approximately 771,248,400 products used annually in Canada. Estimated cost for tampon use was $37.44 a year (similar to the retail cost of 1 menstrual cup). Subjective vaginal discomfort was initially higher in the menstrual cup group, but the discomfort decreased with continued use. There was no significant difference in physician-diagnosed urovaginal symptoms between the 2 groups. CONCLUSION: Both of the menstrual management methods evaluated were well tolerated by subjects. Menstrual cups are a satisfactory alternative to tampons and have the potential to be a sustainable solution to menstrual management, with moderate cost savings and much-reduced environmental effects compared with tampons. Trial registration number C06-0478 (ClinicalTrials.gov). PMID- 21673198 TI - Attractiveness of family medicine for medical students: influence of research and debt. AB - OBJECTIVE: To examine the association between students' personal characteristics, backgrounds, and medical schools and their intention to enter a family medicine (FM) specialty. DESIGN: Descriptive study using data from the 2007 National Physician Survey. SETTING: Canada. PARTICIPANTS: Clinical (n=1109) and preclinical (n=829) medical student respondents to the 2007 National Physician Survey. MAIN OUTCOME MEASURES: The main variable was hoping to enter an FM specialty, and 40 independent variables were included in regression and classification-tree models. RESULTS: Fewer than 1 medical student in 3 (30.2% at the preclinical level and 31.4% at the clinical level) hoped to enter into an FM career. Those who did were more likely to be female, were slightly older, were more frequently married or living with partners, were typically born in Canada, and were more likely to have previous exposure to non-urban environments. The most important predictor for both populations was the debt related to medical studies, which acted in the opposite direction of whether or not students were interested in research. Students interested in research were attracted by specialties with high earning potential, while those not interested in research looked for short residency programs, such as FM, so they could begin to pay off debt sooner. Therefore, the interest in research appears to be inversely related to the choice of FM. CONCLUSION: Less than one-third of medical students were looking for residencies in FM in Canada. This is far below the goals of 45% set at the national level and 50% set by some provinces like Quebec. Debt and interest in research have strong influences on the choice of residency by medical students. PMID- 21673202 TI - Who wants to be a family physician? PMID- 21673199 TI - Must we appear to be all-knowing?: patients' and family physicians' perspectives on information seeking during consultations. AB - OBJECTIVE: To compare patients' opinions about family physicians looking up medical information during consultations with family physicians' expectations of how patients would respond to their using sources to find answers to medical questions. DESIGN: Survey. SETTING: North York, Ont. PARTICIPANTS: One hundred fifty-three family practice patients, 54 family physicians, and 21 family practice residents. MAIN OUTCOME MEASURES: Patients' self-reported confidence in their family physicians and their perceptions of the quality of care after seeing physicians look up medical information, both without specifying the physician's source of information and with reference to several specific information media. Family physicians' predictions for how patients would respond to their using resources to answer medical questions. RESULTS: When the information source used by physicians was not specified, 9% and 7% of patients reported decreased confidence and perceived lower quality of care, respectively. When the information source used by physicians was specified, the proportions of negative responses for patients' confidence and their perceptions of quality of care were 39% and 31%, respectively, for Internet search engines (ISEs); 8% and 7% for online resources designed for physicians (ORDP); 27% and 27% for personal digital assistants (PDAs); and 10% and 9% for hard-copy medical textbooks (HMTs). When the information source was not specified, 32% and 12% of physicians expected patients to report negative responses for confidence and perceptions of quality of care, respectively. When the information source was specified, 51% and 33% of physicians expected patients to report negative responses for confidence and perceptions of quality of care, respectively, for their use of ISEs; 16% and 8% for ORDP; 20% and 12% for PDAs; and 36% and 21% for HMTs. Younger patients were more likely to respond negatively to physicians' use of resources, especially if the source was an ISE (P<.001). Physicians earlier in their careers were more likely to expect negative patient responses (P<.05). CONCLUSION: Family physicians overestimated the decrease in patients' confidence caused by seeing them look up medical questions. While most patients responded positively, a substantial proportion of younger patients reported decreased confidence. Patients believed the best sources of information were ORDP and HMTs. PMID- 21673204 TI - Smoking cessation and neuropsychiatric adverse events: are family physicians caught between a rock and a hard place? PMID- 21673205 TI - Toronto's G20 one year later: missed opportunity for a Canadian contribution to global health. PMID- 21673206 TI - The tragic trajectory. PMID- 21673207 TI - Depression in family practice. PMID- 21673208 TI - Complementary and alternative medicine for the treatment of major depressive disorder. AB - OBJECTIVE: To review the clinical evidence supporting complementary and alternative medicine interventions for treating major depressive disorder. QUALITY OF EVIDENCE: PubMed was searched from January 1966 to February 2010 using the term depressive disorder in combination with St John's wort, S adenosylmethionine (SAM-e), exercise, acupuncture, omega-3 fatty acids, and folate. Only relevant human trials were selected. MAIN MESSAGE: In a large meta analysis, St John's wort was found to be equivalent to antidepressant drugs with fewer side effects. Exercise reduced depressive scores in 3 meta-analyses. Omega 3 fatty acids reduced depressive scores in a meta-analysis of 16 trials, but publication bias was identified. Oral SAM-e monotherapy reduced depressive scores in 4 of 5 small randomized controlled trials. Folate deficiency is associated with more severe and refractory depression, and supplementation reduced depressive scores in 2 of 3 randomized controlled trials. Acupuncture demonstrated limited efficacy in 1 meta-analysis and 5 other trials. CONCLUSION: St John's wort and regular exercise appear effective in the treatment of depression. Acupuncture appears ineffective for depression, but it might offer other health benefits. Other promising therapies include SAM-e, omega-3 fatty acid, and folic acid supplementation in selected patients; further study is warranted. PMID- 21673209 TI - Safety of skin care products during pregnancy. AB - QUESTION: Many of my female patients complain about acne, unwanted hair growth, and other skin problems that have only developed since they became pregnant. Are products used for these types of benign skin conditions safe to use in pregnancy, as it is understandable that women want to look their best at this important time in their lives? ANSWER: With the exception of hydroquinone, which has a relatively high systemic absorption rate, and tretinoin, for which the evidence is controversial, these products act locally and therefore produce minimal systemic levels. Consequently, in most cases women can deal with these cosmetically unappealing skin conditions without compromising the safety of their unborn children. PMID- 21673210 TI - Anti-staphylococcal treatment in dermatitis. AB - QUESTION: A 10-year-old boy with atopic dermatitis (AD) came for consultation with an exacerbation. He suffered from pruritus and multiple erythematous skin lesions, identified as inflamed but not infected. Because skin colonization with Staphylococcus aureus is very common in AD and can worsen the skin condition, is it reasonable to add topical antibiotic treatment to the anti-inflammatory treatment in this case? ANSWER: Skin colonization with S aureus is prevalent in children and adults with AD, and can aggravate skin inflammation. Although topical combination creams with steroids and antibiotics are widely used for AD flare-ups, their superiority over anti-inflammatory treatment alone is not well established. Antibiotic treatment, whether systemic or topical, should be reserved for cases in which explicit signs of infection are present. PMID- 21673211 TI - Managing hiccups. PMID- 21673212 TI - Vascular intervention for multiple sclerosis. PMID- 21673213 TI - Central hypothyroidism. PMID- 21673214 TI - Dermacase. Can you identify this condition? Senile hemangioma. PMID- 21673215 TI - Dermacase. Can you identify this condition? Nevus depigmentosus. PMID- 21673216 TI - Ophthaproblem. Can you identify this condition? Pseudoexfoliation syndrome. PMID- 21673217 TI - Dermacase. Can you identify this condition? Eosinophilic pustular folliculitis. PMID- 21673218 TI - Part 7. Pathogenic beliefs. PMID- 21673219 TI - Pay-for-performance incentives for preventive care: views of family physicians before and after participation in a reminder and recall project (P-PROMPT). AB - OBJECTIVE: The Provider and Patient Reminders in Ontario: Multi-Strategy Prevention Tools (P-PROMPT) project was designed to increase the rates of delivery of 4 targeted preventive care services to eligible patients in primary care network and family health network practices eligible for pay-for-performance incentives. DESIGN: Self-administered fax-back surveys completed before and after participation in the P-PROMPT project. SETTING: Southwestern Ontario. PARTICIPANTS: A total of 246 physicians from 24 primary care network or family health network practices across 110 different sites. INTERVENTIONS: The P-PROMPT project provided several tools and services, including physician and patient reminders, office management tools, and administrative database integration. MAIN OUTCOME MEASURES: Physicians' views about the delivery of preventive health services and pay-for-performance incentives before and after participation in the P-PROMPT project. RESULTS: The preintervention survey was completed by 86.2% (212 of 246) of physicians and the postintervention survey was completed by 53.3% (131 of 246) of physicians; 46.7% (114 of 246) of the physicians completed both surveys. Overall, 80.5% of physicians indicated that the P-PROMPT project was useful (scores of 5 or higher on a 7-point Likert scale). Patient reminder letters (89.1%), physician approval lists of eligible patients (75.6%), administrative assistance with management fees (79.8%), and annual bonus calculations (75.2%) were rated as the most useful features of the program. Compared with the preintervention survey, there were statistically significant increases in the mean agreement scores that the established target levels and bonuses provided appropriate financial incentive to substantially increase the uptake of mammography (P=.012) and Papanicolaou tests (P=.003) but not to increase uptake of annual influenza vaccination or childhood immunizations. There were statistically significant changes in the mean ratings of relying on an opportunistic approach (P<.001), increased agreement about the effectiveness of the current approach to delivery of preventive care (P<.001), and increased use of preventive management fees to recall patients (P<.001). CONCLUSION: The preventive care management program and P-PROMPT were viewed favourably by most respondents and were perceived to be useful in improving delivery of preventive health care services. PMID- 21673220 TI - An unusual teacher. PMID- 21673222 TI - Patient self-report and medical records: measuring agreement for binary data. PMID- 21673223 TI - Advancing Canada's family medicine curriculum: Triple C. PMID- 21673224 TI - At the heart of the matter. PMID- 21673226 TI - Renal perfusion: noninvasive measurement with multidetector CT versus fluorescent microspheres in a pig model. AB - PURPOSE: To validate the measurement of renal perfusion with multidetector computed tomography (CT) with a low-rate injection of contrast medium (ie, 3 mL/sec) through a catheter placed peripherally with gamma variate extended modeling in a pig model, compared with a reference method of fluorescent microspheres. MATERIALS AND METHODS: This study was approved by the Institutional Animal Care and Use Committee. Renal perfusion was measured in 10 anesthetized pigs simultaneously with multidetector CT and with fluorescent microspheres, which are the reference standard for measuring regional renal perfusion. In each pig, measurements were obtained under three conditions. These were dopamine infusion, dopamine infusion with vascular expansion, and angiotensin II infusion. Aortic and cortical time-attenuation curves were modeled to measure renal perfusion with the gamma variate model. The renal perfusion measurements with the multidetector CT and that with microspheres were compared with least squares regression analysis and Bland-Altman plots. RESULTS: Perfusion as measured with multidetector CT and that as measured with microspheres were strongly correlated (rho = 0.93, P < .0001). Multidetector CT renal perfusion with dopamine infusion (3.13 mL/min/g +/- 0.53) was not changed after volume expansion (3.37 mL/min/g +/ 0.75, P = .35) but was significantly decreased after angiotensin II injection (2.01 mL/min/g +/- 0.57, P = .0001). CONCLUSION: Multidetector CT provides reliable measurements of single-kidney perfusion with peripheral low-rate contrast medium injection. PMID- 21673227 TI - Intrinsic damage to the major white matter tracts in patients with different clinical phenotypes of multiple sclerosis: a voxelwise diffusion-tensor MR study. AB - PURPOSE: To apply voxelwise analysis of diffusion-tensor (DT) magnetic resonance (MR) tractography and T2-weighted MR lesion measurements to characterize intrinsic damage to the brain white matter (WM) tracts and the relation of this damage to the presence and location of focal lesions among the main clinical phenotypes of multiple sclerosis (MS). MATERIALS AND METHODS: The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Brain dual-echo and DT MR images were obtained in 172 patients with MS (22 [13%] with clinically isolated syndromes [CIS] suggestive of MS, 51 [30%] with relapsing-remitting [RR] MS, 44 [26%] with secondary progressive MS, 20 [12%] with benign MS, 35 [20%] with primary progressive MS) and 46 healthy control subjects. Probability maps of the major brain WM tracts were produced. Between-group comparisons were assessed by using analysis of covariance. RESULTS: Compared with the healthy control subjects, the patients with CIS had significantly increased (P < .001) mean diffusivity, axial diffusivity, and radial diffusivity in the majority of WM tracts. The primary progressive MS group showed diffuse increases in mean, axial, and radial diffusivity, with fractional anisotropy (FA) damage involving the majority of WM tracts. No relevant difference in diffusivity measures was found between the CIS and RR-MS groups. Compared with the benign MS group, the RR-MS group had reduced FA values in all WM tracts and decreased axial diffusivity in the majority of tracts. The secondary progressive MS group had pronounced damage to the majority of tracts and, compared with the benign MS group, pronounced FA alteration of the tracts relevant for motor impairment. CONCLUSION: Voxelwise assessment of DT MR index abnormalities is a rewarding strategy for understanding the heterogeneity of clinical MS phenotypes. PMID- 21673228 TI - Acute chest pain investigation: utility of cardiac CT angiography in guiding troponin measurement. AB - PURPOSE: To assess the impact on length of stay and rate of major adverse cardiovascular events of a cardiac computed tomographic (CT) angiography-guided algorithm to examine patients who present to the emergency department (ED) with low- to intermediate-risk chest pain. MATERIALS AND METHODS: The study was approved by the institutional review board, and all patients gave written informed consent. Two hundred three consecutive patients (mean age, 55 years +/- 11 [standard deviation]; 123 men) with low- to intermediate-risk ischemic-type chest pain were prospectively enrolled. Patients underwent initial cardiac CT angiography with subsequent treatment determined by reference to findings at cardiac CT angiography; patients without overt plaque were immediately discharged from the hospital, patients with nonobstructive plaque and mild-to-moderate stenoses were discharged after a negative 6-hour troponin level, and patients with severe stenoses were admitted to the hospital. Discharged patients were followed up for a mean of 14.2 months. Additionally, length of stay and safety outcomes among these patients were compared with those in 102 consecutive patients with low- to intermediate-risk chest pain who presented to the ED and underwent a standard of care (SOC) work-up without cardiac CT angiography. One way analysis of variance with Bonferroni correction was used to compare length of stay between groups. RESULTS: Cardiac CT angiography findings in the 203 patients who underwent cardiac CT angiography were as follows: Sixty-five (32%) patients had no plaque, 107 (53%) had nonobstructive plaque, and 31 (15%) had severe stenoses. At follow-up, there were no deaths or cases of acute coronary syndrome (cardiac CT angiography, 0%, 95% confidence interval [CI]: 0%, 1.85%; SOC, 0%, 95% CI: 0%, 3.63%), and the rate of readmission to the hospital because of chest pain was higher with the SOC approach (9% vs 1%, P = .01). Mean ED length of stay was lower with cardiac CT angiography (6.62 hours +/- 0.38 after a single troponin level and 9.15 hours +/- 0.30 after serial troponin levels) than with the SOC approach (11.62 hours +/- 0.47, P < .001). CONCLUSION: Tailoring troponin measurement to cardiac CT angiography findings is safe and allows early discharge of patients with low- to intermediate-risk chest pain, resulting in reduced length of stay. PMID- 21673229 TI - Rectal cancer: assessment of complete response to preoperative combined radiation therapy with chemotherapy--conventional MR volumetry versus diffusion-weighted MR imaging. AB - PURPOSE: To determine diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging for assessment of complete tumor response (CR) after combined radiation therapy with chemotherapy (CRT) in patients with locally advanced rectal cancer (LARC) by means of volumetric signal intensity measurements and apparent diffusion coefficient (ADC) measurements and to compare the performance of DW imaging with that of T2-weighted MR volumetry. MATERIALS AND METHODS: A retrospective analysis of 50 patients with LARC, for whom clinical and imaging data were retrieved from a previous imaging study approved by the local institutional ethical committee and for which all patients provided informed consent, was conducted. Patients underwent pre- and post-CRT standard T2 weighted MR and DW MR. Two independent readers placed free-hand regions of interest (ROIs) in each tumor-containing section on both data sets to determine pre- and post-CRT tumor volumes and tumor volume reduction rates (volume). ROIs were copied to an ADC map to calculate tumor ADCs. Histopathologic findings were the standard of reference. Receiver operating characteristic (ROC) curves were generated to compare performance of T2-weighted and DW MR volumetry and ADC. The intraclass correlation coefficient (ICC) was used to evaluate interobserver variability and the correlation between T2-weighted and DW MR volumetry. RESULTS: Areas under the ROC curve (AUCs) for identification of a CR that was based on pre CRT volume, post-CRT volume, and volume, respectively, were 0.57, 0.70, and 0.84 for T2-weighted MR versus 0.63, 0.93, and 0.92 for DW MR volumetry (P = .15, .02, .42). Pre- and post-CRT ADC and ADC AUCs were 0.55, 0.54, and 0.51, respectively. Interobserver agreement was excellent for all pre-CRT measurements (ICC, 0.91 0.96) versus good (ICC, 0.61-0.79) for post-CRT measurements. ICC between T2 weighted and DW MR volumetry was excellent (0.97) for pre-CRT measurements versus fair (0.25) for post-CRT measurements. CONCLUSION: Post-CRT DW MR volumetry provided high diagnostic performance in assessing CR and was significantly more accurate than T2-weighted MR volumetry. Post-CRT DW MR was equally as accurate as volume measurements of both T2-weighted and DW MR. Pre-CRT volumetry and ADC were not reliable. PMID- 21673230 TI - Dissected sentinel lymph nodes of breast cancer patients: characterization with high-spatial-resolution 7-T MR imaging. AB - PURPOSE: To investigate the association of 7-T magnetic resonance (MR) imaging characteristics with metastatic nodal invasion, determined with histopathologic assessment in dissected sentinel lymph nodes of breast cancer patients. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. From November 2008 to July 2010, 114 dissected lymph nodes from 33 women (mean age, 57 years; range, 31-80 years) with breast cancer were included. For morphological analysis, three-dimensional (3D) T1-weighted fat-suppressed fast field- (gradient-) echo (isotropic resolution, 180 MUm) MR was performed; 3D nodal dimensions, maximum cortical thickness, and presence of fatty hilum were noted. For quantitative parametric analysis, two-dimensional T1-weighted and 3D T2-, T2*-, and diffusion-weighted images were acquired. Statistical analysis included generalized estimating equations (GEEs), forward and backward stepwise regression analyses, and calculation of positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Of 114 nodes, 26 (23%) were malignant. Morphological criteria showed weak discriminatory power: A fatty center was absent in 35% of malignant nodes and 30% of benign nodes (P = .9). Nodal volume and length-width ratio were not significantly different (P = .11 and .75, respectively). Cortical thickness (threshold level, 3 mm; P = .02) showed 91% NPV for malignancy and 95% NPV for presence of macrometastases. Quantitative parametric analyses showed comparable mean T1, T2, and T2* relaxation time constants and apparent diffusion coefficient for metastatic and benign nodes: 991 msec, 30 msec, and 18 msec and 0.17 mm2/sec versus 1035 msec (P = .14), 31 msec (P = .001; not significant after GEE), and 15 msec (P = .002) and 0.20 mm2/sec (P = .38), respectively. Mean T2* alone offered an additive discriminatory effect for identification of metastatic nodes. Consistent with the notion of pannodal changes accompanying tumor infiltration, mean T2* differed significantly even if only micrometastases were present. The interindividual differences were small, precluding easy clinical implementation. CONCLUSION: Morphological criteria showed poor discriminatory power, even with very-high-spatial-resolution imaging. T2* quantification allowed identification of metastatic nodal invasion. PMID- 21673232 TI - Introduction to special issue: Critical essays on health care reform. PMID- 21673231 TI - Enhancing mitochondrial respiration suppresses tumor promoter TPA-induced PKM2 expression and cell transformation in skin epidermal JB6 cells. AB - Differentiated cells primarily metabolize glucose for energy via the tricarboxylic acid cycle and oxidative phosphorylation, but cancer cells thrive on a different mechanism to produce energy, characterized as the Warburg effect, which describes the increased dependence on aerobic glycolysis. The M2 isoform of pyruvate kinase (PKM2), which is responsible for catalyzing the final step of aerobic glycolysis, is highly expressed in cancer cells and may contribute to the Warburg effect. However, whether PKM2 plays a contributing role during early cancer development is unclear. In our studies, we have made an attempt to elucidate the effects of varying mitochondrial respiration substrates on skin cell transformation and expression of PKM2. Tumorigenicity in murine skin epidermal JB6 P+ (promotable) cells was measured in a soft agar assay using 12-O tetradecanoylphorbol-13-acetate (TPA) as a tumor promoter. We observed a significant reduction in cell transformation upon pretreatment with the mitochondrial respiration substrate succinate or malate/pyruvate. We observed that increased expression and activity of PKM2 in TPA-treated JB6 P+ cells and pretreatment with succinate or malate/pyruvate suppressed the effects. In addition, TPA treatment also induced PKM2 whereas PKM1 expression was suppressed in mouse skin epidermal tissues in vivo. In comparison with JB6 P+ cells, the nonpromotable JB6 P- cells showed no increase in PKM2 expression or activity upon TPA treatment. Knockdown of PKM2 using a siRNA approach significantly reduced skin cell transformation. Thus, our results suggest that PKM2 activation could be an early event and play a contributing role in skin tumorigenesis. PMID- 21673234 TI - Big ideas, broken institutions, and the wrath at the grass roots. PMID- 21673235 TI - Delegated governance in the Affordable Care Act. PMID- 21673236 TI - They're back: the public plan, the reincarnation of Harry and Louise, and the limits of Obamacare. PMID- 21673237 TI - You call it public, I call it private, let's call the whole thing off? PMID- 21673238 TI - Too big to fail: the enactment of health care reform. PMID- 21673240 TI - The elements of surprise: how health reform happened. PMID- 21673241 TI - It was a different time: Obama and the unique opportunity for health care reform. PMID- 21673242 TI - Why reform happened. PMID- 21673243 TI - Muddling through the muddled middle. PMID- 21673244 TI - Interest-group influence on the Patient Protection and Affordability Act of 2010: winners and losers in the health care reform debate. PMID- 21673245 TI - The politics of ideas: where did the public option come from and where is it going? PMID- 21673246 TI - Federalism and the Patient Protection and Affordable Care Act of 2010: the Founding Fathers would not be surprised. PMID- 21673247 TI - The states' role under the Patient Protection and Affordable Care Act. PMID- 21673249 TI - Throwing darts: Americans' elusive search for health care cost control. PMID- 21673250 TI - Health reform: avoiding the backlash. PMID- 21673251 TI - A progressive turn of events. PMID- 21673252 TI - Do we really want to control health care spending? PMID- 21673253 TI - The real constitutional problem with the Affordable Care Act. PMID- 21673254 TI - Civilized medicine: physicians and health care reform. PMID- 21673256 TI - Prevention and public health. PMID- 21673257 TI - Getting to universal coverage with better safety-net programs for the uninsured. PMID- 21673258 TI - Behavioral health and health care reform. PMID- 21673259 TI - At least we're still free to choose to die at home: a CLASS Act. PMID- 21673260 TI - Affordability of health insurance to small business: implications of the Patient Protection and Affordable Care Act. PMID- 21673262 TI - The Medicaid platform: can the termites be kept at bay? PMID- 21673263 TI - "Obama lies, grandma dies": the uncertain politics of Medicare and the Patient Protection and Affordable Care Act. PMID- 21673265 TI - Health reform 2010: the missing philosophical premises in the long-running health care debate. PMID- 21673266 TI - American health reform in comparative perspective: big bang, blueprint, or mosaic? PMID- 21673267 TI - Obama's health reform in European perspective. PMID- 21673269 TI - Regulating the U.S. health care system: failure in motion. PMID- 21673270 TI - Patient Protection and Affordable Care Act cost-containment choices: the case for incentive-based approaches. PMID- 21673271 TI - Why we need health care reform now. PMID- 21673272 TI - Health care reform as a halfway technology. PMID- 21673274 TI - Health reform: the politics of implementation. PMID- 21673275 TI - America's critical juncture: the Affordable Care Act and its reverberations. PMID- 21673276 TI - Proteomic analysis and discovery using affinity proteomics and mass spectrometry. AB - Antibody-based microarrays are a rapidly evolving affinity-proteomic methodology that recently has shown great promise in clinical applications. The resolution of these proteomic analyses is, however, directly related to the number of data points, i.e. antibodies, included on the array. Currently, this is a key bottleneck because of limited availability of numerous highly characterized antibodies. Here, we present a conceptually new method, denoted global proteome survey, opening up the possibility to probe any proteome in a species-independent manner while still using a limited set of antibodies. We use context-independent motif-specific antibodies directed against short amino acid motifs, where each motif is present in up to a few hundred different proteins. First, the digested proteome is exposed to these antibodies, whereby motif-containing peptides are enriched, which then are detected and identified by mass spectrometry. In this study, we profiled extracts from human colon tissue, yeast cells lysate, and mouse liver tissue to demonstrate proof-of-concept. PMID- 21673278 TI - Paroxysmal dystonia as a rare initial manifestation of multiple sclerosis. AB - Multiple sclerosis is an uncommon disease in childhood and adolescence and is rarely associated with movement disorders other than tremor. The differential diagnosis is difficult to establish when, particularly, movement disorder presents as the initial manifestation of multiple sclerosis. Video electroencephalography monitoring is the gold-standard method for the differential diagnosis of epileptic and paroxysmal nonepileptic events, including movement disorders and psychogenic seizures. This article presents a patient with paroxysmal dystonia secondary to multiple sclerosis who previously was diagnosed and treated as having conversion disorder and epilepsy. The utility of video electroencephalography monitoring during the process of differential diagnosis is discussed. PMID- 21673277 TI - Copeptin does not add diagnostic information to high-sensitivity troponin T in low- to intermediate-risk patients with acute chest pain: results from the rule out myocardial infarction by computed tomography (ROMICAT) study. AB - PURPOSE: Copeptin, a stable peptide derived from the AVP precursor, has been linked to presence and severity of myocardial ischemia. We sought to evaluate the predictive value of copeptin and its incremental value beyond that of high sensitivity cardiac troponin T (hs-cTnT) in patients with acute chest pain and low to intermediate risk for acute coronary syndrome (ACS). METHODS: We recruited patients who presented with acute chest pain to the emergency department and had a negative initial conventional troponin T test (<0.03 MUg/L). In all patients, hs-cTnT and copeptin measurements were taken. Each patient also underwent cardiac computed tomography (CT) and coronary angiography. RESULTS: Baseline copeptin concentrations, in contrast to hs-cTnT, were not significantly higher in patients with ACS than in those without (P = 0.24). hs-cTnT showed an earlier rise in patients with ACS than copeptin, when analyses were stratified by time. A copeptin concentration >=7.38 pmol/L had a negative predictive value (NPV) of 94% and a sensitivity of 51%, whereas hs-cTnT (>=13.0 pg/mL) had a NPV of 96% and a sensitivity of 63%. The combination of copeptin and hs-cTnT resulted in a lower diagnostic accuracy than hs-cTnT alone. Finally, on cardiac CT, copeptin concentrations were not associated with coronary artery morphology, although they were related to the presence of left ventricular dysfunction (P = 0.02). CONCLUSIONS: Among patients with acute chest pain and low to intermediate risk for ACS, copeptin concentrations are not independently predictive of ACS and do not add diagnostic value beyond that of hs-cTnT measurements. PMID- 21673279 TI - Long-term open-label study of adjunctive topiramate in infants with refractory partial-onset seizures. AB - Data from 2 studies (phase 1 and phase 3) in infants <2 years old (N = 284; mean [SD] age, 12[6.3] months) with refractory partial-onset seizures were pooled to assess the long-term safety up to 1 year (primary objective) and tolerability of adjunctive topiramate treatment (mean treatment duration = 282 days). Monthly seizure rate summaries were also assessed. During the open-label extensions of these studies, study medication was first titrated to a dose of 25 mg/kg/d with subsequent uptitration to the maximum dosage tolerated, or seizure freedom, or a maximum of 60 mg/kg/d, whichever occurred first. The most common treatment emergent adverse events (>=30%) were fever (52%), respiratory tract infections (51%), anorexia (35%), and acidosis (31%). Mean (SD) changes from pretreatment baseline to endpoint in Z scores for growth parameters were as follows: -0.82 (1.19) (body weight), -0.45 (1.60) (body length), and -0.36 (1.02) (head circumference).Tolerability in infants was consistent with previous studies. PMID- 21673280 TI - Influence of nerve growth factor in endometriosis-associated symptoms. AB - To investigate the role of the nerve growth factor (NGF) in the development of dysmenorrhea/pelvic pain in patients with endometriosis, we performed a prospective, clinical, blind study. Peritoneal fluids (PFs) were obtained from patients with histologically proven endometriosis. Patients with endometriosis were divided into 7 different groups depending on their preoperative pain score and symptomatology: patients with no pain, patients with minimal pain (dysmenorrhea, pelvic pain, or both), and patients with severe pain (dysmenorrhea, pelvic pain, or both) and were used for the neuronal growth assay with cultured chicken dorsal root ganglia (DRG) and for Western blot analyses. Dorsal root ganglia were stained with anti-calcitonin gene-related peptide (CGRP) and anti-growth-associated protein 43 (GAP 43). Peritoneal fluids from patients with endometriosis induce neurite outgrowth. There was no significant difference in the outgrowth between the 7 pain groups. Western blot analyses showed a moderate NGF expression in the PFs from patients with endometriosis, without significant differences in the 7 pain groups. The present study suggests that the neurotrophic properties of endometriotic tissues are endometriosis- and not pain associated. PMID- 21673281 TI - A model for preconceptional prediction of recurrent early-onset preeclampsia: derivation and internal validation. AB - OBJECTIVE: To develop a model to identify women at very low risk of recurrent early-onset preeclampsia. METHODS: We enrolled 407 women who had experienced early-onset preeclampsia in their first pregnancy, resulting in a delivery before 34 weeks' gestation. Preeclampsia was defined as hypertension (systolic blood pressure >=140 mm Hg and/or diastolic blood pressure >=90 mm Hg) after 20 weeks' gestation with de novo proteinuria (>=300 mg urinary protein excretion/day). Based on the previous published evidence and expert opinion, 5 predictors (gestational age at previous birth, prior small-for-gestational-age newborn, fasting blood glucose, body mass index, and hypertension) were entered in a logistic regression model. Discrimination and calibration were evaluated after adjusting for overfitting by bootstrapping techniques. RESULTS: Early-onset disease recurred in 28 (6.9%) of 407 women. The area under the receiver operating characteristic (ROC) curve of the model was 0.65 (95% CI: 0.56-0.74). Calibration was good, indicated by a nonsignificant Hosmer-Lemeshow test (P = .11). Using a predicted absolute risk threshold of, for example, 4.6% (ie, women identified with an estimated risk either above or below 4.6%), the sensitivity was 100%, with a specificity of 26%. In such a strategy, no women who developed preeclampsia were missed, while 98 of the 407 women would be regarded as low risk of recurrent early-onset preeclampsia, not necessarily requiring intensified antenatal care. CONCLUSION: Our model may be helpful in the identification of women at very low risk of recurrent early-onset preeclampsia. Before widespread application, our model should be validated in other populations. PMID- 21673282 TI - Endometriotic implants regress in rat models treated with puerarin by decreasing estradiol level. AB - Phytoestrogens, which have a weak estrogenic effect, bind to estrogen receptors (ERs), thereby competing with estradiol, have an antiestrogenic effect on women of reproductive age with high estrogenic level. Herein, we examined the ability of the phytoestrogen Puerarin to treat endometriosis in rat models of endometriosis. In total, 75 adult, mature female Sprague-Dawley rats in which endometriotic implants were successfully induced by transplanting autologous endometrial tissue to ectopic sites were used in this study. Oral gavage of Puerarin (at doses of 600, 200, or 60 mg/kg per day) or Danazol (80 mg/kg per day) started 4 weeks after implantation. Control model rats received vehicle alone. After administration for 4 weeks, the weight of the ectopic implants, estradiol concentration, as well as ER-alpha and Aromatase P450 (P450arom) expression in different groups of rat tissues were evaluated after treatment. The endometriotic tissue weight and serum estrogen levels were significantly lower in high, medium, low dose of Puerarin and Danazol treatment groups than that in control group (P < .05 or P < .01). Low-dose Puerarin inhibited P450arom expression and significantly reduced estrogen levels in endometriotic tissue (P < .01). Three doses of Puerarin had no adverse effects on liver, kidney, and ovary, whereas high-dose Puerarin administration caused thinner bone trabecula with distortion and breakage and Danazol administration caused mild or moderate hepatic cell damage. These data demonstrate that Puerarin was able to effectively suppress the growth and development of ectopic endometrium in the rat endometriosis model, even at low doses, suggesting it may be an effective treatment for endometriosis. PMID- 21673283 TI - Food and Drug Administration regulation of food safety. PMID- 21673284 TI - The cover. Monet painting in his garden at Argenteuil. PMID- 21673285 TI - A piece of my mind. Cyanosis. PMID- 21673286 TI - New guidance covers ways to prevent and treat hypertension in elderly patients. PMID- 21673287 TI - Report calls for US funding to speed global health research and innovation. PMID- 21673288 TI - Medical students' paradox: drug company materials biased yet helpful, they say. PMID- 21673289 TI - Trauma and long-term mortality. PMID- 21673290 TI - Shadowing physicians. PMID- 21673291 TI - Shadowing physicians. PMID- 21673292 TI - Shadowing physicians. PMID- 21673293 TI - In vitro propagation of human prepubertal spermatogonial stem cells. PMID- 21673294 TI - Paid malpractice claims for adverse events in inpatient and outpatient settings. AB - CONTEXT: An analysis of paid malpractice claims may provide insight into the prevalence and seriousness of adverse medical events in the outpatient setting. OBJECTIVE: To report and compare the number, magnitude, and type of paid malpractice claims for events in inpatient and outpatient settings. DESIGN AND SETTING: Retrospective analysis of malpractice claims paid on behalf of physicians in outpatient and inpatient settings using data from the National Practitioner Data Bank from 2005 through 2009. We evaluated trends in claims paid by setting, characteristics of paid claims, and factors associated with payment amount. MAIN OUTCOME MEASURES: Number of paid claims, mean and median payment amounts, types of errors, and outcomes of errors. RESULTS: In 2009, there were 10,739 malpractice claims paid on behalf of physicians. Of these paid claims, 4910 (47.6%; 95% confidence interval [CI], 46.6%-48.5%) were for events in the inpatient setting, 4448 (43.1%; 95% CI, 42.1%-44.0%) were for events in the outpatient setting, and 966 (9.4%; 95% CI, 8.8%-9.9%) involved events in both settings. The proportion of payments for events in the outpatient setting increased by a small but statistically significant amount, from 41.7% (95% CI, 40.9%-42.6%) in 2005 to 43.1% (95% CI, 42.1%-44.0%) in 2009 (P < .001 for trend across years). In the outpatient setting, the most common reason for a paid claim was diagnostic (45.9%; 95% CI, 44.4%-47.4%), whereas in the inpatient setting the most common reason was surgical (34.1%; 95% CI, 32.8%-35.4%). Major injury and death were the 2 most common outcomes in both settings. Mean payment amount for events in the inpatient setting was significantly higher than in the outpatient setting ($362,965; 95% CI, $348,192-$377,738 vs $290,111; 95% CI, $278,289 $301,934; P < .001). CONCLUSION: In 2009, the number of paid malpractice claims reported to the National Practitioner Data Bank for events in the outpatient setting was similar to the number in the inpatient setting. PMID- 21673295 TI - Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. AB - CONTEXT: A high level of the phosphate-regulating hormone fibroblast growth factor 23 (FGF-23) is associated with mortality in patients with end-stage renal disease, but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease. OBJECTIVE: To evaluate FGF-23 as a risk factor for adverse outcomes in patients with chronic kidney disease. DESIGN, SETTING, AND PARTICIPANTS: A prospective study of 3879 participants with chronic kidney disease stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. MAIN OUTCOME MEASURES: All-cause mortality and end-stage renal disease. RESULTS: At study enrollment, the mean (SD) estimated glomerular filtration rate (GFR) was 42.8 (13.5) mL/min/1.73 m(2), and the median FGF-23 level was 145.5 RU/mL (interquartile range [IQR], 96-239 reference unit [RU]/mL). During a median follow-up of 3.5 years (IQR, 2.5-4.4 years), 266 participants died (20.3/1000 person-years) and 410 reached end-stage renal disease (33.0/1000 person-years). In adjusted analyses, higher levels of FGF-23 were independently associated with a greater risk of death (hazard ratio [HR], per SD of natural log transformed FGF-23, 1.5; 95% confidence interval [CI], 1.3-1.7). Mortality risk increased by quartile of FGF-23: the HR was 1.3 (95% CI, 0.8-2.2) for the second quartile, 2.0 (95% CI, 1.2-3.3) for the third quartile, and 3.0 (95% CI, 1.8-5.1) for the fourth quartile. Elevated fibroblast growth factor 23 was independently associated with significantly higher risk of end-stage renal disease among participants with an estimated GFR between 30 and 44 mL/min/1.73 m(2) (HR, 1.3 per SD of FGF-23 natural log-transformed FGF-23; 95% CI, 1.04-1.6) and 45 mL/min/1.73 m(2) or higher (HR, 1.7; 95% CI, 1.1-2.4), but not less than 30 mL/min/1.73 m(2). CONCLUSION: Elevated FGF-23 is an independent risk factor for end-stage renal disease in patients with relatively preserved kidney function and for mortality across the spectrum of chronic kidney disease. PMID- 21673297 TI - Improving postdischarge outcomes in patients hospitalized for acute heart failure syndromes. PMID- 21673298 TI - Changing concepts of Alzheimer disease. PMID- 21673296 TI - Television viewing and risk of type 2 diabetes, cardiovascular disease, and all cause mortality: a meta-analysis. AB - CONTEXT: Prolonged television (TV) viewing is the most prevalent and pervasive sedentary behavior in industrialized countries and has been associated with morbidity and mortality. However, a systematic and quantitative assessment of published studies is not available. OBJECTIVE: To perform a meta-analysis of all prospective cohort studies to determine the association between TV viewing and risk of type 2 diabetes, fatal or nonfatal cardiovascular disease, and all-cause mortality. DATA SOURCES AND STUDY SELECTION: Relevant studies were identified by searches of the MEDLINE database from 1970 to March 2011 and the EMBASE database from 1974 to March 2011 without restrictions and by reviewing reference lists from retrieved articles. Cohort studies that reported relative risk estimates with 95% confidence intervals (CIs) for the associations of interest were included. DATA EXTRACTION: Data were extracted independently by each author and summary estimates of association were obtained using a random-effects model. DATA SYNTHESIS: Of the 8 studies included, 4 reported results on type 2 diabetes (175,938 individuals; 6428 incident cases during 1.1 million person-years of follow-up), 4 reported on fatal or nonfatal cardiovascular disease (34,253 individuals; 1052 incident cases), and 3 reported on all-cause mortality (26,509 individuals; 1879 deaths during 202,353 person-years of follow-up). The pooled relative risks per 2 hours of TV viewing per day were 1.20 (95% CI, 1.14-1.27) for type 2 diabetes, 1.15 (95% CI, 1.06-1.23) for fatal or nonfatal cardiovascular disease, and 1.13 (95% CI, 1.07-1.18) for all-cause mortality. While the associations between time spent viewing TV and risk of type 2 diabetes and cardiovascular disease were linear, the risk of all-cause mortality appeared to increase with TV viewing duration of greater than 3 hours per day. The estimated absolute risk differences per every 2 hours of TV viewing per day were 176 cases of type 2 diabetes per 100,000 individuals per year, 38 cases of fatal cardiovascular disease per 100,000 individuals per year, and 104 deaths for all cause mortality per 100,000 individuals per year. CONCLUSION: Prolonged TV viewing was associated with increased risk of type 2 diabetes, cardiovascular disease, and all-cause mortality. PMID- 21673300 TI - Surveillance bias in outcomes reporting. PMID- 21673299 TI - Enhancing national policy and programs to address elder abuse. PMID- 21673301 TI - Malpractice risk in ambulatory settings: an increasing and underrecognized problem. PMID- 21673302 TI - Superficial corneal growth. PMID- 21673303 TI - The extraordinary Dr Biggs. PMID- 21673304 TI - JAMA patient page. Ovarian cancer. PMID- 21673306 TI - Developmental exposure to di(2-ethylhexyl) phthalate impairs endocrine pancreas and leads to long-term adverse effects on glucose homeostasis in the rat. AB - -Di(2-ethylhexyl) phthalate (DEHP), a typical endocrine-disrupting chemical (EDC), is widely used as plasticizer. DEHP exposure in humans is virtually ubiquitous, and those undergoing certain medical procedures can be especially high. In this study, we investigated whether developmental DEHP exposure disrupted glucose homeostasis in the rat and whether this was associated with the early impairment in endocrine pancreas. Pregnant Wistar rats were administered DEHP (1.25 and 6.25 mg.kg(-1).day(-1)) or corn oil throughout gestation and lactation by oral gavage. Body weight, glucose and insulin tolerance, and beta cell morphometry and function were examined in offspring during the growth. In this study, developmental DEHP exposure led to abnormal beta-cell ultrastructure, reduced beta-cell mass, and pancreatic insulin content as well as alterations in the expression of genes involved in pancreas development and beta-cell function in offspring at weaning. At adulthood, female DEHP-exposed offspring exhibited elevated blood glucose, reduced serum insulin, impaired glucose tolerance, and insulin secretion. Male DEHP-exposed offspring had increased serum insulin, although there were no significant differences in blood glucose at fasting and during glucose tolerance test. In addition, both male and female DEHP-exposed offspring had significantly lower birth weight and maintained relatively lower body weight up to 27 wk of age. These results suggest that developmental exposure to DEHP gives rise to beta-cell dysfunction and the whole body glucometabolic abnormalities in the rat. DEHP exposure in critical periods of development can be a potential risk factor, at least in part, for developing diabetes. PMID- 21673305 TI - Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity. AB - Hepatic vasculature is not thought to pose a permeability barrier for diffusion of macromolecules from the bloodstream to hepatocytes. In contrast, in extrahepatic tissues, the microvasculature is critically important for insulin action, because transport of insulin across the endothelial cell layer is rate limiting for insulin-stimulated glucose disposal. However, very little is known concerning the role in this process of pericytes, the mural cells lining the basolateral membrane of endothelial cells. PDGF-B is a growth factor involved in the recruitment and function of pericytes. We studied insulin action in mice expressing PDGF-B lacking the proteoglycan binding domain, producing a protein with a partial loss of function (PDGF-B(ret/ret)). Insulin action was assessed through measurements of insulin signaling and insulin and glucose tolerance tests. PDGF-B deficiency enhanced hepatic vascular transendothelial transport. One outcome of this change was an increase in hepatic insulin signaling. This correlated with enhanced whole body glucose homeostasis and increased insulin clearance from the circulation during an insulin tolerance test. In obese mice, PDGF-B deficiency was associated with an 80% reduction in fasting insulin and drastically reduced insulin secretion. These mice did not have significantly higher glucose levels, reflecting a dramatic increase in insulin action. Our findings show that, despite already having a high permeability, hepatic transendothelial transport can be further enhanced. To the best of our knowledge, this is the first study to connect PDGF-B-induced changes in hepatic sinusoidal transport to changes in insulin action, demonstrating a link between PDGF-B signaling and insulin sensitivity. PMID- 21673308 TI - Lipid signatures of unstable atheromas: fossils or a step toward personalized lipidomics-metabolomics? PMID- 21673309 TI - Genetic links between circulating cells and cardiovascular risk. PMID- 21673307 TI - Cutaneous hypothalamic-pituitary-adrenal axis homolog: regulation by ultraviolet radiation. AB - The hypothalamic-pituitary-adrenal (HPA) axis maintains basal and stress-related homeostasis in vertebrates. Skin expresses all elements of the HPA axis including corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), ACTH, beta endorphin (beta-END) with corresponding receptors, the glucocorticoidogenic pathway, and the glucocorticoid receptor (GR). To test the hypothesis that cutaneous responses to environmental stressors follow the organizational structure of the central response to stress, the activity of the "cutaneous HPA" axis homolog was investigated after exposure to ultraviolet radiation (UVR) wavelengths of UVA (320-400 nm), UVB (280-320 nm), and UVC (100-280 nm) in human skin organ culture and in co-cultured keratinocytes/melanocytes. The level of stimulation of CRH, POMC, MC1R, MC2R, CYP11A1, and CYP11B1 genes was dependent on UV wavelengths and doses, with the highest effects observed for highly energetic UVC and UVB. ELISA and Western assays showed significant production of CRH, POMC, ACTH, and CYP11A1 proteins and of cortisol, with a decrease in GR expression only after UVB and UVC. However, beta-END expression was also stimulated by UVA. Immunocytochemistry localized the deposition of the aforesaid antigens predominantly to the epidermis with additional accumulation of CRH, beta-END, and ACTH in the dermis. UVR-stimulated CYP11A1 expression was seen in the basal layer of the epidermis and cells of adjacent dermis. Thus, the capacity to activate or change the spatial distribution of the cutaneous HPA axis elements is dependent on highly energetic wavelengths (UVC and UVB), implying a dependence of a local stress response on their noxious activity with overlapping or alternative mechanisms activated by UVA. PMID- 21673310 TI - Gauging the risk of arrhythmic death by common genetic variants: resurgence of the sinister QT. PMID- 21673311 TI - Arrhythmogenic cardiomyopathy: transgenic animal models provide novel insights into disease pathobiology. PMID- 21673312 TI - Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. PMID- 21673313 TI - Regulatory elements in noncoding DNA in the chromosome 9p21 locus. PMID- 21673314 TI - IKKepsilon: a kinase at the intersection of signaling and membrane traffic. AB - The ability to coordinate membrane trafficking events in space and time is of fundamental importance in biology. Polarized trafficking is essential for processes as diverse as cytokinesis, regulated endocytosis, cell motility, and morphogenesis, yet the interface between cellular signaling systems and the trafficking machinery remains ill defined. Using Drosophila mechanosensory bristle growth as a paradigm for polarized trafficking, a study has uncovered a role for localized activation of the inhibitor of nuclear factor kappaB kinase, subtype epsilon (IKKepsilon) at the tip of these bristles, where it regulates the trafficking of recycling endosomal vesicles into and out of the bristle tip. IKKepsilon phosphorylates the Rab11 effector Nuf (which is encoded by nuclear fallout), and in doing so coordinates the interaction between Nuf and the motor protein dynein, which regulates the directionality of membrane traffic by a "motor-switching" mechanism. Similar results in mammalian systems suggest that IKKepsilon-dependent phosphorylation of Rab11 effectors is an evolutionarily conserved mechanism by which cells may regulate polarized growth, and studies of vesicle trafficking in cytokinesis support the concept of motor switching as a generic mechanism to modulate the distribution of endosomes. Phosphorylation of other Rab11 effectors also modulates polarized trafficking in other experimental systems, which hints that similar mechanisms may be widely used to control the directionality of membrane traffic. PMID- 21673315 TI - Structure of a pentavalent G-actin*MRTF-A complex reveals how G-actin controls nucleocytoplasmic shuttling of a transcriptional coactivator. AB - Subcellular localization of the actin-binding transcriptional coactivator MRTF-A is controlled by its interaction with monomeric actin (G-actin). Signal-induced decreases in G-actin concentration reduce MRTF-A nuclear export, leading to its nuclear accumulation, whereas artificial increases in G-actin concentration in resting cells block MRTF-A nuclear import, retaining it in the cytoplasm. This regulation is dependent on three actin-binding RPEL motifs in the regulatory domain of MRTF-A. We describe the structures of pentavalent and trivalent G actin*RPEL domain complexes. In the pentavalent complex, each RPEL motif and the two intervening spacer sequences bound an actin monomer, forming a compact assembly. In contrast, the trivalent complex lacked the C-terminal spacer- and RPEL-actins, both of which bound only weakly in the pentavalent complex. Cytoplasmic localization of MRTF-A in unstimulated fibroblasts also required binding of G-actin to the spacer sequences. The bipartite MRTF-A nuclear localization sequence was buried in the pentameric assembly, explaining how increases in G-actin concentration prevent nuclear import of MRTF-A. Analyses of the pentavalent and trivalent complexes show how actin loads onto the RPEL domain and reveal a molecular mechanism by which actin can control the activity of one of its binding partners. PMID- 21673316 TI - TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. AB - The basal-like subtype of breast cancer has an aggressive clinical behavior compared to that of the luminal subtype. We identified the microRNAs (miRNAs) miR 221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs and showed that expression of miR-221/222 decreased expression of epithelial-specific genes and increased expression of mesenchymal-specific genes, and increased cell migration and invasion in a manner characteristic of the epithelial-to mesenchymal transition (EMT). The transcription factor FOSL1 (also known as Fra 1), which is found in basal-like breast cancers but not in the luminal subtype, stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of the epidermal growth factor receptor (EGFR) or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. Furthermore, miR-221/222 mediated reduction in E-cadherin abundance depended on their targeting the 3' untranslated region of the GATA family transcriptional repressor TRPS1 (tricho rhino-phalangeal syndrome type 1), which inhibited EMT by decreasing ZEB2 (zinc finger E-box-binding homeobox2) expression. We conclude that by promoting EMT, miR-221/222 may contribute to the more aggressive clinical behavior of basal-like breast cancers. PMID- 21673317 TI - Letter by Layland et al regarding article, "Validation of intravascular ultrasound-derived parameters with fractional flow reserve for assessment of coronary stenosis severity". PMID- 21673319 TI - Letter by Dregelid regarding article, "Intra-arterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized start, placebo-controlled pilot trial (PROVASA)". PMID- 21673320 TI - Letter by Y-Hassan regarding article, "Simple or complex stenting for bifurcation coronary lesions: a patient-level pooled analysis of the Nordic Bifurcation Study and the British Bifurcation Coronary Study". PMID- 21673321 TI - Letter by Movahed regarding article, "Simple or complex stenting for bifurcation coronary lesions: a patient-level pooled analysis of the Nordic Bifurcation Study and the British Bifurcation Coronary Study". PMID- 21673322 TI - Atherosclerotic renal artery stenosis: flaws in estimated glomerular filtration rate and the problem of progressive kidney injury. PMID- 21673323 TI - Radiation exposure in cardiovascular medicine: how do we protect our patients and ourselves? PMID- 21673324 TI - Left main pseudoaneurysm after postpartum coronary dissection. PMID- 21673325 TI - Cerebellum proteomics addressing the cognitive deficit of rats perinatally exposed to the food-relevant polychlorinated biphenyl 138. AB - Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals by mechanisms that remain unknown. Recently, it has been shown that developmental exposure to 2,2',3,4,4',5'-hexachlorobiphenyl (PCB138), a food-relevant PCB congener, decreases the learning ability of young rats. The aim of this study was to characterize the effect of perinatal exposure to PCB138 on the brain proteome profile in young rats in order to gain insight into the mechanisms underlying PCB138 neurotoxicity. Comparison of the cerebellum proteome from 3-month-old unexposed and PCB138-exposed male offspring was performed using state-of-the-art label-free semiquantitative mass spectrometry method. Biological pathways associated with Ca(2+) homeostasis and androgen receptor signaling pathways were primarily disrupted. These perturbations may contribute toward a premature ageing like proteome profile of the cerebellum that is triggered by PCB138 exposure in males. Our proteomic data provide insights into the phenomena that may be contributing to the PCB138 neurotoxicity effects observed in laboratory rodents and correlate with PCB exposure and decreased cognitive functions in humans. As such, this study highlights the importance of PCB138 as a risk factor in developmental neurotoxicity in laboratory rodents and humans. PMID- 21673326 TI - Repeated developmental exposure of mice to chlorpyrifos oxon is associated with paraoxonase 1 (PON1)-modulated effects on cerebellar gene expression. AB - Microarray analysis was used to examine effects of repeated postnatal exposure to chlorpyrifos oxon (CPO) on gene expression in the cerebellum of genetically modified mice. The high-density lipoprotein-associated enzyme paraoxonase 1 (PON1) plays a significant role in the detoxication of CPO, which is present in exposures and generated from chlorpyrifos (CPF) in vivo following exposure. Two factors are important in modulating toxicity of CPO, the Q192R PON1 polymorphism and PON1 plasma level, which is low at birth and increases throughout postnatal development. Mice used in these studies included wild type (PON1(+/+)), PON1 knockout (PON1(-/-)), and two transgenic lines (tgHuPON1(Q192), tgHuPON1(R192)) expressing either human PON1(Q192) or PON1(R192) on the PON1(-/-) background. PON1(R192) hydrolyzes CPO more efficiently than PON1(Q192). All four genotypes exposed to CPO (0.35 or 0.50 mg/kg/day) daily from postnatal day (PND) 4 to PND 21 showed significant differences in gene expression on PND 22 compared with controls. Pathway analysis and Gene Set Analysis revealed multiple pathways and gene sets significantly affected by CPO exposure, including genes involved in mitochondrial dysfunction, oxidative stress, neurotransmission, and nervous system development. Comparison between genotypes revealed specific genes, gene sets, and pathways differentially affected between tgHuPON1(Q192) and tgHuPON1(R192) mice and between PON1(-/-) and PON1(+/+) mice following CPO exposure. Repeated CPO exposure also resulted in a dose-related decrease in brain acetylcholinesterase activity during postnatal development in PON1(-/-) and tgHuPON1(Q192) mice but not in PON1(+/+) or tgHuPON1(R192) mice. These findings indicate that PON1 status plays a critical role in modulating the effects of neonatal CPO exposure in the developing brain. PMID- 21673327 TI - Tributyltin synergizes with 20-hydroxyecdysone to produce endocrine toxicity. AB - One of the great challenges facing modern toxicology is in predicting the hazard associated with chemical mixtures. The development of effective means of predicting the toxicity of chemical mixtures requires an understanding of how chemicals interact to produce nonadditive outcomes (e.g., synergy). We hypothesized that tributyltin would elicit toxicity in daphnids (Daphnia magna) by exaggerating physiological responses to 20-hydroxyecdysone signaling via synergistic activation of the retinoid X receptor (RXR):ecdysteroid receptor (EcR) complex. Using reporter gene assays, we demonstrated that RXR, alone, is activated by a variety of ligands including tributyltin, whereas RXR:EcR heterodimers were not activated by tributyltin. However, tributyltin, in combination with the daphnid EcR ligand 20-hydroxyecdysone, caused concentration dependent, synergistic activation of the RXR:EcR reporter. Electrophoretic mobility shift assays revealed that tributyltin did not enhance the activity of 20-hydroxyecdysone by increasing binding of the receptor complex to a DR-4 DNA binding site. Exposure of daphnids to elevated concentrations of 20 hydroxyecdysone caused premature and incomplete ecdysis resulting in death. Tributyltin exaggerated this effect of exogenous 20-hydroxyecdysone. Further, exposure of daphnids to tributyltin enhanced the inductive effects of 20 hydroxyecdysone on expression of the 20-hydroxyecdysone-inducible gene HR3. Continuous, prolonged exposure of maternal daphnids to concentrations of tributyltin resulted in mortality concurrent with molting. Taken together, these results demonstrate that xenobiotics, such as tributyltin, can interact with RXR to influence gene expression regulated by the heterodimeric partner to RXR. The result of such interactions can be toxicity due to inappropriate or exaggerated hormonal signaling. The application of the in vitro/in vivo approach used in this study is discussed in relation to modeling of nonadditive interactions among constituents of chemical mixtures. PMID- 21673328 TI - Comparative oxidative metabolism of BDE-47 and BDE-99 by rat hepatic microsomes. AB - Polybrominated diphenyl ethers (PBDEs) are flame-retardant chemicals that have become ubiquitous environmental pollutants. 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) and 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) are among the most prevalent PBDEs detected in humans, wildlife, and abiotic environmental matrices. The purpose of this study was to investigate the oxidative metabolism of BDE-47 and BDE-99 in rat hepatic microsomes by comparing metabolite formation rates, kinetic parameters associated with metabolite formation, and the effects of prototypical cytochrome P450 (CYP) inducers. The CYP enzymes involved were also identified. Incubation of BDE-47 with hepatic microsomes from phenobarbital treated rats generated a total of five hydroxylated (OH-BDE) metabolites, among which 4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether (4'-OH-BDE-49) and 3-hydroxy 2,2',4,4'-tetrabromodiphenyl ether (3-OH-BDE-47) were the major metabolites, as identified using authentic standards and quantified by liquid chromatography/mass spectrometry. Incubations of BDE-99 with hepatic microsomes from dexamethasone treated rats produced a total of seven hydroxylated metabolites, among which 4 hydroxy-2,2',3,4',5-pentabromodiphenyl ether (4-OH-BDE-90) and 6'-hydroxy 2,2',4,4',5-pentabromodiphenyl ether (6'-OH-BDE-99) were the major metabolites. Although the overall rate of oxidative metabolism of BDE-99 by hepatic microsomes was greater than that of BDE-47, para-hydroxylation involving a National Institutes of Health shift mechanism represented a major metabolic pathway for both PBDE congeners. Among the rat recombinant CYP enzymes tested, CYP2A2 and CYP3A1 were the most active in BDE-47 and BDE-99 metabolism, respectively. However, CYP1A1 exhibited the highest activity for 4'-OH-BDE-49 and 6'-OH-BDE-99 formation, and CYP3A1 exhibited the highest activity for 3-OH-BDE-47 and 4-OH-BDE 90 formation. Collectively, the results demonstrate that oxidative metabolism of BDE-47 and BDE-99 is mediated by distinct but overlapping sets of CYP enzymes and represents a key process that determines the bioaccumulation of BDE-47 and BDE-99 in mammals. PMID- 21673329 TI - Intra-articular therapy to treat septic arthritis in a dog. AB - A 6 yr old female spayed Labrador retriever was examined for severe pain and a nonweight-bearing right forelimb lameness due to swelling and wounds with direct communication into the elbow joint. The medical management of beta hemolytic Streptococcus septic arthritis with needle lavage of the joint, systemic and local antibiotic therapy, and analgesic therapy is described. This case provides information on the need to address septic arthritis in the dog as an emergency situation and the treatment with intra-articular medication. Earlier medical management for septic joints could be considered in dogs to help decrease the long-term complications that can result from septic arthritis. PMID- 21673330 TI - Chronic prostatitis, cystitis, pyelonephritis, and balanoposthitis in a cat. AB - An adult, intact male domestic shorthair presented for preputial swelling and urinary incontinence. A caudal abdominal mass was palpated. A transabdominal ultrasound examination showed severe prostatomegaly with abnormal tissue extending along the urethra. The cat was euthanized due to the owner's financial constraints and the veterinarians' suspicion of a poor long-term prognosis. Biopsies showed chronic active inflammation of the prostate, bladder, kidneys, ureters, penis, and prepuce most consistent with a chronic infectious process. Reports of feline prostatic disease of any kind are rare. Chronic prostatitis may have a more favorable prognosis than feline prostatic adenocarcinoma, currently the most commonly reported disease of the feline prostate. PMID- 21673331 TI - Clinical and imaging findings in five dogs with intracranial blastomycosis (Blastomyces dermatiditis). AB - Fungal infections affecting the central nervous system are rare. The purpose of this study was to describe clinical and imaging findings in dogs with intracranial blastomycosis (Blastomyces dermatiditis). The radiology database was searched retrospectively for patients with a diagnosis of intracranial blastomycosis which had computed tomography performed as part of their diagnostic work-up. Medical records and imaging studies were reviewed. Five dogs met the inclusion criteria. Major presenting complaints were stertor/nasal discharge (n=2), exophthalmos (n=1), and seizures (n=2). Clinical and laboratory findings were variable. Computed tomographic examination revealed a single contrast enhancing intra-axial mass (n=1), a nasal mass disrupting the cribriform plate (n=3), and an intracranial mass extending into the orbit and nasal cavity (n=1). Findings in intracranial blastomycosis in dogs are variable, and the disease may mimic other inflammatory disorders or neoplasia. PMID- 21673332 TI - Successful therapy of vitamin D-dependant rickets in a kitten. AB - A 7 mo old, 2.4 kg, intact female kitten was evaluated for an inability to walk after falling out of the owner's arms. Diagnostic testing abnormalities included hypocalcemia, low ionized calcium, and elevated intact parathyroid hormone concentration. The 25-hydroxyvitamin D level was normal. Radiographic abnormalities included generalized osteopenia, a nondisplaced, folding fracture of the proximal right fibula, and sclerosis with a compression fracture of the proximal right tibia. Based on these findings and response to calcium carbonate and calcitriol therapy, a diagnosis of vitamin D-dependent rickets was made. Reports of similar cases in veterinary medicine are sparse and no other reports to date document radiographic abnormalities with a successful therapeutic outcome. PMID- 21673333 TI - Tibial tuberosity advancement for treatment of CrCL injury: complications and owner satisfaction. AB - The purpose of this retrospective study of 171 dogs that underwent 193 tibial tuberosity advancement (TTA) surgeries was to describe complications and owner satisfaction associated with the procedure. Complications occurred in 21 cases (11%). Subsequent meniscal tear was the most common complication (10/193, 5.2%). Increasing body weight (P=0.02-0.04) and small cage size (P=0.06) were significantly associated with postsurgical complications. Ninety-two percent of owners were satisfied with the outcome of the TTA procedure, but only 84% stated that they would be willing to have the procedure performed again. The authors concluded that TTA had a complication rate and owner satisfaction similar to other tibial osteotomies for the surgical correction of cranial cruciate ligament disease. PMID- 21673334 TI - Gestational diabetes mellitus with diabetic ketoacidosis in a Yorkshire terrier bitch. AB - A 6 yr old pregnant Yorkshire terrier bitch presented 62 days after mating with an acute history of vomiting and coughing. The owners also reported that the dog was polyuric and polydypsic for the last 2 weeks. Complete blood count, serum biochemistry, and urinalysis revealed hyperglycemia, ketonemia, ketonuria, and metabolic acidosis. Diabetic ketoacidosis was diagnosed and after emergency treatment, including fluid therapy, prophylactic antibiotics, and regular insulin, the bitch whelped six healthy normal puppies. Two weeks after treatment, the bitch was clinically normal with normal fructosamine levels. To the authors' knowledge, this is the first reported case of gestational diabetes mellitus in a small breed dog. PMID- 21673335 TI - A case of lymphocytic-plasmacytic jejunitis diagnosed by double-balloon enteroscopy in a dog. AB - A 3 yr old male English setter dog was presented for evaluation of a 6-wk history of intermittent diarrhea. After standard gastroduodenoscopy and colonoscopy showed normal mucosa, double-balloon endoscopy (DBE) was used via both oral and anal approaches. Gross changes consistent with inflammation in the jejunum were seen, and biopsy specimens were obtained. Histologic analysis confirmed a diagnosis of lymphocytic-plasmacytic jejunitis. Clinical remission of the disease occurred after 3 mo of therapy with prednisone, metronidazole, and a novel protein diet. Use of DBE has not been previously reported in dogs with inflammatory bowel disease, and isolated lymphocytic-plasmacytic jejunitis has not been described. The described cases of intestinal inflammatory disease diagnosed by conventional endoscopy were related to pathologic changes in the duodenum, ileum or colon, but not the jejunum. The main advantage of the DBE technique allowed examination of portions of the small intestine (jejunum) that were not commonly accessible by standard endoscopic techniques, and permitted a minimally invasive collection of biopsy samples compared with surgical biopsy. This case highlights the need to consider using DBE in animals with gastrointestinal disorders, whose symptoms are not readily explained by routine tests, conventional endoscopy, and dietary or therapeutic trials. PMID- 21673336 TI - Video-assisted thoracoscopic surgery for pneumothorax induced by migration of a K wire to the chest. AB - A 2 yr old female English setter dog was admitted for acute dyspnea. The dog underwent treatment of a T9T10 thoracic vertebral fracture subluxation at the authors' institution 15 mo earlier. Upon admission, a chest X-ray revealed a pneumothorax and a metallic foreign body in the left hemithorax. An emergency video-assisted thoracoscopic surgery was successfully performed to remove a 4.6 mm long Kirschner wire that migrated from the thoracic vertebral column to the thoracic cavity. The operating time was 27 min. The dog made an uneventful recovery and was discharged on the third day after surgery. Pneumothorax should be considered in patients that develop acute dyspnea and have a history of wire fixation in the thoracic vertebral column. Video-assisted thoracoscopic surgery is a safe and effective treatment of this condition. PMID- 21673337 TI - An unusual presentation of granulocytic anaplasmosis in a young dog. AB - Canine granulocytic anaplasmosis is a disease diagnosed in many areas of the United States, with the highest prevalence reported in dogs in the upper midwestern, northeastern, and western states. It is also found in several European countries. Anaplasmosis can manifest with a wide range of clinicopathologic findings. A 20 wk old puppy was presented with physical examination and laboratory findings atypical of the disease. In addition to other signs, abdominal effusion was detected. Diagnostic evaluation confirmed that the puppy was positive for anaplasmosis. No morulae were found in peripheral white blood cells, but morulae were apparent in the white cells of the abdominal effusion. Leukopenia was observed, characterized by neutropenia, as opposed to the lymphopenia and eosinopenia typically seen with the disease. Blast cells were also seen in the peripheral blood, and reactive lymphocytes were noted in the bone marrow. The patient responded well to doxycycline therapy. All hematologic and physical abnormalities resolved. PMID- 21673338 TI - The influence of topical unsaturated fatty acids and essential oils on normal and atopic dogs. AB - Seven dogs with atopic dermatitis and six normal dogs were treated with a spot-on product containing essential oils and unsaturated fatty acids q 7 days for 8 wk. Seven additional atopic dogs received a daily spray containing similar ingredients to the spot-on. In all dogs, transepidermal water loss (TEWL) was measured before and after treatment using a closed chamber device. In atopic dogs, a validated lesion score (canine atopic dermatitis extent and severity index, CADESI) was determined and pruritus was assessed with a visual analog scale before and after treatment. The mean CADESI scores in atopic dogs decreased with the spot-on (P=0.0043) and with the spray (P=0.0366). Similarly, the pruritus scores decreased with the spot-on (P=0.266) and with the spray (P=0.0177). There was a significant difference between the TEWL values of healthy and atopic dogs on the abdomen (P=0.0181) and back (P=0.0123). TEWL decreased significantly on the back after treatment with the spray (P=0.016), but not on the abdomen (P=0.078). Adverse effects were not observed. The results of this pilot study indicate that topical fatty acids and essential oils are a useful treatment option for canine atopic dermatitis. PMID- 21673339 TI - Radiography, 99mTc-HDP, and 111In labeled vitamin B12 SPECT of canine osteosarcoma: a comparative study. AB - The objective of this article was to compare radiography, planar bone scintigraphy, and single-photon emission computed tomography (SPECT) to determine the size of osteosarcomas in long bones of dogs. Ten dogs with osteosarcoma in six radii, two humeri, one tibia, and one ulna were evaluated. Macroslides, mediolateral radiographs, planar scintigrams, and sagittal images from SPECT scans were used to obtain measurements. On the scintigraphic images, the edges of the tumor were established using the activity profile imaging tool. The radiographic magnification was factored. The mean percentage of tumor size overestimation was 9.29% on mediolateral radiographs, 5.35% on planar scintigrams, and 33.25% on SPECT images. The correlation coefficient adjusted for sample size was significantly higher (P<0.01) for technetium 99m ((99m)Tc) hydroxyethylene diphosphonate (HDP) (75.5%) and radiography (61.3%) compared with indium 111-vitamin B(12) (28.3%). The correlation coefficient for (99m)Tc-HDP was higher than that obtained for radiographs; however, statistical difference between the two variables was not demonstrated (P>0.05). (99m)Tc bone scan is a good estimator of intramedullary size of osteosarcoma in long bones when the activity profile tool to determine the margin of the tumor is used. PMID- 21673340 TI - Failure to reverse prolonged vecuronium-induced neuromuscular blockade with edrophonium in an anesthetized dog. AB - A case of prolonged muscle relaxation after vecuronium in an anesthetized dog is presented. After using peripheral nerve stimulation to confirm partial recovery of neuromuscular transmission, administration of 0.5 mg/kg IV of intravenous edrophonium failed to complete the reversal process. Subsequent administration of neostigmine resulted in complete recovery from blockade. Without monitoring neuromuscular function with a peripheral nerve stimulator until reversal was complete, it was very likely this patient would have been extubated with incomplete neuromuscular transmission. Several factors affecting the duration of neuromuscular blockade and its reversal are addressed. PMID- 21673341 TI - Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation. AB - The mechanism of cytotoxicity of farnesyltransferase inhibitors is incompletely understood and seems to vary depending on the cell type. To identify potential determinants of sensitivity or resistance for study in the accompanying clinical trial (Witzig et al, page 4882), we examined the mechanism of cytotoxicity of tipifarnib in human lymphoid cell lines. Based on initial experiments showing that Jurkat variants lacking Fas-associated death domain or procaspase-8 undergo tipifarnib-induced apoptosis, whereas cells lacking caspase-9 or overexpressing Bcl-2 do not, we examined changes in Bcl-2 family members. Tipifarnib caused dose dependent up-regulation of Bim in lymphoid cell lines (Jurkat, Molt3, H9, DoHH2, and RL) that undergo tipifarnib-induced apoptosis but not in lines (SKW6.4 and Hs445) that resist tipifarnib-induced apoptosis. Further analysis demonstrated that increased Bim levels reflect inhibition of signaling from c-Raf to MEK1/2 and ERK1/2. Additional experiments showed that down-regulation of the Ras guanine nucleotide exchange factor RasGRP1 diminished tipifarnib sensitivity, suggesting that H-Ras or N-Ras is a critical farnesylation target upstream of c-Raf in lymphoid cells. These results not only trace a pathway through c-Raf to Bim that contributes to tipifarnib cytotoxicity in human lymphoid cells but also identify potential determinants of sensitivity to this agent. PMID- 21673342 TI - DC-like cell-dependent activation of human natural killer cells by the bisphosphonate zoledronic acid is regulated by gammadelta T lymphocytes. AB - Bisphosphonates are mainly used for the inhibition of osteoclast-mediated bone resorption but also have been shown to induce gammadelta T-cell activation. Using IL-2-primed cultures of CD56(+) peripheral blood mononuclear cells, we show here that zoledronic acid (zoledronate) could induce IFN-gamma production not only in gammadelta T lymphocytes but, surprisingly, also in natural killer (NK) cells in a manner that depended on antigen-presenting cells, which share properties of inflammatory monocytes and dendritic cells (DCs; here referred to as DC-like cells). In the presence of gammadelta T lymphocytes, DC-like cells were rapidly eliminated, and NK cell IFN-gamma production was silenced. Conversely, in the absence of gammadelta T lymphocytes, DC-like cells were spared, allowing NK cell IFN-gamma production to proceed. gammadelta T cell-independent NK cell activation in response to zoledronate was because of downstream depletion of endogenous prenyl pyrophosphates and subsequent caspase-1 activation in DC-like cells, which then provide mature IL-18 and IL-1beta for the activation of IL-2-primed NK cells. Pharmacologic inhibition of caspase-1 almost abolished IFN-gamma production in NK cells and gammadelta T lymphocytes, indicating that caspase-1 mediated cytokine maturation is the crucial mechanism underlying innate lymphocyte activation in response to zoledronate. PMID- 21673343 TI - Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. AB - The release of histones from dying cells is associated with microvascular thrombosis and, because histones activate platelets, this could represent a possible pathogenic mechanism. In the present study, we assessed the influence of histones on the procoagulant potential of human platelets in platelet-rich plasma (PRP) and in purified systems. Histones dose-dependently enhanced thrombin generation in PRP in the absence of any trigger, as evaluated by calibrated automated thrombinography regardless of whether the contact phase was inhibited. Activation of coagulation required the presence of fully activatable platelets and was not ascribable to platelet tissue factor, whereas targeting polyphosphate with phosphatase reduced thrombin generation even when factor XII (FXII) was blocked or absent. In the presence of histones, purified polyphosphate was able to induce thrombin generation in plasma independently of FXII. In purified systems, histones induced platelet aggregation; P-selectin, phosphatidylserine, and FV/Va expression; and prothrombinase activity. Blocking platelet TLR2 and TLR4 with mAbs reduced the percentage of activated platelets and lowered the amount of thrombin generated in PRP. These data show that histone-activated platelets possess a procoagulant phenotype that drives plasma thrombin generation and suggest that TLR2 and TLR4 mediate the activation process. PMID- 21673344 TI - Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. AB - BH3 mimetics are a new class of proapo-ptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the pro-survival function of one or more Bcl-2 related proteins. Agents that inhibit Bcl-x(L) induce rapid platelet death that leads to thrombocytopenia; however, their impact on the function of residual circulating platelets remains unclear. In this study, we demonstrate that the BH3 mimetics, ABT-737 or ABT-263, induce a time- and dose-dependent decrease in platelet adhesive function that correlates with ectodomain shedding of the major platelet adhesion receptors, glycoprotein Ibalpha and glycoprotein VI, and functional down-regulation of integrin alpha(IIb)beta(3). Analysis of platelets from mice treated with higher doses of BH3 mimetics revealed the presence of a subpopulation of circulating platelets undergoing cell death that have impaired activation responses to soluble agonists. Functional analysis of platelets by intravital microscopy revealed a time-dependent defect in platelet aggregation at sites of vascular injury that correlated with an increase in tail bleeding time. Overall, these studies demonstrate that Bcl-x(L)-inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets. PMID- 21673345 TI - Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked antileukemia reactivity and safety. AB - Adoptive T-cell therapy for malignancies using redirected T cells genetically engineered by tumor antigen-specific T-cell receptor (TCR) gene transfer is associated with mispairing between introduced and endogenous TCR chains with unknown specificity. Therefore, deterioration of antitumor reactivity and serious autoimmune reactivity are major concerns. To address this problem, we have recently established a novel retroviral vector system encoding siRNAs for endogenous TCR genes (siTCR vector). In this study, to test the clinical application of siTCR gene therapy for human leukemia, we examined in detail the efficacy and safety of WT1-siTCR-transduced T cells. Compared with conventional WT1-TCR (WT1-coTCR) gene-transduced T cells, these cells showed significant enhancement of antileukemia reactivity resulting from stronger expression of the introduced WT1-specific TCR with inhibition of endogenous TCRs. Notably, WT1 siTCR gene-transduced T cells were remarkably expandable after repetitive stimulation with WT1 peptide in vitro, without any deterioration of antigen specificity. WT1-siTCR gene-transduced T cells from leukemia patients successfully lysed autologous leukemia cells, but not normal hematopoietic progenitor cells. In a mouse xenograft model, adoptively transferred WT1-siTCR gene-transduced T cells exerted distinct antileukemia efficacy but did not inhibit human hematopoiesis. Our results suggest that gene-immunotherapy for leukemia using this WT1-siTCR system holds considerable promise. PMID- 21673346 TI - How I treat adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I. ATL carries a bad prognosis because of intrinsic chemoresistance and severe immunosuppression. In acute ATL, Japanese trials demonstrated that although combinations of chemotherapy improved response rate, they failed to achieve a significant impact on survival. Patients with chronic and smoldering ATL have a better prognosis, but long-term survival is poor when these patients are managed with a watchful waiting policy or with chemotherapy. Recently, a worldwide meta-analysis revealed that the combination of zidovudine and IFN-alpha is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. ATL lymphoma patients still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine/IFN. To prevent relapse, clinical trials assessing consolidative targeted therapies such as arsenic/IFN combination or novel monoclonal antibodies are needed. Finally, allogeneic BM transplantation should be considered in suitable patients. PMID- 21673347 TI - Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma. AB - The efficacy of retreatment with immunomodulatory drugs (IMiDs) among patients with multiple myeloma who received this class of drugs for initial therapy is unknown. We studied 140 patients who received either thalidomide-dexamethasone (81; 58%) or lenalidomide-dexamethasone (59; 42%) as first-line therapy of multiple myeloma followed by repeat IMiD (thalidomide [34; 24%] or lenalidomide [106; 76%]) as one of the salvage regimens. A median of 2 treatments (range, 1 6), including a stem cell transplant in 105 patients (75%), were administered before IMiD-based salvage therapy. The median time from diagnosis to repeat exposure to IMiD was 28 months. Among the 113 evaluable patients, 50 (44%) achieved at least a partial response, and 63 (56%) achieved less than a partial response to repeat IMiD. Response rates with lenalidomide retreatment were higher than with repeat administration of thalidomide. PMID- 21673348 TI - The relationship between bone, hemopoietic stem cells, and vasculature. AB - A large body of evidence suggests hemopoietic stem cells (HSCs) exist in an endosteal niche close to bone, whereas others suggest that the HSC niche is intimately associated with vasculature. In this study, we show that transplanted hemopoietic stem and progenitor cells (HSPCs) home preferentially to the trabecular-rich metaphysis of the femurs in nonablated mice at all time points from 15 minutes to 15 hours after transplantation. Within this region, they exist in an endosteal niche in close association with blood vessels. The preferential homing of HSPCs to the metaphysis occurs rapidly after transplantation, suggesting that blood vessels within this region may express a unique repertoire of endothelial adhesive molecules. One candidate is hyaluronan (HA), which is highly expressed on the blood vessel endothelium in the metaphysis. Analysis of the early stages of homing and the spatial dis-tribution of transplanted HSPCs at the single-cell level in mice devoid of Has3-synthesized HA, provides evidence for a previously undescribed role for HA expressed on endothelial cells in directing the homing of HSPCs to the metaphysis. PMID- 21673349 TI - Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice. AB - Hematopoietic stem cells (HSCs) are rare residents of the bone marrow responsible for the lifelong production of blood cells. Regulation of the balance between HSC self-renewal and differentiation is central to hematopoiesis, allowing precisely regulated generation of mature blood cells at steady state and expanded production at times of rapid need, as well as maintaining ongoing stem cell capacity. Erg, a member of the Ets family of transcription factors, is deregulated in cancers; and although Erg is known to be required for regulation of adult HSCs, its precise role has not been defined. We show here that, although heterozygosity for functional Erg is sufficient for adequate steady-state HSC maintenance, Erg(+/Mld2) mutant mice exhibit impaired HSC self-renewal after bone marrow transplantation or during recovery from myelotoxic stress. Moreover, although mice functionally compromised for either Erg or Mpl, the receptor for thrombopoietin, a key regulator of HSC quiescence, maintained sufficient HSC activity to sustain hematopoiesis, Mpl(-/-) Erg(+/Mld2) compound mutant mice displayed exacerbated stem cell deficiencies and bone marrow failure. Thus, Erg is a critical regulator of adult HSCs, essential for maintaining self-renewal at times of high HSC cycling. PMID- 21673351 TI - Emergency department intervention for high-risk elders: identification strategy and randomised controlled trial to reduce hospitalisation and institutionalisation. PMID- 21673350 TI - Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B cell lymphoma. AB - Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m(2) intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821. PMID- 21673352 TI - Factors affecting long-term care use in Hong Kong. PMID- 21673353 TI - Advance directive and preference of old age home residents for community model of end-of-life care in Hong Kong. PMID- 21673354 TI - Patient self-management and the role of pharmacists: developing a consensus-based policy framework. PMID- 21673355 TI - Cervical cancer prevention through cytologic and human papillomavirus DNA screening in Hong Kong Chinese women. PMID- 21673356 TI - Incentives and barriers to adopting the family doctor model in Hong Kong: an in depth qualitative study of the views, knowledge, and attitudes of patients. PMID- 21673357 TI - Utilisation patterns of primary health care services in Hong Kong: does having a family doctor make any difference? PMID- 21673358 TI - Patient morbidity and management patterns of community-based primary health care services in Hong Kong. PMID- 21673359 TI - New anti-smoking legislation on second-hand smoke exposure of children in homes. PMID- 21673360 TI - New anti-smoking legislation on youth smoking and quitting behaviours via a smoking cessation hotline. PMID- 21673361 TI - Gut clock: implication of circadian rhythms in the gastrointestinal tract. AB - Circadian and seasonal rhythms are a fundamental feature of all living organisms and their organelles. Biological rhythms are responsible for daily food intake; the period of hunger and satiety is controlled by the central pacemaker, which resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and communicates with tissues via bidirectional neuronal and humoral pathways. The molecular basis for circadian timing in the gastrointestinal tract (GIT) involves interlocking transcriptional/translational feedback loops which culminate in the rhythmic expression and activity of a set of clock genes and related hormones. Interestingly, it has been found that clocks in the GIT are responsible for the periodic activity (PA) of its various segments and transit along the GIT; they are localized in special interstitial cells, with unstable membrane potentials located between the longitudinal and circular muscle layers. The rhythm of slow waves is controlled in various segments of the GIT: in the stomach (about 3 cycles per min), in the duodenum (12 cycle per min), in the jejunum and ileum (from 7 to 10 cycles per min), and in the colon (12 cycles per min). The migrating motor complex (MMC) starts in the stomach and moves along the gut causing peristaltic contractions when the electrical activity spikes are superimposed on the slow waves. GIT hormones, such as motilin and ghrelin, are involved in the generation of MMCs, while others (gastrin, ghrelin, cholecystokinin, serotonin) are involved in the generation of spikes upon the slow waves, resulting in peristaltic or segmental contractions in the small (duodenum, jejunum ileum) and large bowel (colon). Additionally, melatonin, produced by neuro-endocrine cells of the GIT mucosa, plays an important role in the internal biological clock, related to food intake (hunger and satiety) and the myoelectric rhythm (produced primarily by the pineal gland during the dark period of the light-dark cycle). This appears to be an endocrine encoding of the environmental light-dark cycle, conveying photic information which is used by organisms for both circadian and seasonal organization. Motor and secretory activity, as well as the rhythm of cell proliferation in the GIT and liver, are subject to many circadian rhythms, mediated by autonomic cells and some enterohormones (gastrin, ghrelin and somatostatin). Disruption of circadian physiology, due to sleep disturbance or shift work, may result in various gastrointestinal diseases, such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD) or peptic ulcer disease. In addition, circadian disruption accelerates aging, and promotes tumorigenesis in the liver and GIT. Identification of the molecular basis and role of melatonin in the regulation of circadian rhythm allows researchers and clinicians to approach gastrointestinal diseases from a chronobiological perspective. Clinical studies have demonstrated that the administration of melatonin improves symptoms in patients with IBS and GERD. Moreover, our own studies indicate that melatonin significantly protects gastrointestinal mucosa, and has strong protective effects on the liver in patients with non-alcoholic steatohepatitis (NASH). Recently, it has been postulated that disruption of circadian regulation may lead to obesity by shifting food intake schedules. Future research should focus on the role of clock genes in the pathophysiology of the GIT and liver. PMID- 21673362 TI - Drug-mediated ototoxicity and tinnitus: alleviation with melatonin. AB - This review evaluates the published basic science and clinical reports related to the role of melatonin in reducing the side effects of aminoglycosides and the cancer chemotherapeutic agent cisplatin, in the cochlea and vestibule of the inner ear. A thorough search of the literature was performed using available databases for the purpose of uncovering articles applicable to the current review. Cochlear function was most frequently evaluated by measuring otoacoustic emissions and their distortion products after animals were treated with cytotoxic drugs alone or in combination with melatonin. Vestibular damage due to aminoglycosides was evaluated by estimating hair cell loss in explanted utricles of newborn rats. Tinnitus was assessed in patients who received melatonin using a visual analogue scale or the Tinnitus Handicap Inventory. Compared to a mixture of antioxidants which included tocopherol, ascorbate, glutathione and N-acetyl cysteine, melatonin, also a documented antioxidant, was estimated to be up to 150 times more effective in limiting the cochlear side effects, evaluated using otoacoustic emission distortion products, of gentamicin, tobramycin and cisplatin. In a dose-response manner, melatonin also reduced vestibular hair cell loss due to gentamicin treatment in explanted utricles of newborn rats. Finally, melatonin (3 mg daily) limited subjective tinnitus in patients. These findings suggest the potential use of melatonin to combat the ototoxicity of aminoglycosides and cancer chemotherapeutic agents. Additional studies at both the experimental and clinical levels should be performed to further document the actions of melatonin at the cochlear and vestibular levels to further clarify the protective mechanisms of action of this ubiquitously-acting molecule. Melatonin's low cost and minimal toxicity profile supports its use to protect the inner ear from drug-mediated damage. PMID- 21673363 TI - Mechanisms of immunological tolerance to the antigens of the central nervous system. Skin-induced tolerance as a new therapeutic concept. AB - The immune system is designed to recognize and eliminate foreign (non-self) antigens. At the same time, there are mechanisms protecting the organism from development of inappropriate immune responses that are harmful to ones own body (allergy, autoimmunity) and those that help to silence the inflammatory responses and allow their resolution. Tolerance to self-antigens is a result of central tolerance (negative selection) and various mechanisms of peripheral tolerance that include anatomical sequestration of self-antigens, deletion of peripheral autoreactive lymphocytes, the development of lymphocyte functional unresponsiveness and action of T regulatory (Treg) cells. This article summarizes current knowledge about mechanisms of immunological tolerance that protect from development of immune responses to self-antigens present in the central nervous system (CNS). Finally, it discusses the subject of skin-induced tolerance as demonstrated in an animal model of autoimmune disease of the CNS, experimental autoimmune encephalomyelitis (EAE). The potential clinical use of this approach to regulate disease will be discussed. PMID- 21673364 TI - 15-deoxy-D12,14-prostaglandin J2 suppresses RANTES expression by inhibiting NADPH oxidase activation in Helicobacter pylori-infected gastric epithelial cells. AB - Peroxisome proliferators-activated receptor-gamma (PPAR-gamma) is a ligand activated transcription factor. 15 deoxy-(12,14) prostaglandin J(2) (15d-PGJ(2)) is a potent PPAR-gamma ligand and acts as an anti-inflammatory agent via PPAR gamma-dependent and independent mechanisms. Helicobacter pylori (H. pylori) induces gastric inflammation by inducing the activation of oxidant-sensitive transcription factor NF-kappaB and cytokine expression in gastric epithelial cells. Since 15d-PGJ(2) inhibits NF-kappaB activation in various cells, it may suppress H. pylori-induced inflammatory signaling and cytokine expression in gastric epithelial cells. The present study aims to determined the effect of 15d PGJ(2) on the activation of inflammatory mediators Jak/Stat (Janus kinase/signal transducers and activators of transcription) and induction of cytokine RANTES in H. pylori-infected gastric epithelial AGS cells. Since NADPH oxidase is a candidate for the production of reactive oxygen species in H. pylori-infected gastric epithelial cells, we determined the effect of 15d-PGJ(2) on the activation of NADPH oxdase. AGS cells were cultured in the presence of H. pylori treated with or without 15d-PGJ(2). The activations of NADPH oxidase and Jak1/Stat3, the levels of H(2)O(2) and RANTES in the medium, and DNA binding activity of Stat3 were assessed. A Jak/Stat3 specific inhibitor AG490 and an inhibitor of NADPH oxidase diphenyleneiodonium (DPI) were treated to determine the direct involvement of Jak/Stat and NADPH oxidase on the production of H(2)O(2) and RANTES in H. pylori-infected cells. H. pylori induced the production of H(2)O(2) and RANTES as well as the activations of NADPH oxidase and Jak1/Stat3, which were inhibited by the treatment of 15d-PGJ(2). DPI suppressed H. pylori-induced alterations similar to 15d-PGJ(2). However, AG490 had no effect on NADPH oxidase activation, but reduced the level of RANTES in the medium released from H. pylori-infected cells. CONCLUSION: NADPH oxidase activation is an upstream signaling of Jak1/Stat3 activation and induction of RANTES in H. pylori-infected AGS cells. 15d-PGJ(2), inhibits the activations of NADPH oxidase and Jak1/Stat3 and RANTES expression, suggesting that 15d-PGJ(2) may be beneficial for the treatment of H. pylori-induced gastric inflammation. PMID- 21673365 TI - A low vitamin A status increases the susceptibility to cigarette smoke-induced lung emphysema in C57BL/6J mice. AB - Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. Cigarette smoke has been considered a major player in the pathogenesis of COPD. The inflamed airways of COPD patients contain several inflammatory cells. Vitamin A metabolites have been implicated in the repair of lung damage. Exposure to cigarette smoke has been shown to depress levels of retinol in lungs of rats. The purpose of this study was to investigate if a low, but not deficient, vitamin A status potentiated susceptibility to the development of cigarette smoke-induced lung emphysema in mice. Mice were bred that were the offspring's of 3 generations of mice that were fed a purified diet containing low levels of vitamin A and exposed to cigarette smoke for 3 months, every weekday. Then, levels of 9-cis, 13-cis, and all-trans retinoic acid, retinol and retinyl palmitate were measured in plasma, liver and right lung lobe. The left lung lobe was used to assess mean linear intercept (Lm), as a measure of smoke-induced lung damage. Average feed intakes were not different between treatment groups. We show that both retinol and retinyl palmitate levels were dramatically decreased in the storage organs of mice on the low vitamin A diet (retinol 2-fold in both lung and liver, and retinyl palmitate 5- fold in lung) which shows that the depletion was successful. However, this treatment did not result in the development of lung emphysema. However, smoke exposure led to a significant increase in Lm in mice with a low vitamin A status compared to the room air-breathing controls. Lung levels of acid retinoids were similar in all mice, irrespective of diet or smoke exposure. Concluding, a low vitamin A status increases the susceptibility to the development of cigarette smoke-induced lung emphysema, possibly because of decreased anti-oxidant capacity in the lungs due to locally reduced retinol and retinyl palmitate levels. These observations indicate that human populations with a low vitamin A status and a high prevalence of smoking may be at increased risk of developing lung emphysema. PMID- 21673366 TI - Influence of nuclear factor-kappaB inhibition on endothelin-1 induced lung edema and oxidative stress in rats. AB - The aim of the present study is to determine the effects of the BAY 11-7082, a nuclear factor-kappaB (NF-kappaB) inhibitor, on endothelin-1 (ET-1) induced lung edema, the level of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-alpha) in the lungs. Experiments were carried out on adult male Wistar-Kyoto rats. The animals were divided into 4 groups: Group I: saline-treated control; Group II: saline followed by ET-1 (12.5 MUg/kg b.w., i.v.); Group III: BAY 11 7082 (10 mg/kg b.w., i.v.) administered one hour before saline; Group IV: BAY 11 7082 (10 mg/kg b.w., i.v.) administered 1 hour before ET-1 (12.5 MUg/kg b.w., i.v.). Injection of ET-1 alone showed a significant (P<0.001) increase in thiobarbituric acid reactive substances (TBARS) and hydrogen peroxide (H(2)O(2)) level as well as a decrease (P<0.01) in GSH level and GSH/GSSG ratio (P<0.02). BAY 11-7082 significantly decreased TBARS (P<0.01) and H(2)O(2) (P<0.05) level as well as improved the redox status (P<0.02) in the lungs. BAY 11-7082 also prevented ET-1 induced lung edema (P<0.05). The concentration of TNF-alpha (P<0.02) and p65 subunit of NF-kappaB signaling compound (P<0.001) was increased in the presence of ET-1, while BAY 11-7082 decreased both TNF-alpha level (P<0.05) and p65 subunit concentration (P<0.01). Our results indicate that BAY 11 7082 plays a protective role in ET-1 induced oxidative lung injury. It successfully prevents lung edema as well as ROS and TNF-alpha overproduction. Our results also highlight the important role of the NF-kappaB pathway in ET-1 induced lung injury and ROS overproduction. PMID- 21673367 TI - Wheezing and asthma may be enhanced by broad spectrum antibiotics used in early childhood. Concept and results of a pharmacoepidemiology study. AB - One of the mechanisms supposed to explain the increasing prevalence of asthma, among children in particular, is the use of antibiotics because they may modify natural microbial exposure and development of the immune system in early childhood. The aim of this study is to investigate the association between the use of various classes of antibiotics (penicillin, cephalosporin and macrolide derivatives) in early childhood and the medical diagnosis of asthma or wheezing reported by mothers over the follow-up after adjustment for potential confounders and respiratory infections. In a population-based sample of 5-year-olds, a part of the ongoing birth cohort study, the standardized interviews on health outcomes, potential confounders (child's gender, maternal atopy, parity, prenatal and postnatal environmental tobacco smoke) and the use of antibiotics were gathered from mothers of 310 children. While the overall use of antibiotics during the early childhood was insignificantly associated with asthma (adjusted OR = 1.65, 95%CI: 0.93 - 2.93), the risk estimates were significant both for macrolide antibiotics (adjusted OR=2.14, 95%CI: 1.16-3.95) and cephalosporins (OR=1.98, 95%CI: 1.14-3.37). The significant excess in IRR (incident risk ratio) of wheezing episodes was related only to the use of macrolide antibiotics (adjusted IRR=1.91, 95%CI: 1.12-3.27). The use of other classes of antibiotics was found not to be associated with the medical diagnosis of asthma or wheezing episodes recorded in the study period. CONCLUSION: as early childhood use of broad spectrum antibiotics is associated with an increased risk of developing asthma in 5-year-olds, it may be hypothesized that the antibiotic- related suppression of allergic inflammatory responses in the course of treatment may later lead to greater than before atopic immune response in Th2 children or an impairment of Th1 immune responses in early childhood. PMID- 21673368 TI - Significant, but limited collateral blood flow increases occur with prolonged training in rats with femoral artery occlusion. AB - This study examined the capacity of collateral dependent blood flow induced by a prolonged treadmill training program, as compared to a low collateral resistance model created by femoral artery to vein (A-V) shunt. Sprague-Dawley rats, with bilateral femoral artery occlusion were confined to cage activity (Sed, n=9) or trained by daily treadmill exercise (Tr, n=15; up to ~350 min/d) for 15 weeks. Another set of animals received a femoral A-V anastomosis in one limb and treated with (n=4) or without VEGF(165) (n=9) infusion for 2 weeks. The contralateral side was used as control. Blood flow (BF) was measured with isotope labeled microspheres. Maximal calf muscle BF increased by 15 week training (up to 100+/ 5.0 ml x min(-1) x 100g(-1) (p<0.05); 0.71+/-0.04 ml x min(-1) x 100g(-1) x mmHg( 1)), a response better (20-25%) than the less demanding training programs used previously. In contrast, femoral A-V shunt with VEGF(165) increased calf muscle conductance to 1.70+/-0.3 ml x min(-1) x 100 g(-1) x mmHg(-1) that is similar to blood flows observed in non-occluded rats during maximal running. Our data indicate that the collateral circuit development is related to the driving stimulus and that exercise training, does not provide a maximal stimulus for adaptation that is possible. Nonetheless, exercise training results in profound increases in exercise capacity associated with this enhanced collateral blood flow. Our results illustrate that vascular adaptations can be much greater when physiologically induced stimuli are enhanced at the time of therapeutic angiogenesis. PMID- 21673369 TI - Role of sensory nerves in gastroprotective effect of anandamide in rats. AB - Previous studies have shown that stimulation of cannabinoid 1 (CB1) receptor protects the gastric mucosa against stress-induced lesion. Aim of the present study was to examine the influence of anandamide on lipid peroxidation and antioxidant defense system in gastric mucosa and the role of sensory nerves in gastroprotective effects of cannabinoids. Studies were performed on rats with intact or ablated sensory nerves (by neurotoxic doses of capsaicin). Gastric lesions were induced by water immersion and restrain stress (WRS). Anandamide was administered at the dose of 0.3, 1.5 or 3.0 MUmol/kg, 30 min before exposure to WRS. CB1 receptor antagonist, AM251 (4.0 MUmol/kg) was administered 40 min before WRS. WRS induced gastric lesions associated with the decrease in gastric blood flow, mucosal DNA synthesis and mucosal activity of superoxide dismutase (SOD). Serum level of interleukin-1beta (IL-1beta) and mucosal level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were increased. Administration of anandamide reduced the ulcers area, generation of MDA+4-HNE and serum level of IL-1beta, and this effect was associated with the reduction in the WRS-induced decrease in gastric mucosal blood flow, mucosal DNA synthesis and SOD activity. Ablation of sensory nerves increased the area of ulcers, serum level of IL-1beta and mucosal content of MDA+4-HNE, whereas mucosal DNA synthesis, SOD activity and blood flow were additionally decreased. In rats with ablation of sensory nerves, administration of anandamide at the high doses (1.5 and 3.0 MUmol/kg) partly reduced deleterious effect of WRS on gastric mucosa, but this effect was weaker than in animals with intact sensory nerves. Low dose of anandamide (0.3 MUmol/kg) was ineffective in the protection of gastric mucosa against the WRS-induced lesions in rats with ablation of sensory nerves. In rats with intact sensory nerves and exposed to WRS, administration of AM251 exhibited deleterious effect. In rats with ablation of sensory nerves and exposed to WRS, AM251 failed to affect mucosal injury in the stomach. We conclude that anandamide reduces the mucosal oxidative stress and exhibits gastroprotective effect against WRS-induced ulcers. These effects are partly mediated by sensory nerves. PMID- 21673370 TI - Transient and stable transfections of mouse myoblasts with genes coding for pro angiogenic factors. AB - Cardiomyocyte loss in the ischaemic heart can be the reason of many complications, eventually being even the cause of patient's death. Despite many promises, cell therapy with the use of skeletal muscle stem cells (SMSC) still remains to be modified and improved. Combined cell and gene therapy seems to be a promising strategy to heal damaged myocardium. In the present study we have investigated the influence of a simultaneous overexpression of two potent pro angiogenic genes encoding the fibroblast growth factor-4 (FGF-4) and the vascular endothelial growth factor-A (VEGF-A) on a myogenic murine C2C12 cell line. We have demonstrated in in vitro conditions that myoblasts which overexpressed these factors exhibited significant changes in the cell cycle and pro-angiogenic potential with only slight differences in the expression of the myogenic genes. There was not observed the influence of transient or stable overexpression of FGF 4 and VEGF on cell apoptosis/necrosis in standard or oxidative stress conditions comparing to non transfected controls. Overall, our results suggest that the possible transplantation of myoblasts overexpressing pro-angiogenic factors may potentially improve the functionality of the injured myocardium although the definite proof must originate from in situ conducted pre-clinical studies. PMID- 21673371 TI - Trans fatty acids induce a proinflammatory response in endothelial cells through ROS-dependent nuclear factor-kappaB activation. AB - It has been shown that increased intake of trans fatty acids (TFAs) is associated with a higher risk of cardiovascular disease. In this study, we have investigated the effects of linoelaidic (LA) and elaidic (EA) acids on the proinflammatory response in endothelial cells, a key step in vascular disease. Human aortic endothelial cells (HAECs) were treated with different concentrations (100 MUmol/l in most experiments) of LA or EA for different periods of time. The surface protein and mRNA expression of ICAM-1 and VCAM-1 were determined by flow cytometry and real time RT-PCR, respectively. Adhesion of leukocytes to TFA treated HAECs was evaluated by an adhesion assay. Activation of nuclear factor kappaB (NF-kappaB) was evaluated by measuring NF-kappaB p65 phosphorylation using flow cytometry. ROS production was determined by the reduction of fluorescent 2',7'-dichlorofluorescein diacetate (DCFH-DA). LA treatment significantly increased protein and mRNA levels of ICAM-1 and VCAM-1, leukocyte adhesion to HAECs, phosphorylation of NF-kappaB and ROS generation. Similar effects were achieved for cells incubated with EA. Experiments with HAECs pretreated with pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB, revealed that both LA and EA-mediated induction of ICAM-1 and VCAM-1 is mainly regulated by NF-kappaB. The ROS production induced by both of the studied acids was inhibited in the presence of diphenyleneiodonium (DPI), a NADPH oxidase inhibitor, suggesting ROS production through the activation of NADPH oxidase. Furthermore, LA or EA-induced ICAM-1 and VCAM-1 expression, activation of NF-kappaB and adhesion of leukocytes to HAECs were abolished in the presence of DPI. CONCLUSION: TFAs present in our diet have a direct proinflammatory effect, which promotes leukocyte adhesion to the endothelium through ROS-dependent NF-kappaB activation. PMID- 21673372 TI - The neuroprotective effect of 2-oxoglutarate in the experimental ischemia of hippocampus. AB - In this study we investigated the potential neuroprotective effect of 2 oxoglutarate (2-OG) on the hippocampus in the transient vessel occlusion ischemia model in the Mongolian gerbil. The morphological and biochemical studies were performed at 7 days after occlusion of carotid arteries. The acute reduction of NeuN-positive neurons in the CA1 pyramidal layer of the hippocampus was accompanied by increased staining intensity for GFAP-positive astrocytes, indicative of glial reaction. The neuron death in the CA1 area coincided with a strong 2.4 fold decrease in the membrane forms of neuronal cell adhesion molecules and elevated levels of astrocyte-specific proteins (soluble GFAP to 2,6 times; filament GFAP to 1,5 times; calcium-binding protein S-100b to 1,6 times). Treatment with 2-oxoglutarate (2.28 g/l drinking water) for between 7 and 21 days attenuated the neuronal death and reactive astrogliosis in this model of experimental ischemia by 20-50%. Our results suggest that 2-OG may prevent the disturbances of neural cells that usually take place during ischemic pathology. PMID- 21673373 TI - The effect of doxycycline on atherogenesis in apoE-knockout mice. AB - Doxycycline at subantimicrobial doses inhibits matrix metalloproteinases (MMPs) activity, and is the only MMP inhibitor which is widely available in clinical practice. The aim of the study was to reveal whether non-specific MMPs inhibition by tetracycline could ameliorate development of atherosclerosis in apolipoprotein E (apoE)-knockout mice. Doxycycline (1.5 mg/ kg b.w./day) administered orally attenuated atherogenesis, measured both by "en face" method (10.25+/-1.7% vs. 15.7+/-2.0%, p<0.05) and "cross-section" method (66,254+/-7,468 MUm(2) vs. 90,687+/-8,521 MUm(2), p<0.05). In-situ zymography showed decrease of the extent of non-specific gelatinase activity in doxycycline-treated mice This is the first report to date describing the effect of doxycycline on atherogenesis in apoE targeted mice. PMID- 21673374 TI - Auriculo-vestibular symptoms related to structural and functional disorders of stomatognatic system. AB - Auriculo-vestibular symptoms are otolaryngological complaints which frequently co occur with functional disorders of masticatory organ. These symptoms include: earache, plugged ears sensation, sudden hearing impairment, burning pain of the throat, tinnitus, and dizziness. The aim of the study was assessment of co occurrence of functional disorders of masticatory organ and auriculo-vestibular symptoms, in patients referred for otolaryngological treatment. Forty-two patients aged 24-46 years of both sexes referred for otolaryngological treatment, because of auriculo-vestibular symptoms, were qualified to our study within the framework of research project. After otolaryngological diagnostics (Department of Otolaryngology), these patients were referred for prosthetic consultation to the Department of Dental Prosthetics of Jagiellonian University Medical College. In Otolaryngology Clinic the following specialist examinations were carried out: basic clinical examinations, including otoscopy, tuning fork trials, tonal and verbal audiometry, and tympanometry. These examinations were supplemented with electronystagmometry. On prosthetic consultation, specialist functional investigations of masticatory organ, and electromyographic assessment of the activity of masseter muscles and the anterior part of the temporal muscle, were carried out. Results of the investigation revealed otolarygological causes of the reported symptoms in 30 patients, whereas in 12 patients (out of 42 patients referred for prosthetic consultation), numerous functional disorders of the stomatognathic system were observed. The investigation confirmed the occurrence of functional disorders in patients with auriculo-vestibular symptoms and appropriateness of treatment by a multi-specialist team. PMID- 21673375 TI - Professor Jerzy Kaulbersz, pioneer of Polish gastroenterology. AB - Jerzy Kaulbersz was undoubtedly the father of experimental gastroenterological physiology in Poland. He pioneered the neural and endocrine aspects of the mechanisms controlling gastric and pancreatic secretion by assessing the influence on this secretion of vagal nerves and endocrine factors such as gastrin, enterogastrone, urogastrone, pituitary, adrenal, thyroid and sex hormones as well as bile, hypoxia and X-ray irradiation. He introduced various models of peptic ulcerations such as induced by pylorus-ligation (Shay ulcers) or Mann-Williamson ulcers to test the influence of neuroendocrine factors on the formation and healing of these ulcerations. This review is designed to commemorate the outstanding contribution to experimental gastroenterology of Professor Kaulbersz, who first studied biology in German universities to obtain the title of Doctor of Natural Philosophy (Ph.D.) in Freiburg in 1913 and then completed medical studies at the Medical Faculty of the Jagiellonian University in Cracow receiving the title of Doctor of Universal Medicine (MD) in 1920. He then joined Department of Physiology of Jagiellonian University in Krakow as its assistant and gradually was appointed docent and finally promoted to professor in this Department, working here as chairman from 1934 to 1964 with only 7 years interruption when he spent the time of World War II in USA, working at various departments of experimental gastroenterology and publishing his outstanding papers in most prestigious physiology ournals such as American Journal of Physiology. He possessed comprehensive knowledge of physiology and was gifted to create and organize Cracow Department of Physiology. Moreover he became co founder of the of Polish Physiological Society, the honorary member of American Physiological Association, honorary member of Polish Society of Gastroenterology and Physiology and received the diploma of Doctor Honoris Causa of Medical Academy in Cracow. This ad memoriam note commemorates his achievements at one hundred twenty anniversary of Prof. Kaulbersz birth with intention to bring his fundamental discoveries to younger physiologists and pharmacologists. PMID- 21673376 TI - Time-dependent contact behavior between diamond and a CNT turf. AB - The elastic and adhesive properties of nominally vertically aligned carbon nanotube (CNT) turfs have been measured using nanoindentation. The perceived stiffness of a CNT turf is dependent on the unloading rate, which decreases at slower unloading rates. Depth-controlled nanoindentation was used to examine adhesion effects. Adhesive loads between the turf and the probe tip increased as the time the tip is in contact with the turf increased. As these effects could be from either more tubes coming into contact with the tip due to relaxation and motion of CNTs relative to one another or each tube in contact increasing its adhesive behavior and sub-contact stiffness due to tube-tube interactions within the turf, electrical resistance measurements during nanoindentation were carried out. When the tip is held at a fixed nominal depth, the current remains constant while the contact load decreases, suggesting the number of tubes in contact with the tip stays constant with time while the relaxation mechanisms in the turf occur at positions lower than the contact surface. These observations, in conjunction with in situ TEM compression test of CNT arrays, are used to describe the relative effects the various length and time scales may have on the perceived properties measured during experiments, including elastic modulus and adhesion for gecko-like dry adhesives. PMID- 21673378 TI - Patterned self-assembly of gold nanoparticles on chemical templates fabricated by soft UV nanoimprint lithography. AB - Chemical templates for the patterned immobilization of gold nanoparticles were fabricated by soft UV nanoimprint lithography. The template structures were fabricated by means of the consecutively performed process steps of nanoimprint lithography, reactive ion etching, chemical functionalization with amino groups, and lift-off of imprint resist. These chemical templates were used for the defined assembly of 20 nm diameter citrate stabilized gold nanoparticles from aqueous solution. By reducing the ionic strength of the solution, one- and zero dimensional particle assemblies were generated on sub-100-nm template structures. By this means, the pattern resolution predefined by the lithography process could be easily enhanced by dilution of the nanoparticle solution. PMID- 21673377 TI - Growth direction modulation and diameter-dependent mobility in InN nanowires. AB - Diameter-dependent electrical properties of InN nanowires (NWs) grown by chemical vapor deposition have been investigated. The NWs exhibited interesting properties of coplanar deflection at specific angles, either spontaneously, or when induced by other NWs or lithographically patterned barriers. InN NW-based back-gated field effect transistors (FETs) showed excellent gate control and drain current saturation behaviors. Both NW conductance and carrier mobility calculated from the FET characteristics were found to increase regularly with a decrease in NW diameter. The observed mobility and conductivity variations have been modeled by considering NW surface and core conduction paths. PMID- 21673379 TI - Physiological responses induced in tomato plants by a two-component nanostructural system composed of carbon nanotubes conjugated with quantum dots and its in vivo multimodal detection. AB - Plant seedlings were exposed to single-walled carbon nanotube-quantum dot conjugates (SWCNT-QD) mixed in the growth medium in order to understand the interactions between these multicomponent nanosystems and plants. A combination of fluorescent and Raman-scattering 2D mapping analysis was used to clearly monitor the presence of the SWCNT-QD conjugates in various parts of the tomato seedlings. We found that the addition of QDs to SWCNTs dramatically changed the biological viability of the tomato plants by significantly accelerating leaf senescence and inhibiting root formation. Although the exposure of SWCNTs only to the plants induced positive effects, the chlorophyll content decreased by 1.5 fold in leaves, and the total weight of the root system decreased four times for the tomato plants exposed to SWCNT-QDs (50 ug ml(-1)) compared to plants grown on regular medium as controls. Our results clearly indicate that the exposure of plants to multicomponent nanomaterials is highly influenced by the presence and bioactivity of each component, individually. Such studies could be the foundation for understanding how complex nanosized systems affect the activity of various biological systems with a major impact on ecotoxicology. PMID- 21673380 TI - Polymer nanocomposite nanomechanical cantilever sensors: material characterization, device development and application in explosive vapour detection. AB - This paper reports an optimized and highly sensitive piezoresistive SU-8 nanocomposite microcantilever sensor and its application for detection of explosives in vapour phase. The optimization has been in improving its electrical, mechanical and transduction characteristics. We have achieved a better dispersion of carbon black (CB) in the SU-8/CB nanocomposite piezoresistor and arrived at an optimal range of 8-9 vol% CB concentration by performing a systematic mechanical and electrical characterization of polymer nanocomposites. Mechanical characterization of SU-8/CB nanocomposite thin films was performed using the nanoindentation technique with an appropriate substrate effect analysis. Piezoresistive microcantilevers having an optimum carbon black concentration were fabricated using a design aimed at surface stress measurements with reduced fabrication process complexity. The optimal range of 8-9 vol% CB concentration has resulted in an improved sensitivity, low device variability and low noise level. The resonant frequency and spring constant of the microcantilever were found to be 22 kHz and 0.4 N m(-1) respectively. The devices exhibited a surface stress sensitivity of 7.6 ppm (mN m(-1))(-1) and the noise characterization results support their suitability for biochemical sensing applications. This paper also reports the ability of the sensor in detecting TNT vapour concentration down to less than six parts per billion with a sensitivity of 1 mV/ppb. PMID- 21673381 TI - Characteristics of CVD graphene nanoribbon formed by a ZnO nanowire hardmask. AB - A graphene nanoribbon (GNR) is an important basic structure to open a bandgap in graphene. The GNR processes reported in the literature are complex, time consuming, and expensive; moreover, the device yield is relatively low. In this paper, a simple new process to fabricate a long and straight graphene nanoribbon with a high yield has been proposed. This process utilizes CVD graphene substrate and a ZnO nanowire as the hardmask for patterning. 8 um long and 50-100 nm wide GNRs were successfully demonstrated in high density without any trimming, and ~ 10% device yield was realized with a top-down patterning process. After passivating the surfaces of the GNRs using a low temperature atomic layer deposition (ALD) of Al(2)O(3), high performance GNR MOSFETs with symmetric drain current-gate-voltage (I(d)-V(g)) curves were demonstrated and a field effect mobility up to ~ 1200 cm(2) V(-1) s(-1) was achieved at V(d) = 10 mV. PMID- 21673382 TI - Toward wafer-scale patterning of freestanding intermetallic nanowires. AB - Individual metal alloy nanowires of constant diameter and high aspect ratio have previously been self-assembled at selected locations on atomic force microscope (AFM) probes by the method reported in Yazdanpanah et al (2005 J. Appl. Phys. 98 073510). This process relies on the room temperature crystallization of an ordered phase of silver-gallium. A parallel version of this method has been implemented in which a substrate, either an array of micromachined tips (similar to tips on AFM probes) or a lithographically patterned planar substrate, is brought into contact with a continuous, nearly planar film of melted gallium. In several runs, freestanding wires are fabricated with diameters of 40-400 nm, lengths of 4-80 um, growth rates of 80-170 nm s( - 1) and, most significantly, with yields of up to 97% in an array of 422 growth sites. These results demonstrate the feasibility of developing a batch manufacturing process for the decoration of wafers of AFM tips and other structures with selectively patterned freestanding nanowires. PMID- 21673383 TI - Error in dynamic spring constant calibration of atomic force microscope probes due to nonuniform cantilevers. AB - Many common atomic force microscope (AFM) spring constant calibration methods regard the AFM probe as a uniform cantilever, neglecting the tip mass and any nonuniformity in the thickness of the probe along its length. This work quantifies the error in the spring constant estimated by the Sader and thermal calibration methods due to nonuniformity in the thickness of the cantilever and the influence of the mass loading effect of the probe tip. Formulae are presented that can be used to compute the uncertainty in cantilever calibration for an arbitrary thickness nonuniformity, or to correct the calibration methods if the thickness nonuniformity is known. The results show that both methods are quite sensitive to nonuniformity. When the first dynamic mode is used in the calibration, the error in the spring constant estimated by either method is between - 4% and 9% for a cantilever whose thickness increases or decreases linearly by 30% along its length. The errors are several times larger if the second or higher dynamic modes are used. To illustrate the proposed methods, a commercial AFM probe that has significant nonuniformity is considered and the error in calibrating this probe is quantified and discussed. For this particular probe, variations in the thickness of the probe over the last 15% of its length are found to significantly reduce the accuracy of the calibration when the thermal method is used, since that method is sensitive to changes in the shape of the eigenmode of the probe near its free end. PMID- 21673384 TI - Nanomechanical characterization by double-pass force-distance mapping. AB - We demonstrate high speed force-distance mapping using a double-pass scheme. The topography is measured in tapping mode in the first pass and this information is used in the second pass to move the tip over the sample. In the second pass, the cantilever dither signal is turned off and the sample is vibrated. Rapid (few kHz frequency) force-distance curves can be recorded with small peak interaction force, and can be processed into an image. Such a double-pass measurement eliminates the need for feedback during force-distance measurements. The method is demonstrated on self-assembled peptidic nanofibers. PMID- 21673385 TI - Highly selective GaN-nanowire/TiO2-nanocluster hybrid sensors for detection of benzene and related environment pollutants. AB - Nanowire-nanocluster hybrid chemical sensors were realized by functionalizing gallium nitride (GaN) nanowires (NWs) with titanium dioxide (TiO(2)) nanoclusters for selectively sensing benzene and other related aromatic compounds. Hybrid sensor devices were developed by fabricating two-terminal devices using individual GaN NWs followed by the deposition of TiO(2) nanoclusters using RF magnetron sputtering. The sensor fabrication process employed standard microfabrication techniques. X-ray diffraction and high-resolution analytical transmission electron microscopy using energy-dispersive x-ray and electron energy-loss spectroscopies confirmed the presence of the anatase phase in TiO(2) clusters after post-deposition anneal at 700 degrees C. A change of current was observed for these hybrid sensors when exposed to the vapors of aromatic compounds (benzene, toluene, ethylbenzene, xylene and chlorobenzene mixed with air) under UV excitation, while they had no response to non-aromatic organic compounds such as methanol, ethanol, isopropanol, chloroform, acetone and 1,3 hexadiene. The sensitivity range for the noted aromatic compounds except chlorobenzene were from 1% down to 50 parts per billion (ppb) at room temperature. By combining the enhanced catalytic properties of the TiO(2) nanoclusters with the sensitive transduction capability of the nanowires, an ultra-sensitive and selective chemical sensing architecture is demonstrated. We have proposed a mechanism that could qualitatively explain the observed sensing behavior. PMID- 21673386 TI - Fabrication of a nanocarrier system through self-assembly of plasma protein and its tumor targeting. AB - Human serum albumin (HSA) nanoparticles hold great promise as a nanocarrier system for targeted drug delivery. The objective of this study was to explore the possibility of preparing size controllable albumin nanoparticles using the disulfide bond breaking reagent beta-mercaptoethanol (beta-ME). The results showed that the protein concentration and temperature had positive effects on the sizes of the albumin nanoparticles, while pH had a negative effect on the rate of nanoparticle formation. The addition of beta-ME induced changes in HSA secondary structure and exposed the hydrophobic core of HSA, leading to the formation of nanoparticles. Human serum albumin nanoparticles could be internalized by MCF-7 cells and mainly accumulated in cytoplasm. After injection in tumor bearing mice, the HSA nanoparticles accumulated in tumor tissues, demonstrating the targeting ability of the nanoparticles. Therefore, human serum albumin can be fabricated into nanoparticles by breaking the disulfide bonds and these nanoparticles exhibit high tumor targeting ability. Human serum albumin nanoparticles could be ideal for the targeted delivery of pharmacologically active substances. PMID- 21673387 TI - Diameter of titanium nanotubes influences anti-bacterial efficacy. AB - Bacterial infection of in-dwelling medical devices is a growing problem that cannot be treated by traditional antibiotics due to the increasing prevalence of antimicrobial resistance and biofilm formation. Here, due to changes in surface parameters, it is proposed that bacterial adhesion can be prevented through nanosurface modifications of the medical device alone. Toward this goal, titanium was created to possess nanotubular surface topographies of highly controlled diameters of 20, 40, 60, or 80 nm, sometimes followed by heat treatment to control chemistry and crystallinity, through a novel anodization process. For the first time it was found that through the control of Ti surface parameters including chemistry, crystallinity, nanotube size, and hydrophilicity, significantly changed responses of both Staphylococcus epidermidis and Staphylococcus aureus (pathogens relevant for orthopaedic and other medical device related infections) were measured. Specifically, heat treatment of 80 nm diameter titanium tubes produced the most robust antimicrobial effect of all surface treatment parameters tested. This study provides the first step toward understanding the surface properties of nano-structured titanium that improve tissue growth (as has been previously observed with nanotubular titanium), while simultaneously reducing infection without the use of pharmaceutical drugs. PMID- 21673388 TI - Synthesis of N-halamine-functionalized silica-polymer core-shell nanoparticles and their enhanced antibacterial activity. AB - N-halamine-functionalized silica-polymer core-shell nanoparticles with enhanced antibacterial activity were synthesized through the encapsulation of silica nanoparticles as support with polymeric N-halamine. The as-synthesized nanoparticles were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive x-ray spectrometry (EDX), dynamic light scattering (DLS), thermogravimetric analysis (TGA), and Fourier transform infrared (FTIR). These N-halamine-functionalized silica-polymer core shell nanoparticles displayed powerful antibacterial performance against both Gram-positive bacteria and Gram-negative bacteria, and their antibacterial activities have been greatly improved compared with their bulk counterparts. Therefore, these N-halamine-functionalized silica-polymer core-shell nanoparticles have the potential for various significant applications such as in medical devices, healthcare products, water purification systems, hospitals, dental office equipment, food packaging, food storage, household sanitation, etc. PMID- 21673389 TI - Silicon nanowire arrays as learning chemical vapour classifiers. AB - Nanowire field-effect transistors are a promising class of devices for various sensing applications. Apart from detecting individual chemical or biological analytes, it is especially interesting to use multiple selective sensors to look at their collective response in order to perform classification into predetermined categories. We show that non-functionalised silicon nanowire arrays can be used to robustly classify different chemical vapours using simple statistical machine learning methods. We were able to distinguish between acetone, ethanol and water with 100% accuracy while methanol, ethanol and 2 propanol were classified with 96% accuracy in ambient conditions. PMID- 21673390 TI - Room-temperature I-V characteristics of a single hollow La2/3Ca1/3MnO3 microparticle. AB - In this work we present an electrical characterization of La2/3Ca1/3MnO3 particles obtained by spray pyrolysis. We optimized the synthesis conditions to obtain the desired compound with the expected structure and the ferromagnetic transition at the same temperature as the bulk material. We found that a post deposition thermal treatment enhances the magnetic properties of the samples. The study of structural, morphological and magnetic properties shows that the walls of the hollow spheres are constituted by grains on the nanometer scale. The I-V characterization shows typical signatures of tunneling transport. This behavior can be associated with the grain boundaries within the microparticle's wall acting as tunnel barriers. PMID- 21673391 TI - Effect of the nanometric scale thickness on the magnetization steps in Ca3Co2O6 thin films. AB - We report on the effect of the film thickness on the magnetic properties of Ca3Co2O6films with an emphasis on the magnetization steps usually observed in the M-H curves below 10 K. Films with thicknesses between 35 and 200 nm all present two magnetic transitions at about T(C1) = 22 K and T(C2) = 10 K, corresponding to a 3D long range ferrimagnetic order and the transition to the formation of a frozen spin state, respectively. The magnetization curves at 10 K exhibit the expected stepped variation. However, by decreasing the thickness below a critical value of about 60 nm, no magnetization plateau is observed when the M-H curve is recorded at 2 K. Moreover, an additional transition in the susceptibility curve is observed at 45 K. These changes can be attributed to the reduced coherence length of the propagation vector along and perpendicular to the chains, and are supported by the magnetization relaxation measurements which indicate a reduction of the relaxation time. These results are helpful for understanding the origin of the magnetization steps in the one-dimensional Ca3Co2O6 cobaltite and confront the theoretical models aimed at explaining the magnetic properties in this system. PMID- 21673392 TI - A molecular dynamics study of the role of relative melting temperatures in reactive Ni/Al nanolaminates. AB - Molecular dynamics (MD) simulations using a recently developed first-principles based embedded-atom-method (EAM) potential are used to simulate the exothermic alloying reactions of a Ni/Al bilayer initially equilibrated at 1200 K. Simulations are performed in the isobaric-isoenthalpic (NPH) ensemble, which provides insight into the influence of pressure on atomic mixing and the subsequent alloying reaction. For pressures lower than 8 GPa, the mechanism of mixing is the same: as mixing and reaction occur at the interface, the heat generated first melts the Al layer, and subsequent mixing leads to further heat generation after which the Ni layer melts, leading to additional mixing until the alloying reactions are completed. However, for simulations at pressures higher than 8 GPa, the reaction does not occur within the time interval of the simulation. The results will be compared with our previous simulations of a Ni/Al bilayer using a different interatomic potential, which predicts substantially different pressure-dependent melting behavior of the pure components. This comparative study suggests that pressure-dependent melting behavior of components of reactive materials can be used to influence reaction rates and mechanisms. PMID- 21673393 TI - Complex magnetic behavior in the novel Kondo lattice compound CeRhSn3. AB - We report the magnetic and transport properties of a new ternary intermetallic compound, CeRhSn3, using magnetic susceptibility, magnetization, specific heat, electrical resistivity, muon-spin relaxation (MUSR) and neutron diffraction investigations. The dc magnetic susceptibility data reveal two magnetic phase transitions at 0.9 and 4 K. The overall behavior of dc susceptibility and magnetization indicates a ferrimagnetic-type phase transition near 4 K. The specific heat data also exhibit sharp lambda-type anomalies at 1 and 4 K. The behavior of the specific heat anomaly under the application of a magnetic field suggests that the 1 K transition is probably related to a transition from a ferri to a ferromagnetic state. The low temperature specific heat exhibits an enhanced Sommerfeld coefficient gamma (~100 mJ mol-1 K-2) due to the formation of a moderate heavy fermion state. The resistivity of CeRhSn3 demonstrates an interplay between the RKKY and Kondo interactions which is further modified by the presence of the crystal electric field. Interestingly, the resistivity of the nonmagnetic reference compound, LaRhSn3, is found to increase with decreasing temperature. Further, the onset of long-range magnetic order below 1 K is confirmed from our MUSR study on CeRhSn3. However, the 4 K transition is not detected in the MUSR and low temperature neutron diffraction data. Analysis of the dc magnetic susceptibility data within the framework of a two-sublattice model of ferrimagnetism supports the ferrimagnetic-type transition at 4 K in CeRhSn3. We have observed an unusual frequency dependence of the peak near 4 K in the ac susceptibility, which shows that the transition temperature shifts toward the lower temperature side with increasing frequency. PMID- 21673394 TI - Guidance of dorsal root ganglion neurites and Schwann cells by isolated Schwann cell topography on poly(dimethyl siloxane) conduits and films. AB - Biomimetic replicas of cellular topography have been utilized to direct neurite outgrowth. Here, we cultured postnatal rat dorsal root ganglion (DRG) explants in the presence of Schwann cell (SC) topography to determine the influence of SC topography on neurite outgrowth. Four distinct poly(dimethyl siloxane) conduits were fabricated within which DRG explants were cultured. To determine the contribution of SC topographical features to neurite guidance, the extent of neurite outgrowth into unpatterned conduits, conduits with randomly oriented SC replicas, and conduits with SC replicas parallel or perpendicular to the conduit long axis was measured. Neurite directionality and outgrowth from DRG were also quantified on two-dimensional SC replicas with orientations corresponding to the four conduit conditions. Additionally, live SC migration and neurite extension from DRG on SC replicas were examined as a first step toward quantification of the interactions between live SC and navigating neurites on SC replicas. DRG neurite outgrowth and morphology within conduits and on two-dimensional SC replicas were directed by the underlying SC topographical features. Maximal neurite outgrowth and alignment to the underlying features were observed into parallel conduits and on parallel two-dimensional substrates, whereas the least extent of outgrowth was observed into perpendicular conduits and on perpendicular two-dimensional replica conditions. Additionally, neurites on perpendicular conditions turned to extend along the direction of underlying SC topography. Neurite outgrowth exceeded SC migration in the direction of the underlying anisotropic SC replica after two days in culture. This finding confirms the critical role that SC have in guiding neurite outgrowth and suggests that the mechanism of neurite alignment to SC replicas depends on direct contact with cellular topography. These results suggest that SC topographical replicas may be used to direct and optimize neurite alignment, and emphasize the importance of SC features in neurite guidance. PMID- 21673395 TI - Electric crosstalk impairs spatial resolution of multi-electrode arrays in retinal implants. AB - Active multi-electrode arrays are used in vision prostheses, including optic nerve cuffs and cortical and retinal implants for stimulation of neural tissue. For retinal implants, arrays with up to 1500 electrodes are used in clinical trials. The ability to convey information with high spatial resolution is critical for these applications. To assess the extent to which spatial resolution is impaired by electric crosstalk, finite-element simulation of electric field distribution in a simplified passive tissue model of the retina is performed. The effects of electrode size, electrode spacing, distance to target cells, and electrode return configuration (monopolar, tripolar, hexagonal) on spatial resolution is investigated in the form of a mathematical model of electric field distribution. Results show that spatial resolution is impaired with increased distance from the electrode array to the target cells. This effect can be partly compensated by non-monopolar electrode configurations and larger electrode diameters, albeit at the expense of lower pixel densities due to larger covering areas by each stimulation electrode. In applications where multi-electrode arrays can be brought into close proximity to target cells, as presumably with epiretinal implants, smaller electrodes in monopolar configuration can provide the highest spatial resolution. However, if the implantation site is further from the target cells, as is the case in suprachoroidal approaches, hexagonally guarded electrode return configurations can convey higher spatial resolution. PMID- 21673396 TI - Bose-Einstein condensation of magnons in polycrystalline gadolinium with nano size grains. AB - We report the observation of Bose-Einstein condensation (BEC) of magnons in nanocrystalline Gd. Employing a self-consistent approach, the variations with magnetic field (H) of the BEC transition temperature, T(c)(H), and the volume, V (H), over which the condensate wavefunction retains its phase coherence, the temperature and magnetic field variations of the chemical potential, MU(T, H), and the average occupation number for the ground state, [linear span]n(0)(T, H)[linear span], are accurately determined from the magnetization, M(T, H), and specific heat, C(T, H), data. The variation of T(c) with magnetic field has the functional form T(c)(H) = T(c)(H = 0) + aH(2/3) that is characteristic of BEC. In conformity with the predictions of BEC theory (i) for T <= T(c), the condensate fraction [linear span]n(0)(T, H)[linear span]/[linear span]n(0)(T = 1.8 K, H)[linear span] at constant H scales with the reduced temperature as [T/T(c)(H)](3/2), (ii) in the limit H->0, MU(T, H) = 0 for T <= T(c) and abruptly falls to large negative values as the temperature exceeds T(c), and (iii) the magnetic-field-induced change in magnon entropy, deduced from both M(T, H) and C(T, H), follows the T(3/2) power law at low temperatures T< 4 K, hopping of the charge carriers following one-dimensional variable range hopping is evident which also gives rise to a positive magnetoresistance (MR) with an enhanced localization length (~5 nm) due to the presence of MWNTs. However, at T < 4 K, the observation of an unconventional positive temperature coefficient of resistivity is attributed to small polaron tunnelling. The exceptionally large negative MR observed in this temperature regime is conjectured to be due to the presence of quasi-1D MWNTs that can aid in lowering the tunnelling barrier across the nanotube-polymer boundary resulting in large delocalization. PMID- 21673398 TI - Triakontadipole and high-order dysprosium multipoles in the antiferromagnetic phase of DyB2C2. AB - Resonant soft x-ray Bragg diffraction at the Dy M(4,5) edges has been used to study Dy multipoles in the combined magnetic and orbitally ordered phase of DyB(2)C(2). The analysis incorporates both the intra-atomic magnetic and quadrupolar interactions between the 3d core and 4f valence shells. Additionally, we introduce to the formalism the interference of magnetic and nonmagnetic oscillators. This allows a determination of the higher-order multipole moments of rank 1 (dipole) to 6 (hexacontatetrapole). The strength of the Dy 4f multipole moments have been estimated as being up to 80% of the quadrupolar moment. PMID- 21673399 TI - Unexpected relationship between interlayer distances and surface/cleavage energies in gamma-TiAl: density functional study. AB - Density functional calculations were performed to study the gamma-TiAl (001), (100), (110) and (111) surfaces. The (100) surface is the most stable under Ti rich conditions, while the Al-termination (110) surface becomes the most stable with the increase of Al chemical potential. We calculate that in gamma-TiAl intermetallic compound the larger the interlayer distance, the larger the surface energy and cleavage energy. This is different from the situation in a pure metal. This phenomenon can be explained by the analysis of the bonding characteristics in gamma-TiAl. In particular there are both metallic and covalent bonds in gamma TiAl, and the strongest covalent bonds mainly focus on the center of three Ti-Al Ti atoms. It is the covalent bonds that affect greatly the cleavage energy, the surface energy and the surface stability. PMID- 21673400 TI - Spin resolved photoelectron spectroscopy of [Mn6(III)Cr(III)]3+ single-molecule magnets and of manganese compounds as reference layers. AB - Properties of the manganese-based single-molecule magnet [Mn(6)(III)Cr(III)](3+) are studied. It contains six Mn(III) ions arranged in two bowl-shaped trinuclear triplesalen building blocks linked by a hexacyanochromate and exhibits a large spin ground state of S(t) = 21/2. The dominant structures in the electron emission spectra of [Mn(6)(III)Cr(III)](3+) resonantly excited at the L(3)-edge are the L(3)M(2, 3)M(2, 3), L(3)M(2, 3)V and L(3)VV Auger emission groups following the decay of the primary p(3/2) core hole state. Significant differences of the Auger spectra from intact and degraded [Mn(6)(III)Cr(III)](3+) show up. First measurements of the electron spin polarization in the L(3)M(2, 3)V and L(3)VV Auger emission peaks from the manganese constituents in [Mn(6)(III)Cr(III)](3+) resonantly excited at the L(3)-edge near 640 eV by circularly polarized synchrotron radiation are reported. In addition spin resolved Auger electron spectra of the reference substances MnO, Mn(2)O(3) and Mn(II)(acetate)(2).4H(2)O are given. The applicability of spin resolved electron spectroscopy for characterizing magnetic states of constituent atoms compared to magnetic circular dichroism (MCD) is verified: the spin polarization obtained from Mn(II)(acetate)(2).4H(2)O at room temperature in the paramagnetic state compares to the MCD asymmetry revealed for a star-shaped molecule with a Mn(4)(II)O(6) core at 5 K in an external magnetic field of 5 T. PMID- 21673401 TI - First-principles study of nitrogen doping in cubic and amorphous Ge2Sb2Te5. AB - We investigated the structural, electronic and vibrational properties of amorphous and cubic Ge(2)Sb(2)Te(5) doped with N at 4.2 at.% by means of large scale ab initio simulations. Nitrogen can be incorporated in molecular form in both the crystalline and amorphous phases at a moderate energy cost. In contrast, insertion of N in the atomic form is very energetically costly in the crystalline phase, though it is still possible in the amorphous phase. These results support the suggestion that N segregates at the grain boundaries during the crystallization of the amorphous phase, resulting in a reduction in size of the crystalline grains and an increased crystallization temperature. PMID- 21673402 TI - Strong coupling of two interacting excitons confined in a nanocavity-quantum dot system. AB - We present a study of the strong coupling between radiation and matter, considering a system of two quantum dots, which are in mutual interaction and interact with a single mode of light confined in a semiconductor nanocavity. We take into account dissipative mechanisms such as the escape of the cavity photons, decay of the quantum dot excitons by spontaneous emission, and independent exciton pumping. It is shown that the mutual interaction between the dots can be measured off-resonance only if the strong coupling condition is reached. Using the quantum regression theorem, a reasonable definition of the dynamical coupling regimes is introduced in terms of the complex Rabi frequency. Finally, the emission spectrum for relevant conditions is presented and compared with the above definition, demonstrating that the interaction between the excitons does not affect the strong coupling. PMID- 21673403 TI - Jahn-Teller mechanism of stripe formation in doped layered La(2-x)Sr(x)NiO4 nickelates. AB - We introduce an effective model for e(g) electrons to describe quasi-two dimensional layered La(2-x)Sr(x)NiO(4) nickelates and study it using correlated wavefunctions on 8 * 8 and 6 * 6 clusters. The effective Hamiltonian includes the kinetic energy, on-site Coulomb interactions for e(g) electrons (intraorbital U and Hund's exchange J(H)) and the coupling between e(g) electrons and Jahn-Teller distortions (static modes). The experimental ground state phases with inhomogeneous charge, spin and orbital order at the dopings x = 1/3 and 1/2 are reproduced very well by the model. Although the Jahn-Teller distortions are weak, we show that they play a crucial role and stabilize the observed cooperative charge, magnetic and orbital order in the form of a diagonal stripe phase at x = 1/3 doping and a chequerboard phase at x = 1/2 doping. PMID- 21673404 TI - The magnetic structure of multiferroic BaMnF4. AB - The multiferroic material BaMnF(4) has been investigated with unpolarized and polarized neutron diffraction. The structure has been shown to be antiferromagnetic. The magnetic moments are aligned at 12 degrees to the b direction in the bc plane, 3 degrees different from the previously determined value. The ferromagnetic component that is indicative of the linear magnetoelectric effect was not observed. PMID- 21673405 TI - Effects of tensile strain on Ag(111) epitaxial growth by kinetic Monte Carlo simulations. AB - The effects of surface strain on epitaxial growth are studied using the kinetic Monte Carlo (KMC) method. The strain dependences of the activation energy barrier and the attempt frequency of each elementary process are evaluated by the embedded atom method interatomic potential. KMC simulations of homoepitaxial growth on a Ag(111) surface with equibiaxial tensile strain are carried out and influences of the surface strain on the nucleation of islands and the surface morphology are investigated. The island density increases due to reduction of the adatom diffusion on the terrace. The averaged coordination number of atoms constituting islands decreases and the island shape is more dendritic. The tensile surface strain leads to an increase in the surface roughness at an early stage of the growth, but at high coverage the roughness is adversely lower for the strained surface. PMID- 21673406 TI - Resting state cortical electroencephalographic rhythms and white matter vascular lesions in subjects with Alzheimer's disease: an Italian multicenter study. AB - Resting state electroencephalographic (EEG) rhythms do not deteriorate with the increase of white matter vascular lesion in amnesic mild cognitive impairment (MCI) subjects [1], although white matter is impaired along Alzheimer's disease (AD). Here we tested whether this is true even in AD subjects. Closed-eye resting state EEG data were recorded in 40 healthy elderly (Nold), 96 amnesic MCI, and 83 AD subjects. White matter vascular lesions were indexed by magnetic resonance imaging recorded in the MCI and AD subjects (about 42% of cases following ADNI standards). The MCI subjects were divided into two sub-groups based on the median of the white matter lesion, namely MCI+ (people with highest vascular load; n = 48) and MCI- (people with lowest vascular load; n = 48). The same was true for the AD subjects (AD+, n = 42; AD-, n = 41). EEG rhythms of interest were delta (2 4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). LORETA software estimated cortical EEG sources. When compared to Nold group, MCI and AD groups showed well known abnormalities of delta and alpha sources. Furthermore, amplitude of occipital, temporal, and limbic alpha 1 sources were higher in MCI+ than MCI- group. As a novelty, amplitude of occipital delta sources was lower in AD+ than AD- group. Furthermore, central, parietal, occipital, temporal, and limbic alpha sources were higher in amplitude in AD+ than AD- group. Amplitude of these sources was correlated to global cognitive status (i.e., Mini Mental State Evaluation score). These results suggest that in amnesic MCI and AD subjects, resting state posterior delta and alpha EEG rhythms do not deteriorate with the increase of white-matter vascular lesion. These rhythms might be more sensitive to AD neurodegenerative processes and cognitive status rather than to concomitant lesions to white matter. PMID- 21673407 TI - Cerebral serotonin 4 receptors and amyloid-beta in early Alzheimer's disease. AB - The 5-HT4 receptor may play a role in memory and learning and 5-HT4 receptor activation has been suggested to modulate acetylcholine release and to reduce amyloid-beta (Abeta) accumulation. The aim of this study was for the first time to investigate the in vivo cerebral 5-HT4 receptor binding in early Alzheimer disease (AD) patients in relation to cortical Abeta burden. Eleven newly diagnosed untreated AD patients (mean MMSE 24, range 19-27) and twelve age- and gender-matched healthy controls underwent a two-hour dynamic [11C]SB207145 PET scan to measure the binding potential of the 5-HT4 receptor. All AD patients and eight healthy controls additionally underwent a [11C]PIB PET scan to measure the cortical Abeta burden. When AD patients were defined on clinical criteria, no difference in cerebral 5-HT4 receptor binding between AD patients and healthy controls was found (p = 0.54). However, when individuals were reassigned to groups according to their amyloid status, the PIB-positive individuals had 13% higher 5-HT4 receptor levels than PIB-negative individuals (p = 0.02) and the importance of classification of groups is emphasized. The 5-HT4 receptor binding was a positively correlated to Abeta burden (p = 0.03) and negatively to MMSE score of the AD patients (p = 0.02). Our data suggests that cerebral 5-HT4 receptor upregulation starts at a preclinical stage of and continues while dementia is still at a mild stage, which contrasts other receptor subtypes. We speculate that this may either be a compensatory effect of decreased levels of interstitial 5-HT, an attempt to improve cognitive function, increase acetylcholine release or to counteract Abeta accumulation. PMID- 21673408 TI - Study of estrogen receptor-alpha and receptor-beta gene polymorphisms on Alzheimer's disease. AB - Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor alpha 1 (ESR1) and estrogen receptor alpha 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE epsilon4 allele adjusted odds ratio = 0.71 [0.57-0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (epsilon4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD. PMID- 21673412 TI - Special issue: Vaccines. PMID- 21673413 TI - Pandemic influenza vaccines and neuraminidase inhibitors: efficacy and side effects. AB - At the time of the outbreak of the pandemic of New Influenza A (H1N1) pandemic influenza vaccines became available via an accelerated registration procedure. In 2005 large stocks of the neuraminidase inhibitor oseltamivir were built up in the Netherlands and other western countries. There was considerable doubt about the efficacy of this medicine. Initially reported positive effects of the drug were largely based on unpublished research, which was sponsored by the manufacturer and was partially written by ghostwriters. There now have been reports of rare and serious side effects. The first reports on the severity of the pandemic in Australia and New Zealand indicated a mild course. PMID- 21673414 TI - The sponsored pandemic of the Mexican flu? AB - The first reports of the New Influenza A (H1N1) spoke of a markedly increased morbidity and mortality. Later it turned out that this flu was a very mild flu. Gradually the role of the WHO was questioned. The definition of a pandemic flu had been changed and there rose doubts about the independency of the experts advising the WHO. It showed that some of these experts had a conflict of interest with the pharmaceutical industry, especially with those producing vaccines and neuraminidase inhibitors. As of june 2010 the WHO declared the outbreak to be a pandemic. This provided the momentum to produce vaccines. At the outbreak of the pandemic in the northern hemisphere, there was sufficient evidence that the pandemic would not be so serious, that a single vaccination was sufficient, that there were strong doubts about the efficacy of oseltamivir and that the drug, although rarely, could have serious side effects. With the stockpiling of neuraminidase inhibitors and with the recommendation of the vaccination political decisions were involved. These decisions should be driven and supported by independent scientific advisory bodies with no room for even the semblance of conflicts of interest. Stronger measures to limit the impact of experts with conflicts of interest on the development of, among others, guidelines are necessary. PMID- 21673415 TI - Monitoring adverse events of vaccines against Mexican flu. AB - In November 2009, a vaccination campaign against Influenza A (H1N1) was started in the Netherlands. The accelerated registration procedure of the vaccines used in this campaign and the use of these vaccines on a large scale indicated a need for real-time safety monitoring. This article looks at the way in which the safety monitoring of the pandemic influenza vaccines was organized in the Netherlands and it gives an overview of the main findings with respect to the two pandemic influenza vaccines, Focetria and Pandemrix, used in the Netherlands. Close monitoring, an efficient processing and analyzing the reports resulted in a close and real-time monitoring of the safety of the vaccines. From 1 November 2009 until 1 March 2010, 7534 reports concerning one or more events possibly related to the administration of both vaccines were received. 2788 of the reports related to Focetria and 4746 of the reports related to Pandemrix. No signals of possible batch-related problems were detected for either vaccine. The profile of the reported adverse events is comparable with the information provided in the Summary of Product Characteristics (SPC). Differences in reported events between both vaccines may be caused by bias and confounding due to the different populations for which these vaccines have been used. PMID- 21673416 TI - Neurological complications of vaccination with outer surface protein A (OspA). AB - A wide range of neurological complications have been reported via the medical literature and the VAERS system after vaccination with recombinant outer surface protein A (OspA) of Borrelia. To explore this issue, 24 patients reporting neurological adverse events (AE) after vaccination with Lymerix, out of a group of 94 patients reporting adverse events after Lymerix vaccination, were examined for causation. Five reports of cerebral ischemia, two transient Ischemic attacks, five demyelinating events, two optic neuritis, two reports of transverse myelitis, and one non-specific demyelinating condition are evaluated in this paper. Caution is raised on not actively looking for neurologic AE, and for not considering causation when the incidence rate is too low to raise a calculable difference to natural occurence. PMID- 21673417 TI - Does seasonal influenza vaccination increase the risk of illness with the 2009 A/H1N1 pandemic virus? AB - This Perspective discusses the following study published in PLoS Medicine: Skowronski DM, De Serres G, Crocroft N, Janjua NZ, Boulianne N, et al. (2010) Association between the 2008-09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring-Summer 2009 : Four Observational Studies from Canada. PLoS Med 7(4): e1000258. doi:10.1371/journal.pmed.1000258. In three case-control studies and a household transmission cohort, Danuta Skowronski and colleagues find an association between prior seasonal flu vaccination and increased risk of 2009 pandemic H1N1 flu. PMID- 21673418 TI - Postlicensure safety evaluation of human papilloma virus vaccines. AB - OBJECTIVE: A summary of postlicensure safety information of HPV vaccines from three sources: VigiBase, the global database of WHO's Programme for International Drug Monitoring, the VAERS report on Gardasil and the RIVM report on Cervarix. METHOD: all AEFI from the three sources were recalculated to a percentage of all AEFI reported for each of the two vaccines. And the safety profile was compared to the safety data in the SPC. RESULTS: Comparison of relative AEFI reporting proportions in the global VigiBase database with VAERS for Gardasil and with RIVM for Cervarix shows a safety profile in VigiBase similar to the result of PMS on a national level in 2 countries. CONCLUSION: The post licensure safety profile of both vaccines is consistent with the data in the SPC of these vaccines. PMID- 21673419 TI - Vaccine safety. AB - Brief reports are presented on Swissmedic's experiences with PaniFlow, a tool to monitor Adverse Events Following Immunization (AEFI) of pandemic influenza (H1N1) 2009 vaccines and UMC's updates on AEFI of these vaccines; on WHO's Global Network for Post-marketing Surveillance of Prequalified Vaccines and India joining the network; the June 2010 meeting of the Global Advisory Committee on Vaccine Safety. PMID- 21673420 TI - New vaccine reports from FDA to the Uppsala Monitoring Centre. PMID- 21673421 TI - Genetic factors in risk assessment for the development of type 2 diabetes mellitus in a small case series. AB - OBJECTIVE: This study aimed to investigate the role of genetic biomarkers in assessing risk for the eventual development of type 2 diabetes mellitus (T2DM). METHODS: Three Maltese women with a history of previous severe GDM and with apparent similar clinical risk factors underwent anthropomorphic and metabolic reassessment 4-7 years post-partum. They were further genotyped for four specific genetic single nucleotide polymorphisms (SNPs) using the qPCR technique for the alleles of SLC2A2 (rs5393A/C), FTO (rs9939609A/T), PCK (rs2071023C/G) and CDKAL1 (rs10946398A/C). RESULTS: While the previous obstetric history of all the cases was similar, the biological status was characterized by an increasing degree of obesity correlating to increasing severity of current carbohydrate intolerance. Genotyping showed that all the tested SNPs were homozygous mutant in the T2DM woman and heterozygous in the impaired glucose tolerance woman. The woman with normal glucose tolerance was shown to be wild type for SLC2A2 (rs5393A/C). CONCLUSIONS: There appeared to be an interrelationship between eventual severity of carbohydrate metabolism abnormalities and the genetic allele status. It would appear that the specific allele-scoring can be used to identify further the potential risk of developing T2DM. PMID- 21673422 TI - An analysis of psychotropic drug sales. Increasing sales of selective serotonin reuptake inhibitors are closely related to number of products. AB - BACKGROUND: Prescribing of selective serotonin reuptake inhibitors (SSRIs) has increased dramatically. OBJECTIVE: To compare the sales of benzodiazepines and SSRIs within the primary care sector in Denmark and relate changes in usage to number of indications and products on the market. METHODS: We used data from various sources to establish the sales curves of psychotropic drugs in the period 1970 to 2007, based on the Anatomic Therapeutic Classification system and Defined Daily Doses. RESULTS: Fluctuations in sales of psychotropic drugs that cannot be explained by disease prevalence were caused by changes in sales of the benzodiazepines and SSRIs. We found a decline in the sales of benzodiazepines after a peak in 1986, likely due to the recognition that they cause dependence. From a low level in 1992, we found that the sales of SSRIs increased almost linearly by a factor of 18, up to 44 DDD per 1000 inhabitants, which was closely related to the number of products on the market that increased by a factor of 16. CONCLUSIONS: Sales of antidepressant drugs are mainly determined by market availability of products indicating that marketing pressures are playing an important role. Thus the current level of use of SSRIs may not be evidence-based, which is supported by studies showing that the effect of SSRIs has been overestimated. PMID- 21673423 TI - Vision. PMID- 21673424 TI - Design of a workstation and its evaluation under the influence of noise and illumination for an assembly task. AB - OBJECTIVE: An experimental research was conducted to design a workstation for a lock manufacturing assembly. PARTICIPANTS: Two experiments were conducted in the present study. Nine male subjects in the age range of 18-35 years participated in the first experiment. For the second experiment, nine subjects in each of the three age groups (viz. 17-22, 23-28 and 29-35 years) volunteered for experimental investigations. METHOD: The designed workstation was evaluated under varying levels of noise and illumination for workers of different age groups. Three different workstations were evaluated. The task was performed by a worker in two different sitting positions and three settings of arms position. RESULTS: It was found that workstation type, backrest support and arms positions were all having a statistically significant effect on task performance. Workstation with work surface to seat height ratio of 1.82 was found to be better when the task was performed using backrest and arms were supported on the work surface. This workstation was evaluated for three different age groups of workers under different levels of noise and illumination. The results of the study showed that age of the worker, illumination level and level of noise were all contributing significantly towards task performance. CONCLUSIONS: The design of a workstation for assembly task would help greatly in creating a better working environment and enhancing the productivity of workers exposed to environmental stressors like noise and illumination. PMID- 21673425 TI - School Based Vision Centers: striving to optimize learning. AB - The successful delivery of comprehensive pediatric vision care after vision screening referral is a longstanding challenge that has significant implications for child wellness. In response to the many known obstacles that prevent the diagnosis and treatment of vision conditions, School-Based Vision Centers have been established in Framingham, MA and Boston, MA to provide easy access to comprehensive vision care following a failed vision screening. These on-site Vision Centers were developed to improve access to comprehensive vision care and treatment thereby correcting vision conditions that can adversely affect student academic achievement, athletic performance, and self-esteem. This paper highlights the collaboration between two public schools in Massachusetts and The New England Eye Institute and describes a multidisciplinary approach to comprehensive care delivery to high-risk pediatric populations in school-based settings. The ultimate goal of this model is to minimize visual barriers that may impede learning in order to maximize academic success and wellness. PMID- 21673426 TI - Which factors affect the chances of paid employment for individuals with visual impairment in Britain? AB - OBJECTIVES: To analyze which factors affect the probability of people registered as blind and visually impaired in Britain being in paid employment. PARTICIPANTS: Consist of 559 registered individuals of working age with a visual impairment. This sub-sample is drawn from the first wave of a larger, nationally representative survey of adults who are blind and visually impaired in Britain. METHODS: After examining descriptive statistics for employment status and key analysis variables, a multivariate analysis is undertaken to assess the relative impact of: demographic and household characteristics, socio-economic status, aspects of visual impairment, including severity and age of onset, and presence of additional disabilities. RESULTS: Educational attainment, housing tenure, registration status (as blind or visually impaired) and having additional disabilities have the strongest impact on the likelihood of an individual registered as visually impaired being in work. CONCLUSIONS: The findings underline the need to examine the varying labor market experiences of groups with different types of disability and the importance of assessing the individual effects of severity of visual impairment, age of onset, and presence of additional disabilities. PMID- 21673427 TI - Individualized functional work evaluation and vision: a case study in reasonable accommodation. AB - A case study is provided where functional capacity evaluation, work place assessment, and driver rehabilitation assessments were combined to produce an individualized functional work evaluation. A human rights complaint was launched by worker who alleged that her employer had determined that her vision impairment rendered her incapable of meeting her job demands, which could not be 'reasonably accommodated'. An evidence based practice approach and clinical reasoning process utilized by the assessor in developing an individualized evaluation is described. The individualized evaluation developed by the assessor is consistent with the clinical trend towards the inclusion of direct observation of actual occupational performance, in making a determination of work ability. The resulting individualized evaluation was integral to the Human Rights Tribunal in determining whether the worker's limitations could be "reasonably accommodated.'' PMID- 21673428 TI - Development of a tool for the assessment of employment preparedness specifically for persons who are blind or partially sighted. AB - OBJECTIVE: To develop a psychometric tool to assess preparedness for employment for persons who are blind or visually impaired. PARTICIPANTS: Two hundred and thirty nine working aged adults who are blind or visually impaired. METHODS: The content for this tool was generated through a literature review and through focus groups with successfully employed persons with vision impairments as well as hiring managers and rehabilitation workers of same. Content of the instrument was enhanced through a survey of persons with vision loss, using the draft instrument and through factor analyses of their responses. RESULTS: Factor analyses of participants' responses resulted in 12 scales each of which assessed a different factor related to employment. Scales had good to excellent reliability with the exception of one scale that had acceptable reliability (as measured by Cronbach's Alpha). CONCLUSION: The CNIB TAPE appears to be an effective instrument for assessing preparedness for employment. PMID- 21673429 TI - The multi-disciplinary nature of low vision rehabilitation--a case report. AB - This paper presents the case of a 47-year-old female with low vision secondary to high myopic macular degeneration who remains active in the work force as a spiritual and religious care coordinator for a large institution. An ophthalmologist with a specialty in low vision rehabilitation initially assessed the client. The ophthalmologist prescribed optical devices which used residual retinal vision available at preferred retinal loci. This availed better vision for viewing targets located at far, near and intermediate distances from the client. An optician provided and dispensed the devices prescribed to the client. Additionally, the ophthalmologist made a referral to an occupational therapist. The occupational therapist conducted a series of sessions to further enhance reading and writing skills and a work place assessment aimed at optimizing workplace conditions in order to achieve optimal functional vision. This case illustrates and emphasizes the multi-disciplinary nature of low vision rehabilitation, which involved in this case co-operation between ophthalmology, occupational therapy and opticianry. PMID- 21673430 TI - Eye-neck interactions triggered by visually deficient computer work. AB - OBJECTIVES: To study the joint occurrence of eye-and-neck/scapular area symptoms and their association with occupational risk factors in a cross-sectional sample of professional information technology users. STUDY POPULATION: The participants consisted of 3,971 employees who worked with computers for a minimum of one hour a day. 2,551 (73%) were men and 945 (27%) women, with an age range of 18 up to 64 years. The mean age was 38.1 (SD=10.7) for men and 37.6 (SD=12.0) for the women. The measures were obtained via a self-administered survey in combination with a visual examination conducted by an optometrist. METHODS: Two complementary logistic regression analyses with forced entry was conducted on n=3,496 (88% adjusted response rate) cases. The effect of ocular symptoms on the risk of reporting musculoskeletal symptoms, or vice versa, was examined first in two separate binominal logistic regression analyses. Age, Gender, Near work variable and Visual functioning variables were included in these analyzes. Variables associated with the risk of developing an increase in either symptom category were also examined in two additional binomial logistic regression analyses. RESULTS: Exposure to spectacles (single vision, multifocal, or progressive correction) in combination with a visual acuity <1 surfaced as a key mediator of symptoms from the neck/scapular area (p<0.01). A vergence disparity (uncompensated vergence error) similarly was associated with an augmented risk of developing an increase in neck/scapular area symptoms (p<0.05). The most influential risk factor for neck/scapular area symptoms were ocular symptoms and vice versa (p<0.0001). CONCLUSIONS: The results support the hypothesis which postulates that eye-neck/scapular area symptoms interaction may be due to a functional coupling from and between the eye-neck/scapular area muscles [28]. PMID- 21673431 TI - Users of assistive technology also require assistance with ergonomics. AB - This case study describes an ergonomics workstation assessment conducted for an administrative worker with vision impairment due to keratoconus. The worker, PT, was provided with multiple assistive technology devices to help her with her work, but this resulted in an overcrowded workspace. The purpose of the workstation assessment was to assist the worker with her workstation arrangement to make it more comfortable and efficient. During the assessment, a range of physical, cognitive and organisational ergonomics issues were identified and addressed. Multidisciplinary teams are often used in the rehabilitation of workers with complex medical problems. An ergonomist can play a valuable role on this team. PMID- 21673432 TI - Tips for computer vision syndrome relief and prevention. PMID- 21673433 TI - Point-of-care pathology with miniature microscopes. AB - Advances in optical designs are enabling the development of miniature microscopes that can examine tissue in situ for early anatomic and molecular indicators of disease, in real time, and at cellular resolution. These new devices will lead to major changes in how diseases are detected and managed, driving a shift from today's diagnostic paradigm of biopsy followed by histopathology and recommended therapy, to non-invasive point-of-care diagnosis with possible same-session definitive treatment. This shift may have major implications for the training requirements of future physicians to enable them to interpret real-time in vivo microscopic data, and will also shape the emerging fields of telepathology and telemedicine. Implementation of new technologies into clinical practice is a complex process that requires bridging gaps between clinicians, engineers and scientists. This article provides a forward-looking discussion of these issues, with a focus on malignant and pre-malignant lesions, by first highlighting some of the clinical areas where point-of-care in vivo microscopy could address unmet needs, and then by reviewing the technological challenges that are being addressed, or need to be addressed, for in vivo microscopy to become a standard clinical tool. PMID- 21673434 TI - Targeting glutathione-S transferase enzymes in musculoskeletal sarcomas: a promising therapeutic strategy. AB - Recent studies have indicated that targeting glutathione-S-transferase (GST) isoenzymes may be a promising novel strategy to improve the efficacy of conventional chemotherapy in the three most common musculoskeletal tumours: osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. By using a panel of 15 drug sensitive and drug-resistant human osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma cell lines, the efficay of the GST-targeting agent 6-(7-nitro 2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has been assessed and related to GST isoenzymes expression (namely GSTP1, GSTA1, GSTM1, and MGST). NBDHEX showed a relevant in vitro activity on all cell lines, including the drug-resistant ones and those with higher GSTs levels. The in vitro activity of NBDHEX was mostly related to cytostatic effects, with a less evident apoptotic induction. NBDHEX positively interacted with doxorubicin, vincristine, cisplatin but showed antagonistic effects with methotrexate. In vivo studies confirmed the cytostatic efficay of NBDHEX and its positive interaction with vincristine in Ewing's sarcoma cells, and also indicated a positive effect against the metastatisation of osteosarcoma cells. The whole body of evidence found in this study indicated that targeting GSTs in osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma may be an interesting new therapeutic option, which can be considered for patients who are scarcely responsive to conventional regimens. PMID- 21673435 TI - Proteomic analysis of MCF-7 breast cancer cell line exposed to leptin. AB - BACKGROUND: Obesity is a well-known factor risk for breast cancer in postmenopausal women. Circulating leptin levels are increased in obese and it has been suggested to play an important role in mammary tumor formation and progression. To contribute to the understanding of the molecular mechanisms underlying leptin action in breast cancer, our aim was to identify proteins regulated by leptin in MCF-7 human breast cancer cells. METHODS: We used two dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) to identify proteins affected by leptin. RESULTS: Thirty proteins were found differentially expressed in MCF-7 cells after 48 h leptin exposure. Proteins regulated by leptin included proteins previously implicated in breast cancer such as catechol-o methyltransferase, cathepsin D, hsp27, serine/threonine-protein phosphatase and regulatory proteins of the Ras signaling pathway. Proteins involved in other cellular functions such as stress response, cytosqueleton remodeling and proteins belonging to ubiquitin-proteasome system, were also identified. Furthermore, leptin-treated cells showed a substantial uptake of the serum carrier proteins albumin and alpha-2-HS-glycoprotein. CONCLUSIONS: This screening reveals that leptin influences the levels of key proteins involved in breast cancer which opens new avenues for the study of the molecular mechanisms linking obesity to breast cancer. PMID- 21673437 TI - Ergonomic products. PMID- 21673438 TI - Ulnar neuropathy at the elbow in computer keyboard operators. AB - OBJECTIVE: This case series sought to determine the prevalence of ulnar neuropathy at the elbow (UNE) by using electrophysiologic criteria among all computer keyboard operators (CKOs) referred over a four-year period (1995-1999) for electrodiagnosis (EDX) due to clinical suspicion of focal upper limb neuropathies. PARTICIPANTS: All CKOs referred to an EDX laboratory for suspicion of focal upper limb neuropathies primarily from private practice physicians, mostly hand surgeons, and an occupational medicine clinic. METHODS: All 148 CKOs underwent NCV studies of the upper limbs, which included segmental studies of the ulnar nerve and were questioned for the presence and distribution pattern of paresthesias in the symptomatic upper limb(s). The CKOs provided the electromyographer with subjective descriptions of their workstation configuration, layout, and basic office equipment. RESULTS: Focal ulnar neuropathy at the elbow (UNE) was identified in 105 out of 148 CKOs referred to an EDX laboratory for clinical suspicion of upper limb focal neuropathies. CONCLUSIONS: Compared with the more prevalent diagnosis of carpal tunnel syndrome (CTS), ulnar neuropathy at the elbow should also be considered among CKOs referred for EDX testing because of suspicion of focal upper limb neuropathies. Clinicians evaluating CKOs for suspicion of focal upper limb neuropathies should routinely ask about symptoms of ulnar neuropathy. PMID- 21673439 TI - A collaborative effort to apply ergonomics to electric utility workers at generating stations. AB - As part of a collaborative approach involving electric utility companies, university researchers, individual contractors and a not-for-profit research institute, two ergonomics teams consisting of skilled utility workers and trained ergonomists, were assembled. These teams were to identify tasks with risk factors for musculoskeletal disorders (MSDs) among workers in fossil-fueled generating stations and and to propose ergonomic interventions for these tasks. One team focused on tasks of electricians and the other focused on tasks of plant operators and mechanics. Several of the tasks were tested in an ergonomics laboratory and at one of the utility's generating stations. We present a sample of the recommended interventions in this paper. An anthropometric analysis of electrical box height recommended the appropriate height for electrical boxes. The results of a field experiment showed that low rolling resistance wheels decreased the forces to initiate and sustain pushing a cart. The same experiment also demonstrated that the forces required to turn a cart with six wheels were lower than the forces equired to turn a cart with four wheels. A collaborative approach to ergonomics proved to be an effective method to identify and assess tasks that are problematic for workers and to develop best practices for these tasks in the electric power industry. This method could be used by other industries in their attempt to decrease the incidence, cost and severity of workplace MSDs. PMID- 21673440 TI - Evaluating the physical demands of three tarping systems for flatbed transport trailers. AB - OBJECTIVE: Tarping and untarping loads on flatbed trailers creates concerns related to falls as well as high musculoskeletal demands. The purpose of this study is to compare the demands and risks present when using three different tarping systems and to determine which system is preferred to reduce demand and injury risks. PARTICIPANTS: Nine male volunteers from a flatbed trucking company participated in the study. METHODS: The truck drivers covered the load on the flatbed trailer using three different tarping systems: manual tarps, sliders, and rack and tarp kits. Multiple measures were used to characterize the three tarping systems, including required forces, identifying injury risk by assessing peak, average and cumulative forces, moments and electromyography, heart rate, and exposure to fall hazards. RESULTS: Manual tarping resulted in greater physical demands and safety risks than the two alternate systems, both of which all participants preferred. The slider method was preferred overall as it has numerous advantages. CONCLUSIONS: The slider and rack and tarp kit methods offered a wide range of benefits including reduced physical demands, reduced exposure to fall hazards as well as improved productivity due to the shorter execution times, but had the disadvantage of being less versatile. PMID- 21673441 TI - A tool for rapid assessment of product usability and universal design: development and preliminary psychometric testing. AB - BACKGROUND: While there are many available tools and methods to evaluate product usability, few have been tested on user groups with disabilities and even fewer systematically consider universal design principles. OBJECTIVE: This paper describes the development and preliminary psychometric testing of the Rapid Assessment of Product Usability & Universal Design (RAPUUD), a 12-item user report tool based on the seven principles of universal design. METHOD: A preliminary set of items was created to elicit ratings of diverse product characteristics (e.g., physical effort, cognitive effort, assistance required, safety). Data were gathered from 61 participants who rated the usability of products they use in their own environments. RESULTS: Each item elicited a full range of responses, with no apparent floor or ceiling effects. Collectively, the 12 items achieved a high internal consistency (Cronbach's alpha=0.80). The data indicate that the tool was sensitive to differences in functional abilities, as well as differences in product characteristics. The instrument was usable for a range of consumer products, though not all items were appropriate for each and every product. CONCLUSION: The results suggest that the instrument could become a pragmatic tool for designers to identify usability problems experienced by a diversity of user populations. PMID- 21673442 TI - Effects of keyboard keyswitch design: a review of the current literature. AB - OBJECTIVE: This article aims to provide designers and researchers with a summary of the current literature regarding the effects of specific keyswitch design parameters on user preference, performance, and biomechanical outcomes. METHODS: Studies which evaluated the effects of keyswitch make force, make travel and over travel on preference, typing speed, errors, keyboard reaction forces and upper extremity EMG are included in the review. Studies which examined possible control strategies employed during keyswitch tapping are also covered. RESULTS: General conclusions that can be drawn from these studies are: greater make forces result in increased keyboard reaction forces and EMG activity, users strike keys with forces 2-7 times the required make force and that they employ a ballistic finger motion to do so. Furthermore, typists tend to prefer kinesthetic and auditory feedback. CONCLUSIONS: Due to the ballistic nature of typing, new keyswitch designs should be aimed at reducing impact forces. Future studies should examine the role of breakaway force and over travel as limited research has been done on the role of these parameters. PMID- 21673443 TI - The Biodex isokinetic dynamometer for knee strength assessment in children: advantages and limitations. AB - OBJECTIVE: To critically appraise the Biodex System 4 isokinetic dynamometer for strength assessment of children. METHODS: Appraisal was based on experiences from two independent laboratories involving testing of 213 children. Issues were recorded and the manufacturer was consulted regarding appropriate solutions. RESULTS: The dynamometer had insufficient height adjustment for alignment of the knee for some children, requiring the construction of padding to better fit the child within the dynamometer. Potential for entrapment of the non-testing leg was evident in the passive and eccentric modes and a leg bracket restraint was constructed. Automated gravity correction did not operate when protocols were linked or data was exported to an external device. CONCLUSIONS: Limitations were noted, some of which were applicable to knee strength testing in general and others which were specific to use with children. However, most of these obstacles could be overcome, making the Biodex System 4 suitable for assessment of knee strength in children. PMID- 21673444 TI - Evaluation of anti-vibration interventions for the hand during sheet metal assembly work. AB - OBJECTIVE: Occupational use of vibrating hand tools contributes to the development of upper extremity disorders. While several types of vibration damping materials are commercially available, reductions in vibration exposure are usually tested in the laboratory rather than in actual work environments. This study evaluated reductions in hand vibration with different vibration damping interventions under actual work conditions. METHODS: Three experienced sheet metal assemblers at a manufacturing facility installed sheet metal fasteners with a pneumatic tool using no vibration damping (bare hand) and each of six anti-vibration interventions (five different gloves and a viscoelastic tool wrap). Vibration was measured with tri-axial accelerometers on the tool and the back of the hand. RESULTS: Unweighted mean vibration measured at the hand showed reduced vibration (p<0.001) for all six interventions (range = 3.07-5.56 m/s(2)) compared to the bare hand condition (12.91 m/s(2)). CONCLUSIONS: All of the interventions were effective at reducing vibration at the hand during testing under usual work conditions. Field testing beyond laboratory-based testing accounts for the influences of worker, tools, and materials on vibration transmission to the body from specific work operations. PMID- 21673445 TI - Ergonomic evaluation of ten single-channel pipettes. AB - Repetitive pipetting is a task that is associated with work-related musculoskeletal disorders of the hand and arm. OBJECTIVE: The purpose of this study was to evaluate the usability and ergonomic performance of commercially available pipettes as determined by user ratings and objective measurements. PARTICIPANTS: Participants were laboratory technicians and scientists at the Lawrence Berkeley National Laboratory with experience performing pipetting tasks. METHODS: Twenty-one experienced pipette users completed a standardized pipetting task with 5 manual and 5 electronic pipettes. After using each pipette, the user rated it for attributes of comfort and usability. RESULTS: Although no single pipette was rated significantly better than all of the others for every attribute tested, some significant differences were found between pipettes. The Rainin Pipet-Lite received the highest overall quality score among manual pipettes, while the Thermo Scientific Finnpipette Novus was the top-ranked electronic pipette. Features correlated with greater hand and arm comfort were lower tip ejection force, lower blowout force, and pipette balance in the hand. CONCLUSIONS: The findings, when considered with participant comments, provide insights into desirable pipette features and emphasize the value of user testing and the importance of the interactions between task, workplace layout, and pipette design. PMID- 21673446 TI - Does elevating and tilting the input device support surface affect typing force and postural exposures of the wrist? AB - OBJECTIVE: Compare wrist kinematics and typing force during computer work across two workstations, one configured according to recommended guidelines with the keyboard support surface flat and near resting elbow height, the other according to users' actual setup and preference, with an elevated, and positively tilted support surface. PARTICIPANTS: Twenty participants completed a standard computer task at the two workstation configurations. METHODS: A thin profile force plate, placed under the keyboard recorded keyboard reaction forces. Twin axis electro goniometers (SG65 Biometrics Ltd, London, UK) affixed to the back of the right and left hand of each subject continuously measured wrist extension/flexion and ulnar/radial deviation. RESULTS: Typing force and wrist kinematics were similar between the two configurations with only 10th percentile ulnar deviation for the right hand showing a borderline significant difference of 1 degrees between the two configurations. CONCLUSION: Elevating and tilting the input device support surface does not necessarily affect typing force and kinematics of the wrist. The combination of the input device support surface and user upper extremities form a complex kinematic system with several degrees of freedom. Wrist postures during computer use are a function of multiple factors other than simply keyboard tilt. PMID- 21673447 TI - The effect of two alternative arm supports on shoulder and upper back muscle loading during pipetting. AB - OBJECTIVE: Pipetting involves static upper arm positions with the pipette held away from the body for sustained periods of time, putting increased musculoskeletal load on the shoulder and upper back. This study explores the effect of using two alternative arm supports while pipetting on muscle loading in the shoulder/neck region. PARTICIPANTS: 15 experienced pipette users participated in this study. METHODS: In a repeated-measures design, participants performed simulated pipetting in a laboratory setting under three arm support conditions: (1) a gel pad on the work surface, (2) a freely-moving counter-balanced forearm support, and (3) no support (control). Surface electromyography (EMG) of the anterior deltoid and upper trapezius muscles were recorded, as well as productivity and subjective usability. RESULTS: Both arm support conditions resulted in significantly lower mean muscle activity of the anterior deltoid and upper trapezius muscles (p<0.001) and significantly higher subjective comfort ratings (p<0.001) compared to the control condition. The freely moving forearm support resulted in significantly lower peak muscle activity in the anterior deltoid compared to the control condition (p<0.001). Productivity was not affected by the arm supports. These findings suggest that arm support may be beneficial in reducing muscle loading and improving comfort in the shoulder and upper back during pipetting. Future studies are needed to measure the impact of these arm supports in the workplace. PMID- 21673448 TI - Protective effect of taurine on diabetic rat endothelial dysfunction. AB - As increasing evidence suggest that oxidative stress plays an important role in the developing angiopathy in diabetes, we studied the effects of taurine, a free radical scavenger, on diabetes induced angiopathy in the rat aorta. Six-week-old male Wistar rats were randomly divided into three groups; control group (Cont), diabetes group (DM) and diabetes group treated with taurine for four weeks, 500 mg/kg/day, intraperitoneally (i.p.) (DM+T). Diabetes was induced by streptozotocin (50 mg/kg i.p.). Four weeks after the induction of diabetes, serum glucose and malondialdehyde concentrations were measured. Additionally, organ bath studies and real-time PCR on muscarinic M(3) receptor and eNOS were performed. Although taurine treatment failed to decrease serum glucose levels, the increased serum malondialdehyde levels in diabetic rats were significantly decreased after taurine treatment. Norepinephrine-induced hyper-contractility as well as acetylcholine-induced, endothelium-dependent hypo-relaxation in diabetes were significantly prevented after taurine treatment. The differences in the expressions of muscarinic M(3) receptor mRNAs were statistically non-significant between groups. Moreover, diabetes-induced up-regulation of eNOS mRNAs was slightly prevented after taurine treatment. These data suggest that taurine acts beneficially against the diabetes-induced vascular dysfunction. Its potential action as a radical scavenger ameliorates the vascular disorders in diabetes. PMID- 21673449 TI - Interaction of histamine and calcitonin gene-related peptide in the formalin induced pain perception in rats. AB - Histamine and calcitonin gene-related peptide (CGRP) contribute to the pain perception. The aim of the present study is to clarify the interaction of histamine and CGRP in the perception of inflammatory pain. The effects of a histamine H1 receptor antagonist (pyrilamine, i.p.), an H2 receptor antagonist (ranitidine, i.p.) and a CGRP antagonist (CGRP 8-37, i.t.) on the formalininduced pain was studied in rats. Pyrilamine and ranitidine produced a dose-dependent antinociceptive response in the first and the second phases of the formalin test. A single administration of pyrilamine (1 mg/kg, i.p.), ranitidine (10 mg/kg, i.p.) or CGRP 8-37 (10 ug/uL, i.t.) had no significant effects on the pain perception in the second phase. A combination of CGRP 8-37 and pyrilamine or ranitidine at these sub-effective doses, however, showed nociceptive response in the second phase. Moreover, a histamine (i.t.)-induced hyperalgesia was completely prevented by treatment with GGRP 8-37 at this dose. Our findings have raised the possibility that the CGRP system has interaction with histamine in the perception of inflammatory pain. PMID- 21673450 TI - Cytokine profile of murine malaria: stage-related production of inflammatory and anti-inflammatory cytokines. AB - Balance between inflammatory and anti-inflammatory cytokines may be important in malaria presentation and outcome. To clarify cytokine interactions that produce pathology of malaria and control infection, C57BL/6 mice were infected with 10(4) parasitized RBCs from a non-lethal strain of Plasmodium yoelii. Kinetics was monitored showing the course of parasitemia, and cytokines were determined by RT PCR from liver and spleen tissues. Inflammatory cytokines such as interferon gamma (IFNgamma), interleukin (IL)-12, IL-6, tumor necrosis factor-alpha (TNFalpha) and anti-inflammatory cytokines, including IL-4 and IL-10, were investigated as key molecules that interact with immune cells in the activation of the immune responses. The production of IFNgamma mRNA was found to be higher on day 7 than on day 21 after infection, and IL-12 and IL-6 showed higher expression in the liver than in the spleen. Though TNFalpha was highly expressed on day 14 after infection and on day 21 in the liver, such expression was decreased on day 21 in the spleen. Anti-inflammatory cytokines showed high expression in both the liver and spleen. The results suggest that a relative balance between inflammatory and anti-inflammatory cytokines is crucial and that the increase of inflammatory cytokine levels during the acute phase of malaria may reflect an early and effective immune response.The counteraction effect of anti-inflammatory cytokines is thought to play a role in limiting progression from uncomplicated malaria to severe life-threatening complications. PMID- 21673451 TI - Activation of Akt leading to NF-kappaB up-regulation in chondrocytes stimulated with fibronectin fragment. AB - Increased fibronectin fragments are thought to contribute to joint destruction in osteoarthritis (OA). However, the mechanism whereby fibronectin fragments cause catabolic activities is not totally understood. While COOH-terminal heparin binding fibronectin fragment (HBFN-f) has been shown to activate nuclear factor (NF)-kappaB pathway, intracellular upstream events that cause NF-kappaB up regulation in response to HBFN-f remain unclear. Thus, this study was aimed to elucidate the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt pathway in NF-kappaB activation by HBFN-f in OA chondrocytes. In chondrocyte monolayer cultures, HBFN-f stimulated nitric oxide (NO) production in association with phosphorylation of NF-kappaB and Akt. Inhibition studies using LY294002 revealed the requirement of PI3K/Akt pathway for NO production and NF-kappaB activation by HBFN-f. Anti-CD44 treatment with anti-CD44 antibody and hyaluronan resulted in significant inhibition of HBFN-f actions on NO, NF-kappaB, and Akt. Herein, we provided the first evidence that HBFN-f activates PI3K/Akt pathway leading to up regulation of NF-kappaB through interaction with CD44. PMID- 21673452 TI - The structural feature surrounding glycated lysine residues in human hemoglobin. AB - Complications derived from diabetes mellitus are caused by nonenzymatic protein glycation at the specific sites. LC/MS/MS was performed for the identification of the tryptic peptides of glycated hemoglobins using glyceraldehyde. After the identification of the glycation or non-glycation site, computer analysis of the structure surrounding the sites was carried out using PDB data (1BZ0). Five glycated lysine residues (Lys-16(alpha), -56(alpha), -8(beta), -82(beta), and 144(beta)) and four non-glycated lysine residues (Lys-7(alpha), -40(alpha), 99(alpha), and -132(beta)) were identified. The non-glycated lysine residues, Lys 7(alpha), -40(alpha), and -132(beta), are most likely to form electrostatic interactions with the beta carboxyl group of Asp-74(alpha), C-terminal His 146(beta), and Glu-7(beta) by virtue of their proximity, which is 2.67-2.91 A (N O). Additionally, there are histidine residues within 4.55-7.38 A (N-N) around eight sites except for Lys-7(alpha). We conclude that the following factors seem to be necessary for glycation of lysine residues: (i) the apparent absence of aspartate or glutamate residues to inhibit the glycation reaction by forming an electrostatic interaction, (ii) the presence of histidine residues for acid-base catalysis of the Amadori rearrangement, and (iii) the presence of an amino acid residue capable of stabilizing a phosphate during proton transfer. PMID- 21673453 TI - Immunohistochemical demonstration of dopamine receptor D2R in the primary cilia of the mouse pituitary gland. AB - Dopamine regulates the synthesis and secretion of prolactin and alpha-MSH/beta endorphin in lactotrophs and melanotrophs, respectively. While a predominant dopamine receptor, D2R, is known to be expressed in both the anterior and intermediate lobes of the pituitary gland, no previous immunohistochemical studies have shown the existence of D2R in the plasma membrane of pituitary endocrine cells. The present study clearly demonstrated a selective localization of the D2R immunoreactivity in primary cilia of lactotrophs and melanotrophs in the mouse adenohypophysis. Another immunoreactivity of D2R was found along the plasma membrane of melanotrophs. The intensity of immunoreactivity for D2R in the primary cilia of lactrotrophs changed during the estrous cycle and with genital conditions in contrast to a consistent immunolabeling in the melanotrophs. Since there is accumulating evidence that the primary cilium functions as a sensory device at a cellular level, the D2R-expressing primary cilia in the pituitary gland may be involved in the sensation of dopamine and dopaminergic compounds though their involvement differs between the anterior and intermediate lobes. PMID- 21673455 TI - Thrombin inhibitor or factor xa inhibitor? -Opening of a New Era of antithrombotic management-. PMID- 21673456 TI - Pathophysiological roles of NADPH oxidase/nox family proteins in the vascular system. -Review and perspective-. AB - It has been established that oxidative stress plays a crucial role in the development and progression of vascular diseases. Besides the mitochondria, the NADPH oxidase/Nox family proteins are now thought to be important origins of the reactive oxygen species that underlie various vascular disease states, such as hypertension, atherosclerosis, angiogenesis, and ischemia/reperfusion injury. This review summarizes the basis of vascular Nox proteins and discusses their pathophysiological roles in the vascular system. PMID- 21673457 TI - Alanine aminotransferase is associated with metabolic syndrome independently of insulin resistance. PMID- 21673458 TI - Comparison of preventive effect on cardiovascular events with different statins. The CIRCLE study-. AB - BACKGROUND: Although statins vary in their effectiveness in lowering low-density lipoprotein cholesterol (LDL-C) and increasing high-density lipoprotein cholesterol (HDL-C) levels, there is little evidence that the degree of these changes can explain cardiac risk reduction in Japan. Our objective was to compare the efficacy of statins on serum lipid levels and to explore the association between those changes and cardiac events in patients after percutaneous coronary intervention (PCI). METHODS AND RESULTS: The 743 consecutive patients who underwent PCI from 2001 to 2008 were retrospectively investigated. Treatment with either atorvastatin or pitavastatin significantly reduced LDL-C compared with pravastatin or no statin. In contrast, only pitavastatin treatment significantly increased HDL-C (13.4 +/- 22.9%, P=0.01 vs. no statin). Each statin significantly prevented major adverse cardiac events (MACE) compared with no statin, and pitavastatin was the most effective of all. Multivariate-adjusted analysis revealed that percent changes of both LDL-C and HDL-C independently predicted the incidence of MACE (hazard ratio [HR]: 1.015; 95% confidence interval [CI]: 1.010 1.020, HR: 0.988; 95%CI: 0.981-0.996, respectively). This relationship was preserved in patients with a baseline HDL-C level <= 45 mg/dl, but not HDL-C level > 45 mg/ml. CONCLUSIONS: The extent of changes in LDL-C and HDL-C with statin treatment would independently alter the risk of cardiac events in Japanese patients for secondary prevention. Statins with varying lipid-modifying ability might provide differing prognosis in patients after PCI. PMID- 21673459 TI - Systolic blood pressure predicts cardiovascular mortality in a farming but not in a fishing community. -A 40-year follow up of the Japanese cohorts of the seven countries study-. AB - BACKGROUND: Blood pressure (BP) is a strong determinant of cardiovascular diseases (CVD). The strength of this association in 2 Japanese communities with different intakes of fish was investigated. METHODS AND RESULTS: The analysis was carried out in the Japanese cohorts of the Seven Countries Study (Tanushimaru and Ushibuka), which were followed for 40 years. We included 1,006 subjects for whom data on baseline BP and relevant potential confounders were available. Data were analysed using multivariable Cox proportional hazard models. In Tanushimaru men, the systolic BP level was strongly directly related to risk of stroke and CVD mortality, with hazard ratios (HR) of 4.42 (2.02-9.70) for stroke and 3.05 (1.73 3.25) for CVD for BP levels >= 140 mmHg compared to <120 mmHg. In Ushibuka, the HR were 1.74 (0.91-3.32) for stroke mortality and 1.66 (1.01-2.75) for CVD mortality for high vs. low systolic BP. With regard to diastolic BP, the associations with stroke and CVD mortality were similar in Tanushimaru and Ushibuka subjects. CONCLUSIONS: This study showed that the well-known relationship of systolic BP with stroke and CVD mortality was more pronounced in the Japanese farming community than in the fishing community. This brings up the hypothesis that the detrimental effect of raised systolic BP could be attenuated by a high intake of fish. PMID- 21673460 TI - Dynamics of plasma active GLP-1 versus insulin and glucose concentrations during GLP-1 infusion in rat model of postprandial hyperglycemia. AB - In vitro studies in isolated pancreas and islets have shown that glucagon-like peptide-1 (GLP-1) promotes insulin release in a typical concentration-dependent manner. In contrast, the relationship between plasma GLP-1 and insulin concentrations in vivo is complicated, because GLP-1-promoted insulin release lowers blood glucose, which influences glucose-dependent insulinotropic ability of GLP-1. GLP-1 also stimulates insulin release via hepatoportal neuronal mechanism. Hence, the dynamic relationship between plasma active GLP-1 vs. insulin and glucose concentrations is obscure. In this study, we aimed to determine in vivo relationships between these parameters in rats. To mimic postprandial state, intraduodenal glucose challenge in anesthetized rats was performed, which can minimize the release of endogenous GLP-1. The glucose challenge induced the 1st phase and 2nd phase insulin release. GLP-1 infusion from jugular vein significantly and concentration-dependently enhanced area under the curve (AUC) of the 1st phase insulin, in which the minimum effective active GLP-1 concentration was 6.6 pmol/l. In contrast, bell-shaped dose responses were observed for both the 2nd phase and total insulin AUCs, in which a significant increase was obtained only with 11 pmol/l of active GLP-1 for total insulin AUC. A statistically significant reduction in the plasma glucose AUC was observed when active GLP-1 concentration was 11 pmol/l and 21 pmol/l. These results indicate that GLP-1 markedly enhances the 1st phase insulin release while less potently the 2nd phase insulin release, possibly due to a negative feedback regulation of beta-cells via reduced plasma glucose levels by the enhanced 1st phase insulin release. PMID- 21673461 TI - Potential benefit of statin therapy for dyslipidemia with chronic kidney disease: Fluvastatin Renal Evaluation Trial (FRET). AB - BACKGROUND: Dyslipidemia is a common complication of chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality of CKD patients. AIM: The aim of the present study was to determine whether fluvastatin, which is mostly characterized by its pleiotropic anti-oxidant effects, has renoprotective effects in dyslipidemic patients with CKD. METHODS: In 43 dyslipidemic patients with CKD taking fluvastatin 10 mg/day, 20 mg/day or 30 mg/day, renal functions as well as lipid profiles were assessed. RESULTS: After 3 months of treatment with fluvastatin, LDL-cholesterol level significantly decreased. Serum creatinine level, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), urinary liver-type fatty acid binding protein (L-FABP) level and urinary 8 hydroxydeoxyguanosine (8-OHdG) level did not change in overall patients. However, in patients with microalbuminuria (baseline UAE >= 30 mg/g.creatinine; n = 23), the UAE significantly decreased [2.43 +/- 0.67 to 1.98 +/- 0.80 log(mg/g.creatinine), p = 0.01]. In patients with high L-FABP group (baseline L FABP >= 11 ug/g.creatinine; n = 18), the urinary L-FABP level was significantly decreased (1.52 +/- 0.45 to 1.26 +/- 0.43 ug/g.creatinine, p < 0.01). In the limited 23 patients with microalbuminuria, the L-FABP level was significantly decreased [1.20 +/- 0.62 to 1.03 +/- 0.49 log(ug/g.creatinine), p = 0.042], although the LDL-cholesterol level (139 +/- 28 to 129 +/- 23 mg/dL, p = 0.08) only showed a tendency to decrease. The 8-OHdG level also was significantly decreased (13.6 +/- 9.6 to 9.8 +/- 3.8 ng/g.creatinine, p = 0.043). In the overall patients, changes in the values for UAE and urinary L-FABP were not correlated with the changes in LDL-levels. CONCLUSION: Fluvastatin reduces both UAE and the urinary L-FABP level, and thus, has renoprotective effects, independent of its lipid lowering effects in dyslipidemic patients with CKD. PMID- 21673462 TI - Analysis of the correlation between non-high density lipoprotein cholesterol and coronary heart disease in elderly Chinese. AB - OBJECTIVE: In the aged population, serum cholesterol is directly correlated with coronary heart disease (CHD) risk. We aimed to investigate the correlation between non-high density lipoprotein cholesterol (non-HDL-C) level and CHD and coronary lesions in an aged population. METHODS: 1,272 cases of old patients who were more than 65 years old and accepted for coronary angiography were analyzed retrospectively. Based on the result of coronary angiography, the patients were divided into control group and CHD group. Further, 767 CHD patients were divided into subgroups according to the number of branches with pathological changes and Gensini score. Serum TC, HDL-C, LDL-C and TG were assayed to measure the level of non-HDL-C. The differences in non-HDL-C among groups were compared, and the correlation between non-HDL-C and coronary artery disease degree was also analyzed. RESULTS: The non-HDL-C level in the CHD group was significantly higher than that in the control group (p < 0.01). Further, the serum non-HDL-C showed an increasing tendency accompanied by the increase in branches with lesions. Compared with patients with single or double coronary artery branches lesions, the non-HDL-C in those with multiple lesions in branches was significantly increased (p < 0.01, p < 0.05). With the aggravation of coronary artery stenosis, the serum non-HDL-C level was gradually increased. The most significant increase was observed in the group with Gensini score of more than 40. There was a significant difference between Gensini score > 40 group and Gensini score of 20 40 group and Gensini score < 20 group, respectively (p < 0.05, p < 0.01). Meanwhile, there were significant positive correlations between the serum non-HDL C level and coronary lesions area and severity (r = 0.147, p < 0.01; r = 0.152, p < 0.01). CONCLUSION: In conclusion, serum non-HDL-C was closely associated with development of CHD and coronary artery lesions severity. PMID- 21673463 TI - Bronchoscopic microsampling for bacterial colony counting in relevant lesions in patients with pulmonary Mycobacterium avium complex infection. AB - OBJECTIVE: The incidence of pulmonary Mycobacterium avium complex (MAC) infections with nodular/bronchiectasis lesions is increasing. However, factors determining deterioration are unknown. In the present study, we investigated quantitative MAC cultures obtained through bronchoscopic microsampling (BMS) from patients with pulmonary MAC infection and analyzed the relationship between MAC culture and the short-term natural history. We also assessed chest computed tomography (CT) findings for the deteriorating factors. DESIGN: For this prospective study, MAC was collected from peripheral lung lesions by BMS through endobronchial ultrasonography. MAC colonies were counted on Middlebrook 7H11 agar. We compared the number of MAC colonies with laboratory data and chest CT findings. PATIENTS: We studied 26 patients with pulmonary MAC infection. RESULTS: The patients were divided into 2 groups: 11 patients in the non-deteriorated group and 15 patients in the deteriorated group. The number of MAC colonies was significantly correlated with deterioration of MAC infection (p < 0.001). In the non-deteriorated group, chest CT scans showed nodular/bronchiectasis lesions in 8 patients (73%) and consolidated lesions in 3 patients (27%). In the deteriorated group, chest CT scans showed nodular/bronchiectasis lesions in 1 patient (7%), consolidated lesions in 6 patients (40%), and cavitary lesions in 8 patients (53%). CONCLUSION: The number of MAC colonies in relevant lesions investigated by BMS was significantly larger in the deteriorated group than in the non deteriorated group. Cavitary and consolidated lesions observed from chest CT scans are thought to indicate a high risk of progression of pulmonary MAC infection. PMID- 21673464 TI - Serous cystic neoplasms of the whole pancreas in a patient with von Hippel-Lindau disease. AB - We describe here a case of von Hippel-Lindau (VHL) disease with a serous cystic neoplasm of the whole pancreas. The patient was a 35-year-old woman suffering from a palpable abdominal tumor. She had a history of hemangioblastomas of the cerebellum. CT revealed large solid tumors in the pancreatic head and body, and multiple cystic lesions in the whole pancreas as well as a right renal tumor. When endoscopic retrograde cholangiopancreatography (ERCP) was performed, bleeding from the duodenal papilla was detected. Since she had some distinguishing clinical features, the diagnosis of VHL disease was made. The preoperative diagnosis of the pancreatic lesion was serous cystic neoplasms with hemosuccus pancreaticus and total pancreatectomy was performed. Histological examination of the specimen revealed serous cystic neoplasms which occupied the entire pancreas. VHL cases operated on for serous cystic neoplasms of the entire pancreas are very rare. PMID- 21673465 TI - Case of primary biliary cirrhosis-autoimmune hepatitis overlap which manifested after delivery. AB - A 34-year-old woman showed liver dysfunction for the first time at 3 months after delivery. Two years later, she was referred to our department with continued liver dysfunction. She fulfilled the criteria for primary biliary cirrhosis (PBC) autoimmune hepatitis (AIH) overlap. Liver dysfunction improved after administration of ursodeoxycholic acid and bezafibrate. To the best of our knowledge this represents the second report of PBC-AIH overlap after delivery and we discuss immunological changes during the perinatal period. PMID- 21673466 TI - Diabetic gangrene in multiple fingers and toes after a dog bite in an elderly patient with type 2 diabetes. AB - A 78-year-old diabetic woman experienced multiple sites of gangrene not only in fingers that were directly bitten by a dog but also in fingers and toes that had not beenbitten. Her glycemic control was fair and microvascular complications were mild. There were no clinical findings related to angitis, collagenosis or severe infection. The fingers and toes with gangrene were amputated. The pathological diagnosis was diabetic gangrene. This report presents a case of multiple sites of gangrene of the fingers and toes after a dog bite in an elderly patient with type 2 diabetes. PMID- 21673467 TI - Recurrent Hashimoto's encephalopathy, showing spontaneous remission: a case report. AB - Hashimoto's encephalopathy (HE) is a rare condition associated with Hashimoto's thyroiditis (HT). It is characterized by neurological/psychiatric symptoms, high levels of anti-thyroid antibodies, non-specific radiological examinations or electroencephalogram abnormalities, and responsiveness to corticosteroid treatment. We describe the case of a man with HE who showed decreased mentality, cognitive impairment, dysarthria, and gait disturbance. The initial attack was improved rapidly by corticosteroid treatment. When the symptoms recurred in 7 months, the patient achieved spontaneous remission without corticosteroid treatment. The recognition of the condition was essential for the prognosis and treatment of this rare disease. PMID- 21673468 TI - A case of mixed medullary and follicular cell carcinoma of the thyroid. AB - A medullary thyroid carcinoma is a malignant tumor derived from the C-cells of the thyroid. Despite their distinct embryological origin, medullary thyroid carcinomas are exceptionally accompanied by a tumor derived from the follicular cells; this is defined as mixed medullary and follicular cell carcinoma. There have been controversies regarding the origin of this rare mixed thyroid carcinoma questioning whether or not a mixed carcinoma originates from a common cancer stem cell. We present a case of mixed medullary and follicular cell carcinoma in which two thyroid carcinomas were found intermingled in the thyroid as well as in the metastatic cervical lymph nodes. We examined the tumor by immunostaining with thyroglobulin, calcitonin, and thyroid transcription factor-1, and also reviewed the literature and discuss the origin of this rare mixed thyroid carcinoma. PMID- 21673469 TI - 21-hydroxylase deficiency associated with male infertility: report of 2 cases with gene analyses. AB - We treated two patients with male infertility due to 21-hydroxylase deficiency. Endocrinologic examinations disclosed low levels of LH and FSH, with elevated ACTH and 17-OH-progesterone in both. In addition, a small testicular tumor was found in Case 1, which disappeared after adrenal replacement. Suppressed gonadotropin levels caused by increased androgen seemed to underlie the sperm dysfunction in these patients. Dexamethasone and then clomiphene were administered in Case 1, and dexamethasone in Case 2. Spermatogenesis was somewhat improved in both patients and pregnancy achieved in Case 2, though spontaneous abortion later occurred. PMID- 21673470 TI - Lengthy diagnostic challenge in a rare case of pulmonary veno-occlusive disease: case report and review of the literature. AB - Pulmonary veno-occlusive disease (PVOD) is a rare and usually survival poor disorder. We report a patient with a long history of progressive dyspnea of over 8 years, who with a diagnosis of chronic cor pulmonale confirmed elsewhere, was ultimately diagnosed as PVOD via histological analysis of a lung biopsy. After treatment with combined bosentan, diuretics and digoxin, his symptoms and function improved. This case highlights that PVOD is an under-recognised and often misdiagnosed disease, especially in its chronic form. Understanding its pathogenesis, its poor response to medical therapy and its dismal prognosis remain challenges for the treatment of PVOD. PMID- 21673471 TI - Meningitis-retention syndrome: first case of urodynamic follow-up. AB - The combination of acute urinary retention and aseptic meningitis has not been well recognized. This combination can be referred to as meningitis-retention syndrome (MRS), when accompanied by no other abnormalities. However, the responsible site of lesions for urinary retention in MRS remains obscure, despite the areflexic detrusor at the time of urinary retention. We recently encountered a man with MRS in whom a urodynamic study was performed twice. In that case, an initially areflexic detrusor became overactive after a 4-month period, suggesting an upper motor neuron bladder dysfunction. PMID- 21673472 TI - Abscess caused by Citrobacter koseri infection: three case reports and a literature review. AB - In this report, we present 3 cases of abscess caused by Citrobacter koseri. All infected patients recovered after initial empirical antibiotic treatment and percutaneous drainage of the abscess. We reviewed the literature and found 9 adult cases of C. koseri abscess. Most of these patients recovered after timely antibiotic treatment and drainage. PMID- 21673473 TI - Deep skin infection of Scedosporium apiospermum in a patient with refractory idiopathic thrombocytopenic purpura. AB - Infection of Scedosporium apiospermum is very rare but is now emerging as an important cause of both localized and disseminated infections in immunocompromised patients. A 62-year-old woman, who had undergone steroid therapy for refractory idiopathic thrombocytopenic purpura and had a history of diffuse large B cell lymphoma, developed a deep skin ulcer complicated with lymphangitis. After culture study demonstrated the presence of S. apiospermum, voriconazole (VRCZ) was administered and prompt improvement was observed. Because it is difficult to distinguish S. apiospermum from Aspergillus by histopathology and S. apiospermum is resistant to amphotericin B, VRCZ should be selected as the first choice of antifungal agent when mold is considered to be the causative organism. PMID- 21673474 TI - Takayasu arteritis with intracranial involvement mimicking epilepsy: case report and review of the literature. AB - The symptoms of Takayasu arteritis (TA) are related to end organ ischemia. Here we present a patient with convulsions and intracranial involvement. A 15-year-old young woman was admitted with the complaint of convulsions since one and a half months previously. Her physical examination showed absent pulses and unobtainable blood pressure in both arms. Electroencephalography was normal. An arcus aorto abdominal aortography, performed for TA prediagnosis, revealed that the subclavian artery ended as a stump at its origin on the right and was occluded by tapering on the left. Arcus aorta was normal. The right renal artery was occluded up to 80-90%. Magnetic resonance imaging of the brain revealed abnormal signal intensity in the deep white matter bilaterally. Cerebral catheter angiography showed focal stenosis of cerebral vessels; it was classified as type V according to the classification of the Takayasu Conference of 1994. A diagnosis of TA was made and 1 mg/kg steroid was given, and after a month methotrexate (15 mg/week) was added. On the tenth treatment day her pulse could be revealed. During the control period she had no convulsion. In young patients TA should be kept in mind as a rare cause in convulsion etiology. Intracranial involvement of TA must be evaluated especially if there is a headache and convulsion. PMID- 21673475 TI - Bleeding from a gastric hyperplastic polyp during anticoagulation therapy. PMID- 21673476 TI - Acute mesenteric ischemia complicated with pneumoperitoneum, pneumoporta, and pneumatosis intestinalis. PMID- 21673477 TI - Notch on the T wave. PMID- 21673478 TI - Unilateral gynecomastia in a young adult. PMID- 21673479 TI - Occurrence of two distinct Theileria lineages in sika deer (Cervus nippon) of Iwate Prefecture, Japan. AB - In the present study, we tried to detect protozoan blood parasites from the liver or blood of 141 Japanese sika deer (Cervus nippon) in Iwate Prefecture of Japan by polymerase chain reaction. Approximately 500-bp amplicons were obtained in 76 (53.9%) of 141 samples by amplification for V4 hyper-variable regions of the 18S rRNA gene, and the amplicons were considered to be DNA of Theileria species. The complete nucleotide sequences (1701-bp) of the 18S rRNA gene were determined in 25 samples and were divided into 8 genotypes that were phylogenetically separated into two distinct lineages showing a monophyletic relation. The two lineages of Theileria were detected in different rates (12 and 88%) from sika deer in Iwate Prefecture. PMID- 21673480 TI - Flow cytometric analysis of lymphocyte proliferative responses to food allergens in dogs with food allergy. AB - Two different allergy tests, antigen-specific immunoglobulin E quantification (IgE test) and flow cytometric analysis of antigen-specific proliferation of peripheral lymphocytes (lymphocyte proliferation test), were performed to examine differences in allergic reactions to food allergens in dogs with food allergy (FA). Thirteen dogs were diagnosed as FA based on clinical findings and elimination diet trials. Seven dogs clinically diagnosed with canine atopic dermatitis (CAD) were used as a disease control group, and 5 healthy dogs were used as a negative control group. In the FA group, 19 and 33 allergen reactions were identified using the serum IgE test and the lymphocyte proliferation test, respectively. Likewise, in the CAD group, 12 and 6 allergen reactions and in the healthy dogs 3 and 0 allergen reactions were identified by each test, respectively. A significant difference was found between FA and healthy dogs in terms of positive allergen detection by the lymphocyte proliferation test, suggesting that the test can be useful to differentiate FA from healthy dogs but not from CAD. Both tests were repeated in 6 of the dogs with FA after a 1.5- to 5 month elimination diet trial. The IgE concentrations in 9 of 11 of the positive reactions decreased by 20-80%, whereas all the positive reactions in the lymphocyte proliferation test decreased to nearly zero (P<0.05), suggesting that lymphocytes against food allergens may be involved in the pathogenesis of canine FA. PMID- 21673481 TI - Whole-blood interferon-gamma release assay for diagnosis of tuberculous lymphadenitis. AB - Tuberculosis remains a major problem for much of the world. Tuberculous lymphadenitis is the most common type of extrapulmonary tuberculosis, although a difficult invasive procedure is required for its diagnosis. We evaluated the usefulness of the whole-blood interferon-gamma release assay (IGRA) for diagnosis of tuberculous lymphadenitis. From January 2008 to October 2010, 108 patients underwent lymph node biopsy and the IGRA concurrently in Wonju Christian Hospital, Yonsei University Wonju College of Medicine. Among the patients, 27 were diagnosed with tuberculous lymphadenitis and 81 were diagnosed with non tuberculous lymphadenitis. The diagnostic performances of the IGRA were evaluated. The median patient age was 33 years (interquartile range [IQR] 23.5 to 48 years), and 28 (25.9%) patients were male. No patient was administered immunosuppressive agents such as high-dose steroids or underwent chemotherapy within 90 days before the IGRA test. The IGRA was positive in 25 of 27 patients with tuberculous lymphadenitis and in 13 of 81 patients with non-tuberculous lymphadenopathy. Therefore, the sensitivity of IGRA was 92.6% (95% CI, 82.0 to 100), and the specificity was 80.2% (95% CI, 71.4 to 89.1). In the patients with positive IGRA results, the INF-gamma concentration was significantly higher in the patients with tuberculous lymphadenitis compared to that in the patients without tuberculous lymphadenitis (15.58 [IQR 6.87 to 45.10] IU/mL versus 0.97 [IQR 0.65 to 2.41] IU/mL, p < 0.001). In conclusion, the IGRA is helpful for the diagnosis of tuberculous lymphadenitis. PMID- 21673482 TI - Prescribing exercise for individuals with type 2 diabetes: recommendations and precautions. AB - An increasing prevalence of obesity and sedentary behavior has strongly contributed to the epidemic of type 2 diabetes mellitus. Although regular exercise improves glycemic control and is associated with reduced morbidity and mortality, many physicians fail to prescribe it. This article highlights the recommended types and quantities of physical activities that can (and should) be undertaken by individuals with type 2 diabetes, along with precautions required to maximize the safety of exercise in those using various medications and in the presence of diabetes-related complications. This article assesses the need for pre-exercise stress testing, reviews the latest exercise prescription recommendations for individuals with type 2 diabetes, and recommends strategies to assist individuals in adopting and maintaining an active lifestyle. PMID- 21673483 TI - A carbohydrate-restricted diet during resistance training promotes more favorable changes in body composition and markers of health in obese women with and without insulin resistance. AB - OBJECTIVE: To determine whether sedentary obese women with elevated levels of homeostatic model assessment (HOMA) insulin resistance (ie, > 3.5) experience greater benefits from an exercise + higher-carbohydrate (HC) or carbohydrate restricted weight loss program than women with lower HOMA levels. METHODS: 221 women (age, 46.5 +/- 12 years; body weight, 90.3 +/- 16 kg; body mass index, 33.8 +/- 5 kg/m(2)) participated in a 10-week supervised exercise and weight loss program. The fitness program involved 30 minutes of circuit-style resistance training 3 days per week. Subjects were prescribed low-fat (30%) isoenergetic diets that consisted of 1200 kcals per day for 1 week (phase 1) and 1600 kcals per day for 9 weeks (phase 2) with HC or higher protein (HP). Fasting blood samples, body composition, anthropometry, resting energy expenditure, and fitness measurements were obtained at 0 and 10 weeks. Subjects were retrospectively stratified into lower (LH) or higher (HH) than 3.5 HOMA groups. Data were analyzed by multivariate analysis of variance with repeated measures and are presented as mean +/- standard deviation changes from baseline. RESULTS: Baseline HOMA levels in the LH group were significantly lower than those in the HH group (LH, 0.6 +/- 0.7; HH, 6.3 +/- 3.4; P = 0.001). Diet and training significantly decreased body weight (-3.5 +/- 3 kg), fat mass (-2.7 +/- 3 kg), blood glucose ( 3%), total cholesterol (-4.5%), low-density lipoproteins (-5%), triglycerides ( 5.9%), systolic blood pressure (-2.6%), and waist circumference (-3.7%), while increasing peak aerobic capacity (7.3%). Subjects in the HP group experienced greater weight loss (-4.4 +/- 3.6 kg vs -2.6 +/- 2.9 kg), fat loss (-3.4 +/- 2.7 kg vs -1.7 +/- 2.0 kg), reductions in serum glucose (3% vs 2%), and decreases in serum leptin levels (-30.8% vs -10.8%) than those in the HC group. Participants in the HH (-14.1%) and HP-HH (-21.6%) groups observed the greatest reduction in serum blood glucose. CONCLUSION: A carbohydrate-restricted diet promoted more favorable changes in weight loss, fat loss, and markers of health in obese women who initiated an exercise program compared with a diet higher in carbohydrate. Additionally, obese women who initiated training and dieting with higher HOMA levels experienced greater reductions in blood glucose following an HP diet. PMID- 21673484 TI - Self-reported physical activity preferences in individuals with prediabetes. AB - PURPOSE: The primary objective of this study was to determine the physical activity (PA) preferences in a sample of individuals with prediabetes. METHODS: Individuals with prediabetes (N = 232) residing in Northern Alberta, Canada completed a mailed questionnaire that assessed demographic and health variables, self-reported PA (Godin Leisure-Time Exercise Questionnaire), and PA preferences. RESULTS: Respondents indicated they would like to be counseled about PA (75%), were physically able to participate (96%), were interested in a PA program for individuals with prediabetes (86%), and were most interested in walking (71%). Activity status, number of comorbidities, level of employment, marital status, body mass index, and time since diagnosis with prediabetes all demonstrated significant influence on different PA preference variables. CONCLUSIONS: There is a demand for PA-related programs for individuals with prediabetes. Incorporating identified PA preferences of those with prediabetes might aid in the development of relevant intervention tools, programs, and strategies to support PA. PMID- 21673485 TI - A review of resistance exercise training in obese adolescents. AB - Resistance training-also known as strength or weight training-has been well recognized by several national organizations as a safe and beneficial exercise modality for the health and well-being of children and adolescents. Resistance exercise improves muscular strength and can improve body composition (eg, increase lean body mass and decrease percent body fat) provided that a sufficient exercise stimulus is prescribed. Effects of resistance exercise training on body composition and metabolic profile are well established in obese adults, but warrant further investigation in obese youth. This article reviews the rationale for including a resistance training component with interventions geared toward overweight and obese adolescents by discussing the effects on various health measures. Shortcomings in published trials, including small, ethnic minority samples of short-duration and low-frequency exercise sessions primarily conducted in prepubertal youth (rather than postpubertal adolescents) limit the generalizability of the published literature on the effectiveness of resistance exercise in obese adolescents. PMID- 21673486 TI - Clinical management of the physically active patient with type 1 diabetes. AB - The prevalence and incidence of type 1 diabetes continues to increase worldwide. Most patients with type 1 diabetes are young at the time of diagnosis and wish to continue leading a physically active life. Although regular exercise, insulin therapy, and proper nutrition are the cornerstone of treatment, there are considerable challenges in managing the active individual with type 1 diabetes. The current recommendation for diabetes management is intensive glycemic control for all patients when possible to help prevent secondary complications. Both insulin pump therapy and multiple daily injections are beneficial treatment options to lower average glucose levels; however, without continuous glucose monitoring, these treatment options typically increase the risk of hypoglycemia. In active patients with type 1 diabetes, the challenges of maintaining good glycemia are complicated by the inability to regulate insulin concentrations during and after exercise. Physiological and psychosocial factors during growth and maturation also provide additional challenges. This article highlights challenges and key strategies for diabetes management in the active individual with type 1 diabetes, including the application of the most recent diabetes technologies. PMID- 21673487 TI - Changes in cardiorespiratory fitness predict changes in body composition from childhood to adolescence: findings from the European Youth Heart Study. AB - BACKGROUND: Several variables, such as waist circumference (WC) and trunk skinfolds (TS), are indicators of body fat. There is interest in evaluating the effect of cardiorespiratory fitness (CRF) measures on changes in these markers from childhood to adolescence. PURPOSE: To examine CRF as a potential predictor of changes in body fat over an 8-year follow-up period in a pediatric population. METHODS: A cohort study of 86 children (44 girls, 42 boys) with a mean age of 9.8 +/- 0.3 years who participated in the Portuguese arm of the European Youth Heart Study in 2000 completed a follow-up evaluation in 2008 at a mean age of 17.0 +/- 0.4 years. Cardiorespiratory fitness, expressed as maximal oxygen consumption (VO2 max) (mL.kg(-1).min(-1)), was assessed during an incremental multistage bicycle test to exhaustion. Physical activity (PA) was objectively measured by accelerometry at both periods of evaluation. Fat mass (FM) was assessed using anthropometric models, sum of TS, and WC. Changes were expressed as a percentage of the baseline value. Comparison of means and linear regression analysis were used for data analysis. RESULTS: While CRF significantly increased among boys (P < 0.05) and decreased in girls (P < 0.01), the percentage of body fat decreased over time in boys (P < 0.01) and increased among girls. Alone, CRF explained 39%, 26%, and 25% of the total variance in WC, FM, and TS, respectively (P < 0.01). Adjusting for PA, sex, and maturation changes, CRF remained a significant predictor of WC (beta = -0.335; P < 0.01), FM (beta = -2.084; P < 0.01), and TS (beta = -1.500; P < 0.01). CONCLUSION: Changes in CRF are a significant predictor of changes in body fat percentage from childhood to adolescence. School-based PA interventions are encouraged to maintain or improve CRF from childhood and throughout adolescence to prevent increased percentages of body fat, particularly in the abdominal region. PMID- 21673488 TI - Exercise and diet, independent of weight loss, improve cardiometabolic risk profile in overweight and obese individuals. AB - Diet and/or exercise are routinely advised as methods for weight loss in overweight/obese individuals, particularly those who are at high risk for cardiovascular disease and type 2 diabetes mellitus. However, physical activity and structured exercise programs rarely result in significant loss of body weight or body fat, and weight-loss diets have extraordinarily high recidivism rates. Despite only modest effects on body weight, exercise and ad libitum nutrient dense diets for overweight/obese individuals have many health benefits, including skeletal muscle adaptations that improve fat and glucose metabolism, and insulin action; enhance endothelial function; have favorable changes in blood lipids, lipoproteins, and hemostatic factors; and reduce blood pressure, postprandial lipemia and glycemia, and proinflammatory markers. These lifestyle-induced adaptations occur independently of changes in body weight or body fat. Thus, overweight/obese men and women who are at increased risk for cardiovascular disease and type 2 diabetes as a result of sedentary lifestyle, poor diet, and excess body weight should be encouraged to engage in regular physical activity and improve their diet, regardless of whether the healthier lifestyle leads to weight loss. PMID- 21673489 TI - Exercise in the management of type 2 diabetes mellitus: what are the benefits and how does it work? AB - In this article, we examine the results from meta-analyses of studies that have focused on the effects of supervised exercise in patients with established type 2 diabetes mellitus. Exercise has been clearly demonstrated to have benefits on blood glucose control (average reduction of glycated hemoglobin, 0.6%) and cardiovascular risk factors. These benefits are observed independently of any change in body mass index and fat mass, and are also seen in older populations. Multiple mechanisms are involved, and the improved insulin-sensitizing effect of exercise training is not restricted to muscle but extends to hepatic and adipose tissue. However, while the benefits of exercise in type 2 diabetes management are undisputable, it is not as easy to draw correlations between clinical benefit and the amount of physical activity included in daily life. Recent studies have shown encouraging results with moderate increases in physical activity, which are feasible for most patients and are sufficient to induce sustained positive changes for 2 years. Thus, the benefits of structured and supervised exercise in patients with type 2 diabetes have been consistently demonstrated. Currently, the primary challenge is to determine how long-term increased physical activity can be durably implemented in a patient's daily life. PMID- 21673490 TI - Intra-articular hyaluronic acid: potential treatment of younger patients with knee injury and/or post-traumatic arthritis. AB - Anterior cruciate ligament (ACL) and meniscal injuries are common in both athletes and the general population. Such injuries may lead to early-onset post traumatic osteoarthritis (OA) in 50% to 60% of patients, regardless of whether patients had reconstruction performed. In younger patients, intra-articular (IA) injection of hyaluronic acid (HA) may be useful for improving short-term outcomes and possibly slowing or arresting the progression of OA. Hyaluronic acid has anti inflammatory, anabolic, and chondroprotective effects, which have been demonstrated in in vitro and animal models of meniscal and ACL injury. Results from several clinical trials and patient series have demonstrated the benefit of IA HA injection in younger patients with acute knee damage, including symptomatic meniscal tears and isolated ACL injury with chondral injury, although evidence for this is less extensive than the large database supporting the use of IA HA injection in older patients with knee OA. Administration of HA has been shown to improve outcomes in patients undergoing knee arthroscopy, and IA HA also has direct antinociceptive effects that may contribute to its benefit in patients with patellofemoral pain. However, the use of IA HA in patients with ACL injury or early OA has been evaluated in only a few studies. Thus, there is a need for larger-scale randomized controlled trials with longer durations of follow-up to provide more definitive evaluation of the efficacy and safety of IA HA in these patients. Such studies provide an opportunity to further elucidate the benefits of IA HA in younger patients with knee damage and may result in appropriate expansion of use in this large population, which has a substantial need for new treatment alternatives. PMID- 21673491 TI - Automated external defibrillators in health and fitness facilities. AB - BACKGROUND: Exercise is encouraged to promote health, but it can be a trigger for sudden cardiac arrest (SCA) in individuals with underlying cardiovascular disease. In 2002, the American Heart Association and the American College of Sports Medicine issued recommendations for the presence of automated external defibrillators (AEDs) in health and fitness facilities. OBJECTIVE: To assess emergency response planning for SCA and review the prevalence and past utilization of AEDs in health and fitness facilities in King County, WA. METHODS: A cross-sectional survey was conducted in 2008 of health and fitness facilities (N = 136) in King County, WA, assessing the 2002 American Heart Association guidelines on AEDs and emergency response planning for SCA. RESULTS: Sixty-three (46%) of 136 facilities completed the survey. Thirty-five percent of the total facilities had < 500 members, 21% had 500 to 1500 members, 16% had 1501 to 2500 members, and 29% had > 2500 members. Sixty-eight percent had an established emergency response plan for SCA. Only 40% of facilities had >= 1 AED on site (mean, 1.7; range, 0-6). Fitness centers with > 1500 members (71%) were more likely to have an AED on site compared with those with < 1500 members (14%) (P < 0.0001). Of the staff trained in cardiopulmonary resuscitation, 83% were fitness instructors, 73% were administrators, and 58% were front desk personnel. Four facilities reported an incident of SCA within the 12 months prior to completing the survey, which was a 6.4% incidence of SCA in responding facilities. All SCA cases occurred in facilities with > 1500 members. Only 2 of the 4 facilities with an SCA had an on-site AED. The individuals who had SCA were all men aged 50 to 65 years, with 2 men successfully resuscitated at the facility. CONCLUSION: There is a substantial gap in guideline implementation between national recommendations and current emergency response planning for SCA in health and fitness facilities. Health and fitness facilities are strategic locations to place AEDs in an effort to improve outcomes from exercise-related SCA. Facilities with general memberships of > 1500 are encouraged to have on-site AEDs, given the high incidence of SCA. PMID- 21673492 TI - Independent and joint associations of physical activity and fitness on stroke in men. AB - INTRODUCTION: Recent studies have demonstrated that physical activity (PA) and cardiorespiratory fitness (CRF) are independent predictors of stroke in men. The combined associations of these 2 factors are not well established. OBJECTIVE: To investigate the independent and joint associations of PA and CRF with fatal, nonfatal, and total stroke in a group of men. METHODS: The current analyses included 45 689 men aged 18 to 100 years who completed baseline sessions between 1970 and 2001. All participants had no known myocardial infarction, stroke, or cancer. Physical activity was measured by questionnaire, and CRF was assessed from a maximal treadmill exercise test. The National Death Index for fatal stroke and mail-back surveys for nonfatal stroke were used to ascertain cases. Cox regression analyses were used to estimate the risk of stroke outcomes. RESULTS: There were 619 cases over 800 582 person-years of observation. Significant inverse associations were observed between CRF and fatal, nonfatal, and total strokes after adjustment for age and examination year (P for trend < 0.05 for each). No associations were found between PA and any of the 3 outcomes after adjusting for other covariates and CRF. Joint associations of 9 PA fitness groups showed less risk for total stroke in the moderate and high fitness categories. CONCLUSION: These findings suggest that CRF is an independent predictor of incident stroke in asymptomatic men. PMID- 21673493 TI - Creatinine and nonprotein nitrogen plasma levels: possible etiopathogenetic factors in rotator cuff tears. AB - OBJECTIVE: To determine the plasma levels of nonprotein nitrogen (NPN) and creatinine in healthy patients with rotator cuff tears. METHODS: The study included 400 subjects. The study group included 200 patients (93 men and 107 women; mean age, 56.8 years; range, 23-81 years) who underwent arthroscopic repair of a rotator cuff tear from 2004 to 2007. The control group included 200 patients (93 men and 107 women; mean age, 53.9 years; range, 20-81 years) who underwent arthroscopy for management of a meniscal tear, with or without articular cartilage damage, in the same period. The 2 groups were frequency matched by age and sex. Measurement of plasma levels of NPN and creatinine were performed in all patients. RESULTS: Patients with rotator cuff tears showed higher plasma NPN levels within the normal range (P = 0.035) than patients with knee disorders (control group). Creatinine levels were comparable (P = 0.66) in both groups. CONCLUSION: There appears to be an association between plasma NPN levels and rotator cuff tears. On the basis of our findings, plasma NPN could be involved in the pathogenesis of rotator cuff tears, although we advocate further research to draw more definitive conclusions. PMID- 21673494 TI - The 6-minute walk test as a predictor of objectively measured aerobic fitness in healthy working-aged adults. AB - There is a paucity of research examining the 6-minute walk test (6MWT) in young to middle-aged healthy individuals, and little is known about the utility of the 6MWT for predicting aerobic fitness. PURPOSE: 1) To characterize the aerobic demand of the 6MWT in a group of healthy working-aged adults; 2) to examine the ability of the 6MWT to objectively differentiate the fitness level between participants; and 3) to create prediction equations for 6MWT distance and maximal oxygen consumption (VO2 max) using the 6MWT results in combination with easily measured anthropometric and demographic variables. METHODS: Participants (N = 44; men, 23; women, 21) completed the 6MWT, VO2 max, and a battery of simple fitness measures. RESULTS: The aerobic demand of the 6MWT was 28.7 +/- 5.7 mL.kg(-1).min( 1) (72.7% +/- 11.6% of VO2 max). Rank order correlation revealed a moderate strength association between 6MWT distance and VO2 max (r = 0.49; P = 0.001). Using stepwise multiple linear regression, we were able to account for 72.4% of the variance in VO2 max using the 6MWT when combined with participant body weight, sex, resting heart rate (HR), and age according to the following equation: VO2 max (mL.kg(-1).min(-1)) = 70.161 + (0.023 * 6MWT [m]) - (0.276 * weight [kg]) - (6.79 * sex, where m = 0, f = 1) - (0.193 * resting HR [beats per minute]) - (0.191 * age [y]). CONCLUSION: The 6MWT is of moderate-to-vigorous intensity, and may be useful in the classification of aerobic fitness, which is associated with health outcomes. Inclusion of further patient characteristics greatly increases the predictive value of the 6MWT for estimating VO2 max, which has important implications for those seeking a noninvasive and simple-to-use determinant of maximal aerobic power. PMID- 21673495 TI - Current concepts in anatomic single- and double-bundle anterior cruciate ligament reconstruction. AB - An anterior cruciate ligament (ACL) tear is one of the most common orthopedic sport injuries. The ACL consists of 2 functional bundles-the anteromedial and posterolateral-which are named for the position of their insertion sites on the tibia. Anatomic ACL reconstruction can be defined as the restoration of the ACL to its native dimensions, collagen orientation, and insertion sites. Some biomechanical studies have demonstrated that anatomic ACL reconstruction can restore knee motion significantly similar to that of the normal knee, as compared with traditional, nonanatomic single-bundle procedures. In vivo kinematic studies have also shown that nonanatomic single-bundle reconstruction fails to restore normal dynamic knee stability in all cases. Accurate restoration of knee kinematics with anatomic ACL reconstruction is critical to protect against the possibility that nonatomic surgical technique could result in early osteoarthritis, which is common in patients who sustain ACL tears. Surgical techniques for ACL reconstruction vary, and if different aspects of the surgery are compared for superiority (eg, single- vs double-bundle techniques), it is necessary that both procedures meet criteria to be designated as "anatomic." By emphasizing the importance of restoring the native anatomy of the knee, surgeons can give their patients the best chance at restoration of joint function and preservation of long-term knee health. PMID- 21673496 TI - Evaluation and treatment of shoulder instability. AB - The shoulder joint has a wide range of motion as a result of a complex interplay of soft tissue and bone structures. It is also the most frequently dislocated joint in the body. Shoulder dislocations are generally classified as traumatic and nontraumatic. There are many specific causes, each of which necessitate individualized treatment modalities. Accurate diagnosis requires a careful history and physical examination. Arthroscopic surgery and advances in imaging have expanded our understanding of anatomy and pathology relevant to shoulder instability and its treatment. Surgery is the treatment of choice for recurrent traumatic instability. Surgery may also be indicated in some first-time traumatic dislocations in young contact athletes, whereas rehabilitation is the initial treatment of choice in older patients with initial instability and in those with nontraumatic dislocations. Results of arthroscopic capsulolabral repair now equal those of open capsulolabral repair and have become the surgical treatment of choice for most patients. However, in cases of recurrent instability and significant bone deficiency of either the glenoid or humeral head, open bone reconstructive procedures are often necessary to ensure successful outcomes. PMID- 21673497 TI - Anthropometric and training variables related to half-marathon running performance in recreational female runners. AB - The relationship between skin-fold thickness and running has been investigated in distances ranging from 100 m to the marathon distance (42.195 km), with the exclusion of the half-marathon distance (21.0975 km). We investigated the association between anthropometric variables, prerace experience, and training variables with race time in 42 recreational, nonprofessional, female half marathon runners using bi- and multivariate analysis. Body weight (r, 0.60); body mass index (r, 0.48); body fat percentage (r, 0.56); pectoral (r, 0.61), mid axilla (r, 0.69), triceps (r, 0.49), subscapular (r, 0.61), abdominal (r, 0.59), suprailiac (r, 0.55), and medial calf (r, 0.53) skin-fold thickness; mean speed of the training sessions (r, -0.68); and personal best time in a half-marathon (r, 0.69) correlated with race time after bivariate analysis. Body weight (P = 0.0054), pectoral skin-fold thickness (P = 0.0068), and mean speed of the training sessions (P = 0.0041) remained significant after multivariate analysis. Mean running speed during training was related to mid-axilla (r, -0.31), subscapular (r, -0.38), abdominal (r, -0.44), and suprailiac (r, -0.41) skin-fold thickness, the sum of 8 skin-fold thicknesses (r, -0.36); and percent body fat (r, -0.31). It was determined that variables of both anthropometry and training were related to half-marathon race time, and that skin-fold thicknesses were associated with running speed during training. For practical applications, high running speed during training (as opposed to extensive training) may both reduce upper-body skin-fold thicknesses and improve race performance in recreational female half-marathon runners. PMID- 21673498 TI - Tuberin and mTOR, a key apoptotic pathway in diabetes. PMID- 21673499 TI - The role of Rae1 in Nup98 fusion-mediated leukemogenesis. PMID- 21673500 TI - Sensitivity of human embryonic and induced pluripotent stem cells to a topoisomerase II poison etoposide. PMID- 21673504 TI - Getting permission: how DNA damage causes centrosome amplification. PMID- 21673501 TI - Unique and redundant functions of ATM and DNA-PKcs during V(D)J recombination. AB - Lymphocyte antigen receptor genes are assembled through the process of V(D)J recombination, during which pairwise DNA cleavage of gene segments results in the formation of four DNA ends that are resolved into a coding joint and a signal joint. The joining of these DNA ends occurs in G1-phase lymphocytes and is mediated by the non-homologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. The ataxia telangiectasia mutated (ATM) and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), two related kinases, both function in the repair of DNA breaks generated during antigen receptor gene assembly. Although these proteins have unique functions during coding joint formation, their activities in signal joint formation, if any, have been less clear. However, two recent studies demonstrated that ATM and DNA-PKcs have overlapping activities important for signal joint formation. Here, we discuss the unique and shared activities of the ATM and DNA-PKcs kinases during V(D)J recombination, a process that is essential for lymphocyte development and the diversification of antigen receptors. PMID- 21673505 TI - Terminology for plant polarity: progress and difficulties. AB - The recent attempts to establish a "natural" terminology for plant polarity are significant as they have identified various problems in the classic terminology of polarity, and arrived at a logical and simple terminology (shootward and rootward). The related issue of polarity changes was also addressed while assuming that cell polarity is conserved throughout the development. PMID- 21673506 TI - Identification and characterization of the Arabidopsis FG-repeat nucleoporin Nup62. AB - Ran is a multifunctional small GTPase that is involved in nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope reformation. Nuclear transport factor 2 (NTF2) facilitates nuclear import of Ran. It binds FxFG repeat containing domains of the nucleoporins Nup62 (vertebrate) and Nsp1p (yeast). Here, we have identified Arabidopsis Nup62 through its sequence similarity to mammalian Nup62 and yeast Nsp1p. A GFP!AtNup62 fusion protein is associated with the nuclear envelope in transgenic Arabidopsis plants and interacts in planta with AtNTF2a, one of the two Arabidopsis NTF2 homologs. Overexpression-based co suppression of AtNup62 leads to severely dwarfed, early-flowering plants, suggesting an important function for Nup62 in plants. PMID- 21673507 TI - Unraveling the regulation of floral fragrance biosynthesis. AB - Floral volatiles are biologically and economically important plant derived chemical compounds. In petunia, floral volatile benzenoid/phenylpropanoid (FVBP) biosynthesis is controlled spatially, developmentally, and hormonally at molecular, metabolic, and biochemical levels. Over the last years, numerous genes have been shown to encode proteins that either directly catalyze a biochemical reaction yielding FVBP compounds, or are involved in metabolite flux prior to the formation of FVBP compounds. This FVBP gene network is specifically and coordinately transcribed. Multiple R2R3-MYB transcription factors are involved in the regulation of genes in the core metabolic pathways leading to a very unique mixture of emitted floral volatiles. The molecular puzzle is not complete, since the functions of the few FVBP transcription factors identified to date do not fully explain the transcriptional regulation of the entire gene network. PMID- 21673508 TI - A cascade signal pathway occurs in self-incompatibility of Pyrus pyrifolia. AB - Pear (Pyrus pyrifolia L.) possesses an S-RNase-based gametophytic self incompatibility (GSI) system, and S-RNase, the self-incompatibility (SI) determinant in the pistil, has also been implicated in the rejection of self pollen and genetically identical pollen. We have demonstrated that S-RNase depolymerises actin cytoskeleton, triggers mitochondrial alteration and DNA degradation in the incompatible pollen tube, which indicates programmed cell death (PCD) may occur in SI response of Pyrus pyrifolia. Recently, we have identified that S-RNase specifically disrupted tip-localized reactive oxygen species (ROS) of incompatible pollen tube via arrest of ROS formation in mitochondria and cell walls in Pyrus pyrifolia. Furthermore, tip-localized ROS disruption not only decreased the Ca(2+) current and depolymerised the actin cytoskeleton, but it also induced nuclear DNA degradation in the pollen tube. The results mentioned above indicate that a cascade signal pathway may occur in SI of Pyrus pyrifolia and PCD is used to terminate the incompatible pollen tubes growth. In this addendum, we review the cascade signal pathway of Pyrus pyrifolia SI. PMID- 21673509 TI - Co-regulation of root hair tip growth by ROP GTPases and nitrogen source modulated pH fluctuations. AB - Growth of plant cells involves tight regulation of the cytoskeleton and vesicle trafficking by processes including the action of the ROP small G proteins together with pH-modulated cell wall modifications. Yet, little is known on how these systems are coordinated. In a paper recently published in Plant Cell and Environment we show that ROPs/RACs function synergistically with NH4NO3-modulated pH fluctuations to regulate root hair growth. Root hairs expand exclusively at their apical end in a strictly polarized manner by a process known as tip growth. The highly polarized secretion at the apex is maintained by a complex network of factors including the spatial organization of the actin cytoskeleton, tip-focused ion gradients and by small G proteins. Expression of constitutively active ROP mutants disrupts polar growth, inducing the formation of swollen root hairs. Root hairs are also known to elongate in an oscillating manner, which is correlated with oscillatory H(+) fluxes at the tip. Our analysis shows that root hair elongation in wild type plants and swelling in transgenic plants expressing a constitutively active ROP11 (rop11(CA)) is sensitive to the presence of NH4(+) at concentrations higher than 1 mM and on NO3(-). The NH4(+) and NO3(-) ions did not affect the localization of ROP in the membrane but modulated pH fluctuations at the root hair tip. Actin organization and reactive oxygen species distribution were abnormal in rop11CA root hairs but were similar to wild type root hairs when seedlings were grown on medium lacking NH4(+) and / or NO3(-). These observations suggest that the nitrogen source-modulated pH fluctuations may function synergistically with ROP regulated signaling during root hair tip growth. Interestingly, under certain growth conditions, expression of rop11 (CA) suppressed ammonium toxicity, similar to auxin resistant mutants. In this Addendum article we discuss these findings and their implications. PMID- 21673510 TI - Common and distinct mechanisms underlying the establishment of adaxial and abaxial polarity in stamen and leaf development. AB - Establishment of adaxial-abaxial polarity is essential for lateral organ development. A stamen consists of a bilaterally symmetrical anther and a radial filament. Using a rice mutant, rod-like lemma, in which establishment of adaxial abaxial polarity is compromised, we found that stamen patterning is likely to be achieved by a unique regulatory mechanism: rearrangement of adaxial-abaxial polarity in the anther, and abaxialization in the filament. These regulations are not found in leaf development. Here, we discuss similarities and differences between the stamen and the leaf in the mechanisms underlying the establishment of adaxial-abaxial polarity. In addition, we propose the idea that the process of establishing adaxial-abaxial polarity in lateral organs is likely to be divided into two phases: a meristem-dependent, followed by a meristem-independent phase. In stamen development, the transition between these two phases is clearly observed as the rearrangement of expression patterns of the adaxial and abaxial marker genes. PMID- 21673511 TI - A novel growth-promoting microbe, Methylobacterium funariae sp. nov., isolated from the leaf surface of a common moss. AB - Land plants (embryophytes) evolved in the presence of prokaryotic microbes. As a result, numerous mutually beneficial associations (symbioses) developed that can be analyzed using a variety of methods. Here we describe the isolation and characterization of a new pink-pigmented facultatively methylotrophic symbiotic bacterium of the genus Methylobacterium (laboratory strain F3.2) that was isolated from the gametophytic phylloids of the common cord moss Funaria hygrometrica Hedw. Plantlets were collected in the field and analyzed in the laboratory. Colonies of methylobacteria were obtained by the agar-impression method. Based on its unique phenotype (the bacterial cells are characterized by fimbriae-like appendages), a comparative 16S rRNA gene (DNA) sequence analysis, and an average DNA-DNA hybridization value of 8,4 %, compared with its most closely related sister taxon, this isolate is described as a new species, Methylobacterium funariae sp. nov. (type strain F3.2). This new epiphytic bacterium inhabits the leaf surface of "primitive" land plants such as mosses and interacts with its host organism via the secretion of phytohormones (cytokinines, auxins). These external signals are perceived by the plant cells that divide and grow more rapidly than in the absence of their prokaryotic phytosymbionts. We suggest that M. funariae sp. nov. uses methanol emitted from the stomatal pores as principal carbon source for cell metabolism. However, our novel data indicate that, in this unique symbiotic plant-microbe interaction, the uptake of amino acids leached from the surface of the epidermal cells of the green host organism may be of importance as microbial carbon- and nitrogen-source. PMID- 21673512 TI - Unraveling the response of plant cells to cytotoxic saponins: role of metallothionein and nitric oxide. AB - A wide range of pharmacological properties are ascribed to natural saponins, in addition to their biological activities against herbivores, plant soil-borne pathogens and pests. As for animal cells, the cytotoxicity and the chemopreventive role of saponins are mediated by a complex network of signal transduction pathways which include reactive oxygen species (ROS) and nitric oxide (NO). The involvement of other relevant components of the saponin-related signaling routes, such as the Tumor Necrosis Factor(TNF)-alpha, the interleukin(IL)-6 and the Nuclear Transcription Factor-kB (NF-kappaB), has been highlighted in animal cells. By contrast, information concerning the response of plant cells to saponins and the related signal transduction pathways is almost missing. To date, there are only a few common features which link plant and animal cells in their response to saponins, such as the early burst in ROS and NO production and the induction of metallothioneins (MTs), small cysteine-rich, metal-binding proteins. This aspect is discussed in the present paper in view of the recent hypothesis that MTs and NO are part of a novel signal transduction pathway participating in the cell response to oxidative stress. PMID- 21673513 TI - Involvement of RD20, a member of caleosin family, in ABA-mediated regulation of germination in Arabidopsis thaliana. AB - The RD20 gene encodes a member of the caleosin family, which is primarily known to function in the mobilization of seed storage lipids during germination. In contrast to other caleosins, RD20 expression is early-induced by water deficit conditions and we recently provided genetic evidence for its positive role in drought tolerance in Arabidopsis. RD20 is also responsive to pathogen infection and is constitutively expressed in diverse tissues and organs during development suggesting additional roles for this caleosin. This addendum describes further exploration of phenotypic alterations in T-DNA insertional rd20 mutant and knock out complemented transgenic plants in the context of early development and susceptibility to a phytopathogenic bacteria. We show that the RD20 gene is involved in ABA-mediated inhibition of germination and does not play a significant role in plant defense against Pseudomonas syringae. PMID- 21673514 TI - Timing the switch to phototrophic growth: a possible role of GUN1. AB - In young Arabidopsis seedlings, retrograde signalling from plastids regulates the expression of photosynthesis-associated nuclear genes in response to the developmental and functional state of the chloroplasts. The chloroplast-located PPR protein GUN1 is required for signalling following disruption of plastid protein synthesis early in seedling development before full photosynthetic competence has been achieved. Recently we showed that sucrose repression and the correct temporal expression of LHCB1, encoding a light-harvesting chlorophyll protein associated with photosystem II, are perturbed in gun1 mutant seedlings. ( 1) Additionally, we demonstrated that in gun1 seedlings anthocyanin accumulation and the expression of the "early" anthocyanin-biosynthesis genes is perturbed. Early seedling development, predominantly at the stage of hypocotyl elongation and cotyledon expansion, is also affected in gun1 seedlings in response to sucrose, ABA and disruption of plastid protein synthesis by lincomycin. These findings indicate a central role for GUN1 in plastid, sucrose and ABA signalling in early seedling development. PMID- 21673515 TI - DCL2 is highly expressed in the egg cell in both rice and Arabidopsis. AB - Small RNAs are riboregulators that play critical roles in eukaryotic cells. They repress gene expression by acting either on DNA to guide sequence elimination and chromatin remodeling, or on RNA to guide cleavage and translation repression. Arabidopsis thaliana and Oryza sativa contain four and six DICER-LIKE (DCL) genes with specialized functions in small RNA biogenesis for RNA interference-related processes. We recently profiled genome-wide gene expression in egg and synergid cells in rice. In this article, we show that OsDCL2, OsDCL4, and OsHEN1 are preferentially expressed in the egg cell. In addition, we revealed that AtDCL2 is also preferentially expressed in the Arabidopsis egg cell. These findings suggest that small RNA pathways are activated in the egg cell in both rice and Arabidopsis. The activation of these pathways in the egg cell might be essential for egg cell maturation, fertilization, or embryogenesis. PMID- 21673517 TI - ATG16L1 polymorphisms are associated with NOD2-induced hyperinflammation. AB - In recent years considerable advances in understanding the pathogenesis of Crohn disease have been achieved, with the identification of susceptibility variants of genes that are part of the autophagy machinery, i.e., ATG16L1 and IRGM. Subsequent functional studies have been conducted to unravel the underlying mechanism of this genetic association. For the ATG16L1 Thr300Ala polymorphism (c.898A > G, rs2241880), it was demonstrated that the risk variant is associated with a reduced capacity of innate immune cells to induce autophagy upon triggering with specific microbial structures such as peptidoglycans, that are specifically recognized by the intracellular pattern-recognition receptor nucleotide oligomerization domain-2 (NOD2). Due to the impaired autophagy activation, autophagosome formation and the subsequent antigen presentation through the major histocompatibility complex are diminished, leading to decreased immune activation. However, these findings arguing for defective host defense mechanisms in individuals bearing the ATG16L1 300Ala variant, and subsequent bacterial persistence in the gut mucosa, provide no conclusive explanation for the excessive inflammation observed in Crohn disease. PMID- 21673516 TI - PML-RARalpha enhances constitutive autophagic activity through inhibiting the Akt/mTOR pathway. AB - Autophagy is a highly conserved, closely regulated homeostatic cellular activity that allows for the bulk degradation of long-lived proteins and cytoplasmic organelles. Its roles in cancer initiation and progression and in determining the response of tumor cells to anticancer therapy are complicated, and only limited investigation has been conducted on the potential significance of autophagy in the pathogenesis and therapeutic response of acute myeloid leukemia. Here we demonstrate that the inducible or transfected expression of the acute promyelocytic leukemia (APL)-specific PML-RARalpha, but not PLZF-RARalpha or NPM RARalpha, fusion protein upregulates constitutive autophagy activation in leukemic and nonleukemic cells, as evaluated by hallmarks for autophagy including transmission electron microscopy. The significant increase in autophagic activity is also found in the leukemic cells-infiltrated bone marrow and spleen from PML RARalpha-transplanted leukemic mice. The autophagy inhibitor 3-methyladenine significantly abrogates the autophagic events upregulated by PML-RARalpha, while the autophagic flux assay reveals that the fusion protein induces autophagy by increasing the on-rate of autophagic sequestration. Furthermore, this modulation of autophagy by PML-RARalpha is possibly mediated by a decreased activation of the Akt/mTOR pathway. Finally, we also show that autophagy contributes to the anti-apoptotic function of the PML-RARalpha protein. Given the critical role of the PML-RARalpha oncoprotein in APL pathogenesis, this study suggests an important role of autophagy in the development and treatment of this disease. PMID- 21673519 TI - JACM special issue on community health workers and community health worker practice. PMID- 21673520 TI - Community health workers "101" for primary care providers and other stakeholders in health care systems. AB - Today's ambulatory care providers face numerous challenges as they try to practice efficient, patient-centered medicine. This article explains how community health workers (CHWs) can be engaged to address many patient- and system-related barriers currently experienced in ambulatory care practices. Community health workers are frontline public health workers who serve as a trusted bridge between community members and health care providers. Among their varied roles, CHWs can educate and support patients in managing their risk factors and diseases and link these patients to needed resources. As shown in this overview (CHW 101), including CHWs as members of multidisciplinary care teams has the potential to strengthen both current and emerging models of health care delivery. PMID- 21673521 TI - Clinical community health workers: linchpin of the medical home. AB - The emerging clinical community health worker model integrates community health workers as integral members of primary care teams inside a medical home. This evaluation documents the case management services provided by 2 clinical community health worker programs at La Clinica del Carino in Hood River, Oregon, and how they affected the care team's ability to deliver efficient, effective primary care. Clinical community health workers have the potential to make a significant impact on clinical efficiency and effectiveness as ambulatory primary care clinics strive to transform into high-quality, patient-centered medical homes and become linchpins in accountable care organizations. PMID- 21673522 TI - Growing your own: community health workers and jobs to careers. AB - This article evaluates the implementation and impact of 5 workforce development programs aimed at achieving skills upgrades, educational advancement, and career development for community health workers (CHWs). Quantitative and qualitative case study data from the national evaluation of the Jobs to Careers: Transforming the Front Lines of Health Care initiative demonstrate that investing in CHWs can achieve measurable worker (eg, raises) and programmatic (eg, more skilled workers) outcomes. To achieve these outcomes, targeted changes were made to the structure, culture, and work processes of employing organizations. These findings have implications for other health care employers interested in developing their CHW workforce. PMID- 21673523 TI - Community health workers then and now: an overview of national studies aimed at defining the field. AB - This article compares and contrasts 3 national studies of the US Community Health Worker (CHW) field spanning 15 years. Findings cover 4 areas of overlap among the 3 studies: CHW Demographics, Core Roles and Competencies, Training and Credentialing, and Career Advancement and Workforce Issues. Implications for the future development of research, practice, and policy are discussed. Authors observe that while health care reform has the potential for increasing funding and recognition of CHWs, it is essential that policies support the full range of CHW roles, including CHWs role as change agents, so that CHWs achieve their full potential to improve health outcomes, reduce health disparities, and work for social justice. PMID- 21673524 TI - Enhancing the intrinsic work motivation of community nutrition educators: how supportive supervision and job design foster autonomy. AB - Mixed-methods research investigated the work motivation of paraprofessional community nutrition educators (CNEs) delivering a long-running public health nutrition program. In interviews, CNEs (n = 9) emphasized "freedom," supportive supervision, and "making a difference" as key sources of motivation. Community nutrition educator surveys (n = 115) confirmed high levels of autonomy, which was associated with supervisors' delegation and support, CNE decision-making on scheduling and curricula, and job satisfaction. Supervisors (n = 32) rated CNEs' job design as having inherently motivating characteristics comparable to professional jobs. Supervisory strategies can complement job design to create structured, supportive contexts that maintain fidelity, while granting autonomy to paraprofessionals to enhance intrinsic work motivation. PMID- 21673525 TI - Exploring strategies to encourage community health outreach by health promotion volunteers in Japan. AB - Japan's health promotion volunteers (HPVs) are individuals who act as a natural helping resource in the community. This study explored the factors associated with vigorous community health outreach by HPVs who promote healthy lifestyles. A cross-sectional survey was conducted in December 2009 that included 822 HPVs in 2 areas. Multiple logistic regression analysis indicated that higher motivation for initial involvement as an HPV, stronger neighborhood networks, and a stronger sense of belonging to the community where they worked were related to vigorous outreach. These findings reveal challenges that HPVs encounter, and also provide recommendations for training HPVs to encourage effective community health outreach. PMID- 21673527 TI - My experience as a community health worker. PMID- 21673528 TI - Community outreach and patient empowerment: collaboration with Navajo Nation CHRs. PMID- 21673529 TI - Health promoters trained by Fundacion EPES: dreamers and brave warriors: that's what we are. PMID- 21673530 TI - Activation among chronically ill older adults with complex medical needs: challenges to supporting effective self-management. AB - Successful chronic care ideally involves patient engagement, but little is known about chronically ill older adults' ability to self-manage their health. This study examines activation among hypertensive patients older than 65 years. Almost 60% of participants scored in the bottom half of the activation scale; only 8% scored at the highest level. Higher activation was associated with higher self ratings of health, health literacy, and receipt of patient-centered care, shorter lengths of stay, and lower depression and hearing impairment levels. Effective self-management support for chronically ill elders will likely require varied strategies and may need to address depression, health literacy, and/or hearing impairments. PMID- 21673531 TI - Turning on the care coordination switch in rural primary care: voices from the practices--clinician champions, clinician partners, administrators, and nurse care managers. AB - This study sought to understand the acceptability and feasibility of office-based nurse care management in medium to large rural primary care practices. A qualitative assessment of Care Management Plus (a focused medical home model for complex patients) implementation was conducted using semistructured interviews with 4 staff cohorts. Cohorts included clinician champions, clinician partners, practice administrators, and nurse care managers. Seven key implementation attributes were: a proven care coordination program; adequate staffing; practice buy-in; adequate time; measurement; practice facilitation; and functional information technology. Although staff was positive about the care coordination concept, model acceptability was varied and additional study is required to determine sustainability. PMID- 21673532 TI - What if ...: you have to say "no" to a patient's request? PMID- 21673534 TI - Pancreatic cancer prevention and the 2010 Dietary Guidelines for Americans. PMID- 21673535 TI - Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment. AB - Pancreatic cancer is notorious for its late presentation, early and aggressive local invasion, metastatic potential, and poor outcome. It presents at a clinically advanced stage that precludes the possibility of surgical resection in most cases and shows constitutive resistance to chemotherapy and radiotherapy in others. As a result, mortality from this disease parallels its incidence rates.Recent breakthroughs in the molecular biology of pancreatic cancer have assisted in translational research, giving hope for individualized therapy and better disease management. Molecular biology tools are guiding early diagnosis, the assessment of prognosis, and isolation of novel, more effective therapeutic targets.This review discusses the signature mutations of pancreatic cancer, implications of these mutations to pancreatic cancer biology, their linked pathways, and recent advances in their understanding as biomarkers as diagnostic, prognostic, and therapeutic tools in dealing with this disease. PMID- 21673536 TI - A novel exon duplication of the cystic fibrosis transmembrane conductance regulator in a patient presenting with adult-onset recurrent pancreatitis. AB - Pancreatitis is a rare occurrence in patients with cystic fibrosis (CF) affecting 1.2% of all patients, but it can be the first presenting sign in approximately 15% of adults with pancreatic sufficiency and a milder CF phenotype. We report a case of a woman with recurrent pancreatitis who has one cystic fibrosis-causing mutation (G551D) and the first known description of a pathologic duplication of exon 19 of the CF transmembrane conductance regulator (CFTR). A 30-year-old white woman with 30 attacks of pancreatitis over a 5-year period starting at age 25 presented to the genetics department. She was found to have a mutation in the SPINK1 gene, IVS3+184T>A, and one cystic fibrosis-causing mutation (G551D) prompting full gene sequencing of the CFTR, revealing an additional duplication of exon 19. Sweat chloride testing was elevated at 97 and 106 mmol/L. Despite normal growth parameters and lung function, it is important to be aware of recurrent pancreatitis as a presenting sign of CF. Comprehensive CF gene analysis is necessary to detect a second CF-causing mutation that may put patients at risk for more severe symptoms of pancreatitis. There is a significant difference in the prevalence of heterozygote mutations between available testing methods. PMID- 21673537 TI - Epidemiology of intraductal papillary mucinous neoplasms of the pancreas: sex differences between 3 geographic regions. PMID- 21673538 TI - Can loperamide cause acute pancreatitis? PMID- 21673539 TI - A unique case of a nonfunctional metastatic pancreatic neuroendocrine tumor transforming into an insulin-secreting tumor with an unusual clinical course. PMID- 21673540 TI - Intravenous fluid therapy successfully prevents renal injury by gemcitabine in patients with pancreatic cancer. PMID- 21673541 TI - Evaluation of cell-free DNA in plasma and serum as early predictors of severity in acute pancreatitis. PMID- 21673542 TI - Significance of measuring IgG and IgG4 during follow-up of autoimmune pancreatitis. PMID- 21673543 TI - Signet ring cell carcinoma of the ampulla of Vater: demonstration of a pancreatobiliary origin. PMID- 21673544 TI - Substance P inhibits pancreatic ductal bicarbonate secretion via neurokinin receptors 2 and 3 in the guinea pig exocrine pancreas. PMID- 21673545 TI - Cholesterol granuloma in the pancreas accompanied by peritoneal disseminated lesions. PMID- 21673546 TI - Isolated pancreatic metastasis from uterine cervical cancer: a case report. PMID- 21673548 TI - Molecular diagnostic tests for human herpesvirus 6. PMID- 21673549 TI - A statement regarding personal belief exemption from immunization mandates: from the Pediatric Infectious Diseases Society, March 2011. PMID- 21673550 TI - Visceral leishmaniasis as a cause of persistent fever in pediatric Hodgkin lymphoma. PMID- 21673551 TI - Detection of mutations in antigenic regions of rotavirus viral proteins 4 and 7 in a child with chronic shedding of rotavirus vaccine-type strain. PMID- 21673552 TI - Serious adverse reactions should be further monitored after influenza A (H1N1) vaccination among children: postmarketing experience with 570,000 vaccinations between October 2009 and August 2010 in Guangzhou, China. PMID- 21673553 TI - Extended antenatal use of triple antiretroviral therapy for prevention of mother to-child transmission of HIV-1 correlates with favorable pregnancy outcomes. AB - OBJECTIVE: To evaluate pregnancy outcomes in a cohort of HIV-infected women receiving triple antiretroviral therapy (ART) for prevention of mother-to-child transmission. METHODS: A retrospective cohort study with review of records of 3273 HIV-positive women receiving prenatal care in Malawi and Mozambique from July 2005 to December 2009 was conducted in Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) centers. Patients were offered nevirapine-based triple ART initiated in pregnancy until 6 months postpartum. Main outcome measures were maternal mortality, abortion/stillbirth, prematurity, and low birth weight. RESULTS: Maternal mortality was 1.2% (42/3273): 7.4% in 68 women with no antenatal ART and 0.7% in 1370 with at least 90 days of antenatal ART [P < 0.001; odds ratio (OR) 0.29 (95% confidence interval [CI] 0.14-0.96]. Abortion/stillbirth was 5.2% (169/3273): 26.5% in 68 women with no ART and 5.0% in 1370 women with at least 90 days of antenatal ART [P < 0.001; OR 0.39 (95% CI 0.27-0.57)]. Prematurity was 19.1%: 70% in 10 women with no antenatal ART and 8.5% in 1330 women with at least 90 days of antenatal ART [P < 0.001; OR 0.15 (95% CI 0.14-0.19)]. Low birth weight was 11.5% (57/496) and not associated with ART duration. The protective effect of antenatal ART against mortality, fetal demise, and prematurity was independent of CD4 strata. Multivariate analysis for BMI, CD4 cell count, virus load, days in care, predelivery length of ART, and hemoglobin demonstrated an independent association between predelivery length of ART and CD4 with maternal mortality, abortion/stillbirth, and prematurity. ART toxicities were infrequent (5.2%). CONCLUSION: Antenatal triple ART reduces adverse pregnancy outcomes in HIV-infected women. PMID- 21673554 TI - Despite an impaired response to IL-7, CD4+EM T cells from HIV-positive patients proliferate normally in response to IL-15 and its superagonist, RLI. AB - OBJECTIVE: In phase I/II trials, IL-7 immunotherapy has been shown to expand CD4(+) T cells. However, expression of the IL-7 receptor alpha-chain, CD127, is reduced on CD4(+) T cells from HIV-positive patients, and defects in CD127 signaling have also been reported. To refine and improve cytokine immunotherapy, it is important to identify stimuli that can restore proliferation of CD4(+) cells with defective responses to IL-7. DESIGN: Observational study comparing viremic HIV-positive patients with HIV-negative controls. METHODS: Peripheral blood mononuclear cells were cultured in the presence of 1 nmol/l IL-2, IL-7, IL 15 or RLI (an IL-15Ralpha/IL-15 fusion protein). Proliferation of different T cell subsets was assessed by carboxyfluorescein succinimidyl ester fluorescence. Expression of CD127 on CD4(+) T-cell subsets was also analyzed. RESULTS: In HIV positive patients, CD127 expression was correlated with CD4(+) T-cell count in the CD4(+)(N) (R(2) = 0.36; P < 0.01) and CD4(+)(CM) (R(2) = 0.45; P < 0.001) populations, whereas CD127 expression on CD4(+)(EM) cells was significantly reduced in HIV-positive individuals compared with controls (P = 0.001) independently of CD4(+) T-cell count. In patients with high CD4(+) T-cell counts, proliferation in response to IL-7 was significantly reduced only in CD4(+)(EM) cells (P < 0.05). RLI, and to a lesser extent IL-15, induced strong proliferation of CD4(+)(EM) cells from both HIV-positive patients and controls. Neither agent stimulated proliferation of CD4(+)(N) or CD4(+)(CM) cells. CONCLUSION: In HIV positive patients, CD4(+)(EM) cells are deficient in both CD127 expression and proliferation in response to IL-7. RLI and IL-15 specifically induced proliferation of CD4(+)(EM) cells, suggesting that they may have a unique potential to complement IL-7 immunotherapy. PMID- 21673555 TI - Development and validation of systems for rational use of viral load testing in adults receiving first-line ART in sub-Saharan Africa. AB - BACKGROUND: World Health Organization (WHO) immunological and clinical criteria for monitoring first-line antiretroviral treatment (ART) offer low accuracy for predicting viral failure. Targeting viral load assays to those at high risk has been recommended and a system to do this has been developed in Cambodia. Systems for use in sub-Saharan African populations were evaluated. METHODS: A new Ugandan based scoring system for targeting viral load assays was developed from data from the first 4 years of a Ugandan cohort (N = 559) receiving first-line ART. The accuracy of this, the Cambodian system and the WHO criteria to predict viral failure, through targeting viral load assays, were compared in a separate population of 496 Ugandans. RESULTS: The new Ugandan scoring system included CD4 cell count, mean cell volume, adherence, and HIV-associated clinical events as predictors of viral failure. In the validation population, the Ugandan system undertook viral load assays in 61 (12.3%) cases offering 20.5% sensitivity and 100% positive predictive value (PPV) to predict viral failure. The Cambodian system undertook viral load assays in 33 (6.7%) cases producing 23.1% sensitivity and 90.0% PPV. WHO criteria recommended viral load assays in 72 (14.5%) cases offering 30.8% sensitivity and 100% PPV. CONCLUSION: Locally developed algorithms based on clinical and immunological criteria may offer little additional accuracy over WHO criteria for targeting viral load assays. When possible, confirming viral load before switching therapy is recommended. Scoring systems are more flexible than WHO criteria in allowing ART providers to choose the proportion of the population that undergo targeted viral load testing. PMID- 21673556 TI - Clinical implications of fixed-dose coformulations of antiretrovirals on the outcome of HIV-1 therapy. AB - The substitution by generic equivalents of some of the drugs included in fixed dose antiretroviral coformulations (FDACs) poses the potential risk of disrupting these combinations and administering the components separately in order to incorporate the new generic drug, which offers a more competitive sales price. This may represent a step backwards in the advances achieved in simplicity and adherence to therapy, posing an increased risk of selective noncompliance of some of the separately administered drug substances. Available antiretroviral drugs must be administered for life in the affected individuals - both children and adults. The FDACs represent a significant advance in the simplification of antiretroviral therapy, facilitating adherence to complex and chronic treatments, and contributing to a quantifiable improvement in patient quality of life. These drug coformulations reduce the risk of treatment error, are associated with a lower risk of hospitalization, and can lessen the possibility of covert monotherapy in situations of selective noncompliance. Thus, FDACs can reduce the risk of selection of HIV-1 resistances, which not only adversely affect the treatment options of the individual patient but also constitute a public health problem, and further increase the cost and complexity of therapy. With the exception of those cases requiring dose adjustments, the preferential use of FDACs should be recommended for the treatment of HIV-1 infection in those situations when the agents included in the coformulation are drugs of choice. PMID- 21673557 TI - Frequency of CXCR4-using viruses in primary HIV-1 infections using ultra-deep pyrosequencing. AB - We used ultra-deep pyrosequencing and the Toulouse Tropism Test phenotypic assay to determine the prevalence of CXCR4-using viruses in 21 patients with primary HIV-1 infections. We found X4-containing virus populations in 9% of patients by ultra-deep pyrosequencing using position-specific scoring matrices (PSSM(X4/R5)) or geno2pheno(5.75) and in 14% using the combined 11/25 and net charge rule. The phenotypic assay identified 9% of CXCR4-using viruses. This confirms that R5 viruses are predominant in primary HIV-1 infections. PMID- 21673559 TI - European mitochondrial DNA haplogroups and liver fibrosis in HIV and hepatitis C virus coinfected patients. AB - BACKGROUND: HIV infection, hepatitis C virus (HCV) liver disease, and mitochondrial DNA (mtDNA) polymorphisms are three possibly interrelated factors that might be associated with progression of liver disease. The aim of this study was to investigate whether mtDNA haplogroups had any influence on liver fibrosis progression in HIV/HCV coinfected patients. METHODS: We carried out a cross sectional study in 231 patients who were genotyped via Sequenom's MassARRAY platform (San Diego, California, USA). Liver fibrosis was estimated based on the METAVIR score. In each patient, fibrosis progression rate (FPR) was calculated by dividing the fibrosis stage (0-4) by the estimated duration of HCV infection in years. RESULTS: The cluster or major haplogroup HV was significantly associated with reduced odds ratios (OR) for advanced fibrosis [OR 0.35, 95% confidence interval (CI) 0.16-0.77, P = 0.009], cirrhosis (OR 0.16, 95% CI 0.04-0.60, P = 0.007), or high FPR (OR 0.43, 95% CI 0.21-0.84, P = 0.015). Within the major haplogroup HV, haplogroup H was significantly associated with an absence of advanced fibrosis (OR 0.40, 95% CI 0.18-0.91, P = 0.029), cirrhosis (OR 0.14, 95% CI 0.03-0.67, P = 0.014), or high FPR (OR 0.47, 95% CI 0.23-0.95, P = 0.035). We also found a significant association with increased odds of cirrhosis (OR 5.25, 95% CI 1.76-15.64, P = 0.003) in the closely related major haplogroup U. CONCLUSION: The mtDNA haplogroups HV and H were associated with slower fibrosis progression, and the haplogroup U was associated with faster fibrosis progression in HIV/HCV coinfected patients. These data suggest that mtDNA haplogroup may play a significant role in liver fibrogenesis during HCV infection. PMID- 21673560 TI - Prevalence and outcome of HIV-associated malignancies among children. AB - OBJECTIVE: To determine the prevalence, associated factors, and outcome of HIV associated malignancies among children enrolling for care at the Baylor-Uganda pediatric HIV clinic in Mulago Hospital, Kampala, Uganda. STUDY DESIGN: This was a retrospective case series involving records review of all HIV-infected patients who received care at the Baylor-Uganda clinic in Kampala, Uganda between 1 January 2004 and 31 December 2008. METHODS: Medical charts of the clinic patients aged 6 weeks to 18 years were retrieved for data abstraction. Data, including patient's age, sex, diagnosis, type of malignancy, anatomic location of the malignancy, pathology report, baseline laboratory results, and outcome of treatment, were abstracted. Proportions of malignancies among different groups were determined. In addition, Kaplan-Meier survival analysis was conducted. Change in CD4 cell percentages from baseline was assessed with the Wilcoxon signed-rank test. RESULTS: A total of 109 children with malignancies presented to the clinic during the study period, making up 1.67% of the total children visiting the clinic. Only two types of malignancies, Kaposi's sarcoma (90.7%) and non-Hodgkin's lymphoma (9.3%), were found. Deaths during follow-up were seen in the first few weeks to months. Upon starting treatment, the CD4 cell percentage increased significantly from a baseline median of 6-14% at 6 months to 15.8% at 12 months of follow-up. CONCLUSION: HIV-associated malignancies remain an important cause of morbidity and mortality among HIV-infected children in Uganda. Many affected children die in the first weeks of treatment, but those who survive mount good immunologic recovery. PMID- 21673558 TI - Treatment switches during pregnancy among HIV-positive women on antiretroviral therapy at conception. AB - OBJECTIVES: To describe antiretroviral therapy (ART) use and clinical status, at start of and during pregnancy, for HIV-positive women receiving ART at conception, including the proportion conceiving on drugs (efavirenz and didanosine) not recommended for use in early pregnancy. METHODS: Women with a pregnancy resulting in a live-birth after 1995 (n = 1537) were identified in an observational cohort of patients receiving HIV care at 12 clinics in the UK by matching records with national pregnancy data. Treatment and clinical data were analysed for 375 women conceiving on ART, including logistic regression to identify factors associated with changing regimen during pregnancy. RESULTS: Of the 375 women on ART, 39 (10%) conceived on dual therapy, 306 (82%) on triple therapy and 30 (8%) on more than three drugs. In total, 116 (31%) women conceived on a regimen containing efavirenz or didanosine (69 efavirenz, 54 didanosine, seven both). Overall, 38% (143) changed regimen during pregnancy, of whom 44% (n = 51) had a detectable viral load around that time. Detectable viral load was associated with increased risk of regimen change [adjusted odds ratio 2.97, 95% confidence interval (CI) (1.70-5.19)], while women on efavirenz at conception were three times more likely to switch than women on other drugs [3.40, (1.84 6.25)]. Regimen switching was also associated with year at conception [0.89, (0.83-0.96)]. CONCLUSION: These findings reinforce the need for careful consideration of ART use among women planning or likely to have a pregnancy in order to reduce viral load before pregnancy and avoid drugs not recommended for early antenatal use. PMID- 21673561 TI - Imbalance between endothelial progenitors cells and microparticles in HIV infected patients naive for antiretroviral therapy. AB - BACKGROUND: Cardiovascular events have been reported among HIV-infected patients following antiretroviral therapy. However, the role of HIV itself in determining vascular damage is less described. Chronic inflammatory state might impair some regulatory endothelium properties leading to its activation, apoptosis or erosion. OBJECTIVES: To evaluate the balance between endothelial progenitor cells and microparticles in HIV-infected antiretroviral drug-naive patients. DESIGN: A case-control study comparing HIV-infected patients (n = 35) with sex-matched and age-matched healthy controls (n = 33). METHODS: Endothelial progenitor cells populations expressing CD34, CD133 and KDR were quantified by flow cytometry. Endothelial-derived microparticles, expressing CD51, and platelet-derived microparticles, expressing CD31/CD42, were also measured. Endothelial function was estimated by flow-mediated dilation. RESULTS: Lower percentages of endothelial progenitor cells (CD34/KDR) were observed in HIV-infected individuals compared with controls (0.02 vs. 0.09%, P = 0.045). In addition, endothelial microparticles concentration was higher in HIV-infected individuals (1963 vs. 436 microparticles/MUl platelet-poor plasma, P = 0.003), with similar number of platelet-derived microparticles among groups. Furthermore, flow-mediated dilation was lower among HIV-infected individuals compared with controls [mean (SEM): 10 (1) and 16% (2), respectively; P = 0.03]. CONCLUSION: Our findings suggest an imbalance between endothelial progenitor cells mobilization and endothelial apoptosis. The alteration in the turnover of endothelial cells may contribute to cardiovascular events in HIV-infected patients. PMID- 21673562 TI - Implementation of free cotrimoxazole prophylaxis improves clinic retention among antiretroviral therapy-ineligible clients in Kenya. AB - OBJECTIVE: To determine whether implementation of free cotrimoxazole (CTX) provision was associated with improved retention among clients ineligible for antiretroviral therapy (ART) enrolled in an HIV treatment program in Kenya. DESIGN: Data were obtained from a clinical cohort for program evaluation purposes. Twelve-month clinic retention was compared among ART-ineligible clients enrolled in the time period before free CTX versus the time period after. METHODS: Statistical comparisons were made using Kaplan-Meier survival curves, log-rank tests, and multivariate Cox proportional hazards models. To exclude potential temporal program changes that may have influenced retention, ART clients before and after the same cut-off date were compared. FINDINGS: Among adult clients enrolled between 2005 and 2007, 3234 began ART within 1 year of enrollment, and 1024 of those who did not start treatment were defined as ART ineligible. ART-ineligible clients enrolled in the period following free CTX provision had higher 12-month retention (84%) than those who enrolled prior to free CTX (63%; P < 0.001). Retention did not change significantly during these periods among ART clients (P = 0.55). In multivariate analysis, ART-ineligible clients enrolled prior to free CTX were more than twice as likely to be lost to follow-up compared to those following free CTX [adjusted hazard ratio (aHR) = 2.64, 95% confidence interval 1.95-3.57, P < 0.001]. CONCLUSION: Provision of free CTX was associated with significantly improved retention among ART ineligible clients. Retention and CD4-monitoring of ART-ineligible clients are essential to promptly identify ART eligibility and provide treatment. Implementation of free CTX may improve retention in sub-Saharan Africa and, via increasing timely ART initiation, provide survival benefit. PMID- 21673563 TI - Original research: online social networking patterns among adolescents, young adults, and sexual offenders. AB - OBJECTIVE: The use of online social networks like Facebook continues to increase rapidly among all age groups and segments of our society, presenting new opportunities for the exchange of sexual information as well as for potentially unsafe encounters between predators and the vulnerable or young. This study surveyed middle school, high school, and college-age students, as well as sexual offenders, regarding their use of social networking sites in order to provide information to better focus education and prevention efforts from nurses and other health care providers. METHODS: Written questionnaires asking about various characteristics of participants' use of social networking sites were distributed to each group and filled out by 404 middle school students, 2,077 high school students, 1,284 students drawn from five traditional four-year colleges, and 466 adults who had committed either an Internet sexual offense or a hands-on sexual offense (in some cases both). RESULTS: Notable findings emerging from our analysis of the questionnaire responses included the following: offenders and students both frequent social networking sites, although at the time of the study offenders reported that they preferred Myspace and students that they preferred Facebook; nearly two-thirds of the Internet offenders said they'd initiated the topic of sex in their first chat session; more than half of the Internet offenders disguised their identity when online; most Internet offenders we surveyed said they preferred communicating with teenage girls rather than teenage boys; high school students' experience with "sexting" (sharing nude photos of themselves or others on cell phones or online) differed significantly according to their sex; a small number of students are being threatened and assaulted by people they meet online; avatar sites such as Second Life were used both by students and offenders, with both child molesters and Internet offenders expressing interest in Second Life. CONCLUSIONS: The use of the Internet presents relatively new and complex issues related to the safety and privacy of adolescents and young adults, and it's crucial that our understanding keep pace with these changes. Possible nurse-initiated policy recommendations include designing technologies and educational programs to help in the identification of suspicious online behaviors; strengthening Internet filters and privacy options for protecting students online; and school outreach for students who are harassed, threatened, or assaulted as a consequence of meeting someone online. PMID- 21673565 TI - Ultrasonographic identification of an anomalous femoral nerve: the fascia iliaca as a key landmark. PMID- 21673564 TI - A Single phenylalanine residue in the main intracellular loop of alpha1 gamma aminobutyric acid type A and glycine receptors influences their sensitivity to propofol. AB - BACKGROUND: The intravenous anesthetic propofol acts as a positive allosteric modulator of glycine (GlyRs) and gamma-aminobutyric acid type A (GABAARs) receptors. Although the role of transmembrane residues is recognized, little is known about the involvement of other regions in the modulatory effects of propofol. Therefore, the influence of the large intracellular loop in propofol sensitivity of both receptors was explored. METHODS: The large intracellular loop of alpha1 GlyRs and alpha1beta2 GABAARs was screened using alanine replacement. Sensitivity to propofol was studied using patch-clamp recording in HEK293 cells transiently transfected with wild type or mutant receptors. RESULTS: Alanine mutation of a conserved phenylalanine residue within the alpha1 large intracellular loop significantly reduced propofol enhancement in both GlyRs (360 +/- 30 vs. 75 +/- 10%, mean +/- SEM) and GABAARs (361 +/- 49% vs. 80 +/- 23%). Remarkably, propofol-hyposensitive mutant receptors retained their sensitivity to other allosteric modulators such as alcohols, etomidate, trichloroethanol, and isoflurane. At the single-channel level, the ability of propofol to increase open probability was significantly reduced in both alpha1 GlyR (189 +/- 36 vs. 22 +/- 13%) and alpha1beta2 GABAAR (279 +/- 29 vs. 29 +/- 11%) mutant receptors. CONCLUSION: In this study, it is demonstrated that the large intracellular loop of both GlyR and GABAAR has a conserved single phenylalanine residue (F380 and F385, respectively) that influences its sensitivity to propofol. Results suggest a new role of the large intracellular loop in the allosteric modulation of two members of the Cys-loop superfamily. Thus, these data provide new insights into the molecular framework behind the modulation of inhibitory ion channels by propofol. PMID- 21673566 TI - Environmental enrichment, administered after establishment of cocaine self administration, reduces lever pressing in extinction and during a cocaine context renewal test. AB - The objective of this study was to test the hypothesis that environmental enrichment (EE) administered to rats previously trained to self-administer cocaine would reduce responding in extinction and in a cocaine-context renewal test. Long-Evans male rats were trained to press an active lever reinforced by cocaine (1.0 mg/kg/injection) under a fixed-ratio 1 schedule of reinforcement (inactive lever presses produced no consequences). After stable responding was established, all rats were given a 10-day break from the operant chambers followed by random assignment to EE (larger cages equipped with visual and auditory stimuli) or control (standard housing) group conditions in which they lived for the remainder of the experiment. Ten days after this move, rats were exposed to 10 extinction-responding sessions in a context different from the one in which self-administration occurred, followed by a context-renewal session occurring in the original self-administration context. The EE group responded significantly less in both the extinction and context-renewal sessions compared with the control group. These results suggest that EE reduces the ability of cocaine-associated stimuli to control cocaine-related responding. PMID- 21673567 TI - Successful corneal autograft after clearance of anterior chamber cytomegalovirus with oral valganciclovir in a patient with multiple failed corneal allografts. AB - PURPOSE: To report a case of recurrent corneal graft failure because of cytomegalovirus (CMV) infection and to demonstrate successful clearance of the virus with oral valganciclovir, confirmed by polymerase chain reaction (PCR) assay. This allowed for a successful corneal autograft to be performed. METHODS: Interventional case report. RESULTS: A 90-year-old white man with 4 previous corneal graft failures in his right eye is presented. His visual acuity was no light perception in the left eye subsequent to ocular trauma. His initial penetrating keratoplasty for pseudophakic bullous keratopathy was from a human leukocyte antigen-matched multiorgan donor who was CMV-seropositive. An anterior chamber paracentesis was performed to exclude an infective etiology. CMV was detected on PCR of aqueous humor. After a 12-week course of oral valganciclovir, a repeat aqueous PCR test confirmed the clearance of CMV. A corneal autograft from his left eye was subsequently performed with good outcome. CONCLUSIONS: We present a case of successful corneal autograft after clearance of CMV from the anterior chamber (PCR confirmed) in a patient treated with oral valganciclovir. PMID- 21673568 TI - Cyclosporine A 1% eye drops for the treatment of subepithelial infiltrates after adenoviral keratoconjunctivitis. AB - PURPOSE: To describe the use of cyclosporine A (CSA) 1% eye drops for the treatment of symptomatic corneal subepithelial infiltrates (SEI) occurring as a sequelae of adenoviral keratoconjunctivitis (AK) that are resistant to tapering of corticosteroid eye drops. METHODS: This is a retrospective case series of patients seen at 2 institutions who had symptomatic corneal SEI occurring after AK that was resistant to tapering of corticosteroid eye drops and who were subsequently treated with CSA 1%. Information gathered included basic demographic information (age and sex), involved eye(s), duration of symptoms, initial best spectacle-corrected visual acuity (BSCVA), type of corticosteroid used, clinical course, and best spectacle-corrected visual acuity at the last follow-up visit. RESULTS: Twelve eyes of 7 patients had symptomatic SEI develop after AK that were responsive to corticosteroid eye drops but were resistant to tapering. After the initiation of CSA eye drops, the corticosteroid eye drops could be tapered, and all eyes could be maintained on CSA eye drops once per day or less. Mean follow up time was 13.0 months (range, 4-28 months). CONCLUSIONS: CSA eye drops may be an effective corticosteroid-sparing agent for the treatment of SEI after AK. The use of CSA in this setting warrants further study. PMID- 21673569 TI - Corneal anesthetic abuse from the use of topical benzonatate (Tessalon Perle). PMID- 21673570 TI - Combined use of subconjunctival and intracorneal bevacizumab injection for corneal neovascularization. AB - PURPOSE: To report on the safety and clinical use of combined subconjunctival and intracorneal bevacizumab for corneal neovascularization. METHODS: The charts of 12 consecutive patients with corneal neovascularization who received combined subconjunctival and intracorneal injections of bevacizumab (2.5 mg/0.1 mL) were reviewed. Patients received 1 to 3 injections of 2.5 mg of bevacizumab (1.25 mg/0.05 mL subconjunctival and 1.25 mg/0.05 mL intrastromal). Morphological changes were assessed clinically by 1 investigator. RESULTS: Combined subconjunctival and intracorneal injections of bevacizumab were effective and well-tolerated. No significant ocular or systemic adverse events were observed during 6.4 months (range, 0.25-22 months) of follow-up. All patients showed a reduction in the neovascularized area. CONCLUSIONS: Short-term results suggest that combined subconjunctival and intracorneal injections of bevacizumab are an effective method for reducing corneal neovascularization. It may be a useful option or adjunct to other treatments in stabilizing or improving vision. PMID- 21673571 TI - Diet and halitosis. AB - PURPOSE OF REVIEW: The present article reviews the current knowledge of halitosis with particular emphasis upon the interplay of diet and disease of the gastrointestinal tract upon oral malodour. RECENT FINDINGS: Transient-altered breath smell usually reflects the effects of foodstuffs, whereas longstanding halitosis is almost always because of oral disease such as gingivitis or periodontitis. There is, however, increasing evidence that upper gastrointestinal tract disease may give rise to halitosis and that extracts of foodstuffs may be future therapeutic agents for the treatment of halitosis derived from the mouth or upper gastrointestinal tract. SUMMARY: There is some interplay between the halitosis and the gastrointestinal tract, and it is possible that the therapy of halitosis may be aided by investigations of the effects of foodstuffs upon bacteria that give rise to volatile sulphur compounds. PMID- 21673572 TI - Commensal bacteria: the link between IBS and IBD? AB - PURPOSE OF REVIEW: To review interactions between the microbiota and the host in irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), emphasizing areas of commonality and divergence. RECENT FINDINGS: Several lines of evidence support a role for the microbiota in the pathogenesis of IBS and IBD. Some implicate the microbiota in a general sense and relate to variations in the composition of the microbiota between IBS, IBD and controls; others relate to the ability of events and interventions that disrupt/modify the microbiota to predispose to the development of IBS and IBD and, others still refer to reports of the ability of antibiotics, prebiotics or probiotics, in selected circumstances, to beneficially alter their clinical course. Enthusiasm for a role for a specific organism in precipitating disease has been largely (and contentiously) linked to IBD. Many issues remain unresolved and must wait for the application of modern microbiological techniques to well characterized populations and well matched controls. SUMMARY: It makes sense, given the size and complexity of the microbiota and its role in homeostasis, that the microbiota and its interactions with the host would play a role in the pathogenesis of IBS and IBD; sorting out the details has proven challenging but does offer new therapeutic avenues for both disorders. PMID- 21673573 TI - Antimicrobial prophylaxis regimens following transplantation. AB - PURPOSE OF REVIEW: Infection remains a major cause of morbidity and mortality following transplantation, and antimicrobial prophylaxis regimens continue to improve. This review summarizes the important studies on prophylaxis following solid organ transplant (SOT) and hematopoietic stem cell transplantation (HSCT) published in the last 18 months. RECENT FINDINGS: Many transplant centers use 100 days of antivirals to prevent cytomegalovirus (CMV) disease after SOT. Randomized trials comparing 100-day regimens to 200 days in high-risk kidney recipients and 12 months in lung transplant patients showed distinct advantages of longer duration CMV prophylaxis. Prevention of hepatitis B virus after transplant is changing as regimens with low dose or no hepatitis B immunoglobulin are being evaluated. International consensus guidelines on the prevention of infection after stem cell transplantation are summarized and newer studies on the prevention of invasive fungal infection in this population are reviewed. SUMMARY: In organ transplantation, routine antibacterial, antiviral, and antifungal regimens need to be tailored to address donor-transmitted infections, serological risk status of recipients, and measurable antifungal drug levels. Recent studies indicate that longer duration prophylaxis for CMV may have advantages in high risk SOT recipients. After HSCT, regimens require adjustment based on immunological risks associated with transplant type and presence of graft vs. host disease. PMID- 21673574 TI - Imaging studies for diagnosing invasive fungal pneumonia in immunocompromised patients. AB - PURPOSE OF REVIEW: The aim is to review imaging advances in invasive fungal pneumonia in cancer and transplant recipients and how their use can help guide treatment. RECENT FINDINGS: Early chest computed tomographic (CT) imaging of immunocompromised patients with neutropenic fever leads to improved survival. Some of the typical CT findings of invasive fungal pneumonia are transitory and are most common during the first week of symptoms. The reversed halo sign, an early sign of disease, is more common in mucormycosis. During the first 10 days of infection, invasive fungal pneumonia nodules may grow on follow-up CT scans, but this does not necessarily equate to worsening disease. Because of the excessive radiation of chest CT and because pulmonary nodule size typically expands during the first few weeks of treatment, follow-up CT scans should be ordered only when therapy changes are dependent on imaging findings. SUMMARY: Early chest CT imaging in immunocompromised patients suspected of having invasive fungal pneumonia can help identify disease early, leading to improved outcome. PMID- 21673575 TI - Recent advances in systemic therapy for advanced endometrial cancer. AB - PURPOSE OF REVIEW: Endometrial cancer is the most common gynaecologic cancer in the western world. Systemic treatments for advanced disease have traditionally included hormonal therapy and chemotherapy. Responses to treatment are short lived and advanced-stage disease remains incurable. Recent research has focused on optimizing chemotherapy regimens, the development of alternative hormonal therapy strategies and the introduction of targeted therapies. The most recent developments in these areas will be reviewed here. RECENT FINDINGS: Phase III trials continue to focus on the optimization of combination chemotherapy regimens. The elucidation of a hormonal pathway central to the control of oestrogen-stimulated cancer growth has led to the development of a new class of hormonal agents currently undergoing evaluation in the clinical trial setting. Increasing understanding of the molecular basis for malignant transformation continues to provide rationale for the development of many targeted therapies. Mammalian target of rapamycin inhibition, in particular, offers further encouraging results in this context. SUMMARY: The development of new hormone treatments and effective targeted therapies will provide new opportunities to improve therapy for women with advanced endometrial cancer. Optimization of therapy will require an approach to personalized therapy in order to guide choice and sequence of therapy and improve survival and quality of life. PMID- 21673576 TI - Severe and polytraumatic injuries among recreational skiers and snowboarders: incidence, demographics and injury patterns in South Tyrol. AB - BACKGROUND: Alpine skiing and snowboarding are popular winter sports. The practice of these sports is related to traumatic injuries, some of which are severe and/or life threatening. OBJECTIVES: To identify the incidence, injury patterns and associated risk factors of severe and polytraumatic injuries in South Tyrol. MATERIALS AND METHODS: During four consecutive winter seasons (2001 2005), data of every patient referred to our emergency department (Bolzano-Bozen) after a skiing or snowboarding accident were collected. One hundred and five patients with an Injury Severity Score of 16 or higher were identified (90 skiers, 15 snowboarders). Statistical descriptive analyses were carried out by producing frequency tables. Chi-square test was performed to verify possible association between injury severity and type of sport. Risk factors for severe injuries were evaluated using logistic regression with robust variance estimators. RESULTS: Traumatic brain injury was the most common injury observed (51 cases), followed by vertebral injury (45 cases); 63% of the patients reported two or more associated injuries. We observed significant associations between severe spine injuries and the following risk factors: snowboarders who reported more severe injuries than skiers [odds ratio=5.89, 95% confidence interval (CI)=1.31, 26.44], age classes of 40-50 years and over 60 years showed an OR of 8.10 (95% CI=1.87, 35.06) and 5.16 (95% CI=1.27, 21.01), respectively, with respect to age class (20-40 years). CONCLUSION: Severe traumatic injuries occur among skiers and snowboarders, and preventive measures such as the use of helmets and educational programs, are necessary. PMID- 21673577 TI - A health insurance company-initiated practice support intervention for optimizing acid-suppressing drug prescriptions in primary care. AB - BACKGROUND: A health insurance-initiated programme to improve cost-effectiveness of acid-suppressing drugs (ASDs). AIM: To evaluate the effect of two different interventions of general practitioner support in reducing drug prescription. MATERIALS AND METHODS: A sequential cluster randomized controlled trial with 90 participating general practitioners in a telephone support (TS) group or practice visit (PV) group. TS group received support in phase-1 (first 6 months), but served as control group in phase-2 (6-12 months period). PV group received no intervention in phase-1, serving as the control group for the TS group, but received support in phase-2. Prescription data were extracted from Agis Health Insurance Database. Outcomes were the proportion of responders to drug reduction and the number of defined daily dose (DDD). Differences in users and DDD were analysed using multilevel regression analysis. RESULTS: At baseline, 3424 patients used ASD chronically (211 DDDs, on average). The difference between TS and control groups among responders was 3.2% [95% confidence interval (CI): 0.8; 5.6] and relative risk was 1.26 (95% CI: 1.06; 1.51). The difference between PV and control groups was not relevant (0.4%, 95% CI: -1.99; 2.79 and relative risk: 1.01, 95% CI: 0.82; 1.20). The difference in DDD per patient was -3.0 (95% CI: 8.9; 2.9) and -5.82 (95% CI: -12.4; 0.73), respectively. CONCLUSION: This health insurance company-initiated intervention had a moderate effect on ASD prescription. In contrast to TS, PVs did not seem to reduce ASD prescription rates. PMID- 21673578 TI - Storage and use of residual newborn screening blood spots: a public policy emergency. PMID- 21673579 TI - Family-provider interactions surrounding the diagnosis of Down syndrome. PMID- 21673580 TI - Technical standards and guidelines for spinal muscular atrophy testing. AB - Spinal muscular atrophy is a common autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. The disease is characterized by progressive symmetrical muscle weakness resulting from the degeneration and loss of anterior horn cells in the spinal cord and brainstem nuclei. The disease is classified on the basis of age of onset and clinical course. Two almost identical SMN genes are present on 5q13: the SMN1 gene, which is the spinal muscular atrophy-determining gene, and the SMN2 gene. The homozygous absence of the SMN1 exon 7 has been observed in the majority of patients and is being used as a reliable and sensitive spinal muscular atrophy diagnostic test. Although SMN2 produces less full-length transcript than SMN1, the number of SMN2 copies has been shown to modulate the clinical phenotype. Carrier detection relies on the accurate determination of the SMN1 gene copies. This document follows the outline format of the general Standards and Guidelines for Clinical Laboratories. It is designed to be a checklist for genetic testing professionals who are already familiar with the disease and methods of analysis. PMID- 21673582 TI - Emergency preparedness for genetics centers, laboratories, and patients: the Southeast Region Genetics Collaborative strategic plan. AB - Emergencies occur unpredictably and interrupt routine genetic care. The events after hurricanes Katrina and Rita have led to the recognition that a coherent plan is necessary to ensure continuity of operations for genetic centers and laboratories, including newborn screening. No geographic region is protected from the effects of a variety of potential emergencies. Regional and national efforts have begun to address the need for such preparedness, but a plan for ensuring continuity of operations by creating an emergency preparedness plan must be developed for each genetic center and laboratory, with attention to the interests of patients. This article describes the first steps in development of an emergency preparedness plan for individual centers. PMID- 21673581 TI - Consideration of patient preferences and challenges in storage and access of pharmacogenetic test results. AB - PURPOSE: Pharmacogenetic testing is one of the primary drivers of personalized medicine. The use of pharmacogenetic testing may provide a lifetime of benefits through tailoring drug dosing and selection of multiple medications to improve therapeutic outcomes and reduce adverse responses. We aimed to assess public interest and concerns regarding sharing and storage of pharmacogenetic test results that would facilitate the reuse of pharmacogenetic data across a lifetime of care. METHODS: We conducted a random-digit-dial phone survey of a sample of the US public. RESULTS: We achieved an overall response rate of 42% (n = 1139). Most respondents indicated that they were extremely or somewhat comfortable allowing their pharmacogenetic test results to be shared with other doctors involved in their care management (90% +/- 2.18%); significantly fewer respondents (74% +/- 3.27%) indicated that they were extremely or somewhat comfortable sharing results with their pharmacist (P < 0.0001). CONCLUSION: Patients, pharmacists, and physicians will all be critical players in the pharmacotherapy process. Patients are supportive of sharing pharmacogenetic test results with physicians and pharmacists and personally maintaining their test results. However, further study is needed to understand which options are needed for sharing, appropriate storage, and patient education about the relevance of pharmacogenetic test results to promote consideration of this information by other prescribing practitioners. PMID- 21673583 TI - Automatic exposure control in pediatric and adult computed tomography examinations: can we estimate organ and effective dose from mean MAS reduction? AB - OBJECTIVES: : The purpose of this study was (i) to measure absorbed dose to radiosensitive organs and estimate the effective dose associated with fixed tube current and automatic exposure control (AEC)-activated standard computed tomography (CT) examinations, and (ii) to investigate the relationship between the average reduction of tube current achieved by AEC and the reduction in organ and effective dose. MATERIALS AND METHODS: : Four physical anthropomorphic phantoms that represent the average individual as neonate, 1-year-old, 5-year old, 10-year-old child, and the Rando phantom that simulates the average adult individual were employed. The phantoms were subjected to standard head and neck, thorax, and abdomen and pelvis scans using a 16-slice CT system. The scans were performed both with fixed tube current and with AEC. Dose measurements were performed for each scan using thermoluminescent dosimeters placed at internal locations in the phantoms and on the phantoms' surface. Dose measurements were performed for all radiosensitive organs according to the 2007 recommendations of the International Commission on Radiologic Protection. Effective dose was estimated on the basis of weighted sum of measured organ absorbed doses (EDMEAS). Percent reduction of organ absorbed dose and effective dose were compared with the mean percent reduction of the tube current. RESULTS: : The percent organ dose reduction achieved when AEC was activated in standard head and neck CT scans ranged from 26.6% to 42% for neonate, 8.1% to 63.8% for 1-year-old, -2.9% to 22.5% for 5-year-old, -8.7% to 44.9% for 10-year-old, and 16.3% to 50.1% for an adult. The corresponding values for thorax scans were found to range from -26.1% to 9.9% for neonate, -2.5% to 37.7% for 1-year-old, -20.8% to 15.4% for 5-year old, -61.9% to 9.3% for 10-year-old, and 5.6% to 42.2% for an adult, whereas the corresponding values for abdomen and pelvis scans were found to range from -12.1% to 29.1% for neonate, -4.9% to 26.6% for 1-year-old, -11.7% to 38.9% for 5-year old, -62.4% to -17.3% for 10-year-old, and 31.0% to 56.8% for an adult. In neonate, the EDMEAS values ranged from 1.18 to 3.23 mSv for fixed tube current and 1.31 to 1.73 mSv for AEC scans. In 1-year-old phantom, the EDMEAS values ranged from 1.71 to 2.82 mSv for fixed tube current and 0.99 to 2.38 mSv for AEC scans. In 5-year-old phantom, the EDMEAS values ranged from 2.03 to 3.72 mSv for fixed tube current and 1.57 to 3.35 mSv for AEC scans. In 10-year-old phantom, the EDMEAS values ranged from 1.56 to 2.88 mSv for fixed tube current and 1.63 to 3.14 mSv for AEC scans. In adult phantom, the EDMEAS values ranged from 3.39 to 8.06 mSv for fixed tube current and 2.28 to 3.83 mSv for AEC scans. Mean mAs reduction is linearly related to the EDMEAS reduction (r = 0.807, P < 0.0001). The absolute percent difference between percent tube current and %EDMEAS reduction was in most cases higher than 15%. CONCLUSIONS: : The reduction in the modulated tube current achieved by AEC should not be used to estimate the reduction in the absorbed dose to exposed radiosensitive organs. Moreover, the reduction in the modulated tube current may only be considered as a rough approximation of the corresponding effective dose reduction. PMID- 21673584 TI - Questionnaire study about the practice of electroconvulsive therapy in Norway. AB - OBJECTIVES: The aim of the study was to describe the contemporary practice of electroconvulsive therapy (ECT) in Norway. METHODS: A 42- item questionnaire on the practice of ECT was sent to all the 125 Norwegian psychiatric hospitals, district psychiatric centers, and child and adolescent psychiatric units in 2004. RESULTS: A total of 67 (54%) psychiatric units responded, including 26 (67%) of 39 psychiatric hospitals, 32 (46%) of 69 district psychiatric centers, and 9 (53%) of 17 child and adolescents units. Trainee psychiatrists mostly administered ECT, with or without supervision, but underwent a training program before administering ECT. Written informed consent was used in 50% of institutions providing ECT. Right unilateral electrode placement was preferred but with variations in dosage strategies. The practice in most of the departments was to discontinue some classes of psychotropics before ECT, mostly benzodiazepines and anticonvulsants. Antidepressants and antipsychotics were most often continued. Continuation/maintenance and ambulatory ECT were used. Most patients benefited from ECT. Headache and memory impairment were frequent but seldom were serious adverse effects. CONCLUSIONS: The administration of ECT in Norway in 2004 was mostly in accordance with international guidelines. All institutions used modified ECT and brief pulse machines, and unilateral ECT was the preferred electrode placement. National guidelines should be developed, as there were great variations in practice among the hospitals. PMID- 21673585 TI - Predictors of bradycardia during the stimulation phase of electroconvulsive therapy. AB - OBJECTIVE: Temporary asystole can be detected at various time points during electroconvulsive treatment. We carefully monitored and documented its incidence during stimulation to evaluate currently known and assumed predictors. METHOD: All treatments over a 20-month period in 2 separate institutions were recorded prospectively. Data from 119 patients comprising 720 treatments were suitable for multiple regression analysis. RESULTS: Electrode placement was the most influential determinant. Treatment series using right unilateral placement (64 patients and 291 traces) produced a mean (SD) asystole duration of 5.64 (2.88) seconds (range, 1.21-11.20 seconds), compared to a duration of 0.80 (0.21) seconds (range, 0.47-1.71 seconds) in bifrontal series (55 patients, 429 traces). Multiple regression analysis showed no independent effect of body weight, age, beta-blocker medication, or preexisting heart block. Stimulus dose and succinylcholine dose had no influence in univariate analyses. Cardiac action in bifrontal treatment series was highly predictable using baseline values. During unilateral stimulation, between-subject differences accounted for 79% of the observed variation. CONCLUSIONS: The heart rate during stimulation depends mainly on electrode positioning. A yet unidentified, probably constitutional factor is responsible for the broad range of asystole duration brought about by right unilateral electrode placement. Any assessment using interindividual analysis will therefore be biased as long as that factor remains unknown. PMID- 21673586 TI - Catatonia among adolescents with Down syndrome: a review and 2 case reports. AB - Catatonia is a relatively common condition with an estimated prevalence of 0.6% to 17% among youth with psychiatric disorders. Certain patient groups, such as those with autism, may be at a particularly high risk for catatonia. Most of the youth with catatonia are males with a diagnosis of a bipolar disorder. We describe here 2 adolescent females, both with Down syndrome, who presented with catatonia not accompanied by significant affective or psychotic symptoms or with a general medical condition. Both patients had functioned well until the onset of catatonic symptoms. In the current classification system used in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, catatonia is described in association with schizophrenia, as a specifier of affective disorders or secondary to general medical conditions. The cases described here highlight the problem with this classification system when patients fail to meet any of the 3 diagnostic categories under which catatonia is currently described. PMID- 21673587 TI - Takotsubo cardiomyopathy after electroconvulsive therapy: a case report and review. AB - Takotsubo cardiomyopathy (TCM) is a syndrome of reversible stress-induced cardiomyopathy associated with profound emotional stress and a variety of medical illnesses and procedures, including electroconvulsive therapy (ECT). We describe 1 case of ECT-induced TCM followed by a successful retrial of ECT. We further discuss the management of ECT-induced TCM and the decision to perform a second trial of ECT in patients with this complication. Given the current understanding of the pathogenesis of TCM, it is appropriate to discontinue ECT during the acute setting of TCM. After the resolution of the acute episode of TCM, a second trial of ECT may be warranted depending on the severity of psychiatric illness (ie, suicidal ideation, catatonia, psychotic symptoms). If a retrial of ECT is performed, oral and intravenous beta-blockers should be used for cardioprotection, and patients should be monitored for signs and symptoms of an evolving cardiomyopathy. It is preferable to perform retrials of ECT-at least initially-in a general hospital setting, where immediate invasive monitoring and intensive treatments are available in the event of acute cardiac failure. PMID- 21673588 TI - Anesthesia for electroconvulsive therapy in early pregnancy. AB - Pharmacological treatment of major psychiatric conditions (eg, schizophrenia, bipolar disorder) is exceptionally difficult during pregnancy. Despite all efforts, medication-resistant life-threatening mental deterioration can emerge with the urgent need for rapid and effective intervention. In these cases, electroconvulsive therapy (ECT) may represent the only valid and safe therapeutic option. Here, we present the challenging medical case of a 31-year-old primigravida with a general medical history of obesity and hypertension, previously diagnosed with bipolar affective disorder, now presenting with severe, therapy-resistant manic agitation. Full symptomatic remission was achieved and preserved with ECT given between the 7th and 22nd gestational weeks, the pregnancy reached full term, and a healthy child was born by cesarean delivery performed because of preeclampsia. Although it is unusual to start ECT this early in pregnancy, with the thorough assessment of potential risk factors and preventive measures taken, it can be the most effective and presumably the least risky treatment approach. By delineating key aspects of both the psychiatric and anesthetic management of this case, we aim to highlight the importance of a close cooperation between all medical fields involved in clinical practice. PMID- 21673589 TI - Remifentanil: a review of its use in electroconvulsive therapy. AB - OBJECTIVE: The primary objectives were to review studies that used remifentanil in electroconvulsive therapy (ECT) and to determine whether remifentanil has potential advantages over other anesthetics. MATERIALS AND METHODS: The author reviewed 12 original studies obtained through a MEDLINE database search that examined remifentanil as an anesthetic in patients receiving ECT. RESULTS: Remifentanil was associated with longer seizure durations when used as the sole anesthetic or as an adjunct when the primary anesthetic dose was lowered. Individual studies reported higher postictal suppression index and lower initial seizure thresholds and less rise in seizure thresholds with remifentanil. Data on hemodynamic effects were mixed but suggested favorable effects with remifentanil when seizure duration was not prolonged. CONCLUSIONS: Studies support the use of remifentanil in ECT, particularly in patients with brief seizures, high seizure thresholds, and postictal hemodynamic instability. Broad variability in study design, selection and dosing of anesthetics, electrode placement, and limited examination of potentially relevant variables such as age, sex, concomitant medications; and stimulus parameters attenuate the certainty of these results. Advantages in safety and efficacy over other anesthetics remain undetermined. Further study of remifentanil in ECT is warranted, given the methodological limitations and exclusion of important outcomes in the current literature. PMID- 21673590 TI - Comparison of electroconvulsive therapy practice between London and Bengaluru. AB - OBJECTIVE: To compare electroconvulsive therapy (ECT) practice between London in the United Kingdom and Bengaluru in India. METHODS: A retrospective case note study was conducted to compare patterns of referrals for ECT in university teaching hospitals in London (n = 46) and Bengaluru (n = 345) during a 1-year period. Further comparison of ECT practice was made for a consecutive series of depressed patients between London (n = 104) and Bengaluru (n = 125). RESULTS: The rates of ECT referral were 0.9% of total annual admissions at the London site and 8.2% at the Bengaluru site. At the Bengaluru site, a higher proportion of patients were referred for ECT with a diagnosis of schizophrenia (P < 0.0001). Compared to the Bengaluru sample, depressed patients treated with ECT in London (n = 104) were older with more treatment resistance (P < 0.0001), had longer inpatient stays, and were less responsive to ECT. CONCLUSIONS: The practice of ECT differed substantially between the London and Bengaluru sites. The relatively limited use of ECT in London reflects local treatment guidelines and may reflect the stigma associated with ECT. Electroconvulsive therapy is more widely used in Bengaluru with good outcomes. Further cross-cultural research is required to study the reasons for such contrasting practices and what constitutes the optimal practice of ECT for health systems in different countries. PMID- 21673591 TI - Electroconvulsive therapy and melancholia: review of the literature and suggestions for further study. AB - It has long been lore in the electroconvulsive therapy (ECT) field that melancholic depression is particularly responsive to ECT, whereas nonmelancholic depressions are less so. Early large case series in the 1940s and 1950s, while using now outdated diagnostic nosologies, did provide some hints to the particular efficacy of what later on would be considered melancholic or endogenous depression. The first systematic studies of this subject in the 1950s and 1960s seemed to confirm the superior response of endogenous depression to ECT. However, with the advent of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, and the first criterion set specifically labeled "melancholia," most modern series of studies have failed to find an association of melancholic symptoms with ECT response. Several problems both with the definition of melancholia and the modern methods of diagnosis and outcome assessment are hypothesized to be at the root of the negative findings of modern studies. Suggestions for future ECT/melancholia studies are offered. PMID- 21673593 TI - The effect of learning curve on the surgical outcome of viscocanalostomy. AB - PURPOSE: To evaluate the influence of learning curve on the surgical outcome of viscocanalostomy. METHODS: Retrospective, interventional study. Chart review of the first consecutive open-angle glaucoma cases that received viscocanalostomy in 1 institution between July 1996 and June 2000. Overall success was defined as no visual field deterioration; postoperative intraocular pressure (IOP) <=20 mm Hg; and IOP reduction >=30% compared with baseline values with or without medication. When medications were not required, success was defined as complete. Demographic, procedural, and postoperative data were tabulated and analyzed. PRIMARY OUTCOME MEASURES: overall and complete success rates. SECONDARY OUTCOME MEASURES: number of glaucoma medications and surgical complications. RESULTS: A total of 180 cases were analyzed. Mean follow-up (+/-SD) was 28.9+/-5.9 months (range, 12-36 mo). Overall success has significantly improved from 64% to 91% when comparing the first 45 to the last 45 cases of the series (Mantel-Cox, P=0.005). Similarly, complete success has significantly improved from 38% to 73% (Mantel-Cox, P=0.004). The mean number of glaucoma medication (+/-SD) significantly decreased from 2.58+/-0.94 before surgery to 0.53+/-0.79 after surgery (Wilcoxon, P<0.001). Surgical complications decreased from 16 in the first 45 cases to 10 in the last 45 cases without reaching statistical significance (Pearson chi, P=0.315). CONCLUSIONS: Viscocanalostomy appears to safely reduce IOP in cases with medically uncontrolled open-angle glaucoma. Mastering viscocanalostomy procedure is achievable after the first 40 cases. PMID- 21673592 TI - Elevation of intraocular pressure in glaucoma patients after automated visual field testing. AB - PURPOSE: To examine whether automated visual field (VF) testing may exert a short term influence on subsequent intraocular pressure (IOP) measurement during the same visit. METHODS: We reviewed patients with primary open-angle glaucoma whose most recent visit occurred at a major academic institution from July to December 2009 and who had 3 visits without intervening changes in glaucoma management within the previous 5 years. Exclusion criteria were patient admittance of nonadherence with medical therapy and documented difficulty of IOP measurement. One hundred nine right eyes from 109 patients were included. IOP obtained within 30 minutes after VF testing was compared with IOP from the previous and next visits without VF testing. Subgroup analyses included the role of reliability of VF test performance, surgical versus medical IOP control, and different topical medications. RESULTS: The average IOP measured after VF testing was 14.9 +/- 4.7 mm Hg, higher than both the previous (13.7 +/- 4.4 mm Hg, P < 0.001) and next visits without VF examination (13.8 +/- 4.4 mm Hg, P < 0.001). A total of 22.9% of patients experienced a more than 20% increase of IOP. Eyes with surgical control had less IOP elevation than eyes with medical control (3.1% +/- 15.9% vs. 11.7% +/- 17.4%, P = 0.009). Users of beta-blockers or alpha-2-agonists had less IOP elevation than eyes controlled with prostaglandins or carbonic anhydrase inhibitors (0.9% +/- 15.1% vs. 9.0% +/- 12.3%, P = 0.030). CONCLUSIONS: This retrospective study suggests that patients with primary open-angle glaucoma experience a small and transient increase in IOP after VF testing and that this effect may be lower after surgical pressure control. PMID- 21673594 TI - Surgical results of Ahmed valve implantation with intraoperative bevacizumab injection in patients with neovascular glaucoma. AB - PURPOSE: To investigate the surgical results of Ahmed valve implantation with intraoperative bevacizumab injection in patients with neovascular glaucoma (NVG). METHODS: A retrospective comparative case series review was conducted on 52 eyes with NVG who underwent Ahmed glaucoma valve implantation with or without intraoperative bevacizumab intravitreal injection. In the intraoperative intravitreous bevacizumab injection group (IVB group, 20 eyes), 1.25 mg of bevacizumab was injected into the vitreous cavity during Ahmed valve implantation. In the control group (32 eyes), only Ahmed valve implantation was performed. Surgical failure was defined when (1) the postoperative intraocular pressure was over 21 mm Hg at consecutive clinic visits, (2) the visual acuity became light perception negative, (3) additional antiglaucomatic surgery was required, or (4) devastating operative or postoperative complications were noted. RESULTS: Although the success rate in the IVB group (70.0%) was higher than that in the control group (62.5%) 1 year after operation, the differences were not statistically significant (P=0.828 by log-rank test). Mean intraocular pressures in the IVB group were significantly lower than those of the control group at 12 and 15 months (P<0.05 by the Mann-Whitney U test). Postoperative complications were similar between the 2 groups. Preoperative history of trabeculectomy was a significant risk factor for surgical failure of Ahmed valve implantation in NVG (relative risk=4.618; P=0.018 by Cox regression model). CONCLUSIONS: Intraoperative IVB injection does not seem to be helpful for better surgical outcomes of Ahmed valve implantation in NVG. A history of trabeculectomy is a risk factor for failure after Ahmed valve implantation in patients with NVG. PMID- 21673595 TI - Angle closure in Caucasians--a pilot, general ophthalmology clinic-based study. AB - PURPOSE: To assess the rate of clinically significant angle closure in a predominantly Caucasian, clinic-based population, and consequently find out whether gonioscopy should be included in the routine ophthalmic examination. METHODS: Patients aged >=40 years with hyperopia >=1 D were consecutively recruited in a community general ophthalmology clinic. Detailed darkroom gonioscopy was done, and primary angle closure was diagnosed if there was iridotrabecular apposition >180 degrees not secondary to an identifiable ocular disorder. Biometric parameters were measured and compared between the eyes with and without angle closure. RESULTS: Eighty-four eyes from 84 patients (aged 61.3+/-8.9 y) were enrolled. There were 52 female (62%) and 32 male. Fourteen patients (16.7%) were diagnosed with angle closure. A statistically significant difference was observed between the eyes with and without angle closure in mean axial length (22.07+/-0.72 vs. 22.61+/-0.97, P=0.028), anterior chamber depth (ACD) (2.45+/-0.33 vs. 2.89+/-0.32, P<0.001), and lens thickness (4.97+/-0.3 vs. 4.62+/-0.4, P=0.002). Degree of hyperopia was marginally significant (3.13+/-2.3 vs. 2.45+/-1.5, P=0.09). In a logistic regression model, only ACD remained statistically significantly different (P=0.016). We tested the ability of ACD to distinguish eyes with angle closure. The area under the receiver operating characteristic curve was 0.824; using a cutoff ACD value of 2.65 mm, sensitivity was 0.786 with a specificity of 0.812. CONCLUSIONS: Clinically significant angle closure, mandating close follow-up or preventive procedures, may be more common in Caucasians than currently thought. We recommend that gonioscopy should be included in the routine ophthalmic examination of all adults with hyperopia. PMID- 21673596 TI - Comparing stereometric parameters between Heidelberg Retinal Tomography 2 and 3 in Asian eyes: the Singapore Malay Eye Study. AB - PURPOSE: To examine the correlation and agreement of stereometric parameters between Heidelberg Retinal Tomograph version 2 (HRT-2) and HRT-3 in a normal Asian population. METHODS: This was a population-based study using data from the Singapore Malay Eye Study. Participants underwent a standardized and complete ophthalmic examination. A confocal laser ophthalmoscope using HRT-2 was used to take retinal images by 2 trained operators. Disc contours were drawn by a single experienced ophthalmologist. Without modifying the contours, the exact images were then exported and analyzed with HRT-3 software. Paired t tests were used to compare mean differences, whereas interclass correlations and Bland-Altman plots were used to assess agreement and trend of Moorfields regression analysis parameters between HRT-2 and HRT-3. RESULTS: A total of 2960 Malay participants [mean age, 58.3 y (SD 10.9); 50.5% female] were included. Average disc size was 2.15 MUm. Interclass correlations and Bland-Altman plots showed good agreement between HRT-2 and HRT-3. However, global disc area, rim area, cup area, cup-disc area ratio, rim-disc area ratio, and rim volume were significantly different between HRT-2 and HRT-3, with all area and rim volume measurements using HRT-2 were approximately 4% larger compared with HRT-3. Analysis of HRT-2 and HRT-3 parameters from different sectors of the scans showed an inconsistent change in measurement values. Cup shape measurement was significantly different in the temporal region compared with the nasal region of the optic nerve head. CONCLUSIONS: There was good correlation between the 2 HRT versions and conversion equations were possible to calibrate HRT-3 parameters from HRT-2 measurements in Asian eyes. However, HRT-2 and HRT-3 showed significant differences in stereometric parameters. Further studies are needed to determine the impact of such differences and in comparative accuracy of HRT-2 versus HRT-3 for diagnosis and monitoring of glaucoma. PMID- 21673597 TI - Surgical management of glaucoma with Molteno3 implant. AB - PURPOSE: To evaluate the outcome of 40 consecutive patients with Molteno3 implantation in uncontrolled glaucoma with at least a 6-month follow-up. MATERIALS AND METHODS: Nonrandomized, interventional, and retrospective clinical study. Failure was defined as IOP >21 mm Hg or less than 20% reduction of intraocular pressure (IOP) from baseline on 2 consecutive follow-up visits, IOP <=5 mm Hg on 2 consecutive follow-up visits, reoperation of glaucoma or loss of light perception vision. RESULTS: The mean preoperative IOP was 34.3+/-9.1 mm Hg, and the mean postoperative IOP at the last follow-up visit was 16.8+/-7.5 mm Hg with a pressure drop of 19.1+/-11.5 mm Hg (56%) (P=0.000; 95% CI 13.5-21.4). The Kaplan-Meier life-table analysis showed a 95% success rate after 6 months and a 71% success rate after 12 months of follow-up. Postoperative complications included cataract (6 eyes), choroidal detachment (3 eyes), flat anterior chamber (2 eyes), malignant glaucoma (2 eyes), encapsulated bleb (2 eyes), corneal decompensation (2 eyes), hyphaema (1 eye), uveitis (1 eye), retinal detachment (1 eye), suprachoroidal hemorrhage (1 eye), tube erosion (1 eye), and phthisis bulbi (1 eye). CONCLUSION: The Molteno3 dual-chamber implant is useful and well tolerated in controlling IOP, but it does not seem to reduce the risk of postoperative hypotony. PMID- 21673598 TI - Aqueous shunt exposure: a retrospective review of repair outcome. AB - PURPOSE: To describe the patient outcomes and factors affecting those outcomes after aqueous shunt exposure repair. PATIENTS AND METHODS: Forty-three eyes from Robert Cizik Eye Clinic and Bascom Palmer Eye Institute from 1995 to 2007 suffered from aqueous shunt exposure and were repaired by participating surgeons. Thirty-three were tube exposures and 7 were plate exposures. The remaining 3 exposure classified complications included a patch graft exposure, an elbow exposure, and 1 unknown complication. Forty eyes were followed for evidence of additional aqueous shunt exposures or additional surgical interventions for 46.6 weeks (40.2 wk) (range: 3 to 168 wk). RESULTS: Seventeen of 40 eyes required additional surgical intervention: 15 (45%) from the tube exposure group and 2 (29%) from the plate exposure group. Five (13%) eyes needed eventual removal of the shunt. Black race, diabetes mellitus, a high number of glaucoma medications before shunt implantation, a history of multiple glaucoma laser procedures, and combination of an initial aqueous shunt implantation with another surgery were found to be associated with a worse outcome after exposure repair. CONCLUSIONS: Intraocular pressure, number of medications, and visual acuity remained stable during follow-up after revision. Diabetes mellitus was associated with a shorter average time between initial repair and reintervention, and 4 other variables were associated with a higher likelihood of reintervention. PMID- 21673599 TI - Determinants of long-term intraocular pressure after phacoemulsification in primary angle-closure glaucoma. AB - AIMS: To determine the preoperative factors associated with long-term intraocular pressure (IOP) after cataract surgery in primary angle-closure glaucoma (PACG). METHODS: The data of 56 PACG patients who had undergone phacoemulsification consecutively were analyzed after detailed chart review. The associations between postoperative IOP and various preoperative factors were determined by multivariate linear regression analyses. RESULTS: The mean postoperative follow up was of 33.0+/-13.6 months. The postoperative IOP decreased (P<0.05 at each visit) from the preoperative level over the years, with a mean percent reduction of 20%. Glaucoma medication number also reduced significantly, except at month 30 (P=0.088), 36 (P=0.585), and 48 (P=0.104). Preoperative factors of higher IOP (P<0.001) and deeper anterior chamber depth (ACD) (P=0.006) were associated with higher postoperative IOP over the years. The multiplication product IOP*ACD accounted for 49% of the IOP variations 1 year after surgery, and eyes with this index less than or equal to 35 were more likely to achieve postoperative IOP readings of less than or equal to 12 mm Hg (odds ratio, 9.2, P=0.001) than those with an index more than 35. CONCLUSIONS: Long-term IOP after phacoemulsification in PACG is positively associated with preoperative IOP and preoperative ACD. PMID- 21673600 TI - Pathomechanical significance of radial head subluxation in the onset of osteochondritis dissecans of the radial head. AB - Osteochondritis dissecans of the elbow mainly involves the capitellum; however, no authors have reported the condition in the radial head with subluxation of the radial head. We report four cases in which osteochondritis dissecans involved the radial head and was accompanied by radial head subluxation. All patients were male and their ages ranged from 11 to 13 years (average, 11.8 years). All lesions were located at the posteromedial aspect of the radial head with anterior subluxation of the radial head. Fragment removal was performed in one case and ulnar osteotomy in two cases; the remaining case was treated conservatively with the prohibition of sports. Three cases had a good outcome, whereas obvious anterior subluxation of the radial head and limitation of elbow flexion remained in the case treated with fragment removal. PMID- 21673601 TI - The results of nonoperative treatment for three- and four-part fractures of the proximal humerus in low-demand patients. AB - OBJECTIVE: To evaluate the results of nonoperative treatment of three- and four part fractures of the proximal humerus in patients who refused surgery or could not undergo surgery because of medical conditions. DESIGN: Retrospective evaluation of prospective collected data. SETTING: Educational and research hospital. Level IV, therapeutic case series. PATIENTS: Eighteen patients (eight three- and 10 four-part fractures) were included. The mean age was 68.2 +/- 13.8 years (range, 39-90 years). The mean follow-up was 39.1 +/- 12.4 months (range, 24-60 months). Patients were grouped into two: Group A being younger than 65 years and Group B 65 years or older. INTERVENTION: Standardized nonoperative treatment and follow-up protocols were used. MAIN OUTCOME MEASUREMENTS: Functional and radiographic assessments were performed in posttreatment first year and at latest follow-up. Constant-Murley scores were also obtained for both shoulders. RESULTS: The mean Constant-Murley score was 61.3 +/- 13.5 (range, 40 85) at latest follow-up. Osteonecrosis was detected in five patients. All patients had significantly lower SF-36 scores for all subscales except mental health than the normal Turkish population. There was no significant difference between three- and four-part fractures regarding age and Constant-Murley scores. The mean Constant-Murley score of the Group A patients with three-part fractures was significantly higher when compared with the Group A patients with four-part fractures. There was no significant difference between patients with and without osteonecrosis regarding fracture types or the Constant-Murley scores at the latest follow-up. CONCLUSIONS: Although the individual fracture type does not have an influence on functional results, these results are better in patients younger than 65 years with three-part fractures. The results of the nonoperative treatment of these fractures are satisfactory even in elderly patients. The radiographic appearances did not correspond with the functional results. PMID- 21673602 TI - An open-label, multicenter, three-stage, phase II study of s-1 in combination with cisplatin as first-line therapy for patients with advanced non-small cell lung cancer. AB - INTRODUCTION: S-1 is a rationally designed oral agent that combines the 5 fluorouracil prodrug tegafur with gimeracil and oteracil, which inhibit 5 fluorouracil degradation by dihydropyrimidine dehydronase and phosphorylation within the gastrointestinal tract, respectively, to increase antineoplastic activity while reducing gastrointestinal toxicity. We investigated the activity and toxicity of S-1 in combination with cisplatin in patients with unresectable non-small cell lung cancer (NSCLC). METHODS: Cisplatin, 75 mg/m, was administered intravenously on day 1, with S-1, 25 mg/m PO two times a day, days 1 to 14, every 21 days for a maximum of six cycles. Primary end point was overall response. RESULTS: A total of 58 patients received at least one cycle of protocol-specified therapy. The best overall response rate was 23.2% (95% confidence interval: 13.0 36.4), and the disease control rate was 67.9%. The median progression-free survival was 4.0 months (95% confidence interval: 3.3-5.5). There did not appear to be any relationship between response to therapy and tumor histology. The most frequently reported adverse events of G3 or more (>=10%) were neutropenia (28%), hyponatremia (19%), diarrhea (17%), hypokalemia (12%), fatigue (10%), dehydration (10%), and deep vein thrombosis (10%). CONCLUSIONS: Although the S-1 + cisplatin regimen used in this study appeared to have a similar level of antitumor activity and toxicity to that of established cisplatin-based doublets in NSCLC, the protocol-specified criteria of sufficient efficacy to warrant further study with an objective response rate >=30% was not achieved. Therefore, while S-1 appears to be a promising agent in NSCLC, further evaluation should be conducted to determine the optimal S-1-based regimen to take forward for additional study. PMID- 21673603 TI - Multimodality approach to the sentinel node: an algorithm for the use of presentinel lymph node biopsy ultrasound (after lymphoscintigraphy) in conjunction with presentinel lymph node biopsy fine needle aspiration cytology. AB - In a recent article by Lam et al. describing the experience of the Sydney Melanoma Unit, a novel term called 'multimodality approach' to the sentinel node (SN) was applied. However, the timing of the use of the tools available in the presented cases should be discussed. An algorithm of which time to use, which tool to detect the correct SN by preoperative ultrasound (US) in combination with an US-guided fine needle aspiration cytology (FNAC) will be proposed and demonstrated using five clinical examples. All examples prove the advantage of a combined strategy to track down the correct and involved SN. A sensitive US power mode, for the amplification of even the slightest changes in vascularization, is the most important tool in our diagnostic preoperative approach. First, reliable US criteria, as recently published must consequently be applied. Second, a FNAC should be performed early enough, even when only early signs are visible. Third, a swift overnight cytology before sentinel lymph node biopsy should be available. US is a method for the early detection of clinically nonevident metastases. Using the proposed algorithm when to perform which part of the multimodality approach, we demonstrated the enormous information out of additionally performed US. In the case of a suspicious US finding, we always perform a FNAC of the node. In the event of a negative finding, the SLND will take place as scheduled. In the case of a positive finding, the patient can directly undergo completion lymph node dissection. PMID- 21673605 TI - Aversive faces activate pain responsive regions in the brain. AB - Recent evidence points to an overlap in the neural systems processing pain and social distress. In this functional MRI study we focus on the possible interplay between the processing of a psychosocial stressor and somatic pain within pain responsive brain regions, the latter being identified in an independent localizer experiment. A paradigm based on emotional induction (Hariri et al., 2000, Neuroreport 11(1):43-48) was combined with moderate heat pain to yield a factorial design with factor 'pain' as somatic stressor and factor 'faces' as nonpainful psychosocial stressor. Pain responsive regions of interest in the insula, SII cortex, and thalamus were activated by the factor 'faces' to a various extent. The hemodynamic response to both factors tends to aggregate in a compressive manner in these regions. PMID- 21673604 TI - Changes in the gene expression profile of A375 human melanoma cells induced by overexpression of multifunctional pigment epithelium-derived factor. AB - Pigment epithelium-derived factor (PEDF) is a broad-spectrum angiogenesis inhibitor that displays potent antimetastatic activity in multiple tumor types. We have previously shown that PEDF prevents primary tumor growth and metastatic spread of human melanoma in mouse experimental models. Consistent with these observations, PEDF expression is lost at the late stages of melanoma progression, allowing melanoma cells to become angiogenic, migratory, and invasive. PEDF's ability to modify the interplay between the host and tumor tissues strongly supports its use as a therapeutic agent for the treatment of metastatic melanoma. However, transition to the clinic requires a more detailed knowledge of the molecular mechanisms underpinning PEDF's activity. In this study, we describe changes in the gene expression profile of A375 human melanoma cells induced by PEDF overexpression. PEDF modulated diverse categories of genes known to be involved in angiogenesis and migration. It downregulated cytokines such as interleukin-8 and extracellular matrix proteins such as collagen IV, while it upregulated fibronectin. Multiple transcripts previously described as contributing to the acquisition of malignant phenotype by melanoma were also diminished by PEDF overexpression, among which we validated galectin 3 and jagged 1. In addition, PEDF downregulated S100beta and melanoma inhibitory activity, which are widely used in the pathological diagnosis of melanoma. Interestingly, PEDF increased the expression of melanophilin and decreased rab27A, which are relevant targets for melanosome transport; suggesting that PEDF could directly impinge on melanocytic lineage-specific processes. Our study identifies new molecular targets and signaling pathways that may potentially contribute to determine PEDF's ability to restrict the aggressiveness of A375 human melanoma cells. PMID- 21673606 TI - Motor somatotopy of extensor indicis proprius and extensor pollicis longus. AB - After tendon transfer of extensor indicis proprius (EIP) to extensor pollicis longus (EPL), rehabilitation is initiated to enhance motor cortex reorganization. However, patients have been described showing thumb extension immediately after the tendon transfer. At cortical level, no evidence supports either of these assumptions. We noninvasively investigated motor cortical source locations of EIP and EPL muscles. Magnetoencephalography was used to identify motor somatotopic map in healthy right-handed participants, who performed voluntary extension at index metacarpophalangeal joint and thumb interphalangeal joint. Motor cortical representation of EIP was more medial than cortical representation of EPL, with mean Euclidean distance of 15.4+/-2.7 mm. Motor somatotopic map of EIP/EPL that was obtained by magnetoencephalography supports 'functional somatotopy' representation of the finger in primary motor cortex. PMID- 21673607 TI - Iconic memory and parietofrontal network: fMRI study using temporal integration. AB - We investigated the neural basis of iconic memory using functional magnetic resonance imaging. The parietofrontal network of selective attention is reportedly relevant to readout from iconic memory. We adopted a temporal integration task that requires iconic memory but not selective attention. The results showed that the task activated the parietofrontal network, confirming that the network is involved in readout from iconic memory. We further tested a condition in which temporal integration was performed by visual short-term memory but not by iconic memory. However, no brain region revealed higher activation for temporal integration by iconic memory than for temporal integration by visual short-term memory. This result suggested that there is no localized brain region specialized for iconic memory per se. PMID- 21673608 TI - Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. AB - BACKGROUND: Brain hypoxia (BH) can aggravate outcome after severe traumatic brain injury (TBI). Whether BH or reduced brain oxygen (Pbto(2)) is an independent outcome predictor or a marker of disease severity is not fully elucidated. OBJECTIVE: To analyze the relationship between Pbto(2), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) and to examine whether BH correlates with worse outcome independently of ICP and CPP. METHODS: We studied 103 patients monitored with ICP and Pbto(2) for > 24 hours. Durations of BH (Pbto(2) < 15 mm Hg), ICP > 20 mm Hg, and CPP < 60 mm Hg were calculated with linear interpolation, and their associations with outcome within 30 days were analyzed. RESULTS: Duration of BH was longer in patients with unfavorable (Glasgow Outcome Scale score, 1-3) than in those with favorable (Glasgow Outcome Scale, 4-5) outcome (8.3 +/- 15.9 vs 1.7 +/- 3.7 hours; P < .01). In patients with intracranial hypertension, those with BH had fewer favorable outcomes (46%) than those without (81%; P < .01); similarly, patients with low CPP and BH were less likely to have favorable outcome than those with low CPP but normal Pbto(2) (39% vs 83%; P < .01). After ICP, CPP, age, Glasgow Coma Scale score, Marshall computed tomography grade, and Acute Physiology and Chronic Health Evaluation II score were controlled for, BH was independently associated with poor prognosis (adjusted odds ratio for favorable outcome, 0.89 per hour of BH; 95% confidence interval, 0.79-0.99; P = .04). CONCLUSION: Brain hypoxia is associated with poor short-term outcome after severe traumatic brain injury independently of elevated ICP, low CPP, and injury severity. Pbto(2) may be an important therapeutic target after severe traumatic brain injury. PMID- 21673609 TI - Endoscopic endonasal approach for nonvestibular schwannomas. AB - BACKGROUND: Nonvestibular schwannomas of the skull base often represent a challenge owing to their anatomic location. With improved techniques in endoscopic endonasal skull base surgery, resection of various ventral skull base tumors, including schwannomas, has become possible. OBJECTIVE: To assess the outcomes of using endoscopic endonasal approach (EEA) for nonvestibular schwannomas of the skull base. METHODS: Seventeen patients operated on for skull base schwannomas by EEA at the University of Pittsburgh Medical Center from 2003 to 2009 were reviewed. RESULTS: Three patients underwent combined approaches with retromastoid craniectomy (n = 2) and orbitopterional craniotomy (n = 1). Three patients underwent multistage EEA. The rest received a single EEA operation. Data on degree of resection were found for 15 patients. Gross total resection (n = 9) and near-total (>90%) resection (n = 3) were achieved in 12 patients (80%). There were no tumor recurrences or postoperative cerebrospinal fluid leaks. In 3 of 7 patients with preoperative sensory deficits of trigeminal nerve distribution, there were partial improvements. Patients with preoperative reduced vision (n = 1) and cranial nerve VI or III palsies (n = 3) also showed improvement. Five patients had new postoperative trigeminal nerve deficits: 2 had sensory deficits only, 1 had motor deficit only, and 2 had both motor and sensory deficits. Three of these patients had partial improvement, but 3 developed corneal neurotrophic keratopathy. CONCLUSION: An EEA provides adequate access for nonvestibular schwannomas invading the skull base, allowing a high degree of resection with a low rate of complications. PMID- 21673610 TI - Suprasellar Rathke cleft cysts: clinical presentation and treatment outcomes. AB - BACKGROUND: Rathke cleft cysts (RCCs), benign remnants of the Rathke pouch typically arising in the sella, sometimes have suprasellar extension. Purely suprasellar RCCs are rarely reported. OBJECTIVE: To compare the presentations, surgical outcomes, and pathology of purely suprasellar RCCs and sellar-based RCCs. METHODS: We retrospectively reviewed records, magnetic resonance images, laboratory results, and pathology of 151 RCC patients surgically managed at our institution from 1989 to 2009. The RCCs were classified as purely sellar (type I, n = 76), sellar with suprasellar extension (type II, n = 56), or purely suprasellar (type III, n = 19). RESULTS: The RCCs with a suprasellar component (types II and III) more commonly presented with visual dysfunction (P < .001). Complete cyst drainage occurred in 89%, 55%, and 38% of type I, II, and III RCCs, respectively (P < .001). Vision improved in 100%, 55%, and 33% and headache improved in 74%, 64%, and 29% of type I, II, and III patients, respectively (P = .02). Temporary or permanent postoperative diabetes insipidus occurred in 5%, 16%, and 21% of type I, II, and III patients, respectively. (P < .001). In a multivariate analysis, RCC type was the only factor predicting recurrence. Kaplan Meier 3-year recurrence/progression rates were 0%, 16%, and 29% for type I, II, and III RCCs, respectively (P < .001, type I vs II, type I vs III; P = .5 type II vs III). CONCLUSION: The RCCs with a suprasellar component are neurosurgically challenging because of their proximity to the optic chiasm and infundibulum. Compared with sellar-based RCCs, RCCs with a suprasellar component more frequently present with visual dysfunction, are more difficult to completely eliminate, recur more frequently, and are associated with higher postoperative endocrine morbidity, and their preoperative visual dysfunction and headache less frequently improve with surgery. These factors must be considered during the treatment of RCCs with a suprasellar component. PMID- 21673611 TI - Is normalized residual activity a good marker of renal output efficiency? AB - BACKGROUND: Output efficiency (OE) and normalized residual activity (NORA) are two parameters that allow quantifying the renal drainage at any moment of renographic acquisition. Although OE is theoretically more accurate than NORA in case of a decreased overall renal function, both parameters present some weaknesses. OBJECTIVES: To compare both parameters and to evaluate whether the clinical information provided by both parameters is identical. METHODS: From a large database of Tc-99m mercaptoacetyltriglycine 3 renographic studies, 450 kidneys were selected covering a large range of ages, overall function, split function, and quality of drainage. NORA and OE were calculated at the end of the 20-min renogram, as well as on the late post erect postmicturition (PM) views. RESULTS: An inverse correlation was observed between NORA 20 and OE 20 (r= 0.926), as well as between NORA PM and OE PM (r=-0.936). Discrepancies were noted in approximately 10% of the kidneys, but main discrepancies, which would result in a different estimation of the quality of drainage, were only observed in 2% of the kidneys. There was no bias in the discordances; OE could reveal a better as well as a worse quality of drainage than NORA. It is likely therefore that imperfections of both parameters might be the cause of the divergences. The stratification of the kidneys according to age, overall renal function, split function, or quality of drainage did not modify the results. CONCLUSION: NORA, being much easier to program, can replace the output efficiency in the evaluation of renal drainage. PMID- 21673612 TI - Persistence of serum bactericidal antibody one year after a booster dose of either a glycoconjugate or a plain polysaccharide vaccine against serogroup C Neisseria meningitidis given to adolescents previously immunized with a glycoconjugate vaccine. AB - BACKGROUND: Bactericidal antibody induced by immunization of infants with serogroup C Neisseria meningitidis (MenC) vaccines wanes rapidly during childhood. Adolescents are at particular risk from meningococcal disease, therefore they might benefit from a booster dose of vaccine. The duration of serologic response to such a booster in adolescents is unknown. METHODS: In a previous study, English schoolchildren, aged 9 to 12 years, who had received a monovalent MenC glycoconjugate vaccine in 1999-2000, were given either a plain polysaccharide vaccine (MenC-PS group, n = 150) or a glycoconjugate vaccine (MenC CRM group, n = 95) at 13 to 15 years of age. In this follow-up study, serum bactericidal antibody titers and specific immunoglobulin G concentrations were assessed 1 year later. Results were compared with unboosted controls of similar age (control group, n = 298). RESULTS: Compliance with study protocol was achieved for 146 of the MenC-PS group, 92 of the MenC-CRM group, and 293 of the control group. Compared with the control group, both the MenC-PS and MenC-CRM groups had a significantly higher (P < 0.0001) geometric mean serum bactericidal antibody titers 1 year after the booster dose (geometric mean titers for MenC-PS group 3388 [95% confidence interval {CI}: 2460-4665]; MenC-CRM group 4417 [95% CI: 2951-6609]; control group 316 [95% CI: 252-396]). Specific immunoglobulin G concentration also rose and remained elevated 1 year after the booster. CONCLUSIONS: A booster dose of MenC vaccine given to adolescents produced a marked rise in bactericidal antibody, which remained elevated 1 year later. Introduction of an adolescent booster of MenC vaccine might provide enhanced long term population control of the disease. PMID- 21673614 TI - Comparison of 20-, 23-, and 25-gauge air infusion forces. AB - PURPOSE: To determine and compare 20-, 23-, and 25-gauge retinal infusion air jet impact pressure (force per unit area) in an experimental setting. METHODS: Experimental laboratory investigation. Infusion cannulas were connected to a compressed air system. A controlled valve mechanism was used to obtain increasing levels of infusion pressure. Each infusion tube was positioned in front of a manual transducer to measure force. Impact pressure was calculated using known formulas in fluid dynamics. RESULTS: The 20-gauge infusion jet showed similar impact pressure values compared with the 23-gauge infusion jet. Both showed higher levels than the 25-gauge infusion jet. This was because of the smaller jet force for the 25-gauge system. CONCLUSION: In this experimental study, both the 23- and the 20-gauge air infusion jet showed higher impact pressure values compared with the 25-gauge air infusion jet. This could be of concern regarding air infusion during 23-gauge vitrectomy since retinal damage has been shown in standard-gauge surgeries. PMID- 21673615 TI - Etiology and revision surgical strategies in failed lumbosacral fixation of adult spinal deformity constructs. AB - STUDY DESIGN: Retrospective case analysis. OBJECTIVE: The purpose of this study was to evaluate the etiology and salvage strategies of failed lumbosacral fixation in adult spinal deformity patients. SUMMARY OF BACKGROUND DATA: When extending a long spinal deformity fusion to the sacrum, the lumbosacral junction is a common site for implant problems and pseudarthrosis. METHODS: Clinical and radiographic results of 33 patients (26 women/seven men; average age, 53.5 years; range, 21-73) diagnosed and treated for lumbosacral fixation failure between 1995 and 2007 were reviewed. Twenty-one of the 33 patients underwent revision surgery at one institution for these failures and were followed postoperatively for more than 2 years (average, 50.7 months). RESULTS: Twenty-nine of these 33 patients had two sacral screws, two patients one sacral screw, and two patients none. Bicortical sacral screws were placed in 18 patients, only 12 had distal fixation to the sacral screws (bilateral iliac screws, n = 9; others, n = 3). Seventeen of 19 patients without distal fixation to the sacral screws had screw loosening/pullout at L5 or S1. Anteriorly at L5-S1: 4/6 bone grafts collapsed, 5 of 15 intervertebral discs without anterior column support collapsed, and two of 12 titanium cages subsided into the endplates. Rod breakage between L5 and S1 (n = 9) was seen only in patients with distal fixation to the sacral screws. Nineteen of 21 revision patients received two bicortical sacral screws, whereas 20 received distal fixation to the sacral screws consisting of bilateral iliac screws in 16. Nineteen patients received anterior column support at L5-S1. Fifteen of 21 revision patients achieved solid fusion at ultimate follow-up; however, six had additional rod breakage or dislodgement at the lumbosacral junction. CONCLUSION: With long fusions to the sacrum in the treatment of spinal deformity, the use of bilateral S1 screws alone may allow for screw loosening/pullout and/or L5-S1 cage/graft collapse/subsidence. Adding bilateral iliac screws and an anterior structural cage/graft at L5-S1 will protect the S1 screws, but may still allow L5-S1 rod breakage/dislodgement because of lumbosacral pseudarthrosis. Revision surgery in these patients remains a challenge. PMID- 21673616 TI - Correlation of radiographic and functional measurements in patients who underwent primary scoliosis surgery in adult age. AB - STUDY DESIGN: Prospective radiographic and clinical analysis. OBJECTIVE: To evaluate whether radiographic spinopelvic parameters correlate with health related quality of life (HRQOL) measures, in the long run, in patients operated on scoliosis in adult age. SUMMARY OF BACKGROUND DATA: There are papers that correlate sagittal radiographic parameters with HRQOL scores for healthy spine as well as for some spinal disorders. However, there are limited studies evaluating correlations between HRQOL measures, radiographic spinopelvic parameters, and age in patients operated on scoliosis in adult age. METHODS: Fifty-nine patients, older than 21 years at surgery time (median: 50.2 years), were operated upon at a single center. All of them suffered mainly frontal deformity, idiopathic or degenerative curves, and long fusions, with more than a 2-year follow-up (median:8.5 years). Full-length freestanding radiographs, including the spine and pelvis, and SRS22 and SF36 instruments, were available for every patient at final follow-up. Sagittal and frontal radiographic parameters and age were analyzed for correlation with HRQOL. A multivariate analysis was performed. RESULTS: No significant correlation was found between frontal parameters and HRQOL measures. Spearman rank order test showed correlation (P < 0.001) between Scoliosis Research Society (SRS) activity and sagittal vertical axis (SVA) (r = -0.44), pelvic tilt (PT) (r = -0.49), and age (r = -0.5). SRS total was correlated (P < 0.004) with PT (r = -0.32) and age (r = -0.41). SF36 physical function correlated (P < 0.001) with SVA (r = -0.44), PT (r = -0.45), and age (r = -0.56). After multivariate analysis, only age and PT persisted as possible predictors of worse SRS activity scores. CONCLUSION: After primary surgery for adult scoliosis, frontal radiographic parameters did not correlate with HRQOL measures. In univariate analysis, patient age, SVA, and PT correlated with activity scores, although the correlation coefficients did not reach high values. After multivariate analysis, SVA was not a predictor of function. PMID- 21673617 TI - Predicting compensation and medical costs of lumbar fusion patients receiving workers' compensation in utah using presurgical biopsychosocial variables. AB - STUDY DESIGN: A retrospective-cohort investigation (N = 245) utilizing a review of patient medical records and costs accrued through the Workers' Compensation Fund of Utah. OBJECTIVE: To replicate a previous study of compensation and medical costs in compensated lumbar fusion patients, to identify changes in costs across time, and to identify biopsychosocial variables predictive of current costs. SUMMARY OF BACKGROUND DATA: Previous studies have demonstrated that medical costs associated with lumbar fusion have been rising drastically. It is unclear whether rising fusion costs are occurring in compensation populations. Prior studies have also demonstrated that costs can be predicted on the basis of presurgical biopsychosocial variables, and there is a need to determine whether such variables are still relevant. METHODS: A retrospective review of patient medical records and compensation and medical costs paid by the Workers' Compensation Fund of Utah was performed. RESULTS: Since the mid-1990s, medical costs for compensated lumbar fusion patients in Utah have risen approximately 174%, whereas compensation costs have increased roughly with the pace of inflation. Wage and assignment to nurse case management predicted compensation costs, whereas assignment to nurse case management also predicted medical costs. CONCLUSION: Medical costs among compensated Utah patients receiving lumbar fusion have risen dramatically since the 1990s, whereas compensation costs have not. Biopsychosocial variables continue to be predictive of these costs, although to a more modest degree than in prior studies. Further investigations should look at other factors leading to increased medical costs. PMID- 21673618 TI - Hybrid grafting using bone marrow aspirate combined with porous beta-tricalcium phosphate and trephine bone for lumbar posterolateral spinal fusion: a prospective, comparative study versus local bone grafting. AB - STUDY DESIGN: A prospective, comparative study. OBJECTIVE: We developed a hybrid graft (HBG) of porous beta-tricalcium phosphate ceramics/percutaneously harvested bone sticks/autologous bone marrow aspirate for lumbar posterolateral fusion (PLF). The aim of this study was to investigate the efficacy of the HBG as a substitute for conventional corticocancellous iliac autografts. SUMMARY OF BACKGROUND DATA: Iliac crest bone graft (ICBG) has been traditionally used as the golden standard for lumbar spinal fusion. The significant complication rate associated with harvesting corticocancellous ICBG, however, has encouraged development of alternative graft substitutes. METHODS: From September 2005, 61 consecutive patients underwent decompressive laminotomy and 1-level instrumented PLF. Each patient in this study had the constructs of the HBG placed on 1 side of the intertransverse process gutter. An autologous local bone graft (LBG) harvested during decompressive laminotomy was placed on the other side as a control. Radiographic evaluation was performed at 6 months, 1 year after surgery, and subsequently on an annual basis. The fusion statuses on either side of vertebra were compared. RESULTS: The flexion-extension motion in the dynamic x rays at the target level decreased over time. Only 1 case exhibited over 5 degrees of angular motion 2 years after surgery. In the evaluation of fusion status, the fusion rate for the HBG side (68.9% at 6 months, 83.6% at 1 year, 93.5% at 2 years) was higher than that for the LBG side (49.2% at 6 months, 75.4% at 1 year, 89.1% at 2 years) with a significant difference at 6 months after surgery. No significant complications at the donor site were found postoperatively. CONCLUSION: The HBG promoted posterolateral spinal fusion without significant donor site morbidity. Because of its efficacy and safety, this hybrid construct seems promising as an alternative to conventional iliac bone grafts for lumbar spinal fusion. PMID- 21673619 TI - The angiogenic capacity from ligamentum flavum subsequent to inflammation: a critical component of the pathomechanism of hypertrophy. AB - STUDY DESIGN: In vitro study about angiogenic potentiality of ligamentum flavum (LF) cells using coculture of human lumbar LF cells and activated macropage-like THP-1 cells. OBJECTIVE: To test our hypothesis that activated LF, which was exposed to inflammation, induces angiogenesis, thus resulting in hypertrophy. SUMMARY OF BACKGROUND DATA: Inflammatory reactions after mechanical stress produce fibrosis and scarring of the LF that result in hypertrophy, a major pathological feature of spinal stenosis. This study evaluated the roles of LF cells in the pathomechanism of hypertrophy, focusing on angiogenesis. METHODS: To determine their response to the inflammatory reaction, human LF cells were cocultured with phorbol myristate acetate-stimulated macrophage-like THP-1 cells. The conditioned media were assayed for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-8, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)-beta1. Naive and macrophage-exposed LF cells that responded to TNF-alpha/IL-1beta were compared using the same outcome measures. Hypertrophied LF tissue was stained by TGF-beta1 primary antibody using immunohistochemical method. RESULTS: Larger quantities of IL-6, IL-8, and VEGF were secreted by cocultured cells than by macrophages alone and LF cells alone combined. Prior macrophage exposure increased the secretion of IL-8 and VEGF in response to TNF-alpha/IL-1beta stimulation whereas IL-6 production was increased in response to IL-1beta. The coculture appeared to increase TGF-beta1 secretion but the level was lower than that for macrophage-like cells alone and LF cells alone combined. CONCLUSION: LF cells interact with macrophage-like cells to produce angiogenesis-related factors except TGF-beta1. Activated LF cells that have been exposed to macrophage, can impact the inducement of angiogenesis related factors, suggesting that fibrosis and scarring during inflammatory reaction is the major pathomechanism of LF hypertrophy. PMID- 21673620 TI - Randomized, controlled, multicenter, clinical trial comparing BRYAN cervical disc arthroplasty with anterior cervical decompression and fusion in China. AB - STUDY DESIGN: Prospective, randomized, controlled, multicenter clinical trial. OBJECTIVE: To compare outcomes of cervical disc arthroplasty with those of anterior cervical decompression and fusion (ACDF) in a Chinese population. SUMMARY OF BACKGROUND DATA: Cervical disc arthroplasty has been found to be superior to ACDF for maintaining range of motion (ROM) at the index spinal segment and possibly will avoid abnormal stress to adjacent segments. METHODS: A total of 120 patients from 3 large hospitals in China were randomly assigned to treatment with cervical disc arthroplasty (n = 60) using the BRYAN prosthesis or ACDF (n = 60) and were observed postoperatively for 24 months. RESULTS: The 2 groups had similar preoperative demographics and baseline characteristics including ROM, neck disability index, and visual analogue scale for neck and arm pain. The total disc replacement (TDR) group had a significantly longer operation time than the ACDF group (P < 0.001). Outcome data obtained after 24 months revealed a significant difference between the groups in mean change from baseline in ROM at the index level (P < 0.001); ROM was maintained in the TDR group but reduced in the ACDF group. There were no significant between-group differences in the baseline changes in neck disability index or visual analogue scale scores for pain. One patient in the TDR group and 4 patients in the ACDF group required reoperations. CONCLUSION: At 24 months after surgery, the cervical disc prosthesis yielded good clinical results while maintaining ROM at the index level. Cervical disc arthroplasty appears to be a viable alternative to ACDF. PMID- 21673621 TI - Assessment of gait in a rat model of myofascial inflammation using the CatWalk system. AB - STUDY DESIGN: Gait analysis and immunohistological analysis in a rat model of myofascial inflammation in low back. OBJECTIVE: To investigate gait in a rat model of myofascial inflammation using the CatWalk gait analysis system. SUMMARY OF BACKGROUND DATA: There are few reports examining low back pain behavior in animal models. The CatWalk is a computer-assisted gait analysis system that provides an automated way to assess gait function and this behavior during pain. METHODS: In a myofascial inflammation group, 0.5 mL of 4% paraformaldehyde buffer and 0.5 mL of 5% Fluoro-Gold (FG) buffer were injected into bilateral multifidus muscles of rats. In a control group, FG buffer alone was injected. Five days after surgery, the gait of rats in both groups was investigated using the CatWalk system. In the present study a total of 36 gait parameters were quantified and used to judge pain-related behavior. Bilateral dorsal root ganglia (DRGs) from L1 to L6 levels were resected, and immunostained for calcitonin gene-related peptide (CGRP). RESULTS: In the myofascial inflammation group, the mean duty cycle (duration of paw contact divided by time between consecutive paw contacts) of each paws (front and hind) were significantly higher and mean stride length (the distance between successive placements of the same paw) of each paws were significantly shorter compared with the control group. Furthermore, mean minimum contact intensity of the complete paw and mean contact intensity of each paws in the myofascial inflammation group were significantly higher compared with the control group. The proportion of CGRP-immunoreactive FG-labeled neurons among all FG-labeled DRG neurons in the myofascial inflammation group was significantly higher than the proportion in the control group. CONCLUSION: These results suggest that myofascial inflammation in low back caused the changes to the rat's gait, including long stands, short stride, and strong paw contact. PMID- 21673622 TI - Nail gun injury to the sacrum: case report and review of the literature. AB - STUDY DESIGN: Case report. OBJECTIVE: Review the literature that relates to nail gun injuries to the spine using a case report illustration. SUMMARY OF BACKGROUND DATA: Approximately 37,000 patients present to the US emergency departments annually with injuries inflicted from nail guns, 60% of which occur in the workplace. METHODS: A case report of a nail gun injury to the sacrum is presented and the pertinent literature is then reviewed. RESULTS: A 21-year-old male roofer presented to the emergency department after suffering an accidental, self inflicted nail gun injury to the midline of his sacrum. The patient was neurologically intact and a computed tomography (CT) of the pelvis with rectal contrast noted the nail to be located midline within the spinal canal at the level of S3 without injury to the rectum. The patient was taken to the operating room for removal of the nail under general anesthesia and exploration of the wound, specifically looking for evidence of a dural tear, which was determined not to be present. The wound was closed primarily and the patient was given 24 hours of intravenous antibiotics followed by 2 weeks of oral antibiotics. At follow-up, the patient had returned to his roofing job full-time and there was no evidence of infection on examination or retained foreign bodies by radiograph. CONCLUSION: On the basis of our experience and a review of the literature, in terms of treating a nail gun injury to the sacrum we recommend the following: exploration in the operating room to investigate the possibility of a dural tear, thorough irrigation, and debridement, especially in the case of barbed nails, and consultation with general surgery to determine if there is any injury to intrapelvic contents before surgery. An infectious disease consultation postoperatively may also assist in proper selection and duration of antibiotic therapy. PMID- 21673623 TI - Severe neurofibromatosis kyphoscoliosis, posterior wedge osteotomy, halo traction, and anterior autograft strut fusion, with 28-year follow-up. AB - STUDY DESIGN: Case report with very long-term follow-up. OBJECTIVE: To demonstrate the lasting value of correction and stabilization with multiple anterior autogenous strut grafting. SUMMARY OF BACKGROUND DATA: Although anterior strut grafting has been shown to be ideal for neurofibromatosis kyphosis, there have been no reports as to whether the benefit is maintained or lost over many years. METHODS: This is a single case report with very long-term follow-up. RESULTS: This adult patient, operated in February 1982, has been followed for 28 years, and is doing very well in life, although her pulmonary capacity is compromised. CONCLUSION: Although patients with severe spine deformity because of neurofibromatosis tend to deteriorate with time, this patient demonstrates that with aggressive correction and fusion management, a long-term good quality of life can be achieved. PMID- 21673624 TI - Reliability of 3 assessment tools used to evaluate randomized controlled trials for treatment of neck pain. AB - STUDY DESIGN: Pragmatic, cross-sectional study. OBJECTIVE: To assess the interrater reliability of 3 tools used by the Cervical Overview Group (COG) for the assessment of the internal validity of randomized controlled trials (RCTs): Jadad, van Tulder, and risk of bias (RoB). SUMMARY OF BACKGROUND DATA: For clinicians to implement evidence-based practice, they need to critically appraise health care literature. Checklists, scales, and domain-based criteria exist to evaluate the internal validity of RCTs for rehabilitation studies, but there is a lack of research reporting the reliability of existing assessment tools. METHODS: Four members of the COG with multiprofessional and methodological background independently evaluated the internal validity of 54 RCTs using prepiloted Jadad and van Tulder reporting forms, and 18 RCTs using RoB, from June 2003 to May 2009. The kappa statistic was calculated for each combination of raters and assessment tools. Standard agreement categorizations were used. RESULTS: For Jadad, 4 of 7 items demonstrated mean kappa statistic ranges from moderate to substantial agreement (mean values, 0.42-0.78), as did 8 of 11 items on the van Tulder tool (mean values, 0.44-0.77). The RoB demonstrated moderate to substantial (mean values, 0.56-0.76) agreement on 3 of 12 items. Consistent substantial agreement was found across all assessment tools for the domain "allocation concealment": Jadad 0.69 (mean range, 0.60-0.77); van Tulder 0.77 (mean range, 0.73-0.81); RoB 0.76 (mean range, 0.65-0.88); and moderate to substantial across 2 tools for the domain "sequence generation": van Tulder 0.53 (mean range, 0.37-0.66) and RoB 0.66 (mean range, 0.45-0.88). Other domains demonstrated slight or fair agreement. CONCLUSION: Consistent interrater agreement was found across the 3 assessment tools for allocation concealment and for 2 tools for sequence generation. However, users should acknowledge that moderate variation exists within other items requiring more judgment. When evaluating rehabilitation RCTs, clinicians should consider limitations of rating certain items within the selected assessment tool. PMID- 21673625 TI - Results and complications after spinal fusion for neuromuscular scoliosis in cerebral palsy and static encephalopathy using luque galveston instrumentation: experience in 93 patients. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To evaluate the results of spine fusion for neuromuscular scoliosis in cerebral palsy and static encephalopathy, using Luque-Galveston technique, with emphasis on the early and late complications, especially those increasing the hospital stay or requiring additional surgery. SUMMARY OF BACKGROUND DATA: There are numerous studies in the literature on the treatment of neuromuscular scoliosis using Luque-Galveston instrumentation analyzing the results and complications. Most series are small and evaluate some of the complications, with none evaluating all the early and late complications and none assessing the impact of the complication on length of hospitalization or the need for additional surgical intervention. METHODS: This was a retrospective review of a consecutive series of patients operated on for neuromuscular scoliosis in cerebral palsy and static encephalopathy with Luque Galveston instrumentation at 1 institution from January 1997 to December 2003. Ninety-three patients were identified. RESULTS: The average age at surgery was 14.3 years, with an average age at follow-up of 18.2 years, and an average follow up of 3.8 years. The mean preoperative scoliosis was 72 degrees with correction postoperatively to a mean of 33 degrees , maintained at 36 degrees at final follow-up. There were 83 early complications in 54 patients, for a complication rate of 58% of patients for the entire study. There were no perioperative deaths or neurological complications. There was only 1 deep wound infection, for an infection rate of 1.1%. Patients with 1 complication had a longer length of stay, 9 versus 7 days, the difference being statistically significant (Mann-Whitney U test, P < 0.001). Two patients required reoperation during the initial hospitalization (1.1%): 1, one for infection and 1 for proximal hook cutout and proximal junction kyphosis. There were a total of 81 late complications in 44 patients, for a late complication rate of 47% of patients for the entire study. The majority of the complications were minor, not requiring additional care or surgery. Seven patients had a pseudarthrosis (7.5%), presenting at an average of 30 months postoperatively. Eight patients underwent 9 procedures for late complications: 5 for repair of a pseudarthrosis, 3 for removal of a prominent iliac screw, and 1 for superior junctional kyphosis. All the pseudarthrosis repairs were solid at follow-up. CONCLUSION: Spinal fusion in neuromuscular scoliosis with Luque-Galveston technique is a safe and effective procedure. Any early complication increased the length of stay, with a low rate of reoperation during the hospitalization. The majority of late complications were minor, not requiring additional care. Pseudarthroses were detected late and were the main reason for additional surgery. PMID- 21673626 TI - Changes in thoracic kyphosis negatively impact sagittal alignment after lumbar pedicle subtraction osteotomy: a comprehensive radiographic analysis. AB - STUDY DESIGN: Consecutive, multicenter retrospective review. OBJECTIVE: To evaluate if change in thoracic kyphosis (TK) has a positive or negative impact on spinopelvic alignment after lumbar pedicle subtraction osteotomy (PSO) with short fusions. SUMMARY OF BACKGROUND DATA: In the setting of sagittal malalignment, the effect of large vertebral resections can now be anticipated in long fusions, but their impact on unfused segments (reciprocal changes [RC]) remains poorly understood. METHODS: A total of 34 adult patients (mean age = 54 years; SD = 12) who underwent lumbar PSO with upper instrumented vertebra below T10 were included. Radiographic analysis included pre- and postassessment of TK, lumbar lordosis (LL), sagittal vertical axis (SVA), T1 spinopelvic inclination (T1SPI), pelvic tilt (PT), and pelvic incidence (PI). Final SVA and PT were analyzed to determine successful realignment. RC in the thoracic spine was designated favorable or unfavorable on the basis of impact on final SVA and PT. RESULTS: Mean PSO resection was 26 degrees . LL increased from 20 degrees to 49 degrees (P < 0.001). SVA improved from 14 to 4 cm (P < 0.001), and PT improved from 33 degrees to 25 degrees (P < 0.001). Mean increase in TK was 13 degrees (P = 0.002) but was unchanged in 11 patients. Five patients had a favorable RC, and 18 patients had an unfavorable RC. Unfavorable RC was attributed to junctional failure in 6 of 18 patients. Significant differences in the unfavorable RC group included age and greater preoperative PT, PI, SVA, and T1SPI. CONCLUSION: Significant postoperative alignment changes can occur through unfused thoracic spinal segments after lumbar PSO. Unfavorable RC may limit optimal correction and lead to clinical failures. Risk factors for unfavorable thoracic RC include older patients, larger preoperative PI and PT, and worse preoperative T1SPI and are not simply due to junctional failure. Care should be taken with selective lumbar fusion and PSO in older patients and in those with severe preoperative spinopelvic parameters. PMID- 21673627 TI - Safety and accuracy of pedicle screws and constructs placed in infantile and juvenile patients. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: To determine the safety of pedicle screws placed in infantile and juvenile patients younger than 10 years of age, and to evaluate the accuracy and the incidence of short and long-term (>2-year follow-up) complications for the screws and construct utilized. SUMMARY OF BACKGROUND DATA: Although much has been written regarding the use of pedicle screws for the treatment of adult and adolescent spinal deformities, few studies have examined complication rates with regard to pedicle screws placed for pediatric spinal deformities in patients younger than 10 years of age. METHODS: Eighty-eight patients treated with 948 pedicle screws placed for a variety of pediatric spinal deformities were performed at a single institution. We evaluated the accuracy of pedicle screw placement via radiographic review by two spinal surgeons not involved in the surgical treatment. RESULTS: The average age at surgery was 6.8 year (range, 1 + 11 to 9 + 11 year). Five hundred ninety-four pedicle screws were placed in the thoracic spine and 354 screws in the lumbar spine. Three screws (0.32%) violated the lateral wall of the pedicle, two screws (0.21%) violated the inferior wall, and three screws (0.32%) were suspected of medial wall violation for a total of eight screws (0.84%) malpositioned. Although short-term complications occurred in nine patients (10.2%) (four-wound infection, two-foot drop, two-respiratory problems, first-sixth cranial nerve palsy), there were no insertion or short-term complications specifically related to the use of pedicle screws. Long-term complications occurred in nine patients (10.2%) (three deformity progression, four-growing rod breakage), whereas two patients required revision surgery because of pullout and prominence of proximal thoracic pedicle screws (n = 4) placed in growing rod constructs (2.3% of patients, 0.4% of screws). CONCLUSION: There were no intraoperative or short-term pedicle screw insertion-related complications and a very low long-term complication rate (2.3% of patients, 0.4% of screws) specifically related to the use of pedicle screws in infantile and juvenile spinal deformity patients. More than 99% of screws were accurately placed. PMID- 21673628 TI - The accuracy of intraoperative O-arm images for the assessment of pedicle screw postion. AB - STUDY DESIGN: Human cadaveric study. OBJECTIVE: The objective of the study was to determine the accuracy of intraoperative O-arm images in determining pedicle screw position using open dissection as the gold standard. SUMMARY OF BACKGROUND DATA: Pedicle screws are widely used in the treatment of various spinal disorders. Postoperative computed tomographic scans are the imaging gold standard to detect pedicle screw malposition. However, a second procedure is necessary if such malpositioned screws have to be revised. The O-arm is an intraoperative scanner that allows revision of a screw without having to return the patient to the operating room for a separate procedure. No previous studies have looked at the accuracy of intraoperative O-arm images in determining pedicle screw position. METHODS: This factorial validation study utilized 9 cadavers in a comparison of intraoperative O-arm images and the dissection gold standard. Four hundred sixteen screws were inserted using 3-dimensional image (O-arm) guidance from C2 to S1. The screw positions were randomized into 3 groups: "IN" (fully contained within the pedicle), "OUT-lateral," or "OUT-medial." After screw insertion, O-arm images were obtained and reviewed in a blinded fashion by 3 independent observers. Dissection identified the true position of the screws. Specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were calculated using dissection results as the gold standard. The interobserver reliability was also determined. RESULTS: The overall accuracy, specificity, sensitivity, PPV, and NPV of O-arm images for the thoracic and lumbar spine were 73%, 76%, 71%, 74%, and 72%, respectively. Accuracy of surgeon perception in the cervical spine was significantly less than in the thoracic and lumbosacral spine. There was substantial interobserver agreement between the 3 readers. CONCLUSION: Intraoperative O-arm images accurately detect significant pedicle screw violations in the thoracic and lumbosacral spine but are less accurate for the cervical spine. PMID- 21673629 TI - Correlation of sacropelvic geometry with disc degeneration in spondylolytic cadaver specimens. AB - STUDY DESIGN: An anatomic study of sacral inclination, pelvic incidence, pelvic lordosis, and disc degeneration in cadaveric lumbar spines. OBJECTIVE: To evaluate the relationship between sacropelvic parameters and disc degeneration in subjects with bilateral spondylolysis at L5. SUMMARY OF BACKGROUND DATA: L5-S1 disc degeneration is greater in patients with spondylolytic defects (L5-S1) than with an intact pars interarticularis secondary to the instability caused by spondylolysis. Sacral inclination, pelvic incidence, and pelvic lordosis affect sagittal balance and axial forces on the L5-S1 disc. METHODS: An observational study was performed on 120 cadaveric specimens with spondylolysis (L5-S1) identified of 3100 total cadaveric specimens. Nine specimens were excluded because of incomplete or degraded skeletal elements; 10 were excluded for having unilateral defects only. The specimens were evaluated for sacral inclination, pelvic incidence, and pelvic lordosis. Disc degeneration and facet arthrosis at L4-L5 and L5-S1 were measured by the classification of Eubanks et al. Linear regression analyses were then used to determine the relationship between sacropelvic parameters and degeneration at the L5-S1 segment, correcting for confounding factors such as age, sex, and race. RESULTS: Linear regression demonstrated a significant association between sacral inclination and disc degeneration at L5-S1 (P = 0.018). Specimens were then divided into two groups, those in the highest quarter of pelvic incidence, and the remainder. Spearman rank correlation demonstrated a significant association between disc degeneration at L5-S1 and the highest quarter of pelvic incidence (P = 0.017). Increasing pelvic lordosis was also associated with an increase in facet arthrosis at L4-L5 (P = 0.006). CONCLUSION: The findings of this study show a relationship between the sacropelvic geometry and the degree of L5-S1 disc degeneration as well as L4 L5 facet degeneration in spondylolytic specimens. This relationship may prove useful in predicting the course of disc degeneration in patients with spondylolysis. PMID- 21673630 TI - Fusion performance of low-dose recombinant human bone morphogenetic protein 2 and bone marrow-derived multipotent stromal cells in biodegradable scaffolds: a comparative study in a large animal model of anterior lumbar interbody fusion. AB - STUDY DESIGN: A large animal study comparing interbody fusion of a bioresorbable scaffold loaded with either low-dose recombinant human bone morphogenetic protein 2 (rhBMP-2) or bone marrow-derived multipotent stromal cells (BMSCs). OBJECTIVE: To compare the quality of fusion resulting from implantation of medical grade poly (epsilon-caprolactone)-20% tricalcium phosphate (mPCL/TCP) scaffolds and two different bone growth stimulating agents. SUMMARY OF BACKGROUND DATA: Nondegradable cages have been used for interbody fusion with good results. However, the overall advantage of lifelong implantation of a nondegradable device remains a subject of ongoing debate. The use of bioresorbable scaffolds might offer superior alternatives. In this study, we evaluated the quality of fusion obtained with two potential bone graft substitutes. METHODS: Eleven Yorkshire pigs underwent a bisegmental (L2/L3; L4/L5) anterior lumbar interbody fusion (ALIF) in four groups, namely: (1) mPCL/TCP + 0.6 mg rhBMP-2; (2) mPCL/TCP + BMSCs; (3) mPCL/TCP (negative control); and (4) autologous bone grafts (positive control). RESULTS. The mean radiographic scores at 9 months were 3.0, 1.7, 1.0, and 1.8 for groups 1 to 4, respectively. The bone volume fraction of group 1 was two-folds higher than group 2. Histology, micro-computed tomographic scanning and biomechanical evaluation demonstrated solid and comparable fusion between groups 1 and 4. However, group 2 showed inferior quality of fusion when compared with groups 1 and 4 while group 3 showed no fusion even at 9 months. In addition, there was no evidence of implant rejection, chronic inflammation or any other complications. CONCLUSION: mPCL/TCP scaffolds loaded with low-dose rhBMP-2 is comparable to autograft bone as a bone graft substitute in this large animal ALIF model. Although BMSCs lagged behind autograft bone and rhBMP-2, evidence of bone ingrowth in this group warrants further investigation. Our results suggest that mPCL/TCP scaffolds loaded with rhBMP-2 or BMSCs may be a viable alternative to conventional cages and autograft bone. PMID- 21673632 TI - The effect of beta-carotene on lumbar osteophyte formation. AB - STUDY DESIGN: Cross-sectional cohort study of elderly people. OBJECTIVE: The relationships of osteophyte formation on plain lumbar radiographs with serum levels of antioxidants (carotenoids, vitamin A, vitamin E) and other factors were investigated to examine whether antioxidants are involved in lumbar spine degeneration. SUMMARY OF BACKGROUND DATA: Antioxidants have inhibitory effects on the onset of many diseases. However, the association of lumbar osteophyte formation with antioxidant levels in the general population has not been investigated. METHODS: The subjects were 286 people (103 men and 183 women; mean age = 68 years) who underwent resident health screening. Osteophyte formation on lumbar lateral radiographs (Nathan classification), lumbar lordosis angles, sacral inclination angles, serum levels of antioxidants, triglyceride levels, body mass index, osteoporosis, back muscle strength, history of alcohol intake, and smoking history were studied in these subjects. RESULTS: Lumbar osteophyte formation was detected in 48 subjects (17%). Osteophyte formation was significantly more common in elderly persons, men, and subjects with a history of alcohol intake; and had a significant correlation with sacral inclination angle. The levels of alpha-tocopherol, beta-tocopherol, zeaxanthin/lutein, cryptoxanthin, lycopene, alpha-carotene, and beta-carotene were significantly lower in subjects with osteophytes. Logistic regression analysis adjusted for all factors showed that a higher age (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02-1.16; P = 0.02) and a low beta-carotene level (OR = 6.7, 95% CI = 1.39-32.6; P = 0.02) were risk factors for osteophyte formation. CONCLUSION: The serum levels of carotenoids and vitamin E were significantly lower in subjects with lumbar osteophyte formation, and a low beta-carotene level was the strongest risk factor for lumbar osteophytes. This is the first evidence of an association between carotenoids and lumbar osteophyte formation. This finding suggests that appropriate dietary intake of antioxidants is important for inhibition of lumbar spine degeneration in a rapidly aging society. PMID- 21673633 TI - Bioluminescence imaging for assessment of immune responses following implantation of engineered heart tissue (EHT). AB - Various techniques of cardiac tissue engineering have been pursued in the past decades including scaffolding strategies using either native or bioartificial scaffold materials, entrapment of cardiac myocytes in hydrogels such as fibrin or collagen and stacking of myocyte monolayers. These concepts aim at restoration of compromised cardiac function (e.g. after myocardial infarction) or as experimental models (e.g. predictive toxicology and substance screening or disease modelling). Precise monitoring of cell survival after implantation of engineered heart tissue (EHT) has now become possible using in-vivo bioluminescence imaging (BLI) techniques. Here we describe the generation of fibrin-based EHT from a transgenic rat strain with ubiquitous expression of firefly luciferase (ROSA/luciferase-LEW Tg; ). Implantation is performed into the greater omentum of different rat strains to assess immune responses of the recipient organism following EHT implantation. Comparison of results generated by BLI and the Enzyme Linked Immuno Spot Technique (ELISPOT) confirm the usability of BLI for the assessment of immune responses. PMID- 21673634 TI - Examining the conformational dynamics of membrane proteins in situ with site directed fluorescence labeling. AB - Two electrode voltage clamp electrophysiology (TEVC) is a powerful tool to investigate the mechanism of ion transport1 for a wide variety of membrane proteins including ion channels, ion pumps, and transporters. Recent developments have combined site-specific fluorophore labeling alongside TEVC to concurrently examine the conformational dynamics at specific residues and function of these proteins on the surface of single cells. We will describe a method to study the conformational dynamics of membrane proteins by simultaneously monitoring fluorescence and current changes using voltage-clamp fluorometry. This approach can be used to examine the molecular motion of membrane proteins site specifically following cysteine replacement and site-directed fluorophore labeling. Furthermore, this method provides an approach to determine distance constraints between specific residues. This is achieved by selectively attaching donor and acceptor fluorophores to two mutated cysteine residues of interest. In brief, these experiments are performed following functional expression of the desired protein on the surface of Xenopus leavis oocytes. The large surface area of these oocytes enables facile functional measurements and a robust fluorescence signal. It is also possible to readily change the extracellular conditions such as pH, ligand or cations/anions, which can provide further information on the mechanism of membrane proteins. Finally, recent developments have also enabled the manipulation of select internal ions following co-expression with a second protein. Our protocol is described in multiple parts. First, cysteine scanning mutagenesis proceeded by fluorophore labeling is completed at residues located at the interface of the transmembrane and extracellular domains. Subsequent experiments are designed to identify residues which demonstrate large changes in fluorescence intensity (<5%) upon a conformational change of the protein. Second, these changes in fluorescence intensity are compared to the kinetic parameters of the membrane protein in order to correlate the conformational dynamics to the function of the protein. This enables a rigorous biophysical analysis of the molecular motion of the target protein. Lastly, two residues of the holoenzyme can be labeled with a donor and acceptor fluorophore in order to determine distance constraints using donor photodestruction methods. It is also possible to monitor the relative movement of protein subunits following labeling with a donor and acceptor fluorophore. PMID- 21673635 TI - Magnetic resonance imaging quantification of pulmonary perfusion using calibrated arterial spin labeling. AB - This demonstrates a MR imaging method to measure the spatial distribution of pulmonary blood flow in healthy subjects during normoxia (inspired O(2), fraction (F(I)O(2)) = 0.21) hypoxia (F(I)O(2) = 0.125), and hyperoxia (F(I)O(2) = 1.00). In addition, the physiological responses of the subject are monitored in the MR scan environment. MR images were obtained on a 1.5 T GE MRI scanner during a breath hold from a sagittal slice in the right lung at functional residual capacity. An arterial spin labeling sequence (ASL-FAIRER) was used to measure the spatial distribution of pulmonary blood flow and a multi-echo fast gradient echo (mGRE) sequence was used to quantify the regional proton (i.e. H(2)O) density, allowing the quantification of density-normalized perfusion for each voxel (milliliters blood per minute per gram lung tissue). With a pneumatic switching valve and facemask equipped with a 2-way non-rebreathing valve, different oxygen concentrations were introduced to the subject in the MR scanner through the inspired gas tubing. A metabolic cart collected expiratory gas via expiratory tubing. Mixed expiratory O(2) and CO(2) concentrations, oxygen consumption, carbon dioxide production, respiratory exchange ratio, respiratory frequency and tidal volume were measured. Heart rate and oxygen saturation were monitored using pulse-oximetry. Data obtained from a normal subject showed that, as expected, heart rate was higher in hypoxia (60 bpm) than during normoxia (51) or hyperoxia (50) and the arterial oxygen saturation (SpO(2)) was reduced during hypoxia to 86%. Mean ventilation was 8.31 L/min BTPS during hypoxia, 7.04 L/min during normoxia, and 6.64 L/min during hyperoxia. Tidal volume was 0.76 L during hypoxia, 0.69 L during normoxia, and 0.67 L during hyperoxia. Representative quantified ASL data showed that the mean density normalized perfusion was 8.86 ml/min/g during hypoxia, 8.26 ml/min/g during normoxia and 8.46 ml/min/g during hyperoxia, respectively. In this subject, the relative dispersion, an index of global heterogeneity, was increased in hypoxia (1.07 during hypoxia, 0.85 during normoxia, and 0.87 during hyperoxia) while the fractal dimension (Ds), another index of heterogeneity reflecting vascular branching structure, was unchanged (1.24 during hypoxia, 1.26 during normoxia, and 1.26 during hyperoxia). Overview. This protocol will demonstrate the acquisition of data to measure the distribution of pulmonary perfusion noninvasively under conditions of normoxia, hypoxia, and hyperoxia using a magnetic resonance imaging technique known as arterial spin labeling (ASL). RATIONALE: Measurement of pulmonary blood flow and lung proton density using MR technique offers high spatial resolution images which can be quantified and the ability to perform repeated measurements under several different physiological conditions. In human studies, PET, SPECT, and CT are commonly used as the alternative techniques. However, these techniques involve exposure to ionizing radiation, and thus are not suitable for repeated measurements in human subjects. PMID- 21673636 TI - Quantitative analysis of cancer metastasis using an avian embryo model. AB - During metastasis cancer cells disseminate from the primary tumor, invade into surrounding tissues, and spread to distant organs. Metastasis is a complex process that can involve many tissue types, span variable time periods, and often occur deep within organs, making it difficult to investigate and quantify. In addition, the efficacy of the metastatic process is influenced by multiple steps in the metastatic cascade making it difficult to evaluate the contribution of a single aspect of tumor cell behavior. As a consequence, metastasis assays are frequently performed in experimental animals to provide a necessarily realistic context in which to study metastasis. Unfortunately, these models are further complicated by their complex physiology. The chick embryo is a unique in vivo model that overcomes many limitations to studying metastasis, due to the accessibility of the chorioallantoic membrane (CAM), a well-vascularized extra embryonic tissue located underneath the eggshell that is receptive to the xenografting of tumor cells (figure 1). Moreover, since the chick embryo is naturally immunodeficient, the CAM readily supports the engraftment of both normal and tumor tissues. Most importantly, the avian CAM successfully supports most cancer cell characteristics including growth, invasion, angiogenesis, and remodeling of the microenvironment. This makes the model exceptionally useful for the investigation of the pathways that lead to cancer metastasis and to predict the response of metastatic cancer to new potential therapeutics. The detection of disseminated cells by species-specific Alu PCR makes it possible to quantitatively assess metastasis in organs that are colonized by as few as 25 cells. Using the Human Epidermoid Carcinoma cell line (HEp3) we use this model to analyze spontaneous metastasis of cancer cells to distant organs, including the chick liver and lung. Furthermore, using the Alu-PCR protocol we demonstrate the sensitivity and reproducibility of the assay as a tool to analyze and quantitate intravasation, arrest, extravasation, and colonization as individual elements of metastasis. PMID- 21673637 TI - Analyzing the function of small GTPases by microinjection of plasmids into polarized epithelial cells. AB - Epithelial cells polarize their plasma membrane into biochemically and functionally distinct apical and basolateral domains where the apical domain faces the 'free' surfaces and the basolateral membrane is in contact with the substrate and neighboring cells. Both membrane domains are separated by tight junctions, which form a diffusion barrier. Apical-basolateral polarization can be recapitulated successfully in culture when epithelial cells such as Madin-Darby Canine Kidney (MDCK) cells are seeded at high density on polycarbonate filters and cultured for several days. Establishment and maintenance of cell polarity is regulated by an array of small GTPases of the Ras superfamily such as RalA, Cdc42, Rab8, Rab10 and Rab13. Like all GTPases these proteins cycle between an inactive GDP-bound state and an active GTP-bound state. Specific mutations in the nucleotide binding regions interfere with this cycling. For example, Rab13T22N is permanently locked in the GDP-form and thus dubbed 'dominant negative', whereas Rab13Q67L can no longer hydrolyze GTP and is thus locked in a 'dominant active' state. To analyze their function in cells both dominant negative and dominant active alleles of GTPases are typically expressed at high levels to interfere with the function of the endogenous proteins. An elegant way to achieve high levels of overexpression in a short amount of time is to introduce the plasmids encoding the relevant proteins directly into the nuclei of polarized cells grown on filter supports using microinjection technique. This is often combined with the co-injection of reporter plasmids that encode plasma membrane receptors that are specifically sorted to the apical or basolateral domain. A cargo frequently used to analyze cargo sorting to the basolateral domain is a temperature sensitive allele of the vesicular stomatitis virus glycoprotein (VSVGts045). This protein cannot fold properly at 39 degrees C and will thus be retained in the endoplasmic reticulum (ER) while the regulatory protein of interest is assembled in the cytosol. A shift to 31 degrees C will then allow VSVGts045 to fold properly, leave the ER and travel to the plasma membrane. This chase is typically performed in the presence of cycloheximide to prevent further protein synthesis leading to cleaner results. Here we describe in detail the procedure of microinjecting plasmids into polarized cells and subsequent incubations including temperature shifts that allow a comprehensive analysis of regulatory proteins involved in basolateral sorting. PMID- 21673638 TI - Using SCOPE to identify potential regulatory motifs in coregulated genes. AB - SCOPE is an ensemble motif finder that uses three component algorithms in parallel to identify potential regulatory motifs by over-representation and motif position preference. Each component algorithm is optimized to find a different kind of motif. By taking the best of these three approaches, SCOPE performs better than any single algorithm, even in the presence of noisy data. In this article, we utilize a web version of SCOPE to examine genes that are involved in telomere maintenance. SCOPE has been incorporated into at least two other motif finding programs and has been used in other studies. The three algorithms that comprise SCOPE are BEAM, which finds non-degenerate motifs (ACCGGT), PRISM, which finds degenerate motifs (ASCGWT), and SPACER, which finds longer bipartite motifs (ACCnnnnnnnnGGT). These three algorithms have been optimized to find their corresponding type of motif. Together, they allow SCOPE to perform extremely well. Once a gene set has been analyzed and candidate motifs identified, SCOPE can look for other genes that contain the motif which, when added to the original set, will improve the motif score. This can occur through over-representation or motif position preference. Working with partial gene sets that have biologically verified transcription factor binding sites, SCOPE was able to identify most of the rest of the genes also regulated by the given transcription factor. Output from SCOPE shows candidate motifs, their significance, and other information both as a table and as a graphical motif map. FAQs and video tutorials are available at the SCOPE web site which also includes a "Sample Search" button that allows the user to perform a trial run. Scope has a very friendly user interface that enables novice users to access the algorithm's full power without having to become an expert in the bioinformatics of motif finding. As input, SCOPE can take a list of genes, or FASTA sequences. These can be entered in browser text fields, or read from a file. The output from SCOPE contains a list of all identified motifs with their scores, number of occurrences, fraction of genes containing the motif, and the algorithm used to identify the motif. For each motif, result details include a consensus representation of the motif, a sequence logo, a position weight matrix, and a list of instances for every motif occurrence (with exact positions and "strand" indicated). Results are returned in a browser window and also optionally by email. Previous papers describe the SCOPE algorithms in detail. PMID- 21673639 TI - Fabrication of electrochemical-DNA biosensors for the reagentless detection of nucleic acids, proteins and small molecules. AB - As medicine is currently practiced, doctors send specimens to a central laboratory for testing and thus must wait hours or days to receive the results. Many patients would be better served by rapid, bedside tests. To this end our laboratory and others have developed a versatile, reagentless biosensor platform that supports the quantitative, reagentless, electrochemical detection of nucleic acids (DNA, RNA), proteins (including antibodies) and small molecules analytes directly in unprocessed clinical and environmental samples. In this video, we demonstrate the preparation and use of several biosensors in this "E-DNA" class. In particular, we fabricate and demonstrate sensors for the detection of a target DNA sequence in a polymerase chain reaction mixture, an HIV-specific antibody and the drug cocaine. The preparation procedure requires only three hours of hands-on effort followed by an overnight incubation, and their use requires only minutes. PMID- 21673640 TI - Direct observation of phagocytosis and NET-formation by neutrophils in infected lungs using 2-photon microscopy. AB - After the gastrointestinal tract, the lung is the second largest surface for interaction between the vertebrate body and the environment. Here, an effective gas exchange must be maintained, while at the same time avoiding infection by the multiple pathogens that are inhaled during normal breathing. To achieve this, a superb set of defense strategies combining humoral and cellular immune mechanisms exists. One of the most effective measures for acute defense of the lung is the recruitment of neutrophils, which either phagocytose the inhaled pathogens or kill them by releasing cytotoxic chemicals. A recent addition to the arsenal of neutrophils is their explosive release of extracellular DNA-NETs by which bacteria or fungi can be caught or inactivated even after the NET releasing cells have died. We present here a method that allows one to directly observe neutrophils, migrating within a recently infected lung, phagocytosing fungal pathogens as well as visualize the extensive NETs that they have produced throughout the infected tissue. The method describes the preparation of thick viable lung slices 7 hours after intratracheal infection of mice with conidia of the mold Aspergillus fumigatus and their examination by multicolor time-lapse 2 photon microscopy. This approach allows one to directly investigate antifungal defense in native lung tissue and thus opens a new avenue for the detailed investigation of pulmonary immunity. PMID- 21673641 TI - Generation and labeling of murine bone marrow-derived dendritic cells with Qdot nanocrystals for tracking studies. AB - Dendritic cells (DCs) are professional antigen presenting cells (APCs) found in peripheral tissues and in immunological organs such as thymus, bone marrow, spleen, lymph nodes and Peyer's patches. DCs present in peripheral tissues sample the organism for the presence of antigens, which they take up, process and present in their surface in the context of major histocompatibility molecules (MHC). Then, antigen-loaded DCs migrate to immunological organs where they present the processed antigen to T lymphocytes triggering specific immune responses. One way to evaluate the migratory capabilities of DCs is to label them with fluorescent dyes. Herewith we demonstrate the use of Qdot fluorescent nanocrystals to label murine bone marrow-derived DC. The advantage of this labeling is that Qdot nanocrystals possess stable and long lasting fluorescence that make them ideal for detecting labeled cells in recovered tissues. To accomplish this, first cells will be recovered from murine bone marrows and cultured for 8 days in the presence of granulocyte macrophage-colony stimulating factor in order to induce DC differentiation. These cells will be then labeled with fluorescent Qdots by short in vitro incubation. Stained cells can be visualized with a fluorescent microscopy. Cells can be injected into experimental animals at this point or can be into mature cells upon in vitro incubation with inflammatory stimuli. In our hands, DC maturation did not determine loss of fluorescent signal nor does Qdot staining affect the biological properties of DCs. Upon injection, these cells can be identified in immune organs by fluorescent microscopy following typical dissection and fixation procedures. PMID- 21673642 TI - Whole cell recording from an organotypic slice preparation of neocortex. AB - We have been studying the expression and functional roles of voltage-gated potassium channels in pyramidal neurons from rat neocortex. Because of the lack of specific pharmacological agents for these channels, we have taken a genetic approach to manipulating channel expression. We use an organotypic culture preparation (16) in order to maintain cell morphology and the laminar pattern of cortex. We typically isolate acute neocortical slices at postnatal days 8-10 and maintain the slices in culture for 3-7 days. This allows us to study neurons at a similar age to those in our work with acute slices and minimizes the development of exuberant excitatory connections in the slice. We record from visually identified pyramidal neurons in layers II/III or V using infrared illumination (IR-) and differential interference contrast microscopy (DIC) with whole cell patch clamp in current- or voltage-clamp. We use biolistic (Gene gun) transfection of wild type or mutant potassium channel DNA to manipulate expression of the channels to study their function. The transfected cells are easily identified by epifluorescence microscopy after co-transfection with cDNA for green fluorescent protein (GFP). We compare recordings of transfected cells to adjacent, untransfected neurons in the same layer from the same slice. PMID- 21673643 TI - Mapping and application of enhancer-trap flippase expression in larval and adult Drosophila CNS. AB - The Gal4/ UAS binary method is powerful for gene and neural circuitry manipulation in Drosophila. For most neurobiological studies, however, Gal4 expression is rarely tissue-specific enough to allow for precise correlation of the circuit with behavioral readouts. To overcome this major hurdle, we recently developed the FINGR method to achieve a more restrictive Gal4 expression in the tissue of interest. The FINGR method has three components: 1) the traditional Gal4/UAS system; 2) a set of FLP/FRT-mediated Gal80 converting tools; and 3) enhancer-trap FLP (ET-FLP). Gal4 is used to define the primary neural circuitry of interest. Paring the Gal4 with a UAS-effector, such as UAS-MJD78Q or UAS Shi(ts), regulates the neuronal activity, which is in turn manifested by alterations in the fly behavior. With an additional UAS-reporter such as UAS-GFP, the neural circuit involved in the specific behavior can be simultaneously mapped for morphological analysis. For Gal4 lines with broad expression, Gal4 expression can be restricted by using two complementary Gal80-converting tools: tub(P)>Gal80> ('flip out') and tub(P)>stop>Gal80 ('flip in'). Finally, investigators can turn Gal80 on or off, respectively, with the help of tissue specific ET-FLP. In the flip-in mode, Gal80 will repress Gal4 expression wherever Gal4 and ET-FLP intersect. In the flip-out mode, Gal80 will relieve Gal4 repression in cells in which Gal4 and FLP overlap. Both approaches enable the restriction of the number of cells in the Gal4-defined circuitry, but in an inverse pattern. The FINGR method is compatible with the vast collection of Gal4 lines in the fly community and highly versatile for traditional clonal analysis and for neural circuit mapping. In this protocol, we demonstrate the mapping of FLP expression patterns in select ET-FLPx2 lines and the effectiveness of the FINGR method in photoreceptor cells. The principle of the FINGR method should also be applicable to other genetic model organisms in which Gal4/UAS, Gal80, and FLP/FRT are used. PMID- 21673644 TI - Whole mount preparation of the adult Drosophila ventral nerve cord for giant fiber dye injection. AB - To analyze the axonal and dendritic morphology of neurons, it is essential to obtain accurate labeling of neuronal structures. Preparing well labeled samples with little to no tissue damage enables us to analyze cell morphology and to compare individual samples to each other, hence allowing the identification of mutant anomalies. In the demonstrated dissection method the nervous system remains mostly inside the adult fly. Through a dorsal incision, the abdomen and thorax are opened and most of the internal organs are removed. Only the dorsal side of the ventral nerve cord (VNC) and the cervical connective (CvC) containing the big axons of the giant fibers (GFs) are exposed, while the brain containing the GF cell body and dendrites remains in the intact head. In this preparation most nerves of the VNC should remain attached to their muscles. Following the dissection, the intracellular filling of the giant fiber (GF) with a fluorescent dye is demonstrated. In the CvC the GF axons are located at the dorsal surface and thus can be easily visualized under a microscope with differential interference contrast (DIC) optics. This allows the injection of the GF axons with dye at this site to label the entire GF including the axons and their terminals in the VNC. This method results in reliable and strong staining of the GFs allowing the neurons to be imaged immediately after filling with an epifluorescent microscope. Alternatively, the fluorescent signal can be enhanced using standard immunohistochemistry procedures suitable for high resolution confocal microscopy. PMID- 21673645 TI - Low-cost cryo-light microscopy stage fabrication for correlated light/electron microscopy. AB - The coupling of cryo-light microscopy (cryo-LM) and cryo-electron microscopy (cryo-EM) poses a number of advantages for understanding cellular dynamics and ultrastructure. First, cells can be imaged in a near native environment for both techniques. Second, due to the vitrification process, samples are preserved by rapid physical immobilization rather than slow chemical fixation. Third, imaging the same sample with both cryo-LM and cryo-EM provides correlation of data from a single cell, rather than a comparison of "representative samples". While these benefits are well known from prior studies, the widespread use of correlative cryo-LM and cryo-EM remains limited due to the expense and complexity of buying or building a suitable cryogenic light microscopy stage. Here we demonstrate the assembly, and use of an inexpensive cryogenic stage that can be fabricated in any lab for less than $40 with parts found at local hardware and grocery stores. This cryo-LM stage is designed for use with reflected light microscopes that are fitted with long working distance air objectives. For correlative cryo-LM and cryo-EM studies, we adapt the use of carbon coated standard 3-mm cryo-EM grids as specimen supports. After adsorbing the sample to the grid, previously established protocols for vitrifying the sample and transferring/handling the grid are followed to permit multi-technique imaging. As a result, this setup allows any laboratory with a reflected light microscope to have access to direct correlative imaging of frozen hydrated samples. PMID- 21673646 TI - Fixed volume or fixed pressure: a murine model of hemorrhagic shock. AB - It is common knowledge that severe blood loss and traumatic injury can lead to a cascade of detrimental signaling events often resulting in mortality. These signaling events can also lead to sepsis and/or multiple organ dysfunction (MOD). It is critical then to investigate the causes of suppressed immune function and detrimental signaling cascades in order to develop more effective ways to help patients who suffer from traumatic injuries. This fixed pressure Hemorrhagic Shock (HS) procedure, although technically challenging, is an excellent resource for investigation of these pathophysiologic conditions. Advances in the assessment of biological systems, i.e. Systems Biology have enabled the scientific community to further understand complex physiologic networks and cellular communication patterns. (14) Hemorrhagic Shock has proven to be a vital tool for unveiling these cellular communication patterns as they relate to immune function. This procedure can be mastered! This procedure can also be used as either a fixed volume or fixed pressure approach. We adapted this technique in the murine model to enhance research in innate and adaptive immune function. Due to their small size HS in mice presents unique challenges. However due to the many available mouse strains, this species represents an unparalleled resource for the study of the biologic responses. The HS model is an important model for studying cellular communication patterns and the responses of systems such as hormonal and inflammatory mediator systems, and danger signals, i.e. DAMP and PAMP upregulation as it elicits distinct responses that differ from other forms of shock. The development of transgenic murine strains and the induction of biologic agents to inhibit specific signaling have presented valuable opportunities to further elucidate our understanding of the up and down regulation of signal transduction after severe blood loss, i.e. HS and trauma. There are numerous resuscitation methods (R) in association with HS and trauma. A fixed volume resuscitation method of solely lactated ringer solution (LR), equal to three times the shed blood volume, is used in this model to study endogenous mechanisms such as remote organ injury and systemic inflammation. This method of resuscitation is proven to be effective in evaluating the effects of HS and trauma. PMID- 21673647 TI - Imaging glycans in zebrafish embryos by metabolic labeling and bioorthogonal click chemistry. AB - Imaging glycans in vivo has recently been enabled using a bioorthogonal chemical reporter strategy by treating cells or organisms with azide- or alkyne-tagged monosaccharides. The modified monosaccharides, processed by the glycan biosynthetic machinery, are incorporated into cell surface glycoconjugates. The bioorthogonal azide or alkyne tags then allow covalent conjugation with fluorescent probes for visualization, or with affinity probes for enrichment and glycoproteomic analysis. This protocol describes the procedures typically used for noninvasive imaging of fucosylated glycans in zebrafish embryos, including: 1) microinjection of one-cell stage embryos with GDP-5-alkynylfucose (GDP-FucAl), 2) labeling fucosylated glycans in the enveloping layer of zebrafish embryos with azide-conjugated fluorophores via biocompatible Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), and 3) imaging by confocal microscopy. The method described here can be readily extended to visualize other classes of glycans, e.g. glycans containing sialic acid and N-acetylgalactosamine, in developing zebrafish and in other living organisms. PMID- 21673648 TI - Modified ES / OP9 co-culture protocol provides enhanced characterization of hematopoietic progeny. AB - The in vitro differentiation of ES cells towards a hematopoietic cell fate is useful when studying cell populations that are difficult to access in vivo and for characterizing the earliest genes involved in hematopoiesis, without having to deal with embryonic lethalities. The ES/OP9 co-culture system was originally designed to produce hematopoietic progeny, without the over production of macrophages, as the OP9 stromal cell line is derived from the calvaria of osteopetrosis mutant mice that lack functional M-CSF. The in vitro ES/OP9 co culture system can be used in order to recapitulate early hematopoietic development. When cultured on OP9 stromal cells, ES cells differentiate into Flk 1+ hemangioblasts, hematopoietic progenitors, and finally mature, terminally differentiated lineages. The standard ES/OP9 co-culture protocol entails the placement of ES cells onto a confluent layer of OP9 cells; as well as, periodic replating steps in order to remove old, contaminating OP9 cells. Furthermore, current protocols involve evaluating only the hematopoietic cells found in suspension and are not optimized for evaluation of ES-derived progeny at each day of differentiation. However, with replating steps and the harvesting of only suspension cells one potentially misses a large portion of ES-derived progeny and developing hematopoietic cells. This issue becomes important to address when trying to characterize hematopoietic defects associated with knockout ES lines. Here we describe a modified ES/mStrawberry OP9 co-culture, which allows for the elimination of contaminating OP9 cells from downstream assays. This method allows for the complete evaluation of all ES-derived progeny at all days of co-culture, resulting in a hematopoietic differentiation pattern, which more directly corresponds to the hematopoietic differentiation pattern observed within the embryo. PMID- 21673649 TI - Coronary artery ligation and intramyocardial injection in a murine model of infarction. AB - Mouse models are a valuable tool for studying acute injury and chronic remodeling of the myocardium in vivo. With the advent of genetic modifications to the whole organism or the myocardium and an array of biological and/or synthetic materials, there is great potential for any combination of these to assuage the extent of acute ischemic injury and impede the onset of heart failure pursuant to myocardial remodeling. Here we present the methods and materials used to reliably perform this microsurgery and the modifications involved for temporary (with reperfusion) or permanent coronary artery occlusion studies as well as intramyocardial injections. The effects on the heart that can be seen during the procedure and at the termination of the experiment in addition to histological evaluation will verify efficacy. Briefly, surgical preparation involves anesthetizing the mice, removing the fur on the chest, and then disinfecting the surgical area. Intratracheal intubation is achieved by transesophageal illumination using a fiber optic light. The tubing is then connected to a ventilator. An incision made on the chest exposes the pectoral muscles which will be cut to view the ribs. For ischemia/reperfusion studies, a 1 cm piece of PE tubing placed over the heart is used to tie the ligature to so that occlusion/reperfusion can be customized. For intramyocardial injections, a Hamilton syringe with sterile 30 gauge beveled needle is used. When the myocardial manipulations are complete, the rib cage, the pectoral muscles, and the skin are closed sequentially. Line block analgesia is effected by 0.25% marcaine in sterile saline which is applied to muscle layer prior to closure of the skin. The mice are given a subcutaneous injection of saline and placed in a warming chamber until they are sternally recumbent. They are then returned to the vivarium and housed under standard conditions until the time of tissue collection. At the time of sacrifice, the mice are anesthetized, the heart is arrested in diastole with KCl or BDM, rinsed with saline, and immersed in fixative. Subsequently, routine procedures for processing, embedding, sectioning, and histological staining are performed. Nonsurgical intubation of a mouse and the microsurgical manipulations described make this a technically challenging model to learn and achieve reproducibility. These procedures, combined with the difficulty in performing consistent manipulations of the ligature for timed occlusion(s) and reperfusion or intramyocardial injections, can also affect the survival rate so optimization and consistency are critical. PMID- 21673650 TI - Gender difference in the association of insulin and the insulin-like growth factor axis with colorectal neoplasia. AB - OBJECTIVE: Accumulating evidence has implicated insulin and the insulin-like growth factor (IGF) axis in colorectal carcinogenesis. Of interest, adiposity is likely to impose a greater risk on men than on women, which indicates that the association of insulin and the IGF axis with colorectal neoplasia may differ by gender. However, epidemiological evidence for this possible gender difference is limited to date. METHODS: We measured plasma concentrations of C-peptide, IGF-I and IGF-binding proteins (IGFBPs) 1 and 3 in 1520 healthy volunteer examinees who underwent total colonoscopy between February 2004 and February 2005, and cross sectionally investigated the association of these biomarkers with colorectal adenoma by gender. An unconditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for colorectal adenoma after adjustment for potential confounders. RESULTS: We observed a positive association of C-peptide and IGF-I (P (trend)<0.001 and 0.02, respectively) and an inverse association of IGFBP-1 (P (trend)=0.002) with colorectal adenoma in men. Adjusted ORs of colorectal adenoma for the highest compared with the lowest quartile were also statistically significant for C peptide (OR: 2.62, 95% CI: 1.71-4.01), IGF-I (OR: 1.63, 95% CI: 1.08-2.46) and IGFBP-1 (OR: 0.49, 95% CI: 0.32-0.75). In contrast, no measurable association was seen in women. Corresponding ORs for C-peptide, IGF-I and IGFBP-1 were 0.98 (95% CI: 0.56-1.71), 0.79 (95% CI: 0.44-1.43) and 1.05 (95% CI: 0.60-1.86), respectively. The gender difference was statistically significant for C-peptide (P (interaction)=0.03) and marginally significant for IGF-I and IGFBP-1 (P (interaction)=0.14 and 0.12, respectively). CONCLUSION: Our observations suggest that insulin and the IGF axis act differently by gender in colorectal carcinogenesis, at least in its early stage. The findings of this study further our understanding of the complexities of the gender difference in the association between adiposity and colorectal neoplasia. PMID- 21673651 TI - Parental perceptions of weight status in children: the Gateshead Millennium Study. AB - OBJECTIVES: To investigate parents' perceptions of weight status in children and to explore parental understanding of and attitudes to childhood overweight. DESIGN: Questionnaires and focus groups within a longitudinal study. SUBJECTS: 536 parents of Gateshead Millennium Study children, of which 27 attended six focus groups. MAIN OUTCOME MEASURES: Parents' perception of their child's weight status according to actual weight status as defined by International Obesity Taskforce (IOTF) cutoffs. Focus group outcomes included parental awareness of childhood overweight nationally and parental approaches to identifying overweight children. RESULTS: The sensitivity of parents recognising if their child was overweight was 0.31. Prevalence of child overweight was underestimated: 7.3% of children were perceived as 'overweight' or 'very overweight' by their parents, 23.7% were identified as overweight or obese using IOTF criteria. 69.3% of parents of overweight or obese children identified their child as being of 'normal' weight. During focus groups parents demonstrated an awareness of childhood overweight being a problem nationally but their understanding of how it is defined was limited. Parents used alternative approaches to objective measures when identifying overweight in children such as visual assessments and comparisons with other children. Such approaches relied heavily on extreme and exceptional cases as a reference point. The apparent lack of relevance of childhood overweight to their child's school or own community along with scepticism towards both media messages and clinical measures commonly emerged as grounds for failing to engage with the issue at a personal level. CONCLUSION: Parents' ability to identify when their child was overweight according to standard criteria was limited. Parents did not understand, use or trust clinical measures and used alternative approaches primarily reliant on extreme cases. Such approaches underpinned their reasoning for remaining detached from the issue. This study highlights the need to identify methods of improving parental recognition of and engagement with the problem of childhood overweight. PMID- 21673652 TI - Adipocyte lipases and lipid droplet-associated proteins: insight from transgenic mouse models. AB - Adipose tissue lipolysis is the catabolic process whereby stored triacylglycerol (TAG) is broken down by lipases into fatty acids and glycerol. Here, we review recent insights from transgenic mouse models. Genetic manipulations affecting lipases are considered first, followed by transgenic models of lipase co-factors and lastly non-lipase lipid droplet (LD)-associated proteins. The central role of hormone-sensitive lipase (HSL), long considered to be the sole rate-limiting enzyme of TAG hydrolysis, has been revised since the discovery of adipose triglyceride lipase (ATGL). It is now accepted that ATGL initiates TAG breakdown producing diacylglycerol, which is subsequently hydrolyzed by HSL. Furthermore, lipase activities are modulated by co-factors whose deletion causes severe metabolic disturbances. Another major advance has come from the description of the involvement of non-lipase proteins in the regulation of lipolysis. The role of perilipins has been extensively investigated. Other newly discovered LD associated proteins have also been shown to regulate lipolysis. PMID- 21673653 TI - Multicenter evaluation of an interdisciplinary 52-week weight loss program for obesity with regard to body weight, comorbidities and quality of life--a prospective study. AB - OBJECTIVES: To determine the effectiveness of a structured multidisciplinary non surgical obesity therapy program on the basis of a temporary low-calorie-diet for 12 weeks, and additional intervention modules to enhance nutritional education, to increase physical activity and to modify eating behavior. DESIGN: Prospective multicenter observational study in obese individuals undergoing a medically supervised outpatient-based 52-week treatment in 37 centers in Germany. SUBJECTS: A total of 8296 participants with a body mass index (BMI) of >30 kg m(-2) included within 8.5 years. MEASUREMENTS: Main outcome measures were body weight loss, waist circumference (WC), blood pressure, quality of life and adverse events. RESULTS: In females, initial body weight was reduced after the 1-year intervention by 19.6 kg (95% confidence intervals 19.2-19.9 kg) and in males by 26.0 kg (25.2-26.8) according to per protocol analysis of 4850 individuals. Intention-to-treat (ITT) analysis revealed a weight reduction of 15.2 kg (14.9 15.6) in females and 19.4 kg (18.7-20.1) in males. Overall, the intervention resulted in mean reduction in WC of 11 cm; it reduced the prevalence of the metabolic syndrome by 50% and the frequency of hypertension from 47 to 29% of all participants (ITT, all P<0.001). The beneficial effects could be documented for up to 3 years and comprised significant improvement of health-related quality of life. The incidence of adverse effects was low; the only event repeatedly observed and possibly related to either the intervention or the underlying disease was biliary disorders. CONCLUSION: The present non-surgical intervention program is a highly effective treatment of obesity grades I-III and obesity related diseases, and therefore, could be a valuable basis for future weight maintenance strategies required for sustained success. PMID- 21673654 TI - EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan. AB - Epidermal growth factor (EGF) signalling regulates growth and differentiation. Here, we examine the function of EGF signalling in Caenorhabditis elegans lifespan. We find that EGF signalling regulates lifespan via the Ras-MAPK pathway and the PLZF transcription factors EOR-1 and EOR-2. As animals enter adulthood, EGF signalling upregulates the expression of genes involved in the ubiquitin proteasome system (UPS), including the Skp1-like protein SKR-5, while downregulating the expression of HSP16-type chaperones. Using reporters for global UPS activity, protein aggregation, and oxidative stress, we find that EGF signalling alters protein homoeostasis in adults by increasing UPS activity and polyubiquitination, while decreasing protein aggregation. We show that SKR-5 and the E3/E4 ligases that comprise the ubiquitin fusion degradation (UFD) complex are required for the increase in UPS activity observed in adults, and that animals that lack SKR-5 or the UFD have reduced lifespans and indications of oxidative stress. We propose that as animals enter fertile adulthood, EGF signalling switches the mechanism for maintaining protein homoeostasis from a chaperone-based approach to an approach involving protein elimination via augmented UPS activity. PMID- 21673655 TI - FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. AB - Netrin-1 induces repulsive axon guidance by binding to the mammalian Unc5 receptor family (Unc5A-Unc5D). Mouse genetic analysis of selected members of the Unc5 family, however, revealed essential functions independent of Netrin-1, suggesting the presence of other ligands. Unc5B was recently shown to bind fibronectin and leucine-rich transmembrane protein-3 (FLRT3), although the relevance of this interaction for nervous system development remained unclear. Here, we show that the related Unc5D receptor binds specifically to another FLRT protein, FLRT2. During development, FLRT2/3 ectodomains (ECDs) are shed from neurons and act as repulsive guidance molecules for axons and somata of Unc5 positive neurons. In the developing mammalian neocortex, Unc5D is expressed by neurons in the subventricular zone (SVZ), which display delayed migration to the FLRT2-expressing cortical plate (CP). Deletion of either FLRT2 or Unc5D causes a subset of SVZ-derived neurons to prematurely migrate towards the CP, whereas overexpression of Unc5D has opposite effects. Hence, the shed FLRT2 and FLRT3 ECDs represent a novel family of chemorepellents for Unc5-positive neurons and FLRT2/Unc5D signalling modulates cortical neuron migration. PMID- 21673656 TI - Architecture of the flagellar rotor. AB - Rotation and switching of the bacterial flagellum depends on a large rotor mounted protein assembly composed of the proteins FliG, FliM and FliN, with FliG most directly involved in rotation. The crystal structure of a complex between the central domains of FliG and FliM, in conjunction with several biochemical and molecular-genetic experiments, reveals the arrangement of the FliG and FliM proteins in the rotor. A stoichiometric mismatch between FliG (26 subunits) and FliM (34 subunits) is explained in terms of two distinct positions for FliM: one where it binds the FliG central domain and another where it binds the FliG C terminal domain. This architecture provides a structural framework for addressing the mechanisms of motor rotation and direction switching and for unifying the large body of data on motor performance. Recently proposed alternative models of rotor assembly, based on a subunit contact observed in crystals, are not supported by experiment. PMID- 21673657 TI - Structural diversity of bacterial flagellar motors. AB - The bacterial flagellum is one of nature's most amazing and well-studied nanomachines. Its cell-wall-anchored motor uses chemical energy to rotate a microns-long filament and propel the bacterium towards nutrients and away from toxins. While much is known about flagellar motors from certain model organisms, their diversity across the bacterial kingdom is less well characterized, allowing the occasional misrepresentation of the motor as an invariant, ideal machine. Here, we present an electron cryotomographical survey of flagellar motor architectures throughout the Bacteria. While a conserved structural core was observed in all 11 bacteria imaged, surprisingly novel and divergent structures as well as different symmetries were observed surrounding the core. Correlating the motor structures with the presence and absence of particular motor genes in each organism suggested the locations of five proteins involved in the export apparatus including FliI, whose position below the C-ring was confirmed by imaging a deletion strain. The combination of conserved and specially-adapted structures seen here sheds light on how this complex protein nanomachine has evolved to meet the needs of different species. PMID- 21673658 TI - The Sm-like RNA chaperone Hfq mediates transcription antitermination at Rho dependent terminators. AB - In Escherichia coli, the essential motor protein Rho promotes transcription termination in a tightly controlled manner that is not fully understood. Here, we show that the general post-transcriptional regulatory protein Hfq associates with Rho to regulate Rho function. The Hfq:Rho complex can be further stabilized by RNA bridging both factors in a configuration that inhibits the ATP hydrolysis and duplex unwinding activities of Rho and that mediates transcription antitermination at Rho-dependent terminators in vitro and in vivo. Antitermination at a prototypical terminator (lambdatR1) requires Hfq binding to an A/U-rich transcript region directly upstream from the terminator. Antitermination is modulated by trans-acting factors (NusG or nucleic acid competitors) that affect Hfq association with Rho or RNA. These data unveil a new Hfq function and a novel transcription regulatory mechanism with potentially important implications for bacterial RNA metabolism, gene silencing, and pathogenicity. PMID- 21673659 TI - A yeast BH3-only protein mediates the mitochondrial pathway of apoptosis. AB - Mitochondrial outer membrane permeabilization is a watershed event in the process of apoptosis, which is tightly regulated by a series of pro- and anti-apoptotic proteins belonging to the BCL-2 family, each characteristically possessing a BCL 2 homology domain 3 (BH3). Here, we identify a yeast protein (Ybh3p) that interacts with BCL-X(L) and harbours a functional BH3 domain. Upon lethal insult, Ybh3p translocates to mitochondria and triggers BH3 domain-dependent apoptosis. Ybh3p induces cell death and disruption of the mitochondrial transmembrane potential via the mitochondrial phosphate carrier Mir1p. Deletion of Mir1p and depletion of its human orthologue (SLC25A3/PHC) abolish stress-induced mitochondrial targeting of Ybh3p in yeast and that of BAX in human cells, respectively. Yeast cells lacking YBH3 display prolonged chronological and replicative lifespans and resistance to apoptosis induction. Thus, the yeast genome encodes a functional BH3 domain that induces cell death through phylogenetically conserved mechanisms. PMID- 21673660 TI - Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus. AB - Patients with advanced solid tumors refractory to and progressing after conventional therapies were treated with three different regimens of low-dose cyclophosphamide (CP) in combination with oncolytic adenovirus. CP was given with oral metronomic dosing (50 mg/day, N = 21), intravenously (single 1,000 mg dose, N = 7) or both (N = 7). Virus was injected intratumorally. Controls (N = 8) received virus without CP. Treatments were well tolerated and safe regardless of schedule. Antibody formation and virus replication were not affected by CP. Metronomic CP (oral and oral + intravenous schedules) decreased regulatory T cells (T(regs)) without compromising induction of antitumor or antiviral T-cell responses. Oncolytic adenovirus given together with metronomic CP increased cytotoxic T cells and induced Th1 type immunity on a systemic level in most patients. All CP regimens resulted in higher rates of disease control than virus only (all P < 0.0001) and the best progression-free (PFS) and overall survival (OS) was seen in the oral + intravenous group. One year PFS and OS were 53 and 42% (P = 0.0016 and P < 0.02 versus virus only), respectively, both which are unusually high for chemotherapy refractory patients. We conclude that low-dose CP results in immunological effects appealing for oncolytic virotherapy. While these first-in-human data suggest good safety, intriguing efficacy and extended survival, the results should be confirmed in a randomized trial. PMID- 21673661 TI - Tumor vascular targeted delivery of polymer-conjugated adenovirus vector for cancer gene therapy. AB - Previously, we generated a cancer-specific gene therapy system using adenovirus vectors (Adv) conjugated to polyethylene glycol (Adv-PEG). Here, we developed a novel Adv that targets both tumor tissues and tumor vasculatures after systemic administration by conjugating CGKRK tumor vasculature homing peptide to the end of a 20-kDa PEG chain (Adv-PEG(CGKRK)). In a primary tumor model, systemic administration of Adv-PEG(CGKRK) resulted in ~500- and 100-fold higher transgene expression in tumor than that of unmodified Adv and Adv-PEG, respectively. In contrast, the transgene expression of Adv-PEG(CGKRK) in liver was about 400-fold lower than that of unmodified Adv, and was almost the same as that of Adv-PEG. We also demonstrated that transgene expression with Adv-PEG(CGKRK) was enhanced in tumor vessels. Systemic administration of Adv-PEG(CGKRK) expressing the herpes simplex virus thymidine kinase (HSVtk) gene (Adv-PEG(CGKRK)-HSVtk) showed superior antitumor effects against primary tumors and metastases with negligible side effects by both direct cytotoxic effects and inhibition of tumor angiogenesis. These results indicate that Adv-PEG(CGKRK) has potential as a prototype Adv with suitable efficacy and safety for systemic cancer gene therapy against both primary tumors and metastases. PMID- 21673662 TI - Modified siRNA structure with a single nucleotide bulge overcomes conventional siRNA-mediated off-target silencing. AB - Off-target gene silencing is a major concern when using RNA interference. Imperfect pairing of the antisense strand with unintended mRNA targets is one of the main causes of small interfering RNA (siRNA) off-target silencing. To overcome this, we have developed "bulge-siRNA," a modified siRNA backbone structure with a single nucleotide (nt) bulge placed in the antisense strand. We found that siRNAs with a bulge at position 2 of the antisense strand were able to discriminate better between perfectly matched and mismatched targets, with no loss in silencing of the intended target. Genome-wide analysis also revealed that the bulge-siRNAs significantly reduced off-target silencing of transcripts with complementarity to the seed region of the siRNA antisense strand. When compared to 2'-methoxy ribosyl (2'-OMe) modified siRNAs previously developed to alleviate antisense off-target silencing; the bulge modification could better discriminate between on- versus off-targets. Our results suggest that the bulge-siRNA structure is a simple, yet superior alternative to chemical modifications for minimizing off-target silencing triggered by conventional siRNA structures. PMID- 21673663 TI - Ultrasonic frogs show extraordinary sex differences in auditory frequency sensitivity. AB - Acoustic communication has an important role in the reproductive behaviour of anurans. Although males of the concave-eared frog (Odorrana tormota) have shown an ultrasonic communication capacity adapted to the intense, predominately low frequency ambient noise from local streams, whether the females communicate with ultrasound remains unclear. Here we present evidence that females exhibit no ultrasonic sensitivity. Acoustic playback experiments show that the calls from male evoke phonotaxis and vocal responses from gravid females, whereas the ultrasonic components (frequencies above 20 kHz) of the calls do not elicit any phonotaxis or vocalization in the females. Electrophysiological recordings from the auditory midbrain reveal an upper frequency limit at 16 kHz in females. Laser Doppler vibrometer measurements show that the velocity amplitude of the tympanic membranes peaks at 5 kHz in females and at ~7 kHz in males. The auditory sex differences in O. tormota imply that ultrasonic hearing has evolved only in male anurans. PMID- 21673664 TI - Flexible concentrator photovoltaics based on microscale silicon solar cells embedded in luminescent waveguides. AB - Unconventional methods to exploit monocrystalline silicon and other established materials in photovoltaic (PV) systems can create new engineering opportunities, device capabilities and cost structures. Here we show a type of composite luminescent concentrator PV system that embeds large scale, interconnected arrays of microscale silicon solar cells in thin matrix layers doped with luminophores. Photons that strike cells directly generate power in the usual manner; those incident on the matrix launch wavelength-downconverted photons that reflect and waveguide into the sides and bottom surfaces of the cells to increase further their power output, by more than 300% in examples reported here. Unlike conventional luminescent photovoltaics, this unusual design can be implemented in ultrathin, mechanically bendable formats. Detailed studies of design considerations and fabrication aspects for such devices, using both experimental and computational approaches, provide quantitative descriptions of the underlying materials science and optics. PMID- 21673665 TI - Global-scale latitudinal patterns of plant fine-root nitrogen and phosphorus. AB - Most water and essential soil nutrient uptake is carried out by fine roots in plants. It is therefore important to understand the global geographic patterns of fine-root nitrogen and phosphorus cycling. Here, by compiling plant root data from 211 studies in 51 countries, we show that live fine roots have low nitrogen (N) and phosphorus (P), but similar N:P ratios when compared with green leaves. The fine-root N:P ratio differs between biomes and declines exponentially with latitude in roots of all diameter classes. This is in contrast to previous reports of a linear latitudinal decline in green leaf N:P, but consistent with nonlinear declines in leaf litter N:P. Whereas the latitudinal N:P decline in both roots and leaves reflects collective influences of climate, soil age and weathering, differences in the shape of the response function may be a result of their different N and P use strategies. PMID- 21673666 TI - Helium penetrates into silica glass and reduces its compressibility. AB - SiO(2) glass has a network structure with a significant amount of interstitial voids. Gas solubilities in silicates are expected to become small under high pressure due to compaction of voids. Here we show anomalous behaviour of SiO(2) glass in helium. Volume measurements clarify that SiO(2) glass is much less compressible than normal when compressed in helium, and the volume in helium at 10 GPa is close to the normal volume at 2 GPa. X-ray diffraction and Raman scattering measurements suggest that voids are prevented from contracting when compressed in helium because helium penetrates into them. The estimated helium solubility is very high and is between 1.0 and 2.3 mol per mole of SiO(2) glass at 10 GPa, which shows marked contrast with previous models. These results may have implications for discussions of the Earth's evolution as well as interpretations of various high-pressure experiments, and also lead to the creation of new materials. PMID- 21673667 TI - Vocalization frequency and duration are coded in separate hindbrain nuclei. AB - Temporal patterning is an essential feature of neural networks producing precisely timed behaviours such as vocalizations that are widely used in vertebrate social communication. Here we show that intrinsic and network properties of separate hindbrain neuronal populations encode the natural call attributes of frequency and duration in vocal fish. Intracellular structure/function analyses indicate that call duration is encoded by a sustained membrane depolarization in vocal prepacemaker neurons that innervate downstream pacemaker neurons. Pacemaker neurons, in turn, encode call frequency by rhythmic, ultrafast oscillations in their membrane potential. Pharmacological manipulations show prepacemaker activity to be independent of pacemaker function, thus accounting for natural variation in duration which is the predominant feature distinguishing call types. Prepacemaker neurons also innervate key hindbrain auditory nuclei thereby effectively serving as a call-duration corollary discharge. We propose that premotor compartmentalization of neurons coding distinct acoustic attributes is a fundamental trait of hindbrain vocal pattern generators among vertebrates. PMID- 21673668 TI - Colossal negative thermal expansion in BiNiO3 induced by intermetallic charge transfer. AB - The unusual property of negative thermal expansion is of fundamental interest and may be used to fabricate composites with zero or other controlled thermal expansion values. Here we report that colossal negative thermal expansion (defined as linear expansion <-10(-4) K(-1) over a temperature range ~100 K) is accessible in perovskite oxides showing charge-transfer transitions. BiNiO(3) shows a 2.6% volume reduction under pressure due to a Bi/Ni charge transfer that is shifted to ambient pressure through lanthanum substitution for Bi. Changing proportions of coexisting low- and high-temperature phases leads to smooth volume shrinkage on heating. The crystallographic linear expansion coefficient for Bi(0.95)La(0.05)NiO(3) is -137*10(-6) K(-1) and a value of -82*10(-6) K(-1) is observed between 320 and 380 K from a dilatometric measurement on a ceramic pellet. Colossal negative thermal expansion materials operating at ambient conditions may also be accessible through metal-insulator transitions driven by other phenomena such as ferroelectric orders. PMID- 21673669 TI - Microorganisms from aphid honeydew attract and enhance the efficacy of natural enemies. AB - Aphids are one of the most serious pests of crops worldwide, causing major yield and economic losses. To control aphids, natural enemies could be an option but their efficacy is sometimes limited by their dispersal in natural environment. Here we report the first isolation of a bacterium from the pea aphid Acyrthosiphon pisum honeydew, Staphylococcus sciuri, which acts as a kairomone enhancing the efficiency of aphid natural enemies. Our findings represent the first case of a host-associated bacterium driving prey location and ovipositional preference for the natural enemy. We show that this bacterium has a key role in tritrophic interactions because it is the direct source of volatiles used to locate prey. Some specific semiochemicals produced by S. sciuri were also identified as significant attractants and ovipositional stimulants. The use of this host-associated bacterium could certainly provide a novel approach to control aphids in field and greenhouse systems. PMID- 21673670 TI - Full-field implementation of a perfect eavesdropper on a quantum cryptography system. AB - Quantum key distribution (QKD) allows two remote parties to grow a shared secret key. Its security is founded on the principles of quantum mechanics, but in reality it significantly relies on the physical implementation. Technological imperfections of QKD systems have been previously explored, but no attack on an established QKD connection has been realized so far. Here we show the first full field implementation of a complete attack on a running QKD connection. An installed eavesdropper obtains the entire 'secret' key, while none of the parameters monitored by the legitimate parties indicate a security breach. This confirms that non-idealities in physical implementations of QKD can be fully practically exploitable, and must be given increased scrutiny if quantum cryptography is to become highly secure. PMID- 21673671 TI - Type Ia supernovae as stellar endpoints and cosmological tools. AB - Empirically, Type Ia supernovae are the most useful, precise, and mature tools for determining astronomical distances. Acting as calibrated candles they revealed the presence of dark energy and are being used to measure its properties. However, the nature of the Type Ia explosion, and the progenitors involved, have remained elusive, even after seven decades of research. But now, new large surveys are bringing about a paradigm shift--we can finally compare samples of hundreds of supernovae to isolate critical variables. As a result of this, and advances in modelling, breakthroughs in understanding all aspects of these supernovae are finally starting to happen. PMID- 21673672 TI - Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels. AB - Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation-pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs. PMID- 21673673 TI - Convergent evolution in locomotory patterns of flying and swimming animals. AB - Locomotion is one of the major energetic costs faced by animals and various strategies have evolved to reduce its cost. Birds use interspersed periods of flapping and gliding to reduce the mechanical requirements of level flight while undergoing cyclical changes in flight altitude, known as undulating flight. Here we equipped free-ranging marine vertebrates with accelerometers and demonstrate that gait patterns resembling undulating flight occur in four marine vertebrate species comprising sharks and pinnipeds. Both sharks and pinnipeds display intermittent gliding interspersed with powered locomotion. We suggest, that the convergent use of similar gait patterns by distinct groups of animals points to universal physical and physiological principles that operate beyond taxonomic limits and shape common solutions to increase energetic efficiency. Energetically expensive large-scale migrations performed by many vertebrates provide common selection pressure for efficient locomotion, with potential for the convergence of locomotory strategies by a wide variety of species. PMID- 21673674 TI - Revealing the high-energy electronic excitations underlying the onset of high temperature superconductivity in cuprates. AB - In strongly correlated systems the electronic properties at the Fermi energy (E(F)) are intertwined with those at high-energy scales. One of the pivotal challenges in the field of high-temperature superconductivity (HTSC) is to understand whether and how the high-energy scale physics associated with Mott like excitations (|E-E(F)|>1 eV) is involved in the condensate formation. Here, we report the interplay between the many-body high-energy CuO(2) excitations at 1.5 and 2 eV, and the onset of HTSC. This is revealed by a novel optical pump supercontinuum-probe technique that provides access to the dynamics of the dielectric function in Bi(2)Sr(2)Ca(0.92)Y(0.08)Cu(2)O(8+delta) over an extended energy range, after the photoinduced suppression of the superconducting pairing. These results unveil an unconventional mechanism at the base of HTSC both below and above the optimal hole concentration required to attain the maximum critical temperature (T(c)). PMID- 21673675 TI - Atomistic mechanism for the activation and desensitization of an AMPA-subtype glutamate receptor. AB - Ionotropic glutamate receptors (iGluRs) mediate fast excitatory synaptic transmission in the central nervous system. Upon agonist binding, an iGluR opens to allow the flow of cations and subsequently enters into a desensitized state. It remains unclear how agonist binding to the ligand-binding domain (LBD) is transmitted to the transmembrane domain (TMD) for channel activation and desensitization. Here we report molecular dynamics simulations of an AMPA (alpha amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype iGluR in explicit water and membrane. Channel opening and closing were observed in simulations of the activation and desensitization processes, respectively. The motions of the LBD-TMD linkers along the central axis of the receptor and in the lateral plane contributed cooperatively to channel opening and closing. The detailed mechanism of channel activation and desensitization suggested by the simulations here is consistent with existing data and may serve as a guide for new experiments and for the design of pharmacological agents. PMID- 21673676 TI - Neural coding in a single sensory neuron controlling opposite seeking behaviours in Caenorhabditis elegans. AB - Unveiling the neural codes for intricate behaviours is a major challenge in neuroscience. The neural circuit for the temperature-seeking behaviour of Caenorhabditis elegans is an ideal system to dissect how neurons encode sensory information for the execution of behavioural output. Here we show that the temperature-sensing neuron AFD transmits both stimulatory and inhibitory neural signals to a single interneuron AIY. In this circuit, a calcium concentration threshold in AFD acts as a switch for opposing neural signals that direct the opposite behaviours. Remote control of AFD activity, using a light-driven ion pump and channel, reveals that diverse reduction levels of AFD activity can generate warm- or cold-seeking behaviour. Calcium imaging shows that AFD uses either stimulatory or inhibitory neuronal signalling onto AIY, depending on the calcium concentration threshold in AFD. Thus, dual neural regulation in opposite directions is directly coupled to behavioural inversion in the simple neural circuit. PMID- 21673677 TI - Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer. AB - BACKGROUND: Glomeruloid microvascular proliferation (GMP), a novel histology based angiogenesis marker, has been associated with decreased survival in several human cancers. METHODS: In this study, we evaluated the ability of GMP to predict clinical response to neoadjuvant chemotherapy in a series of locally advanced breast cancers (n=112). RESULTS: Presence of GMP (21% of the cases) was significantly associated with high-grade tumours and TP53 mutations in addition to the basal-like and HER2 subtypes of breast cancer as defined by gene expression data. GMP was correlated to a gene expression signature for tumour hypoxia response. The GMP pattern was also significantly associated with lack of treatment response and progressive disease (P=0.004). INTERPRETATION: The findings suggest that GMP might be able to predict the lack of response to neoadjuvant chemotherapy in locally advanced breast cancer. Whether GMP may be an independent predictor compared with other factors including TP53 mutation status and tumour grade needs confirmation in larger studies. PMID- 21673678 TI - The minimal incubation period from the onset of Barrett's oesophagus to symptomatic adenocarcinoma. AB - BACKGROUND: The interval between the onset of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) can be termed the incubation period. However, the unrecorded onset of BO precludes its direct observation. METHODS: Determining the range of intervals between BO diagnosis and OAC within the longest observational BO follow-up study. Exclusion criteria were presence of high-grade dysplasia (HGD) or OAC at baseline, death within <2 years of BO diagnosis, oesophagectomy without HGD/OAC and loss to follow-up. A total of 133 patients (M/F 73/60) were taken into account. RESULTS: In 1967 person years of follow-up there were 13 cases of HGD/OAC, (0.66% p.a.; 95% CI 0.58-0.74), 96 patients died without HGD/OAC and 24 survived without HGD/OAC. The mean intervals between BO diagnosis and either HGD/OAC, death or end of follow-up were 10.8, 12.6 and 25.5 years, respectively, and the mean ages at endpoint were 72.5, 80.0 and 68.3 years, respectively. The survivors without HGD/OAC had a lower age at BO diagnosis (mean 42.8 vs 61.2 and 67.4 years, P<0.001). Baseline presence of low grade dysplasia was associated with progression to HGD/OAC (log rank P<0.001). CONCLUSION: The Rotterdam BO follow-up cohort revealed a long incubation period between onset of BO and development of HGD/OAC, in patients without HGD/OAC at baseline as illustrated by 24 patients diagnosed with BO at a young age and followed for a mean period of 25.5 years. Their tumour-free survival established a minimum incubation period, suggesting a true incubation period of three decades or more. PMID- 21673679 TI - Increased mobilisation of circulating endothelial progenitors in von Hippel Lindau disease and renal cell carcinoma. AB - BACKGROUND: Circulating endothelial cells (CECs) are a candidate biomarker for monitoring angiogenesis in cancer. Circulating endothelial cell subsets are mobilised by angiogenic mediators. Because of the highly angiogenic phenotype of renal cell carcinoma (RCC), we sought to assess the potential of CECs as a marker of RCC in patients with von Hippel-Lindau (VHL) disease and those with sporadic RCC. METHODS: We performed multicolour flow cytometry to enumerate CECs in patients with RCC, patients with VHL disease with and without RCC, and normal subjects. Two subsets of CECs were evaluated: mature CECs (mCECs) and circulating endothelial progenitors (CEPs). RESULTS: In patients with VHL disease and RCC and those with sporadic RCC (N=10), CEPs and the CEP:mCEC ratio were higher than in normal subjects (N=17) (median CEPs: 0.97 vs 0.19 cells MUl(-1), respectively, P<0.01; median CEP:mCEC: 0.92 vs 0.58, respectively, P=0.04). However, in patients with VHL without RCC, CECs were not increased. In paired pre- and post nephrectomy RCC patient samples (N=20), CEPs decreased after surgery (median difference 0.02 cells MUl(-1), -0.06 to 1.2; P=0.05). CONCLUSION: Circulating endothelial progenitors were elevated in RCC, but not in patients with VHL without RCC. Circulating endothelial progenitor enumeration merits further investigation as a monitoring strategy for patients with VHL. PMID- 21673680 TI - Molecular alterations associated with liver metastases development in colorectal cancer patients. AB - BACKGROUND: Understanding the molecular biology of colorectal cancer (CRC) provides opportunities for effective personalised patient management. We evaluated whether chromosomal aberrations, mutations in the PI(3)K signalling pathway and the CpG-island methylator phenotype (CIMP) in primary colorectal tumours can predict liver metastases. METHODS: Formalin-fixed paraffin-embedded material from primary colorectal tumours of three different groups were investigated: patients with CRC without metastases (M0, n=39), patients who were treated with hyperthermal intraperitoneal chemotherapy for CRC metastases confined to the peritoneum (PM, n=46) and those who had isolated hepatic perfusion for CRC metastases confined to the liver (LM, n=48). RESULTS: All samples were analysed for DNA copy number changes, PIK3CA, KRAS, BRAF mutations, CIMP and microsatellite instability. The primary CRCs of the LM group had significantly higher frequency of amplified chromosome 20q (P=0.003), significantly fewer mutations in the PI(3)K signalling pathway (P=0.003) and fewer CIMP high tumours (P=0.05). There was a strong inverse correlation between 20q and the PI(3)K pathway mutations. CONCLUSION: The development of CRC liver metastases is associated with amplification of chromosome 20q and not driven by mutations in the PI(3)K signalling pathway. PMID- 21673681 TI - PEA3/ETV4-related transcription factors coupled with active ERK signalling are associated with poor prognosis in gastric adenocarcinoma. AB - BACKGROUND: Transcription factors often play important roles in tumourigenesis. Members of the PEA3 subfamily of ETS-domain transcription factors fulfil such a role and have been associated with tumour metastasis in several different cancers. Moreover, the activity of the PEA3 subfamily transcription factors is potentiated by Ras-ERK pathway signalling, which is itself often deregulated in tumour cells. METHODS: Immunohistochemical patterns of PEA3 expression and active ERK signalling were analysed and mRNA expression levels of PEA3, ER81, MMP-1 and MMP-7 were determined in gastric adenocarcinoma samples. RESULTS: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in gastric adenocarcinomas. PEA3 is upregulated at the protein level in gastric adenocarcinomas and both PEA3/ETV4 and ER81/ETV1 are upregulated at the mRNA level in gastric adenocarcinoma tissues. This increased expression correlates with the expression of a target gene associated with metastasis, MMP-1. Enhanced ERK signalling is also more prevalent in late-stage gastric adenocarcinomas, and the co-association of ERK signalling and PEA3 expression also occurs in late stage gastric adenocarcinomas. Furthermore, the co-association of ERK signalling and PEA3 expression correlates with decreased survival rates. CONCLUSIONS: This study shows that members of the PEA3 subfamily of transcription factors are upregulated in gastric adenocarcinomas and that the simultaneous upregulation of PEA3 expression and ERK pathway signalling is indicative of late-stage disease and a poor survival prognosis. PMID- 21673682 TI - Attenuation of muscle atrophy by an N-terminal peptide of the receptor for proteolysis-inducing factor (PIF). AB - BACKGROUND: Atrophy of skeletal muscle in cancer cachexia has been attributed to a tumour-produced highly glycosylated peptide called proteolysis-inducing factor (PIF). The action of PIF is mediated through a high-affinity membrane receptor in muscle. This study investigates the ability of peptides derived from the 20 N terminal amino acids of the receptor to neutralise PIF action both in vitro and in vivo. METHODS: Proteolysis-inducing factor was purified from the MAC16 tumour using an initial pronase digestion, followed by binding on DEAE cellulose, and the pronase was inactivated by heating to 80 degrees C, before purification of the PIF using affinity chromatography. In vitro studies were carried out using C(2)C(12) murine myotubes, while in vivo studies employed mice bearing the cachexia-inducing MAC16 tumour. RESULTS: The process resulted in almost a 23,000 fold purification of PIF, but with a recovery of only 0.004%. Both the D- and L forms of the 20mer peptide attenuated PIF-induced protein degradation in vitro through the ubiquitin-proteosome proteolytic pathway and increased expression of myosin. In vivo studies showed that neither the D- nor the L-peptides significantly attenuated weight loss, although the D-peptide did show a tendency to increase lean body mass. CONCLUSION: These results suggest that the peptides may be too hydrophilic to be used as therapeutic agents, but confirm the importance of the receptor in the action of the PIF on muscle protein degradation. PMID- 21673683 TI - Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. AB - BACKGROUND: Cholangiocarcinoma (CC) is a highly malignant carcinoma. We attempted to clarify the prognostic significance of c-Met overexpression and its association with clinicopathological factors in patients with CC. PATIENTS AND METHODS: One hundred and eleven patients with intrahepatic CC (IHCC) and 136 patients with extrahepatic CC (EHCC) who had undergone curative surgery were divided immunohistologically into c-Met(high) and c-Met(low) groups. Clinicopathological factors and outcomes were compared between the groups. c-Met and epidermal growth factor receptor (EGFR) expression was also examined in 10 CC cell lines. RESULTS: The positivity of c-Met was 45.0% in IHCC and 68.4% in EHCC; c-Met(high) expression was demonstrated in 11.7% of IHCC and 16.2% of EHCC. c Met(high) expression was significantly correlated with the 5-year survival rate for CC overall (P=0.0046) and for IHCC (P=0.0013), histopathological classification in EHCC, and for EGFR overexpression in both IHCC and EHCC. Coexpression and coactivation of c-Met and EGFR were also observed in CC cell lines. Multivariate analysis revealed that c-Met(high) expression was an independent predictor of poor overall and disease-free survival in patients with IHCC. CONCLUSIONS: c-Met overexpression is associated with EGFR expression and is a poor prognostic factor in CC. PMID- 21673684 TI - Circulating microRNAs in plasma of patients with oesophageal squamous cell carcinoma. AB - BACKGROUND: Several recent studies demonstrated that microRNAs (miRNAs) are stably detectable in plasma/serum. We hypothesised that plasma miRNAs concentrations contributed to potential biomarkers in patients with oesophageal squamous cell carcinoma (ESCC). METHODS: We selected three oncogenic miRNAs (miR 21, miR-184, miR-221) and one tumour suppressive miRNA (miR-375), which are frequently reported in squamous cell carcinoma, as candidate targets for this plasma miRNA assay. This study was divided into three steps: (1) Determination of appropriate plasma miRNAs in preliminary tests. (2) Evaluation of whether the plasma miRNA assays could monitor tumour dynamics. (3) Validation study on the clinical application of plasma miRNA assays in 50 ESCC patients and 20 healthy volunteers. RESULTS: (1) In preliminary tests, the plasma level of miR-21 was significantly higher (P=0.0218) and that of miR-375 (P=0.0052) was significantly lower in ESCC patients than controls. (2) The high plasma miR-21 levels reflected tumour levels in all cases (100%). The plasma level of miR-21 was significantly reduced in postoperative samples (P=0.0058). (3) On validation analysis, the plasma level of miR-21 tended to be higher in ESCC patients (P=0.0649), while that of miR-375 was significantly lower (P<0.0001) and the miR-21/miR-375 ratio was significantly higher (P<0.0001) in ESCC patients than in controls. The value of the area under the receiver-operating characteristic curve (AUC) was 0.816 for the miR-21/miR-375 ratio assay. Patients with a high plasma level of miR-21 tended to have greater vascular invasion (P=0.1554) and to show a high correlation with recurrence (P=0.0164). CONCLUSION: Detection of circulating miRNAs might provide new complementary tumour markers for ESCC. PMID- 21673685 TI - XELOX vs FOLFOX-4 as first-line therapy for metastatic colorectal cancer: NO16966 updated results. AB - BACKGROUND: We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer. METHODS: NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 * 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed. RESULTS: The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 * 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85-1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83-1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4. CONCLUSION: Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer. PMID- 21673688 TI - In these pages...life transitions and movies. PMID- 21673686 TI - DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6. AB - BACKGROUND: There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases. METHODS: Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan. RESULTS: In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan. CONCLUSION: Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers. PMID- 21673689 TI - Adolescent transition: Ordinary People (1980), Fly Away Home (1996), and (500) Days Of Summer (2009). AB - Five important transitional tasks of adolescent development are (i) taming the upsurge of desires and impulses, both sexual and aggressive, into constructive and creative directions; (ii) establishing independence from infantile family ties (while maintaining some involvement with the family of origin); (iii) reconciling self-preoccupations with social attachments; (iv) reworking identifications, especially sexual; and (v) establishing romantic attachments and solidifying ongoing stable love relationships. These tasks are illustrated with the help of three movies, namely Ordinary People, Fly Away Home, and (500) Days of Summer. PMID- 21673687 TI - CTGF is overexpressed in malignant melanoma and promotes cell invasion and migration. AB - BACKGROUND: Malignant melanoma cells are known to have altered expression of growth factors compared with normal human melanocytes. These changes most likely favour tumour growth and progression, and influence tumour environment. The induction of transforming growth factor beta1, 2 and 3 as well as BMP4 and BMP7 expression in malignant melanoma has been reported before, whereas the expression of an important modulator of these molecules, connective tissue growth factor (CTGF), has not been investigated in melanomas until now. METHODS: Expression of CTGF was analysed in melanoma cell lines and tissue samples by qRT-PCR and immunohistochemistry. To determine the regulation of CTGF expression in malignant melanoma, specific siRNA was used. Additionally, migration, invasion and attachment assays were carried out. RESULTS: We were able to demonstrate that CTGF expression is upregulated in nine melanoma cell lines and in primary and metastatic melanoma in situ. The transcription factor HIF-1alpha was revealed as a positive regulator for CTGF expression. Melanoma cells, in which CTGF expression is diminished, show a strong reduction of migratory and invasive properties when compared with controls. Further, treatment of normal human epidermal melanocytes with recombinant CTGF leads to an increase of migratory and invasive behaviour of these cells. CONCLUSION: These results suggest that CTGF promotes melanoma cell invasion and migration and, therefore, has an important role in the progression of malignant melanoma. PMID- 21673690 TI - Developmental tasks of early marriage: Barefoot in the Park (1967), Raising Arizona (1987), The Quiet Man (1952). AB - Using three Hollywood movies as a springboard, the authors offer a discussion of the psychosocial challenges faced by an individual entering a marital relationship. Keeping their attention on both intrapsychic and interpersonal factors, as well as the group matrix surrounding the couple, the authors discuss the subtleties of identity transformation, evolution of true mutuality, distance related conflicts, and the deeper synthesis of affection and sensuality in the setting of early marriage. Their portrayal of this adult developmental phase is intended to help clinicians evolve greater empathy with newly married individuals. PMID- 21673691 TI - Psychological tasks associated with divorce: Eat, Pray, Love (2010), An Unmarried Woman (1978), and Kramer vs. Kramer (1979). AB - The dependency paradox (Feeney) states that independence actually can result from being in a nurturing relationship. Those who divorce often have the opposite notion that independence will occur without a relationship. The movies Eat, Pray, Love, An Unmarried Woman, and Kramer vs. Kramer examine divorce from different angles. The protagonists in all three movies grow through the process of divorce, each achieving a level of autonomy that seemed unattainable within their marriage. This paper aims to explore the concept of divorce in light of the dependency paradox by examining the self-differentiation achieved and the consequences of such independence for both the individual and, in Kramer vs. Kramer, for the child involved. PMID- 21673692 TI - Psychological aspects of retirement: About Schmidt (2002), and Everybody's Fine (2009). AB - With the films About Schmidt and Everybody's Fine as his main point of reference, the author elucidates the complex and often melancholic sojourn that follows ordinary men's retirement from their jobs. As this usually occurs during late middle age, the complicating variable of spousal loss, departure of children from the family home, a failing body, and social marginalization also get added to the picture. The vicissitudes of the resulting intrapsychic and interpersonal upheaval can lead to depressive withdrawal or a renewed effort at finding meaning in life. Ego resilience is tested and sublimation and creativity, if possible, save the day. PMID- 21673693 TI - Death, rejuvenation and immortality in film: On Golden Pond (1981), Cat on a Hot Tin Roof (1958) and Cocoon (1985). AB - This paper seeks to highlight the developmental tasks of late adulthood with the help of three Hollywood movies. These tasks include: (i) struggling to maintain physical integrity, (ii) handling the "wound of mortality", (iii) maintaining activity and sexuality, and (iv) becoming wise. Among other challenges faced by an individual during this phase of life are loss of love objects, illness and possible compromise of mental functions, de-cathexis of material possessions and coming to terms with one's approaching death. All sorts of healthy and unhealthy psychosocial maneuvers come to the surface as a result of these stresses. This paper illustrates these dilemmas and their potential solutions via a discussion of three movies. PMID- 21673704 TI - Do nonsteroidal anti-inflammatory drugs prevent melanoma? PMID- 21673705 TI - Generating consensus research goals and treatment strategies for pemphigus and pemphigoid: The 2010 JC Bystryn Pemphigus and Pemphigoid Meeting. PMID- 21673707 TI - The search for a chemoprevention agent effective against melanoma: considerations and challenges. AB - Studies examining the potential chemopreventive properties of nonsteroidal anti inflammatory drugs (NSAIDs) against melanoma report widely varying results. The construction and interpretation of these studies are hampered by many factors, including limited knowledge of the pathogenesis of melanoma, leading to difficulties in determining the relevant factors in the administration of chemopreventive agents and difficulties in assessing long-term use of nonprescription medications. The study by Curiel-Lewandrowski et al. reported in this issue is an important contribution to the literature, but the final verdict regarding the chemopreventive properties of NSAIDs against melanoma is yet to come. PMID- 21673708 TI - Gene therapy for keratin genodermatoses: striving forward but obstacles persist. AB - D'Alessandro and colleagues have investigated stress responses in keratinocyte cell lines lacking keratin 14 (K14-null mutation). In this issue, they describe the use of this model to assess the extent of phenotypic rescue achievable by wild-type K14 in the absence of a dominant negative mutation. This work provides proof that, in principle, transfection of wild-type K14 on a null background can significantly normalize the cell and reduce stress responses. However, hurdles to gene therapy in vivo persist because the majority of patients with keratin genodermatoses have heterozygous dominant negative mutations, which are more disruptive than those of the null state. Although correction in the laboratory is now relatively routine, gene delivery to the skin of patients and stable correction of mutations remain major challenges. PMID- 21673709 TI - Integrating chemistry and immunology in allergic contact dermatitis: more questions than answers? AB - In this issue, Simonsson and colleagues shed light on the chemical mechanisms determining hapten formation in the skin, which precede the elicitation of an antigen-specific immune response in allergic contact dermatitis. Combining fluorescence microscopy, proteomics, and mass spectrometry, the investigators identified keratins K5 and K14, particularly cysteine 54 of K5, in the human basal epidermal layer as the major molecular targets of caged thiol-reactive fluorescent haptens (i.e., bromobimanes). Anti-keratin antibody responses in mice exposed to bromobimanes suggest the generation of immunogenic epitopes by cysteine-reactive haptens. Although many issues await further investigation, Simonsson and co-workers' observations advance our understanding of the molecular basis of hapten-protein complex formation in skin. PMID- 21673710 TI - The cornified envelope: a first line of defense against reactive oxygen species. AB - Human skin serves as a barrier against multiple environmental insults, including pathogenic microorganisms, pollutants, toxic chemicals, and UV radiation. In the outermost layer of the epidermis, the cornified envelope functions as a mechanical and permeability barrier. In this issue, Vermeij et al. report a novel function of cornified envelope proteins as a first-line antioxidant barrier to protect the body from damage induced by reactive oxygen species. PMID- 21673711 TI - Forgot your HAT? CBP might be to blame. PMID- 21673713 TI - Pleurone, a novel human neutrophil elastase inhibitor from the fruiting bodies of the mushroom Pleurotus eryngii var. ferulae. PMID- 21673714 TI - Two new doramectin analogs from Streptomyces avermitilis NEAU1069: fermentation, isolation and structure elucidation. PMID- 21673715 TI - Up-regulation of A-type potassium currents protects neurons against cerebral ischemia. AB - Excitotoxicity is the major cause of many neurologic disorders including stroke. Potassium currents modulate neuronal excitability and therefore influence the pathological process. A-type potassium current (I(A)) is one of the major voltage dependent potassium currents, yet its roles in excitotoxic cell death are not well understood. We report that, following ischemic insults, the I(A) increases significantly in large aspiny (LA) neurons but not medium spiny (MS) neurons in the striatum, which correlates with the higher resistance of LA neurons to ischemia. Activation of protein kinase Calpha increases I(A) in LA neurons after ischemia. Cultured neurons from transgenic mice lacking both Kv1.4 and Kv4.2 subunits exhibit an increased vulnerability to ischemic insults. Increase of I(A) by recombinant expression of Kv1.4 or Kv4.2 is sufficient in improving the survival of MS neurons against ischemic insults both in vitro and in vivo. These results, taken together, provide compelling evidence for a protective role of I(A) against ischemia. PMID- 21673716 TI - Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis. AB - Vitamin E consists of tocopherols and tocotrienols, in which alpha-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3+/-3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke. PMID- 21673717 TI - Allostatic regulation of neuronal excitability by transient ischemia. PMID- 21673718 TI - Long-term effect of exercise on bone mineral density and body composition in post menopausal ex-elite athletes: a retrospective study. AB - OBJECTIVES: The aim of this retrospective study was to determine the long-term effect of exercise on bone mineral density (BMD), bone mineral content (BMC) and body composition (BC) in post-menopausal women who were elite athletes during their youth compared with sedentary controls. SUBJECTS/METHODS: It is a retrospective study and carried out in an outpatient clinic. A total of 48 post menopausal women (54-73 years of age) were enrolled. Ex-elite athletes with long term (>20 years) histories of significant training and performance were divided into two groups: weight-bearing sports (runners, n=12) and non-weight-bearing sports (swimmers, n=12). The athletes were age matched with sedentary controls (n=24). BMD, BMC and BC were measured using dual-energy X-ray absorptiometry. Healthcare and sport activity histories were evaluated using a questionnaire. RESULTS: No significant differences were found with regard to body weight, height, body mass index and hours of activity between the two groups of athletes. There were no significant differences in activity levels between athletes and controls at the time of this study. BMD and BMC were not significantly different between athletes; they were significantly higher in athletes than in controls (P<0.001). Although the ex-athletes did not significantly differ in BC, left and right lean arm mass and arm BMD were significantly higher in swimmers than in runners (P<0.0001). CONCLUSIONS: The high level of physical activity observed in female athletes is associated with improved muscle mass, BMD and BMC, and physical activity during youth seems to have a beneficial effect on bone mass and helps to prevent bone loss due to aging. PMID- 21673719 TI - Modifying effect of maternal nutritional status on the impact of maternal multiple micronutrient supplementation on birthweight in Indonesia. AB - BACKGROUND/OBJECTIVE: Low birthweight (LBW) and intrauterine growth restriction are linked with maternal nutritional status during pregnancy, and maternal supplementation with multiple micronutrients (MMNs) is reported to increase birthweight. Responses to MMN, however, might be modified by maternal nutrition. SUBJECTS/METHODS: To examine the differential effects of maternal nutritional status on birthweight responses to prenatal MMN supplementation, data from the Supplementation with Multiple Micronutrient Intervention Trial, a cluster randomized trial in Indonesia was analyzed. Birthweight outcomes of 7001 infants whose mothers received iron/folic acid were compared with 7292 infants whose mothers received MMN. The modifying effects of maternal short-term nutritional status (mid-upper arm circumference (MUAC) and long-term nutritional status (height) on the birthweight response to MMN supplementation were assessed. RESULTS: For women with higher MUAC (>=23.5 cm), MMN increased mean birthweight by 33 g (95% confidence interval (CI): -1 to 66, P=0.06) and significantly reduced LBW by 21% (relative risk: 0.79, 95% CI: 0.64-0.99, P=0.04). The modifying effect of MUAC on mean birthweight, LBW and small for gestational age was significant. There was no evidence of a modifying effect of maternal height on the response to MMN. CONCLUSIONS: Supplementation with MMN in pregnancy increased birthweight, but maternal nutritional status modified this response, with infants born to women with better short-term nutrition having greater birthweight response. PMID- 21673722 TI - Emotion in the brain: of low roads, high roads and roads less travelled. PMID- 21673723 TI - Synaptic plasticity: finely tuning caspase function. PMID- 21673720 TI - Repertoire of microglial and macrophage responses after spinal cord injury. AB - Macrophages from the peripheral circulation and those derived from resident microglia are among the main effector cells of the inflammatory response that follows spinal cord trauma. There has been considerable debate in the field as to whether the inflammatory response is good or bad for tissue protection and repair. Recent studies on macrophage polarization in non-neural tissues have shed much light on their changing functional states. In the context of this literature, we discuss the activation of macrophages and microglia following spinal cord injury, and their effects on repair. Harnessing their anti inflammatory properties could pave the way for new therapeutic strategies for spinal cord trauma. PMID- 21673725 TI - DNA replication: Pif1 overcomes a quadruplex hurdle. PMID- 21673726 TI - Mechanotransduction: YAP and TAZ feel the force. PMID- 21673727 TI - Actin up for Hippo. PMID- 21673728 TI - X inactivation: a histone protects from reprogramming by the frog. PMID- 21673733 TI - Inherited IgA glycosylation pattern in IgA nephropathy and HSP nephritis: where do we go next? AB - New data from Kiryluk et al. show the importance of genetic factors in determining the profile of serum IgA1 O-glycoforms in IgA nephropathy and Henoch Schonlein purpura nephritis. Elevated serum levels of poorly galactosylated IgA1 O-glycoforms do not, however, appear sufficient in themselves to cause nephritis in these two diseases, and a 'second hit' is necessary before changes in IgA1 glycosylation translate into clinical disease. The challenge now is to determine what these genetic factors are. PMID- 21673734 TI - Erythropoiesis-stimulating agents and pure red-cell aplasia: you can't fool Mother Nature. AB - Subtle alterations in the properties of biopharmaceutical agents may increase their immunogenicity and lead to the production of autoantibodies. Biosimilar agents may not undergo the same quality control in their production, packaging, storage, and distribution as their patented competitors. The extensive use of biosimilar erythropoiesis-stimulating agents led to an epidemic of pure red-cell aplasia in Thailand. The response of Thai regulators may be a model for other countries as the use of biosimilar agents expands. PMID- 21673735 TI - SGK3: a novel regulator of renal phosphate transport? AB - Phosphate is a key constituent of several important molecules, and hyperphospatemia has been associated with increased cardiovascular mortality. The kidney plays a crucial role in phosphate metabolism, as it is able to modulate phosphate excretion. Serum- and glucocorticoid-inducible kinase 3 (SGK3) has been shown to regulate a wide variety of transport systems. Bhandaru et al. suggest that SGK3 may have a significant role in the regulation of renal tubular phosphate transport. PMID- 21673736 TI - Hypertension as a mitochondrial and metabolic disease. AB - The molecular pathophysiology of hypertension is probably like a jigsaw puzzle of different but overlapping sets of factors and pathways that vary from one patient or one group of patients to another. Mitochondrial and metabolic abnormalities could be crucial pieces of this puzzle. PMID- 21673738 TI - Possible other causative risk factors in patients with chronic renal disease who had a history of hemolytic uremic syndrome. PMID- 21673739 TI - Paraprotein 'zippers'. PMID- 21673740 TI - Colonization of Ireland: revisiting 'the pygmy shrew syndrome' using mitochondrial, Y chromosomal and microsatellite markers. AB - There is great uncertainty about how Ireland attained its current fauna and flora. Long-distance human-mediated colonization from southwestern Europe has been seen as a possible way that Ireland obtained many of its species; however, Britain has (surprisingly) been neglected as a source area for Ireland. The pygmy shrew has long been considered an illustrative model species, such that the uncertainty of the Irish colonization process has been dubbed 'the pygmy shrew syndrome'. Here, we used new genetic data consisting of 218 cytochrome (cyt) b sequences, 153 control region sequences, 17 Y-intron sequences and 335 microsatellite multilocus genotypes to distinguish between four possible hypotheses for the colonization of the British Isles, formulated in the context of previously published data. Cyt b sequences from western Europe were basal to those found in Ireland, but also to those found in the periphery of Britain and several offshore islands. Although the central cyt b haplotype in Ireland was found in northern Spain, we argue that it most likely occurred in Britain also, from where the pygmy shrew colonized Ireland as a human introduction during the Holocene. Y-intron and microsatellite data are consistent with this hypothesis, and the biological traits and distributional data of pygmy shrews argue against long-distance colonization from Spain. The compact starburst of the Irish cyt b expansion and the low genetic diversity across all markers strongly suggests a recent colonization. This detailed molecular study of the pygmy shrew provides a new perspective on an old colonization question. PMID- 21673741 TI - Complex inheritance of larval adaptation in Plutella xylostella to a novel host plant. AB - Studying the genetics of host shifts and range expansions in phytophagous insects contributes to our understanding of the evolution of host plant adaptation. We investigated the recent host range expansion to pea, in the pea-adapted strain (P strain) of the crucifer-specialist diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae). Larval survivorship on the novel host plant pea and a typical crucifer host (kale) was measured in reciprocal F(1), F(2) and backcrosses between the P-strain and a strain reared only on crucifers (C strain). Reciprocal F(1) hybrids differed: offspring from P-strain mothers survived better on pea, indicating a maternal effect. However, no evidence for sex-linkage was found. Backcrosses to the P-strain produced higher survivorship on pea than C-strain backcrosses, suggesting recessive inheritance. In a linkage analysis with amplified fragment length polymorphism markers using P-strain backcrosses, two, four and five linkage groups contributing to survival on pea were identified in three different families respectively, indicating oligogenic inheritance. Thus, the newly evolved ability to survive on pea has a complex genetic basis, and the P-strain is still genetically heterogeneous and not yet fixed for all the alleles enabling it to survive on pea. Survivorship on kale was variable, but not related to survivorship on pea. This pattern may characterize the genetic inheritance of early host plant adaptation in oligophagous insect species. PMID- 21673742 TI - Origin and evolution of SINEs in eukaryotic genomes. AB - Short interspersed elements (SINEs) are one of the two most prolific mobile genomic elements in most of the higher eukaryotes. Although their biology is still not thoroughly understood, unusual life cycle of these simple elements amplified as genomic parasites makes their evolution unique in many ways. In contrast to most genetic elements including other transposons, SINEs emerged de novo many times in evolution from available molecules (for example, tRNA). The involvement of reverse transcription in their amplification cycle, huge number of genomic copies and modular structure allow variation mechanisms in SINEs uncommon or rare in other genetic elements (module exchange between SINE families, dimerization, and so on.). Overall, SINE evolution includes their emergence, progressive optimization and counteraction to the cell's defense against mobile genetic elements. PMID- 21673744 TI - Evidence for the equal resilience of Triodia spp. (Poaceae), from different functional groups, to frequent fire dating back to the late Pleistocene. AB - Species with different regenerative responses to fire are hypothesised to coexist by utilising the different temporal and spatial niche opportunities created by the stochasticity of the fire regime. This is strongly supported by observations of instability of species' presence and abundance at the local scale while these are stable at the community scale. However, observations of species coexistence in fire-prone communities are limited to several decades only. To improve the robustness of this hypothesis, coalescent analysis, using chloroplast microsatellites, was undertaken on three sympatric species of Triodia from different functional groups in the fire-prone Kimberley region of Western Australia. The results inferred that T. bitextura, an obligate resprouter, Triodia sp., an obligate seeder, and T. epactia, a facultative resprouter, had mean T(mrca) values of 65k, 40k and 111k generations, respectively. Using a mutation rate of 3.2 * 10(-5) and a generation time of 5 years gave T(mrca) values of 436k, 203k and 556 k years, respectively. These results provide evidence for the coexistence of these species to the same fire regime dating back to the late Pleistocene. It also demonstrates the long-term resilience of an obligate seeder, Triodia sp., in a frequently burnt environment at the community scale. PMID- 21673743 TI - Recombination rate variation in closely related species. AB - Despite their importance to successful meiosis and various evolutionary processes, meiotic recombination rates sometimes vary within species or between closely related species. For example, humans and chimpanzees share virtually no recombination hotspot locations in the surveyed portion of the genomes. However, conservation of recombination rates between closely related species has also been documented, raising an apparent contradiction. Here, we evaluate how and why conflicting patterns of recombination rate conservation and divergence may be observed, with particular emphasis on features that affect recombination, and the scale and method with which recombination is surveyed. Additionally, we review recent studies identifying features influencing fine-scale and broad-scale recombination patterns and informing how quickly recombination rates evolve, how changes in recombination impact selection and evolution in natural populations, and more broadly, which forces influence genome evolution. PMID- 21673745 TI - Detection of epistatic interactions in association mapping populations: an example from tetraploid potato. AB - Epistatic interactions among loci are expected to contribute substantially to variation of quantitative traits. The objectives of our research were to (i) compare a classical mixed-model approach with a combined mixed-model and analysis of variance approach for detecting epistatic interactions; (ii) examine using computer simulations the statistical power to detect additive-additive, additive dominance and dominance-dominance epistatic interactions and (iii) detect epistatic interactions between candidate genes for resistance to leaf blight in a set of tetraploid potato clones. Our study was based on the genotypic and phenotypic data of 184 tetraploid potato cultivars as well as computer simulations. The number of significant (alpha* =1 * 10(-6)) epistatic interactions ranged for the three examined traits from 3 to 32. Our findings suggested that the combined mixed-model and analysis of variance approach leads in comparison with the classical mixed-model approach not to an increased rate of false-positives. The results of the computer simulations suggested that, if molecular markers are available that are in high LD (D'>0.9) with the trait coding loci, the statistical power to detect epistatic interactions, which explain 5-10% of the phenotypic variance, was of a size that seems promising for their detection. PMID- 21673746 TI - Opinions and intentions of parents of an autistic child toward genetic research results: two typical profiles. AB - Returning results to research participants is increasingly acknowledged in research ethics guidelines. But few research teams actually do it or provide mechanisms for offering it as an option. We explored the perspective of parents of an autistic child participating in genetic research. In all, 388 questionnaires were sent to 194 parents; 158 questionnaires were completed (89 mothers and 69 fathers), giving a response rate of 41%. 97% of respondents (n=153) fully expressed a strong desire to receive research results, either general or individual ones. The survey solicited parents' opinions as to what means could be put in place to return research results. The majority held the research team responsible for returning individual results (79.7%, n=126). They indicated that it should occur at the completion of the research project (69%, n=109), by mail (75.3%, n=119). Over three quarters felt the Ministry of Health should cover the associated costs (77.8%, n=123). If the communication of individual findings, whether positive or negative, were to be possible, these would allow some respondents 'to be prepared for the future' (37%, n=57), without necessarily having practical benefits (21%, n=32), but at least bringing them 'relief or understanding' (14%, n=21). Moreover, parents were clear about the difference between research and clinical settings. This study underlines the importance of broadening the discussion about the communication of research results, especially individual ones. We believe that the integration of different perspectives--those of researchers, clinicians, ethics committees and participants--will enrich the debate and offer enlightenment for future ethical guidelines. PMID- 21673747 TI - Characterization of autosomal copy-number variation in African Americans: the HyperGEN Study. AB - African Americans are a genetically diverse population with a high burden of many, common heritable diseases. However, our understanding of genetic variation in African Americans is substandard because of a lack of published population based genetic studies. We report the distribution of copy-number variation (CNV) in African Americans collected as part of the Hypertension Genetic Epidemiology Network (HyperGEN) using the Affymetrix 6.0 array and the CNV calling algorithms Birdsuite and PennCNV. We present population estimates of CNV from 446 unrelated African-American subjects randomly selected from the 451 families collected within HyperGEN. Although the majority of CNVs discovered were individually rare, we found the frequency of CNVs to be collectively high. We identified a total of 11 070 CNVs greater than 10 kb passing quality control criteria that were called by both algorithms - leading to an average of 24.8 CNVs per person covering 2214 kb (median). We identified 1541 unique copy-number variable regions, 309 of which did not overlap with the Database of Genomic Variants. These results provide further insight into the distribution of CNV in African Americans. PMID- 21673749 TI - Approximate analytical scattering phase function dependent on microphysical characteristics of dust particles. AB - The approximate bulk-scattering phase function of a polydisperse system of dust particles is derived in an analytical form. In the theoretical solution, the particle size distribution is modeled by a modified gamma function that can satisfy various media differing in modal radii. Unlike the frequently applied power law, the modified gamma distribution shows no singularity when the particle radius approaches zero. The approximate scattering phase function is related to the parameters of the size distribution function. This is an important advantage compared to the empirical Henyey-Greenstein (HG) approximation, which is a simple function of the average cosine. However, any optimized value of average cosine of the HG function cannot provide the information on particle microphysical characteristics, such as the size distribution function. In this paper, the mapping between average cosine and the parameters of size distribution function is given by a semianalytical expression that is applicable in rapid numerical simulations on various dust populations. In particular, the modal radius and half width can be quickly estimated using the presented formulas. PMID- 21673748 TI - Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. AB - A large fraction of sequence variants of unknown significance (VUS) of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 may induce splicing defects. We analyzed 53 VUSs of BRCA1 or BRCA2, detected in consecutive molecular screenings, by using five splicing prediction programs, and we classified them into two groups according to the strength of the predictions. In parallel, we tested them by using functional splicing assays. A total of 10 VUSs were predicted by two or more programs to induce a significant reduction of splice site strength or activation of cryptic splice sites or generation of new splice sites. Minigene-based splicing assays confirmed four of these predictions. Five additional VUSs, all at internal exon positions, were not predicted to induce alterations of splice sites, but revealed variable levels of exon skipping, most likely induced by the modification of exonic splicing regulatory elements. We provide new data in favor of the pathogenic nature of the variants BRCA1 c.212+3A>G and BRCA1 c.5194-12G>A, which induced aberrant out-of-frame mRNA forms. Moreover, the novel variant BRCA2 c.7977-7C>G induced in frame inclusion of 6 nt from the 3' end of intron 17. The novel variants BRCA2 c.520C>T and BRCA2 c.7992T>A induced incomplete skipping of exons 7 and 18, respectively. This work highlights the contribution of splicing minigene assays to the assessment of pathogenicity, not only when patient RNA is not available, but also as a tool to improve the accuracy of bioinformatics predictions. PMID- 21673750 TI - From the channel model of an InSb-based superresolution optical disc system to impulse response and resolution limits. AB - The signal model of a superresolution optical channel can be an efficient tool for developing components of an associated high-density optical disc system. While the behavior of the laser diode, aperture, lens, and detector are properly described, a general mathematical model of the superresolution disc itself has not yet been available until recently. Different approaches have been made to describe the properties of a mask layer, mainly based on temperature- or power dependent nonlinear effects. A complete signal-based or phenomenological optical channel model--from non-return-to-zero inverted input to disc readout signal--has recently been developed including the reflectivity of a superresolution disc with InSb used for the mask layer. In this contribution, the model is now extended and applied to a moving disc including a land-and-pit structure, and results are compared with data read from real superresolution discs. Both impulse response and resolution limits are derived and discussed. Thus the model provides a bridge from physical to readout signal properties, which count after all. The presented approach allows judging of the suitability of a mask layer material for storage density enhancement already based on static experiments, i.e., even before developing an associated disc drive. PMID- 21673751 TI - Laser-textured silicon photodiode with broadband spectral response. AB - A femtosecond-laser-textured Si photodetector is reported. Broadband spectral optical response is detected from UV to NIR. A quantum efficiency of greater than 80% from 490 nm to 780 nm has been achieved. The quantum efficiency at 245 nm is 62%, which is comparable to UV-enhanced Si photodiodes. The bandwidth of a 250 MUm-diameter device is 60 MHz. PMID- 21673752 TI - On determination of sign of the piezo-optic coefficients using torsion method. AB - We have shown that a high-accuracy torsion method recently developed by the authors for measuring piezo-optic coefficients allows determining not only the absolute value of the coefficients but also their sign. The techniques and experimental procedures used for determination of the sign are described in detail and proven based on studies of alpha-BaB2O4 and LiNbO3 crystals. The piezo optic coefficients are determined for both crystals, and a combination of the corresponding photoelastic coefficients is determined for the case of alpha BaB2O4 crystals. PMID- 21673753 TI - Post-hydrogen-loaded draw tower fiber Bragg gratings and their thermal regeneration. AB - The idea of Bragg gratings generated during the drawing process of a fiber dates back almost 20 years. The technical improvement of the draw tower grating (DTG) process today results in highly reliable and cost-effective Bragg gratings for versatile application in the optical fiber sensor market. Because of the single pulse exposure of the fiber, the gratings behave typically like type I gratings with respect to their temperature stability. This means that such gratings only work up to temperatures of about 300 degrees C. To increase temperature stability, we combined DTG arrays with hydrogen postloading and a thermal regeneration process that enables their use in high-temperature environments. The regenerated draw tower gratings are demonstrated to be suitable for temperatures of more than 800 degrees C. PMID- 21673754 TI - Design of a vector-sum integrated microwave photonic phase shifter in silicon-on insulator waveguides. AB - An orthogonal vector-sum integrated microwave photonic phase shifter (IMWPPS), consisting of mode-order converter multiplexers (MOCMs), a variable optical power splitter (VOPS), an optical switch (OS) and fixed time delay lines (FTDLs), was theoretically demonstrated in a silicon-on-insulator wafer. MOCMs, as a key element of our device, were employed to generate orthogonal vector signals and served as lossless optical combiners. Combining with the thermo-optical VOPS, OS and FTDLs, the microwave phase shift of 0~2pi could be achieved by a refractive index variation of 0~15*10(-3) in the millimeter wave band. The corresponding tuning resolution was about 1.64 degrees / degrees C. This work, for the first time to our knowledge, provides an attractive solution to transferring a vector sum method based bulk MWPPS into a integrated one, which is very important for large-scale optically controlled phase array antenna. PMID- 21673755 TI - Methodology for detection of carbon monoxide in hot, humid media by telecommunication distributed feedback laser-based tunable diode laser absorption spectrometry. AB - Detection of carbon monoxide (CO) in combustion gases by tunable diode laser spectrometry is often hampered by spectral interferences from H2O and CO2. A methodology for assessment of CO in hot, humid media using telecommunication distributed feedback lasers is presented. By addressing the R14 line at 6395.4 cm(-1), and by using a dual-species-fitting technique that incorporates the fitting of both a previously measured water background reference spectrum and a 2f-wavelength modulation lineshape function, percent-level concentrations of CO can be detected in media with tens of percent of water (c(H2O)<=40%) at T<=1000 degrees C with an accuracy of a few percent by the use of a single reference water spectrum for background correction. PMID- 21673756 TI - Photoacoustic holographic imaging of absorbers embedded in silicone. AB - Light absorbing objects embedded in silicone have been imaged using photoacoustic digital holography. The photoacoustic waves were generated using a pulsed Nd:YAG laser, lambda=1064 nm, and pulse length=12 ns. When the waves reached the silicone surface, they were measured optically along a line using a scanning laser vibrometer. The acoustic waves were then digitally reconstructed using a holographic algorithm. The laser vibrometer is proven to be sensitive enough to measure the surface velocity due to photoacoustic waves generated from laser pulses with a fluence allowed for human tissue. It is also shown that combining digital holographic reconstructions for different acoustic wavelengths provides images with suppressed noise and improved depth resolution. The objects are imaged at a depth of 16.5 mm with a depth resolution of 0.5 mm. PMID- 21673757 TI - Range separation performance and optimal pulse-width prediction of a three dimensional flash laser detection and ranging using the Cramer-Rao bound. AB - This paper derives the Cramer-Rao bound (CRB) on range separation estimation of two point sources interrogated by a three-dimensional flash laser detection and ranging (LADAR) system. An unbiased range separation estimator is also derived to compare against the bound. Additionally, the CRB can be expressed as a function of two LADAR design parameters (range sampling and transmitted pulse width), which can be selected in order to optimize the expected range resolution between two point sources. Given several range sampling capabilities, the CRB and simulation show agreement that there is an optimal pulse width where a shorter pulse width would increase estimation variance due to undersampling of the pulse and a longer pulse width would degrade the resolving capability. Finally, the optimal pulse-width concept is extended to more complex targets and a normalized pulse definition. PMID- 21673758 TI - Phase error compensation for three-dimensional shape measurement with projector defocusing. AB - This paper analyzes the phase error for a three-dimensional (3D) shape measurement system that utilizes our recently proposed projector defocusing technique. This technique generates seemingly sinusoidal structured patterns by defocusing binary structured patterns and then uses these patterns to perform 3D shape measurement by fringe analysis. However, significant errors may still exist if an object is within a certain depth range, where the defocused fringe patterns retain binary structure. In this research, we experimentally studied a large depth range of defocused fringe patterns, from near-binary to near-sinusoidal, and analyzed the associated phase errors. We established a mathematical phase error function in terms of the wrapped phase and the depth z. Finally, we calibrated and used the mathematical function to compensate for the phase error at arbitrary depth ranges within the calibration volume. Experimental results will be presented to demonstrate the success of this proposed technique. PMID- 21673759 TI - Measurement method of Stokes parameters using a quarter-wave plate with phase difference errors. AB - The Stokes parameters (S0, S1, S2, and S3) of monochromatic light can be measured using the adjustable azimuth settings of a quarter-wave plate and a polarizer. When measuring the Stokes parameters of light of an arbitrary wavelength, the measurement of S3 is affected by the phase difference error Deltaq(lambdai), due to the mismatch with respect to wavelength with the quarter-wave plate. In this method, Deltaq(lambdai), due to such a mismatch of incident light of arbitrary wavelength, can be overcome by a judicious choice of azimuth settings of the quarter-wave plate and the use of a polarizer; however, the use of a precision quarter-wave plate is necessary. The present paper proposes a measurement method of Stokes parameters of incident light of arbitrary wavelength using a quarter wave plate with phase difference errors. PMID- 21673760 TI - Improvement of the performance of the twisted-nematic liquid-crystal display as a phase modulator. AB - A twisted-nematic liquid-crystal display (TN-LCD) placed between two linear polarizers (P) generally produces coupled intensity and phase modulations. For the purpose of phase-only modulation, quarter-wave plates (QWPs) are often used in front of or behind the LCD. In this paper, we demonstrate theoretically and experimentally the QWPs' effect on the modulation properties of the TN-LCD based on the general Jones matrix descriptions for all the devices, which circumvents the inconvenience of the traditional method on the basis of the TN-LCD's internal parameters. We prove that the phase modulation depth of the TN-LCD can be further increased in the configuration of P1-QWP1-LCD-QWP2-P2 with each component properly oriented, provided that the mean intensity transmission is decreased to a lower level. By observing the diffracted patterns of the Ronchi phase grating or blazed grating addressed onto the TN-LCD, we verify the validity of the proposed method. Improved reconstructed image quality from the kinoform loaded on the TN-LCD is obtained in this configuration. This approach is valuable when the TN-LCD is employed as a phase modulator, especially for the modern, thinner TN LCD. PMID- 21673761 TI - Differential Rayleigh scattering method for measurement of polarization and intermodal beat length in optical waveguides and fibers. AB - We propose a modification of the Rayleigh scattering method, which allows for measurement of polarization and intermodal beat length in single-mode and few mode channel waveguides and optical fibers. A significant sensitivity increase is achieved by taking two high-resolution photographs in oblique scattered light of pi-shifted intensity distributions produced by interference of polarization or spatial modes and applying Fourier analysis to the differential image. In the case of polarization beat length measurements, the pi-phase shift is obtained by switching the polarization state at the fiber input, while in intermodal measurements, the pi-phase shifting is realized by changing the excitation conditions. The usefulness of the method for characterization of channel waveguides and optical fibers is demonstrated in several examples. Moreover, we show that the combination of the spectral interferometry method with the proposed method allows for broadband measurements of differential phase and group effective indices. PMID- 21673762 TI - Cloud detection performance of spaceborne visible-to-infrared multispectral imagers. AB - We investigate the cloud detection efficiency of existing and future spaceborne visible-to-infrared imagers, focusing on several threshold tests for cloud detection over different types of ground surfaces, namely, the ocean, desert, vegetation, semibare land, and cryosphere. In this investigation, we used the CLoud and Aerosol Unbiased Decision Intellectual Algorithm (CLAUDIA), which was developed for unbiased cloud detection. It was revealed that imagers with fewer bands than the Moderate Resolution Imaging Spectroradiometer tend to have cloudy shifts. An imager without any infrared bands could yield cloudy shifts up to 17% over the ocean. To avoid false recognition of Sun glint as clouds, the 0.905 and 0.935 MUm bands are needed in addition to the infrared bands. In reflectance ratio tests, the 0.87 and 1.6 MUm bands can effectively distinguish clouds from desert. In the case of desert, thermal-infrared bands are ineffective when the desert surface temperature is low during winter. The 3.9 and 11 MUm bands are critical for distinguishing between clear and cloudy pixels over snow-/ice covered areas. The results and discussions of this research can guide CLAUDIA users in the optimization of thresholds. Here, we propose a virtual imager called the cloud detection imager, which has seven or eight bands for efficient cloud detection. PMID- 21673763 TI - Design of a 10 PW (150 J/15 fs) peak power laser system with Ti:sapphire medium through spectral control. AB - We designed a 10 PW (150 J-15 fs) laser system based on the use of titanium doped sapphire power amplifiers. The solution is to provide an overall compensating spectral gain narrowing and shifting technique for obtaining a controlled output spectrum. PMID- 21673764 TI - Proposal for postfabrication fine-tuning of three-port photonic crystal channel drop filters by means of optofluidic infiltration. AB - We are proposing a procedure to reconfigure a three-port photonic crystal channel drop filter with two point-defect resonant cavities coupled to a bus and a drop W1-type waveguide, by means of selective optofluidic infiltration. Simulations show that, by selective infiltration of cavities and the air holes of the two parallel line defects that are partially surrounding the bus waveguide of the proposed channel drop filter (CDF), besides fine-tuning of the cavities resonant frequencies to the desired values, one can also fine-tune the CDF phase to an optimum condition for achieving optimum drop efficiency for any given resonant frequency. We have used the 2D finite difference time domain and plane wave method to perform the numerical simulations. PMID- 21673765 TI - Liquid crystal infiltrated photonic crystal fibers for electric field intensity measurements. AB - The application of nematic liquid crystal infiltrated photonic crystal fiber as a sensor for electric field intensity measurement is demonstrated. The device is based on an intrinsic sensing mechanism for electric fields. The sensor probe, which consists of a 1 cm infiltrated section of photonic crystal fiber with a lateral size of ~125 MUm, is very compact with small size and weight. A simple all-fiber design for the sensor is employed in an intensity based measurement scheme. The transmitted and reflected power of the infiltrated photonic crystal fiber is shown to have a linear response with the applied electric field. The sensor is operated in the telecommunication window at 1550 nm. The temperature dependence of the device at this operating wavelength is also experimentally studied and discussed. These structures can be used to accurately measure electric field intensity and can be used for the fabrication of all-fiber sensors for high electric field environments as both an in-line and reflective type point sensor. PMID- 21673766 TI - Wide-angle, nonmechanical beam steering with high throughput utilizing polarization gratings. AB - We introduce and demonstrate a ternary nonmechanical beam steering device based on polarization gratings (PGs). Our beam steering device employs multiple stages consisting of combinations of PGs and wave plates, which allows for a unique three-way (ternary) steering design. Ultrahigh efficiency (~100%) and polarization sensitive diffraction of individual PGs allow wide steering angles (among three diffracted orders) with extremely high throughput. We report our successful demonstration of the three-stage beam steerer having a 44 degrees field of regard with 1.7 degrees resolution at 1550 nm wavelength. A substantially high throughput of 78%-83% is observed that is mainly limited by electrode absorption and Fresnel losses. PMID- 21673767 TI - Optical response of laser-doped silicon carbide for an uncooled midwave infrared detector. AB - An uncooled mid-wave infrared (MWIR) detector is developed by doping an n-type 4H SiC with Ga using a laser doping technique. 4H-SiC is one of the polytypes of crystalline silicon carbide and a wide bandgap semiconductor. The dopant creates an energy level of 0.30 eV, which was confirmed by optical spectroscopy of the doped sample. This energy level corresponds to the MWIR wavelength of 4.21 MUm. The detection mechanism is based on the photoexcitation of electrons by the photons of this wavelength absorbed in the semiconductor. This process modifies the electron density, which changes the refractive index, and, therefore, the reflectance of the semiconductor is also changed. The change in the reflectance, which is the optical response of the detector, can be measured remotely with a laser beam, such as a He-Ne laser. This capability of measuring the detector response remotely makes it a wireless detector. The variation of refractive index was calculated as a function of absorbed irradiance based on the reflectance data for the as-received and doped samples. A distinct change was observed for the refractive index of the doped sample, indicating that the detector is suitable for applications at the 4.21 MUm wavelength. PMID- 21673768 TI - Propagation of Bessel beams from a dielectric to a conducting medium. AB - Recently, the use of Bessel beams in evaluating the possibility of using them for a new generation of ground penetrating radar systems has been considered. Therefore, an analysis of the propagation of Bessel beams in conducting media is worthwhile. We present here an analysis of this type. Specifically, for normal incidence we analyze the propagation of a Bessel beam coming from a perfect dielectric and impinging on a conducting medium, i.e., the propagation of a Bessel beam generated by refracted inhomogeneous waves. The remarkable and unexpected result is that the incident Bessel beam does not change its shape even when propagating in the conducting medium. PMID- 21673769 TI - High-speed digital color imaging pyrometry. AB - Temperature measurements of high-explosive and combustion processes are difficult to obtain due to the speed and environment of the events. To overcome these challenges, we have characterized and calibrated a digital high-speed color camera that may be used to measure the temperature of such events. A two-color ratio method is used to calculate a temperature using the color filter array raw image data and a graybody assumption. If the raw image data are not available, temperatures may be calculated from the processed images or movies, depending on proper analysis of the digital color imaging pipeline. We analyze three transformations within the pipeline (demosaicing, white balance, and gamma correction) to determine their effect on the calculated temperature. Using this technique with a Phantom color camera, we have measured the temperature of exploded C-4 charges. The surface temperature of the resulting fireball was found to rapidly increase after detonation, and subsequently decayed to a constant value of approximately 1980 K. PMID- 21673771 TI - Spot size effects in miniaturized moving-optical-wedge interferometer. AB - In this paper we study the effect of diffraction on the performance of a miniaturized moving-optical-wedge interferometer. By using the Gaussian model, we calculate the degradation of the interferometer visibility due to diffraction effects. We use this model to optimize the detector size required to obtain maximum visibility and study its effect on resolution of Fourier transform spectrometers based on a moving-optical-wedge interferometer. A comparison between these effects in Michelson and wedge interferometers is also presented showing the advantage of the moving-optical-wedge interferometer in suppressing the diffraction effects with respect to the Michelson interferometer. PMID- 21673770 TI - High-sensitivity photovoltaic responses in manganite-based heterojunctions on Si substrates for weak light detection. AB - We have fabricated and characterized a weak light photodetector in a heterojunction composed of manganite La0.4Ca0.6MnO3 and n-type Si. High sensitivity photoresponse properties were investigated. The responsivities of open-circuit photovoltage and short-circuit photocurrent reach ~1000 V/mJ and ~30 A/mJ, respectively, without any amplification bias under irradiation by 20 ps-wide and 355, 532, and 1064-nm-wavelength laser pulses in nanojoule to microjoule order. The present results demonstrate that the manganite-based heterojunction on Si substrate has potential applications in weak light detection from ultraviolet to near-infrared light. PMID- 21673772 TI - Phase mapping and wavefront analysis based on multi-illumination light fields generated by a spatial light modulator. AB - We present a new multi-illumination technique for the determination of the phase maps of unknown phase objects and wavefronts based on their diffraction patterns. A spatial light modulator is used to generate a sequence of probe-light fields that illuminate the unknown object producing different diffraction patterns. Compared with similar diffraction-pattern-based approaches, our technique benefits from a motionless multiview operation and a significantly improved deconvolution algorithm convergence speed (tens of iterations versus hundreds). Computer simulations indicate that the extra information brought by the different diffraction patterns prevents convergence of the phase retrieval algorithm to spurious local minima solutions and results in faster convergence. We describe an experimental system built based on our approach using readily available, relatively low-cost components. Successful reconstructions of test targets from experimental diffraction patterns confirm the feasibility of the technique. Major sources of error are identified, solutions to these problems suggested, and potential extensions to multiresolution analysis of unknown wavefronts are proposed. PMID- 21673773 TI - Navy Prototype Optical Interferometer observations of geosynchronous satellites. AB - Using a 15.9 m baseline at the Navy Prototype Optical Interferometer (NPOI), we have successfully detected interferometric fringes in observations of the geosynchronous satellite (geosat) DirecTV-9S while it glinted on two nights in March 2009. The fringe visibilities can be fitted by a model consisting of two components, one resolved (?3.7 m) and one unresolved (~1.1 m). Both the length of the glint and the specular albedos are consistent with the notion that the glinting surfaces are not completely flat and scatter reflected sunlight into an opening angle of roughly 15 degrees . Enhancements to the NPOI that would improve geosat observations include adding an infrared capability, which could extend the glint season, and adding larger, adaptive-optics equipped telescopes. Future work may test the feasibility of observing geosats with aperture-masked large telescopes and of developing an array of six to nine elements. PMID- 21673775 TI - Electrically switchable holographic liquid crystal/polymer Fresnel lens using a Michelson interferometer. AB - A holographic technique for fabricating an electrically switchable liquid crystal/polymer composite Fresnel lens is reported. A Michelson interferometer is used to produce the required Fresnel pattern, by placing a convex lens into one path of the interferometer. Simplicity of the method and the possibility of fabricating different focal length lenses in a single arrangement are advantages of the method. The performance of the fabricated lens was demonstrated and its electro-optical properties were investigated for its primary focal length. PMID- 21673776 TI - On-sky multiwavelength phasing of segmented telescopes with the Zernike phase contrast sensor. AB - Future extremely large telescopes will adopt segmented primary mirrors with several hundreds of segments. Cophasing of the segments together is essential to reach high wavefront quality. The phasing sensor must be able to maintain very high phasing accuracy during the observations, while being able to phase segments dephased by several micrometers. The Zernike phase contrast sensor has been demonstrated on-sky at the Very Large Telescope. We present the multiwavelength scheme that has been implemented to extend the capture range from +/-lambda/2 on the wavefront to many micrometers, demonstrating that it is successful at phasing mirrors with piston errors up to +/-4.0 MUm on the wavefront. We discuss the results at different levels and conclude with a phasing strategy for a future extremely large telescope. PMID- 21673777 TI - Optical polarimetry for noninvasive glucose sensing enabled by Sagnac interferometry. AB - Optical polarimetry is used in pharmaceutical drug testing and quality control for saccharide-containing products (juice, honey). More recently, it has been proposed as a method for noninvasive glucose sensing for diabetic patients. Sagnac interferometry is commonly used in optical gyroscopes, measuring minute Doppler shifts resulting from mechanical rotation. In this work, we demonstrate that Sagnac interferometers are also sensitive to optical rotation, or the rotation of linearly polarized light, and are therefore useful in optical polarimetry. Results from simulation and experiment show that Sagnac interferometers are advantageous in optical polarimetry as they are insensitive to net linear birefringence and alignment of polarization components. PMID- 21673778 TI - Measurement of duty cycles of metal grating masks formed on dielectric substrates. AB - A nondestructive method for measuring the duty cycles of metal grating masks formed on top of dielectric substrates is proposed. For a near-normal angle of incidence, the zeroth diffracted order transmission efficiency curves for both TE and TM polarized probe lights, as a function of duty cycles, behave linearly in the duty cycle ranging from 0 to 1. By comparing the measured efficiencies, or the ratio of zeroth-order transmission efficiency for TM polarization to that for TE polarization, with that of the rigorous-coupled wave analysis (RCWA) method for a fixed grating period and depth, one can determine the duty cycle of the grating. By selecting the probe light appropriately, the measurement errors originating from deviations of the incident angle and grating depth can be negligible. This method is applicable for all metal gratings, which are not easy to measure nondestructively due to fine grooves smaller than the wavelength. This method is simple, accurate, nondestructive, and low-cost. The results of experimental verification are presented and show excellent agreement with scanning electron microscope images. PMID- 21673779 TI - Fiber optic hot-wire flowmeter based on a metallic coated hybrid long period grating/fiber Bragg grating structure. AB - In this work an all-optical hot-wire flowmeter based on a silver coated fiber combining a long period grating and a fiber Bragg grating (FBG) structure is proposed. Light from a pump laser at 1480 nm propagating down the fiber is coupled by the long period grating into the fiber cladding and is absorbed by the silver coating deposited on the fiber surface over the Bragg grating structure. This absorption acts like a hot wire raising the fiber temperature locally, which is effectively detected by the FBG resonance shift. The temperature increase depends on the flow speed of the surrounding air, which has the effect of cooling the fiber. It is demonstrated that the Bragg wavelength shift can be related to the flow speed. A flow speed resolution of 0.08 m/s is achieved using this new configuration. PMID- 21673780 TI - Kernel wavelet-Reed-Xiaoli: an anomaly detection for forward-looking infrared imagery. AB - This paper describes a new kernel wavelet-based anomaly detection technique for long-wave (LW) forward-looking infrared imagery. The proposed approach called kernel wavelet-Reed-Xiaoli (wavelet-RX) algorithm is essentially an extension of the wavelet-RX algorithm (combination of wavelet transform and RX anomaly detector) to a high-dimensional feature space (possibly infinite) via a certain nonlinear mapping function of the input data. The wavelet-RX algorithm in this high-dimensional feature space can easily be implemented in terms of kernels that implicitly compute dot products in the feature space (kernelizing the wavelet-RX algorithm). In the proposed kernel wavelet-RX algorithm, a two-dimensional wavelet transform is first applied to decompose the input image into uniform subbands. A number of significant subbands (high-energy subbands) are concatenated together to form a subband-image cube. The kernel RX algorithm is then applied to this subband-image cube. Experimental results are presented for the proposed kernel wavelet-RX, wavelet-RX, and the classical constant false alarm rate (CFAR) algorithm for detecting anomalies (targets) in a large database of LW imagery. The receiver operating characteristic plots show that the proposed kernel wavelet-RX algorithm outperforms the wavelet-RX as well as the classical CFAR detector. PMID- 21673781 TI - Continuous wave, dual-wavelength-pumped supercontinuum generation in an all-fiber device. AB - We propose a continuous wave dual-wavelength-pumped scheme for visible supercontinuum (SC) generation. The scheme is numerically studied in this paper. In the scheme, the dual-wavelength pump source is produced through a four-wave mixing process in a photonic crystal fiber. SC generation is numerically investigated by solving the generalized nonlinear Schrodinger equation. The results verify that the visible SC can be generated by the scheme, which implies that the scheme is promising for generating visible SC with high spectral power densities. PMID- 21673783 TI - Inverse relationships for reflection diagnostics of uniaxially anisotropic nanoscale films on isotropic materials. AB - The possibilities of determining the parameters of uniaxially anisotropic ultrathin nonabsorbing dielectric films on absorbing or transparent isotropic substrates by surface differential reflectance measurements are analyzed. The analysis is based on analytical reflection formulas obtained in the framework of a long-wavelength approximation. It is shown that, in the case of transparent substrates, it is always possible to determine the thickness of a uniaxially ultrathin film and its four parameters of anisotropy (optical constants n(o) and n(e) and angles theta and phi) simultaneously. However, for such films on absorbing substrates, it is possible to decouple the thickness and optical constants by differential reflectance measurements only if theta?0. The accuracy of the obtained analytic formulas for determining the parameters of ultrathin films is estimated by computer simulations where the reflection problem was solved numerically on the basis of the rigorous electromagnetic theory for anisotropic layered systems. PMID- 21673782 TI - Calculation of the modulation transfer function for object brightness distribution function oriented along any direction in axis-symmetrical optical systems. AB - The literature deals with the modulation transfer function (MTF) only for object brightness distribution functions (OBDFs) oriented along the meridional and sagittal directions. This paper addresses computation of the geometrical MTF for an off-axis source point when the OBDF is oriented along any arbitrarily defined direction. This study finds that the MTF is not a monotonic increasing or decreasing function when the direction of the OBDF is changing. Consequently, the extreme MTF values may occur when the OBDF is aligned at any direction between the meridional and sagittal directions. Four theorems are provided for the MTF and the phase shift variations that take place when the OBDF is translated or rotated. It is found that the MTF and the phase shift are symmetrical or antisymmetrical about certain directions. Thus, to observe all possible changes in the MTF and the phase shift, it is sufficient to rotate the OBDF through a range of just 90 degrees . The presented method is based on a recent irradiance method for MTF computation that does not rely on counting the number of ray hits on a mesh, making the method immune to effects of grid size and thus improving traditional accuracy. PMID- 21673784 TI - Determination of quantum efficiency in fluorescing turbid media. AB - A method is proposed to estimate the optical parameters in a fluorescing turbid medium with strong absorption for which traditional Kubelka-Munk theory is not applicable, using a model for the radiative properties of optically thick fluorescent turbid media of finite thickness proposed in 2009 [J. Opt. Soc. Am. A26, 1896 (2009)]. The method is successfully applied to uncoated papers with different thicknesses. It is found that the quantum efficiency of fluorescent whitening agents (FWAs) is nearly independent of the fiber type, FWA type, FWA concentration, and filler additive concentration used in this study. The results enable an estimation of the model parameters as function of the FWA concentration and substrate composition. This is necessary in order to use the model for optimizing fluorescence in the paper and textile industries. PMID- 21673785 TI - Slightly off-axis interferometry for microscopy with second wavelength assistance. AB - Slightly off-axis interferometry for microscopy has been performed, where the dc term of the interferogram is suppressed by the object wave in another wavelength. One wavelength of the laser beam (red light) is used to generate the slightly off axis interferogram, while the second wavelength (blue light) is employed to measure the transmittance of the specimen. Both the red light and blue light are recorded simultaneously by a color CCD camera and can be separated without cross talk via the red-green-blue components. The dc term of the slightly off-axis interferogram of red light is suppressed with the object wave of blue light. As a consequence, the requirement on the off-axis angle between the object and reference waves is relaxed as well as the requirement on the resolving power of CCD camera. PMID- 21673786 TI - Theory for optimal design of waveguiding light concentrators in photovoltaic microcell arrays. AB - Efficiency of ultrathin flexible solar photovoltaic silicon microcell arrays can be significantly improved using nonimaging solar concentrators. A fluorophore is introduced to match the solar spectrum and the low-reflectivity wavelength range of Si, reduce the escape losses, and allow the nontracking operation. In this paper we optimize our solar concentrators using a luminescent/nonluminescent photon transport model. Key modeling results are compared quantitatively to experiments and are in good agreement with the latter. Our solar concentrator performance is not limited by the dye self-absorption. Bending deformations of the flexible solar collectors do not result in their indirect gain degradation compared to flat solar concentrators with the same projected area. PMID- 21673787 TI - Realization of fiber-based laser Doppler vibrometer with serrodyne frequency shifting. AB - We demonstrate a laser Doppler vibrometer (LDV) based on the serrodyne frequency shifting technique. A proof-of-principle system is implemented on the basis of fiber-optic components but opens the way toward an ultracompact integrated LDV system on a silicon chip. With a low laser power of 50 MUW, the serrodyne LDV was able to measure submicrometer vibrations with frequencies in the audio range. PMID- 21673788 TI - Neurally and mathematically motivated architecture for language and thought. AB - Neural structures of interaction between thinking and language are unknown. This paper suggests a possible architecture motivated by neural and mathematical considerations. A mathematical requirement of computability imposes significant constraints on possible architectures consistent with brain neural structure and with a wealth of psychological knowledge. How language interacts with cognition. Do we think with words, or is thinking independent from language with words being just labels for decisions? Why is language learned by the age of 5 or 7, but acquisition of knowledge represented by learning to use this language knowledge takes a lifetime? This paper discusses hierarchical aspects of language and thought and argues that high level abstract thinking is impossible without language. We discuss a mathematical technique that can model the joint language thought architecture, while overcoming previously encountered difficulties of computability. This architecture explains a contradiction between human ability for rational thoughtful decisions and irrationality of human thinking revealed by Tversky and Kahneman; a crucial role in this contradiction might be played by language. The proposed model resolves long-standing issues: how the brain learns correct words-object associations; why animals do not talk and think like people. We propose the role played by language emotionality in its interaction with thought. We relate the mathematical model to Humboldt's "firmness" of languages; and discuss possible influence of language grammar on its emotionality. Psychological and brain imaging experiments related to the proposed model are discussed. Future theoretical and experimental research is outlined. PMID- 21673789 TI - Sometimes sperm whales (Physeter macrocephalus) cannot find their way back to the high seas: a multidisciplinary study on a mass stranding. AB - BACKGROUND: Mass strandings of sperm whales (Physeter macrocephalus) remain peculiar and rather unexplained events, which rarely occur in the Mediterranean Sea. Solar cycles and related changes in the geomagnetic field, variations in water temperature and weather conditions, coast geographical features and human activities have been proposed as possible causes. In December 2009, a pod of seven male sperm whales stranded along the Adriatic coast of Southern Italy. This is the sixth instance from 1555 in this basin. METHODOLOGY/PRINCIPAL FINDINGS: Complete necropsies were performed on three whales whose bodies were in good condition, carrying out on sampled tissues histopathology, virology, bacteriology, parasitology, and screening of veins looking for gas emboli. Furthermore, samples for age determination, genetic studies, gastric content evaluation, stable isotopes and toxicology were taken from all the seven specimens. The animals were part of the same group and determined by genetic and photo-identification to be part of the Mediterranean population. Causes of death did not include biological agents, or the "gas and fat embolic syndrome", associated with direct sonar exposure. Environmental pollutant tissue concentrations were relatively high, in particular organochlorinated xenobiotics. Gastric content and morphologic tissue examinations showed a prolonged starvation, which likely caused, at its turn, the mobilization of lipophilic contaminants from the adipose tissue. Chemical compounds subsequently entered the blood circulation and may have impaired immune and nervous functions. CONCLUSIONS/SIGNIFICANCE: A multi-factorial cause underlying this sperm whales' mass stranding is proposed herein based upon the results of postmortem investigations as well as of the detailed analyses of the geographical and historical background. The seven sperm whales took the same "wrong way" into the Adriatic Sea, a potentially dangerous trap for Mediterranean sperm whales. Seismic surveys should be also regarded as potential co-factors, even if no evidence of direct impact has been detected. PMID- 21673790 TI - The Puf-family RNA-binding protein Puf2 controls sporozoite conversion to liver stages in the malaria parasite. AB - Malaria is a vector-borne infectious disease caused by unicellular, obligate intracellular parasites of the genus Plasmodium. During host switch the malaria parasite employs specialized latent stages that colonize the new host environment. Previous work has established that gametocytes, sexually differentiated stages that are taken up by the mosquito vector, control expression of genes required for mosquito colonization by translational repression. Sexual parasite development is controlled by a DEAD-box RNA helicase of the DDX6 family, termed DOZI. Latency of sporozoites, the transmission stage injected during an infectious blood meal, is controlled by the eIF2alpha kinase IK2, a general inhibitor of protein synthesis. Whether RNA-binding proteins participate in translational regulation in sporozoites remains to be studied. Here, we investigated the roles of two RNA-binding proteins of the Puf-family, Plasmodium Puf1 and Puf2, during sporozoite stage conversion. Our data reveal that, in the rodent malaria parasite P. berghei, Puf2 participates in the regulation of IK2 and inhibits premature sporozoite transformation. Inside mosquito salivary glands puf2- sporozoites transform over time to round forms resembling early intra-hepatic stages. As a result, mutant parasites display strong defects in initiating a malaria infection. In contrast, Puf1 is dispensable in vivo throughout the entire Plasmodium life cycle. Our findings support the notion of a central role for Puf2 in parasite latency during switch between the insect and mammalian hosts. PMID- 21673791 TI - Evolution and taxonomic classification of human papillomavirus 16 (HPV16)-related variant genomes: HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. AB - BACKGROUND: Human papillomavirus 16 (HPV16) species group (alpha-9) of the Alphapapillomavirus genus contains HPV16, HPV31, HPV33, HPV35, HPV52, HPV58 and HPV67. These HPVs account for 75% of invasive cervical cancers worldwide. Viral variants of these HPVs differ in evolutionary history and pathogenicity. Moreover, a comprehensive nomenclature system for HPV variants is lacking, limiting comparisons between studies. METHODS: DNA from cervical samples previously characterized for HPV type were obtained from multiple geographic regions to screen for novel variants. The complete 8 kb genomes of 120 variants representing the major and minor lineages of the HPV16-related alpha-9 HPV types were sequenced to capture maximum viral heterogeneity. Viral evolution was characterized by constructing phylogenic trees based on complete genomes using multiple algorithms. Maximal and viral region specific divergence was calculated by global and pairwise alignments. Variant lineages were classified and named using an alphanumeric system; the prototype genome was assigned to the A lineage for all types. RESULTS: The range of genome-genome sequence heterogeneity varied from 0.6% for HPV35 to 2.2% for HPV52 and included 1.4% for HPV31, 1.1% for HPV33, 1.7% for HPV58 and 1.1% for HPV67. Nucleotide differences of approximately 1.0% - 10.0% and 0.5%-1.0% of the complete genomes were used to define variant lineages and sublineages, respectively. Each gene/region differs in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) /noncoding region 2 (NCR2) >upstream regulatory region (URR)> E6/E7 > E2/L2 > E1/L1. CONCLUSIONS: These data define maximum viral genomic heterogeneity of HPV16-related alpha-9 HPV variants. The proposed nomenclature system facilitates the comparison of variants across epidemiological studies. Sequence diversity and phylogenies of this clinically important group of HPVs provides the basis for further studies of discrete viral evolution, epidemiology, pathogenesis and preventative/therapeutic interventions. PMID- 21673792 TI - Cell-free H-cluster synthesis and [FeFe] hydrogenase activation: all five CO and CN- ligands derive from tyrosine. AB - [FeFe] hydrogenases are promising catalysts for producing hydrogen as a sustainable fuel and chemical feedstock, and they also serve as paradigms for biomimetic hydrogen-evolving compounds. Hydrogen formation is catalyzed by the H cluster, a unique iron-based cofactor requiring three carbon monoxide (CO) and two cyanide (CN-) ligands as well as a dithiolate bridge. Three accessory proteins (HydE, HydF, and HydG) are presumably responsible for assembling and installing the H-cluster, yet their precise roles and the biosynthetic pathway have yet to be fully defined. In this report, we describe effective cell-free methods for investigating H-cluster synthesis and [FeFe] hydrogenase activation. Combining isotopic labeling with FTIR spectroscopy, we conclusively show that each of the CO and CN- ligands derive respectively from the carboxylate and amino substituents of tyrosine. Such in vitro systems with reconstituted pathways comprise a versatile approach for studying biosynthetic mechanisms, and this work marks a significant step towards an understanding of both the protein-protein interactions and complex reactions required for H-cluster assembly and hydrogenase maturation. PMID- 21673794 TI - Novel roles of cAMP receptor protein (CRP) in regulation of transport and metabolism of carbon sources. AB - CRP (cAMP receptor protein), the global regulator of genes for carbon source utilization in the absence of glucose, is the best-studied prokaryotic transcription factor. A total of 195 target promoters on the Escherichia coli genome have been proposed to be under the control of cAMP-bound CRP. Using the newly developed Genomic SELEX screening system of transcription factor-binding sequences, however, we have identified a total of at least 254 CRP-binding sites. Based on their location on the E. coli genome, we predict a total of at least 183 novel regulation target operons, altogether with the 195 hitherto known targets, reaching to the minimum of 378 promoters as the regulation targets of cAMP-CRP. All the promoters selected from the newly identified targets and examined by using the lacZ reporter assay were found to be under the control of CRP, indicating that the Genomic SELEX screening allowed to identify the CRP targets with high accuracy. Based on the functions of novel target genes, we conclude that CRP plays a key regulatory role in the whole processes from the selective transport of carbon sources, the glycolysis-gluconeogenesis switching to the metabolisms downstream of glycolysis, including tricarboxylic acid (TCA) cycle, pyruvate dehydrogenase (PDH) pathway and aerobic respiration. One unique regulation mode is that a single and the same CRP molecule bound within intergenic regions often regulates both of divergently transcribed operons. PMID- 21673795 TI - Human umbilical cord blood cells restore brain damage induced changes in rat somatosensory cortex. AB - Intraperitoneal transplantation of human umbilical cord blood (hUCB) cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury. PMID- 21673796 TI - A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice. AB - For prevention of HIV infection many currently licensed anti-HIV drugs and new ones in the pipeline show potential as topically applied microbicides. While macaque models have been the gold standard for in vivo microbicide testing, they are expensive and sufficient numbers are not available. Therefore, a small animal model that facilitates rapid evaluation of potential candidates for their preliminary efficacy is urgently needed in the microbicide field. We previously demonstrated that RAG-hu humanized mouse model permits HIV-1 mucosal transmission via both vaginal and rectal routes and that oral pre-exposure chemo-prophylactic strategies could be tested in this system. Here in these proof-of-concept studies, we extended this system for topical microbicide testing using HIV-1 as the challenge virus. Maraviroc, a clinically approved CCR5 inhibitor drug for HIV treatment, was formulated as a microbicide gel at 5 mM concentration in 2.2% hydroxyl ethyl cellulose. Female RAG-hu mice were challenged vaginally with HIV-1 an hour after intravaginal application of the maraviroc gel. Our results showed that maraviroc gel treated mice were fully protected against vaginal HIV-1 challenge in contrast to placebo gel treated mice which all became infected. These findings highlight the utility of the humanized mouse models for microbicide testing and, together with the recent data from macaque studies, suggest that maraviroc is a promising candidate for future microbicide clinical trials in the field. PMID- 21673797 TI - Dazzle camouflage affects speed perception. AB - Movement is the enemy of camouflage: most attempts at concealment are disrupted by motion of the target. Faced with this problem, navies in both World Wars in the twentieth century painted their warships with high contrast geometric patterns: so-called "dazzle camouflage". Rather than attempting to hide individual units, it was claimed that this patterning would disrupt the perception of their range, heading, size, shape and speed, and hence reduce losses from, in particular, torpedo attacks by submarines. Similar arguments had been advanced earlier for biological camouflage. Whilst there are good reasons to believe that most of these perceptual distortions may have occurred, there is no evidence for the last claim: changing perceived speed. Here we show that dazzle patterns can distort speed perception, and that this effect is greatest at high speeds. The effect should obtain in predators launching ballistic attacks against rapidly moving prey, or modern, low-tech battlefields where handheld weapons are fired from short ranges against moving vehicles. In the latter case, we demonstrate that in a typical situation involving an RPG7 attack on a Land Rover the reduction in perceived speed is sufficient to make the grenade miss where it was aimed by about a metre, which could be the difference between survival or not for the occupants of the vehicle. PMID- 21673798 TI - Sponge mass mortalities in a warming Mediterranean Sea: are cyanobacteria harboring species worse off? AB - Mass mortality events are increasing dramatically in all coastal marine environments. Determining the underlying causes of mass mortality events has proven difficult in the past because of the lack of prior quantitative data on populations and environmental variables. Four-year surveys of two shallow-water sponge species, Ircinia fasciculata and Sarcotragus spinosulum, were carried out in the western Mediterranean Sea. These surveys provided evidence of two severe sponge die-offs (total mortality ranging from 80 to 95% of specimens) occurring in the summers of 2008 and 2009. These events primarily affected I. fasciculata, which hosts both phototrophic and heterotrophic microsymbionts, while they did not affect S. spinosulum, which harbors only heterotrophic bacteria. We observed a significant positive correlation between the percentage of injured I. fasciculata specimens and exposure time to elevated temperature conditions in all populations, suggesting a key role of temperature in triggering mortality events. A comparative ultrastructural study of injured and healthy I. fasciculata specimens showed that cyanobacteria disappeared from injured specimens, which suggests that cyanobacterial decay could be involved in I. fasciculata mortality. A laboratory experiment confirmed that the cyanobacteria harbored by I. fasciculata displayed a significant reduction in photosynthetic efficiency in the highest temperature treatment. The sponge disease reported here led to a severe decrease in the abundance of the surveyed populations. It represents one of the most dramatic mass mortality events to date in the Mediterranean Sea. PMID- 21673799 TI - Constructing biological pathways by a two-step counting approach. AB - Networks are widely used in biology to represent the relationships between genes and gene functions. In Boolean biological models, it is mainly assumed that there are two states to represent a gene: on-state and off-state. It is typically assumed that the relationship between two genes can be characterized by two kinds of pairwise relationships: similarity and prerequisite. Many approaches have been proposed in the literature to reconstruct biological relationships. In this article, we propose a two-step method to reconstruct the biological pathway when the binary array data have measurement error. For a pair of genes in a sample, the first step of this approach is to assign counting numbers for every relationship and select the relationship with counting number greater than a threshold. The second step is to calculate the asymptotic p-values for hypotheses of possible relationships and select relationships with a large p-value. This new method has the advantages of easy calculation for the counting numbers and simple closed forms for the p-value. The simulation study and real data example show that the two-step counting method can accurately reconstruct the biological pathway and outperform the existing methods. Compared with the other existing methods, this two-step method can provide a more accurate and efficient alternative approach for reconstructing the biological network. PMID- 21673800 TI - Neuronal function and dysfunction of Drosophila dTDP. AB - BACKGROUND: TDP-43 is an RNA- and DNA-binding protein well conserved in animals including the mammals, Drosophila, and C. elegans. In mammals, the multi-function TDP-43 encoded by the TARDBP gene is a signature protein of the ubiquitin positive inclusions (UBIs) in the diseased neuronal/glial cells of a range of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). METHODOLOGY/PRINCIPAL FINDINGS: We have studied the function and dysfunction of the Drosophila ortholog of the mammalian TARDBP gene, dTDP, by genetic, behavioral, molecular, and cytological analyses. It was found that depletion of dTDP expression caused locomotion defect accompanied with an increase of the number of boutons at the neuromuscular junctions (NMJ). These phenotypes could be rescued by overexpression of Drosophila dTDP in the motor neurons. In contrast, overexpression of dTDP in the motor neurons also resulted in reduced larval and adult locomotor activities, but this was accompanied by a decrease of the number of boutons and axon branches at NMJ. Significantly, constitutive overexpression of dTDP in the mushroom bodies caused smaller axonal lobes as well as severe learning deficiency. On the other hand, constitutive mushroom body-specific knockdown of dTDP expression did not affect the structure of the mushroom bodies, but it impaired the learning ability of the flies, albeit moderately. Overexpression of dTDP also led to the formation of cytosolic dTDP (+) aggregates. CONCLUSION/SIGNIFICANCE: These data together demonstrate the neuronal functions of dTDP, and by implication the mammalian TDP 43, in learning and locomotion. The effects of mis-expression of dTDP on Drosophila NMJ suggest that eukaryotic TDP-43 guards against over development of the synapses. The conservation of the regulatory pathways of functions and dysfunctions of Drosophila dTDP and mammalian TDP-43 also shows the feasibility of using the flies as a model system for studying the normal TDP-43 function and TDP-43 proteinopathies in the vertebrates including human. PMID- 21673802 TI - Expanding the understanding of biases in development of clinical-grade molecular signatures: a case study in acute respiratory viral infections. AB - BACKGROUND: The promise of modern personalized medicine is to use molecular and clinical information to better diagnose, manage, and treat disease, on an individual patient basis. These functions are predominantly enabled by molecular signatures, which are computational models for predicting phenotypes and other responses of interest from high-throughput assay data. Data-analytics is a central component of molecular signature development and can jeopardize the entire process if conducted incorrectly. While exploratory data analysis may tolerate suboptimal protocols, clinical-grade molecular signatures are subject to vastly stricter requirements. Closing the gap between standards for exploratory versus clinically successful molecular signatures entails a thorough understanding of possible biases in the data analysis phase and developing strategies to avoid them. METHODOLOGY AND PRINCIPAL FINDINGS: Using a recently introduced data-analytic protocol as a case study, we provide an in-depth examination of the poorly studied biases of the data-analytic protocols related to signature multiplicity, biomarker redundancy, data preprocessing, and validation of signature reproducibility. The methodology and results presented in this work are aimed at expanding the understanding of these data-analytic biases that affect development of clinically robust molecular signatures. CONCLUSIONS AND SIGNIFICANCE: Several recommendations follow from the current study. First, all molecular signatures of a phenotype should be extracted to the extent possible, in order to provide comprehensive and accurate grounds for understanding disease pathogenesis. Second, redundant genes should generally be removed from final signatures to facilitate reproducibility and decrease manufacturing costs. Third, data preprocessing procedures should be designed so as not to bias biomarker selection. Finally, molecular signatures developed and applied on different phenotypes and populations of patients should be treated with great caution. PMID- 21673803 TI - Direct observation of dimerization between different CREB1 isoforms in a living cell. AB - Cyclic AMP-responsive element binding protein 1 (CREB1) plays multiple functions as a transcription factor in gene regulation. CREB1 proteins are also known to be expressed in several spliced isoforms that act as transcriptional activators or repressors. The activator isoforms, possessing the functional domains for kinase induction and for interaction with other transcriptional regulators, act as transcriptional activators. On the other hand, some isoforms, lacking those functional domains, are reported to be repressors that make heterodimers with activator isoforms. The complex and ingenious function for CREB1 arises in part from the variation in their spliced isoforms, which allows them to interact with each other. To date, however, the dimerization between the activator and repressor isoforms has not yet been proved directly in living cells. In this study, we applied fluorescence cross-correlation spectroscopy (FCCS) to demonstrate direct observation of dimerization between CREB1 activator and repressor. The FCCS is a well established spectroscopic method to determine the interaction between the different fluorescent molecules in the aqueous condition. Using differently labeled CREB1 isoforms, we successfully observed the interaction of CREB1 activator and repressor via dimerization in the nuclei of cultured cells. As a result, we confirmed the formation of heterodimer between CREB1 activator and repressor isoforms in living cells. PMID- 21673801 TI - Serotonergic contribution to boys' behavioral regulation. AB - OBJECTIVES: Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure. METHOD: Participants were 23 boys (age 10 years) with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered. RESULTS: Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter. CONCLUSIONS: The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors. PMID- 21673804 TI - The effectiveness of RNAi in Caenorhabditis elegans is maintained during spaceflight. AB - BACKGROUND: Overcoming spaceflight-induced (patho)physiologic adaptations is a major challenge preventing long-term deep space exploration. RNA interference (RNAi) has emerged as a promising therapeutic for combating diseases on Earth; however the efficacy of RNAi in space is currently unknown. METHODS: Caenorhabditis elegans were prepared in liquid media on Earth using standard techniques and treated acutely with RNAi or a vector control upon arrival in Low Earth Orbit. After culturing during 4 and 8 d spaceflight, experiments were stopped by freezing at -80 degrees C until analysis by mRNA and microRNA array chips, microscopy and Western blot on return to Earth. Ground controls (GC) on Earth were simultaneously grown under identical conditions. RESULTS: After 8 d spaceflight, mRNA expression levels of components of the RNAi machinery were not different from that in GC (e.g., Dicer, Argonaute, Piwi; P>0.05). The expression of 228 microRNAs, of the 232 analysed, were also unaffected during 4 and 8 d spaceflight (P>0.05). In spaceflight, RNAi against green fluorescent protein (gfp) reduced chromosomal gfp expression in gonad tissue, which was not different from GC. RNAi against rbx-1 also induced abnormal chromosome segregation in the gonad during spaceflight as on Earth. Finally, culture in RNAi against lysosomal cathepsins prevented degradation of the muscle-specific alpha-actin protein in both spaceflight and GC conditions. CONCLUSIONS: Treatment with RNAi works as effectively in the space environment as on Earth within multiple tissues, suggesting RNAi may provide an effective tool for combating spaceflight-induced pathologies aboard future long-duration space missions. Furthermore, this is the first demonstration that RNAi can be utilised to block muscle protein degradation, both on Earth and in space. PMID- 21673805 TI - Visual advantage in deaf adults linked to retinal changes. AB - The altered sensory experience of profound early onset deafness provokes sometimes large scale neural reorganisations. In particular, auditory-visual cross-modal plasticity occurs, wherein redundant auditory cortex becomes recruited to vision. However, the effect of human deafness on neural structures involved in visual processing prior to the visual cortex has never been investigated, either in humans or animals. We investigated neural changes at the retina and optic nerve head in profoundly deaf (N = 14) and hearing (N = 15) adults using Optical Coherence Tomography (OCT), an in-vivo light interference method of quantifying retinal micro-structure. We compared retinal changes with behavioural results from the same deaf and hearing adults, measuring sensitivity in the peripheral visual field using Goldmann perimetry. Deaf adults had significantly larger neural rim areas, within the optic nerve head in comparison to hearing controls suggesting greater retinal ganglion cell number. Deaf adults also demonstrated significantly larger visual field areas (indicating greater peripheral sensitivity) than controls. Furthermore, neural rim area was significantly correlated with visual field area in both deaf and hearing adults. Deaf adults also showed a significantly different pattern of retinal nerve fibre layer (RNFL) distribution compared to controls. Significant correlations between the depth of the RNFL at the inferior-nasal peripapillary retina and the corresponding far temporal and superior temporal visual field areas (sensitivity) were found. Our results show that cross-modal plasticity after early onset deafness may not be limited to the sensory cortices, noting specific retinal adaptations in early onset deaf adults which are significantly correlated with peripheral vision sensitivity. PMID- 21673807 TI - Of black swans and tossed coins: is the description-experience gap in risky choice limited to rare events? AB - When faced with risky decisions, people tend to be risk averse for gains and risk seeking for losses (the reflection effect). Studies examining this risk-sensitive decision making, however, typically ask people directly what they would do in hypothetical choice scenarios. A recent flurry of studies has shown that when these risky decisions include rare outcomes, people make different choices for explicitly described probabilities than for experienced probabilistic outcomes. Specifically, rare outcomes are overweighted when described and underweighted when experienced. In two experiments, we examined risk-sensitive decision making when the risky option had two equally probable (50%) outcomes. For experience based decisions, there was a reversal of the reflection effect with greater risk seeking for gains than for losses, as compared to description-based decisions. This fundamental difference in experienced and described choices cannot be explained by the weighting of rare events and suggests a separate subjective utility curve for experience. PMID- 21673808 TI - iTRAQ-coupled 2-D LC-MS/MS analysis of membrane protein profile in Escherichia coli incubated with apidaecin IB. AB - Apidaecins are a series of proline-rich, 18- to 20-residue antimicrobial peptides produced by insects. They are predominantly active against the gram-negative bacteria. Previous studies mainly focused on the identification of their internal macromolecular targets, few addressed on the action of apidaecins on the molecules, especially proteins, of bacterial cell membrane. In this study, iTRAQ coupled 2-D LC-MS/MS technique was utilized to identify altered membrane proteins of Escherichia coli cells incubated with one isoform of apidaecins--apidaecin IB. Cell division protease ftsH, an essential regulator in maintenance of membrane lipid homeostasis, was found to be overproduced in cells incubated with apidaecin IB. Its over-expression intensified the degradation of cytoplasmic protein UDP-3 O-acyl-N- acetylglucosamine deacetylase, which catalyzes the first committed step in the biosynthesis of the lipid A moiety of LPS, and thus leaded to the further unbalanced biosynthesis of LPS and phospholipids. Our findings suggested a new antibacterial mechanism of apidaecins and perhaps, by extension, for other proline-rich antimicrobial peptides. PMID- 21673806 TI - Biosynthesis of promatrix metalloproteinase-9/chondroitin sulphate proteoglycan heteromer involves a Rottlerin-sensitive pathway. AB - BACKGROUND: Previously we have shown that a fraction of the matrix metalloproteinase-9 (MMP-9) synthesized by the macrophage cell line THP-1 was bound to a chondroitin sulphate proteoglycan (CSPG) core protein as a reduction sensitive heteromer. Several biochemical properties of the enzyme were changed when it was bound to the CSPG. METHODOLOGY/PRINCIPAL FINDINGS: By use of affinity chromatography, zymography, and radioactive labelling, various macrophage stimulators were tested for their effect on the synthesis of the proMMP-9/CSPG heteromer and its components by THP-1 cells. Of the stimulators, only PMA largely increased the biosynthesis of the heteromer. As PMA is an activator of PKC, we determined which PKC isoenzymes were expressed by performing RT-PCR and Western Blotting. Subsequently specific inhibitors were used to investigate their involvement in the biosynthesis of the heteromer. Of the inhibitors, only Rottlerin repressed the biosynthesis of proMMP-9/CSPG and its two components. Much lower concentrations of Rottlerin were needed to reduce the amount of CSPG than what was needed to repress the synthesis of the heteromer and MMP-9. Furthermore, Rottlerin caused a minor reduction in the activation of the PKC isoenzymes delta, epsilon, theta and upsilon (PKD3) in both control and PMA exposed cells. CONCLUSIONS/SIGNIFICANCE: The biosynthesis of the proMMP-9/CSPG heteromer and proMMP-9 in THP-1 cells involves a Rottlerin-sensitive pathway that is different from the Rottlerin sensitive pathway involved in the CSPG biosynthesis. MMP-9 and CSPGs are known to be involved in various physiological and pathological processes. Formation of complexes may influence both the specificity and localization of the enzyme. Therefore, knowledge about biosynthetic pathways and factors involved in the formation of the MMP-9/CSPG heteromer may contribute to insight in the heteromers biological function as well as pointing to future targets for therapeutic agents. PMID- 21673809 TI - Clinical symptoms of skin, nails, and joints manifest independently in patients with concomitant psoriasis and psoriatic arthritis. AB - This study correlated assessment tools for evaluating the severity of skin, nail, and joint symptoms in patients with psoriasis (Pso) and psoriatic arthritis (PsA). Adults with plaque Pso (with or without PsA) were enrolled from four U.S. institutions. Patients were evaluated using a novel 10-area Linear Psoriasis Area and Severity Index (XL-PASI), Psoriatic Arthritis Assessment (PsAA), Psoriatic Arthritis Screening and Evaluation Questionnaire (PASE), Nail Assessment (NA) and Joint Assessment (JA) tools, Psoriasis Weighted Extent and Severity Index (PWESI), and Lattice Physician Global Assessment (LS-PGA). Correlations between assessment tools and individual items in the assessment tools were performed. Data from 180 patients (55 with PsA) were analyzed. Highest correlations between tools (r = 0.77-0.88) were between the XL-PASI, PWESI and LS-PGA. Individual items in the XL-PASI correlated with items in the PWESI for extent skin symptoms, but not for all body areas. Overall, correlations were seen between hands and feet, between face and scalp, and between buttocks, chest, and back. Only low correlation was seen between items assessing joint symptoms with items assessing skin symptoms. These data support the notion that the complex phenotype of psoriatic disease requires instruments that assess the severity of skin, nails, and joints separately. PMID- 21673810 TI - Isolation and characterization of a metastatic hybrid cell line generated by ER negative and ER positive breast cancer cells in mouse bone marrow. AB - BACKGROUND: The origin and the contribution of breast tumor heterogeneity to its progression are not clear. We investigated the effect of a growing orthotopic tumor formed by an aggressive estrogen receptor (ER)-negative breast cancer cell line on the metastatic potential of a less aggressive ER-positive breast cancer cell line for the elucidation of how the presence of heterogeneous cancer cells might affect each other's metastatic behavior. METHODS: ER positive ZR-75 1/GFP/puro cells, resistant to puromycin and non-tumorigenic/non-metastatic without exogenous estrogen supplementation, were injected intracardiacally into mice bearing growing orthotopic tumors, formed by ER negative MDA-MB-231/GFP/Neo cells resistant to G418. A variant cell line B6, containing both estrogen dependent and -independent cells, were isolated from GFP expressing cells in the bone marrow and re-inoculated in nude mice to generate an estrogen-independent cell line B6TC. RESULTS: The presence of ER negative orthotopic tumors resulted in bone metastasis of ZR-75-1 without estrogen supplementation. The newly established B6TC cell line was tumorigenic without estrogen supplementation and resistant to both puromycin and G418 suggesting its origin from the fusion of MDA MB-231/GFP/Neo and ZR-75-1/GFP/puro in the mouse bone marrow. Compared to parental cells, B6TC cells were more metastatic to lung and bone after intracardiac inoculation. More significantly, B6TC mice also developed brain metastasis, which was not observed in the MDA-MB-231/GFP/Neo cell-inoculated mice. Low expression of ERalpha and CD24, and high expression of EMT-related markers such as Vimentin, CXCR4, and Integrin-beta1 along with high CD44 and ALDH expression indicated stem cell-like characteristics of B6TC. Gene microarray analysis demonstrated a significantly different gene expression profile of B6TC in comparison to those of parental cell lines. CONCLUSIONS: Spontaneous generation of the novel hybrid cell line B6TC, in a metastatic site with stem cell-like properties and propensity to metastasize to brain, suggest that cell fusion can contribute to tumor heterogeneity. PMID- 21673811 TI - Psychometric curve and behavioral strategies for whisker-based texture discrimination in rats. AB - The rodent whisker system is a major model for understanding neural mechanisms for tactile sensation of surface texture (roughness). Rats discriminate surface texture using the whiskers, and several theories exist for how texture information is physically sensed by the long, moveable macrovibrissae and encoded in spiking of neurons in somatosensory cortex. However, evaluating these theories requires a psychometric curve for texture discrimination, which is lacking. Here we trained rats to discriminate rough vs. fine sandpapers and grooved vs. smooth surfaces. Rats intermixed trials at macrovibrissa contact distance (nose >2 mm from surface) with trials at shorter distance (nose <2 mm from surface). Macrovibrissae were required for distant contact trials, while microvibrissae and non-whisker tactile cues were used for short distance trials. A psychometric curve was measured for macrovibrissa-based sandpaper texture discrimination. Rats discriminated rough P150 from smoother P180, P280, and P400 sandpaper (100, 82, 52, and 35 um mean grit size, respectively). Use of olfactory, visual, and auditory cues was ruled out. This is the highest reported resolution for rodent texture discrimination, and constrains models of neural coding of texture information. PMID- 21673812 TI - A 50% reduction of excitability but not of intercellular coupling affects conduction velocity restitution and activation delay in the mouse heart. AB - INTRODUCTION: Computer simulations suggest that intercellular coupling is more robust than membrane excitability with regard to changes in and safety of conduction. Clinical studies indicate that SCN5A (excitability) and/or Connexin43 (Cx43, intercellular coupling) expression in heart disease is reduced by approximately 50%. In this retrospective study we assessed the effect of reduced membrane excitability or intercellular coupling on conduction in mouse models of reduced excitability or intercellular coupling. METHODS AND RESULTS: Epicardial activation mapping of LV and RV was performed on Langendorff-perfused mouse hearts having the following: 1) Reduced excitability: Scn5a haploinsufficient mice; and 2) reduced intercellular coupling: Cx43(CreER(T)/fl) mice, uninduced (50% Cx43) or induced (10% Cx43) with Tamoxifen. Wild type (WT) littermates were used as control. Conduction velocity (CV) restitution and activation delay were determined longitudinal and transversal to fiber direction during S(1)S(1) pacing and S(1)S(2) premature stimulation until the effective refractory period. In both animal models, CV restitution and activation delay in LV were not changed compared to WT. In contrast, CV restitution decreased and activation delay increased in RV during conduction longitudinal but not transverse to fiber direction in Scn5a heterozygous animals compared to WT. In contrast, a 50% reduction of intercellular coupling did not affect either CV restitution or activation delay. A decrease of 90% Cx43, however, resulted in decreased CV restitution and increased activation delay in RV, but not LV. CONCLUSION: Reducing excitability but not intercellular coupling by 50% affects CV restitution and activation delay in RV, indicating a higher safety factor for intercellular coupling than excitability in RV. PMID- 21673814 TI - Comprehensive molecular sampling yields a robust phylogeny for geometrid moths (Lepidoptera: Geometridae). AB - BACKGROUND: The moth family Geometridae (inchworms or loopers), with approximately 23,000 described species, is the second most diverse family of the Lepidoptera. Apart from a few recent attempts based on morphology and molecular studies, the phylogeny of these moths has remained largely uninvestigated. METHODOLOGY/PRINCIPAL FINDINGS: We performed a rigorous and extensive molecular analysis of eight genes to examine the geometrid affinities in a global context, including a search for its potential sister-taxa. Our maximum likelihood analyses included 164 taxa distributed worldwide, of which 150 belong to the Geometridae. The selected taxa represent all previously recognized subfamilies and nearly 90% of recognized tribes, and originate from all over world. We found the Geometridae to be monophyletic with the Sematuridae+Epicopeiidae clade potentially being its sister-taxon. We found all previously recognized subfamilies to be monophyletic, with a few taxa misplaced, except the Oenochrominae+Desmobathrinae complex that is a polyphyletic assemblage of taxa and the Orthostixinae, which was positioned within the Ennominae. The Sterrhinae and Larentiinae were found to be sister to the remaining taxa, followed by Archiearinae, the polyphyletic assemblage of Oenochrominae+Desmobathrinae moths, Geometrinae and Ennominae. CONCLUSIONS/SIGNIFICANCE: Our study provides the first comprehensive phylogeny of the Geometridae in a global context. Our results generally agree with the other, more restricted studies, suggesting that the general phylogenetic patterns of the Geometridae are now well-established. Generally the subfamilies, many tribes, and assemblages of tribes were well supported but their interrelationships were often weakly supported by our data. The Eumeleini were particularly difficult to place in the current system, and several tribes were found to be para- or polyphyletic. PMID- 21673813 TI - Beta-carotene reduces body adiposity of mice via BCMO1. AB - Evidence from cell culture studies indicates that beta-carotene-(BC)-derived apocarotenoid signaling molecules can modulate the activities of nuclear receptors that regulate many aspects of adipocyte physiology. Two BC metabolizing enzymes, the BC-15,15'-oxygenase (Bcmo1) and the BC-9',10'-oxygenase (Bcdo2) are expressed in adipocytes. Bcmo1 catalyzes the conversion of BC into retinaldehyde and Bcdo2 into beta-10'-apocarotenal and beta-ionone. Here we analyzed the impact of BC on body adiposity of mice. To genetically dissect the roles of Bcmo1 and Bcdo2 in this process, we used wild-type and Bcmo1(-/-) mice for this study. In wild-type mice, BC was converted into retinoids. In contrast, Bcmo1(-/-) mice showed increased expression of Bcdo2 in adipocytes and beta-10'-apocarotenol accumulated as the major BC derivative. In wild-type mice, BC significantly reduced body adiposity (by 28%), leptinemia and adipocyte size. Genome wide microarray analysis of inguinal white adipose tissue revealed a generalized decrease of mRNA expression of peroxisome proliferator-activated receptor gamma (PPARgamma) target genes. Consistently, the expression of this key transcription factor for lipogenesis was significantly reduced both on the mRNA and protein levels. Despite beta-10'-apocarotenoid production, this effect of BC was absent in Bcmo1(-/-) mice, demonstrating that it was dependent on the Bcmo1-mediated production of retinoids. Our study evidences an important role of BC for the control of body adiposity in mice and identifies Bcmo1 as critical molecular player for the regulation of PPARgamma activity in adipocytes. PMID- 21673815 TI - Fibro-vascular coupling in the control of cochlear blood flow. AB - BACKGROUND: Transduction of sound in the cochlea is metabolically demanding. The lateral wall and hair cells are critically vulnerable to hypoxia, especially at high sound levels, and tight control over cochlear blood flow (CBF) is a physiological necessity. Yet despite the importance of CBF for hearing, consensus on what mechanisms are involved has not been obtained. METHODOLOGY/PRINCIPAL FINDINGS: We report on a local control mechanism for regulating inner ear blood flow involving fibrocyte signaling. Fibrocytes in the super-strial region are spatially distributed near pre-capillaries of the spiral ligament of the albino guinea pig cochlear lateral wall, as demonstrably shown in transmission electron microscope and confocal images. Immunohistochemical techniques reveal the inter connected fibrocytes to be positive for Na+/K+ ATPase beta1 and S100. The connected fibrocytes display more Ca(2+) signaling than other cells in the cochlear lateral wall as indicated by fluorescence of a Ca(2+) sensor, fluo-4. Elevation of Ca(2+) in fibrocytes, induced by photolytic uncaging of the divalent ion chelator o-nitrophenyl EGTA, results in propagation of a Ca(2+) signal to neighboring vascular cells and vasodilation in capillaries. Of more physiological significance, fibrocyte to vascular cell coupled signaling was found to mediate the sound stimulated increase in cochlear blood flow (CBF). Cyclooxygenase-1 (COX 1) was required for capillary dilation. CONCLUSIONS/SIGNIFICANCE: The findings provide the first evidence that signaling between fibrocytes and vascular cells modulates CBF and is a key mechanism for meeting the cellular metabolic demand of increased sound activity. PMID- 21673816 TI - Coordinated movements prevent jamming in an Emperor penguin huddle. AB - For Emperor penguins (Aptenodytes forsteri), huddling is the key to survival during the Antarctic winter. Penguins in a huddle are packed so tightly that individual movements become impossible, reminiscent of a jamming transition in compacted colloids. It is crucial, however, that the huddle structure is continuously reorganized to give each penguin a chance to spend sufficient time inside the huddle, compared with time spent on the periphery. Here we show that Emperor penguins move collectively in a highly coordinated manner to ensure mobility while at the same time keeping the huddle packed. Every 30-60 seconds, all penguins make small steps that travel as a wave through the entire huddle. Over time, these small movements lead to large-scale reorganization of the huddle. Our data show that the dynamics of penguin huddling is governed by intermittency and approach to kinetic arrest in striking analogy with inert non equilibrium systems, including soft glasses and colloids. PMID- 21673817 TI - Current Status and New Developments in Breast MRI. AB - SUMMARY: Breast magnetic resonance imaging (MRI) is the most sensitive imaging modality for the detection of breast cancer. Its specificity is equivalent to that of mammography. Nowadays, breast MRI is an absolutely essential breast imaging method. Technical innovations allow dynamic contrast-enhanced (DCE) MRI of both breasts with high image quality. Thereby, DCE breast MRI should always be performed with regard to current standards. New quantitative techniques such as diffusion-weighted MRI are promising. However, they still have potential pitfalls, in particular with regard to the diagnosis of non-mass lesions and small breast lesions. Ongoing technical innovations can possibly help to further optimize breast MRI. PMID- 21673818 TI - Minimally Invasive Biopsy Methods - Diagnostics or Therapy? Personal Opinion and Review of the Literature. AB - SUMMARY: This article provides an overview of different minimally invasive biopsy (MIB) methods for preoperative assessment of suspicious and indeterminate breast lesions. Accuracy depends on the choice of method and on lesion characteristics. An additional aspect deals with the question whether or not MIB is a suitable therapeutic approach in selected lesions. PMID- 21673819 TI - Breast Sonography - 2D, 3D, 4D Ultrasound or Elastography? AB - SUMMARY: The aim of this publication is to give an answer to the question whether 2D, 3D and 4D sonography of the breast can be replaced by elastography or whether elastography is an adjunct tool to B-mode imaging. The Breast Imaging and Reporting Data System (BI-RADS) ultrasound (US) descriptors of a lesion besides vascularity are based on B-mode imaging. US elastography displays the mechanical tissue properties. This information can be obtained by freehand compression and decompression. Acoustic radiation force impulse imaging (ARFI) produces stress with low-frequency push pulses. Manual compression by the transducer is not necessary. Shear wave elastography (SWE) is the combination of ARFI and the measurement of the consecutive shear wave propagations in the tissue. A quantification of the elasticity in kilopascal (kPa) is offered. Discussing B mode imaging and elastography combined with the literature, elastography is seen as an addition to B-mode imaging with the potential to increase the specificity of the B-mode imaging-based BI-RADS assessment. In spite of additional elasticity information, the sensitivity remains high. A time-saving diagnostic algorithm for 2D, 3D US and elastography is described. In conclusion, it must be said that elasticity is not a stand-alone US modality able to replace 2D and 3D sonography. PMID- 21673820 TI - Mammography Screening: Evidence, History and Current Practice in Germany and Other European Countries. AB - SUMMARY: In this review, we describe the history, evidence, and current practice of mammography screening in Europe and the newly implemented screening program in Germany. We report results of the first screening rounds in North Rhine Westphalia and compare these with reference values set by the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis. Finally, we summarize and compare performance indicators of the organized screening program in England, Italy, North Rhine-Westphalia and The Netherlands. Based on results of the first screening rounds, we conclude that the digital mammography screening program in North Rhine-Westphalia performs well and complies with the European guidelines. Besides relatively low attendance rates of approximately 53%, implementation of the German organized breast cancer screening program was successful. PMID- 21673822 TI - Financial Quality Control of In-Patient Chemotherapy in Germany: Are Additional Payments Cost-Covering for Pharmaco-Oncological Expenses? AB - SUMMARY: BACKGROUND: Cost-covering in-patient care is increasingly important for hospital providers in Germany, especially with regard to expensive oncological pharmaceuticals. Additional payments (Zusatzentgelte; ZE) on top of flat rate diagnose-related group (DRG) reimbursement can be claimed by hospitals for in patient use of selected medications. To verify cost coverage of in-patient chemotherapies, the costs of medication were compared to their revenues. METHOD: From January to June 2010, a retrospective cost-revenue study was performed at a German obstetrics/gynecology university clinic. The hospital's pharmacy list of inpatient oncological therapies for breast and gynecological cancer was checked for accuracy and compared with the documented ZEs and the costs and revenues for each oncological application. RESULTS: N = 45 in-patient oncological therapies were identified in n = 18 patients, as well as n = 7 bisphosphonate applications; n = 11 ZEs were documented. Costs for oncological medication were ? 33,752. The corresponding ZE revenues amounted to only ? 13,980, resulting in a loss of ? 19,772. All in-patient oncological therapies performed were not cost-covering. Data discrepancy, incorrect documentation and cost attribution, and process aborts were identified. CONCLUSIONS: Routine financial quality control at the medicine-pharmacy administration interface is implemented, with monthly comparison of costs and revenues, as well as admission status. Non-cost-covering therapies for in-patients should be converted to out-patient therapies. Necessary adjustments of clinic processes are made according to these results, to avoid future losses. PMID- 21673821 TI - Molecular Imaging in Breast Cancer - Potential Future Aspects. AB - SUMMARY: Molecular imaging aims to visualize and quantify biological, physiological, and pathological processes at cellular and molecular levels. Recently, molecular imaging has been introduced into breast cancer imaging. In this review, we will present a survey of the molecular imaging techniques that are either clinically available or are being introduced into clinical imaging. We will discuss nuclear imaging and multiparametric magnetic resonance imaging as well as the combined application of molecular imaging in the assessment of breast lesions. In addition, we will briefly discuss other evolving molecular imaging techniques, such as phosphorus magnetic resonance spectroscopic imaging and sodium imaging. PMID- 21673823 TI - Association between the TNF-alpha-238G>A and TGF-beta1 L10P Polymorphisms and Breast Cancer Risk: A Meta-Analysis. AB - SUMMARY: BACKGROUND: The tumor necrosis factors alpha and beta (TNF-alpha, TNF beta) can regulate a wide range of cellular responses and facilitate tumor growth and progression. However, the effects of the polymorphisms TNF-alpha-238G>A and transforming growth factor (TGF)-beta1 L10P on breast cancer risk are still unclear or inconclusive. MATERIALS AND METHODS: In order to provide a full estimation of the association with breast cancer, a meta-analysis of the most valid literature was performed by searching the databases PubMed, Web of Science, ScienceDirect, EBSCO, CNKI, and Google Scholar. RESULTS: For TNF-alpha-238G>A, 3 studies including 35,578 cases and 38,095 controls were selected. For TGF-beta1 L10P, 11 studies including 7,903 cases and 8,797 controls were selected. For TNF alpha-238G>A, a significant association with breast cancer risk was found in the recessive model (odds ratio = 0.954, 95% confidence interval 0.912-0.998), but other models did not reach significance. For TGF-beta1 L10P, no significant correlations were found. CONCLUSIONS: Our study indicates that TNF-alpha-238G>A may be associated with breast cancer incidence, although significance is weak. Its role as an indicator for cancer diagnosis should be studied more. Moreover, for TGF-beta1 L10P, further comprehensive meta-analyses are necessary. PMID- 21673824 TI - Chyle Leak Following Axillary Lymph Node Clearance - a Benign Complication: Review of the Literature. AB - SUMMARY: CASE REPORT: An 82-year-old patient underwent a mastectomy and axillary lymph node clearance for a large multicentric lobular cancer of the left breast. On day 11 after her operation, white viscous fluid was noted in her axillary drain. METHODS: We analysed case reports in the literature, noting the interval between surgery and diagnosis of chyle, the duration of the chyle leak, the volume of chyle during the first 24 h, the median volume and the administered treatment. RESULTS: 25 cases were reported in 13 publications. Our case was unusual in that chyle was noted 11 days after surgery. In most cases, chyle leakage subsides spontaneously by simply leaving the drain in situ. CONCLUSIONS: A conservative observant approach appears appropriate in most cases. Only for persistent and large-volume leaks, dietary intervention (medium-chain lipid diet, nil by mouth, total parenteral nutrition) is justified. Surgery with re exploration of the axilla and oversewing of the chyle duct can be used as the last reserve for persistent chyle leaks. PMID- 21673825 TI - Synchronous Parotid and Thyroid Gland Metastases from Breast Cancer. AB - SUMMARY: BACKGROUND: Metastases to the parotid and thyroid glands from breast cancer are rare and have a poor prognosis. CASE REPORT: We present the case of a patient with breast carcinoma and synchronous involvement of both the parotid and thyroid gland, and review the literature on this subject. CONCLUSION: Metastatic malignancy in clinically suspect thyroid and parotid nodules could be detected more frequently with routine use of fine needle aspiration biopsy. PMID- 21673826 TI - A dynamical model for describing behavioural interventions for weight loss and body composition change. AB - We present a dynamical model incorporating both physiological and psychological factors that predicts changes in body mass and composition during the course of a behavioral intervention for weight loss. The model consists of a three compartment energy balance integrated with a mechanistic psychological model inspired by the Theory of Planned Behavior (TPB). The latter describes how important variables in a behavioural intervention can influence healthy eating habits and increased physical activity over time. The novelty of the approach lies in representing the behavioural intervention as a dynamical system, and the integration of the psychological and energy balance models. Two simulation scenarios are presented that illustrate how the model can improve the understanding of how changes in intervention components and participant differences affect outcomes. Consequently, the model can be used to inform behavioural scientists in the design of optimised interventions for weight loss and body composition change. PMID- 21673828 TI - Mediators of the Effect of Parental Incarceration on Adolescent Externalizing Behaviors. AB - Over the past two decades, the number of children with parents in prison has increased substantially. Using structural equation modeling with prospective longitudinal data gathered as part of the ongoing Linking the Interests of Families and Teachers (LIFT) trial, the study tests a theoretical model which examines the direct and indirect relationships of four specific domains (parental incarceration, social advantage, parent mental and physical health, effective parenting) as they relate to youth antisocial behavior in the 5th, 8th, and 10th grades. Across all three grades, the relationship between parental incarceration and youth antisocial behaviors was mediated through a complex set of both direct and indirect pathways involving social advantage, parent health, and effective parenting. The total amount of variation explained by the models for youth externalizing ranged from .60 (in 5th grade) to .21 (in 10th grade). The total effects in all the refined models were small. PMID- 21673827 TI - Electrodeposition on nanofibrous polymer scaffolds: Rapid mineralization, tunable calcium phosphate composition and topography. AB - We developed a straightforward, fast, and versatile technique to fabricate mineralized nanofibrous polymer scaffolds for bone regeneration in this work. Nanofibrous poly(l-lactic acid) scaffolds were fabricated using both electrospinning and phase separation techniques. An electrodeposition process was designed to deposit calcium phosphate on the nanofibrous scaffolds. Such scaffolds contain a high quality mineral coating on the fiber surface with tunable surface topography and chemical composition by varying the processing parameters, which can mimic the composition and structure of natural bone extracellular matrix and provide a more biocompatible interface for bone regeneration. PMID- 21673829 TI - The effect of input data transformations on object-based image analysis. AB - The effect of using spectral transform images as input data on segmentation quality and its potential effect on products generated by object-based image analysis are explored in the context of land cover classification in Accra, Ghana. Five image data transformations are compared to untransformed spectral bands in terms of their effect on segmentation quality and final product accuracy. The relationship between segmentation quality and product accuracy is also briefly explored. Results suggest that input data transformations can aid in the delineation of landscape objects by image segmentation, but the effect is idiosyncratic to the transformation and object of interest. PMID- 21673830 TI - View-independent Contour Culling of 3D Density Maps for Far-field Viewing of Iso surfaces. AB - In many applications, iso-surface is the primary method for visualizing the structure of 3D density maps. We consider a common scenario where the user views the iso-surfaces from a distance and varies the level associated with the iso surface as well as the view direction to gain a sense of the general 3D structure of the density map. For many types of density data, the iso-surfaces associated with a particular threshold may be nested and never visible during this type of viewing. In this paper, we discuss a simple, conservative culling method that avoids the generation of interior portions of iso-surfaces at the contouring stage. Unlike existing methods that perform culling based on the current view direction, our culling is performed once for all views and requires no additional computation as the view changes. By pre-computing a single visibility map, culling is done at any iso-value with little overhead in contouring. We demonstrate the effectiveness of the algorithm on a range of bio-medical data and discuss a practical application in online visualization. PMID- 21673831 TI - Highly-efficient single-cell capture in microfluidic array chips using differential hydrodynamic guiding structures. AB - This paper presents a highly efficient single cell capture scheme using hydrodynamic guiding structures in a microwell array. The implemented structure has a capturing efficiency of >80%, and has a capacity to place individual cells into separated microwells, allowing for the time-lapse monitoring on single cell behavior. Feasibility was tested by injecting microbeads (15 MUm in diameter) and prostate cancer PC3 cells in an 8*8 microwell array chip and >80% of the microwells were occupied by single ones. Using the chips, the number of cells required for cell assays can be dramatically reduced and this will facilitate overcoming a huddle of assays with scarce supply of cells. PMID- 21673832 TI - High-sensitivity and wide-directivity ultrasound detection using high Q polymer microring resonators. AB - Small size ultrahigh Q polymer microrings working at near visible wavelength have been experimentally demonstrated as ultralow noise ultrasound detectors with wide directivity at high frequencies (>20 MHz). By combining a resist reflow and a low bias continuous etching and passivation process in mold fabrication, imprinted polymer microrings with drastically improved sidewall smoothness were obtained. An ultralow noise-equivalent pressure of 21.4 Pa over 1-75 MHz range has been achieved using a fabricated detector of 60 MUm diameter. The device's wide acceptance angle with high sensitivity considerably benefits ultrasound-related imaging. PMID- 21673833 TI - Economic Evaluation of a School-based Combined Program with a Targeted Pit and Fissure Sealant and Fluoride Mouth Rinse in Japan. AB - BACKGROUND: In Niigata prefecture, Japan, a system has been developed based on a school-based fluoride mouth rinse program as follows; students with caries susceptible teeth are screened in a school dental examination, and encouraged to receive sealant placement in local dental clinics. However, the cost effectiveness of sealant application in the public health has been questioned. The aim of this study was to estimate of the cost-effectiveness and cost-benefit ratio for a school-based combined program with fluoride mouth rinse and targeted fissure sealant in children residing in non-fluoridated areas in Japan. PARTICIPANTS: The analysis was based on comparing an intervention group with two cohorts in the 8-year-old (n=66) and 11-year-old (n=58) participating in the combined program for four and seven years, respectively, with a control group of the same grades (n=43 and n=54 respectively). METHODS: The study measured mean differences in number of decayed and filled teeth (DFT) between the study groups and a combined program cost per child during study periods. The cost effectiveness ratio was expressed as an individual annual program cost per DFT averted. In the cost-benefit ratio the mean difference in treatment cost between groups (program benefit) was compared to program cost. RESULTS: The mean reduced DFT differences between groups were 1.44 in 8-year-old and 3.17 in 11-year-old children. The cost-effectiveness ratio was Y 493 in the 8-year-old and Y 202 in the 11-year-old, respectively. The cost-benefit ratio was 1.84 in 8-year-old children and 2.42 in 11-year-old. CONCLUSION: This combined program indicated acceptable cost-effectiveness and cost -benefit ratio. PMID- 21673835 TI - Cardiovascular risk among university students from developed and developing nations. AB - BACKGROUND: A key aspect in halting global increase in cardiovascular events is prevention and especially prevention at an early age. Unfortunately, global data regarding cardiovascular risk factors in the young are limited. Therefore the objectives of this study were to identify the most common cardiovascular risk factors among young adults in a university setting in both developed and developing countries. METHODS: Lifestyle and cardiovascular risk factors (smoking status, rates of physical activity, alcohol use, family history, blood pressure, fasting lipid panel, fasting blood glucose) were prospectively evaluated in young adults at three different university settings [University of Michigan (Ann Arbor, USA), University of Kalamoon (Deratiah, Syria), and Kakatiya University (Warangal, India)]. RESULTS: A total of 296 subjects (mean age and standard deviation 22 +/- 3 years) were evaluated. Rates of current smoking were markedly higher (p < 0.001) in Syria (43%) compared with the USA (6.2%) and India (1.7%). Subjects in India were significantly (p < 0.001) less likely to engage in physical activity (20.2%) compared with the USA (90.7%) and Syria (68.8%). Fasting blood glucose levels and body mass index were significantly higher (p < 0.001) in Syria as compared to other countries. Significant differences were also noted in LDL, HDL, and triglycerides among the three sites. CONCLUSIONS: Cardiovascular risk factors among young adults in a university setting vary depending on global setting. Based upon the results of this study, targeted interventional programs based on risk findings from individual countries may be a reasonable future strategy to help reduce long term cardiovascular morbidity and mortality. PMID- 21673834 TI - The vulnerable plaque: the real villain in acute coronary syndromes. AB - The term "vulnerable plaque" refers to a vascular lesion that is prone to rupture and may result in life-threatening events which include myocardial infarction. It consists of thin-cap fibroatheroma and a large lipid core which is highly thrombogenic. Acute coronary syndromes often result from rupture of vulnerable plaques which frequently are only moderately stenosed and not visible by conventional angiography. Several invasive and non-invasive strategies have been developed to assess the burden of vulnerable plaques. Intravascular ultrasound provides a two-dimensional cross-sectional image of the arterial wall and can help assess the plaque burden and composition. Optical coherent tomography offers superior resolution over intravascular ultrasound. High-resolution magnetic resonance imaging provides non-invasive imaging for visualizing fibrous cap thickness and rupture in plaques. In addition, it may be of value in assessing the effects of treatments, such as lipid-lowering therapy. Technical issues however limit its clinical applicability. The role of multi-slice computed tomography, a well established screening tool for coronary artery disease, remains to be determined. Fractional flow reserve (FFR) may provide physiological functional assessment of plaque vulnerability; however, its role in the management of vulnerable plaque requires further studies. Treatment of the vulnerable patient may involve systemic therapy which currently include statins, ACE inhibitors, beta-blockers, aspirin, and calcium-channel blockers and in the future local therapeutic options such as drug-eluting stents or photodynamic therapy. PMID- 21673836 TI - Theory and developments in an unobtrusive cardiovascular system representation: ballistocardiography. AB - Due to recent technological improvements, namely in the field of piezoelectric sensors, ballistocardiography - an almost forgotten physiological measurement - is now being object of a renewed scientific interest.Transcending the initial purposes of its development, ballistocardiography has revealed itself to be a useful informative signal about the cardiovascular system status, since it is a non-intrusive technique which is able to assess the body's vibrations due to its cardiac, and respiratory physiological signatures.Apart from representing the outcome of the electrical stimulus to the myocardium - which may be obtained by electrocardiography - the ballistocardiograph has additional advantages, as it can be embedded in objects of common use, such as a bed or a chair. Moreover, it enables measurements without the presence of medical staff, factor which avoids the stress caused by medical examinations and reduces the patient's involuntary psychophysiological responses.Given these attributes, and the crescent number of systems developed in recent years, it is therefore pertinent to revise all the information available on the ballistocardiogram's physiological interpretation, its typical waveform information, its features and distortions, as well as the state of the art in device implementations. PMID- 21673837 TI - Thiadiazine derivatives as antiprotozoal new drugs. AB - The 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione scaffold have found many applications in recent years. This review is aimed at highlighting the most important aspects about these compounds: synthesis, spectroscopic characterization and antiprotozoan activities. How the chemical nature of N substituents influences the overall activity / cytotoxicity profile will also be discussed. PMID- 21673838 TI - Cholesteryl ester transfer protein gene and effectiveness of lipid lowering of atorvastatin. AB - Cholesteryl ester transfer protein (CETP) plays a key role in lipid metabolism. Thus, variations in the CETP gene may be clinically relevant. Newly started atorvastatin users (n=212) were genotyped for CETP genetic variants (TaqIB and I405V). Homozygotes for B1 allele of TaqIB polymorphism had lower plasma high density lipoprotein cholesterol (HDL-C) compared with B1B2 or B2B2 genotypes (p=0.03, for each). Homozygotes for I allele of I405V polymorphism had lower plasma HDL-C compared with IV or VV genotypes (p=0.001, for each). In the whole population, the B1 carriers increased HDL-C levels by 4% after atorvastatin treatment, compared with B2 carriers, where a 4% decrease occurred (p=0.03). Also homozygotes for B1 allele decreased triglyceride levels to a lesser, though not significant, degree compared to B1B2 or B2B2 genotypes. CETP TaqIB or I405V polymorphisms seem to modify the lipid lowering response to atorvastatin treatment. This knowledge may help design more effective hypolipidaemic treatment. PMID- 21673839 TI - Meta-analyses and orthodontic evidence-based clinical practice in the 21 century. AB - INTRODUCTION: Aim of this systematic review was to assess the orthodontic related issues which currently provide the best evidence as documented by meta-analyses, by critically evaluating and discussing the methodology used in these studies. MATERIAL AND METHODS: Several electronic databases were searched and handsearching was also performed in order to identify the corresponding meta analyses investigating orthodontic related subjects. In total, 197 studies were retrieved initially. After applying specific inclusion and exclusion criteria, 27 articles were identified as meta-analyses treating orthodontic-related subjects. RESULTS: Many of these 27 papers presented sufficient quality and followed appropriate meta-analytic approaches to quantitatively synthesize data and presented adequately supported evidence. However, the methodology used in some of them presented weaknesses, limitations or deficiencies. Consequently, the topics in orthodontics which currently provide the best evidence, include some issues related to Class II or Class III treatment, treatment of transverse problems, external apical root resorption, dental anomalies, such as congenital missing teeth and tooth transposition, frequency of severe occlusal problems, nickel hypersensitivity, obstructive sleep apnea syndrome, and computer-assisted learning in orthodontic education. CONCLUSIONS: Only a few orthodontic related issues have been so far investigated by means of MAs. In addition, for some of these issues investigated in the corresponding MAs no definite conclusions could be drawn, due to significant methodological deficiencies of these studies. According to this investigation, it can be concluded that at the begin of the 21(st) century there is evidence for only a few orthodontic related issues as documented by meta-analyses, and more well-conducted high quality research studies are needed to produce strong evidence in order to support evidence-based clinical practice in orthodontics. PMID- 21673840 TI - Detection of HIV-1 in Saliva: Implications for Case-Identification, Clinical Monitoring and Surveillance for Drug Resistance. AB - BACKGROUND: Saliva tests that detect antibodies are used to diagnose HIV infection. The goal of this study was to determine whether saliva could be used for nucleic acid-based tests to measure HIV-1 virus load (VL) and detect drug resistance. METHODS: 69 HIV infected individuals provided 5-10 ml of saliva and blood samples. Viral RNA was isolated from saliva and dried blood spots using the Nuclisens extraction. Saliva VL was measured using a modified Amplicor assay, and genotyping was performed using an in-house RT-PCR/sequencing protocol. Plasma VLs were obtained from concurrently drawn clinical tests. RESULTS: Thirty-six of 47 (77%) plasma viremic patients had measurable saliva HIV-1 RNA. Paired plasma and saliva HIV RNA levels were significantly correlated (Spearman's correlation = .6532, p<.0001), but saliva VL was typically lower. Three of 22 patients with undetectable plasma VL (<50 copies/ml) had detectable saliva HIV RNA. Eleven of 30 patients with undetectable saliva RNA had detectable plasma HIV-1 RNA. Comparison of the protease and reverse transcriptase gene sequences from paired saliva and plasma of 20 patients showed less than 1% difference overall, and few resistance-related amino acid differences CONCLUSIONS: Most patients with plasma virus >50 copies/mL had detectable saliva HIV RNA, and the genotypic data was highly concordant between saliva and plasma. In patients with high levels of plasma HIV RNA, saliva might be useful in identifying viremia and evaluating drug resistance. PMID- 21673841 TI - Rare concurrence of apical hypertrophic cardiomyopathy and effusive constrictive pericarditis. AB - A 78-year-old man with a history of pulmonary tuberculosis was referred for preoperative evaluation of cardiac function. Echocardiography and cardiac cine magnetic resonance imaging (MRI) indicated apical hypertrophic cardiomyopathy (HCM), a thickened visceral pericardium, and a large pericardial effusion. Cardiac late gadolinium-enhanced MRI revealed pericardial inflammation or fibrosis. Apical HCM with concurrent effusive constrictive pericarditis was diagnosed. Further studies are required to elucidate the pathophysiology of this condition. PMID- 21673842 TI - Salivary markers for oral cancer detection. AB - Oral cancer refers to all malignancies that arise in the oral cavity, lips and pharynx, with 90% of all oral cancers being oral squamous cell carcinoma. Despite the recent treatment advances, oral cancer is reported as having one of the highest mortality ratios amongst other malignancies and this can much be attributed to the late diagnosis of the disease. Saliva has long been tested as a valuable tool for drug monitoring and the diagnosis systemic diseases among which oral cancer. The new emerging technologies in molecular biology have enabled the discovery of new molecular markers (DNA, RNA and protein markers) for oral cancer diagnosis and surveillance which are discussed in the current review. PMID- 21673844 TI - Cell chip array for microfluidic proteomics enabling rapid in situ assessment of intracellular protein phosphorylation. AB - We discuss the ability to perform fluorescent immunocytochemistry, following cell fixation, using a microfluidic array of primary, nonadherent, single CD34+ stem cells. The technique requires small cell samples and proceeds with no cell loss, making it well-suited to monitoring these rare patient-derived cells. The chip allows us to correlate live cell dynamics across arrays of individual cells with post-translational modifications of intracellular proteins, following their exposure to drug treatments. Results also show that due to the microfluidic environment, the time scale of cell fixation was significantly reduced compared to conventional methods, leading to greater confidence in the status of the protein modifications studied. PMID- 21673843 TI - Nutrition During Pregnancy and the Effect of Carbohydrates on the Offspring's Metabolic Profile: In Search of the "Perfect Maternal Diet". AB - Fetal growth and development is primarily dependent upon the nutritional, hormonal and metabolic environment provided by the mother. A wartime famine study in Holland first showed that a low food intake reduces the glucose offered to the fetus and thus produces smaller size infants at birth. Maternal glucose regulation is however affected by numerous factors including physiological changes of pregnancy (e.g. insulin resistance [IR]), pathological conditions (e.g. gestational diabetes mellitus) and maternal nutrition. Maternal glucose is substantially influenced by the type of carbohydrates in the diet through its direct effect on glycemia. The rate at which each carbohydrate raises blood glucose levels after ingestion, can be measured via the dietary glycemic index (GI). Carbohydrate type and the GI of the diet enhance or inhibit abnormal hyperglycemia during pregnancy caused by either pathological conditions or the inability of the mother to cope with the physiological IR of pregnancy. In turn, maternal gestational hyperglycemia may be involved in the pathogenesis of IR, impaired glucose tolerance, type 2 diabetes mellitus, the Metabolic Syndrome and subsequent cardiovascular diseases in adult offspring. A low GI maternal diet has been associated with measurable benefits to the offspring. These include a positive effect on altering maternal blood glucose production, insulinemia and reduced adiposity as well as fetal and placental insulin and glucose regulation, fetal growth, birth weight and offspring adiposity. We review the possible links between dietary carbohydrate in health during pregnancy and the effect of maternal carbohydrate ingestion on programming the offspring's metabolic profile. PMID- 21673845 TI - System-level simulation of liquid filling in microfluidic chips. AB - Liquid filling in microfluidic channels is a complex process that depends on a variety of geometric, operating, and material parameters such as microchannel geometry, flow velocity/pressure, liquid surface tension, and contact angle of channel surface. Accurate analysis of the filling process can provide key insights into the filling time, air bubble trapping, and dead zone formation, and help evaluate trade-offs among the various design parameters and lead to optimal chip design. However, efficient modeling of liquid filling in complex microfluidic networks continues to be a significant challenge. High-fidelity computational methods, such as the volume of fluid method, are prohibitively expensive from a computational standpoint. Analytical models, on the other hand, are primarily applicable to idealized geometries and, hence, are unable to accurately capture chip level behavior of complex microfluidic systems. This paper presents a parametrized dynamic model for the system-level analysis of liquid filling in three-dimensional (3D) microfluidic networks. In our approach, a complex microfluidic network is deconstructed into a set of commonly used components, such as reservoirs, microchannels, and junctions. The components are then assembled according to their spatial layout and operating rationale to achieve a rapid system-level model. A dynamic model based on the transient momentum equation is developed to track the liquid front in the microchannels. The principle of mass conservation at the junction is used to link the fluidic parameters in the microchannels emanating from the junction. Assembly of these component models yields a set of differential and algebraic equations, which upon integration provides temporal information of the liquid filling process, particularly liquid front propagation (i.e., the arrival time). The models are used to simulate the transient liquid filling process in a variety of microfluidic constructs and in a multiplexer, representing a complex microfluidic network. The accuracy (relative error less than 7%) and orders-of-magnitude speedup (30 000X-4 000 000X) of our system-level models are verified by comparison against 3D high-fidelity numerical studies. Our findings clearly establish the utility of our models and simulation methodology for fast, reliable analysis of liquid filling to guide the design optimization of complex microfluidic networks. PMID- 21673846 TI - Why local guidelines? PMID- 21673847 TI - Saudi Oncology Society clinical management guidelines for prostate cancer. AB - In this report, guidelines for the evaluation, medical and surgical management of testicular germ cell tumors is presented. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7th edition. The recommendations are presented with supporting level of evidence. PMID- 21673848 TI - Saudi Oncology Society clinical management guidelines for testicular germ cell tumors. AB - In this report, guidelines for the evaluation, medical and surgical management of testicular germ cell tumors is presented. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7th edition. The recommendations are presented with supporting level of evidence. PMID- 21673849 TI - Saudi Oncology Society clinical management guidelines for renal cell carcinoma. AB - In this report, guidelines for the evaluation, medical and surgical management of renal cell carcinoma is presented. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7(th) edition. The recommendations are presented with supporting evidence level. PMID- 21673850 TI - Saudi Oncology Society clinical management guidelines for urinary bladder cancer. AB - In this report guidelines for the evaluation, medical and surgical management of transitional cell carcinoma of urinary bladder is presented. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7(th) edition. The recommendations are presented with supporting level of evidence. PMID- 21673852 TI - Surgery as a public health intervention: common misconceptions versus the truth. PMID- 21673853 TI - Public health round-up. PMID- 21673854 TI - Fetal alcohol syndrome: dashed hopes, damaged lives. AB - Since the term was coined about 40 years ago, fetal alcohol syndrome has slowly become recognized as a public health issue. Alicestine October reports from South Africa's Western Cape province, which has the highest reported rate in the world. PMID- 21673855 TI - From awareness to action. AB - Regina Rabinovich manages a portfolio of more than US$ 1 billion of grants in infectious disease work at the Bill & Melinda Gates Foundation. She talks with Sarah Cumberland about the challenges and successes of working in global health. PMID- 21673856 TI - Maternal multiple micronutrient supplementation and pregnancy outcomes in developing countries: meta-analysis and meta-regression. AB - OBJECTIVE: To systematically review randomized controlled trials comparing the effect of supplementation with multiple micronutrients versus iron and folic acid on pregnancy outcomes in developing countries. METHODS: MEDLINE and EMBASE were searched. Outcomes of interest were birth weight, low birth weight, small size for gestational age, perinatal mortality and neonatal mortality. Pooled relative risks (RRs) were estimated by random effects models. Sources of heterogeneity were explored through subgroup meta-analyses and meta-regression. FINDINGS: Multiple micronutrient supplementation was more effective than iron and folic acid supplementation at reducing the risk of low birth weight (RR: 0.86, 95% confidence interval, CI: 0.79-0.93) and of small size for gestational age (RR: 0.85; 95% CI: 0.78-0.93). Micronutrient supplementation had no overall effect on perinatal mortality (RR: 1.05; 95% CI: 0.90-1.22), although substantial heterogeneity was evident (I(2) = 58%; P for heterogeneity = 0.008). Subgroup and meta-regression analyses suggested that micronutrient supplementation was associated with a lower risk of perinatal mortality in trials in which > 50% of mothers had formal education (RR: 0.93; 95% CI: 0.82-1.06) or in which supplementation was initiated after a mean of 20 weeks of gestation (RR: 0.88; 95% CI: 0.80-0.97). CONCLUSION: Maternal education or gestational age at initiation of supplementation may have contributed to the observed heterogeneous effects on perinatal mortality. The safety, efficacy and effective delivery of maternal micronutrient supplementation require further research. PMID- 21673857 TI - Differences in the availability of medicines for chronic and acute conditions in the public and private sectors of developing countries. AB - OBJECTIVE: To investigate potential differences in the availability of medicines for chronic and acute conditions in low- and middle-income countries. METHODS: Data on the availability of 30 commonly-surveyed medicines - 15 for acute and 15 for chronic conditions - were obtained from facility-based surveys conducted in 40 developing countries. Results were aggregated by World Bank country income group and World Health Organization region. FINDINGS: The availability of medicines for both acute and chronic conditions was suboptimal across countries, particularly in the public sector. Generic medicines for chronic conditions were significantly less available than generic medicines for acute conditions in both the public sector (36.0% availability versus 53.5%; P = 0.001) and the private sector (54.7% versus 66.2%; P = 0.007). Antiasthmatics, antiepileptics and antidepressants, followed by antihypertensives, were the drivers of the observed differences. An inverse association was found between country income level and the availability gap between groups of medicines, particularly in the public sector. In low- and lower-middle income countries, drugs for acute conditions were 33.9% and 12.9% more available, respectively, in the public sector than medicines for chronic conditions. Differences in availability were smaller in the private sector than in the public sector in all country income groups. CONCLUSION: Current disease patterns do not explain the significant gaps observed in the availability of medicines for chronic and acute conditions. Measures are needed to better respond to the epidemiological transition towards chronic conditions in developing countries alongside current efforts to scale up treatment for communicable diseases. PMID- 21673858 TI - Effect on road traffic injuries of criminalizing road traffic offences: a time series study. AB - OBJECTIVE: To determine the effect of criminalizing some traffic behaviours, after the reform of the Spanish penal code in 2007, on the number of drivers involved in injury collisions and of people injured in traffic collisions in Spain. METHODS: This study followed an interrupted times-series design in which the number of drivers involved in injury collisions and of people injured in traffic collisions in Spain before and after the criminalization of offences were compared. The data on road traffic injuries in 2000-2009 were obtained from the road traffic collision database of the General Traffic Directorate. The dependent variables were stratified by sex, age, injury severity, type of road user, road type and time of collision. Quasi-Poisson regression models were fitted with adjustments for time trend, seasonality, previous interventions and national fuel consumption. FINDINGS: The overall number of male drivers involved in injury collisions dropped (relative risk, RR: 0.93; 95% confidence interval, CI: 0.89 0.97) after the reform of the penal code, but among women no change was observed (RR: 0.99; 95% CI: 0.95-1.03). In addition, 13 891 men (P < 0.01) were prevented from being injured. Larger reductions were observed among young male drivers and among male motorcycle or moped riders than among the drivers of other vehicles. CONCLUSION: The findings suggest that criminalizing certain traffic behaviours can improve road safety by reducing both the number of drivers involved in injury collisions and the number of people injured in such collisions. PMID- 21673859 TI - Socioeconomic inequalities in hospital births in China between 1988 and 2008. AB - OBJECTIVE: To assess trends in hospital births in China during 1988-2008 in an effort to determine if efforts to overcome financial barriers to giving birth in hospital have reduced the access gap between the rich and the poor. METHODS: Cross-sectional data obtained from four National Health Service Surveys were used to determine trends in hospital births during 1988-2008. Crude and adjusted annual rates were calculated by means of Poisson regression and were used to define trends across socioeconomic regions and households in different income quintiles. FINDINGS: In 2008 women throughout China were giving birth in hospital almost universally except in region IV, the most remote rural region, where the percentage of hospital births was only 60.8. Hospital births in this region had increased steadily before 2002, but after that year the upward trend slowed down. During 1988-2001 the average yearly increase had been 21%, but in 2002-2008 it dropped to 10% (P = 0.0031). Inequalities between socioeconomic regions were greater than among individual households belonging to different income strata. By 2008 the difference between low- and high-income households in the proportion of hospital births had become very small (96.1% and 87.7% of high- and low-income households, respectively, gave birth in hospital that year). CONCLUSION: Most Chinese women now give birth in hospital, but the poorest rural region is still lagging behind. A more active and comprehensive approach will be needed to increase hospital births in these remote, hard-to-reach populations. PMID- 21673860 TI - Challenges in developing national HIV guidelines: experience from the eastern Mediterranean. AB - OBJECTIVE: To appraise the process of development and clinical content of national human immunodeficiency virus (HIV) clinical practice guidelines of countries in the eastern Mediterranean and to formulate recommendations for future guideline development and adaptation. METHODS: Twenty-three countries in the World Health Organization (WHO) Eastern Mediterranean and United Nations Children's Fund Middle East and North Africa regions were invited to submit national HIV clinical practice guidelines for review. The guideline development methodology was assessed using an adaptation of the Appraisal of Guidelines Research and Evaluation (AGREE) instrument and guideline content, using a checklist to evaluate concordance with WHO 2006 generic guidelines. FINDINGS: Twelve countries submitted 20 guidelines developed between 2004 and 2009. Median scores were poor (i.e. < 0.6) for the methodological quality domains of rigour of development, stakeholder involvement and applicability and flexibility. Scores were better for the domains of scope and purpose (median: 0.82, interquartile range, IQR: 0.58-0.89) and clarity and presentation (median: 0.67, IQR: 0.50 0.78). Concerning guideline content, recommended first-line treatment and eligibility criteria for antiretroviral therapy (ART) in adults were in line with WHO recommendations in most guidelines. However, recommendations on antiretroviral prophylaxis for the prevention of vertical HIV transmission, diagnosis and treatment of HIV infection in infants, monitoring patients on ART, treatment failure and co-morbidities were often lacking. CONCLUSION: The large majority of national HIV clinical practice guidelines had methodological weaknesses and content inaccuracies. Countries require assistance with the adaptation process to ensure that guidelines are valid and up to date and accurately reflect WHO global clinical care recommendations for patients with HIV. PMID- 21673861 TI - Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV infected children: ANRS 12103 phase II trial. AB - OBJECTIVE: To assess 12-month survival, pharmacokinetics, immunologic and virologic efficacy, tolerance, compliance and drug resistance in HIV-infected children in Bobo-Dioulasso, Burkina Faso, receiving once-daily highly-active antiretroviral therapy as a combination of didanosine (DDI), lamivudine (3TC) and efavirenz (EFV). METHODS: In the ANRS 12103 open phase II trial, HIV-infected children were examined at inclusion and monthly thereafter. CD4+ T-lymphocyte (CD4) count, plasma concentration of ribonucleic acid (RNA) of human immunodeficiency virus type 1 (HIV-1) and haematologic and biochemical parameters were measured at baseline and every trimester. HIV-1 resistance testing was performed in case of viral escape. Drug plasma concentrations were determined with high-performance liquid chromatography. FINDINGS: From February 2006 to November 2007, 51 children (39% girls) with a mean age of 6.8 years were enrolled and treated for 12 months. At baseline, Z scores for mean weight-for-age and mean height-for-age were -2.01 and -2.12, respectively. Mean CD4% was 9.0. Median plasma HIV-1 RNA viral load was 5.51 log(10) copies per millilitre (cp/ml). Two children (3.9%) died and another 11 (22%) suffered 13 severe clinical events. At month 12, mean WAZ had improved by 0.63 (P < 0.001) and mean HAZ by 0.57 (P < 0.001). Mean CD4% had risen to 24 (P < 0.001). Viral load was below 300 RNA cp/ml in 81% of the children; HIV resistance mutations were detected in 11 (21.6%). CONCLUSION: The once-a-day combination of DDI + 3TC + EFV is an alternative first line treatment for HIV-1-infected children. Dose adjustment should further improve efficacy. PMID- 21673862 TI - Spatial heterogeneity of haemoglobin concentration in preschool-age children in sub-Saharan Africa. AB - OBJECTIVE: To determine whether blood haemoglobin concentration in preschool-age children (< 5 years of age) is geographically heterogeneous in sub-Saharan Africa and describe its association with environmental variables that drive anaemia of different etiologies. METHODS: Data were obtained on 24 277 preschool-age children in western Africa (2862 cluster sites) and 25 343 in eastern Africa (2999 cluster sites) from the 2001-2007 Demographic and Health Surveys (DHS) for sub-Saharan Africa. Cluster sites were linked to environmental information on distance to perennial water body, elevation, land surface temperature and normalized difference vegetation index (NDVI; a proxy for rainfall) in a geographical information system. Statistical associations with environmental variables were determined using multivariate regression models, and the spatial dependence of haemoglobin concentration unexplained by these factors was quantified using semivariograms. FINDINGS: In eastern Africa, the lowest haemoglobin concentrations (< 70 g/l) occurred in small clusters throughout the region; in western Africa, they occurred in a large cluster straddling the border between Burkina Faso and Mali. Our results show significant continent-wide associations between haemoglobin concentration and environmental variables, particularly in western Africa for land surface temperature and NDVI, and in eastern Africa for elevation. Residual spatial dependence was significant, and the magnitude was greater in western than in eastern Africa. CONCLUSION: The distribution of anaemia is driven by large-scale environmental factors, and the epidemiological drivers differ in western and eastern Africa. Strategies for anaemia control in preschool-age children in sub-Saharan Africa should be tailored to local conditions, taking into account the specific etiology and prevalence of anaemia. PMID- 21673863 TI - Neurobiologically realistic determinants of self-organized criticality in networks of spiking neurons. AB - Self-organized criticality refers to the spontaneous emergence of self-similar dynamics in complex systems poised between order and randomness. The presence of self-organized critical dynamics in the brain is theoretically appealing and is supported by recent neurophysiological studies. Despite this, the neurobiological determinants of these dynamics have not been previously sought. Here, we systematically examined the influence of such determinants in hierarchically modular networks of leaky integrate-and-fire neurons with spike-timing-dependent synaptic plasticity and axonal conduction delays. We characterized emergent dynamics in our networks by distributions of active neuronal ensemble modules (neuronal avalanches) and rigorously assessed these distributions for power-law scaling. We found that spike-timing-dependent synaptic plasticity enabled a rapid phase transition from random subcritical dynamics to ordered supercritical dynamics. Importantly, modular connectivity and low wiring cost broadened this transition, and enabled a regime indicative of self-organized criticality. The regime only occurred when modular connectivity, low wiring cost and synaptic plasticity were simultaneously present, and the regime was most evident when between-module connection density scaled as a power-law. The regime was robust to variations in other neurobiologically relevant parameters and favored systems with low external drive and strong internal interactions. Increases in system size and connectivity facilitated internal interactions, permitting reductions in external drive and facilitating convergence of postsynaptic-response magnitude and synaptic-plasticity learning rate parameter values towards neurobiologically realistic levels. We hence infer a novel association between self-organized critical neuronal dynamics and several neurobiologically realistic features of structural connectivity. The central role of these features in our model may reflect their importance for neuronal information processing. PMID- 21673864 TI - Effects of heterogeneous and clustered contact patterns on infectious disease dynamics. AB - The spread of infectious diseases fundamentally depends on the pattern of contacts between individuals. Although studies of contact networks have shown that heterogeneity in the number of contacts and the duration of contacts can have far-reaching epidemiological consequences, models often assume that contacts are chosen at random and thereby ignore the sociological, temporal and/or spatial clustering of contacts. Here we investigate the simultaneous effects of heterogeneous and clustered contact patterns on epidemic dynamics. To model population structure, we generalize the configuration model which has a tunable degree distribution (number of contacts per node) and level of clustering (number of three cliques). To model epidemic dynamics for this class of random graph, we derive a tractable, low-dimensional system of ordinary differential equations that accounts for the effects of network structure on the course of the epidemic. We find that the interaction between clustering and the degree distribution is complex. Clustering always slows an epidemic, but simultaneously increasing clustering and the variance of the degree distribution can increase final epidemic size. We also show that bond percolation-based approximations can be highly biased if one incorrectly assumes that infectious periods are homogeneous, and the magnitude of this bias increases with the amount of clustering in the network. We apply this approach to model the high clustering of contacts within households, using contact parameters estimated from survey data of social interactions, and we identify conditions under which network models that do not account for household structure will be biased. PMID- 21673865 TI - Brownian dynamics simulation of nucleocytoplasmic transport: a coarse-grained model for the functional state of the nuclear pore complex. AB - The nuclear pore complex (NPC) regulates molecular traffic across the nuclear envelope (NE). Selective transport happens on the order of milliseconds and the length scale of tens of nanometers; however, the transport mechanism remains elusive. Central to the transport process is the hydrophobic interactions between karyopherins (kaps) and Phe-Gly (FG) repeat domains. Taking into account the polymeric nature of FG-repeats grafted on the elastic structure of the NPC, and the kap-FG hydrophobic affinity, we have established a coarse-grained model of the NPC structure that mimics nucleocytoplasmic transport. To establish a foundation for future works, the methodology and biophysical rationale behind the model is explained in details. The model predicts that the first-passage time of a 15 nm cargo-complex is about 2.6+/-0.13 ms with an inverse Gaussian distribution for statistically adequate number of independent Brownian dynamics simulations. Moreover, the cargo-complex is primarily attached to the channel wall where it interacts with the FG-layer as it passes through the central channel. The kap-FG hydrophobic interaction is highly dynamic and fast, which ensures an efficient translocation through the NPC. Further, almost all eight hydrophobic binding spots on kap-beta are occupied simultaneously during transport. Finally, as opposed to intact NPCs, cytoplasmic filaments-deficient NPCs show a high degree of permeability to inert cargos, implying the defining role of cytoplasmic filaments in the selectivity barrier. PMID- 21673866 TI - Extracting message inter-departure time distributions from the human electroencephalogram. AB - The complex connectivity of the cerebral cortex is a topic of much study, yet the link between structure and function is still unclear. The processing capacity and throughput of information at individual brain regions remains an open question and one that could potentially bridge these two aspects of neural organization. The rate at which information is emitted from different nodes in the network and how this output process changes under different external conditions are general questions that are not unique to neuroscience, but are of interest in multiple classes of telecommunication networks. In the present study we show how some of these questions may be addressed using tools from telecommunications research. An important system statistic for modeling and performance evaluation of distributed communication systems is the time between successive departures of units of information at each node in the network. We describe a method to extract and fully characterize the distribution of such inter-departure times from the resting-state electroencephalogram (EEG). We show that inter-departure times are well fitted by the two-parameter Gamma distribution. Moreover, they are not spatially or neurophysiologically trivial and instead are regionally specific and sensitive to the presence of sensory input. In both the eyes-closed and eyes-open conditions, inter-departure time distributions were more dispersed over posterior parietal channels, close to regions which are known to have the most dense structural connectivity. The biggest differences between the two conditions were observed at occipital sites, where inter-departure times were significantly more variable in the eyes-open condition. Together, these results suggest that message departure times are indicative of network traffic and capture a novel facet of neural activity. PMID- 21673868 TI - Imaging of melanoma: usefulness of ultrasonography before and after contrast injection for diagnosis and early evaluation of treatment. AB - High-frequency ultrasound (8-14 MHz) is routinely used to display cutaneous melanomas. Maximum thickness measurement (Breslow index) has been shown to be well correlated to histologic findings for lesions of more than 0.75 mm. Some morphological criteria (strong delineation, hypoechoic texture, homogeneity) have been reported to help differentiate between malignant and benign pigmented blue lesions, but remain insufficient. Vascular ultrasound analysis using Doppler mode provides additional information and showed good specificity for malignancy (90% 100%), but variable sensitivity (34%-100%). Recent advances in ultrasound imaging allow functional evaluation. Likewise, dynamic contrast-enhanced ultrasound using contrast medium injection and specific perfusion and quantification software showed promising results in clinical and preclinical trials for early prediction of tumor response to target treatments. PMID- 21673869 TI - Venous ulcer review. AB - CLINICAL QUESTION: What is the best treatment for venous ulcers? RESULTS: Compression aids ulcer healing. Pentoxifylline can aid ulcer healing. Artificial skin grafts are more effective than other skin grafts in helping ulcer healing. Correction of underlying venous incompetence reduces ulcer recurrence. IMPLEMENTATION: POTENTIAL PITFALLS TO AVOID ARE: Failure to exclude underlying arterial disease before application of compression.Unusual-looking ulcers or those slow to heal should be biopsied to exclude malignant transformation. PMID- 21673870 TI - Controversies on cosmetic outcomes in black women after breast conservation therapy: hyperperception or hyperpigmentation? AB - Multiple studies have reported inferior cosmetic outcomes after breast conservation surgery and adjuvant radiation therapy in black women. However, cosmetic analysis scales contemporarily utilized in the field of radiation oncology rely largely on subjective visual and tactile perception. These methods are undeniably fraught with intraobserver and interobserver variability. Herein, we uncover how and why these methods may unwittingly and disparately misjudge cosmetic outcomes in black women, and the clinical ramifications thereof. In addition, we highlight more objective cosmetic outcomes assessment programs that promise to yield more reproducible and unbiased results. PMID- 21673871 TI - Minimally invasive aesthetic procedures in young adults. AB - Age is a significant factor in modifying specific needs when it comes to medical aesthetic procedures. In this review we will focus on young adults in their third decade of life and review minimally invasive aesthetic procedures other than cosmetics and cosmeceuticals. Correction of asymmetries, correction after body modifying procedures, and facial sculpturing are important issues for young adults. The implication of aesthetic medicine as part of preventive medicine is a major ethical challenge that differentiates aesthetic medicine from fashion. PMID- 21673873 TI - GCR Graduates From Nursery School on a Fast Track to Editorial Excellence. PMID- 21673872 TI - Skin displacement analysis (SDA): a tool for the quantitative evaluation of skin movements elicited by underlying muscles in the face and neck area. AB - BACKGROUND: Quantitative numerical analysis of skin displacement triggered by muscles inserting the overlaying skin would be useful for monitoring the inhibition of mimetic muscles. METHODS: By using removable grid markings and digital photographs, skin displacement analysis (SDA) was performed on 13 patients pre-treatment and on Days 1, 2, 3, and 7 after injection of 18 units of botulinum toxin type A (BoNT/A) in the fronto-glabellar area. RESULTS: At baseline, amplitudes of horizontal skin displacement with fronto-glabellar contraction showed a linear increase along the eyebrow laterally from the midline; mean values (+/-standard deviation [SD]) 15 and 30 mm lateral to the midline were 3.2 +/- 1.0 mm (range, 1.9-4.9 mm) and 6.5 +/- 1.4 mm (range 4.0-8.5 mm), respectively. After injection of BoNT/A, maximum horizontal skin displacement 30 mm lateral to the midline showed a mean reduction (+/-SD) to 62% +/- 23% at Day 2 and to 17% +/- 16% at Day 7; corresponding values 15 mm lateral to the midline were 62% +/- 29% and 15% +/- 20%, respectively. In all cases, the reduction in horizontal skin displacement compared with pre-injection levels was statistically significant (P < 0.001). CONCLUSION: SDA is a feasible method for the quantitative evaluation of skin movements elicited by muscles inserting the overlaying skin in the face and neck area. PMID- 21673874 TI - Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis. AB - BACKGROUND: We performed a retrospective analysis of data from a phase II study evaluating sorafenib in patients with advanced hepatocellular carcinoma (HCC) to assess differences in safety and efficacy based on Child-Pugh (CP) status (A/B). METHODS: Patients received sorafenib 400 mg PO bid. We analyzed safety, pharmacokinetic (PK), and efficacy data in the two CP groups. RESULTS: Ninety eight patients were CP A; 38 were CP B, with a median duration of therapy of 4 and 1.8 months, respectively. Grade 3/4 adverse events in the CP A and B groups, respectively, included hyperbilirubinemia (14% and 53%), ascites (3% and 5%), and encephalopathy (3% and 13%). Median overall survival (OS) in the CP A group was 9.5 months, compared with 3.2 months in the CP B population. Responses were limited in both groups. AUC and C(max) values were comparable between the two groups. CONCLUSIONS: Due to the lack of randomization against placebo or no therapy in this study, it is unclear if the more frequent worsening of liver cirrhosis and outcome of CP B patients are drug related or due to disease progression, or both. As expected, outcome was poorer in patients with CP B than in those with CP A cirrhosis. The hyperbilirubinemia seen in both groups may be at least partly related to inhibition of UGT1A1 by sorafenib. PK profiles were similar in the two groups. More data are needed to confirm and more fully understand the safety and efficacy of sorafenib in patients with advanced HCC and CP B cirrhosis. PMID- 21673875 TI - Longitudinal Quality-of-Life Analysis of RTOG 94-05 (Int 0123):A Phase III Trial of Definitive Chemoradiotherapy for Esophageal Cancer. AB - BACKGROUND: Longitudinal quality of life (QoL) was compared for patients with esophageal cancer receiving definitive chemoradiotherapy (CRT) with conventional dose (CD) vs. high-dose (HD) radiotherapy as used in the RTOG phase III 94-05 trial (Intergroup 0123). METHODS: Between June 12, 1995, and July 1, 1999, 236 patients with cT1-4NxM0 esophageal cancer were randomized to CD CRT (50.4 Gy and concurrent 5-fluorouracil and cisplatin) vs. HD CRT (64.8 Gy and the same chemotherapy). QoL was assessed using the Functional Assessment of Cancer Therapy, Head & Neck (version 2) at baseline, after CRT, at 8 months from the start of CRT, and at 1 year. RESULTS: Of 218 eligible patients, 166 participated in pretreatment QoL assessments (82 HD, 84 CD). Patients with >=10% weight loss and Karnofsky Performance Status 60-80 were less likely to participate (P = .02 and P = .002, respectively). Pretreatment characteristics for participating patients were similar in both arms. At CRT completion, 96 patients completed QoL (46 HD, 50 CD) assessment. Total mean QoL was significantly lower in the HD arm (P = .02) and remained lower at 8 and 12 months after the start of CRT, but these values did not reach statistical significance. Change in mean QoL from baseline to each of the three subsequent assessment time points did not differ significantly between the two treatment arms. CONCLUSIONS: For patients treated with definitive CRT for esophageal cancer, radiation dose escalation to 64.8 Gy does not significantly improve QoL. These results provide additional evidence that radiotherapy to 50.4 Gy should remain the standard of care. PMID- 21673877 TI - HER2 Testing in Gastric/Gastroesophageal Junction Adenocarcinomas: Unique Features of a Familiar Test. AB - Using the standard slide-based techniques of immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), it has been firmly established that human epidermal growth factor receptor 2 (HER2) is overexpressed in adenocarcinoma of the upper gastrointestinal tract. In the ToGA trial, the addition of the monoclonal antibody trastuzumab to a standard regimen of cisplatin and fluoropyrimidine resulted in a clinically and statistically significant benefit in terms of response rate, median progression-free survival, and median overall survival in HER2-positive patients. Major differences exist, however, between HER2 testing in gastric/gastroesophageal junction (GEJ) cancer versus breast cancer, and the ToGA trial employed a significant modification of the breast cancer scoring criteria. As trastuzumab approaches regulatory approval in the United States for gastric/GEJ cancer, it is critical that pathologists and diagnostic laboratories learn and apply the unique criteria for assessing gastric/GEJ tumors for their HER2 status defined by the ToGA investigators, as they ready themselves for the approximately 50,000 new specimens that will be tested for HER2 status by both IHC and FISH each year. PMID- 21673876 TI - Current management of inflammatory bowel disease and colorectal cancer. AB - INFLAMMATORY BOWEL DISEASES (IBDS) CAN BE DIVIDED INTO TWO MAJOR DISORDERS: ulcerative colitis and Crohn's disease. Although IBD-associated colorectal cancer (IBD-CRC) accounts for only 1-2% of all cases of colorectal cancer, IBD with colon involvement is among the top three high-risk conditions for colorectal cancer. Today, colorectal cancer accounts for approximately 10-15% of all deaths among IBD patients. Indeed, patients with IBD colitis are six times more likely to develop colorectal cancer than the general population and have a higher frequency of multiple synchronous colorectal cancers. Since IBD-CRC was first described in 1925, the colon remains the primary site of neoplasms in IBD patients today. Ulcerative colitis-associated colorectal cancer is most common in the rectum and sigmoid colon, whereas Crohn's disease-associated colorectal cancer is evenly distributed between the different colon segments. Chemoprevention of colorectal cancer remains an important goal, and colonoscopy surveillance programs are critical to early detection in these patients. Newer methods, such as chromoendoscopy, are currently being investigated as complementary techniques to enhance early detection of dysplasia and cancer in this high-risk population. We present a comprehensive review of the relationship between inflammatory bowel disease and colorectal cancer. Major themes covered include risk factors for IBD-CRC and the molecular pathobiology of progression from dysplasia to cancer, endoscopic surveillance and new methods for early detection of dysplasia, approaches to prevention of IBD-CRC, and current recommendations and controversies regarding the treatment of dysplasia. In particular, disagreement has arisen over optimal management of low-grade dysplasia, with some IBD experts now advocating close colonoscopic surveillance of patients with low-grade dysplasia rather then total colectomy. PMID- 21673878 TI - Long-term survival for pancreatic cancer: a matter of hope, courage, or genetics? PMID- 21673879 TI - Leptomeningeal carcinomatosis as the only manifestation of disease in recurrent gastroesophageal cancers. PMID- 21673880 TI - Atypical metastases of the gastrointestinal stromal sarcoma. PMID- 21673881 TI - RNAi2011: Gene Regulation by Small RNAs. PMID- 21673882 TI - Deoxyuridines from the marine sponge associated actinomycete Streptomyces microflavus. AB - One new nucleoside derivative, named 3-acetyl-5-methyl-2'-deoxyuridine (1), along with two known compounds 3,5-dimethyl-2'-deoxyuridine (2) and 3-methyl-2' deoxyuridine (3), were isolated from the cultures of Streptomyces microflavus. This strain was an associated actinomycete isolated from the marine sponge Hymeniacidon perlevis collected from the coast of Dalian (China). Their structures were elucidated by detailed NMR and MS spectroscopic analysis as well as comparison with literature data. PMID- 21673883 TI - Oral administration of skin gelatin isolated from Chum salmon (Oncorhynchus keta) enhances wound healing in diabetic rats. AB - Care for diabetic wounds remains a significant clinical problem. The present study was aimed at investigating the effect of skin gelatin from Chum Salmon on defective wound repair in the skin of diabetic rats. Full-thickness excisional skin wounds were made in 48 rats, of which 32 were diabetes. The diabetic rats were orally treated daily for 14 days with skin gelatin from Chum Salmon (2 g/kg) or its vehicle. Sixteen non-diabetic control rats received the same amount of water as vehicle-treated non-diabetic rats. Rats were killed to assess the rate of wound closure, microvessel density (MVD), vascular endothelial growth factor (VEGF), hydroxyproline (HP) contents in wound tissues and nitrate in plasma and wound tissue at 7 and 14 days after wounding. Skin gelatin-treated diabetic rats showed a better wound closure, increased MVD, VEGF, hydroxyproline and NO contents and a reduced extent of inflammatory response. All parameters were significant (P < 0.05) in comparison to vehicle-treated diabetic group. In light of our finding that skin gelatin of Chum Salmon promotes skin wound repair in diabetic rats, we propose that oral administration of Chum Salmon skin gelatin might be a beneficial method for treating wound disorders associated with diabetes. PMID- 21673884 TI - Effects of oral glucosamine hydrochloride administration on plasma free amino acid concentrations in dogs. AB - We examined the effects of oral glucosamine hydrochloride (GlcN), N-acetyl-D glucosamine (GlcNAc) and d-glucose (Glc) administration on plasma total free amino acid (PFAA) concentrations in dogs. The PFAA concentrations increased in the control group and the GlcNAc group at one hour after feeding, and each amino acid concentration increased. On the other hand, in the GlcN group and the Glc group PFAA concentrations decreased at one hour after feeding. A significant decrease in amino acid concentration was observed for glutamate, glycine and alanine. Our results suggest the existence of differences in PFAA dynamics after oral administration of GlcN and GlcNAc in dogs. PMID- 21673885 TI - The biological deep sea hydrothermal vent as a model to study carbon dioxide capturing enzymes. AB - Deep sea hydrothermal vents are located along the mid-ocean ridge system, near volcanically active areas, where tectonic plates are moving away from each other. Sea water penetrates the fissures of the volcanic bed and is heated by magma. This heated sea water rises to the surface dissolving large amounts of minerals which provide a source of energy and nutrients to chemoautotrophic organisms. Although this environment is characterized by extreme conditions (high temperature, high pressure, chemical toxicity, acidic pH and absence of photosynthesis) a diversity of microorganisms and many animal species are specially adapted to this hostile environment. These organisms have developed a very efficient metabolism for the assimilation of inorganic CO2 from the external environment. In order to develop technology for the capture of carbon dioxide to reduce greenhouse gases in the atmosphere, enzymes involved in CO2 fixation and assimilation might be very useful. This review describes some current research concerning CO2 fixation and assimilation in the deep sea environment and possible biotechnological application of enzymes for carbon dioxide capture. PMID- 21673886 TI - Anti-phytopathogenic activities of macro-algae extracts. AB - Aqueous and ethanolic extracts obtained from nine Chilean marine macro-algae collected at different seasons were examined in vitro and in vivo for properties that reduce the growth of plant pathogens or decrease the injury severity of plant foliar tissues following pathogen infection. Particular crude aqueous or organic extracts showed effects on the growth of pathogenic bacteria whereas others displayed important effects against pathogenic fungi or viruses, either by inhibiting fungal mycelia growth or by reducing the disease symptoms in leaves caused by pathogen challenge. Organic extracts obtained from the brown-alga Lessonia trabeculata inhibited bacterial growth and reduced both the number and size of the necrotic lesion in tomato leaves following infection with Botrytis cinerea. Aqueous and ethanolic extracts from the red-alga Gracillaria chilensis prevent the growth of Phytophthora cinnamomi, showing a response which depends on doses and collecting-time. Similarly, aqueous and ethanolic extracts from the brown-alga Durvillaea antarctica were able to diminish the damage caused by tobacco mosaic virus (TMV) in tobacco leaves, and the aqueous procedure is, in addition, more effective and seasonally independent. These results suggest that macro-algae contain compounds with different chemical properties which could be considered for controlling specific plant pathogens. PMID- 21673887 TI - Carotenoid beta-ring hydroxylase and ketolase from marine bacteria-promiscuous enzymes for synthesizing functional xanthophylls. AB - Marine bacteria belonging to genera Paracoccus and Brevundimonas of the alpha Proteobacteria class can produce C40-type dicyclic carotenoids containing two beta-end groups (beta rings) that are modified with keto and hydroxyl groups. These bacteria produce astaxanthin, adonixanthin, and their derivatives, which are ketolated by carotenoid beta-ring 4(4')-ketolase (4(4')-oxygenase; CrtW) and hydroxylated by carotenoid beta-ring 3(3')-hydroxylase (CrtZ). In addition, the genus Brevundimonas possesses a gene for carotenoid beta-ring 2(2')-hydroxylase (CrtG). This review focuses on these carotenoid beta-ring-modifying enzymes that are promiscuous for carotenoid substrates, and pathway engineering for the production of xanthophylls (oxygen-containing carotenoids) in Escherichia coli, using these enzyme genes. Such pathway engineering researches are performed towards efficient production not only of commercially important xanthophylls such as astaxanthin, but also of xanthophylls minor in nature (e.g., beta-ring(s) 2(2')-hydroxylated carotenoids). PMID- 21673888 TI - Genetic approach for the fast discovery of phenazine producing bacteria. AB - A fast and efficient approach was established to identify bacteria possessing the potential to biosynthesize phenazines, which are of special interest regarding their antimicrobial activities. Sequences of phzE genes, which are part of the phenazine biosynthetic pathway, were used to design one universal primer system and to analyze the ability of bacteria to produce phenazine. Diverse bacteria from different marine habitats and belonging to six major phylogenetic lines were investigated. Bacteria exhibiting phzE gene fragments affiliated to Firmicutes, Alpha- and Gammaproteobacteria, and Actinobacteria. Thus, these are the first primers for amplifying gene fragments from Firmicutes and Alphaproteobacteria. The genetic potential for phenazine production was shown for four type strains belonging to the genera Streptomyces and Pseudomonas as well as for 13 environmental isolates from marine habitats. For the first time, the genetic ability of phenazine biosynthesis was verified by analyzing the metabolite pattern of all PCR-positive strains via HPLC-UV/MS. Phenazine production was demonstrated for the type strains known to produce endophenazines, 2-hydroxy phenazine, phenazine-1-carboxylic acid, phenazine-1,6-dicarboxylic acid, and chlororaphin as well as for members of marine Actinobacteria. Interestingly, a number of unidentified phenazines possibly represent new phenazine structures. PMID- 21673889 TI - Bioactivity of benthic and picoplanktonic estuarine cyanobacteria on growth of photoautotrophs: inhibition versus stimulation. AB - Understanding potential biochemical interactions and effects among cyanobacteria and other organisms is one of the main keys to a better knowledge of microbial population structuring and dynamics. In this study, the effects of cyanobacteria from benthos and plankton of estuaries on other cyanobacteria and green algae growth were evaluated. To understand how the estuarine cyanobacteria might influence the dynamics of phytoplankton, experiments were carried out with the freshwater species Microcystis aeruginosa and Chlorella sp., and the marine Synechocystis salina and Nannochloropsis sp. exposed to aqueous and organic (70% methanol) crude extracts of cyanobacteria for 96 h. The most pronounced effect observed was the growth stimulation. Growth inhibition was also observed for S. salina and M. aeruginosa target-species at the highest and lowest concentrations of cyanobacterial extracts. The methanolic crude extract of Phormidium cf. chalybeum LEGE06078 was effective against S. salina growth in a concentration dependent manner after 96 h-exposure. All of the cyanobacterial isolates showed some bioactivity on the target-species growth, i.e., inhibitory or stimulating effects. These results indicate that the analyzed cyanobacterial isolates can potentially contribute to blooms' proliferation of other cyanobacteria and to the abnormal growth of green algae disturbing the dynamic of estuarine phytoplankton communities. Since estuaries are transitional ecosystems, the benthic and picoplanktonic estuarine cyanobacteria can change both freshwater and marine phytoplankton succession, competition and bloom formation. Furthermore, a potential biotechnological application of these isolates as a tool to control cyanobacteria and microalgae proliferation can be feasible. This work is the first on the subject of growth responses of photoautotrophs to cyanobacteria from Atlantic estuarine environments. PMID- 21673890 TI - Neuroprotective effects of marine algae. AB - The marine environment is known as a rich source of chemical structures with numerous beneficial health effects. Among marine organisms, marine algae have been identified as an under-exploited plant resource, although they have long been recognized as valuable sources of structurally diverse bioactive compounds. Presently, several lines of studies have provided insight into biological activities and neuroprotective effects of marine algae including antioxidant, anti-neuroinflammatory, cholinesterase inhibitory activity and the inhibition of neuronal death. Hence, marine algae have great potential to be used for neuroprotection as part of pharmaceuticals, nutraceuticals and functional foods. This contribution presents an overview of marine algal neuroprotective effects and their potential application in neuroprotection. PMID- 21673891 TI - Antiproliferative activity of violaxanthin isolated from bioguided fractionation of Dunaliella tertiolecta extracts. AB - Dunaliella tertiolecta (DT) was chemically investigated to isolate molecules inhibiting cancer cell proliferation and inducing apoptosis in vitro. The potency to inhibit cell growth was used for the bio-guided fractionation and isolation of active compounds using chromatographic techniques. The DT dichloromethane extract exhibited a strong anti-proliferative activity on MCF-7 and LNCaP cells, and was further fractionated and sub-fractionated by RP-HPLC. High resolution mass spectrometry and spectrophotometric analysis unequivocally identified violaxanthin as the most antiproliferative molecule present in DT DCM extract. Violaxanthin purified from DT induced MCF-7 dose-dependent growth inhibition in continuous and discontinuous treatments, at concentrations as low as 0.1 MUg.mL-1 (0.17 MUM). Phosphatidylserine exposure, typical of early apoptosis, was observed after 48 h treatment at 8 MUg.mL-1 (13.3 MUM) but no DNA fragmentation, characteristic of late apoptosis steps, could be detected even after 72 h treatment at 40 MUg.mL-1 (66.7 MUM). Taken together, our results demonstrate the strong antiproliferative activity of violaxanthin on one human mammary cancer cell line, and suggest that studying the pharmacology of violaxanthin and pharmacomodulated derivatives on cancer cells may allow potent antiproliferative drugs to be obtained. PMID- 21673892 TI - Three bianthraquinone derivatives from the mangrove endophytic fungus Alternaria sp. ZJ9-6B from the South China Sea. AB - Three new bianthraquinone derivatives, alterporriol K (1), L (2) and M (3), along with six known compounds were obtained from extracts of the endophytic fungus Alternaria sp. ZJ9-6B, isolated from the mangrove Aegiceras corniculatum collected in the South China Sea. Their structures were elucidated by one- and two-dimensional NMR spectroscopy, MS data analysis and circular dichroism measurements. Compounds 1, 2 and 3 were first isolated alterporriols with a C-2-C 2' linkage. The crystallographic data of tetrahydroaltersolanol B (7) was reported for the first time. In the primary bioassays, alterporriol K and L exhibited moderate cytotoxic activity towards MDA-MB-435 and MCF-7 cells with IC50 values ranging from 13.1 to 29.1 MUM. PMID- 21673893 TI - Balticolid: a new 12-membered macrolide with antiviral activity from an ascomycetous fungus of marine origin. AB - A new 12-membered macrolide, balticolid (1) was isolated from the EtOAc extract of the culture broth of fungal strain 222 belonging to the Ascomycota, which was found on driftwood collected from the coast of the Greifswalder Bodden, Baltic Sea, Germany. The structure of balticolid was determined to be (3R,11R), (4E,8E) 3-hydroxy-11-methyloxacyclododeca-4,8-diene-1,7-dione using extensive spectral data as well as the modified Mosher ester method. Balticolid (1) displayed anti HSV-1 activity with an IC50 value of 0.45 MUM. PMID- 21673894 TI - Anti-proliferative activity of meroditerpenoids isolated from the brown alga Stypopodium flabelliforme against several cancer cell lines. AB - The sea constitutes one of the most promising sources of novel compounds with potential application in human therapeutics. In particular, algae have proved to be an interesting source of new bioactive compounds. In this work, six meroditerpenoids (epitaondiol, epitaondiol diacetate, epitaondiol monoacetate, stypotriol triacetate, 14-ketostypodiol diacetate and stypodiol) isolated from the brown alga Stypopodium flabelliforme were tested for their cell proliferation inhibitory activity in five cell lines. Cell lines tested included human colon adenocarcinoma (Caco-2), human neuroblastoma (SH-SY5Y), rat basophilic leukemia (RBL-2H3), murine macrophages (RAW.267) and Chinese hamster fibroblasts (V79). Antimicrobial activity of the compounds was also evaluated against Staphylococcus aureus, Salmonella typhimurium, Proteus mirabilis, Bacillus cereus, Enterococcus faecalis and Micrococcus luteus. Overall, the compounds showed good activity against all cell lines, with SH-SY5Y and RAW.267 being the most susceptible. Antimicrobial capacity was observed for epitaondiol monoacetate, stypotriol triacetate and stypodiol, with the first being the most active. The results suggest that these molecules deserve further studies in order to evaluate their potential as therapeutic agents. PMID- 21673895 TI - Volatile constituents, inorganic elements and primary screening of bioactivity of black coral cigarette holders. AB - Black corals (BC) have been used for a long time in Chinese medicine, and may have some pharmaceutical functions when used as material for cigarette holders in southeast China. This study is aimed to investigate the bioactivities of volatile constituents in BC and to explore the folklore behind the use of BC cigarette holders (BCCHs). We extracted the volatile constituents of BC by supercritical fluid extraction (SFE) with carbon dioxide (CO2-SFE), then identified and analyzed the constituents by gas chromatography-mass spectrometry (GC-MS). In total, 15 components were reliably identified in BC and found to be biologically active. These included triethyl phosphate, butylated hydroxytoluene, cedrol, n hexadecanoic acid, squalene, and cholesterol. Meanwhile 13 inorganic elements (P, Ca, Mg, S, B, Si, Fe, Cu, Zn, Ba, etc.) were determined by inductively coupled plasma spectrometer (ICPS). In the bioactivity tests, the BC extract (BCE) showed a scavenging activity of 2,2-diphenyl-1-picrylhydrazyl free radicals and hydroxyl radicals by phenanthroline-Fe (II) oxidation and moderate inhibition of Gram positive microorganisms. The antioxidant and antimicrobial activities of BC, which are related to the active chemical composition, may explain the perceived benefit for cigarette smokers who use BCCHs. PMID- 21673896 TI - Bioactive indole derivatives from the South Pacific marine sponges Rhopaloeides odorabile and Hyrtios sp. AB - Indole derivatives including bromoindoles have been isolated from the South Pacific marine sponges Rhopaloeides odorabile and Hyrtios sp. Their structures were established through analysis of mass spectra and 1D and 2D NMR spectroscopic data. Their potential inhibitory phospholipase A2 (PLA2), antioxidant and cytotoxic activities were evaluated. The new derivative 5,6-dibromo-L-hypaphorine (9) isolated from Hyrtios sp. revealed a weak bee venom PLA2 inhibition (IC50 0.2 mM) and a significant antioxidant activity with an Oxygen Radical Absorbance Capacity (ORAC) value of 0.22. The sesquiterpene aureol (4), also isolated from Hyrtios sp., showed the most potent antioxidant activity with an ORAC value of 0.29. PMID- 21673897 TI - Screening of microorganisms producing cold-active oxidoreductases to be applied in enantioselective alcohol oxidation. An Antarctic survey. AB - Several microorganisms were isolated from soil/sediment samples of Antarctic Peninsula. The enrichment technique using (RS)-1-(phenyl)ethanol as a carbon source allowed us to isolate 232 psychrophile/psychrotroph microorganisms. We also evaluated the enzyme activity (oxidoreductases) for enantioselective oxidation reactions, by using derivatives of (RS)-1-(phenyl)ethanol as substrates. Among the studied microorganisms, 15 psychrophile/psychrotroph strains contain oxidoreductases that catalyze the (S)-enantiomer oxidation from racemic alcohols to their corresponding ketones. Among the identified microorganisms, Flavobacterium sp. and Arthrobacter sp. showed excellent enzymatic activity. These new bacteria strains were selected for optimization study, in which the (RS)-1-(4-methyl-phenyl)ethanol oxidation was evaluated in several reaction conditions. From these studies, it was observed that Flavobacterium sp. has an excellent enzymatic activity at 10 degrees C and Arthrobacter sp. at 15 and 25 degrees C. We have also determined the growth curves of these bacteria, and both strains showed optimum growth at 25 degrees C, indicating that these bacteria are psychrotroph. PMID- 21673898 TI - Molecular evolution of multiple arylalkylamine N-acetyltransferase (AANAT) in fish. AB - Arylalkylamine N-acetyltransferase (AANAT) catalyzes the transfer of an acetyl group from acetyl coenzyme A (AcCoA) to arylalkylamines, including indolethylamines and phenylethylamines. Multiple aanats are present in teleost fish as a result of whole genome and gene duplications. Fish aanat1a and aanat2 paralogs display different patterns of tissue expression and encode proteins with different substrate preference: AANAT1a is expressed in the retina, and acetylates both indolethylamines and phenylethylamines; while AANAT2 is expressed in the pineal gland, and preferentially acetylates indolethylamines. The two enzymes are therefore thought to serve different roles. Here, the molecular changes that led to their specialization were studied by investigating the structure-function relationships of AANATs in the gilthead seabream (sb, Sperus aurata). Acetylation activity of reciprocal mutated enzymes pointed to specific residues that contribute to substrate specificity of the enzymes. Inhibition tests followed by complementary analyses of the predicted three-dimensional models of the enzymes, suggested that both phenylethylamines and indolethylamines bind to the catalytic pocket of both enzymes. These results suggest that substrate selectivity of AANAT1a and AANAT2 is determined by the positioning of the substrate within the catalytic pocket, and its accessibility to catalysis. This illustrates the evolutionary process by which enzymes encoded by duplicated genes acquire different activities and play different biological roles. PMID- 21673899 TI - Coupled folding and specific binding: fishing for amphiphilicity. AB - Proteins are uniquely capable of identifying targets with unparalleled selectivity, but, in addition to the precision of the binding phenomenon, nature has the ability to find its targets exceptionally quickly. Transcription factors for instance can bind to a specific sequence of nucleic acids from a soup of similar, but not identical DNA strands, on a timescale of seconds. This is only possible with the enhanced kinetics provided for by a natively disordered structure, where protein folding and binding are cooperative processes. The secondary structures of many proteins are disordered under physiological conditions. Subsequently, the disordered structures fold into ordered structures only when they bind to their specific targets. Induced folding of the protein has two key biological advantages. First, flexible unstructured domains can result in an intrinsic plasticity that allows them to accommodate targets of various size and shape. And, second, the dynamics of this folding process can result in enhanced binding kinetics. Several groups have hypothesized the acceleration of binding kinetics is due to induced folding where a "fly-casting" effect has been shown to break the diffusion-limited rate of binding. This review describes experimental results in rationally designed peptide systems where the folding is coupled to amphiphilicity and biomolecular activity. PMID- 21673900 TI - Overcoming the recalcitrance for the conversion of kenaf pulp to glucose via microwave-assisted pre-treatment processes. AB - This study evaluates the pre-treatment of cellulose from kenaf plant to yield sugar precursors for the production of ethanol or butanol for use as biofuel additives. In order to convert the crystalline cellulosic form to the amorphous form that can undergo enzymatic hydrolysis of the glycosidic bond to yield sugars, kenaf pulp samples were subjected to two different pre-treatment processes. In the acid pre-treatment, the pulp samples were treated with 37.5% hydrochloric acid in the presence of FeCl(3) at 50 degrees C or 90 degrees C whereas in the alkaline method, the pulp samples were treated with 25% sodium hydroxide at room temperature and with 2% or 5% sodium hydroxide at 50 degrees C. Microwave-assisted NaOH-treatment of the cellulose was also investigated and demonstrated to be capable of producing high glucose yield without adverse environmental impact by circumventing the use of large amounts of concentrated acids i.e., 83-85% phosphoric acid employed in most digestion processes. The treated samples were digested with the cellulase enzyme from Trichoderma reesei. The amount of glucose produced was quantified using the Quantichrom(TM) glucose bioassay for assessing the efficiency of glucose production for each of the treatment processes. The microwave-assisted alkaline pre-treatment processes conducted at 50 degrees C were found to be the most effective in the conversion of the crystalline cellulose to the amorphous form based on the significantly higher yields of sugar produced by enzymatic hydrolysis compared to the untreated sample. PMID- 21673901 TI - pH dependent molecular self-assembly of octaphosphonate porphyrin of nanoscale dimensions: nanosphere and nanorod aggregates. AB - Self-assembled nanostructures of zwitterionic octaphosphanatoporphyrin 1, of either nanoparticles or nanorods, depending on small changes in the pH, is demonstrated based on the J-aggregates. Porphyrin 1 self-assembled into nanosphere aggregates with a diameter of about 70-80 nm in the pH range 5-7, and nanorod aggregates were observed at pH 8.5. Hydrogen bonding, pi-pi stacking and hydrophilic interactions play important roles in the formation of this nanostructure morphology. Nanostructures were characterized by UV/Vis absorbance, fluorescence, atomic force microscopy (AFM) and transmission electron microscopy (TEM). This interesting pH dependent self-assembly phenomenon could provide a basis for development of novel biomaterials. PMID- 21673903 TI - Use of a reflectance spectroscopy accessory for optical characterization of ZnO Bi(2)O(3)-TiO(2) ceramics. AB - The optical band-gap energy (E(g)) is an important feature of semiconductors which determines their applications in optoelectronics. Therefore, it is necessary to investigate the electronic states of ceramic ZnO and the effect of doped impurities under different processing conditions. E(g) of the ceramic ZnO + xBi(2)O(3) + xTiO(2), where x = 0.5 mol%, was determined using a UV-Vis spectrophotometer attached to a Reflectance Spectroscopy Accessory for powdered samples. The samples was prepared using the solid-state route and sintered at temperatures from 1140 to 1260 degrees C for 45 and 90 minutes. E(g) was observed to decrease with an increase of sintering temperature. XRD analysis indicated hexagonal ZnO and few small peaks of intergranular layers of secondary phases. The relative density of the sintered ceramics decreased and the average grain size increased with the increase of sintering temperature. PMID- 21673902 TI - Integrated lipidomics in the secreted phospholipase A(2) biology. AB - Mammalian genomes encode genes for more than 30 phospholipase A(2)s (PLA(2)s) or related enzymes, which are subdivided into several subgroups based on their structures, catalytic mechanisms, localizations and evolutionary relationships. More than one third of the PLA(2) enzymes belong to the secreted PLA(2) (sPLA(2)) family, which consists of low-molecular-weight, Ca(2+)-requiring extracellular enzymes, with a His-Asp catalytic dyad. Individual sPLA(2) isoforms exhibit unique tissue and cellular localizations and enzymatic properties, suggesting their distinct pathophysiological roles. Recent studies using transgenic and knockout mice for several sPLA(2) isoforms, in combination with lipidomics approaches, have revealed their distinct contributions to various biological events. Herein, we will describe several examples of sPLA(2)-mediated phospholipid metabolism in vivo, as revealed by integrated analysis of sPLA(2) transgenic/knockout mice and lipid mass spectrometry. Knowledge obtained from this approach greatly contributes to expanding our understanding of the sPLA(2) biology and pathophysiology. PMID- 21673904 TI - IL-8 and cathepsin B as melanoma serum biomarkers. AB - Melanoma accounts for only a small portion of skin cancer but it is associated with high mortality. Melanoma serum biomarkers that may aid early diagnosis or guide therapy are needed clinically. However, studies of serum biomarkers have often been hampered by the serum interference that causes false readouts in immunological tests. Here we show that, after using a special buffer to eliminate the serum interference, IL-8 and cathepsin B levels were significantly elevated in melanoma patients (p < 0.05). More importantly, the combination of IL-8 and cathepsin B were also studied as a prognosis marker for melanoma mortality. Our study provides a novel approach to examine serum biomarkers. PMID- 21673905 TI - Zeranol down-regulates p53 expression in primary cultured human breast cancer epithelial cells through epigenetic modification. AB - Epidemiological studies have suggested that there are many risk factors associated with breast cancer. Silencing tumor suppressor genes through epigenetic alterations play critical roles in breast cancer initiation, promotion and progression. As a growth promoter, Zeranol (Z) has been approved by the FDA and is widely used to enhance the growth of beef cattle in the United States. However, the safety of Z use as a growth promoter is still under debate. In order to provide more evidence to clarify this critical health issue, the current study investigated the effect of Z on the proliferation of primary cultured human normal and cancerous breast epithelial cells (PCHNBECs and PCHBCECs, respectively) isolated from the same patient using MTS assay, RT-PCR and Western blot analysis. We also conducted an investigation regarding the mechanisms that might be involved. Our results show that Z is more potent to stimulate PCHBCEC growth than PCHNBEC growth. The stimulatory effects of Z on PCHBCECs and PCHBCECs may be mediated by its down-regulating expression of the tumor suppressor gene p53 at the mRNA and protein levels. Further investigation showed that the expression of DNA methylatransferase 1 mRNA and protein levels is up-regulated by treatment with Z in PCHBCECs as compared to PCHNBECs, which suggests a role of Z in epigenetic modification involved in the regulation of p53 gene expression in PCHBCECs. Our experimental results imply the potentially adverse health effect of Z in breast cancer development. Further study is continuing in our laboratory. PMID- 21673907 TI - Distribution and molecular characterization of beta-glucans from hull-less barley bran, shorts and flour. AB - Six hull-less barley cultivars widely grown in China were roller-milled to produce bran, shorts and flour fractions. The distribution and molecular characteristics of beta-glucans from the three roller-milled fractions were investigated. The beta-glucan contents in the six hull-less barley cultivars varied from 4.96% to 7.62%. For all the six cultivars, the shorts fraction contained the highest concentration of beta-glucan (8.12-13.01%), followed by bran (6.15-7.58%) and flour (2.48-2.95%). Crude beta-glucans were prepared from the three roller-milled fractions using aqueous sodium carbonate (pH 10). These preparations contained 45.38-71.41% beta-glucan, 10.81-17.26% arabinoxylan, 2.6 9.6% protein, 2.7-9.0% starch, and 5.23-9.68% ash. Purification using alpha amylase and beta-xylanase in combination with pH adjustment and dialysis produced high purity beta-glucan preparations (91-95%). The molecular weight (Mw) of beta glucan preparations from roller-milled fractions ranged from 117,600 to 852,400 g/mol. beta-Glucan from flour had higher Mw than those from shorts and bran within the same cultivar, and beta-glucan preparations from bran had the lowest Mw. PMID- 21673908 TI - Light-emitting devices with conjugated polymers. AB - This article introduces a previous study and tremendous progress in basic theoretical modeling, material developments and device engineering for polymer light-emitting devices (PLEDs). PMID- 21673906 TI - Mechanisms of estrogens' dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia. AB - Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings. PMID- 21673909 TI - Cancer stem-like cells enriched in Panc-1 spheres possess increased migration ability and resistance to gemcitabine. AB - Pancreatic cancer is one of the most lethal malignancies with poor prognosis. Previously, we found that a subpopulation of cancer stem cells (CSCs) in the Panc 1 pancreatic cancer cell line could propagate to form spheres. Here we characterized the malignant phenotypes of the pancreatic cancer stem CD44+/CD24+ cells, which were enriched under sphere forming conditions as analyzed by flow cytometry. These cells demonstrated increased resistance to gemcitabine and increased migration ability. Moreover, these cells exhibited epithelial to mesenchymal transition characterized by a decreased level of the epithelial marker E-cadherin and an increased level of the mesenchymal marker vimentin. Notably, abnormal expression of Bmi-1, ABCG2, Cyclin D1 and p16 were found in Panc-1 CSCs. Our results suggest that targeted inhibition of CSCs represents a novel therapeutic approach to overcome chemoresistance and metastasis of pancreatic cancer. PMID- 21673910 TI - Combined 3D-QSAR modeling and molecular docking studies on pyrrole-indolin-2-ones as Aurora A kinase inhibitors. AB - Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r(2) (cv) values of 0.726 and 0.566, and r(2) values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex docking studies revealed that the sulfo group, secondary amine group on indolin-2 one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed. PMID- 21673911 TI - Photopyroelectric spectroscopic studies of ZnO-MnO(2)-Co(3)O(4)-V(2)O(5) ceramics. AB - Photopyroelectric (PPE) spectroscopy is a nondestructive tool that is used to study the optical properties of the ceramics (ZnO + 0.4MnO(2) + 0.4Co(3)O(4) + xV(2)O(5)), x = 0-1 mol%. Wavelength of incident light, modulated at 10 Hz, was in the range of 300-800 nm. PPE spectrum with reference to the doping level and sintering temperature is discussed. Optical energy band-gap (E(g)) was 2.11 eV for 0.3 mol% V(2)O(5) at a sintering temperature of 1025 degrees C as determined from the plot (rhohupsilon)(2)versushupsilon. With a further increase in V(2)O(5), the value of E(g) was found to be 2.59 eV. Steepness factor 'sigma(A)' and 'sigma(B)', which characterize the slope of exponential optical absorption, is discussed with reference to the variation of E(g). XRD, SEM and EDAX are also used for characterization of the ceramic. For this ceramic, the maximum relative density and grain size was observed to be 91.8% and 9.5 MUm, respectively. PMID- 21673912 TI - Non-linear electrohydrodynamics in microfluidic devices. AB - Since the inception of microfluidics, the electric force has been exploited as one of the leading mechanisms for driving and controlling the movement of the operating fluid and the charged suspensions. Electric force has an intrinsic advantage in miniaturized devices. Because the electrodes are placed over a small distance, from sub-millimeter to a few microns, a very high electric field is easy to obtain. The electric force can be highly localized as its strength rapidly decays away from the peak. This makes the electric force an ideal candidate for precise spatial control. The geometry and placement of the electrodes can be used to design electric fields of varying distributions, which can be readily realized by Micro-Electro-Mechanical Systems (MEMS) fabrication methods. In this paper, we examine several electrically driven liquid handling operations. The emphasis is given to non-linear electrohydrodynamic effects. We discuss the theoretical treatment and related numerical methods. Modeling and simulations are used to unveil the associated electrohydrodynamic phenomena. The modeling based investigation is interwoven with examples of microfluidic devices to illustrate the applications. PMID- 21673913 TI - The composition and organization of cytoplasm in prebiotic cells. AB - This article discusses the hypothesized composition and organization of cytoplasm in prebiotic cells from a theoretical perspective and also based upon what is currently known about bacterial cytoplasm. It is unknown if the first prebiotic, microscopic scale, cytoplasm was initially contained within a primitive, continuous, semipermeable membrane, or was an uncontained gel substance, that later became enclosed by a continuous membrane. Another possibility is that the first cytoplasm in prebiotic cells and a primitive membrane organized at the same time, permitting a rapid transition to the first cell(s) capable of growth and division, thus assisting with the emergence of life on Earth less than a billion years after the formation of the Earth. It is hypothesized that the organization and composition of cytoplasm progressed initially from an unstructured, microscopic hydrogel to a more complex cytoplasm, that may have been in the volume magnitude of about 0.1-0.2 MUm(3) (possibly less if a nanocell) prior to the first cell division. PMID- 21673914 TI - The role of alpha-dystrobrevin in striated muscle. AB - Muscular dystrophies are a group of diseases that primarily affect striated muscle and are characterized by the progressive loss of muscle strength and integrity. Major forms of muscular dystrophies are caused by the abnormalities of the dystrophin glycoprotein complex (DGC) that plays crucial roles as a structural unit and scaffolds for signaling molecules at the sarcolemma. alpha Dystrobrevin is a component of the DGC and directly associates with dystrophin. alpha-Dystrobrevin also binds to intermediate filaments as well as syntrophin, a modular adaptor protein thought to be involved in signaling. Although no muscular dystrophy has been associated within mutations of the alpha-dystrobrevin gene, emerging findings suggest potential significance of alpha-dystrobrevin in striated muscle. This review addresses the functional role of alpha-dystrobrevin in muscle as well as its possible implication for muscular dystrophy. PMID- 21673915 TI - Preliminary study of conformation and drug release mechanism of doxorubicin conjugated glycol chitosan, via cis-aconityl linkage, by molecular modeling. AB - An investigation of the structure and drug release mechanism of a drug delivery system is proposed on the basis of semi-empirical and ab initio computations in vacuum stage. Cis-aconityl linkage is used to improve the interaction between an anti-cancer agent, doxorubicin, and a glycol chitosan biopolymer. It has been found that the doxorubicin-conjugated glycol chitosan carrier has more stability. The stability is increased when the lengths of the polyethylene glycol (PEG) chains in the glycol chitosan biopolymer are increased. Cis-aconityl can release doxorubicin under appropriate environmental conditions. Relative energies of this mechanism in an acid condition, as determined by B3LYP/6-31G//PM3, are 122.41, 119.27, 160.18 and 222.22 kcal/mol, and by the B3LYP/6-31G//HF/6-31G method are 54.23, 109.28, 219.98 and 980.49 kcal/mol, with mono-, di-, tri-, and quanta ethylene glycol, respectively. In a normal condition, the relative energies are above 300 kcal/mol for all reactions. Therefore, cis-aconityl will release doxorubicin in an acid solution but not in a normal condition. The glycol chitosan polymer can be degraded in an acid solution as well. Long PEG chains influence the release mechanism of doxorubicin. The proposed length of the PEG chain is di-ethylene glycol. These simulation results agree well with various reported experimental data. PMID- 21673916 TI - Docetaxel-loaded pluronic p123 polymeric micelles: in vitro and in vivo evaluation. AB - In this work, novel docetaxel (DTX) -loaded Tween 80-free Pluronic P123 (P123) micelles with improved therapeutic effect were developed. The freeze-dried DTX loaded P123 micelles (DTX-micelles) were analyzed by HPLC, TEM and DLS to determine the DTX loading, micelle morphology, size, respectively. The in vitro cytotoxic activity of DTX-micelles in HepG2, A549 and malignant melanoma B16 cells were evaluated by MTT assay. The corresponding in vivo antitumor efficacy was assessed in Kunming mice bearing B16 tumor after intravenous administration. The DTX-loading and efficiency into the micelles were 2.12 +/- 0.09% and 86.34 +/ 3.32%, respectively. The DTX-micelles were spherical with a mean particle size of 50.7 nm and size distribution from 22 to 84 nm, which suggested that they should be able to selectively accumulate in solid tumors by means of EPR effect, with a zeta potential of -12.45 +/- 3.24 mV. The in vitro release behavior of DTX from DTX-micelles followed the Weibull equation. Compared with Duopafei((r)), DTX micelles showed higher cytotoxicity against HepG2 (P < 0.01), A549 (P < 0.05) and B16 (P < 0.01) cells. In addition, DTX-micelles exhibited remarkable antitumor activity and reduced toxicity on B16 tumor in vivo. The tumor inhibition rates (TIR) of DTX-micelles was 91.6% versus 76.3% of Duopafei((r)) (P < 0.01). These results suggested that P123 micelles might be considered as an effective DTX delivery system. PMID- 21673917 TI - Remarks on muscle contraction mechanism II. Isometric tension transient and isotonic velocity transient. AB - Mitsui and Ohshima (2008) criticized the power-stroke model for muscle contraction and proposed a new model. In the new model, about 41% of the myosin heads are bound to actin filaments, and each bound head forms a complex MA(3) with three actin molecules A1, A2 and A3 forming the crossbridge. The complex translates along the actin filament cooperating with each other. The new model well explained the experimental data on the steady filament sliding. As an extension of the study, the isometric tension transient and isotonic velocity transient are investigated. Statistical ensemble of crossbridges is introduced, and variation of the binding probability of myosin head to A1 is considered. When the binding probability to A1 is zero, the Hill-type force-velocity relation is resulted in. When the binding probability to A1 becomes finite, the deviation from the Hill-type force-velocity relation takes place, as observed by Edman (1988). The characteristics of the isometric tension transient observed by Ford, Huxley and Simmons (1977) and of the isotonic velocity transient observed by Civan and Podolsky (1966) are theoretically reproduced. Ratios of the extensibility are estimated as 0.22 for the crossbridge, 0.26 for the myosin filament and 0.52 for the actin filament, in consistency with the values determined by X-ray diffraction by Wakabayashi et al. (1994). PMID- 21673918 TI - Evaluation of potential reference genes for relative quantification by RT-qPCR in different porcine tissues derived from feeding studies. AB - Five potential reference genes for RT-qPCR application, namely histone H3, beta actin, GAPDH, ubiquitin and 18S rRNA, were evaluated for normalization of gene expression in four selected tissues (liver, kidney, thyroid and abdominal fat). Tissues were derived from fattening pigs exposed to different amounts and type of dietary iodine. Two software applications (geNorm and NormFinder) were used to evaluate the stability of the potential reference genes. All studied genes displayed high expression stability but different stability patterns between the investigated tissues. The results suggest GAPDH and 18S rRNA as reference genes applicable in all tissues investigated. Beta-actin and histone H3 are suitable reference genes for all tissues investigated except fat. In contrast, ubiquitin should be excluded from use as a reference gene in the porcine tissues analyzed due to variations in expression levels, despite the good expression stability. PMID- 21673919 TI - Synthesis of molecularly imprinted polymers for amino acid derivates by using different functional monomers. AB - Fmoc-3-nitrotyrosine (Fmoc-3-NT) molecularly imprinted polymers (MIPs) were synthesized to understand the influence of several functional monomers on the efficiency of the molecular imprinting process. Acidic, neutral and basic functional monomers, such as acrylic acid (AA), methacrylic acid (MAA), methacrylamide (MAM), 2-vinylpyridine (2-VP), 4-vinylpyridine (4-VP), have been used to synthesize five different polymers. In this study, the MIPs were tested in batch experiments by UV-visible spectroscopy in order to evaluate their binding properties. The MIP prepared with 2-VP exhibited the highest binding affinity for Fmoc-3NT, for which Scatchard analysis the highest association constant (2.49 * 10(4) M(-1)) was obtained. Furthermore, titration experiments of Fmoc-3NT into acetonitrile solutions of 2-VP revealed a stronger bond to the template, such that a total interaction is observed. Non-imprinted polymers as control were prepared and showed no binding affinities for Fmoc-3NT. The results are indicative of the importance of ionic bonds formed between the -OH residues of the template molecule and the pyridinyl groups of the polymer matrix. In conclusion, 2-VP assists to create a cavity which allows better access to the analytes. PMID- 21673920 TI - Experimental construction of BMP2 and VEGF gene modified tissue engineering bone in vitro. AB - The purpose of this study was to investigate the feasibility and advantages of constructing a novel tissue engineering bone, using beta-tricalcium phosphate (beta-TCP) and rat bone marrow mesenchymal stem cells (MSCs), modified with human bone morphogenetic protein 2 gene (hBMP2) and human vascular endothelial growth factor 165 gene (hVEGF165), through lentiviral transfection. Both genes were successfully co-expressed in the co-transfection group for up to eight weeks confirmed by enzyme-linked immunosorbent assay (ELISA). After seeding MSCs onto the scaffolds, scanning electron microscopy (SEM) observation showed that MSCs grew and proliferated well in co-transfection group at 7 and 14 days. There was no significant difference among all the groups in hoechst DNA assay for cell proliferation for 14 days after cell seeding (P > 0.05), but the highest alkaline phosphatase (ALP) activity was observed in the co-transfection group at 14 days after cell seeding (p < 0.01). These results demonstrated that it was advantageous to construct tissue engineering bone using beta-TCP combined with MSCs lentivirally co-transfected with BMP2 and VEGF165, providing an innovative way for treating bone defects. PMID- 21673921 TI - The effect of Zn-Al-hydrotalcites composited with calcium stearate and beta diketone on the thermal stability of PVC. AB - A clean-route synthesis of Zn-Al-hydrotalcites (Zn-Al-LDHs) using zinc oxide and sodium aluminate solution has been developed. The as-obtained materials were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). The effects of metal ions at different molar ratios on the performance of hydrotalcites were discussed. The results showed that the Zn-Al-hydrotalcites can be successfully synthesized at three different Zn/Al ratios of 3:1, 2:1 and 1:1. Thermal aging tests of polyvinyl chloride (PVC) mixed with Zn-Al-LDHs, calcium stearate (CaSt(2)) and beta-diketone were carried out in a thermal aging test box by observing the color change. The results showed that Zn-Al-LDHs can not only enhance the stability of PVC significantly due to the improved capacity of HCl-adsorption but also increase the initial stability and ensure good-initial coloring due to the presence of the Zn element. The effects of various amounts of Zn-Al-LDHs, CaSt(2) and beta-diketone on the thermal stability of PVC were discussed. The optimum composition was determined to be 0.1 g Zn-Al-LDHs, 0.15 g CaSt(2) and 0.25 g beta diketone in 5 g PVC. PMID- 21673922 TI - Importance of the long-chain fatty acid beta-hydroxylating cytochrome P450 enzyme YbdT for lipopeptide biosynthesis in Bacillus subtilis strain OKB105. AB - Bacillus species produce extracellular, surface-active lipopeptides such as surfactin that have wide applications in industry and medicine. The steps involved in the synthesis of 3-hydroxyacyl-coenzyme A (CoA) substrates needed for surfactin biosynthesis are not understood. Cell-free extracts of Bacillus subtilis strain OKB105 synthesized lipopeptide biosurfactants in presence of l amino acids, myristic acid, coenzyme A, ATP, and H(2)O(2), which suggested that 3 hydroxylation occurs prior to CoA ligation of the long chain fatty acids (LCFAs). We hypothesized that YbdT, a cytochrome P450 enzyme known to beta-hydroxylate LCFAs, functions to form 3-hydroxy fatty acids for lipopeptide biosynthesis. An in-frame mutation of ybdT was constructed and the resulting mutant strain (NHY1) produced predominantly non-hydroxylated lipopeptide with diminished biosurfactant and beta-hemolytic activities. Mass spectrometry showed that 95.6% of the fatty acids in the NHY1 biosurfactant were non-hydroxylated compared to only ~61% in the OKB105 biosurfactant. Cell-free extracts of the NHY1 synthesized surfactin containing 3-hydroxymyristic acid from 3-hydroxymyristoyl-CoA at a specific activity similar to that of the wild type (17 +/- 2 versus 17.4 +/- 6 ng biosurfactant min(-1).ng.protein(-1), respectively). These results showed that the mutation did not affect any function needed to synthesize surfactin once the 3-hydroxyacyl-CoA substrate was formed and that YbdT functions to supply 3 hydroxy fatty acid for surfactin biosynthesis. The fact that YbdT is a peroxidase could explain why biosurfactant production is rarely observed in anaerobically grown Bacillus species. Manipulation of LCFA specificity of YbdT could provide a new route to produce biosurfactants with activities tailored to specific functions. PMID- 21673923 TI - Novel application of cyclolipopeptide amphisin: feasibility study as additive to remediate polycyclic aromatic hydrocarbon (PAH) contaminated sediments. AB - To decontaminate dredged harbor sediments by bioremediation or electromigration processes, adding biosurfactants could enhance the bioavailability or mobility of contaminants in an aqueous phase. Pure amphisin from Pseudomonas fluorescens DSS73 displays increased effectiveness in releasing polycyclic aromatic hydrocarbons (PAHs) strongly adsorbed to sediments when compared to a synthetic anionic surfactant. Amphisin production by the bacteria in the natural environment was also considered. DSS73's growth is weakened by three model PAHs above saturation, but amphisin is still produced. Estuarine water feeding the dredged material disposal site of a Norman harbor (France) allows both P. fluorescens DSS73 growth and amphisin production. PMID- 21673924 TI - Combined 3D-QSAR, molecular docking and molecular dynamics study on derivatives of peptide epoxyketone and tyropeptin-boronic acid as inhibitors against the beta5 subunit of human 20S proteasome. AB - An abnormal ubiquitin-proteasome is found in many human diseases, especially in cancer, and has received extensive attention as a promising therapeutic target in recent years. In this work, several in silico models have been built with two classes of proteasome inhibitors (PIs) by using 3D-QSAR, homology modeling, molecular docking and molecular dynamics (MD) simulations. The study resulted in two types of satisfactory 3D-QSAR models, i.e., the CoMFA model (Q(2) = 0.462, R(2) (pred) = 0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q(2) = 0.622, R(2) (pred) = 0.821) for tyropeptin-boronic acid derivatives (TBA). From the contour maps, some key structural factors responsible for the activity of these two series of PIs are revealed. For EPK inhibitors, the N-cap part should have higher electropositivity; a large substituent such as a benzene ring is favored at the C6-position. In terms of TBA inhibitors, hydrophobic substituents with a larger size anisole group are preferential at the C8-position; higher electropositive substituents like a naphthalene group at the C3-position can enhance the activity of the drug by providing hydrogen bond interaction with the protein target. Molecular docking disclosed that residues Thr60, Thr80, Gly106 and Ser189 play a pivotal role in maintaining the drug-target interactions, which are consistent with the contour maps. MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall. These results can offer useful theoretical references for designing more potent PIs. PMID- 21673925 TI - Dietary sources of fiber intake and its association with socio-economic factors among Flemish preschool children. AB - The objectives were to assess total dietary fiber intake, identify the major sources of dietary fiber, and examine its association with socio-economic factors among Flemish preschoolers. Three-day estimated dietary records were collected from a representative sample of preschoolers 2.5-6.5 years old (n = 661; 338 boys, 323 girls). The mean dietary fiber intake (13.4 g/d) was lower than the intake level recommended by the Belgian Superior Health Council (70% boys and 81% girls below the guidelines). The most important contributor was the group of bread and cereals (29.5%), followed by fruits (17.8%), potatoes and grains (16.0%), energy-dense, low-nutritious foods (12.4%), and vegetables (11.8%). Multiple linear regression analyses showed that total fiber intake was associated with maternal education and parents' employment. Overall, fiber intakes from high nutritious foods (vegetables and fruits) were higher in preschoolers of higher educated mothers and those with one or both parents being employed. In conclusion, the majority of the preschoolers had dietary fiber intakes below the recommended level. Hence, dietary fiber should be promoted among parents of preschoolers and low socio-economic status families should be addressed in particular. PMID- 21673926 TI - Separation and purification of sulforaphane from broccoli by solid phase extraction. AB - A simple solid-phase extraction (SPE) method for the determination of sulforaphane in broccoli has been developed. The optimal conditions were found to be use of a silica SPE cartridge, and ethyl acetate and dichloromethane as washing and eluting solvents, respectively, which could eliminate interferences originating from the broccoli matrix. The extracts were sufficiently clean to be directly injected into high-performance liquid chromatography (HPLC) for further chromatographic analysis. Good linearity was obtained from 0.05 to 200 MUg/mL (r = 0.998) for sulforaphane with the relative standard deviations less than 3.6%. The mean recoveries of sulforaphane from broccoli were more than 90.8% and the detection limit (S/N = 3:1) was 0.02 MUg/mL. The SPE method provides a higher yield of sulforaphane from crude extracts compared to conventional liquid-liquid extraction. PMID- 21673927 TI - Changes of constituents and activity to apoptosis and cell cycle during fermentation of tea. AB - Tea is believed to be beneficial for health, and the effects of the fermentation process on its contributions to apoptosis and cell cycle arrest of gastric cancer cells have not been completely investigated. In this study, the chemical components in green tea, black tea and pu-erh tea aqueous extracts were analyzed and compared. The polysaccharide and caffeine levels were substantially higher in the fermented black tea and pu-erh tea, while the polyphenol level was higher in the unfermented green tea. Hence, a treatment of tea aqueous extract and the components, which are emerging as promising anticancer agents, were pursued to determine whether this treatment could lead to enhance apoptosis and cell cycle arrest. In the human gastric cancer cell line SGC-7901, the cell viability and flow cytometry analysis for apoptotic cells indicated effects in a dose-dependent inhibition manner for the three tea treatment groups. The apoptosis rates were found to be elevated after 48 h of treatment with 31.2, 125, and 500 MUg/mL of green tea extract, the higher catechins content may be involved in the mechanism. Cell cycle was arrested in S phase in the fermented black tea and pu-erh tea, and the populations were significantly decreased in G2/M phases, possibly due to the oxidation of tea polyphenols, which causes an increase of theabrownins. CCC-HEL-1 normal cells were not sensitive to tea extract. These findings suggest that the fermentation process causes changes of the compounds which might be involved in the changes of cell proliferation inhibition, apoptosis induction and cell cycle arrest. PMID- 21673928 TI - Chitin scaffolds in tissue engineering. AB - Tissue engineering/regeneration is based on the hypothesis that healthy stem/progenitor cells either recruited or delivered to an injured site, can eventually regenerate lost or damaged tissue. Most of the researchers working in tissue engineering and regenerative technology attempt to create tissue replacements by culturing cells onto synthetic porous three-dimensional polymeric scaffolds, which is currently regarded as an ideal approach to enhance functional tissue regeneration by creating and maintaining channels that facilitate progenitor cell migration, proliferation and differentiation. The requirements that must be satisfied by such scaffolds include providing a space with the proper size, shape and porosity for tissue development and permitting cells from the surrounding tissue to migrate into the matrix. Recently, chitin scaffolds have been widely used in tissue engineering due to their non-toxic, biodegradable and biocompatible nature. The advantage of chitin as a tissue engineering biomaterial lies in that it can be easily processed into gel and scaffold forms for a variety of biomedical applications. Moreover, chitin has been shown to enhance some biological activities such as immunological, antibacterial, drug delivery and have been shown to promote better healing at a faster rate and exhibit greater compatibility with humans. This review provides an overview of the current status of tissue engineering/regenerative medicine research using chitin scaffolds for bone, cartilage and wound healing applications. We also outline the key challenges in this field and the most likely directions for future development and we hope that this review will be helpful to the researchers working in the field of tissue engineering and regenerative medicine. PMID- 21673930 TI - Natural-synthetic hybrid polymers developed via electrospinning: the effect of PET in chitosan/starch system. AB - Chitosan is an amino polysaccharide found in nature, which is biodegradable, nontoxic and biocompatible. It has versatile features and can be used in a variety of applications including films, packaging, and also in medical surgery. Recently a possibility to diversify chitosan properties has emerged by combining it with synthetic materials to produce novel natural-synthetic hybrid polymers. We have studied structural and thermophysical properties of chitosan + starch + poly(ethylene terephthalate) (Ch + S + PET) fibers developed via electrospinning. Properties of these hybrids polymers are compared with extant chitosan containing hybrids synthesized by electrospinning. Molecular interactions and orientation in the fibers are analyzed by infrared and Raman spectroscopies respectively, morphology by scanning electron microscopy and thermophysical properties by thermogravimetric analysis and differential scanning calorimetry. Addition of PET to Ch + S systems results in improved thermal stability at elevated temperatures. PMID- 21673929 TI - Differential responses to blood pressure and oxidative stress in streptozotocin induced diabetic Wistar-Kyoto rats and spontaneously hypertensive rats: effects of antioxidant (honey) treatment. AB - Oxidative stress is implicated in the pathogenesis and/or complications of hypertension and/or diabetes mellitus. A combination of these disorders increases the risk of developing cardiovascular events. This study investigated the effects of streptozotocin (60 mg/kg; ip)-induced diabetes on blood pressure, oxidative stress and effects of honey on these parameters in the kidneys of streptozotocin induced diabetic Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Diabetic WKY and SHR were randomized into four groups and received distilled water (0.5 mL) and honey (1.0 g/kg) orally once daily for three weeks. Control SHR had reduced malondialdehyde (MDA) and increased systolic blood pressure (SBP), catalase (CAT) activity, and total antioxidant status (TAS). SBP, activities of glutathione peroxidase (GPx) and glutathione reductase (GR) were elevated while TAS was reduced in diabetic WKY. In contrast, SBP, TAS, activities of GPx and GR were reduced in diabetic SHR. Antioxidant (honey) treatment further reduced SBP in diabetic SHR but not in diabetic WKY. It also increased TAS, GSH, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, activities of GPx and GR in diabetic SHR. These data suggest that differences in types, severity, and complications of diseases as well as strains may influence responses to blood pressure and oxidative stress. PMID- 21673931 TI - Detecting molecular features of spectra mainly associated with structural and non structural carbohydrates in co-products from bioEthanol production using DRIFT with uni- and multivariate molecular spectral analyses. AB - The objective of this study was to use DRIFT spectroscopy with uni- and multivariate molecular spectral analyses as a novel approach to detect molecular features of spectra mainly associated with carbohydrate in the co-products (wheat DDGS, corn DDGS, blend DDGS) from bioethanol processing in comparison with original feedstock (wheat (Triticum), corn (Zea mays)). The carbohydrates related molecular spectral bands included: A_Cell (structural carbohydrates, peaks area region and baseline: ca. 1485-1188 cm(-1)), A_1240 (structural carbohydrates, peak area centered at ca. 1240 cm(-1) with region and baseline: ca. 1292-1198 cm( 1)), A_CHO (total carbohydrates, peaks region and baseline: ca. 1187-950 cm(-1)), A_928 (non-structural carbohydrates, peak area centered at ca. 928 cm(-1) with region and baseline: ca. 952-910 cm(-1)), A_860 (non-structural carbohydrates, peak area centered at ca. 860 cm(-1) with region and baseline: ca. 880-827 cm( 1)), H_1415 (structural carbohydrate, peak height centered at ca. 1415 cm(-1) with baseline: ca. 1485-1188 cm(-1)), H_1370 (structural carbohydrate, peak height at ca. 1370 cm(-1) with a baseline: ca. 1485-1188 cm(-1)). The study shows that the grains had lower spectral intensity (KM Unit) of the cellulosic compounds of A_1240 (8.5 vs. 36.6, P < 0.05), higher (P < 0.05) intensities of the non-structural carbohydrate of A_928 (17.3 vs. 2.0) and A_860 (20.7 vs. 7.6) than their co-products from bioethanol processing. There were no differences (P > 0.05) in the peak area intensities of A_Cell (structural CHO) at 1292-1198 cm(-1) and A_CHO (total CHO) at 1187-950 cm(-1) with average molecular infrared intensity KM unit of 226.8 and 508.1, respectively. There were no differences (P > 0.05) in the peak height intensities of H_1415 and H_1370 (structural CHOs) with average intensities 1.35 and 1.15, respectively. The multivariate molecular spectral analyses were able to discriminate and classify between the corn and corn DDGS molecular spectra, but not wheat and wheat DDGS. This study indicated that the bioethanol processing changes carbohydrate molecular structural profiles, compared with the original grains. However, the sensitivities of different types of carbohydrates and different grains (corn and wheat) to the processing differ. In general, the bioethanol processing increases the molecular spectral intensities for the structural carbohydrates and decreases the intensities for the non-structural carbohydrates. Further study is needed to quantify carbohydrate related molecular spectral features of the bioethanol co products in relation to nutrient supply and availability of carbohydrates. PMID- 21673933 TI - Synthesis, characterization and thermal studies of Zn(II), Cd(II) and Hg(II) complexes of N-methyl-N-phenyl dithiocarbamate: the single crystal structure of [(C(6)H(5))(CH(3))NCS(2)](4)Hg(2). AB - Zn(II), Cd(II) and Hg(II) complexes of N-methyl-N-phenyl dithiocarbamate have been synthesized and characterized by elemental analysis and spectral studies (IR, (1)H and (13)C-NMR). The single crystal X-ray structure of the mercury complex revealed that the complex contains a Hg centre with a distorted tetrahedral coordination sphere in which the dinuclear Hg complex resides on a crystallographic inversion centre and each Hg atom is coordinated to four S atoms from the dithiocarbamate moiety. One dithiocarbamate ligand acts as chelating ligand while the other acts as chelating bridging ligand between two Hg atoms, resulting in a dinuclear eight-member ring. The course of the thermal degradation of the complexes has been investigated using thermogravimetric and differential thermal analyses techniques. Thermogravimetric analysis of the complexes show a single weight loss to give MS (M = Zn, Cd, Hg) indicating that they might be useful as single source precursors for the synthesis of MS nanoparticles and thin films. PMID- 21673932 TI - Chitin-based materials in tissue engineering: applications in soft tissue and epithelial organ. AB - Chitin-based materials and their derivatives are receiving increased attention in tissue engineering because of their unique and appealing biological properties. In this review, we summarize the biomedical potential of chitin-based materials, specifically focusing on chitosan, in tissue engineering approaches for epithelial and soft tissues. Both types of tissues play an important role in supporting anatomical structures and physiological functions. Because of the attractive features of chitin-based materials, many characteristics beneficial to tissue regeneration including the preservation of cellular phenotype, binding and enhancement of bioactive factors, control of gene expression, and synthesis and deposition of tissue-specific extracellular matrix are well-regulated by chitin based scaffolds. These scaffolds can be used in repairing body surface linings, reconstructing tissue structures, regenerating connective tissue, and supporting nerve and vascular growth and connection. The novel use of these scaffolds in promoting the regeneration of various tissues originating from the epithelium and soft tissue demonstrates that these chitin-based materials have versatile properties and functionality and serve as promising substrates for a great number of future applications. PMID- 21673934 TI - Chaperoning roles of macromolecules interacting with proteins in vivo. AB - The principles obtained from studies on molecular chaperones have provided explanations for the assisted protein folding in vivo. However, the majority of proteins can fold without the assistance of the known molecular chaperones, and little attention has been paid to the potential chaperoning roles of other macromolecules. During protein biogenesis and folding, newly synthesized polypeptide chains interact with a variety of macromolecules, including ribosomes, RNAs, cytoskeleton, lipid bilayer, proteolytic system, etc. In general, the hydrophobic interactions between molecular chaperones and their substrates have been widely believed to be mainly responsible for the substrate stabilization against aggregation. Emerging evidence now indicates that other features of macromolecules such as their surface charges, probably resulting in electrostatic repulsions, and steric hindrance, could play a key role in the stabilization of their linked proteins against aggregation. Such stabilizing mechanisms are expected to give new insights into our understanding of the chaperoning functions for de novo protein folding. In this review, we will discuss the possible chaperoning roles of these macromolecules in de novo folding, based on their charge and steric features. PMID- 21673936 TI - Continuous spatial tuning of laser emissions in a full visible spectral range. AB - In order to achieve a continuous tuning of laser emission, the authors designed and fabricated three types of cholesteric liquid crystal cells with pitch gradient, a wedge cell with positive slope, a wedge cell with negative slope, and a parallel cell. The length of the cholesteric liquid crystal pitch could be elongated up to 10 nm, allowing the lasing behavior of continuous or discontinuous spatial tuning determined by the boundary conditions of the cholesteric liquid crystal cell. In the wedge cell with positive slope, the authors demonstrated a continuous spatial laser tuning in the near full visible spectral range, with a tuning resolution less than 1 nm by pumping with only a single 355 nm laser beam. This continuous tuning behavior is due to the fact that the concentration of pitch gradient matches the fixed helical pitch determined by the cell thickness. This characteristic continuous spatial laser tuning could be confirmed again by pumping with a 532 nm laser beam, over 90 nm in the visible spectral range. The scheme of the spatial laser tuning in the wedge cell bearing a pitch gradient enabled a route to designing small-sized optical devices that allow for a wide tunability of single-mode laser emissions. PMID- 21673935 TI - Effect of Ligusticum wallichii aqueous extract on oxidative injury and immunity activity in myocardial ischemic reperfusion rats. AB - We investigated the efficacy of Ligusticum wallichi aqueous extract (LWE) for myocardial protection against ischemia-reperfusion injury. Rats were fed for five weeks with either a control diet (sham and ischemia reperfusion (IR) model control groups) or a diet mixed with 0.2%, 0.4% or 0.6% Ligusticum wallichi extract. At the end of the five week period, hearts were excised and subjected to global ischemia for 30 min followed by reperfusion for 2 h. The hearts were compared for indices of oxidative stress and immunity activities. Administration of Ligusticum wallichi extract significantly decreased serum TNF-alpha, IL-6, IL 8, NO, MIP-1alpha, CRP and myocardium MDA levels, and serum CK, LDH and AST activities, and increased myocardium Na(+)-K(+)-ATPase, Ca(2+)-Mg(2+)-ATPase, NOS, SOD, CAT, GSH-Px and TAOC activities. The results indicate that Ligusticum wallichii extract treatment can enhance myocardial antioxidant status and improve the immunity profile in ischemic-reperfusion rats. PMID- 21673937 TI - Amyloidogenic properties of a D/N mutated 12 amino acid fragment of the C terminal domain of the Cholesteryl-Ester Transfer Protein (CETP). AB - The cholesteryl-ester transfer protein (CETP) facilitates the transfer of cholesterol esters and triglycerides between lipoproteins in plasma where the critical site for its function is situated in the C-terminal domain. Our group has previously shown that this domain presents conformational changes in a non lipid environment when the mutation D(470)N is introduced. Using a series of peptides derived from this C-terminal domain, the present study shows that these changes favor the induction of a secondary beta-structure as characterized by spectroscopic analysis and fluorescence techniques. From this type of secondary structure, the formation of peptide aggregates and fibrillar structures with amyloid characteristics induced cytotoxicity in microglial cells in culture. These supramolecular structures promote cell cytotoxicity through the formation of reactive oxygen species (ROS) and change the balance of a series of proteins that control the process of endocytosis, similar to that observed when beta amyloid fibrils are employed. Therefore, a fine balance between the highly dynamic secondary structure of the C-terminal domain of CETP, the net charge, and the physicochemical characteristics of the surrounding microenvironment define the type of secondary structure acquired. Changes in this balance might favor misfolding in this region, which would alter the lipid transfer capacity conducted by CETP, favoring its propensity to substitute its physiological function. PMID- 21673938 TI - Recent advances in conjugated polymers for light emitting devices. AB - A recent advance in the field of light emitting polymers has been the discovery of electroluminescent conjugated polymers, that is, kind of fluorescent polymers that emit light when excited by the flow of an electric current. These new generation fluorescent materials may now challenge the domination by inorganic semiconductor materials of the commercial market in light-emitting devices such as light-emitting diodes (LED) and polymer laser devices. This review provides information on unique properties of conjugated polymers and how they have been optimized to generate these properties. The review is organized in three sections focusing on the major advances in light emitting materials, recent literature survey and understanding the desirable properties as well as modern solid state lighting and displays. Recently, developed conjugated polymers are also functioning as roll-up displays for computers and mobile phones, flexible solar panels for power portable equipment as well as organic light emitting diodes in displays, in which television screens, luminous traffic, information signs, and light-emitting wallpaper in homes are also expected to broaden the use of conjugated polymers as light emitting polymers. The purpose of this review paper is to examine conjugated polymers in light emitting diodes (LEDs) in addition to organic solid state laser. Furthermore, since conjugated polymers have been approved as light-emitting organic materials similar to inorganic semiconductors, it is clear to motivate these organic light-emitting devices (OLEDs) and organic lasers for modern lighting in terms of energy saving ability. In addition, future aspects of conjugated polymers in LEDs were also highlighted in this review. PMID- 21673939 TI - Circulating microRNAs: potential biomarkers for cancer. AB - Cancer is the leading cause of death in the world. Development of minimally invasive biomarkers for early detection of cancer is urgently needed to reduce high morbidity and mortality associated with malignancy. MicroRNAs (miRNAs) are small regulatory RNAs that modulate the activity of specific mRNA targets and play important roles in a wide range of physiologic and pathologic processes. Recently, miRNAs were found to be dysregulated in a variety of diseases including cancer. Emerging evidence suggests that miRNAs are involved in tumor initiation and progression. Together, the different expression profiles of miRNAs in cancer, and the stability of circulating miRNAs, make them new potentially clinical biomarkers for cancer diagnosis, classification, therapeutic decisions, and prognosis. PMID- 21673940 TI - Cloning, soluble expression and purification of high yield recombinant hGMCSF in Escherichia coli. AB - Expression of human granulocyte macrophage colony stimulating factor (hGMCSF), a cytokine of therapeutic importance, as a thioredoxin (TRX) fusion has been investigated in Escherichia coli BL21 (DE3) codon plus cells. The expression of this protein was low when cloned under the T7 promoter without any fusion tags. High yield of GMCSF was achieved (~88 mg/L of fermentation broth) in the shake flask when the gene was fused to the E. coli TRX gene. The protein was purified using a single step Ni(2+)-NTA affinity chromatography and the column bound fusion tag was removed by on-column cleavage with enterokinase. The recombinant hGMCSF was expressed as a soluble and biologically active protein in E. coli, and upon purification, the final yield was ~44 mg/L in shake flask with a specific activity of 2.3 * 10(8) U/mg. The results of Western blot and RP-HPLC analyses, along with biological activity using the TF-1 cell line, established the identity of the purified hGMCSF. In this paper, we report the highest yield of hGMCSF expressed in E. coli. The bioreactor study shows that the yield of hGMCSF could be easily scalable with a yield of ~400 mg/L, opening up new opportunities for large scale production hGMCSF in E. coli. PMID- 21673941 TI - In vitro ability of currently available oximes to reactivate organophosphate pesticide-inhibited human acetylcholinesterase and butyrylcholinesterase. AB - We have in vitro tested the ability of common, commercially available, cholinesterase reactivators (pralidoxime, obidoxime, methoxime, trimedoxime and HI-6) to reactivate human acetylcholinesterase (AChE), inhibited by five structurally different organophosphate pesticides and inhibitors (paraoxon, dichlorvos, DFP, leptophos-oxon and methamidophos). We also tested reactivation of human butyrylcholinesterase (BChE) with the aim of finding a potent oxime, suitable to serve as a "pseudocatalytic" bioscavenger in combination with this enzyme. Such a combination could allow an increase of prophylactic and therapeutic efficacy of the administered enzyme. According to our results, the best broad-spectrum AChE reactivators were trimedoxime and obidoxime in the case of paraoxon, leptophos-oxon, and methamidophos-inhibited AChE. Methamidophos and leptophos-oxon were quite easily reactivatable by all tested reactivators. In the case of methamidophos-inhibited AChE, the lower oxime concentration (10(-5) M) had higher reactivation ability than the 10(-4) M concentration. Therefore, we evaluated the reactivation ability of obidoxime in a concentration range of 10( 3)-10(-7) M. The reactivation of methamidophos-inhibited AChE with different obidoxime concentrations resulted in a bell shaped curve with maximum reactivation at 10(-5) M. In the case of BChE, no reactivator exceeded 15% reactivation ability and therefore none of the oximes can be recommended as a candidate for "pseudocatalytic" bioscavengers with BChE. PMID- 21673942 TI - Safety and effectiveness of point-of-care monitoring devices in patients on oral anticoagulant therapy: a meta-analysis. AB - BACKGROUND: Point-of-care devices (POCDs) for monitoring long-term oral anticoagulation therapy (OAT) may be a useful alternative to laboratory-based international normalized ratio [INR] testing and clinical management. PURPOSE: To determine clinical outcomes of the use of POCDs for OAT management by performing a meta-analysis. Previous meta-analyses on POCDs have serious limitations. DATA SOURCES: PubMed, the Cochrane Library, DIALOG, MEDLINE, EMBASE, BIOSIS Previews and PASCAL databases. STUDY SELECTION: Randomized controlled trials of patients on long-term OAT, comparing anticoagulation monitoring by POCD with laboratory INR testing and clinical management. DATA EXTRACTION: 1) rates of major hemorrhage; 2) rates of major thromboembolic events; 3) percentage of time that the patient is maintained within the therapeutic range; 4) deaths. Outcomes were compared using a random-effects model. Summary measures of rates were determined. The quality of studies was assessed using the Jadad scale. DATA SYNTHESIS: Seventeen articles (16 studies) were included. Data analysis showed that POCD INR testing reduced the risk of major thromboembolic events (odds ratio [OR] = 0.51; 95% confidence interval [CI] 0.35-0.74), was associated with fewer deaths (OR = 0.58; 95% CI = 0.38-0.89), and resulted in better INR control compared with laboratory INR testing. No significant difference between the two management modalities with respect to odds ratios for major hemorrhage was found. LIMITATIONS: Quality scores varied from 1 to 3 (out of a maximum of 5). Only 3 studies defined how thromboembolic events would be diagnosed, casting doubt on the accuracy of the reporting of thromboembolic events. The studies suggest that only 24% of patients are good candidates for self-testing and self-management. Compared with patients managed with laboratory-based monitoring, POCD patients underwent INR testing at a much higher frequency and received much more intensive education on OAT management. CONCLUSIONS: The use of POCDs is safe and may be more effective than laboratory-based monitoring. However, most patients are not good candidates for self-testing and self-management. Patient education and frequency of testing may be the most important factors in successful PODC management. Definitive conclusions about the clinical benefits provided by self testing and self-management require more rigorously designed trials. PMID- 21673943 TI - Up close and personal: poverty and human development. AB - POVERTY AND HEALTH ARE INEXTRICABLY LINKED: poverty diminishes access to health care (whether through reduced ability to pay, a lack of knowledge about when to seek health care or a lack of adequate services within reach), increases exposure to disease and other illness (for example, through exposure to dangerous workplaces), and is related to reduced access to clean water, housing and sanitation. PMID- 21673944 TI - The socioeconomic impact of the chikungunya viral epidemic in India. PMID- 21673945 TI - Clinic entrance interviews: a new method to assess needs after a sudden impact disaster. AB - BACKGROUND: After a Sudden impact disasters (SID), relief workers and coordinators require information on the size and location of the affected population as well as the character and magnitude of their immediate needs. METHODS: The study was performed in the mountainous Bagh district, a part of the autonomous state of Azad Jammu and Kashmir in Pakistan. Semi-structured interviews were conducted daily at either of the three health centres or the district hospital in which MSF was working. RESULTS: The MSF facility-based survey results on mortality and injury in Bagh Tehsil corresponded to those from the community-based Army survey. This indicates that regular selection of consecutive arrivals at the entrance of a health facility may provide a fairly geographically representative population sample in a SID context. Our findings suggest that the sample was large enough to provide useful estimates on the main pattern of post-earthquake needs in the study area. PMID- 21673946 TI - The bitten man: Reflections on international health. PMID- 21673947 TI - Little seid. PMID- 21673948 TI - Past, present and future: experiences and lessons from telehealth projects. AB - Information communications technology has been a focus of the work of the International Development Research Centre (IDRC) since 1970, when this organization was formed in Canada with the goal of helping to improve the health of people in developing countries (http://www.idrc.ca). In this article, we focus on the field of telemedicine in developing countries and its role in improving health, using examples from the experience of the IDRC. PMID- 21673949 TI - Prokinetic drug utility in the treatment of gastroesophageal reflux esophagitis: a systematic review of randomized controlled trials. AB - BACKGROUND: Esophagitis caused by gastroesophageal reflux disease (GERD) results in appreciable morbidity and economic burden. No systematic review has addressed the effectiveness of prokinetic drugs in the treatment of GERD esophagitis in adults. OBJECTIVE: To determine the utility of prokinetic drugs in improving symptoms and endoscopic lesions in patients with GERD esophagitis. METHODS: We included randomized controlled trials that compared prokinetic drugs with placebo. A systematic search included the Cochrane Controlled Trial Register, MEDLINE, CINAHL, LILACS, EMBASE, a manual search of books and article references, and contact with pharmaceutical companies. Reviewers assessed methodological quality and extracted data that were combined using a random effects model. RESULTS: Eighteen articles met the eligibility criteria; of these, 13 used prokinetic drugs alone, 4 tested prokinetic drugs as additional therapy in patients receiving histamine-2 receptor blockers, and 1 tested them in patients receiving proton pump inhibitors. Seven studies evaluated clinical improvement only, 5 addressed endoscopic improvement only, and 6 reported both outcomes. Four studies failed to provide adequate data for pooling; 3 of the 4 reported results that suggested symptomatic benefit with prokinetic agents. Nine studies (379 patients) that provided the required data suggested a higher incidence of clinical improvement with prokinetic drugs versus placebo (relative risk [RR] 1.70, 95% confidence interval [CI] 1.37-2.12, heterogeneity p = 0.47, I(2) = 0%). Clinical improvement occurred in 53 out of 175 patients (30%) of the control group; applying the relative risk of 1.70 and associated confidence interval suggests that absolute increases in patients improved might vary from 18% to 41% (number needed to treat approximately 3 to 6). Improvement was similar in 4 studies in which the prokinetic agent was added to an antisecretory drug. The funnel plot, however, suggests the possibility of publication bias. Eleven studies (887 patients) suggested a higher likelihood of endoscopic improvement or healing esophagitis with prokinetic drugs (RR 1.26, 95% CI 1.03-1.53) but with significant heterogeneity (heterogeneity p = .05, I(2) = 46.2%) that we couldn't explain with an a priori hypothesis. When we evaluated endoscopic healing as the main outcome we observed a trend toward better results in the treatment group, also with inexplicable heterogeneity (RR 1.36, CI 95% 0.97-1.89, I(2) = 61%). CONCLUSIONS: Randomized controlled trials provide moderate-quality evidence that prokinetic drugs improve symptoms in patients with reflux esophagitis and low quality evidence that they have an impact on endoscopic healing. PMID- 21673950 TI - Does the evidence show that prokinetic agents are effective in healing esophagitis and improving symptoms of GERD? AB - Gastroesophageal reflux disease (GERD) is common in affluent societies, and its prevalence is also on the rise in developing regions such as Southeast Asia.1 When heartburn and regurgitation are the dominant symptoms, a diagnosis of GERD can be made. Manzotti and colleagues report in Open Medicine the findings of a systematic review in which they evaluate the use of prokinetic agents in the treatment of reflux esophagitis. PMID- 21673951 TI - Breast cancer prevention in women with a BRCA1 or BRCA2 mutation. PMID- 21673952 TI - Numerical modeling of fluid flow in solid tumors. AB - A mathematical model of interstitial fluid flow is developed, based on the application of the governing equations for fluid flow, i.e., the conservation laws for mass and momentum, to physiological systems containing solid tumors. The discretized form of the governing equations, with appropriate boundary conditions, is developed for a predefined tumor geometry. The interstitial fluid pressure and velocity are calculated using a numerical method, element based finite volume. Simulations of interstitial fluid transport in a homogeneous solid tumor demonstrate that, in a uniformly perfused tumor, i.e., one with no necrotic region, because of the interstitial pressure distribution, the distribution of drug particles is non-uniform. Pressure distribution for different values of necrotic radii is examined and two new parameters, the critical tumor radius and critical necrotic radius, are defined. Simulation results show that: 1) tumor radii have a critical size. Below this size, the maximum interstitial fluid pressure is less than what is generally considered to be effective pressure (a parameter determined by vascular pressure, plasma osmotic pressure, and interstitial osmotic pressure). Above this size, the maximum interstitial fluid pressure is equal to effective pressure. As a consequence, drugs transport to the center of smaller tumors is much easier than transport to the center of a tumor whose radius is greater than the critical tumor radius; 2) there is a critical necrotic radius, below which the interstitial fluid pressure at the tumor center is at its maximum value. If the tumor radius is greater than the critical tumor radius, this maximum pressure is equal to effective pressure. Above this critical necrotic radius, the interstitial fluid pressure at the tumor center is below effective pressure. In specific ranges of these critical sizes, drug amount and therefore therapeutic effects are higher because the opposing force, interstitial fluid pressure, is low in these ranges. PMID- 21673953 TI - A better anti-diabetic recombinant human fibroblast growth factor 21 (rhFGF21) modified with polyethylene glycol. AB - As one of fibroblast growth factor (FGF) family members, FGF21 has been extensively investigated for its potential as a drug candidate to combat metabolic diseases. In the present study, recombinant human FGF21 (rhFGF21) was modified with polyethylene glycol (PEGylation) in order to increase its in vivo biostabilities and therapeutic potency. At N-terminal residue rhFGF21 was site selectively PEGylated with mPEG20 kDa-butyraldehyde. The PEGylated rhFGF21 was purified to near homogeneity by Q Sepharose anion-exchange chromatography. The general structural and biochemical features as well as anti-diabetic effects of PEGylated rhFGF21 in a type 2 diabetic rat model were evaluated. By N-terminal sequencing and MALDI-TOF mass spectrometry, we confirmed that PEG molecule was conjugated only to the N-terminus of rhFGF21. The mono-PEGylated rhFGF21 retained the secondary structure, consistent with the native rhFGF21, but its biostabilities, including the resistance to physiological temperature and trypsinization, were significantly enhanced. The in vivo immunogenicity of PEGylated rhFGF21 was significantly decreased, and in vivo half-life time was significantly elongated. Compared to the native form, the PEGylated rhFGF21 had a similar capacity of stimulating glucose uptake in 3T3-L1 cells in vitro, but afforded a significantly long effect on reducing blood glucose and triglyceride levels in the type 2 diabetic animals. These results suggest that the PEGylated rhFGF21 is a better and more effective anti-diabetic drug candidate than the native rhFGF21 currently available. Therefore, the PEGylated rhFGF21 may be potentially applied in clinics to improve the metabolic syndrome for type 2 diabetic patients. PMID- 21673954 TI - Hepatitis C virus NS3 protein can activate the Notch-signaling pathway through binding to a transcription factor, SRCAP. AB - Persistent infections of hepatitis C virus (HCV) are known to be a major risk factor for causing hepatocellular carcinomas. Nonstructural protein 3 (NS3) of HCV has serine protease and RNA helicase domains, and is essential for the viral replication. Further, NS3 is also considered to be involved in the development of HCV-induced hepatocellular carcinomas. In this report, we focus on the function of NS3 protein, and propose a novel possible molecular mechanism which is thought to be related to the tumorigenesis caused by the persistent infection of HCV. We identified SRCAP (Snf2-related CBP activator protein) as a NS3 binding protein using yeast two-hybrid screening, and a co-immunoprecipitation assay demonstrated that NS3 can bind to SRCAP in mammalian cells. The results of a reporter gene assay using Hes-1 promoter which is known to be a target gene activated by Notch, indicate that NS3 and SRCAP cooperatively activate the Hes-1 promoter in Hep3B cells. In addition, we show in this report that also p400, which is known as a protein closely resembling SRCAP, would be targeted by NS3. NS3 exhibited binding activity also to the 1449-1808 region of p400 by a co-immunoprecipitation assay, and further the activation of the Notch-mediated transcription of Hes-1 promoter by NS3 decreased significantly by the combined silencing of SRCAP and p400 mRNA using short hairpin RNA. These results suggest that the HCV NS3 protein is involved in the activation of the Notch-signaling pathway through the targeting to both SRCAP and p400. PMID- 21673955 TI - Resveratrol increases glucose induced GLP-1 secretion in mice: a mechanism which contributes to the glycemic control. AB - Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo. PMID- 21673956 TI - Derivation of high purity neuronal progenitors from human embryonic stem cells. AB - The availability of human neuronal progenitors (hNPs) in high purity would greatly facilitate neuronal drug discovery and developmental studies, as well as cell replacement strategies for neurodegenerative diseases and conditions, such as spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Here we describe for the first time a method for producing hNPs in large quantity and high purity from human embryonic stem cells (hESCs) in feeder-free conditions, without the use of exogenous noggin, sonic hedgehog or analogs, rendering the process clinically compliant. The resulting population displays characteristic neuronal-specific markers. When allowed to spontaneously differentiate into neuronal subtypes in vitro, cholinergic, serotonergic, dopaminergic and/or noradrenergic, and medium spiny striatal neurons were observed. When transplanted into the injured spinal cord the hNPs survived, integrated into host tissue, and matured into a variety of neuronal subtypes. Our method of deriving neuronal progenitors from hESCs renders the process amenable to therapeutic and commercial use. PMID- 21673957 TI - Investigation of association between PFO complicated by cryptogenic stroke and a common variant of the cardiac transcription factor GATA4. AB - Patent foramen ovale (PFO) is associated with clinical conditions including cryptogenic stroke, migraine and varicose veins. Data from studies in humans and mouse suggest that PFO and the secundum form of atrial septal defect (ASDII) exist in an anatomical continuum of septal dysmorphogenesis with a common genetic basis. Mutations in multiple members of the evolutionarily conserved cardiac transcription factor network, including GATA4, cause or predispose to ASDII and PFO. Here, we assessed whether the most prevalent variant of the GATA4 gene, S377G, was significantly associated with PFO or ASD. Our analysis of world indigenous populations showed that GATA4 S377G was largely Caucasian-specific, and so subjects were restricted to those of Caucasian descent. To select for patients with larger PFO, we limited our analysis to those with cryptogenic stroke in which PFO was a subsequent finding. In an initial study of Australian subjects, we observed a weak association between GATA4 S377G and PFO/Stroke relative to Caucasian controls in whom ASD and PFO had been excluded (OR = 2.16; p = 0.02). However, in a follow up study of German Caucasians no association was found with either PFO or ASD. Analysis of combined Australian and German data confirmed the lack of a significant association. Thus, the common GATA4 variant S377G is likely to be relatively benign in terms of its participation in CHD and PFO/Stroke. PMID- 21673958 TI - Hippocampal gene expression analysis highlights Ly6a/Sca-1 as candidate gene for previously mapped novelty induced behaviors in mice. AB - In this study, we show that the covariance between behavior and gene expression in the brain can help further unravel the determinants of neurobehavioral traits. Previously, a QTL for novelty induced motor activity levels was identified on murine chromosome 15 using consomic strains. With the goal of narrowing down the linked region and possibly identifying the gene underlying the quantitative trait, gene expression data from this F(2)-population was collected and used for expression QTL analysis. While genetic variation in these mice was limited to chromosome 15, eQTL analysis of gene expression showed strong cis-effects as well as trans-effects elsewhere in the genome. Using weighted gene co-expression network analysis, we were able to identify modules of co-expressed genes related to novelty induced motor activity levels. In eQTL analyses, the expression of Ly6a (a.k.a. Sca-1) was found to be cis-regulated by chromosome 15. Ly6a also surfaced in a group of genes resulting from the network analysis that was correlated with behavior. Behavioral analysis of Ly6a knock-out mice revealed reduced novelty induced motor activity levels when compared to wild type controls, confirming functional importance of Ly6a in this behavior, possibly through regulating other genes in a pathway. This study shows that gene expression profiling can be used to narrow down a previously identified behavioral QTL in mice, providing support for Ly6a as a candidate gene for functional involvement in novelty responsiveness. PMID- 21673959 TI - Simplification and shift in cognition of political difference: applying the geometric modeling to the analysis of semantic similarity judgment. AB - Perceiving differences by means of spatial analogies is intrinsic to human cognition. Multi-dimensional scaling (MDS) analysis based on Minkowski geometry has been used primarily on data on sensory similarity judgments, leaving judgments on abstractive differences unanalyzed. Indeed, analysts have failed to find appropriate experimental or real-life data in this regard. Our MDS analysis used survey data on political scientists' judgments of the similarities and differences between political positions expressed in terms of distance. Both distance smoothing and majorization techniques were applied to a three-way dataset of similarity judgments provided by at least seven experts on at least five parties' positions on at least seven policies (i.e., originally yielding 245 dimensions) to substantially reduce the risk of local minima. The analysis found two dimensions, which were sufficient for mapping differences, and fit the city block dimensions better than the Euclidean metric in all datasets obtained from 13 countries. Most city-block dimensions were highly correlated with the simplified criterion (i.e., the left-right ideology) for differences that are actually used in real politics. The isometry of the city-block and dominance metrics in two-dimensional space carries further implications. More specifically, individuals may pay attention to two dimensions (if represented in the city-block metric) or focus on a single dimension (if represented in the dominance metric) when judging differences between the same objects. Switching between metrics may be expected to occur during cognitive processing as frequently as the apparent discontinuities and shifts in human attention that may underlie changing judgments in real situations occur. Consequently, the result has extended strong support for the validity of the geometric models to represent an important social cognition, i.e., the one of political differences, which is deeply rooted in human nature. PMID- 21673960 TI - Prolonged depression-like behavior caused by immune challenge: influence of mouse strain and social environment. AB - Immune challenge by bacterial lipopolysaccharide (LPS) causes short-term behavioral changes indicative of depression. The present study sought to explore whether LPS is able to induce long-term changes in depression-related behavior and whether such an effect depends on mouse strain and social context. LPS (0.83 mg/kg) or vehicle was administered intraperitoneally to female CD1 and C57BL/6 mice that were housed singly or in groups of 4. Depression-like behavior was assessed with the forced swim test (FST) 1 and 28 days post-treatment. Group housed CD1 mice exhibited depression-like behavior 1 day post-LPS, an effect that leveled off during the subsequent 28 days, while the behavior of singly housed CD1 mice was little affected. In contrast, singly housed C57BL/6 mice responded to LPS with an increase in depression-like behavior that was maintained for 4 weeks post-treatment and confirmed by the sucrose preference test. Group-housed C57BL/6 mice likewise displayed an increased depression-like behavior 4 weeks post-treatment. The behavioral changes induced by LPS in C57BL/6 mice were associated with a particularly pronounced rise of interleukin-6 in blood plasma within 1 day post-treatment and with changes in the dynamics of the corticosterone response to the FST. The current data demonstrate that immune challenge with LPS is able to induce prolonged depression-like behavior, an effect that depends on genetic background (strain). The discovery of an experimental model of long-term depression-like behavior after acute immune challenge is of relevance to the analysis of the epigenetic and pathophysiologic mechanisms of immune system-related affective disorders. PMID- 21673961 TI - Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium. AB - The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04); the OR was 1.09 (CI: 0.99-1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged <=50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women. PMID- 21673962 TI - Regulation of petrobactin and bacillibactin biosynthesis in Bacillus anthracis under iron and oxygen variation. AB - BACKGROUND: Bacillus anthracis produces two catecholate siderophores, petrobactin and bacillibactin, under iron-limited conditions. Here, we investigate how variable iron and oxygen concentrations influence the biosynthetic output of both siderophores in B. anthracis. In addition, we describe the differential levels of transcription of select genes within the B. anthracis siderophore biosynthetic operons that are responsible for synthesis of petrobactin and bacillibactin, during variable growth conditions. METHODOLOGY/PRINCIPAL FINDINGS: Accumulation of bacillibactin in B. anthracis Sterne (34F(2)) and in a mutant lacking the major superoxide dismutase (DeltasodA1) was almost completely repressed by the addition of 20 uM of iron. In contrast, petrobactin synthesis in both strains continued up to 20 uM of iron. Accumulation of petrobactin and bacillibactin showed a slight increase with addition of low levels of paraquat-induced oxidative stress in wild type B. anthracis Sterne. Cultures grown with high aeration resulted in greater accumulation of petrobactin relative to low aeration cultures, and delayed the repressive effect of added iron. Conversely, iron depleted cultures grown with low aeration resulted in increased levels of bacillibactin. No difference was found in overall superoxide dismutase (SOD) activity or transcriptional levels of the sodA1 and sodA2 genes between iron depleted and iron-replete conditions at high or low aeration, suggesting that SOD regulation and iron metabolism are separate in B. anthracis. The highest transcription of the gene asbB, part of the petrobactin biosynthetic operon, occurred under iron-limitation with high aeration, but transcription was readily detectable even under iron-replete conditions and in low aeration. The gene dhbC, a member of the bacillibactin biosynthetic operon, was only transcribed under conditions of iron-depletion, regardless of growth aeration. CONCLUSION: These data suggest that bacillibactin regulation is highly sensitive to iron concentration. In contrast, although regulation of petrobactin is less dependent on iron, it is likely subject to additional levels of regulation that may contribute to virulence of B. anthracis. PMID- 21673963 TI - HPLC-UV, MALDI-TOF-MS and ESI-MS/MS analysis of the mechlorethamine DNA crosslink at a cytosine-cytosine mismatch pair. AB - BACKGROUND: Mechlorethamine [ClCH(2)CH(2)N(CH(3))CH(2)CH(2)Cl], a nitrogen mustard alkylating agent, has been proven to form a DNA interstrand crosslink at a cytosine-cytosine (C-C) mismatch pair using gel electrophoresis. However, the atomic connectivity of this unusual crosslink is unknown. METHODOLOGY/PRINCIPAL FINDINGS: HPLC-UV, MALDI-TOF-MS, and ESI-MS/MS were used to determine the atomic connectivity of the DNA C-C crosslink formed by mechlorethamine, MALDI-TOF-MS of the HPLC-purified reaction product of mechlorethamine with the DNA duplex d[CTCACACCGTGGTTC]*d[GAACCACCGTGTGAG] (underlined bases are a C-C mismatch pair) indicated formation of an interstrand crosslink at m/z 9222.088 [M-2H+Na](+). Following enzymatic digestion of the crosslinked duplex by snake venom phosphodiesterase and calf intestinal phosphatase, ESI-MS/MS indicated the presence of dC-mech-dC [mech = CH(2)CH(2)N(CH(3))CH(2)CH(2)] at m/z 269.2 [M](2+) (expected m/z 269.6, exact mass 539.27) and its hydrolytic product dC-mech-OH at m/z 329.6 [M](+) (expected m/z 329.2). Fragmentation of dC-mech-dC gave product ions at m/z 294.3 and 236.9 [M](+), which are both due to loss of the 4-amino group of cytosine (as ammonia), in addition to dC and dC+HN(CH(3))CH = CH(2), respectively. The presence of m/z 269.2 [M](2+) and loss of ammonia exclude crosslink formation at cytosine N(4) or O(2) and indicate crosslinking through cytosine N(3) with formation of two quaternary ammonium ions. CONCLUSIONS: Our results provide an important addition to the literature, as the first example of the use of HPLC and MS for analysis of a DNA adduct at the N(3) position of cytosine. PMID- 21673964 TI - Experimental therapy of ovarian cancer with synthetic makaluvamine analog: in vitro and in vivo anticancer activity and molecular mechanisms of action. AB - The present study was designed to determine the biological effects of novel marine alkaloid analog 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2 de]quinolin-8(1H)-one (FBA-TPQ) on human ovarian cancer cells for its anti-tumor potential and the underlying mechanisms as a novel chemotherapeutic agent. Human ovarian cancer cells (A2780 and OVCAR-3), and Immortalized non-tumorigenic human Ovarian Surface Epithelial cells (IOSE-144), were exposed to FBA-TPQ for initial cytotoxicity evaluation (via MTS assay kit, Promega). The detailed in-vitro (cell level) and in-vivo (animal model) studies on the antitumor effects and possible underlying mechanisms of action of the compounds were then performed. FBA-TPQ exerted potent cytotoxicity against human ovarian cancer A2780 and OVCAR-3 cells as an effective inhibitor of cell growth and proliferation, while exerting lesser effects on non-tumorigenic IOSE-144 cells. Further study in the more sensitive OVCAR-3 cell line showed that it could potently induce cell apoptosis (Annexin V FITC assay), G2/M cell cycle arrest (PI staining analysis) and also dose dependently inhibit OVCAR-3 xenograft tumors' growth on female athymic nude mice (BALB/c, nu/nu). Mechanistic studies (both in vitro and in vivo) revealed that FBA-TPQ might exert its activity through Reactive Oxygen Species (ROS)-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in OVCAR-3 cells, which is in accordance with in vitro microarray (Human genome microarrays, Agilent) data analysis (GEO accession number: GSE25317). In conclusion, FBA-TPQ exhibits significant anticancer activity against ovarian cancer cells, with minimal toxicity to non-tumorigenic human IOSE-144 cells, indicating that it may be a potential therapeutic agent for ovarian cancer. PMID- 21673965 TI - Nanoscale footprints of self-running gallium droplets on GaAs surface. AB - In this work, the nanoscale footprints of self-driven liquid gallium droplet movement on a GaAs (001) surface will be presented and analyzed. The nanoscale footprints of a primary droplet trail and ordered secondary droplets along primary droplet trails are observed on the GaAs surface. A well ordered nanoterrace from the trail is left behind by a running droplet. In addition, collision events between two running droplets are investigated. The exposed fresh surface after a collision demonstrates a superior evaporation property. Based on the observation of droplet evolution at different stages as well as nanoscale footprints, a schematic diagram of droplet evolution is outlined in an attempt to understand the phenomenon of stick-slip droplet motion on the GaAs surface. The present study adds another piece of work to obtain the physical picture of a stick-slip self-driven mechanism in nanoscale, bridging nano and micro systems. PMID- 21673966 TI - Mutant versions of the S. cerevisiae transcription elongation factor Spt16 define regions of Spt16 that functionally interact with histone H3. AB - In eukaryotic cells, the highly conserved FACT (FAcilitates Chromatin Transcription) complex plays important roles in several chromatin-based processes including transcription initiation and elongation. During transcription elongation, the FACT complex interacts directly with nucleosomes to facilitate histone removal upon RNA polymerase II (Pol II) passage and assists in the reconstitution of nucleosomes following Pol II passage. Although the contribution of the FACT complex to the process of transcription elongation has been well established, the mechanisms that govern interactions between FACT and chromatin still remain to be fully elucidated. Using the budding yeast Saccharomyces cerevisiae as a model system, we provide evidence that the middle domain of the FACT subunit Spt16--the Spt16-M domain--is involved in functional interactions with histone H3. Our results show that the Spt16-M domain plays a role in the prevention of cryptic intragenic transcription during transcription elongation and also suggest that the Spt16-M domain has a function in regulating dissociation of Spt16 from chromatin at the end of the transcription process. We also provide evidence for a role for the extreme carboxy terminus of Spt16 in functional interactions with histone H3. Taken together, our studies point to previously undescribed roles for the Spt16 M-domain and extreme carboxy terminus in regulating interactions between Spt16 and chromatin during the process of transcription elongation. PMID- 21673967 TI - Yeast Bax inhibitor, Bxi1p, is an ER-localized protein that links the unfolded protein response and programmed cell death in Saccharomyces cerevisiae. AB - Bax inhibitor-1 (BI-1) is an anti-apoptotic gene whose expression is upregulated in a wide range of human cancers. Studies in both mammalian and plant cells suggest that the BI-1 protein resides in the endoplasmic reticulum and is involved in the unfolded protein response (UPR) that is triggered by ER stress. It is thought to act via a mechanism involving altered calcium dynamics. In this paper, we provide evidence that the Saccharomyces cerevisiae protein encoded by the open reading frame, YNL305C, is a bona fide homolog for BI-1. First, we confirm that yeast cells from two different strain backgrounds lacking YNL305C, which we have renamed BXI1, are more sensitive to heat-shock induced cell death than wildtype controls even though they have indistinguishable growth rates at 30 degrees C. They are also more susceptible both to ethanol-induced and to glucose induced programmed cell death. Significantly, we show that Bxi1p-GFP colocalizes with the ER localized protein Sec63p-RFP. We have also discovered that Deltabxi1 cells are not only more sensitive to drugs that induce ER stress, but also have a decreased unfolded protein response as measured with a UPRE-lacZ reporter. Finally, we have discovered that deleting BXI1 diminishes the calcium signaling response in response to the accumulation of unfolded proteins in the ER as measured by a calcineurin-dependent CDRE-lacZ reporter. In toto, our data suggests that the Bxi1p, like its metazoan homologs, is an ER-localized protein that links the unfolded protein response and programmed cell death. PMID- 21673968 TI - 3',4'-Dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat mesenteric arteries. AB - BACKGROUND: 3',4'-Dihydroxyflavonol (DiOHF) is an effective antioxidant that acutely preserves nitric oxide (NO) activity in the presence of elevated reactive oxygen species (ROS). We hypothesized that DiOHF treatment (7 days, 1 mg/kg per day s.c.) would improve relaxation in mesenteric arteries from diabetic rats where endothelial dysfunction is associated with elevated oxidant stress. METHODOLOGY/PRINCIPAL FINDINGS: In mesenteric arteries from diabetic rats there was an increase in ROS, measured by L-012 and 2',7'-dichlorodihydrofluorescein diacetate fluorescence. NADPH oxidase-derived superoxide levels, assayed by lucigenin chemiluminescence, were also significantly increased in diabetic mesenteric arteries (diabetes, 4892+/-946 counts/mg versus normal 2486+/-344 counts/mg, n = 7-10, p<0.01) associated with an increase in Nox2 expression but DiOHF (2094+/-300 counts/mg, n = 10, p<0.001) reversed that effect. Acetylcholine (ACh)-induced relaxation of mesenteric arteries was assessed using wire myography (pEC(50) = 7.94+/-0.13 n = 12). Diabetes significantly reduced the sensitivity to ACh and treatment with DiOHF prevented endothelial dysfunction (pEC(50), diabetic 6.86+/-0.12 versus diabetic+DiOHF, 7.49+/-0.13, n = 11, p<0.01). The contribution of NO versus endothelium-derived hyperpolarizing factor (EDHF) to ACh-induced relaxation was assessed by evaluating responses in the presence of TRAM 34+apamin+iberiotoxin or N-nitro-L-arginine+ODQ respectively. Diabetes impaired the contribution of both NO (maximum relaxation, R(max) diabetic 24+/-7 versus normal, 68+/-10, n = 9-10, p<0.01) and EDHF (pEC(50), diabetic 6.63+/-0.15 versus normal, 7.14+/-0.12, n = 10-11, p<0.01) to endothelium-dependent relaxation. DiOHF treatment did not significantly affect the EDHF contribution but enhanced NO-mediated relaxation (R(max) 69+/-6, n = 11, p<0.01). Western blotting demonstrated that diabetes also decreased expression and increased uncoupling of endothelial NO synthase (eNOS). Treatment of the diabetic rats with DiOHF significantly reduced vascular ROS and restored NO-mediated endothelium-dependent relaxation. Treatment of the diabetic rats with DiOHF also increased eNOS expression, both in total and as a dimer. CONCLUSIONS/SIGNIFICANCE: DiOHF improves NO activity in diabetes by reducing Nox2-dependent superoxide production and preventing eNOS uncoupling to improve endothelial function. PMID- 21673969 TI - Rule-guided executive control of response inhibition: functional topography of the inferior frontal cortex. AB - BACKGROUND: The human inferior frontal cortex (IFC) is a large heterogeneous structure with distinct cytoarchitectonic subdivisions and fiber connections. It has been found involved in a wide range of executive control processes from target detection, rule retrieval to response control. Since these processes are often being studied separately, the functional organization of executive control processes within the IFC remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: We conducted an fMRI study to examine the activities of the subdivisions of IFC during the presentation of a task cue (rule retrieval) and during the performance of a stop-signal task (requiring response generation and inhibition) in comparison to a not-stop task (requiring response generation but not inhibition). We utilized a mixed event-related and block design to separate brain activity in correspondence to transient control processes from rule-related and sustained control processes. We found differentiation in control processes within the IFC. Our findings reveal that the bilateral ventral-posterior IFC/anterior insula are more active on both successful and unsuccessful stop trials relative to not-stop trials, suggesting their potential role in the early stage of stopping such as triggering the stop process. Direct countermanding seems to be outside of the IFC. In contrast, the dorsal-posterior IFC/inferior frontal junction (IFJ) showed transient activity in correspondence to the infrequent presentation of the stop signal in both tasks and the left anterior IFC showed differential activity in response to the task cues. The IFC subdivisions also exhibited similar but distinct patterns of functional connectivity during response control. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that executive control processes are distributed across the IFC and that the different subdivisions of IFC may support different control operations through parallel cortico-cortical and cortico-striatal circuits. PMID- 21673970 TI - RyRCa2+ leak limits cardiac Ca2+ window current overcoming the tonic effect of calmodulinin mice. AB - Ca(2+) mediates the functional coupling between L-type Ca(2+) channel (LTCC) and sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR), participating in key pathophysiological processes. This crosstalk manifests as the orthograde Ca(2+)-induced Ca(2+)-release (CICR) mechanism triggered by Ca(2+) influx, but also as the retrograde Ca(2+)-dependent inactivation (CDI) of LTCC, which depends on both Ca(2+) permeating through the LTCC itself and on SR Ca(2+) release through the RyR. This latter effect has been suggested to rely on local rather than global Ca(2+) signaling, which might parallel the nanodomain control of CDI carried out through calmodulin (CaM). Analyzing the CICR in catecholaminergic polymorphic ventricular tachycardia (CPVT) mice as a model of RyR-generated Ca(2+) leak, we evidence here that increased occurrence of the discrete local SR Ca(2+) releases through the RyRs (Ca(2+) sparks) cause a depolarizing shift in activation and a hyperpolarizing shift in isochronic inactivation of cardiac LTCC current resulting in the reduction of window current. Both increasing fast [Ca(2+)](i) buffer capacity or depleting SR Ca(2+) store blunted these changes, which could be reproduced in WT cells by RyRCa(2+) leak induced with Ryanodol and CaM inhibition.Our results unveiled a new paradigm for CaM-dependent effect on LTCC gating and further the nanodomain Ca(2+) control of LTCC, emphasizing the importance of spatio-temporal relationships between Ca(2+) signals and CaM function. PMID- 21673971 TI - Intracellular targeting specificity of novel phthalocyanines assessed in a host parasite model for developing potential photodynamic medicine. AB - Photodynamic therapy, unlikely to elicit drug-resistance, deserves attention as a strategy to counter this outstanding problem common to the chemotherapy of all diseases. Previously, we have broadened the applicability of this modality to photodynamic vaccination by exploiting the unusual properties of the trypanosomatid protozoa, Leishmania, i.e., their innate ability of homing to the phagolysosomes of the antigen-presenting cells and their selective photolysis therein, using transgenic mutants endogenously inducible for porphyrin accumulation. Here, we extended the utility of this host-parasite model for in vitro photodynamic therapy and vaccination by exploring exogenously supplied photosensitizers. Seventeen novel phthalocyanines (Pcs) were screened in vitro for their photolytic activity against cultured Leishmania. Pcs rendered cationic and soluble (csPcs) for cellular uptake were phototoxic to both parasite and host cells, i.e., macrophages and dendritic cells. The csPcs that targeted to mitochondria were more photolytic than those restricted to the endocytic compartments. Treatment of infected cells with endocytic csPcs resulted in their accumulation in Leishmania-containing phagolysosomes, indicative of reaching their target for photodynamic therapy, although their parasite versus host specificity is limited to a narrow range of csPc concentrations. In contrast, Leishmania pre-loaded with csPc were selectively photolyzed intracellularly, leaving host cells viable. Pre-illumination of such csPc-loaded Leishmania did not hinder their infectivity, but ensured their intracellular lysis. Ovalbumin (OVA) so delivered by photo-inactivated OVA transfectants to mouse macrophages and dendritic cells were co-presented with MHC Class I molecules by these antigen presenting cells to activate OVA epitope-specific CD8+T cells. The in vitro evidence presented here demonstrates for the first time not only the potential of endocytic csPcs for effective photodynamic therapy against Leishmania but also their utility in photo-inactivation of Leishmania to produce a safe carrier to express and deliver a defined antigen with enhanced cell-mediated immunity. PMID- 21673972 TI - Nitric oxide-induced activation of the AMP-activated protein kinase alpha2 subunit attenuates IkappaB kinase activity and inflammatory responses in endothelial cells. AB - BACKGROUND: In endothelial cells, activation of the AMP-activated protein kinase (AMPK) has been linked with anti-inflammatory actions but the events downstream of kinase activation are not well understood. Here, we addressed the effects of AMPK activation/deletion on the activation of NFkappaB and determined whether the AMPK could contribute to the anti-inflammatory actions of nitric oxide (NO). METHODOLOGY/PRINCIPAL FINDINGS: Overexpression of a dominant negative AMPKalpha2 mutant in tumor necrosis factor-alpha-stimulated human endothelial cells resulted in increased NFkappaB activity, E-selectin expression and monocyte adhesion. In endothelial cells from AMPKalpha2(-/-) mice the interleukin (IL)-1beta induced expression of E-selectin was significantly increased. DETA-NO activated the AMPK and attenuated NFkappaB activation/E-selectin expression, effects not observed in human endothelial cells in the presence of the dominant negative AMPK, or in endothelial cells from AMPKalpha2(-/-) mice. Mechanistically, overexpression of constitutively active AMPK decreased the phosphorylation of IkappaB and p65, indicating a link between AMPK and the IkappaB kinase (IKK). Indeed, IKK (more specifically residues Ser177 and Ser181) was found to be a direct substrate of AMPKalpha2 in vitro. The hyper-phosphorylation of the IKK, which is known to result in its inhibition, was also apparent in endothelial cells from AMPKalpha2(+/+) versus AMPKalpha2(-/-) mice. CONCLUSIONS: These results demonstrate that the IKK is a direct substrate of AMPKalpha2 and that its phosphorylation on Ser177 and Ser181 results in the inhibition of the kinase and decreased NFkappaB activation. Moreover, as NO potently activates AMPK in endothelial cells, a portion of the anti-inflammatory effects of NO are mediated by AMPK. PMID- 21673974 TI - Prefrontal Brain Activation During Emotional Processing: A Functional Near Infrared Spectroscopy Study (fNIRS). AB - The limbic system and especially the amygdala have been identified as key structures in emotion induction and regulation. Recently research has additionally focused on the influence of prefrontal areas on emotion processing in the limbic system and the amygdala. Results from fMRI studies indicate that the prefrontal cortex (PFC) is involved not only in emotion induction but also in emotion regulation. However, studies using fNIRS only report prefrontal brain activation during emotion induction. So far it lacks the attempt to compare emotion induction and emotion regulation with regard to prefrontal activation measured with fNIRS, to exclude the possibility that the reported prefrontal brain activation in fNIRS studies are mainly caused by automatic emotion regulation processes. Therefore this work tried to distinguish emotion induction from regulation via fNIRS of the prefrontal cortex. 20 healthy women viewed neutral pictures as a baseline condition, fearful pictures as induction condition and reappraised fearful pictures as regulation condition in randomized order. As predicted, the view-fearful condition led to higher arousal ratings than the view neutral condition with the reappraise-fearful condition in between. For the fNIRS results the induction condition showed an activation of the bilateral PFC compared to the baseline condition (viewing neutral). The regulation condition showed an activation only of the left PFC compared to the baseline condition, although the direct comparison between induction and regulation condition revealed no significant difference in brain activation. Therefore our study underscores the results of previous fNIRS studies showing prefrontal brain activation during emotion induction and rejects the hypothesis that this prefrontal brain activation might only be a result of automatic emotion regulation processes. PMID- 21673976 TI - Infective Endocarditis: Identification of Catalase-Negative, Gram-Positive Cocci from Blood Cultures by Partial 16S rRNA Gene Analysis and by Vitek 2 Examination. AB - Streptococci, enterococci and Streptococcus-like bacteria are frequent etiologic agents of infective endocarditis and correct species identification can be a laboratory challenge. Viridans streptococci (VS) not seldomly cause contamination of blood cultures. Vitek 2 and partial sequencing of the 16S rRNA gene were applied in order to compare the results of both methods. STRAINS ORIGINATED FROM TWO GROUPS OF PATIENTS: 149 strains from patients with infective endocarditis and 181 strains assessed as blood culture contaminants. Of the 330 strains, based on partial 16S rRNA gene sequencing results, 251 (76%) were VS strains, 10 (3%) were pyogenic streptococcal strains, 54 (16%) were E. faecalis strains and 15 (5%) strains belonged to a group of miscellaneous catalase-negative, Gram-positive cocci. Among VS strains, respectively, 220 (87,6%) and 31 (12,3%) obtained agreeing and non-agreeing identifications with the two methods with respect to allocation to the same VS group. Non-agreeing species identification mostly occurred among strains in the contaminant group, while for endocarditis strains notably fewer disagreeing results were observed.Only 67 of 150 strains in the mitis group strains obtained identical species identifications by the two methods. Most VS strains belonging to the groups of salivarius, anginosus, and mutans obtained agreeing species identifications with the two methods, while this only was the case for 13 of the 21 bovis strains. Pyogenic strains (n=10), Enterococcus faecalis strains (n=54) and a miscellaneous group of catalase negative, Gram-positive cocci (n=15) seemed well identified by both methods, except that disagreements in identifications in the miscellaneous group of strains occurred for 6 of 15 strains. PMID- 21673977 TI - Acridine and acridinones: old and new structures with antimalarial activity. AB - Since emergence of chloroquine-resistant Plasmodium falciparum and reports of parasite resistance to alternative drugs, there has been renewed interest in the antimalarial activity of acridines and their congeners, the acridinones. This article presents literature compilation of natural acridinone alkaloids and synthetic 9-substituted acridines, acridinediones, haloalcoxyacridinones and 10-N substituted acridinones with antimalarial activity. The review also provides an outlook to antimalarial modes of action of some described compounds. PMID- 21673973 TI - Characterization of a Drosophila Alzheimer's disease model: pharmacological rescue of cognitive defects. AB - Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Abeta(40) and Abeta(42), the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a gamma-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions. PMID- 21673978 TI - Single-Breathhold Four-Dimensional Assessment of Left Ventricular Morphological and Functional Parameters by Magnetic Resonance Imaging Using the VAST Technique. AB - INTRODUCTION: The accurate and reproducible assessment of cardiac volumes, function, and mass is of paramount importance in cardiology. In the present study we sought to determine whether the 3D cine-magnetic resonance (MR) technique, using the variable asymmetric sampling in time (VAST) approach, provided an accurate assessment of LV functional parameters when compared with the conventional 2D cine-MR technique. METHODS: A total of 43 consecutive patients referred for a CMR examination for clinical reasons and 14 healthy volunteers were included in the study. Cine images were acquired using a steady-state free precession pulse sequence. Two different multiphase acquisitions were performed: conventional 2D cine-MR and 3D cine-MR. The short-axis cine images acquired by both cine-MR techniques were used for the quantitative assessment of LV end diastolic, end-systolic and stroke volumes, LV mass and ejection fraction. RESULTS: All CMR examinations were completed successfully, with both cine-MR imaging techniques yielding interpretable diagnostic results in all patients. Regarding the quantitative assessment, Bland-Altman analyses demonstrated a good agreement between the measurements of both cine-MR techniques for all LV parameters. In addition, the agreement between 2D and 3D cine-MR techniques for the qualitative assessment of LV global function was perfect (kappa = 1.0, P<0.001) for the two observers in consensus. The assessment performed by the third independent observer also demonstrated very good agreement (kappa = 0.88, P<0.001). CONCLUSION: The single breathhold 3D cine-MR technique provides an accurate and reproducible quantitative assessment of LV volumes, mass and function when compared with the conventional 2D cine-MR method. PMID- 21673979 TI - Antero-posterior EEG spectral power gradient as a correlate of extraversion and behavioral inhibition. AB - Several studies have shown that individual-specific patterns of cortical spectral power distribution are relatively stable across time and experimental conditions. The antero-posterior EEG spectral power gradient (APSPG) emerged as the most prominent feature associated with important personality characteristics. In this study this phenomenon is further investigated in relation to its stability and association with different personality traits. It has been shown that APSPG is generally more pronounced during resting baseline than during inter-trial interval and post-stimulus period. Its association with personality variables is similar for different frequency bands and is mostly preserved during different experimental conditions. Relatively higher oscillatory activity in frontal than in posterior cortical sites is more frequently observed in subjects with higher behavioral inhibition (BIS) and lower Sociability. Source localization analysis showed that both high BIS/low Sociability and high APSPG are associated with higher oscillatory activity in medial cortices associated with emotion processing (mostly the cingulate gyrus). This association could be tentatively explained by higher vigilance and emotional tension in introverted and behaviorally inhibited subjects. PMID- 21673980 TI - A non-dimensional analysis of hemodialysis. AB - BACKGROUND: Non-dimensional analysis is a powerful approach that can be applied to multivariate problems to better understand their behaviour and interpret complex interactions of variables. It is has not been rigorously applied to the parameters that define renal dialysis treatments and may provide insight into the planning of hemodialysis treatments. METHODS: Buckingham's non-dimensional approach was applied to the parameters that define hemodialysis treatments. Non dimensional groups were derived with knowledge of a mass transfer model and independent of it. Using a mass transfer model, the derived non-dimensional groups were plotted to develop an understanding of key relationships governing hemodialysis and toxin profiles in patients with end-stage renal disease. RESULTS: Three non-dimensional groups are sufficient to describe hemodialysis, if there is no residual renal function (RRF). The non-dimensional groups found represent (1) the number of half-lives that characterize the mass transfer, (2) the toxin concentration divided by the rise in toxin concentration without dialysis for the cycle time (the inverse of the dialysis frequency), and (3) the ratio of dialysis time to the cycle time. If there is RRF, one additional non dimensional group is needed (the ratio between cycle time and intradialytic elimination rate constant). Alternate non-dimensional groups can be derived from the four unique groups. CONCLUSIONS: Physical interpretation of the non dimensional groups allows for greater insight into the parameters that determine dialysis effectiveness. This technique can be applied to any toxin and facilitates a greater understanding of dialysis treatment options. Quantitative measures of dialysis adequacy should be based on dimensional variables. PMID- 21673981 TI - Anthroposophic therapy for migraine: a two-year prospective cohort study in routine outpatient settings. AB - BACKGROUND AND METHODS: Anthroposophic treatment for migraine is provided by physicians and includes special artistic and physical therapies and special medications. We conducted a prospective cohort study of 45 consecutive adult outpatients (89% women) starting anthroposophic treatment for migraine under routine conditions. Main outcomes were Average Migraine Severity (physician and patient ratings 0-10, primary outcome), Symptom Score (patient rating, 0-10), and quality of life (SF-36); main follow-up time point was after six months. RESULTS: The anthroposophic treatment modalities used were medications (67% of patients), eurythmy therapy (38%), art therapy (18%), and rhythmical massage therapy (13%). Median therapy duration was 105 days. In months 0-6, conventional prophylactic antimigraine medications were used by 14% (n=5/36) of evaluable patients. From baseline to six-month follow-up, physician-rated Average Migraine Severity improved by 3.14 points (95% confidence interval 2.40-3.87, p<0.001); patient rated Average Migraine Severity improved by 2.82 points (2.05-3.64, p<0.001); and Symptom Score improved by 2.32 points (1.68-2.95, p<0.001). In addition, three SF 36 scales (Social Functioning, Bodily Pain, Vitality), the SF-36 Physical Component summary measure, and the SF-36 Health Change item improved significantly. All improvements were maintained at last follow-up after 24 months. Patients not using conventional prophylactic antimigraine medications had improvements similar to the whole cohort. CONCLUSIONS: Patients with migraine under anthroposophic treatment had long-term improvement of symptoms and quality of life. Although the pre-post design of the present study does not allow for conclusions about comparative effectiveness, study findings suggest that anthroposophic therapies may be useful in the long-term care of patients with migraine. PMID- 21673982 TI - Conservation and diversity of seed associated endophytes in Zea across boundaries of evolution, ethnography and ecology. AB - Endophytes are non-pathogenic microbes living inside plants. We asked whether endophytic species were conserved in the agriculturally important plant genus Zea as it became domesticated from its wild ancestors (teosinte) to modern maize (corn) and moved from Mexico to Canada. Kernels from populations of four different teosintes and 10 different maize varieties were screened for endophytic bacteria by culturing, cloning and DNA fingerprinting using terminal restriction fragment length polymorphism (TRFLP) of 16S rDNA. Principle component analysis of TRFLP data showed that seed endophyte community composition varied in relation to plant host phylogeny. However, there was a core microbiota of endophytes that was conserved in Zea seeds across boundaries of evolution, ethnography and ecology. The majority of seed endophytes in the wild ancestor persist today in domesticated maize, though ancient selection against the hard fruitcase surrounding seeds may have altered the abundance of endophytes. Four TRFLP signals including two predicted to represent Clostridium and Paenibacillus species were conserved across all Zea genotypes, while culturing showed that Enterobacter, Methylobacteria, Pantoea and Pseudomonas species were widespread, with gamma-proteobacteria being the prevalent class. Twenty-six different genera were cultured, and these were evaluated for their ability to stimulate plant growth, grow on nitrogen-free media, solubilize phosphate, sequester iron, secrete RNAse, antagonize pathogens, catabolize the precursor of ethylene, produce auxin and acetoin/butanediol. Of these traits, phosphate solubilization and production of acetoin/butanediol were the most commonly observed. An isolate from the giant Mexican landrace Mixteco, with 100% identity to Burkholderia phytofirmans, significantly promoted shoot potato biomass. GFP tagging and maize stem injection confirmed that several seed endophytes could spread systemically through the plant. One seed isolate, Enterobacter asburiae, was able to exit the root and colonize the rhizosphere. Conservation and diversity in Zea-microbe relationships are discussed in the context of ecology, crop domestication, selection and migration. PMID- 21673983 TI - Systematic neighborhood observations at high spatial resolution: methodology and assessment of potential benefits. AB - There is a growing body of public health research documenting how characteristics of neighborhoods are associated with differences in the health status of residents. However, little is known about how the spatial resolution of neighborhood observational data or community audits affects the identification of neighborhood differences in health. We developed a systematic neighborhood observation instrument for collecting data at very high spatial resolution (we observe each parcel independently) and used it to collect data in a low-income minority neighborhood in Dallas, TX. In addition, we collected data on the health status of individuals residing in this neighborhood. We then assessed the inter rater reliability of the instrument and compared the costs and benefits of using data at this high spatial resolution. Our instrument provides a reliable and cost effect method for collecting neighborhood observational data at high spatial resolution, which then allows researchers to explore the impact of varying geographic aggregations. Furthermore, these data facilitate a demonstration of the predictive accuracy of self-reported health status. We find that ordered logit models of health status using observational data at different spatial resolution produce different results. This implies a need to analyze the variation in correlative relationships at different geographic resolutions when there is no solid theoretical rational for choosing a particular resolution. We argue that neighborhood data at high spatial resolution greatly facilitates the evaluation of alternative geographic specifications in studies of neighborhood and health. PMID- 21673984 TI - The requirement for pre-TCR during thymic differentiation enforces a developmental pause that is essential for V-DJbeta rearrangement. AB - T cell development occurs in the thymus and is critically dependent on productive TCRbeta rearrangement and pre-TCR expression in DN3 cells. The requirement for pre-TCR expression results in the arrest of thymocytes at the DN3 stage (beta checkpoint), which is uniquely permissive for V-DJbeta recombination; only cells expressing pre-TCR survive and develop beyond the DN3 stage. In addition, the requirement for TCRbeta rearrangement and pre-TCR expression enforces suppression of TCRbeta rearrangement on a second allele, allelic exclusion, thus ensuring that each T cell expresses only a single TCRbeta product. However, it is not known whether pre-TCR expression is essential for allelic exclusion or alternatively if allelic exclusion is enforced by developmental changes that can occur in the absence of pre-TCR. We asked if thymocytes that were differentiated without pre-TCR expression, and therefore without pause at the beta checkpoint, would suppress all V-DJbeta rearrangement. We previously reported that premature CD28 signaling in murine CD4(-)CD8(-) (DN) thymocytes supports differentiation of CD4(+)CD8(+) (DP) cells in the absence of pre-TCR expression. The present study uses this model to define requirements for TCRbeta rearrangement and allelic exclusion. We demonstrate that if cells exit the DN3 developmental stage before TCRbeta rearrangement occurs, V-DJbeta rearrangement never occurs, even in DP cells that are permissive for D-Jbeta and TCRalpha rearrangement. These results demonstrate that pre-TCR expression is not essential for thymic differentiation to DP cells or for V-DJbeta suppression. However, the requirement for pre-TCR signals and the exclusion of alternative stimuli such as CD28 enforce a developmental "pause" in early DN3 cells that is essential for productive TCRbeta rearrangement to occur. PMID- 21673985 TI - Mycobacterium tuberculosis complex mycobacteria as amoeba-resistant organisms. AB - BACKGROUND: Most environmental non-tuberculous mycobacteria have been demonstrated to invade amoebal trophozoites and cysts, but such relationships are largely unknown for members of the Mycobacterium tuberculosis complex. An environmental source has been proposed for the animal Mycobacterium bovis and the human Mycobacterium canettii. METHODOLOGY/PRINCIPAL FINDINGS: Using optic and electron microscopy and co-culture methods, we observed that 89+/-0.6% of M. canettii, 12.4+/-0.3% of M. tuberculosis, 11.7+/-2% of M. bovis and 11.2+/-0.5% of Mycobacterium avium control organisms were phagocytized by Acanthamoeba polyphaga, a ratio significantly higher for M. canettii (P = 0.03), correlating with the significantly larger size of M. canetti organisms (P = 0.035). The percentage of intraamoebal mycobacteria surviving into cytoplasmic vacuoles was 32+/-2% for M. canettii, 26+/-1% for M. tuberculosis, 28+/-2% for M. bovis and 36+/-2% for M. avium (P = 0.57). M. tuberculosis, M. bovis and M. avium mycobacteria were further entrapped within the double wall of <1% amoebal cysts, but no M. canettii organisms were observed in amoebal cysts. The number of intracystic mycobacteria was significantly (P = 10(-6)) higher for M. avium than for the M. tuberculosis complex, and sub-culturing intracystic mycobacteria yielded significantly more (P = 0.02) M. avium organisms (34*10(4) CFU/mL) than M. tuberculosis (42*10(1) CFU/mL) and M. bovis (35*10(1) CFU/mL) in the presence of a washing fluid free of mycobacteria. Mycobacteria survived in the cysts for up to 18 days and cysts protected M. tuberculosis organisms against mycobactericidal 5 mg/mL streptomycin and 2.5% glutaraldehyde. CONCLUSIONS/SIGNIFICANCE: These data indicate that M. tuberculosis complex organisms are amoeba-resistant organisms, as previously demonstrated for non tuberculous, environmental mycobacteria. Intercystic survival of tuberculous mycobacteria, except for M. canettii, protect them against biocides and could play a role in their life cycle. PMID- 21673987 TI - The acceptability of Internet-based treatment and characteristics of an adult sample with obsessive compulsive disorder: an Internet survey. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a disabling anxiety disorder, but most individuals delay seeking treatment. Internet-based cognitive behavioural therapy (iCBT) is an innovative service delivery method that may help to improve access to care, but the acceptability to consumers of such programs has not yet been established. METHODOLOGY: People with symptoms of OCD were invited to complete an online survey enquiring about demographic characteristics, symptom severity, and acceptability of Internet-based treatment. Demographic and symptom severity data were compared with people with OCD identified in a national epidemiological survey and with a sample of patients with OCD from a specialist outpatient anxiety clinic. PARTICIPANTS: 129 volunteers to an online Internet survey, 135 patients at a specialist anxiety disorders outpatient clinic, and 297 cases identified in a national epidemiological survey. MAIN MEASURES: Demographic characteristics, and severity of symptoms as measured by the Kessler 10-Item scale, the 12-item World Health Organisation Disability Assessment Schedule Second Edition and the Yale Brown Obsessive Compulsive Scale-Self Report Version. PRINCIPAL FINDINGS: The Internet sample was similar demographically but reported more severe symptoms than the comparison groups, although had similar severity of symptoms of OCD compared with other clinical samples reported in the literature. Participants reported Internet-based treatment for OCD would be highly acceptable. CONCLUSIONS: Internet-based treatment may reduce barriers to accessing treatment to people with OCD. Individuals in this study were similar demographically to other samples and had similar severity of symptoms as those identified in other clinical samples, suggesting that Internet-based treatment using techniques employed in face-to-face treatment may be effective in this group. Internet-based treatments for OCD need to be developed and evaluated. PMID- 21673986 TI - Activated K-ras and INK4a/Arf deficiency cooperate during the development of pancreatic cancer by activation of Notch and NF-kappaB signaling pathways. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, suggesting that novel strategies for the prevention and treatment of PDAC are urgently needed. K-ras mutations are observed in >90% of pancreatic cancer, suggesting its role in the initiation and early developmental stages of PDAC. In order to gain mechanistic insight as to the role of mutated K-ras, several mouse models have been developed by targeting a conditionally mutated K-ras(G12D) for recapitulating PDAC. A significant co operativity has been shown in tumor development and metastasis in a compound mouse model with activated K-ras and Ink4a/Arf deficiency. However, the molecular mechanism(s) by which K-ras and Ink4a/Arf deficiency contribute to PDAC has not been fully elucidated. METHODOLOGY/PRINCIPAL FINDINGS: To assess the molecular mechanism(s) that are involved in the development of PDAC in the compound transgenic mice with activated K-ras and Ink4a/Arf deficiency, we used multiple methods, such as Real-time RT-PCR, western blotting assay, immunohistochemistry, MTT assay, invasion, EMSA and ELISA. We found that the deletion of Ink4a/Arf in K ras(G12D) expressing mice leads to PDAC, which is in part mediated through the activation of Notch and NF-kappaB signaling pathways. Moreover, we found down regulation of miR-200 family, which could also play important roles in tumor development and progression of PDAC in the compound transgenic mice. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the activation of Notch and NF kappaB together with the loss of miR-200 family is mechanistically linked with the development and progression of PDAC in the compound K-ras(G12D) and Ink4a/Arf deficient transgenic mice. PMID- 21673988 TI - Increasing the analytical sensitivity by oligonucleotides modified with para- and ortho-twisted intercalating nucleic acids--TINA. AB - The sensitivity and specificity of clinical diagnostic assays using DNA hybridization techniques are limited by the dissociation of double-stranded DNA (dsDNA) antiparallel duplex helices. This situation can be improved by addition of DNA stabilizing molecules such as nucleic acid intercalators. Here, we report the synthesis of a novel ortho-Twisted Intercalating Nucleic Acid (TINA) amidite utilizing the phosphoramidite approach, and examine the stabilizing effect of ortho- and para-TINA molecules in antiparallel DNA duplex formation. In a thermal stability assay, ortho- and para-TINA molecules increased the melting point (Tm) of Watson-Crick based antiparallel DNA duplexes. The increase in Tm was greatest when the intercalators were placed at the 5' and 3' termini (preferable) or, if placed internally, for each half or whole helix turn. Terminally positioned TINA molecules improved analytical sensitivity in a DNA hybridization capture assay targeting the Escherichia coli rrs gene. The corresponding sequence from the Pseudomonas aeruginosa rrs gene was used as cross-reactivity control. At 150 mM ionic strength, analytical sensitivity was improved 27-fold by addition of ortho TINA molecules and 7-fold by addition of para-TINA molecules (versus the unmodified DNA oligonucleotide), with a 4-fold increase retained at 1 M ionic strength. Both intercalators sustained the discrimination of mismatches in the dsDNA (indicated by DeltaTm), unless placed directly adjacent to the mismatch--in which case they partly concealed DeltaTm (most pronounced for para-TINA molecules). We anticipate that the presented rules for placement of TINA molecules will be broadly applicable in hybridization capture assays and target amplification systems. PMID- 21673989 TI - Regional regulation of transcription in the bovine genome. AB - Eukaryotic genes are distributed along chromosomes as clusters of highly expressed genes termed RIDGEs (Regions of IncreaseD Gene Expression) and lowly expressed genes termed anti-RIDGEs, interspersed among genes expressed at intermediate levels or not expressed. Previous studies based on this observation suggested a dual mechanism of gene regulation, where, in addition to transcription factors, the chromosomal domain influences the expression level of their embedded genes. The objectives here were to provide evidence for the existence of chromosomal regional regulation of transcription in the bovine genome, to analyse the genomic features of genes located within RIDGEs versus anti-RIDGEs and tissue-specific genes versus housekeeping and to examine the genomic distribution of genes subject to positive selection in bovines. Gene expression analysis of four brain tissues and the anterior pituitary of 28 cows identified 70 RIDGEs and 41 anti-RIDGEs (harbouring 3735 and 1793 bovine genes respectively) across the bovine genome which are significantly higher than expected by chance. Housekeeping genes (defined here as genes expressed in all five tissues) were over-represented within RIDGEs but tissue-specific genes (genes expressed in only one of the five tissues) were not. Housekeeping genes and genes within RIDGEs had, in general, higher expression levels and GC content but shorter gene lengths and intron lengths than tissue-specific genes and genes within anti-RIDGES. Our findings suggest the existence of chromosomal regional regulation of transcription in the bovine genome. The genomic features observed for genes within RIDGEs and housekeeping genes in bovines agree with previous studies in several other species further strengthening the hypothesis of selective pressure to keep the highly and widely expressed genes short and compact for transcriptional efficiency. Further, positively selected genes were found non-randomly distributed on the genome with a preference for RIDGEs and regions of intermediate gene expression compared to anti-RIDGEs. PMID- 21673990 TI - Monitoring of gene expression in bacteria during infections using an adaptable set of bioluminescent, fluorescent and colorigenic fusion vectors. AB - A family of versatile promoter-probe plasmids for gene expression analysis was developed based on a modular expression plasmid system (pZ). The vectors contain different replicons with exchangeable antibiotic cassettes to allow compatibility and expression analysis on a low-, midi- and high-copy number basis. Suicide vector variants also permit chromosomal integration of the reporter fusion and stable vector derivatives can be used for in vivo or in situ expression studies under non-selective conditions. Transcriptional and translational fusions to the reporter genes gfp(mut3.1), amCyan, dsRed2, luxCDABE, phoA or lacZ can be constructed, and presence of identical multiple cloning sites in the vector system facilitates the interchange of promoters or reporter genes between the plasmids of the series. The promoter of the constitutively expressed gapA gene of Escherichia coli was included to obtain fluorescent and bioluminescent expression constructs. A combination of the plasmids allows simultaneous detection and gene expression analysis in individual bacteria, e.g. in bacterial communities or during mouse infections. To test our vector system, we analyzed and quantified expression of Yersinia pseudotuberculosis virulence genes under laboratory conditions, in association with cells and during the infection process. PMID- 21673991 TI - Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy. AB - BACKGROUND: Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs) that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB) reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. AIMS: To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB), a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated. METHODS: The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR) and release of the CAP-18 peptide/protein in stool (Western blot). PRINCIPAL FINDINGS: Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon. CONCLUSION: Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from secondary respiratory infections that frequently are the lethal causes in dysentery. PMID- 21673992 TI - Species richness and trophic diversity increase decomposition in a co-evolved food web. AB - Ecological communities show great variation in species richness, composition and food web structure across similar and diverse ecosystems. Knowledge of how this biodiversity relates to ecosystem functioning is important for understanding the maintenance of diversity and the potential effects of species losses and gains on ecosystems. While research often focuses on how variation in species richness influences ecosystem processes, assessing species richness in a food web context can provide further insight into the relationship between diversity and ecosystem functioning and elucidate potential mechanisms underpinning this relationship. Here, we assessed how species richness and trophic diversity affect decomposition rates in a complete aquatic food web: the five trophic level web that occurs within water-filled leaves of the northern pitcher plant, Sarracenia purpurea. We identified a trophic cascade in which top-predators--larvae of the pitcher-plant mosquito--indirectly increased bacterial decomposition by preying on bactivorous protozoa. Our data also revealed a facultative relationship in which larvae of the pitcher-plant midge increased bacterial decomposition by shredding detritus. These important interactions occur only in food webs with high trophic diversity, which in turn only occur in food webs with high species richness. We show that species richness and trophic diversity underlie strong linkages between food web structure and dynamics that influence ecosystem functioning. The importance of trophic diversity and species interactions in determining how biodiversity relates to ecosystem functioning suggests that simply focusing on species richness does not give a complete picture as to how ecosystems may change with the loss or gain of species. PMID- 21673993 TI - Evaluation of cell cycle arrest in estrogen responsive MCF-7 breast cancer cells: pitfalls of the MTS assay. AB - Endocrine resistance is a major problem with anti-estrogen treatments and how to overcome resistance is a major concern in the clinic. Reliable measurement of cell viability, proliferation, growth inhibition and death is important in screening for drug treatment efficacy in vitro. This report describes and compares commonly used proliferation assays for induced estrogen-responsive MCF-7 breast cancer cell cycle arrest including: determination of cell number by direct counting of viable cells; or fluorescence SYBR(r)Green (SYBR) DNA labeling; determination of mitochondrial metabolic activity by 3-(4,5-dimethylthiazol-2-yl) 5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay; assessment of newly synthesized DNA using 5-ethynyl-2'-deoxyuridine (EdU) nucleoside analog binding and Alexa Fluor(r) azide visualization by fluorescence microscopy; cell-cycle phase measurement by flow cytometry. Treatment of MCF-7 cells with ICI 182780 (Faslodex), FTY720, serum deprivation or induction of the tumor suppressor p14ARF showed inhibition of cell proliferation determined by the Trypan Blue exclusion assay and SYBR DNA labeling assay. In contrast, the effects of treatment with ICI 182780 or p14ARF-induction were not confirmed using the MTS assay. Cell cycle inhibition by ICI 182780 and p14ARF-induction was further confirmed by flow cytometric analysis and EdU-DNA incorporation. To explore this discrepancy further, we showed that ICI 182780 and p14ARF-induction increased MCF 7 cell mitochondrial activity by MTS assay in individual cells compared to control cells thereby providing a misleading proliferation readout. Interrogation of p14ARF-induction on MCF-7 metabolic activity using TMRE assays and high content image analysis showed that increased mitochondrial activity was concomitant with increased mitochondrial biomass with no loss of mitochondrial membrane potential, or cell death. We conclude that, whilst p14ARF and ICI 182780 stop cell cycle progression, the cells are still viable and potential treatments utilizing these pathways may contribute to drug resistant cells. These experiments demonstrate how the combined measurement of metabolic activity and DNA labeling provides a more reliable interpretation of cancer cell response to treatment regimens. PMID- 21673994 TI - Catechin suppresses an array of signalling molecules and modulates alcohol induced endotoxin mediated liver injury in a rat model. AB - Induction of nuclear factor kappa B (NF-kappaB)-mediated gene expression has been implicated in the pathogenesis of alcoholic liver disease through enhanced production of reactive oxygen species and pro-inflammatory mediators. The present study was carried out to investigate the role of catechin as a chain breaking inhibitor against experimental alcoholic liver injury. Rats were administered 35% v/v ethanol orally at a dose of 10 g/Kg/day for two weeks, followed by 14 g/Kg/day for 10 weeks. Catechin (50 mg/Kg) was co-supplemented after 4 weeks of alcohol treatment till the end of the dosing period. Following chronic alcohol exposure, rats developed endotoxemia and severe pathological changes in the liver such as pronounced fatty change, vacuolar degeneration and inflammation. These changes were accompanied by activation of NF-kappaB and induction of inflammatory and cytotoxic mediators leading to increased level of tumor necrosis factor alpha, enhanced formation of malondialdehyde in the liver followed by drastic alterations in the hepatic antioxidant defense systems. Additionally, nitrite levels and lactate dehydrogenase activities were also significantly elevated on chronic alcohol consumption. Alcohol exposure also increased the number of micronucleated cells indicating that alcohol abuse may again be associated with the nuclear changes. Supplementation with catechin ameliorated the alcohol induced liver injury by downregulating the endotoxin-mediated activation of initial signalling molecule NF-kappaB and further going downstream the signalling cascade including tumor necrosis factor-alpha, nitric oxide and reactive oxygen species and by enhancing the antioxidant profile. These observations correlated well with the histological findings. Moreover, a remarkable decrease in the percentage of micronucleated cells was observed with catechin supplementation indicating an apparent protection against alcohol-induced toxicity. These findings suggest that catechin may alleviate experimental alcoholic liver disease by suppressing induction of NF-kappaB, a key component of signalling pathway, thus forming a pharmacological basis for designing novel therapeutic agents against alcohol induced endotoxin-mediated liver injury. PMID- 21673995 TI - The role of calcineurin/NFAT in SFRP2 induced angiogenesis--a rationale for breast cancer treatment with the calcineurin inhibitor tacrolimus. AB - Tacrolimus (FK506) is an immunosuppressive drug that binds to the immunophilin FKBPB12. The FK506-FKBP12 complex associates with calcineurin and inhibits its phosphatase activity, resulting in inhibition of nuclear translocation of nuclear factor of activated T-cells (NFAT). There is increasing data supporting a critical role of NFAT in mediating angiogenic responses stimulated by both vascular endothelial growth factor (VEGF) and a novel angiogenesis factor, secreted frizzled-related protein 2 (SFRP2). Since both VEGF and SFRP2 are expressed in breast carcinomas, we hypothesized that tacrolimus would inhibit breast carcinoma growth. Using IHC (IHC) with antibodies to FKBP12 on breast carcinomas we found that FKBP12 localizes to breast tumor vasculature. Treatment of MMTV-neu transgenic mice with tacrolimus (3 mg/kg i.p. daily) (n = 19) resulted in a 73% reduction in the growth rate for tacrolimus treated mice compared to control (n = 15), p = 0.003; which was associated with an 82% reduction in tumor microvascular density (p<0.001) by IHC. Tacrolimus (1 uM) inhibited SFRP2 induced endothelial tube formation by 71% (p = 0.005) and inhibited VEGF induced endothelial tube formation by 67% (p = 0.004). To show that NFATc3 is required for SFRP2 stimulated angiogenesis, NFATc3 was silenced with shRNA in endothelial cells. Sham transfected cells responded to SFRP2 stimulation in a tube formation assay with an increase in the number of branch points (p<0.003), however, cells transfected with shRNA to NFATc3 showed no increase in tube formation in response to SFRP2. This demonstrates that NFATc3 is required for SFRP2 induced tube formation, and tacrolimus inhibits angiogenesis in vitro and breast carcinoma growth in vivo. This provides a rationale for examining the therapeutic potential of tacrolimus at inhibiting breast carcinoma growth in humans. PMID- 21673996 TI - Changes in global gene expression in response to chemical and genetic perturbation of chromatin structure. AB - DNA methylation is important for controlling gene expression in all eukaryotes. Microarray analysis of mutant and chemically-treated Arabidopsis thaliana seedlings with reduced DNA methylation revealed an altered gene expression profile after treatment with the DNA methylation inhibitor 5-aza-2' deoxycytidine (5-AC), which included the upregulation of expression of many transposable elements. DNA damage-response genes were also coordinately upregulated by 5-AC treatment. In the ddm1 mutant, more specific changes in gene expression were observed, in particular for genes predicted to encode transposable elements in centromeric and pericentromeric locations. These results confirm that DDM1 has a very specific role in maintaining transcriptional silence of transposable elements, while chemical inhibitors of DNA methylation can affect gene expression at a global level. PMID- 21673998 TI - Extracellular matrix peptides of Artemia cyst shell participate in protecting encysted embryos from extreme environments. AB - BACKGROUND: Many species of the brine shrimp Artemia are found in various severe environments in many parts of the world where extreme salinity, high UV radiation levels, high pH, anoxia, large temperature fluctuations, and intermittent dry conditions are often recorded. To withstand adverse environments, Artemia undergoes an oviparous developmental pathway to release cysts whereas, under favorable conditions, swimming nauplius larvae are formed directly via an ovoviviparous pathway. In the former case these cysts have an extraordinary ability to keep the embryos protected from the harsh environment for long periods. This is achieved through the protection by a complex out-wrapping cyst shell. However, the formation and function of the cyst shell is complex; the details remain largely unclear. PRINCIPAL FINDING: A shell gland-specific gene (SGEG2) was cloned and identified from a suppression subtractive hybridization library. Western blot analysis showed that SGEG2 presumably requires post translational proteolysis in order to be processed into two mature peptides (SGEG2a and 2b). The three matrix peptides (SGEG1 reported previously, 2a, and 2b) were found to distribute throughout the cyst shell. The results of gene knockdown by RNAi and subsequent resistance to environmental stresses assays indicated that these matrix peptides are required for cyst shell formation and are involved in protecting the encysted embryos from environmental stress. CONCLUSIONS/SIGNIFICANCE: This study revealed that extracellular matrix peptides participate in protecting embryos from extreme salinity, UV radiation, large temperature fluctuations and dry environments, thereby facilitating their survival. The cyst shell provides an excellent opportunity to link the ecological setting of an organism to the underlying physiological and biochemical processes enabling its survival. The cyst shell material has also a high potential to become an excellent new biomaterial with a high number of prospective uses due, specifically, to such biological characteristics. PMID- 21673997 TI - Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses. AB - Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p<0.005 in the first two collections and p<10(-4) by meta-analysis were further genotyped in the latter two collections. A novel risk variant, rs2000811, in intron2 of the myelin basic protein (MBP) at chromosome 18q23 showed strong association with RA (p = 2.7*10(-8), OR 1.23, 95% CI: 1.14 1.32). The transcription of MBP was significantly elevated with the risk allele compared to the alternative allele (p<0.001). We also established by immunohistochemistry that MBP was expressed in the synovial lining layer of RA patients, the main target of inflammation in the disease. Circulating autoantibody against MBP derived from human brain was quantified by ELISA between patients with RA, other connective tissue diseases and healthy controls. As a result, the titer of anti-MBP antibody was markedly higher in plasma of RA patients compared to healthy controls (p<0.001) and patients with other connective tissue disorders (p<0.001). ELISA experiment using citrullinated recombinant MBP revealed that a large fraction of anti-MBP antibody in RA patients recognized citrullinated MBP. This is the first report of a genetic study in RA implicating MBP as a potential autoantigen and its involvement in pathogenesis of the disease. PMID- 21673999 TI - Population genetic analysis of Plasmodium falciparum parasites using a customized Illumina GoldenGate genotyping assay. AB - The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum. PMID- 21674000 TI - Immunological and cardiometabolic risk factors in the prediction of type 2 diabetes and coronary events: MONICA/KORA Augsburg case-cohort study. AB - BACKGROUND: This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population based MONICA/KORA Augsburg cohort. METHODS AND FINDINGS: Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC), changes in Akaike's information criterion (DeltaAIC), integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF beta1, sE-selectin, sICAM-1; all measured in nonfasting serum) increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes) increased the AUC to 0.803 (DeltaAUC [95% CI] 0.111 [0.092 0.149] and 0.113 [0.093-0.149], respectively, compared to the basic model). The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (DeltaAUC [95% CI] 0.044 [0.028-0.066] compared to the cardiometabolic risk model). Corresponding AUCs for incident coronary events were 0.807, 0.825 (DeltaAUC [95% CI] 0.018 [0.013-0.038] compared to the basic model), 0.845 (DeltaAUC [95% CI] 0.038 [0.028-0.059] compared to the basic model) and 0.851 (DeltaAUC [95% CI] 0.006 [0.003-0.021] compared to the cardiometabolic risk model), respectively. CONCLUSIONS: Inclusion of multiple inflammation-related biomarkers into a basic model and into a model including cardiometabolic risk factors significantly improved the prediction of type 2 diabetes and coronary events, although the improvement was less pronounced for the latter endpoint. PMID- 21674001 TI - Retinoic acid-treated pluripotent stem cells undergoing neurogenesis present increased aneuploidy and micronuclei formation. AB - The existence of loss and gain of chromosomes, known as aneuploidy, has been previously described within the central nervous system. During development, at least one-third of neural progenitor cells (NPCs) are aneuploid. Notably, aneuploid NPCs may survive and functionally integrate into the mature neural circuitry. Given the unanswered significance of this phenomenon, we tested the hypothesis that neural differentiation induced by all-trans retinoic acid (RA) in pluripotent stem cells is accompanied by increased levels of aneuploidy, as previously described for cortical NPCs in vivo. In this work we used embryonal carcinoma (EC) cells, embryonic stem (ES) cells and induced pluripotent stem (iPS) cells undergoing differentiation into NPCs. Ploidy analysis revealed a 2 fold increase in the rate of aneuploidy, with the prevalence of chromosome loss in RA primed stem cells when compared to naive cells. In an attempt to understand the basis of neurogenic aneuploidy, micronuclei formation and survivin expression was assessed in pluripotent stem cells exposed to RA. RA increased micronuclei occurrence by almost 2-fold while decreased survivin expression by 50%, indicating possible mechanisms by which stem cells lose their chromosomes during neural differentiation. DNA fragmentation analysis demonstrated no increase in apoptosis on embryoid bodies treated with RA, indicating that cell death is not the mandatory fate of aneuploid NPCs derived from pluripotent cells. In order to exclude that the increase in aneuploidy was a spurious consequence of RA treatment, not related to neurogenesis, mouse embryonic fibroblasts were treated with RA under the same conditions and no alterations in chromosome gain or loss were observed. These findings indicate a correlation amongst neural differentiation, aneuploidy, micronuclei formation and survivin downregulation in pluripotent stem cells exposed to RA, providing evidence that somatically generated chromosomal variation accompanies neurogenesis in vitro. PMID- 21674002 TI - Glucokinase regulatory protein genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome. AB - Glucokinase Regulatory Protein (GCKR) plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been of considerable interest, due to their potential to reduce metabolic syndrome (MetS) risk. OBJECTIVE: To examine whether genetic variability at the GCKR gene locus was associated with the degree of insulin resistance, plasma concentrations of C-reactive protein (CRP) and n-3 PUFA in MetS subjects. DESIGN: Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA-B, plasma concentrations of C-peptide, CRP, fatty acid composition and the GCKR rs1260326 P446L polymorphism, were determined in a cross-sectional analysis of 379 subjects with MetS participating in the LIPGENE dietary cohort. RESULTS: Among subjects with n-3 PUFA levels below the population median, carriers of the common C/C genotype had higher plasma concentrations of fasting insulin (P = 0.019), C peptide (P = 0.004), HOMA-IR (P = 0.008) and CRP (P = 0.032) as compared with subjects carrying the minor T-allele (Leu446). In contrast, homozygous C/C carriers with n-3 PUFA levels above the median showed lower plasma concentrations of fasting insulin, peptide C, HOMA-IR and CRP, as compared with individuals with the T-allele. CONCLUSIONS: We have demonstrated a significant interaction between the GCKR rs1260326-P446L polymorphism and plasma n-3 PUFA levels modulating insulin resistance and inflammatory markers in MetS subjects. Further studies are needed to confirm this gene-diet interaction in the general population and whether targeted dietary recommendations can prevent MetS in genetically susceptible individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT00429195. PMID- 21674003 TI - Genetic polymorphisms of a novel vascular susceptibility gene, Ninjurin2 (NINJ2), are associated with a decreased risk of Alzheimer's disease. AB - BACKGROUND: Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously. METHODS: A total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n = 423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association. RESULTS: Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR) = 0.43; 95% confidence interval (CI)= 0.23-0.80; rs12425791: AOR= 0.33, 95% CI= 0.12-0.96]. Five common haplotypes (cumulative frequency= 97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p = 0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR= 0.32, 95% CI= 0.11-0.94). No associations were observed for VaD. CONCLUSION: Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk. PMID- 21674004 TI - Assessing the utility of thermodynamic features for microRNA target prediction under relaxed seed and no conservation requirements. AB - BACKGROUND: Many computational microRNA target prediction tools are focused on several key features, including complementarity to 5'seed of miRNAs and evolutionary conservation. While these features allow for successful target identification, not all miRNA target sites are conserved and adhere to canonical seed complementarity. Several studies have propagated the use of energy features of mRNA:miRNA duplexes as an alternative feature. However, different independent evaluations reported conflicting results on the reliability of energy-based predictions. Here, we reassess the usefulness of energy features for mammalian target prediction, aiming to relax or eliminate the need for perfect seed matches and conservation requirement. METHODOLOGY/PRINCIPAL FINDINGS: We detect significant differences of energy features at experimentally supported human miRNA target sites and at genome-wide sites of AGO protein interaction. This trend is confirmed on datasets that assay the effect of miRNAs on mRNA and protein expression changes, and a simple linear regression model leads to significant correlation of predicted versus observed expression change. Compared to 6-mer seed matches as baseline, application of our energy-based model leads to ~3-5-fold enrichment on highly down-regulated targets, and allows for prediction of strictly imperfect targets with enrichment above baseline. CONCLUSIONS/SIGNIFICANCE: In conclusion, our results indicate significant promise for energy-based miRNA target prediction that includes a broader range of targets without having to use conservation or impose stringent seed match rules. PMID- 21674006 TI - Genome-wide association study of schizophrenia in Japanese population. AB - Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology. PMID- 21674005 TI - Broad surveys of DNA viral diversity obtained through viral metagenomics of mosquitoes. AB - Viruses are the most abundant and diverse genetic entities on Earth; however, broad surveys of viral diversity are hindered by the lack of a universal assay for viruses and the inability to sample a sufficient number of individual hosts. This study utilized vector-enabled metagenomics (VEM) to provide a snapshot of the diversity of DNA viruses present in three mosquito samples from San Diego, California. The majority of the sequences were novel, suggesting that the viral community in mosquitoes, as well as the animal and plant hosts they feed on, is highly diverse and largely uncharacterized. Each mosquito sample contained a distinct viral community. The mosquito viromes contained sequences related to a broad range of animal, plant, insect and bacterial viruses. Animal viruses identified included anelloviruses, circoviruses, herpesviruses, poxviruses, and papillomaviruses, which mosquitoes may have obtained from vertebrate hosts during blood feeding. Notably, sequences related to human papillomaviruses were identified in one of the mosquito samples. Sequences similar to plant viruses were identified in all mosquito viromes, which were potentially acquired through feeding on plant nectar. Numerous bacteriophages and insect viruses were also detected, including a novel densovirus likely infecting Culex erythrothorax. Through sampling insect vectors, VEM enables broad survey of viral diversity and has significantly increased our knowledge of the DNA viruses present in mosquitoes. PMID- 21674007 TI - SNPs occur in regions with less genomic sequence conservation. AB - Rates of SNPs (single nucleotide polymorphisms) and cross-species genomic sequence conservation reflect intra- and inter-species variation, respectively. Here, I report SNP rates and genomic sequence conservation adjacent to mRNA processing regions and show that, as expected, more SNPs occur in less conserved regions and that functional regions have fewer SNPs. Results are confirmed using both mouse and human data. Regions include protein start codons, 3' splice sites, 5' splice sites, protein stop codons, predicted miRNA binding sites, and polyadenylation sites. Throughout, SNP rates are lower and conservation is higher at regulatory sites. Within coding regions, SNP rates are highest and conservation is lowest at codon position three and the fewest SNPs are found at codon position two, reflecting codon degeneracy for amino acid encoding. Exon splice sites show high conservation and very low SNP rates, reflecting both splicing signals and protein coding. Relaxed constraint on the codon third position is dramatically seen when separating exonic SNP rates based on intron phase. At polyadenylation sites, a peak of conservation and low SNP rate occurs from 30 to 17 nt preceding the site. This region is highly enriched for the sequence AAUAAA, reflecting the location of the conserved polyA signal. miRNA 3' UTR target sites are predicted incorporating interspecies genomic sequence conservation; SNP rates are low in these sites, again showing fewer SNPs in conserved regions. Together, these results confirm that SNPs, reflecting recent genetic variation, occur more frequently in regions with less evolutionarily conservation. PMID- 21674008 TI - Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. AB - BACKGROUND: The evidence that red and processed meat influences colorectal carcinogenesis was judged convincing in the 2007 World Cancer Research Fund/American Institute of Cancer Research report. Since then, ten prospective studies have published new results. Here we update the evidence from prospective studies and explore whether there is a non-linear association of red and processed meats with colorectal cancer risk. METHODS AND FINDINGS: Relevant prospective studies were identified in PubMed until March 2011. For each study, relative risks and 95% confidence intervals (CI) were extracted and pooled with a random-effects model, weighting for the inverse of the variance, in highest versus lowest intake comparison, and dose-response meta-analyses. Red and processed meats intake was associated with increased colorectal cancer risk. The summary relative risk (RR) of colorectal cancer for the highest versus the lowest intake was 1.22 (95% CI = 1.11-1.34) and the RR for every 100 g/day increase was 1.14 (95% CI = 1.04-1.24). Non-linear dose-response meta-analyses revealed that colorectal cancer risk increases approximately linearly with increasing intake of red and processed meats up to approximately 140 g/day, where the curve approaches its plateau. The associations were similar for colon and rectal cancer risk. When analyzed separately, colorectal cancer risk was related to intake of fresh red meat (RR(for 100 g/day increase) = 1.17, 95% CI = 1.05-1.31) and processed meat (RR (for 50 g/day increase) = 1.18, 95% CI = 1.10-1.28). Similar results were observed for colon cancer, but for rectal cancer, no significant associations were observed. CONCLUSIONS: High intake of red and processed meat is associated with significant increased risk of colorectal, colon and rectal cancers. The overall evidence of prospective studies supports limiting red and processed meat consumption as one of the dietary recommendations for the prevention of colorectal cancer. PMID- 21674009 TI - From in vivo to in vitro: dynamic analysis of Plasmodium falciparum var gene expression patterns of patient isolates during adaptation to culture. AB - Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var gene family, plays a crucial role in disease virulence through its involvement in binding to various host cellular receptors during infection. Growing evidence suggests that differential expression of the various var subgroups may be involved in parasite virulence. To further explore this issue, we have collected isolates from symptomatic patients in south China-Myanmar border, and characterized their sequence diversity and transcription profiles over time of var gene family, and cytoadherence properties from the time of their initial collection and extending through a two month period of adaptation to culture. Initially, we established a highly diverse, DBLalpha (4 cysteines) subtype enriched, but unique local repertoire of var-DBL1alpha sequences by cDNA cloning and sequencing. Next we observed a rapid transcriptional decline of upsA- and upsB-subtype var genes at ring stage through qRT-PCR assays, and a switching event from initial ICAM-I binding to the CD36-binding activity during the first week of adaptive cultivation in vitro. Moreover, predominant transcription of upsA var genes was observed to be correlated with those isolates that showed a higher parasitemia at the time of collection and the ICAM-1-binding phenotype in culture. Taken together, these data indicate that the initial stage of adaptive process in vitro significantly influences the transcription of virulence-related var subtypes and expression of PfEMP1 variants. Further, the specific upregulation of the upsA var genes is likely linked to the rapid propagation of the parasite during natural infection due to the A-type PfEMP1 variant-mediated growth advantages. PMID- 21674010 TI - Levels and patterns of nucleotide variation in domestication QTL regions on rice chromosome 3 suggest lineage-specific selection. AB - Oryza sativa or Asian cultivated rice is one of the major cereal grass species domesticated for human food use during the Neolithic. Domestication of this species from the wild grass Oryza rufipogon was accompanied by changes in several traits, including seed shattering, percent seed set, tillering, grain weight, and flowering time. Quantitative trait locus (QTL) mapping has identified three genomic regions in chromosome 3 that appear to be associated with these traits. We would like to study whether these regions show signatures of selection and whether the same genetic basis underlies the domestication of different rice varieties. Fragments of 88 genes spanning these three genomic regions were sequenced from multiple accessions of two major varietal groups in O. sativa- indica and tropical japonica--as well as the ancestral wild rice species O. rufipogon. In tropical japonica, the levels of nucleotide variation in these three QTL regions are significantly lower compared to genome-wide levels, and coalescent simulations based on a complex demographic model of rice domestication indicate that these patterns are consistent with selection. In contrast, there is no significant reduction in nucleotide diversity in the homologous regions in indica rice. These results suggest that there are differences in the genetic and selective basis for domestication between these two Asian rice varietal groups. PMID- 21674013 TI - Green synthesis and characterization of gelatin-based and sugar-reduced silver nanoparticles. AB - Silver nanoparticles (Ag-NPs) have been successfully prepared with simple and "green" synthesis method by reducing Ag(+) ions in aqueous gelatin media with and in the absence of glucose as a reducing agent. In this study, gelatin was used for the first time as a reducing and stabilizing agent. The effect of temperature on particle size of Ag-NPs was also studied. It was found that with increasing temperature the size of nanoparticles is decreased. It was found that the particle size of Ag-NPs obtained in gelatin solutions is smaller than in gelatin glucose solutions, which can be related to the rate of reduction reaction. X-ray diffraction, ultraviolet-visible spectra, transmission electron microscopy, and atomic force microscopy revealed the formation of monodispersed Ag-NPs with a narrow particle size distribution. PMID- 21674011 TI - Fecal microbiota in premature infants prior to necrotizing enterocolitis. AB - Intestinal luminal microbiota likely contribute to the etiology of necrotizing enterocolitis (NEC), a common disease in preterm infants. Microbiota development, a cascade of initial colonization events leading to the establishment of a diverse commensal microbiota, can now be studied in preterm infants using powerful molecular tools. Starting with the first stool and continuing until discharge, weekly stool specimens were collected prospectively from infants with gestational ages <=32 completed weeks or birth weights<=1250 g. High throughput 16S rRNA sequencing was used to compare the diversity of microbiota and the prevalence of specific bacterial signatures in nine NEC infants and in nine matched controls. After removal of short and low quality reads we retained a total of 110,021 sequences. Microbiota composition differed in the matched samples collected 1 week but not <72 hours prior to NEC diagnosis. We detected a bloom (34% increase) of Proteobacteria and a decrease (32%) in Firmicutes in NEC cases between the 1 week and <72 hour samples. No significant change was identified in the controls. At both time points, molecular signatures were identified that were increased in NEC cases. One of the bacterial signatures detected more frequently in NEC cases (p<0.01) matched closest to gamma Proteobacteria. Although this sequence grouped to the well-studied Enterobacteriaceae family, it did not match any sequence in Genbank by more than 97%. Our observations suggest that abnormal patterns of microbiota and potentially a novel pathogen contribute to the etiology of NEC. PMID- 21674014 TI - Molecular buffer using a PANDA ring resonator for drug delivery use. AB - A novel design of molecular buffer for molecule storage and delivery using a PANDA ring resonator is proposed. The optical vortices can be generated and controlled to form the trapping tools in the same way as the optical tweezers. In theory, the trapping force is formed by the combination between the gradient field and scattering photons, which is reviewed. By using the intense optical vortices generated within the PANDA ring resonator, the required molecules can be trapped and moved (transported) dynamically within the wavelength router or network, ie, a molecular buffer. This can be performed within the wavelength router before reaching the required destination. The advantage of the proposed system is that a transmitter and receiver can be formed within the same system, which is available for molecule storage and transportation. PMID- 21674015 TI - Synthesis of silver nanoparticles in montmorillonite and their antibacterial behavior. AB - Silver nanoparticles (Ag NPs) were synthesized by the chemical reducing method in the external and interlamellar space of montmorillonite (MMT) as a solid support at room temperature. AgNO(3) and NaBH(4) were used as a silver precursor and reducing agent, respectively. The most favorable experimental conditions for synthesizing Ag NPs in the MMT are described in terms of the initial concentration of AgNO(3). The interlamellar space limits changed little (d spacing = 1.24-1.47 nm); therefore, Ag NPs formed on the MMT suspension with d average = 4.19-8.53 nm diameter. The Ag/MMT nanocomposites (NCs), formed from AgNO(3)/MMT suspension, were characterizations with different instruments, for example UV-visible, PXRD, TEM, SEM, EDXRF, FT-IR, and ICP-OES analyzer. The antibacterial activity of different sizes of Ag NPs in MMT were investigated against Gram-positive, ie, Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) and Gram-negative bacteria, ie, Escherichia coli, Escherichia coli O157:H7, and Klebsiella pneumoniae, by the disk diffusion method using Mueller Hinton agar (MHA). The smaller Ag NPs were found to have significantly higher antibacterial activity. These results showed that Ag NPs can be used as effective growth inhibitors in different biological systems, making them applicable to medical applications. PMID- 21674017 TI - The changes of T lymphocytes and cytokines in ICR mice fed with Fe3O4 magnetic nanoparticles. AB - The aim of this article is to study the changes inhibited T lymphocytes and cytokines related to the cellular immunity in ICR (imprinting control region) mice fed with Fe(3)O(4) magnetic nanoparticles (Fe(3)O(4)-MNPs). The Fe(3)O(4) MNPs were synthesized, and their characteristics such as particle size, zeta potential, and X-ray diffraction patterns were measured and determined. All ICR mice were sacrificed after being exposed to 0, 300, 600, and 1200 mg/kg of Fe(3)O(4)-MNPs by single gastric administration for 14 days. Splenocytes proliferation was indicated with stimulate index by MTT assay; release of cytokines in the serum of ICR mice was detected by enzyme-linked immunosorbent assay, and the phenotypic analyses of T-lymphocyte subsets were performed using flow cytometry. Our results indicated that there were no significant differences in splenocyte proliferation and release of cytokines between exposed and control groups. Furthermore, there was no significant difference in the proportions of T lymphocyte subsets in the low-dose Fe(3)O(4)-MNPs group when compared to the control group, but the proportions of CD3(+)CD4(+) and CD3(+)CD8(+) T-lymphocyte subsets both in the medium- and high-dose Fe(3)O(4)-MNPs groups were higher than those in the control group. It is concluded that a high dose of Fe(3)O(4)-MNPs, to some extent, could influence in vivo immune function of normal ICR mice. PMID- 21674016 TI - Application of hyperthermia induced by superparamagnetic iron oxide nanoparticles in glioma treatment. AB - Gliomas are a group of heterogeneous primary central nervous system (CNS) tumors arising from the glial cells. Malignant gliomas account for a majority of malignant primary CNS tumors and are associated with high morbidity and mortality. Glioblastoma is the most frequent and malignant glioma, and despite the recent advances in diagnosis and new treatment options, its prognosis remains dismal. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetic hyperthermia (MHT), which consists of heat generation in the region of the tumor through the application of magnetic nanoparticles subjected to an alternating magnetic field (AMF), has shown positive results in both preclinical and clinical assays. The aim of this review is to assess the relevance of hyperthermia induced by magnetic nanoparticles in the treatment of gliomas and to note the possible variations of the technique and its implication on the effectiveness of the treatment. We performed an electronic search in the literature from January 1990 to October 2010, in various databases, and after application of the inclusion criteria we obtained a total of 15 articles. In vitro studies and studies using animal models showed that MHT was effective in the promotion of tumor cell death and reduction of tumor mass or increase in survival. Two clinical studies showed that MHT could be applied safely and with few side effects. Some studies suggested that mechanisms of cell death, such as apoptosis, necrosis, and antitumor immune response were triggered by MHT. Based on these data, we could conclude that MHT proved to be efficient in most of the experiments, and that the improvement of the nanocomposites as well as the AMF equipment might contribute toward establishing MHT as a promising tool in the treatment of malignant gliomas. PMID- 21674018 TI - Novel formulation and evaluation of a Q10-loaded solid lipid nanoparticle cream: in vitro and in vivo studies. AB - Solid lipid nanoparticles (SLNs) of coenzyme Q10 (CoQ10) were formulated by a high-pressure homogenization method. The best formulation of SLN dispersion consisted of 13% lipid (cetyl palmitate or stearic acid), 8% surfactant (Tween 80 or Tego Care 450), and water. Stability tests, particle size analysis, differential scanning calorimetry, transmission electron microscopy, and release study were conducted to find the best formulation. A simple cream of CoQ10 and a cream containing CoQ10-loaded SLNs were prepared and compared on volunteers aged 20-30 years. SLNs with particle size between 50 nm and100 nm exhibited the most suitable stability. In vitro release profiles of CoQ10 from simple cream, SLN alone, and CoQ10-loaded SLN cream showed prolonged release for SLNs compared with the simple cream, whereas there was no significant difference between SLN alone and SLN in cream. In vitro release studies also demonstrated that CoQ10-loaded SLN and SLN cream possessed a biphasic release pattern in comparison with simple cream. In vivo skin hydration and elasticity studies on 25 volunteers suggested good dermal penetration and useful activity of Q10 on skin as a hydratant and antiwrinkle cream. PMID- 21674019 TI - Formulation and evaluation of Bacillus coagulans-loaded hypromellose mucoadhesive microspheres. AB - Development of a novel delivery system has been attempted to deliver viable probiotic cells into the gut for a prolonged period of time while maintaining high numbers of viable cells within the formulation throughout the shelf-life of the product and during the gastrointestinal transit. Core mucoadhesive microspheres of Bacillus coagulans were developed employing several grades of hypromellose, a mucoadhesive polymer, following coacervation and phase separation technique and were subsequently enteric-coated with hypromellose phthalate. Microspheres were evaluated for percent yield; entrapment efficiency; in vitro swelling; surface morphology; particle size, size distribution, and zeta potential; flow property, mucoadhesion property by the ex vivo mucoadhesive strength test and the in vitro wash off test; in vitro release profile and release kinetic; in vivo probiotic activity; and stability. The values for the kinetic constant and regression coefficient of model-dependent approaches and the difference factor (f(1)), the similarity factor (f(2)), and the Rescigno index (xi(1) and xi(2)) of model independent approaches were determined for comparing in vitro dissolution profiles. Freeze dried B. coagulans cells were successfully formulated as enteric-coated mucoadhesive microspheres with satisfactory physical structure and yield. The viability of B. coagulans was maintained in the simulated gastric conditions and during processing; in simulated intestinal conditions exhibiting mucoadhesion, and controlling and extending the viable cell release following zero-order; and was satisfactorily stable at room temperature. Test results depict statistically significant effects of the hypromellose grade and their concentration on the performance and release profile of formulations. PMID- 21674020 TI - The preparation of 3,5-dihydroxy-4-isopropylstilbene nanoemulsion and in vitro release. AB - We have reported a novel procedure to prepare 3,5-dihydroxy-4-isopropylstilbene (DHPS) nanoemulsion, using a low-energy emulsification method. Based on the phase diagram, the optimum prescription of nanoemulsion preparation was screened. With polyoxyethylenated castor oil (EL-40) as the surfactant, ethanol as the co surfactant, and isopropyl myristate (IPM) as the oil phase, the DHPS nanoemulsion was obtained with a transparent appearance, little viscosity, and spherically uniform distribution verified by transmission electron microscopy and laser scattering analyzer. The nanoemulsion was also determined by FT-Raman spectroscopy. The DHPS nanoemulsion demonstrated good stability and stable physical and chemical properties. The nanoemulsion dramatically improved the transdermal release of DHPS (from 8.02 MUg . cm(-2) to 273.15 MUg . cm(-2)) and could become a favorable new dosage form for DHPS. PMID- 21674021 TI - Ibuprofen-loaded poly(lactic-co-glycolic acid) films for controlled drug release. AB - Ibuprofen- (IBU) loaded biocompatible poly(lactic-co-glycolic acid) (PLGA) films were prepared by spreading polymer/ibuprofen solution on the nonsolvent surface. By controlling the weight ratio of drug and polymer, different drug loading polymer films can be obtained. The synthesized ibuprofen-loaded PLGA films were characterized with scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry. The drug release behavior of the as-prepared IBU-loaded PLGA films was studied to reveal their potential application in drug delivery systems. The results show the feasibility of the as-obtained films for controlling drug release. Furthermore, the drug release rate of the film could be controlled by the drug loading content and the release medium. The development of a biodegradable ibuprofen system, based on films, should be of great interest in drug delivery systems. PMID- 21674022 TI - Risk-targeted selection of agricultural holdings for post-epidemic surveillance: estimation of efficiency gains. AB - Current post-epidemic sero-surveillance uses random selection of animal holdings. A better strategy may be to estimate the benefits gained by sampling each farm and use this to target selection. In this study we estimate the probability of undiscovered infection for sheep farms in Devon after the 2001 foot-and-mouth disease outbreak using the combination of a previously published model of daily infection risk and a simple model of probability of discovery of infection during the outbreak. This allows comparison of the system sensitivity (ability to detect infection in the area) of arbitrary, random sampling compared to risk-targeted selection across a full range of sampling budgets. We show that it is possible to achieve 95% system sensitivity by sampling, on average, 945 farms with random sampling and 184 farms with risk-targeted sampling. We also examine the effect of ordering samples by risk to expedite return to a disease-free status. Risk ordering the sampling process results in detection of positive farms, if present, 15.6 days sooner than with randomly ordered sampling, assuming 50 farms are tested per day. PMID- 21674023 TI - Value of routine sinus radiography in the diagnostic work-up of ill returned travelers: critical appraisal in a cohort of 765 travelers. AB - BACKGROUND: Upper respiratory tract problems, eg, acute sinusitis are frequently occurring illnesses in returned travelers. The most accurate and cost-effective method for diagnosing these upper respiratory tract illnesses in hospital-based settings remains an area of uncertainty. In the present retrospective cohort study, the usefulness of routine sinus radiography in the diagnostic work-up of ill returned travelers was evaluated. METHODS: This study was done at the Institute for Tropical Diseases in Rotterdam, and included all returned travelers who were ill with symptoms lasting less than one month in the period 2007-2009 and had sinus radiography on admission. Traveler demographic (including travel history), clinical, and laboratory data were collected on admission, and sinus radiography findings evaluated for their diagnostic power to predict sinusitis. RESULTS: One hundred and sixty-five (22%) of 765 ill returned travelers had abnormal sinus radiography; more than half of the abnormal radiographic findings comprised mucosal membrane thickening of the sinuses. More than half of the travelers with abnormal sinus radiography had no upper respiratory tract symptoms at admission, which raises doubt about the clinical relevance of abnormal radiographic findings. Travelers with abnormal sinus radiography were more likely to receive nasal decongestants (relative risk 18.2, confidence interval 9.4-35.1) but not antibiotics. CONCLUSION: The results of the present study indicate that there is no additional value for routine sinus radiography in the diagnostic work up of ill returned travelers. PMID- 21674024 TI - Intravenous moxifloxacin in routine hospital treatment of respiratory tract infections in China: results of a multicenter, noninterventional study. AB - OBJECTIVE: To investigate the effectiveness, safety, and tolerability of moxifloxacin (MXF) (intravenous [IV] or sequential therapy [IV followed by oral]) under daily treatment conditions in a large number of patients with respiratory tract infections. DESIGN: Patients with a diagnosis of respiratory tract infection should be treated with MXF IV and/or tablets 400 mg once daily for a duration at the physician's discretion. For each patient, the physician documented data at an initial visit and at the end of therapy (EOT) visit and/or, in the case of sequential therapy, an interim visit when the patient switched to oral treatment. RESULTS: A total of 1953 patients treated with MXF were documented and were valid for an effectiveness and safety evaluation. An improvement was observed in 98.1% (n = 1911/1949) of patients treated with MXF. Recovery was documented in 89.9% (n = 1754/1951) of the patients. At the EOT visit, severity of infection was assessed to be "relieved" or at least "improved" in 96.5% (n = 1873/1940) of the patients. Physicians assessed overall effectiveness as "good" or "very good" in 93.3% (n = 1822/1953) of all patients. The physicians' overall tolerability rating was "very good" or "good" in 93.5% (n = 1827/1953) of all patients. The incidence rates of adverse events (AEs) and adverse drug reactions (ADRs) were 0.72% (n = 14) and 0.67% (n = 13), respectively. One serious AE "falling white blood cell count" occurred (0.05%), which was also defined as a serious ADR and resolved. CONCLUSION: MXF was generally well tolerated and highly effective in the treatment of different respiratory tract infections. The incidence of AEs and ADRs was low. The efficacy, safety, and tolerability information collected in this study confirms the clinical safety profile of MXF and its value as antibiotic treatment for respiratory tract infections. PMID- 21674025 TI - Multimodal neurophysiological and psychometric evaluation among patients with systemic lupus erythematosus. AB - OBJECTIVE: To determine some of the neuropsychiatric manifestations of systemic lupus erythematosus (SLE) by applying multimodal neurophysiological and psychometric studies. PATIENTS AND METHODS: Twenty-six SLE patients were evaluated for neurological and psychiatric disorders and compared with 26 healthy controls matched for age, sex, education, and social class. The severity of SLE disease was assessed. Each subject was subjected to the following examinations: laboratory, neurophysiology, magnetic resonance imaging of the brain, transcranial duplex, Modified Mini-mental State Examination, Cognitive Assessment Scale Inventory, Hamilton Depression Scale, and Hamilton Anxiety Scale. RESULTS: The mean age of subjects was 25.9 +/- 8.9 years. The most prevalent neurological manifestations were (in order of frequency) anxiety in 17 cases (65.4%), depression in 15 cases (57.7%), headache in 10 cases (38.5%), peripheral neuropathy in 7 cases (26.9%), seizures in 6 cases (23.1%), psychosis in 5 cases (19.2%), dementia in 4 cases (15.4%), radiculopathy in 4 cases (15.4%), myositis in 3 cases (11.5%), and stroke in 2 cases (7.7%). There was a significant affection in amplitude of the ulnar nerve, cognitive function impairment, and electroencephalography changes. There was a significant increased mean velocity and decreased Pulsatility Index of the most studied intracranial vessels in the patients. CONCLUSION: The use of multimodal neurophysiological, transcranial duplex, and psychometric scales increases the sensitivity for detecting nervous system involvement. PMID- 21674027 TI - Glucose-lowering effect of DLBS3233 is mediated through phosphorylation of tyrosine and upregulation of PPARgamma and GLUT4 expression. AB - BACKGROUND: DLBS3233 is a standardized extract combination containing Lagerstroemia speciosa and Cinnamomum burmannii. The effect of DLBS3233 on glucose uptake, adiponectin secretion, and insulin signaling was examined in this study. METHODS: 3T3 Swiss albino preadipocytes and adipocytes were used to investigate gene expression detected using the reverse transcription polymerase chain reaction method. Immunoblotting assay and in vitro glucose uptake assay were also carried out in the experiment. RESULTS: DLBS3233 was seen to increase phosphorylation at the tyrosine residue of the insulin receptor substrate. DLBS3233 was also found to enhance the expression of genes associated with increased insulin signaling and sensitivity, such as peroxisome proliferator activated receptor gamma, phosphatidylinositol-3 kinase, Akt, and glucose transporter 4. In addition, glucose transporter 4 protein levels were seen to increase as a result of DLBS3233 administration. The combination of extracts also increased glucose uptake and adiponectin secretion, and decreased resistin secretion significantly relative to control cells. Moreover, DLBS3233 administered to insulin-resistant Wistar rats showed an ability to control blood sugar, insulin levels, and other lipoproteins, including high-density lipoprotein, low-density lipoprotein, triglycerides, and total cholesterol. CONCLUSION: DLBS3233, as a combination of herbal extracts, holds promise in the treatment of type 2 diabetes, and possibly also in prevention of the disease. PMID- 21674026 TI - Urinary tract infections in women: etiology and treatment options. AB - Urinary tract infections (UTI) are common among the female population. It has been calculated that about one-third of adult women have experienced an episode of symptomatic cystitis at least once. It is also common for these episodes to recur. If predisposing factors are not identified and removed, UTI can lead to more serious consequences, in particular kidney damage and renal failure. The aim of this review was to analyze the factors more commonly correlated with UTI in women, and to see what possible solutions are currently used in general practice and specialized areas, as well as those still under investigation. A good understanding of the possible pathogenic factors contributing to the development of UTI and its recurrence will help the general practitioner to interview the patient, search for causes that would otherwise remain undiscovered, and to identify the correct therapeutic strategy. PMID- 21674028 TI - Wave speed in excitable random networks with spatially constrained connections. AB - Very fast oscillations (VFO) in neocortex are widely observed before epileptic seizures, and there is growing evidence that they are caused by networks of pyramidal neurons connected by gap junctions between their axons. We are motivated by the spatio-temporal waves of activity recorded using electrocorticography (ECoG), and study the speed of activity propagation through a network of neurons axonally coupled by gap junctions. We simulate wave propagation by excitable cellular automata (CA) on random (Erdos-Renyi) networks of special type, with spatially constrained connections. From the cellular automaton model, we derive a mean field theory to predict wave propagation. The governing equation resolved by the Fisher-Kolmogorov PDE fails to describe wave speed. A new (hyperbolic) PDE is suggested, which provides adequate wave speed v() that saturates with network degree , in agreement with intuitive expectations and CA simulations. We further show that the maximum length of connection is a much better predictor of the wave speed than the mean length. When tested in networks with various degree distributions, wave speeds are found to strongly depend on the ratio of network moments / rather than on mean degree , which is explained by general network theory. The wave speeds are strikingly similar in a diverse set of networks, including regular, Poisson, exponential and power law distributions, supporting our theory for various network topologies. Our results suggest practical predictions for networks of electrically coupled neurons, and our mean field method can be readily applied for a wide class of similar problems, such as spread of epidemics through spatial networks. PMID- 21674029 TI - Multiple phenotypes in adult mice following inactivation of the Coxsackievirus and Adenovirus Receptor (Car) gene. AB - To determine the normal function of the Coxsackievirus and Adenovirus Receptor (CAR), a protein found in tight junctions and other intercellular complexes, we constructed a mouse line in which the CAR gene could be disrupted at any chosen time point in a broad spectrum of cell types and tissues. All knockouts examined displayed a dilated intestinal tract and atrophy of the exocrine pancreas with appearance of tubular complexes characteristic of acinar-to-ductal metaplasia. The mice also exhibited a complete atrio-ventricular block and abnormal thymopoiesis. These results demonstrate that CAR exerts important functions in the physiology of several organs in vivo. PMID- 21674030 TI - Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum. AB - BACKGROUND: ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation. METHODOLOGY/PRINCIPAL FINDINGS: Ileum mucosa was obtained every 3-4 h for 24 h in male and female B6D2F(1) and B6CBAF(1) mice synchronized with light from Zeitgeber Time (ZT)0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days) was administered at the sex- and strain-specific times corresponding to least (ZT11-15) or largest drug-induced body weight loss (ZT23-03-07). Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p<0.05). ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003). Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF(1) (p = 0.0006). CONCLUSIONS/SIGNIFICANCE: Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan. This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery. PMID- 21674031 TI - Invasive cyprinid fish in Europe originate from the single introduction of an admixed source population followed by a complex pattern of spread. AB - The Asian cyprinid fish, the topmouth gudgeon (Pseudorasbora parva), was introduced into Europe in the 1960s. A highly invasive freshwater fish, it is currently found in at least 32 countries outside its native range. Here we analyse a 700 base pair fragment of the mitochondrial cytochrome b gene to examine different models of colonisation and spread within the invasive range, and to investigate the factors that may have contributed to their invasion success. Haplotype and nucleotide diversity of the introduced populations from continental Europe was higher than that of the native populations, although two recently introduced populations from the British Isles showed low levels of variability. Based on coalescent theory, all introduced and some native populations showed a relative excess of nucleotide diversity compared to haplotype diversity. This suggests that these populations are not in mutation drift equilibrium, but rather that the relative inflated level of nucleotide diversity is consistent with recent admixture. This study elucidates the colonisation patterns of P. parva in Europe and provides an evolutionary framework of their invasion. It supports the hypothesis that their European colonisation was initiated by their introduction to a single location or small geographic area with subsequent complex pattern of spread including both long distance and stepping-stone dispersal. Furthermore, it was preceded by, or associated with, the admixture of genetically diverse source populations that may have augmented its invasive-potential. PMID- 21674032 TI - Effects of surface passivation on gliding motility assays. AB - In this study, we report differences in the observed gliding speed of microtubules dependent on the choice of bovine casein used as a surface passivator. We observed differences in both speed and support of microtubules in each of the assays. Whole casein, comprised of alpha(s1), alpha(s2), beta, and kappa casein, supported motility and averaged speeds of 966+/-7 nm/s. Alpha casein can be purchased as a combination of alpha(s1) and alpha(s2) and supported gliding motility and average speeds of 949+/-4 nm/s. Beta casein did not support motility very well and averaged speeds of 870+/-30 nm/s. Kappa casein supported motility very poorly and we were unable to obtain an average speed. Finally, we observed that mixing alpha, beta, and kappa casein with the proportions found in bovine whole casein supported motility and averaged speeds of 966+/-6 nm/s. PMID- 21674033 TI - Prevalence of drug-resistant tuberculosis in mainland China: systematic review and meta-analysis. AB - BACKGROUND: The spread of drug-resistant tuberculosis (TB) is one of the major public health problems in the world. Surveillance of anti-TB drug resistance is important for monitoring TB control strategies. However, the status of drug resistant TB in China has been reported inconsistently. METHODS: We systematically reviewed published studies on drug-resistant TB in China until March 31, 2011, and quantitatively summarized prevalence and patterns of anti-TB drug resistance among new cases and previously treated cases, respectively. RESULTS: Ninety-five eligible articles, published during 1993-2011, were included in this review. The meta-analyses showed that the prevalence of drug-resistant TB in new cases was 27.9% (95% CI, 25.6%-30.2%) (n/N = 27,360/104,356) and in previously treated cases was 60.3% (95% CI, 56.2%-64.2%) (n/N = 30,350/45,858). Furthermore, in these two study populations, the prevalence of multiple drug resistance was found to be 5.3% (95% CI, 4.4%-6.4%) (n/N = 8810/101,718) and 27.4% (95% CI, 24.1%-30.9%) (n/N = 10,486/44,530) respectively. However, the results were found to be frequently heterogeneous (p for Q tests <0.001). The most common resistance was observed for isoniazid among both study populations. Different patterns of drug resistance were observed in the subgroup analysis with respect to geographic areas, drug susceptibility testing methods and subject enrollment time. CONCLUSIONS: Results of meta-analyses indicated a severe status of drug-resistant TB in China, which attaches an importance to strength TB prevention and control. PMID- 21674034 TI - On the accuracy of language trees. AB - Historical linguistics aims at inferring the most likely language phylogenetic tree starting from information concerning the evolutionary relatedness of languages. The available information are typically lists of homologous (lexical, phonological, syntactic) features or characters for many different languages: a set of parallel corpora whose compilation represents a paramount achievement in linguistics. From this perspective the reconstruction of language trees is an example of inverse problems: starting from present, incomplete and often noisy, information, one aims at inferring the most likely past evolutionary history. A fundamental issue in inverse problems is the evaluation of the inference made. A standard way of dealing with this question is to generate data with artificial models in order to have full access to the evolutionary process one is going to infer. This procedure presents an intrinsic limitation: when dealing with real data sets, one typically does not know which model of evolution is the most suitable for them. A possible way out is to compare algorithmic inference with expert classifications. This is the point of view we take here by conducting a thorough survey of the accuracy of reconstruction methods as compared with the Ethnologue expert classifications. We focus in particular on state-of-the-art distance-based methods for phylogeny reconstruction using worldwide linguistic databases. In order to assess the accuracy of the inferred trees we introduce and characterize two generalizations of standard definitions of distances between trees. Based on these scores we quantify the relative performances of the distance-based algorithms considered. Further we quantify how the completeness and the coverage of the available databases affect the accuracy of the reconstruction. Finally we draw some conclusions about where the accuracy of the reconstructions in historical linguistics stands and about the leading directions to improve it. PMID- 21674036 TI - Bacterial sepsis in Brazilian children: a trend analysis from 1992 to 2006. AB - BACKGROUND: The objective of this study was to determine the epidemiology of hospitalized pediatric sepsis in Brazil (1992-2006) and to compare mortality caused by sepsis to that caused by other major childhood diseases. METHODS AND FINDINGS: We performed a retrospective descriptive study of hospital admissions using a government database of all hospital affiliated with the Brazilian health system. We studied all hospitalizations in children from 28 days through 19 years with diagnosis of bacterial sepsis defined by the criteria of the International Classification of Diseases (ICD), (Appendix S1). Based on the data studied from 1992 through 2006, the pediatric hospital mortality rate was 1.23% and there were 556,073 pediatric admissions with bacterial sepsis with a mean mortality rate of 19.9%. There was a case reduction of 67% over 1992-2006 (p<0.001); however, the mortality rate remained unchanged (from 1992-1996, 20.5%; and from 2002-2006, 19.7%). Sepsis-hospital mortality rate was substantially higher than pneumonia (0.5%), HIV (3.3%), diarrhea (0.3%), undernutrition (2.3%), malaria (0.2%) and measles (0.7%). The human development index (HDI) and mortality rates (MR) by region were: North region 0.76 and 21.7%; Northeast region 0.72 and 27.1%; Central-West 0.81 and 23.5%; South region 0.83 and 12.2% and Southeast region 0.82 and 14.8%, respectively. CONCLUSIONS: We concluded that sepsis remains an important health problem in children in Brazil. The institution of universal primary care programs has been associated with substantially reduced sepsis incidence and therefore deaths; however, hospital mortality rates in children with sepsis remain unchanged. Implementation of additional health initiatives to reduce sepsis mortality in hospitalized patients could have great impact on childhood mortality rates in Brazil. PMID- 21674035 TI - Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. AB - The contribution of natural killer T (NKT) cells to the pathogenesis of metabolic abnormalities of obesity is controversial. While the combined genetic deletion of NKT and CD8(+) T-cells improves glucose tolerance and reduces inflammation, interpretation of these data have been complicated by the recent observation that the deletion of CD8(+) T-cells alone reduces obesity-induced inflammation and metabolic dysregulation, leaving the issue of the metabolic effects of NKT cell depletion unresolved. To address this question, CD1d null mice (CD1d(-/-)), which lack NKT cells but have a full complement of CD8(+) T-cells, and littermate wild type controls (WT) on a pure C57BL/6J background were exposed to a high fat diet, and glucose intolerance, insulin resistance, dyslipidemia, inflammation, and obesity were assessed. Food intake (15.5+/-4.3 vs 15.3+/-1.8 kcal/mouse/day), weight gain (21.8+/-1.8 vs 22.8+/-1.4 g) and fat mass (18.6+/-1.9 vs 19.5+/-2.1 g) were similar in CD1d(-/-) and WT, respectively. As would be expected from these data, metabolic rate (3.0+/-0.1 vs 2.9+/-0.2 ml O(2)/g/h) and activity (21.6+/-4.3 vs 18.5+/-2.6 beam breaks/min) were unchanged by NKT cell depletion. Furthermore, the degree of insulin resistance, glucose intolerance, liver steatosis, and adipose and liver inflammatory marker expression (TNFalpha, IL-6, IL-10, IFN-gamma, MCP-1, MIP1alpha) induced by high fat feeding in CD1d(-/-) were not different from WT. We conclude that deletion of NKT cells, in the absence of alterations in the CD8(+) T-cell population, is insufficient to protect against the development of the metabolic abnormalities of diet-induced obesity. PMID- 21674037 TI - Role of ox-PAPCs in the differentiation of mesenchymal stem cells (MSCs) and Runx2 and PPARgamma2 expression in MSCs-like of osteoporotic patients. AB - BACKGROUND: Mesenchymal stem cells (MSCs) can differentiate into osteoblasts and adipocytes and conditions causing bone loss may induce a switch from the osteoblast to adipocyte lineage. In addition, the expression of Runx2 and the PPARgamma2 transcription factor genes is essential for cellular commitment to an osteogenic and adipogenic differentiation, respectively. Modified lipoproteins derived from the oxidation of arachidonate-containing phospholipids (ox-PAPCs: POVPC, PGPC and PEIPC) are considered important factors in atherogenesis. METHODOLOGY: We investigated the effect of ox-PAPCs on osteogenesis and adipogenesis in human mesenchymal stem cells (hMSCs). In particular, we analyzed the transcription factor Runx2 and the PPARgamma2 gene expression during osteogenic and adipogenic differentiation in absence and in presence of ox-PAPCs. We also analyzed gene expression level in a panel of osteoblastic and adipogenic differentiation markers. In addition, as circulating blood cells can be used as a "sentinel" that responds to changes in the macro- or micro-environment, we analyzed the Runx2 and the PPARgamma2 gene expression in MSCs-like and ox-PAPC levels in serum of osteoporotic patients (OPs). Finally, we examined the effects of sera obtained from OPs in hMSCs comparing the results with age-matched normal donors (NDs). PRINCIPAL FINDINGS: Quantitative RT-PCR demonstrated that ox-PAPCs enhanced PPARgamma2 and adipogenic gene expression and reduced Runx2 and osteoblast differentiation marker gene expression in differentiating hMSCs. In OPs, ox-PAPC levels and PPARgamma2 expression were higher than in NDs, whereas Runx2 was lower than in ND circulant MSCs-like. CONCLUSIONS: Ox-PAPCs affect the osteogenic differentiation by promoting adipogenic differentiation and this effect may appear involved in bone loss in OPs. PMID- 21674038 TI - Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. AB - The development of mammalian fetal germ cells along oogenic or spermatogenic fate trajectories is dictated by signals from the surrounding gonadal environment. Germ cells in the fetal testis enter mitotic arrest, whilst those in the fetal ovary undergo sex-specific entry into meiosis, the initiation of which is thought to be mediated by selective exposure of fetal ovarian germ cells to mesonephros derived retinoic acid (RA). Aspects of this model are hard to reconcile with the spatiotemporal pattern of germ cell differentiation in the human fetal ovary, however. We have therefore examined the expression of components of the RA synthesis, metabolism and signalling pathways, and their downstream effectors and inhibitors in germ cells around the time of the initiation of meiosis in the human fetal gonad. Expression of the three RA-synthesising enzymes, ALDH1A1, 2 and 3 in the fetal ovary and testis was equal to or greater than that in the mesonephros at 8-9 weeks gestation, indicating an intrinsic capacity within the gonad to synthesise RA. Using immunohistochemistry to detect RA receptors RARalpha, beta and RXRalpha, we find germ cells to be the predominant target of RA signalling in the fetal human ovary, but also reveal widespread receptor nuclear localization indicative of signalling in the testis, suggesting that human fetal testicular germ cells are not efficiently shielded from RA by the action of the RA-metabolising enzyme CYP26B1. Consistent with this, expression of CYP26B1 was greater in the human fetal ovary than testis, although the sexually dimorphic expression patterns of the germ cell-intrinsic regulators of meiotic initiation, STRA8 and NANOS2, appear conserved. Finally, we demonstrate that RA induces a two-fold increase in STRA8 expression in cultures of human fetal testis, but is not sufficient to cause widespread meiosis-associated gene expression. Together, these data indicate that while local production of RA within the fetal ovary may be important in regulating the onset of meiosis in the human fetal ovary, mechanisms other than CYP26B1-mediated metabolism of RA may exist to inhibit the entry of germ cells into meiosis in the human fetal testis. PMID- 21674039 TI - Phenylpropanoid glycoside analogues: enzymatic synthesis, antioxidant activity and theoretical study of their free radical scavenger mechanism. AB - Phenylpropanoid glycosides (PPGs) are natural compounds present in several medicinal plants that have high antioxidant power and diverse biological activities. Because of their low content in plants (less than 5% w/w), several chemical synthetic routes to produce PPGs have been developed, but their synthesis is a time consuming process and the achieved yields are often low. In this study, an alternative and efficient two-step biosynthetic route to obtain natural PPG analogues is reported for the first time. Two galactosides were initially synthesized from vanillyl alcohol and homovanillyl alcohol by a transgalactosylation reaction catalyzed by Kluyveromyces lactis beta galactosidase in saturated lactose solutions with a 30%-35% yield. To synthesize PPGs, the galactoconjugates were esterified with saturated and unsaturated hydroxycinnamic acid derivatives using Candida antarctica Lipase B (CaL-B) as a biocatalyst with 40%-60% yields. The scavenging ability of the phenolic raw materials, intermediates and PPGs was evaluated by the 2,2-diphenyl-1 picrylhydrazyl radical (DPPH*) method. It was found that the biosynthesized PPGs had higher scavenging abilities when compared to ascorbic acid, the reference compound, while their antioxidant activities were found similar to that of natural PPGs. Moreover, density functional theory (DFT) calculations were used to determine that the PPGs antioxidant mechanism proceeds through a sequential proton loss single electron transfer (SPLET). The enzymatic process reported in this study is an efficient and versatile route to obtain PPGs from different phenylpropanoid acids, sugars and phenolic alcohols. PMID- 21674040 TI - Glycogen synthase kinase 3 beta (GSK3beta) phosphorylates the RNAase III enzyme Drosha at S300 and S302. AB - The canonical microRNA (miRNA) pathway commences with the enzymatic cleavage of the primary gene transcript (pri-miRNA) by the RNAase III enzyme Drosha in the nucleus into shorter pre-miRNA species that are subsequently exported to the cytoplasm for further processing into shorter, mature miRNA molecules. Using a series of reporter constructs, we have previously demonstrated that phosphorylation of Drosha at Ser 300 and 302 was required for its nuclear localization. Here, we identify GSK3beta as the culprit kinase. We demonstrate that Drosha is unable to selectively localize to the nucleus in cells deficient in GSK3beta. These findings expand the substrate base of GSK3beta to include a central component of the miRNA biogenesis pathway. PMID- 21674041 TI - Chemical elemental distribution and soil DNA fingerprints provide the critical evidence in murder case investigation. AB - BACKGROUND: The scientific contribution to the solution of crime cases, or throughout the consequent forensic trials, is a crucial aspect of the justice system. The possibility to extract meaningful information from trace amounts of samples, and to match and validate evidences with robust and unambiguous statistical tests, are the key points of such process. The present report is the authorized disclosure of an investigation, carried out by Attorney General appointment, on a murder case in northern Italy, which yielded the critical supporting evidence for the judicial trial. METHODOLOGY/PRINCIPAL FINDINGS: The proportional distribution of 54 chemical elements and the bacterial community DNA fingerprints were used as signature markers to prove the similarity of two soil samples. The first soil was collected on the crime scene, along a corn field, while the second was found in trace amounts on the carpet of a car impounded from the main suspect in a distant location. The matching similarity of the two soils was proven by crossing the results of two independent techniques: a) elemental analysis via inductively coupled plasma mass spectrometry (ICP-MS) and optical emission spectrometry (ICP-OES) approaches, and b) amplified ribosomal DNA restriction analysis by gel electrophoresis (ARDRA). CONCLUSIONS: Besides introducing the novel application of these methods to forensic disciplines, the highly accurate level of resolution observed, opens new possibilities also in the fields of soil typing and tracking, historical analyses, geochemical surveys and global land mapping. PMID- 21674042 TI - Association of ORAI1 haplotypes with the risk of HLA-B27 positive ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammation of the sacroiliac joints, spine and peripheral joints. The aetiology of ankylosing spondylitis is still unclear. Previous studies have indicated that genetics factors such as human leukocyte antigen HLA-B27 associates to AS susceptibility. We carried out a case control study to determine whether the genetic polymorphisms of ORAI1 gene, a major component of store-operated calcium channels that involved the regulation of immune system, is a susceptibility factor to AS in a Taiwanese population. We enrolled 361 AS patients fulfilled the modified New York criteria and 379 controls from community. Five tagging single nucleotides polymorphisms (tSNPs) at ORAI1 were selected from the data of Han Chinese population in HapMap project. Clinical statuses of AS were assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Global Index (BAS-G). Our results indicated that subjects carrying the minor allele homozygote (CC) of the promoter SNP rs12313273 or TT homozygote of the SNP rs7135617 had an increased risk of HLA-B27 positive AS. The minor allele C of 3'UTR SNP rs712853 exerted a protective effect to HLA B27 positive AS. Furthermore, the rs12313273/rs7135617 pairwise allele analysis found that C-G (OR 1.69, 95% CI 1.27, 2.25; p = 0.0003) and T-T (OR 1.75, 95% CI 1.36, 2.27; p<0.0001) haplotypes had a significantly association with the risk of HLA-B27-positive AS in comparison with the T-G carriers. This is the first study that indicate haplotypes of ORAI1 (rs12313273 and rs7135617) are associated with the risk of HLA-B27 positive AS. PMID- 21674043 TI - Bayesian action-perception computational model: interaction of production and recognition of cursive letters. AB - In this paper, we study the collaboration of perception and action representations involved in cursive letter recognition and production. We propose a mathematical formulation for the whole perception-action loop, based on probabilistic modeling and bayesian inference, which we call the Bayesian Action Perception (BAP) model. Being a model of both perception and action processes, the purpose of this model is to study the interaction of these processes. More precisely, the model includes a feedback loop from motor production, which implements an internal simulation of movement. Motor knowledge can therefore be involved during perception tasks. In this paper, we formally define the BAP model and show how it solves the following six varied cognitive tasks using bayesian inference: i) letter recognition (purely sensory), ii) writer recognition, iii) letter production (with different effectors), iv) copying of trajectories, v) copying of letters, and vi) letter recognition (with internal simulation of movements). We present computer simulations of each of these cognitive tasks, and discuss experimental predictions and theoretical developments. PMID- 21674044 TI - Electron transfer function versus oxygen delivery: a comparative study for several hexacoordinated globins across the animal kingdom. AB - Caenorhabditis elegans globin GLB-26 (expressed from gene T22C1.2) has been studied in comparison with human neuroglobin (Ngb) and cytoglobin (Cygb) for its electron transfer properties. GLB-26 exhibits no reversible binding for O(2) and a relatively low CO affinity compared to myoglobin-like globins. These differences arise from its mechanism of gaseous ligand binding since the heme iron of GLB-26 is strongly hexacoordinated in the absence of external ligands; the replacement of this internal ligand, probably the E7 distal histidine, is required before binding of CO or O(2) as for Ngb and Cygb. Interestingly the ferrous bis-histidyl GLB-26 and Ngb, another strongly hexacoordinated globin, can transfer an electron to cytochrome c (Cyt-c) at a high bimolecular rate, comparable to those of inter-protein electron transfer in mitochondria. In addition, GLB-26 displays an unexpectedly rapid oxidation of the ferrous His-Fe His complex without O(2) actually binding to the iron atom, since the heme is oxidized by O(2) faster than the time for distal histidine dissociation. These efficient mechanisms for electron transfer could indicate a family of hexacoordinated globin which are functionally different from that of pentacoordinated globins. PMID- 21674045 TI - Solution structures of the acyl carrier protein domain from the highly reducing type I iterative polyketide synthase CalE8. AB - Biosynthesis of the enediyne natural product calicheamicins gamma(1) (I) in Micromonospora echinospora ssp. calichensis is initiated by the iterative polyketide synthase (PKS) CalE8. Recent studies showed that CalE8 produces highly conjugated polyenes as potential biosynthetic intermediates and thus belongs to a family of highly-reducing (HR) type I iterative PKSs. We have determined the NMR structure of the ACP domain (meACP) of CalE8, which represents the first structure of a HR type I iterative PKS ACP domain. Featured by a distinct hydrophobic patch and a glutamate-residue rich acidic patch, meACP adopts a twisted three-helix bundle structure rather than the canonical four-helix bundle structure. The so-called 'recognition helix' (alpha2) of meACP is less negatively charged than the typical type II ACPs. Although loop-2 exhibits greater conformational mobility than other regions of the protein with a missing short helix that can be observed in most ACPs, two bulky non-polar residues (Met(992), Phe(996)) from loop-2 packed against the hydrophobic protein core seem to restrict large movement of the loop and impede the opening of the hydrophobic pocket for sequestering the acyl chains. NMR studies of the hydroxybutyryl- and octanoyl-meACP confirm that meACP is unable to sequester the hydrophobic chains in a well-defined central cavity. Instead, meACP seems to interact with the octanoyl tail through a distinct hydrophobic patch without involving large conformational change of loop-2. NMR titration study of the interaction between meACP and the cognate thioesterase partner CalE7 further suggests that their interaction is likely through the binding of CalE7 to the meACP-tethered polyene moiety rather than direct specific protein-protein interaction. PMID- 21674046 TI - Integrative DNA methylation and gene expression analyses identify DNA packaging and epigenetic regulatory genes associated with low motility sperm. AB - BACKGROUND: In previous studies using candidate gene approaches, low sperm count (oligospermia) has been associated with altered sperm mRNA content and DNA methylation in both imprinted and non-imprinted genes. We performed a genome-wide analysis of sperm DNA methylation and mRNA content to test for associations with sperm function. METHODS AND RESULTS: Sperm DNA and mRNA were isolated from 21 men with a range of semen parameters presenting to a tertiary male reproductive health clinic. DNA methylation was measured with the Illumina Infinium array at 27,578 CpG loci. Unsupervised clustering of methylation data differentiated the 21 sperm samples by their motility values. Recursively partitioned mixture modeling (RPMM) of methylation data resulted in four distinct methylation profiles that were significantly associated with sperm motility (P = 0.01). Linear models of microarray analysis (LIMMA) was performed based on motility and identified 9,189 CpG loci with significantly altered methylation (Q<0.05) in the low motility samples. In addition, the majority of these disrupted CpG loci (80%) were hypomethylated. Of the aberrantly methylated CpGs, 194 were associated with imprinted genes and were almost equally distributed into hypermethylated (predominantly paternally expressed) and hypomethylated (predominantly maternally expressed) groups. Sperm mRNA was measured with the Human Gene 1.0 ST Affymetrix GeneChip Array. LIMMA analysis identified 20 candidate transcripts as differentially present in low motility sperm, including HDAC1 (NCBI 3065), SIRT3 (NCBI 23410), and DNMT3A (NCBI 1788). There was a trend among altered expression of these epigenetic regulatory genes and RPMM DNA methylation class. CONCLUSIONS: Using integrative genome-wide approaches we identified CpG methylation profiles and mRNA alterations associated with low sperm motility. PMID- 21674047 TI - Activation of cytotoxic and regulatory functions of NK cells by Sindbis viral vectors. AB - Oncolytic viruses (OVs) represent a relatively novel anti-cancer modality. Like other new cancer treatments, effective OV therapy will likely require combination with conventional treatments. In order to design combinatorial treatments that work well together, a greater scrutiny of the mechanisms behind the individual treatments is needed. Sindbis virus (SV) based vectors have previously been shown to target and kill tumors in xenograft, syngeneic, and spontaneous mouse models. However, the effect of SV treatment on the immune system has not yet been studied. Here we used a variety of methods, including FACS analysis, cytotoxicity assays, cell depletion, imaging of tumor growth, cytokine blockade, and survival experiments, to study how SV therapy affects Natural Killer (NK) cell function in SCID mice bearing human ovarian carcinoma tumors. Surprisingly, we found that SV anti-cancer efficacy is largely NK cell-dependent. Furthermore, the enhanced therapeutic effect previously observed from Sin/IL12 vectors, which carry the gene for interleukin 12, is also NK cell dependent, but works through a separate IFNgamma-dependent mechanism, which also induces the activation of peritoneal macrophages. These results demonstrate the multimodular nature of SV therapy, and open up new possibilities for potential synergistic or additive combinatorial therapies with other treatments. PMID- 21674048 TI - Association between TAS2R38 gene polymorphisms and colorectal cancer risk: a case control study in two independent populations of Caucasian origin. AB - Molecular sensing in the lingual mucosa and in the gastro-intestinal tract play a role in the detection of ingested harmful drugs and toxins. Therefore, genetic polymorphisms affecting the capability of initiating these responses may be critical for the subsequent efficiency of avoiding and/or eliminating possible threats to the organism. By using a tagging approach in the region of Taste Receptor 2R38 (TAS2R38) gene, we investigated all the common genetic variation of this gene region in relation to colorectal cancer risk with a case-control study in a German population (709 controls and 602 cases) and in a Czech population (623 controls and 601 cases). We found that there were no significant associations between individual SNPs of the TAS2R38 gene and colorectal cancer in the Czech or in the German population, nor in the joint analysis. However, when we analyzed the diplotypes and the phenotypes we found that the non-taster group had an increased risk of colorectal cancer in comparison to the taster group. This association was borderline significant in the Czech population, (OR = 1.28, 95% CI 0.99-1.67; P(value) = 0.058) and statistically significant in the German population (OR = 1.36, 95% CI 1.06-1.75; P(value) = 0.016) and in the joint analysis (OR = 1.34, 95% CI 1.12-1.61; P(value) = 0.001). In conclusion, we found a suggestive association between the human bitter tasting phenotype and the risk of CRC in two different populations of Caucasian origin. PMID- 21674049 TI - Fast x-ray fluorescence microtomography of hydrated biological samples. AB - Metals and metalloids play a key role in plant and other biological systems as some of them are essential to living organisms and all can be toxic at high concentrations. It is therefore important to understand how they are accumulated, complexed and transported within plants. In situ imaging of metal distribution at physiological relevant concentrations in highly hydrated biological systems is technically challenging. In the case of roots, this is mainly due to the possibility of artifacts arising during sample preparation such as cross sectioning. Synchrotron x-ray fluorescence microtomography has been used to obtain virtual cross sections of elemental distributions. However, traditionally this technique requires long data acquisition times. This has prohibited its application to highly hydrated biological samples which suffer both radiation damage and dehydration during extended analysis. However, recent advances in fast detectors coupled with powerful data acquisition approaches and suitable sample preparation methods can circumvent this problem. We demonstrate the heightened potential of this technique by imaging the distribution of nickel and zinc in hydrated plant roots. Although 3D tomography was still impeded by radiation damage, we successfully collected 2D tomograms of hydrated plant roots exposed to environmentally relevant metal concentrations for short periods of time. To our knowledge, this is the first published example of the possibilities offered by a new generation of fast fluorescence detectors to investigate metal and metalloid distribution in radiation-sensitive, biological samples. PMID- 21674050 TI - Assessing perceived risk and STI prevention behavior: a national population-based study with special reference to HPV. AB - INTRODUCTION: To better understand trends in sexually transmitted infection (STI) prevention, specifically low prevalence of condom use with temporary partners, the aim of this study was to examine factors associated with condom use and perceptions of STI risk amongst individuals at risk, with the underlying assumption that STI risk perceptions and STI prevention behaviors are correlated. METHODS: A national population-based survey on human papillomavirus (HPV) and sexual habits of young adults aged 18-30 was conducted in Sweden in 2007, with 1712 men and 8855 women participating. Regression analyses stratified by gender were performed to measure condom use with temporary partners and STI risk perception. RESULTS: Men's condom use was not associated with STI risk perception while women's was. Awareness of and disease severity perceptions were not associated with either condom use or risk perception though education level correlated with condom use. Women's young age at sexual debut was associated with a higher risk of non-condom use later in life (OR 1.95 95% CI: 1.46-2.60). Women with immigrant mothers were less likely to report seldom/never use of condoms with temporary partners compared to women with Swedish-born mothers (OR 0.53 95% CI: 0.37-0.77). Correlates to STI risk perception differ substantially between sexes. Number of reported temporary partners was the only factor associated for both men and women with condom use and STI risk perception. CONCLUSIONS: Public health interventions advocating condom use with new partners could consider employing tactics besides those which primarily aim to increase knowledge or self perceived risk if they are to be more effective in STI reduction. Gender-specific prevention strategies could be effective considering the differences found in this study. PMID- 21674051 TI - Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo. AB - BACKGROUND: DC are activated by pathogen-associated molecular patterns (PAMPs), and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine science due to their adjuvant potential, it is unclear whether and how PAMPs may affect DC viability. We aimed to elucidate the possible apoptotic mechanisms that control activated DC lifespan in response to PAMPs, particularly in vivo. METHODOLOGY/PRINCIPAL FINDINGS: We report that polyinosinic:polycytidylic acid (PolyIC, synthetic analogue of dsRNA) induces dramatic apoptosis of mouse splenic conventional DC (cDC) in vivo, predominantly affecting the CD8alpha subset, as shown by flow cytometry-based analysis of splenic DC subsets. Importantly, while Bim deficiency conferred only minor protection, cDC depletion was prevented in mice lacking Bim plus one of three other BH3-only proteins, either Puma, Noxa or Bid. Furthermore, we show that Type I Interferon (IFN) is necessary and sufficient for DC death both in vitro and in vivo, and that TLR3 and MAVS co-operate in IFNbeta production in vivo to induce DC death in response to PolyIC. CONCLUSIONS/SIGNIFICANCE: These results demonstrate for the first time in vivo that apoptosis restricts DC lifespan following activation by PolyIC, particularly affecting the CD8alpha cDC subset. Such DC apoptosis is mediated by the overlapping action of pro-apoptotic BH3-only proteins, including but not solely involving Bim, and is driven by Type I IFN. While Type I IFNs are important anti-viral factors, CD8alpha cDC are major cross presenting cells and critical inducers of CTL. We discuss such paradoxical finding on DC death with PolyIC/Type I IFN. These results could contribute to understand immunosuppression associated with chronic infection, and to the optimization of DC-based therapies and the clinical use of PAMPs and Type I IFNs. PMID- 21674052 TI - Bcl-x(L) blocks a mitochondrial inner membrane channel and prevents Ca2+ overload mediated cell death. AB - Apoptosis is an active process that plays a key role in many physiological and pathological conditions. One of the most important organelles involved in apoptosis regulation is the mitochondrion. An increase in intracellular Ca(2+) is a general mechanism of toxicity in neurons which occurs in response to different noxious stimuli like excitotoxicity and ischemia producing apoptotic and necrotic cell death through mitochondria-dependent mechanisms. The Bcl-2 family of proteins modulate the release of pro-apoptotic factors from the mitochondrial intermembrane space during cell death induction by different stimuli. In this work, we have studied, using single-cell imaging and patch-clamp single channel recording, the mitochondrial mechanisms involved in the neuroprotective effect of Bcl-x(L) on Ca(2+) overload-mediated cell death in human neuroblastoma SH-SY5Y cells. We have found that Bcl-x(L) neuroprotective actions take place at mitochondria where this antiapoptotic protein delays both mitochondrial potential collapse and opening of the permeability transition pore by preventing Ca(2+) mediated mitochondrial multiple conductance channel opening. Bcl-x(L) neuroprotective actions were antagonized by the Bcl-x(L) inhibitor ABT-737 and potentiated by the Ca(2+) chelator BAPTA-AM. As a consequence, this would prevent free radical production, mitochondrial membrane permeabilization, release from mitochondria of pro-apoptotic molecules, caspase activation and cellular death. PMID- 21674053 TI - Cytokine effects on gap junction communication and connexin expression in human bladder smooth muscle cells and suburothelial myofibroblasts. AB - BACKGROUND: The last decade identified cytokines as one group of major local cell signaling molecules related to bladder dysfunction like interstitial cystitis (IC) and overactive bladder syndrome (OAB). Gap junctional intercellular communication (GJIC) is essential for the coordination of normal bladder function and has been found to be altered in bladder dysfunction. Connexin (Cx) 43 and Cx45 are the most important gap junction proteins in bladder smooth muscle cells (hBSMC) and suburothelial myofibroblasts (hsMF). Modulation of connexin expression by cytokines has been demonstrated in various tissues. Therefore, we investigate the effect of interleukin (IL) 4, IL6, IL10, tumor necrosis factor alpha (TNFalpha) and transforming growth factor-beta1 (TGFbeta1) on GJIC, and Cx43 and Cx45 expression in cultured human bladder smooth muscle cells (hBSMC) and human suburothelial myofibroblasts (hsMF). METHODOLOGY/PRINCIPAL FINDINGS: HBSMC and hsMF cultures were set up from bladder tissue of patients undergoing cystectomy. In cytokine stimulated cultured hBSMC and hsMF GJIC was analyzed via Fluorescence Recovery after Photo-bleaching (FRAP). Cx43 and Cx45 expression was assessed by quantitative PCR and confocal immunofluorescence. Membrane protein fraction of Cx43 and Cx45 was quantified by Dot Blot. Upregulation of cell-cell communication was found after IL6 stimulation in both cell types. In hBSMC IL4 and TGFbeta1 decreased both, GJIC and Cx43 protein expression, while TNFalpha did not alter communication in FRAP-experiments but increased Cx43 expression. GJ plaques size correlated with coupling efficacy measured, while Cx45 expression did not correlate with modulation of GJIC. CONCLUSIONS/SIGNIFICANCE: Our finding of specific cytokine effects on GJIC support the notion that cytokines play a pivotal role for pathophysiology of OAB and IC. Interestingly, the effects were independent from the classical definition of pro- and antiinflammatory cytokines. We conclude, that connexin regulation involves genomic and/or post-translational events, and that GJIC in hBSMC and hsMF depend of Cx43 rather than on Cx45. PMID- 21674054 TI - Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. AB - Malignant melanoma represents the third common cause of brain metastasis, having the highest propensity to metastasize to the brain of all primary neoplasms in adults. Since the central nervous system lacks a lymphatic system, the only possibility for melanoma cells to reach the brain is via the blood stream and the blood-brain barrier. Despite the great clinical importance, mechanisms of transmigration of melanoma cells through the blood-brain barrier are incompletely understood. In order to investigate this question we have used an in vitro experimental setup based on the culture of cerebral endothelial cells (CECs) and the A2058 and B16/F10 melanoma cell lines, respectively. Melanoma cells were able to adhere to confluent brain endothelial cells, a process followed by elimination of protrusions and transmigration from the luminal to the basolateral side of the endothelial monolayers. The transmigration process of certain cells was accelerated when they were able to use the routes preformed by previously transmigrated melanoma cells. After migrating through the endothelial monolayer several melanoma cells continued their movement beneath the endothelial cell layer. Melanoma cells coming in contact with brain endothelial cells disrupted the tight and adherens junctions of CECs and used (at least partially) the paracellular transmigration pathway. During this process melanoma cells produced and released large amounts of proteolytic enzymes, mainly gelatinolytic serine proteases, including seprase. The serine protease inhibitor Pefabloc(r) was able to decrease to 44-55% the number of melanoma cells migrating through CECs. Our results suggest that release of serine proteases by melanoma cells and disintegration of the interendothelial junctional complex are main steps in the formation of brain metastases in malignant melanoma. PMID- 21674055 TI - Implications of central obesity-related variants in LYPLAL1, NRXN3, MSRA, and TFAP2B on quantitative metabolic traits in adult Danes. AB - BACKGROUND: Two meta-analyses of genome-wide association studies (GWAS) have suggested that four variants: rs2605100 in lysophospholipase-like 1 (LYPLAL1), rs10146997 in neuroxin 3 (NRXN3), rs545854 in methionine sulfoxide reductase A (MSRA), and rs987237 in transcription factor activating enhancer-binding protein 2 beta (TFAP2B) associate with measures of central obesity. To elucidate potential underlying phenotypes we aimed to investigate whether these variants associated with: 1) quantitative metabolic traits, 2) anthropometric measures (waist circumference (WC), waist-hip ratio, and BMI), or 3) type 2 diabetes, and central and general overweight and obesity. METHODOLOGY/PRINCIPAL FINDINGS: The four variants were genotyped in Danish individuals using KASPar(r). Quantitative metabolic traits were examined in a population-based sample (n = 6,038) and WC and BMI were furthermore analyzed in a combined study sample (n = 13,507). Case control studies of diabetes and adiposity included 15,326 individuals. The major G-allele of LYPLAL1 rs2605100 associated with increased fasting serum triglyceride concentrations (per allele effect (beta) = 3%(1;5(95%CI)), p(additive) = 2.7*10(-3)), an association driven by the male gender (p(interaction) = 0.02). The same allele associated with increased fasting serum insulin concentrations (beta = 3%(1;5), p(additive) = 2.5*10(-3)) and increased insulin resistance (HOMA-IR) (beta = 4%(1;6), p(additive) = 1.5*10(-3)). The minor G-allele of rs10146997 in NRXN3 associated with increased WC among women (beta = 0.55cm (0.20;0.89), p(additive) = 1.7*10(-3), p(interaction) = 1.0*10( 3)), but showed no associations with obesity related metabolic traits. The MSRA rs545854 and TFAP2B rs987237 showed nominal associations with central obesity; however, no underlying metabolic phenotypes became obvious, when investigating quantitative metabolic traits. None of the variants influenced the prevalence of type 2 diabetes. CONCLUSION/SIGNIFICANCE: We demonstrate that several of the central obesity-associated variants in LYPLAL1, NRXN3, MSRA, and TFAP2B associate with metabolic and anthropometric traits in Danish adults. However, analyses were made without adjusting for multiple testing, and further studies are needed to confirm the putative role of LYPLAL1, NRXN3, MSRA, and TFAP2B in the pathophysiology of obesity. PMID- 21674056 TI - The serotonin 5-HT7Dro receptor is expressed in the brain of Drosophila, and is essential for normal courtship and mating. AB - The 5-HT(7) receptor remains one of the less well characterized serotonin receptors. Although it has been demonstrated to be involved in the regulation of mood, sleep, and circadian rhythms, as well as relaxation of vascular smooth muscles in mammals, the precise mechanisms underlying these functions remain largely unknown. The fruit fly, Drosophila melanogaster, is an attractive model organism to study neuropharmacological, molecular, and behavioral processes that are largely conserved with mammals. Drosophila express a homolog of the mammalian 5-HT(7) receptor, as well as homologs for the mammalian 5-HT(1A), and 5-HT(2), receptors. Each fly receptor couples to the same effector pathway as their mammalian counterpart and have been demonstrated to mediate similar behavioral responses. Here, we report on the expression and function of the 5-HT(7)Dro receptor in Drosophila. In the larval central nervous system, expression is detected postsynaptically in discreet cells and neuronal circuits. In the adult brain there is strong expression in all large-field R neurons that innervate the ellipsoid body, as well as in a small group of cells that cluster with the PDF positive LNvs neurons that mediate circadian activity. Following both pharmacological and genetic approaches, we have found that 5-HT(7)Dro activity is essential for normal courtship and mating behaviors in the fly, where it appears to mediate levels of interest in both males and females. This is the first reported evidence of direct involvement of a particular serotonin receptor subtype in courtship and mating in the fly. PMID- 21674057 TI - Clinical predictors of immune reconstitution following combination antiretroviral therapy in patients from the Australian HIV Observational Database. AB - BACKGROUND: A small but significant number of patients do not achieve CD4 T-cell counts >500 cells/ul despite years of suppressive cART. These patients remain at risk of AIDS and non-AIDS defining illnesses. The aim of this study was to identify clinical factors associated with CD4 T-cell recovery following long-term cART. METHODS: Patients with the following inclusion criteria were selected from the Australian HIV Observational Database (AHOD): cART as their first regimen initiated at CD4 T-cell count <500 cells/ul, HIV RNA<500 copies/ml after 6 months of cART and sustained for at least 12 months. The Cox proportional hazards model was used to identify determinants associated with time to achieve CD4 T-cell counts >500 cells/ul and >200 cells/ul. RESULTS: 501 patients were eligible for inclusion from AHOD (n = 2853). The median (IQR) age and baseline CD4 T-cell counts were 39 (32-47) years and 236 (130-350) cells/ul, respectively. A major strength of this study is the long follow-up duration, median (IQR) = 6.5(3-10) years. Most patients (80%) achieved CD4 T-cell counts >500 cells/ul, but in 8%, this took >5 years. Among the patients who failed to reach a CD4 T-cell count >500 cells/ul, 16% received cART for >10 years. In a multivariate analysis, faster time to achieve a CD4 T-cell count >500 cells/ul was associated with higher baseline CD4 T-cell counts (p<0.001), younger age (p = 0.019) and treatment initiation with a protease inhibitor (PI)-based regimen (vs. non nucleoside reverse transcriptase inhibitor, NNRTI; p = 0.043). Factors associated with achieving CD4 T-cell counts >200 cells/ul included higher baseline CD4 T cell count (p<0.001), not having a prior AIDS-defining illness (p = 0.018) and higher baseline HIV RNA (p<0.001). CONCLUSION: The time taken to achieve a CD4 T cell count >500 cells/ul despite long-term cART is prolonged in a subset of patients in AHOD. Starting cART early with a PI-based regimen (vs. NNRTI-based regimen) is associated with more rapid recovery of a CD4 T-cell count >500 cells/ul. PMID- 21674058 TI - Mitotic arrest in teratoma susceptible fetal male germ cells. AB - Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma susceptible and non-susceptible mouse strains. This study examines the entry of fetal germ cells into the male pathway and mitotic arrest in 129T2/SvJ mice. We find that although the entry of fetal germ cells into mitotic arrest is similar between 129T2/SvJ, C57Bl/6 and CD1 mice, there were significant differences in the size and germ cell content of the testis cords in these strains. In 129T2/SvJ mice germ cell mitotic arrest involves upregulation of p27(KIP1), p15(INK4B), activation of RB, the expression of male germ cell differentiation markers NANOS2, DNMT3L and MILI and repression of the pluripotency network. The germ-line markers DPPA2 and DPPA4 show reciprocal repression and upregulation, respectively, while FGFR3 is substantially enriched in the nucleus of differentiating male germ cells. Further understanding of fetal male germ cell differentiation promises to provide insight into disorders of the testis and germ cell lineage, such as testis tumour formation and infertility. PMID- 21674060 TI - Tumor endothelium marker-8 based decoys exhibit superiority over capillary morphogenesis protein-2 based decoys as anthrax toxin inhibitors. AB - Anthrax toxin is the major virulence factor produced by Bacillus anthracis. The toxin consists of three protein subunits: protective antigen (PA), lethal factor, and edema factor. Inhibition of PA binding to its receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) can effectively block anthrax intoxication, which is particularly valuable when the toxin has already been overproduced at the late stage of anthrax infection, thus rendering antibiotics ineffectual. Receptor-like agonists, such as the mammalian cell expressed von Willebrand factor type A (vWA) domain of CMG2 (sCMG2), have demonstrated potency against the anthrax toxin. However, the soluble vWA domain of TEM8 (sTEM8) was ruled out as an anthrax toxin inhibitor candidate due to its inferior affinity to PA. In the present study, we report that L56A, a PA-binding affinity-elevated mutant of sTEM8, could inhibit anthrax intoxication as effectively as sCMG2 in Fisher 344 rats. Additionally, pharmacokinetics showed that L56A and sTEM8 exhibit advantages over sCMG2 with better lung-targeting and longer plasma retention time, which may contribute to their enhanced protective ability in vivo. Our results suggest that receptor decoys based on TEM8 are promising anthrax toxin inhibitors and, together with the pharmacokinetic studies in this report, may contribute to the development of novel anthrax drugs. PMID- 21674059 TI - p53 transactivation and the impact of mutations, cofactors and small molecules using a simplified yeast-based screening system. AB - BACKGROUND: The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. METHODOLOGY/PRINCIPAL FINDINGS: Given the many factors that might influence p53 function, including expression levels, mutations, cofactor proteins and small molecules, we expanded our previously described yeast-based system to provide the opportunity for efficient investigation of their individual and combined impacts in a miniaturized format. The system integrates i) variable expression of p53 proteins under the finely tunable GAL1,10 promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1. CONCLUSIONS/SIGNIFICANCE: We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins. PMID- 21674061 TI - Evidence for divergent evolution of growth temperature preference in sympatric Saccharomyces species. AB - The genus Saccharomyces currently includes eight species in addition to the model yeast Saccharomyces cerevisiae, most of which can be consistently isolated from tree bark and soil. We recently found sympatric pairs of Saccharomyces species, composed of one cryotolerant and one thermotolerant species in oak bark samples of various geographic origins. In order to contribute to explain the occurrence in sympatry of Saccharomyces species, we screened Saccharomyces genomic data for protein divergence that might be correlated to distinct growth temperature preferences of the species, using the dN/dS ratio as a measure of protein evolution rates and pair-wise species comparisons. In addition to proteins previously implicated in growth at suboptimal temperatures, we found that glycolytic enzymes were among the proteins exhibiting higher than expected divergence when one cryotolerant and one thermotolerant species are compared. By measuring glycolytic fluxes and glycolytic enzymatic activities in different species and at different temperatures, we subsequently show that the unusual divergence of glycolytic genes may be related to divergent evolution of the glycolytic pathway aligning its performance to the growth temperature profiles of the different species. In general, our results support the view that growth temperature preference is a trait that may have undergone divergent selection in the course of ecological speciation in Saccharomyces. PMID- 21674062 TI - Linking self-incompatibility, dichogamy, and flowering synchrony in two Euphorbia species: alternative mechanisms for avoiding self-fertilization? AB - BACKGROUND: Plant species have several mechanisms to avoid selfing such as dichogamy or a self-incompatibility response. Dichogamy in a single flower may reduce autogamy but, to avoid geitonogamy, plants must show flowering synchronization among all their flowers (i.e. synchronous dichogamy). It is hypothesized that one species would not simultaneously show synchronous dichogamy and self-incompatibility because they are redundant mechanisms to reduce selfing; however, this has not been accurately assessed. METHODOLOGY/PRINCIPAL FINDINGS: This expectation was tested over two years in two natural populations of the closely related Mediterranean spurges Euphorbia boetica and E. nicaeensis, which completely avoid autogamy by protogyny at the cyathia level. Both spurges showed a high population synchrony (Z<79), and their inflorescences flower synchronously. In E. nicaeensis, there was no overlap among the cyathia in anthesis of successive inflorescence levels and the overlap between sexual phases of cyathia of the same inflorescence level was uncommon (4-16%). In contrast, E. boetica showed a high overlap among consecutive inflorescence levels (74-93%) and between sexual phases of cyathia of the same inflorescence level (48-80%). The flowering pattern of both spurges was consistent in the two populations and over the two successive years. A hand-pollination experiment demonstrated that E. nicaeensis was strictly self-compatible whereas E. boetica was partially self incompatible. CONCLUSIONS/SIGNIFICANCE: We propose that the complex pattern of synchronized protogyny in E. nicaeensis prevents geitonogamous crosses and, consequently, avoids selfing and inbreeding depression. In E. boetica, a high probability of geitonogamous crosses may occur but, alternatively, this plant escapes selfing through a self-incompatibility response. We posit that synchronous dichogamy and physiological self-incompatibility do not co-occur in the same species because each process is sufficiently effective in avoiding self fertilization. PMID- 21674063 TI - Nitric oxide enhances desiccation tolerance of recalcitrant Antiaris toxicaria seeds via protein S-nitrosylation and carbonylation. AB - The viability of recalcitrant seeds is lost following stress from either drying or freezing. Reactive oxygen species (ROS) resulting from uncontrolled metabolic activity are likely responsible for seed sensitivity to drying. Nitric oxide (NO) and the ascorbate-glutathione cycle can be used for the detoxification of ROS, but their roles in the seed response to desiccation remain poorly understood. Here, we report that desiccation induces rapid accumulation of H(2)O(2), which blocks recalcitrant Antiaris toxicaria seed germination; however, pretreatment with NO increases the activity of antioxidant ascorbate-glutathione pathway enzymes and metabolites, diminishes H(2)O(2) production and assuages the inhibitory effects of desiccation on seed germination. Desiccation increases the protein carbonylation levels and reduces protein S-nitrosylation of these antioxidant enzymes; these effects can be reversed with NO treatment. Antioxidant protein S-nitrosylation levels can be further increased by the application of S nitrosoglutathione reductase inhibitors, which further enhances NO-induced seed germination rates after desiccation and reduces desiccation-induced H(2)O(2) accumulation. These findings suggest that NO reinforces recalcitrant seed desiccation tolerance by regulating antioxidant enzyme activities to stabilize H(2)O(2) accumulation at an appropriate concentration. During this process, protein carbonylation and S-nitrosylation patterns are used as a specific molecular switch to control antioxidant enzyme activities. PMID- 21674064 TI - The RNA helicase Rm62 cooperates with SU(VAR)3-9 to re-silence active transcription in Drosophila melanogaster. AB - Gene expression is highly dynamic and many genes show a wide range in expression over several orders of magnitude. This regulation is often mediated by sequence specific transcription factors. In addition, the tight packaging of DNA into chromatin can provide an additional layer of control resulting in a dynamic range of gene expression covering several orders of magnitude. During transcriptional activation, chromatin barriers have to be eliminated to allow an efficient progression of the RNA polymerase. This repressive chromatin structure has to be re-established quickly after it has been activated in order to tightly regulate gene activity. We show that the DExD/H box containing RNA helicase Rm62 is targeted to a site of rapid induction of transcription where it is responsible for an increased degree of methylation at H3K9 at the heat shock locus after removal of the heat shock stimulus. The RNA helicase interacts with the well characterized histone methyltransferase SU(VAR)3-9 via its N-terminus, which provides a potential mechanism for the targeting of H3K9 methylation to highly regulated genes. The recruitment of SU(VAR)3-9 through interaction with a RNA helicase to a site of active transcription might be a general mechanism that allows an efficient silencing of highly regulated genes thereby enabling a cell to fine tune its gene activity over a wide range. PMID- 21674065 TI - CD40 signaling synergizes with TLR-2 in the BCR independent activation of resting B cells. AB - Conventionally, signaling through BCR initiates sequence of events necessary for activation and differentiation of B cells. We report an alternative approach, independent of BCR, for stimulating resting B (RB) cells, by involving TLR-2 and CD40--molecules crucial for innate and adaptive immunity. CD40 triggering of TLR 2 stimulated RB cells significantly augments their activation, proliferation and differentiation. It also substantially ameliorates the calcium flux, antigen uptake capacity and ability of B cells to activate T cells. The survival of RB cells was improved and it increases the number of cells expressing activation induced deaminase (AID), signifying class switch recombination (CSR). Further, we also observed increased activation rate and decreased threshold period required for optimum stimulation of RB cells. These results corroborate well with microarray gene expression data. This study provides novel insights into coordination between the molecules of innate and adaptive immunity in activating B cells, in a BCR independent manner. This strategy can be exploited to design vaccines to bolster B cell activation and antigen presenting efficiency, leading to faster and better immune response. PMID- 21674066 TI - Polarity changes in the transmembrane domain core of HIV-1 Vpu inhibits its anti tetherin activity. AB - Tetherin (BST-2/CD317) is an interferon-inducible antiviral protein that restricts the release of enveloped viruses from infected cells. The HIV-1 accessory protein Vpu can efficiently antagonize this restriction. In this study, we analyzed mutations of the transmembrane (TM) domain of Vpu, including deletions and substitutions, to delineate amino acids important for HIV-1 viral particle release and in interactions with tetherin. The mutants had similar subcellular localization patterns with that of wild-type Vpu and were functional with respect to CD4 downregulation. We showed that the hydrophobic binding surface for tetherin lies in the core of the Vpu TM domain. Three consecutive hydrophobic isoleucine residues in the middle region of the Vpu TM domain, I15, I16 and I17, were important for stabilizing the tetherin binding interface and determining its sensitivity to tetherin. Changing the polarity of the amino acids at these positions resulted in severe impairment of Vpu-induced tetherin targeting and antagonism. Taken together, these data reveal a model of specific hydrophobic interactions between Vpu and tetherin, which can be potentially targeted in the development of novel anti-HIV-1 drugs. PMID- 21674067 TI - Axonal transmission in the retina introduces a small dispersion of relative timing in the ganglion cell population response. AB - BACKGROUND: Visual stimuli elicit action potentials in tens of different retinal ganglion cells. Each ganglion cell type responds with a different latency to a given stimulus, thus transforming the high-dimensional input into a temporal neural code. The timing of the first spikes between different retinal projection neurons cells may further change along axonal transmission. The purpose of this study is to investigate if intraretinal conduction velocity leads to a synchronization or dispersion of the population signal leaving the eye. METHODOLOGY/PRINCIPAL FINDINGS: We 'imaged' the initiation and transmission of light-evoked action potentials along individual axons in the rabbit retina at micron-scale resolution using a high-density multi-transistor array. We measured unimodal conduction velocity distributions (1.3+/-0.3 m/sec, mean +/- SD) for axonal populations at all retinal eccentricities with the exception of the central part that contains myelinated axons. The velocity variance within each piece of retina is caused by ganglion cell types that show narrower and slightly different average velocity tuning. Ganglion cells of the same type respond with similar latency to spatially homogenous stimuli and conduct with similar velocity. For ganglion cells of different type intraretinal conduction velocity and response latency to flashed stimuli are negatively correlated, indicating that differences in first spike timing increase (up to 10 msec). Similarly, the analysis of pair-wise correlated activity in response to white-noise stimuli reveals that conduction velocity and response latency are negatively correlated. CONCLUSION/SIGNIFICANCE: Intraretinal conduction does not change the relative spike timing between ganglion cells of the same type but increases spike timing differences among ganglion cells of different type. The fastest retinal ganglion cells therefore act as indicators of new stimuli for postsynaptic neurons. The intraretinal dispersion of the population activity will not be compensated by variability in extraretinal conduction times, estimated from data in the literature. PMID- 21674072 TI - Water and sediment quality of dry season pools in a dryland river system: the upper Leichhardt River, Queensland, Australia. AB - This article presents the geochemical characteristics and physicochemical properties of water and sediment from twelve semi-permanent, dryland pools in the upper Leichhardt River catchment, north-west Queensland, Australia. The pools were examined to better understand the quality of sediments and temporary waters in a dryland system with a well-established metal contamination problem. Water and sediment sampling was conducted at the beginning of the hydroperiod in May and September 2007. Water samples were analyzed for major solute compositions (Ca, Na, K, Mg, Cl, SO(4), HCO(3)) and water-soluble (operationally defined as the <0.45 MUm fraction) metals (Cd, Cu, Pb, Zn). Sediment samples were analyzed for total extractable and bioaccessible metals (As, Cd, Cu, Pb, Zn), elemental composition and grain morphology. At the time of sampling a number of pools contained water and sediment with elevated concentrations, compared to Australian regulatory guidelines, of Cu (maximum: water 28 MUg L(-1); sediment 770 mg kg( 1)), Pb (maximum: water 3.4 MUg L(-1); sediment 630 mg kg(-1)) and Zn (maximum: water 150 MUg L(-1); sediment 780 mg kg(-1)). Concentrations of Cd and As in pools were relatively low and generally within Australian regulatory guideline values. Localized factors, such as the interaction of waters with anthropogenic contaminants from modern and historic mine wastes (i.e. residual smelter and slag materials), exert influence on the quality of pool waters. Although the pools of the upper Leichhardt River catchment are contaminated, they do not appear to be the primary repository of water and sediment associated metals when compared to materials in the remainder channel and floodplain. Nevertheless, a precautionary approach should be adopted to mitigating human exposure to contaminated environments, which might include the installation of appropriate warning signs by local health and environmental authorities. PMID- 21674074 TI - Reversible piezo- and photochromic behaviors accompanied by emission color switching of two anthracene-containing organic molecules. AB - Crystalline samples of 3(5)-(9-anthryl)pyrazole and its one derivative exhibit interesting piezochromic behaviors with the emission colors differently changing from blue to green and from green to blue, respectively, upon grinding. PMID- 21674073 TI - Molecular characterization of antibiotic resistance in enterococci recovered from seagulls (Larus cachinnans) representing an environmental health problem. AB - Antimicrobial resistance and the mechanisms implicated were studied in 54 enterococci recovered from 57 seagull fecal samples. Almost 78% of the recovered enterococci showed resistance against one or more antibiotics and these isolates were identified to the species level. E. faecium was the most prevalent species (52.4%). High percentages of erythromycin and tetracycline resistances were found among our isolates (95.2%), and lower percentages were identified to other antibiotics. Most of the tetracycline-resistant strains carried the tet(M) and/or tet(L) genes. Genes associated with Tn916/Tn1545 and/or Tn5397 transposons were detected in 45% of tetracycline-resistant isolates. The erm(B) gene was detected in 65% of erythromycin-resistant isolates. The vat(D) and vat(E) genes were present in 5.9% and 11.8% of quinupristin/dalfopristin-resistant isolates, respectively. The ant(6)-Ia gene was identified in 57.1% of streptomycin resistant isolates. All nine kanamycin-resistant isolates carried the aph(3)' IIIa gene. The cat(A) gene was found in two chloramphenicol-resistant isolates. Seagulls should be considered a risk species for spreading in the environment antimicrobial resistant enterococci and can serve as a sentinel for antibiotic pressure from the surrounding farm and urban setting. PMID- 21674075 TI - Formation of linear supramolecular polymers that is based on host-guest assembly in water. AB - Cucurbit[n]urils (n = 7, 8) and thiazole orange (TO) dyes in aqueous media were found to form host-guest inclusions in different stoichiometries. Supramolecular structures and linear supramolecular polymers were observed through the hydrophobic effect and pi-pi interactions in aqueous solution. PMID- 21674076 TI - Optical methods for sensing glucose. AB - This critical review covers the present state of the art in optical sensing of glucose. Following an introduction into the significance of (continuous) sensing of glucose and a brief look back, we discuss methods based on (a) monitoring the optical properties of intrinsically fluorescent or labeled enzymes, their co enzymes and co-substrates; (b) the measurement of the products of enzymatic oxidation of glucose by glucose oxidase; (c) the use of synthetic boronic acids; (d) the use of Concanavalin A; and (e) the application of other glucose-binding proteins. We finally present an assessment in terms of the advantages and disadvantages of the various methods (237 references). PMID- 21674077 TI - Small-molecule discovery from DNA-encoded chemical libraries. AB - Researchers seeking to improve the efficiency and cost effectiveness of the bioactive small-molecule discovery process have recently embraced selection-based approaches, which in principle offer much higher throughput and simpler infrastructure requirements compared with traditional small-molecule screening methods. Since selection methods benefit greatly from an information-encoding molecule that can be readily amplified and decoded, several academic and industrial groups have turned to DNA as the basis for library encoding and, in some cases, library synthesis. The resulting DNA-encoded synthetic small-molecule libraries, integrated with the high sensitivity of PCR and the recent development of ultra high-throughput DNA sequencing technology, can be evaluated very rapidly for binding or bond formation with a target of interest while consuming minimal quantities of material and requiring only modest investments of time and equipment. In this tutorial review we describe the development of two classes of approaches for encoding chemical structures and reactivity with DNA: DNA-recorded library synthesis, in which encoding and library synthesis take place separately, and DNA-directed library synthesis, in which DNA both encodes and templates library synthesis. We also describe in vitro selection methods used to evaluate DNA-encoded libraries and summarize successful applications of these approaches to the discovery of bioactive small molecules and novel chemical reactivity. PMID- 21674078 TI - Thiocyanate and nitrite analysis using miniaturised isotachophoresis on a planar polymer chip. AB - A new method has been developed to improve the determination of thiocyanate using isotachophoresis. This method uses complexation with copper(II) as a mechanism for improving the separation of thiocyanate from chlorate and perchlorate. By using a pH of 3.25 the method can also be used to analyse nitrite. Separations were carried out using a miniaturised poly(methyl methacrylate) (PMMA) separation device. Linearity was observed from 1.25 to 75 mg dm(-3) with a correlation coefficient of 0.998 for both thiocyanate and nitrite. Limits of detection for these two species were calculated to be 0.8 mg dm(-3) and 0.9 mg dm(-3) respectively. The method was successfully applied to the analysis of these anions in a range of samples including explosive residues. PMID- 21674079 TI - Straightforward four-component access to spiroindolines. AB - Spiroindolines could be synthesized via a very convenient one-pot procedure combining a Ugi coupling and a new copper-catalyzed oxidative process at a peptidyl position. Due to the nature of the first step, this method offers a straightforward access to complex alkaloids with four points of molecular diversity. PMID- 21674080 TI - Microporous sulfur-doped carbon from thienyl-based polymer network precursors. AB - Porous sulfur-doped carbon was synthesised by using a thienyl-based polymer network as a precursor. The sulfur amount varies from 5-23 m% while the materials show microporosity with BET surface areas of up to 711 m(2) g(-1). PMID- 21674081 TI - Designing label-free DNA sequences to achieve controllable turn-off/on fluorescence response for Hg2+ detection. AB - Controllable turn off/on fluorescent sensors for Hg(2+) detection were developed by designing different label-free DNA sequences and using the minor groove dye of DAPI. These assays exhibit high sensitivity and selectivity, with the detection limits of 5 nM and 1.5 nM for turn off and turn on sensors, respectively. PMID- 21674082 TI - Therapeutic applications of gold complexes: lipophilic gold(III) cations and gold(I) complexes for anti-cancer treatment. AB - Gold and its complexes have long been known to display unique biological and medicinal properties. Extensive cell-based (in vitro) and animal (in vivo) studies have revealed the potent anti-cancer activities of diverse classes of gold(I) and gold(III) complexes. Most of the reported anti-cancer active gold complexes are highly cytotoxic and unstable under physiological conditions, which hamper their development to be launched clinically. Several clinical reports showed that lipophilic organic cations are promising anti-cancer drug candidates targeting to mitochondria. Through metal-ligand coordination, gold(I) and gold(III) ions can form stable lipophilic cations containing organic ligands having tunable lipophilicity and diverse functionalities. The present highlight summarizes the recent development of lipophilic gold(III) cations and gold(I) complexes with promising anti-cancer activities. PMID- 21674083 TI - Single-crystal NaY(MoO4)2 thin plates with dominant {001} facets for efficient photocatalytic degradation of dyes under visible light irradiation. AB - Single-crystal NaY(MoO(4))(2) thin plates dominated by high-energy {001} facets were hydrothermally synthesized under relatively mild conditions, free of organic additives, seeds and templates. The as-obtained NaY(MoO(4))(2) thin plates showed an excellent visible-light-responding photocatalytic activity for degradation of dyes in water. PMID- 21674084 TI - In situ synthesis and photoluminescence of Eu3+ doped Y(OH)3@beta-NaYF4 core shell nanotubes. AB - Eu(3+) doped Y(OH)(3)@beta-NaYF(4) core-shell nanotubes were prepared by an in situ synthesis method. The photoluminescence properties were studied under different excitation wavelengths. When the excitation wavelength is 363, 380, and 397 nm, the spectral configurations are similar, and are different from that under 414 nm excitation. The peak location of (7)F(0)->(5)D(3) shifted with excitation wavelength, indicating that the nanocrystals have multiple luminescence centers or emitting states. PMID- 21674085 TI - Fe(III) complex of biuret-amide based macrocyclic ligand as peroxidase enzyme mimic. AB - An Fe(III) complex of a biuret-amide based macrocyclic ligand that exhibits both excellent reactivity for the activation of H(2)O(2) and high stability, especially at low pH and high ionic strength, is reported. PMID- 21674086 TI - Probing the 4f states of ceria by tunneling spectroscopy. AB - Low-temperature scanning tunneling microscopy and spectroscopy have been employed to analyze the local electronic structure of the (111) surface of a ceria thin film grown on Ru(0001). On pristine, defect-free oxide terraces, the empty 4f states of Ce(4+) ions appear as the only spectral feature inside the 6 eV oxide band gap. In contrast, occupied states are detected between -1.0 and -1.5 eV below E(Fermi) in conductance spectra of different point and line defects, such as surface oxygen vacancies, grain boundaries and step edges. They are assigned to partially filled 4f states localized at the Ce(3+) ions. The presence of excess electrons indicates the oxygen-deficient nature of the direct oxide environment. The f state spectroscopy with the STM allows us to probe the spatial distribution of Ce(3+) ions in the ceria surface, providing unique insight into the local reduction state of this chemically important material system. PMID- 21674087 TI - XPS revelation of tungsten edges as a potential donor-type catalyst. AB - We report an efficient yet simple technology of photoelectron spectroscopic purification for identifying the capability of, and direction of charge flow in, a catalyst in a reaction, which has enabled the finding, for the first time, of the similarity of the valence band of tungsten edges to that of Rh adatoms and Ag/Pd alloy and hence suggested that W undercoordinated atoms could be a suitable candidate for replacing the costly Rh adatoms and Ag/Pd alloy as a cheaper, richer, and efficient donor-type catalyst for CO and NO oxidation applications. The new technology and new findings will be stimulating to the community for new catalyst design and identification and provide a better understanding of the electronic process of a catalytic reaction associated with undercoordinated atoms. PMID- 21674097 TI - Dynamic modeling and analysis of cancer cellular network motifs. AB - With the advent of high-throughput biology, we now routinely scan cells and organisms at practically all levels, from genome to protein, metabolism, signaling and other cellular functions. This methodology allowed biological studies to move from a reductionist approach, such as isolation of specific pathways and mechanisms, to a more integrative approach, where biological systems are seen as a network of interconnected components that provide specific outputs and functions in response to stimuli. Recent literature on biological networks demonstrates two important concepts that we will consider in this review: (i) cellular pathways are highly interconnected and should not be studied separately, but as a network; (ii) simple, recurrent feedback motifs within the network can produce very specific functions that favor their modular use. The first theme differs from the traditional approach in biology because it provides a framework (i.e., the network view) in which large datasets are analyzed with an unbiased view. The second theme (feedback motifs) shows the importance of locally analyzing the dynamic properties of biological networks in order to better understand their functionality. We will review these themes with examples from cell signaling networks, gene regulatory networks and metabolic pathways. The deregulation of cellular networks (metabolism, signaling etc.) is involved in cancer, but the size of the networks and resulting non-linear behavior do not allow for intuitive reasoning. In that context, we argue that the qualitative classification of the 'building blocs' of biological networks (i.e. the motifs) in terms of dynamics and functionality will be critical to improve our understanding of cancer biology and rationalize the wealth of information from high-throughput experiments. From the examples highlighted in this review, it is clear that dynamic feedback motifs can be used to provide a unified view of various cellular processes involved in cancer and this will be critical for future research on personalized and predictive cancer therapies. PMID- 21674098 TI - A novel enzymatic bioelectrode system combining a redox hydrogel with a carbon NanoWeb. AB - A novel bioelectrode system has been prepared in which an enzyme and a conducting polymer hydrogel are combined in a nanostructured scaffold. The latter consists of fibres of carbon NanoWeb, grown by chemical vapour deposition onto reticulated vitreous carbon (RVC). The catalytic currents produced by this new bioelectrode system are significantly larger than those obtained using conventional electrodes. PMID- 21674099 TI - Fluorescent one-dimensional nanostructures from a group of uniform materials based on organic salts. AB - Herein we report the synthesis of a fluorescent organic salt through anion exchange and the subsequent fabrication of 1D-nanostructures via a facile templating method. PMID- 21674100 TI - Nonequilibrium transport in quantum impurity models: exact path integral simulations. AB - We simulate the nonequilibrium dynamics of two generic many-body quantum impurity models by employing the recently developed iterative influence-functional path integral method [Phys. Rev. B: Condens. Matter, 2010, 82, 205323]. This general approach is presented here in the context of quantum transport in molecular electronic junctions. Models of particular interest include the single impurity Anderson model and the related spinless two-state Anderson dot. In both cases we study the time evolution of the dot occupation and the current characteristics at finite temperature. A comparison to mean-field results is presented, when applicable. PMID- 21674101 TI - Bis(diamino-diamido)-tetrathiafulvalene, a redox active sensor for proton, anions, and cations. AB - A bis(diamino-diamido) tetrathiafulvalene (TTF) derivative H(4)L(2) has been designed and synthesized. Experiments of pH titration reveal that integrating the redox active TTF unit with the diamino-diamido moiety adds new properties to the traditional ligand. Oxidation of the TTF moiety increases the acidity of the amido group, and the coordination of metal ions is also sensitive to the oxidation state of the ligand. This compound is capable of acting as a leaving or accepting ligand for proton and metal ions. The electrochemistry of the protonated TTF derivative of H(4)L(2) was studied in the presence of a series of oxo anions and metal cations. The results indicate that the redox potentials selectively respond to HC(2)O(4)(-) and SO(4)(2-) anions, and Ni(II) and Cu(II) cations. Solid-state structures of a cation-anion salt H(8)L(2).2SO(4).8H(2)O and a nickel coordination compound [Ni(2)L(2)].2DMF have been characterized by means of X-ray crystallography which are helpful in understanding the inter-ion interactions. PMID- 21674102 TI - Destabilisation of magnesium hydride by germanium as a new potential multicomponent hydrogen storage system. AB - MgH(2) has too high an operating temperature for many hydrogen storage applications. However, MgH(2) ball-milled with Ge leads to a thermodynamic destabilisation of >50 kJ mol(-1)(H(2)). This has dramatically reduced the temperature of dehydrogenation to 130 degrees C, opening up the potential for Mg based multicomponent systems as hydrogen stores for a range of applications. PMID- 21674103 TI - Stability improvement of Cu3(BTC)2 metal-organic frameworks under steaming conditions by encapsulation of a Keggin polyoxometalate. AB - Cu(3)(BTC)(2) with an incorporated Keggin polyoxometalate was demonstrated to be stable under steaming conditions up to 483 K, while the isostructural HKUST-1 degrades and transforms into [Cu(2)OH(BTC)(H(2)O)](n).2nH(2)O from 343 K onwards. PMID- 21674104 TI - Highly active Pd nanoparticles dispersed on amine functionalized layered double hydroxide for Suzuki coupling reaction. AB - The synthesis of well dispersed palladium nanoparticles (1-5 nm) on diamine functionalized LDH is reported. The heterogeneous catalyst displayed unprecedented activity in Suzuki coupling reaction. PMID- 21674105 TI - In situ dynamic measurements of the enhanced SERS signal using an optoelectrofluidic SERS platform. AB - A novel active surface-enhanced Raman scattering (SERS) platform for dynamic on demand generation of SERS active sites based on optoelectrofluidics is presented in this paper. When a laser source is projected into a sample solution containing metal nanoparticles in an optoelectrofluidic device and an alternating current (ac) electric field is applied, the metal nanoparticles are spontaneously concentrated and assembled within the laser spot, form SERS-active sites, and enhance the Raman signal significantly, allowing dynamic and more sensitive SERS detection. In this simple platform, in which a glass slide-like optoelectrofluidic device is integrated into a conventional SERS detection system, both dynamic concentration of metal nanoparticles and in situ detection of SERS signal are simultaneously possible with only a single laser source. This optoelectrofluidic SERS spectroscopy allows on-demand generation of 'hot spots' at specific regions of interest, and highly sensitive, reliable, and stable SERS measurements of the target molecules in a tiny volume (~500 nL) of liquid sample without any fluidic components and complicated systems. PMID- 21674106 TI - Easy access to CF2-containing molecules based on the reaction of 2,2,3,3 tetrafluorooxetane with various nucleophiles. AB - 2,2,3,3-Tetrafluorooxetane reacted easily with organolithium reagents to give 1,1,3-trisubstituted 2,2-difluoropropan-1-ols in good to excellent yields. On the other hand, the reaction with Grignard reagent led to 3-bromo-1,1-disubstituted 2,2-difluoropropan-1-ols in good yields. On treating with lithium enolates, generated from enol silyl ethers and MeLi/LiBr, the corresponding 1-bromo-2,2 difluoro-3,5-dicarbonyl compounds were obtained in fair to good yields. 3-Iodo 2,2-difluoropropanoate, prepared readily from 2,2,3,3-tetrafluorooxetane and NaI, reacted successfully with various silyl enol ethers in the presence of a radical initiator to provide the corresponding coupling products in good yields. PMID- 21674107 TI - Drug release from hydrazone-containing peptide amphiphiles. AB - Hydrolytically-labile hydrazones in peptide amphiphiles were studied as degradable tethers for release of the drug nabumetone from nanofiber gels. On resin addition of the novel compound tri-Boc-hydrazido adipic acid to a lysine epsilon-amine allowed for precise placement of a hydrazide in a peptide sequence. PMID- 21674108 TI - Silica precipitation with synthetic silaffin peptides. AB - Silaffins are highly charged proteins which are one of the major contributing compounds that are thought to be responsible for the formation of the hierarchically structured silica-based cell walls of diatoms. Here we describe the synthesis of an oligo-propyleneamine substituted lysine derivative and its incorporation into the KXXK peptide motif occurring repeatedly in silaffins. N(epsilon)-alkylation of lysine was achieved by a Mitsunobu reaction to obtain a protected lysine derivative which is convenient for solid phase peptide synthesis. Quantitative silica precipitation experiments together with structural information about the precipitated silica structures gained by scanning electron microscopy revealed a dependence of the amount and form of the silica precipitates on the peptide structure. PMID- 21674109 TI - Flustramine inspired synthesis and biological evaluation of pyrroloindoline triazole amides as novel inhibitors of bacterial biofilms. AB - Anti-biofilm agents have been developed based upon the flustramine family of alkaloids isolated from Flustra foliacea. A Garg interrupted Fischer indolization reaction was employed to access a core pyrroloindoline scaffold that was subsequently employed to create a pyrroloindoline triazole amide library. Screening for the ability to modulate biofilm formation against strains of Gram positive and Gram-negative bacteria identified several compounds with low micromolar, non-toxic IC(50) values. PMID- 21674110 TI - Comparison of a calculated and measured XANES spectrum of alpha-Fe2O3. AB - Comparison and prediction of the experimental XANES spectrum is a good measurement of the quality of the electronic structure calculations employed, and their ability to predict electronic transitions in solids. Here we present a comparison between BLYP + U and hybrid-BLYP calculations regarding the geometric, magnetic and electronic structures of alpha-Fe(2)O(3) (hematite). Several values of U and different percentages of Fock-exchange have been screened to see how their contributions affect different properties of hematite, paying particular attention to the electronic structure. To estimate the quality of the various methods the calculated density-of-states were compared to the experimentally collected XANES spectrum of the iron K-edge, providing information about the orbitals describing the conduction band. We find that in agreement with previous studies DFT + U and hybrid-functional simulations can correctly predict the character of the valence band, but only Fock-exchange higher than 30% or U-values equal or larger than 6 eV properly reproduce the order between the t(g) and e orbitals in the conduction band, and can, therefore, be used to study and predict XANES spectra and electronic transitions in hematite. PMID- 21674111 TI - Hydrogen-bonded structures for self-aggregates of 2,5-dimethylpyrrole and its binary clusters with pyrrole studied by IR cavity ringdown spectroscopy. AB - N-H...pi hydrogen-bonded (H-bonded) structures were studied by applying vibrational spectroscopy to self-aggregate clusters of 2,5-dimethylpyrrole (DMPy) and its binary clusters with pyrrole (Py). The NH stretching vibrations of jet cooled clusters were observed by IR cavity ringdown spectroscopy. A combination of experiments and density functional theory calculations revealed the stable structures, intermolecular binding energies, and harmonic vibrational frequencies. The IR spectrum of the DMPy self-aggregate clusters was very similar in spectral features to that of the Py clusters in a previous work. The observed NH stretching vibrations at 3505, 3420, 3371, and 3353 cm(-1) are simultaneously red-shifted by ~25 cm(-1) from the Py monomer, dimer, trimer, and tetramer, respectively. Based on a spectral analogy of DMPy with Py, and a consistency of the calculated harmonic frequencies with experiments, the H-bonded structures of the DMPy clusters were determined to be of a T-shape for a dimer and a cyclic for a trimer and a tetramer. For the DMPy-Py binary clusters, we discussed the stability and geometry of the N-H...pi interactions in the T-shaped dimer and the cyclic trimer. The binary dimer showed the only single NH stretch at 3419 cm(-1) in the IR spectrum. A vibrational analysis of the H-bonded NH stretches as well as the calculated stabilization energies deduced that only the binary dimer by DMPy as an acceptor and Py as a donor can exist in a supersonic jet. For binary trimers, NH stretches were observed due to both (DMPy)(2)-(Py)(1) and (DMPy)(1) (Py)(2). They were found to have different vibrational patterns from each other; the former showed three dispersed NH stretches, and the other had two quasi degenerate NH stretches. Throughout this study, we also considered the intermolecular geometries, such as the H-bond distance and the angle in terms of the methyl group substitution effect. PMID- 21674112 TI - A new reducing agent to prepare single-layer, high-quality reduced graphene oxide for device applications. AB - We report on a novel, efficient, and one-step approach to prepare single-layer reduced graphene oxide (RGO) suspensions and films using hydroxylamine hydrochloride. The effective chemical reduction of GO was evidenced by a significant increase in the C/O ratio and five orders of magnitude decrease in the GO resistance. Field-effect transistor gas sensors were fabricated using as produced RGO sheets and the resulting sensor exhibited a fast response and a high sensitivity to low-concentration target gases at room temperature. PMID- 21674113 TI - Facile fabrication of chitosan-calcium carbonate nanowall arrays and their use as a sensitive non-enzymatic organophosphate pesticide sensor. AB - Novel nanowall arrays of CaCO(3)-chitosan (CaCO(3)-chi) were deposited onto a cathodic substrate by a facile one-step electrodeposition approach. Results demonstrate that chitosan plays an important role in the formation of nanowall arrays. Freestanding well-aligned CaCO(3)-chi nanowall arrays were observed to be uniformly distributed over the whole substrate with a lateral dimension in the micrometre size and an average pore size of ~400 nm. The as-formed CaCO(3)-chi nanowall arrays featuring interlaced porous network architecture, large surface area, and open boundaries, are highly efficient in the capture of organophosphate pesticides (OPs). Combined with stripping voltammetry, a highly sensitive non enzymatic OPs sensor was fabricated using the prepared CaCO(3)-chi nanowall arrays for solid phase extraction (SPE). The detection limit for methyl parathion (MP) in aqueous solutions was determined to be 0.8 ng mL(-1) (S/N = 3). The resulting sensor made of novel CaCO(3)-chi nanowall arrays exhibits good reproducibility and acceptable stability. This work not only provides a facile and effective route for the preparation of CaCO(3)-chi nanowall arrays, but also offers a new promising protocol for OPs analysis. PMID- 21674114 TI - Photoisomerization of azobenzene derivatives confined in gold nanoparticle aggregates. AB - Photoisomerization is an important reaction that confers photoresponsive functionality on nanoparticles. Although photoisomerization of molecules forming self-assembled monolayers on two-dimensional surfaces or three-dimensional clusters has been studied, a detailed picture of interactions of molecules undergoing isomerization with nanoparticles is not available. In this paper, we report on the photoisomerization of azobenzene derivatives spatially confined in gold nanoparticle (AuNP) aggregates. AuNP aggregates allow us to simultaneously probe the structural changes of molecules via surface-enhanced Raman spectroscopy (SERS) and the accompanying changes in interparticle interactions via surface plasmon couplings. AuNP aggregates are formed by the adsorption of synthesized azobenzene-derivatized sulfides (Az) onto the surfaces of AuNPs. The photoisomerization of the adsorbed Az from trans to cis by excitation at 365 nm causes the AuNPs to move close to each other in the aggregates, leading to a redshift of the surface plasmon coupling band in the UV-vis spectra and a concomitant rise in SERS intensity. SERS spectra reveal that the vibrational modes containing the N=N stretching character redshift upon irradiation, suggesting that the N=N bond is significantly weakened when Az is in the cis form in the AuNP aggregates. The weakening of the N=N bond is attributed to the interaction of the N=N bond, which is more exposed to the outside in the cis conformation, with the nearby AuNPs that have come closer by the isomerization of adsorbed Az. We find that backisomerization from cis to trans occurs much faster in the AuNP aggregates (k = 1.9 * 10(-2) min(-1)) than in solution (k = 1.3 * 10( 3) min(-1)) because of the reduced N=N bond order of cis-Az in the aggregates. PMID- 21674115 TI - Growth of sputter-deposited gold nanoparticles in ionic liquids. AB - The growth of gold nanoparticles (NPs) synthesized by sputter deposition on an ionic liquid surface is studied in situ in the bulk phase of the ionic liquids (ILs) 1-butyl-3-methylimidazolium dicyanamide [C(1)C(4)Im][N(CN)(2)], 1-butyl-3 methylimidazolium bis(trifluoromethanesulfonyl)amide [C(1)C(4)Im][Tf(2)N], 1 butyl-3-methylimidazolium tetrafluoroborate [C(1)C(4)Im][BF(4)], 1-butyl-3 methylimidazolium hexafluorophosphate [C(1)C(4)Im][PF(6)] and 1-butyl-3 methylimidazolium triflate [C(1)C(4)Im][TfO]. It is found that primary nanoparticles with a diameter smaller than 2.5 nm are present in the sample immediately after sputtering. Growth of these primary particles proceeds after the end of the sputtering process and stops when the nanoparticles reach a certain size. Depending on the viscosity of the ionic liquid this growth process can proceed several hours to several days. The growth speed is fastest for the least viscous ionic liquid and follows the trend [C(1)C(4)Im][N(CN)(2)] > [C(1)C(4)Im][Tf(2)N] > [C(1)C(4)Im][TfO] > [C(1)C(4)Im][BF(4)] > [C(1)C(4)Im][PF(6)]. It is also found that a higher concentration of sputtered gold results in faster growth of the gold nanoparticles. A discussion on the growth mechanism of sputtered gold NPs is included. PMID- 21674116 TI - Ultracold collisions and reactions of vibrationally excited OH radicals with oxygen atoms. AB - We report a quantum dynamics study of O + OH (v = 1, j = 0) collisions on its ground electronic state, employing two different potential energy surfaces: the DIMKP surface by Kendrick and Pack, and the XXZLG surface by Xu et al. A time independent quantum mechanical method based on hyperspherical coordinates has been adopted for the dynamics calculations. Energy-dependent probabilities and rate coefficients are computed for the elastic, inelastic, and reactive channels over the collision energy range E(coll) = 10(-10)-0.35 eV, for J = 0 total angular momentum. Initial state-selected reaction rate coefficients are also calculated from the J = 0 reaction probabilities by applying a J-shifting approximation, for temperatures in the range T = 10(-6)-700 K. Our results show that the dynamics of the collisional process and its outcome are strongly influenced by long-range forces, and chemical reactivity is found to be sensitive to the choice of the potential energy surface. For O + OH (v = 1, j = 0) collisions at low temperatures, vibrational relaxation of OH competes with reactive scattering. Since long-range interactions can facilitate vibrational relaxation processes, we find that the DIMKP potential (which explicitly includes van der Waals dispersion terms) favours vibrational relaxation over chemical reaction at low temperatures. On the DIMKP potential in the ultracold regime, the reaction rate coefficient for O + OH (v = 1, j = 0) is found to be a factor of thirteen lower than that for O + OH (v = 0, j = 0). This significantly high reactivity of OH (v = 0, j = 0), compared to that of OH (v = 1, j = 0), is attributed to enhancement caused by the presence of a HO(2) quasibound state (scattering resonance) with energy near the O + OH (v = 0, j = 0) dissociation threshold. In contrast, the XXZLG potential does not contain explicit van der Waals terms, being just an extrapolation by a nearly constant function at large O OH distances. Therefore, long-range potential couplings are absent in calculations using the XXZLG surface, which does not induce vibrational relaxation as efficiently as the DIMKP potential. The XXZLG potential leads to a slightly higher reactivity (a factor of 1.4 higher) for O + OH (v = 1, j = 0) compared to that for O + OH (v = 0, j = 0) at ultracold temperatures. Overall, both potential surfaces yield comparable values of reaction rate coefficients at low temperatures for the O + OH (v = 1, j = 0) reaction. PMID- 21674117 TI - Magnetic micropillars as a tool to govern substrate deformations. AB - Magnetic actuated microdevices can be used to achieve several complex functions in microfluidics and microfabricated devices. For example, magnetic mixers and magnetic actuators have been proposed to help handling fluids at a small scale. Here, we present a strategy to create magnetically actuated micropillar arrays. We combined microfabrication techniques and the dispersion of magnetic aggregates embedded inside polymeric matrices to design micrometre scale magnetic features. By creating a magnetic field gradient in the vicinity of the substrate, well defined forces were applied on these magnetic aggregates which in turn induced a deflection of the micropillars. By dispersing either spherical aggregates or magnetic nanowires into the gels, we can induce synchronized motions of a group of pillars or the movement of isolated pillars under a magnetic field gradient. When combined with microfabrication processes, this versatile tool leads to local as well as global substrate actuations within a range of dimensions that are relevant for microfluidics and biological applications. PMID- 21674118 TI - 100 mm dynamic stencils pattern sub-micrometre structures. AB - Dynamic stencil lithography uses a moving shadow-mask to draw patterns by having directionally evaporated material deposited through the stencil apertures onto the substrate. Sub-micrometre, two-dimensional patterning is demonstrated at full 100 mm wafer scale, with two examples emphasizing this technique's unique features. Structures having a width-modulated height below a certain aperture size are fabricated by moving the stencil according to a two-dimensional trajectory. Variable-period gratings are obtained by translating a row of apertures at different orientations with respect to the row's axis. Despite the long deposition sequences one could envision for a stencil in dynamic mode, the apertures' active life-time in the sub-micrometre domain remains limited by the material's accretion on the membrane, resulting in the eventual clogging of the openings. A novel solution to this problem containing a micro-heater embedded in the membrane is described and its effectiveness in preventing material from clogging the apertures is demonstrated. PMID- 21674119 TI - Visible-light-induced photoelectrochemical behaviors of Fe-modified TiO2 nanotube arrays. AB - Fe-modified TiO(2) nanotube arrays (TiO(2) NTs) were prepared by annealing amorphous TiO(2) NTs whose surface was covered with Fe(3+) by a dip-coating procedure, and characterized by scanning electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy and UV-visible reflectance spectroscopy. The photoelectrochemical properties were evaluated by the photocurrent response and photoelectrocatalytic (PEC) degradation of methylene orange (MO) and 4 chlorophenol in water under visible-light irradiation (lambda > 420 nm). The results showed that a Fe-modified TiO(2) NTs electrode exhibited a larger photocurrent response and higher PEC activity for the degradation of organic pollutants than a pure TiO(2) NTs electrode. At a bias potential of 0.4 V, the photocurrent response of a 0.5 M Fe-modified TiO(2) NTs electrode exceeded that of a pure TiO(2) NTs electrode by a factor of about 10, and the PEC degradation rates of MO and 4-chlorophenol on a 0.5 M Fe-modified TiO(2) NTs electrode exceeded those on a pure TiO(2) NTs electrode by a factor of about 2.5. The larger photocurrent response and higher PEC activity of Fe-modified TiO(2) NTs could be attributed to the enhancement of separation of charge-carriers at the external electric field and the extension of the light response range of TiO(2) to the visible-light region with the narrowing of the band gap. PMID- 21674120 TI - Controlled release of reagents in capillary-driven microfluidics using reagent integrators. AB - The integration and release of reagents in microfluidics as used for point-of care testing is essential for an easy and accurate operation of these promising diagnostic devices. Here, we present microfluidic functional structures, which we call reagent integrators (RIs), for integrating and releasing small amounts of dried reagents (ng quantities and less) into microlitres of sample in a capillary driven microfluidic chip. Typically, a RI is less than 1 mm(2) in area and has an inlet splitting into a central reagent channel, in which reagents can be loaded using an inkjet spotter, and two diluter channels. During filling of the microfluidic chip, spotted reagents reconstitute and exit the RI with a dilution factor that relates to the relative hydraulic resistance of the channels forming the RI. We exemplify the working principle of RIs by (i) distributing ~100 pg of horseradish peroxidase (HRP) in different volume fractions of a 1 MUL solution containing a fluorogenic substrate for HRP and (ii) performing an immunoassay for C-reactive protein (CRP) using 450 pg of fluorescently labeled detection antibodies (dAbs) that reconstitute in ~5 to 30% of a 1 MUL sample of human serum. RIs preserve the conceptual simplicity of lateral flow assays while providing a great degree of control over the integration and release of reagents in a stream of sample. We believe RIs to be broadly applicable to microfluidic devices as used for biological assays. PMID- 21674121 TI - Nerve growth factor concentrations in the synovial fluid from healthy dogs and dogs with secondary osteoarthritis. AB - OBJECTIVE: To measure the concentrations of nerve growth factor (NGF) in the synovial fluid from normal dogs and dogs with osteoarthritis (OA) secondary to common joint disorders. METHODS: Nerve growth factor synovial concentrations were measured by ELISA assay in 50 dogs divided into three groups: 12 healthy, 16 affected by acute lameness within seven days before enrolment, and 22 with chronic lameness persisting by more than one month before enrolment and accompanied by radiological signs of OA. Both acute and chronic lameness were secondary to orthopaedic diseases involving the shoulder, elbow and stifle joints. Nerve growth factor synovial concentrations were compared between means for healthy and acute groups and between the three groups using an F-test. Significance level was set at p <0.05. RESULTS: Nerve growth factor was detected in all canine synovial fluid samples. However, the mean synovial NGF concentration of healthy dogs (3.65 +/- 2.18 pg/ml) was not significantly different from the mean value in dogs with acute lameness (6.45 +/- 2.45 pg/ml) (p = 0.79). Conversely, the mean synovial NGF concentration in dogs with chronic lameness (20.19 +/- 17.51 pg/ml) was found to be significantly higher than that found in healthy dogs (p <0.01). CLINICAL SIGNIFICANCE: This study demonstrates for the first time the presence of NGF in canine synovial fluid and its increased concentrations in dogs with chronic lameness compared to healthy dogs and dogs with acute lameness. The association between chronic lameness and raised synovial concentrations may suggest an involvement of NGF in OA inflammation and chronic pain. PMID- 21674122 TI - Asthma and psychological dysfunction. AB - Despite effective treatment, asthma outcomes remain suboptimal. Anxiety and depression occur more commonly in people with asthma than expected, and are associated with poor asthma outcomes. The direction of the relationship and the mechanisms underlying it are uncertain. Whether screening for and treating co morbid anxiety and depression can improve asthma outcomes is unclear from the current evidence. Primary care clinicians treating asthma should be aware of the possibility of psychological dysfunction in asthmatics, particularly those with poor control. Further research is required to assess the importance of detecting and treating these conditions in community asthma care. PMID- 21674123 TI - Differential methylation hybridization profiling identifies involvement of STAT1 mediated pathways in breast cancer. AB - Many cancer-related genes are regulated by an epigenetic mechanism through modification of the methylation status of CpG sites at the promoter. This study was carried out at a genome-wide scale to mine genes in which the methylation of CpG sites is altered in breast cancer tissues. Differential methylation hybridization analysis was conducted using a chromosomal DNA mixture of ten normal and cancer tissue sets. A CpG microarray harboring 237,220 CpG sites of the whole genome was interrogated and the resulting methylation level differences, as well as the RNA expression differences, between the normal and cancer sets for selected genes were verified in breast cell lines by methylation specific PCR and real-time PCR analyses. As a result, we identified and verified novel genes that were hypermethylated in breast cancer, such as NRN1, CA5B and RPIA. Pathway analysis of the genes with altered methylation patterns identified the involvement of a differentiation-related network of genes whose activity may be heavily regulated by STAT1 in breast tumorigenesis. Our results suggest that epigenetic dysregulation of cellular processes relevant to STAT1-dependent cellular differentiation may be intimately involved in breast carcinogenesis. These findings lend credence to the possibility of using tumor-specific alterations in methylation patterns as biomarkers in estimating prognosis and assessing treatment options for breast cancer. PMID- 21674124 TI - Pharmacological inhibition of the Hedgehog pathway prevents human rhabdomyosarcoma cell growth. AB - The Hedgehog pathway functions as an organizer in embryonic development. Recent studies have shown that mutation of the PTCH1 gene involved in the Hedgehog pathway affects rhabdomyosarcoma development. However, the expression of Hedgehog pathway molecules in human rhabdomyosarcoma cells has not been well clarified. In addition, the effect of pharmacological inhibition of the Hedgehog pathway is not known. We investigated the expression of the genes involved in the Hedgehog pathway using human rhabdomyosarcoma cell lines and biopsy specimens. Further, we evaluated the effect of pharmacological inhibition of the Hedgehog pathway using cyclopamine or GANT61 by WST assay, cell proliferation assay and cell death detection assay. Real-time PCR revealed that human rhabdomyosarcoma cell lines and biopsy specimens overexpressed the following genes: Sonic hedgehog, Indian hedgehog, Desert hedgehog, PTCH1, SMO, GLI1, GLI2 and ULK3. Immunohistochemistry revealed that rhabdomyosarcoma cell lines and biopsy specimens expressed SMO and GLI2. Inhibition of SMO by cyclopamine slowed the growth of human rhabdomyosarcoma cell lines. Similarly, inhibition of GLI by GANT61 slowed the growth of human rhabdomyosarcoma cell lines. Inhibition of cell proliferation and apoptotic cell death together prevented the growth of rhabdomyosarcoma cells by cyclopamine and GANT61 treatment. Our findings suggest that pharmacological inhibition of the Hedgehog pathway may be a useful approach for treating rhabdomyosarcoma patients. PMID- 21674125 TI - YM155, a selective survivin suppressant, inhibits tumor spread and prolongs survival in a spontaneous metastatic model of human triple negative breast cancer. AB - Metastatic triple negative breast cancer [TNBC, with negative expression of estrogen and progesterone receptors and no overexpression of HER2/neu (ErbB-2)] remains a major therapeutic challenge because of its poor overall prognosis and lack of optimal targeted therapies. Survivin has been implicated as an important mediator of breast cancer cell growth and dysfunctions in apoptosis, and its expression correlates with a higher incidence of metastases and patient mortality; thus, survivin is an attractive target for novel anti-cancer agents. In previous studies, we identified YM155 as a small molecule that selectively suppresses survivin expression. YM155 inhibits the growth of a wide range of human cancer cell lines. Tumor regression induced by YM155 is associated with decreased intratumoral survivin expression, increased apoptosis and a decreased mitotic index. In the present study, we evaluated the antitumor efficacy of YM155 both in vitro and in vivo using preclinical TNBC models. We found that YM155 suppressed survivin expression, including that of its splice variants (survivin 2B, deltaEx3 and 3B), resulting in decreased cellular proliferation and spontaneous apoptosis of human TNBC cells. In a mouse xenograft model, continuous infusion of YM155 led to the complete regression of subcutaneously established tumors. Furthermore, YM155 reduced spontaneous metastases and significantly prolonged the survival of animals bearing established metastatic tumors in the MDA-MB-231-Luc-D3H2-LN orthotopic model. These results suggest that the survivin suppressing activity of YM155 may offer a novel therapeutic option for patients with metastatic TNBC. PMID- 21674126 TI - Hypermethylation of promoter regions of the APC1A and p16INK4a genes in relation to prognosis and tumor characteristics in cervical cancer patients. AB - Hypermethylation of the O6-MGMT, p14ARF, p16INK4a, RASSF1A and APC1A genes are unfavourable prognostic markers in colorectal cancer (CRC). We hypothesized that they could be related to prognosis also in cervical cancer. Methylation was studied in DNA extracts from surgical specimens of cancer tissue by novel pyrosequencing methods. In 109 patients (90 squamous cell carcinomas, 19 adenocarcinomas), we found that hypermethylation of the APC1A gene promoter occurred in 8.3% of patients, and of p16INK4a in 1.8%. APC1A hypermethylation was significantly related to more advanced FIGO stage of the tumor (P=0.013), larger tumor diameter (P=0.049) and distant recurrence-free survival (P=0.0007), but not with locoregional recurrence rate, age, HPV status, DNA ploidy, tumor grade or malignancy grading score. We conclude that methylation of the APC1A promoter in cervical cancer, as diagnosed by pyrosequencing, is significantly related to major biological characteristics of the tumor, and may be a new predictor of poor prognosis in cervical cancer. PMID- 21674127 TI - Antitumor activity of NRC-AN-019 in a pre-clinical breast cancer model. AB - Breast cancer is the second most frequently diagnosed tumor in women. Overexpression of human epidermal growth factor receptors (EGFRs) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior and response to systemic therapy. In this study, we describe a novel compound (NRC-AN-019), which has better antitumor activity than Lapatinib. Here, we demonstrate that NRC-AN-019 is more effective in inhibiting angiogenic potential and proliferation of both MDAMB231 and HTB20/BT474 cells. FACS analysis shows that NRC-AN-019 treatment caused the accumulation of MDAMB231 and BT474 cells in the sub G0/1 phase in a dose-dependent manner and was accompanied by increased PARP cleavage, which is indicative of apoptosis. In addition, we observed inhibition of EGFR phosphorylation in both MDAMB231 and BT474 cells. From our animal studies using SCID mice implanted with BT474 cells, we observed dose-dependent inhibition of tumor growth in NRC-AN-019-treated animals compared to controls or Lapatinib-treated mice at comparable concentrations. The dose dependent inhibition of EGFR phosphorylation was confirmed by immunohistochemical analysis of tumor sections. In vitro results demonstrate that NRC-AN-019 is superior to Lapatinib in EGFR-overexpressing cells and has strong anti angiogenic, anti-proliferative and pro-apoptotic properties in an EGFR overexpressing background (BT474). In vivo studies demonstrate that the antitumor activity of NRC-AN-019 is better over Lapatinib. These results suggest that NRC AN-019 has greater therapeutic potential in the treatment of Her-2-positive breast cancer. PMID- 21674128 TI - DNA damage signaling in response to 5-fluorouracil in three colorectal cancer cell lines with different mismatch repair and TP53 status. AB - We studied patterns of DNA damage signaling and cell cycle response to clinically relevant (bolus) and high doses of 5-fluorouracil (5-FU) in three colorectal cancer cell lines with differing MMR and TP53 status in an attempt to better understand how 5-FU exerts its cytotoxicity. The ATM/CHEK2/ CHEK1 signaling pathway was not activated in response to bolus 5-FU in the MMR-deficient cell lines HCT116 (TP53-proficient or TP53-depleted) and HCT15 (TP53-deficient), consistent with negligible/reparable DNA damage and no cell death. The pattern of DNA damage checkpoint activation in bolus 5-FU-treated HT29 (TP53-deficient/MMR proficient) cultures suggested SSB formation (CHEK1 activation) followed by DSB formation (CHEK2 activation and increased phospho-H2AX levels), but no cell death suggested that DNA repair capacity was not overwhelmed. High-dose 5-FU treatment led to activation of ATM/CHEK2/TP53 (not CHEK1) in TP53-proficient and TP53 depleted HCT116 (later CHEK2 activation relative to TP53-proficient) cultures; HCT15 cultures had ATM activation only. These data and increased phospho-H2AX levels indicated DSB formation; apoptosis was induced in both cell lines indicating irreparable DNA damage. TP53-depleted HCT116 cultures also had DSBs after high-dose 5-FU treatment but experienced a (transient) G1/S cell cycle arrest that protected them from apoptosis. TP53 phosphorylation at Ser20/33/37 was seen in TP53-proficient HCT116 cultures regardless of 5-FU concentration at >=4 h following treatment, indicating TP53 stabilization/transcriptional activation. Overall, activation of ATM, CHEK1 and/or CHEK2 and phospho-H2AX levels reflected the nature of 5-FU-induced DNA damage and indi-cated when DNA damage was significant (5-FU-dose-dependent). DNA repair and cell cycle responses to 5-FU-induced DNA damage were distinctly affected by MMR and TP53 (role in BER/NER) functionalities, but MMR deficiency especially seemed to confer less overall sensitivity to 5-FU. PMID- 21674129 TI - Pituitary adenylate cyclase-activating polypeptide mRNA expression in rat testis and epididymis during postnatal development and experimental cryptorchidism. AB - In the present study, the expression of pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA was investigated in rat testis and epididymis during postnatal development and experimental cryptorchidism using reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization. The results revealed that i) in the testis, PACAP mRNA expression was first detected on day 20 after birth and gradually increased from day 20 to reach a maximum level on day 60, mainly in the spermatocytes and round spermatids; ii) in the epididymis, PACAP mRNA was first detected on day 10 after birth and remained at higher levels from day 40; iii) the levels of PACAP mRNA in the testis and epididymis markedly decreased in a time-dependent manner from 1 week after cryptorchid surgery until they had almost disappeared at 4 weeks. These results suggested that the pattern of PACAP mRNA expression is developmentally dependent in both the testis and epididymis, and the expression of PACAP mRNA is regulated by the local temperature within the testis. In conclusion, the pattern of expression of PACAP in the testis and epididymis suggests a possible role of PACAP in spermatogenesis and sperm maturation. PMID- 21674130 TI - Effects of mechanical strain on ANK, ENPP1 and TGF-beta1 expression in rat endplate chondrocytes in vitro. AB - We investigated the effects of mechanical strain on the progressive ankylosis (ANK) gene and extracellular nucleotide phosphatase/phosphodiesterase (ENPP)1 mRNA expression and TGF-beta1 protein expression in rat endplate chondrocytes in vitro. Endplate chondrocytes were isolated and cultured in vitro. Following identification with toluidine blue and immunocytochemical staining, chondrocytes were subjected to 10% elongation with various frequencies (0.5, 1, 1.5 and 2 Hz) using a Flexercell Tension Plus system at various intervals (3, 6, 12, 24, 36 and 48 h). As a control, cells that had been cultured statically on the same type of plate but were not subjected to stretch were also observed. Real-time reverse transcription-polymerase chain reaction and the enzyme-linked immunosorbent assay were used to study the effects of mechanical strain on ANK and ENPP1 mRNA expression and TGF-beta1 concentration in the supernatant, respectively. Following treatment, the shape of the chondrocytes displayed a significant change from the original polygon to a typical spindle cell morphology; and the arrangement of the cells exhibited a change from a haphazard arrangement to an alignment with a certain direction. In the 0.5 Hz, 24-h group, the ANK gene expression was significantly increased compared to the control group (P<0.05); whereas in the other groups, the ANK and ENPP1 expression levels were reduced. With the increased frequencies in the 24-h group, the ANK gene expression gradually reduced. Changes in the expression of ANK and ENPP1 followed similar trends. TGF-beta1 in the supernatant increased gradually in each frequency group, with a clear increase in the 0.5 Hz group. We conclude that various frequencies of mechanical strain can affect the expression of ANK, ENPP1 and endogenous TGF beta1 in endplate chondrocytes. Our results indicate that 0.5 Hz, 24 h may be the optimal stimulation condition to prevent calcification occurrence and to maintain the function of endplate chondrocytes. PMID- 21674131 TI - Takayasu's arteritis mimicking unilateral pulmonary artery agenesis in a child with severe pulmonary hypertension and right heart failure: a diagnostic dilemma. AB - Affliction of the pulmonary arteries in Takayasu's arteritis is uncommon. Moreover the incidence of pulmonary artery involvement in this condition is often underestimated because of asymptomatic nature in most patients. Severe involvement may however present with pulmonary artery hypertension and hemoptysis, which may prove to be fatal. This case report describes a 9-year-old girl with severe pulmonary hypertension and right heart failure secondary to total occlusion of the right pulmonary artery. Detailed clinical examination and computed tomography (CT) angiography confirmed this diagnosis. PMID- 21674132 TI - Determinants of intracranial hemorrhage incidence in patients on oral anticoagulation followed at the Lahey clinic. AB - Oral anticoagulation with warfarin is widely used to treat venous and arterial thromboembolic disease (Ansell et al. Chest 133(6 suppl):160S-198S, 2008). Its administration is associated with a risk of intracranial hemorrhage (ICH), a devastating complication which usually results in death or severe disability (Fang et al. Am J Med,120(8):700-705, 2007; Rosand et al. Arch Intern Med, 164(8):880-884, 2004). The international normalized ratio (INR) is one of the factors which can help determine the risk of ICH in a given individual (Singer et al. Circ Cardiovasc Qual Outcomes, 2(4):297-304, 2009). Using the DoseResponse((r)) patient database at our institution, we carried a retrospective nested matched case-control study to identify patient characteristics associated with the occurrence of ICH. The database was queried for the years 2004-2009. Each case was matched by month to four control patients having a routine INR determination for the monitoring of chronic anticoagulation. The following characteristics were captured: bleeding type, INR, age, sex, blood pressure, hemoglobin, creatinine, presence or history of pertinent comorbid conditions, intake of antiplatelet agents (aspirin or thienopyridine) and indication for anticoagulation. The relationship between those risk factors and the odds ratio of ICH was determined with conditional logistic regression. Fifty cases of ICH were retrieved. When correcting for pertinent variables, the odds ratio of ICH increased significantly for higher INR values, with a quadratic relationship noted in the model. Increasing mean blood pressure seemed to be associated with a higher risk of ICH, also in an exponential manner. Rising hemoglobin values on the other hand seemed to have a protective effect against such events. About 50% of cases of ICH occurred in or below the therapeutic INR range. The intake of antiplatelet agent was found to be associated with ICH in univariate analysis only. The INR is an important predictor for the incidence of ICH, but in this study an elevated measurement was found in only half of cases. Mean blood pressure appears to be another important determinant of the risk of ICH in the anticoagulated patient population. PMID- 21674133 TI - Pulmonary thromboembolism in an East African tertiary referral hospital. AB - Pulmonary thromboembolism (PTE) is a frequent cause of mortality in Kenya, but its characteristics are hardly reported in Subsaharan Africa. To describe the pattern of PTE among black Africans, in a Kenyan referral hospital. Retrospective study at Kenyatta National Hospital (KNH), Nairobi, Kenya. Records of patients seen between January 2005 and December 2009 were examined for mode of diagnosis, comorbidities, age, gender, treatment and outcome. Data were analyzed using SPSS version 15.0 and are presented in tables and bar charts. One hundred and twenty eight (60 male; 68 female) cases were analyzed. Diagnosis was made by clinical evaluation, a Well's score of >4.0, high D-dimer levels and ultrasound demonstration of a proximal deep venous thrombosis (DVT, 35.9%), lung spiral computer tomography (CT, 50%), multidetector CT (7.8%) and angiography (6.3%). Most frequent comorbidities included DVT (36%); hypertension (18.8%); pulmonary tuberculosis (PTB, 12.5%); HIV infection (10.9%), pueperium, diabetes mellitus and cigarette smoking (9.4% each). Mean age was 40.8 years (range 5-86 years) with a peak between 30 and 50 years. Over 46% of patients were aged 40 years and less. Male:female ratio was 1:1.13. All the patients were treated with anticoagulants and thrombolytics with only one having embolectomy. Ninety-two patients (71.9%) recovered, 18.8% of them with cor pulmonale, while 28.1% died. PTE is not uncommon in Kenya. It affects many individuals below 40 years without a gender bias, and carries high morbidity and mortality. Associated comorbidities include venous thrombosis, lifestyle conditions and communicable diseases. Control measures targeting both are recommended. PMID- 21674134 TI - A national survey of Italian physicians' attitudes towards end-of-life decisions following the death of Eluana Englaro: reply to M.Y. Rady. PMID- 21674135 TI - Modern medicine and the Hippocratic tradition of medicine: restoring professional values. PMID- 21674136 TI - Efficacy and safety of hizentra(r), a new 20% immunoglobulin preparation for subcutaneous administration, in pediatric patients with primary immunodeficiency. AB - Subcutaneous IgG treatment for primary immunodeficiencies (PI) is particularly well suited for children because it does not require venous access and is mostly free of systemic adverse events (AEs). In a prospective, open-label, multicenter, single-arm, Phase III study, 18 children and five adolescents with PI were switched from previous intravenous (IVIG) or subcutaneous (SCIG) IgG treatment to receive dose-equivalent, weekly subcutaneous infusions of Hizentra((r)) for 40 weeks. Mean IgG trough levels were maintained in patients previously on SCIG, or increased in those previously on IVIG, regardless of age. No serious bacterial infections were reported during the efficacy period of the study. The rates of non-serious infections were 4.77 (children) and 5.18 (adolescents) infections per patient per year. Related AEs were observed in seven children (38.9%) and two adolescents (40%). Three serious AEs and two AEs leading to discontinuation (all unrelated) were reported in children. Hizentra((r)) is an effective and well tolerated treatment for pediatric patients. PMID- 21674139 TI - Impact of adrenomedullin on dextran sulfate sodium-induced inflammatory colitis in mice: insights from in vitro and in vivo experimental studies. AB - BACKGROUND: Although adrenomedullin (AM) is known to ameliorate inflammatory processes, few data exist regarding the effect of AM on inflammatory colitis. Therefore, we examined the effect of AM on inflammatory response in vitro and in vivo colitis model. METHODS: In mice experimental colitis induced by 3% dextran sulfate sodium (DSS) in drinking water for 7 days, AM with 225-900 MUg/kg in 0.5 ml of saline or saline alone were given intraperitoneally once a day. In the in vitro experiment, we determined the cytokine response in THP-1 cell activated by lipopolysaccharide with or without AM of 10 nM. Additionally, we performed wound healing assay in Caco-2 cell interfered by DSS with or without AM of 100 nM. RESULTS: In the colitis model, AM significantly reduced the disease activity index, histological score, and local production of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 in accordance with reduction of serum amyloid A levels. Secretion of TNF-alpha in lipopolysaccharide-stimulated THP-1 cells was significantly reduced in the presence of AM. The distance of wound healing interfered by 0.25% DSS was significantly improved in the presence of AM of 100 nM. CONCLUSIONS: These results demonstrate that AM could ameliorate DSS-induced experimental colitis possibly through suppression of systemic and local production of cytokines such as TNF-alpha, associated with acceleration of ulcer reepithelialization and colon tissue regeneration. PMID- 21674137 TI - A distinct role of CD4+ Th17- and Th17-stimulated CD8+ CTL in the pathogenesis of type 1 diabetes and experimental autoimmune encephalomyelitis. AB - Both CD4(+) Th17-cells and CD8(+) cytotoxic T lymphocytes (CTLs) are involved in type 1 diabetes and experimental autoimmune encephalomyelitis (EAE). However, their relationship in pathogenesis of these autoimmune diseases is still elusive. We generated ovalbumin (OVA)- or myelin oligodendrocyte glycoprotein (MOG) specific Th17 cells expressing RORgammat and IL-17 by in vitro co-culturing OVA pulsed and MOG(35-55) peptide-pulsed dendritic cells (DC(OVA) and DC(MOG)) with CD4(+) T cells derived from transgenic OTII and MOG-T cell receptor mice, respectively. We found that these Th17 cells when transferred into C57BL/6 mice stimulated OVA- and MOG-specific CTL responses, respectively. To assess the above question, we adoptively transferred OVA-specific Th17 cells into transgenic rat insulin promoter (RIP)-mOVA mice or RIP-mOVA mice treated with anti-CD8 antibody to deplete Th17-stimulated CD8(+) T cells. We demonstrated that OVA-specific Th17 stimulated CTLs, but not Th17 cells themselves, induced diabetes in RIP-mOVA. We also transferred MOG-specific Th17 cells into C57BL/6 mice and H-2K(b-/-) mice lacking of the ability to generate Th17-stimulated CTLs. We further found that MOG-specific Th17 cells, but not Th17-activated CTLs induced EAE in C57BL/6 mice. Taken together, our data indicate a distinct role of Th17 cells and Th17 stimulated CTLs in the pathogenesis of TID and EAE, which may have great impact on the overall understanding of Th17 cells in the pathogenesis of autoimmune diseases. PMID- 21674140 TI - Comparison of clinical presentation of respiratory tract infections in H1N1/09 positive and H1N1/09-negative patients. AB - The true burden of influenza in children is difficult to assess and is probably underestimated as clinical signs are usually nonspecific, and formal viral identification is rarely searched. In this study, we compare the clinical features of infections related to the new H1N1/09 influenza virus with infections due to other respiratory viruses in children consulting in a tertiary care pediatric hospital in Geneva. Between October 1, 2009 and February 10, 2010, 109 patients were recruited, with a median of age of 7 years (range 0.1-18). There were 75 H1N1/09-positive patients (69%), and 32 (43%) had identified risk factors such as asthma or a history of wheezing. Fever (87%), cough (92%), and rhinitis (85%) were the most frequent reported presenting symptoms in both patient groups. H1N1/09-positive patients were significantly older (median of 8.2 vs. 4.6 years) and were more likely to have risk factors (43% vs. 24%) and myalgias (41% vs. 20%). H1N1/09-negative patients had more wheezing episodes (29% vs. 9%), higher rates of dyspnea (28% vs. 20%) and of hospital admissions (35% vs. 16%). CONCLUSION: Clinical signs cannot reliably differentiate H1N1/09-positive and H1N1/09-negative patients, although we found a higher proportion of myalgias in H1N1/09-positive patients. Severity of disease was lower in H1N1/09-positive than in H1N1/09-negative patients, mostly because of a higher proportion of asthma/wheezing episodes among H1N1/09-negative patients. PMID- 21674141 TI - Acute hemorrhagic edema of young children: a concise narrative review. AB - Acute hemorrhagic edema of young children is an uncommon but likely underestimated cutaneous leukocytoclastic vasculitis. The condition typically affects infants 6-24 months of age with a history of recent respiratory illness with or without course of antibiotics. The diagnosis is made in children, mostly nontoxic in appearance, presenting with nonpruritic, large, round, red to purpuric plaques predominantly over the cheeks, ears, and extremities, with relative sparing of the trunk, often with a target-like appearance, and edema of the distal extremities, ears, and face that is mostly non-pitting, indurative, and tender. In boys, the lesions sometimes involve the scrotum and, more rarely, the penis. Fever, typically of low grade, is often present. Involvement of body systems other than skin is uncommon, and spontaneous recovery usually occurs within 6-21 days without sequelae. In this condition, laboratory tests are non contributory: total blood cell count is often normal, although leukocytosis and thrombocytosis are sometimes found, clotting studies are normal, erythrocyte sedimentation rate and C-reactive protein test are normal or slightly elevated, complement level is normal, autoantibodies are absent, and urinalysis is usually normal. Experienced physicians rapidly consider the possible diagnosis of acute hemorrhagic edema when presented with a nontoxic young child having large targetoid purpuric lesions and indurative swelling, which is non-pitting in character, and make the diagnosis either on the basis of clinical findings alone or supported by a skin biopsy study. PMID- 21674142 TI - Examining the discharge practices of surgeons at a large medical center. AB - We investigate the discharge practices at a large medical center. Specifically, we look for indications that patients are being discharged sooner because of hospital bed-capacity constraints. Using survival analysis techniques, we find statistically significant evidence to indicate that surgeons adjust their discharge practices to accommodate the surgical schedule and number of available recovery beds. We find higher discharge rates on days when utilization is high. We also find an increased discharge rate on days when more surgeries are scheduled. Our findings suggest that discharge decisions are made with bed capacity constraints in mind. We discuss possible explanations for this, as well as the medical and managerial implications of our findings. PMID- 21674143 TI - Outcome based state budget allocation for diabetes prevention programs using multi-criteria optimization with robust weights. AB - We consider the problem of outcomes based budget allocations to chronic disease prevention programs across the United States (US) to achieve greater geographical healthcare equity. We use Diabetes Prevention and Control Programs (DPCP) by the Center for Disease Control and Prevention (CDC) as an example. We present a multi criteria robust weighted sum model for such multi-criteria decision making in a group decision setting. The principal component analysis and an inverse linear programming techniques are presented and used to study the actual 2009 budget allocation by CDC. Our results show that the CDC budget allocation process for the DPCPs is not likely model based. In our empirical study, the relative weights for different prevalence and comorbidity factors and the corresponding budgets obtained under different weight regions are discussed. Parametric analysis suggests that money should be allocated to states to promote diabetes education and to increase patient-healthcare provider interactions to reduce disparity across the US. PMID- 21674144 TI - Prophylactic intravenous immunoglobulin during autologous haemopoietic stem cell transplantation for multiple myeloma is not associated with reduced infectious complications. AB - Patients with multiple myeloma undergoing autologous haemopoietic stem cell transplantation (ASCT) are at high risk for infectious complications. Peri transplant intravenous immunoglobulin (IVIG) has been used with the aim of reducing these risks. Our retrospective, non-randomised study of peri-transplant IVIG use and effect on infectious complications in 266 ASCTs for myeloma from 2000 to 2009 at a major metropolitan referral centre for haematological malignancies found no difference between those receiving peri-transplant IVIG (0.4 g/kg) (n=130) and those who were not (n=110) with regard to bloodstream infections, pneumonia, urinary tract or gastrointestinal infections. When analysed according to pre-transplant therapy (conventional chemotherapy versus novel agents), there was no significant difference in infectious complications between those who did or did not receive peri-transplant IVIG. In conclusion, our study did not show a benefit for the use of peri-transplant IVIG (0.4 g/kg) to reduce infectious complications in a large cohort of patients with myeloma undergoing ASCT. In the absence of data supporting efficacy in this context, there appears to be no benefit in the routine use of IVIG for this purpose. PMID- 21674145 TI - Alterations of hemostatic parameters in the early development of allogeneic hematopoietic stem cell transplantation-related complications. AB - Thrombotic events are common and potentially fatal complications in patients receiving hematopoietic stem cell transplantation (HSCT). Early diagnosis is crucial but remains controversial. In this study, we investigated the early alterations of hemostatic parameters in allogeneic HSCT recipients and determined their potential diagnostic values in transplantation-related thrombotic complications and other post-HSCT events. Results from 107 patients with allogeneic HSCT showed higher levels of plasma plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and tissue-plasminogen activator (t-PA) and a lower level of plasma protein C after transplantation. No change was found for prothrombin time, antithrombin III, D: -dimer, and activated partial thromboplastin time following HSCT. Transplantation-related complications (TRCs) in HSCT patients were defined as thrombotic (n=8), acute graft-versus-host disease (aGVHD, n=45), and infectious (n=38). All patients with TRCs, especially the patients with thrombotic complications, presented significant increases in the mean and maximum levels of PAI-1 during the observation period. Similarly, a high maximum t-PA level was found in the thrombotic group. In contrast, apparent lower levels of mean and minimum protein C were observed in the TRC patients, especially in the aGVHD group. Therefore, the hemostatic imbalance in the early phase of HSCT, reflecting prothrombotic state and endothelial injury due to the conditioning therapy or TRCs, might be useful in the differential diagnosis of the thrombotic complication from other TRCs. PMID- 21674146 TI - Dual-room 1.5-T intraoperative magnetic resonance imaging suite with a movable magnet: implementation and preliminary experience. AB - We hereby report our initial clinical experience of a dual-room intraoperative magnetic resonance imaging (iMRI) suite with a movable 1.5-T magnet for both neurosurgical and independent diagnostic uses. The findings from the first 45 patients who underwent scheduled neurosurgical procedures with iMRI in this suite (mean age, 41.3 +/- 12.0 years; intracranial tumors, 39 patients; cerebral vascular lesions, 5 patients; epilepsy surgery, 1 patient) were reported. The extent of resection depicted at intraoperative imaging, the surgical consequences of iMRI, and the clinical practicability of the suite were analyzed. Fourteen resections with a trans-sphenoidal/transoral approach and 31 craniotomies were performed. Eighty-two iMRI examinations were performed in the operating room, while during the same period of time, 430 diagnostic scans were finished in the diagnostic room. In 22 (48.9%) of 45 patients, iMRI revealed accessible residual tumors leading to further resection. No iMRI-related adverse event occurred. Complete lesion removal was achieved in 36 (80%) of all 45 cases. It is concluded that the dual-room 1.5-T iMRI suite can be successfully integrated into standard neurosurgical workflow. The layout of the dual-room suite can enable the maximum use of the system and save costs by sharing use of the 1.5-T magnet between neurosurgical and diagnostic use. Intraoperative MR imaging may provide valuable information that allows intraoperative modification of the surgical strategy. PMID- 21674147 TI - Postoperative intracranial haemorrhage and remote cerebellar haemorrhage. PMID- 21674148 TI - Pituitary insufficiency after operation of supratentorial intra- and extraaxial tumors outside of the sellar-parasellar region? AB - Recent studies investigating pituitary function after non-sellar brain tumor surgery showed that up to 38.2% of patients have pituitary insufficiency (PI). It has been assumed that the operation causes the PI, but preoperative hormone testing, which would have been necessary to prove this assumption, was not performed. The objective of this study is to answer the question if indeed microsurgery is the culprit of PI in patients with operatively treated non-sellar brain tumors. In this prospective trial, 54 patients with supratentorial non sellar tumors were included. The basal levels of cortisol, prolactin, testosterone, estrogen, IGF-1, fT3, fT4, STH, TSH, ACTH, FSH, and LH were recorded preoperatively on days 1 and 7 after surgery. If basal hormone screening revealed an abnormality, a releasing hormone assay was performed. Before surgery, 24 of the 54 patients (44.4%) already had PI. Additional 25 patients showed either hypocortisolism or hypothyreoidism. As those patients had been pre-treated with dexamethasone and L-thyroxine, these findings were considered not to represent PI but drug effects. Hormone testing on days 1 and 7 after surgery revealed no changes. With 44.4% PI is a frequent finding in brain tumor patients already before surgery. The factors causing preoperative PI remain yet to be identified. The endocrine results after surgery are unchanged which rules out that surgery is the cause of PI. PMID- 21674149 TI - A convolution/superposition method using primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance: a theoretical study on 10-MV X-ray dose calculations in thorax-like phantoms. AB - A convolution/superposition method is proposed for use with primary and scatter dose kernels formed for energy bins of X-ray spectra reconstructed as a function of off-axis distance. It should be noted that the number of energy bins is usually about ten, and that the reconstructed X-ray spectra can reasonably be applied to media with a wide range of effective Z numbers, ranging from water to lead. The study was carried out for 10-MV X-ray doses in water and thorax-like phantoms with the use of open-jaw-collimated fields. The dose calculations were made separately for primary, scatter, and electron contamination dose components, for which we used two extended radiation sources: one was on the X-ray target and the other on the flattening filter. To calculate the in-air beam intensities at points on the isocenter plane for a given jaw-collimated field, we introduced an in-air output factor (OPF(in-air)) expressed as the product of the off-center jaw collimator scatter factor (off-center S (c)), the source off-center ratio factor (OCR(source)), and the jaw-collimator radiation reflection factor (RRF(c)). For more accurate dose calculations, we introduce an electron spread fluctuation factor (F (fwd)) to take into account the angular and spatial spread fluctuation for electrons traveling through different media. PMID- 21674150 TI - Dyslipidemic diabetic serum increases lipid accumulation and expression of stearoyl-CoA desaturase in human macrophages. AB - Type 2 diabetes and dyslipidemia are risk factors for cardiovascular disease. However, mechanisms by which hypertriglyceridemia influences atherogenesis remain unclear. We examined effects of dyslipidemic diabetic serum on macrophage lipid accumulation as a model of foam cell formation. Normal human macrophages were cultured in media supplemented with 10% serum from non-diabetic normolipidemic or non-diabetic hypercholesterolemic adults versus adults with Type 2 diabetes; diabetes and hypertriglyceridemia; or diabetes and hypercholesterolemia. Exposure to diabetic sera resulted in increased macrophage fatty acids (2-3 fold higher, both saturated and unsaturated). Macrophage expression of CD36, scavenger receptor A (SR-A) and stearoyl-CoA desaturase (SCD) was increased, most prominently in macrophages exposed to hypertriglyceridemic diabetic serum (twofold increase in CD36 and fourfold increase in SCD, p < 0.05). In these conditions, RNA inhibition of CD36 reduced macrophage free cholesterol (163.9 +/- 10.5 vs. 221.9 +/- 26.2 mmol free cholesterol/g protein, p = 0.04). RNA inhibition of SCD decreased macrophage fatty acid content, increased ABCA1 level and enhanced cholesterol efflux (18.0 +/- 3.9 vs. 8.0 +/- 0.8% at 48 h, p = 0.03). Diabetic dyslipidemia may contribute to accelerated atherosclerosis via alterations in macrophage lipid metabolism favoring foam cell formation. Increased expression of CD36 and SR-A would facilitate macrophage lipid uptake, while increased expression of SCD could block compensatory upregulation of ABCA1 and cholesterol efflux. Further studies are needed to clarify whether modulation of macrophage lipid metabolism might reduce progression of diabetic atherosclerosis. PMID- 21674151 TI - Psilocybin occasioned mystical-type experiences: immediate and persisting dose related effects. AB - RATIONALE: This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. OBJECTIVES: This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. METHODS: Participants were 18 adults (17 hallucinogen naive). Five 8-h sessions were conducted individually for each participant at 1 month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up. RESULTS: Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. CONCLUSIONS: Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed. PMID- 21674152 TI - Changes of concentrations, shipment amounts and ecological risk of pesticides in river water flowing into Lake Biwa. AB - A survey of various pesticide contaminations was performed for water in Yanamune River flowing into Lake Biwa from 1988 to 2009. Ten pesticides (diazinon and fenitrothion as insecticides, iprobenfos and isoprothiolane as fungicides and chlornitrofen, thiobencarb, molinate, bromobutide, simetryne and pretilachlor as herbicides) were selected and concentration changes of the pesticides were evaluated based on their shipment amounts. Yearly maximum concentrations of eight of the pesticides in Yanamune River water were compared with their no observed effect concentration and their predicted no effect concentration values and initial ecological risk assessment was conducted for five pesticides (diazinon, fenitrothion, iprobenfos, isoprothiolane and thiobencarb) by their predicted no effect concentration values. All of the diazinon (0.01-0.28 MUg/L) and fenitrothion (0.005-0.31 MUg/L) concentrations from 1988 to 2007, the iprobenfos (2.7 and 2.4 MUg/L) concentrations in 1988 and 1990 and the thiobencarb (0.24-2.7 MUg/L) concentrations in 1988, 1992, 1993 and 1995 exceeded their predicted no effect concentration (PNEC) (0.00026, 0.00021, 1.0 and 0.17 MUg/L) values. PMID- 21674153 TI - Determination of black carbon in fine particles using a semi-continuous method at two sites in the city of Guadalajara, Mexico, during 2007. AB - The black carbon is a pollutant species primarily emitted from the combustion of fossil fuels (diesel). Their concentrations associated to PM2.5 were monitoring at two sites in the city of Guadalajara. From January to May (except April), downtown site shown 2.7, 2.6, 4.0 and 2.3 times higher monthly concentrations. The dry season two showed higher concentrations respect to at least one of the others seasons (p < 0.0001) at each site, probably due to atmospheric conditions less favorable for the dispersal of pollutants. During the 24 h period were observed at the year two peaks of concentrations: the highest morning peak and lower night peak, both probably related to anthropogenic activity. PMID- 21674154 TI - Marker-assisted prediction of non-additive genetic values. AB - It has become increasingly clear from systems biology arguments that interaction and non-linearity play an important role in genetic regulation of phenotypic variation for complex traits. Marker-assisted prediction of genetic values assuming additive gene action has been widely investigated because of its relevance in artificial selection. On the other hand, it has been less well studied when non-additive effects hold. Here, we explored a nonparametric model, radial basis function (RBF) regression, for predicting quantitative traits under different gene action modes (additivity, dominance and epistasis). Using simulation, it was found that RBF had better ability (higher predictive correlations and lower predictive mean square errors) of predicting merit of individuals in future generations in the presence of non-additive effects than a linear additive model, the Bayesian Lasso. This was true for populations undergoing either directional or random selection over several generations. Under additive gene action, RBF was slightly worse than the Bayesian Lasso. While prediction of genetic values under additive gene action is well handled by a variety of parametric models, nonparametric RBF regression is a useful counterpart for dealing with situations where non-additive gene action is suspected, and it is robust irrespective of mode of gene action. PMID- 21674156 TI - Immunohistochemical localization of autophagosomal membrane-associated protein LC3 in granular cell tumor and schwannoma. AB - Granular cell tumor (GCT) is a neoplasm derived from Schwann cell or (in cases arising in the neurohypophysis) pituicyte and is characterized by abundant cytoplasm filled with numerous eosinophilic granules, which have been considered autophagolysosomes on the basis of their ultrastructure. To confirm that the formation of these granules is related to an autophagy phenomenon, 12 cases of GCT (including two cases of GCT of the neurohypophysis) were studied immunohistochemically using an antibody against LC3 (microtubule-associated protein 1 light chain 3, a specific marker of autophagy). All cases of GCT showed granular immunoreactivity for LC3 in the cytoplasm of tumor cells, indicating that the formation of intracytoplasmic granules in GCT is closely related to an autophagy phenomenon. For elucidation of the relationship between GCT and schwannoma, 20 cases of schwannoma were similarly studied using the anti-LC3 antibody. In eight of 20 cases, a small number of tumor cells showed granular immunoreactivity for LC3, suggesting an increased autophagic activity in some schwannomas and further reinforcing the close relationship between GCT and schwannoma. PMID- 21674157 TI - p63 expression in adamantinoma. AB - Adamantinoma is a rare primary bone neoplasm with epithelial differentiation that is frequently associated with a concomitant fibrous component. Clinical, cytogenetic and histomorphologic overlap has previously been described with osteofibrous dysplasia, thereby suggesting a relationship between these two lesions. We performed a retrospective review of our archives to characterize the clinical and pathologic aspects of adamantinoma and osteofibrous dysplasia diagnosed at our institution, and to compare the expression patterns of p63 and keratin. Nine cases of adamantinoma (six classical, three osteofibrous dysplasia like) and 11 cases of osteofibrous dysplasia were identified. The epithelial component in adamantinoma was found to stain for p63. Rare cells expressing p63 were also identified in eight cases of osteofibrous dysplasia. Expression of p63 was not identified in any of the five cases of fibrous dysplasia controls. The presence of staining for p63, albeit rare, in osteofibrous dysplasia supports the notion of a possible relationship between osteofibrous dysplasia and adamantinoma. Furthermore, our results suggest that, in some situations, p63 may be useful in helping differentiate metastatic carcinoma from adamantinoma. PMID- 21674158 TI - Are we ready to move away from nature?: the rapamycin story. PMID- 21674159 TI - Pattern of triptan use and cardiovascular coprescription: a pharmacoepidemiological study in Italy. AB - PURPOSE: We evaluated the incidence, prevalence, and patterns of triptan use with a special focus on patients who also received cardiovascular drugs, considered as a deviation from appropriate triptan use. METHODS: We collected data on prescriptions reimbursed in between 2006 and 2008 in an Italian region. Patients receiving at least one prescription of triptans from January to December 2007 were divided in two populations: new users (without triptan prescriptions in 2006), and already in treatment. All patients were followed for 12 months in terms of both triptan use and cardiovascular coprescriptions. RESULTS: One-year prevalence of triptan use was 0.8%, whereas the incidence was 0.4%. New users accounted for 47.5% of total users (34,915). The percentages of very frequent users (>120 and >180 dosage unit per year) were about double among those already in treatment (26.6% and 15.3%, respectively) and new users (1% and 0.3%; p < 0.01). Patients starting with the lowest dose of tablet formulation were more likely to interrupt therapy after their first prescription (p < 0.01). Many users aged >65 received concomitant cardiovascular therapies: 36.6% among new users and 64.3% for already in treatment (p < 0.01). In both groups, about 5% of elderly patients received coprescriptions, suggesting a high deviation from appropriate triptan use. CONCLUSIONS: A higher percentage of very frequent users was detected in patients already in treatment compared with new users. Moreover, the percentage of nonnegligible triptan recipients were in age groups for which the drug is not recommended by the product label (<=18 years and >65) and who had cardiovascular coprescriptions suggestive of vasoconstrictive risk. PMID- 21674160 TI - Effect of weathering on abundance and release of potentially toxic elements in soils developed on Lower Cambrian black shales, P. R. China. AB - This paper examines the geochemical features of 8 soil profiles developed on metalliferous black shales distributed in the central parts of the South China black shale horizon. The concentrations of 21 trace elements and 8 major elements were determined using ICP-MS and XRF, respectively, and weathering intensity (W) was calculated according to a new technique recently proposed in the literature. The data showed that the black shale soils inherited a heterogeneous geochemical character from their parent materials. A partial least square regression model and EF(bedrock) (enrichment factor normalized to underlying bedrock) indicated that W was not a major control in the redistribution of trace metals. Barium, Sn, Cu, V, and U tended to be leached in the upper soil horizons and trapped by Al and Fe oxides, whereas Sb, Cd, and Mo with negative EF values across the whole profiles may have been leached out during the first stage of pedogenesis (mainly weathering of black shale). Compared with the Chinese average soils, the soils were strongly enriched in the potentially toxic metals Mo, Cd, Sb, Sn, U, V, Cu, and Ba, among which the 5 first listed were enriched to the highest degrees. Elevated concentrations of these toxic metals can have a long-term negative effect on human health, in particular, the soils in mining areas dominated by strongly acidic conditions. As a whole, the black shale soils have much in common with acid sulfate soils. Therefore, black shale soils together with acid sulfate soils deserve more attention in the context of metal exposure and human health. PMID- 21674161 TI - Decreasing the configurational entropy and the hydrophobicity of EBV-derived peptide 11389 increased its antigenicity, immunogenicity and its ability of inducing IL-6. AB - Peptide 11389 from CD21-binding region of EBV-gp350/220 protein binds to PBMCs inducing IL-6 expression and inhibiting EBV-binding to PBMCs. In addition, anti peptide 11389 antibodies recognize EBV-infected cells and inhibit both EBV infection and IL-6 production in PBMCs. We have postulated that native structure stabilization of peptide 11389 sequence can increase its biological activity. The strategy was to modify its sequence to restrict the number of structures that peptide 11389 could acquire in solution (decreasing peptide's configurational entropy) and to weaken the non-relevant intermolecular interactions (decreasing its hydrophobicity), preserving CD21-interacting residues and structure as displayed in the native protein. Thirteen analog peptides were designed and synthesized; most of them were monomers containing an intra-chain disulfide bridge. Analog peptides 34058, 34060, 34061, 34296, 34298, 34299 and 34300 inhibited EBV invasion of PBMCs. Peptides 34059, 34060, 34295 and 34297 induced IL-6 levels in PBMCs (EC50=3.4, 3.3, 0.5, 0.5 MUM, respectively) at higher potency than peptide 11389 (EC50=5.8 MUM). Peptides 34057, 34059, 34060, 34301 and 34302 interacted with anti-EBV antibodies with affinities from 3 to 50 times higher than peptide 11389. Most of analog peptides were highly immunogenic and elicited antibodies that cross-react with EBV. In conclusion, we have designed peptides displaying higher biological activity than peptide 11389. PMID- 21674162 TI - Multi-walled carbon nanotubes as solid-phase extraction adsorbents for the speciation of cobalamins in seafoods by liquid chromatography. AB - Multi-walled carbon nanotubes (MWCNTs) were evaluated as potential adsorbents for miniaturized solid-phase extraction coupled to liquid chromatography. The adsorption capacity of this sorbent was applied to assess the speciation of four cobalamins representing the various forms of vitamin B(12). The preconcentration on the MWCNTs was based on the retention of analytes by introducing the sample online into the mini-column system. Dimethyl sulfoxide was used to elute the retained vitamins for liquid chromatographic analysis. The experimental conditions of the continuous flow device, which affect the enrichment procedure, such as the type and amount of nanotubes, the volume, pH and flow rate of the sample solution, and the eluent and its volume, were optimized. For detection purposes, a diode array device was used and good resolution was obtained with a mobile-phase acetonitrile-phosphate buffer and gradient elution. Specificity was demonstrated by the retention characteristics and UV spectra and by comparing the peak purity index with commercial standards. Linearity, precision, recovery, and sensitivity were satisfactory. Detection limits ranged from 0.35 to 30 ng mL(-1). The method was successfully applied to the determination of cobalamins in seafoods, which were extracted from the sample with a buffer solution using an ultrasonic probe. The reliability of the procedure was checked by analyzing a certified reference material. PMID- 21674163 TI - UHPLC-ESI-MS/MS method for direct analysis of drugs of abuse in oral fluid for DUID assessment. AB - An ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method for the direct analysis in oral fluid (OF) of several abused drugs and metabolites in a single chromatographic run was set up and validated. Amphetamine, methamphetamine, morphine, O-6-monoacetylmorphine, cocaine, codeine, methylenedioxymethamphetamine (MDMA), methylenedioxyethylamphetamine, methylenedioxyamphetamine, methadone, benzoylecgonine (BEG), Delta9-tetrahydrocannabinol (THC), ketamine, and cocaethylene were determined in a single chromatographic run with no sample pretreatment, after addition of the respective deuterated internal standards. The method was designed to perform a confirmation analysis on the residual OF samples after the preliminary on-site screening test, and it was applied on preservative buffers from different devices (Mavand Rapidstat, Concateno DDS, and Greiner Bio One) or on neat OF samples. The method was suitable to be applied to the small amounts of sample available for the confirmatory analysis after the preliminary on-site screening or on undiluted OF samples. Limits of detection varied from 5 (morphine) to 0.2 ng/mL (methamphetamine, MDMA, BEG, and cocaethylene). The method was linear for all the substances involved, giving quadratic correlation coefficients of >0.99 in all the different preservative buffers checked. In addition, repeatability and accuracy were satisfactory for the majority of the substances, except for a few cases. The developed method was subsequently applied to 466 residual samples from on-site screening performed by police officers. Of these samples, 74 showed the presence of cocaine and metabolites; THC was detected in 49 samples. Two samples showed codeine and morphine while MDMA was detected in 11 samples and ketamine in four samples. PMID- 21674164 TI - Degradation of bromoxynil octanoate by strain Acinetobacter sp. XB2 isolated from contaminated soil. AB - Bromoxynil octanoate (BOO), the most widespread herbicide applied to maize, is potentially toxic to both animals and humans. In this article, a highly effective BOO-degrading bacterial strain, XB2, was isolated from the soil of a herbicide factory. The strain was identified as an Acinetobacter sp. based on its 16S rRNA gene sequence analysis, morphological, physiological, and biochemical properties. This strain could use BOO as its sole carbon source and could degrade 100 mg l( 1) BOO to non-detectable levels in 72 h (h). The optimal pH and temperature for strain XB2's growth and degradation of BOO in MSM are 7.0 and 30 degrees C, respectively. We propose the following pathway of BOO degradation by strain XB2: the first step is the scission of the ester bond to form bromoxynil, bromoxynil then transformed to 3,5-dibromo-4-hydroxybenzoic acid due to the hydrolysis of nitriles, and debromination finally results in the formation of 3-bromo-4 hydroxybenzoic acid. Inoculating BOO-treated soil samples with strain XB2 resulted in a higher rate of BOO degradation than in non-inoculated soil, regardless of whether the soil had previously been sterilized. PMID- 21674165 TI - Actimicrobium antarcticum gen. nov., sp. nov., of the family Oxalobacteraceae, isolated from Antarctic coastal seawater. AB - A Gram-negative, non-motile, catalase- and oxidase- positive, strictly aerobic, and short rod-shaped bacterium that was designated strain KOPRI 25157(T) was isolated from coastal seawater sample in Antarctica. The temperature and pH ranges for growth on R2A agar were 10-20 degrees C, and 5.0-10.0, respectively. Phylogenetic analyses of the 16S rRNA gene sequence of strain KOPRI 25157(T) showed it to belong to the family Oxalobacteraceae of the class Betaproteobacteria, and it formed a distinct clade from other recognized members of the family. DNA G + C content was 65.9 mol%. Major ubiquinone was Q-8. Predominant cellular fatty acids were C(16:1) omega7c/15 iso 2OH (56.4%) and C(16:1) (30.5%). Major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, and unknown lipid. On the basis of these data, it is proposed that strain KOPRI 25157(T) is the representative of a novel genus, for which the name Actimicrobium gen. nov. is proposed in the family Oxalobacteraceae. The type strain for Actimicrobium antarcticum sp. nov. is KOPRI 25157(T) (=JCM 16673(T)=KCTC 23040(T)). PMID- 21674166 TI - Co-existence, phylogeny and putative role of Wolbachia and yeast-like symbiont (YLS) in Kerria lacca (Kerr). AB - This study reports the first detection of Wolbachia and yeast-like symbiont (YLS) harbored in Kerria lacca (Kerr), a scale insect, latter of which produces an economically important natural resin, known as lac. Wolbachia was detected using PCR amplification and sequencing of 16S rDNA; and further confirmation and phylogenetic analysis was carried out by fast evolving wsp gene. Neighbor-joining and maximum parsimonious (MP) analysis showed that this strain belongs to subgroup "ori" of Wolbachia super group B of arthropods. Wolbachia of K. lacca is hereby designated as "wKerlac" according to Wolbachia nomenclature system. Histological study revealed the presence of yeast-like endosymbiont, which was also confirmed by PCR amplification of 18S rDNA. Phylogenetic analysis revealed that YLS of K. lacca is quite distinct from YLS of aphid, planthoppers, and beetles. Putative roles of Wolbachia in lecanoid chromosome system of sex determination and in biased sex ratio of K. lacca populations; and YLS in nutritional supplementation and detoxifying substances which are deleterious to K. lacca, are hereby, suggested. PMID- 21674167 TI - Improvement of lentiviral transfer vectors using cis-acting regulatory elements for increased gene expression. AB - Lentiviral vectors are an important tool for gene delivery in vivo and in vitro. The success of gene transfer approaches relies on high and stable levels of gene expression. To this end, several molecular strategies have been employed to manipulate these vectors towards improving gene expression in the targeted animal cells. Low gene expression can be accepted due to the weak transcription from the majority of available mammalian promoters; however, this obstacle can be in part overcome by the insertion of cis-acting elements that enhance gene expression in various expression contexts. In this work, we created different lentiviral vectors in which several posttranscriptional regulatory elements, namely the Woodchuck hepatitis posttranscriptional regulatory element (WPRE) and different specialized poly(A) termination sequences (BGH and SV40) were used to develop vectors leading to improved transgene expression. These vectors combine the advantages of restriction enzyme/ligation-independent cloning eliminating the instability and recombinogenic problems occurring from traditional cloning methods in lentiviral expression vectors and were tested by expressing GFP and the firefly Luciferase reporter gene from different cellular promoters in different cell lines. We show that the promoter activity varies between cell lines and is affected by the lentiviral genomic context. Moreover, we show that the combination of the WPRE element with the BGH poly(A) signal significantly enhances transgene expression. The vectors herein created can be easily modified and adapted without the need for extensive recloning making them a valuable tool for viral vector development. PMID- 21674168 TI - Microbial community engineering for biopolymer production from glycerol. AB - In this work, the potential of using microbial community engineering for production of polyhydroxyalkanoates (PHA) from glycerol was explored. Crude glycerol is a by-product of the biofuel (biodiesel and bioethanol) industry and potentially a good substrate for bioplastic production. A PHA-producing microbial community was enriched based on cultivation in a feast-famine regime as successfully applied before for fatty acids-based biopolymer production. A glycerol-fed sequencing batch reactor operated at a 2-day liquid and biomass residence time and with feast-famine cycles of 24 h was used to enrich a mixed community of PHA producers. In a subsequent fed-batch PHA production step under growth-limiting conditions, the enriched mixed community produced PHA up to a dry weight content of 80 wt.%. The conversion efficiency of substrate to PHA on electron basis was 53%. Since glycerol is entering the metabolic pathways of the cell in the glycolytic pathway, it was anticipated that besides PHA, polyglucose could be formed as storage polymer as well. Indeed, polyglucose was produced in low amounts (~ 10 wt.%). The results indicated that the feast-famine-based enrichment strategy was comparably successful to obtain a microbial community compared to fatty acids-based enrichment described before. PMID- 21674169 TI - Case report: torsion of a cryptorchid testicle in an infant. PMID- 21674170 TI - Genetic characterization of highly pathogenic H5N1 avian influenza viruses isolated from poultry farms in Egypt. AB - Twenty-four avian influenza viruses were collected from poultry farms in three different governorates in Egypt during the years 2006-2009 and genetically characterized. All the isolates were confirmed to be type A and subtype H5 influenza virus by chromatographic strip test and hemagglutination inhibition assay. The sequence and phylogenetic data revealed that all Egyptian isolates cluster together and belong to subclade 2.2.1 of the H5N1 virus of Eurasian origin. Within the clade, Egyptian isolates were classified into three major groups (A, B, and C) based on genetic similarity and chronology of the isolation. The majority of the recent isolates belonged to subgroup A. Interestingly, four strains, which were isolated from the same farm with two of the samples collected on the same day, were located in separate subgroups. In addition, the difference in topology between HA and NS phylogenetic trees, which indicates possible difference in dynamics of genetic evolution in two genes, was observed. Genetic characterization data of H5N1 isolates obtained from farms with different vaccination histories indicate the vaccines currently being used in Egypt do not provide adequate level of protection. Our study provides additional evidence for the need for updated vaccine and warrants continuous monitoring of H5N1 influenza virus in Egypt. PMID- 21674171 TI - Short-term mechanical management of cardiogenic shock. AB - OPINION STATEMENT: Cardiogenic shock (CS), a state of cardiac dysfunction that results in systemic hypoperfusion and end-organ dysfunction, is associated with high in-hospital mortality. Various forms of mechanical circulatory support have been used to treat CS. First employed in the 1960s, the intra-aortic balloon pump (IABP) has been a mainstay in the treatment of acute CS. However, the IABP is unable to provide adequate support in many patients, and newer technologies, including extracorporeal membrane oxygenation and percutaneous ventricular assist devices, appear to be more effective in reversing CS. These devices are also useful for supporting patients during complex percutaneous coronary intervention. Perhaps most importantly, they can be used as a bridge to decision or definitive therapy in CS patients who are potential candidates for surgical ventricular assist devices or cardiac transplantation. PMID- 21674172 TI - Drug-induced autoimmune-like hepatitis: a diagnostic challenge. PMID- 21674173 TI - Montelukast was inefficient in maintaining steroid-induced remission in adult eosinophilic esophagitis. AB - BACKGROUND AND AIMS: Leukotriene D4 is produced by and functions as a chemotactic factor for eosinophils. Eosinophilic esophagitis (EoE) is characterized by esophageal eosinophilic infiltration, determining structural changes and dismotility symptoms. Montelukast, a selective leukotriene D4 receptor antagonist, has gained increasing consideration as a therapeutic agent for EoE. However, limited available information has shown that montelukast is not effective in reducing eosinophilic infiltration. Our paper aims at evaluating whether montelukast could be consider as a steroid-sparing therapy by assessing its efficacy in maintaining both clinical and histopathological remission achieved after topical corticosteroids in adult EoE patients. METHODS: Eleven consecutively diagnosed adult EoE patients were prospectively studied. Esophageal biopsies were obtained before and after a 6-month treatment with fluticasone propionate 400 MUg/twice a day. Immediately after that, montelukast 10 mg/day was instituted. A new endoscopy was foreseen after a new 3-month period, or as soon as the patients presented esophageal symptoms. Symptoms were assessed by using a questionnaire before and after fluticasone propionate treatment and after montelukast therapy. RESULTS: Eosinophils density into the esophageal epithelium and lamina propria was significantly reduced after a 6-month treatment with topical steroids (P = 0.003) and increased to levels similar to baseline level into the first 3 months after treatment with montelukast. Baseline symptom scores significantly decreased after treatment with topical steroids (P = 0.003) and increased again after montelukast therapy, but baseline levels improved. CONCLUSIONS: Montelukast was not efficient in maintaining the histopathological or clinical response achieved by topical steroids in adult EoE patients. PMID- 21674174 TI - Aberrant methylation of different DNA repair genes demonstrates distinct prognostic value for esophageal cancer. AB - BACKGROUND: DNA mismatch repair (MMR) deficiency results in a strong mutator phenotype and high-frequency microsatellite instability (MSI-H), which are the hallmarks of many tumors. AIM: The objective of this study is to investigate the promoter CpG island methylation status of mismatch repair genes human mutL homolog 1 (hMLH1), human mutS homolog 2 (hMSH2), and O(6)-methylguanine-DNA methyltransferase (MGMT) in esophageal squamous cell carcinoma (ESCC) and its roles in alkylating agents chemotherapy. METHODS: Real-time methylation-specific polymerase chain reaction (PCR) (real-time MSP) was employed to detect promoter CpG island methylation of the hMLH1, hMSH2, as well as MGMT genes in 235 surgical tumor tissue samples from ESCC patients and their corresponding normal tissue samples. RESULTS: Promoter CpG island methylation of hMLH1, hMSH2, and MGMT were detectable in 43.4, 28.9, and 40.4% of ESCC tumor DNA, respectively, and the loss rates of hMLH1, hMSH2, and MGMT protein expression were 48.6, 34.5, and 40.9% in tumor tissues, respectively. For the entire population of 235 ESCC patients who were enrolled in operating treatment combined with radiotherapy and chemotherapy with alkylating agents, there was a significant difference in the overall survival between patients with methylated MGMT promoter and those with an unmethylated MGMT promoter (P < 0.05). CONCLUSION: Promoter CpG island methylation may be a frequent event in ESCC carcinogenesis. Detection of the methylated sequences of hMLH1, hMSH2, and MGMT appears to be promising as a predictive factor in primary ESCC. PMID- 21674175 TI - Serum immunoglobulin a concentration is an independent predictor of liver fibrosis in nonalcoholic steatohepatitis before the cirrhotic stage. AB - BACKGROUND AND AIMS: The similarity of alcoholic liver disease and nonalcoholic steatohepatitis (NASH) in terms of pathogenic mechanisms suggests that immunoglobulin A (IgA) may play an important role in the pathogenesis of NASH. We aimed to determine whether serum IgA concentrations allow a diagnosis of liver fibrosis in NASH. METHODS: We compared serum IgA concentrations between 108 patients with stages 0-2 NASH and 19 patients with stage 3 NASH. RESULTS: In a univariate analysis, age (P < 0.0001), gender (P = 0.0039), serum albumin level (P = 0.0192), AST (P < 0.0001), AST/ALT ratio (P < 0.0001), platelet count (P = 0.0027), hyaluronic acid level (P < 0.0001), fasting blood sugar (FBS) (P = 0.0013), IRI (P = 0.0001), prothrombin time (%) (P = 0.0287), IgA (P < 0.0001), total sum of IgG, IgA, and IgM (P = 0.0049), and IgA/(IgG + IgA + IgM) (P = 0.0105) were significantly elevated in severe-stage NASH patients compared with the early-stage NASH group. Multiple logistic regression analysis showed that in severe-stage NASH patients, only serum IgA concentrations were significantly elevated (P = 0.0225) relative to early-stage NASH patients. The area under the curve (AUC) of serum IgA concentrations was 0.758 for detecting severe-stage NASH compared with early-stage NASH. CONCLUSIONS: Serum IgA concentration could be a useful independent predictor for assessing the pre-cirrhotic progression of NASH. PMID- 21674176 TI - Additive effects of glycaemia and dyslipidaemia on risk of cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register. AB - AIMS/HYPOTHESIS: The study aimed to assess the relative importance of the control of HbA(1c) and total cholesterol/HDL-cholesterol ratio (TC/HDL) on risk of cardiovascular disease (CVD). METHODS: In 22,135 participants with type 2 diabetes (age 30-75 years, 15% with previous CVD) followed for 5 years, baseline and annually updated mean HbA(1c) and TC/HDL were analysed and also categorised in combinations of quartiles. Outcomes were fatal/non-fatal CHD, stroke, CVD and total mortality. RESULTS: In all participants, HRs per 1 SD increase in updated mean HbA(1c) or TC/HDL using Cox regression analysis were 1.13 (95% CI 1.07, 1.19) and 1.31 (1.25, 1.37) for CHD, 1.15 (1.06, 1.24) and 1.25 (1.17, 1.34) for stroke, 1.13 (1.08, 1.18) and 1.29 (1.24, 1.34) for CVD (all p < 0.001), and 1.07 (1.02, 1-13; p = 0.01) and 1.18 (1.12, 1.24; p < 0.001) for total mortality, respectively, adjusted for clinical characteristics and traditional risk factors. The p value for the interaction between HbA(1c) and TC/HDL was 0.02 for CHD, 0.6 for stroke and 0.1 for CVD. Adjusted mean 5-year event rates in a Cox model, in combinations of quartiles of updated mean TC/HDL and HbA(1c) (lowest <3.1 mmol/l and 5.0-6.4% [31-46 mmol/mol]; <3.1 mmol/l and >=7.8% [>=62 mmol/mol]; >=4.6 mmol/l and 5.0-6.4% 31-46 mmol/mol; and highest >=4.6 mmol/l and >=7.8% [>=62 mmol/mol]), were 4.8%, 7.0%, 9.1% and 14.5% for CHD, and 7.1%, 9.9%, 12.8% and 19.4% for CVD, respectively. Adjusted HRs for highest vs lowest combinations were 2.24 (1.58-3.18) for CHD and 2.43 (1.79-3.29) for CVD (p < 0.001). CONCLUSIONS/INTERPRETATION: Hyperglycaemia and hyperlipidaemia were less than additive for CHD and additive for other endpoints, with the lowest risk at lowest combination levels and a considerable increase in absolute risk at high combination levels. PMID- 21674177 TI - Plasma procalcitonin and risk of type 2 diabetes in the general population. PMID- 21674178 TI - Dynamics of blood electrolytes in repeated hyper- and/or hypoglycaemic events in patients with type 1 diabetes. AB - AIMS/HYPOTHESIS: Electrolyte disturbances are well-known consequences of the diabetic pathology. However, less is known about the cumulative effects of repeated changes in glycaemia, a characteristic of diabetes, on the electrolyte balance. We therefore investigated the ionic profiles of patients with type 1 diabetes during consecutive hyper- and/or hypoglycaemic events using the glucose clamp. METHODS: In protocol 1, two successive hyperglycaemic excursions to 18 mmol/l were induced; in protocol 2, a hypoglycaemic excursion (2.5 mmol/l) was followed by a hyperglycaemic excursion (12 mmol/l) and another hypoglycaemic episode (3.0 mmol/l). RESULTS: Blood osmolarity increased during hyperglycaemia and was unaffected by hypoglycaemia. Hyperglycaemia induced decreases in plasma Na(+) Cl(-) and Ca(2+) concentrations and increases in K(+) concentrations. These changes were faithfully reproduced during a second hyperglycaemia. Hypoglycaemia provoked rapid and rapidly reversible increases in Na(+), Cl(-) and Ca(2+). In sharp contrast, K(+) levels displayed a rapid and substantial fall from which they did not fully recover even 2 h after the re-establishment of euglycaemia. A second hypoglycaemia caused an additional fall. CONCLUSIONS/INTERPRETATION: Repeated hyperglycaemia events do not lead to any cumulative effects on blood electrolytes. However, repeated hypoglycaemias are cumulative with respect to K(+) levels due to a very slow recovery following hypoglycaemia. These results suggest that recurring hypoglycaemic events may lead to progressively lower K(+) levels despite rapid re-establishment of euglycaemia. This warrants close monitoring of plasma K(+) levels combined with continuous glucose monitoring particularly in patients under intensive insulin therapy who are subject to repeated hypoglycaemic episodes. TRIAL REGISTRATION: Clinicaltrial.gov NCT01060917. PMID- 21674179 TI - Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations. AB - AIMS/HYPOTHESIS: Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K(ATP)) channel mutations causing HH in the proband. METHODS: We studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the K(ATP) channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the (86)Rb flux assay. RESULTS: The mutant channels all showed a lack of (86)Rb efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic. CONCLUSIONS/INTERPRETATION: The phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus. PMID- 21674180 TI - Quantification of the interceptor action of caffeine on the in vitro biological effect of the anti-tumour agent topotecan. AB - Using published in vitro data on the dependence of the percentage of apoptosis induced by the anti-cancer drug topotecan in a leukaemia cell line on the concentration of added caffeine, and a general model of competitive binding in a system containing two aromatic drugs and DNA, it has been shown to be possible to quantify the relative change in the biological effect just using a set of component concentrations and equilibrium constants of the complexation of the drugs. It is also proposed that a general model of competitive binding and parameterization of that model may potentially be applied to any system of DNA targeting aromatic drugs under in vitro conditions. The main reasons underpinning the proposal are the general feature of the complexation of aromatic drugs with DNA and their interaction in physiological media via hetero-association. PMID- 21674181 TI - RNA dimerization monitored by fluorescence correlation spectroscopy. AB - Fluorescence correlation spectroscopy (FCS) provides a versatile tool to investigate molecular interaction under native conditions, approximating infinite dilution. One precondition for its application is a sufficient difference between the molecular weights of the fluorescence-labelled unbound and bound ligand. In previous studies, an 8-fold difference in molecular weights or correspondingly a 1.6-fold difference in diffusion coefficients was required to accurately distinguish between two diffusion species by FCS. In the presented work, the hybridization of two complementary equally sized RNA single strands was investigated at an excellent signal-to-noise ratio enabled by the highly photostable fluorophore Atto647N. The fractions of ssRNA and dsRNA were quantified by applying multicomponent model analysis of single autocorrelation functions and globally fitting several autocorrelation functions. By introducing a priori knowledge into the fitting procedure, 1.3- to 1.4-fold differences in diffusion coefficients of single- and double-stranded RNA of 26, 41, and 54 nucleotides could be accurately resolved. Global fits of autocorrelation functions of all titration steps enabled a highly accurate quantification of diffusion species fractions and mobilities. At a high signal-to-noise ratio, the median of individually fitted autocorrelation functions allowed a robust representation of heterogeneous data. These findings point out the possibility of studying molecular interaction of equally sized molecules based on their diffusional behavior, which significantly broadens the application spectrum of FCS. PMID- 21674182 TI - Vertebral body stapling as an alternative in the treatment of idiopathic scoliosis. AB - OBJECTIVE: Unilateral vertebral body stapling as a fusionless alternative to control curvature progression in patients with idiopathic scoliosis (IS). INDICATIONS: Skeletally immature patients (Risser 0 or 1) with IS measuring 20-45 degrees and correction of the curvature <20 degrees on side-bending X-rays. CONTRAINDICATIONS: Congenital scoliosis, curvature above T4 or below L4, thoracic kyphosis >40 degrees . SURGICAL TECHNIQUE: Unilateral disc-sparing staples are placed at the convex side. A thoracoscopic approach can be used for thoracic curves and a mini-open retroperitoneal approach for lumbar curves. POSTOPERATIVE MANAGEMENT: Early ambulation on postoperative day 1 is encouraged. There are no absolute activity restrictions, and no bracing beyond 4 weeks is required. RESULTS: A total of 28 patients (4 males, 24 females; average age at operation 9.4 years) met all inclusion criteria and had a minimum 2-year follow-up (range 2 5.3 years). The success rate (improvement or stabilization of the curvature) was 86% for thoracic curves <35 degrees and all lumbar curves meeting the indications. PMID- 21674183 TI - Short-term treatment effects of quad-helix on maxillomandibular expansion in patients with maxillary incisor crowding. AB - The purpose of this study was to evaluate the effects of the maxillary arch expansion on maxillomandibular arch widths in patients treated with the quad helix versus untreated controls. The treatment group consisted of 50 consecutive patients treated for maxillary incisor crowding with a quad-helix appliance in the early mixed dentition. Lateral cephalograms and dental casts taken at the start (T0) and end (T1) of the quad-helix treatment were obtained. The control group consisted of 50 untreated patients with the same type of malocclusion. Two consecutive lateral cephalograms and dental casts of each untreated patient were taken at about the same time as T0 and T1. All these study materials were analyzed for comparison between the two groups. The mean ages at T0 and T1 in the two groups were about the same. The maxillary first molars moved and tipped distally in the treatment group and mesially in the control group. The quad-helix treatment actually expanded the mandibular and maxillary arches concurrently. The more the maxillary arch widths were expanded and the less the maxillary first molars were inclined distally, the more the mandibular arch widths were expanded. The quad-helix activation caused lingual tipping and mesiobuccal rotation of the maxillary first molars. The mesiobuccal rotation of the maxillary first molars could turn molar occlusal relationships for the better from Class II to Class I. The quad-helix treatment gives rise to spontaneous expansion of the mandibular arch concurrent with maxillary expansion in the early mixed dentition patients with maxillary incisor crowding. PMID- 21674184 TI - Current evidence on the relationship between CYP1B1 polymorphisms and lung cancer risk: a meta-analysis. AB - The association between single-nucleotide polymorphisms (SNPs) of the CYP1B1 gene and lung cancer risk is still ambiguous. In this meta analysis, we assessed 10 case-control studies included 7,067 cases and 9,374 controls of the association between CYP1B1 SNPs of Leu432Val (rs1056836, 432C>G), Asn453Ser (rs1800440, 453A>G), Ala119Ser (rs1056827, 119G>T), Arg48Gly (rs10012, 48C>G) and the risk of lung cancer. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of association between the polymorphism and lung cancer risk under codominant model, dominant model and additive model respectively. Although there were limitations, this meta analysis indicated that individuals with 432GG genotype had a 39.7% higher risk of having lung cancer than those with the 432CC genotype, and individuals with the 432G allele had a 26.3% increased risk as well. An increased risk of lung cancer of 2.13 fold was observed in individuals with 119TT genotype. For Arg48Gly, individuals with 48GG genotype had a significantly increased risk of lung cancer compared with individuals with 48CC (OR 3.859; 95% CI 2.536-5.87). Elevated risk of lung cancer were observed in dominant model (OR 2.115; 95% CI 1.653-2.705) as well. The risk of lung cancer was elevated as the frequency of G allele increased in additive model (P = 0.000). For individuals with the polymorphism at codon 453, no evidence of such association was observed. Furthermore, a possible association between the CYP1B1 polymorphism at codon 432 and the lung cancer could be detected in individuals of Caucasian origin, while a negative association was suggested in Asians and African-Americans. An increased lung cancer risk was also found in women with polymorphism at codon 453. These results are supportive for the hypothesis that the CYP1B1 432GG, 119TT and 48GG genotypes are low-penetrance risk factors for developing lung cancer, and further studies are needed to validate these associations. PMID- 21674185 TI - The protective effect of quercetin on long-term alcohol consumption-induced oxidative stress. AB - Long-term alcohol consumption can cause oxidative stress and cytokines induction, which are associated with free radicals. Quercetin, one of the most widely distributed flavonoids in plants, is a natural antioxidant. We investigated the hypothesis that quercetin could prevent the ethanol-induced oxidative stress and decreases tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (INF gamma) as pro-inflammatory cytokines. Twenty-eight rats were randomly divided into control group (C), ethanol treatment group (EtOH) (~1 ml/day, 80%; 2 g/kg body wt), intragastrically (i.g.), quercetin treatment group (Q), (100 mg/kg-body wt per 3 days) i.g. and ethanol plus quercetin treatment group (EtOH + Q) (1 ml/day, 80% of ethanol and 100 mg/kg-body wt of quercetin per 3 days) i.g. for 30 days Plasma thiobarbituric acid reactive substance (TBARS) levels and protein carbonyl content were significantly higher in the EtOH group than the C group (P < 0.01). On the other hand, TBARS level and protein carbonyl content in the EtOH + Q group was decreased significantly by quercetin (P < 0.05, P < 0.01; respectively). While GSH levels in whole blood decreased in EtOH group compared to C group, they increased significantly by quercetin (P < 0.05). Plasma ALT, TNF alpha and IFN-gamma levels increased significantly in the EtOH group compared to control group (P < 0.05, P < 0.01, P < 0.01, respectively), but they decreased significantly in the EtOH + Q group in comparison with EtOH group (P < 0.05, P < 0.01, P < 0.01, respectively). Our results demonstrate that quercetin treatment may provide a protection as reflected by decreased plasma TBARS, protein carbonyls, TNF-alpha, INF-gamma and ALT levels against ethanol-induced oxidative damage. PMID- 21674186 TI - Predictive potential of microsatellite markers on heterosis of fecundity in crossbred sheep. AB - Small Tail Han (STH) sheep is a famous Chinese local breed and has perfect prolificacy performance, but it is inferior to imported mutton sheep breeds on meat production. In this study, six imported male sheep populations (White Suffolk, Black Suffolk, Texel, Dorper, South African Mutton Merino and East Friesian) were crossbred with STH female sheep respectively. The heterosis values of litter size, average daily gain (ADG) and feed conversion ratio (FCR) of crossbred sheep were analyzed for seeking the optimal cross. Meanwhile 28 microsatellite markers were used to measure the genetic distance between imported populations and STH population. Regression between the genetic distance and heterosis was analyzed for evaluating potential of microsatellite on predicting heterosis. Results showed a significant positive linear correlation (r = 0.892, P < 0.05) between heterosis of litter size and genetic distance D (A) of six crosses. This implied that these microsatellite markers had moderate potential to forecast heterosis of litter size in sheep. Results of this study also indicated that South African Mutton Merino and East Friesian sheep would be the optimal sire breeds for the litter size and might bring the greatest economic benefit in six imported populations; Suffolk sheep could be prior consideration as sire breeds when breeding objective focused on ADG. Finally these results provided valuable information for Chinese sheep industry. PMID- 21674187 TI - Enzymatic and biological characteristics of enolase in Brucella abortus A19. AB - Brucella abortus is the etiological agent of brucellosis, a disease causing human public health problems as well as major economic losses in domestic animal industries. In this study, the enolase gene of B. abortus A19 was cloned, sequenced and expressed in Escherichia coli BL21. Bacterial-expressed enolase protein (His-eno) was purified and its ability to catalyze the conversion of 2 phosphoglycerate (2-PGE) to phosphoenolpyruvate (PEP) (hereon referred to as enolase activity) was analyzed. Michaelis constant (K(m)) and maximum reaction velocity (V(max)) of the reaction was determined to be 2.0 * 10(-3) M and 178 MUM l(-1)min(-1), respectively. Factors influencing the enolase activity of His-eno, such as pH, the presence of metal ions and temperature were investigated in vitro. The results showed that His-eno exhibited maximal enolase activity in pH 8.5 reaction buffer containing 10 mM MgSO(4) at 37 degrees C. In addition to studying the enzyme activity, binding assays were performed to provide insights into the function of His-eno on pathogenesis and immunity. His-eno exhibits fibronectin-binding ability in immunoblotting assay, suggesting that enolase may play a role in B. abortus colonization, persistence, and invasion of host tissue. Furthermore, Western blot demonstrated His-eno's binding ability to 34 bovine B. abortus positive sera, suggesting that future studies may find enolase a useful as a diagnostic marker or a vaccine candidate for brucellosis. PMID- 21674188 TI - Inhibition of gap junction channel attenuates the migration of breast cancer cells. AB - Gap junction provides intercellular communications that play a critical role in invasion of metastatic cancer cells. However, the effects of inhibiting this pathway in breast cancer cell migration have not been investigated. Here, we present data demonstrating that functional blockade of gap junctions during the formation of monolayer decreased the levels of aligned fibers of actin between neighboring breast cancer cells. Furthermore, gap junction inhibitors attenuated the invasion ability of highly metastatic MDA-MB-231 cells, but had no significant effects on less invasive MCF-7 cells, which caused by shRANKL. Our work is the first to demonstrate the inhibitory effect of gap junction channel inhibitors on the migration of highly invasive breast cancer cells. PMID- 21674189 TI - Characterization of PRNP and SPRN coding regions from atypical scrapie cases diagnosed in Poland. AB - Scrapie, a fatal transmissible spongiform encephalopathy (TSE) occurs in two phenotypes: classical and atypical. Many authors point out that the polymorphism of three codons (136, 154, 171) of the PRNP (PrP gene) is associated with a sheep susceptibility to classical scrapie. Until now, only one PRNP gene variant coding phenylalanine at codon 141 has been found to be associated with atypical scrapie. Another recently identified and interesting candidate gene for scrapie susceptibility in sheep is an SPRN gene coding for Shadoo protein (Sho). Sho is a highly interspecies conserved protein and an insertion/deletion (indel) found in a sheep Sho gene was associated with classical scrapie occurrence. Here we determined the polymorphism of PRNP and SPRN genes in nine atypical scrapie cases (six in native born sheep and three in imported sheep) and compared these results with a control group of healthy animals comprising six corresponding Polish sheep breeds. In atypical scrapie cases five PRNP diplotypes were identified: A(136)R(154)Q(171)/ARQ, AHQ/ARQ, ARR/ARQ, ARR/AHQ and AHQ/AHQ. The ARR/AHQ diplotype was found only in imported sheep. A previously unobserved SNP in PRNP (E224K) was also found in both atypical scrapie and in a few control animals. In the ORF of the SPRN gene, six SNPs and one indel were identified. None of these variations was exclusive for scrapie animals and they were probably, naturally occurring polymorphisms. Special attention was given to the 6-bp indel SPRN polymorphism which was previously associated with classical scrapie occurrence. PMID- 21674190 TI - Relative gene expression of bile salt hydrolase and surface proteins in two putative indigenous Lactobacillus plantarum strains under in vitro gut conditions. AB - Probiotic bacteria must overcome the toxicity of bile salts secreted in the gut and adhere to the epithelial cells to enable their better colonization with extended transit time. Expression of bile salt hydrolase and other proteins on the surface of probiotic bacteria can help in better survivability and optimal functionality in the gut. Two putative Lactobacillus plantarum isolates i.e., Lp9 and Lp91 along with standard strain CSCC5276 were used. A battery of six housekeeping genes viz. gapB, dnaG, gyrA, ldhD, rpoD and 16S rRNA were evaluated by using geNorm 3.4 excel based application for normalizing the expression of bile salt hydrolase (bsh), mucus-binding protein (mub), mucus adhesion promoting protein (mapA), and elongation factor thermo unstable (EF-Tu) in Lp9 and Lp91. The maximal level of relative bsh gene expression was recorded in Lp91 with 2.89 +/- 0.14, 4.57 +/- 0.37 and 6.38 +/- 0.19 fold increase at 2% bile salt concentration after 1, 2 and 3 h, respectively. Similarly, mub and mapA genes were maximally expressed in Lp9 at the level of 20.07 +/- 1.28 and 30.92 +/- 1.51 fold, when MRS was supplemented with 0.05% mucin and 1% each of bile and pancreatin (pH 6.5). However, in case of EF-Tu, the maximal expression of 42.84 +/- 5.64 fold was recorded in Lp91 in the presence of mucin alone (0.05%). Hence, the expression of bsh, mub, mapA and EF-Tu could be considered as prospective biomarkers for screening of novel probiotic lactobacillus strains for optimal functionality in the gut. PMID- 21674191 TI - Leisure sport activity as a trigger for acute coronary events in men without known coronary artery disease : a single-center case study. AB - INTRODUCTION: Leisure sport activity (LSA) is gaining in importance among middle aged and senior men in the German population. There is a consensus that regular aerobic exercise at moderate intensities and increased physical fitness are associated with a reduced risk of fatal and nonfatal acute cardiac events (ACE) in middle-aged individuals. However, vigorous exercise (VE) can acutely and transiently increase the risk of an ACE in susceptible individuals. There is an ongoing discussion as to whether preparticipation screening may prevent such events. This case study characterizes patients participating in LSA who had not been involved in preparticipation screening prior to their ACE. METHODS: In the period between June 2003 and July 2009, all consecutive patients with an ACE presenting at the catheter laboratory were retrospectively screened for VE that had occurred during LSA. All 13 men with previously unknown coronary artery disease (CAD) had exercised regularly. All patients underwent coronary angiography. This study characterized clinical parameters, duration of LSA, coronary diagnostic procedure, as well as therapeutic intervention. RESULTS: In seven patients, cardiovascular (CV) risk factors comprised arterial hypertension in seven, hyperlipidemia in seven, smoking or former smoking in two, family history of CV disease in four, and previous peripheral atherosclerotic disease in two. The culprit lesion was identified in seven patients in the left anterior descending artery, in four in the right coronary artery, and in two in the circumflex artery. The mean left ventricular ejection fraction was 65% (45-84). The mean complexity of the lesions using the syntax score was 17 (2-36). PCI was performed in 12 patients, while one patient was transferred for coronary artery bypass grafts. All patients survived their ACE. CONCLUSION: This case study supports the data indicating that ACE in men with previously unknown CAD is not uncommon during LSA. This patient cohort provides data on a group of patients who might benefit from preparticipation screening. PMID- 21674192 TI - T-staging of rectal cancer: accuracy of 3.0 Tesla MRI compared with 1.5 Tesla. AB - OBJECTIVES: Magnetic resonance imaging (MRI) is not accurate in discriminating T1 2 from borderline T3 rectal tumors. Higher resolution on 3 Tesla-(3T)-MRI could improve diagnostic performance for T-staging. The aim of this study was to determine whether 3T-MRI compared with 1.5 Tesla-(1.5T)-MRI improves the accuracy for the discrimination between T1-2 and borderline T3 rectal tumors and to evaluate reproducibility. METHODS: 13 patients with non-locally advanced rectal cancer underwent imaging with both 1.5T and 3T-MRI. Three readers with different expertise evaluated the images and predicted T-stage with a confidence level score. Receiver operator characteristics curves with areas under the curve (AUC) and diagnostic parameters were calculated. Inter- and intra-observer agreements were calculated with quadratic kappa-weighting. Histology was the reference standard. RESULTS: Seven patients had pT1-2 tumors and six had pT3 tumors. AUCs ranged from 0.66 to 0.87 at 1.5T vs. 0.52-0.82 at 3T. Mean overstaging rate was 43% at 1.5T and 57% at 3T (P = 0.23). Inter-observer agreement was kappa 0.50 0.71 at 1.5T vs. 0.15-0.68 at 3T. Intra-observer agreement was kappa 0.71 at 1.5T and 0.76 at 3T. CONCLUSIONS: This is the first study to compare 3T with 1.5T MRI for T-staging of rectal cancer within the same patients. Our results showed no difference between 3T and 1.5T-MRI for the distinction between T1-2 and borderline T3 tumors, regardless of expertise. The higher resolution at 3T-MRI did not aid in the distinction between desmoplasia in T1-2-tumors and tumor stranding in T3-tumors. Larger studies are needed to acknowledge these findings. PMID- 21674193 TI - Current concepts in transarterial chemoembolization of hepatocellular carcinoma. AB - Transarterial chemoembolization (TACE) has the potential to improve survival in patients with intermediate stage hepatocellular carcinoma (HCC). Careful selection of patients is mandatory to gain survival benefit and safe quality of life. Basic principles of TACE in HCC include selective treatment via intrahepatic and extrahepatic arteries, proper management of side effects and continuation of treatment guided by imaging. After conventional TACE, based on delivery of cytotoxic drugs emulsified in iodized oil and embolization of various types of particles, has been used for more than 20 years, the new concept of drug eluting microspheres has been introduced. This technology effectively combines enhanced local drug delivery and ischemic embolization effects. Clinical studies showed intensified local necroses and reduced systemic toxic side effects compared to conventional TACE. Embolization of HCC with sub-100 MUm particles penetrating deeply into the tumor vascular bed is another promising new option. Very effective devascularization of HCC nodules has been shown after 40 MUm bland embolizations, however, potential risks like passage of particles into hepatic veins and systemic circulation have to be considered. Today the indication for TACE in intermediate stage HCC patients is widely accepted; however, there is no clear methodical standard so far. Further studies are necessary to define how to adapt various available methods to individual HCC and patients characteristics. PMID- 21674194 TI - Endoscopic findings in patients presenting with dysphagia: analysis of a national endoscopy database. AB - Dysphagia is a common problem and an indication for upper endoscopy. There is no data on the frequency of the different endoscopic findings and whether they change according to demographics or by single versus repeat endoscopy. To determine the prevalence of endoscopic findings in patients with dysphagia and whether findings differ in regard to age, gender, ethnicity, and repeat procedure. This was a retrospective study using a national endoscopic database (CORI). A total of 30,377 patients underwent esophagogastroduodenoscopy (EGD) for dysphagia of which 4,202 patients were repeat endoscopies. Overall frequency of endoscopic findings was determined by gender, age, ethnicity, and single vs. repeat procedures. Esophageal stricture was the most common finding followed by normal, esophagitis/ulcer (EU), Schatzki ring (SR), esophageal food impaction (EFI), and suspected malignancy. Males were more likely to undergo repeat endoscopies and more likely to have stricture, EU, EFI, and suspected malignancy (P = 0.001). Patients 60 years or older had a higher prevalence of stricture, EU, SR, and suspected malignancy (P < 0.0001). Esophageal stricture was most common in white non-Hispanic patients compared to other ethnic groups. In patients undergoing repeat EGD, stricture, SR, EFI, and suspected malignancy were more common (P < 0.0001). The prevalence of endoscopic findings differs significantly by gender, age, and repeat procedure. The most common findings in descending order were stricture, normal, EU, SR, EFI, and suspected malignancy. For patients undergoing a repeat procedure, normal and EU were less common and all other abnormal findings were significantly more common. PMID- 21674195 TI - Neuroschistosomiasis. AB - Schistosomiasis (bilharzia) is a neglected tropical disease caused by digenetic trematode platyhelminths of the genus Schistosoma. Neuroschistosomiasis is one of the most severe clinical outcomes associated with schistosome infection. Neurological complications early during the course of infection are thought to occur through in situ egg deposition following aberrant migration of adult worms to the brain or spinal cord. The presence of eggs in the CNS induces a cell mediated Th2-driven periovular granulomatous reaction. The mass effect of thousands of eggs and the large granulomas concentrated within the brain or spinal cord explain the signs and symptoms of increased intracranial pressure, myelopathy, radiculopathy and subsequent clinical sequelae. Myelopathy (acute transverse myelitis and subacute myeloradiculopathy) of the lumbosacral region is the most common neurological manifestation of S. mansoni or S. haematobium infection, whereas acute encephalitis of the cortex, subcortical white matter, basal ganglia or internal capsule is typical of S. japonicum infection. Cerebral complications include encephalopathy with headache, visual impairment, delirium, seizures, motor deficits and ataxia, whereas spinal symptoms include lumbar pain, lower limb radicular pain, muscle weakness, sensory loss and bladder dysfunction. The finding of eggs in the stool or a positive serology, provides supportive but not direct evidence of neuroschistosomiasis. A definitive diagnosis can only be made with histopathological study showing Schistosoma eggs and granulomas. Schistosomicidal drugs (notably praziquantel), steroids and surgery are currently used for the treatment of neuroschistosomiasis. During the 'acute phase' of the disease, neuroschistosomiasis is treated with corticosteroids which are augmented with a course of praziquantel once female worm ovipositioning commences. Surgery should be reserved for special cases such as in those with evidence of medullary compression and in those who deteriorate despite clinical management. PMID- 21674196 TI - Lacosamide as add-on in brain tumor-related epilepsy: preliminary report on efficacy and tolerability. AB - Lacosamide (LCM) is an antiepileptic drug (AED) that has demonstrated a good efficacy in controlling seizures as an add-on in adult epilepsy. To date, there have been no studies on LCM in patients with brain tumor-related epilepsy (BTRE). To evaluate efficacy and tolerability of LCM as an add-on in BTRE, we followed 14 patients suffering from BTRE who had already been treated with other AEDs and who had not experienced adequate seizure control. Eleven patients underwent chemotherapy while being treated with LCM. Mean duration of follow up was 5.4 months (min < 1 max 10 months). Mean seizure number in the last month prior to the introduction of LCM had been 15.4. At last follow-up, the mean seizure number was reduced to 1.9/month. Lacosamide mean dosage was of 332.1 mg/day (min 100 max 400 mg/day). Responder rate was 78.6%. One patient discontinued LCM because of side-effects. There were no other reported side-effects. Preliminary data on the use of LCM in add-on in patients with BTRE indicate that this drug may represent a valid alternative as an add-on in this particular patient population. However, larger samples are necessary in order to draw definitive conclusions. PMID- 21674197 TI - From unresponsive wakefulness to minimally conscious PLUS and functional locked in syndromes: recent advances in our understanding of disorders of consciousness. AB - Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in the absence of behavioural signs of consciousness. Given these new findings, the diagnostic errors and their potential effects on treatment as well as concerns regarding the negative associations intrinsic to the term vegetative state, the European Task Force on Disorders of Consciousness has recently proposed the more neutral and descriptive term unresponsive wakefulness syndrome. When vegetative/unresponsive patients show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients' behaviours: MCS+ describes high-level behavioural responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS- describes low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli). Finally, patients who show non-behavioural evidence of consciousness or communication only measurable via para-clinical testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness. PMID- 21674198 TI - Which neurological diseases are most likely to be associated with "symptoms unexplained by organic disease". AB - Many patients with a diagnosis of neurological disease, such as multiple sclerosis, have symptoms or disability that is considered to be in excess of what would be expected from that disease. We aimed to describe the overall and relative frequency of symptoms 'unexplained by organic disease' in patients attending general neurology clinics with a range of neurological disease diagnoses. Newly referred outpatients attending neurology clinics in all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded their initial neurological diagnoses and also the degree to which they considered the patient's symptoms to be explained by organic disease. Patients completed self report scales for both physical and psychological symptoms. The frequency of symptoms unexplained by organic disease was determined for each category of neurological disease diagnoses. 3,781 patients participated (91% of those eligible). 2,467 patients had a diagnosis of a neurological disease (excluding headache disorders). 293 patients (12%) of these patients were rated as having symptoms only "somewhat" or "not at all" explained by that disease. These patients self-reported more physical and more psychological symptoms than those with more explained symptoms. No category of neurological disease was more likely than the others to be associated with such symptoms although patients with epilepsy had fewer. A substantial proportion of new outpatients with diagnoses of neurological disease also have symptoms regarded by the assessing neurologist as being unexplained by that disease; no single neurological disease category was more likely than others to be associated with this phenomenon. PMID- 21674199 TI - Derivation of multipotent nestin(+)/CD271 (-)/STRO-1 (-) mesenchymal-like precursors from human embryonic stem cells in chemically defined conditions. AB - The successful establishment of stem cell-based therapies requires multipotent, immunocompatible stem cells, highly efficient strategies for direct differentiation, and most importantly, optimal culture conditions for large-scale expansion of such cell populations. Other than adult tissues, human embryonic stem cells (hESCs) represent another infinitely expansible source for mesenchymal stem cell (MSC) derivation. Here, we reproducibly derived a population of Nestin(+)/CD271(-)/STRO-1(-) mesenchymal-like precursors from hESCs (hESC-MPs) in chemically defined conditions, without requiring any serum or serum replacement of animal origin, based on a Y-27632-assisted monolayer culture system. These cells showed slim fibroblastic morphology, and satisfied the criteria of MSCs including self-renewal, the expression of multiple MSC-specific markers and the ability to differentiate into osteoblasts, adipocytes and chondrocytes. Compared with previously reported hESC-derived MSCs, our hESC-MPs were more multipotent, and could differentiate into representative derivatives of all three embryonic germ layers including mature smooth muscle cells, cardiomyocytes, functional hepatocytes and neural cells expressing various neurotransmitter phenotypes, making them an attractive cell source for regenerative medicine. PMID- 21674200 TI - Pancytopenia due to pyrimethamine triggered by transplant-associated microangiopathy after allogeneic bone marrow transplantation. AB - Toxoplasmosis is one of the life-threatening infections that can occur after hematopoietic stem cell transplantation (HSCT) and also solid organ transplantation. The standard treatment for toxoplasmosis is combination therapy with pyrimethamine and sulfadiazine, both of which inhibit folate metabolism. Therefore, therapy with these agents could result in marrow toxicity including megaloblastic anemia or pancytopenia, which is reversible or preventable with folate supplementation. Transplant-associated microangiopathy (TAM) is another situation where folate is required to compensate for increased erythropoiesis due to hemolysis after allogeneic HSCT. Here, we report a case of severe marrow toxicity manifesting as pancytopenia due to low-dose pyrimethamine, which was triggered by TAM after HSCT. PMID- 21674201 TI - Improving the quality of multifocal visual evoked potential results by calculating multiple virtual channels. AB - PURPOSE: To introduce a method for improvement of multifocal VEP (mfVEP) recordings by prediction of waveforms at multiple positions on the surface of the skull. METHODS: Fifteen healthy participants (mean age 24 +/- 3.8 years) underwent mfVEP recordings from 3 surface positions. Two methods of a best-of mfVEP approach were used and compared. In the first, a standard procedure, further data from 3 calculated channels were used. In the second approach, mfVEPs were obtained by using data derived from 40 virtual electrode positions on the basis of predictions from dipole source calculations. RESULTS: The mean signal-to noise ratios (SNRs) of the best-of-mfVEPs of both methods were compared. The SNR was significantly higher for mfVEP data using additional virtual recordings revealed by dipole source determination (2.87 vs. 3.36; P < 0.035). CONCLUSION: We conclude that multichannel prediction of mfVEP responses based on dipole source calculation significantly improves the quality of the examination results compared with the currently prevalent standard method. PMID- 21674203 TI - Extensor digiti minimi transfer for thumb extension in a patient with hypoplastic thumb extensor tendons and absent extensor indicis proprius. PMID- 21674202 TI - Effect of vitamin K on bone mineral density: a meta-analysis of randomized controlled trials. AB - A number of randomized controlled trials (RCTs) examining the role of vitamin K on bone mineral density (BMD) have yielded inconsistent results. We performed a meta-analysis of these trials to assess the effect of vitamin K on BMD. We searched MEDLINE, EMBASE and CENTRAL for relevant studies of RCTs examining the role of vitamin K on BMD. Data on participants, interventions, and outcomes were extracted and the quality of all included trials assessed. Primary outcomes for analysis were absolute changes in BMD (mg/cm(2)) at the lumbar spine and femoral neck. Relative changes (percentage change) in BMD at the lumbar spine were also assessed. Vitamin K supplementation was shown to be efficacious in increasing BMD at the lumbar spine but not the femoral neck. The weighted mean difference (WMD) in BMD absolute change was 21.60 mg/cm(2) [95% confidence interval (CI) 3.63, 39.56] at the lumbar spine and 0.25 mg/cm(2) (95% CI -2.64, 3.14) at the femoral neck. The WMD in BMD relative change was 1.27% (95% CI 0.47, 2.06) at the lumbar spine and 0.17 (95% CI -0.21, 0.54) at the femoral neck. Subgroup analysis revealed that ethnic difference, gender, and vitamin K type were associated with variable effects on BMD at the lumbar spine. The modest overall treatment effects for vitamin K on BMD observed in this review may be biased and should be interpreted with caution. Further studies are required to address factors relating to the observed effects of vitamin K on BMD. PMID- 21674204 TI - Features of hindfoot 3D kinetics in flat foot in ankle-joint maximal dorsiflexion and plantarflexion. AB - BACKGROUND: It is difficult to evaluate the kinematics of flat foot from 2D images, and no definitive methods have so far been established to diagnose flat foot. This study evaluated hindfoot kinetics through the progression of posterior tibial tendon dysfunction (PTTD) in patients with stages II and III PTTD flat foot compared with those in normal patients under dorsiflexion and plantarflexion conditions using 3D computed tomography (CT) reconstruction images. MATERIALS: CT images were taken of 26 normal and 32 flat feet in neutral, plantarflexion, and dorsiflexion positions of the ankle joint, from which 3D virtual models were made of each hindfoot bone. The 3D bone motion of these models was calculated using volume merge methods in three major planes. RESULTS: Tibiotalar-joint motion in ankle-joint plantarflexion became less plantarflexed (normal -41.2 degrees , stage II -33.5 degrees , stage III -25.3 degrees ) and less adducted (normal -13.9 degrees , stage II -10.7 degrees , stage III -5.6 degrees ) as the stage progressed. Talocalcaneal-joint motion in stage III became more plantarflexed (normal -0.8 degrees , stage II -3.0 degrees , stage III -8.7 degrees ) and more adducted (normal -0.3 degrees , stage II -4.7 degrees , stage III -10.3 degrees ) as the stage progressed. Talonavicular-joint motion in stage III became more plantarflexed (normal -7.2 degrees , stage II -7.6 degrees , stage III -14.9 degrees ) and more adducted (normal 1.0 degrees , stage II -7.3 degrees , stage III -17.9 degrees ) as the stage progressed. CONCLUSIONS: Tibiotalar-joint plantarflexion decreased and talocalcaneal and talonavicular joint adduction increased in the maximal ankle-joint plantarflexion in stage II in comparison with normal cases. Tibiotalar-joint plantarflexion and adduction were decreased and of the talocalcaneal and talonavicular joints increased in stage III in comparison with stage II cases. PMID- 21674205 TI - Controlling the aggregation and rate of release in order to improve insulin formulation: molecular dynamics study of full-length insulin amyloid oligomer models. AB - Insulin is a hormone that regulates the physiological glucose level in human blood. Insulin injections are used to treat diabetic patients. The amyloid aggregation of insulin may cause problems during the production, storage, and delivery of insulin formulations. Several modifications to the C-terminus of the B chain have been suggested in order to improve the insulin formulation. The central fragments of the A and B chains (LYQLENY and LVEALYL) have recently been identified as beta-sheet-forming regions, and their microcrystalline structures have been used to build a high-resolution amyloid fibril model of insulin. Here we report on a molecular dynamics (MD) study of single-layer oligomers of the full-length insulin which aimed to identify the structural elements that are important for amyloid stability, and to suggest single glycine mutants in the beta-sheet region that may improve the formulation. Structural stability, aggregation behavior and the thermodynamics of association were studied for the wild-type and mutant aggregates. A comparison of the oligomers of different sizes revealed that adding strands enhances the internal stability of the wild-type aggregates. We call this "dynamic cooperativity". The secondary structure content and clustering analysis of the MD trajectories show that the largest aggregates retain the fibril conformation, while the monomers and dimers lose their conformations. The degree of structural similarity between the oligomers in the simulation and the fibril conformation is proposed as a possible explanation for the experimentally observed shortening of the nucleation lag phase of insulin with oligomer seeding. Decomposing the free energy into electrostatic, van der Waals and solvation components demonstrated that electrostatic interactions contribute unfavorably to the binding, while the van der Waals and especially solvation effects are favorable for it. A per-atom decomposition allowed us to identify the residues that contribute most to the binding free energy. Residues in the beta-sheet regions of chains A and B were found to be the key residues as they provided the largest favorable contributions to single-layer association. The positive ??G (mut) values of 37.3 to 1.4 kcal mol(-1) of the mutants in the beta-sheet region indicate that they have a lower tendency to aggregate than the wild type. The information obtained by identifying the parts of insulin molecules that are crucial to aggregate formation and stability can be used to design new analogs that can better control the blood glucose level. The results of our simulation may help in the rational design of new insulin analogs with a decreased propensity for self-association, thus avoiding injection amyloidosis. They may also be used to design new fast-acting and delayed-release insulin formulations. PMID- 21674206 TI - Transformation of the theta-phase in Mg-Li-Al alloys: a density functional theory study. AB - In Mg-Li-Al alloys, theta-phase MgAlLi(2) is a strengthening and metastable phase which is liable to be transformed to the equilibrium phase AlLi on overaging. While the structural details of the theta-phase MgAlLi(2) and the microscopic transformation are still unknown. In this paper, the structure of MgAlLi(2) unit cell was determined through X-ray powder diffraction simulation. Microscopic transformation process of theta-phase MgAlLi(2) was discussed in detail using first principles method. PMID- 21674207 TI - Complex selection on life-history traits and the maintenance of variation in exaggerated rostrum length in acorn weevils. AB - Trophic interactions can trigger the development of exaggerated specialized characters and promote morphological diversification. For example, acorn weevils (genus Curculio) present strikingly long rostrums, which are used by females to perforate oviposition holes through the seed coat. Species exhibiting longer rostrums are known to exploit larger acorns, and therefore rostrum length is thought to be subject to selection to match the preferred acorn type. However, rostrum length is strongly correlated with body size, and morphological divergence could result from either selection on rostrum length for optimal food exploitation or from other pressures acting on body size. We collected infested acorns at oak forests where the large Curculio elephas and the small-bodied Curculio glandium co-occur. There were no interspecific differences in adult female body size to rostrum length allometric relationships, and rostrum length is equally correlated with body size in either species. MtDNA-based species identification showed that C. glandium larvae were present within acorns of all sizes, whereas C. elephas larvae were restricted to acorns above a minimum size, irrespective of oak species. Hence, exploitation of large acorns can hardly have triggered rostrum enlargement, as the small sized C. glandium adults (with short rostrums) could perforate and oviposit in both small and large acorns. Rather, increased rostrum length is probably a by-product of the larger body sizes of individuals emerging from bigger acorns, which allow increased larval size and enhance larval survival likelihood. Summarizing, when exaggerated feeding traits co-vary with other body features, interspecific morphological variability may result from contrasting selective pressures acting on these correlated characters. PMID- 21674208 TI - A successful strategy for surgical treatment of Boerhaave's syndrome. AB - BACKGROUND: This retrospective single-institution study presents a successful treatment strategy for Boerhaave's syndrome. METHODS: During 1995-2008, 15 patients with spontaneous esophageal perforation were treated. Patients were grouped according to time from symptoms to referral (early, <24 h; late, >24 h). In group I (early, n = 8 patients) treatment comprised primary surgical esophageal repair in seven cases and endoscopic clipping in one case. In group II (late, n = 7 patients) treatment comprised esophagectomy without primary reconstruction (4 cases) or controlled esophagocutaneous fistula (3 cases). Measures of outcome included age (years), delay to diagnosis (h), severe sepsis on admission, mortality, and hospital and intensive care unit (ICU) stay. RESULTS: The overall hospital mortality rate was 6.6% (1/15), being 0% (0/8) in group I and 14.2% (1/7) in group II. Patient age (49.6 vs. 68.6 years, P < 0.0001), delay to diagnosis (17.75 vs. 69 h, P < 0.0001), severe sepsis on admission (0 vs. 4, P = 0.0256), and ICU stay (4 vs. 14 days, P = 0.006) were all greater in group II. CONCLUSIONS: Early diagnosis and carefully selected therapeutic tactics can reduce the mortality rate of Boerhaave's syndrome to an acceptably low level. Methods of organ preservation and minimally invasive techniques can be applied successfully in the treatment. PMID- 21674209 TI - Cervical disc herniation producing acute Brown-Sequard syndrome: dynamic changes documented by intraoperative neuromonitoring. AB - INTRODUCTION: Brown-Sequard syndrome is an incomplete spinal cord lesion characterized by ipsilateral loss of motor function and contralateral loss of pain and temperature sensitivity, reflecting a hemi-compression or hemi-section of the spinal cord. Cervical disc herniation is an exceptional cause of this syndrome. MATERIAL AND METHODS: We report a case of cervical disc herniation causing Brown-Sequard syndrome in a patient with an unusually rapid neurological deterioration associated to cervical extension, which was documented by neuromonitoring. CONCLUSION: A prompt diagnosis, followed by spinal cord decompression should be warranted. Intraoperative neuromonitoring is a useful tool in preservation of neurologic function in these cases. PMID- 21674210 TI - Paradoxical motion in L5-S1 adult spondylolytic spondylolisthesis. AB - INTRODUCTION: In patients with spondylolisthesis, it is assumed that flexion accentuates anterior displacement, whereas extension causes some reduction. Paradoxical movement-where flexion causes reduction of spondylolisthesis and extension increases the anterior translation, is rarely described. In this study, we investigate the prevalence of paradoxical motion in patients with L5-S1 spondylolytic spondylolisthesis and why this abnormal motion occurs. MATERIALS AND METHODS: Flexion and extension radiographs of 41 patients with grade I and II spondylolytic spondylolisthesis of the L5-S1 segment were analysed. Patients who had previous lumbar spine surgery, recent lumbar spine trauma, those more than 50 years of age and those with poor quality radiographs were excluded. RESULTS: There were 24 male and 17 female patients. The average age was 32.7 years. Of the 41 patients, 29 (70.7%) showed no significant instability. Six (15%) patients showed anterolisthesis, where flexion accentuated the forward displacement, while further six (15%) patients showed paradoxical motion. Statistical analyses found that patients with paradoxical motion had a significantly higher slip angle. CONCLUSION: In this study, we have demonstrated that: (1) paradoxical motion in spondylolytic spondylolisthesis is more common than previously thought. (2) Patients without anterolisthesis during flexion in dynamic radiographs may still have (paradoxical) instability. (3) Paradoxical motion may be more common in patients with a low sacral slope and increased lumbosacral lordosis. PMID- 21674211 TI - Veillonella spondylodiscitis in a healthy 76-year-old lady. AB - PURPOSE: To report a case of Veillonella spondylodiscitis in a healthy 76-year old lady. METHODS: A previously healthy 76-year-old lady presented with worsening axial back pain at the thoracolumbar junction, fever and loss of weight. Examination revealed deep tenderness over the thoracolumbar junction with painful and restricted spinal movements. The lower limb motor power, sensation and reflexes were normal. RESULTS: Radiographs of the lumbosacral spine showed evidence of spinal instability with lateral translation and loss of disc space at L1-L2. MRI scans revealed fluid intensity within the L1-L2 disc with infective debris elevating the posterior longitudinal ligament and narrowing the spinal canal. Both tissue and blood cultures were positive for the anaerobic organism, Veillonella. A staged anterior-posterior spinal surgery followed by an extended course of antibiotics resulted in the clinical improvement and normalisation of blood parameters. A review of the literature on Veillonella infections is also presented. CONCLUSION: The aim of this report is to bring Veillonella spondylodiscitis to the attention of spinal surgeons and infectious disease specialists and discuss the management options. PMID- 21674212 TI - Blunt traumatic vertebral artery injury: a clinical review. AB - Blunt traumatic vertebral injury (TVAI) is frequently associated with head and neck injury and is being detected with increasing frequency due to improved imaging of the trauma patient. In a few cases, it can lead to potentially fatal posterior circulation ischaemia There is debate in the literature regarding whether TVAI should be actively screened for and, if so, how. Management of TVAI may be conservative, medical (antiplatelet agents or anticoagulation), endovascular or open surgery. We review the literature concerning the mechanisms and presentation of TVAI following blunt injury and the current screening recommendations. Management strategies proposed are based on the radiological grade and clinical severity of TVAI, where high-grade symptomatic injuries and high-grade injuries in patients where anticoagulation is contraindicated are treated endovascularly and asymptomatic or low-grade injuries are managed with anticoagulation where it is not contraindicated. Follow-up is via CT angiography to assess for resolution of the injury. PMID- 21674213 TI - Biomechanical in vitro evaluation of the complete porcine spine in comparison with data of the human spine. AB - The purpose of this study was to provide quantitative biomechanical properties of the whole porcine spine and compare them with data from the literature on the human spine. Complete spines were sectioned into single joint segments and tested in a spine tester with pure moments in the three main anatomical planes. Range of motion, neutral zone and stiffness parameters of the spine were determined in flexion/extension, right/left lateral bending and left/right axial rotation. Comparison with data of the human spine reported in the literature showed that certain regions of the porcine spine exhibit greater similarities than others. The cervical area of C1-C2 and the upper and middle thoracic sections exhibited the most similarities. The lower thoracic and the lumbar area are qualitatively similar to the human spine. The remaining cervical section from C3 to C7 appears to be less suitable as a model. Based on the biomechanical similarities of certain regions of the porcine and human spines demonstrated by this study results, it appears that the use of the porcine spine could be an alternative to human specimens in the field of in vitro research. However, it has to be emphasized that the porcine spine is not a suitable biomechanics surrogate for all regions of the human spinal column, and it should be carefully considered whether other specimens, for example from the calf or sheep spine, represent a better alternative for a specific scientific question. It should be noted that compared with human specimens each animal model always only represents a compromise. PMID- 21674214 TI - Further observations on retromolar fibreoptic orotracheal intubation in patients with severe trismus. PMID- 21674215 TI - Selective inner hair cell loss in prematurity: a temporal bone study of infants from a neonatal intensive care unit. AB - Premature birth is a well-known risk factor for sensorineural hearing loss in general and auditory neuropathy in particular. However, relatively little is known about the underlying causes, in part because there are so few relevant histopathological studies. Here, we report on the analysis of hair cell loss patterns in 54 temporal bones from premature infants and a control group of 46 bones from full-term infants, all of whom spent time in the neonatal intensive care unit at the Hospital de Ninos in San Jose, Costa Rica, between 1977 and 1993. The prevalence of significant hair cell loss was higher in the preterm group than the full-term group (41% vs. 28%, respectively). The most striking finding was the frequency of selective inner hair cell loss, an extremely rare histopathological pattern, in the preterm vs. the full-term babies (27% vs. 3%, respectively). The findings suggest that a common cause of non-genetic auditory neuropathy is selective loss of inner hair cells rather than primary damage to the cochlear nerve. PMID- 21674216 TI - Changing mortality for motor neuron disease in France (1968-2007): an age-period cohort analysis. AB - The incidence and mortality of motor neuron disease (MND) increase with age and appear to have increased with time. The examination of period and cohort effects using age-period-cohort (APC) models can help characterize temporal trends. Our objective was to describe mortality from MND in France (1968-2007), and to examine the role of age, period of death, and birth-cohort on changes in mortality. The number of people who died from MND and population statistics (1968 2007) were extracted from French national records. Annual standardized (age/sex) mortality ratios (SMRs) were computed. Using Poisson regression, APC models examined the relationship between mortality rates and age, period of death, and birth-cohort in subjects aged 40-89 years. Deviance/degrees-of-freedom ratios evaluated model fit; ratios close to one indicated adequate fit. Between 1968 and 2007, 38,863 individuals died from MND (mortality rate = 1.74/100,000); 37,624 were aged 40-89 years. SMRs increased from 54 (95% CI = 49-59) in 1968 to 126 (120-132) in 2007. Male-to-female ratios declined from 1.80 in 1968 to 1.45 in 2007. Changing mortality rates were best explained by cohort effects (deviance/degrees-of-freedom = 1.09). The relative risk of dying from MND increased markedly for persons born between 1880 and 1920, and more slowly after 1920. In conclusion, mortality rates for MND increased between 1968 and 2007, and more rapidly in women than men. This increase was better explained by the birth cohort of individuals than by period effects. Changing environmental exposures may be a possible explanation and these findings warrant the continued search for environmental risk factors for MND. PMID- 21674217 TI - Ethnic variations in mortality in pre-school children in Denmark, 1973-2004. AB - The objective of the study was to describe ethnic differences in under-five-years mortality in Denmark according to maternal country of origin. We conducted a large registry-linkage study of all singleton live-born children from mothers born in Denmark and from the ten largest migrant groups (n = 1,841,450). Study outcomes were death before the age of 5 years from all causes combined and the most frequent death causes. Results showed that children of mothers of Turkish, Pakistani, Somali and Iraqi origin had an elevated risk of dying before the age of five compared to offspring of mothers born in Denmark, with hazards ratios and 95% confidence intervals of 1.48 (1.31-1.67), 1.97 (1.68-2.32), 1.70 (1.29-2.25), and 1.92 (1.41-2.62), respectively. Ethnic differences were also observed in the underlying causes of death. Children of mothers born in Former Yugoslavia, Lebanon, Norway, Sweden, Iran, and Afghanistan did not differ in under-five-years mortality from ethnic Danish children. Adjustments for household income did not attenuate the risk estimates. In conclusion, we found excess child mortality in some migrant groups, but not in all. The differences could not be explained by socioeconomic status. PMID- 21674219 TI - A case of sarcoidosis developing as sarcoid myopathy concomitant with systemic sclerosis and review of the literature. AB - A 65-year-old man was diagnosed with systemic sclerosis on the basis of skin thickening and positivity of anti-Scl-70 antibodies. Because myogenic enzymes, such as creatinine phosphokinase and aldorase, were also elevated, myopathy or myositis associated with systemic sclerosis was considered. Muscle magnetic resonance imaging and gallium scintigraphy did not show abnormalities. Findings of muscle biopsy demonstrated presence of noncaseating granulomas with multinucleated giant cells. In addition, serum angiotensin-converting enzyme and lysozyme were elevated, and therefore a diagnosis of sarcoid myopathy was made. Further, renal sarcoidosis was revealed with renal biopsy. Prednisolone (40 mg/day) improved both the myopathy and nephritis. Sarcoid myopathy is a rare condition, but it should be considered when myogenic enzymes are elevated in the patient with systemic sclerosis. Further, muscle biopsy may be essential to make an accurate diagnosis in such condition. PMID- 21674218 TI - A prospective study of the association between vigorous physical activity during pregnancy and length of gestation and birthweight. AB - Current US pregnancy-related physical activity recommendations do not provide specific guidance for vigorous intensity activity. We examined the associations between vigorous physical activity during pregnancy and length of gestation and birthweight. METHODS: Women were recruited before 10 weeks gestation. At 13-16 weeks gestation, participants reported the type, frequency, and duration of their typical weekly vigorous physical activities. Activity domains included recreational, occupational, household, and child/adult care. Infant birth date was obtained from medical or vital records; if unavailable, self-report was used. Birthweight (from vital records) was studied among term births. We analyzed gestational age among 1,647 births using discrete-time survival analysis. We used logistic and linear regression to analyze preterm birth (birth at <37 weeks) and birthweight, respectively. Vigorous recreational activity was associated with longer gestation (any vs. none, hazard ratio (HR) [95% CI]: 0.85 [0.70, 1.05]) and we did not detect any dose-response association. Higher frequency of vigorous recreational activity sessions (adjusted for total volume of activity) was associated with a decreased odds of preterm birth (>= 4 sessions/week vs. 0 or 1, OR [95% CI]: 0.08 (0.006, 1.0). Birthweight was not associated with physical activity measures. In summary, vigorous physical activity does not appear to be detrimental to the timing of birth or birthweight. Our data support a reduced risk of preterm birth with vigorous recreational activity, particularly with increased frequency of recreational activity sessions. Future studies should investigate the components of physical activity (i.e., intensity, duration, and frequency) in relation to birth outcomes. PMID- 21674220 TI - Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33. AB - To investigate the role of interleukin (IL)-33 in rheumatoid arthritis (RA) patients, we measured the serum levels of IL-33 in RA patients before and after the administration of etanercept. Twenty-four patients with RA were treated with etanercept. Clinical and laboratory examinations, including serum levels of C reactive protein (CRP) and hemoglobin (Hb); white blood cell (WBC) and red blood cell (RBC) counts; and the Disease Activity Score of 28 joints including CRP (DAS28-CRP), were performed at the baseline and at 3 and 6 months after the initial treatment with etanercept. The mean serum IL-33 levels had decreased significantly at 3 and 6 months after the initial treatment with etanercept. Serum IL-33 levels showed a significant correlation with the number of tender joints, CRP, DAS28-CRP, and the WBC count, and an inverse correlation with the RBC count and Hb level. These findings indicated that the decrease of serum IL-33 levels was a novel function of etanercept, shown for the first time in this study. Measurement of serum levels of IL-33 may become a useful control marker for RA treatment. PMID- 21674221 TI - The anatomy of fluid-yielding ducts in breast cancer. AB - The concept of an intraductal approach to evaluate the breast microenvironment assumes direct access to the cancer-containing duct. Central duct access to the cancer-affected lobe is essential if cytology or cell markers are to be useful indicators of pre-malignant change. Access to the cancer-bearing lobe would be less important if field change effects of malignant change were predominantly supra-lobar. The aim of this study was to determine how often duct lavage fluid drains the breast cancer-affected segment. 58 patients undergoing mastectomy for breast cancer were recruited among which 47 had at least one fluid-yielding duct. Following duct lavage, fluid-yielding ducts were perfused ex vivo with Polyurethane Elastomer (PU4ii) resin. Specimens were sliced sagittally, and the extent of resin perfusion and anatomical relationship to the cancer-affected segment was recorded. Computed tomography (CT) scanning was performed on selected mastectomies before cut-up for a feasibility study of 3D duct reconstruction. The median number of fluid-yielding ducts cannulated per cancer-affected breast was 2 (range 1-4). 35/47 (74%) mastectomy specimens were successfully cannulated for resin perfusion. 29/35 (83%) showed tracing of the cancer-affected duct system, 6/35 resin perfusions traced duct systems unaffected by cancer and 12/35 perfusions extravasated. The proportion of sagittal breast slices perfused by resin was 13-68% (median 43%). Volume rendering CT showed it is feasible to produce a simulated image of the perfused ducts. Duct access to the cancer containing segment is feasible in the majority of patients. Fluid-yielding ducts proportionately drain a significant volume of the breast. Large symptomatic cancers may cause obstruction with distal collapse. Further quantitative study of breast perfusion CT scans may be helpful for estimating the volume fraction of breast tissue perfused by fluid-yielding ducts. The intraductal approach is a valid concept for biomarker assessment of cancer-containing breast segments. PMID- 21674222 TI - Cancer-associated retinopathy presenting as retinal vasculitis with a negative ERG suggestive of on-bipolar cell pathway dysfunction. AB - A 62-year-old female patient presented to our clinic complaining of a 2 month history of shimmering photopsias and floaters. An ocular examination, fluorescein angiography, and electrophysiological testing were obtained that suggested either an inflammatory retinal vasculitis or a paraneoplastic syndrome. Melanoma associated retinopathy was highly suspected despite the absence of previous history for cutaneous melanoma since an electronegative scotopic ERG was recorded on standard flash electroretinography. Additional investigations revealed the presence of a primary breast tumor with secondary lung and pancreatic metastasis that led to the diagnosis of cancer-associated retinopathy. The patient received chemotherapy and 4 months after the initial presentation her visual complaints but also her retinal function showed marked improvement. Cancer-associated retinopathy needs to be considered in patients presenting with retinal vasculitis and electrophysiological testing can tailor the approach in these cases. PMID- 21674223 TI - Intake and potential health risk of butyltin compounds from seafood consumption in Korea. AB - Concentrations of butyltin compounds (BTs) were determined in 47 species of seafood commonly consumed in Korea to investigate intakes of BTs from seafood consumption and the potential health risks to the Korean population. The concentrations of BTs (the sum of dibutyltin and tributyltin) in seafood ranged from less than the limit of detection to 96.3 ng/g wet weight, which are levels similar to those reported for other countries. The intake of BTs from seafood consumption by the general population was estimated to be 17.2 ng/kg body weight/day. Fish accounted for 50% of the total intakes of BT, and the next contributor was cephalopods (26%). The estimated intakes for males and females were 18.6 and 15.7 ng/ kg body weight/day, respectively. Among the age groups investigated, children (<2 years and 3-6 years) had higher intakes of BTs compared with adults. The estimated intake of BTs for Korean population groups was 5-8% of the tolerable daily intake of 250 ng/ kg body weight/day set by the European Food Safety Authority. Our results suggest that the Korean population is not expected to exceed the threshold value for adverse health effects. PMID- 21674224 TI - Evaluating integrated watershed management using multiple criteria analysis--a case study at Chittagong Hill Tracts in Bangladesh. AB - Criteria and indicators assessment is one of the ways to evaluate management strategies for mountain watersheds. One framework for this, Integrated Watershed Management (IWM), was employed at Chittagong Hill Tracts region of Bangladesh using a multi-criteria analysis approach. The IWM framework, consisting of the design and application of principles, criteria, indicators, and verifiers (PCIV), facilitates active participation by diverse professionals, experts, and interest groups in watershed management, to explicitly address the demands and problems to measure the complexity of problems in a transparent and understandable way. Management alternatives are developed to fulfill every key component of IWM considering the developed PCIV set and current situation of the study area. Different management strategies, each focusing on a different approach (biodiversity conservation, flood control, soil and water quality conservation, indigenous knowledge conservation, income generation, watershed conservation, and landscape conservation) were assessed qualitatively on their potential to improve the current situation according to each verifier of the criteria and indicator set. Analytic Hierarchy Process (AHP), including sensitivity analysis, was employed to identify an appropriate management strategy according to overall priorities (i.e., different weights of each principle) of key informants. The AHP process indicated that a strategy focused on conservation of biodiversity provided the best option to address watershed-related challenges in the Chittagong Hill Tracts, Bangladesh. PMID- 21674225 TI - Socio-economic features of commercial fishery in the bordering upper Danube River area of Serbia. AB - The multidisciplinary socio-economic study of fisheries in the bordering part of the Danube River between Serbia and Croatia (at the following sites: Apatin, Backa Palanka, Backo Novo Selo, Bezdan, and Sombor) that was performed in order to investigate various aspects of fish resource utilization (management, policy of protection and exploitation of freshwater fishery resources, present fisheries legislation, catch statistics), was realized during 2004 and 2005. Data were collected via survey with a structured interview. Socio-economic circumstances, together with ecological factors, have had an influence on the fish stock and number of commercial fishermen. Awareness of the occurring problems, both economic and ecological ones, is apparent, regardless of whether it is assessed in the field of commercial or recreational fishing. Fishery sector in Serbia is in a prolonged process of transition, with the enforcement of fishing regulations, but also the lack of control that leaves space for illegal commercial fishing. The statements, consciousness, experience and behavior of commercial fishermen represent a good basis for planning the sustainable development of fishing in this section of the Danube River. PMID- 21674226 TI - Geochemical position of Pb, Zn and Cd in soils near the Olkusz mine/smelter, South Poland: effects of land use, type of contamination and distance from pollution source. AB - The soils adjacent to an area of historical mining, ore processing and smelting activities reflects the historical background and a mixing of recent contamination sources. The main anthropogenic sources of metals can be connected with historical and recent mine wastes, direct atmospheric deposition from mining and smelting processes and dust particles originating from open tailings ponds. Contaminated agriculture and forest soil samples with mining and smelting related pollutants were collected at different distances from the source of emission in the Pb-Zn-Ag mining area near Olkusz, Upper Silesia to (a) compare the chemical speciation of metals in agriculture and forest soils situated at the same distance from the point source of pollution (paired sampling design), (b) to evaluate the relationship between the distance from the polluter and the retention of the metals in the soil, (c) to describe mineralogy transformation of anthropogenic soil particles in the soils, and (d) to assess the effect of deposited fly ash vs. dumped mining/smelting waste on the mobility and bioavailability of metals in the soil. Forest soils are much more affected with smelting processes than agriculture soils. However, agriculture soils suffer from the downward metal migration more than the forest soils. The maximum concentrations of Pb, Zn, and Cd were detected in a forest soil profile near the smelter and reached about 25 g kg(- 1), 20 g kg(- 1) and 200 mg kg(- 1) for Pb, Zn and Cd, respectively. The metal pollutants from smelting processes are less stable under slightly alkaline soil pH then acidic due to the metal carbonates precipitation. Metal mobility ranges in the studied forest soils are as follows: Pb > Zn ~ Cd for relatively circum-neutral soil pH (near the smelter), Cd > Zn > Pb for acidic soils (further from the smelter). Under relatively comparable pH conditions, the main soil properties influencing metal migration are total organic carbon and cation exchange capacity. The mobilization of Pb, Zn and Cd in soils depends on the persistence of the metal-containing particles in the atmosphere; the longer the time, the more abundant the stable forms. The dumped mining/smelting waste is less risk of easily mobilizable metal forms, however, downward metal migration especially due to the periodical leaching of the waste was observed. PMID- 21674227 TI - Effect of pendimethalin and quizalofop on N2-fixing bacteria in relation to availability of nitrogen in a Typic Haplustept soil of West Bengal, India. AB - An experiment was conducted under laboratory conditions to investigate the effect of two systemic herbicides viz., pendimethalin and quizalofop, at their recommended field rates (1.0 kg and 50 g active ingredient ha(- 1), respectively) on the growth and activities of non-symbiotic N(2)-fixing bacteria in relation to mineralization and availability of nitrogen in a Typic Haplustept soil. Both the herbicides, either singly or in a combination, stimulated the growth and activities of N(2)-fixing bacteria resulting in higher mineralization and availability of nitrogen in soil. The single application of quizalofop increased the proliferation of aerobic non-symbiotic N(2)-fixing bacteria to the highest extent while that of pendimethalin exerted maximum stimulation to their N(2) fixing capacity in soil. Both the herbicides, either alone or in a combination, did not have any significant difference in the stimulation of total nitrogen content and availability of exchangeable NH(4)(+) while the solubility of NO(3)( ) was highly manifested when the herbicides were applied separately in soil. PMID- 21674228 TI - Preface to the special issue on MAF11 Conference proceedings. PMID- 21674229 TI - The ABA-mediated switch between submersed and emersed life-styles in aquatic macrophytes. AB - Hydrophytes comprise aquatic macrophytes from various taxa that are able to sustain and to complete their lifecycle in a flooded environment. Their ancestors, however, underwent adaptive processes to withstand drought on land and became partially or completely independent of water for sexual reproduction. Interestingly, the step backwards into the high-density aquatic medium happened independently several times in numerous plant taxa. For flowering plants, this submersed life-style is especially difficult as they need to erect their floral organs above the water surface to be pollinated. Moreover, fresh-water plants evolved the adaptive mechanism of heterophylly, which enabled them to switch between a submersed and an emersed leaf morphology. The plant hormone abscisic acid (ABA) is a key factor of heterophylly induction in aquatic plants and is a major switch between a submersed and emersed life. The mechanisms of ABA signal perception and transduction appear to be conserved throughout the evolution of basal plants to angiosperms and from terrestrial to aquatic plants. This review summarizes the interplay of environmental factors that act through ABA to orchestrate adaptation of plants to their aquatic environment. PMID- 21674230 TI - Physiological and metabolic diversity in the yeast Kluyveromyces marxianus. AB - Kluyveromyces marxianus is homothallic hemiascomycete yeast frequently isolated from dairy environments. It possesses phenotypic traits such as enhanced thermotolerance, inulinase production, and rapid growth rate that distinguish it from its closest relative Kluyveromyces lactis. Certain of these traits, notably fermentation of lactose and inulin to ethanol, make this yeast attractive for industrial production of ethanol from inexpensive substrates. There is relatively little known, however, about the diversity in this species, at the genetic, metabolic or physiological levels. This study compared phenotypic traits of 13 K. marxianus strains sourced from two European Culture Collections. A wide variety of responses to thermo, osmotic, and cell wall stress were observed, with some strains showing multi-stress resistance. These traits generally appeared unlinked indicating that, as with other yeasts, multiple resistance/adaptation pathways are present in K. marxianus. The data indicate that it should be possible to identify the molecular basis of traits to facilitate selection or engineering of strains adapted for industrial environments. The loci responsible for mating were also identified by genome sequencing and PCR analysis. It was found that K. marxianus can exist as stable haploid or diploid cells, opening up additional prospects for future strain engineering. PMID- 21674231 TI - Metaxa: a software tool for automated detection and discrimination among ribosomal small subunit (12S/16S/18S) sequences of archaea, bacteria, eukaryotes, mitochondria, and chloroplasts in metagenomes and environmental sequencing datasets. AB - The ribosomal small subunit (SSU) rRNA gene has emerged as an important genetic marker for taxonomic identification in environmental sequencing datasets. In addition to being present in the nucleus of eukaryotes and the core genome of prokaryotes, the gene is also found in the mitochondria of eukaryotes and in the chloroplasts of photosynthetic eukaryotes. These three sets of genes are conceptually paralogous and should in most situations not be aligned and analyzed jointly. To identify the origin of SSU sequences in complex sequence datasets has hitherto been a time-consuming and largely manual undertaking. However, the present study introduces Metaxa ( http://microbiology.se/software/metaxa/ ), an automated software tool to extract full-length and partial SSU sequences from larger sequence datasets and assign them to an archaeal, bacterial, nuclear eukaryote, mitochondrial, or chloroplast origin. Using data from reference databases and from full-length organelle and organism genomes, we show that Metaxa detects and scores SSU sequences for origin with very low proportions of false positives and negatives. We believe that this tool will be useful in microbial and evolutionary ecology as well as in metagenomics. PMID- 21674232 TI - Eligibility criteria of Doctorate in Medicine (Medical Gastroenterology) - is the change justified? AB - Eligibility criteria of Doctorate in Medicine (DM) in Medical Gastroenterology had been changed recently by Medical Council of India from MD/DNB in General Medicine and Pediatrics to only that of General Medicine. As DM (Pediatric Gastroenterology) has not come up in a big way in India, this will only lead to shortage of skilled manpower in near future in this emerging field. Enthusiastic pediatricians will also be reluctant to take the discipline, as DM degrees in other broad (adult) superspecialities are open to them. PMID- 21674233 TI - Editorial: the ACPSEM diagnostic imaging TEAP project. PMID- 21674234 TI - Free energies for coarse-grained proteins by integrating multibody statistical contact potentials with entropies from elastic network models. AB - We propose a novel method of calculation of free energy for coarse grained models of proteins by combining our newly developed multibody potentials with entropies computed from elastic network models of proteins. Multi-body potentials have been of much interest recently because they take into account three dimensional interactions related to residue packing and capture the cooperativity of these interactions in protein structures. Combining four-body non-sequential, four-body sequential and pairwise short range potentials with optimized weights for each term, our coarse-grained potential improved recognition of native structure among misfolded decoys, outperforming all other contact potentials for CASP8 decoy sets and performance comparable to the fully atomic empirical DFIRE potentials. By combing statistical contact potentials with entropies from elastic network models of the same structures we can compute free energy changes and improve coarse grained modeling of protein structure and dynamics. The consideration of protein flexibility and dynamics should improve protein structure prediction and refinement of computational models. This work is the first to combine coarse grained multibody potentials with an entropic model that takes into account contributions of the entire structure, investigating native-like decoy selection. PMID- 21674236 TI - Chemical shift correlation at high MAS frequencies employing low-power symmetry based mixing schemes. AB - An approach for conveniently implementing low-power CN ( n ) (nu) and RN ( n ) (nu) symmetry-based band-selective mixing sequences for generating homo- and heteronuclear chemical shift correlation NMR spectra of low gamma nuclei in biological solids is demonstrated. Efficient magnetisation transfer characteristics are achieved by selecting appropriate symmetries requiring the application of basic RF elements of relatively long duration and numerically tailoring the RF field modulation profile of the basic element. The efficacy of the approach is experimentally shown by the acquisition of (15)N-(13)C dipolar and (13)C-(13)C scalar and dipolar coupling mediated chemical shift correlation spectra at representative MAS frequencies. PMID- 21674237 TI - Sphingosylphosphorylcholine attenuated beta-amyloid production by reducing BACE1 expression and catalysis in PC12 cells. AB - Abnormal accumulation of beta-amyloid (Abeta) is the main characteristic of Alzheimer's disease (AD) brain and Abeta peptides are generated from proteolytic cleavages of amyloid precursor protein (APP) by beta-site APP-converting enzyme 1 (BACE1) and presenilin 1 (PS1). Sphingosylphosphorylcholine (SPC), a choline containing sphingolipid, showed suppressive effect on Abeta production in PC12 cells which stably express Swedish mutant of amyloid precursor protein (APPsw). SPC (> 3 MUM) significantly lowered the accumulation of Abeta40/42 and the expression of BACE1. However, the transcriptions of other APP processing enzymes like ADAM10 and PS1 were not affected by the SPC addition. Meanwhile, phosphocholine (PC) or other lysophospholipids, such as lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), sphingosyl-1-phosphate (S1P), did not alter BACE1 expression. Down-regulatory effect of SPC on BACE1 expression appeared to be mediated by NF-kappaB which is known to suppress the trans-activation of BACE1 promoter in PC12 cells. Here, the nuclear tanslocation of NF-kappaB was enhanced by SPC treatment in immune-fluorescent image analysis and NF-kappaB reporter assay. Furthermore, the catalytic activities of BACE1 and BACE2 were dose dependently inhibited by SPC displaying IC50 values of 2.79 MUM and 12.05 MUM, respectively. Overall, these data suggest that SPC has the potential to ameliorate Abeta pathology in neurons by down-regulating the BACE1-mediated amyloidogenic pathway. PMID- 21674238 TI - Identification of novel alpha-synuclein isoforms in human brain tissue by using an online nanoLC-ESI-FTICR-MS method. AB - Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated alpha-synuclein (alpha-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of alpha-syn in brain tissue homogenates. N-terminally acetylated full-length alpha-syn (Ac-alpha-syn1-140) and two N-terminally acetylated C-terminally truncated forms of alpha-syn (Ac-alpha-syn1-139 and Ac-alpha-syn1-103) were found. The different forms of alpha-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of alpha-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA). PMID- 21674239 TI - Effects of taurine on nitric oxide and 3-nitrotyrosine levels in spleen during endotoxemia. AB - Taurine (2-aminoethanesulfonic acid) is a free sulfur-containing beta-amino acid which has antioxidant, antiinflammatory and detoxificant properties. In the present study, the role of endotoxemia on peroxynitrite formation via 3 nitrotyrosine (3-NT) detection, and the possible antioxidant effect of taurine in lipopolysaccharide (LPS)-treated guinea pigs were aimed. 40 adult male guinea pigs were divided into four groups; control, endotoxemia, taurine and taurine+endotoxemia. Animals were administered taurine (300 mg/kg), LPS (4 mg/kg) or taurine plus LPS intraperitoneally. After 6 h of incubation, when highest blood levels of taurine and endotoxin were attained, the animals were sacrificed and spleen samples were collected. The amounts of 3-nitrotyrosine and taurine were measured by HPLC, and reactive nitrogen oxide species (NOx) which are stable end products of nitric oxide was measured spectrophotometrically in spleen tissues. LPS administration significantly decreased the concentration of taurine whilst increased levels of 3-NT and NOx compared with control group. It was determined that taurine treatment decreased the levels of 3-nitrotyrosine and NOx in taurine+endotoxemia group. The group in which taurine was administered alone, contradiction to well-known antioxidant effect, taurine caused elevated concentration of 3-NT and NOx. This data suggest that taurine protects spleen against oxidative damage in endotoxemic conditions. However, the effect of taurine is different when it is administered alone. In conclusion, taurine may act as an antioxidant during endotoxemia, and as a prooxidant in healthy subjects at this dose. PMID- 21674240 TI - Demonstrations of AIDS-associated malignancies and infections at FDG PET-CT. AB - HIV infection results in profound alterations of immunologic function that render the patient severely immunocompromised, and susceptible to malignancies and opportunistic infections. Three AIDS-defining malignancies include Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL) and invasive cervical cancer. In AIDS patients, KS is often aggressive and multifocal, with visceral involvement and widespread cutaneous and nodal spread; NHL is always high grade and often widely disseminated at the time of diagnosis with frequent involvement of extranodal sites; cervical cancer is invasive and has greater likelihood of progression and metastasis. Although there are very sparse systemic data available in the literature, limited studies has shown that FDG PET-CT is a valuable imaging technique in the diagnosis, staging, restaging and monitoring therapeutic response in these malignancies. In addition, a unique application of FDG PET/CT is the differentiation of cerebral lesions between lymphoma and toxoplasmosis in AIDS patients, which cannot be reliably achieved with either CT or MRI. HIV associated opportunistic infections may involve different pathogens and multiple tissues, organs or systems. Some preliminary observations have revealed a promising role of FDG PET-CT in the diagnosis and identification of these infections such as tuberculosis, fever of unknown origin, pneumocystis pneumonia and candidiasis. However, it should be stressed that FDG PET-CT alone has no role in identifying the pathology of abnormalities. FDG PET-CT, at best, can localize the sites of abnormalities and impact on patient's management in clinical decision making. PMID- 21674241 TI - BMP-4 expression has prognostic significance in advanced serous ovarian carcinoma and is affected by cisplatin in OVCAR-3 cells. AB - Several angiogenesis-promoting factors have prognostic significance in ovarian cancer. The objective of this study was to evaluate whether traditional chemotherapy affects angiogenesis-related factors in ovarian carcinoma and to assess the clinical significance of these effects. To screen for angiogenesis related factors of possible relevance, OVCAR-3 and A2780 ovarian cancer cells were treated with IC(50) doses of cisplatin (CDDP) or docetaxel, or with bevacizumab, and mRNA expression of several angiogenesis-related factors was analyzed. Thrombospondin-1 (TSP-1), bone morphogenetic protein-4 (BMP-4), endothelin-1, and placental growth factor-2 were statistically significantly induced by CDDP. At protein level, CDDP also induced hypoxia-inducible factor 1alpha but not vascular endothelial growth factor. In carcinoma samples taken before and after platinum-based neoadjuvant chemotherapy from 28 patients with advanced, high-grade serous ovarian carcinoma, CD105 and factors most induced by CDDP (TSP-1 and BMP-4) were analyzed by immunohistochemistry. Strong expression of BMP-4 before chemotherapy was an independent prognostic factor of longer progression-free time (p = 0.002) and overall survival (p = 0.02), but it was not associated with neovascularization (as evaluated by CD105). However, changes in BMP-4 expression in samples analyzed before and after chemotherapy (observed in 22/28 patients) were not associated with prognosis. TSP-1 expression was not associated with clinical parameters. Our results indicate that in serous ovarian carcinoma, BMP-4 has prognostic significance, which is not angiogenesis-related. We also show that CDDP induces several angiogenesis-related growth factors in vitro and future studies are warranted to clarify the clinical significance of this phenomenon. PMID- 21674242 TI - Differential expression of Oct4 in HPV-positive and HPV-negative cervical cancer cells is not regulated by DNA methyltransferase 3A. AB - The colony-forming ability of cervical cancer is affected by many factors. Oct4, an important transcription factor, is highly expressed in several tumors and promotes the colony-forming ability of cancer cells. Thus, it is considered a potential target for the treatment of cancer. However, we know little about the expression level of Oct4 and its epigenetic regulatory mechanism in cervical cancer cells. In this study, we are the first to observe that human papillomavirus (HPV)-positive cervical cancer cell lines (HeLa, Caski) have a stronger colony-forming ability than HPV-negative cervical cancer cell lines (C 33A). Moreover, the expression level of Oct4 in both HeLa and Caski cells was also higher than that in C-33A cells. We then confirmed that there was a negative correlation between the expression of Oct4 and DNMT3A in these three types of cervical cancer cells, whereas DNA methyltransferase 1 and 3B had no differences among the cell lines. However, after DNA methylation in both key regulatory regions of the Oct4 gene and the genomic levels were analyzed, we found that DNA methyltransferase 3A could neither regulate the expression of Oct4 nor affect the whole level of genomic DNA methylation. These results suggest three points: (1) Oct4 might be treated as a new target for the treatment of cervical cancer, (2) we could not inhibit the expression of Oct4 by DNA demethylation, and (3) HPV virus might initiate cervical carcinogenesis by upregulation of Oct4 expression. PMID- 21674243 TI - The oncofetal gene survivin promotes cell proliferation and survival in primary human osteoblastic cells. AB - Survivin, the smallest member of the inhibitor of apoptosis gene family, is critical for the regulation of mitosis and maintenance of cell viability during embryonic development and cancer, while not being detectable in most adult differentiated tissues. We know little about whether survivin plays any physiological or pathophysiological role in the adult musculoskeletal system. We studied the expression of survivin in primary human osteoblastic cells and its biological functions in vitro. Survivin was detected by immunoblotting and real time PCR. Subcellular localization was analyzed by immunofluorescence. Transfection of siRNA and plasmids coding for wild-type survivin was performed to study survivin function, i.e., proliferation and apoptosis assays. Survivin mRNA and protein are expressed in primary human osteoblastic cells. During interphase survivin localizes predominantly to the cytoplasmic compartment, which is relevant for the organization of the spindle apparatus during mitosis. Survivin knockdown resulted in an arrest of the cell cycle at the G(2)/M phase and increased rates of apoptosis. Elevated levels of survivin in primary human osteoblasts enhanced proliferation and cell viability. Taken together, we demonstrate for the first time that survivin is expressed in primary human osteoblastic cells on the mRNA and protein levels. Our results indicate that survivin is a critical factor for cell division and cell viability in primary human osteoblastic cells. Learning more about survivin's role in human osteoblasts could be an important step toward understanding the complex processes involved in bone homeostasis and remodeling. PMID- 21674244 TI - Phenotype of distinct primary sensory afferent subpopulations and caspase-3 expression following axotomy. AB - Specific sensory neuronal subpopulations show contrasting responses to peripheral nerve injury, as shown by the axotomy-induced death of many cutaneous sensory neurons whilst muscular sensory afferents survive an identical insult. We used a novel combination of retrograde neuronal tracing with immunohistochemistry and laser microdissection techniques, in order to describe the neurochemistry of medial gastrocnemius (muscular sensory afferents) and sural (cutaneous sensory afferents) branches of the rat sciatic nerve and relate this to the pro-apoptotic caspase-3 gene expression following nerve transection. Our results demonstrated distinctions in medial gastrocnemius and sural neuron populations with the most striking difference in the respective proportions of isolectin B4 (IB4) staining neurons (3.7 V 32.8%). The mean neuronal area of the medial gastrocnemius (MG) neurons was larger than that of the sural (SUR) neurons (1,070.8 V 646.2 MUm2) and each phenotypic group was significantly smaller in sural neurons than in MG neurons. At 1 week post-axotomy, MG neurons markedly downregulated caspase-3, whilst SUR neurons upregulated caspase-3 gene expression; this may be attributable to the differing IB4-positive composition of the subpopulations. These findings provide further clarification in the understanding of two distinct neuronal populations used increasingly in nerve injury models. PMID- 21674245 TI - Tracking the performance, energetics and biomechanics of international versus national level swimmers during a competitive season. AB - The purpose of this study was to track and compare the changes of performance, energetic and biomechanical profiles of international (Int) and national (Nat) level swimmers during a season. Ten Portuguese male swimmers (four Int and six Nat level subjects) were evaluated on three different time periods (TP(1), TP(2), TP(3)) of the 2009-2010 season. Swimming performance was assessed based on official time's lists of the 200-m freestyle event. An incremental set of 7 * 200 m swims was applied to assess the energetic and biomechanical data. Measurements were made of: (1) velocity at the 4 mmol of lactate levels (V4), stroke index at V4 (SI@V4) and propelling efficiency at V4 (eta (p)@V4), as energetic estimators; (2) stroke length at V4 (SL@V4) and stroke frequency at V4 (SF@V4), as biomechanical variables. The results demonstrated no significant variations in all variables throughout the season. The inter-group comparison pointed out higher values for Int swimmers, with statistical differences for the 200 m performance in all time periods. Near values of the statistical significance were demonstrated for the SI@V4 in TP(1) and TP(3). The tracking based on K values was high only for the SI@V4. It is concluded that a high stability can be observed for elite swimmers performance, energetic and biomechanical profiles throughout a single season. Int swimmers are able to maintain a higher energetic and biomechanical capacity than Nat ones at all times. The SI@V4 may be used as an indicator of performance variation. PMID- 21674246 TI - Physiological responses in rock climbing with repeated ascents over a 10-week period. AB - The purpose was to analyze the physiological responses and energy expenditure during repeated ascents of the same climbing route over a 10-week period. Nine climbers completed nine ascents of a specific route spaced 1 week apart. Expired air was analyzed continuously during each ascent, and time of ascent was recorded to the nearest second. Energy expenditure during climbing (EE(CLM)), and during climbing +10 min recovery (EE(TOT)) was calculated by the Weir and Zuntz equations. Differences among ascents 1, 4, 6 and 9 were analyzed by repeated measures ANOVA. Climbing time was longer for ascent 1 compared with ascents 4, 6 and 9 (P < 0.001). Differences were found for EE(CLM) (kcal; P < 0.001), between ascent 1 versus 6 and 9 and ascent 4 versus 9, using both Zuntz and Weir equations. Also, differences were observed in EE for recovery (P < 0.05) and EE(TOT) (P < 0.05) using both equations. Repeated ascents of a climbing route decreased the climbing time and absolute energy expenditure during climbing. Initially, the decrease in climbing energy expenditure is accompanied by an increase in energy expenditure during recovery; however, by the ninth ascent, the total energy expenditure of the task is lower than for ascent 1. PMID- 21674248 TI - Marked increase in substance use among young people after L'Aquila earthquake. PMID- 21674247 TI - [Diagnosis and treatment of acute pancreatitis. Current recommendations]. AB - Acute pancreatitis is a potentially life-threatening illness, with a short time frame for diagnosis and treatment. A number of recent experimental and clinical multicentre trials as well as meta-analyses have provided more far-reaching recommendations compared to previous guidelines. To answer 12 key questions, we performed a review of recent literature and current guidelines. Diagnosis can be made on the basis of history, physical examination and serum lipase alone. Cholestatic parameters and upper abdominal ultrasound enable verification of biliary etiology. Poor prognostic indicators include elevated blood sugar, BUN and hematocrit. The latter suggests early, adequate volume replacement, which should be tailored to the clinical picture, echocardiography and/or modern hemodynamic parameters. In addition to opiate analgesia, meta-analyses support the use of endoscopic retrograde cholangiography in pancreatitis of biliary origin, antibiotics in necrotizing pancreatitis and early enteral feeding. Even where necrosis is present, conservative management (radiologically or endoscopically placed drains) is appropriate. PMID- 21674249 TI - Association of expression of kruppel-like factor 4 and kruppel-like factor 5 with the clinical manifestations of breast cancer. AB - Kruppel-like factors (KLFs) are import modulators of cell proliferation, differentiation, and transformation and have recently been considered possible prognostic factors in breast cancer. In this study, we investigated the correlation between KLF4 and KLF5 expression and the clinical manifestations of breast cancer by immunohistochemical analysis. We observed increased KLF4 and KLF5 expression in tumor cells (invasive and in situ carcinomas), consistent KLF4 and KLF5 expression in in situ and invasive carcinomas, significant associations between KLF4 expression and tumor grade (p = 0.033), size (p = 0.035) and stage (p = 0.006), and an association between KLF5 expression and tumor grade (p = 0.033). Interestingly, we observed a relationship between increasing age and KLF4 expression (p = 0.007), with a tendency towards greater expression in tumor cells in patients over 50 years old. Moreover, KLF5 nuclear localization was restricted to non-tumor breast ducts and lobules; however, loss of nuclear expression of KLF5 in in situ and invasive carcinomas was observed. Although the mechanism of the loss of KLF5 nuclear expression is not clear, this phenomenon may imply a possible tumor-suppressor-like role for KLF5 in breast cancer tumorigenesis. The expression of KLF4 and KLF5 in breast cancer patients in Taiwan is similar to that in Western countries, except for the uncertainty surrounding its prognostic significance. Further clarification of the underlying mechanisms of KLF4 and KLF5 expression and their correlations with breast cancer outcomes is necessary. PMID- 21674250 TI - Stromal expression of CD34, alpha-smooth muscle actin and CD26/DPPIV in squamous cell carcinoma of the skin: a comparative immunohistochemical study. AB - Invasion pathogenesis is one of the most complicated issues in the literature. There are numerous studies concerning the tumor markers implicated in the preinvasive-invasive tumor sequence. Despite ample studies on the invasion pathogenesis of cutaneous melanomas, there is limited and dispersed work presently available on non-melanoma skin cancer. The vast knowledge in the literature concerning this issue in squamous cell carcinoma comes mostly from the studies of the oral cavity, esophagus, larynx, and cervix. In this study, we investigated tumor-free neighboring stroma and tumor stroma in squamous cell carcinomas (SCCs) of the skin as well as keratoacanthomas (KAs) with respect to the presence of stromal CD34-positive (CD34+) fibrocytes and alpha-smooth muscle actin-positive (alpha-SMA+) myofibroblasts using seborrheic keratosis (SKs) and non-tumoral skin samples as controls. We also evaluated the stromal expression pattern of CD26/DPPIV (CD26), a tumor suppressor gene product that also has immunoregulatory properties. Immunohistochemistry was performed on samples of 31 SCC, 8 KA, 15 SK and 10 non-tumoral skin samples. Peri-tumoral stroma from resection margins was also evaluated. We found that CD34 and alpha-SMA demonstrated significantly different staining between benign and malignant squamous skin lesions consisting of a loss of CD34+ fibrocytes paralleled by a gain of alpha-SMA+ myofibroblasts in malignant tumor stroma. Additionally, it was shown that CD26 expression was lower in tumor stroma when compared to that of tumor neighboring stroma. However, we concluded that this finding may be attributable to the solar elastosis areas in the peritumoral tissue, which shows diffuse strong positivity for this marker. PMID- 21674251 TI - Increase of urinary concentrations of 8-hydroxy-2'-deoxyguanosine in diesel exhaust emission inspector exposed to polycyclic aromatic hydrocarbons. AB - PURPOSE: The objectives of this study were to explore the factors influencing urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in diesel engine exhaust emission inspectors (inspectors), the association between polycyclic aromatic hydrocarbons (PAHs) exposure and fine particulate matter (PM(2.5)) levels in diesel exhaust particles (DEPs), and the PAHs exposure levels in diesel vehicle emission inspection stations (inspection stations). METHODS: Twenty-eight inspectors and a control group of thirty-eight individuals matched by age and gender were recruited for this study. Fifteen ambient air samples and eighty-four personal air samples were monitored during 3-day work periods using a repeated measures study design in each inspection station. Airborne samples were analyzed with a fluorescence detector and by high-performance liquid chromatography. Urinary 8-OHdG was measured in 168 pre- and post-work urine samples from inspectors, and in 38 urine samples from controls. RESULTS: The concentrations of PAHs in DEP(2.5) (PM(2.5) in DEPs) were significantly and positively related to urinary log(10) 8-OHdG levels after adjusting for smoking status and BMI. Statistically, there was a significant correlation between air log(10) PAHs and air log(10) PM(2.5) concentrations in inspectors. Fifteen PAHs compounds within DEP(2.5) revealed the concentrations ranged from 5.18 to 22.93 ng/m(3) in ambient air monitoring and 1.03 to 12.60 ng/m(3) in personal air monitoring. CONCLUSIONS: This study is the first to indicate an association between occupational PAHs exposure from DEP(2.5) at an inspection station and an increased excretion of urinary 8-OHdG in inspectors. In addition, this study also found smoking is not a confounder in inspectors exposed to PAHs in DEP(2.5). PMID- 21674252 TI - Cause-specific mortality in professional flight crew and air traffic control officers: findings from two UK population-based cohorts of over 20,000 subjects. AB - OBJECTIVE: Flight crew are exposed to several potential occupational hazards. This study compares mortality rates in UK flight crew to those in air traffic control officers (ATCOs) and the general population. METHODS: A total of 19,489 flight crew and ATCOs were identified from the UK Civil Aviation Authority medical records and followed to the end of 2006. Consented access to medical records and questionnaire data provided information on demographic, behavioral, clinical, and occupational variables. Standardized mortality ratios (SMR) were estimated for these two occupational groups using the UK general population. Adjusted mortality hazard ratios (HR) for flight crew versus ATCOs were estimated via Cox regression models. RESULTS: A total of 577 deaths occurred during follow up. Relative to the general population, both flight crew (SMR 0.32; 95% CI 0.30, 0.35) and ATCOs (0.39; 0.32, 0.47) had lower all-cause mortality, mainly due to marked reductions in mortality from neoplasms and cardiovascular diseases, although flight crew had higher mortality from aircraft accidents (SMR 42.8; 27.9, 65.6). There were no differences in all-cause mortality (HR 0.99; 95% CI 0.79, 1.25), or in mortality from any major cause, between the two occupational groups after adjustment for health-related variables, again except for those from aircraft accidents. The latter ratios, however, declined with increasing number of hours. CONCLUSIONS: The low all-cause mortality observed in both occupational groups relative to the general population is consistent with a strong "healthy worker effect" and their low prevalence of smoking and other risk factors. Mortality among flight crew did not appear to be influenced by occupational exposures, except for a rise in mortality from aircraft accidents. PMID- 21674254 TI - The urgent need for universities to comprehensively address global climate change across disciplines and programs. AB - I review the status of scientific, political, and moral problems of global climate change (GCC) and, based on lessons from environmental and sustainability programs in universities, demonstrate that universities have had a lethargic response to urgent needs to mitigate the problems. I explore reasons for the response, and conclude that there is an urgent need for comprehensive and wide ranging change in universities to help mitigate GCC. My discussion is focused on those within universities as well as those in environmental professions regardless of their areas of specialization. PMID- 21674255 TI - Giant cell tumour of the flexor tendon sheath of the hand: analysis of 27 cases. AB - Giant cell tumour of the tendon sheath (GCTTS) is a slowly progressing benign tumour arising from synovial cells of tendon sheaths. It is one of the most common soft tissue tumours in the hand. We report a retrospective study of 27 proven GCTTS of the hand. The mean length of follow-up was 4.5 years (17 months 8.5 years). Radiographic findings are useful and may prove of great diagnostic value. The positive diagnosis was provided by the pathology examination after complete excision that was performed in all patients. The recurrence was noted in two surgically managed cases. The excision should be meticulous and complete in order to avoid recurrence. PMID- 21674256 TI - Sibling sex ratio and birth order in early-onset gender dysphoric adolescents. AB - Several sibship-related variables have been studied extensively in sexual orientation research, especially in men. Sibling sex ratio refers to the ratio of brothers to sisters in the aggregate sibships of a group of probands. Birth order refers to the probands' position (e.g., first-born, middle-born, last-born) within their sibships. Fraternal birth order refers to their position among male siblings only. Such research was extended in this study to a large group of early onset gender dysphoric adolescents. The probands comprised 94 male-to-female and 95 female-to-male gender dysphoric adolescents. The overwhelming majority of these were homosexual or probably prehomosexual. The control group consisted of 875 boys and 914 girls from the TRAILS study. The sibling sex ratio of the gender dysphoric boys was very high (241 brothers per 100 sisters) compared with the expected ratio (106:100). The excess of brothers was more extreme among the probands' older siblings (300:100) than among their younger siblings (195:100). Between-groups comparisons showed that the gender dysphoric boys had significantly more older brothers, and significantly fewer older sisters and younger sisters, than did the control boys. In contrast, the only notable finding for the female groups was that the gender dysphoric girls had significantly fewer total siblings than did the control girls. The results for the male probands were consistent with prior speculations that a high fraternal birth order (i.e., an excess of older brothers) is found in all homosexual male groups, but an elevated sibling sex ratio (usually caused by an additional, smaller excess of younger brothers) is characteristic of gender dysphoric homosexual males. The mechanisms underlying these phenomena remain unknown. PMID- 21674257 TI - Increased risk of cigarette smoking among immigrant children and girls in Hong Kong: an emerging public health issue. AB - Despite global progress in tobacco control, data are needed for subgroups with increased risk of tobacco use for more effective smoking prevention. Survey data from a random sample of 6,486 youth in grades 7, 8 and 9 were derived from the project Chinese Student Health Survey. Prevalence and hazards of smoking onset were compared by gender and immigrant status. Mediation analysis was used to assess factors that may mediate the impact of immigrant status on smoking. Immigrant students had a much higher risk of hazards of smoking initiation than non-immigrant students. Parental monitoring and parental smoking significantly mediated the effect of immigrant status on early smoking onset. In addition, gender differences in the prevalence of smoking and hazards of smoking onset in our study were smaller than those reported by others targeting non-Hong Kong Chinese youth. Findings of this study imply that immigrant children and girls in Hong Kong are at increased risk to tobacco use. Special attention should be paid to these subgroups for prevention intervention. Prevention intervention for immigrant children should address parental smoking and parental monitoring. Reduced gender difference in smoking among Hong Kong youth suggests an emerging trend for more Chinese girls on the Mainland to smoke along with the rapid socioeconomic development. PMID- 21674258 TI - An experimental study of COMP (cartilage oligomeric matrix protein) in the rabbit menisci. AB - INTRODUCTION: Secondary knee osteoarthritis (OA) is currently associated with meniscal injuries, but the pathogenesis is unclear. We analyzed the distribution of cells and cartilage oligomeric matrix protein (COMP) and its changes in the early stages of degeneration in meniscus. METHOD: Ten New Zealand rabbits underwent anterior cruciate ligament (ACL)-transection of the right knee-joint. Left knee-joints were used as controls. The animals were killed at 4 and 12 weeks. Gross injuries in meniscus and articular cartilage were scored. Meniscal tissues were immunostained with a specific antibody against COMP, with Ki-67, using TUNEL-assay and alcian blue stain. The number of cells was counted. RESULTS: At 4 weeks post-ACL-transection, 2/5 of the operated knees showed articular damages and medial menisci tears. Menisci showed a weak increase of cells, higher in cells under division and an increase of apoptosis, COMP and proteoglycans. At 12 weeks, 5/5 of the medial menisci and 2/5 of lateral menisci presented tears, and osteoarthritic changes were seen in the cartilage of all the operated knees. Meniscal cells reverted to normal number, while active cell division decreased below normal, apoptotic events were still high, COMP remained elevated, and glycosaminoglycans were even more elevated. CONCLUSION: Extracellular matrix changes and altered cell distribution occur early in the degenerative meniscus. There is a close relationship between changes in the articular cartilage and the menisci at the onset of secondary OA. PMID- 21674259 TI - Similar rye A and B chromosome organization in meristematic and differentiated interphase nuclei. AB - Supernumerary (B) chromosomes of rye are not required for plant development and exhibit a reduced transcription activity. These special features inspired us to analyse whether there are differences between A and B chromatin organization in interphase nuclei. Applying fluorescence in situ hybridization, we found that both rye A and B chromosomes added to hexaploid wheat showed in meristematic nuclei a string-like shape and a clear Rabl orientation. In 4C differentiated leaf nuclei, a more relaxed chromatin structure, round-shaped chromosome territories and a less pronounced Rabl configuration were found. Also, the observed random association of homologues in 2C and 4C nuclei indicated in general a similar behaviour of A and B chromosomes. Whereas in differentiated 4C nuclei A sister centromeres are separated, B sister centromeres align in nearly all nuclei. In short, despite the different transcription activity of A and B chromosomes, both types of chromosomes exhibit a similar organization in meristematic and differentiated interphase nuclei. But the deletion of a B chromosome segment responsible for non-disjunction during gametogenesis induces released sister centromeres also in some interphase nuclei of somatic tissue. Hence, the control of rye B chromosome non-disjunction is also active in sporophytic cells. PMID- 21674260 TI - Body-worn sensor design: what do patients and clinicians want? AB - User preferences need to be taken into account in order to be able to design devices that will gain acceptance both in a clinical and home setting. Sensor systems become redundant if patients or clinicians do not want to work with them. The aim of this systematic review was to determine both patients' and clinicians' preferences for non-invasive body-worn sensor systems. A search for relevant articles and conference proceedings was performed using MEDLINE, EMBASE, Current Contents Connect, and EEEI explore. In total 843 papers were identified of which only 11 studies were deemed suitable for inclusion. A range of different clinically relevant user groups were included. The key user preferences were that a body-worn sensor system should be compact, embedded and simple to operate and maintain. It also should not affect daily behavior nor seek to directly replace a health care professional. It became apparent that despite the importance of user preferences, they are rarely considered and as such there is a lack of high quality studies in this area. We therefore would like to encourage researchers to focus on the implications of user preferences when designing wearable sensor systems. PMID- 21674262 TI - Precipitation in and supersaturation of contents of the upper small intestine after administration of two weak bases to fasted adults. AB - PURPOSE: To evaluate precipitation in and supersaturation of intestinal contents after administration of pharmacologically relevant doses of dipyridamole and ketoconazole to 12 healthy adults. METHODS: On two separate days each subject was administered in stomach 240 ml aqueous solutions of two dipyridamole doses (30/90 mg) and two ketoconazole doses (100/300 mg). Physicochemical characteristics, total drug content, and drug concentration were measured in individual intestinal contents (<=7 ml) aspirated at specific times post-dosing. Drug concentration after incubation (37 degrees C/48 h) and equilibrium solubility were measured. Precipitate crystallinity was evaluated by x-ray powder diffraction. RESULTS: Precipitated fraction was minimal (dipyridamole, <=7%) or limited (ketoconazole, <=16%). Ketoconazole precipitates were mostly amorphous. Depending on dose, intestinal contents with pH > 3.6 were supersaturated with dipyridamole up to 10 and 30 min and with ketoconazole up to 30 and 50 min post-administration. Intestinal contents with pH > 5 and concentration of micellar components <5 mM were supersaturated with ketoconazole or dipyridamole, but precipitated fraction was significant only for ketoconazole. After incubation, crystalline precipitates were found in almost all samples. Slow precipitation of base and/or precipitation of other phases account for this observation. CONCLUSIONS: Intralumenal precipitation of weakly alkaline, lipophilic, high permeability drugs may not be substantial. Estimating intestinal supersaturation in regard to free base is inadequate as other phases may precipitate. PMID- 21674263 TI - Improved ziprasidone formulations with enhanced bioavailability in the fasted state and a reduced food effect. AB - PURPOSE: To develop and characterize new formulations of ziprasidone with a reduced food effect achieved by increasing exposure in the fasted state. METHODS: Formulations were developed utilizing the following solubilization technologies: inclusion complex of ziprasidone mesylate and cyclodextrin, ziprasidone free base nano-suspension, and semi-ordered ziprasidone HCl in polymer matrix. Pharmacokinetic studies were conducted with these formulations to examine the bioavailability of test formulations in fasted and fed state compared to commercial capsules (Geodon(r)) dosed in the fed state. RESULTS: All formulations containing solubilized ziprasidone showed either no food effect or a reduced food effect compared to commercial capsules. Two formulations when taken in the fasted or fed state were comparable to the commercial capsules dosed in the fed state with respect to total exposure. However, peak concentrations were ~30-40% higher. CONCLUSIONS: Pharmacokinetic studies indicated solubilization technologies can be employed to successfully increase the extent of ziprasidone absorption in the fasted state, thereby reducing the food effect. Such formulations could provide simple and convenient dosing while retaining the familiar safety and efficacy profile of currently marketed capsules. PMID- 21674264 TI - Development and in vitro-in vivo evaluation of fenretinide-loaded oral mucoadhesive patches for site-specific chemoprevention of oral cancer. AB - PURPOSE: To develop fenretinide oral mucoadhesive patch formulations and evaluate their in vitro and in vivo release performance for future site-specific chemoprevention of oral cancer. METHODS: Solubilization of fenretinide in simulated saliva (SS) was studied by incorporating nonionic surfactants (Tween(r) 20 and 80, and Brij(r) 35 and 98), bile salts (sodium salt of cholic, taurocholic, glycocholic, and deoxycholic acids), phospholipid (lecithin), and novel polymeric solubilizer (Souplus(r)). Adhesive (polycarbophil: hydroxypropyl methylcellulose 4KM) and drug release (Fenretinide/Eudragit(r) RL PO with or without solubilizers) layers were prepared by solvent casting. Oral mucoadhesive patches were formed by attaching drug and adhesive layers onto backing layer (TegadermTM film). Physical state of drug in Eudragit(r) films was examined by X ray diffraction (XRD). Evaluation of in vitro and in vivo fenretinide release from the patch was conducted in SS containing 5%w/v sodium deoxycholate and rabbits, respectively. Fenretinide was quantified by HPLC. RESULTS: Tween(r) 20 and 80, Brij(r) 98, and sodium deoxycholate exhibited the highest fenretinide solubilization potential among the solubilizers. Drug loading efficiency in Eudragit(r) films was 90%-97%. XRD suggested fenretinide was amorphous in solubilizer-free and solubilizer-loaded films. Solubilizer-free patch exhibited poor in vitro and in vivo controlled drug release behavior. Increases in drug loading (5-10 wt%) or changes in polymeric matrix permeability did not provide continuous drug release. Co-incorporation of either single or mixed solubilizers in fenretinide/Eudragit(r) patches, (20 wt% Tween(r) 20, Tween(r) 80 and sodium deoxycholate or 20 wt% Tween(r) 80 + 40 wt% sodium deoxycholate solubilizers) led to significantly improved continuous in vitro/in vivo fenretinide release. CONCLUSION: Fenretinide/Eudragit(r) RL PO patches with 20 wt% Tween(r) 80 + 40 wt% sodium deoxycholate solubilizers exhibit excellent release behavior for further preclinical and/or clinical evaluation in oral cancer chemoprevention. PMID- 21674265 TI - Differences in Toll-like receptor expression and cytokine production after stimulation with heat-killed Gram-positive and Gram-negative bacteria. AB - Innate immune surveillance in the blood is executed mostly by circulating monocytes, which recognise conserved bacterial molecules such as peptidoglycan and lipopolysaccharide. Toll-like receptors (TLR) play a central role in microbe associated molecular pattern detection. Here, we compared the differences in TLR expression and cytokine production after stimulation of peripheral blood cells with heat-killed Gram-negative and Gram-positive human pathogens Neisseria meningitidis, Escherichia coli, Staphylococcus aureus and Streptococcus pneumoniae. We found that TLR2 expression is up-regulated on monocytes after stimulation with S. aureus, S. pneumoniae, E. coli and N. meningitidis. Moreover, TLR2 up-regulation was positively associated with increasing concentrations of Gram-positive bacteria, whereas higher concentrations of Gram-negative bacteria, especially E. coli, caused a milder TLR2 expression increase compared with low doses. Cytokines were produced in similar dose-dependent profiles regardless of the stimulatory pathogen; however, Gram-negative pathogens induced higher cytokine levels than Gram-positive ones at same concentrations. These results indicate that Gram-positive and Gram-negative bacteria differ in their dose dependent patterns of induction of TLR2 and TLR4, but not in cytokine expression. PMID- 21674266 TI - A study on the dynamics of the zraP gene expression profile and its application to the construction of zinc adsorption bacteria. AB - Zinc ion plays essential roles in biological chemistry. Bacteria acquire Zn(2+) from the environment, and cellular concentration levels are controlled by zinc homeostasis systems. In comparison with other homeostatic systems, the ZraSR two component system was found to be more efficient in responding to exogenous zinc concentrations. To understand the dynamic response of the bacterium ZraSR two component system with respect to exogenous zinc concentrations, the genetic circuit of the ZraSR system was integrated with a reporter protein. This study was helpful in the construction of an E. coli system that can display selective metal binding peptides on the surface of the cell in response to exogenous zinc. The engineered bacterial system for monitoring exogenous zinc was successfully employed to detect levels of zinc as low as 0.001 mM, which directly activates the expression of chimeric ompC(t)--zinc binding peptide gene to remove zinc by adsorbing a maximum of 163.6 MUmol of zinc per gram of dry cell weight. These results indicate that the engineered bacterial strain developed in the present study can sense the specific heavy metal and activates a cell surface display system that acts to remove the metal. PMID- 21674267 TI - Modified pleural tenting for prevention of anastomotic leak after Ivor Lewis esophagogastrectomy. AB - BACKGROUND: The most dangerous complication following esophagogastrectomy for esophageal cancer is anastomotic leakage. Surgical interventions described did not have a major impact in reducing the risk of occurrence. On the other hand, pleural tenting has been used for more than a decade by thoracic surgeons to prevent prolonged air leak after formal upper lobectomy with excellent results. METHODS: A retrospective analysis of 114 cases of esophagogastrectomy for cancer of esophagus or cardioesophageal junction is presented. Patients have been divided in 2 groups. In group B modified pleural tenting was used to prevent a potential anastomotic leak, while in group A, the control group, pleural tenting was not used. Evaluation of modified pleural tenting in preventing anastomotic leakage was the aim of the study. RESULTS: The pleural tenting group showed a significant decrease in anastomotic leak. In 1 patient versus 8 in group without pleural tenting the complication appeared (P = .032). The risk for an anastomotic leakage in group without pleural tenting was almost 9 times greater (odds ratio: 9.143, 95% confidence interval: lower bound 1.104, upper bound 75.708). The 30 day mortality, although lower in pleural tenting group, was not statistically significant. CONCLUSIONS: Pleural tenting is a safe, fast, and effective technique for prevention of anastomotic leakage after Ivor Lewis esophagogastrectomy. Subpleural blanketing of intrathoracic anastomosis could diminish the consequences of a possible anastomotic leak. PMID- 21674268 TI - Efficacy of surgical microwave therapy in patients with unresectable hepatocellular carcinoma. AB - BACKGROUND: We aimed to evaluate the efficacy and long-term outcome in surgical microwave therapy (MW) for patients with unresectable hepatocellular carcinoma (HCC). METHODS: An institutional review board approved and single-institutional study of surgical MW of unresectable HCC was conducted from May 2003 to December 2010. The median follow-up period was 19 months (range 1-77 months). RESULTS: A total of 60 patients underwent 143 surgical MW for unresectable HCC. Of these, 15 patients had initial HCC and 45 had recurrent HCC. The median tumor size of HCC was 1.95 cm (range 0.8-3.3 cm). The median numbers of nodules that underwent surgical MW were 2 (range 1-9). Multinodular type was found in 33 patients (55%). Morbidity was 18.3%, and there was zero mortality. Also, 3 patients (5%) had incomplete MW. Of the 60 patients, 39 (65%) had recurrence, and 7 (11.6%) had local recurrence. The 1- and 3-year recurrence-free survival rates of the patients who underwent surgical MW for initial HCC were 55.1 and 36.7%, respectively, and those for recurrent HCC were 41.6% and 8.8%, respectively. A tumor size >= 2.0 cm and multiple nodules were selected as independent and significant indicators for recurrence of the disease. The 1-, 3-, and 5-year overall survival rates after the surgical MW procedure were 93.9, 53.8, and 43.1%, respectively. A level of des-gamma carboxyprothrombin (DCP) was an independent and significant indicator for overall survival. CONCLUSIONS: Surgical MW is an effective method for treating initial or recurrent unresectable HCC, and it can be undergone safely. PMID- 21674269 TI - The predictive value of postoperative clinical risk scores for outcome after hepatic resection: a validation analysis in 807 patients. AB - BACKGROUND: Although early postoperative risk stratification might allow a more precise prediction of outcomes after hepatic resection, evaluation of different postoperative clinical risk indices has been lacking. METHODS: A total of 1,219 patients underwent hepatic resection between January 2002 and 2010, and 807 patients were eligible for final analyses. The model for end stage liver disease (MELD) score, the "50-50 criteria," and the International Study Group of Liver Surgery (ISGLS) definition of posthepatectomy liver failure (PHLF) were assessed as clinical risk scores on postoperative day 5. Risk factors for morbidity and mortality were analyzed using multivariate logistic regression analyses. RESULTS: The overall morbidity and mortality rates were 43 and 6%, respectively. Sensitivity of the MELD score, the 50-50 criteria and the PHLF for prediction of morbidity and mortality were 55, 6, 23 and 71, 26, 65%. On multivariate analyses MELD score [odds ratio (OR) 2.06; 95% confidence interval (95% CI) 1.41-3.02] and PHLF (5.61; 2.73-11.55) were associated with morbidity, whereas this association did not reach statistical significance for the 50-50 criteria (3.64; 0.78-17.02). The 50-50 criteria (16.45; 3.50-77.25) and PHLF (13.80; 4.27-44.61) were identified as powerful, independent predictors of mortality. This association was less strong for the MELD score (2.86; 0.98-8.31). CONCLUSION: Postoperative clinical risk scores are associated independently with outcome after hepatic resection. Owing to lack of sensitivity only the MELD score can be recommended for early prediction of overall morbidity, whereas the MELD score and the PHLF enabled adequate risk stratification regarding perioperative mortality. PMID- 21674270 TI - Changes in psychosocial functioning 1 year after mastectomy alone, delayed breast reconstruction, or immediate breast reconstruction. AB - BACKGROUND: In this study, we report on the changes in psychosocial functioning over 1 year following breast cancer surgery in 3 groups of women, including those with mastectomy alone, those with mastectomy and immediate reconstruction, and those with delayed reconstruction. METHODS: Women with breast cancer at 2 teaching hospitals in Ontario who were undergoing mastectomy alone, mastectomy with immediate reconstruction, or delayed reconstruction were asked to complete a battery of psychosocial questionnaires at their preoperative appointment and 1 year following surgery. RESULTS: A total of 190 women consented to participate in the study and completed the presurgical questionnaires. There were no presurgical differences between the 3 groups in quality of life, anxiety, depression, or sexual functioning. However, women who were undergoing delayed breast reconstruction (i.e., already had a mastectomy) had higher levels of body stigma (P = 0.01), body concerns (P = 0.002), and transparency (P = 0.002) than women who were undergoing mastectomy alone or mastectomy with immediate reconstruction. Of these women, 158 (83.2%) completed the 1-year follow-up. There were no significant differences in any of the psychosocial functioning scores between the 3 groups. DISCUSSION: Contrary to the assumed psychological benefits of breast reconstruction, psychological distress was evident among women regardless of reconstruction or timing of reconstruction. Further, psychosocial functioning (including quality of life, sexual functioning, cancer-related distress, body image, depression, and anxiety) was not different at 1-year postsurgery between women with mastectomy alone, mastectomy with immediate reconstruction, and delayed reconstruction. These results suggest that women need psychosocial support after breast cancer diagnosis, even if they have breast reconstruction. PMID- 21674271 TI - The revised ACPGBI model is a simple and accurate predictor of operative mortality after potentially curative resection of colorectal cancer. AB - BACKGROUND: The Association of Coloproctology of Great Britain and Ireland (ACPGBI) risk-adjustment model for colorectal cancer surgery has been recently revised. The aim of the present study was to compare the performance of the revised ACPGBI model, the original ACPGBI model, P-POSSUM, and CR-POSSUM, in the prediction of operative mortality after resection of colorectal cancer. METHODS: A total of 423 patients who underwent potentially curative resection of colorectal cancer at a single institution (1997-2007) were included. Data used in the construction of the ACPGBI model was collected prospectively. The models were compared by examining observed to expected (O:E) ratios, the Hosmer-Lemeshow (H L) goodness-of-fit test, and area under the receiver operator characteristic curve (AUC) analysis. RESULTS: The 30-day mortality rate was 4%. The performance of the models was as follows: revised ACPGBI model (O:E ratio = 1.05, AUC = 0.73, H-L = 11.02), original ACPGBI model (O:E ratio = 0.58, AUC = 0.76, H-L = 14.23), P-POSSUM (O:E ratio = 0.87, AUC = 0.79, H-L = 10.63), and CR-POSSUM (O:E ratio = 0.63, AUC = 0.84, H-L = 15.84). In subgroup analysis, the revised ACPGBI model performed well in both elective cases (O:E ratio = 1.06) and emergency cases (O:E ratio = 0.91). CONCLUSIONS: The revised ACPGBI model is simple to construct and accurately predicts operative mortality after potentially curative resection of colorectal cancer. PMID- 21674273 TI - Total exertion: zen, psychoanalysis, life. AB - This paper integrates Zen and psychoanalytic concepts; introduces the Zen concept of total exertion; elaborates the profound implications that the notion of total exertion has for the psychoanalytic encounter and the psychotherapist's capacity for maintaining an optimal attentional stance; addresses anxiety-driven interferences to both the psychoanalytic process and deepened Zen practice. Clinical vignettes, personal experiences, poetry and psychoanalytic theory serve to demonstrate the abstract aspects of the discussion. PMID- 21674272 TI - Survival and quality of life following cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis of colonic origin. AB - BACKGROUND: Peritoneal carcinomatosis of colonic origin (PCC) is a life threatening diagnosis. Cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC) offers patients the prospect of long-term survival with alleviation of symptoms. METHODS: Patients underwent HIPEC for PCC and completed questionnaires preoperatively (T1) and after surgery at 3 (T2), 6 (T3), and 12 (T4) months. Questionnaires included the Functional Assessment of Cancer Therapy-Colon (FACT-C), Brief Pain Inventory (BPI), SF-36 Medical Outcomes Study Survey (SF-36), Center for Epidemiologic Studies-Depression Scale (CES-D), and the ECOG Performance Status Rating. RESULTS: A total of 62 patients were assessed before surgery. Median overall survival was 18 months, with 71.3 +/- 6.3% survival at 1 year. Emotional well-being (P = .0007) improved after HIPEC. Social/family well-being (P = .065) and the colon subscale (P = .061) of the FACT worsened at T2, but recovered by T3. One-third to one-half of patients reported depressive symptoms over the course of the study. Pain scores increased above BL at T2, but decreased below BL at T3 and T4. CONCLUSIONS: Emotional well being is improved after CS + HIPEC despite complications that may affect short-term recovery. Most patients remaining in the study recover to preoperative levels of functioning between 3 and 6 months after surgery. For some, survival can be attained without major decrement in QOL at 1 year. QOL concerns must be a key component in the evaluation for patients with PCC for CS and HIPEC. PMID- 21674274 TI - Religion and the DSM: from pathology to possibilities. AB - Many individuals seeking psychological services refer to their religious or spiritual beliefs during treatment (Shafranske and Maloney in Psychotherapy 27: 72-78, 1990). Although psychology has consistently pathologized religion and/or spirituality in the past, it is vital that clinicians understand their impact on diagnosis and treatment. The evolution of the DSM, as explored in this manuscript, is evidence of continued attempts to expand clinicians' religious and/or spiritual sensitivity. In order for religion to be incorporated as a cultural component, psychologists need appropriate training. The author concludes with a case illustration and recommendations for continued development of religion as a cultural factor in the DSM-V. PMID- 21674275 TI - Public health problems in the medieval statutes of Croatian Adriatic coastal towns: from public morality to public health. AB - The article seeks out the regulations about public health in the oldest medieval statutes of fourteen cities of the eastern Croatian Adriatic coast, between the thirteenth and sixteenth century. The research revealed numerous examples of direct or indirect ways of protecting public health. Through the analyzed documents, a noteworthy relationship between public morality and public health can be noted. The described rules are important as a reflection of awareness about public health as a condition of survival and progress in the past. They witness a progressive transition from an original common law into a written law as well as the impact that religion had in influencing people's general opinion and lifestyle in light of public health problems. PMID- 21674276 TI - The expression of Mcl-1 in human cervical cancer and its clinical significance. AB - Recently, the role of anti-apoptotic Mcl-1 in human carcinogenesis has become an area of great interest as overexpression of the protein has been reported in association with various types of cancer. The aim of this study was to investigate the expression profile of Mcl-1 in cervical cancer and to assess its clinical significance. Immunohistochemistry was used in the detection of Mcl-1 expression as well as the proliferation index of Ki-67, both in cervical cancer and in corresponding normal tissue. Western blotting analysis was also used for the detection of Mcl-1. The data was correlated with clinicopathological features. Survival analysis was performed to assess prognostic significance. Mcl 1 was overexpressed in cervical cancer tissue when compared with corresponding normal tissue. High expression of Mcl-1 was significantly associated with histological grade (P = 0.039), tumor size (P = 0.024) and lymph node involvement (P = 0.002). Overexpression of Ki-67 was associated with lymph node involvement (P = 0.015) and disease stage (P = 0.012). Spearman rank correlation test demonstrated a positive correlation between Mcl-1 and Ki-67 (P < 0.05). Using Kaplan-Meier analysis, a comparison of survival curves of low versus high expressers of Mcl-1 and Ki-67 revealed a highly significant difference in human cervical cancer tissue (P < 0.05), which suggests that overexpression of Mcl-1 and Ki-67 is associated with a poorer prognosis. Our results suggest that Mcl-1 may play an important role in cervical cancer and that it may have potential as a biomarker and therapeutic target. Its evaluation with Ki-67 may provide reliable prognostic information on cervical cancer. PMID- 21674277 TI - The role of RhoC in the proliferation and apoptosis of hepatocellular carcinoma cells. AB - In this study, we examined the effects of RhoC expression on the growth and apoptosis of human hepatocellular carcinoma cells (HCCs) in vitro in order to gain more understanding of its potential as a therapeutic target gene. We knocked down the endogenous expression levels of RhoC in human HCCs, BEL-7402, using siRNA and ectopically expressed RhoC in untransformed hepatocytes, HL7702. Stable cell lines were established, and cell growth was examined by MTT and colony formation assays, cell proliferation examined by silver nitrate staining of AgNORs, and cell cycle distribution examined by flow cytometry. RT-PCR analysis was performed to determine the mRNA expression levels of RhoC and cell cycle related genes. Finally, the effect of RhoC expression on apoptosis was also examined by flow cytometry, agarose gel electrophoresis of fragmented DNA, Wright staining, and RT-PCR analysis for genes regulating apoptosis. Compared to the parental and control siRNA (siCtrl)-transfected BEL-7402 cells, the siRhoC transfected cells exhibited significantly reduced cell growth, cell proliferation, percentage of cells in the S-G2/M phase, and expression of Cyclin D1, CDK4, and Bcl2. Knockdown of RhoC expression in BEL-7402 cells also significantly increased the percentage of cells in the G0/G1 phase, cellular apoptosis, and expression of p21, p16, and Bax. Furthermore, ectopic expression of RhoC in HL7702 cells led to a significant increase in cell growth compared to parental or siCtrl-transfected cells. These data suggest that RhoC is a key regulator of cell growth and apoptosis in HCC cells, making it a potential target for gene therapy. PMID- 21674279 TI - Advanced techniques for removal of retrievable inferior vena cava filters. AB - Inferior vena cava (IVC) filters have proven valuable for the prevention of primary or recurrent pulmonary embolism in selected patients with or at high risk for venous thromboembolic disease. Their use has become commonplace, and the numbers implanted increase annually. During the last 3 years, in the United States, the percentage of annually placed optional filters, i.e., filters than can remain as permanent filters or potentially be retrieved, has consistently exceeded that of permanent filters. In parallel, the complications of long- or short-term filtration have become increasingly evident to physicians, regulatory agencies, and the public. Most filter removals are uneventful, with a high degree of success. When routine filter-retrieval techniques prove unsuccessful, progressively more advanced tools and skill sets must be used to enhance filter retrieval success. These techniques should be used with caution to avoid damage to the filter or cava during IVC retrieval. This review describes the complex techniques for filter retrieval, including use of additional snares, guidewires, angioplasty balloons, and mechanical and thermal approaches as well as illustrates their specific application. PMID- 21674278 TI - The occurrence of pneumonia diagnosis among neurosurgical patients: the definition matters. AB - BACKGROUND: Diagnosis of pneumonia in the hospital setting is a challenge due to the absence of a generally accepted pneumonia definition. METHODS: We prospectively evaluated six different clinical criteria for diagnosing pneumonia- physician's diagnosis (A), was compared to common methods, i.e., general surveillance method (B), consensus clinical criteria (C), and other three criteria (D, E, and F) among 390 neurosurgical patients treated in either the intensive care unit or the neurosurgical ward in a university hospital. RESULTS: The frequencies of pneumonia cases were: group A, 66 (16.9%); group B, 41 (10.1%); and group C, 55 (14.1%). Only 28 pneumonia cases were identified by all three criteria. The kappa values were: between A and B, 0.42 (95% confidence interval, CI; 0.27-0.57); between A and C, 0.49 (95% CI; 0.35-0.63); and between B and C, 0.68 (95% CI; 0.55-0.80). In group A, there were 34 false positive cases according to criterion B and 25 according to criterion C. Pneumonia cases were identified according to criterion D in 13 (3.3%), E in 35 (9.0%), and F in 51 (13.1%) cases, respectively. CONCLUSIONS: There was great variability in the presence of pneumonia among neurosurgical patients, depending on the criteria used. Our results support the idea that a more exact method for pneumonia diagnosis should be implemented to obtain more reliable results in this important infection of hospitalized patients, which is also used for benchmarking purposes. Furthermore, it seems important to treat all clinically suspected pneumonia cases whether or not the surveillance criteria are fulfilled. PMID- 21674280 TI - The role of interventional radiology in the management of abdominal visceral artery aneurysms. AB - Abdominal visceral artery aneurysms (VAA) include true and false aneurysms. The majority are asymptomatic and are discovered on cross-sectional imaging performed for unrelated clinical indications. With the maturation of techniques and devices used for embolization procedures and the treatment of aneurysms in other locations, most VAAs are now suitable for treatment by minimally invasive transcatheter techniques. The choice of technique used greatly depends on the local anatomy of the VAA and the experience of the interventional radiologist in complex vascular interventional techniques. PMID- 21674281 TI - Embolization therapy for traumatic splenic lacerations. AB - PURPOSE: This study was designed to evaluate the clinical success, complications, and transfusion requirements based on the location of and agents used for splenic artery embolization in patients with splenic trauma. METHODS: A retrospective study was performed of patients with splenic trauma who underwent angiography and embolization from September 2000 to January 2010 at a level I trauma center. Electronic medical records were reviewed for demographics, imaging data, technical aspects of the procedure, and clinical outcomes. RESULTS: Fifty patients were identified (34 men and 16 women), with an average age of 48 (range, 16-80) years. Extravasation was seen on initial angiography in 27 (54%) and was absent in 23 (46%). All 27 patients with extravasation were embolized, and 18 of 23 (78.2%) without extravasation were embolized empirically. Primary clinical success was similar (>75%) across all embolization locations, embolic agents, and grades of laceration treated. Of 45 patients treated, 9 patients (20%) were embolized in the main splenic artery, 34 (75.6%) in the splenic hilum, and 2 (4.4%) were embolized in both locations. Partial splenic infarctions developed in 47.3% treated in the splenic hilum compared with 12.5% treated in the main splenic artery. There were four (8.9%) mortalities: two occurred in patients with multiple critical injuries and two from nonbleeding etiologies. CONCLUSIONS: Embolization of traumatic splenic artery injuries is safe and effective, regardless of the location of treatment. Embolization in splenic hilar branches may have a higher incidence of infarction. The grade of laceration and agents used for embolotherapy did not impact the outcomes. PMID- 21674282 TI - Working memory in the oldest-old: evidence from output serial position curves. AB - In the present study, we examined adult age differences in short-term and working memory performance in middle-aged (45-64 years), young-old (65-74 years), old-old (75-89 years), and oldest-old adults (90 years and over) in the Louisiana Healthy Aging Study. Previous research suggests that measures of working memory are more sensitive to age effects than are simple tests of short-term memory Bopp and Verhaeghen (Journal of Gerontology: Psychological Sciences 60:223-233, 2005), Myerson, Emery, White, and Hale, (Aging, Neuropsychology, and Cognition 10:20-27, 2003). To test this hypothesis, we examined output serial position curves of recall data from three span tasks: forward and backward digit span and size judgment span. Participants' recall patterns in the size judgment span task revealed that the two oldest groups of adults showed the largest decreases in recall performance across output serial positions, but did not differ significantly from each other. Correlation analyses indicated the strongest negative correlation with age occurred with the size judgment span task. Implications of these findings for understanding strategic processing abilities in late life are discussed. PMID- 21674283 TI - Are there bilingual advantages on nonlinguistic interference tasks? Implications for the plasticity of executive control processes. AB - It has been proposed that the unique need for early bilinguals to manage multiple languages while their executive control mechanisms are developing might result in long-term cognitive advantages on inhibitory control processes that generalize beyond the language domain. We review the empirical data from the literature on nonlinguistic interference tasks to assess the validity of this proposed bilingual inhibitory control advantage. Our review of these findings reveals that the bilingual advantage on conflict resolution, which by hypothesis is mediated by inhibitory control, is sporadic at best, and in some cases conspicuously absent. A robust finding from this review is that bilinguals typically outperform monolinguals on both compatible and incompatible trials, often by similar magnitudes. Together, these findings suggest that bilinguals do enjoy a more widespread cognitive advantage (a bilingual executive processing advantage) that is likely observable on a variety of cognitive assessment tools but that, somewhat ironically, is most often not apparent on traditional assays of nonlinguistic inhibitory control processes. PMID- 21674284 TI - A rare presentation of renal Wegener granulomatosis in a child. AB - We present a rare case of Wegener granulomatosis of the kidney in childhood. The diagnosis was suggested on imaging due to a combination of clinical symptoms, the lack of improvement with antibiotic therapy, and the absence of signs of inflammation on renal imaging. It was confirmed by histological examination following biopsy. The features and appearance of renal Wegener granulomatosis are described, and the differential diagnosis for a childhood renal mass is discussed. PMID- 21674285 TI - PHACE syndrome: MRI of intracerebral vascular anomalies and clinical findings in a series of 12 patients. AB - BACKGROUND: PHACE (posterior fossa defects, haemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities) syndrome describes a constellation of abnormalities that can occur in association with segmental craniofacial infantile haemangioma. OBJECTIVE: To report the spectrum of clinical and imaging abnormalities seen in a cohort of children. MATERIALS AND METHODS: A retrospective review of the clinical and imaging records of all patients diagnosed with PHACE syndrome between 1998 and 2009 was performed. Information sought included patient demographics, craniofacial segments involved, imaging findings and other extracutaneous abnormalities. RESULTS: Twelve patients were diagnosed with PHACE syndrome over 11 years. All patients had a segmental craniofacial haemangioma. Involved facial segments, in order of frequency, were frontotemporal (12), maxillary (8), mandibular (5) and frontonasal (1). The most common extracutaneous abnormalities were neurovascular anomalies (10), with many patients having multiple anomalies. The spectrum of arterial anomalies ranged from hypoplasia (9) to ectasia (3), anomalous origin/course (2) and persistent fetal anastomosis (2). Other anomalies found included cardiac anomalies (3), coarctation of the aorta (2), posterior fossa malformations (1) and sternal region anomalies (1). CONCLUSION: Intracranial anomalies are the most common extracutaneous feature of PHACE syndrome. The contribution of the radiologist in the recognition of such anomalies is important for the diagnosis of PHACE syndrome. PMID- 21674287 TI - Iatrogenic neonatal type B aortic dissection: comprehensive MRI-based diagnosis and follow-up. AB - Neonatal aortic dissection is rare and most frequently iatrogenic. Decision making and appropriate imaging are highly challenging for pediatric cardiologists and radiologists. We present MRI and echocardiographic findings in the follow-up at 6 months of age of a boy with a conservatively treated iatrogenic neonatal aortic dissection (type B). To evaluate the morphology of the aortic arch and descending aorta, we carried out multidirectional time-resolved three-dimensional flow-analysis and contrast-enhanced MR angiography (CE-MRA). The MRI and Doppler echocardiographic results were closely comparable. Three-dimensional visualization helped assess details of blood flow acceleration and alteration caused by the dissection, and played a key role in our deciding not to treat surgically. PMID- 21674286 TI - Noninvasive measurement of liver iron concentration at MRI in children with acute leukemia: initial results. AB - BACKGROUND: Routine assessment of body iron load in patients with acute leukemia is usually done by serum ferritin (SF) assay; however, its sensitivity is impaired by different conditions including inflammation and malignancy. OBJECTIVE: To estimate, using MRI, the extent of liver iron overload in children with acute leukemia and receiving blood transfusions, and to examine the association between the degree of hepatic iron overload and clinical parameters including SF and the transfusion iron load (TIL). MATERIAL AND METHODS: A total of 25 MRI measurements of the liver were performed in 15 children with acute leukemia (mean age 9.75 years) using gradient-echo sequences. Signal intensity ratios between the liver and the vertebral muscle (L/M ratio) were calculated and compared with SF-levels. TIL was estimated from the cumulative blood volume received, assuming an amount of 200 mg iron per transfused red blood cell unit. RESULTS: Statistical analysis revealed good correlation between the L/M SI ratio and TIL (r = -0.67, P = 0.002, 95% confidence interval CI = -0.83 to -0.34) in patients with acute leukemia as well as between L/M SI ratio and SF (r = -0.76, P = 0.0003, 95% CI = -0.89 to -0.52). CONCLUSION: SF may reliably reflect liver iron stores as a routine marker in patients suffering from acute leukemia. PMID- 21674288 TI - A five to seven year follow-up comparing computer-assisted vs freehand TKR with regard to clinical parameters. AB - PURPOSE: Computer-assisted knee surgery has become established in routine clinical practice. Still, there is no study investigating midterm clinical outcome after five to seven years postoperatively. We aimed to test the hypothesis that there is no difference either for subjective [Western Ontario and McMaster Universities (WOMAC) scores] or for objective (Knee Society Score, degree of flexion) criteria between computer-assisted total knee replacement (TKR) and freehand TKR after 5.6-7.3 years. METHODS: We performed a matched-pair analysis; 100 patients who received a primary TKR were investigated after a median follow-up of 6.25 years. Group A was operated on with the support of a computer system, while surgery on patients in group B was performed with the freehand technique. We determined WOMAC Score, Knee Society Score and degree of flexion. RESULTS: Overall we found similar results for WOMAC Score [group A: 42.98 (SD 13.80); group B: 41.54 (SD 15.01; p = 0.62)], Knee Society Score [group A: 168.20 (SD 21.94); group B: 166.60 (SD 21.44; p = 0.71)] and range of motion [group A: 106 degrees (SD 9.19); group B 107 degrees (SD 7.44; p = 0.62)]. CONCLUSIONS: No significant differences in midterm clinical outcome were found after TKR performed in the freehand vs computer-assisted technique. PMID- 21674289 TI - Pre-operative frontal plane malalignment predicts the extension gap asymmetry in knee osteoarthritis. AB - PURPOSE: In contrast to bone cuts, soft-tissue releases cannot be planned sufficiently prior to total knee arthroplasty (TKA). Intra-operative evaluation of the extension gap after tibial or femoral resection may result in an unnecessarily excessive bone resection. The present study examines whether extension gap asymmetry can be calculated from the pre-operative long standing X ray. METHODS: In this retrospective study, 32 patients with navigated unconstrained TKA were included. The pre-operative malalignment was measured on long standing X-rays and compared with the extension gap asymmetry that was documented by the navigation system intra-operatively. RESULTS: The mean pre operative malalignment was 9.8 degrees (20 degrees valgus to 14.8 degrees varus). The intra-operatively measured extension gap showed a mean asymmetry of 3.4 +/- 2.4 mm. Both correlated following the equation: asymmetry [mm] = 0.35 * malalignment [ degrees ] (R = 0.855, P < 0.001). CONCLUSIONS: We recommend planning the intra-operative release and tibial bone cut using long standing X rays. PMID- 21674290 TI - Surgical correction of kyphotic deformity in spinal tuberculosis. AB - PURPOSE: Approximately 5% of patients with spinal tuberculosis will develop a severe kyphotic deformity resulting in increased potential for pain, spinal cord compression, cardiopulmonary dysfunction, costopelvic impingement and cosmetic concerns. This manuscript reviews the evaluation and surgical management of tuberculous kyphosis. METHODS: This is a review article. RESULTS: Risk factors for the development of severe kyphosis include those who develop spinal tuberculosis as children, multiple vertebral body involvement and thoracic spine involvement. These complications can be prevented by early diagnosis and treatment of spinal tubercular lesions at stages with little to no deformity. When tubercular lesions result in progression of kyphosis to more than 50 degrees, the deformity should be surgically corrected to avoid problems associated with sagittal imbalance. There are several operations described for the treatment of kyphosis secondary to tuberculous spondylitis. The type of the operation depends on the magnitude of correction required. CONCLUSIONS: Anterior, posterior and combined techniques as well as osteotomies and vertebral column resection have been described to correct spinal alignment and restore sagittal balance. PMID- 21674291 TI - A novel recirculating flow-perfusion bioreactor for periosteal chondrogenesis. AB - PURPOSE: Previous research indicated that engineered cartilage was soft and fragile due to less extracellular matrix than native articular cartilage. Consequently, the focus of this study was mostly confined to application in vitro function. In order to generate 3D engineered cartilage resembling native articular cartilage, we developed a recirculating flow-perfusion bioreactor to simulate the motion of a native diarthrodial joint by offering shear stress and hydrodynamic pressure simultaneously. MATERIALS: The bioreactor we developed offers steady oscillating laminar flow (maximum shear stress of 250 dyne/cm(2)) and hydrodynamic pressure (increased from 0 to 15 psi) simultaneously. The periosteal explants were harvested from the proximal medial tibiae of rabbits and fixed onto PCL scaffold with four corner sutures and cambium layer facing upward, then these periosteal composites (periosteum/ PCL) were placed into the culture chamber of our bioreactor for six weeks in vitro culture. RESULTS: The cartilage yield in our recirculating bioreactor was 75-85%. The outcome was better than the 65-75% in the spinner flask bioreactor (shear stress only) and 17% in static culture. In addition, there was a significant difference in the cell morphology and zonal organisation among the three methods of culture; the engineered cartilage in the recirculating bioreactor presented many more characteristics of native articular cartilage. CONCLUSIONS: If the environment of culture provides the shear stress and hydrodynamic pressure simultaneously, the composition of the engineered cartilage resembles native articular cartilage, including their ECM composition, cell distribution, zonal organisation and mechanical properties. PMID- 21674292 TI - Up-regulation expressions of lysyl oxidase family in Anterior Cruciate Ligament and Medial Collateral Ligament fibroblasts induced by Transforming Growth Factor Beta 1. AB - PURPOSE: The lysyl oxidase (LOX) family plays a crucial role in the formation and stabilisation of extracellular matrix (ECM) by catalysing the cross-linking of collagen and elastin, implicating its important fundamental roles in injury healing. A high level of transforming growth factor-beta(1) (TGF-beta(1)) accompanies the inflammatory phase of an injury of the knee joint. Our purpose was to detect the expressions of the LOX family in anterior cruciate ligament (ACL) and medial collateral ligament (MCL) response to TGF-beta(1). METHODS: This study used reversed transcript PCR, real time quantitative PCR and Western blot for analyses. RESULTS: The results showed significant increases in mRNA levels of LOX family members. At 5 ng/ml concentration of TGF-beta(1,) the gene profiles of LOXs showed most active, and LOX and LOXL-3 showed increasing peaks at 12 hours after TGF-beta(1) treatment (LOX: 7.2, 8.8-fold and LOXL-3: 3.8, 5.4-fold compared with normal controls in ACL and MCL, respectively); LOXL-1, LOXL-2 and LOXL-4 reached their highest amounts at six hours (LOXL-1: 1.9, 2.4-fold; LOXL-2: 14.8, 16.2-fold; LOXL-4: 2.5, 4.4-fold in ACL and MCL, respectively). Protein assays revealed that LOXs in ACL cells had relatively lower response to TGF beta(1) compared with those in MCL cells. CONCLUSIONS: The differential expression and activities of LOXs might help to explain the intrinsic difference between ACL and MCL, and LOXs could imply a potential capability for ACL healing. PMID- 21674293 TI - In vivo three-dimensional motion analysis of the shoulder joint during internal and external rotation. AB - PURPOSE: The purpose of this study was to assess accurately the three-dimensional movements of the scapula and humerus relative to the thorax during internal/external rotation motion with abduction of the shoulder joint. METHODS: Ten right shoulders of ten healthy volunteers were examined using a wide-gantry open magnetic resonance imaging (MRI) system. MRI was performed every 30 degrees from 90 degrees external rotation to 90 degrees internal rotation of the shoulder joint. RESULTS: The contribution ratio of the scapulothoracic joint was 12.5% about the long axis of the humerus during internal/external rotation motion. With arm position changes from 90 degrees external rotation to 60 degrees internal rotation, most movement was performed by the glenohumeral joint. Conversely, at internal rotation of >=60 degrees , the scapula began to markedly tilt in the anterior direction. At 90 degrees internal rotation, the scapula was significantly tilted anteriorly (p < 0.05) when compared with the other positions. CONCLUSIONS: We clarified the existence of a specific scapulohumeral motion pattern, whereby the glenohumeral joint moves with internal rotation and the scapulothoracic joint moves with anterior tilt together with internal rotation motion of the shoulder joint. PMID- 21674294 TI - A new technique of upper eyelid blepharoplasty using the orbicularis muscle flap. AB - BACKGROUND: Blepharoplasty of the upper eyelids is one of the most commonly performed procedures in aesthetic plastic surgery. The orbicularis muscle flap technique provides good results for patients with atonic skin and an atonic orbicularis muscle when there is excessive fullness in the lateral aspect of the upper lid. This flap also can be used to contain a prominent lacrimal gland or retro-orbicularis oculi fat (ROOF) without dangerous removal of the last one. METHODS: A total of 30 patients underwent upper lid blepharoplasty through a supratarsal incision approach. Dissection of the orbicularis muscle flap was made 5-8 mm above the supratarsal fold. Before the muscle flap suspension, the excess skin and fat pad were removed. The flap suspension was achieved with its rotation and motion of a tunnel in the suborbicularis plane, which anchored it on the periosteum of the orbital lateral rim of the frontal bone with a permanent suture. RESULTS: This technique restores the sharp and crisp tarsal folds and pretarsal show with deepening of the orbitopalpebral sulcus. The orbicularis muscle flap also can be proposed for cases with a ptosis of the lateral upper lid. The authors believe this technique reduces the risk for "rounding" of the eyelid and produces better contact of the lid with the ocular globe. CONCLUSIONS: The orbicularis muscle flap procedure is a feasible technique that can be used reliably to reshape the lateral upper lid. It would be a useful addition to the armamentarium of the plastic surgeon who is called on to perform upper blepharoplasty. PMID- 21674295 TI - Bulgarians vs the other European populations: a mitochondrial DNA perspective. AB - To define the matrilineal relationships between Bulgarians and other European populations, we have evaluated the mitochondrial DNA (mtDNA) variation in a sample of 855 Bulgarian subjects from the mtDNA perspective. The molecular survey was performed by sequencing ~750 bp of the control region, which resulted in 557 different haplotypes, and by a subsequent restriction fragment length polymorphism analysis to confirm haplogroup/subhaplogroup affiliation. The classification was carried out according to the most updated criteria as reported by van Oven and Kayser (Hum Mutat 30:386-394, 2009), allowing the identification of 45 mitochondrial clades. The observed pattern of mtDNA variation indicates that the Bulgarian mitochondrial pool is geographically homogeneous across the country, and that is characterized by an overall extremely high frequency of western Eurasian lineages. In the principal component analysis, Bulgarians locate in an intermediate position between Eastern European and Mediterranean populations, which is in agreement with historical events. Thus, while the Mediterranean legacy could be attributed to the Thracians, indigenous people that firstly inhabited the Balkans, the Eastern contribution is likely due to the Proto-Bulgarians originating from the Middle East and to the Slavs migrating from northeast Europe. PMID- 21674296 TI - Why is it crucial to test anti-lice repellents? AB - It is difficult to stop lice propagation just by treating infested heads, since reinfections are possible just a few hours after a successful elimination of all lice from a child's head by application of an active anti-louse product. Therefore, several products have been developed that claim to have a louse repellent activity; however, definite proofs are scarce. The present study involving two louse repellents (Linicin(r) Preventive Spray, Picksan(r) NoLice) and three substances (at 10% dilution) known for their general repellency activity shows that there are much more difficulties to repel lice when compared to other insects or even ticks. Thus, it must be feared that several repellents on the market might have used a problematical test system and thus might not be as effective as they claim. PMID- 21674297 TI - The marine myxosporean Sigmomyxa sphaerica (Thelohan, 1895) gen. n., comb. n. (syn. Myxidium sphaericum) from garfish (Belone belone (L.)) uses the polychaete Nereis pelagica L. as invertebrate host. AB - Sigmomyxa sphaerica (Thelohan, 1892) gen. n. (Myxozoa, Myxosporea) with myxosporean stages in the gall bladder of Belone belone (L.) (Teleostei, Belonidae) uses the polychaete Nereis pelagica L. (Nereidae) from shallow water in the northern Oresund, Denmark, as invertebrate host. The nearly spherical tetractinomyxon-type actinospores of S. sphaerica differ from those of two species of Ellipsomyxa which also use Nereis spp. as invertebrate host. Pansporocysts of S. sphaerica were not seen. S. sphaerica is redescribed on the basis of myxospore stages from B. belone and actinospores from N. pelagica, and the phylogenetic affinities examined on the basis of ribosomal small subunit gene sequences. S. sphaerica is closest related to Ellipsomyxa spp., and is not congeneric with morphologically similar Myxidium spp. from gadids. This is the fifth elucidated two-host life cycle of a marine myxozoan. PMID- 21674298 TI - The role of oct-1 in the regulation of tracheal antimicrobial peptide (TAP) and lingual antimicrobial peptide (LAP) expression in bovine mammary epithelial cells. AB - Lingual antimicrobial peptide (LAP) and tracheal antimicrobial peptide (TAP) are two important beta-defensins of antimicrobial peptide family, which are evolutionarily conserved effector molecules of the innate immune response. Although known to be sensitive to pathogenic challenge, the control of their expression remains unclear. Both LAP and TAP genes showed constitutive and inducible expression in bovine mammary epithelial tissues, and the aim of this study was to investigate the mechanisms underlying their expression and regulation. Reporter plasmids fused with 5' regions of the two gene promoter regions were constructed and transiently transfected into a bovine mammary epithelial (BME) cell line. Initial serial deletion of the promoter regions from both genes identified two positive regulatory elements within the 1 kb regions upstream the transcription start sites, which co-operatively contribute to LAP and TAP gene expression. Further luciferase reporter assays revealed that an enhancer and a 61-bp region proximal to both genes are important for basal expression and regulation of transcription. Electrophoretic mobility shift assays (EMSA) indicated the involvement of the Oct-1 protein-DNA complex in regulating the promoter activity, which was confirmed by super shift EMSA with Oct-1 antibody and by knockdown of Oct-1 with small interfering RNA. The Oct-1 binding motif was also shown to be responsive to phorbol 12-myristate 13-acetate but not LPS stimulation. The results from this study clearly demonstrate the involvement of the Oct-1 transcription factor in the regulation of LAP and TAP expression. PMID- 21674299 TI - A comparison of wild-type, old and modern tomato cultivars in the interaction with the arbuscular mycorrhizal fungus Glomus mosseae and the tomato pathogen Fusarium oxysporum f. sp. lycopersici. AB - The effect of the arbuscular mycorrhizal symbiosis (AM) varies in plant cultivars. In the present study, we tested whether wild-type, old and modern tomato cultivars differ in the parameters of the AM interaction. Moreover, the bioprotective effect of AM against the soilborne tomato pathogen Fusarium oxysporum f. sp. lycopersici (Fol) was tested in the different cultivars. Ten tomato cultivars were inoculated with the arbuscular mycorrhizal fungus (AMF) Glomus mosseae alone or in combination with Fol. At the end of the experiment, AM root colonization, Fusarium infection, and the plant fresh weight was determined. The tomato cultivars differed in their susceptibility to AMF and Fol, but these differences were not cultivar age dependent. In all the cultivars affected by Fol, mycorrhization showed a bioprotective effect. Independent of the cultivar age, tomato cultivars differ in their susceptibility to AMF and Fol and the bioprotective effect of mycorrhization, indicating that the cultivar age does not affect the AM parameters tested in this study. PMID- 21674300 TI - Tracheomalacia after reoperation for an adenomatous goiter located in a unique position. AB - Tracheomalacia after thyroidectomy is a life-threatening situation. However, it is difficult to predict postoperative tracheal obstruction with certainty. A case of a 74-year-old woman with a long-standing adenomatous goiter (98 g) is reported. She had undergone partial right lobe thyroidectomy 54 years earlier. After total thyroidectomy, she was reintubated and required a tracheostomy because of tracheomalacia. The right residual thyroid tumor weighed only 5 g, but it extended to the retrotracheal space. Because the right lobe had stretched the membranous wall of the trachea over a long period of time, the tracheal lumen was thought to have collapsed because of loss of the foundation of the tracheal cartilage (the residual right lobe) along with the supportive surrounding tissue (the left lobe) after surgery. The present case suggests that the occurrence of tracheomalacia could be attributed to reoperation and retrotracheal extension. Thus far, six preoperative predictive factors for the development of severe postoperative respiratory obstruction have been reported: goiter for more than 5 years, preoperative recurrent laryngeal nerve palsy, significant tracheal narrowing and/or deviation, retrosternal extension, difficult endotracheal intubation, and thyroid cancer. Two more factors, reoperation and retrotracheal extension of tumor, may also be risks for airway obstruction after thyroidectomy. PMID- 21674301 TI - Optimal timing of hypothermia in relation to myocardial reperfusion. AB - Two previous clinical trials investigating hypothermia as an adjunct therapy for myocardial infarction have failed. Recently a pilot study has demonstrated a significant reduction in infarct size. The aims of this study were to elucidate the effects of hypothermia on reperfusion injury and to investigate the optimal hypothermia protocol for a future clinical trial. Pigs (40-50 kg) were anesthetized and a normal pig temperature of 38 degrees C was established utilizing an endovascular temperature modulating catheter. The pigs were randomized to a combination hypothermia group (1,000 ml of 4 degrees C saline solution and endovascular cooling, n = 8), or to normothermic controls (n = 8). A PCI balloon was then inflated in the LAD for 40 min (control) or 45 min with hypothermia induced during the last 5 min. Furthermore, hypothermia induced by cold saline alone (n = 8), and prolonged combination hypothermia during reperfusion (n = 7) were also examined. Infarct size and area at risk were determined ex vivo after 4 h of reperfusion using gadolinium-enhanced MRI and Tc 99-tetrofosmin SPECT, respectively. All pigs in the combination hypothermia group were cooled to <35 degrees C within 5 min. Combination hypothermia reduced IS/AAR by 18% compared with normothermic controls despite 5 min longer ischemic time (61 +/- 5 vs. 74 +/- 4%, p = 0.03). Cold saline did not reduce IS/AAR. Prolonging hypothermia treatment after onset of reperfusion by an additional 45 min over that used in a previous paper did not confer any additional benefit. The cardioprotective effects of hypothermia treatment are due to an attenuation of myocardial injury during both ischemia and reperfusion. The results suggest that a hypothermia protocol using a cold saline infusion and endovascular cooling enables hypothermia to be induced in a clinical setting without delaying reperfusion therapy. PMID- 21674303 TI - [Contrast-enhanced ultrasound of skeletal muscle]. AB - Functional imaging can increase the role of imaging in muscular diseases, as alterations of muscle morphology alone are non-specific for a particular disease. A good example for these functional imaging techniques is to use contrast enhanced ultrasound (CEUS) to visualize and quantify in vivo (patho-) physiological information about the skeletal muscle microcirculation. Perfusion, i.e. the blood flow per tissue unit including capillary flow, is an important functional parameter. Pathological changes of skeletal muscle perfusion can be found in various clinical conditions, such as degenerative or inflammatory myopathy or peripheral arterial disease (PAD). This article reviews the theoretical basics of functional radiological techniques for assessing skeletal muscle perfusion and focuses on applications of microvascular imaging by CEUS which has improved the diagnosis of these muscular disorders. For evaluation of myositis, CEUS is more efficient in the diagnostic work-up than routine b-mode ultrasound because CEUS can detect inflammation-induced muscular hyperperfusion in acute myositis. This has already been demonstrated by high-mechanical index techniques using a first generation ultrasound contrast agent. Low-mechanical index CEUS techniques that require the use of a second generation contrast agent allow real-time quantification of muscular microcirculation at rest and during exercise. Using this CEUS method, the influence of different exercise intensities on the microcirculation of the exercising muscle becomes detectable. Moreover, the arterial perfusion reserve in PAD can be adequately examined using low mechanical index CEUS. Initial findings have shown that the arterial perfusion reserve in patients suffering from PAD is reduced in comparison to healthy volunteers. In conclusion, modern CEUS techniques can offer deeper insights in muscular (patho-) physiology than just illustrating unspecific myopathic manifestations using conventional diagnostic imaging, such as edematous or lipomatous changes, hypertrophy or atrophy. PMID- 21674305 TI - Surgical treatment for achalasia: when should it be performed, and for which patients? AB - Achalasia is a rare motor disorder of the esophagus, characterized by the absence of peristalsis and impaired swallow-induced relaxation. In the past decade, evidence has been accumulated suggesting that achalasia may be an immune-mediated inflammatory disorder. With the advent of minimally invasive surgery, laparoscopic Heller myotomy (LHM) has slowly shifted the treatment of achalasia toward the greater use of surgical therapy. The goal of both surgical and nonsurgical treatment is to eliminate the outflow obstruction afforded by a nonrelaxing sphincter, relieving dysphagia and maintaining a barrier against gastroesophageal reflux (GER). Endoscopic botulinum toxin injection (EBTI) is safe, easy to perform, inexpensive, and effective in aged patients, and it is especially effective when the lower esophageal pressure is hypertonic. This therapeutic option is reserved for patients too ill to undergo any surgical procedure. Pneumatic dilation (PD) has been shown to be an effective and inexpensive treatment with few adverse effects. The long-term success rate of PD seems to drop progressively over time. Heller myotomy (HM) has shown the best clinical efficacy in achalasia as a first-line treatment. Multiple endoscopic treatments are associated with poorer outcomes after HM. EBTI also makes LHM more difficult and results in a worse surgical outcome. The inferior symptomatic outcomes after thoracoscopic HM may be caused by the difficulty in extending an adequate myotomy onto the stomach from the chest and the inability to create a fundoplication. LHM with Dor's fundoplication (LHM + Dor) is effective and is safer procedure for avoiding GER, dysphagia, mucosal perforation, and a pseudodiverticulum. LHM + Dor is also effective in the presence of sigmoid achalasia, but the clinical result is not as good as nonsigmoid achalasia. A few patients need esophagectomy for surgical failure of HM. However, considering the risk of esophagectomy, LHM + Dor is the first treatment option for patients with achalasia regardless of the degree of esophageal dilatation. This procedure is therefore considered to be an effective and safe treatment for patients of any age or with any condition. PMID- 21674307 TI - Can we change the operative criteria for the MAZE procedure combined with valve surgery in the era of radiofrequency devices? AB - PURPOSE: After radiofrequency (RF) ablation became available, the indication of MAZE procedure conducted with bipolar RF was expanded. We examined the efficacy and feasibility of the RF MAZE procedure in valve surgery and identified the predictors of atrial fibrillation (AF) recurrence. METHODS: Forty-four patients had permanent AF at the time of operation and underwent a biatrial RF MAZE procedure. Univariate and multivariate analysis for the predictor of permanent AF recurrence and follow-up studies were performed. RESULTS: Of the patients, 37 (84.1%) were in non-AF rhythm at discharge and 25 (80.6%) were at the latest follow-up (mean, 2.1 +/- 1.2 years). In stepwise multivariate analysis, left atrial dimension (LAD) > 61.5 mm was an independent predictor of early-term recurrence of AF (P = 0.006) and late-term recurrence (P = 0.038) as well. F-wave voltage <0.1 mV was significant in univariate analysis but was not significant in multivariate analysis for predictor of late-term AF recurrence. Avoidance of AF in the late term was 56% for LAD > 60 mm whereas it was 91% for LAD <= 60 mm (P = 0.043), 67% for F-wave < 0.1 mV compared to 100% for F-wave >= 0.1 mV (P = 0.031), and 43% for LAD > 60 mm and F-wave < 0.1 mV compared to 91% for LAD <= 60 mm and/or F-wave >= 0.1 mV (P = 0.016), respectively. Although avoidance of AF in the late term was lower in patients with LAD > 60 mm or F-wave < 0.1 mV, more than half of these patients were free from AF in the late term. CONCLUSION: LA size was assumed to be a simple and strong predictor of recurrent AF in this procedure. Predictive criteria that had been widely employed for the "cut-and sew" MAZE procedure accompanied with valve surgery can be expanded in the MAZE procedure with RF devices. PMID- 21674306 TI - Atrial fibrillation after esophagectomy: an indicator of postoperative morbidity. AB - PURPOSE: The relevance of new-onset atrial fibrillation (AF) after esophagectomy remains poorly defined. This study's primary goal is to better define the incidence, clinical patterns, and outcomes associated with the development of AF after esophagectomy. METHODS: The study is a retrospective review of patients undergoing esophagectomy at a single academic center between May 1996 and December 2007. Patients with new-onset AF were evaluated by univariate and multivariate analyses for risk factors associated with AF onset and outcomes. RESULTS: New-onset AF was noted in 32 of 156 (20.5%) patients after esophagectomy. Most (16/32, 50%) developed AF within 48 h, and 28 of 32 (87.5%) developed new AF within 72 h of surgery. Pulmonary complications were more frequent in patients with AF than those without AF (59.4% vs. 15.3%, P < 0.01) and usually immediately preceded or occurred concurrently with AF. Anastomotic leaks were significantly more common in patients with AF than those without (28.1% vs. 6.45%, P < 0.01) and were identified, on average, 4.2 days after the onset of AF. In the multivariate analysis, anastomotic leaks, pulmonary complications, and number of complications were significantly associated with AF. Although 60-day survival was worse for patients developing AF (P < 0.01), multivariate analysis suggests that non-AF complications were the independent predictor of mortality. CONCLUSION: New-onset AF after esophagectomy is associated with anastomotic leaks, pulmonary complications, and decreased 60-day survival. Although pulmonary complications typically occurred coincident with the onset of AF, anastomotic leaks were usually diagnosed 4 days after AF onset. New postesophagectomy AF should prompt vigilance for the presence of other concurrent complications. PMID- 21674308 TI - Thoracoscopic surgery for pulmonary metastases after chemotherapy using a tailor made virtual lung. AB - PURPOSE: Details with regard to the standard criteria for a therapeutic metastasectomy and the use of video-assisted thoracic surgery (VATS) remain elusive. To evaluate the feasibility of VATS using a tailor-made virtual lung for patients with pulmonary metastases after chemotherapy, we reviewed the following cases. METHODS: Clinical data from October 2006 to April 2010 were obtained from patients who received chemotherapy before a pulmonary metastasectomy (lobectomy or segmentectomy). VATS was the primarily selected surgical approach except for treating hilar lesions. A lobectomy was performed when the metastasis was greater than 3.0 cm in diameter or located deeply in the lobe. Tailor-made virtual lungs were created using three-dimensional multidetector computed tomography before lobectomy on a routine basis. The virtual lung consisted of three-dimensional pulmonary vessels, a tracheobronchial tree, pulmonary parenchyma, and tumors. RESULTS: Twelve operations, consisting of 1 segmentectomy, 10 lobectomies, and 1 wedge bronchoplasty upper lobectomy, were performed on 11 patients during the study period. VATS was completed in 10 of these 12 operations. The mean operative time for the lobectomies was 257 min, and the mean operative bleeding volume was 215 ml. Two cases experienced postoperative transient atrial fibrillation, and no mortalities associated with these operations were reported. CONCLUSION: VATS was performed safely in instances of metastasectomy after chemotherapy, and the tailor-made virtual lung assisted in lung orientation during the operation. PMID- 21674309 TI - En bloc resection and extended replacement of the infected aortic arch. AB - We present the technical details of en bloc resection and extended replacement of an infected aortic arch. A 74-year-old man underwent emergent surgery under a diagnosis of impending rupture of an infected aortic arch aneurysm. The patient's chest was entered through a median sternotomy with a left thoracotomy at the fourth intercostal space. After dissection of the left phrenic and left recurrent nerves, the infected aortic arch was widely excised en bloc under circulatory arrest with selective cerebral perfusion. It was replaced with a rifampicin bonded prosthetic graft. The prosthesis and anastomoses were covered with a harvested omental flap. Although an appropriate approach and supportive therapy are indispensable, en bloc resection of the infected tissue is an important technique when treating infected aortic aneurysms. PMID- 21674310 TI - Correction of tetralogy of Fallot in an adult using a stented bioprosthetic valved conduit. AB - A 55-year-old man with tetralogy of Fallot successfully underwent correction using a valved conduit. He was diagnosed as having congenital heart disease during childhood, but no surgical intervention was performed. Cyanosis and dyspnea on effort had progressed gradually. Catheterization showed a left ventricular end diastolic volume of 126 ml, and the pulmonary arteries had sufficient diameters. To prevent postoperative pulmonary regurgitation, we planned to use a bioprosthetic valved conduit for right ventricular outflow tract reconstruction. At 4.5 years after the operation he is in New York Heart Association functional class I. The catheterization performed 1.5 years after the surgery showed no pressure gradient between the right ventricle and the pulmonary artery. Thus, total correction of tetralogy of Fallot in an adult can be achieved safely, and the use of a bioprosthetic stented valved conduit can be beneficial. PMID- 21674311 TI - Successful excision of a saphenous vein graft aneurysm with different methods. AB - Aneurysm of an aortocoronary saphenous vein graft (SVG) is a rare but potentially fatal complication after coronary artery bypass grafting (CABG). Prevention of cerebral infarction or myocardial infarction due to the intraluminal debris from the SVG aneurysm is an important issue during surgical procedures. We report two patients with SVG aneurysms located in the proximal and distal portions of the SVG body, respectively. The surgical strategy for each case was determined according to the location of the aneurysm. We used low-flow cardiopulmonary bypass without aortic clamping in one patient and cardiac arrest with aortic clamping in the other. Both patients were discharged without sequelae. PMID- 21674312 TI - Infective endocarditis in a child caused by Cardiobacterium hominis after right ventricular outflow tract reconstruction using an expanded tetrafluoroethylene conduit. AB - Cardiobacterium hominis, a member of the HACEK group of organisms, is a rare cause of endocarditis. We report a case of infective endocarditis caused by C. hominis in a male child who had undergone right ventricular outflow tract (RVOT) reconstruction using an expanded polytetrafluoroethylene conduit for tetralogy of Fallot with pulmonary atresia. Two days before admission, the patient suffered from exertional shortness of breath. Right ventricular hypertension was confirmed and RVOT stenosis was suspected based on the echocardiography findings. A CT scan revealed vegetation above the cusp of the conduit. An emergency operation was performed to avoid a pulmonary embolism due to large friable vegetation. C. hominis was cultured from the blood and the vegetation, prompting a diagnosis of prosthetic valve endocarditis. The patient was discharged after a 6-week course of intravenous ceftriaxone therapy. PMID- 21674313 TI - Starr-Edwards valves at the aortic and mitral positions implanted for 39 years. AB - Cloth-covered Starr-Edwards caged ball valves implanted in the aortic and mitral valve positions for 39 years were extracted. Both showed valve dysfunction resulting from pannus overgrowth. The metal cages of the Starr-Edwards valves were covered with worn cloth. This case indicates the extended durability of Starr-Edwards valves and the importance of the design and materials of prosthetic heart valves to avoid pannus overgrowth and prosthetic valve abrasion. PMID- 21674314 TI - Castleman's disease along the left tracheobronchial tree with a difficult preoperative diagnosis. AB - A 39-year-old man was referred to our hospital because of an asymptomatic middle mediastinal tumor. A preliminary histological diagnosis of the tumor by bronchoscopy was difficult to obtain because the tumor was located along the left tracheobronchial tree, which is difficult to approach. The tumor was resected through a right anteroaxillary thoracotomy without any major complications, and histopathological examination revealed that the lesion was Castleman's disease, hyaline-vascular type. Radiological findings of the lesion were typical; however, the rarity of the tumor made the imaging diagnosis difficult. If a lesion is located along the tracheobronchial tree, Castleman's disease should be considered in the differential diagnosis. PMID- 21674315 TI - Postoperative pleural effusion in living lobar lung transplant donors. AB - In living-donor lobar lung transplantation, the importance of donor safety should be emphasized because of the necessity of placing two donors at risk for each recipient. Approximately 3% of donors were reportedly readmitted to hospitals owing to complications after the donor surgery. Herein, we report two cases of living lobar lung transplant donors who exhibited accumulation of pleural effusion after discharge and were readmitted for treatment. The mechanism of this complication was not clearly elucidated, but surgeons should not ignore the possibility of pleural effusion necessitating readmission in living-donor lobar lung transplant donors. PMID- 21674316 TI - Acute empyema with intractable pneumothorax associated with ruptured lung abscess caused by Mycobacterium avium. AB - Nontuberculous mycobacterial lung disease rarely features pleural involvement. Therapeutic strategies for this situation have not been well established. We present a case of acute empyema with intractable pneumothorax associated with ruptured lung abscess caused by Mycobacterium avium in an immunocompromised patient. Combined treatment that included multidrug antibiotic therapy and nonresectional surgery resulted in a good outcome. PMID- 21674317 TI - Computed tomography findings of the progress of calcification in extraskeletal osteosarcoma without calcification derived from the pleura. AB - An asymptomatic 77-year-old man presented with a mass in his right thoracic paravertebral region. Calcification was not detected in the tumor on initial computed tomography. However, the tumor grew rapidly and calcification subsequently appeared. Surgical resection was performed, and the histological diagnosis was extraskeletal osteosarcoma of the pleura. Only a few cases of primary pleural extraskeletal osteosarcoma have been reported in the literature, and there have been few descriptions of the imaging features. Extraskeletal osteosarcoma should be included in the differential diagnosis of older men with rapidly growing mass lesions derived from the pleura. PMID- 21674318 TI - Main bronchial sleeve resection and bronchoplasty without removing lung parenchyma. AB - We applied main bronchial sleeve resections without removing lung parenchyma and bronchoplasty in two patients with metastatic lung cancer and squamous cell carcinoma in situ. Main bronchial sleeve resection without removing lung parenchyma is generally considered technically difficult, as the remaining lung prevents the surgeon from obtaining good operative views; this means that the bronchial anastomosis must be performed in the deep, narrow space of the thorax. However, the two patients showed excellent results. Postoperative bronchoscopy ensured patency of the bronchial lumen in both patients. We believe that the surgeon can obtain a good operative view by resecting Botallo's ligament or by traction of the trachea and main pulmonary artery in cases involving lesions such as polypoid tumors toward the internal lumen of the bronchus, leading to successful results. PMID- 21674319 TI - Papillary muscle approximation and relocation with a loop technique for mitral complex repair. AB - Undersized mitral annuloplasty alone is not always sufficient to repair functional mitral regurgitation resulting from left ventricular enlargement; the repair requires a three-dimensional approach to the mitral complex. We introduce a surgical procedure that combines papillary muscle approximation to correct lateral shift and papillary muscle relocation using the loop technique to correct the apical shift with accuracy and technical ease. PMID- 21674320 TI - Time-resolved microfocused small-angle X-ray scattering investigation of the microfluidic concentration of charged nanoparticles. AB - We describe the concentration process of a dispersion of silica nanoparticles undergoing evaporation in a dedicated microfluidic device. Using microfocused small-angle X-ray scattering, we measure in time and space both the concentration field of the dispersion and its structure factor. We show that the electrostatic interactions affect the concentration rate by strongly enhancing the collective diffusion coefficient of the nanoparticle dispersion. En route towards high concentrations, the nanoparticles eventually undergo a liquid-solid phase transition in which we evidence crystallites of micron size. PMID- 21674321 TI - Site-specific labeling of proteins for single-molecule FRET measurements using genetically encoded ketone functionalities. AB - Studies of protein structure and function using single-molecule fluorescence resonance energy transfer (smFRET) benefit dramatically from the ability to site specifically label proteins with small fluorescent dyes. Genetically encoding the unnatural amino acid (UAA) p-acetylphenylalanine is an efficient way to introduce commercially available fluorescent tags with high yield and specificity. This protocol describes the expression in Escherichia coli of proteins containing this UAA in response to the amber stop codon TAG. Proteins were purified with high yield and subsequently labeled with the hydroxylamine derivative of Alexa Fluor(r) 488 functioning as a fluorescent donor dye. The proteins were then labeled via maleimide coupling chemistry at a unique cysteine with the acceptor dye Alexa Fluor(r) 594 to yield a dual-labeled protein ready for subsequent smFRET observation. PMID- 21674322 TI - Enzymatically catalyzed conjugation of a biodegradable polymer to proteins and small molecules using microbial transglutaminase. AB - Hydroxyethyl starch (HES) is a water-soluble, biodegradable derivative of starch that is widely used in biomedicine as a plasma volume expander. Due to its favorable properties, HES is currently being investigated at the industrial and academic levels as a biodegradable polymer substitute for polyethylene glycol. To date, only chemical methods have been suggested for HESylation; unfortunately, however, these may have negative effects on protein stability. To address this issue, we have developed an enzymatic method for protein HESylation using recombinant microbial transglutaminase (rMTG). rMTG enzyme is able to catalyze the replacement of the amide ammonia at the gamma-position in glutamine residues (acyl donors) with a variety of primary amines (acyl acceptors), including the amino group of lysine (Lys). To convert HES into a suitable substrate for rMTG, the polymer was derivatized with either N-carbobenzyloxy glutaminyl glycine (Z QG) or hexamethylenediamine to act as an acyl donor or acyl acceptor, respectively. Using SDS-PAGE, it was possible to show that the modified HES successfully coupled to test compounds, proving that it is accepted as a substrate by rMTG. Overall, the enzymatic approach described in this chapter provides a facile route to produce biodegradable polymer-drug and polymer-protein conjugates under relatively mild reaction conditions. PMID- 21674323 TI - Synthesis of drug/dye-incorporated polymer-protein hybrids. AB - We present here a general methodology for significantly increasing the number of dye/drug molecules that can be attached per protein molecule. As a demonstration of this approach, poly(acrylic acid) (PAA)-based near-infrared fluorescence (NIRF) dye- and glucose-incorporated novel copolymers were synthesized, which were further employed for bioconjugation to avidin and bovine serum albumin (BSA). In this method, azide-terminated poly(tert-butyl acrylate) was synthesized via atom transfer radical polymerization (ATRP). Subsequent deprotection was performed to yield poly(acrylic acid) (PAA) possessing a reactive chain-end. A one-pot sequential amidation of the PAA with the amine derivatives of a near infrared fluorescent dye (ADS832WS) and glucose produced NIRF dye-incorporated water-soluble copolymers. End-group modifications were performed to produce alkyne/biotin-terminated copolymers, which were further employed to generate dye incorporated polymer-protein hybrids via the biotin-avidin interaction with avidin or by "click" bioconjugation with azide-modified BSA. PMID- 21674324 TI - Dye/DNA conjugates as multiple labels for antibodies in sensitive fluorescence immunoassays. AB - Fluorescence immunoassays are widely used in life science research, medical diagnostics, and environmental monitoring due to the intrinsically high specificity, simplicity, and versatility of immunoassays as well as the availability of a large variety of fluorescent labeling molecules. However, the sensitivity of immunoassays needs to be improved further to meet the ever increasing demands of the new proteomics era. We have developed a novel and simple method to increase immunoassay sensitivity by attaching multiple fluorescent labels on an antibody with a dye/DNA conjugate. Our strategy is to use a DNA fragment as a molecular carrier to attach multiple fluorescent dyes to an antibody at a single site. The dye/DNA conjugate is not presynthesized, but rather formed in situ as part of the immunoassay. Our results demonstrate that by using a 219-bp DNA fragment in conjunction with SYBR Green I fluorescent DNA binder, the sensitivity of both direct and competitive fluorescence immunoassays is improved by orders of magnitude, reaching a lower detection limit of 1.9 pg/mL for 17beta-estradiol. PMID- 21674325 TI - Chemoselective modification of viral proteins bearing metabolically introduced "clickable" amino acids and sugars. AB - The inherent difficulty of performing chemical modifications of proteins in a truly site-specific fashion is often compounded by the need to work within complex biological settings. In order to alleviate this complication, targets can be "prelabeled" metabolically with unnatural residues, which allow access to highly selective bioorthogonal reactions. Due to their small size, permissibility within biosynthetic pathways and access to reactions with high specificity, azides provide excellent bioorthogonal handles. This two-step labeling process is emerging as a highly effective means to modify therapeutic proteins. In this chapter, we take this strategy a step further and apply chemoselective ligation to remodel the surfaces of adenoviruses. Despite the large number of ongoing clinical trials involving these complex mammalian viruses, new methods for their facile, flexible surface modification are necessary to drive the development of next-generation therapeutics. Here we demonstrate the modification of azides on adenoviral surfaces via a straightforward chemoselective protocol based on copper assisted "click" chemistry. This method provides access to a wide array of effector functionalities without sacrificing infectivity. PMID- 21674326 TI - Preparation of peptide and other biomolecular conjugates through chemoselective ligations. AB - The synthesis of molecular conjugates through chemoselective ligations represents a very convenient strategy to prepare complex macromolecules with diverse functional elements. Herein, we describe chemical methods based on the preparation of chemoselectively addressable peptides allowing successive oxime ligations and/or alkyne-azide cycloaddition ("click") reactions of various biomolecules. This modular synthetic approach can be applied to a broad range of purposes. PMID- 21674327 TI - New fluorescent substrates of microbial transglutaminase and its application to peptide tag-directed covalent protein labeling. AB - Transglutaminase (TGase) is an enzyme that catalyzes the post-translational covalent cross-linking of Gln- and Lys-containing peptides and/or proteins according to its substrate specificity. We have recently designed a variety of Gln-donor fluorescent substrates of microbial transglutaminase (MTG) from Streptomyces mobaraensis and evaluated their potential use in MTG-mediated covalent protein labeling. The newly designed substrates are based on the relatively broad substrate recognition of MTG for the substitution of the N terminal group of a conventional TGase substrate, benzyloxycarbonyl-L glutaminylglycine (Z-QG). It is revealed that MTG is capable of accepting a diverse range of fluorophores in place of the N-terminal moiety of Z-QG when linked via a suitable linker. Here, we show the potential utility of a new fluorescent substrate for peptide tag-directed covalent protein labeling by employing fluorescein-4-isothiocyanate-beta-Ala-QG as a model Gln-donor substrate for MTG. PMID- 21674328 TI - Covalent conjugation of poly(ethylene glycol) to proteins and peptides: strategies and methods. AB - PEGylation, the covalent linking of PEG chains, has become the leading drug delivery approach for proteins. This technique initiated its first steps almost 40 years ago, and since then, a variety of methods and strategies for protein polymer coupling have been devised. PEGylation can give a number of relevant advantages to the conjugated protein, such as an important in vivo half-life prolongation, a reduction or an abolishment of immunogenicity, and a reduction of aggregation. Furthermore, the technique has demonstrated a great degree of versatility and efficacy--not only PEG-protein conjugates have reached the commercial marketplace (with nine types of derivatives), but a PEG-aptamer and PEGylated liposomes are now also available. Most of this success is due to the development of several PEGylation strategies and to the large selection of PEGylating agents presently at hand for researchers. Nevertheless, this technique still requires a certain level of familiarity and knowledge in order to achieve a positive outcome for a PEGylation project. To draw general guidelines for conducting PEGylation studies is not always easy or even possible because such experiments often require case-by-case optimization. On the other hand, several common methods can be used as starting examples for the development of tailor made coupling conditions. Therefore, this chapter aims to provide a basic introduction to a wide range of PEGylation procedures for those researchers who may not be familiar with this field. PMID- 21674329 TI - Extending the scope of site-specific cysteine bioconjugation by appending a prelabeled cysteine tag to proteins using protein trans-splicing. AB - Incorporating synthetic probes site-specifically into proteins is of central interest in several areas of biotechnology and protein chemistry. Bioconjugation techniques provide a simple and effective means of chemically modifying a protein. In particular, covalent chemical modifications of cysteine residues belong to one of the most important reactions due to the unique reactivity of its thiol moiety and the relatively low abundance of this amino acid in proteins. However, such types of modifications cannot be performed in a regioselective fashion when one or more additional cysteines are present. To address this limitation, we have developed an approach where a short cysteine-containing tag (Cys-Tag) fused to one part of a split intein and modified at its sulfhydryl group can be used to label proteins by trans-splicing with a protein of interest (POI) fused to the other half of the split intein. In this way, it is possible to selectively label a protein containing multiple cysteines. The artificially split Mycobacterium xenopi GyrA intein and the Synechocystis sp. DnaB intein were highly suitable for this purpose and were successfully used for the labeling of several proteins. This approach enables a simple route for labeling proteins by site-specific cysteine bioconjugation with any one of several commercially available cysteine-modifying probes. PMID- 21674330 TI - Polyethylenimine bioconjugates for imaging and DNA delivery in vivo. AB - Polyamine polymers are among the commonest polymers used in biomedicine. Among polyamine -polymers, polyethylenimine (PEI) may be used as an efficient delivery vehicle for nucleic acids (DNA, RNA, etc.) or employed as a versatile imaging probe in vivo. In this chapter, the preparation of various PEI bioconjugates will be fully explained and discussed. PMID- 21674331 TI - Synthesis of a glycomimetic oligonucleotide conjugate by 1,3-dipolar cycloaddition. AB - A glycomimetic oligonucleotide conjugate bearing four galactose residues on a mannose core is -synthesized using oligonucleotide solid-phase synthesis and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC, or "click" chemistry). To achieve this purpose, new building blocks (including the solid support and phosphoramidites) are synthesized and used on a DNA synthesizer to generate a tetraalkyne oligonucleotide, which is then conjugated with a galactose azide derivative by click chemistry to afford the desired 3'-tetragalactosyl mannose oligonucleotide conjugate. The procedures described in this chapter provide a general approach for the synthesis of novel glycoconjugates that can be immobilized to a DNA chip via DNA-directed immobilization to study, for example, their multivalent interactions with lectins in cellular targeting/uptake, etc. PMID- 21674332 TI - Site-specific DNA labeling by Staudinger ligation. AB - Site-specific and chemoselective labeling of DNA is still a difficult task. The Staudinger ligation is a bioorthogonal reaction between azides and phosphines that requires no catalyst to proceed, allowing for mild reaction conditions. The reaction may be extended for site-specific labeling of DNA using azido-modified triphosphates, which can be incorporated site-specifically into DNA strands by DNA polymerases in a template-dependent manner. The azido-modified DNA, in turn, can be labeled by suitable phosphines. This protocol describes (1) the synthesis of an azido-TTP analogue; (2) the enzymatic synthesis of azido-modified DNA; (3) the synthesis of suitable phosphine labels; and (4) the labeling of azido-DNA with biotin-phosphine by Staudinger ligation with approximately 70% conversion. PMID- 21674333 TI - Improved cellular uptake of antisense peptide nucleic acids by conjugation to a cell-penetrating peptide and a lipid domain. AB - Unaided cellular uptake of RNA interference agents such as antisense oligonucleotides and siRNA is extremely poor, and in vivo bioavailability is also limited. Thus, effective delivery strategies for such potential drugs are in high demand. Recently, a novel approach using a class of short cationic peptides known as cell-penetrating peptides (CPPs) is attracting wide attention for a variety of biologically active molecules. CPP-mediated delivery is typically based on the covalent conjugation of the (therapeutic) cargo to CPPs, and is particularly relevant for the delivery of noncharged RNA interference agents such as peptide nucleic acids (PNAs) and morpholino oligomers. Although chemical conjugation to a variety of CPPs significantly improves the cellular uptake of PNAs, the bioavailability (and hence antisense activity) of CPP-PNA -conjugates is still highly limited by endocytotic entrapment. We have found, however, that this low bioavailability can be significantly improved by chemical conjugation to a lipid domain ("Lip," such as a fatty acid), thereby creating "CatLip"-conjugates. The cellular uptake of these conjugates is conveniently evaluated using a sensitive cellular assay system based on a splicing correction of a mutated luciferase gene in HeLa pLuc705 cells by targeting antisense oligonucleotides to a cryptic splice site. Further improvement in the delivery of CatLip-PNA conjugates is achieved by using auxiliary agents/treatments (e.g., chloroquine, calcium ions, or photosensitizers) to induce endosomal disruption. PMID- 21674334 TI - Synthesis of oligonucleotide-peptide conjugates for biomedical and technological applications. AB - Oligonucleotide-peptide conjugates have attracted considerable interest especially for biomedical uses. In the first part of this chapter, we describe protocols for the stepwise synthesis of oligonucleotides carrying peptide sequences at the 3'-end on a single support. The resulting oligonucleotide peptide conjugates may be used as exogenous effectors for the specific control of gene expression. In the second part of this chapter, detailed postsynthetic conjugation protocols to introduce peptide sequences into oligonucleotide sequences are also presented. PMID- 21674335 TI - Amphiphilic DNA block copolymers: nucleic acid-polymer hybrid materials for diagnostics and biomedicine. AB - DNA-polymer conjugates have been recognized as versatile functional materials in many different fields ranging from nanotechnology to diagnostics and biomedicine. They combine the favorable properties of nucleic acids and synthetic polymers. Moreover, joining both structures with covalent bonds to form bioorganic hybrids allows for the tuning of specific properties or even the possibility of evolving completely new functions. One important class of this type of material is amphiphilic DNA block copolymers, which, due to microphase separation, can spontaneously adopt nanosized micelle morphologies with a hydrophobic core and a DNA corona. These DNA nano-objects have been explored as vehicles for targeted gene and drug delivery, and also as programmable nanoreactors for organic reactions. Key to the successful realization of these potential applications is that (1) DNA block copolymer conjugates can be fabricated in a fully automated fashion by employing a DNA synthesizer; (2) hydrophobic compounds can be loaded within their interior; and (3) they can be site-specifically functionalized by a convenient nucleic acid hybridization procedure. This chapter aims to broaden the range of biodiagnostic and biomedical applications of these materials by providing a comprehensive outline of the preparation and characterization of multifunctional DNA-polymer nanoparticles. PMID- 21674336 TI - Chemically selective liposome surface glyco-functionalization. AB - Liposome surface functionalization facilitates the enormous potential applications of liposomes, such as stabilizing and targeting carrier systems for delivering active molecules in biomedical research and applications. Cell surface carbohydrates have been an attractive model system for liposome surface functionalization for enhanced biomedical applications, such as site-specific and ligand-directed drug and gene delivery, multivalent inhibition, and vaccine adjuvant applications. The present protocol describes an efficient and chemically selective liposome surface glyco-functionalization method based on Staudinger ligation performed in phosphate-buffered saline buffer (pH 7.4) at room temperature. Specifically, a carbohydrate derivative carrying a spacer with an azide group is conjugated onto the surface of preformed liposomes carrying terminal triphenylphosphine groups. The compatibility of the reaction conditions for liposome surface functionalization was confirmed with dynamic light scattering and kinetic experiments monitoring the leakage of entrapped 5,6 carboxyfluorescein. PMID- 21674337 TI - Bioconjugation using mutant glycosyltransferases for the site-specific labeling of biomolecules with sugars carrying chemical handles. AB - This chapter presents a technique that employs mutant glycosyltransferase enzymes for the site-specific bioconjugation of biomolecules via a glycan moiety to facilitate the development of a targeted drug delivery system. The target specificity of this methodology is based on unique sugar residues that are present on glycoproteins or engineered glycopeptides. The glycosyltransferases used in this approach have been manipulated in a way that confers the ability to transfer a modified sugar residue with a chemical handle to a sugar moiety of the glycoprotein or to a polypeptide tag of an engineered nonglycoprotein. The availability of the modified sugar moiety thus makes it possible to link cargo molecules at specific sites. The cargo may be comprised of, for example, biotin or fluorescent tags for detection, imaging agents for magnetic resonance imaging (MRI), or cytotoxic drugs for cancer therapy. PMID- 21674338 TI - Lipid-core-peptide system for self-adjuvanting synthetic vaccine delivery. AB - Disadvantages of classical vaccines, such as the risk of an autoimmune reaction, might be overcome by using a subunit vaccine containing the minimal microbial components necessary to stimulate appropriate immune responses. However, vaccines based on minimal epitopes suffer from poor immunogenicity and require the use of an additional immunostimulant (adjuvant). Only a few adjuvants have been permitted for use with vaccines intended for human administration. We have developed several vaccine candidates based on a lipid-core-peptide (LCP) system. This system has self-adjuvanting properties, and it can be used for the delivery of a variety of epitopes to produce vaccine candidates against a targeted disease. The LCP system is easily assembled by simple stepwise Boc solid-phase peptide synthesis. PMID- 21674339 TI - Coupling carbohydrates to proteins for glycoconjugate vaccine development using a pentenoyl group as a convenient linker. AB - Carbohydrates are important molecular targets in the development of vaccines against cancer, viral and bacterial infections, and many other diseases. However, carbohydrates are usually poorly immunogenic and cannot induce a T cell-dependent immune response that is necessary for effective immunity. To overcome this problem, carbohydrate antigens have to be coupled to an immunogenic carrier molecule, such as a protein, to improve their immunogenicity. To this end, many carbohydrate-protein coupling methods have been developed. A recently established method is based on the introduction of an azido group to carbohydrate antigens during their syntheses, and after the carbohydrate antigens are synthesized, the azido group can be selectively reduced to a free amino group, to which a 4 pentenoyl group can be readily and regiospecifically attached. Thereafter, the C=C bond of the pentenoyl group is ozonolyzed to generate a reactive aldehyde functionality, through which the carbohydrate antigens are linked to carrier proteins by reductive amination. Since the azido group is orthogonal to most transformations involved in carbohydrate synthesis, it can be introduced at an early stage of the synthesis. Moreover, since the pentenoyl group, as well as its aldehyde derivative, is attached to the carbohydrate antigens after they are synthesized, this would significantly simplify the synthetic design of complex carbohydrates, including the design of protecting tactics. PMID- 21674340 TI - Conjugation of LPS-derived oligosaccharides to proteins using oxime chemistry. AB - Conjugates of bacterial polysaccharides covalently bound to a carrier protein are among licensed human vaccines. Immunization of adults and children with these vaccines results in induction of saccharide-specific antibodies composed mainly of the IgG class. Depending on the choice of coupling technique, saccharides can be attached to a protein by either multiple- or single-point attachments. While the first method is suitable for high molecular mass polysaccharides, the second one is beneficial for low-molecular mass compounds such as synthetic carbohydrates or bacterial oligosaccharides obtained by different degradation procedures. This chapter describes a method for coupling low-molecular mass lipopolysaccharide (LPS)-derived oligosaccharides composed of a core or a short O specific polysaccharide-core fragment (O-SPC) to a carrier protein by a single point attachment. Conjugation is performed between the carbonyl group of the reducing terminal of 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) exposed after acid hydrolyses of LPS and the aminooxy group of a bifunctional linker bound to the protein. This is an efficient reaction that can be carried out quickly and under mild conditions. Conjugates thus prepared using this approach preserve the external nonreducing end of the sugar chain and can induce antibodies to both conjugate components. Consequently, this method is highly suitable for the preparation of LPS-based human vaccines. PMID- 21674341 TI - Site-specific chemical modification of a glycoprotein fragment expressed in yeast. AB - Site-specific modification of glycoproteins has wide application in both biochemical and biophysical studies. This method describes the conjugation of synthetic molecules to the N-terminus of a glycoprotein fragment, viz., human immunoglobulin G subclass 1 fragment crystallizable (IgG1 Fc), by native chemical ligation. The glycosylated IgG1 Fc is expressed in a glycosylation-deficient yeast strain. The N-terminal cysteine is generated by the endogenous yeast protease Kex2 in the yeast secretory pathway. The N-terminal cysteine is then conjugated with a biotin thioester to produce a biotinylated, glycosylated IgG1 Fc using native chemical ligation. PMID- 21674342 TI - On-resin convergent synthesis of a glycopeptide from HIV gp120 containing a high mannose type N-linked oligosaccharide. AB - This chapter describes a rapid and efficient approach for the solid-phase synthesis of N-linked glycopeptides that utilizes on-resin glycosylamine coupling to produce N-linked glycosylation sites. In this method, the full-length nonglycosylated peptide is first synthesized on a solid-phase support using standard Fmoc chemistry. The glycosylation site is then introduced through an orthogonally protected 2-phenylisopropyl (PhiPr) aspartic acid (Asp) residue. After selective deprotection of the Asp residue, a high mannose type oligosaccharide glycosylamine is coupled on-resin to the free Asp side chain to form a N-glycosidic bond. Subsequent protecting group removal and peptide cleavage from the resin ultimately yields the desired glycopeptide. This strategy provides an effective route for conducting glycosylation reactions on a solid phase support, simplifies the process of glycopeptide purification relative to solution-phase glycopeptide synthesis strategies, and enables the recovery of potentially valuable, un-reacted oligosaccharides. This approach has been applied to the solid-phase synthesis of the N-linked high mannose glycosylated form of peptide T (ASTTTNYT), a fragment of the HIV-1 envelope glycoprotein gp120. PMID- 21674343 TI - Design and synthesis of novel functional lipid-based bioconjugates for drug delivery and other applications. AB - The modification of biologicals such as proteins/peptides, small molecules, and other polymers with lipids provides an efficient method for mediating their insertion into liposomes and lipid-core micellar nanocarriers. In this chapter, we describe several representative protocols developed in our laboratory for the bioconjugation of liposomes and lipid-core micelles for drug/gene delivery and diagnostic imaging applications. PMID- 21674344 TI - Chemical functionalization and bioconjugation strategies for atomic force microscope cantilevers. AB - Over the last decade, scanning probe microscopy (SPM) techniques, such as atomic force microscopy (AFM), have played an important role in a variety of biophysical research efforts. This straightforward technique has the capability to measure forces down to a few hundred piconewtons, which enables the observation of unique events within or between single molecules. However, in order to successfully carry out these types of biophysical measurements, the anchoring of the biomolecules of interest to the scanning probe cantilever tip needs to be of sufficient strength to avoid rupture prior to the analysis of the specific interaction to be probed. Hence, a covalent linkage of the biomolecule to the SPM probe tip is generally preferred. It is also advantageous to have a long-chain functional linker to separate the biomolecule from the SPM probe tip so as to minimize unwanted interactions between the substrate surface and the tip and to "isolate" the biomolecular forces being probed. The most common materials for SPM cantilevers are silica and silicon nitride, and there are several surface chemistry approaches available to achieve a covalent linkage to such types of materials. In this chapter, we present various strategies and detailed protocols for conducting surface modifications suitable for biomolecular attachment to AFM probe surfaces or other hydroxylated surfaces. The strategies described build upon an initial surface activation treatment using the convenient gas-phase deposition of an organosilane and incorporate various passivation schemes and biomolecular immobilization techniques. PMID- 21674345 TI - Chemoselective protein and peptide immobilization on biosensor surfaces. AB - Site-specific immobilization of proteins and peptides on a sensor surface represents a significant challenge for bioanalytical applications such as surface plasmon resonance (SPR). The most common protocols for covalent protein immobilization usually result in heterogeneous presentation of the ligand at the surface, which can in some instances yield conflicting results with analogous data obtained in solution. Here, we discuss two complementary and generic bioconjugation methods that allow chemoselective immobilization of peptides and proteins via either their C-terminus (native chemical ligation) or their N terminus (oxime ligation). While the protocols described in this chapter were designed for use in a Biacore instrument, the methods should also be applicable to other SPR instruments and, with slight adjustments, to many other types of bioanalytical applications that rely on protein-functionalized surfaces. PMID- 21674346 TI - Fabrication of dynamic self-assembled monolayers for cell migration and adhesion studies. AB - How cells interact with the extracellular matrix (ECM) is important for a number of fundamental -processes in cell biology. However, the ECM is highly complex and in order to simplify the matrix for cell biological studies, it has been modeled with self-assembled monolayers (SAMs) of alkanethiolates on gold substrates. In this chapter, we outline procedures to create dynamic surfaces by functionalizing SAMs. SAMs based on quinone, oxyamine, and alcohol-terminated thiols were used to immobilize cell adhesive peptides with spatial control. Cells were seeded to these surfaces to provide cell co-culture -patterns suitable for biological studies. PMID- 21674347 TI - DNA detection using functionalized conducting polymers. AB - A well-defined DNA bioconjugated surface is a key component in the development of efficient biosensor platforms for diseases, ranging from point-of-care detection of pathogens and viruses to personalized diagnostics and medication, as well as for drug discovery, forensics, and food technology. We herein describe a universal and rapid methodology to construct such surfaces based on functionalized conducting polymer thin films. The conducting polymers combine sensing properties with the ability to act as signal transducers for the biorecognition event. We have shown that biosensor designs based on conducting polymers display a number of advantageous features, such as a long-term stability, label-free sensing, fast analysis, and the capability to apply both electrochemical and fluorescent protocols for DNA detection. PMID- 21674348 TI - Preparation and dynamic patterning of supported lipid membranes mimicking cell membranes. AB - In this chapter, we describe standardized protocols for the self-assembly of supported lipid bilayers (SLBs) from liposomes with lipid compositions mimicking eukaryote and prokaryote cell membranes. Such SLBs can also contain lipids with polymeric and glycosylated headgroups. Furthermore, we present protocols on how to manipulate the adsorption and desorption of membranes on indium tin oxide (ITO) electrodes, which allows for the creation of patterned and in situ regenerated SLB arrays that can be used to study electrochemically mediated membrane processes in a microarray format. PMID- 21674349 TI - Enzyme immobilization on reactive polymer films. AB - Immobilized enzymes are currently used in many bioanalytical and biomedical applications. This protocol describes the use of thin films of maleic anhydride copolymers to covalently attach enzymes directly to solid supports at defined concentrations. The concentration and activity of the surface-bound enzymes can be tuned over a wide range by adjusting the concentration of enzyme used for immobilization and the physicochemical properties of the polymer platform, as demonstrated here for the proteolytic enzyme Subtilisin A. The versatile method presented allows for the immobilization of biomolecules containing primary amino groups to a broad variety of solid carriers, ranging from silicon oxide surfaces to standard polystyrene well plates and metallic surfaces. The approach can be used to investigate the effects of immobilized enzymes on cell adhesion, and on the catalysis of specific reactions. PMID- 21674350 TI - Characterization of protein-membrane binding interactions via a microplate assay employing whole liposome immobilization. AB - Protein-cell membrane binding interactions control numerous vital biological processes, many of which can go awry during disease onset. However, the study of these events is complicated by the complexity of the membrane bilayer. These efforts would benefit from a rapid and easily accessible method for characterizing protein-membrane recognition events. Herein, we describe a microplate-based method for the detection of protein-membrane binding that employs whole liposome immobilization using a biotin anchor. First, control studies are detailed to test for nonspecific liposome immobilization (fluorescence assay; see Subheading 3.2), and to ensure that liposomes remain intact on the microplate surface (dye leakage assay; see Subheading 3.3). Finally, a protein-membrane binding detection assay is described through the example of protein kinase Calpha binding to surface-immobilized whole liposomes (see Subheading 3.4). PMID- 21674351 TI - A bioconjugated phospholipid polymer biointerface with nanometer-scaled structure for highly sensitive immunoassays. AB - This method relates to the preparation of a phospholipid polymer platform and the immobilization of an antibody as a bioaffinity ligand onto the platform to construct a biointerface for highly sensitive immunoassays. The specific phospholipid polymer used in this work is poly[2-methacryloyloxyethyl phosphorylcholine (MPC)-co-n-butyl methacrylate (BMA)-co-p-nitrophenyloxycarbonyl poly(ethylene glycol) methacrylate (MEONP)] (PMBN). The PMBN surface could immobilize specific antibodies through covalent chemical bonding by the reaction between MEONP units and amino groups in the antibody. In addition, the PMBN surface could prevent nonspecific protein adsorption from an analyte sample without the use of blocking reagents based on the fundamental properties of the MPC units. Furthermore, a nanometer-scaled particle deposition surface is constructed with PMBN by an electrospray deposition method to enhance the sensitivity by increasing the overall surface area of the biointerface. PMID- 21674352 TI - Purification, functionalization, and bioconjugation of carbon nanotubes. AB - Bioconjugation of carbon nanotubes (CNTs) with biomolecules promises exciting applications such as biosensing, nanobiocomposite formulation, design of drug vector systems, and probing protein interactions. Pristine CNTs, however, are virtually water-insoluble and difficult to evenly disperse in a liquid matrix. Therefore, it is necessary to attach molecules or functional groups to their sidewalls to enable bioconjugation. Both noncovalent and covalent procedures can be used to conjugate CNTs with a target biomolecule for a specific bioapplication. This chapter presents a few selected protocols that can be performed at any wet chemistry laboratory to purify and biofunctionalize CNTs. The preparation of CNTs modified with metallic nanoparticles, especially gold, is also described since biomolecules can bind and self-organize on the surfaces of such metal-decorated CNTs. PMID- 21674353 TI - Functional integration of membrane proteins with nanotube and nanowire transistor devices. AB - Biological molecules perform a sophisticated array of transport and signaling functions that rival anything that the modern electronics industry can create. Incorporating such building blocks into nanoelectronic devices could enable new generations of electronic circuits that use biomimetics to perform complicated tasks. Such types of circuits could ultimately blur the interface between living biological organisms and synthetic structures. Our laboratory has recently developed a versatile and flexible platform for integrating ion channels and pumps into single-walled carbon nanotube (SWNT) and silicon nanowire (SiNW) transistor devices, in which membrane proteins are embedded in a lipid bilayer shell covering the nanotube or nanowire component. In this chapter, we provide details for the fabrication of these devices and outline procedures for incorporating biological molecules into them. In addition, we also provide several examples of the use of these devices to couple biological transport to electronic signaling. PMID- 21674354 TI - Single-step conjugation of antibodies to quantum dots for labeling cell surface receptors in mammalian cells. AB - Labeling of cell surface receptors in living cells can be achieved using antibody conjugated semiconductor quantum dots (QDs). The inherent photostable property of QDs can be exploited for understanding the arrangement and distribution of receptors in the plasma membrane. We describe herein methods that allow conjugation of antibodies to QDs in a single step without the formation of side products. This protocol can be adapted universally for any type of QD structure with a coating of free amino groups. PMID- 21674355 TI - A practical strategy for constructing nanodrugs using carbon nanotubes as carriers. AB - Carbon nanotubes, acting as nanocarriers, can be combined with drug molecules through various chemical or physical routes in which hydrophilic modifications of the nanotubes are required. Such types of hydrophilic modifications typically involve addition reactions at the nanotube sidewalls, the reactions of nanotube bound carboxylic groups, and/or coating of the nanotubes with amphiphilic molecules. In this chapter, we introduce detailed approaches for covalently linking drug compounds to multiwalled carbon nanotubes, as well as labeling the synthesized drug-bearing carbon nanotube conjugates with fluorescent or radioactive molecules. PMID- 21674356 TI - Design and synthesis of biofunctionalized metallic/magnetic nanomaterials. AB - Organic solvent-soluble nanocrystals suitable for magnetic resonance imaging are prepared by two routes, namely, a coprecipitation method and a multiple-step thermal decomposition method (seed-mediated growth). The size, shape, crystallinity, phase, and composition of the prepared nanocrystals are determined by various characterization techniques, including transmission electron microscopy, vibrating-sample magnetometer, X-ray diffraction, and inductively coupled plasma mass spectroscopy. Subsequently, the organic-soluble nanocrystals are rendered water-soluble by two methods, the microemulsion method and the ligand exchange method, for biomedical applications. Detailed protocols for the preparation of water-soluble nanocrystals, as well as procedures for drug-loading and antibody conjugation to the water-soluble nanocrystals are provided. PMID- 21674357 TI - Three new flavonoid glycosides from Oxytropis myriophylla. AB - Three new flavonoids, myriophylloside I, II and III, were isolated from Oxytropis myriophylla (Leguminosae), together with four known flavonoid glycosides: isorhamnetin-3-O-beta-D-glucoside, isorhamnetin-3-O-alpha-L-arabinosyl(1->6)-beta D-glucoside, quercetin and rutin. The structural elucidations of all the compounds were based on extensive spectroscopic methods, including HRESIMS and 2D NMR experiments (HSQC, HMBC, (1)H-(1)H COSY and HSQC-TOCSY), UV, IR and chemical evidence, together with comparison with reference values. PMID- 21674358 TI - Successful switch to tenofovir after suboptimal response to entecavir in an immunocompromised patient with chronic hepatitis B and without genotypic hepatitis B virus resistance. AB - We report a case of an immunocompromised patient affected by chronic hepatitis B virus (HBV) with high basal HBV viremia (>8 log(10) IU/ml) who failed an entecavir regimen, despite the absence of primary or secondary drug resistance mutations. The patient achieved sustained virological success (serum HBV DNA <12 IU/ml) when tenofovir was added to the treatment. This case highlights the difficulty in choosing an optimal therapy in such specific conditions and supports the concept of tailoring therapy (including combination regimens) on the basis of the particular conditions of each individual patient. PMID- 21674359 TI - Clinical utility and prospective comparison of ultrasonography and computed tomography imaging in staging of neck metastases in head and neck squamous cell cancer in an Indian setup. AB - BACKGROUND: Preoperative lymph node screening of all neck compartments is favored by clinicians for the management of the neck. The presence of a metastatic node on one side of the neck reduces the 5-year survival rate to 50%, and the presence of a metastatic node on both sides of the neck reduces the 5-year survival rate to 25%. MATERIALS AND METHODS: This study compared the evaluation of lymph node metastases by ultrasonography (USG) and computed tomography (CT) in patients with squamous cell cancer of the head and neck region. RESULTS: Five hundred and eighty-four patients with squamous cell cancer of the head and neck were prospectively evaluated for the presence of cervical lymph node metastases. All patients underwent clinical examination (palpation), USG and CT imaging. Neck dissection was performed in all the patients, and the results of the preoperative evaluation were correlated with the surgical and histopathological findings. Metastases in neck nodes were identified in 148 patients by histopathological examination. Doppler USG correctly identified 136 node-positive patients (n = 148; sensitivity 91.8%, specificity 97%). CT imaging correctly identified 122 patients with metastatic lymph nodes (n = 148; sensitivity 83%, specificity 93%). Positive predictive values of USG and CT imaging were 95.6% and 91.3%, respectively, whereas the negative predictive values of these two imaging studies were 95.4% and 89.6%, respectively. CONCLUSIONS: The accuracy and sensitivity of USG in detection of cervical lymph node metastases make it a potentially promising and cheap preoperative tool for staging neck node metastases and optimizing the treatment plan for surgeons, especially in countries such as India. PMID- 21674360 TI - Expression of myeloperoxidase and gene mutations in AML patients with normal karyotype: double CEBPA mutations are associated with high percentage of MPO positivity in leukemic blasts. AB - The percentage of myeloperoxidase (MPO)-positive blast cells is a simple and highly significant prognostic factor in AML patients. It has been reported that the high MPO group (MPO-H), in which >50% of blasts are MPO activity positive, is associated with favorable karyotypes, while the low MPO group (<=50% of blasts are MPO activity positive, MPO-L) is associated with adverse karyotypes. The MPO H group shows better survival even when restricted to patients belonging to the intermediate chromosomal risk group or those with a normal karyotype. It has recently been shown that genotypes defined by the mutational status of NPM1, FLT3, and CEBPA are associated with treatment outcome in patients with cytogenetically normal AML. In this study, we aimed to evaluate the relationship between MPO positivity and gene mutations found in normal karyotypes. Sixty AML patients with normal karyotypes were included in this study. Blast cell MPO positivity was assessed in bone marrow smears stained for MPO. Associated genetic lesions (the NPM1, FLT3-ITD, and CEBPA mutations) were studied using nucleotide sequencing. Thirty-two patients were in the MPO-L group, and 28 patients in the MPO-H group. FLT3-ITD was found in 11 patients (18.3%), NPM1 mutations were found in 19 patients (31.7%), and CEBPA mutations were found in 11 patients (18.3%). In patients with CEBPA mutations, the carrying two simultaneous mutations (CEBPA (double-mut)) was associated with high MPO expression, while the mutant NPM1 without FLT3-ITD genotype was not associated with MPO activity. Both higher MPO expression and the CEBPA (double-mut) genotype appeared to be associated with improved overall survival after intensive chemotherapy. Further studies are required to determine the importance of blast MPO activity as a prognostic factor, especially in CEBPA wild-type patients with a normal karyotype. PMID- 21674361 TI - Synthesis and characterization of self-assembled DNA nanostructures. AB - The past decade witnessed the fast evolvement of structural DNA nanotechnology, which uses DNA as blueprint and building material to construct artificial nanostructures. Using branched DNA as the main building block (also known as a "tile") and cohesive single-stranded DNA (ssDNA) ends to designate the pairing strategy for tile-tile recognition, one can rationally design and assemble complicated nanoarchitectures from specifically designed DNA oligonucleotides. Objects in both two- and three-dimensions with a large variety of geometries and topologies have been built from DNA with excellent yield; this development enables the construction of DNA-based nanodevices and DNA-template directed organization of other molecular species. The construction of such nanoscale objects constitutes the basis of DNA nanotechnology. This chapter describes the protocol for the preparation of ssDNA as starting material, the self-assembly of DNA nanostructures, and some of the most commonly used methods to characterize the self-assembled DNA nanostructures. PMID- 21674362 TI - Protocols for self-assembly and imaging of DNA nanostructures. AB - Programed molecular structures allow us to research and make use of physical, chemical, and biological effects at the nanoscale. They are an example of the "bottom-up" approach to nanotechnology, with structures forming through self assembly. DNA is a particularly useful molecule for this purpose, and some of its advantages include parallel (as opposed to serial) assembly, naturally occurring "tools," such as enzymes and proteins for making modifications and attachments, and structural dependence on base sequence. This allows us to develop one, two, and three dimensional structures that are interesting for their fundamental physical and chemical behavior, and for potential applications such as biosensors, medical diagnostics, molecular electronics, and efficient light harvesting systems. We describe five techniques that allow one to assemble and image such structures: concentration measurement by ultraviolet absorption, titration gel electrophoresis, thermal annealing, fluorescence microscopy, and atomic force microscopy in fluids. PMID- 21674363 TI - Self-assembly of metal-DNA triangles and DNA nanotubes with synthetic junctions. AB - The site-specific insertion of organic and inorganic molecules into DNA nanostructures can provide unique structural and functional capabilities. We have demonstrated the inclusion of two types of molecules. The first is a diphenylphenanthroline (dpp, 1) molecule that is site specifically inserted into DNA strands and which can be used as a template to create metal-coordinating pockets. These building blocks can then be used to assemble metal-DNA 2D and 3D structures, including metal-DNA triangles, described here. The second insertion is a triaryl molecule that provides geometric control in the preparation of 2D single-stranded DNA templates. These can be designed to further assemble into geometrically well-defined nanotubes. Here, we detail the steps involved in the construction of metal-DNA triangles and DNA nanotubes using these methods. PMID- 21674364 TI - DNA-templated Pd conductive metallic nanowires. AB - We here present a protocol for the metallization of DNA scaffolds by palladium. The method is based on the initial slow precipitation of palladium oxide onto DNA strands. A reduction step follows to create conductive metallic nanowires. The slow oxide precipitation approach enables the formation of thin and continuous coatings on the DNA strands with negligible parasitic metallization of the remaining substrate surface. PMID- 21674365 TI - A method to map spatiotemporal pH changes inside living cells using a pH triggered DNA nanoswitch. AB - A few cellular compartments maintain acidic environments in their interiors that are crucial for their proper function. Alteration in steady state organelle pH is closely linked to several diseases. Although a few probes exist to measure pH of cell compartments, each has several associated limitations. We present a high performance pH sensor, a DNA nanoswitch, a convenient method to map spatiotemporal pH changes in endocytic pathways. DNA has been used to make a variety of nanoswitches in vitro . However, the present DNA nanoswitch functions as a pH sensing device equally efficiently intracellularly as it does in vitro. This DNA nanoswitch functions as a FRET-based pH sensor in the pH regime of 5.5 7, with high dynamic range between pH 5.8 and 7. It is efficiently engulfed by Drosophila hemocytes through endocytosis and can be used to measure the acidity of the endocytic vesicles that it marks during their maturation till their lysosomal stage. PMID- 21674366 TI - Control of helical handedness in DNA and PNA nanostructures. AB - Helical handedness and the twist and tilt parameters of the base pairs in duplex DNA can be affected by base sequence variation and change in environmental conditions as occurs in the transformation between right-handed B-DNA and left handed Z-DNA. For duplexes of DNA with oligonucleotide analogs such as peptide nucleic acids (PNAs), less is known about the effects on structure such as the base pair twist and tilt parameters and handedness. However, in PNA:PNA duplexes, the absence of chiral information determining helical handedness allows the relationship between preferred helical handedness and structural design to be manipulated and, therefore, better understood. In this chapter, we report a protocol for switching between B- and Z-DNA:DNA duplexes, and the experimental procedures for obtaining right- or left-handed PNA:PNA duplexes. PMID- 21674367 TI - G-quartet, G-quadruplex, and G-wire regulated by chemical stimuli. AB - Guanine-rich DNA, which is widely distributed in the human genome, can fold into a supramolecular structure called the G-wire. The G-wire possesses promising characteristics as a functional element for various applications in vitro and in vivo. Here, we describe the preparative procedures for the G-wire and signatures of G-wire formation. Procedures for the regulation of G-wire formation by chemical stimuli will be useful for in vivo and in vitro applications. PMID- 21674368 TI - Preparation and atomic force microscopy of quadruplex DNA. AB - The purpose of this chapter is to provide detailed instructions for the preparation and atomic force microscopy (AFM) imaging of linear chains of quadruplex DNA (a.k.a. "G-wire DNA"). Successful self-assembly of long chain quadruplex DNA requires pure concentrated guanine-rich oligonucleotide sequence (GROs) and monovalent cations in a growth buffer. AFM imaging of individual G wire DNA strands requires many carefully monitored steps, including substrate preparation, G-wire concentration, adsorption onto substrate, rinsing, drying, appropriate selection/use of imaging probes, and dry atmosphere imaging conditions. Detailed step-wise instructions are provided. PMID- 21674369 TI - Synthesis of long DNA-based nanowires. AB - Here we describe novel procedures for production of DNA-based nanowires. This include synthesis and characterization of the one-to-one double-helical complex of poly(dG)-poly(dC), triple-helical poly(dG)-poly(dG)-poly(dC) and G4-DNA, which is a quadruple-helical form of DNA. All these types of DNA-based molecules were synthesized enzymatically using Klenow exo(-) fragment of DNA Polymerase I. All the above types of nanowires are characterized by a narrow-size distribution of molecules. The contour length of the molecules can be varied from tens to hundreds of nanometers. These structures possess improved conductive and mechanical properties with respect to a canonical random-sequenced DNA and can possibly be used as wire-like conducting or semiconducting nanostructures in the field of nanoelectronics. PMID- 21674370 TI - G-wire synthesis and modification with gold nanoparticle. AB - DNA molecules are well known for containing the genetic information of an individual. Furthermore, DNA is a biopolymer with the potential of building up nanoscale structures. These structures can be addressed sequence specifically and, therefore, they allow connecting and arranging with subnanometer accuracy.The extended work of the group of Nadrian Seeman (Nature 421:427-431, 2003) has shown that the self-assembly of DNA molecules offers great potential for the creation of bottom-up nanostructures for nanoelectronics, biosensors, and programmable molecular machines. Rothemund (Nature 440:297-302, 2006) has shown that it is possible to generate a wide variety of 2D nanostructures by the assembly of synthetic desoxyoligonucleotides and M13mp18 DNA via Watson-Crick base pairing. Furthermore, DNA can form three- and four-stranded structures which offer even more possibilities for molecular construction. This chapter will deal with four-stranded DNA structures (G-wires) created from 10-bp deoxynucleotide units. Our focus will be especially on the synthesis, individualization, modification with gold nanoparticles, and characterization by high-resolution scanning force microscopy (AFM). PMID- 21674371 TI - Preparation of DNA nanostructures with repetitive binding motifs by rolling circle amplification. AB - A long one-dimensional single-stranded DNA (ssDNA) molecule with a periodic sequence motif is an attractive building block for DNA nanotechnology because it allows the positioning of oligonucleotide-labeled particles or molecules with high spatial resolution via molecular self-assembly simply by hybridization reactions. In vitro enzymatic isothermal rolling circle amplification (RCA) produces such long concatemeric ssDNA molecules. These are complementary in sequence to their circular template. In this chapter, the preparation of stretched and surface-attached RCA products at the single molecule level is described. The methods presented comprise the enzymatic circularization of a ssDNA oligonucleotide, the covalent coupling of amino-modified primers to carboxylated fluorescence beads, the preparation of a hydrophobic glass substrate, the RCA in a flow-through system, the postsynthetic staining and stretching of the RCA products as well as the microscopic observation of individual ssDNA molecules. PMID- 21674372 TI - Controlled confinement of DNA at the nanoscale: nanofabrication and surface bio functionalization. AB - Nanopatterned arrays of biomolecules are a powerful tool to address fundamental issues in many areas of biology. DNA nanoarrays, in particular, are of interest in the study of DNA-protein interactions and for biodiagnostic investigations. In this context, achieving a highly specific nanoscale assembly of oligonucleotides at surfaces is critical. In this chapter, we describe a method to control the immobilization of DNA on nanopatterned surfaces; the nanofabrication and the bio functionalization involved in the process will be discussed. PMID- 21674373 TI - Templated assembly of DNA origami gold nanoparticle arrays on lithographically patterned surfaces. AB - Artificial DNA nanostructures such as DNA origami have garnered significant interest as templates for sub-20 nm lithography because their rational design allows for the incorporation of binding sites to assemble nanocomponents with 6 nm resolution. In addition, their overall size of 100 nm is easily accessible by top-down lithographic methods. Combining the strengths of top-down lithography and bottom-up self-assembly using DNA nanostructures may provide a commercially viable route to fabricating electronic and photonic devices with nanometer-scale features. We have demonstrated just such a comprehensive process in which 5 nm gold nanoparticles are first assembled in high yield on DNA origami. The constructs are then organized, rinsed, and dried on patterned silicon substrates, yielding large area arrays of both origami and nanoparticles. PMID- 21674374 TI - DNA-modified single crystal and nanoporous silicon. AB - The functionalization of silicon as elemental crystalline wafer, nanoporous layers, or nanocrystalline particles with DNA oligonucleotides using automated solid phase synthesis is described. The procedures provide semiconductor surfaces covalently modified with oligomers suitable for capturing complementary oligonucleotide strands. PMID- 21674375 TI - The atomic force microscopy as a lithographic tool: nanografting of DNA nanostructures for biosensing applications. AB - Current in vitro techniques cannot accurately identify small differences in concentration in samples containing few molecules in single or few cells. Nanotechnology overcomes these limitations with the possibility of measuring protein amounts down to a hundred molecules and subnanomolar concentrations and in nanoliter to picoliter volumes. The nanoscale approach, therefore, permits measurements in samples consisting of single or few cells. Atomic force microscopy (AFM) nanografting can be utilized to prepare DNA nanopatches of different sizes (from few hundreds of nanometers to few microns in size) onto which DNA-antibody conjugates can be anchored through DNA-directed immobilization. AFM height measurements are used to assess the binding of the proteins as well as their subsequent interaction with other components, such as specific proteins from the serum. Recent results have contributed to demonstrate that nanografted patch arrays are well suited for application in biosensing and could enable the fabrication of multifeature protein nanoarrays. PMID- 21674376 TI - Trapping and immobilization of DNA molecules between nanoelectrodes. AB - DNA is one of the most promising molecules for nanoscale bottom-up fabrication. For both scientific studies and fabrication of devices, it is desirable to be able to manipulate DNA molecules, or self--assembled DNA constructions, at the single unit level. Efficient methods are needed for precisely attaching the single unit to the external measurement setup or the device structure. So far, this has often been too cumbersome to achieve, and consequently most of the scientific studies are based on a statistical analysis or measurements done for a sample containing numerous molecules in liquid or in a dry state. Here, we explain a method for trapping and attaching nanoscale double-stranded DNA (dsDNA) molecules between nanoelectrodes. The method is based on dielectrophoresis and gives a high yield of trapping only single or a few molecules, which enables, for example, transport measurements at the single -molecule level. The method has been used to trap different dsDNA fragments, sizes varying from 27 to 8,416 bp, and also DNA origami constructions. We also explain how confocal microscopy can be used to determine and optimize the trapping parameters. PMID- 21674377 TI - DNA contour length measurements as a tool for the structural analysis of DNA and nucleoprotein complexes. AB - The atomic force microscope (AFM) is a widely used tool to image DNA and nucleoprotein complexes at the molecular level. This is because the AFM is relatively easy to operate, has the capability to image biomolecules under aqueous solutions, and, most importantly, can image mesoscopic macromolecular structures that are too complex to be studied by X-ray or NMR and too small to be visualized with the optical microscope. Although there are many AFM studies about the structure and the physical properties of DNA, only in few cases a rigorous method has been applied to analyze AFM images. This chapter describes procedures to prepare DNA and nucleoprotein complexes for AFM imaging and methods used to carry out simple image measurements to obtain structural data. In particular, methods to measure DNA contour length and the volume of free or DNA-bound proteins are presented and discussed. PMID- 21674378 TI - DNA molecular handles for single-molecule protein-folding studies by optical tweezers. AB - In this chapter, we describe a method that extends the use of optical tweezers to the study of the folding mechanism of single protein molecules. This method entails the use of DNA molecules as molecular handles to manipulate individual proteins between two polystyrene beads. The DNA molecules function as spacers between the protein and the beads, and keep the interactions between the tethering surfaces to a minimum. The handles can have different lengths, be attached to any pair of exposed cysteine residues, and be used to manipulate both monomeric and polymeric proteins. By changing the position of the cysteine residues on the protein surface, it is possible to apply the force to different portions of the protein and along different molecular axes. Circular dichroism and enzymatic activity studies have revealed that for many proteins, the handles do not significantly affect the folding behavior and the structure of the tethered protein. This method makes it possible to study protein folding in the physiologically relevant low-force regime of optical tweezers and enables us to monitor processes - such as refolding events and fluctuations between different molecular conformations - that could not be detected in previous force spectroscopy experiments. PMID- 21674379 TI - Optimal practices for surface-tethered single molecule total internal reflection fluorescence resonance energy transfer analysis. AB - Single molecule fluorescence microscopy can be used to follow the mechanics of molecular biology processes in real time. However, many factors, from flow cell preparation to improper data analysis can negatively impact single molecule fluorescence resonance energy transfer (smFRET) experiments. Here, we describe some best practices for ensuring that smFRET data are of the highest quality. In addition to instrumentation, we describe sample preparation and data analysis. PMID- 21674380 TI - Engineering mononucleosomes for single-pair FRET experiments. AB - In DNA nanotechnology, DNA is used as a structural material, rather than as an information carrier. The structural organization of the DNA itself determines accessibility to its underlying information content in vivo. Nucleosomes form the basic level of DNA compaction in eukaryotic nuclei. Nucleosomes sterically hinder enzymes that must bind the nucleosomal DNA, and hence play an important role in gene regulation. In order to understand how accessibility to nucleosomal DNA is regulated, it is necessary to resolve the molecular mechanisms underlying conformational changes in the nucleosome. Exploiting bottom-up control, we designed and constructed nucleosomes with fluorescent labels at strategically chosen locations to study nucleosome structure and dynamics in molecular detail with single-pair Fluorescence Resonance Energy Transfer (spFRET) microscopy. Using widefield total internal reflection fluorescence (TIRF) microscopy on immobilized molecules, we observed and quantified DNA breathing dynamics on individual nucleosomes. Alternatively, fluorescence microscopy on freely diffusing molecules in a confocal detection volume allows a fast characterization of nucleosome conformational distributions. PMID- 21674381 TI - Measuring DNA-protein binding affinity on a single molecule using optical tweezers. AB - DNA-protein interactions may be observed on single molecules with a variety of techniques. However, quantifying the binding affinity is difficult and often requires many (~100) individual events to characterize the interaction. We use a single lambda DNA molecule that provides a lattice of binding sites for proteins. Extending and relaxing the tethered molecule reversibly melts DNA, allowing it to be converted between double-stranded (ds) and single-stranded (ss) forms. By monitoring changes in the properties of the DNA as a function of added protein concentration and fitting to binding models, the DNA-protein interaction may be characterized and quantified. As an example, the high mobility group protein HMGB1(box A + B) is observed to stabilize dsDNA. Measuring the strength of this effect allows us to determine the equilibrium association constant for HMGB1(box A + B) binding to dsDNA. PMID- 21674382 TI - Modeling nanopores for sequencing DNA. AB - Using nanopores to sequence DNA rapidly and at a low cost has the potential to radically transform the field of genomic research. However, despite all the exciting developments in the field, sequencing DNA using a nanopore has yet to be demonstrated. Among the many problems that hinder development of the nanopore sequencing methods is the inability of current experimental techniques to visualize DNA conformations in a nanopore and directly relate the microscopic state of the system to the measured signal. We have recently shown that such tasks could be accomplished through computation. This chapter provides step-by step instructions of how to build atomic scale models of biological and solid state nanopore systems, use the molecular dynamics method to simulate the electric field-driven transport of ions and DNA through the nanopores, and analyze the results of such computational experiments. PMID- 21674383 TI - The road ahead for rehabilitation robotics. PMID- 21674384 TI - ZeroG: overground gait and balance training system. AB - A new overground body-weight support system called ZeroG has been developed that allows patients with severe gait impairments to practice gait and balance activities in a safe, controlled manner. The unloading system is capable of providing up to 300 lb of static support and 150 lb of dynamic (or constant force) support using a custom-series elastic actuator. The unloading system is mounted to a driven trolley, which rides along an overhead rail. We evaluated the performance of ZeroG's unloading system, as well as the trolley tracking system, using benchtop and human-subject testing. Average root-mean-square and peak errors in unloading were 2.2 and 7.2 percent, respectively, over the range of forces tested while trolley tracking errors were less than 3 degrees, indicating the system was able to maintain its position above the subject. We believe training with ZeroG will allow patients to practice activities that are critical to achieving functional independence at home and in the community. PMID- 21674385 TI - Retraining of interjoint arm coordination after stroke using robot-assisted time independent functional training. AB - We have developed a haptic-based approach for retraining of interjoint coordination following stroke called time-independent functional training (TIFT) and implemented this mode in the ARMin III robotic exoskeleton. The ARMin III robot was developed by Drs. Robert Riener and Tobias Nef at the Swiss Federal Institute of Technology Zurich (Eidgenossische Technische Hochschule Zurich, or ETH Zurich), in Zurich, Switzerland. In the TIFT mode, the robot maintains arm movements within the proper kinematic trajectory via haptic walls at each joint. These arm movements focus training of interjoint coordination with highly intuitive real-time feedback of performance; arm movements advance within the trajectory only if their movement coordination is correct. In initial testing, 37 nondisabled subjects received a single session of learning of a complex pattern. Subjects were randomized to TIFT or visual demonstration or moved along with the robot as it moved though the pattern (time-dependent [TD] training). We examined visual demonstration to separate the effects of action observation on motor learning from the effects of the two haptic guidance methods. During these training trials, TIFT subjects reduced error and interaction forces between the robot and arm, while TD subject performance did not change. All groups showed significant learning of the trajectory during unassisted recall trials, but we observed no difference in learning between groups, possibly because this learning task is dominated by vision. Further testing in stroke populations is warranted. PMID- 21674386 TI - Variable structure pantograph mechanism with spring suspension system for comprehensive upper-limb haptic movement training. AB - Numerous haptic devices have been developed for upper-limb neurorehabilitation, but their widespread use has been largely impeded because of complexity and cost. Here, we describe a variable structure pantograph mechanism combined with a spring suspension system that produces a versatile rehabilitation robot, called Universal Haptic Pantograph, for movement training of the shoulder, elbow, and wrist. The variable structure is a 5-degree-of-freedom (DOF) mechanism composed of 7 joints, 11 joint axes, and 3 configurable joint locks that reduce the number of system DOFs to between 0 and 3. The resulting device has eight operational modes: Arm, Wrist, ISO (isometric) 1, ISO 2, Reach, Lift 1, Lift 2, and Steer. The combination of available work spaces (reachable areas) shows a high suitability for movement training of most upper-limb activities of daily living. The mechanism, driven by series elastic actuators, performs similarly in all operational modes, with a single control scheme and set of gains. Thus, a single device with minimal setup changes can be used to treat a variety of upper-limb impairments that commonly afflict veterans with stroke, traumatic brain injury, or other direct trauma to the arm. With appropriately selected design parameters, the developed multimode haptic device significantly reduces the costs of robotic hardware for full-arm rehabilitation while performing similarly to that of single mode haptic devices. We conducted case studies with three patients with stroke who underwent clinical training using the developed mechanism in Arm, Wrist, and/or Reach operational modes. We assessed outcomes using Fugl-Meyer Motor Assessment and Wolf Motor Function Test scores showing that upper-limb ability improved significantly following training sessions. PMID- 21674387 TI - Potential of robots as next-generation technology for clinical assessment of neurological disorders and upper-limb therapy. AB - Robotic technologies have profoundly affected the identification of fundamental properties of brain function. This success is attributable to robots being able to control the position of or forces applied to limbs, and their inherent ability to easily, objectively, and reliably quantify sensorimotor behavior. Our general hypothesis is that these same attributes make robotic technologies ideal for clinically assessing sensory, motor, and cognitive impairments in stroke and other neurological disorders. Further, they provide opportunities for novel therapeutic strategies. The present opinionated review describes how robotic technologies combined with virtual/augmented reality systems can support a broad range of behavioral tasks to objectively quantify brain function. This information could potentially be used to provide more accurate diagnostic and prognostic information than is available from current clinical assessment techniques. The review also highlights the potential benefits of robots to provide upper-limb therapy. Although the capital cost of these technologies is substantial, it pales in comparison with the potential cost reductions to the overall healthcare system that improved assessment and therapeutic interventions offer. PMID- 21674388 TI - Upper-limb robot-assisted therapy in rehabilitation of acute stroke patients: focused review and results of new randomized controlled trial. AB - The successful motor rehabilitation of stroke patients requires early intensive and task-specific therapy. A recent Cochrane Review, although based on a limited number of randomized controlled trials (RCTs), showed that early robotic training of the upper limb (i.e., during acute or subacute phase) can enhance motor learning and improve functional abilities more than chronic-phase training. In this article, a new subacute-phase RCT with the Neuro-Rehabilitation-roBot (NeReBot) is presented. While in our first study we used the NeReBot in addition to conventional therapy, in this new trial we used the same device in substitution of standard proximal upper-limb rehabilitation. With this protocol, robot patients achieved similar reductions in motor impairment and enhancements in paretic upper-limb function to those gained by patients in a control group. By analyzing these results and those of previous studies, we hypothesize a new robotic protocol for acute and subacute stroke patients based on both treatment modalities (in addition and in substitution). PMID- 21674389 TI - Psychological state estimation from physiological recordings during robot assisted gait rehabilitation. AB - Robot-assisted treadmill training is an established intervention used to improve walking ability in patients with neurological disorders. Although it has been shown that attention to the task is a key factor for successful rehabilitation, the psychological state of patients during robot-assisted gait therapy is often neglected. We presented 17 nondisabled subjects and 10 patients with neurological disorders a virtual-reality task with varying difficulty levels to induce feelings of being bored, excited, and overstressed. We developed an approach to automatically estimate and classify a patient's psychological state, i.e., his or her mental engagement, in real time during gait training. We used psychophysiological measurements to obtain an objective measure of the current psychological state. Automatic classification was performed by a neural network. We found that heart rate, skin conductance responses, and skin temperature can be used as markers for psychological states in the presence of physical effort induced by walking. The classifier achieved a classification error of 1.4% for nondisabled subjects and 2.1% for patients with neurological disorders. Using our new method, we processed the psychological state data in real time. Our method is a first step toward real-time auto-adaptive gait training with potential to improve rehabilitation results by optimally challenging patients at all times during exercise. PMID- 21674390 TI - Efficacy of rehabilitation robotics for walking training in neurological disorders: a review. AB - Robotic technologies are becoming more prevalent for treating neurological conditions in clinical settings. We conducted a literature search of original articles to identify all studies that examined the use of robotic devices for restoring walking function in adults with neurological disorders. We evaluated and rated each study using either the Physiotherapy Evidence Database scale for randomized controlled trials (RCTs) or the Downs and Black scale for non-RCTs. We reviewed 30 articles (14 RCTs, 16 non-RCTs) that examined the effects of locomotor training with robotic assistance in patients following stroke, spinal cord injury (SCI), multiple sclerosis (MS), traumatic brain injury (TBI), and Parkinson disease (PD). This review supports that locomotor training with robotic assistance is beneficial for improving walking function in individuals following a stroke and SCI. Gait speed and endurance were not found to be significantly different among patients with motor incomplete SCI after a variety of locomotor training approaches. Limited evidence demonstrates that locomotor training with robotic assistance is beneficial in populations of patients with MS, TBI, or PD. We discuss clinical implications and decision making in the area of gait rehabilitation for neurological dysfunction. PMID- 21674391 TI - Short-term ankle motor performance with ankle robotics training in chronic hemiparetic stroke. AB - Cerebrovascular accident (stroke) often results in impaired motor control and persistent weakness that may lead to chronic disability, including deficits in gait and balance function. Finding ways to restore motor control may help reduce these deficits; however, little is known regarding the capacity or temporal profile of short-term motor adaptations and learning at the hemiparetic ankle. Our objective was to determine the short-term effects of a single session of impedance-controlled ankle robot ("anklebot") training on paretic ankle motor control in chronic stroke. This was a double-arm pilot study on a convenience sample of participants with chronic stroke (n = 7) who had residual hemiparetic deficits and an equal number of age- and sex-matched nondisabled control subjects. Training consisted of participants in each group playing a target-based video game with the anklebot for an hour, for a total of 560 movement repetitions in dorsiflexion/plantar flexion ranges followed by retest 48 hours later. Task difficulty was adjusted to ankle range of motion, with robotic assistance decreased incrementally across training. Assessments included robotic measures of ankle motor control on unassisted trials before and after training and at 48 hours after training. Following exposure to the task, subjects with stroke improved paretic ankle motor control across a single training session as indexed by increased targeting accuracy (21.6 +/- 8.0 to 31.4 +/- 4.8, p = 0.05), higher angular speeds (mean: 4.7 +/- 1.5 degrees/s to 6.5 +/- 2.6 degrees/s, p < 0.01, peak: 42.8 +/- 9.0 degrees/s to 45.6 +/- 9.4 degrees/s, p = 0.03), and smoother movements (normalized jerk: 654.1 +/- 103.3 s(-2) to 537.6 +/- 86.7 s(-2), p < 0.005, number of speed peaks: 27.1 +/- 5.8 to 23.7 +/- 4.1, p < 0.01). In contrast, nondisabled subjects did not make statistically significant gains in any metric after training except in the number of successful passages (32.3 +/- 7.5 to 36.5 +/- 6.4, p = 0.006). Gains in all five motor control metrics were retained (p > 0.05) at 48 hours in both groups. Robust maintenance of motor adaptation in the robot-trained paretic ankle over 48 hours may be indicative of short-term motor learning. Our initial results suggest that the anklebot may be a flexible motor learning platform with the potential to detect rapid changes in ankle motor performance poststroke. PMID- 21674392 TI - Pilot study to test effectiveness of video game on reaching performance in stroke. AB - Robotic systems currently used in upper-limb rehabilitation following stroke rely on some form of visual feedback as part of the intervention program. We evaluated the effect of a video game environment (air hockey) on reaching in stroke with various levels of arm support. We used the Arm Coordination Training 3D system to provide variable arm support and to control the hockey stick. We instructed seven subjects to reach to one of three targets covering the workspace of the impaired arm during the reaching task and to reach as far as possible while playing the video game. The results from this study showed that across subjects, support levels, and targets, the reaching distances achieved with the reaching task were greater than those covered with the video game. This held even after further restricting the mapped workspace of the arm to the area most affected by the flexion synergy (effectively forcing subjects to fight the synergy to reach the hockey puck). The results from this study highlight the importance of designing video games that include specific reaching targets in the workspace compromised by the expression of the flexion synergy. Such video games would also adapt the target location online as a subject's success rate increases. PMID- 21674393 TI - Robot-assisted upper-limb therapy in acute rehabilitation setting following stroke: Department of Veterans Affairs multisite clinical trial. AB - This randomized, controlled, multisite Department of Veterans Affairs clinical trial assessed robot-assisted (RA) upper-limb therapy with the Mirror Image Movement Enabler (MIME) in the acute stroke rehabilitation setting. Hemiparetic subjects (n = 54) received RA therapy using MIME for either up to 15 hours (low dose) or 30 hours (high-dose) or received up to 15 hours of additional conventional therapy in addition to usual care (control). The primary outcome measure was the Fugl-Meyer Assessment (FMA). The secondary outcome measures were the Functional Independence Measure (FIM), Wolf Motor Function Test, Motor Power, and Ashworth scores at intake, discharge, and 6-month follow-up. Mean duration of study treatment was 8.6, 15.8, and 9.4 hours for the low-dose, high-dose, and control groups, respectively. Gains in the primary outcome measure were not significantly different between groups at follow-up. Significant correlations were found at discharge between FMA gains and the dose and intensity of RA. Intensity also correlated with FMA gain at 6 months. The high-dose group had greater FIM gains than controls at discharge and greater tone but no difference in FIM changes compared with low-dose subjects at 6 months. As used during acute rehabilitation, motor-control changes at follow-up were no less with MIME than with additional conventional therapy. Intensity of training with MIME was positively correlated with motor-control gains. PMID- 21674394 TI - A portable powered ankle-foot orthosis for rehabilitation. AB - Innovative technological advancements in the field of orthotics, such as portable powered orthotic systems, could create new treatment modalities to improve the functional out come of rehabilitation. In this article, we present a novel portable powered ankle-foot orthosis (PPAFO) to provide untethered assistance during gait. The PPAFO provides both plantar flexor and dorsiflexor torque assistance by way of a bidirectional pneumatic rotary actuator. The system uses a portable pneumatic power source (compressed carbon dioxide bottle) and embedded electronics to control the actuation of the foot. We collected pilot experimental data from one impaired and three nondisabled subjects to demonstrate design functionality. The impaired subject had bilateral impairment of the lower legs due to cauda equina syndrome. We found that data from nondisabled walkers demonstrated the PPAFO's capability to provide correctly timed plantar flexor and dorsiflexor assistance during gait. Reduced activation of the tibialis anterior during stance and swing was also seen during assisted nondisabled walking trials. An increase in the vertical ground reaction force during the second half of stance was present during assisted trials for the impaired subject. Data from nondisabled walkers demonstrated functionality, and data from an impaired walker demonstrated the ability to provide functional plantar flexor assistance. PMID- 21674395 TI - Quantitative evaluations of ankle spasticity and stiffness in neurological disorders using manual spasticity evaluator. AB - Spasticity and contracture are major sources of disability in people with neurological impairments that have been evaluated using various instruments: the Modified Ashworth Scale, tendon reflex scale, pendulum test, mechanical perturbations, and passive joint range of motion (ROM). These measures generally are either convenient to use in clinics but not quantitative or they are quantitative but difficult to use conveniently in clinics. We have developed a manual spasticity evaluator (MSE) to evaluate spasticity/contracture quantitatively and conveniently, with ankle ROM and stiffness measured at a controlled low velocity and joint resistance and Tardieu catch angle measured at several higher velocities. We found that the Tardieu catch angle was linearly related to the velocity, indicating that increased resistance at higher velocities was felt at further stiffer positions and, thus, that the velocity dependence of spasticity may also be position-dependent. This finding indicates the need to control velocity in spasticity evaluation, which is achieved with the MSE. Quantitative measurements of spasticity, stiffness, and ROM can lead to more accurate characterizations of pathological conditions and outcome evaluations of interventions, potentially contributing to better healthcare services for patients with neurological disorders such as cerebral palsy, spinal cord injury, traumatic brain injury, and stroke. PMID- 21674396 TI - Effect of robot-assisted versus conventional body-weight-supported treadmill training on quality of life for people with multiple sclerosis. AB - This study describes the effect of body-weight-supported treadmill training (BWSTT) on quality of life (QoL) for multiple sclerosis (MS) patients. Thirteen individuals with MS and gait impairment randomly received two blocks of six biweekly training sessions: (1) robot-assisted BWSTT then BWSTT alone (R-T) or (2) BWSTT alone then robot-assisted BWSTT (T-R). No statistically significant differences were found between robot-assisted BWSTT and unassisted BWSTT for improving QoL outcome measures. The change in Physical Component Summary scores from baseline to the end of the 12 training sessions improved significantly more in the R-T than the T-R group. Within-participant longitudinal changes in QoL for all participants from both groups combined showed significant improvements in 5 of the 13 QoL measures. The results of this pilot study suggest that both types of BWSTT may improve QoL for people with gait dysfunction secondary to MS. PMID- 21674397 TI - Rebuttal to Gravely et al. Validity of PTSD diagnoses in VA administrative data: comparison of VA administrative PTSD diagnoses to self-reported PTSD Checklist scores. J Rehabil Res Dev. 2011; 48(1):21-30. Available from: http://www.rehab.research.va.gov/jour/11/481/pdf/gravely.pdf. PMID- 21674398 TI - Discovery and collaboration for exceptional health care: Research Week 2011 celebrates research progress through partnership. PMID- 21674399 TI - Environmental design--an expanding role in hearing rehabilitation for older adults. PMID- 21674400 TI - Preliminary analysis of posttraumatic stress disorder screening within specialty clinic setting for OIF/OEF veterans seeking care for neck or back pain. AB - Escalating prevalence estimates of posttraumatic stress disorder (PTSD) among recently returning Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans highlight the need for early detection and management for reducing chronic mental illness and disability. Because PTSD and chronic pain are common comorbid conditions among veterans, PTSD screening within specialty clinic settings addressing musculoskeletal pain may be of value. This retrospective study evaluated measures of diagnostic value for the PTSD Checklist (PCL) for a sample (n = 79) of OIF/OEF veterans seeking care for neck or back pain within a Department of Veterans Affairs specialty clinic. Because published accounts of optimal PCL cutoff scores vary considerably, we used receiver operating characteristic curves to identify whether the optimal PCL cutoff score for the sample differed from a conventional cutoff score of 50. A clinical psychologist experienced in diagnosing and managing PTSD confirmed the diagnosis of PTSD for 37 veterans through a review of clinical records. The prevalence of diagnosed PTSD was 46.8%, with an optimal PCL cutoff score of 44. These findings may guide future research and influence clinical practice regarding PTSD screening for recently returning veterans with chronic pain. PMID- 21674401 TI - Audiometric thresholds and prevalence of tinnitus among male veterans in the United States: data from the National Health and Nutrition Examination Survey, 1999-2006. AB - Hearing loss and tinnitus are the two most prevalent service-connected disabilities among U.S. veterans. The number of veterans receiving compensation and services from the Department of Veterans Affairs (VA) for these conditions continues to increase annually. However, the majority of veterans in the United States do not use VA medical centers or clinics for healthcare and do not receive VA compensation payments. Therefore, the prevalence of hearing loss and tinnitus among U.S. veterans is unknown. This study used National Health and Nutrition Examination Survey data to estimate the prevalence of these auditory conditions among male veterans. Between 1999 and 2006, pure tone audiometric data collected from 845 male veterans were compared with pure tone thresholds collected from 2,086 male nonveterans. We used questionnaire data collected between 1999 and 2004 to calculate and compare the prevalence of tinnitus for 2,174 veterans and 4,995 nonveterans. In general, pure tone thresholds did not differ significantly between veterans and nonveterans for most frequencies tested (500-8,000 Hz). The overall prevalence of tinnitus was greater for veterans than that for nonveterans (p < 0.001), with statistically significant differences in the 50 to 59 and 60 to 69 age groups. PMID- 21674402 TI - Responsiveness of the Canadian occupational performance measure. AB - This study evaluated the responsiveness of the Canadian Occupational Performance Measure (COPM), an individualized, client-centered outcome measure for the identification and evaluation of self-perceived occupational performance problems. We recruited 152 consecutive patients with various diagnoses, admitted to the outpatient clinic of two occupational therapy departments, to complete a COPM interview and three self-reported health status questionnaires on two occasions: prior to the start of occupational therapy treatment and 3 months later. The three questionnaires were the Sickness Impact Profile (SIP68), the Disability and Impact Profile (DIP), and the Impact on Participation and Autonomy (IPA). We assessed criterion responsiveness by calculating the area under the curve (AUC) for the receiver operating characteristic curve and the optimal cutoff values for the COPM scores.To determine construct responsiveness, we calculated correlations between the change in COPM scores and the change in the SIP68, DIP, and IPA scores. The AUC ranged from 0.79 to 0.85, and the optimal cut off values for the performance scores and satisfaction scores ranged from 0.9 to 1.9.We found significant positive correlations between the COPM scores and the SIP68, DIP, and IPA scores. The capability of the COPM to detect changes in perceived occupational performance issues is supported. PMID- 21674403 TI - Performance testing of collision-avoidance system for power wheelchairs. AB - The Drive-Safe System (DSS) is a collision-avoidance system for power wheelchairs designed to support people with mobility impairments who also have visual, upper limb, or cognitive impairments. The DSS uses a distributed approach to provide an add-on, shared-control, navigation-assistance solution. In this project, the DSS was tested for engineering goals such as sensor coverage, maximum safe speed, maximum detection distance, and power consumption while the wheelchair was stationary or driven by an investigator. Results indicate that the DSS provided uniform, reliable sensor coverage around the wheelchair; detected obstacles as small as 3.2 mm at distances of at least 1.6 m; and attained a maximum safe speed of 4.2 km/h. The DSS can drive reliably as close as 15.2 cm from a wall, traverse doorways as narrow as 81.3 cm without interrupting forward movement, and reduce wheelchair battery life by only 3%. These results have implications for a practical system to support safe, independent mobility for veterans who acquire multiple disabilities during Active Duty or later in life. These tests indicate that a system utilizing relatively low cost ultrasound, infrared, and force sensors can effectively detect obstacles in the vicinity of a wheelchair. PMID- 21674404 TI - Reliability of standardized assessment for adults who are deafblind. AB - This study assessed the reliability of the interRAI Community Health Assessment (interRAI CHA) and Deafblind Supplement (DbS). The interRAI CHA and DbS represents a multidimensional, standardized assessment instrument for use with adults (18 and older) who are deafblind. The interrater reliability of the instrument was tested through the completion of dual assessments with 44 individuals who were deafblind in the province of Ontario, Canada. Overall, nearly 50% of items had a kappa value of at least 0.60, indicating fair to substantial agreement for these items. Several items related to psychosocial well being, mood, and sense of involvement had kappa scores of less than 0.40. However, among these items with low kappa values, most (78%) showed at least 70% agreement between the two assessors. The internal consistency of several health subscales, embedded within the assessment, was also very good and ranged from 0.63 to 0.93. The interRAI CHA and DbS represents a reliable instrument for assessing adults with deafblindness to better understand their needs, abilities, and preferences. PMID- 21674405 TI - Decreased central fatigue in multiple sclerosis patients after 8 weeks of surface functional electrical stimulation. AB - Effective treatments for multiple sclerosis (MS)-associated central fatigue have not been established. Surface functional electrical stimulation (FES), which can challenge the peripheral neuromuscular system without overloading the central nervous system, is a relatively safe therapeutic strategy. We investigated the effect of 8 weeks of surface FES training on the levels of general, central, and peripheral fatigue in MS patients. Seven of nine individuals with MS (average age: 42.86 +/- 13.47 years) completed 8 weeks of quadriceps muscle surface FES training. Maximal voluntary contraction, voluntary activation level, twitch force, General Fatigue Index (FI), Central Fatigue Index (CFI), Peripheral Fatigue Index, and Modified Fatigue Impact Scale (MFIS) scores were determined before and after training. The results showed that FI (p = 0.01), CFI (p = 0.02), and MFIS (p = 0.02) scores improved significantly after training. Improvements in central fatigue contributed significantly to improvements in general fatigue (p < 0.01). The results of the current study showed that central fatigue was a primary limitation in patients with MS during voluntary exercise and that 8 weeks of surface FES training for individuals with MS led to significantly reduced fatigue, particularly central fatigue. PMID- 21674406 TI - Techniques to measure rigidity of ankle-foot orthosis: a review. AB - We performed this review to provide a clearer understanding of how to effectively measure ankle-foot orthosis (AFO) rigidity. This information is important to ensure appropriate orthotic intervention in the treatment of patients with pathological gait. The two main approaches to the investigation of AFO rigidity are (1) bench-testing analyses, in which an AFO is fixed or attached to a measurement device, and (2) functional analyses, in which measurements are taken while a subject is walking with an AFO in situ. This review summarizes and classifies the current state of knowledge of AFO rigidity testing methods. We analyzed the strengths and weaknesses of the methods in order to recommend the most reliable techniques to measure AFO rigidity. The information obtained from this review article would, therefore, benefit both clinicians and engineers involved in the application and design of AFOs. PMID- 21674407 TI - Evaluations of neuromuscular dynamics of hyperactive reflexes poststroke. AB - Tendon reflexes are widely used in clinics to conveniently evaluate various neurological disorders. This study characterized neuromuscular dynamics of tendon reflexes at the elbow with multiple quantitative measures in both patients with stroke and nondisabled controls. We employed a handheld instrumented hammer to tap the triceps muscle tendon at various elbow flexion angles and measured the tapping force, triceps electromyography, and elbow extension torque to characterize neuromuscular dynamics of tendon reflexes quantitatively in terms of the tendon reflex gain, contraction rate, half relaxation rate, reflex loop delay, and reflex threshold in tapping force. We found that the tendon reflex gain, contraction rate, and half relaxation rate were significantly higher while the reflex threshold was significantly lower across different joint angles in patients with stroke than in nondisabled controls (p < 0.05), indicating hyperactive neurological state and muscle contraction dynamics poststroke. This study presents a convenient and quantitative method to evaluate reflex excitability and muscle contraction dynamics. PMID- 21674408 TI - New method for determining apparent axial center of rotation of lumbar and thoracic spine segments. AB - One main question in spinal kinematics is the determination of the spine's apparent axial center of rotation. Previous research on this topic has yielded contradictory results. The objective of this study was to determine the apparent axial center of rotation for seven lumbar and six thoracic spinal segments by developing and validating a new method. A custom six-degree-of-freedom device, allowing full range of motion, was used with motion recording and analysis software. This system tracked a grid of markers on a specimen when rotational torque was applied in both clockwise and counterclock wise directions at 3.53 Nm, 7.05 Nm, 10.58 Nm, and 14.10 Nm. The area encompassing the apparent axial center of rotation was determined by identifying the five markers with the least amount of motion. The marker angular displacement was calculated as the angle between a virtual line drawn between two points in the initial and final torque conditions. Rotation in both directions was averaged. The lumbar and thoracic spinal segments averaged an apparent axial center of rotation at the posterior border of the vertebral endplates and the anterior border of the spinal canal, with average clockwise to counterclockwise angular displacement ratios of 0.87 and 0.97, respectively. PMID- 21674409 TI - Cognitive impairment as barrier to engagement in vocational services among veterans with severe mental illness. AB - Vocational services (VS), particularly supported employment models, have clear advantages for assisting adults with severe mental illness (SMI) in returning to the workplace, but a majority of eligible individuals with SMI do not receive any type of VS. The reasons for nonparticipation in VS remain poorly understood, and the potential contribution of cognitive impairment as a barrier to entry has not been explored. The present study uses a pathways-to-care design to examine the specific contribution of cognitive functioning to entry into VS among veterans with SMI. We examined 179 veterans with both SMI and un- or underemployment who completed a work history, the Pathways To Care Inventory, and the Trail-Making Test, Part B. Analysis revealed that veterans with SMI and moderate to severe cognitive impairment took significantly longer to progress through pathways-to care than those with SMI and mild or no cognitive impairment. These results suggest that identifying veterans with SMI and cognitive impairment early and providing them with integrated and adjunct services may help them navigate VS. PMID- 21674410 TI - Lung vasculitis and alveolar hemorrhage. PMID- 21674411 TI - Pathogenesis of lung vasculitis. AB - Vasculitides that affect the lung represent a diverse group of diseases with various systemic clinical manifestations, and include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), Churg-Strauss syndrome (CSS), and anti-glomerular basement membrane (anti-GBM) disease (Goodpasture syndrome). The etiologies of these diseases remain largely unknown. Although the pathogenic mechanisms of each differ, these diseases overlap by the presence of anti-neutrophil cytoplasmic autoantibodies in the vast majority of patients with MPA and GPA, and a substantial minority of patients with CSS and anti-GBM disease. This article reviews the current understanding of the pathogenesis of these four disease entities. PMID- 21674412 TI - Lung vasculitis and alveolar hemorrhage: pathology. AB - Pulmonary vasculitides are a diverse group of limited and systemic disorders associated with inflammation of pulmonary vessels and parenchyma. These diseases often have distinctive clinical, serological, and histopathological features extrapulmonary sites of involvement, circulating autoantibodies, predispositions for small or large vessels, and others. Some have characteristic inflammatory lesions; others are characterized by the absence of such lesions. Frequently pathological findings overlap, rendering classification, and diagnosis a challenge. The anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel diseases constitute the major pulmonary vasculitides. These include Wegener granulomatosis (WG), Churg Strauss syndrome (CSS), and microscopic polyangiitis (MPA). Less frequently, diseases such as polyarteritis nodosa, Takayasu arteritis, Behcet syndrome, and connective tissue diseases may involve pulmonary vessels, but these entities are better associated with extrapulmonary disease. Diffuse alveolar hemorrhage (DAH) is a severe manifestation of pulmonary vasculitis. DAH is most commonly seen in small-vessel vasculitides, specifically MPA and WG. Other syndromes associated with DAH include Goodpasture syndrome, Henoch-Schonlein purpura, and systemic lupus erythematosus. Less commonly, DAH may be secondary to infection or drugs/toxins. Furthermore, in the absence of discernable systemic disease, DAH may be idiopathic-referred to as isolated pulmonary capillaritis (IPC) or idiopathic pulmonary hemosiderosis (IPH), depending on the presence of capillaritis. PMID- 21674413 TI - Epidemiology and etiology of wegener granulomatosis, microscopic polyangiitis, churg-strauss syndrome and goodpasture syndrome: vasculitides with frequent lung involvement. AB - This review focuses on the epidemiological characteristics and etiologies of four primary systemic vasculitides with frequent lung involvement, namely Wegener granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and Goodpasture syndrome (GPS). Elucidation of the mechanisms underlying these vasculitides with frequent lung involvement is complicated by their rarity, which hampers the undertaking of large-scale studies; difficulties in classification; and their multifaceted clinical presentations, which infer the existence of several etiologic pathways. Notwithstanding, epidemiological research showed some evidence for international, interethnic, and temporal variations of the frequencies of these four vasculitides; led to the identification of several genetic and environmental risk factors; and provided insight on the extent to which genes and environment might contribute to their development. Available data support the concept that WG, MPA, CSS, and GPS have unique and shared risk determinants. Although the precise causes of these vasculitides are not yet fully understood and the development of prevention strategies is out of our reach at present, current knowledge enables the formulation of etiologic hypotheses to provide caregivers and their patients with valuable information on the nature of these rare entities. PMID- 21674414 TI - Wegener granulomatosis (granulomatosis with polyangiitis): evolving concepts in treatment. AB - Wegener granulomatosis (WG), the most common of the pulmonary granulomatous vasculitides, typically involves the upper respiratory tract, lower respiratory tract (bronchi and lung), and kidney, with varying degrees of disseminated vasculitis. THE TERM GRANULOMATOSIS WITH POLYANGIITIS (WEGENER) WAS RECENTLY PROPOSED TO REPLACE THE OLDER TERM, WG. THE TERM GRANULOMATOSIS WITH POLYANGIITIS CAN BE ABBREVIATED TO GPA, WITH THE IDEA THAT THE EPONYM WEGENER WOULD BE OMITTED OVER TIME. Cardinal histologic features include a necrotizing vasculitis involving small vessels, extensive "geographic" necrosis, and granulomatous inflammation. Clinical manifestations of WG are protean; virtually any organ can be involved. The spectrum and severity of the disease are heterogeneous, ranging from indolent disease involving only one site to fulminant, multiorgan vasculitis. The pathogenesis of WG has not been elucidated, but both cellular and humoral components are involved. Circulating antibodies against cytoplasmic components of neutrophils [anti-neutrophil cytoplasmic antibodies (c-ANCAs)] likely play a role in the pathogenesis, and often correlate with activity of the disease. Treatment strategies are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic WG. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (e.g., methotrexate, azathioprine) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening WG. Recent studies suggest that rituximab may be useful for induction therapy or CYC-refractory WG. The role of other immunomodulatory agents (including trimethoprim-sulfamethoxazole) is also explored. PMID- 21674415 TI - Churg-strauss syndrome: clinical symptoms, complementary investigations, prognosis and outcome, and treatment. AB - Churg-Strauss syndrome (CSS), first described in 1951, is a rare vasculitis of small- and medium-sized vessels. It is characterized by a constant association with asthma and eosinophilia, and by the presence of anti-myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibodies (ANCA) in ~40% of the patients. Vasculitis typically develops in a previously asthmatic and eosinophilic middle-aged patient and most frequently involves the peripheral nerves and skin. Other organs, however, may be affected and must be screened for vasculitis, especially those associated with a poorer prognosis, such as the heart, kidney, and gastrointestinal tract, as assessed by the recently revised Five-Factor Score (FFS). Overall survival of CSS patients is excellent, but relapses are not uncommon and require maintenance or steroid-sparing therapies, depending on the original FFS-based prognosis at diagnosis. All patients require corticosteroids, often for prolonged periods, combined with immunosuppressants [e.g., induction (cyclophosphamide) and maintenance therapy (azathioprine)], for those with poorer prognoses. Recent insights, especially concerning clinical differences associated with ANCA status, showed that CSS patients might constitute a heterogeneous group, both clinically and pathogenically. Future therapies might reflect these differences more strongly. PMID- 21674416 TI - Alveolar hemorrhage in vasculitis: primary and secondary. AB - Diffuse alveolar hemorrhage (DAH) in primary and secondary vasculitis occurs when capillaritis is present. The diagnosis of DAH is considered in patients who develop progressive dyspnea with alveolar opacities on chest imaging (with density ranging from ground glass to consolidation) that cannot be explained otherwise. Hemoptysis, a valuable sign, is often absent. A decline of blood hemoglobin level over a few days without hemolysis or any hemorrhage elsewhere should be an alert for DAH. Bronchoalveolar lavage, retrieving bright red fluid, is the best diagnostic clue. Lung biopsy is not recommended. A search for anti neutrophil cytoplasmic autoantibodies (ANCAs) is mandatory. Once DAH is diagnosed and hemodynamic as well as infectious causes have been excluded, ANCA-associated vasculitis is taken into account (mainly microscopic polyangiitis or Wegener granulomatosis, and, exceptionally, Churg-Strauss syndrome). Drug-induced DAH, especially antithyroid drugs such as propylthiouracil may be coupled with ANCA. Isolated DAH with capillaritis with or without ANCA is rare. DAH in systemic lupus erythematosus is either associated or not with capillaritis. Treatment of DAH should target the underlying disorder. In the primary vasculitides, corticosteroids and immunosuppressants, especially cyclophosphamide, are the mainstay of therapy, but plasma exchange, particularly in severe DAH, is the rule, although evidence of its effectiveness is awaited. PMID- 21674417 TI - ANCA: associated lung fibrosis. AB - The possible link between pulmonary fibrosis, anti-neutrophil cytoplasmic autoantibody (ANCA) positivity, and vasculitis is poorly understood. During the past 6 years, five retrospective case-control studies have been published. These studies suggest that pulmonary fibrosis (PF) is an underestimated manifestation of ANCA-associated vasculitis. Common clinical characteristics include older age (around 70 years), constant positivity of myeloperoxidase (MPO)-ANCA and the poor prognosis of the pulmonary disease. The diagnosis of PF often predates the development of vasculitis. There are no significant differences of pulmonary function parameters, bronchoalveolar lavage analysis, or high-resolution computed tomographic (HRCT) findings between ANCA-associated PF and idiopathic pulmonary fibrosis (IPF). The high mortality rate of ANCA-associated PF indicates that a search for ANCAs should be performed at diagnosis in every patient with PF because the presence of ANCAs increases the risk of development of vasculitis and should promote specific monitoring of patients with positive MPO-ANCA. PMID- 21674418 TI - Pulmonary: renal syndrome with a focus on anti-GBM disease. AB - Pulmonary-renal syndrome is a potentially life-threatening combination of pulmonary hemorrhage and acute renal failure. Several pathological entities can cause this syndrome. This review discusses the diagnostic strategy required to initiate appropriate therapy. Rapid serological testing and appropriate interpretation can be of great additive diagnostic value. Also discussed are the pathogenesis, therapy, and outcome of anti-glomerular basement membrane disease, one of the pathological entities that can cause pulmonary-renal syndrome. PMID- 21674419 TI - Management of alveolar hemorrhage in lung vasculitides. AB - Alveolar hemorrhage (AH) is an important pulmonary manifestation of small vessel vasculitis because severe presentations are the most common vasculitic cause of early death. Renal vasculitis is usually present with AH; the combination is known as pulmonary-renal syndrome. Early diagnosis and intensive therapy are of particular importance to reduce early mortality and improve longer-term outcomes. The commonest immune-mediated cause of AH is anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) (80%), with other vasculitides, including systemic lupus erythematosus and anti-glomerular basement membrane disease accounting for 20%. One quarter of AAV patients develop AH, which when mild is associated with a good outcome, but mortality rises to 50% for cases with respiratory failure requiring ventilator support. The prognosis of AH in the other vasculitides is generally favorable, but cases are rare and experience is limited. Treatment follows similar regimens to those for other AAV presentations, although when severe there is widespread use of parenteral glucocorticoids together with plasma exchange. These interventions have developed empirically supported by a theoretical rationale but have not been validated by randomized clinical trials. Sepsis and cardiovascular and thromboembolic events are important early complications. and long-term follow-up is required to monitor for and prevent relapse and manage disease-related damage. A minority of cases develop on a background of pulmonary fibrosis, or progressive pulmonary fibrosis develops after vasculitis has gone into remission. PMID- 21674420 TI - Immunosuppressive and cytotoxic therapy: pharmacology, toxicities, and monitoring. AB - Treatment strategies for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are evolving. Cyclophosphamide (CYC) plus corticosteroids (CSs) is the mainstay of therapy for generalized, multisystemic AAV. Historically, the combination of CYC plus CS was used for a minimum of 12 months, but concern about late toxicities associated with CYC has led to novel treatment approaches. Currently, short-course (3 to 6 months) induction treatment with CYC plus CS, followed by maintenance therapy with less toxic agents (eg, methotrexate, azathioprine, mycophenolate mofetil) is recommended. Further, methotrexate combined with CS may be adequate for limited, non-life-threatening AAV. Recent studies suggest that rituximab may be useful for induction therapy or for CYC refractory AAV. This article reviews the key agents used to treat AAV, with a focus on pharmacology, toxicities, and monitoring. PMID- 21674421 TI - [The "Wide Awake Approach" in hand surgery: a comfortable anaesthesia method without a tourniquet]. AB - BACKGROUND: The prohibition against the use of local anaesthetics in combination with adrenaline in hand surgery focused on publications of the past is lacking. Many recent publications show good results using adrenaline in hand surgery, especially no higher rate of skin necrosis was seen. Based on this, we started using the "wide awake approach" in elective outpatient hand surgery in 2008. PURPOSE: The goals of this retrospective study are twice, to evaluate a) whether the use of local anaesthesia with adrenalin in selected outpatient hand surgical procedures will not - as reported in the recent literature - lead to a high complication rate, and b) the patient?s satisfaction with the 'wide awake approach". PATIENTS AND METHODS: From 2/2008 to 1/2009 151 patients underwent carpal tunnel release, release of the first extensor compartment, and trigger finger release using the "wide awake approach" without use of a tourniquet. The mixture for local anaesthesia was lidocain 1% together with adrenaline (1:100 000). In spring 2009 the patients answered a questionnaire with items about pain (VAS), comfort and complications. In addition the patients were asked, whether they would choose the "wide awake approach" again. RESULTS: We received 119 questionnaires (78.8%). Pain during injection of the local anaesthetics was on average 2.86 (0-10) at the VAS, and 0.88 (0-10) during the procedure itself. 12 patients (10%) needed a second shot of the local anaesthetics. 95 (79.9%) patients felt "extremely well" or ""well", 24 (20.1%) felt ""less well" or "extremely less well" during the operation. 83% of the patients would choose this form of anaesthesia again, if a further operation is necessary; 9% would prefer another form of anaesthesia. CONCLUSION: The so called "wide awake approach" with the use of local anaesthetics added with adrenaline in the elective hand surgery is a safe and comfortable anaesthesia method. There are no valid reasons to adhere to the prohibition against the use of local anaesthetics with adrenaline in hand surgery. PMID- 21674422 TI - [Current standards in surgery - the lead topic of the 35th Berlin Surgeons Congress held in Brandenburg an der Havel on September 2 and 3, 2010]. PMID- 21674423 TI - [Successful implementation of an "in-hospital resuscitation team" in a university hospital]. AB - BACKGROUND AND OBJECTIVE: Resuscitation is the most important emergency action in a life-threatening cardiopulmonary arrest. The organizational, personnel and equipment requirements for an optimal treatment of emergency patients in a university hospital are described, as well as the short- and mid-term results. PATIENTS AND METHODS: Retrospective analysis of 132 cases of cardiopulmonary resuscitation based on a two-pages reporting form whose completion by the involved physician and intensive care nurse is mandatory after each event. RESULTS: About 65 % of all events were triggered by cardiac and respiratory causes. In 50 % of all cases there was an acute life-threatening situation, requiring an intubation in 46 % and mechanical reventilation in 42 % of all cases. One third of all patients who were successfully reanimated were discharged alive from hospital after the intensive care treatment. CONCLUSION: A well organized and adequately equipped resuscitation team is the basis for achieving optimal chances of survival in life-threatening emergencies. This is especially so in large university hospitals with often care for patients with multiple morbidities. PMID- 21674424 TI - [Multiple Sister Mary Joseph's nodules in a patient with gastric cancer]. AB - HISTORY AND CLINICAL FINDINGS: A 52-year-old patient presented with a 6-months history of painful, progressive erythematous periumbilical papules and nodules. Seven months previously, an advanced stage of an adenocarcinoma of the stomach with peritoneal carcinosis and malignant ascites had been diagnosed. INVESTIGATIONS: Clinical examination showed ten firm, painful, umbilicated, erythematous, polygonal papules and nodules (size up to 7 mm), partly covered with central hemorrhagic crusts or scales. The histological examination revealed epithelial cell clusters infiltrating the dermis and forming tubular structures. The prominent nuclei varied in size, some were vacuolated. Signet ring structures were visible in the tumor. Immunohistochemical staining revealed MNF116 expressing tumor cells, consistent with a moderately differentiated adenocarcinoma. DIAGNOSIS: Multiple Sister Mary Joseph's nodules - periumbilical skin metastases from gastric carcinoma. TREATMENT AND COURSE: The previous palliative chemotherapy with capecitabine will be expanded by irinotecan after completion of local iradiation of an esophageal stenosis. The patient declined additional local therapeutic options such as excision or electric chemotherapy. CONCLUSION: Sister Mary Joseph's nodule is a rare, umbilical cutaneous metastatic tumor originating from advanced metastatic intraabdominal or intrapelvic malignancies. Our case is remarkable because of the number of the umbilical and periumbilical, but otherwise characteristic nodules. Sister Mary Joseph's nodules are associated with a dismal prognosis. As they may precede cancer diagnosis, histological investigation of suspect umbilical nodules should be performed. PMID- 21674425 TI - [74 year-old man with dyspnea and edema of the lower legs. Restrictive pericarditis]. PMID- 21674426 TI - [Asymptomatic aortic stenosis]. AB - In patients with symptomatic severe aortic stenosis (AS) therapeutic decision is straightforward and aortic valve replacement is strongly recommended. In asymptomatic AS patients clinical strategy is controversial and challenging. Prospective studies suggest a watchful waiting approach in the majority of patients with regular follow-up exams. Defining symptomatic status related to the disease can be particularly difficult in the elderly and patients with comorbidities. A robust measurement of AS severity is mandatory in this context. Nevertheless some patients with asymptomatic AS benefit from early valve replacement and reliable risk stratification for identification of high-risk patients is of importance. This review article will outline relevant clinical studies and guidelines on management of asymptomatic AS patients. PMID- 21674427 TI - [Meeting the needs of the European working time directive in german medical profession]. AB - The legal obligation of the European Working Time Directive with its implementation into a German Working Hours Act requires German hospitals to give up old structures and requires the implementation of new working time models. The failure of the revision of the European Working Time Directive in April 2009 prevented that any changes of status quo might happen in the near future. Fundamental terms of the working law for the medical area have been elucidated and have been implemented into concrete calculation formulas. The planned working time has been clearly determined. Particularly, on-call duties and a signed "OptOut-declaration" have huge effects on the upper limit of the working time that is to be determined. Shift duty leads to the greatest limitations of the upper limit of the working time. The Working Hours Act defines the maximal, available, individual working time budget and thus the working time budget of a hospital and it limits the maximal availability of the service providers of a hospital as well as defining the maximal personnel costs. Transparency in this area lays the foundation for an effective time management and the creation of new working time models in accordance with the European Working Time Directive as well as the Working Hours Act and the "TVA" (labour contract for doctors at municipal hospitals). It is possible, with the knowledge of the maximal working time budget and the thereof resulting personnel costs, to calculate the economical revenues better. The reallocation of the working time of doctors enables efficiency enhancement. It is necessary to demand a clear definition of the tasks of doctors with the consequential discharge of tasks that should not/do not belong to the responsibilities of a doctor. This would lead to a more attractive working environment for doctors at hospitals and thus to an improvement of the care of the patients. The implementation of the European Time Directive is not to be seen as unrealizable, as has been generally heard; instead, it enables the urgently necessary structural reform at German hospitals. PMID- 21674428 TI - [Antithrombotic therapy in patients with atrial fibrillation: a comment on the European guidelines]. PMID- 21674430 TI - [Rapid thoracic swelling]. PMID- 21674431 TI - [The ergometry stress test and its interpretation]. PMID- 21674432 TI - Leukoencephalopathy with vanishing white matter: serial MRI of the brain and spinal cord including diffusion tensor imaging. AB - Vanishing white matter disease (VWM) is one of the most frequent inherited childhood white matter disorders. We present the brain and spinal cord disease progression on serial conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in a 4-year-old boy. Consecutive MRI examinations demonstrated a progression of the signal abnormalities in the cerebral white matter. Globally, apparent diffusion coefficient (ADC) values as well as axial and radial diffusivity increased over time, while fractional anisotropy (FA) values decreased. Involvement of the cervical posterior spinal tracts and mild global spinal cord atrophy was found. In conclusion, serial MRI and DTI studies may help to better understand the selective injury of the myelin and axons in VWM disease. These data may help in monitoring disease progression. Our data also show that complete neuroimaging work-up in VWM should also include the spinal cord. PMID- 21674433 TI - A quarter century of pharmacognostic research on Panamanian flora: a review. AB - Panama is a unique terrestrial bridge of extreme biological importance. It is one of the "hot spots" and occupies the fourth place among the 25 most plant-rich countries in the world, with 13.4 % endemic species. Panamanian plants have been screened for a wide range of biological activities: as cytotoxic, brine shrimp toxic, antiplasmodial, antimicrobial, antiviral, antioxidant, immunosuppressive, and antihypertensive agents. This review concentrates on ethnopharmacological uses of medicinal plants employed by three Amerindian groups of Panama and on selected plants with novel structures and/or interesting bioactive compounds. During the last quarter century, a total of approximately 390 compounds from 86 plants have been isolated, of which 160 are new to the literature. Most of the work reported here has been the result of many international collaborative efforts with scientists worldwide. From the results presented, it is immediately obvious that the Panamanian flora is still an untapped source of new bioactive compounds. PMID- 21674434 TI - Sharing the benefits of biodiversity: a new international protocol and its implications for research and development. AB - Equitable sharing of the benefits of biodiversity is one of the main objectives of the Convention on Biological Diversity (CBD). Yet understanding of the CBD rules and principles on access and benefit sharing, as well as how they apply to biodiversity-based research and development remains limited. In October 2010, the CBD adopted additional rules on access and benefit sharing. These rules--known as the Nagoya Protocol--provide clarification on several important issues, including the applicability of access and benefit sharing to research on biochemical compounds and processes. As a result, the Nagoya Protocol constitutes an important opportunity for institutions, organizations, and companies committed to ethical practices regarding biodiversity. PMID- 21674435 TI - Cytotoxicity of ethanolic extracts of Artemisia annua to Molt-4 human leukemia cells. AB - Although dihydroartemisinin (DHA) and other artemisinin derivatives have selective toxicity towards cancer cells, Artemisia annua (A. annua) extracts containing artemisinin have not been evaluated for their anticancer potential. Our main goal was to assess the anticancer effect of ethanolic leaf extracts of A. annua from Brazilian and Chinese origins (with DHA as a comparison) on normal and cancer cells. Leukocytes and leukemia (Molt-4) cells were counted at 0, 24, 48, and 72 hr after treatment with extracts having artemisinin concentrations of 0, 3.48, 6.96, and 13.92 ug/mL. Also, we assessed the antioxidant capacity of these extracts using the oxygen radical absorbance capacity (ORAC) test. Both extracts had high antioxidant capacity and toxicity towards Molt-4 cells. DHA was significantly more potent (p < 0.05) in killing Molt-4 cells than Brazilian extract at 48 and 72 hr and Chinese extract at 72 hr. In Molt-4 cells, LD50 values for Brazilian and Chinese extracts were comparable at all time points and not significantly different from DHA at 24 hr. In leukocytes, DHA, Chinese extract, and Brazilian extract had LD50 values of 760.42, 13.79, and 28.23 ug/mL of artemisinin, respectively, indicating a better safety index for the Brazilian extract compared to that of the Chinese extract at 24 hr. However, at 48 and 72 hr, the toxicity in leukocytes for any of the treatment groups was not significantly different. These experiments suggest that these extracts may have potential application in cancer treatment. PMID- 21674436 TI - Comparative analyses of chromatographic fingerprints of the roots of Polygonum multiflorum Thunb. and their processed products using RRLC/DAD/ESI-MS(n). AB - The dried roots of Polygonum multiflorum Thunb. (Heshouwu) and their processed products (Zhi-heshouwu) are widely used in traditional Chinese medicine, yet their therapeutic effects are different. Previous investigations focused mainly on the differences between Heshouwu and Zhi-heshouwu in the contents of several known compounds. In this study, a rapid resolution liquid chromatography-diode array detection/electrospray ionization tandem mass spectrometry (RRLC/DAD/ESI MS(n)) method was developed for the comparative analysis of the components of Heshouwu and Zhi-heshouwu. A total of 23 compounds were identified or tentatively characterized. We found that 16 batches of Heshouwu and 15 batches of Zhi heshouwu samples shared eight compounds, including gallic acid; 3,5,4' tetrahydroxylstilbene-2,3-di-O-glucoside, CIS-2,3,5,4'-tetrahydroxylstilbene-2-O- beta-D-glucoside, trans-2,3,5,4'-tetrahydroxylstilbene-2-O- beta-D-glucoside, emodin-8-O- beta-D-glucoside, physcion-8-O- beta-D-glucoside, emodin, and physcion. Nevertheless, the relative amounts of gallic acid, emodin, and physcion were very high in Zhi-heshouwu samples compared to those in Heshouwu samples. Six compounds disappeared after processing and were unique for Heshouwu: catechin, flavanol gallate dimer, polygonimitin B, emodin-1-O-glucoside, emodin-8-O-(6'-O malonyl)-glucoside, and physcion-8-O-(6'-O-malonyl)-glucoside. Three compounds were unique for Zhi-heshouwu: hydroxymaltol, 2,3-dihydro-3,5-dihydroxy-6-methyl 4(H)-pyran-4-one, and 5-hydroxymethyl furfural. These results suggest that the types and relative amounts of the chemical components of Heshouwu and Zhi heshouwu are different. PMID- 21674437 TI - Differentiation of Cuscuta chinensis and Cuscuta australis by HPLC-DAD-MS analysis and HPLC-UV quantitation. AB - Cuscuta chinensis and Cuscuta australis, the two botanical sources of the Chinese herbal medicine Tu-Si-Zi, were distinguished from each other based on qualitative and quantitative chemical analysis. By HPLC-DAD-MS, a total of 36 compounds were characterized from these two Cuscuta species, including 14 flavonoids, 17 quinic acid derivatives, and 5 lignans. In addition, HPLC-UV was applied to determine seven major compounds (6 flavonoids plus chlorogenic acid) in 27 batches of Tu-Si Zi. The results revealed that the amounts of the three classes of compounds varied significantly between the species. C. australis contained more flavonoids but less quinic acid derivatives and lignans than C. chinensis. Particularly, the amounts of kaempferol and astragalin in C. australis were remarkably higher than in C. chinensis. This finding could be valuable for the quality control of Tu-Si Zi. PMID- 21674438 TI - Medicinal plants from Jordan in the treatment of diabetes: traditional uses vs. in vitro and in vivo evaluations--part 2. AB - Diabetes mellitus is the most common metabolic disorder affecting millions worldwide. It is recognized as a global major health problem. As alternatives to the available orthodox medicines, plants are considered a potential source for the treatment of diabetes within traditional ethnomedicine practices. In the Jordanian traditional medicine a significant selection of ethnobotanicals is promoted for their antidiabetic activity. Literature surveys demonstrate the benefit of several ethnobotanicals as antidiabetic agents evaluated in in vitro and in vivo systems in the form of their crude extracts and/or isolated pure compounds with varying degrees of hypoglycemic or antihyperglycemic bioactivities. This mini review discusses the preparatory forms in which these plants are consumed, their reported phytoconstituents, and the results of their reported antidiabetic bioactivity. PMID- 21674439 TI - Five new diarylpropan-1-ols from Combretum yunnanense. AB - Five new 1,3-diarylpropan-1-ols, combretol A-E (1- 5), together with one known coumarin (6) and ten known triterpenes (7-16), were isolated from Combretum yunnanense. Their structures were determined by spectroscopic investigation, including 1H and 13C NMR, NOESY, HSQC, HMBC, and HRESIMS analyses. This is the first report on the occurrence of 1,3-diarylpropan-1-ols and coumarin in the Combretum genus including C. yunnanense. Also, to the best of our knowledge, 1,3 diarylpropan-1-ols are rare in nature. PMID- 21674440 TI - Drimane-type sesquiterpenes from Polygonum hydropiper. AB - One new drimane-type sesquiterpenoid, 3 beta-angeloyloxy-7-epifutronolide (1), and one new natural product, polygonumate (2), along with six known drimane-type sesquiterpenes [dendocarbin L (3), (+) winterin (4), (+) fuegin (5), changweikangic acid A (6), futronolide (7), and 7-ketoisodrimenin (8)] were isolated from the whole plant of Polygonum hydropiper Linn. Their structures were determined using spectroscopic techniques. Single-crystal X-ray diffraction study on dendocarbin L (3) and 13C-NMR spectroscopic data of (+) winterin (4) are described for the first time. Compound 6 was evaluated for inhibitions of alpha chymotrypsin, acetylcholinesterase, and butyrylcholinesterase enzymes. PMID- 21674441 TI - Cytotoxic furanogermacranolides from the flowers of Helianthus angustifolius. AB - The dichloromethane extract of the flowers of Helianthus angustifolius L. (Asteraceae, Heliantheae) was investigated in vitro for its cytotoxic activity using human cancer cell lines: CCRF-CEM leukemia, MDA-MB-231 breast cancer, U251 glioblastoma, HCT 116 colon cancer cells, and the human lung fibroblast cell line MRC-5. Cytotoxicity-guided fractionation led to the isolation of four related heliangolide-type sesquiterpene lactones. The structures were elucidated by means of NMR spectroscopy and high-resolution mass spectrometry. Of the investigated compounds, 8-methacrylyl-4,15-iso-atriplicolide (1) showed the highest activity against all tested cancer cell lines with IC50 values ranging from 0.26 +/- 0.01 uM for CCRF-CEM cells to 4.22 +/- 0.26 uM for MRC-5 cells. PMID- 21674442 TI - Cytotoxic triterpenoids from Azadirachta indica. AB - Two new tirucallane triterpenoids, 24,25-epoxy-3 beta-hydroxy-20-oxo-7 tirucallene (1) and 22,23;24,25-diepoxy-3 beta-hydroxy-7-tirucallene (2), and a new tetranortriterpenoid, 4 alpha-hydroperoxy-6- O-acetylnimbandiol (3), along with eight known compounds, were isolated from the branches and leaves of Azadirachta indica. Their structures were elucidated through spectroscopic and chemical methods. The cytotoxic assay showed that the abundant constituent nimbolide (8) had obvious cytotoxic activities against HL-60, SMMC7721, A549, MCF 7, and SW-480 cell lines, with IC50 values of 0.8 +/- 0.1, 2.2 +/- 0.2, 1.9 +/- 1.3, 4.5 +/- 1.1, and 2.3 +/- 0.1 uM, respectively. PMID- 21674443 TI - [Reconstruction of isolated axillary nerve lesions: clinical and electrophysiological long-term results]. AB - PURPOSE: The purpose of this retrospective study was the clinical and electrophysiological assessment of long-term results following surgical treatment of isolated axillary nerve lesions. PATIENTS AND METHOD: 10 patients, who underwent axillary nerve reconstruction using a nerve graft (80%) or a neurolysis alone (20%), with a follow-up period of 6.7 years (1.6-10.8 years) on average, were included in the study. In addition to the clinical examination, we examined reinnervation by electrophysiological methods and analysed their correlation to clinical results. RESULTS: 30% of the patients had muscle strength of M5 and full active range of motion of 180 degrees , 40% reached M4 and averaged 170 degrees (80-180 degrees ), 30% of the patients M3 and 65 degrees (40-90 degrees ). In patients with M5, muscle compound action potential averaged 40% of the contralateral side (21-62%), in patients with M4 36% (29-58%), and in patients with M3 7% (3-11%). Good results were associated with younger patient age, a short delay prior to the operation and neurolysis alone (indicated by intraoperative electroneurography). CONCLUSION: The good results confirm our treatment algorithm for isolated axillary nerve lesions by neurolysis alone or reconstruction with autologous nerve transplantation. Measurement of compound muscle action potential is a valuable addition to difficult clinical assessment, as its amplitude enables quantification of axillary nerve recovery. PMID- 21674444 TI - [Neurostimulation and localization]. PMID- 21674445 TI - [Positive life events and mood disorders: longitudinal evidence for a chaotic life-course hypothesis]. AB - BACKGROUND: In psychiatric research it is often assumed that detrimental effects of negative life events on mental health can be buffered by a number of positive life events. However, there is no convincing empirical evidence that this assumption is correct; it can even be argued that positive life events act as additional stressors rather than as buffers, leading to a continuation of a chaotic life course and an increase in the risk of affective disorders. AIM: To find out whether positive life events were associated with a higher risk of the occurrence of mood disorders and whether such an association could be explained by a number of negative life events that individuals had experienced. METHOD: We used data from 4,796 adults, aged 18-64, collected at two measurement moments (i.e. 1997 and 1999) of NEMESIS, a Dutch prospective-epidemiological study. As a basis for our measurements we used dsm-iii-r diagnoses of major depressive disorders and dysthymia and the Life Events and Difficulties Schedules LEDS. RESULTS: A multivariate (MPlus) path analysis demonstrated that positive life events were not, in themselves, significantly predictive of affective disorders. Positive life events were only related to the risk of mood disorders when they co occurred with a high number of negative life events. CONCLUSIONS: In accordance with a chaotic life-course hypothesis, positive events were not found to buffer the detrimental impact of negative life events, but when they are part of an erratic course of life they can pose an extra threat to an individual's mental health. PMID- 21674446 TI - [Group treatment of violent adolescents at a forensic psychiatric clinic: first results]. AB - BACKGROUND: Up till now in the Netherlands no controlled studies haven been published regarding the effect of outpatient treatment of violent adolescents at a psychiatric clinic. AIM: To investigate in an explanatory study the results of group treatment of violent adolescents (aggression control therapy) performed at the forensic outpatient clinic 'het Dok' in Rotterdam. METHOD: First of all, personality traits and problem behaviours of the patients were compared with those of a group of secondary vocational students. Then we compared the traits and behaviour of those who completed the treatment with those of the patients who dropped out. In order to determine the therapy results, patients were measured at three moments; during uptake, at the beginning of treatment and at the end of treatment. RESULTS: Patients appeared to score significantly higher on the trait anger and on hostility than the secondary vocational students but significantly lower on social anxiety. Patients who completed the therapy scored significantly lower on psychopathy than the patients who dropped out early. During the waiting list period there was no change in the problem behaviours of the patients. Patients who completed the therapy demonstrated significant decrease in physical aggression. However, the size effect appeared to be small. CONCLUSION: Aggression control therapy at a forensic psychiatric outpatient clinic seems to result in a significant decrease in self-reported physically aggressive behaviour in violent adolescents. PMID- 21674447 TI - [Transcranial magnetic stimulation as a treatment for depression]. AB - BACKGROUND: The high incidence of depressive disorder in the Netherlands calls for additional forms of therapy. Transcranial magnetic stimulation (TMS) is a form of non-invasive brain stimulation that has been investigated in the last 15 years in order to find out whether this form of stimulation is effective in the treatment of depression. AIM: To discover whether TMS has proved effective in the treatment of depressed patients. RESULTS: Results show that tms treatment is safe when applied to the frontal lobes of the cerebral cortex and that the therapeutic effect is comparable to the effect of psychotherapy and antidepressants. Future studies should concentrate on an increase in efficiency by providing more insight into the working mechanisms and the effect of individual differences. Follow-up studies are needed to investigate the duration of the antidepressive effect. CONCLUSION: TMS seems to be a promising tool for the treatment of depressive disorders. However, there are many questions and uncertainties about the efficiency and applicability of TMS. PMID- 21674448 TI - [A theoretical model for transcultural psychiatry]. AB - BACKGROUND: Patients of non-Western origin quite often fail to complete their course of treatment. The reasons are generally unclear. aim To suggest ways of tackling the problems in transcultural psychiatric practice. METHOD: A theoretical model is presented, derived from clinical practice. The model provides insight into essentials of transcultural psychiatry. The model is based on the following: two interpretations of the concept of culture, an elaboration of the university-relativity dichotomy and a subdivision of the clinician's work into three sections. These sections are: building a trusting relationship, making a diagnosis and carrying out treatment suited to the patient's needs. RESULTS: The psychiatrist's attitude to his patient varies according to the phase of treatment, sometimes it is more relativistic, at other times it is more universalistic. CONCLUSION: The compliance of non-Western patients will probably increase when the clinician adopts a more relativistic approach during the phase of building a relationship with the patient and probably also during some parts of the treatment phase so that he can come closer to meeting the patient's expectations. PMID- 21674450 TI - ['Histrionic personality disorder with regression and conversion': a meningioma]. AB - A 47-year-old woman, who was believed to be suffering from histrionic personality disorder with regression and conversion, was finally diagnosed with a frontal meningioma. Patients with meningiomas can present with a variety of psychiatric symptoms, sometimes even before neurological symptoms occur. The diagnosis is often delayed because the symptoms are misleading and it is difficult to modify a psychiatric diagnosis once this has been made. Discussion focuses on the characteristic signs of a meningioma, the reasons for delays in diagnosis and the indications for brain-imaging on psychiatric patients. PMID- 21674449 TI - [Can I have some sunshine to cheer me up? vitamin D deficiency and depression in the elderly]. AB - Vitamin D deficiency is very common in the elderly, and the geriatric patient is probably at even greater risk. Vitamin D plays an important role in calcium homeostasis; recent studies point to a possible causal link between vitamin D deficiency and the development and severity of depression. In this article we focus on an 80-year-old patient with depression and severe vitamin D deficiency and give advice on the diagnosis and treatment of vitamin D deficiency. To supplement the current multidisciplinary guidelines on depression, we recommend routine testing of serum vitamin D level prior to confirming the diagnosis of depression in the elderly. PMID- 21674451 TI - [Reaction on 'two subjects, each with a brain lesion and each prone to criminal behaviour: a plea for the involvement of a behavioural neurologist in the forensic psychiatric evaluation of such cases']. PMID- 21674452 TI - [Reaction on 'beat the blues']. PMID- 21674453 TI - Ultrasound-guided puncture of the femoral artery for total percutaneous aortic aneurysm repair. AB - PURPOSE: The purpose of this study was to evaluate the outcomes of ultrasound guided femoral artery access for total percutaneous endovascular repair of abdominal and thoracic aortic aneurysms. MATERIALS AND METHODS: Total percutaneous aneurysm repair of the abdominal and thoracic aorta was performed in 52 consecutive patients (46 males, 6 females; mean age, 64.6+/-16 years; age range, 24-93 years) in a total of 85 access arteries. Of the aortic aneurysms repaired, 33 were abdominal, and 19 were thoracic. Ultrasound- guided puncture of the access artery was performed in all patients. The access artery was closed with a Prostar XL device at the end of the procedure. RESULTS: The outer diameter of the vascular sheaths or the stent graft system ranged from 14 F to 27 F. All but one patient achieved successful closure of the arterial puncture with the closure device. One patient required surgical cutdown because of device failure. Two patients required long-duration manual compression. Technical success was achieved in 49 patients (94%). Forty-five patients (87%) were discharged on the first postoperative day. There were no complications of the access arteries one day or one month postoperatively, as determined by ultrasonography and computed tomography examinations, respectively. The mean diameters of the access arteries prior to and one month after the procedure were unchanged, as demonstrated by computed tomography. CONCLUSION: Ultrasound-guided puncture of the common femoral artery for percutaneous closure of the access site has a high technical success rate and a very low complication rate. The addition of ultrasound guidance decreases the difficulty of the procedure and helps to avoid some of its complications. PMID- 21674454 TI - AIDS-related primary Kaposi sarcoma of the nasopharynx. AB - Primary nasopharyngeal Kaposi sarcoma is extremely rare, as only 1 case has been previously reported in the literature. We report a new case, which occurred in a 37-year-old man with a known history of acquired immune deficiency syndrome (AIDS). The patient presented with complaints of recurrent epistaxis and postnasal hemorrhage. Endoscopic examination detected a bluish, smooth, firm, nonpulsatile mass in the nasopharyngeal wall. Histopathologic findings on biopsy were consistent with Kaposi sarcoma. The tumor was successfully treated with radiotherapy. Kaposi sarcoma should be considered in the differential diagnosis of any AIDS patient who presents with recurrent unilateral nasal bleeding. PMID- 21674455 TI - Aggressive fibromatosis of the neck treated with a combination of chemotherapy and indomethacin. AB - Aggressive fibromatosis (desmoid tumor) of the neck is rare. When feasible, surgery is the best treatment option. However, complete excision with negative margins is not possible in most cases because of the involvement of vascular and nervous structures. Also, surgery results in poor functional and aesthetic outcomes. Sometimes debulking surgery with positive margins is performed, but the anatomy of the neck is a challenge for oncologic surgeons, and recurrences are not uncommon. Radiotherapy is seldom employed for the same reasons. On the other hand, systemic treatment with chemotherapy, hormone therapy, and noncytotoxic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) has been used with good results. We report a case of inoperable aggressive fibromatosis of the neck that was successfully treated for about 21 months with a combination of chemotherapy and the NSAID indomethacin. As far as we know, this is the first reported use of a combination of chemotherapy and an anti-inflammatory drug in the treatment of aggressive fibromatosis of the neck. We also review the literature on cases of aggressive fibromatosis of the neck that have been reported over the past 12 years. PMID- 21674456 TI - Osteomyelitis of the temporal bone in identical twin infants. AB - Osteomyelitis of the skull base almost always occurs in elderly patients with diabetes; however, it may occur in patients with compromised immune function regardless of their age. We present the cases of a pair of immunocompetent, 2 year-old identical twins who experienced osteomyelitis of the temporal bone almost exactly 1 year apart. An incident such as this, in this age group, has never been reported in the literature. PMID- 21674457 TI - An unusual cause of foreign-body sensation in the throat: a displaced superior cornu of the thyroid cartilage. AB - Foreign-body sensation is a nonspecific symptom of aerodigestive tract diseases. We describe the case of a 42-year-old man who presented with a foreign-body sensation in the throat that was found to be caused by a displaced superior cornu of the thyroid cartilage. Such a displacement is not well known, but we believe that it may not be rare. These cases can be overlooked and misdiagnosed as chronic nonspecific pharyngitis or laryngopharyngeal reflux. However, a careful laryngoscopic examination by an otolaryngologist who considers the possibility of such a pathology may result in an accurate diagnosis, which might spare an affected patient from a lifelong pharmacotherapeutic regimen. PMID- 21674458 TI - Ectopic canine associated with a dentigerous cyst in the maxilla. AB - Ectopic eruption of a tooth is common in the dental arch, palate, and nose, but it is rare in the maxillary antrum. We present the case of a 35-year-old man with an ectopic canine and an associated dentigerous cyst in the maxillary sinus that masqueraded as an antrochoanal polyp. PMID- 21674459 TI - Lateral sinus thrombosis in children: a review. AB - A retrospective study was undertaken to review the clinical presentation, evaluation, management, and outcome of otogenic lateral sinus thrombosis (LST) in children. All pediatric patients with LST seen in our department between 1999 and 2007 were included; there were 9 cases involving 6 boys and 3 girls whose ages ranged from 8 to 12 years. They had all been treated with antibiotics elsewhere prior to admission, and the duration of symptoms before admission ranged from 5 to 18 days. The most common presenting symptoms were ear discharge, headache, otalgia, and fever. Radiologic evaluation included computed tomography and magnetic resonance imaging. All patients underwent radical mastoidectomy with incision of the lateral sinus and removal of its content. There were no deaths. Pseudomonas and Proteus spp were the most commonly identified organisms. Otogenic LST still poses a serious threat that warrants immediate attention and care. It is often associated with other intracranial complications, such as cerebellar abscess. Computed tomography and magnetic resonance imaging play an important role in the management of this disease. Early and aggressive surgical intervention of this otogenic complication can potentially minimize mortality. PMID- 21674460 TI - Otomyiasis of the mastoid cavity: an unusual complication of cotton-swab use. PMID- 21674461 TI - Self-induced subcutaneous facial emphysema in a prisoner: report of a case. AB - Subcutaneous cervicofacial emphysema is a rare condition that results from various causes. Initially it might be misdiagnosed and managed as other clinical entities, such as angioedema. We report a case of self-induced subcutaneous facial emphysema in a prisoner who sought better living conditions by simulating an emergency. PMID- 21674463 TI - The cost-effectiveness of specific allergen immunotherapy. PMID- 21674462 TI - Nasopharyngeal dendritic cell sarcoma, not otherwise specified, in a 34-year-old man. AB - Dendritic cell sarcoma, not otherwise specified (NOS), is an entity that is poorly defined because of its rarity and poorly understood pathogenesis. It is characterized by positive immunohistochemical staining for S-100 and CD1a, along with an absence of cytoplasmic Birbeck granules on electron microscopy. We report the case of a surgically inaccessible nasopharyngeal dendritic cell sarcoma, NOS, in a 34-year-old man. Treatment with chemotherapy along with adjuvant radiation therapy was successful in decreasing the size of the nasopharyngeal mass, and the patient remained free of any evidence of recurrence nearly 5 years after treatment. PMID- 21674464 TI - Endoscopic view of bilateral Haller cell ostia. PMID- 21674465 TI - Bilateral vocal fold polyps with occult sulcus mucosal bridge. PMID- 21674466 TI - Cervicothoracic malignant peripheral nerve sheath tumor. PMID- 21674467 TI - A simple method of earlobe lesion excision and repair. PMID- 21674468 TI - Is virtual endoscopy of the middle ear useful? AB - Virtual endoscopy is a relatively new imaging technology in otology, and therefore data on its efficacy in clinical situations are limited. We conducted a prospective study to evaluate the clinical relevance of radiologic diagnoses based on virtual endoscopy of the middle ear. Our patient population was made up of 30 adults who were scheduled to undergo surgery to correct conductive hearing loss of unknown etiology. Virtual endoscopy was performed on three-dimensional images that were constructed from images obtained with conventional two dimensional computed tomography (CT). Findings on virtual endoscopy were then compared with the subsequent surgical findings. Virtual endoscopy suggested a middle ear pathology in 19 patients and a normal middle ear in 11 patients. Postoperatively, we found that the virtual diagnoses correlated moderately well with the surgical findings in the group of patients with predicted pathology; 13 of these 19 patients were found to have middle ear problems such as ossicular chain anomalies, otosclerosis, and cholesteatoma (positive predictive value: 68%). However, among the 11 patients whose middle ear structures were radiologically predicted to be normal, only 2 had negative middle ear findings on surgical exploration; of the remaining 9 patients, 8 had otosclerosis and 1 had malleus fixation (negative predictive value: 18%). Thus, the sensitivity and specificity of virtual endoscopy were 59 and 25%, respectively. Virtual endoscopy provides images from a surgeon's perspective, and so it has the potential to be useful in the preoperative evaluation of the middle ear cavity. With ongoing advancements in computer systems and imaging techniques, the cost, reliability, and efficacy of virtual endoscopy may improve. However, further clinical validation and cost-benefit analysis are required before we can determine if it has any additional advantages over conventional two-dimensional CT. PMID- 21674469 TI - Comparison of maxillary sinus specimens removed during Caldwell-Luc procedures and traditional maxillary sinus antrostomies. AB - The cases of 80 patients who underwent Caldwell-Luc surgery for the treatment of chronic rhinosinusitis between 2002 and 2007 at Vanderbilt University Medical Center's Department of Otolaryngology were reviewed. Data on demographics, comorbidities, details of surgery, surgical pathology, and histology were collected. These data were compared with those of 40 patients who underwent standard functional endoscopic sinus surgery in 2007. Statistically significant differences were found in terms of mean patient age, sex, mean number of sinuses surgically addressed, number of prior surgeries, and tissue eosinophil counts. Microscopic examination revealed the presence of "necrotic bone" in 2 Caldwell Luc specimens, and "necrotic debris" in 2 other Caldwell-Luc specimens. No similar finding was seen in the control group. Caldwell-Luc is a surgery of last resort for patients who fail aggressive interventions for maxillary sinus disease. The mucosal lining of this small group of patients appears to be different from that of patients who respond favorably to functional endoscopic sinus surgery. PMID- 21674470 TI - Reconstruction of the paralyzed face. AB - Facial nerve paralysis can be difficult to treat because it presents a variety of functional, aesthetic, and psychosocial challenges. The goals of treatment include facial symmetry at rest, corneal protection, oral competence, restoration of voluntary and spontaneous facial movements, and minimal synkinesis. A multitude of static and dynamic procedures have been used to achieve these goals. Facial nerve reapproximation or interpositional grafting is associated with the best end results. The results of dynamic procedures are generally better than those of static procedures. Optimal reconstruction of the paralyzed face usually requires multiple surgeries with both types of procedures. Patients must be extensively counseled regarding expected results before they embark on what is an oftentimes lengthy reconstructive process. In this article, we discuss the anatomy of the facial nerve, the etiologic factors associated with facial nerve paralysis, the evaluation of the patient with facial paralysis, and the various surgical options for static and dynamic reconstruction of the paralyzed face. We also review the literature. PMID- 21674471 TI - Discrete-choice preference comparison between patients and doctors for the surgical management of oesophagogastric cancer. AB - BACKGROUND: Establishing preferences for surgery is paramount to preoperative patient counselling. This study aimed to prioritize and compare preferences of patients and doctors towards surgery for oesophagogastric cancer, to aid the counselling process. METHODS: A discrete-choice questionnaire containing hypothetical scenarios was designed to test patient preferences for six treatment attributes: mortality, morbidity, quality of life (QoL), cure rate, hospital type and surgeon's reputation. The survey was mailed to all patients who underwent oesophagogastric cancer resection from 2008 to 2009 at two teaching hospital sites. All doctors at these sites with previous experience in counselling patients for cancer surgery were also identified and presented with the survey. Results were analysed using a random-effects probit regression model. Spearman correlation was used to compare participants' implicit choices from the discrete choice scenarios (their true preferences) with their explicit choices from the direct ranking of preferences (their perceived preferences). RESULTS: Eighty-one patients and 90 doctors completed the survey. Some 15 per cent of patients and 31 per cent of doctors based their choices solely on QoL. In order of importance, patients based their implicit responses on QoL (beta = 1.19), cure rate (beta = 0.82), morbidity (beta = - 0.70), surgeon's reputation (beta = 0.60), mortality (beta = - 0.57) and hospital type (beta = 0.26). Doctors similarly indicated QoL (beta = 1.14) and hospital type (beta = 0.31) as highest and lowest preferences respectively, but placed far greater emphasis on mortality (beta = - 0.80) than morbidity (beta = - 0.35). Implicit and explicit preferences correlated only for morbidity and surgeon's reputation in the patient cohort. CONCLUSION: Clinicians may better meet patients' expectations and facilitate informed decision-making if QoL, cure rate and morbidity are emphasized foremost. A similar study employing preoperative patients is warranted for further clarification of preferences. PMID- 21674472 TI - Discrete-choice preference comparison between patients and doctors for the surgical management of oesophagogastric cancer (Br J Surg DOI: 10.1002/bjs.7537). PMID- 21674473 TI - Systematic review and meta-analysis on the rate of postoperative venous thromboembolism in orthopaedic surgery in Asian patients without thromboprophylaxis. AB - BACKGROUND: Postoperative venous thromboembolism (VTE) is a common life threatening complication after surgery. This review analysed the rate and mortality of VTE after orthopaedic surgery in Asia. METHODS: Inclusion criteria were: prospective study; deep vein thrombosis (DVT) diagnosed by venography or ultrasonography; hip fracture surgery (HFS), total hip arthroplasty (THA) or total knee arthroplasty (TKA); and no thromboprophylaxis. The pooled proportion was back-calculated by Freeman-Tukey variant transformation, using a random effects model. RESULTS: Twenty-two studies (total population 2454) published from 1979 to 2009 were included. Using venography, the pooled rates of all-site, proximal, distal and isolated distal DVT were 31.7, 8.9, 22.5 and 18.8 per cent respectively. With duplex ultrasonography, the respective rates were 9.4, 5.9, 5.9 and 5.8 per cent. After THA or HFS, using venography, the pooled rates of all site and proximal DVT were 25.8 and 9.6 per cent; with ultrasonography, the respective rates were 10.8 and 7.2 per cent. In TKA groups, using venography, the pooled rates of all-site and proximal DVT were 42.5 and 8.7 per cent; with ultrasonography, the respective rates were 9.5 and 5.2 per cent. The overall pooled rates of symptomatic DVT and symptomatic pulmonary embolism (PE) were 4.5 and 0.6 per cent. No patient died from PE (pooled rate 0.2 per cent). CONCLUSION: None of these Asian patients undergoing orthopaedic surgery died from VTE. Pooled rates of proximal and symptomatic DVT were lower than in Western reports. PMID- 21674474 TI - Dephosphorylation of Bcl-10 by calcineurin is essential for canonical NF-kappaB activation in Th cells. AB - Antigen-specific stimulation of T helper (Th) cells initiates signaling cascades that ultimately result in the activation of the transcription factors NF-kappaB, NFAT, and AP-1 which regulate, together with other factors, many T-cell functions such as cytokine production, proliferation, and differentiation. Ordered assembly and different phosphorylation events, along with subcellular translocation of the CARMA1/Bcl-10/MALT1 complex, determine NF-kappaB activation after T-cell receptor (TCR) triggering. We now provide evidence that inhibition of the Ser/Thr phosphatase calcineurin (CaN) prevents dephosphorylation of Bcl-10. CaN, in constant interaction with the Bcl-10/MALT1 complex, is able to dephosphorylate Bcl-10. The CaN inhibitor cyclosporine A (CsA) converts a transient phosphorylation of Bcl-10 Ser138 during the immediate early phase of T-cell activation into a persistent state. Thus, subsequent processes such as IKKbeta phosphorylation, IkappaBalpha degradation, p65 nuclear translocation, and DNA binding are diminished. Consistently, CsA treatment does not affect the phosphorylation pattern of the upstream kinase PKCtheta. Together, our findings demonstrate that CaN functions as a critical signaling molecule during Th cell activation, regulating Bcl-10 phosphorylation and thereby NF-kappaB activation. PMID- 21674475 TI - IL-9 is important for T-cell activation and differentiation in autoimmune inflammation of the central nervous system. AB - Experimental autoimmune encephalomyelitis (EAE) is generally believed to be an autoimmune disease of the central nervous system (CNS) caused by myelin-specific Th1 and/or Th17 effector cells. The underlying cellular and molecular mechanisms, however, are not fully understood. Using mice deficient in IL-9 (IL-9(-/-) ), we showed that IL-9 plays a critical role in EAE. Specifically, IL-9(-/-) mice developed significantly less severe EAE than their WT counterparts following both immunization with myelin proteolipid protein (PLP)(180-199) peptide in the presence of Complete Freund's Adjuvant (CFA), and adoptive transfer of PLP(180 199) peptide-specific effector T cells from WT littermates. EAE-resistant IL-9(-/ ) mice exhibited considerably fewer infiltrating immune cells in the CNS, with lower levels of IL-17 and IFN-gamma expression, than their WT littermates. Further studies revealed that null mutation of the IL-9 gene resulted in significantly lower levels of PLP(180-199) peptide-specific IL-17 and IFN-gamma production. Moreover, IL-9(-/-) memory/activated T cells exhibited decreased C-C chemokine receptors (CCR)2, CCR5, and CCR6 expression. Interestingly, IL-10 was significantly increased in IL-9(-/-) mice compared with WT littermates. Importantly, we found that IL-9-mediated Th17-cell differentiation triggers complex STAT signaling pathways. PMID- 21674476 TI - Penetration of antibody-opsonized cells by the membrane attack complex of complement promotes Ca(2+) influx and induces streamers. AB - We have reported that during complement-mediated cytolysis of B cells promoted by the CD20 mAbs rituximab or ofatumumab (OFA), long, thin structures that we call streamers (>= 3 cell diameters) are rapidly generated and grow out from the cell surface. Streamers appear before cells are killed and contain opsonizing mAbs and membrane lipids. By exploiting the differential Ca(2+) requirements of discrete steps in the complement cascade, we determined that mAb-opsonized cells first tagged with C3b using C5-depleted serum are killed on addition of serum and EDTA, but the cells do not produce streamers. Also, cells first opsonized with OFA are lysed in serum containing Mg-EGTA by the alternative complement pathway but streamers are not produced. These findings indicate that Ca(2+) influx is necessary for streamer formation. Other mAbs that promote complement-mediated cytolysis also induce streamers on target cells. Streamer-like structures called nanotubes have been reported in several cellular systems, and are thought to promote intercellular communication/signaling. We tested whether this signaling could influence the susceptibility of neighboring cells contacted by streamers to complement attack and found that complement-mediated cytolysis of OFA-opsonized cells increases the resistance of unopsonized indicator cell populations to subsequent lysis when these cells are exposed to OFA and complement. PMID- 21674477 TI - Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7 H1 in hepatocellular carcinoma patients. AB - Substantial evidence indicates that inflammation is a critical component of tumor progression. The proinflammatory IL-17-producing cells have recently been detected in tumors, but the effect of IL-17 on antigen-presenting cells in tumors is presently unknown. We recently found that B7-H1(+) macrophages (Mphis) were enriched predominantly in the peritumoral stroma of hepatocellular carcinomas (HCCs). Here, we found a positive correlation between IL-17-producing cells and B7-H1-expressing Mphis in the same area. The B7-H1(+) monocytes/Mphis from HCC tissues expressed significantly more HLA-DR, CD80, and CD86 than B7-H1(-) cells. Accordingly, IL-17 could activate monocytes to express B7-H1 in a dose-dependent manner. Although culture supernatants derived from hepatoma cells also induced B7 H1 expression on monocytes, IL-17 additionally increased hepatoma-mediated B7-H1 expression. Autocrine inflammatory cytokines released from IL-17-activated monocytes stimulated B7-H1 expression. Moreover, these IL-17-exposed monocytes effectively suppressed cytotoxic T-cell immunity in vitro; the effect could be reversed by blocking B7-H1 on those monocytes. Consistent with this, cytotoxic T cells from HCC tissues expressed significant B7-H1 receptor programmed death 1 (PD-1) and exhibited an exhausted phenotype. These data reveal a fine-tuned collaborative action between different stromal cells to counteract T-cell responses in tumors. Such IL-17-mediated immune tolerance should be considered for the rational design of effective immune-based anti-cancer therapies. PMID- 21674478 TI - Direct activation of mTOR in B lymphocytes confers impairment in B-cell maturation andloss of marginal zone B cells. AB - The tuberous sclerosis complex (TSC), composed of TSC1/TSC2 heterodimers, is inhibitory to the mammalian target of rapamycin (mTOR). Deletion of either TSC1 or TSC2 renders mTOR constitutively active. To directly explore the impact of mTOR activation on B-cell development, we conditionally deleted TSC1 in murine B cells. This led to impairment in B-cell maturation. Unexpectedly, and in contrast to Akt activation, marginal zone (MZ) B cells were significantly reduced. Administration of rapamycin partially corrected the MZ defect, indicating a direct role for mTOR in controlling MZ development. When challenged with a T-cell dependent antigen, TSC1 KO mice responded less efficiently. Consistent with the MZ defects, TSC1 KO mice did not respond at all to T-independent antigens. Because activation of Akt upstream of TSC and mTOR yields the reverse phenotype with respect to MZ development, we conclude that, physiologically, Akt simultaneously emits two opposing signals that counterbalance each other in the control of B-cell differentiation. PMID- 21674480 TI - Reducing or increasing beta-cell apoptosis without inflammation does not affect diabetes initiation in neonatal NOD mice. AB - The presentation of islet antigens in the pancreatic LNs (PLNs) of mice is a developmentally regulated process. It has been hypothesized that, during physiological tissue remodeling, a wave of neonatal beta-cell apoptosis may initiate diabetes in autoimmune-prone strains of mice. If true, increasing or decreasing physiological beta-cell apoptosis in neonatal NOD mice should alter the time-course of antigen presentation in the PLNs. We used transgenic over expression of either an anti-apoptotic protein (Bcl-2) or a toxic transgene (rat insulin promoter-Kb) in mouse beta cells to reduce or increase neonatal beta-cell apoptosis, respectively. Neither intervention affected the timing of antigen presentation in the PLNs or the initiation of islet infiltration. This suggests that under physiological conditions and in the absence of inflammation, neonatal beta-cell apoptosis in NOD mice is not the trigger for antigen presentation in the draining LNs. PMID- 21674479 TI - IL-33 induces skin inflammation with mast cell and neutrophil activation. AB - Psoriasis is a common chronic autoimmune condition of the skin characterized by hyperplasia of epidermal keratinocytes associated with pro-inflammatory cytokines. IL-33 is a new member of the IL-1 superfamily that signals through the ST2 receptor and was originally defined as an inducer of T helper 2 (Th2) cytokines. Recently, broader immune activatory potential has been defined for IL 33 particularly via mast cell activation and neutrophil migration. Here, we show that ST2(-/-) mice exhibit reduced cutaneous inflammatory responses compared with WT mice in a phorbol ester-induced model of skin inflammation. Furthermore, injections of IL-33 into the ears of mice induce an inflammatory skin lesion. This inflammatory response was partially dependent on mast cells as mast cell deficient mice (Kit(W-sh/W-sh) ) showed delayed responses to IL-33. IL-33 also recruited neutrophils to the ear, an effect mediated in part by increased production of the chemokine KC (CXCL1). Finally, we show that IL-33 expression is up-regulated in the epidermis of clinical psoriatic lesions, compared with healthy skin. These results therefore demonstrate that IL-33 may play a role in psoriasis-like plaque inflammation. IL-33 targeting may provide a new treatment strategy for psoriasis. PMID- 21674481 TI - Type I interferons suppress CD4+ T-cell-dependent parasite control during blood stage Plasmodium infection. AB - During blood-stage Plasmodium infection, large-scale invasion of RBCs often occurs before the generation of cellular immune responses. In Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice, CD4(+) T cells controlled parasite numbers poorly, instead providing early help to pathogenic CD8(+) T cells. Expression analysis revealed that the transcriptional signature of CD4(+) T cells from PbA infected mice was dominated by type I IFN (IFN-I) and IFN-gamma-signalling pathway-related genes. A role for IFN-I during blood-stage Plasmodium infection had yet to be established. Here, we observed IFN-alpha protein production in the spleen of PbA-infected C57BL/6 mice over the first 2 days of infection. Mice deficient in IFN-I signalling had reduced parasite burdens, and displayed none of the fatal neurological symptoms associated with PbA infection. IFN-I substantially inhibited CD4(+) T-bet(+) T-cell-derived IFN-gamma production, and prevented this emerging Th1 response from controlling parasites. Experiments using BM chimeric mice revealed that IFN-I signalled predominantly via radio sensitive, haematopoietic cells, but did not suppress CD4(+) T cells via direct signalling to this cell type. Finally, we found that IFN-I suppressed IFN-gamma production, and hampered efficient control of parasitaemia in mice infected with non-lethal Plasmodium chabaudi. Thus, we have elucidated a novel regulatory pathway in primary blood-stage Plasmodium infection that suppresses CD4(+) T cell-mediated parasite control. PMID- 21674482 TI - Alternate pathways for Bcl6-mediated regulation of B cell to plasma cell differentiation. AB - The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. PMID- 21674483 TI - The binding activity of Mel-18 at the Il17a promoter is regulated by the integrated signals of the TCR and polarizing cytokines. AB - We have previously shown that in differentiated T-helper (Th)1 and Th2 cells, polycomb group (PcG) proteins are associated differentially with the promoters of the signature cytokine genes. The correlation of the binding activity of PcG proteins with gene expression is unusual, since they are well known as epigenetic regulators that maintain transcriptional silencing. Here we show that in Th17 cells, the more phenotypically flexible Th lineage, the PcG proteins Mel-18 and less strikingly Ezh2 are associated differentially with the Il17a promoter. Using the RNAi approach, we found that Mel-18 and Ezh2 positively regulate the expression of Il17a and Il17f. The inducible binding of Mel-18 and Ezh2 at the Il17a promoter was dependent on signaling pathways downstream of the TCR. However, a continuous presence of TGF-beta, the cytokine that is necessary to maintain Il17a expression, was required to preserve the binding activity of Mel 18, but not of Ezh2, following restimulation. The binding of Mel-18 at the Il17a promoter was correlated with the recruitment of the lineage-specifying transcription factor RORgammat. Altogether, our results suggest that in Th17 cells the TCR and polarizing cytokines synergize to modulate the binding activity of Mel-18 at the Il17a promoter, and consequently to facilitate Il17a expression. PMID- 21674484 TI - Psychology and my gallbladder: an insider's account. AB - The subjective experience of the psychologist-author when addressing and undergoing a surgical procedure is described, including-consistent with his own theoretical and technical orientation--the use of various brief therapy and hypnotherapy methods. A narrative of events is presented with interspersed comments about internal processes and reflections. A discussion of "Lessons Learned and Offered," including various comments about personal therapy (therapist as patient), then completes the article. PMID- 21674485 TI - CaMKII is differentially localized in synaptic regions of Kenyon cells within the mushroom bodies of the honeybee brain. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) has been linked to neuronal plasticity associated with long-term potentiation as well as structural synaptic plasticity. Previous work in adult honeybees has shown that a single CaMKII gene is strongly expressed in the mushroom bodies (MBs), brain centers associated with sensory integration, and learning and memory formation. To study a potential role of CaMKII in synaptic plasticity, the cellular and subcellular distribution of activated (phosphorylated) pCaMKII protein was investigated at various life stages of the honeybee using immunocytochemistry, confocal microscopy, and western blot analyses. Whereas at pupal stages 3-4 most parts of the brain showed high levels of pCaMKII immunoreactivity, the protein was predominantly concentrated in the MBs in the adult brain. The results show that pCaMKII is present in a specific subpopulation of Kenyon cells, the noncompact cells. Within the olfactory (lip) and visual (collar) subregion of the MB calyx neuropil pCaMKII was colocalized with f-actin in postsynaptic compartments of microglomeruli, indicating that it is enriched in Kenyon cell dendritic spines. This suggests a potential role of CaMKII in Kenyon cell dendritic plasticity. Interestingly, pCaMKII protein was absent in two other types of Kenyon cells, the inner compact cells associated with the multimodal basal ring and the outer compact cells. During adult behavioral maturation from nurse bees to foragers, pCaMKII distribution remained essentially similar at the qualitative level, suggesting a potential role in dendritic plasticity of Kenyon cells throughout the entire life span of a worker bee. PMID- 21674486 TI - Exuberant growth and synapse formation of olfactory sensory neuron axonal arborizations. AB - Neural connections in the adult nervous system are established with a high degree of precision. Several examples throughout the nervous system indicate that this precision is achieved by first establishing an initial exuberant immature pattern of connectivity that is then sculpted into the adult pattern via pruning. This often emerges as an activity-dependent process. In the olfactory system, sensory axons from neurons expressing the same odorant receptor project with high precision to specific glomerular structures in the olfactory bulb. This process undergoes maturation-dependent refinements that are not fully understood. Due to technical impediments that have made it difficult to focus on single axons, it is unknown whether olfactory sensory projections are established in an exuberant fashion. Here we developed a novel technique of electroporation that allowed us to simultaneously label single olfactory sensory neuron (OSN) axonal arbors and their presynaptic specializations. Using this method we were able to incorporate plasmids into OSNs at an immature stage, thereby allowing a time-course study of axonal arbor development and synapse formation in single olfactory sensory axons. We observed that the number of branch points, the total branch length, and the number and density of presynaptic specializations peaked at postnatal day 8 and decreased afterwards. Our data demonstrate that olfactory sensory axons develop in an exuberant way, both in terms of branch growth and synaptic composition. We hypothesize that exuberant branches and synapses are eliminated to achieve the mature pattern in a process likely to be regulated by neural activity. PMID- 21674488 TI - Axons with highly branched terminal regions successfully regenerate across spinal midline transections in the adult cat. AB - We recently reported that some, but not all, axotomized propriospinal commissural interneurons (PCI) of the adult mammal can regenerate through spinal midsagittal transection injury sites (Fenrich and Rose [2009] J Neurosci 29:12145-12158). In this model, regenerating axons grow through a lesion site surrounded by a dense deposition of chondroitin sulfate proteoglycans (CSPG), which are typically inhibitory to regenerating axons. However, the mechanisms that lead some regenerating axons to grow through spinal cord injury (SCI) sites while others remain trapped in the CSPG zones or retract to their soma remain unknown. As a first step toward elucidating these mechanisms, here we show that the ability of PCI axons to regenerate across a SCI site depends on the branching patterns of their distal terminals. Using 3D reconstruction techniques through multiple serial sections and immunohistochemical analyses, we found that at 7 days postinjury a majority of PCI axons terminated in CSPG zones ipsilateral of the spinal midline. Conversely, at 9 days postinjury some PCI axons had regenerated across the midline, but others terminated outside the CSPG zones near their soma. Furthermore, we show that the most successful regenerators were those with the most extensive branching patterns, whereas those that terminated outside the CSPG zones had terminal regions indistinguishable from dystrophic terminals. Our results demonstrate that the morphological characteristics of regenerating axons play an important role in their ability to regenerate across SCI sites, and that the branching patterns of some regenerating axons are more extensive and have a far greater complexity than previously reported. PMID- 21674491 TI - Peroxiredoxin distribution in the mouse brain with emphasis on neuronal populations affected in neurodegenerative disorders. AB - Redox changes are observed in neurodegenerative diseases, ranging from increased levels of reactive oxygen/nitrogen species and disturbance of antioxidant systems, to nitro-oxidative damage. By reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides, peroxiredoxins (Prdxs) represent a major potential protective barrier against nitro-oxidative insults in the brain. While recent works have investigated the putative role of Prdxs in neurodegenerative disorders, less is known about their expression in the healthy brain. Here we used immunohistochemistry to map basal expression of Prdxs throughout C57BL/6 mouse brain. We first confirmed the neuronal localization of Prdx2-5 and the glial expression of Prdx1, Prdx4, and Prdx6. Then we performed an in-depth analysis of neuronal Prdx distribution in the brain. Our results show that Prdx2 5 are widely detected in the different neuronal populations, and especially well expressed in the olfactory bulb, in the cerebral cortex, in pons nuclei, in the red nucleus, in all cranial nerve nuclei, in the cerebellum, and in motor neurons of the spinal cord. In contrast, Prdx expression is very low in the dopaminergic neurons of substantia nigra pars compacta and in the CA1/2 pyramidal cells of hippocampus. This low basal expression may contribute to the vulnerability of these neurons to nitro-oxidative attacks occurring in Parkinson's disease and Alzheimer's disease. In addition, we found that Prdx expression levels are unevenly distributed among neurons of a determined region and that distinct regional patterns of expression are observed between isoforms, reinforcing the hypothesis of the nonredundant function of Prdxs. PMID- 21674490 TI - Morphologic and immunohistochemical organization of the human habenular complex. AB - The habenular complex (HbCpx) is a phylogenetically conserved brain structure located in the epithalamus of vertebrates. Despite its fundamental role in decision-making processes and the proposed link between habenular dysfunction and neuropsychiatric conditions, little is known about the structural and functional organization of the HbCpx in humans. The goal of this study was thus to provide a first systematic morphologic and immunohistochemical analysis of the human HbCpx to begin dissecting its nuclear and subnuclear organization. Our results confirmed that the human HbCpx is subdivided into medial (MHb) and lateral (LHb) nuclei, each showing a large degree of intranuclear morphologic heterogeneity. Analysis of serially stained sections using a combination of morphologic and immunohistochemical criteria allowed the distinction of five subnuclei in both the MHb and LHb. Overall, the observed subnuclear organization of the MHb in humans resembles the organization of subnuclei in the MHb of rats. The shape, relative size, and intranuclear organization of the LHb, however, show significant differences. The contribution of the LHb to the entire HbCpx is about five times larger in humans than in rats. Noteworthy, a dorsal domain of the LHb that contains afferent myelinated fibers from the stria medullaris and shows GABA (B) -R(1) immunoreactive cells, appears substantially enlarged in humans when compared to rats. This feature seems to account for a large part of the relative growth in size of the LHb in humans and opens the intriguing possibility of an increased influence of limbic and striatal afferents into the LHb of humans. PMID- 21674489 TI - Forebrain mapping of secretoneurin-like immunoreactivity and its colocalization with isotocin in the preoptic nucleus and pituitary gland of goldfish. AB - Secretoneurin, a 33-34 amino acid neuropeptide derived from the proteolytic processing of the secretogranin-II precursor protein, is reasonably well conserved in evolution. Goldfish secretoneurin shares >75% similarity overall with other vertebrate secretoneurin sequences. The secretoneurin peptide has numerous functions that include neuroinflammation, neurotransmitter release, and neuroendocrine regulation. A detailed description of the central distribution of secretoneurin immunoreactivity is only known for the rat. Using our polyclonal antibody against the central, conserved core of the secretoneurin peptide we studied the distribution of secretoneurin-like immunoreactivity in the goldfish brain. Secretoneurin immunoreactivity was found in the olfactory bulb, entopeduncular nucleus, preoptic nucleus, lateral part of the lateral tuberal nucleus, posterior periventricular nucleus, nucleus of the posterior recess, the nucleus of the saccus vasculosus, and nucleus isthmi. Secretoneurin immunoreactive fibers were found in the dorsal part of the dorsal telencephalon, ventral and lateral parts of the ventral telencephalon, periventricular preoptic nucleus, pituitary, and the ventrocaudal aspect of the nucleus of the lateral recess. The most conspicuous secretoneurin immunoreactivity was found in the magnocellular and parvocellular cells of the preoptic nucleus that project to the pituitary. Double-labeling studies indicated coexpression with isotocin, the fish homolog of mammalian oxytocin. Clear colabeling for secretoneurin and isotocin in fibers terminating in the neurointermediate lobe suggests that secretoneurin maybe coreleased with isotocin. Previous work indicates that secretoneurin stimulates the release of luteinizing hormone from the goldfish anterior pituitary. Our findings further support a reproductive role for secretoneurin and related peptides, given the importance of oxytocin family peptides in reproductive behavior in vertebrates. PMID- 21674495 TI - Organization of the serotonergic innervation of the feeding (buccal) musculature during the maturation of the pond snail Lymnaea stagnalis: a morphological and biochemical study. AB - The serotonergic innervation of the buccal musculature responsible for feeding (radula protraction) was investigated during the maturation of the pond snail, Lymnaea stagnalis L., applying light and electron microscopic immunohistochemistry and biochemical approaches. According to epifluorescence and laser confocal microscopy, the first 5-HT-like-immunoreactive (5-HTLIR) processes appeared on the surface of the musculature at the postmetamorphic E80% embryonic stage. Until hatching, the innervation continued to increase in density, showing axon arborizations with projections into the deeper muscle levels. An adult-like pattern of 5-HTLIR innervation appeared at P2-P3 juvenile stages. At the ultrastructural level, close (16-20 nm) but mostly unspecialized neuromuscular contacts were formed by both unlabeled and 5-HTLIR axon profiles from the E80% embryonic stage. Labeled processes were also found located relatively far from the muscle cells. An HPLC assay showed a gradual increase of the 5-HT level in the buccal mass during development. The buccal mass was characterized by a single component high-affinity 5-HT uptake system, and 5-HT release could be evoked by 100 mM K(+) and blocked in Ca(2+) -free medium. It is suggested that 5-HT plays a wide modulatory role in the peripheral feeding system and is also involved in the functional maturation of the muscle system. PMID- 21674497 TI - Postnatal changes in the distribution and density of neuronal nuclei and doublecortin antigens in domestic chicks (Gallus domesticus). AB - To understand better the rate of neurogenesis and the distribution of new neurons in posthatch domestic chicks, we describe and compare the expression of the neuronal nuclei protein (NeuN, a.k.a. Fox-3) and doublecortin antigens in the whole brain of chicks 2 days, 8 days, and 14 weeks posthatch. In the forebrain ventricular and paraventricular zones, the density of bromodeoxyuridine-, NeuN-, and doublecortin-labeled cells was compared between chicks 24 hours and 7 days after an injection of bromodeoxyuridine (2 and 8 days posthatch, respectively). The distribution of NeuN-labeled neurons was similar to Nissl-stained tissue, with the exception of some areas where neurons did not express NeuN: cerebellar Purkinje cells and olfactory bulb mitral cells. The ventral tegmental area of 2 day-old chicks was also faintly labeled. The distribution of doublecortin was similar at all timepoints, with doublecortin-labeled profiles located throughout all forebrain areas as well as in the cerebellar granule cell layer. However, doublecortin labeling was not detectable in any midbrain or brainstem areas. Our data indicate that a significant number of new neurons is still formed in the telencephalon of posthatch domestic chicks, whereas subtelencephalic areas (except for the cerebellum) finish their neuronal expansion before hatching. Most newly formed cells in chicks leave the paraventricular zone after hatching, but a pool of neurons stays in the vicinity of the ventricular zone and matures in situ within 7 days. Proliferating cells often migrate laterally along forebrain laminae into still-developing brain areas. PMID- 21674487 TI - Morphology of superior colliculus- and middle temporal area-projecting neurons in primate primary visual cortex. AB - Layers 5 and 6 of primate primary visual cortex (V1) harbor morphologically diverse cell groups that have corticocortical and corticosubcortical projections. Layer 6 middle temporal area (MT)-projecting neurons are particularly interesting, as they are the only deep-layer cortical neurons that provide both corticocortical feedforward inputs (to area MT) and corticosubcortical feedback projections (to superior colliculus [SC]) (Fries et al. [1985] Exp Brain Res 58:613-616). However, due to limitations in anatomical tracing techniques, little is known about the detailed morphologies of these cells. We therefore applied a genetically modified rabies virus as a retrograde tracer to fill the dendrites of projection neurons with green fluorescent protein (GFP) (Wickersham et al. [2007] Nat Methods 4:47-49). We injected virus into SC or area MT of macaque monkeys and examined labeled cells in V1. Two-thirds of labeled neurons following SC injections were found in layer 5, consisting of "tall-tufted" and "nontufted" cells; the remaining cells were layer 6 "nontufted." Area MT injections labeled neurons in layers 4B and 6, as previously described (Shipp and Zeki [1989] Eur J Neurosci 1:309-332). The layer 6 neurons projecting to MT were remarkably similar to the layer 6 SC-projecting neurons. In contrast to the dense and focused dendritic arbors of layer 5 "tall-tufted" pyramids, all "nontufted" cells had sparse, but unusually long basal dendrites. The nontufted cells closely resemble Meynert cells (le Gros Clark [1942] J Anat 76:369-376; Winfield et al. [1983] Proc R Soc Lond B Biol Sci 217:129-139), but the full in vivo reconstructions presented here show that their basal dendrites can extend much further (up to 1.2 mm) and are less asymmetric than inferred from Golgi reconstructions. PMID- 21674498 TI - Novel organization and development of copepod myelin. i. ontogeny. AB - Nerve impulse conduction is greatly increased by myelin, a multilayered membranous sheath surrounding axons. Best known from and most extensively investigated among vertebrates, a few invertebrates, including some superfamilies of copepod, have functionally and structurally similar myelin-like sheaths surrounding their axons. We examined the development of myelin ultrastructure in Bestiolina similis, a paracalanoid copepod. Development occurred in a novel way: initial myelination always appeared first as a partial layer, which in later stages came to encircle an axon completely. This partial myelin first appeared in a single pair of reidentifiable fibers, at the second naupliar stage. Two additional pairs of reidentifiable fibers also became partially myelinated by the third naupliar stage. The number of myelin layers in this trio of axon pairs increased with development, but, at any one stage, each axon had the same number of layers along its entire length. These axons disappeared after the copepodite metamorphosis. After metamorphosis, the fiber that took over as largest in the nerve cord became the most heavily myelinated and was identified as the lateral dorsal giant fiber. The rate of myelination was also characterized in the antennular nerve as a representative of the peripheral nervous system. As axons became larger, they were more likely to be partially, and then completely, myelinated, the latter having a lower ratio of axon core to fiber diameter than the former. Copepod myelin is an instructive example of convergent evolution, with far-reaching consequences for nervous system functioning and the behavior that nervous systems subserve. PMID- 21674496 TI - Characterization of the bed nucleus of the stria terminalis in the forebrain of anuran amphibians. AB - Major common features have been reported for the organization of the basal telencephalon in amniotes, and most characteristics were thought to be acquired in the transition from anamniotes to amniotes. However, gene expression, neurochemical, and hodological data obtained for the basal ganglia and septal and amygdaloid complexes in amphibians (anamniotic tetrapods) have strengthened the idea of a conserved organization in tetrapods. A poorly characterized region in the forebrain of amniotes has been the bed nucleus of the stria terminalis (BST), but numerous recent investigations have characterized it as a member of the extended amygdala. Our study analyzes the main features of the BST in anuran amphibians to establish putative homologies with amniotes. Gene expression patterns during development identified the anuran BST as a subpallial, nonstriatal territory. The BST shows Nkx2.1 and Lhx7 expression and contains an Islet1-positive cell subpopulation derived from the lateral ganglionic eminence. Immunohistochemistry for diverse peptides and neurotransmitters revealed that the distinct chemoarchitecture of the BST is strongly conserved among tetrapods. In vitro tracing techniques with dextran amines revealed important connections between the BST and the central and medial amygdala, septal territories, medial pallium, preoptic area, lateral hypothalamus, thalamus, and prethalamus. The BST receives dopaminergic projections from the ventral tegmental area and is connected with the laterodorsal tegmental nucleus and the rostral raphe in the brainstem. All these data suggest that the anuran BST shares many features with its counterpart in amniotes and belongs to a basal continuum, likely controlling similar reflexes, reponses, and behaviors in tetrapods. PMID- 21674501 TI - Novel organization and development of copepod myelin. ii. nonglial origin. AB - Nerve-impulse conduction is greatly speeded by myelin sheaths in vertebrates, oligochaete annelids, penaeid and caridean shrimp, and calanoid copepods. In the first three invertebrate cases, myelin arises from glial cells, as it does in vertebrates. The contribution of the glial cells to the layered structure of the myelin is clear: their nuclei are either embedded in the layers or reside in contiguous cytoplasmic compartments, and their cell membranes are seen to be continuous with those of the myelin layers. However, with calanoids, the association with glial cells presumed necessary to generate the myelin has never been satisfactorily identified. We have conducted a systematic examination of thin sections through different parts of the copepod nervous system to identify the structural organization of copepod myelin and the likely mechanism for its formation. We find that myelination appears to commence by laying down and compacting a cisternal tongue against the inside of the axolemma. This is followed by the successive layering and compaction of additional tongues to create a stack of tongues. The margins of the tongues then expand to encircle the interior of a neurite, meeting and fusing to form complete concentric myelin. No sign of glial involvement could be detected at any stage. Unlike glially derived myelin, the extracellular tracer lanthanum did not penetrate between the myelin layers in copepods, further evidence against a glial source. We believe this to be the first demonstration of a nonglial origin for myelin in any species. PMID- 21674500 TI - Requirement for the paired-like homeodomain transcription factor VSX1 in type 3a mouse retinal bipolar cell terminal differentiation. AB - Retinal bipolar cells make up a class of at least 11 distinct interneurons that have been classified through morphological and molecular approaches. Previous work has shown that the paired-like homeodomain transcription factor Vsx1 is essential for the proper development of a subset of these interneurons. In Vsx1 null mice, bipolar cells are properly specified but exhibit terminal differentiation defects characterized by reduced expression of OFF bipolar cell markers and defects in OFF visual signaling. Here, we further examined the role of Vsx1 in OFF bipolar cells using recently identified cell-type-specific markers. In contrast to its previously characterized expression in type 2 OFF bipolar cells, Vsx1 expression was not detected in type 3 OFF bipolar cells, by either immunohistological or transgenic reporter labeling approaches. This observation was unexpected given previous findings that Cabp5 immunolabeling of type 3 bipolar cell axon terminals is reduced in Vsx1-null mice. However, we observed reduced levels of the type 3a bipolar cell marker hyperpolarization activated and cyclic nucleotide-gated channel 4 (HCN4) in Vsx1-null mice, which is consistent with a requirement for Vsx1 in type 3 bipolar cell differentiation. In contrast, expression of the type 3b bipolar cell marker regulatory subunit RII beta of protein kinase A was unchanged. Despite the absence of Vsx1 in mature type 3 bipolar cells, colabeling of Vsx1 and HCN4 was observed at postnatal stages. These findings reveal a role for Vsx1 in type 3a bipolar cells and suggest that Vsx1 function is required transiently in this cell type during the postnatal period. PMID- 21674505 TI - Effect of zinc and its form of supply on production and quality of coffee beans. AB - BACKGROUND: In Brazil, the usual forms of zinc (Zn) supply to coffee plants have limitations that compromise the element availability to the plant. This study proposes to test an alternative approach to supplying the nutrient to Coffea arabica L. using trunk implanted zinc tablets. Additionally, the effect of Zn on the production and quality of coffee beans was also evaluated. RESULTS: The highest total coffee bean production was recorded in plants implanted with Zn tablets (TA), while the lowest was recorded in the control treatment, without zinc supply (WZn), reaching a bianual production of 188.2 and 130.1 60-kg bags of processed beans per hectare, respectively. In the treatments where Zn were applied as tablet implantation or as foliage spraying (SZn); the bean size was larger, while the grain electrical conductivity and potassium leaching were lower compared with WZn. CONCLUSION: Zn supply via tablet implantation into tree trunks provides yield and quality similar to those obtained by foliage spraying. Independent of the form of supply, Zn positively influences the production and quality of coffee beans. PMID- 21674507 TI - Bio-screening of a few green seaweeds from India for their cytotoxic and antioxidant potential. AB - BACKGROUND: It has been evidenced in several epidemiological studies that seaweeds when consumed as diet protect against several chronic oxidative stress related diseases. Seaweeds, raw, cooked, or dried, are used as food in many cultures, although not very popularly in India. Globally, several studies have indicated that seaweeds are a rich source of phenolic compounds and have antioxidant properties. In the present study, we screened methanolic extracts (MEs) of five species of green seaweeds commonly found in India for their cytotoxic activity by brine shrimp lethality assay and antioxidant properties using various in vitro assays, including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, reducing power and metal ion chelating assays. RESULTS: A markedly variable, dose-dependent activity was observed in all the seaweed extracts relative to their total phenolic content. Statistical analysis indicated a significantly strong correlation between the DPPH radical scavenging activity and total phenolic content (R(2) = 0.88, P < 0.05) as well as reducing power and total phenolic content (R(2) = 0.99, P < 0.01) of the dry MEs. Also, a very poor correlation between total phenolic content and metal chelating activity (R(2) = 0.13, P > 0.05) was noted. None of the seaweed extracts were potently cytotoxic. CONCLUSION: The underlying results endorse seaweeds as a rich, novel source of antioxidant compounds needing systemic exploration. PMID- 21674506 TI - Effect of xylose on the molecular and particle size distribution of peanut hydrolysate in Maillard reaction system. AB - BACKGROUND: The Maillard reaction is a complex series of reactions between reducing sugars and amino groups. Changing any of reaction parameters would alter the reaction pathway. This study investigated the effect of xylose concentration on the molecular and particle size distribution of Maillard reaction products (MRPs) derived from peanut hydrolysate and xylose to discuss their formation mechanism. RESULTS: Molecular weight and particle size distribution analyses indicated that both peptide degradation and peptide cross-linking occurred during the Maillard reaction. Heat treatment would make the high-molecular-weight peptides degrade into low-molecular-weight peptides and free amino acids. Maillard reaction increased the molecular weight and particle sizes of products as the xylose concentration increased from 1% to 4%. CONCLUSION: The study shows that both peptide degradation and peptide cross-linking occurred during the Maillard reaction. The thermal degradation product (TDP) and MRPs had significantly different molecular size distribution, and the particle size distribution of TDPs and MRPs had similar change tendency to that of the molecular size distribution. These would provide an insight into the formation mechanism of MRPs. PMID- 21674508 TI - Moisture-induced caking of beverage powders. AB - BACKGROUND: Beverage powders can exhibit caking during storage due to high temperature and moisture conditions, leading to consumer dissatisfaction. Caking problems can be aggravated by the presence of sensitive ingredients. The caking behaviour of cocoa beverage powders, with varying amounts of a carbohydrate sensitive ingredient, as affected by climate conditions was studied in this work. Sorption isotherms of beverage powders were determined at water activities (a(w) ) ranging from 0.1 to 0.6 in a moisture sorption analyser by gravimetry and fitted to the Brunauer-Emmett-Teller (BET) or the Guggenheim-Anderson-de Boer (GAB) equation. Glass transition temperatures (T(g) ) at several a(w) were analysed by differential scanning calorimetry and fitted to the Gordon-Taylor equation. Deduced T(g) = f(a(w) ) functions helped to identify stability or caking zones. Specific experimental methods, based on the analysis of mechanical properties of powder cakes formed under compression, were used to quantify the degree of caking. Pantry tests complemented this study to put in evidence the visual perception of powder caking with increasing a(w) . RESULTS: The glass transition approach was useful to predict the risks of caking but was limited to products where T(g) can be measured. On the other hand, quantification of the caking degree by analysis of mechanical properties allowed estimation of the extent of degradation for each product. CONCLUSION: This work demonstrated that increasing amounts of a carbohydrate sensitive ingredient in cocoa beverages negatively affected their storage stability. PMID- 21674503 TI - PSCA mRNA expression in preoperatively negative prostate biopsies predicts incidental prostate cancer in patients undergoing transurethral resection of the prostate for benign prostatic hyperplasia. AB - BACKGROUND: Recent data showed that prostate stem cell antigen (PSCA) mRNA expression is predictive of the subsequent cancer in BPH patients treated with TURP. This study was to determine whether PSCA mRNA expression in preoperatively negative biopsies identified the presence of incidental prostate cancer (IPCa) on TURP tissues analysis. METHODS: PSCA in situ hybridization was performed in preoperatively negative prostatic biopsies taken from 592 enrolled BPH patients. Predictive performance of PSCA mRNA for IPCa was evaluated by the Cox proportional hazards models. RESULTS: PSCA mRNA positivity in negative biopsy specimens was detected in 84 (14.2%) of 592 men. Of those 84 patients, 57 were histopathologically identified as having PCa on their TURP tissues. None of the rest 508 men with negative PSCA mRNA expression were diagnosed with IPCa. Spearman's rank correlation coefficient showed that PSCA mRNA expression levels were correlated significantly and positively with Gleason score (r = 0.80, P < 0.001) and clinical stage (r = 0.86, P < 0.001). A multivariate Cox model demonstrated that only PSCA mRNA positivity was predictive of the IPCa presence on TURP (HR = 4.04; 95% CI: 2.12-5.42; P < 0.001), with the concordance index of 0.878. CONCLUSION: PSCA mRNA positivity in negative biopsies is a promising marker for the presence of IPCa in BPH patients. PMID- 21674492 TI - Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain. AB - The hormones leptin and ghrelin act in apposition to one another in the regulation of body weight homeostasis. Interestingly, both leptin receptor expression and ghrelin receptor expression have been observed within many of the same nuclei of the central nervous system (CNS), suggesting that these hormones may act on a common population of neurons to produce changes in food intake and energy expenditure. In the present study we explored the extent of this putative direct leptin and ghrelin interaction in the CNS and addressed the question of whether a loss of ghrelin signaling would affect sensitivity to leptin. Using histological mapping of leptin receptor and ghrelin receptor expression, we found that cells containing both leptin receptors and ghrelin receptors are mainly located in the medial part of the hypothalamic arcuate nucleus. In contrast, coexpression was much less extensive elsewhere in the brain. To assess the functional consequences of this observed receptor distribution, we explored the effect of ghrelin receptor deletion on leptin sensitivity. In particular, the responses of ad libitum-fed, diet-induced obese and fasted mice to the anorectic actions of leptin were examined. Surprisingly, we found that deletion of the ghrelin receptor did not affect the sensitivity to exogenously administrated leptin. Thus, we conclude that ghrelin and leptin act largely on distinct neuronal populations and that ghrelin receptor deficiency does not affect sensitivity to the anorexigenic and body weight-lowering actions of leptin. PMID- 21674504 TI - Molecularly imprinted solid-phase extraction combined with high-performance liquid chromatography for analysis of trace olaquindox residues in chick feeds. AB - BACKGROUND: Olaquindox, one of the antimicrobial growth accelerants, is usually used as a feed additive in livestock production to improve feed efficiency. Due to health concerns over possible carcinogenic, mutagenic and photoallergenic effects of olaquindox on animals, the development of a simple, rapid and sensitive analytical method for determination of olaquindox is crucial and necessary. RESULTS: In this paper, a novel and hydrophilic functionalised material of olaquindox-imprinted polymer was synthesised in aqueous solution by a surface molecular imprinting in combination with a sol-gel process. This imprinted material was characterised by Fourier transform infrared, scanning electron microscopy, and static and kinetic adsorption experiments, and results showed that it had good recognition and selective ability, and fast adsorption desorption dynamics for olaquindox. Applying the prepared material as sorbent, a method of molecularly imprinted solid-phase extraction (MISPE) for separation and analysis of olaquindox residues in feeds coupled with HPLC was presented. Under the selected MISPE condition, the detection limit (S/N = 3) for olaquindox was 68.0 ng L(-1), the RSD for five replicate extractions of 50 ug L(-1) olaquindox was 9.8%. The blank chick feed samples spiked with olaquindox at 0.0025 and 0.010 mg g(-1) levels were extracted and determined by the developed method, with recoveries ranging from 90% to 96%. CONCLUSION: This method was applied for enrichment and analysis of olaquindox in animal feed samples with good accuracy and repeatability. This study will provide a sensitive and fast method for the monitoring of olaquindox residues in foods. PMID- 21674511 TI - Real-time ultrasound elastography in the diagnosis and differential diagnosis of subacute thyroiditis. AB - PURPOSE: To assess the value of real-time sonographic (US) elastography in the diagnosis of subacute thyroiditis (SAT). METHODS: This study included 29 lesions from 20 patients with SAT, 33 nodules from 24 patients with multinodular goiter, and 27 nodules from 23 patients with thyroid cancer. Eighty-nine lesions in these patients were examined by grayscale US and real-time US elastography. An elasticity score (ES), based on four classes of tissue stiffness (class 1 for soft lesions; class 2 and 3 for lesions intermediate in stiffness; class 4 for inelastic lesions), was introduced. The distribution of ESs for SAT and multinodular goiter or thyroid cancer was compared. Also, the correlation between serum-free thyroxine (FT4) concentrations and ESs for lesions in patients with SAT was analyzed. RESULTS: Nineteen of 29 SAT lesions had an ES of 3; the rest had an ES of 4. Of 33 multinodular goiter nodules, 5 had an ES of 1, 23 had an ES of 2, and 5 had an ES of 3. Eleven of 27 malignant thyroid nodules had an ES of 3; 15 had an ES of 4, and 1 had an ES of 2. In the distribution of ESs, there was a statistically significant difference between SAT lesions and multinodular goiter nodules (p < 0.05), but there was no significant difference between SAT lesions and malignant nodules (p > 0.05). No correlation existed between serum FT4 concentrations and ESs for the lesions in patients with SAT (p > 0.05). CONCLUSIONS: Real-time US elastography does not provide conclusive information in the diagnosis and differential diagnosis of SAT due to its inability to distinguish between SAT and thyroid cancer. PMID- 21674512 TI - Prenatal diagnosis of scalp cyst with spontaneous regression. AB - Fetal scalp cysts are rare, and they may be easily misdiagnosed as meningoceles or encephaloceles. A 38-year-old pregnant woman was referred to our hospital for ultrasound examination, which revealed a small cyst above the skull with no defect in the skull. The cyst could not be seen on follow-up ultrasound examinations. After delivery, a three-dimensional CT scan of the head revealed no defect in skull and scalp. Fetal scalp cysts usually require surgical excision after birth, but can regress without any treatment. PMID- 21674516 TI - Cardiomyopathy of Duchenne muscular dystrophy: current understanding and future directions. AB - Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy and occurs in 1 in 3500 male births. Improved survival due to improvements in clinical care of the musculoskeletal and respiratory systems has led to an increased incidence of cardiomyopathy. Cardiac-related deaths are now seen in approximately 20% of DMD patients. Our current understanding of DMD cardiomyopathy has increased significantly over the past 10 years, but further research is required to improve cardiac treatment and outcomes in DMD. This review provides a summary of the current literature and discussion of potential new therapies for DMD cardiomyopathy. PMID- 21674509 TI - Water mobility within arabinoxylan and beta-glucan films studied by NMR and dynamic vapour sorption. AB - BACKGROUND: The main purpose of this research was to determine the impact of the structure and organisation of polysaccharides on the hydration properties of the cell walls of cereal grains. In order to remodel the lamellar assembly of arabinoxylan (AX) and (1 -> 3)(1 -> 4)-beta-D-glucan (BG) within the endosperm cell walls, films were prepared and analysed using dynamic vapour sorption and time domain nuclear magnetic resonance spectroscopy. RESULTS: The water diffusivities within the AX and BG films were measured at 20 degrees C by observing the water sorption kinetics within a mathematical model based on Fick's second law. The evolution of spin-spin relaxation times of water protons measured by increasing the temperature is explained by the additional contributions of motion of the protons of polysaccharides and/or rapid chemical exchanges of protons between water and hydroxyl groups of polysaccharides. CONCLUSION: The difference between patterns of water behaviour within the AX and BG films can be related to the difference in their nanostructures. The smaller nanopores of the BG films cause their nanostructure to be more compact. PMID- 21674494 TI - A-kinase anchoring protein 150 expression in a specific subset of TRPV1- and CaV 1.2-positive nociceptive rat dorsal root ganglion neurons. AB - Modulation of phosphorylation states of ion channels is a critical step in the development of hyperalgesia during inflammation. Modulatory enhancement of channel activity may increase neuronal excitability and affect downstream targets such as gene transcription. The specificity required for such regulation of ion channels quickly occurs via targeting of protein kinases and phosphatases by the scaffolding A-kinase anchoring protein 79/150 (AKAP79/150). AKAP79/150 has been implicated in inflammatory pain by targeting protein kinase A (PKA) and protein kinase C (PKC) to the transient receptor potential vanilloid 1 (TRPV1) channel in peripheral sensory neurons, thus lowering threshold for activation of the channel by multiple inflammatory reagents. However, the expression pattern of AKAP150 in peripheral sensory neurons is unknown. Here we identify the peripheral neuron subtypes that express AKAP150, the subcellular distribution of AKAP150, and the potential target ion channels in rat dorsal root ganglion (DRG) slices. We found that AKAP150 is expressed predominantly in a subset of small DRG sensory neurons, where it is localized at the plasma membrane of the soma, axon initial segment, and small fibers. Most of these neurons are peripherin positive and produce C fibers, although a small portion produce Adelta fibers. Furthermore, we demonstrate that AKAP79/150 colocalizes with TRPV1 and Ca(V) 1.2 in the soma and axon initial segment. Thus AKAP150 is expressed in small, nociceptive DRG neurons, where it is targeted to membrane regions and where it may play a role in the modulation of ion channel phosphorylation states required for hyperalgesia. PMID- 21674519 TI - Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. AB - INTRODUCTION: Myasthenia gravis (MG) patients with autoantibodies to muscle specific tyrosine kinase (MuSK) represent a distinct subset of those with this disease. Treatment and outcomes data in these patients are limited and conflicting. METHODS: We reviewed 110 MuSK-MG patients from two large clinics in Italy and the USA. RESULTS: Thirty-nine to 49% of patients with generalized, acetylcholine receptor antibody (AChR-Ab)-negative MG had MuSK-MG. Eighty-five percent were female, with disease onset typically in the fourth decade. Ocular and/or bulbar symptoms were present at onset in 79% of those studied. Eighty-five percent were MGFA class III or greater, and crisis occurred in 28%. Plasma exchange (PLEX) produced improvement in 93%, whereas only 61% improved after intravenous immunoglobulin. Long-term outcomes were comparable to those of patients with AChR-Ab-positive MG. CONCLUSIONS: MuSK-MG has a marked female predominance with frequent oculobulbar weakness and crises. Many patients deteriorate rapidly early in the disease, and PLEX is usually the preferred treatment. Long-term outcomes are similar to those of patients with AChR-Ab(+) MG. PMID- 21674493 TI - Stability of presynaptic vesicle pools and changes in synapse morphology in the amygdala following fear learning in adult rats. AB - Changes in synaptic strength in the lateral amygdala (LA) that occur with fear learning are believed to mediate memory storage, and both presynaptic and postsynaptic mechanisms have been proposed to contribute. In a previous study we used serial section transmission electron microscopy (ssTEM) to observe differences in dendritic spine morphology in the adult rat LA after fear conditioning, conditioned inhibition (safety conditioning), or naive control handling (Ostroff et al. [2010] Proc Natl Acad Sci U S A 107:9418-9423). We have now reconstructed axons from the same dataset and compared their morphology and relationship to the postsynaptic spines between the three training groups. Relative to the naive control and conditioned inhibition groups, the ratio of postsynaptic density (PSD) area to docked vesicles at synapses was greater in the fear-conditioned group, while the size of the synaptic vesicle pools was unchanged. There was significant coherence in synapse size between neighboring boutons on the same axon in the naive control and conditioned inhibition groups, but not in the fear-conditioned group. Within multiple-synapse boutons, both synapse size and the PSD-to-docked vesicle ratio were variable between individual synapses. Our results confirm that synaptic connectivity increases in the LA with fear conditioning. In addition, we provide evidence that boutons along the same axon and even synapses on the same bouton are independent in their structure and learning-related morphological plasticity. PMID- 21674499 TI - Cyto- and chemoarchitecture of the hypothalamic paraventricular nucleus in the C57BL/6J male mouse: a study of immunostaining and multiple fluorescent tract tracing. AB - The paraventricular nucleus of the hypothalamus (PVH) plays a critical role in the regulation of autonomic, neuroendocrine, and behavioral activities. This understanding has come from extensive characterization of the PVH in rats, and for this mammalian species we now have a robust model of basic PVH neuroanatomy and function. However, in mice, whose use as a model research animal has burgeoned with the increasing sophistication of tools for genetic manipulation, a comparable level of PVH characterization has not been achieved. To address this, we employed a variety of fluorescent tract tracing and immunostaining techniques in several different combinations to determine the neuronal connections and cyto- and chemoarchitecture of the PVH in the commonly used C57BL/6J male mouse. Our findings reveal a distinct organization in the mouse PVH that is substantially different from the PVH of male rats. The differences are particularly evident with respect to the spatial relations of two principal neuroendocrine divisions (magnocellular and parvicellular) and three descending preautonomic populations in the PVH. We discuss these data in relation to what is known about PVH function and provide the work as a resource for further studies of the neuronal architecture and function of the mouse PVH. PMID- 21674502 TI - Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models. AB - Ribosomal stress is an important, yet poorly understood, mechanism that results in activation of the p53 tumour suppressor. We present a mutation in the ribosomal protein Rpl27a gene (sooty foot ataxia mice), isolated through a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for p53 pathway defects, that shares striking phenotypic similarities with high p53 mouse models, including cerebellar ataxia, pancytopenia and epidermal hyperpigmentation. This phenocopy is rescued in a haploinsufficient p53 background. A detailed examination of the bone marrow in these mice identified reduced numbers of haematopoietic stem cells and a p53-dependent c-Kit down-regulation. These studies suggest that reduced Rpl27a increases p53 activity in vivo, further evident with a delay in tumorigenesis in mutant mice. Taken together, these data demonstrate that Rpl27a plays a crucial role in multiple tissues and that disruption of this ribosomal protein affects both development and transformation. PMID- 21674510 TI - Evaluation of focal hepatic lesions with ultrasound contrast agents. AB - Ultrasound contrast agents have gained wide acceptance for the detection and characterization of focal liver lesions. This pictorial essay reviews the growing body of evidence that supports the use of modern ultrasound contrast agents and illustrates the enhancement characteristics of commonly encountered focal liver lesions. Pathologies discussed include metastases, hepatocellular carcinomas, focal nodular hyperplasia, hepatocellular adenomas, hemangiomas, abscesses, complex cysts, and focal fatty deposition. PMID- 21674520 TI - Accuracy of electromyography needle placement in cadavers: non-guided vs. ultrasound guided. AB - INTRODUCTION: Accuracy of needle electromyography is typically ensured by use of anatomical landmarks and auditory feedback related to voluntary activation of the targeted muscle; however, in certain clinical situations, landmarks may not be palpable, auditory feedback may be limited or not present, and targeting a specific muscle may be more critical. In such settings, image guidance might significantly enhance accuracy. METHODS: Two electromyographers with different levels of experience examined 14 muscles in each of 4 fresh-frozen cadaver lower limbs. Each muscle was tested a total of eight times; four fine wires were inserted without ultrasound (US) guidance and four were inserted under US guidance. Overall accuracy as well as accuracy rates for the individual electromyographers were calculated. RESULTS: Non-guided needle placement was significantly less accurate than US-guided needle placement, particularly in the hands of less experienced electromyographers, supporting the use of real-time US guidance in certain challenging situations in the electromyography laboratory. PMID- 21674518 TI - An interactive voice response diary for patients with non-dystrophic myotonia. AB - INTRODUCTION: Non-dystrophic myotonia (NDM) is caused by mutations in muscle chloride and sodium channels. Currently, there is no standardized instrument for documenting symptom frequency and severity in NDM. METHODS: Subjects used an automated, interactive, telephone-based voice response diary (IVR) to record frequency and severity of stiffness, weakness, pain, and tiredness once a week for 8 weeks, after their baseline visits. RESULTS: We describe the IVR and report data on 76 subjects for a total of 385 person-weeks. Overall there were 5.1 calls per subject. Forty-eight subjects called in 5 or more times, and 14 called in 8 times. Stiffness was both the most frequent and severe symptom. Warm-up and handgrip myotonia were associated with higher severity scores for stiffness. CONCLUSIONS: IVR is a convenient technology to allow patient reporting of repeated and real-time symptom frequency and severity, and it is presently being used in a trial of mexiletine in NDM. PMID- 21674517 TI - Median nerve changes following steroid injection for carpal tunnel syndrome. AB - INTRODUCTION: Neuromuscular ultrasound is a painless, radiation-free, high resolution imaging modality for assessment of the peripheral nervous system. The purpose of this study was to use neuromuscular ultrasound to assess the changes that occur in the median nerve after steroid injection for carpal tunnel syndrome (CTS). METHODS: Ultrasound and nerve conduction studies were performed at baseline and 1 week, 1 month, and 6 months after steroid injection in 19 individuals (29 wrists) with CTS. RESULTS: Significant changes were noted in median nerve cross-sectional area (P < 0.001), mobility (P = 0.001), and vascularity (P = 0.042) at the distal wrist crease after steroid injection, and the nerve cross-sectional area correlated with symptom score and electrodiagnostic parameters. Changes in the ultrasonographic parameters were seen within 1 week of injection. CONCLUSIONS: These findings suggest neuromuscular ultrasound is potentially helpful for the assessment of individuals undergoing treatment for CTS, as typical changes can be expected after successful treatment injection. PMID- 21674521 TI - Anatomical study of the infrapatellar branch of the saphenous nerve using ultrasonography. AB - INTRODUCTION: The purpose of this study was to determine whether ultrasonography allows precise assessment of the course and relations of the infrapatellar branch of the saphenous nerve. METHODS: This work, initially undertaken in 5 cadavers, was followed by high-resolution ultrasonographic study in 10 healthy volunteers. The location and relations of the infrapatellar branch of the saphenous nerve to the adjacent anatomical structures were analyzed. The course of the nerve was classified according to its relation to the sartorius muscle as posterior or penetrating. RESULTS: The infrapatellar branch of the saphenous nerve could be identified consistently along the majority of its course by ultrasonography. Useful landmarks for the detection of the nerve could be defined. Some anatomical variations were noted. CONCLUSIONS: The infrapatellar branch of the saphenous nerve can be depicted by ultrasonography. Precise mapping of its anatomical course may have significant clinical applications. PMID- 21674522 TI - Evaluation of periodic electrodiagnostic measurements to monitor motor recovery after different peripheral nerve lesions in the rat. AB - INTRODUCTION: The advantage of minimally invasive electrodiagnostic methods for periodic evaluation of reinnervation at predefined time intervals does not seem to be widely recognized. In this study, using a rat model, we assessed the utility of periodic electrodiagnostic measurements for monitoring ongoing motor recovery after peripheral nerve injuries of differing severity. METHODS: In a comparative study, either unilateral sciatic nerve crush injury (n = 10), end-to end coaptation (n = 5), or 10-mm nerve autotransplantation (n = 10) were performed. During the 6-16-week period thereafter compound muscle action potentials (CMAPs) were recorded percutaneously every week in anesthetized animals. Motor nerve conduction velocity and percentage of axon loss were calculated and compared with footprint analyses (static sciatic index, SSI) and evaluations of sensory recovery. RESULTS: Our results clearly demonstrate that, although SSI measurements reliably demonstrated progress of regeneration after nerve crush injury only, differences in electrodiagnostically determined values precisely remodeled differences in axonal regeneration, which was confirmed by histomorphometric analysis of axonal regeneration. CONCLUSIONS: Percutaneous electrodiagnostic measurements enable reliable estimation of axonal regeneration parameters such as myelination and nerve fiber density and display in close proximity the actual status of axonal regeneration. PMID- 21674523 TI - Palliative care services in families of males with Duchenne muscular dystrophy. AB - INTRODUCTION: Palliative care services that address physical pain and emotional, psychosocial, and spiritual needs may benefit individuals with Duchenne muscular dystrophy (DMD). METHODS: The objective of this study was to describe the palliative care services that families of males with DMD report they receive. A questionnaire was administered to families of males with DMD born prior to January 1, 1982. Thirty-four families responded. RESULTS: Most families (85%) had never heard the term palliative care. Only attendant care and skilled nursing services showed much usage, with 44% and 50% indicating receipt of these services, respectively. Receipt of other services was reported less frequently: pastoral care (27%); respite care (18%); pain management (12%); and hospice care (6%). Only 8 respondents (25%) reported having any type of directive document in place. CONCLUSION: The data suggest a need for improved awareness of palliative care and related services among families of young men with DMD. PMID- 21674525 TI - Transcranial direct current stimulation does not modulate motor cortex excitability in patients with amyotrophic lateral sclerosis. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive disease caused by the degeneration of upper and lower motor neurons. The etiology of ALS is unclear, but there is evidence that loss of cortical inhibition could be related to motor neuron degeneration. We sought to determine whether cathodal transcranial direct current stimulation (tDCS) can reduce cortical excitability in patients with ALS. METHODS: Three sessions of cathodal tDCS, lasting 7, 11, or 15 minutes, were performed in 10 patients and 10 healthy controls. Corticospinal excitability was measured before and after the tDCS. RESULTS: Cathodal tDCS induced a consistent decrease in corticospinal excitability in healthy controls, but not in ALS patients. CONCLUSIONS: The failure of tDCS to produce an excitability shift in the patients supports the potential diagnostic value of tDCS as a marker of upper motor neuron involvement. However, variation in corticospinal excitability measurements both inter- and intraindividually will limit its usefulness. PMID- 21674527 TI - Brachial plexopathy as a rare presenting manifestation of scorpion envenomation. AB - We report a patient who experienced a rare manifestation of an acute, severe brachial plexopathy as the initial complication of scorpion (presumed Hemiscorpius lepturus species) envenomation. Features suggesting conduction block, due to either proximal demyelination or ion channel dysfunction, along with axonal loss were seen on serial electrophysiological studies. Possible mechanisms of the brachial plexopathy include direct compression from tissue edema or a toxic effect on the membrane channels along the nerve. PMID- 21674529 TI - AANEM position statement on neuromuscular medicine qualifications. PMID- 21674524 TI - Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms. AB - INTRODUCTION: Ryanodine receptor gene (RYR1) mutations have been associated with central core disease (CCD), multiminicore/minicore/multicore disease (MmD), and susceptibility to malignant hyperthermia (MH). METHODS: Patients with muscle symptoms in adulthood, who had features compatible with CCD/MmD, underwent clinical, histological, and genetic (RYR1 and SEPN1 genes) evaluations. Published cases of CCD and MmD with adult onset were also reviewed. RESULTS: Eight patients fulfilled the criteria for further analysis. Five RYR1 mutations, 4 of them unreported, were detected in 3 patients. Compound heterozygosity was proven in 1 case. CONCLUSIONS: To our knowledge, this is the only report of adult onset associated with recessive RYR1 mutations and central core/multiminicores on muscle biopsy. Although adult patients with CCD, MmD, and minimally symptomatic MH with abnormal muscle biopsy findings usually have a mild clinical course, differential diagnosis and carrier screening is crucial for prevention of potentially life-threatening reactions to general anesthesia. PMID- 21674528 TI - Epidermolysis bullosa with late-onset muscular dystrophy and plectin deficiency. AB - Epidermolysis bullosa associated with muscular dystrophy is a rare, autosomal recessive form of epidermolysis bullosa simplex caused by mutations in the plectin gene, PLEC1. We describe a phenotypically mild case due to compound heterozygous mutations in PLEC1 (2677_2685del and the novel mutation Q1644X). Clinical features included mild skin blistering since birth, slowly progressive and late-onset upper limb-predominant weakness, facial weakness, ptosis, incomplete ophthalmoplegia, and paroxysmal atrial fibrillation. PMID- 21674530 TI - Myasthenia gravis exacerbation after cetirizine administration. PMID- 21674536 TI - A method for visualization of surface texture anisotropy in different scales of observation. AB - Anisotropy of functional surfaces can in many practical cases significantly influence the surface function. Tribological contacts in sheet forming and engine applications are good examples. This article introduces and exemplifies a method for visualization of anisotropy. In a single graph, surface texture properties related to the anisotropy as a function of scale are plotted. The anisotropy graph can be used to explain anisotropy properties of a studied surface such as texture direction and texture strength at different scales of observation. Examples of milled steel surfaces and a textured steel sheet surface are presented to support the proposed methodology. Different aspects of the studied surfaces could clearly be seen at different scales. Future steps to improve filtering techniques and an introduction of length-scale analysis are discussed. PMID- 21674531 TI - Too much, too soon? PMID- 21674526 TI - Prior heat stress effects fatigue recovery of the elbow flexor muscles. AB - INTRODUCTION: Long-lasting alterations in hormones, neurotransmitters, and stress proteins after hyperthermia may be responsible for the impairment in motor performance during muscle fatigue. METHODS: Subjects (n = 25) performed a maximal intermittent fatigue task of elbow flexion after sitting in either 73 degrees or 26 degrees C to examine the effects of prior heat stress on fatigue mechanisms. RESULTS: The heat stress increased the tympanic and rectal temperatures by 2.3 degrees and 0.82 degrees C, respectively, but there was full recovery prior to the fatigue task. Although prior heat stress had no effects on fatigue-related changes in volitional torque, electromyographic (EMG) activity, torque relaxation rate, motor evoked potential (MEP) size, and silent period (SP) duration, prior heat stress acutely increased the pre-fatigue relaxation rate and chronically prevented long-duration fatigue (P < 0.05). CONCLUSIONS: These findings indicate that prior passive heat stress alone does not alter voluntary activation during fatigue, but prior heat stress and exercise produce longer-term protection against long-duration fatigue. PMID- 21674541 TI - Safety study of transcutaneous focused ultrasound for non-invasive skin tightening in Asians. AB - BACKGROUND AND OBJECTIVES: Transcutaneous intense focused ultrasound has emerged as a novel technology for non-invasive skin tightening. The objective of this study was to evaluate the safety profile of a transcutaneous focused ultrasound device for the treatment of facial skin laxity in Asians. MATERIALS AND METHODS: The patients received one to three full-face treatments with the transcutaneous focused ultrasound device. Three transducers (7.0 MHz, 3.0 mm focal depth; 7.0 MHz, 4.5 mm focal depth; 4.0 MHz, 4.5 mm focal depth) were used to deliver a single pass of microthermal coagulation zones without any topical anesthetics. Standardized photos were taken at baseline and at each follow-up with the Canfield Visia CR system(r) and were assessed by two independent physicians. Adverse effects were assessed up to 6 months post treatment. Subjective assessments in terms of pain and tolerability were also evaluated with patient questionnaires. RESULTS: Forty nine Chinese patients (skin types III-IV, mean age 53.3) completed a total of 68 treatment sessions. Transient erythema and edema were seen in the majority of patients. Focal bruising was present in up to 25% of treatment sessions. Two cases of post-inflammatory hyperpigmentation were seen on the forehead at 1-month post-treatment. One patient experienced focal twitching over the lower eyelid at 1-month follow-up, which was clinically consistent with hemifacial spasm and was unrelated to the ultrasound device. The degree of pain during treatment was recorded as severe in 54.4% of treatment sessions. CONCLUSIONS: Transcutaneous intense focused ultrasound appeared to be safe for non-invasive facial skin tightening in Asians. Adverse events were mild and transient. Pain control during treatment should be optimized. No serious permanent or delayed side effects were noted up to 6 months post treatment. PMID- 21674539 TI - High resolution at low beam energy in the SEM: resolution measurement of a monochromated SEM. AB - The resolution of secondary electron low beam energy imaging of a scanning electron microscope equipped with a monochromator is quantitatively measured using the contrast transfer function (CTF) method. High-resolution images, with sub-nm resolutions, were produced using low beam energies. The use of a monochromator is shown to quantitatively improve the resolution of the SEM at low beam energies by limiting the chromatic aberration contribution to the electron probe size as demonstrated with calculations and images of suitable samples. Secondary electron image resolution at low beam energies is ultimately limited by noise in the images as shown by the CTFs. PMID- 21674538 TI - A comparison of methods to evaluate the behavior of finite element models with rough surfaces. AB - Finite element (FE) modeling of rough surfaces is becoming increasingly common. However, the quality of the assumptions being made in these models, and thus the quality of the models themselves, is often unclear. Decisions about the geometry of the surface to be modeled, including the size of the surface to be modeled, the lateral resolution of the measured surface data to be used, and the formulation of the probabilistic surface to be used, can have a significant effect on a model's behavior. Similarly, varying model parameters, including the FE mesh density, can change the results by a factor of three or more. This work examines some of the metrics that can be used to evaluate the influence of these assumptions and parameters on FE models with rough surfaces and discusses the relative merits of each option. In particular, qualitative comparison of result plots, quantitative comparison and convergence of results parameters, qualitative and quantitative comparison of distributions of result values over various model dimensions, and more sophisticated comparison techniques inspired by image and signal processing are discussed. PMID- 21674537 TI - Discrimination of surface wear on obsidian tools using LSCM and RelA: pilot study results (area-scale analysis of obsidian tool surfaces). AB - This pilot study tests the reliability of laser scanning confocal microscopy (LSCM) to quantitatively measure wear on experimental obsidian tools. To our knowledge, this is the first use of confocal microscopy to study wear on stone flakes made from an amorphous silicate like obsidian. Three-dimensional surface roughness or texture area scans on three obsidian flakes used on different contact materials (hide, shell, wood) were documented using the LSCM to determine whether the worn surfaces could be discriminated using area-scale analysis, specifically relative area (RelA). When coupled with the F-test, this scale sensitive fractal analysis could not only discriminate the used from unused surfaces on individual tools, but was also capable of discriminating the wear histories of tools used on different contact materials. Results indicate that such discriminations occur at different scales. Confidence levels for the discriminations at different scales were established using the F-test (mean square ratios or MSRs). In instances where discrimination of surface roughness or texture was not possible above the established confidence level based on MSRs, photomicrographs and RelA assisted in hypothesizing why this was so. PMID- 21674542 TI - Targeting of sebaceous glands by delta-aminolevulinic acid-based photodynamic therapy: An in vivo study. AB - BACKGROUND AND OBJECTIVES: Wide application of ALA-PDT for acne is limited due to relative strong side effects, such as pain and erythema. The objective of this study was to establish a protocol for ALA-PDT that would provide specific destruction of sebaceous glands at the lowest concentrations and shortest contact times of ALA. MATERIALS AND METHODS: The rhino (hr(rh) hr(rh) ) murine model, an experimental acne model, was used in this study. A freshly prepared hydrophilic ALA hydrochloride ointment (2.5%, 5%, and 20%) was applied to the backs of 16 week-old male rhino mice. The fluorescence intensity (FI) of ALA-induced protoporphyrin IX (ALA-PpIX) on the skin was measured by spectrofluorometry. Skin samples were taken at 1, 2, and 4 hours after ALA application to determine the tissue distribution of ALA-PpIX by fluorescence microscopy. Light irradiation was also performed with a broadband light source (600-1100 nm, 15 J/cm2 , 60 mW/cm2) with subsequent histological examination 1 day after treatment. RESULTS: Prominent increases of ALA-PpIX were observed 1 hour after application of 5% and 20% ALA, while no increase was observed with 2.5% ALA until 2 hours. A direct correlation was found between ALA concentration and ALA-PpIX FI. While no fluorescence was detected 1 hour after application of 2.5% or 5% ALA, 20% ALA produced a strong fluorescence in the epidermis, utricle walls, and sebaceous glands. Histological evaluation showed no damage to skin treated with 2.5% ALA PDT incubated for 1 hour. Damage was still focused within the sebaceous glands with longer incubation times. Increased ALA concentrations resulted in more prominent damage to the epidermis and sebaceous glands, with deeper damage to the dermis when longer incubation times were used. CONCLUSION: Focused damage of sebaceous glands can be achieved with ALA-PDT when low concentrations of ALA (2.5 5.0%) and short incubation times (to 2 hours) were used. PMID- 21674535 TI - Effect of spironolactone on patients with atrial fibrillation and structural heart disease. AB - BACKGROUND: Several studies have shown that the modulation of fibrotic scar in cardiac diseases has beneficial effects on cardiac arrhythmias. In addition, recent reports suggest a potential role of mineralocorticoid receptor upregulation in atrial fibrillation (AF). The role of spironolactone, a mineralocorticoid receptor blocker and a potent antifibrotic agent, in AF is as yet unexplored. The aim of this study was to determine if spironolactone, a mineralocorticoid receptor blocker with potent antifibrotic properties, has beneficial effects on AF. HYPOTHESIS: Spironolactone therapy in patients with atrial fibrillation provides additional clinical benefits in addition to the current conventional pharmacological agents. METHODS: A comprehensive retrospective analysis was performed on 83 patients with AF, including 23 who were treated with spironolactone for >=3 months. The combined primary outcome of hospitalization for AF or direct current cardioversion (DCCV) was compared between patients treated with spironolactone in addition to the usual care for AF and those receiving conventional medical therapy alone. RESULTS: Patients receiving spironolactone had significantly fewer primary outcome events (AF related hospitalizations or DCCV) (22% vs 53%, P = 0.027). CONCLUSIONS: Spironolactone therapy is associated with a reduction in the burden of AF, as reflected by a combination of hospitalizations for AF and DCCV. Larger randomized controlled studies should be performed to evaluate the efficacy and safety of spironolactone as an adjunctive therapy for patients with AF. PMID- 21674534 TI - Liquid formulation of pentoxifylline is a poorly tolerated treatment for duchenne dystrophy. AB - INTRODUCTION: In this study we performed an open-label, pilot study of an orally administered liquid formulation of immediate-release pentoxifylline (PTX) on patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety, and tolerability were assessed. METHODS: The tolerability and safety of PTX and measures of muscle strength and function were evaluated during 12 months of treatment. RESULTS: Seventeen boys with DMD, between 4 and 8 years of age, were enrolled at one of five Cooperative International Neuromuscular Research Group (CINRG) centers. Only 9 were able to complete the 12-month PTX treatment phase; the primary reason for discontinuation was adverse events. Intolerable gastrointestinal side effects were experienced by 65% of participants. Two participants had severe leukopenia that resolved with medication withdrawal. CONCLUSIONS: Open-label treatment with a liquid formulation of immediate-release PTX resulted in a high incidence of adverse events in boys with DMD. Poor tolerability of this PTX formulation precluded adequate assessment of efficacy. PMID- 21674544 TI - Multi-excitation fluorescence spectroscopy for analysis of non-alcoholic fatty liver disease. AB - BACKGROUND AND OBJECTIVES: The increasing incidence of non-alcoholic fatty liver diseases (NAFLD) and the consequent progression to cirrhosis is expected to become a major cause of liver transplantation. This will exacerbate the organ donor shortage and mean that 'marginal' fatty liver grafts are more frequently used. Autofluorescence spectroscopy is a fast, objective, and non-destructive method to detect change in the endogenous fluorophores distribution and could prove to be a valuable tool for NAFLD diagnosis and transplant graft assessment. MATERIALS AND METHODS: A system was constructed consisting of a fibre probe with two laser diodes that provided excitation light at 375 and 405 nm, and an imaging spectrograph system. This was used to distinguish fluorescence spectra acquired from the harvested livers from mice with NAFLD of differing severity (healthy, mild steatotic and steatohepatitic). The fluorescence data were entered into a sparse multiclass probabilistic algorithm for disease classification. Histopathology, thiobarbituric acid reactive substances (TBARS) and alanine transaminase (ALT) assays were conducted in addition to the fluorescence measurements RESULTS: TBARS and ALT assays enabled differentiation of the steatohepatitic group from the mild steatosis and control groups (P <= 0.028) but failed to separate the mild steatotic group from the control group. The three groups were all clearly differentiated from each other using fluorescence spectroscopy, and classification accuracy was found to be 95%. CONCLUSION: Fluorescence spectroscopy appears to be a promising approach for the analysis of diseased liver tissue. PMID- 21674540 TI - Interstitial PDT for vascular anomalies. AB - INTRODUCTION: Photodynamic therapy is a proven therapeutic modality in the management of variety of pathologies involving the human body. Our aim in this clinical study is to prospectively evaluate the outcome following interstitial photodynamic therapy for patients with vascular anomalies. Patients' reports on quality of life with clinical and radiological evaluation were the main end point parameters used to assess the outcome. MATERIALS AND METHODS: Forty-three patients were referred to the UCLH Head and Neck Centre for treatment of vascular anomalies of the head and neck, including: infantile and congenital haemangiomas, venous, lymphatic and arteriovenous malformations. After multidisciplinary discussion, all patients underwent interstitial photodynamic therapy under general anaesthesia, using 0.15 mg/kg mTHPC as the photosensitising agent. Following treatment, patients were followed-up for a mean of 21 months. RESULTS: Fifteen out of nineteen patients who presented with long-term pain reported improvement after treatment. Also, 7/8 reported significant reduction of bleeding related to their vascular anomaly. Improvement of swelling was reported by 28/35 patients; while reduction of infection episodes was evident in 8/11 patients and 31/36 reported reduction in the disfigurement caused by their pathology. Significant reduction of swallowing problems was reported in 9/12 patients, and breathing problems in 7/9 patients. Clinical assessment showed that half of the patients had 'good response' to the treatment. Moderate clinical response was reported by 13 (30.2%) patients. Radiological assessment comparing imaging 6-week post-PDT to the baseline showed moderate response in 11 (25.6%) patients and significant response in 15 (34.9%) patients. CONCLUSION: This study on 43 patients with vascular anomalies undergoing interstitial photodynamic therapy provided evidence that PDT is a successful modality in the management of these pathologies that are resistant to conventional modalities, with minimal side effects. PMID- 21674545 TI - Induction of autologous mesenchymal stem cells in the bone marrow by low-level laser therapy has profound beneficial effects on the infarcted rat heart. AB - BACKGROUND AND OBJECTIVES: The adult mammalian heart is known to have a very limited regenerative capacity following acute ischemia. In this study we investigated the hypothesis that photobiostimulation of autologous bone-marrow derived mesenchymal stem cells (MSCs) by low-level laser therapy (LLLT) applied to the bone marrow (BM), may migrate to the infarcted area and thus attenuate the scarring processes following myocardial infarction (MI). MATERIALS AND METHODS: Sprague-Dawley rats underwent experimental MI. LLLT (Ga-Al-As diode laser, power density 10 mW/cm2, for 100 seconds) was then applied to the BM of the exposed tibia at different time intervals post-MI (20 minutes and 4 hours). Sham-operated infarcted rats served as control. RESULTS: Infarct size and ventricular dilatation were significantly reduced (76% and 75%, respectively) in the laser treated rats 20 minutes post-MI as compared to the control-non-treated rats at 3 weeks post-MI. There was also a significant 25-fold increase in cell density of c kit+ cells in the infarcted area of the laser-treated rats (20 minutes post-MI) as compared to the non-laser-treated controls. CONCLUSION: The application of LLLT to autologous BM of rats post-MI offers a novel approach to induce BM derived MSCs, which are consequently recruited from the circulation to the infarcted heart and markedly attenuate the scarring process post-MI. PMID- 21674543 TI - Sub-surface, micrometer-scale incisions produced in rodent cortex using tightly focused femtosecond laser pulses. AB - BACKGROUND AND OBJECTIVE: Techniques that allow targeted, micrometer-scale disruption in the depths of biological tissue, without affecting overlying structures or causing significant collateral damage, could potentially lead to new surgical procedures. We describe an optical technique to make sub-surface incisions in in vivo rodent brain and characterize the relationship between the cut width and maximum depth of these optical transections as a function of laser energy. MATERIALS AND METHODS: To produce cuts, high intensity, femtosecond laser pulses were tightly focused into and translated within the cortex, through a craniotomy, in anesthetized rodents. Imaging of stained brain slices was used to characterize cut width and maximum cutting depth. RESULTS: Cut width decreased exponentially as a function of depth and increased as the cube root of laser energy, but showed about 50% variation at fixed depth and laser energy. For example, at a laser energy of 13 uJ, cut width decreased from 158 +/- 43.1 um (mean +/- standard deviation) to 56 +/- 33 um over depths of approximately 200 800 um, respectively. Maximal cut depth increased logarithmically with laser energy, with cut depths of up to 1 mm achieved with 13 uJ pulses. We further showcased this technique by selectively cutting sub-surface cortical dendrites in a live, anesthetized transgenic mouse. CONCLUSIONS: Femtosecond laser pulses provide the novel capacity for precise, sub-surface, cellular-scale cuts for surgical applications in optically scattering tissues. PMID- 21674546 TI - Dual Effect of low-level laser therapy (LLLT) on the acute lung inflammation induced by intestinal ischemia and reperfusion: Action on anti- and pro inflammatory cytokines. AB - BACKGROUND AND OBJECTIVE: It is unknown if pro- and anti-inflammatory mediators in acute lung inflammation induced by intestinal ischemia and reperfusion (i-I/R) can be modulated by low-level laser therapy (LLLT). STUDY DESIGN/MATERIAL AND METHODS: A controlled ex vivo study was developed in which rats were irradiated (660 nm, 30 mW, 0.08 cm2 of spot size) on the skin over the right upper bronchus 1 hour post-mesenteric artery occlusion and euthanized 4 hours later. For pretreatment with anti-tumor necrosis factor (TNF) or IL-10 antibodies, the rats received either one of the agents 15 minutes before the beginning of reperfusion. METHODS: Lung edema was measured by the Evans blue extravasation and pulmonary neutrophils influx was determined by myeloperoxidase (MPO) activity. Both TNF and IL-10 expression and protein in lung were evaluated by RT-PCR and ELISA, respectively. RESULTS: LLLT reduced the edema (80.1 +/- 41.8 ug g-1 dry weight), neutrophils influx (0.83 +/- 0.02 * 106 cells ml-1), MPO activity (2.91 +/- 0.60), and TNF (153.0 +/- 21.0 pg mg-1 tissue) in lung when compared with respective control groups. Surprisingly, the LLLT increased the IL-10 (0.65 +/- 0.13) in lung from animals subjected to i-I/R. Moreover, LLLT (0.32 +/- 0.07 pg ml-1) reduced the TNF-alpha level in RPAECs when compared with i-I/R group. The presence of anti-TNF or IL-10 antibodies did not alter the LLLT effect on IL-10 (465.1 +/- 21.0 pg mg-1 tissue) or TNF (223.5 +/- 21.0 pg mg-1 tissue) in lung from animals submitted to i-I/R. CONCLUSION: The results indicate that the LLLT attenuates the i-I/R-induced acute lung inflammation which favor the IL-10 production and reduce TNF generation. PMID- 21674547 TI - A diagnostic system for articular cartilage using non-destructive pulsed laser irradiation. AB - BACKGROUND AND OBJECTIVES: Osteoarthritis involves dysfunction caused by cartilage degeneration, but objective evaluation methodologies based on the original function of the articular cartilage remain unavailable. Evaluations for osteoarthritis are mostly based simply on patient symptoms or the degree of joint space narrowing on X-ray images. Accurate measurement and quantitative evaluation of the mechanical characteristics of the cartilage is important, and the tissue properties of the original articular cartilage must be clarified to understand the pathological condition in detail and to correctly judge the efficacy of treatment. We have developed new methods to measure some essential properties of cartilage: a photoacoustic measurement method; and time-resolved fluorescence spectroscopy. MATERIALS AND METHODS: A nanosecond-pulsed laser, which is completely non-destructive, is focused onto the target cartilage and induces a photoacoustic wave that will propagate with attenuation and is affected by the viscoelasticity of the surrounding cartilage. We also investigated whether pulsed laser irradiation and the measurement of excited autofluorescence allow real time, non-invasive evaluation of tissue characteristics. RESULTS: The decay time, during which the amplitude of the photoacoustic wave is reduced by a factor of 1/e, represents the key numerical value used to characterize and evaluate the viscoelasticity and rheological behavior of the cartilage. Our findings show that time-resolved laser-induced autofluorescence spectroscopy (TR-LIFS) is useful for evaluating tissue-engineered cartilage. CONCLUSIONS: Photoacoustic measurement and TR-LIFS, predicated on the interactions between optics and living organs, is a suitable methodology for diagnosis during arthroscopy, allowing quantitative and multidirectional evaluation of the original function of the cartilage based on a variety of parameters. PMID- 21674549 TI - Noninvasive laser coagulation of the human vas deferens: optical and thermal simulations. AB - BACKGROUND AND OBJECTIVES: Successful noninvasive laser coagulation of the canine vas deferens, in vivo, has been previously reported. However, there is a significant difference between the optical properties of canine and human skin. In this study, Monte Carlo (MC) simulations of light transport through tissue and heat transfer simulations are performed to determine the feasibility of noninvasive laser vasectomy in humans. MATERIALS AND METHODS: A laser wavelength of 1,064 nm was chosen for deep optical penetration in tissue. MC simulations determined the spatial distribution of absorbed photons inside the tissue layers (epidermis, dermis, and vas). The results were convolved with a 3-mm-diameter laser beam, and then used as the spatial heat source for the heat transfer model. A laser pulse duration of 500 milliseconds, pulse rate of 1 Hz, and cryogen spray cooling were incident on the tissue for 60 seconds. Average laser power (5-9 W), cryogen pulse duration (60-100 milliseconds), cryogen cooling rate (0.5-1.0 Hz), and increase in optical transmission due to optical clearing (0-50%) were studied. RESULTS: After application of an optical clearing agent (OCA) to increase skin transmission by 50%, an average laser power of 6 W, cryogen pulse duration of 60 milliseconds, and cryogen cooling rate of 1 Hz resulted in vas temperatures of approximately 58 degrees C, sufficient for thermal coagulation, while 1 mm of the skin surface (epidermis and dermis) remained at a safe temperature of approximately 45 degrees C. CONCLUSIONS: MC and heat transfer simulations indicate that it is possible to noninvasively thermally coagulate the human vas deferens without adverse effects (e.g., scrotal skin burns), if an OCA is applied to the skin prior to the procedure. PMID- 21674548 TI - Photochemical tissue bonding: a potential strategy for treating limbal stem cell deficiency. AB - BACKGROUND AND OBJECTIVE: To determine the feasibility of attaching human amniotic membrane (HAM), pre-cultured with limbal stem cells (LSCs), to cornea using a novel, light-activated tissue bonding method. MATERIALS AND METHODS: LSCs were isolated from rabbit eyes, and then cultured on de-epithelialized HAM to create grafts (HAM/LSC). These were then transplanted onto rabbit eyes with surgically created limbal stem cell deficiency (LSCD). The grafts were secured either by sutures or by a light-activated method called photochemical tissue bonding (PTB). Outcomes included corneal opacity, inflammation, neovascularization, and collagen alignment. RESULTS: The isolated and cultured cells were verified to be LSCs based on their K19+/intergrin beta1+/P63+/K3 profile. Securing the HAM/LSC graft with PTB provided better outcomes. At 28 days post-surgery, the corneal opacity scores were significantly lower after securing the graft with PTB compared with suture attachment (0.8 +/- 0.5 vs. 1.8 +/- 0.5, P < 0.01). Similarly, neovascularization scores were lower after PTB (0.8 +/- 0.5 vs. 1.5 +/- 0.6, P < 0.01). Quantification of MPO and CD31 levels from immunofluorecent staining indicated that PTB stimulated less neutrophil infiltration (5.3 +/- 2.2 vs. 13.3 +/- 3.1, P < 0.01) and less new blood vessels formation (2.0 +/- 0.8 vs. 6.3 +/- 1.3, P < 0.01) at the wound site. The collagen alignment in PTB-treated corneas, as shown by immunofluorescence and second harmonic generation image, was better organized in the PTB-treated group than in the suture group. CONCLUSION: Bonding LSC grafts with PTB produced improved outcomes compared to suture attachment. This light-activated method is a promising modality for treating patients with LSCD. PMID- 21674550 TI - Fetal obstructive uropathy: impact of renal histopathological changes on prenatal interventions. PMID- 21674553 TI - Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of randomized, controlled trials and implications for the future. AB - Response-guided pegylated interferon (peg-IFN) plus ribavirin (P/R) therapy trials on genotype (G)1 and G2/G3 hepatitis C virus-infected patients provide contradictory results. We conducted meta-analyses of randomized, controlled trials to address (1) the benefit of a 72-week extended-duration therapy in G1 slow responders and (2) adequate shortened duration therapy in G1 and G2/G3-rapid responders. Seventeen trials were selected, including 624 G1 rapid responders, 570 G1 slow responders, and 2,062 G2/G3 rapid responders. Virologic outcomes and treatment discontinuation data were collected from published articles and by asking investigators. Pooled estimates of sustained virologic response (SVR), relapse, and dropouts were calculated using the random effects model, considering the variability of shortened duration, ribavirin dose, genotype, and baseline viral load. In G1 slow responders, a 72-week extended duration increased SVR (+10.7%; 95% CI [confidence interval]: +4.4% to + 17.1%), decreased relapse ( 12.3%; 95% CI: -25.4% to 0%), and did not significantly increase drop-out rates (+4.5%; 95% CI: -0.6% to + 9.6%). The benefit of extended duration was lower when using a weight-based ribavirin regimen (+8.7%; 95% CI: +1.7% to + 15.8%). In G1 rapid responders, a 24-week shortened duration decreased SVR (-12.5%; 95% CI: 19.2% to -5.8%) and increased relapse rates (+8.8%; 95% CI: +2.9% to + 14.8%). Such differences were not significant in patients with baseline viral load <400,000 UL/mL (-4.4%; 95% CI: -9.8% to + 1%). In G2/G3 rapid responders, SVR was more common for standard 24-week duration than for shortened durations (+4.1%; 95% CI: +0.1% to + 8.5), but this benefit was not significant when ribavirin was weight-adjusted and the short duration was 16 weeks (-1.7%; 95% CI: -6.1% to + 2.7%) and for G2 patients (+1.6%; 95% CI: -0.2% to + 5.5%). CONCLUSION: Long durations of P/R therapy improve SVR, regardless of genotype. This effect is nonetheless negligible in rapid responders, with the most favorable conditions for SVR (G2, G1 with low viral load, and G3 with weight-adjusted ribavirin regimen). PMID- 21674552 TI - Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin beta1 signaling in human hepatocellular carcinoma. AB - Angiopoietin-like protein 4 (ANGPTL4) plays complex and often contradictory roles in vascular biology and tumor metastasis, but little is known about its function in hepatocellular carcinoma (HCC) metastasis. In the present study, we showed that hypoxia-inducible factor 1alpha (HIF-1alpha) directly up-regulates ANGPTL4, and its stableness positively correlates with ANGPTL4 expression in HCC tissue. Overexpression of ANGPTL4 significantly increased HCC cell transendothelial migration in vitro and intrahepatic and distal pulmonary metastasis in vivo, whereas silencing ANGPTL4 expression or treatment with a neutralizing antibody specific for ANGPTL4 protein resulted in a reduced transendothelial migration. We also found that serum ANGPTL4 is higher in HCC patients, compared to healthy control, and correlates with intrahepatic metastasis and histological grade. Further, secreted ANGPTL4 promotes transendothelial migration and metastasis of HCC cells in vitro and in vivo through the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) of human umbilical vein endothelial cells and the activation of the VCAM-1/integrin beta1 axis. CONCLUSION: ANGPTL4 is a target gene of HIF-1alpha and acts as an important regulator in the metastasis of HCC. Serum ANGPTL4 correlates with tumor progression and metastasis and might be used to indicate prognosis in HCC patients. PMID- 21674554 TI - The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. AB - Distinguishing drug-induced liver injury (DILI) from idiopathic autoimmune hepatitis (AIH) can be challenging. We performed a standardized histologic evaluation to explore potential hallmarks to differentiate AIH versus DILI. Biopsies from patients with clinically well-characterized DILI [n = 35, including 19 hepatocellular injury (HC) and 16 cholestatic/mixed injury (CS)] and AIH (n = 28) were evaluated for Ishak scores, prominent inflammatory cell types in portal and intra-acinar areas, the presence or absence of emperipolesis, rosette formation, and cholestasis in a blinded fashion by four experienced hepatopathologists. Histologic diagnosis was concordant with clinical diagnosis in 65% of cases; but agreement on final diagnosis among the four pathologists was complete in only 46% of cases. Interface hepatitis, focal necrosis, and portal inflammation were present in all evaluated cases, but were more severe in AIH (P < 0.05) than DILI (HC). Portal and intra-acinar plasma cells, rosette formation, and emperiopolesis were features that favored AIH (P < 0.02). A model combining portal inflammation, portal plasma cells, intra-acinar lymphocytes and eosinophils, rosette formation, and canalicular cholestasis yielded an area under the receiver operating characteristic curve (AUROC) of 0.90 in predicting DILI (HC) versus AIH. All Ishak inflammation scores were more severe in AIH than DILI (CS) (P <= 0.05). The four AIH-favoring features listed above were consistently more prevalent in AIH, whereas portal neutrophils and intracellular (hepatocellular) cholestasis were more prevalent in DILI (CS) (P < 0.02). The combination of portal inflammation, fibrosis, portal neutrophils and plasma cells, and intracellular (hepatocellular) cholestasis yielded an AUC of 0.91 in predicting DILI (CS) versus AIH. CONCLUSION: Although an overlap of histologic findings exists for AIH and DILI, sufficient differences exist so that pathologists can use the pattern of injury to suggest the correct diagnosis. PMID- 21674555 TI - Genetic variation in interleukin-28B locus is associated with spontaneous clearance of HCV in children with non-1 viral genotype infection. PMID- 21674556 TI - Role of ethnicity in overweight and obese patients with nonalcoholic steatohepatitis. AB - The role of ethnicity in determining disease severity in nonalcoholic steatohepatitis (NASH) remains unclear. We recruited 152 patients with biopsy proven NASH, 63% of whom were Hispanic and 37% of whom were Caucasian. Both groups were well matched for age, sex, and total body fat. We measured: (1) liver fat by magnetic resonance imaging and spectroscopy; (2) fasting plasma glucose, fasting plasma insulin (FPI), and free fatty acid (FFA) levels; (3) total body fat by dual energy x-ray absorptiometry (DXA); (4) liver and muscle insulin sensitivity (insulin clamp with 3-[(3)H] glucose); (5) insulin resistance at the level of the liver (fasting endogenous glucose production derived from 3-[(3)H] glucose infusion * FPI) and adipose tissue (fasting FFA * FPI). Liver fat was slightly, but not significantly, higher in Hispanic vs. Caucasian patients (27 +/ 2% vs. 24 +/- 2%, p = 0.16). However, this trend did not translate into worse liver steatosis, necroinflammation or fibrosis. Patients with NASH had severe hepatic, adipose tissue and muscle insulin resistance versus healthy subjects without NASH nonalcoholic fatty liver disease, but there were no differences between both ethnic groups on these parameters. However, Hispanics versus Caucasians with type 2 diabetes mellitus (T2DM) had a trend for worse hepatic/adipose tissue insulin resistance and fibrosis. CONCLUSION: When Hispanic and Caucasian patients with NASH are well matched for clinical parameters, particularly for adiposity, slightly higher liver fat content is not associated with worse hepatic insulin resistance or more severe NASH on histology. Hispanic ethnicity does not appear to be a major determinant of disease severity in NASH, although those with diabetes may be at greater risk of fibrosis. Given the higher risk of T2DM in Hispanics, long-term studies are needed to define their risk of disease progression. PMID- 21674558 TI - Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. AB - Interleukin-22 (IL-22), one of the cytokines secreted by T helper 17 (Th17) cells, was recently reported to be a novel inflammation driver through STAT3 signaling activation. We aimed to investigate the role of IL-22 expression in hepatocellular carcinoma (HCC). We demonstrated significant up-regulation of IL 22 in human HCC tumor infiltrated leukocytes (TILs) compared to peripheral lymphocytes. Moreover, IL-22 expression was significantly higher in Edmondson Grade III-IV HCC patients versus Grade I-II, confirmed by both real-time polymerase chain reaction and immunohistochemistry. Both IL-22 receptor alpha and IL-23 were highly expressed in HCC and adjacent cirrhotic tissues compared to normal controls. Enhanced tumor growth and metastasis was found in mice that underwent subrenal transplantation of MHCC-97H cells cotransplanted with IL-22+ TILs cells. STAT3 phosphorylation and up-regulation of downstream genes Bcl-2, Bcl-XL, CyclinD1, and vascular endothelial growth factor (VEGF) promoted tumor growth and metastasis. In vitro studies confirmed the tumor-promoting and antiapoptotic effect of IL-22, as well as IL-6. In the mouse chronic hepatitis and HCC model, sustained and increased IL-22 expression and STAT3 activation were found in liver tissues. A linear correlation was demonstrated between IL-22 expression and hepatic complementary proliferation. An in vivo diethyl nitrosamine-induced mouse HCC model verified that tumor formation was significantly decreased in IL-22 knockout mice. CONCLUSION: Excessive IL-22 can be found in the HCC microenvironment, leading to tumor growth, inhibition of apoptosis, and promotion of metastasis due to STAT3 activation. PMID- 21674564 TI - Hairy cell leukaemia: biological and clinical overview from immunogenetic insights. AB - Hairy cell Leukaemia (HCL) is a rare neoplasm of peripheral B cells which represents a paradox in oncology. Despite its largely unknown origin and behaviour, HCL is one of the few example of dramatic success in the treatment of a malignancy. The recent steps forward to understanding the biology of HCL from immunogenetic and genomic studies have recently provided new insight into diagnosis and prognosis. Several data from immunoglobulin gene (IG) analysis have provided hints regarding the cell of origin and the ongoing selective interactions of the tumour BCR with environmental stimuli. It has also recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome and aggressive disease. These observations suggest a central role of the tumour B cell receptor in defining the outcome of HCL and that that IG gene analysis may have biological and prognostic relevance. Hopefully, IG analysis will help tailor treatment strategies for the most aggressive cases. PMID- 21674561 TI - Both innate and adaptive immunity mediate protective immunity against hepatitis C virus infection in chimpanzees. AB - Understanding the immunological correlates associated with protective immunity following hepatitis C virus (HCV) reexposure is a prerequisite for the design of effective HCV vaccines and immunotherapeutics. In this study we performed a comprehensive analysis of innate and adaptive immunity following HCV reexposure of two chimpanzees that had previously recovered from HCV-JFH1 infection. One of the chimpanzees, CH10274, became protected from active viremia by repeated challenges with homologous HCV-JFH1 and developed neutralizing antibodies, but was later infected with high-level viremia by a heterologous challenge with the HCV H77 virus that persisted for more than 1 year. The other chimpanzee, CH10273, was protected from a similar, heterologous H77 challenge without any evidence of neutralizing antibodies. Peripheral HCV-specific T-cell responses were present in both chimpanzees after challenges and, interestingly, the overall magnitude of response was lower in uninfected CH10273, which, however, exhibited a more robust CD8+ T-cell response. CH10273 showed higher hepatic expression of CD8 and CD56 (natural killer) markers than CH10274 did shortly after inoculation with H77. The heightened T-cell response was associated with an enhanced hepatic production of interferons (both type I and II) and interferon-stimulated genes (ISGs) in CH10273. Therefore, protection or clearance of HCV reinfection upon heterologous rechallenge depends on the activation of both intrahepatic innate and cellular immune responses. Furthermore, our results suggest that serum neutralizing antibodies may contribute to early control of viral replication and spread after homologous HCV rechallenges but may not be sufficient for a long-term protective immunity. CONCLUSION: Our study shows that protective immunity against HCV reinfection is orchestrated by a complex network of innate and adaptive immune responses. PMID- 21674571 TI - Practical aspects of the oral new anticoagulants. AB - After years of only oral vitamin K antagonists, there are new many new antithrombotic agents in development and on entering the marketplace. This review will analyze clinical trial results for these new agents-especially dibigatran, rivaroxaban, and apixiban. Also to be discussed are practical aspects of use of these new agents such monitoring, reversal, and use before procedures. PMID- 21674566 TI - Prenatal immune challenge compromises development of upper-layer but not deeper layer neurons of the mouse cerebral cortex. AB - Maternal infection during pregnancy is an environmental risk factor for the offspring to develop severe brain disorders, including schizophrenia. However, little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and emergence of cognitive and behavioral dysfunctions later in life. By injecting the viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) into mice, we investigated the influence of maternal immune challenge during pregnancy on the development of the cerebral cortex, a responsive organ for cognition. Stimulation of the maternal immune system did not influence the cell number or density of the cortical neurons of postnatal 10-day-old and 8-week-old offspring, whereas gene expressions of upper-layer-specific transcription factors were significantly reduced, without affecting those of the deeper-layer ones. Moreover, the prenatal Poly I:C injection impaired synaptic development of the upper-layer neurons at a later stage, and there was a decrease in the synaptophysin- and glutamic acid decarboxylase-67-positive puncta surrounding the neuronal cell bodies and an increase in the dendritic spine density in postnatal 8-week-old offspring. Considering their importance for cognitive function, the specific abnormalities in the development of upper-layer neuronal phenotypes may underlie the development of psychiatric brain and behavioral dysfunctions emerging after in utero exposure to an infection. PMID- 21674569 TI - Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease. AB - We studied whether combinations of botanical extracts enriched in either Delta(9) tetrahydrocannabinol (Delta(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3 nitropropionate (3NP) that were given combinations of Delta(9)-THC- and CBD enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Delta(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Delta(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Delta(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies. PMID- 21674557 TI - Tumor-secreted lysophostatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts. AB - Hepatocellular carcinoma (HCC) occurs in fibrotic liver as a consequence of underlying cirrhosis. The goal of this study was to investigate how the interaction between HCC cells and stromal fibroblasts affects tumor progression. We isolated and characterized carcinoma-associated fibroblasts (CAFs) and paired peritumoral tissue fibroblasts (PTFs) from 10 different patients with HCC and performed coculture experiments. We demonstrated a paracrine mechanism whereby HCC cells secrete lysophostatidic acid (LPA), which promotes transdifferentiation of PTFs to a CAF-like myofibroblastic phenotype. This effect is mediated by up regulation of specific genes related to a myo/contractile phenotype. After transdifferentiation, PTFs expressed alpha-smooth muscle actin (alpha-SMA) and enhanced proliferation, migration, and invasion of HCC cells occur. A pan-LPA inhibitor (alpha-bromomethylene phosphonate [BrP]-LPA), or autotaxin gene silencing, inhibited this PTF transdifferentiation and the consequent enhanced proliferation, migration, and invasion of HCC cells. In vivo, PTFs coinjected with HCC cells underwent transdifferentiation and promoted tumor progression. Treatment with BrP-LPA blocked transdifferentiation of PTFs, down-regulated myofibroblast-related genes, and slowed HCC growth and progression. Patients with larger and metastatic HCC and shorter survival displayed higher serum levels of LPA. Analysis of microdissected tissues indicated that stroma is the main target of the LPA paracrine loop in HCC. As a consequence, alpha-SMA-positive cells were more widespread in tumoral compared with paired peritumoral stroma. CONCLUSION: Our data indicate that LPA accelerates HCC progression by recruiting PTFs and promoting their transdifferentiation into myofibroblasts. Inhibition of LPA could prove effective in blocking transdifferentiation of myofibroblasts and tumor progression. PMID- 21674560 TI - Prolonged hepatomegaly in mice that cannot inactivate bacterial endotoxin. AB - Transient hepatomegaly often accompanies acute bacterial infections. Reversible, dose-dependent hepatomegaly also occurs when animals are given intravenous infusions of bacterial lipopolysaccharide (LPS). We found that recovery from LPS induced hepatomegaly requires a host enzyme, acyloxyacyl hydrolase (AOAH), that inactivates LPS. When we challenged Aoah(-/-) mice with low doses of LPS or gram negative bacteria, their livers remained enlarged (as much as 80% above normal) many weeks longer than did the livers of Aoah(+/+) animals. When compared with livers from LPS-primed Aoah(+/+) mice, LPS-primed Aoah(-/-) livers had (1) more numerous and larger Kupffer cells, (2) intrasinusoidal leukocyte aggregates and activated sinusoidal endothelial cells, and (3) sustained production of interleukin (IL)-10 and messenger RNAs (mRNAs) for tumor necrosis factor (TNF), IL-10, and IRAK-M. Depleting Kupffer cells decreased the liver enlargement by ~40%, whereas depletion of neutrophils, dendritic cells, natural killer (NK) cells, NK-T cells, or B cells had no effect. Pretreatment with dexamethasone almost completely prevented prolonged hepatomegaly in Aoah(-/-) mice, whereas neutralizing TNF or interleukin-1beta was only partially effective. In contrast, an antagonistic antibody to the IL-10 receptor increased LPS-induced hepatomegaly by as much as 50%. CONCLUSION: our findings suggest that persistently active LPS induces Kupffer cells to elaborate mediators that promote the accumulation of leukocytes within enlarged sinusoids. Large increases in IL-10 and several other modulatory molecules are unable to prevent prolonged hepatomegaly in mice that cannot inactivate LPS. The striking findings in this mouse model should encourage studies to find out how AOAH contributes to human liver physiology and disease. PMID- 21674576 TI - Infrequent occurrence of MPL exon 10 mutations in polycythemia vera and post polycythemia vera myelofibrosis. PMID- 21674577 TI - Bone marrow trephine biopsy findings in essential thrombocythemia. PMID- 21674565 TI - Blocking p75 (NTR) receptors alters polyinnervationz of neuromuscular synapses during development. AB - High-resolution immunohistochemistry shows that the receptor protein p75(NTR) is present in the nerve terminal, muscle cell, and glial Schwann cell at the neuromuscular junction (NMJ) of postnatal rats (P4-P6) during the synapse elimination period. Blocking the receptor with the antibody anti-p75-192-IgG (1-5 MUg/ml, 1 hr) results in reduced endplate potentials (EPPs) in mono- and polyinnervated synapses ex vivo, but the mean number of functional inputs per NMJ does not change for as long as 3 hr. Incubation with exogenous brain-derived neurotrophic factor (BDNF) for 1 hr (50 nM) resulted in a significant increase in the size of the EPPs in all nerve terminals, and preincubation with anti-p75-192 IgG prevented this potentiation. Long exposure (24 hr) in vivo of the NMJs to the antibody anti-p75-192-IgG (1-2 MUg/ml) results in a delay of postnatal synapse elimination and even some regrowth of previously withdrawn axons, but also in some acceleration of the morphologic maturation of the postsynaptic nicotinic acetylcholine receptor (nAChR) clusters. The results indicate that p75(NTR) is involved in both ACh release and axonal retraction during postnatal axonal competition and synapse elimination. PMID- 21674572 TI - Partial and total monosomal karyotypes in myelodysplastic syndromes: comparative prognostic relevance among 421 patients. AB - Myelodysplastic syndromes (MDS) include a group of heterogeneous hematological disorders with a variable risk of leukemic evolution and short survival. Around 40-50% of patients show abnormal karyotypes that are mostly characterized by monosomies or deletions. Cytogenetic findings are an independent prognostic factor and the International prognostic scoring system (IPSS) differentiates three cytogenetic categories, despite the Intermediate one being heterogeneous. The aim of this study, including 421 Argentinean patients with primary MDS, is to characterize the cytogenetic profile, to test its prognostic value and to compare partial and monosomal karyotypes against other cytogenetic findings. An abnormal karyotype (median survival: 26 months) was observed in 176 patients. The presence of complex karyotypes, number of alterations, and the IPSS cytogenetic groups showed significant differences for predicting outcome. Behavior of patients with isolated deletions (median survival: 49 months) did not differ from those with normal karyotype (56 months, P = 0.654) or Good prognostic findings (43 months, P = 0.371). However, a worse prognosis was observed when another alteration was added (31 months, P = 0.043). Karyotypes with autosomal monosomies (median survival: 16 months) had a prognostic impact similar to other Poor cytogenetic findings (17 months, P = 0.626). In our population classified according to French American-British (FAB) or World Health Organization (WHO), this new categorization of cytogenetic abnormalities, recognizing three different risk groups, showed an independent prognostic impact and a better discriminating power than the IPSS categories. It can be concluded that all isolate deletions (excluding 7q-) are good prognostic findings and all monosomies (excluding Y chromosome loss) are bad indicators. PMID- 21674580 TI - Intrafollicular neoplasia/"in situ" lymphoma: a proposal for morphology and immunodiagnostic classification. PMID- 21674567 TI - S100B and neurofibromin immunostaining and X-inactivation patterns of laser microdissected cells indicate a multicellular origin of some NF1-associated neurofibromas. AB - Neurofibromatosis 1 (NF1) is an autosomal dominant disease that predisposes individuals to developing benign neurofibromas. Some features and consequences of NF1 appear to result from partial deficiency of neurofibromin (Nfn), the NF1 gene protein product, as a result of haploinsufficiency for the NF1 gene. Other features and consequences of NF1 appear to involve total deficiency of Nfn, which arises as a result of either loss of function of the second NF1 allele or excess degradation of Nfn produced by the second allele in a particular clone of cells. We used immunofluorescence to assess the presence of Nfn in putative Schwann cells (S100B(+) ) and non-Schwann cells (S100B(-) ) in 36 NF1-derived benign neurofibromas classified histologically as diffuse or encapsulated. The S100B(+) /Nfn(-) cell population made up only 18% +/- 10% (mean +/- standard deviation) of the neurofibroma cells in both the diffuse and encapsulated neurofibromas. The proportion of S100B(+) /Nfn(+) cells was significantly higher and the proportion of S100B(-) /Nfn(-) cells was significantly lower in diffuse neurofibromas than in encapsulated neurofibromas. We isolated S100B(+) /Nfn(+) , S100B(+) /Nfn(-) , and S100B(-) /Nfn(+) cells by laser microdissection and, using X-chromosome inactivation profiles, assessed clonality for each cell type. We showed that, although some neurofibromas include a subpopulation of S100B(+) /Nfn(-) cells consistent with clonal expansion of a Schwann cell progenitor that has lost function of both NF1 alleles, other neurofibromas do not show evidence of monoclonal proliferation of Schwann cells. Our findings suggest that, although clonal loss of neurofibromin function is probably involved in the development of some NF1-associated neurofibromas, other pathogenic processes also occur. PMID- 21674559 TI - Utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. AB - Elevated serum immunoglobulin G4 (sIgG4) is a feature of autoimmune pancreatitis (AIP) and IgG4-associated cholangitis (IAC); a >2-fold increase in sIgG4 is considered highly specific for these disorders. Many patients with IAC present with biliary strictures and obstructive jaundice, making cholangiocarcinoma (CCA) an important differential diagnosis. We determined the value of sIgG4 in distinguishing IAC from CCA. sIgG4 levels were measured in a test cohort of 126 CCA and 50 IAC patients. The results were confirmed in a validation cohort of 161 CCA and 47 IAC patients. Of the 126 CCA patients in the test cohort, 17 (13.5%) had elevated sIgG4 (>140 mg/dL) and four (3.2%) had a >2-fold (>280 mg/dL) increase. Primary sclerosing cholangitis (PSC) was present in 31/126 CCA patients, of whom seven (22.6%) had elevated sIgG4 and two (6.5%) had a >2-fold elevation. Of the 50 IAC patients, 39 (78.0%) had elevated sIgG4 and 25 (50.0%) had a >2-fold increase. The results in the validation cohort were consistent with those of the test cohort. CONCLUSION: Although elevated sIgG4 levels are characteristic of IAC, some patients with CCA, particularly with PSC, have elevated sIgG4 levels, including a small percentage with a more than a 2-fold increase in sIgG4. Therefore, sIgG4 elevation alone does not exclude the diagnosis of CCA. Depending on the prevalence of the two diagnoses, the use of a 2-fold cutoff for sIgG4 may not reliably distinguish IAC from CCA. At a cutoff of 4 times the upper limit of normal, sIgG4 is 100% specific for IAC. PMID- 21674581 TI - Choosing the right TKI for chronic myeloid leukemia: when the truth lies in "long term" safety and efficacy. PMID- 21674578 TI - The JAK2 exon 12 mutations: a comprehensive review. AB - A variety of acquired mutations targeting JAK2 exon 12 are present in those patients with the myeloproliferative neoplasm, polycythemia vera, that lack the more common JAK2V617F mutation. Both mutation types perturb erythropoiesis, with individuals presenting with a raised hematocrit, reduced serum erythropoietin levels, and erythropoietin-independent erythroid progenitor cells. However, there are also phenotypic differences that, until recently, precluded a significant proportion of patients with a JAK2 exon 12 mutation from receiving an appropriate diagnosis. Here, we review the literature published on the JAK2 exon 12 mutations and compare the biology associated with these mutations with that of JAK2V617F. PMID- 21674573 TI - Identification of prognostic factors for plerixafor-based hematopoietic stem cell mobilization. AB - The introduction of plerixafor has enabled successful collection of stem cells in the majority of patients with lymphoma or myeloma in whom previous attempts at mobilization have failed. However, a proportion of patients have been shown to be resistant to this mobilization regimen. To identify the factors that impair stem cell mobilization and collection with plerixafor, we reviewed the data for 197 patients who had undergone mobilization with plerixafor and granulocyte-colony stimulating factor in Central Europe. Predictors of mobilization failure were evaluated using logistic regression analysis. Among the 197 patients mobilized, the target of >=2.0 * 10(6) CD34+ cells/kg was collected from 133 (67.5%). Our analysis revealed that previous treatment with lenalidomide, bortezomib, melphalan, radiotherapy, or autologous stem cell transplantation and regimen of plerixafor use in combination with chemotherapy had no significant effect on the efficiency of collection. In contrast, an age >=65 years (odds ratio 0.331, 95% CI: 0.112-0.977, P < 0.05), a diagnosis of non-Hodgkin's lymphoma (odds ratio 0.277, 95% CI: 0.124-0.622, P < 0.01), and treatment with >= four chemotherapy regimens (odds ratio 0.366, 95% CI: 0.167-0.799, P < 0.05) were associated significantly with failed mobilization. The rate of successful mobilizations was decreased in patients treated with purine analogues (odds ratio 0.323, 95% CI: 0.096-1.094, P = 0.07) but increased in female patients (odds ratio 1.961, CI: 0.943-4.080, P = 0.07). Patients who are characterized by the above negative features could benefit potentially from further improvement in the mobilization strategy. PMID- 21674562 TI - Efficient production of Fah-null heterozygote pigs by chimeric adeno-associated virus-mediated gene knockout and somatic cell nuclear transfer. AB - Hereditary tyrosinemia type I (HT1) results in hepatic failure, cirrhosis, and hepatocellular carcinoma (HCC) early in childhood and is caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (FAH). In a novel approach we used the chimeric adeno-associated virus DJ serotype (AAV-DJ) and homologous recombination to target and disrupt the porcine Fah gene. AAV-DJ is an artificial chimeric AAV vector containing hybrid capsid sequences from three naturally occurring serotypes (AAV2, 8, and 9). The AAV-DJ vector was used to deliver the knockout construct to fetal pig fibroblasts with an average knockout targeting frequency of 5.4%. Targeted Fah-null heterozygote fibroblasts were used as nuclear donors for somatic cell nuclear transfer (SCNT) to porcine oocytes and multiple viable Fah-null heterozygote pigs were generated. Fah-null heterozygotes were phenotypically normal, but had decreased Fah transcriptional and enzymatic activity compared to wildtype animals. CONCLUSION: This study is the first to use a recombinant chimeric AAV vector to knockout a gene in porcine fibroblasts for the purpose of SCNT. In using the AAV-DJ vector we observed targeting frequencies that were higher than previously reported with other naturally occurring serotypes. We expect that the subsequent generation of FAH-null homozygote pigs will serve as a significant advancement for translational research in the areas of metabolic liver disease, cirrhosis, and HCC. PMID- 21674579 TI - Novel CUX1 missense mutation in association with 7q- at leukemic transformation of MPN. PMID- 21674570 TI - Characterization of NTera2/D1 cells as a model system for the investigation of cannabinoid function in human neurons and astrocytes. AB - The limited availability and potential to culture primary human brain cells means that there is still a need for cell lines that reliably model human neurons and glial cells. The human-derived NTera2/D1 (NT2) cell line is a promising tool from which both neuronal (NT2N) and astrocytic (NT2A) cells can be derived in vitro. Here we have investigated the potential to use this cell model to investigate the endocannabinoid system in the CNS. Through immunocytochemical characterization with a range of neuronal and glial markers, we found that these cell lines differentiate into cells with immature neuronal and astrocytic phenotypes, respectively. By real-time PCR, immunocytochemistry, and functional inhibition of cAMP accumulation, the cannabinoid 1 receptors were identified only on NT2N cells, consistent with high levels of expression of this receptor in neuronal cells of the CNS. No evidence of cannabinoid 2 receptor expression was found on any of the NT2 cell types. Both the precursors and the differentiated NT2N and NT2A cells demonstrated mRNA expression for the key enzymes involved in endocannabinoid synthesis and degradation. This work establishes a cannabinergic phenotype in NT2N and NT2A cells, providing an alternative human derived renewable cell model for investigation of cannabinoid receptor function and endocannabinoid synthesis and metabolism in the CNS. PMID- 21674568 TI - Pituitary adenylyl cyclase-activating peptide counteracts hedgehog-dependent motor neuron production in mouse embryonic stem cell cultures. AB - Pituitary adenylyl cyclase-activating peptide (PACAP; ADCYAP1) is a neuropeptide that regulates a wide array of functions within the brain and periphery. We and others have previously demonstrated that PACAP and its high-affinity receptor PAC1 are expressed in the embryonic mouse neural tube, suggesting that PACAP plays a role in early brain development. Moreover, we previously showed that PACAP antagonizes the mitotic action of Sonic hedgehog (Shh) in postnatal cerebellar granule precursors. In the present study, we demonstrate that PACAP completely blocked Shh-dependent motor neuron generation from embryonic stem cell cultures and reduced mRNA levels of the Shh target gene Gli-1 and several ventral spinal cord patterning genes. In vivo examination of motor neuron and other patterning markers in embryonic day 12.5 spinal cords of wild-type and PACAP deficient mice by immunofluorescence, on the other hand, revealed no obvious alterations in expressions of Islet1/2, MNR2, Lim1/2, Nkx2.2, or Shh, although the Pax6-positive area was slightly expanded in PACAP-deficient spinal cord. Caspase-3 staining revealed low, and similar, numbers of cells undergoing apoptosis in embryonic wild-type vs. PACAP-deficient spinal cords, whereas a slight but significant increase in number of mitotic cells was observed in PACAP deficient mice. Thus, although PACAP has a strong capacity to counteract Shh signaling and motor neuron production in vitro, corresponding patterning defects associated with PACAP loss may be obscured by compensatory mechanisms. PMID- 21674574 TI - Predictors of complete responses with denileukin diftitox in cutaneous T-cell lymphoma. PMID- 21674582 TI - Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia. AB - OBJECTIVE: Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia-ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry. METHODS: Thirty-six newborn piglets were randomized (all groups n = 9), with intervention from 2 to 26 hours, to: (1) normothermia; (2) normothermia + 24 hours 50% inhaled xenon; (3) 24 hours hypothermia (33.5 degrees C); or (4) 24 hours hypothermia (33.5 degrees C) + 24 hours 50% inhaled xenon. Serial MRS was acquired before, during, and up to 48 hours after hypoxia ischemia. RESULTS: Mean arterial blood pressure was lower in all treatment groups compared with normothermia (p < 0.01) (although >40mmHg); the combined therapy group required more fluid boluses (p < 0.05) and inotropes (p < 0.001). Compared with no intervention, both hypothermia and xenon-augmented hypothermia reduced the temporal regression slope magnitudes for phosphorus-MRS inorganic phosphate/exchangeable phosphate pool (EPP) and phosphocreatine/EPP (both p < 0.05); for lactate/N-acetylaspartate (NAA), only xenon-augmented hypothermia reduced the slope (p < 0.01). Xenon-augmented hypothermia also reduced transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)(+) nuclei and caspase 3 immunoreactive cells in parasagittal cortex and putamen and increased microglial ramification in midtemporal cortex compared with the no treatment group (p < 0.05). Compared with hypothermia, however, combination treatment did not reach statistical significance for any measure. Lactate/NAA showed a strong positive correlation with TUNEL; nucleotide triphosphate/EPP showed a strong negative correlation with microglial ramification (both p < 0.01). INTERPRETATION: Compared with no treatment, xenon-augmented hypothermia reduced cerebral MRS abnormalities and cell death markers in some brain regions. Compared with hypothermia, xenon-augmented hypothermia did not reach statistical significance for any measure. The safety and possible improved efficacy support phase II trials. PMID- 21674575 TI - High prevalence of polyclonal hypergamma-globulinemia in adult males in Ghana, Africa. AB - Chronic antigenic stimulation is associated with hypergamma-globulinemia. Higher rates of hypergamma-globulinemia in tropical populations are maintained even with migration to temperate regions. We conducted a population-based screening study to assess the prevalence and risk factors for hypergamma-globulinemia in Ghana, Africa. 917 Ghanaian males (50-74 years) underwent in-person interviews and health examinations. Serum from all persons was analyzed by electrophoresis performed on agarose gel; serum with a discrete/localized band was subjected to immunofixation. 54 persons with monoclonal proteins were excluded and 17 samples were insufficient for analysis. Using logistic regression and Chi-square statistics we analyzed patterns of hypergamma-globulinemia. Among 846 study subjects, the median gamma-globulin level was 1.86 g/dL. On the basis of a U.S. reference, 616 (73%) had hypergamma-globulinemia (>1.6 g/dL) and 178 (21%) had gamma-globulin levels >2.17 gm/dl. On multivariate analyses, lower education status (P = 0.0013) and never smoking (P = 0.038) were associated with increased gamma-globulin levels. Self-reported history of syphilis was associated with hypergamma-globulinemia. We conclude that three quarters of this population-based adult Ghanaian male sample had hypergamma-globulinemia with gamma-globulin levels >1.6 g/dL. Future studies are needed to uncover genetic and environmental underpinnings of our finding, and to define the relationship between hypergamma globulinemia, monoclonal gammopathy of undetermined significance (MGUS), and multiple myeloma. PMID- 21674584 TI - Predictive value of neurologic prognostic indicators in hypothermia after cardiac arrest. PMID- 21674590 TI - Chronic cerebrospinal venous insufficiency and susceptibility to multiple sclerosis. PMID- 21674586 TI - The blood-spinal cord barrier: morphology and clinical implications. AB - The blood-spinal cord barrier (BSCB) is the functional equivalent of the blood brain barrier (BBB) in the sense of providing a specialized microenvironment for the cellular constituents of the spinal cord. Even if intuitively the BSCB could be considered as the morphological extension of the BBB into the spinal cord, evidence suggests that this is not so. The BSCB shares the same principal building blocks with the BBB; nevertheless, it seems that morphological and functional differences may exist between them. Dysfunction of the BSCB plays a fundamental role in the etiology or progression of several pathological conditions of the spinal cord, such as spinal cord injury, amyotrophic lateral sclerosis, and radiation-induced myelopathy. This review summarizes current knowledge of the morphology of the BSCB, the methodology of studying the BSCB, and the potential role of BSCB dysfunction in selected disorders of the spinal cord, and finally summarizes therapeutic approaches to the BSCB. PMID- 21674592 TI - Improvement of the cytotoxicity and tumor selectivity of glycyrrhetinic acid by derivatization with bifunctional amino acids. AB - Glycyrrhetinic acid (GA) is a major ingredient of the dried extract of licorice roots; its antitumor activity is low compared to other members of the triterpenoic family. For example, oleanolic acid, betulin or betulinic acid are more cytotoxic with a pronounced activity for tumor cells. GA, however, is easily to earn, cheap and shows apoptotic effects on tumor cells--like the other triterpenoic acids. These facts bring GA and derivatives in the focus of our scientific interest. Here we tried to improve the poor cytotoxicity of GA by simple derivatization. Thus, we selected various glutamyl and aspartyl substituents for the synthesis of C(3) esters of GA methyl ester. A short (3-5 steps) synthesis was elaborated that allowed to access more effective compounds. One compound, methyl 3beta 3-(O-benzyl-L-glutamyl)-11-oxo-olean-12-en-30-oate (5), having a glutamyl substituent with a benzyl protected side chain showed up to 67-fold higher cytotoxicity and an up to 140-fold better selectivity towards tumor cells than parent GA. All compounds were evaluated by a sulforhodamine B assay as well as by a trypan blue test and extra acridine orange/ethidium bromide tests for apoptosis. PMID- 21674585 TI - Targeting the p53 pathway to protect the neonatal ischemic brain. AB - OBJECTIVE: To investigate whether inhibition of mitochondrial p53 association using pifithrin-MU (PFT-MU) represents a potential novel neuroprotective strategy to combat perinatal hypoxic-ischemic (HI) brain damage. METHODS: Seven-day-old rats were subjected to unilateral carotid artery occlusion and hypoxia followed by intraperitoneal treatment with PFT-MU, an inhibitor of p53 mitochondrial association or PFT-alpha an inhibitor of p53 transcriptional activity. Cerebral damage, sensorimotor and cognitive function, apoptotic pathways (cytosolic cytochrome c, Smac/DIABLO, active caspase 3), and oxidative stress (lipid peroxidation and PARP-1 cleavage) were investigated. RESULTS: PFT-MU treatment completely prevented the HI-induced increase in mitochondrial p53 association at 3 hours and reduced neuronal damage at 48 hours post-HI. PFT-MU had long-term (6 10 weeks post-HI) beneficial effects as sensorimotor and cognitive outcome improved and infarct size was reduced by ~79%. Neuroprotection by PFT-MU treatment was associated with strong inhibition of apoptotic pathways and reduced oxidative stress. Unexpectedly, PFT-MU also inhibited HI-induced upregulation of p53 target genes. However, the neuroprotective effect of inhibiting only p53 transcriptional activity by PFT-alpha was significantly smaller and did not involve reduced oxidative stress. INTERPRETATION: We are the first to show that prevention of mitochondrial p53 association by PFT-MU strongly improves functional outcome and decreases lesion size after neonatal HI. PFT-MU not only inhibits mitochondrial release of cytochrome c, but also inhibits oxidative stress. We propose that as a consequence nuclear accumulation of p53 and transcription of proapoptotic target genes are prevented. In conclusion, targeting p53 mitochondrial association by PFT-MU may develop into a novel and powerful neuroprotective strategy. PMID- 21674593 TI - Interactions of cadmium and zinc impact their toxicity to the earthworm Aporrectodea caliginosa. AB - Individual and binary mixture effects of Cd and Zn on mortality of the earthworm Aporrectodea caliginosa were investigated in one soil type. Mutual, systemic interactions of Cd and Zn were assessed over a broad range of concentration combinations. Exposures were expressed as measured total concentrations in soil, porewater concentrations, and CaCl(2)-extractable concentrations. The Cd-Zn and Zn-Cd interactions in soil were estimated by comparing partition coefficients (K(d)) of one metal in the presence and absence of the second metal. Simple patterns of mixture toxicity (additive, antagonistic, or synergistic) were evaluated by the toxic unit approach. The more complex patterns (dose ratio dependent or dose level dependent) were quantified by the MIXTOX model. The partitioning of Cd and Zn between soil and pore water was affected neither by their concentration nor presence of the other metal, and metal partitioning remained linear at all exposure levels tested. The effect of the Cd and Zn mixtures on mortality of A. caliginosa was mainly antagonistic, and the magnitude of antagonism (1.1- 2.7 toxic units) was dependent upon both the relative concentrations of Cd and Zn and the concentration magnitudes. Interactions of both metals occurred at the organism level and were manifested in terms of effects (28-d median lethal concentrations). The present study highlights the importance of identifying the relative influence of various interactions from external exposure to internal assimilation in evaluating mixture toxicity. PMID- 21674594 TI - Variability of urodynamic parameters in patients with overactive bladder. AB - AIMS: To report interpatient, intrapatient, and study site variability of urodynamic study (UDS) parameters in patients with overactive bladder (OAB). METHODS: Fifty-eight patients with OAB participated in a randomized, double blind, placebo-controlled, urodynamic trial of an experimental OAB drug. Patients underwent 3 serial cystometries (CMGs) at three times: screening, pre-dose, and 4 hr postdose. This post hoc analysis describes intrapatient, interpatient, and site variability for the 6 CMGs prior to administration of study drug. Sites were given standard procedures for equipment calibration and UDS technique. Instilled volumes and pressures were recorded at first sensation of filling, first desire to void (FDV), strong desire to void (SDV), and maximum cystometric capacity (MCC). RESULTS: The UDS volume endpoint with the smallest observed within-patient variability based on coefficient of variation (%CV) was MCC (%CV 24). Pressure measurements of all bladder sensations had larger within-patient variability than volume (MCC %CV 105). The between-patient variability was greater than within patient variability for all bladder sensation volumes. Between-patient MCC variability for the 6 pre-treatment CMGs ranged from %CV of 50 to 58, whereas the within-patient %CV for MCC was 21-23. Excellent reproducibility was observed for bladder volume for MCC (intraclass correlation coefficients, range: 0.80-0.84). The between-site variability was large, as demonstrated by the mean volumes by site for MCC (132-397 ml). CONCLUSIONS: MCC was the most reproducible sensation. Pressure measurements were substantially more variable than volume. Between patient variability was substantially greater than within-patient variability. The observed intersite variability suggests that despite detailed instructions, sensations may not have been measured in a consistent manner across sites. PMID- 21674597 TI - Repeated Botulinum-A toxin injection in the treatment of neuropathic bladder dysfunction and poor bladder compliance in children with myelomeningocele. AB - AIMS: To evaluate the efficacy of intradetrusor injection of Botulinum-A toxin (BoNT/A) in children with neuropathic bladder dysfunction and poor bladder compliance, due to meningomyelocele. METHODS: We retrospectively reviewed the charts of 11 children (mean age 6.7 +/- 5.3 years) with neuropathic bladder and poor bladder compliance (mean 7 ml/cmH(2) O) treated with intradetrusor injection of BoNT/A. After urodynamic evaluation a standardized injection was performed. The authors describe their results in 11 children after the first (5*) or repeated (6*) BoNT/A injections. Re-evaluation was performed 3 and 12 months after each injection. RESULTS: Three months after injection detrusor pressure decreased by 17% and bladder capacity increased by 33%. In all but 1 patient bladder compliance stayed poor. Twelve months after treatment patients still had an effect but the values were already reverting towards preoperative levels. With repeated injections we achieved a similar effect on capacity and detrusor pressure as after the first injection. Overall, bladder compliance normalized (>20 cmH(2) O) in only 1 patient. CONCLUSIONS: The results confirmed the positive temporary effect of BoNT/A on detrusor pressure and bladder capacity in children with myelomeningocele, even after repeated injections. Nevertheless, bladder compliance stayed severely pathological. Whether an earlier treatment may prevent poor bladder compliance is a yet unanswered question. PMID- 21674587 TI - Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury. AB - OBJECTIVE: Perinatal brain injury is a major cause of neurodevelopmental handicaps. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to cell damage and death, including caspase-dependent apoptosis. Caspase-2 (Casp2; Nedd-2, Ich-1) is a developmentally regulated initiator caspase, which poorly cleaves other caspases but can initiate mitochondrial outer membrane permeabilization. We have investigated if Casp2 could mediate perinatal ischemic brain damage. METHODS: Casp2 expression in human neonatal brains and developmental patterns in rats and mice were evaluated. Casp2-deficient (Casp2(-/ )), wild-type (WT), and heterozygous (Casp2(+/-)) newborn C57BL/6 mice were subjected to hypoxia-ischemia (unilateral carotid occlusion + exposure to 10% oxygen for 50 minutes) or intracerebral injection of the excitotoxic N-methyl-D aspartate-receptor agonist ibotenate. In addition, Casp2 specific siRNAs were preinjected into the brain of WT newborn mice 24 hours before ibotenate treatment. Brain tissues were examined by immunohistochemical staining (cresyl violet, MAP2, NF68, Casp2, Casp3) and Western blotting. Lesion volumes and injury in the cortical plates and white matter were quantified together with activated Casp3. RESULTS: Casp2 is highly expressed in the neonatal brain. Casp2-deficient mice subjected to hypoxia-ischemia at postnatal day 9 present significantly lower cerebral infarction, reduced white matter injury, and reduced Casp3 activation in the thalamus and hippocampus. Both Casp2(-/-) mice and siRNA-administered WT mice conferred reduction of gray and white matter injury after excitotoxic insult at postnatal day 5. Casp3 activation was also found reduced in Casp2-deficient mice subjected to excitotoxicity. INTERPRETATION: These data suggest for the first time a role of Casp2 in neonatal brain damage. PMID- 21674596 TI - Is sensory testing during lead placement crucial for achieving positive outcomes after sacral neuromodulation? AB - AIMS: Motor and sensory responses help guide lead placement during staged neuromodulation procedures. However, eliciting sensory responses requires lighter anesthesia. We evaluated the impact of assessing sensory responses during quadripolar tined lead placement on outcomes in subjects with refractory voiding symptoms. METHODS: Adults who had a sacral lead placed were identified from our prospective neuromodulation database and grouped by whether they had intraoperative sensory testing or not. History, operative data, and implantable permanent generator (IPG) implant, lead revision and device explant rates were collected from medical records. Symptoms were evaluated with the Interstitial Cystitis Symptom Index/Problem Index (ICSI-PI) and scaled global response assessments (GRA) for the first 24 months post IPG placement. Data were analyzed using Pearson's Chi-square, Fisher's Exact, or Wilcoxon rank test. RESULTS: Of 141 subjects (82% female), 86 (61%) had sensory testing and 55 (39%) did not. Sensory and no sensory testing groups were not significantly different on demographics, urologic diagnosis, IPG implant rates (76/84; 90% and 48/55; 87% respectively) or mean operative time (37.9 +/- 13.9 minutes vs. 35.5 +/- 11.6). Within 4 years, 19/141 (13.5%) were revised and/or explanted. For explant alone, 11/86 (13%) in the sensory and only 3/55 (5.5%) in the no sensory group (P = 0.16) were explanted. Overall, ICSI-PI scores improved over time (P < 0.0001) and most reported improvement on the GRA at each time point, but no differences were seen between groups. CONCLUSIONS: Intraoperative sensory testing during sacral lead placement does not necessarily improve IPG implantation rates or clinical outcomes of neuromodulation. PMID- 21674583 TI - Carotid atherosclerosis and progression of brain atrophy: the SMART-MR study. AB - OBJECTIVE: Atherosclerosis has been implicated in the development of brain atrophy. However, support for this association comes from cross-sectional studies. METHODS: Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with symptomatic atherosclerotic disease (mean age +/- standard deviation, 58 +/- 10 years; 80% men), magnetic resonance imaging of the brain was performed in 1,232 patients at baseline (2001-2005) and in 663 patients at follow-up (2006-2009). Brain segmentation was used to quantify total brain volume, cortical gray matter volume, and ventricular volume as indicators of global, cortical, and subcortical atrophy. At baseline, measurements of carotid intima-media thickness (CIMT) and carotid stenosis were performed. Carotid stenosis was classified into groups 0 of 50%, 50 of 70% (moderate), and >70% (severe) and into unilateral or bilateral stenosis. RESULTS: Cross-sectional regression analyses showed that both increased CIMT and carotid stenosis were associated with decreased relative total brain and cortical gray matter volume. Our prospective findings showed that after a mean follow-up of 3.9 years (range, 3.0-5.8 years), CIMT and moderate stenosis were not related to progression of brain atrophy. Only severe or bilateral carotid stenosis was related to progression of global atrophy (beta [95% confidence interval (CI)], -0.52% [-0.84 to -0.20%], -0.94% [-1.45 to -0.43%]), cortical atrophy (beta [95% CI], -0.75% [-1.37 to -0.13%], -1.34% [-2.32 to -0.35%]), and subcortical atrophy (beta [95% CI], 0.06% [-0.02 to 0.16%], 0.13% [0.01 to 0.28%]). INTERPRETATION: In a study of patients with atherosclerotic disease with 4 years of follow-up, only severe or bilateral carotid stenosis, and not moderate carotid stenosis and increased CIMT, were associated with progression of brain atrophy. PMID- 21674595 TI - Prospective study of the impact on quality of life of cystectomy with ileal conduit urinary diversion for neurogenic bladder dysfunction. AB - OBJECTIVES: Neurogenic bladder dysfunction has a negative impact on the patient's quality of life (QoL). Cystectomy with ileal conduit urinary diversion is a treatment option in patients in failure after conservative management. The objective of this study was to evaluate the impact of ileal conduit urinary diversion on the QoL of patients with neurogenic bladder dysfunction. MATERIALS AND METHODS: From March 2004 to November 2010, 48 patients (36 women and 12 men with a mean age of 50.6 +/- 11.8 years) treated by cystectomy with ileal conduit urinary diversion for neurogenic bladder dysfunction, prospectively completed, before and after surgery, two self-administered QoL questionnaires. Neurological diseases were multiple sclerosis in 38 cases, spinal cord injury in 7 cases, and other neurological disease in 3 cases. Cystectomy was performed by laparoscopy in all patients. QoL was measured by using two self-administered questionnaires, one questionnaire specific for urinary disorders validated in neurological patients, Qualiveen(r), and the generic SF36-v2(r) questionnaire. Data were compared by Student's t test. RESULTS: Comparison of the Qualiveen(r) self-administered questionnaire scores and indices before and after surgery showed that, after surgery, patients presented a significant reduction of limitations (0.57 +/- 0.64 vs. 1.55 +/- 1.35, P < 0.001), constraints (2.12 +/- 0.83 vs. 2.64 +/- 1.12, P = 0.046) scores and the SIUP index (1.29 +/- 0.65 vs. 1.79 +/- 0.95, P = 0.015). No significant change in SF36-v2(r) scores was observed postoperatively. CONCLUSIONS: Ileal conduit urinary diversion improves the urinary QoL of patients with neurogenic bladder dysfunction by decreasing limitations and constraints induced by urinary disorders, but has no impact on general QoL. PMID- 21674588 TI - Neurovascular coupling is impaired in slow walkers: the MOBILIZE Boston Study. AB - OBJECTIVE: Neurovascular coupling may be involved in compensatory mechanisms responsible for preservation of gait speed in elderly people with cerebrovascular disease. Our study examines the association between neurovascular coupling in the middle cerebral artery and gait speed in elderly individuals with impaired cerebral vasoreactivity. METHODS: Twenty-two fast and 20 slow walkers in the lowest quartile of cerebral vasoreactivity were recruited from the MOBILIZE Boston Study. Neurovascular coupling was assessed in bilateral middle cerebral arteries by measuring cerebral blood flow during the N-Back task. Cerebral white matter hyperintensities were measured for each group using magnetic resonance imaging. RESULTS: Neurovascular coupling was attenuated in slow compared to fast walkers (2.8%; 95% confidence interval [CI], -0.9 to 6.6 vs 8.2%; 95% CI, 4.7 11.8; p = 0.02). The odds ratio of being a slow walker was 6.4 (95% CI, 1.7-24.9; p = 0.007) if there was a high burden of white matter hyperintensity; however, this risk increased to 14.5 (95% CI, 2.3-91.1; p = 0.004) if neurovascular coupling was also attenuated. INTERPRETATION: Our results suggest that intact neurovascular coupling may help preserve mobility in elderly people with cerebral microvascular disease. PMID- 21674591 TI - Treatable neurological disorders misdiagnosed as Creutzfeldt-Jakob disease. AB - OBJECTIVE: Heightened awareness of Creutzfeldt-Jakob disease (CJD) among physicians and the lay public has led to its frequent consideration in the differential diagnosis of patients with rapidly progressive dementia (RPD). Our goal was to determine which treatable disorders are most commonly mistaken for CJD. METHODS: We performed a retrospective clinical and neuropathological review of prion-negative brain autopsy cases referred to the US National Prion Disease Pathology Surveillance Center at Case Western Reserve University from January 2006 through December 2009. RESULTS: Of 1,106 brain autopsies, 352 (32%) were negative for prion disease, 304 of which had adequate tissue for histopathological analysis. Alzheimer disease (n = 154) and vascular dementia (n = 36) were the 2 most frequent diagnoses. Seventy-one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (n = 20), cerebellar (n = 14), or extrapyramidal (n = 12) signs, myoclonus (n = 12), visual disturbance (n = 9), and akinetic mutism (n = 5); a typical electroencephalogram occurred only once. Neuropathological diagnoses included immune-mediated disorders (n = 26), neoplasia (n = 25, most often lymphoma), infections (n = 14), and metabolic disorders (n = 6). INTERPRETATION: In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill World Health Organization criteria. RPD with positive 14-3-3 cerebrospinal fluid protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive magnetic resonance imaging features of prion disease, is likely to improve diagnostic accuracy. PMID- 21674589 TI - Japanese macaque encephalomyelitis: a spontaneous multiple sclerosis-like disease in a nonhuman primate. AB - OBJECTIVE: To describe Japanese macaque encephalomyelitis (JME), a spontaneous inflammatory demyelinating disease occurring in the Oregon National Primate Research Center's (ONPRC) colony of Japanese macaques (JMs, Macaca fuscata). METHODS: JMs with neurologic impairment were removed from the colony, evaluated, and treated with supportive care. Animals were humanely euthanized and their central nervous systems (CNSs) were examined. RESULTS: ONPRC's JM colony was established in 1965 and no cases of JME occurred until 1986. Since 1986, 57 JMs spontaneously developed a disease characterized clinically by paresis of 1 or more limbs, ataxia, or ocular motor paresis. Most animals were humanely euthanized during their initial episode. Three recovered, later relapsed, and were then euthanized. There was no gender predilection and the median age for disease was 4 years. Magnetic resonance imaging of 8 cases of JME revealed multiple gadolinium-enhancing T(1) -weighted hyperintensities in the white matter of the cerebral hemispheres, brainstem, cerebellum, and cervical spinal cord. The CNS of monkeys with JME contained multifocal plaque-like demyelinated lesions of varying ages, including acute and chronic, active demyelinating lesions with macrophages and lymphocytic periventricular infiltrates, and chronic, inactive demyelinated lesions. A previously undescribed gamma-herpesvirus was cultured from acute JME white matter lesions. Cases of JME continue to affect 1% to 3% of the ONPRC colony per year. INTERPRETATION: JME is a unique spontaneous disease in a nonhuman primate that has similarities with multiple sclerosis (MS) and is associated with a novel simian herpesvirus. Elucidating the pathogenesis of JME may shed new light on MS and other human demyelinating diseases. PMID- 21674598 TI - Pulsed magnetic stimulation with a high-frequency continuous magnetic stimulator (SMN-X) does not exert an adverse effect on genital organs and the estrous cycle in female Iar:Wistar-Imamichi rats. AB - AIMS: To histopathologically verify whether high-frequency continuous stimulation exerts adverse effects on genital organs (uterus and ovaries) and the estrous cycle in rats through comparison of 3 groups. METHODS: The device studied was a high-frequency continuous magnetic stimulator (SMN-X, Nihon Kohden, Tokyo). Thirteen female Iar:Wistar-Imamichi rats (SPF) were randomly divided into 3 groups: active treatment (MS) group (n = 7), sham treatment group, where rats were placed on a table 1 m away from the stimulator so that they could hear the sounds of the stimulator (n = 3) and control (no treatment) group (n = 3). The MS group underwent thirty-six 25-minute sessions of pulsed magnetic stimulation at the maximum output level (560 mT peak) (once/day, 5 days/week). At the end of the study period, the uterus and ovaries were removed for histological examinations. Estradiol and progesterone levels were assayed and the estrous cycle, bodyweight gain and daily behaviors were recorded. RESULTS: From results of histopathology and endocrinology, assays of the estrous cycle, and recordings of bodyweight gain and organ weight, no adverse effects of long-term pulsed magnetic stimulation were noted. There were no significant intergroup differences with regard to any item evaluated. CONCLUSION: In the study setting, SMN-X did not exert any adverse effect on the uterus, ovaries, estrous cycle and hormone levels as well as blood cell counts, bodyweight gain and daily behavior in female SPF rats. The present results may be a step forward in the discussion of the safety of SMN-X for clinical use in humans. PMID- 21674551 TI - 5-HT radioligands for human brain imaging with PET and SPECT. AB - The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT(1A), 5-HT(1B), 5-HT(2A), and 5-HT(4) receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging. PMID- 21674600 TI - Quality control in urodynamics and the role of software support in the QC procedure. AB - AIMS: This article aims to identify quality control (QC) best practice, to review published QC audits in order to identify how closely good practice is followed, and to carry out a market survey of the software features that support QC offered by urodynamics machines available in the UK. METHODS AND RESULTS: All UK distributors of urodynamic systems were contacted and asked to provide information on the software features relating to data quality of the products they supply. The results of the market survey show that the features offered by manufacturers differ greatly. Automated features, which can be turned off in most cases, include: cough recognition, detrusor contraction detection, and high pressure alerts. There are currently no systems that assess data quality based on published guidelines. A literature review of current QC guidelines for urodynamics was carried out; QC audits were included in the literature review to see how closely guidelines were being followed. This review highlights the fact that basic QC is not being carried out effectively by urodynamicists. CONCLUSION: Based on the software features currently available and the results of the literature review there is both the need and capacity for a greater degree of automation in relation to urodynamic data quality and accuracy assessment. Some progress has been made in this area and certain manufacturers have already developed automated cough detection. PMID- 21674599 TI - Expression of apoptotic factors in vaginal tissues from women with urogenital prolapse. AB - AIMS: Increased apoptotic activity in pelvic tissues may contribute to development of pelvic floor disorders. We evaluated expression of apoptotic factors (Bcl-2 family) in vaginal tissues from women with pelvic organ prolapse (POP) and how these factors correlate with severity of prolapse. METHODS: mRNA and protein expression of anti-apoptotic and pro-apoptotic factors in vaginal tissues from subjects and controls were determined by real-time PCR and Western blot. Severity of prolapse was staged using POP-Q criteria. RESULTS: Differential expression of Bcl-2 family factors was observed in protein rather than in gene expression. During the secretory phase, the anti-apoptotic (Bcl-2, Bcl-xl) and pro-apoptotic protein (Bax) were upregulated in controls compared to cases (P < 0.05). The ratios of Bcl-2/Bax and Bcl-2/Bad, which determine cellular sensitivity to induction of apoptosis, were higher in controls versus cases. Higher ratios indicate reduced cellular sensitivity to apoptosis. Protein expression of Bax and Bad was higher in women with severe compared to mild prolapse (P < 0.05). CONCLUSION: Increased expression of Bad, Bax, and decreased ratios of Bcl-2/Bax, Bcl-2/Bad suggest increased apoptotic activity or sensitivity to induction of apoptosis in vaginal tissues of women with POP. PMID- 21674601 TI - Lineage identification and genealogical relationships among captive Galapagos tortoises. AB - Genetic tools have become a critical complement to traditional approaches for meeting short- and long-term goals of ex situ conservation programs. The San Diego Zoo (SDZ) harbors a collection of wild-born and captive-born Galapagos giant tortoises (n = 22) of uncertain species designation and unknown genealogical relationships. Here, we used mitochondrial DNA haplotypic data and nuclear microsatellite genotypic data to identify the evolutionary lineage of wild-born and captive-born tortoises of unknown ancestry, to infer levels of relatedness among founders and captive-born tortoises, and assess putative pedigree relationships assigned by the SDZ studbook. Assignment tests revealed that 12 wild-born and five captive-born tortoises represent five different species from Isabela Island and one species from Santa Cruz Island, only five of which were consistent with current studbook designations. Three wild-born and one captive-born tortoise were of mixed ancestry. In addition, kinship analyses revealed two significant first-order relationship pairs between wild-born and captive-born tortoises, four second-order relationships (half-sibling) between wild-born and captive tortoises (full-sibs or parent-offspring), and one second order relationship between two captive-born tortoises. Of particular note, we also reconstructed a first-order relationship between two wild-born individuals, violating the founder assumption. Overall, our results contribute to a worldwide effort in identifying genetically important Galapagos tortoises currently in captivity while revealing closely related founders, reconstructing genealogical relationships, and providing detailed management recommendations for the SDZ tortoises. PMID- 21674602 TI - Historical and current records of aquarium cetaceans in China. AB - The number of cetaceans housed in aquariums in China is increasing. Detailed information on the historical and current population status has not been reported, despite its importance for successful breeding and population management. Questionnaires were conducted between December 2006 and May 2009, and the information was used to construct studbooks. Our survey showed that 10 species had been introduced to aquariums since 1978, including 26 (with 15 in the current population) finless porpoises (Neophocaena phocaenoides), 5 (5) false killer whales (Pseudorca crassidens), 94 (80) common bottlenose dolphins (Tursiops truncatus), 48 (30) Indo-Pacific bottlenose dolphins (Tursiops aduncus), 36 (32) beluga whales (Delphinapterus leucas), 10 (10) pantropical spotted dolphins (Stenella attenuata), 8 (8) Risso's dolphins (Grampus griseus), 2 (2) short-finned pilot whales (Globicephala macrorhynchus), 2 (2) Pacific white sided dolphins (Lagenorhynchus obliquidens), and 5 (0) baiji dolphins (Lipotes vexillifer). The number of cetaceans has increased markedly in the past 32 years, especially since 1995. Currently, 184 individuals are under human care throughout China, a number larger than any other country with an International Species Information System membership. In addition, the Annual Survival Rates of bottlenose dolphins (0.959) and beluga whales (0.968) were found higher than those reported previously (0.93-0.951 and 0.94-0.954, respectively). PMID- 21674603 TI - Effects of combination birth control on estrous behavior in captive western lowland gorillas, Gorilla gorilla gorilla. AB - Combination birth control pills (CBC) are one of the most common birth control methods used for western lowland gorillas (Gorilla gorilla gorilla) housed in zoos. Since zoos are interested in maintaining as many natural behaviors as possible, it is important to know how contraception may affect social and sexual interactions among group members. Although some data are available regarding the influence of the pill on sexual behavior in human females, no data are available on its effects on gorilla estrous behavior. We examined temporal trends of estrous, aggressive, affiliative, and activity budget data in four females on CBC at the Lincoln Park Zoo in Chicago, IL. Behavioral data were collected using point sampling, all-occurrence records, and one-zero sampling. Estrous behavior occurred in less than 1% of observations. Using all-occurrence and one-zero sampling, estrous behavior occurred more frequently in week one of the cycle than any other week. The focal females exhibited affiliative, aggressive, and activity budget data evenly across their cycles. There were also no temporal trends in proximity to the silverback. Females varied by the types of estrous behavior they exhibited. We give a hormonal explanation for the prevalence of estrous behaviors in week one, and recommendations for effective behavioral sampling of gorilla estrous behavior. PMID- 21674604 TI - Can zoo records help answer behavioral research questions? The case of the left handed lemurs (Lemur catta). AB - Most zoos keep comprehensive records, which potentially form a database for use in answering some research questions, such as in veterinary and population management research. They have not, however, been widely used to answer questions about animal behavior and welfare. Here we try to assess the usefulness to behavioral research of two sorts of zoo records (ARKS, the Animal Records Keeping System, and student dissertations held on file) to test the hypothesis that ring tailed lemurs with a left limb preference experience more negative social lives. We found that, as predicted, lemurs with a left limb preference (LH) received more aggression and were involved in less grooming than nonleft-preferent lemurs (NLH), though the differences were not statistically significant. Contrary to prediction, LH lemurs had fewer reported woundings than NLH lemurs, but again the difference was not statistically significant. We found that the ARKS reports did not contain sufficient quantified and systematic behavioral data for our purposes, although otherwise they provided an excellent context for interpreting results. The student dissertations were also of limited use, primarily because of the small time frame in which they were carried out. Because of these shortcomings we were unable to distinguish whether our inability to find significant effects was due to biological (perhaps hand preference had no consequences for the lemurs) or data reasons. We suggest that closer liaison between zoo research staff, zoo record keepers and academic supervisors could help to improve the usefulness of zoo records for behavioral research. PMID- 21674606 TI - Interactions of environmental conditions and mechanical loads have influence on matrix turnover by nucleus pulposus cells. AB - Disc degeneration is associated with several changes in the physicochemical environment of intervertebral disc cells. Nucleus pulposus (NP) cells in the center of degenerated discs are exposed to decreased glucose supply, osmolarity, pH, and oxygen levels. To understand the complexity of these interactions on a cellular level, we designed standardized experiments in which we compared responses to these environmental factors under normal levels with those seen under two different degrees of disc degeneration. We hypothesized that these changes in environmental stimuli influence gene expression of matrix proteins and matrix degrading enzymes and alter their responses to cyclic hydrostatic pressure (HP). Our results suggest that a simulation of degenerative conditions influences the degradation of disc matrix through impairing matrix formation and accelerating matrix resorption via up- or down-regulation of the respective target genes. The greatest effects were seen for decreases in glucose concentration and pH. Low oxygen had little influence. HP had little direct effect but appeared to counteract matrix degradation by reducing or inverting some of the adverse effects of other stimuli. For ongoing in vitro studies, interactions between mechanical stimuli and factors in the physicochemical environment should not be ignored as these could markedly influence results. PMID- 21674607 TI - Normal shoulder muscular activation and co-ordination during a shoulder elevation task based on activities of daily living: an electromyographic study. AB - Studies of normal shoulder function have often failed to consider the inter relationship between different muscle groups in activities relevant to daily life. Upper limb functional status was assessed in 12 healthy male volunteers using the Functional Impairment Test-Hand, Neck, Shoulder and Arm test (FIT HaNSA). Electromyography was then used to study the activity and coordination of 13 muscles (10 by surface electrodes, 3 by fine-wire intramuscular electrodes) around the shoulder during a dynamic movement task based on the shelf-lifting task in FIT-HaNSA. Muscles were grouped for analysis into deltoid (anterior, middle, and posterior divisions), adductors (latissimus dorsi and teres major), rotator cuff (supraspinatus, infraspinatus, and subscapularis), and elbow flexor (brachioradialis, biceps brachii) groups. There were no significant inter-session effects. Using cross-correlation analysis to investigate the whole time-course of activation, there were highly significant positive correlations (p < 0.001) between the deltoid and rotator cuff, the deltoid and adductor and the adductor and rotator cuff groups, and a significant negative correlation between the deltoid and elbow flexor groups (p = 0.031). We conclude that the deltoid, adductor, and rotator cuff muscles all contribute to the muscular component of glenohumeral joint stability. Muscular stability can be adapted as required to meet task-specific demands. PMID- 21674605 TI - Induction of fracture repair by mesenchymal cells derived from human embryonic stem cells or bone marrow. AB - Development of novel therapeutic approaches to repair fracture non-unions remains a critical clinical necessity. We evaluated the capacity of human embryonic stem cell (hESC)-derived mesenchymal stem/stromal cells (MSCs) to induce healing in a fracture non-union model in rats. In addition, we placed these findings in the context of parallel studies using human bone marrow MSCs (hBM-MSCs) or a no cell control group (n = 10-12 per group). Preliminary studies demonstrated that both for hESC-derived MSCs and hBM-MSCs, optimal induction of fracture healing required in vitro osteogenic differentiation of these cells. Based on biomechanical testing of fractured femurs, maximum torque, and stiffness were significantly greater in the hBM-MSC as compared to the control group that received no cells; values for these parameters in the hESC-derived MSC group were intermediate between the hBM-MSC and control groups, and not significantly different from the control group. However, some evidence of fracture healing was evident by X-ray in the hESC-derived MSC group. Our results thus indicate that while hESC-derived MSCs may have potential to induce fracture healing in non unions, hBM-MSCs function more efficiently in this process. Additional studies are needed to further modify hESCs to achieve optimal fracture healing by these cells. PMID- 21674608 TI - Lessons from understanding the role of community hospital director in Thailand: clinician versus manager. AB - In 2001, Thailand adopted the Universal Health Coverage (UHC) policy. This policy focuses on primary health care (PHC), with the aim of reforming the Thai health system to provide health services to all, regardless of a person's ability to pay. The community hospital director (CHD) is the middle manager of the provincial health system and the leader of the district health system of Thailand. In recent reforms the emphasis for improving efficiency lies with changes in the provision of primary health services at the community level and this entails understanding the role of the CHD. A qualitative study, utilizing individual interviews and a focus group discussion, was undertaken in order to understand the factors affecting the implementation of rural health care in Thailand. Findings identified several barriers that limit the role of the CHD and a major result of the study was recognition of the dual role of the CHD as both clinician and manager. This study concluded that the goal of the UHC policy in providing equity of access to PHC to all citizens may not be achieved unless the role of CHDs is supported with training in health management and PHC and is supported by the government. PMID- 21674609 TI - When co-payments for physician visits can affect supply as well as demand: findings from a natural experiment in Israel's national health insurance system. AB - In 1998, Israel's national health insurance system introduced a modest co-payment for visits to specialist physicians. This study takes advantage of a natural experiment in which 15% of the population--the poor and disabled--was exempted from these co-payments. It used the micro-level panel data of three large health plans on the physician visits of 50,000 members per plan in 1997-2001. The data indicate that, following introduction of the co-payment, specialist visits increased among non-exempt members, relative to exempt members, of two health plans that together account for two-thirds of the population. This paper illustrates how, unlike the Health Insurance Experiment and other US studies of cost sharing, the structure of the co-payment in Israel may have inadvertently limited the incentive to decrease consumer demand and may have created an incentive for the health plans to increase visit rates, especially among the non exempt members. Other countries that have implemented co-payment systems with exemptions may benefit from the Israeli experience in designing and evaluating their systems. PMID- 21674612 TI - 'Health transformation programme' in Turkey: an assessment. AB - The aim of this study is to assess the 'Health Transformation Programme' (HTP) in Turkey announced in 2003. This assessment has been made according to the ultimate performance goals of a health care system, such as improvement in health status, financial risk protection and satisfaction with health care. This study provides a brief history of health policy since 1980, when the Turkish health care system began to transform with the introduction of both structural adjustment and market oriented reform policy. The main aim of these reforms was increasing efficiency. Reform proposals of the 1990s focused on the introduction of a general health insurance (GHI) system, decentralization, introduction of a family medicine scheme, purchaser-provider split, contracting-out, quasi-markets and improvement of management information systems. Like the reform proposals of the 1990s, HTP has eight components, the major ones being a new role for the Ministry of Health (MoH), introduction of a GHI system, reorganization of health service delivery and human resources development. No component of HTP has yet been sufficiently realized. Therefore, despite some improvements, Turkish people continue to face low health status and a low level of financial risk protection. More research needs to be done for the determination of satisfaction with health services. PMID- 21674613 TI - The conception of administrators regarding the formation of a healthcare consortium in Pernambuco, Brazil: a case study. AB - The formation of healthcare consortia is a management strategy adopted by a number of cities in Brazil in order to minimize the difficulties the population has in access to services of greater technological complexity. As administrators are the main governmental actors in the promotion of this strategy, the aim of the present study was to identify the motives, expectations and difficulties faced by the mayors, and secretaries of health that make up a healthcare consortium undergoing a formation process in the rural, coastal zone of the state of Pernambuco. A descriptive, qualitative, case study was conducted. Data collection was carried out through semi-structured interviews held with mayors and secretaries of health of the municipalities participating in the consortium. Data were analyzed by means of content analysis, using the NVivo 2.0 software program. The administrators cited difficulty in access to specialized services and the high cost of transporting patients to distant locations for treatment as motives for the formation of the consortium. With the implantation of this healthcare strategy, the expectations are a reduction in costs regarding patient transportation, an increase in access to services of greater complexity, and negotiations with other spheres of government. The main difficulties faced are political-partisan conflicts and excessive bureaucracy. Although there were no considerable divergences in the administrators' perceptions, it was evident that those who initiated the formation of the consortium offered a deeper, more detailed discourse, thereby demonstrating greater involvement when compared to those who offered continuity to the process. PMID- 21674614 TI - Cost analysis and efficiency of sub-district health facilities in two districts in Ghana. AB - To establish the full costs borne by sub-district health facilities in providing services, we analysed the costs and revenues of 10 sub-district health facilities located in two districts in Ghana. The full costs were obtained by considering staff costs, cost of utilities, cost of using health facility equipment, cost of non-drug consumables, equipment maintenance expenses, amounts spent on training, community information sessions and other outreach activities as well as all other costs incurred in running the facilities. We found that (i) a large proportion of sub-district health facility costs is made up of staff salaries; (ii) at all facilities, internally generated funds (IGFs) are substantially lower than costs incurred in running the facilities; (iii) average IGF is several times higher in one district than the other; (iv) wide variations exist in efficiency indicators and (v) there is some evidence that sub-district health facilities may not necessarily be financially more efficient than hospitals in using financial resources. We suggest that the study should be replicated in other districts; but in the mean time, the health authorities should take note of the conclusions and recommendations of this study. Efforts should also be made to improve record keeping at these facilities. PMID- 21674616 TI - Improved method for quantification of regional cardiac function in mice using phase-contrast MRI. AB - Phase-contrast magnetic resonance imaging is a technique that allows for characterization of regional cardiac function and for measuring transmural myocardial velocities in human hearts with high temporal and spatial resolution. The application of this technique (also known as tissue phase mapping) to murine hearts has been very limited so far. The aim of our study was to implement and to optimize tissue phase mapping for a comprehensive assessment of murine transmural wall motion. Baseline values for regional motion patterns in mouse hearts, based on the clinically used American Heart Association's 17-segment model, were established, and a detailed motion analysis of mouse heart for the entire cardiac cycle (including epicardial and endocardial motion patterns) is provided. Black blood contrast was found to be essential to obtain reproducible velocity encoding. Tissue phase mapping of the mouse heart permits the detailed assessment of regional myocardial velocities. While a proof-of-principle application in a murine ischemia-reperfusion model was performed, future studies are warranted to assess its potential for the investigation of systolic and diastolic functions in genetically and surgically manipulated mouse models of human heart disease. PMID- 21674617 TI - Restricted or severely hindered diffusion of intramyocellular lipids in human skeletal muscle shown by in vivo proton MR spectroscopy. AB - Although magnetic resonance spectroscopy can be used as a unique tool to study molecular diffusion, it is rarely used to measure the diffusion properties of intramyocellular and extramyocellular lipids. Lipids have very low apparent diffusion coefficients (ADCs), which make these measurements difficult and necessitate strong diffusion gradients and long diffusion times. Consequence is that these measurements have inherently low signal-to-noise ratio and are prone to artifacts. The addition of physiological triggering and individual storage and processing of the spectra is seen to be a possible approach to maximize signal intensity and achieve high reproducibility of the experiments. Thus, the optimized measurement protocol was used to investigate the diffusion properties of lipids in human skeletal muscle in vivo. At a diffusion time of about 110 ms, intramyocellular lipids show a significantly lower ADC (2.0 * 10(-6) mm(2)/s, 95% confidence interval 1.10 * 10(-6) to 2.94 * 10(-6) mm(2)/s) than extramyocellular lipids (1.58 * 10(-5) mm(2)/s, 95% confidence interval 1.41 * 10(-5) to 1.75 * 10(-5) mm(2)/s). Because the chemical properties of both lipid pools can be assumed to be similar, the difference can only be attributed to restricted or severely hindered diffusion in the intramyocellular droplets. PMID- 21674615 TI - QUantitative Imaging of eXtraction of oxygen and TIssue consumption (QUIXOTIC) using venular-targeted velocity-selective spin labeling. AB - While oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO(2)) are fundamental parameters of brain health and function, a robust MRI based mapping of OEF and CMRO(2) amenable to functional MRI (fMRI) has not been established. To address this issue, a novel method called QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption, or QUIXOTIC, is introduced. The key innovation in QUIXOTIC is the use of velocity-selective spin labeling to isolate MR signal exclusively from postcapillary venular blood on a voxel-by-voxel basis. Measuring the T(2) of this venular-targeted blood allows calibration to venular oxygen saturation (Y(v)) via theoretical and experimental T(2) versus blood oxygen saturation relationships. Y(v) is converted to OEF, and baseline CMRO(2) is subsequently estimated from OEF and additional cerebral blood flow and hematocrit measurements. Theory behind the QUIXOTIC technique is presented, and implications of cutoff velocity (V(CUTOFF)) and outflow time parameters are discussed. Cortical gray matter values obtained with QUIXOTIC in 10 healthy volunteers are Y(v) = 0.73 +/- 0.02, OEF = 0.26 +/- 0.02, and CMRO(2) = 125 +/- 15 MUmol/100 g min. Results are compared to global measures obtained with the T(2) relaxation under spin tagging (TRUST) technique. The preliminary data presented suggest that QUIXOTIC will be useful for mapping Y(v), OEF, and CMRO(2), in both clinical and functional MRI settings. PMID- 21674618 TI - The functional microstructure of tendon collagen revealed by high-field MRI. AB - T2 was used in this study to assess tendon microstructure. Two unloaded digital extensor tendons were bent such that their long axes were imaged throughout 180 degrees with respect to B0. T2-weighted images reveal periodic banding (~200 MUm) when tendons were oriented at +/-55 degrees with respect to B0. Five pairs of tendons were used to study the influence of load on T2W MRI: one tendon of each pair was loaded with a 7.8-N mass, and both tendons were fixed in formalin then imaged at 55 degrees to B0. MRI banding was present in the unloaded, but not loaded, tendons. In unloaded tendons, polarized-light microscopy revealed collagen crimp with a periodicity similar to MRI. In loaded tendons, there was a strain-induced extinction of periodicity on both MRI and polarized-light microscopy. These studies confirm that crimp is detectable by high-field MRI and could serve as an in vivo index of physiological strains in collagenous tissues. PMID- 21674619 TI - A novel assay of biofilm antifungal activity reveals that amphotericin B and caspofungin lyse Candida albicans cells in biofilms. AB - The ability of Candida albicans to form drug-resistant biofilms is an important factor in its contribution to human disease. Assays to identify and characterize molecules with activity against fungal biofilms are crucial for the development of drugs with improved anti-biofilm activity. Here we report the application of an adenylate kinase (AK)-based cytotoxicity assay of fungal cell lysis to the characterization of agents active against C. albicans biofilms. We have developed three protocols for the AK assay. The first measures AK activity in the supernatants of biofilms treated with antifungal drugs and can be performed in parallel with a standard 2,3-bis-(2-methoxy-4-nitro-5-sulphophenyl)-2H tetrazolium-5-caboxanilide-based biofilm susceptibility assay; a second, more sensitive protocol measures the AK activity present within the biofilm matrix; and a third procedure allows the direct visualization of lytic activity toward biofilms formed on catheter material. Amphotericin B and caspofungin, the two most effective anti-biofilm drugs currently used to treat fungal infections, both directly lyse planktonic C. albicans cells in vitro, leading to the release of AK into the culture medium. These studies serve to validate the AK-based lysis assay as a useful addition to the methods for the characterization of antifungal agents active toward biofilms and provide insights into the mode of action of amphotericin B and caspofungin against C. albicans biofilms. PMID- 21674620 TI - People's policies for the health of the poor globally. AB - In this paper, we argue that the dominant role played by governments of the developed countries in global health policies is a critical but often an ignored factor in contributing to the lack of progress in global health. The solution to this challenge lies in efforts to 'democratise' global decision making and to argue for a greater say of the poor globally in policies affecting them. Although there are potentially many ways to achieve this, the paper proposes 'communitarian claims' as one way to have the voice of people globally involved and to make decisions about how best to allocate resources globally. It is argued that such claims can be advanced at a practical level through 'citizens' juries' as evident from the experience in Australia. That experience and with increasing evidence from elsewhere, there is a strong indication from communities of desires for a very different set of values to underpin healthcare than the Australian and other governments, in partnership with global institutions, deliver. PMID- 21674621 TI - Mutation in 5' upstream region of GCHI gene causes familial dopa-responsive dystonia. PMID- 21674622 TI - A cost analysis of intraoperative microelectrode recording during subthalamic stimulation for Parkinson's disease. AB - Deep brain stimulation of the subthalamic nucleus is the standard of care for treating medically intractable Parkinson's disease. Although the adjunct of microelectrode recording improves the targeting accuracy of subthalamic nucleus deep brain stimulation in comparison with image guidance alone, there has been no investigation of the financial cost of intraoperative microelectrode recording. This study was performed to address this issue. A comprehensive literature search of large subthalamic nucleus deep brain stimulation series (minimum, 75 patients) was performed, revealing a mean operating room time of 223.83 minutes for unilateral and 279.79 minutes for simultaneous bilateral implantation. The baseline operating room time was derived from the published operating room time for subthalamic nucleus deep brain stimulation without microelectrode recording. The total cost (operating room, anesthesia, neurosurgery) was then calculated based on hospitals geographically representative of the entire United States. The average cost for subthalamic nucleus deep brain stimulation implantation with microelectrode recording per patient is $26,764.79 for unilateral, $33,481.43 for simultaneous bilateral, and $53,529.58 for staged bilateral. For unilateral implantation, the cost of microelectrode recording is $19,461.75, increasing the total cost by 267%. For simultaneous bilateral implantation, microelectrode recording costs $20,535.98, increasing the total cost by 159%. For staged bilateral implantation, microelectrode recording costs $38,923.49, increasing the total cost by 267%. Microelectrode recording more than doubles the cost of subthalamic nucleus deep brain stimulation for Parkinson's disease and more than triples the cost for unilateral and staged bilateral procedures. The cost burden of microelectrode recording to subthalamic nucleus deep brain stimulation requires the clinical efficacy of microelectrode recording to be proven in a prospective evidence-based manner in order to curtail the potential for excessive financial burden to the health care system. PMID- 21674623 TI - Functional imaging of subthalamic nucleus deep brain stimulation in Parkinson's disease. AB - Deep brain stimulation of the subthalamic nucleus is an accepted treatment for the motor complications of Parkinson's disease. The therapeutic mechanism of action remains incompletely understood. Although the results of deep brain stimulation are similar to the results that can be obtained by lesional surgery, accumulating evidence from functional imaging and clinical neurophysiology suggests that the effects of subthalamic nucleus-deep brain stimulation are not simply the result of inhibition of subthalamic nucleus activity. Positron emission tomography/single-photon emission computed tomography has consistently demonstrated changes in cortical activation in response to subthalamic nucleus deep brain stimulation. However, the technique has limited spatial and temporal resolution, and therefore the changes in activity of subcortical projection sites of the subthalamic nucleus (such as the globus pallidus, substantia nigra, and thalamus) are not as clear. Clarifying whether clinically relevant effects from subthalamic nucleus-deep brain stimulation in humans are mediated through inhibition or excitation of orthodromic or antidromic pathways (or both) would contribute to our understanding of the precise mechanism of action of deep brain stimulation and may allow improvements in safety and efficacy of the technique. In this review we discuss the published evidence from functional imaging studies of patients with subthalamic nucleus-deep brain stimulation to date, together with how these data inform the mechanism of action of deep brain stimulation. PMID- 21674624 TI - Balance and falls in Parkinson's disease: a meta-analysis of the effect of exercise and motor training. AB - This systematic review with meta-analysis aimed to determine the effects of exercise and motor training on the performance of balance-related activities and falls in people with Parkinson's disease. Sixteen randomized and quasi-randomized controlled trials that assessed the efficacy of exercise and/or motor training against no intervention or placebo intervention were included. The primary outcome measures were balance-related activity performance (15 trials) and falls (2 trials). The pooled estimate of the effect of exercise and motor training indicated significantly improved balance-related activity performance (Hedges' g, 0.33; 95% confidence interval, 0.11-0.55; P=.003), but there was no evidence of an effect on the proportion of fallers (risk ratio, 1.02; 95% confidence interval, 0.66-1.58, P=.94). Balance-related activity performance improved to a greater extent in the trials of programs involving highly challenging balance training, but the difference in effect sizes was not statistically significant (P=.166). Exercise and motor training can improve the performance of balance related activities in people with Parkinson's disease. However, further research is required to determine if falls can be prevented in this population. PMID- 21674625 TI - Are the yips a task-specific dystonia or "golfer's cramp"? AB - This study compared golfers with and without the yips using joint movement and surface electromyographic detectors. Fifty golfers (25 with and 25 without complaints of the yips) were studied while putting. All putts were videotaped. Surface electromyography assessed arm cocontraction. A CyberGlove II (Immersion Technologies, Palo Alto, CA) assessed right-arm angular movements. Primary analysis was done by subjective complaint of the yips, whereas secondary analysis was done by video evidence of an involuntary movement. When grouped by subjective complaints, there were no differences in any movement parameter. When grouped by video evidence of an involuntary movement, yips cases had more (P < 0.001) angular movement in wrist pronation/supination and a trend (P = 0.08) for wrist flexor/extensor cocontraction (yips: 7 of 17, 41.2%; no yips: 6 of 33, 18.2%). Golfers with video evidence of an involuntary movement while putting have excessive rotation of the right wrist in a pronation/supination motion and, as previously reported, a trend for wrist flexor/extensor cocontraction. PMID- 21674626 TI - Drug-induced parkinsonism: a review of 17 years' experience in a regional pharmacovigilance center in France. AB - Besides antipsychotics, several drugs can induce parkinsonism. We review spontaneous notifications of drug-induced or -worsened parkinsonism to a French regional pharmacovigilance center between 1993 and 2009. During these 17 years, 20,855 adverse drug reactions have been reported, including 155 (0.7%) cases of drug-induced or -worsened parkinsonism. Most of the notifications have involved aged patients (48% between 60 and 79 years) and females (60%). "Seriousness" was found in 43.9% of cases. Worsening of parkinsonism occurred in 28 patients suffering from idiopathic Parkinson's disease. Sixty-nine percent of drug-induced or -worsened parkinsonism cases were observed during the first 3 months after introduction of the "suspect" drug (involving mainly central dopaminergic antagonists). A second peak (20%) was found 12 months after drug introduction (mainly caused by calcium channel blockers). The most frequently reported parkinsonian symptom was rigidity (78.7%). The three cardinal symptoms were found in 37.4% of notifications. Evolution was favorable (after partial or complete withdrawal of suspect drug[s]) in 88.7% of cases. Among the 261 suspect drugs, most involved central dopaminergic antagonists (49%), followed by antidepressants (8%), calcium channel blockers (5%), peripheral dopaminergic antagonists (5%), and H1 antihistamines (5%). Cases with lithium, valproic acid, amiodarone, anticholinesterases, or trimetazidine were also found. Three notifications were the result of pharmacokinetic interactions. We found that drug-induced or worsened parkinsonism is an often "serious," but reversible, adverse drug reaction. It occurred more frequently between 60 and 79 years. Rigidity was the most frequently reported symptom. Approximately 50% of drug-induced or -worsened parkinsonism cases spontaneously reported were related to drugs other than antipsychotics. Drug-induced or -worsened parkinsonism can also be explained by pharmacokinetic drug interactions. PMID- 21674627 TI - Specific alpha4beta2 nicotinic acetylcholine receptor binding of [F-18]nifene in the rhesus monkey. AB - OBJECTIVE: [F-18]Nifene is a PET radioligand developed to image alpha4beta2* nicotinic acetylcholine receptors (nAChR) in the brain. This work assesses the in vivo binding and imaging characteristics of [F-18]nifene in rhesus monkeys for the development of PET experiments examining nAChR binding. METHODS: Dynamic PET imaging experiments with [F-18]nifene were acquired in four anesthetized Macaca mulatta (rhesus) monkeys using a microPET P4 scanner. Data acquisition was initiated with a bolus injection of 109 +/- 17 MBq [F-18]nifene and the time course of the radioligand in the brain was measured for up to 120 min. For two experiments, a displacement dose of (-)nicotine (0.03 mg kg(-1) , i.v.) was given 45-60 min post injection and followed 30 min later with a second [F-18]nifene injection to measure radioligand nondisplaceable uptake. Time activity curves were extracted in the regions of the antereoventral thalamus (AVT), lateral geniculate nucleus region (LGN), frontal cortex, and the cerebellum (CB). RESULTS: The highest levels of [F-18]nifene uptake were observed in the AVT and LGN. Target-to-CB ratios reached maximum values of 3.3 +/- 0.4 in the AVT and 3.2 +/- 0.3 in the LGN 30-45 min postinjection. Significant binding of [F-18]nifene was observed in the subiculum, insula cortex, temporal cortex, cingulate gyrus, frontal cortex, striatum, and midbrain areas. The (-)nicotine displaced bound [F 18]nifene to near background levels within 15 min postdrug injection. No discernable displacement was observed in the CB, suggesting its potential as a reference region. Logan graphical estimates using the CB as a reference region yielded binding potentials of 1.6 +/- 0.2 in the AVT and 1.3 +/- 0.1 in the LGN. The postnicotine injection displayed uniform nondisplaceable uptake of [F 18]nifene throughout gray and white brain matter. CONCLUSIONS: [F-18]Nifene exhibits rapid equilibration and a moderately high target to background binding profile in the alpha4beta2* nAChR rich regions of the brain, thus providing favorable imaging characteristics as a PET radiotracer for nAChR assay. PMID- 21674628 TI - beta8 integrin is essential for neuroblast migration in the rostral migratory stream. AB - Neurogenesis in the post-natal brain occurs in two primary locations: the subgranular layer of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles. Following differentiation, neuroblasts within the SVZ migrate several millimeters to the olfactory bulbs (OBs) via a distinct anatomic route, or rostral migratory stream (RMS). The genes that govern neuroblast directional migration, and particularly those encoding cell adhesion and signaling factors, remain largely uncharacterized. Here, we report that the extracellular matrix adhesion receptor, beta8 integrin, is essential for proper neuroblast chain formation and directional navigation in the RMS. Primary neuroblasts isolated from the mouse brain express robust levels of beta8 integrin protein, and selective ablation of beta8 integrin gene expression in neuroblasts leads to aberrant chain migration and size-reduced OBs. These integrin-dependent defects can be recapitulated ex vivo using isolated neurospheres or SVZ explants. Collectively, these data identify essential cell-intrinsic functions for beta8 integrin in regulating neuroblast polarity and directional navigation in the mouse forebrain. PMID- 21674629 TI - A randomized, double-blind, placebo-controlled trial to evaluate efficacy and tolerability of an optimized botanical combination in the management of patients with primary hypercholesterolemia and mixed dyslipidemia. AB - This study compared the efficacy and tolerability of an optimized botanical combination containing policosanol, tomato extract, orally bioavailable grape procyanidins and Oenothera biennis oil against placebo in the management of patients with primary hypercholesterolemia and mixed dyslipidemia. Such a combination is endowed with biological properties targeted to cholesterol control and vasoprotection. This randomized, double-blind, parallel-group trial consisted of a 6 week treatment period following 4 week baseline period, and a 2 week post treatment follow-up. At baseline, both the groups were comparable to each other. Both the active treatment and the placebo group included 30 patients (active treatment: mean age 46.80 +/- 7.43 years, nine males; placebo: mean age 45.50 +/- 6.76 years, eight males). Significant reductions in the LDL-cholesterol (LDL-C; 17.33% from baseline, p < 0.001) and total cholesterol (TC; -13.38% from baseline, p < 0.0001) values over the treatment period were observed with the tested product. The treatment also resulted in reductions in C-reactive protein (CRP), malondialdehyde (MDA) and superoxide dismutase (SOD) values, which are indices of oxidative stress. This rational combination of different compounds is effective and safe in lowering the elevated LDL-C and TC values. It is also effective in the modulation of the oxidation indices values; however, a further long term study in a larger population would be needed in order to confirm these preliminary findings. PMID- 21674630 TI - Effect of total glycosides from Eucommia ulmoides seed on bone microarchitecture in rats. AB - Du-Zhong is one of the most important tonic herbs in traditional Chinese medicine for the treatment of bone fractures and other bone diseases. The present study examined whether Du-Zhong seed extract named total glycosides from Eucommia ulmoides seed (TGEUS) could display an increased effect on bone density and bone strength of the femur in rats. Sprague-Dawley rats were used and randomly assigned to the normal group and the TGEUS group (400 mg/kg body weight/day). Daily oral administration of TGEUS was found to increase significantly the biomechanical quality of the femur. The mechanical changes were associated with a bone mineral density (BMD) increase or even with some improvements in microarchitecture. Micro-CT analysis of the distal femur showed that TGEUS significantly increased the bone volume/tissue volume (BV/TV), connectivity density (Conn.D), trabecular number (Tb.N) and trabecular thickness (Tb.Th), and decreased trabecular separation (Tb.Sp) and the structure model index (SMI) in normal rats. To conclude, TGEUS taken orally increased bone density and altered bone histomorphology, suggesting that TGEUS might be a potential alternative medicine for the treatment of postmenopausal osteoporosis. PMID- 21674631 TI - Analgesic and antiinflammatory activity of kaur-16-en-19-oic acid from Annona reticulata L. bark. AB - Kaur-16-en-19-oic acid was isolated from the bark of Annona reticulata and studied for its analgesic and antiinflammatory activity. Analgesic activity was assessed using the hot plate test and acetic acid-induced writhing, and the antiinflammatory activity using the carrageenan induced rat paw oedema method. Kaur-16-en-19-oic acid, at doses of 10 and 20 mg/kg, exhibited significant (p < 0.05) analgesic and antiinflammatory activity. These activities were comparable to the standard drugs used, and furthermore the analgesic effect of kaur-16-en-19 oic acid was blocked by naloxone (2 mg/kg) in both analgesic models. PMID- 21674632 TI - Sida cordifolia leaf extract reduces the orofacial nociceptive response in mice. AB - In this study, we describe the antinociceptive activity of the ethanol extract (EE), chloroform (CF) and methanol (MF) fractions obtained from Sida cordifolia, popularly known in Brazil as "malva branca" or "malva branca sedosa". Leaves of S. cordifolia were used to produce the crude ethanol extract and after CF and MF. Experiments were conducted on Swiss mice using the glutamate and formalin-induced orofacial nociception. In the formalin test, all doses of EE, CF and MF significantly reduced the orofacial nociception in the first (p < 0.001) and second phase (p < 0.001), which was also naloxone-sensitive. In the glutamate induced nociception test, only CF and MF significantly reduced the orofacial nociceptive behavior with inhibition percentage values of 48.1% (100 mg/kg, CF), 56.1% (200 mg/kg, CF), 66.4% (400 mg/kg, CF), 48.2 (200 mg/kg, MF) and 60.1 (400 mg/kg, MF). Furthermore, treatment of the animals with EE, CF and MF was not able to promote motor activity changes. These data demonstrate that S. cordifolia has a pronounced antinociceptive activity on orofacial nociception. However, pharmacological and chemical studies are necessary in order to characterize the responsible mechanisms for this antinociceptive action and also to identify other bioactive compounds present in S. cordifolia. PMID- 21674633 TI - Inhibitory effects of costunolide isolated from Laurus nobilis on IgE-induced degranulation of mast cell-like RBL-2H3 cells and the growth of Y16 pro-B cells. AB - This study investigated the inhibitory effects of costunolide isolated from the leaves of Laurus nobilis L. (Lauraceae) on basophil-mediated allergic reactions and interleukin (IL)-5-mediated B cell growth. The effects of costunolide on beta hexosaminidase (a key parameter of degranulation) release and IL-4 expression in rat basophilic leukemia (RBL-2H3) cells were determined by measuring beta hexosaminidase activity and by semi-quantitative RT-PCR, respectively. The effects of costunolide on Y16 pro-B cell viability and growth were determined by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay. Costunolide was found significantly to inhibit beta-hexosaminidase activity (p < 0.01) and IL-4 transcription in RBL-2H3 cells in a dose-dependent manner. Its 50% inhibitory concentration (IC50 ) was 34 uM, while that of the positive control, ketotifen, was 24 uM (IL-4 mRNA transcription). Moreover, costunolide dose dependently suppressed pro-B cell growth in IL-5-stimulated Y16 cells. These results provide evidence that costunolide stabilizes mast cells by inhibiting IgE mediated degranulation and inhibits IL-5-stimulated B cell growth. PMID- 21674635 TI - Endoplasmic reticulum calcium pumps and cancer. AB - Endoplasmic reticulum calcium homeostasis is involved in a multitude of signaling, as well as "house-keeping" functions that control cell growth, differentiation or apoptosis in every human/eukaryotic cell. Calcium is actively accumulated in the endoplasmic reticulum by Sarco/Endoplasmic Reticulum Calcium transport ATPases (SERCA enzymes). SERCA-dependent calcium transport is the only calcium uptake mechanism in this organelle, and therefore the regulation of SERCA function by the cell constitutes a key mechanism to adjust calcium homeostasis in the endoplasmic reticulum depending on the cell type and its state of differentiation. The direct pharmacological modulation of SERCA activity affects cell differentiation and survival. SERCA expression levels can undergo significant changes during cell differentiation or tumorigenesis, leading to modified endoplasmic reticulum calcium storage. In several cell types such as cells of hematopoietic origin or various epithelial cells, two SERCA genes (SERCA2 and SERCA3) are simultaneously expressed. Expression levels of SERCA3, a lower calcium affinity calcium pump are highly variable. In several cell systems SERCA3 expression is selectively induced during differentiation, whereas during tumorigenesis and blastic transformation SERCA3 expression is decreased. These observations point at the existence of a cross-talk, via the regulation of SERCA3 levels, between endoplasmic reticulum calcium homeostasis and the control of cell differentiation, and show that endoplasmic reticulum calcium homeostasis itself can undergo remodeling during differentiation. The investigation of the anomalies of endoplasmic reticulum differentiation in tumor and leukemia cells may be useful for a better understanding of the contribution of calcium signaling to the establishment of malignant phenotypes. PMID- 21674634 TI - Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction. AB - In mammalian tissues, uptake of Ca(2+) and Mn(2+) by Golgi membranes is mediated by the secretory pathway Ca(2+) -ATPases, SPCA1 and SPCA2, encoded by the ATP2C1 and ATP2C2 genes. Loss of one copy of the ATP2C1 gene, which causes SPCA1 haploinsufficiency, leads to squamous cell tumors of keratinized epithelia in mice and to Hailey-Hailey disease, an acantholytic skin disease, in humans. Although the disease phenotypes resulting from SPCA1 haploinsufficiency in mice and humans are quite different, each species-specific phenotype is remarkably similar to those arising as a result of null mutations in one copy of the ATP2A2 gene, encoding SERCA2, the endoplasmic reticulum (ER) Ca(2+) pump. SERCA2 haploinsufficiency, like SPCA1 haploinsufficiency, causes squamous cell tumors in mice and Darier's disease, also an acantholytic skin disease, in humans. The phenotypic similarities between SPCA1 and SERCA2 haploinsufficiency in the two species, and the general functions of the two pumps in consecutive compartments of the secretory pathway, suggest that the underlying disease mechanisms are similar. In this review, we discuss evidence supporting the view that chronic Golgi stress and/or ER stress resulting from Ca(2+) pump haploinsufficiencies leads to activation of cellular stress responses in keratinocytes, with the predominance of proapoptotic pathways (although not necessarily apoptosis itself) leading to acantholytic skin disease in humans and the predominance of prosurvival pathways leading to tumors in mice. PMID- 21674637 TI - Plasma membrane calcium ATPases and cancer. AB - The plasma membrane calcium ATPases (PMCAs) are vital regulators of basal Ca(2+) and shape the nature of intracellular free Ca(2+) transients after cellular stimuli and are thus regulators of a plethora of cellular processes. Studies spanning many years have identified that at least some cancers are associated with a remodeling of PMCA isoform expression. This alteration in Ca(2+) efflux capacity may have a variety of consequences including reduced sensitivity to apoptosis and increases in the responsiveness of cancer cells to proliferative stimuli. In this review we provide an overview of studies focused on PMCAs in the context of cancer. We discuss how the remodeling of PMCA expression could provide a survival and/or growth advantage to cancer cells, as well as the potential of pharmacological agents that target specific PMCA isoforms to be novel therapies for the treatment of cancer. PMID- 21674636 TI - Calcium and bone disease. AB - Calcium transport and calcium signaling are of basic importance in bone cells. Bone is the major store of calcium and a key regulatory organ for calcium homeostasis. Bone, in major part, responds to calcium-dependent signals from the parathyroids and via vitamin D metabolites, although bone retains direct response to extracellular calcium if parathyroid regulation is lost. Improved understanding of calcium transporters and calcium-regulated cellular processes has resulted from analysis of genetic defects, including several defects with low or high bone mass. Osteoblasts deposit calcium by mechanisms including phosphate and calcium transport with alkalinization to absorb acid created by mineral deposition; cartilage calcium mineralization occurs by passive diffusion and phosphate production. Calcium mobilization by osteoclasts is mediated by acid secretion. Both bone forming and bone resorbing cells use calcium signals as regulators of differentiation and activity. This has been studied in more detail in osteoclasts, where both osteoclast differentiation and motility are regulated by calcium. PMID- 21674638 TI - Fructooligosaccharides suppress high-fat diet-induced fat accumulation in C57BL/6J mice. AB - Two experiments were performed to examine the effects of fructooligosaccharides (FOS) on the development of obesity. In the first experiment, Wistar rats were orally administered a 2.5 g/kg body weight lipid emulsion containing FOS, and the subsequent elevation of plasma triglycerides was significantly suppressed compared with that in rats receiving lipid emulsion alone. In the second experiment, C57BL/6J male mice were fed a high-fat "western" diet with or without 2.5% FOS supplementation (n = 10/group) ad libitum for 12 weeks. Body weight and percent body fat were lower in mice fed FOS than in controls. Furthermore, the weight of the visceral adipose tissue, and the weight and triglyceride content of the liver were significantly lower in the high-fat + FOS group. Fecal excretion of lipids was markedly enhanced by FOS consumption. These results indicate that dietary FOS suppress high-fat diet-induced body fat accumulation, and inhibit intestinal absorption of dietary fat. PMID- 21674639 TI - Calcium signaling dysfunction in heart disease. AB - In the heart, Ca(2+) is crucial for the regulation of contraction and intracellular signaling, processes, which are vital to the functioning of the healthy heart. Ca(2+) -activated signaling pathways must function against a background of large, rapid, and tightly regulated changes in intracellular free Ca(2+) concentrations during each contraction and relaxation cycle. This review highlights a number of proteins that regulate signaling Ca(2+) in both normal and pathological conditions including cardiac hypertrophy and heart failure, and discusses how these pathways are not regulated by the marked elevation in free intracellular calcium ([Ca(2+) ](i)) during contraction but require smaller sustained increases in Ca(2+) concentration. In addition, we present published evidence that the pool of Ca(2+) that regulates signaling is compartmentalized into distinct cellular microdomains and is thus distinct from that regulating contraction. PMID- 21674640 TI - Coenzyme Q(10) , endothelial function, and cardiovascular disease. AB - Since the time a precise role of coenzyme Q(10) (CoQ(10) ) in myocardial bioenergetics was established, the involvement of CoQ in the pathophysiology of heart failure was hypothesized. This provided the rationale for numerous clinical trials of CoQ(10) as adjunctive treatment for heart failure. A mild hypotensive effect of CoQ was reported in the early years of clinical use of this compound. We review early human and animal studies on the vascular effects of CoQ. We then focus on endothelial dysfunction in type 2 diabetes and the possible impact on this condition of antioxidants and nutritional supplements, and in particular the therapeutic effects of CoQ. The effect of CoQ(10) on endothelial dysfunction in ischemic heart disease is also reviewed together with recent data highlighting that treatment with CoQ(10) increases extracellular SOD activity. PMID- 21674641 TI - Non-mitochondrial coenzyme Q. AB - The key role of coenzyme Q (ubiquinone or Q) is in mitochondrial and prokaryotic energetics. Less well investigated is the basis for its presence in eukaryotic membrane locations other than mitochondria and in plasma where both antioxidant and potentially more targeted roles are indicated. Included in the latter is that of a lipid-soluble electron transfer intermediate that serves as the transmembrane component of plasma membrane and Golgi apparatus electron transport, which regulates cytosolic NAD(+) /NADH ratios and is involved in vectorial membrane displacements and in the regulation of cell growth. Important protective effects on circulating lipoproteins and in the prevention of coronary artery disease ensue not only from the antioxidant role of CoQ(10) but also from its ability to directly block protein oxidation and superoxide generation of the TM-9 family of membrane proteins known as age-related NADH oxidase or arNOX (ENOX3) and their shed forms that appear after age 30 and some of which associate specifically with low-density lipoprotein particles to catalyze protein oxidation and crosslinking. PMID- 21674642 TI - Mitochondria, calcium, and endoplasmic reticulum stress in Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta (SNPC) and the presence of intracytoplasmatic inclusions known as Lewy bodies, largely composed of alpha-synuclein (alpha-syn). PD is a multifactorial disease and its etiology remains largely elusive. Although more than 90% of the cases are sporadic, mutations in several nuclear encoded genes have been linked to the development of autosomal recessive and dominant familial parkinsonian syndromes (Bogaerts et al. (2008) Genes Brain Behav 7, 129-151), enhancing our understanding of biochemical and cellular mechanisms contributing to the disease. Many cellular mechanisms are thought to be involved in the dopaminergic neuronal death in PD, including oxidative stress, intracellular Ca(2+) homeostasis impairment, and mitochondrial dysfunctions. Furthermore, endoplasmic reticulum (ER) stress together with abnormal protein degradation by the ubiquitin proteasome system is considered to contribute to the PD pathogenesis. This review covers all the aspects related to the molecular mechanisms underlying the interplay between mitochondria, ER, and proteasome system in PD-associated neurodegeneration. PMID- 21674643 TI - Molecules and roles of mitochondrial calcium signaling. AB - Mitochondrial Ca(2+) homeostasis is an important component of the calcium mediated cellular response to extracellular stimuli. It controls key organelle functions, such as aerobic metabolism and the induction of apoptotic cell death, and shapes the spatiotemporal pattern of the cytosolic [Ca(2+)] increase. We here summarize both the main roles of Ca(2+) signals within mitochondria and the emerging molecular information that is starting to unravel the composition of the signaling apparatus and reveal potential pharmacological targets in this process of utmost pathophysiological relevance. PMID- 21674644 TI - Huntington's disease, calcium, and mitochondria. AB - Huntington's disease (HD) is caused by a mutation that increases the number of CAG repeats in the gene encoding for the protein Huntingtin (Htt). The mutation results in the pathological expansion of the polyQ stretch that is normally present within the N-terminal region of Htt. Even if Htt is ubiquitously expressed in tissues, the changes in the protein finally result in the clinical manifestation of motor and cognitive impairments observed in HD patients. The molecular ethiology of the disease is obscure: a number of cellular and animal models are used as essential tools in experimental approaches aimed at understanding it. Biochemical changes have been described that correlate with the malfunction of HD neurons (primarily in the striatum): consensus is gradually emerging that the dyshomeostasis of Ca(2+) and/or mitochondria stress are important factors in the linkage of the Htt mutation to the onset and progression of the disease. Here, we present a succint overview of the changes of Htt, of its possible effect on the transcription of critical genes and of its causative role in the disturbance of the neuronal Ca(2+) homeostasis. Particular emphasis will be placed on the role of mitochondria as key player in the molecular pathogenesis of the disease. PMID- 21674645 TI - Calcium signaling and disease: preface. PMID- 21674646 TI - A primer on determining the dietary requirements for folate. PMID- 21674647 TI - Human neural tube defects: genetic causes and prevention. AB - Neural tube defects (NTDs) are severe congenital malformations affecting 1-2 in 1,000 live births, whose etiology is multifactorial, involving environmental and genetic factors. NTDs arise as consequence of the failure of fusion of the neural tube early during embryogenesis. NTDs' pathogenesis has been linked to genes involved in folate metabolism, consistent with an epidemiologic evidence that 70% of NTDs can be prevented by maternal periconceptional supplementation. However, polymorphisms in such genes are not linked in all populations, suggesting that other genetic factors and environmental factors could be involved. Animal models have provided crucial mechanistic information and possible candidate genes to explain susceptibility to NTDs. A crucial role has been assigned to the planar cell polarity (PCP) pathway, a highly conserved, non-canonical Wnt-frizzled dishevelled signaling cascade that plays a key role in establishing and maintaining polarity in the plane of the epithelium and in the process of convergent extension during gastrulation and neurulation in vertebrates. The Loop tail (Lp) mouse that develops craniorachischisis carry missense mutations in the PCP core gene Vangl2, that is the mammalian homolog of the Drosophila Strabismus/Van gogh (Stbm/Vang). The presence of mutations in human VANGL1 and VANGL2 genes encourages us to extend the investigation to other PCP genes that, with VANGL, play an essential role in neurulation during development. PMID- 21674648 TI - More folic acid, the five questions: why, who, when, how much, and how. AB - In recent years, a number of studies have been performed to evaluate the possible health benefits of an increased intake of folic acid (FA) on human health. However, the only well-documented benefit emerging from randomized controlled trials, nonrandomized interventions trials, and observational studies is the risk reduction of neural tube defects (NTDs). NTDs are congenital malformations that include anencephaly, encephalocele, and spina bifida caused by the failure of fusion of the neural tube that normally closes between 22nd and 28th day since conception (on an average 40-42th day after the first day of last menstrual period). The occurrence of NTDs varies among population between 0.8 and 3 per 1,000, and it is estimated that 324,000 pregnancies are affected every year worldwide. More FA can decrease the NTDs risk up to 0.6 per 1,000 births. Other malformations as congenital heart defects, cleft lip, and limb deficiencies can be most probably also reduced. To decrease the NTDs risk, it is recommended that all women capable of becoming pregnant should have more FA. The goal is that every woman could start her pregnancy with an optimal folate status, estimated today to be as more than 906 nmol/L of red blood cell folate concentration. More FA can be obtained through a strict Mediterranean pattern of nutrition and healthy life style, fortified food, supplements. Women and health authorities can choose the most appropriate strategy. Monitoring folate status of women during the periconceptional period is an essential way to evaluate the success of the preferred strategy. PMID- 21674649 TI - Folic acid fortification: why not vitamin B12 also? AB - Folic acid fortification of cereal grains was introduced in many countries to prevent neural tube defect occurrence. The metabolism of folic acid and vitamin B12 intersect during the transfer of the methyl group from 5 methyltetrahydrofolate to homocysteine catalyzed by B12-dependent methioine synthase. Regeneration of tetrahydrofolate via this reaction makes it available for synthesis of nucleotide precursors. Thus either folate or vitamin B12 deficiency can result in impaired cell division and anemia. Exposure to extra folic acid through fortification may be detrimental to those with vitamin B12 deficiency. Among participants of National Health And Nutrition Examination Survey with low vitamin B12 status, high serum folate (>59 nmol/L) was associated with higher prevalence of anemia and cognitive impairment when compared with normal serum folate. We also observed an increase in the plasma concentrations of total homocysteine and methylmalonic acid (MMA), two functional indicators of vitamin B12 status, with increase in plasma folate under low vitamin B12 status. These data strongly imply that high plasma folate is associated with the exacerbation of both the biochemical and clinical status of vitamin B12 deficiency. Hence any food fortification policy that includes folic acid should also include vitamin B12. PMID- 21674651 TI - Changes in the metabolic profile of rat liver after alpha-tocopherol deficiency as revealed by metabolomics analysis. AB - Metabolomics is an approach in which the profiles of metabolites in different tissues and/or biofluids are investigated to understand the changes induced following a modulation. We used this approach to investigate the biochemical effects of alpha-tocopherol in the liver using a rat model. Rats (21-day-old) were fed either an alpha-tocopherol-sufficient control (n = 10) or an alpha tocopherol-deficient (n = 10) diet for 2 months before sacrifice. Livers were homogenized in methanol-chloroform-water (3 : 1 : 1, v/v/v), and the polar phase extracts of the liver samples were analyzed using (1) H NMR. Multivariate statistical analysis of the data was performed using principal component analysis and orthogonal partial least squares-discriminant analysis. Identification of (1) H NMR signals was performed primarily using the Human Metabolome Database, Biological Magnetic Resonance Data Bank and previous literature, and confirmed by spiking with metabolites and applying two-dimensional NMR. The statistical analysis revealed that alpha-tocopherol deficiency caused an increase in carnitine, choline, L-valine, L-lysine, tyrosine and inosine content and a reduction in glucose and uridine 5'-monophosphate content. Changes in carnitine and glucose suggest a possible shift in energy metabolism. PMID- 21674650 TI - Assessment of multiparametric MRI in a human glioma model to monitor cytotoxic and anti-angiogenic drug effects. AB - Early imaging or blood biomarkers of tumor response is needed to customize anti tumor therapy on an individual basis. This study evaluates the sensitivity and relevance of five potential MRI biomarkers. Sixty nude rats were implanted with human glioma cells (U-87 MG) and randomized into three groups: one group received an anti-angiogenic treatment (Sorafenib), a second a cytotoxic drug [1,3-bis(2 chloroethyl)-1-nitrosourea, BCNU (Carmustine)] and a third no treatment. The tumor volume, apparent diffusion coefficient (ADC) of water, blood volume fraction (BVf), microvessel diameter (vessel size index, VSI) and vessel wall integrity (contrast enhancement, CE) were monitored before and during treatment. Sorafenib reduced tumor CE as early as 1 day after treatment onset. By 4 days after treatment onset, tumor BVf was reduced and tumor VSI was increased. By 14 days after treatment onset, ADC was increased and the tumor growth rate was reduced. With BCNU, ADC was increased and the tumor growth rate was reduced 14 days after treatment onset. Thus, the estimated MRI parameters were sensitive to treatment at different times after treatment onset and in a treatment-dependent manner. This study suggests that multiparametric MR monitoring could allow the assessment of new anti-tumor drugs and the optimization of combined therapies. PMID- 21674653 TI - (13)C MR reporter probe system using dynamic nuclear polarization. AB - Reporter-based cell detection and localization in vivo may become an important imaging tool with the emergence of cellular therapy. With the strong signal enhancement provided by dynamic nuclear polarization, an NMR-based reporter probe system utilizing specific enzyme expression and activity can potentially provide stable, high-resolution visualization of the cells of interest noninvasively. In this work, a proof-of-concept (13) C MR reporter system, using the aminoacylase-1 reporter gene (Acy-1) and prepolarized [1-(13) C]N-acetyl-L-methionine as the paired substrate, was developed. Using a 3-T MR scanner, the feasibility of detecting and imaging de-acetylation of the prepolarized (13) C-labeled substrate by the aminoacylase-1 enzyme was demonstrated with purified protein in solution by dynamic (13) C MRS and two-dimensional MRSI experiments. The potential to perform targeted MRI of cells using this system was also demonstrated by (13) C MR measurement of aminoacylase-1 activity in HEK 293 cells transfected with the Acy-1 gene. The de-acetylation of the substrate was not observed in control cells. PMID- 21674652 TI - In vivo MRSI of hyperpolarized [1-(13)C]pyruvate metabolism in rat hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC), the primary form of human adult liver malignancy, is a highly aggressive tumor with average survival rates that are currently less than 1 year following diagnosis. Most patients with HCC are diagnosed at an advanced stage, and no efficient marker exists for the prediction of prognosis and/or response(s) to therapy. We have reported previously a high level of [1 (13)C]alanine in an orthotopic HCC using single-voxel hyperpolarized [1 (13)C]pyruvate MRS. In the present study, we implemented a three-dimensional MRSI sequence to investigate this potential hallmark of cellular metabolism in rat livers bearing HCC (n = 7 buffalo rats). In addition, quantitative real-time polymerase chain reaction was used to determine the mRNA levels of lactate dehydrogenase A, nicotinamide adenine (phosphate) dinucleotide dehydrogenase quinone 1 and alanine transaminase. The enzyme levels were significantly higher in tumor than in normal liver tissues within each rat, and were associated with the in vivo MRSI signal of [1-(13)C]alanine and [1-(13)C]lactate after a bolus intravenous injection of [1-(13)C]pyruvate. Histopathological analysis of these tumors confirmed the successful growth of HCC as a nodule in buffalo rat livers, revealing malignancy and hypervascular architecture. More importantly, the results demonstrated that the metabolic fate of [1-(13)C]pyruvate conversion to [1-(13)C]alanine significantly superseded that of [1-(13)C]pyruvate conversion to [1-(13)C]lactate, potentially serving as a marker of HCC tumors. PMID- 21674654 TI - Noninvasive quantification of human brain antioxidant concentrations after an intravenous bolus of vitamin C. AB - Until now, the lack of a means to detect a deficiency or to measure the pharmacologic effect in the human brain in situ has been a hindrance to the development of antioxidant-based prevention and treatment of dementia. In this study, a recently developed (1) H MRS approach was applied to quantify key human brain antioxidant concentrations throughout the course of an aggressive antioxidant-based intervention. The concentrations of the two most abundant central nervous system chemical antioxidants, vitamin C and glutathione, were quantified noninvasively in the human occipital cortex prior to and throughout 24 h after bolus intravenous delivery of 3 g of vitamin C. Although the kinetics of the sodium-dependent vitamin C transporter and physiologic blood vitamin C concentrations predict theoretically that brain vitamin C concentration will not increase above its homeostatically maintained level, this theory has never been tested experimentally in the living human brain. Therefore, human brain vitamin C and glutathione concentrations were quantified noninvasively using MEGA-PRESS double-edited (1) H MRS and LCModel. Healthy subjects (age, 19-63 years) with typical dietary consumption, who did not take vitamin supplements, fasted overnight and then reported for the measurement of baseline antioxidant concentrations. They then began controlled feeding which they adhered to until after vitamin C and glutathione concentrations had been measured at 2, 6, 10 and 24 h after receiving intravenous vitamin C. Two of the twelve studies were sham controls in which no vitamin C was administered. The main finding was that human brain vitamin C and glutathione concentrations remained constant throughout the protocol, even though blood serum vitamin C concentrations spanned from the low end of the normal range to very high. PMID- 21674655 TI - Combined (1)H and (31)P spectroscopy provides new insights into the pathobiochemistry of brain damage in multiple sclerosis. AB - (1)H MRSI has evolved as an important tool to study the onset and progression of brain damage in multiple sclerosis. Abnormal increases in total creatine, total choline and myoinositol have been noted in multiple sclerosis. However, the pathobiochemical mechanisms related to these changes are still largely unclear. The combination of (1)H MRSI and (1)H-decoupled (31)P MRSI can specify to what extent phosphorylated components of total creatine and total choline contribute to this increase. Combined (1)H and (31)P MRSI data were obtained at 3 T in 22 patients with multiple sclerosis and in 23 healthy controls, and aligned with structural MRI to allow for correction for partial volume effects caused by cerebrospinal fluid and lesion load. A significant increase in total creatine was found in multiple sclerosis, and this was attributed to equal changes in the phosphorylated and unphosphorylated components. The concentrations of the putative glial markers total creatine and myoinositol in lesion-free (1)H MRSI voxels correlated with the global lesion load. We conclude that changes in total creatine are not related to altered energy metabolism, but rather indicate gliosis. Together with the increase in myoinositol, total creatine can be considered as a biomarker for disease severity. A significant total choline increase was mainly a result of choline components not visible by (31)P MRS. The origin of this residual choline fraction remains to be investigated. PMID- 21674656 TI - MRI and quantitative autoradiographic studies following bolus injections of unlabeled and (14)C-labeled gadolinium-diethylenetriaminepentaacetic acid in a rat model of stroke yield similar distribution volumes and blood-to-brain influx rate constants. AB - In previous studies on a rat model of transient cerebral ischemia, the blood and brain concentrations of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) following intravenous bolus injection were repeatedly assessed by dynamic contrast-enhanced (DCE)-MRI, and blood-to-brain influx rate constants (K(i)) were calculated from Patlak plots of the data in areas with blood-brain barrier (BBB) opening. For concurrent validation of these findings, after completing the DCE MRI study, radiolabeled sucrose or alpha-aminoisobutyric acid was injected intravenously, and the brain disposition and K(i) values were calculated by quantitative autoradiography (QAR) assay employing the single-time equation. To overcome two of the shortcomings of this comparison, the present experiments were carried out with a radiotracer virtually identical to Gd-DTPA, Gd-[(14)C]DTPA, and K(i) was calculated from both sets of data by the single-time equation. The protocol included 3 h of middle cerebral artery occlusion and 2.5 h of reperfusion in male Wistar rats (n = 15) preceding the DCE-MRI Gd-DTPA and QAR Gd [(14)C]DTPA measurements. In addition to K(i) , the tissue-to-blood concentration ratios, or volumes of distribution (V(R) ), were calculated. The regions of BBB opening were similar on the MRI maps and autoradiograms. Within them, V(R) was nearly identical for Gd-DTPA and Gd-[(14)C]DTPA, and K(i) was slightly, but not significantly, higher for Gd-DTPA than for Gd-[(14)C]DTPA. The K(i) values were well correlated (r = 0.67; p = 0.001). When the arterial concentration-time curve of Gd-DTPA was adjusted to match that of Gd-[(14)C]DTPA, the two sets of K(i) values were equal and statistically comparable with those obtained previously by Patlak plots (the preferred, less model-dependent, approach) of the same data (p = 0.2-0.5). These findings demonstrate that this DCE-MRI technique accurately measures the Gd-DTPA concentration in blood and brain, and that K(i) estimates based on such data are good quantitative indicators of BBB injury. PMID- 21674657 TI - A review of fetal volumetry: the need for standardization and definitions in measurement methodology. AB - Volume charts of fetal organs and structures vary considerably among studies. This review identified 42 studies reporting normal volumes, namely for fetal brain (n = 3), cerebellum (n = 4), liver (n = 6), femur (n = 2), lungs (n = 15), kidneys (n = 3) and first-trimester embryo (n = 9). The differences among median volumes were expressed both in percentage form and as standard deviation scores. Wide discrepancies in reported normal volumes make it extremely difficult to diagnose pathological organ growth reliably. Given its magnitude, this variation is likely to be due to inconsistencies in volumetric methodology, rather than population differences. Complicating factors include the absence of clearly defined anatomical landmarks for measurement; inadequate assessment and reporting of method repeatability; the inherent difficulty in validating fetal measurements in vivo against a reference standard; and a multitude of mutually incompatible three-dimensional (3D) imaging formats and software measuring tools. An attempt to standardize these factors would improve intra- and inter-researcher agreement concerning reported volumetric measures, would allow generalization of reference data across different populations and different ultrasound systems, and would allow quality assurance in 3D fetal biometry. Failure to ensure a quality control process may hamper the wide use of 3D ultrasound. PMID- 21674658 TI - Contingent screening for Down syndrome completed in the first trimester: a multicenter study. AB - OBJECTIVE: To assess a new contingent screening strategy for Down syndrome completed in the first trimester. METHODS: First-trimester screening combining nuchal translucency thickness measurement and assessment of serum analytes (combined test) was offered to pregnant women who presented for prenatal care during the first trimester to nine health centers and community hospitals in the area served by the Catalan Public Health Service. If an intermediate risk (1/101 1/1000) for Down syndrome was identified, women were referred to the Hospital Clinic Barcelona for risk reassessment that included the use of secondary ultrasound markers (nasal bone, ductus venosus blood flow and tricuspid flow). Intermediate-risk women were divided into two subgroups for further analysis: high-intermediate risk (1/101-1/250) and low-intermediate risk (1/251-1/1000). We compared feasibility and efficacy of both combined and contingent screening strategies. RESULTS: The combined test, the first screening stage, was performed in 16 001 pregnant women, of whom 1617 (10.1%) were found to have an intermediate risk. Further division of this group showed that 1.8% (n = 289) of women were at high-intermediate risk and 8.3% (n = 1328) at low-intermediate risk. The contingent screening strategy significantly reduced the false-positive rate, from 3.0% to 1.3-1.8% (P < 0.001), without affecting the detection rate (which was 75 79% and 76%, with and without the contingent screening strategy, respectively). However, only 45% of intermediate-risk patients underwent the second screening step due to a preference among high-intermediate-risk (1/101-1/250) women for invasive testing and to low uptake among low-intermediate-risk (1/251-1/1000) women. CONCLUSIONS: The proposed first-trimester contingent strategy reduces the screen false-positive rate without impacting on the detection rate of Down syndrome. The low compliance observed in our study may prevent its use in certain populations. PMID- 21674659 TI - Longitudinal study of aortic isthmus Doppler in appropriately grown and small-for gestational-age fetuses with normal and abnormal umbilical artery Doppler. AB - OBJECTIVE: To establish reference ranges using longitudinal data for aortic isthmus (AoI) Doppler indices in appropriate-for-gestational-age (AGA) fetuses and to document the longitudinal trends in a cohort of small-for-gestational-age (SGA) fetuses with normal umbilical artery Doppler and in fetuses with intrauterine growth restriction (IUGR) and abnormal umbilical artery Doppler. METHODS: AoI Doppler reference ranges were established from longitudinal data on 72 AGA singleton fetuses. Reliability of AoI Doppler flow measurements at two different sites and reproducibility between two operators was reviewed. A prospective longitudinal study of AoI Doppler indices in 48 SGA fetuses with normal umbilical artery Doppler and 10 IUGR fetuses was performed. RESULTS: The AoI pulsatility index (PI) and peak systolic velocity (PSV) in AGA fetuses showed a significant increase with gestational age. Analysis of intra- and interoperator variability revealed no significant mean difference in measurements of AoI-PI or AoI-PSV. Observations of AoI-PI and AoI-PSV from SGA fetuses did not differ significantly from those of AGA or IUGR fetuses. Retrograde flow in the AoI did not predate changes in the ductus venosus in IUGR fetuses. CONCLUSIONS: Reference ranges for fetal AoI Doppler parameters in AGA fetuses constructed using longitudinal data are consistent with those obtained from cross-sectional data. The AoI Doppler parameters in SGA fetuses did not differ from those in AGA fetuses. Preterm IUGR fetuses did not manifest alterations in AoI-PI or AoI-PSV prior to changes in biophysical profile or ductus venosus Doppler. Further large scale prospective studies are needed to determine whether AoI Doppler parameters are of any value in timing delivery or reducing adverse neurodevelopmental outcome. PMID- 21674660 TI - Endometrioid ovarian carcinoma in a woman with a history of infertility and multiple in-vitro fertilization treatment cycles. AB - Ovarian cancer is rarely diagnosed during assisted reproduction. Several case control and cohort studies have described its incidence within the infertile population well after the assisted reproductive process. We present a case of endometrioid adenocarcinoma that developed during the ovarian stimulation process and show corresponding ultrasound images of its development. PMID- 21674662 TI - Quantitation of protein-protein interactions by thermal stability shift analysis. AB - Thermal stability shift analysis is a powerful method for examining binding interactions in proteins. We demonstrate that under certain circumstances, protein-protein interactions can be quantitated by monitoring shifts in thermal stability using thermodynamic models and data analysis methods presented in this work. This method relies on the determination of protein stabilities from thermal unfolding experiments using fluorescent dyes such as SYPRO Orange that report on protein denaturation. Data collection is rapid and straightforward using readily available real-time polymerase chain reaction instrumentation. We present an approach for the analysis of the unfolding transitions corresponding to each partner to extract the affinity of the interaction between the proteins. This method does not require the construction of a titration series that brackets the dissociation constant. In thermal shift experiments, protein stability data are obtained at different temperatures according to the affinity- and concentration dependent shifts in unfolding transition midpoints. Treatment of the temperature dependence of affinity is, therefore, intrinsic to this method and is developed in this study. We used the interaction between maltose-binding protein (MBP) and a thermostable synthetic ankyrin repeat protein (Off7) as an experimental test case because their unfolding transitions overlap minimally. We found that MBP is significantly stabilized by Off7. High experimental throughput is enabled by sample parallelization, and the ability to extract quantitative binding information at a single partner concentration. In a single experiment, we were able to quantify the affinities of a series of alanine mutants, covering a wide range of affinities (~ 100 nM to ~ 100 MUM). PMID- 21674661 TI - A designed redox-controlled caspase. AB - Caspases are a powerful class of cysteine proteases. Introduction of activated caspases in healthy or cancerous cells results in induction of apoptotic cell death. In this study, we have designed and characterized a version of caspase-7 that can be inactivated under oxidizing extracellular conditions and then reactivated under reducing intracellular conditions. This version of caspase-7 is allosterically inactivated when two of the substrate-binding loops are locked together via an engineered disulfide. When this disulfide is reduced, the protein regains its full function. The inactive loop-locked version of caspase-7 can be readily observed by immunoblotting and mass spectrometry. The reduced and reactivated form of the enzyme observed crystallographically is the first caspase 7 structure in which the substrate-binding groove is properly ordered even in the absence of an active-site ligand. In the reactivated structure, the catalytic dyad cysteine-histidine are positioned 3.5 A apart in an orientation that is capable of supporting catalysis. This redox-controlled version of caspase-7 is particularly well suited for targeted cell death in concert with redox-triggered delivery vehicles. PMID- 21674663 TI - Integration of cell-free protein coexpression with an enzyme-linked immunosorbent assay enables rapid analysis of protein-protein interactions directly from DNA. AB - Assays that integrate detection of binding with cell-free protein expression directly from DNA can dramatically increase the pace at which protein-protein interactions (PPIs) can be analyzed by mutagenesis. In this study, we present a method that combines in vitro protein production with an enzyme-linked immunosorbent assay (ELISA) to measure PPIs. This method uses readily available commodity instrumentation and generic antibody-affinity tag interactions. It is straightforward and rapid to execute, enabling many interactions to be assessed in parallel. In traditional ELISAs, reporter complexes are assembled stepwise with one layer at a time. In the method presented here, all the members of the reporter complex are present and assembled together. The signal strength is dependent on all the intercomponent interaction affinities and concentrations. Although this assay is straightforward to execute, establishing proper conditions and analysis of the results require a thorough understanding of the processes that determine the signal strength. The formation of the fully assembled reporter sandwich can be modeled as a competition between Langmuir adsorption isotherms for the immobilized components and binding equilibria of the solution components. We have shown that modeling this process provides semiquantitative understanding of the effects of affinity and concentration and can guide strategies for the development of experimental protocols. We tested the method experimentally using the interaction between a synthetic ankyrin repeat protein (Off7) and maltose binding protein. Measurements obtained for a collection of alanine mutations in the interface between these two proteins demonstrate that a range of affinities can be analyzed. PMID- 21674664 TI - Comparative functional analysis of the human macrophage chitotriosidase. AB - This work analyses the chitin-binding and catalytic domains of the human macrophage chitotriosidase and investigates the physiological role of this glycoside hydrolase in a complex mechanism such as the innate immune system, especially its antifungal activity. Accordingly, we first analyzed the ability of its chitin-binding domain to interact with chitin embedded in fungal cell walls using the beta-lactamase activity reporter system described in our previous work. The data showed that the chitin-binding activity was related to the cell wall composition of the fungi strains and that their peptide-N-glycosidase/zymolyase treatments increased binding to fungal by increasing protein permeability. We also investigated the antifungal activity of the enzyme against Candida albicans. The antifungal properties of the complete chitotriosidase were analyzed and compared with those of the isolated chitin-binding and catalytic domains. The isolated catalytic domain but not the chitin-binding domain was sufficient to provide antifungal activity. Furthermore, to explain the lack of obvious pathologic phenotypes in humans homozygous for a widespread mutation that renders chitotriosidase inactive, we postulated that the absence of an active chitotriosidase might be compensated by the expression of another human hydrolytic enzyme such as lysozyme. The comparison of the antifungal properties of chitotriosidase and lysozyme indicated that surprisingly, both enzymes have similar in vitro antifungal properties. Furthermore, despite its more efficient hydrolytic activity on chitin, the observed antifungal activity of chitotriosidase was lower than that of lysozyme. Finally, this antifungal duality between chitotriosidase and lysozyme is discussed in the context of innate immunity. PMID- 21674666 TI - Biocompatible micelles based on comb-like PEG derivates: formation, characterization, and photo-responsiveness. AB - A novel comb-like derivative CPEG-g-DNQ was prepared by incorporating light responsive 2-diazo-1,2-naphthoquinone (DNQ) groups into the structure of comb like poly(ethylene glycol) (CPEG). DLS and TEM results showed that CPEG-g-DNQ self-assembled into spherical micelles with an average size of about 135 nm in water. Upon exposure to light, the micelles could be disrupted because of the conversion of hydrophobic DNQ to hydrophilic 3-indenecarboylic acid. Additionally, hydrophobic coumarin 102 was successfully loaded into the micelles and photo-induced ON-OFF release was demonstrated by fluorescence spectroscopy. MTT assay revealed that the micelles are biocompatible. These photo-responsive micelles might have great potential for controlled release of hydrophobic drugs. PMID- 21674665 TI - Penicillin-binding protein 5 can form a homo-oligomeric complex in the inner membrane of Escherichia coli. AB - Penicillin-binding protein 5 (PBP5) is a DD-carboxypeptidase, which cleaves the terminal D-alanine from the muramyl pentapeptide in the peptidoglycan layer of Escherichia coli and other bacteria. In doing so, it varies the substrates for transpeptidation and plays a key role in maintaining cell shape. In this study, we have analyzed the oligomeric state of PBP5 in detergent and in its native environment, the inner membrane. Both approaches indicate that PBP5 exists as a homo-oligomeric complex, most likely as a homo-dimer. As the crystal structure of the soluble domain of PBP5 (i.e., lacking the membrane anchor) shows a monomer, we used our experimental data to generate a model of the homo-dimer. This model extends our understanding of PBP5 function as it suggests how PBP5 can interact with the peptidoglycan layer. It suggests that the stem domains interact and the catalytic domains have freedom to move from the position observed in the crystal structure. This would allow the catalytic domain to have access to pentapeptides at different distances from the membrane. PMID- 21674667 TI - Prognostic factors for T1-T2 squamous cell carcinomas of the mobile tongue: A retrospective cohort study. AB - BACKGROUND: The aim of this study was to identify factors predicting poor prognosis at the time of early oral tongue carcinoma diagnosis. METHODS: A retrospective cohort study was carried out on 70 patients with T1 or T2 squamous cell carcinoma of the mobile tongue treated with primary surgical treatment. RESULTS: In all, 47% of patients received adjuvant treatment. Local recurrence was observed in 29% and regional recurrence in 26%. With a median follow-up of 7.3 years for living patients, 5-year actuarial overall, disease-specific, and disease-free survival rates were 48%, 61%, and 42%, respectively. The presence of poor histological differentiation increased the overall risk of death. Tumor thickness and posterior lingual location independently increased overall and disease-specific risk of death. Concurrent or previous diagnosis of oral lichen significantly increased the risk of disease-specific death and disease recurrence. CONCLUSIONS: This study corroborates several known prognostic factors and indicates that diagnosis of oral lichen planus may be a risk factor for disease recurrence. PMID- 21674668 TI - Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: a prospective clinical trial. AB - BACKGROUND: Metastatic head and neck squamous cell carcinoma with an unknown primary is an uncommon but important problem. PET/CT, as an adjunct to diagnosis, is potentially useful but has never been studied in a prospective, single-blinded clinical trial. METHODS: In all, 20 subjects with cervical metastases from an unknown head and neck primary were enrolled in a prospective clinical trial. A standard protocol was used in both clinic and operating room (OR). Study surgeons were blinded to the PET/CT result upon completion of the standard work-up. RESULTS: PET/CT increased the detection of a primary site from 25% to 55% (5 vs 11 subjects). This difference was statistically and clinically significant (p = .03, McNemar's test). There was 1 false negative PET/CT scan. CONCLUSIONS: An unknown primary should be diagnosed only after a complete head and neck examination, flexible endoscopy, and CT or MRI. PET/CT performed prior to panendoscopy will increase the diagnostic yield in the unknown head and neck primary population, leading to more targeted, and less morbid, treatment. PMID- 21674669 TI - Value of fluorescence endoscopy for the early diagnosis of laryngeal cancer and its precursor lesions. AB - BACKGROUND: Fluorescence endoscopy is used for the early detection and delineation of laryngeal cancer and its precursor lesions. No systematic review of these promising imaging techniques has yet been performed. METHODS: A systematic review of the published literature and meta-analysis of data extracted from 16 included studies were performed. A total of 1000 laryngeal lesions were examined by autofluorescence endoscopy (AFE), 318 mucosal changes by induced fluorescence endoscopy (IFE), and 679 laryngeal pathologies underwent normal white light endoscopy (WLE). RESULTS: In identifying precancerous and cancerous lesions of the larynx, sensitivity (91% vs 73%), specificity (84% vs 79%), and accuracy (88% vs 77%) of AFE were superior to WLE alone, whereas IFE showed an even higher sensitivity (95% vs 73%) at the expense of specificity (62% vs 79%). Therefore, AFE also achieved a higher specificity (84% vs 62%) and accuracy (88% vs 76%) than did IFE in detecting these kinds of lesions. However, the sensitivity (91% vs 95%) did not differ significantly between both methods. CONCLUSIONS: This meta-analysis confirms that fluorescence endoscopy is highly effective in the early diagnosis of laryngeal cancer and its precursor lesions. Thus, AFE can be used immediately without drug administration or possible side effects, whereas IFE is more suited for the detection of recurrent disease following initial surgery. PMID- 21674670 TI - Role of panendoscopy to identify synchronous second primary malignancies in patients with oral cavity and oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Tobacco use increases the risk for squamous cell carcinoma (SCC) of the upper aerodigestive tract. The reported incidence of synchronous second primary tumors in head and neck cancer is approximately 10%. Therefore, patients with oral cancer have routinely undergone "panendoscopy" consisting of direct laryngoscopy, bronchoscopy, and esophagoscopy. Recent studies indicate increasing numbers of upper aerodigestive tumors occurring in nonsmoking populations who may have a lesser risk for second primary tumors. The purpose of this study was to evaluate the utility of performing "panendoscopy" to identify second primary tumors in these patient populations. METHODS: A retrospective study of 64 consecutive patients at a university head and neck surgery practice was performed. A cohort of patients with oral cavity or oropharyngeal SCC with no tobacco history who underwent diagnostic panendoscopy were compared with similarly staged patients with a current or past history of tobacco use. Operative reports were examined for synchronous primaries, and epidemiologic data were collected. Subgroup analysis of incidence of synchronous primaries with regard to smoking status, age, sex, T classification, N classification, and location of primary tumor was also carried out. Student's t test statistical analysis was used to ascertain significance. RESULTS: No synchronous second primary malignancies were discovered in the nonsmoking patients. In all, 12.1% of smoking patients were diagnosed with synchronous primary cancers on panendoscopy, and this difference was significant (p = .0392). CONCLUSIONS: Routine panendoscopy of the upper aerodigestive tract in patients who have never smoked is unlikely to result in identification of synchronous second primary tumors. PMID- 21674671 TI - Surgical site infection after preoperative neoadjuvant chemotherapy in patients with locally advanced oral squamous cell carcinoma. AB - BACKGROUND: We investigated whether preoperative neoadjuvant chemotherapy is associated with increased surgical site infection (SSI) rate in patients with locally advanced oral cancer. METHODS: In this hospital-based study, we retrospectively reviewed over 2000 chart records of patients with oral cavity cancer from March 1994 to December 2007. Those who received neoadjuvant chemotherapy were identified and matched for age, sex, tumor classification, primary site, and reconstruction methods to hospitalized patients who did not receive chemotherapy. Data were analyzed for the relationship between chemotherapy and SSI. RESULTS: A total of 306 patients were enrolled for final analyses. The overall postoperative SSI rate was 31.0%. The SSI rate in patients after neoadjuvant chemotherapy was similar to that in patients who did not receive the chemotherapy (33.3% vs 29.9%, p = .631). CONCLUSIONS: Preoperative neoadjuvant chemotherapy was not associated with increased SSI rate in patients with locally advanced oral cancer. PMID- 21674672 TI - Impact of continuous intraoperative neuromonitoring on autonomic nervous system during thyroid surgery. AB - BACKGROUND: Continuous intraoperative neuromonitoring (CIONM) via vagal nerve stimulation (VNS) is a new option for recurrent laryngeal nerve (RLN) protection during thyroid surgery. The aim of this study was to evaluate the safety of VNS for CIONM and to assess its effects on the autonomic nervous system (ANS) through analyzing heart rate variability (HRV). METHODS: In a prospective, nonrandomized controlled study 5 patients received VNS for CIONM and 5 were operated on with conventional intermittent intraoperative neuromonitoring (IONM). HRV was analyzed in accord with patient-specific reference values. RESULTS: VNS resulted in significantly altered ANS balance. Relative parasympathetic activity increased during VNS. Yet, no relevant cardiac arrhythmias or hemodynamic alterations were observed during VNS. CONCLUSION: HRV analysis revealed a distinct impact of VNS for CIONM on ANS balance. VNS caused parasympathetic predominance that was not countered by increased sympathetic activity. PMID- 21674673 TI - Increased frequencies of CD4+ CD25+ FOXP3+ regulatory T cells in human nasal inverted papilloma. AB - BACKGROUND: The purpose of this study was to investigate the presence of CD4(+) CD25(+) FOXP3(+) regulatory T (Treg) cells both in peripheral blood and local tumors in patients with nasal inverted papilloma (NIP). METHODS: By using flow cytometry, the frequencies of CD4(+) CD25(+) FOXP3(+) Treg cells in both peripheral blood and tissues from 18 patients with NIP and 8 control subjects were determined. CCL22 and CCL17 proteins in NIP tumors were analyzed by using enzyme-linked immunosorbent assay. The suppressive capacity of Treg cells was estimated by WST-8 and enzyme-linked immunosorbent assay (ELISA; interferon-gamma [IFN-gamma] and interleukin-4 [IL-4]) analysis. RESULTS: Patients with NIP showed increased CD4(+) CD25(+) FOXP3(+) Treg cell frequencies in tumor tissues and CD4(+) T cell fraction rather than in peripheral blood. CCL22 increased in NIP tumors. Phytohemagglutinin (PHA)-induced proliferation and cytokine production of CD4(+) CD25(-) T cells were suppressed equally well by CD4(+) CD25(high) cells from both patients with NIP and controls. CONCLUSION: Our study demonstrated the increased frequencies of CD4(+) CD25(+) FOXP3(+) Treg cells in NIP tumors, which might be influenced by CCL22. PMID- 21674674 TI - Development of consensus guidelines for venous thromboembolism prophylaxis in patients undergoing microvascular reconstruction of the mandible. AB - BACKGROUND: The purpose of this study was to determine how guidelines for venous thromboembolism prophylaxis can be applied to patients undergoing microsurgical reconstruction of the mandible. METHODS: Retrospective review of our institutional use of thromboprophylaxis and the associated outcomes in 114 patients (58 free fibular flaps and 56 osteocutaneous radial forearm flaps). RESULTS: Twenty-two patients (19.3%) received only intermittent pneumatic compression. Overall, 80.7% received postoperative chemoprophylaxis. Sixty-four percent initiated chemoprophylaxis within 24 hours after surgery. Only 13.2% received the recommended frequency of chemoprophylaxis. One patient had development of a pulmonary embolism. Four patients undergoing chemoprophylaxis had development of neck hematomas; in each case the cause of bleeding could be attributed to a cause distinct from chemoprophylaxis. CONCLUSIONS: No consistent chemoprophylaxis protocol was followed. Chemoprophylaxis was not associated with an increased risk of bleeding. Physician education is the next step in decreasing variations in chemoprophylaxis and adopting guidelines similar to The American College of Chest Physicians. PMID- 21674675 TI - Correlation of dyskerin expression with active proliferation independent of telomerase. AB - BACKGROUND: Dyskerin, which is an important component of the telomerase complex and is needed for normal telomerase activity, is frequently overexpressed in neoplasia. Dyskerin also plays an essential role in ribosome biogenesis. Because protein synthesis increases during tumorigenesis, this led us to hypothesize that dyskerin expression would be upregulated independently of the cell immortalization mechanism. METHODS: Dyskerin and telomerase reverse transcriptase (TERT) expression were examined in oral squamous cell carcinomas (OSCC) and patient-matched controls, as well as in a panel of telomerase-positive and telomerase-negative cells. Antisense inhibition of TERT was used to test the effects of downregulation of telomerase on dyskerin expression. RESULTS: Dyskerin was frequently overexpressed in OSCC and in immortalized and transformed keratinocytes relative to primary cells, independently of TERT and telomerase activity. Instead, dyskerin expression strongly correlated with cell proliferation rates. CONCLUSIONS: The role of dyskerin in tumorigenesis does not correlate with its function within the telomerase complex. PMID- 21674677 TI - The concentration index of a binary outcome revisited. AB - The binary variable is one of the most common types of variables in the analysis of income-related health inequalities. I argue that while the binary variable has some unusual properties, it shares many of the properties of the ratio-scale variable and hence lends itself to both relative and absolute inequality analyses, albeit with some qualifications. I argue that criticisms of the normalization I proposed in an earlier paper, and of the use of the binary variable for inequality analysis, stem from a misrepresentation of the properties of the binary variable, as well as a switch of focus away from relative inequality to absolute inequality. I concede that my normalization is not uncontentious, but, in a way, that has not previously been noted. PMID- 21674676 TI - Review of cytomegalovirus shedding in bodily fluids and relevance to congenital cytomegalovirus infection. AB - Congenital cytomegalovirus (CMV) infections are a leading cause of sensorineural hearing loss (SNHL) and neurological impairment. Congenital transmission of CMV can occur with maternal primary infection, reactivation, or reinfection during pregnancy. We reviewed studies of CMV shedding in bodily fluids (defined as CMV detected by culture or CMV DNA detected by polymerase chain reaction). Following diagnosis at birth, children with congenital CMV infection exhibited the highest prevalences of CMV shedding (median = 80%, number of sample population prevalences [N] = 6) and duration of shedding, with a steep decline by age five. Healthy children attending day care shed more frequently (median = 23%, N = 24) than healthy children not attending day care (median = 12%, N = 11). Peak shedding prevalences in children occurred at 1-2 years of age, confirming that young children are the key transmission risk for pregnant women. CMV shedding among children was more prevalent in urine specimens than in oral secretions (median prevalence difference = 11.5%, N = 12). Adults with risk factors such as STD clinic attendance had higher shedding prevalences (median = 22%, N = 20) than adults without risk factors (median = 7%, N = 44). In adults with risk factors, CMV was shed more frequently in urine; in adults without risk factors genital shedding was most common. The prevalence of CMV shedding in nine sample populations of pregnant women increased with advancing gestation. In seven sample populations of children with congenital CMV infection, higher viral load at birth was consistently associated with an elevated risk of SNHL. Higher CMV viral load at birth also consistently correlated with the presence of symptoms of congenital CMV at birth. Published 2011. This article is a US Government work and is in the public domain in the USA. PMID- 21674678 TI - Reply to Guido Erreygers and Tom Van Ourti's comment on 'The concentration index of a binary outcome revisited'. PMID- 21674679 TI - Putting the cart before the horse. A comment on Wagstaff on inequality measurement in the presence of binary variables. PMID- 21674684 TI - Embryonic development of the self-fertilizing mangrove killifish Kryptolebias marmoratus. AB - The mangrove killifish, Kryptolebias marmoratus, is a self-fertilizing vertebrate offering vast potential as a model species in many biological disciplines. Previous studies have defined developmental stages but lacked visual representations of the various embryonic structures. We offer detailed photographic images of K. marmoratus development with revised descriptions. An improved dechorionation method was developed to provide high resolution photographs, in addition to a microinjection technique enabling cell marking in the yolk syncytial layer. Embryos were also treated with PTU (1-phenyl 2 thiourea), an inhibitor of melanogenesis, to provide optical transparency revealing internal structures in late stages of development. Chemical exposures (PTU and retinoic acid) demonstrated that K. marmoratus embryos were sensitive to chemicals, illustrating further their usefulness in developmental biology studies. Our data suggest that K. marmoratus embryos are easily used and manipulated, supporting the use of this hermaphroditic vertebrate as a strong comparative model system in embryology, evolution, genetics, environmental and medical biology. PMID- 21674680 TI - A contextual approach to understanding breast cancer survivorship among Latinas. AB - OBJECTIVES: The purpose of this review is to describe the empirical literature on the health-related quality of life (HRQOL) in Latina breast cancer survivors by exploring the social determinants of health. In framing the key domains of survivors' quality of life within a ecological-contextual model that evaluates individual and societal contributions to health outcomes, we provide a comprehensive landscape of the diverse factors constituting Latina survivors' lived experiences and their resultant quality of life outcomes. METHODS: We retrieved 244 studies via search engines and reference lists, of which 37 studies met the inclusion criteria. RESULTS: Findings document the importance of the social determinants of HRQOL, with studies documenting ecological and contextual factors accounting for significant variance in HRQOL outcomes. Our review identifies a dearth of research examining community-, institutional-, and policy level factors, such as health care access, legal and immigration factors, physical and built environments, and health care affordability and policies affecting Latina breast cancer survivors' HRQOL. CONCLUSIONS: Overall research on Latina breast cancer survivorship is sparse, with even greater underrepresentation within longitudinal and intervention studies. Results highlight a need for clear documentation of the comprehensive care needs of underserved cancer survivors and interventions considering integrated systems of care to address the medical and ecological factors known to impact the HRQOL of breast cancer survivors. PMID- 21674687 TI - Alkali-like myosin light chain-1 (myl1) is an early marker for differentiating fast muscle cells in zebrafish. AB - During myogenesis, muscle precursors become divided into either fast- or slow twitch fibres, which in the zebrafish occupy distinct domains in the embryo. Genes encoding sarcomeric proteins specific for fast or slow fibres are frequently used as lineage markers. In an attempt to identify and evaluate early definitive markers for cells in the fast-twitch pathway, we analysed genes encoding proteins contributing to the fast sarcomeric structures. The previously uncharacterized zebrafish alkali-like myosin light chain gene (myl1) was found to be expressed exclusively in cells in the fast-twitch pathway initiated at an early stage of fast fibre differentiation. Myl1 was expressed earlier, and in a more fibre type restricted manner, than any of the previously described and frequently used fast myosin light and heavy chain and troponin muscle markers mylz2, mylz3, tnni2, tnnt3a, fMyHC1.3. In summary, this study introduces a novel marker for early differentiating fast muscle cells. PMID- 21674686 TI - A combination of enhancer/silencer modules regulates spatially restricted expression of cadherin-7 in neural epithelium. AB - The spatially restricted expression of cadherin-7 to the intermediate domain of the neural epithelium and in migrating neural crest cells during early neural development is potentially regulated by multiple signaling inputs. To identify the regulatory modules involved in regulation of cadherin-7, evolutionary conserved non-coding sequences in the cadherin-7 locus were analyzed. This led to the identification of an evolutionary conserved region of 606 bp (ECR1) that together with the cadherin-7 promoter recapitulates endogenous cadherin-7 expression in intermediate neural tube, spinal motor neurons, interneurons, and dorsal root ganglia. Deletion analysis of ECR1 revealed a 19-bp block that is essential for ECR1 enhancer activity, while two separate blocks of 10 and 12 bp were found to be essential for ECR1 silencer activity in the dorsal and ventral neural epithelium, respectively. Together, these data provide an insight into tissue-specific regulatory regions that might be involved in regulation of cadherin-7 gene expression. PMID- 21674685 TI - Abelson tyrosine kinase is required for Drosophila photoreceptor morphogenesis and retinal epithelial patterning. AB - Coordinated differentiation and morphogenesis transform the Drosophila retina from a layer of epithelial cells into a complex three-dimensional organ. In this study we show that the Abelson (Abl) tyrosine kinase localizes to the dynamically remodeling apical-junctional membrane domains of the developing photoreceptor cells. Analyses of abl mutant clone phenotypes demonstrate that abl is required for enriched localization of adherens junction and apical polarity complex proteins at photoreceptor-photoreceptor cell junctions and apical membrane domains, respectively, for rhabdomere generation and for spatial organization of ommatidial cells along the apical-basal axis of the epithelium. Loss of abl does not alter expression or localization of Enabled (Ena) nor does heterozygosity for ena dominantly suppress the abl phenotypes, suggesting the downstream effector mechanisms used by Abl in the eye may differ from those used in the embryo. Together our results reveal a prominent role for Abl in coordinating multiple aspects of photoreceptor morphogenesis. PMID- 21674688 TI - The Prx1 limb enhancers: targeted gene expression in developing zebrafish pectoral fins. AB - Limbs represent an excellent model to study the induction, growth, and patterning of several organs. A breakthrough to study gene function in various tissues has been the characterization of regulatory elements that allow tissue-specific interference of gene function. The mouse Prx1 promoter has been used to generate limb-specific mutants and overexpress genes in tetrapod limbs. Although zebrafish possess advantages that favor their use to study limb morphogenesis, there is no driver described suitable for specifically interfering with gene function in developing fins. We report the generation of zebrafish lines that express enhanced green fluorescent protein (EGFP) driven by the mouse Prx1 enhancer in developing pectoral fins. We also describe the expression pattern of the zebrafish prrx1 genes and identify three conserved non-coding elements (CNEs) that we use to generate fin-specific EGFP reporter lines. Finally, we show that the mouse and zebrafish regulatory elements may be used to modify gene function in pectoral fins. PMID- 21674689 TI - Plasticity of neural crest-placode interaction in the developing visceral nervous system. AB - The reciprocal relationship between rhombomere (r)-derived cranial neural crest (NC) and epibranchial placodal cells derived from the adjacent branchial arch is critical for visceral motor and sensory gangliogenesis, respectively. However, it is unknown whether the positional match between these neurogenic precursors is hard-wired along the anterior-posterior (A/P) axis. Here, we use the interaction between r4-derived NC and epibranchial placode-derived geniculate ganglion as a model to address this issue. In Hoxa1(-/-) b1(-/-) embryos, r2 NC compensates for the loss of r4 NC. Specifically, a population of r2 NC cells is redirected toward the geniculate ganglion, where they differentiate into postganglionic (motor) neurons. Reciprocally, the inward migration of the geniculate ganglion is associated with r2 NC. The ability of NC and placodal cells to, respectively, differentiate and migrate despite a positional mismatch along the A/P axis reflects the plasticity in the relationship between the two neurogenic precursors of the vertebrate head. PMID- 21674690 TI - Tract-based magnetic resonance spectroscopy of the cingulum bundles at 7 T. AB - The cingulum bundle is a white matter fiber bundle in the human brain that is believed to be implicated in various neurological and psychiatric diseases. Subtle disease-related differences in metabolite concentrations in the cingulum tracts that may underlie these diseases may be detected using MR spectroscopic information. However, to date, limited signal to noise and lack of spatial resolution have prevented a reliable and reproducible measurement of metabolites in the cingulum bundle in vivo. Here we propose a new method that combines MR spectroscopic imaging at 7 T with fiber tracking to select only those MR spectroscopy voxels that are actually part of the cingulum bundles. The spectra of the selected spectroscopy voxels are processed per voxel and then combined yielding one spectrum at high spectral resolution for each cingulum bundle. In this way sensitivity is increased, as large parts of the cingulum are included while partial volume effects with both gray matter and white matter from other tracts is kept to a minimum. Three healthy volunteers were scanned to assess the feasibility of the method. For all three healthy volunteers spectra for the left and right cingulum tracts were computed, partial volume fractions calculated and metabolite fractions were quantified yielding similar results suggesting that tract-based MR spectroscopy allows us to study metabolic concentrations of individual white matter fiber bundles with high sensitivity and high specificity. PMID- 21674692 TI - Engagement of amygdala in third-person view of face-to-face interaction. AB - Humans often watch interactions between other people without taking part in the interaction themselves. Strikingly little is, however, known about how gestures and expressions of two interacting humans are processed in the observer's brain, since the study of social cues has mostly focused on the perception of solitary humans. To investigate the neural underpinnings of the third-person view of social interaction, we studied brain activations of subjects who observed two humans either facing toward or away from each other. Activations within the amygdala, posterior superior temporal sulcus (pSTS), and dorsomedial prefrontal cortex (dmPFC) were sensitive to the interactional position of the observed people and distinguished humans facing toward from humans facing away. The amygdala was most sensitive to face-to-face interaction and did not differentiate the humans facing away from the pixelated control figures, whereas the pSTS dissociated both human stimuli from the pixel figures. The results of the amygdala reactivity suggest that, in addition to regulating interpersonal distance towards oneself, the amygdala is involved in the assessment of the proximity between two other persons. PMID- 21674691 TI - Selective BOLD responses to individual finger movement measured with fMRI at 3T. AB - Although the gross somatotopic organization of the posterior bank of the precentral gyrus is well established, a fine scale organization of the representations of the digits of the hand has not been fully characterized. Previous neuroimaging studies have failed to find clear evidence for a specificity of digit representations in motor cortex, but rather report a distributed network of control. Reported here are the results of two experiments; in Experiment 1 a sequential finger tapping task produced strong blood oxygen level dependent (BOLD) responses in the contralateral precentral gyrus, but there was a lack of specificity for distinguishing individual representations. A randomly ordered task did accomplish this goal. In the second experiment, a randomly ordered finger-tapping task was used and the findings demonstrated BOLD responses in clusters of voxels specific to movement of a single digit. The region of interest defined for each digit comprised several noncontiguous clusters. A "selectivity index" was developed to quantify the magnitude of the BOLD response to the movement of a specific digit, relative to BOLD response associated with movement of other digits. Strong evidence of BOLD selectivity (albeit not exclusivity) was found in the hemisphere contralateral to the cued digit; however, there was no evidence for an orderly spatial topography. These findings demonstrate that a selectivity of activation is quantifiable, supports a theory of noncontiguous distribution of control, and provides a method for comparing between healthy and impaired populations and investigating changes following training or intervention. PMID- 21674693 TI - Motor imagery evokes increased somatosensory activity in Parkinson's disease patients with tremor. AB - Parkinson's disease (PD) is surprisingly heterogeneous: some patients have a prominent resting tremor, while others never develop this symptom. Here we investigate whether the functional organization of the voluntary motor system differs between PD patients with and without resting tremor, and whether these differences relate to the cerebral circuit producing tremor. We compared 18 PD patients with marked tremor, 20 PD patients without tremor, and 19 healthy controls. Subjects performed a controlled motor imagery task during fMRI scanning. We quantified imagery-related cerebral activity by contrasting imagery of biomechanically difficult and easy movements. Tremor-related activity was identified by relating cerebral activity to fluctuations in tremor amplitude, using electromyography during scanning. PD patients with tremor had better behavioral performance than PD patients without tremor. Furthermore, tremulous PD patients showed increased imagery-related activity in somatosensory area 3a, as compared with both healthy controls and to nontremor PD patients. This effect was independent from tremor-related activity, which was localized to the motor cortex, cerebellum, and thalamic ventral intermediate nucleus (VIM). The VIM, with known projections to area 3a, was unique in showing both tremor- and imagery related responses. We conclude that parkinsonian tremor influences motor imagery by modulating central somatosensory processing through the VIM. This mechanism may explain clinical differences between PD patients with and without tremor. PMID- 21674694 TI - Neurodegeneration in friedreich's ataxia is associated with a mixed activation pattern of the brain. A fMRI study. AB - Friedreich's ataxia (FRDA) is associated with a distributed pattern of neurodegeneration in the spinal cord and the brain secondary to selective neuronal loss. We used functional MR Imaging (fMRI) to explore brain activation in FRDA patients during two motor-sensory tasks of different complexity, i.e. continuous hand tapping and writing of "8" figure, with the right dominant hand and without visual feedback. Seventeen FRDA patients and two groups of age matched healthy controls were recruited. Task execution was monitored and recorded using MR-compatible devices. Hand tapping was correctly performed by 11 (65%) patients and writing of the "8" by 7 (41%) patients. After correction for behavioral variables, FRDA patients showed in both tasks areas of significantly lower activation in the left primary sensory-motor cortex and right cerebellum. Also left thalamus and right dorsolateral prefrontal cortex showed hypo activation during hand tapping. During writing of the "8" task FRDA patients showed areas of higher activation in the right parietal and precentral cortex, globus pallidus, and putamen. Activation of right parietal cortex, anterior cingulum, globus pallidus, and putamen during writing of the "8" increased with severity of the neurological deficit. In conclusion fMRI demonstrates in FRDA a mixed pattern constituted by areas of decreased activation and areas of increased activation. The decreased activation in the primary motor cortex and cerebellum presumably reflects a regional neuronal damage, the decreased activation of the left thalamus and primary sensory cortex could be secondary to deafferentation phenomena, and the increased activation of right parietal cortex and striatum might have a possible compensatory significance. PMID- 21674695 TI - Disruption of limbic white matter pathways in mild cognitive impairment and Alzheimer's disease: a DTI/FDG-PET study. AB - BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) affect the limbic system, causing medial temporal lobe (MTL) atrophy and posterior cingulate cortex (PCC) hypometabolism. Additionally, diffusion tensor imaging (DTI) studies have demonstrated that MCI and AD involve alterations in cerebral white matter (WM) integrity. OBJECTIVES: To test if (1) patients with MCI and AD exhibit decreases in the integrity of limbic WM pathways; (2) disconnection between PCC and MTL, manifested as disruption of the cingulum bundle, contributes to PCC hypometabolism during incipient AD. METHODS: We measured fractional anisotropy (FA) and volume of the fornix and cingulum using DTI in 23 individuals with MCI, 21 with mild-to-moderate AD, and 16 normal control (NC) subjects. We also measured PCC metabolism using (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in AD and MCI patients. RESULTS: Fornix FA and volume were reduced in MCI and AD to a similar extent. Descending cingulum FA was reduced in AD while volume was reduced in MCI and even more so in AD. Both FA and volume of the fornix and descending cingulum reliably discriminated between NC and AD. Fornix FA and descending cingulum volume also reliably discriminated between NC and MCI. Only descending cingulum volume reliably discriminated between MCI and AD. In the combined MCI-AD cohort, PCC metabolism directly correlated with both FA and volume of the descending cingulum. CONCLUSIONS: Disruption of limbic WM pathways is evident during both MCI and AD. Disconnection of the PCC from MTL at the cingulum bundle contributes to PCC hypometabolism during incipient AD. PMID- 21674696 TI - Evidence for intact local connectivity but disrupted regional function in the occipital lobe in children and adolescents with schizophrenia. AB - It has long been known that specific visual frequencies result in greater blood flow to the striate cortex. These peaks are thought to reflect synchrony of local neuronal firing that is reflective of local cortical networks. Since disrupted neural connectivity is a possible etiology for schizophrenia, our goal was to investigate whether localized connectivity, as measured by aberrant synchrony, is abnormal in children and adolescents with schizophrenia. Subjects included 25 children and adolescents with schizophrenia and 39 controls matched for age and gender. Subjects were scanned on a Siemens 3 Tesla Trio scanner while observing flashing checkerboard presented at either 1, 4, 8, or 12 Hz. Image processing included both a standard GLM model and a Fourier transform analysis. Patients had significantly smaller volume of activation in the occipital lobe compared to controls. There were no differences in the integral or percent signal change of the hemodynamic response function for each of the four frequencies. Occipital activation was stable during development between childhood and late adolescence. Finally, both patients and controls demonstrated an increased response between 4 and 8 Hz consistent with synchrony or entrainment in the neuronal response. Children and adolescents with schizophrenia had a significantly lower volume of activation in the occipital lobe in response to the flashing checkerboard task. However, features of intact local connectivity in patients, such as the hemodynamic response function and maximal response at 8 Hz, were normal. These results are consistent with abnormalities in regional connectivity with preserved local connectivity in early-onset schizophrenia. PMID- 21674697 TI - Temporally remote destabilization of prediction after rare breaches of expectancy. AB - While neural signatures of breaches of expectancy and their immediate effects have been investigated, thus far, temporally more remote effects have been neglected. The present fMRI study explored neural correlates of temporally remote destabilization of prediction following rare breaches of expectancy with a mean delay of 14 s. We hypothesized temporally remote destabilization to be reflected either in an attenuation of areas related to long-term memory or in an increase of lateral fronto-parietal loops related to the encoding of new stimuli. Monitoring a deterministic 24-digit sequence, subjects were asked to indicate occasional sequential omissions by key press. Temporally remote destabilization of prediction was expected to be revealed by contrasting sequential events whose equivalent was omitted in the preceding sequential run n-1 (destabilized events) with sequential events without such history (nondestabilized events). Temporally remote destabilization of prediction was reflected in an attenuation of activity in the dorsal frontomedian cortex (Brodmann Area (BA) 9) bilaterally. Moreover, activation of the left medial BA 9 was enhanced by contrasting nondestabilized events with breaches. The decrease of dorsal frontomedian activation in the case of destabilized events might be interpreted as a top-down modulation on perception causing a less expectation-restricted encoding of the current stimulus and hence enabling the adaptation of expectation and prediction in the long run. PMID- 21674698 TI - Brief report: a bioassay to identify primary human prostate cancer repopulating cells. AB - Cancer cells are heterogeneous in both their phenotypes and ability to promote tumor growth and spread. Xenografting is used to identify the most highly capable cells of regenerating tumors, referred to as cancer repopulating cells. Because prostate cancers (PCa's) rarely grow as xenografts, indentifying PCa repopulating cells has not been possible. Here, we report improved methods to xenograft localized primary PCa tissues using chimeric grafts with neonatal mouse mesenchyme. Xenograft survival of tumor tissue was significantly increased by neonatal mesenchyme (six of six patients, 66% of grafts, versus four of six patients, 41% of grafts) and doubled the proliferation index of xenografted cancer cells. When applied to isolated PCa cells, neonatal mesenchyme effectively reconstituted PCa's and increased xenograft survival (four of nine patients; 32% of grafts with mesenchyme and 0% without), and supported active cancer cell proliferation. Using this assay, we showed that unfractionated alpha2beta1integrin(hi) and alpha2beta1integrin(lo) cells from primary localized PCa's demonstrated tumor formation at comparable rates, similar to previous reports using metastatic specimens. Thus, this new protocol efficiently established tumors and enabled proliferative expansion of both intact tumor tissue and fractionated cancer cells, providing a bioassay to identify and therapeutically target PCa repopulating cells. PMID- 21674699 TI - Functional characterization of quiescent keratinocyte stem cells and their progeny reveals a hierarchical organization in human skin epidermis. AB - Although homeostatic renewal of human skin epidermis is achieved by the combined activity of quiescent stem cells (SCs) and their actively cycling progeny, whether these two populations are equipotent in their capacity to regenerate tissue has not been determined in biological assays that mimic lifelong renewal. Using fluorescence activated cell separation strategy validated previously by us, human epidermis was fractionated into three distinct subsets: that is, alpha 6briCD71(dim) , alpha 6briCD71(bri) , and alpha 6dim with characteristics of keratinocyte stem, transient amplifying, and early differentiating cells, respectively. The global gene expression profile of these fractions was determined by microarray, confirming that the alpha 6briCD71(dim) subset was quiescent, the alpha 6briCD71(bri) was actively cycling, and the alpha 6dim subset expressed markers of differentiation. More importantly, functional evaluation of these populations in an in vivo model for tissue reconstitution at limiting cell dilutions revealed that the quiescent alpha 6briCD71(dim) fraction was the most potent proliferative and tissue regenerative population of the epidermis, capable of long-term (LT) epidermal renewal from as little as 100 cells for up to 10 weeks. In contrast, the cycling alpha 6briCD71(bri) fraction was the first to initiate tissue reconstitution, although this was not sustained in the LT, while differentiating alpha 6dim cells possessed the lowest demonstrable tissue regenerative capacity. Our data suggest that in human skin, the epidermal proliferative compartment is not composed of equipotent cells, but rather is organized in a functionally hierarchical manner with the most potent quiescent SCs at its apex (i.e., alpha 6briCD71(dim) ) followed by cycling progenitors (i.e., alpha 6briCD71(bri) ) and finally early differentiating keratinocytes (i.e., alpha 6dim). PMID- 21674700 TI - Concise review: toward stem cell-based therapies for retinal neurodegenerative diseases. AB - Loss of sight due to irreversible retinal neurodegeneration imposes a significant disease burden on both patients and society. Glaucoma and age-related macular degeneration are the commonest neurodegenerative blinding diseases in the developed world, and both are becoming increasingly prevalent as populations age. Our heavy reliance on our sense of sight means that visual loss often severely restricts day-to-day life, making it difficult to function without additional support. Visual impairment also limits employment possibilities, adding to the economic burden. Current therapies for many degenerative retinopathies are limited in their efficacy, often treating the effects of disease rather than the underlying causes. Consequently, the development of novel adjunctive neuroprotective and neuroregenerative treatments are important goals. Evidence from animal models suggests that stem cells could be useful as part of novel new treatment strategies for eye disease. The accessibility of the eye and extensive repertoire of available surgical techniques may facilitate the translation of stem cell-based therapies, for example, via transplantation, to the retina more rapidly than to other parts of the central nervous system. This concise review will examine how cell therapies are being applied experimentally for neuroregenerative and neuroprotective treatment of currently incurable degenerative retinal diseases. Furthermore, recent progress toward clinical translation of such therapies will be highlighted. PMID- 21674701 TI - Debrided skin as a source of autologous stem cells for wound repair. AB - Major traumatic injuries to the body, such as large surface area burns, limit the availability of autologous stem cell populations for wound repair. This report demonstrates that even after severe burn trauma to the body, resident stem cells present within the subcutaneous adipose tissue survive and are available for therapeutic uses. Debrided skin from wounded areas contains subcutaneous adipose tissue and can yield approximately 1.5 * 10(5) to 2.5 * 10(5) cells per milliliter of tissue. This observation indicates that tissue, which is normally discarded, could be a valuable source of stem cells. Initial immunohistochemistry of the debrided tissue localized platelet-derived growth factor receptor beta(+) (PDGFR-beta(+) ) cells to perivascular niches of vascular beds. It was immunophenotypically confirmed that the cell isolates are stem cells and designated as debrided skin adipose-derived stem cells (dsASCs). Gene expression analysis of stem cell specific transcripts showed that the dsASCs maintained their stemness over serial passages. Furthermore, dsASCs were able to differentiate into adipogenic, osteogenic, and vascular cell lineages. Finally, an in vivo excision wound model in athymic rats demonstrated that the dsASCs are engrafted within a wound bed after 12 days. These data provide the first evidence that subcutaneous adipose tissue from discarded burned skin contains a viable population of stem cells that can be used for wound repair and skin regenerative therapies. PMID- 21674702 TI - Folding and assembly of TMD 6-related segments of DMT 1 in trifluoroethanol aqueous solution. AB - Divalent metal-ion transporter 1 (DMT1) belongs to a large class of metal-ion transporters that drive the translocation of a wide range of divalent metal substrates across membranes toward the cytosol with couple of protons. Two highly conserved histidines in the sixth transmembrane domain (TMD6) are essential for metal transport activity in DMT1. In the present study, we determine the high resolution structures of three 25-residue peptides, corresponding to TMD6 of the wildtype DMT1 (the segment 255-279) and its H267A and H272A mutants, in 30% TFE d(2) aqueous solution by the combined use of circular dichroism (CD) and NMR spectroscopies. The wildtype peptide forms an 'alpha-helix-extended segment-alpha helix' structure with two helices spanning over Gly258-Ala262 and Met265-Lys277 linked by a hinge at residues Val263-Ile264. The H267A mutation reduces the hinge to one residue (Ile264), while the H272A mutation extends the flexible region of the central part from Val263 to His267. Diffusion-ordered spectroscopy (DOSY) study demonstrates that all the peptides are self-assembly as trimer in 30% TFE d(2) aqueous solution. The H272A substitution decreases the intermolecular interaction whereas the H267A substitution may enhance the intermolecular interaction. The specific structure of the discontinuous helix and the self assembly feature of DMT1-TMD6 may be crucial for its biological function. The changes in conformation and intermolecular interaction induced by histidine substitution may be correlated with the deficiency of DMT1 in metal-ion permeation. PMID- 21674703 TI - Characterization of Escherichia coli isolated from gut biopsies of newly diagnosed patients with inflammatory bowel disease. AB - BACKGROUND: Mucosal-associated Escherichia coli may play a role in the pathogenesis of inflammatory bowel diseases (IBDs). In this study we assessed mucosal-associated E. coli in adults at the time of first diagnosis. MATERIALS AND METHODS: E. coli were isolated from 59 right colon biopsies of 34 newly diagnosed adult IBD patients (Crohn's disease [CD] = 23, ulcerative colitis [UC] = 11) and 25 healthy controls (HC). Strains were serotyped, phylotyped into A, B1, B2, or D, and tested for their ability to survive in macrophages. The presence of various virulence factors was also assessed. The fimH subunit of type 1 fimbriae was sequenced and phylogenetically analyzed. RESULTS: A total of 65 E. coli were isolated from CD (29 isolates from 23 patients), UC (11 isolates from 11 patients), and HC (25 isolates from 25 subjects). All E. coli were positive for fimH, crl, and cgsA and negative for vt1, vt2, hlyA, cnf, and eae. Significant positive associations were between CD and in between CD and afae (P = 0.002), and between UC and ompA (P = 0.02), afae (P = 0.03), and USP (P = 0.04). The B2+D phylotype was significantly associated with inflammation (P = 0.04) as it was with serine protease autotransporters (SPATE), malX, ompA, and kpsMTII (P < 0.05). Macrophage survival was the highest in UC-isolated E. coli (P = 0.04). FimH amino acid substitutions N91S, S99N, and A223V were associated with IBD (P < 0.05). CONCLUSIONS: Adherent invasive E. coli are present at first diagnosis, suggesting that they may have a role in the early stages of disease onset. PMID- 21674704 TI - Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. AB - BACKGROUND: Chronic intestinal inflammation culminates in cancer and a link to Toll-like receptor-4 (TLR4) has been suggested by our observation that TLR4 deficiency prevents colitis-associated neoplasia. In the current study we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis-associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa. METHODS: Mice transgenic for a constitutively active TLR4 under the intestine specific villin promoter (villin-TLR4 mice) were treated with dextran sodium sulfate (DSS) for acute colitis and azoxymethane (AOM)-DSS TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis (UC) and UC-associated cancer. The effect of an antagonist TLR4 antibody (Ab) was tested in prevention of colitis-associated neoplasia in the AOM-DSS model. RESULTS: Villin-TLR4 mice were highly susceptible to both acute colitis and colitis-associated neoplasia. Villin-TLR4 mice had increased epithelial expression of COX-2 and mucosal PGE2 production at baseline. Increased severity of colitis in villin-TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all colitis-associated cancer and progressively increased with grade of dysplasia. As a proof of principle, a TLR4/MD-2 antagonist antibody inhibited colitis-associated neoplasia in the mouse model. CONCLUSIONS: Our results show that regulation of TLRs can affect the outcome of both acute colitis and its consequences, cancer. Targeting TLR4 and other TLRs may ultimately play a role in prevention or treatment of colitis associated cancer. PMID- 21674705 TI - Apoptosis resistance of mucosal lymphocytes and IL-10 deficiency in patients with steroid-refractory Crohn's disease. AB - BACKGROUND: Apoptosis resistance of T-cells is considered an abnormality of immune pathways in Crohn's disease (CD). It has been previously shown that corticosteroids induce apoptosis of cells involved in inflammation. Thus, our aim was to assess the apoptosis of mononuclear cells and pro/antiinflammatory cytokines in the intestinal mucosa of patients with active CD, related to steroid response, and identify cellular and molecular factors that may predict this response to therapy. METHODS: Patients with CD (n = 26), ulcerative colitis (UC) (n = 32), and controls (n = 10) were prospectively studied with mucosal biopsies before and 7-10 days after corticosteroid treatment. Immunophenotype and apoptosis of T and B lymphocytes, plasma cells, and macrophages were assessed by flow cytometry, immunohistochemistry, and immunofluorescence. The cytokine expression pattern was evaluated by quantitative polymerase chain reaction (PCR). RESULTS: Apoptosis resistance of T and B lymphocytes was observed only in steroid refractory and -dependent CD patients as compared to responsive patients (P = 0.032; P = 0.004, respectively), being evident after steroid treatment. Interleukin (IL)-10 was markedly increased at baseline in steroid-responsive patients compared to the nonresponders (P = 0.006; sensitivity: 88.8%; specificity: 66.6% to predict steroid response). CONCLUSIONS: Apoptosis resistance of mucosal T and B cells in steroid-refractory and -dependent CD patients appears during the evolution of the acute phase, limiting its clinical application as a predictor marker. In contrast, increased expression of IL-10 at an early stage of active steroid-sensitive CD patients supports its usefulness at predicting a good steroid response. Steroid-dependent and -refractory CD patients share similar molecular and cellular pathophysiological mechanisms. PMID- 21674706 TI - VEGF164 isoform specific regulation of T-cell-dependent experimental colitis in mice. AB - BACKGROUND: Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), two widespread diseases of unknown, multifactorial etiology. Colitis pathology involves a pathological angiogenic response where increases in vascular density participate in colitis histopathology. Vascular endothelial growth factor-A (VEGF-A) is a potent angiogenesis stimulator known to be involved in pathological angiogenesis in several diseases including colitis. However, the pathogenic importance of specific VEGF-A isoforms during T-cell mediated experimental colitis remains largely unknown. METHODS: The CD4+ CD45RB(high) T-cell transfer model of experimental colitis was used for these studies. The VEGF lac-Z transgenic reporter mouse was used to examine specific cellular sources of VEGF-A production. The VEGF164 aptamer (Macugen), adenoviral VEGF164, and the VEGF Trap were used to evaluate pathological importance. RESULTS: VEGF lac-Z reporter mice experiments showed that both infiltrating T cells and local tissue cells produce VEGF-A in the colon during disease. Inhibition of VEGF164 using a highly selective RNA aptamer significantly attenuated CD4+ CD45RB(high) T-cell-dependent experimental colitis by reducing pathological angiogenesis and inflammatory pathology. Conversely, broad-spectrum VEGF inhibition with VEGF Trap did not attenuate disease, nor did adenoviral VEGF164 overexpression significantly alter colitis pathology. CONCLUSIONS: VEGF164 is actively produced by multiple cell types during T-cell-mediated colitis. Importantly, specific inhibition of the VEGF164 isoform during T-cell mediated colitis dose-dependently attenuated disease progression, while broad scale inhibition of all VEGF-A isoforms was not therapeutically beneficial. PMID- 21674708 TI - Two independent genetic factors responsible for the associations of the IBD5 locus with Crohn's disease in the Czech population. AB - BACKGROUND: The role of the IBD5 locus in development of Crohn's disease (CD) has not been clarified. In the Czech population we examined its genetic association using variants of the SLC22A4 (rs1050152), SLC22A5 (rs2631367), two single nucleotide polymorphisms (SNPs) shown to be associated with CD in genome-wide studies (rs6596075 and rs2188962), and four SNPs previously shown to tag the haplotype blocks 4, 7, 9, 10 of the IBD5 locus (IGR2063b_1, IGR2230a_1, IGR100Xa_1, IGR3236a_1). METHODS: The genotype, phenotype, and allelic frequencies were compared between 469 unrelated patients with CD (177 pediatric onset, 292 adult-onset) and 470 unrelated healthy controls, all Caucasians of Czech ancestry. RESULTS: The most significant difference between patients and controls was found for the SNP rs6596075 (odds ratio [OR] = 0.70 for the G allele; 95% CI 0.52-0.94) in the dominant model and SNP IGR2063b_1 (OR = 1.38 for the G allele; 95% CI 1.14-1.67) in the log-additive model. We found a strong linkage disequilibrium across the IBD5 locus except rs6596075. The haplotype consisting of minor alleles of all tested SNPs except rs6596075 was carried by 31% patients and 23% control subjects (OR = 1.35, 95% CI 1.06-1.72). The association of variants in SLC22A4 and SLC22A5 was dependent on this risk haplotype, while the strong association of the rs6596075 was seemingly independent. In the analysis of subphenotypes we found only an association of the penetrating disease with rs6596075 (OR = 2.13; 95% CI 1.31-3.47). CONCLUSIONS: Our study confirms the importance of IBD5 in determining CD susceptibility, and demonstrates that two independent genetic factors may be responsible for the association observed within this locus. PMID- 21674707 TI - Maternal obesity induces sustained inflammation in both fetal and offspring large intestine of sheep. AB - BACKGROUND: Both maternal obesity and inflammatory bowel diseases (IBDs) are increasing. It was hypothesized that maternal obesity induces an inflammatory response in the fetal large intestine, predisposing offspring to IBDs. METHODS: Nonpregnant ewes were assigned to a control (Con, 100% of National Research Council [NRC] recommendations) or obesogenic (OB, 150% of NRC) diet from 60 days before conception. The large intestine was sampled from fetuses at 135 days (term 150 days) after conception and from offspring lambs at 22.5 +/- 0.5 months of age. RESULTS: Maternal obesity enhanced mRNA expression tumor necrosis factor (TNF)alpha, interleukin (IL)1alpha, IL1beta, IL6, IL8, and monocyte/macrophage chemotactic protein-1 (MCP1), as well as macrophage markers, CD11b, CD14, and CD68 in fetal gut. mRNA expression of Toll-like receptor (TLR) 2 and TLR4 was increased in OB versus Con fetuses; correspondingly, inflammatory NF-kappaB and JNK signaling pathways were also upregulated. Both mRNA expression and protein content of transforming growth factor (TGF) beta was increased. The IL-17A mRNA expression and protein content was higher in OB compared to Con samples, which was associated with fibrosis in the large intestine of OB fetuses. Similar inflammatory responses and enhanced fibrosis were detected in OB compared to Con offspring. CONCLUSIONS: Maternal obesity induced inflammation and enhanced expression of proinflammatory cytokines in fetal and offspring large intestine, which correlated with increased TGFbeta and IL17 expression. These data show that maternal obesity may predispose offspring gut to IBDs. PMID- 21674709 TI - Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey. AB - BACKGROUND: Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients. METHODS: Evaluation questionnaires at baseline, week 6, and week 26 were completed by gastroenterologists in hospitals and private practices. Adverse events were evaluated according to World Health Organization (WHO) guidelines. RESULTS: Sixty patients (38F/22M) were included; 53% had complicated disease (stricturing or penetrating), 45% had undergone prior CD-related surgery. All patients had prior exposure to systemic steroids, 96% to immunomodulators, 73% to infliximab, and 43% to adalimumab. A significant decrease of the Harvey-Bradshaw Index (HBI) was observed under CZP therapy (12.2 +/- 4.9 at week 0 versus 6.3 +/- 4.7 at week 6 and 6.7 +/- 5.3 at week 26, both P < 0.001). Response and remission rates were 70% and 40% (week 6) and 67% and 36%, respectively (week 26). The complete perianal fistula closure rate was 36% at week 6 and 55% at week 26. The frequency of adverse drug reactions attributed to CZP was 5%. CZP was continued in 88% of patients beyond week 6 and in 67% beyond week 26. CONCLUSIONS: In a population of CD patients with predominantly complicated disease behavior, CZP proved to be effective in induction and maintenance of response and remission. This series provides the first evidence of CZP's effectiveness in perianal fistulizing CD in clinical practice. PMID- 21674710 TI - Practice of gastroenterologists in treating flaring inflammatory bowel disease patients with clostridium difficile: antibiotics alone or combined antibiotics/immunomodulators? AB - BACKGROUND: The optimal management of Clostridium difficile infection (CDI) in flaring inflammatory bowel disease (IBD) patients has not been defined. Limited data suggest that coadministration of immunomodulators (IM) with antibiotics (AB) results in a worse outcome. We investigated the prevalent practice among North American gastroenterologists in this scenario. METHODS: A structured questionnaire presented the clinical cases of two hospitalized patients with ulcerative colitis and concomitant CDI, either with or without prior IM treatment. The questionnaire was distributed to a sample of gastroenterologists at medical centers across North America. Respondents were requested to denote their therapeutic choices for these patients. RESULTS: The survey included 169 gastroenterologists, 122 from the US and 47 from Canada, with an average of 12 +/ 10 years of experience in gastroenterology. Forty-two (25%) of the respondents were IBD experts. Seventy-seven (46%) respondents elected to add an IM in combination with AB, whereas 82/169 (54%) treated the flare with AB alone (P = NS). The rate of administering combined AB+IM was similar for the IBD experts and the non-IBD experts. Only 11% of respondents withdrew maintenance azathioprine upon the diagnosis of CDI. More IBD experts stopped azathioprine treatment compared to the non-IBD experts (12/42 versus 6/127, P < 0.001). Overall, 65% of surveyed gastroenterologists stated they believe these patients are afflicted by two simultaneous but separate disease processes. CONCLUSIONS: There is significant disagreement among gastroenterologists on whether combination AB+IM or AB alone should be given to IBD patients with CDI-associated flares. Controlled trials are needed to investigate the optimal management approach to this clinical dilemma. PMID- 21674711 TI - Validating Crohn's disease activity indices for use in assessing postoperative recurrence. AB - BACKGROUND: The Crohn's Disease Activity Index (CDAI) has been used in medical trials with scores <150 indicative of remission. Its value in assessing postoperative recurrence is unknown. The objective of this study was to explore the utility of the CDAI in determining the presence or absence of symptomatic disease recurrence in patients having previously undergone ileocolic resection for Crohn's disease. METHODS: Ninety-three patients underwent clinical and colonoscopic evaluation within 12 months of ileocolic resection. Endoscopic appearance was assessed using the Rutgeerts score (i0-i4). Symptomatic disease recurrence was defined by the composite of symptom severity warranting therapy and an endoscopic score >= i2. CDAI scores were calculated. Comparisons were made using the receiver operator curve (ROC). RESULTS: Thirty-nine (42%) patients had recurrent disease (22% symptomatic, 20% endoscopic only) at 12 months. Median CDAI for symptomatic recurrence was 198 (interquartile range [IQR]: 106-293), 80 for asymptomatic subjects (IQR 35-115). The area under the ROC curve for symptomatic disease and CDAI was 0.78 (95% confidence interval [CI] 0.64-0.91). Recurrence was best predicted by a CDAI of >= 148 (sensitivity 70%, specificity 81%). A strong linear relationship existed between the CDAI and Inflammatory Bowel Disease Questionnaire (r = 0.82). CONCLUSIONS: The CDAI performs reasonably well in the postoperative setting and 150 appears the best cutpoint for indicating symptomatic disease. However, it is likely not suitable for use as the primary outcome measure. These data suggest that a combination of symptom assessment plus endoscopic evidence of recurrence should remain the gold standard definition for assessing outcomes in postoperative CD trials. PMID- 21674712 TI - Primary intestinal lymphoma in patients with inflammatory bowel disease: a descriptive series from the prebiologic therapy era. AB - BACKGROUND: Primary intestinal lymphoma in the setting of inflammatory bowel disease (IBD) is uncommon and may be associated with immune suppressive therapy. We report clinical features and outcomes in patients with both conditions prior to use of biologic therapy. METHODS: All patients with primary intestinal lymphoma and IBD at our institution from 1960-2000 were retrospectively identified. Data reported are frequency (proportion) or median (interquartile range). Kaplan-Meier analysis was performed. RESULTS: Fifteen patients were identified: 14 (93%) were male, 10 (66%) had Crohn's disease. Median age at diagnosis of IBD and lymphoma was 30 (22-51) and 47 (28-68) years, respectively, with bloody diarrhea the most common presenting symptom for each diagnosis. Lymphoma location was colorectal in nine (60%), small bowel in four (27%), and one (6.25%) each: stomach, duodenum, and ileal pouch. Treatments were surgery plus chemotherapy (n = 6), surgery alone (n = 3), chemotherapy alone (n = 2), chemotherapy and radiation (n = 1), surgery and radiation (n = 1); two patients died before treatment. Most patients (n = 11, 73%) were Ann Arbor stages I or II. Large cell B-type histology was most common (n = 9, 60%). Three patients died within 30 days of lymphoma diagnosis. Survival free of death from lymphoma at 1- and 5-years was 78% and 63%, respectively, and was associated with advanced lymphoma stage (P = 0.004). CONCLUSIONS: Diagnosis and treatment of primary intestinal lymphoma in patients with IBD can be challenging and requires a high index of suspicion. Optimal survival requires multimodality therapy. PMID- 21674713 TI - Chronic fatigue is more prevalent in patients with inflammatory bowel disease than in healthy controls. AB - BACKGROUND: Fatigue is a common symptom in chronic disease. Few studies, however, have focused on fatigue related to inflammatory bowel disease (IBD). The aim was to determine the prevalence of fatigue in IBD and to identify demographic and clinical factors that influence fatigue. METHODS: Patients in remission and with mild and moderate IBD completed the Fatigue Questionnaire (FQ). Higher FQ scores indicate greater levels of fatigue. In addition, demographic and clinical variables were obtained. Corresponding FQ data from healthy controls (HC) are based on 2287 Norwegian citizens. RESULTS: In total, 140 patients were included, mean age 43.9 years (SD 16.4), male/female = 61/79, ulcerative colitis (UC) / Crohn's disease (CD) = 92/48. Total fatigue (TF) was 14.4, 14.7, and 12.2 for UC, CD, and HC, respectively. Chronic fatigue (CF), defined as substantial fatigue with duration more than 6 months, was reported in 29% (14/48) of CD and 22% (20/92) of UC compared to 11% (260/2287) of HC (P < 0.001 for both diagnoses). Linear regression analysis confirmed hemoglobin values, present gastrointestinal symptoms, and altered sleep to be the most important predictors of CF. CONCLUSIONS: Chronic fatigue is more common in patients with UC and CD compared with healthy controls. IBD symptoms, hemoglobin values, and altered sleep patterns are significant predictors of CF. PMID- 21674714 TI - Self-reported adherence to medical treatment prior to and during pregnancy among women with ulcerative colitis. AB - BACKGROUND: Adherence to medical treatment among women with ulcerative colitis (UC) prior to and during pregnancy has never been investigated. The aim was to examine predictors for and prevalence rates of nonadherence to maintenance treatment among women with UC prior to and during pregnancy. METHODS: We identified 115 women with UC having given birth during 2000-2005 within a population of 1.6 million. They received a questionnaire about predictors and adherence and relapses were registered. We retrieved information on medical treatment from prescription databases and used logistic regression to estimate prevalence odds ratios (POR) for nonadherence by different predictors. RESULTS: Among 93 (81%) respondents, 63 (68%) reported taking medication, 53 of whom had filled prescriptions for relevant medication, yielding a positive predictive value of self-reported use of medical treatment of 84.1% (95% confidence interval [CI] 72.7-92.1). Approximately 60% reported adhering to medical treatment. Those who received counseling regarding medical treatment were less likely to be nonadherent compared with no counseling, especially during pregnancy (POR 0.2, 95% CI 0.04-0.94). Of those who were nonadherent, fear of a negative effect on fertility/fetus was stated as the reason by 23% prior to and by 50% during pregnancy. Notably, 40.3% reported an episode of relapse during the pregnancy period, compared with 13.6% in the period 6 months prior to pregnancy. CONCLUSIONS: Adherence was high despite fear of a negative effect on fertility or the fetus. Counseling predicted higher adherence. This may be important because our study suggests an increase in UC activity during pregnancy. PMID- 21674716 TI - Ability of commonly used prediction equations to predict resting energy expenditure in children with inflammatory bowel disease. AB - BACKGROUND: Paediatric onset inflammatory bowel disease (IBD) may cause alterations in energy requirements and invalidate the use of standard prediction equations. Our aim was to evaluate four commonly used prediction equations for resting energy expenditure (REE) in children with IBD. METHODS: Sixty-three children had repeated measurements of REE as part of a longitudinal research study yielding a total of 243 measurements. These were compared with predicted REE from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict equations using the Bland-Altman method. RESULTS: Mean (+/-SD) age of the patients was 14.2 (2.4) years. Mean measured REE was 1566 (336) kcal per day compared with 1491 (236), 1441 (255), 1481 (232), and 1435 (212) kcal per day calculated from Schofield, Oxford, FAO/WHO/UNU, and Harris-Benedict, respectively. While the Schofield equation demonstrated the least difference between measured and predicted REE, it, along with the other equations tested, did not perform uniformly across all subjects, indicating greater errors at either end of the spectrum of energy expenditure. Smaller differences were found for all prediction equations for Crohn's disease compared with ulcerative colitis. CONCLUSIONS: Of the commonly used equations, the equation of Schofield should be used in pediatric patients with IBD when measured values are not able to be obtained. PMID- 21674715 TI - Disease activity, behavioral dysfunction, and health-related quality of life in adolescents with inflammatory bowel disease. AB - BACKGROUND: Approximately 20%-25% of all inflammatory bowel disease (IBD) cases have an onset in childhood or adolescence. Beyond disease severity, little is known regarding determinants of health-related quality of life (HRQOL) in this population. This study aimed to identify behavioral correlates of HRQOL and examine behavioral/emotional dysfunction (e.g., internalizing/externalizing symptoms) as the mechanism through which disease severity impacts HRQOL. METHODS: In all, 62 adolescents (mean = 15.47 years, standard deviation [SD] = 1.42) with IBD (79% Crohn's disease) and their parents were recruited from one of two pediatric IBD specialty clinics located in the Midwest or Northeast region of the United States. Participants completed a demographic questionnaire, the Youth Self Report version of the Child Behavior Checklist, and the IMPACT-III. Disease severity was calculated for Crohn's disease and ulcerative colitis using standardized measures. RESULTS: Greater disease severity, externalizing symptoms, and internalizing symptoms were all independently associated with lower HRQOL. Furthermore, internalizing symptoms partially mediated the relationship between disease activity and HRQOL, reducing the effect of disease severity on HRQOL from 22% to 9% in the mediation model. A Sobel test examining the significance of the indirect effect of disease severity on HRQOL via behavioral dysfunction was marginally nonsignificant (P =.053). CONCLUSIONS: Nondisease-specific variables (e.g., behavioral dysfunction) play an important role in impacting HRQOL. Behavioral dysfunction serves as the mechanism through which disease severity partially impacts HRQOL. Continued research to identify other predictors of HRQOL in pediatric IBD will greatly enhance our future ability to design interventions to improve HRQOL and maximize health outcomes. PMID- 21674717 TI - Prognostic factors and long-term clinical outcomes for surgical patients with intestinal Behcet's disease. AB - BACKGROUND: To date there have been few studies regarding the efficacy of surgical treatment and related prognostic factors following intestinal resection in patients with intestinal Behcet's disease (BD). Here we investigated the long term clinical outcomes and related prognostic factors after surgical treatment for intestinal BD. METHODS: We reviewed the medical records of 72 patients with intestinal BD who underwent surgery between March 1986 and May 2010. Prognostic factors were identified by univariate analysis using the Kaplan-Meier method, the log-rank test, and multivariate analysis using Cox proportional hazards regression models. RESULTS: Recurrence after surgical treatment was observed in 42 (58.3%) patients and reoperations were performed in 22 (30.6%) patients. The cumulative recurrence rates after surgical treatment were 29.2% at 2 years and 47.2% at 5 years; the cumulative reoperation rates were 12.5% at 2 years and 22.2% at 5 years. Multivariate analysis identified volcano-shaped ulcers, higher C-reactive protein (CRP) levels (>= 4.4 mg/dL), and the presence of intestinal perforations detected by pathology as independent predictive factors for recurrence. Moreover, volcano-shaped ulcers, higher CRP levels (>= 4.4 mg/dL), and a history of postoperative steroid therapy were independent predictive factors for reoperation. CONCLUSIONS: According to the current study, volcano shaped ulcers, higher CRP levels, a history of postoperative steroid therapy, and the presence of intestinal perforations detected by pathology were factors of a poor prognosis. Careful follow-up is required in surgical patients with these risk factors, who are at high risk for recurrence and reoperation. PMID- 21674718 TI - Perioperative complications in inflammatory bowel disease. AB - Almost 50% of patients with inflammatory bowel disease (IBD) will undergo surgery for their disease at some stage of its clinical course. Complications seen following surgery may occur early or late in the postoperative period. Patient factors, including active inflammatory disease, malnutrition, and use of immunosuppressant medications, make these patients a challenging surgical group and at increased risk for surgical complications. The purpose of this review is to characterize the complications that are commonly seen following surgery in patients with IBD and to discuss the surgical and patient factors that may influence their development. PMID- 21674719 TI - Emerging role of hydrogen sulfide in colonic physiology and pathophysiology. AB - Hydrogen sulfide (H2S) is a toxic gas that is now recognized as an important mediator of many physiological processes. In the colon, H2S is produced both endogenously and by naturally occurring sulfate-reducing bacteria (SRB). The full arrays of its effects in the gastrointestinal tract are still being elucidated, but they range from motility to carcinogenesis. We examined the evidence relating to H2S as a modulator of colonic function and disease. H2S is implicated in modulation of colonic compliance through its action on smooth muscle. There is also evidence linking H2S to colonic nociception, inflammatory bowel disease (IBD), and colorectal cancer. The exact mechanisms and pathways by which H2S exerts its multitude of effects are not yet fully understood, but its involvement in physiological and pathophysiological conditions of the colon is becoming evident. Elucidating the intricate effects of H2S in the colon and understanding the exact nature of its interactions with the colon makes pharmacological modulation of H2S production and metabolism potential targets for treatment of a multitude of colonic conditions in the future. PMID- 21674720 TI - Principal component analysis of mRNA levels of genes related to inflammation and fibrosis in rats treated with TNBS or glutamine. PMID- 21674721 TI - Feasibility of anti-VEGF agent bevacizumab in patients with Crohn's disease. PMID- 21674722 TI - Myocarditis associated with infliximab: a case report and review of the literature. PMID- 21674723 TI - ATG16L1 contribution to Crohn's disease risk in Sicily. PMID- 21674724 TI - Asymptomatic pulmonary cryptococcosis in a patient with Crohn's disease on infliximab: case report. PMID- 21674725 TI - Increased expression of discs large homolog 5 gene (DLG5) in ulcerative colitis patients compared to healthy individuals. PMID- 21674726 TI - Can elderly people be treated safely with anti-TNF agents? PMID- 21674727 TI - Efficacy of long-interval cytapheresis on steroid-dependent refractory ulcerative colitis. PMID- 21674728 TI - Wnt2 inhibits enteric bacterial-induced inflammation in intestinal epithelial cells. AB - BACKGROUND: Wnt signaling plays an essential role in gastrointestinal epithelial proliferation. Most investigations have focused on developmental and immune responses. Bacterial infection can be chronic and increases the risk of inflammatory bowel disease and colitis-associated cancer. However, we lack studies on how bacteria regulate Wnt proteins and how Wnts modulate the host responses to enteric bacteria. This study investigated the effects of Salmonella and Escherichia coli on Wnt2, one of the Wnt family members, in intestinal epithelia cells. METHODS: Using cultured epithelial cells, a Salmonella-colitis mouse model, and a gnotobiotic mouse model, we found that Wnt2 mRNA and protein expression levels were elevated after bacterial infection. Enteric bacteria regulate Wnt2 location in the intestine. Furthermore, we found that elevation of Wnt2 was a strategy for host defense by inhibiting cell apoptosis and inflammatory responses to infection. RESULTS: Using Wnt2 siRNA analysis, we show enhanced inflammatory cytokine IL-8 in epithelial cells. Cells overexpressed Wnt2 had less bacterial-induced IL-8 secretion. AvrA is a bacterial protein that inhibits inflammation by stabilizing beta-catenin, the downstream target of Wnt. We found that the stabilization of Wnt2 was regulated through ubiquitination. Moreover, the bacterial protein AvrA from Salmonella and E. coli stabilized Wnt2 protein expression in vivo. In an ex-germ-free system, E. coli F18 expressing AvrA increased Wnt2 expression and changed Wnt2 distribution in intestine. CONCLUSIONS: Wnt2 contributes to host protection in response to enteric bacteria. Our findings thus reveal a previously undefined role of Wnt for host-pathogen interaction and inflammation. PMID- 21674729 TI - Limited effect of capsaicin in T-cell transfer colitis. PMID- 21674730 TI - Third case: Another pediatric patient with pyostomatitis vegetans and oral granuloma as one of the initial symptoms of Crohn's disease. PMID- 21674731 TI - Stopping immunomodulators and biologics in inflammatory bowel disease patients in remission. AB - The emergence of biologic response modifiers and earlier use of immunomodulators for inflammatory bowel disease (IBD) patients have improved outcomes. Durable remissions have been achieved in many IBD patients on these treatments, but the duration of treatment and identifying which patients may stop therapy is yet unresolved. Recently, the term very deep remission (defined as clinical remission [CDAI < 150] and endoscopic remission) has been applied to patients on immunomodulators/biologics who have no clinical symptoms or objective signs of inflammatory disease. Whether or not patients who achieve and maintain a very deep remission may successfully stop treatment is not known. This article will review the current data on stopping treatment in IBD and identify certain factors that are associated with a high relapse rate after discontinuing treatment. Where evidence-based data are lacking, the authors provide their opinion. PMID- 21674732 TI - Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory bowel disease: a prospective study. AB - BACKGROUND: Since immunomodulators and antitumor necrosis factor (TNF) agents are increasingly used to treat inflammatory bowel disease (IBD), it is recommended to administer antipneumococcal vaccination to prevent opportunistic pneumonia. There is some evidence that concomitant immunosuppression may impair the immune response to vaccination. We aimed to evaluate the response rates to pneumococcal vaccination in four different treatment groups (mesalamine, azathioprine, infliximab, infliximab plus azathioprine). METHODS: In all, 96 patients with IBD (54 with Crohn's disease; 42 with ulcerative colitis) were administered a 23 valent polysaccharide pneumococcal vaccine (PSV-23). The levels of antipneumococcal antibodies were measured prior to and at least 3 weeks after vaccination. Response rates and risk factors for impaired immunosuppression were investigated. Patients on mesalamine were used as a control group. RESULTS: Patients administered infliximab or the combination immunosuppressive therapy had significantly lower response rates to vaccination (57.6% and 62.5%, respectively) compared with the group on mesalamine (88.6%; P < 0.05 for both comparisons). Azathioprine alone did not influence the response rate to vaccination (78.9%; P = 0.43 vs. mesalamine group). Mean antibody titers after vaccination were significantly lower in patients under infliximab or combined immunosuppression than controls (P < 0.05). Immunosuppression with infliximab or combination therapy significantly decreased the likelihood of responding to vaccination (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.04-0.64, P = 0.009, and OR = 0.21, 95% CI 0.05-0.91, P = 0.038, respectively). Pneumococcal vaccination was generally safe and well tolerated. CONCLUSIONS: Anti-TNF therapy alone or in combination with azathioprine impairs the response to pneumococcal vaccination in patients with IBD. All patients with IBD should therefore be vaccinated before starting anti-TNF therapy. PMID- 21674733 TI - The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster as a therapeutic suicide gene of breast cancer cells. AB - BACKGROUND: The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) was investigated for its broader substrate specificity and higher catalytic rate as a suicide gene in a combined gene/chemotherapy of cancer. METHODS: To evaluate the effects of nucleoside analog phosphorylation by Dm-dNK in vitro and in vivo, we generated a replication-deficient retroviral vector expressing Dm-dNK to transduce human breast cancer cells MCF7 (ER+) and MDA-MB-231 (ER-). We further determined the enzymatic activity and the sensitivity of the nontransduced and Dm-dNK-transduced 231/dNK and MCF7/dNK cells to the pyrimidine nucleoside analogs araC and araT. RESULTS: The data obtained show that Dm-dNK is enzymatically active and its overexpression in the nuclei of breast cancer cells results in an increased sensitivity to the nucleoside analogs araC and araT in vitro. Furthermore, subcutaneously transplanted 231/dNK cells were significantly inhibited after araC treatment, whereas nontransduced cancer cells continued to grow and develop in vivo. CONCLUSIONS: These results suggest that the Dm-dNK/nucleoside analog system could be a novel therapeutic strategy for treating breast cancer and improving anti-tumor efficacy, as well as for optimizing approaches for suicide gene therapy. PMID- 21674734 TI - Enhanced delivery of monomethoxypoly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly l-lysine nanoparticles loading platelet-derived growth factor BB small interfering RNA by ultrasound and/or microbubbles to rat retinal pigment epithelium cells. AB - BACKGROUND: A novel small interfering RNA (siRNA) delivery method based on the combined use of nanoparticles (NPs) with ultrasound (US) and/or microbubbles (MBs) was introduced in the present study. We investigated the efficacy and safety of US and/or MBs-enhanced delivery of monomethoxypoly(ethylene glycol) poly(lactic-co-glycolic acid)-poly l-lysine (mPEG-PLGA-PLL) NPs loading platelet derived growth factor BB (PDGF-BB) siRNA to rat retinal pigment epithelium (RPE) J cells. METHODS: The effect of US and/or MBs on the delivery of NPs containing Cy3-labeled siRNA was evaluated by fluorescence microscopy and flow cytometry. Potential toxicity of NPs and cell viability under different conditions of US and/or MBs were assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide method. RESULTS: The results obtained showed that low intensity US or 15-20% MBs could increase the delivery efficiency of a lower concentration of mPEG-PLGA-PLL NPs loading siRNA to RPE-J cells, whereas the combination of US with MBs under the optimal conditions for the enhancement of NPs delivery did not further increase the cellular uptake of NPs compared to either US or MBs alone (p = 0.072 and p = 0.488, respectively). Under the optimal condition for US-enhanced NPs delivery, the enhanced PDGF-BB gene silencing with a combination of US and NPs encapsulating siRNA resulted in a significant decrease of mRNA and protein expression levels compared to NPs alone. CONCLUSIONS: US and/or MBs could be used safely to enhance the delivery of NPs loading siRNA to rat RPE-J cells. A combination of the chemical (mPEG-PLGA-PLL NPs loading siRNA) and physical (US) approaches could more effectively downregulate the mRNA and protein expression of PDGF-BB. PMID- 21674735 TI - Adeno-associated virus-mediated expression of acid sphingomyelinase decreases atherosclerotic lesion formation in apolipoprotein E(-/-) mice. AB - BACKGROUND: The secretory form of acid sphingomyelinase (ASM) is postulated to play a key role in the retention and aggregation of lipoproteins in the subendothelial space of the arterial wall by converting sphingomyelin in lipoproteins into ceramide. The present study aimed to determine whether the level of circulating ASM activity affects lesion development in mouse model of atherosclerosis. METHODS: Apolipoprotein E deficient (ApoE(-/-) ) mice were injected intravenously with a recombinant adeno-associated virus (AAV8-ASM) that constitutively expressed high levels of human ASM in liver and plasma. RESULTS: Plasma sphingomyelin levels were reduced at early but not later time points after the administration of AAV8-ASM despite persistently elevated circulating ASM. No change in serum lipoprotein levels was observed. Thirteen or 17 weeks after the administration of AAV8-ASM, the amount of plaque formation in the aortic sinus was comparable to that of mice treated with a control AAV. CONCLUSIONS: Unexpectedly, the lesion area of the entire aorta was reduced significantly in the AAV8-ASM virus-treated group. Hepatic expression and secretion of ASM into the circulation did not accelerate or exacerbate, but rather decreased, lesion formation in ApoE(-/-) mice. Thus, plasma ASM activity does not appear to be rate limiting for plaque formation during atherogenesis. PMID- 21674736 TI - A single direct injection into the left ventricular wall of an adeno-associated virus 9 (AAV9) vector expressing extracellular superoxide dismutase from the cardiac troponin-T promoter protects mice against myocardial infarction. AB - BACKGROUND: Localized administration of a highly efficient gene delivery system in combination with a cardiac-selective promoter may provide a favorable biosafety profile in clinical applications such as coronary artery bypass graft surgery, where regions of myocardium can be readily injected to protect them against the potential threat of future ischemic events. METHODS: Adeno-associated virus (AAV) vectors expressing luciferase or enhanced green fluorescent protein (eGFP) packaged into AAV serotypes 1, 2, 6, 8 and 9 were injected into the left ventricular (LV) wall of adult mice to determine the time course, magnitude and distribution of gene expression. An AAV9 vector expressing extracellular superoxide dismutase (EcSOD) from the cardiac troponin T (cTnT) promoter was then directly injected into the LV wall of adult mice. Myocardial infarction was induced 4 weeks after injection and infarct size was determined by triphenyltetrazolium chloride and phthalo blue staining. RESULTS: Serotypes AAV 9, 8, 1 and 6 provided early onset of gene expression in the heart with minimal extra-cardiac gene expression. AAV9 provided the highest magnitude of gene expression. Immunostaining for eGFP showed expression spanning the anterior to posterior walls from the mid ventricle to the apex. A single direct injection of the AAV9 vector bearing EcSOD ( n = 5) decreased the mean infarct size by 50% compared to the eGFP control group (n = 8) (44 +/- 7% versus 22 +/- 5%; p = 0.04). CONCLUSIONS: AAV serotype 9 is highly efficient for cardiac gene delivery, as evidenced by early onset and high-level gene expression. AAV9-mediated, cardiac selective overexpression of EcSOD from the cTnT promoter significantly reduced infarct size in mice. PMID- 21674737 TI - Effect of poly(ADP-ribose) polymerase 1 on integration of the adeno-associated viral vector genome. AB - BACKGROUND: Adeno-associated virus type 2 (AAV) has the ability to target integration of its DNA into a specific locus of the human genome. Site-specific AAV integration is mediated by viral Rep proteins, although the role of cellular factors involved in this process is largely unknown. Recent studies provide evidence showing that cellular DNA repair proteins are involved in targeted integration of AAV, although their specific roles are not well defined. METHODS: In the present study, we investigated the interaction between Rep and proteins of the back-up nonhomologous end-joining pathway (B-NHEJ). We then analyzed the effect of one of these proteins, poly(ADP-ribose) polymerase 1 (PARP1) on AAV integration. RESULTS: We show that AAV Rep interacts with B-NHEJ members DNA ligase III and PARP1 but does not associate with the scaffolding factor XRCC1. Moreover, PARP1 and Rep bind directly and not via DNA-protein interactions. We also found that Rep increases the enzymatic activity of PARP1 potentially through the endonuclease activity of Rep. Finally, we demonstrate that both chemical inhibition of PARP1 and PARP1 depletion using small hairpin RNA enhance integration of the AAV genome in HeLa cells. CONCLUSIONS: The findings of the present study indicate that manipulation of PARP1 activity could be used as a tool for developing new, effective AAV-based therapies for the treatment of genetic diseases and cancer. PMID- 21674739 TI - Confusion and neo-confusion: corrole isomers with an NNNC core. PMID- 21674738 TI - Intravenous injection of irradiated tumor cell vaccine carrying oncolytic adenovirus suppressed the growth of multiple lung tumors in a mouse squamous cell carcinoma model. AB - BACKGROUND: Although cancer therapy using replication-selective oncolytic adenoviruses has been available for many years, its anti-tumor efficacy is suboptimal as a result of low and nonspecific infectivity that depends on coxsackie adenovirus receptor expression of the target cancer and normal cells, and generation of an anti-adenovirus neutralizing antibody. In addition, concerns of triggering a severe innate immune response against the adenovirus limit the systemic administration. We developed the carrier cell-based oncolytic virus system (CBOVS) using irradiated tumor cells as carrier cells and concealing the adenovirus (Ad-IAI.3B) inside to improve the specific infectivity. We investigated the anti-tumor effect of CBOVS in a multiple lung tumor mouse model. METHODS: The ability of CBOVS to infect Ad-IAI.3B to the target cancer cells was examined in vitro in the presence of anti-adenovirus antibodies. To evaluate the systemic effect of CBOVS, we intravenously injected CBOVS into mice with lung tumors (KLN205 cell lines). RESULTS: CBOVS enhanced the infectivity of Ad-IAI.3B to tumor cells in the presence of anti-adenovirus antibodies in vitro. Intravenous injections of CBOVS produced an accumulation of the adenovirus in the lung-bearing tumors and produced a strong anti-tumor effect in vivo. Furthermore, lymphocytes collected from the CBOVS-treated mice induced an increase in cytokines related to the Th1 response (interferon-gamma, interleukin-12) by pulsing with KLN205. CONCLUSIONS: These findings suggest that CBOVS could protect adenoviruses from neutralizing antibodies and systemically deliver them to lung tumors. Furthermore, CBOVS appears to have potential as a tumor cell vaccine that activates cytotoxic immunity against cancer cells. PMID- 21674740 TI - Highly enantioselective cyclopropenation reaction of 1-alkynes with alpha-alkyl alpha-diazoesters catalyzed by dirhodium(II) carboxylates. PMID- 21674741 TI - One-pot synthesis of an 125I-labeled trifunctional reagent for multiscale imaging with optical and nuclear techniques. PMID- 21674742 TI - Powerful insight into catalytic mechanisms through simultaneous monitoring of reactants, products, and intermediates. PMID- 21674743 TI - An X-Y addressable matrix odor-releasing system using an on-off switchable device. PMID- 21674744 TI - QM/MM nonadiabatic decay dynamics of 9H-adenine in aqueous solution. AB - The photoinduced nonadiabatic decay dynamics of 9H-adenine (hereafter, adenine) in aqueous solution were investigated by surface-hopping simulations within a quantum mechanical/molecular mechanical (QM/MM) framework. The QM subsystem (adenine) was treated at the semiempirical OM2/MRCI level, whereas the MM solvent (water) was described by the TIP3P force field model. Classical molecular dynamics (MD) simulations were used to generate snapshots with different solvent configurations and geometries. For a representative number of these snapshots, the energy minima of the lowest electronic states and the most important conical intersections were located by QM/MM geometry optimization. Surface-hopping QM/MM MD simulations were performed for all selected snapshots to study the nonadiabatic dynamics after photoexcitation, including the two lowest excited singlet states, which are both populated in the initial photoexcitation due to strong vibronic coupling in the Franck-Condon region. The simulations yield ultrafast S(2)-S(1) decay within 40 fs and S(1)-S(0) internal conversion to the ground state within 410 fs, which is consistent with recent experimental results from time-resolved spectroscopy. PMID- 21674745 TI - Structure-function relationships of new lipids designed for DNA transfection. AB - Cationic liposome/DNA complexes can be used as nonviral vectors for direct delivery of DNA-based biopharmaceuticals to damaged cells and tissues. To obtain more effective and safer liposome-based gene transfection systems, two cationic lipids with identical head groups but different chain structures are investigated with respect to their in vitro gene-transfer activity, their cell-damaging characteristics, and their physicochemical properties. The gene-transfer activities of the two lipids are very different. Differential scanning calorimetry and synchrotron small- and wide-angle X-ray scattering give valuable structural insight. A subgel-like structure with high packing density and high phase-transition temperature from gel to liquid-crystalline state are found for lipid 7 (N'-2-[(2,6-diamino-1-oxohexyl)amino]ethyl-2,N bis(hexadecyl)propanediamide) containing two saturated chains. Additionally, an ordered head-group lattice based on formation of a hydrogen-bond network is present. In contrast, lipid 8 (N'-2-[(2,6-diamino-1-oxohexyl)amino]ethyl-2 hexadecyl-N-[(9Z)-octadec-9-enyl]propanediamide) with one unsaturated and one saturated chain shows a lower phase-transition temperature and a reduced packing density. These properties enhance incorporation of the helper lipid cholesterol needed for gene transfection. Both lipids, either pure or in mixtures with cholesterol, form lamellar phases, which are preserved after addition of DNA. However, the system separates into phases containing DNA and phases without DNA. On increasing the temperature, DNA is released and only a lipid phase without intercalated DNA strands is observed. The conversion temperatures are very different in the two systems studied. The important parameter seems to be the charge density of the lipid membranes, which is a result of different solubility of cholesterol in the two lipid membranes. Therefore, different binding affinities of the DNA to the lipid mixtures are achieved. PMID- 21674746 TI - Daytime reactions of 1,8-cineole in the troposphere. AB - Relative rate coefficients for the gas-phase reaction of chlorine atoms (Cl) and hydroxyl radicals (OH) with 1,8-cineole were determined by Fourier-transform infrared (FTIR) spectroscopy between 285 and 313 K at atmospheric pressure. The temperature dependence of both reactions shows simple Arrhenius behaviour which can be represented by the following expressions (in units of cm(3) molecule(-1) s(-1)): k(1,8-cineole+OH)=(6.28 +/- 6.53) * 10(-8) exp[(-2549.3 +/- 155.7)/T] and k(1,8-cineole+Cl)=(1.35 +/- 1.07) * 10(-10) exp[(-151.6 +/- 237.7)/T]. Major products of the titled reactions were identified by solid-phase microextraction (SPME) coupled to a GC-MS. Additionally, the first step of the reaction was theoretically studied by ab initio calculations and a reaction mechanism is proposed. PMID- 21674747 TI - Cation-pi and lone pair-pi interactions combined in one: the first experimental evidence of (H3O-lp)+...pi-system binding in a crystal. PMID- 21674748 TI - Wet-chemical preparation of Ce3+-activated K2LaX5 (X = Cl, Br or I) phosphors. AB - There has been a renewed interest in Ce(3+) -activated halide phosphors due to applications as scintillation detectors, especially for positron emission tomography. For K(2) LaCl(5), the light yield increases and the energy resolution (FWHM) improves with increasing Ce(3+) doping. K(2) LaX(5) compounds are also important as laser hosts for the mid-IR range. K(2) LaCl(5):Nd crystals show bright mid-IR luminescence, which makes them a candidate for IR laser materials. Efficient emission in the IR range has also been reported in K(2) LaCl(5):U(3+). A one-step, wet chemical process for preparing Ce(3+)-activated K(2) LaCl(5) phosphor is described. Intense luminescence of Ce(3+) can be observed in the as prepared powders without any heat treatment. The availability of such powders opens up several exciting possibilities, such as growing single crystals without going to the high temperatures required for melting the constituent chlorides, or even obtaining processed, transparent, Ce(3+)-activated materials without taking recourse to crystal growth. PMID- 21674749 TI - ATP bioluminescence rapid detection of total viable count in soy sauce. AB - The adenosine triphosphate (ATP) bioluminescence rapid determination method may be useful for enumerating the total viable count (TVC) in soy sauce, as it has been previously used in food and beverages for sanitation with good precision. However, many factors interfere with the correlation between total aerobic plate counts and ATP bioluminescence. This study investigated these interfering factors, including ingredients of soy sauce and bacteria at different physiological stages. Using the ATP bioluminescence method, TVC was obtained within 4 h, compared to 48 h required for the conventional aerobic plate count (APC) method. Our results also indicated a high correlation coefficient (r = 0.90) between total aerobic plate counts and ATP bioluminescence after filtration and resuscitation with special medium. The limit of quantification of the novel detection method is 100 CFU/mL; there is a good linear correlation between the bioluminescence intensity and TVC in soy sauce in the range 1 * 10(2) -3 * 10(4) CFU/mL and even wider. The method employed a luminescence recorder (Tristar LB 941) and 96-well plates and could analyse 50-100 samples simultaneously at low cost. In this study, we evaluated and eliminated the interfering factors and made the ATP bioluminescence rapid method available for enumerating TVC in soy sauce. PMID- 21674750 TI - Benchmark study on glyphosate-resistant cropping systems in the United States. Part 1: Introduction to 2006-2008. AB - Glyphosate-resistant (GR) crop technology has dramatically impacted agriculture. The adoption of GR systems in canola, maize, cotton, soybean and sugar beets has been widespread in the United States. However, weed scientists are concerned that growers' current herbicide programs and weed management tactics will affect their sustainability and effectiveness. Without proper management, the potential for weed populations to express a high degree of resistance to glyphosate will adversely impact the utility of glyphosate. In 2005, weed scientists from six universities initiated a long-term research study to assess the sustainability of GR technology. This paper introduces five other articles in this series. Over 150 fields of at least 10 ha were selected to participate in a long-term field-scale study, and each field was split in half. On one-half the grower continued using the current weed management program; on the other half the grower used academic recommended herbicide resistance best management practices. Field data were collected in 2006-2008 to determine the impact of the two weed management programs on weed populations, diversity, seedbank, crop yields and economic returns. This long-term study will provide invaluable data for determining the sustainability and profitability of diversified weed management programs designed to lower the risk of evolving weed resistance to glyphosate. PMID- 21674751 TI - Method for rapid detection of the PvCesA3 gene allele conferring resistance to mandipropamid, a carboxylic acid amide fungicide, in Plasmopara viticola populations. AB - BACKGROUND: The occurrence of carboxylic acid amide (CAA)-fungicide-resistant Plasmopara viticola populations is becoming a serious problem in the control of grapevine downy mildew worldwide. RESULTS: The authors have developed a method, which utilises PCR-RFLP, for the rapid detection of resistance to the CAA fungicide mandipropamid in P. viticola populations. With this method, a glycine to-serine substitution at codon 1105 of the cellulose synthase gene PvCesA3 of CAA-fungicide-resistant P. viticola was easily detected, although no resistant P. viticola was detected from 398 isolates in Japan. CONCLUSION: It is proposed that the PCR-RFLP method is a reliable tool for the rapid detection of CAA-fungicide resistant P. viticola isolates. Only 4 h was required from the sampling of symptoms to the phenotyping of fungicide resistance. PMID- 21674752 TI - Determining the source of house flies (Musca domestica) using stable isotope analysis. AB - BACKGROUND: Intensive livestock units frequently produce flies in large numbers that, on migration, cause nuisance to the occupants of neighbouring dwellings. The resolution of such problems is often reliant on the unequivocal identification of the origin of the flies, particularly when several potential sources exist. This study evaluated stable isotope analysis as a method for differentiating adult houseflies (Musca domestica) on the basis of their dietary history so as to determine their likely source. RESULTS: Flies were reared in the laboratory on several substrates, including chicken and cattle manure, laboratory diet and household vegetable waste. Different fly parts (wings, heads and legs) and whole flies were analysed immediately after eclosion and after 10 days. The delta(13) C and delta(15) N values for adults that had developed on each diet type were highly distinct. Both isotopic ratios altered markedly after maintaining the flies for 10 days on a diet of cane sugar solution. CONCLUSIONS: Stable isotope analysis readily differentiated flies that had developed on a range of substrates. The technique, therefore, shows potential to be employed to determine the likely source of various nuisance insects, and to contribute to the abatement of such problems. PMID- 21674753 TI - Fumigant toxicity of lemon eucalyptus oil constituents to acaricide-susceptible and acaricide-resistant Tetranychus urticae. AB - BACKGROUND: This study was aimed at assessing the fumigant toxicity of 14 essential oil constituents from lemon eucalyptus, Eucalyptus citriodora Hook, and another ten known compounds to females of acaricide-susceptible, chlorfenapyr resistant, fenpropathrin-resistant, pyridaben-resistant and abamectin-resistant strains of Tetranychus urticae Koch. RESULTS: Menthol (LC(50) , 12.9 ug cm(-3) ) was the most toxic compound, followed by citronellyl acetate (16.8 ug cm(-3) ), against the susceptible females. High toxicity was also produced by beta citronellol, citral, geranyl acetate and eugenol (LC(50) , 21.7-24.6 ug cm(-3) ). The fumigant toxicity of these compounds was almost identical against females from either of the susceptible and resistant strains, indicating that the compounds and acaricides do not share a common mode of action or elicit cross resistance. CONCLUSION: Global efforts to reduce the level of highly toxic synthetic acaricides in the agricultural environment justify further studies on materials derived from lemon eucalyptus oil, particularly menthol and citronellyl acetate, as potential acaricides for the control of acaricide-resistant T. urticae as fumigants with contact action. PMID- 21674754 TI - Systemic resistance induced in Arabidopsis thaliana by Trichoderma asperellum SKT 1, a microbial pesticide of seedborne diseases of rice. AB - BACKGROUND: Trichoderma asperellum SKT-1 is a microbial pesticide of seedborne diseases of rice. To investigate the mechanisms of disease suppression in SKT-1, the ability to induce systemic resistance by SKT-1, or its cell-free culture filtrate (CF), was tested using Arabidopsis thaliana Col-0 plants. RESULTS: Both SKT-1 and its CF elicit an induced systemic resistance against the bacterial leaf speck pathogen Pseudomonas syringae pv. tomato DC3000 in Col-0 plants. Involvement of plant hormones in the induced resistance by SKT-1 and CF was assessed using Arabidopsis genotypes such as the jasmonic acid (JA)-resistant mutant jar1, the ethylene (ET)-resistant mutant etr1, the plant impaired in salicylic acid (SA) signalling transgenic NahG and the mutant npr1 impaired in NPR1 activity. In soil experiments using SKT-1, no significant disease suppression effect was observed in NahG transgenic plants or npr1 mutant plants. Expression levels of SA-inducible genes such as PR-1, PR-2 and PR-5 increased substantially in the leaves of Col-0 plants. Expression levels of JA/ET-induced genes such as PDF1.2a, PR-3, PR-4 and AtVsp1 were also induced, but the levels were not as high as for SA-inducible genes. In a hydroponic experiment using CF from SKT-1, all Arabidopsis genotypes showed an induced systemic resistance by CF and increased expression levels of JA/ET- and SA-inducible genes in leaves of CF treated plants. CONCLUSION: The SA signalling pathway is important in inducing systemic resistance to colonisation by SKT-1, and both SA and JA/ET signalling pathways combine in the signalling of induced resistance by CF. These results indicate that the response of A. thaliana is different from that found in root treatments with barley grain inoculum and CF from SKT-1. PMID- 21674755 TI - Energy drinks: another red flag for the liver allograft. PMID- 21674756 TI - Cerebral sinus venous thrombosis in a child with hyperthyroidism. PMID- 21674757 TI - Applicability of 2009 international consensus terminology and criteria for immune thrombocytopenia to a clinical pediatric population. AB - BACKGROUND: Since pediatric immune thrombocytopenia (ITP) is relatively infrequent, comparisons among clinical studies are critical but have previously been limited by differences in terminology. In 2009, an international working group (IWG) developed consensus criteria to enhance comparability in future studies in adults and children. METHODS: We performed a retrospective medical record review of all pediatric ITP patients seen at a single children's hospital with a first visit between 2003 and 2010 and applied both historical (criteria(Hist) ) and IWG (criteria(IWG) ) ITP criteria to available clinical data. RESULTS: Among the 505 patients seen for ITP over 7 years, 98% could be classified as "acute" or "chronic" ITP using the criteria(Hist) , while only 90.7% could be classified as "newly diagnosed," "persistent," or "chronic" ITP using the criteria(IWG) (P < 0.01). Only 33.7% met criteria(IWG) for severe ITP, whereas 77.4% met criteria(Hist) for severe ITP. A striking difference was that overall response to therapies was lower if the criteria(IWG) were used rather than the criteria(Hist) , particularly for IVIG (55.4% vs. 70%, P = 0.02) and rituximab (35.3% vs. 83.3% P = 0.05). Only 2 subjects (0.4%) met the criteria(IWG) for refractory ITP. CONCLUSIONS: Most ITP patients could easily be classified using the 2009 criteria(IWG) . Limitations to applying the criteria(IWG) included absence of treatment response durations, incomplete definition of pediatric "refractory ITP," and exclusion of secondary ITP. Nevertheless, the criteria(IWG) were more clinically relevant given the reliance on definitions based on bleeding and their ability to be applied prospectively. The utility of using the criteria(IWG) within prospective trials remains to be determined. PMID- 21674759 TI - Immunomodulatory drugs in autoimmune lymphoproliferative syndrome (ALPS). PMID- 21674760 TI - Contribution of fibrinolytic tests to the differential diagnosis of veno occlusive disease complicating pediatric hematopoietic stem cell transplantation. AB - BACKGROUND: Veno-occlusive disease (VOD) is a major complication following hematopoietic stem cell transplantation (HSCT). Its diagnosis is based on clinical criteria, which have a limited sensitivity. Increased plasminogen activator inhibitor-1 (PAI-1) levels have been suggested as a marker of VOD. We aimed to prospectively evaluate how the fibrinolytic parameters behaved to discriminate VOD from other liver disorders occurring after HSCT in a pediatric population. PROCEDURES: A total of 195 HSCT were performed on 161 children and VOD complicated 11 cases (6.8%). Alanine aminotransferase, total bilirubin, PAI-1 antigen (PAI-1:Ag) and activity, t-PA antigen, D-dimer, prothrombin time, activated partial thromboplastin time, antithrombin, fibrinogen, and platelet counts were measured in 105 HSCT before and then weekly for 1 month after HSCT. RESULTS: An early, significant increase in the fibrinolytic parameters was seen in patients who developed VOD, even before VOD was diagnosed clinically, by comparison with patients without complications or those with non-VOD liver disorders. The combined increase in bilirubin, D-dimer, and PAI-1:Ag levels beyond the normal range distinguished VOD cases from other liver complications with a high sensitivity and specificity. CONCLUSIONS: Our study demonstrates that fibrinolytic tests can help diagnose VOD after HSCT in the pediatric population. PMID- 21674758 TI - Response to steroids predicts response to rituximab in pediatric chronic immune thrombocytopenia. AB - BACKGROUND: Treatment choice in pediatric immune thrombocytopenia (ITP) is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies. METHODS: The objective of this study was to evaluate univariate and multivariable predictors of platelet count response to rituximab. After local IRB approval, 565 patients with chronic ITP enrolled and met criteria for this study in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and October 2010. Treatment response was defined as a post-treatment platelet count >= 50,000/ul within 16 weeks of rituximab and 14 days of steroids. Treatment response data were captured both retrospectively at enrollment and then prospectively. RESULTS: Eighty (14.2%) patients were treated with rituximab with an overall response rate of 63.8% (51/80). Univariate correlates of response to rituximab included the presence of secondary ITP and a positive response to steroids. In multivariable analysis, response to steroids remained a strong correlate of response to rituximab, OR 6.8 (95% CI 2.0-23.0, P = 0.002). Secondary ITP also remained a strong predictor of response to rituximab, OR 5.6 (95% CI 1.1-28.6, P = 0.04). Although 87.5% of patients who responded to steroids responded to rituximab, 48% with a negative response to steroids did respond to rituximab. CONCLUSION: In the NACIR, response to steroids and presence of secondary ITP were strong correlates of response to rituximab, a finding not previously reported in children or adults. PMID- 21674761 TI - Childhood cancer survivorship educational resources in North American pediatric hematology/oncology fellowship training programs: a survey study. AB - BACKGROUND: Childhood cancer survivors require life-long care by clinicians with an understanding of the specific risks arising from the prior cancer and its therapy. We surveyed North American pediatric hematology/oncology training programs to evaluate their resources and capacity for educating medical trainees about survivorship. PROCEDURE: An Internet survey was sent to training program directors and long-term follow-up clinic (LTFU) directors at the 56 US and Canadian centers with pediatric hematology/oncology fellowship programs. Perceptions regarding barriers to and optimal methods of delivering survivorship education were compared among training program and LTFU clinic directors. RESULTS: Responses were received from 45/56 institutions of which 37/45 (82%) programs require that pediatric hematology/oncology fellows complete a mandatory rotation focused on survivorship. The rotation is 4 weeks or less in 21 programs. Most (36/45; 80%) offer didactic lectures on survivorship as part of their training curriculum, and these are considered mandatory for pediatric hematology/oncology fellows at 26/36 (72.2%). Only 10 programs (22%) provide training to medical specialty trainees other than pediatric hematology/oncology fellows. Respondents identified lack of time for trainees to spend learning about late effects as the most significant barrier to providing survivorship teaching. LTFU clinic directors were more likely than training program directors to identify lack of interest in survivorship among trainees and survivorship not being a formal or expected part of the fellowship training program as barriers. CONCLUSIONS: The results of this survey highlight the need to establish standard training requirements to promote the achievement of basic survivorship competencies by pediatric hematology/oncology fellows. PMID- 21674762 TI - Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. AB - BACKGROUND: This study aimed to investigate the prevalence of mutations in the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK in Chinese pediatric patients with EBV HLH. METHODS: Sixty-seven pediatric patients diagnosed with EBV-HLH in Beijing Children's Hospital were recruited. Nucleotide sequences of all exons and their flanking intronic sequences of PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK were amplified by PCR followed by direct sequencing. RESULTS: Eight patients were identified with heterozygous, compound heterozygous, or homozygous mutations in PFR1, UNC13D, and XIAP. Three missense mutations (c.83G>A, c.503G>A, c.632C>T) were found in PRF1 of two males and two females. Compound heterozygous c.93C>G and c.1066C>T were found in PRF1 of a 2.5-year-old female. Four different mutations were found in UNC13D of two patients: compound nonsense heterozygous mutations c.766C>T and c.1215C>G were found in one male and two splicing mutations c.1596+1G>C and c.2709+1G>A were found in another male. A heterozygous mutation c.1099+2T>C in XIAP was found in a 4-year-old male. No detrimental mutations were identified in STX11, SH2D1A, or ITK. NK cell activity did not differ between the eight FHL patients and the remaining patients. There was no statistical difference in clinical features and laboratory data for these two subgroups with biallelic and heterozygous mutations. CONCLUSIONS: Seven novel mutations in PRF1, UNC13D, and XIAP were identified in EBV-HLH patients. Only a fraction of the Chinese children with EBV-HLH have genetic defects in PRF1, UNC13D, and XIAP. There were no gene mutations of PRF1/UNC13D/STX11/SH2D1A/XIAP/ITK in the majority of Chinese child patients with EBV-HLH. PMID- 21674763 TI - High-grade brain tumors in siblings with biallelic MSH6 mutations. AB - Biallelic germline mutations of Constitutional mismatch repair-deficiency syndrome (CMMR-D) genes, MLH1, MSH2, MSH6, and PMS2 are characterized by increased risk of childhood malignancy. We report a case with CMMR-D caused by novel homozygous MSH6 mutations leading to gliomatosis cerebri and T-ALL in an 11 year-old female and glioblastoma multiforme in her 10-year-old brother, both with rapid progression of the diseases. A literature review on brain tumors in CMMR-D families shows that they are treatment-resistant and lead to early death. Identification of patients with CMMR-D is critical, and specific cancer screening programs with early surgery are recommended. PMID- 21674765 TI - Long-term complications in totally implantable venous access devices: randomized study comparing subclavian and internal jugular vein puncture. AB - BACKGROUND: This prospective randomized study evaluated complications related to long-term totally implantable catheters in oncologic children and adolescents by comparing venopunction performed either in the jugular or subclavian vein. METHODS: A total of 83 catheters were implanted from January 2004 to April 2006 and followed-up until March 2008. Patients were randomly allocated to the subclavian or jugular vein group. The endpoint was complications that led to catheter revision or catheter removal. RESULTS: Six patients were excluded, 43 had the catheter implanted in the subclavian and 34 in the jugular vein. Subclavian catheters were used for up to 12.6 months, while jugular catheters were kept in place for up to 14.8 months (P = 0.38). No statistical differences were found between the groups concerning age, sex, leukocyte count, platelet count, type of admission (in or outpatient), or previous chemotherapy regimens. When analyzed individually, long-term complications did not present statistically significant differences either. Infection occurred in 20 and 11% (P = 0.44), while catheter embolism took place in 23 and 8% (P = 0.11) of patients with subclavian and jugular catheters, respectively. A statistical difference was seen in the total number of complications, which occurred in 48 and 23% (P = 0.02) of patients in the subclavian and in the jugular groups, respectively. CONCLUSIONS: Catheters implanted by puncture in the subclavian vein were more prone to late complications than those implanted in the jugular vein. PMID- 21674766 TI - Thirty-day readmission rates following hospitalization for pediatric sickle cell crisis at freestanding children's hospitals: risk factors and hospital variation. AB - BACKGROUND: Readmission within 30 days after hospitalization for sickle cell crisis was developed by The National Association of Children's Hospitals (NACHRI) to improve hospital quality, however, there have been few studies validating this. PROCEDURE: We performed a retrospective examination of 12,104 hospitalizations for sickle crisis from July 1, 2006 and December 31, 2008 at 33 freestanding children's hospitals in the Pediatric Health Information System (PHIS) database. Hospitalizations met NACHRI criteria; inpatient admission, APR DRG code 662, age < 18, discharge home, and length of stay within 2 SD of the mean. We describe 30-day readmission rates, identify factors associated with readmission accounting for patient-level clustering and compare unadjusted versus adjusted variation in readmission rates. RESULTS: We identified 4,762 patients with 12,104 qualifying hospitalizations (1-30 per patient). Two thousand seventy four (17%) hospitalizations resulted in a readmission within 30 days. Significant factors associated with readmission were age (OR 1.06/year, P < 0.0001), inpatient use of steroids (OR 1.48, P = 0.01) admission for pain without other sickle complications (OR 1.52, P < 0.0001) and simple transfusion (OR 0.58, P = 0.0002). There was significant variation in readmission rates between hospitals, even after accounting for clustering by patient and hospital case mix. CONCLUSIONS: In a sample of free-standing children's hospitals, 17% of hospitalizations for sickle cell crisis result in readmission within 30 days. Older patients, those treated with steroids and those admitted for pain are more likely to be readmitted; simple transfusion is protective. Even after adjusting for case mix substantial hospital variation remains, but specific hospital to hospital comparisons differ depending on the exact methods used. PMID- 21674767 TI - Evaluation of diagnostic performance of CT for detection of tumor thrombus in children with Wilms tumor: a report from the Children's Oncology Group. AB - BACKGROUND: Pre-operative assessment of intravascular extension of Wilms tumor is essential to guide management. Our aim is to evaluate the diagnostic performance of multidetector CT in detection of tumor thrombus in Wilms tumor. PROCEDURE: The study population was drawn from the first 1,015 cases in the AREN03B2 study of the Children's Oncology Group. CT scans of children with (n = 62) and without (n = 111) tumor thrombus at nephrectomy were independently reviewed by two radiologists, blinded to patient information. Doppler sonography results were obtained from institutional radiology reports, as Doppler requires real-time evaluation. The diagnostic performance of CT and Doppler for detection of tumor thrombus was determined using nephrectomy findings as reference standard. RESULTS: In the primary nephrectomy group, tumor thrombus detection sensitivity, specificity of CT was 65.6, 84.8%, and Doppler was 45.8, 95.7%, respectively. In this group, sensitivity of CT, Doppler for detection of cavoatrial thrombus was 84.6 and 70.0%, respectively. In the secondary nephrectomy group, tumor thrombus detection sensitivity, specificity of CT was 86.7, 90.6%, and Doppler was 66.7, 100.0%, respectively. In this group, sensitivity of CT, Doppler for detection of cavoatrial thrombus was 96.0 and 68.8%, respectively. Pre-operative Doppler evaluation performed in 108/173 cases, detected 3 cases with intravenous extension (2 in renal vein, 1 in IVC at renal vein level) that were missed at CT. CONCLUSIONS: CT can accurately identify cavoatrial tumor thrombus that will impact surgical approach. Routine Doppler evaluation, after CT has already been performed, is not required in Wilms tumor. PMID- 21674768 TI - Comparison of piperacillin tazobactam and cefoperazone sulbactam monotherapy in treatment of febrile neutropenia. AB - BACKGROUND: Monotherapy has tended to replace the combination therapy in emprical treatment of febrile neutropenia. There is no reported trial which compares the efficacy of cefoperazone-sulbactam (CS) and piperacillin-tazobactam (PIP/TAZO) monotherapies in the treatment of febrile neutropenia. In this prospective randomized study, we aimed to compare the safety and efficacy of CS versus PIP/TAZO as empirical monotherapies in febrile neutropenic children with cancer. PROCEDURE: The study included febrile, neutropenic children hospitalized at our center for cancer. They were randomly selected to receive CS 100 mg/kg/day or PIP/TAZO 360 mg/kg/day. Duration of fever and neutropenia, absolute neutrophil count, modification, and success rate were compared between the two groups. Resolution of fever without antibiotic change was defined as success and resolution of fever with antibiotic change or death of a patient was defined as failure. Modification was defined as changing the empirical antimicrobial agent during a febrile episode. RESULTS: One hundred and two febrile neutropenic episodes were documented in 55 patients with a median age of 4 years. In 50 episodes CS and in 52 episodes PIP/TAZO was used. Duration of fever and neutropenia, neutrophil count, age, sex, and primary disease were not different between two groups. Success rates in the CS and PIP/TAZO groups were respectively 56 and 62% (P > 0.05). Modification rate between two groups showed no significant difference (P > 0.05). No serious adverse effect occurred in either of the groups. CONCLUSION: CS and PIP/TAZO monotherapy are both safe and effective in the initial treatment of febrile neutropenia in children with cancer. PMID- 21674769 TI - Selection of methods for assessing sediment toxicity in California bays and estuaries. AB - Toxicity tests are often used in sediment assessment programs. However, the choice of methods has been largely limited to acute tests. Where sublethal methods have been used, there has been little consistency among programs in the types of the sublethal tests used. The goal of this study was to develop a method for choosing a suite of acute and sublethal tests for use in a California statewide assessment program, and to develop a set of method-specific thresholds for classifying the degree of toxicity within a multiple line of evidence framework consisting of sediment chemistry, benthic community structure, and sediment toxicity. A group of candidate methods was evaluated using feasibility and performance criteria. Toxicity thresholds were calculated based on test variability and sensitivity. As a result of the evaluation, 3 acute toxicity methods using amphipods (Eohaustorius estuarius, Rhepoxynius abronius, and Leptocheirus plumulosus), and 2 sublethal methods using a polychaete and mussel embryos (Neanthes arenaceodentata growth and Mytilus galloprovincialis embryo development at the sediment-water interface) were selected for recommendation. Thresholds for toxicity categories corresponding to Nontoxic, Low Toxicity, Moderate Toxicity, and High Toxicity were developed for each test method. Although these toxicity categories and thresholds provide a consistent framework for the interpretation of test results among different methods, additional research is needed to determine their effectiveness for predicting impacts to benthic communities. PMID- 21674770 TI - Trophic magnification factors: considerations of ecology, ecosystems, and study design. AB - Recent reviews by researchers from academia, industry, and government have revealed that the criteria used by the Stockholm Convention on persistent organic pollutants under the United Nations Environment Programme are not always able to identify the actual bioaccumulative capacity of some substances, by use of chemical properties such as the octanol-water partitioning coefficient. Trophic magnification factors (TMFs) were suggested as a more reliable tool for bioaccumulation assessment of chemicals that have been in commerce long enough to be quantitatively measured in environmental samples. TMFs are increasingly used to quantify biomagnification and represent the average diet-to-consumer transfer of a chemical through food webs. They differ from biomagnification factors, which apply to individual species and can be highly variable between predator-prey combinations. The TMF is calculated from the slope of a regression between the chemical concentration and trophic level of organisms in the food web. The trophic level can be determined from stable N isotope ratios (delta(15) N). In this article, we give the background for the development of TMFs, identify and discuss impacts of ecosystem and ecological variables on their values, and discuss challenges and uncertainties associated with contaminant measurements and the use of delta(15) N for trophic level estimations. Recommendations are provided for experimental design, data treatment, and statistical analyses, including advice for users on reporting and interpreting TMF data. Interspecies intrinsic ecological and organismal properties such as thermoregulation, reproductive status, migration, and age, particularly among species at higher trophic levels with high contaminant concentrations, can influence the TMF (i.e., regression slope). Following recommendations herein for study design, empirical TMFs are likely to be useful for understanding the food web biomagnification potential of chemicals, where the target is to definitively identify if chemicals biomagnify (i.e., TMF > or < 1). TMFs may be less useful in species- and site specific risk assessments, where the goal is to predict absolute contaminant concentrations in organisms in relation to threshold levels. PMID- 21674771 TI - Genetic drift. The ancient Egyptian dwarfs of the pyramids: the high official and the female worker. AB - The existence of dwarfism is amply documented in ancient Egypt due to the rich biological and artistic legacies. In previous articles published in this journal, I discussed the roles of people with skeletal dysplasia in ancient Egyptian civilization. In this article I, along with my Egyptian and American colleagues, describe two skeletons of dwarfs that date to 2700-2184 BCE and were unearthed from a funerary complex near the Great Pyramids in Giza. The first skeleton belongs to a high official, Per-ni-ankh-w, who died between 45 and 50 years of age. His statue is on display in the Egyptian Museum of Cairo. The second skeleton belongs to a pregnant female worker found with a fetus in situ. Her estimated age at death was 25-30 years. She most likely died during childbirth due to a small pelvic outlet as supported by her narrow sacrum. The fetal bones appear normal. Radiological examination of both skeletons confirmed the clinical diagnosis of achondroplasia. Ancient Egyptians concerned themselves with the search for spiritual fulfillment through the tradition of moral teachings. Amenemope, a wise man who lived during the reign of Amenhotep III (1391-1354 BCE), advocated respect toward individuals with disabilities: Do not jeer at a blind man nor tease a dwarf, Neither interfere with the condition of a cripple. Do not taunt a man who is in the hand of God, Nor scowl at him if he errs. In summary, artistic, biological, and written resources indicate that dwarfs were well integrated in ancient Egyptian society. PMID- 21674772 TI - Comparison of segmentation algorithms for fluorescence microscopy images of cells. AB - The analysis of fluorescence microscopy of cells often requires the determination of cell edges. This is typically done using segmentation techniques that separate the cell objects in an image from the surrounding background. This study compares segmentation results from nine different segmentation techniques applied to two different cell lines and five different sets of imaging conditions. Significant variability in the results of segmentation was observed that was due solely to differences in imaging conditions or applications of different algorithms. We quantified and compared the results with a novel bivariate similarity index metric that evaluates the degree of underestimating or overestimating a cell object. The results show that commonly used threshold-based segmentation techniques are less accurate than k-means clustering with multiple clusters. Segmentation accuracy varies with imaging conditions that determine the sharpness of cell edges and with geometric features of a cell. Based on this observation, we propose a method that quantifies cell edge character to provide an estimate of how accurately an algorithm will perform. The results of this study will assist the development of criteria for evaluating interlaboratory comparability. PMID- 21674773 TI - Multiple stained samples are not appropriate compensation controls. PMID- 21674774 TI - Flow cytometry immunophenotyping for the evaluation of bone marrow dysplasia. AB - The pathological hallmark of myelodysplastic syndromes (MDS) is marrow dysplasia, which represents the basis of the WHO classification of these disorders. This classification provides clinicians with a useful tool for defining the different subtypes of MDS and determining individual prognosis. The WHO proposal has raised some concern regarding minimal diagnostic criteria particularly in patients with normal karyotype without robust morphological markers of dysplasia (such as ring sideroblasts or excess of blasts). Therefore, there is clearly a need to refine the accuracy to detect marrow dysplasia. Flow cytometry (FCM) immunophenotyping has been proposed as a tool to improve the evaluation of marrow dysplasia. Rationale for the application of FCM in the diagnostic work up of MDS is that immunophenotyping is an accurate method for quantitative and qualitative evaluation of hematopoietic cells and that MDS have been found to have abnormal expression of several cellular antigens. To become clinically applicable, FCM analysis should be based on parameters with sufficient specificity and sensitivity, data should be reproducible between different operators and the results should be easily understood by clinicians. In this report, we reviewed the most relevant progresses in detection of marrow dysplasia by FCM in MDS as defined by WHO criteria. PMID- 21674775 TI - Cardamine sp. - A review on its chemical and biological profiles. PMID- 21674776 TI - Phytochemical and biological studies of Lycium medicinal plants. PMID- 21674777 TI - Chemical and biological studies of soft corals of the nephtheidae family. PMID- 21674778 TI - Reinvestigation of coenzyme Q10 isolation from Sporidiobolus johnsonii. AB - There is considerable current interest in coenzyme Q10 (CoQ10) from a medical perspective. CoQ10 has been shown to alleviate the side effects of statin drugs, for instance, and so there is a push to find naturally high producers of the compound. Sporidiobolus johnsonii (S. johnsonii) has been reported to produce CoQ10 in studies that used only standards on thin-layer chromatography (TLC) and also suggested the production of coenzyme Q9 (CoQ9). This work set out to verify CoQ9/CoQ10 production in S. johnsonii and quantify as appropriate. We show that S. johnsonii produces CoQ10 but found no evidence for CoQ9 biosynthesis. The specific production of CoQ10 was noted at 10 mg/g dry cell weight (DCW) in media supplemented with 4-hydroxybenzoic acid (HBA). This makes S. johnsonii a naturally high CoQ10 producer. New methods for extraction and purification of CoQ10 are also discussed, and identification of a closely eluting side product under normal phase isolation is reported. PMID- 21674779 TI - Rational design, synthesis, biological evaluation, homology and docking studies of coumarin derivatives as alpha1 -adrenoceptor antagonists. AB - According to a three-point pharmacophore for some uro-selective alpha(1) adrenoceptor (AR) antagonists, a novel class of coumarin (=2H-1-benzopyran-2-one) derivatives have been successfully designed and synthesized with high efficacies for alpha(1) -AR. These synthesized coumarin derivatives exhibited high efficacies towards alpha(1) -AR in in vitro pharmacological assays. Compared with prazosin (pK(i) value of 8.77), among those coumarins, tolylpiperazine substituted derivatives, 7 and 8, have comparable pK(i) values of 8.81 and 8.77, respectively. The trend in efficacies of these coumarin derivatives towards alpha(1A) -adrenoceptor was further rationalized by intensive molecular docking. Our work demonstrated that the designed coumarin derivatives can inhibit alpha(1) -AR in vitro. These findings will provide a guide for further studies of the medical therapy of benign prostatic hyperplasia (BPH). PMID- 21674780 TI - Intraspecific variation of Chiliadenus iphionoides essential oil in Israel. AB - Chiliadenus iphionoides (Asteraceae), a shrub endemic to the Mediterranean region and widespread throughout Israel, is used in the traditional eastern Mediterranean medicine. Although recent research confirmed its pharmacological potential, C. iphionoides essential oil has not been adequately characterized chemically. Essential-oil samples were collected from representative wild populations throughout Israel and characterized by GC/MS analysis. Considerable interpopulation variation was found for the composition of the essential oils. Multivariate analysis showed a significant correlation between the chemical composition and the geographic location, with three main chemotypes identified. PMID- 21674781 TI - Phylogenetic relationships of the genus Chamaecyparis inferred from leaf essential oil. AB - The species differentiation between Chamaecyparis formosensis, C. obtusa var. formosana, and C. obtusa, based on the composition of the leaf essential oils, was studied. The characterization of the oils by GC-FID and GC/MS analyses showed remarkable differences between these three essential oils. Cluster analysis (CA) and principal-component analysis (PCA) distinguished three groups of essential oils. The C. formosensis oil was dominated by alpha-pinene while those isolated from C. obtusa var. formosana and C. obtusa were characterized by high levels of (-)-thujopsene and alpha-terpinyl acetate, respectively. Moreover, the phylogenetic relationships of the genus Chamaecyparis were in agreement with previous findings based on morphological and molecular evidence. In addition, the essential oils from C. obtusa var. formosana could be classified into three chemical types, according to their different characteristic main compounds (beta elemol, (-)-thujopsene, and cis-thujopsenal). The biochemical correlations between the major constituents of the Chamaecyparis species were examined and their relationship is discussed. PMID- 21674782 TI - An entry to curcuphenol/elvirol core structures via a retro-Aldol reaction. AB - Analogs of curcuphenol/elvirol, naturally occurring bisabolane sesquiterpenes, were prepared in six steps from alkyl-alpha-tetralones employing an aromatization reaction of cyclic dienone precursors and olefination of the key aldehyde intermediates. The in vitro antifungal activities of 6a, 6b, 6d, and 6g are also reported. PMID- 21674783 TI - Isolation of novel phenolic compounds with multidrug resistance (MDR) reversal properties from Onychium japonicum. AB - We isolated seven novel compounds, namely, 3',4',6-trihydroxy-2,4-dimethoxy-3 (3",4"-dihydroxybenzyl)chalcone (1), 3',6-dihydroxy-2,4,4'-trimethoxy-3-(3",4" dihydroxybenzyl)chalcone (2), alpha,beta-dihydro-3',6-dihydroxy-2,4,6'-trimethoxy 3-(3",4"-dihydroxybenzyl)chalcone (3), 3',4,4'-trihydroxy-2,6-dimethoxychalcone (4), 4',5,7-trihydroxy-6-(3",4"-dihydroxybenzyl)flavone (5), 3-(3',4' dihydroxybenzyl)-6,7-dihydroxycoumarin (6), 3-(3',4'-dihydroxyphenyl)-3,4 dihydroisocoumarin (7), as well as a known compound, 3',4',7-trihydroxy-5 methoxyflavanone (8) from the whole grass of Onychium japonicum, and elucidated their structures by spectroscopic methods. Compounds 1-3 exhibited significant multidrug resistance (MDR) reversal effects on MCF-7/ADR and Bel-7402/5-Fu cell lines. PMID- 21674784 TI - Chemical composition and antioxidant activities of different polysaccharides from the roots of Angelica dahurica. AB - The total crude polysaccharides (CADPs), isolated from the roots of Angelica dahurica by H(2) O extraction, EtOH precipitation, and dialysis, and the four fractions ADP1, ADP2, ADP3, and ADP4, obtained by gel filtration of the CADPs, were analyzed to characterize their composition and evaluated for their antioxidant activity using different in vitro tests such as the malondialdehyde (MDA)-production, the ferrous ion (Fe(2+) )-chelating, and the HO(.) radical scavenging assays. The predominant neutral monosaccharides in the four fractions were identified as arabinose, galactose, and glucose, while the composition and ratio of the monosaccharides were different between the fractions. The CADPs and its fractions were found to significantly inhibit lipid peroxidation, chelate Fe(2+) , and scavenge HO(.) radicals, indicating that these polysaccharides possessed antioxidant activity. Among the four fractions, ADP4 exhibited the strongest antioxidant activity, which was stronger than that of the control antioxidant vitamin E (Vit E). Taken together, the chemical composition of these polysaccharides might affect their antioxidant activity, and ADP4 could be explored as a source of potential novel natural antioxidants for food and pharmaceutical purposes. PMID- 21674785 TI - Components of essential oils extracted from leaves and shoots of abies species in Japan. AB - The essential oils extracted from the leaves and the shoots of five Abies species (Pinaceae) growing in Japan, i.e., A. firma, A. homolepis, A. veitchii, A. mariesii, and A. sachalinensis, were characterized by GC-FID and GC/MS analyses. The yields of the essential oils extracted from A. sachalinensis were the highest among them. A significant amount of alpha-pinene was contained in the essential oils of all the Abies species examined. In A. homolepis and A. veitchii, significant differences in the content of the essential oils were found depending on whether these were extracted from the leaves or from the shoots. Regarding the enantiomeric ratio of alpha-pinene, the (+)-enantiomer was predominant in the oil extracted from the leaves of A. firma, while (-)-alpha-pinene was present in higher amounts in the oils of A. veitchii (leaves and shoots), A. mariesii (leaves and shoots), and A. sachalinensis (shoots). The fact that there may be a quantitative and qualitative difference in the components of the essential oils extracted from the different parts of a plant was investigated by cluster analysis. PMID- 21674786 TI - Evaluation of the antimicrobial potential of two flavonoids isolated from limnophila plants. AB - The antimicrobial potential of two bioflavonoids, i.e., 5,7-dihydroxy-4',6,8 trimethoxyflavone (1) and 5,6-dihydroxy-4',7,8-trimethoxyflavone (2), isolated from Limnophila heterophylla Benth. and L. indica (Linn.) Druce (Scrophulariaceae), respectively, were evaluated against the microbial strains Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Alternaria solani, and Candida albicans. Compounds 1 and 2 exhibited moderate but broad antimicrobial activities against both Gram-positive and Gram negative bacteria and also against the fungal pathogens. Moreover, the mechanism of action of 1 and 2 on the cellular functions or structures of some of the microorganisms was studied. Compound 1 showed a bactericidal effect against E. coli and S. aureus (MICs of 200 and 250 MUg/ml, resp.), while compound 2 was found to effectively kill B. subtilis by cell lysis. The growth of A. solani and C. albicans was inhibited by compounds 1 and 2, respectively. The effects of the flavonoids on the cellular structures and the carbohydrate metabolic pathways were studied by scanning electron microscopy (SEM) of the treated cells and by assessing the specific activity of key enzymes of the pathways, respectively. At sublethal doses, they enhanced the activity of gluconeogenic fructose bisphosphatase, but decreased the activity of phosphofructokinase and isocitrate dehydrogenase, the key enzymes of the Embden?Meyerhof?Parnas pathway and the tricarboxylic acid cycle, respectively. PMID- 21674787 TI - In vitro cytotoxic activity of extracts and isolated constituents of Salvia leriifolia Benth. against a panel of human cancer cell lines. AB - In the course of recent efforts to identify new potential antiproliferative active principles, Salvia leriifolia extracts and isolated constituents were evaluated for their cytotoxic activity against a panel of human cancer cell lines, including renal adenocarcinoma (ACHN), amelanotic melanoma (C32), colorectal adenocarcinoma (Caco-2), lung large cell carcinoma (COR-L23), malignant melanoma (A375), lung carcinoma (A549), and hepatocellular carcinoma (Huh-7D12) cells. The hexane and CH(2) Cl(2) extracts showed the strongest cytotoxic activity against the C32 cell line with IC(50) values of 11.2 and 13.6 MUg/ml, respectively, and the AcOEt extract was the most active extract against the COR-L23 cell line (IC(50) of 20.9 MUg/ml). Buchariol, a sesquiterpene obtained by biofractionation of the CH(2) Cl(2) extract, exhibited a higher activity than the positive control vinblastine against the C32 and A549 cell lines (IC(50) values of 2.1 and 12.6 MUM, resp.). Interesting results were also obtained for naringenin, a flavonoid isolated from the AcOEt extract, which exhibited a strong cytotoxic activity against the C32, LNCaP, and COR-L23 cell lines (IC(50) values of 2.2, 7.7, and 33.4 MUM, resp.), compared to vinblastine (IC(50) values of 3.3, 32.2, 50.0 MUM, resp.). None of the tested compounds affected the proliferation of skin fibroblasts (142BR), suggesting a selective activity against tumor cells. PMID- 21674788 TI - A new neolignan and a new sesterterpenoid from the stems of Picrasma quassioides Bennet. AB - A new dihydrobenzofuran-type neolignan, picrasmalignan A (1), and a new sesterterpene lactone, 2'-isopicrasin A (4), were isolated from the stems of Picrasma quassioides Bennet, along with four known compounds, comprising two neolignans, 2 and 3, a sesterterpene lactone, 5, and a flavonol, 6. The structures of these compounds were determined by detailed analysis of NMR and MS data, and comparison with the literature data. Compounds 1-6 were tested for their anti-inflammatory activity, and 1-3 and 6 showed potent inhibitory activities on nitric oxide, tumor necrosis factor-alpha, and interleukin-6 production in mouse monocyte-macrophage RAW 264.7 stimulated by lipopolysaccharide (LPS). PMID- 21674789 TI - Phytochemical analysis and antimicrobial activity of Cardaria draba (L.) Desv. volatiles. AB - Two different volatile isolates from the aerial parts of Cardaria draba (L.) Desv., obtained either by hydrodistillation (Extract I) or by CH(2) Cl(2) extraction subsequent to hydrolysis by exogenous myrosinase (Extract II), were characterized by GC-FID and GC/MS analyses. The main volatiles obtained by hydrodistillation, i.e., 4-(methylsulfanyl)butyl isothiocyanate (1; 28.0%) and 5 (methylsulfanyl)pentanenitrile (2; 13.8%), originated from the degradation of glucoerucin. In Extract I, also volatiles without sulfur and/or nitrogen were identified. These were mostly hexadecanoic acid (10.8%), phytol (10.2%), dibutyl phthalate (4.5%), and some other compounds in smaller percentages. Extract II contained mostly glucosinolate degradation products. They originated from glucoraphanin, viz., 4-(methylsulfinyl)butyl isothiocyanate (3; 69.2%) and 5 (methylsulfinyl)pentanenitrile (4; 4.5%), glucosinalbin, viz., 2-(4 hydroxyphenyl)acetonitrile (5; 7.2%), and glucoerysolin, viz., 4 (methylsulfonyl)butyl isothiocyanate (6; 5.0%). Moreover, the volatile samples were evaluated for their antimicrobial activity using the disc-diffusion method and determining minimum inhibitory concentrations (MIC). All volatile isolates expressed a wide range of growth inhibition activity against both Gram-positive and Gram-negative bacteria and fungi. The MIC values varied between 4 and 128 MUg/ml. PMID- 21674790 TI - Lyonin A, a new 9,10-Secograyanotoxin from Lyonia ovalifolia. AB - Phytochemical studies on the branches and leaves of Lyonia ovalifolia yielded a new grayanane diterpenoid, lyonin A (1), together with two known compounds, secorhodomollolides A and D (2 and 3, resp.). The structure of 1 was elucidated by combination of 1D- and 2D-NMR, and MS analyses. Compound 1 turned out to be a new, highly O-acylated grayanane diterpenoid, of which ring B has undergone an oxidative cleavage between C(9) and C(10), yielding a system differing from the previously reported grayanane type with a 5/7/6/5 ring system. Results of the cAMP regulation activity assay showed that compounds 2 and 3 at 50 MUM induced a significantly decreased cAMP level in N1E-115 neuroblastoma cells (p<0.001), indicating neuropharmacological potential. PMID- 21674791 TI - Fast and selective extraction of chloramphenicol from soil by matrix solid-phase dispersion using molecularly imprinted polymer as dispersant. AB - The molecularly imprinted polymer (MIP) was synthesized and used as dispersant of matrix solid-phase dispersion (MSPD) for the extraction of chloramphenicol (CAP) in soil samples. The satisfactory recovery of CAP was obtained by the optimized extraction conditions: 1:2 as the ratio of sample to MIPs; 5 min as the dispersion time; 30% aqueous methanol as washing solvent and methanol as elution solvent. The CAP extracted from soil was determined by LC-MS/MS. The slight ion suppression phenomenon was observed for the CAP when the sample was cleaned up by MSPD with MIP as dispersant, when compared with C18 as MSPD dispersant, which caused significant ion suppression. LOD of CAP is 4.1 ng/g. RSDs of intra- and inter-day tests ranging from 3.1 to 6.2% and from 3.9 to 8.3% are obtained. At all three fortified levels (20, 100 and 500 ng/g), recoveries of CAP are in the range of 86.9-92.6%. The effect of ageing time of spiked soil sample on the CAP recovery was examined. The CAP recovery decreased from 91.0 to 36.9% when the ageing time changed from 1 day to 4 wk. PMID- 21674792 TI - Preparation of molecularly imprinted polymer by surface imprinting technique and its performance for adsorption of dibenzothiophene. AB - The novel surface imprinted polymer composites (MIP/K(2)Ti(4)O(9)) were prepared using dibenzothiophene (DBT) as the template, 4-vinylpyridine as the functional monomer and potassium tetratitanate whisker (K(2)Ti(4)O(9)) as the carrier. The synthetic product was characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. Parameters influencing DBT adsorption such as contact time, temperature and DBT initial concentration were investigated. The adsorption kinetics were evaluated with the pseudo-first-order and pseudo-second order models, and the adsorption isotherms were fitted by Langmuir and Freundlich models. Selectivity experiments showed that MIP/K(2)Ti(4)O(9) exhibited excellent recognition capacity and binding affinity to DBT compared with the comparative substrates. MIP/K(2)Ti(4)O(9) could also be easily regenerated and reused ten times with only about 20% loss of adsorption capacity. PMID- 21674793 TI - Retention properties of macroporous spongy monolith and its application for concentration of polyaromatic hydrocarbons. AB - We report the fundamental chromatographic retention properties of spongy monolith that was previously reported as a novel separation medium for the effective pretreatment of environmental pollutants. According to the detailed examination on liquid chromatographic evaluations using hydrophobic, hydrophilic, and polyaromatic compounds as solutes, the spongy monolith consisted of poly(ethylene co-vinyl acetate) and having macroporous co-continuous structures showed the selective retention ability for polyaromatic hydrocarbons (PAHs), especially coplanar compounds, whereas lower selectivity was observed for typical hydrophobic and hydrophilic compounds compared with the commonly used C18 medium. Moreover, we demonstrate the effective preconcentration of benzo[a]pyrene using a spongy monolith as a pretreatment column of an online column switching HPLC system. PMID- 21674794 TI - Capillary columns for reversed-phase CEC prepared via surface functionalization of polymer monolith with aromatic selectors. AB - Macroporous crosslinked organic polymers based on N-acryloxysuccinimide (NAS) and ethylene dimethacrylate (EDMA) were prepared in the confines of 75 MUm id fused silica capillaries by photoinitiated free radical copolymerization in the presence of 2-2'-azobisisobutyronitrile as initiator and toluene as porogen. Monoliths with good mechanical strength, large porosity as well as surface reactive sites (succinimide leaving groups) could be obtained. Nucleophilic aromatic derivatives, namely benzylamine, phenylbutylamine and naphthylamine were grafted on the monolith surface to introduce pi-conjugated ligands to develop particular selectivity. Successful achievement of the post-copolymerization functionalization was ascertained on the basis of in situ chemical characterization by means of Raman spectroscopy. Electrochromatographic properties of pi-functionalized poly(NAS-co-EDMA) regarding alkylbenzenes, polycyclic aromatic hydrocarbons, anilines and phenols were evaluated in terms of retention, selectivity and resolution. The as-designed monolithic columns exhibited pi-pi interaction in addition to hydrophobic interaction due to the aromatic and non-polar nature of the surface-grafted aromatic selectors. One of the major results of this study is that monolithic columns with mixed selectivity providing high potentiality for the separation of solutes with varied chemical structure variation can be obtained by the surface grafting of the appropriate selector. Herein, an example is given for the phenylbutylamine functionalized poly(NAS-co-EDMA) where the butyl and phenyl fragments afford enhanced hydrophobic and pi-selectivity, respectively. PMID- 21674795 TI - Brush-like copolymer as a physically adsorbed coating for protein separation by capillary electrophoresis. AB - A brush-like copolymer consisting of poly(ethylene glycol) methyl ether methacrylate and N,N-dimethylacrylamide (PEGMA-DMA) was synthesized and used as a novel static physically adsorbed coating for protein separation by capillary electrophoresis for the first time, in order to stabilize electroosmotic flow (EOF) and suppress adsorption of proteins onto the capillary wall. Very stable and low EOF was obtained in PEGMA-DMA-coated capillary at pH 2.2-7.8. The effects of molar ratio of PEGMA to DMA, copolymer molecular mass, and pH on the separation of basic proteins were discussed. A comparative study of bare capillary with PEGMA-DMA-coated capillary for protein separation was also performed. The basic proteins could be well separated in PEGMA-DMA-coated capillary over the investigated pH range of 2.8-6.8 with good repeatability and high separation efficiency because the copolymer coating combines good protein resistant property of PEG side chains with excellent coating ability of PDMA contained backbone. Finally, the coating was successfully applied to the fast separation of other protein samples, such as protein mixture and egg white, which reveals that it is a potential coating for further proteomics analysis. PMID- 21674796 TI - Novel extraction approach for liquid samples: stir cake sorptive extraction using monolith. AB - In this study, a new extraction approach for liquid samples--stir cake sorptive extraction using monoliths as extractive medium was developed. The preparation procedure of stir cake is very simple. First, monolithic cake is synthesized according to the in situ polymerization of monolith; then, the cake is inserted in an original unit (holder), which is constructed from a syringe cartridge and allows the magnetic stirring of the cake during the extraction process. The effects of dimension of monolithic cake and unit design on the extraction performance were optimized in detail. To demonstrate the usability of this new extraction approach, poly(vinylimidazole-divinylbenzene) was prepared and acted as the extractive cake. The analysis of steroid hormones in milk samples by the combination of stir cake with high-performance liquid chromatography with diode array detection, was selected as a paradigm for the practical evaluation of stir cake sorptive extraction. Under the optimized extraction conditions, low detection limits (S/N=3) and quantification limits (S/N=10) of the proposed method for the target analytes were achieved within the range between 0.33-0.69 and 1.08-2.28 MUg/L, respectively. The method also showed good linearity, repeatability, high feasibility and acceptable recoveries. Because the monolithic cake does not contact with the vessel wall during stirring, there is no friction loss of extractive medium and the stir cake can be used for more than 1000 h. PMID- 21674797 TI - The peroxide stress response of Bacillus licheniformis. AB - The oxidative stress response of Bacillus licheniformis after treatment with hydrogen peroxide was investigated at the transcriptome, proteome and metabolome levels. In this comprehensive study, 84 proteins and 467 transcripts were found to be up or downregulated in response to the stressor. Among the upregulated genes were many that are known to have important functions in the oxidative stress response of other organisms, such as catalase, alkylhydroperoxide reductase or the thioredoxin system. Many of these genes could be grouped into putative regulons by genomic mining. The occurrence of oxidative damage to proteins was analyzed by a 2-DE-based approach. In addition, we report the induction of genes with hitherto unknown functions, which may be important for the specific oxidative stress response of B. licheniformis. The genes BLi04114 and BLi04115, that are located adjacent to the catalase gene, were massively induced during peroxide stress. Furthermore, the genes BLi04207 and BLi04208, which encode proteins homologous to glyoxylate cycle enzymes, were also induced by peroxide. Metabolomic analyses support the induction of the glyoxylate cycle during oxidative stress in B. licheniformis. PMID- 21674798 TI - Differential expression of intermediate filaments in the process of developing hepatic steatosis. AB - Obesity causes changes in fatty acid metabolism that consequently leads to fatty liver. To identify the possible proteins involved in the processes of obesity, we performed a proteomic analysis of obesity-induced mouse liver. Male C57BL/6J mice that were fed a high-fat diet (HFD) for 24 wk, developed hepatic steatosis characterized by considerable increase in free fatty acid (FFA) and triglyceride levels. Body weights were measured weekly and other measurements at weeks 2, 6, 12, 16, and 24. 2-D-based proteomic analysis revealed that, compared with the normal diet (ND) (n=50), high-fat diet (n=50) changed the expression of 12 protein (8 up and 4 downregulated, by a 1.5* fold change and more, p<0.05). The most pronounced difference was observed in intermediate microfilament (IF) cytoskeleton proteins. In particular, vimentin (vim) as well as cytokeratins (CK 8 and CK-18) were significantly upregulated in obese animals. Moreover, the level of caspase-generated IF fragment was also positively correlated with the degree of steatosis. The results suggest a significant alteration in IF organization during the development of hepatic steatosis leading to inflammation. The expression profile of selected proteins including vim was validated by Western blot, microarray analysis, and hepatocyte morphology by immunohistochemistry. Our results suggest that vim, like CK-18, may be a useful marker for predicting obesity and liver disease. PMID- 21674799 TI - ErbB2-associated changes in the lysosomal proteome. AB - Late endosomes and lysosomes (hereafter referred to as lysosomes) play an essential role in the turnover of cellular macromolecules and organelles. Their biochemical characterization has so far depended on purification methods based on either density gradient centrifugations or magnetic purification of iron-loaded organelles. Owing to dramatic changes in lysosomal density and stability associated with lysosomal diseases and cancer, these methods are not optimal for the comparison of normal and pathological lysosomes. Here, we introduce an efficient method for the purification of intact lysosomes by magnetic immunoprecipitation with antibodies against the vacuolar-type H(+) -ATPase. Quantitative MS-based proteomics analysis of the obtained lysosomal membranes identified 60 proteins, most of which have previously been associated with the lysosomal compartment. Interestingly, the lysosomal membrane proteome was significantly altered by the ectopic expression of an active form of the ErbB2 oncogene, which renders the cells highly metastatic. The furthermost ErbB2 associated changes included increased levels of CD63, S100A11 and ferritin heavy chain. Overall, our data introduce the antibody-based purification of lysosomes as a suitable method for the characterization of lysosomes from a variety of pathological conditions with altered lysosomal density and stability. PMID- 21674800 TI - Proteomics of corynebacteria: From biotechnology workhorses to pathogens. AB - Corynebacteria belong to the high G+C Gram-positive bacteria (Actinobacteria) and are closely related to Mycobacterium and Nocardia species. The best investigated member of this group of almost seventy species is Corynebacterium glutamicum, a soil bacterium isolated in 1957, which is used for the industrial production of more than two million tons of amino acids per year. This review focuses on the technical advances made in proteomics approaches during the last years and summarizes applications of these techniques with respect to C. glutamicum metabolic pathways and stress response. Additionally, selected proteome applications for other biotechnologically important or pathogenic corynebacteria are described. PMID- 21674801 TI - The progress made in determining the Mycobacterium tuberculosis structural proteome. AB - Mycobacterium tuberculosis is a highly infectious pathogen that is still responsible for millions of deaths annually. Effectively treating this disease typically requires a course of antibiotics, most of which were developed decades ago. These drugs are, however, not effective against persistent tubercle bacilli and the emergence of drug-resistant stains threatens to make many of them obsolete. The identification of new drug targets, allowing the development of new potential drugs, is therefore imperative. Both proteomics and structural biology have important roles to play in this process, the former as a means of identifying promising drug targets and the latter allowing understanding of protein function and protein-drug interactions at atomic resolution. The determination of M. tuberculosis protein structures has been a goal of the scientific community for the last decade, who have aimed to supply a large amount of structural data that can be used in structure-based approaches for drug discovery and design. Only since the genome sequence of M. tuberculosis has been available has the determination of large numbers of tuberculosis protein structures been possible. Currently, the molecular structures of 8.5% of all the pathogen's protein-encoding ORFs have been determined. In this review, we look at the progress made in determining the M. tuberculosis structural proteome and the impact this has had on the development of potential new drugs, as well as the discovery of the function of crucial mycobaterial proteins. PMID- 21674802 TI - Proteomics of the oxidative stress response induced by hydrogen peroxide and paraquat reveals a novel AhpC-like protein in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a ubiquitous pathogen most typically associated with wound infections, but also the main cause of mortality in patients suffering from cystic fibrosis (CF). The ability to adapt to oxidative stress associated with host immune defense may be one mechanism by which P. aeruginosa establishes infection in the cystic fibrosis lung and eventually out-competes other pathogenic bacteria to persist into chronic infection. We utilized a proteomics approach to identify the proteins associated with the oxidative stress response of P. aeruginosa PAO1 to hydrogen peroxide and superoxide-inducing paraquat. 2-DE and MS allowed for the identification of 59 and 58 protein spots that were statistically significantly altered following H(2) O(2) and paraquat treatment, respectively. We observed a unique mass and pI pattern for alkylhydroperoxide reductase C (AhpC) that was replicated by hypothetical protein PA3529 following treatment with 10 mM H(2) O(2) . AhpC belongs to the 2-Cys peroxiredoxin family and is a redox enzyme responsible for removing peroxides in bacterial cells. MS analysis showed that PA3529 was altered by the formation of a dimer via a disulfide bond in a manner analogous to that known for AhpC, and by cysteine overoxidation to Cys-sulfonic acid (SO(3) H) postoxidative stress. PA3529 is therefore a functional AhpC paralog expressed under H(2) O(2) stress. Following paraquat-induced oxidative stress, we also observed the overabundance and likely oxidative modification of a second hypothetical antioxidant protein (PA3450) that shares sequence similarity with 1-Cys peroxiredoxins. Other induced proteins included known oxidative stress proteins (superoxide dismutase and catalase), as well as those involved in iron acquisition (siderophore biosynthesis and receptor proteins FpvA and FptA) and hypothetical proteins, including others predicted to be antioxidants (PA0848). These data suggest that P. aeruginosa contains a plethora of novel antioxidant proteins that contribute to its increased resistance against oxidative stress. PMID- 21674803 TI - Protein acetylation in prokaryotes. AB - Protein acetylation plays a critical regulatory role in eukaryotes but until recently its significance and function in bacteria and the archaea were obscure. It is now clear, however, that prokaryotes have the capacity to acetylate both the alpha-amino groups of N-terminal residues and the epsilon-amino groups of lysine side chains. In this review, we bring together information indicating that such acetylation is widespread and that it is likely to regulate fundamental cellular processes. We particularly focus on lysine acetylation, which recent studies show can occur in proteins involved in transcription, translation, pathways associated with central metabolism and stress responses. Intriguingly, specific acetylated lysine residues map to critical regions in the three dimensional structures of key proteins, e.g. to active sites or to surfaces that dock with other major cellular components. Like phosphorylation, acetylation appears to be an ancient reversible modification that can be present at multiple sites in proteins, thereby potentially producing epigenetic combinatorial complexity. It may be particularly important in regulating central metabolism in prokaryotes due to the requirement for acetyl-CoA and NAD(+) for protein acetyltransferases and Sir2-type deacetylases, respectively. PMID- 21674804 TI - Surface shaving as a versatile tool to profile global interactions between human serum proteins and the Staphylococcus aureus cell surface. AB - The human commensal bacterium Staphylococcus aureus is renowned as a causative agent of severe invasive diseases. Upon entering the bloodstream, S. aureus can infect almost every tissue and organ system in the human body. To withstand insults from the immune system upon invasion, several immune-evasive mechanisms have evolved in S. aureus, such as complement inhibition by secreted proteins and IgG-binding by surface-exposed protein A. While it is generally accepted that S. aureus cells bind a range of host factors for various purposes, no global analyses to profile staphylococcal host factor binding have so far been performed. Therefore, we explored the possibility to profile the binding of human serum proteins to S. aureus cells by "surface shaving" with trypsin and subsequent MS analysis of liberated peptides. This resulted in the identification of several components of the complement system, the platelet factor 4 and the isoform 1 of the inter-alpha-trypsin inhibitor heavy chain H4 on the staphylococcal cell surface. We conclude that surface shaving is a versatile tool to profile global interactions between human serum proteins and the S. aureus cell surface. PMID- 21674805 TI - Layer-by-layer assembled multilayer films of methoxypoly(ethylene glycol)-block poly(alpha,l-glutamic acid) and chitosan with reduced cell adhesion. AB - A methoxypoly(ethylene glycol)-block-poly(alpha,L-glutamic acid) (mPEGGA) diblock copolymer is synthesized. Using QCM measurements, it is shown that (CS/mPEGGA)(n) film construction takes place over two build-up stages (exponential-to-linear). UV-vis spectra reveal the regular increase of the multilayer film growth at different molecular weights of mPEGGA. Contact angle and surface morphology investigation prove that the hydrophilicity of CS/mPEGGA multilayer film-modified substrate becomes better and the surface becomes rough. Significantly reduced cell adhesion is observed on the CS/mPEGGA multilayer film coated surface. PMID- 21674806 TI - Oxazoline-based antimicrobial oligomers: synthesis by CROP using supercritical CO2. AB - A method using supercritical CO(2) to obtain biocompatible 2-oxazoline-based oligomers quaternized with different amines is described. The synthesized oligo(2 oxazoline)s display partial carbamic-acid insertion at one end. The syntheses of quaternary oligo(2-bisoxazoline)s and linear oligoethylenimine hydrochlorides are reported. Oligo(2-methyl-2-oxazoline) and oligo(2-bisoxazoline) quaternized with N,N-dimethyldodecylamine are the most efficient biocidal agents showing fast killing rates against Staphylococcus aureus and Escherichia coli. Linear oligoethylenimine hydrochloride shows the lowest MIC values but higher killing times against both bacteria. Based on the antimicrobial activity studies, a cooperative action of carbamic acid with the ammonium end group is proposed. PMID- 21674807 TI - Scientists contemplate unexplained death in Austrian Alps. AB - The recent EMBO Molecular Medicine Workshop on Cell Death and Disease was held this past March in the picturesque Alpen ski-town of Obergurgl, Austria. Scientists working on diverse mechanisms and pathways of cell death convened to present and discuss their current research. Topics included not only cell death signalling pathways, their etiology in human disease, and potential avenues for therapeutic intervention, but also new approaches and perspectives for understanding the subtle mechanisms regulating cell fate. PMID- 21674809 TI - Polyphosphates and pyrophosphates of pentopyranoses and pentofuranoses as allosteric effectors of human hemoglobin: synthesis, molecular recognition, and oxygen release. AB - Perphosphorylated pentopyranoses and pentofuranoses were synthesized from parent carbohydrates as potential allosteric effectors of hemoglobin (Hb). The construction of seven- and eight-membered cyclic pyrophosphates was also carried out successfully on most of the pentoses. All final compounds were tested for their efficiency on oxygen release from human Hb. Most proved to be efficient allosteric effectors, some of them with an affinity toward Hb and an effect on oxygen release from Hb approaching that of myo-inositol hexakisphosphate, which is one of the most active allosteric effectors of Hb. The efficacy was higher for free phosphates than for pyrophosphates. PMID- 21674808 TI - Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice. AB - Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin ('mini agrin') or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients. PMID- 21674810 TI - Small molecule binding to proteins: affinity and binding/unbinding dynamics from atomistic simulations. PMID- 21674811 TI - An unmet medical need: advances in endoscopic imaging of colorectal neoplasia. AB - Gastrointestinal cancer is a major public health problem worldwide. Detection of early neoplastic lesions in gastrointestinal tract is essential for cure, because prognosis and survival are related to the size and stage of malignant lesions. Endoscopic screening and treatment of polyps could prevent approximately 80% of colorectal cancer (CRC). However, white-light endoscopy is an imperfect technology since miss rates of up to 25% have been reported and polyps without malignant potential were treated without benefit but with additional costs and risks to the patient. There are several known "human" predictors of an inadequate colonoscopy. These include patient characteristics such as poor bowel preparation, female gender, or inpatient status. Skills of the endoscopists are also an important issue. Therefore, a variety of advanced technologies has been attempted to overcome these issues. These new endoscopic imaging techniques allow a more precise classification of mucosal alterations with selection of patients for invasive therapy or surveillance. Further, molecular and functional imaging techniques could identify novel targets for therapies and new prospects to access response to therapies. However, at the "end of the day" a better endoscopic approach for CRC screening and surveillance depends on a good bowel preparation, a trained endoscopist spending sufficient time on a detailed examination together with an advanced endoscope. PMID- 21674812 TI - Binocular maps in Xenopus tectum: Visual experience and the development of isthmotectal topography. AB - Xenopus frogs have a prominent binocular field that develops as a consequence of the migration of the eyes during the remodeling of the head during and after metamorphosis. In the optic tectum, a topographic representation of the ipsilateral eye develops during this same period. It is relayed indirectly, via the nucleus isthmi. In the early stages of binocular development, the topographic matching of the ipsilateral input to the retinotectal input from the contralateral eye is largely governed by chemical cues, but the ultimate determinant of the ipsilateral map is binocular visual input. Visual input is such a dominant factor that abnormal visual input resulting from unilateral eye rotation can induce isthmotectal axons to alter their trajectories dramatically, even shifting their terminal zones from one pole of the tectum to the other. This plasticity normally is high only during a 3-4-month critical period of late tadpole-early juvenile life, but the critical period can be extended indefinitely by dark-rearing. N-methyl-D-aspartate (NMDA) receptors are involved in this process; plasticity can be blocked or promoted by chronic treatment with NMDA antagonists or agonists, respectively. Cholinergic nicotinic receptors on retinotectal axons are likely to play an essential role as well. Modifications in the polysialylation of neural cell adhesion molecule are correlated with the state of plasticity. The circuitry underlying binocular plasticity is not yet fully understood but has proved not to be a simple convergence of ipsilateral and contralateral inputs onto the same targets. PMID- 21674814 TI - Bronchoalveolar lavage improves diagnostic accuracy in patients with diffuse lung disease. AB - Bronchoalveolar lavage (BAL) is an established diagnostic tool in diffuse parenchyma lung disease. The objective of the present study was designed to investigate whether immunophenotyping affects BAL results and improves diagnostic accuracy. BAL from 61 patients was included in the study. The patients were also submitted to transbronchial biopsy, with a final diagnosis of granulomatous disease [tuberculosis (TB), n = 20; sarcoidosis (SARC), n = 3; and hypersensitivity pneumonitis (HP), n = 4]; idiopathic interstitial pneumonias (IIPs) [idiopathic pulmonary fibrosis (IPF), n = 9; organizing pneumonia (OP), n = 17]; and lung cancer (LC), n = 8. Immunohistochemistry and histomorphometry were used to identify and quantify type 1 and type 2 alveolar epithelial cells, macrophages, CD3+T-cells, CD4+T-cells, CD8+T-cells, and CD20+B-cells in BAL. These markers were correlated with a database and pulmonary function tests. The cellular, inflammatory, and immune components of BAL varied among the diagnostic groups and were negatively correlated with age and smoking history. An increased quantity of lymphocyte surface markers CD3 (P < 0.05) and CD20 (P = 0.01) was seen in IIPs. Patients with a pattern of OP had a higher proportion of type 2 alveolar epithelial cells; patients with SARC had a higher density of CD20+B cells and CD4+T-helper cells; and patients with HP had a higher proportion of CD8+T-cytotoxic cells. A positive association was found between the density of type I alveolar epithelial cells and forced vital capacity. The immunophenotyping affects the cellular, inflammatory, or immune constituents of BAL and improved the diagnostic accuracy in diffuse parenchymal lung disease. PMID- 21674815 TI - Capsular perstraction as a novel methodology for the recovery and purification of geldanamycin. AB - The molecular complex "Heat shock protein 90" has become a novel target for anticancer drugs in recent times on account of its ability to perform as a chaperone toward proteins involved in cancer progression. The geldanamycin binds to this complex with high affinity and prevents it from performing correctly, which results in tumor destruction. The aim of this study was to investigate the feasibility of applying liquid-core microcapsules as a novel technique (termed "capsular perstraction"), for the recovery and purification of geldanamycin from culture media. Results demonstrated how this procedure was capable of rapidly extracting >70% of geldanamycin from culture media using a liquid-core volume to medium ratio of only 1%. Optimum conditions for removal, including agitation speed, microcapsule size, and membrane thickness were examined, and it was shown how the stagnant aqueous film around the microcapsules was the main resistance to mass transfer. A volumetric mass transfer coefficient of 5.66*10(-6) m/s was obtained for the highest agitation speed (400 rpm), which was considerable greater compared to the value of 0.88*10(-6) m/s achieved for the lowest speed of 100 rpm. Removal of geldanamycin from microcapsules was also examined to fully investigate the potential of such particles for in situ product recovery, and it was demonstrated how the methodology can be used as a simple mechanism for purifying the compound (>99%) through solvent extraction and crystallization. The results of this work demonstrate the novel use of capsular perstraction as a methodology for the recovery and purification of geldanamycin from culture environments. PMID- 21674816 TI - Screening 64 cultivars Catharanthus roseus for the production of vindoline, catharanthine, and serpentine. AB - The leaves of Catharanthus roseus (L.) G. Don. are a valuable source of the terpenoid indole alkaloid (TIA) anticancer drugs, vinblastine and vincristine. In particular, the precursor molecules vindoline and catharanthine are harvested from leaves and used for the semisynthetic production of vinblastine and vincristine. Because of this application, catharanthine and vindoline can be used to screen for high-yielding TIA cultivars. In this study, we compared the TIA concentrations in the leaves of 64 different cultivars of C. roseus in the soil experiments. The highest concentration of serpentine was found in Cooler Rose Hot (461+/-46 MUg/g DW). Concentrations of vindoline (2082+/-113 MUg/g DW) and catharanthine (2903+/-384 MUg/g DW) were highest in Pacifica Peach. To eliminate the abiotic and biotic effects of the soils on the plant growth, sterile agar experiments were performed to investigate the TIA concentrations and mRNA transcript levels of selected TIA pathway genes. Six cultivars were investigated (two each of the high level, mid level, and low level producers of TIAs). PMID- 21674817 TI - Design of a stirred multiwell bioreactor for expansion of CD34+ umbilical cord blood cells in hypoxic conditions. AB - Besides having a metabolic role, oxygen is recognized as an important signaling stimulus for stem cells. In hematopoiesis, hypoxia seems to favor stem cell self renewal. In fact, long-term repopulating hematopoietic stem cells reside in bone marrow at concentrations as low as 1% oxygen. However, O2 concentration is difficult to control in vitro. Thermodynamically, we found significant differences between O2 solubility in different media, and in presence of serum. Furthermore, we verified that medium equilibration with a hypoxic atmosphere requires several hours. Thus, in a static culture, the effective O2 concentration in the cell immediate microenvironment is difficult to control and subject to concentration gradients. Stirred systems improve homogeneity within the culture volume. In this work, we developed a stirred bioreactor to investigate hypoxia effect on the expression of stem cell markers in CD34+ cells from umbilical cord blood. The stirring system was designed on top of a standard six-well plate to favor continuity with conventional static conditions and transfer of culture protocols. The bioreactor volume (10 mL/well) is suitable for cell expansion and multiparametric flow cytometry analyses. First, it was tested at 21% O2 for biocompatibility and other possible effects on the cells compared to static conditions. Then, it was used to study c-kit expression of CD34+ cells at 5% O2, using 21%-O2 cultures as a control. In hypoxia we found that CD34+ cells maintained a higher expression of c-kit. Further investigation is needed to explore the dynamics of interaction between oxygen- and c-kit-dependent pathways at the molecular level. PMID- 21674813 TI - Multiple transcription factor families regulate axon growth and regeneration. AB - Understanding axon regenerative failure remains a major goal in neuroscience, and reversing this failure remains a major goal for clinical neurology. Although an inhibitory central nervous system environment clearly plays a role, focus on molecular pathways within neurons has begun to yield fruitful insights. Initial steps forward investigated the receptors and signaling pathways immediately downstream of environmental cues, but recent work has also shed light on transcriptional control mechanisms that regulate intrinsic axon growth ability, presumably through whole cassettes of gene target regulation. Here we will discuss transcription factors that regulate neurite growth in vitro and in vivo, including p53, SnoN, E47, cAMP-responsive element binding protein (CREB), signal transducer and activator of transcription 3 (STAT3), nuclear factor of activated T cell (NFAT), c-Jun activating transcription factor 3 (ATF3), sex determining region Ybox containing gene 11 (Sox11), nuclear factor kappa-light chain enhancer of activated B cells (NFkappaB), and Kruppel-like factors (KLFs). Revealing the similarities and differences among the functions of these transcription factors may further our understanding of the mechanisms of transcriptional regulation in axon growth and regeneration. PMID- 21674818 TI - Synthesis and characterization of gold glyconanoparticles functionalized with sugars of sweet Sorghum syrup. AB - Gold glyconanoparticles were synthesized by a simple, rapid, and eco-friendly method by using sweet Sorghum syrup for application in biomedicine and biotechnology. The nanostructures of the prepared gold nanoparticles were confirmed by using UV-visible absorbance, TEM, SAED, FTIR, EDAX, XRD, and photoluminescence analyses. The formation of gold nanoparticles at both room and boiling temperatures and kinetics of the reaction were monitored by UV-visible spectroscopy and TEM studies. TEM analysis revealed that the obtained nanoparticles were mono-dispersed and spherical in shape with an average particle size of 7 nm. The size of the nanoparticles was influenced by the concentration of Sorghum syrup. The presence of elemental gold was confirmed by EDAX analysis. Based on the FTIR analysis, it was observed that the sugars present in the Sorghum syrup possibly acts as capping agents. The zeta potential analysis revealed that the glyconanoparticles were negatively charged with a potential of 25 mV. The XRD and SAED patterns also suggest that the nanoparticles were crystalline in nature and these particles were found to exhibit visible photoluminescence. Fructose and glucose present in sweet Sorghum syrup were demonstrated as responsible sugars for the reduction of gold ions, and sucrose stabilized the formed nanoparticles. The proposed mechanism for the formation and stabilization of gold glyconanoparticles is based on the phenomenon of "macromolecular crowding." This is the first report on the use of sweet Sorghum syrup for the green synthesis of gold glyconanoparticles at both room and boiling temperatures. PMID- 21674819 TI - Techno-economic evaluation of an inclusion body solubilization and recombinant protein refolding process. AB - Expression of recombinant proteins in Escherichia coli is normally accompanied by the formation of inclusion bodies (IBs). To obtain the protein product in an active (native) soluble form, the IBs must be first solubilized, and thereafter, the soluble, often denatured and reduced protein must be refolded. Several technically feasible alternatives to conduct IBs solubilization and on-column refolding have been proposed in recent years. However, rarely these on-column refolding alternatives have been evaluated from an economical point of view, questioning the feasibility of their implementation at a preparative scale. The presented study assesses the economic performance of four distinct process alternatives that include pH induced IBs solubilization and protein refolding (pH_IndSR); IBs solubilization using urea, dithiothreitol (DTT), and alkaline pH followed by batch size-exclusion protein refolding; inclusion bodies (IBs) solubilization using urea, DTT, and alkaline pH followed by simulated moving bed (SMB) size-exclusion protein refolding, and IBs solubilization using urea, DTT and alkaline pH followed by batch dilution protein refolding. The economic performance was judged on the basis of the direct fixed capital, and the production cost per unit of product (P(C)). This work shows that (1) pH_IndSR system is a relatively economical process, because of the low IBs solubilization cost; (2) substituting beta-mercaptoethanol for dithiothreithol is an attractive alternative, as it significantly decreases the product cost contribution from the IBs solubilization; and (3) protein refolding by size-exclusion chromatography becomes economically attractive by changing the mode of operation of the chromatographic reactor from batch to continuous using SMB technology. PMID- 21674820 TI - Croatian genetic heritage: Y-chromosome story. AB - The aim of this article is to offer a concise interpretation of the scientific data about the topic of Croatian genetic heritage that was obtained over the past 10 years. We made a short overview of previously published articles by our and other groups, based mostly on Y-chromosome results. The data demonstrate that Croatian human population, as almost any other European population, represents remarkable genetic mixture. More than 3/4 of the contemporary Croatian men are most probably the offspring of Old Europeans who came here before and after the Last Glacial Maximum. The rest of the population is the offspring of the people who were arriving in this part of Europe through the southeastern route in the last 10,000 years, mostly during the neolithization process. We believe that the latest discoveries made with the techniques for whole-genome typing using the array technology, will help us understand the structure of Croatian population in more detail, as well as the aspects of its demographic history. PMID- 21674821 TI - Forensic DNA databases in Western Balkan region: retrospectives, perspectives, and initiatives. AB - The European Network of Forensic Science Institutes (ENFSI) recommended the establishment of forensic DNA databases and specific implementation and management legislations for all EU/ENFSI members. Therefore, forensic institutions from Bosnia and Herzegovina, Serbia, Montenegro, and Macedonia launched a wide set of activities to support these recommendations. To assess the current state, a regional expert team completed detailed screening and investigation of the existing forensic DNA data repositories and associated legislation in these countries. The scope also included relevant concurrent projects and a wide spectrum of different activities in relation to forensics DNA use. The state of forensic DNA analysis was also determined in the neighboring Slovenia and Croatia, which already have functional national DNA databases. There is a need for a 'regional supplement' to the current documentation and standards pertaining to forensic application of DNA databases, which should include regional-specific preliminary aims and recommendations. PMID- 21674822 TI - Clinical potential and challenges of using genetically modified cells for articular cartilage repair. AB - Articular cartilage defects do not regenerate. Transplantation of autologous articular chondrocytes, which is clinically being performed since several decades, laid the foundation for the transplantation of genetically modified cells, which may serve the dual role of providing a cell population capable of chondrogenesis and an additional stimulus for targeted articular cartilage repair. Experimental data generated so far have shown that genetically modified articular chondrocytes and mesenchymal stem cells (MSC) allow for sustained transgene expression when transplanted into articular cartilage defects in vivo. Overexpression of therapeutic factors enhances the structural features of the cartilaginous repair tissue. Combined overexpression of genes with complementary mechanisms of action is also feasible, holding promises for further enhancement of articular cartilage repair. Significant benefits have been also observed in preclinical animal models that are, in principle, more appropriate to the clinical situation. Finally, there is convincing proof of concept based on a phase I clinical gene therapy study in which transduced fibroblasts were injected into the metacarpophalangeal joints of patients without adverse events. To realize the full clinical potential of this approach, issues that need to be addressed include its safety, the choice of the ideal gene vector system allowing for a long-term transgene expression, the identification of the optimal therapeutic gene(s), the transplantation without or with supportive biomaterials, and the establishment of the optimal dose of modified cells. As safe techniques for generating genetically engineered articular chondrocytes and MSCs are available, they may eventually represent new avenues for improved cell-based therapies for articular cartilage repair. This, in turn, may provide an important step toward the unanswered question of articular cartilage regeneration. PMID- 21674824 TI - An assessment of scientific and technical aspects of closed investigations of canine forensics DNA--case series from the University of California, Davis, USA. AB - AIM: To describe and assess the scientific and technical aspects of animal forensic testing at the University of California, Davis. The findings and recommendations contained in this report are designed to assess the past, evaluate the present, and recommend reforms that will assist the animal forensic science community in providing the best possible services that comply with court standards and bear judicial scrutiny. METHODS: A batch of 32 closed files of domestic dog DNA cases processed at the University of California, Davis, between August 2003 and July 2005 were reviewed in this study. The case files comprised copies of all original paperwork, copies of the cover letter or final report, laboratory notes, notes on analyses, submission forms, internal chains of custody, printed images and photocopies of evidence, as well as the administrative and technical reviews of those cases. RESULTS: While the fundamental aspects of animal DNA testing may be reliable and acceptable, the scientific basis for forensic testing animal DNA needs to be improved substantially. In addition to a lack of standardized and validated genetic testing protocols, improvements are needed in a wide range of topics including quality assurance and quality control measures, sample handling, evidence testing, statistical analysis, and reporting. CONCLUSION: This review implies that although a standardized panel of short tandem repeat and mitochondrial DNA markers and publicly accessible genetic databases for canine forensic DNA analysis are already available, the persistent lack of supporting resources, including standardized quality assurance and quality control programs, still plagues the animal forensic community. This report focuses on closed cases from the period 2003-2005, but extends its scope more widely to include other animal DNA forensic testing services. PMID- 21674825 TI - New cell separation technique for the isolation and analysis of cells from biological mixtures in forensic caseworks. AB - AIM: To isolate mucosal cells of the perpetrator in a sexual assault case from a complex mixture of his mucosal cells and the victim's skin by micromanipulation prior to genomic analysis. METHODS: To capture and analyze mucosal cells we used the micromanipulation with on-chip low volume polymerase chain reaction (LV-PCR). Consensus DNA profiles were generated from 5 replicate experiments. RESULTS AND CONCLUSIONS: We validated the use of micromanipulation with on-chip LV-PCR for genomic analysis of complex biological mixtures in a fatal rape case. The perpetrator's mucosal cells were captured from nipple swabs of the victim, and a single-source DNA profile was generated from cell mixtures. These data suggest that micromanipulation with on-chip LV-PCR is an effective forensic tool for the analysis of specific cells from complex samples. PMID- 21674823 TI - Ethical aspects of human biobanks: a systematic review. AB - AIM: To systematically assess the existing literature on ethical aspects of human biobanks. METHOD: We searched the Web of Science and PubMed databases to find studies addressing ethical problems in biobanks with no limits set (study design, study population, time period, or language of publication). All identified articles published until November 2010 were included. We analyzed the type of published articles, journals publishing them, involvement of countries/institutions, year of publication, and citations received, and qualitatively assessed every article in order to identify ethical issues addressed by the majority of published research on human biobanking. RESULTS: Hundred and fifty four studies satisfied our review criteria. The studies mainly came from highly developed countries and were all published in the last two decades, with over half of them published in 2009 or 2010. They most commonly discussed the informed consent, privacy and identifiability, return of results to participants, importance of public trust, involvement of children, commercialization, the role of ethics boards, international data exchange, ownership of samples, and benefit sharing. CONCLUSIONS: The focus on ethical aspects is strongly present through the whole biobanking research field. Although there is a consensus on the old and most typical ethical issues, with further development of the field and increasingly complex structure of human biobanks, these issues will likely continue to arise and accumulate, hence requiring constant re-appraisal and continuing discussion. PMID- 21674826 TI - Second generation sequencing allows for mtDNA mixture deconvolution and high resolution detection of heteroplasmy. AB - AIM: To use parallel array pyrosequencing to deconvolute mixtures of mitochondrial DNA (mtDNA) sequence and provide high resolution analysis of mtDNA heteroplasmy. METHODS: The hypervariable segment 1 (HV1) of the mtDNA control region was analyzed from 30 individuals using the 454 GS Junior instrument. Mock mixtures were used to evaluate the system's ability to deconvolute mixtures and to reliably detect heteroplasmy, including heteroplasmic differences between 5 family members of the same maternal lineage. Amplicon sequencing was performed on polymerase chain reaction (PCR) products generated with primers that included multiplex identifiers (MID) and adaptors for pyrosequencing. Data analysis was performed using NextGENe(r) software. The analysis of an autosomal short tandem repeat (STR) locus (D18S51) and a Y-STR locus (DYS389 I/II) was performed simultaneously with a portion of HV1 to illustrate that multiplexing can encompass different markers of forensic interest. RESULTS: Mixtures, including heteroplasmic variants, can be detected routinely down to a component ratio of 1:250 (20 minor variant copies with a coverage rate of 5000 sequences) and can be readily detected down to 1:1000 (0.1%) with expanded coverage. Amplicon sequences from D18S51, DYS389 I/II, and the second half of HV1 were successfully partitioned and analyzed. CONCLUSIONS: The ability to routinely deconvolute mtDNA mixtures down to a level of 1:250 allows for high resolution analysis of mtDNA heteroplasmy, and for differentiation of individuals from the same maternal lineage. The pyrosequencing approach results in poor resolution of homopolymeric sequences, and PCR/sequencing artifacts require a filtering mechanism similar to that for STR stutter and spectral bleed through. In addition, chimeric sequences from jumping PCR must be addressed to make the method operational. PMID- 21674827 TI - Estimating the number of contributors to two-, three-, and four-person mixtures containing DNA in high template and low template amounts. AB - AIM: To develop guidelines to estimate the number of contributors to two-, three , and four-person mixtures containing either high template DNA (HT-DNA) or low template DNA (LT-DNA) amounts. METHODS: Seven hundred and twenty-eight purposeful two-, three-, and four-person mixtures composed of 85 individuals of various ethnicities with template amounts ranging from 10 to 500 pg were examined. The number of alleles labeled at each locus and the number of labeled different and repeating alleles at each locus as well over all loci for 2 HT-DNA or 3 LT-DNA replicates were determined. Guidelines based on these data were then evaluated with 117 mixtures generated from items handled by known individuals. RESULTS: The number of different alleles over all loci and replicates was used to initially categorize mixtures. Ranges were established based on the averages plus and minus 2 standard deviations, and to encompass all observations, the maximum and the minimum values. To differentiate samples that could be classified in more than one grouping, the number of loci with 4 or more repeating or different alleles, which were specific to three- and four-person mixtures, were verified. Misclassified samples showed an extraordinary amount of allele sharing or stutter. CONCLUSIONS: These guidelines proved to be useful tools to distinguish low template and high template two-, three-, and four-person mixtures. Due to the inherent higher probability of allele sharing, four-person mixtures were more challenging. Because of allelic drop-out, this was also the case for samples with very low amounts of template DNA or extreme mixture ratios. PMID- 21674828 TI - Discovering the 60 years old secret: identification of the World War II mass grave victims from the island of Daksa near Dubrovnik, Croatia. AB - AIM: To describe the organization, field work, forensic anthropological examination, and DNA analysis conducted to identify the victims from a World War II mass grave found on the Dalmatian island of Daksa near Dubrovnik (Croatia) in 2009. METHODS: Excavation of the site was performed according to standard archeological procedures. Basic anthropological examination was made to determine the minimum number of victims, sex, age at death, and height. The bones with pathological and traumatic changes were identified. DNA was extracted from powdered bones and relatives' blood samples. Y-chromosome and autosomal short tandem repeats (STR) were used to establish the relationship of the remains with the putative family members. RESULTS: The remains were found to belong to at least 53 distinctive victims. All were male, mostly with gunshot wounds to the head. DNA analysis and cross-matching of the samples with relatives resulted in 14 positive identifications using the Y-chromosomal STRs and 4 positive identifications using the autosomal STRs. CONCLUSIONS: This study showed that even in cases of more than 50-year-old, highly degraded human remains from mass graves, Y-chromosomal and autosomal STRs analysis can contribute to identification of the victims. PMID- 21674829 TI - Genetic analysis of 7 medieval skeletons from the Aragonese Pyrenees. AB - AIM: To perform a genetic characterization of 7 skeletons from medieval age found in a burial site in the Aragonese Pyrenees. METHODS: Allele frequencies of autosomal short tandem repeats (STR) loci were determined by 3 different STR systems. Mitochondrial DNA (mtDNA) and Y-chromosome haplogroups were determined by sequencing of the hypervariable segment 1 of mtDNA and typing of phylogenetic Y chromosome single nucleotide polymorphisms (Y-SNP) markers, respectively. Possible familial relationships were also investigated. RESULTS: Complete or partial STR profiles were obtained in 3 of the 7 samples. Mitochondrial DNA haplogroup was determined in 6 samples, with 5 of them corresponding to the haplogroup H and 1 to the haplogroup U5a. Y-chromosome haplogroup was determined in 2 samples, corresponding to the haplogroup R. In one of them, the sub-branch R1b1b2 was determined. mtDNA sequences indicated that some of the individuals could be maternally related, while STR profiles indicated no direct family relationships. CONCLUSIONS: Despite the antiquity of the samples and great difficulty that genetic analyses entail, the combined use of autosomal STR markers, Y-chromosome informative SNPs, and mtDNA sequences allowed us to genotype a group of skeletons from the medieval age. PMID- 21674830 TI - Y-short tandem repeat haplotype and paternal lineage of the Ezhava population of Kerala, south India. AB - AIM: To analyze the haplotype of the Ezhava population of Kerala, south India, using 8 short tandem repeat (STR) loci on the Y chromosome and trace the paternal genetic lineage of the population. METHODS: Whole blood samples (n=104) were collected from unrelated healthy men of the Ezhava population over a period of one year from October 2009. Genomic DNA was extracted by salting out method. All samples were genotyped for the 8 Y-STR loci by the AmpFiSTR Y-filer PCR Amplification Kit. The haplotype and allele frequencies were determined by direct counting and analyzed using Arlequin 3.1 software, and molecular variance was calculated with the Y-chromosome haplotype reference database online analysis tool, www.yhrd.org. RESULTS: Among the 104 examined haplotypes, we found 98 unique ones. The average gene diversity was 0.669, with the highest diversity of 0.9462 observed for the biallelic Y-STR marker DYS 385. The allele frequency among DYS loci varied between 0.0096 and 0.75. Out of the 104 haplotypes, 10 were identical to the Jat Sikh population of Punjab, which is the greatest number among the Indian populations, and 4 to the Turkish population, which is the greatest number among the European populations. According to the allele frequency of Y-STR, the Ezhavas were genetically more similar to the Europeans (60%) than to the East Asians (40%). CONCLUSION: The vast majority of haplotypes were observed only once, reflecting the enormous genetic heterogeneity of the Ezhavas. Based on the genotype, the Ezhavas showed more resemblance to Jat Sikh population of Punjab and the Turkish populations than to the East Asians, hence indicating a paternal lineage of European origin. PMID- 21674831 TI - Prevalence of 845G>A HFE mutation in Slavic populations: an east-west linear gradient in South Slavs. AB - AIM: To compare A allele frequencies of the 845G>A mutation of 10 Slavic populations in central, eastern, and southern Europe between each other and with other European populations. METHODS: The 845G>A mutation from the DNA of 400 Polish neonates collected in 2005-2006 was analyzed by polymerase chain reaction restriction fragment length polymorphism. The data were compared with reports from other countries. RESULTS: We identified 381 GG homozygotes, 18 GA heterozygotes, and 1 AA homozygote. The 845A allele frequency was 2.5%, which makes the summary figure for Poland from this and previous studies 3.5%. The average prevalence for Poland and other West Slavic countries was 3.6%, similar to Russia (inhabited by the East Slavs, 3.5%). The average prevalence in South Slavic countries was 2.2%, gradually decreasing from 3.6% in Slovenia to 0% in Bulgaria, with a longitudinal linear gradient (adjusted R(2)=0.976, P<0.001). CONCLUSIONS: The West and East Slavs, together with Finland, Estonia, Germany, Austria, Hungary, Slovenia, and Croatia, form a group with 845A allele frequencies between 3% and 4%. In the South Slavs, there is a gradual decline in the prevalence of 845A allele from northwest to southeast, with a surprisingly exact east-west linear gradient. PMID- 21674832 TI - Y-chromosomal diversity of the Valachs from the Czech Republic: model for isolated population in Central Europe. AB - AIM: To evaluate Y-chromosomal diversity of the Moravian Valachs of the Czech Republic and compare them with a Czech population sample and other samples from Central and South-Eastern Europe, and to evaluate the effects of genetic isolation and sampling. METHODS: The first sample set of the Valachs consisted of 94 unrelated male donors from the Valach region in northeastern Czech Republic border-area. The second sample set of the Valachs consisted of 79 men who originated from 7 paternal lineages defined by surname. No close relatives were sampled. The third sample set consisted of 273 unrelated men from the whole of the Czech Republic and was used for comparison, as well as published data for other 27 populations. The total number of samples was 3244. Y-short tandem repeat (STR) markers were typed by standard methods using PowerPlex(r) Y System (Promega) and Yfiler(r) Amplification Kit (Applied Biosystems) kits. Y chromosomal haplogroups were estimated from the haplotype information. Haplotype diversity and other intra- and inter-population statistics were computed. RESULTS: The Moravian Valachs showed a lower genetic variability of Y-STR markers than other Central European populations, resembling more to the isolated Balkan populations (Aromuns, Csango, Bulgarian, and Macedonian Roma) than the surrounding populations (Czechs, Slovaks, Poles, Saxons). We illustrated the effect of sampling on Valach paternal lineages, which includes reduction of discrimination capacity and variability inside Y-chromosomal haplogroups. Valach modal haplotype belongs to R1a haplogroup and it was not detected in the Czech population. CONCLUSION: The Moravian Valachs display strong substructure and isolation in their Y chromosomal markers. They represent a unique Central European population model for population genetics. PMID- 21674833 TI - Genetic variation at 5 new autosomal short tandem repeat markers (D10S1248, D22S1045, D2S441, D1S1656, D12S391) in a population-based sample from Maghreb region. AB - AIM: To investigate allele distribution and genetic parameters of a population based sample from Maghreb region. METHODS: Allele frequencies for 5 new autosomal short tandem repeat (STR) markers (D10S1248, D22S1045, D2S441, D1S1656, and D12S391) and several forensic parameters were determined for 95 unrelated individuals. RESULTS: The combined power of discrimination and power of exclusion for the 5 loci were high (0.9999991 and 0.9954757, respectively). Allele frequencies were compared with previously published population data. Significant differences were found between Maghreb population and all other populations at the locus D2S441. Also, significant differences were found between the Maghreb and the African American population at the D22S1045, D1S1656, and D12S391 loci, between Maghreb and Caucasian population at the D1S1656 locus, and between Maghreb and Hispanic population at the D22S1045 locus. CONCLUSIONS: Typing of the 5 new STR loci may provide a useful addition to the previously established sets of autosomal STRs. PMID- 21674834 TI - Autosomal short tandem repeat genetic variation of the Basques in Spain. AB - AIM: To examine population genetic structure and hypotheses of the origin of the modern Basque population in Spain using autosomal short tandem repeat (STR) data from individuals living in 27 mountain villages in the provinces of Alava, Vizcaya, Guipuzcoa, and Navarre, by comparing Basque autosomal STR variation with that of neighboring populations in Europe, as well as proposed ancestral populations in North Africa and the Caucasus. METHODS: Allele frequencies for 9 autosomal STR loci (D3S1358, D5S818, D7S820, D8S1179, D13S317, D18S51, D21S11, FGA, and vWA) and several population genetic parameters were determined for the 4 provinces in the Basque region of Spain (n=377). Heterozygosity within the Basque population was measured using a locus-by-locus analysis of molecular variance. Relationships between the Basques and other populations were examined using a multidimensional scaling (MDS) plot of Shriver's DSW distance matrix. RESULTS: Heterozygosity levels in the Basque provinces were on the low end of the European distribution (0.805-0.812). The MDS plot of genetic distances revealed that the Basques differed from both the Caucasian and North African populations with respect to autosomal STR variation. CONCLUSIONS: Autosomal STR analysis does not support the hypotheses of a recent common ancestor between the Basques and populations either from the Caucasus or North Africa. PMID- 21674836 TI - Application of microsatellite loci on the chromosome X for rapid prenatal detection of the chromosome X numerical abnormalities. AB - AIM: To determine the value of short-tandem repeat markers on the chromosome X (X STR) for prenatal diagnostics of the chromosome X numerical disorders. METHODS: We investigated the genetic variability of 5 X-markers (DXS9895, DXS6810, DXS6803, GATA172D05, and HPRTB) in 183 healthy Croatian individuals (90 men and 93 women). We also tested 13 patients with X chromosome disorders (Turner syndrome--6 cases; Klinefelter syndrome--5 cases, and Triple X syndrome--2 cases). The analysis was performed using polymerase chain reaction amplification with specific primers and electrophoresis on a polyacrylamide gel. The study was performed in 2010. RESULTS: Our sample showed no significant differences in allelic frequencies of the investigated X-markers from other European populations. A set of 5 X-STR markers was sufficiently informative for a successful determination of the chromosome X numerical abnormalities. CONCLUSION: Since no false positive or negative results were observed, diagnostic value of the investigated X-STR loci for prenatal detection of chromosome X numerical disorders was confirmed. Our study represents an important step toward an improved prenatal diagnostics in Croatia. PMID- 21674835 TI - Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein. AB - AIM: To analyze the genesis of hypertrophic cardiomyopathy on a large cohort of patients from molecular genetics point of view and perform the functional analysis of the 3D molecular model of defective myosin-7 protein in silico. METHODS: The study enrolled 153 patients with diagnosed hypertrophic cardiomyopathy from different parts of the Czech Republic. DNA samples were analyzed for mutations in exons 21 and 22 of the MYH7 gene, which have been associated with high mutation clustering. The 3D model of human myosin-7 was built using the x-ray structure of nucleotide-free scallop myosin S1 as the structural template. We performed de novo structure prediction of mutant and wild type peptides spanning the 769-788 amino acids region of the myosin-7 protein. RESULTS: The Arg870His and Asp778Val amino acid alterations were found in 2 unrelated patients with a severe form of hypertrophic cardiomyopathy. The Asp778Val variation was chosen for subsequent 3D molecular modeling in silico. The mutation of the Asp by Val not only changes the character of the interaction pattern with other amino acids or ions but Val, being a small hydrophobic amino acid, can also completely change the stability of the region. CONCLUSION: Mutation location in the MYH7 gene and changes in amino acid composition may have a crucial negative impact on the outcome of the disease in patients with hypertrophic cardiomyopathy. In addition, a mutation that changes the charge of the amino acid is more likely to affect protein function than a conservative mutation. PMID- 21674837 TI - Association of NOS3 tag polymorphisms with hypoxic-ischemic encephalopathy. AB - AIM: To test the association of NOS3 gene with hypoxic-ischemic encephalopathy (HIE). METHODS: The study included 110 unrelated term or preterm born children (69 boys and 41 girls) with HIE and 128 term and preterm born children (60 boys and 68 girls) without any neurological problems after the second year of life. Children with perinatal HIE fulfilled the diagnostic criteria for perinatal asphyxia. All children were admitted to the Clinical Hospital Split between 1992 and 2008. We analyzed 6 tagging single nucleotide polymorphisms (SNP) within NOS3 gene (rs3918186, rs3918188, rs1800783, rs1808593, rs3918227, rs1799983), in addition to previously confirmed NOS3-associated SNP rs1800779. Genotyping was conducted using real-time polymerase chain reaction (PCR). Association analyses were performed according to allelic and genotypic distribution. RESULTS: Allelic test did not show any SNP association with HIE. SNP rs1808593 showed genotype association (P=0.008) and rs1800783-rs1800779 TG haplotype showed an association with HIE (P<0.001). The study had 80% statistical power to detect (alpha=0.05) an effect with odds ratio (OR)=2.07 for rs3918186, OR=1.69 for rs3918188, OR=1.70 for rs1800783, OR=1.80 for rs1808593, OR=2.10 for rs3918227, OR=1.68 for rs1800779, and OR=1.76 for rs1799983, assuming an additive model. CONCLUSION: Despite the limited number of HIE patients, we observed genotypic and haplotype associations of NOS3 polymorphisms with HIE. PMID- 21674838 TI - Genetic examination of the putative skull of Jan Kochanowski reveals its female sex. AB - We report the results of genetic examination of the putative skull of Jan Kochanowski (1530-1584), a great Polish renaissance poet. The skull was retrieved in 1791 by historian Tadeusz Czacki from the Kochanowski family tomb and became the property of the Czartoryskis Museum in Krakow. An anthropological study in 1926 questioned its male origin, which raised doubts about its authenticity. Our report presents genetic evidence that resolves this dispute. From the sole tooth we obtained a sufficient amount of DNA to perform the analysis of nuclear markers. The analysis of the sex-informative part of intron 1 in amelogenin, genotyped using AmpFiSTR(r) NGM PCR Amplification Kit and Powerplex(r) ESI17 Kit human identification systems, revealed the female origin of the tooth. The female origin was further confirmed by the analysis of a portion of amelogenin intron 2, a microsatellite marker located on the X chromosome, as well as by a lack of signal from Y chromosomal microsatellite markers and the sex-determining region Y marker. Data obtained for two hypervariable regions, HVI and HVII, in mitochondrial DNA showed that mtDNA haplotype was relatively frequent among contemporary Europeans. The analysis of a set of single nucleotide polymorphisms relevant for prediction of the iris color indicated an 87% probability that the woman had hazel or brown eye color. PMID- 21674839 TI - Identification of tumor specimens by DNA analysis in a case of histocytological paraffin tissue block swapping. AB - We report on a patient who was diagnosed with high-grade breast carcinoma by all the pre-surgery clinical evidence of malignancy, but histopathological reports did not reveal any such tumor residue in the post-surgical tissue block. This raised a suspicion that either exchange of block, labeling error, or a technical error took place during gross examination of the tissue. The mastectomy residue was unprocurable to sort out the problem. So, two doubtful paraffin blocks were sent for DNA fingerprinting analysis. The partial DNA profiles (8-9/15 loci) were obtained from histocytological blocks. The random matching probability for both the paraffin blocks and the patient's blood were found to be 1 in 4.43E4, 1.89E6, and 8.83E13, respectively for Asian population. Multiplex short tandem repeat analysis applied in this case determined that the cause of tumor absence was an error in gross examination of the post-surgical tissue. Moreover, the analysis helped in justifying the therapy given to the patient. Thus, with DNA fingerprinting technique, it was concluded that there was no exchange of the blocks between the two patients operated on the same day and the treatment given to the concerned patient was in the right direction. PMID- 21674840 TI - Novel duplication on chromosome 16 (q12.1-q21) associated with behavioral disorder, mild cognitive impairment, speech delay, and dysmorphic features: case report. AB - We report on the 10-year follow-up and clinical, cytogenetic, and molecular investigation of a girl admitted for evaluation because of speech delay, learning difficulties, aggressive behavior, and dysmorphic facial features that included high forehead, round face, epicanthic folds, low-set dysplastic ears, flat nasal bridge, long flat philtrum, thin upper lip, small mouth, and short neck. The analysis of high-resolution GTG- and CTG-banding chromosomes suggested a de novo direct duplication of 16q12-q21 region and fluorescence in situ hybridization analysis with whole-chromosome specific 16 probe confirmed that the duplicated genetic material originated from the chromosome 16. Subsequently, array-based comparative genomic hybridization analysis with a~75 kb resolution showed a 9.92 Mb gain on the long arm of chromosome 16 at bands q12.1 through q21. To the best of our knowledge, this is the first case of duplication 16q12.1q21 described in literature. Several genes within the duplicated region are possibly correlated with clinical features present in our patient. Clinical and cytogenetic findings were compared with the small number of reported patients with pure duplications 16q, partially overlapping the one in our patient. Clinical phenotype seems to be distinctive between the proximal-intermediate and intermediate-distal regions of the long arm of the chromosome 16. In particular, we observed a set of dysmorphic features that could present a characteristic dup 16q11.2-q13 phenotype. The present study illustrates the advantages of an integrative approach using both conventional and molecular techniques for the precise characterization and genotype-phenotype correlation in patients with dysmorphism, behavioral problems, and learning difficulties. PMID- 21674842 TI - Faith, hope and love. PMID- 21674841 TI - Biomedical journal editing: elements of success. PMID- 21674843 TI - The future of health care in Croatia. PMID- 21674844 TI - Current standards and future strategies in immunochemotherapy of non-Hodgkin's lymphoma. AB - The therapeutic options for B-cell non-Hodgkin's lymphoma (NHL) have dramatically expanded with the advent of immune-based treatments. The monoclonal antibody anti CD20 rituximab represents the best example of these advances and has quickly become incorporated into the therapeutic armamentarium for this hematological disease. In addition, other antibodies are eventually becoming part of treatment approaches to NHL. Furthermore, the role of therapeutic vaccines continues to be an important ongoing research question. Despite this success, several questions on how to optimize the use of monoclonal antibodies in NHL remain open since the best administration schedules, as well as the optimal duration of immunotherapy still have to be determined. Finally the development of resistance to treatment remains the main limit of this innovative approach, necessitating the development of strategies to circumvent resistance itself. This review will summarize the state of the art of antibody-based immunotherapy of NHL and discuss prospective approaches to improve the benefit of these treatments in patients. PMID- 21674845 TI - Cancer stem cells and malignant gliomas. From pathophysiology to targeted molecular therapy. AB - High grade gliomas, the most frequent and most malignant brain cancers, grow rapidly and infiltrate the cerebrospinal axis causing deficits in cognition, mobility, balance or speech and are typically resistant to radiation and chemotherapy. Despite recent progress, WHO grade III and IV gliomas still represent a great challenge in oncology, with overall poor outcomes and inevitable lethality. While radiotherapy and temozolomide are considered the standard first-line approach for therapy of newly diagnosed malignant gliomas, the treatment protocols for recurrent tumors remain ill-defined. Increasing evidence suggests that tumors of the central nervous system are derived from proliferatively active neural stem cells residing in defined neuropoietic niches of the adult brain. These cancer stem cells, also identified in other tumors, provide a reservoir of cells with self-renewal capabilities, can maintain the tumor by generating differentiated non-stem tumor cells and are responsible for recurrences after ablative neurosurgical therapy and chemoradiotherapy. The only way to successfully control recurrent malignant gliomas and even hope for a cure in the future is by combining standard chemotherapy with immunotherapy. Despite the apparent improvements of current treatments, it should be realized that the characteristic brain tumor niche may provide recurrent gliomas an "escape mechanism" from anticancer treatments. Thus, the use of targeted molecular therapy drugs may effectively inhibit or at least slow down cancer stem cell proliferation and stop the brain microenvironment from allowing furtive invasion and proliferation of highly aggressive malignant gliomas. PMID- 21674846 TI - Skeletal metastases: an update of the literature with pictorial review. AB - The skeleton is one of the common places were many tumors metastasize. Skeletal metastases may profoundly affect the patients' quality of life by making them unable to move freely and help themselves, while in some cases impingement upon the CNS structures can cause neurologic symptoms. Early diagnosis of bone metastases is therefore very important in order to prevent severe debilitating conditions. We review the role of different diagnostic methods available for the detection of bone metastases, as well as their response to treatment: bone scintigraphy, plain films, computed tomography (CT) and magnetic resonance imaging (MRI). The role of positron emission tomography (PET) and PET/CT is also discussed. PMID- 21674847 TI - Progress but not enough: the 2009 (7th) revision of the American Joint Committee on Cancer (AJCC) for melanoma staging and classification. AB - In 2009 the American Joint Committee on Cancer (AJCC) examined for the first time the mitotic rate of the primary melanoma as a new covariate in a revised staging and classification system. In a multifactorial analysis mitotic rate was the second most powerful predictor of survival after tumour thickness, reaffirming the findings of earlier studies. Analyses demonstrated a highly significant correlation between increasing mitotic rate and declining survival rates. Despite these findings some of the intrinsic weaknesses of the 2001 staging and classification system for melanoma remain apparent in the 7th revision of 2009 and are discussed in this paper. PMID- 21674848 TI - Multimodal approach to therapy-related neuropathic pain in breast cancer. AB - PURPOSE: This study evaluated the effects of the multimodal therapy (gabapentin non steroidal anti inflammatory drug [NSAID]-morphine) on intensity and relief of treatmentrelated neuropathic pain in patients with breast cancer. METHODS: This study involved 75 breast cancer outpatients who had previously undergone anti neoplastic therapy (surgery, chemotherapy, radiotherapy). The patients were randomly divided into 3 groups, which were formed depending on the planned analgesic therapy (gabapentin, gabapentin- NSAID, gabapentin-NSAID-morphine). Each group was a control group to itself. The pain intensity difference and scores of daily activities were collated and assessed by the modified Brief Pain Inventory (BPI) questionnaire (VAS/Likert Scale). Monitoring the additional medication and side effects optimized the therapy efficiency evaluation. RESULTS: During this 6-week study, the decrease of pain intensity was significant in all 3 groups (p <0.0001). Although there was intergroup difference, it was statistically not significant (p >0.05). The variant analysis of pain relief showed differences both among and within the groups in the first 3 weeks of the study (F(1)=7.79, p=0.000; F(2)=7.01, p=0.001; F(3) =5.49, p=0.001). The multimodal group needed the least of additional medication and the variant analysis showed a statistically significant difference (p=0.001) from the 4th week of the trial period. The correlation between the increase trend of side effects and the frequency of additional medication was significant (p <0.05). CONCLUSION: The multimodal therapy ensures adequate cancer-related neuropathic pain control with minimal side effects. PMID- 21674849 TI - PTEN protein expression in postmenopausal steroid receptor positive early breast cancer patients treated with adjuvant tamoxifen. AB - PURPOSE: Since one of possible causes of resistance to antiestrogen therapy in steroid receptor positive (SR+) breast cancer (BC) patients is an alteration of PTEN (phosphatase and tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopausal patients with steroid SR+ BC treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) statuses and disease outcome. METHODS: This was a retrospective analysis of 78 postmenopausal stage I/II SR(+)BC patients treated with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry. RESULTS: The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62.8%) patients with ductal and in 26/35 (74.3%) patients with lobular carcinomas; and PTEN(-) status in 16/43 (37.2%) patients with ductal and in 9/35 (25.7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 patients: 14/53 (26.4%) of PTEN(+) BC subgroup and 24/25 (96%) of PTEN(-) subgroup (x(2), p=0.018). There were no significant associations between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression. Patients with PTEN(-) had significantly shorter disease-free interval (DFI) and overall survival (OS) (for both, log rank test, p <0.01) compared to PTEN(+) BC patients. CONCLUSION: Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR(+) BC patients treated with adjuvant tamoxifen. PMID- 21674850 TI - Correlation between c-erbB2 expression, lymphovascular invasion and other biological and clinical prognostic factors and preoperative tumor markers in patients with early-stage and locally advanced breast cancer. AB - PURPOSE: To evaluate the correlation between c-erbB2 expression, lymphovascular invasion and other biological and clinical prognostic variables and preoperative CA 15-3 and CEA levels in patients with early-stage and locally advanced breast cancer. METHODS: Preoperative serum concentrations of CA 15- 3 and CEA were measured in 123 patients undergoing surgical treatment for stage I-III breast cancer and the association between these markers and clinical and biological variables were evaluated. RESULTS: With cut-off values of 45 U/ml (CA 15-3) and 2.5 ng/ml (CEA), the sensitivity for CA 15-3 and CEA was 10% and 24% and their mean values were 23 U/ml and 2.32 ng/ml, respectively. A significant correlation between preoperative levels of CA 15-3 and CEA was noticed (p=0.023). Preoperative CA 15-3 levels were significantly higher in patients with tumors > 5 cm (p<0.0001), with positive axillary lymph nodes (p=0.04), with increasing nodal burden (p= 0.025) and in patients with stage III disease (p=0.003). Tumor size >5 cm (p=0.002), increasing axillary nodal burden (p=0.02) and stage III disease (p<0.0001) were also significantly correlated with CEA values above the cut-off level. There were no correlations between CA 15-3 and CEA levels and other variables including c-erbB2 expression, age, grade, hormone receptor status, and lymphovascular invasion. CONCLUSION: Preoperative CA 15-3 and CEA levels are significantly correlated with tumor size, axillary nodal status and stage in patients with non-metastatic breast carcinoma. No correlation between preoperative values of CA15-3/CEA and c-erbB2 status, lymphovascular invasion and other prognostic factors was detected. PMID- 21674851 TI - The potential role of hypofractionated accelerated radiotherapy to cosmesis for stage I-II breast carcinoma: a prospective study. AB - PURPOSE: To evaluate the acute and late effects as well as the cosmetic results of an accelerated hypofractionated radiotherapeutic schedule in breast cancer irradiation. METHODS: Fifty-four patients with stage I-II invasive breast cancer receiving postoperative radiotherapy (RT) after lumpectomy and axillary node dissection were studied. All patients received RT with 6 MV linear accelerator with a total tumor dose of 53 Gy (Equivalent dose-EQD2- 60 Gy), 2.65 Gy per fraction, in 20 fractions. Acute and late effects as well as cosmetic results were assessed using the European Organization for Research and Treatment of Cancer and Radiation Therapy Oncology Group (EORTC-RTOG) Cosmetic Rating System. RESULTS: By the end of RT 66.7% of the patients developed no toxicity, while 24.1% showed grade 1 and 9.3% grade 2 acute skin toxicity. After 6 months 90.7% of women showed grade 0 late toxicity while 100% of women recovered completely 2 years after RT. There was no local or distant recurrence during 5-year follow up. CONCLUSION: The accelerated hypofractionated schedule appears to be an acceptable alternative to the traditional longer RT schedules, without late toxicity. PMID- 21674852 TI - Prognostic factors and treatment outcomes in patients with operated endometrial cancer: analysis of 674 patients at a single institution. AB - PURPOSE: Endometrial carcinoma is the most prevalent gynecologic tumor in developed countries. The aim of the present study was to evaluate the clinical characteristics of the patients with endometrial cancer. METHODS: Six hundred and seventy-four patients who had received postoperative therapy were retrospectively investigated. Of the cases, 186 were only monitored, whereas 43 received intracavitary radiotherapy (ICRT) and 54 external beam radiotherapy (EBRT). Two hundred and fifty-nine patients received both EBRT plus ICRT. Eight patients received chemotherapy (CT), whereas 24 patients received both CT and EBRT plus ICRT. RESULTS: Statistical analyses revealed that age, menopausal status, tumor histology, stage, grade, tumor diameter, myometrial invasion, lymphovascular space invasion (LVI), positive cytology of abdominal fluid/washings, omental involvement, adnexal involvement and the type of the therapy significantly affected both the overall survival (OS) and disease- free survival (DFS). Survival was poor in patients over 60 years of age, who had advanced stage (higher than FIGO stage 2a), grade III tumor and myometrial invasion >50%. CONCLUSION: Age was the most important factor associated with local relapse while survival was affected by age, grade, myometrial invasion and stage. PMID- 21674853 TI - The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of recurrent advanced ovarian cancer: a prospective study. AB - PURPOSE: Ovarian cancer is the leading cause of death from gynecological cancer. The current treatment of this type of cancer consists of cytoreductive surgery (CRS) and systemic chemotherapy. The aim of this study was to examine if the hyperthermic intraoperative chemotherapy (HIPEC) is an alternative modality to treat this category of patients along with a second attempt of surgical resection and second or third line systemic chemotherapy. METHODS: Forty-eight patients suffering from advanced ovarian cancer (FIGO stages III and IV) who recurred after initial treatment with conservative or debulking surgery and systemic chemotherapy were included in this study. Twenty-four patients (group A) were treated with CRS followed by HIPEC and then systemic chemotherapy. Due to various reasons the remaining 24 patients (group B) were treated with CRS and systemic chemotherapy alone. RESULTS: The median survival for group A was 19.4 months vs. 11.2 months in group B (p <0.05). One-year survival was 85% in group A vs. 35% in group B (p <0.05). The 3-year survival rate was 50% in group A vs. 18%. in group B (p <0.01). The resection status was found to be a significant predictor of overall survival (p <0.05). Patients with peritoneal cancer index (PCI) score < 15 appeared also to have longer survival. CONCLUSION: The use of HIPEC along with the extent of the disease and the extent of cytoreduction play an important role in the survival of patients with a recurrence in an initially advanced ovarian cancer. PMID- 21674854 TI - Mitomycin-C in combination with fluoropyrimidines in the treatment of metastatic colorectal cancer after oxaliplatin and irinotecan failure. AB - PURPOSE: To retrospectively evaluate the efficacy and tolerability of mitomycin-C (MMC) in combination with fluoropyrimidines as salvage 3rd -or 4th-line therapy in metastatic colorectal cancer (MCRC) patients. METHODS: All patients in this study had previously failed oxaliplatin and irinotecan-based chemotherapy. Patients were treated with MMC (6 mg/m(2) intravenously/i.v.) on day 1 in combination with either oral UFT (500 mg/m(2)) and oral leucovorin (LV) (30 mg) on days 1-14 every 3 weeks (group A) or infusional 5-fluorouracil (5-FU) by deGramont regimen with i.v. LV (200 mg/m(2)) on days 1 and 2, every 2 weeks (group B). RESULTS: Thirty-nine MCRC patients were analyzed. Twenty-two of them were in group A and 17 in group B. Thirty-three were evaluable for clinical efficacy. The clinical benefit in the intent-to-treat (ITT) population was 30.8%. Median progression free survival (PFS) was 6 months (95% confidence interval/ CI 4-8) and median overall survival (OS) 9 months (95% CI 6.5-11.5). Median PFS was 3 months (95% CI 2.4-3.6) in group A and 7 months (95% CI 5.1-8.9) in group B (p=0.009). Median OS was 7 months (95% CI 4.3-9.7) in group A and 12 months (95% CI 5.4-18.6) in group B (p=0.422). The combination of MMC and fluoropyrimidines was generally well tolerated. The most common severe toxicities were nausea and vomiting, neutropenia, hepatotoxicity and diarrhea. CONCLUSION: MMC in combination with fluoropyrimidines is safe and active in heavily-pretreated MCRC patients. This combination remains a viable option in these patients. However, better therapies are urgently needed. PMID- 21674855 TI - Site impact on colorectal cancer biological behavior in terms of clinicopathological and molecular features. AB - PURPOSE: We investigated the biological behavior of proximal and distal colorectal adenocarcinomas (CRC), intending to determine specific segmental differences, possibly arising from the distinct genetic pathways involved in their development. METHODS: Thirty-six proximal and 83 distal cancers were comparatively and retrospectively analyzed, regarding tumor stage, grade and Ki 67, p53 and Bcl-2 immunohistochemical expression. RESULTS: Proximal tumors were more likely to be poorly differentiated (p=0.005) and to exhibit low Ki-67 and p53 expression (<20% and <= 30% stained nuclei respectively; p=0.026 and 0.0014, respectively). Distal lesions were more likely to be moderately differentiated (p=0.001), to display moderate Ki-67 expression (20-50% stained nuclei, p= 0.013) and p53 staining higher than 30% stained nuclei (p= 0.0014). Such segmental variations regarding mainly p53 and to a lesser extent Ki-67 were seen within most of the specific sub-groups of patients (stratified by stage, grade, gender and age). An association between Bcl-2 expression and distal site was also observed among females (p=0.008). CONCLUSION: Proximal and distal cancers displayed different clinicopathological and molecular patterns, reinforcing the proposal that they are genetically and biologically different entities. Potential clinical applications of these findings should be investigated. PMID- 21674856 TI - The significance of DNA image cytometry and Edmondson-Steiner grading on prognosis after curative resection of hepatocellular carcinoma. AB - PURPOSE: Hepatocellular carcinoma (HCC) is the commonest primary cancer of the liver. Hepatic resection remains the main curative option, although the incidence of disease recurrence in the remaining hepatic parenchyma is high and accounts for the leading cause of death post resection. For this reason, the need to identify prognostic factors which may determine treatment response and survival is of paramount importance. In this study we assessed whether DNA image cytometry and Edmondson-Steiner grading could be used as prognostic factors in a cohort of patients with HCC undergoing radical hepatic resection. METHODS: Forty-four patients with HCC who underwent radical resection were retrospectively analyzed. Histological grading according to Edmondson and Steiner and DNA ploidy using DNA image cytometry, were the two parameters analyzed. Pearson's x(2) or Fisher's exact tests were used to test for any associations between categorical variables. Univariate semi-parametric Cox proportional hazard regression models were used to assess the effect of explanatory variables on death. All reported p values were based on two-sided tests and compared to a significance level of 0.05. RESULTS: In univariate Cox regression analysis, adverse survival outcome was strongly associated with high DNA score and advanced histological grading. Patients with ploidy score >2.2 had 3.95 times higher probability of death, as compared to those with ploidy score <= 2.2. Edmondson-Steiner grades III and IV were also associated with 20.49 and 34.47 higher probability of death respectively as compared to grade I. CONCLUSION: Our results validate the prognostic significance of DNA image cytometry and Edmondson-Steiner grading following curative resection of HCC. PMID- 21674857 TI - Clinical and histopathological study of angiogenesis in multiple myeloma. AB - PURPOSE: Angiogenesis is an essential component in the growth and progression of multiple myeloma (MM). We studied the clinical significance of angiogenesis in patients with MM estimated by precise counting of the number of vessels (i.e. microvessel density, MVD) and compared these results with the results obtained using semi-quantitative grading of angiogenesis. METHODS: Fifty-nine newly diagnosed cases of MM were analyzed with respect to clinical features, laboratory findings, histological features, angiogenesis parameters, and response to treatment. Bone marrow microvessels were examined using immunohistochemical staining for CD34. Bone marrow angiogenesis was estimated by two different methods. The mean number of vessels per area in each sample was characterized as the MVD. Microvessels were counted manually on light microscopy in 3 hot spots at *400 magnification. Semiquantitative estimation of angiogenesis was based on visual assessment of slides at *100 magnification. Each slide was assigned as low, intermediate or high intensity of angiogenesis. RESULTS: The median MVD was 15 vessels per 3 hot spots (range 1-89). Intensity of angiogenesis was assigned as low in 24 (40.7%) patients, intermediate in 17 (28.8%) and high in 18 (30.5%). Significant correlation between intensity of angiogenesis (estimated using both methods) and histological grade, extent of bone marrow infiltration, proliferative activity of myeloma cells and poor survival was found. Semiquantitatively assessed intensity of angiogenesis additionally correlated with clinical stage. There was a statistically highly significant correlation between MVD and semi-quantitatively estimated intensity of angiogenesis (p <0.001). CONCLUSION: Tumor-associated angiogenesis is an important prognostic feature in MM and should be routinely done on bone marrow biopsies of these patients. Simple semiquantitative grading of angiogenesis can be recommended for daily practice, as an alternative method for complicated and time-consuming estimation of MVD. PMID- 21674858 TI - Frequency of BCR-ABL fusion transcripts in Serbian patients with chronic myeloid leukemia. AB - PURPOSE: The aim of this study was to analyze the occurrence of the most frequent BCR-ABL transcript variants (b3a2, b2a2 and e1a2) in Serbian patients with chronic myeloid leukemia (CML) and compare it with the occurrence reported in other populations. METHODS: We analyzed peripheral blood and bone marrow samples of 136 Serbian patients with CML by RT-PCR and cytogenetic methods. RESULTS: In 100 patients (73.5%) the b3a2 and in 34 (25%) the b2a2 forms of BCR-ABL were detected. One (0.75%) patient was BCR-ABL negative, but in lymphoblastic transformation he expressed the e1a2 [corrected] transcript of BCR-ABL. One (0.75%) patient displayed both b2a2 and b3a2 forms of BCR-ABL. Analysis of this group according to karyotype showed b3a2 predominance (79%) in patients with classic t(9;22); b2a2 was found in 20% and both b2a2 and b3a2 forms in 1%. In variant translocations b3a2 in 65% and b2a2 in 35% of the patients were detected. In contrast, the subgroup with normal karyotype expressed slight predominance of the b2a2 form (50%); b3a2 was found in 43% of the patients and one patient (7%) displayed e1a2. CONCLUSION: Predominance of the b3a2 form in Serbian patients with CML is in concordance with other relevant investigations, conducted mostly on Caucasian ethnic groups, but in contrast to the study performed on the Mestizo ethnic group in Ecuador. Slight predominance of the b2a2 form was also noticed among the patients with normal karyotype. PMID- 21674859 TI - Frequency and prognostic impact of FLT3/ITD mutation in patients with acute myeloid leukaemia. AB - PURPOSE: This study was designed to evaluate the prevalence and the prognostic significance of fms-like tyrosine kinase-3 internal tandem duplication (FLT3/ITD), in acute myeloid leukaemia (AML). METHODS: We reviewed 123 newly diagnosed AML patients who have been treated at the Clinic of Hematology, Clinical Center of Nis, Serbia, during a 5-year period. The correlation between presence of the FLT3/ITD mutation and the subtype of disease according to FAB classification, white blood cell count, incidence of early relapse (<12 months) and overall survival was studied. RESULTS: Among 103 patients for whom molecular analyses had been done, FLT3/ITD mutation was present in 46 (44.7%) cases; the highest frequency was seen in the M0 subtype (63.6%), and the lowest in the M1 subtype (16.7%). There were no statistically significant differences in the FLT3/ITD presence for the 3 groups of patients having different leucocyte counts. The FLT3/ITD mutation was associated with a higher incidence of early relapse compared with no mutation cases (78.7 vs. 21.4%; p < 0.001), and with a shorter survival time (<40 vs. >60 months; p < 0.001). CONCLUSION: The FLT3/ITD mutation is a poor prognostic factor, which occurs frequently in AML, and is associated with higher incidence of early disease relapse and shorter overall survival. PMID- 21674860 TI - Malignancies after rituximab treatment: just coincidence or more? AB - PURPOSE: Rituximab has been successfully used in the treatment of B-cell non Hodgkin's lymphoma (NHL) and some autoimmune diseases nearly for a decade. Several other malignancies and CD20-negative lymphomas have been reported in the literature after rituximab treatment. We aimed to investigate whether there is an association between rituximab treatment and the development of second malignancies. METHODS: A detailed search in English language literature on reports about rituximab treatment and secondary malignancies was made through Medline. The papers were reviewed and the cases were summarized according to secondary tumor types, intervals between rituximab treatment and second malignancy occurrence, indications for rituximab treatment and cytotoxic chemotherapy administration. RESULTS: There were 26 previously reported cases of CD20-negative lymphoma and solid tumors after rituximab treatment. The median age of these cases was 62 years (range 34-80). The median time period from the initiation of rituximab treatment to diagnosis of second malignancies was 5 months (range 1-40). The most frequently reported solid tumors were skin tumors (squamous cell carcinoma and Merkel cell carcinoma) (n=7; 27%), CD20-negative lymphomas (n=5; 20%), Kaposi sarcoma (n=4; 15%), and others (n=10; 38%). CONCLUSION: Association between rituximab and subsequent development of second malignancies might be a coincidence. However, we suggest close monitoring for second malignancies, particularly skin tumors, in patients treated with rituximab. This issue should be evaluated in further studies. PMID- 21674861 TI - Expression analysis of genes involved in epigenetic regulation and apoptosis in human malignant haematopoietic cell lines treated with 5-azacytidine. AB - PURPOSE: The aim of this study was to investigate the modulation of the expression status of 10 different genes involved in epigenetic regulation and apoptosis by the DNA methyltransferase (DNMT) inhibitor 5-azacytidine (5-Aza), as markers of response to treatment, in two different human malignant haematopoietic cell lines. METHODS: In our analysis we used the SybrGreen technology and gene specific primers for the qRT-PCR analysis of 10 genes, in cDNA of PC-MDS and K562 cell lines, treated by 1 micromole of 5-Aza for 24h. RESULTS: DNMT1 and DNMT3A showed statistically significant decrease of expression in 5-Aza-treated PC-MDS cells, whereas DNMT3B showed significantly decreased expression in 5-Aza-treated K562 cells. The members of the Bcl- 2 family of apoptosis-regulating genes Bcl-2 and Bax showed statistically significant differences in expression, in comparison with non-treated PC-MDS cells. Our most interesting result was the significant upregulation (re-expression) of p15, in 5-Aza-treated PC-MDS cells. CONCLUSION: The re-expression of p15 in PC-MDS cell line evaluated by qRT-PCR makes this novel cell line a suitable model for the studies of pharmacologic demethylation as a plausible mechanism resulting in hematologic response in myelodysplastic syndrome (MDS). PMID- 21674862 TI - Treatment and clinicopathologic predictors for adenoid cystic carcinomas of the head and neck. AB - PURPOSE: To retrospectively evaluate the management and clinicopathologic predictors of outcome of adenoid cystic carcinoma (ACC) patients treated and followed at our Department. METHODS: Data on 41 patients treated between 2000 and 2006 at the University of Istanbul, Institute of Oncology, were reviewed. Factors affecting recurrence, distant metastasis and survival were evaluated. RESULTS: There were 22 (53.6%) major salivary and 19 (46.3%) minor salivary gland tumors. Eighteen patients (43.9%) had solid histologic type tumor. Twenty-one (51%) patients had perineural invasion and 28 (68.2%) high grade tumors. Sixteen (39%) patients had stage I disease, 12 (29.1%) stage II and 13 (31.5%) stage III. Thirty-two patients (78.4%) had radical and 9 (21.9%) partial resection. Thirty one patients (75.6%) received adjuvant postoperative radiotherapy (RT). Eight patients (19.5%) suffered locoregional relapse and 9 (21%) distant metastases. Two patients (4.8%) died from ACC and 7 (17%) from other causes. The median follow-up was 48 months (range 24-60). Disease free survival (DFS) at 2 and 3 years were 78% and 58%, respectively. Overall survival (OS) at 2 years and 3 years were 87% and 80%, respectively. Median time to locoregional relapse and distant metastasis was 28 and 32 months, respectively. Seven of 9 patients with distant metastasis had solid tumor subtype. Distant metastasis occurred more frequently in patients with tumors of major salivary glands (66%). Sites of distant metastasis were lung alone (n=5), bone alone (n=2) and 2 patients had both lung and bone metastasis. There was no statistically significant relationship between clinical T stage and solid histology with locoregional relapse (p <0.05). Surgical resection type and perineural invasion were significant prognostic factors for locoregional relapse (p=0.03). T stage (p=0.001), grade (p=0.02) and solid histology (p=0.003) were prognostic factors associated with DFS. Prognostic factors associated with OS were grade (p= 0.001), clinical T stage (p=0.02), solid histology (p=0.01), radical excision (p=0.04) and perineural invasion (p=0.001). CONCLUSION: ACC is a neoplasm in which early diagnosis is important because it is a slow-growing tumor producing diffuse invasion. Distant metastasis and locoregional relapse can be predicted by solid histologic subtype, high grade, type of surgery, perineural invasion and tumor stage. The most frequent sites of metastasis are lung and bone. PMID- 21674863 TI - Percutaneous imaging-guided radiofrequency ablation of small renal cell carcinoma: techniques and outcomes of 24 treatment sessions in 18 consecutive patients. AB - PURPOSE: To evaluate the early clinical experience associated with percutaneous imaging-guided radiofrequency ablation (RFA) in patients with renal cell carcinoma (RCC). METHODS: Eighteen consecutive patients with RCC were treated with percutaneous RFA sessions (24 sessions for 19 solitary RCC in 18 patients: 15 patients underwent a single RFA session, 3 had 2 sessions and one 3 sessions). Treatment indications were localized, solid renal mass <4.5 cm, comorbidities precluding surgery, high operation risk, and refusal to perform surgery. During 23 sessions, RFA was performed using computed tomography (CT) guidance and in one session it was guided by ultrasonography. The average patient age was 76.8+/-7.6 years (range 64-89), and the average renal mass size 3.3 +/-0.7 cm (range 2.0 4.5). Follow-up imaging was performed at 3- and 6-month intervals and yearly thereafter. Successful treatment was defined as lack of enhancement of the treated region on follow-up CT studies. RESULTS: RFA was technically successful in all patients. After the last imaging control, 17 of the 19 tumors were completely necrotic according to the imaging criteria (the secondary clinical success rate was 89.5%). Thirteen tumors were not visible on the first follow-up imaging control (the primary clinical success rate was 68.4% - 13 of 19). In 4 of the 6 patients residual tumors were successfully re-ablated, while in 2 patients repeated RFAs were not performed at the time of writing this report. Five patients (20.8%) developed treatmentrelated complications, including mild pain, large perirenal abscess, mild perirenal hematoma and transient elevation of the white blood cell count. The mean follow-up period was 25.3+/-16.8 months (range 1 51). CONCLUSION: RFA is effective and safe treatment option of exophytic RCC <5 cm in diameter in patients not suitable for surgery due to serious concomitant diseases or advanced age. PMID- 21674864 TI - Concomitant temozolomide and radiotherapy versus radiotherapy alone for treatment of newly diagnosed glioblastoma multiforme. AB - PURPOSE: To study the efficacy and safety of radiotherapy (RT) with concomitant and subsequent temozolomide in comparison to RT alone in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM) after brain surgical intervention. METHODS: Twenty patients received cranial fractionated RT (60 Gy total dose: 2 Gy/day, 5 days/week, for 6 weeks) with concomitant oral temozolomide (75 mg/m(2)/day x 7 days/ week, for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/day * 5 days every 28 days for 6 cycles). Another 20 patients received only cranial RT (Co-60 teletherapy, 60 Gy in 30 fractions). RESULTS: At the end of the study the median time to progression free survival (PFS) was 13 months in the temozolomide plus RT treatment group and 5 months in the RT-alone group (p=0.0001). Median overall survival (OS) in the temozolomide plus RT and the RT-alone group was 19 and 11.5 months, respectively (p=0.0264). The main side effect in the temozolomide plus RT group was myelosuppression. Concomitant treatment resulted in grade 3 hematologic toxicity in 6 patients. CONCLUSION: These data show that the combination of temozolomide, concomitant and subsequent to RT seems more effective than RT alone in patients with newly diagnosed GBM and that multimodality treatment is safe and well tolerated. PMID- 21674865 TI - Serum granulocyte colony-stimulating factor levels in gliomas. AB - PURPOSE: Apart from its known effects on granulopoiesis, granulocyte-colony stimulating factor (G-CSF) is also involved in growth and progression of malignant cells. In this study we report the serum G-CSF levels and their relationship with survival in patients with glial cell tumors. METHODS: Serum G CSF levels of 17 patients (10 male, 7 female, median age 55 years, range 19-75), with histologically proven glial cell tumors and of 17 sex- and age-matched healthy controls were assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS: All patients were treated with radiotherapy and concomitant temozolomide, followed by temozolomide alone. Eight patients were treated with carboplatin plus cyclophosphamide combination as second-line chemotherapy. The median follow-up was 21 months (4-42). The median OS was 36 months (95% CI, 15.7 56.4). Serum G-CSF levels in glioma patients and healthy controls were 44.14 +/- 18.89 pg/ ml and 28.84+/-15.65 pg/ml, respectively (p=0.027). There was no significant correlation between survival time and serum G-CSF levels (r=0.384; p=0.217). CONCLUSION: Serum G-CSF levels were high in glioma patients compared with healthy controls and they may be involved in tumor progression, but the G CSF role in prognosis was not clarified. Further studies with larger numbers of patients must be conducted to elucidate the role of G-CSF in glial cell tumors. PMID- 21674866 TI - Linkage analysis and detection of somatic, postzygous RB1 mutations in Serbian retinoblastoma patients. AB - PURPOSE: The etiology of retinoblastoma (RB) is mutational inactivation of two RB1 alleles, the prototype of tumor suppressor gene. The aim of this research was to reveal sporadic, postzygous RB1 gene mutations, in particular loss of heterozygosity (LOH), from formalin-fixed, paraffin-embedded tumor samples in RB patients, as well as tracking RB1 allele inheritance in 10 RB families. METHODS: The mutational studies were carried out in the peripheral blood lymphocytes' DNA of 4 bilateral and 12 unilateral RB patients and DNAs from tumors from 3 bilateral and 10 unilateral patients. Tumor samples were collected from the same patients whose blood was analyzed. DNA was extracted and linkage analysis and microsatellite markers method were performed. LOH for two RB1 intragenic markers was analyzed. RESULTS: Ten LOH were found in the area of two intragene microsatellite loci. Linkage analysis revealed inheritance of RB1 alleles in 10 families. LOH was found in 63.16% of tumors. CONCLUSION: Peripheral blood lymphocytes' DNA gives better results as a control group for somatic mutations than DNA isolated from eye tissue outside the tumor. Linkage analysis is essential for identifying the individual risk, offering the possibility of an adequate genetic counseling in familial RB. PMID- 21674868 TI - N-acetylcysteine ameliorates nitrosative stress on radiation-inducible damage in rat liver. AB - PURPOSE: The present study was designed to investigate the potential radioprotective effects of N-acetylcysteine (NAC) on radiation-induced nitrosative stress caused by gamma irradiation (single dose, 6 Gy) in rat liver. METHODS: The rats (n=40) were divided randomly and equally into 4 groups: Control (C), Radiation (R), R+NAC (received irradiation and 1,000 mg/kg of NAC) and R+WR 2721 (received irradiation and 200 mg/kg of WR-2721). Liver tissue of each animal was harvested and utilized for 3-nitrotyrosine (3-NT) detection using high performance liquid chromatography- ultraviolet (HPLC-UV) system. RESULTS: In the R rats, 3-NT levels significantly increased when compared to those of the C rats (p<0.05). There were no significant differences in the 3-NT levels among R+NAC and R+WR-2721 rats. Histologically examined liver tissue samples showed no obvious differences. CONCLUSION: The present study suggests that irradiation has a negative effect on the cellular proteins by enhancing 3-NT formation. The prophylactic use of NAC seems to reduce the nitrosative damage during radiotherapy. PMID- 21674867 TI - Apple pomace: antiradical activity and antiproliferative action in HeLa and HT- 29 human tumor cell lines. AB - PURPOSE: Apple pomace is an easily accessible source of bioactive compounds which can be used for various purposes in the food, pharmaceutical and cosmetic industry. Six types of apple pomace extracts were tested to study their health benefits, free radical scavenging and antiproliferative activities. METHODS: The radical scavenging activity was determined by electron spin resonance (ESR) spectroscopy. Antiproliferative action was measured using MTT [3-(4,5 dimethylthiazol- 2-yl)2,5-diphenyl tetrazolium bromide] colorimetric assay in cervix epithelioid carcinoma (HeLa) and colon adenocarcinoma (HT-29) human cancer cell lines. RESULTS: All extracts suppressed the formation of 2,2-diphenyl- 1 picrylhydrazyl (DPPH?) and hydroxyl-free radical in a dose-dependent manner. In the presence of 12.5 mg/ ml Pinova, Reinders and Nectar pomace extract, the ESR DPPH? signals vanished. The ?OH was completely scavenged in the presence of 45 mg/ml or higher concentration of the investigated extracts. Pinova and Braeburn pomace extracts showed the strongest antiproliferative activity against the investigated human cancer cell lines. Also, HeLa cells were found more sensitive than HT-29 cells to all extracts. CONCLUSION: Although the relationship between radical scavenging activities and phenolic contents or flavonol glycosides (R(2)>=0.80) was high, there were no significant correlations between the total phenolic contents or individual phenolic compounds and the antiproliferative activity. PMID- 21674869 TI - Invasive mechanical ventilation in cancer patients. Prior non invasive ventilation is a poor prognostic factor. AB - PURPOSE: Prior non invasive ventilation (NIV) is associated with an increased mortality in patients with haematological malignancies and acute respiratory failure treated by invasive mechanical ventilation (IMV). We have assessed whether NIV failure is an independent prognostic factor for hospital discharge in a general cancer population treated by IMV. METHODS: 106 patients with solid tumors and 58 patients with haematological malignancies were eligible for this retrospective study; 41 were treated by NIV before IMV. RESULTS: The main indications for mechanical ventilation were sepsis/shock (35%), acute respiratory failure (33%), cardiopulmonary resuscitation (16%) and neurologic disease (10%). Respectively, 35%, 28% and 24% of the patients were extubated, discharged from the intensive care unit (ICU) and from the hospital. For patients treated with NIV prior to IMV, the rates were 22%, 17% and 10%, respectively. In multivariate analysis, 3 variables were independently associated with a decreased probability of being discharged from the hospital: NIV use before IMV (odds ratio/OR=0.30, 95% confidence interval/CI: 0.09-0.95; p=0.04); leukopenia (OR=0.21, 95% CI: 0.06 0.77; p=0.02) and serum bilirubin >1.1 mg/dl (OR=0.38, 95% CI: 0.16-0.94; p=0.04). CONCLUSION: NIV failure before IMV is an independent poor prognostic factor in cancer patients treated by IMV. PMID- 21674871 TI - Pulse carboxyhemoglobin-oximetry and cigarette smoking. AB - PURPOSE: We used a pulse carbon monoxide (CO)-oximeter to measure the levels of carboxyhemoglobin (COHb) in smokers and non-smokers. Our goal was to determine if this device could not only define smoking status, but also to increase accuracy of self-reported data at various surveys on smoking. METHODS: Thirty-four healthy volunteers participated in this study. Twenty-two of them were current daily smokers; 12 participants were non-smokers who lived alone or with a nonsmoker, and who worked in non-smoking environment. Nicotine dependency level was determined by the modified Fagerstrom questionnaire. Blood COHb levels were measured with a pulse CO-oximeter (Masimo, Radical 7). RESULTS: The COHb levels in both moderate/heavy smokers and light smokers increased significantly after they smoked a single cigarette. This increase persisted for more than 6 h in the moderate/heavy smokers, while in the light smokers COHb levels returned to the baseline level after one hour. The pulse rate of all smokers increased significantly 20 min after smoking. CONCLUSION: We conclude that the CO-oximeter can detect smoking by moderate/heavy smokers and light smokers if they smoked 6 h or 20 min earlier, respectively. We concluded that it could be used as a validation test for smoking at the time of admission to the surgical facility and to increase smoking abstinence during preoperative and postoperative periods. This noninvasive, simple and inexpensive test may also be used at various surveys to increase accuracy of self-reports on smoking. PMID- 21674870 TI - Metastatic lung disease treated with pemetrexed-docetaxel combination chemotherapy. AB - PURPOSE: According to the ASCO guidelines 4 cytotoxic agents are used in colorectal cancer. Numerous agents have not been used or tested and thus their effectiveness is not known. Herein we present the preliminary data of a trial whose objective was to investigate the effectiveness to 2 combined agents in patients with heavily pretreated adenocarcinomas. METHODS: Ten patients have been recruited up until now. Colorectal adenocarcinoma was the primary disease in 7 patients, gastric cancer in 2, and endometrial adenocarcinoma in one. All patients had undergone at least 2 lines of previous chemotherapy during 2-3 years before the trial. The lungs were the only or main site of metastases in all patients. Chemotherapy agents used were pemetrexed 500 mg/m(2) and docetaxel 75 mg/m(2), repeated every 3 weeks, with a plan to administer 6 cycles. RESULTS: The mean number of cycles were 3 (range 1-6). Total number of cycles 33. No serious toxicity was detected. One patient had complete response, 3 partial response, 5 stable disease, 1 disease progression. Median survival was 6 months (range 2-12+ months). CONCLUSION: The effectiveness of the pemetrexed-docetaxel combination in heavily pretreated adenocarcinoma patients justifies their use when no other alternative exists. PMID- 21674872 TI - Real-time ultrasound-guided fine needle cytology of the thyroid gland by capillary action. A modified technique without aspiration. AB - PURPOSE: To present a modified technique of real-time (Rt) ultrasound-guided (Ug) fine-needle (FN) cytology of thyroid nodules without aspiration (RtUg-FNNAC). METHODS: We retrospectively studied 958 patients with 1202 thyroid nodules referred to our institution between January 2009-January 2010. The efficacy of RtUg-FNNAC was determined by the number of satisfactory specimens that were obtained. Furthermore, we compared the RtUg-FNNAC results with the surgical histological results. RESULTS: All specimens were adequate for diagnosis. Two hundred and twelve (22.1% patients with malignant cytological findings and 20 (2.1%) with indeterminate cytological findings were referred for surgery. All nodules with malignant and indeterminate cytological findings were confirmed histologically. From 20 indeterminate cytological findings 17 (85%) were malignant. From 66 patients with initial benign RtUg-FNNAC who were subjected to surgery the results were true negative in 65 and false negative in 1. Finally, RtUg-FNNAC was true positive in 229 cases and false positive in 3. The overall sensitivity, specificity, positive predictive value and negative predictive value of RtUg-FNNAC were 99.6, 95.6, 98.7 and 98.7%, respectively. Accuracy for the detection of malignancy was 98.7%. CONCLUSION: RtUg-FNNAC is a technique that combines the benefits of real time US-guidance with those of capillary action sampling, maximizing cellular yield and minimizing bloody artefacts in cytologic examination. PMID- 21674873 TI - Mechanisms behind the aspirin use and decreased breast cancer incidence. PMID- 21674874 TI - Primary breast mantle cell lymphoma with atypical relapse patterns. PMID- 21674875 TI - Resection of giant follicular thyroid carcinoma infiltrating the trachea. PMID- 21674876 TI - Recurrent episodes of recall dermatitis of irradiated breast after LHRH agonist administration. PMID- 21674877 TI - BRCA-deficient and triple negative breast cancers: is olaparib effective in both subtypes? PMID- 21674878 TI - Uterine cancer through the works of the eccentric Auguste Joseph Lutaud (1847- 1925), famous gynaecologist, publisher and intellectual of the 19th century. AB - Auguste Lutaud was standing for almost half century in front of the French and International stage for his controversy and eccentric personality, his undisputed authority in gynecology, his writings and his publishing success. Thanks to his writings, he is considered as the main propagator of the prevailing ideas on uterine cancer diagnosis and treatment. PMID- 21674880 TI - Couples testing may provide benefits to U.S. gay population. PMID- 21674879 TI - Transmission. Breastfeeding may cause drug resistance in infants. PMID- 21674881 TI - Study looks at ban on HIV-positive organ donation. PMID- 21674882 TI - Privacy is not a right when government interest exists. PMID- 21674883 TI - Scientist filed claims of disability discrimination too late. PMID- 21674884 TI - Women and depression. It is not clear what underlies the gender gap in this mood disorder. PMID- 21674885 TI - Assertive community treatment. This individualized, comprehensive care benefits patients with severe mental illness. PMID- 21674886 TI - New insights into the nocebo response. Research is providing clues about a phenomenon that is the exact opposite of the placebo response. PMID- 21674887 TI - Study strengthens evidence that early marijuana use increases risk of psychosis. PMID- 21674888 TI - My daughter tells me her new roommate is afraid to leave a 10-block area around their apartment in New York City. She has something called agoraphobia. What is that? PMID- 21674889 TI - Phase II study of weekly paclitaxel following fixed three cycles of S-1-based chemotherapy for advanced gastric cancer. AB - BACKGROUND/AIMS: Awareness of the clinical importance of second-line chemotherapy for incurable gastric cancer has been increasing. To assess the clinical validity of the new concept that second-line chemotherapy following predetermined cycles of first-line chemotherapy would improve survival, we conducted a phase II study. METHODOLOGY: Patients with pathologically proven incurable gastric adenocarcinoma and adequate organ functions were enrolled. S-1 or S-1 plus cisplatin was administered as first-line chemotherapy. The number of cycles of S-1-based chemotherapy was determined to be three as a maximum unless there was disease progression. The treatment was followed by weekly administration of paclitaxel. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and safety. RESULTS: Thirty-seven patients were eligible for enrollment. Twenty-eight patients (76%) underwent the second-line chemotherapy with paclitaxel after completion of S-1-based chemotherapy or disease progression. Treatment-related grade 3 or 4 toxicity was noted in 14 patients during S-1-based chemotherapy, and in 6 patients during paclitaxel treatment. The median survival time was 455 days and the median progression-free survival was 229 days. CONCLUSIONS: Sequential set chemotherapy with three cycles of S-1-based chemotherapy followed by weekly paclitaxel is feasible. The survival results are equivalent to those of other current regimens using S-1. PMID- 21674890 TI - [Superbugs from elsewhere]. PMID- 21674891 TI - [Herpes simplex virus infections, an update for the practitioner]. AB - The herpesviruses HSV-1 and -2 classically infect the oral and genital area respectively. They descend from a common ancestor but have evolved separately since several million years, getting each adapted to these areas. Thus, while both can infect either site, HSV-1 reactivates often orally, while HSV-2 does so in the genital area. The followings facts are stressed, because we think they are new, or worth attention regarding HSV epidemiology (plateauing of the HSV-2 epidemic in the US, growing share of HSV-1 as a genital herpes agent), clinical expression (extra-oral and extra-genital lesions, severity of gingivostomatitis), diagnosis (confusing herpes and zoster in the trigeminal and sacral areas) and treatment (relative worth of suppressive and episodic treatments of genital herpes, as well as shortening of these latter, and treatment of gingivostomatitis and herpes labialis). PMID- 21674892 TI - [Diabetic foot infection: a multidisciplinary approach]. AB - Diabetic foot infection is a frequent, multifactorial and multifacettal disease. Its management requires an interdisciplinary collaboration. Multiple medical and surgical specialties are enrolled for its prevention and treatment, for good reasons. Concomitant management by various specialists shows a significant reduction in amputation rates. We review the issues of this interdisciplinary collaboration. PMID- 21674893 TI - [Varicella during pregnancy: consequences for the mother and the newborn]. AB - In our area, varicella is a frequent and essentially benign childhood disease. In contrast, the disease course is likely to be more severe or complicated in the adult, particularly so in the pregnant woman. There is a definite risk of congenital varicella syndrome when the chickenpox occurs during the first 20 weeks of pregnancy. This syndrome predominantly affects the skin, the subcutaneous tissue, muscles and bones, as well as the central nervous system, and can bring about major functional sequellae. In case of chickenpox occurring at the very end of pregnancy, transplacental transfer of the virus may result in a perinatal varicella disease. We propose a approach of each of these different situations. PMID- 21674894 TI - [Controversies regarding the pathogenesis of cardiovascular diseases in HIV patients]. AB - Controversies regarding the pathogenesis of cardiovascular diseases in HIV patients Since the introduction of HAART (Highly active anti-retroviral therapy), the incidence of cardiovascular events has risen in patients infected with HIV. This development is mainly due to the increased survival in these patients. Nonetheless, the pathogenic effects of HIV on the principal components of haemostasis (endothelium, platelets and the clotting cascade) are the subject of numerous ongoing research studies, and are becoming an argument for starting HAART or for modifying the components of an established therapy. The aim of this article is to raise clinician awareness regarding the issue of cardiovascular disease in the HIV-infected patient. PMID- 21674895 TI - [Urinary tract infections in adults]. AB - Urinary tract infections are commonly seen by general practitioners. Quinolones are frequently prescribed in this setting. The emergence of resistance to these antibiotics has led to new guidelines for the management of uncomplicated UTI, based on the use of fosfomycin and furadantine. This article reviews the epidemiology, pathogenesis, diagnostic and treatment of urinary tract infections in adults. PMID- 21674896 TI - [Critical pathway for community-acquired pneumonia]. AB - A clinical pathway is a methodological tool for standardizing medical practice, improving the quality and efficiency of care delivery, and enhancing the diffusion of evidence-based medicine. Despite the fact that a majority of trials have shown that the use of clinical pathways improves certain specific outcomes such as length of stay or complications, the overall impact of these pathways in the clinical setting has yet to be documented. In the setting of community acquired pneumonia, a few observational and one large randomized trial have shown positive effects on various outcomes. We describe in this article the clinical pathway for community-acquired pneumonia developed at our institution. PMID- 21674898 TI - [Management of neglected diseases: efficacy of an innovative approach]. PMID- 21674897 TI - [Iron therapy: proof of efficacy and good clinical practice]. AB - Efficacy of iron therapy, whether oral or intravenous, on biological markers of body iron stores is well recognized in medical literature, but current studies are heterogeneous, of sometimes dubious quality, and rarely address clinical outcomes. Precise practical guidelines appear available only for indications related to kidney disease. First-line intravenous use is reserved for situations comprising chronic renal failure, or patients presenting with malabsorption syndromes such as in inflammatory bowel disease. In all other situations, because of the non-negligible risk of hypersensitivity reactions, intravenous iron use is considered justified only in clinically sustained indications, for patients in whom oral administration of iron is unsatisfactory or impossible. PMID- 21674900 TI - [Miscellaneous ethics (2)]. PMID- 21674899 TI - [France bans all techniques of lipolysis]. PMID- 21674901 TI - [How to live better with dying?]. PMID- 21674902 TI - [My hospital]. PMID- 21674903 TI - [Freelance hurdlers]. PMID- 21674904 TI - [Freelance nursing at the crossroads]. PMID- 21674905 TI - [3 health policy priorities are launched]. PMID- 21674906 TI - [Bringing light into the dark emotional landscape]. PMID- 21674907 TI - [Strong relationships strengthen children]. PMID- 21674908 TI - [There are still some problems to solve]. PMID- 21674909 TI - ["I could touch heaven today"]. PMID- 21674910 TI - [Appeal against the decision paid off]. PMID- 21674911 TI - [Supporting the backbone of the team]. PMID- 21674912 TI - [From dream to nightmare]. PMID- 21674913 TI - [What happens when night falls?]. PMID- 21674914 TI - [Suitable packaging and... stay calm!]. PMID- 21674915 TI - [Of buried pain]. PMID- 21674916 TI - [Health figures]. PMID- 21674917 TI - [Endogenous affective disorders: problems of systematics and typology]. AB - A classification of endogenous affective disorders based on clinical manifestations of a concrete disease is proposed. It reflects one of the stages of investigations into the structure of psychopathological manifestations of depressive and maniacal disorders. Further studies may provide data for the adjustment of the classification to the current diagnostic strategies. PMID- 21674918 TI - [Endogenous anesthetic depressions (psychopathology and typology)]. AB - The psychopathological structure of anesthetic depressions was studied in 80 patients with progredient schizophrenia. Three variants of anesthetic depression were distinguished, viz, anxiety anesthesia with agitation, sensorial psychic anesthesia, and multiple depersonalization symptoms; melancholic anesthesia with the depressive triad, self-reproach ideas and sensorial ideatory psychic anesthesia; anesthesia proper with ideatory psychic anesthesia as the main or sole manifestation of depression. The study revealed transitions of these variants in the structure of schizophrenic episodes from anxiety anesthetic to melancholic anesthetic and further on to purely anesthetic ones. The latter type of depression proved refractory to antidepressive therapy and tended to persist for a long time. PMID- 21674919 TI - [Clinical and psychopathological aspects of endogenous apathetic depressions]. AB - The study included 45 patients with endogenous apathetic depressions differing in clinical picture and psychopathological structure. Typological classification of these depressions into 3 variants dominated by decreased interests, initiative or will is proposed. The problem of nosological identification of apathetic depressions is discussed. Dynamics of these conditions in the structure of endogenous affective diseases and paroxysmal progredient schizophrenia is described. PMID- 21674920 TI - [Clinico-psychopathological features and dynamic aspects of long-standing and chronic endogenous depressions]. AB - Long-sanding depressions are defined as protracted depressive conditions lasting at least 2 years with subsequent spontaneous or therapeutic high-quality remission (intermission) and fully reversed depressive disorders, recovery of the premorbid psychic functions, personality traits and quality of life. Two variants of long-standing depressions, simple and polymorphic, are distinguished based on peculiarities of the psychopathological structure. The practicability of classification of long-standing depressions and their dynamics by phase states is discussed. Chronic depressive states are distinctive for well-apparent polymorphism of disorders and gradual aggravation of depressive symptoms up to neurosis-like and delusional register without a tendency toward spontaneous normalization and with only low-quality therapeutic remission with residual productive symptomatology. Four types of chronic depressions are distinguished: melancholic, apathoadynamic, depressive-hypochondriac, and depressive depersonalizing. Three variants of dynamics of chronic depressions are described: dynamic-inert, dynamic-labile, and dynamic with continuous aggravation of the disorder. The appropriateness of discussion of chronic depressions in terms of protracted progressive attacks and conservation of their psychopathological basis throughout the period of the disease is considered. The principles of therapy of long-standing and chronic endogenous depressions are briefly outlined. PMID- 21674921 TI - [Depressions in Alzheimer's disease]. AB - The aim of this work was to study clinical and pathogenetic aspects of depression associated with Alzheimer disease (AD) in 65 patients. Depressive symptoms are shown to frequently occur in all types of the disease and at all stages of its therapy. A variety of syndromic variants of depression are identified in the structure of dementia: anxiety (35.4%), apathetic (29.2%), delusional (16.9%), hypochondriac (10.8%), melancholic (7.7%). Situation-reactive, endoreactive, and endogenous types of depression were distinguished depending on its pathogenetic mechanisms. Great variety of clinical and psychopathological manifestations and mechanisms of depressive pathology in AD suggests its heterogeneous character. PMID- 21674922 TI - [Psychopathology of acute paraphrenic syndrome, its typological forms and their relation to variants of paroxysm-like progredient schizophrenia]. AB - A total of 60 patients with different forms of paroxysm-like progredient schizophrenia were examined to clarify psychopathology of acute paraphrenic syndrome in different variants of the disease. Three typological variants were distinguished: with picturesque delirium, manifestations of Knadinsky-Clerambault syndrome, and confabulation disorders. It was shown that paroxysm-like progredient schizophrenia akin to recurrent one is characterized by acute paraphrenic syndrome with picturesque delirium; paroxysm-like progredient schizophrenia akin to juvenile malignant one is characterized by acute paraphrenic syndrome dominated by Knadinsky-Clerambault syndrome and picturesque delirium; paroxysm-like progredient schizophrenia akin to paranoid one is characterized by acute paraphrenic syndrome dominated by Knadinsky-Clerambault syndrome or acute paraphrenic syndrome with confabulation disorders. The study confirms specificity of acute paraphrenic syndrome for paroxysm-like progredient schizophrenia PMID- 21674923 TI - [Psychopathology and clinical features of oneiroid-catatonic conditions during endogenous diseases]. AB - Psychopathology and clinical features of oneiroid-catatonic conditions during endogenous diseases remain a topical problem in modem psychiatry. The author describes psychopathologcal features of oneiroid depending on the form of the affect and presents new data on its relation to peculiarities of the development of attacks. PMID- 21674924 TI - [Paroxysmal and paroxysmal-like conditions during schizophrenia]. AB - The clinical picture of paroxysm-like progredient schizophrenia in 104 patients was characterized by a combination of schizophrenic symptomatology, paroxismal and paroxysm-like disorders. Investigation of their psychopathological structure showed that they differ from that of epileptic paroxysms. The data obtained provide a basis for distinguishing a special variant of endogenous process and developing criteria for typological classification of paroxismal and paroxysm like disorders. PMID- 21674925 TI - [Clinical psychiatry and the problem of investigation of new psychopharmacological agents]. AB - Problems of future development of psychopathology and clinical psychopharmacology are discussed. It is shown that the study of efficacious psychopharmacological agents is closely related to the study of the psychopathological structure of psychic disorders, problems of therapeutic resistance and maintenance treatment. PMID- 21674926 TI - [Prognosis of probability of the development of atrial fibrillation after successful surgical correction of mitral valvular disease]. AB - The estimation of frequency of occurence of atrial fibrillation in patients with mitral valvular diseases was made before operation and at the early postoperative period. A logistic regressive analysis has shown that the appearance of atrial fibrillation in long-term periods is influenced by 4 independent preoperative factors: preoperative atrial fibrillation, age, anterior-posterior size of the left atrium, diagnosis of rheumatism. The dependence of the appearance of atrial fibrillation on the preoperative status of the patient was detected. A statistical model having the prognostic value 89.6% has been constructed. The model is good in use, reliable and can be effectively used in everyday clinical practice in order to determine the probability of the appearance of atrial fibrillation at the postoperative period of the concrete patient and decision on necessity of surgical ablation. PMID- 21674927 TI - [Causes of the appearance of abdominal adhesions after primary aseptic operations on the gastrointestinal tract and the method of their prophylactics]. AB - The author describes the phenomenon of infection of the abdominal cavity through the intestinal suture with million of microbes and formulated an original hypothesis of the cause of abdominal adhesions after primary aseptic operations on the gastrointestinal tract according to which the appearance of postoperative abdominal adhesions was due to infection through physically hermetic intestinal suture. As opposed to well known hypotheses, this hypothesis explains all unclear facts of postoperative adhesions. On its basis a simple and effective method of prophylactics of postoperative abdominal adhesions was developed which results in the formation only of adhesions of the omentum with the intestinal suture without abdominal adhesion. The use of the method gave positive results in clinical practice. PMID- 21674928 TI - [Acute gastroduodenal bleedings against the background of diabetes mellitus]. AB - The authors have analyzed results of treatment of 60 patients with acute gastroduodenal bleedings against the background of diabetes mellitus. The main methods of diagnosis are the endoscopic and laboratory methods. In 60% of the patients the source of bleeding was acute erosion-ulcerous lesions, in 40% chronic ulcers. Choice of the method of treatment depended on the source of bleeding, the degree of carbohydrate metabolism, the spectrum of concomitant pathology. Endoscopic hemostasis is the method of choice in treatment of acute and chronic ulcers of high risk of relapses in somatically burdend patients. PMID- 21674929 TI - [Specific features of medico-diagnostic strategy for cholesterosis of the gallbladder]. AB - The work shows the incidence, criteria of the diagnosis and indications for surgical treatment of patients with cholesterosis of the gallbladder. An analysis of the results of examination and treatment of 3426 patients with diseases of the gallbladder has shown that the ultrasonic method of diagnostics allows detection of the cholesterosis form and determination of treatment strategy. PMID- 21674930 TI - [Antioxidant therapy for acute thrombosis of hemorrhoidal nodes]. AB - Under observation there were 45 patients with different degree of acute thrombosis of hemorrhoidal nodes. Hemorrhoidectomy after Milligan-Morgan was fulfilled in all the patients. Laboratory analyses have shown increased lipid peroxidation (LP) and weakened antioxidant defense (AOD) in the patients before treatment. Against the background of the therapy with antioxidant thioctacide there were considerably decreased inflammatory phenomena by the operation moment, rapid normalization of LP and AOD, substantially decreased number of complications in the postoperative period and early labor rehabilitation of the patients. PMID- 21674931 TI - [Surgical correction of damage in complex treatment of patients with metabolic syndrome]. AB - The authors have analyzed results of treatment of 407 patients subjected to different bariatric interventions. In 359 out of them there were different bariatric operations, in 48 patients intragastric balloons were placed. Correcting plastic operations were fulfilled in 36 patients within 1-2 years after bariatric intervention. It was found that bariatric intervention fulfilled in earlier age groups would prevent the development of metabolic syndrome (MS) in patients with obesity at later date. Combined operations are most effective bariatric intervention compared with all main elements of MS. Correcting plastic operations are expedient after bariatric interventions against the background of stabilized decrease of body mass that allows getting valuable therapeutic and esthetic effect, improvement of quality of life of patients. PMID- 21674932 TI - [Assessment of surgical correction of parameters of the vertebral-motor segment in traumas and degenerative diseases of the vertebral column]. AB - Retrospective clinico-radial data obtained in 163 patients were compared with traumas and degenerative diseases of the vertebral column of those who were treated by decompressive and decompressive-stabilizing interventions. Characteristic alterations were determined such as considerably decreased area of the spinal canal (in 44.2% of the patients), intervertebral foramen (in 57.7%) and the volume of intervertebral canal (in 66.3%), which allowed specification of the character and volume of the operative interventions and objective assessment of adequacy of surgical correction. PMID- 21674933 TI - [Surgical treatment of anorectal diseases in children]. AB - The authors have analyzed results of treatment of 189 children aged from 6 months to 3 years and older, using different variants of operations. It was shown that positive immediate and long-term results in patients with high and mean forms of anorectal diseases were obtained after posteriorsagittal and abdomino posteriorsagittal anoplasty. PMID- 21674934 TI - [Analysis of results of prehospital treatment of complicated purulent diseases of upper extremity]. AB - An analysis of 2848 cases of complicated purulent diseases of upper extremities has determined the main errors of the prehospital treatment of the infection. Irrational self-reliant and ambulatory treatment resulted in the appearance of marked functional and anatomical defects of the affected extremity which lead to considerable economical costs. The following principal ways to solve the found problems were established: sanitary-educational work among the population, training of the ambulatory link of specialists to learn modern aspects of the diagnosis and treatment of purulent diseases of upper extremities. PMID- 21674935 TI - [Choice of the operation for perforated ulcers of the stomach and duodenum]. AB - Actual questions of diagnostics and treatment of 776 patients with perforated gastroduodenal ulcers are discussed. The most informative method of the diagnosis, particularly covered perforation, is laparoscopy. Decision on the operation must be individually grounded. Radical operations were performed in 599 patients with 2% postoperative lethality. Lethality after suturing of the perforation was 10.3%, after resection operations--4.1%, after suturing the perforation in combination with selective proximal vagotomy--0.3%. PMID- 21674936 TI - [Gastroduodenal bleedings as a problem of emergency surgery]. AB - An analysis of 3938 observations gave data on the frequency of different causes of gastrointestinal bleedings, specific features of performing endoscopies during making diagnosis, endoscopic signs of gastrointestinal bleedings, possible technical diagnostic and tactical errors, methods of endoscopic hemostasis. Modern national and foreign digital endoscopes are assessed. PMID- 21674937 TI - [Successful treatment of patients with a severe combined trauma]. PMID- 21674938 TI - [Practical value of certain prognostic scales in wound dystrophy]. AB - The authors gave comparative characteristics of the data available in literature and the scales of evaluation of the severity and prognosis of wound dystrophy used by them. PMID- 21674939 TI - [Is the technisism of surgery guilty in insufficient professional level of the present-day doctor?]. PMID- 21674940 TI - [Two views]. PMID- 21674941 TI - [Clinical picture, diagnosis and prognosis of surgical treatment of hypophisis adenomas in women with disturbed reproductive function]. PMID- 21674942 TI - [Methods of extracorporeal hemocorrection in treatment of atherosclerosis]. PMID- 21674943 TI - [Polymer prostheses for hernioplasty: production, properties, possible improvements]. PMID- 21674944 TI - [Evolution of the technology of using synthetic implants in hernioplasty]. PMID- 21674945 TI - [Etiopathogenetic aspects and diagnostics of recurrent echinococcosis of the liver]. PMID- 21674946 TI - [The up-to-date data on congenital contracture of the elbow joint]. PMID- 21674947 TI - [Structural genomic damages in workers of plutonium production]. AB - The research objective is assessment of structural genomic damages in plutonium workers. The study group included the Mayak nuclear workers subject to chronic occupational exposure to incorporated 239Pu and/or external gamma-rays. The analysis was performed based on the culture of lymphocytes in peripheral blood. The yield of intra-chromosomal exchange aberrations of chromosomal type on stained slides was analyzed using in situ fluorescent hybridization, mBAND. Linear relationships were revealed between (a) the total yield of chromosomal type aberrations (e.g. intra- and inter-chromosomal ones) and an absorbed dose from external exposure of the red bone marrow to gamma-rays, an absorbed dose from internal exposure to a-radiation from incorporated 239Pu; and (b) the yield of intra-chromosomal exchange aberrations of chromosomal type and an absorbed dose from exposure of the red bone marrow to 239Pu and 239Pu body burden. PMID- 21674948 TI - [Effect of low doses of low-intensity ionizing radiation on the DNA structure and functions]. AB - Chronic effects of low doses of low intensity ionizing radiation (IR) on biological objects have now become of great social significance. This has given a considerable impetus to research into biological effects and mechanisms of such exposures both in Russia and abroad. This paper provides an overview of physicochemical and molecular bases of the IR influence at small doses and the ways of cell protection from the radiation damage, as well as the analysis of characteristic features and differences in the effects of radiation at small and high doses. We consider the DNA radiation damage both in cell cultures and in vivo, as well as processes and results of their repair. Particular attention is paid to the changes in the basic paradigms of radiation biological effects of small doses. PMID- 21674949 TI - [Influence of ionizing radiation, application of iron ions and their chelate complexes on the oxidative status of blood serum of rats]. AB - Influence of ionizing radiation, ions of iron and their chelate complexes on the oxidative status of blood serum of rats has been investigated. Animals were irradiated by gamma-rays 60Co at a dose of 4 Gy. Ions of iron and iron chelates with nitrilotriacetic acid and citric acid were introduced into animals intra abdominally at a doze of 10 mg of iron on 1 kg of body weight. The oxidative status of blood serum was determined according to the estimated content of oxidizing peroxide equivalents which oxidize ferrous iron in ferric iron with the subsequent estimation of ferric iron by means of xylenol orange. We also estimated the total content of iron in blood serum using ferrozine as an indicator. The oxidative status was defined 24 and 96 hours after irradiation and 2 hours after introduction of iron ions and their chelates. The research conducted has shown that the concentration of oxidizing peroxide equivalents in serum and the total iron concentration increase 1.47 times and 1.63 times correspondingly 24 hours after irradiation. The increase in the content of oxidizing peroxide equivalents and iron owing to Fenton's reaction can lead to the appearance of OH* radical and raise the level of damage of nuclear and membrane structures in irradiated cells. 2 hours after introduction of iron ions and their chelates, the content of oxidizing peroxide equivalents increased in the blood serum of irradiated and non-irradiated rats, and the maximum effect was observed when introducing ferrous iron and its chelate with citric acid. PMID- 21674950 TI - [Peculiarities of modifying influence of the factors forming the functional status of the central nervous system on dynamics of the rat higher nervous activity disturbances totally exposed to electron and gamma-radiation at a dose of 100 Gy]. AB - The dynamics of using a stabilized motor defensive conditioned reflex of active avoidance in "shuttle-box" in rats after the total influence of high energy electrons and gamma-rays at a dose of 100 Gy and a modifying influence of the two most important factors forming the functional status of the central nervous system: the stage of the conditioned reflex consolidation and typological peculiarities of the higher nervous activity have been investigated. The influence of both types of ionizing radiation has been shown to cause far more profound disturbances of non consolidated conditioned reflexes in comparison with the automatized conditioned reflexes and provoke an inverted picture of disturbances in the animals with opposed peculiarities of the higher nervous activity. The qualitative picture of the dynamics of disturbances that are caused by these types of radiation is identical. In summary, the studied conditions that form the functional status of the central nervous system determine the nature of neuroradiation syndrome to a greater extent than differences in the effectiveness of these types of radiation. PMID- 21674951 TI - [Radioprotective properties of indralin combined with cystamine and mexamine]. AB - The study of indralin radioprotective properties at its joint application with cystamine and mexamine was carried out in the experiments on inbred mice and rats. The mice and rats were exposed to whole-body y-irradiation at a dose of 9.0 and 9.5 Gy, correspondingly. A combined parenteral administration ofindralin and cystamine at a dose of 25 mg/kg showed ponentiaton of indralin radioprotective properties up to a level of the ED50 effect versus the absence of or a weak radioprotective effect in the case of their separate application. In the experiments on rats, indralin (50 mg/kg) and mexamine (12 mg/kg) injected intraperitoneally almost completely eliminated the animal mortality from the intestinal syndrome of acute radiation sickness amounting in the control radiation group to 60% on the 7th day after exposure to radiation at a dose of 9.5 Gy. However, at the above conditions, radioprotectors at these doses had a low-level radioprotective action at the onset of the bone marrow syndrome of acute radiation sickness. Combined application of indralin and mexamine at the same doses and at the same conditions led to a radiation protection 50% as high as in the case when radioprotectors were applied separately at a double dose. PMID- 21674952 TI - [The influence of combined application of quercetin and indralin on post irradiation repair of hematopoiesis in acute radiation injury]. AB - Experiments on mice-hybrids F1(CBA x C57B1/6) have detected a favorable effect of the associated application of quercetin (30-60 minutes before y-exposure of an animal) and a radioprotectant of urgent action indralin (in the case of its application after y-exposure) on a post-irradiation repair of the hematopoietic tissue in acute radiation sickness after y-exposure at a non-lethal dose of 6.7 Gy, which manifested itself in the accelerated formation of endogenous spleen colonies and spleen mass recovery, as well as in the lesser degree of leukopenia on the 12th and the 16th day after acute radiation injury. Quercetin per se did not have a radio-protective effect. PMID- 21674953 TI - [Peculiarities of metabolism of UV-irradiated lymphocytes]. AB - The influence of UV-light (240-390 nm) at a dose of 151 and 755 J/m2 on the functional properties of lymphocyte metabolism key enzymes from donors' human blood: lactate dehydrogenase (LDH), cytochrome c oxidase, succinate dehydrogenase (SDH), Ca2(+)-ATPase of plasma membranes has been investigated. It has been revealed that photoinactivation of enzymes immediately after UV-irradiation which leads to the decrease of the ATP content in lymphocytes is replaced by the increased activity of the enzymes under investigation during daily incubation of lymphocytes. As a result, the level of ATP in photo-modified lymphocytes does not differ from that in native cells before incubation. This indicates the normalization of biochemical processes in lymphocytes influenced by UV-light applied in autotransfusion of UV-irradiated blood. PMID- 21674954 TI - [Level of receptor complex molecule expression of human blood T-lymphocytes under conditions of their UV-irradiation]. AB - The influence of a wide range of doses of UV-light (240-390 nm) on the expression level of receptor complex molecules (CD3, CD4, CD8 markers) on the membrane surface of human blood T-lymphocytes has been studied using flow cytometry and enzyme linked immunosorbent assay. UV-light at small and medium doses (15 1, 453 and 906 J/m2) has been established to have a unidirectional (activating) effect on the expression level of receptor complex molecules, and at a high dose of 1359 J/m2 it can either increase (CD4 and CD8 markers) or reduce (CD3 complexes) the quantity of the analyzed molecules on the membrane surface of T-lymphocytes. PMID- 21674955 TI - [Assessment of soil degradation in regions of nuclear power explosions at Semipalatinsk Nuclear Test Site]. AB - Degree of the soil cover degradation at the "Balapan" and "Experimental field" test sites was assessed based on Allium-test of soil toxicity results and international guidelines on radioactive restriction of solid materials (IAEA, 2004) and environment (Smith, 2005). Soil cover degradation maps of large-scale (1 : 25000) were made. The main part of the area mapped belongs to high contaminated toxic degraded soil. A relationship between the soil toxicity and the total radionuclide activity concentrations was found to be described by power functions. When the calculated value (equal to 413-415 Bq/kg of air dry soil) increases, the soil becomes toxic for plants. This value is 7.8 times higher than the maximal value for background territories (53 Bq/kg) surrounding SNTS. Russian sanitary and hygienic guidelines (Radiation safety norms, 2009; Sanitary regulations of radioactive waste management, 2003) underestimate the degree of soil radioactive contamination for plants. PMID- 21674956 TI - [Method of radiocapacity factor assessment in study of cross adaptations of plants]. AB - Adaptation of plants to the action of gamma-irradiation and cadmium chloride has been studied in the experiments on water culture of maize plants. A new method of registration of the biological object state at the conditions of the stress factor action - "the method of radiocapacity factor" based on the measurement of the culture medium radio-activity during the incubation process of vegetative objects has been developed. The method offered has allowed us to estimate in dynamics an integrated condition of the root system exposed to stimulating and inhibiting doses of acute gamma-irradiation. Application of the pattern of radio adaptive response has allowed us to reveal it using both a conventional technique - by registering the values of growing parameters, and the radiocapacity factor method. PMID- 21674957 TI - [Experimental study of 241Am transfer from herbal food to organs and tissues of crucian carp]. AB - Freshwater fishes (Carassius auratus gibelio, crucian carp) were fed through catheter with homogenized biomass of submerged macrophytes labeled with transuranium element 241Am. The intensity of excretion of americium and its accumulation in organs and tissues of fishes were investigated. The highest release of americium (up to 70%) was recorded on the second day after feeding. 94 98% of americium were excreted during 3-4 days; however, americium was also recorded in the excrements after 11 days. Americium was registered in organs and tissues of fishes, including those tissues that had no direct contact with americium (bones and muscles). This implies assimilation of americium via digestive tract. The activity concentration of americium in bones (11 Bq/kg, fresh mass) was twice as high as that in muscles, heads and external tissues and organs (skin, scales and fins). The highest activity concentration of americium was registered in viscera (33 Bq/kg, 48% of the total activity in the body). Accumulation of americium in muscles enhances the probability of the further transfer of americium along a food chain. PMID- 21674958 TI - [Palladin Institute of Biochemistry, NAS of Ukraine on the 85th anniversary of the Institute foundation]. PMID- 21674959 TI - [Transformation of glyco- and phospholipids in plant cell membranes under phosphorus starvation conditions]. AB - This review provides new insight on regulatory system in plant phosphorus metabolism - the transformation of lipid components, including phospho- and glycolipids whose transformation is a sensitive parameter of phosphate (P(i)) deficiency of plants. The combination of genetic, biochemical and physiological approaches to the study of transformations of phospho- and glycolipids revealed the compensatory mechanisms of the phospholipids substitution by glycolipids in membranes that allow plants to adapt to conditions of limiting P(i) and are essential for plant survival. The mechanisms of biosynthesis, transformation of phospho- and glycolipids and transcriptional regulation of genes involved in their synthesis at P(i) starvation are analysed. PMID- 21674960 TI - [Identification of low-molecular inhibitors of proteinase ASK1]. AB - Protein kinase ASK1 (Apoptosis signal-regulating kinase 1) plays a key role in cell differentiation, aging and apoptosis. High activity of the kinase is associated with several pathologies. The ASK1 inhibitors might be therapeutic for patients with neurodegenerative, cardiovascular diseases and fibrous histiocytoma. In this work the identification of ASK1 inhibitors was performed by the methods of computer modeling and biochemical testing in vitro. The virtual screening experiments were carried out targeting the ATP binding site of ASK1 by browsing the database which contained 164 840 compounds of diverse chemical classes. The best-scored 300 ligands have been taken for the kinase assay analysis. In vitro tests revealed that derivatives of 2-thioxo-thiazolidin-4-one exhibited inhibitory activity against ASK1. The most active compound was 5-bromo 3-(4-oxo-2-thioxo-thiazolidin-5-ylidene)-1,3-dihydro-indol-2-one (IC50 = 2 microM). Binding mode for inhibitors of this class with ASK1 ATP-binding site was proposed. Our results can be used for further optimization and developing more potent and selective inhibitors of ASK1. PMID- 21674961 TI - [Molecular mechanisms of transitions induced by cytosine analogue: comparative quantum-chemical study]. AB - Using the simplest molecular models at the MP2/6-311++G(2df,pd)//B3LYP/6 311++G(d,p) level of the theory it has been shown for the first time that in addition to traditional incorporational errors caused by facilitated (compared with the canonical DNA bases cytosine (Cyt)) tautomerization of 6-(2-deoxy-beta-D ribofuranosyl)-3,4-dihydro-6H,8H-pyrimido[4,5-c][1,2]oxazin-7-one (DCyt), this mutagen causes the replication errors, increasing one million times the population of mispair Gua.DCyt* (asterisk marked mutagenic tautomer) as compared with mispair Gua.Cyt*. It is also proved that DCyt in addition to traditional incorporational errors also induces similar errors by an additional mechanism - due to a facilitated tautomerization of the wobble base pair Ade.DCyt (compared to the same pair Ade.Cyt) to a mispair Ade.DCyt* which is quasirisomorphic Watson Crick base pair. Moreover, the obtained results allowed interpreting non inconsistently the existing experimental NMR data. PMID- 21674962 TI - [Quantum-chemical investigation of the elementary molecular mechanisms of pyrimidine-purine transversions]. AB - Purine-purine mispairs of DNA (thus involving template base in anti-conformation along the glycosidic bond and base of the incoming nucleotide - in syn conformation) leading to pyrimidine-purine "transversions"-type point mutations were revealed and characterized at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in vacuum approach adequately modeling hydrophobic environment of the active centre of high-fidelity replicative DNA-polymerases. PMID- 21674964 TI - [Analysis of the expression of RET/PTC oncogenes in post-chernobyl papillary thyroid carcinomas of patients from different age groups]. AB - A comparative analysis of the expression of both, RET/PTC1 and RET/PTC3 oncogenes in papillary thyroid carcinomas (PTC) of patients from different age groups was carried out. Those were the following groups: children (mean age - 13 years, mean latency period - 13 years), young adults (mean age - 24 years, mean latency period - 14 years), adults (mean age - 38 years, mean latency period - 22 years). The presence of RET/PTC oncogenes was detected using polymerase chain reaction. In all cases the samples of both tumor and normal thyroid tissue were studied. It was established that induction of both, RET/PTC1 and RET/PTC3 rearrangements was present only in carcinoma samples. In PTCs the percentage of RET/PTC-positive tumors with increasing the age of patients has been decreasing. It should be noted that the part of carcinomas with induction of RET/PTC1 did not change with increasing the age of patients. At the same time the frequency of RET/PTC3 rearrangements with the increasing both the latency period and age of patients, significantly decreased. In conclusion, our data can evidence for the presence of correlation between the age of patients, latency period and induction of RET/PTC3 oncogenes. PMID- 21674963 TI - [Effect of silver nanoparticles on the expression of 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase-2 mRNA and its alternative splice variants in different rat organs]. AB - Bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2 (PFKFB 2) is represented by several alternative splice variants and plays a significant role in the glycolysis regulation in the brain, lung, testis and heart cells. The expression of PFKFB-2 mRNA and its alternative splice variants in these rat vital organs after single intratracheal injection of silver nanoparticles was studied. It was shown that the expression of PFKFB-2 mRNA is significantly changed in different rat tissues under silver nanoparticles action. The effect of silver nanoparticles on the expression of PFKFB-2 mRNA was observed one day after its injection to animals. In 3 and 14 days the effect of silver nanoparticles was increased (in testes) or kept on the approximately same level (in other investigated tissues). The expression of PFKFB-2 mRNA in most tissues is returned to its control levels one year after the injection of silver nanoparticles to the rats. It was also shown that the expression of alternative splice variants of PFKFB-2 mRNA without functional activity of 6-phosphofructo-2-kinase is significantly increased in different tissues 1, 3 and 14 days after single injection of silver nanoparticles. The results of this investigation demonstrate clearly that silver nanoparticles significantly affect the expression of PFKFB-2 mRNA on the alternative splicing level in different vital organs and show their effect on the important mechanisms of metabolism regulation in the cells on the level of key enzyme gene expression. PMID- 21674965 TI - [The state of lipid peroxidation and antioxidant protection system in parietal cells under experimental chronic atrophic gastritis development]. AB - The lipid peroxidation state and the system functioning of antioxidant protection in parietal cells under rat chronic atrophic gastritis development was investigated. It was detected that the compensatory increase of superoxide dismutase and catalase activity did not affect the lipoperoxidation process and this resulted in accumulation of toxic TBA reactive substances and diene conjugates during the whole stages of the experimental pathology development. It was shown that the reserved power of the glutathione antioxidant system is sufficient to provide adoptable response in the acute period of the disease owing to increasing intracellular found of the reduced glutathione, but it is insufficient to prevent its decreasing in parietal cells in case of the chronic atrophic gastritis development. Our findings suggest that glutathione system is involved in processes of gastric atrophy. The obtained results testify about considerable system dysfunctions of lipid peroxidation and the antioxidant protection in processes of the rat experimental atrophic gastritis development. PMID- 21674966 TI - [Age-related peculiarities of antioxidant system functioning in the blood of ostriches]. AB - The intensity of lipid peroxidation, activity of some enzymes antioxidant system superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, amount of recovered glutathione and ceruloplasmin in the blood serum of ostriches in a period from 6- to 60-month age were first investigated. The increase of concentration of lipid peroxidation products is accompanied by the decline of amount of general lipids in the ostriches blood. Every life cycle period of ostriches is characterized by the indexes of functioning of the antioxidant system and intensity of accumulation intermediate lipid peroxidation products inherent in it. The pubescence period and intensive oviposition are characterized by the increase of products lipid peroxidation concentration and decrease of antioxidant enzymes activity, which can testify to the exhaustion of protective possibilities of enzymatic link of antioxidant defence. PMID- 21674967 TI - [Intensity of internucleosome DNA fragmentation in tissues of the adrenal glands in patients with hormonally inactive tumours]. AB - Internucleosomal fragmentation of DNA that was isolated from the extratumour tissue of patients with hormonally active and inactive tumors, the tissues of hormonally active and inactive tumors, and also the hyperplastic adrenal tissue in patients with Itsenko-Cushing disease was studied in agarose gel using the method of electrophoresis. It has been established that the intensity of DNA fragmentation in hormonally inactive tumours did not differ from the tissue that was surrounding such tumours, and only a decrease in the mononucleosome level was revealed. The increased level of oligonucleosomas with the size of 200-800 p. o. owing to the high content of tri- and tetraoligonucleosomas was noted in the extratumour tissue of patients with hormonally active tumours, the hyperplastic tissue and in the tissue of aldosteromas, corticosteromas, and pheochromocytomas. Data obtained evidenced for the stimulating effect of the adrenal complex hormones and the adrenal meduliar layer on apoptotic processes both in the cells of extratumor adrenal tissue and in the tumor cells secreting hormonal abundance. PMID- 21674968 TI - [State of the system of antioxidant defense in tissues of the black sea turbot during the spawning]. AB - The system of antioxidant (AO) defense and processes of lipid peroxidation (LP) of the Black Sea turbot Psetta (Scophtalmus) maxima maeotica (L., 1758) have been investigated during the spawning season. The activity of glutathione peroxidase (GP), glutathione reductase (GR), catalase and content of reduced glutathione (GSH) and TBA-reactive products have been determined in gonads, gills, liver, red and white muscles of males and females at different stages of gonad's maturity (V and VI stages). The peculiarities of AO complex and LP depended on tissue specificity and sexual distinctions of the turbot have been found. The turbot females at VI stage were found to have the most significant changes. In gonads and liver the level of TBA-reactive products decreased. In gonads the activities of GP and GR decreased, but the level of GSH increased. In gills of these females the activity of GP and the level of GSH increased, while in the red muscles the activity of catalase raised. In white muscles the activity of GR dropped. In the males' tissues of the turbot at VI stage the growth of the activity of GP in gills and GSH content in white muscles have been found. In all tissues of males the decrease of the TBA-reactive products content has been observed. PMID- 21674969 TI - [Isolation and properties of lectins from cell walls of wheat seedlings infected by Fusarium graminearum and treated by salicylic acid]. AB - Lectins from cell walls of wheat seedlings in normal conditions and infected by Fusarium sp. and treated by salicylic acid were isolated by the methods of gel filtration, affinity chromatography and isoelectric focusing, their biochemical properties were studied. It is shown that isolated preparations of lectins suppressed the development of colonies of fungus Fusarium graminearum. A conclusion was made on the possibility of employment of isolated lectins in the molecular-breeding programs on raising wheat resistance towards fusariosis. PMID- 21674970 TI - [Change of the content of lipids and their fatty acid composition in egg yolks and liver of breeding hens and embryos depending on the level of carotenoids in their diet]. AB - The paper presents the results of studies on the content of total lipids, phospholipids and total lipids' fatty acid composition of Shaver-579 breeding hens' liver, egg yolk and 19 days embryo's liver. The reverse dependence is established between the content of unsaturated fatty acids in lipids of egg yolk and intensity index of lipid metabolism in the liver of 19 days embryo. PMID- 21674971 TI - [Archeological laboratory results or microbiology of the time?]. PMID- 21674972 TI - [Mix-ups, medication errors and incorrect prescriptions. Generic prescribing- now!]. PMID- 21674973 TI - [Unequal follow-up of Swedish patients with malignant melanoma. The place of residence decisive for the patient's follow up]. PMID- 21674975 TI - [Takotsubo syndrome possible also in obstructive coronary vessel disease. The conditions do not exclude each other according to two case reports]. PMID- 21674974 TI - [Methotrexate an alternative for young persons with Crohn disease]. PMID- 21674976 TI - [Indwelling catheter--serious problem affecting a smaller group in geriatric residential facilities. An observation study of catheter-related events]. PMID- 21674977 TI - [High time to introduce "eCall" system for quicker help to injured in traffic accidents]. PMID- 21674978 TI - [Jussi Bjorling's heart rate was 200 beats per minute]. PMID- 21674979 TI - [Forbidden ovum donation]. PMID- 21674980 TI - [30 years German Pediatric Nursing Professional Society. Anniversary event]. PMID- 21674981 TI - [1st completion of family health and pediatric nursing GFKiKP curriculum in the DRK Krefeld Sisterhood e.V. in North Rhine Westphalia]. PMID- 21674982 TI - [How clothing impacts our work. Researchers correlate clothing to mental performance]. PMID- 21674983 TI - [Unusual learning: development of creative processes and promoting individual awareness at the interface of social and societal problems with reference to current research in neurology. Report of 2 projects for the elementary level schools in cultural education ]. PMID- 21674984 TI - [How does the mother of a child with ADHD experience her situation? (II)]. PMID- 21674985 TI - [Child therapy network serves the increasing online need of parents searching for specialized physicians]. PMID- 21674986 TI - [Interview regarding the book "Short Pediatric Cancer Textbook" (interview by Hardy-Thorsten Panknin)]. PMID- 21674987 TI - [Sick (disabled) children in South Africa - how are they cared for?]. PMID- 21674988 TI - [A desire for spicy food is masochism. Similar mechanism also with sparkling mineral water]. PMID- 21674989 TI - [Studying for a successful future. Common project of the RheinAhrCampus, the Marienhaus GmbH and the Bonn Community Hospital - dual curriculum in nursing business management starts in the winter semester 2011/2012]. PMID- 21674990 TI - [Value of omega-3 fatty acids in different periods of life]. PMID- 21674992 TI - [Dear Readers]. PMID- 21674991 TI - A correction to the research article titled: "Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells" by A. S. Little, K. Balmanno, M. J. Sale, S. Newman, J. R. Dry, M. Hampson, P. A. W. Edwards, P. D. Smith, S. J. Cook. AB - The acquisition of resistance to protein kinase inhibitors is a growing problem in cancer treatment. We modeled acquired resistance to the MEK1/2 (mitogen activated or extracellular signal-regulated protein kinase kinases 1 and 2) inhibitor selumetinib (AZD6244) in colorectal cancer cell lines harboring mutations in BRAF (COLO205 and HT29 lines) or KRAS (HCT116 and LoVo lines). AZD6244-resistant derivatives were refractory to AZD6244-induced cell cycle arrest and death and exhibited a marked increase in ERK1/2 (extracellular signal regulated kinases 1 and 2) pathway signaling and cyclin D1 abundance when assessed in the absence of inhibitor. Genomic sequencing revealed no acquired mutations in MEK1 or MEK2, the primary target of AZD6244. Rather, resistant lines showed a marked up-regulation of their respective driving oncogenes, BRAF600E or KRAS13D, due to intrachromosomal amplification. Inhibition of BRAF reversed resistance to AZD6244 in COLO205 cells, which suggested that combined inhibition of MEK1/2 and BRAF may reduce the likelihood of acquired resistance in tumors with BRAF600E. Knockdown of KRAS reversed AZD6244 resistance in HCT116 cells as well as reduced the activation of ERK1/2 and protein kinase B; however, the combined inhibition of ERK1/2 and phosphatidylinositol 3-kinase signaling had little effect on AZD6244 resistance, suggesting that additional KRAS effector pathways contribute to this process. Microarray analysis identified increased expression of an 18-gene signature previously identified as reflecting MEK1/2 pathway output in resistant cells. Thus, amplification of the driving oncogene (BRAF600E or KRAS13D) can drive acquired resistance to MEK1/2 inhibitors by increasing signaling through the ERK1/2 pathway. However, up-regulation of KRAS13D leads to activation of multiple KRAS effector pathways, underlining the therapeutic challenge posed by KRAS mutations. These results may have implications for the use of combination therapies. PMID- 21674993 TI - Appetite suppressants as adjuncts for weight loss. PMID- 21674994 TI - Gosta Bruce. 1947-2010. PMID- 21674995 TI - Zongji Wu. 1909-2010. PMID- 21674996 TI - Edda Farnetani. 1936-2010. PMID- 21674997 TI - An improved synthesis of scopoletin. PMID- 21674998 TI - Healthcare reform's winners and losers. AB - This year's mid-term elections produced a new set of winners and losers, and with the dramatic shift in power that occurred, much of the legislation passed by the 111th Congress will be re-examined in the coming years. The Patient Protection and Affordable Care Act (PPACA), a keystone accomplishment of our current Congress and the signature wealth redistribution program of the Obama presidency, produced its own set of winners and losers. Now - before this period of introspection begins--seems an appropriate time to identify the PPACA winners and losers under the law as it is currently written. PMID- 21674999 TI - ECG of the month. Bigeminal rhythm VI. PMID- 21675000 TI - A 29-year old woman presenting with abdominal pain and vomiting. PMID- 21675001 TI - Radiology case of the month. Tumefactive multiple sclerosis. PMID- 21675002 TI - Severe hypokalemia and hematuria: a case of Munchausen's syndrome. PMID- 21675003 TI - Traumatic bilateral carotid artery dissection. AB - INTRODUCTION: Bilateral carotid artery dissection following blunt trauma is a rare but potentially lethal injury if not diagnosed early and treated. CASE REPORT: We report a collision patient who suffered bilateral asymptomatic carotid artery dissections. He also had multiple fractures of the pelvis and upper and lower extremities. The patient was managed acutely with aspirin. He underwent open reduction and internal fixation of fractures without complication and was discharged home on aspirin. DISCUSSION: Carotid artery dissections are increasingly being recognized in blunt trauma patients. Management options include systemic anticoagulation versus antiplatelet therapy. The need to acutely address the carotid artery injury must be balanced with the need for hemostasis with associated solid organ injury and/or future operative procedures. CONCLUSIONS: Carotid artery dissections should be screened for in patients with appropriate mechanism of injury. This case report details the successful management of a patient of bilateral carotid artery dissection and other major orthopedic injuries using aspirin. PMID- 21675004 TI - Genetic association studies in peripheral arterial disease. AB - Peripheral artery disease (PAD) is a major health problem worldwide, affecting millions of patients. Although cardiovascular risk factors such as diabetes mellitus, tobacco abuse, hypertension, and hypercholesterolemia have been associated with the development of PAD, the possible existence of an inherited genetic predisposition to PAD has been investigated in numerous familial aggregation studies. A link between genetics and PAD may open new avenues for prevention of this morbid and mortal disorder. This is an overview of the potential association of genetics and PAD. PMID- 21675005 TI - Massive thoracic lipoma: a case report. AB - A 60-year-old woman with a massive left intra-thoracic lipoma presented with worsening dyspnea. A computed tomographic scan revealed an 18 x 10 x 24 cm intra thoracic mass, which was compressing the left lung and shifting the mediastinum to the right. At operative resection, a large, well-encapsulated, intrathoracic lipoma was discovered that weighed 2,556 grams. Histologic evaluation confirmed that the mass consisted of benign adipose tissue. PMID- 21675006 TI - Low birth weight is not associated with type 2 diabetes in African American children in New Orleans. AB - OBJECTIVES: We sought to determine if low birth weight (LBW) occurs more frequently in African American children with type 2 diabetes (T2D), and if patients with LBW differ metabolically. STUDY DESIGN: We collected birth weight, anthropometric and metabolic data from African American children with T2D born in New Orleans from clinic charts. Comparable birth weight data from all African American infants born in New Orleans were obtained from Louisiana state vital statistics. RESULTS: In African American patients with T2D, 14.3% had LBW compared to 13.9% in the reference population (z = 0.997, p = 0.33). There was no difference between LBW and non-LBW patients with regard to body mass index (BMI) at diagnosis, presenting insulin, c-peptide, glucose levels, or HbA1c one year post diagnosis. CONCLUSIONS: African American children with T2D were not enriched with LBW individuals. LBW patients were not anthropometrically or metabolically different from non-LBW T2D patients. Thus prenatal factors may not be the driving force in the development of T2D in African American children. PMID- 21675007 TI - A regulatory approach to health care reform. AB - Although the technical prowess of American medicine is widely appreciated, considerable concern centers on the delivery and financing of health care, and, in particular, on issues of cost and access. Progress in addressing these concerns has been slow in coming with standard approaches to reform failing to win wide approval. It is here suggested that a series of relatively straightforward regulatory reforms could redirect the medical delivery enterprise and reduce many of the distortions that plague it today. These regulatory reforms center on insurance portability, the elimination of discounting, insurance reform, the provision of provider-specific outcomes data, and technology assessment. These regulatory changes offer the prospect of making the system more rational and efficient, while minimizing rationing and avoiding major institutional change. They also may stimulate additional novel suggestions for reform. PMID- 21675008 TI - Dr. Octave Pavy, Arctic explorer. PMID- 21675009 TI - Mental disorders and medical comorbidity. PMID- 21675010 TI - Are you covered by workers' comp. while walking outdoors on break? Huda-Lee v. Baxter County Regional Hospital, 2011 Ark. 31,10-212 S.W.3d (2/3/2011)-AR. PMID- 21675011 TI - Nurse's conviction for taking fentanyl from OR affirmed. Case on point: State v. Erwin, 2011 VT 41 209-309 A.2d (4/7/2011)-VT. PMID- 21675012 TI - MA: Panel ordered case v. RN dismissed: appellate court ordered reinstatement of case. Donaldson v. Payne, 940 N.E.2d 897 (2/8/2011)-MA. PMID- 21675013 TI - RN prevailed on retaliatory termination. Case on point: Nelson v. County of St. Louis, A10-676 MNCA (2/8/2011)-MN. PMID- 21675014 TI - The "sacred space" of healing. PMID- 21675015 TI - Foreword. Towards implementing medical ethics and bioethics education in Lebanon. PMID- 21675016 TI - [Bioethics in Lebanon. Definition and legislation]. PMID- 21675017 TI - [Bioethics in the Arab world. Analytical study and regulations]. PMID- 21675018 TI - Is medical ethics education effective? PMID- 21675019 TI - Ethical issues in assisted reproductive technologies. PMID- 21675020 TI - [Is good genetic counseling possible with good ethical principals?]. AB - A good genetic counseling, followed by appropriate examinations, sometimes requires the participation of any family members--parents, grandparents, aunts, uncles, cousins--thus leading to accurate knowledge of the genome of each individual. This is far from inconsequential. While genetic testing can disrupt life plans, influence the choice of spouse or procreation, or a sense of guilt among healthy individuals, they may also reveal some families information not sought from the first glance as false paternity or a positive result from a person still asymptomatic. How then react? Is there an appropriate attitude to adopt? If yes, which one? Is it free of any side effects? PMID- 21675021 TI - [Dangerous relations]. PMID- 21675022 TI - Democratization of medical education is needed to effective teaching of bioethics. PMID- 21675023 TI - Gaps in end-of-life care. AB - End-of-life care is an important aspect of medical practice. Individual physicians and the medical community must be committed to the compassionate and competent provision of care to dying patients and their families. Patients rightfully expect their physicians to care for them and provide them with medical assistance as they are dying. To care properly for patients near the end of life, the physician must understand that palliative care entails addressing physical, psychosocial, and spiritual needs and that patients may at times require palliative treatment in an acute care context. To provide palliative care, the physician must be up to date on the proper use of opioids and the legality and propriety of using high doses of opioids as necessary to relieve suffering. Good symptom control; ongoing involvement with the patient; and physical, psychological, and spiritual support are the hallmarks of quality end-of-life care. Care of patients near the end of life, however, has a moral, psychological, and interpersonal intensity that distinguishes it from most other clinical encounters. With appropriate education, physicians can play a key role to improve care for patients and families who are living with advanced life-threatening illness. Although some issues (e.g., the role of physician-assisted death in addressing suffering) remain very controversial, there is much common ground based on the application of the four major principles of medical ethics, nonmaleficence, beneficence, autonomy, and justice. PMID- 21675025 TI - First Regional Conference on Biomedical Ethics in Medical Schools. Organized by the Salim El-Hoss Bioethics and Professionalism Program at AUB-FM. PMID- 21675024 TI - The lures of modern medicine. AB - The profession of medicine is first and foremost a moral enterprise. Yet, modern day medicine has suffered from a number of flaws that led to some of its downfalls. This article looks at the profession of medicine from a contemporary lens. What has gone wrong? What does it mainly suffer from? What is the central issue that should be dealt with in order to help the profession of medicine regain its status as an ideal and moral endeavour. While I do not allege that one article is enough to unveil all that is needed to say, this article at least sheds the light on some of the important issues that we cannot afford to brush aside any longer. PMID- 21675026 TI - IUPS outreach strategy. Stage 1: outreach to member societies. PMID- 21675027 TI - Quantitative analysis of six gene products as candidate markers of early placental villi development in the human. AB - Early placental development is critical for successful pregnancy. Recently, we have reported that -70 genes were differentially expressed in human placental villi between 6- and 8- weeks of gestation in cDNA-based expression arrays for 400 PCR products, of which six specific gene products (COL4A4, CXCR4, ERBB2, HDAC1, HPRT1, and TNFRSF1A) appeared intriguing. In the present study we have examined expressions of these six candidate genes in placental villi obtained from 6-weeks, 7-weeks and 8-weeks (n = 6 for each group) human placental samples using quantitative real time RTPCR. We observed that there was considerable concordance (>95% confidence) in pair-wise analysis of transcript profiles between the two methods, however, absolute quantitative values as measured by quantitative RTPCR differed from those obtained from cDNA-based array analysis for 2 gene products (CXCR4 and ERBB2) out of 6 genes. No significant change was observed in the steady state expression of COL4A4 and HPRT1 during the time period examined. However, there was significant decrease in CXCR4 for 7-weeks (P < 0.01) and 8-weeks (P < 0.05) samples, and significant (P < 0.05) increase was seen for ERBB2 in 7-weeks and 8-weeks as compared to 6-weeks samples with no change between 7-weeks and 8-weeks samples. Moreover, significant (P < 0.05) increase for HDAC1 and decrease for TNFRSF1A was observed in 8-weeks samples as compared to 6-weeks samples with no change observed between 6-weeks and 7-weeks samples. We infer that it is essential that cDNA array-based data are verified in terms of quantitative estimates preferably by quantitative PCR before their use for any exploratory purpose. Taking together our previous array based data and the present study we conclude that a categorical balance exists between the expression of ERBB2 and HDAC1 genes affecting cell proliferation and differentiation in one hand, and CXCR4 and TNFRSF1A affecting chemotaxis, inflammatory response and apoptosis on the other hand. The expression of these genes appear important for the early development of human placental villi. PMID- 21675028 TI - Angiogenic growth factor responses to long-term treadmill exercise in mice. AB - We sought to determine whether VEGF and other angiogenic growth factors and their receptors might be subject to negative feedback regulation during two weeks of treadmill-exercise conditioning in inbred strains of mice. C57BL/6 mice exhibited greater VEGF mRNA and protein responses in gastrocnemius muscle to a single bout of treadmill exercise compared to BALB/c mice. The patterns of VEGF, VEGFR1, VEGFR2, Ang2 and Tie2 mRNA expression in gastrocnemius muscles of C57BL/6 mice during long-term exercise support the hypothesis that they may be subject to negative feedback regulation. The combination of expression patterns for growth factors and their receptors suggests that multiple layers of control mechanisms may exist to prevent angiogenesis following a single bout of exercise and to promote angiogenesis following long-term exercise. PMID- 21675029 TI - Anxiolytic and antidepressant activities of methanol extract of Aegle marmelos leaves in mice. AB - The objective of the present study was to evaluate the anxiolytic and antidepressant activities of methanol extract of Aegle marmelos (AM) leaves as well as its interaction with conventional anxiolytic and antidepressant drugs using elevated plus maze and tail suspension test in mice. Albino mice were treated with AM (75, 150 and 300 mg/kg, po), imipramine (20 mg/kg, po), fluoxetine (20 mg/kg, po), and combination of sub-effective dose of AM with imipramine or fluoxetine. Effects were observed on (a) time spent on (b) number of entries into (c) number of stretch attend postures (d) number of head dips in arms of elevated plus maze and on duration of immobility in tail suspension test. Effects of pretreatment with prazosin (0.062 mg/kg, po), haloperidol (0.1 mg/kg, po) and baclofen (10 mg/kg, po) were also studied on AM induced decrease in duration of immobility. Effects of AM (75, 150 and 300 mg/kg po) were observed on locomotor activity using photoactometer. Results showed that AM significantly (P<0.05) and dose dependently increased proportionate time spent on and number of entries into open arms while decreased number of stretch attend postures and head dips in closed arms. Dose dependent and significant (P<0.05) anti-immobility effect was found in mice treated with AM. Combination of AM (75 mg/kg, po) with imipramine (5 mg/ kg, po) or fluoxetine (5 mg/kg, po) also produced significant (P<0.05) anxiolytic and antidepressant activity. Antidepressant activity of AM (150 mg/kg, po) was significantly (P<0.05) decreased by prazosin, haloperidol and baclofen. Methanol extract showed insignificant (P>0.05) effect on locomotor activity of mice. It is concluded that AM possess potential anxiolytic and antidepressant activities and it enhances the anxiolytic and antidepressant activities of imipramine and fluoxetine. PMID- 21675030 TI - Pulmonary function test in traffic police personnel in Pondicherry. AB - Traffic policemen working in the busy traffic signal areas get exposed to the vehicular emissions for years together. The fumes, chemicals and particles present in the emission are reported to be damaging to the lung functions of these individuals. Since there were no data available on the PFT parameters of traffic police personnel of Pondicherry, this study was taken up to assess the effect of traffic air pollution on their pulmonary functions. PFT parameters were recorded in age- and BMI-matched 30 traffic police personnel (study group) and 30 general police personnel (control group) of male gender. As chronic smoking is known to be a critical factor in altering lung function, PFT parameters were compared between the smokers as well as nonsmokers of both the groups. In nonsmokers, there was significant decrease in VC (P < 0.05), FEV1 (P < 0.01), FEF 25 (P < 0.05) and PIF (P < 0.05) in study group compared to the control group. In smokers, there was significant decrease in VC (P < 0.05), FEV1 (P <00001), PEF (P < 0.0001), MVV (P < 0.0001), FEF-25 (P < 0.0001), and PIF (P < 0.01) in study group compared to the control group. These changes indicate restriction to the lung expansion, obstruction and narrowing of the airways in traffic police personnel compared to the general police personnel. This may be due to exposure to vehicular pollution for several hours in a day for many years causing decreased functional capacity of the lungs and chronic smoking worsens the condition. PMID- 21675031 TI - Comparison of self-reported benzodiazepine use and urinalysis among consecutive treatment seekers at a tertiary care drug dependence treatment centre. AB - Information provided by drug dependent patients might be incomplete and/or discrepant. Benzodiazepines are frequently abused, but not necessarily reported, even bythe treatment seeking population. The study aims to compare the self reported benzodiazepine use with a quick and effective urinalysis method. A total of 51 consecutive adult patients were included after an informed consent during their first visit to a tertiary care drug dependence treatment centre. The socio demographic and clinical details were recorded on a semi-structured proforma. Patients were specifically asked for ever, current and recent benzodiazepine use and thereafter ten ml urine sample was collected to perform urinalysis with cassette test for benzodiazepines. The sample, predominantly males, had a mean age of 37.86 +/-10.46 years. The common primary drugs of use were heroin (52.9%), alcohol (23.5%) and other opioids (21.6%). Drug use was uninterrupted in most of users (72.5%) and ranged from one to forty years. The recent benzodiazepine use was reported by 21.6% of all users whereas urinalysis by cassette test was positive in 50.9% of the treatment seekers. Denial among users was 69.2% and denial among negative self report was 45%. A poor level of agreement (K) was found between results of self-report and urinalysis for all the treatment seekers. Self report of benzodiazepine use is highly questionable among treatment seekers. The urinalysis with cassette test is a quick objective method which is recommended for routine screening. PMID- 21675032 TI - Effect of Nigella sativa seeds on the glycemic control of patients with type 2 diabetes mellitus. AB - Diabetes mellitus is a common chronic disease affecting millions of people world wide. Standard treatment is failing to achieve required correction of blood glucose in many patients. Therefore, there is a need for investigating potential hypoglycemic drugs or herbs to improve glycemic control in diabetic patients. Nigella sativa seeds were used as an adjuvant therapy in patients with diabetes mellitus type 2 added to their anti-diabetic medications. A total of 94 patient were recruited and divided randomly into three dose groups. Capsules containing Nigella sativa were administered orally in a dose of 1, 2 and 3 gm/day for three months. The effect of Nigella sativa on the glycemic control was assessed through measurement of fasting blood glucose (FBG), blood glucose level 2 hours postprandially (2 hPG), and glycosylated hemoglobin (HbA1c). Serum C-peptide and changes in body weight were also measured. Insulin resistance and beta-cell function were calculated usin the homeostatic model assessment (HOMA2). Nigella sativa at a dose of 2 gm/day caused significant reductions in FBG, 2hPG, and HbA1 without significant change in body weight. Fasting blood glucose was reduced by an average of 45, 62 and 56 mg/dl at 4, 8 and 12 weeks respectively. HbAlC was reduced by 1.52% at the end of the 12 weeks of treatment (P<0.0001). Insulin resistance calculated by HOMA2 was reduced significantly (P<0.01), while B-cell function was increased (P<0.02) at 12 weeks of treatment. The use of Nigella sativa in a dose of 1 gm/day also showed trends in improvement in all the measured parameters but it was not statistically significant from the baseline. However, no further increment in the beneficial response was observed with the 3 gm/day dose. The three doses of Nigella sativa used in the study did not adversely affect either renal functions or hepatic functions of the diabetic patients throughout the study period. IN CONCLUSION: the results of this study indicate that a dose of 2 gm/ day of Nigella sativa might be a beneficial adjuvant to oral hypoglycemic agents in type 2 diabetic patients. PMID- 21675033 TI - Glycine enhances glutamate-induced excitation in ventromedial hypothalamic neurons in awake rats. AB - The finding that glycine potentiates N-methyl-D-aspartate (NMDA) receptor mediated responses, has tremendously changed our understanding of glutamatergic synaptic transmission in the brain. Although the phenomenon has been confirmed in number of preparations, it is yet to be demonstrated in awake animals. Further, the controversy that glycine binding sites of NMDA receptor are saturated in vivo or not, can be best verified in awake animals. Here, we have demonstrated that glycine enhanced glutamate-induced neuronal discharges in the ventromedial nucleus of the hypothalamus of awake behaving rats using microiontophoresis technique, suggesting that the glycine binding sites of NMDA receptor are not saturated under physiological conditions. PMID- 21675034 TI - Analysis of depolarization-induced outward currents in goat chondrocytes using the patch clamp technique. AB - This study analyzes outward currents in freshly isolated goat chondrocytes patched in the whole cell mode. Capacitance tracings were recorded from the cells by the time domain method. The average capacitance was 6.33 pF +/- 2.15pF (Mean +/- SD, n = 60). The range was 2.7 pF to 11.2 pF. A family of outward currents was seen when the cell was depolarized from -70 mV to +70 mV in 10 mV increments. The current density at +60 mV varied from 125 pA/pF to 2410 pA/pF. The currents were inhibited by 10 mM tetraethylammonium chloride (TEA) and the current-voltage profile suggests that these are voltage gated K+ channels. The currents were also recordable in a chloride-free external solution, thereby proving that these currents are not chloride currents. There was no evidence of voltage-gated sodium channels in these cells. PMID- 21675035 TI - Gender based alteration in color perception. AB - Human beings are able to perceive hundreds of shades of color which depends on the three types of cone system and various ratios of stimulation in response to different wavelengths. Perceptually and cognitively, men and women may experience appearance of color differently. Therefore, this study was planned to assess and compare color vision in male and female subjects. This study was carried out in the department of Physiology, SGRRIM&HS, Dehradun on 60 ocular healthy subjects (equal number of males and females) of 17-22 years of age group. The task was to match 22 test color strips with 2 shade charts of different colors. Total number of correct answers and total time taken in matching all the test color strips with the shade charts was recorded in both the sexes and analyzed. The results of this study showed that overall, females gave more correct responses (P < 0.001) and also took less time (P < 0.01) than males. Color wise also, females gave more correct responses especially for red (P < .001) and green color (P < 0.01). The conclusion states that the females can see more shades of colors than males. PMID- 21675036 TI - Age associated increase in intima media thickness in adults. AB - Carotid Imaging is the Gold Standard that provides useful information about the structure and function of carotid arteries. It is used to measure carotid intima media thickness and provides useful information about the cardiovascular status of an individual so that early preventive measures for any future risk can be introduced. High resolution B-mode ultrasound imaging has emerged as one of the methods of choice for determining the anatomic extent of atherosclerosis and its progression and for assessing cardiovascular risks. These measurements correlate well with other pathologic changes. The present study was undertaken to see the relation of the intimal thickening with age using B-mode carotid ultrasound imaging technique. 60 subjects in the age group of 20-85 years were included in the study. As arterial parameters are markedly altered by essential hypertension and other risk factors, subjects showing these risk factors were excluded. A significant association between advancing age and intima-media thickness (P < 0.0000001) was found and increase in the luminal diameter of the carotid arteries was observed but it was not statistically significant (P>0.05). Age is an independent risk factor for increased IMT which predicts future coronary events. The intima media thickness (IMT) of the common carotid artery measured by ultrasound imaging has been shown to be reliable and early marker of systemic atherosclerosis. Routine use of this technique in clinical settings could improve our ability to decide on preventive therapies to reduce the risk for development of clinical PMID- 21675037 TI - Auditory evaluation of the microcephalic children with brain stem evoked response audiometry (BERA). AB - Microcephaly implies a reduced occipito-frontal circumference (< 2 Standard Deviation of normal) and therefore a small brain size, which is usually associated with different neurodeficit. Intactness of the auditory pathway in microcephalic as well as normal children was assessed by Brain stem Evoked Response Audiometry (BERA) to locate the exact site of lesion resulting in the auditory impairment, so that appropriate early rehabilitative measures can be taken. The study revealed that absolute peak latency of wave V, inter peak latencies of III-V and I-V were significantly higher (P- value < 0.05 in each case) in microcephalics than the normal children. Auditory impairment in microcephaly is a common neurodeficit that can be authentically assessed by BERA. The hearing impairment in microcephalics is mostly due to insufficiency of central components of auditory pathway at the level of brainstem, function of peripheral structures being almost within normal limit. PMID- 21675038 TI - Maximal power output during incremental exercise by resistance and endurance trained athletes. AB - This study was aimed at comparing the maximal power output by resistance trained and endurance trained athletes during incremental exercise. Thirty male athletes who received resistance training (Group I) and thirty male athletes of similar age group who received endurance training (Group II) for a period of more than 1 year were chosen for the study. Physical parameters were measured and exercise stress testing was done on a cycle ergometer with a portable gas analyzing system. The maximal progressive incremental cycle ergometer power output at peak exercise and carbon dioxide production at VO2max were measured. Highly significant (P < 0.001) differences existed in values of maximal power output and carbon dioxide production at VO2max for group I and group II. The higher power displayed by group I when compared to group II could be due to variations in adaptations that happen in them due to different types of training. Similar studies could serveas a biofeedback and perk up the athlete's performance. PMID- 21675039 TI - A study of auditory reaction time in different phases of the normal menstrual cycle. AB - Reaction time is an indirect index of processing capabilities of the central nervous system. The present study was carried out to determine if there is any alteration of simple auditory reaction time across the normal menstrual cycle. In this study, reaction time of 100 female medical and paramedical students was recorded in different phases of their menstrual cycle namely premenstrual, menstrual, middle of proliferative, middle of secretory phase and on the expected day of ovulation. Results were expressed as mean, standard deviation and statistically analyzed using student's paired 't' test. On comparing each phase with the corresponding adjacent phases auditory reaction time was significantly increased (P<0.05) in premenstrual phase and on the expected day of ovulation. Thus fluctuating levels of sex steroids across normal menstrual cycle affect sensory motor association of an individual. PMID- 21675040 TI - Trans-differentiation of a duodenal phenotype on duodenal transplantation of different normal tissues in F344 rats. AB - The mechanisms regulating stem cell differentiation and self-renewal are largely unknown. Our ultimate goal is to be able to regulate somatic stem cell differentiation and proliferation. In the present study the ability of trans differentiation was studied when different normal tissue types were transplanted into the duodenum in rats. Pieces of ear (skin), bladder, trachea, diaphragm, pyloric gland, and forestomach from 8-week old GFP-F344 rats were transplanted into the duodenum of F344 rats. Goblet cells with alcian-blue PAS positive mucin and brash border with alkaline phosphatase (ALP) activity appeared in tissues implanted into the duodenum. In addition, GFP-positive duodenal mucosa was observed in all cases by immunohistochemical staining. Moreover, the GFP-positive cells were found to carry the GFP transgene by PCR analysis, indicating that the bladder, trachea, ear (skin), diaphragm, pyloric gland, and forestomach tissues showed a multipotential ability for differentiation. These results indicated that stem cells within tissues have a multipotential ability, trans-differentiating into different organs when transplanted into different environments. PMID- 21675041 TI - Regression of a primary pulmonary adenocarcinoma after zoledronic acid monotherapy. AB - Bisphosphonates are widely used for the treatment of metastatic skeletal tumors and hypercalcemia resulting from malignant tumors. Zoledronic acid (ZOL), a third generation bisphosphonate agent, was recently demonstrated to show synergistic antitumor activity of ZOL when combined with chemotherapy in lung cancer patients. However, whether ZOL exerts direct antitumor activity on lung cancer remains unclear. Here, we report an atypical case encountered while treating a 57 year-old woman with pulmonary adenocarcinoma and multiple metastases of the liver, left adrenal gland, and bone. The nonskeletal lesions, consisting of the primary lesion and hepatic metastasis, regressed after treatment with ZOL alone. We believe this case demonstrates a possible antitumor effect of ZOL against lung cancer. PMID- 21675042 TI - Alcohol-induced persistent mild cognitive impairment with successful withdrawal from alcohol dependence--a case report. AB - An 81-year-old man diagnosed with alcohol-induced persistent mild cognitive impairment consulted our clinic presenting with gait disturbance. Between the ages of 20 and 53 years, his alcohol consumption was 1.8 liters of alcoholic sake per day. However, from the age of 53 years onward, his consumption decreased to 360 ml per day. The patient had alcoholic neuropathy, mild cognitive impairment, and alcoholic cerebellar disorder. His score on the revised version of Hasegawa's Dementia Scale (HDS-R) was 22 and his clinical dementia rating (CDR) was 0.5. His score on the Japanese version of the Mini-Mental State Examination (MMSE) was 22. These scores indicated mild cognitive impairment (MCI). He had delusions and confabulations, without impairment of date and place orientation. Magnetic resonance imaging (MRI) demonstrated enlarged ventricles, sulcal widening, and brain atrophy. He was provided with medication and counseling to treat his alcohol abuse. He accepted our treatment and is presently doing well after 1 year 2 months of treatment. PMID- 21675043 TI - Portal-systemic shunt between the inferior mesenteric vein and inferior vena cava in a patient with hepatic encephalopathy: successful occlusion by balloon occluded retrograde transvenous obliteration. AB - A large shunt between the inferior mesenteric vein (IMV) and the inferior vena cava (IVC) is a rare type of portosystemic shunt in patients with hepatic encephalopathy. We report a patient with hepatic encephalopathy due to a large IMV-IVC shunt who was successfully treated by balloon-occluded retrograde transvenous obliteration. The procedure involved a combination of 11 metallic coils and 5 ml of 5% ethanolamine oleate with iopamidol as the sclerosing agent. After complete obliteration of the shunt, his symptoms disappeared. At 2-years follow-up he was free of clinical symptoms, the size of his liver had slightly increased, and his liver function was preserved. PMID- 21675044 TI - Advanced esophageal cancer with situs inversus totalis successfully treated with chemoradiotherapy followed by esophagectomy: case report. AB - We report a case of advanced esophageal cancer successfully treated with neoadjuvant chemoradiotherapy followed by esophagectomy in a 53-year-old man with situs inversus totalis. Upper gastrointestinal endoscopy in a clinical examination revealed a tumor in the lower third of the esophagus, and moderately differentiated squamous cell carcinoma was diagnosed from the biopsy findings. He was referred to us and the disease was diagnosed as esophageal cancer (clinical T3N1M0, cStage III) after further evaluation. According to the therapeutic strategy of our department, neoadjuvant chemoradiotherapy was commenced. The regimen was composed of radiotherapy (2 Gy/day, 5 days/week, 4weeks, total 40Gy) with cisplatin (70 mg/m2/day, day 1) and 5-FU (700 mg/m2/day, day 1-4). We performed a subtotal esophagectomy with radical lymph node dissection through a left thoracotomy because of the existence of situs inversus totalis. The thoracic operation could be performed with relatively safety because the organs were arranged in a mirror image of their normal positions. On the other hand, it was relatively difficult to construct a gastric tube. In particular, ligation of the gastrosplenic ligaments was difficult and this led to increased blood loss compared with usual operation. Histopathological examination revealed no residual carcinoma at the site of the primary focus. The patient has been followed up periodically on an outpatient basis and has remained free of recurrence for longer than 2 years 5 months after surgery. PMID- 21675045 TI - [Conception of the history of science in the interpretation of Bogdan Suchodolski]. AB - In the article is presented the conception of the history of science in the interpretation of Bogdan Suchodolski. Having described the conception of the history of science created by George Sarton (1884-1956), whose thought was influenced by positivistic philosophy of August Comte, the idea of the history of science of Johan Nordstr6m (1891-1967), who was inspired by the system of Wilhelm Dilthey, and the materialistic conception of the history of science, which was represented, among others, by John Desmond Bernal (1901-1971), the author is making an attempt at revealing to what extent Bogdan Suchodolski was inspired by the above-mentioned visions of the history of science. Having defined the history of science as the history of scientific activity of people and their consciousness formed by the activity, Bogdan Suchodolski applied in the field of his own conception of the history of science the ideas that were put forward by German thinkers and philosophers, and were connected with a way of understanding culture as the constant development of national awareness, which can be exemplified with different dimensions of culture. Undoubtedly, identifying the history of Polish science with constitutive element of the history of national culture and paying attention to the conceptions tending not only to explaining, but also understanding phenomena, B. Suchodolski was influenced by Alfred Vierkandt's and Wilhelm Dilthey's thought. The present article includes several reflections on the conception of the history of science, which was created by B. Suchodolski. Among others, we can find here detailed information on how B. Suchodolski understood: the history of science, its subject, aim and methodology; its status in modern social consciousness and as the history of truth; relations between history of science and theory of science and scientific policy, history of science and the problem of unity and diversity of scientific thinking, history of science and ideas, history of culture and technology, and sources of scientific progress. PMID- 21675046 TI - [Artur Wolynski--A forgotten Polish historian in Italy in the second half of the 19th century]. AB - Artur Wolynski (1844-1893) was, undoubtedly, one of the most interesting personages of Polish emigres after January Uprising. He belonged to these circles of Polish emigres, who were able to reconcile their patriotic aspirations with realities and interest of the countries that entertained them. As far as Wolynski is concerned, it found its expression in the efforts that were made in order to assimilate two nations--Polish and Italian people--appealing to the common history and familiar cultural traditions. An important element of integrating all the above-discussed actions was his scientific activity. The mentioned activity included, first of all, his studies on Nicolaus Copernicus and Galileo Galilei. In the article were analyzed more comprehensive scientific descriptions dedicated to Copernicus and Galileo prepared by Wolynski, and their significance and opinions on them of the learned, whose works treated on Copernicus and Galileo as well. Secondly, in the field of scientific activity of Wolyniski, one can also observe his researches and the process of elaborating sources for Polish and Italian his tory, particularly concerning the 17th century. However, most of his attention Wolynski paid to collecting and working out the materials concerning January Uprising. Speaking a modern language, one can say that Wolynski in a way polled the insurgents of January Uprising sending to them an appropriate list of questions, additionally allowing for their biographies. In the paper was also included a detailed description of this broad initiative together with its results. Up till now, not much attention has been paid to this significant scientific activity and its contexts. So, the present article is to remind of meritorious personage of Wolynski, and particularly of his output within the realm of history of science, history of Polish and Italian relationships, and of the role he played in bequeathing memory of January Uprising. PMID- 21675047 TI - [History of Polish botanical and mycological researches on sheets of land of Antarctic and Sub-Antarctic in the years 1977-2009]. AB - The work includes a description of the period from the moment of setting up Polish Polar Station on King George Island (1977) to the end of International Polar Year IV in 2009. Researches on flower plants focused, among others, on plants' morphology, morphological composition of the pollen and anatomical ultra structure of the leaves. There were also carried out biochemical and other searches for the internal mutability. Within physiological studies one concentrated on the problem of reaction to temperature stress. Biological researches focused mainly on solving taxonomic and bio-geographic problems. Finally, were published several monographs and, among others, the first in history complete description of moss' flora of the whole of Antarctic (2008). Research works over algae included also such issues as floristics, bio-geography, taxonomy and ecology (for instance, the rookery's impact on distribution of algae, or the influence of inanimate factors on dynamics of condensing the Diatoma in different water and soil-bound tanks). Up till now, within mycological investigations has been identified a variety of lichen fungi that for the most part of Antarctic are a novelty. There were scientifically described new for science genera and species of Western Antarctic. Lichenological studies were made in the field of taxonomy, geography, lichenometry, biochemistry of lichens, lichenoindication, ecophysiology and from the point of analysis of base metals' content. There were also described new for science species. Since 1991, were published the results of searches for the base metals' content and vestigial chemical elements in lichens' thallus. Ecophysiological researches concerned both micro-climatic conditions' impact on primary production and lichens' adaptation to a very cold climate. One discovered a mechanism of two-phase hydratization/dehydratization of lichens' thallus. On the ground of palaeobotanical analyzes was reconstructed a development of flora in Western Antarctic from the late Cretaceous period to the beginning of Melville's continental glaciation. One singled out three floristic stages and were reconstructed their peculiarities in the development of flora. There was also described an early Jurassic flora of Hope Bay (Polwysep Antarktyczny - Antarctic Peninsula) that turned out to be the richest Jurassic flora in the world. From that point of view were analyzed new species of mineral plants. Ecological researches concentrated on the problems connected with several issues and, among others, with the processes of settlement and succession, distribution and ecology of land biotopes, changes in their spatial structure, and state of biotopes' biological mass. The second group of issues concerned the anthropogenous impacts. One also analyzed early stages of synanthropization of flora. Another important issue was recognizing an extent of the pollution of the environment, particularly with base metals. In the years 1977-2009 were published, at least, 426 notes, articles and monographs that were a result of botanical and mycological researches on sheets of land of Antarctic and Sub-Antarctic. PMID- 21675048 TI - [The medical profession in the 19th century: professionalization, development of professional associations and social insurance up to the World War I]. PMID- 21675049 TI - [Medical profession of the Weimar Republic. Social status and self representation in the "Medical Society Paper"/"German Medical Paper" 1919-1932]. PMID- 21675050 TI - [Medical self perception. Summary remarks on the self representation of the medical profession and medical status in the Weimar Republic]. PMID- 21675051 TI - The history of simple analgesics. PMID- 21675052 TI - Daily sedation interruption; a glass half empty? PMID- 21675053 TI - Clinical determination of brain death. PMID- 21675054 TI - Does the pulmonary artery catheter still have a role in the perioperative period? AB - The pulmonary artery catheter (PAC) was introduced into clinical practice in the early 1970s. Its use quickly expanded beyond patients with acute myocardial infarction to critically ill patients in the intensive care unit. Increasingly, it was used in the perioperative period in patients having major cardiac and noncardiac surgery. Publication of large observational studies suggested that patients with a PAC were more likely to suffer major morbidity or mortality, but this was difficult to assess because patients who had a PAC inserted were often sick, with more severe pathology, and were therefore more likely to die. The PAC is a monitoring device and information alone is unlikely to influence outcome unless it is linked to a proven therapy. Several thousand articles on the use of the PAC now exist, but in general, the quality of this literature is poor Much of the data are not randomised, have small sample sizes and include patients with greatly differing pathological states. It is unclear which, if any, of the PAC guided therapies are actually beneficial for patients. Despite these flaws, there is no clear evidence of benefit, nor harm, in cardiac, intensive care or perioperative patients. Selected indications for the PAC may remain, such as complex cardiac surgery or solid organ transplantation. However, its routine use is difficult to justify and increasingly, most of the haemodynamic data available from the PAC can be obtained less invasively with echocardiography. PMID- 21675055 TI - Erythropoietin as a novel brain and kidney protective agent. AB - Erythropoietin is a 30.4 kDa glycoprotein produced by the kidney, which is mostly known for its physiological function in regulating red blood cell production in the bone marrow Accumulating evidence, however suggests that erythropoietin has additional organ protective effects, which may specifically be useful in protecting the brain and kidneys from injury. Experimental evidence suggests that these protective mechanisms are multi-factorial in nature and may include inhibition of apoptotic cell death, stimulation of cellular regeneration, inhibition of deleterious pathways and promotion of recovery. In this article we review the physiology of erythropoietin, assess previous work that supports the role of erythropoietin as a general tissue protective agent and explain the mechanisms by which it may achieve this tissue protective effect. We then focus on specific laboratory and clinical data that suggest that erythropoietin has a strong brain protective and kidney protective effect. In addition, we comment on the implications of these studies for clinicians at the bedside and for researchers designing controlled trials to further elucidate the true clinical utility of erythropoietin as a neuroprotective and nephroprotective agent. Finally, we describe EPO-TBI, a double-blinded multi-centre randomised controlled trial involving the authors that is being conducted to investigate the organ protective effects of erythropoietin on the brain, and also assesses its effect on the kidneys. PMID- 21675056 TI - Intensity of continuous renal replacement therapies in patients with severe sepsis and septic shock: a systematic review and meta-analysis. AB - The purpose of this study was to assess the efficacy of continuous renal replacement therapies in patients with severe sepsis or septic shock, with or without acute kidney injury. We performed a systematic search in Medline, Embase, Web of Knowledge, Cochrane Library and Clinicaltrials.gov and a hand search of the retrieved studies. We included both randomised controlled clinical trials and subgroups of randomised trials that assessed the effect of continuous renal replacement therapies (at traditional or high doses) and reported clinical outcomes in adult patients with severe sepsis or septic shock. The study selection and data extraction were performed by duplicate. Analysis of heterogeneity and meta-analysis was performed according to the Cochrane Collaboration guidelines for conducting systematic reviews of interventions. Twelve studies (1895 patients) met the inclusion criteria. Pooling of all studies resulted in a mortality risk ratio of 0.96 (95% confidence interval 0.83 to 1.12). The studies showed moderate statistical heterogeneity (I2 statistic 52%, P = 0.02). The effect on mortality was not modified (interaction P values non significant) by the dose of continuous renal replacement therapies, the severity of illness or the risk of bias. The available evidence suggests that these therapies in patients with severe sepsis or septic shock are not associated with an improvement in other outcomes such as haemodynamics, pulmonary gas exchange, multiple organ dysfunction syndrome or length of stay. The best available evidence does not support the routine use of continuous renal replacement therapies (at traditional or high doses) in patients with severe sepsis or septic shock. PMID- 21675057 TI - The critical care costs of the influenza A/H1N1 2009 pandemic in Australia and New Zealand. AB - The aim of this study was to determine the critical care and associated hospital costs for 2009 influenza A/H1N1 patients admitted to intensive care units (ICU) in Australia and New Zealand during the southern hemisphere winter All 762 patients admitted to ICUs in Australian and New Zealand between 1 June and 31 August 2009 with confirmed 2009 H1N1 influenza A were included. Costs were assigned based on ICU and hospital length-of-stay, using data from a single Australian ICU which estimated the daily cost of an ICU bed, along with published costs for a ward bed. Additional costs were assigned for allied health, overheads and extracorporeal membrane oxygenation services. The median (interquartile range) ICU and total hospital costs per patient were AU$35,942 ($10,269 to $82,152) and AU$51,294 ($22,849 to $110,340) respectively, while the mean (standard deviation) ICU and total hospital costs per patient were AU$63,298 ($78,722) and AU$85,395 ($147,457), respectively. A multivariate analysis found death was significantly associated with a reduction in the log of total costs, while the use of mechanical ventilation and ICU admission with viral pneumonitis/acute respiratory distress syndrome or secondary bacterial pneumonia were significantly associated with an increase in the log of total costs. The cost of 2009 H1N1 patients in ICU was significantly higher than the previously published costs for an average ICU admission, and the total cost of treating 2009 H1N1 patients in ICU admitted during winter 2009 was more than $65,000,000. PMID- 21675058 TI - Effect of daily sedative interruption on sleep stages of mechanically ventilated patients receiving midazolam by infusion. AB - Daily sedative interruption (DSI) may reduce excessive sedation and shorten the duration of mechanical ventilation. It is not clear, however, how DSI affects sleep characteristics. For patients receiving mechanical ventilation, we compared the effect on sleep quality of DSI and continuous sedation (CS). Twenty-two mechanically ventilated patients who were receiving midazolam by infusion were randomly assigned to two groups, DSI (n = 11) or CS (n = 11). In the DSI group, sedatives were interrupted until the patients awoke and expressed discomfort, after which midazolam or opioids were administered intermittently as needed during the daytime (0600 to 2100 hours); during the night (2100 to 0600) midazolam was administered intravenously to maintain Ramsay sedation scale 4 to 5. In the CS group, the sedatives were titrated to obtain Ramsay sedation scale 4 to 5 throughout the day. The polysomnography of each patient was recorded continuously over a 24 hour period. Sleep stages were analysed using Rechtschaffen and Kales criteria. In the DSI group, the amount of stage 3 and 4 non-rapid eye movement sleep (slow wave sleep) was longer (6 vs 0 minutes, P = 0.04) and rapid eye movement sleep was longer than in CS (54 vs 0 minutes, P = 0.02). In the CS group, total sleep time during night-time was longer (8.7 vs 7.3 hours, P = 0.047) and frequency of arousal was lower (2.2 vs 4.4 event/hour, P = 0.03) than those in the DSI group. All mechanically ventilated patients demonstrated abnormal sleep architecture, but, compared with CS, DSI increased the amount of slow wave sleep and rapid eye movement sleep. PMID- 21675059 TI - Meta-analysis of randomised controlled trials on daily sedation interruption for critically ill adult patients. AB - Sedation is often used to improve comfort, reduce anxiety and stress and to facilitate nursing care of critically ill patients in the intensive care unit. This meta-analysis examined the benefits and risks of daily sedation interruption in critically ill adult patients. A total of five randomised controlled trials, comparing daily sedation interruption with no interruption in 699 critically ill patients, from the Cochrane controlled trials register, Embase and MEDLINE databases (1966 to April 2010) were identified and subject to meta-analysis. With the limited data available, daily sedation interruption was not associated with a significant reduction in duration of mechanical ventilation, length of intensive care unit and hospital stay, or mortality. Daily sedation interruption was associated with a reduced risk of requiring tracheostomy (odds ratio 0.57, 95% confidence interval 0.35 to 0.92, P = 0.02; F = 3%) but not an increased risk of removal of the endotracheal tube by the patients (odds ratio 1.3, 95% confidence interval 0.41 to 4.10, P = 0.65; F = 49%). The current evidence suggests that daily sedation interruption appears to be safe, but the significant heterogeneity and small sample sizes of the existing studies suggest that large randomised controlled studies with long-term survival follow-up are needed before daily sedation interruption can be recommended as a standard sedation practice for critically ill adult patients. PMID- 21675060 TI - Rohrer's constant, K2, as a factor of determining inspiratory resistance of common adult endotracheal tubes. AB - The aim of the study was to calculate the in vitro inspiratory resistance (R(ETT)) of adult endotracheal tubes (ETT), via the end-inspiratory occlusion method, and to apply this method in vivo in order to estimate R(ETT) value in real time. By plotting R(ETT) over inspiratory flow (V) and calculating Rohrer's coefficients of linear and nonlinear resistance, K1 and K2 respectively, we determined the resistive behaviour of each ETT. Peak and plateau pressures were recorded at both proximal and distal sites of the ETT after applying a three second occlusion under constant flow. Distal pressure was obtained via an intraluminal catheter R(ETT) was calculated as (P(peak) - P(plateau))/(V), at both sites. R(ETT) value resulted from the difference R(proximal) - R(distal). Graph R(ETT) over (V) was plotted and Rohrer's constants were calculated by the method of least squares. For ETTs with inner diameter 9.0, 8.5, 8.0, 7.5, 7.0 and 6.5 mm, K2 was 2.42, 3.05, 4.65, 6.01, 9.17 and 12.80 cmH2O/l/s, respectively. The intraluminal catheter increased R(ETT) No.7.0 by an average of 49%. Finally, ten patients with partially obstructed ETTs were tested and K2 in vivo constants found to be higher than their corresponding in vitro values (P value 0.00012). Therefore, knowing the performing size of an ETT may help the clinicians identify ETT obstruction and deal with weaning problems. PMID- 21675061 TI - Myocardial injury in remifentanil-based anaesthesia for off-pump coronary artery bypass surgery: an equipotent dose of sevoflurane versus propofol. AB - This randomised controlled trial compared the effect of equipotent anaesthetic doses of sevoflurane (S group) versus propofol (P group), during remifentanil based anaesthesia for off-pump coronary artery bypass surgery, on myocardial injury. Either sevoflurane or propofol was titrated to maintain bispectral index values between 40 and 50. In both groups, a targeted concentration of remifentanil 20 ng x ml(-1) was maintained during anaesthesia. The concentrations of creatine kinase MB and troponin I were measured before the start of surgery, on admission to the intensive care unit, and at 12 and 24 hours after intensive care unit admission. The postoperative values of creatine kinase MB (S group: 15.08 +/- 18.97, 20.78 +/- 20.92, 12.76 +/- 12.82 vs 2.09 +/- 1.54 ng x ml(-1); P group: 10.99 +/- 13.15 27.16 +/- 56.55 11.88 +/- 18.80 vs 1.84 +/- 1.67 ng x ml( 1)) and troponin I (S group: 3.56 +/- 5.19, 566 +/- 7.89, 3.35 +/- 4.55 vs 0.52 +/- 1.90 ng x ml(-1); P group: 2.42 +/- 3.33, 4.11 +/- 6.01, 3.04 +/- 5.31 vs 0.43 +/- 1.28 ng x ml(-1)) were significantly higher than preoperative values in both groups but there were no significant differences between the two groups. There were no significant differences in time to extubation (S group, 476 +/- 284 minutes; P group, 450 +/- 268 minutes) and intensive care unit length of stay (S group, 2775 +/- 1449 minutes; P group, 2797 +/- 1534 minutes) between the two groups. In conclusion, sevoflurane and propofol at equipotent doses guided by bispectral index with remifentanil 20 ng x ml(-1) had similar creatine kinase MB and troponin I values. PMID- 21675062 TI - Effect of a blood conservation device in patients with preserved admission haemoglobin in the intensive care unit. AB - An important iatrogenic cause of anaemia in the intensive care unit is loss of the discarded blood during phlebotomy via indwelling vascular catheters. A closed system blood conservation device has previously been shown to reduce the need for blood transfusion and to blunt the decrease of haemoglobin in intensive care unit patients. However such a device may not benefit patients who are admitted with a relatively preserved haemoglobin. In this sub-group analysis of a before-and after study, 128 patients had admission haemoglobin > or =115 g/l and did not receive any blood transfusions while in the intensive care unit. In the control group of 50 patients a blood conservation device was not used, while in the active group of 78 patients the device was used. Use of the blood conservation device did not affect the haemoglobin trends when both groups were compared using the general linear model. For patients with admission haemoglobin > or = 115 g/l, use of a blood conservation device does not affect the subsequent rate of haemoglobin decline in the intensive care unit. These patients are unlikely to benefit from the use of such devices. PMID- 21675063 TI - Intrabronchial airway pressures in intubated patients during bronchoscopy under volume controlled and pressure controlled ventilation. AB - Bronchoscope insertion through an endotracheal tube increases airflow resistance. Constant tidal volume (T(v)) ventilation can be maintained by augmenting the inspiratory pressure, but increased outflow resistance cannot be compensated for. Air trapping distal to the tube may lead to higher airway pressures in volume controlled (VC) mode and reduced T(v) in pressure controlled (PC) mode. Increased end-expiratory airway pressures will not be detected by ventilator pressure sensors. In mechanically ventilated and sedated patients, the effects of bronchoscope insertion on intrabronchial pressures were recorded by a pressure transducer distal to the endoscope. In half of the patients, the ventilator was set in VC mode prior to bronchoscope insertion, keeping the previous T(v) constant. In the other half the ventilator was set in PC mode, keeping previous peak inspiratory pressures constant. All patients underwent sequences of VC-PC-VC or PC-VC-PC ventilation with two-minute intervals between mode-changes. In VC mode, bronchoscope insertion increased peak airway pressure from 29 cmH2O (22 to 43) to 41 cmH2O (36 to 49) (P = 0.012) and end-expiratory airway pressure from 11 cmH2O (6 to 18) to 22.5 cmH2O (15 to 30) (P = 0.012). There were no significant changes in T(v), P(a)CO2 or P(a)O2 after two minutes. In PC mode, peak airway pressure was unchanged and end-expiratory airway pressure increased from 9.5 cmH2O (7 to 10) to 10.5 cmH2O (9 to 18) (P = 0.017). Median T(v) was reduced from 673 ml (585 to 800) to 450 ml (408 to 560) (P = 0.012); median P(a)CO2 increased from 5.7 kPa to 6.5 kPa (P = 0.012). Using distal measurement, positive end expiratory airway pressure increased markedly in VC mode but only marginally in PC mode after bronchoscope insertion. PMID- 21675064 TI - The effect of the sitting upright or 'beachchair' position on cerebral blood flow during anaesthesia for shoulder surgery. AB - The sitting upright or 'beachchair' position is commonly used for shoulder arthroscopic surgery. There is a theoretical concern that anaesthetised patients placed in this posture are at risk of reduced cerebral blood flow (CBF), especially if there is associated hypotension. This study investigated the effect of anaesthetic-induced hypotension on estimated cerebral blood flow in patients placed in the beachchair position for shoulder surgery. Forty patients were randomised to either sedation (propofol infusion 10 to 20 mg x hour 1, n = 20) or general anaesthesia using sub minimum alveolar concentration of sevoflurane (n = 20). All patients received an interscalene brachial plexus regional block. Internal carotid artery blood flow was measured using the time averaged velocity of the spectral Doppler waveform, and was then used as an estimate of global CBF. Following a pre-anaesthesia study, measurement of internal carotid artery blood flow was made before and after beachchair positioning, and at five-minute intervals during surgery. Beachchair positioning during general anaesthesia significantly decreased the mean arterial pressure (34 +/- 10 mmHg) compared to sedation (4 +/- 2 mmHg, P < 0.01), and vasopressor therapy was required more often. However, CBF remained constant in both anaesthetised (P = 0.83) and sedated patients (P = 0.68) despite beachchair positioning, and the fall in mean arterial pressure in the anaesthetised patients. There was no significant difference in CBF between groups (P = 0.91). These findings indicate that in patients in the beachchair position receiving sevoflurane anaesthesia, CBF is maintained when mean arterial pressure is above 70 mmHg, consistent with intact autoregulation. PMID- 21675065 TI - The relationship between blood lactate and survival following the use of adrenaline in the treatment of septic shock. AB - This prospective observational study evaluates the relationship between adrenaline, lactate and intensive care unit survival in septic shock. Forty patients requiring adrenaline therapy for a first episode of septic shock acquired > 24 hours after admission to the intensive care unit had blood lactate levels measured two-hourly over a 24-hour period. Adrenaline therapy was escalated until target mean arterial pressure was reached. The lactate index was calculated as the ratio of maximum lactate increase to the adrenaline increase. Lactate increased from 2.3 to 2.9 mmol x l(-1) (P = 0.024) and the mean adrenaline increase was 0.14 microg x kg'.minute(-1). Peak lactate correlated with peak adrenaline (rho = 0.34, P = 0.032). Lactate index was the only independent predictor of survival after controlling for age and Acute Physiological and Chronic Health Evaluation II score (odds ratio 1.14, 95% confidence interval 1.03 to 1.26, P = 0.009). A high lactate following adrenaline administration may be a beneficial and appropriate response. PMID- 21675066 TI - Mini-ventilation for improved oxygenation during lung resection surgery. AB - Lung separation is frequently used during lung resection to facilitate surgery and hypoxaemia may occur because of increasing pulmonary shunt. In this study, we tested a method of mini-ventilation to the non-dependent lung and compared it to continuous positive airway pressure (CPAP) to improve oxygenation during lung resection. Thirty-eight adult patients participated in this randomised, single blinded crossover study. Following lung separation, mini-ventilation and CPAP of 5 cmH2O were alternately applied every 15 minutes to the non-dependent lung. Mini ventilation was performed by a portable time-cycled ventilator with a respiratory rate of 8 breaths/minute and a tidal volume of 0.1 to 0.15 l. Arterial blood gases, peak inspiratory pressure, the dynamic compliance in the dependent lung and the surgeon's evaluation of the surgical field exposure were recorded. The arterial oxygen partial pressure was significantly higher during mini-ventilation compared to CPAP (379 vs 228 mmHg). No difference was noted in the dependent lung peak inspiratory pressure or in the dynamic compliance. The surgical conditions were similar with both methods in 53% of the patients, while the surgeon preferred CPAP in 44% and mini-ventilation in 3%. In conclusion, mini-ventilation is a simple method which improves oxygenation during lung resection. However due to interference with surgical field exposure, it should be reserved for cases in which CPAP does not relieve hypoxaemia. PMID- 21675067 TI - Observational study of anaesthetists' fresh gas flow rates during anaesthesia with desflurane, isoflurane and sevoflurane. AB - Reducing excessive fresh gas flow rates (FGF) is an established and simple strategy to reduce the administration of volatile anaesthetic agents. We studied clinicians' FGF use to understand better why two previous clinical trials achieved significant reductions in FGF by using feedback to anaesthetists. Anaesthesia information management system data from a US academic medical centre were analysed retrospectively. One year of data starting from July 2008 had 11,170 cases. Fresh gas flow rates were measured each minute during cases. Anaesthetists were more likely to choose FGF of multiples of 1 l/minute and 0.5 l/minute than random. However the pattern was too inconsistent to be of economic or psychological importance and thus is not needed when describing a target FGF. Cumulative distributions of FGF were shifted to the left for desflurane and isoflurane compared to sevoflurane (i.e. cost comparisons among agents may need to use different target FGF). Variation in mean FGF among anaesthetists was small. Even if all anaesthetists had identical mean FGF, the standard deviation of FGF among cases would be reduced by less than 0.1 l/minute for all agents. Most of the achievable reductions in FGF were small reductions in FGF for the many cases with < 3 l/minute. These results show that departments choosing to use inexpensive automatic email feedback on FGF should target all anaesthetists and focus on variation in FGF among anaesthetists' cases. PMID- 21675069 TI - Anaesthesia trainees' exposure to regional anaesthesia in an Australian tertiary adult teaching hospital. AB - The purpose of this study was to quantify the exposure of anaesthetic trainees to regional anaesthesia in an Australian tertiary adult teaching hospital. We reviewed data collected on all regional blocks performed by the anaesthetic department over a two-year period. The data was then broken down to give an estimate of the number of each block performed by each training year group. There was an average of 27.7 full-time equivalent trainees attached to the department. Trainees performed a total of 1374 blocks over this period. The average number of blocks performed by basic training year one trainees each year was 6.5, basic training year two trainees 13.5, advanced training year one trainees 14.9, advanced training year two trainees 19.1, advanced training year three trainees 23.1 and regional fellows 144.0. The number of total blocks and the proportion of advanced blocks increased with increasing level of training while supervision declined. Trainees in the two regional fellowship positions (7% of the trainee pool) performed 42% of the 1374 blocks. Factors that may influence the exposure of trainees to regional anaesthesia and the assessment of competency are considered. PMID- 21675068 TI - Variability in adequacy of ventilation during transport of cardiac surgery patients: a cohort study. AB - Inadequate ventilation of intubated patients during transport from the operating theatre to the intensive care unit with attendant hypercarbia may adversely affect haemodynamics. In a retrospective observational study, we assessed the incidence of inadequate ventilation during transport from the operating theatre to the intensive care unit in 99 consecutive cardiac surgery patients admitted to our university tertiary hospital. Demographic, clinical, arterial blood gas and haemodynamic measurements were made on arrival in the intensive care unit after cardiac surgery. The relationships between arterial carbon dioxide tension (P(a)CO2), mean pulmonary artery pressure (MPAP) and other relevant haemodynamic variables were explored. Overall, hypocarbia (P(a)CO2 < 35 mmHg) occurred in 18.2% of patients, while 28.3% of patients had hypercarbia (P(a)CO2 > 45 mmHg). Pulmonary hypertension was common, with nearly half of the cohort having MPAP > or = 25 mmHg and 17.2% > or = 30 mmHg. However there was no association between P(a)CO2 and MPAP (R2 = 0.0076, P = 0.39). Contrary to expectation, neither hypercarbia nor high MPAP were associated with measured adverse outcomes, although this may have been because we studied an insufficient number of patients with extreme values. Associations of higher MPAP, which would be expected to compromise cardiovascular status, included acidaemia, hypoxia and the requirement for noradrenaline. These factors define a group of high-risk patients who should receive particular attention and who should be the focus of future studies. PMID- 21675070 TI - A checklist for streamlining organ donation after cardiac death. AB - There is currently a shortage of organ donors to meet the demands of transplantation waiting lists. In recent years there has been renewed interest in donation after cardiac death in order to increase the pool of potential donors. The Organ and Tissue Authority has recently developed a national policy for donation after cardiac death. We describe here a checklist that is used by our hospital-based staff for organ donation which outlines important steps in the donation after cardiac death process. PMID- 21675071 TI - Retrospective audit of blood transfusion and comparison with haemoglobin concentration in patients undergoing elective primary and revision lower limb arthroplasty. AB - We retrospectively audited the incidence of blood transfusion and related this to preoperative haemoglobin levels in 181 patients undergoing lower limb arthroplasty over a six-month period. This included 102 primary total knee replacements, 52 primary total hip replacements, 11 revision total knee replacements and 16 revision total hip replacements. The overall incidence of transfusion was 16.0%. The incidence in primary arthroplasty was 11% (9.8% for total knee replacements and 13.5% for total hip replacements), and in revision surgery was 44.4% (27.3% for total knee replacements and 56.3% for total hip replacements). Combining data for primary total knee replacements and primary total hip replacements, a preoperative haemoglobin threshold of 120 g/l divided patients into high and low risk groups for transfusion. Below or equal to this threshold the incidence of transfusion was 47.7%; above this threshold the incidence was 7.2%. We suggest that patients having primary lower limb arthroplasty with a preoperative haemoglobin of 120 g/l or less should undergo investigation of their anaemia and optimisation of erythropoeisis. PMID- 21675072 TI - Successful treatment of peripartum massive pulmonary embolism with extracorporeal membrane oxygenation and catheter-directed pulmonary thrombolytic therapy. AB - Chronic thromboembolic pulmonary hypertension during pregnancy is uncommon but is associated with maternal mortality in excess of 35%. We report a case of decompensated thromboembolic pulmonary hypertension requiring emergency caesarean section and postpartum treatment with extracorporeal membrane oxygenation and thrombolytic therapy with urokinase. The use of extracorporeal membrane oxygenation, catheter-directed pulmonary thrombolytic therapy and other pulmonary vasodilators for management of this life-threatening disease is discussed. PMID- 21675073 TI - Quantification of volume loss and haemodynamic changes of Gelofusine-induced anaphylaxis during cardiopulmonary bypass. AB - A patient undergoing anaesthesia for coronary artery bypass surgery developed what was subsequently confirmed to be an anaphylactic reaction to succinylated gelatin (Gelofusine). By virtue of being on cardiopulmonary bypass, rapid detection, quantification and treatment of volume loss (by vasodilatation and extravasation) was possible. The patient required 51 ml/kg of resuscitative fluids in the 15 minutes after onset of anaphylaxis, or 73% of her calculated preoperative blood volume. Alpha-adrenoceptor agonists and vasopressin were required to manage ongoing vasoplegia. This case emphasises the importance of volume resuscitation and vasopressors in the treatment of anaphylaxis. PMID- 21675074 TI - Concurrent intracardiac metastasis in a patient with intestinal perforation. AB - The administration of anaesthesia to subjects with intracardiac lesions poses the potential for cardiac complications. Cardiac metastases should be identified in susceptible cases and transthoracic echocardiography performed to elucidate the nature of the cardiac lesions. We describe a case of an intracardiac metastasis in a 65-year-old subject with a small bowel tumour leading to intestinal perforation and presenting for surgical treatment. Oncological assessment of the situation, in conjunction with the anaesthetic risks, led to abandonment of surgery and palliative treatment. PMID- 21675075 TI - A rare case of antepartum posterior reversible encephalopathy syndrome. AB - Pre-eclampsia and eclampsia are well-known causative factors of posterior reversible encephalopathy syndrome (PRES). There are only a few reported cases of antepartum PRES. We report a 25-year-old primigravid woman who presented with eight months of amenorrhoea and an abrupt onset of eclampsia associated with a history of a fall. A computed tomography scan ruled out intracranial haemorrhage and PRES was diagnosed. She responded well to supportive care, labour was induced and maternal and neonatal outcomes were good. Antepartum PRES poses different challenges to those of PRES in non-obstetric or postpartum patients, because of the additional management aspects required to ensure foetal wellbeing. We were posed with a difficult decision about the disadvantages of caesarean section versus those of vaginal delivery in our patient. PMID- 21675076 TI - Failure to visualise the superior laryngeal nerve using ultrasound imaging. PMID- 21675077 TI - Dexmedetomidine and procedural sedation: the AusPAR a TGA resource. PMID- 21675078 TI - 2011--The global year against acute pain. PMID- 21675079 TI - Delayed airway compromise following extubation of adult patients who required surgical drainage of Ludwig's angina: comment on three coronial cases. PMID- 21675080 TI - Hypocoagulation state in severe systemic inflammatory response syndrome/sepsis is consistent with endogenous heparinoid effect as detected by thromboelastography. PMID- 21675081 TI - Vallecular cyst in a newborn: a challenging airway. PMID- 21675082 TI - Transfusion reactions in pregnancy: the tip of the iceberg? PMID- 21675083 TI - TruView laryngoscope versus Macintosh laryngoscope for vocal cords visualisation after thyroid and parathyroid surgery. PMID- 21675084 TI - A new Visual Stylet (Discopo): early clinical experience in patients with difficult intubation. PMID- 21675085 TI - Malposition of thoracostomy tubes leading to missed haemothorax and tension pneumothorax. PMID- 21675087 TI - What have shorter working hours for doctors achieved? PMID- 21675086 TI - Acceptability of chewing gum for postoperative nausea and vomiting prevention in high risk patients: a pilot study. PMID- 21675088 TI - Paediatric asthma--some questions answered. PMID- 21675089 TI - Vitamin D nutrient intake for all life stages. PMID- 21675090 TI - Room for improvement--syphilis; knowledge and delayed diagnosis among sexual health clinic attendees. AB - Cases of early infectious syphilis are increasing in Ireland. A questionnaire distributed to sexual health clinic attendees assessed syphilis knowledge. A telephone survey in patients with secondary syphilis explored potential delays in diagnosis. 272 questionnaires were completed. 54% of respondents were male, 222 (81.6%) were Irish.31/268 (12%) who stated their sexual orientation were men who have sex with men (MSM). 226 (83%) had heard of syphilis. MSM had better knowledge compared to heterosexual males (p<0.05). Contact details were available for 60 patients with secondary syphilis. 37 patients were surveyed. 31/37 (84%) recalled symptoms prior to diagnosis, mean duration of symptoms 53 days (range 7 168). 23/37 (62%) reported consulting at least one physician before attending sexual health services. 12/23 (52%) were given an alternate or no diagnosis. Greater awareness of syphilis signs and symptoms is needed amongst patients and healthcare providers to prevent delayed diagnosis leading to ongoing transmission. PMID- 21675091 TI - Looked after children in Dublin and their mental health needs. AB - Children in care in Ireland have increased by 27% in the last decade. This population is recognized to be among the most vulnerable. This study aims to describe their placement histories, service use and mental health needs. Data was obtained on 174 children (56.5% of eligible sample) with a mean age of 10.83 (SD = 5.04). 114 (65.5%) were in care for three years or more. 29 (16.7%) did not have a SW and 49 (37.7%) had no GP 50 (28.7%) were attending CAMHS. Long term care, frequent placement changes and residential setting were significantly related with poorer outcomes and increased MH contact. Given the increase in numbers in care and the overall decrease in resource allocation to health and social care, individual care planning and prioritizing of resources are essential. PMID- 21675092 TI - Radical prostatectomy outcome when performed with PSA above 20 ng/ml. AB - Many centres currently do not offer radical prostatectomy (RP) to men with high risk localised prostate cancer due to concerns regarding poor outcome, despite evidence to the contrary. We identified 18 men undergoing RP with serum PSA >20 ng/ml (high-risk by National Comprehensive Cancer Network definition) and minimum follow-up of 12 years (mean 13.5). Mean preoperative PSA was 37.0 ng/ml (Range 21.1-94.0). Prostatectomy pathology reported extracapsular disease in 16 (88.9%), positive surgical margins in 15 (83%) and positive pelvic lymph nodes in 5 (27.8%). Overall and cancer-specific survival at 5 and 10-years was 83.3%, 88.2%, 72% and 76.5% respectively. With complete follow-up 11 (61.1%) are alive, and 5 (27.8%) avoided any adjuvant therapy. Complete continence (defined as no involuntary urine leakage and no use of pads) was achieved in 60%, with partial continence in the remainder. We conclude that surgery for this aggressive variant of localised prostate cancer can result in satisfactory outcome. PMID- 21675093 TI - An audit of current practice and management of metastatic spinal cord compression at a regional cancer centre. AB - Metastatic spinal cord compression (MSCC) is an oncological emergency requiring prompt recognition and management to preserve neurological function and mobility. We performed an audit to assess current practice of MSCC against current best practice as outlined by NICE. Our retrospective audit identified 10 patients from January to December 2009 with confirmed MSCC. The most common primary tumours were prostate 3 (30%), breast 3 (30%) and lung 2 (20%). Pain was the main presenting symptom 9 (90%), followed by weakness 7 (70%) and sensory changes 1 (10%). 5 (50%) had MRI within 24 hours and only 6 (60%) underwent full MRI scan. 8 (80%) had corticosteroids before MRI scan. 6 (60%) received radiotherapy within 24 hours. Only 4 (40%) were referred to orthopaedics and none of these patients had been recommended surgery. Up 14 days following radiological confirmation of MSCC, the number of patients who were unable to walk increased by 20%. Only 5 (50%) were discharged during this period of study. Our audit reported a number of variances in management compared to NICE guideline. These can be improved by following a'fast track' referral pathway and regular education for junior doctors and primary care doctors. PMID- 21675094 TI - Introducing random safety audits (RSA) in a neonatal intensive care unit (NICU). AB - Random safety audits (RSA) have been shown to be effective in improving standards of clinical practice. 19 data collection audits were performed relating to hygiene, safe prescribing, oxygen pulse oximetry monitoring and documentation in keeping with the requirements of the new Medical Practitioners Act (MPA) 2007. Hygiene audits (range from 20/25 to 21/21 80%-100%) and safe prescribing audits (range from 23/25 to 25/25 86%-100%) achieved n=25 100% compliance with unit guidelines over a 3 month period. Compliance with oxygen pulse oximetry monitoring guideline limits improved from 4/27 (15%) to 9/16 (56%). Compliance with requirement and use of Physician IMC registration number in documentation was only 10/18 (56%). RSA's led to improvements in hygiene and prescribing. Compliance with oxygen monitoring guideline limits highlighted the need for greater education. Awareness of legal requirements relating to documentation improved but this has not translated into a change in practice. RSA's can facilitate real time quality improvement in daily clinical practice. PMID- 21675095 TI - A survey of patients' attitudes to clinical research. AB - Every year hundreds of patients voluntarily participate in clinical trials across Ireland. However, little research has been done as to how patients find the experience. This survey was conducted in an attempt to ascertain clinical trial participants' views on their experience of participating in a clinical trial and to see and how clinical trial participation can be improved. One hundred and sixty-six clinical trial participants who had recently completed a global phase IV cardiovascular endpoint clinical trial were sent a 3-page questionnaire. Ninety-one (91%) respondents found the experience of participating in a clinical trial a good one with 85 (84.16%) respondents saying they would recommend participating in a clinical trial to a friend or relative and eighty-five (87.63%) respondents feeling they received better healthcare because they had participated in a clinical trial. PMID- 21675096 TI - Quality of care in the management of major obstetric haemorrhage. AB - Substandard care is reported to occur in a large number of cases of major obstetric haemorrhage (MOH). A prospective audit was carried out by a multidisciplinary team at our hospital over a one year period to assess the quality of care (QOC) delivered to women experiencing MOH. MOH was defined according to criteria outlined in the Scottish Audit of Maternal Morbidity (SAMM). 31 cases were identified yielding an incidence of 3.5/1000 deliveries. The predominant causes were uterine atony 11 (35.4%), retained products of conception 6 (19.3%) and placenta praevia/accreta 6 (19.3%). Excellent initial resuscitation and monitoring was noted with a high level of senior staff input. Indicators of QOC compared favourably with the SAMM. Areas for improvement were identified. This pilot study demonstrates the feasibility of detailed prospective data collection in MOH in a busy Dublin obstetric unit with a view to developing a national audit. Standardization of definitions allows for international comparisons. PMID- 21675097 TI - Nodal presentation of seminoma. AB - We report a 38 year old male with metastatic seminoma in an inguinal lymph node and regression of the primary testis tumour with a past history of orchiopexy--an extremely rare occurrence. PMID- 21675098 TI - Cutaneous reactions to adalimumab administration. AB - Patients receiving antitumour necrosis factor-alpha treatment may develop cutaneous reactions. This human monoclonal antibody is used in the treatment of chronic inflammatory diseases, including arthritis and inflammatory bowel disease. A variety of side effects have been documented ranging from infection and vasculitis through to systemic lupus erythematosus and psoriasis. We report on two arthritic patients treated with adalimumab (Humira, Abbot Laboratories, IL, USA) who developed new onset rashes that resolved with discontinuation of therapy. The frequency of these cutaneous reactions has not been fully established and may benefit from a centralised registry. PMID- 21675099 TI - Alexia without agraphia. AB - Alexia without agraphia (also called pure alexia or word blindness) was the first of the disconnection syndromes (syndromes caused by disconnection of the right from the left cerebral hemisphere through interruption of the communication pathways between them) to be described. Dejerine in 1892 reported a patient who developed this syndrome after an infarct of the left occipital lobe and splenium of the corpus callosum. We describe a patient who developed alexia without agraphia due to an embolic left occipital lobe infarct extending to the posterior commissure and splenium of the corpus callosum. PMID- 21675100 TI - An Irish biobank network for patient-focused research. PMID- 21675101 TI - Razor blades, heparin and protamine--a potent mix. PMID- 21675102 TI - [Effect of femoral offset reconstruction on pelvic stability during gait after total hip arthroplasty]. AB - OBJECTIVE: To investigate the effect of femoral offset reconstruction on pelvic stability during gait after total hip arthroplasty. METHODS: According to the inclusion criteria, 29 patients undergoing unilateral total hip arthroplasty between January 2000 and December 2005 were selected. There were 10 males and 19 females with an average age of 64.3 years (range, 33-75 years). The affected hips included 15 left hips and 14 right hips. The follow-up time was from 5 to 10 years (mean, 7.7 years). The Harris score was 90 to 100 (mean, 97) at last follow up. The femoral offset ratio (FOR) was calculated by measuring the femoral offset of the bilateral hips on radiograph, and then the patients were divided into 2 groups: group A (the femoral offset of diseased hip was less than that of normal hip, n=10) and group B (the femoral offset of diseased hip was greater than that of normal hip, n=19). The pelvis kinematic variables were measured by three dimensional gait analysis to collect the magnitude of pelvic oblique angle (POA). RESULTS: In group A, the FOR was 0.81 +/- 0.08 and the POA was (-0.42 +/- 0.91) degrees. In group B, the FOR was 1.27 +/- 0.15 and the POA was (1.02 +/- 0.94) degrees. For the normal hip, the POA was (1.15 +/- 0.85) degrees. The POA was significantly less in group A than in group B and the normal limb (P < 0.05). The difference in POA had no significance between group B and the normal hip (P > 0.05). The POA was positive relative with FOR (r = 0.534, P = 0.003), and the regression equation was y = -2.551 + 2.781x. CONCLUSION: The femoral offset reconstruction is crucial to improve hip abductor function and gait. PMID- 21675103 TI - [Minimal invasive fixation for acetabular fracture with three dimensional fluoro images based on navigation]. AB - OBJECTIVE: To evaluate the security and effectiveness of minimal invasive fixation with three dimensional (3D) fluoro-images based on navigation system in the management of acetabular fractures. METHODS: Between August 2008 and January 2010, 12 patients with acetabular fractures were treated with percutaneous screw fixation under the guidance of 3D fluoro-images based on navigation system after closed reduction. There were 7 males and 5 females, aged 28-57 years (mean, 38.1 years). Fractures were caused by traffic accident in 9 cases, and falling from height in 3 cases. According to AO classification, there were 1 case of A2.2 type, 3 cases of A2.3 type, 2 cases of A3.2 type, 2 cases of A3.3 type, 1 case of B2.2 type, 1 case of B3.2 type, 1 case of C2.1 type, and 1 case of C2.3 type. The interval from injury to hospitalization was 4 hours to 3 days (mean, 1.2 days). RESULTS: Totally 28 screws were implanted. The average time to implant 1 screw was 24.8 minutes. Twenty-seven screws were placed correctly with a successful rate of 96.4%, only 1 screw was reinserted for deviation. All the screws were checked by the 3D fluoro-images, which showed they were not in the joint space after fixation. The results were the same as that by CT scanning. Incisions healed by first intention, and no implant failure occurred. All 12 patients were followed up 7 to 24 months with an average of 16.8 months. At last follow-up, fracture union was achieved in all patients with satisfactory screw fixation. CONCLUSION: The minimal invasive fixation with 3D fluoro-images based on navigation system makes the surgery for the nondisplaced acetabular fracture more precise and time-saving, minimizes the surgery injury, and improves the clinical results with less complications. PMID- 21675104 TI - [Treatment of Pipkin type I fracture of femoral head associated with posterior dislocation of the hip]. AB - OBJECTIVE: To evaluate and compare the outcomes of simple closed reduction, selective fragment excision after closed reduction, and emergency fragment excision and reduction in the treatment of Pipkin type I fracture of femoral head associated with posterior dislocation of the hip. METHODS: Between January 2002 and January 2008, 24 patients with Pipkin type I fracture of the femoral head associated with posterior dislocation of the hip were treated with simple closed reduction (closed reduction group, n=8), with selective fragment excision after closed reduction (selective operation group, n=8), and with emergency fragment excision and reduction (emergency operation group, n=8). In the closed reduction group, there were 6 males and 2 females with an average age of 37.6 years (range, 19-56 years); injuries were caused by traffic accident in 6 cases, by falling from height in 1 case, and by crushing in 1 case with a mean disease duration of 3.1 hours (range, 1.0-7.5 hours); and the interval from injury to reduction was (4.00 +/- 2.14) hours. In the selective operation group, there were 7 males and 1 female with an average age of 37.3 years (range, 21-59 years); injuries were caused by traffic accident in 7 cases and by falling from height in 1 case with a mean disease duration of 3.2 hours (range, 1.0-6.0 hours); and the interval from injury to reduction was (3.90 +/- 1.47) hours. In the emergency operation group, there were 5 males and 3 females with an average age of 35.5 years (range, 20-58 years); injuries were caused by traffic accident in 5 cases, by falling from height in 1 case, and by crushing in 2 cases with a mean disease duration of 3.3 hours (range, 1.5-6.5 hours); and the interval from injury to open reduction was (5.10 +/- 2.04) hours. There was no significant difference in the age, gender, disease duration, and interval from injury to reduction among 3 groups (P > 0.05). RESULTS: All wounds in selective operation group and emergency operation group healed primarily. All the patients were followed up 24 to 58 months (mean, 38.7 months). According to Thompson-Epstein system, the excellent and good rates were 50.0% (4/8) in the closed reduction group, 87.5% (7/8) in the selective operation group, and 87.5% (7/8) in the emergency operation group at 24 months after operation, showing significant difference among 3 groups (chi2 = 9.803, P = 0.020). Heterotopic ossification was found in 1 case (12.5%) of the closed reduction group, in 4 cases (50.0%) of the selective operation group, and in 4 cases (50.0%) of the emergency operation group, and avascular necrosis of femoral head was found in 2 cases (25.0%) of the closed reduction group; there was no significant difference in complications among 3 groups (P > 0.05). CONCLUSION: The treatment of Smith-Petersen approach and fragment excision by selective operation or emergency operation has similar outcome, which are better than the treatment of simple closed reduction. PMID- 21675105 TI - [Treatment of avascular necrosis of femoral head after femoral neck fracture with pedicled iliac bone graft]. AB - OBJECTIVE: To explore the effectiveness of pedicled iliac bone graft transposition for treatment of avascular necrosis of femoral head (ANFH) after femoral neck fracture. METHODS: Between June 2002 and December 2006, 22 cases (22 hips, 16 left hips and 6 right hips) of ANFH after femoral neck fracture were treated with iliac bone graft pedicled with ascending branch of the lateral femoral circumflex vessels. There were 18 males and 4 females with an age range from 28 to 48 years (mean, 37.5 years). The time from injury to internal fixation was 2-31 days, and all fractures healed within 12 months after internal fixation. The ANFH was diagnosed at 15-40 months (mean, 22 months) after internal fixation. The ANFH duration was 3-11 months (mean, 8 months). According to Association Research Circulation Osseous (ARCO) staging system, 2 hips were classified as stage IIa, 3 hips as stage IIb, 3 hips as stage IIc, 3 hips as stage IIIa, 7 hips as stage IIIb, and 4 hips as stage IIIc. The preoperative Harris hip score (HHS) was 64.10 +/- 5.95. RESULTS: All incisions healed by first intention and the patients had no complication of lung embolism, sciatic nerve injury, lower limb deep venous thrombosis, and numbness and pain of donor site. All patients were followed up 2.5 to 6.3 years (mean, 4.8 years). The fracture healing time was 8 12 months, and no femoral neck fracture recurred. The HHS was 90.20 +/- 5.35 at last follow-up, showing significant difference when compared with the preoperative value (t = -18.447, P = 0.000). The hip function were excellent in 11 hips, good in 10 hips, fair in 1 hip, and the excellent and good rate was 95.5%. Four hips were radiographically progressed in ARCO staging, 18 hips remained stable with a stable rate of 81.8%. CONCLUSION: Pedicled iliac bone graft transposition is an ideal option for treatment of ANFH after internal fixation of femoral neck fracture for the advantages of femoral head revascularization, sufficient cancellous bone supply, and relatively simple procedure. PMID- 21675106 TI - [Diagnosis and treatment of unilateral gluteal muscle contracture]. AB - OBJECTIVE: To investigate the pathogenesis, diagnosis, and treatment of unilateral gluteal muscle contracture. METHODS: Between January 1990 and September 2009, 41 patients with unilateral gluteal muscle contracture were treated and the clinical data were retrospectively analysed. Among them, 24 were male and 17 were female with an age range from 6 to 29 years (mean, 12 years). Thirty-nine patients had a definite history of repeat intragluteal injection. The locations were the left side in 9 cases and the right side in 32 cases. The main clinical manifestations included lameness and abnormal gait. The medical examination showed pelvic oblique and relative inequality of lower limbs with a mean difference of 2.1 cm (range, 1.2-3.8 cm) in the distance form navel to malleolus medials. The X-ray films of pelvis showed outpouching trochanter of femur and pelvic oblique. The CT scans showed no abnormal finding except pelvic oblique and gluteal muscle contracture. The arc longitudinal incision was made into the posterolateral area nearby the greater trochanter and then lysis of the gluteal muscles was performed, followed by the skin traction of both legs and rehabilitation exercise. RESULTS: All incisions healed by first intention. Forty one patients were followed up 1-20 years (mean, 5 years), and the signs of gluteal muscle contracture disappeared. After 1 year of operation, 34 patients had equal leg length, 5 patients had mild pelvic oblique, and 2 patients had obvious pelvic oblique. According to LIU Guohui et al. evaluation standard, the results were excellent in 33 cases, good in 6 cases, and poor in 2 cases with an excellent and good rate of 95.12% at 1 year after operation. CONCLUSION: Unilateral gluteal muscle contracture leads to pelvic oblique and inequality of lower limbs, and it can be cured with the surgical release of the gluteal muscle contracture by the arc longitudinal incision into the posterolateral area nearby the greater trochanter, combined with postoperative skin traction and rehabilitation exercises. PMID- 21675107 TI - [Effect of glucocorticoid on production of reactive oxygen species in bone microvascular endothelial cells]. AB - OBJECTIVE: Glucocorticoid is the main cause of non-traumatic avascular necrosis of femoral head. To explore the changes of reactive oxygen species (ROS) in the bone microvascular endothelial cells treated with glucocorticoid so as to investigate the pathogenesis of steroid-induced avascular necrosis of femoral head. METHODS: The cancellous bone of femoral head was harvested from voluntary donators undergoing total hip arthroplasty, and then the bone microvascular endothelial cells were isolated by enzyme digestion. The cells at passage 3 were cocultured with different concentrations of hydrocortisone (0, 0.03, 0.10, 0.30, and 1.00 mg/mL) for 24 hours. MTT assay was used for the inhibitory rate of cell proliferation, flow cytometry for apoptosis rate, and fluorescence probe for the production of ROS and xanthine oxidase (XOD). RESULTS: At 2-3 days primary culture, the cells were spindle and arranged like cobbles and they reached confluence after 1 week. The inhibitory rates of cell proliferation in 0.03, 0.10, 0.30, and 1.00 mg/mL groups were 20.22% +/- 2.97%, 22.94% +/- 4.52%, 43.98% +/- 3.35%, and 78.29% +/- 3.85%, respectively; and 2 high-concentration groups (0.30 and 1.00 mg/mL groups) were significantly higher (P < 0.05) than 2 low concentration groups (0.03 and 0.10 mg/mL groups). The apoptosis rates in 0, 0.03, 0.10, 0.30, and 1.00 mg/mL groups were 0.10% +/- 0.01%, 0.23% +/- 0.02%, 1.83% +/- 0.04%, 6.34% +/- 0.11%, and 15.33% +/- 0.53%, respectively; 2 high concentration groups (0.30 and 1.00 mg/mL groups) were significantly higher (P < 0.05) than 0 mg/mL group. In 0, 0.30, and 1.00 mg/mL groups, the ROS levels were 57.35 +/- 7.11, 120.47 +/- 15.68, and 166.15 +/- 11.57, respectively, and the XOD levels were 0.017 9 +/- 0.000 9, 0.028 3 +/- 0.0017, and 0.067 7 +/- 0.0041, respectively; there were significant differences in the levels of ROS and XOD among 3 groups (P < 0.05). CONCLUSION: Increasing of ROS production in bone microvascular endothelial cells can be induced by high concentration glucocorticoid, and it can result in cell injury. PMID- 21675108 TI - [Surgical treatment of stiff metacarpophalangeal joint after hand injury]. AB - OBJECTIVE: To discuss the surgical procedures and curative effect of stiff 2-5 metacarpophalangeal (MP) joints after crash injury in hand. METHODS: Between January 2006 and June 2009, 7 cases of stiff 2-5 MP joints were treated by releasing the stiff MP joints and reconstructing the function of lumbrical muscle in one stage. There were 6 males and 1 female with an average age of 32 years (range, 18-56 years). All injuries were caused by crash. Six cases suffered from multiple metacarpal fracture or complex dislocation of MP joint and 1 case suffered from complete amputation at level of middle palm of hand. The interval from initial wound healing to hospitalization was 3 to 15 months. Before operation, the X-ray films showed fracture healed and the results of nipping paper test were positive. All hands were treated with physical therapy for 1 month. After the plaster external fixation for 6 weeks, the physical therapy and function training were given. RESULTS: All wounds healed by first intention. The patients had no joint instability and extensor tendon side-slipping with normal finger function. Six patients were followed up from 6 months to 3 years. The extension and flexion of MP joint were 0 degree and 67-90 degrees, respectively. The average grip strength of injured dominant hand reached 86.70% of normal side and non-dominant hand reached 66.70% of normal side. The average injured dominant tip pinch strength reached 83.52% of normal side and non-dominant tip pinch strength reached 61.30% of normal side. Based on total active motion (TAM) system of Chinese Medical Association for Hand Surgery, the results were excellent in 4 cases, good in 1 case, and fair in 1 case; the excellent and good rate was 83.33%. CONCLUSION: In patients with stiff MP joint and lumbrical muscle defect, releasing stiff MP joint and reconstructing lumbrical function in one stage can recover the function of MP joint and achieve good outcome. Physical therapy plays an important role before operation. PMID- 21675109 TI - [Failure cause of posterior approach orthopaedic operation of thoracolumbar hemivertebra and strategies of revision]. AB - OBJECTIVE: To explore the failure cause of posterior approach orthopaedic operation of thoracolumbar hemivertebra, and to summary strategies of revision. METHODS: The clinical data from 9 cases undergoing posterior approach orthopaedic operation failure of thoracolumbar hemivertebra between June 2003 and June 2008, were retrospectively analyzed. There were 5 males and 4 females with a median age of 12 years (range, 1 year and 10 months to 24 years). All malformations were identified as fully segmented hemivertebra from the original medical records and X-ray films, including 2 cases in thoracic vertebra, 5 cases in thoracolumbar vertebra, and 2 cases in lumbar vertebra. The preoperative scoliotic Cobb angle was (45.4 +/- 17.4) degrees, and kyphotic Cobb angle was (29.8 +/- 22.0) degrees. The reason of primary surgical failure were analyzed and spinal deformity was corrected again with posterior revision. RESULTS: All surgeries were finished successfully. The operation time was 3.0-6.5 hours (mean, 4.5 hours), and the perioperative bleeding was 400-2 500 mL (mean, 950 mL). All incisions healed by first intention; no infection or deep venous thrombosis occurred. Numbness occurred in unilateral lower extremity of 1 case postoperatively, and the symptom was relieved completely after treatment of detumescence and neural nutrition. All cases were followed up 12-30 months (mean, 18 months). No pseudoarthrosis and implant failure occurred. The X-ray films showed that the bone grafts completely fused within 8-14 months (mean, 11 months) after operation. The Cobb angles of scoliosis and kyphosis at 1 week after operation and the last follow-up were obviously improved when compared with preoperative ones, showing significant differences (P < 0.05). No obvious correction loss was observed either in coronal or sagittal plane. CONCLUSION: The failure causes of posterior approach orthopaedic operation are hemivertebra processing, selection of fixation and fusion range, and selection of internal fixation. If the strategies of revision are made after the above-mentioned failure causes are considered, the clinical results will be satisfactory. PMID- 21675110 TI - [Therapy of thoracolumbar vertebra tumor by total spondylectomy and spine reconstruction through posterior approach]. AB - OBJECTIVE: To explore the surgical procedure and effectiveness of total spondylectomy and spine reconstruction through posterior approach to treat thoracolumbar vertebra tumor. METHODS: Between June 2004 and July 2008, 14 cases of thoracolumbar vertebra tumor underwent one-stage total spondylectomy through posterior approach and spine reconstruction with posterior pedicle screw system and bone graft. There were 11 males and 3 females with a mean age of 47.2 years (range, 36-60 years). The disease duration was 3-15 months. Affected segments included T3 in 1 case, T4 in 3 cases, T8 in 3 cases, T9 in 2 cases, T10 in 3 cases, T12 in 1 case, and L1 in 1 case. The postoperative pathological results were 3 cases of bony giant cell tumor, 1 case of osteoblastoma, 2 cases of osteosarcoma, and 8 cases of metastatic tumor. According to Tomita et al. grading system, there were 1 case of type II, 5 cases of type III, 3 cases of type IV, and 5 cases of type V. According to Frankel classification of preoperative spinal cord function, 3 cases were rated as grade B, 4 as grade C, 5 as grade D, and 2 as grade E. RESULTS: Wound healing by first intention was obtained in all cases, and no blood vessel and nerve injury occurred. Fourteen patients were followed up 11-64 months (mean, 32.5 months). The local pain was relieved significantly. At 6 8 months after operation, the X-ray films and CT showed that bone graft fusion at Bridwell I grade was achieved. At 10 months, the postoperative spinal cord function was improved from grade B to grade D in 2 cases, from grade C to grade D in 1 case, and the other 9 cases reached grade E. The patients had normal walking function. Two patients died of liver metastasis and brain metastasis at 11 and 15 months postoperatively, respectively; 1 patient with osteoscarcoma died of lung metastasis at 16 months; and 1 case of osteoscarcoma developed local recurrence at 8 months postoperatively. Internal fixation was reliable without loosening and breakage and the spine was stable. CONCLUSION: Total spondylectomy and spine reconstruction through posterior approach is an effective method with advantages of relative minimal injury, radical tumor excision, low local recurrence, and adequate spinal cord decompression. PMID- 21675111 TI - [Application of various materials in reconstruction of laryngotracheal framework]. AB - OBJECTIVE: To investigate the effectiveness of various materials in reconstruction of laryngotracheal framework and to analyze the advantages, disadvantage, and indication of each material. METHODS: The clinical data were retrospectively analyzed, from 337 laryngotracheal stenosis patients undergoing laryngotracheal framework reconstruction with various materials between October 1986 and October 2006. There were 229 males and 108 females aged from 2 to 54 years (median, 23.5 years). According to Cotton's grading criteria for laryngotracheal stenosis, there were 94 cases of grade II, 218 cases of grade III, and 25 cases of grade IV, and all accompanied by laryngotracheal framework defect of 1-5 cm. The costal cartilage autograft was performed in 157 cases, thyroid cartilage graft in 27 cases, nasal septal cartilage graft in 8 cases, sternohyoid myocutaneous rotary door flap graft in 104 cases, hyoid bone flap of sternocleidomastoideus graft in 7 cases, musculo-periosteum flap of sternocleidomastoideus with clavicular periosteum in 21 cases, hydroxyapatite artificial tracheal ring graft in 10 cases, and pedicle myocutaneous flap with "C" shape nickel-titanic alloy net graft in 3 cases. Silastic T-tube was used after reconstruction for 6-12 months. RESULTS: Infection occurred in 5 cases and the incisions healed by second intention, the others achieved healing of incision by first intention. Intratracheal granulation formation occurred in 23 cases and choke when taking food in 6 cases; they were all cured after symptomatic treatment. After operation, 4 cases failed to be followed up and 12 cases did not recover, including 6 cases of costal cartilage autograft, 1 case of hyoid bone flap of sternocleidomastoideus graft, and 5 cases of sternohyoid myocutaneous rotary door flap graft. A total of 321 patients were followed up for 1-10 years (mean, 3.5 years). The patients had no laryngotracheal restenosis with good swallowing function and respiratory function. CONCLUSION: Different materials of laryngotracheal framework reconstruction have advantages and disadvantage respectively. The appropriate material should be selected according to the special details of pathological change, and the satisfactory curative effect may be obtained. PMID- 21675112 TI - [Vertical trapezius myocutaneous flap for repairing soft tissue defect after head and neck tumor resection]. AB - OBJECTIVE: To introduce the experience of the clinical application of vertical trapezius myocutaneous flap in repairing soft tissue defects after head and neck tumor resection. METHODS: Between June 2008 and February 2010, 12 cases of soft tissue defect caused by head and neck tumor resection were repaired with vertical trapezius myocutaneous flap. There were 9 males and 3 females with an age range from 32 to 76 years (median, 54 years). Twelve cases including 2 cases of basal cell carcinoma of orbital skin, 2 cases of squamous cell carcinoma of the parotid gland, 2 cases of submandibular gland malignant mixed tumor, 2 cases of metastatic lymph nodes of nasopharyngea carcinoma after radiotherapy, 1 case of squamous cell carcinoma of tongue, and 3 cases of squamous cell carcinoma of occipital skin, and all were classified as TNM stages T3 or T4. The area of soft tissue defect ranged from 13 cm x 6 cm to 25 cm x 13 cm. The vertical trapezius myocutaneous flap ranged from 14 cm x 7 cm to 26 cm x 14 cm and was transferred to repair defect tissue in the homolateral wounds after tumor resection and neck dissection homochronously. The donor sites were sutured directly. RESULTS: All incisions healed primarily without infection. Eleven flaps survived except 1 flap with edge necrosis, which was cured after dressing change. Subcutaneous hematocele and effusion occurred in 2 cases on the back after tube was removed at 7 days postoperatively, and they were cured by sucked and pressured dressing. Eleven patients were followed/up 1-3 years (mean, 2 years). Nine cases had no tumor recurrence and the flaps had satisfactory appearance; the abduction function of shoulder joint were normal. One case of orbit basal cell carcinoma occurred 3 months after operation and 1 case of nasopharyngeal carcinoma died of brain metastasis 12 months after operation. CONCLUSION: It is an easy and simple therapy to repair head and neck soft tissue defect using the vertical trapezius myocutaneous flap, which can meet the needs of repairing tissue defect of head and neck. PMID- 21675113 TI - [Surgical treatment of chronic osteomyelitis of the skull]. AB - OBJECTIVE: To summarize the treatment of chronic osteomyelitis of the skull and its effectiveness. METHODS: Between January 2004 and February 2009, 24 patients with chronic osteomyelitis of skull were diagnosed and treated, including 16 males and 8 females with an average age of 45.6 years (range, 18-56 years). The mean disease duration was 5.8 years (range, 3-11 years). The causes included infection after craniotomy in 3 cases, burn in 15 cases, and electrical injury in 6 cases, and the lesion was located at the frontal and parietal of the skull in 10 cases, at the temporal and parietal of skull in 8 cases, and at the occipital of the skull in 6 cases. The soft tissue defects ranged from 7 cm x 6 cm to 19 cm x 12 cm, and the skull defects ranged from 5 cm x 4 cm to 10 cm x 7 cm. After wide thorough debridement of necrotic tissue, soft tissue defects were repaired with adjacent scalp flap in 12 cases, trapezius myocutaneous flap in 6 cases, and free anterolateral thigh flap in 6 cases; the flap size ranged from 8 cm x 7 cm to 20 cm x 13 cm. The donor sites were sutured directly or covered with split thickness skin. RESULTS: All pathological examinations showed pyogenic osteomyelitis of the skull, and localized squamous carcinoma was found in 1 case. One patient had sub-flap infection at 2 weeks after operation, and healing was achieved after surgical removal of residual tissue; the remaining flaps survived, and incision healed by first intention. All patients were followed up 10 months to 4 years with an average of 2 years after operation. The color and texture of the flaps were good. No recurrence of osteomyelitis happened during follow-up. The patient diagnosed as having localized squamous carcinoma was followed up 4 years without recurrence. At 3 to 6 months after operation, 8 patients had headache or felt dizzy, and the skull was reconstructed by the titanium meshes. CONCLUSION: In patients with chronic osteomyelitis of skull, the infected foci should be cleaned out thoroughly as early as possible, and the skin flap or myocutaneous flap is used to repair the wounds, thus the good results can be achieved. PMID- 21675114 TI - [Effectiveness of perforator flaps for elderly patients with ischia-sacral ulcers]. AB - OBJECTIVE: To investigate the operative technique and the effectiveness of perforator flaps for the treatment of elderly patients with ischia-sacral ulcers. METHODS: Between January 2005 and June 2010, 29 elderly patients with ischia sacral ulcers were treated. There were 16 males and 13 females, aged from 61 to 75 years (mean, 68 years), including 11 cases of degree III and 18 cases of degree IV according to the standard of the National Pressure Ulcer Advisory Panel (NPUAP). The disease duration was from 5 months to 10 years (median, 5.5 years). The size of ulcers ranged from 7 cm x 6 cm to 12 cm x 10 cm. Of them, 8 cases were companied by cerebral vascular disorders, 6 cases by Alzheimer disease, 11 cases by paraplegia, and 4 cases by others. The flap size ranged from 8 cm x 6 cm to 14 cm x 12 cm. The donor sites were sutured directly. RESULTS: Distal flap necrosis occurred in 3 cases (10.3%) 2 days after operation and healed after symptomatic treatment, and the remaining flaps survived and wound healed by first intention with first intention rate of 89.7%. The incisions of donor sites healed primarily. Two cases (6.9%) had infection 1 week after operation and 1 case (3.4%) had wound dehiscence 10 days after operation. Twenty-seven patients were followed up 6 months to 5 years (mean, 3 years). Two cases recurred at 1 and 3 years after operation, respectively. One died of infection, and the other healed by debridement and suture. The flaps of other patients had good texture, color, and elasticity. CONCLUSION: As long as the indications are controlled strictly, good effectiveness can be achieved in the treatment of elderly patients with ischia-sacral ulcers by using perforator flaps. PMID- 21675115 TI - [Repair of wounds with Achilles tendon exposure]. AB - OBJECTIVE: To investigate the application and clinical result of flap in the repair of wounds with Achilles tendon exposure. METHODS: Between May 2006 and May 2010, 21 patients with Achilles tendon skin defects were treated with microsurgical reconstruction. There were 15 males and 6 females, aged 7-63 years with a median of 34 years. The defect causes included sport injury in 4 cases, wheel twist injury in 7 cases, crush injury in 5 cases, chronic ulcer in 3 cases, and Achilles tendon lengthening in 2 cases. The areas of wounds with Achilles tendon exposure ranged from 2 cm x 2 cm to 10 cm x 8 cm. After debridement, wounds were repaired with the medial malleolus fasciocutaneous flap (5 cases), sural neurocutaneous vascular flap (8 cases), foot lateral flap (2 cases), foot medial flap (2 cases), and peroneal artery perforator flap (4 cases). The size of the flaps ranged from 3 cm x 3 cm to 12 cm x 10 cm. The donor sites were either sutured directly or covered with intermediate split thickness skin grafts. The Achilles tendon rupture was sutured directly (2 cases) or reconstructed by the way of Abraham (2 cases). RESULTS: All flaps survived and wounds healed by first intention except 2 flaps with edge necrosis. Twenty-one patients were followed up 6-18 months (mean, 12 months). The flaps had good appearance and texture without abrasion or ulceration. The walking pattern was normal, and the two point discrimination was 10-20 mm with an average of 14 mm. The American Orthopedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale assessment revealed that 10 patients had an excellent result, 7 had a good result, 3 had a fair result, and 1 had a poor result with an excellent and good rate of 81.0%. Fourteen cases could lift the heels with power; 5 cases could lift the heels without power slightly; and 2 cases could not lift the heels. CONCLUSION: The wounds with Achilles tendon exposure should be repaired as soon as possible by appropriate flap according to the condition of wound. PMID- 21675116 TI - [Promotion effect of nuclear factor kappa B p65 on early fracture healing of rat radius by elevating prostaglandins E2 production and regulating inhibitor of DNA binding 2 protein expression]. AB - OBJECTIVE: Series of complicated molecule signal pathway are involved in the bone regeneration. To explore the possibility of nuclear factor kappa B (NF-kappaB) which is taken as the "key activation" during the fracture healing and provide the laboratory evidence for the gene therapy of nonunion or delayed union of fractures. METHODS: Thirty-three adult male Wistar rats (weighing 180-220 g) were selected and divided randomly into 4 groups: group A (the control group, n=3), the rigth lower segments of radius were injected with normal saline 0.3 mL for 7 days, once per day; group B (Bay 11-7082 injection group, n=6), the middle and distal radius were injected with normal saline containing 50 pmol/L NF-kappaB inhibitor Bay 11-7082 0.3 mL for 7 days, once per day; group C (fracture group, n=12), the right middle and distal radius were cut by a sharp scissors to form per fracture model; and group D (Bay 11-7082 treatment group, n=12), based on group C, 0.3 mL of 50 micromol/L Bay 11-7082 were injected into the fracture site for 7 days, once per day. The callus tissues were harvested at 3, 7, 14, and 28 days after fracture for Western blot analysis, alkaline phosphatase (ALP) activity assessment, prostaglandins E2 (PGE2) production assay, and histological observation. RESULTS: The rats of all groups were survival till the experiment completion. At 3 and 7 days after injection, there was no significant difference in the ALP activity and PGE2 production between group B and group A (P > 0.05); but group C was significantly higher than group A (P < 0.01) and group D was significantly lower than group A (P < 0.01). The expressions of NF-kappaB p65, bone morphogenetic protein 7 (BMP-7), and inhibitor of DNA binding 2 (Id2) were observed at fracture sites of 4 groups. There was no significant difference in the expressions of NF-kappaB p65, BMP-7, and Id2 between group B and group A (P > 0.05); the expressions of NF-kappaB p65 and BMP-7 were significantly higher and the expression of Id2 was significantly lower in group C than group A (P < 0.01); and the expressions of NF-kappaB p65 and BMP-7 were significantly lower and the expression of Id2 was significantly higher in group D than group A (P < 0.01). The histological observation showed that a lot of osseous callus formed in group C at 14 and 28 days. CONCLUSION: but osseous callus just began to form in group D at 28 days. NF-kappaB p65 can facilitate early fracture healing of rat radius by elevating the PGE2 production and regulating BMP-7 and Id2 expression. PMID- 21675117 TI - [Preliminary study on appropriate concentration gradient of nerve growth factor in promoting fracture healing]. AB - OBJECTIVE: To study the effect of local application of different concentrations of nerve growth factor (NGF) on fracture healing, and to further search for the appropriate concentration gradient of NGF to promote fracture healing. METHODS: Seventy-five adult male Sprague Dawley rats, weighing (220.0 +/- 2.5) g, were made the right tibia fracture model at 1 cm distal from the tibial tubercle and randomly divided into 5 groups (groups A, B, C, D, and E, n=15). Fractures were treated with 0.3 mL normal saline containing different concentration of NGF (0.00648 x 10(-2), 0.032 40 x 10(-1), 0.16200 x 10(-2), and 0.81000 x 10(-2) microg/g) in groups A, B, C, and D, respectively, and the same amount of normal saline in group E. After 2, 4, and 6 weeks, the specimens were harvested from 5 rats of each group to perform the biochemical test and histological observation. Before the rats were sacrificed, the arteriovenous blood was taken from the eye ball to test the alkaline phosphatase (ALP) activity. RESULTS: After 2, 4, and 6 weeks, the gross observation showed that the size and hardness of bone tissue and callus tissue growth gradually increased in groups A, B, C, and D, and group D was higher than groups A, B, C, and E. The X-ray films showed that the calcified area gradually increased in groups A, B, C, and D, and group D was higher than groups A, B, C, and E. The histological observation showed that the trabecular quality and maturity in group D were better than those in groups A, B, C, and E. Group D was significantly higher than groups A, B, C, and E (P < 0.05) in the gray values of callus tissue and the calcium content of callus tissue at 4 and 6 weeks, in the wet weight of callus tissue at 2 and 4 weeks, and in the ALP content of serum at 2 weeks. The trabecula surface index of osteoblast, the trabecular volume, and the trabecular width decreased as time in the order of groups A, B, C, and D, which were higher than those of group E; group D was the highest, showing significant differences when compared with the other groups (P < 0.05). CONCLUSION: The local application of NGF can promote fracture healing in rats. The high concentration gradient of NGF (0.81000 x 10(-2) microg/g) has an obvious promotion role on fracture healing. PMID- 21675118 TI - [Preventive effect of polypropylene mesh bonded norvancomycin slow-release microsphere on Staphylococcus aureus infection of incisional hernia repair model]. AB - OBJECTIVE: Mesh infection may occur after incisional hernia repair using prosthetic mesh. Preparation of antibiotics-bonded meshes to prevent infection is one of the solutions. To evaluate the anti-infection effect of polypropylene mesh bonded norvancomycin slow-release microsphere by preparing the rat model of incisional hernia repair contaminated with Staphylococcus aureus. METHODS: The norvancomycin slow-release microspheres were prepared by emulsion and solvent evaporation method and they were bonded to polypropylene mesh (50 mg/mesh). The appearance of the microspheres was observed using scanning electronic microscope (SEM). The content of norvancomycin in microspheres and the release rate of the norvancomycin in norvancomycin-bonded polypropylene mesh were detected using high performance liquid chromatography method. The rat models of incisional hernia were developed in 40 healthy Sprague Dawley rats, aged 10-11 weeks and weighing 200-250 g. The rats were divided randomly into the experimental group (norvancomycin-bonded polypropylene mesh repair, n=20) and the control group (polypropylene mesh repair, n=20). And then the mesh was contaminated with Staphylococcus aureus. The wound healing was observed after operation. At 3 weeks after operation, the mesh and the tissue around the mesh were harvested to perform histological observation and to classify the inflammatory reaction degree. RESULTS: The norvancomycin microsphere had integrated appearance and smooth surface with uniform particle diameter, 64% of particle diameter at 60 to 100 microm, and the loading-capacity of norvancomycin was 19.79%. The norvancomycin-bonded polypropylene patch had well-distributed surface and the loading-capacity of norvancomycin was (7.90 +/- 0.85) mg/cm2. The release time of norvancomycin in vitro could last above 28 days and the accumulative release rate was 72.6%. The rats of 2 groups all survived to experiment completion. Wound infection occurred in 2 rats of the experimental group (10%) and 20 rats of the control group (100%), showing significant difference (chi2 = 32.727 3, P = 0.0000). The inflammatory reaction in experimental group was not obvious, grade I in 16 rats and grade II in 4 rats, and numerous inflammatory cell infiltration occurred in the control group, grade II in 3 rats and grade III in 17 rats, showing significant difference (chi2 = 32.314, P = 0.000). CONCLUSION: The polypropylene mesh bonded norvancomycin slow-release microsphere has definite anti-infection effect in rat model of incisional hernia repair contaminated by Staphylococcus aureus. PMID- 21675119 TI - [Histological study on sciatic nerve repair at different angles in rats]. AB - OBJECTIVE: To discuss the effect of sciatic nerve repair at different angles on the neural regeneration in rats. METHODS: Seventy-two male Sprague Dawley rats were randomly divided into groups A, B, C, and D with 18 rats in each group. The right sciatic nerve was transected at 30, 45, 60, and 90 degrees in groups A, B, C, and D, respectively, and then was repaired. The morphologic assessment of nerve regeneration was performed by gross observation, the wet weight recovery rate of gastrocnemius, histological and ultrastructural observations at 1, 2, and 3 months after operation. RESULTS: Three months later, the wet weight recovery rate of gastrocnemius, motor nerve conduction velocity and action potential of sciatic nerve, axonal diameter, medullary sheath thickness, and medullated nerve fiber counting in groups A and B were significantly better than those in groups C and D (P < 0.01); but no significant difference was found between group A and group B (P > 0.05), and between group C and group D (P > 0.05). CONCLUSION: End to-end neurorrhaphy at 30-45 degrees can effectively promote the sciatic nerve regeneration in rats. PMID- 21675120 TI - [Epidemiological features of acute hand injuries in daily life in Beijing area]. AB - OBJECTIVE: To study the composition, distribution, and influencing factors of acute hand injuries in daily life in the Beijing area by analyzing the clinical data from patients with acute hand injuries. METHODS: Between April 1st 2005 to September 30th 2005, 2575 patients with acute hand injuries in daily life from Beijing area were investigated by questionnaire. The epidemiological factors were analyzed, including gender, age, injury time, injury cause, accident place, injury mechanism, and location. RESULTS: The 2 575 patients injuried in daily life accounted for 49.2% of all. Most of them were young males, and the male to female ratio was 3.3:1. Most of the patients were 21-30 years old. The most common accident place was resting place (43.3%), and next was outdoors (28.8%) and leisure place (20.0%). Accidental injury was the major injury cause, accounted for 51.0%, followed by injury after drinking (16.1%) and violence (15.5%). The major injury mechanism was cutting (52.23%), followed by collision (16.04%) and falling (15.18%). A total of 2 405 patients were right hander, and handedness affected the distribution of injured hands significantly. Open injuries accounted for 70.7% of the patients, and the tissues in deep layer were involved in the injury in 54.4% of all. CONCLUSION: Hand injury in daily life is a common problem, which has its own epidemiological features. More appropriate measures should be taken to decrease the incidence. PMID- 21675121 TI - [Feasibility of bone marrow mesenchymal stem cells differentiation in diabetic pancreatic microenvironment]. AB - OBJECTIVE: The bone marrow mesenchymal stem cells (BMSCs) have the capacity to differentiate into insulin-producing cells (IPCs) in vitro. However, low differentiation efficiency and poor maturity are the main obstacles. To investigate the feasibility of BMSCs differentiation into IPCs in diabetic pancreatic microenvironment of pigs. METHODS: BMSCs were isolated and purified from the bone marrow of a 4-week-old male pig. Fifteen female pigs (aged 8 to 10 weeks, weighing 8 to 10 kg) were randomly divided into 3 groups: normal control group (group A, n=5), diabetic control group (group B, n=5), and BMSCs transplanted group (group C, n=5). The pigs of groups B and C were treated by auris vein injections of streptozocin and alloxan for 3 days to induce diabetes mellitus (DM) model, whose blood glucose level 2 days all greater than 17 mmol/L was successful DM model. A total of 1.1 mL of the 3rd passage BMSCs labeled with enhanced green fluorescent protein (EGFP), with cell density of 5 x 10(7)/ mL, were injected into subcapsular pancreas of group C at multiple points, normal saline at the same dosage into those of groups A and B. After 30 days of monitoring blood glucose, the histological analysis of islet number and size were done; the immunofluorescence staining was used to detect the protein expression of insulin in the new-formed islets. The EGFP+ cells were collected from the sections using laser-capture microdissection; RT-PCR was used to detect insulin mRNA and pancreatic and duodenal homeobox factor 1 (PDX1) mRNA expressions from EGFP+ cells, and the insulin and sex determining region of the Y chromosome (SRY) genes were detected by fluorescence in situ hybridization (FISH). RESULTS: The blood glucose level decreased significantly in group C when compared with that in group B from 18 days and gradually decreased with time (P < 0.05). The histological observation showed that the number of islets was increased significantly in group C when compared with that in group B (10.9 +/- 2.2 vs. 4.6 +/- 1.4, P < 0.05), and there was no significant difference when compared with that in group A (10.9 +/- 2.2 vs.12.6 +/- 2.6, P > 0.05). The size of new-formed islets in group C was significantly smaller than that in group A [(47.2 +/- 19.6) microm vs. (119.6 +/- 27.7) microm, P < 0.05]. The immunofluorescence staining showed that new-formed islets of group C expressed insulin protein. RT-PCR showed that the microdissected EGFP+ cells of group C expressed insulin mRNA and PDX-1 mRNA. FISH showed that the new-formed islet cells of group C contained SRY gene in Y chromosome and insulin double positive cells. CONCLUSION: BMSCs can differentiate into IPCs in diabetic pancreatic microenvironment of pigs. PMID- 21675122 TI - [Preliminary study on autologous bone marrow mononuclear cells transplantation for lower limb chronic venous ulcer]. AB - OBJECTIVE: To investigate the effectiveness of autologous bone marrow mononuclear cells transplantation on lower limb chronic venous ulcer. METHODS: Between May 2009 and September 2010, 17 patients with lower limb chronic venous ulcer were treated with autologous bone marrow mononuclear cells transplantation (transplantation group) and 10 patients treated without cells transplantation served as control group. In the transplantation group, there were 9 males and 8 females with age of (33.3 +/- 6.1) years, including 11 cases of simple great saphenous vein varicosity and 6 cases of chronic venous insufficiency; the area of ulcer was (4.39 +/- 2.46) cm2; and the duration of ulcer ranged from 3 months to 6 years. In the control group, there were 4 males and 6 females with age of (39.2 +/- 10.3) years, including 7 cases of simple great saphenous vein varicosity and 3 cases of chronic venous insufficiency; and the area of ulcer was (5.51 +/- 2.63) cm2; and the duration of ulcer ranged from 3 months to 2 years. All patients in both groups were classified as C6 according to clinical etiology anatomy pathophysiology (CEAP) classification. No significant difference was found in the general data between 2 groups (P > 0.05). The healing process of ulcer was observed. The granulation tissue was harvested for HE staining before operation and at 3 days after operation in the transplantation group. The microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression of ulcer granulation tissue were observed. RESULTS: In the transplantation group, ulcer healing was accelerated; complete healing was observed in 15 cases, partial healing in 1 case, and no healing in 1 case with the median healing time of 22 days. However, in the control group, the healing process was slower; complete healing of ulcer was observed in 7 cases and no healing in 3 cases with the median healing time of 57.5 days. There was significant difference in the healing time between 2 groups (Z = 0.001 4, P = 0.0027). HE staining showed a great number of microvessels in the granulation tissue in the transplantation group. The immunohistochemical staining showed that MVD was significantly increased (t = 3.120, P = 0.008) after cell transplantation (32.1 +/- 12.8) when compared with that before transplantation (22.1 +/- 6.7). The VEGF expression after transplantation (8.05% +/- 5.10%) was increased slightly when compared with that before transplantation (6.13% +/- 4.20%), but the difference was not significant (t = 1.150, P = 0.268). CONCLUSION: Autologous bone marrow mononuclear cells transplantation can stimulate granulation tissue growth and improve ulcer healing. PMID- 21675123 TI - [Effects of a novel borate bioglass on osteoblast behavior in vitro]. AB - OBJECTIVE: As a bioactive material, the osteogenic activity of borate bioglass has been proved. To design a novel borate bioglass according to an improved formula and to investigate the effects of the borate bioglass on osteoblasts in vitro for further research and potential clinical application. METHODS: The novel Na2O-K2O-MgO-CaO-P205-B203-SrO borate bioglass was prepared by melting process. The initial and secondary extracts were prepared according to ISO10993-12: 2007 respectively with different extract time of 0-24 hours and 24-48 hours. The osteoblasts (MC3T3-E1) of the 5th-15th passages from mouse were cocultured with the initial (initial extract group) and secondary (secondary extract group) extracts, respectively, to assess the effects of the borate bioglass on the cell proliferation, protein synthesis, alkaline phosphatase (ALP) activity, cell apoptosis, and cell migration; while alpha-MEM medium without addition of extract served as control group. RESULTS: The absorbance values at 450 nm were 0.3560 +/- 0.0187, 0.331 0 +/- 0.025 4, and 0.2040 +/- 0.0138 in initial extract, secondary extract, and control groups, respectively, showing significant differences among 3 groups (P < 0.05). The total protein contents were (382.847 +/- 9.521), (226.071 +/- 5.847), and (220.248 +/- 8.213) U in initial extract, secondary extract, and control groups, respectively; there were significant differences between initial extract group and control group, and between initial extract group and secondary group (P < 0.05), but there was no significant difference between secondary extract group and control group (P > 0.05). However, no significant difference was observed in the ALP activity [(0.01301 +/- 0.00039), (0.012 93 +/- 0.00044), and (0.012 92 +/- 0.000 35) U/mg], apoptosis rate (7.03% +/- 1.95%, 6.46% +/- 2.88%, and 6.18% +/- 2.21%), horizontal migration [(137.50 +/- 11.43), (134.98 +/- 10.50), (135.21 +/- 8.66) microm], and transmembrane cell number [(10.92 +/- 4.99), (10.07 +/- 2.50), and (9.81 +/- 2.64) cells/field] among initial extract, secondary extract, and control groups (P > 0.05). CONCLUSION: This novel borate bioglass has excellent cytocompatibility, which plays regulatory effects on the cell proliferation, secretion, and migration. PMID- 21675124 TI - [Systematic review of autologous hemopoietic stem cell transplantation for peripheral arterial disease]. AB - OBJECTIVE: To evaluate the effectiveness and safety of autologous hemopoietic stem cell implantation for peripheral arterial disease (PAD). METHODS: Randomized controlled trials (RCTs) were identified from CBM (1978 to September 2010), CNKI (1979 to September 2010), MEDLINE (1950 to September 2010), Pubmed (1950 to September 2010), Embase (1970 to September 2010), and Cochrane library (issue 4, 2010). The papers of the RCTs of clinical therapeutic studies on PAD treated by autologous hemopoietic stem cell implantation were included and analyzed according to the criteria of the Cochrane handbook. RESULTS: Eight RCTs involving 280 patients and 322 extremities were included, with majority of trials of low methodological quality. Meta-analysis indicated that autologous hemopoietic stem cell transplantation had an increased ulcer cure rate [RD = 0.38, 95% CI = (0.25, 0.50)], a significant improvement in the ankle brachial index [MD = 0.11, 95% CI = (0.04, 0.18)], transcutaneous oxygen tension [MD = 7.33, 95% CI = (3.14, 11.51)], and pain-free walking distance [SMD = 1.35, 95% CI = (0.90, 1.79)], a significant reduction in rest pain scores [MD = 1.70, 95% CI= (2.15, 1.25)], and a significant benefit in terms of limb salvage [RD = 0.19, 95% CI = (-0.31, 0.07)]. Only 2 trials reported the side effects of autologous hemopoietic stem cell transplantation, such as limbs swelling and concentrations of serum creatine phosphokinase increasing, and the long-term safety was not reported. CONCLUSION: Based on the review, autologous hemopoietic stem cell transplantation may have positive effect on "no-option" patients with PAD. However, the evidence is not strong enough due to the general low methodological quality, so we can not draw a reliable conclusion about the effects of autologous stem cell transplantation for PAD at the moment. Further larger, randomized, double blind, placebo-controlled, and multicenter trials are needed. PMID- 21675125 TI - [Progress of methods of inducing bone marrow mesenchymal stem cells into chondrocytes in vitro]. AB - OBJECTIVE: To review the research progress of the current methods of inducing bone marrow mesenchymal stem cells (BMSCs) to chondrogenic differentiation in vitro so as to provide references for researches in cartilage tissue engineering. METHODS: Various methods of inducing BMSCs differentiation into the chondrogenic lineage in vitro in recent years were extensively reviewed and analyzed. RESULTS: Adding exogenous growth factors is still the mainly method of inducing BMSCs differentiation into the chondrogenic lineage; among the members, transforming growth factor beta (TGF-beta) family is recognized as the most important chondrogenic induction factor. Other important inducing factors include various chemical factors, physical factors, transgenic methods, and the microenvironmental induction. But the problems of low inducing efficiency and unstable inducing effects still exist. CONCLUSION: The progress of chondrogenic induction of BMSCs promotes its utilization in cartilage tissue engineering. Further researches are needed for establishing more efficient, simpler, and safer inducing methods. PMID- 21675126 TI - [Progress of metacarpal and phalange lengthening]. AB - OBJECTIVE: To review the methods of metacarpal and phalange lengthening and to point out the problems at present as well as to predict the trend of development in the field. METHODS: Domestic and abroad literature concerning the methods of metacarpal and phalange lengthening in recent years was reviewed extensively and thoroughly analyzed. RESULTS: At present, there are many methods to treat the short finger disability, but the methods of metacarpal and phalange lengthening have an advantage, which include closed osteotomy lengthening, callus lengthening, and modified Ilizarov method. Each surgical method has its advantages and limitations. However, the part of osteotomy, the length and speed, and the postoperative complications etc. have been disputed. CONCLUSION: The modified Ilizarov method has the advantages of simple operation, minimal invasion, and less complications, but the long-term results of each treatment method are unknown and need more further studies. PMID- 21675127 TI - [Research progress of treatment of carpal tunnel syndrome]. AB - OBJECTIVE: To review the progress in the treatment method of carpal tunnel syndrome (CTS). METHODS: Recent literature concerning the treatment method of CTS was extensively reviewed, analyzed, and summarized. RESULTS: Wrist splinting and local steroid injection are effective in patients with mild to moderate CTS in the short-term, however, patients with recurrent CTS have to accept surgical treatment. The main operative patterns include open carpal tunnel release (OCTR), mini-OCTR, and endoscopic carpal tunnel release. CONCLUSION: The final conclusion of the most effective method to treat CTS needs more clinical researches, and surgical treatment is one method recommended by some scholars. PMID- 21675128 TI - [Antibiotic resistance--what we have to do now?]. AB - Antibiotics introduced about 60 years ago as miracle drugs are getting less effications. This is a result of the emergence and dynamic dissemination of resistance due to the clonal spread of resistant strains and horizontal gene transfer. This has decreased therapeutic options and has reached an alarming level, a threat to public health and patient care. The WHO and ECDC call for immediate action aimed at the introduction of rationale therapy, and the enhancement of microbiological diagnostics and infection control programs. Lack of action in this field may lead to a post antibiotic era. PMID- 21675129 TI - [Infections and the possibility of controlling them]. AB - Infections are accompanied by people from the beginning of the world. They were responsible for the disasters in the history of mankind. For this reason, the analyze of the nature of viral and bacterial pathogens is still conducting, with particular reference to inhibition of their proliferation. The rational antibiotic therapy becomes the basis of conduct in risk caused by infection. PMID- 21675130 TI - [Renaissance of infectious diseases]. AB - According to the report of the National Institutes of Health (NIH) in Bethesda, Maryland, USA, infectious diseases are one of the eight most common causes of illness since 1990. Due to breaking down barriers of interspecies, the state of immunosuppression, widespread use of antibiotics, there are still new threats, and earlier known to cause disease of a different course, resistant to previously effective therapies. The evolution of infectious diseases directs our attention primarily on the validity of the principles of rational antibiotic use to the increasing resistance of microorganisms. The movements of the opponents of vaccination appear to be more effective than the planned education of doctors and their patients, and the absence of sufficient administrative control performance of vaccination, raises a serious problem in contemporary clinical researcher. Infectious diseases will continue to exist as long as host organisms. It is important to the fight against them, making the best use of expertise and funds. In such a situation, the balance may move to benefit us--humans. PMID- 21675131 TI - [Contemporary clinical diagnostics of respiratory tract infections]. AB - The patient population at risk pulmonary infections has increased during the last decade. The spectrum of organisms causing infections has also grown, most of them are viruses Baseline diagnostic assessment include history, clinical examination, radiography and measurements of procalcitonin (PCT), highly sensitive C-reactive protein (hsCRP) and leukocyte count. PCT represents a good biological marker for difficult diagnoses in critically ill patients and is superior to CRP. Chest x rays seldom give enough information to determine the exact cause of the abnormality, but they can help a doctor to determine whether and which other tests are needed to make a diagnosis. Microbiologic advances have helped to facilitate the laboratory diagnosis of some pathogens. Cultures of respiratory specimens are some times useful but the gold standard for diagnosis of pulmonary infection is blood culture. Immunoassays are available for the detection of antigen in nasopharyngeal secretions (respiratory syncytial virus, influenza), and in urine (Legionella spp.). Rapid-culture techniques are available for the culture and detection of various viruses. Recently PCR-based techniques and RT PCR assist in the detection of Legionella, Chlamydia, Mycoplasma, Pneumocystis carinii and mycobacteria species. This article presents a practical approach to the differential diagnosis of pulmonary infections. PMID- 21675132 TI - [History of antibiotics and sulphonamides discoveries]. AB - In the 19th century, the effect of mould on bacterial colonies was investigated. In 1921, Alexander Fleming examined systemic fluids and observed some substances called lyzosomes which were capable of dissolving bacteria. In 1928, he discovered that a specific mould species inhibited the development of Staphylococcus bacteria. The species was known as Pencillium notatum and the filtrate was called penicillin. In 1940, Howard Florey and Ernst Chain worked out the industrial production of penicillin. All three researchers were awarded the Nobel Prize in 1945, and since then the era of antibiotics has been initiated. In 1935, Gerhard Domagk discovered the first sulphonamide--prontosil rubrum. Four years later he received the Noble Prize. PMID- 21675133 TI - [Antibiotics in primary care]. AB - Discovered in the forties of the twentieth century antimicrobial agents have changed the world. Currently, due to their overuse, we are threatened by the increasing resistance of bacteria to antibiotics, and soon we may face a threat of inability to fight these pathogens. For that reason, the world, European and national organizations introduce antibiotics protection programs. In Poland since 2004, the National Program of Protection of Antibiotics is being held. The concept of rational antibiotic therapy is associated not only with the appropriate choice of therapy or antimicrobial dosage but also with a reduction in costs associated with a refund of medicines. Antibiotics are prescribed mostly by primary care physicians (GP), and about one fifth of visits to family doctor's office ends with prescribing antimicrobial drug. These trends are probably related to both the difficulty in applying the differential diagnosis of viral and bacterial infection in a primary care doctor's office, as well as patient's conviction about the effectiveness of antibiotic therapy in viral infections. However, although patients often want to influence the therapeutic decisions and ask their doctor for prescribing antimicrobial drug, the right conversation with a doctor alone is the critical component in satisfaction with medical care. Many countries have established standards to clarify the indications for use of antibiotics and thereby reduce their consumption. The next step is to monitor the prescribing and use of these drugs and to assess the rise of drug resistance in the area. In Poland, the recommendations regarding outpatient respiratory tract infections treatment were published and usage of antimicrobial agents monitoring has begun. However, lack of publications covering a broad analysis of antibiotic therapy and drug resistance on Polish territory is still a problem. Modem medicine has yet another tool in the fight against bacteria--they are bacteriophages. Phage therapy is unfortunately still an experimental therapy and its use has many limitations. To preserve antibiotics healing abilities, we must follow the rules of rational antibiotic therapy, and primary health care is a place where the physician can significantly contribute to deterioration or protection of antibiotics. PMID- 21675134 TI - [Clinical effectiveness and costs of antibiotics in respiratory infections]. AB - Antibiotics have made a significant contribution to improving the health of patients suffering from bacterial infections. Today in an era of high health costs and limited resources more than ever, doctors in the ambulatory care and hospitals must effectively manage the use of antibiotics to control costs and preserve their usefulness. To achieve this goal, antibiotic management must evolve from simplistic antibiotic cost containment to more complex, appropriate use program that are founded on clinical outcomes-based pharmacoeconomic analyses. The findings of pharmacoeconomic analysis indicate that the cost effectiveness of antibiotics is influenced by many factors, including diagnosis, comparative costs and comparative effectiveness, resistance, compliance, and treatment failure. Moreover, external factors like guideline implementation and funding source should be considered in such assessment. The successful application of pharmacoeconomic principles to antimicrobial therapy requires maximizing therapeutic effectiveness while minimizing costs, with the primary on pharmacokinetic considerations. This article reviews the various pharmacoeconomic factors that affect antibiotic costs used in respiratory infections treatment in relation to patients and institutions. PMID- 21675136 TI - [Management of opportunistic infections of the respiratory system]. AB - The aim of this article is to review observations in the area of opportunistic infections of the respiratory system in patients with innate and acquired immunodeficiency (among them in human immunodeficiency virus and acquired immunodeficiency syndrome). Since the immunodeficiency was first characterized, it has been associated with enhanced susceptibility to opportunistic infection, and life-threatening infections of the lung. In this paper there are presented risk factors for immunodeficiency and opportunistic infections, microorganisms (bacteria, viruses and fungi) which can be the responsible for opportunistic infections. Author analyzed problems connected with difficulties during diagnosis and treatment of these infections. PMID- 21675135 TI - [Diagnosis and treatment of pneumonias]. AB - The right management of patients with pneumonia is crucial for effectiveness of therapy and decrease of patient mortality. There are few classifications of type and severity of pneumonias. In clinical practice the most useful is division on community and hospital acquired infections. This paper concerns recommendations and information for diagnosis and treatment of community-acquired pneumonia and hospital-acquired pneumonia. PMID- 21675137 TI - [Antimicrobial therapy of severe infections in critically ill patients]. AB - Antimicrobial therapy of severe infections in critically ill patients becomes an important clinical problem. One of the reason is increasing resistance of pathogens to antibiotics. In this paper the current problems of the treatment of severe infections in Intensive Care Units' patients were discussed as well as benefits of modern antimicrobial agents were presented. PMID- 21675138 TI - [Antibiotic therapy in nephrology]. AB - The use of antibiotics in patients with kidney diseases is associated mainly with urinary tract infections (UTI) and urosepsis. Treatment of bacterial infections not related to UTI in patients with chronic renal failure is usually more complicated than in subjects with normal renal function. The high incidence of UTI, recurrent and chronic character of these disorders make them difficult to cure. In all these situations it is important to use effective drugs, without nephrotoxicity, with minimal risk of building up the resistance. Due to the increasing number of dialysis patients, especially treated with hemodialysis, it becomes essential to use effective antibacterial therapy in this group of patients, including infections specific for this kind of treatment. Proper mode of treatment adjusted to type of renal replacement therapy (hemodialysis, peritoneal dialysis or continuous renal replacement therapy) is very important. PMID- 21675139 TI - [Antibiotic therapy in community acquired pneumonia in children]. AB - Pneumonia is still the main cause of initiation antibiotic therapy in children, despite the fact that according to the newest epidemiological data, its incidence seems to be lower. In this paper current data concerning etiology, diagnostics and guidelines are discussed. The empirical antibiotic therapy of childhood pneumonia in different age groups is described. Author showed future trends in research necessary to solve controversies in present guidelines. PMID- 21675140 TI - [Antibiotic therapy in asthma exacerbation and in cystic fibrosis in children]. AB - Antibiotics have significant role in the treatment of respiratory diseases. The main aim of their use is to treat infection, but anti-inflammatory properties of macrolides are also beneficial in selected diseases. The role of antibiotics in the therapy of asthma exacerbation can be neglected and should be limited to exceptional situations of bacterial infections which are very rare. During last few years the role of atypical infections in asthma inception, induction of exacerbation and modification of chronic course of disease has been discussed. Antibiotics play significant role in cystic fibrosis therapy. They are especially recommended during exacerbation, when new pathogens are revealed and in chronic Pseudomonas aeruginosa infection. This paper includes the principal rules of antibiotics therapy in patients with cystic fibrosis. The role of azithromycin in antiinflammatory therapy in this group of patients is also presented. PMID- 21675141 TI - [Effectiveness and tolerance of antibiotics in pediatrics patients]. AB - Antibiotics represent the most widely prescribed therapeutic agents. Preschool children being most exposed to antibiotic drugs, especially in the community setting. Unnecessary antibiotic prescribing remains the cardinal contributing factor to the development of antibiotic resistance. Early antibiotic exposure, especially to broad-spectrum antibiotics, may suppress the developing immune system and produce a reduced anti-allergic response. Early antibiotic use in children is associated with an increased risk for asthma. PMID- 21675142 TI - [Infections caused by respiratory viruses and the possibility of controlling them]. AB - Respiratory viruses are pathogens that the most commonly cause infectious diseases in human beings. This is connected with the specificity of how the infection occurs and because of this, the feasibility of the wide dissemination of disease in the general population. Places that are especially conducive to spread of respiratory viruses are areas where the population density is increased -in this way the virus can quickly become a dominate health problem. The WHO has included respiratory infections as the second most common cause of death among children up to the age of 5. Cases of severe infection, especially those caused by the influenza virus, usually occurs in high-risk groups, namely infants, the elderly or in people whose immune system is insufficient. Illness caused by respiratory viruses may be further complicated by various types of co-infections with other viruses or bacteria. Only in the case of influenza we are able to utilise preventative vaccinations as well as anti-influenza drugs. PMID- 21675143 TI - [Antiviral drugs]. AB - It is 50 years since the first antiviral drug--JUDR for the local herpes keratitis was introduced and over 25 years since HIV/AIDS was isolated and the Noble Prize in Medicine and Physiology was given to its discovers. Now, there are 50 antiviral drugs, in which 25 are for HIV, the others are for herpes virus, shingles, cytomegalovirus, hepatitis virus and influenza A virus. Drugs for hemorrhagic fever Ebola and Marbourg as well as Denga fever are under way In the paper the current knowledge on chemotherapy and prophylaxis is presented in the following viral infections: HIV, HBV, HCV, CMV, HSV, shingles and other. The paper also demonstrates different groups of antiviral drugs, their use and efficacy. Mechanisms of infections and activity of antiviral drugs are analyzed. PMID- 21675144 TI - [Drug resistant tuberculosis]. AB - Drug-resistant tuberculosis, and particularly multidrug-resistant tuberculosis (MDR-TB) and extensive drug resistant TB (XDR-TB) as an increasing health problem and a serious challenge to TB control programs. MDR-Tb and XDR-TB are highly lethal in people living with HIV, with case of fatality rates of over 90%. At the same time, there are not many drugs effective in TB chemotherapy. Information about susceptibility patterns of Mycobacterium tuberculosis isolates against antituberculosis drugs is important aspect of tuberculosis control, and surveillance and analysis of local rates of TB drug resistance is helpful in the detection and monitoring of the extent of MDR and XDR strains, indicating the quality of TB control in the country. In 1994, The World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) launched a global project on anti-tuberculosis drug resistance surveillance. From 1994 through 2009, the global project has collected data from areas representing almost 60% of the world's TB cases. A survey found that multi-drug tuberculosis has become established worldwide. WHO estimated that 50 million people were infected with drug-resistant strains of M. tuberculosis. The classification of drug resistance as primary or acquired is used as an indicator of the efficiency of national tuberculosis programs and in the adjustment and development of these programs. The rate of primary drug resistance is interpreted as an epidemiological indicator for long-term surveillance of the quality of tuberculosis treatment in the community. The rate of acquired drug resistance reflects the efficacy of management of individual patients Since 1999, WHO developed DOTS-Plus strategy which can help how to manage MDR-TB using second line drugs in low- and middle-income countries within DOTS strategy. Poland joined the global project and in 1997 carried out its first simultaneous survey on primary and acquired drug resistance in tuberculosis patients exactly according WHO/IUATLD recommendations and protocols. Until now 4 surveys have been performed. Drug resistance in tuberculosis patients have been monitored in Poland for a long time. In period of recent 30 years the mean frequency of resistant was on the similar level with very low rate of RMP mono-resistance to M. tuberculosis. Both type of resistance MDR and XDR have been found in Polish tuberculosis patients. PMID- 21675145 TI - [Antibiotic therapy in skin diseases]. AB - Antibiotics are used for systemic and topical skin diseases treatment, taking advantage of their antiseptic, bacteriostatic and also their anti-inflammatory and immunomodulating properties. In case of localized external skin layers infections, a topical treatment is adequate. In case of widespread and deeper infections a systemic treatment is needed. The latter dermatological diseases are mostly treated by beta-lactam antibiotics (penicillins and cefalosporins) macrolides and tetracycline. In topical treatment mostly erythromycin, clindamycin, mupirocyne and fusidic acid are used. Most common bacterial skin diseases, where topical treatment is sufficient are: impetigo contagiosa, folliculitis and erythrasma. Systemic treatment is required in case of: severe staphylococcal and streptococcal infections, sexually transmitted diseases, secondary bacterial infections (i.e. associated to severe AD or lower leg arterial and venous ulceration), acne vulgaris, rosacea and dermatosis with bacterial antigens pathogenesis influence (i.e. psoriasis, guttate parapsoriasis and angitis). Antibiotic resistance is one of the most worrying problems during the treatment; this is why a targeted therapy, with results guarantee, is mostly appropriate. PMID- 21675146 TI - [Microbiological causes of antibiotic therapy failure in respiratory tract infections]. AB - This article reviews the most important aspects of antibiotic treatment failure in respiratory tract infection which may occur with empirical as well as under target antibiotic therapy. Potential risk factors leading or predisposing to treatment failure exist in hospital acquired infections which cover polymicrobial aetiology with high multidrug resistance bacteria, changed conditions of pharmacokinetic and pharmacodynamic (PK/PD) parameters of antibiotics, bioavailability, drug interactions and inactivation. Microbial determinants of treatment failure includes bacterial physiology in laboratory cultures and inside the host, inadequate drug choice, lack of knowledge of PK/PD parameters with insufficient antibiotic level in target tissue. Differences between microbial in vitro tests and clinical outcome can be caused by varied CFU concentration, growing phase, nutritional, pH and redox conditions. Many factors of treatment failure are focused on bacterial biofilm structure and phenomenon of small-colony variants (SCVs) which both display reduced susceptibility to antimicrobial agents protected by matrix feature, enhanced production of PIA and by slow multiplication of biofilm forming cells. PMID- 21675147 TI - [Aging of the immune system]. AB - The immune system theory of aging is that the rate of aging is largely controlled by the immune system. As we age, the numbers of critical cells in the immune system decrease and become less functional. Accumulating data are documenting an inverse relationship between immune status, response to health, and longevity, suggesting that the immune system becomes less effective with advancing age and that this is clinically relevant. The mechanisms and consequences of age associated immune alterations are briefly reviewed here. PMID- 21675148 TI - [Bacteriostatical possibilities of electromagnetic fields]. AB - The elaboration of new methods for controlling bacterial infections becomes increasingly important, especially in view of constraints of standard antibiotic therapy confronted with the expansion of resistant and biofilm-producing strains. The implementation of electromagnetic field as an agent impairing the growth of pathogenic bacteria may present one of the potential solutions. This paper describes the meaning of electromagnetic field as the factor naturally influencing bacterial physiology and communication processes, also reviewing its previous and future potential therapeutic utilization. PMID- 21675149 TI - [Pharmacokinetics of modern antibiotics]. AB - Antibiotics are used to remove the pathogen responsible for inflammatory reactions of the organism. To achieve this goal, it is necessary to know the pharmacokinetic and the spectrum of its actions. Good penetration and proper dosage of an antibiotic allows for the effective concentration at the site of inflammation. Currently available antibiotics have good pharmacokinetic parameters that allow the pathogen eradication and destruction of the biofilm. PMID- 21675150 TI - ACOs: time for ED managers to get involved, shape how their departments will add value. AB - Even with a proposed rule outlining how accountable care organizations (ACO) will be structured under fee-for-service Medicare, emergency medicine experts are concerned about how ACOs will impact patient access to the ED. Further, some see a clear need to beef-up case management staff, while others say ED managers need to get involved with ACO-development now so their interests and concerns are represented. Under a proposed rule unveiled by the Department of Health and Human Services, a handful of quality indicators will require the tracking of ED visits related to certain ambulatory care-sensitive conditions; experts say it could be a challenge for ED staff to differentiate between appropriate and inappropriate use of the ED. EDs that figure out how to contribute value under the ACO mission will be better positioned to prosper under the new model. The ACO model is likely to add considerable complexity to billing and reimbursement. PMID- 21675151 TI - Study finds ways to boost care coordination between emergency and primary care providers. AB - A new report suggests that poor communication between emergency and primary care providers has had a negative impact on care, and that this interface requires significant improvement if the country is to move toward more cost-effective care delivery models that prioritize quality. There are no easy solutions to the problem, but some health care organizations are making strides by using alternative communications modalities and by finding ways to strengthen the relationships between emergency and primary care physicians. Health systems and affiliated PCPs who utilize electronic health records (EHR) are better able to coordinate care with each other, but EHRs are not a silver bullet to the problem. In addition to documenting care tasks in the medical record, scribes can fill in care-coordination gaps by making follow-up calls to PCPs or specialists, or sending pages where appropriate. Some health systems are seeking to address prob lematic handoffs between the ED and PCPs by developing protocols that include care-coordination steps for diagnoses that are associated with high ED utilization. PMID- 21675152 TI - New standards address patient-centered communications. AB - The Joint Commission soon will be holding hospital accountable for new standards that focus on making sure that patient needs regarding communications are identified and met. Standards that take effect in July 2011 focus on making sure patients are offered the opportunity to have a support person present during their care. Additional standards, to take effect later, call for hospitals to identify and accommodate language or other communications requirements. The fast pace and high stress of the ED environment create added challenges in meeting patient communications needs. PMID- 21675153 TI - Use appropriate tools, strategies to overcome challenges of communicating in an emergency setting. PMID- 21675154 TI - Consider relationship-building activities, alternative communications strategies to boost care coordination, quality. PMID- 21675155 TI - ACOs, RACs, and ICD-10--updates for the ED. PMID- 21675156 TI - Slash door-to-doc time, boost patient satisfaction with staff-driven improvement effort. AB - With patient satisfaction in the single digits and door-to-doc times unacceptably high, the ED at Sumner Regional Medical Center in Gallatin, TN, initiated a staff driven improvement effort aimed at weeding out inefficiencies. By putting the triage process under close scrutiny, staff members were able to eliminate dozens of tasks from the triage process, thereby slashing wait times. ED patient satisfaction has gone from the 5th percentile to the 98th percentile in just four months. A 44-step triage process has been streamlined into four steps, and average door-to-doc times have decreased from 67 minutes to 18 minutes. Further improvements are anticipated when ED administrators put staff scheduling under the same scrutiny. PMID- 21675157 TI - PPACA one year later. PMID- 21675158 TI - Massive postpartum hemorrhage: recombinant factor VIIa use is safe but not effective. AB - OBJECTIVE: Postpartum hemorrhage is a leading cause of maternal mortality. Massive transfusion in obstetric patients is rare. Recombinant Factor VIIa (rFVIIa) use in trauma patients with massive transfusion is efficacious. Our goal was to evaluate the safety and efficacy of rFVIIa use in obstetric patients with massive postpartum hemorrhage (MPH). METHODS: Patients records with MPH from 2003 to 2006 were reviewed. Data collected were demographics, APACHE II scores, International Normalized Ratio (INR), fibrinogen level, blood product administration, rates of pulmonary embolism (PE), deep vein thrombosis (DVT), myocardial infarction (MI), hysterectomy, and mortality. Continuous variables within groups were analyzed with paired t-test, and independent t-test between groups. Categorical variables were compared via chi2 or Fishers Exact test and significance was denoted by a p < or = 0.05. RESULTS: Twenty-seven patients with MPH were investigated, eight received rFVIIa (study group) and 19 did not (control group). All patients received a massive transfusion, six units of packed red blood cells (pRBCs), via a massive transfusion protocol. The study group's mean APACHE II score 25.8 +/- 8.5, predicted mortality of 56.2 percent, was higher than control, p = 0.009. An increase in transfused units of cryoprecipitate, p < 0.001, pRBCs, p = 0.004, decrease in INR, p < 0.001, and length of stay in the high risk obstetrical unit, p = 0.019, existed in the study group. Hysterectomy was required in 85.7 percent of the study group. No patients developed a DVT, PE, or MI and all survived. CONCLUSIONS: Recombinant Factor VIIa use in MPH is safe, improves coagulopathy, was not effective in decreasing blood product transfusion requirements, and may contribute to an improved predicted mortality. PMID- 21675159 TI - Top ten reasons physicians are sued for malpractice. PMID- 21675160 TI - Compromise, control, and compliance. PMID- 21675161 TI - Nutrition needs linked approach. PMID- 21675162 TI - Rising malnutrition rates prompt call for greater power to be given to nurses. PMID- 21675163 TI - Benzodiazepines and falls risk. What measures can I take to help prevent patients in my care from falling? PMID- 21675164 TI - Minimising the risk of polypharmacy. AB - Polypharmacy holds particular risks for the older population, which nurses are in a good position to recognise and minimise. The aim of this article is to highlight the reasons why polypharmacy presents such a risk to older people and to consider what actions can be taken to address this problem. PMID- 21675165 TI - Providing tailored residential care to the Asian community. AB - For Asian families struggling to maintain the tradition of looking after elders, Aashna House in south London provides an alternative. It offers culturally specific care, supported by a team of 32 staff of Asian origin. This article examines how care and recruitment processes have been modified to take into account the different cultural backgrounds of residents. PMID- 21675166 TI - Sociocultural context of nutrition in care homes. AB - AIM: To investigate factors that influenced nutritional care provided in two different types of residential care settings. METHODS: The study used qualitative methods, including focus group interviews with relevant staff members, individual interviews with managers and residents of the care homes and their informal carers, observation of food preparation and mealtimes throughout the day and analysis of appropriate documents. FINDINGS: Data were analysed thematically, and this article describes one of the four main themes that emerged: the relationship between social context and residents' eating and drinking experiences. CONCLUSION: Greater understanding of the sociocultural context of eating and drinking in residential care settings may be used to inform nursing practice in relation to meeting older people's nutritional needs in other settings. PMID- 21675167 TI - Palliative care in patients with chronic obstructive pulmonary disease. AB - This article considers the place of palliative and end of life care in the management of people with end-stage chronic obstructive pulmonary disease (COPD). This respiratory disease has considerable morbidity and mortality, which affect patients, their families and carers, and healthcare provision. Many nurses working with older people will encounter patients with advancing COPD which may be their main problem or part of multiple comorbidities. This article aims to help nurses recognise declining respiratory status and understand the challenges faced by this particular group of patients, their families and carers. It follows recommendations that end of life care should be considered and dealt with in this group of patients (Department of Health 2008, National Clinical Guideline Centre 2010). It explores palliation and end of life and then considers more practical applications to support nursing care at the end stage of the disease. PMID- 21675168 TI - He is listening to you now. PMID- 21675169 TI - How to manipulate drugs so they can be given to children. PMID- 21675170 TI - Estimating nursing requirements using bed occupancy levels. PMID- 21675171 TI - Pre-operative fasting guidelines for children having day surgery. AB - Communication between child, family and health professionals is an important component in promoting effective clinical practice for children undergoing day surgery involving a general anaesthetic. This is crucial in relation to pre operative fasting. Two local audits of whether families adhered to existing guidelines showed that many parents did not follow the fasting instructions. This article explores the reasons behind this finding, and suggests that adherence to the best practice guidelines may be improved by a one-to-one discussion at the pre-admission clinic or by offering families the opportunity to ask questions by text message. PMID- 21675172 TI - Liability and collaborative working. AB - Team working is the basis of contemporary healthcare practice. For children and their parents, or carers, this does not pose a particular problem as long as team members work together and there is adequate information sharing between all the professional groups. This article discusses the issues relating to team working and liability. PMID- 21675173 TI - Adverse drug reactions: causes, types, pathways and mechanisms. AB - An adverse drug reaction is defined as an appreciably harmful or unpleasant reaction resulting from an intervention related to having received medication. This article describes adverse drug reactions in children and young people, their causes, types, pathways and mechanisms. Part two, to be published in June, will address the rights of those who are offered and receive prescribed drugs. PMID- 21675174 TI - A technique for nurses to use when educating families about cleft nutrition. AB - This article outlines the development of a technique devised to aid nurses and other health professionals when helping parents understand why good feeding techniques are of particular importance in children with cleft palates. The demonstration tool was developed by the author while on a trip organised by a charity to central India to perform corrective surgery on children with cleft lip and palate deformities. The author visited Nagpur in central India with a charity called the Northern Cleft Foundation. He PMID- 21675175 TI - Complementary and alternative medicine use in children with life-limiting conditions. AB - AIM: To quantify use of complementary and alternative medicine (CAM) in children with non-malignant, life-limiting illness. METHOD: A self-administered questionnaire was sent to families who received care from a community children's nursing and psychology team for children with non-malignant, life-limiting conditions. RESULTS: A total of 32 per cent of respondents had used up to seven types of CAM for their child and 43.4 per cent had used CAM for themselves or other family members. Most parents used CAM to enhance general wellbeing rather than treat specific diagnoses. A total of 58.3 per cent felt the therapy was helpful, 50 per cent had tried conventional medicine first, and 63.9 per cent of users discussed their use of CAM with a doctor or community nurse. CONCLUSION: The rate of CAM use is significantly higher in this population than found in many previous cross-sectional studies. This may reflect the different needs and expectations of families with children with non-malignant, life-limiting illnesses. PMID- 21675176 TI - Is viewing ostracism on television distressing? AB - Being ostracized can be a painful and distressing experience and can lead to subsequent aggression by the victim. However, it is unknown whether watching someone else be ostracized either in real life or on television is similarly distressing. The purpose of the current study was to examine what type of distress (if any) is induced after viewing ostracism on television. The study consisted of 50 participants, half who viewed a movie clip containing ostracism and half who viewed a control clip. Physiological and self-report data revealed that viewing ostracism was distressing to participants. In particular, participants who viewed the ostracism clip reported a lower sense of belonging, self esteem, and mood, and a greater increase in heart rate and skin conductivity than those who viewed the control clip. PMID- 21675177 TI - Self and social judgments of ability: beyond distributional information. AB - In a given domain, low-skill individuals typically evaluate the ability level of other people more favorably than high-skill individuals. The current study tests whether this tendency continues to occur even when people have unambiguous distributional information available through which to judge others. Students received distributional information detailing their percentile rank in a statistics course and the percentile rank of another student in the course. Then, students were asked to evaluate their own and the other students' statistics ability. Students evaluated the other person's ability more favorably when their own rank in the course was low rather than high. Therefore, people may use themselves as a standard of comparison when they judge others even when more diagnostic sources of information are available. PMID- 21675178 TI - Sociosexual orientation, commitment, and infidelity: a mediation analysis. AB - Individuals with an unrestricted sociosexual orientation (SO) are less committed to their romantic relationships and more likely to engage in infidelity. Furthermore, commitment is negatively associated with tendencies to cheat. However, no previous research has examined the possible mediating role of commitment in the relationship between SO and infidelity. The current study examined whether commitment mediated the relationship between SO and willingness to engage in three types of cheating behaviors (Ambiguous, Deceptive, and Explicit). Results suggested that commitment partially mediated the relationship between SO and infidelity, such that unrestricted individuals had lower commitment, which in turn led to a greater likelihood of cheating. Implications of this association and directions for future research are discussed. PMID- 21675179 TI - Do state laws concerning homosexuals reflect the preeminence of conservative liberal individual differences? AB - The present study was conducted to determine whether individual-level correlates of sexual prejudice (i.e., conservatism-liberalism, religious fundamentalism, educational levels, urbanism, income, and living in the South) are predictive at the state level of laws restricting homosexual behaviors and desires. Criterion 1 was a multifaceted index of state laws concerning gay men and lesbians; Criterion 2 was an index of state laws regarding same-sex partnerships. Multiple regression strategies showed that state conservatism-liberalism, as determined from the responses of 141,798 individuals aggregated at the state level (Erikson, Wright, & McIver, 1993), was the prime state-level predictor of both criteria. For Criterion 1, only Southern state status accounted for additional variance (4.2%) above the 54.8% already accounted for by conservatism-liberalism. For Criterion 2, no other variables accounted for variance beyond the 44.6% accounted for by state conservatism-liberalism. PMID- 21675180 TI - Does suppressing the thought of a self-relevant stigma affect interpersonal interaction? AB - In the current study, we examined the effects of women's suppressing negative gender stereotypes while interacting with a male confederate. Compared with control participants, those who suppressed negative thoughts about women's ability experienced less self-confidence, lower self-esteem, and were more nonverbally submissive during the interaction, particularly if they were high in stigma consciousness (Pinel, 1999). These findings illustrate the negative intra- and interpersonal consequences of stigma suppression. PMID- 21675181 TI - Transfer of attachment functions and adjustment among young adults in China. AB - This study was designed to examine the process of attachment transfer from parents to peers, as well as factors related to this transfer process among Mainland Chinese. A total of 147 Chinese college students (with a mean age of 21.44) completed questionnaires that measured attachment style, attachment transfer, attachment support from various figures, loneliness, positive/negative affects, and self-esteem. Major findings of the current study include the following: (a) Hazan and Shaver's sequential model of attachment transfer was generalized to the Chinese sample; (b) the extent of attachment transfer was found to be associated with participants' emotional states (loneliness and positive affect) and was a significant predictor of these emotional states beyond the effects of attachment style and attachment support. As one of the first studies exploring the phenomenon of attachment transfer among young Chinese adults, conceptual and applied implications of these findings are discussed. PMID- 21675182 TI - Biological explanations and stigmatizing attitudes: using essentialism and perceived dangerousness to predict antistigma intervention effectiveness. AB - The theory of essentialism suggests that biological explanations of stigmatized behavior may not be effective at decreasing stigmatizing attitudes. The effects of biological explanations on stigmatizing attitudes were the topic of two experiments. In the first experiment, participants (N = 243) perceived a biological explanation as a less effective in relation to dangerousness and social distancing attitudes about mental illness than about homosexuality. The second experiment (N = 113) compared the effect of biological and free choice explanations on stigmatizing attitudes about abnormal sexual and eating behaviors. The results indicated that a biological explanation increased belief in essentialism and was most effective for attitudes related to anger and blame. These results suggest that the effectiveness of biological explanations as an antistigma tool varies according to the attitude and stigmatized group. PMID- 21675183 TI - Costs and benefits of autonomy when learning a task: an experimental approach. AB - Previous findings suggested that the positive relationship between autonomy and learning outcomes (such as improved task performance) only holds up until a certain optimum level of autonomy has been reached. This assumption was investigated in an experimental study where 95 participants had to learn a computer task. During the learning phase, we manipulated autonomy, distinguishing among no, moderate, and full autonomy. The results revealed that, when learning a task, having autonomy is preferred to having no autonomy. However, increases in autonomy beyond a certain level (i.e., full versus moderate autonomy) will not yield additional advantages regarding the motivation to learn and learning outcomes, and may have disadvantages in terms of learning efficiency. PMID- 21675184 TI - Does the Defining Issues Test measure ethical judgment ability or political position? AB - This article addresses the construct validity of the Defining Issues Test of ethical judgment (DIT/DIT-2). Alleging a political bias in the test, Emler and colleagues (1983, 1998, 1999, 2007), show that conservatives score higher when asked to fake as liberals, implying that they understand the reasoning associated with "higher" moral development but avoid items they see as liberally biased. DIT proponents challenge the internal validity of faking studies, advocating an explained-variance validation. This study takes a new approach: Adult participants complete the DIT-2, then evaluate the raw responses of others to discern political orientation and ethical development. Results show that individuals scoring higher on the DIT-2 rank others' ethical judgment in a way consistent with DIT-2-based rankings. Accuracy at assessing political orientation, however, is low. Results support the DIT-2's validity as a measure of ethical development, not an expression of political position. PMID- 21675185 TI - Still stable after all these years: perceptions of sexual harassment in academic contexts. AB - This research examined perceptions of sexual harassment in academic contexts using data sets collected in 1990 (Time 1) and 2000 (Time 2). We assessed the influence of two individual variables--gender and gender role--and one contextual variable--power of the harasser--on perceptions of harassment. When the harasser was a higher-power individual, participants perceived more vignettes as examples of sexual harassment, viewed female targets more positively, and evaluated male harassers more negatively. Contrary to prediction, participants viewed male harassers less negatively at Time 2 than at Time 1. Despite increased media attention and educational interventions, comparisons to the earlier findings highlight remarkable stability in perceptions of harassment over time. PMID- 21675186 TI - Cultural variations in the sexual marketplace: gender equality correlates with more sexual activity. AB - Sexual economics theory assumes that heterosexual communities can be analyzed as marketplaces in which men offer women resources such as love, respect, money, and commitment in exchange for sex. In response to economic, political, and other disadvantages, women collectively restrict their sexuality to maintain a low supply relative to male demand, thereby ensuring a high price. Hence, we tested the hypothesis that sexual norms and practices would be more restrictive in countries marked by gender inequality than in countries where the genders were more equal. An international online sex survey (N>317,000) yielded four measures of sexual activity, and 37 nations' means on all four measures were correlated with independent (World Economic Forum) ratings of gender equality. Consistent with predictions, relatively high gender equality was associated with more casual sex, more sex partners per capita, younger ages for first sex, and greater tolerance/approval of premarital sex. PMID- 21675187 TI - How consumers respond to the behavior of missing a free gift promotion: inaction inertia effect on products offered as free gifts. AB - Inaction inertia describes the phenomenon that an individual is unlikely to act on an attractive opportunity after having bypassed an even more attractive one. The results of two experiments indicate that after missing an initial opportunity to obtain a product as a free gift during a promotional period, the inaction inertia effect reduces the likelihood of consumers buying the product at a discounted price (second, inferior opportunity), particularly if the free gift has a high regular price. Additionally, according to the results of Experiment 2, those consumers are less likely to buy a product that has been offered previously as a free gift when a greater total quantity of the free gift is offered during a promotional period. Moreover, the mediation analysis results indicate that anticipated regret and valuation significantly impact the mediating role of inaction inertia. PMID- 21675188 TI - [Forestalling policy as a strategic objective of space biology and medicine at the present time point]. AB - The article ushers into the acrimonious debates about paths of innovative development and criticality of fundamental sciences in technological progress for Russia security, and breakthrough potential. Among the alternative routes of technical development are different forms of priority boost of growing points in which Russia has attained and held steadily the leading position occupying a prominent segment in the international division of labor. Space effort of Russia gives a model example of successful implementation of the national program and demonstrates leadership in this area of human activities. The article presents analysis of the factors and circumstances that predetermined the winning in the early, Gagarin's period of piloted space flights of the forefront position of the country as well as the vector of cosmonautics' advance for many years ahead Despite the host of issues with implementation of the ISS utilization program and planning of exploration missions to the Moon and Mars, the unique experience of preparations and carrying out investigations and tests with humans in space, the enormous groundwork in fundamental biomedical researches over the past 50 years of piloted flights allow optimistic prognosis of gaining headway with essentially new ambitious space projects. The key question is whether the forestalling policy of priority development of piloted cosmonautics as the most integrated and science intensive sector of innovation techniques will be realized. The answer will guide near- and long-term future of the space industry and, consequently, the fortune of national fundamental space sciences, space biomedicine being its part and parcel. PMID- 21675189 TI - [Redistribution of body liquids in the conditions of microgravity and simulation of its effects]. AB - The review is devoted to shifting of blood and other liquids along the body axis toward the cranium end in microgravity and during simulation of the zero-g physiological effects. The body liquids redistribution excites a number of consistent physiological reactions as well as a cascade of secondary adaptation processes. Changes occur in central venous pressure and size of the heart cavities, renal function and hormonal volumoregulation entailing the adaptive shifts in body liquid segments. Hemodynamic changes in the splanchnic vascular system affect functioning of the abdominal organs. Measures of pharmacological correction expedite human adaptation to unusual environments. PMID- 21675190 TI - [Adaptation of humans to walking in semi-hard and flexible space suits under terrestrial gravity]. AB - The spacesuit donning-on procedure can be viewed as the combining of two kinematic circuits into a single human-spacesuit functional system (HSS) for implementation of extravehicular operations. Optimal human-spacesuit interaction hinges on controllability and coordination of HSS mobile components, and also spacesuit slaving to the central nervous system (CNS) mediated through the human locomotion apparatus. Analysis of walking patterns in semi-hard and flexible spacesuits elucidated the direct and feedback relations between the external (spacesuit) and external (locomotion apparatus and CNS) circuits Lack of regularity in the style of spacesuit design creates difficulties for the direct CNS control of locomotion. Consequently, it is necessary to modify the locomotion command program in order to resolve these difficulties and to add flexibility to CNS control The analysis also helped trace algorithm of program modifications with the ultimate result of induced (forced) walk optimization. Learning how to walk in spacesuit Berkut requires no more than 2500 single steps, whereas about 300 steps must be made to master walk skills in spacesuit SKV. PMID- 21675191 TI - [Psychophysiological adaptation and communication behavior of human operator during 105-day isolation]. AB - Purpose of the study was to assess effects of 105-d isolation on language behavior and psychophysiological status of volunteered subjects. Software NOOJ was used to determine frequency of mentioning in written reports notions falling into the categories of "Needs", "Activity", "Negation" and "Social regulation". Well-being, activity and mood were assessed with the SAN questionnaire and urine cortisol measurement. Correlation of the content-analysis results with phases of adaptation to extended isolation and confinement made it possible to elicit specific features of language behavior of the small group members, at the time of simulated autonomy, specifically. Besides, the computerized content-analysis enabled a quantitative description of communication strategy as a function of psychophysiological adaptation to stressful factors of the simulation experiment. PMID- 21675193 TI - [Scatological investigations during 105-day isolation]. AB - Dynamics of the gastrointestinal functioning was reconstructed by analysis of the scatological data from volunteered subjects before, on days 16, 35, 45, 60, 90 and after completion of 105-day isolation experiment. The analysis showed that scatological investigations performed in the conditions imitating life in an exploration vehicle environment are instrumental in detecting deviations in the GI function indicative of pancreas excretory and hepar biliary excretion and synthetic hypofunction that can be responsible for intestinal dysfunction. Normalization of scatological parameters following the experiment witnesses to functional genesis of the changes observed during the exploration mission simulation. PMID- 21675192 TI - [Studies of the blood antioxidant system and oxygen-transporting properties of human erythrocytes during 105-day isolation]. AB - Effects of strict 105-d isolation on blood antioxidant status, erythrocyte membrane processes and oxygen-binding properties of hemoglobin were studied in 6 male volunteers (25 to 40 y.o.) in ground-based simulation of a mission to Mars (experiment Mars-105). The parameters were measured using venous blood samples collected during BDC, on days 35, 70 and 105 of the experiment and on days 7 and 14-15 after its completion. Methods of biochemistry (determination of enzyme activity and thin-layer chromatography) and biophysical (laser interference microscopy, Raman spectroscopy) showed changes in relative content of lipid and phospholipid fractions suggesting growth of membrane microviscosity and increase in TBA-AP (active products of lipids peroxidation interacting with thiobarbituric acid). A significant increase in glucose-6-phosphate dehydrogenase and superoxide dismutase activities against reduction of catalase activity points to both reparative processes in erythrocytes and disbalance between the number of evolving active forms of oxygen and antioxidant protection mechanisms in cells. Hemoglobin sensitivity of oxygen and blood level of oxyhemoglobin were found to increase, too. It is presumed that adaptation of organism to stresses experienced during and after the experiment may destroy balance of the antioxidant protection systems which is conducive to oxidation of membrane phospholipids, alteration of their content, increase of membrane microviscosity and eventual failure of the gas-exchange function of erythrocytes. PMID- 21675194 TI - [Express diagnostics of microbial status of humans in 14- and 105-day isolation]. AB - Automated digital image microscopy was used to evaluate skin microbial populations in 14- and 105-day isolation experiments within the Mars-500 project. PMID- 21675195 TI - [Cytological and cytogenetic studies of cells of Mongolian gerbils' retinal epithelium and marrow following 12-day space flight]. AB - The paper report the results of studying mitotic activity and cytogenetic disorders in marrow and retinal epithelium cells of Mongolian gerbils in 21 - 23 hrs. of landing space apparatus Foton-M3, and the animals of synchronous and vivarium controls. Cells of the space flown gerbils displayed a statistically significant (p < 0.05) gain in the ratio of mitosis prophases and metaphases to the sum of ana- and telophases (1.7 +/- 0.3 and 2 +/- 0.1, respectively) as compared to these parameters in the synchronous and vivarium controls, where the ratio made up 0.6 +/- 0.1 and 0.7 +/- 0.1, respectively. Frequency of aberrant mytoses in the form of bridges was increased equally in both types of cells. Patterns of chromosome damages occurred in flight infer that the major portion of changes was not due to chromosome breakage but adhesion and ensuing wrong disjunction. These results seem to have been caused by acute g-stress to organism during re-entry and return from micro-g to the normal gravity. PMID- 21675196 TI - [Content of energy substrates in fibers of postural muscle soleus and its antagonist in the condition of support deprivation]. AB - The investigation had the purpose to measure energy substrates in different fibers of 3- and 14-d suspended postural m. soleus and its main antagonist - anterior tibial muscle in rats. Hindlimb suspension served as a model of gravitational unloading. After suspension, left m. soleus or anterior tibial muscle was extracted. Serial cross-sections were subject to histochemical staining by Oil Red O (Sigma) for determination of intracellular triglycerides or by Schiff's reagent and iododic acid (Sigma-ALDRICH) for determination of glycogen and simultaneous immunohistochemical fibers typing by antibodies to heavy types I and II myosin chains (NCL-MHCs and NCL-MHCf, Novocastra). Analysis of intracellular energy substrates showed that both types of fibers in the anterior tibial muscle had accumulated triglycerides by week-2 of suspension. At the same time, glycogen level in equally slow and fast fibers of m. soleus and fast fibers anterior tibial muscle decreased substantially after 3 days of suspension but returned to baseline value by day 14. These changes are likely to be linked with altered activity of the muscles and hormonal factor. PMID- 21675197 TI - [Effect of strength-building training on manifestation of pressor reflex from working muscles receptors]. AB - Ten young normal volunteers and 8 armrestlers worked with forearm muscles till refusal at 30% of maximal arbitrary force. Work was either static or rhythmic with alternation of 20-s period of contraction and relaxation and followed by post-work arterial occlusion of the forearm muscles (PWAO). Heart rate (HR), blood pressure (BP) and muscular vessels-related sympathetic activity (MRSA) were measured continuously. MRSA was registered in n. peroneus using the microneurographic technique. Static work and subsequent PWAO produced different BP and MRSA neither in sportsmen nor amateurs. On the contrary, rhythmic work followed by PWAO suppressed the muscle pressor reflex in sportsmen significantly. The authors consider possible origination of the effect by change in energy supply to working muscles, enhanced extraction of metabolites, and sensory decrement of sportsmen's muscular receptors. PMID- 21675198 TI - [Lipid peroxidation and antioxidant protection system in cosmonauts following short-term missions to the International Space Station]. AB - Blood serum of Russian members (n = 21) of the 8 to 12-day visiting missions to the ISS was analyzed before and after mission for products of lipid peroxidation, i.e. diene conjugates, malone dialdehyde, Schiff bases and tocopherol, the primary lipid antioxidant. No reliable change was found in the parameters postflight as compared with preflight values. It may be concluded that 14 days in orbital flight and the factors of re-entry and early recovery do not affect significantly the mechanisms of free radical lipid oxidation and functioning of the antioxidant protection system. PMID- 21675199 TI - [Psychophysiological signs of hyperuricemy in military personnel]. AB - It was shown that concentration of uric acid in blood is dependent on person's neurotic type. People combining high working potential, assertions and work concentration with continuous hypersympathycotonia exhibit psychosomatic predisposition and are at risk of cardiovascular pathology. Neuromuscular relaxation and cognitive-behavior training can be recommended to prevent cardiovascular disorders. PMID- 21675200 TI - [Vasopressin: molecular mechanisms of antidiuretic effect]. AB - Body water balance is regulated by vasopressin, and multiple studies now have revealed essential role of aquaporins in this process. This review summarizes recent advances related to molecular events underlying the short-term control of water permeability which occurs via vesicular trafficking of AQP2 to the cell apical membrane, and long-term control through changes in the gene expression and the abundance of AQP-2, -3 and -4. The action of vasopressin on water permeability is counterbalanced by several factors such as prostaglandin E2, bradykinin, dopamin, endotelin-1 and others. Changes in AQP-2 expression / trafficking are of particular importance in pathological conditions characterized by both diluting and concentration defect of renal function. PMID- 21675201 TI - [The cardiac hormonal system as a link in hemodynamic regulation and water-salt homeostasis]. AB - Classic and modern data on natriuretic peptide hormones that are synthesized in cardiac atria and participate in hemodynamic and water-salt balance regulation are summarized in this paper. Cumulated data on polypeptide variety, their structure, intracellular syntheses, physiological effects and concentration alterations during model experiments and cardiovascular pathology are presented. Unsolved problems including methods of plasma peptides concentration measurements, their role in heart failure development, and their clinical significance are discussed. PMID- 21675202 TI - [Effect of interleukin-1beta and interleukin-4 on serum albumin parameters in rats with various behavioural characteristics]. AB - We studied the effects of pro-inflammatory cytokine interleukin-1beta and antiinflammatory cytokine interleukin-4 on serum albumin parameters in rats with various behavioural characteristics in the open-field test. Under control conditions, the total concentration of serum albumin in active animals was higher than in passive those. However, the ratio of the effective-to-total concentration of albumin (i.e., binding capacity of this protein) was greater in passive rats. Administration of interleukins was accompanied by a decrease in the total content and effective concentration of albumin in passive and, particularly, in active rats. The initial intergroup differences in the ratio of the effective-to-total concentration of albumin were not found after injection of immunomodulating agents. It was mainly related to a more significant increase in this parameter in active animals. An increase in the binding capacity of albumin after cytokine treatment could be associated with conformational changes in the protein molecule. We believe that interleukin-1b and interleukin-4 exert similar effects on the properties of binding sites of serum albumin in rats with various behavioural characteristics. PMID- 21675203 TI - [Effect of acute hypoxia on the intensity of free radical processes in the basal nuclei of the brain, and the rat behaviour in the open field test under conditions of altered photoperiod]. AB - The effect of acute hypoxia on the intensity of free radical processes in the basal nuclei (the nucleus caudatus, globus pallidus. nucleus accumbens. amygdaloid complex) of the brain, and the rat behaviour in the open field test has been studied under conditions of altered photoperiod. It has been shown that constant darkness levels the effect of acute hypoxia on the intensity of lipid peroxidation, preserves the activity of superoxide dismutase and catalase at a higher level, lowers the activity of glutathione peroxidase. Under light, the sensitivity of basal nuclei neurons to acute hypoxia is enhanced, the latter being reflected in intensification of lipid peroxidation at the expense of increased formation of dien conjugates. The activity of catalase at that considerably exceeds the level of even intact rats in all the structures. It has been established that an altered photoperiod modulates the effect of acute hypoxia on the parameters of rat's activity in the open field, the character of their change depending on the nature of a photophase change. PMID- 21675204 TI - [The effect of lateral inclinations upon optokinetic and postoptokinetic nystagmus in pigeons]. AB - Optokinetic stimulation with the angle velocity 10 degrees/s was carried out in pigeons in differently bent postures. No difference in effects of dynamic and static inclinations upon optokinetic and postoptokinetic nystagmus was found. Neither any rigid connection was found between the inclination direction and the sign of the response change. The data obtained are at variance with the hypothesis of gravity-dependent changes of the "velocity accumulator" time constant as the only cause of changes in the optokinetic and postoptokinetic responses under conditions of dynamic or static inclinations. PMID- 21675205 TI - [The size of cells providing interhemispheric and intrahemispheric connections in the visual cortex of binocular vision-impaired cats]. AB - The size (somatic area) of 658 cells located in layers 2/3 of cortical areas 17, 18 of both hemispheres in intact monocularly deprived and bilateral strabismic cats was measured. These cells were retrogradely labelled after injections of horseradish peroxidase into ocular dominance columns in areas 17, 18. In all groups of cats, the mean somatic area of callosal cells was significantly larger than the mean somatic area of intrahemispheric cells. It was found that the mean somatic area of callosal cells was increased by 26.6% in monocularly deprived cats and by 20.2% in strabismic cats in relation to the mean somatic area of callosal cells in intact cats. In addition, the mean somatic area of intrahemispheric cells in monocularly deprived cats was indistinguishable from the mean somatic area of intrahemispheric cells in strabismic cats and in intact cats. It is concluded that early binocular vision impairments produce enlargement of callosal cells' size in the visual cortex. PMID- 21675206 TI - [The state of the contralateral motor center of the rat gastrocnemius muscle after unilateral damage of sciatic nerve]. AB - Effects of unilateral damage of the rat sciatic nerve on the spinal motor centre of contralateral gastrocnemius muscle were investigated. The state of contralateral gastrocnemius muscle centre was assessed using the method of paired monosynaptic testings and posttetanic potentiation of reflex response on days 1, 5 and 10 after nerve damage. The obtained data indicate changes in reflex activity of contralateral motor centre in these conditions. The activation of contralateral reflex systems after nerve damage seems to provide regenerative reorganisation of the motor control in the conditions of traumatic influence. PMID- 21675207 TI - [Electrophysiological and psychophysical studies of the effect of duration of presenting textures on the recognition threshold]. AB - We studied the dependence of correct response number, response time, and the main characteristics of visual evoked potentials on the time of the stimuli presenting. The coincidence of the recognition temporal thresholds and occurrence of differences in the visual EPs suggests that the temporal characteristics of these processes differ in different subjects. Two groups of observers were distinguished with different temporal characteristics of perception and the EP development. PMID- 21675208 TI - [The functional prognosis of physical working ability under conditions of extreme high altitude]. AB - The physical performance of climbers, those making high-altitude ascensions up to 8000 m, without additional oxygen was measured. Some functional criteria of the organism adaptation to exhausting physical loading at the high altitudes were selected. It was established that the forecasting of a successful ascension could be improved if the potential maximal oxygen uptake was added to the standard definition parameters of aerobic metabolism such as the maximal oxygen uptake and anaerobic threshold of oxygen uptake. The potential maximal oxygen uptake is considered to be the parameter of maximal oxygen uptake reserve growing in condition of realization of adaptive reaction to hypoxia. PMID- 21675209 TI - [Trends of angiosperm genome evolution]. AB - Direction of evolutionary variability of parameters of genome size and structurally functional activity of plants on life forms groups and angiosperms taxa are analyzed. It is shown that, in the Cretaceous-Cenozoic, their nuclear genome tended to increase. Functional genome efficiency (intensity of functions per 1 pg of DNA) decreased from as much as possible high at trees and lianas of rain and monsoonal forests of the Paleogene to minimum at shrubs, perennial and annual grasses of meadow-steppe vegetation which had appeared in the neogene. Important for the vegetation environmental changes in temperature, humidity and CO2 concentration in an adverse direction are discussed as the cause of evolutionary genome size growth and decrease in its functional efficiency. Price for phylogenetic adaptogenesis of angiosperms to the step Cenozoic climate cooling was 4-fold and more genome growth. PMID- 21675210 TI - [Lysosomal membrane permeabilization as apoptogenic factor]. AB - Lysosomal membrane labilizing agents (incl. proapoptotic proteins of Bcl-2 family, LAPF, p53), estimation of lysosomal membrane permeabilization in living cells, the new data on differential permeabilization of lysosomal membranes, membrane stabilizing factors (incl. Hsp70), relations between lysosomal membrane damage, and initiation of apoptosis were considered. Signal effect of lysosomal membrane permeabilization is caused preferentially by release of cathepsin B and D in cytosol. Subsequent numerous pathways of apoptogenic signalization include proteolytic attack/activation on signal cytosolic proteins, mitochondria, procaspases, cell nuclei. The mainstream of the cell damage is connected with activation pf proapoptotic Bid and Bax, leading to permeabilization of the outer mitochondrial membrane, release of cytochrome c into cytosol and activation of caspase cascade. Translocation of the lysosoma enzymes in cytosol is capable to induce both the caspase-dependent and caspase-independent paths of apoptosis. PMID- 21675211 TI - [Culture of human amniotic fluid stem cells in 3D collagen matrix]. AB - Most of the researchers attribute amniotic fluid stem cells (AF SCs) to mesenchymal stem cells (MSCs). However, AF SCs express both mesenchymal and epithelial markers, which distinguishes them from postnatal MSCs. Cultivation in the three-dimensional matrix provides a different look at the nature of these cells. We showed that, in 3D collagen gel, AF SCs form epithelial structures (tubules and cysts). Active contraction of the gel during the first days of cultivation, which is characteristic if mesenchymal cells, does not occur. Electron microscopic study showed that typical to epithelial cell adherent junctions are formed between AF SCs. On the other hand, AF SCs continue to express MSCs markers during cultivation in the gel. Thus, AF SCs may not be true mesenchymal cells because they can display properties of epithelial cells. Perhaps these cells undergo epithelial-mesenchymal transition, the process which actively takes place during embryogenesis. PMID- 21675212 TI - [Epithelial intestine cells transdifferentiate into bladder urothelium in experiments in vivo]. AB - The autoplastic surgery by intestine tissue has been used for reconstructive therapy of the urinary tract since the middle of the last century; however, cell mechanisms of the urothelium engraftment are still obscure. Intestine stem cells possess plasticity and presumably enable after the autoplastic surgery to transdifferentiate into mature cells of urinary tract. Using the preliminary developed in vivo model for evaluation of somatic cells transdifferentiation into urothelium, we have found that the epithelial intestine cells producing Gfp transdifferentiate into the cryoinjured bladder urothelium of the syngenetic C57BL mice. Gfp was detected in the bladder tissue of mice-recipients using reverted polymerase chain reaction, primary fluorescence and immunofluorescence, while colocalization of the Gfp and Her-4 revealing similar to urothelium staining pattern was demonstrated in a few urothelium cells by double immunohistochemical staining of the bladder tissue with specific antibodies. The results obtained suggest that epithelial intestine cells enable to transdifferentiate into bladder urothelium, however the transdifferentiation level is low and presumably can not provide full functional urothelium engraftment in the case of autoplastic bladder surgery by intestine tissue. PMID- 21675213 TI - [Differences in functional activity of cultivated human vascular endothelium received from different donors]. AB - Endothelium of blood vessels in the organism is involved in carrying out numerous functions in normal and pathological processes. Development of the method of isolation and cultivation of endothelial cells has made it possible to model the processes occurring in vascular endothelium. Unlike continuous cell lines, research on primary cell cultures lead to wide variation in results. In this study, spontaneous production of markers characterizing functional activities of endothelium were compared in endothelium cultures derived from umbilical cords of 20 donors. It was found that, based on the production levels of all investigated markers after 3 hours of cell cultivation, these cultures can be divided into high- and low-producing. Analysis of cytokine profiles revealed that the level of spontaneous production of IL-1beta in these groups did not vary during cell cultivation up to 24 and 48 hours, whereas the levels of IL-6 and IL-8 production increased to 24 and 48 hours, and the difference between groups became leveled; the increase in production of TNFalpha occurred only in cultures of low-producing group. The increase in amounts of sP- and sE-selectin in cultural medium was observed only under cultivation of low-producing cultures, whereas the increase in sICAM-1 was noted under cultivation of highly-producing cultures; the increase of sPECAM-1 was revealed under cultivation of both highly- and low-producing cultures. So, the difference in the levels of this CAM between the groups remained. The levels of sVE-cadherin in cultural medium did not vary in the course of cell cultivation. The levels of nitrite reflecting the amount of NO were increased in cultural medium in all cultures, and the difference between the groups remained; concentration of endotelin-1 was increased, however the values of this marker in the cultural medium of several cultures were similar, therefore, it was not possible to create groups reflecting levels of its production. The levels of von Willebrand Factor were increased in cultural medium under cultivation of cultures of both groups, however the difference between the groups did not remain. The levels of matrix metalloproteinase-1 in cultural medium increased under cultivation of cell cultures. Hence, endothelial cultures from different donors differ in their ability to produce markers of functional activity, and reflect the features of cell donors. The results obtained allow modeling the processes occurring in vascular endothelium taking into account the individual characteristics of cultures, and suggest the possibility of a more thorough approach to evaluating the results obtained using primary endothelium cultures. PMID- 21675214 TI - [Effect of magnetic nanoparticles Fe3O4 on viability, attachment and spreading of cells isolated from fetuses and new-born rats]. AB - This study shows that toxic effect of non-modified nanoparticles of Fe3O4 in vitro depends on metabolic and morphological condition of cells, derived from fetuses and newborn rats. During the cultivation of cells with magnetic nanoparticles, the new-born rats. During the cultivation of cells with magnetic nanoparticles, the latter bind to the cell surface and penetrate into the intracellular space. In this case, sorption of nanoparticles on the cell surface makes it difficult for cells to adhere to substrate, and the absorption by spread cells may prevent their proliferation. Magnetic nanoparticles are well absorbed by the upper layer of cellular aggregates. In this case, the cells of the inner layer remain intact. Consequently, the cell aggregates are able to respond to the constant magnetic field. These aggregates could potentially by used in cell transplantation for directed cell delivery. PMID- 21675215 TI - [NADP increases the level of histone H2AX phosphorylation in mouse heart cells after ionizing radiation]. AB - Phosphorylation of replaceable histone H2AX occurs in megabase chromatin domains around DNA double-strand breaks (DSBs), and this modification called gamma-H2AX can be used as an effective marker for DSBs repair and DNA damage response. Using Western blotting and immunohistochemistry techniques we have studied here the influence of exogenous nicotinamide adenine dinucleotide phosphate (NADP) which could potentially increase the intracellular level of NAD+ and on the level of gamma-H2AX formation in mouse heart cells after ionizing radiation (IR). We have found that injection of NAD+ in different doses immediately after IR causes an increased level of gamma-H2AX in mouse heart cells 20 min after IR at the dose of 3 Gy compared to control mice after IR exposure. It indicates that it could be a relationship between intracellular NAD+ content and DNA damage response in vivo. PMID- 21675216 TI - [The effect of Rho-kinase inhibition depends on the nature of factors that modify endothelial permeability]. AB - Endothelium lining the inner surface of all vessels plays barrier role and regulates permeability of vascular walls controling the exchange between circulating blood and tissue fluids. Disturbance of normal functions (endothelial dysfunction) can be caused by both internal, and external factors. Endothelial dysfunction is characterized by increased vascular wall permeability observed in many human diseases. Dysfunction is also a drug side effect of oncological diseases treatment by mitosis-blocking medications. Depolymerization of microtubules is the first step in the cascade of reactions leading to endothelial barrier dysfunction, and this stage is universal, it does not depend upon the nature of a factor provoking dysfunction. To develop the strategy of barrier dysfunction prevention, we are supposed here to find out to what stage the endothelial cell cytoskeleton reaction during the development of barrier dysfunction is universal. It has been found that the cascade stages, which follow the microtubule depolymerization and are connected with Rho-Rho-kinases activity, have the features depending on the factor provoking barrier dysfunction. Under suppression of Rho-kinase activity, the reaction of actin filaments does not depend on what substance caused dysfunction. But the microtubule system responds to the treatment varies depending on the dysfunction-provoking factor. Unlike thrombin, under the conditions of Rho-kinase activity suppression, nocodazole renders more strong effect, as much as possible destroying both dynamic, and stable microtubules. Thus, regardless of the dysfunction provoking factor, the initial stages of dysfunction connected with the depolymerization of microtubules appear to be unalterable. Consequently, endothelial cell defence strategy should be based on cytoplasmatic microtubules protectors application instead of employment of the factors involved in the cascade at later stages as we assumed earlier. PMID- 21675217 TI - [Fragmentation of the coding region chromatin of trp-dioxygenase (to) and tyr aminotransferase (tat) genes in their active and repressed state by micrococcal nuclease]. AB - The blot-hybridization technique-assisted we have studied the pattern of fragmentation by mirococcal nuclease (MNase) of DNA tyr-aminotransferase (tat) and trp-dioxygenase (to) genes in active (in rat cell liver nuclei) and repressed (in brain nuclei) states. It was provided, over a wide range of enzyme concentration two types of fragments are mainly produced: near full-size to- and tat-transcription unit (19,000 and 11,000 bp, respectively) and their large (from 1500 bp) heterogeneous in length. To-and tat-fragments of both kinds are preserved in hydrolyzates at limit of MNase digestion of total chromatin DNA when nuclease breaks occur in nearly all accessible sites of chromatin. This means that these fragments originate from two distinct subsets of transcription units coexistent in liver nuclei. The first of them do not contain MNase accessible sites over their entire length, whereas in other resistant regions alternate with rare irregular located MNase-sensitive segments. We presume that resistance to MNase within transcription units is peculiar to the competent genes. As a result of transcription MNase-sensitive areas arise which possibly flank elongating RNA polymerases. PMID- 21675218 TI - Effect of additional carbon source and moisture level on xylanase production by Cochliobolus sativus in solid fermentation. AB - The fungus Cochliobolus sativus has been shown to be an efficient producer ofxylanase from an industrial point ofview. The addition of extra carbon sources and the initial moisture content of the solid-state fermentation were found to have a marked influence on the xylanase production by C. sativus Cs6 strain. Xylan and starch resulted in an increased xylanase production (1469.4 and 1396.56 U/g, respectively) after 8 days of incubation. Optimal initial moisture content for xylanase production was 80%. The cultivation systems can easily be modified to enhance the productivity of the enzyme formation by C. sativus Cs6, which will facilitate the scale up processes for mass production. PMID- 21675219 TI - Phylogenetic analysis of culturable marine bacteria in sediments from the South Korean Yellow Sea. AB - Biogeochemical and microbiological characterization of marine sediments taken from the Yellow Sea of South Korea was carried out. One hundred and thirty six bacterial strains were isolated, characterized and phylogenetic relationship was evaluated. The gene sequences of 16S rDNA regions were examined to study the phylogenetic analysis of bacterial community in the marine sediments. Among 136 isolates, 5 bacterial isolates were identified as novel members, remaining 131 isolates were fall into 5 major linkages of bacterial phyla represented as follows: Firmicutes, alpha, gamma-Proteobacteria, High G + C and Bacteroidetes. Bacterial community in sediments mainly dominated by Firmicutes (58.77%) and followed by gamma-Pateobacteria (38.16%). Gamma-Proteobacteria domain highly diverged and mainly consists of the genera Vibrio, Marinobacterium, Photobacterium, Pseudoalteromonas, Oceanisphaera, Halomonas, Alteromonas, Stenotrophomonas and Pseudomonas. Total N and Organic matter content in Yellow Sea of South Korea were relatively high. The Total-N content in the sediments was varied from 177.31 to 1974.96 (mg/kg) and organic matter ranged from 0.82 to 4.23 (g/100 g). The current research work provides clear explanation obtained for the phylogenetic affiliation of the culturable bacterial community in sediments of South Korean Yellow Sea and revealed the relationship with biogeochemical characteristics of the sediments. PMID- 21675220 TI - [Neurobiology of addictive behavior]. AB - Addictive behavior developes after repeated substance use and it typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to the drug use than to other activities. Relapse, the resumption of drug taking after periods of abstinence, remains the major problem for the treatment of addiction. The process of drug addiction shares striking commonalities with neural plasticity associated with natural reward learning and memory and is caused primarily by drug-induced sensitization in the brain mesocorticolimbic systems that attribute incentive salience to reward-associated stimuli. The switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control. Current neurophysiologic evidence suggests that the development of addiction is to some extent due to neurochemical stimulation of the midbrain dopaminergic system that is traditionally considered as a 'common neural currency' for rewards of most kinds. Addictions are a result of the interplay of multiple genetic and environmental factors. They are characterized by phenotypic and genetic heterogeneity as well as polygenicity. Environmental factors are crucial in addiction vulnerability and resistese too. PMID- 21675221 TI - [Developmental continuity of working memory from infancy to preschool age]. AB - The objective of the paper was to study the developmental continuity of working memory function from infancy to preschool age. At the age of 10 to 11 months 44 participants completed delayed response task (A-not-B) that measures working memory function. Between 5 and 7 years of age the same participants performed three tasks assessing working memory for temporal order in auditory and visual modalities and a control task measuring short-term visuospatial memory. The dependence of temporal-order memory at preschool age on individual level of infant working memory was found for all methods of measurement despite the differences in way of presentation and reproducing of the stimuli order. Results indicate direct continuity in the development of working memory function from infancy to preschool age. PMID- 21675222 TI - [Effect of daytime nap on consolidation of declarative memory in humans]. AB - We studied effects of a daytime nap (1 hour) with including only NREM sleep on performance of declarative memory task (60 semantically unrelated word pairs) and general functional state. During training, procedure of learning of 30 word pairs was presented once, and that of the other 30 pairs was repeated twice. Strength of the task acquisition was tested. Subjects participated in two experiments: basic and control one. After learning participants either took a nap (basic experiment) or kept awake looking movies (control experiment). In 4.5 hours after the training session all the subjects were retested. As compared to the subjects who stayed awake during the training-retesting interval, subjects who had a NREM nap demonstrated enhanced performance. Concerning the strength of task acquisition, sleep-dependent performance was observed only for the word pairs learned once. Naps did not affect the functional state assessed by the reaction time dynamics and psychological testing. PMID- 21675223 TI - [Comparative analysis of ethanol effects on the spatial organization of biopotentials under conditions of open and closed eyes during different types of thinking]. AB - Effects of low doses of ethanol on indices of spatial organization of cortical potentials (spatial synchronization, coherence, spectral power and information power index) under the closed- and open-eyes conditions and during performance of divergent and convergent non-verbal and verbal tasks. Ethanol effect was shown to be more expressed under the open eyes-conditions as compared to that with the closed eyes. This finding may be associated with the greater effect of the stream of afferent information in the former case. Changes in topographical characteristics of the spatial synchronization of cortical potentials were more clearly localized and "specific" during divergent thinking as compared to the convergent type. Changes in the spectral power and information-power index testify to greater sensitivity to ethanol of divergent type of thinking as compared to convergent type. Psychological testing of stress resistance and impulsivity also showed a greater effect of ethanol on divergent thinking. PMID- 21675224 TI - [Spatial organization of biopotentials and decision-making time during purposeful mental activity in humans]. AB - Features of spatial organization of neocortical potentials were studied in subjects with different decision-making time during performing the task of memorizing and subsequently reproducing, on a monitor screen, a sequence of signals. The subjects with a short decision-making time differed from those with a long decision-making time in a higher level of the intra- and interhemispheric coherence in alpha EEG frequency band different neocortical areas during reproduction of a signal sequence (coherence in the frontal, central and parietal areas; coherence between the right central and the left frontal, central, parietal, occipital and temporal areas; coherence between the left occipital and both the frontal areas). PMID- 21675225 TI - [Interaction of amygdalar neurons of active and passive rabbits in negative emotional situations]. AB - Interaction of basal and central nuclear neurons of amygdala was studied by plotting histograms of crosscorrelation in passive and active rabbits exposed to emotionally significant stimuli. The behavior of animals was studied in the open field, light-dark test and during presentation of emotionally significant stimuli. Rabbits of different typological groups applied a certain behavioral strategy in a variety of behavioral tests. Intergroup differences were revealed in the interaction of neighboring cells of amygdala. Passive rabbits (as comparied to active rabbits) demonstrated more excitatory connections and less inhibitory connections with the latency from 50 to 150 ms. Interactions with the delta1-range and theta2-range frequencies in passive animals were more rarely observed. The asymmetry of the interhemispheric neuronal interaction in amygdala with the right dominance was revealed in passive but not active animals. The results testify that amygdala is involved in the choice of behavioral strategy, and the level of its activation is higher in passive animals. PMID- 21675226 TI - [Functional motor asymmetry in three species of mouse rodents from natural populations]. AB - Motor asymmetry of paws was studied in three species of mouse rodents (Apodemus agrarius, Clethrionomys glareolus, Clethrionomys rutilus) from natural populations. The prevalence of right-hand asymmetry was revealed in both males and females of all studied species. The spatial and temporal variability of asymmetry structures was shown. The increased number of left-handed rodents was observed in unfavorable habitats. A possible adaptive role of the functional motor asymmetry exemplified by small rodents is discussed. PMID- 21675227 TI - [The influence of ZnCl2 injected into the neostriatum on locomotor behavior of rats]. AB - The influence of two-week daily microinjections of ZnCl2 into the rostral region of neostriatum on the locomotor behavior of Wistar rats in chronic experiments was studied. The 1-mcg dose of ZnCl2 decreased spontaneous locomotor activity in the "open field" and, beginning with the 5th day of microinjections, inhibited a shuttle-box conditioned avoidance reflex. The reflex recovered only in the first week after the injection withdrawal. The 0.1-mcg dose of ZnCl2 to a lesser extent affected the parameters of conditioned avoidance, whereas the level of spontaneous locomotor activity in this group of animals increased. The observed changes in rat behavior may be associated with the concentration-dependent influence of zinc ions on the ion channels in the membranes of neostriatum neurons, including glutamate activated. The possibility to control the activity of ion channels in a chronic behavioral experiment by zinc ion concentration is discussed. PMID- 21675228 TI - [Changes in the electrical activity of the medial septal region, piriform cortex and amygdala during epileptogenesis in the model of temporal lobe epilepsy]. AB - Local field potentials (EEGs) in the medial septal area, amygdala and piriform cortex were recorded in waking guinea pigs in the control and during epileptogenesis in the model of chronic temporal lobe epilepsy (lithium pilocarpin model of status epilepticus). Analysis of changes in rhythmical activity and interstructural relations was carried out at different stages of epileptogenesis. Increased frequency of rhythmic activity in delta, theta, and alphabands was observed during epileptogenesis. Correlation relations between the activities of the medical septum with the piriform cortex and amygdala clearly decreased to 5 months after development of status epilepticus. Changes in the frequency of oscillations and structural correlations developed in time from two months on and reached a maximum 5 months after the status epilepticus development. It point to intensification of the pathological changes during formation of the epileptic focus. A possible role of the observed EEG changes in the formation of a pathological centre is discussed. PMID- 21675229 TI - [Does antiabsence drug ethosuximide exert antidepressant effect?]. AB - Antiabsence drug ethosuximide (300 mg/kg/day in drinking water for 17 days) produced an antidepressant effect (a decrease in immobility time in forced swimming test) only in WAG/Rij rats genetically predisposed to absence epilepsy only at age of 5 months when spike-wave discharges well pronounced. On rats without spike-wave discharges (21-day-old WAG/Rij and Wistar rats at the age of both at 21 day and 5 months), ethosuximide didn't produce the antidepressant effect but tended to increases the immobility time and significantly decreases the number of divings (active behavior oriented to escape from stressful situation). Ethosuximide didn't substantially change the anxiety level in WAG/Rij rats but significantly enhanced anxiety in 21-day-old Wistar rats. The results suggest that ethosuximide is not possessed of antidepressant potential unrelated to its suppressive effect on spike-wave discharges. PMID- 21675230 TI - [Participation of puncta adherentia junctions in the formation of synaptic connections between a dentate fascia graft and the host brain]. AB - The fetal dentate fascia of Wistar rats on the 20th day of gestation was heterotopically grafted into the somatosensory neocortex of adult rats. Granule cells of a graft projected their axons (mossy fibers) to the host brain and established synaptic contacts with inappropriate targets. The organization of ectopic mossy fiber synapses was studied by electron microscopy. It was shown that ectopic synapses reproduce the structural determinants of hippocampal giant synapses and induce a subcellular reorganization of postsynaptic neocortex dendrites. Using morphometric analysis, a significant increase was found in the number of discrete puncta adherentia junctions and their total length in ectopic synapses as compared with the control group. The data obtained indicate that puncta adherentia contacts participate in the structural and chemical adaptation of neuronal targets to alien axons growing from transplants. PMID- 21675231 TI - [Method for estimation of ERP topography instability degree and its application in the experimental task of target letter discrimination]. AB - A new method for estimation of human event-related potential (ERP) topography instability was developed. It was applied to the visual ERPs evoked in the experimental task of target letter discrimination. Periods of stable topography corresponding to the main ERP waves and those of unstable topography between them were revealed. Dependence of stability and instability characteristics on relevance of stimuli was disclosed: mean ERP magnitude (potential field power) of stable periods and duration of N1-P3a unstable interval were higher for target letters than for nontarget ones. Possible mechanisms of these effects are discussed. PMID- 21675232 TI - [Meiotic restitution in amphihaploids in the tribe Triticeae]. AB - In haploid and diploid organisms of the plant kingdom, meiotic division of diploid cells proceeds in two consecutive stages, with DNA replicating only once. In amphihaploids (interspecific or iontergeneric hybrids), where homologs are absent, the reduction of the chromosome number does not occur, meiosis is abnormal, and the plants are sterile. Gamete viability in F1 hybrids is ensured by a single division when chromosomes are separated into sister chromatids in either the first or the second division. Such gametes ensure partial fertility of amphihaploids, thereby facilitating their survival and stabilization of the polygenome. The frequency of the formation of viable gametes varies from a few cases to 98.8% in different anthers of the hybrids. Here, studies on the cytological mechanisms and genetic control of chromosome unreduction or restitution in different amphihaploids of the tribe Triticeae are reviewed. The current notions on the control of formation of restitution nuclei based on the principles of a prolonged metaphase I and different types of meiocytes. The main terms used for systematization of restitution mechanisms are first-division restitution (FDR), single-division meiosis (SDM), and unreductional meiotic cell division (UMCD). It has been assumed that archesporial cells of remote hybrids may have two cell division programs, the meiotic and the mitoyic ones. The possible approaches to the analysis of the genetic control of chromosome restitution in amphihaploids are discussed. PMID- 21675233 TI - [Chromatin and DNA damage repair]. AB - In eukaryotic cells, inheritance of both exact DNA sequence and its arrangement into the chromatin is critical for maintaining stability of the genome. Various DNA lesions induced by endogenous and exogenous factors make this maintenance problematic. To understand completely how cells resolve this problem the knowledge on the nature of these lesions, their detection, and repair within the chromatin environment should be integrated. Understanding of these processes is complicated by multiple types of DNA lesions and repair pathways, as well as the intricate organization of the chromatin. Recent advances in all these directions help to get insight on the repair regulation of DNA within the chromatin at the molecular and cellular level. PMID- 21675234 TI - [Duration of the cell cycle phases in mutants for the tumor suppressor Merlin in Drosophila melanogaster]. AB - The cell cycle duration was estimated in Drosophila melanogaster mutants for the tumor suppressor Merlin with the use of different approaches. Experiments on induction of mosaic clones in tissues of the larval wing imaginal disc showed that the cell cycle in mutant discs is shorter than that in control. Flow fluorescence cytometry revealed no differences between mutant and normal animals in the relative duration of the cell cycle phases, which suggests proportional shortening of the cell cycle phases. The study with pulse-labeled mitoses confirmed these results and showed that the length of the cell cycle is 7 h (S phase duration 3 h) in control individuals and 5 h (S phase duration 2 h) in Merlin gene mutants. PMID- 21675235 TI - [Analysis of blastomogenic activity of mammal carcinogens in Drosophila using the wts(P4) allele and RNA interference-induced p53 silencing]. AB - The test for somatic mutagenesis and recombination in Drosophila is one of the widely used approaches for determination of possible carcinogenic effects of chemical compounds. The use of heterozygotes for mutant tumor suppressor gene wts enables more direct evaluation of the blastomogenic effects of chemical compounds, by tumor formation in the adult flies. This study presents evaluation of the SMART effectiveness upon the use of Drosophila heterozygotes for the wts(P4) gene, first included into the test system. The increase of the test resolution capacity compared to the literature data for the wts(P2) allele was observed. Using wts(P4) heterozygotes, a total of 20 carcinogenic compounds, and their slightly carcinogenic and noncarcinogenic analogs were tested. Specificity of the method was about 100%, and sensitivity depended on the type of the agent tested. The latter was absolute for the direct action carcinogens, with respect to carcinogens, requiring the metabolic activation. The sensitivity was elective and was limited by the presence of the enzymes capable of activating of these compounds. To increase the test sensitivity, the RNA interference-mediated silencing of the Drosophila p53 functional activity was successfully applied. Moreover, the frequency of wts tumor induction considerably increased both in spontaneous and induced mutagenesis conditions. PMID- 21675236 TI - [Analysis of the chromocenter DNA composition in polytene chromosomes of Drosophila orena ovarian nurse cells]. AB - Chromocenter DNA fragments of polytene chromosomes of Drosophila orena ovarian nurse cells were cloned from a region-specific library (Dore 1) in a plasmid vector to yield 133 clones. A total of 76 clones were selected and sequenced. The total length of the sequenced fragments was 23940 bp. Analysis with several software packages revealed various repetitive sequences among the fragments of the Dore 1 library, including mobile genetic elements (25 fragments homologous to various LTR retrotransposons, five fragments homologous to LINEs, three fragments homologous to Helitrons, one fragment homologous to Polinton, and one fragment homologous to the mini-me non-LTR retrotransposon), four minisatellites, a satellite (SAR_DM), the (TATATG)n simple sequence repeat, and a low-complexity T rich repeat. Sequences homologous to protein-coding genes were also found in the Dore 1 library. Various repetitive DNA sequences and gene homologs were identified as conserved sequences of pericentric heterochromatin of polytene chromosomes of ovarian nurse cells in nine species of the melanogaster species subgroup. PMID- 21675237 TI - [Comparison of the adaptive potential for Rhizobium leguminosarum bv. viceae nodule bacterial populations isolated in natural ecosystems and agrocenoses]. AB - Polymorphism analysis was performed in Rhizobium leguminosarum bv. viceae populations isolated from geographically distant regions of Ukraine and Middle Asia. Examination of cultural, biochemical, and symbiotic traits revealed interpopulation differences, which were attributed to the difference in conditions between natural ecosystems and agrocenoses. Vetch has high species diversity and is not cultivated in Middle Asia, and the corresponding rhizobial population displayed higher genetic diversity and higher polymorphism of adaptive traits ensuring saprophytic development in soil and the rhizosphere, including melanin synthesis (35%) and active exopolysaccharide production (90%). Strains of the Ukrainian population had a lower exopolysaccharide production (10%), did not produce melanin, had higher herbicide resistance, and utilized glucose and succinate (main components of plant root exudation) as carbon sources. Strains capable of efficient symbiosis with Vicia villosa Roth. had a higher frequency in the Middle Asian than in the Ukrainian population, especially among strains isolated from soil (80 and 35%, respectively). In addition, strains of the Middle Asian population better competed for nodulation. It was assumed that the formation of rhizobial populations in vetch cultivation regions (Ukraine) is aimed at adaptation to ectosymbiotic (rhizospheric) interactions with plants and anthropogenic stress factors, while strains of the vetch original center (Middle Asia) are mostly adapted to the endosymbiotic interaction and to natural edaphic stress factors. PMID- 21675238 TI - [Comparative molecular cytogenetic characterization of partial wheat-wheatgrass hybrids]. AB - The chromosomal composition of the Zernokormovaya 169, Istra 1, Ostankinskaya, and Otrastayushchaya 38 cultivars of octoploid partial wheat-wheatgrass hybrids was studied using genomic in situ hybridization (GISH). Differentiation of wheatgrass chromosomes by the distribution of the GISH signal along the chromosome was revealed. The wheatgrass chromosomes of the hybrid cultivars studied in the work differed in the type of differentiation, centromeric index, and absolute size. The cytogenetic distinctions of these chromosomes revealed by us can be used in making crosses and in studying the transmission through gametes of additional wheatgrass chromosomes. PMID- 21675239 TI - [Two novel meiotic restitution mechanisms in haploid maize (Zea mays L.)]. AB - Two original mechanisms of nuclear restitution related to different processes of meiotic division of pollen mother cells (PMCs) have been found in male meiosis of the lines of maize haploids no. 2903 and no. 2904. The first mechanism, which is characteristic of haploid no. 2903, consists in spindle deformation (bend) in the conventional metaphase-anaphase I. This leads to asymmetric incomplete cytokinesis with daughter cell membranes in the form of incisions on the mother cell membrane. As a result, the chromosomes of the daughter nuclei are combined into a common spindle during the second meiotic division, and a dyad of haploid microspores is formed at the tetrad stage. The frequency of this abnormality is about 50%. The second restitution mechanism, which has been observed in PMCs of haploid no. 2904, results from disturbance of the fusion of membrane vesicles (plastosomes) at the moment of formation of daughter cell membranes and completion of cytokinesis in the first meiotic division. This type of cell division yields a binuclear monad. In the second meiotic division, the chromosomes of the daughter nuclei form a common spindle, and meiosis results in a dyad of haploid microspores. The frequency of this abnormality is as high as 15%. As a result, haploid lines no. 2903 and no. 2904 partly restore fertility. PMID- 21675240 TI - [Comparative analysis of genetic structure in natural populations of two Arabidopsis species with different degree of panmixia]. AB - Comparative analysis of genetic structure of northern natural populations of two Arabidopsis species with different degrees of panmixia was performed. The variability of 121 RAPD loci in seven populations of model plant A. thaliana possessing high degree of self fertility was studied together with 93 RAPD loci in population of cross-pollinating species A. lyrata ssp. petraea. The population of A. l. petraea demonstrated higher level of genetic variability (P 99% = 62.50%; H(exp) = 0.169) than the populations of A. Thaliana, which is obviously connected with biological features of reproduction of the species. A significant level of genetic variability (P 99% = 42.27%; H(exp) = 0.126) was revealed in populations of A. thaliana, which is not typical for self-pollinating plant species. The high population polymorphism of A. thaliana in the northern part of its range may be connected with adverse environmental conditions. The genetic distances between populations of the species studied (average DN = 0.494) confirm close relatedness between A. thaliana and A. l. petraea. PMID- 21675241 TI - [Development of commercially valuable traits in hexaploid triticale lines with Aegilops introgressions as dependent on the genome composition]. AB - Introgressive hybridization is an efficient means to improve the genetic diversity of cultivated cereals, including triticale. To identify the triticale lines with Aegilops introgressions, genotyping was carried out with ten lines obtained by crossing hexaploid triticale with genome-substitution forms of the common wheat cultivar Avrora: Avrolata (AABBUU), Avrodes (AABBSS), and Avrotika (AABBTT). The genome composition of the triticale lines was studied by in situ hybridization, and recombination events involving Aegilops and/or common wheat chromosomes were assumed for nine out of the ten lines. Translocations involving rye chromosomes were not observed. Substitutions for rye chromosomes were detected in two lines resulting from crosses with Avrolata. Genomic in situ hybridization (GISH) with Ae. umbellulata DNA and molecular genetic analysis showed that chromosome 1R was substituted with Ae. umbellulata chromosome 1U in one of the lines and that 2R(2U) substitution took place in the other line. Fluorescence in situ hybridization (FISH) with the Spelt 1 and pSc119.2 probes revealed a translocation from Ae. speltoides to the long arm of chromosome 1B in one of the two lines resulting from crosses with Avrodes and a translocation in the long arm of chromosome 7B in the other line. In addition, the pSc119.2 probe revealed chromosome 1B rearrangements in four lines resulting from crosses with Avrolata and in a line resulting from crosses with Avrotika. The lines were tested for main productivity parameters. A negative effect on all productivity parameters was demonstrated for Ae. umbellulata chromosome 2U. The overwinter survival in all of the lines was similar to or even higher than in the original triticale cultivars. A substantial increase in winter resistance as compared with the parental cultivar was observed for the line carrying the T7BS-7SL translocation. The line with the 1R(1U) chromosome substitution seemed promising for the baking properties of triticale. PMID- 21675242 TI - [Variability of a cytochrome b region in different chromosome races and populations of the common shrew Sorex araneus L., 1758]. AB - The nucleotide sequence (572 bp) of the cytochrome b gene of the common shrew Sorex araneus was analyzed. In total, 92 animals of five chromosome races from 12 localities were studied. The median haplotype network has a pronounced star-like structure. The central haplotype common for all samples, except for the southern island sample of the race Sok, accounts for about 36%. The main characteristics of molecular variation in our work correspond to those obtained in other studies. We revealed the lack of a correlation between the genetic and geographic distances and also population structurization of the species. On the basis of variation of the haplotypes in the samples, a scenario of colonization of the postglacial territories by females of one or several close matrilines with subsequent rapid subdivision of the population into independent populations is discussed. PMID- 21675243 TI - Assessment of genomic imprinting of PPP1R9A, NAP1L5 and PEG3 in pigs. AB - Imprinted genes play significant roles in the regulation of fetal growth and development, function of the placenta, and maternal nurturing behaviour in mammals. At present, few imprinted genes have been reported in pigs compared to human and mouse. In order to increase understanding of imprinted genes in swine, a polymorphism-based approach was used to assess the imprinting status of three porcine genes in 12 tissue types, obtained from F1 pigs of reciprocal crosses between Rongchang and Landrace pure breeds. In contrast to human and mouse homologues, porcine PPP1R9A was not imprinted, and was found to be expressed in all tissues examined. The expression of porcine NAP1L5 was detected in pituitary, liver, spleen, lung, kidney, stomach, small intestine, skeletal muscle, fat, ovary, and uterus, but undetectable in heart. Furthermore, porcine NAP1L5 was paternally expressed in the tissues where it's expression was observed. For PEG3, pigs expressed the paternal allele in skeletal muscle, liver, spleen, kidney, and uterus, but biallele in heart, lung, fat, stomach, small intestine, and ovary. Our data indicate that tissue distribution of the three gene differs among mammals, and the imprinting of NAP1L5 and PEG3 is well conserved. PMID- 21675244 TI - [Transthyretin gene V30M, H90N, and del9 mutations in cardiomyopathy patients from St. Petersburg]. AB - A search of transthyretin (TTP) gene mutations was conducted in patients with cardiomyopathies from St. Petersburg. Mutations H90N, V30M, G47A, and deletion (del9) of nucleotides GACTTCTCC in position 6776 from the start codon of the TTP gene (in position 98782 according to reference sequence AC079096 (NCBI) was found. The H90N mutation in the third exon of TTP gene was detected in a son of a cardiomyopathy patient and in his mother, which lacked any clinical manifestations. Mutations V30M and G47A in exon 2 of TTP gene were found in heterozygous and homozygous state, respectively, in one of the probands. Deletion (del9) was revealed in a patient with cardiomyopathy and in his two daughters from different marriages, who had no clinical manifestations of the disease. All the mutations revealed in this study were previously identified in other populations. PMID- 21675245 TI - [An allelism test for quantitative trait genes]. AB - Analytical modeling has been used to test assumptions on the mode of inheritance of a quantitative trait in the course of diallel crossing between pure strains that are sufficient for adequacy of a simple regression model. This model frequently proved to be adequate in analysis of numerous data on diallel crossings of wheat and maize. An allelism test for quantitative trait genes has been suggested. Computer simulation has been used to estimate the effect of random experimental errors and deviations from the suggested model. PMID- 21675246 TI - [Inhibition of DD2R gene expression in the corpus allatum activates alkaline phosphatase in female Drosophila melanogaster]. AB - Tissue-specific inhibition of the expression of the D2-like dopamine receptor gene (DD2R) in the corpus allatum (CA), which is a gland that synthesizes the juvenile hormone (JH), was tested for effect on alkaline phosphatase (AP) activity and the intensity of the AP response to heat stress (stress reactivity) in female Drosophila melanogaster. AP activity and AP stress reactivity in transgenic females with lower DD2R expression in the CA were higher than in control flies. A pharmacological elevation in JH increased AP activity in females of the control strains. DD2R was assumed to mediate the inhibitory effect of dopamine of JH synthesis in the CA of D. melanogaster. PMID- 21675247 TI - [AFLP marking of the genotypes of leek (Allium porrum) varieties]. AB - The results of the AFLP analysis of 16 leek (Allium porrum) accessions and related species of the sections of the genus Allium are presented. Restriction enzymes and primer combinations for the identification of the genotypes of the A. porrum accessions were chosen. As a result, 265 polymorphic AFLP fragments were amplified for 25 analyzed genotypes, and specific spectra of DNA fragments were obtained for each accession. A total of 24 fragments specific for the A. porrum genome was detected, of which only two characterized the genotypes of individual accessions. A wide range of genetic diversity (0.11-0.32) was revealed for the A. porrum varieties and lines used in the analysis. The highest level of similarity in the analyzed set of accessions was found between A. porrum and sand leek (A. scorodoprasum). PMID- 21675248 TI - Novel polymorphic microsatellite DNA markers from Malaysian giant freshwater prawn, Macrobrachium rosenbergii. AB - Seven single locus microsatellite markers were characterized in Malaysian giant freshwater prawn, Macrobrachium rosenbergii from an enriched genomic library Primer pairs were designed to flank the repeat sequences and the loci characterized for this species. The bands resulting from the PCR amplifications of these eight microsatellite loci were polymorphic with the number of alleles ranging from 8 to 26 alleles per locus, whereas the observed heterozygosity ranged from 0.0641 to 0.6564. These newly developed microsatellite markers should prove to be useful for population studies and in the management of genetic variations in broodstocks of freshwater prawn, M. rosenbergii. PMID- 21675249 TI - [Polymorphic variants of ALOX5AP gene and the risk of acute stroke development in the Russian population]. AB - A protein capable of activating 5-lipoxygenase (ALOX5AP) is considered a presumable risk factor of acute stroke development. Polymorphic variants of the ALOX5AP gene were examined. Two ALOX5AP gene polymorphisms (SG13S114 (rs10507391) and SG13S32 (rs9551963)), which previously had shown association with the risk of ischemic stroke in other populations, were studied. These single nucleotide polymorphisms were analyzed using a sample of acute stroke patients (N = 1320) and a control sample (N = 467). No statistically significant associations were found between acute stroke and the ALOX5AP gene polymorphisms examined. PMID- 21675250 TI - [The 20th anniversary of the Russian Respiratory Society]. PMID- 21675251 TI - [Leptin and activity of tumor necrosis factor alpha relations with parameters of the trophologic status and digestion in patients with chronic obstructive pulmonary disease]. AB - AIM: To study effects of leptin regulation of energy and activity of TNF-alpha on the trophologic status and digestion of main nutrients in patients with stable chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: Somatometric methods were used to examine trophologic status in 93 patients with stable COPD. Of them, 22 had stage I, 36 - stage II, 35 patients - stage III. Serum leptin was measured with enzyme immunoassay (EIA) using DSL kit (USA), TNF-alpha and receptors sTNF-R55 and -R75 with EIA (kits BioSource, Belgium). The absorption was assessed biochemically and with radionuclide investigation. Body fat was estimated by bioelectric impedance (OmRon BF-302, Japan). RESULTS: The level of circulating leptin decreased with progression of COPD and correlated with body fat depletion (r = 0.88 +/- 0.12). Activation of the TNF-alpha system was detected in the presence and progression of trophologic insufficiency (TI) in patients with COPD stage II and III. A correlation was found between an elevated level of circulating TNF-alpha and enhanced fat and 131-I-albumin excretion, subnormal excretion of D-xylose. CONCLUSION: Low blood serum leptin concentration in patients with moderate and severe stable COPD correlates with fat tissue depletion reflecting reduced energetic potential of adipocytes. High TNF-alpha concentration in the serum was seen only in TI and its progression. This evidences for cytokine involvement in induction of metabolic disorders in COPD patients. Elevated concentration of circulating TNF-alpha closely correlated with excretion of higher quantities of fats, protein, low excretion of D-xylose and proves its involvement in TI development in COPD patients. Activation of TNF alpha system in COPD does not influence leptin concentration in blood serum as it functions as an independent physiological system. PMID- 21675252 TI - [Epidemiological characteristics of chronic obstructive pulmonary disease in the Middle Volga Region]. AB - AIM: To study epidemiology and risk of chronic obstructive pulmonary disease (COPD) in environmental and climatic conditions of a large industrial center of the Middle Volga Region (the city of Samara). MATERIAL AND METHODS: The questionnaire survey was made in 2063 participants (903 males and 1160 females, the response rate 73.68%) divided into four age groups: 30-39, 40-49, 50-59, 60 years and older. The epidemiological study employed the standard questionnaire based of European coal and Steel Association questionnaire (1993). All the patients with identified respiratory problems were examined clinically and functionally to verify COPD diagnosis. RESULTS: High COPD rate was detected in Samara--14.49% of 2063 males and females examined (18.72% in males and 11.21% in females, p < 0.001). Leading COPD risk factors include old age, male gender, tobacco smoking, prior respiratory infections, chronic diseases of the upper respiratory tract, polluted environment, unmarried status, low education, alcoholism. CONCLUSION: Prevalence of COPD in population of Samara is close to that in other large industrial centers of Russia but lower than in larger cities of Europe and in populations of industrial workers. It depends on the age and has special characteristics in males and females. PMID- 21675253 TI - [Bronchial obstruction in patients with rheumatoid arthritis]. AB - AIM: To estimate the incidence of bronchial obstruction (BO) in patients with rheumatoid arthritis (RA) and BO comorbidity with respiratory symptoms and structural alterations of the lower respiratory tract (LRT) by findings of multislice computer tomography (MCT) of the lungs. MATERIAL AND METHODS: Clinical examination, spirometry, body plethysmography, MCT of the lungs were made in 104 non-smokers with RA and 100 patients free of RA and chronic respiratory diseases. RESULTS: Incompletely reversible generalized BO was diagnosed in 19 (18%), distal bronchial obstruction in 27 (26%) patients. Bronchial permeability weakly correlated with severity of respiratory symptoms. BO was associated in RA patients with structural changes in LRT as shown by MCT of the lungs: thicker wall and irregular lumen of the visual bronchi, the presence of bronchoectases and signs of bronchiolith. Structural changes of LRT were detected by MCT of the lungs in 57 (55%) RA patients. CONCLUSION: RA patients often develop incompletely reversible BO with microsymptoms probably due to diffuse deforming lesion of the LRT. BO in RA progresses because of LRT rheumatoid lesion extention to bronchioles. RA patients' external respiratory function should be regularly examined with conduction of MCT in detection of ventilatory disorders. PMID- 21675254 TI - [Quality of life in patients with moderate and severe bronchial asthma]. AB - AIM: To study quality of life (QoL) in patients with bronchial asthma (BA). MATERIAL AND METHODS: QoL in bronchial asthma patients (49 males and 57 females with moderate asthma, 40 males and 50 females with severe asthma) was evaluated with application of the Saint George Hospital Respiratory Questionnaire, clinical and functional tests. RESULTS: It was found that males with BA less emotionally response to stress due to the disease and estimate their QoL as lower compared with BA females. CONCLUSION: Some indicators of QoL in bronchial asthma are determined, differencies in QoL estimation by males and females and in different asthma severity are observed. PMID- 21675255 TI - [Clinico-scintigraphic characteristics and oxidation in community-acquired pneumonia: correlations with the size of pulmonary tissue infiltrative lesion]. AB - AIM: To investigate clinicoscintigraphic characteristics and oxidation in blood erythrocyte and plasma in debut of community-acquired pneumonia (CAP) with different size of inflammatory infiltrate. MATERIAL AND METHODS: A total of 200 patients with non-severe CAP were examined. Additional 35 CAP patients (20 patients with segmentary and 15 patients with polysegmentary infiltrative pulmonary lesion) and 10 healthy volunteers have undergone ventilation-perfusion pulmoscintigraphy and biochemical investigation of oxidation in blood plasma and erythrocytes. RESULTS: In CAP onset more distinct clinical manifestations were characteristic for patients with polysegmentary pulmonary infiltrate. The degree of activation of lipid peroxidation did not depend on the size of the inflammation focus. In CAP, irrespective of the size of pulmonary infiltrate, there is a similar bilateral rise of alveolar-capillary permeability for radioactive aerosol. CONCLUSION: In CAP clinical signs of systemic inflammation differ depending on the spread of infiltrative process in the lungs. Analysis of oxidation in erythrocytes and plasma shows that in formation of acute inflammation most essential is involvement of at least one segment of the lungs in the pathological process. At the level of molecules and cells, including target organ, oxidative metabolism undergoes dysregulation involving the whole body and similar to that in inflammation of several pulmonary segments. Irrespective of the size of infiltrative lesion, radioaerosol permeability rises similarly in both the lungs evidencing systemic affection of the structures of alveolar-capillary membrane of the lungs. PMID- 21675256 TI - [Specific features of endogenic autorosette formation in peripheral blood of patients with pneumonia]. AB - AIM: To estimate intensity of endogenic autorosette formation in peripheral blood of pneumonia patients and convalescents. MATERIAL AND METHODS: The study included 100 patients treated for pneumonia (75 males, 45 females, mean age 48.0 +/- 1.0 years) and 40 healthy controls (20 males, 20 females, mean age 47.5 +/- 1.1 years). Capillary blood smears stained by Romanovsky-Gimse from all the patients and controls were examined for rosettes (total number of autorosettes, number of autorosettes with exocytic erythrocyte lysis) at admission to hospital, at discharge from hospital and 2-3 weeks after the discharge. RESULTS: The controls had a few autorosettes in the peripheral blood. At admission to hospital pneumonia patients had a much higher level of autorosettes and those with the lysis. At discharge from hospital the number of autorosettes in the patients reduced 1.5 fold, on week 2-3 after the discharge--2.3 fold but remained high. This reflects a slow attenuation of the inflammation or effects of medication. An increase in the number of autorosettes and autorosettes with lysis is accompanied with a decrease in erythrocyte count and hemoglobin content in the blood. CONCLUSION: Time course changes in endogenic autorosette formation in peripheral blood can serve an additional marker of pneumonia treatment and rehabilitation efficacy. PMID- 21675257 TI - [Efficacy of immunovenin in patients with community-acquired pneumonia]. AB - AIM: To study efficacy of human immunoglobulin for intravenous administration (immunovenin) in the treatment of patients with community-acquired pneumonia (CAP). MATERIAL AND METHODS: Two groups of CAP patients participated in the trial. Group 1 (n = 35) received standard therapy. Group 2 (n = 33) received standard therapy plus immunovenin. RESULTS: CAP patients had immune disorders. Combined treatment of CAP with administration of immunovenin relieved clinical symptoms of the disease, improved immunological status. Group 1 patients demonstrated symptoms of the disease and defects in immunity for a long time. CONCLUSION: Addition of immunovenin to standard therapy of CAP improves immunological parameters, efficacy of CAP treatment. PMID- 21675258 TI - [Experience in perfection of outpatient pulmonological service]. AB - AIM: To obtain objective information on the quality of pulmonological outpatient care for patients living in the North Administrative District (NAD) of Moscow; to propose methods of this care improvement. MATERIAL AND METHODS: An epidemiological study of Moscow NAD population was made to detect respiratory diseases, to assess qualification of district physicians in management of most prevalent chronic diseases of the respiratory system: bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD). RESULTS: The epidemiological study has revealed standard errors of district physicians in management of BA and COPD patients. Effective measures on reduction of the typical mistakes are proposed. CONCLUSION: More active detection of respiratory diseases in Moscow population is recommended. PMID- 21675259 TI - [Genetic polymorphisms coding hemostasis protein synthesis and venous thromboembolic complications in Moscow population]. AB - AIM: To estimate incidence of carriage of genetic polymorphisms coding hemostasis protein synthesis in patients with venous thromboembolic complications (VTEC) and healthy subjects in Moscow population; to detect VTEC genetic prognostic factors among the polymorphisms. MATERIAL AND METHODS: A total of 111 patients with the history of deep vein thrombosis and/or pulmonary artery thromboembolism were examined. The control groups consisted of 197 healthy volunteers. Eleven polymorphisms in 7 genes coding hemostasis protein synthesis were investigated: V Leiden G1691A factor, G20210A prothrombin, C677T methylentetrahydrofolatreductase, A1298C methylentetrahydrofolatreductase, type 1 plasminogen activator inhibitor, 4G/5G promoter region, XIII V34L coagulation factor, IIIa L33P thrombocytic glycoprotein, C282Y hemochromatosis, G854A beta fibrinogen, G455A beta-fibrinogen, C249T beta-fibrinogen. RESULTS: Polymorphisms of the genes coding hemostasis protein synthesis were detected in all the patients and controls. The carriage occurred with the same frequency, respectively. By one-factor analysis, VTEC was associated with carriage of three heterozygous genotypes: V Leiden factor (p < 0.001), prothrombin (p = 0.052) and hemochromatosis (p = 0.048). Multifactor regression analysis has shown that only carriage of heterozygous polymorphism of V Leiden factor gene is a genetic prognostic factor of VTEC in Moscow population (p = 0.001, RR = 7.00, 95% CI 22 21.7). CONCLUSION: Genetic polymorphisms coding hemostasis protein synthesis are not a rare finding in Moscow population and occur in all the examinees (both patients and healthy subjects) in different combinations. Only carriage of V Leiden factor heterozygous genotype is a genetic prognostic factor of VTEC in Moscow population and is associated with a 7-fold increase of VTEC risk. PMID- 21675260 TI - [A case of myocardial infarction of anatomically right but functionally left ventricle in a middle-aged male patient with isolated corrected transposition of the major vessels]. AB - The article is devoted to a rare congenital heart disease--corrected transposition of the major vessels. A hemodynamic scheme of the disease, its probable prognosis, possible development of arrhythmia, impairment of conduction and cardiac failure are described. A case is reported of myocardial infarction of anatomically right arterial ventricle in a middle-aged patient with isolated corrected transposition of the major vessels to illustrate a possible variant of the disease course. PMID- 21675261 TI - [Development of acute myeloid leukemia from donor cells after allogeneic peripheral blood stem cell transplantation in a female patient with acute monoblastic leukemia]. AB - Development of leukemia from donor cells is a rare complication of allogeneic blood stem cells (BSC). The paper describes a case of evolving acute myeloid leukemia of a graft in a patient with resistant acute monoblastic leukemia after related allogeneic peripheral BSC transplantation. The rarity of this complication, difficulties in providing evidence for the donor origin of a leukemic clone demonstrate a need for all-round careful dynamic assessment of the hematopoietic system after allogeneic transplantation, by applying the current cytogenetic (fluorescence in situ hybridization) and molecular (hypervariable genomic region amplification test using the polymerase chain reaction, hypervariable number of tandem repeats (VNTR), and short number of tandem repeats (STR)) techniques, which permits errors to be avoided in the assessment of a clinical situation and in the diagnosis of leukemia from donor cells. There is no developed policy for treatment of acute graft-versus-leukemia. PMID- 21675262 TI - [Obstructive sleep apnea in therapeutic practice]. AB - Obstructive respiratory sleep disorders are usually covered by the term obstructive sleep apnea/hypopnea syndrome (OSAHS). Prevalence of OSAHS in general population reaches 14%. In population of Europe and North America OSAHS occurs in each seventh and may run with such complications as day drowse, hypodynamia, obesity, hypertension, coronary heart disease, arrhythmia. The article proposes algorithms of diagnosis and step-by-step correction of OSAHS (patent N 2197893, 23.05.2000) the efficacy of which has been proved for the last 10 years in 2586 patients. PMID- 21675263 TI - [Determination of clinical phenotypes of chronic obstructive pulmonary disease--a new treatment approach]. AB - Chronic obstructive pulmonary disease (COPD) is a syndrome including a group of obstructive diseases showing both similar features and marked differences. At present, clinicians try to describe various COPD phenotypes reflecting different characteristics of the patients which can be useful in respect of COPD course, prognosis and effective treatment. The article is devoted to approaches to COPD phenotypes definition, gives descriptions of some possible phenotypes and analyses clinical trials of modern COPD treatment modalities in different phenotypes. PMID- 21675264 TI - [The role of free radical oxidation and endothelial dysfunction in the onset and progression of chronic obstructive pulmonary disease]. AB - Risk factors and basic mechanisms of chronic obstructive pulmonary disease are reviewed. An original definition of this pathology is presented taking into consideration leading pathogenetic processes in the bronchi, pulmonary parenchyma, pulmonary vessels, functional disorders and clinical syndromes. PMID- 21675265 TI - [Microcirculatory disorders in hypertension, atherosclerosis, diabetes mellitus]. AB - Fundamental investigations of the role of the endothelium and cell periphery in regulation of vascular tonicity in the last decade of the XX century brought a radical revision of the former conception of circulation. It was discovered that distribution of blood in the arteries depends on operational requirements of the tissues and organs, it is not determined by integrating mechanisms of neuroendocrine regulation. Problems of hemodynamics and microcirculation give rise to much discussion now because neurogenic hypophysis of cardiovascular disease development still has many supporters among medical profession. Progressive disturbances of circulation and hemodynamics may be produced by diseases known as nosological entities for many years. Arterial hypertension often plays a leading role in common polymorbid combinations. It is important to include in basic treatment additional modalities taking consideration of existing at the moment leading risk factors. This involves an individual approach to choice of therapy. PMID- 21675266 TI - [Multiple myeloma: innovations in diagnosis]. AB - Multiple myeloma (MM) belongs to the group of paraproteinemic hemoblastosis. Its clinical picture varies but the main clinical presentation is bone tumor proliferation resultant from enhanced resorption of tumor tissue related to bone marrow infiltration with plasmic cells, activation of osteoclasts. This leads to marked ossalgic syndrome and pathological bone fragility. MM often runs with nephropathy, immunodepression, hemopoietic disorders. Non-specific clinical manifestations of MM cause difficulties in making accurate diagnosis. Our clinic introduces innovative high-tech methods of examination including MR tomography of the body which detects the disease at early stages and, finally, allows us to prolong the patient's life. PMID- 21675267 TI - [Primary lymphoma of the heart: difficulties in diagnosis and treatment]. AB - Primary lymphoma of the heart (non-Hodgkin's lymphoma primarily of B-cells affecting first the heart and pericardium) is a rare disease which accounts for 1.3-2.0% of all primary tumors of the heart. A case is reported of a 43-year-old male patient with a cardioverter-defibrillator implanted at the age of 38 years for management of ventricular tachycardia paroxysms and AB-block of the second third degree. The patient also had hypertrophic cardiomyopathy, moderate pressure gradient on the pulmonary artery valve and pericardial effusion. Later he had two cardiac tamponades (serous punctuate). From the age of 42 years breathlessness, right ventricular wall thickness, right heart pressure and pulmonary artery pressure aggravated. The patient has undergone ballon plastic surgery of the pulmonary artery valve. At the age of 43 computed tomography detected massive tumor of the heart and mediastinum first diagnosed as sarcoma but later specified as lymphoma. Endobronchial biopsy specimens contained the tissue of diffuse large B-cell lymphoma, the liver and lymph nodes were also involved. After the first course of effective polychemotherapy (CHOP) the patient died of mesenterial thrombosis. Diagnostic difficulties and problems of treatment policy are discussed. PMID- 21675268 TI - [Chronodiagnostic potentialities of the symbolic dynamics method]. AB - AIM: To assess diagnostic potential of cardiac rhythm symbolic dynamics. MATERIAL AND METHODS: PhysyoNet base data on ECG heart rhythm for 24 hours were analysed by characteristics of the symbolic lines: size of vocabularies and entropic properties of symbol distribution in the lines. The following ECGs were analysed: 54 ECGs of healthy individuals with normal sinus rhythm aged 28.5-76 years; 44 ECGs of patients with congestive cardiac failure aged 34-79 years; 84 ECGs of patients with cardiac fibrillation aged 34-79 years; 19 ECGs of patients with sudden cardiac death syndrome aged 34-79 years. RESULTS: The index of variety of cardiac rhythm regulation is proposed which is effective not only for analysis of 24-h but also of 40-60 min rhythmograms. CONCLUSION: The quantitative analysis of symbolic dynamics can be used for differential chronodiagnosis of different cardiac diseases. Application of words which vary by length allows examination of rhythms with different time scale, detection and comparison of hierarchical desynchronization. PMID- 21675269 TI - [Novel endoscopic terminology: NBI visualization]. AB - AIM: To develop new criteria of gastric and duodenal mucosa image assessment using endoscopic system for narrow band imaging (NBI). MATERIAL AND METHODS: Endoscopic and morphological findings were compared in 460 patients with different chronic diseases of the stomach and duodenum. Esophagogastroduodenoscopy was made according to the standard technique by the gastroduodenoscope EVIS EXERA-II GIF H180 (Olympus, Japan) with NBI-system. Biopsy material was studied by standard pathomorphological techniques. RESULTS: The novel system of the visual picture evaluation during conduction of endoscopic investigations in monochromatic light provides higher significance of identification of inflammatory and destructive processes in mucosa including foci of structural alterations, their location and extent. CONCLUSION: We propose a protocol for description of the endoscopic picture in conduction of examinations with application of the NBI-system of visualization in monochromatic light. It can help physicians to correctly estimate the image and interpret the detected changes. PMID- 21675270 TI - [Clinical significance of intravital morphological investigation of the liver]. AB - AIM: To demonstrate great importance of intravital morphological examination of the liver for differential diagnosis of chronic diffuse diseases (CDD) of the liver. MATERIAL AND METHODS: A complete clinical examination, needle or intraoperative biopsy of the liver were made in 1045 patients with chronic diseases of the liver. Structural features of hepatic tissue were studied histologically. Variational statistics was used for analysis. RESULTS: Viral markers were detected in 373 patients (HCV in 53%, TTV in 10%, HBV in 16%, HGV in 6%, CMV in 3%). Chronic hepatitis (CH) was caused by combined viral infection in 12% cases. CH variants were verified morphologically in 64% patients with provisional diagnosis CH. Objective evaluation of structural changes severity rested on algorithms of semiquantitative determination of the index of histological activity and fibrosis index. Hepatic cirrhosis of viral or alcohol etiology was detected in 4.8%, primary biliary cirrhosis--in 11.2%, non-alcoholic fatty disease of the liver--in 11.2% patients. Impaired glucose tolerance is an essential factor predisposing to non-alcohol fatty disease of the liver. Detection of vacuole-like nuclei in periportal hepatocytes is an early morphological sign of the fatty disease. Three percent of the patients had signs of minimal portal cholangitis. This correlated with TTV detection. CONCLUSION: Life-time morphological examination of the liver specifies activity and stage of the process in chronic hepatitis, confirms or detects abnormalities in hepatic architectonics, identifies clinically significant changes in cellular and intercellular components of hepatic tissue, detects and verifies rare hepatic affection. Such information is of importance for optimization of treatment policy and improvement of prognosis in CDD of the liver. PMID- 21675271 TI - [Results of 24-h pH monitoring in patients with gastroesophageal reflux disease before and after fundoplication]. AB - AIM: To study informative value of 24-h pH monitoring in registration of gastroesophageal and duodenogastroesophageal reflux (GER, DGER) in patients with gastroesophageal reflux disease (GERD) before and after surgical treatment. MATERIAL AND METHODS: A total of 39 GERD patients after laparoscopic fundoplication entered the study: 12 (39%) males and 27 (61%) females, mean age 47.6 +/- 3.2 years. pH monitoring was made with domestic device Gastroscan-24 before operation and one year after it. Esophagogastroscopy and polypositional roentgenoscopy of the upper gastroduodenal tract were made also before operation and after 1-year follow-up. RESULTS: Before operation, mean pH in the gastric body was 1.7 +/- 1.28, De Meester index 40.4 +/- 8.91, esophageal acidity index (EAI) 22.3 +/- 1.59, the number of acid GER 59.2 +/- 9.41, number of DGER 14.3 +/ 3.47. After laparoscopic fundoplication--3.3 +/- 1.52, 8.7 +/- 5.71 (p < 0.05), 2.5 +/- 0.62 (p < 0.05), 24.4 +/- 8.6 (p < 0.05), 6.5 +/- 3.63, respectively. Five patients (12.8%) examined before the operation had clinicoendoscopic picture of GERD, but normal values of De Meester index and EAI. CONCLUSION: 24-h pH monitoring can estimate both gastroesophageal and duodenoesophagogastric refluxes, but esophageal and gastric pH monitoring only are not sufficient for decision on treatment policy. Such decision should be taken individually for each patient after the analysis of the results of complete clinical examination, symptoms and the disease history. PMID- 21675272 TI - [Changes in orthogonal ECG in hypertensive patients taking different antihypertensive therapy]. AB - AIM: To ascertain changes in orthogonal ECG in hypertensive patients taking different antihypertensive treatment. MATERIAL AND METHODS: Orthogonal ECG parameters and those of 24-h blood pressure monitoring (BPM) were examined before and after antihypertensive treatment with different drugs in 95 hypertensive patients aged 47 +/- 1 years. Of them, 14 patients received trandolapril+verapamil SR for 2 months, 13 patients--candesartan for 3 months, 25 patients--ramipril for 5 months, 26 patients--carvedilol for 4 months, 10 patients--atenolol for 8 months, 7 patients--doxasozine for 5 months. RESULTS: 24 h BPM parameters improved in all the groups. Initially, conventional ECG evidence on left ventricular hypertrophy was not seen in 86% patients. Dynamics of orthogonal ECG showed that parameters which increase in left ventricular hypertrophy decrease in response to treatment in patients with baseline values above the median. Parameters G and Gx, which in left ventricular hypertrophy diminish, rise significantly in patients with baseline values under median due to therapy. Treatment with impact on renin-angiotensin system reduced voltage parameters of orthogonal ECG, improved G characterizing repolarisation. Treatment with adrenoreceptors blockers reduced IADI. CONCLUSION: The analysis of parameters of orthogonal ECG reveals positive dynamics in response to treatment in patients with insignificant changes on ECG in short follow-up. Drugs of different groups change different parameters of orthogonal ECG. PMID- 21675273 TI - [Echocardiographic assessment of left ventricular myocardial deformation by automatic functional image in patients with sigmoid interventricular septum]. AB - AIM: To assess a new method of automatic functional image for estimation of maximal systolic longitudinal strain of left ventricular (L) myocardium in patients with sigmoid interventricular septum (IVS) with normal LV ejection fraction. MATERIAL AND METHODS: Maximal systolic longitudinal strain was compared in patients with sigmoid IVS (SIVS) and in 21 patients of the control group. RESULTS: Compared to controls, patients with SIVS have significantly greater global longitudinal systolic LV strain in two septal segments in the region of sigmoid-shape IVS. CONCLUSION: Local aggravation of maximal systolic longitudinal LV myocardium strain in SIVS zone can be one of the causes of dynamic obstruction of the efferent LV tract. PMID- 21675274 TI - [Outpatient prophylaxis and treatment of arterial hypertension with application of mobile telephone systems and Internet techniques]. AB - AIM: To compare clinical efficacy of standard outpatient follow-up of hypertensive patients with efficacy of such follow-up with application of internet techniques and mobile telephone systems (ITMTS). MATERIAL AND METHODS: Two groups of hypertensive patients were examined: group 1 (n=97, 45% females, age 49 +/- 11 years) on one-year ITMTS follow-up; group 2 (n=102, 50% females, age 51 +/- 11 years) on standard one-year follow-up. Clinical efficacy was assessed by the rate of achievement and maintenance of target blood pressure, dynamics of modifiable risk factors (smoking, obesity) for a year. RESULTS: Withdrawal in group 1 was 36%, target blood pressure was achieved in 77% patients vs. 12% in group 2 (p < 0.001). CONCLUSION: Introduction of ITMTS technologies into outpatient clinics activity considerably raises efficacy of outpatient treatment of hypertensive patients. PMID- 21675275 TI - [Efficacy and safety of the first made in Russia alphabeta long-acting adrenoblocker proxodolol in patients with arterial hypertension of the second degree]. AB - AIM: To study efficacy and safety of a new dose and dosage form of proxodolol--a beta-adrenoblocker with alpha1-adrenoblocking activity--in patients with moderate arterial hypertension (AH). MATERIAL AND METHODS: A total of 60 patients with verified diagnosis of essential AH of the second degree were randomized into two groups: group 1 (n=40) received proxodolol, group 2 (n=20) was given carvedilol. The trial lasted for 89 days. RESULTS: The trial demonstrates that proxodolol is highly effective and safe in the treatment of AH. CONCLUSION: Proxodolol is effective and safe in hypertension, in a dose 120 mg its activity is the same as carvedilol in a dose 25 mg. PMID- 21675276 TI - [A protective effect of GLY272SER polymorphism of GNB3 gene in development of essential hypertension and its relations with environmental hypertension risk factors]. AB - AIM: To study associations of C825T (rs5443) and G272S (rs16932941) polymorphisms of GNB3 gene in Russian population of the Central Chernozem region with essential hypertension (EH) risk; to elicit the role of environmental risk factors in realization of EH predisposition in this gene genotypes carriers. MATERIAL AND METHODS: We studied DNA samples obtained from 205 EH patients and 207 healthy individuals. EH patients were treated in Kursk hospitals. Genotyping of GNB3 gene polymorphisms was conducted by polymerase chain reaction and restriction analysis. RESULTS: Prevalence of 82ST allele of GNB3 gene in EH patients and healthy individual was 0.334 and 0.295, respectively, of 272S allele--0.037 and 0.058, respectively. We found no significant differences by prevalence of genotypes of gene GNB3 polymorphisms C825T and G272S in EH patients and healthy individuals. Non-smoking carriers of 272GS genotype had a low risk of EH (OR 0.42 in 95% CI from 0.18 to 0.97; p = 0.04). Smokers had no protective effect of this genotype. The protective effect of 272GS genotype was also found in individuals with low or moderate alcohol drinking habits (OR 0.29 in 95% CI from 0.11 to 0.77, p = 0.02) and in individuals without chronic exposure to stress (OR 0.29 in 95% CI from 0.09 to 0.91, p = 0.04). In contrast, hard drinkers and patients exposed to chronic stress had no protective effect of heterozygous genotype 272GS of gene GNB3. CONCLUSION: G272S polymorphism of GNB3 gene can be considered as a new genetic marker of predisposition to EH. The protective effect depends of environmental factors associated with high risk to develop EH. PMID- 21675277 TI - [Clinical statistics and effectiveness of different treatments of idiopathic thrombocytopenic purpura]. AB - AIM: To ascertain efficacy of modern treatment methods in idiopathic thrombocytopenic purpura (ITP), to characterize basic indications for administration of these methods; perspective trends in ITP therapy. MATERIAL AND METHODS: The article presents 20-year experience in observation and treatment of 1000 ITP patients gained from 1988 by the department of standardization of blood disease treatment methods on the basis of a consultative and outpatient department of Hematological Research Center. The results were assessed by conventional ITP treatment lines. RESULTS: First-line therapy--glucocorticoids- provided remission in 70% patients, long-term (60 months and longer) in 14%, prednisolone resistance was in 19% patients.Intravenous immunoglobulin provided a rapid hemostatic effect (in 1-2 days) in all the patients. A positive response to treatment was seen in 86% patients but it was short-term (for a year and longer in 27%, resistance to the drug--14%). Second line treatment--splenectomy--is the most effective treatment: 80% remission, 32% patients had remission for longer than 60 months. Resistance occurred in 6% patients. Ineffectiveness of treatment in 20% patients stimulated the search for new pathogenetic treatment among synthetic analogues of thrombopoietin. Clinical trials proved high efficacy of two of them--eltrombopag and romiplostim (86-87% response), possible maintenance of remission in long-term interrupted administration of low doses. CONCLUSION: Modern ITP treatment allows a complete management of hemorrhagic syndrome and deep thrombocytopeny in 80% patients with provision of good quality of life and ability to work. Introduction into clinical practice of thrombopoietin analogues improves treatment results including in 20% patients resistant to all treatments in the absence of marked side effects even in long-term 3-year administration of such medication. PMID- 21675278 TI - [Changes in paradoxical emboly readiness in divers with open oval window of the interatrial septum]. AB - AIM: To study development of paradoxical emboly readiness (PER) in the process of diving. MATERIAL AND METHODS: Examination and observation covered 46 inexperienced divers (beginning divers--BD), 51 experienced divers (diving experience more than 3 years, ED) and 98 healthy individuals not interested in diving. The examinees were follow-up for 20 years. All of them had no organic cardiovascular pathology. PER was detected by the method of imitation modeling of underwater emboly using prolonged infusion contrast echocardiography (PICE) with hydrogen peroxide solution. The intensity of right-left interatrial bypass (RLIAB) was determined by the number of microblebs penetrating in PICE in the left heart. In the BD group PICE was made each 3 years of diving experience, in ED group--each 3-5 years of further diving experience. RESULTS: Diving leads to activation of RLIAB, the number of divers with PER increases. Bypass and PER intensity grows in BD group. In ED group PER increased but RLIAB changed insignificantly. CONCLUSION: Our investigation confirms unfavourable effects of diving on RLIAB of blood in persons with open oval window (OOW) enhancing PER. Further investigations should be made on effects of diving on hemodynamic disorders due to OOW. PMID- 21675279 TI - [B-cell lymphoma in a woman with chronic hepatitis C and mixed cryoglobulinemia of type 2]. AB - A report is presented of a rare case of B-cell non-Hodgkin's lymphoma and severe exacerbation of cryoglobulinic vasculitis which developed in a female patient with chronic hepatitis C four years after achievement of a persistent virusological response to antivirus treatment. Causes of a specific course of the disease and development of the tumor in the absence of HCV in blood serum are discussed: latent HCV-infection in immune cells with persistent antigenic stimulation of B-lymphocytes, possibility of HCV-independent lymphoproliferation. PMID- 21675280 TI - [Renin-angiotensin-aldosteron system: evolution of views from renin discovery to nowadays. Perspectives of therapeutic block]. AB - Recent revolution in the knowledge about structure, physiological and pathophysiological effects of renin-angiotensin-aldosteron system (RAAS) took place recently when it was discovered that local synthesis of all the RAAS components occurs in target organs and their tissues (the heart, kidneys, vessels, brain tissues). It was found that besides classic RAAS acting via activation of angiotensin II (Ang-II) and its receptors, there is an alternative RAAS opposed to atherogenic potential of Ang-II. Renin and prorenin are shown to have both enzymatic and hormonal activities. Wider understanding appeared of extrarenal effects of aldosteron, its non-genomic activity. The above discoveries open new opportunities for pharmacological regulation of RAAS activity, which enables more effectively correct overactivity of this system in organs at risk of negativeAng-II impact. PMID- 21675281 TI - Mental workload associated with operating an agricultural sprayer: an empirical approach. AB - Agricultural spraying involves two major tasks: guiding a sprayer in response to a GPS navigation device, and simultaneous monitoring of rear-attached booms under various illumination and terrain difficulty levels. The aim of the present study was to investigate the effect of illumination, task difficulty, and task level on the mental workload of an individual operating an agricultural sprayer in response to a commercial GPS lightbar, and to explore the sensitivity of the NASA TLX and SSWAT subjective rating scales in discriminating the subjective experienced workload under various task, illumination, and difficulty levels. Mental workload was measured using performance measures (lateral root mean square error and reaction time), physiological measures (0.1 Hz power of HRV, latency of the P300 component of event-related potential, and eye-glance behavior), and two subjective rating scales (NASA-TLX and SSWAT). Sixteen male university students participated in this experiment, and a fixed-base high-fidelity agricultural tractor simulator was used to create a simulated spraying task. All performance measures, the P300 latency, and subjective rating scales showed a common trend that mental workload increased with the change in illumination from day to night, with task difficulty from low to high, and with task type from single to dual. The 0.1 Hz power of HRV contradicted the performance measures. Eye-glance data showed that under night illumination, participants spent more time looking at the lightbar for guidance information. A similar trend was observed with the change in task type from single to dual. Both subjective rating scales showed a common trend of increasing mental workload with the change in illumination, difficulty, and task levels. However, the SSWAT scale was more sensitive than the NASA-TLX scale. With the change in illumination, difficulty, and task levels, participants spent more mental resources to meet the increased task demand; hence, the illumination, task difficulty, and task level affected the mental workload of an agricultural sprayer operator operating a sprayer in response to a GPS lightbar. PMID- 21675282 TI - Perceived physical and psychosocial exposure and health symptoms of dairy farm staff and possible associations with dairy cow health. AB - The aim of this study was to gain a deeper understanding of work-related physical and psychosocial exposure and health symptoms of farm staff working in indoor loose-housing dairy systems in Sweden, and to examine possible associations between exposure and health symptoms of farm staff and disease incidence in their dairy herds. A sample of 41 farm owners or managers and 20 directly employed farm workers participated, each from a Swedish dairy farm with loose-housed cows. Mailed questionnaires comprising 29 questions were used to create four separate indices representing physical exposure, psychosocial exposure, physical symptoms, and psychosocial symptoms. Cow herd incidence rates of common veterinary-reported clinical diseases were calculated based on official records. Partial Spearman rank correlation was used to analyze associations. The study confirmed that physical and psychosocial exposure and health symptoms are not uncommon among owners/managers and employed workers. The study also found that farm owners/managers experience more physical symptoms in dairy herds with lower cow disease incidence rates, while more frequent or intensive exposure to negative psychosocial work environment factors among employed dairy workers is associated with a high herd disease incidence rate. PMID- 21675283 TI - Compliance with NAGCAT work practices recommendations for youth cleaning service alleys in stall barns. AB - Unintentional injury is the leading cause of death in the U.S. among persons 1 to 44 years of age. Over one million children and adolescents in the U.S. live, work, and/or play on farms, where injury risk is relatively high compared to other settings. In an attempt to reduce the number of childhood agricultural injuries occurring on farms, the North American Guidelines for Children's Agricultural Tasks (NAGCAT) was developed to assist parents or other caregivers in assigning developmentally appropriate chores to youth exposed to agricultural hazards. The results presented here are from a longitudinal study in which we obtained (self-reported) daily chore, injury, and safety behavior data from children and adolescents. We focused on one NAGCAT chore, cleaning a service alley in a stall barn, in order to estimate the extent of compliance with specific work practice recommendations contained in the NAGCAT. Our results indicated that among the four NAGCAT-recommended safety practices for cleaning service alleys in stall barns (wearing nonskid shoes, leather gloves, a respirator, and eye protection), wearing non-skid shoes was the only safety practice reported with any degree of regularity. Overall, boys were more likely to wear non-skid shoes compared to girls. In addition, older youth were generally more likely to report higher work practice compliance compared to younger youth. PMID- 21675284 TI - Occupational all-terrain vehicle deaths among workers 18 years and older in the United States, 1992-2007. AB - The objective of this study was to summarize basic information on the characteristics of work-related A TV deaths among civilian persons 18 years of age or older in the U.S. from 1992 through 2007. Work-related ATV death data were obtained through the Bureau of Labor Statistics' annual Census of Fatal Occupational Injuries. From 1992 to 2007, 297 work-related ATV deaths occurred among persons over 17 in the U.S. Ninety-two percent were male, 93% were white, 23% were ages 18 to 34, 51% were ages 35 to 64, and 26% were ages > or = 65. Half of the fatal incidents involved overturns resulting in head and chest injuries. Sixty percent of crashes occurred on farms and 20% occurred on highways. The fatality rate among agricultural production workers was significantly higher than the rates in all other industries. While more in-depth analysis of incident and exposure data for this growing problem will more clearly define personal risk and causal factors in the long term, in the short term, stronger emphasis must be placed on the development of prevention strategies, particularly focused on older workers in the agriculture production industry. PMID- 21675285 TI - Adoption of rollover protective structures (ROPS) on U.S. farm tractors by state: 1993-1995, 2001, and 2004. AB - This research compares state-level rollover protective structure (ROPS) prevalence rates from the early and mid-1990s to those observed in the years 2001 and 2004. In addition, state-level ROPS prevalence rates are compared to state level tractor overturn fatality rates. Tractor data for 1993-1995 and for 2001 and 2004 for all tractors and ROPS-equipped tractors in use on U.S. farms were derived from surveys conducted for NIOSH by the USDA-NASS. Changes in ROPS prevalence rates at the state level between the two time periods were assessed using a two-sample paired t-test with unequal sample sizes. Poisson regression was used to assess the association between ROPS prevalence rates and tractor overturn fatality rates at the state level. Overall, 49 of the 50 states had an observed increase in the percentage of farm tractors equipped with ROPS from 1993 1995 to 2001 and 2004. This increase was statistically significant for 34 states. Large shifts in ROPS prevalence were found within individual states and in clusters of states. These include a major increase in the southeastern U.S. and some western states. However, a core of states in the northeast (many of them in or near the Appalachian Mountains) through the upper midwest remain in the bottom quartile for ROPS prevalence. For the years 1992 through 2004, the highest fatality rates were observed in many of the same states that were identified previously as having persistently low ROPS prevalence rates. There is a clear relationship between low state-level ROPS prevalence rates and high state specific tractor overturn fatality rates. While progress has been made in increasing the percentage of ROPS-equipped farm tractors, it is projected that ROPS prevalence rates will not reach a protective level nationally until after 2015. Regionally, the northeast and midwest will not reach protective levels of ROPS-equipped tractors until after 2020. Based on the adoption rates observed, tractor overturn rates will likely continue to be a more localized, but significant, public health issue for several states beyond the year 2020. The results of this study show the geographic areas of the U.S. where the greatest need exists, and where a greater emphasis should be placed on ROPS promotion activities. However, addressing this public health issue on a large scale will require resources and an organized commitment, which have historically been lacking. PMID- 21675286 TI - Planes, trains, and automobiles...and HIT. PMID- 21675287 TI - Herpes zoster in immunocompromised patients: a review and report of two cases. PMID- 21675288 TI - Shedding light on your moonlighting contract. PMID- 21675289 TI - Chili anyone? PMID- 21675290 TI - Vision, voice, and visibility: the tipping point. PMID- 21675291 TI - Embracing technology to improve school health services. PMID- 21675292 TI - The Patient Protection and Affordable Care Act: what does it mean for the students in our care! PMID- 21675293 TI - Autism spectrum disorder: clinical considerations for the school nurse. PMID- 21675294 TI - What is the role of the school nurse in sexual health education? AB - Sexual health information must be readily available to teens and delivered using both formal and informal means. By forming partnerships and sharing resources with health education teachers, social workers, guidance counselors, administrators, students, families, and the community, school nurses can improve access to information and resources to mitigate the negative consequences of early, unprotected, or forced sexual intercourse. Open communication with teens will allow them to obtain the information they need to make responsible decisions and access care when needed. For information on YRBS data for individual states, visit the CDC Youth Online website at http://apps.nccd.cdc.gov/ youthonline/App/Default.aspx. YRBS data are collected on six categories: unintentional injuries and violence, tobacco use, alcohol and other drug use, sexual behaviors, dietary behaviors, and physical inactivity. The site includes data from 1991 to 2009 and allows tables and graphs related to various health topics to be created. PMID- 21675295 TI - Paid sick days: the missing link in protecting children's health. PMID- 21675296 TI - The traffic light diet can lower risk for obesity and diabetes. PMID- 21675297 TI - National School Nurse Day: reflections from a relative of Florence Nightingale. PMID- 21675299 TI - Shed or You're Dead: 7 unconventional strategies that every nurse needs to know to stay alive and thrive! PMID- 21675300 TI - From local school nurse to national advocate. AB - School nurses are on the front lines of our nation's schools and play a critical role in caring for emergencies, chronic medical conditions, and everyday health care needs. We advocate for health needs on a one-to-one basis as well as in the communities in which we serve. On any given day a scenario can present that brings national attention. April 23, 2009, was my day. PMID- 21675301 TI - Ms. school nurse goes to Washington. PMID- 21675302 TI - Child Nutrition Act Reauthorization, Part 1. Major highlights of the Healthy, Hunger-Free Kids Act of 2010. PMID- 21675303 TI - Child Nutrition Act Reauthorization, Part 2. How school nurses took a stand and helped a bill become law. PMID- 21675304 TI - Nurses in the Congress: What does it mean for NASN? PMID- 21675305 TI - NASN position statement: health care reform. AB - The National Association of School Nurses supports health care reform legislation passed in 2010 in the form of the Patient Protection and Affordable Health Care Act, PL 111-14. This legal framework for health care addresses some of the documented needs and goals pertinent to the healthcare of our nation's school students. PMID- 21675306 TI - NASN position statement: the role of the school nurse and school-based health centers. AB - The National Association of School Nurses holds the position that a combination of school nursing services and school-based health centers (SBHCs) can facilitate positive health outcomes for students. SBHC services complement the work of the school nurses, who are responsible for the entire population of students, by providing a referral site for students without another medical home. SBHCs may provide primary nursing, medical, dental, mental health and other services to those students enrolled in the SBHC program. When available, SBHCs should be integrated with school nursing services to provide a continuum of health services to keep students healthy, in school, and ready to learn. Funding for SBHCs and school nurses typically comes from different sources, so the relationship should by complementary and not competitive. PMID- 21675307 TI - Race and the local politics of punishment in the new world of welfare. AB - To illuminate how race affects the usage of punitive tools in policy implementation settings, we analyze sanctions imposed for noncompliant client behavior under welfare reform. Drawing on a model of racial classification and policy choice, we test four hypotheses regarding client race, local context, and sanctioning. Based on longitudinal and cross-sectional multilevel analyses of individual-level administrative data, we find that race plays a significant role in shaping sanction implementation. Its effects, however, are highly contingent on client characteristics, local political contexts, and the degree to which state governments devolve policy control to local officials. PMID- 21675308 TI - Managing the critical transition from volume to value. AB - Experts say value-based health care delivery truly is the wave of the future. Learn what you need to do to get ready to embrace the change. PMID- 21675309 TI - Meet Steven Liu--physician, inventor, entrepreneur and CEO. AB - Discover how a hospitalist resident concerned about losing track of patient encounters built a multi-million dollar computerized record company that started out in his home. PMID- 21675310 TI - Cyclical vs. structural economic weakness: the effects on physician mobility and recruiting. PMID- 21675311 TI - Reporting quality data on your hospital website: what? why? how? AB - Explore the challenges in making performance improvement data publicly available on hospital websites, and consider some practical tips and suggestions for aligning organizational goals with community and consumer needs. PMID- 21675312 TI - Influencing hand hygiene at spectrum health. AB - Gain insights into the six sources that both motivate and enable people to change through personal, social, and structural forces, and see how they were used to improve hand-washing patterns at a large health care system. PMID- 21675313 TI - The psychology of organizational structure in integrated health systems. AB - Examine a social learning theory model as a framework to guide health system leaders as they consider the psychology of organizational design as it pertains to the successful integration. PMID- 21675314 TI - Responding to the recovery audit contractor program: a system-wide approach. AB - After a long development period, the national Recovery Audit Contractor (RAC) program is now fully operational Read about how one large hospital system structured its RAC team and management process. PMID- 21675315 TI - Concurrent utilization review: getting it right. PMID- 21675316 TI - The workforce challenges of end-of-life issues. AB - Health care organizations, along with non-health-related industries, need to do a better job helping workers who are caring for sick or elderly relatives. PMID- 21675317 TI - Am I demoralizing my staff?--10 questions to ask. AB - Examine 10 questions that all physician leaders should ask themselves periodically to ensure that they are leading, and not bringing down, their staff. PMID- 21675319 TI - Twitter: an essential tool for every physician leader. PMID- 21675318 TI - Process redesign is key to successful IT deployment. PMID- 21675320 TI - How to give difficult feedback. PMID- 21675321 TI - Standing out on a panel: creating a memorable impression. PMID- 21675322 TI - Alcohol, drugs, and links to sexual risk behaviors among a sample of Virginia college students. AB - This project was significant in that it administered the National College Health Risk Behavior Survey (NCHRBS), a health risk assessment, to a sample of students at three public universities in Virginia. Virginia was never included in the original or subsequent nationwide assessments using this instrument. This health risk assessment is comprehensive, easy to administer, and free. The NCHRBS assesses risk behaviors in six categories including: (1) behaviors that contribute to unintentional and intentional injuries; (2) tobacco use; (3) alcohol and other drug use; (4) sexual behaviors that contribute to unintended pregnancy and STDs, including the HIV infection; (5) unhealthy dietary behaviors; and (6) physical inactivity. This article focuses on student responses to questions about alcohol and other drugs and sexual behaviors linked to the use of these substances. It provided baseline data on health risk behaviors of college students which can help determine wellness/health education course objectives and health promotion programming and services provided to the students within the universities. In addition, this project provided protocol to expand use of the survey statewide. PMID- 21675323 TI - Project success' effects on substance use-related attitudes and behaviors: a randomized controlled trial in alternative high schools. AB - Using a randomized controlled effectiveness trial, we examined the effects of Project SUCCESS on a range of secondary outcomes, including the program's mediating variables. Project SUCCESS, which is based both on the Theory of Reasoned Action and on Cognitive Behavior Theory, is a school-based substance use prevention program that targets high-risk students. We recruited two groups of alternative high schools in successive academic years, and randomly assigned schools in each group to either receive the intervention (n = 7) or serve as a control (n = 7). Students completed surveys prior to and following the administration of the program, and again 1 year later. Although participation in Project SUCCESS significantly increased students' perceptions of harm resulting from alcohol and marijuana use, students in the control group reported greater increases in peer support. We also found conflicting evidence in two opposing trends related to students' perceptions of the prevalence and acceptability of substance use. Therefore, the effects of Project SUCCESS on substance use-related beliefs and behaviors must be considered mixed. PMID- 21675324 TI - Personality, drug preference, drug use, and drug availability. AB - This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967) theories. Drug preference was measured by the method of paired-comparison and personality was measured with the Zuckerman Kuhlman Personality Questionnaire-50 CC. Contrary to expectations, high compared with low scorers on Sociability and Impulsive-Sensation Seeking preferred depressants. Surprisingly, low compared with high scorers on neuroticism did not differ in preference for alcohol. As in the previous study, drug preference, use, and availability were highly correlated, although ease of availability was slightly more predictive of drug use than drug preference. Clinical and theoretical implications are discussed. PMID- 21675325 TI - Dimensionality and psychometric analysis of an alcohol protective behavioral strategies scale. AB - OBJECTIVE: The current study examined the dimensionality of a protective behavioral strategies (PBS) measure among undergraduate, predominantly freshmen (92.5%) college students reporting recent alcohol use (n = 320). METHOD: Participants completed a web-based survey assessing 22 PBS items. Factor analyses determined the underlying factor structure of the items. Congruence of the factor structure among gender and racial sub-groups was examined by rotating the sub groups' matrices via the Procrustes rotation method. Reliability analyses determined internal consistency. RESULTS: A 2-factor solution was retained utilizing 17 of the original items. Both PBS sub-scales (Limits and Avoidance) had acceptable internal consistency across all samples. CONCLUSIONS: This PBS Scale was determined to be bi-dimensional and reliable. The dimensions suggest two underlying foci: ways to limit alcohol intake and ways to avoid alcohol intake while socializing. Practical implications of these findings are discussed. PMID- 21675326 TI - Substance use and its relationship to family functioning and self-image in adolescents. AB - This study examined associations between substance use, family functioning, and self-image among four ethnic adolescent groups. Three thousand three hundred and fifteen 8th and 9th grade students were recruited from 10 schools in Los Angeles County. Participants completed a paper-and-pencil survey regarding their alcohol and marijuana use, along with their perceived family functioning and self-image and other demographic variables. Ordinal logistic regression was performed to examine associations. Results indicated that both family functioning and self image were significantly associated with alcohol and marijuana use. Those who scored lower on family functioning and self-image were at increased risk for substance use. Furthermore, students who scored low in both family functioning and self-image were about twice as likely to report using alcohol. PMID- 21675327 TI - Alcohol prevention strategies on college campuses and student alcohol abuse and related problems. AB - This study examined the relationship between colleges' alcohol abuse prevention strategies and students' alcohol abuse and related problems. Alcohol prevention coordinators and first year students in 22 colleges reported whether their schools were implementing 48 strategies in six domains, and students (N = 2041) completed another survey concerning their use of alcohol and related consequences. Colleges were most likely to prevent alcohol use in public places on campus and the delivery and use of kegs. Four alcohol prevention domains were inversely associated with at least one of five outcomes related to student alcohol abuse or related consequences, and the alcohol policy and enforcement domain was inversely associated with all outcomes. Colleges should pay particular attention to strategies related to policy and enforcement. PMID- 21675328 TI - Special issue: Effectiveness of occupational therapy services in mental health practice. PMID- 21675329 TI - Occupational therapy interventions for employment and education for adults with serious mental illness: a systematic review. AB - In this systematic review, we investigated research literature evaluating the effectiveness of occupational therapy interventions focusing on participation and performance in occupations related to paid and unpaid employment and education for people with serious mental illness. The review included occupation- and activity-based interventions and interventions addressing performance skills, aspects of the environment, activity demands, and client factors. The results indicate that strong evidence exists for the effectiveness of supported employment using individual placement and support to result in competitive employment. These outcomes are stronger when combined with cognitive or social skills training. Supported education programs emphasizing goal setting, skill development, and cognitive training result in increased participation in educational pursuits. The evidence for instrumental activities of daily living interventions that targeted specific homemaking occupations and supported parenting was limited but positive. Environmental cognitive supports, such as signs, and other compensatory strategies are useful in managing maladaptive behavior. PMID- 21675330 TI - Occupational therapy interventions for recovery in the areas of community integration and normative life roles for adults with serious mental illness: a systematic review. AB - This systematic review investigated research literature evaluating the effectiveness of occupational therapy interventions focusing on recovery in the areas of community integration and normative life roles for people with serious mental illness. The review included occupation- and activity-based interventions and interventions addressing performance skills and performance patterns, aspects of context and environment, activity demands, and client factors. The results indicated that the evidence of the effectiveness of social skills training is moderate to strong. The evidence for the effectiveness of life skills and instrumental activities of daily living (IADLs) training to improve performance is moderate, as is the evidence for neurocognitive training paired with skills training in the areas of work, social participation, and IADLs. The evidence for client-centered intervention and increased intensity and duration of treatment is limited but positive, and the evidence that providing intervention in the natural context is more beneficial than in the clinic setting is inconclusive. PMID- 21675331 TI - Effectiveness of activity-based group work in community mental health: a systematic review. AB - Activity-based group work is widely used by occupational therapists in mental health settings (Lloyd, King, & Bassett, 2002), but the evidence to support this intervention is unclear. We therefore conducted a systematic review focused on the question, "Is activity-based group work effective in helping people with severe and enduring mental illness in community settings improve their functional ability and/or reduce their mental health symptoms?" We used a wide-ranging search strategy, including electronic searching, hand searching, citation searching, and use of gray literature, and identified 136 potentially relevant papers. After assessment of relevance and quality, only 3 articles met the minimum criteria. Heterogeneity and flaws in quality meant it was not possible to make specific inferences for practice from the studies. Large-scale rigorous research, in the form of randomized controlled trials, is urgently needed to identify whether activity-based group work is effective. PMID- 21675332 TI - Randomized controlled pilot study of an occupational time-use intervention for people with serious mental illness. AB - OBJECTIVE: We assessed the efficacy and clinical utility of a new occupational time-use intervention, Action Over Inertia, designed to improve occupational balance and engagement among community-dwelling people with serious mental illness. METHOD: Using a randomized controlled design, we assigned 24 participants to an intervention group or standard care group. Participants were community-dwelling people with serious mental illness receiving assertive community treatment services. Data on time use, occupational balance, and engagement were collected and compared at baseline and 12-wk posttest. RESULTS: Eighteen participants completed the pilot study. Treatment group participants increased their occupational balance by spending an average of 47 min more per day in activity than the control group (p = .05). Differences in occupational engagement were not shown, but evidence of clinical utility was found. CONCLUSION: This pilot study of Action Over Inertia has shown evidence of efficacy and clinical utility. PMID- 21675333 TI - Cognitive predictors of life skill intervention outcomes for adults with mental illness at risk for homelessness. AB - OBJECTIVE: We investigated the effectiveness of a life skills intervention for people with mental illness who have been homeless. METHOD: In this longitudinal outcomes study, we used Situated Learning Theory (Lave & Wenger, 1991) to provide group and individual sessions to 38 participants from two housing programs after completing baseline Allen Cognitive Level Screen-2000 (ACLS-2000; Allen Conferences, 2000) and Practical Skills Tests (PSTs). Data were analyzed using linear mixed-effects regression models. RESULTS: The PST scores of participants with higher ACLS-2000 scores significantly increased over time (food management, p = .021; money management, p = .039; safe community participation, p = .02). Participants with lower ACLS-2000 scores demonstrated an even greater change over time. CONCLUSION: Most participants, including those with lower ACLS-2000 scores, improved and retained life skills knowledge over time, challenging the premise that people with mental illness should be excluded from mixed-level group interventions. PMID- 21675334 TI - Effectiveness of occupational goal intervention for clients with schizophrenia. AB - OBJECTIVE: The effectiveness of Occupational Goal Intervention (OGI) in clients with schizophrenia was compared with that of the Frontal Executive Program and a control group. METHOD: We used a quasi-experimental design with 18 adult participants ages 20-38 who were randomly assigned to three groups. Testing was performed before treatment, after treatment, and at 6-mo follow-up (Time 2). Instruments assessed executive functions (EFs) and activity and participation. Participants received 18 treatment sessions over a period of 6-8 wk. RESULTS: We found no significant differences among the groups on pretest-posttest change; however, we did find significant differences within groups before and after intervention and moderate to high effect sizes. The OGI group showed relative improvement on all measures of EF and activity and participation. Most participants' achievements were maintained at Time 2. CONCLUSIONS: Results provide initial support for the OGI's effectiveness for clients with schizophrenia. Further studies are needed to verify these initial findings. PMID- 21675335 TI - Effect of a DVD intervention on therapists' mental health practices with older adults. AB - PURPOSE: We tested the effectiveness of an educational intervention in DVD format aimed at strengthening the mental health practices of occupational therapists working with older adults. METHOD: The DVD intervention was tested in a pretest posttest design. Occupational therapists (n = 30) completed a brief knowledge and attitude questionnaire; a chart review (n = 383) of therapists' (n = 20) patients at 3 mo before and 3 mo after DVD training was also conducted. RESULTS: Questionnaire data showed that the percentage of therapists with correct answers increased 20%-30% for 5 of the 11 knowledge items. Chart review data showed therapists spoke more often with their older patients about mood, depression, and cognitive impairment; screened more often for depression and cognitive impairment; and reported findings more often to the treatment team after training. CONCLUSION: Educational interventions can significantly improve therapists' mental health practice with older adults. PMID- 21675336 TI - Executive dysfunction and depressive symptoms associated with reduced participation of people with severe congestive heart failure. AB - OBJECTIVE: We investigated participation levels and relationships among cognition, depression, and participation for people with severe congestive heart failure (CHF). METHOD: People with severe CHF (New York Heart Association Class III or IV) awaiting heart transplantation (N = 27) completed standardized tests of cognition and self-report measures of executive dysfunction, depressive symptoms, and participation. RESULTS: Possible depression (64%) and cognitive impairment (15%-59%) were prevalent. Participants reported significant reductions in participation across all activity domains since CHF diagnosis (ps < .001). Worse executive dysfunction and depressive symptoms were associated with reduced participation and together accounted for 35%-46% of the variance in participation (ps < .01). CONCLUSION: Participation restrictions associated with CHF are not limited to physically demanding activities and are significantly associated with executive dysfunction and depression. Cardiac rehabilitation should address cognitive and psychological functioning in the context of all life situations instead of focusing solely on physical function and disability. PMID- 21675338 TI - Relationships between sensory modulation and social supports and health-related quality of life. AB - OBJECTIVE: We explored the relationships between sensory modulation and health related quality of life (HRQOL), social supports, and mental health symptoms of anxiety and depression. METHOD: Twenty-eight adult volunteers ages 18-60 participated in the study. Fourteen adults were sensory overresponsive (SOR), and 14 adults in a matched comparative group were not sensory overresponsive (NSOR). All participants were tested using self-administered measures of sensory processing. RESULTS: Significant differences were found between SOR and NSOR groups on symptoms of anxiety, depression, and 4 of 8 indicators of HRQOL. CONCLUSION: Several analyses exploring the relationships among the variables tested suggest that sensory response style, whether comparing SOR and NSOR groups or exploring the correlation of the response quadrants of the Adolescent/Adult Sensory Profile, appears significantly and differentially related to symptoms of affective mental health and quality-of-life indicators, including social participation. PMID- 21675337 TI - Level of function at discharge as a predictor of readmission among inpatients with schizophrenia. AB - OBJECTIVE: We retrospectively assessed the effect of social-, cognitive-, and task-oriented functioning levels at hospital discharge on the readmission rate of patients with schizophrenia. METHOD: We assessed the functional capability of 71 inpatients (37 men and 34 women), mean age 41.3 (standard deviation = 11.9 yr), who underwent daily occupational therapy interventions, at admission and at discharge using a comprehensive function score. We examined readmission rates up to 6.8 yr after discharge. RESULTS: Function scores improved significantly during the hospital stay (p < .001). Patients with a higher comprehensive function score (75th percentile) at the end of the index admission had a significantly lower readmission rate (p < .05). A higher comprehensive function score (75th percentile) at discharge was a better predictor for readmission than the Brief Psychiatric Rating Score (25th percentile). CONCLUSION: These findings demonstrate the predictive value of occupational therapy functional monitoring at discharge for risk of readmission and the importance of cognitive/functional interventions for long-lasting remission. PMID- 21675339 TI - Personal factors predictive of health-related lifestyles of community-dwelling older adults. AB - We explored personal factors that can predict health-related lifestyles of community-dwelling older adults. A convenience sample of 253 older adults was recruited to complete the Health Enhancement Lifestyle Profile (HELP), a comprehensive measure of health-promoting behaviors. Data were analyzed through univariate correlational/comparative statistics followed by stepwise multiple regression analysis to determine significant predictor variables for different aspects of health-related lifestyle. Personal health conditions, including the number of chronic diseases or impairments and self-rated health, were two strong predictors for the HELP (R2 = .571, p < .0001). Demographic characteristics, including age, gender, race, education, and employment status, also demonstrated varied degrees of capability for predicting the different HELP scales (e.g., Exercise, Diet, Leisure). When developing individualized plans for older adults in community settings, occupational therapists should consider the clients' strengths and vulnerabilities potentially derived from personal health factors and demographic attributes to yield more effective lifestyle interventions. PMID- 21675340 TI - The terms occupation and activity over the history of official occupational therapy publications. AB - The history of articles in the American Journal of Occupational Therapy and its predecessors reflects trends and changes in professional terminology and the thoughts underlying that terminology. In this study, we investigate use of occupation, activity, and related terms across 9 decades of occupational therapy literature from the 1920s to the 2000s. The literature for 3 years of each of the 9 decades was scanned electronically. A random numbers table was used to equalize the number of words across decades, and a computer search function was used to determine each term's frequency of use for each decade. Results indicated that the term occupation was widely used in the 1920s but then declined until the 1980s. With a rapid increase in use in the 2000s, the term occupation actually appeared more often than it did in the 1920s. The term activity appeared infrequently in the 1920s but gained popularity from the 1930s to the 1960s. From the 1970s to the 1990s, the use of both terms was quite low. This study shows that basic occupational therapy terminology has fluctuated dramatically over time. Given the essential link between terminology and theory, these changes arguably reflect authors' and editors' changing viewpoints on the profession's fundamental nature. PMID- 21675341 TI - Journal quality metrics: options to consider other than impact factors. AB - Journal quality metrics (also referred to as bibliometrics), such as impact factors, are increasingly being used as a measure of researchers' and educators' success and prestige. Occupational therapists who submit articles to peer reviewed journals may face a professional and research dilemma: Do they submit their articles to journals that largely have a professional audience and potentially do not have an impact factor, or do they opt not to publish their research material in occupational therapy-oriented journals? Occupational therapy authors can consider other journal quality metric alternatives, in addition to the impact factor option, including the Eigenfactor Score, Article Influence Score, h-index, SCImago Journal Rank (SJR), Source Normalised Impact per Paper (SNIP), and discipline-specific generated journal quality measures. These other journal quality metrics can be important reference points for occupational therapists who publish and may encourage authors to publish in journals relevant to the discipline. This process, in turn, will build the occupational therapy body of knowledge as well as provide an essential, growing reference source for evidence-based practice. PMID- 21675342 TI - Review of occupational therapy research in the practice area of children and youth. AB - We conducted a systematic review focusing on articles in the occupational therapy practice category of Children and Youth published in the American Journal of Occupational Therapy over the 2-yr period of 2009-2010. We used the frameworks of the International Classification of Functioning, Disability and Health (ICF) and Positive Youth Development (PYD) to explore occupational therapy research progress toward the goals of the Centennial Vision. We organized 46 research articles by research type and classified them within these two frameworks. Most reviewed published research investigated variables representing constructs falling within the ICFdomains of Body Functioning and Activity. The effect of occupational therapy interventions on PYD resided primarily in building competence. To meet the tenets of the Centennial Vision, occupational therapists must document changes in children's engagement in everyday life situations and build the evidence of occupational therapist's efficacy in facilitating participation. PMID- 21675344 TI - The prevalence of self-harm behaviors in a consecutive sample of cardiac stress test patients. AB - While self-harm behavior has been studied in various psychiatric populations, particularly the behaviors of suicide attempts and completions, little empirical data exists on the lifetime prevalence of various self-harm behaviors in non psychiatric populations. In the present study, using a cross-sectional approach and a self-report survey methodology, we examined the lifetime prevalence of 22 self-harm behaviors in a consecutive sample of 250 patients undergoing cardiac stress testing. Results indicated that abuse alcohol was most common (17.2%) followed by promiscuity (10.4%); 6% reported a previous suicide atatempt. Findings indicate areas of clinician inquiry for self-harm behaviors in non psychiatric patients. PMID- 21675343 TI - Beliefs and attitudes of French family practitioners toward depression: the impact of training in mental health. AB - OBJECTIVE: To study, in a sample of French Family Practitioners (FPs), beliefs and attitudes toward depression and how they vary according to training received in mental health. METHODS: The Depression Attitude Questionnaire (DAQ) was completed by 468 FPs from all regions of France, recruited by pharmaceutical company representatives to attend focus groups on the management of depression in general practice. RESULTS: A three-factor model was derived from the DAQ, accounting for 37.7% of the total variance. The correlations between individual items of each component varied from 0.4 to 0.65, with an overall internal consistency of 0.47 (Cronbach's alpha). FPs had an overall neutral position on component 1, professional ease, a positive view on the origins of depression and its amenability to change (component 2), and a belief in the necessity of medication and the benefit of antidepressant therapy (component 3). Training in mental health, specifically through continuing medical education and postgraduate psychiatric hospital training, was significantly and positively associated with both professional ease and a medication approach to treating depression. CONCLUSION: This study is the first description of the beliefs and attitudes of French FPs toward depression using a standardized measure, the DAQ, despite the instrument's limited psychometric properties. It shows the positive effect of training in mental health on attitudes toward depression. PMID- 21675345 TI - Treatment of co-morbid mental illness in primary care: how to minimize weight gain, diabetes, and metabolic syndrome. AB - In patients with mental illness the increased risk from cardiovascular disease appears to be related to the increased incidence of obesity, hypertension, and diabetes mellitus. Barriers to the medical care in this patient population include diminished adherence to treatment and preventative recommendations, lack of willingness to engage in self-care activities, decreased access to affordable medical care, underestimation of risk by physicians, and adverse effects of commonly prescribed psychiatric medications. When managing patients with mental illness it is necessary to estimate the patient's metabolic and cardiovascular risk, monitor BMI, waist circumference, fasting glucose, and lipid profile regularly, evaluate psychiatric medications metabolic risk, and choose less "metabolically threatening" drugs. The promotion of healthy lifestyle choices among persons with serious mental illness is essential not only as part of their recovery, but as an integral part of preventing metabolic changes and weight gain linked to their illness and medication side effects. In patients with mental illness and co-morbid diabetes, metabolic syndrome, and obesity, psychiatrist and primary care clinicians should collaborate to establish a plan for healthy lifestyle habits (diet and activity regimen), encourage weight loss, and follow up regularly using multispecialty teams to improve management. PMID- 21675346 TI - Screening for depression with a brief questionnaire in a primary care setting: validation of the two questions with help question (Malay version). AB - OBJECTIVE: To determine the diagnostic accuracy of the two questions with help question (TQWHQ) in the Malay language. The two questions are case-finding questions on depression, and a question on whether help is needed was added to increase the specificity of the two questions. METHOD: This cross sectional validation study was conducted in a government funded primary care clinic in Malaysia. The participants included 146 consecutive women patients receiving no psychotropic drugs and who were Malay speakers. The main outcome measures were sensitivity, specificity, and likelihood ratios of the two questions and help question. RESULTS: The two questions showed a sensitivity of 99% (95% confidence interval 88% to 99.9%) and a specificity of 70% (62% to 78%), respectively. The likelihood ratio for a positive test was 3.3 (2.5 to 4.5) and the likelihood ratio for a negative test was 0.01 (0.00 to 0.57). The addition of the help question to the two questions increased the specificity to 95% (89% to 98%). CONCLUSION: The two qeustions on depression detected most cases of depression in this study. The questions have the advantage of brevity. The addition of the help question increased the specificity of the two questions. Based on these findings, the TQWHQ can be strongly recommended for detection of depression in government primary care clnics in Malaysia. Translation did not apear to affect the validity of the TQWHQ. PMID- 21675347 TI - Childhood parental loss and bipolar spectrum in obese bariatric surgery candidates. AB - BACKGROUND: Early adverse experiences such as sexual, verbal, or physical abuse and parental neglect have been associated with a higher risk of weight or eating problems in adulthood, and death or prolonged separation from parents during childhood has been implicated as a correlate of adult psychiatric disorders that are widely represented in obese subjects seeking bariatric surgery. OBJECTIVE: The aim of this study was to examine the rate of childhood parental loss in obese bariatric surgery candidates and explore its association with a psychiatric diagnosis and clinical and weight/eating-related characteristics. METHODS: The current and lifetime psychiatric diagnoses of 120 consecutive bariatric patients undergoing pre-surgical psychiatric consultation were assessed using a modified version of the Structured Clinical Interview for DSM-IV (SCID-CV), and information relating to parental death or separation before the age of 17 years was collected using a semi-structured interview. The rate of childhood parental loss was compared with that of an always slender population sharing the same psychiatric diagnosis. RESULTS: 91.7% of the obese subjects were diagnosed as having a bipolar spectrum disorder. Overall, 28% of the patients reported a childhood parental death or separation. Early parental loss was not equally distributed in the different diagnostic subgroups, being more frequent in those with bipolar II disorders; the always slender subjects with bipolar II disorders showed a lower rate of early parental loss. CONCLUSIONS: The study findings confirm the association between obesity and bipolar disorders and suggest that early parental loss may play a role in the development of obesity in bipolar II subjects. PMID- 21675348 TI - Depression and reasons for living among AIDS patients: protecting quality of life when the end is in sight. AB - BACKGROUND: Patients with AIDS are at risk for becoming depressed, pessimistic, and may begin to desire to die. The desire to live may remain strong in AIDS patients through the maintenance of physical health and a lack of pain. However, improvement in physical health is not always followed by resurgence in the will to live. Psychological variables may be important for protecting reasons for living in AIDS patients. AIMS: The current study was designed to examine protective factors associated with the will to live among AIDS patients, including physical functioning, depression, and quality of life. METHOD: Sixty eight AIDS patients participated in the current study during their outpatient visits to an infectious disease unit. Self-report questionnaires were administered to assess depression, quality of life, a variety of physical health variables, and reasons for living. RESULTS: Analyses revealed that reasons for living reported by AIDS patients were best understood by overall quality of life. Depression was associated with pessimistic beliefs about the medical illness. Depression was not significantly related to physical functioning or role limitations. CONCLUSIONS: AIDS patients with poor physical functioning may maintain important reasons for living if a high sense of quality of life is achieved. The assessment and treatment of quality of life in AIDS patients should include strategies that foster a sense of achievement, strengthen interpersonal relationships, and increase positive self-expression. PMID- 21675349 TI - Association between psychopathological factors and joint hypermobility syndrome in a group of undergraduates from a French university. AB - OBJECTIVE: To explore the frequency of Joint Hypermobility Syndrome (JHS) among university students and assess whether a relationship exists between this collagen condition and certain psychological variables. METHOD: A cross-sectional sample of 365 undergraduates at a French university was assessed with the Brighton's criteria for JHS, Somatosensory Amplification Scale (SSAS), Liebowitz Social Anxiety Scale (LSAS), and Hospital Anxiety and Depression Scale (HADS). RESULTS: 39.5% of the participants met Brighton's criteria for JHS. Scores of somatosensory amplification were higher among participants with JHS (t = -2.98; p = 0.03) independent of gender. Female participants with JHS had higher scores in depression (t = -2.01; p = 0.04) and general anxiety (t = -2.35; p = 0.01) than women without JHS. The percentage of males with a medium/high level of social anxiety was greater among participants with JHS (78.6% vs. 41.7%; chi2 = 6.18;p = 0.01). Logistic regression demonstrated that male sex and low level of somatosensory amplification are variables contrary to the presence of JHS. CONCLUSION: JHS is a frequent condition among young people evaluated. JHS is associated with psychological distress and higher levels of somatosensory amplification. PMID- 21675350 TI - Relationship between smoking and family history of smoking in schizophrenia patients. AB - BACKGROUND: The rate of smoking is known to be high in patients with schizophrenia. The purpose of this study was to quantitatively examine the relationship between smoking and family history of smoking in patients with schizophrenia. METHODS: The sample consisted of 172 patients (mean age: 54 years, 55% male) hospitalized in a general psychiatric hospital. They were asked by a physician whether they smoked. Family histories of smoking and schizophrenia were assessed among first- and third-degree relatives. RESULTS: Ninety-eight patients (57%) were identified as having smoked at some point. Multiple logistic regression analysis showed that smoking was significantly associated with family histories of smoking among both first- and third-degree relatives, controlling for the effects of age, sex, and family history of schizophrenia. The smoking rates were significantly higher in those with a family history of smoking, but not a family history of schizophrenia, than among those without a family history of either smoking or schizophrenia. However, this difference did not reach statistical significance among those with a family history of schizophrenia. CONCLUSION: Smoking is greatly influenced by family history of smoking in patients with schizophrenia, especially among those without a family history of schizophrenia. The association between smoking and family history of smoking was inconclusive among those patients with schizophrenia who also had a family history of schizophrenia. PMID- 21675351 TI - SCIRehab: a test of practice-based evidence methodology. PMID- 21675352 TI - The SCIRehab project: analyzing multidisciplinary inpatient spinal cord injury rehabilitation treatment--second phase. PMID- 21675353 TI - The SCIRehab project: treatment time spent in SCI rehabilitation. Inpatient treatment time across disciplines in spinal cord injury rehabilitation. AB - BACKGROUND/OBJECTIVE: Length of stay (LOS) for rehabilitation treatment after spinal cord injury (SCI) has been documented extensively. However, there is almost no published research on the nature, extent, or intensity of the various treatments patients receive during their stay. This study aims at providing such information on a large sample of patients treated by specialty rehabilitation inpatient programs. METHODS: Six hundred patients with traumatic SCI admitted to six rehabilitation centers were enrolled. Time spent on various therapeutic activities was documented by each rehabilitation clinician after each patient encounter. Patients were grouped by neurologic level and completeness of injury. Total time spent by each rehabilitation discipline over a patient's stay and total minutes of treatment per week were calculated. Ordinary least squares stepwise regression models were used to identify patient and injury characteristics associated with time spent in rehabilitation treatment overall and within each discipline. RESULTS: Average LOS was 55 days (standard deviation 37), during which 180 (106) hours of treatment were received, or 24 (5) hours per week. Extensive variation was found in the amount of treatment received, between and within neurologic groups. Total hours of treatment provided throughout a patient's stay were primarily determined by LOS, which in turn was primarily predicted by medical acuity. Variation in minutes per week of treatment delivered by individual disciplines was predicted poorly by patient and injury characteristics. CONCLUSIONS: Variations between and within SCI rehabilitation patient groups in LOS, minutes of treatment per week overall, and for each rehabilitation discipline are large. Variation in treatment intensity was not well explained by patient and injury characteristics. In accordance with practice based evidence methodology, the next step in the SCIRehab study will be to determine which treatment interventions are related with positive outcomes (at 1 year post injury), after controlling for patient and injury differences. PMID- 21675354 TI - The SCIRehab project: treatment time spent in SCI rehabilitation. Physical therapy treatment time during inpatient spinal cord injury rehabilitation. AB - BACKGROUND/OBJECTIVE: To describe the nature and distribution of activities during physical therapy (PT) delivered in inpatient spinal cord injury (SCI) rehabilitation and discuss predictors (patient and injury characteristics) of the amount of time spent in PT for specific treatment activities. METHODS: Six hundred patients from six inpatient SCI centers were enrolled in the SCIRehab study. Physical therapists documented details, including time spent, of treatment provided during 37 306 PT sessions that occurred during inpatient SCI rehabilitation. Ordinary least squares regression models associated patient and injury characteristics with time spent in specific PT activities. RESULTS: SCIRehab patients received a mean total of 55.3 hours of PT over the course of their rehabilitation stay. Significant differences among four neurologic groups were seen in the amount of time spent on most activities, including the most common PT activities of strengthening exercises, stretching, transfer training, wheelchair mobility training, and gait training. Most PT work (77%) was provided in individual therapy sessions; the remaining 23% was done in group settings. Patient and injury characteristics explained only some of the variations seen in time spent on wheelchair mobility, transfer and bed mobility training, and range of motion/ stretching. CONCLUSION: Analysis yielded both expected and unexpected trends in SCI rehabilitation. Significant variation was seen in time spent on PT activities within and among injury groups. Providing therapeutic strengthening treatments consumed the greatest proportion of PT time. About one-quarter of all PT services were provided in group settings. Details about services provided, including time spent, will serve as a starting point in detailing the optimal treatment delivery for maximal outcomes. PMID- 21675355 TI - The SCIRehab project: treatment time spent in SCI rehabilitation. Occupational therapy treatment time during inpatient spinal cord injury rehabilitation. AB - BACKGROUND: Occupational therapy (OT) is a critical component of the rehabilitation process after spinal cord injury (SCI), the constitution of which has not been studied or documented in full detail previously. OBJECTIVE: To describe the type and distribution of SCI rehabilitation OT activities, including the amount of time spent on evaluation and treatment, and to discuss predictors (patient and injury characteristics) of the amount of time dedicated to OT treatment activities. METHODS: Six inpatient rehabilitation centers enrolled 600 patients with traumatic SCI in the first year of the SCIRehab. Occupational therapists documented 32 512 therapy sessions including time spent and specifics of each therapeutic activity. Analysis of variance and contingency tables/chi square tests were used to test differences across neurologic injury groups for continuous and categorical variables. RESULTS: SCIRehab patients received a mean total of 52 hours of OT over the course of their rehabilitation stay. Statistically significant differences among four neurologic injury groups were seen in time spent on each OT activity. The activities that consumed the most OT time (individual and group sessions combined) were strengthening/endurance exercises, activities of daily living (ADLs), range of motion (ROM)/stretching, education, and a grouping of 'therapeutic activities' that included tenodesis training, fine motor activities, manual therapy, vestibular training, edema management, breathing exercise, cognitive retraining, visual/perceptual training desensitization, and don/doff adaptive equipment. Seventy-seven percent of OT work occurred in individual treatment sessions, with the most frequent OT activity involving ADLs. The variation in time (mean minutes per week) spent on OT ROM/stretching, ADLs, transfer training, assessment, and therapeutic activities can be explained in part by patient and injury characteristics, such as admission Functional Independence Measure (FIM) score, neurologic injury group, and the medical severity of illness score. CONCLUSION: OT treatment patterns for patients with traumatic SCI show much variation in activity selection and time spent on activities, within and among neurologic level of injury groups. Some of the variation can be explained by patient and injury characteristics. Almost all patients with SCI participated in strengthening/ endurance and ROM/stretching exercises during OT treatment and these two activities are where the most time was spent when therapy provided in individual and group settings was combined. ADL work consumed the most time in individual therapy sessions. PMID- 21675356 TI - The SCIRehab project: treatment time spent in SCI rehabilitation. Therapeutic recreation treatment time during inpatient rehabilitation. AB - OBJECTIVE: Following spinal cord injury (SCI), certified therapeutic recreation specialists (CTRSs) work with patients during rehabilitation to re-create leisure lifestyles. Although there is much literature available to describe the benefits of recreation, little has been written about the process of inpatient or outpatient rehabilitation therapeutic recreation (TR) programs or the effectiveness of such programs. To delineate how TR time is used during inpatient rehabilitation for SCI. METHODS: Six rehabilitation centers enrolled 600 patients with traumatic SCI for an observational study. CTRSs documented time spent on each of a set of specific TR activities during each patient encounter. Patterns of time use are described, for all patients and by neurologic category. Ordinary least-squares stepwise regression models are used to identify patient and injury characteristics predictive of total treatment time (overall and average per week) and time spent in TR activities. RESULTS: Ninety-four percent of patients enrolled in the SCIRehab study participated in TR. Patients received a mean total of 17.5 hours of TR; significant differences were seen in the amount of time spent in each activity among and within neurologic groups. The majority (76%) of patients participated in at least one structured therapeutic outing. Patient and injury characteristics explained little of the variation in time spent within activities. CONCLUSION: The large amount of variability seen in TR treatment time within and among injury group categories, which is not explained well by patient and injury characteristics, sets the stage for future analyses to associate treatments with outcomes. PMID- 21675357 TI - The SCIRehab project: treatment time spent in SCI rehabilitation. Speech-language pathology treatment time during inpatient spinal cord injury rehabilitation: the SCIRehab project. AB - BACKGROUND/OBJECTIVE: Following spinal cord injury (SCI), speech-language pathologists (SLPs) perform assessments and provide treatment for swallowing, motor speech, voice, and cognitive-communication disorders that result from the SCI and/or co-occurring brain injuries. This paper describes the nature and distribution of speech-language pathology (SLP) activities delivered during inpatient SCI rehabilitation and discusses predictors (patient and injury characteristics) of the amount of time spent in specific SLP treatment activities. METHODS: Six rehabilitation centers enrolled 600 patients with traumatic SCI for an observational study of acute inpatient rehabilitation treatment (SCIRehab). SLPs documented the details of assessment and treatment and time spent on each of a set of specific SLP activities during each patient encounter. Patterns of time use are described for all patients by neurological injury category. Ordinary least squares stepwise regression models are used to identify patient and injury characteristics predictive of treatment time in the specific SLP activities identified. RESULTS: SLP consults were requested for 40% of SCIRehab patients. Fifty-seven percent of these patients received intense therapy (defined as more than five sessions during the rehabilitation stay); the remainder received primarily evaluation or less intense services (one to five sessions). The patients who participated in intense treatment received a mean total of 16.1 hours (range 2.5-105.2 hours, standard deviation (SD) 16.5, median 9.7 hours) of SLP; significant differences were seen in the amount of time spent in each activity among neurological injury groups. Cognitive-communication and swallowing therapy were the most common SLP activities. Patients with motor levels of injury at C1-C4 spent the highest percentage of their therapy time working on swallowing therapy while patients with low tetraplegia and paraplegia, and those classified as AIS D (regardless of motor level of injury) focused the greatest percentage of time on cognitive-communication work. Patient and injury characteristics explained a portion of the variation in time spent on cognitive communication therapy but did not explain the variation in time spent on swallowing and other SLP treatment activities. CONCLUSION: The need for swallowing and cognitive treatment by SLP is common during inpatient rehabilitation due to dysfunction resulting from use of artificial airways and feeding approaches, as well as secondary brain injuries. The large amount of variability seen in SLP treatment time, which is not explained well by patient and injury characteristics, sets the stage for future analyses to associate treatments with outcomes. PMID- 21675358 TI - The SCIRehab project: treatment time spent in SCI rehabilitation. Psychology treatment time during inpatient spinal cord injury rehabilitation. AB - BACKGROUND: Rehabilitation psychologists are integral members of spinal cord injury (SCI) rehabilitation teams. OBJECTIVE: To describe specific information regarding types and intensity of treatments delivered by rehabilitation psychologists to patients with various levels of SCI. METHODS: Utilizing a taxonomy of psychological interventions as a framework, rehabilitation psychologists documented time spent on specific psychology interventions for each interaction they had with 600 patients with traumatic SCI at 6 inpatient SCI rehabilitation centers. Associations of patient and injury characteristics with time spent on various psychological interventions were examined using ordinary least squares stepwise regression models. RESULTS: Psychologists focus the majority of the time they spend with patients with SCI on psychotherapeutic interventions of processing emotions, emotional adjustment, and family coping, while educational efforts focus mostly on coping and adjusting to the new injury. There was wide variation in the amount of time spent on psychotherapeutic and psychoeducational interventions; patient, injury, and clinician characteristics explained little of the variation in time spent. CONCLUSIONS: Variations observed in psychological treatment delivery mirror real-world human complexity and clinical experience; they are not explained well by patient and injury characteristics and set the stage for future analyses to associate treatments with outcomes. PMID- 21675359 TI - The SCIRehab project: treatment time spent in SCI rehabilitation. Nursing bedside education and care management time during inpatient spinal cord injury rehabilitation. AB - BACKGROUND: Nurses are an integral part of the spinal cord injury (SCI) rehabilitation team and provide significant education to the patient and family about the intricacies of living with SCI, as well as help manage the care process. OBJECTIVE: This is the second in a series of reports by clinical nursing leaders involved in the SCIRehab research project, a multi-center, 5-year study to record and analyze details of SCI inpatient rehabilitation, with focus on descriptions of time spent by nurses on bedside education and care management. METHODS: Six hundred patients with traumatic SCI were enrolled at six rehabilitation centers. Nurses providing usual care to patients with SCI documented the content and amount of time spent on each bedside interaction using portable electronic devices with customized software or a newly developed customized page in electronic documentation systems; this included details of education or care management. Patient and injury characteristics, including level and nature of injury, were taken from the medical record. RESULTS: Nursing data for this report were derived from 42 048 shifts of nursing care. The mean total of nursing education and care management per patient was 30.6 hours (range 1.2 126.1, standard deviation (SD) 20.7, median 25.5). The mean number of minutes per week was 264.3 (range 33.2-1253, SD 140.9, median 241.9). The time that nurses spent on each activity was significantly different in each neurological injury group. Fifty percent of care management time was devoted to psychosocial support, while medication, skin care, bladder, bowel, and pain management were the main education topics. CONCLUSIONS: Nurses in SCI rehabilitation spend a significant amount of time providing education and psychosocial support to patients and their families. Typically, this is not included in traditional documentation systems. Quantification of these interventions will allow researchers to discern whether there are pertinent associations between the time spent on bedside activities and patient outcomes. The data will also be relevant for patient care planning and acuity staffing. PMID- 21675360 TI - The SCIRehab project: social work and case management. Social work and case management treatment time during inpatient spinal cord injury rehabilitation. AB - BACKGROUND: There is a lack of published evidence regarding the amount and type of social work and case management (SW/CM) services that an individual with traumatic spinal cord injury (SCI) receives during acute inpatient rehabilitation. Such information is needed to assist in resource planning, benchmarking, and research on interventions and outcomes. METHODS: As part of the SCIRehab study social workers and case managers at six inpatient rehabilitation facilities documented details (including time spent) about the interventions provided to 600 patients with traumatic SCI during acute inpatient rehabilitation. Associations between patient and injury characteristics and time spent on these activities were examined. RESULTS: Patients received a mean total of 10 hours of SW/CM services, with a mean of 72.8 total minutes per week. The majority of the patients received SW/CM time spent on interdisciplinary conferencing on the patient's behalf (96%), discharge planning and services (89%), financial planning (67%), community/in-house services (66%), supportive counseling (56%), and initial assessment (54%). A minority of the patients received peer advocacy (12%), classes (24%), and education topics (30%). Total hours per stay and minutes per week varied by level of injury group. The most time per week was dedicated to patients with high tetraplegia ASIA Impairment Scale (AIS) A-C and the least to patients with C5-C8 AIS A-C. The patient and injury characteristics studied did not explain the variance seen in time spent on specific SW/CM services. CONCLUSIONS: These descriptive data may be helpful in resource planning to anticipate and address individual patient needs and to plan for department-level training and hiring. These data also may pave the way to studying relationships of interventions with patient outcomes. PMID- 21675361 TI - Weight gain following spinal cord injury: a pilot study. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVE: To define the temporal course of weight gain in persons with new spinal cord injury (SCI), and to identify predictors of weight gain in this population. SETTING: A United States Department of Veterans Affairs (VA) SCI Unit. METHODS: A retrospective chart review in a VA SCI Unit was conducted. Participants (n = 85) included all persons with new SCI completing initial rehabilitation at the center between 1998 and 2006. Outcome measures were mean change in body mass index (BMI) between rehabilitation admission and final follow-up, time of greatest BMI change, and distribution of participants by BMI classification. These measures were also examined relative to SCI level, American Spinal Injury Association Impairment Scale (AIS) grade, primary mode of mobility, and age at rehabilitation admission. RESULTS: Mean BMI increased by 2.3 kg/m2 between rehabilitation admission (mean 45 days post-injury) and final follow-up (mean 5 years post-injury). The distribution of participants shifted from lower BMI classifications at rehabilitation admission to higher BMI classifications at final follow-up. For participants transitioning from normal to overweight or obese, the greatest increase occurred during the first year after acute rehabilitation. Neurological level, impairment category, primary mode of mobility, and age at rehabilitation admission did not significantly predict BMI change. BMI at rehabilitation admission correlated significantly with BMI at final follow-up (P < 0.0005). CONCLUSIONS: These findings confirm a significant increase in BMI after new SCI and suggest that persons with new SCI are at greatest weight gain risk during the first year following acute rehabilitation. PMID- 21675363 TI - Nerve allograft transplantation for functional restoration of the upper extremity: case series. AB - BACKGROUND: Major trauma to the spinal cord or upper extremity often results in severe sensory and motor disturbances from injuries to the brachial plexus and its insertion into the spinal cord. Functional restoration with nerve grafting neurotization and tendon transfers is the mainstay of treatment. Results may be incomplete due to a limited supply of autologous material for nerve grafts. The factors deemed most integral for success are early surgical intervention, reconstruction of all levels of injury, and maximization of the number of axonal conduits per nerve repair. OBJECTIVE: To report the second series of nerve allograft transplantation using cadaveric nerve graft and our experience with living-related nerve transplants. PARTICIPANTS: Eight patients, seven men and one woman, average age 23 years (range 18-34), with multi-level brachial plexus injuries were selected for transplantation using either cadaveric allografts or living-related donors. METHODS: Grafts were harvested and preserved in the University of Wisconsin Cold Storage Solution at 5 degrees C for up to 7 days. The immunosuppressive protocol was initiated at the time of surgery and was discontinued at approximately 1 year, or when signs of regeneration were evident. Parameters for assessment included mechanism of injury, interval between injury and treatment, level(s) of deficit, post-operative return of function, pain relief, need for revision surgery, complications, and improvement in quality of life. RESULTS: Surgery was performed using living-related donor grafts in six patients, and cadaveric grafts in two patients. Immunosuppression was tolerated for the duration of treatment in all but one patient in whom early termination occurred due to non-compliance. There were no cases of graft rejection as of most recent followup. Seven patients showed signs of regeneration, demonstrated by return of sensory and motor function and/or a migrating Tinel's sign. One patient was non-compliant with the post-operative regimen and experienced minimal return of function despite a reduction in pain. CONCLUSIONS: Despite the small number of subjects, it appears that nerve allograft transplantation may be performed safely, permitting non-prioritized repair of long-segment peripheral nerve defects and maximizing the number of axonal conduits per nerve repair. For patients with long, multi-level brachial plexus injuries or combined upper and lower extremity nerve deficits, the use of nerve allograft allows a more complete repair that may translate into greater functional restoration than autografting alone. PMID- 21675362 TI - Comparison of coronary artery calcification scores and National Cholesterol Education program guidelines for coronary heart disease risk assessment and treatment paradigms in individuals with chronic traumatic spinal cord injury. AB - OBJECTIVE: To investigate the risk of coronary heart disease (CHD) in individuals with spinal cord injury (SCI) according to the National Cholesterol Educational Program (NCEP) guidelines and CT coronary artery calcium scores (CCS). RESEARCH: Cross-sectional study of consecutive sample of males with SCI presenting to a single site for CHD risk assessment. PARTICIPANTS/METHODS: Males age 45-70 with traumatic SCI (American Spinal Injury Association (ASIA) A, B, and C) injured for at least 10 years with no prior history of clinical CHD. Medical history, blood pressure, and fasting lipid panel were used to calculate risk for CHD with the use of the Framingham risk score (FRS). Risk and treatment eligibility status was assessed based on NCEP/FRS recommendations and by presence and amount of CCS. Percent agreement (PA) and kappa were calculated between the two algorithms. Spearman correlations were calculated between CCS and FRS and individual risk factors. RESULTS: A total of 38 men were assessed; 18 (47.4%) had CCS > 0. The PA between NCEP/FRS assessment and CCS was 18% with a kappa of -0.03. 11 (28.9%) had CCS > 100 or >75th percentile for their age, sex, and race, which might qualify them for lipid-lowering treatment. Only 26 were placed into the same treatment category by NCEP/FRS and CCS, for a PA of 68% with a kappa of 0.35. In all, 20 (52.6%) were eligible for lipid-lowering treatment by either NCEP/FRS (n=9) or CCS (n = 11). Seven subjects were above the treatment threshold based on CCS, but not NCEP/FRS and five subjects were above the NCEP/FRS threshold, but not CCS. Just four subjects were eligible by both algorithms. CCS only correlated with FRS (r = 0.508, P = 0.001) and age (r = 0.679, P < 0.001). PMID- 21675364 TI - Aggressive bladder carcinoma in an HIV-positive man with tetraplegia and neurogenic bladder. AB - BACKGROUND/OBJECTIVE: Patients with neurogenic bladder secondary to spinal cord injury who are managed long term with an indwelling catheter are known to be at increased risk for transitional cell carcinoma of the bladder. Immunosuppression is a known risk factor for malignancies that often are more aggresSive than those seen in normal populations. METHOD: Case report and discussion of management recommendations. RESULTS: We summarize the case of a 44-year-old HIV-positive C5 C6 incomplete tetraplegic male (date of injury 1980), who was diagnosed with transitional cell carcinoma of the bladder and succumbed to disease within 6 months of diagnosis. The patient was a non-smoker who was never managed with an indwelling catheter. There has been no such case reported in the literature. CONCLUSIONS: HIV infection in the presence of a neurogenic bladder may carry an increased risk of aggressive bladder malignancy. More studies are warranted to determine whether routine annual screening with cystoscopy in all patients with HIV and neurogenic bladder is indicated. PMID- 21675366 TI - Pool safety for Texas kids. PMID- 21675365 TI - Concurrent respiratory resistance training and changes in respiratory muscle strength and sleep in an individual with spinal cord injury: case report. AB - CONTEXT: Quality sleep possesses numerous benefits to normal nighttime and daytime functioning. High-level spinal cord injury (SCI) often impacts the respiratory muscles that can lead to poor respiratory function during sleep and negatively affect sleep quality. The impact of respiratory muscle training (RMT) on sleep quality, as assessed by overnight polysomnography (PSG), is yet to be determined among the spinal cord-injured population. This case report describes the effects of 10 weeks of RMT on the sleep quality of a 38-year-old male with cervical SCI. METHODS: Case report. FINDINGS/RESULTS: The subject completed overnight PSG, respiratory muscle strength assessment, and subjective sleepiness assessment before and after 10 weeks of RMT. The post-test results indicated improvements in sleep quality (e.g. fewer electroencephalographic (EEG) arousals during sleep) and daytime sleepiness scores following RMT. CONCLUSION/CLINICAL RELEVANCE: Respiratory activity has been proven to impact EEG arousal activity during sleep. Arousals during sleep lead to a fragmented sleeping pattern and affect sleep quality and daytime function. Our subject presented with a typical sleep complaint of snoring and excessive sleepiness. The subject's pre-test PSG demonstrated a large number of arousals during sleep. It is important for all individuals complaining of problems during sleep or daytime problems associated with sleep (i.e. excessive daytime sleepiness) to seek medical attention and proper evaluation. PMID- 21675367 TI - Can I use chlorhexidine as the only irrigating solution in my endodontic treatments? PMID- 21675368 TI - Fritz Heitmann: Hunter, dentist, hardware baron, and Houston leader. AB - Frederick (Fritz) A. Heitmann was a Houston business and civic leader in the late 1800's and early 1900's. He succeeded his father in the family hardware business, was hugely successful, and was known for helping establish the Houston Ship Channel among other large projects. His great success obscured his earlier contribution to the frontier as a dentist in the gold fields of Colorado. His father insisted he learn a skill independent of fluctuations in the business world. He apprenticed himself to a dentist and used those abilities, along with others, to gain a large stake to build the business. Also, he had strong opinions, and liked to talk. He told his story to his grandson, and his grandson's buddy, the co-author of this article. PMID- 21675369 TI - Old McConnell had a chair. PMID- 21675370 TI - Oral and maxillofacial pathology case of the month. Kaposi's sarcoma. PMID- 21675371 TI - Sound advice: Tips for choosing the right telephone system for your business. PMID- 21675372 TI - Orthopaedic pathology. PMID- 21675373 TI - Orthopaedic specimen preparation: what pathologists should know and do. AB - The purpose of this article is to stress the importance of imaging studies to the surgical pathologist when studying orthopaedic specimens and to emphasize specimen preparation, including sawing and decalcification techniques. PMID- 21675374 TI - Metabolic bone diseases. PMID- 21675375 TI - Genetic diseases of bones and joints. AB - Genetic factors play roles in many diseases. Often these factors are ill defined and unpredictable. Other diseases are caused by specific single gene mutations and are passed to offspring in Mendelian inheritance patterns. There are over 5000 documented Mendelian disorders; over 500 of these affect bones and joints. Some of these single gene disorders affect many tissues, and the skeletal system is one of many organ systems involved. The surgical pathologist must often diagnose these disorders. Important examples are neurofibromatosis, Gaucher's disease, and alkaptonuria. Other single gene disorders almost exclusively affect the skeleton. These disorders are the skeletal dysplasias and 372 have been documented. These disorders are classified using radiographic, clinical, and molecular data. The most common dysplasias are osteogenesis imperfecta, achondroplasia, and osteopetrosis. The surgical pathologist usually does not play a role in the diagnosis of skeletal dysplasias. However, histologic studies often elucidate the pathophysiologic basis of these diseases and proper collection of tissues is important for the evolving understanding of the molecular basis of these disorders. PMID- 21675376 TI - Tumors and diseases of the joint. AB - A variety of different diseases affect the synovium, including infection, noninfectious immunologic inflammatory conditions, degenerative arthroses, crystal deposits, trauma, and tumors. Tumors of the synovium are relatively uncommon. Any mesenchymal tumor may arise in the synovium, but most recapitulate its normal counterpart including synoviocytes, blood vessels, fat, and fibrous tissue. These tumors can arise in any synovial lined structures both within joints and in extraarticular locations. Most synovial tumors are benign. Malignant tumors are rare but important to recognize because many are aggressive and must be treated appropriately. Among common nonneoplastic conditions that affect the synovium and surrounding structures are crystal deposits such as monosodium urate crystals, calcium pyrophosphate dihydrate crystals, and hydroxyapatite crystals. These crystal deposits may be asymptomatic or cause severe pain or chronic joint destruction. Their accurate identification is important to guide appropriate therapy. PMID- 21675378 TI - Surgical pathology of joint prostheses. AB - Joint arthroplasty is a commonly performed surgical procedure that provides significant benefit to the patient. The prosthetic devices are composed of combinations of polyethylene, ceramics, metal alloys, bone cement, and silicone and are associated with complications as well as eventual failure from wear and corrosion. The pathologic findings of these processes are complex and require accurate interpretation to help guide therapy and identify the underlying biological mechanisms. PMID- 21675377 TI - Inflammatory diseases of the bones and joints. AB - The inflammatory diseases of the bones and joints encompass infections and the consequences of immunologically mediated local and systemic disease. Infections involve bones (osteomyelitis) and joints (septic arthritis) separately as well as together and result in necrosis with inflammatory features determined by the duration of the infection. In many cases, the infecting organism, whether bacterial, fungal or mycobacterial, is present within the infected site, but occasionally is no longer identifiable locally despite the persistence of infection-related phenomena. Granulomatous infections in bones and joints require distinction from Sarcoidosis. The diagnosis of the immunologically mediated inflammatory diseases, such as RA, depends as much on the clinical features as on the histologic ones, with a few findings that might point to one or the other in ambiguous cases. Any discussion of inflammatory arthropathies should at least mention Osteoarthritis, if for no other reason than to compare it with the traditionally regarded inflammatory diseases. However, there has been increasing interest on the potential role that synovial inflammation may play in the pathogenesis of this vary common arthritis. Ultimately, the diagnosis of the inflammatory diseases of the bones and joints requires the synthesis of information from many sources: clinical, serological, microbiological, radiographic, and pathological. PMID- 21675379 TI - Benign bone tumors--recent developments. AB - Benign bone tumors frequently pose a diagnostic challenge for general surgical pathologists. Accurate pathologic diagnosis requires careful clinical and radiological correlation. The most significant recent advances in some benign bone tumors have occurred at the molecular and cytogenetic level. The detection of clonal chromosomal aberrations, various specific molecular genetic events, and the description of the bone cell signaling pathways in the field of osteoimmunology have provided a better understanding of the pathophysiology of certain tumors and an important aid in the diagnostic workup and differential diagnosis of some bone lesions demonstrating overlapping clinical and pathologic features. Future directions include prognostic and therapeutic applications of these findings. Newer less invasive therapeutic techniques and medical management have been developed for the treatment of certain benign bone tumors. PMID- 21675380 TI - Primary malignant bone tumors--recent developments. AB - Primary malignant bone tumors are rare sarcomas with an estimated frequency of about 2900 new cases per year; they constitute less than 0.2% of all cancers diagnosed in the United States. The diagnosis and management of these neoplasms require a team approach, which includes orthopaedic surgeons, radiologists, pathologists, and oncologists. With this approach and current treatment modalities, the 5-year survival for the most common malignant bone tumors, osteosarcoma and Ewing sarcoma, are 70% and 60%, respectively. This review will summarize recent developments and advances in molecular pathogenesis of the more common primary malignant bone neoplasms. PMID- 21675381 TI - Reactive bone lesions mimicking neoplasms. AB - Reactive lesions of bone and soft tissue can appear alarming on histologic examination because they are often cellular and have atypical (activated) cytologic features, such as distinct nucleoli and mild hyperchromasia, and mitotic activity. Reactive lesions of bone and periosteum also produce bone and cartilage matrix, resulting in confusion with osteosarcoma or chondrosarcoma. Careful attention to key cytomorphological features such as the pattern of bone formation, uniform appearance of cells, and absence of atypical mitoses should help identify the reactive nature of a lesion. Correlation with clinical and radiological findings is also imperative to avoid misclassification of the tumor because reactive lesions often arise at sites where osteosarcoma and chondrosarcoma are rare (e.g., the hand) and lack aggressive radiological features. In this review we discuss reactive lesions of bone that are commonly confused with malignant neoplasms and that the practicing pathologist is likely to encounter at some point. Several of these lesions have had characteristic chromosomal translocations documented in recent years, but continue to be included as reactive lesions based on their overall clinicopathological features. PMID- 21675382 TI - Medical devices; ear, nose, and throat devices; classification of the wireless air-conduction hearing aid. Final rule. AB - The Food and Drug Administration (FDA) is classifying the wireless air-conduction hearing aid into class II (special controls). The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 21675383 TI - Assessing the financial health of Medicaid managed care plans and the quality of patient care they provide. AB - In many states, Medicaid programs have contracted out the delivery of health care services to publicly traded health plans that are focused on managing the care of Medicaid members. Under the health reform law, states will be expanding the enrollment of their Medicaid programs and these publicly traded companies are expected to capitalize on this growing market. This study examined how publicly traded health plans differ from non-publicly traded ones in terms of administrative expenses, quality of care, and financial stability and found publicly traded plans that focused primarily on Medicaid enrollees paid out the lowest percentage of their Medicaid premium revenues in medical expenses and reported the highest percentage in administrative expenses across different types of health plans. The publicly traded plans also received lower scores for quality of care measures related to preventive care, treatment of chronic conditions, members' access to care, and customer service. PMID- 21675384 TI - Editorial. PMID- 21675385 TI - [Aortic valve construction]. PMID- 21675386 TI - Is self-regulation under threat? PMID- 21675388 TI - Mastering all you survey--part 1. PMID- 21675387 TI - Role models. PMID- 21675389 TI - Confronting the negativity devil head on. PMID- 21675390 TI - Diane Doran: research wins out. PMID- 21675391 TI - EMR: A brave new world? PMID- 21675392 TI - Benefits of volunteering. PMID- 21675393 TI - A study of factors affecting moving-forward behavior among people with spinal cord injury. AB - Enhancing self-efficacy, self-perception, and social support can be an effective way for people with spinal cord injury (SCI) to move forward. The purpose of this study was to explore relationships between "moving-forward behavior" and demographic and disease characteristics, self-efficacy, self-perception, and social support among people with SCI. The study was designed as a descriptive correlation, cross-sectional study. The participants were selected using cluster random sampling (n = 210) through the Spinal Injury Association in Taiwan. A statistically significant relationship was found between moving-forward behavior and age (t = -2.30, p < .05), self-efficacy (gamma = -0.25, p < .01), and self perception (gamma = -0.39, p < .01). Age (odds ratio [OR] = 0.964, p < .05) and self-perception (OR = 0.824, p < .05) were both significant predictors of moving forward behavior. PMID- 21675394 TI - Home health nurses' perceived care errors. AB - The Institute of Medicine (IOM) estimates that every year 44,000 to 98,000 people die due to errors in hospitals, costing approximately $37.6 billion each year (2000). However, limited data are available detailing the extent of healthcare errors outside of hospitals. A cross-sectional study was conducted to assess how home health nurses perceive and deal with errors. A convenience sample of home health agencies (N = 33) located in a Southeastern state participated in the study. Packets containing sealed surveys, a flier, and a description of the study were mailed to the nurses. Nurses were asked to complete a survey about their most significant care error and how they responded. Results from the study on home health nurses' perceptions (N = 203) indicate that the perceived care errors were medication (40%), laboratory (15.5%), wound care (6.5%), scheduling and wrong patient visits (6%), teaching-care errors (5%), and needle sticks (1%). Medication errors remain the most commonly occurring error in the home healthcare area. PMID- 21675395 TI - A nurse-led approach to preventing pressure ulcers. AB - This article discusses a nurse-led multidisciplinary approach that care providers can use to reduce pressure ulcers (PUs) within their organizations. Given the current understanding of PU etiology and prevention, evidence-based prevention protocols and pressure-relief strategies serve as critical foundational principles that must be applied to significantly influence PU prevalence and incidence. Because nursing plays an important role in rehabilitation facility management, nurses' expertise, leadership, and knowledge make nursing the most appropriate discipline to design protocols, implement innovative solutions, and lead the charge for PU prevention. PMID- 21675396 TI - Use of the functional independence measure for outcomes measurement in acute inpatient rehabilitation. AB - Assessment of functional status is a major responsibility for professionals practicing in rehabilitation facilities. Functional assessment tools have been created to meet this need. One of the most widely used tools is the Functional Independence Measure (FIM). Data from the FIM are used to examine patient outcomes for several purposes. This article explores the rationale for use of the FIM as an outcomes measure and research regarding the validity, reliability, responsiveness, and utility of this tool. Limitations of this instrument, future research needs, and implications for rehabilitation professionals also are discussed. PMID- 21675397 TI - Better to light a single candle. AB - The following is a clinical narrative that describes one nurse's attempt to motivate a patient who had recently sustained an injury that caused quadriplegia and the practice implications that arose from "silo" thinking between disciplines. PMID- 21675398 TI - The effect of social support on functional recovery and wellbeing in older adults following joint arthroplasty. AB - Projections by the U.S. Census Bureau indicate a continual rise in the population of older adults. Along with increased dependency among older adults, chronic illness and aging may have attendant social and personal concerns in the areas of health care, community health services, and quality of life. Direct and indirect costs of osteoarthritis are $120 billion per year in medical treatment and lost wages. Every year more than 300,000 knee replacements and 120,000 hip replacements are performed in the United States (Sapountzi-Krepia et al., 2007). A large percentage of joint replacement patients have now assumed responsibility for their recovery process. This exploratory study assessed and measured social support and evaluated its impact on functional recovery and well-being in older adults after joint arthroplasty. Although social support, associated with the covariates of "living arrangements" and "age," demonstrated a positive relationship with perceived wellbeing, no relationship was demonstrated with high or low levels of social support and functional recovery. PMID- 21675399 TI - Cancer survival in Africa, Asia, the Caribbean and Central America. Foreword. PMID- 21675400 TI - Cancer survival in Africa, Asia, the Caribbean and Central America. Introduction. AB - The dearth of reliable survival statistics from developing countries was very evident until the mid-1990s. This prompted the International Agency for Research on Cancer (IARC) to undertake a project that facilitated hands-on-training and thereby transfer of knowledge and technology on cancer survival analysis to a majority of researchers from the participating population-based cancer registries, which culminated in the publication of the first volume of the IARC scientific publication on Cancer Survival in Developing Countries in 1998. The present study is the second in the series with wider geographical coverage and is based on data from 27 registries in 14 countries in Africa, Asia, the Caribbean and Central America. The calendar period of registration of incident cases for the present study ranges between 1990 and 2001. Data on 564 606 cases of 1-56 cancer sites from different registries are reported. Data from eleven registries were utilized for eliciting survival trend and seventeen registries for reporting survival by clinical extent of disease. Besides chapters on every registry and general chapters on methodology, database and overview, the availability of online comparative statistics on cancer survival data by participating registries or cancer site in the form of tables or graphs is an added feature (available online at http://survcan.iarc.fr). PMID- 21675401 TI - Stastistical methods for cancer survival analysis. AB - Adequate and complete follow-up is a prerequisite for the conduct of any survival study. Passive follow-up relies on routine availability of mortality data through unique data linkage possibilities, while active follow-up supplements mortality ascertainment, for which there are a variety of methods. Cox proportional-hazard model was employed to test whether censoring was random in presence of loss to follow-up. Absolute survival probability was estimated by the actuarial method following semi-complete approach for all registries, and the period approach was also used wherever possible. Expected survival probability for registries was estimated from the respective country-, age- and sex-specific abridged life tables. Relative survival, as the ratio of absolute to expected survival, was calculated to exclude the effect arising from different background mortalities. To account for the differences in the age structure of the cancer cases, relative survival was adjusted for age and reported as age-standardized relative survival. Estimated incident cancer cases from less-developed countries together for every classified cancer site served as the standard population. Weights were assigned to individual patients, depending on their age, and standardization was carried out using weighted individual data. Analyses were done using the publicly available macros in SAS software. PMID- 21675402 TI - Loss-adjusted hospital and population-based survival of cancer patients. AB - This chapter presents formulae that methodologically adjust for losses, and gives examples describing magnitude of bias in survival estimates without such adjustment. Loss-adjusted survival is estimated under the assumption that survival of patients Lost to follow-up is the same as that for patients with known follow-up time and similar characteristics of different prognostic factors at first entry. The observed number of Losses to follow-up is then relocated into expected numbers of death and survivors on this basis. Standard methods, such as the actuarial one, are then applied with the sum of observed and expected outcome events. A total of 336 hospital series of treated new breast cancer cases from Mumbai with 24% lost to follow-up revealed a substantial bias of 7 per cent units for 3-year survival estimated with (54%) and without (61%) loss-adjustment. Stepwise adjustment of losses established that increasing the number of prognostic factors explained the bias better. Population-based series comprising 13 371 cases of top ranking cancers from Chennai, with loss to follow-up ranging from 7-24%, revealed negligible bias, ranging from 0-2% in 5-year survival by the loss-adjusted approach for different cancers. Data source seems to affect the need for loss-adjustment, and the loss-adjusted approach is recommended when hospital-based cancer registry data of a low- or medium-resource country are used to evaluate the outcome of cancer patients. PMID- 21675403 TI - Cancer survival in Africa, Asia, the Caribbean and Central America: database and attributes. AB - Thirty-one registries in 17 countries submitted data for systematic and centralized scrutiny. Data on 564 606 cases of different cancers ranging 1-56 sites/types from 27 registries in 14 low-/medium-resource countries in Eastern and Western Africa, the Caribbean, Central America and four regions of Asia, registered during 1990-2001 (period varying for individual registries) were reported. The database for this survival study comprised data that were classified as mandatory and optional. Mandatory variables provided by all registries included case-ID, age at diagnosis, sex, incidence date, most valid basis of diagnosis, cancer site/type (ICD-10 codes C00-96), vital status at follow-up and corresponding date. Clinical extent of disease was prominent among the optional variables provided by 17 registries and analysed. The grouping of cancer sites for analysis was based on standard norms, and only categories with at least 25 cases were reported. Cases registered based on a death certificate only, cases lacking any follow-up after initial registration, or cases rejected based on validation checks were excluded from the survival analysis. An easy guide to contents in subsequent chapters, especially tables and graphs describing data quality indices, survival statistics and online dynamic functions, is provided. PMID- 21675404 TI - Cancer survival in Hong Kong SAR, China, 1996-2001. AB - The Hong Kong cancer registry was established in 1963, and cancer registration is done by passive and active methods. The registry contributed data on 45 cancer sites or types registered during 1996-2001 for this survival study. Follow-up has been carried out by passive methods with median follow-up ranging from 4-60 months. The proportion of cases with histologically verified cancer diagnosis ranged from 38-100%; death certificates only (DCOs) ranged from 0-11%; 83-99% of total registered cases were included for survival analysis. The 5-year age standardized relative survival exceeded 100% for lip and non-melanoma skin followed by thyroid (94%) and testicular (92%) cancers. The corresponding survival for common cancers were breast (90%), colon (61%), liver and Lung (22%), nasopharynx (70%), rectum (59%) and stomach (39%). The 5-year relative survival by age group showed a decreasing trend with increasing agegroups for most cancers. A decreasing survival with increasing clinical extent of disease was noted. PMID- 21675405 TI - Cancer survival in Qidong, China, 1992-2000. AB - The Qidong cancer registry was established in 1972, and registration of cases is done by active and passive methods. The registry contributed data on 33 cancer sites or types registered during 1992-2000 for this survival study. Data on 22 cancers registered during 1972-2000 were utilized to elicit the survival trend by period and cohort approaches. Follow-up was done by a mixture of active and passive methods, with median follow-up ranging from 2-25 months. The proportion of cases with histologically verified cancer diagnosis ranged from 9-100%, and 87 100% of total registered cases were included for survival analysis. The top ranking cancers on 5-year age-standardized relative survival (%) were thyroid (78%), breast (58%), corpus uteri (54%), larynx (51%) and urinary bladder (42%). The corresponding survival rates for common cancers were liver (6%), lung (7%) and stomach (18%). The 5-year relative survival by age group fluctuated and showed no distinct pattern or trend. The comparison of 5-year relative survival trend by cohort and period approaches revealed that period survival closely predicted the survival experience of cancer cases diagnosed in that period for most cancers. PMID- 21675406 TI - Cancer survival in Shanghai, China, 1992-1995. AB - The Shanghai cancer registry, established in 1963, is the oldest one in mainland China; cancer registration is entirely done by passive methods. The registry contributed data on 52 cancer sites or types registered during 1992-1995 for this survival study. The methods of follow-up have been a mixture of both active and passive ones, with median follow-up ranging 3-81 months. The proportion with histologically verified diagnosis for various cancers ranged from 14-95%; death certificates only (DCOs) ranged from 0-2% and 98-100% of total registered cases were included for survival analysis. The top ranking cancers on 5-year age standardized relative survival (%) were thyroid (90%), non-melanoma skin (86%), penis (84%), corpus uteri (82%) and testis (80%). The corresponding survival rates for common cancers were lung (16%), stomach (30%), liver (9%), breast (78%) and colon (48%). The 5-year relative survival by age group reveals an inverse relationship for most cancers. An increasing trend in the 5-year absolute andrelative survival was noted for all cancers registered in 1992-1995 compared to 1988-1991. PMID- 21675407 TI - Cancer survival in Tianjin, China, 1991-1999. AB - The Tianjin cancer registry was established in 1978, and registration of cases is done by the active method. The registry contributed data on 51 cancer sites or types registered during 1991-1999 for this survival study. Follow-up has been a mixture of both active and passive methods, with median follow-up ranging from 5 77 months. The proportion with histologically verified diagnosis for various cancers ranged from 21-95% and 97-100% of total registered cases were included for survival analysis. The top-ranking cancers by 5-year age-standardized relative survival (%) were renal pelvis (101%), lip (99%), corpus uteri (91%), penis and nonmelanoma skin (90%) and thyroid (89%). The corresponding survival for common cancers were lung (31%), stomach (41%), Liver (25%) and breast (82%). The 5-year relative survival by age group reveals an inverse relationship for a few cancers and fluctuated for most cancers. Period survival closely predicted the survival experience of cancer cases diagnosed in that period, with the 5-year relative survival in 1991-1995 by period approach being more or less similar to survival by cohort approach in 1996-1999 for most cancers. PMID- 21675408 TI - Cancer survival in Costa Rica, 1995-2000. AB - The Costa Rica national tumour registry was founded in 1976 and nationwide data collection commenced in 1980. Cancer registration is predominantly done by passive methods. The registry contributed data on survival for invasive cancers of breast and cervix and in situ cancer of the cervix registered during 1995 2000. Followup has been carried out predominantly by passive methods, with median follow-up ranging from 31-47 months. The proportion of cases with histological confirmation of cancer diagnosis was 92% for invasive cancers and almost 100% for in-situ cancer of the cervix; death certificates only (DCOs) comprised 3%, and 78 86% of total cases registered were included for survival analysis. The one-, three- and five-year relative survival were 93%, 77% and 68%, respectively for breast cancer; the corresponding figures for invasive cervix cancer were 83%, 61% and 54%, respectively. The five-year relative survival for in-situ cervix cancer was 99%. A decreasing survival with increasing age group at diagnosis was noted for in-situ cancer of the cervix, while it fluctuated for invasive breast and cervix cancers. A decreasing survival with increasing clinical extent of disease was noted for invasive breast and cervix cancers. PMID- 21675409 TI - Cancer survival in Cuba, 1994-1995. AB - The population-based cancer registry in Cuba is a national cancer registry established in 1964; cancer registration is entirely done by passive methods. Data on survival from 13 cancer sites or types registered during 1994-1995 are reported. Follow-up has been carried out predominantly by passive methods, with median follow-up ranging from 13-54 months. The proportion with histologically verified diagnosis for various cancers ranged between 34-100%; death certificates only (DCOs) comprised 8-50%; 50-89% of total registered cases were included for the survival analysis. The 5-year age-standardized relative survival for selected cancers were breast (69%), colon (41%), cervix (56%), urinary bladder (64%), rectum (48%) and non-Hodgkin lymphoma (49%). The 5-year relative survival by age group showed no distinct pattern or trend, and was fluctuating. A decreasing survival with increasing clinical extent of disease was noted for all cancers studied. The data on survival trend revealed that the 5-year relative survival of most cancers diagnosed in 1994-1995 was greater than that in 1988-1989. PMID- 21675410 TI - Cancer survival in the Gambia, 1993-1997. AB - The national cancer registry of the Gambia was established in 1986 as part of the Gambia Hepatitis Intervention Study in collaboration with IARC, France; Medical Research Council (MRC) Laboratories of the UK; and the Government of the Gambia at MRC, Banjul. Registration of incident cancer cases is done by active and passive methods. For this study, the registry contributed data on survival for six cancer sites or types registered during 1993-1997. Follow-up has been carried out predominantly by active methods with median follow-up ranging between 1-6 months. The proportion of histologically verified diagnosis for various cancers ranged between 1-45%, and 54-82% of total registered cases were included for survival analysis. Complete follow-up at five years from the incidence date ranged between 81-98% for different cancers. The 5-year age-standardized relative survival for selected cancers were cervix (23%), non-Hodgkin lymphoma (22%), breast (10%), stomach (4%) and liver (3%). The 5-year relative survival by age group showed fluctuations with no definite pattern or trend emerging, and with no survivors in many age intervals. PMID- 21675411 TI - Cancer survival in Barshi, India, 1993-2000. AB - The rural cancer registry of Barshi, Paranda and Bhum, was the first of its kind in India and was established in 1987. Registration of cases is carried out entirely by active methods. Data on survival from 15 cancer sites or types registered during 1993-2000 are reported in this study. Follow-up has been carried out predominantly by active methods, with median follow-up time ranging between 2-49 months for different cancers. The proportion of histologically verified diagnosis for various cancers ranged between 73-98%; death certificates only (DCOs) comprised 0-2%; 98-100% of total registered cases were included for survival analysis. Complete follow-up at five years ranged between 96-100% for different cancers. The 5-year age-standardized relative survival rates for selected cancers were non-melanoma skin (86%), penis (63%), breast (61%), cervix (32%), mouth (23%), hypopharynx (11%) and oesophagus (4%). The 5-year relative survival by age group did not display any particular pattern. Five-year relative survival trend between 1988-1992 and 1993-2000 showed a marked decrease for cancers of the tongue, hypopharynx, stomach, rectum, larynx, lung and penis; but a notable increase for breast and non-Hodgkin lymphoma. PMID- 21675412 TI - Cancer survival in Bhopal, India, 1991-1995. AB - The Bhopal population-based cancer registry was established in 1986 under the national cancer registry programme to investigate the after-effect of a gas leak in 1984. Cancer registration is done entirely by active methods. The registry is contributing data on survival for 16 cancer sites or types registered during 1991 1995. Follow-up of cases was done by active methods with median follow-up time ranging between 8-44 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged between 61-100%; death certificates only (DCOs) comprised 0-2%; 50-92% of total registered cases were included for survival analysis. The 5-year age-standardized relative survival rates for common cancers were mouth (34%), cervix (31%), breast (25%), tongue (12%), oesophagus (3%) and lung (1%). The 5-year relative survival by age group showed that survival was the highest in the youngest age group (45 years and below) for a majority of cancers. A decreasing survival with increasing clinical extent of disease was noted for most cancers studied. PMID- 21675413 TI - Cancer survival in Chennai (Madras), India, 1990-1999. AB - The Madras metropolitan tumour registry was established in 1981, and registration of incident cancer cases is entirely done by active method. Data on survival for 20 cancer sites or types registered during 1990-1999 are reported. Follow-up has been carried out predominantly by active methods with a median follow-up time ranging between 2-28 months for different cancers. The proportion of histologically verified diagnosis for various cancers ranged between 45-100%; death certificates only (DCOs) comprised 0-5%; 68-95% of total registered cases were included for survival analysis. Complete follow-up at five years ranged between 83-96%. The 5-year age-standardized relative survival rates for common cancers were cervix (60%), breast (47%), stomach (8%), oesophagus (9%), lung (6%) and mouth (36%). The 5-year relative survival by age group portrayed either an inverse relationship or fluctuated. A majority of cases were diagnosed with regional spread of disease, and survival decreased with increasing extent of disease. The absolute difference in 5-year relative survival of most cancers diagnosed in 1984-1989 and1990-1999 ranged between 2-3%, with lesser survival in the latest period in most instances. PMID- 21675414 TI - Cancer survival in Karunagappally, India, 1991-1997. AB - The rural cancer registry of Karunagappally was established in 1990 to study cancer occurrence due to high natural background radiation in the coastal area of Kerala state. Cancer registration was done by active methods. The registry contributed data on survival for 22 cancer sites or types registered during 1991 1997. Follow-up has been carried out predominantly by active methods, with median follow-up time ranging between 3-57 months for various cancers. The proportion of histologically verified diagnosis for different cancers ranged between 39-100%; death certificates only (DCOs) comprised 0-25%; 75-100% of total registered cases were included for survival analysis. The 5-year age-standardized relative survival rates for common cancers were lung (6%), breast (45%), cervix (55%), mouth (42%), oesophagus (14%) and tongue (31%). Five-year relative survival by age group showed no distinct pattern or trend for most cancers. A majority of cases are diagnosed with a regional spread of disease among cancers of the tongue (48%), oral cavity (66%), hypopharynx (54%), larynx (46%), cervix (61%) and breast (53%); survival decreases with increasing extent of disease. PMID- 21675415 TI - Cancer survival in Mumbai (Bombay), India, 1992-1999. AB - The Bombay cancer registry is the second oldest population-based cancer registry in Asia, and the first of its kind in India. It was established in 1963, and registration of cases is done by active methods. Data on survival from 28 cancer sites or types registered during 1992-1999 are reported. Follow-up has been carried out predominantly by active methods, with median follow-up ranging between 1-51 months for different cancers. The proportion of histologically verified diagnosis for various cancers ranged between 41-100%; death certificates only (DCOs) comprised 0-15%; 84-99% of total registered cases were included for survival analysis. Complete follow-up at five years ranged from 85-92% for different cancers. The 5-year age-standardized relative survival rates for common cancers were breast (48%), cervix (44%), lung (11%), oesophagus (14%), oral cavity (35%) and non-Hodgkin lymphoma (34%). The 5-year relative survival by age group portrayed either an inverse relationship or was fluctuating. Cases with a regional spread of disease were the highest for cancers of the tongue, oral cavity, larynx and cervix; survival decreased with the increasing extent of disease for all cancers studied. PMID- 21675416 TI - Cancer survival in South Karachi, Pakistan, 1995-1999. AB - The Karachi cancer registry established in 1995 was the first population-based cancer registry in Pakistan. Cancer registration is done by active methods. The registry contributed data on survival for selected cancers of the head and neck registered during 1995-1999. FoLlow-up has been carried out predominantly by active methods with the median follow-up time ranging between 29-36 months for different cancers. The proportion of histologically verified diagnosis for various cancers ranged between 98-100%; there were no cases as death certificates only (DCOs); 86-93% of total registered cases were included for survival analysis. Five-year followup ranged between 67-76%. The 5-year age-standardized relative survival rates was the highest for cancer of the salivary gland (44%), followed by oral cavity (40%), tongue (39%) and tonsil (3%). Five-year relative survival by age group did not display any pattern or trend and was fluctuating. A majority of cases have been diagnosed with a regional spread of disease: tongue (51%), oral cavity (53%), salivary gland (46%) and tonsil (79%) and survival decreased with increasing extent of disease for these cancers. PMID- 21675417 TI - Cancer survival in Manila, Philippines, 1994-1995. AB - The population-based cancer registry in Manila, Philippines, called the Philippine Cancer Society-Manila Cancer Registry, was established in 1983. Cancer registration is pursued by active methods. The registry contributed survival data on a random sample of total incident cancers of breast (500), cervix (500), colon and rectum (300) registered in 1994-1995. Follow-up has been carried out by passive and active methods, with median follow-up ranging between 15-33 months for different cancers. The proportion of histologically verified diagnosis for various cancers ranged between 78-88%; 74-83% of the total submitted cases were included for survival analysis. Complete follow-up at five years was available in 75-82% of cases. Five-year age-standardized relative survival rates was the highest for cancer of the breast (52%) followed by colon (49%), cervix (36%) and rectum (31%). Five-year relative survival by age group did not display any pattern or trend and was fluctuating. A decreasing survival with increasing extent of disease was noted for all cancers. PMID- 21675418 TI - Breast cancer survival in Rizal, Philippines, 1996-1997. AB - The department of health-Rizal cancer registry (DOH-RCR) was the first population based cancer registry in the Philippines, established in 1974. Even though cancer is reportable by legislation, cancer registration is pursued by active methods. Data on survival from cancer of the breast registered in 1996-1997 are reported. Followup was carried out by passive and active methods. The proportion of cases with a histological confirmation of cancer diagnosis was 90%; death certificates only (DCOs) constituted 6%; 81% of the total registered were included for the survival analysis. Complete follow-up at five years from the incidence date was 30%. Relative survival rates at one, three and five years were 89%, 56% and 37%, respectively. Five-year age-standardized relative survival was 35%. Five-year relative survival by age group did not display any pattern or trend, and was fluctuating. A majority of cases were diagnosed with a regional spread of disease (44%) followed by localized stage (17%). Five-year absolute survival ratesby extent of disease were localized (65%), regional (35%), distant metastasis (12%) and unknown (35%). Thetrend of 5-year survival for breast cancer decreased from 46% in 1987 to 37% in 1996-1997. PMID- 21675419 TI - Cancer survival in Busan, Republic of Korea, 1996-2001. AB - The Busan cancer registry was established in 1996; cancer registration is done by passive and active methods. The registry contributed survival data for 48 cancer sites or types registered during 1996-2001. Follow-up information has been gleaned predominantly by passive methods with median follow-up ranging between 1 57 months for various cancers. The proportion with histologically verified diagnosis for different cancers ranged between 20-100%; death certificates only (DCOs) comprised 0-53%; 47-100% of total registered cases were included for survival analysis. The top-ranking cancers on 5-year age-standardized relative survival rates were penis (94%), thyroid (91%), non-melanoma skin (89%), placenta (86%), breast (76%), Hodgkin lymphoma (75%) and testis (72%). Five-year relative survival by age group showed a decreasing trend with increasing age groups for cancers of the nasopharynx, gall bladder, lung, bone, soft tissue, breast, cervix, corpus uteri, thyroid, multiple myeloma, lymphoid leukaemia and myeloid leukaemia or was fluctuating for other cancers. PMID- 21675420 TI - Cancer survival in Incheon, Republic of Korea, 1997-2001. AB - The Incheon cancer registry was established in 1997. Cancer is not a notifiable disease, hence registration of cases is done by active methods. The registry contributed survival data for 42 cancer sites or types registered during 1997 2001. The follow-up information has been obtained predominantly by passive methods, with median follow-up ranging between 1-44 months for various cancers. The proportion with histologically verified diagnosis for different cancers ranged between 16-100%; death certificates only (DCOs) comprised 0-51%; 49-100% of total registered cases were included for the survival analysis. The top ranking cancers on 5-year age-standardized relative survival rates were testis (98%), thyroid (90%), ureter (87%), adrenal gland (86%), nonmelanoma skin (83%), corpus uteri (82%), Hodgkin lymphoma (81%), breast and cervix (74%). Five-year relative survival by age group showed a decreasing trend with increasing age groups for cancers of the stomach, small intestine, colon, gall bladder, larynx, lung, breast, cervix and ovary, and was fluctuating for other cancers. PMID- 21675421 TI - Cancer survival in Seoul, Republic of Korea, 1993-1997. AB - The Seoul cancer registry was established in 1991. Cancer is a notifiable disease, and registration of cases is done by passive and active methods. The registry contributed survival data for 56 cancer sites or types registered during 1993-1997. Follow-up information has been gleaned predominantly by passive methods with median follow-up ranging between 5-82 months for various cancers. The proportion with histologically verified diagnosis for different cancers ranged between 23-99%; death certificates only (DCOs) comprised 0-67%; 33-100% of total registered cases were included for survival analysis. The top-ranking cancers on 5-year age-standardized relative survival rates were testis and placenta (95%), thyroid (93%), non-melanoma skin (93%), corpus uteri (79%), renal pelvis (77%), cervix (76%), Hodgkin lymphoma (75%), breast (74%) and prostate (74%). Five-year relative survival by age group showed a decreasing trend with increasing age groups for cancers of the small intestine, colon, gall bladder, cervix, corpus uteri, ovary, kidney, urinary bladder and thyroid, or was fluctuating for other cancers. PMID- 21675422 TI - Breast cancer survival in Riyadh, Saudi Arabia, 1994-1996. AB - The national cancer registry in Saudi Arabia has functioned since 1994, collecting population-based incidence data on malignant and in situ tumours. Cancer registration is carried out by both passive and active methods. The registry contributed data on survival from cancer of the breast registered in 1994-1996 from Riyadh province. Follow-up was carried out predominantly by active methods, and the median follow-up was 57 months. The proportion of cases with a histological confirmation of breast cancer diagnosis was almost 100%; there were no cases registered based on death certificate only (DCO); 93% of total cases registered were included in the survival analysis. Complete follow-up at five years was 80%. Relative survival rates at one, three and five years were 96%, 83% and 65%, respectively. Five-year age-standardized relative survival was 65%. Five year relative survival by age group did not show any pattern and was fluctuating. Five-year absolute survival by extent of disease was localized (70%), regional (56%), distant metastasis (57%) and unknown (62%). PMID- 21675423 TI - Cancer survival in Singapore, 1993-1997. AB - The Singapore cancer registry is a national registry established in 1968. Cancer registration is done by passive methods. The registry contributed survival data on 45 cancer sites or types registered during 1993-1997. Data on 34 cancers registered during 1968-1997 were utilized for survival trend by period and cohort approaches. Follow-up was done by passive methods, with median follow-up ranging between 2-72 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged between 27-100%; death certificates only (DCOs) comprised 0-7%; 76-100% of total registered cases were included for the survival analysis. The top-ranking cancers on 5-year age-standardized relative survival rates were nonmelanoma skin (96%), thyroid (90%), testis (88%), corpus uteri (77%), breast (74%), Hodgkin lymphoma (73%) and penis (70%). Five year relative survival by age group showed either a decreasing trend with increasing age groups or was fluctuating. Localized stage of disease ranged between 18-65% for various cancers and survival decreased with increasing extent of disease. Period survival closely predicted survival experience of cancers diagnosed in that period, and an increasing trend in period survival over different periods indicated an improved prognosis for cancers diagnosed in those calendar periods. PMID- 21675424 TI - Cancer survival in Chiang Mai, Thailand, 1993-1997. AB - The Chiang Mai tumour registry was established in 1978 as a hospital-based cancer registry, and population-based cancer registration started in 1986, with retrospective data collection on cancer incidence and mortality since 1983. Registration of cases is done by active methods. Data on survival for 36 cancer sites or types registered during 1993-1997 are reported here. Follow-up has been carried out predominantly by active methods, with median follow-up ranging between 1-39 months for different cancers. The proportion of histologically verified diagnosis for various cancers ranged between 28-100%; death certificate only (DCO) cases comprised 0-56%; 33-92% of total registered cases were included for survival analysis. Complete followup at five years ranged from 59-100% for different cancers. The 5-year age-standardized relative survival rates was the highest for Hodgkin lymphoma (70%) followed by thyroid (65%), cervix (57%), breast (56%) and corpus uteri (49%). The 5-year relative survival by age group showed either an inverse relationship or was fluctuating. An overwhelmingly high proportion of cases were diagnosed with a regional spread of disease, ranging between 44-82% for different cancers and survival decreased with increasing extent of disease for all cancers studied. PMID- 21675425 TI - Cancer survival in Khon Kaen, Thailand, 1993-1997. AB - The Khon Kaen cancer registry was established in 1984 as a hospital-based cancer registry, and population-based cancer registration started in 1988 with retrospective data collection from 1985. Cancer registration is done by passive and active methods. Data on survival for 13 cancer sites or types registered during 1993-1997 were reported. Follow-up was done by active methods, with median follow-up ranging between 8-32 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged between 54-100%; death certificates only (DCOs) comprised 0-5%; 85-97% of total registered cases were included for survival analysis. Five-year follow-up ranged from 40-83%. Five year age-standardized relative survival rates for common cancers were cervix (58%), breast (61%), colon (39%), ovary (43%), non-Hodgkin lymphoma (42%) and rectum (43%). Five-year relative survival by age group portrayed an inverse relationship or was fluctuating. Five-year survival was the highest for localized disease, followed by the regional and distant metastasis categories. Trends in 5 year relative survival in 1993-1997 compared to 1985-1992 showed a marked increase for cancers of the rectum, breast, ovary, Hodgkin and non-Hodgkin lymphomas and decrease for cancers of the lip and larynx. PMID- 21675426 TI - Cancer survival in Lampang, Thailand, 1990-2000. AB - The Lampang cancer registry was established in 1995, with retrospective data collection since 1988. Cancer registration is currently done by passive methods. The registry is contributing data on survival for 40 cancer sites or types registered during 1990-2000. Follow-up has been carried out by passive and active methods with median follow-up ranging from 1-74 months for different cancers. The proportion having a histologically verified diagnosis for various cancers ranged between 30-100%; death certificate only (DCO) cases comprised 0-33%; 67-100% of total registered cases were included for survival analysis. Complete follow-up at five years ranged from 96-100% for different cancers. The 5-year age-standardized relative survival rate was the highest for skin non-melanoma (85%) followed by lip (81%), thyroid (74%), corpus uteri (71%) and penis (71%). The 5-year relative survival by age group showed a fluctuating trend. An overwhelmingly high proportion of cases were diagnosed with a regional spread of disease, ranging from 35-68% for different cancers, and survival was decreasing with increasing extent of disease for most cancers studied. PMID- 21675427 TI - Cancer survival in Songkhla, Thailand, 1990-1999. AB - The Songkhla registry, besides being hospital-based, has population-based cancer registration data available since 1990. Cancer registration is done by active methods. The registry is contributing data on survival for 36 cancer sites or types registered during 1990-1999. Follow-up has been carried out by passive and active methods with median follow-up ranging from 3-71 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged between 52-100%; death certificate only (DCO) cases comprised 0 34%; 54-93% of total registered cases were included for survival analysis. Complete followup at five years ranged from 50-85% for different cancers. Five year age-standardized relative survival rates of common cancers were cervix (59%), lung (7%), breast (59%), thyroid (86%), oesophagus (11%), liver (2%), nonmelanoma skin (75%), colon (45%) and oral cavity (33%). Five-year relative survival by age group did not reveal any pattern or trend and was fluctuating. A majority were diagnosed with regional spread of disease, and survival decreased with increasing clinical extent of disease. PMID- 21675428 TI - Cancer survival in Izmir, Turkey, 1995-1997. AB - The Izmir cancer registry, the first population-based cancer registry in Turkey, was established in 1992. Cancer registration is now done by active methods. The registry contributed data on survival for 12 cancer sites or types registered in 1995-1997. Follow-up was predominantly done by active methods with median follow up ranging between 17-72 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged between 84-100%; there were no death certificate only (DCO) cases; 98-100% of total registered cases were included for the survival analysis. Complete follow-up at five years ranged from 79-98% for different cancers. Five-year age-standardized relative survival rates of common cancers were breast (77%), urinary bladder (70%), Larynx (69%), colon (53%), rectum (52%), non-Hodgkin Lymphoma (50%) and cervix (58%). Five-year relative survival by age group portrayed decreasing survival with increasing age at diagnosis for cancer of the cervix, and was fluctuating for other cancers. Decreasing survival with increasing clinical extent of disease was also noted. PMID- 21675429 TI - Cancer survival in Kampala, Uganda, 1993-1997. AB - The Kampala cancer registry was established in 1954 as a population-based cancer registry, and registration of cases is done by active methods. The registry contributed data on survival for 15 cancer sites or types registered in 1993 1997. For Kaposi sarcoma, only a random sample of the total incident cases was provided for survival study. Follow-up has been carried out predominantly by active methods, with median follow-up ranging from 4-26 months. The proportion with histologically verified diagnosis for various cancers ranged between 36-83%; death certificate only (DCO) cases were negligible; 58-92% of total registered cases were included for survival analysis. Complete follow-up at five years ranged between 47-87% for different cancers. Five-year age-standardized relative survival rates for selected cancers were Kaposi sarcoma (22%), cervix (19%), oesophagus (5%), non-Hodgkin lymphoma (26%), breast (36%) and prostate (46%). None survived beyond 5 years for cancers of the stomach and lung. Five-year relative survival by age group was fluctuating with no definite pattern or trend emerging and no survivors in many age intervals. PMID- 21675430 TI - Cancer survival in Harare, Zimbabwe, 1993-1997. AB - The Zimbabwe national cancer registry was established in 1985 as a population based cancer registry covering Harare city. Cancer is not a notifiable disease, and registration of cases is done by active methods. The registry contributed data on randomly drawn sub-samples of Harare resident cases among 17 common cancer sites or types registered during 1993-1997 from black and white populations. Follow-up was carried out predominantly by active methods with median follow-up ranging from 1-54 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged from 20-100%; death certificate only (DCO) cases comprised 0-34%; 58-97% of total registered cases were included for survival analysis. Complete follow-up at five years ranged from 94-100%. Five-year age-standardized relative survival rates of selected cancers among both races combined were cervix (42%), breast (68%), Kaposi sarcoma (4%), liver (3%), oesophagus (12%), stomach (20%) and lung (14%). Survival was markedly higher among white than black populations for most cancers with adequate cases. Five-year relative survival by age group was fluctuating, with no definite pattern or trend. PMID- 21675431 TI - An overview of cancer survival in Africa, Asia, the Caribbean and Central America: the case for investment in cancer health services. AB - Population-based cancer survival data, a key indicator for monitoring progress against cancer, are reported from 27 population-based cancer registries in 14 countries in Africa, Asia, the Caribbean and Central America. In China, Singapore, the Republic of Korea, and Turkey, the 5-year age-standardized relative survival ranged from 76-82% for breast, 63-79% for cervical, 71-78% for bladder, and 44-60% for large-bowel cancer. Survival did not exceed 22% for any cancer site in The Gambia, or 13% for any cancer site except breast (46%) in Uganda. For localized cancers of the breast, large bowel, larynx, ovary, urinary bladder and for regional diseases at all sites, higher survival rates were observed in countries with more rather than less developed health services. Inter and intra-country variations in survival imply that the levels of development of health services and their efficiency to provide early diagnosis, treatment and clinical follow-up care have a profound impact on survival from cancer. These are reliable baseline summary estimates to evaluate improvements in cancer control and emphasise the need for urgent investment to improve awareness, population based cancer registration, early detection programmes, health-services infrastructure, and human resources in these countries in the future. PMID- 21675432 TI - An exercise in backwards logic: how expanding the Family and Medical Leave Act can enhance business continuity & productivity during a public health emergency. PMID- 21675433 TI - For love or money: an analysis of the contractual regulation of reproductive surrogacy. PMID- 21675434 TI - Commentary. PMID- 21675435 TI - Crafting legislation to prevent cyberbullying: the use of education, reporting, and threshold requirements. PMID- 21675436 TI - An integrated response to sexting: utilization of parents and schools in deterrence. PMID- 21675437 TI - The preferential treatment of employer-provided health care: time for a change? PMID- 21675438 TI - Down on the pharm: the juvenile prescription drug abuse epidemic and the necessity of holding parents criminally liable for making drugs accessible in their homes. PMID- 21675439 TI - Combined maternal serum inhibin A and embryonic/ fetal heart rate for the prediction of pregnancy outcome in a first-trimester threatened abortion. AB - OBJECTIVE: To examine the value of combined maternal serum inhibin A and embryonic/fetal heart rate to predict the pregnancy outcome in a first-trimester threatened abortion. MATERIALS AND METHOD: This was a prospective observational study. The authors measured maternal serum inhibin A and the embryonic/fetal heart rate in women with a clinical diagnosis of a threatened abortion and in normal pregnant women. The main outcome measured was ongoing normal pregnancies. RESULTS: Thirty women with threatened abortions and 30 normal pregnant women were followed. Three women with threatened abortions ended in failed pregnancies. The mean embryonic/fetal heart rate and the median of serum inhibin A in the threatened abortion group were not different from the control group. In women with threatened abortions and failing pregnancies, the embryonic/fetal heart rate (101.7 +/- 20.1 beats/min) was significantly lower than in women with threatened abortions but ongoing pregnancies (163.3 +/- 19.7 beats/min, p = 0.024). Serum inhibin A in women with threatened abortions and failing pregnancies was not different from women with threatened abortions but ongoing pregnancies (median) 274.0 vs. 559.9 pg/mL, p = 0.388). When using serum inhibin A combined with embryonic/fetal heart rate, or only embryonic/fetal heart rate, the sensitivity and specificity for predicting an ongoing pregnancy were 100% and 50% or 100% and 100%, respectively. CONCLUSION: Combined maternal serum inhibin A and embryonic/fetal heart rate is not better than embryonic/fetal heart rate for predicting the pregnancy outcome in a first-trimester threatened abortion. PMID- 21675440 TI - Rectal misoprostol in management of retained placenta: a contradictory result. AB - BACKGROUND: Retained placenta is one of the common problems in obstetric practice. The most common procedure to manage cases with retained placenta is manual removal of placenta (MROP) under general anesthesia. Recent data indicates that misoprostol may be helpful in decreasing the rate of MROP. OBJECTIVE: To assess the efficacy of rectal misoprostol in women with delayed placental separation. MATERIAL AND METHOD: A descriptive, retrospective cohort was conducted. All pregnant women with retained placenta longer than 30 minutes after fetal delivery, either in second or third trimester that received 800 mcg rectal misoprostol were included in the present study. Successful treatment was defined as spontaneous placental expulsion within 30 minutes after rectal misoprostol administration. RESULTS: The rate of spontaneous placental expulsion within 30 minutes after misoprostol administration was very low, only three out of 20 cases (15%). CONCLUSION: High dose rectal misoprostol does not give a promising result in cases of retained placenta. It is ineffective to facilitate placental separation in cases of retained placenta and does not seem to decrease the rate of MROP. PMID- 21675441 TI - Sensitivity and specificity of modified 100-g oral glucose tolerance tests for diagnosis of gestational diabetes mellitus. AB - OBJECTIVE: To study the sensitivity and specificity of the modified 100-g oral glucose tolerance test for diagnosis of gestational diabetes mellitus (GDM). MATERIAL AND METHOD: Medical records of pregnant women attending the antenatal clinic of King Chulalongkorn Memorial Hospital, Thailand, who underwent a 100-g oral glucose tolerance test (OGTT) during March 2004 to September 2009, were retrospectively reviewed. Three modified criteria were proposed for diagnosis of GDM. The screening efficacy of the modified criteria were assessed, using the National Diabetes Data Group (NDDG) criterion as gold standard. RESULTS: A total of 729 records were reviewed, 511 were included for analysis. Using the NDDG criterion as the gold standard, the modified II criterion has the highest sensitivity of 96.8%, and the highest accuracy of 90.8%. The modified II criterion can detect the same proportion of maternal and neonatal complications, compared to the NDDG criterion. CONCLUSION: The modified II criterion, using the fasting plasma glucose and 2-hour plasma glucose measurements, showed high sensitivity and accuracy, with moderate specificity for diagnosis of GDM. Its potential use as an alternative to standard 100-g OGTT should be evaluated in the prospective study. PMID- 21675442 TI - Antibiotic prescription for adults with acute diarrhea at King Chulalongkorn Memorial Hospital, Thailand. AB - BACKGROUND: In Thailand, acute diarrhea is one of the most common problems among ambulatory patients at the outpatient department (OPD). Overuse of antibiotics is associated with increased rates of antibiotic-resistant bacteria, unnecessary increased cost of treatment, and significant incidence of adverse effects. In Thailand, how frequently antibiotic is prescribed in adult patients with acute diarrhea is not known. MATERIAL AND METHOD: The authors performed a retrospective study in all adult patients with acute diarrhea attending at the OPD of King Chulalongkorn Memorial Hospital, Bangkok, Thailand between August 2009 and January 2010 as ambulatory basis. All data regarding epidemiology, clinical features, and treatment were evaluated. RESULTS: There were 390 [255 females (65.4%) and 135 males (34.6%)] patients during the study period. There were 91 (23.3%) with inflammatory diarrhea and 209 (76.7%) patients with non-inflammatory diarrhea. Only 36 (9.2%) patients had stool examination and culture results. Of 13 (36.1%) patients with positive stool cultures, four (11.1%) patients had Vibrio parahaemolyticus, two (5.7%) patients each had non-O1 Vibrio cholerae, Cryptosporidium parvum, or Plesiomonas shigelloides and V. parahaemolyticus, and one (2.9%) patient each had P. shigelloides, P. shigelloides and Salmonella, or group D Salmonella. Three hundred fifty three (90.5%) and 37 (9.5%) patients were treated by residents and faculty staffs, respectively One hundred and seventy-six (45.1%) patients received antibiotics, which included norfloxacin (128 patients, 72.7%), ciprofloxacin (34, 19.3%), ceftriaxone and ciprofloxacin (6, 3.4%), ceftriaxone (5, 2.8%), ceftriaxone and norfloxacin (2, 1.1%), amoxicillin (1, 0.6%), and ofloxacin (1, 0.6%). One hundred and forty-eight of 353 (41.9%) residents and 28 of 37 (75.7%) faculty staffs prescribed antibiotics. According to the recommendations by WHO, the rate of overuse of antibiotics was 48.9% (86 of 176 patients). CONCLUSION: There is a very high rate of overuse of antibiotics in Chulalongkorn Hospital. Both attributing physician- and patient-related factors should be evaluated before implementing an effective strategy to change prescribing behavior. PMID- 21675443 TI - Central nervous system infections in HIV-infected patients hospitalized at King Chulalongkorn Memorial Hospital. AB - BACKGROUND: Central nervous system (CNS) infections are among one of the most common complications in HIV-infected patients. The present study aimed to determine the etiologies, clinical features, treatment, and outcomes of all CNS infections in HIV-infected patients. MATERIAL AND METHOD: A retrospective study was carried out in all adult HIV-infected patients with CNS infection who were hospitalized at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, from January 1, 2007 to December 31, 2008. Medical records ofthe patients were identified by extensively searching the disease codes based on International Classification ofDiseases-10, all microbiological data, and all histopathological data. RESULTS: One hundredforty eight patients were enrolled. There were 103 males (69.6%) with the mean age of 36.1 +/- 8.9 years (range 15 to 75 years). Among 93 patients with available data, the median and percentage of CD4 cell count during hospitalization were 64.0 cells/microlitre and 6% (range 1-684 cells/microlitre and 1-57%). Among 106 patients with known HIV infection, 67 patients (63.2%) had received antiretroviral therapy with the mean duration of 1.6 +/- 2.1 years. The most common CNS infection was cryptococcal meningitis (56 patients, 37.8%), followed by tuberculosis (53, 35.8%), toxoplasmosis (19, 12.8%), progressive multifocal leukoencephalopathy (6, 4.1%), varicella-zoster virus (VZV) meningitis (4, 2.7%), brain abscess (3, 2.1%), cytomegalovirus radiculomyelitis (2, 1.4%), pneumococcal meningitis (2, 1.4%), herpes simplex encephalitis, Epstein-Barr virus-related primary CNS lymphoma, and HIV-associated myelopathy (1 patient, each, 0.7%). Twenty-two patients died, accounting for the mortality rate of 14.9%. Of these 22 patients, tuberculous meningitis was the most common cause (9 patients, 16.9%), followed by cryptococcal meningitis (9, 16.1%), VZV encephalitis, Aspergillus brain abscess, herpes simplex encephalitis, and pneumococcal meningitis (1, 4.8% each). CONCLUSION: To the authors' knowledge, this is the first comprehensive study in Thailand to investigate the etiologies, clinical manifestations, and outcomes of all CNS infections in AIDS patients. There are a high number of patients with tuberculosis and severe immunodeficiency in the present study. The authors' findings suggest an urgent need to actively search and treat most HIV-infected patients in the community before they become severely immunocompromised. PMID- 21675444 TI - The efficacy of silver mesh dressing compared with silver sulfadiazine cream for the treatment of pressure ulcers. AB - BACKGROUND: Controlling infection and promoting healing should be aims of pressure ulcer treatment along with improving a patient's general condition and relieving pressure. Many pressure ulcers present with cavities, tracks or a combination of these. A new silver mesh dressing (Tegaderm Ag Mesh dressing) has the ability to contour around and conform to irregular surfaces of a wound bed. OBJECTIVE: To evaluate the efficacy of a silver mesh dressing compared with silver sulfadiazine cream for pressure ulcer treatment. MATERIAL AND METHOD: A prospective, randomized, clinical trial was conducted in patients with pressure ulcers grade III or IV. The patients were divided randomly by computer into two 20 patient-groups. The study period was eight weeks for each patient. Demographic data, wound size, wound photography, and bacterial wound culture were recorded at the beginning of the study and every two weeks thereafter. Wound beds were covered with silver sulfadiazine cream in the control group and silver mesh dressing in the experimental group. Dressings were changed twice a day in the control group and every three days in the experimental group. RESULTS: Forty-five patients enrolled in the present study but only 40 patients finished the study. Twenty patients in each group finished the eight-week study. The mean healing rates and the percentage of reduction in PUSH score at eight-week were better in the study group than in the control group but they were not statistically significant. Better changing in bacteriological study after the treatment was shown in both groups. The estimated average cost of the treatment in the mesh group was 263 USD per patient while it was 1812 USD in the cream one (p = 0.0001). Silver mesh dressing can be adapted very well on the bed, can control infection, and promote wound healing. Wound reduction was greater in the experimental group than the control group. The cost of treatment, using silver mesh was cheaper than using silver sulfadiazine cream significantly. CONCLUSION: Silver mesh dressings is one of the choices for pressure ulcer treatment with good healing rate, minimal care and lower overall cost. PMID- 21675445 TI - Prevalence of pin-site infection: the comparison between silver sulfadiazine and dry dressing among open tibial fracture patients. AB - OBJECTIVE: Pin-site infection is one of the most troublesome complications of external fixation. The present study aimed to compare the rate of pin-site infection following silver sulfadiazine with dry dressing. MATERIAL AND METHOD: This was a prospective randomized controlled study among 30 clients that compared the outcome of pin dressing using silver sulfadiazine (study group = 15) with dry dressing (control = 15). All eligible subjects of open tibial fracture had an emergency debridement with external fixation. Pin tract infection was considered to be present if superficial inflammation (erythema, cellulitis), serous or purulent discharge occurred around a pin site and deep infection of osteolysis around the pin, and sequestrum. RESULTS: Seven subjects (46.7%) had pin-site infection in the present study group while six subjects (40.0%) had it in the control group, with comparable severity. CONCLUSION: There was no significant difference in prevalence of pin-site infection between both groups (p = 0.97). Therefore, either silver sulfadiazine or dry dressing could be advocated. PMID- 21675446 TI - Tarsal fracture operation in cicatricial entropion. AB - BACKGROUND: Cicatricial entropion is a common eyelid condition encountered by ophthalmologists. There is a variety of procedures to correct this condition, in which tarsal fracture procedure is one of them. However, recurrence has been a problem and success rate should be calculated. MATERIAL AND METHOD: This retrospective non-comparative interventional case series on patients with cicatricial entropion corrected by tarsal fracture technique was conducted at King Chulalongkorn Memorial Hospital between 2003 and 2007. The success rate was evaluated. RESULTS: Most patients were female (81%) with the mean age of 62.2 (SD 20.1) years old. The success rate of tarsal fracture was 74.2%. After the reoperations of the recurrent cases, the success rate reached up to 87.1%. CONCLUSION: Tarsal fracture is a simple, quickly-performed, and less time consuming procedure. It should be considered as an initial operation for cicatricial entropion. PMID- 21675447 TI - The impact of central corneal thickness on intraocular pressure measured by non contact tonometry. AB - OBJECTIVE: To investigate the impact of central corneal thickness (CCT) on the intraocular pressure (IOP) measurement by non-contact tonometry (NCT). MATERIAL AND METHOD: Eye examination data of normal volunteers aged between 18-96 years and intraocular pressure less than 22 mmHg were retrospectively reviewed. Subjects with possible conditions that affected the results of CCT and IOP measurement by NCT were excluded. The data of CCT and IOP measurements by NCT were obtained. Linear and multiple regression analysis were used to evaluate the influence of CCT and age on IOP measurement by NCT. RESULTS: Four hundred and thirty seven eyes of 437 subjects were enrolled. The mean age was 49.05 +/- 18.84 years. The average CCT was 524.56 +/- 32.40 microns and the mean IOP measurement by NCT was 13.85 +/- 2.81 mmHg. Linear regression model showed a significant negative correlation between CCT and subject age (p < 0.001), but had a positive correlation between CCT and IOP measurement by NCT (p = 0.006). CONCLUSION: CCT has a significant impact on IOP measurement by NCT. The finding suggests that CCT is an important parameter for interpretation of IOP measurement by NCT. PMID- 21675448 TI - Ultrasound biomicroscopy measured anterior and posterior chamber diameters--a novel way to evaluate angle-closure glaucoma. AB - OBJECTIVE: To investigate anterior and posterior chamber diameters in primary angle-closure (PAC) and to correlate them to the angle opening parameters. MATERIAL AND METHOD: Fifty eyes of PAC and 45 age-matched controls underwent ultrasound biomicroscopy (UBM; model P60, Paradigm Medical Industries Inc., Salt Lake City, UT) scanning. Superior, inferior temporal and nasal angle opening parameters were obtained. Anterior chamber diameter, indicated by angle-to-angle diameter (AAD) and posterior chamber diameter indicated by sulcus-to-sulcus diameter (SSD), were analyzed. RESULTS: Mean age was not different between PAC and controls, 59.80 +/- 9.11 versus 56.33 +/- 13.39, respectively (p = 0.140). PAC demonstrated a relatively smaller eye than the controls; e.g., corneal diameter; anterior chamber depth (ACD) and axial length, (all p < 0.05). AAD was shorter in PAC than the controls, 10.16 +/- 0.58 versus 10.88 +/- 0.55 mm, (p < 0.001). AAD was correlated to PAS extent (r = -0.358), ACD (r = 0.659), SSD (r = 0.636) and scleral spur to iris root insertion (r = 0.505), (all p < 0.001). SSD was also smaller in PAC than controls, 10.16 +/- 0.45 versus 10.52 +/- 0.52 mm, (p = 0.001). CONCLUSION: Crowded anterior segment of PAC can be demonstrated by a novel parameter of AAD and SSD, obtained with a newer model of UBM. The shorter AAD indicates the greater PAS extent and smaller angle. Both parameters are independent to scleral spur, and are simple to evaluate PAC. PMID- 21675449 TI - The effectiveness of clinical practice guideline for nasopharyngeal and oropharyngeal cancer to reduce acute treatment toxicity from concurrent chemoradiation. AB - OBJECTIVE: To evaluate the effectiveness of clinical practice guideline (CPG) for nasopharyngeal carcinoma (NPC) and oropharyngeal carcinoma (OPC) on reducing acute toxicity during concurrent chemoradiation (CRT). MATERIAL AND METHOD: The prospective study enrolled 74 patients diagnosed of NPC and OPC that underwent concurrent CRT. The feasibility of CPG was evaluated. RESULTS: Each checkpoint in CPG is feasible with 76% compliance of three in four points and 24% complete allpoints. Overall grade 3 or 4 skin reaction and mucositis are 9 and 8% respectively. CONCLUSION: CPG that consisted of preventive methods to reduce acute skin and oral mucosa toxicities in NP and OP patients is easy to follow with 24 to 100% compliance. This can be feasible with consideration about immobilization device and energy treatment machine. PMID- 21675450 TI - The value of MDCT scans in differentiation between benign and malignant gallbladder wall thickening. AB - OBJECTIVE: To evaluate the value of MDCT in differentiation of gallbladder carcinoma from other benign conditions in patients with thickened gallbladder wall. MATERIAL AND METHOD: MDCT of 125 patients, 18 gallbladder carcinomas and 107 other benign conditions were retrospectively reviewed. Various direct and indirect CT findings of benign and malignant gallbladder diseases were evaluated. Differences in CT findings between benign and malignancy were calculated using Chi-square test and odds ratio. Additionally, the wall enhancement pattern was evaluated and categorized into five types, according to the presence of striation, thickness of the outer and inner layers, and degree of enhancement of each layer compared with that of normal liver parenchyma. The diagnostic performance of enhancement pattern analysis on MDCT was analyzed. RESULTS: Five direct and five indirect CT findings including wall irregularity focal wall thickening, discontinuous mucosa, submucosal edema, polypoid mass, direct invasion to adjacent organ, biliary obstruction, regional and paraaortic lymphadenopathy and distant metastasis show significant differences between benign and malignancy. The thickened gallbladder wall with one-layer heterogeneous enhancement (type 1) was significantly associated with malignancy. By using type 1 enhancement pattern as the predictor for malignancy, the sensitivity, specificity, and accuracy of MDCT for detection of malignancy was 78%, 94% and 92%, respectively. CONCLUSION: MDCT is a reliable diagnostic method for differentiating between benign and malignant thickened gallbladder wall. Focal and irregular wall thickening are two direct signs that most associated with malignancy. Moreover, the one-layer heterogeneous enhancement of gallbladder wall is suggestive of malignancy. PMID- 21675451 TI - Association between exhaled carbon monoxide and oral health status in active and passive smokers. AB - BACKGROUND: Few studies so far have evaluated the association between oral health status and level of carbon monoxide in the exhaled breath (exhaled CO). OBJECTIVE: Evaluate the relationship between oral health status, namely dental caries and periodontitis, and exhaled carbon monoxide in active and passive smokers. MATERIAL AND METHOD: The analytic cross-sectional study sample comprised of 296 Thai adults, aged 30-72 years, residing in an urban district of Khon Kaen province, Thailand during the year 2007, who received exhaled carbon monoxide measurement, oral examination, and interview. Spearman correlation tests were employed to determine the relation between exhaled carbon monoxide and dental caries. In addition, the relationship between exhaled carbon monoxide and periodontitis was evaluated using Mann-Whitney U Test. RESULTS: The results revealed no relationship between exhaled carbon monoxide and oral health status among passive smokers. Moreover, the relationship between exhaled carbon monoxide and dental caries among active smokers did not exist when education was adjusted. CONCLUSION: There is no relationship between exhaled carbon monoxide and oral health status in both active and passive smokers. PMID- 21675452 TI - Validation study of the Thai ID Pain Scale. AB - OBJECTIVE: To translate the ID Pain scale into Thai and validate this scale. MATERIAL AND METHOD: The 6-item ID Pain scale was translated into Thai. The final version was tested in 100 patients. Sensitivity, specificity, and predictive validity were calculated. RESULTS: Twenty-four patients were neuropathic, 49 were nociceptive and 27 were mixed pain. Forty-six patients have chronic pain. Seventy five were female. Sensitivity and specificity for diagnosis of neuropathic pain were 83% and 80%. The predictive validity using area under the ROC curve of the neuropathic, mixed and nociceptive pain groups were 0.890 (95% CI 0.824-0.955), 0.587 (95% CI 0.464-0.709) and 0.147 (95% CI 0.071-0.224), respectively. CONCLUSION: The Thai ID Pain scale is brief convenient to complete and had good predictive validity for screening of neuropathic pain. Prediction validity of mixed pain is moderate and of nociceptive pain is low. PMID- 21675453 TI - Prevalence of low back pain among rice farmers in a rural community in Thailand. AB - OBJECTIVE: To determine the prevalence of low back pain (LBP) among rice farmers in a rural community in Phitsanulok, Thailand. MATERIAL AND METHOD: A cross sectional survey was conducted among 283 rice farmers in Wangnamkhu subdistrict, Muang district, Phitsanulok province, a rural community in Lower Northern Thailand. Face-to-face interviews with a structured closed-end questionnaire were performed to collect information on the presence of LBP in lifetime, within the last 12 months prior to and at the time of the present study. RESULTS: The lifetime, 1-year (12-month) and point prevalence rates of LBP were 77%, 56% and 49%, respectively. No relationship between age and LBP was found. However women (61%) had significantly greater 1-year prevalence than men (51%). Ninety-five percent of LBP rice farmers were chronic (experiencing pain longer than 12 weeks) with a mean duration of 292 weeks (5.6 years). CONCLUSION: The prevalence of LBP among Thai rice farmers is high. Further research should investigate risk factors among this group of the population to design appropriate preventive measures. PMID- 21675454 TI - Reversible cerebral vasoconstriction syndrome with increased intracranial pressure, probably related to altitude changes and windy winter travelling. AB - Reversible cerebral vasoconstriction syndrome (RCVS) has reversible multifocal narrowing of the cerebral arteries. Respiratory alkalosis in high altitude studies cause impairment of the central nervous system, presumably by cerebral vasoconstriction. A 54 year-old woman presented with a 1-week of throbbing headache around her forehead while travelling in moderately high altitude, during a windy winter. Sudden severe headache had progressed and developed bilateral lower visual fields defect along with mild weakness of her right leg on the next day. Magnetic resonance (MR) imaging revealed acute ischemic process at both occipital, parasagittal left parietal and right frontal area. MR venography was negative but MR angiography showed multifocal narrowing of both anterior and posterior circulations. Lumbar puncture revealed the opening pressure of 240 mmH2O but normal CSF profiles. Blood tests, including complete blood count, protein C, protein S, antithrombin III, high-sensitivity C-reactive protein, immunologic and antibody profiles were normal. Dexamethasone and low-molecular weight heparin were given because the intracranial vasculitis and cerebral venous thrombosis could not be ruled out. Visual fields and right leg problems had fully recovered on the second day and second week respectively. Prednisolone was discontinued at the fourth week. MR imaging and MR angiography were repeated in the sixteenth week and revealed old infarction at the left posterior parietal area but narrowing segment of arterial systems were no longer seen. There were a few previous reported cases of RCVS in Asian counties. The authors proposed that altitude changes from travelling to the moderately high altitude and cold windy winter weather were the predisposing factors for the attack of RCVS. PMID- 21675455 TI - Carotid dissection causing stroke in a 13-year-old boy with mild hyperhomocysteinemia: case report. AB - The author describes a 13-year-old Thai boy who developed stroke caused by carotid dissection and found mild elevation of plasma homocysteine (tHcy). The patient improved after anticoagulation therapy and his plasma tHcy decreased after vitamin supplement. With long-term follow-up, he is having normal neurological condition. This case proposes that the pathogenesis of carotid dissection may associate with mild hyperhomocysteinemia. PMID- 21675457 TI - Compassion fatigue and the health service professional. PMID- 21675456 TI - Bilateral endogenous endophthalmitis in disseminated NTM infection: a case report. AB - A 47-year-old Thai female with underlying Sweet's syndrome and disseminated non tuberculous mycobacterial infection presented with a history of blurred vision on both eyes after being lost to follow-up for eight months. The visual acuity was hand motion on the right eye and counting finger on the left eye. There was moderate inflammation in the anterior chamber and vitreous cavity. Multiple foci of round chorioretinitis were found throughout the fundus on both eyes. The patient denied intravitreous tapping and antibiotic injection. Nevertheless, specimens from several sites were collected for culture and sensitivity test. The result of the culture and sensitivity test revealed rapidly growing mycobacteria on specimens taken from the right inguinal lymph node. The presented case may demonstrate the rare event of bilateral endogenous endophthalmitis with chorioretinitis arising from non-tuberculous mycobacterial infection. The pattern of chorioretinitis demonstrated by the presented report may provide useful clinical information for this rare condition. PMID- 21675458 TI - Community health care paramedic. PMID- 21675459 TI - Celebration 100 years resolution recognizes Nurses Association for its contributions. PMID- 21675460 TI - Time to get political over reforms. PMID- 21675461 TI - Waiting times expected to increase over coming year. PMID- 21675462 TI - Shine a light: nurses find ways to improve care and cut costs. PMID- 21675463 TI - Rate of respiration: the forgotten vital sign. AB - Respiratory rate is an early indicator of physiological deterioration and should be recorded with other vital signs in patients who present to emergency departments. This article highlights the importance of recording patients' respiratory rates and describes their place in initial patient assessments. It also reviews findings from an audit of ED patients' notes over a short period to discover whether their respiratory rates had been recorded. These support the results of similar studies in the literature, which show that, despite their importance, respiration rates are documented less often than other vital signs. PMID- 21675464 TI - An end in sight for avoidable blindness. AB - This article reports on the experiences of nurse volunteers who help treat avoidable eye conditions among the world's poorest people. PMID- 21675465 TI - Refining a triage system for use in emergency departments. AB - This article reports on the implementation of an adapted version of the Manchester triage system (Mackway-Jones et al 1997) in a Dutch hospital to allow trained nurse practitioners to treat patients with minor injuries or illnesses, and to assess, treat and discharge patients autonomously. The project has helped to prevent long waits in emergency departments for patients with less urgent conditions. PMID- 21675466 TI - The limping child: an unusual finding of fracture to the fibula. AB - The limping child is a common presentation to emergency and other unscheduled care facilities with many potential diagnoses that are often age specific. This article describes how emergency department nurses should manage and treat 'toddler's fracture', and provides an unusual case study of the presentation. PMID- 21675467 TI - Choosing the right pain relief for patients with soft-tissue injuries. AB - The use of non-steroidal anti-inflammatory drugs (NSAIDs) in the management of soft-tissue injuries such as ankle sprains is well established in both minor injury and pre-hospital environments. There is much debate, however, over whether NSAIDs delay healing and contribute to long-term joint instability. This article examines the effects and potential side effects of NSAIDs, and considers alternative prescribing options for treating soft-tissue injuries. PMID- 21675468 TI - Better communication in the emergency department. AB - BACKGROUND: The emergency nurse practitioner (ENP) role has evolved since the 1980s, when it was introduced into emergency departments (EDs) in the UK (Tye 1997). Nowadays, ENPs see, treat and refer or discharge patients autonomously. They also document patient histories and are expected to communicate effectively with patients who have complex needs. The role has expanded for several reasons, including the need to reduce doctors' working hours, but mainly to make more flexible use of services. Meanwhile, as ED attendances increase (Thompson et aL 2010), ENPs are placed under increasing pressure and may be forced to spend less time with patients than was expected of them when the ENP role was originally devised. This can affect patient history taking and communication, and may lead to poorer patient outcomes and satisfaction. AIM: This article concerns a literature review undertaken by the author to identify and overcome the limitations to effective history taking and communication among ENPs. It also highlights good practice in the management of emergency and urgent-care patients with complex needs. METHODS: There is little primary research on history taking and communication pressures in emergency care but, after a systematic literature search of the British Nursing Index, CINAHL and Medline databases, the author identified eight research articles on the subject. RESULTS: Three themes emerged from the review: interruptions, overload and barriers. According to the review findings, interruptions occur more often in EDs than in primary care settings, and senior doctors and senior nurses are interrupted more often than other staff. These interruptions can increase information overload, leading to medical errors and adverse clinical outcomes. The main barrier to effective history taking is a failure to understand patients who have poor command of the English language. CONCLUSION: The author's recommendations for practice include increasing the number of staff and training them in managing pressure, communicating effectively with patients, and ensuring where appropriate that doors and curtains are closed to reduce the number and extent of interruptions. PMID- 21675469 TI - Not just a load of epidurals! PMID- 21675470 TI - Normal birth or spontaneous vertex delivery? AB - The declining normal birth rate and increasing Caesarean Section (CS) rates have been a worldwide cause for concern and debate for two decades. In the United Kingdom (UK) normal birth rates have fallen from 70 per cent in the 1970s to 46.7 per cent in 2009 (Birth Choice UK 2011). As normal birth rates continue to fall, researchers and advocates of normality are focusing on the midwife's role in response to this decline. The language and definitions used to classify normality and normal birth are contentious issues leading to confusion for midwives and women. This paper seeks to contribute to the debates around defining and promoting normality. PMID- 21675471 TI - Challenging current practice: the evidence behind the timing of cord clamping. AB - Immediate clamping of the umbilical cord is an intervention that has developed over the last century as birth moved into the hospital setting (Mercer 2001). Whilst active management in the third stage of labour is widely practised, midwives are encouraged to re-evaluate their management strategies during this stage, since immediate clamping of the umbilical cord interferes with the physiological process of normal childbirth and should be justified (Begley et al 2010; Gyte 1994). Exploration of the physiological and research based evidence would indicate that the practice of umbilical cord clamping at birth needs to be raised with the whole multi-disciplinary team in order to influence practice (Anderson 2005; ICM 2003). PMID- 21675472 TI - We're all in it together! AB - My main aim in working as an independent midwife over the last three years has been to provide a level of continuity and stability for the woman and family not always possible within the NHS. While aiming to provide excellent clinical care I also provide up-to-date evidence based information, such as guidelines for women from the Royal College of Obstetrics and Gynaecology (RCOG) or the National Institute for Clinical Excellence (NICE) which enables the woman's choices to be informed. In the course of a woman's care it is frequently necessary to work together with health professionals within the NHS. The following story both exemplified for me the way things can work when we collaborate fully with one another and was also an incredibly positive experience for all involved. PMID- 21675473 TI - This real nappy week, make sure you are clued up on going real. AB - Today disposable nappies are widely accepted as the norm and this idea is backed up by regular advertising on television, in parenting magazines, in Bounty packs, at baby shows and also by the dominance of them on our supermarket shelves. Real Nappies, in comparison are much less prominent. So the trusted information that you, as a midwife, provide, is vital to helping parents make an informed choice. It doesn't mean that parents should be made to feel guilty for the choice they make, it is about ensuring that parents have access to all the information that they need to make a choice for themselves. PMID- 21675474 TI - Every birth the best birth: women centred care in Nottingham. AB - Nottingham University Hospitals (NUH) NHS Trust aspired to increase and maintain its focus on normality in childbirth in its two large maternity units. It achieved this by employing two Leads for Women Centred Care Midwives. This article describes some of the measures taken to promote normal childbirth and empower women and midwives to re-focus on the normal aspects of giving birth. Such measures include; setting up a normal birth focus group for staff, developing study days and a normal birth skills package for staff, work to de medicalise the birthing environment, one to one care in labour audits, active birth workshops for women and their birthing partners and virtual tours of the maternity unit. The authors hope this may give midwives and staff in other obstetric units ideas and ways in which they can focus on normalising childbirth for all women they care for. PMID- 21675475 TI - A care pathway: delayed active management of the third stage of labour. AB - Challenging the current National Institute for Clinical Excellence guidelines (NICE 2007), this paper will identify and discuss the evidence to support a care pathway for delayed active management of the third stage of labour, which promotes a delay in the administration of the uterotonic drug and delayed cord clamping (DCC). Current evidence highlights that clamping and cutting the umbilical cord once pulsation has ceased allows the baby to receive additional blood from the placenta, which in turn increases the baby's blood volume and significantly reduces instances of anaemia. The research available to support DCC and the benefits this provides to the newborn with little adverse effect to the mother could possibly be enough to change current practice to create Delayed Active Management as a third stage option for women. PMID- 21675477 TI - Reading, evaluating and interpreting phenomenological research. PMID- 21675476 TI - Creating change in improbable places: the Birth Project Group. AB - The Birth Project Group, a collaborative initiative based in Edinburgh and Dublin and comprising practising midwives, academics and birth advocates, held its second weekend workshop in April 2010. This brought together those involved in working to sustain and strengthen changes to the contemporary birth culture so as to promote normality. This article reports on the feedback from some of the attendees, which included parents, midwives and student midwives. PMID- 21675478 TI - Skin-to-skin contact. Part one: just an hour of your time... AB - A growing body of evidence suggests that extended skin-to-skin contact between mother and baby immediately after birth provides numerous and significant benefits including regulating heartbeat and temperature for the baby, protecting against infections, and promoting feelings of calm and wellbeing in both mother and baby. As a result the Baby Friendly Initiative has increased the amount of time that mothers and babies should spend in skin contact to one hour minimum, and much more where possible. PMID- 21675480 TI - Labouring the point. PMID- 21675479 TI - Blood tests for investigating maternal wellbeing. AB - It is the midwife's role to assess the client's general health, explore her medical, surgical, menstrual, gynaecological, obstetric, psycho-emotional, social and family history thoroughly to ascertain if there are indicators of potential complications in her pregnancy, labour and birth and puerperium. In this article we examine the case of Carla; as there is history of thyroid dysfunction in her family, this could be an indicator towards a diagnosis of thyroid pathology. PMID- 21675481 TI - Improving with experience. PMID- 21675482 TI - Health organisations agree that ministers' 'listening exercise' offers chance for change. PMID- 21675483 TI - Weighing up the pros and cons of internal staff banks. PMID- 21675484 TI - Age-old question. PMID- 21675485 TI - Balancing quality with productivity. AB - Nurses are often forced to defend themselves about whether they provide value for money. The issue prompted the authors to explore how nurses spend their time and to identify their unique contribution to leading and providing care for patients. This article describes the methodology used and reports the findings. Results were compared with other acute NHS and international organisations and the information is being used to determine how to make best use of nursing time, provide value for money and focus on improving the patient experience. PMID- 21675486 TI - Staff and patient involvement in benchmarking to improve care. AB - This article outlines work undertaken to relaunch Essence of Care benchmarking at Nottingham University Hospitals NHS Trust (NUH), a 1,665-bed teaching hospital based on two sites. The eight high impact actions for nurses and midwives (NHS Institute 2009) have been aligned with Essence of Care to develop comprehensive tools for quality improvement at local level. This has resulted in increased patient feedback and enhanced staff ownership and involvement in quality improvement processes and raising standards of care. As a national pilot site for the Productive Ward programme (NHS Institute 2007), NUH has developed links between the two initiatives, reviewing ward processes, increasing direct patient feedback and providing a wealth of data relating to quality of care and patient safety issues. PMID- 21675487 TI - Collaborative project to co-ordinate care for patients with dementia. AB - Health leaders from across Suffolk joined together in a collaborative action learning project to identify ways of offering more productive and personalised care for patients with dementia and their carers. The project revealed a range of factors necessary for success, notably professional collaboration and effective facilitation. The outcome was a range of evidenced-based recommendations to improve care and efficiency, as well as ensuring that the quality, innovation, productivity and prevention (QIPP) agenda was met. The lessons can be applied not just in dementia care, but to other long-term and complex care situations. PMID- 21675488 TI - Using a training needs analysis framework in career development. AB - This is the second of two articles looking at the use of training needs analysis frameworks to streamline the provision of continuing professional development (CPD) in healthcare settings. The first article described the process and academic strategy used to design the framework. Part two describes how one department has used the tool to identify and address staff training and CPD needs, and how this has helped meet individual, departmental and organisational objectives. PMID- 21675489 TI - Safety is my priority. AB - Delilah Hesling was appointed safety ombudsman at Brighton and Sussex University Hospital NHS Trust last August. Five years ago, the trust was at the centre of a scandal when nurse Margaret Haywood exposed patient neglect by filming undercover for a BBC documentary. Ms Hesling's role is to provide an independent service to foster a transparent, accountable culture that acknowledges failures and acts to prevent any recurrences. PMID- 21675490 TI - Impending changes in diagnostic nomenclature: will ICD-10 be obsolete by implementation time? PMID- 21675491 TI - What is Kindler syndrome? PMID- 21675492 TI - Primary anetoderma. PMID- 21675493 TI - Dengue fever. PMID- 21675494 TI - Doxepin cream vs betamethasone cream for treatment of chronic skin lesions due to sulfur mustard. AB - Oral doxepin was shown to reduce chronic pruritus due to sulfur mustard. The present study compared the effects of topical doxepin 5% with betamethasone 1% for the treatment of pruritus in veterans exposed to sulfur mustard. This investigator-blinded, randomized, clinical trial was conducted in an outpatient dermatology clinic. Seventy-five men who were exposed to sulfur mustard 23 to 28 years ago during the Iran-Iraq war who complained of pruritus were randomized to receive doxepin cream 5% (n = 40) or betamethasone cream 0.1% (n = 35) twice a day for 6 weeks. Pruritus severity and Dermatology Life Quality Index (DLQI) were evaluated before and after each treatment. Both groups showed significant improvement regarding pruritus (P < .05), burning sensation, skin dryness (P < .001), and skin scaling (P < 0.05). The lesions of all regions significantly reduced after treatments (P < .05), except those on the head, face, and genitalia. Pruritus, visual analog scores, and DLQI significantly decreased (P < .01, P < .01, and P < .001, respectively) in doxepin- and betamethasone-treated groups, and there was no difference between groups. All DLQI subscores decreased after both type of treatments (P < .01). Equal efficacy of doxepin cream and betamethasone suggest that doxepin is a potential alternative to control pruritus caused by sulfur mustard in exposed veterans. PMID- 21675495 TI - Follicular variant of seborrheic dermatitis: is it identical to Malassezia folliculitis? AB - Follicular accentuation in some patients with seborrheic dermatitis of the back and chest has been recognized for more than a century. The recognition of Malassezia folliculitis in recent decades has led to some confusion regarding categorization of these cases. The author proposes that there is sufficient clinical variation between the typical case of Malassezia folliculitis and patients with follicular seborrheic dermatitis to justify continued separation of these entities until further study provides more clarification. PMID- 21675496 TI - Primary anetoderma: a cutaneous marker of antiphospholipid antibodies. AB - Primary anetoderma is a rare idiopathic disease of the skin characterized by circumscribed areas of slack skin and loss of elastic fibers found on histopathologic examination. It has been related to systemic lupus erythematosus and other immune diseases. In recent years, however, its association with antiphospholipid antibodies has been highlighted, and it should be considered a clinical manifestation of these antibodies. PMID- 21675497 TI - Fabry disease. AB - Fabry disease (FD) is an X-linked lysosomal disorder caused by the deficient activity of the enzyme alpha-galactosidase A, which leads to multisystemic storage of globotriaosylceramide in visceral tissues and vascular endothelium. FD manifests primarily in affected hemizygous men, with a wide range of clinical signs in heterozygous women. Acroparesthesias, angiokeratomas, pain crisis, and cornea verticillata are early manifestations of FD. With age, severe complications involving the kidneys, heart, and brain cause considerable morbidity and premature death. Although the clinical onset of FD occurs in childhood, diagnosis is often delayed or missed. In men, the diagnosis must be confirmed biochemically by demonstration of decreased levels of alpha galactosidase A activity. In women, the disease is diagnosed by identification of a mutation in the alpha-galactosidase A gene. Until a few years ago, the existing treatment for FD was based on clinical manifestations, but the advent of enzyme replacement therapy should stimulate the identification of the signs and symptoms suggestive of this disorder to allow earlier diagnosis and treatment. PMID- 21675498 TI - Calcipotriene 0.005% and betamethasone dipropionate 0.064% combination topical suspension (Taclonex Scalp). PMID- 21675499 TI - The next frontier of sunscreen protection. PMID- 21675500 TI - Epinephrine: friend or foe? PMID- 21675501 TI - Tufted hair folliculitis in a patient affected by pachydermoperiostosis: case report and videodermoscopic features. AB - A 25-year-old man presented with Touraine-Solente-Gole syndrome (primary pachydermoperiostosis), with an area of inflammatory dermatosis (12-month evolution) of the scalp at the cranial vertex. The patient presented with arthropathy, clubbing of the digits, diffuse periostosis, pachydermia of the hands and feet, and periosteal hyperostosis of the knee. Facial seborrhea and sebaceous gland hyperplasia were evident (Figure 1A and 1B and Figure 2A and 2B). Examination of the scalp revealed an erythematous pruritic plaque with erosions, crusts, and pustules, on which multiple tufts of 10 to 20 normal-looking hairs emerged from single follicular openings (Figure 3A). Slight pressure on the perifollicular areas resulted in the discharge of purulent material through the dilated follicular openings. Cervical and occipital lymph nodes were not enlarged, and the patient was in generally good health. Routine laboratory findings were normal. Immunologic studies, including a screening for antinuclear antibody, complement, and immunoglobulins, were normal. Both potassium hydroxide staining and fungal culture were negative. Bacteriologic culture of purulent material taken from the affected area was positive for Staphylococcus aureus. Videodermoscopy of the lesion showed rarefied interfollicular twisted red loops centered around actively affected follicles and white dots with absence of normal vascular pattern (Figure 3B). These dermoscopy patterns are markers for folliculitis decalvans, of which tufted hair folliculitis (THF) is a clinical variant. Histologic examination showed hair plugging, a dense perifollicular infiltrate of plasma cells, lymphocytes, neutrophils, and large areas of scarring and fibrosis, which would confirm suspected THE THF was diagnosed on the grounds of clinical, microbiologic, histologic, and videodermoscopy data. The patient was treated with amoxicillin 875 mg plus clavulanic acid 125 mg twice daily and topical nadifloxacin 1% twice daily for 20 days, achieving substantial clinical improvement. One month after antimicrobial therapy, a single area of cicatricial alopecia with a few hair tufts emerging from single orifices was observed, and no new lesions or symptoms had appeared. PMID- 21675502 TI - Familial juvenile generalized pustular psoriasis: response to methotrexate. AB - Two siblings with generalized pustular psoriasis were admitted to the hospital. Case 1: A 7-year-old girl presented with recurrent episodes of multiple pinhead sized pustules all over her body since the age of 3. The current episode began a week prior to the onset of the lesions. On cutaneous examination, she had generalized erythema topped with tiny pustules, scales, and crusting (Figure 1A). A Gram stain performed from the pustule and cultures taken from the pus and blood were sterile. Histopathology of the pustule was suggestive of pustular psoriasis (Figure 2). Hemoglobin was 8.8 g%. Other hematologic, microbiologic, and radiologic investigations were normal. Treatment was started with methotrexate, to which she responded dramatically with reduction in appearance of new lesions, erythema, and scaling. After 4 weeks of treatment, there was almost 90% clearance of skin lesions. Case 2: A 3-year-old boy, brother of the patient in case 1, presented with similar complaints for the past week. The episode was preceded by high-grade fever. He had generalized erythema, scaling, and edema and multiple pinhead-sized pustules, some of which were arranged in an annular configuration (Figure 1B). All investigations, as in case 1, were normal except for hypocalcemia (Ca2+ = 8.8 g%) and generalized rarefaction on x-rays of both the ankle joints. Treatment was started with prednisolone (because of poor general condition) and methotrexate. Following therapy, significant improvement was evident with reduction in erythema and cessation of appearance of new pustules. The dose of prednisolone was gradually tapered after 3 weeks and then stopped. PMID- 21675503 TI - Vitiligo and alopecia areata associated with subclinical/clinical hypothyroidism. AB - The parents of an 18-year-old woman had noticed white hair while combing their daughter's hair 12 years ago. They found tiny white spots on her scalp, but she was asymptomatic. The spots have since progressed. Examination of the affected skin on the scalp was marked by the presence of a chalky/ivory white macule, 8 to 10 cm in diameter, conforming to that of segmental (zosteriformis) vitiligo (Figure 1). The lesions were located on the temporoparietal region of the scalp. The hair over the macules was white (leukotrichia) and dry, coarse, and brittle. The patient's nails were thin and dull. Her thyroid profile revealed the following: triiodothyronine, 1.12 nmol/L (0.95-2.5 nmol/L); thyroxine, 69.21 nmol/L (60.0-120.0 nmol/L); and thyroid-stimulating hormone, 6.26 microIU/mL (0.25-5.00 microIU/mL), indicative of primary hypothyroidism. Liver and renal function tests were within normal limits. A lipid profile revealed the following: total lipids, 503.8 mg% (400-700 mg %); triglycerides, 123.0 mg % (160 mg %); cholesterol, 212.0 mg % (150-250 mg %); high-density lipoprotein, 43.1 mg % (30 63 mg %); and low-density lipoprotein, 144.3 mg % (50 mg %). Electrocardiographic findings were normal. History of tiredness, constipation, depression, sensitivity to cold, weight gain, muscle weakness, cramps, and increased menstrual flow supported the diagnosis. The patient was administered 100 microg of thyroxine once a day along with methoxsalen, the dose of which was calculated at 0.6 mg/kg to 0.7 mg/kg body weight per day given on alternate days, followed 2 hours later by exposure to UV-A (1 J/cm2) irradiation (psoralen-UV-A [PUVA]), supplemented by 1 mg of beta-methasone, 150 mg of levamisole on 2 consecutive days per week, and an antioxidant. During the course of 7 weeks, the macules (13 exposures) had become erythematous, with an appearance of perifollicular/ marginal pigmentation. Repeat examination showed a thyroid profile of total triiodothyronine (T3), 127.3 microg/dL (86-186); total thyroxine (T4), 6.54 microg/dL (4.5-12.5 microg/dL); and thyroid-stimulating hormone (TSH), 0.32 microIU/mL (0.3-5.6 microIU/mL), supplemented by antithyroid microsomal peroxidase antibodies (thyroid microsomal antibody and thyroid peroxidase), 21.9 IU/mL (1-40 IU/mL), and antithyroglobulin antibodies, 78.1 U/mL (1-100 U/mL). During the patient's treatment period, 4 other patients with clinical symptoms and signs of long-standing hypothyroidism developed vitiligo, the duration of which was variable in each patient (Table I). All of the patients were taking thyroxin. Thyroid and lipid profiles were performed periodically to evaluate the progress (Table I). These patients were also treated with PUVA therapy and thyroxin. During the course of treatment, 2 of the patients noticed asymptomatic, progressive, localized, and well-circumscribed hair loss at the temporal region of the scalp that extended to involve the vertex, conforming to findings of alopecia areata (Figure 2A and Figure 2B). PMID- 21675504 TI - An unusual cutaneous manifestation of Crohn's disease. AB - A 61-year-old man with a 12-year history of quiescent Crohn's disease on mesalamine presented to his gastroenterologist in April 2009, complaining of abdominal cramping, diarrhea, and a 25-lb weight loss over 6 weeks. He did not respond to prednisone 50 mg and 6-mercaptopurine 100 mg daily. Abdominal computed tomography findings revealed diffuse submucosal edema consistent with extensive colitis. Colonoscopy demonstrated diffuse inflammation with erythema, friability, and shallow ulcerations in the rectum and colon. Biopsies were consistent with Crohn's colitis. He was admitted for infliximab infusion for his unremitting diarrhea. Five days before admission, the patient noted mild swelling and redness of the left lower eyelid, which progressed to involve the right lower eyelid with frank pus draining from both eyes. He had no visual impairment or eye pain. Two days before admission, an ophthalmologist prescribed a steroid eyedrop with no relief. He also complained of seropurulent painful skin lesions on his face and scalp, which spread to involve his upper trunk and proximal arms. On admission to the hospital, dermatology, ophthalmology, and infectious disease consultations were obtained to rule out disseminated infection before initiation of infliximab therapy. The patient was afebrile and hemodynamically stable. His oral mucosa was normal. He had prominent bilateral lower eyelid edema, erythema, and superficial erosions with hemorrhagic crusting and frank green purulent drainage from both eyes, with crusting along the lower lash line and bilateral sclera injection (Figure 1). On his scalp, face, trunk, and proximal extremities, he had 25 to 30 erythematous, 4- to 8-mm papulopustules with narrow red halos, some with central necrosis and crusting (Figure 2). Cultures from the purulent ocular drainage and pustules on the trunk and arms were all negative for bacteria, virus, and fungi. Gram stain from the eye drainage showed polymorphonuclear leukocytes without organisms. Tissue cultures were negative for bacterial, fungal, and mycobacterial infection. Skin biopsy taken from the central upper back demonstrated subcorneal pustules with areas of eroded epidermis and collections of neutrophils in the superficial dermis (Figure 3). Special stains were negative for organisms. He received infliximab infusion 5 mg/kg for a total dose of 420 mg over 2 hours. Within 48 hours of infusion, there was notable decrease in size of lesions, in addition to reduction of purulent drainage from both eyes. The patient was discharged home following infliximab infusion. His skin lesions resolved during a period of 2 weeks, leaving small pink atrophic scars. He received his second infusion of infliximab 2 weeks after discharge with continued improvement in his gastrointestinal symptoms. PMID- 21675505 TI - Cutaneous manifestations of Strongyloides stercoralis hyperinfection in an HIV seropositive patient. AB - A 41-year-old human immunodeficiency virus (HIV)-positive man was hospitalized with complaints of a 4-week history of nausea and vomiting, associated with decreased oral intake, and a 4-day history of frontal headache and fever. His medical history was significant for a gunshot wound to the head 3 years prior, with a residual seizure disorder. He also had two previous hospitalizations, both for culture-negative bacterial meningitis; the first episode occurred 12 months before admission and the second episode occurred 5 months later. At that time, he was found to be positive for serum antibodies against HIV and a CD4+ T-lymphocyte count of 126/mm3. He had no known drug allergies and was not receiving any medication. On admission, the patient was febrile (104.0 degrees F) and hypotensive (blood pressure, 92/40 mm Hg). Pertinent physical examination findings included cachexia with bitemporal wasting, dry mucus membranes, adherent white patches on the oral mucosa, and negative Kernig's and Brudzinski's signs. His laboratory results revealed macrocytic anemia, a decreased serum sodium of 125 mEq/L, and a normal total leukocyte count with a CD4+ T-lymphocyte count < 50/mm3. Lumbar puncture opening pressure was elevated at 160 mm Hg, and cerebrospinal fluid analysis showed an increased white cell count of 97/microL (84% lymphocytes), a decreased glucose level of 26 mg/dL, and a decreased protein level of 42 mg/dL. The patient was started on empiric therapy that included intravenous ampicillin and cefotaxime, oral Bactrim, and clotrimazole lozenges for thrush. Cerebrospinal fluid culture was positive for Escherichia coli, sensitive to cefotaxime. Two days later, the patient developed fine, erythematous, nonblanchable macules primarily on his abdomen, with minimal involvement of his thorax and back. His skin lesions remained unchanged for the next 2 weeks. Repeat lumbar puncture was performed after 14 days of cefotaxime. The cerebrospinal fluid analysis showed an elevated white cell count of 7/microL (100% lymphocytes), a decreased glucose level of 53 mg/dL, and a decreased protein level of 33 mg/dL. The cerebrospinal fluid culture was now positive for Pseudomonas aeruginosa resistant to cefotaxime. The patient was started on imipenem. On day 34 of his admission, the patient became tachypneic with complaints of dyspnea. A chest roentgenogram revealed bilateral patchy infiltrates. He was transferred to the intensive care unit and intubated for hypoxemic respiratory failure (arterial blood gas values on 6 L of oxygen: pH, 7.46; bicarbonate, 23; and oxygen saturation, 37). That evening, the patient was also noted to have diffuse petechiae and purpura in a reticulated pattern over his abdomen (Figure 1A and 1B), most heavily concentrated in the periumbilical region, extending to the axillae and upper thighs. A 3x3-mm punch biopsy from abdominal skin demonstrated Strongyloides stercoralis larvae in the dermis (Figure 2A and 2B). His sputum specimen was teeming with adult S stercoralis worms (Figure 3) and, subsequently, numerous S stercoralis larvae were observed not only from the bronchoalveolar lavage but also from the nasogastric fluid specimen. These findings confirmed the diagnosis of disseminated strongyloidiasis. On hospital day 35, the patient was doing poorly and was started on thiabendazole (1250 mg twice daily for 28 days). Nine days later, ivermectin (4.5 mg once daily for 3 days for 2 courses) was also added. He continued to clinically deteriorate. The patient died 31 days after systemic antihelminthic treatment was initiated. PMID- 21675519 TI - Health care reform: what's in it for nursing? PMID- 21675520 TI - R-E-S-P-E-C-T: What it means to be a nurse in New Jersey today. PMID- 21675521 TI - Strengthening nurse leadership in New Jersey. PMID- 21675522 TI - Chronic disease self management: an important take-home message for your patients. PMID- 21675523 TI - We've only just begun: New Jersey State Nurses Association and electronic voting. PMID- 21675524 TI - Leader up. PMID- 21675525 TI - Nursing's shining moment in the health policy arena. PMID- 21675526 TI - Health reform and NJ nurses. PMID- 21675527 TI - Dr. Peter Buerhaus' perspective on the short- and long-term outlook for registered nurses in the US. PMID- 21675528 TI - MDA Board adopts access-to-care recommendations. PMID- 21675529 TI - One letter can make a difference. PMID- 21675530 TI - Patient fact sheet. Oral health and your heart. PMID- 21675531 TI - Access and barriers: two sides of dentistry's biggest issue. PMID- 21675532 TI - Can a private equity firm own a dental practice? PMID- 21675533 TI - Communication and the cultural divide. PMID- 21675534 TI - Dental ethics and the sudden closure of chain dental offices. PMID- 21675535 TI - Now may be the time to refinance your personal and business debt. PMID- 21675536 TI - A frequently asked question: is it functional or cosmetic? PMID- 21675537 TI - Growing strong at 25. PMID- 21675538 TI - Dual ADA/AGD membership: a great idea for new dentists. PMID- 21675539 TI - Facial cellulitis secondary to dens invaginatus: a case report. AB - We describe a case of dens invaginatus in an unerupted permanent maxillary lateral incisor, which led to facial cellulitis in a 10-year-old girl. We review the importance of recognizing dens invaginatus and present strategies for preventing loss of vitality in the affected tooth. PMID- 21675540 TI - Interview with the president-elect: Dr. William A. Hadlock. PMID- 21675541 TI - Creating a lean dental office: the benefits of implementing electronic claims technology. PMID- 21675542 TI - Preschool boys' development of emotional self-regulation strategies in a sample at risk for behavior problems. AB - Little longitudinal research has been conducted on changes in children's emotional self-regulation strategy (SRS) use after infancy, particularly for children at risk. In this study, the authors examined changes in boys' emotional SRS from toddlerhood through preschool. Repeated observational assessments using delay of gratification tasks at ages 2, 3, and 4 years were examined with both variable- and person-oriented analyses in a low-income sample of boys (N = 117) at risk for early problem behavior. Results were consistent with theory on emotional SRS development in young children. Children initially used more emotion focused SRS (e.g., comfort seeking) and transitioned to greater use of planful SRS (e.g., distraction) by 4 years of age. Person-oriented analysis using trajectory analysis found similar patterns from 2 to 4 years, with small groups of boys showing delayed movement away from emotion-focused strategies or delay in the onset of regular use of distraction. The results provide a foundation for future researchers to examine the development of SRS in low-income young children. PMID- 21675543 TI - Ethnic differences in teacher-oriented achievement motivation: a study among early adolescent students in the Netherlands. AB - Among 4th-6th-grade students (165 girls, 150 boys) in the Netherlands, the author examined ethnic differences in two aspects of teacher-oriented academic motivation: working in order to please the teacher and dependence on the teacher for academic help. Given higher levels of power distance in Turkish and Moroccan versus Dutch culture, both measures and their correlates were compared for 132 Turkish- and Moroccan-Dutch students, and 183 ethnic Dutch students. Analyses showed that Turkish- and Moroccan-Dutch students scored higher on pleasing the teacher and dependence on the teacher. For them, but not for the ethnic Dutch students, teacher-oriented motivation was positively related to intrinsic motivation and perceived academic competence. Also, students from all groups reported more dependence on the teacher and more intrinsic motivation the more they appreciated their teachers. Results support the notion that teacher-oriented extrinsic motivation is autonomous, rather than controlled for students from power-distant cultures. PMID- 21675544 TI - Does a quarterlife crisis exist? AB - In this study, the authors examined quarterlife crisis, defined in the popular press as an identity crisis that leaves recent college graduates depressed, anxious, and full of doubt. To determine if a unique crisis exists, 4 groups of young adults (recent high school [n = 23] and college [n = 117] graduates in the workforce, present undergraduate [n = 75], and graduate [n = 57] students) completed self-report measures assessing identity development, future time perspective, social support, coping, depression, anxiety, and job and life satisfaction. No support was found for a quarterlife crisis among these 4 groups. Working high school graduates displayed the highest anxiety, followed by present undergraduates. Depression was predicted by family support and identity commitment. Job satisfaction was associated with income and support from friends. Life satisfaction was associated with income, social support from friends and family, and identity commitment. PMID- 21675545 TI - Adult age and gender differences in perceptions of facial attractiveness: beauty is in the eye of the older beholder. AB - The authors examined ratings of facial attractiveness, rankings of faces and reasons given by young, middle-aged, and older men and women for young, middle aged, and older male and female face attractiveness. No support for predictions derived from similarity, interest, and cohort hypotheses was obtained. In support of the expertise hypothesis, young and middle-aged adults rated younger faces as more attractive than old faces, whereas older adults rated all aged faces equally. In support of the crone hypothesis, older female faces were rated the lowest of all faces. Theoretical implications and real-world applications are discussed. PMID- 21675546 TI - The reciprocal relations between teachers' perceptions of children's behavior problems and teacher-child relationships in the first preschool year. AB - To examine the reciprocal relations between teacher-child relationships and children's behavior problems, the authors analyzed cross-lagged longitudinal data on teacher-child relationships and children's internalizing and externalizing problems using a structural equation modeling approach. The homeroom teachers of 105 first-year preschoolers aged 2-3 years filled in the Student-Teacher Relationship Scale and the Child Behavior Checklist/2-3, first at 3 months after the children's preschool entrance and then at the end of the first preschool year. Results showed significant cross-wave reciprocal relations between externalizing problems and teacher-child conflict and significant cross-wave relation from early internalizing problems to later teacher-child conflict. However, the cross-wave associations between internalizing and externalizing problems and teacher-child closeness were not significant. PMID- 21675547 TI - Children's sense of belonging and parental social capital derived from school. AB - Parents' chance to seek help from other parents of schoolchildren attending the same school is an aspect of parental social capital. This social capital is supposed to contribute to schoolchildren's present sense of belonging to their school, society, and country. The relationship between social capital and a child's sense of belonging may vary as a function of the child's prior sense of belonging. Social capital may give a deeper encouragement or positive effect to children with higher prior sense of belonging (the strength building perspective) or to children with lower prior sense of belonging (the need fulfillment perspective). The author surveyed 289 parents and their schoolchildren in Grades 4-9 in Hong Kong, China, to ascertain which of the two perspectives holds. The results indicated that parental social capital was more highly associated with a child's present belongingness if his or her prior belongingness was high rather than low. This interaction effect is supportive of the strength building perspective. PMID- 21675548 TI - Development and validation of the Efficacious Self-Presentation Scale. AB - A new self-report measure of adolescent's self-presentation is described. The self-report scale was administered to 760 16-19-year-old subjects. Results of a factor analysis supported 6 identifiable factors reflecting different concepts, theoretically discussed, related to self-presentation: ability to regulate self image, social sensitivity, body self-confidence, social self-confidence, social openness, and social desirability. The scale showed good convergent validity and internal consistency. Assertive tactics were predicted through ability to regulate self-image, social self-confidence, and social openness, whereas defensive tactics were predicted only through social openness and social sensitivity. The implications of the findings for future theoretical and empirical development of research in this field are discussed. PMID- 21675549 TI - Developmental trajectories of marijuana use from adolescence to adulthood: personality and social role outcomes. AB - Longitudinal trajectories of marijuana use from adolescence into adulthood were examined for adverse life-course outcomes among African-Americans and Puerto Ricans. Data for marijuana use were analyzed at four points in time and on participants' personality attributes, work functioning, and partner relations in adulthood using growth mixture modeling. Each of the three marijuana-use trajectory groups (maturing-out, late-onset, and chronic marijuana-users) had greater adverse life-course outcomes than a nonuse or low-use trajectory group. The chronic marijuana-use trajectory group was highly associated with criminal behavior and partners' marijuana use in adulthood. Treatment programs for marijuana use should also directly address common adverse life-course outcomes users may already be experiencing. PMID- 21675550 TI - Challenging an authorial attribution: vocabulary and emotion in a translation of Goethe's Faust attributed to Samuel Taylor Coleridge. AB - This article disputes the stylometric attribution of an anonymous English 1821 translation of Goethe's German verse drama Faust to the poet an critic Samuel Taylor Coleridge. The translation was compared to four known Coleridgean dramas, two of which were translations from German. Evidence challenging Coleridge's authorship came from words used proportionally more often by Coleridge, words used proportionally more often by the unknown translator, differential employment of parallel word forms ("O" and "hath" for Coleridge, "oh" and "has" for the translator), and differences in the undertones of the two vocabularies, as measured by the Dictionary of Affect in Language (Coleridge's undertones were less pleasant and more abstract). Some problems with the stylometry of the challenged attribution to Coleridge are noted. PMID- 21675551 TI - Depression and suicidality in obese patients. AB - A study of 70 obese patients indicated the presence of severe depression in 32% of the sample and some suicidal risk in 23%. Given this high prevalence, health professionals should always explore the presence of depression and suicidality in obese patients. PMID- 21675552 TI - Emotional intelligence in women caregivers with depressive symptoms. AB - The emotional intelligence of a sample of 59 women caregivers (M age = 51.1 yr.) with depressive symptoms was compared with that of a sample of adult women from the general population (M age = 50.7 yr.). No group differences were observed on the Trait Meta-Mood Scale's three dimensions of emotional intelligence across age, socioeconomic status, or education level. Compared with the general population sample, the caregivers group scored significantly lower on Attention to Feelings and Mood Repair. PMID- 21675553 TI - GRE requirements and student perceptions of fictitious clinical psychology graduate programs. AB - The influence of Graduate Record Examination (GRE) requirements on undergraduate students' perceptions of a fictitious clinical psychology graduate program was examined. The more rigorous a program's GRE requirement, the more highly students were expected to rate the program on quality, reputation, challenge of curriculum, attractiveness, and their willingness to apply. 140 undergraduate participants read and rated one of three possible program descriptions that differed only with regard to the stated GRE requirements. Although the effects were small, participants rated the program requiring a minimum combined GRE score of 1,200 (verbal and quantitative) as higher in quality and as having a more challenging curriculum compared to the program that required the GRE but with no minimum score. Although preliminary, these findings are consistent with previous research demonstrating that graduate school applicants use GRE requirements in their evaluation of graduate programs. PMID- 21675554 TI - Adding information may increase overconfidence in accuracy of knowledge retrieval. AB - Feelings of retrospective confidence concerning the accuracy of a chosen answer might rely, among other things, on the amount of available information, regardless of its correctness. 43 participants, 26 women and 17 men (M age = 23.4 yr., SD = 3.5) in an intact group design, answered nine easy and nine difficult binary forced-choice questions and rated their confidence regarding the correctness of their choices. Participants were randomly assigned to one of three groups, differing in the additional information provided regarding the questions: a control group provided with no additional information, a correct information group, and a misleading information group. Performance was worst in the misleading information group, yet no difference in confidence was found between the correct and misleading information groups. The findings were interpreted as supporting the hypothesis that feelings of confidence partly reflect peripheral factors, indirectly related to choice processes. PMID- 21675555 TI - Development of an Individualism-Collectivism Scale revisited: a Korean sample. AB - A 13-item Individualism-Collectivism scale comprising source of identity, goal priority, mode of social relation, and norm acceptance is presented. A validation of this scale was conducted using a survey of 773 Korean employees. An exploratory factor analysis and a second-order confirmatory factor analysis supported the measure as having theoretical face validity and acceptable internal consistency reliability. Among the four facets, goal priority most strongly predicted the general Individualism-Collectivism latent factor. PMID- 21675556 TI - A test of the validity of the IS PATH WARM warning signs for suicide. AB - The 10 warning signs for suicide, encapsulated in the mnemonic IS PATH WARM, did not differentiate between genuine suicide notes and those written by people simulating a suicidal crisis or between notes written by completed suicides and those written by attempted suicides. PMID- 21675557 TI - Effects of aging and divided attention on recognition memory processes for single and associative information. AB - In the divided attention paradigm to test age-related associative memory deficits, whether the effects of divided attention occur at encoding or retrieval has not been clarified, and the effect on retention has not been studied. This study explored whether and how much divided attention at either encoding, retention, or retrieval diminished accuracy in recognizing a single feature (object or location) and associated features (object+location) by 23 elderly people (13 women; M age = 70.6 yr., SD = 2.8) recruited from a neighborhood community circle, and 29 female college students (M age = 20.8 yr., SD = 1.1). The results showed a significant decline in memory performance for both age groups due to divided attention in location and associative memory at retention, suggesting that the retention process demands attentional resources. Overall, regardless of their relative deficiency in associative memory, older adults showed an effect of divided attention comparable to that of younger adults in a recognition task. PMID- 21675558 TI - Evaluation of a social skills program based on social learning theory, implemented in a school setting. AB - Using a sample of 647 Canadian children in kindergarten to Grade 3 (325 boys, 322 girls), the present study evaluated the perceived effectiveness of Skillstreaming (McGinnis & Goldstein, 2003), a widely known social skills program implemented to target the development of four skill sets, i.e., listening, following directions, problem-solving, and knowing when to tell. Results indicated significant postprogram improvements in all skills as well as in ratings of overall prosociality obtained from both classroom teachers and mental health staff, with medium to large effect sizes obtained from teachers' and mental health professionals' ratings, respectively. Additional analyses yielded significant but weak moderator effects of grade and preprogram prosocial functioning for teacher ratings but no consistent moderator effects for children's sex or school location (i.e., urban versus rural) regardless of rater. PMID- 21675559 TI - War stress and late-life mortality in World War II male civilian resistance veterans. AB - The mental and physical health of 146 Dutch males exposed to severe war stress during their young adulthood were examined in 1986-1987 when they were at ages 61 to 66 years. The veterans' data were compared with a randomly selected population based sample of same-aged males. In 2005, 70% of the war stress veterans had died, and only 35% of the comparison group. The baseline quality of life was significantly poorer in the war stress veterans than in the comparison group. Baseline variables explained 42% of the increased risk of mortality among war stress veterans. Smoking was the largest single contributor to mortality. PMID- 21675560 TI - Perpetration of Sexual Coercion and Victim of Sexual Coercion Scales: development and validation. AB - The purpose of this research was to create two scales, one to measure the tendency to perpetrate sexual coercion and one the tendency to be a victim of sexual coercion (Study 1), and to provide data validating the scales (Studies 2 and 3). Using the rational method of scale construction, two 13-item scales were constructed: the Perpetrator of Sexual Coercion Scale and the Victim of Sexual Coercion Scale. Construct validity (Study 2) was based on significant correlations with measures of engaging in promiscuous sex and abuse of alcohol. Support was found for the hypothesis (Study 3) that sexual coercion, being a victim of sexual coercion, alcohol abuse, and sexual promiscuity were associated with the pursuit of immediate pleasure through alcohol and sex. PMID- 21675561 TI - Factor structure of the Spanish version of the Object-Spatial Imagery and Verbal Questionnaire. AB - The reliability and factor structure of the Spanish version of the Object-Spatial Imagery and Verbal Questionnaire (OSIVQ) were assessed in a sample of 213 Spanish university graduates. The questionnaire measures three types of processing preferences (verbal, object imagery, and spatial imagery). Principal components analysis with varimax rotation identified three factors, corresponding to the three scales proposed in the original version, explaining 33.1% of the overall variance. Cronbach's alphas were .72, .77, and .81 for the verbal, object imagery, and spatial imagery scales, respectively. PMID- 21675562 TI - Executive functioning and positive psychological characteristics: a replication and extension. AB - Positive psychological characteristics and executive function are correlated with gratitude, satisfaction with life, and forgiveness. The goal of this study was to replicate these findings while examining two additional constructs, namely, hope and optimism. 113 students (25 men, 88 women) between the ages of 17 to 24 years (M = 19.4, SD = 1.5) volunteered to participate. Positive correlations between executive function and gratitude were found but mixed results were obtained for forgiveness and satisfaction with life. Hope and optimism correlated positively with executive function and hierarchical multiple regression analysis indicated that they contributed significantly to the explanation of executive functioning. Further investigation into relationships between executive functioning, its neurobiological substrates, and positive psychological attributes is recommended. PMID- 21675563 TI - Effect of visual-verbal load and spatial compatibility on stimulus response. AB - This study examined the effects of visual-verbalload (as measured by a visually presented reading-memory task with three levels) on a visual/auditory stimulus response task. The three levels of load were defined as follows: "No Load" meant no other stimuli were presented concurrently; "Free Load" meant that a letter (A, B, C, or D) appeared at the same time as the visual or auditory stimulus; and "Force Load" was the same as "Free Load," but the participants were also instructed to count how many times the letter A appeared. The stimulus-response task also had three levels: "irrelevant," "compatible," and "incompatible" spatial conditions. These required different key-pressing responses. The visual stimulus was a red ball presented either to the left or to the right of the display screen, and the auditory stimulus was a tone delivered from a position similar to that of the visual stimulus. Participants also processed an irrelevant stimulus. The results indicated that participants perceived auditory stimuli earlier than visual stimuli and reacted faster under stimulus-response compatible conditions. These results held even under a high visual-verbal load. These findings suggest the following guidelines for systems used in driving: an auditory source, appropriately compatible signal and manual-response positions, and a visually simplified background. PMID- 21675564 TI - Test-retest reliability of the Frankfurt Complaint Questionnaire. AB - Long-term reliability of the Frankfurt Complaint Questionnaire (FCQ) was investigated in two follow-up studies of participants with psychosis using a test retest method. In the first study (N = 56), the duration of the follow-up ranged from 6 months to 2 years; Spearman rho was .62 for the abridged (18 items) Spanish version of the questionnaire. In Study 2 (N = 21), in participants with stable schizophrenia, the follow-up ranged from 8 to 11 years; test-retest Spearman rho was .83 for the French version of the questionnaire. Subjective experiences could constitute, in psychosis-prone people, traits or markers of psychotic vulnerability. PMID- 21675565 TI - Factors in the fatigue of heavy vehicle drivers. AB - This study assessed work-related and driver-related factors in fatigue among Finnish heavy vehicle drivers. 683 professional drivers responded to a questionnaire, 27.8% of whom reported often feeling fatigue during their work shifts. Of the respondents, 27.5% reported having momentarily fallen asleep at the wheel while driving during the past year. Almost half (46.8%) of the fatigued drivers estimated the reasons for momentarily falling asleep were work-related. Long working shifts and short sleeps significantly increased the risk of momentarily falling asleep at the wheel. The risk of fatigue was the highest for the drivers who were unable to choose the time of their breaks. PMID- 21675566 TI - A factor analytic study of the COPE Questionnaire by sex of respondents. AB - This work examined the effect of sex on factor structure of a Chinese version of the 1989 COPE questionnaire with a sample of 617 Hong Kong adolescents (Mdn age = 14 yr.). Some scales had low internal consistency reliability for both sexes. Not all 15 scales could be identified as unique factors through exploratory factor analysis separately for both sexes (275 boys, 338 girls, 4 unknown). In a second order factor analysis, both sexes' data had factors related to problem-focused coping and avoidance/escaping coping, and these two factors were only weakly correlated. An emotion-focused factor was observed in girls' data, but not boys' data. PMID- 21675567 TI - Religiosity and HIV risk behaviors in African-American students. AB - The participants were 256 African-American students between the ages of 18 and 25, from two historically Black universities. The purpose of this study was to see how dimensions of religiosity and spirituality influenced the HIV risk behavior in African-American college students. Each participant completed the Expressions of Spirituality Inventory (ESI) and a survey of sexual attitudes, beliefs, and behaviors. The data were analyzed using a series of ANOVAs, t tests, and correlations. The results from the study confirmed that there was a relationship between religiosity/spirituality and one's tendency to engage in HIV risk behaviors in the population of African-American college students. Interestingly, this study was able to reveal that traditional indicators of religiosity, such as association and church attendance, were not predictors of any of the risky sexual behaviors or attitudes. The portions of religiosity with the greatest impact on these behaviors were the Experiential/Phenomenological, the Existential Well-being, and the Cognitive dimensions, with high scores on each indicative of less likelihood of engaging in risky sexual behaviors. PMID- 21675568 TI - Associations of social relationships with consultation for symptoms of depression: a community study of depression in older men and women in Quebec. AB - To assess associations between social relationships and consultation for symptoms of depression, data from a representative sample of 2,811 French-speaking community-dwelling older adults in Quebec were used. Less than half of the older adults meeting DSM criteria for depression (N = 379; 47.1%) had sought consultation about their depression-relevant symptoms in the preceding 12 months. Having a cohabitant partner or having children were not associated with frequency of consultation for women. Men without a partner tended to consult more frequently than men with a cohabiting partner (OR = 2.5; 95% CI = 0.81, 7.88). None of the men without a confidant had consulted. Among the 67 men with a confidant, consultation was more frequent among those not cohabiting with a partner (70%) than among those with a cohabiting partner (46%). The influence of social relationships on consultation for depression differed in men and women in this population of depressed elderly people in Quebec. PMID- 21675569 TI - Behaviors and attitudes of normally developing children toward their intellectually disabled siblings. AB - This study investigated behaviors of children who have normal development toward their siblings with intellectual disabilities. 9- to 17-year-old normally developing siblings (55 girls, 39 boys) of 94, 5- to 15-year-old mentally disabled children (51 girls, 43 boys) who were attending a special education and rehabilitation center were enrolled in the study. Data were gathered by using a general information form and the Schaeffer Sibling Behavior Rating Scale. Age of the disabled child did not have a significant effect on siblings' behaviors, while knowledge of family about the diagnosis and educational status of their child with intellectual disabilities affected sibling behaviors. PMID- 21675570 TI - Financial satisfaction and financial stressors in marital satisfaction. AB - Using a sample of 310 married respondents from one U.S. Midwestern state, a test was conducted to examine the association of financial satisfaction and financial stressors in a spouse's decision to stay married to the same person or leave the relationship. The role of demographic and socioeconomic variables, religiosity, psychological constructs, financial satisfaction, and financial stressors as factors influencing marital satisfaction was tested. Financial stressors were measured using a list of financial stressors adapted from the literature. Financial satisfaction was measured with a one-item scale. The Kansas Marital Satisfaction Scale was used as a validation tool to assess whether individuals would marry or not marry again. Religiosity and financial satisfaction were positively associated with marital satisfaction. A negative interaction between financial satisfaction and financial stressors was also noted. Findings suggest that respondents who are financially satisfied tend to be more stable in their marriages. PMID- 21675571 TI - Age-related trends of interference control in school-age children and young adults in the Stroop color-word test. AB - In this cross-sectional study, differences in interference control, one component of executive function, were investigated among three age groups, 15 early childhood (7- to 8-yr.-olds), 25 middle childhood (9- to 12-yr.-olds), and 20 young adults (21- to 30-yr.-olds). Participants were administered a computer version of the Stroop color-word test with an oral response; correct responses, response time (RT), and the interference ratio were examined. The data indicated that (1) most of the participants showed no errors in word reading, color-naming, and incongruent color-naming tasks; (2) in word-reading and color-naming tasks, RT for 7- to 8-yr.-olds was longer than that for 9- to 12-yr.-olds, while RT of 9 to 12-yr.-olds and young adults were comparable; (3) in an incongruent color naming task, RT for 7- to 8-yr.-olds was longer than RT for 9- to 12-yr.-olds, which was longer than RT for young adults; and (4) the interference ratio was higher in 7- to 8-yr.-olds than in 9- to 12-yr.-olds, which was higher than in young adults. These results suggested the difference in interference control between early and middle childhood reported on the go/no-go task and the stop signal procedure would be observed in the Stroop color-word paradigm as well. The utility of this modified Stroop color-word test for those with intellectual and developmental disabilities was discussed. PMID- 21675572 TI - Cognitive appraisals of stereotype threat. AB - Using the cognitive appraisal conceptualisation of the transactional model of stress, the goal was to assess how victims of stereotype threat respond to this situation in terms of primary appraisals (threat/challenge) and to investigate whether those appraisals may mediate the relation between stereotype threat and performance. Results show that, while participants from North Africa living in France did appraise the situation more as a threat and less as a challenge, only challenge appraisal mediated between stereotype threat and performance. PMID- 21675573 TI - Mimicry and propagation of prosocial behavior in a natural setting. AB - This study tested, in a natural setting, the effect of mimicry on people's disposition toward helping others and the extent to which this helping behavior is extended to people not directly involved in the mimicry situation. In the main street of a busy town, men (n = 101) and women (n = 109) passersby were encountered and asked for directions. These passersby were subjected to mimicry by naive confederates who mimicked either verbal behavior alone or verbal and nonverbal behaviors together, including arm, hand, and head movements. In the control condition, passersby were not mimicked. Following this first encounter, each subject was then met further down the street by a second confederate who asked for money. The results show that people who had been mimicked complied more often with a request for money and gave significantly more, suggesting they were more helpful and more generous toward other people, even complete strangers. PMID- 21675574 TI - Association between just world beliefs and perceptions of counterproductive workplace behaviors. AB - 320 adults rated 48 counterproductive workplace behaviors (CWBs) on a 9-point scale, from petty to serious offense, and also completed the Just World Beliefs scale. Ratings of the seriousness of the CWBs indicated considerable variability in perceptions, with theft and physical violence rated most strongly. A factor analysis yielded five interpretable factors. Older participants were more likely to rate as more serious all counterproductive workplace behaviors. PMID- 21675575 TI - "Publish or perish" is alive and well: a re-analysis of Landrum and Clump (2004). AB - A re-analysis was undertaken of Landrum and Clump's data reporting the results of a survey of search committee chairs' criteria for evaluating applicants for psychology faculty positions. Results indicated that 5 factors emerged from their agreement items (measuring agreement with specific statements about submitted applications) and 4 factors emerged from their importance items (measuring prioritization of specific application characteristics). Several of these factors, especially one focusing upon teaching and research emphasis, are useful to different degrees. These results suggest that public institutions with graduate programs differ from other institutions on criteria for applicants in several ways, particularly in their emphasis on research over teaching. Results may help applicants to better focus their efforts in the application process. PMID- 21675576 TI - Prediction of intrinsic motivation and sports performance using 2 x 2 achievement goal framework. AB - The purpose of this study was to examine the influence of 2 x 2 achievement goals on intrinsic motivation and performance in handball. Participants were 164 high school athletes. All completed the 2 x 2 Achievement Goals Questionnaire for Sport and the Intrinsic Motivation subscale of the Sport Motivation Scale; the coach for each team rated his athletes' overall sports performance. Using simultaneous-regression analyses, mastery-approach goals positively predicted both intrinsic motivation and performance in sports, whereas performance avoidance goals negatively predicted sports performance. These results suggest that athletes who pursue task mastery and improvement of their competence perform well and enjoy their participation. In contrast, those who focus on avoiding normative incompetence perform poorly. PMID- 21675577 TI - Comparative analysis of a client's verbal responses in counseling sessions: quantitative case study. AB - This study investigated how the in-session change in a client's verbal behavior might influence the effectiveness of counseling sessions. 10 sessions of counseling with a male undergraduate suffering from depressive mood were conducted by a humanistically oriented counselor. The two most effective and the two least effective sessions were identified according to the client's evaluation of the effectiveness of counseling sessions. Results indicated that over the three segments of the most effective sessions, the client gradually increased responses that indicated exploration of his own emotions, thoughts, and behaviors. By contrast, the client continued talking mainly about past events in a storytelling manner throughout the least effective sessions. PMID- 21675578 TI - Variable effects of humor styles on organizational outcomes. AB - The relationship between individual humor styles and several organizational variables was investigated: stress, satisfaction with coworkers, team cooperation, and organizational commitment. Four humor styles from the Humor Styles Questionnaire were measured. Survey results of 349 participants indicated different humor styles (affiliative, self-enhancing, aggressive, and self defeating) can have either a positive or negative effect on organizational outcomes. Results suggested that both researchers and practitioners can benefit from having a better understanding of how different humor styles affect people and outcomes in organizations. PMID- 21675579 TI - Reliability and construct validity of the College Student Stress Scale. AB - Reliability and construct validity of the 11-item College Student Stress Scale were investigated with exploratory (N = 273) and confirmatory factor analyses (N = 185) in undergraduate college students. Two factors were observed; however, reliability of the 3-item factor was too low and one item failed to load on either factor. A 7-item measure (Factor 1) had acceptable reliability (.81) and good convergence with the Perceived Stress Scale. This measure was significantly correlated with Neuroticism, Test Anxiety, and Self-efficacy for Learning, but not Social Desirability or age. PMID- 21675580 TI - Message framing and color combination in the perception of medical information. AB - A 2 x 2 between-subjects design was used to examine the effects of message framing (gain vs loss) and color combination (red background with white characters vs white background with black characters) on 120 university students' perception of materials promoting the H1N1 flu vaccine and their willingness to receive the vaccine after they had read the materials. Each participant completed a 6-item questionnaire, and the results of an analysis of variance showed that participants rated vaccine information presented through loss-framed messages as having greater interest and leading to greater understanding. Loss-framed messages presented on a white background with black characters significantly increased the willingness of the participants to receive the vaccine. PMID- 21675581 TI - Test-retest reliability and construct validity of the Helplessness, Hopelessness, and Haplessness Scale in patients with anxiety disorders. AB - In a sample of 100 Turkish psychiatric patients with diagnoses of anxiety disorders, Lester's Helplessness, Hopelessness, and Haplessness inventory had moderate estimates of internal consistency, test-retest reliability, and construct validity. PMID- 21675582 TI - Low-acid diet for recalcitrant laryngopharyngeal reflux: therapeutic benefits and their implications. AB - OBJECTIVES: Laryngopharyngeal reflux (LPR) is an expensive, high-prevalence disease with a high rate of medical treatment failure. In the past, it was mistakenly believed that pepsin was inactive above pH 4; however, human pepsin has been reported to be active up to pH 6.5. In addition, it has been shown by Western blot analysis that laryngeal biopsy samples from patients with symptomatic LPR have tissue-bound pepsin. The clinical impact of a low-acid diet on the therapeutic outcome in LPR has not been previously reported. To provide data on the therapeutic benefit of a strict, virtually acid-free diet on patients with recalcitrant, proton pump inhibitor (PPI)-resistant LPR, I performed a prospective study of 20 patients who had persistent LPR symptoms despite use of twice-daily PPIs and an H2-receptor antagonist at bedtime. METHODS: The reflux symptom index (RSI) score and the reflux finding score (RFS) were determined before and after implementation of the low-acid diet, in which all foods and beverages at less than pH 5 were eliminated for a minimum 2-week period. The subjects were individually counseled, and a printed list of acceptable foods and beverages was provided. RESULTS: There were 12 male and 8 female study subjects with a mean age of 54.3 years (range, 24 to 72 years). The symptoms in 19 of the 20 subjects (95%) improved, and 3 subjects became completely asymptomatic. The mean pre-diet RSI score was 14.9, and the mean post-diet RSI score was 8.6 (p = 0.020). The mean pre-diet RFS was 12.0, and the mean post-diet RFS was 8.3 (p < 0.001). CONCLUSIONS: A strict low-acid diet appears to have beneficial effects on the symptoms and findings of recalcitrant (PPI-resistant) LPR. Further study is needed to assess the optimal duration of dietary acid restriction and to assess the potential role of a low-acid diet as a primary treatment for LPR. This study has implications for understanding the pathogenesis, cell biology, and epidemiology of reflux disease. PMID- 21675583 TI - Effects of liquid type, delivery method, and bolus volume on penetration aspiration scores in healthy older adults during flexible endoscopic evaluation of swallowing. AB - OBJECTIVES: The type of liquid (eg, water or milk) that should be used during flexible endoscopic evaluation of swallowing (FEES) has received little investigation. Aspiration may vary as a function of the thin liquid type used during FEES. METHODS: We measured the effects of liquid type (water, skim milk, 2% milk, and whole milk; all dyed with green food coloring), delivery method (cup and straw), and bolus volume (5, 10, 15, and 20 mL) on Penetration-Aspiration Scale (PAS) scores in 14 healthy older adults (mean, 75 years; range, 69 to 85 years). Each participant generated 32 swallows. RESULTS: The PAS scores differed significantly by liquid type (p = 0.003) and by bolus volume (p = 0.017), but not by delivery method (p = 0.442). The PAS scores were significantly greater for 2% milk and whole milk than for skim milk and water (p < 0.05), and for 20 mL versus smaller volumes. Penetration and aspiration were observed on 113 (25%) and 15 (3%) of 448 swallows, respectively. CONCLUSIONS: These findings suggest that both milk and water should be used during FEES for an accurate assessment of aspiration status. PMID- 21675584 TI - Acute supraglottitis in adults. AB - OBJECTIVES: Adult supraglottitis is a potentially life-threatening airway infection. We reviewed the management and outcome of supraglottitis in 169 adults admitted to Liverpool Hospital between 1999 and 2009. METHODS: A retrospective review was conducted of all admissions with supraglottitis in patients at least 18 years of age. The diagnosis was confirmed by fiberoptic nasolaryngoscopy or direct laryngoscopy under general anesthesia. The main outcome measure was the need for intubation or tracheotomy. Univariate analysis was performed to determine factors that led to a worse outcome. RESULTS: There were 80 men and 89 women in the cohort, with a median age of 51 years. Of these, 140 patients were admitted to the intensive care unit for a mean duration of 2 days. The common symptoms and signs at presentation were odynophagia and dysphagia (94%), dysphonia (65%), and stridor (33%). Endotracheal intubation was performed in 16 patients, and an awake tracheotomy was required in 4 patients. Dexamethasone acetate was used in 103 patients. Thirty-five patients had diabetes mellitus as a comorbidity. The presence of diabetes was predictive of the need for intubation or tracheotomy (p < 0.05), and the use of steroids was predictive of an intensive care unit stay of 24 hours or less (p < 0.05). CONCLUSIONS: Fiberoptic laryngoscopy is the gold standard for diagnosis of supraglottitis, and close airway monitoring is crucial. Conservative management of the airway is a viable option, but the presence of diabetes makes airway intervention more likely. The use of steroids aids in symptom alleviation and hastens resolution of airway swelling, with no negative sequelae. PMID- 21675585 TI - Morphology of human fungiform papillae after severing chorda tympani nerve. AB - OBJECTIVES: We aimed to clarify the postoperative morphology of the fungiform papillae (FP) of the tongue in patients who recovered gustatory function after the chorda tympani nerve was severed during middle ear surgery. METHODS: Fifty four patients with normal preoperative gustatory function measured by electrogustometry (EGM) were included. The proximal and distal stumps of the severed nerves were re-adapted or re-approximated during surgery to promote regeneration of the nerve. The EGM thresholds over 2 years after surgery were compared with preoperative values. At the same time, the morphological characteristics of the FP in the midlateral region of the tongue were recorded with a digital microscope. RESULTS: One month after surgery, EGM showed no response in any patients. At a time point of more than 2 years, the FP showed complete atrophy and no response to EGM on the surgical side in 21 of the 54 patients. In 16 patients who showed complete recovery of the EGM threshold (below 20 microA), the FP showed an almost normal appearance, and the mean number of FP was 77.5% (10 +/- 4.1 papillae per square centimeter) of that on the contralateral side (12.9 +/- 4.9 papillae per square centimeter; p > 0.05). CONCLUSIONS: The morphology of the FP was maintained in patients who recovered gustatory function after the chorda tympani nerve was severed. Because the results indicate regeneration of the taste buds, further observation is needed to detect regenerated taste buds in the FP. PMID- 21675586 TI - Determination of predictive factors of tracheobronchial prosthesis removal: stent brands are crucial. AB - OBJECTIVES: We sought to describe in a retrospective study our experience in the endoscopic management of tracheobronchial stenoses over 20 years and to determine prognostic factors of stent removal. METHODS: We analyzed the medical records of 166 patients (111 male and 55 female) who underwent the placement of a prosthesis for all causes of tracheobronchial stenosis between 1990 and 2009. RESULTS: Overall, 34% of the patients had their stents removed. The incidence of complications for the first stent was 0.08 per patient-month. One hundred five patients (63%) had no complications. In univariate analysis, stent removal was significantly linked with the stent brand. In multivariate analysis, taking into account the causes of stenosis, the stent brand appeared to be the only factor that significantly influenced stent removal. Finally, stenosis with more than 1 stent replacement was most prone to repeat endoscopies. CONCLUSIONS: Even though endoscopic stent placement is a relatively safe and effective treatment for tracheobronchial stenoses, particularly in cases with malignancy, complications led to stent removal in about one third of cases. The type of stent chosen is crucial. PMID- 21675587 TI - Long-term effects of hearing aids on word recognition scores. AB - OBJECTIVES: The purpose of this study was to retrospectively examine how monaurally fitted hearing aids affected word recognition scores in patients with bilateral symmetric sensorineural hearing loss. METHODS: Sixty-six patients from 2 separate institutions were included in this study. In addition to having bilateral symmetric sensorineural hearing loss due to presbycusis, each patient had to have worn a single hearing aid for at least 5 months and have valid pre aid and post-aid audiograms. Word recognition scores were analyzed with a table of confidence levels generated by Thornton and Raffin that determined the probability of differences between word recognition scores. RESULTS: Hearing aids did not improve or preserve word recognition scores to the degree that has been previously reported in the literature. The unaided (control) ear demonstrated a decrease in word recognition scores over time, as was expected from previous studies. The aided ears demonstrated a similar decline in word recognition scores when compared to the unaided ears. When the conventional confidence level of 0.05 was used, the aided ears showed no advantage over the unaided (control) ears. CONCLUSIONS: These findings are not consistent with the acclimatization first reported by Silman et al in 1993. Such a discrepancy in the results calls for further studies to evaluate just how effective unilateral hearing aids are in patients with bilateral symmetric sensorineural hearing loss. PMID- 21675588 TI - Clinical outcomes of sinogenic intracranial suppuration: the Alder Hey experience. AB - OBJECTIVES: The aim of this study was to present a series of cases of sinogenic intracranial suppuration in a pediatric tertiary referral center and to review the long-term outcomes of the patients. METHODS: We performed a retrospective review of the hospital database and the patient case notes. RESULTS: Over 10 years, 14 patients were identified. The clinical presentations at the time of admission tended to include headache, vomiting, pyrexia, limb weakness, and decreased level of consciousness, in decreasing order of frequency. Sinonasal symptoms such as discharge and obstruction were only present in 36% and 21% of cases, respectively. The most common intracranial complication was subdural empyema in the frontal lobe region. The mortality rate was 21% (3 of 14). The remaining 11 patients remained alive at latest follow-up. The average follow-up period after hospital discharge was 19 months (median, 15 months; range, 6 to 64 months). No significant complications were noted in 4 patients, who had returned to normal daily activities at 6 months of follow-up. A significant proportion of patients who survived have some form of neurologic sequelae, although 64% of cases became asymptomatic in the 12 months following hospital discharge. CONCLUSIONS: The significant risk of morbidity and mortality of this disease requires a multidisciplinary approach that is best delivered at a tertiary referral center. PMID- 21675589 TI - Effect of type I tympanoplasty on the quality of life of children. AB - OBJECTIVES: Quality-of-life issues related to chronic otitis media (COM) include physical symptoms, emotional symptoms, hearing loss, speech symptoms, social symptoms, and parents' emotional symptoms. In this study we evaluated the effects of tympanoplasty on the quality of life of pediatric patients. METHODS: In a questionnaire-based outcome study, we reviewed 56 of 78 pediatric patients with COM who were treated with type I tympanoplasty at our institution between December 2008 and February 2010. All patients were asked to fill out the COM-5 questionnaire with their parents, before operation and 6 months after operation. Preoperative and postoperative total ear scores, preoperative and postoperative ear scores with an intact tympanic membrane, preoperative and postoperative ear scores with a perforated tympanic membrane, and preoperative and postoperative audiological results were assessed. RESULTS: After type I tympanoplasty, 45 patients (80.3%) had successful closure of the tympanic membrane, but 11 patients (19.7%) had unsuccessful closure of the tympanic membrane. There was a significant decrease in physical suffering, hearing loss, emotional distress, activity limitations, and caregiver's concerns scores in patients with intact tympanic membranes after operation (p < 0.01). CONCLUSIONS: Children with COM had a significant increase in their quality of life after successful tympanoplasty. Our results also suggested that tympanoplasty was successful in pediatric patients with COM. PMID- 21675590 TI - Novel model to assess laryngeal function, innervation, and reinnervation. AB - OBJECTIVES: Laryngeal paralysis remains an unsolved problem, and the behavior of the laryngeal muscles following injury to the native innervation appears to be a function of denervation and reinnervation. The aim of the present study was to develop a reliable, accurate, and multifaceted animal model for study of laryngeal function, innervation, and reinnervation. METHODS: A spontaneous breathing anesthesia technique, suspension laryngoscopy, endoscopic evaluation of the rat larynx, and transoral injection of a retrograde neuronal tracer, hydroxystilbamidine (FluoroGold), were developed. We submitted 14 rats to the developed technique to map the brain stem projections of the superior laryngeal nerve and the recurrent laryngeal nerve and to determine the feasibility and accuracy of the endoscopic injection technique. RESULTS: This endoscopic technique provided full evaluation of the rat larynx. We performed transoral endoscopic injection of FluoroGold and transcervical application of the tracer to transected superior laryngeal and recurrent laryngeal nerves in 14 different rats and successfully created a neural projection map for the superior laryngeal nerve, the recurrent laryngeal nerve, and the cervical ganglia. CONCLUSIONS: A reliable, accurate model for the characterization of laryngeal function, routes of innervation, and sources of spontaneous reinnervation following recurrent laryngeal nerve resection has been developed. This stable and reproducible model can serve as a dependable tool in future investigations of laryngeal nerve injury and recovery. PMID- 21675591 TI - Pharyngocutaneous fistula after total laryngectomy: Less common with mechanical stapler closure. AB - OBJECTIVES: The aim of the study was to compare the incidences of pharyngocutaneous fistula after total laryngectomy between patients who underwent manual and mechanical suturing for pharyngoesophageal closure. METHODS: In a retrospective and prospective nonrandomized clinical study conducted at a single tertiary medical center between May 2002 and April 2009, we compared the incidence of pharyngocutaneous salivary fistula between two groups of patients after total laryngectomy. Sixty-one consecutive patients who underwent mechanical suturing with a 60-mm linear stapler (group A) were prospectively enrolled, and 121 patients who had undergone manual suturing (group B) were retrospectively reviewed. RESULTS: The groups were similar in terms of age, gender, comorbidities, TNM (tumor, node, metastasis) stage, and laryngeal tumor extension. The incidence of pharyngocutaneous salivary fistula was 4.9% in group A and 19.8% in group B (p = 0.014). CONCLUSIONS: Mechanical stapler closure of the pharynx after total laryngectomy was associated with a significant reduction in the incidence of pharyngocutaneous fistula compared with manual suture in selected cases. PMID- 21675592 TI - Radiolocalization of sentinel lymph nodes in clinically N0 laryngeal and hypopharyngeal cancers. AB - OBJECTIVES: We sought to analyze the characteristics of radioactive lymph nodes with metastatic disease and to explore methods for the localization of sentinel lymph nodes (SLNs) with radionuclide in clinically N0 laryngeal and hypopharyngeal cancer. METHODS: Forty-five patients with T1-T4 and clinically N0 laryngeal and hypopharyngeal cancer were recruited. For each patient, a peritumoral submucosal injection of 99mTc-labeled sulfur colloid was administered, and lymph node mapping was performed by lymphoscintigraphy 2 hours after injection. The SLNs were localized during operation by a hand-held gamma probe 10 to 12 hours after the injection, and we defined the radioactive counts from the parotideomasseteric region as background values. All lymph nodes that had accumulated radioactivity were harvested and initially termed as SLNs. Selective neck dissection was performed in all patients. The SLN specimens were sent for formal paraffin-embedded sectioning, serial sectioning, and immunohistochemical assay. The results were compared to those for the remaining lymphadenectomy specimen. Resection of the primary tumor depended on its location and the T classification. RESULTS: Sentinel lymph nodes were identified in 41 of 45 patients (51 necks). Sentinel lymph nodes with occult metastases were found in 13 patients (15 necks). In a false-negative case, metastasis was found in a nonsentinel lymph node in 1 of the neck specimens. The SLN identification rate was 92.7%, the sensitivity was 93.7%, the false-negative rate was 6.3%, and the accuracy was 98.0%. In 11 of the 15 necks (73.3%) with pathologically positive SLNs, metastasis was found in the node with the highest radioactivity. Harvesting the first 3 nodes with the highest radioactive counts may identify patients with occult metastatic disease. CONCLUSIONS: Excision of the first 3 SLNs with the highest radioactive counts can be used to accurately identify the status of cervical lymph node metastases in patients with clinically N0 laryngeal or hypopharyngeal cancer. PMID- 21675593 TI - EEG does not predict response of manic patients to atypical antipsychotics. PMID- 21675594 TI - Clinical benefit to patients suffering from recurrent migraine headaches and who opted to stop medication and take a neurofeedback treatment series. PMID- 21675595 TI - Multimodal brain imaging. PMID- 21675596 TI - Bihemispheric cerebral FDG PET correlates of cognitive dysfunction as assessed by the CERAD in Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by a variety of cognitive deficits which can be reliably assessed by the neuropsychological test battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), but the cerebral changes underlying the respective cognitive deficits are only partly understood. Measures of severity of dementia in AD as well as delayed episodic memory performance in mild cognitive impairment significantly correlated with bihemispheric cerebral glucose hypometabolism. We therefore hypothesized that the CERAD cognitive battery may represent cerebral dysfunction of both hemispheres in patients with AD. In 32 patients with AD, cerebral glucose metabolism was investigated using positron-emission-tomography with 18Fluorodeoxyglucose (FDG PET) and associated with the test scores of the CERAD cognitive battery by statistical parametric mapping. Episodic memory scores significantly correlated with temporopari etal glucose metabolism of both hemispheres while delayed episodic memory significantly was correlated with the right frontotemporal cortices. Verbal fluency and naming scores significantly correlated with glucose metabolism in left temporoparietal and right frontal cortices, whereas constructional praxis predominantly correlated significantly with the bilateral precuneus. In conclusion, the results of our study demonstrate that not only memory function but also functions of language and constructional praxis in AD are associated with glucose metabolism as revealed by FDG PET in subsets of uni- and bilateral brain areas. The findings of our study for the first time demonstrate that in AD neuropsychological deficits as assessed by the CERAD refer to different cerebral sites of both hemispheres. PMID- 21675597 TI - High-frequency oscillations in schizophrenia. AB - Neural oscillations and their synchronization may represent a versatile signal to realize flexible communication within and between cortical areas. There is extensive evidence that cognitive functions depending on coordination of distributed neural responses are associated with synchronized oscillatory activity, suggesting a functional mechanism of neural oscillations in cortical networks. In addition to their role in normal brain functioning, there is increasing evidence that altered oscillatory activity may be associated with certain neuropsychiatric disorders, such as schizophrenia, that involve dysfunctional cognition and behavior. In the present paper, the focus is on the role of high-frequency oscillations for cortical computations through establishing correlations between the modulation of oscillations in the beta/gamma frequency range and specific cognitive processes during normal brain functioning and in schizophrenia. Specifically, it is suggested that in addition to oscillations in the low (30-60 Hz) gamma-band range, gamma-band oscillations > 60 Hz may have a crucial role for the understanding of cognitive dysfunctions in schizophrenia. Perspectives for future research will be discussed in relationship to methodological issues, the utility of neural oscillations as a biomarker and the neurodevelopmental hypothesis of schizophrenia. PMID- 21675598 TI - On the origin and suddenness of absences in genetic absence models. AB - The origin of spike-wave discharges (SWDs), typical for absences, has been debated for at least half a century. While most classical views adhere to a thalamic oscillatory machinery and an active role of the cortex in modifying normal oscillations into pathological SWDs, recent studies in genetic models such as WAG/Rij and GAERS rats have challenged this proposal. It seems now well established that SWDs originate from the deep layers of the somatosensory cortex, that the activity quickly spreads over the cortex and invades the thalamus. The reticular thalamic nucleus and other thalamic nuclei provide a resonance circuitry for the amplification, spreading and entrainment of the SWDs. Conclusive evidence has been found that the changed functionality of HCN1 channels is a causative factor for the changes in local excitability and age dependent increase in SWD. Furthermore, upregulation of two subtypes of Na+ channels, reduction of GABAB and mGlu 2/3 receptors might also play a role in the local increased excitability in WAG/Rij rats. Signal analytical studies have also challenged the view that SWDs occur suddenly from a normal background EEG. SWDs are recruited cortical responses and they develop from increasing associations within and between cortical layers and subsequently subcortical regions, triggered by the simultaneous occurrence of theta and delta precursor activity in the cortex and thalamus in case both structures are in a favorable condition, and increased directional coupling between cortex and thalamus. It is hypothesized that the cortex is the driving force throughout the whole SWD and is also responsible for its end. PMID- 21675599 TI - Simultaneous EEG/fMRI analysis of the resonance phenomena in steady-state visual evoked responses. AB - The stability of the steady-state visual evoked potentials (SSVEPs) across trials and subjects makes them a suitable tool for the investigation of the visual system. The reproducible pattern of the frequency characteristics of SSVEPs shows a global amplitude maximum around 10 Hz and additional local maxima around 20 and 40 Hz, which have been argued to represent resonant behavior of damped neuronal oscillators. Simultaneous electroencephalogram/functional magnetic resonance imaging (EEG/fMRI) measurement allows testing of the resonance hypothesis about the frequency-selective increases in SSVEP amplitudes in human subjects, because the total synaptic activity that is represented in the fMRI-Blood Oxygen Level Dependent (fMRI-BOLD) response would not increase but get synchronized at the resonance frequency. For this purpose, 40 healthy volunteers were visually stimulated with flickering light at systematically varying frequencies between 6 and 46 Hz, and the correlations between SSVEP amplitudes and the BOLD responses were computed. The SSVEP frequency characteristics of all subjects showed 3 frequency ranges with an amplitude maximum in each of them, which roughly correspond to alpha, beta and gamma bands of the EEG. The correlation maps between BOLD responses and SSVEP amplitude changes across the different stimulation frequencies within each frequency band showed no significant correlation in the alpha range, while significant correlations were obtained in the primary visual area for the beta and gamma bands. This non-linear relationship between the surface recorded SSVEP amplitudes and the BOLD responses of the visual cortex at stimulation frequencies around the alpha band supports the view that a resonance at the tuning frequency of the thalamo-cortical alpha oscillator in the visual system is responsible for the global amplitude maximum of the SSVEP around 10 Hz. Information gained from the SSVEP/fMRI analyses in the present study might be extrapolated to the EEG/fMRI analysis of the transient event-related potentials (ERPs) in terms of expecting more reliable and consistent correlations between EEG and fMRI responses, when the analyses are carried out on evoked or induced oscillations (spectral perturbations) in separate frequency bands instead of the time-domain ERP peaks. PMID- 21675601 TI - Nurses to fight changes to pay. PMID- 21675600 TI - Approaches for the integrated analysis of structure, function and connectivity of the human brain. AB - Understanding the organization of the human brain is the fundamental prerequisite for appreciating the neural dysfunctions underlying neurological or psychiatric disorders. One major challenge in this context is the presence of multiple organizational aspects, in particular the regional differentiation in structure and function on one hand and the integration by inter-regional connectivity on the other. We here review these fundamental distinctions and introduce current methods for mapping regional specialization. The main focus of this review is to provide an overview over the different concepts and methods for assessing connections and interactions in the brain, in particular anatomical, functional and effective connectivity. In this context, we focus less on technical details and more on the comparative description of strengths and weaknesses of different aspects of connectivity as well as different methods for examining a particular aspect. This overview closes by raising several open questions on the conceptual and empirical relationship between different approaches towards understanding brain structure, function and connectivity. PMID- 21675602 TI - "It's the responsibility of all nurses to maintain registration". PMID- 21675603 TI - "Giving people drugs they don't really need won't get my vote". PMID- 21675604 TI - Administration time becomes patient time as an out-of-hours service adopts a blackberry system to take calls and access records on the move. PMID- 21675605 TI - "Never accept that pain is a normal part of growing old". PMID- 21675606 TI - Compassion: what history teaches us. AB - Although the government and nursing bodies agree that patients have a right to be treated with compassion, reports such as the Health Service Ombudsman's Care and Compassion? Have criticised the NHS, and nurses in particular, for lacking this quality. This article considers how compassion has been characterised by nurse writers and educators throughout the profession's history and considers what lessons can be learnt by the profession today. PMID- 21675607 TI - IV therapy in the community. AB - Community i.v. therapy services can be of significant benefit to both patients and the NHS. They can prevent hospital admissions and facilitate early discharge, improve patient safety by reducing the risk of infection and improve choice by enabling patients to stay in their homes. However, the availability, standard and uniformity of these services varies throughout the UK. This article describes the benefits of delivering i.v. therapy in the community and provides guidance for nurses on setting up a service. PMID- 21675608 TI - A flying start for the newly qualified. PMID- 21675609 TI - Are newly qualified nurses prepared for practice? AB - BACKGROUND: While many people find starting a new job stressful, the transition from student to newly qualified nurse comes with additional pressures, as being unprepared could harm patients. AIM: To investigate whether newly qualified nurses in the UK feel prepared for practice, exploring their experiences and expectations as they make the transition from student to registered practitioner. METHOD: A review of the literature was carried out to look at newly qualified nurses' experiences of becoming staff nurses within adult nursing, and to identify if there were gaps in that body of knowledge that could be addressed to support them. RESULTS: There is still a significant gap between theory and practice and ward managers' expectations of newly qualified nurses can be unrealistic. Some newly qualified nurses learnt to cope with being "thrown in at the deep end" but this is not always the best way of making the transition to becoming a staff nurse. The pressures of a busy ward environment means that soon to-be qualified students are being treated as part of the workforce, and their learning needs are not a priority. CONCLUSION: Introducing a mandatory preceptorship programme would assist in smoothing the transition from student to staff nurse. PMID- 21675611 TI - Be active in creating your professional image. PMID- 21675610 TI - Right by design. PMID- 21675612 TI - Surgical services and transformation of civil hospital during "August War 2008" in Georgia. AB - Structural transformation of a civil hospital into a military one during "August War 2008" (August 8-12) in Georgia is presented. Damage-control principles, such as hemorrhage control, liver-packing and abdominal tamponade, gastrointestinal tract resection without formation of anastomoses, and other temporary interventions were prioritized. This provided a chance to empty the hospital in a short period to provide the admission of an increased number of combat casualties. There were soldiers from Georgian troops, civilians, and captives of war. The number of total admitted patients was 739. Fifty-two patients were operated on in the surgery department. The following operations were carried out: removal of foreign bodies from the neck region, 6 cases; isolated thoracotomy, pulmorrhaphy, and drainage, 2 cases; laparotomy, hepatorrhaphy, gastrorrhaphy, splenectomy, resection of small intestine, and colostomy, 18 cases; combined operations (thoracotomy plus laparotomy), 9 cases; extended debridement and dressing of wounds, 11 cases; angiosurgical operations, 4 cases; and coloplasty, 2 cases. There were 2 cases of mortality, 1 case of rethoracotomy, and 3 cases of relaparotomy: 2 because of intracavital bleeding and 1 because of sanation. PMID- 21675613 TI - Curative resection of transverse colon cancer via minilaparotomy. AB - Minilaparotomy has been reported to be a minimally invasive alternative to laparoscopically assisted surgery. We retrospectively evaluated the usefulness of minilaparotomy for the resection of transverse colon cancer, which has generally been considered difficult to resect laparoscopically. Patients for whom curative resection was attempted for transverse colon cancer (n = 21) or sigmoid colon cancer (n = 81) via minilaparotomy (skin incision, < or = 7cm) were analyzed. The 2 groups did not significantly differ in terms of success rate of minilaparotomy (90.5% versus 97.5%), age, sex, pathologic stage, body mass index, operative time (mean, 133.5 minutes versus 122.5 minutes), blood loss (119.7 mL versus 92.4 mL), number of lymph nodes harvested, incidence of postoperative complications (9.5% versus 12.3%), postoperative length of stay, and 5-year disease-free survival rate (86.6% versus 79.6%). Minilaparotomy is feasible, safe, and favorable in terms of early oncologic outcome in patients with transverse colon cancer as well as those with sigmoid colon cancer. PMID- 21675614 TI - Clinical importance of surgical treatment of low rectal carcinoma in anus preserving procedure--an analysis of 86 cases. AB - We investigated the methods and experiences of an anus-preserving procedure in curative resection of low rectal carcinoma. Eighty-six patients with low rectal carcinoma underwent Dixon's procedure with device assistance. Patients were then observed for the effects of operation. The operation was successful in all patients. Pathologic examination of specimens revealed negative margins. Complications such as anastomotic leakage were found in 7 cases. All patients recovered well. Device assistance may contribute to the successful performance of anus-preserving procedure in low rectal carcinoma. Whether the anus can be preserved or not depends on the accurate measurement of the distal length of the rectum. A meticulous hemostasis and avoidance of tension on the stoma are key measures for avoiding anastomotic leakage. PMID- 21675615 TI - Review of third and fourth re-excision for narrow or positive margins of invasive and intraductal carcinoma. AB - The trend in breast surgery has shifted toward breast conservation. We reviewed our third and fourth breast re-excision cases, with an analysis of various factors used in making this decision. A retrospective analysis identified 585 patients who underwent re-excision surgery for positive or close margins of invasive carcinoma or ductal carcinoma in situ (DCIS). Of these patients 75 (13%) and 17 (3%) underwent third and fourth re-excisions, respectively. The indication for a third re-excision was the presence of positive and/or close (< or = 1 mm) margins for invasive carcinoma or DCIS in 72/75 patients. A third re-excision was done 31 days (range 8-123 days) after the second re-excision. Re-excision of margins was done in 45 (60%) patients, whereas 30 (40%) patients underwent mastectomy. Residual tumor mandated a fourth re-excision in 17 patients, which was done 45 days (range 14-87 days) after the third surgery. Re-excision of margins was done in 6 patients, whereas 11 patients underwent mastectomy. Involved or close margins with DCIS were the most common indication for re excision, accounting for 61/75 (82%) of third and 16/17 (94%) of fourth re excisions. Histopathology revealed that 28/75 (37%) of third and 7/17 (41%) of fourth re-excision patients had no residual tumor. In conclusion, the majority of re-excisions was done for margins < 1 mm. Lower rates of re-excision were noted in well-differentiated invasive carcinomas. A close or involved DCIS margin was more likely to lead to a third and even a fourth re-excision. The absence of residual tumors in 40% of patients undergoing third and fourth re-excisions calls for a review of margin guidelines for breast re-excision. PMID- 21675616 TI - A meta-analysis of outcomes after routine aspiration of the gallbladder during cholecystectomy. AB - We conducted a meta-analysis of published literature comparing outcomes after aspirating (ASP) the gallbladder versus nonaspiration (NASP). Electronic databases were searched from January 1985 to November 2009. A meta-analysis was performed to obtain a summative outcome. Two randomized, controlled trials involving 360 patients were analyzed. A total of 180 patients were in the ASP group, and 180 were in the NASP group. There was no significant increase in operative time in the ASP group compared with the NASP group [random-effects model: standardized mean difference, -0.72; 95% confidence interval (CI), -2.16, 0.71; z = 0.99; df = 1; P = 0.32], but there was significant heterogeneity among trials (Q = 42.4; P < 0.001; I2 = 98%). Patients undergoing ASP were less likely to have a gallbladder perforation [random-effects model: risk ratio (RR), 0.42; 95% CI, 0.19, 0.96; z = 2.05; df = 1; P < 0.05], but no difference was found regarding the loss of gallstones (random-effects model: RR, 1.33; 95% CI, 0.30, 5.85; z = 0.38; df = 1; P = 0.70). No difference was seen for liver bed bleeding (P = 0.43) or overall 30-day infection rates (P = 0.66). After aspiration, gallbladder perforation rates may be lower. This does not appear to translate into decreased loss of gallstones or infection rates. There was no significant difference between techniques in blood loss from the liver bed. Further randomized, controlled trials and follow-up studies are required to confirm these results and to establish long-term sequelae. PMID- 21675617 TI - Blood conservation in surgery: current concepts and practice. AB - Blood conservation is based on the principle of avoiding allogeneic blood transfusion with the aim of improving outcome and protecting patients' rights. Surgical patients receive a significant proportion of the allogeneic blood transfused in the hospital. Blood conservation in surgery greatly reduces overall allogeneic blood use, thereby reducing costs, hazards, and adverse outcomes. Blood conservation techniques aim to lower the "transfusion trigger," optimize the hematocrit, minimize blood loss, and optimize tissue oxygenation. Successful blood conservation involves a combination of techniques tailored to the individual patient. It requires planning and a multidisciplinary team approach but usually little technology. Bloodless medicine and surgery programs represent the gold standard in blood conservation. Blood conservation is evidence based, and it results in faster recovery, lower morbidity, lower mortality, shorter hospital stay, lower cost, and better patient (and physician) satisfaction while avoiding the hazards of allogeneic blood transfusion. Blood conservation is thus the current standard of care. PMID- 21675618 TI - Complications of videolaparoscopic cholecystectomy: a retrospective analysis of 1037 consecutive cases. AB - The authors describe some of the complications that appear more frequently with laparoscopic cholecystectomy than open cholecystectomy and the mechanisms underlying the occurrence of bile duct injuries, making reference to 0.58% of bile duct injuries in 1037 consecutive laparoscopic cases and the possibility of treatment. PMID- 21675619 TI - Solitary rectal ulcer syndrome: exploring possible management options. AB - Solitary rectal ulcer syndrome (SRUS) is a rare condition with various causes that results in ischemic injury. The aim of this study was to assess the clinical findings, diagnosis, and outcomes of treatment in patients with SRUS. Between 1992 and 2006, a retrospective review was undertaken for all patients diagnosed with SRUS. Fifty-eight patients were diagnosed with SRUS. Among patients with paradoxic rectal spasm (PRS), lesions disappeared in 1 of 3 given applied biofeedback treatment, and in 2 of 4 injected with Botulinum toxin (Botox). Twenty-three patients underwent appropriate surgical treatment. Overall, postoperative improvement was seen in 18 patients (78.2%). In conclusion, every patient with SRUS must be assessed for causative disease. Treatment should include conservative approaches such as Botox injection; in patients with pelvic floor disorders, surgical treatment should be considered. PMID- 21675620 TI - Pathology studies of combined radical resection of seminal vesicle in the treatment of rectal cancer. AB - To inhibit local recurrence of rectal cancer, it is very important to ensure that there is a sufficient circumferential resection margin. We evaluated pathology studies of combined radical resection of seminal vesicles in the treatment of rectal cancer. We analyzed data from 7 cases of combined radical resection of the seminal vesicle in the treatment of rectal cancer; we also analyzed data from 35 control cases without seminal vesicle resection. The circumferential resection margin averaged 5.97 mm for cases that had combined radical resection of the seminal vesicle, and this was significantly longer than for cases without resection (P < 0.001). Local recurrence was not seen in cases that had combined radical resection of the seminal vesicle, whereas 3 cases (5.9%) occurred in the group that did not undergo resection. Combined radical resection of the seminal vesicle in patients with rectal cancer ensures that the distance of the circumferential resection margin is sufficient to inhibit local recurrence. PMID- 21675621 TI - Surgical treatment of intramuscular, infiltrating lipoma. AB - Lipoma may occasionally be found within the muscle, which is the intramuscular, infiltrating lipoma. Intramuscular, infiltrating lipoma is an uncommon lesion, and local recurrence can be expected if the surgical margin is not clear. We report 8 patients in a 2-year period diagnosed with intramuscular, infiltrating lipoma who were treated by marginal excision combined with wide excision in the Department of Orthopaedic Surgery, Changhua Christian Hospital. The surgical results were satisfactory, and no local recurrence was noted in an average followup period of 40 months. Surgical excision is the best way to treat the symptomatic intramuscular, infiltrating lipoma. Careful preoperative evaluation and complete tumor excision with clear margins are most important to ensure successful surgical results. PMID- 21675622 TI - Carotid endarterectomy: outcome of "old-fashioned" approach. AB - The purpose of this study is to assess the 30-day postoperative incidence of death, myocardial infarction, stroke, wound complication, and cranial nerve damage after carotid endarterectomy using induced hypertension (systolic pressure > or = 160 mmHg), selective shunting, and primary closure. We retrospectively analyzed the records of 206 patients who underwent a total of 239 carotid endarterectomy surgeries between January 2002 and August 2009 to identify the impact of selective shunting and primary closure on morbidity and mortality. Two hundred thirty-nine surgeries were performed on 206 patients. The study population was 55% men and 45% women with average age of 67 years (range 33-85 years). Of these patients, 181 had hypertension (88%), 82 had diabetes (40%), 73 had peripheral vascular disease (35%), 107 had coronary artery disease (52%), 142 had tobacco abuse (69%), and 146 had dyslipidemia (71%). Twenty-six patients (13%) presented with history of stroke, 77 (37%) with transient ischemic attack (TIA), 14 (7%) with amaurosis fugax, and 108 (52%) were asymptomatic. The average internal carotid stenosis was 74% as indicated by duplex, computed tomography, magnetic resonance imaging, or angiogram. Of the 239 surgeries, 3 (1%) required patch closure, and 7 (3%) required shunt. Thirty-day postoperative complication rates are as follows: stroke, 3 (1.3%); TIA, 4 (1.7%); bleeding, 5 (2.1%); superficial wound infection, 2 (0.8%); heart attack, 1 (0.4%); cranial nerve injury, 0; and hospital death, 0. One patient (0.4%) died at home from an unknown cause. In conclusion, carotid endarterectomy with selective shunting and primary closure is a safe and effective surgical means of preventing stroke. PMID- 21675623 TI - Two cases of diverticulitis in patients with Williams syndrome. AB - Williams syndrome is rare and associated with physical anomalies and mental retardation. It is a disease resulting from a gene deletion of chromosome 7. The main concurrent medical conditions typically associated with Williams syndrome are heart defects such as supravalvular aortic stenosis, mental retardation, and unusual physical characteristics. It is also associated with colon diverticulosis and diverticulitis. In the present article, we report on 2 cases of diverticulitis in patients with Williams syndrome, in whom surgery was performed. In many cases of diverticulitis in patients with Williams syndrome, surgical treatment is indicated. It is important to take diverticulitis into consideration when examining a patient with Williams syndrome presenting with abdominal pain and consider surgical treatment if necessary. PMID- 21675624 TI - Hydatid disease presenting as cutaneous fistula: review of a rare clinical presentation. AB - Hydatid disease has a worldwide distribution as a result of more global travel. Liver and lungs are the most common sites for the primary hydatid cysts in the human body. We managed a 68-year-old man who presented with abdominal distension and umbilical fistula, discharging daughter cysts. Ultrasound imaging of the abdomen showed hepatic hydatid cyst forming a fistula at the umbilicus. The patient underwent a laparotomy with partial cystectomy and excision of the fistula tract. The umbilicus healed after the procedure. The patient did not have any recurrences in 5 years of follow-up. Spontaneous cutaneous fistulization of liver hydatid cyst is a rare presentation. A detailed literature search revealed 15 cases published in all languages. Hydatid disease presenting as an umbilical fistula has not been reported yet. We summarize all these cases including the presentation, findings, management, and outcome. Combined surgical and medical treatment is successful in healing of hepatic hydatid cutaneous fistula. PMID- 21675625 TI - Simultaneous laparoscopic resection of colorectal cancer and synchronous metastatic liver tumor. AB - Laparoscopic colorectal resection has been applied to advanced colorectal cancer. Synchronous liver metastasis of colorectal cancer would be treated safely and effectively by simultaneous laparoscopic colorectal and hepatic resection. Seven patients with colorectal cancer and synchronous liver metastasis treated by simultaneous laparoscopic resection were analyzed retrospectively. Three patients received a hybrid operation using a small skin incision, 2 patients underwent hand-assisted laparoscopic surgery using a small incision produced for colonic anastomosis, and 2 patients were treated with pure laparoscopic resection. The mean total operation duration was 407 minutes, and mean blood loss was 207 mL. Negative surgical margins were achieved in all cases. Mean postoperative hospital stay was 16.4 days. No recurrence at the surgical margin was observed in the liver. For selected patients with synchronous liver metastasis of colorectal cancer, simultaneous laparoscopic resection is useful for minimizing operative invasiveness while maintaining safety and curability, with satisfying short- and long-term results. PMID- 21675626 TI - Invasive micropapillary carcinoma of the ascending colon--a report of a case. AB - Micropapillary carcinoma (MC) has been recently recognized to be a rare but distinctive variant of adenocarcinoma. At present, only a limited number of colorectal MC cases have been reported. We present a case of MC of the ascending colon with distant metastasis. A 61-year-old female patient was hospitalized with a complaint of abdominal pain. A diagnostic work-up revealed cancer of the ascending colon with multiple lung metastases. The patient underwent a right hemicolectomy with lymph node dissection. A peritoneal nodule was observed in the abdominal cavity during surgery, and this nodule was also resected. The pathologic findings of the colon tumor revealed components of conventional tubular adenocarcinoma and micropapillary carcinoma. Lymph nodes and a peritoneal nodule revealed tubular adenocarcinoma. MC is a rare disease but has high malignant potential. In the present case the tumor was small in size, but the patient had a peritoneal and multiple lung metastases. PMID- 21675627 TI - Laparoscopic splenectomy for atraumatic splenic rupture. AB - A traumatic splenic rupture (ASR) is a rare clinical entity. Several underlying benign and malignant conditions have been described as a leading cause. We report on a case of ASR in a 41-year-old man treated with laparoscopic splenectomy. Considering ASR as a life-threatening condition, a prompt diagnosis can be life saving. PMID- 21675628 TI - Perforation of the small bowel due to metastasis from tongue cancer. AB - Distant small bowel metastases from head and neck squamous cell carcinomas are extremely rare, and tongue cancer metastasizing to the small bowel has not been previously reported. We describe a 40-year-old male patient who underwent subtotal gross laryngectomy for squamous cell carcinoma of the tongue in February 2007 and then presented in November 2008 with severe abdominal pain. Abdominal computed tomography (CT) and X-rays revealed free air, suggesting intestinal perforation. Emergency surgery revealed a 10-mm perforation at the ileum and a palpable hard tumor at the perforation site. The ileum was resected, and pathologic findings showed squamous cell carcinoma at the perforation site, which was consistent with metastasis from tongue cancer. PMID- 21675629 TI - The importance of purchasing strategies for the health care sector. PMID- 21675630 TI - Hospital demand variations: suggested instruments for hospital managers. AB - Hospitals worldwide face variations in demand for inpatient care. The accurate forecasting of future demand assists hospitals in programming short-term needs such as staff and supplies, and long-term needs such as beds and buildings. The existence of the appropriate methodological instruments, applied by hospital managers, could help them smooth down upcoming patient flows. This work presents two such instruments: first, a univariate autoregressive moving average method, and second, a multivariate model. By applying these to the Greek National Health System, we have found significant demand variations. The univariate method provides more accurate forecasting of future unexpected demand. PMID- 21675631 TI - Measuring availability, affordability and management of essential medicines in public hospitals of Burkina Faso. AB - In Burkina Faso, improving healthcare services and the availability of pharmaceutical products constitute a growing concern for the population. This study objective was to evaluate the availability, prices, and sales revenue for a grouping of 50 basic medications in public hospitals from 29 September-29 December 2009. The method used to study the prices, availability, affordability and price components from Health Action International (HAI) and the World Health Organization (WHO) has been used to collect and analyze the data. The results show that the average ratio between the pharmaceutical budget and that of the health centre is 16.18. The average rate of availability was 77.69%. The purchasing price from the hospitals providers is approximately the same as the international reference prices (1.12). The public hospitals selling price to the public was double the buying price from their provider (2.20). The total sales revenue from the first three trimesters of 2009 was 708,740,495 FCFA (Euro 1,080,397). This revenue accounted for roughly 23.02% of the total costs for available pharmaceuticals during the period (3,078,938,053 FCFA/Euro 4,693,503). PMID- 21675632 TI - International overview of hospital procurement. AB - This article was written by four French hospital director students at the Ecole des Hautes Etudes en Sante Publique (EHESP-School of Public Health) from a study conducted jointly with students at the Grenoble School of Management to present an international overview of hospital procurement methods in ten countries. An analysis of these methods showed that there was a general trend towards group purchasing, with some common aims in terms of costs and performance and some differences in legislation (competition), size of the public sector and centralization or decentralization. PMID- 21675633 TI - Centralized distribution: reducing ownership costs by streamlining hospital logistics. AB - All Quebecers have access to a public health system that enables them to receive high-quality healthcare, regardless of their individual ability to pay. With the aim of improving effectiveness and efficiency and achieving cost savings in managing public funds allotted to the healthcare network, SigmaSante intends implementing a central distribution of medical supplies needed by healthcare facilities in Montreal and Laval, Quebec, as has been done in many other jurisdictions for numerous years. PMID- 21675634 TI - The challenges of collaborative procurement in the healthcare sector. AB - The article points out the new challenges of collaborative procurement in the healthcare sector. The research focuses on the optimization of healthcare purchasing through the reduction of costs without any prejudice to the quality of healthcare performances, but also assuring rationalization and innovation. Moreover, the importance of collaborative procurement is particularly evident considering the ensuing valorization of the diverse professional skills and their use of strategic purchasing power in their relationships with economic operators. PMID- 21675635 TI - E-procurement in hospitals. AB - This article describes the history, current status, advantages of and opposition to the implementation of e-procurement in hospitals and examines the results of its implementation in a psychiatric hospital. PMID- 21675636 TI - The value of group purchasing organizations in the United States. AB - This article examines the valuable role of group purchasing organizations (GPOs) in hospital purchasing in the United States. For over 100 years old GPOs have helped hospitals and other health care providers realize savings and create contracting efficiencies by aggregating purchasing volume to negotiate discounts with manufacturers, distributors and other vendors. The US has recently enacted a series of healthcare reforms to correct some of the historical concerns regarding cost, quality and access. GPOs are expected to continue to play a critical role in the business of hospital purchasing and may potential export that other countries may wish to examine. PMID- 21675637 TI - Pooling procurement in the Belgian hospital sector. AB - The Belgian hospital sector is following the example of a number of other European countries and for more than ten years now, has been striving to pool its medical supplies and equipment purchases in a bid to reduce costs. The various experiments of which we are aware come under both opportunist purchases and initiatives which are designed to encourage local-regional contracts. These attempts have now all come to nothing or are struggling in the absence of a structured and professional approach. In 2005, the Saint Luc University Clinic in Brussels decided to set up a high-performance purchasing department, the aim being to centre its initiatives around TCO or Total Cost of Ownership. Following an analysis of the various experiments into pooling procurement in hospitals in Europe, the Saint Luc University Clinic decided on a central procurement agency model, in accordance with new legislation on public procurement. This article seeks to highlight the prerequisites which are vital for a procurement pooling initiative, without underestimating the risks and limitations of implementing such a change in procurement practices. The Mercure central procurement agency is now the largest interhospital purchasing structure in Belgium. PMID- 21675638 TI - Beyond the bottom line. PMID- 21675639 TI - The nurse practitioner will see you now. AB - A host of factors are pushing mid-level providers into more prominent roles in hospitals, and the results are quality care, reduced costs and physicians freed up to handle tougher cases. PMID- 21675640 TI - Revisiting rapid response. AB - Advocates say they are lifesavers, while critics call them Band-Aids. It's time for a second look at rapid-response teams and the clinicians who staff them. PMID- 21675641 TI - Ready for a relationship? AB - Before a hospital seeks a change in control, trustees need to identify their organization's strengths, weaknesses, goals and partner criteria. PMID- 21675642 TI - Where will they go? AB - Identifying post-acute care partners should be a top priority for hospitals hoping to decrease readmissions and prepare for bundled reimbursement. PMID- 21675643 TI - Begin the transformation. PMID- 21675644 TI - Coalition for the future. PMID- 21675645 TI - Reining in avoidable readmissions. PMID- 21675646 TI - Hospital systems. PMID- 21675647 TI - In support of our youngest patients. PMID- 21675648 TI - Are your immunizations up to date? PMID- 21675649 TI - When patients won't agree to exams and X-rays. PMID- 21675650 TI - The ADA opposes a worldwide ban on mercury products. PMID- 21675651 TI - Should I let my office manager hire her daughter? PMID- 21675652 TI - A hygienist is stealing my patients! PMID- 21675653 TI - Waste management as an educational imperative. PMID- 21675654 TI - Is your staff 'cliquing'? PMID- 21675655 TI - CBCT for ortho diagnosis should be the exception, not the rule. PMID- 21675656 TI - "The future is bright! you better put on your sunglasses"! PMID- 21675657 TI - A sheep in wolves' clothing? Dental radiation exposure and thyroid cancer. PMID- 21675658 TI - Fluoride varnish: the top choice for professionally applied fluoride. AB - Although various modes of delivery for professionally applied fluoride exist, one form has emerged that combines caries prevention efficacy with safety and versatility. The American Dental Association Council on Scientific Affairs recommends fluoride varnish as the only professionally applied fluoride for moderate to high risk patients of all age groups. In addition to demonstrating effectiveness equivalent to fluoride gels, fluoride varnish provides improved safety and acceptability. Furthermore, fluoride varnish has shown promise in preventing dental caries in special groups, such as orthodontic patients and the elderly. PMID- 21675659 TI - Using patient charts to increase revenue. PMID- 21675660 TI - Dr. Graham 'Mike' Pierce--meet this Harbor Springs dentist who continues a three generation dental practice. PMID- 21675661 TI - Fog lifting in wake of recession. PMID- 21675662 TI - Raising the bar on quality. PMID- 21675663 TI - On the road: Providers a steadying force in Michigan economy. PMID- 21675664 TI - Corporate compliance essentials. PMID- 21675665 TI - The impact factor. PMID- 21675666 TI - Health literacy and its association with diabetes knowledge, self-efficacy and disease self-management among African Americans with diabetes mellitus. AB - The purpose of this descriptive correlational study was to examine health literacy and its association with diabetes knowledge, perceived self-efficacy and disease self-management among African Americans with diabetes mellitus. Fifty English-speaking, adult African American participants with diabetes mellitus were recruited from a community health center and a church located in the Midwestern United States. Data were collected at a single point in time utilizing the Rapid Estimate of Adult Literacy in Medicine (REALM), Diabetes Knowledge Test (DKT), Diabetes Self-efficacy Scale, and Summary of Diabetes Self-care Activities (SDSCA) Questionnaire. Bivariate associations were identified for health literacy with diabetes knowledge level; diabetes knowledge level with dietary self-care activities; and self-efficacy with dietary, exercise, and foot care self-care activities. Diabetes knowledge level and self-efficacy were independent predictors for dietary self-care activities, while self efficacy was the sole independent predictor for foot self-care. Means for health literacy and diabetes self-care activities were influenced by demographic factors examined. PMID- 21675667 TI - Faculty participation in institutional decision making at two Historically Black Institutions. AB - This qualitative study was designed to explore the extent and types of challenges encountered in achieving governance at two Historically Black Colleges and Institutions (HBCUs) among tenured faculty and upper level administrators. A 12 item interview protocol consisting of open-ended questions was utilized to compile the data from six tenured faculty and six upper level administrators from the private HBCU, and six tenured faculty and five upper level administrators from the public HBCU. Findings differed between groups and institutions. The perceptions of shared institutional governance reflected that decision making is often predetermined by administration, and use adoption of top down decision making ignores the role of faculty in shared institutional governance. PMID- 21675668 TI - Hypertension improvement through healthy lifestyle modifications. AB - Hypertension is the major risk factor for the development of cardiovascular and renal disease. This disease has a disproportionate effect on African Americans when compared to other races. The purpose of this project was to examine the effectiveness of healthy lifestyle modifications on blood pressure control among hypertensive African American adults. Thirty-six individuals participated in the 12-week project, with a 67% retention rate. Weekly sessions included interactive educational and walking components. Initial and final BMI measurements were recorded. Participants completed health risk assessments; pre and post questionnaires; and, daily logs ofblood pressure measurement, dietary consumption, and physical activity levels. Data were collected from the logs, BMI measurements, and questionnaires. Overall, the results revealed that participants experienced an increase in healthy lifestyle modification adoption resulting in blood pressure control improvement. Implementation of healthy lifestyle modifications is crucial in providing quality patient care to hypertensive individuals. PMID- 21675669 TI - Highlighting the association side. PMID- 21675670 TI - Preventing catheter/tubing misconnections: much needed help is on the way! PMID- 21675671 TI - Healthy aging should drive health care reform. PMID- 21675672 TI - On the same page. PMID- 21675673 TI - Drug aids bone grown in perio patients. PMID- 21675674 TI - Dental erosion and tooth wear. PMID- 21675676 TI - Sports drinks and dental erosion. AB - Sports drinks were originally developed to improve hydration and performance in athletes taking part in intense or endurance sporting events. These drinks contain relatively high amounts of carbohydrates (sugars), salt, and citric acid. These ingredients create the potential for dental ramifications and overall public health consequences such as obesity and diabetes. High intake of sports drinks during exercise, coupled with xerostomia from dehydration, may lead to the possibility of erosive damage to teeth. PMID- 21675675 TI - Diagnosis and management of dental wear. AB - Dental wear is loss of tooth structure resulting from erosion, attrition, abrasion, and, possibly, abfraction. Clinical/experimental data suggest no single damaging mechanism but rather simultaneous interaction of these destructive processes. The most important interaction is abrasion/attrition potentiated by dental erosion. Awareness of this pathosis is not well-appreciated by the public and dental professionals because the signs may be subtle. This article focuses on the recognition, diagnosis, and management of dental wear. PMID- 21675677 TI - Changing damaging beverage behavior: your CDA at work. AB - The California Dental Association's vision statement places promoting the public's oral health as a top priority of the association. The past 10 years have seen CDA and CDA Foundation activities collectively improve the public's oral health in a multitude of ways. Some have been directed specifically at reducing the detrimental effects the consumption of beverages with high sugar content and carbonation has on oral health. PMID- 21675678 TI - The effect of nutrition and diet on dental structure integrity. AB - Nutritional intake and dietary habits affect the structural integrity of the primary and permanent dentition. This happens through the indirect effect of nutrition on tooth development, as well as through the direct effect associated with the erosive characteristics of the diet. Evaluation of a patient's dietary history, coupled with the ability to implement targeted educational strategies relevant to the individual's ethnicity, will ensure success of normal tooth development and dental structure integrity free of erosive effects. PMID- 21675679 TI - Interaction of dental erosion and bruxism: the amplification of tooth wear. AB - Bruxism and erosion are important to identify during a dental examination. By understanding the etiologies of both processes, a management strategy can be implemented to decrease their effects. Management for bruxism, clenching, and parafunction can include medications, cognitive behavioral therapy, and dental appliances. Bruxism, clenching, and parafunction combined with dental erosion can cause dental wear to increase faster than any component alone. PMID- 21675680 TI - Decision-making in the management of the patient with dental erosion. AB - The clinical signs of dental erosion are initially subtle; yet they often progress because the patient remains asymptomatic, unaware, and uninformed. Erosion typically works synergistically with abrasion and attrition to cause loss of tooth structure, making diagnosis and management complex. The purpose of this article is to outline clinical examples of patients with dental erosion that highlight the strategy of early identification, patient education, and conservative restorative management. PMID- 21675681 TI - Go green save green. PMID- 21675682 TI - Build your dream team. PMID- 21675683 TI - Leverage the power of prepaid debit cards. PMID- 21675684 TI - You could be history without a medical history. PMID- 21675686 TI - How to deal with back pain. PMID- 21675685 TI - Let's take the next great leap forward. PMID- 21675687 TI - Top tips for pulling a loose tooth ... and ensuring a visit from the tooth fairy! PMID- 21675688 TI - I vant to drink your blood. PMID- 21675689 TI - When friends ask you to be the expert, ONS resources are here to help. PMID- 21675690 TI - What's new in neuro-oncology? PMID- 21675691 TI - What is the journey for patients with brain tumors? PMID- 21675693 TI - Manage anxiety and depression in patients and nurses. PMID- 21675692 TI - Neuropathy and neuropathic pain measures: which tool is most valid? PMID- 21675694 TI - The case of the horrible hives. PMID- 21675695 TI - Adoptive cell transfer targets new cancer antigen. PMID- 21675696 TI - Is your patient experiencing post-traumatic stress after a cancer diagnosis? PMID- 21675697 TI - Celebrate oncology nursing month by helping to shape the future of nursing. PMID- 21675699 TI - Nurse navigator: the missing piece of the head and neck cancer care continuum. PMID- 21675698 TI - Selling yourself in today's job market. Negotiate to enhance your nursing career. PMID- 21675700 TI - Model for best practice: nurse practitioner facilitated percutaneous tracheostomy service. AB - CONTEXT: In 2007, a tracheostomy nurse practitioner role was created to facilitate the percutaneous tracheostomy service that was established in 2005 at an urban academic tertiary care facility. The purpose of the tracheostomy nurse practitioner's role was to provide comprehensive care to tracheostomy patients. OBJECTIVE: To determine whether the addition of a tracheostomy nurse practitioner to the percutaneous tracheostomy service improves (i) standard of care (ii) efficiency of care, and (iii) patient outcomes. DESIGN: Retrospective electronic patient record and chart review comparing data before and after the addition of a tracheostomy nurse practitioner to the percutaneous tracheostomy service. METHODS: A total of 110 patients who underwent percutaneous tracheostomy in 2006 and 2008 (n = 55) were randomly selected for the study. Data were collected regarding standard of care, efficiency (n = 55) of care, and patient outcomes. SETTING: Urban, academic, tertiary care medical center OUTCOME MEASURES: Standard of care: (1) use of tracheostomy screening tool, 2) obtaining consent, 3) completeness of consent with patient's name, date, time, and signatures of patient/family, provider and witness, 4) performance of timeout, 5) use of tracheostomy postoperative order set, 6) documentation of a procedure note in the chart, and 7) and documentation of operative note in electronic patient record), efficiency of care: timeliness of the service, and patient outcomes: intensive care unit and hospital length of stay, and documented complications. RESULTS: Between 2006 and 2008, there were statistically significant improvements in 4 of 7 measures of standard of care, use of a tracheostomy screening tool, completeness of consent (documentation of time when consent was completed and presence of signature of witness), performance of time outs, and use of postoperative order set. Between 2006 and 2008, there was also a statistically significant improvement in timeliness of the service. However, there were no significant differences in the three patient outcome measures before and after the addition of the service. CONCLUSIONS: The nurse practitioner facilitated tracheostomy service significantly improved standard of care and efficiency. Relevance to Nursing: Nurse Practitioner facilitated tracheostomy service is an innovative approach to managing tracheostomy patients. The role of the advanced practice nurse as described in this study can be adopted by other institutions to improve the standard of care and efficiency of care. PMID- 21675701 TI - IOM report on the future of nursing update. PMID- 21675702 TI - Extraordinary larynx transplant restores voice, sense of taste, smell to California woman. World's second documented voice box transplant. PMID- 21675703 TI - Functional evaluation of bacteriophage T4 Rad50 signature motif residues. AB - The repair of DNA double-strand breaks (DSBs) is essential to maintaining the integrity of the genome, and organisms have evolved a conserved mechanism to facilitate their repair. In eukaryotes, archaea, and some bacteriophage, a complex made up of Mre11 and Rad50 (MR complex), which are a nuclease and ATPase, respectively, is involved in the initial processing of DSBs. Rad50 is a member of the ATP Binding Cassette (ABC) protein superfamily, the members of which contain an important Signature motif that acts in trans to complete the dimeric ATP binding site. To explore the functional relevance of this motif, four of its five residues were mutated in bacteriophage T4 Rad50, and their respective ATPase and nuclease activities were evaluated. The mutations reveal the functional roles of the Signature motif in ATP binding, hydrolysis, and cooperativity. In several mutants, the degree of DNA activation of ATP hydrolysis activity is reduced, indicating that the Signature motif is involved in allosteric signal transmission between the DNA and ATP binding sites of the MR complex. ATP hydrolysis is not required for nuclease activity when the probe is near the beginning of the DNA substrate; however, when an internal probe is used, decreases in ATPase activity have substantial effects on nuclease activity, suggesting that ATP hydrolysis is involved in translocation of the complex. Unexpectedly, the ATP hydrolysis and nuclease activities are not directly correlated with each other, and each mutation appears to differentially affect the exonuclease activity of Mre11. PMID- 21675704 TI - Pterostilbene suppresses benzo[a]pyrene-induced airway remodeling. AB - This study has two novel findings: it is not only the first to demonstrate inflammatory cytokines, which are produced by the bronchial epithelium after exposure to benzo[a]pyrene (BaP) and contribute to airway remodeling by increasing human bronchial smooth muscle cells (BSMC) proliferation and migration, but also the first to reveal that pterostilbene, a constituent of grapes and berries, reverses BaP-mediated airway remodeling. Human bronchial epithelial cell lines BEAS-2B and HBE135-E6E7 (HBE) were treated with BaP, and then the condition medium (CM) was harvested, which was then added to BSMC. Cultures of BSMC with BaP-BEAS-2B-CM and -HBE-CM increased BSMC proliferation and migration, which are major features in asthma remodeling. Exposure of BEAS-2B and HBE to BaP caused epithelial cells to produce inflammatory cytokines IL-8, which subsequently induced BSMC proliferation and migration. Moreover, pterostilbene is more potent than resveratrol in suppressing BaP-mediated airway remodeling. This study suggests that pterostilbene is capable of preventing BaP-associated asthma. PMID- 21675705 TI - Polyhedral oligomeric silsesquioxane (POSS) suppresses enzymatic degradation of PCL-based polyurethanes. AB - In this Article, we studied the enzymatic hydrolytic biodegradation behavior of a novel multiblock thermoplastic polyurethane (TPU) system, which incorporates polyhedral oligomeric silsesquioxane (POSS) into linear biodegradable thermoplastic polyurethanes containing poly(epsilon-caproactone) (PCL) and polyethylene glycol (PEG) blocks. The biodegradation behavior of POSS-PCL-PEG TPUs was characterized by proton nuclear magnetic resonance spectroscopy ((1)H NMR), differential scanning calorimetry (DSC), tensile tests, scanning electron microscopy (SEM), and wavelength dispersive X-ray spectrometry (WDS) after enduring 22-day accelerated enzymatic hydrolytic degradation tests. POSS incorporation significantly suppressed in vitro enzymatic hydrolytic degradation of PCL-PEG-based multiblock TPUs by a surface passivation mechanism. WDS observations revealed that the covalently bonded POSS moieties developed a near continuous and robust POSS-layer after initial degradation, which prevented ester bonds of PCL from enzymatic attack, thereby inhibiting further degradation. These striking results provide a new strategy to fabricate the polyester-based biostable thermoplastic polyurethanes (TPUs) of potential use in long-term surgical implants. PMID- 21675706 TI - Synthesis of uniform and dispersive calcium carbonate nanoparticles in a protein cage through control of electrostatic potential. AB - We have synthesized calcium carbonate nanoparticles (Ca-NPs) in the cavity of a cage-shaped protein, apoferritin, by regulating the electrostatic potential of the molecule. The electrostatic potential in the cavity was controlled by pH changes resulting from changes in the dissolved carbon dioxide (CO(2)) concentration in the reaction solution. Recombinant L-apoferritin was mixed with a suspension of calcium carbonate (CaCO(3)), and the mixture was pressurized with gaseous CO(2) at 2 MPa. The pH of the solution decreased from 9.3 to 4.4; the CaCO(3) dissolved during pressurization, and then precipitated after the pressure was reduced to ambient. After repeating the pressurization/depressurization process three times, about 70% of the apoferritin molecules were found to contain nanoparticles with an average diameter of 5.8 +/- 1.2 nm in their cavity. Energy dispersive X-ray spectroscopy and electron diffraction analysis showed that the nanoparticles were calcite, one of the most stable crystal forms of CaCO(3). Electrostatic potential calculations revealed a transition in the potential in the apoferritin cavity, from negative to positive, below pH 4.4. The electrostatic potential change because of the change in pH was crucial for ion accumulation. Since the Ca-NPs synthesized by this method were coated with a protein shell, the particles were stably dispersed in solution and did not form aggregates. These Ca-NPs may be useful for medical applications such as synthetic bone scaffolds. PMID- 21675707 TI - Coordination polymers of hexacyanotrimethylenecyclopropanediide and its monoanionic radical: synthesis, structure, and magnetic properties. AB - The first examples of polymeric complexes that contain the polynitrile dianion hexacyanotrimethylenecyclopropanediide (HCTMCP(2-)) were isolated and their magnetic properties have been explored. Complexes of the form (n TBA)(2)[M(HCTMCP)(2)(H(2)O)(2)] (1) (M = Mn(II), Fe(II), Co(II), Cd(II)) possess (4,4) sheet structures with large cavities that contain the tetra-n-butylammonium (n-TBA) countercations. Synthesis using sodium as the countercation yields a family of products with the general form [M(S)(4)M(S)(2)(HCTMCP)(2)] (S = EtOH, M = Fe(II) (2); S = MeOH, M = Co(II) or Zn(II) (3)). These complexes adopt a variety of two-dimensional (2D) structures. The complex [Mn(3)(HCTMCP)(2)(H(2)O)(12)](HCTMCP).6(H(2)O) (4) contains cationic (6,3) sheets with the counteranion and solvent molecules encapsulated within the hexagonal windows. Complexes 1-4 display weak antiferromagnetic coupling in all cases. The first example of a complex that contains the CN-coordinated monoanionic radical HCTMCP (*-), [Cu(HCTMCP)(MeCN)(2)] (5) is described. This one-dimensional (1D) coordination polymer, containing tetrahedral Cu(I) centers, displays medium strength antiferromagnetic coupling that is mediated through pi-interactions between the radical anions on adjacent chains. PMID- 21675708 TI - Non-innocent ligand behavior of a bimetallic Ni Schiff-base complex containing a bridging catecholate. AB - The geometric and electronic structure of a bimetallic Ni Schiff-base complex and its one-electron oxidized form have been investigated in the solid state and in solution. The two salen units in the neutral complex 1 are linked via a bridging catecholate function. The one-electron oxidized form [1](+) was determined to exist as a ligand radical species in solution, with the electron hole potentially localized on the redox-active dioxolene, the phenolate ligands, or delocalized over the entire ligand system. Electrochemical experiments and UV-vis-NIR spectroscopy, in combination with density functional theory (DFT) calculations, provide insight into the locus of oxidation and the degree of delocalization in this system. The one-electron hole for [1](+) was determined experimentally to be localized on the dioxolene bridge with a small amount of spin density on the outer phenolate moieties predicted by the calculations. The resonance Raman spectrum of [1](+) (lambda(ex) = 413 nm) in CH(2)Cl(2) solution clearly exhibited a new band at 1315 cm(-1) in comparison to 1, which is predicted to be a combination of dioxolene ring and C-O bond stretching modes, consistent with oxidation of the bridging moiety in [1](+). Analysis of the NIR bands for [1](+), in association with time-dependent DFT calculations, suggests that the low energy bands are ligand to ligand charge transfer transitions from the terminal phenolates to the central dioxolene unit. In combination, this data is consistent with a description of the overall electronic structure of [1](+) as a bridge localized semiquinone ligand radical species. This is in contrast to the mixed valence ground state description for many one-electron oxidized Ni salen monomer systems, and analysis in terms of intervalence charge transfer (IVCT) theory. PMID- 21675709 TI - Directed ortho-metalation-cross-coupling strategies. One-pot Suzuki reaction to biaryl and heterobiaryl sulfonamides. AB - A general synthesis of stable ortho-boropinacolato aryl and heteroaryl sulfonamides by directed ortho-metalation (DoM) and either MeOBPin or i-PrOBpin electrophile quench, 3 -> 4, is described. A one-pot metalation-Suzuki cross coupling procedure for the synthesis of biaryls and heterobiaryls, 3 -> 5, and a complementary DoM-Ir-catalyzed boronation sequence (Scheme 6 ) are delineated. PMID- 21675710 TI - Effect of ozonation on the estrogenicity and androgenicity of oil sands process affected water. AB - There is increasing environmental concern about the volume of oil sands process affected water (OSPW) produced by the oil sands industry in Alberta, Canada. There is limited knowledge of the toxic effects of OSPW and one of the primary organic constituents, naphthenic acids (NAs), which are thought to be one of the toxic constituents of OSPW. OSPW and NAs can have endocrine disrupting potential. The NAs in OSPW are persistent, but ozonation can significantly reduce concentrations of NA, while increasing their biodegradability, and consequently reduce OSPW toxicity. However, it is of concern that OSPW ozonation might generate hydroxylated cycloaliphatics with endocrine disrupting potential. In this study, the estrogen receptor- (ER) and androgen receptor- (AR) mediated effects of OSPW and ozone-treated OSPW were investigated in vitro by use of T47D kbluc (estrogen responsive) and MDA-kb2 (androgen responsive) cells. Ozonation neither attenuated nor intensified the estrogenicity of OSPW. The estrogenic responses to untreated OSPW and ozone treated OSPW were 2.58(+/-0.22)-fold and 2.48(+/-0.13)-fold greater than those of controls, respectively. Exposure to untreated OSPW produced significant antiandrogenicity in the presence of 0.01, 0.05, or 0.1 nM testosterone (T), while ozone-treated OSPW produced significant antiandrogenicity in the presence of 0.01 or 0.05 nM T. Exposure to untreated and ozone-treated OSPW also caused potentiation of androgen receptor-mediated effects of T. OSPW could cause estrogenic and antiandrogenic effects through receptor mediated pathways, and ozonation can partially mitigate the OSPW antiandrogenicity as well as androgen potentiating effect, without increasing estrogen potency. PMID- 21675711 TI - Glycoside bond formation via acid-base catalysis. AB - Acid-base catalyzed glycosyl donor and then glycosyl acceptor activation with phenylboron difluoride or diphenylboron fluoride permits hydrogen bond mediated intramolecular S(N)2-type glycosidation in generally high anomeric selectivity. PMID- 21675712 TI - The [NiFe]-hydrogenase of the cyanobacterium Synechocystis sp. PCC 6803 works bidirectionally with a bias to H2 production. AB - Protein film electrochemistry (PFE) was utilized to characterize the catalytic activity and oxidative inactivation of a bidirectional [NiFe]-hydrogenase (HoxEFUYH) from the cyanobacterium Synechocystis sp. PCC 6803. PFE provides precise control of the redox potential of the adsorbed enzyme so that its activity can be monitored under changing experimental conditions as current. The properties of HoxEFUYH are different from those of both the standard uptake and the "oxygen-tolerant" [NiFe]-hydrogenases. First, HoxEFUYH is biased toward proton reduction as opposed to hydrogen oxidation. Second, despite being expressed under aerobic conditions in vivo, HoxEFUYH is clearly not oxygen tolerant. Aerobic inactivation of catalytic hydrogen oxidation by HoxEFUYH is total and nearly instantaneous, producing two inactive states. However, unlike the Ni-A and Ni-B inactive states of standard [NiFe]-hydrogenases, both of these states are quickly (<90 s) reactivated by removal of oxygen and exposure to reducing conditions. Third, proton reduction continues at 25-50% of the maximal rate in the presence of 1% oxygen. Whereas most previously characterized [NiFe] hydrogenases seem to be preferential hydrogen oxidizing catalysts, the cyanobacterial enzyme works effectively in both directions. This unusual catalytic bias as well as the ability to be quickly reactivated may be essential to fulfilling the physiological role in cyanobacteria, organisms expected to experience swings in cellular reduction potential as they switch between aerobic conditions in the light and dark anaerobic conditions. Our results suggest that the uptake [NiFe]-hydrogenases alone are not representative of the catalytic diversity of [NiFe]-hydrogenases, and the bidirectional heteromultimeric enzymes may serve as valuable models to understand the diverse mechanisms of tuning the reactivity of the hydrogen activating site. PMID- 21675714 TI - Vibrational spectroscopy of microhydrated conjugate base anions. AB - Conjugate-base anions are ubiquitous in aqueous solution. Understanding the hydration of these anions at the molecular level represents a long-standing goal in chemistry. A molecular-level perspective on ion hydration is also important for understanding the surface speciation and reactivity of aerosols, which are a central component of atmospheric and oceanic chemical cycles. In this Account, as a means of studying conjugate-base anions in water, we describe infrared multiple photon dissociation spectroscopy on clusters in which the sulfate, nitrate, bicarbonate, and suberate anions are hydrated by a known number of water molecules. This spectral technique, used over the range of 550-1800 cm(-1), serves as a structural probe of these clusters. The experiments follow how the solvent network around the conjugate-base anion evolves, one water molecule at a time. We make structural assignments by comparing the experimental infrared spectra to those obtained from electronic structure calculations. Our results show how changes in anion structure, symmetry, and charge state have a profound effect on the structure of the solvent network. Conversely, they indicate how hydration can markedly affect the structure of the anion core in a microhydrated cluster. Some key results include the following. The first few water molecules bind to the anion terminal oxo groups in a bridging fashion, forming two anion water hydrogen bonds. Each oxo group can form up to three hydrogen bonds; one structural result, for example, is the highly symmetric, fully coordinated SO(4)(2-)(H(2)O)(6) cluster, which only contains bridging water molecules. Adding more water molecules results in the formation of a solvent network comprising water-water hydrogen bonding in addition to hydrogen bonding to the anion. For the nitrate, bicarbonate, and suberate anions, fewer bridging sites are available, namely, three, two, and one (per carboxylate group), respectively. As a result, an earlier onset of water-water hydrogen bonding is observed. When there are more than three hydrating water molecules (n > 3), the formation of a particularly stable four-membered water ring is observed for hydrated nitrate and bicarbonate clusters. This ring binds in either a side-on (bicarbonate) or top-on (nitrate) fashion. In the case of bicarbonate, additional water molecules then add to this water ring rather than directly to the anion, indicating a preference for surface hydration. In contrast, doubly charged sulfate dianions are internally hydrated and characterized by the closing of the first hydration shell at n = 12. The situation is different for the (-)O(2)C(CH(2))(6)CO(2-) (suberate) dianion, which adapts to the hydration network by changing from a linear to a folded structure at n > 15. This change is driven by the formation of additional solute-solvent hydrogen bonds. PMID- 21675715 TI - Do two-dimensional "noble gas atoms" produce molecular honeycombs at a metal surface? AB - Anthraquinone self-assembles on Cu(111) into a giant honeycomb network with exactly three molecules on each side. Here we propose that the exceptional degree of order achieved in this system can be explained as a consequence of the confinement of substrate electrons in the pores, with the pore size tailored so that the confined electrons can adopt a noble-gas-like two-dimensional quasi-atom configuration with two filled shells. Formation of identical pores in a related adsorption system (at different overall periodicity due to the different molecule size) corroborates this concept. A combination of photoemission spectroscopy with density functional theory computations (including van der Waals interactions) of adsorbate-substrate interactions allows quantum mechanical modeling of the spectra of the resultant quasi-atoms and their energetics. PMID- 21675716 TI - Mapping the subcellular protein distribution in three human cell lines. AB - The subcellular locations of proteins are closely related to their function and constitute an essential aspect for understanding the complex machinery of living cells. A systematic effort has been initiated to map the protein distribution in three functionally different cell lines with the aim to provide a subcellular localization index for at least one representative protein from all human protein encoding genes. Here, we present the results of more than 3500 proteins mapped to 16 subcellular compartments. The results indicate a ubiquitous protein expression with a majority of the proteins found in all three cell lines and a large portion localized to two or more compartments. The inter-relationships between the subcellular compartments are visualized in a protein-compartment network based on all detected proteins. Hierarchical clustering was performed to determine how closely related the organelles are in terms of protein constituents and compare the proteins detected in each cell type. Our results show distinct organelle proteomes, well conserved across the cell types, and demonstrate that biochemically similar organelles are grouped together. PMID- 21675717 TI - Antioxidant and antiproliferative activities of loach ( Misgurnus anguillicaudatus ) peptides prepared by papain digestion. AB - Loach protein hydrolysates (LPH) prepared by papain digestion were fractionated into four fractions, LPH-I (MW > 10 kDa), LPH-II (MW = 5-10 kDa), LPH-III (MW = 3 5 kDa), LPH-IV (MW < 3 kDa), and the in vitro antioxidant and antiproliferative (anticancer) activities of all fractions were determined. LPH-IV showed the lowest IC(50) value (16.9 +/- 0.21 mg/mL) for hydroxyl radical scavenging activity and the highest oxygen radical scavenging capacity (ORAC) value (reaching 215 +/- 5.9 mM Trolox/100 g loach peptide when the concentration was 60 MUg/mL). Compared with other fractions, LPH-IV also exhibited stronger antiproliferative activity for human liver (HepG2), breast (MCF-7), and colon (Caco-2) cancer cell lines in a dose-dependent manner. When the protein concentration was 40 mg/mL, the HepG2 and MCF-7 cell proliferation of LPH-IV reached 7 and 4%, respectively, with no significant difference from those of LPH (8 and 7%, p > 0.05), with significantly less growth than those of LPH-I, LPH-II, and LPH-III, respectively (p < 0.05). The Caco-2 colon cell proliferation of LPH IV was 12.8- and 8.7-fold smaller than those of LPH-I and LPH-II, respectively (p < 0.05). All of the fractions had a greater ability to inhibit Caco-2 colon cancer cell proliferation than to inhibit HepG2 liver cancer and MCF-7 breast cancer cell proliferation. The ORAC values of most of the fractions correlated (R(2) > 0.86, p < 0.01) with the antiproliferative activity of the three cancer cell lines, suggesting that higher antioxidant activity leads to better antiproliferative activity. However, further mechanistic and human clinical studies of the anticancer activity of loach protein hydrolysate fractions are needed. PMID- 21675718 TI - Influence of surface-energy components of Ni-P-TiO2-PTFE nanocomposite coatings on bacterial adhesion. AB - The influence of total surface energy on bacterial adhesion has been investigated intensively with the frequent conclusion that bacterial adhesion is less on low energy surfaces. However, there are also a number of contrary findings that high energy surfaces have a smaller biofouling tendency. Recently, it was found that the CQ ratio, which is defined as the ratio of Lifshitz-van der Waals (LW) apolar to electron donor surface-energy components of substrates, has a strong correlation to bacterial adhesion. However, the electron donor surface-energy components of substrates varied over only a very limited range. In this article, a series of Ni-P-TiO(2)-PTFE nanocomposite coatings with wide range of surface energy components were prepared using an electroless plating technique. The bacterial adhesion and removal on the coatings were evaluated with different bacteria under both static and flow conditions. The experimental results demonstrated that there was a strong correlation between bacterial attachment (or removal) and the CQ ratio. The coatings with the lowest CQ ratio had the lowest bacterial adhesion or the highest bacterial removal, which was explained using the extented DLVO theory. PMID- 21675720 TI - Mechanized silica nanoparticles: a new frontier in theranostic nanomedicine. AB - Medicine can benefit significantly from advances in nanotechnology because nanoscale assemblies promise to improve on previously established therapeutic and diagnostic regimes. Over the past decade, the use of delivery platforms has attracted attention as researchers shift their focus toward new ways to deliver therapeutic and/or diagnostic agents and away from the development of new drug candidates. Metaphorically, the use of delivery platforms in medicine can be viewed as the "bow-and-arrow" approach, where the drugs are the arrows and the delivery vehicles are the bows. Even if one possesses the best arrows that money can buy, they will not be useful if one does not have the appropriate bow to deliver the arrows to their intended location. Currently, many strategies exist for the delivery of bioactive agents within living tissue. Polymers, dendrimers, micelles, vesicles, and nanoparticles have all been investigated for their use as possible delivery vehicles. With the growth of nanomedicine, one can envisage the possibility of fabricating a theranostic vector that could release powerful therapeutics and diagnostic markers simultaneously and selectively to diseased tissue. In our design of more robust theranostic delivery systems, we have focused our attention on using mesoporous silica nanoparticles (SNPs). The payload "cargo" molecules can be stored within this robust domain, which is stable to a wide range of chemical conditions. This stability allows SNPs to be functionalized with stimulus-responsive mechanically interlocked molecules (MIMs) in the shape of bistable rotaxanes and psuedorotaxanes to yield mechanized silica nanoparticles (MSNPs). In this Account, we chronicle the evolution of various MSNPs, which came about as a result of our decade-long collaboration, and discuss advances in the synthesis of novel hybrid SNPs and the various MIMs which have been attached to their surfaces. These MIMs can be designed in such a way that they either change shape or shed off some of their parts in response to a specific stimulus, such as changes in redox potential, alterations in pH, irradiation with light, or the application of an oscillating magnetic field, allowing a theranostic payload to be released from the nanopores to a precise location at the appropiate time. We have also shown that these integrated systems can operate not only within cells, but also in live animals in response to pre existing biological triggers. Recognizing that the theranostics of the future could offer a fresh approach to the treatment of degenerative diseases including cancer, we aim to start moving out of the chemical domain and into the biological one. Some MSNPs are already being tested in biological systems. PMID- 21675721 TI - The importance of chemistry in creating well-defined nanoscopic embedded therapeutics: devices capable of the dual functions of imaging and therapy. AB - Nanomedicine is a rapidly evolving field, for which polymer building blocks are proving useful for the construction of sophisticated devices that provide enhanced diagnostic imaging and treatment of disease, known as theranostics. These well-defined nanoscopic objects have high loading capacities, can protect embedded therapeutic cargo, and offer control over the conditions and rates of release. Theranostics also offer external surface area for the conjugation of ligands to impart stealth characteristics and/or direct their interactions with biological receptors and provide a framework for conjugation of imaging agents to track delivery to diseased site(s). The nanoscopic dimensions allow for extensive biological circulation. The incorporation of such multiple functions is complicated, requiring exquisite chemical control during production and rigorous characterization studies to confirm the compositions, structures, properties, and performance. We are particularly interested in the study of nanoscopic objects designed for treatment of lung infections and acute lung injury, urinary tract infections, and cancer. This Account highlights our work over several years to tune the assembly of unique nanostructures. We provide examples of how the composition, structure, dimensions, and morphology of theranostic devices can tune their performance as drug delivery agents for the treatment of infectious diseases and cancer. The evolution of nanostructured materials from relatively simple overall shapes and internal morphologies to those of increasing complexity is driving the development of synthetic methodologies for the preparation of increasingly complex nanomedicine devices. Our nanomedicine devices are derived from macromolecules that have well-defined compositions, structures, and topologies, which provide a framework for their programmed assembly into nanostructures with controlled sizes, shapes, and morphologies. The inclusion of functional units within selective compartments/domains allows us to create (multi)functional materials. We employ combinations of controlled radical and ring-opening polymerizations, chemical transformations, and supramolecular assembly to construct such materials as functional entities. The use of multifunctional monomers with selective polymerization chemistries affords regiochemically functionalized polymers. Further supramolecular assembly processes in water with further chemical transformations provide discrete nanoscopic objects within aqueous solutions. This approach echoes processes in nature, whereby small molecules (amino acids, nucleic acids, saccharides) are linked into polymers (proteins, DNA/RNA, polysaccharides, respectively) and then those polymers fold into three-dimensional conformations that can lead to nanoscopic functional entities. PMID- 21675722 TI - Raman and inelastic neutron scattering study on a melt-infiltrated composite of NaAlH4 and nanoporous carbon. AB - Inelastic neutron scattering and Raman scattering spectra of a melt-infiltrated composite of NaAlH(4) and active carbon fibers have been measured at low temperature for two sample conditions: as prepared and subjected to hydrogen desorption-absorption cycling. After a careful data analysis, the present experimental results have been compared to the corresponding spectroscopic data taken from bulk NaAlH(4) and Na(3)AlH(6). Evident signatures induced by infiltration process onto the NaAlH(4) phonon bands have been detected, showing up as a strong peak broadening and smoothing together with, in some cases, an energy shift. Traces of Na(3)AlH(6), appearing as an extra intensity between 130 and 200 meV, seem also confirmed. A substantial agreement between neutron and Raman measurements has been found for the as-prepared melt-infiltrated sample, while for the cycled sample the two techniques produced rather dissimilar results. However, this apparent discrepancy can be explained by considering the different penetration depths of the two spectroscopic probes. Further work, both experimental and based on ab initio simulations, is surely needed in order to rationalize the finding of the present measurements. PMID- 21675724 TI - Luminescence properties and quenching mechanisms of Ln(Tf2N)3 complexes in the ionic liquid bmpyr Tf2N. AB - The emission properties, including luminescence lifetimes, of the lanthanide complexes Ln(Tf(2)N)(3) (Tf(2)N = bis(trifluoromethanesulfonyl)amide); Ln(3+) = Eu(3+), Tm(3+), Dy(3+), Sm(3+), Pr(3+), Nd(3+), Er(3+)) in the ionic liquid bmpyr Tf(2)N (bmpyr = 1-n-butyl-1-methylpyrrolidinium) are presented. The luminescence quantum efficiencies, eta, and radiative lifetimes, tau(R), are determined for Eu(3+)((5)D(0)), Tm(3+)((1)D(2)), Dy(3+)((4)F(9/2)), Sm(3+)((4)G(5/2)), and Pr(3+)((3)P(0)) emission. The luminescence lifetimes in these systems are remarkably long compared to values typically reported for Ln(3+) complexes in solution, reflecting weak vibrational quenching. The 1.5 MUm emission corresponding to the Er(3+) ((4)I(13/2)->(4)I(15/2)) transition, for example, exhibits a lifetime of 77 MUs. The multiphonon relaxation rate constants are determined for 10 different Ln(3+) emitting states, and the trend in multiphonon relaxation is analyzed in terms of the energy gap law. The energy gap law does describe the general trend in multiphonon relaxation, but deviations from the trend are much larger than those normally observed for crystal systems. The parameters determined from the energy gap law analysis are consistent with those reported for crystalline hosts. Because Ln(3+) emission is known to be particularly sensitive to quenching by water in bmpyr Tf(2)N, the binding properties of water to Eu(3+) in solutions of Eu(Tf(2)N)(3) in bmpyr Tf(2)N have been quantified. It is observed that water introduced into these systems binds quantitatively to Ln(3+). It is demonstrated that Eu(Tf(2)N)(3) can be used as a reasonable internal standard, both for monitoring the dryness of the solutions and for estimating the quantum efficiencies and radiative lifetimes for visible emitting [Ln(Tf(2)N)(x)](3-x) complexes in bmpyr Tf(2)N. PMID- 21675723 TI - Selenium moderates mercury toxicity in free-ranging freshwater fish. AB - Due to the extremely high affinity of selenium (Se) to mercury (Hg), Se sequesters Hg and reduces its biological availability in organisms. However the converse is also true. Hg sequesters Se, causing Hg to inhibit the formation of Se dependent enzymes while supplemental Se supports their continued synthesis. Hence, whether or not toxic effects accompany exposure to Hg depends upon the tissue Se:Hg molar ratio of the organism. The main objective of the present study was to investigate how levels of Hg and Se affected metallothionein (MT) induction in free-ranging brown trout, Salmo trutta, from Lake Mjosa, Norway (a Se depauperate lake). MT is proposed as a sensitive biomarker of potential detrimental effects induced by metals such as Hg. Emphasis was addressed to elucidate if increased tissue Se:Hg molar ratios and Se levels affected the demands for MT in the trout. The Se:Hg molar ratio followed by tissue Se levels were most successful for assessing the relationship between metal exposure and MT levels in the trout. Thus, Hg in molar excess over Se was a stronger inducer of MT synthesis than tissue Hg levels in the trout, supporting the assumption that Se has a prominent protective effect against Hg toxicity. Measuring Hg in animals may therefore provide an inadequate reflection of the potential health risks to humans and wildlife if the protective effects of Se are not considered. PMID- 21675725 TI - Azadibenzophospholes: functional building blocks with pronounced electron acceptor character. AB - A series of azadibenzophospholes with varying location of the nitrogen center has been synthesized and comprehensively characterized. In the context of the study, suitably brominated phenylpyridine precursors were accessed via Suzuki-Miyaura cross-coupling for the first time. Despite being nonfluorescent, X-ray crystallographic studies of two azadibenzophosphole oxides revealed planar conjugated scaffolds with high degree of pi-conjugation. The P-oxidized species were found to show desirable reversible reduction features that support promising electron-accepting properties of the materials. The presence of the nitrogen as well as phosphorus centers within the scaffold allowed for further functionalization with transition metals, as well as methyl groups that result in altered absorption and redox features for the materials. Subsequent bromination of the scaffold selectively occurred at the exocyclic P-phenyl group, as confirmed via X-ray crystallography. This halogenation allowed for further modification of the system via catalytic cross-coupling with pyridine. PMID- 21675726 TI - Further investigation into maple syrup yields 3 new lignans, a new phenylpropanoid, and 26 other phytochemicals. AB - Maple syrup is made by boiling the sap collected from certain maple ( Acer ) species. During this process, phytochemicals naturally present in tree sap are concentrated in maple syrup. Twenty-three phytochemicals from a butanol extract of Canadian maple syrup (MS-BuOH) had previously been reported; this paper reports the isolation and identification of 30 additional compounds (1-30) from its ethyl acetate extract (MS-EtOAc) not previously reported from MS-BuOH. Of these, 4 compounds are new (1-3, 18) and 20 compounds (4-7, 10-12, 14-17, 19, 20, 22-24, 26, and 28-30) are being reported from maple syrup for the first time. The new compounds include 3 lignans and 1 phenylpropanoid: 5-(3",4"-dimethoxyphenyl) 3-hydroxy-3-(4'-hydroxy-3'-methoxybenzyl)-4-(hydroxymethyl)dihydrofuran-2-one (1), (erythro,erythro)-1-[4-[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1 (hydroxymethyl)ethoxy]-3,5-dimethoxyphenyl]-1,2,3-propanetriol (2), (erythro,threo)-1-[4-[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1 (hydroxymethyl)ethoxy]-3,5-dimethoxyphenyl]-1,2,3-propanetriol (3), and 2,3 dihydroxy-1-(3,4- dihydroxyphenyl)-1-propanone (18), respectively. In addition, 25 other phenolic compounds were isolated including (threo,erythro)-1-[4-[(2 hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1-(hydroxymethyl)ethoxy]-3-methoxyphenyl] 1,2,3-propanetriol (4), (threo,threo)-1-[4-[(2-hydroxy-2-(4-hydroxy-3 methoxyphenyl)-1-(hydroxymethyl)ethoxy]-3-methoxyphenyl]-1,2,3-propanetriol (5), threo-guaiacylglycerol-beta-O-4'-dihydroconiferyl alcohol (6), erythro-1-(4 hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxypropyl)-2,6-dimethoxyphenoxy]-1,3 propanediol (7), 2-[4-[2,3-dihydro-3-(hydroxymethyl)-5-(3-hydroxypropyl)-7 methoxy-2-benzofuranyl]-2,6-dimethoxyphenoxy]-1-(4-hydroxy-3-methoxyphenyl)-1,3 propanediol (8), acernikol (9), leptolepisol D (10), buddlenol E (11), (1S,2R)-2 [2,6-dimethoxy-4-[(1S,3aR,4S,6aR)-tetrahydro-4-(4-hydroxy-3,5-dimethoxyphenyl) 1H,3H-furo[3,4-c]furan-1-yl]phenoxy]-1-(4-hydroxy-3-methoxyphenyl)-1,3 propanediol (12), syringaresinol (13), isolariciresinol (14), icariside E4 (15), sakuraresinol (16), 1,2-diguaiacyl-1,3-propanediol (17), 2,3-dihydroxy-1-(4 hydroxy-3,5-dimethoxyphenyl)-1-propanone (19), 3-hydroxy-1-(4-hydroxy-3,5 dimethoxyphenyl)propan-1-one (20), dihydroconiferyl alcohol (21), 4 acetylcatechol (22), 3',4',5'-trihydroxyacetophenone (23), 3,4-dihydroxy-2 methylbenzaldehyde (24), protocatechuic acid (25), 4 (dimethoxymethyl)pyrocatechol (26), tyrosol (27), isofraxidin (28), and 4 hydroxycatechol (29). One sesquiterpene, phaseic acid (30), which is a known metabolite of the phytohormone abscisic acid, was also isolated from MS-EtOAc. The antioxidant activities of MS-EtOAc (IC(50) = 75.5 MUg/mL) and the pure isolates (IC(50) ca. 68-3000 MUM) were comparable to that of vitamin C (IC(50) = 40 MUM) and the synthetic commercial antioxidant butylated hydroxytoluene (IC(50) = 3000 MUM), in the diphenylpicrylhydrazyl radical scavenging assay. The current study advances scientific knowledge of maple syrup constituents and suggests that these diverse phytochemicals may impart potential health benefits to this natural sweetener. PMID- 21675727 TI - Targeted indocyanine-green-loaded calcium phosphosilicate nanoparticles for in vivo photodynamic therapy of leukemia. AB - Leukemia is one of the most common and aggressive adult cancers, as well as the most prevalent childhood cancer. Leukemia is a cancer of the hematological system and can be divided into a diversity of unique malignancies based on the onset of the disease as well as the specific cell lineages involved. Cancer stem cells, including recently identified leukemia stem cells (LSCs), are hypothesized to be responsible for cancer development, relapse, and resistance to treatment, and new therapeutics targeting these cellular populations are urgently needed. Nontoxic and nonaggregating calcium phosphosilicate nanoparticles (CPSNPs) encapsulating the near-infrared fluoroprobe indocyanine green (ICG) were recently developed for diagnostic imaging and drug delivery as well as for photodynamic therapy (PDT) of solid tumors. Prior studies revealed that specific targeting of CPSNPs allowed for enhanced accumulation within breast cancer tumors, via CD71 targeting, or pancreatic cancer tumors, via gastrin receptor targeting. In the present study, ICG-loaded CPSNPs were evaluated as photosensitizers for PDT of leukemia. Using a novel bioconjugation approach to specifically target CD117 or CD96, surface features enhanced on leukemia stem cells, in vitro ICG-CPSNP PDT of a murine leukemia cell line and human leukemia samples were dramatically improved. Furthermore, the in vivo efficacy of PDT was dramatically enhanced in a murine leukemia model by utilizing CD117-targeted ICG-CPSNPs, resulting in 29% disease free survival. Altogether, this study demonstrates that leukemia-targeted ICG loaded CPSNPs offer the promise to effectively treat relapsing and multidrug resistant leukemia and to improve the life of leukemia patients. PMID- 21675728 TI - Combined carbometalation-zinc homologation-allylation reactions as a new approach for alkoxyallylation of aldehydes. AB - The combined carbometalation reaction of ynol ethers followed by a zinc homologation and further allylation reactions lead to an efficient preparation of allylic vicinal diols. The stereochemical outcome of the reaction shows that the substituent of the aldehyde occupies a pseudoaxial position in a Zimmerman Traxler transition state. PMID- 21675730 TI - Particle deposition onto Janus and patchy spherical collectors. AB - An Eulerian model (convection-diffusion-migration equation) is presented to study colloid deposition behavior on Janus and patchy spherical collectors using Happel cell geometry. The model aims to capture the effect of the collector surface charge heterogeneity on the particle deposition rate. Two separate cases of surface charge distribution are presented. In the first case, the surface heterogeneity is modeled as half the collector favoring deposition and the other half hindering it (Janus collectors). For the second case, the surface heterogeneity is modeled as alternate stripes of attractive and repulsive regions on the collector (patchy collectors). The model also considers fluid flow approaching the collector at different angles in addition to the standard gravity assisted and gravity hindered flow conditions to analyze the effect of the collector orientation on the deposition. It was observed that particles tend to deposit at the edges of the favorable stripes and the extent of this preferential accumulation varies along the tangential position of the collector due to the nonuniform nature of the collector. The predicted deposition behavior is compared to the patchwise heterogeneity model. The study brings to fore how recent developments in synthesis of chemically heterogeneous particles and beads can be used for improved particle capture in porous media and for designing filter beds with enhanced life. PMID- 21675729 TI - Bioorthogonal chemical reporters for analyzing protein lipidation and lipid trafficking. AB - Protein lipidation and lipid trafficking control many key biological functions in all kingdoms of life. The discovery of diverse lipid species and their covalent attachment to many proteins has revealed a complex and regulated network of membranes and lipidated proteins that are central to fundamental aspects of physiology and human disease. Given the complexity of lipid trafficking and the protein targeting mechanisms involved with membrane lipids, precise and sensitive methods are needed to monitor and identify these hydrophobic molecules in bacteria, yeast, and higher eukaryotes. Although many analytical methods have been developed for characterizing membrane lipids and covalently modified proteins, traditional reagents and approaches have limited sensitivity, do not faithfully report on the lipids of interest, or are not readily accessible. The invention of bioorthogonal ligation reactions, such as the Staudinger ligation and azide-alkyne cycloadditions, has provided new tools to address these limitations, and their use has begun to yield fresh insight into the biology of protein lipidation and lipid trafficking. In this Account, we discuss how these new bioorthogonal ligation reactions and lipid chemical reporters afford new opportunities for exploring the biology of lipid-modified proteins and lipid trafficking. Lipid chemical reporters from our laboratory and several other research groups have enabled improved detection and large-scale proteomic analysis of fatty-acylated and prenylated proteins. For example, fatty acid and isoprenoid chemical reporters in conjunction with bioorthogonal ligation methods have circumvented the limited sensitivity and hazards of radioactive analogues, allowing rapid and robust fluorescent detection of lipidated proteins in all organisms tested. These chemical tools have revealed alterations in protein lipidation in different cellular states and are beginning to provide unique insights in mechanisms of regulation. Notably, the purification of proteins labeled with lipid chemical reporters has allowed both the large-scale analysis of lipidated proteins as well as the discovery of new lipidated proteins involved in metabolism, gene expression, and innate immunity. Specific lipid reporters have also been developed to monitor the trafficking of soluble lipids; these species are enabling bioorthogonal imaging of membranes in cells and tissues. Future advances in bioorthogonal chemistry, specific lipid reporters, and spectroscopy should provide important new insight into the functional roles of lipidated proteins and membranes in biology. PMID- 21675731 TI - Palladium-catalyzed oxidative rearrangement of diaryl alkenyl carbinols to beta,beta-diaryl alpha,beta-unsaturated ketones. AB - An unusual oxidative palladium-catalyzed rearrangement of diaryl alkenyl carbinols to beta,beta-diaryl alpha,beta-unsaturated ketones is described. The geometry of the alkene product is not determined by the electronic nature of the aryl substitutents but rather is determined by substitution pattern on the aryl rings. The reaction proceeds in good yields, utilizes oxygen at atmospheric pressure as the terminal oxidant, and tolerates a variety of functional groups on the aryl rings. PMID- 21675732 TI - Migration kinetics of oxygen vacancies in Mn-modified BiFeO3 thin films. AB - Migration kinetics of oxygen vacancies in BiFe(0.95)Mn(0.05)O(3) thin film were investigated by the temperature -dependent leakage current as well as the electric field and temperature-dependent impedance spectroscopy. The BiFe(0.95)Mn(0.05)O(3) is of an abnormal leakage behavior, and an Ohmic conduction is observed regardless of varied temperatures and electric fields. The temperature-dependent impedance spectroscopy under different resistance states is used to illuminate different leakage behavior between BiFe(0.95)Mn(0.05)O(3) and pure BiFeO(3). The impedance spectroscopy under a high resistance state shows that the first ionization of oxygen vacancies is responsible for the dielectric relaxation and electrical conduction of BiFe(0.95)Mn(0.05)O(3) in the whole temperature range of 294 to 474 K; the BiFeO(3) exhibits similar dielectric relaxation and electrical conduction behavior in the low-temperature range of 294 374 K, whereas the short-range motion of oxygen vacancies was involved in the high-temperature range of 374-474 K. The impedance spectroscopy under a low resistance state demonstrates that the dielectric relaxation and conduction mechanisms almost keep unchanged for BiFe(0.95)Mn(0.05)O(3), whereas the hopping electrons of Fe(2+)-V(O)(*)-Fe(3+) and Fe(2+)-Fe(3+) are responsible for its dielectric relaxation and conduction mechanism of BiFeO(3). Different impedance spectroscopy under low and high resistance states confirms that an abnormal leakage behavior of BiFe(0.95)Mn(0.05)O(3) is related to different migration kinetics of oxygen vacancies, obviously differing from that of BiFeO(3). PMID- 21675733 TI - Relationship between the thermally induced reorientations of aromatic solvate molecules in Cu(hfac)2-nitroxide breathing crystals and the character of the magnetic anomaly. AB - A new group of "breathing" crystals has been synthesized. These are aromatic solvates of the copper(II) hexafluoroacetylacetonate complex with spin-labeled pyrazole Cu(hfac)(2)L.0.5Solv, where L is 2-(1-butyl-1H-pyrazol-4-yl)-4,4,5,5 tetramethyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl and Solv is benzene, toluene, ethylbenzene, propylbenzene, butylbenzene, styrene, o-xylene, m-xylene, p-xylene, 1,4-bis(trifluoromethyl)benzene, 1-methyl-4-ethylbenzene, 1-methyl-4 vinylbenzene, 1,4-diethylbenzene, 1,2,3-trimethylbenzene, or 1,2,4 trimethylbenzene. The main feature of Cu(hfac)(2)L.0.5Solv single crystals is their remarkable mechanical stability and ability to undergo thermally induced structural rearrangements accompanied by spin-crossover-like phenomena. The structures of Cu(hfac)(2)L.0.5Solv solvates are similar and based on mutually parallel {Cu(hfac)(2)L}(infinity) heterospin chains with a "head-to-head" motif. The localization of voids with guest molecules being the same in all crystals, the temperature dependence of the effective magnetic moment (MU(eff)) for Cu(hfac)(2)L.0.5Solv is determined by the structure of the guest molecules, along which the polymer chains are "gliding" when the temperature changes. When the temperature decreased from 300 to 100-50 K, MU(eff) decreased, abruptly or gradually, from 2.7-2.4 to ~1.8 beta for the majority of Cu(hfac)(2)L.0.5Solv except the solvates with benzene, toluene, and 1,4-bis(trifluoromethyl)benzene. When Cu(hfac)(2)L.0.5C(6)H(6) and Cu(hfac)(2)L.0.5CH(3)-C(6)H(5) were cooled to 50 K, MU(eff) decreased to ~2.1-2.2 beta. When Cu(hfac)(2)L.0.5(1,4-(CF(3))(2) C(6)H(4)) was cooled to 50 K, MU(eff) initially decreased from ~2.7 to 1.9 beta and then abruptly increased to ~2.4 beta. A single-crystal X-ray diffraction analysis of each solvate within a temperature range wider than the range of magnetic anomaly temperatures revealed a complex interrelated dynamics of the aromatic solvent guest molecules and heterospin chains. The dynamics largely depended on the orientation of the solvent guest molecules relative to the polymer chains. An analysis of the thermally induced phase transformations revealed a relationship between the structural rearrangement of Cu(hfac)(2)L.0.5Solv and the form of the magnetic anomaly on the MU(eff)(T) curve and between the structural rearrangement of the solvate and the temperature of the magnetic effect. PMID- 21675734 TI - Rectification of nanopores at surfaces. AB - At the nanoscale, methods to measure surface charge can prove challenging. Herein we describe a general method to report surface charge through the measurement of ion current rectification of a nanopipette brought in close proximity to a charged substrate. This method is able to discriminate between charged cationic and anionic substrates when the nanopipette is brought within distances from ten to hundreds of nanometers from the surface. Further studies of the pH dependence on the observed rectification support a surface-induced mechanism and demonstrate the ability to further discriminate between cationic and nominally uncharged surfaces. This method could find application in measurement and mapping of heterogeneous surface charges and is particularly attractive for future biological measurements, where noninvasive, noncontact probing of surface charge will prove valuable. PMID- 21675735 TI - Substrate recognition of the membrane-associated sialidase NEU3 requires a hydrophobic aglycone. AB - The human neuraminidases (NEU) consist of a family of four isoforms (NEU1-NEU4). Members of this enzyme family are proposed to have important roles in health and disease through regulation of the composition of cellular sialosides. The NEU3 isoform is a membrane-associated enzyme that cleaves glycolipid substrates. However, few reports have examined the substrate specificity of the enzyme for non-natural substrates. We report here a series of 11 synthetic trisaccharides that feature modifications of the aglycone or the Neu5Ac residue of an octyl beta sialyllactoside. The time course of substrate cleavage by NEU3 was monitored using an electrospray ionization mass spectrometry assay to obtain relative rates (k(rel)). We observed that NEU3 substrate activity was directly dependent upon the hydrophobicity of the aglycone but had no apparent requirement for features of the ceramide headgroup. We also observed that trisaccharides with incorporated azide groups in the Neu5Ac residue at either C9 or the N5-Ac position were substrates, and in the case of the N5-azidoacetyl derivative, the activity was superior to that of GM3. However, the incorporation of larger aryl groups was tolerated only at C9, but not at N5-Ac. We propose a two-site model for enzyme recognition, requiring interaction at both the Neu5Ac residue and the hydrophobic aglycone. PMID- 21675736 TI - Ring-opening polymerization of cyclic esters and trimethylene carbonate catalyzed by aluminum half-salen complexes. AB - A series of ONO-tridentate Schiff base ligands derived from chiral and achiral amino alcohols and amino acids were synthesized and reacted with AlEt(3) to provide dimeric aluminum complexes. These complexes were tested for the ring opening polymerization (ROP) of rac-lactide at 70 degrees C in toluene, producing poly(lactide) with up to 82% isotacticity. The most active of these aluminum complexes was chosen to perform ring-opening homopolymerizations of rac lactide, trimethylene carbonate (TMC), rac-beta-butyrolactone (rac-beta-BL), delta-valerolactone (delta-VL), and epsilon-caprolactone (epsilon-CL). Kinetic parameters were investigated, and each polymerization was found to be first order with respect to monomer concentration. Fractional orders were observed with respect to catalyst concentration, indicating catalyst aggregation during the polymerization processes. Activation parameters were determined for all monomers, with their DeltaG(?) values at 90 degrees C being in the order rac-lactide ~ rac beta-BL > delta-VL > TMC ~ epsilon-CL. Fineman-Ross and kinetic studies of the copolymerization of rac-lactide and delta-VL both indicate that the rate of rac lactide enchainment is higher than that of delta-VL, resulting in a tapered copolymer. In addition, single crystals of one of these aluminum complexes were grown in the presence of rac-lactide and characterized using X-ray crystallography. The unit cell contains two lactide monomers, one D- and one L lactide, adding further proof that polymerization takes place via an enantiomorphic site control mechanism. PMID- 21675737 TI - Probing ionophore selectivity in argon-tagged hydrated alkali metal ion-crown ether systems. AB - Crown ethers are an important family of compounds that are closely related to naturally occurring ionophores. Thus, crown ethers are useful in modeling the size-selective behavior of ionophores. Using a combination of infrared predissociation spectroscopy and density functional theory calculations, we have investigated M(+)(18-crown-6 ether)(H(2)O)(1-4) Ar complexes, where M = Li, Na, K, Rb and Cs in the gas phase. The argon-tagging technique was used to lower the internal energies (effective temperatures ~100 K), yielding well-resolved spectra in the OH stretching region for systems containing up to three waters. Spectral changes were monitored as both the size of the ion and degree of hydration were varied. While there is not a particular spectroscopic signature of gas-phase selectivity reported in this work, the unique role that K(+) plays in the systems studied, as a "bridge" between the smaller and larger alkali metal ions, is consistent with the well-known special affinity for K(+) by 18-crown-6 ether in the aqueous phase. PMID- 21675739 TI - Bioavailability of iron from wheat aegilops derivatives selected for high grain iron and protein contents. AB - A coupled in vitro digestion/Caco-2 model was employed to assess iron bioavailability from wheat Aegilops derivatives selected for high iron and protein contents. The iron content in wheat genotypes used in this study correlated to a great extent with both protein (r = 0.80) and phytate (r = 0.68) contents. The iron bioavailability was based on Caco-2 cell ferritin formation from cooked digests of these derivatives (relative to WL711 control) and correlated positively with dialyzable iron (r = 0.63) and total iron content (r = 0.38) but not with the phytate content. The apparently decreased phytate/iron molar ratios, however, correlated negatively (r = -0.42) with the iron bioavailability, justifying the utilization of these parameters in biofortification programs. Iron bioavailability in the derivatives increased up to 1.5-fold, corresponding to a 1.5-2.2-fold increase observed in iron content over control. These data suggest that biofortification for iron proportionately leading to higher iron bioavailability will be the most feasible and cost effective approach to combat micronutrient deficiency. PMID- 21675738 TI - On the mechanism of targeting of phage fusion protein-modified nanocarriers: only the binding peptide sequence matters. AB - The integration of pharmaceutical nanocarriers with phage display techniques is emerging as a new paradigm for targeted cancer nanomedicines. We explored the direct use of landscape phage fusion proteins for the self-assembly of phage derived binding peptides to liposomes for cancer cell targeting. The primary purpose of this study was to elucidate the targeting mechanism with a particular emphasis on the relative contributions of the two motifs that make up the landscape phage fusion protein (a binding peptide and the phage pVIII coat protein) to the targeting efficiency. Using transmission electron microscopy and dynamic light scattering, we confirmed the formation of phage-liposomes. Using FACS analysis, fluorescence microscopy, and fluorescence photospectrometry, we found that liposomes modified with MCF-7-specific phage fusion proteins (MCF-7 binding peptide, DMPGTVLP, fused to the phage PVIII coat protein) provided a strong and specific association with target MCF-7 cancer cells but not with cocultured, nontarget cells including C166-GFP and NIH3T3. The substitution for the binding peptide fused to phage pVIII coat protein abolished the targeting specificity. The addition of free binding peptide, DMPGTVLP, competitively inhibited the interaction of MCF-7-specific phage-liposomes with target MCF-7 cells but showed no reduction of MCF-7-associated plain liposomes. The proteolysis of the binding peptide reduced MCF-7 cell-associated phage-liposomes in a proteinase K (PK) concentration-dependent manner with no effect on the binding of plain liposomes to MCF-7 cells. Overall, only the binding peptide motif was involved in the targeting specificity of phage-liposomes. The presence of phage pVIII coat protein did not interfere with the targeting efficiency. PMID- 21675740 TI - Encapsulation of anion/cation in the central cavity of tetrameric polyoxometalate, composed of four trititanium(IV)-substituted alpha-Dawson subunits, initiated by protonation/deprotonation of the bridging oxygen atoms on the intramolecular surface. AB - Preparation and structural characterization of a novel polyoxometalate (POM), [(P(2)W(15)Ti(3)O(60.5))(4)(NH(4))](35-) 1, i.e., an encapsulated NH(4)(+) cation species in the central cavity of a tetramer (called the Dawson tetramer) constituted by trititanium(IV)-substituted alpha-Dawson POM substructure, are described. POM 1 was synthesized by several different methods and unequivocally characterized by complete elemental analysis, thermogravimetric and differential thermal analysis (TG/DTA), FTIR spectroscopy, solution ((15)N{(1)H}, (31)P, (183)W) NMR spectroscopy, and X-ray crystallography. First, POM 1 was synthesized by a reaction of NH(4)Cl in aqueous solution with a precursor, which was derived by thermal treatment of a monomeric triperoxotitanium(IV)-substituted Dawson POM, [alpha-1,2,3-P(2)W(15)(TiO(2))(3)O(56)(OH)(3)](9-) 2, for 3 h in an electric furnace at 200 degrees C. The encapsulated NH(4)(+) cation in 1 was confirmed by (15)N{(1)H} NMR measurement and X-ray crystallography. As another synthesis of 1, a direct exchange of the Cl(-) anion encapsulated in [{alpha-1,2,3 P(2)W(15)Ti(3)O(57.5)(OH)(3)}(4)Cl](25-) 3 with the NH(4)(+) cation was attained by neutralizing an aqueous solution containing 3 with the addition of aqueous NH(3) (the initial pH of ca. 2-2.5 was changed to 6.4), followed by adding NH(4)Cl. It has been clarified that the conditions as to whether the anion or the cation is encapsulated in the central cavity of the Dawson tetramer were significantly related to the protonation/deprotonation of the bridging oxygen atoms on the intramolecular surface, Ti-O-Ti/Ti-OH-Ti sites constituting the Dawson subunits. PMID- 21675741 TI - Strain-driven Moire superstructures of epitaxial graphene on transition metal surfaces. AB - STM images of multidomain epitaxial graphene on Pt(111) have been combined with a geometrical model to investigate the origin of the coincidence Moire superstructures. We show that there is a relation between the appearance of a particular Moire periodicity and the minimization of the absolute value of the strain between the graphene and the substrate for the different orientations between both atomic lattices. This model predicts all the stable epitaxial graphene structures that can be grown on transition metal surfaces, and we have made use of it for reproducing previously published data from different authors. Its validity suggests that minimization of the strain within the coincident graphene unit-cell due to a strong local interaction is the driving force in the formation of Moire superstructures. PMID- 21675742 TI - Compatibilization of immiscible polymer blends using graphene oxide sheets. AB - By taking the advantage of the unique amphiphilic structure of graphene oxide sheets (GOSs), we develop here a new and effective strategy for compatibilizing immiscible polymer blends. With the incorporation of only 0.5 wt % GOSs into immiscible polyamide/polyphenylene oxide (PA/PPO, 90/10) blends, the droplet diameter of the dispersed minor phase (PPO) is dramatically reduced by more than 1 order of magnitude, indicating a largely improved compatibility in the GOS filled polymer blends. As a result, the ductility of GOS-compatibilized polymer blends is notably elevated. The compatibilizing effect of GOSs should be due to the fact that GOSs can exhibit strong interactions with both PA and PPO phases, thus minimizing their interfacial tension. Moreover, unlike traditional copolymer compatibilizers, GOSs can also act as reinforcing fillers in polymer blends, thus remarkably enhancing their mechanical strength and thermal stability. Considering the inexpensive sources (graphite powders) and extraordinary properties of GOSs, this work may open up opportunities to produce new compatibilizers that are of great interest in the industrial field. PMID- 21675743 TI - Graphene as cellular interface: electromechanical coupling with cells. AB - Interfacing cells with nanomaterials such as graphene, nanowires, and carbon nanotubes is useful for the integration of cellular physiology with electrical read outs. Here we show the interfacing of graphene sheets on the surface of yeast cells, leading to electromechanical coupling between the sheets and the cells. The cells are viable after the interfacing. The response caused by physiologically stressing the cells by exposure to alcohols, which causes a change in cell volume, can be observed in the electrical signal through graphene. The change in the cell volume leads to straining of the sheets, forming wrinkles which reduce the electrical conductivity. As the dynamic response of the cell can be observed, it is possible to differentiate between ethanol, 2-propanol, and water. We believe this will lead to further development of cell-based electrical devices and sensors. PMID- 21675744 TI - Structural stability of boron clusters with octahedral and tetrahedral symmetries. AB - The structural stability of cagelike boron clusters with octahedral and tetrahedral symmetries has been investigated by means of first-principles calculations. Twenty-eight cluster models, ranging from B(10) to B(66), were systematically constructed using regular and semiregular polyhedra as prototypes. The binding energies per atom were, on the whole, slightly lower than those of icosahedral clusters B(80) and B(100), which are supposed to be the most stable in the icosahedral group. The larger clusters did not always have higher binding energies. Isothermal molecular dynamics simulations were performed to determine the deformation temperatures at which clusters began to break or change their structures. We found eight clusters that had nonzero deformation temperatures, indicating that they are in metastable states. The octahedral cluster B(18) had the highest deformation temperature among these, similar to that of icosahedral B(80) and B(100). The analysis of the electronic structure of B(18) showed that it attained this high stability owing to Jahn-Teller distortion. PMID- 21675745 TI - Mutual diffusion occurring at the interface between La0.6Sr0.4Co0.8Fe0.2O3 cathode and Gd-doped ceria electrolyte during IT-SOFC cell preparation. AB - The microstructure and local chemistry of the interface between the screen printed La(0.6)Sr(0.4)Co(0.8)Fe(0.2)O(3) (LSCF) thin film cathode and Gd-doped ceria (GDC) electrolyte substrate have been investigated. Elemental distribution analyses, by energy-dispersive X-ray spectroscopy operated in scanning transmission electron microscopy (STEM) mode, illustrate that all constituent elements in GDC and LSCF mutually diffuse across the LSCF/GDC interface, with equal diffusion length. This leads to the formation of mutual diffusion zones at the LSCF/GDC interfaces, with the resultant mixture of diffusing ions being associated with specific valence state changes, as verified by STEM electron energy loss spectroscopy analyses. Moreover, this mutual diffusion can result in microstructural changes, where superstructure formation is accompanied by enhancement of oxygen vacancy ordering at this region. Such mutual diffusion and associated microstructure evolution is considered to be detrimental to fuel cell efficiency and should be suppressed by lowering cell fabrication temperatures. PMID- 21675746 TI - Surface of liquid water: three-body interactions and vibrational sum-frequency spectroscopy. AB - Phase-sensitive vibrational sum-frequency experiments on the water surface, using isotopic mixtures of water and heavy water, have recently been performed. The experiments show a positive feature at low frequency in the imaginary part of the susceptibility, which has been difficult to interpret, and impossible to reproduce using two-body (pairwise-additive) water simulation models. We have reparameterized a new three-body simulation model for liquid water, and with this model we calculate the imaginary part of the sum-frequency susceptibility, finding good agreement with experiment for dilute HOD in D(2)O. Theoretical analysis provides a molecular-level structural interpretation of these new and exciting experiments. In particular, we do not find evidence of any special ice like ordering at the surface of liquid water. PMID- 21675747 TI - Synthesis of one-dimensional potassium tungsten bronze with excellent near infrared absorption property. AB - Potassium tungsten oxide nanofibers were successfully synthesized via a facile hydrothermal reaction route in the presence of sulfate. After reduction under a reductive atmosphere of H(2)(5 vol %)/N(2), the potassium tungsten oxide transformed to potassium tungsten bronze. Because of the lack of free electrons, the potassium tungsten oxide (K(x)WO(3+x/2)) showed no NIR shielding performance; however, the potassium tungsten bronze (K(x)WO(3)) showed promising optical characteristics such as high transmittance for visible light, as well as high shielding performance for near-infrared lights, indicating its potential application as a solar filter. Meanwhile, the potassium tungsten bronze (K(x)WO(3)) showed strong absorption of near-infrared light and instantaneous conversion of photoenergy to heat. PMID- 21675749 TI - Solvent-exfoliated graphene at extremely high concentration. AB - We describe three related methods to disperse graphene in solvents with concentrations from 2 to 63 mg/mL. Simply sonicating graphite in N-methyl-2 pyrrolidinone, followed by centrifugation, gives dispersed graphene at concentrations of up to 2 mg/mL. Filtration of a sonicated but uncentrifuged dispersion gives a partially exfoliated powder that can be redispersed at concentrations of up to 20 mg/mL. However, this process can be significantly improved by removing any unexfolaited graphite from the starting dispersion by centrifugation. The centrifuged dispersion can be filtered to give a powder of exfoliated few-layer graphene. This powder can be redispersed at concentrations of at least 63 mg/mL. The dispersed flakes are ~1 MUm long and ~3 to 4 layers thick on average. Although some sedimentation occurs, ~26-28 mg/mL of the dispersed graphene appears to be indefinitely stable. PMID- 21675748 TI - Bound anions differentially stabilize multiprotein complexes in the absence of bulk solvent. AB - The combination of ion mobility separation with mass spectrometry is an emergent and powerful structural biology tool, capable of simultaneously assessing the structure, topology, dynamics, and composition of large protein assemblies within complex mixtures. An integral part of the ion mobility-mass spectrometry measurement is the ionization of intact multiprotein complexes and their removal from bulk solvent. This process, during which a substantial portion of protein structure and organization is likely to be preserved, imposes a foreign environment on proteins that may cause structural rearrangements to occur. Thus, a general means must be identified to stabilize protein structures in the absence of bulk solvent. Our approach to this problem involves the protection of protein complex structure through the addition of salts in solution prior to desorption/ionization. Anionic components of the added salts bind to the complex either in solution or during the electrospray process, and those that remain bound in the gas phase tend to have high gas phase acidities. The resulting 'shell' of counterions is able to carry away excess energy from the protein complex ion upon activation and can result in significant structural stabilization of the gas-phase protein assembly overall. By using ion mobility mass spectrometry, we observe both the dissociation and unfolding transitions for four tetrameric protein complexes bound to populations of 12 different anions using collisional activation. The data presented here quantifies, for the first time, the influence of a large range of counterions on gas-phase protein structure and allows us to rank and classify counterions as structure stabilizers in the absence of bulk solvent. Our measurements indicate that tartrate, citrate, chloride, and nitrate anions are among the strongest stabilizers of gas-phase protein structure identified in this screen. The rank order determined by our data is substantially different when compared to the known Hofmeister salt series in solution. While this is an expected outcome of our work, due to the diminished influence of anion and protein solvation by water, our data correlates well to expected anion binding in solution and highlights the fact that both hydration layer and anion-protein binding effects are critical for Hofmeister-type stabilization in solution. Finally, we present a detailed mechanism of action for counterion stabilization of proteins and their complexes in the gas-phase, which indicates that anions must bind with high affinity, but must dissociate readily from the protein in order to be an effective stabilizer. Anion-resolved data acquired for smaller protein systems allows us to classify anions into three categories based on their ability to stabilize protein and protein complex structure in the absence of bulk solvent. PMID- 21675750 TI - A new route to size and population control of silver clusters on colloidal TiO2 nanocrystals. AB - Formation of hybrid Ag-TiO(2) nanocrystals (NCs) in which Ag clusters are uniformly deposited on individual TiO(2) NC surface has been achieved by using hydrophobic surfactant-capped TiO(2) NCs in combination with a photodeposition technique. The population of Ag clusters on the individual TiO(2) NC surface can be controlled by the degree of hydrophobicity (e.g., the number of vacant sites) on the TiO(2) NC surface while their size may be altered simply by varying irradiation time. A reversible change in color of the resulting hybrid Ag-TiO(2) NCs is induced by alternating UV light and visible-light illumination; however, the size and population of Ag clusters on TiO(2) NCs are almost unchanged. Furthermore, these materials also exhibit much higher photocatalytic performance as compared to that of Ag supported on commercial TiO(2)-P25. PMID- 21675751 TI - A facile method to crystallize amorphous anodized TiO2 nanotubes at low temperature. AB - Anodic growth of TiO(2) nanotubes has attracted intensive interests recently. However, the as-prepared TiO(2) nanotubes are usually amorphous and they generally need to be crystallized by sintering above 450 degrees C. Here, we report on a facile method to crystallize amorphous anodized TiO(2) nanotubes at a low temperature. We find that, simply by immersing them into hot water, the anodized TiO(2) nanotubes can be transformed from amorphous to crystalline state at a temperature as low as 92 degrees C. Results indicate that the hot water treatment might be a versatile strategy to crystallize amorphous anodized TiO(2) nanotubes at low temperature. Field-emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction analysis, UV-vis spectroscopy, and Brunauer-Emmett-Teller (BET) analysis via N(2) adsorption are used to characterize the resulting samples. In addition, the TiO(2) nanotubes in powder form are taken as photocatalysts to explore their potential applications. Results indicate that the sample after 35 h of hot water treatment shows the highest photoactivity, which is as efficient as the commercial photocatalyst Degussa P25. The photocatalytic testing results demonstrate that the hot water treatment reported in this study can be an alternative approach to the conventional methods. PMID- 21675753 TI - Heterostructured bismuth molybdate composite: preparation and improved photocatalytic activity under visible-light irradiation. AB - A heterostructured photocatalyst containing the same Bi, Mo, and O elements (Bi(3.64)Mo(0.36)O(6.55)/Bi(2)MoO(6)) was realized by a facile hydrothermal method. The heterostructured composite was characterized by powder X-ray diffraction, selected-area electron diffraction, scanning electron microscopy, and high-resolution electron microscopy. The Bi(3.64)Mo(0.36)O(6.55)/Bi(2)MoO(6) composite exhibited notable enhanced photocatalytic activity compared to Bi(2)MoO(6) or Bi(3.64)Mo(0.36)O(6.55) in the photocatalytic degradation of rhodamine B and phenol under visible-light irradiation. More interestingly, it is found that the heterostructured composite could mineralize organic substances into CO(2) efficiently. This study offered a clue for the design of an efficient photocatalyst in the application of environmental treatment. PMID- 21675752 TI - Direct plant tissue analysis and imprint imaging by desorption electrospray ionization mass spectrometry. AB - The ambient mass spectrometry technique, desorption electrospray ionization mass spectrometry (DESI-MS), is applied for the rapid identification and spatially resolved relative quantification of chlorophyll degradation products in complex senescent plant tissue matrixes. Polyfunctionalized nonfluorescent chlorophyll catabolites (NCCs), the "final" products of the chlorophyll degradation pathway, are detected directly from leaf tissues within seconds and structurally characterized by tandem mass spectrometry (MS/MS) and reactive-DESI experiments performed in situ. The sensitivity of DESI-MS analysis of these compounds from degreening leaves is enhanced by the introduction of an imprinting technique. Porous polytetrafluoroethylene (PTFE) is used as a substrate for imprinting the leaves, resulting in increased signal intensities compared with those obtained from direct leaf tissue analysis. This imprinting technique is used further to perform two-dimensional (2D) imaging mass spectrometry by DESI, producing well resolved images of the spatial distribution of NCCs in senescent leaf tissues. PMID- 21675754 TI - Concise total synthesis of (-)-8-epigrosheimin. AB - A highly efficient route was developed to synthesize (-)-8-epigrosheimin in four steps from aldehyde 2 based on a substrate-controlled method. The key steps of the synthesis included (1) a stereo- and regioselective allylation addition, (2) an intramolecular translactonization, and (3) an aldehyde-ene cyclization. PMID- 21675755 TI - Stereocontrolled synthesis of alpha-amino-alpha'-alkoxy ketones by a copper catalyzed cross-coupling of peptidic thiol esters and alpha-alkoxyalkylstannanes. AB - A stereocontrolled synthesis of alpha-amino-alpha'-alkoxy ketones is described. This pH-neutral copper(I) thiophene-2-carboxylate (CuTC)-catalyzed cross-coupling of amino acid thiol esters and chiral nonracemic alpha-alkoxyalkylstannanes gives alpha-amino-alpha'-alkoxy ketones in good to excellent yields with complete retention of configuration at the alpha-amino- and alpha-alkoxy-substituted stereocenters. PMID- 21675757 TI - Electrodeposition of hierarchical ZnO nanorod-nanosheet structures and their applications in dye-sensitized solar cells. AB - We present a two-step electrochemical deposition process to synthesize hierarchical zinc oxide (ZnO) nanorod-nanosheet structures on indium tin oxide (ITO) substrate, which involves electrodeposition of ZnO nanosheet arrays on the conductive glass substrate, followed by electrochemical growth of secondary ZnO nanorods on the backbone of the primary ZnO nanosheets. The formation mechanism of the hierarchical nanostructure is discussed. It is demonstrated that annealing treatment of the primary nanosheets synthesized by the first-step deposition process plays a key role in synthesizing the hierarchical nanostructure. Photovoltaic properties of dye-sensitized solar cells (DSSCs) based on hierarchical ZnO nanostructures are investigated. The hierarchical ZnO nanorod nanosheet DSSC exhibits improved device performance compared to the DSSC constructed using photoelectrode of bare ZnO nanosheet arrays. The improvement can be attributed to the enhanced dye loading, which is caused by the enlargement of internal surface area within the nanostructure photoelectrode. Furthermore, we perform a parametric study to determine the optimum geometric dimensions of the hierarchical ZnO nanorod-nanosheet photoelectrode through adjusting the preparation conditions of the first- and second-step deposition process. By utilizing a hierarchical nanostructure photoelectrode with film thickness of about 7 MUm, the DSSC with an open-circuit voltage of 0.74 V and an overall power conversion efficiency of 3.12% is successfully obtained. PMID- 21675756 TI - Adsorption of lead(II) on O2-plasma-oxidized multiwalled carbon nanotubes: thermodynamics, kinetics, and desorption. AB - O(2)-plasma-oxidized multiwalled carbon nanotubes (po-MWCNTs) have been used as an adsorbent for adsorption of lead(II) in water. Scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and Raman spectroscopy measurements show that the bulk properties of MWCNTs were not changed after O(2) plasma oxidation. The adsorption capacity of MWCNTs for lead(II) was greatly enhanced after plasma oxidation mainly because of the introduction of oxygen containing functional groups onto the surface of MWCNTs. The removal of lead(II) by po-MWCNTs occurs rather quickly, and the adsorption kinetics can be well described by the pseudo-second-order model. The adsorption isotherm of lead(II) onto MWCNTs fits the Langmuir isotherm model. The adsorption of lead(II) onto MWCNTs is strongly dependent upon the pH values. X-ray photoelectron spectroscopy analysis shows that the adsorption mechanism is mainly due to the chemical interaction between lead(II) and the surface functional groups of po-MWCNTs. The thermodynamic parameters (DeltaH degrees , DeltaS degrees , and DeltaG degrees ) calculated from the adsorption isotherms suggest that the adsorption of lead(II) onto MWCNTs is endothermic and spontaneous. The regeneration performance shows that lead(II) can be easily regenerated from po-MWCNTs by altering the pH values of the solution. PMID- 21675758 TI - Triplet-triplet annihilation in a series of poly(p-phenylene) derivatives. AB - We have studied the temperature dependence of phosphorescence (Ph) and delayed fluorescence (DF) in two series of poly(p-phenylene) derivatives within a temperature range from 10 to 300 K under quasi-stationary conditions. One set of materials consists of the dimer, trimer, and polymer of ethylhexyl-substituted poly(fluorene) (PF2/6) and thus allows us to assess the effects of oligomer length. The second series addresses the influence of energetic disorder and conjugation length by being composed of the polymers alkoxy-substituted poly(p phenylene) (DOO-PPP), poly(indenofluorene) (PIF), and ladder-type poly(p phenylene) (MeLPPP). Under low light intensities, the DF features a maximum at a certain temperature T(max). For the dimer and trimer, the T(max) coincides with the temperature at which the phosphorescence has decayed to 1/2 of the value at 10 K, while T(max) shifts to lower temperature values along the series DOO-PPP, PIF, and MeLPPP and approaches T = 0 K for MeLPPP. By applying conventional kinetic equations we show that the occurrence of a maximum in the DF intensity is the consequence of generalized thermally activated triplet exciton transport toward quenching sites. We find the quenching rates at 0 K to be in the range of 1 s(-1) for the polymers, while they are more than an order of magnitude lower for the oligomers. PMID- 21675759 TI - Room temperature current injection polariton light emitting diode with a hybrid microcavity. AB - The strong light-matter interaction within a semiconductor high-Q microcavity has been used to produce half-matter/half-light quasiparticles, exciton-polaritons. The exciton-polaritons have very small effective mass and controllable energy momentum dispersion relation. These unique properties of polaritons provide the possibility to investigate the fundamental physics including solid-state cavity quantum electrodynamics, and dynamical Bose-Einstein condensates (BECs). Thus far the polariton BEC has been demonstrated using optical excitation. However, from a practical viewpoint, the current injection polariton devices operating at room temperature would be most desirable. Here we report the first realization of a current injection microcavity GaN exciton-polariton light emitting diode (LED) operating under room temperature. The exciton-polariton emission from the LED at photon energy 3.02 eV under strong coupling condition is confirmed through temperature-dependent and angle-resolved electroluminescence spectra. PMID- 21675760 TI - pH-Sensitive vesicles and rheological properties of PFLA/NaOH/H2O and PFLA/LiOH/H2O systems. AB - The formation of pH-sensitive vesicles and the rheological properties of the mixtures of perfluorolauric acid (PFLA) and its salts (PFL-Na and PFL-Li) neutralized via NaOH or LiOH were investigated in aqueous solution. When the right mixing ratios of the ionized to nonionzed PFLA molecules with a very high Krafft point are established, vesicles can spontaneously form at room temperature. The vesicles spontaneously formed in the PFLA/PFL-Na/H(2)O system with the rigid fluorocarbon chains were determined by atomic force microscopy images. Compared to those of hydrocarbon amphiphiles, these vesicle samples, which can be kept for 2 years at room temperature, are more stable. The phase transition from the vesicle phase to the lamellar lyotropic liquid crystal phase with the increase of pH was determined by freeze-fracture transmission electron microscopy images in the PFLA/PFL-Li/H(2)O system. The system of perfluoro fatty acid vesicles exhibits much more interesting rheological properties, compared to hydrocarbon fatty acid vesicles. The perfluoro fatty acid vesicle solutions display a much higher yield stress and viscoelastic properties, which depend on two factors: (i) the fluorinated alkyl chains of PFL(-), which are in the crystalline state at room temperature because of their rigid chains compared to analogous hydrocarbon chains, and (ii) the packing of the vesicles, which is very dense. This is the first time that pH-sensitive vesicles exhibiting birefringence were constructed through ionizing perfluoro fatty acid, which may direct primarily toward acquiring an understanding of the mechanism of vesicles depending on the right mixing ratios of the ionized to the nonionzed perfluoro fatty acid molecules with a very high Krafft point and secondarily to expand the development of fluorinated surfactants in both fundamental research and practical applications. PMID- 21675761 TI - Nongenetic reprogramming of a fungal highly reducing polyketide synthase. AB - The biosynthesis of the fungal metabolite tenellin from Beauveria bassiana CBS110.25 was investigated in the presence of the epigenetic modifiers 5 azacytidine and suberoyl bis-hydroxamic acid and under conditions where individual genes from the tenellin biosynthetic gene cluster were silenced. Numerous new compounds were synthesized, indicating that the normal predominant biosynthesis of tenellin is just one outcome out of a diverse array of possible products. The structures of the products reveal key clues about the programming selectivities of the tenellin polyketide synthase. PMID- 21675762 TI - Aggregation behavior of SDS/CTAB catanionic surfactant mixture in aqueous solution and at the air/water interface. AB - Herein, we report the aggregation behavior of catanionic mixtures of the anionic surfactant sodium dodecyl sulfate (SDS) and the cationic surfactant cetyltrimethylammonium bromide (CTAB) in solution and at the air/water interface obtained by the Langmuir-Blodgett (LB) technique. We employed Fourier transform infrared spectroscopy, in situ phase-contrast inverted microscopy, scanning electron microscopy, and atomic force microscopy to characterize the systems in solution, at the air/water interface, and in LB films. We found spherical vesicles at the SDS/CTAB ratio of 35/65 in aqueous solution and an ordered aggregated morphology called surface micelles at SDS/CTAB ratios of 35/65 to 65/35 at the air/water interface. Other mixtures (SDS/CTAB = 90/10, 10/90) were found to contain mostly disordered aggregated microstructures. An in situ time dependent study of surface micelle formation at the air/water interface showed micelle ripening through the fusion of smaller micelles. These micelles were successfully immobilized on a glass substrate by the LB technique. Overall, the study might find application in the fundamental science of the physical chemistry of surfactant systems, as well as in the preparation of drug delivery system. PMID- 21675763 TI - Integrated scanning Kelvin probe-scanning electrochemical microscope system: development and first applications. AB - The integration of a scanning Kelvin probe (SKP) and a scanning electrochemical microscope (SECM) into a single SKP-SECM setup, the concept of the proposed system, its technical realization, and first applications are presented and discussed in detail. A preloaded piezo actuator placed in a grounded stainless steel case was used as the driving mechanism for oscillation of a Pt disk electrode as conventionally used in SECM when the system was operated in the SKP mode. Thus, the same tip is recording the contact potential difference (CPD) during SKP scanning and is used as a working electrode for SECM imaging in the redox-competition mode (RC-SECM). The detection of the local CPD is established by amplification of the displacement current at an ultralow noise operational amplifier and its compensation by application of a variable backing potential (V(b)) in the external circuit. The control of the tip-to-sample distance is performed by applying an additional alternating voltage with a much lower frequency than the oscillation frequency of the Kelvin probe. The main advantage of the SKP-SECM system is that it allows constant distance measurements of the CPD in air under ambient conditions and in the redox-competition mode of the SECM in the electrolyte of choice over the same sample area without replacement of the sample or exchange of the working electrode. The performance of the system was evaluated using a test sample made by sputtering thin Pt and W films on an oxidized silicon wafer. The obtained values of the CPD correlate well with known data, and the electrochemical activity for oxygen reduction is as expected higher over Pt than W. PMID- 21675764 TI - Reductive transformation of birnessite by aqueous Mn(II). AB - Reaction of aqueous Mn(II) with hexagonal birnessite at pH 7.5 causes reductive transformation of birnessite into feitknechtite (beta-Mn(III)OOH) and manganite (gamma-Mn(III)OOH) through interfacial electron transfer from adsorbed Mn(II) to structural Mn(IV) atoms and arrangement of product Mn(III) into MnOOH, summarized by Mn(II) + Mn(IV)O(2) + 2 H(2)O -> 2 Mn(III)OOH + 2 H(+). Feitknechtite is the initial transformation product, and subsequently converted into the more stable manganite polymorph during ongoing reaction with Mn(II). Feitknechtite production is observed at Mn(II) concentrations 2 orders of magnitude below thermodynamic thresholds, reflecting uncertainty in thermodynamic data of Mn-oxide minerals and/or specific interactions between Mn(II) and birnessite surface sites facilitating electron exchange. Under oxic conditions, feitknechtite formation through surface-catalyzed oxidation of Mn(II) by O(2) leads to additional Mn(II) removal from solution relative to anoxic systems. These results indicate that Mn(II) may be an important moderator of the reductive arm of Mn-oxide redox cycling, and suggest a controlling role of Mn(II) in regulating the solubility and speciation of phyllomanganate-reactive metal pollutants including Co, Ni, As, and Cr in geochemical environments. PMID- 21675765 TI - Two-dimensional solvent-mediated phase transformation in lipid membranes induced by sphingomyelinase. AB - The spatial pattern changes in model raft membranes during sphingomyelinase (SMase)-induced solvent-mediated phase transformation are characterized in terms of a model that combines three major kinetic processes suggested by experimental observations: the release of sphingomyelin (SM) by the dissolution of SM-enriched domains within the raft membrane, the diffusion of SM from the dissolution sites to the reaction site in a solvent-like fluid lipid phase, and the consumption of SM by the enzymatic reaction at this reaction site, termed an SMase feature. Such processes may be responsible for the control of morphological changes in cell membrane organization, which are suggested to influence the signal transduction through the cell membrane walls. The model predictions are shown to be consistent with our previously reported experimental results. We numerically evaluated the range of possible scenarios of spatial pattern change and provide analytical expressions for SM-domain-area change rates and total dissolution times for several limiting cases. The model results suggest that it may be possible to tune the pattern changes by adjusting the relative importance of each of the three kinetic processes, which can be discriminated through experimentally measurable time-dependent SM concentration distributions or SM-domain-area variations with time. PMID- 21675766 TI - Direct C-H arylation of purine on solid phase and its use for chemical libraries synthesis. AB - C(8)-H direct arylation of purine derivatives immobilized on Wang resin is described. The purine skeleton was immobilized via C(6)-regioselective substitution of 2,6-dichloropurine with polymer-supported amines. After N(9) alkylation with two different alkyl iodides and C(2) substitution with two selected amines, reaction conditions for C(8)-H arylation were developed and optimized. Various aryl bromides and aryl iodides were used for the reaction affording the target 2,6,8,9-tetrasubstituted purines in very good purity. The same reaction conditions were also applied for the synthesis of 2,6,8 trisubstituted purines, however, yields were lower. The methodology is applicable for high throughput synthesis of chemical libraries comprised of purine scaffold. PMID- 21675767 TI - The next chapter in MOF pillaring strategies: trigonal heterofunctional ligands to access targeted high-connected three dimensional nets, isoreticular platforms. AB - A new pillaring strategy, based on a ligand-to-axial approach that combines the two previous common techniques, axial-to-axial and ligand-to-ligand, and permits design, access, and construction of higher dimensional MOFs, is introduced and validated. Trigonal heterofunctional ligands, in this case isophthalic acid cores functionalized at the 5-position with N-donor (e.g., pyridyl- or triazolyl-type) moieties, are designed and utilized to pillar pretargeted two-dimensional layers (supermolecular building layers, SBLs). These SBLs, based on edge transitive Kagome and square lattices, are cross-linked into predicted three-dimensional MOFs with tunable large cavities, resulting in isoreticular platforms. PMID- 21675768 TI - Raman and photocurrent imaging of electrical stress-induced p-n junctions in graphene. AB - Electrostatically doped graphene p-n junctions can be formed by applying large source-drain and source-gate biases to a graphene field-effect transistor, which results in trapped charges in part of the channel gate oxide. We measure the temperature distribution in situ during the electrical stress and characterize the resulting p-n junctions by Raman spectroscopy and photocurrent microscopy. Doping levels, the size of the doped graphene segments, and the abruptness of the p-n junctions are all extracted. Additional voltage probes can limit the length of the doped segments by acting as heat sinks. The spatial location of the identified potential steps coincides with the position where a photocurrent is generated, confirming the creation of p-n junctions. PMID- 21675769 TI - From single to multiple Ag-layer modification of Au nanocavity substrates: a tunable probe of the chemical surface-enhanced Raman scattering mechanism. AB - We present experimental and computational results that enlighten the mechanisms underlying the chemical contribution to surface-enhanced Raman scattering (SERS). Gold void metallic arrays electrochemically covered either by a Ag monolayer or 10-100 Ag layers were modified with a self-assembled monolayer of 4 mercaptopyridine as a molecular Raman probe displaying a rich and unexpected Raman response. A resonant increase of the Raman intensity in the red part of the spectrum is observed that cannot be related to plasmon excitations of the cavity array. Notably, we find an additional 10-20 time increase of the SERS amplification upon deposition of a single Ag layer on the Au substrate, which is, however, almost quenched upon deposition of 10 atomic layers. Further deposition of 100 atomic Ag layers results in a new increase of the SERS signal, consistent with the improved plasmonic efficiency of Ag bulk-like structures. The SERS response as a function of the Ag layer thickness is analyzed in terms of ab initio calculations and a microscopic model for the SERS chemical mechanism based on a resonant charge transfer process between the molecular HOMO state and the Fermi level in the metal surface. We find that a rearrangement of the electronic charge density related to the presence of the Ag monolayer in the Au/Ag/molecule complex causes an increase in the distance between the HOMO center of charge and the metallic image plane that is responsible for the variation of Raman enhancement between the studied substrates. Our results provide a general platform for studying the chemical contribution to SERS, and for enhancing the Raman efficiency of tailored Au-SERS templates through electrochemical modification with Ag films. PMID- 21675771 TI - Soil and glass surface photodegradation of etofenprox under simulated california rice growing conditions. AB - Photolysis is an important degradation process to consider when evaluating a pesticide's persistence in a rice field environment. To simulate both nonflooded and flooded California rice field conditions, the photolytic degradation of etofenprox, an ether pyrethroid, was characterized on an air-dried rice soil and a flooded rice soil surface by determination of its half-life (t(1/2)), dissipation rate constant (k) and identification and quantitation of degradation products using LC/MS/MS. Photodegradation was also characterized on a glass surface alone to rule out confounding soil factors. Measured photolytic dissipation rates were used as input parameters into a multimedia environmental fate model to predict etofenprox persistence in a rice field environment. Photolytic degradation proceeded at a faster rate (0.23/day, t(1/2) = 3.0 days) on the flooded soil surface compared to the air-dried surface (0.039/day, t(1/2) = 18 days). Etofenprox degradation occurred relatively quickly on the glass surface (3.1/day, t(1/2) = 0.23 days or 5.5 h) compared to both flooded and air dried soil layers. Oxidation of the ether moiety to the ester was the major product on all surfaces (max % yield range = 0.2 +/- 0.1% to 9.3 +/- 2.3%). The hydroxylation product at the 4' position of the phenoxy phenyl ring was detected on all surfaces (max % yield range = 0.2 +/- 0.1% to 4.1 +/- 1.0%). The air-dried soil surface did not contain detectable residues of the ester cleavage product, whereas it was quantitated on the flooded soil (max % yield = 0.6 +/- 0.3%) and glass surface (max % yield = 3.6 +/- 0.6%). Dissipation of the insecticide in dark controls was significantly different (p < 0.05) compared to the light exposed surfaces indicating that degradation was by photolysis. Laboratory studies and fate model predictions suggest photolysis will be an important process in the overall degradation of etofenprox in a rice field environment. PMID- 21675770 TI - Quantum mechanical investigation of the effect of catalyst fluorination in the intermolecular asymmetric Stetter reaction. AB - The asymmetric intermolecular Stetter reaction was investigated using the B3LYP and M06-2X functionals. Fluorination of a triazolium bicyclic catalyst had been found to significantly influence reaction yields and enantiomeric ratios. Computations indicate that the improved reactivity of the fluorinated catalyst is due to better electrostatic interactions between the nitroalkene and catalyst. Computational investigations of preferred conformations of the ground state catalyst and acyl anion equivalent, and the transition structures leading to both enantiomers of the products, are reported. PMID- 21675772 TI - Effects of bonding types and functional groups on CO2 capture using novel multiphase systems of liquid-like nanoparticle organic hybrid materials. AB - Novel liquid-like nanoparticle organic hybrid materials (NOHMs) which possess unique features including negligible vapor pressure and a high degree of tunability were synthesized and their physical and chemical properties as well as CO(2) capture capacities were investigated. NOHMs can be classified based on the synthesis methods involving different bonding types, the existence of linkers, and the addition of task-specific functional groups including amines for CO(2) capture. As a canopy of polymeric chains was grafted onto the nanoparticle cores, the thermal stability of the resulting NOHMs was improved. In order to isolate the entropy effect during CO(2) capture, NOHMs were first prepared using polymers that do not contain functional groups with strong chemical affinity toward CO(2). However, it was found that even ether groups on the polymeric canopy contributed to CO(2) capture in NOHMs via Lewis acid-base interactions, although this effect was insignificant compared to the effect of task-specific functional groups such as amine. In all cases, a higher partial pressure of CO(2) was more favorable for CO(2) capture, while a higher temperature caused an adverse effect. Multicyclic CO(2) capture tests confirmed superior recyclability of NOHMs and NOHMs also showed a higher selectivity toward CO(2) over N(2)O, O(2) and N(2). PMID- 21675773 TI - Rules for anionic and radical ring closure of alkynes. AB - This work reexamined the stereoelectronic basis for the "favored attack trajectories" regarding the nucleophilic and radical cyclizations of alkynes. In contrast to the original Baldwin rules, the acute attack angle of a nucleophile leading to the proposed endo-dig preference for the formation of small cycles is less favorable stereoelectronically than the alternative obtuse trajectory leading to the formation of exo-dig products. For smaller cycles, this intrinsic stereoelectronic preference can be masked by the greater thermodynamic stability of the less strained endo-products. Unbiased comparison of competing cyclization attacks has been accomplished via dissection of the activation barrier into the intrinsic barrier and thermodynamic component via Marcus theory. Intrinsic barriers of thermoneutral reactions strongly favor exo-dig closures, in full accord with the greater magnitude of two-electron bond forming interactions for the obtuse trajectory. This analysis agrees very well with experimental observations of efficient 3-exo-dig and 4-exo-dig cyclizations predicted to be unfavorable by the Baldwin rules and with the calculated 3-exo-/4-endo-, 4-exo-/5 endo-, and 5-exo-/6-endo-dig selectivities in the cyclizations of carbon-, nitrogen-, and oxygen-centered nucleophiles. The generality of these predictions is confirmed by analogous trends for the related radical cyclizations where the stereoelectronically favorable exo-closures are also preferred kinetically, with a few exceptions where a large difference in product stability skews the intrinsic stereoelectronic trends. PMID- 21675774 TI - Palladium-catalyzed coupling of haloalkynes with allyl acetate: a regio- and stereoselective synthesis of (Z)-beta-haloenol acetates. AB - A Pd-catalyzed coupling of haloalkynes with allyl acetate has been reported, providing a convenient method for the stereoselective synthesis of (Z)-beta haloenol acetates in good yields. The synthetic utility of this method is demonstrated by the formation of functionalized enol acetates via the Suzuki Miyaura or Sonogashira coupling of the resulting (Z)-beta-haloenol acetate products. PMID- 21675775 TI - Synthesis of quinazolin-4(3H)-ones via Pd(II)-catalyzed intramolecular C(sp2)-H carboxamidation of N-arylamidines. AB - An efficient synthesis of quinazolin-4(3H)-ones from N-arylamidines, through palladium-catalyzed intramolecular C(sp(2))-H carboxamidation, has been developed. The reaction, carried out in the presence of 1.0 equiv of CuO as oxidant under atmospheric pressure of CO, provides diversified 2 aryl(alkyl)quinazolin-4(3H)-ones in reasonable to good yields from N arylamidines, which are readily derived from anilines and nitriles. Compared with existing approaches to quinazolin-4(3H)-ones, the current strategy features atom economy and step-efficiency. PMID- 21675776 TI - Development of endocannabinoid-based chemical probes for the study of cannabinoid receptors. AB - We report the synthesis of new chemical probes (1a,b, 2a-c, 3a-c) based on the structure of the main endocannabinoids for their use in biological systems directly or via click chemistry. As proof of concept, 2-arachidonyl glyceryl ether based biotinylated 3b enables direct visualization of CB(1) receptor in cells. These results represent the starting point for the development of advanced small molecule chemical probes able to generate valuable information about the cannabinoid receptors. PMID- 21675778 TI - Theoretical treatment of redox processes involving lanthanide(II) compounds: reactivity of organosamarium(II) and organothulium(II) complexes with CO2 and pyridine. AB - An effective methodology to deal with the theoretical treatment on the redox chemistry of divalent organolanthanide complexes is reported and has been tested on two representative substrates, pyridine and CO(2), with two different metals (samarium and thulium). An influence of the ancillary ligands, namely, C(5)Me(5) (Cp*) or (2,3,4,5-tetramethylphospholyl) (Tmp), on the one- or two-electron oxidation processes is observed. The theoretical results are in excellent agreement with the experimental observations indicating the efficiency of the method. PMID- 21675777 TI - New 2-heterocyclyl-imidazo[2,1-i]purin-5-one derivatives as potent and selective human A3 adenosine receptor antagonists. AB - A series of 4-allyl/benzyl-7,8-dihydro-8-methyl/ethyl-2 [(substituted)isoxazol/pyrazol-3/5-yl]-1H-imidazo[2,1-i]purin-5(4H)-ones has been synthesized and evaluated in radioligand binding assays to determine their affinities at the human A(1), A(2A), and A(3) adenosine receptors. Efficacy at the hA(2B) AR and antagonism of selected ligands at the hA(3) AR were also assessed through cAMP experiments. All of the synthesized molecules exhibited high affinity at the hA(3) AR (K(i) values ranging from 1.46 to 44.8 nM), as well as remarkable selectivity versus A(1), A(2A), and A(2B) AR subtypes. Compound (R) 4-allyl-8-ethyl-7,8-dihydro-2-(3-methoxy-1-methyl-1H-pyrazol-5-yl)-1H-imidazo[2,1 i]purin-5(4H)-one (R-33) was found to be the most potent and selective ligand of the series (K(i) hA(3) = 1.46 nM, K(i) hA(2A)/K(i) hA(3) > 3425; IC(50) hA(2B)/K(i) hA(3) > 3425; K(i) hA(1)/K(i) hA(3) = 1729). Molecular modeling studies were helpful in rationalizing the available structure-activity relationships along with the selectivity profiles of the new series of ligands. PMID- 21675779 TI - kT-scale colloidal interactions in high frequency inhomogeneous AC electric fields. I. Single particles. AB - We report nonintrusive optical microscopy measurements of single micrometer-sized silica and polystyrene colloids in inhomogeneous AC electric fields as a function of field amplitude and frequency. By using a Boltzmann inversion of the time averaged sampling of single particles within inhomogeneous electric fields, we sensitively measure induced dipole-field interactions on the kT energy scale and fN force scale. Measurements are reported for frequencies when the particle polarizability is greater and less than the medium, as well as the crossover between these conditions when dipole-field interactions vanish. For all cases, the measured interactions are well-described by theoretical potentials by fitting a nondimensional induced dipole-field magnitude. While silica dipole-field magnitudes are well-described by existing electrokinetic models, the polystyrene results suggest an anomalously high surface conductance. Sensitive measurements of dipole-field interactions in this work provide a basis to understand dipole dipole interactions in particle ensembles in the same measurement geometry in part II. PMID- 21675780 TI - kT-scale colloidal interactions in high-frequency inhomogeneous AC electric fields. II. Concentrated ensembles. AB - We report nonintrusive optical microscopy measurements of ensembles of polystyrene colloids in inhomogeneous AC electric fields as a function of field frequency and particle size. By using an inverse Monte Carlo (MC) simulation analysis of time-averaged particle microstructures, we sensitively measure induced dipole-dipole interactions on the kT energy scale. Measurements are reported for frequencies when the particle polarizability is greater and less than the medium, as well as the crossover between these conditions when dipole dipole interactions vanish. By using measured single dipole-field interactions and associated parameters from Part I as input in the inverse analysis, the dipole-dipole interactions in this work are accurately modeled with no adjustable parameters for conditions away from the crossover frequency (i.e., |f(CM)| > 0). As dipolar interactions vanish at the crossover, a single frequency-dependent parameter is introduced to account for microstructures that appear to result from weak AC electro-osmotic flow induced interactions. By connecting quantitative measures of equilibrium microstructures and kT-scale dipole-field and dipole dipole interactions, our findings provide a basis to understand colloidal assembly in inhomogeneous AC electric fields. PMID- 21675781 TI - Imaging mass spectrometry provides fingerprints for distinguishing hepatocellular carcinoma from cirrhosis. AB - MALDI imaging mass spectrometry (MALDI IMS) is a powerful tool for comprehending the spectrum of peptides/proteins expressed in tissue sections. The aim of the present study was to investigate, using MALDI IMS, the proteome of hepatocellular carcinomas (HCC) and to compare it with peritumoral cirrhosis so as to characterize new biomarkers of HCC. Frozen liver tissues corresponding to HCC and background cirrhosis (n = 30) were selected and subjected to MALDI IMS. We found a set of proteins/peptides with a differential intensity level that most accurately delineated cancer from adjacent cirrhotic tissue. Using a support vector machine algorithm, we generated a classification model in the train set that enabled segmenting images from the independent validation set and that in most cases matched histologic analysis. The most discriminating peak (m/z 8565) more intense in HCC was characterized as the monomeric ubiquitin. An immunohistochemical study in a large series of HCC/cirrhosis sampled on tissue microarray supported that ubiquitin was overexpressed in HCC. We demonstrated also that this increase was not related to an upregulation of ubiquitin gene transcription in HCC, thus suggesting a post-transcriptional mechanism. This approach might provide a new tool for diagnosis of difficult HCC cases and an opportunity for identifying candidate biomarkers. PMID- 21675782 TI - Excitation migration, quenching, and regulation of photosynthetic light harvesting in photosystem II. AB - Excitation energy transfer and quenching in LHCII aggregates is considered in terms of a coarse-grained model. The model assumes that the excitation energy transfer within a pigment-protein complex is much faster than the intercomplex excitation energy transfer, whereas the quenching ability is attributed to a specific pigment-protein complex responsible for the nonphotochemical quenching (NPQ). It is demonstrated that the pump-probe experimental data obtained at low excitation intensities for LHCII aggregates under NPQ conditions can be equally well explained at two limiting cases, either describing the excitation kinetics in the migration-limited or in the trap-limited regime. Thus, it is concluded that low excitation conditions do not allow one to unambiguously define the relationship between the mean times of excitation migration and trapping. However, this could be achieved by using high excitation conditions when exciton exciton annihilation is dominant. In this case it was found that in the trap limited regime the excitation kinetics in the aggregate should be almost insensitive to the excitation density, meaning that singlet-singlet annihilation has little effect on the NPQ decay kinetics, whereas in the migration-limited case there is a clear intensity dependence. In order to account for the random distribution of the NPQ-traps within the LHCII aggregates, excitation diffusion in a continuous medium with random static traps was considered. This description demonstrates a very good correspondence to the experimental fluorescence kinetics assuming a lamellar (quasi-3D) structure of the antenna characterized by the dimension d=2.4 and therefore justifying the diffusion-limited approach on which the model is based. Using the coarse-grained model to describe the aggregate we estimate one NPQ-trap per 100 monomeric LHCII complexes. Finally we discuss the origin of the traps responsible for excitation quenching under NPQ conditions. PMID- 21675783 TI - Ion specific effects on the structure of molten AF-ZrF4 systems (A+ = Li+, Na+, and K+). AB - The structure of AF-ZrF(4) system (A(+) = Li(+), Na(+), K(+)) compounds in the liquid state is studied using an approach combining EXAFS spectroscopy with molecular dynamics simulations. A very good agreement is observed between the two techniques, which allows us to propose a quantitative description of the liquids. From the Zr(4+) solvation shell point of view, we observe a progressive stabilization of the 7-fold and then of the 6-fold coordinated complexes when passing from Li(+) to Na(+) and K(+) as a "counterion". Particular attention is given to the systems consisting of 35 mol % of ZrF(4). At that particular composition, the ZrF(6)(2-) complex predominates largely whatever the nature of the alkali. The calculated vibrational properties of this complex are in excellent agreement with a previous Raman spectroscopy experiment on molten KF ZrF(4). The most important differences are observed for the lifetime of these octahedral units, which increases importantly with the size of the monovalent cation. On a larger scale, an intense first sharp diffraction peak is observed for the Zr(4+)-Zr(4+) partial structure factor, which can be attributed to the correlations between the octahedral units formed. PMID- 21675786 TI - An exact stoichiometric representation of the resonance energy. AB - The energetic measure of aromaticity usually referred to as resonance energy (RE) is shown to possess a remarkable stoichiometric interpretation. Namely, the RE may be uniquely partitioned into a linear sum of contributions associated with group additivity (GA) response reactions (RERs). This new result is a powerful tool for critical analyses of various energetic approaches to RE. In particular, the single reaction scheme approach that is routinely used to evaluate RE is shown to be a particular case of the general GA method. PMID- 21675787 TI - Comparison of the photochemical behaviors of alpha-tocopherol and its acetate in organic and aqueous micellar solutions. AB - Photoionization is known to take place when alpha-tocopherol (TOH) is excited to the S(1) state in a polar medium. It has been previously suggested that TO(*) is formed only as a result of proton release by TOH(*+), a process that is expected to occur, in a protic solvent, on the subnanosecond time scale. Recent redeterminations of the molar absorption coefficients of e(aq)(-) (Hare J. Phys. Chem. A 2010, 114, 1766) and of TOH(*+) and TO(*) (Naqvi J. Phys. Chem. A 2010, 114, 10795) have paved the way for testing the above suggestion, even if subnanosecond time resolution is not available, since it implies the equality of [e(aq)(-)](0) and [TO(*)](0), where [...](0) denotes the concentration of the enclosed species immediately after a nanosecond laser pulse. Nanosecond pump probe spectroscopy of TOH in aqueous micellar solution (AMS) and two organic solvents with similar polarities (acetonitrile and methanol) has revealed that prompt formation of TO(*) through dissociation (TOH + hnu -> TO(*) + H(*)) is not negligible even in AMS. In acetonitrile, TOH(*+) and TO(*) are formed with comparable yields, and the former converts quantitatively into TO(*) within 15 MUs. In methanol, TO(*) was observed, but no evidence was found for electron ejection from TOH. Only one photoproduct, namely TO(*), could be detected when alpha-tocopherol acetate (TOAc) was excited to the S(1) state in several polar and nonpolar solvents; TOAc has been found to be a more efficient energy degrader than TOH. PMID- 21675788 TI - Enhancement of blood compatibility of poly(urethane) substrates by mussel inspired adhesive heparin coating. AB - Heparin immobilization on surfaces has drawn a great deal of attention because of its potential application in enhancing blood compatibility of various biomedical devices such as catheters, grafts, and stents. Existing methods for the heparin immobilization are based on covalent linkage formation and electrostatic interaction between substrates and heparin molecules. However, complicated multistep procedures and uncontrolled desorption of heparin are limitations of these methods. In this work, we report a new heparin derivative that exhibits robust adhesion on surfaces. The derivative, called hepamine, was prepared via conjugation of dopamine, a mussel-inspired adhesive moiety, onto a heparin backbone. Immersion of poly(urethane) substrates into an aqueous solution of hepamine resulted in robust heparin coating of the poly(urethane), the most widely used polymeric material for blood-contacting medical devices. The hepamine coated poly(urethane) substrate showed significant inhibition of blood coagulation and platelet adhesion. The use of hepamine for surface modification is advantageous for several reasons: for example, no chemical pretreatment of the substrates is necessary, and surface functionalization is a simple, one-step procedure. Thus, the heparin immobilization method described herein is an excellent alternative approach for the introduction of heparin molecules onto surfaces. PMID- 21675789 TI - A mixed quantum-classical molecular dynamics study of the hydroxyl stretch in methanol/carbon tetrachloride mixtures: equilibrium hydrogen-bond structure and dynamics at the ground state and the infrared absorption spectrum. AB - We present a mixed quantum-classical molecular dynamics study of the structure and dynamics of the hydroxyl stretch in methanol/carbon tetrachloride mixtures. One of the methanol molecules is tagged, and its hydroxyl stretch is treated quantum-mechanically, while the remaining degrees of freedom are treated classically. The adiabatic Hamiltonian of the quantum-mechanical hydroxyl is diagonalized on-the-fly to obtain the corresponding adiabatic energy levels and wave functions which depend parametrically on the instantaneous configuration of the classical degrees of freedom. The dynamics of the classical degrees of freedom are in turn affected by the quantum-mechanical state of the tagged hydroxyl stretch via the corresponding Hellmann-Feynman forces. The ability of five different force-field combinations to reproduce the experimental absorption infrared spectrum of the hydroxyl stretch is examined for different isotopomers and on a wide range of compositions. It is found that, in addition to accounting for the anharmonic nature of the hydroxyl stretch, one also has to employ polarizable force fields and account for the damping of the polarizability at short distances. The equilibrium ground-state hydrogen-bonding structure and dynamics is analyzed, and its signature on the absorption infrared spectrum of the hydroxyl stretch is investigated in detail. Five different hydroxyl stretch subpopulations are identified and spectrally assigned: monomers (alpha), hydrogen bond acceptors (beta), hydrogen-bond donors (gamma), simultaneous hydrogen-bond donors and acceptors (delta), and simultaneous hydrogen-bond donors and double acceptors (epsilon). The fundamental transition frequencies of the alpha and beta subpopulations are found to be narrowly distributed and to overlap, thereby giving rise to a single narrow band whose intensity is significantly diminished by rotational relaxation. The fundamental transition frequency distributions of the gamma, delta, and epsilon subpopulations are found to be broader and to partially overlap, thereby giving rise to a single broad band which is red shifted relative to the alphabeta band. The gammadeltaepsilon band is also found to be inhomogeneously broadened and unaffected by rotational relaxation. The exchange rates between the different subpopulations and corresponding branching ratios are reported and explained. Finally, nonlinear mapping relations between the hydroxyl transition frequency and bond length and the electric field along the hydroxyl bond axis are established, which can be used to reduce the computational cost of the mixed quantum-classical treatment to that of a purely classical molecular dynamics simulation. PMID- 21675790 TI - Combination of diffusive gradient in a thin film probe and IC-ICP-MS for the simultaneous determination of CH3Hg+ and Hg2+ in oxic water. AB - A diffusive gradient in thin film technique (DGT) was combined with ion chromatography and inductively coupled plasma mass spectrometry (IC-ICP-MS) for the in situ simultaneous quantification of CH(3)Hg(+) and Hg(2+) in aquatic environments. After diffusing through an agarose diffusive layer, the Hg species accumulated in a thiol-functionalized resin layer and were extracted using acidic thiourea solution to form stable thiourea-Hg complexes that were separated and detected via ion chromatography and ICP-MS, respectively. The effective diffusion coefficients of CH(3)Hg(+) and Hg(2+) complexes in the agarose diffusion layer with chloride were 5.26 (+/-0.27) * 10(-6) and 4.02 (+/-0.10) * 10(-6) cm(2) s( 1), respectively. The effective diffusion coefficients of CH(3)Hg(+) and Hg(2+) complexes in the agarose diffusion layer with dissolved organic matter was 3.57 (+/-0.29) * 10(-6) and 2.16 (+/-0.19) * 10(-6) cm(2) s(-1), respectively. The practical method detection limits are 0.1 and 0.7 ng L(-1) for CH(3)Hg(+) and Hg(2+) respectively for three weeks deployment. Lower detection limits would be possible by employing a thinner agarose diffusive layer and/or by deploying the probes longer. The method can measure time averaged CH(3)Hg(+) and Hg(2+) concentrations simultaneously in oxic water, making it useful as an in situ monitoring tool. PMID- 21675791 TI - Single-particle characterization of summertime Antarctic aerosols collected at King George Island using quantitative energy-dispersive electron probe X-ray microanalysis and attenuated total reflection Fourier transform-infrared imaging techniques. AB - Single-particle characterization of Antarctic aerosols was performed to investigate the impact of marine biogenic sulfur species on the chemical compositions of sea-salt aerosols in the polar atmosphere. Quantitative energy dispersive electron probe X-ray microanalysis was used to characterize 2900 individual particles in 10 sets of aerosol samples collected between March 12 and 16, 2009 at King Sejong Station, a Korean scientific research station located at King George Island in the Antarctic. Two size modes of particles, i.e., PM(2.5 10) and PM(1.0-2.5), were analyzed, and four types of particles were identified, with sulfur-containing sea-salt particles being the most abundant, followed by genuine sea-salt particles without sulfur species, iron-containing particles, and other species including CaCO(3)/CaMg(CO(3))(2), organic carbon, and aluminosilicates. When a sulfur-containing sea-salt particle showed an atomic concentration ratio of sulfur to sodium of >0.083 (seawater ratio), it is regarded as containing nonsea-salt sulfate (nss-SO(4)(2-)) and/or methanesulfonate (CH(3)SO(3)(-)), which was supported by attenuated total reflection Fourier transform-infrared imaging measurements. These internal mixture particles of sea-salt/CH(3)SO(3)(-)/SO(4)(2-) were very frequently encountered. As nitrate-containing particles were not encountered, and the air masses for all of the samples originated from the Pacific Ocean (based on 5-day backward trajectories), the oxidation of dimethylsulfide (DMS) emitted from phytoplanktons in the ocean is most likely to be responsible for the formation of the mixed sea-salt/CH(3)SO(3)(-)/SO(4)(2-) particles. PMID- 21675792 TI - Nanocrystals composed of alternating shells of Pd and Pt can be obtained by sequentially adding different precursors. AB - This paper describes a layer-by-layer epitaxial approach to the synthesis of multishelled nanocrystals composed of alternating shells of Pd and Pt by starting with seeds made of Pd or Pt nanocrystals. The synthesis was conducted by sequentially adding PtCl(4)(2-) and PdCl(4)(2-) salt precursors into a system containing either Pd or Pt seeds (in the shape of cuboctahedrons, octahedrons, plates, or cubes) together with a weak reducing agent such as citric acid (CA). The slow reduction kinetics associated with CA played an important role in the epitaxial growth of one metal on the other, resulting in the formation of Pd-Pt multishelled nanocrystals. Owing to the capping effect of CA for {111} facets of Pd and Pt, the multishelled nanocrystals tended to be enclosed by {111} facets in the form of octahedrons or thin plates, depending on the shapes of the Pd or Pt seeds: octahedrons for cuboctahedral, cubic, or octahedral seeds, and plates for platelike seeds. PMID- 21675793 TI - Fluorescent liposomes for differential interactions with glycosaminoglycans. AB - We have successfully synthesized a lipid containing the pyranine dye as the hydrophilic headgroup. This lipid was incorporated into liposomes with 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine as the major component. The resultant liposomes displayed differential modulations in fluorescence emission intensity in the presence of nanomolar concentrations of different glycosaminoglycans. Linear discriminant analysis of the fluorescence response data demonstrate that the liposomes are able to distinguish between different GAGs. In addition, we also demonstrate that the liposomes incorporating the pyranine lipid are able to distinguish between dilute serum from healthy individuals and serum containing elevated chondroitin sulfate (simulated serum from an Alzheimer's disease patient). PMID- 21675795 TI - Polymer nanogels grafted from nanopatterned surfaces studied by AFM force spectroscopy. AB - Nanopatterned cross-linked polymers are important for applications with controlled mechanical properties. Grafted linear and cross-linked polydimethylacrylamide gels on micro- and nanopatterns were created using iniferter-driven quasi-living radical polymerization combined with conventional photolithography and nanosphere lithography. Micropatterned linear polymers reproduce the expected scaling behavior at moderate grafting density. The addition of cross-linker to the polymerization solution leads to an increased tendency of early termination as determined by AFM force spectroscopy. Similarly, nanopatterned linear polymers show reduced thickness in agreement with the expected scaling relationship for nanoisland grafts that have reduced lateral confinement. The addition of cross-linker reintroduces some of the lateral confinement for the length of polymers reported here. The mechanical properties of both the micro- and nanopatterned linear as well as cross-linked polymers were analyzed using an algorithm to objectively determine the contact point in AFM force spectroscopy and two independent Hertz-based analysis approaches. The obtained Young's moduli are close to those expected for homogeneous thick polymer films and are independent of pattern size. Our results demonstrate that polymeric nanopillars with controlled elastic modulus can be fabricated using irreversible cross-linkers. They also highlight some of the factors that must be considered for successful fabrication of grafted nanopillars of defined mechanical and structural properties. PMID- 21675794 TI - Extracellular disulfide bonds support scavenger receptor class B type I-mediated cholesterol transport. AB - Scavenger receptor class B type I (SR-BI) binds high-density lipoprotein (HDL) and mediates the selective uptake of cholesteryl esters (CE). Although the extracellular domain of SR-BI is critical for function, the structural characteristics of this region remain elusive. Using sulfhydryl labeling strategies, we report the novel finding that all six cysteine (Cys) residues in the extracellular domain of SR-BI are involved in disulfide bond formation that is intramolecular by nature. We hypothesized that an SR-BI conformation stabilized by extracellular disulfide bonds is a prerequisite for SR-BI-mediated cholesterol transport. Thus, single-Cys mutant SR-BI receptors (C251S-, C280S-, C321S-, C323S-, C334S-, and C384S-SR-BI), as well as Cys-less SR-BI, a mutant SR BI receptor void of all Cys residues, were created, and plasma membrane localization was confirmed. Functional assays revealed that C280S-, C321S-, C323S , and C334S-SR-BI and Cys-less SR-BI mutant receptors displayed weakened HDL binding and subsequent selective uptake of HDL-CE. However, only C323S-SR-BI and Cys-less SR-BI were unable to mediate wild-type levels of efflux of free cholesterol (FC) to HDL. None of the Cys mutations disrupted SR-BI's ability to redistribute plasma membrane FC. Taken together, the intramolecular disulfide bonds in the extracellular domain of SR-BI appear to maintain the receptor in a conformation integral to its cholesterol transport functions. PMID- 21675796 TI - Dynamic adsorption and structure of interfacial bilayers adsorbed from lipopeptide surfactants at the hydrophilic silicon/water interface: effect of the headgroup length. AB - Lipopeptides are an important group of biosurfactants expressed by microorganisms. Because they are well-known for being biocompatible, biodegradable, and highly surface active, they are attractive for a wide range of applications. Natural lipopeptide surfactants are however impure; it is hence difficult to use them for exploring the structure-function relation. In this work, a series of cationic lipopeptide surfactants, C(14)K(n) (n = 1-4), where C denotes the myristic acyl chain and K denotes lysine (Lys), have been synthesized, and their interfacial behavior has been characterized by studying their adsorption at the silicon/water interface (bearing a thin native oxide layer) using spectroscopic ellipsometry and neutron reflection (NR). The dynamic adsorption was marked by an initial fast step within the first 2-3 min followed by a slow molecular relaxation process over the subsequent 20-30 min. The initial rate of time-dependent adsorption and the equilibrated adsorbed amount showed a steady decrease with increasing n, indicating the impact of the molecular size, structure, and charge. NR revealed the formation of sandwiched bilayers from C(14)K(n), similar to conventional surfactants such as nonionic C(12)E(6) and cationic C(16)TAB. However, the electrostatic attraction between K and the silica surface caused confinement of the K groups, forcing the head segments into a predominantly flat-on conformation. This characteristic structural feature was confirmed by the almost constant thickness of the headgroup regions ranging from 8 to 11 A as determined from NR combined with partial deuterium labeling to the acyl tail. An increase in area per molecular pair with n resulted directly from increasing the footprint. As a result, the hydrophobic back-to-back tail mixing and acyl chain tilting rose with n. The extent of chain-head intermixing became so intensified that the C(14)K(4) bilayer could be approximated to a uniform layer distribution. PMID- 21675797 TI - Surface nanobubbles as a function of gas type. AB - We experimentally investigate the nucleation of surface nanobubbles on PFDTS coated silicon as a function of the specific gas dissolved in water. In each case, we restrict ourselves to equilibrium conditions (c = 100%, T(liquid) = T(substrate)). Not only is nanobubble nucleation a strong function of gas type, but there also exists an optimal system temperature of ~35 -40 degrees C where nucleation is maximized, which is weakly dependent on gas type. We also find that the contact angle is a function of the nanobubble radius of curvature for all gas types investigated. Fitting this data allows us to describe a line tension that is dependent on the type of gas, indicating that the nanobubbles sit on top of adsorbed gas molecules. The average line tension was tau ~ -0.8 nN. PMID- 21675799 TI - Chiral ruthenabicyclic complexes: precatalysts for rapid, enantioselective, and wide-scope hydrogenation of ketones. AB - A novel ruthenabicyclic complex with base shows excellent catalytic activity in the asymmetric hydrogenation of ketones. The turnover frequency of the hydrogenation of acetophenone reaches about 35,000 min(-1) in the best case, affording 1-phenylethanol in >99% ee. Several aliphatic and base-labile ketones are smoothly converted to the corresponding alcohols in high enantioselectivity. The catalytic cycle for this hydrogenation, in which the ruthenabicyclic structure of the catalyst is maintained, is proposed on the basis of the deuteration experiment and spectroscopic analysis data. PMID- 21675800 TI - Rennet-induced aggregation of heated pH-adjusted skim milk. AB - Heated (20-100 degrees C/0-30 min) skim milks (pH 6.5-7.1) were diluted in buffer (pH 7.0). Rennet was added, and the particle size with time was measured. For all samples, the size initially decreased (lag phase) and then increased (aggregation phase). Milks heated at <=60 degrees C had short lag phases and rapid aggregation phases regardless of pH. Milks heated at >60 degrees C at pH 6.5 had long lag phases and slow aggregation phases. As the pH increased, the lag phase shortened and the aggregation phase accelerated. The aggregation time was correlated with the level of whey protein associated with the casein micelles and with the level of kappa-casein dissociated from the micelles. Heated milks formed weak gels when renneted. It is proposed that the milks heated at low pH have whey proteins associated with the casein micelles and that these denatured whey proteins stabilize the micelles to aggregation by rennet and therefore inhibit gelation. In the milks heated at higher pH, the whey proteins associate with kappa-casein in the serum and, on rennet treatment, the kappa-casein-depleted micelles and the serum-phase whey protein/kappa-casein complexes aggregate; however, the denatured whey proteins stabilize the aggregates so that gelation is still inhibited. PMID- 21675798 TI - 1,N2-Etheno-2'-deoxyguanosine adopts the syn conformation about the glycosyl bond when mismatched with deoxyadenosine. AB - The oligodeoxynucleotide 5'-CGCATXGAATCC-3'.5'-GGATTCAATGCG-3' containing 1,N(2) etheno-2'-deoxyguanosine (1,N(2)-epsilondG) opposite deoxyadenosine (named the 1,N(2)-epsilondG.dA duplex) models the mismatched adenine product associated with error-prone bypass of 1,N(2)-epsilondG by the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) and by Escherichia coli polymerases pol I exo(-) and pol II exo(-). At pH 5.2, the T(m) of this duplex was increased by 3 degrees C as compared to the duplex in which the 1,N(2)-epsilondG lesion is opposite dC, and it was increased by 2 degrees C compared to the duplex in which guanine is opposite dA (the dG.dA duplex). A strong NOE between the 1,N(2)-epsilondG imidazole proton and the anomeric proton of the attached deoxyribose, accompanied by strong NOEs to the minor groove A(20) H2 proton and the mismatched A(19) H2 proton from the complementary strand, establish that 1,N(2)-epsilondG rotated about the glycosyl bond from the anti to the syn conformation. The etheno moiety was placed into the major groove. This resulted in NOEs between the etheno protons and T(5) CH(3). A strong NOE between A(20) H2 and A(19) H2 protons established that A(19), opposite to 1,N(2)-epsilondG, adopted the anti conformation and was directed toward the helix. The downfield shifts of the A(19) amino protons suggested protonation of dA. Thus, the protonated 1,N(2) epsilondG.dA base pair was stabilized by hydrogen bonds between 1,N(2)-epsilondG N1 and A(19) N1H(+) and between 1,N(2)-epsilondG O(9) and A(19)N(6)H. The broad imino proton resonances for the 5'- and 3'-flanking bases suggested that both neighboring base pairs were perturbed. The increased stability of the 1,N(2) epsilondG.dA base pair, compared to that of the 1,N(2)-epsilondG.dC base pair, correlated with the mismatch adenine product observed during the bypass of 1,N(2) epsilondG by the Dpo4 polymerase, suggesting that stabilization of this mismatch may be significant with regard to the biological processing of 1,N(2)-epsilondG. PMID- 21675801 TI - Fenofibrate: a review of its lipid-modifying effects in dyslipidemia and its vascular effects in type 2 diabetes mellitus. AB - Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-alpha. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL C levels, and promoting a shift to larger low-density lipoprotein particles. In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline. In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy. Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms. In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels. PMID- 21675802 TI - A note on the replicator equation with explicit space and global regulation. AB - A replicator equation with explicit space and global regulation is considered. This model provides a natural framework to follow frequencies of species that are distributed in the space. For this model, analogues to classical notions of the Nash equilibrium and evolutionary stable state are provided. A sufficient condition for a uniform stationary state to be a spatially distributed evolutionary stable state is presented and illustrated with examples. PMID- 21675803 TI - A simple analysis of vaccination strategies for rubella. AB - We consider an SEIR epidemic model with vertical transmission introduced by Li, Smith and Wang, [23], and apply optimal control theory to assess the effects of vaccination strategies on the model dynamics. The strategy is chosen to minimize the total number of infectious individuals and the cost associated with vaccination. We derive the optimality system and solve it numerically. The theoretical findings are then used to simulate a vaccination campaign for rubella in China. PMID- 21675804 TI - A note for the global stability of a delay differential equation of hepatitis B virus infection. AB - The global stability for a delayed HIV-1 infection model is investigated. It is shown that the global dynamics of the system can be completely determined by the reproduction number, and the chronic infected equilibrium of the system is globally asymptotically stable whenever it exists. This improves the related results presented in [S. A. Gourley,Y. Kuang and J.D.Nagy, Dynamics of a delay differential equation model of hepatitis B virus infection, Journal of Biological Dynamics, 2(2008), 140-153]. PMID- 21675805 TI - Persistent high incidence of tuberculosis among immigrants in a low-incidence country: impact of immigrants with early or late latency. AB - Spread of tuberculosis (TB) due to the immigration from some developing countries with high TB incidence to developed countries poses an increasing challenge in the global TB control. Here a simple compartmental TB model with constant immigration, early and late latency is developed in order to investigate the impact of new immigrants with latent TB on the overall TB incidence, and to compare the difference contributed by different proportions of latently-infected new immigrants with high or low risk to develop active TB shortly after arrival. The global dynamics of the system is completely classified, numerical simulations are carried out for different scenarios, and potential applications to public health policy are discussed. PMID- 21675806 TI - Modeling the effects of carriers on transmission dynamics of infectious diseases. AB - An S-Ic-I-R epidemic model is investigated for infectious diseases that can be transmitted through carriers, infected individuals who are contagious but do not show any disease symptoms. Mathematical analysis is carried out that completely determines the global dynamics of the model. The impacts of disease carriers on the transmission dynamics are discussed through the basic reproduction number and through numerical simulations. PMID- 21675807 TI - Optimal nutritional intake for fetal growth. AB - The regular nutritional intake of an expectant mother clearly affects the weight development of the fetus. Assuming the growth of the fetus follows a deterministic growth law, like a logistic equation, albeit dependent on the nutritional intake, the ideal solution is usually determined by the birth-weight being pre-assigned, for example, as a percentage of the mother's average weight. This problem can then be specified as an optimal control problem with the daily intake as the control, which appears in a Michaelis-Menten relationship, for which there are well-developed procedures to follow. The best solution is determined by requiring minimum total intake under which the preassigned birth weight is reached. The algorithm has been generalized to the case where the fetal weight depends in a detailed way on the cumulative intake, suitably discounted according to the history. The optimality system is derived and then solved numerically using an iterative method for the specific values of parameter. The procedure is generic and can be adapted to any growth law and any parameterisation obtained by the detailed physiology. PMID- 21675808 TI - Stability analysis and application of a mathematical cholera model. AB - In this paper, we conduct a dynamical analysis of the deterministic cholera model proposed in [9]. We study the stability of both the disease-free and endemic equilibria so as to explore the complex epidemic and endemic dynamics of the disease. We demonstrate a real-world application of this model by investigating the recent cholera outbreak in Zimbabwe. Meanwhile, we present numerical simulation results to verify the analytical predictions. PMID- 21675809 TI - Malaria model with stage-structured mosquitoes. AB - A simple SEIR model for malaria transmission dynamics is formulated as our baseline model. The metamorphic stages in the mosquito population are then included and a simple stage-structured mosquito population model is introduced, where the mosquito population is divided into two classes, with all three aquatic stages in one class and all adults in the other class, to keep the model tractable in mathematical analysis. After a brief investigation of this simple stage-structured mosquito model, it is incorporated into the baseline model to formulate a stage-structured malaria model. A basic analysis for the stage structured malaria model is provided and it is shown that a theoretical framework can be built up for further studies on the impact of environmental or climate change on the malaria transmission. It is also shown that both the baseline and the stage-structured malaria models undergo backward bifurcations. PMID- 21675810 TI - Optimal number of sites in multi-site fisheries with fish stock dependent migrations. AB - We present a stock-effort dynamical model of a fishery subdivided into fishing zones. The stock corresponds to a fish population moving between these zones, on which they are harvested by fishing fleets. We consider a linear chain of identical fishing zones. Fish movements between the zones, as well as vessels displacements, are assumed to take place at a faster time scale than the variation of the stock and the change of the fleet size. The vessels movements between the fishing areas are assumed to be stock dependent, i.e. the larger the stock density is in a zone the more vessels tends to remain in it. We take advantage of these two time scales to derive a reduced model governing the dynamics of the total harvested stock and the total fishing effort. Under some assumption, we obtain either a stable equilibrium or a stable limit cycle which involves large cyclic variations of the total fish stock and fishing effort. We show that there exists an optimal number of fishing zones that maximizes the total catch at equilibrium. We discuss the results in relation to fish aggregating devices (FADs) fisheries. PMID- 21675811 TI - Numerical characterization of hemodynamics conditions near aortic valve after implantation of Left Ventricular Assist Device. AB - Left Ventricular Assist Devices (LVADs) are implantable mechanical pumps that temporarily aid the function of the left ventricle. The use of LVADs has been associated with thrombus formation next to the aortic valve and close to the anastomosis region, especially in patients in which the native cardiac function is negligible and the aortic valve remains closed. Stagnation points and recirculation zones have been implicated as the main fluid dynamics factors contributing to thrombus formation. The purpose of the present study was to develop and use computer simulations based on a fluid-structure interaction (FSI) solver to study flow conditions corresponding to different strategies in LVAD ascending aortic anastomosis providing a scenario with the lowest likelihood of thrombus formation. A novel FSI algorithm was developed to deal with the presence of multiple structures corresponding to different elastic properties of the native aorta and of the LVAD cannula. A sensitivity analysis of different variables was performed to assess their impact of flow conditions potentially leading to thrombus formation. It was found that the location of the anastomosis closest to the aortic valve (within 4 cm away from the valve) and at the angle of 30 minimizes the likelihood of thrombus formation. Furthermore, it was shown that the rigidity of the dacron anastomosis cannula plays almost no role in generating pathological conditions downstream from the anastomosis. Additionally, the flow analysis presented in this manuscript indicates that compliance of the cardiovascular tissue acts as a natural inhibitor of pathological flow conditions conducive to thrombus formation and should not be neglected in computer simulations. PMID- 21675812 TI - Robust uniform persistence in discrete and continuous dynamical systems using Lyapunov exponents. AB - This paper extends the work of Salceanu and Smith [12, 13] where Lyapunov exponents were used to obtain conditions for uniform persistence ina class of dissipative discrete-time dynamical systems on the positive orthant of R(m), generated by maps. Here a united approach is taken, for both discrete and continuous time, and the dissipativity assumption is relaxed. Sufficient conditions are given for compact subsets of an invariant part of the boundary of R(m+) to be robust uniform weak repellers. These conditions require Lyapunov exponents be positive on such sets. It is shown how this leads to robust uniform persistence. The results apply to the investigation of robust uniform persistence of the disease in host populations, as shown in an application. PMID- 21675813 TI - Global dynamics of the chemostat with different removal rates and variable yields. AB - In this paper, we consider a competition model between n species in a chemostat including both monotone and non-monotone growth functions, distinct removal rates and variable yields. We show that only the species with the lowest break-even concentration survives, provided that additional technical conditions on the growth functions and yields are satisfied. We construct a Lyapunov function which reduces to the Lyapunov function used by S. B. Hsu [SIAM J. Appl. Math., 34 (1978), pp. 760-763] in the Monod case when the growth functions are of Michaelis Menten type and the yields are constant. Various applications are given including linear, quadratic and cubic yields. PMID- 21675814 TI - The replicability of oncolytic virus: defining conditions in tumor virotherapy. AB - The replicability of an oncolytic virus is measured by its burst size. The burst size is the number of new viruses coming out from a lysis of an infected tumor cell. Some clinical evidences show that the burst size of an oncolytic virus is a defining parameter for the success of virotherapy. This article analyzes a basic mathematical model that includes burst size for oncolytic virotherapy. The analysis of the model shows that there are two threshold values of the burst size: below the first threshold, the tumor always grows to its maximum (carrying capacity) size; while passing this threshold, there is a locally stable positive equilibrium solution appearing through transcritical bifurcation; while at or above the second threshold, there exits one or three families of periodic solutions arising from Hopf bifurcations. The study suggests that the tumor load can drop to a undetectable level either during the oscillation or when the burst size is large enough. PMID- 21675815 TI - Defining candidate drug characteristics for Long-QT (LQT3) syndrome. AB - Mutations of the SCN5A gene can significantly alter the function of cardiac myocyte sodium channels leading to increased risk of ventricular arrhythmia. Over the past decade, detailed Markov models of the action potential of cardiac cells have been developed. In such models, the effects of a drug can be treated as alterations in on- and off rates between open and inactivated states on one hand, and blocked states on the other hand. Our aim is to compute the rates specifying a drug in order to: (a) restore the steady-state open probability of the mutant channel to that of normal wild type channels; and (b) minimize the difference between whole cell currents in drugged mutant and wild type cells. The difference in the electrochemical state vector of the cell can be measured in a norm taking all components and their dynamical properties into account. Measured with this norm, the difference between the state of the mutant and wild-type cell was reduced by a factor of 36 after the drug was introduced and by factors of 4 over mexitiline and 25 over lidocaine. The results suggest the potential to synthesize more effective drugs based on mechanisms of action of existing compounds. PMID- 21675816 TI - Sveir epidemiological model with varying infectivity and distributed delays. AB - In this paper, based on an SEIR epidemiological model with distributed delays to account for varying infectivity, we introduce a vaccination compartment, leading to an SVEIR model. By employing direct Lyapunov method and LaSalle's invariance principle, we construct appropriate functionals that integrate over past states to establish global asymptotic stability conditions, which are completely determined by the basic reproduction number R( V) (0). More precisely, it is shown that, if R( V) (0) <= 1, then the disease free equilibrium is globally asymptotically stable; if R( V) (0) > 1, then there exists a unique endemic equilibrium which is globally asymptotically stable. Mathematical results suggest that vaccination is helpful for disease control by decreasing the basic reproduction number. However, there is a necessary condition for successful elimination of disease. If the time for the vaccinees to obtain immunity or the possibility for them to be infected before acquiring immunity can be neglected, this condition would be satisfied and the disease can always be eradicated by some suitable vaccination strategies. This may lead to over-evaluating the effect of vaccination. PMID- 21675817 TI - Factors connected with the female sex seem to play an important role in differentiated thyroid cancer. AB - AIM: The aim of the study was to analyze whether female sex hormones and other factors connected with the female sex could increase the risk of differentiated thyroid cancer (DTC). MATERIAL AND METHODS: Ninety-nine patients with a mean age +/- SD of 40.5 +/- 5.9 years with DTC and 51 healthy women with a mean age of 36.52 +/- 8.3 years were examined. Gynecological and obstetric histories were taken and serum estradiol and progesterone levels were analyzed in all women. RESULTS: Patients with DTC had more frequent menstrual cycle disturbances, used hormone-containing medicines more frequently, were mulitiparous more frequently, had spontaneous miscarriages more frequently, and their duration of lactation was significantly shorter than in controls. The mean serum estradiol level +/- SD in women with DTC was significantly higher than that in the controls, in the follicular phase 193.74 +/- 66.31 vs. 157.63 +/- 42.88 pmol/L and in the luteal phase 519 +/- 176.9 vs. 369 +/- 71.49 pmol/L. The mean serum progesterone level +/- SD was higher in the controls than in DTC patients in the follicular phase: 2.11 +/- 0.70 vs. 1.38 +/- 0.56 nmol/L; in the luteal phase: 20.95 +/- 17.46 vs. 17.31 +/- 12.28 nmol/L. CONCLUSIONS: The results of these studies imply that estrogens may at least modify the proliferation of thyroid cancer cells. The sex hormones probably intensify the actions of other carcinogens as well. PMID- 21675818 TI - Mitigation of radiation-induced lung injury by genistein and EUK-207. AB - PURPOSE: We examined the effects of genistein and/or Eukarion (EUK)-207 on radiation-induced lung damage and investigated whether treatment for 0-14 weeks (wks) post-irradiation (PI) would mitigate late lung injury. MATERIALS AND METHODS: The lungs of female Sprague-Dawley (SD) rats were irradiated with 10 Gy. EUK-207 was delivered by infusion and genistein was delivered as a dietary supplement starting immediately after irradiation (post irradiation [PI]) and continuing until 14 wks PI. Rats were sacrificed at 0, 4, 8, 14 and 28 wks PI. Breathing rate was monitored and lung fibrosis assessed by lung hydroxyproline content at 28 wks. DNA damage was assessed by micronucleus (MN) assay and 8 hydroxy-2-deoxyguanosine (8-OHdG) levels. The expression of the cytokines Interleukin (IL)-1alpha, IL-1beta, IL-6, Tumor necrosis factor (TNF)-alpha and Transforming growth factor (TGF)-beta1, and macrophage activation were analyzed by immunohistochemistry. RESULTS: Increases in breathing rate observed in the irradiated rats were significantly reduced by both drug treatments during the pneumonitis phase and the later fibrosis phase. The drug treatments decreased micronuclei (MN) formation from 4-14 wks but by 28 wks the MN levels had increased again. The 8-OHdG levels were lower in the drug treated animals at all time points. Hydroxyproline content and levels of activated macrophages were decreased at 28 wks in all drug treated rats. The treatments had limited effects on the expression of the cytokines. CONCLUSION: Genistein and EUK-207 can provide partial mitigation of radiation-induced lung damage out to at least 28 wks PI even after cessation of treatment at 14 wks PI. PMID- 21675819 TI - Infrastructure to support ultra high throughput biodosimetry screening after a radiological event. AB - PURPOSE: After a large-scale radiological event, there will be a pressing need to assess, within a few days, the radiation doses received by tens or hundreds of thousands of individuals. This is for triage, to prevent treatment locations from being overwhelmed, in what is sure to be a resource limited scenario, as well as to facilitate dose-dependent treatment decisions. In addition there are psycho social considerations, in that active reassurance of minimal exposure is a potentially effective antidote to mass panic, as well as long-term considerations, to facilitate later studies of cancer and other long-term disease risks. MATERIALS AND METHODS: As described elsewhere in this issue, we are developing a Rapid Automated Biodosimetry Tool (RABiT). The RABiT allows high throughput analysis of thousands of blood samples per day, providing a dose estimate that can be used to support clinical triage and treatment decisions. RESULTS: Development of the RABiT has motivated us to consider the logistics of incorporating such a system into the existing emergency response scenarios of a large metropolitan area. We present here a view of how one or more centralized biodosimetry readout devices might be incorporated into an infrastructure in which fingerstick blood samples are taken at many distributed locations within an affected city or region and transported to centralized locations. CONCLUSIONS: High throughput biodosimetry systems offer the opportunity to perform biodosimetric assessments on a large number of persons. As such systems reach a high level of maturity, emergency response scenarios will need to be tweaked to make use of these powerful tools. This can be done relatively easily within the framework of current scenarios. PMID- 21675820 TI - Review of the persistence of gastroesophageal reflux disease in children, adolescents and adults: does gastroesophageal reflux disease in adults sometimes begin in childhood? AB - OBJECTIVE: Understanding the natural history and outcomes of gastroesophageal reflux disease (GERD) in children could help to identify patients at risk of having GERD complications during adulthood. This review aimed to assess evidence of whether GERD in children or adolescents persists into adulthood. MATERIAL AND METHODS: PubMed searches (1966-2010) identified longitudinal studies of GERD extending from childhood/infancy into adulthood, as well as longitudinal studies within pediatric age groups. RESULTS: In one study, heartburn during childhood was more often recalled by adults with reflux symptoms than by those without (30% vs. 9%; p < 0.001), as was medication or surgery for GERD (both p < 0.01). Another study found that GERD symptoms were more common in adults diagnosed with reflux esophagitis during childhood/adolescence than in those who were not (46% vs. 30%). Regurgitation during infancy increased the risk of feeding problems after 1 year (odds ratio 4.2 (95% confidence interval: 1.4-12.0)) and of reflux symptoms at 9 years of age (relative risk 2.3 (95% confidence interval: 1.3 4.0)). In one study, abnormal esophageal histology persisted in infants after 12 months without reflux symptoms. A proportion (59-100%: three studies) of patients with reflux symptoms and/or reflux esophagitis during the pediatric years still required treatment after 1-8 years. In another study, however, just 7% of patients with healed reflux esophagitis relapsed after 9 months without treatment. CONCLUSION: The limited available evidence suggests that some infants, children, and adolescents with GERD are more likely than those without GERD to have symptoms later in life. PMID- 21675822 TI - Assessment of side-effects by Ludox TMA silica nanoparticles following a dietary exposure on the bumblebee Bombus terrestris. AB - We assessed lethal and sublethal side-effects of Ludox TMA silica nanoparticles on a terrestrial pollinator, Bombus terrestris (Linnaeus), via a dietary exposure. Dynamic light scattering analysis confirmed that silica Ludox TMA nanoparticles remained in suspension in the drinking sugar water. Exposure of bumblebee microcolonies during 7 weeks to the different nanoparticle concentrations (high: 34, 170 and 340 mg/l and low: 34 and 340 MUg/l) did not cause worker mortality compared to the controls. Also no effect on the worker foraging behavior was observed after exposure to nanoparticles concentrations up to 340 MUg/l. In contrast, the high concentrations (>=34 mg/l) resulted in a total loss of reproduction. Using histological analysis we confirmed severe midgut epithelial injury in intoxicated workers (>=34 mg/l). Despite the fact that these concentrations are much higher than the predicted environmental concentrations, precaution is still needed as information regarding their fate in the terrestrial environment and their potency to bioaccumulate and biomagnificate is lacking. PMID- 21675823 TI - The human heart releases cardiotrophin-1 after coronary artery bypass grafting with cardiopulmonary bypass. AB - OBJECTIVES: Cardiotrophin-1 (CT-1) is closely linked to many cardiovascular diseases, such as myocardial infarction and heart failure, and exhibits cardioprotective effect in ischemia-reperfusion injury. The present study was designed to investigate the course of CT-1 in patients undergoing on-pump coronary artery bypass grafting (CABG), and to evaluate the relationship between plasma CT-1 levels and postoperative cardiac function. METHODS: Twenty-four patients undergoing elective CABG were studied. Radial artery blood samples were collected before cardiopulmonary bypass (CPB), 5 min and 20 min after reperfusion, and 1 h, 6 h, 12 h and 24 h after CPB. Coronary sinus blood samples were collected before CPB, 5 min and 20 min after reperfusion. Plasma CT-1 levels were measured using the ELISA method. Hemodynamic data were collected. RESULTS: Peripheral CT-1 levels did not change significantly postoperatively. Trans myocardial CT-1 levels increased significantly 5 min and 20 minutes after reperfusion as compared to baseline. A weak positive correlation (r = 0.408, p = 0.048) was found between trans-myocardial CT-1 levels at 20 min after reperfusion and CI at 12 h after CPB. CONCLUSIONS: The heart secretes CT-1 after ischemic injury. The precise effect of CT-1 in CABG needs further investigation. PMID- 21675821 TI - Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population. AB - OBJECTIVE: The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. PATIENTS AND METHODS: 373 patients with hemochromatosis detected through routine health check-ups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 +/- 5.8 years. The degree of liver fibrosis and survival were analyzed. RESULTS: Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. CONCLUSION: Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation. PMID- 21675824 TI - Principles underlying the Bilingual Aphasia Test (BAT) and its uses. AB - The Bilingual Aphasia Test (BAT) is designed to be objective (so it can be administered by a lay native speaker of the language) and equivalent across languages (to allow for a comparison between the languages of a given patient as well as across patients from different institutions). It has been used not only with aphasia but also with any condition that results in language impairment (Alzheimer's, autism, cerebellar lesions, developmental language disorders, mild cognitive impairment, motor neuron disease, multiple sclerosis, Parkinson's, vascular dementia, etc.). It has also been used for research purposes on non brain-damaged unilingual and bilingual populations. By means of its 32 tasks, it assesses comprehension and production of implicit linguistic competence and metalinguistic knowledge (which provide indications for apposite rehabilitation strategies). Versions of the BAT are available for free download at www.mcgill.ca/linguistics/research/bat/. PMID- 21675825 TI - Severe hypoglycaemia in drug-treated diabetic patients needs attention: a population-based study. AB - OBJECTIVE: To study one-year incidence and risk factors of severe hypoglycaemias (SH) in adult drug-treated diabetic patients living in two Finnish communities. DESIGN: The episodes of SH and their risk factors were identified from local ambulance registers, from the databases of local health care units, and from patient questionnaires. SETTING: The target population consisted of all drug treated diabetic patients from the two middle-sized communities in southern Finland, altogether 1776 patients. The study was retrospective. SUBJECTS: A total of 1469 patients (82.7% of the target population) gave informed consent for the use of their medical records and 1325 patients (74.6% of the target population) returned the detailed 36-item questionnaire. RESULTS: Of type 1 and type 2 insulin-treated diabetic patients, 14.6% and 1.0%, respectively, needed ambulance or emergency room care (incidence of 30.5 and 3.0 per 100 patient years). However, 31.0% of type 1 and 12.3% of type 2 diabetic patients reported at least one episode of SH (incidence of 72.0 and 27.0 per 100 patient years). Of all insulin-treated patients, 53 (7.8%) reported three or more episodes of SH. Significant independent risk factors for SH were depression, daily exercise, and nephropathy but not glycaemic control. CONCLUSION: The incidence of SH was high in both types of insulin-treated diabetic patients. However, the recurrent episodes of SH were clustered in a small minority of insulin-treated patients with diabetes. The risk of SH should be considered when assessing the treatment target for an individual diabetic patient. PMID- 21675826 TI - Dynamics of rabbit brain edema in focal lesion and perilesion area after traumatic brain injury: a MRI study. AB - To understand the dynamics of brain edema in different areas after traumatic brain injury (TBI) in rabbit, we used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) to monitor blood brain barrier (BBB) permeability and cytotoxic brain edema after weight drop induced TBI in rabbit. The dynamics of BBB permeability and brain edema were quantified using K(trans) and apparent diffusion coefficient (ADC) in the focal and perifocal lesion areas, as well as the area contralateral to the lesion. In the focal lesion area, K(trans) began to increase at 3 h post-TBI, peaked at 3 days, and decreased gradually while remaining higher than sham injury animals at 7 and 30 days. ADC was more variable, increased slightly at 3 h, decreased to its lowest value at 7 days, then increased to a peak at 30 days. In the perifocal lesion area, K(trans) began to increase at 1 day, peaked at 3-7 days, and returned to control level by 30 days. ADC showed a trend to increase at 1 day, followed by a continuous increase thereafter. In the contralateral area, no changes in K(trans) and ADC were observed at any time-point. These data demonstrate that different types of brain edema predominate in the focal and perifocal lesion areas. Specifically cytotoxic edema was predominant in the focal lesion area while vasogenic edema predominated in the perifocal area in acute phase. Furthermore, secondary opening of the BBB after TBI may appear if secondary injury is not controlled. BBB damage may be a driving force for cytotoxic brain edema and could be a new target for TBI intervention. PMID- 21675827 TI - Trends in blood pressure control in patients with type 2 diabetes: data from the Swedish National Diabetes Register (NDR). AB - We assessed blood pressure (BP) trends in patients with type 2 diabetes from a national diabetes register using three cross-sectional samples (aged 30?85 years) in 2005, 2007 and 2009, and in patients from 2005 followed individually until 2009. The prevalence of hypertension was 87% among all 180 369 patients in 2009, although lower in subgroups with ages 30?39, 40?49 and 50?59 years: 40%, 60% and 77%. In the three cross-sectional surveys, mean BP decreased (141/77?136/76 mmHg), uncontrolled BP? 140/90 mmHg decreased (58?46%), and antihypertensive drug treatment (AHT) increased (73?81%). Comparatively in 79 185 patients followed individually for 5 years, mean BP decreased (141/77?137/75 mmHg), uncontrolled BP ?140/90 mmHg decreased (58?47%) and AHT increased (73?82%). Independent predictors of BP decrease were BMI decrease (stronger) and increase in AHT. AHT occurred among 81% of all patients in 2009. In 57 645 patients on AHT followed individually, mean BP decreased (143/77?138/75 mmHg) and uncontrolled BP ?140/90 mmHg decreased (63?50%). Among 5164 patients with nephropathy on AHT followed individually, BP <130/80 mmHg increased (12?21%). In conclusion, BP control improved from 2005 to 2009, relative to BMI decrease and AHT increase, although still about half had BP ?140/90 mmHg. PMID- 21675828 TI - SCORE model underestimates cardiovascular risk in hypertensive patients: results of the Polish Hypertension Registry. AB - OBJECTIVE. The aim of the present study was to compare the effectiveness of Systemic COronary Risk Evaluation (SCORE) charts and European Society of Hypertension/European Society of Cardiology (ESH/ESC) hypertension guidelines for identifying high-risk hypertensive patients. METHODS. The data on hypertensive patients was collected using the Polish Hypertension Registry. We enrolled 636 patients (357 females and 279 males, mean age 54.4 (+/-) 7.9 years) from hypertension centres in Poland. RESULTS. Only 3.5% of the subjects had no additional risk factors. Thirty-six per cent of the patients had three or more risk factors. Metabolic syndrome was found in 40.1% of the patients. According to the SCORE charts, 9.0% of females and 27.2% of males had high to very high cardiovascular risk (p < 0.001). Taking into account risk factors and the metabolic syndrome, 55.7% of females and 56.3% of males (p = NS) had high or very high additional cardiovascular risk according to the 2007 ESH/ESC guidelines. For both females and males, the prevalence of high to very high risk was greater (p < 0.001) from the calculation based on the 2007 ESH/ESC guidelines than from the SCORE charts. Fifty-two per cent of patients classified as low to moderate risk according to the SCORE system, had high or very high risk according to the 2007 ESH/ESC guidelines. CONCLUSIONS. The SCORE charts seem to underestimate the burden of the cardiovascular risk among hypertensive patients. The cardiovascular risk, especially in the hypertensive female population, seems to be much higher when estimated according to the 2007 ESH/ESC guidelines. PMID- 21675829 TI - Phaeochromocytoma in a 86-year-old patient presenting with reversible myocardial dysfunction. AB - BACKGROUND. Phaeochromocytomas and paragangliomas are rare, mostly benign catecholamine-producing tumours of chromaffin cells of the adrenal medulla or of extra-adrenal paraganglia. Phaeochromocytoma may occur at any age, the greatest frequency being in the fourth and fifth decades. Only on extremely rare occasions does the tumour develop in the very old patients. METHODS. We are describing an 86-year-old patient with phaeochromocytoma, presenting with reversible myocardial dysfunction. RESULTS. This very old patient with phaeochromocytoma had hypertension characterized by labile blood pressure values and increased daytime blood pressure variability. This patient exhibited reversible myocardial dysfunction suggestive for "catecholaminergic cardiomyopathy", as the complication of phaeochromocytoma. After surgical removal of the tumour, recovery of left ventricular function was documented by echocardiography showing normalization of systolic function and improvement of diastolic function. CONCLUSION. Phaeochromocytomas are rare forms of secondary hypertension, but should be considered in the differential diagnosis, regardless of age, even in very old patients. PMID- 21675830 TI - On bias in medical research; reflections on present salt-cholesterol controversies. AB - A common form of biased reporting is to avoid quoting evidence that contradicts the authors' interpretation of scientific data. Against this background the recommendations by the Institute of Medicine of the National Academies of USA (IOM) regarding a population-based policy of salt restriction have been reviewed. It is suggested that the recommendations may not be valid since some important evidence has not been included in the IOM analysis. PMID- 21675831 TI - Genetic testing for metastasis: potential for improved cancer treatment. PMID- 21675832 TI - Discovery of a metastatic pathway: implications for future cancer treatment. PMID- 21675833 TI - The potential for LOXL2 as a target for future cancer treatment. PMID- 21675835 TI - A comprehensive review of S-1 in the treatment of advanced gastric adenocarcinoma. AB - Gastric cancer is the fourth most common malignancy worldwide with Japan, Korea, Taiwan, China, Mongolia and many countries in South America and eastern Europe, as well as parts of the Middle East, contributing to the majority of cases. In the USA, it was estimated that approximately 10,620 deaths would be caused by gastric cancer in 2010. Gastric cancer is often diagnosed in its advanced stages. Current first-line treatment for advanced gastric cancer (AGC) using triplet combination chemotherapy containing a platinum-based compound, a fluoropyrimidine with an anthracycline (frequently added in Europe) or a taxane (more often used in the USA and elsewhere) has resulted in higher response rates and modest improvement in overall survival compared with doublet combinations. However, triplet combinations can be associated with increased toxicity compared with the doublets and patient selection becomes important. A desirable research strategy is to improve outcomes of patients with AGC by identifying treatments that are effective, convenient and safe. The interest in oral agents compared with intravenous agents is mounting. One oral fluoropyrimidine, S-1, is novel as it combines tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. S-1 is approved in Japan, China, Taiwan, Korea and Singapore for the treatment of patients with gastric cancer, and more recently has been approved in 27 European countries to treat AGC. Initial clinical trials in the USA and Europe observed diarrhea as the dose-limiting toxicity; however, initial Japanese studies reported myelosuppression as the dose-limiting toxicity. The differing dose tolerance in these two populations is likely due to polymorphisms in the CYP2A6 gene. Based on our review of Phase II and III studies, we conclude that S-1 is a convenient oral fluoropyrimidine that provides safety advantage over intravenous fluorouracil without compromising efficacy against AGC. PMID- 21675836 TI - Anticancer effects of metformin and its potential use as a therapeutic agent for breast cancer. AB - Metformin is an orally available, biguanide derivative that is widely used in the treatment of Type 2 diabetes. Recent preclinical data have demonstrated that it can also act as an anticancer agent by activation of AMPK and subsequent inhibition of mTOR. Metformin is currently being investigated in several Phase II/III clinical trials. This article will review the current evidence for its mechanism of action, efficacy in preclinical and clinical models, and toxicity. Ongoing and planned studies evaluating the impact of metformin on breast cancer outcomes are also discussed. PMID- 21675837 TI - Diagnostic molecular biomarkers for malignant pleural effusions. AB - Malignant pleural effusions (MPEs) are a common and important cause of cancer related mortality and morbidity. Prompt diagnosis using minimally invasive tests is important because the median survival after diagnosis is only 4-9 months. Pleural fluid cytology is pivotal to current MPE diagnostic algorithms but has limited sensitivity (30-60%). Consequently, many patients need to undergo invasive diagnostic tests such as thoracoscopic pleural biopsy. Recent genomic, transcriptomic, methylation and proteomic studies on cells within pleural effusions have identified novel molecular diagnostic biomarkers that demonstrate potential in complementing cytology in the diagnosis of MPEs. Several challenges will need to be addressed prior to the incorporation of these molecular tests into routine clinical diagnosis, including validation of molecular diagnostic markers in well-designed prospective, comparative and cost-effectiveness studies. Ultimately, minimally invasive diagnostic tests that can be performed quickly will enable clinicians to provide the most effective therapies for patients with MPEs in a timely fashion. PMID- 21675838 TI - Examining the role of cyclin D1 in breast cancer. AB - Cyclin D1 overexpression is found in more than 50% of human breast cancers and causes mammary cancer in transgenic mice. Dysregulation of cyclin D1 gene expression or function contributes to the loss of normal cell cycle control during tumorigenesis. Recent studies have demonstrated that cyclin D1 conducts additional specific functions to regulate gene expression in the context of local chromatin, promote cellular migration and inhibit mitochondrial metabolism. It is anticipated that these additional functions contribute to the pathology associated with dysregulated cyclin D1 abundance. This article discusses evidence that examines the significance of cyclin D1 in breast cancer with emphasis on its role in breast cancer stem cell expansion. PMID- 21675839 TI - Identifying responders to trastuzumab therapy in breast cancer. AB - In breast cancer, HER2-targeted therapy with trastuzumab has gained significant attention, owing to the dramatic response observed in a subset of HER2-positive patients. The mechanisms of action are complex and not fully understood, and much effort has been spent in order to identify responders. Good patient management, side effects of the humanized monoclonal antibody and socioeconomics all demand that the drug should be administered only to the patients who will benefit from it. This has been a difficult task and contributions to solve it have been proposed from a variety of research. In this article we describe some of these contributions based on the literature and provide our viewpoint as to which identifiers will emerge in the following decade. PMID- 21675840 TI - Evolution from active surveillance to focal therapy in the management of prostate cancer. AB - Organ-preserving therapies are widely accepted in many facets of medicine and, more recently, in oncology. For example, partial nephrectomy is now accepted as a preferred alternative over radical nephrectomy for small (up to 4 cm or T1) tumors. Focal therapy (FT) is another organ-preserving strategy applying energy (cryotherapy, laser ablation and/or high-intensity focused ultrasound) to destroy tumors while leaving the majority of the organ, surrounding tissue and structures unscathed and functional. Owing to the perceived multifocality of prostate cancer (PCa) technology limitations, in the past PCa was not considered suitable for FT. However, with the rise of active surveillance for the management of low-risk PCa in carefully selected patients, FT is emerging as an alternative. This is owing to technology improvements in imaging and energy-delivery systems to ablate tissue, as well as the realization that many men and clinicians still desire tumor control. With the postulated ability to ablate tumors with minimal morbidity, FT may have found a role in the management of PCa; the aim of FT a being long-term cancer control without the morbidity associated with radical therapies. Data for FT in PCa have been derived from case series and small Phase I trials, with larger cohort studies with longer follow-up having only just commenced. More data from large trials on the safety and efficacy of FT are required before this approach can be recommended in men with PCa. Importantly, studies must confirm that no viable cancer cells remain in the region of ablation. FT might eventually prove to be a 'middle ground' between active surveillance and radical treatment, combining minimal morbidity with cancer control and the potential for retreatment. PMID- 21675841 TI - Reducing excessive toxicity in ovarian cancer treatment: a personalized approach. AB - The management of ovarian cancer is not only multifactorial, but also patient specific. Different treatment modalities lead to varying levels of toxicity and individual patient responses, necessitating a personalized approach to each treatment plan. Surgical treatment along with first-line and salvage chemotherapies, are standard modalities but recent innovations in chemotherapy delivery and innovative therapy with mechanism of action are reviewed in this article. Extensive experience with standard chemotherapy has outlined algorithms for managing various toxicities. The focus of treatment may ultimately point towards palliative care and clinicians must be comfortable and well versed in addressing this important option. Overall, management of ovarian cancer requires a multi-faceted approach, keeping the patients' overall health, curative goals and well-being at the forefront. It is nearly impossible to detail exact management plans for every possible toxicity for every patient; formulating personalized treatment plans should be based on evidence and clinician experience, all part of the art of medicine. The objective of this article is to highlight the most frequently encountered and most limiting toxicities of current standard therapies for epithelial ovarian cancer. PMID- 21675845 TI - Inhibition effect of tetrandrine on haze formation after Epi-LASIK surgery in rabbits. AB - PURPOSE: To observe the inhibitory effect of tetrandrine on haze formation after Epi-LASIK surgery in rabbits. MATERIALS AND METHODS: Twenty-seven healthy New Zealand rabbits were selected and underwent Epi-LASIK surgery. According to a self comparison principle, these rabbits were randomly divided into three groups. The first group was treated with tetrandrine eye drops (Tet), the second (negative control, NC) group was treated with pure solvent, and the third group was treated with fluorometholone (FML) solvent. Haze grades of each group were respectively observed by slit lamp exam at half-month, one month, and two months after surgery. After corneal tissues were extracted, optical microscopy, Sirius Red staining, immunohistochemistry, and semi-quantitative RT-PCR tests were conducted, in order to test collagen formation of operated eyes after surgery and expression of transformation growth factor beta 2 (TGF-beta(2)) in corneal stroma. RESULTS: At a half month and one month after surgery, haze grades and type III collagen expression in Tet and FML groups were significantly lower than that in NC groups (P < 0.01). No statistical difference was observed between Tet and FML groups. Immunohistochemistry showed that, at each time point after surgery, expressions of TGF-beta(2) protein in Tet and FML groups were significantly lower than that in the NC group (P < 0.01), whereas there was no statistical difference between Tet and FML groups. The expression level of TGF beta(2) protein increased, reaching its peak one month after surgery. RT-PCR also showed that, at each point after surgery, the TGF-beta(2) mRNA expression in Tet and FML groups was lower than that in the NC group (P < 0.01), nevertheless no statistical difference was observed between Tet and FML groups. CONCLUSIONS: Like FML, Tet could inhibit haze formation in rabbits after Epi-LASIK surgery, possible through TGF-beta(2)-collagen-III pathway. PMID- 21675846 TI - Glaucoma and clinical characteristics in Vietnamese Americans. AB - PURPOSE: To assess the proportions of glaucoma types and clinical characteristics in Vietnamese Americans in a single-center, retrospective study. METHODS: Medical charts of Vietnamese-American patients who visited a single private practice in Northern California from 1998-2007 were reviewed. The main outcome measures included the distribution and characteristics of glaucoma types, and clinical parameters associated with the presence of various glaucomas. RESULTS: Data from 2247 patients aged 18-98 years were reviewed. Glaucoma was determined for 305 patients (13.6%). Among this group, 54.8% had primary open-angle glaucoma (POAG), 26.9% had primary angle-closure glaucoma (PACG), 13.4% had mixed mechanism glaucoma (MMG), and 4.9% had secondary glaucoma. In the MMG group (41 patients), 27 patients who initially had open angles developed narrow angles and underwent laser peripheral iridotomy (LPI) with a mean follow up of 6.4 years from the time of iridotomy. The other 13 patients had glaucoma progression with open angles after LPI. One POAG patient had neovascular glaucoma due to retinal vein occlusion several years later. Compared to the PACG group, the MMG group had significantly lower baseline intraocular pressure (25.0 vs. 20.2 mmHg, p = 0.007) but with no difference in biometry. CONCLUSIONS: POAG is the major type of glaucoma in this clinic-based Vietnamese population. However, Vietnamese appear to have a relatively higher proportion of PACG than Caucasians and those of African descent. It is recommended that gonioscopy be part of the regular eye check-up for adult Vietnamese patients. PMID- 21675847 TI - Becoming a surgical scholar. AB - The essence of becoming a surgical scholar resides in understanding that the search for a surgeon/research scholar/mentor is the predominant factor for the medical student or surgical resident in realizing this goal. The surgeon/researcher/mentor will teach and direct the new protege as to the best manner for advancing in surgical scholasticism. A surgical scholar publishes and presents papers, as well as writing grants for peer-reviewed consideration. In addition, the surgical scholar may also write chapters, editorials and commentaries. In these areas of publications the surgeon/researcher/mentor can offer the best of his/her repertoire by assembling a good plan for the young student. The student, in turn, will be alert to optimizing the lessons of his/her mentor. That is how surgical scholars are born! PMID- 21675848 TI - Galileo's contribution to modern orthopaedics. AB - INTRODUCTION: Galileo Galilei (1564-1642), world-renowned Italian mathematician, astronomer, physicist and philosopher, made many contributions to science. The objective of this study is to demonstrate that Galileo's discovery of scaling principles permitted others to define and advance orthopaedic research and clinical sciences. METHODS: The science and scaling principles of Galileo Galilei were extensively analyzed by reviewing his 1638 original work Discorsi e Demostrazioni Matematiche Intorno a Due Nuove Scienze. Works about Galileo's science were reviewed for the concept of the scaling principles and with the idea of shedding light on how his work influenced modern orthopaedics. RESULTS: Galileo strictly adhered to the Copernican heliocentric theory with the sun at the center of the universe, which caused him aggravation and made him the target of inquisition rage at the end of his prodigious life. With his attention away from the cosmos, Galileo--through the voices of Salviati, Sagredo and Simplicio in the Discourses on Two New Sciences--defined how scaling was important to the movement and function of objects. Galileo introduced important advances in scaling laws, which contributed to the development of the field of biomechanics. This discipline, in many ways, has defined modern clinical and research orthopaedics. DISCUSSION: Galileo, by introducing the principles of scaling, permitted their application to human physical capacity, to bone and tissue response after injury, and to clinical treatment of injuries. Galileo in this way made important contributions to the practice of modern orthopaedics. PMID- 21675849 TI - Matrix metalloproteinase imbalance in inguinal hernia formation. AB - BACKGROUND: Emerging evidence supports the role of matrix metalloproteinases (MMPs) in hernia formation. However, the imbalance between the proteolytic activity of MMPs and their endogenous inhibitors (TIMPs) has not been investigated. The aim of the present study was to determine changes of MMP and TIMP levels in patients with inguinal hernia. METHODS: Two matrix metalloproteinases (MMP-9 and MMP-2) and their main inhibitors TIMP-1 and TIMP-2 were evaluated in consecutive patients undergoing inguinal hernia repair and control subjects. MMP/TIMP quantification was performed using ELISA in abdominal fascia tissue specimens and preoperative plasma samples. RESULTS: Tissue explants from hernia patients produced significantly higher levels of MMP-9 and MMP-2, and reduced TIMP-1 and TIMP-2 concentrations compared to those of controls. In plasma, a reverse correlation was found regarding the concentrations of MMPs; the circulating levels of MMP-9 and MMP-2 were significantly lower in patients with inguinal hernia than controls. Furthermore, hernia patients were found to have elevated plasma levels of TIMP-2 and reduced plasma levels of TIMP-1. CONCLUSIONS: The imbalance in MMP/TIMP activity indicates a dysregulation of the extracellular matrix degradation process in patients with inguinal hernia. The results of the present study suggest that impaired collagen metabolism may be an underlying pathophysiological mechanism of inguinal hernia formation. PMID- 21675850 TI - N-acetyl-cysteine improves anastomotic wound healing after radiotherapy in rats. AB - AIM: This study was designed to determine the effects of intraperitoneally or orally administered N-acetylcysteine (NAC) on anastomotic healing of irradiated rats. METHODS: Thirty-two male Wistar albino rats were randomized into four groups containing 8 rats each: I; standard resection plus anastomosis, II; radiation plus standard resection plus anastomosis, III; radiation plus standard resection plus anastomosis plus oral NAC, IV; radiation plus standard resection plus anastomosis plus intraperitoneal NAC. Four types of assessment were performed: bursting pressure, hydroxiproline (OHP) content, histopathology, and biochemical evaluation, including serum malondialdehyde (MDA), advanced oxidation protein products (AOPP), reduced glutathione (GSH) and superoxide dismutase (SOD) activities. RESULTS: Group comparisons demonstrated that bursting pressure was significantly higher in NAC treated rats. The mean tissue OHP concentration in the anastomotic tissue was significantly lower in irradiated rats (group II) than in the other groups. NAC treatment caused increased activity of SOD and GSH. In contrast, MDA levels were found to be decreased in groups III and IV. Histopathological analysis revealed that NAC administration, either orally or intraperitoneally, leads to a better anastomotic healing in terms of reepithelialization, perianastomotic fibrosis, ischemic necrosis, and muscle layer destruction. CONCLUSION: The present study supports the hypothesis that NAC administration alleviates the negative effects of radiotherapy on anastomotic healing. Nevertheless, the underlying mechanisms responsible for this protective effect is unknown today. PMID- 21675851 TI - Over-the-wire intravascular ultrasound in an animal model of pulmonary hypertension. AB - BACKGROUND: Intravascular ultrasound (IVUS) measures prognostically important pulsatile flow indexes in patients with pulmonary hypertension (PH). IVUS catheters traditionally require a guiding catheter for placement which can impact hemodynamics in small infants because the guiding catheter renders the atrioventricular valve incompetent. METHODS: Domestic swine (1.4-2.2 kg) were raised in isobaric normoxia (n = 4) or hypoxia (n = 3, FiO(2) 10-12%) for 72 hr for induction of PH. Cardiac catheterization and intravascular imaging was performed using a 3.5-Fr 20-MHz Eagle Eye Gold catheter (Volcano Corp., CA, USA) over a 0.014'' guide wire. Intima-media thickness (IMT) was measured and relative area change and vascular pulsatility were calculated. RESULTS: The IVUS probe was easily manipulated over a 0.014'' wire without hemodynamic compromise in all animals. The IMT was thicker in the hypoxic group than the normoxic group (0.19 +/- 0.03 mm vs. 0.31 +/- 0.04 mm, p = .067). Hypoxic animals had systolic PH (39.66 +/- 2.51 vs. 21.75 +/- 2.87 mmHg, p = .02). Systemic arterial pressures between the groups were the same (hypoxic 68 +/- 10.44 vs. normoxic 79.75 +/- 14.84 mmHg, p = .26). Vascular pulsatility was similar (hypoxic 24 +/- 2.64 vs. 20.25 +/- 0.57%, p = .18). However, the arterial wall distensibility was significantly different (0.98 +/- 0.2 vs. 2.01 +/- 1.38 %/mmHg, p = .04). CONCLUSIONS: Monorail IVUS imaging without a guide catheter overcomes a major limitation for use in infants and small animal experimental models by avoiding hemodynamic compromise. This would be a valuable tool for assessment of PH in the research and clinical setting. PMID- 21675852 TI - Evaluation of ischemia-reperfusion liver injury by near-infrared spectroscopy in an experimental swine model: the effect of desferoxamine. AB - INTRODUCTION: Ischemia-reperfusion (I-R) injury has long been regarded a primary factor for the physiological dysfunction that can occur following major liver resection performed under vascular control. The aim of our study was to assess the effect of treatment with desferoxamine (DFO), a potent antioxidative agent, monitoring the I-R injury on a porcine model of major hepatectomy. MATERIALS AND METHODS: Twelve female pigs were allocated to control (n = 6) and DFO groups (n = 6) and underwent 30 min of liver ischemia, during which a >=30% hepatectomy was performed, followed by six hours of postoperative monitoring. The DFO group animals were preconditioned with a continuous iv solution of DFO to a total dose of 100 mg/kg during their postoperative period. Liver remnants (~70% of initial liver volume) were evaluated by means of infrared spectroscopy, serum lactate measurement of the systemic, portal and hepatic vein blood, and by immunohistochemical assessment of apoptosis in consecutive liver biopsies. RESULTS: DFO group demonstrated considerably faster restoration of tissue oxygenation (92.33% vs. 80%, p < .05) and serum lactate values (1.23 mmol/l vs. 2.27 mmol/l, p < .05). Moreover, apoptosis as estimated by TUNEL and caspase-3 staining was significantly lower in the DFO group (0.06% vs. 1.17% and 1.17% vs. 2%, respectively, p < .05). The severity of the I-R injury showed a linear correlation to the restoration of tissue oxygenation, as estimated by infrared spectroscopy (r(2) = 0.81, p < .01). CONCLUSION: Iron chelation with DFO appears to attenuate I-R injury of the liver remnant following hepatectomy, as reflected by faster restoration of tissue oxygenation and lower apoptotic activity. PMID- 21675853 TI - Demethylbellidifolin inhibits proliferation and activation of hepatic stellate cells. AB - The effects of demethylbellidifolin (DMB), a xanthone compound extracted from Swertia davidi Franch, on activation of hepatic stellate cells (HSC) were investigated. Rat HSC line HSC-T6 cultured in vitro showed an activated status, which expressed alpha-smooth muscle actin (alpha-SMA) and synthesized collagen I. Treated with different concentrations (10, 20, or 40 MUM) of DMB for 12 -48 hr could markedly inhibit cell proliferation reflected by MTT and [(3)H]thymidine incorporation assays, and downregulate the expressions of both alpha-SMA and collagen I in HSC-T6 cells. Also, such treatment concentration-dependently downregulated both mRNA and protein expressions of transforming growth factor beta1 (TGF-beta1) and connective tissue growth factor (CTGF). The expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) was very low in activated HSC-T6, which could be significantly upregulated by treatment with DMB. Furthermore, PPAR-gamma antagonist PD68235 (5-20 MUM) markedly blocked these effects of DMB mentioned above. In summary, DMB inhibits HSC proliferation and activation, which may be related to activating PPAR-gamma-mediated pathway. PMID- 21675854 TI - Tumor necrosis factor-alpha in liver ischemia/reperfusion injury. AB - The pathophysiology of hepatic ischemia/reperfusion injury (IRI) includes a number of complex and diverse mechanisms involving interactions between hepatocytes, Kupffer cells, neutrophils, macrophages, sinusoidal endothelial cells, and platelets. Tumor Necrosis Factor-alpha (TNF-alpha), a cytokine produced by numerous cell types in response to inflammatory stimuli, is a well known mediator during ischemia/reperfusion (IR) that plays a central role in injury to hepatocytes. TNF-alpha has a multifactorial effect in hepatic IRI because of the many interactions between TNF-alpha and reactive oxygen species, nitric oxide, adhesion molecules, and various cytokines and chemokines. The intracellular cascades that TNF-alpha triggers and their downstream effects are clearly presented throughout this manuscript. With these mechanisms in mind, ischemic preconditioning and pharmacological interventions with potential clinical application to prevent or attenuate IRI will be emphasized. PMID- 21675857 TI - A novel 5-bp deletion in Clarin 1 in a family with Usher syndrome. AB - BACKGROUND: To identify the genetic defect in a Lebanese family with two sibs diagnosed with Usher Syndrome. MATERIALS AND METHODS: Exome capture and sequencing were performed on DNA from one affected member using Agilent in solution bead capture, followed by Illumina sequencing. RESULTS: This analysis revealed the presence of a novel homozygous 5-bp deletion, in Clarin 1 (CLRN1), a known gene responsible for Usher syndrome type III. The deletion is inherited from both parents and segregates with the disease phenotype in the family. The 5 bp deletion, c.301_305delGTCAT, p.Val101SerfsX27, is predicted to result in a frameshift and protein truncation after 27 amino acids. Sequencing all the coding regions of the CLRN1 gene in the proband did not reveal any other mutation or variant. CONCLUSION: Here we describe a novel deletion in CLRN1. Our data support previously reported intra familial variability in the clinical features of Usher syndrome type I and III. PMID- 21675858 TI - Biodistribution and biocompatibility of DMSA-stabilized maghemite magnetic nanoparticles in nonhuman primates (Cebus spp.). AB - AIM: This work represents the first reported investigation on the effects of magnetic nanoparticles (MNPs) in nonhuman primates. Biodistribution, biocompatibility and nanotoxicity of maghemite nanoparticles stabilized with dimercaptosuccinic acid (DMSA) were accessed. MATERIALS & METHODS: A control animal was used and three other animals were intravenously injected with DMSA MNPs and euthanized 12 h, 30 and 90 days following administration. Extracted organs were processed by histological techniques. An additional animal was used to collect blood samples to complementarily assess biocompatibility 12 h, 7, 15, 30, 60 and 90 days after DMSA-MNP injection. RESULTS: DMSA-MNPs were preferentially addressed to the lungs, liver and kidneys. Hematological and serum biochemical results corroborated histological findings, supporting DMSA-MNP biocompatibility while preserving both hepatic and renal normal activity. CONCLUSION: DMSA-MNPs were preferentially distributed to the lung, liver and kidneys. Furthermore, DMSA-MNPs were considered biocompatible, supporting their application as a promising nanomaterial platform for future biomedical use. PMID- 21675859 TI - Macrophage scavenger receptor A mediates the uptake of gold colloids by macrophages in vitro. AB - AIMS: While numerous studies have reported on nanoparticle uptake by phagocytic cells, the mechanisms of this uptake are poorly understood. A metastudy of research focusing on biological particulate matter has postulated that nanoparticles cannot be phagocytosed and therefore must enter cells via pinocytosis. The purpose of this study was to identify the route(s) of uptake of gold nanoparticles in vitro and to determine if these route(s) depend on particle size. MATERIALS & METHODS: The parent RAW264.7 cell line and its derivatives, transduced with a virus carrying siRNA to macrophage scavenger receptor A, were used as model phagocytes. Citrate-stabilized gold colloids were used as model nanoparticles. We used chemical inhibitors known to interfere with specific routes of particulate uptake. We developed multifocal light microscopy methods including multifocal stack analysis with NIH ImageJ software to analyze cell uptake. RESULTS: Irrespective of size, gold nanoparticles are internalized by macrophages via multiple routes, including both phagocytosis and pinocytosis. If either route was blocked, the particles entered cells via the other route. CONCLUSION: Gold nanoparticles with hydrodynamic sizes below 100 nm can be phagocytosed. Phagocytosis of anionic gold colloids by RAW264.7 cells is mediated by macrophage scavenger receptor A. PMID- 21675860 TI - Endoscopic management of intraoperative small bowel laceration during natural orifice translumenal endoscopic surgery: a blinded porcine study. AB - BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES) has recently gained great enthusiasm, but there is concern regarding the ability to endoscopically manage complications purely via natural orifices. AIM: To assess the feasibility of endoscopically managing enteral perforation during NOTES using currently available endoscopic accessories. METHODS: Twelve pigs underwent transgastric or transcolonic endoscopic exploration. Full-thickness enterotomies were intentionally created to mimic accidental small bowel lacerations during NOTES. These lacerations were then closed with endoclips. In the blinded arm of the study, small bowel repair was performed by a second blinded endoscopist. Adequate closure of the laceration was confirmed with a leak test. Primary access sites were closed with endoclips or T-anchors. At necropsy, the peritoneal cavity was inspected for abscesses, bleeding, or damage to surrounding structures. The enterotomy site was examined for adequacy of closure, adhesions, or evidence of infection. RESULTS: Fifteen small bowel lacerations were performed in 12 animals. Successful closure was achieved in all 10 cases in the nonblinded arm. Survival animals had an uncomplicated postoperative course and all enterotomy sites were well healed without evidence of necrosis, adhesions, abscess, or bleeding at necropsy. Leak test was negative in all animals. In the blinded arm, both small intestinal lacerations could not be identified by the blinded endoscopist. Necropsy revealed open small bowel lacerations. CONCLUSION: Small intestinal injuries are difficult to localize with currently available flexible endoscopes and accessories. Endoscopic clips, however, may be adequate for closure of small bowel lacerations if the site of injury is known. PMID- 21675861 TI - Laparoscopic intraoperative biliary ultrasonography: findings during laparoscopic cholecystectomy for acute disease. AB - Laparoscopic cholecystectomy (LC) is one of the most commonly performed operations, yet the frequency of bile duct injury remains unacceptably high, and up to 25% of urgent LCs are converted to the open approach. Intraoperative laparoscopic biliary ultrasonography (IOUS) allows identification of portal structures before division of any structure, but the impact of IOUS on LC for acute biliary disease has not been clearly reported. A retrospective review was conducted of all patients who underwent cholecystectomy over a 29-month period. IOUS was performed after release of the medial and lateral peritoneal attachments of the gallbladder. Of the 65 patients, 43 (66%) had an urgent operation. Mean operative time was 89.6 minutes (range 45 to 196 minutes). IOUS was used routinely, when available, in 50 patients (77%). The biliary anatomy was completely observed in 48 patients (96%). IOUS identified significant biliary abnormalities in 20 patients (40%) including presence of a foreshortened cystic duct (CD) (<1 cm) in 7 patients (14%), common bile duct stones in 4 patients (8%), abnormal CD anatomy in 4 patients (8%), and abnormal vascular anatomy in 8 patients (16%). No patient was converted to open operation, no bile duct injury occurred, and no patient required subsequent biliary intervention. IOUS is effective at observing biliary anatomy in the setting of acute disease, and may be a useful tool during these difficult cases. PMID- 21675862 TI - Toll-like receptor 4/nuclear factor-kappa B pathway is involved in myocardial injury in a rat chronic stress model. AB - Chronic stress is considered to predispose to various cardiovascular events such as coronary artery disease, hypertension, and even heart failure. In this study, rats were exposed to stress for 1 day, 1, 2, 3, and 4 weeks to establish a chronic stress model. A specific toll-like receptor 4 (TLR4) antagonist eritoran was used to block the activity of TLR4. On the second day after the last stress exposure, the animals were killed. The expression of TLR4 mRNA and nuclear factor kappa B (NF-kappaB) DNA-binding activity in the myocardium were measured using reverse transcriptase polymerase chain reaction and electrophoretic mobility shift assay. The proinflammatory cytokines such as tumor necrosis factor (TNF) alpha and interleukin (IL-6) in myocardium were assayed by enzyme-linked immunosorbent assay. Myocardial injury was evident after chronic stress for 2 weeks. The TLR4 mRNA expression reached a peak after stress for 1 week. It was sustained at a stable level after stress exposure for 3 weeks and was restored to a nearly normal level in the fourth week. NF-kappaB DNA-binding activity was significantly enhanced after the stress for 1 day and markedly enhanced again after a 2-week stress exposure. It was weakened and reached a normal level after stress exposure for 4 weeks. The levels of TNF-alpha and IL-6 gradually increased and reached peaks after stress for 4 weeks. Meanwhile, eritoran significantly decreased the TLR4 mRNA expression and NF-kappaB activity in rats from the 2-week stress group. However, it did not downregulate the levels of TNF-alpha and IL-6. Importantly, it significantly improved the myocardial injury induced by the chronic stress. In conclusion, TLR4/NF-kappaB participates in myocardial injury during chronic stress. PMID- 21675863 TI - Detection and characterization of Giardia duodenalis and Cryptosporidium spp. on swine farms in Ontario, Canada. AB - As part of the C-EnterNet surveillance program of the Public Health Agency of Canada, 122 pooled swine manure samples from 10 farms in Ontario, Canada were collected and tested for Giardia and Cryptosporidium. Giardia duodenalis cysts and Cryptosporidium spp. oocysts were detected using immunofluorescence microscopy. Nested-polymerase chain reaction protocols were performed to amplify the small subunit rRNA gene and the beta-giardin gene for G. duodenalis, and the small subunit rRNA gene and the heat shock protein-70 gene for Cryptosporidium spp. The DNA amplicons were sequenced to determine genotypes and species. A mixed multivariable method was used to compare the presence of Giardia and Cryptosporidium in different stages of production. Both Giardia cysts and Cryptosporidium oocysts were present on all tested farms, with 50.8% of the samples positive for G. duodenalis and 44.3% positive for Cryptosporidium spp. by microscopy, and 66.4% and 55.7%, respectively, positive by polymerase chain reaction (PCR). No significant agreement was observed between microscopy and PCR method to detect Giardia and Cryptosporidium (p<0.05). The prevalence of Giardia in manure pits and finisher pigs did not differ (p>0.05), however, it was less frequent (odds ratio, OR=0.21 [0.07, 0.63]) among sows. Cryptosporidium was more likely (OR=3.6 [1.3, 9.9]) to be detected in manure pits and weaners (OR=3.3 [1.1, 10.0]) compared to finisher pigs, and it was less frequent (OR=0.06 [0.007, 0.55]) in sows than in finishers (p<0.05). DNA sequencing demonstrated that 92.1% of the Giardia isolates were Assemblage B and 7.9% were Assemblage E. The most prevalent Cryptosporidium were Cryptosporidium parvum (55.4%), and Cryptosporidium sp. pig genotype II (37.5%). These findings indicate that the occurrence of zoonotic isolates of G. duodenalis and Cryptosporidium is very high on swine farms in southern Ontario, and that there is a potential for transmission between swine and humans by means of cyst and oocyst contaminated water or foods. PMID- 21675864 TI - Identification of persistent subtypes of Campylobacter jejuni by pulsed-field gel electrophoresis in Finland. AB - The genetic diversity of Campylobacter jejuni strains isolated from Finnish patients was studied by typing 508 strains by pulsed-field gel electrophoresis: 311 were isolated from domestically acquired infections and 197 from travel related infections. The strains were systematically selected from a larger collection of previously serotyped strains isolated during two 1-year sampling periods. The four most common SmaI profiles accounted for 45% of the domestic strains but only 3% of the travel-related strains. Of the domestic strains, 69% belonged to SmaI subtypes found during both sampling periods. The predominating SmaI subtypes and strains that were not digested by SmaI were typed by KpnI. Analyzing the temporal diversity of the pulsed-field gel electrophoresis profiles revealed six common persistent SmaI/KpnI subtypes among the domestic strains. Five of them have been identified in cattle, and two in chickens with a temporal association with human infections. PMID- 21675865 TI - Altered stress responses in children exposed to early adversity: a systematic review of salivary cortisol studies. AB - Pathological stress responses are implicated in numerous disorders. Hypothalamic pituitary-adrenal axis function is influenced by gene-environment interaction, with early-life environmental adversity having long-lasting effects. We examine the evidence that, in humans, these effects are apparent from infancy. We systematically reviewed published findings on cortisol response to a stressor, in 0-5-year-olds already exposed to adversity. Adversity was defined as a negative environmental influence present post-conception. We searched Ovid MEDLINE (1950 May 2010), EMBASE (1980-May 2010) and PsychINFO (1806-May 2010). We included peer reviewed, English language studies that analysed salivary cortisol before and after a standardised stressor. We identified 30 studies, of which 27 reported a significant effect of adversity on the cortisol response to stress. Six of these demonstrated an effect of prenatal substance exposure. Thirteen studies found that psychosocial adversity increased cortisol reactivity. Three studies reported that cortisol reactivity could be normalised by intervention programmes. The studies were heterogeneous, both in nature of adversity studied and in stressor used, precluding meta-analysis and assessment of publication bias. Our review presents evidence that adversity disrupts the stress response from an early age. Longitudinal studies are required to determine whether effects persist, alter with time, or are reversible with intervention. PMID- 21675866 TI - A structured public health approach to increasing rates and duration of breastfeeding in Romania. AB - BACKGROUND: Studies indicate that since 1990, rates of breastfeeding initiation and duration in Eastern Europe, including Romania, have decreased. Most breastfeeding promotion efforts in Romania have focused on in-hospital care, with an emphasis on training clinicians. Prior studies report that about 88% of Romanian mothers initiate breastfeeding in the hospital; however, these same studies report limited breastfeeding duration. We posit that an important problem is lack of support and education in the weeks and months following the birth. The nature of this problem suggests the need for an integrated and structured public health solution. METHODS: Based on our independent research, the results of an international maternal and child health (MCH) conference, and consultation with Romanian and American experts, we propose use of the public health problem solving paradigm to support breastfeeding in Romania. RESULTS: This article presents a conceptual model showing the integration of input, output, and process components and a logic model explicating possible interventions (or needs) and barriers to breastfeeding. We propose a public health solution that begins with a new MCH within the public health training structure at a major Romanian university and a summer course bringing together Romanian and American students to study MCH, including breastfeeding. CONCLUSIONS: We believe that these two courses will promote enthusiasm and generate ideas to develop community-based interventions as well as policy recommendations to increase breastfeeding duration in Romania. We suggest that this public health problem-solving approach provides an integrated way of maintaining and increasing breastfeeding; furthermore, this approach could be broadly used in Eastern Europe. PMID- 21675867 TI - Nonmydriatic retinal image review at time of endocrinology visit results in short term HbA1c reduction in poorly controlled patients with diabetic retinopathy. AB - OBJECTIVES: The objective of this study was to evaluate the effect of discussing retinal findings following nonmydriatic retinal imaging during an endocrinology visit on subsequent HbA1c in poorly controlled diabetic patients with diabetic retinopathy (DR). MATERIALS AND METHODS: During a visit to an endocrinologist, patients with DR and documented HbA1c >= 8.0% within the preceding month were assigned to either addition of nonmydriatic imaging and discussion of retinal findings or standard endocrinology evaluation alone. Ophthalmology care was otherwise the same in both groups. Changes in HbA1c were evaluated 3 months later. RESULTS: One hundred thirteen (94%) of the original 120 subjects completed the study. The mean HbA1c change in the retinal imaging group was a decline of 1.35%, whereas the control group had a 0.26% increase. Controlling for gender, age, duration of diabetes, presence of hypertension, and use of insulin, the difference between groups was significant (p<0.0003). CONCLUSIONS: Nonmydriatic imaging and discussion of retinal findings during an endocrinologist visit may contribute, at least in the short term, to improved glycemic control in patients with DR and elevated HbA1c. PMID- 21675868 TI - Development of a fluorescence resonance energy transfer peptide library technology for detection of protease contaminants in protein-based raw materials used in diagnostic assays. AB - Protease impurities in raw materials used in enzyme immunoassays can impair assay performance. This risk may be greatly decreased if incoming protein-based raw materials are controlled for protease impurities or if protease inhibitors are used in the assay formulations. As many different proteases might occur in protein raw materials, it is desirable to have a general test for protease contamination. With the help of a fluorescence resonance energy transfer peptide library containing about 2.5 million peptides, we have succeeded in establishing such a system, with sensitivity in the nanogram range for known proteases. Protease contamination was found to differ between different raw materials and was correlated with assay performance. Protease activity in contaminated raw materials could be suppressed to various degrees with different chemical inhibitors or by thermal treatment. This technology is suited for the control of incoming protein-based raw materials used for enzyme immunoassays, as well as for the optimization of the use of protein inhibitors or thermal treatment of protein based raw materials for the inactivation of proteases. PMID- 21675869 TI - Introduction of a modular automated voltage-clamp platform and its correlation with manual human Ether-a-go-go related gene voltage-clamp data. AB - In investigating ion channel pharmacology, the manual patch clamp is still considered the gold standard for data quality, notwithstanding the major drawbacks of low throughput and the need for skilled operators. The automated patch clamp platform CytoPatchTM Instrument overcomes these restrictions. Its modular fully automated design makes it possible to obtain scalable throughput without the need for well-trained operators. Its chip design and perfusion system reproduces the manual patch technique, thus ensuring optimal data quality. Further, the use of stably transfected frozen cells, usable immediately after thawing, eliminates the cell quality impairment and low success rates associated with a running cell culture and renders screening costs accurately calculable. To demonstrate the applicability of this platform, 18 blinded compounds were assessed for their impact on the cardiac human Ether-a-go-go related gene K(+) channel. The IC(50) values obtained by the CytoPatch Instrument using the frozen human embryonic kidney 293 cells showed a high correlation (R(2)=0.928) with those obtained from manual patch clamp recordings with human embryonic kidney 293 cells from a running cell culture. Moreover, this correlation extended to sticky compounds such as terfenadine or astemizole. In conclusion, the CytoPatch Instrument operated with frozen cells ready to use directly after thawing provides the same high data quality known from the manual voltage clamp and has the added benefit of enhanced throughput for use in ion channel screening and safety assessment. PMID- 21675870 TI - A flow cytometry-based assay for screening FimH antagonists. AB - Urinary tract infections (UTIs), including cystitis and pyelonephritis, affect a large proportion of the population and account for significant medical costs. In more than 80% of UTIs, uropathogenic Escherichia coli (UPEC) is the causative pathogen. The initial step in the pathogenesis of the infection is the adherence of UPEC to the human bladder epithelium, enabling the invasion into the host cells and the development of UTIs. This process is mediated by the lectin FimH located on type I pili and enables UPECs to attach to oligomannosides of the glycoprotein uroplakin Ia presented on uroepithelial cells. FimH antagonists such as alpha-d-mannopyranosides have been shown to interfere with the attachment of UPEC to their host cells, thus providing a novel therapeutic opportunity for the treatment and prevention of UTIs. In this article, we report a flow cytometry based assay to evaluate the potential of FimH antagonists for the prevention of the infection of the human urinary bladder cell line 5637 by UPEC strain UTI89. The assay was optimized and validated, and the inhibitory potency of different alpha-d-mannopyranosides was determined. Finally, the IC(50) values measured by the flow cytometry-based assay were compared with those reported for other assay formats. PMID- 21675871 TI - Rat primary hepatocytes show enhanced performance and sensitivity to acetaminophen during three-dimensional culture on a polystyrene scaffold designed for routine use. AB - The in vitro evaluation of hepatotoxicity is an essential stage in the research and development of new pharmaceuticals as the liver is one of the most commonly impacted organs during preclinical toxicity studies. Fresh primary hepatocytes in monolayer culture are the most commonly used in vitro model of the liver but often exhibit limited viability and/or reduction or loss of important liver specific functions. These limitations could potentially be overcome using three dimensional (3D) culture systems, but their experimental nature and limited use in liver toxicity screening and drug metabolism has impaired their uptake into commercial screening programs. In this study we use a commercially available polystyrene scaffold developed for routine 3D cell culture to maintain primary rat hepatocytes for use in metabolism and toxicity studies over 72 h. We show that primary hepatocytes retain their natural cuboidal morphology with significantly higher viability (>74%) than cells grown in monolayer culture (maximum of 57%). Hepatocytes in the 3D scaffolds exhibit differential expression of genes associated with phase I, II, and III drug metabolism under basal conditions compared with monolayer culture and can be induced to stably express significantly higher levels of the cytochrome-P450 enzymes 1A2, 2B1, and 3A2 over 48 h. In toxicity studies the hepatocytes in the 3D scaffolds also show increased sensitivity to the model toxicant acetaminophen. These improvements over monolayer culture and the availability of this new easy to use 3D scaffold system could facilitate the uptake of 3D technologies into routine drug screening programs. PMID- 21675872 TI - Validation of a patch clamp screening protocol that simultaneously measures compound activity in multiple states of the voltage-gated sodium channel Nav1.2. AB - Hyperactivity of voltage-gated sodium channels underlies, at least in part, a range of pathological states, including pain and epilepsy. Selective blockers of these channels may offer effective treatment of such disorders. Currently employed methods to screen for sodium channel blockers, however, are inadequate to rationally identify mechanistically diverse blockers, limiting the potential range of indications that may be treated by such agents. Here, we describe an improved patch clamp screening assay that increases the mechanistic diversity of sodium channel blockers being identified. Using QPatch HT, a medium-throughput, automated patch clamp system, we tested three common sodium channel blockers (phenytoin, lidocaine, and tetrodotoxin) with distinct mechanistic profiles at Nav1.2. The single-voltage protocol employed in this assay simultaneously measured the compound activity in multiple states, including the slow inactivated state, of the channel. A long compound incubation period (10 s) was introduced during channel inactivation to increase the probability of identifying "slow binders." As such, phenytoin, which preferentially binds with slow kinetics to the fast inactivated state, exhibited significantly higher potency than that obtained from a brief exposure (100 ms) used in typical assays. This assay also successfully detected the use-dependent block of tetrodotoxin, a well-documented property of this molecule yet unobserved in typical patch clamp protocols. These results indicate that the assay described here can increase the likelihood of identification and mechanistic diversity of sodium channel blockers from a primary screen. It can also be used to efficiently guide the in vitro optimization of leads that retain the desired mechanistic properties. PMID- 21675873 TI - A nonsynonymous variant I248L of the adenosine A3 receptor is associated with coronary heart disease in a Latvian population. AB - Adenosine plays an important part in the cardiac response to ischemia and reperfusion. The human adenosine receptor A3 (A3R), along with other adenosine receptors, is involved in mediation of those effects. The aim of the study was to ascertain whether the nonsynonymous single-nucleotide polymorphism (SNP) I248L (reference SNP ID: rs35511654) located in the A3R gene is associated with coronary heart disease (CHD). DNA samples from 683 individuals with CHD and from 826 control subjects selected from the Latvian Genome Database were successfully screened for rs35511654 using the TaqMan SNP Genotyping Assay. We observed a significantly decreased frequency of the rs35511654 C allele in a group of CHD patients compared with that in controls (p = 0.009). The association remained significant after adjustment for age, sex, and other nongenetic factors (p = 0.02). These results suggest that A allele of rs35511654 may predispose to CHD. PMID- 21675874 TI - Assessing risks and benefits of nonhormonal treatments for vasomotor symptoms in perimenopausal and postmenopausal women. AB - BACKGROUND: Vasomotor symptoms (VMS); (hot flushes and night sweats) are the most common menopausal complaint for which women seek treatment. Several therapies can be considered to help manage these complaints. The objective of this review is to assess the risks and benefits of available and emerging therapeutic options for the management of menopausal VMS. METHODS: A review of the literature was conducted based on relevant publications identified through a PubMed search for clinical trials of agents used in the treatment of VMS. RESULTS: Hormone therapy (HT) remains the most effective treatment available, but there will always remain a need for nonhormonal options. Evidence does not support the efficacy of alternative or over-the-counter products, such as phytoestrogens and black cohosh, and their long-term safety is largely unknown. There is evidence supporting the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the management of VMS from clinical trials of paroxetine, venlafaxine, and desvenlafaxine. Gabapentin appears to be effective, but the doses required may cause poor tolerability and reduced patient adherence. Data also suggest that clonidine has a modest effect at the expense of considerable adverse effects. CONCLUSIONS: Choosing an appropriate treatment approach for the management of VMS requires careful assessment of the riskbenefit ratio of each alternative, as well as individual patient preference. PMID- 21675875 TI - Self-detection remains a key method of breast cancer detection for U.S. women. AB - PURPOSE: The method by which breast cancer is detected becomes a factor for long term survival and should be considered in treatment plans. This report describes patient characteristics and time trends for various methods of breast cancer detection in the United States. METHODS: The 2003 National Health Interview Survey (NHIS), a nationally representative self-report health survey, included 361 women survivors diagnosed with breast cancer between 1980 and 2003. Responses to the question, How was your breast cancer found? were categorized as accident, self-examination, physician during routine breast examination, mammogram, and other. We examined responses by income, race, age, and year of diagnosis. RESULTS: Most women survivors (57%) reported a detection method other than mammographic examination. Women often detected breast cancers themselves, either by self-examination (25%) or by accident (18%). CONCLUSIONS: Despite increased use of screening mammography, a large percentage of breast cancers are detected by the patients themselves. Patient-noted breast abnormalities should be carefully evaluated. PMID- 21675877 TI - The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. AB - Normal human pregnancy is considered a state of enhanced oxidative stress. In pregnancy, it plays important roles in embryo development, implantation, placental development and function, fetal development, and labor. However, pathologic pregnancies, including gestational diabetes mellitus (GDM), are associated with a heightened level of oxidative stress, owing to both overproduction of free radicals and/or a defect in the antioxidant defenses. This has important implications on the mother, placental function, and fetal well being. Animal models of diabetes have confirmed the important role of oxidative stress in the etiology of congenital malformations; the relative immaturity of the antioxidant system facilitates the exposure of embryos and fetuses to the damaging effects of oxidative stress. Of note, there are only a few clinical studies evaluating the potential beneficial effects of antioxidants in GDM. Thus, whether or not increased antioxidant intake can reduce the complications of GDM in both mother and fetus needs to be explored. This review provides an overview and updated data on our current understanding of the complications associated with oxidative changes in GDM. PMID- 21675876 TI - Smoking cessation program with exercise improves cardiovascular disease biomarkers in sedentary women. AB - BACKGROUND: Several cardiovascular disease (CVD) biomarkers sensitive to tobacco exposure have been identified, but how tobacco use cessation impacts them is less clear. We sought to investigate the effects of a smoking cessation program with an exercise intervention on CVD biomarkers in sedentary women. METHODS: This is a cohort study on a subsample of a 2*2 factorial randomized controlled trial (RCT) (exercise setting: home vs. facility; level of exercise counseling: prescription only vs. prescription and adherence counseling) conducted January 2004 through December 2007. The analyses were completed in October 2010. In the greater Boston area, 130 sedentary female smokers aged 19-55 completed a 15-week program. All participants received nicotine replacement therapy (transdermal patch) and brief behavioral counseling for 12 weeks. They all received an exercise prescription on a moderate intensity level. All exercise interventions lasted for 15 weeks, from 3 weeks precessation until 12 weeks postcessation. Main outcome measures were selected CVD biomarkers hypothesized to be affected by smoking cessation or exercise measured at baseline and 12 weeks postcessation. RESULTS: Independent of tobacco abstinence, improvement was seen in inflammation (white blood cells [WBC]), prothrombotic factor (red blood cells [RBC]), and cardiovascular fitness level (maximum oxygen consumption [Vo(2)max]). This suggests that even if complete abstinence is not achieved, reduction in tobacco exposure and increase in exercise can improve the cardiovascular risk profile. A significant decrease was seen for total cholesterol and the total cholesterol high-density lipoprotein cholesterol (HDL-C): ratio only among the abstainers. The heart rate was reduced among all participants, but this decrease was more profound among abstainers. A significant weight gain and body mass index (BMI) increase were observed among abstainers and those who relapsed. We also found an increase in hemoglobin A1c (Hb A1c), although significant only when the groups were combined. CONCLUSIONS: A smoking cessation intervention including exercise reduced tobacco-induced cardiovascular damage selectively within 3 months. PMID- 21675878 TI - Fryns anophthalmia-plus syndrome in an 18-week-old fetus. AB - Fryns anophthalmia-plus syndrome is a very rare condition initially described by Fryns and colleagues in 1995 in a pair of siblings of nonconsanguineous parents. Since that time, only a few cases have been reported, most of them in newborns and young children. Clinical presentation is variable and includes anophthalmia/microphthalmia, cleft lip/palate, and other facial deformities. Furthermore, skeletal, central nervous system, and endocrine anomalies have been described. We report the case of a male fetus of 18 weeks of gestation with normal karyotype and findings matching Fryns anophthalmia-plus syndrome. Pregnancy was terminated because of sonographically proven facial midline defects and a marked cerebral ventriculomegaly. Macroscopic and histological findings obtained at autopsy showed extreme bilateral microphthalmia, unilateral cleft palate, unilateral nasal deformity, and low-set ears. Skeletal anomalies included 13 pairs of ribs, premature ossification of the calcaneus, and talipes. PMID- 21675879 TI - Pentalogy or hexalogy of Cantrell? AB - Pentalogy of Cantrell (PC) is a rare congenital syndrome involving the abdominal wall, sternum, diaphragm, pericardium, and heart. The embryonic period in which PC develops coincides with that of umbilical cord (UC) formation. The aim of the following study was to address the question of whether PC is associated with UC pathologies. Four cases, prenatally identified between 2002 and 2008, were enrolled in this study. Umbilical cord pathologies defined as single umbilical artery, short cord, or UC with atypical coiling pattern were retrospectively assessed on stored ultrasound images and from autopsy reports. The literature regarding PC and UC pathologies was reviewed. Three singleton pregnancies and 1 monoamniotic twin pregnancy with twin reversed arterial perfusion sequence were reviewed. All had a normal karyotype. Three showed the classical PC stigmata, with ectopia cordis. One fetus had no ectopia cordis; this case had a normal UC, whereas all others fetuses showed a short UC with atypical coiling pattern. Of 26 publications dealing with PC, the UC was described in only 8 cases, 7 of which were abnormal. There seems to be a strong correlation between the PC and UC abnormalities, in particular in cases with ectopia cordis. We speculate that the insult leading to the classical malformations of PC and UC abnormalities is the same or the sequence of malformations itself may alter the early fetoplacental blood flow and therefore the normal development of the UC angioarchitecture. PMID- 21675880 TI - The risks and benefits of 5alpha-reductase inhibitors for prostate-cancer prevention. PMID- 21675881 TI - Weighing the benefits of high-dose simvastatin against the risk of myopathy. PMID- 21675882 TI - Images in clinical medicine. Toxic effects of levamisole in a cocaine user. PMID- 21675884 TI - The polio endgame. PMID- 21675883 TI - Interactive medical case. A sleeping giant. PMID- 21675885 TI - Advancing health care equity through improved data collection. PMID- 21675886 TI - The ER, 50 years on. PMID- 21675887 TI - The waits that matter. PMID- 21675888 TI - Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil. AB - BACKGROUND: Because postlicensure surveillance determined that a previous rotavirus vaccine, RotaShield, caused intussusception in 1 of every 10,000 recipients, we assessed the association of the new monovalent rotavirus vaccine (RV1) with intussusception after routine immunization of infants in Mexico and Brazil. METHODS: We used case-series and case-control methods to assess the association between RV1 and intussusception. Infants with intussusception were identified through active surveillance at 69 hospitals (16 in Mexico and 53 in Brazil), and age-matched infants from the same neighborhood were enrolled as controls. Vaccination dates were verified by a review of vaccination cards or clinic records. RESULTS: We enrolled 615 case patients (285 in Mexico and 330 in Brazil) and 2050 controls. An increased risk of intussusception 1 to 7 days after the first dose of RV1 was identified among infants in Mexico with the use of both the case-series method (incidence ratio, 5.3; 95% confidence interval [CI], 3.0 to 9.3) and the case-control method (odds ratio, 5.8; 95% CI, 2.6 to 13.0). No significant risk was found after the first dose among infants in Brazil, but an increased risk, albeit smaller than that seen after the first dose in Mexico--an increase by a factor of 1.9 to 2.6 - was seen 1 to 7 days after the second dose. A combined annual excess of 96 cases of intussusception in Mexico (approximately 1 per 51,000 infants) and in Brazil (approximately 1 per 68,000 infants) and of 5 deaths due to intussusception was attributable to RV1. However, RV1 prevented approximately 80,000 hospitalizations and 1300 deaths from diarrhea each year in these two countries. CONCLUSIONS: RV1 was associated with a short-term risk of intussusception in approximately 1 of every 51,000 to 68,000 vaccinated infants. The absolute number of deaths and hospitalizations averted because of vaccination far exceeded the number of intussusception cases that may have been associated with vaccination. (Funded in part by the GAVI Alliance and the U.S. Department of Health and Human Services.). PMID- 21675889 TI - Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans. AB - BACKGROUND: Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed. METHODS: We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A-specific enzyme-linked immunosorbent assay. RESULTS: In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P<0.001). In study A, the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine. Safety profiles were similar across vaccine groups, although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and induration at the vaccination site. Adverse events were consistent with age-specific morbidity in the study areas; no serious vaccine related adverse events were reported. CONCLUSIONS: The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine. (Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation; Controlled-Trials.com numbers, ISRCTN78147026 and ISRCTN87739946.). PMID- 21675890 TI - Vaccine-derived poliomyelitis 12 years after infection in Minnesota. AB - A 44-year-old woman with long-standing common variable immunodeficiency who was receiving intravenous immune globulin suddenly had paralysis of all four limbs and the respiratory muscles, resulting in death. Type 2 vaccine-derived poliovirus was isolated from stool. The viral capsid protein VP1 region had diverged from the vaccine strain at 12.3% of nucleotide positions, and the two attenuating substitutions had reverted to the wild-type sequence. Infection probably occurred 11.9 years earlier (95% confidence interval [CI], 10.9 to 13.2), when her child received the oral poliovirus vaccine. No secondary cases were identified among close contacts or 2038 screened health care workers. Patients with common variable immunodeficiency can be chronically infected with poliovirus, and poliomyelitis can develop despite treatment with intravenous immune globulin. PMID- 21675891 TI - Auditing access to specialty care for children with public insurance. AB - BACKGROUND: Health care reform has expanded eligibility to public insurance without fully addressing concerns about access. We measured children's access to outpatient specialty care to identify disparities in providers' acceptance of Medicaid and the Children's Health Insurance Program (CHIP) versus private insurance. METHODS: Between January and May 2010, research assistants called a stratified, random sample of clinics representing eight specialties in Cook County, Illinois, which has a high proportion of specialists. Callers posed as mothers of pediatric patients with common health conditions requiring outpatient specialty care. Two calls, separated by 1 month, were placed to each clinic by the same person with the use of a standardized clinical script that differed by insurance status. RESULTS: We completed 546 paired calls to 273 specialty clinics and found significant disparities in provider acceptance of Medicaid-CHIP versus private insurance across all tested specialties. Overall, 66% of Medicaid-CHIP callers (179 of 273) were denied an appointment as compared with 11% of privately insured callers (29 of 273) (relative risk, 6.2; 95% confidence interval [CI], 4.3 to 8.8; P<0.001). Among 89 clinics that accepted both insurance types, the average wait time for Medicaid-CHIP enrollees was 22 days longer than that for privately insured children (95% CI, 6.8 to 37.5; P=0.005). CONCLUSIONS: We found a disparity in access to outpatient specialty care between children with public insurance and those with private insurance. Policy interventions that encourage providers to accept patients with public insurance are needed to improve access to care. PMID- 21675892 TI - Images in clinical medicine. Bilateral hilar and mediastinal lymphadenopathy. PMID- 21675893 TI - Case records of the Massachusetts General Hospital. Case 18-2011. A 35-year-old HIV-positive woman with headache and altered mental status. PMID- 21675894 TI - Rotavirus vaccination and intussusception--act two. PMID- 21675895 TI - Elastogenesis in the vaginal wall and pelvic-organ prolapse. PMID- 21675896 TI - Bevacizumab for retinopathy of prematurity. PMID- 21675897 TI - Bevacizumab for retinopathy of prematurity. PMID- 21675898 TI - Bevacizumab for retinopathy of prematurity. PMID- 21675899 TI - Bevacizumab for retinopathy of prematurity. PMID- 21675901 TI - Apixaban in patients with atrial fibrillation. PMID- 21675902 TI - Apixaban in patients with atrial fibrillation. PMID- 21675904 TI - Multiple myeloma. PMID- 21675906 TI - Renal improvement in myeloma with bortezomib plus plasma exchange. PMID- 21675907 TI - Streptococcal pharyngitis. PMID- 21675909 TI - Erlotinib or gefitinib for non-small-cell lung cancer. PMID- 21675910 TI - Erlotinib or gefitinib for non-small-cell lung cancer. PMID- 21675912 TI - Mutations in CYP24A1 and idiopathic infantile hypercalcemia. AB - BACKGROUND: Vitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. METHODS: We used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system. RESULTS: Sequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25 dihydroxyvitamin D(3) degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations. CONCLUSIONS: The presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants. PMID- 21675913 TI - Why states are so miffed about Medicaid--economics, politics, and the "woodwork effect". PMID- 21675914 TI - Managed competition for Medicare? Sobering lessons from The Netherlands. PMID- 21675916 TI - Introduction to theme "membrane protein folding and insertion". AB - This volume of the Annual Review of Biochemistry contains three reviews on current developments in membrane protein research: Grigoryan et al. "Transmembrane Communication: General Principles and Lessons from the Structure and Function of the M2 Proton Channel, K+ Channels, and Integrin Receptors," Hagan et al. "beta-Barrel Membrane Protein Assembly by the Bam Complex," and Dalbey et al. "Assembly of Bacterial Inner Membrane Proteins." In this short introduction, I discuss these reviews in the larger context of where the field of membrane protein biochemistry is heading. PMID- 21675915 TI - From serendipity to therapy. AB - My postdoctoral training in the biosynthesis of plant polysaccharides at the University of California, Berkeley, led me, rather improbably, to study mucopolysaccharide storage disorders in the intramural program of the National Institutes of Health (NIH). I have traced the path from studies of mucopolysaccharide turnover in cultured cells to the development of therapy for patients. The key experiment started as an accident, i.e., the mixing of cells of different genotypes, resulting in correction of their biochemical defect. This serendipitous experiment led to identification of the enzyme deficiencies in the Hurler and Hunter syndromes, to an understanding of the biochemistry of lysosomal enzymes in general, and to the cell biology of receptor-mediated endocytosis and targeting to lysosomes. It paved the way for the development of enzyme replacement therapy with recombinant enzymes. I have also included studies performed after I moved to the University of California, Los Angeles (UCLA), including a recent unexpected finding in a neurodegenerative mucopolysaccharide storage disease, the Sanfilippo syndrome, with implications for therapy. PMID- 21675917 TI - Mass spectrometry in the postgenomic era. AB - Mass spectrometry (MS) is rapidly becoming an essential tool for biologists and biochemists in their efforts to throw light on molecular mechanisms within cellular systems. Used in unison with genome sequence data, MS has developed into the method of choice for identifying proteins, elucidating their posttranslational modifications, and reading out their functional interactions. Variations of the method have even begun to enable accurate mass determination of intact protein complexes, allowing for direct determination of subunit stoichiometry and the interactions between the subunits. Advances in mass spectrometric technologies have also led to great improvements in our ability to probe and define many of the other key molecular players in cells, including the all important lipid components. We provide here some perspectives on the explosion of applications of MS to protein science, systems biology, proteomics, lipidomics, and cell biology in general. PMID- 21675919 TI - DNA replicases from a bacterial perspective. AB - Bacterial replicases are complex, tripartite replicative machines. They contain a polymerase, polymerase III (Pol III), a beta2 processivity factor, and a DnaX complex ATPase that loads beta2 onto DNA and chaperones Pol III onto the newly loaded beta2. Bacterial replicases are highly processive, yet cycle rapidly during Okazaki fragment synthesis in a regulated way. Many bacteria encode both a full-length tau and a shorter gamma form of DnaX by a variety of mechanisms. gamma appears to be uniquely placed in a single position relative to two tau protomers in a pentameric ring. The polymerase catalytic subunit of Pol III, alpha, contains a PHP domain that not only binds to a prototypical epsilon Mg2+ dependent exonuclease, but also contains a second Zn2+-dependent proofreading exonuclease, at least in some bacteria. This review focuses on a critical evaluation of recent literature and concepts pertaining to the above issues and suggests specific areas that require further investigation. PMID- 21675918 TI - Biochemistry of mobile zinc and nitric oxide revealed by fluorescent sensors. AB - Biological mobile zinc and nitric oxide (NO) are two prominent examples of inorganic compounds involved in numerous signaling pathways in living systems. In the past decade, a synergy of regulation, signaling, and translocation of these two species has emerged in several areas of human physiology, providing additional incentive for developing adequate detection systems for Zn(II) ions and NO in biological specimens. Fluorescent probes for both of these bioinorganic analytes provide excellent tools for their detection, with high spatial and temporal resolution. We review the most widely used fluorescent sensors for biological zinc and nitric oxide, together with promising new developments and unmet needs of contemporary Zn(II) and NO biological imaging. The interplay between zinc and nitric oxide in the nervous, cardiovascular, and immune systems is highlighted to illustrate the contributions of selective fluorescent probes to the study of these two important bioinorganic analytes. PMID- 21675921 TI - Structure-function relationships of the G domain, a canonical switch motif. AB - GTP-binding (G) proteins constitute a class of P-loop (phosphate-binding loop) proteins that work as molecular switches between the GDP-bound OFF and the GTP bound ON state. The common principle is the 160-180-residue G domain with an alpha,beta topology that is responsible for nucleotide-dependent conformational changes and drives many biological functions. Although the G domain uses a universally conserved switching mechanism, its structure, function, and GTPase reaction are modified for many different pathways and processes. PMID- 21675920 TI - Enzymatic transition states, transition-state analogs, dynamics, thermodynamics, and lifetimes. AB - Experimental analysis of enzymatic transition-state structures uses kinetic isotope effects (KIEs) to report on bonding and geometry differences between reactants and the transition state. Computational correlation of experimental values with chemical models permits three-dimensional geometric and electrostatic assignment of transition states formed at enzymatic catalytic sites. The combination of experimental and computational access to transition-state information permits (a) the design of transition-state analogs as powerful enzymatic inhibitors, (b) exploration of protein features linked to transition state structure, (c) analysis of ensemble atomic motions involved in achieving the transition state, (d) transition-state lifetimes, and (e) separation of ground-state (Michaelis complexes) from transition-state effects. Transition state analogs with picomolar dissociation constants have been achieved for several enzymatic targets. Transition states of closely related isozymes indicate that the protein's dynamic architecture is linked to transition-state structure. Fast dynamic motions in catalytic sites are linked to transition-state generation. Enzymatic transition states have lifetimes of femtoseconds, the lifetime of bond vibrations. Binding isotope effects (BIEs) reveal relative reactant and transition-state analog binding distortion for comparison with actual transition states. PMID- 21675922 TI - Genetic diversity of the ordinary strain of Potato virus Y (PVY) and origin of recombinant PVY strains. AB - The ordinary strain of Potato virus Y (PVY), PVY(O), causes mild mosaic in tobacco and induces necrosis and severe stunting in potato cultivars carrying the Ny gene. A novel substrain of PVY(O) was recently reported, PVY(O)-O5, which is spreading in the United States and is distinguished from other PVY(O) isolates serologically (i.e., reacting to the otherwise PVY(N)-specific monoclonal antibody 1F5). To characterize this new PVY(O)-O5 subgroup and address possible reasons for its continued spread, we conducted a molecular study of PVY(O) and PVY(O)-O5 isolates from a North American collection of PVY through whole-genome sequencing and phylogenetic analysis. In all, 44 PVY(O) isolates were sequenced, including 31 from the previously defined PVY(O)-O5 group, and subjected to whole genome analysis. PVY(O)-O5 isolates formed a separate lineage within the PVY(O) genome cluster in the whole-genome phylogenetic tree and represented a novel evolutionary lineage of PVY from potato. On the other hand, the PVY(O) sequences separated into at least two distinct lineages on the whole-genome phylogenetic tree. To shed light on the origin of the three most common PVY recombinants, a more detailed phylogenetic analysis of a sequence fragment, nucleotides 2,406 to 5,821, that is present in all recombinant and nonrecombinant PVY(O) genomes was conducted. The analysis revealed that PVY(N:O) and PVY(N-Wi) recombinants acquired their PVY(O) segments from two separate PVY(O) lineages, whereas the PVY(NTN) recombinant acquired its PVY(O) segment from the same lineage as PVY(N:O). These data suggest that PVY(N:O) and PVY(N-Wi) recombinants originated from two separate recombination events involving two different PVY(O) parental genomes, whereas the PVY(NTN) recombinants likely originated from the PVY(N:O) genome via additional recombination events. PMID- 21675923 TI - Olpidium bornovanus-mediated germination of ascospores of Monosporascus cannonballus: a host-specific rhizosphere interaction. AB - Monosporascus cannonballus, a host-specific root-infecting ascomycete, is the causal agent of a destructive disease of melon (Cucumis melo L.) known as vine decline. Ascospores germinate only in the rhizosphere of melon plants growing in field soil. However, no germination occurs in the rhizosphere of melon plants if the field soil is heated to temperatures >50 degrees C prior to infestation with ascospores. This observation suggested that germination is mediated by one or more heat-sensitive members of the soil microflora. Although bacteria or actinomycetes were heretofore suspected as the germination-inducing microbes, our data demonstrate that Olpidium bornovanus, an obligate, host-specific, root infecting zoosporic fungus, is responsible. In four experiments conducted in autoclaved field soil amended with various population densities of culturally produced ascospores, significant ascospore germination was recorded only in the rhizosphere of cantaloupe seedlings colonized by O. bornovanus. PMID- 21675924 TI - Soil suppressiveness against the disease complex of the soybean cyst nematode and sudden death syndrome of soybean. AB - The ecology of the complex of soybean cyst nematode (SCN) and sudden death syndrome (SDS) of soybean was investigated under soybean monoculture in two field experiments from 2003 to 2007. Initially, susceptible soybean 'Spencer' was planted while inoculating Fusarium virguliforme into nonfumigated or preseason fumigated plots (methyl bromide, MB, at 450 kg/ha), and SCN and SDS were monitored. In one field, SCN population densities declined in nonfumigated but increased in fumigated plots. After years of limited SDS in 2003 and 2004, SDS developed later in nonfumigated than fumigated plots. In 2006 in the greenhouse, nondisturbed or disturbed soil cores (10-cm diameter, 30-cm depth) from field plots received two two-level factors: (i) nonfumigated or fumigated (1,070 kg/ha MB); and (ii) noninoculated or inoculated with 9,000 second-stage juveniles of SCN. At harvest, nonfumigated cores from nonfumigated plots had fewer nematodes and less SDS regardless of disturbance or inoculation than the corresponding fumigated cores and any cores from fumigated plots. In the second field, SCN became detectable after 2003 during the monoculture in nonfumigated plots and lagged in fumigated plots; both treatments had low levels of SDS. Exploiting the suppressiveness of the first field could allow for biological control of SDS and SCN in soybean production. PMID- 21675925 TI - Recent advances in immunotherapy for the treatment of prostate cancer. AB - INTRODUCTION: Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development. AREAS COVERED: An autologous antigen presenting cell vaccine loaded with prostate acid phosphatase conjugated with GM-CSF, sipuleucel-T confers a survival advantage in men with metastatic castration-resistant prostate cancer (CRPC) and is now FDA approved based on the IMPACT trial. A poxvirus-based vaccine, PROSTVAC-VF TRICOM targeting prostate-specific antigen (PSA), has demonstrated improved survival in a randomized Phase II trial of patients with metastatic CRPC. Novel T lymphocyte checkpoint inhibitors of cytotoxic T lymphocyte antigen 4 and programmed death-1 are also emerging. Recognition of improved survival without an earlier clinical signal of activity by conventional criteria has led to new guidelines to evaluate immunotherapeutic agents. The clinical benefit of combining vaccines with chemotherapy, radiotherapy and other immunotherapeutic and biologic agents is being evaluated in the context of disappointing results of combination GVAX vaccine and docetaxel chemotherapy. EXPERT OPINION: To build on the success of early phase trials, efforts must be made to optimize vaccine approaches and patient selection. PMID- 21675926 TI - Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1: a patent survey. AB - INTRODUCTION: Vascular adhesion protein-1 (VAP-1)/semicarbazide-sensitive amine oxidase (SSAO) is an adhesion protein involved in leukocyte trafficking and inflammatory processes, with a special amine oxidase activity. Inhibitors have been mainly developed for treating chronic inflammatory disorders. The utility of inhibitors as antiangiogenic agents in ophthalmological and oncological diseases is currently under evaluation. SSAO substrates may mimic several insulin effects, although their utility for the treatment of diabetes is still far from being fully understood. AREAS COVERED: This paper reviews the patent literature of SSAO/VAP-1 inhibitors and substrates, for the period of 1990 - 2010. The current stage of SSAO/VAP-1-interacting agents published in patents is described, along with their chemical structures and pharmacological uses. EXPERT OPINION: SSAO/VAP 1 is a promising anti-inflammatory target. Another important field for therapeutic application of these inhibitors may be ophthalmology, due to their antiangiogenic effects. SSAO substrates might also be of therapeutic value in the treatment of diabetes; however, more extensive research has to be undertaken to validate this approach. PMID- 21675927 TI - Reproductive component vaccine developments for contraceptive and non contraceptive uses. AB - INTRODUCTION: There has been no novel contraceptive development since 'the Pill', 50 years ago. Despite the subsequent steady increase in the use of contraceptives, the contraceptive needs of a significant proportion of the world population have not yet been met. The key need is for novel, effective, practical, long-lasting, affordable, non-steroidal contraceptives. Immunocontraception, based on vaccination against components of the reproductive system that do not affect other physiological systems, fulfils most of the criteria of such a contraceptive. To date, immunocontraceptives have been developed for animal use and the application to human contraception is an exciting proposition. In addition, immunocontraceptive research has provided a greater understanding of the vaccination against 'self-antigens' and has led to non-contraceptive developments for these vaccines. AREAS COVERED: This review provides an understanding of the historic context of immunocontraceptives and the progress that has been made. In some cases, the contraceptive aspect has been abandoned, but the knowledge gained has enabled other therapeutic advances. EXPERT OPINION: Reproductive research is still an important area and innovations continue to arise, which offer hope for new therapeutics in reproduction and related fields. PMID- 21675928 TI - Coincidental associations do not provide proof for the etiology of autism. PMID- 21675929 TI - Folate-conjugated methoxy poly (ethylene glycol)/poly (L-Alanine) amphiphilic block copolymeric micelles for targeted delivery of paclitaxel. AB - Folate has been used as a targeting moiety of various anticancer agents to increase their cellular uptake within target cells since folate receptors(FR) are vastly overexpressed in many tumors. In this study, amphiphilic block copolymers composed of methoxy poly (ethylene glycol)(MPEG) and poly(L-Alanine)(PALA) were synthesized and then conjugated with folate to produce a folate receptor-targeted drug carrier for tumor-specific drug delivery. The structure of the copolymers was confirmed by 1HNMR. The CMC values of MPEG-PALA(PLAM) and FOL-PALA-MPEG(FOL PLAM) were 0.678 * 10-5 mol/L and 0.864 * 10-5 mol/L, respectively. The paclitaxel loaded micelles prepared from PLAM and FOL-PLAM both exhibited spherical shapes and nano-scale dimensions. The average diameter, encapsulation efficiency(EE), drug loading efficiency(LC) were 55 nm, 80.6%, 20.2% for the PLAM micelles and 75 nm, 69.7%, 17.4% for FOL-PLAM micelles. Furthermore, in vitro release study indicated that the release rate of paclitaxel from both drug-loaded micelles was slow and sustained. PMID- 21675930 TI - EMPACT syndrome. AB - Phenytoin is commonly used an antiepileptic medication for seizure prophylaxis in patients with brain metastases. In these oncology patients group, phenytoin induced severe adverse reactions may occur. Antiepileptic, particularly phenytoin induced severe skin reactions including Stevens-Johnson syndrome (SJS) and bullous form of erythema multiforme have been reported in the patients treated with cranial irradiation due to brain metastasis. The acronym EMPACT (Erythema Multiforme associated with Phenytoin And Cranial radiation Therapy) was recently described as a clinical entity. Herein, we report a 36-year-old female with breast carcinoma, who developed EMPACT syndrome after treating with cranial radiation therapy for brain metastasis and phenytoin for seizure prophylaxis. PMID- 21675931 TI - Chronic exposure to particles caused bronchioloalveolar carcinoma in a patient with cryptogenic organizing pneumonia evaluated by elemental analysis. AB - An 81-year-old Japanese man had organizing pneumonia (OP), and he had worked as a painter and had a history of exposure of various paints over 20 years. The major features on computed tomography (CT) in patients were cryptogenic organizing pneumonia (COP) showing airspace consolidation, and air bronchograms were consistent finding in consolidation in right lung of S10. Such parenchymal abnormalities were clinically and pathologically diagnosed COP and the lesion was improved by corticosteroid therapy. About 1.5 years later, similar shadows emerged in new locations of right S4 and left S8, and these were bronchioloalveolar carcinoma (BAC) classified as adenocarcinoma. BAC causes similar X-ray changes to COP and inflammation accompanying BAC can also respond to corticosteroids, which may lead to delay in the diagnosis of BAC associated with COP. These radiological features lead to difficulty in making a diagnosis of new parenchymal diseases. The present patient had been painter, and metals of carcinogens were proven in both tissue of COP and BAC. Here, we reported a painter with COP and new-onset BAC who had been exposed to particles proven by elemental analysis. The combination of COP with BAC is considered uncommon, but the risk of BAC may increase when there is a history of particle inhalation. PMID- 21675932 TI - The effects of Bifidobacteria on the lipid profile and oxidative stress biomarkers of male rats fed thermally oxidized soybean oil. AB - Over the years, there has been concern about the changes taking place in heated oils and the effects on individuals consuming them. The present study investigated the effects of a diet containing thermally oxidized soybean oil (TO) or TO supplemented with probiotic Bifidobacteria (TO+Pro) on the serum lipid profile and oxidative stress biomarkers of male rats. The data showed several indicators of oil deterioration after thermal processing, including high levels of % free fatty acid (FFA; 15-fold), acid value (AV; 14-fold), peroxide value (8 fold), p-anisidine value (AnV; 39-fold), total oxidation value (TOTOX; 19-fold), thiobarbituric acid-reactive substances (TBARS) value (8.5-fold), and trans-FA (TFA) isomers (2.5-fold) compared to the control. The rats that were fed a diet containing TO showed a significant (p < 0.05) decrease in body weight gain, food efficiency values, and liver weight. Furthermore, the total cholesterol and low density lipoprotein (LDL) levels were increased, while the high-density lipoprotein (HDL) level was decreased in blood serum samples. High levels of TBARS, superoxide dismutase (SOD), and glutathione reductase (GR) activities were also detected in the livers, kidneys, testes, and brains of rats. Interestingly, a diet containing TO+Pro restored all biological parameters to their control values. The present data suggested that Bifidobacteria may ameliorate the serum lipid profile and oxidative stress biomarkers that are generated in animals that are fed a TO diet. PMID- 21675933 TI - Image guided surgical navigation integrating "mirroring" computational planning based on intra-operative cone-beam CT imaging: a promising new approach for management of primary bilateral midfacial fractures. AB - Cosmetic and functional re-establishment following primary or secondary treatment of comminuted and complex midfacial fractures remains a challenge for surgeons. Computer Assisted Surgery (CAS) has revolutionized the conceptualization and approach to these reconstructions and has become a reliable part of the surgical armamentarium. Computer aided design/modeling (CAD/CAM) software that allows "mirroring" planning coupled to navigation systems has dramatically improved surgical strategies in reconstructive surgery of the craniomaxillofacial skeleton, particularly with respect to the prediction of suitable symmetric bone repositioning. So far, however, use of this approach has been limited to unilateral cases, with a non-fractured contralateral side being considered the condition sine qua non for the application of such a technique and the "mirroring" planning being performed on pre-operative CT imaging. We report a case of complex primary reconstruction in a patient presenting with bilateral midfacial fractures, using complete intra-operative sequence processing with a navigation system integrating "mirroring" computational planning based on a mobile C-arm cone-beam computed tomography (CBCT) scan with a flat-panel detector. To the best of our knowledge, no similar cases have yet been reported involving the use of this sequencing method in the primary management of bilateral midfacial fracture reconstruction. PMID- 21675934 TI - Computer navigated total knee arthroplasty: aspects of a single unit's experience of 777 cases. AB - The use of computer navigation and conventional techniques in total knee arthroplasty remains controversial. Advocates of computer navigated techniques cite better alignment of components and reduced morbidity associated with avoidance of intramedullary instrumentation as a rationale for their use. In contrast, proponents of conventional techniques argue that better alignment does not correlate with a better functional outcome and that the conventional approach avoids the perceived risk of fracture associated with bicortical insertion of navigation tracker pins. All total knee arthoplasties performed at our institution are prospectively monitored for life in a dedicated Joint Replacement Assessment Clinic (JRAC). Patients are reviewed by physiotherapists, independent of the surgeons who performed surgery, both preoperatively and at six weeks, three and six months, and one, two and five years postoperatively (and every five years thereafter). Patients are assessed using validated outcome measures (Knee Society Score, Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, Short Form SF-36 Health Survey (version 2) and a patient satisfaction score). In addition, at 6 months post surgery, a CT scan of each implanted prosthesis is performed using the Perth CT knee protocol. The findings of a single unit's experience of 777 navigated primary total knee replacements are discussed and critically compared to the body of literature that currently relates to this controversial topic. PMID- 21675935 TI - Direct measurement of acetabular radiographic version using an ordinary goniometer: a precision study. AB - OBJECTIVE: The acetabular version following total hip arthroplasty is an important prognostic factor. Computer navigation serves as a precise tool during hip arthroplasty, which requires precise measurement to verify the effect of the procedure. Wan and colleagues have reported an innovative method for measuring acetabular radiographic version with an ordinary goniometer. Our objective was to study the precision of this method. METHODS: We derived the underlying mathematical principle of Wan's method and produced a correction formula and chart. Forty-eight computer-synthesized radiographs were used to study the method and its mathematical correction. Ten real radiographs were used to detect intra observer difference. The paired t-test was used for statistical analysis. RESULTS: There was a significant difference between synthetic acetabular radiographic version and the measurement obtained with Wan's method (p < 0.05), but there was no difference after mathematical correction (p = 0.15). For smaller radiographic version (<20(o)), there was no statistical difference using Wan's method (p = 0.054). CONCLUSIONS: The method of Wan and colleagues can be used when acetabular radiographic version is less than 20 degrees . For larger radiographic versions, however, mathematical correction is necessary to obtain precise results. PMID- 21675936 TI - The nano spray dryer B-90. AB - INTRODUCTION: Spray drying is an extremely well-established technology for the production of micro-particulate powders suited for a variety of drug delivery applications. In recent years, the rise in nanomedicine has placed increased pressure on the existing systems to produce nanoparticles in good yield and with a narrow size distribution. However, the separation and collection of nanoparticles with conventional spray dryer set ups is extremely challenging due to their typical low collection efficiency for fine particles < 2 MUm. Currently, nanoparticles have to be agglomerated into larger microparticles, via a two-step approach, in order to collect them in a sizeable amount. However, this method has to contend with the issue of adequate redispersibility of the primary particles to reap the full benefits of nanosizing. AREAS COVERED: An overview on the advances in spray drying technology is provided in this review with particular emphasis on the novel Buchi(r) Nano Spray Dryer B-90. Readers will appreciate the limitations of conventional spray drying technology, understand the mechanisms of the Buchi(r) Nano Spray Dryer B-90, and also learn about the strengths and shortcomings of the system. EXPERT OPINION: The Buchi(r) Nano Spray Dryer B-90 offers a new, simple and alternative approach for the production of nanoparticles suited for a variety of drug delivery applications. PMID- 21675937 TI - Study on the relationship between mean platelet volume and platelet distribution width with coronary artery lesion in children with Kawasaki disease. AB - Mean platelet volume (MPV) and platelet distribution width (PDW) are correlated with platelet function and may be a more sensitive index than platelet number as a marker of clinical interest in various disorders. Therefore, this study was designed to answer the following questions: do MPV and PDW levels change in Kawasaki disease (KD), is there any relation between CAL in children with MPV and PDW and whether MPV and PDW might support a diagnosis of incomplete KD. A total of 309 KD patients and 160 sex-age matched healthy subjects were enrolled into the study. For all subjects following tests were performed: MPV, PDW, platelet count, white blood cells counts (WBC), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Patients with CALs were assigned to three groups depending on the extent of CALs which were visualized by echocardiography: dilatation and/or ectasia, aneurysm and giant aneurysms. We compared patients with fever and four or five of the principal criteria (complete KD, cKD) to the other patients (iKD). Compared with healthy controls a significant decrease in MPV and PDW (p < 0.001 and p < 0.05, respectively) and increase in WBC, platelet count, CRP and ESR (p all < 0.001) was noted in children with KD. There were no statistically differences in MPV and PDW between KD with CALs and KD without CALs (p > 0.05). However, MPV and PDW were significantly lower in patients with iKD than in group with cKD (p = 0.003, p = 0.014, respectively). It was first shown that patients with KD have lower MPV and PDW than control subjects. The diagnosis of iKD is challenging but can be supported by the presence of lower MPV and PDW. PMID- 21675938 TI - Nutritional status of Makushi Amerindian children and adolescents of Guyana. AB - BACKGROUND: Amazonian Indians are in the midst of a rapid cultural transition. The developments affecting Amazonian Indians present an opportunity to address important public health problems through public and private initiatives, but to do so it is imperative to begin with information on the health status of these peoples and the underlying factors affecting it. However, relatively few such data are available for this vast region. AIM: This study describes the nutritional status of Makushi Amerindians of Guyana and considers several variables which might help to explain it. SUBJECTS AND METHODS: Data for 792 Makushi, 0-20 years of age from 11 villages are considered. Outcome variables considered are anthropometric markers of growth and nutritional status; specifically height-for-age, weight-for-height and body-mass index. Predictor variables explored are age, sex, relative isolation, number of siblings, season of birth, diet and morbidity. Fisher's exact test, chi-square, Pearson's correlation and multiple regression were used to assess possible relationships between these variables. RESULTS: Relative to other Amazonian Indians, the Makushi have a lower rate of linear-growth faltering and a higher rate of linear growth faltering relative to non-Amerindian Guyanese. Males, older cohorts, those living in isolated villages or born in the wet season showed higher rates of growth faltering. CONCLUSION: Makushi nutritional status may be explained by sex, age, relative isolation, family size, season of birth, dietary intake and infectious disease. PMID- 21675939 TI - Combined effects of coffee consumption and serum gamma-glutamyltransferase on serum C-reactive protein in middle-aged and elderly Japanese men and women. AB - BACKGROUND: The association between coffee intake and circulating levels of C reactive protein (CRP) may be modified by oxidative stress. The authors examined the relation of coffee consumption to serum CRP considering potential inter actions of serum gamma-glutamyltransferase (GGT) and bilirubin. METHODS: The subjects included 4455 men and 5942 women aged 49-76 years who participated in the baseline survey of a cohort study on lifestyle-related diseases in Fukuoka, Japan. Geometric means of serum CRP and 95% confidence intervals across the category of coffee intake stratified by serum GGT and bilirubin were estimated using multiple linear regression. RESULTS: Serum CRP concentrations were progressively lower with higher intake of coffee in men with high serum GGT (p for trend=0.009), but not in those with low serum GGT (p for trend=0.73) and GGT modified the association (p for interaction=0.03). Women showed no association between coffee intake and CRP whether serum GGT was low or high. There was no effect modification of serum bilirubin on the association between coffee intake and CRP in either men or women. CONCLUSIONS: These results support a protective effect of coffee intake against systematic inflammation in middle-aged and elderly Japanese men and imply that such an effect may be stronger in elevated oxidative stress. PMID- 21675940 TI - Differential expression of CDC25 phosphatases splice variants in human breast cancer cells. AB - BACKGROUND: CDC25 phosphatases control cell cycle progression by activating cyclin dependent kinases. The three CDC25 isoforms encoding genes are submitted to alternative splicing events which generate at least two variants for CDC25A and five for both CDC25B and CDC25C. An over-expression of CDC25 was reported in several types of cancer, including breast cancer, and is often associated with a poor prognosis. Nevertheless, most of the previous studies did not address the expression of CDC25 splice variants. Here, we evaluated CDC25 spliced transcripts expression in anti-cancerous drug-sensitive and resistant breast cancer cell lines in order to identify potential breast cancer biomarkers. METHODS: CDC25 splice variants mRNA levels were evaluated by semi-quantitative RT-PCR and by an original real-time RT-PCR assay. RESULTS: CDC25 spliced transcripts are differentially expressed in the breast cancer cell lines studied. An up regulation of CDC25A2 variant and an increase of the CDC25C5/C1 ratio are associated to the multidrug-resistance in VCREMS and DOXOR breast cancer cells, compared to their sensitive counterpart cell line MCF-7. Additionally, CDC25B2 transcript is exclusively over-expressed in VCREMS resistant cells and could therefore be involved in the development of certain type of drug resistance. CONCLUSIONS: CDC25 splice variants could represent interesting potential breast cancer prognostic biomarkers. PMID- 21675941 TI - IFCC international conventional reference procedure for the measurement of free thyroxine in serum: International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group for Standardization of Thyroid Function Tests (WG STFT)(1). AB - The IFCC Working Group for Standardization of Thyroid Function Tests proposes a candidate international conventional reference procedure (RMP) for measurement of the amount-of-substance concentration of free thyroxine in plasma/serum at physiological pH 7.40 and temperature (37.0 degrees C). The unit for reporting measurement results is, by convention, pmol/L. The RMP is based on equilibrium dialysis isotope dilution-liquid chromatography/tandem mass spectrometry (ED-ID LC/tandem MS). The rationale for proposing a conventional RMP is that, because of the physical separation step, it is unknown whether the measurement truly reflects the concentration of free thyroxine (FT4) in serum. Therefore, the ED part of the RMP has to strictly adhere to the following conditions: use of a dialysis buffer with a biochemical composition resembling the ionic environment of serum/plasma as closely as possible; buffering of the sample to a pH of 7.40 (at 37.0 degrees C) before dialysis, however, without additional dilution; dialysis in a device with a dialysand/dialysate compartment of identical volume and separated by a membrane of regenerated cellulose and adequate cut-off; thermostatic control of the temperature during dialysis at 37.0 degrees C+/-0.50 degrees C. The convention does not apply to the ID-LC/tandem MS part, provided it is eligible to be nominated for review by the Joint Committee for Traceability in Laboratory Medicine. Here, we describe the ED procedure, inclusive its validation and transferability, in greater detail. We recommend a protocol for successful calibration, measurement and monitoring of the accuracy/trueness and precision of the candidate conventional RMP. For details on our ID-LC/tandem MS procedures, we refer to the Supplement. PMID- 21675942 TI - Estimated liver fibrosis and its impact on all-cause mortality of HCV monoinfected and HCV/HIV-coinfected drug users. AB - Progression of liver fibrosis is associated with the risk of cirrhosis and end stage liver disease. We aimed to evaluate fibrosis of the liver using three non invasive indexes (FIB-4, Forns, and Pohl score) and its association with mortality of HCV-monoinfected and HCV/HIV-coinfected drug users. PATIENTS AND METHODS: longitudinal study in patients admitted to substance abuse treatment between 1994 and 2006. Socio-demographic data, drug use characteristics, blood samples for laboratory tests, and serology for HIV and hepatitis C virus infections were collected at admission. Patients were followed-up until December 2006 and mortality was ascertained through hospital charts and death certificates. RESULTS: Four hundred and ninety-seven patients were included (83.1% men); median age at admission was 31 years (IQR: 27-35). The main drugs of abuse were opiates (89.5%) and cocaine (8.3%). Thirty-two percent of patients reported daily alcohol consumption. The estimated prevalence of advanced liver fibrosis (ALF) was higher among HCV/HIV-coinfected patients (9.2% to 17.3% depending on the index analyzed) than among the HCV-monoinfected patients (3% to 3.5%). Odds ratio (OR) for ALF were 3.3 to 6.0 times higher in coinfected patients as compared to the HCV-monoinfected. After a median follow-up time of 7.7 years (IQR: 4.1-9.9 years), almost 20% of patients had died. The estimated ALF at admission was associated with an increased risk of death (RR 1.85 to 3.89 depending on the index). Among those with ALF, mortality rates were similar in HCV-monoinfected and HCV/HIV-coinfected patients, as determined by the FIB-4 and Forns indexes. CONCLUSIONS: Estimation of liver fibrosis using serum markers may help with clinical decisions to facilitate access to treatment of chronic hepatitis C in this population. PMID- 21675944 TI - Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit. AB - The prevalence of type 2 diabetes is evolving globally at an alarming rate. This fact is mainly the result of our global lifestyle "modernization" that has resulted in overweight and obesity. Dysfunction of peroxisome proliferator activated receptor-gamma (PPAR-gamma) has been implicated in the development of insulin resistance, while a reduce expression of many PPAR-gamma regulated genes has been observed in an obese diabetic state. Thiazolidinediones (TZDs) are potent exogenous agonists of PPAR-gamma, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Preclinical and clinical studies have demonstrated that apart from their glucose-lowering activity, these drugs also regulate the production of inflammatory mediators by cells that play a pivotal role in the pathogenesis of atherosclerosis. This paper summarizes the evolving changes observed in an enlarged adipose tissue and examines the activity of TZDs in their main cellular targets. It also discusses whether these cellular pleiotropic effects can result in a clinically meaningful outcome, in terms of cardiovascular benefit, in this population. PMID- 21675943 TI - The therapeutic potential of adenosine triphosphate as an immune modulator in the treatment of HIV/AIDS: a combination approach with HAART. AB - Extracellular adenosine triphosphate (eATP) is a potent molecule that has the capacity to modulate various aspects of cell functions including gene expression. This element of modulation is essential to the role of ATP as a therapeutic agent. The hypothesis presented is that ATP can have an important impact on the treatment of HIV infection. This is supported in part by published research, although a much greater role for ATP is suggested than prior authors ever thought possible. ATP has the ability to enhance the immune system and could thus improve the host's own defense mechanisms to eradicate the virus-infected cells and restore normal immune function. This could provide effective therapy when used in conjunction with highly active antiretroviral therapies (HAART) to eliminate the latently infected cells. The key lies in applying ATP through the methodology described. This article presents a strategy for using ATP therapeutically along with background evidence to substantiate the importance of using ATP in the treatment of HIV infection. PMID- 21675945 TI - Purification of a chitin-binding protein from Moringa oleifera seeds with potential to relieve pain and inflammation. AB - Moringa oleifera Lam. is a perennial multipurpose tree that has been successfully used in folk medicine to cure several inflammatory processes. The aim of this study was to purify and characterize a chitin-binding protein from Moringa oleifera seeds, named Mo-CBP4, and evaluate its antinociceptive and anti inflammatory effects in vivo. The protein was purified by affinity chromatography on chitin followed by ion exchange chromatography. Acetic acid-induced abdominal constrictions assay was used for the antinociceptive and anti-inflammatory activity assessments. Mo-CBP4 is a glycoprotein (2.9% neutral carbohydrate) composed of two protein subunits with apparent molecular masses of 28 and 18 kDa (9 kDa in the presence of reducing agent). The intraperitoneal injection of Mo CBP4 (3.5 and 10 mg/kg) into mice 30 min before acetic acid administration potently and significantly reduced the occurrence of abdominal writhing in a dose dependent manner by 44.7% and 100%, respectively. In addition, the oral administration of the protein (10 mg/kg) resulted in 18% and 52.8% reductions in abdominal writhing when given 30 and 60 min prior to acetic acid administration, respectively. Mo-CBP4, when administered by intraperitoneal route, also caused a significant and dose-dependent inhibition of peritoneal capillary permeability induced by acid acetic and significantly inhibited leukocyte accumulation in the peritoneal cavity. In conclusion, this pioneering study describes that the chitin binding protein Mo-CBP4, from M. oleifera seeds, exhibits anti-inflammatory and antinociceptive properties and scientifically supports the use of this multipurpose tree in folk medicine. PMID- 21675946 TI - Identification of binding epitope for anti-rabies virus glycoprotein single-chain Fv fragment FV57. AB - Single-chain Fv fragment (scFv) of anti-rabies glycoprotein (G protein) has been recommended as a new agent for detecting and neutralizing lethal rabies virus. In this study, we constructed scFv that corresponded to the FV fragment of CR57, a monoclonal antibody against rabies virus, and called it FV57. Despite its virus neutralization activity, FV57 may or may not recognize the same epitope as that recognized by CR57. To resolve this issue, the binding epitope of rabies virus G protein recognized by FV57 was identified. A recombinant rabies virus G protein fragment (RVG179; residues 179-281) comprising several epitopes was expressed in E.coli, purified, and the specificity of its binding with FV57 was determined. In addition, a peptide (abbreviated as EP, residues 224-236) comprising the known epitope of G protein to which CR57 binds was synthesized and the potency of its binding with FV57 was also determined. The results showed that FV57 could specifically bind to RVG179 and EP. Competitive ELISA experiments indicated that RVG179 and EP were able to compete with the rabies virus G protein for binding with FV57. Since no other epitope within residues 224- 236 has been reported, except for the epitope to which CR57 binds (residues 226-231), the epitope recognized by FV57 was the same as its intact antibody CR57. This demonstrated that the complementarity-determining regions (CDRs) of the heavy and light chains of FV57 have folded into the correct conformation as those of CR57. PMID- 21675947 TI - Vascular smooth muscle relaxation by a lectin from Pisum arvense: evidences of endothelial NOS pathway. AB - The vasorelaxant effect of the lectin of Pisum arvense (PAL) seeds was investigated in rat aorta. PAL (10-100 ug/ml) was applied on aorta rings, with or without endothelium, pre-contracted with phenylephrine (Phe; 0.1 uM). Participation of endothelium derived relaxant factors was evaluated incubating the tissue with indomethacin (10 uM), L-nitro arginine methyl ester (L-NAME, 100 uM) and tetraethylammonium (TEA, 5 mM) before addition of PAL. The role of the lectin domain was investigated by addition of PAL into tissue in presence of glucose (3x 10-5 M), or N-acetyl Dglucosamine (GlcNAc; 3 x 10-4 M). The importance of extracellular calcium (Ca2+e) or interaction with muscarinic receptors in the relaxant effect was evaluated by addition of PAL into aorta rings containing calcium free solution (OCa) and atropine (1 u M), respectively. PAL induced concentration-dependent relaxation in endothelized aorta (IC50 =58.38 +/- 1.87 ug/ml), which was reversed by L-NAME and glucose. The lectin effect was totally inhibited when the preparation was inserted in OCa, but not in presence of atropine. Summarizing, our data showed a relaxant effect of PAL in isolated rat aorta rings in presence of endothelium, suggestive of interaction between the lectin carbohydrate binding sites with specific receptors located in vascular endothelial cells leading to nitric oxide synthase activation. This effect seems to require Ca2+e but is independent on muscarinic receptors interaction. PMID- 21675948 TI - Involvement of propeptides in formation of catalytically active metalloproteinase from Thermoactinomyces sp. AB - The metalloproteinase from Thermoactinomyces sp. 27a (Mpr) represents secretory thermolysin-like metalloproteinases of the M4 family. The Thermoactinomyces enzyme is synthesized as a precursor consisting of a signal peptide, N-terminal propeptide, mature region, and C-terminal propeptide. The functional molecule lacks the signal peptide, N-terminal propeptide, and C-terminal propeptide, which indicates the processing of these regions. Until now, it remained unclear if the N-terminal propeptide is involved in the formation and functioning of Mpr, and the role of the C-terminal propeptide was also unclear. In this work, a Bacillus subtilis AJ73 strain expressing Mpr without the C-terminal propeptide- encoding region being involved has been obtained. The absence of the Mpr C-terminal propeptide had no significant effect on the formation of the functional molecule and did not interfere with the protease secretion in B. subtilis AJ73 cells. Strains producing the N-terminal propeptide, mature region, and mature region covalently bound to the N-terminal propeptide were generated from Escherichia coli BL-21(DE3) cells. Functionally active Mpr forms could be produced only in the presence of the N-terminal propeptide, either covalently bound to the mature region (in cis) or as a separate molecule (in trans). Thus, the Mpr three dimensional structure is formed according to the propeptide-assisted mechanism with no requirement of a covalent bond between the N-terminal propeptide and mature region. Moreover, Mpr variants generated in cis and in trans differed in their specificity for certain synthetic substrates. PMID- 21675949 TI - Carbonyldiimidazole (CDI) mediated synthesis of Nalpha-protected amino acid azides: application to the one-pot preparation of ureidopeptides. AB - Synthesis of Nalpha-protected amino acyl azides starting from corresponding acids via the carbonyldiimidazole (CDI) activation is described. The protocol is extended for a one-pot preparation of ureido peptides that circumvents the isolation of acyl azide and isocyanate intermediates. The reaction was accomplished without using any additives and base. The protocol is simple, clean, high yielding and free from racemization. PMID- 21675950 TI - An RGD-Modified Endostatin Peptide Expressed at E. coli Shows Anti-Tumor Activity In vivo. AB - Tumor vasculatures express high levels of alpha(V)beta(3)/alpha(V)beta(5) and alpha(5)beta(1) integrins. Peptide containing the RGD (Arg-Gly-Asp) sequence, which is present in ligands of integrins, is effective in targeting therapeutic reagents to tumor vascular endothelium. In this study, we investigated whether the biological activity of endostatin 27 peptides can be enhanced by the addition of an integrin targeting sequence. RGDRGD and GGGRGD sequence were added to the carboxyl terminus of endostatin 27 and 25 peptides, respectively. Modification of endostatin 27 peptides with the RGD motif showed specific and increased binding to endothelial cells and the increased binding is consistent with improved antiangiogenic property. RGD-modified endostatin 27 peptides was more effective than human endostatin and endostatin 27 peptides in inhibiting liver cancer growth in athymic mice. These finding indicates that addition of a vascular targeting sequence can enhance the biological activity of an antiangiogenic peptides molecule. PMID- 21675951 TI - Synthesis and Pseudomonas lipase inhibition study of stereoisomers of decahydro-2 naphthyl-N-n-butylcarbamate. AB - (2S,4aR,8aS)-Cis,cis-, (2R,4aS,8aR)-cis,cis-, rac-cis,cis-, and rac-trans,cis decahydro-2-naphthyl-N-n-butylcarbamates are synthesized from condensation of (2S,4aR,8aS)-cis,cis-, (2R,4aS,8aR)-cis,cis-, rac-cis,cis-, and rac trans,cisdecahydro- 2-naphthols, respectively, with n-butyl isocyanate in the presence of triethylamine in dichloromethane. Optically pure (2S,4aR,8aS)-(-)- and (2R,4aS,8aR)-(+)-cis,cis-decahydro-2-naphthols are resolved by the porcine pancreatic lipase- catalyzed acetylation of decahydro-2-naphthols with vinyl acetate in t-butyl methyl ether. Absolute configurations of (2S,4aR,8aS)-(-)- and (2R,4aS,8aR)-(+)- cis,cis-decahydro-2-naphthols are determined from the 19F NMR spectra of their Mosher's ester derivatives. (2S,4aR,8aR)-Trans,cis- and (2R,4aS,8aS)-trans,cis-decahydro-2-naphthols can't be resolved from the porcine pancreatic lipase-catalyzed acetylation of decahydro-2-naphthols with vinyl acetate in t-butyl methyl ether. For the inhibitory potency of Pseudomonas lipase, (2S,4aR,8aS)-cis,cis-decahydro-2-naphthyl-N-n-butylcarbamate is 3.5 times more potent than (2R,4aS,8aR)-cis,cis-decahydro-2-naphthyl-N-n-butylcarbamate; racemic cis,cis-decahydro- 2-naphthyl-N-n-butylcarbamate is about the same with trans,cis-decahydro-2-naphthyl-N-n-butylcarbamate. These inhibitors also show similar effects on porcine pancreatic lipase. PMID- 21675952 TI - Comparison of human and shirbot (Cyprinidae: Barbus grypus) hemoglobin: a structure-function prospective. AB - Hemoglobin is a tetrameric protein with two alpha and two beta subunits binds oxygen in a cooperative manner. In dominant tetrameric form of fish hemoglobin carry more than 90 percent of oxygen from gill to tissues at 20 degrees C. The tetrameric form of fish hemoglobin is changed to monomeric form at low oxygen pressure in order to increase its oxygen affinity. This is one of adaptive mechanisms used by different kinds of fish. The major aim of this paper is to study the molecular basis of shirbot hemoglobin adaptation mechanism to various environmental conditions. Using different methods such as ion exchange chromatography, UV-Vis, fluorescence and circular dichroism spectroscopy, we extracted the main tetrameric fraction of shirbot hemoglobin and studied the structural characteristics of shirbot and human hemoglobins in a comparative way. Our results showed that tetrameric form of shirbot hemoglobin has less stable and loosely folded structure in contrast to human hemoglobin. Our data also indicate, in case of exposure to life-threatening environmental factors such as low oxygen level, acidic pH, oxidizing chemicals and other water pollutants especially detergents (surfactants) triggering tetramer to monomer dissociation in shirbot hemoglobin is more prominently than in human hemoglobin. The resulting monomer of hemoglobin has more oxygen affinity and could take up oxygen more strongly even at low pressure. We hypothesize that this mechanism helps shirbot to adapt and to survive at such harsh environment. The mechanism that is may be adapted by other fish species. PMID- 21675953 TI - Parkinson's Disease: A Role for the Immune System. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of catecholaminergic neurons in several brain regions. The motor symptoms of the disease are related to degeneration of the midbrain dopaminergic neurons, which occurs some time after the disease has begun. Both the innate and adaptive immune systems appear to play a role in the neurodegenerative process, and may contribute to disease progression. Here we review the neuropathology of PD with attention focused on the involvement of the innate immune cells (microglia) and the adaptive immune cells (T lymphocytes). In addition, we discuss animal models of the disease with emphasis on a progressive rat model which allows a detailed analysis of how the immune system contributes to neurodegeneration both during early and late stages of degeneration. Finally, for the early detection and treatment of PD, we discuss immunotherapy approaches. PMID- 21675955 TI - WITHDRAWN: AB - Ahead of Print article withdrawn by publisher. PMID- 21675954 TI - Activation of human platelets by 2-arachidonoylglycerol: role of PKC in NO/cGMP pathway modulation. AB - We demonstrated that the endocannabinoid 2-arachidonoylglycerol (2-AG) activated dose-dependently washed human platelets and increased intracellular calcium levels. Moreover 2-AG activated protein kinase C measured as p47pleckstrin phosphorylation. These parameters were prevented by the tromboxane A2 receptor antagonist SQ29548, by phospholipase C pathway (U73122) and protein kinase C (GF109203X) inhibitors. No effect on 2-AG-induced platelet activation and calcium elevation in the presence of inhibitors of fatty acid amide hydrolase or monoacylglycerol lipase was observed. In addition we have shown that 2-AG dose dependently increased NO and cGMP levels. These effects were abolished by U73122, GF109203X, EGTA and the intracellular calcium chelator BAPTA/AM. Moreover, 2-AG enhanced eNOS activity through the phosphorylation of its positive regulatory residue ser1177 and by dephosphorylation of the negative one thr495. The eNOS ser1177 phosphorylation was inhibited by U73122 and GF109203X but it was unaffected by the PI3K/AKT pathway inhibitors LY294002 and MK2206. The dephosphorylation of thr495 was reversed by low concentrations of calyculin A. Taken together these data suggest that 2-AG behaves as a true platelet agonist stimulating PKC activation and calcium elevation. Likely 2-AG can modulate platelet activation by increasing NO levels through eNOS activation. PMID- 21675956 TI - Safety of vascular endothelial and hepatocyte growth factor gene therapy in patients with critical limb ischemia. AB - The present clinical trial analyzed the safety of gene therapy using plasmidial constructs expressing vascular endothelial and hepatocyte growth factors in patients with critical limb ischemia. The study included 43 patients: 29 in the treatment group and 14 allocated to the placebo group. The primary end points were the rate of major amputations and the clinical safety of the method. Secondary end points were improvement of pain at rest, walking ability and the ankle/brachial pressure index. The overall major amputation rate was 31.04% in the treatment group and 71.42% in the placebo group (p = 0.029). Pain at rest was improved in 65% of patients in the gene therapy group and in 7% in the placebo group (p = 0.0006). There were no significant adverse effects in the treatment group. CONCLUSION: Gene therapy with vascular endothelial and hepatocyte growth factors is therapeutically safe and reduces the rate of major amputations and relieves pain at rest in patients with critical limb ischemia. PMID- 21675957 TI - Neuroprotective efficacy of the peroxisome proliferator-activated receptor-gamma ligand in chronic cerebral hypoperfusion. AB - Chronic cerebral hypoperfusion can cause learning and memory impairment and neuronal damage resembling the effects observed in vascular dementia. PPAR-gamma agonists were shown to modulate inflammatory response and neuronal death following cerebral ischemia. The present study was designed to evaluate possible neuroprotective effects of rosiglitazone, a PPAR-gamma agonist, in rat model of chronic cerebral hypoperfusion. Cerebral hypoperfusion was induced by permanent bilateral occlusion of the common carotid arteries. Oral administration of rosiglitazone (1.5, 3, and 6 mg/kg/day) or vehicle was carried out for 5 weeks, starting one week before the surgery. Cognitive performance was assessed using the Morris water maze. The density of S100B protein-immunoreactive astrocytes and the OX-42-labeled microglial activation were estimated. Synaptogenesis was also evaluated by the measurement of synaptophysin, the pre-synaptic vesicular protein, level via western blotting technique. Cerebral hypoperfusion for 30 days induced a significant cognitive impairment along with hyperactivation of both microglial and astroglial cells, and reduction of synaptophysin level. Rosiglitazone treatment (3 and 6 mg/kg) not only suppressed the activation of astrocytes and microglia markedly but also alleviated the impairment of memory and increased the synaptophysin level. In conclusion, our results suggest that the chronic administration of rosiglitazone significantly prevents chronic cerebral hypoperfusion-induced brain damage, at least, partly through suppressing glial activation and preserving synaptic plasticity. Thus, it appears that rosiglitazone may be a promising pharmacological agent in the development of therapeutic approaches for the prevention or treatment of cerebrovascular diseases. PMID- 21675959 TI - Monitoring protein-protein interactions in mammalian cells by trans-SUMOylation. AB - Protein-protein interactions are essential for almost all cellular processes, hence understanding these processes mainly depends on the identification and characterization of the relevant protein-protein interactions. In the present paper, we introduce the concept of TRS (trans-SUMOylation), a new method developed to identify and verify protein-protein interactions in mammalian cells in vivo. TRS utilizes Ubc9-fusion proteins that trans-SUMOylate co-expressed interacting proteins. Using TRS, we analysed interactions of 65 protein pairs co expressed in HEK (human embryonic kidney)-293 cells. We identified seven new and confirmed 16 known protein interactions, which were determined via endogenous SUMOylation sites of the binding partners or by using SUMOylation-site tags respectively. Four of the new protein interactions were confirmed by GST (glutathione transferase) pull-down and the p38alpha-Edr2 interaction was verified by co-localization analysis. Functionally, this p38alpha-Edr2 interaction could possibly be involved in the recruitment of p38alpha to the polycomb chromatin-remodelling complex to phosphorylate Bmi1. We also used TRS to characterize protein-interaction domains of the protein kinase pairs p38alpha-MK2 [MK is MAPK (mitogen-activated protein kinase)-activated protein kinase] and ERK3 (extracellular-signal-regulated kinase 3)-MK5 and of the p38alpha-p53 complex. The ability of TRS to monitor protein interactions in mammalian cells in vivo at levels similar to endogenous expression makes it an excellent new tool that can help in defining the protein interactome of mammalian cells. PMID- 21675958 TI - CD133+ glioblastoma stem-like cells induce vascular mimicry in vivo. AB - Glioblastoma is one of the most angiogenic malignancy, the neoplastic vessels of which are likely to arise by angiogenesis and vasculogenesis. An alternative mechanism of tumor vasculature is described, termed vasculogenic mimicry, by which highly aggressive tumor cells can form vessel-like structures themselves, by virtue of their high cellular plasticity. Evidence suggests that cancer stem cells acquire a multi-potent plastic phenotype and show vasculogenic potential. In this study, we report that glioblastoma stem-like cells (GSCs) can form vasculogenic mimicry in tumor xenografts and express pro-vascular molecules. We isolated GSCs from resected human glioblastoma tissues and demonstrated their stemness, differentiation, and in vivo tumor-initiating potential. Through a limiting dilution assay, CD133+ (CD133(+)-GSC) and CD133- (CD133(-)-GSC) subpopulation of GSCs were obtained. Orthotopic xenotransplantation study revealed that these two subpopulations of GSCs shared similar efficacy in tumor formation but showed distinct intratumor vasculature. In comparison with CD133(-) GSC, a highly vascularized anaplastic tumor, mimicking vasculogenic mimicry, was found in CD133(+)-GSC-derived tumor xenografts. Subsets of CD133(+)-GSC but not CD133(-)-GSC were capable of vascular smooth muscle-like cell differentiation, in vitro and in vivo. In tumor xenografts, endothelium-associated CD31 gene was detected in implanted CD133(-)-GSC and exclusively dispersed within the tumor tissues. Although the detailed action mechanisms required further investigation, this study demonstrated the vasculogenic capacity of brain GSCs and their cellular plasticity. The results of expression of pro-vascular molecules and differentiation of vascular-like cells suggest that GSCs may contribute to form vessel-like structures and provide a blood supply for glioblastoma cells. PMID- 21675960 TI - Structural analysis of the Sil1-Bip complex reveals the mechanism for Sil1 to function as a nucleotide-exchange factor. AB - Sil1 functions as a NEF (nucleotide-exchange factor) for the ER (endoplasmic reticulum) Hsp70 (heat-shock protein of 70 kDa) Bip in eukaryotic cells. Sil1 may catalyse the ADP release from Bip by interacting directly with the ATPase domain of Bip. In the present study we show the complex crystal structure of the yeast Bip and the NEF Sil1 at the resolution of 2.3 A (1 A=0.1 nm). In the Sil1-Bip complex structure, the Sil1 molecule acts as a 'clamp' which binds lobe IIb of the Bip ATPase domain. The binding of Sil1 causes the rotation of lobe IIb ~ 13.5 degrees away from the ADP-binding pocket. The complex formation also induces lobe Ib to swing in the opposite direction by ~ 3.7 degrees . These conformational changes open up the nucleotide-binding pocket in the Bip ATPase domain and disrupt the hydrogen bonds between Bip and bound ADP, which may catalyse ADP release. Mutation of the Sil1 residues involved in binding the Bip ATPase domain compromise the binding affinity of Sil1 to Bip, and these Sil1 mutants also abolish the ability to stimulate the ATPase activity of Bip. PMID- 21675961 TI - Norcantharidin inhibits proliferation and fibronectin expression of HK-2 cells induced by albumin in vitro. AB - The present study aims to observe the effects of NCTD (norcantharidin) on proliferation and FN (fibronectin) expression in human renal proximal tubular epithelial cell line (HK-2) induced by albumin in vitro. HK-2 cells were divided into control group, albumin group and different concentration of NCTD intervention groups. Proliferation of HK-2 cells was determined by MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide], FN protein in culture media of HK-2 cells was examined by ELISA, and FN mRNA was analysed by RT-PCR (reverse transcription-PCR). We chose less than 5.0 mg/l of NCTD as the experimental concentration for the cytotoxicity test. MTT score was higher in the albumin group than in the control group (P<0.05). As compared with that of the albumin group, MTT score and FN protein concentration decreased, FN mRNA significantly down-regulated in NCTD intervention groups respectively (P<0.05). Our study showed that NCTD could inhibit the albumin-induced cell proliferation and FN expression in HK-2 cells, which might further prove the anti-fibrotic role of NCTD in proteinuria-associated tubulointerstitial damage. PMID- 21675962 TI - Mesenchymal stem cell injection ameliorates chronic renal failure in a rat model. AB - CKD (chronic kidney disease) has become a public health problem. The therapeutic approaches have been able to reduce proteinuria, but have not been successful in limiting disease progression. In this setting, cell therapies associated with regenerative effects are attracting increasing interest. We evaluated the effect of MSC (mesenchymal stem cells) on the progression of CKD and the expression of molecular biomarkers associated with regenerative effects. Adult male Sprague Dawley rats subjected to 5/6 NPX (nephrectomy) received a single intravenous infusion of 0.5*106 MSC or culture medium. A sham group subjected to the same injection was used as the control. Rats were killed 5 weeks after MSC infusion. Dye tracking of MSC was followed by immunofluorescence analysis. Kidney function was evaluated using plasma creatinine. Structural damage was evaluated by H&E (haematoxylin and eosin) staining, ED-1 abundance (macrophages) and interstitial alpha-SMA (alpha-smooth muscle actin). Repairing processes were evaluated by functional and structural analyses and angiogenic/epitheliogenic protein expression. MSC could be detected in kidney tissues from NPX animals treated with intravenous cell infusion. This group presented a marked reduction in plasma creatinine levels and damage markers ED-1 and alpha-SMA (P<0.05). In addition, treated rats exhibited a significant induction in epitheliogenic [Pax-2, bFGF (basic fibroblast growth factor) and BMP-7 (bone morphogenetic protein-7)] and angiogenic [VEGF (vascular endothelial growth factor) and Tie-2] proteins. The expression of these biomarkers of regeneration was significantly related to the increase in renal function. Many aspects of the cell therapy in CKD remain to be investigated in more detail: for example, its safety, low cost and the possible need for repeated cell injections over time. Beyond the undeniable importance of these issues, what still needs to be clarified is whether MSC administration has a real effect on the treatment of this pathology. It is precisely to this point that the present study aims to contribute. PMID- 21675963 TI - Study of neurocognitive endophenotypes in drug-naive obsessive-compulsive disorder patients, their first-degree relatives and healthy controls. AB - OBJECTIVE: Obsessive-compulsive disorder (OCD) is a debilitating heritable neuropsychiatric condition. Attempts to delineate genetic contributions in OCD have met with limited success, with an ongoing search for neurocognitive endophenotypes. In this study, an attempt has been made to study and compare the neurocognitive functioning of patients with OCD, their first-degree relatives (FDRs) and healthy controls. METHOD: A cross-sectional design study was carried out with thirty dyads of patients with OCD, their FDRs and thirty matched healthy controls and screened using Mini International Neuropsychiatric Interview, Verbal Adult Intelligence Scale, Yale Brown Obsessive-Compulsive Scale, Montgomery Asberg Depression Rating Scale, International Personality Disorder Examination (Anankastic personality scale).Tests of National Institute of Mental Health and Neurosciences Neuropsychological Battery were used to assess domains of attention, verbal memory, visual memory, set-shifting, response inhibition, planning and visuoconstructive abilities. spss version 14.0 was used for descriptive and analytical data analysis. RESULTS: There were no statistically significant differences between patients with OCD and their FDRs on neurocognitive domains of delayed verbal recall, set-shifting, response inhibition and visuoconstructive abilities (P > 0.05) which were impaired compared with healthy controls. Significant differences (P < 0.05) on domains of attention, planning time and visual memory were noted between FDRs and patients. CONCLUSION: The present study supports set-shifting and inhibitory control and proposes visuoconstructive abilities and delayed verbal recall as potential endophenotypes for OCD. PMID- 21675964 TI - Parameter recovery and model selection in mixed Rasch models. AB - This study examines the precision of conditional maximum likelihood estimates and the quality of model selection methods based on information criteria (AIC and BIC) in mixed Rasch models. The design of the Monte Carlo simulation study included four test lengths (10, 15, 25, 40), three sample sizes (500, 1000, 2500), two simulated mixture conditions (one and two groups), and population homogeneity (equally sized subgroups) or heterogeneity (one subgroup three times larger than the other). The results show that both increasing sample size and increasing number of items lead to higher accuracy; medium-range parameters were estimated more precisely than extreme ones; and the accuracy was higher in homogeneous populations. The minimum-BIC method leads to almost perfect results and is more reliable than AIC-based model selection. The results are compared to findings by Li, Cohen, Kim, and Cho (2009) and practical guidelines are provided. PMID- 21675965 TI - Assessing the contribution family data can make to case-control studies of rare variants. AB - When pathogenic variants are rare then even among cases the proportion of subjects possessing a variant might be low, meaning that very large samples might be required to conclusively demonstrate evidence of an effect. Relatives of subjects within a case-control sample might provide useful additional information. The method of model-free linkage analysis implemented in MFLINK was adapted to incorporate linkage disequilibrium (LD) parameters in order to test for an effect of a putative pathogenic variant in complete LD with a disease locus. The effect of adding in to the analysis relatives of cases and controls found to carry the variant was investigated. When affected siblings or cousins of cases possessing the variant were incorporated they had a large effect on the results obtained. The evidence for involvement increased or reduced as expected, depending on whether or not the relatives themselves were found to possess the variant. The size of the effect was large relative to that expected from just increasing the size of a standard case-control sample. Affected relatives offer a valuable resource to assist the interpretation of case-control studies of rare variants. The method is capable of including other relative types and can deal with complex pedigrees. PMID- 21675967 TI - Conservative models: parametric entropy vs. temporal entropy in outcomes. AB - The geologic architecture in aquifer systems affects the behavior of fluid flow and the dispersion of mass. The spatial distribution and connectivity of higher permeability facies play an important role. Models that represent this geologic structure have reduced entropy in the spatial distribution of permeability relative to models without structure. The literature shows that the stochastic model with the greatest variance in the distribution of predictions (i.e., the most conservative model) will not simply be the model representing maximum disorder in the permeability field. This principle is further explored using the Shannon entropy as a single metric to quantify and compare model parametric spatial disorder to the temporal distribution of mass residence times in model predictions. The principle is most pronounced when geologic structure manifests as preferential-flow pathways through the system via connected high-permeability sediments. As per percolation theory, at certain volume fractions the full connectivity of the high-permeability sediments will not be represented unless the model is three-dimensional. At these volume fractions, two-dimensional models can profoundly underrepresent the entropy in the real, three-dimensional, aquifer system. Thus to be conservative, stochastic models must be three-dimensional and include geologic structure. PMID- 21675966 TI - The role of P2X7 purinergic receptors in inflammatory and nociceptive changes accompanying cyclophosphamide-induced haemorrhagic cystitis in mice. AB - BACKGROUND AND PURPOSE: ATP is released in response to cellular damage, and P2X7 receptors have an essential role in the onset and maintenance of pathological changes. Haemorrhagic cystitis (HC) is a well-known adverse effect of therapy with cyclophosphamide used for the treatment of many solid tumours and autoimmune conditions. Here we have evaluated the role of P2X7 receptors in a model of HC induced by cyclophosphamide. EXPERIMENTAL APPROACH: Effects of pharmacological antagonism or genetic deletion of P2X7 receptor on cyclophosphamide-induced HC in mice was assessed by nociceptive and inflammatory measures. In addition, the presence of immunoreactive P2X7 receptors was assessed by immunohistochemistry. KEY RESULTS: Pretreatment with the selective P2X7 receptor antagonist A-438079 or genetic ablation of P2X7 receptors reduced nociceptive behaviour scores in the HC model. The same strategies decreased both oedema and haemorrhage indices, on macroscopic or histological evaluation. Treatment with A-438079 decreased the staining for c-Fos in the lumbar spinal cord and brain cortical areas. Treatment with A-438079 also prevented the increase of urinary bladder myeloperoxidase activity and macrophage migration induced by cyclophosphamide and reduced the tissue levels of IL-1beta and TNF-alpha. Finally, P2X7 receptors were markedly up regulated in the bladders of mice with cyclophosphamide-induced HC. CONCLUSIONS AND IMPLICATIONS: P2X7 receptors were significantly involved in a model of HC induced by cyclophosphamide. Pharmacological inhibition of these receptors might represent a new therapeutic option for this pathological condition. PMID- 21675968 TI - Headache disorders in the millennium cohort: epidemiology and relations with combat deployment. AB - OBJECTIVE: Characterize migraine and other headache disorders within a large population-based US military cohort, with an emphasis on the temporal association between military deployment and exposure to combat. BACKGROUND: Little research has been published on the prevalence of headache disorders in the US military population, especially in relation to overseas deployments and exposure to combat. A higher than expected prevalence of migraine has previously been reported among deployed US soldiers in Iraq, suggesting an association. Headache disorders, including migraine, could have important effects on the performance of service members. METHODS: A total of 77,047 US active-duty, Reserve, and National Guard members completed a baseline questionnaire between July 2001 to June 2003 for the Millennium Cohort Study. Headache disorders were assessed using the following survey-based measures: self-reported history of provider-diagnosed migraine, recurrent severe headache within the past year, and recent headaches/bothered a lot within the past 4 weeks. Follow-up surveys were completed on average 3 years after baseline (mean=2.7 years; range=11.4 months to 4.5 years). RESULTS: The overall male and female prevalence of self-reported headache conditions at baseline were: provider-diagnosed migraine, 6.9% and 20.9%, respectively; recurrent severe headache, 9.4% and 22.3%, respectively; and bothered a lot by headaches, 3.4% and 10.4%, respectively. Combat deployers had significantly higher odds of any new-onset headache disorders than non-deployers (adjusted odds ratios=1.72 for men, 1.84 for women; 95% confidence intervals, 1.55-1.90 for men, 1.55-2.18 for women), while deployers without combat exposure did not. CONCLUSIONS: Deployed personnel with reported combat exposure appear to represent a higher risk group for new-onset headache disorders. The identification of populations at higher risk of development of headache provides support for targeted interventions. PMID- 21675969 TI - Use of antimigraine treatments by general practitioners. AB - OBJECTIVES: To assess headache treatment patterns in 2 groups: general practitioners (GPs) who suffered from migraine themselves (GP-M) and GPs having a close family member with migraine (GP-CFM). The secondary objective was to assess the impact of migraine on activities of daily living in these 2 groups. BACKGROUND: Personal experience of migraine may influence prescribing practices of physicians treating patients with migraine. Little data are available on perceptions of migraine by GPs. METHODS: This was an observational, cross sectional, pharmacoepidemiological survey conducted in primary care in France. Most GPs completed 1 of 2 questionnaires, and GPs belonging to both groups could complete both. Data were collected on headache treatments used (GP-M) or prescribed (GP-CFM), and on self-reported (GP-M) or described (GP-CFM) migraine features and impact on daily activities. RESULTS: The most frequently reported acute headache treatments in both groups were triptans and non-steroidal anti inflammatory drugs (>75% of GPs); >81% of GPs in both groups were satisfied with acute headache treatments. Only 6.9% of the GP-M group used and 17.2% of the GP CFM group prescribed a prophylactic treatment, which was considered satisfactory by 46.2% and 56.1%, respectively. In the preceding 3 months, 79.4% of the GP-M group reported handicap in daily activities due to migraine, 23.6% interruption of extraprofessional activities and 7.6% interruption of work. In the GP-CFM group, 32.6% described interruption of extraprofessional activities and 57.3% interference with daily activities or work. CONCLUSIONS: Acute headache treatment prescribed by French GPs for their own migraines or those of their relatives respect practice guidelines and is considered as effective and satisfactory. Use of prophylactic medication is low and its effectiveness perceived as limited. Better use of prophylactic treatments may attenuate the impact of migraine on daily activities. PMID- 21675970 TI - Bifocal nummular headache: a series of 6 new cases. AB - OBJECTIVE: We aimed to report 6 new cases of bifocal nummular headache (NH), showing their clinical characteristics and comparing them with those formerly described. BACKGROUND: NH is a focal head pain felt in a small, well circumscribed, coin-shaped area. Among all the reported cases (over 200), 6 patients localized their pain in 2 or more separate areas. METHODS: We reviewed all patients diagnosed with NH at the headache clinics of 2 tertiary hospitals, searching for cases with head pain in 2 different areas. RESULTS: Six patients (4 female, 2 male; age at onset 40.8 +/- 19.1, range 24-69 years) presented with bifocal NH. The shape and size of both painful areas were identical in each patient. They were located at symmetrical points of either side in 3 patients, while 2 patients had both symptomatic areas on the same side of the head. The chronological pattern was synchronous in 2 patients, and the other 4 showed an additive pattern with onset intervals between the 2 areas ranging from 2 months to 30 years. Pain intensity was slightly different in each area in 4 of the cases. Four patients were treated with a preventive (gabapentin or carbamazepine) with good clinical response. CONCLUSION: Although not frequently found, some patients may have bifocal or multifocal NH. PMID- 21675971 TI - Reply to: "Response to: Migraine and vertigo: a marriage of convenience?". PMID- 21675972 TI - Key papers given at the IAAP Congress in Montreal last year. PMID- 21675973 TI - Introduction. AB - These papers were presented at the 7(th) meeting between Freudian and Jungian analysts held at the Montreal Congress of the International Association of Analytical Psychology (IAAP) in August 2010. The introduction describes the history and themes of previous meetings and discusses the choice of theme for the Montreal meeting. Both primal phantasies and archetypes imply a structural approach to psychological function but in different theoretical terms. These theoretical differences may also be emblematic of clinical differences between a focus on the sexual aspects of infancy in the Freudian tradition and a focus on ongoing emergence and transformation towards a goal of self-becoming in the Jungian tradition. The discussion aimed to test these hypotheses through the presentation of a single case history by Joseph Cambray (IAAP, USA), followed by commentaries from Eduardo Gastelumendi (IPA, Peru) and Verena Kast (IAAP, Switzerland). PMID- 21675974 TI - Moments of complexity and enigmatic action: a Jungian view of the therapeutic field. AB - In presenting clinical case material for a panel on archetypes and/or primal phantasies an initial discussion of archetypes as emergent phenomena organizing 'moments of complexity' is given(1) . The relationship of such moments to 'moments of meeting' as developed by the Boston Change Process Study Group is commented on and explored within the context of the case. A condensed report of a multi-year analytic treatment of a bipolar patient having a severe trauma history is offered for discussion. Several unusual, enigmatic events are detailed to illustrate the occurrence of moments of complexity. Dreams highlighting psychological transformation stemming from a changing relationship to emerging archetypal material related to a psychotic process in the patient are offered to further detailed moments of complexity. PMID- 21675975 TI - Comment on 'the case of Melanie' by Joseph Cambray. AB - The discussion comments firstly on the role of synchronicity which seems so natural and significant for Jungians but which Freudians would think no more than interesting coincidences. This gives an idea of how different the two schools' approach to the psyche can be. Some theoretical elaboration is made regarding archetypes and primal phantasies: primal phantasies are much related to sexuality, but sexuality understood as intimately linked to the great mysteries of life. The discussion of the clinical work shows more similarities than differences. This suggests that for both perspectives the clinical is sovereign. As we know, respect and care for the patient's evolution, true concern for the patient and skilful use of technique remain the most important indicators of successful therapeutic work in the different psychotherapeutic approaches. PMID- 21675976 TI - Comments on 'the case of Melanie' and the reaction of Eduardo Gastelumendi. AB - Following an attempt to connect the theory of archetypes with the theory of primal phantasies, the commentary refers to how moments of complexity may be differentiated in terms of 'now moments' and concludes with an amplification of the 'black woman' in Melanie's dream related to a black woman in an important Austrian fairy tale. PMID- 21675977 TI - A thematic dialogue: towards a conclusion and a follow-up. AB - Following the themed debate that took place after the panel, we reconsidered and explored further our hypotheses in light of the comments made by our colleagues. Clearly, it is the structural approach that underlies both the Freudian primal phantasies and the Jungian archetypes, while taking account at the same time that their approaches are informed by contemporary emergentist theories. Our discussion centred on the divergences in the cases of psychosis and neurosis, on the roles, in turn, of a return to childhood and the play of archaic representations, on the transference and countertransference functions and finally on the need to pay attention to what are deemed synchronous moments in the event. PMID- 21675978 TI - A Jungian contribution to a dynamic systems understanding of disorganized attachment. AB - This panel emerged from shared clinical concerns when working with adult patients whose presentation style was reminiscent of a disorganized (Type D) infant attachment pattern. Psychotherapeutic work with such patients poses complicated transference and countertransference dilemmas which are addressed by all four panellists via theory and clinical vignettes. In common is an interest in contemporary attachment, neuroscience and trauma theories and their relationship to analytical psychology. Intergenerational trauma seems to be a salient factor in the evolution of fragmented and fragmenting interactions that lead to failures in self-coherence and healthy interpersonal relationships. Such early relational trauma is compounded by further episodes of abuse and neglect leading to failure in a core sense of self. These clinicians share how they have integrated theory and practice in order to help dissociated and disorganized patients to transform their dark and extraordinary suffering through implicit and explicit experiences with the analyst into new, life giving patterns of relationship with self and others. The alchemy of transformation, both positive and negative, is evident in the case material presented. PMID- 21675979 TI - Dissociation and shame: shadow aspects of multiplicity. PMID- 21675980 TI - The role of disorganized attachment and insecure environment in the development of pathological dissociation and multiple identities. PMID- 21675981 TI - Attachment, sensitivity and agency: the alchemy of analytic work. PMID- 21675982 TI - Panel: What could be Jungian about Human Rights work? AB - The question of whether Jungian analysts should move beyond the consulting room to engage with mental health issues that pertain to the collective is the focus of this paper. Two narratives are presented: one from the view point of a psychiatrist in Occupied Palestine, the other from the conflicted situation which faces an Israeli analyst. Despite the strong ambivalence that is experienced on both sides, there is a willingness to meet and to take a standpoint without necessarily coming to a resolution. A third position is offered by describing experiences from the South African perspective. The African notion of Ubuntu is offered as a moral entry point that states that community goes beyond one's own; from this point of view, Jungian analysts can do no other than to act. PMID- 21675983 TI - Introduction: Fragmentation of the Unus Mundus. AB - This panel is a series of presentations by a father and his three sons. The first is a critique of the concept of the Unus Mundus, an idea that goes back at least as far as Plato's Cave in western intellectual history. A longing for unchanging foundational ideas lies at the core of much of our culture, psychology, and theology. The subsequent presentations describe various unforeseen, destructive results stemming from the perspective of the Unus Mundus. The first example is of persons with Alzheimer's disease, whose singular subjectivity is often ignored because they are seen as a category. They are 'Alzheimer-ed', subtly enabling those around them to avoid an anxiety-producing encounter with their enigmatic otherness. Another important perspective is the modernist re-construction of city spaces that has resulted in the loss of an organic sense of containment. The lengthy horizon of the grand boulevards seemed like openings upon infinity, often provoking panic and agoraphobia, as seen in the work of Edvard Munch. Lastly, the genocidal tendencies of modern times epitomize the dangers of totalizing, Utopian ideas. Violent elimination may be visited upon groups or peoples who are deemed 'impure', as besmirching idealized social visions. Such examples illustrate some of the ethical dangers of conceptualizations related to the Unus Mundus. PMID- 21675984 TI - Facing the 'Alzheimer-ed subject'. PMID- 21675985 TI - Agoraphobia, infinite space, and epistemic rupture: Europe at the end of the 19th century. PMID- 21675986 TI - Genocide, categorical certainty, and the truth: questions from the Khmer Rouge Tribunal. PMID- 21675987 TI - Faith and the practising analyst. AB - In this brief essay, I reflect on three questions: What is 'faith' in a modern and post-modern cultural context? Do I, a Jungian analyst, have 'faith' or do I not? Does having 'faith' or not make a difference in the practice of analysis? I make reference to Jung's understanding of 'faith' and his frequent disclaimers about making metaphysical claims. I conclude that a post-credal 'faith' is possible for contemporary Jungian analysts, that I do have such a faith personally, and that in my experience this makes a significant difference in analytic practice at least with some patients. Traditional faith statements must be translated into depth psychological terms, however, in order for them to be applicable in post-modern, multicultural contexts. PMID- 21675988 TI - John Beebe in conversation with Beverley Zabriskie. AB - John Beebe speaks with Beverley Zabriskie about the central motifs of his life and depth psychological experience, and how these informed his choice of vocation as psychiatrist, Jungian analyst, educator and author. Dr. Beebe narrates how he moved beyond the fate assigned the son of a needy mother and abandoning father. He illustrates how the role his family expected him to fill constellated archetypal motifs--the magical or divine curative child, the whiz kid--from which he had then to disidentify for the sake of becoming an individual with a personal voice and capacity to express his own true values. He tells of his differentiation and search for completion through the perspective of Jung's psychological types theory. He also reflects on the evolution of Jungian analytic theory and practice generally, his editorship of the JAP and the San Francisco Jung Institute Library Journal, his confrontation with analytic homophobia, and the emerging quality of professional and personal relationships in relation to ethics and to love. He assesses Jung's courage and integrity as displayed through the release of Jung's Red Book, and his own quest for an organic and psychological moral stance expressed in his benchmark book, Integrity in Depth. PMID- 21675992 TI - Chaotic homes and school achievement: a twin study. AB - BACKGROUND: Chaotic homes predict poor school performance. Given that it is known that genes affect both children's experience of household chaos and their school achievement, to what extent is the relationship between high levels of noise and environmental confusion in the home, and children's school performance, mediated by heritable child effects? This is the first study to explore the genetic and environmental pathways between household chaos and academic performance. METHOD: Children's perceptions of family chaos at ages 9 and 12 and their school performance at age 12 were assessed in more than 2,300 twin pairs. The use of child-specific measures in a multivariate genetic analysis made it possible to investigate the genetic and environmental origins of the covariation between children's experience of chaos in the home and their school achievement. RESULTS: Children's experience of family chaos and their school achievement were significantly correlated in the expected negative direction (r = -.26). As expected, shared environmental factors explained a large proportion (63%) of the association. However, genetic factors accounted for a significant proportion (37%) of the association between children's experience of household chaos and their school performance. CONCLUSIONS: The association between chaotic homes and poor performance in school, previously assumed to be entirely environmental in origin, is in fact partly genetic. How children's home environment affects their academic achievement is not simply in the direction environment -> child -> outcome. Instead, genetic factors that influence children's experience of the disordered home environment also affect how well they do at school. The relationship between the child, their environment and their performance at school is complex: both genetic and environmental factors play a role. PMID- 21675993 TI - The dopamine D2 receptor gene, perceived parental support, and adolescent loneliness: longitudinal evidence for gene-environment interactions. AB - BACKGROUND: Loneliness is a common problem in adolescence. Earlier research focused on genes within the serotonin and oxytocin systems, but no studies have examined the role of dopamine-related genes in loneliness. In the present study, we focused on the dopamine D2 receptor gene (DRD2). METHODS: Associations among the DRD2, sex, parental support, and loneliness were examined in a longitudinal study spanning five annual waves (N = 307). RESULTS: Using Latent Growth Curve Modeling, DRD2 genotype was not directly related to loneliness. Interactions were found between parental support and DRD2 genotype, showing that adolescents with the A2A2 genotype who perceived little support from their parents had the highest baseline levels of loneliness. Adolescents with an A1 allele were not susceptible to the rewarding effect of parental support. CONCLUSIONS: The present study is the first to examine the role of the DRD2 genotype in loneliness. Our results contribute to a further understanding of the environmental and genetic basis of loneliness in adolescence. PMID- 21675995 TI - Steatitis in wild sharptooth catfish, Clarias gariepinus (Burchell), in the Olifants and lower Letaba Rivers in the Kruger National Park, South Africa. AB - Large numbers of adult Nile crocodiles, Crocodylus niloticus (Laurenti), died from pansteatitis during autumn and winter 2008 in the lower Letaba and Olifants River gorge in the Kruger National Park, South Africa. Consequently, the health status of fish from these waters was investigated. The study presents the pathological findings in fish inhabiting these rivers within the boundaries of the Park. Changes typical of steatitis were diagnosed in many of the larger specimens of sharptooth catfish, Clarias gariepinus (Burchell), caught within the Olifants River gorge. These fish carried large amounts of mesenteric fat with characteristic small brown granulomata within the adipose tissue. Necrosis and inflammation of the adipose tissues, with characteristic ceroid accumulation within the resultant granulomata and the associated aggregation of ceroid containing macrophages, were demonstrated histologically and were typical of steatitis. Other changes included mild thickening and pallor of the gill tissues and swollen, orange, fatty livers. Focal hepatic lipidosis was demonstrated histologically, and special stains revealed storage of large amounts of iron in the livers. Blood smears revealed chromatin clumping in erythrocyte nuclei and nuclear and cell membrane irregularities. This is the first record of steatitis in wild-caught C. gariepinus. PMID- 21675994 TI - Magnesium and anabolic hormones in older men. AB - Optimal nutritional and hormonal statuses are determinants of successful ageing. The age associated decline in anabolic hormones such as testosterone and insulin like growth factor 1 (IGF-1) is a strong predictor of metabolic syndrome, diabetes and mortality in older men. Studies have shown that magnesium intake affects the secretion of total IGF-1 and increase testosterone bioactivity. This observation suggests that magnesium can be a modulator of the anabolic/catabolic equilibrium disrupted in the elderly people. However, the relationship between magnesium and anabolic hormones in men has not been investigated. We evaluated 399 >=65-year-old men of CHIANTI in a study population representative of two municipalities of Tuscany (Italy) with complete data on testosterone, total IGF 1, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS) and serum magnesium levels. Linear regression models were used to test the relationship between magnesium and testosterone and IGF-1. Mean age of the population was 74.18 +/- 6.43 (years +/- SD, age range 65.2-92.4). After adjusting for age, magnesium was positively associated with total testosterone (beta +/- SE, 34.9 +/- 10.3; p = 0.001) and with total IGF-1 (beta +/- SE, 15.9 +/- 4.8; p = 0.001). After further adjustment for body mass index (BMI), log (IL 6), log (DHEAS), log (SHBG), log (insulin), total IGF-1, grip strength, Parkinson's disease and chronic heart failure, the relationship between magnesium and total testosterone remained strong and highly significant (beta +/- SE, 48.72 +/- 12.61; p = 0.001). In the multivariate analysis adjusted for age, BMI, log (IL-6), liver function, energy intake, log (insulin), log (DHEAS), selenium, magnesium levels were also still significantly associated with IGF-1 (beta +/- SE, 16.43 +/- 4.90; p = 0.001) and remained significant after adjusting for total testosterone (beta +/- SE, 14.4 +/- 4.9; p = 0.01). In a cohort of older men, magnesium levels are strongly and independently associated with the anabolic hormones testosterone and IGF-1. PMID- 21675996 TI - Koi herpesvirus epizootic in cultured carp and koi, Cyprinus carpio L., in Taiwan. AB - Koi herpesvirus (KHV) poses a significant threat to cultured koi and common carp, both Cyprinus carpio L. Since the first reported case in Israel in 1998, KHV has rapidly spread worldwide. This study investigates the spread of KHV to Taiwan by collecting 49 cases of suspected common carp and koi infections from 2003 to 2005 for analysis. Clinical signs included lethargy, anorexia, increased respiratory movements and uncoordinated swimming. Hyperaemia, haemorrhage on body surface and necrotic gill filaments were recorded. Gill epithelial hyperplasia, necrosis and eosinophilic intranuclear inclusion bodies were observed by histological examination, while virions were detected using transmission electron microscopy. By detecting the presence of the KHV thymidine kinase (TK) gene and the KHV 9/5 gene using polymerase chain reaction (PCR), 37 cases were identified as KHV positive, and the cumulative mortality of infected fish was 70-100%. Positive cases showed identical sequences for the genes analysed, implying that they were of the same origin. For the KHV 9/5 gene sequence, these cases exhibited 100% identity with the Japanese strain (TUMST1, accession number AP008984) and 99% identity with the Israeli (KHV-I, DQ177346) and US (KHV-U, DQ657948) strains. Additionally, a loop-mediated isothermal amplification (LAMP) assay was performed and found to be more sensitive than PCR tests, suggesting its potential use as a rapid diagnostic method for KHV. This is the first epidemiological study of KHV infection in cultured common carp and koi in Taiwan. PMID- 21675997 TI - Detection of antigenic proteins expressed by lymphocystis virus as vaccine candidates in olive flounder, Paralichthys olivaceus (Temminck & Schlegel). AB - Although the major capsid proteins (MCPs) of lymphocystis disease virus (LCDV) have been characterized, little is known about the host-derived immune response to MCPs and other LCDV antigenic proteins. To identify antigenic proteins of LCDV that could be used as vaccine candidates in olive flounder, Paralichthys olivaceus, we analysed the viral proteins responsible for its virulence by applying immuno-proteomics. LCDV proteins were separated by one-dimensional gel electrophoresis, transferred to polyvinylidene difluoride membrane, and probed with homogeneous P. olivaceus antisera elicited by LCDV natural infection and vaccination with formalin-killed LCDV. Four immune-reactive proteins were obtained at 68-, 51-, 41- and 21 kDa using antisera collected from natural infection while two proteins at 51- and 21 kDa exhibited response to antisera from vaccinated fish, indicating that the latter two proteins have vaccine potential. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and nanoelectrospray MS/MS, the 51 and 21 kDa proteins were identified as MCP and an unknown protein, respectively. PMID- 21675998 TI - Epizootic Nocardia infection in cultured weakfish, Cynoscion regalis (Bloch and Schneider). PMID- 21675999 TI - Transition of stable isotope ratios of leaf water under simulated dew formation. AB - Dew formation, a common meteorological phenomenon, is expected to intensify in the future. Dew can influence the H218O and HDO isotopic compositions of leaf water (delta(L) ), but the phenomenon has been neglected in many experimental and modelling studies. In this study, the dew effect on delta(L) was investigated with a dark plant chamber in which dew formation was introduced. The H218O and HDO compositions of water vapour, dew water and leaf water of five species were measured for up to 48 h of dew exposure. Our results show that the exchanges of H218O and HDO in leaf water with the air continued in the darkness when the net H216O flux was zero. Our estimates of the leaf conductance using the isotopic mass balance method ranged from 0.035 to 0.087 mol m-2 s-1, in broad agreement of the night-time stomatal conductance reported in the literature. In our experiments, the conductance of the C3 species was 0.04 +/- 0.01 mol m-2 s-1 and that of the C3 plants was 0.10 +/- 0.04 mol m-2 s-1. At the end of 16 h dew exposure, 72 (+/-17) and 94 (+/-11)% of the leaf water came from dew according to the 18O and D tracer, respectively. PMID- 21676000 TI - High temperature triggers the metabolism of S-nitrosothiols in sunflower mediating a process of nitrosative stress which provokes the inhibition of ferredoxin-NADP reductase by tyrosine nitration. AB - High temperature (HT) is considered a major abiotic stress that negatively affects both vegetative and reproductive growth. Whereas the metabolism of reactive oxygen species (ROS) is well established under HT, less is known about the metabolism of reactive nitrogen species (RNS). In sunflower (Helianthus annuus L.) seedlings exposed to HT, NO content as well as S-nitrosoglutathione reductase (GSNOR) activity and expression were down-regulated with the simultaneous accumulation of total S-nitrosothiols (SNOs) including S nitrosoglutathione (GSNO). However, the content of tyrosine nitration (NO(2) Tyr) studied by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) and by confocal laser scanning microscope was induced. Nitroproteome analysis under HT showed that this stress induced the protein expression of 13 tyrosine-nitrated proteins. Among the induced proteins, ferredoxin-NADP reductase (FNR) was selected to evaluate the effect of nitration on its activity after heat stress and in vitro conditions using 3 morpholinosydnonimine (SIN-1) (peroxynitrite donor) as the nitrating agent, the FNR activity being inhibited. Taken together, these results suggest that HT augments SNOs, which appear to mediate protein tyrosine nitration, inhibiting FNR, which is involved in the photosynthesis process. PMID- 21676001 TI - Neural and behavioral mechanisms of impulsive choice in alcohol use disorder. AB - BACKGROUND: Alcohol dependence has repeatedly been associated with impulsive choice, or the inability to choose large delayed rewards over smaller, but more immediate rewards. However, the neural basis of impulsive choice in alcohol use disorders (AUDs) is not well understood. METHODS: One hundred fifty-one individuals with a range of alcohol use from social drinking to severe alcohol dependence completed a delay discounting task while undergoing functional magnetic resonance imaging. Participants received customized trials designed to ensure an approximately equivalent number of immediate responses. RESULTS: Delaying gratification recruited regions involved in cognitive control, conflict monitoring, and the interpretation of somatic states. Individuals with more severe alcohol use problems showed increased discounting of delayed rewards and greater activation in several regions including supplementary motor area, insula/orbitofrontal cortex, inferior frontal gyrus, and the precuneus. CONCLUSIONS: These results suggest that impulsive choice in alcohol dependence is the result of functional anomalies in widely distributed, but interconnected brain regions involved in cognitive and emotional control. Furthermore, our results suggest that the neural mechanisms of impulsive choice in AUD both overlaps with that observed in previous studies, and shows that individuals with AUD recruit additional mechanisms when making intertemporal choices. PMID- 21676002 TI - Effects of energy drinks mixed with alcohol on behavioral control: risks for college students consuming trendy cocktails. AB - BACKGROUND: There has been a dramatic rise in the consumption of alcohol mixed with energy drinks (AmED) in young people. AmED have been implicated in risky drinking practices and greater accidents and injuries have been associated with their consumption. Despite the increased popularity of these beverages (e.g., Red Bull and vodka), there is little laboratory research examining how the effects of AmED differ from alcohol alone. This experiment was designed to investigate if the consumption of AmED alters neurocognitive and subjective measures of intoxication compared with the consumption of alcohol alone. METHODS: Participants (n=56) attended 1 session where they were randomly assigned to receive one of 4 doses (0.65 g/kg alcohol, 3.57 ml/kg energy drink, AmED, or a placebo beverage). Performance on a cued go/no-go task was used to measure the response of inhibitory and activational mechanisms of behavioral control following dose administration. Subjective ratings of stimulation, sedation, impairment, and level of intoxication were recorded. RESULTS: Alcohol alone impaired both inhibitory and activational mechanisms of behavioral control, as evidenced by increased inhibitory failures and increased response times compared to baseline performance. Coadministration of the energy drink with alcohol counteracted some of the alcohol-induced impairment of response activation, but not response inhibition. For subjective effects, alcohol increased ratings of stimulation, feeling the drink, liking the drink, impairment, and level of intoxication, and alcohol decreased the rating of ability to drive. Coadministration of the energy drink with alcohol increased self-reported stimulation, but resulted in similar ratings of the other subjective effects as when alcohol was administered alone. CONCLUSIONS: An energy drink appears to alter some of the objective and subjective impairing effects of alcohol, but not others. Thus, AmED may contribute to a high-risk scenario for the drinker. The mix of impaired behavioral inhibition and enhanced stimulation is a combination that may make AmED consumption riskier than alcohol consumption alone. PMID- 21676003 TI - The contribution of parental alcohol use disorders and other psychiatric illness to the risk of alcohol use disorders in the offspring. AB - BACKGROUND: Few population-based studies have investigated associations between parental history of alcoholism and the risk of alcoholism in offspring. The aim was to investigate in a large cohort the risk of alcohol use disorders (AUD) in the offspring of parents with or without AUD and with or without hospitalization for other psychiatric disorder (OPD). METHODS: Longitudinal birth cohort study included 7,177 men and women born in Copenhagen between October 1959 and December 1961. Cases of AUD were identified in 3 Danish health registers and cases of OPD in the Danish Psychiatric Central Register. Offspring registration with AUD was analyzed in relation to parental registration with AUD and OPD. Covariates were offspring gender and parental social status. RESULTS: Both maternal and paternal registration with AUD significantly predicted offspring risk of AUD (odds ratios 1.96; 95% CI 1.42 to 2.71 and 1.99; 95% CI 1.54 to 2.68, respectively). The association between maternal, but not paternal, OPD and offspring AUD was also significant (odds ratios 1.46; 95% CI 1.15 to 1.86 and 1.26; 95% CI 0.95 to 1.66, respectively). Other predictors were male gender and parental social status. A significant interaction was observed between paternal AUD and offspring gender on offspring AUD, and stratified analyses showed particularly strong associations of both paternal and maternal AUD with offspring AUD in female cohort members. CONCLUSIONS: Parental AUD was associated with an increased risk of offspring AUD independent of other significant predictors, such as gender, parental social status, and parental psychiatric hospitalization with other diagnoses. Furthermore, this association appeared to be stronger among female than male offspring. The results suggest that inherited factors related to alcoholism are at least as important in determining the risk of alcoholism among daughters as among sons. PMID- 21676004 TI - Ethanol alters BDNF-induced Rho GTPase activation in axonal growth cones. AB - BACKGROUND: The effects of ethanol on development of postmitotic neurons include altered neurite outgrowth and differentiation, which may contribute to neuropathology associated with fetal alcohol spectrum disorders. We previously reported that ethanol exposure alters axon growth dynamics in dissociated cultures of rat hippocampal pyramidal neurons. Given the important regulatory role of small Rho guanosine triphosphatases (GTPases) in cytoskeletal reorganization associated with axon growth, and reports that ethanol alters whole cell Rho GTPase activity in other cell types, this study explored the hypothesis that ethanol alters Rho GTPase activity specifically in axonal growth cones. METHODS: Fetal rat hippocampal pyramidal neurons were maintained in dissociated cultures for 1 day in control medium or medium containing 11 to 43 mM ethanol. Some cultures were also treated with brain-derived neurotrophic factor (BDNF), an activator of Rac1 and Cdc42 GTPases that promotes axon extension. Levels of active Rho GTPases in growth cones were measured using in situ binding assays for GTP-bound Rac1, Cdc42, and RhoA. Axon length, growth cone area, and growth cone surface expression of tyrosine kinase B (TrkB), the receptor for BDNF, were assessed by digital morphometry and immunocytochemistry. RESULTS: Although ethanol increased the surface area of growth cones, the levels of active Rho GTPases in axonal growth cones were not affected in the absence of exogenous BDNF. In contrast, ethanol exposure inhibited BDNF-induced Rac1/Cdc42 activation in a dose-dependent manner and increased RhoA activation at the highest concentration tested. Similar TrkB expression was observed on the surface of axonal growth cones of control and ethanol-treated neurons. CONCLUSIONS: These results reveal an inhibitory effect of ethanol on growth cone signaling via small Rho GTPases during early stages of hippocampal development in vitro, and suggest a mechanism whereby ethanol may disrupt neurotrophic factor regulation of axon growth and guidance. PMID- 21676005 TI - Outcomes of patients with alcohol use disorders experiencing healthcare associated infections. AB - BACKGROUND: Healthcare-associated infections (HAI) affect 1.7 million patients annually in the United States, and patients with alcohol use disorders (AUD) are at increased risk of developing HAI. HAI have been shown to substantially increase the hospital length of stay, mortality, and cost. In a cohort of patients with HAI, we sought to determine mortality, cost, and hospital length of stay attributable to AUD. METHODS: Using the Nationwide Inpatient Sample for the year 2007, the largest all-payer database of hospitalized patients comprising approximately 1,000 hospitals, we performed a retrospective cohort study of all patients who developed healthcare-associated pneumonia or sepsis. We excluded patients who were transferred from another healthcare facility, who were diagnosed with community-acquired infections, immunosuppression, or cancer. Logistic regression was computed to calculate attributable mortality. Linear regression analyses were computed to determine cost and hospital length of stay alpha = 10(-10) . RESULTS: A total of 149,892 patients developed HAI, and 8,830 (5.9%) had a co-diagnosis of AUD. Patients with AUD were younger, more likely to be men, less likely to be Asian, and more likely to be Hispanic. Patients with AUD were more likely to have tobacco dependence, less likely to be electively admitted to the hospital, and less likely to undergo surgery. They also had lower severity of illness, lower income, and were more likely to be in academic medical centers. Logistic regression revealed that AUD was an independent predictor of increased mortality: Odds ratio = 1.71, 95% confidence interval (CI) [1.626; 1.799], p < 10(-10) . Linear regression demonstrated that AUD independently predicted increased hospital length of stay by 2 days: Patients with AUD had a length of stay of 13 days, 95% CI [12.4; 13.6] compared with 11 days, 95% CI [11.1; 11.4] for patients without AUD, p < 10(-10) . Linear regression also revealed that patients with AUD had a higher hospital cost: $34,826, 95% CI [32,415.71; 37,416.52] for patients with AUD compared with $27,167, 95% CI [25,703.18; 28,714.05] for patients without AUD, p < 10(-10) . CONCLUSIONS: Patients with AUD who experience HAI have worse outcomes compared with patients without AUD. Patients with AUD have higher mortality, longer hospital length of stay, and higher costs. Studies aimed at decreasing the morbidity and mortality of HAI in patients with AUD are warranted. PMID- 21676007 TI - Analysis and interpretation of specific ethanol metabolites, ethyl sulfate, and ethyl glucuronide in sewage effluent for the quantitative measurement of regional alcohol consumption. AB - BACKGROUND: The quantitative measurement of urinary metabolites in sewage streams and the subsequent estimation of consumption rates of the parent compounds have previously been demonstrated for pharmaceuticals and narcotics. Ethyl sulfate and ethyl glucuronide are excreted in urine following the ingestion of alcohol, and are useful biomarkers for the identification of acute alcohol consumption. This study reports a novel ion-exchange-mediated chromatographic method for the quantitative measurement of ethyl sulfate and ethyl glucuronide in sewage effluent, and presents a novel calculation method for the purposes of relating the resulting sewage concentrations with rates of alcohol consumption in the region. METHODS: A total of 100 sewage samples covering a 25-day period were collected from a treatment plant servicing approximately 500,000 people, and analyzed for levels of ethyl sulfate and ethyl glucuronide. The resulting data were then used to estimate combined alcohol consumption rates for the region, and the results were compared with alcohol related sales statistics for the same region. RESULTS: Ethyl glucuronide was found to be unstable in sewage effluent. Ethyl sulfate was stable and measurable in all samples at concentrations ranging from 16 to 246 nM. The highest concentrations of the alcohol biomarker were observed during weekend periods. Sixty one percent of the total mass of ethyl sulfate in sewage effluent corresponds to alcohol consumption on Friday and Saturday. Sales statistics for alcohol show that consumption in the region is approximately 6,750 kg/d. The quantity of ethyl sulfate passing through the sewage system is consistent with consumption of 4,900 to 7,800 kg/d. CONCLUSIONS: Sewage epidemiology assessments of ethyl sulfate can provide accurate estimates of community alcohol consumption, and detailed examination of the kinetics of this biomarker in sewage streams can also identify time-dependent trends in alcohol consumption patterns. PMID- 21676008 TI - Impact of motivational changes on drinking outcomes in pharmacobehavioral treatment for alcohol dependence. AB - BACKGROUND: Psychological factors such as motivation to change and self-efficacy influence drinking outcomes in alcohol-dependent individuals who are enrolled in pharmacobehavioral studies. Previous results from our research clinic indicated that initial stage of change of heavy drinkers enrolled in a pharmacobehavioral trial was significantly associated with alcohol consumption. However, overall empirical findings regarding the consistency and extent of the connection between motivational factors and behavior are mixed. This may be in part because of the impact of changes in motivation over the course of treatment and/or characteristics of the individuals receiving the intervention. Our goal in the present study was to examine the extent to which levels of motivation and self efficacy changed during the treatment phase of a pharmacobehavioral treatment trial, and the extent to which these variables affected drinking behavior in subsets of alcohol-dependent individuals. METHODS: We conducted an exploratory evaluation of changes in motivation, temptation to drink, confidence to abstain, and drinking behavior over time during the treatment phase of a pharmacobehavioral study involving 321 alcohol-dependent individuals. We also examined the extent to which individual variables such as initial drinking severity, onset of alcohol dependence, and medication status influenced changes in motivation, self-efficacy, and drinking behavior. RESULTS: Participants reported improvements in motivation to change, self-efficacy for change, and drinking behaviors over the course of treatment. As hypothesized, motivation to change and self-efficacy for change were related to specific dimensions of posttreatment drinking. Heavy drinkers reported more improvement in drinking behaviors than did nonheavy drinkers. Early-onset drinkers who were on medication reduced their drinking more than those on placebo, and these drinking changes appear to be partially mediated by reductions in temptation. CONCLUSIONS: Reductions in drinking occur and are predicted by increased motivation to change, reduced temptation to drink, and increased confidence to abstain in this population of alcoholic-dependent individuals. Early and late onset and heavy drinkers and those taking medications displayed differential changes in drinking behavior, some of which were explained by the mediating effects of self-efficacy. This is a first step in understanding more about which alcoholic individuals respond best to treatment and what mechanisms may be involved in the changes in drinking and drinking-specific changes in frequency and intensity of drinking. PMID- 21676006 TI - Alcohol-binding sites in distinct brain proteins: the quest for atomic level resolution. AB - Defining the sites of action of ethanol on brain proteins is a major prerequisite to understanding the molecular pharmacology of this drug. The main barrier to reaching an atomic-level understanding of alcohol action is the low potency of alcohols, ethanol in particular, which is a reflection of transient, low-affinity interactions with their targets. These mechanisms are difficult or impossible to study with traditional techniques such as radioligand binding or spectroscopy. However, there has been considerable recent progress in combining X-ray crystallography, structural modeling, and site-directed mutagenesis to define the sites and mechanisms of action of ethanol and related alcohols on key brain proteins. We review such insights for several diverse classes of proteins including inwardly rectifying potassium, transient receptor potential, and neurotransmitter-gated ion channels, as well as protein kinase C epsilon. Some common themes are beginning to emerge from these proteins, including hydrogen bonding of the hydroxyl group and van der Waals interactions of the methylene groups of ethanol with specific amino acid residues. The resulting binding energy is proposed to facilitate or stabilize low-energy state transitions in the bound proteins, allowing ethanol to act as a "molecular lubricant" for protein function. We discuss evidence for characteristic, discrete alcohol-binding sites on protein targets, as well as evidence that binding to some proteins is better characterized by an interaction region that can accommodate multiple molecules of ethanol. PMID- 21676009 TI - Alcohol dependence in men: reliability and heritability. AB - BACKGROUND: The assessment of a Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) life-time history of alcohol dependence (LTH AD) has been found to be moderately reliable and substantially heritable. However, in studies of the heritability of LTH-AD, measurement error could not be discriminated from the true unique environmental effects. The aims of this study were to: (i) estimate the reliability of LTH-AD in a population based sample, (ii) identify characteristics of LTH-AD predicting a reliable diagnosis, (iii) investigate the heritability of LTH-AD as a function of diagnostic confidence, and (iv) to estimate the genetic and environmental influences on LTH-AD correcting for measurement error. METHODS: An unselected sample of 4,203 male twins was interviewed twice approximately 1-year apart assessing DSM-IV LTH-AD over the same period of life. Logistic regression was used to identify clinical features that predict a reliable diagnosis LTH-AD. Genetic and environmental influences on reliable LTH-AD were examined using structural equation models. RESULTS: Reliability of the diagnosis of LTH-AD was moderate (kappa = 0.54) and was predicted by the number of AD symptoms, treatment seeking, duration of most severe episode, and a great deal of time spent to obtain, use, or recover from alcohol use (DSM-IV AD criterion #5). Using an index of caseness, heritability of LTH-AD increased as a function of diagnostic confidence. Accounting for errors of measurement in a multivariate twin model, the heritability of LTH-AD increased from 55 to 71%. CONCLUSIONS: Reliably diagnosed LTH-AD can be predicted by characteristics relevant to the disorder. LTH-AD appears to be a moderately reliable disorder of high heritability. PMID- 21676010 TI - New insight into stratification of anaerobic methanotrophs in cold seep sediments. AB - Methane seepages typically harbor communities of anaerobic methane oxidizers (ANME); however, knowledge about fine-scale vertical variation of ANME in response to geochemical gradients is limited. We investigated microbial communities in sediments below a white microbial mat in the G11 pockmark at Nyegga by 16S rRNA gene tag pyrosequencing and real-time quantitative PCR. A vertical stratification of dominating ANME communities was observed at 4 cmbsf (cm below seafloor) and below in the following order: ANME-2a/b, ANME-1 and ANME 2c. The ANME-1 community was most numerous and comprised single or chains of cells with typical rectangular morphology, accounting up to 89.2% of the retrieved 16S rRNA gene sequences. Detection rates for sulfate-reducing Deltaproteobacteria possibly involved in anaerobic oxidation of methane were low throughout the core. However, a correlation in the abundance of Candidate division JS-1 with ANME-2 was observed, indicating involvement in metabolisms occurring in ANME-2-dominated horizons. The white microbial mat and shallow sediments were dominated by organisms affiliated with Sulfurovum (Epsilonproteobacteria) and Methylococcales (Gammaproteobacteria), suggesting that aerobic oxidation of sulfur and methane is taking place. In intermediate horizons, typical microbial groups associated with methane seeps were recovered. The data are discussed with respect to co-occurring microbial assemblages and interspecies interactions. PMID- 21676011 TI - An investigation of the safety and pharmacokinetics of the novel TRPV1 antagonist XEN-D0501 in healthy subjects. AB - AIMS: XEN-D0501, a novel TRPV1 antagonist, is being developed to treat overactive bladder. This study investigated the safety and pharmacokinetics of repeat-dose XEN-D0501 in healthy subjects. METHODS: The study was conducted in two parts. Part 1 was a double-blind, randomized, placebo-controlled, two-way crossover study in three cohorts of 12 young male subjects. Each subject received XEN-D0501 and placebo (in random order) twice daily for 13 days, with a final single dose on day 14. Doses of 1, 2.5 and 5 mg XEN-D0501 were investigated. Part 2 was an open-label, randomized, two-way crossover study in male and female subjects (45 to 65 years). Subjects received single doses of 5 mg XEN-D0501 under fasted and fed conditions in random order. Blood sampling and safety assessments were conducted throughout the study. RESULTS: XEN-D0501 was rapidly absorbed (t(max) generally 0.5-4 h post dose). XEN-D0501 exposure increased less than proportionally to dose over the range studied and exhibited minimal accumulation with twice daily dosing. Food had no clinically relevant effects on the pharmacokinetics of XEN-D0501. There were no severe or serious adverse events and all doses were well tolerated. A dose-related increase in body temperature was seen with XEN-D0501 which attenuated over time. Differences from placebo in mean maximum core body temperatures were 0.22 degrees C, 0.5 degrees C and 0.74 degrees C following 1 mg, 2.5 mg and 5 mg twice daily XEN-D0501. The observed increase in body temperature was not considered to be of clinical concern. CONCLUSIONS: XEN-D0501 appeared safe and well tolerated at doses up to 5 mg twice daily for 14 days in healthy subjects. PMID- 21676012 TI - Identification of the srtC1 transcription start site and catalytically essential residues required for Actinomyces oris T14V SrtC1 activity. AB - In Actinomyces oris T14V, sortase SrtC1 mediates the assembly of type 1 fimbriae. We analyzed the effects of the conserved residues (H184, H204, F213, Y236, L263, T265, C266 and R275) on the SrtC1 activity by site-directed mutagenesis. We identified three essential conserved residues (H204, Y236 and C266) that are critical for the assembly of type 1 fimbriae in this organism. rapid amplification of cDNA ends analyses and reverse transcriptase-PCR results indicate that srtC1 was transcribed together with the putative adhesin gene fimQ and major structural subunit gene fimP as a single polycistronic mRNA. PMID- 21676013 TI - Active and silent members in the mlr gene cluster of a microcystin-degrading bacterium isolated from Lake Taihu, China. AB - The microcystin-degrading genes, mlr, are important participants in the degradation process of hepatotoxic microcystins for several bacterial species. However, their expression status during degrading microcystins is still unknown. In order to study this expression process, we isolated a novel microcystin degrading bacterial strain, sequenced its mlr gene cluster and examined the expression of the mlrA gene at different concentrations of microcystin LR. The expression of mlrA increased slightly at 0.4 mg L-1, and was significantly upregulated at 2.0 mg L-1. Frameshift mutations were found in the mlrB* gene, and the mRNA of mlrB* could not be detected in the total RNA extracts of Novosphingobium sp. THN1. We conclude that mlrA is actively involved in the microcystin-degrading process, but mlrB* has lost its activity in this bacterial strain. PMID- 21676014 TI - Coronary risk assessment and arterial age calculation using coronary artery calcium scoring and the Framingham Risk Score. PMID- 21676015 TI - Echocardiographic evaluation of left ventricular filling pressures validated against an implantable left ventricular pressure monitoring system. AB - BACKGROUND: Aim of this study was to assess the ability of different echocardiographic indices to evaluate left ventricular (LV) filling pressures in patients with reduced LV function. METHODS: In 5 patients scheduled for aortocoronary bypass surgery, a telemetric intraventricular pressure sensor was implanted. Over 6 months, these patients underwent a total of 21 echocardiographic examinations with a simultaneous recording of left ventricular mean (LVMDP) and end-diastolic pressure (LVEDP). The following echocardiographic parameters were extracted from the transmitral flow profile: early (E) and late (A) diastolic flow velocity, deceleration time of the E-wave (DT) and the isovolumic relaxation time (IVRT). Early diastolic velocity of the mitral ring (E') was recorded using pulsed-wave tissue Doppler echocardiography. RESULTS: All patients were in NYHA class III and mean ejection fraction was 30%. E correlated only moderately with LVMDP (r =-0.60, P = 0.003), but revealed the highest area under the receiver operating characteristic curve for the prediction of an elevated LVMDP > 12 mmHg (AUC = 0.94, sensitivity of 92% and specificity of 86%, cut-off value 7.5 cm/s). E/A > 1 predicted LVEDP > 15 mmHg with a sensitivity of 87% and a specificity of 80%. E/E' was not correlated with LVMDP or LVEDP. CONCLUSION: Although linear correlation between echocardiographic parameters and diastolic LV pressures reached statistical significance, the correlation coefficients were low. However, in these patients with severely reduced LV function due to ischemic heart disease conventional echocardiographic parameters of transmitral flow showed higher predictive values for elevated LV filling pressures than E/E'. PMID- 21676016 TI - Left ventricular function in hypertension: new insight by speckle tracking echocardiography. AB - BACKGROUND: Conventional transthoracic echocardiography (TTE) and tissue Doppler imaging (TDI) are usually unable to reveal very early subtle abnormalities in left ventricular (LV) systolic function caused by hypertension, prior to manifestation of hypertrophy (LVH). This study was undertaken to assess whether speckle tracking echocardiography (STE) provides more insight into early hypertension-induced LV systolic dysfunction, with the purpose of identifying patients at higher risk for heart failure (HF). METHODS: Fifty-one patients (56.5 +/- 14 years) and 51 controls (52 +/- 12.6 years) were enrolled. According to the presence or absence of LVH, patients were classified as LVH((+)) and LVH((-)) , respectively. Global longitudinal function was calculated by TDI, global strains [longitudinal (LS), radial (RS), and circumferential (CS)] and twist were assessed by STE. RESULTS: Conventional TTE showed a LV diastolic dysfunction with normal systolic function in all patients. TDI was able to detect a systolic dysfunction only in the LVH((+)) group (P < 0.001) whereas STE revealed an impairment of systolic LS in all patients, including those without hypertrophy (P = 0.02). Furthermore, in the LVH((+)) group, STE showed reduced RS and increased CS and twist. These last alterations were observed with respect to both controls (RS: P = 0.02; CS: P = 0.05; twist: P < 0.001) and LVH((-)) patients (RS: P = 0.01; CS: P = 0.003; twist: P = 0.001). CONCLUSION: In hypertensive patients, STE provides more detailed information than conventional echocardiography and TDI, since it reveals a systolic dysfunction before hypertrophy occurs (Stage A of ACC/AHA classification of HF) and identifies some early LV mechanic changes that might improve the clinical management of these patients. PMID- 21676017 TI - The influence of circadian variations on echocardiographic parameters in healthy people. AB - BACKGROUND: Our aim was to investigate whether diastolic functions, myocardial velocities and pulmonary vein flow show diurnal variation within a 24-hour day. METHOD AND RESULTS: Fourty-four healthy subjects with no history of cardiovascular or systemic diseases (32 males, 12 females; mean age 34.7 +/- 8.7 years, mean BMI: 25.5 +/- 3.5 kg/m(2)) were enrolled in this study. None of the subjects had a history, symptoms or signs of cardiovascular or systemic diseases or were taking drugs of any kind. All underwent echocardiographic examination at 7 a.m., 1 p.m., 7 p.m., and 1 a.m. M-mode systolic, diastolic velocities and pulmonary vein flow measurements were obtained. There were no differences in systolic and diastolic blood pressures and heart rate. The left atrial diameter was greater at 1 p.m. (3.80 +/- 0.44; P = 0.031). The isovolumic contraction time (ICT) was found to be the shortest (41 +/- 12 msn; P = 0.050), and ejection time (ET) the longest (290 +/- 31 msn; P = 0.017) at the 1 am measurements. The mitral myocardial performance index (MPI) was lowest during the 1 a.m. measurements (0.42 +/- 0.11; P = 0.001). The systolic myocardial velocities (Sm) obtained from the septum and inferior region were significantly higher at 1 p.m. and lower at 7 a.m. (9.17 +/- 1.79, 10.25 +/- 2.29; 8.11 +/- 1.06, 8.63 +/- 1.49; P < 0.05). The late diastolic velocities obtained from the lateral, inferior and anterior regions were higher at 1 p.m. and 7 p.m. CONCLUSION: The left ventricular diameter and ejection fraction did not exhibit circadian variations. However, our data indicate that some parameters reflecting diastolic function, systolic myocardial velocities and MPI, as well as left atrial diameter change at different times of the day, independent of blood pressure and heart rate. PMID- 21676018 TI - Right atrial speckle tracking analysis as a novel noninvasive method for pulmonary hemodynamics assessment in patients with chronic systolic heart failure. AB - BACKGROUND: The right atrium (RA) plays multiple roles in the cardiac cycle. The reservoir phase of the RA is a dynamic rather than a static phase of cardiac cycle and RA deformation is dependent on pulmonary pressures exerted on the right ventricle and, therefore, backwards on the RA. The purpose of this study was to assess the accuracy and the clinical applicability of the speckle tracking echocardiography (STE) evaluation of the RA in predicting the invasive systolic pulmonary artery pressure (SPAP) in patients with systolic heart failure (HF) undergoing right heart catheterization (RHC). METHODS: Thirty-one hemodynamically stable, in-clinic HF patients who were undergoing RHC were included. Doppler echocardiography and RHC catheterization were simultaneously performed. Echocardiographic measures and STE where obtained as peak atrial longitudinal strain (PALS), RA strain rate, and time to peak longitudinal strain (TPLS). RA PALS was inversely correlated with invasively assessed SPAP (r =-0.81; P < 0.001) while RA strain directly correlated with SPAP (r = 0.82; P < 0.001). RA PALS and strain rate retained this correlation even after nitroprusside challenge test (r =-0.81; P < 0.001 and r = 0.91; P < 0.001, respectively). Area under the curve optimal cutoffs for predicting the SPAP > 50 mmHg were for RA PALS 10.3% (AUC:0.93, sensitivity: 100%, specificity: 78%). CONCLUSION: RA STE showed a significant correlation with pulmonary pressure. RA assessment with STE can predict pulmonary artery hypertension in HF patients. This result is consistent with nitroprusside challenge test. Although RA STE is not routinely used, its evaluation may implement right heart evaluation in HF patients. PMID- 21676020 TI - Explaining Michigan: developing an ex post theory of a quality improvement program. AB - CONTEXT: Understanding how and why programs work-not simply whether they work-is crucial. Good theory is indispensable to advancing the science of improvement. We argue for the usefulness of ex post theorization of programs. METHODS: We propose an approach, located within the broad family of theory-oriented methods, for developing ex post theories of interventional programs. We use this approach to develop an ex post theory of the Michigan Intensive Care Unit (ICU) project, which attracted international attention by successfully reducing rates of central venous catheter bloodstream infections (CVC-BSIs). The procedure used to develop the ex post theory was (1) identify program leaders' initial theory of change and learning from running the program; (2) enhance this with new information in the form of theoretical contributions from social scientists; (3) synthesize prior and new information to produce an updated theory. FINDINGS: The Michigan project achieved its effects by (1) generating isomorphic pressures for ICUs to join the program and conform to its requirements; (2) creating a densely networked community with strong horizontal links that exerted normative pressures on members; (3) reframing CVC-BSIs as a social problem and addressing it through a professional movement combining "grassroots" features with a vertically integrating program structure; (4) using several interventions that functioned in different ways to shape a culture of commitment to doing better in practice; (5) harnessing data on infection rates as a disciplinary force; and (6) using "hard edges." CONCLUSIONS: Updating program theory in the light of experience from program implementation is essential to improving programs' generalizability and transferability, although it is not a substitute for concurrent evaluative fieldwork. Future iterations of programs based on the Michigan project, and improvement science more generally, may benefit from the updated theory present here. PMID- 21676021 TI - Assessing the evaluability of complex public health interventions: five questions for researchers, funders, and policymakers. AB - CONTEXT: Evidence to support government programs to improve public health often is weak. Recognition of this "knowledge gap" has led to calls for more and better evaluation, but decisions about priorities for evaluation also need to be addressed in regard to financial restraint. METHODS: Using England's Healthy Community Challenge Fund as a case study, this article presents a set of questions to stimulate and structure debate among researchers, funders, and policymakers and help make decisions about evaluation within and between complex public health interventions as they evolve from initial concept to dissemination of full-scale intervention packages. FINDINGS: This approach can be used to identify the types of knowledge that might be generated from any evaluation, given the strength of evidence available in response to each of five questions, and to support a more systematic consideration of resource allocation decisions, depending on the types of knowledge required. CONCLUSIONS: The principles of this approach may be generalizable, and should be tested and refined for other complex public health and wider social interventions. PMID- 21676022 TI - How health care organizations are using data on patients' race and ethnicity to improve quality of care. AB - CONTEXT: Racial and ethnic disparities in the quality of health care are well documented in the U.S. health care system. Reducing these disparities requires action by health care organizations. Collecting accurate data from patients about their race and ethnicity is an essential first step for health care organizations to take such action, but these data are not systematically collected and used for quality improvement purposes in the United States. This study explores the challenges encountered by health care organizations that attempted to collect and use these data to reduce disparities. METHODS: Purposive sampling was used to identify eight health care organizations that collected race and ethnicity data to measure and reduce disparities in the quality and outcomes of health care. Staff, including senior managers and data analysts, were interviewed at each site, using a semi-structured interview format about the following themes: the challenges of collecting and collating accurate data from patients, how organizations defined a disparity and analyzed data, and the impact and uses of their findings. FINDINGS: To collect accurate self-reported data on race and ethnicity from patients, most organizations had upgraded or modified their IT systems to capture data and trained staff to collect and input these data from patients. By stratifying nationally validated indicators of quality for hospitals and ambulatory care by race and ethnicity, most organizations had then used these data to identify disparities in the quality of care. In this process, organizations were taking different approaches to defining and measuring disparities. Through these various methods, all organizations had found some disparities, and some had invested in interventions designed to address them, such as extra staff, extended hours, or services in new locations. CONCLUSION: If policymakers wish to hold health care organizations accountable for disparities in the quality of the care they deliver, common standards will be needed for organizations' data measurement, analysis, and use to guide systematic analysis and robust investment in potential solutions to reduce and eliminate disparities. PMID- 21676023 TI - Primary health care in Canada: systems in motion. AB - CONTEXT: During the 1980s and 1990s, innovations in the organization, funding, and delivery of primary health care in Canada were at the periphery of the system rather than at its core. In the early 2000s, a new policy environment emerged. METHODS: This policy analysis examines primary health care reform efforts in Canada during the last decade, drawing on descriptive information from published and gray literature and from a series of semistructured interviews with informed observers of primary health care in Canada. FINDINGS: Primary health care in Canada has entered a period of potentially transformative change. Key initiatives include support for interprofessional primary health care teams, group practices and networks, patient enrollment with a primary care provider, financial incentives and blended-payment schemes, development of primary health care governance mechanisms, expansion of the primary health care provider pool, implementation of electronic medical records, and quality improvement training and support. CONCLUSIONS: Canada's experience suggests that primary health care transformation can be achieved voluntarily in a pluralistic system of private health care delivery, given strong government and professional leadership working in concert. PMID- 21676026 TI - Use of congeneric assessment to reveal the linked genetic histories of two threatened fishes in the Murray-Darling Basin, Australia. AB - The intensely regulated Murray-Darling Basin in southeastern Australia is the nation's most extensive and economically important river system, and it contains fragmented populations of numerous fish species. Among these is the Murray hardyhead (Craterocephalus fluviatilis), a species listed as endangered (International Union for Conservation of Nature Red List) in the mid-1990 s prior to its acute decline with the progression of a severe drought that began in 1997. We compared the genetic structure of Murray hardyhead with 4 congeneric species (Darling hardyhead[C. amniculus], Finke hardyhead[C. centralis], Lake Eyre hardyhead[C. eyresii], and unspecked hardyhead[C. stercusmuscarum]), selected on the basis of their taxonomic or biological similarity to Murray hardyhead, in order to affirm species boundaries and test for instances of introgressive hybridization, which may influence species ecology and conservation prospects. We used allozyme (52 loci) and mtDNA markers (1999 bp of ATPase and cytochrome b) to provide a comparative genetic assessment of 139 Murray hardyhead, which represented all extant and some recently extirpated populations, and 71 congeneric specimens from 12 populations. We confirmed that Murray hardyhead and Darling hardyhead are taxonomically distinct and identified a number of potential conservation units, defined with genetic criteria, in both species. We also found allozyme and mtDNA evidence of historic genetic exchange between these 2 allopatric species, apparently involving one population of each species at the geographic edge of the species' ranges, not in the most proximate populations sampled. Our results provide information on species boundaries and offer insight into the likely causes of high genetic diversity in certain populations, results which are already being used to guide national recovery planning and local action. Given the prevalence of incorrect taxonomies and introgression in many organismal groups, we believe these data point to the need to commence genetic investigations of any threatened species from an initially broad taxonomic focus. PMID- 21676024 TI - An economic history of Medicare part C. AB - CONTEXT: Twenty-five years ago, private insurance plans were introduced into the Medicare program with the stated dual aims of (1) giving beneficiaries a choice of health insurance plans beyond the fee-for-service Medicare program and (2) transferring to the Medicare program the efficiencies and cost savings achieved by managed care in the private sector. METHODS: In this article we review the economic history of Medicare Part C, known today as Medicare Advantage, focusing on the impact of major changes in the program's structure and of plan payment methods on trends in the availability of private plans, plan enrollment, and Medicare spending. Additionally, we compare the experience of Medicare Advantage and of employer-sponsored health insurance with managed care over the same time period. FINDINGS: Beneficiaries' access to private plans has been inconsistent over the program's history, with higher plan payments resulting in greater choice and enrollment and vice versa. But Medicare Advantage generally has cost more than the traditional Medicare program, an overpayment that has increased in recent years. CONCLUSIONS: Major changes in Medicare Advantage's payment rules are needed in order to simultaneously encourage the participation of private plans, the provision of high-quality care, and to save Medicare money. PMID- 21676027 TI - Cost-effectiveness of translocation options for a threatened waterbird. AB - Reintroduction of captive-reared animals has become increasingly popular in recent decades as a conservation technique, but little is known of how demographic factors affect the success of reintroductions. We believe whether the increase in population persistence associated with reintroduction is sufficient to warrant the cost of rearing and relocating individuals should be considered as well. We examined the trade-off between population persistence and financial cost of a reintroduction program for Crested Coots (Fulica cristata). This species was nearly extirpated from southern Europe due to unsustainable levels of hunting and reduction in amount and quality of habitat. We used a stochastic, stage-based, single-sex, metapopulation model with site-specific parameters to examine the demographic effects of releasing juveniles or adults in each population for a range of durations. We parameterized the model with data from an unsuccessful reintroduction program in which juvenile captive-bred Crested Coots were released between 2000 and 2009. Using economic data from the captive-breeding program, we also determined whether the strategy that maximized abundance coincided with the least expensive strategy. Releasing adults resulted in slightly larger final abundance than the release of nonreproductive juveniles. Both strategies were equally poor in achieving a viable metapopulation, but releasing adults was 2-4 times more expensive than releasing juveniles. To obtain a metapopulation that would be viable for 30 years, fecundity in the wild would need to increase to the values observed in captivity and juvenile survival would need to increase to almost unity. We suggest that the most likely way to increase these vital rates is by increasing habitat quality at release sites. PMID- 21676028 TI - Comparison of modern and historical fish catches (AD 750-1400) to inform goals for marine protected areas and sustainable fisheries. AB - We tested the unsustainable fishing hypothesis that species in assemblages of fish differ in relative abundance as a function of their size, growth rates, vagility, trophic level, and diet by comparing species composition in historical bone middens, modern fisheries, and areas closed to fishing. Historical data came from one of the earliest and most enduring Swahili coastal settlements (approximately AD 750-1400). Modern data came from fisheries near the archeological site and intensively harvested fishing grounds in southern Kenya. The areas we sampled that were closed to fishing (closures) were small (<28 km(2) ) and permanent. The midden data indicated changes in the fish assemblage that are consistent with a weak expansion of fishing intensity and the unsustainable fishing hypothesis. Fishes represented in the early midden assemblages from AD 750 to 950 had longer life spans, older age at maturity, and longer generation times than fish assemblages after AD 950, when the abundance of species with longer maximum body lengths increased. Changes in fish life histories during the historical period were, however, one-third smaller than differences between the historical and modern assemblages. Fishes in the modern assemblage had smaller mean body sizes, higher growth and mortality rates, a higher proportion of microinvertivores, omnivores, and herbivores, and higher rates of food consumption, whereas the historical assemblage had a greater proportion of piscivores and macroinvertivores. Differences in fish life histories between modern closures and modern fishing grounds were also small, but the life histories of fishes in modern closures were more similar to those in the midden before AD 950 because they had longer life spans, older age at maturity, and a higher proportion of piscivores and macroinvertivores than the modern fisheries. Modern closures and historical fish assemblages were considerably different, although both contained species with longer life spans. PMID- 21676029 TI - Evidence of local adaptation in the demographic response of American ginseng to interannual temperature variation. AB - Bioclimatic envelope models of species' responses to climate change are used to predict how species will respond to increasing temperatures. These models are frequently based on the assumption that the northern and southern boundaries of a species' range define its thermal niche. However, this assumption may be violated if populations are adapted to local temperature regimes and have evolved population-specific thermal optima. Considering the prevalence of local adaptation, the assumption of a species-wide thermal optimum may be violated for many species. We used spatially and temporally extensive demographic data for American ginseng (Panax quinquefolius L.) to examine range-wide variation in response of population growth rate (lambda) to climatic factors. Our results suggest adaptation to local temperature, but not precipitation. For each population, lambda was maximized when annual temperatures were similar to site specific, long-term mean temperatures. Populations from disparate climatic zones responded differently to temperature variation, and there was a linear relation between population-level thermal optima and the 30-year mean temperature at each site. For species that are locally adapted to temperature, bioclimatic envelope models may underestimate the extent to which increasing temperatures will decrease population growth rate. Because any directional change from long-term mean temperatures will decrease population growth rates, all populations throughout a species' range will be adversely affected by temperature increase, not just populations at southern and low-elevation boundaries. Additionally, when a species' local thermal niche is narrower than its range-wide thermal niche, a smaller temperature increase than would be predicted by bioclimatic envelope approaches may be sufficient to decrease population growth. PMID- 21676030 TI - Extinction risk in endemic marine fishes. PMID- 21676031 TI - Meta-analysis of the effectiveness of marked wire in reducing avian collisions with power lines. AB - Collisions of birds with power transmission and distribution lines have been documented for many species, and cause millions of casualties worldwide. Attempts to reduce mortality from such collisions include placing bird flight diverters (i.e., wire markers in the form of, e.g., spirals, swivels, plates, or spheres) on static and some electrified wires to increase their visibility. Although studies of the effectiveness of such devices have yielded contradictory results, the implementation of flight diverters is increasing rapidly. We reviewed the results of studies in which transmission or distribution wires were marked and conducted a meta-analysis to examine the effectiveness of flight diverters in reducing bird mortality. We included in our meta-analysis all studies in which researchers searched for carcasses of birds killed by a collision with wires. In those studies that also included data on flight frequency, we examined 8 covariates of effectiveness: source of data, study design, alternate design (if marked and unmarked spans were alternated in the same line), periodicity of searches for carcasses, width of the search transect, and number of species, lines, and stretches of wire searched. The presence of flight diverters was associated with a decrease in bird collisions. At unmarked lines, there were 0.21 deaths/1000 birds (n =339,830) that flew among lines or over lines. At marked lines, the mortality rate was 78% lower (n =1,060,746). Only the number of species studied had a significant influence on effect size; this was larger in studies that addressed more species. When comparing mortality at marked and unmarked lines, we recommend use of the same time intervals and habitats and standardizing the periodicity of carcass searches. PMID- 21676032 TI - Ambient ultraviolet B radiation and prevalence of infection by Batrachochytrium dendrobatidis in two amphibian species. AB - Chytridiomycosis, the emerging disease caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd) is responsible for declines and extirpations of amphibian populations worldwide. Environmental covariates modify the host-Bd interaction and thus affect the ongoing spread of the pathogen. One such covariate may be the intensity of ultraviolet B (UV-B) radiation. In a field experiment conducted in Laguna Grande de Penalara (central Spain), a mountainous region where the presence of Bd has been documented since 1997, we analyzed the potential effect of environmental UV-B (daily maximum 2.5-3.9 W/m(2) ) on the susceptibility of larvae of the common toad (Bufo bufo) to Bd. The proportion of infected individuals increased as tadpoles developed. The prevalence of Bd was significantly lower in tadpoles exposed to environmental UV-B intensities (2.94%) than in tadpoles not exposed to the radiation (9.72%). This finding mirrors that seen for a second amphibian species, the European midwife toad (Alytes obstetricans), for which conditional prevalence (i.e., prevalence of infection conditioned on the probability of a site being infected) across the Iberian Peninsula was inversely correlated with the intensity of UV-B. PMID- 21676033 TI - Pentraxin 3 predicts complicated course of febrile neutropenia in haematological patients, but the decision level depends on the underlying malignancy. AB - OBJECTIVES: This study aimed at assessing the cut-off levels for pentraxin 3 (PTX3) in predicting complications of neutropenic fever (bacteraemia, septic shock) in haematological patients. METHODS: A prospective study during 2006-2009 was performed at haematology ward in Kuopio University Hospital. A patient was eligible for the study if having neutropenic fever after intensive therapy for acute myeloid leukaemia (AML) (n = 32) or non-Hodgkin lymphoma (NHL) (n = 35). Blood cultures were taken, and maximal PTX3 and C-reactive protein (CRP) were evaluated during d0 to d3 from the beginning of fever onset. RESULTS: The level of PTX3 was associated with both the underlying malignancy and the presence of complications, with highest level in NHL patients with complicated course of febrile neutropenia and lowest in AML patients with non-complicated course. The cut-off level of PTX3 to predict complications was ten-fold in patients with NHL (115 MUg/L) in comparison with patients with AML (11.5 MUg/L). In combined analysis based on separate cut-offs, PTX3 predicted complications of febrile neutropenia with sensitivity of 0.86, specificity of 0.83, positive predictive value of 0.57 and negative predictive value of 0.96. CONCLUSIONS: PTX3 was superior to CRP in predicting complicated course of febrile neutropenia, but only when the effect of the underlying malignancy had been taken into account. PMID- 21676034 TI - Editorial comment to mercaptoacetyltriglycine-3 renogram is not superior to estimated glomerular filtration rate measurement for the prediction of long-term renal function after nephrectomy. PMID- 21676035 TI - Effect of cryopreservation on apoptotic-like events and its relationship with cryocapacitation of buffalo (Bubalus bubalis) sperm. AB - This study investigated the apoptosis-like events associated with cryopreservation process and their relationship with cryocapacitation in buffalo (Bubalus bubalis) sperm. A total of 49 semen ejaculates from seven bulls were studied for structural changes in sperm following cryopreservation. Apoptotic changes were detected by assays specific for translocation of phosphatidylserine (PS) to the cell surface, alterations in membrane permeability and mitochondrial membrane potential (MMP), and DNA integrity. A significant (p < 0.01) percentage of cryopreserved sperm showed externalization of PS and early apoptotic changes and lowered MMP when compared with the fresh sperm. Freezing and thawing of sperm increased permeability to YOPRO-1, an impermeant fluorescent dye. However, on TUNEL staining, cryopreserved sperm showed no breach in DNA integrity. The sperm capacitation status was evaluated by chlortetracycline (CTC) fluorescence pattern, in which a significant (p < 0.01) percentage of cryopreserved sperm were found to be capacitated. The capacitated sperm (Pattern B) was positively correlated with the aforementioned apoptotic events. In conclusion, cryopreservation process induced early apoptosis-like changes in buffalo sperm, and a close link exists between cryocapacitation and apoptosis during cryopreservation of sperm. PMID- 21676036 TI - Characterization of immunoreactive IGF-I pattern during the peri-ovulatory period of the oestrous cycle of thoroughbred mares and its relation to other hormones. AB - The aim of this study was to characterize ir-IGF-I pattern and its relation to other hormones during the oestrous cycle in mares. Nine non-pregnant non lactating pluriparous thoroughbred mares were used. The studied mares were examined ultrasonically and bled daily to follow the ovarian changes and the hormonal milieu for a complete Interovulatory interval (IOI). Two (minor and major) follicular waves were characterized per IOI in thoroughbred mares. The largest follicle of the first follicular wave (DF1) was firstly detected at D - 1.75 +/- 0.47 with a growth rate of 2.78 +/- 0.14mm/day and maximum diameter of 22.45 +/- 0.75mm on day 6.65 +/- 0.82. The largest follicle of the second follicular wave (DF2) had a growth rate of 2.15 +/- 0.29 mm/day, reached a maximum diameter of 42.70 +/- 2.63 mm on D 19.25 +/- 0.43. Ir-IGF-I increased significantly prior to ovulation and had a similar pattern to oestrogen (r = 0.84, p < 0.05), suggesting that the ovarian follicles are the main source of circulating ir-IGF-I during the oestrous cycle of mares and that ir-IGF-I may be a crucial factor in follicular differentiation and maturation. In conclusion, this study demonstrated that ir-IGF-I is secreted during the oestrous phase of the cycle concomitant with the development of the future ovulatory dominant follicle, and it may act in synergy with other hormones for the selection and differentiation of the dominant follicle. PMID- 21676037 TI - Brain stimulation over Broca's area differentially modulates naming skills in neurotypical adults and individuals with Asperger's syndrome. AB - In the present study we tested the hypothesis that, in subjects with Asperger's syndrome (ASP), the dynamics of language-related regions might be abnormal, so that repetitive transcranial magnetic stimulation (rTMS) over Broca's area leads to differential behavioral effects as seen in neurotypical controls. We conducted a five-stimulation-site, double-blind, multiple crossover, pseudo-randomized, sham-controlled study in 10 individuals with ASP and 10 age- and gender-matched healthy subjects. Object naming was assessed before and after low-frequency rTMS of the left pars opercularis, left pars triangularis, right pars opercularis and right pars triangularis, and sham stimulation, as guided stereotaxically by each individual's brain magnetic resonance imaging. In ASP participants, naming improved after rTMS of the left pars triangularis as compared with sham stimulation, whereas rTMS of the adjacent left opercularis lengthened naming latency. In healthy subjects, stimulation of parts of Broca's area did not lead to significant changes in naming skills, consistent with published data. Overall, these findings support our hypothesis of abnormal language neural network dynamics in individuals with ASP. From a methodological point of view, this work illustrates the use of rTMS to study the dynamics of brain-behavior relations by revealing the differential behavioral impact of non-invasive brain stimulation in a neuropsychiatric disorder. PMID- 21676038 TI - Indirect pathway between the primary auditory and visual cortices through layer V pyramidal neurons in V2L in mouse and the effects of bilateral enucleation. AB - Visual cortical areas are activated by auditory stimuli in blind mice. Direct heteromodal cortical connections have been shown between the primary auditory cortex (A1) and primary visual cortex (V1), and between A1 and secondary visual cortex (V2). Auditory afferents to V2 terminate in close proximity to neurons that project to V1, and potentially constitute an effective indirect pathway between A1 and V1. In this study, we injected a retrograde adenoviral vector that expresses enhanced green fluorescent protein under a synapsin promotor in V1 and biotinylated dextran amine as an anterograde tracer in A1 to determine: (i) whether A1 axon terminals establish synaptic contacts onto the lateral part of V2 (V2L) neurons that project to V1; and (ii) if this indirect cortical pathway is altered by a neonatal enucleation in mice. Complete dendritic arbors of layer V pyramidal neurons were reconstructed in 3D, and putative contacts between pre synaptic auditory inputs and postsynaptic visual neurons were analysed using a laser-scanning confocal microscope. Putative synaptic contacts were classified as high-confidence and low-confidence contacts, and charted onto dendritic trees. As all reconstructed layer V pyramidal neurons received auditory inputs by these criteria, we conclude that V2L acts as an important relay between A1 and V1. Auditory inputs are preferentially located onto lower branch order dendrites in enucleated mice. Also, V2L neurons are subject to morphological reorganizations in both apical and basal dendrites after the loss of vision. The A1-V2L-V1 pathway could be involved in multisensory processing and contribute to the auditory activation of the occipital cortex in the blind rodent. PMID- 21676040 TI - Phase inversion of neural activity in the olfactory and visual systems of a night migratory bird during migration. AB - Olfactory and visual sensory mechanisms seem to play a critical role in migratory orientation and navigation. How these two mechanisms are functionally linked with other migratory processes is unknown. We investigated this, in relation to the profound behavioural shift that occurs during migration in the night-migratory blackheaded bunting (Emberiza melanocephala). Photosensitive unstimulated birds singly housed in activity cages were subjected to long days (LD 16/8). The activity of each bird was continuously monitored. Daily activity pattern defined the nonmigratory phase (no nocturnal activity) and migratory phase (intense nocturnal activity, Zugunruhe). Body mass and testis size were measured at the beginning and end of the experiment. Long days induced the migratory phenotype (body fattening and Zugunruhe) and testis maturation. The c-fos (Fos) immunoreactivity, as marker of the neural activity of the olfactory and visual subsystems, was measured at midday (8 h after lights-on) and midnight (4 h after lights-off) after the first seven long days (nonmigratory phase) and after seven nights of the Zugunruhe (migratory phase). In the nonmigratory phase, Fos-like immunoreactive (Fos-lir) cells in the olfactory and visual subsystems were high in the day and low at night. In the migratory phase, this was reversed; Fos-lir cells were high at night and low in the day. The phase inversion of neural activity in the olfactory and visual systems in parallel with the behavioral shift suggests a functional coupling between the systems governing migratory flight (expressed as Zugunruhe) and migratory orientation and navigation. PMID- 21676039 TI - Dopamine D4 receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina. AB - In the mammalian retina, dopamine binding to the dopamine D4 receptor (D4R) affects a light-sensitive pool of cyclic AMP by negatively coupling to the type 1 adenylyl cyclase (AC1). AC1 is the primary enzyme controlling cyclic AMP production in dark-adapted photoreceptors. A previous study demonstrated that expression of the gene encoding AC1, Adcy1, is downregulated in mice lacking Drd4, the gene encoding the D4R. The present investigation provides evidence that D4R activation entrains the circadian rhythm of Adcy1 mRNA expression. Diurnal and circadian rhythms of Drd4 and Adcy1 mRNA levels were observed in wild-type mouse retina. Also, rhythms in the Ca2+-stimulated AC activity and cyclic AMP levels were observed. However, these rhythmic activities were damped or undetectable in mice lacking the D4R. Pharmacologically activating the D4R 4 h before its normal stimulation at light onset in the morning advances the phase of the Adcy1 mRNA expression pattern. These data demonstrate that stimulating the D4R is essential in maintaining the normal rhythmic production of AC1 from transcript to enzyme activity. Thus, dopamine/D4R signaling is a novel zeitgeber that entrains the rhythm of Adcy1 expression and, consequently, modulates the rhythmic synthesis of cyclic AMP in mouse retina. PMID- 21676041 TI - Brain-derived neurotrophic factor is increased in serum and skin levels of patients with chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous urticaria is triggered by many direct and indirect aggravating factors including autoreactive/autoimmune mechanisms, infections, non-allergic and pseudoallergic intolerance reactions. However, the role of neuroimmune mechanisms in chronic spontaneous urticaria so far is unclear. OBJECTIVE: Thus, we wanted to address the regulation of the neurotrophin brain-derived neurotrophic factor (BDNF) in serum and inflammatory skin of patients with chronic spontaneous urticaria in comparison to subjects with healthy skin. METHODS: Fifty adult patients with chronic spontaneous urticaria and 23 skin-healthy subjects were studied. Chronic spontaneous urticaria was defined as recurrent weals for more than 6 weeks. Autologous serum skin test was performed in all patients with chronic spontaneous urticaria and BDNF serum levels were analysed by enzyme immunoassay in all subjects. Furthermore, skin biopsies were taken from weals of eight patients with chronic spontaneous urticaria as well as from healthy skin of eight controls to evaluate the expression of BDNF and its receptors including tyrosine kinase (trk) B and pan neurotrophin receptor p75(NTR) by immunohistochemistry. RESULTS: BDNF serum levels were detectable in all subjects studied. However, BDNF levels were significantly higher in patients with chronic spontaneous urticaria compared to non-atopic skin-healthy controls (P<0.001). Furthermore, epidermal and dermal expression of BDNF and epidermal expression of p75(NTR) was significantly higher in patients with chronic spontaneous urticaria compared with controls (P<0.05 0.001). There was no difference with regard to the expression of trkB between chronic spontaneous urticaria and controls and no difference in BDNF serum levels between autologous serum skin test-positive (n=23) and -negative (n=27) patients with chronic spontaneous urticaria. CONCLUSIONS AND CLINICAL RELEVANCE: This study shows that BDNF is increased in serum and diseased skin of patients with chronic spontaneous urticaria, suggesting a role for neurotrophins in the pathophysiology of this chronic inflammatory skin disease. Further studies are needed to address the functional role of BDNF on key target effector cells in chronic spontaneous urticaria to establish new therapeutic implications. PMID- 21676042 TI - Airway dysfunction in nasal polyposis: a spectrum of asthmatic disease? AB - BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) represents an interesting model to investigate the existence of a non-allergic unified airway. The factors associated with airway dysfunction in CRSwNP are not fully understood. OBJECTIVE: To assess the impact of nasal disease on lower airway dysfunction in CRSwNP. METHODS: Fifty-seven patients with CRSwNP underwent spirometry, nasal endoscopy, exhaled nitric oxide, methacholine bronchial challenge, blood sampling for total IgE, eosinophil count and radioallergosorbent testing (NCT00788749). Three phenotypic groups were identified: 'asthma group' (asthma diagnosis); 'inflammatory group' [no asthma diagnosis, but elevated fractionated exhaled nitric oxide (FE(NO)) and/or bronchial-hyperreactivity (BHR)]; and 'non-inflammatory group' (no asthma diagnosis, no BHR and normal FE(NO)). Group comparisons, univariate and multivariate analyses were performed to examine associations with airway dysfunction. RESULTS: FEV(1) and FEF(25-75%) were reduced in asthma, but there was no difference between the non-asthmatic groups. Total IgE and eosinophils were elevated in asthma vs. the non inflammatory group, but there was no difference for asthma vs. inflammatory groups. BHR was the only significant predictor of FEV(1) (P<0.001). For FEF(25 75), BHR and eosinophil count were independent predictors (P<0.001 and P=0.04). Nasal outcomes were not predictors of spirometry. CONCLUSION AND CLINICAL RELEVANCE: In CRSwNP there is asymptomatic airway dysfunction suggestive of an asthmatic phenotype. Impairment of lung function is significantly associated with BHR and eosinophilia but not parameters of nasal disease suggesting that severity of airway dysfunction relates to the spectrum of asthma rather than rhinosinusitis. Lower airway dysfunction is common in CRSwNP but does not correlate to the severity of nasal disease. Signs and symptoms of asthma should be sought and treated in CRSwNP. PMID- 21676043 TI - What factors influence the prevalence and accuracy of nursing diagnoses documentation in clinical practice? A systematic literature review. AB - AIM: To identify what determinants influence the prevalence and accuracy of nursing diagnosis documentation in clinical practice. BACKGROUND: Nursing diagnoses guide and direct nursing care. They are the foundation for goal setting and provide the basis for interventions. The literature mentions several factors that influences nurses' documentation of diagnoses, such as a nurse's level of education, patient's condition and the ward environment. DESIGN: Systematic review. METHOD: MEDLINE and CINAHL databases were searched using the following headings and keywords: nursing diagnosis, nursing documentation, hospitals, influence, utilisation, quality, implementation and accuracy. The search was limited to articles published between 1995-October 2009. Studies were only selected if they were written in English and were primary studies addressing factors that influence nursing diagnosis documentation. RESULTS: In total, 24 studies were included. Four domains of factors that influence the prevalence and accuracy of diagnoses documentation were found: (1) the nurse as a diagnostician, (2) diagnostic education and resources, (3) complexity of a patient's situation and (4) hospital policy and environment. CONCLUSION: General factors, which influence decision-making, and nursing documentation and specific factors, which influence the prevalence and accuracy of nursing diagnoses documentation, need to be distinguished. To support nurses in documenting their diagnoses accurately, we recommend taking a comprehensive perspective on factors that influence diagnoses documentation. A conceptual model of determinants that influence nursing diagnoses documentation, as presented in this study, may be helpful as a reference for nurse managers and nurse educators. RELEVANCE TO CLINICAL PRACTICE: This review gives hospital management an overview of determinants for possible quality improvements in nursing diagnoses documentation that needs to be undertaken in clinical practice. PMID- 21676044 TI - Sudden informal caregivers: the lived experience of informal caregivers after an unexpected event. AB - AIM: The purpose of this qualitative study was to understand the lived experience of individuals taking on the role of informal adult caregivers after an unexpected event involving a relative. BACKGROUND: The literature on the development of the role of informal caregivers widely recognises that protecting and promoting the quality of life of caregivers should be a priority for health professionals. However, knowledge about how individuals develop as sudden caregivers is scarce, with existing knowledge centring mainly on the physical aspects of caregiving. What it means to become a caregiver or to experience role redefinition remains largely unclear. DESIGN: Hermeneutic phenomenology provided the framework that guided this study. METHODS: Unstructured interviews were used for collecting data. We used Van Manen's approach to analyse data and to reveal themes. Reflexivity and collaborative analysis were used to address rigour. RESULTS: From caregivers' interviews (n = 14), four main themes were identified: losing control over time, feeling alone, failing expectations and taking over someone else's life. CONCLUSIONS: The caregiving experience is characterised as a transition process or a period of ongoing focussing and de-focussing. The extent to which caregivers feel connected with others, redefine their personal use of time and feel comfortable with their new responsibilities indicates how they are managing this transition and how well they are achieving balance in their new role, i.e. from feeling 'exclusively' a caregiver to being 'also' a caregiver. RELEVANCE TO CLINICAL PRACTICE: Facilitating successful transitions is within the scope of the role of professional nurses. Information about the meaning that caregivers attribute to their experience - relationships, options and strategies is crucial, as it will help nurses to plan, assess and design adequate nursing interventions to support informal caregivers, especially in unexpected situations. PMID- 21676045 TI - Connecting the sun to flowering in sunflower adaptation. AB - Species living in seasonal environments often adaptively time their reproduction in response to photoperiod cues. We characterized the expression of genes in the flowering-time regulatory network across wild populations of the common sunflower, Helianthus annuus, that we found to be adaptively differentiated for photoperiod response. The observed clinal variation was associated with changes at multiple hierarchical levels in multiple pathways. Paralogue-specific changes in FT homologue expression and tissue-specific changes in SOC1 homologue expression were associated with loss and reversal of plasticity, respectively, suggesting that redundancy and modularity are gene network characteristics easily exploited by natural selection to produce evolutionary innovation. Distinct genetic mechanisms contribute to convergent evolution of photoperiod responses within sunflower, suggesting regulatory network architecture does not impose strong constraints on the evolution of phenotypic plasticity. PMID- 21676046 TI - The Orebro prevention programme revisited: a cluster-randomized effectiveness trial of programme effects on youth drinking. AB - AIMS: This study aimed to assess the effectiveness of the Orebro prevention programme (OPP), an alcohol misuse prevention programme that aims to reduce youth drinking by changing parental behaviour. DESIGN: Cluster-randomized trial, with schools assigned randomly to the OPP or no intervention. SETTING: Forty municipal schools in 13 counties in Sweden. PARTICIPANTS: A total of 1752 students in the 7th grade and 1314 parents were assessed at baseline. Students' follow-up rates in the 8th and 9th grades were 92.1% and 88.4%, respectively. MEASUREMENTS: Classroom questionnaires to students and postal questionnaires to parents were administered before randomization and 12 and 30 months post-baseline. FINDINGS: Two-level logistic regression models, under four different methods of addressing the problem of loss to follow-up, revealed a statistically significant programme effect for only one of three drinking outcomes under one loss-to-follow-up method, and that effect was observed only at the 12-month follow-up. CONCLUSIONS: The Orebro prevention programme as currently delivered in Sweden does not appear to reduce or delay youth drunkenness. PMID- 21676047 TI - Safety and efficacy of high-intensity focused ultrasound atop coronary arteries during epicardial catheter ablation. AB - BACKGROUND: Coronary arterial injury continues to be a limitation of epicardial catheter ablation using currently available energy sources. Application of high intensity focused ultrasound (HIFU) energy may avoid such injury due to its theoretical ability to focus energy beyond the ablation element and create lesions at depth. OBJECTIVE: This study evaluated the safety of HIFU applications delivered directly over the left anterior descending (LAD) artery in an open chest swine model. METHODS: Ten swine underwent median sternotomy. A prototype HIFU probe was placed atop the LAD. Forty-three therapies along the LAD (60 seconds/6 watt) were analyzed. Three, 3, and 4 swine were studied at 2, 4, and 8 weeks and subsequently sacrificed. Lesions were scored (0-4) depending on the percent circumferential involvement of arteries. RESULTS: Lesion area increased minimally from 54.5 +/- 18.0 mm(2) at 2 weeks to 56.9 +/- 20.6 mm(2) at 8 weeks, and depth increased moderately from 13.2 +/- 2.5 mm to 15.5 +/- 3.4 mm. At 2, 4, and 8 weeks, the mean injury score of the LAD was 0.8 +/- 0.3, 1.5 +/- 0.9, and 2.0 +/- 0.7. No/minimal arterial injury was seen in 64% of all sections. However, a progressive increase in injury resulted in 89% of all sections showing any injury at 8 weeks. One animal developed occlusion of the distal LAD. CONCLUSIONS: HIFU has the potential to create deep ventricular lesions with relative sparing of the LAD. The incremental arterial damage noted over time warrants further evaluation to support the viability of focusing ultrasound energy beyond vulnerable critical structures to ablate deeper targets. PMID- 21676048 TI - Enhancing systems to improve the management of acute, unscheduled care. AB - For acutely ill patients, health care services are available in many different settings, including hospital-based emergency departments (EDs), retail clinics, federally qualified health centers, and outpatient clinics. Certain conditions are the sole domain of particular settings: stabilization of critically ill patients can typically only be provided in EDs. By contrast, many conditions that do not require hospital resources, such as advanced radiography, admission, and same-day consultation can often be managed in clinic settings. Because clinics are generally not open nights, and often not on weekends or holidays, the ED remains the only option for face-to-face medical care during these times. For patients who can be managed in either setting, there are many open research questions about which is the best setting, because these venues differ in terms of access, costs of care, and potentially, quality. Consideration of these patients must be risk-adjusted, as patients may self-select a venue for care based upon perceived acuity. We present a research agenda for acute, unscheduled care in the United States developed in conjunction with an Agency for Healthcare Research and Quality-funded conference hosted by the American College of Emergency Physicians in October 2009, titled "Improving the Quality and Efficiency of Emergency Care Across the Continuum: A Systems Approach." Given the possible increase in ED utilization over the next several years as more people become insured, understanding differences in cost, quality, and access for conditions that may be treated in EDs or clinic settings will be vital in guiding national health policy. PMID- 21676049 TI - Using information technology to improve the quality and safety of emergency care. AB - With the 2010 federal health care reform passage, a renewed focus has emerged for the integration of electronic health records (EHRs) into the U.S. health care system. A consensus conference in October 2009 met to discuss the future research agenda with regard to using information technology (IT) to improve the future quality and safety of emergency department (ED) care. The literature is mixed as to how the use of computerized provider order entry (CPOE), clinical decision support (CDS), EHRs, and patient tracking systems has improved or degraded the safety and quality of ED care. Such mixed findings must be considered in the national push for rapid implementation of health IT. We present a research agenda addressing the major questions that are posed by the introduction of IT into ED care; these questions relate to interoperability, patient flow and integration into clinical work, real-time decision support, handoffs, safety-critical computing, and the interaction between IT systems and clinical workflows. PMID- 21676051 TI - Frequent users of emergency department services: gaps in knowledge and a proposed research agenda. AB - Frequent use of emergency department (ED) services is often perceived to be a potentially preventable misuse of resources. The underlying assumption is that similar and more appropriate care can be delivered outside of EDs at a lower cost. To reduce costs and incentivize more appropriate use of services, there have been efforts to design interventions to transition health care utilization of frequent users from EDs to other settings such as outpatient clinics. Many of these efforts have succeeded in smaller trials, but wider use remains elusive for varying reasons. There are also some fundamental problems with the assumption that all or even the majority of frequent ED use is misuse and invoking reasons for that excessive use. These tenuous assumptions become evident when frequent users as a group are compared to less frequent users. Specifically, frequent users tend to have high levels of frequent ED use, have a higher severity of illness, be older, have fewer personal resources, be chronically ill, present for pain-related complaints, and have government insurance (Medicare or Medicaid). Because of the unique characteristics of the population of frequent users, we propose a research agenda that aims to increase the understanding of frequent ED use, by: 1) creating an accepted categorization system for frequent users, 2) predicting which patients are at risk for becoming or remaining frequent users, 3) implementing both ED- and non-ED-based interventions, and 4) conducting qualitative studies of frequent ED users to explore reasons and identify factors that are subject to intervention and explore specific differences among populations by condition, such as mental illness and heart failure. PMID- 21676050 TI - Critical pathways for post-emergency outpatient diagnosis and treatment: tools to improve the value of emergency care. AB - The decision to admit a patient to the hospital after an emergency department (ED) visit is expensive, frequently not evidence-based, and variable. Outpatient critical pathways are a promising approach to reduce hospital admission after emergency care. Critical pathways exist to risk stratify patients for potentially serious diagnoses (e.g., acute myocardial infarction [AMI]) or evaluate response to therapy (e.g., community-acquired pneumonia) within a short time period (i.e., less than 36 hours), to determine if further hospital-based acute care is needed. Yet, such pathways are variably used while many patients are admitted for conditions for which they could be treated as outpatients. In this article, the authors propose a model of post-ED critical pathways, describe their role in emergency care, list common diagnoses that are amenable to critical pathways in the outpatient setting, and propose a research agenda to address barriers and solutions to increase the use of outpatient critical pathways. If emergency providers are to routinely conduct rapid evaluations in outpatient or observation settings, they must have several conditions at their disposal: 1) evidence-based tools to accurately risk stratify patients for protocolized care, 2) systems of care that reliably facilitate workup in the outpatient setting, and 3) a medical environment conducive to noninpatient pathways, with aligned risks and incentives among patients, providers, and payers. Increased use of critical pathways after emergency care is a potential way to improve the value of emergency care. PMID- 21676052 TI - Research priorities for palliative and end-of-life care in the emergency setting. AB - Palliative care focuses on the physical, spiritual, psychological, and social care from diagnosis to cure or death of a potentially life-threatening illness. When cure is not attainable and end of life approaches, the intensity of palliative care is enhanced to deliver the highest quality care experience. The emergency department (ED) frequently cares for patients and families during the end-of-life phase of the palliative care continuum. The intersection between palliative care and emergency care continues to be more clearly defined. Currently, there is a mounting body of evidence to guide the most effective strategies for improving palliative and end-of-life care in the ED. In a workgroup session at the 2009 Agency for Healthcare Research and Quality (AHRQ)/American College of Emergency Physicians (ACEP) conference "Improving the Quality and Efficiency of Emergency Care Across the Continuum: A Systems Approach," four key research questions arose: 1) which patients are in greatest need of palliative care services in the ED, 2) what is the optimal role of emergency clinicians in caring for patients along a chronic trajectory of illness, 3) how does the integration and initiation of palliative care training and services in the ED setting affect health care utilization, and 4) what are the educational priorities for emergency clinical providers in the domain of palliative care? Workgroup leaders suggest that these four key questions may be answered by strengthening the evidence using six categories of inquiry: descriptive, attitudinal, screening, outcomes, resource allocation, and education of clinicians. PMID- 21676054 TI - A randomized trial of a multicomponent cessation strategy for emergency department smokers. AB - OBJECTIVES: The objective was to determine the efficacy of an emergency department (ED)-based smoking cessation intervention. METHODS: This study was a randomized trial conducted from January 2006 to September 2007 at an urban ED that treats 90,000 adults per year. Discharged adults who smoked at least 10 cigarettes per day were randomized to 1) usual care, receiving a smoking cessation brochure; or 2) enhanced care, receiving the brochure, a motivational interview (MI), nicotine patches, and a phone call at 3 days. Interventions were performed by a peer educator trained in tobacco treatment. Blinded follow-up was performed at 3 months. RESULTS: A total of 338 subjects were enrolled, mean (+/ SD) age was 40.2 (+/-12.0) years, 51.8% were female, and 56.5% were either self pay or Medicaid. Demographic and clinical variables were comparable between groups. Enhanced and usual care arms showed similar cessation rates at 3 months (14.7% vs. 13.2%, respectively). The proportion of subjects making a quit attempt (69.2% vs. 66.5%) and decrease in daily cigarette use (five vs. one; all p > 0.05) were also similar. In logistic modeling, factors associated with quitting included any tobacco-related International Classification of Diseases, ninth revision (ICD-9), code for the ED visit (odds ratio [OR]= 3.42, 95% confidence interval [CI] = 1.61 to 7.26) or subject belief that the ED visit was tobacco related (OR = 2.47, 95% CI = 1.17 to 5.21). Conversely, subjects who reported having a preexisting tobacco-related illness were less likely to quit (OR = 0.22, 95% CI = 0.10 to 0.50). CONCLUSIONS: The primary endpoint was negative, reflecting a higher-than-expected quit rate in the control group. Subjects whose ED visit was tobacco-related, based either on physician diagnosis or subject perception, were more than twice as likely to quit. These data suggest that even low-intensity screening and referral may prompt substantial numbers of ED smokers to quit or attempt to quit. PMID- 21676053 TI - Discriminative accuracy of novel and traditional biomarkers in children with suspected appendicitis adjusted for duration of abdominal pain. AB - OBJECTIVES: The objective was to assess the accuracy of novel and traditional biomarkers in patients with suspected appendicitis as a function of duration of symptoms. METHODS: This was a prospective cohort study, conducted in a tertiary care emergency department (ED). The authors enrolled children 3 to 18 years old with acute abdominal pain of less than 96 hours and measured serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), white blood cell (WBC) count, and absolute neutrophil count (ANC). Final diagnosis was determined by histopathology or telephone follow-up. Trends in biomarker levels were examined based on duration of abdominal pain. The accuracy of biomarkers was assessed with receiver operating characteristic (ROC) curves. Optimal cut-points and test performance characteristics were calculated for each biomarker. RESULTS: Of 280 patients enrolled, the median age was 11.3 years (interquartile range [IQR] = 8.6 to 14.8), 57% were male, and 33% had appendicitis. Median IL-6, median CRP, mean WBC count, and mean ANC differed significantly (p < 0.001) between patients with nonperforated appendicitis and those without appendicitis; median IL-8 levels did not differ between groups. In nonperforated appendicitis, median IL-6, WBC, and ANC levels were maximal at less than 24 hours of pain, while CRP peaked between 24 and 48 hours. In perforated appendicitis, median IL-8 levels were highest by 24 hours, WBC count and IL-6 by 24 to 48 hours, and CRP after 48 hours of pain. The WBC count appeared to be the most useful marker to predict appendicitis in those with fewer than 24 or more than 48 hours of pain, while CRP was the most useful in those with 24 to 48 hours of pain. CONCLUSIONS: In this population, the serum levels and accuracy of novel and traditional biomarkers varies in relation to duration of abdominal pain. IL-6 shows promise as a novel biomarker to identify children with appendicitis. PMID- 21676055 TI - A novel emergency department dysphagia screen for patients presenting with acute stroke. AB - OBJECTIVES: Dysphagia is a common complication for emergency department (ED) patients presenting with acute stroke (AS). Recent stroke recommendations have suggested that EDs screen patients with AS for dysphagia prior to administering anything by mouth. This study sought to develop and test a novel ED dysphagia screen to be used in this population. METHODS: A multidisciplinary approach was used to create a novel dysphagia screen performed by ED nurses during the initial evaluation of patients with suspected AS. The screen consists of five questions of which any single affirmative answer signified possible dysphagia. A prospective cohort study was conducted to evaluate the performance of this screen in detecting dysphagia after AS. Patients were followed for 30 days, and true dysphagia was determined if the patient had an abnormal modified barium swallow study (MBS), had placement of a feeding tube, or was placed on a dysphagia diet after assessment by a speech pathologist. The authors performed a substudy to determine agreement using a blinded kappa (kappa) assessment with a convenience sample of 40 patients. RESULTS: Over a 21-month period, 283 patients met eligibility for analysis. The rate of cerebral infarction in this cohort was 245 (87%). The rates for true dysphagia, pneumonia, and death were 91 (32%), 26 (9%), and 18 (6%), respectively. The dysphagia screen had a sensitivity of 95% (95% confidence [CI] = 88% to 98%) and a negative likelihood ratio of 0.1 (95% CI = 0.04 to 0.2). The inter-rater agreement assessed by kappa was substantial (0.69, 95% CI = 0.55 to 0.83). CONCLUSIONS: These data suggest that this dysphagia screen may be a valuable tool for detecting dysphagia in ED patients presenting with AS. The simple screen can be performed by nursing personnel and appears to perform well with good agreement. Given the overall rate of dysphagia in one third of AS patients, the use of an ED dysphagia screen appears warranted. PMID- 21676056 TI - A randomized controlled trial of capnography in the correction of simulated endotracheal tube dislodgement. AB - OBJECTIVES: Unrecognized dislodgement of an endotracheal tube (ETT) during the transport of an intubated patient can have life-threatening consequences. Standard methods to monitor these patients, such as pulse oximetry and physical examination, are both subject to inaccuracies with patient movement and ambient noise. Capnography provides a continuous and objective measure of ventilation that can alert a provider immediately to an airway problem. The objective of this study was to determine through simulation if capnography decreases time to correction of dislodged ETTs during the transport of intubated patients, in comparison to standard monitoring. METHODS: Paramedics and paramedic students were randomized as to whether or not they had capnography available to them in addition to standard monitoring during a simulated scenario. In the scenario, subjects monitored an intubated baby who subsequently experiences a dislodgement of the ETT during interfacility transport. Time to correction of the ETT dislodgement was the primary outcome. The secondary outcome was correction of dislodgement prior to decline in pulse oximetry. RESULTS: Fifty-three subjects were enrolled in the study, with complete data on 50 subjects. Median time to correction of ETT dislodgement was 2.02 minutes (95% confidence interval [CI] = 1.22 to 4.12 minutes) for the capnography group versus 4.00 minutes (95% CI = 3.35 to 5.50 minutes) in the standard monitoring group (p = 0.05). Forty-eight percent of subjects using capnography corrected the ETT dislodgement prior to decline in pulse oximetry compared with 12% of controls (p = 0.01). There were no differences in time to correction of dislodgement based on years of experience, perceived comfort, reported adequacy of teaching, or past use of capnography. CONCLUSIONS: The addition of capnography to standard monitoring significantly improves recognition of ETT dislodgement and reduces the time to correction of dislodged ETTs by prehospital providers in a simulated pediatric transport setting. PMID- 21676058 TI - Pediatric emergency health care providers' knowledge, attitudes, and experiences regarding emergency contraception. AB - OBJECTIVES: The objective was to describe knowledge, attitudes, and experiences regarding emergency contraception (EC) among pediatric emergency health care providers (HCPs). METHODS: This multicenter, focus group study elicited thoughts and experiences from pediatric emergency HCPs about EC. Participants were physicians, nurse practitioners (NPs), and nurses in one of three urban, geographically distinct, pediatric emergency departments (EDs). A professional moderator used a semistructured format for sessions, which were audiotaped, transcribed, and analyzed for recurrent themes. Participants provided demographic information and completed a written survey evaluating EC knowledge. RESULTS: Eighty-five HCPs (41 physicians, eight NPs, and 36 nurses) participated in 12 focus groups. Overall knowledge about EC was poor. Participants identified barriers including cost, privacy, knowledge, and provider refusal. Provision of EC for adolescents was supported by the majority of physicians and NPs; however, many nurses were not supportive, especially following consensual intercourse. The authors identified use of social judgment by nurses as a novel barrier to EC provision. The majority of HCPs did not support screening for potential EC need. The majority of physicians and NPs felt obligated to provide adolescents with all contraceptive options, while more nurses supported provider refusal to provide EC. CONCLUSIONS: This study identified important HCP perceptions and barriers about EC provision in the pediatric ED. These findings may inform future efforts to improve EC provision for adolescents. Specifically, future studies to evaluate the differences in attitudes between nurses, physicians, and NPs, and the use of social judgment in EC provision, are warranted. PMID- 21676057 TI - Comparison of clinical performance of cranial computed tomography rules in patients with minor head injury: a multicenter prospective study. AB - OBJECTIVES: The objective was to compare the predictive performance of three previously derived cranial computed tomography (CT) rules, the Canadian CT Head Rule (CCHR), the New Orleans Criteria (NOC), and National Emergency X-Ray Utilization Study (NEXUS)-II, for detecting clinically important traumatic brain injury (TBI) and the need for neurosurgical intervention in patients with blunt head trauma. METHODS: This was a prospective, multicenter, observational cohort study of patients with blunt head trauma from June 2008 to May 2009. The historical and physical examination components of the CCHR, NOC, and NEXUS-II were documented on a data collection form and the performance of each of the three rules was compared. Patient eligibility for each specific rule was defined exactly as previously described for each specific rule. To compare the three decision rules in terms of sensitivity and specificity, an intersection cohort satisfying inclusion criteria of all three decision rules was derived. The primary outcome was clinically important TBI, and the secondary outcome was neurosurgical intervention. The sensitivity and specificity of each rule were calculated with 95% confidence intervals (95% CIs). We also calculated the potential reduction rate in cranial CT scan utilization realized by theoretical implementation of these rules. RESULTS: A total of 7,131 patients were prospectively enrolled, including 692 (9.7%) with clinical TBI. Among the enrolled population, patients eligible for CCHR, NOC, and NEXUS-II totaled 696, 677, and 2,951, respectively. The sensitivity and specificity for clinically important brain injury were as follows: CCHR, 112 of 144 (79.2%, 95% CI = 70.8% to 86.0%) and 228 of 552 (41.3%, 95% CI = 37.3% to 45.5%); NOC, 91 of 99 (91.9%, 95% CI = 84.7% to 96.5%) and 125 of 558 (22.4%, 95% CI = 19.0% to 26.1%); and NEXUS-II, 511 of 576 (88.7%, 95% CI = 85.8% to 91.2%) and 1,104 of 2,375 (46.5%, 95% CI = 44.5% to 48.5%). The sensitivity and specificity for neurosurgical intervention were as follows: CCHR, 100% (95% CI = 59.0% to 100.0%) and 38.3% (95% CI = 34.5% to 41.9%); NOC, 100% (95% CI = 54.1% to 100.0%) and 20.4% (95% CI = 17.4% to 23.7%); and NEXUS-II, 95.1% (95% CI = 90.1% to 98.0%) and 41.4% (95% CI = 39.5% to 43.2%). Among the enrolled population, intersection patients of CCHR, NOC, and NEXUS-II totaled 588. The sensitivity and specificity for clinically important brain injury were as follows: CCHR, 73 of 98 (74.5%, 95% CI = 64.7% to 82.8%) and 201 of 490 (41.0%, 95% CI = 36.6% to 45.5%); NOC, 89 of 98 (90.8%, 95% CI = 83.3% to 95.7%) and 112 of 490 (22.9%, 95% CI = 19.2% to 26.8%); and NEXUS-II, 82 of 98 (83.7%, 95% CI = 74.8% to 90.4%) and 172 of 490 (35.1%, 95% CI = 30.9% to 39.5%). The potential reduction in emergency CT scans by using these decision rules would have been higher with the NEXUS-II rule (39.6%, 95% CI = 37.8% to 41.4%) than with the CCHR rule (27.0%, 95% CI = 23.7% to 30.3%) or NOC rule (20.2%, 95% CI = 17.2% to 23.3%). CONCLUSIONS: For clinically important TBI, the three cranial CT decision rules had much lower sensitivities in this population than the original published studies, while the specificities were comparable to those studies. The sensitivities for neurosurgical intervention, however, were comparable to the original studies. The NEXUS-II rule showed the highest reduction rate for CT scans compared to other rules, but failed to identify all undergoing neurosurgical intervention for their original inclusion cohort. PMID- 21676059 TI - Predictors of 30-day cardiovascular events in patients with prior percutaneous coronary intervention or coronary artery bypass grafting. AB - OBJECTIVES: Risk stratification of patients with potential acute coronary syndrome (ACS) is difficult. Patients with prior revascularization are considered higher risk, but they can also have symptoms from noncardiac causes. This study evaluated whether the presenting clinical characteristics were predictive of an increased risk of 30-day cardiovascular events in patients with prior revascularization presenting to the emergency department (ED) with symptoms of potential ACS. METHODS: This was a secondary analysis of the DISPO-ACS study, a 2000-patient, four-site, randomized controlled trial of patients presenting with potential ACS. Process outcomes were evaluated using point-of-care cardiac markers compared to standard laboratory-based markers. Data included demographics, history, presenting symptoms, laboratory and electrocardiogram (ECG) results, hospital course, and 30-day cardiovascular events (death, acute myocardial infarction [AMI], revascularization). The association between presenting characteristics and 30-day cardiovascular events was assessed using univariable analysis and logistic regression; odds ratios (ORs) with 95% confidence intervals (CIs) are given. RESULTS: Of 2,000 patients enrolled, 611 had prior revascularization (538 percutaneous coronary intervention [PCI], 232 coronary artery bypass graft [CABG], 159 both). The mean (+/-SD) age was 66 (+/ 14) years, 44% were female, and 22% were black. By 30 days, 101 patients (17%) had cardiovascular events (81 during the index visit, 20 during follow-up). There were four deaths, 28 AMIs, and 67 revascularizations within 30 days; 20 patients had multiple endpoints. Being male (OR = 1.67, 95% CI = 1.07 to 2.62) or nonblack (OR = 1.95, 95% CI = 1.07 to 3.56) or having a family history of coronary artery disease (CAD; OR = 2.09, 95% CI = 1.32 to 3.3), elevated lipids (OR = 1.71, 95% CI = 1.04 to 2.82), prior AMI (OR = 1.79, 95% CI = 1.16 to 2.76), abnormal ECG on arrival (OR = 2.1, 95% CI = 1.33 to 3.34), and a positive initial troponin (OR = 14.7, 95% CI = 6.8 to 32.2) were predictive of cardiovascular events. The multivariable model found family history of CAD (OR = 2.06, 95% CI = 1.26 to 3.36), abnormal initial ECG (OR = 1.89, 95% CI = 1.16 to 3.09), and positive initial troponin (OR = 13.3, 95% CI = 5.9 to 29.6) remained predictive of 30-day cardiovascular events. CONCLUSIONS: In patients with prior revascularization, the initial ECG and early cardiac marker elevations, but not clinical presentation, predict odds of 30-day death, AMI, or revascularization. PMID- 21676061 TI - Assessing clinical reasoning skills in scenarios of uncertainty: convergent validity for a Script Concordance Test in an emergency medicine clerkship and residency. AB - OBJECTIVES: The Script Concordance Test (SCT) is a new method of assessing clinical reasoning in the face of uncertainty. An SCT item consists of a short clinical vignette followed by an additional piece of information and asks how this new information affects the learner's decision regarding a possible diagnosis, investigational study, or therapy. Scoring is based on the item responses of a panel of experts in the field. This study attempts to provide additional validity evidence in the realm of emergency medicine (EM). METHODS: This observational study examined the performance of medical students, EM residents, and expert emergency physicians (EPs) on an SCT in the area of general EM (SCT-EM) at one of the largest medical schools in the United States. The 59 item SCT-EM was developed for a fourth-year required clerkship in EM. The results on the SCT-EM were compared between different levels of clinical experience. Results were also compared to performance on other measures to evaluate convergent validity. RESULTS: The SCT-EM was given to 314 fourth-year medical students (MS4), 40 EM residents, and 13 EPs during the study period. Mean differences between the three different groups of test takers was statistically significant (p < 0.0001). The range of scores for the MS4s was 42% to 77% and followed a normal distribution. Among the residents, performance on the SCT-EM and the EM in-training examination were significantly correlated (r = 0.69, p < 0.001); among the MS4s who later matched into EM residency programs, performance on the SCT-EM and United States Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge (Step 2-CK) exam was also significantly correlated (r = 0.56, p < 0.001). CONCLUSIONS: The SCT-EM shows promise as an assessment that can be used to measure clinical reasoning skills in the face of uncertainty. Future research will compare performance on the SCT to other measures of clinical reasoning abilities. PMID- 21676060 TI - Nystagmus assessments documented by emergency physicians in acute dizziness presentations: a target for decision support? AB - OBJECTIVES: Dizziness is a common presenting complaint to the emergency department (ED), and emergency physicians (EPs) consider these presentations a priority for decision support. Assessing for nystagmus and defining its features are important steps for any acute dizziness decision algorithm. The authors sought to describe nystagmus documentation in routine ED care to determine if nystagmus assessments might be an important target in decision support efforts. METHODS: Medical records from ED visits for dizziness were captured as part of a surveillance study embedded within an ongoing population-based cohort study. Visits with documentation of a nystagmus assessment were reviewed and coded for presence or absence of nystagmus, ability to draw a meaningful inference from the description, and coherence with the final EP diagnosis when a peripheral vestibular diagnosis was made. RESULTS: Of 1,091 visits for dizziness, 887 (81.3%) documented a nystagmus assessment. Nystagmus was present in 185 of 887 (20.9%) visits. When nystagmus was present, no further characteristics were recorded in 48 of the 185 visits (26%). The documentation of nystagmus (including all descriptors recorded) enabled a meaningful inference about the localization or cause in only 10 of the 185 (5.4%) visits. The nystagmus description conflicted with the EP diagnosis in 113 (80.7%) of the 140 visits that received a peripheral vestibular diagnosis. CONCLUSIONS: Nystagmus assessments are frequently documented in acute dizziness presentations, but details do not generally enable a meaningful inference. Recorded descriptions usually conflict with the diagnosis when a peripheral vestibular diagnosis is rendered. Nystagmus assessments might be an important target in developing decision support for dizziness presentations. PMID- 21676062 TI - Clearing the smoke: behavioral interventions in the emergency department. PMID- 21676063 TI - Trauma registries: history, logistics, limitations, and contributions to emergency medicine research. AB - Trauma registries have been designed to serve a number of purposes, including quality improvement, injury prevention, clinical research, and policy development. Since their inception over 30 years ago, there are increasingly more institutions with trauma registries, many of which submit data to a national trauma registry. The goal of this review is to describe the history, logistics, and characteristics of trauma registries and their contribution to emergency medicine and trauma research. Discussed in this review are the limitations of trauma registries, such as variability in quality and type of the collected data, absence of data pertaining to long-term and functional outcomes, prehospital information, and complications as well as other methodologic obstacles limiting the utility of registry data in clinical and epidemiologic research. PMID- 21676065 TI - Conference proceedings-improving the quality and efficiency of emergency care across the continuum: a systems approach. AB - In October 2009, the American College of Emergency Physicians (ACEP) convened a conference held in Boston, Massachusetts, to outline critical issues in emergency care quality and efficiency and to develop a series of research agendas and projects aimed at addressing important questions about how to improve acute, episodic care. The aim of the conference was to describe how hospital-based emergency department (ED) systems could provide solutions for broader delivery problems in the U.S. health care system. The conference featured keynote speakers Drs. Carolyn Clancy (Director, Agency for Healthcare Research and Quality) and Elliott Fisher (Director, Center for Health Policy Research at Dartmouth Medical School). Panels focused on: 1) systems and workflow redesign to improve health care and 2) improving coordination of care for high-cost patients. Additional sessions were conducted to develop five research agendas on the following topics: 1) health information technology; 2) demand for acute care services; 3) frequent, high-cost users of emergency care; 4) critical pathways for post-emergency care diagnosis and treatment; and 5) end-of-life and palliative care in the ED. PMID- 21676066 TI - Salvage lymphadenectomy for cervical lymph node recurrence after esophagectomy for squamous cell carcinoma of the thoracic esophagus. AB - Prognosis of patients with recurrent esophageal cancer is usually unsatisfactory. We have successfully treated five patients with cervical node recurrence after esophagectomy with multimodal treatment including salvage lymphadenectomy. In order to clarify the efficacy of salvage surgery for cervical node recurrence, we have reviewed the clinical course and prognosis of these patients. From August 2004 to December 2007, 30 patients with 33 recurrent sites were treated in the Department of Surgery, Iizuka Hospital. Among these patients, there were five patients with recurrence limited within the cervical nodes. Salvage cervical lymphadenectomy was performed for all five patients. Curative resection was achieved in four patients and reduction surgery followed by planned chemoradiotherapy was performed in another patient. All stations including the suspicious node were dissected and a partial sternotomy was added for one patient whose recurrent tumor was located in the right recurrent nerve node. There was no mortality and one minor complication (subcutaneous hemorrhage) was observed. Median duration of hospital stay was 7 days. Adjuvant chemotherapy was performed for all patients. Median follow-up period was 54 months and all patients are alive without relapse of the disease. Salvage cervical lymphadenectomy is a safe and effective treatment for patients with cervical node recurrence after esophagectomy. PMID- 21676064 TI - Research priorities for high-quality geriatric emergency care: medication management, screening, and prevention and functional assessment. AB - BACKGROUND: Geriatric adults represent an increasing proportion of emergency department (ED) users and can be particularly vulnerable to acute illnesses. Health care providers have recently begun to focus on the development of quality indicators (QIs) to define a minimal standard of care. OBJECTIVES: The original objective of this project was to develop additional ED-specific QIs for older patients within the domains of medication management, screening and prevention, and functional assessment, but the quantity and quality of evidence were insufficient to justify unequivocal minimal standards of care for these three domains. Accordingly, the authors modified the project objectives to identify key research opportunities within these three domains that can be used to develop QIs in the future. METHODS: Each domain was assigned one or two content experts who created potential QIs based on a systematic review of the literature, supplemented by expert opinion. Candidate QIs were then reviewed by four groups: the Society for Academic Emergency Medicine (SAEM) Geriatric Task Force, the SAEM Geriatric Interest Group, and audiences at the 2008 SAEM Annual Meeting and the 2009 American Geriatrics Society Annual Meeting, using anonymous audience response system technology as well as verbal and written feedback. RESULTS: High quality evidence based on patient-oriented outcomes was insufficient or nonexistent for all three domains. The participatory audiences did not reach a consensus on any of the proposed QIs. Key research questions for medication management (three), screening and prevention (two), and functional assessment (three) are presented based on proposed QIs that the majority of participants accepted. CONCLUSIONS: In assessing a minimal standard of care by which to systematically derive geriatric QIs for medication management, screening and prevention, and functional assessment, compelling clinical research evidence is lacking. Patient-oriented research questions that are essential to justify and characterize future QIs within these domains are described. PMID- 21676067 TI - Black esophagus. PMID- 21676068 TI - Wireless ambulatory pH studies: manometric or endoscopic guidance? AB - Wireless pH studies are widely used to assess the presence and severity of gastroesophageal reflux disease. We hypothesized that sedation or air insufflation during a preceding endoscopy may systematically alter results. A retrospective review of ambulatory pH studies completed between January 2008 and April 2010 was performed. The pH capsule was placed 6 cm above the endoscopically determined location of the squamocolumnar junction or 5 cm above the manometrically localized upper border of the lower esophageal sphincter (LES). A total of 356 patients (65% women) underwent pH studies using the BRAVO system (GIVEN Imaging, Yoqneam, Israel). In 186 patients (E-P), the capsule was placed during endoscopy. In 170 patients (M-P), capsule placement was based on manometric determination of LES boundaries using pharyngeal anesthesia only. Endoscopic placement was successful in all cases, whereas two patients could not tolerate capsule insertion with topical anesthesia only. The mean recording time did not differ between the two groups (E-P: 2468 +/- 38 min; M-P: 2415 +/- 40 min). The number of patients with abnormal findings on day 1 but normal results for day 2 was similar with 15% for E-P compared with 11% for M-P. However, there was a significant difference in total acid exposure times between days 1 and 2 for endoscopically (day 1: 7.3 +/- 1.2; day 2: 4.8 +/- 0.5; P < 0.01), but not manometrically based placement (day 1: 7.7 +/- 0.7; day 2: 7.2 +/- 0.6). There was no difference in the number of symptoms between days or groups (E-P day 1:13.4 +/- 1.3; E-P day 2: 16.0 +/- 1.6; M-P day 1: 14.1 +/- 2.1; M-P day 2: 15.7 +/- 2.0). Similarly, the symptom sensitivity index did not differ significantly between days and groups (E-P: day 1: 4.1 +/- 0.5; day 2: 5.9 +/- 0.8; M-P: day 5.3 +/- 0.8; day 2: 5.7 +/- 0.8). The majority of patients tolerate insertion of a wireless pH monitoring capsule without sedation. Unsedated placement did not negatively affect total recording times. Although endoscopy resulted in higher acid exposure on day one it did not significantly increase the overall fraction of abnormal tests. If confirmed in prospective studies, the more consistent findings and a potential to lower cost favor manometrically guided capsule placement. PMID- 21676069 TI - History of pediatric regional anesthesia. AB - The history of local and regional anesthesia began with the discovery of the local anesthetic properties of cocaine in 1884. Shortly afterwards nerve blocks were being attempted for surgical anesthesia. Bier introduced spinal anesthesia in 1898, two of his first six patients being children. Spinal anesthesia became more widely used with the advent of better local anesthetics, stovaine and procaine in 1904-1905. Caudals and epidurals came into use in children much later. In the early years these blocks were performed by surgeons but as other doctors began to give anaesthetics the specialty of anesthesia evolved and these practitioners gradually took over this role. Specific reports of their use in children have increased as pediatric anesthesia has developed. Spinals and other local techniques had periods of greater and lesser use and have not been universally employed. Initial loss of popularity seemed to relate to improvements in general anaesthesia. The advent of lignocaine (1943) and longer acting bupivacaine (1963) and increasing concern about postoperative analgesia in the 1970-1980s, contributed to the increased use of blocks. PMID- 21676070 TI - Do multiple renal arteries in the remnant kidney have a negative influence on kidney donors after kidney donation? AB - AIM: To investigate whether the presence of multiple renal arteries in the remnant kidney has implications for lower renal function or increased incidence of hypertension. METHODS: We reviewed the intraoperative and follow-up data of 101 live kidney donors who underwent nephrectomies at our institution. Sixty-nine donors (68.3%) had single artery in the remnant kidney (Group A), while 32 donors (31.7%) had multiple renal arteries in the remnant kidney (Group B). We compared the demographic and intraoperative data between the two groups. The follow-up data of donors in each group were divided into three subgroups based on the length of the follow-up period (12-24 months, 24-48 months and >=48 months). Subgroups were created based on blood pressure and serum creatinine level. The deltablood pressure (follow-up blood pressure minus preoperative blood pressure) and deltaserum creatinine (follow-up serum creatinine minus preoperative serum creatinine) in each subgroup in Group A were compared with the counterparts in Group B. RESULTS: Renal arterial stenosis and calcification of renal arterial wall were not observed in all donors. There were no significant differences in the intraoperative characteristics (e.g. age, body mass index, operative duration and estimated blood loss) between the two groups. In addition, the blood pressure and serum creatinine level among subgroups within each group were similar. Furthermore, significant differences in deltablood pressure and deltaserum creatinine were not observed between subgroups within the same follow-up period. Recipient survival rate and serum creatinine level were similar and acceptable in both groups. CONCLUSIONS: The presence of multiple renal arteries in the remnant kidney does not have additional negative influence on kidney donors after kidney donation. PMID- 21676071 TI - Successful pregnancy after simultaneous pancreas-kidney transplantation from a brain-dead donor: the first case report in Japan. AB - Simultaneous pancreas-kidney transplantation is a revolutionary medical procedure to cure diabetes mellitus and its complications in one step. For women with type 1 diabetes mellitus and end-stage renal disease, this procedure not only treats their disease but may also allow them to have children. Worldwide, 77 pregnancies from 43 pancreas-kidney recipients have been reported. Here, we present the first case report of successful pregnancy after simultaneous pancreas-kidney transplantation from a brain-dead donor in Japan. She conceived spontaneously 32 months after transplantation. Her pregnancy course was favorable except for mild rejection of the grafted pancreas and development of gestational diabetes. She delivered a 2882-g healthy infant in October 2010. Pregnancy after simultaneous pancreas-kidney transplantation is discussed. PMID- 21676072 TI - Disseminated intravascular coagulation as the presenting sign of gastric cancer during pregnancy. AB - Gastric cancer during pregnancy is rare and the outcome is generally poor. A 36 year-old woman in the 28th week of gestation was complicated with disseminated intravascular coagulation (DIC), and she was diagnosed with gastric cancer with bone marrow metastasis. Cesarean delivery followed by sequential methotrexate (100 mg/m2) and 5-fluorouracil (600 mg/m2) chemotherapy was conducted. DIC was successfully managed with blood transfusion and chemotherapy. She has received chemotherapy in the outpatient clinic. This report is the second case of a pregnant woman with DIC as the initial manifestation of advanced gastric cancer. Prompt diagnosis and chemotherapy increases the chances of a relatively favorable outcome even in advanced gastric cancer presenting with DIC due to bone marrow involvement. PMID- 21676073 TI - Serum lipids level assessed in early pregnancy and risk of pre-eclampsia. AB - AIM: The purpose of this study investigated the relationship between early pregnancy plasma lipid concentrations and risk of pre-eclampsia. MATERIAL AND METHODS: In a prospective cohort study, maternal blood samples were collected between 10-20 weeks of gestation. From the cohort, we selected 30 women who developed pre-eclampsia and 320 who remained normotensive and served as control subjects. Linear logistic regression test was used for confounding factors identification. RESULTS: Women who subsequently developed pre-eclampsia had higher concentrations of fasting plasma, total cholesterol and triglycerides than in those remaining normotensive group. After using linear logistic regression analyses for the potential confounding factors, triglyceride concentrations were significantly higher in pre-eclamptic cases as compared with control. CONCLUSION: Early pregnancy dyslipidemia, particularly hypertriglyceridemia appears associated with increased risk of pre-eclampsia. PMID- 21676074 TI - The Doppler cerebroplacental ratio predicts non-reassuring fetal status in intrauterine growth restricted fetuses at term. AB - AIM: To investigate whether cerebroplacental ratio (CPR) can be a useful marker to predict non-reassuring fetal status (NRFS) in small for gestational age (SGA) infants at term. MATERIAL AND METHODS: Three hundred and nine singleton SGA infants delivered between 37 and 41 weeks of gestation were included in this study. SGA infants were defined as birthweight less than 10th percentile for gestational age. Doppler measurements were recorded once a week until delivery. The incidence of NRFS or an emergency cesarean delivery, and relationship between CPR and NRFS in SGA infants were compared with appropriate for gestational age (AGA) infants at term, and a receiver-operator characteristics curve analysis was performed. RESULTS: The incidences of NRFS was significantly higher in SGA (27.8%) infants compared with in AGA infants (18.0%), and the rate of emergency cesarean delivery was significantly higher in SGA (14.6%) infants compared with AGA infants (8.3%). CPR was obtained from 63 SGA infants, and 16 out of 63 cases (25.4%) resulted in NRFS. The infants complicated with NRFS showed significantly lower CPR values compared with those without NRFS (1.05 +/- 0.2 vs 1.23 +/- 0.2, P = 0.013), while middle cerebral artery resistance index and 'umbilical artery resistance index were not statistically different between the two groups. A cut off value of CPR 1.1 based on the receiver-operator characteristics curve provided the best combination with 62.5% sensitivity and 74.5% specificity to predict NRFS occurrence. CONCLUSIONS: The SGA infants complicated with NRFS showed significantly lower CPR values compared with those without NRFS. PMID- 21676076 TI - Comparison of risk factors for major obstetric complications between Western countries and Japan: a case-cohort study. AB - AIM: The aim of this study was to demonstrate the differences in risk factors for obstetrical complications between Japan and Western countries. MATERIAL AND METHODS: Using the Perinatal Database of the Japan Society for Obstetrics and Gynecology, we studied singleton deliveries after 22 weeks of gestation (n = 242 715) at 125 centers of the perinatal network in Japan from 2001 through 2005 as a base cohort. In total, 3749 births (1.5% of the base cohort) were randomly selected as a subcohort. We compared the rate of risk factors in the cases with ten obstetrical complications with that in the subcohort (case-cohort study). RESULTS: Almost all of the evaluated risk factors were common between Western countries and Japan. Older age at pregnancy was a common risk factor for pregnancy-induced hypertension, placental abruption, placenta previa, and placenta accreta/increta/percreta. On the other hand, younger age at pregnancy was a common risk factor for eclampsia and preterm delivery. Smoking during pregnancy was a common risk factor for pregnancy-induced hypertension, preterm premature rupture of the membranes, preterm delivery, cervical insufficiency, chorioamnionitis, and placental abruption. In vitro fertilization and embryo transfer was a common risk factor for cervical insufficiency, placenta previa, and placenta accreta/increta/percreta. CONCLUSION: This case-cohort study in Japan clarified the common risk factors between Western countries and Japan as well as the risk factors indigenous to Japanese women. To identify the risk factors for a disease in a specific country, we should use data derived from its population. PMID- 21676075 TI - Organism diversity between women with and without bacterial vaginosis as determined by polymerase chain reaction denaturing gradient gel electrophoresis and 16S rRNA gene sequence. AB - AIMS: The aim of this study was to characterize the different structures of microbial communities between 20 healthy women and 17 bacterial vaginosis (BV) positive women of reproductive age using denaturing gradient gel electrophoresis (DGGE). MATERIAL AND METHODS: Vaginal samples from 17 BV-positive and 20 BV negative women were subjected to DNA extraction, and amplified with eubacterial 16S rRNA gene-specific primers via polymerase chain reaction. The polymerase chain reaction products were separated using DGGE. Bands were excised, re amplified, purified and sequenced. DNA sequences were compared with GenBank database. Phylip software packages were used to calculate sequencing data and form a phylogenetic tree to identify the genetic relations for microbiota inhabited in vaginal ecosystems of BV-positive women. RESULTS: In total, 28 kinds of organisms were detected that comprised BV(+) vagina microbial community, varying from three to nine kinds with an average of 5.71 kinds per woman. Only seven species were detected in BV(-) women, ranging between one and five species with an average of 2.40 species per woman, which was significantly lower than that detected in BV(+) women (t = 7.39, P < 0.001). A strain of Uncultured Lactobacillus sp. clone EHFS1_S05c (29/37; 78.38%) was most commonly presented in both BV-negative and BV-positive women, but the mean proportion of this Lactobacillus sp. strain to the whole microbial population colonized in the vaginal tract of BV(-) women was sharply higher than that calculated from BV(+) women (t = 2.92, P < 0.01). CONCLUSIONS: The findings indicate further diversity in the category of vaginal microorganisms associated with BV. The presence of Gardnerella vaginalis is not necessary as a sign for gynecologists to determine whether or not a woman is affected by BV. PMID- 21676077 TI - Expression of vascular endothelial growth factor C correlates with a poor prognosis based on analysis of prognostic factors in patients with cervical carcinomas. AB - AIM: The aim of this study was to specifically investigate the clinicopathological role of expression of vascular endothelial growth factor C (VEGF-C) as well as the correlation with clinical outcomes in cervical cancer. METHOD: We carried out a comparative analysis of data from a prospective observational study of 82 patients with cervical carcinomas who underwent radical hysterectomy with bilateral adnexectomy and bilateral pelvic lymphadenectomy from January 2001 to January 2005. RESULTS: VEGF-C mRNA was identified in tumor tissues from 42 patients. In univariate analysis by Fisher's exact probability test, VEGF-C expression was significantly associated with lymph node metastasis (LNM) (pN1) (P < 0.01). In multivariate analysis by Binary logistic regression analysis, LNM was the independent relevant factor for VEGF-C mRNA expression in tumor tissues. In univariate analysis by the log-rank test, the overall 5-year survival rate of the patients with VEGF-C mRNA expression in tumor tissues was significantly lower than that of the patients without VEGF-C mRNA expression (47.6% vs. 87.5%; P < 0.01). The overall 5-year survival rate of the patients with LNM was significantly lower than that of the patients without LNM (50.0% vs 80.4%; P < 0.01). According to Cox regression multivariate analysis, VEGF-C mRNA expression in tumor tissues and LNM were independent, relevant factors for 5-year survival rate, respectively. CONCLUSIONS: Expression of VEGF-C is related to lymph node metastasis (pN1), and is a prognostic indicator for cervical cancer. PMID- 21676078 TI - Acute kidney injury complicating septic unsafe abortion: clinical course and treatment outcomes of 44 cases. AB - AIM: The aim of this study was to present the clinical course and treatment outcomes of patients with acute kidney injury (AKI) after septic unsafe abortion. MATERIAL AND METHODS: Medical records of patients with AKI after septic unsafe abortion admitted at Khon Kaen Hospital between January 2003 and December 2009 were reviewed. RESULTS: Forty-four patients with an average age of 24.3 years were included and 25% were teenage girls. The most common method of induced abortion was transvaginal chemical injection (81.8%). One patient had a hysterectomy due to severe peritonitis and sepsis that was not responsive to medical treatment. AKI developed on day 4.5 +/- 3.6 with the range of onset 1-14 days after induced abortion. Oliguric AKI was present in 70.4% of patients with the mean duration of oliguria of 7.4 +/- 5 days. Seventeen patients required dialysis. The mortality rate was 9%. The average duration of recovery from AKI was 24.8 +/- 16.6 days. CONCLUSIONS: Conservative treatment of AKI-related septic unsafe abortion was dialysis without hysterectomy. The treatment results were minimal morbidity and mortality. Conservative management may be a better alternative to hysterectomy for the treatment of septic unsafe abortion with AKI. However the current study was a retrospective study, and we were not able to obtain certain follow-up data, such as fertility outcomes after recovery. Therefore, further study of these issues should be considered. PMID- 21676079 TI - Rebuilding the labor curve during neuraxial analgesia. AB - AIM: The aim of this study was to examine the pattern of labor progression among nulliparous women under neuraxial analgesia to obtain a new, specific reference labor curve and to compare the different effects of epidural and combined spinal epidural (CSE) analgesia on the progression of labor. MATERIAL AND METHODS: This perspective cohort study was carried out in the Obstetrics and Gynecology tertiary care unit. Six hundred nulliparous parturients were enrolled. A total of 545 nulliparous women were assigned to receive either epidural (272) or CSE (273) analgesia during labor. RESULTS: The mean duration of the first stage was 4 h and 30 min (SD 1.52 h) and the mean duration of the second stage was 1 h and 10 min (SD 0.43). In the second stage, the CSE analgesia labors showed an overall faster progression compared to the epidural labors but both lasted longer than the duration reported by Zhang (53 min) and Friedman (39 min). Both the first and the second-stage duration were significantly lower if neuraxial analgesia was performed as a CSE procedure with respect to the simple epidural procedure (first stage 4 h and 1 min vs. 4 h and 60 min, P = 0.043; second stage 1 h and 5 min vs 1 h and 15 min, P = 0.0356). CONCLUSIONS: The pattern of labor progression in contemporary obstetrics differs significantly from the Friedman curve. Based on these observations, we can obtain a more comprehensive knowledge of the partogram's modifications due to the analgesia. PMID- 21676080 TI - Rate of negative appendectomy in pregnant women in Benin City, Nigeria. AB - AIM: This study was an analysis of women diagnosed with acute appendicitis in pregnancy, to appraise the maternal and fetal outcomes and explore the correlations with negative appendectomy. MATERIAL AND METHODS: A retrospective study was undertaken at the University of Benin Teaching Hospital, Nigeria. The service delivery records of all pregnant women who underwent appendectomy for acute appendicitis from January 2000 to December 2009 were analyzed. RESULTS: Among 16,173 deliveries, 23 pregnant women were diagnosed with acute appendicitis. The age of the women ranged between 15 and 34 years (median = 26 years), while the majority (65.2%) were nulliparous. The mean gestational age at presentation was 21.1 +/- 6.9 weeks with up to 15 (65.2%) patients presenting in the second trimester. Eighteen (78.3%) patients had histopathologically proven appendicitis giving a negative appendectomy rate of 21.7%. Postoperative complications were noted in eight (34.8%) patients. Half of these occurred within the negative appendectomy group. The negative appendectomy group also contributed significantly to the adverse obstetric outcome: preterm labor, 8.7% of 21.7%, preterm delivery, 4.5% of 13.6% and a fetal loss rate of 4.3% of 13%. One maternal death occurred in the group with diseased appendix giving a maternal mortality rate of 4.3%. CONCLUSIONS: While a higher index of suspicion among clinicians will ensure earlier diagnosis and improve the associated maternal and fetal prognosis, the need to reduce the negative laparotomy rate is highlighted by the high rate of adverse obstetric outcomes amongst the negative appendectomy group. PMID- 21676081 TI - Effect of antithyroid drug on chick embryos during the last week of development: delayed hatching and decreased cerebellar acetylcholinesterase activity. AB - AIM: Hypothyroid state during embryogenesis disturbs normal growth and brain development, influencing later life. To evaluate the harmful consequences of the state during embryogenesis using an animal model, we inhibited thyroid hormone biosynthesis in chick embryos by using methimazole (MMI). MATERIAL AND METHODS: Typically, embryos were treated with MMI (20 umol/egg) on day 14, and examined on specific days. RESULTS: Of the control embryos, 94% hatched on day 21, whereas 0% and 60% of MMI-treated embryos hatched on days 21 and 24, respectively. MMI retarded the rates of bodyweight gain as well as liver and heart development, and delayed hatching. However, the external differences in appearance and differences in the weights of the newly hatched control chicks on day 21 and the MMI-treated chicks on day 24 were less obvious. Embryos treated with MMI exhibited increased mass in their brain parts on day 24. Most notably, the treatment resulted in a 1.35-fold increase in cerebellum weight compared to that of the untreated animals. Acetylcholinesterase activity in the cerebellum on the day of hatching decreased significantly to 0.85-fold that of the untreated controls. Thyroid hormone receptor beta mRNA was detected from day 12 and dramatically expressed from day 19 to the day of hatching. CONCLUSION: The 'fertilized hen's egg-chick embryo-chick system' is an appropriate animal model for investigating the hypothyroid state during embryogenesis. Decreased cerebellar acetylcholinesterase activity after MMI treatment was assumed to relate to a mechanism of motor and cognitive deficits in congenital hypothyroidism. PMID- 21676082 TI - Experience managing postpartum hemorrhage at Minia University Maternity Hospital, Egypt: no mortality using external aortic compression. AB - AIM: To compare maternal mortality and morbidity due to postpartum hemorrhage (PPH) at Minia University Maternity Hospital, El-Minia, Egypt, before and while external aortic compression was applied as an adjunct intervention, and to identify the effect of aortic compression. METHODS: The obstetric data and outcomes of women with PPH were compared for the period 1999 through 2007, when only a regular PPH management protocol was followed, and for 2008 through 2009, when external aortic compression was applied before initiating the protocol. The El-Minia aortic compression device (EACD) was used in 2008 and the manual aortic compression maneuver (MACM) in 2009. Outcomes and treatment measures were analyzed by the *2 test and multivariate regression. RESULTS: During the first period, PPH annually caused 1-6 deaths and 22-31 severe conditions, such as acute renal failure, loss of consciousness, anemia persisting after treatment, postpartum infection, or the need for a hysterectomy. The incidence of PPH declined from 4.6% in 1999 to 0.9% at the end of the study. In 2008 and 2009, there were no deaths due to PPH and only four complications were recorded in each of these two years. Regression analysis identified aortic compression as the second most effective measure preventing severe shock and death, with blood transfusions being the first. The almost similar results reached with the EACD and MACM allow a choice, but fewer units of blood were needed following application of the device. CONCLUSIONS: Including the EACD and MACM in the regular management protocol may improve the outcome of severe PPH. PMID- 21676083 TI - Comparison of vaginal misoprostol tablets and prostaglandin E2 gel for the induction of labor in premature rupture of membranes at term: a randomized comparative trial. AB - AIM: To compare immediate induction with vaginal misoprostol tablets and immediate induction with vaginal dinoprostone (naturally occurring prostaglandin E2 [PGE2]) gel in women with premature rupture of membranes (PROM) at term. METHODS: Two hundred and twelve women with PROM at term were assigned randomly to receive either an intravaginal 25 ug misoprostol tablet, 4-hourly, with a maximum of five doses, or 0.5 mg intravaginal PGE2 gel, 6-hourly, with a maximum of two doses. The primary outcome measures were the admission-to-delivery interval and the induction-to-delivery interval. Secondary outcomes included cesarean section rate, mode of delivery, and maternal and neonatal safety outcome. Results were calculated applying Fisher's exact test, chi2-test, t-test and calculating the P value using an alpha level of 0.05 for Type I errors. RESULTS: The mean time from admission to delivery was 13.53 h in the misoprostol group and 12.30 h in the PGE2 group (P = 0.090). The induction-to-delivery interval was also comparable between the groups (10.75 h vs. 9.37 h), while the cesarean section rate did not differ significantly between them (7.61% vs. 15.30%). More women in the misoprostol group had an instrumental delivery (12.38% vs. 2.94%). The only significant difference in neonatal outcome was a greater number of babies born with Apgar score < 7 at 1 min in the misoprostol group. Maternal outcomes were not significantly different, except for a higher number of digital vaginal examinations in the misoprostol group. CONCLUSION: Vaginal misoprostol is equally efficacious in labor induction and demonstrates a similar fetal and maternal safety profile to PGE2 gel. PMID- 21676084 TI - Tracking speakers' false beliefs: is theory of mind available earlier for word learning? AB - Happe and Loth (2002) describe word learning as a 'privileged domain' in the development of a theory of mind. We test this claim in a series of experiments based on the Sally-Anne paradigm. Three- and 4-year-old children's ability to represent others' false beliefs was investigated in tasks that required the child either to predict the actions of a protagonist in a story or to learn the meaning of a new word used by the protagonist. Experiment 1 replicated previous findings of better performance in a false belief word-learning task compared to a false belief action-prediction task. However, systematic manipulation of the task parameters in Experiments 2 and 3 revealed that this performance discrepancy disappeared when tasks were equated in their 'referential pull' (Perner, Rendl & Garnham, 2007). We conclude that the notion of a precocious theory of mind for word learning is not required to explain dissociations in performance on false belief tasks. PMID- 21676085 TI - Evidence for a specific cross-modal association deficit in dyslexia: an electrophysiological study of letter-speech sound processing. AB - The phonological deficit theory of dyslexia assumes that degraded speech sound representations might hamper the acquisition of stable letter-speech sound associations necessary for learning to read. However, there is only scarce and mainly indirect evidence for this assumed letter-speech sound association problem. The present study aimed at clarifying the nature and the role of letter speech sound association problems in dyslexia by analysing event-related potentials (ERP) of 11-year-old dyslexic children to speech sounds in isolation or combined with letters, which were presented either simultaneously with or 200 ms before the speech sounds. Recent studies with normal readers revealed that letters systematically modulated speech sound processing in an early (mismatch negativity or MMN) and late (Late Discriminatory Negativity or LDN) time-window. The amplitude of the MMN and LDN to speech sounds was enhanced when speech sounds were presented with letters. The dyslexic readers in the present study, however, did not exhibit any early influences of letters on speech sounds even after 4 years of reading instruction, indicating no automatic integration of letters and speech sounds. Interestingly, they revealed a systematic late effect of letters on speech sound processing, probably reflecting the mere association of letters and speech sounds. This pattern is strongly divergent from that observed in age matched normal readers, who showed both early and late effects, but reminiscent of that observed in beginner normal readers in a previous study (Froyen, Bonte, van Atteveldt & Blomert, 2009). The finding that the quality of letter-speech sound processing is directly related to reading fluency urges further research into the role of audiovisual integration in the development of reading failure in dyslexia. PMID- 21676086 TI - Learning to read changes children's phonological skills: evidence from a latent variable longitudinal study of reading and nonword repetition. AB - Individual differences in nonword repetition are associated with language and literacy development, but few studies have considered the extent to which learning to read influences phonological skills as indexed by nonword repetition performance. We explored this question using a latent variable longitudinal design. Reading, oral language and nonword repetition were assessed in 215 children at age 6 years and one year later at age 7. Reading at 6 years predicted growth in nonword repetition between 6 and 7 years, independent of the effects of oral language skills and the autoregressive effect of nonword repetition at 6 years, but nonword repetition was not a longitudinal predictor of the growth of reading. These findings demonstrate that learning to read has a powerful effect on children's language processing systems. We consider how learning to read might influence speech processing, and discuss the implications of our findings for theoretical accounts of reading disorder. PMID- 21676087 TI - Effects of joint attention on long-term memory in 9-month-old infants: an event related potentials study. AB - Joint attention develops during the first year of life but little is known about its effects on long-term memory. We investigated whether joint attention modulates long-term memory in 9-month-old infants. Infants were familiarized with visually presented objects in either of two conditions that differed in the degree of joint attention (high versus low). EEG indicators in response to old and novel objects were probed directly after the familiarization phase (immediate recognition), and following a 1-week delay (delayed recognition). In immediate recognition, the amplitude of positive slow-wave activity was modulated by joint attention. In the delayed recognition, the amplitude of the Pb component differentiated between high and low joint attention. In addition, the positive slow-wave amplitude during immediate and delayed recognition correlated with the frequency of infants' looks to the experimenter during familiarization. Under both high- and low-joint-attention conditions, the processing of unfamiliar objects was associated with an enhanced Nc component. Our results show that the degree of joint attention modulates EEG during immediate and delayed recognition. We conclude that joint attention affects long-term memory processing in 9-month old infants by enhancing the relevance of attended items. PMID- 21676088 TI - Only self-generated actions create sensori-motor systems in the developing brain. AB - Previous research shows that sensory and motor systems interact during perception, but how these connections among systems are created during development is unknown. The current work exposes young children to novel 'verbs' and objects through either (a) actively exploring the objects or (b) by seeing an experimenter interact with the objects. Results demonstrate that the motor system is recruited during auditory perception only after learning involved self generated interactions with objects. Action observation itself led to above baseline activation in one motor region during visual perception, but was still significantly less active than after self-generated action. Therefore, in the developing brain, associations are built upon real-world interactions of body and environment, leading to sensori-motor representations of both objects and words. PMID- 21676089 TI - Using confirmatory factor analysis to understand executive control in preschool children: sources of variation in emergent mathematic achievement. AB - Latent variable modeling methods have demonstrated utility for understanding the structure of executive control (EC) across development. These methods are utilized to better characterize the relation between EC and mathematics achievement in the preschool period, and to understand contributing sources of individual variation. Using the sample and battery of laboratory tasks described in Wiebe, Espy and Charak (2008), latent EC was related strongly to emergent mathematics achievement in preschool, and was robust after controlling for crystallized intellectual skills. The relation between crystallized skills and emergent mathematics differed between girls and boys, although the predictive association between EC and mathematics did not. Two dimensions of the child 's social environment contributed to mathematics achievement: social network support through its relation to EC and environmental stressors through its relation with crystallized skills. These findings underscore the need to examine the dimensions, mechanisms, and individual pathways that influence the development of early competence in basic cognitive processes that underpin early academic achievement. PMID- 21676090 TI - The development of a phonological illusion: a cross-linguistic study with Japanese and French infants. AB - In adults, native language phonology has strong perceptual effects. Previous work has shown that Japanese speakers, unlike French speakers, break up illegal sequences of consonants with illusory vowels: they report hearing abna as abuna. To study the development of phonological grammar, we compared Japanese and French infants in a discrimination task. In Experiment 1, we observed that 14-month-old Japanese infants, in contrast to French infants, failed to discriminate phonetically varied sets of abna-type and abuna-type stimuli. In Experiment 2, 8 month-old French and Japanese did not differ significantly from each other. In Experiment 3, we found that, like adults, Japanese infants can discriminate abna from abuna when phonetic variability is reduced (single item). These results show that the phonologically induced /u/ illusion is already experienced by Japanese infants at the age of 14 months. Hence, before having acquired many words of their language, they have grasped enough of their native phonological grammar to constrain their perception of speech sound sequences. PMID- 21676091 TI - Diet and gender influences on processing and discrimination of speech sounds in 3 and 6-month-old infants: a developmental ERP study. AB - Early post-natal nutrition influences later development, but there are no studies comparing brain function in healthy infants as a function of dietary intake even though the major infant diets differ significantly in nutrient composition. We studied brain responses (event-related potentials; ERPs) to speech sounds for infants who were fed either breast milk (BF), milk-based formula (MF), or soy formula (SF) during the first 6 months of life. Two syllables presented in an oddball paradigm elicited a late positive wave (P350) from temporal and frontal brain regions involved in language processes. All groups showed significantly greater response amplitudes to the infrequent syllable across sites at 3 months and frontally at 6 months, but significant discrimination at temporal sites was only observed at 6 months in BF infants. Decreases in response amplitudes from 3 to 6 months were greater for the frequently presented syllable, most prominent in BF infants, and greater in females than males. The results indicate greater syllable discrimination in BF than formula-fed infants, but whether this can be attributed to dietary influences alone remains unclear. Feeding method and background factor differences between breastfed and formula-fed infants may also contribute to the observed differences. The general absence of differences between formula-fed groups is notable and suggests that milk-based formula and soy formula equally support brain development and function during the first post natal 6 months. Finally, the results indicate gender differences in the development of neural and temporal processes involved in sensory discrimination, and suggest that at 6 months these processes are better developed in females. PMID- 21676092 TI - Developmental differences in prefrontal activation during working memory maintenance and manipulation for different memory loads. AB - The ability to keep information active in working memory is one of the cornerstones of cognitive development. Prior studies have demonstrated that regions which are important for working memory performance in adults, such as dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and superior parietal cortex, become increasingly engaged across school-aged development. The primary goal of the present functional MRI study was to investigate the involvement of these regions in the development of working memory manipulation relative to maintenance functions under different loads. We measured activation in DLPFC, VLPFC, and superior parietal cortex during the delay period of a verbal working memory task in 11-13-year-old children and young adults. We found evidence for age-related behavioral improvements in working memory and functional changes within DLPFC and VLPFC activation patterns. Although activation profiles of DLPFC and VLPFC were similar, group differences were most pronounced for right DLPFC. Consistent with prior studies, right DLPFC showed an interaction between age and condition (i.e. manipulation versus maintenance), specifically at the lower loads. This interaction was characterized by increased activation for manipulation relative to maintenance trials in adults compared to children. In contrast, we did not observe a significant age-dependent load sensitivity. These results suggest that age-related differences in the right DLPFC are specific to working memory manipulation and are not related to task difficulty and/or differences in short-term memory capacity. PMID- 21676093 TI - Deaf and hearing children: a comparison of peripheral vision development. AB - This study investigated peripheral vision (at least 30 degrees eccentric to fixation) development in profoundly deaf children without cochlear implantation, and compared this to age-matched hearing controls as well as to deaf and hearing adult data. Deaf and hearing children between the ages of 5 and 15 years were assessed using a new, specifically paediatric designed method of static perimetry. The deaf group (N = 25) were 14 females and 11 males, mean age 9.92 years (range 5-15 years). The hearing group (N = 64) were 34 females, 30 males, mean age 9.13 years (range 5-15 years). All participants had good visual acuity in both eyes (< 0.200 LogMAR). Accuracy of detection and reaction time to briefly presented LED stimuli of three light intensities, at eccentricities between 30 degrees and 85 degrees were measured while fixation was maintained to a central target. The study found reduced peripheral vision in deaf children between 5 and 10 years of age. Deaf children (aged 5-10 years) showed slower reaction times to all stimuli and reduced ability to detect and accurately report dim stimuli in the far periphery. Deaf children performed equally to hearing children aged 11-12 years. Deaf adolescents aged 13-15 years demonstrated faster reaction times to all peripheral stimuli in comparison to hearing controls. Adolescent results were consistent with deaf and hearing adult performances wherein deaf adults also showed significantly faster reaction times than hearing controls. Peripheral vision performance on this task was found to reach adult-like levels of maturity in deaf and hearing children, both in reaction time and accuracy of detection at the age of 11-12 years. PMID- 21676094 TI - Strength of default mode resting-state connectivity relates to white matter integrity in children. AB - A default mode network of brain regions is known to demonstrate coordinated activity during the resting state. While the default mode network is well characterized in adults, few investigations have focused upon its development. We scanned 9-13-year-old children with diffusion tensor imaging and resting-state functional magnetic resonance imaging. We identified resting-state networks using Independent Component Analysis and tested whether the functional connectivity between the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) depends upon the maturation of the underlying cingulum white matter tract. To determine the generalizability of this relationship, we also tested whether functional connectivity depends on white matter maturity between bilateral lateral prefrontal cortex (lateral PFC) within the executive control network. We found a positive relationship between mPFC-PCC connectivity and fractional anisotropy of the cingulum bundle; this positive relationship was moderated by the age of the subjects such that it was stronger in older children. By contrast, no such structure-function relationship emerged between right and left lateral PFC. However, functional and structural connectivity of this tract related positively with cognitive speed, fluency, and set-switching neuropsychological measures. PMID- 21676095 TI - Maternal and paternal plasma, salivary, and urinary oxytocin and parent-infant synchrony: considering stress and affiliation components of human bonding. AB - Studies in mammals have implicated the neuropeptide oxytocin (OT) in processes of bond formation and stress modulation, yet the involvement of OT in human bonding throughout life remains poorly understood. We assessed OT in the plasma, saliva, and urine of 112 mothers and fathers interacting with their 4-6-month-old infants. Parent-infant interactions were micro-coded for parent and child's social behaviors and for the temporal coordination of their socio-affective cues. Parents were interviewed regarding their attachment to the infant and reported on bonding to own parents, romantic attachment, and parenting stress. Results indicated that OT in plasma (pOT) and saliva (sOT) were inter-related and were unrelated to OT in urine (uOT). pOT and sOT in mothers and fathers were associated with parent and child's social engagement, affect synchrony, and positive communicative sequences between parent and child. uOT was related to moments of interactive stress among mothers only, indexed by the co-occurrence of infant negative engagement and mother re-engagement attempts. pOT and sOT were associated with mothers' and fathers' attachment relationships throughout life: to own parents, partner, and infant, whereas uOT correlated with relationship anxiety and parenting stress among mothers only. Similar to other mammals, OT is involved in human attachment and contingent parenting. The dual role of OT in stress and affiliation underscores its complex involvement in processes of social bonding throughout life. PMID- 21676096 TI - Exploring the perceptual spaces of faces, cars and birds in children and adults. AB - While much developmental research has focused on the strategies that children employ to recognize faces, less is known about the principles governing the organization of face exemplars in perceptual memory. In this study, we tested a novel, child-friendly paradigm for investigating the organization of face, bird and car exemplars. Children ages 3-4, 5-6, 7-8, 9-10, 11-12 and adults were presented with 50/50 morphs of typical and atypical face, bird and car parent images. Participants were asked to judge whether the 50/50 morph more strongly resembled the typical or the atypical parent image. Young and older children and adults showed a systematic bias to the atypical faces and birds, but no bias toward the atypical cars. Collectively, these findings argue that by the age of 3, children encode and organize faces, birds and cars in a perceptual space that is strikingly similar to that of adults. Category organization for both children and adults follows Krumhansl's (1978) distance-density principle in which the similarity between two exemplars is jointly determined by their physical appearance and the density of neighboring exemplars in the perceptual space. PMID- 21676097 TI - A statistical estimate of infant and toddler vocabulary size from CDI analysis. AB - For the last 20 years, developmental psychologists have measured the variability in lexical development of infants and toddlers using the MacArthur-Bates Communicative Development Inventories (CDIs) - the most widely used parental report forms for assessing language and communication skills in infants and toddlers. We show that CDI reports can serve as a basis for estimating infants' and toddlers'total vocabulary sizes, beyond serving as a tool for assessing their language development relative to other infants and toddlers. We investigate the link between estimated total vocabulary size and raw CDI scores from a mathematical perspective, using both single developmental trajectories and population data. The method capitalizes on robust regularities, such as the overlap of individual vocabularies observed across infants and toddlers, and takes into account both shared knowledge and idiosyncratic knowledge. This statistical approach enables researchers to approximate the total vocabulary size of an infant or a toddler, based on her raw MacArthur-Bates CDI score. Using the model, we propose new normative data for productive and receptive vocabulary in early childhood, as well as a tabulation that relates individual CDI measures to realistic lexical estimates. The correction required to estimate total vocabulary is non-linear, with a far greater impact at older ages and higher CDI scores. Therefore, we suggest that correlations of developmental indices to language skills should be made to vocabulary size as estimated by the model rather than to raw CDI scores. PMID- 21676098 TI - Intonational phrase structure processing at different stages of syntax acquisition: ERP studies in 2-, 3-, and 6-year-old children. AB - This study explored the electrophysiology underlying intonational phrase processing at different stages of syntax acquisition. Developmental studies suggest that children's syntactic skills advance significantly between 2 and 3 years of age. Here, children of three age groups were tested on phrase-level prosodic processing before and after this developmental phase, while their brain activity was recorded. The Closure Positive Shift (CPS), which indexes the perception of intonational phrasing in adults, served as dependent variable. The event-related brain potentials of 3- and 6-year-olds, but not of 21-month-olds, showed a CPS. These results suggest that prosodic phrase processing, as indicated by the CPS, is established only later during children's development, pointing to a close interaction of prosody and syntax acquisition. PMID- 21676099 TI - Early development of object unity: evidence for perceptual completion in newborns. AB - The present study aimed to investigate whether perceptual completion is available at birth, in the absence of any visual experience. An extremely underspecified kinetic visual display composed of four spatially separated fragments arranged to give rise to an illusory rectangle that occluded a vertical rod (illusory condition) or rotated so as not to elicit perceptual grouping (control condition) was constructed. After newborns' ability to detect the particular kind of rod-and box display used in the present study had been probed (Experiment 1), they were habituated to the illusory rod-and-box display (Experiment 2), to the control display that did not contain illusory contours (Experiment 3), and to a standard real rod-and-box display akin to those used in previous infants' studies (Experiment 4). Newborns perceived the rod as a connected unit either in the illusory condition (Experiment 2) or in the real condition (Experiment 4), as documented by a preference for a broken rod over a complete rod during the test phase, but not when the occluder was absent (Experiment 3). In all experiments newborns showed no preference between the two test stimuli (control condition), avoiding the possibility that newborns have a spontaneous preference for one test display over the other. Overall, the results of the present study provide evidence that the ability to achieve object unity (1) stems from intrinsic properties of the human perceptual system and (2) is operative from birth, given the right conditions. PMID- 21676100 TI - Kindergarten children's sensitivity to geometry in maps. AB - Geometrical concepts are critical to a host of human cognitive achievements, from maps to measurement to mathematics, and both the development of these concepts, and their variation by gender, have long been studied. Most studies of geometrical reasoning, however, present children with materials containing both geometric and non-geometric information, and with tasks that are open to multiple solution strategies. Here we present kindergarten children with a task requiring a focus on geometry: navigation in a small-scale space by a purely geometric map. Children spontaneously extracted and used relationships of both distance and angle in the maps, without prior demonstration, instruction, or feedback, but they failed to use the sense information that distinguishes an array from its mirror image. Children of both genders showed a common profile of performance, with boys showing no advantage on this task. These findings provide evidence that some map-reading abilities arise prior to formal instruction, are common to both genders, and are used spontaneously to guide children's spatial behavior. PMID- 21676101 TI - Evidence for motor planning in monkeys: rhesus macaques select efficient grips when transporting spoons. AB - McCarty and colleagues (1999) developed the elevated spoon task to measure motor planning in human infants. In this task, a spoon containing food was placed on an elevated apparatus that supported both ends of the spoon. The handle was oriented to the left or right on different trials. We presented naive adult rhesus monkeys (Macaca mulatta) with the elevated spoon problem, and observed how monkeys learned the affordances of spoons over sessions. Strikingly, monkeys developed two different strategies for efficient spoon transport in just 12 to 36 trials. In subsequent testing with a novel double bowl spoon approximately 1 year later, monkeys demonstrated that they were attending to the baited spoon bowl and continued to select efficient grips for transporting the spoon. Monkey data were contrasted with previous studies in human infants using a perception-action perspective in an effort to understand the fundamentals of tool use and motor planning that may be common in the development of these abilities across species and their origins in human behavior. PMID- 21676102 TI - Socioeconomic gradients and child development in a very low income population: evidence from Madagascar. AB - Our objectives were to document and examine socioeconomic gradients across a comprehensive set of child development measures in a population living in extreme poverty, and to interpret these gradients in light of findings from the neuroscience literature. We assessed a nationally representative sample of 3-6 year-old children (n = 1332) from 150 communities of Madagascar using standard tests of development. We found that children whose families were in the top wealth quintile or whose mothers had secondary education performed significantly better across almost all measures of cognitive and language development and had better linear growth compared with children of women in the lowest wealth quintile or women with no education. These differences between children of low and high socioeconomic position were greatest for receptive language, working memory, and memory of phrases. The mean difference in the scores between children in the highest and lowest socioeconomic status categories doubled between age 3 and age 6, and the biggest gaps across socioeconomic position by age 6 were in receptive language and sustained attention. Our results suggest that even within the context of extreme poverty, there are strong associations between family socioeconomic status and child development outcomes among preschool children, and that the language and executive function domains exhibit the largest gradients. PMID- 21676103 TI - Preschoolers joke with jokers, but correct foreigners. AB - Thirty- and 36-month-old English speakers' (N = 106) ability to produce jokes, distinguish between humorous and sincere intentions, and distinguish between English- and foreign-language speakers, was examined in two tasks. In the Giving task, an experimenter requested one of two familiar objects, and a confederate always gave her the wrong object. In the Naming task, the confederate mislabeled familiar objects. In the English-speaking conditions, the confederate laughed after doing the wrong thing (English-Humor) or said, 'There!' (English-Sincere). In the Foreign conditions, the French- or Italian-speaking confederate laughed (Foreign-Humor) or said, 'D'accord!' or 'Va bene!' (Foreign-Sincere). When preschoolers were subsequently requested to give and name the same objects and a new set of familiar objects they were significantly more likely to imitate and 'do the wrong thing' in the Humor versus Sincere, and in the English versus Foreign conditions. PMID- 21676104 TI - What's mine is mine: twelve-month-olds use possessive pronouns to identify referents. AB - This research investigated 12-month-olds' ability to use person-specific language to determine to which of several absent things a person is referring. Infants were introduced to two experimenters who played separately with a different ball. One researcher asked infants to retrieve her object when both balls were hidden. Infants selected the correct object when researchers used the pronoun my, but failed to do so when the was used. The present research provides the first evidence of 12-month-olds' comprehension of possessive pronouns and indicates that infants use person-specific language to resolve reference. PMID- 21676105 TI - Constraints on infants' musical rhythm perception: effects of interval ratio complexity and enculturation. AB - Effects of culture-specific experience on musical rhythm perception are evident by 12 months of age, but the role of culture-general rhythm processing constraints during early infancy has not been explored. Using a habituation procedure with 5- and 7-month-old infants, we investigated effects of temporal interval ratio complexity on discrimination of standard from novel musical patterns containing 200-ms disruptions. Infants were tested in three ratio conditions: simple (2:1), which is typical in Western music, complex (3:2), which is typical in other musical cultures, and highly complex (7:4), which is relatively rare in music throughout the world. Unlike adults and older infants, whose accuracy was predicted by familiarity, younger infants were influenced by ratio complexity, as shown by their successful discrimination in the simple and complex conditions but not in the highly complex condition. The findings suggest that ratio complexity constrains rhythm perception even prior to the acquisition of culture-specific biases. PMID- 21676106 TI - Electrophysiological evidence for the magnocellular-dorsal pathway deficit in dyslexia. AB - In adults, the onset of coherent motion compared to random motion in a random dot kinematogram leads to a right hemispheric amplitude advantage of the N2 response. The source of this asymmetry is believed to lie in the motion selective MT+ cortex. Here, we tested whether the right tempo-parietal N2 component shows a similar regularity in children. In particular, we were interested in whether coherent vs. incoherent motion modulates the amplitude of N2 similarly in dyslexic and control children. We found higher N2 amplitude for coherent compared to random motion in the right hemisphere for controls but not for dyslexics. This effect was related to topographical differences of N2 amplitude for random motion between the studied groups and was accompanied by longer reaction times to random motion in dyslexic compared to control children. Furthermore, a negative correlation between the amplitude of N2 for random motion and spelling errors was observed in both groups, which is consistent with previous findings linking the magnocellular-dorsal (MD) pathway with orthographic skills. These data support the hypothesis of subtle deficiencies in the MD pathway in dyslexia. PMID- 21676107 TI - Prenatal cigarette exposure and infant learning stimulation as predictors of cognitive control in childhood. AB - Prenatal exposures to neurotoxins and postnatal parenting practices have been shown to independently predict variations in the cognitive development and emotional-behavioral well-being of infants and children. We examined the independent contributions of prenatal cigarette exposure and infant learning stimulation, as well as their inter-relationships in predicting variations in the proficiency of executive attention, a core element of cognitive control and self regulation. Participants were an ethnic-racially, socio-economically diverse sample of 249 children followed from birth in the Project on Human Development in Chicago Neighborhoods. We obtained histories of prenatal exposure to alcohol, cigarettes, and other drugs, and we assessed socio-economic status and learning stimulation during a home visit when the participants were infants. In childhood we utilized the Attention Networks Test to assess the proficiency of executive attention during two home visits, one year apart. Accounting for age, SES, prenatal alcohol exposure, and baseline performance, we found that prenatal cigarette exposure impaired the speed of executive attention. Infant learning stimulation mitigated these effects, and predicted better accuracy of executive attention as well, suggestive of both protective and health promoting effects. Effect sizes for these relations, whether examined independently or by their inter-relationships, were comparable to if not greater in magnitude than the effects of age on speed and accuracy, highlighting the importance of these very early experiences in shaping the proficiency of self-regulation. Since executive attention is central to cognitive control and self-regulation, previously described relations between prenatal cigarette exposure, parenting practices, and some forms of childhood psychopathology may be contingent on how early learning stimulation contributes to the proficiency of executive attention through direct and indirect effects. Furthermore, considering the prolonged developmental trajectory of executive attention, interventions to support provision of learning stimulation may mitigate poor outcomes for some at-risk children by promoting development of more proficient executive attention. PMID- 21676109 TI - Bridging the gap between the other and me: the functional role of motor resonance and action effects in infants' imitation. AB - This paper investigates a two-stage model of infants' imitative learning from observed actions and their effects. According to this model, the observation of another person's action activates the corresponding motor code in the infants' motor repertoire (i.e. leads to motor resonance). The second process guiding imitative behavior results from the observed action effects. If the modeled action is followed by a salient action effect, the representation of this effect (i.e. perceptual code) will be associated with the activated motor code. If the infant later aims to obtain the same effect, the corresponding motor program will be activated and the model's action will therefore be imitated. Accordingly, the model assumes that for the imitation of novel actions the modeled action needs to elicit sufficient motor resonance and must be followed by a salient action effect. Using the head touch imitation paradigm, we tested these two assumptions derived from the model. To this end, we manipulated whether the actions demonstrated to the infants were or were not in the motor repertoire, i.e. elicited stronger or less strong motor resonance, and whether they were followed by salient action effects or not. The results were in line with the proposed two stage model of infants' imitative learning and suggest that motor resonance is necessary, but not sufficient for infants' imitative learning from others' actions and their effects. PMID- 21676108 TI - Shape, color and the other-race effect in the infant brain. AB - The 'other-race' effect describes the phenomenon in which faces are difficult to distinguish from one another if they belong to an ethnic or racial group to which the observer has had little exposure. Adult observers typically display multiple forms of recognition error for other-race faces, and infants exhibit behavioral evidence of a developing other-race effect at about 9 months of age. The neural correlates of the adult other-race effect have been identified using ERPs and fMRI, but the effects of racial category on infants' neural response to face stimuli have to date not been described. We examine two distinct components of the infant ERP response to human faces and demonstrate through the use of computer-generated 'hybrid' faces that the observed other-race effect is not the result of low-level sensitivity to 3D shape and color differences between the stimuli. Rather, differential processing depends critically on the joint encoding of race-specific features. PMID- 21676110 TI - Controlling attention to gaze and arrows in childhood: an fMRI study of typical development and Autism Spectrum Disorders. AB - Functional magnetic resonance imaging was used to examine functional anatomy of attention to social (eye gaze) and nonsocial (arrow) communicative stimuli in late childhood and in a disorder defined by atypical processing of social stimuli, Autism Spectrum Disorders (ASD). Children responded to a target word ('LEFT'/'RIGHT') in the context of a distracting arrow or averted gaze pointing in a direction that was congruent, incongruent, or neutral (bar without arrowheads, central gaze) relative to the target word. Despite being irrelevant to the target task, both arrow and averted gaze facilitated responses (Congruent vs. Neutral trials) to the same extent in the two groups and led to interference (Incongruent vs. Congruent trials), which was greater from arrows in ASD than control children. In the brain, interaction between group and distracter-domain was observed in frontal-temporal regions during facilitation and frontal-striatal regions during interference. During facilitation, regions associated with attention to gaze in control children (left superior temporal sulcus, premotor) were associated with attention to arrows in ASD children; gaze was associated with medial temporal involvement in ASD children. During interference, regions associated with arrows in control children (anterior cingulate, right caudate) were activated in response to gaze in ASD children; further, left dorsolateral prefrontal cortex, a region not observed in control children, was activated during gaze-interference in ASD children. Thus, functional anatomy was atypical in ASD children during spontaneous processing of social and nonsocial communicative cues. PMID- 21676112 TI - Caution: critical illness policies. PMID- 21676111 TI - Toddlers use speech disfluencies to predict speakers' referential intentions. AB - The ability to infer the referential intentions of speakers is a crucial part of learning a language. Previous research has uncovered various contextual and social cues that children may use to do this. Here we provide the first evidence that children also use speech disfluencies to infer speaker intention. Disfluencies (e.g. filled pauses 'uh' and 'um') occur in predictable locations, such as before infrequent or discourse-new words. We conducted an eye-tracking study to investigate whether young children can make use of this distributional information in order to predict a speaker's intended referent. Our results reveal that young children (ages 2;4 to 2;8) reliably attend to speech disfluencies early in lexical development and are able to use disfluencies in online comprehension to infer speaker intention in advance of object labeling. Our results from two groups of younger children (ages 1;8 to 2;2 and 1;4 to 1;8) suggest that this ability emerges around age 2. PMID- 21676113 TI - Death: the ultimate clinical diagnosis. PMID- 21676115 TI - Managed clinical networks: scope, evidence and feasibility. PMID- 21676114 TI - Bleeding risk with oral anticoagulation--new frontiers and new questions. PMID- 21676116 TI - A renaissance for cardio-metabolic surgery: better outcomes and lower costs? PMID- 21676117 TI - Adherence to lipid-lowering agents among 11,042 patients in clinical practice. AB - AIMS: Dyslipidaemia is a poorly-controlled condition in clinical practice largely because of poor adherence to medication regimens by patients. This study evaluated the levels of and factors associated with adherence to lipid-lowering agents in a large Chinese population. METHODS: From a validated clinical database, we included all patients who attended any public, primary care clinics in one large Territory of Hong Kong for medication refill at least twice during the study period January 2004 to June 2007. The major outcome variable was Medication Possession Ratio (MPR), an internationally-recognised metric to measure drug adherence. The factors associated with optimal drug adherence (MPR >= 0.8) were evaluated by multivariate regression analysis. RESULTS: From 11,042 eligible patients, 90% were adherent. After adjusting for patients' age, gender, socioeconomic status, service type, district of residence, visit type (new visits vs. follow-up visits), the number of comorbidities and the drug class (statin vs. fibrates), older patients [aged 50-59 years; adjusted odds ratio (AOR) 1.30, p = 0.009; 60-69 years; AOR 1.53, p < 0.001; >= 70 years; AOR 1.72, p < 0.001], attendance in family medicine specialist clinics (FMSC; AOR 1.56, p < 0.001), follow-up visits (AOR 2.93, p < 0.001) and the presence of comorbidities (one comorbidity; AOR 1.45, p < 0.001; >= 2 comorbidities; AOR 1.56, p < 0.001) were associated with optimal drug adherence. DISCUSSION AND CONCLUSION: These findings carry an implication that younger subjects, new patients, visitors in clinics other than FMSC and those without comorbidities should receive more meticulous monitoring of their medication-taking behaviour. Future studies should evaluate the major reasons for non-adherence among them. PMID- 21676118 TI - Are the risk factors listed in warfarin prescribing information associated with anticoagulation-related bleeding? A systematic literature review. AB - Warfarin significantly reduces thromboembolic risk, but perceptions of associated bleeding risk limit its use. The evidence supporting the association between bleeding and individual patient risks factors is unclear. This systematic review aims to determine the strength of evidence supporting an accentuated bleeding risk when patients with risk factors listed in the warfarin prescribing information are prescribed the drug. A systematic literature search of MEDLINE and Cochrane CENTRAL was conducted to identify studies reporting multivariate relationships between prespecified covariates and the risk of bleeding in patients receiving warfarin. The prespecified covariates were identified based on patient characteristics for bleeding listed in the warfarin package insert. Each covariate was evaluated for its association with specific types of bleeding. The quality of individual evaluations was rated as 'good', 'fair' or 'poor' using methods consistent with those recommended by the Agency for Healthcare Research and Quality (AHRQ). Overall strength of evidence was determined using the Grading of Recommendations Assessment, Development (GRADE) criteria and categorised as 'insufficient', 'very low', 'low', 'moderate' or 'high'. Thirty-four studies, reporting 134 multivariate evaluations of the association between a covariate and bleeding risk were identified. The majority of evaluations had a low strength of evidence for the association between covariates and bleeding and none had a high strength of evidence. Malignancy and renal insufficiency were the only two covariates that had a moderate strength of evidence for their association with major and minor bleeding respectively. The associations between covariates listed in the warfarin prescribing information and increased bleeding risk are not well supported by the medical literature. PMID- 21676119 TI - Budesonide/formoterol vs. salmeterol/fluticasone in COPD: a systematic review and adjusted indirect comparison of pneumonia in randomised controlled trials. AB - AIMS: This analysis was designed to provide a comparison between budesonide/formoterol and salmeterol/fluticasone for the relative incidence of pneumonia adverse events, pneumonia serious adverse events and pneumonia-related mortality in patients being treated for chronic obstructive pulmonary disease. METHODS: An initial literature search revealed no suitable head-to-head trials between budesonide/formoterol and salmeterol/fluticasone and therefore a systematic review was conducted to find randomised controlled trials providing data for input into an adjusted indirect comparison of the two combination treatments using placebo as a common comparator. The Bucher adjusted indirect comparison method was used to calculate odds ratios and 95% confidence intervals. RESULTS: Eight salmeterol/fluticasone trials and four budesonide/formoterol trials were identified as being relevant for the analyses. The proportion of patients experiencing a pneumonia adverse event was significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.47; 95% confidence interval, 0.28-0.80). The proportion of patients experiencing a pneumonia serious adverse event was also significantly lower with budesonide/formoterol than salmeterol/fluticasone (odds ratio, 0.41; 95% confidence interval, 0.19-0.86). However, there were too few events to draw any firm conclusions on pneumonia-related mortality. CONCLUSIONS: The results of the indirect comparison support the hypothesis that budesonide/formoterol is associated with fewer pneumonia events than salmeterol/fluticasone in chronic obstructive pulmonary disease. The limitations of the analysis are that the results from a single study, TORCH, have a large bearing on the overall findings of the analysis, and that there is heterogeneity in the length and the dosing of the included studies, although it does not appear that heterogeneity affected the reported results. Another important limitation is the lack of predefined diagnostic standards for pneumonia in these studies. PMID- 21676120 TI - Application of antimicrobial stewardship to optimise management of community acquired pneumonia. AB - The aim of this study was to review the application of antimicrobial stewardship principles to the management of community-acquired pneumonia (CAP). Data from 14 published clinical studies, meta-analyses and practice guidelines regarding the application of antimicrobial stewardship strategies to the management of CAP were identified and analysed. In the context of CAP, application of stewardship strategies (alone or in combination) has been shown to increase physician awareness of guidelines, improve appropriate antimicrobial use and reduce unnecessary antimicrobial prescribing. In addition, application has had a profound favourable impact on patient outcomes, including decreased 30-day mortality and in-hospital mortality rates, reduced length of hospital stay, reduced treatment failure rates and reduced healthcare costs. Antimicrobial stewardship programmes have been demonstrated to successfully increase the level of appropriate antibiotic prescribing, reduce pathogen resistance and improve clinical outcomes in the management of CAP within hospitals. Studies have also shown that adherence to evidence-based guidelines, even at the level of the individual clinician, can have a profound and positive impact on patient outcomes and healthcare costs. Adherence to evidence-based guidelines can have a profound and positive impact on patient outcomes and healthcare costs. PMID- 21676121 TI - Prevalence and detection rate of underlying disease in men with erectile dysfunction receiving phosphodiesterase type 5 inhibitors in the United Kingdom: a retrospective database study. AB - AIM: To determine the rate of newly detected underlying disease in men receiving their first (index) phosphodiesterase type 5 inhibitor (PDE5i) prescription. METHODS: This non-interventional, retrospective study used anonymised patient records from UK general practices identified from the THIN database. Records of men aged >= 18 years, who received an index PDE5i prescription between January 1999 and June 2008 and with a continuous medical history (>= 60 months) before the index prescription were included. Primary end-points were the prevalence of underlying disease prior to the index prescription and to establish the detection rate, defined as cumulative incidence of such a diagnosis in the 3 months following the index prescription. Assessments included comparison with age matched controls, comparison with identical time periods immediately before and 1 year after, index prescription, and changes over time during the study period. Descriptive statistics, analysis of proportions and multivariate logistic regression analysis were used. RESULTS: Among the 24,708 patients receiving a PDE5i, the prevalence of any underlying diagnosis before the index prescription was 70.23%; prevalence of vasculogenic disease was highest (48.20%). The detection rate of any underlying disease was 11.53%, and again highest for vasculogenic disease (4.07%). Compared with an age-matched control population, the additional detection rate of an unknown underlying disease at PDE5i prescription was 45 for hypertension, 61 for hypercholesterolaemia, 38 for diabetes and 5 for hypogonadism per 10,000 men. CONCLUSION: Only a minority of men with erectile dysfunction have a previously undiagnosed important underlying disease that is uncovered at the time of an initial PDE5i prescription by a GP. PMID- 21676122 TI - Deaths after chiropractic: a comment. PMID- 21676124 TI - Screening for the detection of impaired fasting glucose, impaired glucose tolerance and type 2 diabetes in welfare homes residents from south-eastern region of Poland. PMID- 21676125 TI - The lithiumeter: a measured approach. AB - BACKGROUND: Lithium has long been recognised for its mood-stabilizing effects in the management of bipolar disorder (BD) but in practice its use has been limited because of real and 'imagined' concerns. This article addresses the need for lithium to be measured with respect to its clinical and functional effects. It introduces a visual scale, termed lithiumeter, which captures the optimal lithium plasma levels for the treatment of BD. METHODS: Key words pertaining to lithium's administration, dosing, and side effects as well as its efficacy in acute and long-term treatment of BD were used to conduct an electronic search of the literature. Relevant articles were identified by the authors and reviewed. RESULTS: This paper outlines the considerations necessary prior to initiating lithium therapy and provides a guide to monitoring lithium plasma levels. Current recommendations for optimal plasma lithium levels in the management of BD are then discussed with respect to indications for use in the acute phases of the illness and maintenance therapy. The risks associated with lithium treatment are also discussed. CONCLUSIONS: The lithiumeter provides a practical guide of optimal lithium levels for the clinical management of BD. PMID- 21676126 TI - The role of disturbed sleep in the early recognition of bipolar disorder: a systematic review. AB - OBJECTIVES: Severely disturbed sleep is known to occur during and shortly prior to the onset of mood episodes in bipolar disorder. Whether alterations in sleep occur parallel and as part of the disease process or whether they represent a trait existent before the onset of the disorder itself remains unclear. METHODS: A systematic review evaluating all published data on the occurrence of disordered sleep prior to the onset of the first mood episode was conducted. RESULTS: The evidence cited within this paper suggests that sleep disturbances frequently precede bipolar disorder by several years and convey an elevated long-term risk for developing any kind of mood disorder. Disordered sleep appears to emerge about the time of puberty and remains persistently elevated in individuals at high risk. CONCLUSION: Disturbed sleep appears to be an early symptom of bipolar disorder but further research, especially longitudinal studies in individuals at high risk, will be required to characterize the type and patterns more precisely. PMID- 21676127 TI - Lithium treatment attenuates muscarinic M(1) receptor dysfunction. AB - OBJECTIVE: Altered muscarinic acetylcholine receptor levels and receptor-coupled signaling processes have been reported in mood disorders. M(1) , one of five muscarinic receptor subtypes, couples to the phospholipase C/protein kinase C and extracellular signal-regulated kinase (ERK) pathways. Mood stabilizers regulate these pathways. MicroRNAs (miRNAs) are small noncoding RNAs that suppress translation in a sequence-selective manner. Lithium downregulates several miRNAs, including let-7b and let-7c. One predicted target of let-7b and let-7c is the M(1) receptor. We hypothesized that miRNAs regulate M(1) receptor translation, and that disrupted M(1) expression leads to aberrant behaviors and disrupted downstream signaling pathways that are rescued by lithium treatment. METHODS: The effects of miRNAs and chronic treatment with mood stabilizers on M(1) levels were tested in primary cultures and in rat frontal cortex. Effects of M(1) ablation and chronic treatment with mood stabilizers on several signaling cascades and M(1) -modulated behaviors were examined in wild-type and M(1) knockout mice. RESULTS: Let-7b, but not let-7c, negatively regulated M(1) levels. Chronic treatment with lithium, but not valproate, increased M(1) levels in the rat cortex. M(1) knockout mice exhibit ERK pathway deficits and behavioral hyperactivity; chronic treatment with lithium attenuated these deficits and hyperactivity. CONCLUSIONS: Lithium treatment can affect M(1) receptor function through intracellular signaling enhancement and, in situations without M(1) ablation, concomitant receptor upregulation via mechanisms involving miRNAs. Muscarinic dysfunction may contribute to mood disorders, while M(1) receptors and the downstream ERK pathway may serve as potential therapeutic targets for alleviating manic symptoms such as psychomotor hyperactivity. PMID- 21676128 TI - The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males. AB - OBJECTIVES: The rs10994336 ANK3 and rs1006737 CACNA1C genetic variants have recently been identified as the most consistent, genome-wide significant risk factors for bipolar disorder, while the CACNA1C variant has also been associated with schizophrenia and major depression. The aim of this study was to examine the phenotypic consequences of the risk CACNA1C and ANK3 alleles in a large homogeneous cohort of healthy young males. METHODS: We recruited 703 randomly selected, healthy army conscripts (mean age 22.1 +/- 3.0 years) from the first wave of the Learning on Genetics of Schizophrenia project in Heraklion, Crete. Of those recruited, 530 subjects entered and completed the study. Subjects were assessed for prepulse inhibition (PPI), startle reactivity, neuropsychology, and personality. RESULTS: UNPHASED analysis revealed that the rs1006737 A-allele was associated with lower extraversion and higher harm avoidance, trait anxiety, and paranoid ideation, while the rs10994336 T-allele was associated with lower novelty seeking and behavioral activation scores (p < 0.01). Both alleles were associated with high startle reactivity (p < 0.05). There were no significant associations with any cognitive task performance or PPI. CONCLUSIONS: The CACNA1C genotype was associated with proneness to anxiety and negative mood, while the ANK3 genotype was associated with proneness to anhedonia. Both risk genotypes were associated with high startle reactivity, suggesting a role of these polymorphisms in threat/stress signal processing, probably in the hippocampus and/or amygdala. None of the risk genotypes affected sensorimotor gating or behavioral performance in an extensive battery of executive function tests in this cohort of healthy males. PMID- 21676129 TI - The genetic and environmental influences of event-related gamma oscillations on bipolar disorder. AB - OBJECTIVES: Gamma oscillations have been proposed to play an important role in neural information coding. There have been a limited number of electrophysiology studies in evoked gamma band responses (GBRs) in bipolar disorder (BPD). It is also unclear whether GBR deficits, if present, are potential endophenotypes for BPD as little is known about the heritability of GBRs. The present study aimed to examine whether GBRs derived from two auditory tasks, the oddball task and the dual-click paradigm, are potential BPD endophenotypes. METHODS: A total of 308 subjects were included in this study: 198 healthy controls, 59 BPD patients (22 monozygotic BPD twins and 37 BPD patients from 31 families), and 51 unaffected relatives. The evoked gamma responses were calculated using a Morlet wavelet transformation. Structural equation modelling was applied to obtain the genetic (heritability) and environment estimates in each GBR variable and their (genetic) overlap with BPD. RESULTS: The heritability estimates of GBR to standard stimuli were 0.51 and 0.35 to target stimuli in the oddball task. However, neither response type was impaired in BPD patients or their unaffected relatives. The heritability estimates of GBR to S1 stimuli were 0.54 and 0.50 to S2 stimuli in the dual-click paradigm. BPD patients had reduced gamma power and suppression to S1 stimuli but their unaffected relatives did not. CONCLUSIONS: Evoked GBRs are heritable traits. However, GBR deficits are not observed in clinically unaffected relatives nor associated with BPD. Gamma responses do not appear to satisfy criteria for being BPD endophenotypes. PMID- 21676130 TI - A functional MRI study of working memory in adolescents and young adults at genetic risk for bipolar disorder: preliminary findings. AB - OBJECTIVES: In this report, we seek to (i) identify a potential neuroimaging endophenotype for bipolar disorder (BD) in emotion regulatory and autonomic circuitry in young first-degree relatives of persons with BD; and (ii) replicate our previous work identifying the functional neuroanatomy of working memory (WM) in an older sample of relatives of persons with BD. METHODS: Ten adolescent and young adult (age 13-24) unmedicated, non-ill, first-degree relatives of persons with BD (RELS) and 10 demographically comparable healthy controls performed a 2 back WM task and a 0-back control task during functional magnetic resonance imaging (fMRI). fMRI data were collected on a 1.5 Tesla scanner and analyzed using SPM-2. Mood was assessed on the day of scanning. RESULTS: The groups did not differ on any demographic, neuropsychological, or in-scanner task performance variables. In contrast to controls, RELS showed (i) weak task-dependent modulation activity in the cerebellar vermis (CV), insula, and amygdala/parahippocampal region, and (ii) exaggerated modulation of activity in the frontopolar cortex and brainstem, even after controlling for potential confounders. Many of the group differences were driven by differences in activity in the low-level (0-back) baseline task. CONCLUSIONS: Young, unmedicated RELS exhibited altered task-dependent modulation of frontopolar, CV, and insula activity during WM, especially during the low-level (0-back) baseline task. Results are largely consistent with our initial study of older adult RELS, suggesting these alterations may represent biomarkers of genetic risk for BD. PMID- 21676131 TI - Negative emotion impacts memory for verbal discourse in pediatric bipolar disorder. AB - OBJECTIVES: Cognitive and emotional deficits have been documented in youth with pediatric bipolar disorder (PBD); however, to date, a systematic evaluation of comprehension and memory for verbally presented information has not been conducted. The effect of emotion on comprehension and memory for verbally presented material also has not been examined. We examined whether youth with PBD have difficulty recalling the big picture (macrostructure) as well as the story details (microstructure). METHODS: A total of 35 youth with PBD and 25 healthy controls completed an Affective Story Task. A psychological processing model allowed for the examination of both the macrostructure and microstructure of language comprehension. RESULTS: Youth with PBD were capable of comprehending the gist of the stories and were not impaired by emotion when comprehending and remembering macrostructure. However, negative emotional material was found to proactively interfere with the encoding and recall of microstructure. Level of depression appeared to impact recall of microstructure, but not macrostructure. CONCLUSIONS: Negatively valenced material may impair subsequent comprehension and memory for details among youth with PBD. This deficit could impact the daily functioning of these youth, as the perception of negative affect may derail aspects of successful comprehension and learning. PMID- 21676132 TI - Multisite, open-label, prospective trial of lamotrigine for geriatric bipolar depression: a preliminary report. AB - AIMS: This is a multisite, 12-week, open-label trial of lamotrigine augmentation in 57 older adults (>= 60 years; mean +/- SD age = 66.5 +/- 6.7 years) with either type I or type II bipolar depression. METHODS: Primary outcome measure was change from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcome measures included Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Bipolar version (CGI-BP), and the WHO-Disability Assessment Schedule II (WHO-DAS II). The Udvalg for Kliniske Undersogelser (UKU) was used to assess side effects. RESULTS: A total of 77.2% of the study subjects had bipolar I disorder. The mean (SD) lamotrigine dose was 150.9 (68.5) mg/day. There was significant improvement in the MADRS, HAM-D, CGI-BP, and in most domains on the WHO-DAS II. For patients for whom final MADRS score was available: 31 (57.4%) met remission criteria and 35 (64.8%) met response criteria. There were 19/57 (33.3%) who dropped out of the study prematurely, with 6 dropouts due to adverse events (4 cases of rash, 1 manic switch, and 1 hyponatremia). Two cases of rash were possibly drug related and were resolved with drug discontinuation. The most common UKU adverse effects were reduced sleep duration (n = 14, 24.6%), weight loss (n = 12, 21.1%), increased dream activity (n = 12, 21.1%), polyuria/polydipsia (n = 11, 19.3%), weight gain (n = 9, 15.8%), diminished sexual desire (n = 9, 15.8%), increased sleep (n = 9, 15.8%), lassitude/fatigue (n = 8, 14%), and unsteady gait (n = 8, 14%). No significant changes in electrocardiogram or laboratory tests were observed. CONCLUSIONS: In bipolar depressed elders, lamotrigine was associated with improvement in depression, psychopathology, and functional status. There was a moderate number of adverse events, although relationship of adverse events (particularly falls) to study medication could not be clearly determined in this uncontrolled trial. Controlled studies are needed to further evaluate efficacy and tolerability of lamotrigine therapy in geriatric bipolar depression. PMID- 21676133 TI - Quality of life and impulsivity in bipolar disorder. AB - OBJECTIVES: Bipolar disorder (BD) is a chronic psychiatric illness that impairs quality of life (QoL) in numerous life domains even when mood symptoms are not present and is characterized by elevated impulsivity. Many of the comorbid conditions that are associated with diminished QoL in BD also involve impulsivity. The objective of this project was to investigate whether impulsivity might mediate the effects of these comorbid conditions on poor QoL. METHODS: A total of 76 participants diagnosed with bipolar I disorder by the Structured Clinical Interview for DSM-IV Axis I disorders completed the Quality of Life in Bipolar Disorder (QoL-BD) scale, the Barratt Impulsivity Scale (BIS-11), and the Positive Urgency Measure (PUM). Participants were also assessed for comorbid DSM IV diagnoses of anxiety, substance use, and impulse control disorders. RESULTS: Several subscales of the BIS-11 as well as the PUM total score were significantly negatively correlated with overall QoL. PUM total score remained a significant predictor of QoL after controlling for comorbid anxiety, substance use, and impulse control disorders. After controlling for impulsivity, comorbid disorders were no longer significantly related to overall QoL. CONCLUSIONS: The data support the hypothesis that impulsivity, specifically positive urgency, is highly correlated with QoL in BD. Impulsivity was found to mediate the relation between QoL and several comorbidities in BD. Interventions targeting impulsivity might help to improve QoL in BD. PMID- 21676135 TI - Impact of an educational program on the management of bipolar disorder in primary care. AB - OBJECTIVE: Government agencies and industry have recently undertaken educational programs for the management of bipolar disorder in primary care, but their medical impact is not well known. Therefore, we conducted a survey among general practitioners to evaluate the impact of the Bipolact Educational Program on the diagnosis and treatment of bipolar disorder. METHODS: A total of 45 general practitioners attending the Bipolact Educational Program (trained group) were compared with a control group of 50 untrained general practitioners on their ability to: (i) diagnose bipolar I and II disorders and (ii) treat bipolar disorder patients appropriately. RESULTS: Trained physicians, but not untrained physicians, showed a significant improvement (p < 0.0001, chi-square test) in the ability to identify patients as having bipolar I (from 10.4% to 28.8%) and bipolar II disorder (from 20.1% to 45.8%). This trend resulted in a strong decrease in nonidentified bipolar disorder patients (from 64.6% to 19.5%). Trained physicians, but not the untrained group, greatly increased the number of prescriptions for mood stabilizers for bipolar disorder patients, from 25.6% to 43.2% (p = 0.0013, chi-square test). Finally, trained physicians reduced the number of antidepressant prescriptions for bipolar disorder patients (the control group also reduced the number of antidepressant prescriptions, suggesting some bias in the survey). CONCLUSION: A well-designed education package on diagnosis and management of bipolar disorder greatly increased the likelihood of physicians correctly assigning a subtype, namely bipolar I or bipolar II disorder, to patients already perceived as having some form of bipolar illness, and to prescribing mood stabilizers instead of antidepressants to these patients. PMID- 21676136 TI - Valuing teamwork: Insights from newly-registered nurses working in specialist mental health services. AB - In this qualitative study, the experiences of a small cohort of registered nurses (RN) during the first 2 years of mental health employment were documented. A total of 13 semistructured interviews were completed from within a specialist mental health setting. Eleven issues were identified: (i) teamwork; (ii) experiential learning; (iii) self-development; (iv) confidence; (v) listening; (vi) rapport; (vii) keen observation; (viii) patience; (ix) empathy; (x) learning from colleagues; and (xi) maintaining a positive approach towards patients. The nurses focused on the here-and-now circumstances, rather than on future plans, or past preparation, and were able to elucidate the qualities and skills that they brought to their clinical work. Participants were most proud of achievements that bridged the personal and professional, such as self-development, working closely with patients to develop rapport, experiential learning, and teamwork. Findings highlight the importance of teamwork to newly-graduated RN entering the mental health environment. It is known that teamwork can convey a sense of belonging and help create an environment in which applied experiential clinical learning can occur. Therefore, it is important that efforts are made to facilitate team building and opportunities for teamwork when new graduates are transitioning into the mental health clinical practice environment. PMID- 21676134 TI - Menstrual effects on mood symptoms in treated women with bipolar disorder. AB - OBJECTIVES: Reports suggest women with bipolar disorder (BD) have high rates of perimenstrual mood worsening. In this prospective study, the authors compared healthy controls and depressed and euthymic BD patients on medications on mood levels, psychosocial function, and physical symptoms in the late luteal versus the early follicular phase. METHODS: At baseline, the lifetime diagnosis of bipolar I disorder or bipolar II disorder, current mood episode, and absence of premenstrual dysphoric disorder in controls were confirmed with the Structured Clinical Interview for DSM-IV Disorders. Subjects were assessed across three menstrual cycles during the late luteal and early follicular phases. Clinicians administered the Structured Interview Guide for the Hamilton Depression Rating Scale and the Mania Rating Scale to assess levels of depression and hypomania/mania, respectively. Subjects completed self-report ratings on psychosocial function and perceived stress and tracked daily mood and physical symptoms on the National Institute of Mental Health LifeChart and the Daily Rating Form. Ovulation was verified objectively with mid-cycle luteinizing hormone urine dipsticks and serum progesterone levels. RESULTS: The sample characteristics were similar among the three patient groups of healthy controls (n = 10), BD-euthymic (n = 6), and BD-depressed (n = 5). The two-way analysis of variance indicated a significant difference among the diagnostic groups on depression scores, psychosocial functioning, and levels of perceived stress. There was no significant difference for menstrual phase or the interaction of menstrual phase by diagnostic group. CONCLUSIONS: Mood symptom level, psychosocial functioning, perceived stress, and physical discomfort were unrelated to menstrual phase in patients with BD. Appropriate maintenance treatment may prevent menstrual related mood symptoms. Use of an objective marker of ovulation is critical for research involving menstrual related outcomes. PMID- 21676137 TI - Constructivism applied to psychiatric-mental health nursing: an alternative to supplement traditional clinical education. AB - With the popularity of accelerated pre-licensure nursing programmes and the growth in nursing student enrolments, traditional clinical education continues to be a challenge to deliver. Nursing faculty members are required to develop and implement educational innovations that achieve effective learning outcomes, while using fewer resources. The purpose of this qualitative study was to explore the effectiveness of a constructivism-based learning project to achieve specific learning outcomes and to supplement approximately 30 clinical hours in a psychiatric-mental health nursing course. Students participated in a 10-week, multistage project that examined life histories, treatment resources, and evidence-based practice, as applied to a single individual with a mental illness. Students reported increased understanding of mental health and illness, developed personal relevance associated with the knowledge gained, and learned to problem solve with regard to nursing care of individuals diagnosed with mental illness. For many students, there also appeared to be a reduction in stigmatized attitudes towards mental illness. Constructivism-based learning is a promising alternative to supplement clinical hours, while effectively achieving learning outcomes. Future research is needed to further validate the use of this method for the learning of course content, as well as the reduction of stigma. PMID- 21676139 TI - When two plus two must not equal four. PMID- 21676140 TI - Prevalence of antimicrobial resistance in intestinal flora of patients undergoing prostatic biopsy: implications for prophylaxis and treatment of infections after biopsy. PMID- 21676143 TI - A consultant-delivered acute urology service: reducing length of stay and improving quality of service. PMID- 21676144 TI - Closing the deal: renorrhaphy during laparoscopic and robotic partial nephrectomy. PMID- 21676145 TI - The evaluation and treatment of nocturia: a consensus statement. AB - What's known on the subject? and What does the study add? Nocturia is currently defined by the International Continence Society (ICS) as the complaint that an individual has to wake at night one or more times to void. It is, however, an underreported, understudied, and infrequently recognized problem in adults. Many factors may contribute to nocturia which are treatable, yet patients do not seek care or the condition may not be identified by providers. This paper aims to help healthcare providers better serve patients who are experiencing nocturia by summarizing current research, clinical approaches, and treatment options. The results of the conference provide a balanced evaluation of the full treatment armamentarium capable of meeting the needs of patients with the manifold causes of nocturia such as nocturnal polyuria, overactive bladder, or benign prostatic hyperplasia. PMID- 21676146 TI - Trends in the care of radical prostatectomy in the United States from 2003 to 2006. PMID- 21676147 TI - Mid-term results for the retroluminar transobturator sling suspension for stress urinary incontinence after prostatectomy. PMID- 21676148 TI - Mid-term results for the retroluminar transobturator sling suspension for stress urinary incontinence after prostatectomy. PMID- 21676149 TI - Elisabeth of Austria (1839-1898). PMID- 21676152 TI - Effects of dietary fibre on subjective appetite, energy intake and body weight: a systematic review of randomized controlled trials. AB - Dietary fibres are believed to reduce subjective appetite, energy intake and body weight. However, different types of dietary fibre may affect these outcomes differently. The aim of this review was to systematically investigate the available literature on the relationship between dietary fibre types, appetite, acute and long-term energy intake, and body weight. Fibres were grouped according to chemical structure and physicochemical properties (viscosity, solubility and fermentability). Effect rates were calculated as the proportion of all fibre control comparisons that reduced appetite (n = 58 comparisons), acute energy intake (n = 26), long-term energy intake (n = 38) or body weight (n = 66). For appetite, acute energy intake, long-term energy intake and body weight, there were clear differences in effect rates depending on chemical structure. Interestingly, fibres characterized as being more viscous (e.g. pectins, beta glucans and guar gum) reduced appetite more often than those less viscous fibres (59% vs. 14%), which also applied to acute energy intake (69% vs. 30%). Overall, effects on energy intake and body weight were relatively small, and distinct dose response relationships were not observed. Short- and long-term effects of dietary fibres appear to differ and multiple mechanisms relating to their different physicochemical properties seem to interplay. This warrants further exploration. PMID- 21676153 TI - A systematic review of the validity and reliability of sedentary behaviour measures used with children and adolescents. AB - The aim of this review was to evaluate the reliability and validity of methods used to assess the multiple components of sedentary behaviour (i.e. screen time, sitting, not moving and existing at low energy expenditure) in children and adolescents. Twenty-six studies met our inclusion criteria and were reviewed. Thirteen studies reported the reliability of self- and proxy-report measures of sedentary behaviour and seven of these were found to have acceptable test-retest reliability. Evidence for the criterion validity of self- and proxy-report measures was examined in three studies with mixed results. Seven studies examined the reliability and/or validity of direct observation and the findings were generally positive. Five studies demonstrated the utility of accelerometers to accurately classify sedentary behaviour. Self-report measures provide reliable estimates of screen time, yet their validity remains largely untested. While accelerometers can accurately classify participants' behaviour as sedentary, they do not provide information about type of sedentary behaviour or context. Studies utilizing measures of sedentary behaviour need to more adequately report on the validity and reliability of the measures used. We recommend the use of objective measures of sedentary behaviour such as accelerometers, in conjunction with subjective measures (e.g. self-report), to assess type and context of behaviour. PMID- 21676151 TI - The neurocognitive connection between physical activity and eating behaviour. AB - As obesity rates increase worldwide, healthcare providers require methods to instill the lifestyle behaviours necessary for sustainable weight loss. Designing effective weight-loss interventions requires an understanding of how these behaviours are elicited, how they relate to each other and whether they are supported by common neurocognitive mechanisms. This may provide valuable insights to optimize existing interventions and develop novel approaches to weight control. Researchers have begun to investigate the neurocognitive underpinnings of eating behaviour and the impact of physical activity on cognition and the brain. This review attempts to bring these somewhat disparate, yet interrelated lines of literature together in order to examine a hypothesis that eating behaviour and physical activity share a common neurocognitive link. The link pertains to executive functions, which rely on brain circuits located in the prefrontal cortex. These advanced cognitive processes are of limited capacity and undergo relentless strain in the current obesogenic environment. The increased demand on these neurocognitive resources as well as their overuse and/or impairment may facilitate impulses to over-eat, contributing to weight gain and obesity. This impulsive eating drive may be counteracted by physical activity due to its enhancement of neurocognitive resources for executive functions and goal oriented behaviour. By enhancing the resources that facilitate 'top-down' inhibitory control, increased physical activity may help compensate and suppress the hedonic drive to over-eat. Understanding how physical activity and eating behaviours interact on a neurocognitive level may help to maintain a healthy lifestyle in an obesogenic environment. PMID- 21676154 TI - Carbamazepine and the active epoxide metabolite are effectively cleared by hemodialysis followed by continuous venovenous hemodialysis in an acute overdose. AB - Hemodialysis (HD) and continuous venovenous hemodialysis (CVVHD) have an unproven role in the management of carbamazepine overdose. Albumin-enhanced CVVHD may accelerate carbamazepine (CBZ) clearance, but no pharmacokinetic data has been reported for traditional CVVHD without albumin enhancement. In addition, it is unclear whether the active CBZ-epoxide metabolite is removed with either mode of dialysis. We present a case of CBZ intoxication successfully managed with sequential HD and CVVHD. The CBZ half-life during CVVHD was 14.7 hours, compared with the patient's endogenous half-life of 30.8 hours. The CBZ-epoxide half-life was 3.2 hours during HD. We conclude that HD and CVVHD provide effective clearance of CBZ and the epoxide metabolite and should be considered in the management of an acute toxic ingestion. PMID- 21676155 TI - Prescription drug monitoring programs serve a vital clinical need. PMID- 21676156 TI - The experience of and coping with lumbopelvic pain among pregnant women in Taiwan. AB - OBJECTIVES: 1) To replicate and extend previous research on the prevalence and characteristics of pregnancy-related lumbopelvic pain, and 2) to examine the associations between pain intensity, pain interference, and pain coping strategies in a sample of women with pregnancy-related lumbopelvic pain. DESIGN: Cross-sectional design. SETTING: An academic public and urban medical center in Taiwan. PATIENTS: Pregnant women without gestational or psychiatric diseases in the 35th to 41st gestational week. INTERVENTIONS: N/A. OUTCOME MEASURES: Questionnaires were used to collect data on demographics, pain intensity, pain interference, and pain coping responses. RESULTS: Of 230 consecutive cases scheduled for an outpatient obstetrics-gynecology clinic appointment, 187 agreed to participate in this study. One hundred and forty (74.9%) of these reported pregnancy-related lumbopelvic pain. Most participants with pain reported it as mild to moderate in severity and that the pain interfered with a number of daily activities. The coping responses used most often for pain management included rest (94.3%), task persistence (87.9%), and asking for assistance (87.1%). CONCLUSION: The results confirmed that pregnancy-related lumbopelvic pain is a common problem that interferes with important activities. Pregnant women use a number of coping strategies to manage lumbopelvic pain. A common use of passive coping responses such as rest and asking for assistance suggest the possibility of a helplessness phenomenon in response to pain among some of the study participants. Education and interventions targeting this may be warranted to minimize the chances that the lumbopelvic pain experienced during pregnancy will develop into a chronic pain problem over time. PMID- 21676157 TI - Medial branch blocks and fresh vertebral compression fractures. AB - Article: Bogduk Nikolai, MacVicar J, Borowczyk J. The pain of vertebral compression fractures can arise in the posterior elements. Pain Med 2010;11:1666 73. PMID- 21676159 TI - 26. Pain in chronic pancreatitis. AB - Chronic pancreatitis is defined as a progressive inflammatory response of the pancreas that has lead to irreversible morphological changes of the parenchyma (fibrosis, loss of acini and islets of Langerhans, and formation of pancreatic stones) as well as of the pancreatic duct (stenosis and pancreatic stones). Pain is one of the most important symptoms of chronic pancreatitis. The pathogenesis of this pain can only partly be explained and it is therefore often difficult to treat this symptom. The management of pain induced by chronic pancreatitis starts with lifestyle changes and analgesics. For the pharmacological management, the three-step ladder of the World Health Organization extended with the use of co analgesics is followed. Interventional pain management may consist of radiofrequency treatment of the nervi splanchnici, spinal cord stimulation, endoscopic stenting or stone extraction possibly in combination with lithotripsy, and surgery. To date, there are no randomized controlled trials supporting the efficacy of radiofrequency and spinal cord stimulation. The large published series reports justify a recommendation to consider these treatment options. Radiofrequency treatment, being less invasive than spinal cord stimulation, could be tested prior to considering spinal cord stimulation. There are several other treatment possibilities such as endoscopic or surgical treatment, pancreatic enzyme supplementation and administration of octreotide and antioxidants. All may have a role in the management of pain induced by chronic pancreatitis. PMID- 21676160 TI - Successful reversal of hyperalgesia/myoclonus complex with low-dose ketamine infusion. AB - We report the successful use of low-dose ketamine infusion for treating a severe episode of painful myoclonus in the lower extremities, associated with opioid induced hyperalgesia (OIH), in a patient who was receiving long-term, high dose intrathecal hydromorphone therapy. A low-dose ketamine infusion immediately relieved the painful myoclonus. It also enabled a reduction in the intrathecal opioid dosage leading to a resolution of the acute symptoms attributed to OIH. PMID- 21676161 TI - Continuous multimechanistic postoperative analgesia: a rationale for transitioning from intravenous acetaminophen and opioids to oral formulations. AB - Good surgical outcomes depend in part on good pain relief, allowing for early mobilization, optimal recovery, and patient satisfaction. Postsurgical pain has multiple mechanisms, and multimechanistic approaches to postoperative analgesia are recommended and may be associated with improved pain relief, lowered opioid doses, and sometimes a lower rate of opioid-associated side effects. Acetaminophen (paracetamol) is a familiar agent for treating many types of pain, including postsurgical pain. Oral acetaminophen has been shown to be safe and effective in a variety of acute pain models. Combination products using a fixed dose of acetaminophen and an opioid have also been effective in treating postsurgical pain. Combination products with acetaminophen have demonstrated an opioid-sparing effect, which inconsistently results in a reduced rate of opioid associated side effects. Intravenous (IV) acetaminophen and an opioid analgesic administered in the perioperative period may be followed by an oral acetaminophen and opioid combination in the postoperative period. Transitioning from an IV acetaminophen and opioid formulation to a similar but oral formulation of the same drugs appears to be a reasonable step in that both analgesic therapies are known to be safe and effective. For postsurgical analgesia with any acetaminophen product, patient education is necessary to be sure that the patient does not concurrently take any over-the-counter products containing acetaminophen and accidentally exceed dose limits. PMID- 21676162 TI - High doses of topical amitriptyline in neuropathic pain: two cases and literature review. AB - Severe chronic neuropathic pain is a challenge to treat, and due to adverse effects of classical oral medication, optimal and effective dose levels are difficult to reach. Therefore, administration of topical analgesics might be an option, due to reduced adverse effects, and increased patient compliance. The aim of this article is to describe two cases treated effectively with topical amitriptyline 5% and 10%, the highest dosage described to date. The first patient was a 39-year-old man, suffering from severe intractable neuropathic pain in feet and hands, due to diabetes mellitus type II (DM-II). After application of amitriptyline 5% the patient experienced a complete relieve only in the hands, whereas after application of amitriptyline 10%, a total reduction of pain occurred within 20 minutes, lasting the whole day. The second patient was a 57 year-old man, suffering for 10 years from progressive sensory disturbances in both feet and increasing pain due to chronic idiopathic axonal polyneuropathy (CIAP). Amitriptyline 5% cream reduced pain in the toes nearly completely, but this was not the case in the heels. Amitriptyline 10% reduced pain in the feet, however, systemic adverse effects occurred, mainly drowsiness. The patient decided to stop topical treatment because of these adverse effects. These two cases suggest an analgesic dose-response effect of topical amitriptyline in painful neuropathy. Systemic adverse effects should be taken into account. PMID- 21676163 TI - Health care costs in patients with painful diabetic peripheral neuropathy prescribed pregabalin or duloxetine. AB - BACKGROUND: Pregabalin and duloxetine are two FDA-approved medications for the treatment of pain associated with diabetic peripheral neuropathy (pDPN). The objective of this study was to compare changes in all-cause and pDPN-related health care costs in patients with pDPN initiated on pregabalin or duloxetine. METHODS: Patients at least 18 years of age initiating pregabalin or duloxetine between March 1, 2006 and December 31, 2008 were identified from a large U.S. managed care plan database. The date of the first pregabalin or duloxetine prescription was defined as the index date. Patients with claims-based evidence of pDPN and who had continuous enrollment for 6-month pre- and post-index periods were selected for study inclusion. Duloxetine patients with depression or generalized anxiety disorder (GAD) were excluded. All-cause and pDPN-related total health care costs (over 6 month pre-index and post-index periods) were analyzed with difference-in-differences (DiD) models. RESULTS: A total of 2,136 patients (1,785 pregabalin and 351 duloxetine) were identified. No significant differences in gender, age, or pre-index Quan-Charlson comorbidity score were observed between the two cohorts. No significant differences (pregabalin vs. duloxetine) in pre-index to post-index change in mean all-cause health care costs ($1,411 vs. $1,560, P = 0.93) or mean pDPN-related health care costs ($704 vs. $240, P = 0.22) were found. The DiD models showed no significant difference in all-cause (mean) costs attributable to pregabalin vs. duloxetine therapy between pre-index and post-index periods (mean cost ratio = 0.97, 95% CI: 0.75 to 1.26), but showed that patients receiving pregabalin had a significantly higher increase in pDPN-related costs compared with patients receiving duloxetine (mean cost ratio = 2.35, 95% CI: 1.01 to 5.46). However, the difference (pre- to post-index) in pDPN-related costs attributable to pregabalin vs. duloxetine therapy was nonsignificant (mean cost ratio = 2.30, 95% CI: 0.93 to 5.68) in a sensitivity analysis in which patients with depression and GAD were excluded from both cohorts. CONCLUSION: No differences were noted in all-cause costs attributable to pregabalin or duloxetine. Although patients receiving pregabalin had a significantly greater pre- to post-index increase in pDPN-related health care costs compared with patients receiving duloxetine, this may have been due to an imbalance in patient exclusion criteria between cohorts. PMID- 21676164 TI - HLA-B*1502 strongly predicts carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Thai patients with neuropathic pain. AB - BACKGROUND: Carbamazepine (CBZ) is one of the standard pharmacological treatments for neuropathic pain. However, its serious adverse drug reactions include Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, HLA-B*1502 allele was implicated as a genetic marker of CBZ-induced SJS/TEN in some Asian epilepsy populations. METHODS: This is a case control study to describe the clinical characteristics of SJS/TEN in Thai patients with neuropathic pain who were treated with CBZ, and to determine the association of HLA-B*1502 in these patients, comparing with those who exposed to CBZ for at least 6 months without any cutaneous reactions. RESULTS: Thirty-four SJS/TEN patients and 40 control patients were included in this study. Mean age of SJS/TEN patients was 47 years. SJS/TEN was developed in 10.8 +/- 1.4 days after initiation of CBZ. HLA-B*1502 allele was found in 32 of 34 SJS/TEN patients (94.1%) but it was found only in 7 of 40 control patients (17.5%). The association was very strong with an odds ratio of 75.4. Sensitivity and specificity of this HLA-B*1502 genotype test were 94.1% and 82.5%, respectively, while the positive predictive value and negative predictive value were 1.43% and 99.98%, respectively. Positive and negative likelihood ratios were 5.37 and 0.07, respectively. CONCLUSIONS: HLA-B*1502 is a strong genetic marker for CBZ-induced SJS/TEN in Thai patients with neuropathic pain. The screening for this marker should be performed prior to initiation of CBZ treatment to assess the risk of this serious side effect. PMID- 21676166 TI - Long-term results of percutaneous lumbar decompression mild((r)) for spinal stenosis. AB - BACKGROUND: Lumbar spinal stenosis (LSS) generally occurs from a combination of degenerative changes occurring in the lumbar spine. These include hypertrophy of ligamentum flavum, facet joint arthritic changes and bulging of the intervertebral disk. Spinal stenosis leads to compression of the lumbar neural elements (cauda equina), which manifests as low back and leg pain especially on standing and walking known as "neurogenic claudication." Current treatment options for LSS are varied. Conservative management, including physical therapy with/without epidural steroid injections, may be adequate for mild stenosis. Surgical decompression is reserved for severe cases and results in variable degrees of success. Patients with moderate-to-severe LSS having ligamentum flavum hypertrophy as a key contributor are generally inappropriately treated or undertreated. This is due to ineffectiveness of conservative therapy and possibility that major surgical compression might be too aggressive. Percutaneous decompression offers a possible solution for this patient population. METHODS: One-year follow-up study was conducted at 11 U.S. sites. Study cohort included 58 mild((r)) percutaneous decompression patients who underwent 170 procedures, the majority treated bilaterally at one or two lumbar levels. Outcome measures included the visual analog scale (VAS), Oswestry Disability Index (ODI), Zurich Claudication Questionnaire (ZCQ), and SF-12v2((r)) Health Survey. RESULTS: No major mild((r)) device or procedure-related complications were reported. One-year data showed significant reduction of pain as measured by VAS. Improvement in physical functionality, mobility, and disability was significant as measured by ZCQ, SF-12v2, and ODI. CONCLUSIONS: At 1 year this 58-patient cohort demonstrated continued excellent safety profile of the mild((r)) procedure and equally important, showed long-term pain relief and improved functionality. PMID- 21676167 TI - Polymorphisms and mutations of ADAMTS13 in the Japanese population and estimation of the number of patients with Upshaw-Schulman syndrome. PMID- 21676165 TI - Preoperative gabapentin for acute post-thoracotomy analgesia: a randomized, double-blinded, active placebo-controlled study. AB - BACKGROUND: The role of preoperative gabapentin in postoperative pain management is not clear, particularly in patients receiving regional blockade. Patients undergoing thoracotomy benefit from epidural analgesia but still may experience significant postoperative pain. We examined the effect of preoperative gabapentin in thoracotomy patients. METHODS: Adults undergoing elective thoracotomy were enrolled in this prospective, randomized, double-blinded, placebo-controlled study, and randomly assigned to receive 600 mg gabapentin or active placebo (12.5 mg diphenhydramine) orally within 2 hours preoperatively. Standardized management included thoracic epidural infusion, intravenous patient-controlled opioid analgesia, acetaminophen and ketorolac. Pain scores, opioid use and side effects were recorded for 48 hours. Pain was also assessed at 3 months. RESULTS: One hundred twenty patients (63 placebo and 57 gabapentin) were studied. Pain scores did not significantly differ at any time point (P = 0.53). Parenteral and oral opioid consumption was not significantly different between groups on postoperative day 1 or 2 (P > 0.05 in both cases). The frequency of side effects such as nausea and vomiting or respiratory depression was not significantly different between groups, but gabapentin was associated with decreased frequency of pruritus requiring nalbuphine (14% gabapentin vs. 43% control group, P < 0.001). The frequency of patients experiencing pain at 3 months post-thoracotomy was also comparable between groups (70% gabapentin vs. 66% placebo group, P = 0.72). CONCLUSIONS: A single preoperative oral dose of gabapentin (600 mg) did not reduce pain scores or opioid consumption following elective thoracotomy, and did not confer any analgesic benefit in the setting of effective multimodal analgesia that included thoracic epidural infusion. PMID- 21676168 TI - Ascidian dermatan sulfates attenuate metastasis, inflammation and thrombosis by inhibition of P-selectin. AB - BACKGROUND: Cancer-associated thrombosis and enduring inflammation are strongly associated with cancer progression and metastasis. Heparin is the mostly clinically used anticoagulant/antithrombotic drug, and has recently been shown to exhibit antimetastatic and anti-inflammatory activities that are linked to inhibition of P-selectin and/or L-selectin. P-selectin-mediated platelet-tumor cell and tumor cell-endothelium interactions facilitate the initial steps of metastasis. OBJECTIVES AND METHODS: The aim of the present study was to determine the capacity of dermatan sulfates to inhibit P-selectin and to test their potential to affect thrombosis, inflammation and metastasis in respective experimental mouse models. RESULTS: Two dermatan sulfates isolated from the ascidians Styela plicata and Phallusia nigra, composed of the same disaccharide core structure (IdoA2-GalNAc)(n) , but sulfated at carbon 4 or 6 of the GalNAc, respectively, have opposed heparin cofactor II (HCII) activities and are potent inhibitors of P-selectin. The ascidian dermatan sulfates effectively attenuated metastasis of both MC-38 colon carcinoma and B16-BL6 melanoma cells and the infiltration of inflammatory cells in a thioglycollate peritonitis mouse model. Moreover, both glycosaminoglycans reduced thrombus size in an FeCl(3) -induced arterial thrombosis model, irrespective of their HCII activities. The analysis of arterial thrombi demonstrated markedly reduced platelet deposition after dermatan sulfate treatment, suggesting that the glycosaminoglycan inhibited P-selectin and thereby the binding of activated platelets during thrombus formation. CONCLUSIONS: Collectively, these findings provide evidence that specific inhibition of P-selectin represents a potential therapeutic target in thrombosis, inflammation and metastasis, and that ascidian dermatan sulfates may serve as antiselectin agents. PMID- 21676169 TI - Heparin-associated thrombocytopenia in 24,401 patients with venous thromboembolism: findings from the RIETE Registry. AB - BACKGROUND: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. OBJECTIVES: We assessed the incidence, risk factors and prognosis of heparin-associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. PATIENTS/METHODS: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25,369 patients with confirmed VTE until February 2009. Among them, 24,401 patients were treated either with UFH or with LMWH, and had available information about the 6-month occurrence of confirmed thrombocytopenia, defined as a platelet count <= 150,000 mm(-3) . RESULTS: One hundred and forty-one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6-month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79-2.17) than in the LMWH group (0.54%, 95% CI 0.44-0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58-9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64-3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH-associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. CONCLUSIONS: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non-cancerous patients. PMID- 21676170 TI - Association between circulating hemostatic measures and dementia or cognitive impairment: systematic review and meta-analyzes. AB - BACKGROUND AND OBJECTIVES: Hemostasis and thrombosis may be important contributors to cognitive decline and dementia. Certain blood markers may assist in diagnosis or management. OBJECTIVES: To collate evidence for the association of circulating hemostatic variables and dementia or cognitive impairment. METHODS: A systematic review of studies describing blood markers of hemostatic function and cognition/dementia. Abstracts were reviewed by two independent assessors and studies selected based on pre-specified criteria. We described methodological quality and performed meta-analyzes where data allowed. RESULTS: From 7103 titles, 485 abstracts and included 21 studies (n = 32,773) were assessed. In two longitudinal studies, the incident of vascular dementia risk was greater for higher D-dimer [hazard ratio (HR): 1.50, 95% confidence interval (CI): 1.15-1.96]. For case-control data, we calculated standardized mean differences (SMD) and 95% CI. Higher levels of: factor (F)VII (SMD: 0.93; 95% CI: 0.60-1.26), fibrinogen (SMD: 1.53; 95% CI: 1.17-1.87), prothrombin fragment 1 and 2 (SMD: 0.64; 95% CI: 0.32-0.96), plasminogen activator inhibitor (SMD: 0.68; 95% CI: 0.26-1.10), D-dimer (SMD: 2.00; 95% CI: 1.59-2.40) and von Willebrand factor (VWF) (SMD: 1.68; 95% CI: 1.30-2.06) showed modest but significant associations with vascular dementia. For patients with any dementia diagnosis, associations were with higher D-dimer (SMD: 0.36; 95% CI: 0.15-0.56) and VWF (SMD: 0.31; 95% CI: 0.11-0.51). For specific cognitive domains, significant (P < 0.001) positive correlations were fibrinogen and speed of processing (0.76; 95% CI: 0.67-0.84), verbal memory (0.69; 95% CI: 0.59-0.79) and non-verbal reasoning (0.57; 95% CI: 0.49-0.65). CONCLUSIONS: The present results suggest a modest association between hemostasis and vascular dementia including increased levels of thrombin generation markers (D-dimer and prothrombin fragment 1 + 2) and endothelial dysfunction (VWF and plasminogen activator inhibitor). Associations are weaker for specific cognitive tests and when all dementias are combined. PMID- 21676171 TI - Recombinase-mediated gene stacking as a transformation operating system. AB - The current method for combining transgenes into a genome is through the assortment of independent loci, a classical operating system compatible with transgenic traits created by different developers, at different times and/or through different transformation techniques. However, as the number of transgenic loci increases over time, increasingly larger populations are needed to find the rare individual with the desired assortment of transgenic loci along with the non transgenic elite traits. Introducing a transgene directly into a field cultivar would bypass the need to introgress the engineered trait. However, this necessitates separate transformations into numerous field cultivars, along with the characterization and regulatory approval of each independent transformation event. Reducing the number of segregating transgenic loci could be achieved if multiple traits are introduced at the same time, a preferred option if each of the many traits is new or requires re-engineering. If re-engineering of previously introduced traits is not needed, then appending a new trait to an existing locus would be a rational strategy. The insertion of new DNA at a known locus can be accomplished by site-specific integration, through a host-dependent homology-based process, or a heterologous site-specific recombination system. Here, we discuss gene stacking through the use of site-specific recombinases. PMID- 21676172 TI - Functions and application of the AP2/ERF transcription factor family in crop improvement. AB - Plants have acquired sophisticated stress response systems to adapt to changing environments. It is important to understand plants' stress response mechanisms in the effort to improve crop productivity under stressful conditions. The AP2/ERF transcription factors are known to regulate diverse processes of plant development and stress responses. In this study, the molecular characteristics and biological functions of AP2/ERFs in a variety of plant species were analyzed. AP2/ERFs, especially those in DREB and ERF subfamilies, are ideal candidates for crop improvement because their overexpression enhances tolerances to drought, salt, freezing, as well as resistances to multiple diseases in the transgenic plants. The comprehensive analysis of physiological functions is useful in elucidating the biological roles of AP2/ERF family genes in gene interaction, pathway regulation, and defense response under stress environments, which should provide new opportunities for the crop tolerance engineering. PMID- 21676173 TI - A transgenic study on affecting potato tuber yield by expressing the rice sucrose transporter genes OsSUT5Z and OsSUT2M. AB - In many plants, sucrose transporters are essential for both sucrose exports from sources and imports into sinks, indicating a function in assimilate partitioning. To investigate whether sucrose transporters can improve the yield of starch plant, potato plants (Solanum tuberosum L. cv. Desiree) were transformed with cDNAs of the rice sucrose transporter genes OsSUT5Z and OsSUT2M under the control of a tuber-specific, class-I patatin promoter. Compared to the controls, the average fructose content of OsSUT5Z transgenic tubers significantly increased. However, the content of the sugars and starch in the OsSUT2M transgenic potato tubers showed no obvious difference. Correspondingly, the average tuber yield, average number of tubers per plant and average weight of single tuber showed no significant difference in OsSUT2M transgenic tubers with controls. In the OsSUT5Z transgenic lines, the average tuber yield per plant was 1.9-fold higher than the controls, and the average number of tubers per plant increased by more than 10 tubers on average, whereas the average weight of a single tuber did not increase significantly. These results suggested that the average number of tubers per plant showed more contribution than the average weight of a single tuber to the tuber yield per plant. PMID- 21676175 TI - Female sexual dysfunction and hormonal status in multiple sclerosis patients. PMID- 21676174 TI - An alternative isomerohydrolase in the retinal Muller cells of a cone-dominant species. AB - Cone photoreceptors have faster light responses than rods and a higher demand for 11-cis retinal (11cRAL), the chromophore of visual pigments. RPE65 is the isomerohydrolase in the retinal pigment epithelium (RPE) that converts all-trans retinyl ester to 11-cis retinol, a key step in the visual cycle for regenerating 11cRAL. Accumulating evidence suggests that cone-dominant species express an alternative isomerase, likely in retinal Muller cells, to meet the high demand for the chromophore by cones. In the present study, we describe the identification and characterization of a novel isomerohydrolase, RPE65c, from the cone-dominant zebrafish retina. RPE65c shares 78% amino acid sequence identity with RPE-specific zebrafish RPE65a (orthologue of human RPE65) and retains all of the known key residues for the enzymatic activity of RPE65. Similar to the other RPE-specific RPE65, RPE65c was present in both the membrane and cytosolic fractions, used all-trans retinyl ester as its substrate and required iron for its enzymatic activity. However, immunohistochemistry detected RPE65c in the inner retina, including Muller cells, but not in the RPE. Furthermore, double immunostaining of dissociated retinal cells using antibodies for RPE65c and glutamine synthetase (a Muller cell marker), showed that RPE65c co-localized with the Muller cell marker. These results suggest that RPE65c is the alternative isomerohydrolase in the intra-retinal visual cycle, providing 11cRAL to cone photoreceptors in cone-dominant species. Identification of an alternative visual cycle will contribute to the understanding of the functional differences of rod and cone photoreceptors. PMID- 21676176 TI - Intraurethral industrial silicone. PMID- 21676178 TI - Vaginal orgasm is more prevalent among women with a prominent tubercle of the upper lip. AB - INTRODUCTION: Recent studies have uncovered multiple markers of vaginal orgasm history (unblocked pelvic movement during walking, less use of immature psychological defense mechanisms, greater urethrovaginal space). Other markers (perhaps of prenatal origin) even without obvious mechanistic roles in vaginal orgasm might exist, and a clinical observation led to the novel hypothesis that a prominent tubercle of the upper lip is such a marker. AIMS: To examine the hypothesis that a prominent tubercle of the upper lip is associated specifically with greater likelihood of experiencing vaginal orgasm (orgasm elicited by penile vaginal intercourse [PVI] without concurrent masturbation). METHODS: Women (N = 258, predominantly Scottish) completed an online survey reporting their frequencies of various sexual activities and corresponding orgasms, age, and the prominence of the tubercle of their upper lip. Social desirability response bias was also assessed. MAIN OUTCOME MEASURES: Multivariate associations of lip tubercle prominence with vaginal orgasm (ever and past month consistency) and with orgasm by other means. RESULTS.: A prominent and sharply raised lip tubercle was associated with greater odds (odds ratio = 12.3) of ever having a vaginal orgasm, and also with greater past month vaginal orgasm consistency (an effect driven by the women who never had a vaginal orgasm), than less prominent lip tubercle categories. Lip tubercle was not associated with social desirability responding, or with orgasm triggered by masturbation during PVI, solitary or partner clitoral or vaginal masturbation, vibrator, or cunnilingus. CONCLUSIONS: The results are discussed in light of the unique nature of vaginal orgasm and the possibility of prenatal developmental influences. PMID- 21676177 TI - Sexual behaviors among adults in Puerto Rico: a population-based study. AB - INTRODUCTION: Given changes in sexual behaviors and norms in the United States, there is a need for current and representative data on sexual behaviors with particular interest in gender, age, and racial/ethnic group differences. AIM: Given the limited data for Hispanics and for Puerto Rico (PR), we described patterns of sexual behaviors and characteristics among a sexually active sample (n=1,575) of adults aged 21-64 years in PR. MAIN OUTCOME MEASURES: The main outcome measures for this study are sexual behaviors including age at sexual initiation, number of sexual partners, vaginal and anal intercourse, and oral sex, among others. METHODS: Data from a population-based cross-sectional study in PR (2005-2008) was analyzed. The prevalence of sexual behaviors and characteristics was described by age-group and gender during the lifetime and in the past 12 months. RESULTS: Overall, 96.8%, 81.6%, and 60.9% of participants had ever engaged in vaginal, oral and anal sex, respectively, whereas 23.7% were seropositive to any of the sexually transmitted infections under study. Sexual initiation<=15 years was reported by 37.8% of men and 21.4% of women; whereas 47.9% of men and 13.2% of women reported to have had >=7 sexual partners in their lifetime. Approximately, 3% of women and 6% of men reported same-sex sexual practices, while history of forced sexual relations was reported by 9.6% of women and 2.5% of men. Sexual initiation<=15 years was more common among individuals aged 21-34 years (41.4% men and 33.6% women) as compared with older cohorts. Although having had >=7 sexual partners over a lifetime among men was similar across age groups, this behavior decreased in older women cohorts. In both genders, the prevalence of oral and anal sex was also lower in the older age cohorts. CONCLUSION: This study provides essential information that can help health professionals understand the sexual practices and needs of the population of PR. PMID- 21676179 TI - Anxious and avoidant attachment, vibrator use, anal sex, and impaired vaginal orgasm. AB - INTRODUCTION: Disturbances in intimate relationships are among the risk factors for female sexual dysfunction. Insecure styles of anxious attachment (preoccupations about abandonment) and avoidant attachment (avoidance of closeness in relationships) are robustly associated with sexual problems, relationship difficulties, and several indices of poorer physical and mental health. Similar indices of poorer sexual, relationship, and health functioning are associated with impairment of orgasm triggered by penile-vaginal stimulation (vaginal orgasm), but unrelated or related to greater frequency of other sexual behaviors. However, research examining the differential association of sexual activities with insecure attachment styles has been lacking. AIMS: The aim of this study was to test the hypotheses that insecure attachment styles are associated with lesser vaginal orgasm consistency, and are unrelated or directly related to greater frequency of other sexual behaviors. METHOD: Seventy coitally experienced women recruited at a Scottish university completed the Revised Experience in Close Relationships scale, and reported their frequency of various sexual behaviors (and corresponding orgasms) in a recent representative month. MAIN OUTCOME MEASURES: The main outcome measures for this study are multivariate correlations of various sexual activities with insecure attachment styles, age, and social desirability response bias. RESULTS: Anxious attachment was associated with lesser vaginal orgasm consistency, but with higher frequency of vibrator and anal sex orgasms. Avoidant attachment was associated with higher frequency of vibrator orgasms. Neither anxious nor avoidant attachment was associated with lifetime number of penile-vaginal intercourse partners. CONCLUSIONS: The results provide evidence that inability to attain a vaginal orgasm is associated with anxious attachment, among other indices of poorer mental health and relatedness. Vaginal orgasm might be the relevant sexual activity for the maintenance of a secure attachment style with a sexual partner and/or more insecurely attached women might have difficulties in attaining vaginal orgasms and be more inclined to sexual activities characterized by more emotional and physical detachment, as part of a characterological discomfort with intimacy. PMID- 21676180 TI - Development and psychometric properties of the Female Sexual Desire Questionnaire (FSDQ). AB - INTRODUCTION: Sexual desire is often evaluated as part of a global assessment of female sexual function, which may not comprehensively evaluate the various facets of this experience. There currently exists a need to develop a psychometrically robust desire-specific measure for women. AIM: The aim of this study was to develop and validate a desire-specific, self-administered instrument that evaluates the multiple facets of sexual desire and factors influencing this experience for partnered heterosexual women, with or without sexual dysfunction. METHODS: Preliminary items for inclusion in the Female Sexual Desire Questionnaire (FSDQ) were identified through a literature review and individual interviews with partnered heterosexual women, mostly from Australia. The resulting instrument was completed by a validation sample of 741 women, aged between 18 and 71 years, who were involved in a heterosexual relationship of between 3 months' and 49 years' duration. MAIN OUTCOME MEASURES: Exploratory factor analysis was used to refine the FSDQ item content and identify the underlying domain structure. The reliability (internal consistency) and validity (convergent validity) of the FSDQ were also evaluated. RESULTS: The final version of the FSDQ consisted of 50 items organized into six domains that characterized the experience of, and factors influencing, sexual desire for heterosexual partnered women: Dyadic Desire, Solitary Desire, Resistance, Positive Relationship, Sexual Self-Image, and Concern. Each domain demonstrated high reliability, as did the overall measure. Evidence of construct validity was ascertained through convergence with the Sexual Desire Inventory and the Hurlbert Index of Sexual Desire. A short-form of the FSDQ, consisting of six items, was also developed. CONCLUSIONS: The FSDQ is a new reliable and valid multidimensional measure designed specifically for evaluating the facets of, and factors influencing, sexual desire among sexually functional and dysfunctional women who are involved in a heterosexual relationship. PMID- 21676181 TI - Female sexual dysfunction in Iranian postmenopausal women: prevalence and correlation with hormonal profile. AB - INTRODUCTION: Female sexual dysfunction is a current and multifactorial status that greatly affects quality of life. Menopause, aging, and probably hormonal instability are some of these drastic factors. AIM: Determine the prevalence of sexual dysfunction in Iranian postmenopausal women and the relationship to serum status of sex hormones and sex hormone binding globulin (SHBG). METHODS: A total of 149 healthy postmenopausal women aged 43-64, nonhormone therapy user, with intact uterus and ovaries, enrolled in the cross-sectional study. MAIN OUTCOME MEASURES: Female sexual function was evaluated by utilizing the Female Sexual Function Index. Hormonal serum concentration was measured by enzyme-linked Immunosorbent Assay (ELISA). Also, free testosterone and free estradiol indexes were calculated. The analysis was performed by using SPSS 16. RESULTS: Mean age of sample was 52.19 +/- 3.76 with 47.48 +/- 36.5 month amenorrhea. In the study, 69.8% of women showed sexual dysfunction in Desire and 61.7% in Arousal, these two being the most affected domains. Lubrication (49.7%), Pain Domain (45.0%), Orgasm (40.3%), and Satisfaction (36.9%) were in later degree among six assessed domains. There was no difference between the two groups-with and without dysfunction-in hormone level and SHBG. CONCLUSION: In Iranian postmenopausal women, Desire and Arousal are the most prevalent menopausal sexual dysfunctions, and Female Sexual Dysfunction is much more than just a hormonal problem. PMID- 21676182 TI - Mediators of sexual functions in women with diabetes. AB - INTRODUCTION: Sexual disorders in women with diabetes mellitus (DM) may not necessarily have only the biological etiology. AIMS: To establish the mediators of sexual functions in the population of women with DM. METHODS: Five hundred seventeen females, aged 18-55 years old, were included in a questionnaire-based, cross-sectional study. This is the second part of the study on sexual functions in females with DM where only females with DM (n=242) were analyzed. Sexual functions were compared between women with type 1 (n=109) and type 2 DM (N=133). MAIN OUTCOME MEASURES: To assess reported female sexual functions by using the Female Sexual Function Index (FSFI) in women with type 1 and type 2 DM. To establish the risk factors of female sexual dysfunction (FSD) in women with DM by using multivariate logistic regression model. RESULTS: Sexual dysfunction was diagnosed in 32.65% (n=64) of women with DM. Women with type 2 DM had a significantly lower number of points scored in all FSFI domains except pain compared to type 1 respondents. The only variables associated with DM significantly influencing sexual functioning were: type 2 diabetes in desire, arousal, as well as in global FSD (odds ratio [OR]=1.40; 2.70 and 3.31, respectively), the presence of retinopathy in lubrication (OR=7.8), and treatment with insulin in satisfaction domain (OR=0.29). Neither the presence of comorbidities, the duration of diabetes, the presence of diabetes complications nor the glycemic control was a moderator of FSD. The strongest significant predictors of FSD were: the presence of depressive symptoms, the importance of sex to the respondent, and satisfaction with the partner as a lover. CONCLUSIONS: Women with DM, especially type 2, are at risk of sexual dysfunctions. Diabetes related factors have little impact on sexual functions in women with DM. Depressive symptoms, partner-related factors, and individual perception of sexuality should be evaluated when counseling females with DM. PMID- 21676183 TI - Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. AB - INTRODUCTION: Increasing interest in the use of supplemental testosterone has led to a heightened focus on the safety of testosterone in elderly males, with a particular emphasis on cardiovascular risk. AIMS: To evaluate, based on available clinical trial data, whether exogenous testosterone administration in middle-aged to elderly men increases cardiovascular risk, and to assess whether these effects differ in hypogonadal vs. eugonadal subjects. METHODS: MEDLINE search from 2004 to present of all meta-analyses and randomized, controlled clinical trials of testosterone administration in male subjects >= 45 years old that included measurements of cardiovascular outcomes or known cardiovascular risk factors before and after treatment with testosterone. MAIN OUTCOME MEASURES: The effects of testosterone treatment on cardiovascular events and cardiovascular risk factors were assessed. RESULTS: In clinical trials where testosterone has been used in patients with preexisting cardiovascular conditions, the effect on disease symptoms has typically been either neutral or beneficial. Based on clinical trial data, testosterone treatment has minimal effect on cardiovascular risk factors with the exception of an increase in hematocrit, which is consistently seen with testosterone treatment, and a decrease in high-density lipoprotein cholesterol, which is an inconsistent response. Responses of hypogonadal and eugonadal men to testosterone treatment in terms of cardiovascular risk are generally similar. Testosterone treatment has not been reported to increase the incidence of cardiovascular events with the possible exception of one trial in frail elderly men. CONCLUSIONS: Available clinical trial data indicate that the use of testosterone in middle-aged to elderly men does not increase cardiovascular risk nor does it unfavorably modify cardiovascular risk profile. Prospective data from large, well-designed, long term trials of testosterone treatment are lacking and will be required to verify the cardiovascular efficacy/safety of chronic treatment. PMID- 21676184 TI - The Global Online Sexuality Survey (GOSS): ejaculatory function, penile anatomy, and contraceptive usage among Arabic-speaking Internet users in the Middle East. AB - INTRODUCTION: Sexuality is a sensitive issue that may be difficult to explore through surveys involving direct contact. Epidemiological studies in this domain are scarce. Online surveys may provide more anonymity and less direct contact encouraging participation. The Global Online Sexuality Survey (GOSS) reports on different aspects of male and female sexuality. The Global Online Sexuality Survey-Arabic-Males (GOSS-AR-M) is the Arabic version reporting on male sexuality. AIM: To evaluate male ejaculatory function, penile size and contraceptive trends among Arabic speakers in the Middle East. METHODS: The survey was randomly offered online to web surfers in the Middle East. MAIN OUTCOME MEASURES: Prevalence of premature ejaculation, ejaculatory latency, penile size and their correlation with erectile function. RESULTS: A total of 82.6% reported various degrees of premature ejaculation, associated with a statically significant decline in erectile function, despite a median intravaginal ejaculatory latency time (IELT) of 5 minutes, 95% confidence interval (CI) of 8.4-9.8. Adjusted to the World Standard Population by the World Health Organization, the collective prevalence was 83.7%. Local anesthetics gave better results and tolerance in delaying ejaculation. Self-measured erect penile length from symphysis pubis to glans was 15.6 cm +/- 4.1, 95% CI = 15.4-15.9, yet, 30% were dissatisfied with size, mainly in the flaccid state, with dissatisfaction being inversely proportional with erectile function. Intrauterine device was the method mostly used by couples, and condoms had a high dissatisfaction rate. CONCLUSION: The prevalence of premature ejaculation appears to surpass that of erectile dysfunction, despite the possibility that it may be overreported considering the acceptable IELT of the population surveyed. Premature ejaculation and concerns over genital size may be considered as risk factors for ED. More male contraceptive measures should be introduced and popularized. Alleviating dissatisfaction with condom utility via health education should be a priority. PMID- 21676185 TI - Fluoxetine chronic treatment inhibits male rat sexual behavior by affecting both copulatory behavior and the genital motor pattern of ejaculation. AB - INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that cause sexual dysfunction. The SSRI fluoxetine (FLX) appears to particularly affect the ejaculatory response. Ejaculation is regulated both at brain and spinal levels. AIM: To study the acute and chronic effects of FLX on male rat copulatory behavior, trying to distinguish between brain and spinal cord FLX induced changes on the ejaculatory response. METHODS: Sexually experienced male rats were intraperitoneally injected with 5 or 10 mg/kg FLX and tested for sexual behavior during 60 minutes on days 1, 7, and 14 of treatment. After a 2-day drug holiday, the males chronically treated with the high FLX dose were spinalized to record spontaneous and mechanically evoked genital motor patterns of ejaculation (GMPEs). In addition, independent groups were used to evaluate the acute effects of 1, 3, or 10 ug/rat FLX (intravenously) on the GMPE. MAIN OUTCOME MEASURES: Number of ejaculatory series and their parameters; electromyographic recordings of the GMPE in the bulbospongiosus muscles and their parameters. RESULTS: Acute FLX injection slightly affected sexual behavior display and dose-dependently inhibited the expression of the GMPE. Chronic FLX treatment did not inhibit copulation but produced deficits in the parameters related to ejaculation after the high dose. In these animals, the response capacity of the spinal generator of ejaculation (SGE) as well as the number of discharges in the GMPE was decreased as a result of chronic FLX treatment. CONCLUSIONS: Chronic FLX treatment produces inhibitory effects on male rat copulation, particularly on ejaculation, some of which are exerted directly at the SGE. PMID- 21676186 TI - Recent and lifelong sexual dysfunction in a female UK population sample: prevalence and risk factors. AB - INTRODUCTION: To date, no studies have tried to explore the prevalence and risk factors of recent and lifelong female sexual dysfunction (FSD) in the United Kingdom using validated questionnaires for the assessment of symptom severity and levels of associated sexual distress. AIM: To estimate the prevalence and comorbidity of recent and lifelong FSD and to further identify potential psychosocial and behavioral risk factors in a nationally representative sample of UK women. METHODS: One thousand four hundred eighty-nine unselected female twin individuals aged 18-85 years. Validated questionnaires, such as the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale, were used for the assessment of symptom severity and degree of sexual distress. MAIN OUTCOME MEASURES: Prevalence and comorbidity of recent and lifelong FSD according to the FSFI cutoff points and the existence of sexual distress. Lifelong FSD refers to an individual's average sexual function ever since they have been sexually active. We further calculated odds ratios (ORs) with 95% confidence interval for FSD. RESULTS: We found that 5.8% of women reported any recent sexual dysfunction and 15.5% reported any lifelong sexual dysfunction. Hyposexual desire was the most prevalent recent and lifelong sexual complaint (21.4% and 17.3%, respectively). High intercorrelations were found for both recent and lifelong FSD (r=0.3-0.7). The most common independent, clinical predictor of recent and lifelong FSD diagnosis was relationship dissatisfaction (OR 1.2-4.5). Experience of abuse (OR 1.6-2.1), increased anxiety, and obsessive compulsive behavior were the most common predictors for lifelong FSD. CONCLUSIONS: The study provides the first UK population-based assessment of recent and lifelong FSD using validated outcome measures and accounting for sexual distress. Our results indicate that FSD is common in the general population and is influenced by psychosocial factors with different pathoetiologies underlying recent and lifelong FSD. PMID- 21676187 TI - Evaluation of sexual function in hypertensive men receiving treatment: a review of current guidelines recommendation. AB - INTRODUCTION: It has been suggested that some classes of antihypertensive drugs may induce or exacerbate sexual and/or erectile dysfunction (ED) more than others. Sexually related side effects of antihypertensive treatment may compromise patient's and partner's quality of life. Often, these side effects can lead to withdrawal or poor compliance with therapy resulting in abnormal blood pressure and associated morbidity. AIM: The aim of this study was to evaluate whether hypertension clinical practice guidelines (CPGs) address ED and/or other sexual issues as either an adverse outcome of chosen therapy or as a factor to consider in treatment decision. METHODS: Hypertension CPGs were identified by searching PubMed (from 2000 to current), the World Wide Web, bibliographies of retrieved guidelines, and official home pages of major medical societies. MAIN OUTCOME MEASURES: The main outcome measures used for this study were guidelines assessment using a set of author-determined survey questions. RESULTS: Twelve CPGs were identified and analyzed. From these 12, only three emphasized the importance of assessing sexual function prior to initiation and/or follow-up of antihypertensive therapy; only five described potential sexual side effects associated with some drugs; only two provided specific management recommendations on commencing antihypertensive therapy in sexually active men or those with preexisting ED and address the timeline of the potential drug-induced impairment of sexual function. CONCLUSIONS: Only a minority of CPGs for the treatment of hypertension consider ED or other sexual issues as either an adverse outcome or as a factor to consider in treatment. Sexual function is an important aspect of quality of life for both the individual and his partner. It is therefore imperative to select therapy with the least possible potential for causing sexual sequelae and enable the best achievable balance between therapeutic efficacy, quality of life, and therapeutic compliance. Based on these results, our proposed algorithm attempts to effectively apply available evidence to clinical practice. PMID- 21676188 TI - Metabolic syndrome, testosterone, and cardiovascular mortality in men. AB - INTRODUCTION: Interactions among testosterone, metabolic syndrome (MetS), and mortality risk in men remain to be elucidated. AIM: To examine relationships among testosterone, MetS, and cardiovascular mortality risk in U.S. men, middle aged and older. METHODS: The analysis included the men aged 40 years and above in Phase 1 (1988-1991) of the Third National Health and Nutrition Examination Survey (NHANES III). Serum testosterone and sex hormone binding globulin were measured, and free testosterone and bioavailable testosterone were calculated. MetS was determined according to the Adult Treatment Panel III (ATP-III) criteria. MAIN OUTCOME MEASURES: Cardiovascular and other causes of mortality were obtained from the NHANES III-linked follow-up file through December 31, 2006. Multivariate Cox regression models were applied to assess associations of interest. RESULTS: Of 596 men included in the analysis, 187 men were found to have MetS. During a median follow-up of 15.6 years, 97 men died of cardiovascular causes (cardiovascular mortality rate: 9.84 and 5.77 per 1,000 person-years for those with and without MetS, respectively). Higher calculated bioavailable testosterone (CBT) was associated with a lower odds of MetS (odds ratio: 0.80 for each ng/mL, 95% confidence interval [CI]: 0.76-0.84, P < 0.001) and lower risk of cardiovascular mortality (hazard ratios [HRs]: 0.72 for each log ng/mL, 95% CI: 0.54-0.96, P = 0.03) in subjects with MetS. The influence of CBT was not observed in those without MetS (HR: 0.84 for each log ng/mL, 95% CI: 0.68-1.04, P = 0.10). CONCLUSIONS: The combination of lower bioavailable testosterone and ATP-III defined MetS is associated with an increased cardiovascular mortality in the men aged 40 years and above. PMID- 21676189 TI - Unique infective complication after routine vasectomy: a case report. AB - INTRODUCTION: We present a case of a 51-year-old gentleman who, after undergoing routine vasectomy, presented with an infected wound 7 days after the procedure- one day after receiving oral sex from his wife. AIM: We hope to present a unique case of an infected wound after oral sex. Group A Streptococcus (GAS) was cultured from the patient's wound and the asymptomatic wife's pharyngeal mucosa. MAIN OUTCOME MEASURES: To educate and expose a rare but potentially devastating postvasectomy complication that, without prompt and aggressive treatment, can lead to significant morbidity. METHODS: The patient was promptly treated and after hydration, broad spectrum antibiotics, and supportive care, patient showed excellent recovery. The wife was also treated with oral antibiotics. RESULTS: Infective complicated are relatively uncommon after routine vasectomy. When present, the vast majority of the infections are treated with a simple course of oral antibiotics. There is strong evidence that establishes oral contact as a vector for transmission of virulent pathogens. Some have linked orogenital transmission of GAS since the 1970s. CONCLUSION: To our knowledge, this is the first reported case of oropharyngeal transmission of GAS that led to rapidly progressive infection of the scrotum following vasectomy. Care should be taken to minimize exposure during postoperative healing. PMID- 21676191 TI - Characterization of three novel HLA-DRB1 alleles, DRB1*03:55, *11:46:02 and *04:92, by exon 2, 3 and 4 sequencing-based typing. AB - Sequencing-based typing of HLA-DRB1 gene, allowed us to characterize three new alleles. DRB1*03:55 shows one nucleotide change regarding DRB1*03:01:01G, resulting in an amino acid replacement at position 80 R > I. DRB1*11:46:02 presents one synonymous nucleotide change at codon 34 (CAG > CAA) with regard to DRB1*11:46:01. Finally, DRB1*04:92 has one nucleotide change from DRB1*04:07:01 at codon 207 in exon 4, producing an amino acid replacement (V > M) in the transmembrane domain. PMID- 21676190 TI - Predictors of contraceptive methods among adolescents and young women residing in Spain. AB - INTRODUCTION: Preventing unwanted pregnancy is considered one of the main preventive measures of a developed health system. AIMS: The aim of the study were to determine the prevalence of contraceptive methods and identify factors associated with the use of contraception by adolescents and young women residents in Spain. METHODS: Descriptive cross-sectional epidemiologic study on the factors determining use of a contraceptive method among sexually active adolescents and young women aged 16-29 years, living in Spain. As the dependent variable, we took the answer to the questions "During the last 12 months, what contraceptive method have you generally used in your sexual relations?" Independent variables were socio-demographic factors, sexual habits, and variables associated with perception of sexual health. Using logistic multivariate regression models, we have estimated the independent effect of each of these variables on the contraceptive methods use. MAIN OUTCOME MEASURES: We used secondary individualized data drawn from the first National Sexual Health Survey conducted in Spain. RESULTS: The male condom seems to be the most widely used (56.7%). The likelihood of using a condom is greater to those who have more than two sexual partners (adjusted odds ratio [AOR]=3.11; 95% confidence interval [CI], 1.72 5.60). Predictors of use of oral contraceptives as the only method are age and having a positive view of one's sexual health (AOR=2.65; 95% CI, 1.28-5.45). Young women with two or more sexual partners were three times likelier to use the double method (AOR=3.83; 95% CI, 1.52-9.65). CONCLUSIONS: The number of sexual partners, information on and importance of sexuality in one's life predicted the use of the condom as the only method. The factors associated with use of oral contraceptives were having a stable sexual partner and good perception of sexual health. The variable most strongly associated with use of the double method was number of sexual partners. PMID- 21676192 TI - DNA barcoding of the ichthyofauna of Taal Lake, Philippines. AB - This study represents the first molecular survey of the ichthyofauna of Taal Lake and the first DNA barcoding attempt in Philippine fishes. Taal Lake, the third largest lake in the Philippines, is considered a very important fisheries resource and is home to the world's only freshwater sardine, Sardinella tawilis. However, overexploitation and introduction of exotic fishes have caused a massive decline in the diversity of native species as well as in overall productivity of the lake. In this study, 118 individuals of 23 native, endemic and introduced fishes of Taal Lake were barcoded using the partial DNA sequence of the mitochondrial cytochrome c oxidase subunit I (COI) gene. These species belong to 21 genera, 17 families and 9 orders. Divergence of sequences within and between species was determined using Kimura 2-parameter (K2P) distance model, and a neighbour-joining tree was generated with 1000 bootstrap replications using the K2P model. All COI sequences for each of the 23 species were clearly discriminated among genera. The average within species, within genus, within family and within order percent genetic divergence was 0.60%, 11.07%, 17.67% and 24.08%, respectively. Our results provide evidence that COI DNA barcodes are effective for the rapid and accurate identification of fishes and for identifying certain species that need further taxonomic investigation. PMID- 21676193 TI - Molecular scatology: how to improve prey DNA detection success in avian faeces? AB - The analysis of prey DNA in faeces is a non-invasive approach to examine the diet of birds. However, it is poorly known how gut transition time, environmental factors and laboratory treatments such as storage conditions or DNA extraction procedures affect the detection success of prey DNA. Here, we examined several of these factors using faeces from carrion crows fed with insect larvae. Faeces produced between 30 min and 4 h post-feeding tested positive for insect DNA, representing the gut transition time. Prey detection was not only possible in fresh but also in 5-day-old faeces. The type of surface the faeces were placed on for these 5 days, however, affected prey DNA detection success: samples placed on soil provided the lowest rate of positives compared to faeces left on leaves, on branches and within plastic tubes. Exposing faeces to sunlight and rain significantly lowered prey DNA detection rates (17% and 68% positives in exposed and protected samples, respectively). Storing faeces in ethanol or in the freezer did not affect molecular prey detection. Extracting DNA directly from larger pieces of faecal pellets resulted in significantly higher prey detection rates than when using small amounts of homogenized faeces. A cetyltrimethyl ammonium bromide-based DNA extraction protocol yielded significantly higher DNA detection rates (60%) than three commercial kits, however, for small amounts of homogenized faeces only. Our results suggest that collecting faeces from smooth, clean and non-absorbing surfaces, protected from sunlight and rain, improves DNA detection success in avian faeces. PMID- 21676194 TI - High-throughput microsatellite isolation through 454 GS-FLX Titanium pyrosequencing of enriched DNA libraries. AB - Microsatellites (or SSRs: simple sequence repeats) are among the most frequently used DNA markers in many areas of research. The use of microsatellite markers is limited by the difficulties involved in their de novo isolation from species for which no genomic resources are available. We describe here a high-throughput method for isolating microsatellite markers based on coupling multiplex microsatellite enrichment and next-generation sequencing on 454 GS-FLX Titanium platforms. The procedure was calibrated on a model species (Apis mellifera) and validated on 13 other species from various taxonomic groups (animals, plants and fungi), including taxa for which severe difficulties were previously encountered using traditional methods. We obtained from 11,497 to 34,483 sequences depending on the species and the number of detected microsatellite loci ranged from 199 to 5791. We thus demonstrated that this procedure can be readily and successfully applied to a large variety of taxonomic groups, at much lower cost than would have been possible with traditional protocols. This method is expected to speed up the acquisition of high-quality genetic markers for nonmodel organisms. PMID- 21676195 TI - Coelomic fluid: a noninvasive source of DNA in earthworms. AB - To investigate whether coelomic fluid secreted by earthworms can be a noninvasive source of DNA, we amplified and sequenced DNA extracted from the coelomic fluid and muscle tissue of eight worms. The sequences obtained using DNA extracted from both sources were identical. All cytochrome c oxidase subunit I (COI) mitochondrial DNA sequences, including those retrieved from GenBank, formed a monophyletic group of Metaphire sieboldi. The results indicate that we successfully extracted total DNA from coelomic fluid secreted by earthworm. PMID- 21676196 TI - De novo transcriptome characterization and development of genomic tools for Scabiosa columbaria L. using next-generation sequencing techniques. AB - Next-generation sequencing (NGS) technologies are increasingly applied in many organisms, including nonmodel organisms that are important for ecological and conservation purposes. Illumina and 454 sequencing are among the most used NGS technologies and have been shown to produce optimal results at reasonable costs when used together. Here, we describe the combined application of these two NGS technologies to characterize the transcriptome of a plant species of ecological and conservation relevance for which no genomic resource is available, Scabiosa columbaria. We obtained 528,557 reads from a 454 GS-FLX run and a total of 28,993,627 reads from two lanes of an Illumina GAII single run. After read trimming, the de novo assembly of both types of reads produced 109,630 contigs. Both the contigs and the >75 bp remaining singletons were blasted against the Uniprot/Swissprot database, resulting in 29,676 and 10,515 significant hits, respectively. Based on sequence similarity with known gene products, these sequences represent at least 12,516 unique genes, most of which are well covered by contig sequences. In addition, we identified 4320 microsatellite loci, of which 856 had flanking sequences suitable for PCR primer design. We also identified 75,054 putative SNPs. This annotated sequence collection and the relative molecular markers represent a main genomic resource for S. columbaria which should contribute to future research in conservation and population biology studies. Our results demonstrate the utility of NGS technologies as starting point for the development of genomic tools in nonmodel but ecologically important species. PMID- 21676197 TI - Development and characterisation of 20 microsatellite loci isolated from the large bent-wing bat, Miniopterus schreibersii (Chiroptera: Miniopteridae) and their cross-taxa utility in the family Miniopteridae. AB - The large bent-wing bat, Miniopterus schreibersii (Kuhl 1819), has a long history of taxonomic uncertainty and many populations are known to be in a state of decline. Microsatellite loci were developed for the taxonomic and population genetic assessment of the Australian complex of this species. Of the 33 primer sets designed for this research, seven (21%) were deemed suitably polymorphic for population-level analyses of the Australian taxa, with five (71%) of these loci revealing moderate to high levels of polymorphism (PIC = 0.56 to 0.91). The cross taxa utility of the M. schreibersii microsatellite markers was assessed in the microbat (Chiroptera) family Miniopteridae. Sub-species and species covering the Miniopteridae's global distribution (with the exception of the Middle East) were selected, numbering 25 taxa in total. Amplification was successful for 26 loci, of which 20 (77%) were polymorphic. High cross-taxa utility of markers was observed with amplification achieved for all taxa for between four (20%) and 20 (100%) loci, and polymorphism was considered moderate to high (PIC = 0.47-0.91) for 12 (60%) of these loci. The high cross-taxa utility of the microsatellites reported herein reveal versatile and cost-effective molecular markers, contributing an important genetic resource for the research and conservation of Miniopteridae species worldwide. PMID- 21676198 TI - Locus-specific protocol for nine different innate immune genes (antimicrobial peptides: beta-defensins) across passerine bird species reveals within-species coding variation and a case of trans-species polymorphisms. AB - We present a locus-specific protocol suitable for the investigation, from extracted DNA, into natural inter- and intra-specific genetic variation in a group of nine innate immune genes, all belonging to the beta-defensin gene family. The products of these genes encode peptides with antimicrobial properties and form part of the innate immune system. The protocol amplifies the exon coding for the peptide that interacts with invading pathogens and is applicable across a wide range of passerine bird species, although with varying success depending on species. In several species tested, we found individuals to be heterozygous at several of the genes, highlighting the existence of coding genetic variation in this part of the immune system. Furthermore, for several of the genes, alleles have been conserved at the amino acid level across taxonomically distant bird species. In one case, we observed the existence of trans-species polymorphisms, often taken as evidence of balancing selection. The method will make it possible to investigate a part of the immune system for which there exists very little information of the genetic variation in wild vertebrate populations, thus making it possible to start investigating the selective forces under which the genes are evolving and the extent to which the found genetic variation is associated with pathogen susceptibility in wild populations. PMID- 21676199 TI - Discovery of single-nucleotide polymorphisms (SNPs) in the uncharacterized genome of the ascomycete Ophiognomonia clavigignenti-juglandacearum from 454 sequence data. AB - The benefits from recent improvement in sequencing technologies, such as the Roche GS FLX (454) pyrosequencing, may be even more valuable in non-model organisms, such as many plant pathogenic fungi of economic importance. One application of this new sequencing technology is the rapid generation of genomic information to identify putative single-nucleotide polymorphisms (SNPs) to be used for population genetic, evolutionary, and phylogeographic studies on non model organisms. The focus of this research was to sequence, assemble, discover and validate SNPs in a fungal genome using 454 pyrosequencing when no reference sequence is available. Genomic DNA from eight isolates of Ophiognomonia clavigignenti-juglandacearum was pooled in one region of a four-region sequencing run on a Roche 454 GS FLX. This yielded 71 million total bases comprising 217,000 reads, 80% of which collapsed into 16,125,754 bases in 30,339 contigs upon assembly. By aligning reads from multiple isolates, we detected 298 SNPs using Roche's GS Mapper. With no reference sequence available, however, it was difficult to distinguish true polymorphisms from sequencing error. Eagleview software was used to manually examine each contig that contained one or more putative SNPs, enabling us to discard all but 45 of the original 298 putative SNPs. Of those 45 SNPs, 13 were validated using standard Sanger sequencing. This research provides a valuable genetic resource for research into the genus Ophiognomonia, demonstrates a framework for the rapid and cost-effective discovery of SNP markers in non-model organisms and should prove especially useful in the case of asexual or clonal fungi with limited genetic variability. PMID- 21676200 TI - AMaCAID: a useful tool for Accurate Marker Choice for Accession Identification and Discrimination. AB - AMaCAID is an R program designed to analyse multilocus genotypic patterns in large samples. It allows (i) the computation of the number and frequency of the different multilocus patterns available in a molecular data set and (ii) the analysis of discriminatory power of each combination of k markers among n available. It thus enables the identification of the minimum number of markers required to distinguish all the observed genotypes and the subset of markers that maximize the number of distinct genotypes. AMaCAID can be used with any kind of molecular markers, on data sets mixing different kinds of markers, but also on qualitative characters like morphological or taxonomic traits. AMaCAID has been built primarily to select subsets of markers for identifying accessions and monitoring their genetic stability during regeneration cycles in an ex situ genebank. It can, however, also be used to screen any kind of data set that characterizes a set of individuals or species (e.g. taxonomic or phylogenetic studies) for discrimination purposes. The size of the assayed sample has no limitation, but the program only performs computations on all combinations of markers when there are less than 25 markers. For larger number of markers/characters, it is possible to ask AMaCAID to screen a large but limited number of combinations of markers. We apply AMaCAID to three data sets involving either molecular or taxonomic data and give some results on the computing time of the program with respect to the size of the data set. PMID- 21676201 TI - jMHC: software assistant for multilocus genotyping of gene families using next generation amplicon sequencing. AB - Genotyping of multilocus gene families, such as the major histocompatibility complex (MHC), may be challenging because of problems with assigning alleles to loci and copy number variation among individuals. Simultaneous amplification and genotyping of multiple loci may be necessary, and in such cases, next-generation deep amplicon sequencing offers a great promise as a genotyping method of choice. Here, we describe jMHC, a computer program developed for analysing and assisting in the visualization of deep amplicon sequencing data. Software operates on FASTA files; therefore, output from any sequencing technology may be used. jMHC was designed specifically for MHC studies but it may be useful for analysing amplicons derived from other multigene families or for genotyping other polymorphic systems. The program is written in Java with user-friendly graphical interface (GUI) and can be run on Microsoft Windows, Linux OS and Mac OS. PMID- 21676202 TI - PRGmatic: an efficient pipeline for collating genome-enriched second-generation sequencing data using a 'provisional-reference genome'. AB - Second-generation sequencing is increasingly being used in combination with genome-enrichment techniques to amplify a large number of loci in many individuals for the purpose of population genetic and phylogeographic analysis. Compiling all the necessary tools to analyse these data is complex and time consuming. Here, we assemble a set of programs and pipe them together with Perl, enabling research laboratories without a dedicated bioinformatician to utilize second-generation sequencing. User input is a folder of the second-generation sequencing reads sorted by individual (in FASTA format) and pipeline output is a folder of multi-FASTA files that correspond to loci (with 2 alleles called per individual). Additional output includes a summary file of the number of individuals per locus, observed and expected heterozygosity for each locus, distribution of multiple hits and summary statistics (theta, Tajima's D, etc.). This user-friendly, open source pipeline, which requires no a priori reference genome because it constructs its own, allows the user to set various parameters (e.g. minimum coverage) in the dependent programs (CAP3, BWA, SAMtools and VarScan) and facilitates evaluation of the nature and quality of data collected prior to analysis in software packages. PMID- 21676203 TI - Nested polymerase chain reaction-based detection of Dothistroma septosporum, red band needle blight of pine, a tool in support of phytosanitary regimes. AB - Red band needle blight is one of the most important foliar diseases of Pinus species and is of increasing international forest health and biosecurity concern. To provide a rapid identification technique for this pathogen in support of official control measures, a nested polymerase chain reaction-based diagnostic assay that employs species-specific primer sets has been developed. The assay is able to detect the presence of the pathogen direct from pine needles, irrespective of host species, to within 10 fg of target DNA, the equivalent of approximately 2-3 ascospores or hyphael cells. PMID- 21676204 TI - Characterization of an intergenic polymorphic site (pp-hC1A_5) in Wolbachia pipientis (wPip). AB - Wolbachia pipientis (wPip) is an intracellular bacterium causing cytoplasmic incompatibility in arthropods, including mosquitoes of the Culex pipiens complex. Here, we present a method useful for genotyping within the wPip group. Primers were designed using a Tandem Repeat Finder program to amplify an intergenic, polymorphic site (pp-hC1A_5) of wPip. The polymorphic site is located between genes that code for polynucleotide phosphorylase and a hypothetical protein (C1A_5). Comparison of these wPip genomic regions from C. pipiens mosquitoes sampled in different geographic regions revealed deletions of fragments that proved useful in phylogenetic analysis. PMID- 21676205 TI - Improved AFLP protocol using dual-suppression PCR and its application to species with large genomes. AB - To improve the amplified fragment length polymorphism assay, dual-suppression PCR was introduced into the preamplification step of the assay. The dual-suppression PCR blocked completely the amplification of fragments with the same sequence (Bsp1407I-Bsp1407I or NlaIII-NlaIII) at both ends and amplified selectively fragments with different adaptor sequences (Bsp1407I-NlaIII) at each end. Two protocols, referred to as A and B, were established for species with medium- and large-sized genomes, respectively. Both protocols incorporated the dual suppression PCR. Protocol A resulted in high-quality electrophoretic profiles for black cottonwood and rice, which have medium-sized genomes. In protocol B, an intensely selective PCR step was added to protocol A. Protocol B yielded profiles for Japanese black pine and Japanese cedar that were improved significantly relative to protocol A: the number of strong peaks increased and that of low peaks decreased. Japanese black pine and Japanese cedar have large genomes. The optimal profiles were generated with a total of eight or nine selective nucleotides. PMID- 21676206 TI - Successful carnivore identification with faecal DNA across a fragmented Amazonian landscape. AB - The use of scat surveys to obtain DNA has been well documented in temperate areas, where DNA preservation may be more effective than in tropical forests. Samples obtained in the tropics are often exposed to high humidity, warm temperatures, frequent rain and intense sunlight, all of which can rapidly degrade DNA. Despite these potential problems, we demonstrate successful mtDNA amplification and sequencing for faeces of carnivores collected in tropical conditions and quantify how sample condition and environmental variables influence the success of PCR amplification and species identification. Additionally, the feasibility of genotyping nuclear microsatellites from jaguar (Panthera onca) faeces was investigated. From October 2007 to December 2008, 93 faecal samples were collected in the southern Brazilian Amazon. A total of eight carnivore species was successfully identified from 71% of all samples obtained. Information theoretic analysis revealed that the number of PCR attempts before a successful sequence was an important negative predictor across all three responses (success of species identification, success of species identification from the first sequence and PCR amplification success), whereas the relative importance of the other three predictors (sample condition, season and distance from forest edge) varied between the three responses. Nuclear microsatellite amplification from jaguar faeces had lower success rates (15-44%) compared with those of the mtDNA marker. Our results show that DNA obtained from faecal samples works efficiently for carnivore species identification in the Amazon forest and also shows potential for nuclear DNA analysis, thus providing a valuable tool for genetic, ecological and conservation studies. PMID- 21676207 TI - Multiplexed microsatellite recovery using massively parallel sequencing. AB - Conservation and management of natural populations requires accurate and inexpensive genotyping methods. Traditional microsatellite, or simple sequence repeat (SSR), marker analysis remains a popular genotyping method because of the comparatively low cost of marker development, ease of analysis and high power of genotype discrimination. With the availability of massively parallel sequencing (MPS), it is now possible to sequence microsatellite-enriched genomic libraries in multiplex pools. To test this approach, we prepared seven microsatellite enriched, barcoded genomic libraries from diverse taxa (two conifer trees, five birds) and sequenced these on one lane of the Illumina Genome Analyzer using paired-end 80-bp reads. In this experiment, we screened 6.1 million sequences and identified 356,958 unique microreads that contained di- or trinucleotide microsatellites. Examination of four species shows that our conversion rate from raw sequences to polymorphic markers compares favourably to Sanger- and 454-based methods. The advantage of multiplexed MPS is that the staggering capacity of modern microread sequencing is spread across many libraries; this reduces sample preparation and sequencing costs to less than $400 (USD) per species. This price is sufficiently low that microsatellite libraries could be prepared and sequenced for all 1373 organisms listed as 'threatened' and 'endangered' in the United States for under $0.5 M (USD). PMID- 21676209 TI - Plasmodial sugar transporters as anti-malarial drug targets and comparisons with other protozoa. AB - Glucose is the primary source of energy and a key substrate for most cells. Inhibition of cellular glucose uptake (the first step in its utilization) has, therefore, received attention as a potential therapeutic strategy to treat various unrelated diseases including malaria and cancers. For malaria, blood forms of parasites rely almost entirely on glycolysis for energy production and, without energy stores, they are dependent on the constant uptake of glucose. Plasmodium falciparum is the most dangerous human malarial parasite and its hexose transporter has been identified as being the major glucose transporter. In this review, recent progress regarding the validation and development of the P. falciparum hexose transporter as a drug target is described, highlighting the importance of robust target validation through both chemical and genetic methods. Therapeutic targeting potential of hexose transporters of other protozoan pathogens is also reviewed and discussed. PMID- 21676210 TI - Inequity in the use of physician services in Norway before and after introducing patient lists in primary care. AB - BACKGROUND: Inequity in use of physician services has been detected even within health care systems with universal coverage of the population through public insurance schemes. In this study we analyse and compare inequity in use of physician visits (GP and specialists) in Norway based on data from the Surveys of Living Conditions for the years 2000, 2002 and 2005. A patient list system was introduced for GPs in 2001 to improve GP accessibility, strengthen the stability of the patient-doctor relationship and ensure equity in the use of health care services for the entire population. METHOD: We measure horizontal inequity by concentration indices and investigate changes in inequity over time when decomposing the concentration indices into the contribution of its determinants. RESULTS: We find that pro-rich inequity in the probability of seeing a private outpatient specialist has declined, but still existed in 2005. CONCLUSION: Improved patient-doctor stability as well as better GP accessibility facilitated by the introduction of patient lists improved access to private specialist services. In particular the less well off benefited from this reform. PMID- 21676208 TI - Evaluation of the mechanism and principles of management of temporomandibular joint dislocation. Systematic review of literature and a proposed new classification of temporomandibular joint dislocation. AB - BACKGROUND: Virtually all the articles in literature addressed only a specific type of dislocation. The aim of this review was to project a comprehensive understanding of the pathologic processes and management of all types of dislodgement of the head of the mandibular condyle from its normal position in the glenoid fossa. In addition, a new classification of temporomandibular joint dislocation was also proposed. METHOD AND MATERIALS: A thorough computer literature search was done using the Medline, Cochrane library and Embase database. Key words like temporo-mandibular joint dislocation were used for the search. Additional manual search was done by going through published home-based and foreign articles. Case reports/series, and original articles that documented the type of dislocation, number of cases treated in the series and original articles. Treatment done and outcome of treatment were included in the study. RESULT: A total of 128 articles were reviewed out which 79 were found relevant. Of these, 26 were case reports, 17 were case series and 36 were original articles. 79 cases were acute dislocations, 35 cases were chronic protracted TMJ dislocations and 311 cases were chronic recurrent TMJ dislocations. Etiology was predominantly trauma in 60% of cases and other causes contributed about 40%. Of all the cases reviewed, only 4 were unilateral dislocation. Various treatment modalities are outlined in this report as indicated for each type of dislocation. CONCLUSION: The more complex and invasive method of treatment may not necessarily offer the best option and outcome of treatment, therefore conservative approaches should be exhausted and utilized appropriately before adopting the more invasive surgical techniques. PMID- 21676211 TI - Intraoperative radiation therapy for advanced cervical metastasis: a single institution experience. AB - BACKGROUND: The purpose of this study is to review our experience with the use of IORT for patients with advanced cervical metastasis. METHODS: Between August 1982 and July 2007, 231 patients underwent neck dissections as part of initial therapy or as salvage treatment for advanced cervical node metastases resulting from head and neck malignancies. IORT was administered as a single fraction to a dose of 15 Gy or 20 Gy in most pts. The majority was treated with 5 MeV electrons (112 pts, 50.5%). RESULTS: 1, 3, and 5 years overall survival (OS) after surgery + IORT was 58%, 34%, and 26%, respectively. Recurrence-free survival (RFS) at 1, 3, and 5 years was 66%, 55%, and 49%, respectively. Disease recurrence was documented in 83 (42.8%) pts. The majority of recurrences were regional (38 pts), as compared to local recurrence in 20 pts and distant failures in 25 pts. There were no perioperative fatalities. CONCLUSIONS: IORT results in effective local disease control at acceptable levels of toxicity. Our results support the initiation of a phase III trial comparing outcomes for patients with cervical metastasis treated with or without IORT. PMID- 21676212 TI - Albuterol enantiomer levels, lung function and QTc interval in patients with acute severe asthma and COPD in the emergency department. AB - BACKGROUND: This observational study was designed to investigate plasma levels of albuterol enantiomers among patients with acute severe asthma or COPD presenting to the emergency department, and the relationship with extra-pulmonary cardiac effects (QTc interval) and lung function. Recent reviews have raised concerns about the safety of using large doses of beta2-agonists, especially in patients with underlying cardiovascular comorbidity. It has been demonstrated that significant extrapulmonary effects can be observed in subjects given nebulised (R/S)-albuterol at a dose of as little as 6.5 mg. METHODS: Blood samples were collected and plasma/serum levels of (R)- and (S)-albuterol enantiomers were determined by LC-MS and LC-MS/MS assay. Extra-pulmonary effects measured at presentation included ECG measurements, serum potassium level and blood sugar level, which were collected from the hospital medical records. RESULTS: High plasma levels of both enantiomers were observed in some individuals, with median (range) concentrations of 8.2 (0.6-24.8) and 20.6 (0.5-57.3) ng/mL for (R)- and (S)- albuterol respectively among acute asthma subjects, and 2.1 (0.0-16.7) to 4.1 (0.0-36.1) ng/mL for (R)- and (S)- albuterol respectively among COPD subjects. Levels were not associated with an improvement in lung function or adverse cardiac effects (prolonged QTc interval). CONCLUSIONS: High plasma concentrations of albuterol were observed in both asthma and COPD patients presenting to the emergency department. Extra-pulmonary cardiac adverse effects (prolonged QTC interval) were not associated with the plasma level of (R)- or (S) albuterol when administered by inhaler in the emergency department setting. Long term effect(s) of continuous high circulating albuterol enantiomer concentrations remain unknown, and further investigations are required. PMID- 21676213 TI - Trauma is danger. AB - BACKGROUND: Trauma is one of the leading causes of death in young adult patients. Many pre-clinical and clinical studies attempt to investigate the immunological pathways involved, however the true mediators remain to be elucidated. Herein, we attempt to describe the immunologic response to systemic trauma in the context of the Danger model. DATA SOURCES: A literature search using PubMed was used to identify pertinent articles describing the Danger model in relation to trauma. CONCLUSIONS: Our knowledge of Danger signals in relation to traumatic injury is still limited. Danger/alarmin signals are the most proximal molecules in the immune response that have many possibilities for effector function in the innate and acquired immune systems. Having a full understanding of these molecules and their pathways would give us the ability to intervene at such an early stage and may prove to be more effective in blunting the post-injury inflammatory response unlike previously failed cytokine experiments. PMID- 21676214 TI - Carbon monoxide affects electrical and contractile activity of rat myocardium. AB - BACKGROUND: Carbon monoxide (CO) is a toxic gas, which also acts in the organism as a neurotransmitter. It is generated as a by-product of heme breakdown catalyzed by heme oxygenase. We have investigated changes in electrical and contractile activity of isolated rat atrial and ventricular myocardium preparations under the influence of CO. METHODS: Standard microelectrode technique was used for intracellular registration of electrical activity in isolated preparations of atrial and ventricular myocardium. Contractions of atrial myocardial stripes were registered via force transducer. RESULTS: CO (10( 4)-10(-3) M) caused prominent decrease of action potential duration (APD) in working atrial myocardium as well as significant acceleration of sinus rhythm. In addition CO reduced force of contractions and other parameters of contractile activity. Inhibitor of heme oxygenase zinc protoporphyrin IX exerts opposite effects: prolongation of action potential, reduction of sinus rhythm rate and enhancement of contractile function. Therefore, endogenous CO, which may be generated in the heart due to the presence of active heme oxygenase, is likely to exert the same effects as exogenous CO applied to the perfusing medium. In ventricular myocardium preparations exogenous CO also induced shortening of action potential, while zinc protoporphyrin IX produced the opposite effect. CONCLUSIONS: Thus, endogenous or exogenous carbon monoxide may act as an important regulator of electrical and contractile cardiac activity. PMID- 21676215 TI - Rab23 is a flagellar protein in Trypanosoma brucei. AB - BACKGROUND: Rab small GTPases are important mediators of membrane transport, and orthologues frequently retain similar locations and functions, even between highly divergent taxa. In metazoan organisms Rab23 is an important negative regulator of Sonic hedgehog signaling and is crucial for correct development and differentiation of cellular lineages by virtue of an involvement in ciliary recycling. Previously, we reported that Trypanosoma brucei Rab23 localized to the nuclear envelope 1, which is clearly inconsistent with the mammalian location and function. As T. brucei is unicellular the potential that Rab23 has no role in cell signaling was possible. Here we sought to further investigate the role(s) of Rab23 in T. brucei to determine if Rab23 was an example of a Rab protein with divergent function in distinct taxa. METHODS/MAJOR FINDINGS: The taxonomic distribution of Rab23 was examined and compared with the presence of flagella/cilia in representative taxa. Despite evidence for considerable secondary loss, we found a clear correlation between a conventional flagellar structure and the presence of a Rab23 orthologue in the genome. By epitope tagging, Rab23 was localized and found to be present at the flagellum throughout the cell cycle. However, RNAi knockdown did not result in a flagellar defect, suggesting that Rab23 is not required for construction or maintenance of the flagellum. CONCLUSIONS: The location of Rab23 at the flagellum is conserved between mammals and trypanosomes and the Rab23 gene is restricted to flagellated organisms. These data may suggest the presence of a Rab23-mediated signaling mechanism in trypanosomes. PMID- 21676216 TI - The knowledge and attitude about HIV/AIDS among Jordanian dental students: (Clinical versus pre clinical students) at the University of Jordan. AB - BACKGROUND: The present study aimed to address the suspected deficiency in the level of understanding of HIV/AIDS among clinical and pre clinical dental students at the University of Jordan. In this cross-sectional study, structured questionnaires were distributed to fifth year dental students (n = 121) and to third year dental students (n = 144) in the academic year 2008/2009. FINDINGS: Significantly higher percentage of fifth-year students compared to third-year students felt that the teaching they received on cross-infection precautions and barrier dentistry was adequate (P < 0.001). Majority (84.2%) of fifth-year students were aware that individual carrying anti-HIV antibodies to be an HIV carrier, only 57.7% of third-year students were aware of this fact (P < 0.001). Majority recognized the association between Kaposi sarcoma, oral candidiasis and hairy leukoplakia with HIV/AIDS but knowledge of the association between HIV/AIDS with less frequent lesions was inadequate.Significantly higher proportion of third-year students compared to fifth-year (39.2% vs. 26.3%) thought that HIV patients should be referred to other centers or support groups for treatment (P = 0.04). CONCLUSIONS: The level of knowledge of Jordanian dental students about HIV and AIDS was generally acceptable; there were inadequacies, however, in their understanding regarding some aspects of AIDS epidemic which demands that dental school curriculum needs some improvement. PMID- 21676218 TI - Social theory and infant feeding. AB - Clinicians, public health advisors, nutritionists and others have been attempting to increase breastfeeding rates for the last few decades, with varying degrees of success. We need social science researchers to help us understand the role of infant feeding in the family. Some researchers in the area of food and nutrition have found Pierre Bourdieu's theoretical framework helpful. In this editorial, I introduce some of Bourdieu's ideas and suggest researchers interested in infant feeding should consider testing these theories. PMID- 21676217 TI - PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or "addictive" to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab. METHODS: Sixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m2 twice daily on a 2-week-on and 1-week off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity. RESULTS: PIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013). CONCLUSIONS: PIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting from PTEN loss or PIK3CA mutations may lead to drug resistance to lapatinib and trastuzumab. PMID- 21676219 TI - Thymic function and T cell parameters in a natural human experimental model of seasonal infectious diseases and nutritional burden. AB - BACKGROUND: The study exploits a natural human experimental model of subsistence farmers experiencing chronic and seasonally modified food shortages and infectious burden. Two seasons existed, one of increased deprivation and infections (Jul-Dec), another of abundance and low infections (Jan-Jun); referred to as the hungry/high infection and harvest/low infection seasons respectively. Prior analysis showed a 10-fold excess in infectious disease associated mortality in young adults born in the hungry/high infection versus harvest/low infection season, and reduced thymic output and T cell counts in infancy. Here we report findings on the role of early life stressors as contributors to the onset of T cell immunological defects in later life. METHODS: We hypothesised that season of birth effects on thymic function and T cell immunity would be detectable in young adults since Kaplan-Meier survival curves indicated this to be the time of greatest mortality divergence. T cell subset analyses by flow-cytometry, sjTRECs, TCRVbeta repertoire and telomere length by PCR, were performed on samples from 60 males (18-23 y) selected to represent births in the hungry/high infection and harvest/low infection RESULTS: Total lymphocyte counts were normal and did not differ by birth season. CD3+ and CD4+ but not CD8+ counts were lower for those born during the hungry/high infection season. CD8+ telomere length also tended to be shorter. Overall, CD8+ TCRVbeta repertoire skewing was observed with 'public' expressions and deletions seen in TCRVbeta12/22 and TCRVbeta24, respectively but no apparent effect of birth season. CONCLUSIONS: We conclude that, although thymic function was unchanged, the CD4+ and CD3+ counts, and CD8+ telomere length results suggested that aspects of adult T cell immunity were under the influence of early life stressors. The endemicity of CMV and HBV suggested that chronic infections may modulate immunity through T cell repertoire development. The overall implications being that, this population is at an elevated risk of premature immunosenescence possibly driven by a combination of nutritional and infectious burden. PMID- 21676220 TI - Efficacy of aerobic exercise and a prudent diet for improving selected lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Studies addressing the effects of aerobic exercise and a prudent diet on lipid and lipoprotein concentrations in adults have reached conflicting conclusions. The purpose of this study was to determine the effects of aerobic exercise combined with a prudent diet on lipid and lipoprotein concentrations in adults. METHODS: Studies were located by searching nine electronic databases, cross-referencing, and expert review. Two independent reviewers selected studies that met the following criteria: (1) randomized controlled trials, (2) aerobic exercise combined with diet recommendations (saturated/trans fat intake less than 10% of total calories and cholesterol less than 300 mg/day and/or fiber intake >= 25 g/day in women and >= 35 grams per day in men), (3) intervention >= 4 weeks, (4) humans >= 18 years of age, (5) published studies, including dissertations and Master's theses, (6) studies published in any language, (7) studies published between January 1, 1955 and May 1, 2009, (8) assessment of one or more of the following lipid and lipoprotein concentrations: total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), ratio of TC to HDL-C, non-HDL-C, low density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Two reviewers independently extracted all data. Random-effects models that account for heterogeneity and 95% confidence intervals were used to pool findings. RESULTS: Of the 1,401 citations reviewed, six studies representing 16 groups (8 intervention, 8 control) and up to 559 men and women (282 intervention, 277 control) met the criteria for analysis. Statistically significant intervention minus control reductions were found for TC (-15.5 mg/dl, 95% CI, -20.3 to -10.7), TC:HDL-C (-0.4 mg/dl, 95% CI, -0.7 to -0.2), LDL-C (-9.2 mg/dl, 95% CI, -12.7 to 5.8) and TG (-10.6 mg/dl, 95% CI, -17.2 to -4.0) but not HDL-C (-0.5 mg/dl, 95% CI, -4.0 to 3.1). Changes were equivalent to reductions of 7.5%, 6.6%, 7.2% and 18.2% respectively, for TC, TC:HDL-C, LDL-C and TG. Because of missing variance statistics, non-HDL-C was excluded. CONCLUSIONS: Aerobic exercise combined with a prudent diet is highly efficacious for improving TC, TC:HDL-C, LDL-C and TG, but not HDL-C concentrations, in adults. However, additional studies are needed, including effectiveness studies using intention-to-treat analysis. PMID- 21676221 TI - Paramedic Initiated Lisinopril For Acute Stroke Treatment (PIL-FAST): study protocol for a pilot randomised controlled trial. AB - BACKGROUND: High blood pressure during acute stroke is associated with poorer stroke outcome. Previous trials have failed to show benefit from lowering blood pressure but treatment may have been commenced too late to be effective. The earliest that acute stroke treatments could be initiated is during contact with the emergency medical services (paramedics). However, experience of pre-hospital clinical trials is limited and logistical challenges are likely to be greater than for trials performed in other settings. We report the protocol for a pilot randomised controlled trial of paramedic initiated blood pressure lowering treatment for hypertension in acute stroke. METHODS: TRIAL DESIGN: Double blind parallel group external pilot randomised controlled trial. SETTING: Participant recruitment and initial treatment by North East Ambulance Service research trained paramedics responding to the emergency call. Continued treatment in three study hospitals. PARTICIPANTS: Target is recruitment of 60 adults with acute arm weakness due to suspected stroke (within 3 hours of symptom onset) and hypertension (systolic BP>160 mmHg). INTERVENTION: Lisinopril 5-10 mg (intervention group), matched placebo (control group), daily for 7 days. Randomisation: Study medication contained within identical pre-randomised "trial packs" carried by research trained paramedics. OUTCOMES: Study feasibility (recruitment rate, compliance with data collection) and clinical data to inform the design of a definitive randomised controlled trial (blood pressure monitoring, National Institute of Health Stroke Scale, Barthel ADL Index, Modified Rankin Scale, renal function). DISCUSSION: This pilot study is assessing the feasibility of a randomised controlled trial of paramedic initiated lisinopril for hypertension early after the onset of acute stroke. The results will inform the design of a definitive RCT to evaluate the effects of very early blood pressure lowering in acute stroke. TRIAL REGISTRATION: EudraCT: 2010-019180 10ClinicalTrials.gov: NCT01066572ISRCTN: 54540667. PMID- 21676222 TI - Enhanced tuberculosis case detection among substitution treatment patients: a randomized controlled trial. AB - BACKGROUND: Historically, HIV, TB (tuberculosis) and illegal drug treatment services in Estonia have been developed as vertical structures. Related health care services are often provided by different health care institutions and in different locations. This may present obstacles for vulnerable groups, such as injecting drug users (IDU), to access the needed services. We conducted a small scale randomized controlled trial to evaluate a case management intervention aimed at increasing TB screening and treatment entry among IDUs referred from a methadone drug treatment program in Johvi, North-Eastern Estonia. FINDINGS: Of the 189 potential subjects, 112 (59%) participated. HIV prevalence was 86% (n = 96) and 7.4% (n = 8) of participants were interferon gamma release assay (IGRA) positive (6.5% were both HIV and IGRA-positive, n = 7). Overall, 44% of participants (n = 49) attended TB clinic, 17 (30%) from control group and 32 (57%) from case management group (p = 0.004). None of the participants were diagnosed with TB. In a multivariate model, those randomized to case management group were more likely to access TB screening services. CONCLUSIONS: These findings demonstrate the urgent need for scaling up TB screening among IDUs and the value of more active approach in referring substitution treatment patients to TB services. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01290081. PMID- 21676223 TI - Comparative genomics of Escherichia coli isolated from patients with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is used to describe a state of idiopathic, chronic inflammation of the gastrointestinal tract. The two main phenotypes of IBD are Crohn's disease (CD) and ulcerative colitis (UC). The major cause of IBD-associated mortality is colorectal cancer. Although both host genetic and exogenous factors have been found to be involved, the aetiology of IBD is still not well understood. In this study we characterized thirteen Escherichia coli strains from patients with IBD by comparative genomic hybridization employing a microarray based on 31 sequenced E. coli genomes from a wide range of commensal and pathogenic isolates. RESULTS: The IBD isolates, obtained from patients with UC and CD, displayed remarkably heterogeneous genomic profiles with little or no evidence of group-specific determinants. No IBD specific genes were evident when compared with the prototypic CD isolate, LF82, suggesting that the IBD-inducing effect of the strains is multifactorial. Several of the IBD isolates carried a number of extraintestinal pathogenic E. coli (ExPEC)-related virulence determinants such as the pap, sfa, cdt and hly genes. The isolates were also found to carry genes of ExPEC-associated genomic islands. CONCLUSIONS: Combined, these data suggest that E. coli isolates obtained from UC and CD patients represents a heterogeneous population of strains, with genomic profiles that are indistinguishable to those of ExPEC isolates. Our findings indicate that IBD-induction from E. coli strains is multifactorial and that a range of gene products may be involved in triggering the disease. PMID- 21676224 TI - Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with obesity, insulin resistance (IR) and diabetes. Continuous positive airway pressure (CPAP) rapidly mitigates OSA in obese subjects but its metabolic effects are not well characterized. We postulated that CPAP will decrease IR, ghrelin and resistin and increase adiponectin levels in this setting. METHODS: In a pre- and post treatment, within-subject design, insulin and appetite-regulating hormones were assayed in 20 obese subjects with OSA before and after 6 months of CPAP use. Primary outcome measures included glucose, insulin, and IR levels. Other measures included ghrelin, leptin, adiponectin and resistin levels. Body weight change were recorded and used to examine the relationship between glucose regulation and appetite-regulating hormones. RESULTS: CPAP effectively improved hypoxia. However, subjects had increased insulin and IR. Fasting ghrelin decreased significantly while leptin, adiponectin and resistin remained unchanged. Forty percent of patients gained weight significantly. Changes in body weight directly correlated with changes in insulin and IR. Ghrelin changes inversely correlated with changes in IR but did not change as a function of weight. CONCLUSIONS: Weight change rather than elimination of hypoxia modulated alterations in IR in obese patients with OSA during the first six months of CPAP therapy. PMID- 21676225 TI - Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. AB - BACKGROUND: Dyskeratosis congenita (DC) is a progressive, multi-system, inherited disorder of telomere biology with high risks of morbidity and mortality from bone marrow failure, hematologic malignancy, solid tumors and pulmonary fibrosis. Hematopoietic stem cell transplantation (HSCT) can cure the bone marrow failure, but it does not eliminate the risks of other complications, for which life-long surveillance is required. Pulmonary fibrosis is a progressive and lethal complication of DC. CASE PRESENTATION: In this report, we describe a patient with DC who developed pulmonary fibrosis seven years after HSCT for severe aplastic anemia, and was successfully treated with bilateral lung transplantation. We also performed a systematic literature review to understand the burden of pulmonary disease in patients with DC who did or did not receive an HSCT. Including our patient, we identified 49 DC patients with pulmonary disease (12 after HSCT and 37 without HSCT), and 509 with no reported pulmonary complications. CONCLUSION: Our current case and literature review indicate that pulmonary morbidity is one of the major contributors to poor quality of life and reduced long-term survival in DC. We suggest that lung transplantation be considered for patients with DC who develop pulmonary fibrosis with no concurrent evidence of multi-organ failure. PMID- 21676226 TI - Outcomes of arthroscopic "remplissage": capsulotenodesis of the engaging large Hill-Sachs lesion. AB - BACKGROUND: A Hill-Sachs lesion of the humeral head after a shoulder dislocation is clinically insignificant in most cases. However, a sizable defect will engage with the anterior rim of the glenoid and cause instability even after anterior glenoid reconstruction. The purpose of this study was to evaluate the outcome of arthroscopic capsulotenodesis of the posterior capsule and infraspinatus tendon ("remplissage") to seal a large engaging Hill-Sachs lesion in an unstable shoulder. METHODS: This was a prospective follow-up study of patients who underwent arthroscopic surgery for recurrent shoulder instability with a large engaging Hill-Sachs lesion from 2007 to 2009. The clinical results were measured preoperatively and postoperatively with the Simple Shoulder test (SST) and the Rowe score for instability. RESULTS: Eleven patients met the inclusion criteria of this study. The mean follow-up time was 30 months (range 24 to 35 months). At the last follow-up, significant improvement was observed in both scores with no recurrent dislocations. The mean SST improved from 6.6 to 11 (p < 0.001). The mean Rowe Score improved from 10.6 to 85 points (p < 0.001). On average patients regained more than 80% of shoulder external rotation. CONCLUSIONS: Arthroscopic remplissage for shoulder instability is an effective soft tissue technique to seal a large engaging Hill-Sachs lesion with respect to recurrence rate, range of motion and shoulder function. PMID- 21676227 TI - Prevalence and risk factors of Hepatitis C among individuals presenting to HIV testing centers, Hawassa city, Southern Ethiopia. AB - BACKGROUND: Hepatitis C virus (HCV), either alone or in combination with Human Immunodeficiency virus (HIV), constitutes a major public health concern. This study was conducted to describe the prevalence and risk factors for HCV infection in people with and without HIV infection. METHODS: Blood samples and data on socio-demographic and risk factors for HCV infection were collected from consecutive 400 HIV- positive and 400 HIV- negative individuals attending HIV testing centers in Hawassa city, from October to December, 2008. All sera were tested for antibody to HCV infection (anti-HCV) using enzyme linked immunosorbent assay (ELISA). Sera positive for anti-HCV were further tested for viral ribonucleic acid (RNA) levels using real-time polymerase chain reaction. RESULTS: The rate of anti-HCV positivity was 10.5% in the HIV- infected individuals compared with 6% in the HIV negative group (p = 0.002). HCV-RNA was detected in 9.1% of anti-HCV positive samples and rates were comparable between HIV- infected and HIV- non-infected individuals. There was no significant difference in odds of HCV infection in participants with and without HCV risk factors in either HIV sero-group. CONCLUSION: HIV infected individuals had significantly higher rate of anti-HCV although most of them showed no evidence of viraemia. Hence, while priority should be given for HIV infected patients, testing those with anti-HCV for HCV-RNA remains important. PMID- 21676228 TI - The influences of patient's trust in medical service and attitude towards health policy on patient's overall satisfaction with medical service and sub satisfaction in China. AB - BACKGROUND: It is widely accepted that patient generates overall satisfaction with medical service and sub satisfaction on the basis of response to patient's trust in medical service and response to patient's attitude towards health policy in China. This study aimed to investigate the correlations between patient's trust in medical service/patient's attitude towards health policy and patient's overall satisfaction with medical service/sub satisfaction in current medical experience and find inspiration for future reform of China's health delivery system on improving patient's overall satisfaction with medical service and sub satisfaction in considering patient's trust in medical service and patient's attitude towards health policy. METHODS: This study collaborated with the National Bureau of Statistics to collect a sample of 3,424 residents from 17 provinces and municipalities in a 2008 China household survey on patient's trust in medical service, patient's attitude towards health policy, patient's overall satisfaction and sub satisfaction in current medical experience. RESULTS: Patient's overall satisfaction with medical service and most kinds of sub satisfaction in current medical experience were significantly influenced by both patient's trust in medical service and patient's attitude towards health policy; among all kinds of sub satisfaction in current medical experience, patient's trust in medical service/patient's attitude towards health policy had the largest influence on patient's satisfaction with medical costs, the influences of patient's trust in medical service/patient's attitude towards health policy on patient's satisfaction with doctor-patient interaction and satisfaction with treatment process were at medium-level, patient's trust in medical service/patient's attitude towards health policy had the smallest influence on patient's satisfaction with medical facilities and hospital environment, while patient's satisfaction with waiting time in hospital was not influenced by patient's trust in medical service/patient's attitude towards health policy. CONCLUSION: In order to improve patient's overall satisfaction with medical service and sub satisfaction in considering patient's trust in medical service and patient's attitude towards health policy, both improving patient's interpersonal trust in medical service from individual's own medical experience/public trust in medical service and improving patient's attitude towards health policy were indirect but effective ways. PMID- 21676229 TI - Early non-invasive cardiac output monitoring in hemodynamically unstable intensive care patients: a multi-center randomized controlled trial. AB - INTRODUCTION: Acute hemodynamic instability increases morbidity and mortality. We investigated whether early non-invasive cardiac output monitoring enhances hemodynamic stabilization and improves outcome. METHODS: A multicenter, randomized controlled trial was conducted in three European university hospital intensive care units in 2006 and 2007. A total of 388 hemodynamically unstable patients identified during their first six hours in the intensive care unit (ICU) were randomized to receive either non-invasive cardiac output monitoring for 24 hrs (minimally invasive cardiac output/MICO group; n = 201) or usual care (control group; n = 187). The main outcome measure was the proportion of patients achieving hemodynamic stability within six hours of starting the study. RESULTS: The number of hemodynamic instability criteria at baseline (MICO group mean 2.0 (SD 1.0), control group 1.8 (1.0); P = .06) and severity of illness (SAPS II score; MICO group 48 (18), control group 48 (15); P = .86)) were similar. At 6 hrs, 45 patients (22%) in the MICO group and 52 patients (28%) in the control group were hemodynamically stable (mean difference 5%; 95% confidence interval of the difference -3 to 14%; P = .24). Hemodynamic support with fluids and vasoactive drugs, and pulmonary artery catheter use (MICO group: 19%, control group: 26%; P = .11) were similar in the two groups. The median length of ICU stay was 2.0 (interquartile range 1.2 to 4.6) days in the MICO group and 2.5 (1.1 to 5.0) days in the control group (P = .38). The hospital mortality was 26% in the MICO group and 21% in the control group (P = .34). CONCLUSIONS: Minimally invasive cardiac output monitoring added to usual care does not facilitate early hemodynamic stabilization in the ICU, nor does it alter the hemodynamic support or outcome. Our results emphasize the need to evaluate technologies used to measure stroke volume and cardiac output--especially their impact on the process of care--before any large-scale outcome studies are attempted. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (Clinical Trials identifier NCT00354211). PMID- 21676230 TI - Acute reduction of serum 8-iso-PGF2-alpha and advanced oxidation protein products in vivo by a polyphenol-rich beverage; a pilot clinical study with phytochemical and in vitro antioxidant characterization. AB - BACKGROUND: Measuring the effects of the acute intake of natural products on human biomarker concentrations, such as those related to oxidation and inflammation, can be an advantageous strategy for early clinical research on an ingredient or product. METHODS: 31 total healthy subjects were randomized in a double-blinded, placebo-controlled, acute pilot study with post-hoc subgroup analysis on 20 of the subjects. The study examined the effects of a single dose of a polyphenol-rich beverage (PRB), commercially marketed as "SoZo((r))", on serum anti-inflammatory and antioxidant markers. In addition, phytochemical analyses of PRB, and in vitro antioxidant capacity were also performed. RESULTS: At 1 hour post-intake, serum values for 8-iso-PGF2-alpha and advanced oxidation protein products decreased significantly by 40% and 39%, respectively. Additionally, there was a trend toward decreased C-reactive protein, and increased nitric oxide levels. Both placebo and PRB treatment resulted in statistically significant increases in hydroxyl radical antioxidant capacity (HORAC) compared to baseline; PRB showed a higher percent change (55-75% versus 23-74% in placebo group), but the two groups did not differ significantly from each other. CONCLUSIONS: PRB produced statistically significant changes in several blood biomarkers related to antioxidant/anti-inflammatory effects. Future studies are justified to verify results and test for cumulative effects of repeated intakes of PRB. The study demonstrates the potential utility of acute biomarker measurements for evaluating antioxidant/anti-inflammatory effects of natural products. PMID- 21676231 TI - Use of 3D-computed tomography angiography for planning the surgical removal of pineal region meningiomas using Poppen's approach: a report of ten cases and a literature review. AB - BACKGROUND: There are several treatment approaches for pineal region meningiomas, such as Poppen's approach, Krause's approach and combinations of the two approaches. We present our experience with the use of 3D-computed tomography angiography for planning the surgical removal of pineal region meningiomas using a suboccipital transtentorial approach (Poppen's approach) and evaluate the role of Poppen's approach. METHODS: During the period from January 2005 to June 2010, ten patients presented to us with pineal region meningioma. MRI was routinely used to define the tumor size, position, and its relevant complications while 3D CTA was applied to define the blood supply of the tumor and the venous complex (VC) shift before operations. Most of the meningiomas had developed at both sides of the tentorial plane and extended laterally with typical characteristics of a pineal region tumor. RESULTS: All tumors were completely removed surgically without any injury to the VC. Postoperative intracranial infection occurred in one case who recovered after antibiotics were given. Postoperative intraventricular hemorrhage and pneumocephalus were found in one case, but fully recovered after conservative treatment. In the nine cases of concurrent hydrocephalus, this was gradually relieved in eight patients and the single case that became aggravated was successfully treated with ventriculoperitoneal shunt. Moreover, the follow-up MRI examinations did not indicate any recurrence of the meningiomas. CONCLUSION: We found that the use of Poppen's approach is strongly supported for the successful removal of pineal region meningiomas without serious complications. PMID- 21676232 TI - Simultaneous integrated boost for adjuvant treatment of breast cancer--intensity modulated vs. conventional radiotherapy: the IMRT-MC2 trial. AB - BACKGROUND: Radiation therapy is an essential modality in the treatment of breast cancer. Addition of radiotherapy to surgery has significantly increased local control and survival rates of the disease. However, radiotherapy is also associated with side effects, such as tissue fibrosis or enhanced vascular morbidity. Modern radiotherapy strategies, such as intensity modulated radiotherapy (IMRT), can shorten the overall treatment time by integration of the additional tumor bed boost significantly. To what extent this might be possible without impairing treatment outcome and cosmetic results remains to be clarified. METHODS/DESIGN: The IMRT-MC2 study is a prospective, two armed, multicenter, randomized phase-III-trial comparing intensity modulated radiotherapy with integrated boost to conventional radiotherapy with consecutive boost in patients with breast cancer after breast conserving surgery. 502 patients will be recruited and randomized into two arms: patients in arm A will receive IMRT in 28 fractions delivering 50.4 Gy to the breast and 64.4 Gy to the tumor bed by integrated boost, while patients in arm B will receive conventional radiotherapy of the breast in 28 fractions to a dose of 50.4 Gy and consecutive boost in 8 fractions to a total dose of 66.4 Gy. DISCUSSION: Primary objectives of the study are the evaluation of the cosmetic results 6 weeks and 2 years post treatment and the 2- and 5-year local recurrence rates for the two different radiotherapy strategies. Secondary objectives are long term overall survival, disease free survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Protocol ID: NCT01322854. PMID- 21676233 TI - The effect of a manual instrumentation technique on five types of premolar root canal geometry assessed by microcomputed tomography and three-dimensional reconstruction. AB - BACKGROUND: Together with diagnosis and treatment planning, a good knowledge of the root canal system and its frequent variations is a necessity for successful root canal therapy. The selection of instrumentation techniques for variants in internal anatomy of teeth has significant effects on the shaping ability and cleaning effectiveness. The aim of this study was to reveal the differences made by including variations in the internal anatomy of premolars into the study protocol for investigation of a single instrumentation technique (hand ProTaper instruments) assessed by microcomputed tomography and three-dimensional reconstruction. METHODS: Five single-root premolars, whose root canal systems were classified into one of five types, were scanned with micro-CT before and after preparation with a hand ProTaper instrument. Instrumentation characteristics were measured quantitatively in 3-D using a customized application framework based on MeVisLab. Numeric values were obtained for canal surface area, volume, volume changes, percentage of untouched surface, dentin wall thickness, and the thickness of dentin removed. Preparation errors were also evaluated using a color-coded reconstruction. RESULTS: Canal volumes and surface areas were increased after instrumentation. Prepared canals of all five types were straightened, with transportation toward the inner aspects of S-shaped or multiple curves. However, a ledge was formed at the apical third curve of the type II canal system and a wide range in the percentage of unchanged canal surfaces (27.4-83.0%) was recorded. The dentin walls were more than 0.3 mm thick except in a 1 mm zone from the apical surface and the hazardous area of the type II canal system after preparation with an F3 instrument. CONCLUSIONS: The 3-D color-coded images showed different morphological changes in the five types of root canal systems shaped with the same hand instrumentation technique. Premolars are among the most complex teeth for root canal treatment and instrumentation techniques for the root canal systems of premolars should be selected individually depending on the 3-D canal configuration of each tooth. Further study is needed to demonstrate the differences made by including variations in the internal anatomy of teeth into the study protocol of clinical RCT for identifying the best preparation technique. PMID- 21676234 TI - Early stage transplantation of bone marrow cells markedly ameliorates copper metabolism and restores liver function in a mouse model of Wilson disease. AB - BACKGROUND: Recent studies have demonstrated that normal bone marrow (BM) cells transplantation can correct liver injury in a mouse model of Wilson disease (WD). However, it still remains unknown when BM cells transplantation should be administered. The aim of this study was to investigate the potential impact of normal BM cells transplantation at different stages of WD to correct liver injury in toxic milk (tx) mice. METHODS: Recipient tx mice were sublethally irradiated (5 Gy) prior to transplantation. The congenic wild-type (DL) BM cells labeled with CM-DiI were transplanted via caudal vein injection into tx mice at the early (2 months of age) or late stage (5 months of age) of WD. The same volume of saline or tx BM cells were injected as controls. The DL donor cell population, copper concentration, serum ceruloplasmin oxidase activity and aspartate aminotransferase (AST) levels in the various groups were evaluated at 1, 4, 8 and 12 weeks post-transplant, respectively. RESULTS: The DL BM cells population was observed from 1 to 12 weeks and peaked by the 4th week in the recipient liver after transplantation. DL BM cells transplantation during the early stage significantly corrected copper accumulation, AST across the observed time points and serum ceruloplasmin oxidase activity through 8 to 12 weeks in tx mice compared with those treated with saline or tx BM cells (all P < 0.05). In contrast, BM cells transplantation during the late stage only corrected AST levels from 4 to 12 weeks post-transplant and copper accumulation at 12 weeks post-transplant (all P < 0.05). No significant difference was found between the saline and tx BM cells transplantation groups across the observed time points (P > 0.05). CONCLUSIONS: Early stage transplantation of normal BM cells is better than late stage transplantation in correcting liver function and copper metabolism in a mouse model of WD. PMID- 21676236 TI - Datura stramonium L. poisoning in a geophagous child: a case report. AB - Datura stramonium L. (DS) is a wild-growing plant widely distributed and easily accessible. It contains a variety of toxic anticholinergic alkaloids such as atropine, hyoscamine, and scopolamine. Voluntary or accidental ingestion can produce severe anticholinergic poisoning. We report an unusual case of DS intoxication occurring in a geophagous young child after accidental ingestion of the plant. Our case is original because of the young age of the victim and the underlying geophagia facilitating the occurrence of poisoning. PMID- 21676235 TI - Progressive dementia associated with ataxia or obesity in patients with Tropheryma whipplei encephalitis. AB - BACKGROUND: Tropheryma whipplei, the agent of Whipple's disease, causes localised infections in the absence of histological digestive involvement. Our objective is to describe T. whipplei encephalitis. METHODS: We first diagnosed a patient presenting dementia and obesity whose brain biopsy and cerebrospinal fluid specimens contained T. whipplei DNA and who responded dramatically to antibiotic treatment. We subsequently tested cerebrospinal fluid specimens and brain biopsies sent to our laboratory using T. whipplei PCR assays. PAS-staining and T. whipplei immunohistochemistry were also performed on brain biopsies. Analysis was conducted for 824 cerebrospinal fluid specimens and 16 brain biopsies. RESULTS: We diagnosed seven patients with T. whipplei encephalitis who demonstrated no digestive involvement. Detailed clinical histories were available for 5 of them. Regular PCR that targeted a monocopy sequence, PAS-staining and immunohistochemistry were negative; however, several highly sensitive and specific PCR assays targeting a repeated sequence were positive. Cognitive impairments and ataxia were the most common neurologic manifestations. Weight gain was paradoxically observed for 2 patients. The patients' responses to the antibiotic treatment were dramatic and included weight loss in the obese patients. CONCLUSIONS: We describe a new clinical condition in patients with dementia and obesity or ataxia linked to T. whipplei that may be cured with antibiotics. PMID- 21676237 TI - Predictors for pathologically confirmed aortitis after resection of the ascending aorta: a 12-year Danish nationwide population-based cross-sectional study. AB - INTRODUCTION: Assessing the prevalence of, and predictors for, pathologically confirmed inflammation of the aorta in Denmark, using a nationwide population based study design. METHODS: We identified all adults with first-time surgery on the ascending aorta between January 1, 1997 and March 1, 2009 in Denmark. Presence of aortic inflammation was ascertained through linkage to a nationwide pathology registry. We used logistic regression to compute prevalence odds ratios (ORs) for sex, age at surgery, cardiovascular risk factors, cancer, connective tissue disease, and infectious diseases associated with the presence of aortitis. RESULTS: A total of 1,210 adults underwent resection of the ascending aorta, of who 610 (50.4%) had tissue submitted for pathological examination. Aortitis was found in 37 (6.1%) patients whose tissue was examined. Ten of the 37 patients were diagnosed with conditions known to be associated with aortitis or aortic aneurysm: five patients with temporal arteritis, one with Crohn's disease, one with rheumatoid arthritis, one with systemic lupus erythematosus, one with infectious aortitis, and one with Marfan's disease. Twenty-seven patients had idiopathic aortitis. Predictors of aortitis included history of connective tissue disease (adjusted OR 4.7, 95% confidence interval (CI) 1.6, 13.6), diabetes (OR 5.2, 95% CI 0.9, 29.7), advanced age (> 67 years OR 2.5, 95% CI 0.8, 7.6), and aortic valve pathology (OR 2.3, 95% CI 1.1, 4.9). CONCLUSIONS: Aortitis was present in 6.1% of adults in Denmark who had pathological examination after resection of the ascending aorta. Predictors of inflammation included connective tissue disease, diabetes, advanced age, and aortic valve pathology. PMID- 21676238 TI - Accidental organophosphate insecticide intoxication in children: a reminder. AB - Misuse of organophosphate insecticides, even in case of domestic application, can be life threatening. We report the case of siblings admitted with respiratory distress, pinpoint pupils and slurred speech. The symptoms appear after spraying the skin by insecticides. Plasma pseudocholinesterase level appeared to be very low, consistent with acute intoxication with organophosphate insecticide.Management of organophosphate poisoning consists of airway management, administration of oxygen and fluid, as well as atropine in increasing doses and pralidoxime. Decontamination of the patient's skin and the removal of the patient's clothes are mandatory in order to avoid recontamination of the patient as well as the surrounding healthcare personnel.Plasma pseudocholinesterase analysis is a cheap and an easy indicator for organophosphate insecticides intoxications and could be used for diagnosis and treatment monitoring. PMID- 21676239 TI - A screen for peptide agonists of the G-CSF receptor. AB - BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is one of the most important pharmacologically used proteins. Potential uses beyond the stimulation of neutrophilic granulocytes are the treatment of CNS disorders. Disadvantages of the G-CSF protein as a drug are its moderate plasma half-life time and considerable production costs. We therefore conducted a screen for peptide agonists derived from the sequence of human G-CSF. FINDINGS: Despite of the high sensitivity of our screening system we could not detect any positive hits in a single peptide approach. In a multiplex approach using a permutation of any combination of 10 different peptides we could also not detect a positive block. CONCLUSIONS: We conclude that larger coherent parts of the protein or dimerising peptides may be needed to achieve activation of the receptor. PMID- 21676240 TI - Smith-Waterman peak alignment for comprehensive two-dimensional gas chromatography-mass spectrometry. AB - BACKGROUND: Comprehensive two-dimensional gas chromatography coupled with mass spectrometry (GC * GC-MS) is a powerful technique which has gained increasing attention over the last two decades. The GC * GC-MS provides much increased separation capacity, chemical selectivity and sensitivity for complex sample analysis and brings more accurate information about compound retention times and mass spectra. Despite these advantages, the retention times of the resolved peaks on the two-dimensional gas chromatographic columns are always shifted due to experimental variations, introducing difficulty in the data processing for metabolomics analysis. Therefore, the retention time variation must be adjusted in order to compare multiple metabolic profiles obtained from different conditions. RESULTS: We developed novel peak alignment algorithms for both homogeneous (acquired under the identical experimental conditions) and heterogeneous (acquired under the different experimental conditions) GC * GC-MS data using modified Smith-Waterman local alignment algorithms along with mass spectral similarity. Compared with literature reported algorithms, the proposed algorithms eliminated the detection of landmark peaks and the usage of retention time transformation. Furthermore, an automated peak alignment software package was established by implementing a likelihood function for optimal peak alignment. CONCLUSIONS: The proposed Smith-Waterman local alignment-based algorithms are capable of aligning both the homogeneous and heterogeneous data of multiple GC * GC-MS experiments without the transformation of retention times and the selection of landmark peaks. An optimal version of the SW-based algorithms was also established based on the associated likelihood function for the automatic peak alignment. The proposed alignment algorithms outperform the literature reported alignment method by analyzing the experiment data of a mixture of compound standards and a metabolite extract of mouse plasma with spiked-in compound standards. PMID- 21676241 TI - Retrospective survey for sialidase activity in Mycoplasma pneumoniae isolates from cases of community-acquired pneumonia. AB - BACKGROUND: Sialidase is a well-known virulence factor of other respiratory pathogens, but was only recently documented to occur in some species of Mycoplasma. The sialidase activity expressed can vary quantitatively among strains within a species of mycoplasma, from undetectable to amounts that correlate positively with strain virulence. Very few isolates of Mycoplasma pneumoniae had ever been examined for sialidase activity, so it was unknown whether sialidase may contribute to diseases involving this species. FINDINGS: No sialidase activity was detected by spectrofluorometric assay of 15 laboratory strains and 91 clinical isolates of M. pneumoniae banked over many years from patients having radiologically-confirmed, uncomplicated community-acquired pneumonia. CONCLUSIONS: The annotated genome of strain M129 (GenBank NC_000912, ATCC 29342), also isolated from a patient with pneumonia, accurately represents the absence of sialidase genes from strains of M. pneumoniae typically associated with uncomplicated community-acquired pneumonia. A possible involvement of sialidase in neurologic or other extra-respiratory manifestations of M. pneumoniae mycoplasmosis remains to be investigated. PMID- 21676242 TI - Rapid screening of innate immune gene expression in zebrafish using reverse transcription - multiplex ligation-dependent probe amplification. AB - BACKGROUND: With the zebrafish increasingly being used in immunology and infectious disease research, there is a need for efficient molecular tools to evaluate immune gene expression in this model species. RT-MLPA (reverse transcription - multiplex ligation-dependent probe amplification) provides a sensitive and reproducible method, in which fluorescently labelled amplification products of unique lengths are produced for a defined set of target transcripts. The method employs oligonucleotide probes that anneal to adjacent sites on a target sequence and are then joined by a heat-stable ligase. Subsequently, multiplex PCR with universal primers gives rise to amplicons that can be analyzed with standard sequencing equipment and relative quantification software. Allowing the simultaneous quantification of around 40 selected markers in a one-tube assay, RT-MLPA is highly useful for high-throughput screening applications. FINDINGS: We employed a dual-colour RT-MLPA probe design for chemical synthesis of probe pairs for 34 genes involved in Toll-like receptor signalling, transcriptional activation of the immune response, cytokine and chemokine production, and antimicrobial defence. In addition, six probe pairs were included for reference genes unaffected by infections in zebrafish. First, we established assay conditions for adult zebrafish infected with different strains of Mycobacterium marinum causing acute and chronic disease. Addition of competitor oligonucleotides was required to achieve peak heights in a similar range for genes with different expression levels. For subsequent analysis of embryonic samples it was necessary to adjust the amounts of competitor oligonucleotides, as the expression levels of several genes differed to a large extent between adult and embryonic tissues. Assay conditions established for one-day-old Salmonella typhimurium-infected embryos could be transferred without further adjustment to five-day-old M. marinum-infected larvae. RT-MLPA results were compared with results of previous transcriptome analyses and with real-time PCR data, demonstrating a good correlation between all expression analysis methods. CONCLUSIONS: The RT-MLPA assay developed in this study provides a rapid, cheap, and robust analysis tool for simultaneous quantification of a set of 34 innate immune response genes. With adjustment of conditions, the assay is suitable for infection studies in both adult and embryonic zebrafish. Application of RT-MLPA will facilitate high-throughput screening of immune responses in the zebrafish model. PMID- 21676243 TI - Healthcare costs in women with metastatic breast cancer receiving chemotherapy as their principal treatment modality. AB - BACKGROUND: The economic costs of treating patients with metastatic breast cancer have been examined in several studies, but available estimates of economic burden are at least a decade old. In this study, we characterize healthcare utilization and costs in the US among women with metastatic breast cancer receiving chemotherapy as their principal treatment modality. METHODS: Using a large private health insurance claims database (2000-2006), we identified all women initiating chemotherapy for metastatic breast cancer with no evidence of receipt of concomitant or subsequent hormonal therapy, or receipt of trastuzumab at anytime. Healthcare utilization and costs (inpatient, outpatient, medication) were estimated on a cumulative basis from date of chemotherapy initiation ("index date") to date of disenrollment from the health plan or the end of the study period, whichever occurred first. Study measures were cumulated over time using the Kaplan-Meier Sample Average (KMSA) method; 95% CIs were generated using nonparametric bootstrapping. Findings also were examined among the subgroup of patients with uncensored data. RESULTS: The study population consisted of 1444 women; mean (SD) age was 59.1 (12.1) years. Over a mean follow-up of 532 days (range: 3 to 2412), study subjects averaged 1.7 hospital admissions, 10.7 inpatient days, and 83.6 physician office and hospital outpatient visits. Mean (95% CI) cumulative total healthcare costs were $128,556 ($118,409, $137,644) per patient. Outpatient services accounted for 29% of total costs, followed by medication other than chemotherapy (26%), chemotherapy (25%), and inpatient care (20%). CONCLUSIONS: Healthcare costs-especially in the outpatient setting--are substantial among women with metastatic breast cancer for whom treatment options other than chemotherapy are limited. PMID- 21676244 TI - Immunoglobulin heavy chains in medaka (Oryzias latipes). AB - BACKGROUND: Bony fish present an immunological system, which evolved independently from those of animals that migrated to land 400 million years ago. The publication of whole genome sequences and the availability of several cDNA libraries for medaka (Oryzias latipes) permitted us to perform a thorough analysis of immunoglobulin heavy chains present in this teleost. RESULTS: We identified IgM and IgD coding ESTs, mainly in spleen, kidney and gills using published cDNA libraries but we did not find any sequence that coded for IgT or other heavy chain isotypes described in fish. The IgM - ESTs corresponded with the secreted and membrane forms and surprisingly, the latter form only presented two constant heavy chain domains. This is the first time that this short form of membrane IgM is described in a teleost. It is different from that identified in Notothenioid teleost because it does not present the typical splicing pattern of membrane IgM. The identified IgD-ESTs only present membrane transcripts, with CMU1 and five Cdelta exons. Furthermore, there are ESTs with sequences that do not have any VH which disrupt open reading frames. A scan of the medaka genome using transcripts and genomic short reads resulted in five zones within a region on chromosome 8 with CMU and Cdelta exons. Some of these exons do not form part of antibodies and were at times interspersed, suggesting a recombination process between zones. An analysis of the ESTs confirmed that no antibodies are expressed from zone 3. CONCLUSIONS: Our results suggest that the IGH locus duplication is very common among teleosts, wherein the existence of a recombination process explains the sequence homology between them. PMID- 21676247 TI - Antiproliferation and cell apoptosis inducing bioactivities of constituents from Dysosma versipellis in PC3 and Bcap-37 cell lines. AB - BACKGROUND: Recently, interest in phytochemicals from traditional Chinese medicinal herbs with the capability to inhibit cancer cells growth and proliferation has been growing rapidly due to their nontoxic nature. Dysosma versipellis as Bereridaceae plants is an endemic species in China, which has been proved to be an important Chinese herbal medicine because of its biological activity. However, systematic and comprehensive studies on the phytochemicals from Dysosma versipellis and their bioactivity are limited. RESULTS: Fifteen compounds were isolated and characterized from the roots of Dysosma versipellis, among which six compounds were isolated from this plant for the first time. The inhibitory activities of these compounds were investigated on tumor cells PC3, Bcap-37 and BGC-823 in vitro by MTT method, and the results showed that podophyllotoxone (PTO) and 4'-demethyldeoxypodophyllotoxin (DDPT) had potent inhibitory activities against the growth of human carcinoma cell lines. Subsequent fluorescence staining and flow cytometry analysis indicated that these two compounds could induce apoptosis in PC3 and Bcap-37 cells, and the apoptosis ratios reached the peak (12.0% and 14.1%) after 72 h of treatment at 20 MUM, respectively. CONCLUSIONS: This study suggests that most of the compounds from the roots of D. versipellis could inhibit the growth of human carcinoma cells. In addition, PTO and DDPT could induce apoptosis of tumor cells. PMID- 21676245 TI - Effects of obesity on bone metabolism. AB - Obesity is traditionally viewed to be beneficial to bone health because of well established positive effect of mechanical loading conferred by body weight on bone formation, despite being a risk factor for many other chronic health disorders. Although body mass has a positive effect on bone formation, whether the mass derived from an obesity condition or excessive fat accumulation is beneficial to bone remains controversial. The underline pathophysiological relationship between obesity and bone is complex and continues to be an active research area. Recent data from epidemiological and animal studies strongly support that fat accumulation is detrimental to bone mass. To our knowledge, obesity possibly affects bone metabolism through several mechanisms. Because both adipocytes and osteoblasts are derived from a common multipotential mesenchymal stem cell, obesity may increase adipocyte differentiation and fat accumulation while decrease osteoblast differentiation and bone formation. Obesity is associated with chronic inflammation. The increased circulating and tissue proinflammatory cytokines in obesity may promote osteoclast activity and bone resorption through modifying the receptor activator of NF-kappaB (RANK)/RANK ligand/osteoprotegerin pathway. Furthermore, the excessive secretion of leptin and/or decreased production of adiponectin by adipocytes in obesity may either directly affect bone formation or indirectly affect bone resorption through up regulated proinflammatory cytokine production. Finally, high-fat intake may interfere with intestinal calcium absorption and therefore decrease calcium availability for bone formation. Unraveling the relationship between fat and bone metabolism at molecular level may help us to develop therapeutic agents to prevent or treat both obesity and osteoporosis. Obesity, defined as having a body mass index >= 30 kg/m2, is a condition in which excessive body fat accumulates to a degree that adversely affects health. The rates of obesity rates have doubled since 1980 and as of 2007, 33% of men and 35% of women in the US are obese. Obesity is positively associated to many chronic disorders such as hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, and certain cancers. It is estimated that the direct medical cost associated with obesity in the United States is ~$100 billion per year.Bone mass and strength decrease during adulthood, especially in women after menopause. These changes can culminate in osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration resulting in increased bone fracture risk. It is estimated that there are about 10 million Americans over the age of 50 who have osteoporosis while another 34 million people are at risk of developing the disease. In 2001, osteoporosis alone accounted for some $17 billion in direct annual healthcare expenditure. Several lines of evidence suggest that obesity and bone metabolism are interrelated. First, both osteoblasts (bone forming cells) and adipocytes (energy storing cells) are derived from a common mesenchymal stem cell and agents inhibiting adipogenesis stimulated osteoblast differentiation and vice versa, those inhibiting osteoblastogenesis increased adipogenesis. Second, decreased bone marrow osteoblastogenesis with aging is usually accompanied with increased marrow adipogenesis. Third, chronic use of steroid hormone, such as glucocorticoid, results in obesity accompanied by rapid bone loss. Fourth, both obesity and osteoporosis are associated with elevated oxidative stress and increased production of proinflammatory cytokines. At present, the mechanisms for the effects of obesity on bone metabolism are not well defined and will be the focus of this review. PMID- 21676248 TI - An alternative pathway for alphavirus entry. AB - The study of alphavirus entry has been complicated by an inability to clearly identify a receptor and by experiments which only tangentially and indirectly examine the process, producing results that are difficult to interpret. The mechanism of entry has been widely accepted to be by endocytosis followed by acidification of the endosome resulting in virus membrane-endosome membrane fusion. This mechanism has come under scrutiny as better purification protocols and improved methods of analysis have been brought to the study. Results have been obtained that suggest alphaviruses infect cells directly at the plasma membrane without the involvement of endocytosis, exposure to acid pH, or membrane fusion. In this review we compare the data which support the two models and make the case for an alternative pathway of entry by alphaviruses. PMID- 21676249 TI - Diarrheal disease risk in rural Bangladesh decreases as tubewell density increases: a zero-inflated and geographically weighted analysis. AB - BACKGROUND: This study investigates the impact of tubewell user density on cholera and shigellosis events in Matlab, Bangladesh between 2002 and 2004. Household-level demographic, health, and water infrastructure data were incorporated into a local geographic information systems (GIS) database. Geographically-weighted regression (GWR) models were constructed to identify spatial variation of relationships across the study area. Zero-inflated negative binomial regression models were run to simultaneously measure the likelihood of increased magnitude of disease events and the likelihood of zero cholera or shigellosis events. The aim of this study was to examine the effect of tubewell density on both the occurrence of diarrheal disease and the magnitude of diarrheal disease incidence. RESULTS: In Matlab, households with greater tubewell density were more likely to report zero cholera or shigellosis events. Results for both cholera and shigellosis GWR models suggest that tubewell density effects are spatially stationary and the use of non-spatial statistical methods is appropriate. CONCLUSIONS: Increasing the amount of drinking water available to households through increased density of tubewells contributed to lower reports of cholera and shigellosis events in rural Bangladesh. Our findings demonstrate the importance of tubewell installation and access to groundwater in reducing diarrheal disease events in the developing world. PMID- 21676250 TI - Need for weight management in Switzerland: findings from National Blood Pressure Week 2009. AB - BACKGROUND: The Swiss Health Survey (SHS) provides the only source of data for monitoring overweight and obesity in the general population in Switzerland. However, this survey reports body mass index (BMI) based on self-reported height and weight, and is therefore subject to measurement errors. Moreover, it is not possible to differentiate between overall and abdominal overweight. In this study, we aimed to gain a better understanding of the need for weight management in the general population of Switzerland by exploring and comparing prevalence rates of BMI and waist circumference (WC) based on physical measurements by trained observers, based on data from the 2009 National Blood Pressure Week (NBPW). METHODS: Sample selection was based on a one-stage cluster design. A total of 385 pharmacies representing 3,600 subjects were randomly selected from pharmacies participating in NBPW. BMI measures based on physical weight and height (NBPW) were compared with self-reported BMI measures from the SHS. BMI and WC measurements from NBPW were then used to produce population estimates of overweight and obesity. RESULTS: BMI-based overall prevalence of overweight and obesity was 43.6%, which was 4.7% higher than the value based on the respective SHS data. Overweight and obesity were more common in men (54.3%) than in women (33.5%). However, the overall prevalence of increased WC in the general population was estimated to be 64.4%, with more women (68.4%) than men (60.1%) exhibiting a WC above the threshold. The prevalence of subjects requiring weight management in the Swiss population remained high, even after adjusting WC for false positive and negative cases. CONCLUSIONS: Firstly, it may be more appropriate for health promotion programs to address the wider group identified by WC, which includes subjects who need to reduce their weight, or gain no further weight. Secondly, the gender differences are reversed depending on the use of WC or BMI to identify subjects suitable for health promotion programs; more women than men are identified by WC, and more men than women using BMI. These differences should be accounted for in gender-specific health promotion programs. PMID- 21676251 TI - Evolution of the mammalian lysozyme gene family. AB - BACKGROUND: Lysozyme c (chicken-type lysozyme) has an important role in host defense, and has been extensively studied as a model in molecular biology, enzymology, protein chemistry, and crystallography. Traditionally, lysozyme c has been considered to be part of a small family that includes genes for two other proteins, lactalbumin, which is found only in mammals, and calcium-binding lysozyme, which is found in only a few species of birds and mammals. More recently, additional testes-expressed members of this family have been identified in human and mouse, suggesting that the mammalian lysozyme gene family is larger than previously known. RESULTS: Here we characterize the extent and diversity of the lysozyme gene family in the genomes of phylogenetically diverse mammals, and show that this family contains at least eight different genes that likely duplicated prior to the diversification of extant mammals. These duplicated genes have largely been maintained, both in intron-exon structure and in genomic context, throughout mammalian evolution. CONCLUSIONS: The mammalian lysozyme gene family is much larger than previously appreciated and consists of at least eight distinct genes scattered around the genome. Since the lysozyme c and lactalbumin proteins have acquired very different functions during evolution, it is likely that many of the other members of the lysozyme-like family will also have diverse and unexpected biological properties. PMID- 21676252 TI - Phylogenomic analyses of malaria parasites and evolution of their exported proteins. AB - BACKGROUND: Plasmodium falciparum is the most malignant agent of human malaria. It belongs to the taxon Laverania, which includes other ape-infecting Plasmodium species. The origin of the Laverania is still debated. P. falciparum exports pathogenicity-related proteins into the host cell using the Plasmodium export element (PEXEL). Predictions based on the presence of a PEXEL motif suggest that more than 300 proteins are exported by P. falciparum, while there are many fewer exported proteins in non-Laverania. RESULTS: A whole-genome approach was applied to resolve the phylogeny of eight Plasmodium species and four outgroup taxa. By using 218 orthologous proteins we received unanimous support for a sister group position of Laverania and avian malaria parasites. This observation was corroborated by the analyses of 28 exported proteins with orthologs present in all Plasmodium species. Most interestingly, several deviations from the P. falciparum PEXEL motif were found to be present in the orthologous sequences of non-Laverania. CONCLUSION: Our phylogenomic analyses strongly support the hypotheses that the Laverania have been founded by a single Plasmodium species switching from birds to African great apes or vice versa. The deviations from the canonical PEXEL motif in orthologs may explain the comparably low number of exported proteins that have been predicted in non-Laverania. PMID- 21676253 TI - A metabolic link between mitochondrial ATP synthesis and liver glycogen metabolism: NMR study in rats re-fed with butyrate and/or glucose. AB - BACKGROUND: Butyrate, end-product of intestinal fermentation, is known to impair oxidative phosphorylation in rat liver and could disturb glycogen synthesis depending on the ATP supplied by mitochondrial oxidative phosphorylation and cytosolic glycolysis. METHODS: In 48 hr-fasting rats, hepatic changes of glycogen and total ATP contents and unidirectional flux of mitochondrial ATP synthesis were evaluated by ex vivo 31P NMR immediately after perfusion and isolation of liver, from 0 to 10 hours after force-feeding with (butyrate 1.90 mg + glucose 14.0 mg.g-1 body weight) or isocaloric glucose (18.2 mg.g-1 bw); measurements reflected in vivo situation at each time of liver excision. The contribution of energetic metabolism to glycogen metabolism was estimated. RESULTS: A net linear flux of glycogen synthesis (~11.10 +/- 0.60 MUmol glucosyl units.h-1.g-1 liver wet weight) occurred until the 6th hr post-feeding in both groups, whereas butyrate delayed it until the 8th hr. A linear correlation between total ATP and glycogen contents was obtained (r2 = 0.99) only during net glycogen synthesis. Mitochondrial ATP turnover, calculated after specific inhibition of glycolysis, was stable (~0.70 +/- 0.25 MUmol.min-1.g-1 liver ww) during the first two hr whatever the force-feeding, and increased transiently about two-fold at the 3rd hr in glucose. Butyrate delayed the transient increase (1.80 +/- 0.33 MUmol.min 1.g-1 liver ww) to the 6th hr post-feeding. Net glycogenolysis always appeared after the 8th hr, whereas flux of mitochondrial ATP synthesis returned to near basal level (0.91 +/- 0.19 MUmol.min-1.g-1 liver ww). CONCLUSION: In liver from 48 hr-starved rats, the energy need for net glycogen synthesis from exogenous glucose corresponds to ~50% of basal mitochondrial ATP turnover. The evidence of a late and transient increase in mitochondrial ATP turnover reflects an energetic need, probably linked to a glycogen cycling. Butyrate, known to reduce oxidative phosphorylation yield and to induce a glucose-sparing effect, delayed the transient increase in mitochondrial ATP turnover and hence energy contribution to glycogen metabolism. PMID- 21676254 TI - Utility of arsenic-treated bird skins for DNA extraction. AB - BACKGROUND: Natural history museums receive a rapidly growing number of requests for tissue samples from preserved specimens for DNA-based studies. Traditionally, dried vertebrate specimens were treated with arsenic because of its toxicity and insect-repellent effect. Arsenic has negative effects on in vivo DNA repair enzymes and consequently may inhibit PCR performance. In bird collections, foot pad samples are often requested since the feet were not regularly treated with arsenic and because they are assumed to provide substantial amounts of DNA. However, the actual influence of arsenic on DNA analyses has never been tested. FINDINGS: PCR success of both foot pad and body skin samples was significantly lower in arsenic-treated samples. In general, foot pads performed better than body skin samples. Moreover, PCR success depends on collection date in which younger samples yielded better results. While the addition of arsenic solution to the PCR mixture had a clear negative effect on PCR performance after the threshold of 5.4 MUg/MUl, such high doses of arsenic are highly unlikely to occur in dried zoological specimens. CONCLUSIONS: While lower PCR success in older samples might be due to age effects and/or DNA damage through arsenic treatment, our results show no inhibiting effect on DNA polymerase. We assume that DNA degradation proceeds more rapidly in thin tissue layers with low cell numbers that are susceptible to external abiotic influences. In contrast, in thicker parts of a specimen, such as foot pads, the outermost horny skin may act as an additional barrier. Since foot pads often performed better than body skin samples, the intention to preserve morphologically important structures of a specimen still conflicts with the aim to obtain optimal PCR success. Thus, body skin samples from recently collected specimens should be considered as alternative sources of DNA. PMID- 21676256 TI - Lipid profiles of female and male Drosophila. AB - BACKGROUND: D. melanogaster is increasingly used as a lipid metabolism model, but the D. melanogaster metabolome is not well studied. A number of studies strongly suggest that lipid metabolism is linked to sexual behavior and gametogenesis. FINDINGS: We determined the levels of 400 different lipids in the non-gonadal soma of D. melanogaster females and males. We found higher levels of saturated cholesterol esters and lysophosphatidylcholine in males, and higher levels of polyunsaturated cholesterol esters in females. We also determined the levels of these lipids in females and males without a germline to determine if the absence of gamete "sinks" for metabolic products, such as yolk and lipid deposits in eggs, altered somatic lipid profiles. We observed little change in lipid profiles between these samples. CONCLUSIONS: Overall lipid compositions are similar between the sexes, although there are differences in saturation states of two lipid classes, where saturated fatty acids were male-biased and polyunsaturated fatty acids were female-biased. The presence of a germline did not significantly influence lipid profiles, raising the possibility that germline-dependent changes in metabolic gene expression patterns serve a homeostatic purpose. PMID- 21676255 TI - Efficacy of hypnosis/guided imagery in fibromyalgia syndrome--a systematic review and meta-analysis of controlled trials. AB - BACKGROUND: Recent systematic reviews on psychological therapies of fibromyalgia syndrome (FMS) did not consider hypnosis/guided imagery (H/GI). Therefore we performed a systematic review with meta-analysis of the efficacy of H/GI in FMS. METHODS: We screened http://ClinicalTrials.gov, Cochrane Library, MEDLINE, PsycINFO and SCOPUS (through December 2010). (Quasi-) randomized controlled trials (CTs) comparing H/GI with controls were analyzed. Outcomes were pain, sleep, fatigue, depressed mood and health-related quality of life (HRQOL). Effects were summarized using standardized mean differences (SMD). RESULTS: Six CTs with 239 subjects with a median of 9 (range 7-12) H/GI-sessions were analysed. The median number of patients in the H/GI groups was 20 (range 8-26). Three studies performed follow-ups. H/GI reduced pain compared to controls at final treatment (SMD -1.17 [95% CI -2.21, -0.13]; p = 0.03). H/GI did not reduce limitations of HRQOL at final treatment (SMD -0.90 [95% CI -2.55, 0.76]; p = 0.29) compared to controls. Effect sizes on fatigue, sleep and depressed mood at final treatment and follow-up and on pain and HRQOL at follow-up were not calculated because of limited data available. The significant effect on pain at final treatment was associated with low methodological and low treatment quality. CONCLUSION: Further studies with better treatment quality and adequate methodological quality assessing all key domains of FMS are necessary to clarify the efficacy of H/GI in FMS. PMID- 21676257 TI - Are primary care practitioners in Barbados following diabetes guidelines? - a chart audit with comparison between public and private care sectors. AB - BACKGROUND: Over 19% of the population >= 40 years of age in Barbados are diabetic. The quality of diabetes primary care is uncertain. FINDINGS: Charts of diabetic and hypertensive patients were randomly sampled at all public and 20 private sector primary care clinics. Charts of all diabetic patients >= 40 years of age were then selected. Processes of care, and quality targets for blood pressure (BP), fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c) were documented.252 charts of diabetic patients (125 public and 127 private) were audited. Patients had the following characteristics: mean age 64 years, female gender 61%, mean duration of diagnosis 9 years, and hypertension diagnosed 78%. Patients had an average of 4.7 clinic visits per year, 66% were prescribed metformin, 68% a sulphonylurea, 25% a statin, 21% insulin, 15% aspirin and 12% a glucosidase inhibitor. Public patients compared to private patients were more likely to be female (77% vs. 46%, p < 0.01); have a longer duration of diagnosis (11.4 vs. 6.6 years, p < 0.01), have more clinic visits per year (5.2 vs. 4.3, p < 0.01), and to be using insulin (28 vs. 15% p = 0.01). Over a 2 year period, the proportion of charts with the following recorded at least once was: BP 98%, weight 80%, FBG 76%, total cholesterol 72%, urine tested for albumin 66%, serum creatinine 62%, dietary advice 61%, exercise advice 49%, lipid profile 48%, foot examination 41%, HbA1c 33%, dietician referral 23%, retinal examination 18%, tobacco use 17%, body mass index 0%, and waist circumference 0%. Public patients were more likely to have recorded: weight (92% vs. 68%, p = < 0.01); tests for total cholesterol (78% vs. 65%, p = 0.02), albuminuria (72% vs. 59%, p = 0.03), serum creatinine (79% vs. 44%, p < 0.01), and foot examination (50% vs. 32%, p = < 0.01); dietician referral (37% vs. 8%, p < 0.01), and tobacco use (26% vs. 8%, p < 0.01). For those tested, the most recent BP was < 140/90 for 43%, HBA1c was < 7% for 28%, and FBG was < 6.7 mmol/L for 27%. CONCLUSIONS: Interventions such as body mass assessment, lifestyle advice, screening for retinopathy, monitoring blood glucose control, and achieving BP and glycaemic targets need improvement. PMID- 21676258 TI - Effectiveness of photodynamic therapy for mammary and extra-mammary Paget's disease: a state of the science review. AB - BACKGROUND: Paget's disease is a rare skin disorder occurring in the breast (mammary) or in the groin, genital, peri-anal and axillary regions (extra mammary). Typical treatment involves surgical excision, which in the case of extra-mammary Paget's disease, can lead to significant morbidity. Photodynamic therapy (PDT) which uses a topical or intravenous photosensitizing agent that is activated by a light source to ablate abnormal tissue, offers a minimally invasive alternative. The purpose of this study was to assess the effectiveness of photodynamic therapy in the treatment of Paget's disease. METHODS: Following Cochrane guidelines, a comprehensive systematic review of all clinical studies and reports examining the use of PDT for mammary and extra-mammary Paget's disease was conducted. Study quality was assessed using the Oxford Levels of Evidence Scale. RESULTS: 21 retrospective and 2 prospective non-comparative studies were identified and included in the review: 9 case reports with 1-2 patients and 14 case series with 1-16 patients. These reports totalled 99 patients with 133 extra-mammary Paget's lesions and 3 patients (with 3 lesions) with mammary Paget's disease. Follow-up periods were typically one year or less, with 77/133 extra-mammary lesions exhibiting complete response to PDT. One recurrent mammary skin lesion and two mammary lesions treated concomitantly with surgery also exhibited complete responses. CONCLUSIONS: Evidence of the effectiveness of PDT for Paget's disease is promising, but limited. This may, in part, be explained by the rarity of the condition, making controlled comparative clinical trials challenging. PMID- 21676259 TI - Factors influencing patient willingness to participate in genetic research after a myocardial infarction. AB - BACKGROUND: Achieving 'personalized medicine' requires enrolling representative cohorts into genetic studies, but patient self-selection may introduce bias. We sought to identify characteristics associated with genetic consent in a myocardial infarction (MI) registry. METHODS: We assessed correlates of participation in the genetic sub-study of TRIUMPH, a prospective MI registry (n = 4,340) from 24 US hospitals between April 2005 and December 2008. Factors examined included extensive socio-demographics factors, clinical variables, and study site. Predictors of consent were identified using hierarchical modified Poisson regression, adjusting for study site. Variation in consent rates across hospitals were quantified by the median rate ratio (MRR). RESULTS: Most subjects consented to donation of their genetic material (n = 3,484; 80%). Participation rates varied greatly between sites, from 40% to 100%. After adjustment for confounding factors, the MRR for hospital was 1.22 (95% confidence interval (CI) 1.11 to 1.29). The only patient-level factors associated with consent were race (RR 0.93 for African Americans versus whites, 95% CI 0.88 to 0.99) and body mass index (RR 1.03 for BMI >= 25, 95% CI 1.01 to 1.06). CONCLUSION: Among patients with an MI there were notable differences in genetic consent by study site, but little association with patient-level factors. This suggests that variation in the way information is presented during recruitment, or other site factors, strongly influence patients' decision to participate in genetic studies. PMID- 21676260 TI - Albumin binding ligands and albumin conjugate uptake by cancer cells. AB - The scope of this short review is to summarise the knowledge gleaned from the fate of drugs transported by albumin upon contact with the target cancer cell or cells in inflamed tissues. The authors expertise covers covalently bound drugs and their cellular uptake and release from albumin. This review therefore aims to deduce what will happen to drugs such as insulin detemir which is considered to bind non-covalently to albumin and may have a fate similar to fatty acids transported by albumin. PMID- 21676261 TI - Inapplicability of advance directives in a paternalistic setting: the case of a post-communist health system. AB - BACKGROUND: The Albanian medical system and Albanian health legislation have adopted a paternalistic position with regard to individual decision making. This reflects the practices of a not-so-remote past when state-run facilities and a totalitarian philosophy of medical care were politically imposed. Because of this history, advance directives concerning treatment refusal and do-not-resuscitate decisions are still extremely uncommon in Albania. Medical teams cannot abstain from intervening even when the patient explicitly and repeatedly solicits therapeutic abstinence. The Albanian law on health care has no provisions regarding limits or withdrawal of treatment. This restricts the individual's healthcare choices. DISCUSSION: The question of 'medically futile' interventions and pointless life-prolonging treatment has been discussed by several authors. Dutch physicians call such interventions 'medisch zinloos' (senseless), and the Netherlands, as one of the first states to legislate on end-of-life situations, actually regulates such issues through appropriate laws. In contrast, leaving an 'advance directive' is not a viable option for Albanian ailing individuals of advanced age. Verbal requests are provided during periods of mental competence, but unfortunately such instructions are rarely taken seriously, and none of them has ever been upheld in a legal or other official forum. SUMMARY: End-of-life decisions, treatment refusal and do-not-resuscitate policies are hazardous options in Albania, from the legal point of view. Complying with them involves significant risk on the part of the physician. Culturally, the application of such instructions is influenced from a mixture of religious beliefs, death coping behaviors and an immense confusion concerning the role of proxies as decision makers. Nevertheless, Albanian tradition is familiar with the notion of 'amanet', a sort of living will that mainly deals the property and inheritance issues. Such living wills, verbally transmitted, may in certain cases include advance directives regarding end-of-life decisions of the patient including refusal or termination of futile medical treatments. Since these living wills are never formally and legally validated, their application is impossible and treatment refusal remains still non practicable. Tricks to avoid institutional treatment under desperate conditions are used, aiming to provide legal coverage for medical teams and relatives that in extreme situations comply with the advice of withholding senseless treatment. PMID- 21676262 TI - Longitudinal study of leptin levels in chronic hemodialysis patients. AB - BACKGROUND: The influence of serum leptin levels on nutritional status and survival in chronic hemodialysis patients remained to be elucidated. We conducted a prospective longitudinal study of leptin levels and nutritional parameters to determine whether changes of serum leptin levels modify nutritional status and survival in a cohort of prevalent hemodialysis patients. METHODS: Leptin, dietary energy and protein intake, biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18 and 24 months following enrollment, in 101 prevalent hemodialysis patients (37% women) with a mean age of 64.6 +/- 11.5 years. Observation of this cohort was continued over 2 additional years. Changes in repeated measures were evaluated, with adjustment for baseline differences in demographic and clinical parameters. RESULTS: Significant reduction of leptin levels with time were observed (linear estimate: -2.5010 +/- 0.57 ng/ml/2 y; p < 0.001) with a more rapid decline in leptin levels in the highest leptin tertile in both unadjusted (p = 0.007) and fully adjusted (p = 0.047) models. A significant reduction in body composition parameters over time was observed, but was not influenced by leptin (leptin-by-time interactions were not significant). No significant associations were noted between leptin levels and changes in dietary protein or energy intake, or laboratory nutritional markers. Finally, cumulative incidences of survival were unaffected by the baseline serum leptin levels. CONCLUSIONS: Thus leptin levels reflect fat mass depots, rather than independently contributing to uremic anorexia or modifying nutritional status and/or survival in chronic hemodialysis patients. The importance of such information is high if leptin is contemplated as a potential therapeutic target in hemodialysis patients. PMID- 21676263 TI - FFCA: a feasibility-based method for flux coupling analysis of metabolic networks. AB - BACKGROUND: Flux coupling analysis (FCA) is a useful method for finding dependencies between fluxes of a metabolic network at steady-state. FCA classifies reactions into subsets (called coupled reaction sets) in which activity of one reaction implies activity of another reaction. Several approaches for FCA have been proposed in the literature. RESULTS: We introduce a new FCA algorithm, FFCA (Feasibility-based Flux Coupling Analysis), which is based on checking the feasibility of a system of linear inequalities. We show on a set of benchmarks that for genome-scale networks FFCA is faster than other existing FCA methods. CONCLUSIONS: We present FFCA as a new method for flux coupling analysis and prove it to be faster than existing approaches. A corresponding software tool is freely available for non-commercial use at http://www.bioinformatics.org/ffca/. PMID- 21676264 TI - Prozone in malaria rapid diagnostics tests: how many cases are missed? AB - BACKGROUND: Prozone means false-negative or false-low results in antigen-antibody reactions, due to an excess of either antigen or antibody. The present study prospectively assessed its frequency for malaria rapid diagnostic tests (RDTs) and Plasmodium falciparum samples in an endemic field setting. METHODS: From January to April 2010, blood samples with P. falciparum high parasitaemia (>= 4% red blood cells infected) were obtained from patients presenting at the Provincial Hospital of Tete (Mozambique). Samples were tested undiluted and 10 fold diluted in saline with a panel of RDTs and results were scored for line intensity (no line visible, faint, weak, medium and strong). Prozone was defined as a sample which showed no visible test line or a faint or weak test line when tested undiluted, and a visible test line of higher intensity when tested 10-fold diluted, as observed by two blinded observers and upon duplicate testing. RESULTS: A total of 873/7,543 (11.6%) samples showed P. falciparum, 92 (10.5%) had high parasitaemia and 76 were available for prozone testing. None of the two Pf-pLDH RDTs, but all six HRP-2 RDTs showed prozone, at frequencies between 6.7% and 38.2%. Negative and faint HRP-2 lines accounted for four (3.8%) and 15 (14.4%) of the 104 prozone results in two RDT brands. For the most affected brand, the proportions of prozone with no visible or faint HRP-2 lines were 10.9% (CI: 5.34-19.08), 1.2% (CI: 0.55-2.10) and 0.1% (CI: 0.06-0.24) among samples with high parasitaemia, all positive samples and all submitted samples respectively. Prozone occurred mainly, but not exclusively, among young children. CONCLUSION: Prozone occurs at different frequency and intensity in HRP-2 RDTs and may decrease diagnostic accuracy in the most affected RDTs. PMID- 21676265 TI - Measles transmission from an anthroposophic community to the general population, Germany 2008. AB - BACKGROUND: In Germany, measles vaccination coverage with two doses is not yet sufficient to prevent regional outbreaks. Among the 16 German federal states, vaccination coverage was lowest in Bavaria with 85% in 2008. From March to mid April 2008, four neighbouring Bavarian counties reported 55 measles-cases mostly linked to an ongoing measles outbreak in an anthroposophic school in Austria. We investigated this outbreak to guide future public health action. METHODS: We applied the German national case-definition for measles and collected data using the national surveillance system and a questionnaire. Measles cases with disease onset a maximum of 18 days apart and spatial contact (e.g. same household, same school) were summed up in clusters. Two different interventions, which were implemented in schools and kindergartens in Bavaria, were compared by their impact on the size and duration of measles clusters. Susceptible persons were excluded from schools or kindergartens either with the first (intervention A) or second (intervention B) measles case occurring in the respective institution. RESULTS: Among the 217 Bavarian measles cases identified from March-July 2008, 28 (13%) cases were attendees of the anthroposophic school in Austria. In total, vaccination status was known in 161 (74%) cases and 156 (97%) of them were not vaccinated. The main factor for non-vaccination was "fear of vaccine-related adverse events" (33%). Twenty-nine (18%) of 161 cases suffered complications. Exclusively genotype D5 was detected. Overall, 184 cases could be epidemiologically grouped into 59 clusters. Of those, 41 clusters could be linked to households and 13 to schools or kindergartens. The effect of intervention A and B was analysed in 10 school or kindergarten clusters. Depending on the respective intervention A or B, the median number of cases per cluster was 3 versus 13 (p = 0.05), and the median duration of a cluster was 3 versus 26 days (p = 0.13). CONCLUSIONS: Introduction of measles virus into a pocket of susceptible persons (e.g. vaccination opponents or sceptics) may lead to large outbreaks in the general population, if the general population's vaccination coverage is below the WHO recommended level. Education on the safety of measles vaccine needs to be strengthened to increase measles vaccination coverage. Early intervention may limit spread in schools or kindergartens. Suspected measles has to be reported immediately to the local health authorities in order to allow intervention as early as possible. PMID- 21676266 TI - Comparative analysis of the ATRX promoter and 5' regulatory region reveals conserved regulatory elements which are linked to roles in neurodevelopment, alpha-globin regulation and testicular function. AB - BACKGROUND: ATRX is a tightly-regulated multifunctional protein with crucial roles in mammalian development. Mutations in the ATRX gene cause ATR-X syndrome, an X-linked recessive developmental disorder resulting in severe mental retardation and mild alpha-thalassemia with facial, skeletal and genital abnormalities. Although ubiquitously expressed the clinical features of the syndrome indicate that ATRX is not likely to be a global regulator of gene expression but involved in regulating specific target genes. The regulation of ATRX expression is not well understood and this is reflected by the current lack of identified upstream regulators. The availability of genomic data from a range of species and the very highly conserved 5' regulatory regions of the ATRX gene has allowed us to investigate putative transcription factor binding sites (TFBSs) in evolutionarily conserved regions of the mammalian ATRX promoter. RESULTS: We identified 12 highly conserved TFBSs of key gene regulators involved in biologically relevant processes such as neural and testis development and alpha globin regulation. CONCLUSIONS: Our results reveal potentially important regulatory elements in the ATRX gene which may lead to the identification of upstream regulators of ATRX and aid in the understanding of the molecular mechanisms that underlie ATR-X syndrome. PMID- 21676267 TI - Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation. AB - BACKGROUND: Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. METHODS: Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1) sham (Group S), which underwent removal of the L6 transverse process; (2) ligated (Group L), which underwent left L5 spinal nerve ligation (SNL); and (3) pretreated (Group P), which underwent L5 SNL and was pretreated with intrathecal 2% lidocaine (50 MUl). Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav1.3 and Nav1.8) in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3) and 7 (POD7). RESULTS: Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up regulation of Nav1.3 and down-regulation of Nav1.8, and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P), as measured on POD3, palliated both mechanical allodynia (p < 0.01) and thermal hyperalgesia (p < 0.001), attenuated Nav1.3 up-regulation (p = 0.003), and mitigated spinal microglial activation (p = 0.026) by inhibiting phosphorylation (activation) of p38 MAP kinase (p = 0.034). p38 activation was also suppressed on POD7 (p = 0.002). CONCLUSIONS: Intrathecal lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav1.3 up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain. PMID- 21676268 TI - NDRG2 inhibits hepatocellular carcinoma adhesion, migration and invasion by regulating CD24 expression. AB - BACKGROUND: The prognosis of most hepatocellular carcinoma (HCC) patients is poor due to the high metastatic rate of the disease. Understanding the molecular mechanisms underlying HCC metastasis is extremely urgent. The role of CD24 and NDRG2 (N-myc downstream-regulated gene 2), a candidate tumor suppressor gene, has not yet been explored in HCC. METHODS: The mRNA and protein expression of CD24 and NDRG2 was analyzed in MHCC97H, Huh7 and L-02 cells. Changes in cell adhesion, migration and invasion were detected by up- or down-regulating NDRG2 by adenovirus or siRNA. The expression pattern of NDRG2 and CD24 in HCC tissues and the relationship between NDRG2 and HCC clinical features was analyzed by immunohistochemical and western blotting analysis. RESULTS: NDRG2 expression was negatively correlated with malignancy in HCC. NDRG2 exerted anti-tumor activity by regulating CD24, a molecule that mediates cell-cell interaction, tumor proliferation and adhesion. NDRG2 up-regulation decreased CD24 expression and cell adhesion, migration and invasion. By contrast, NDRG2 down-regulation enhanced CD24 expression and cell adhesion, migration and invasion. Immunohistochemical analysis of 50 human HCC clinical specimens showed a strong correlation between NDRG2 down-regulation and CD24 overexpression (P = 0.04). In addition, increased frequency of NDRG2 down-regulation was observed in patients with elevated AFP serum level (P = 0.006), late TNM stage (P = 0.009), poor differentiation grade (P = 0.002), tumor invasion (P = 0.004) and recurrence (P = 0.024). CONCLUSIONS: Our findings indicate that NDRG2 and CD24 regulate HCC adhesion, migration and invasion. The expression level of NDRG2 is closely related to the clinical features of HCC. Thus, NDRG2 plays an important physiological role in HCC metastasis. PMID- 21676269 TI - Results and current approach for Brachial Plexus reconstruction. AB - We review our experience treating 335 adult patients with supraclavicular brachial plexus injuries over a 7-year period at the University of Southern Santa Catarina, in Brazil. Patients were categorized into 8 groups, according to functional deficits and roots injured: C5-C6, C5-C7, C5-C8 (T1 Hand), C5-T1 (T2 Hand), C8-T1, C7-T1, C6-T1, and total palsy. To restore function, nerve grafts, nerve transfers, and tendon and muscle transfers were employed. Patients with either upper- or lower-type partial injuries experienced considerable functional return. In total palsies, if a root was available for grafting, 90% of patients had elbow flexion restored, whereas this rate dropped to 50% if no roots were grafted and only nerve transfers performed. Pain resolution should be the first priority, and root exploration and grafting helped to decrease or eliminate pain complaints within a short time of surgery. PMID- 21676270 TI - Molecular characterization and infectivity of a Tomato leaf curl New Delhi virus variant associated with newly emerging yellow mosaic disease of eggplant in India. AB - BACKGROUND: Begomoviruses have emerged as serious problem for vegetable and fiber crops in the recent past, frequently in tropical and subtropical region of the world. The association of begomovirus with eggplant yellow mosaic disease is hitherto unknown apart from one report from Thailand. A survey in Nagpur, Central India, in 2009-2010 showed severe incidence of eggplant yellow mosaic disease. Here, we have identified and characterized a begomovirus responsible for the newly emerging yellow mosaic disease of eggplant in India. RESULTS: The complete DNA-A and DNA-B genomic components of the causative virus were cloned and sequenced. Nucleotide sequence analysis of DNA-A showed that it shared highest 97.6% identity with Tomato leaf curl New Delhi virus India[India:Udaipur:Okra:2007] and lowest 87.9% identity with Tomato leaf curl New Delhi virus-India[India:NewDelhi:Papaya:2005], while DNA-B showed highest 94.1% identity with ToLCNDV-IN[IN:UD:Ok:07] and lowest 76.2% identity with ToLCNDV-India[India:Lucknow]. Thus, it appears that this begomovirus is a variant of ubiquitous ToLCNDV and hence, we suggest the name ToLCNDV India[India:Nagpur:Eggplant:2009] for this variant. The pathogenicity of ToLCNDV IN[IN:Nag:Egg:09] isolate was confirmed by agroinfiltraion and dimeric clones of DNA-A and DNA-B induced characteristic yellow mosaic symptoms in eggplants and leaf curling in tomato plants. CONCLUSION: This is the first report of a ToLCNDV variant moving to a new agriculturally important host, eggplant and causing yellow mosaic disease. This is also a first experimental demonstration of Koch's postulate for a begomovirus associated with eggplant yellow mosaic disease. PMID- 21676271 TI - Role of anesthesiology curriculum in improving bag-mask ventilation and intubation success rates of emergency medicine residents: a prospective descriptive study. AB - BACKGROUND: Rapid and safe airway management has always been of paramount importance in successful management of critically ill and injured patients in the emergency department. The purpose of our study was to determine success rates of bag-mask ventilation and tracheal intubation performed by emergency medicine residents before and after completing their anesthesiology curriculum. METHODS: A prospective descriptive study was conducted at Nikoukari Hospital, a teaching hospital located in Tabriz, Iran. In a skills lab, a total number of 18 emergency medicine residents (post graduate year 1) were given traditional intubation and bag-mask ventilation instructions in a 36 hour course combined with mannequin practice. Later the residents were given the opportunity of receiving training on airway management in an operating room for a period of one month which was considered as an additional training program added to their Anesthesiology Curriculum. Residents were asked to ventilate and intubate 18 patients (Mallampati class I and ASA class I and II) in the operating room; both before and after completing this additional training program. Intubation achieved at first attempt within 20 seconds was considered successful. Successful bag-mask ventilation was defined as increase in ETCo2 to 20 mm Hg and back to baseline with a 3 L/min fresh gas-flow and the adjustable pressure limiting valve at 20 cm H2O. An attending anesthesiologist who was always present in the operating room during the induction of anesthesia confirmed the endotracheal intubation by direct laryngoscopy and capnography. Success rates were recorded and compared using McNemar, marginal homogeneity and paired t-Test tests in SPSS 15 software. RESULTS: Before the additional training program in the operating room, the participants had intubation and bag-mask ventilation success rates of 27.7% (CI 0.07-0.49) and 16.6% (CI 0-0.34) respectively. After the additional training program in the operating room the success rates increased to 83.3% (CI 0.66-1) and 88.8% (CI 0.73-1), respectively. The differences in success rates were statistically significant (P = 0.002 and P = 0.0004, respectively). CONCLUSIONS: The success rate of emergency medicine residents in airway management improved significantly after completing anesthesiology rotation. Anesthesiology rotations should be considered as an essential component of emergency medicine training programs. A collateral curriculum of this nature should also focus on the acquisition of skills in airway management. PMID- 21676273 TI - Fetal lipopolysaccharide exposure modulates diet-dependent gut maturation and sensitivity to necrotising enterocolitis in pre-term pigs. AB - Uterine infections during pregnancy predispose to pre-term birth and postnatal morbidity, but it is unknown how prenatal bacterial exposure affects maturation of the immature gut. We hypothesised that a prenatal exposure to gram-negative lipopolysaccharide (LPS) has immunomodulatory effects that improve resistance towards necrotising enterocolitis (NEC) in pre-term neonates. At approximately 85 % gestation, pig fetuses were injected intramuscularly with saline or LPS (0.014 mg/kg), or intra-amniotically with LPS (0.4 mg/kg). Pigs were delivered by caesarean section 3-5 d later and fed colostrum (C) or formula (F) for 48 h. Gut indices did not differ between pigs injected intramuscularly with saline or LPS, and these groups were therefore pooled into two control groups according to diet (control-F, n 32 and control-C, n 11). Control-F pigs showed reduced villus heights, mucosal structure, gut integrity, digestive enzymes, elevated NEC incidence (38 v. 0 %, P < 0.05) and several differentially expressed immune related genes, relative to control-C pigs. Compared with the control-F and control-C groups, values in formula-fed pigs given intra-amniotic LPS formula (n 17) were intermediate for villus height, enzyme activities, intestinal permeability and NEC incidence (18 %, P = 0.2 relative to control-F), and numbers of differentially expressed immune genes. In conclusion, prenatal exposure of the fetal gut to Gram-negative bacteria may modulate the immediate postnatal response to an enteral diet and colonising bacteria. PMID- 21676274 TI - Carnosic acid-rich rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and improves cholesterol levels and glycaemia in mice on a high-fat diet. AB - Rosemary (Rosmarinus officinalis L.) extracts (RE) are natural antioxidants that are used in food, food supplements and cosmetic applications; exert anti inflammatory and anti-hyperglycaemic effects; and promote weight loss, which can be exploited to develop new preventive strategies against metabolic disorders. Therefore, the aim of the present study was to evaluate the preventive effects of rosemary leaf extract that was standardised to 20 % carnosic acid (RE) on weight gain, glucose levels and lipid homeostasis in mice that had begun a high-fat diet (HFD) as juveniles. The animals were given a low-fat diet, a HFD or a HFD that was supplemented with 500 mg RE/kg body weight per d (mpk). Physiological and biochemical parameters were monitored for 16 weeks. Body and epididymal fat weight in animals on the HFD that was supplemented with RE increased 69 and 79 % less than those in the HFD group. Treatment with RE was associated with increased faecal fat excretion but not with decreased food intake. The extract also reduced fasting glycaemia and plasma cholesterol levels. In addition, we evaluated the inhibitory effects of RE in vitro on pancreatic lipase and PPAR-gamma agonist activity; the in vitro findings correlated with our observations in the animal experiments. Thus, the present results suggest that RE that is rich in carnosic acid can be used as a preventive treatment against metabolic disorders, which merits further examination at physiological doses in randomised controlled trials. PMID- 21676272 TI - Enrichment of a microbial community performing anaerobic oxidation of methane in a continuous high-pressure bioreactor. AB - BACKGROUND: Anaerobic oxidation of methane coupled to sulphate reduction (SR-AOM) prevents more than 90% of the oceanic methane emission to the atmosphere. In a previous study, we demonstrated that the high methane pressure (1, 4.5, and 8 MPa) stimulated in vitro SR-AOM activity. However, the information on the effect of high-pressure on the microbial community structure and architecture was still lacking. RESULTS: In this study we analysed the long-term enrichment (286 days) of this microbial community, which was mediating SR-AOM in a continuous high pressure bioreactor. 99.7% of the total biovolume represented cells in the form of small aggregates (diameter less then 15 MUm). An increase of the total biovolume was observed (2.5 times). After 286 days, the ANME-2 (anaerobic methanotrophic archaea subgroup 2) and SRB (sulphate reducing bacteria) increased with a factor 12.5 and 8.4, respectively. CONCLUSION: This paper reports a net biomass growth of communities involved in SR-AOM, incubated at high-pressure. PMID- 21676275 TI - Colours of fruit and vegetables and 10-year incidence of CHD. AB - The colours of the edible part of fruit and vegetables indicate the presence of specific micronutrients and phytochemicals. The extent to which fruit and vegetable colour groups contribute to CHD protection is unknown. We therefore examined the associations between fruit and vegetables of different colours and their subgroups and 10-year CHD incidence. We used data from a prospective population-based cohort including 20 069 men and women aged 20-65 years who were enrolled between 1993 and 1997. Participants were free of CVD at baseline and completed a validated 178-item FFQ. Hazard ratios (HR) for the association between green, orange/yellow, red/purple, white fruit and vegetables and their subgroups with CHD were calculated using multivariable Cox proportional hazards models. During 10 years of follow-up, 245 incident cases of CHD were documented. For each 25 g/d increase in the intake of the sum of all four colours of fruit and vegetables, a borderline significant association with incident CHD was found (HR 0.98; 95 % CI 0.97, 1.01). No clear associations were found for the colour groups separately. However, each 25 g/d increase in the intake of deep orange fruit and vegetables was inversely associated with CHD (HR 0.74; 95 % CI 0.55, 1.00). Carrots, their largest contributor (60 %), were associated with a 32 % lower risk of CHD (HR 0.68; 95 % CI 0.48, 0.98). In conclusion, though no clear associations were found for the four colour groups with CHD, a higher intake of deep orange fruit and vegetables and especially carrots may protect against CHD. PMID- 21676276 TI - Angular dependence of the ion-induced secondary electron emission for He+ and Ga+ beams. AB - In recent years, novel ion sources have been designed and developed that have enabled focused ion beam machines to go beyond their use as nano-fabrication tools. Secondary electrons are usually taken to form images, for their yield is high and strongly dependent on the surface characteristics, in terms of chemical composition and topography. In particular, the secondary electron yield varies characteristically with the angle formed by the beam and the direction normal to the sample surface in the point of impact. Knowledge of this dependence, for different ion/atom pairs, is thus the first step toward a complete understanding of the contrast mechanism in scanning ion microscopy. In this article, experimentally obtained ion-induced secondary electron yields as a function of the incidence angle of the beam on flat surfaces of Al and Cr are reported, for usual conditions in Ga+ and He+ microscopes. The curves have been compared with models and simulations, showing a good agreement for most of the angle range; deviations from the expected behavior are addressed and explanations are suggested. It appears that the maximum value of the ion-induced secondary electron yield is very similar in all the studied cases; the yield range, however, is consistently larger for helium than for gallium, which partially explains the enhanced topographical contrast of helium microscopes over the gallium focused ion beams. PMID- 21676277 TI - Contraception use and associations with intimate partner violence among women in Bangladesh. AB - This study examines the association between contraception use and intimate partner violence (IPV) among women of reproductive age in Bangladesh. The observational study of 10,996 women used the chi-squared test and logistic regressions to assess the associations. Almost 80% of all respondents had used contraceptives at some point in their lives. About half of the respondents (48%) were victims of physical violence, while 11% experienced sexual abuse from their husbands. Urban residents, higher educated women and women aged 20-44 were more likely to use contraceptives than their peers in rural areas, those with lower education and those in their late forties (45-49 years). Women exposed to physical violence were almost two times (OR 1.93, CI 1.55-2.41) more likely to use contraceptives compared with their non-abused peers. Sexual abuse had no significant association with contraceptive use. Physical violence is a predictor for higher levels of contraceptive use among women in Bangladesh. The findings emphasize the importance of screening for IPV at health care centres. The differences in urban and rural contraceptive use and IPV exposure identified by the study have policy implications for service delivery and planning. PMID- 21676278 TI - Can mothers judge the size of their newborn? Assessing the determinants of a mother's perception of a baby's size at birth. AB - Birth weight is known to be closely related to child health, although as many infants in developing countries are not weighed at birth and thus will not have a recorded birth weight it is difficult to use birth weight when analysing the determinants of child illness. It is common to use a proxy for birth weight instead, namely the mother's perception of the baby's size at birth. Using DHS surveys in Cambodia, Kazakhstan and Malawi the responses to this question were assessed to indicate the relationship between birth weight and mother's perception. The determinants of perception were investigated using multilevel ordinal regression to gauge if they are different for infants with and without a recorded birth weight, and to consider if there are societal or community influences on perception of size. The results indicate that mother's perception is closely linked to birth weight, although there are other influences on the classification of infants into size groups. On average, a girl of the same birth weight as a boy will be classified into a smaller size category. Likewise, infants who died by the time of the survey will be classified as smaller than similarly heavy infants who are still alive. There are significant variations in size perception between sampling districts and clusters, indicating that mothers mainly judge their child for size against a national norm. However, there is also evidence that the size of infants in the community around the newborn also has an effect on the final size perception classification. Overall the results indicate that mother's perception of size is a good proxy for birth weight in large nationally representative surveys, although care should be taken to control for societal influences on perception. PMID- 21676279 TI - Strongyloides ratti: transplantation of adults recovered from the small intestine at different days after infection into the colon of naive and infection-primed Wistar rats, and the effect of antioxidant treatment on large intestinal parasitism. AB - Strongyloides ratti (Nagoya strain) is unique in that a portion of adults parasitizing the small intestine withstands 'worm expulsion', which starts at around day 8 post-infection (p.i.) by host immunity, and establishes in the large intestine after day 19 p.i. To investigate the mechanism, adults obtained from the small intestine at day 7 or 19 p.i. were transplanted into the colon of infection-primed immune rats. Adults obtained at day 7 p.i. were rejected quickly, whereas those obtained at day 19 p.i. could establish infection. Moreover, the body length and the number of intrauterine eggs increased in the large intestine. In a separate experiment, large intestinal parasitism was abolished by the treatment of host rats with an anti-oxidant, butylated hydroxyanisole. These results indicate that small intestinal adults between days 7 and 19 p.i. acquired the ability to parasitize the large intestine of immune rats, and that free radicals produced by the host may have played a significant role in the process. PMID- 21676280 TI - Antioxidant enzymes induced by repeated intake of excess energy in the form of high-fat, high-carbohydrate meals are not sufficient to block oxidative stress in healthy lean individuals. AB - It has been reported that high-fat, high-carbohydrate (HFHC) meals increase oxidative stress and inflammation. We examined whether repeated intake of excess energy in the form of HFHC meals alters reactive oxygen species (ROS) generation and the expression levels of antioxidant enzymes and mitochondrial proteins in mononuclear cells, and to determine whether this is associated with insulin resistance. We recruited healthy lean individuals (n 10). The individuals were divided into two groups: one group (n 5) ingested 10878.4 kJ/d (2600 kcal/d; 55 70 % carbohydrate, 9.5-16 % fat, 7-20 % protein) recommended by the Dietary Reference Intake for Koreans for 4 d and the other group (n 5) ingested a HFHC meal containing 14 644 kJ/d (3500 kcal/d). Then, measurements of blood insulin and glucose levels, together with suppressor of cytokine signalling-3 (SOCS-3) expression levels, were performed in both groups. Also, cellular and mitochondrial ROS levels as well as malondialdehyde (MDA) levels were measured. Expression levels of cytosolic and mitochondrial antioxidant enzymes, and mitochondrial complex proteins were analysed. Repeated intake of HFHC meals induced an increase in homeostasis model of assessment-insulin resistance (HOMA IR), together with an increase in SOCS-3 expression levels. While a single intake of the HFHC meal increased cytosolic and mitochondrial ROS, repeated intake of HFHC meals reduced them and increased the levels of MDA, cytosolic and mitochondrial antioxidant enzymes, and several mitochondrial complex proteins. Repeated intake of HFHC meals induced cellular antioxidant mechanisms, which in turn increased lipid peroxidation (MDA) and SOCS-3 expression levels, induced hyperinsulinaemia and increased HOMA-IR, an index of insulin resistance. In conclusion, excess energy added to a diet can generate detrimental effects in a short period. PMID- 21676281 TI - Using proton magnetic resonance spectroscopy to identify mild cognitive impairment. AB - BACKGROUND: Single-volume proton magnetic resonance spectroscopy (1H MRS) has considerable diagnostic potential for Alzheimer's disease (AD). This study investigated 1H MRS in specific regions of the brain, the posterior cingulate gyri (PCG) and the hippocampus, in patients with AD, amnestic mild cognitive impairment (aMCI), and in normal control subjects. METHODS: 1H MRS analysis was carried out on 47 patients with AD, 32 patients with aMCI and 56 normal control subjects (NC group). Volumes of the PCG and hippocampus were assessed, and the metabolic signals of N-acetylaspartate (NAA), choline compounds (Cho), myo inositol (mI), and creatine (Cr) were quantified. RESULTS: In the PCG, differences between the test groups were found in NAA/Cr, Cho/Cr, mI/Cr and NAA/mI ratios. Group differences were also found in mI/Cr and NAA/mI ratios in the left hippocampus, and in mI/Cr and NAA/mI ratios in the right hippocampus. NAA/Cr ratios increased in the PCG between AD and aMCI patients, and between aMCI and NC patients. Conversely, mI/Cr ratios in the PCG and left hippocampus decreased across AD, aMCI, and NC subjects. In discriminate and ROC (Receiver Operating Characteristic) analyses, a NAA/Cr ratio of <= 1.50 in the PCG indicated optimal potential for discriminating between aMCI patients and normal control subjects. Discriminating potential was also found to be high for a NAA/mI ratio in the PCG of <= 2.72. Despite significant differences between NC and aMCI patients in the mI/Cr ratio in the PCG and in the NAA/mI ratio in the left hippocampus, their sensitivity and specificity were all lower than 75%. CONCLUSION: Proton MRS of the PCG using the NAA/Cr ratio as a metabolic marker indicates considerable potential for distinguishing between aMCI and NC subjects. PMID- 21676282 TI - Environmental and genetic pathways between early pubertal timing and dieting in adolescence: distinguishing between objective and subjective timing. AB - BACKGROUND: Early pubertal timing in girls is associated with elevated risk for dieting and eating pathology. The relative importance of biological versus socio environmental mechanisms in explaining this association remains unclear. Moreover, these mechanisms may differ between objective measures of pubertal development and girls' subjective perceptions of their own maturation. METHOD: The sample comprised 924 sister pairs from the National Longitudinal Study of Adolescent Health. Objective pubertal timing (menarcheal age), girls' perceptions of pubertal status and timing relative to peers, dieting and disordered eating behaviors were assessed during a series of confidential in-home interviews. RESULTS: Behavioral genetic models indicated that common genetic influences accounted for the association between early menarcheal age and increased risk for dieting in adolescence. In contrast, girls' subjective perceptions of their timing relative to peers were associated with dieting through an environmental pathway. Overall, subjective and objective measures of pubertal timing accounted for 12% of the variance in dieting. CONCLUSIONS: Genetic differences in menarcheal age increase risk for dieting among adolescent girls, while girls' perceptions of their maturation represent an environmentally mediated risk. PMID- 21676283 TI - The reporting of mental disorders research in British media. AB - BACKGROUND: While the media may significantly influence public attitudes and government policies affecting the research agenda, how mental health research is reported in the media has been virtually unstudied. The aim of this study was to examine stories concerning mental health research published on the British Broadcasting Corporation (BBC) website between 1999 and 2008 and in New Scientist between 2008 and 2010. METHOD: Stories were retrieved from on-line archives. Story content was coded and assessed against: 'disease burden' of mental disorders; the general corpus of research papers in mental health and the countries from which they originated; the journals in which cited papers were published; and funding sources. RESULTS: A total of 1015 BBC stories reporting mental health research and 133 New Scientist stories were found. The distribution of stories did not reflect 'disease burden'; research on dementia was over represented, while depression and alcohol were under-represented. There was an emphasis on biological research while stories on psychological interventions were rare. UK research was over-represented. Research funded by government and private non-profit sources was over-represented. Commentators from Alzheimer's Disease charities were prominent. CONCLUSIONS: Consideration of reported stories may suggest approaches to working with the media to improve the public understanding of, and support for, mental health research. The role of commentators may be especially important. PMID- 21676284 TI - Poor childhood mental health may explain linkages between trauma, cannabis use and later psychotic experiences. PMID- 21676286 TI - Comments on 'Bullying victimization in youths and mental health problems: much ado about nothing?'. PMID- 21676285 TI - Replication in two independent population-based samples that childhood maltreatment and cannabis use synergistically impact on psychosis risk. AB - BACKGROUND: There may be biological plausibility to the notion that cannabis use and childhood trauma or maltreatment synergistically increase the risk for later development of psychotic symptoms. To replicate and further investigate this issue, prospective data from two independent population-based studies, the Greek National Perinatal Study (n=1636) and The Netherlands Mental Health Survey and Incidence Study (NEMESIS) (n=4842), were analyzed. METHOD: Two different data sets on cannabis use and childhood maltreatment were used. In a large Greek population-based cohort study, data on cannabis use at age 19 years and childhood maltreatment at 7 years were assessed. In addition, psychotic symptoms were assessed using the Community Assessment of Psychic Experiences (CAPE). In NEMESIS, the Composite International Diagnostic Interview (CIDI) was used to assess psychotic symptoms at three different time points along with childhood maltreatment and lifetime cannabis use. RESULTS: A significant adjusted interaction between childhood maltreatment and later cannabis use was evident in both samples, indicating that the psychosis-inducing effects of cannabis were stronger in individuals exposed to earlier sexual or physical mistreatment [Greek National Perinatal Study: test for interaction F(2, 1627)=4.18, p=0.02; NEMESIS: test for interaction chi2(3)=8.08, p=0.04]. CONCLUSIONS: Cross-sensitivity between childhood maltreatment and cannabis use may exist in pathways that shape the risk for expression of positive psychotic symptoms. PMID- 21676287 TI - Fish consumption in relation to other foods in the diet. AB - Our aim was to investigate whether fish consumption is associated with the consumption of other healthy foods. The study population consisted of 2605 men and 3199 women from the nationally representative Health 2000 survey and 114 professional fishermen and 114 fishermen's wives (the Fishermen substudy) in Finland. Dietary data were collected using a calibrated (i.e. determined to have relative validity) FFQ. Model-adjusted means for food consumption and P values for linear trend were calculated across fish consumption tertiles. Those with the highest fish consumption had the highest consumption of vegetables, fruit and berries, potatoes, oil and wine even after adjusting for other food groups. The consumption of red meat and sausages had a tendency to decrease across fish consumption tertiles but the associations were inconsistent in the study populations. In conclusion, fish consumption had a positive linear association with the consumption of some other healthy foods such as vegetables, fruit, berries, and oil both in the general population of Finland and in a population with high fish consumption. Additional adjustment for other food groups had a clear effect on some of the studied associations. Therefore, when evaluating the health effects of fish consumption, confounding by other foods characterising a healthy diet needs to be considered. PMID- 21676288 TI - Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases. AB - Diseases of the central nervous system (CNS) pose a significant health challenge, but despite their diversity, they share many common features and mechanisms. For example, endothelial dysfunction has been implicated as a crucial event in the development of several CNS disorders, such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, human immunodeficiency virus (HIV)-1-associated neurocognitive disorder and traumatic brain injury. Breakdown of the blood-brain barrier (BBB) as a result of disruption of tight junctions and transporters, leads to increased leukocyte transmigration and is an early event in the pathology of these disorders. The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease. Furthermore, the physiology and pathophysiology of endothelial cells are closely linked to the functioning of their mitochondria, and mitochondrial dysfunction is another important mediator of disease pathology in the brain. The high concentration of mitochondria in cerebrovascular endothelial cells might account for the sensitivity of the BBB to oxidant stressors. Here, we discuss how greater understanding of the role of BBB function could lead to new therapeutic approaches for diseases of the CNS that target the dynamic properties of brain endothelial cells. PMID- 21676291 TI - Precis of 'The Origin of Concepts'. AB - A theory of conceptual development must specify the innate representational primitives, must characterize the ways in which the initial state differs from the adult state, and must characterize the processes through which one is transformed into the other. The Origin of Concepts (henceforth TOOC) defends three theses. With respect to the initial state, the innate stock of primitives is not limited to sensory, perceptual, or sensorimotor representations; rather, there are also innate conceptual representations. With respect to developmental change, conceptual development consists of episodes of qualitative change, resulting in systems of representation that are more powerful than, and sometimes incommensurable with, those from which they are built. With respect to a learning mechanism that achieves conceptual discontinuity, I offer Quinian bootstrapping. TOOC concludes with a discussion of how an understanding of conceptual development constrains a theory of concepts. PMID- 21676289 TI - Oncolytic virotherapy for pancreatic cancer. AB - Within the past decade, many oncolytic viruses (OVs) have been studied as potential treatments for pancreatic cancer and some of these are currently under clinical trials. The applicability of certain OVs, such as adenoviruses, herpesviruses and reoviruses, for the treatment of pancreatic cancer has been intensively studied for several years, whereas the applicability of other more recently investigated OVs, such as poxviruses and parvoviruses, is only starting to be determined. At the same time, studies have identified key characteristics of pancreatic cancer biology that provide a better understanding of the important factors or pathways involved in this disease. This review aims to summarise the different replication-competent OVs proposed as therapeutics for pancreatic cancer. It also focuses on the unique biology of these viruses that makes them exciting candidate virotherapies for pancreatic cancer and discusses how they could be genetically manipulated or combined with other drugs to improve their efficacy based on what is currently known about the molecular biology of pancreatic cancer. PMID- 21676321 TI - Special section: Bioethics beyond borders 2011. PMID- 21676290 TI - Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. AB - Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood-brain barrier (BBB) restricts the delivery of many small and large molecules into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumour mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumour. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain-tumour-cell barrier (a barrier due to expression of efflux transporters in tumour cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumour and the invasive glioma cells. PMID- 21676322 TI - In the ruins of Babel: pitfalls on the way toward a universal language for research ethics and benefit sharing. AB - At the end of a paper on international research ethics published in the July August 2010 issue of the Hastings Center Report, London and Zollman argue the need for grounding our duties in international medical and health-related research within a broader normative framework of social, distributive, and rectificatory justice. The same goes for Thomas Pogge, who, in a whole range of publications during the past years, has argued for a human-rights-based approach to international research. In a thought-provoking paper in the June 2010 issue of the American Journal of Bioethics, Angela J. Ballantyne argues that "the global bioethics priority" in medical and health-related research ethics today is how to do research fairly in an unjust world. PMID- 21676323 TI - Sprinting research and spot jogging regulation: the state of bioethics in Cameroon. AB - Cameroon is a Central African country lying at latitude 6 degrees N and longitude 12 degrees E. The country has a surface area of circa 475,442 square kilometers, and is bordered by several other African countries: Nigeria, Chad, the Central African Republic, the Republic of Congo, Equatorial Guinea, and Gabon. With a population of nearly 20 million inhabitants, Cameroon is a very diverse country, geographically, culturally, and linguistically. PMID- 21676324 TI - Ethics, kawa, and the constitution: transformation of the system of ethical review in Aotearoa New Zealand. AB - New Zealand is a South Pacific nation with a history of British colonization since the 19th century. It has a population of over four million people and, like other indigenous societies such as in Australia and Canada, Maori are now a minority in their land, and their experience of colonization is that of being dominated by settlers to the detriment of their own systems of society. PMID- 21676325 TI - Assisting countries in establishing national bioethics committees: UNESCO's Assisting Bioethics Committees project. AB - The Universal Declaration on Bioethics and Human Rights adopted by UNESCO in 2005 advocates for the establishment of independent, multidisciplinary, and pluralist ethics committees at national, regional, local, or institutional levels. The purpose of these committees is (a) to evaluate the relevant ethical, legal, scientific, and social issues related to research involving human beings; (b) to provide advice on ethical problems in clinical settings; (c) to assess scientific and technological development, formulate recommendations, and contribute to the preparation of guidelines; and (d) to foster debate, education, and public awareness of and engagement in bioethics (Article 19). Already in the very first draft of the Declaration the need to promote and establish national bioethics committees was mentioned. Although the text was gradually elaborated, the same basic idea has been preserved throughout the process of drafting, negotiating, and adopting the text. PMID- 21676326 TI - Clinical ethics committees in Norway: what do they do, and does it make a difference? AB - The first clinical ethics committees (CEC) in Norway were established in 1996. This started as an initiative from hospital clinicians, the Norwegian Medical Association, and health authorities and politicians. Norwegian hospitals are, by and large, publicly funded through taxation, and all inpatient treatment is free of charge. Today, all the 23 hospital trusts (providing specialized and hospital based healthcare services to the Norwegian population of 4.9 million people) have established at least one committee. Center for Medical Ethics (SME), University of Oslo, receives an annual amount of US$335,000 from the Ministry of Health and Care Services to coordinate the committees and to facilitate competency building for committee members. PMID- 21676327 TI - Implications of recent developments in Ireland for the status of the embryo. AB - One of the most significant developments in the area of reproductive health in Ireland is the Roche v. Roche [2009] case. The case concerned a woman who wished to implant cryopreserved embryos made with a former partner, against the partner's wishes. Of particular interest are questions about the status of the embryo: in Ireland the life of "the unborn" is constitutionally protected. Therefore the courts in Roche had to decide whether embryos were "unborn" within the meaning of the Irish Constitution. PMID- 21676328 TI - Four themes in recent Swedish bioethics debates. AB - A wide variety of bioethical themes have recently been debated and researched in Sweden, including genetic screening, HPV vaccination strategies, end-of-life care, injustices and priority setting in healthcare, dual-use research, and the never-ending story of scientific fraud. Also, there are some new events related to Swedish biobanking that might be of general interest. Here we will concentrate on four themes: end-of-life care, dual-use research, scientific fraud, and biobanking. PMID- 21676329 TI - Does the United States do it better? A comparative analysis of liver allocation protocols in the United Kingdom and the United States. AB - NHS Blood and Transplant (NHSBT) is responsible for the procurement and allocation of human organs in the United Kingdom. Its main role is to "ensure that organs donated for transplant are matched and allocated to patients in a fair and unbiased way." NHSBT's liver allocation policies are underpinned by the National Liver Transplant Standards, a document published by the Department of Health in 2005 to oversee patient care, patient assessment, liver allocation and transplantation, education and training, and research and development. NHSBT has developed its own liver allocation protocols under the powers assigned to it by the Department of Health, which include a "super-urgent" liver allocation policy, a Liver Allocation Sequence, and pediatric candidate liver allocation protocols. PMID- 21676330 TI - Public understanding of neural prosthetics in Germany: ethical, social, and cultural challenges. AB - Since the development of the first neural prosthesis, that is, the cochlear implant in 1957, neural prosthetics have been one of the highly promising, yet most challenging areas of medicine, while having become a clinically accepted form of invasiveness into the human body. Neural prosthetic devices, of which at least one part is inserted into the body, interact directly with the nervous system to restore or replace lost or damaged sensory, motor, or cognitive functions. This field is not homogenous and encompasses a variety of technologies, which are in various stages of development. Some devices are well established in clinical practice and have become routine, such as cochlear implants. By comparison, other technologies are in experimental phases and still need to be further developed to achieve the desired results. PMID- 21676331 TI - Bioethics in Serbia: institutions in need of philosophical debate. AB - This paper is structured in three sections. The first discusses the institutional framework pertaining to bioethics in Serbia. The functioning of this framework is critically assessed and a number of recommendations for its improvement presented. It is also emphasized that philosophers are underrepresented in public debate on bioethics in Serbia. Second, this underrepresentation will be related to two issues that figure prominently in Serbian society but are not accompanied by corresponding bioethical discourses: the first is abortion and the second is the largely unrestricted use of neuropharmacology since the 1990s, both for therapeutic and for cosmetic/recreational purposes. Finally, the perspective of bioethics in Serbia is addressed. It is asserted that this perspective can be based on the enhancement of public philosophical debate on bioethical issues, especially those with notable features in Serbian society (such as abortion and neuropharmacology). Such enhancement would also strengthen the corresponding institutional and legal frameworks PMID- 21676332 TI - Egg cell preservation and the right to die in the Netherlands: citizens' choices and the limits of medicine. AB - It is a funny thing with the Dutch. On one hand, they seem preoccupied with death and adamant that patients be allowed to decide for themselves in what way they want to die. On the other, contrary to popular belief, the Dutch physician is allotted a very influential role in treatment decisions, far more prominent than in many other Western countries. From an American perspective Dutch professional ethics may seem quite paternalistic: a patient's freedom to decide to have a particular medical treatment is limited by the physician's professional assessment of the medical need of this treatment. The question arises: What is the relationship between the professional responsibility of Dutch physicians and the right of Dutch patients to decide for themselves? This question is illustrated by the ongoing national debate in The Netherlands on euthanasia and the growing demand for a further reaching right to self-determination concerning ending one's life. However, contrary to popular belief, not all Dutch ethical debate concerns end-of-life questions. PMID- 21676333 TI - Tensions between medical professionals and patients in mainland China. AB - In China, state investment into public hospitals has radically decreased since the early 1980s and has brought on the dismantling of the healthcare system in most parts of the country, especially in rural areas. As a result of this overhaul, the majority of public hospitals have needed to compete in the so called socialist market economy. The market economy stimulated public hospitals to modernize, take on highly qualified medical professionals, and dispense new therapies and drugs. At same time, liberalization has clearly affected the attitude and behavior of both medical professionals and the general public. The public has many concerns about the healthcare system for various reasons: there are long hospital waiting lists, patients experience difficulties in obtaining an appointment to see a qualified doctor, and, over the past decades, there has been an increase in out-of-pocket healthcare expenditure. These and other changes in post-reform China have radically reshaped the doctor-patient interaction, which is increasingly eroded by tension and violence. PMID- 21676334 TI - Does a fish need a bicycle? Animals and evolution in the age of biotechnology. AB - Animals, in the age of biotechnology, are the subjects of a myriad of scientific procedures, interventions, and modifications. They are created, altered, and experimented upon--often with highly beneficial outcomes for humans in terms of knowledge gained and applied, yet not without concern also for the effects upon the experimental subjects themselves: consideration of the use of animals in research remains an intensely debated topic. Concerns for animal welfare in scientific research have, however, been primarily directed at harm to and suffering of animal subjects and their prevention. Little attention has been paid to the benefits research might potentially produce for animals themselves and the interests that some animals may therefore have in the furtherance of particular avenues of science. PMID- 21676335 TI - A comparison of student performance between two instructional delivery methods for a healthcare ethics course. AB - Healthcare ethics has become part of the standard curriculum of students in the health professions. The goals of healthcare ethics education are to give students the skills they need to identify, assess, and address ethical issues in clinical practice and to develop virtuous practitioners. Incorporating the medical humanities into medical school, for example, is intended to foster empathy and professionalism among students and to provide mechanisms for enhanced physician well-being. Yet, despite the long-standing inclusion of the humanities in nursing curricula, increases in the amount and kinds of scientific knowledge essential for clinical practice has resulted in the erosion of the "humanistic arts" from nursing education. One potential solution to this challenge comes with the increase in interprofessional education, where students in a variety of healthcare professions programs come together to learn about issues common to all healthcare fields. PMID- 21676336 TI - Amacrine-to-amacrine cell inhibition: Spatiotemporal properties of GABA and glycine pathways. AB - We measured the spatial and temporal properties of GABAergic and glycinergic inhibition to amacrine cells in the whole-mount rabbit retina. The amacrine cells were parsed into two morphological classes: narrow-field cells with processes spreading less than 200 MUm and wide-field cells with processes extending more than 300 MUm. The inhibition was also parsed into two types: sustained glycine and transient GABA. Narrow-field amacrine cells receive 1) very transient GABAergic inhibition with a fast onset latency of 140 +/- 16 ms decaying to 30% of the peak level within 208 +/- 27 ms elicited broadly over a lateral distance of up to 1500 MUm and 2) sustained glycinergic inhibition with a medium onset latency of 286 +/- 23 ms that was elicited over a spatial area often broader than the processes of the narrow-field amacrine cells. Wide-field amacrine cells received sustained glycinergic inhibition but no broad transient GABAergic inhibition. Surprisingly, neither of these amacrine cell classes received sustained local GABAergic inhibition, commonly found in an earlier study of ganglion cells. PMID- 21676338 TI - Ultraviolet irradiation and the mechanisms underlying its inactivation of infectious agents. AB - We review the principles of ultraviolet (UV) irradiation, the inactivation of infectious agents by UV, and current applications for the control of microorganisms. In particular, wavelengths between 200 and 280 nm (germicidal UV) affect the double-bond stability of adjacent carbon atoms in molecules including pyrimidines, purines and flavin. Thus, UV inactivation of microorganisms results from the formation of dimers in RNA (uracil and cytosine) and DNA (thymine and cytosine). The classic application of UV irradiation is the inactivation of microorganisms in biological safety cabinets. In the food-processing industry, germicidal UV irradiation has shown potential for the surface disinfection of fresh-cut fruit and vegetables. UV treatment of water (potable and wastewater) is increasingly common because the process is effective against a wide range of microorganisms, overdose is not possible, chemical residues or by-products are avoided, and water quality is unaffected. UV has been used to reduce the concentration of airborne microorganisms in limited studies, but the technology will require further development if it is to gain wider application. For bioaerosols, the primary technical challenge is delivery of sufficient UV irradiation to large volumes of air, but the absence of UV inactivation constants for airborne pathogens under a range of environmental conditions (temperature, relative humidity) further compounds the problem. PMID- 21676339 TI - Staphylococcus aureus small colony variants (SCVs) and their role in disease. AB - Persistent or difficult-to-treat Staphylococcus aureus infections in animals and humans may be related to small colony variants (SCVs) that can hide inside host cells and modulate host defenses. S. aureus SCVs have gained much attention in human medicine but have been underestimated and overlooked in veterinary medicine. Recently, an SCV isolated from a dairy cow with a history of chronic mastitis was shown to possess similar phenotypic and transcriptomic properties to those of human SCVs. SCVs form small, colorless, non-hemolytic colonies after 48 h, are only slowly coagulase positive, fail to ferment mannitol, and can revert to the parental phenotype. The phenotype of SCVs is mostly related to alterations in hemin and/or menadione biosynthesis or to thymidine deficiency. Transcriptomic analysis of SCVs shows up-regulation of genes involved in glycolytic and arginine deiminase pathways, capsular biosynthesis; increased sigma B activity; and down regulation of genes for alpha-hemolysin, coagulase and effector molecule RNA III of the global virulence regulator Agr. Similar results are reported at the protein level. SCVs are less virulent but successful persisters in infection models. SCVs persist longer and at higher numbers within non-phagocytes than do their parents. SCVs survive within spacious vacuoles up to 24 h within cultured bovine mammary epithelial cells, likely due to up-regulation of protective mechanisms that counteract the lethal acidic environment of the phagolysosome. Persistence of SCVs within host cells may explain failures in antimicrobial therapy and vaccinations. PMID- 21676337 TI - Role of LRRK2 kinase dysfunction in Parkinson disease. AB - Parkinson disease is a common and usually sporadic neurodegenerative disorder. However, a subset of cases are inherited and, of these, mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of disease. Here, we will discuss recent progress in understanding how LRRK2 mutations lead to disease and how this might have therapeutic implications. The effect of mutations on LRRK2 enzyme function provides clues as to which functions of the protein are important to disease. Recent work has focused on the kinase and GTP-binding domains of LRRK2, and it is assumed that these will be therapeutically important, although there is a substantial amount of work to be done to address this hypothesis. PMID- 21676340 TI - Effect of porcine circovirus type 2 (PCV2) infection on reproduction: disease, vertical transmission, diagnostics and vaccination. AB - Porcine circovirus type 2 (PCV2) causes great economic losses in growing pigs and there are several reviews on disease manifestations and lesions associated with PCV2 in growing pigs. Reproductive failure in breeding herds, predominately associated with increased numbers of mummies and non-viable piglets at parturition, is one of the disease manifestations of PCV2 infection. Boars shed low amounts of infectious PCV2 in semen for extended time periods, and vertical transmission of PCV2 to fetuses during PCV2 viremia of the dam has been experimentally confirmed. However, intrauterine-infected piglets often are clinically normal. Nevertheless, pigs infected with PCV2 by the intrauterine route can be born viremic, possibly contributing to horizontal spread of PCV2 within the breeding herd and into the nursery. Shedding of PCV2 in semen and prevalence of intrauterine-infected piglets can both be greatly reduced by PCV2 vaccination well ahead of expected PCV2 exposure. This review is a discussion on current knowledge on the effects of PCV2 infection in the dam and in in utero fetuses, including clinical signs, lesions, diagnosis and prevention through vaccination. Infection of boars with PCV2, the potential for PCV2 transmission via semen and prevention of PCV2 shedding are also discussed. PMID- 21676341 TI - A review of hemorrhagic septicemia in cattle and buffalo. AB - Hemorrhagic septicemia (HS), an acute, fatal and septicemic disease of cattle and buffaloes caused by Pasteurella multocida, is important in tropical regions of the world, especially in African and Asian countries. The prevalence of disease has been well documented with predominant isolation of P. multocida serotypes B:2 and E:2. Conventional methods of identification such as serotyping, biotyping, antibiogram determination and pathogenicity as well as molecular methods (P. multocida-specific polymerase chain reaction (PCR), a serogroup B-specific PCR assay, multiplex capsular typing system and loop-mediated isothermal amplification techniques) and characterization (restriction endonuclease analysis, randomly amplified polymorphic DNA analysis, repetitive extragenic palidromic PCR and enterobacterial repetitive intergenic consensus PCR analysis) are applied in parallel for rapid epidemiological investigations of HS outbreaks. Although several vaccine formulations including alum precipitated, oil adjuvant and multiple emulsion vaccines are commercially available, the quest for suitable broadly protective HS vaccines with long-lasting immunity is on the upsurge. Concurrently, attempts are being made to unravel the mysteries of the pathogen and its virulence factors, pathogenesis and determinants of protective immunity as well as diversity among strains of P. multocida. This review highlights the advances in these various aspects of HS. PMID- 21676342 TI - Nutritional and physiological role of medium-chain triglycerides and medium-chain fatty acids in piglets. AB - Medium-chain fatty acids (MCFAs) are found at higher levels in milk lipids of many animal species and in the oil fraction of several plants, including coconuts, palm kernels and certain Cuphea species. Medium-chain triglycerides (MCTs) and fatty acids are efficiently absorbed and metabolized and are therefore used for piglet nutrition. They may provide instant energy and also have physiological benefits beyond their energetic value contributing to several findings of improved performance in piglet-feeding trials. MCTs are effectively hydrolyzed by gastric and pancreatic lipases in the newborn and suckling young, allowing rapid provision of energy for both enterocytes and intermediary hepatic metabolism. MCFAs affect the composition of the intestinal microbiota and have inhibitory effects on bacterial concentrations in the digesta, mainly on Salmonella and coliforms. However, most studies have been performed in vitro up to now and in vivo data in pigs are still scarce. Effects on the gut-associated and general immune function have been described in several animal species, but they have been less studied in pigs. The addition of up to 8% of a non-esterified MCFA mixture in feed has been described, but due to the sensory properties this can have a negative impact on feed intake. This may be overcome by using MCTs, allowing dietary inclusion rates up to 15%. Feeding sows with diets containing 15% MCTs resulted in a lower mortality of newborns and better development, particularly of underweight piglets. In conclusion, MCFAs and MCTs offer advantages for the improvement of energy supply and performance of piglets and may stabilize the intestinal microbiota, expanding the spectrum of feed additives supporting piglet health in the post-weaning period. PMID- 21676343 TI - A live vaccine from Brucella abortus strain 82 for control of cattle brucellosis in the Russian Federation. AB - During the first half of the twentieth century, widespread regulatory efforts to control cattle brucellosis due to Brucella abortus in the Union of Soviet Socialist Republics were essentially non-existent, and control was limited to selective test and slaughter of serologic agglutination reactors. By the 1950s, 2 3 million cattle were being vaccinated annually with the strain 19 vaccine, but because this vaccine induced strong, long-term titers on agglutination tests that interfered with identification of cattle infected with field strains of B. abortus, its use in cattle was discontinued in 1970. Soviet scientists then began a comprehensive program of research to identify vaccines with high immunogenicity, weak responses on agglutination tests and low pathogenicity in humans, as a foundation for widespread control of cattle brucellosis. While several new vaccines that induced weak or no responses on serologic agglutination tests were identified by experiments in guinea pigs and cattle, a large body of experimental and field studies suggested that the smooth-rough strain SR82 vaccine combined the desired weak agglutination test responses with comparatively higher efficacy against brucellosis. In 1974, prior to widespread use of strain SR82 vaccine, over 5300 cattle farms across the Russian Federation were known to be infected with B. abortus. By January 2008, only 68 cattle farms in 18 regions were known to be infected with B. abortus, and strain SR82 continues to be the most widely and successfully used vaccine in many regions of the Russian Federation. PMID- 21676344 TI - Human and porcine Taenia solium infections in Mozambique: identifying research priorities. AB - The objective of this paper is to critically review and summarize available scientific and lay literature, and ongoing studies on human and porcine cysticercosis in Mozambique to identify knowledge gaps and direct immediate and long-term research efforts. Data on the spatial distribution and prevalence of the disease in human and swine populations are scarce and fragmented. Human serological studies have shown that 15-21% of apparently healthy adults were positive for cysticercosis antibodies or antigen, while in neuropsychiatric patients seroprevalence was as high as 51%. Slaughterhouse records indicate a countrywide occurrence of porcine cysticercosis, while studies have shown that 10 35% of pigs tested were seropositive for cysticercosis antibodies or antigen. Current research in Mozambique includes studies on the epidemiology, molecular biology, diagnosis and control of the disease. Future research efforts should be directed at better understanding the epidemiology of the disease in Mozambique, particularly risk factors for its occurrence and spread in human and swine populations, documenting the socio-economic impact of the disease, identifying critical control points and evaluating the feasibility and epidemiological impact of control measures and development of local level diagnostic tools for use in humans and swine. PMID- 21676345 TI - Determinants of branded prescription medicine prices in OECD countries. AB - This paper investigates the determinants of the prices of branded prescription medicines across different regulatory settings and health care systems, taking into account their launch date, patent status, market dynamics and the regulatory context in which they diffuse. By using volume-weighted price indices, this paper analyzes price levels for a basket of prescription medicines and their differences in 15 OECD countries, including the United States and key European countries, the impact of distribution margins and generic entry on public prices and to what extent innovation, by means of introducing newer classes of medicines, contributes to price formation across countries. In doing so, the paper seeks to understand the factors that contribute to the existing differences in prices across countries, whether at an ex-factory or a retail level. The evidence shows that retail prices for branded prescription medicines in the United States are higher than those in key European and other OECD countries, but not as high as widely thought. Large differences in prices are mainly observed at an ex-factory level, but these are not the prices that consumers and payers pay. Cross-country differences in retail prices are actually not as high as expected and, when controlling for exchange rates, these differences can be even smaller. Product age has a significant effect on prices in all settings after having controlled for other factors. Price convergence is observed across countries for newer prescription medicines compared with older medicines. There is no evidence that originator brand prices fall after generic entry in the United States, a phenomenon known as the 'generics paradox'. Finally, distribution and taxes are important determinants of retail prices in several of the study countries. To the extent that remuneration of the distribution chain and taxation are directly and proportionately linked to product prices this is likely to persist over time. PMID- 21676346 TI - Burden of acute gastroenteritis and healthcare-seeking behaviour in France: a population-based study. AB - In France surveillance underestimates the true burden of acute gastroenteritis (AG). We conducted a population-based, retrospective cross-sectional telephone survey between May 2009 and April 2010 in order to obtain more accurate estimates of the incidence and the burden of AG and to describe healthcare-seeking behaviour for AG. Of the 10 080 persons included in the survey, 260 respondents reported 263 episodes of AG. The incidence rate of AG was estimated at 0.33 cases/person-year (95% CI 0.28-0.37). It was highest in children aged <5 years and declined with age. Thirty-three percent (95% CI 27-40) of the AG cases consulted a physician and 76% (95% CI 70-82) used medication. Our results indicate that there are more than 21 million episodes of AG each year in France. These results allow a more accurate interpretation of the data derived from existing AG surveillance systems. PMID- 21676347 TI - Spatial epidemiology of suspected clinical leptospirosis in Sri Lanka. AB - Leptospirosis is one of the most widespread zoonoses in the world. A large outbreak of suspected human leptospirosis began in Sri Lanka during 2008. This study investigated spatial variables associated with suspected leptospirosis risk during endemic and outbreak periods. Data were obtained for monthly numbers of reported cases of suspected clinical leptospirosis for 2005-2009 for all of Sri Lanka. Space-time scan statistics were combined with regression modelling to test associations during endemic and outbreak periods. The cross-correlation function was used to test association between rainfall and leptospirosis at four locations. During the endemic period (2005-2007), leptospirosis risk was positively associated with shorter average distance to rivers and with higher percentage of agriculture made up of farms <0.20 hectares. Temporal correlation analysis of suspected leptospirosis cases and rainfall revealed a 2-month lag in rainfall-case association during the baseline period. Outbreak locations in 2008 were characterized by shorter distance to rivers and higher population density. The analysis suggests the possibility of household transmission in densely populated semi-urban villages as a defining characteristic of the outbreak. The role of rainfall in the outbreak remains to be investigated, although analysis here suggests a more complex relationship than simple correlation. PMID- 21676348 TI - A multi-tiered time-series modelling approach to forecasting respiratory syncytial virus incidence at the local level. AB - Respiratory syncytial virus (RSV) is the most common cause of documented viral respiratory infections, and the leading cause of hospitalization, in young children. We performed a retrospective time-series analysis of all patients aged <18 years with laboratory-confirmed RSV within a network of multiple affiliated academic medical institutions. Forecasting models of weekly RSV incidence for the local community, inpatient paediatric hospital and paediatric intensive-care unit (PICU) were created. Ninety-five percent confidence intervals calculated around our models' 2-week forecasts were accurate to +/-9.3, +/-7.5 and +/-1.5 cases/week for the local community, inpatient hospital and PICU, respectively. Our results suggest that time-series models may be useful tools in forecasting the burden of RSV infection at the local and institutional levels, helping communities and institutions to optimize distribution of resources based on the changing burden and severity of illness in their respective communities. PMID- 21676349 TI - Genetic characterization of Vibrio cholerae O1 strains isolated in Zambia during 1996-2004 possessing the unique VSP-II region of El Tor variant. AB - New variants of Vibrio cholerae O1 have appeared in different time-frames in various endemic regions, especially in Asia and Africa. Sixty-nine strains of V. cholerae O1 isolated in Zambia between 1996 and 2004 were investigated by various genotypic techniques to determine the lineage of virulence signatures and clonality. All strains were positive for Vibrio seventh pandemic Islands (VSP)-I and VSP-II and repeat toxin (RTX) gene clusters attesting their El Tor lineage. Interestingly, strains isolated in recent times (2003-2004) were identified as an altered variant (El Tor biotype that harbours El Tor type rstR but produce classical ctxB) that replaced completely the progenitor El Tor strains prevalent in 1996-1997. Recent altered variant strains differed from prototype El Tor strains isolated earlier in that these strains lacked two ORFs, VC0493 and VC0498, in the VSP-II region. PFGE analysis revealed two major clonal lineages in the strains; cluster A represented the strains isolated before 2003 and cluster B the altered strains isolated in 2003-2004. Cluster A was closely related to prototype El Tor reference strain isolated in Bangladesh in 1971. Cluster B was found to be matched with Bangladeshi altered strains but was different from the hybrid strains isolated from Mozambique and Bangladesh. This report provides important information on the genesis of altered strains of V. cholerae O1 isolated in Zambia and emphasizes the need for further studies to follow the trends of evolutionary changes. PMID- 21676350 TI - Risk factors associated with typhoid fever in children aged 2-16 years in Karachi, Pakistan. AB - We analysed the data from the control group in a typhoid vaccine trial in Karachi to assess the differences in individual-, household- and cluster-level characteristics for developing typhoid fever. The annual incidence of typhoid in children aged 2-16 years in the control arm of the vaccine trial was 151/100 000 population. After adjustment, the risk of typhoid was lower with increasing age [risk ratio (RR) 0.89, 95% confidence interval (CI) 0.83-0.95], was higher with an increase in population density (RR 1.13, 95% CI 1.05-1.21) and was lower in the households using a safe drinking-water source (RR 0.63, 95% CI 0.41-0.99). Typhoid fever affects younger children living in areas of high population density and lack of access to safe water in Pakistan. A combination of environmental and biological interventions is required to prevent the continued epidemiological and economic impact of typhoid fever in high-risk areas of Pakistan. PMID- 21676351 TI - Decreasing prevalence of brucellosis in red deer through efforts to control disease in livestock. AB - When a pathogen infects a number of different hosts, the process of determining the relative importance of each host species to the persistence of the pathogen is often complex. Removal of a host species is a potential but rarely possible way of discovering the importance of that species to the dynamics of the disease. This study presents the results of a 12-year programme aimed at controlling brucellosis in cattle, sheep and goats and the cascading impacts on brucellosis in a sympatric population of red deer (Cervus elaphus) in the Boumort National Game Reserve (BNGR; NE Spain). From February 1998 to December 2009, local veterinary agencies tested over 36 180 individual blood samples from cattle, 296 482 from sheep and goats and 1047 from red deer in the study area. All seropositive livestock were removed annually. From 2006 to 2009 brucellosis was not detected in cattle and in 2009 only one of 97 red deer tested was found to be positive. The surveillance and removal of positive domestic animals coincided with a significant decrease in the prevalence of brucellosis in red deer. Our results suggest that red deer may not be able to maintain brucellosis in this region independently of cattle, sheep or goats, and that continued efforts to control disease in livestock may lead to the eventual eradication of brucellosis in red deer in the area. PMID- 21676352 TI - Molecular and phylogenetic analysis of Greek measles 2010 strains. AB - Although elimination of measles virus (MV) by 2010 was a revised target, a new epidemic has been ongoing in Greece and other European countries. The purpose of this study was the molecular and phylogenetic analysis of the Greek MV circulating strain. Twenty-four MV strains isolated from clinical samples during the 2010 outbreak were genotyped and studied in terms of nucleotide variation and phylogeny. All of the detected viruses were of the D4 genotype, which is circulating in Greece in the Roma population of Bulgarian nationality, the Greek Roma population and the Greek non-minority population, as well as in other EU countries. Phylogenetic analysis revealed that these viruses belonged to subgroup 4 of D4 MV strains. It is essential to continue epidemiological surveillance of measles in Greece to monitor the transmission pattern of the virus and the effectiveness of measles immunization, which eventually will lead to its elimination. PMID- 21676353 TI - A brief review of foodborne zoonoses in China. AB - Foodborne zoonoses have a major impact on public health in China. Its booming economy and rapid socioeconomic changes have affected food production, food supplies and food consumption habits, resulting in an increase in the number of outbreaks of foodborne zoonoses. Both emerging and re-emerging foodborne zoonoses have attracted increasing national and international attention in recent years. This paper briefly reviews the main foodborne zoonoses that have had a major impact on public health over the last 20 years in China. The major causative microorganisms, including foodborne bacteria, parasites and viruses, are discussed. The prevention and control of foodborne zoonoses are difficult challenges in China. The information provided here may aid the development of effective prevention and control strategies for foodborne zoonoses. PMID- 21676354 TI - Individual and contextual determinants of the duration of diarrhoeal episodes in preschool children: a longitudinal study in an urban setting. AB - This study investigated individual and contextual factors associated with the duration of diarrhoeal episodes in 693 young children living in a large Brazilian city who were followed-up for at least 3 months. The outcome is analysed as a continuous variable, by means of a hierarchical conceptual model organizing the factors in meaningful blocks. A total of 2397 episodes were recorded (median duration 2 days, interquartile range 1-3 days). Low percentage of households connected to the sewerage system in the neighbourhood, low family purchasing power, high agglomeration, mother aged <19 years, low zinc content in child's diet, and episode severity were significantly associated with longer duration (0.26-0.69 days more). Purchasing power effect was largely mediated by environmental conditions, characteristics of the child, and hygienic behaviour. Environmental conditions acted as a possible effect modifier, enhancing the effect on duration of diarrhoea of the child not having being vaccinated against measles or breastfed for >6 months. PMID- 21676355 TI - Wide dissemination of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella spp. in acute care and rehabilitation hospitals. AB - A prospective surveillance system for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-E) and ESBL-producing Klebsiella spp. (ESBL-K) was implemented in 39 German hospitals with the aim of determining the incidence densities (IDs) of community-onset and hospital-onset cases and of identifying risk factors for high IDs of hospital-onset cases. During 2008, 2081 ESBL-E/K cases were documented. ESBL-E cases (n=1330, 63.9%) were more common than ESBL-K cases (n=751, 36.1%), but a higher proportion of ESBL-K cases (59%) than of ESBL E cases (39.5%) were hospital-onset cases. The mean IDs were 0.54 (range 0-2.53) per 1000 patient-days for all ESBL-EK cases, 0.29 (range 0-1.81) per 1000 patient days for community-onset ESBL-EK cases and 0.25 (range 0-1.82) per 1000 patient days for hospital-onset ESBL-EK cases. Regression analysis showed a linear association between the IDs of community-onset and hospital-onset cases. The wide dissemination of ESBL-E and ESBL-K emphasizes the need for hospital-wide surveillance to guide control measures. PMID- 21676356 TI - Infection and immunity for human parvovirus B19 in patients with febrile exanthema. AB - The contribution of parvovirus B19 (B19V) as a causative agent of febrile exanthema (FE) in Cordoba, Argentina, was analysed by detection of viral DNA, and specific IgM and IgG. Serum from 141 patients with FE who were negative for measles and rubella, collected during 2005-2009, plus serum from 31 healthy individuals, were assayed. B19V was the aetiological agent in 14.9% of all FE cases, and in 39.1% in an epidemic year (2007). B19V DNA was detected in 47.6% of IgM-positive FE patients, 30.2% of IgM-negative/IgG-positive FE patients, and 9.7% of healthy controls, indicating B19V long-term infection in ~10% of immunocompetent individuals. Persistent B19V DNA was significantly more frequent in children than adults and in males than females. All patients with acute B19V infection had rash and fever, 85.7% had adenopathy, and only 14.3% had arthropathy. This is the first follow-up study of markers of infection and immunity for B19V infection in Argentina. PMID- 21676357 TI - Molecular-based detection of non-culturable and emerging campylobacteria in patients presenting with gastroenteritis. AB - From January 2009 to May 2010, 436 faecal samples from patients with diarrhoeal illness in Southern Ireland were identified as Campylobacter genus-positive by an automated multiplex PCR; however, 204 (46.8%) of these samples were culture negative for campylobacters. A combination of Campylobacter-specific uniplex PCR and 16S rRNA sequencing confirmed the presence of Campylobacter DNA in 191 (93.6%) of the culture-negative samples. Species-specific PCR identified C. jejuni (50.7%) C. ureolyticus (41%) and C. coli (5.7%) as the most prevalent species while C. fetus, C. upsaliensis, C. hyointestinalis and C. lari accounted for 10% of culture-negative samples; mixed Campylobacter spp. were detected in 11% of samples. We conclude that non-culturable Campylobacter spp. are responsible for a considerable proportion of human enteritis and the true incidence of infection is likely to be significantly underestimated where conventional Campylobacter culture methods are used in isolation. PMID- 21676358 TI - Space-time pattern of hepatitis A in Spain, 1997-2007. AB - In Spain hepatitis A is a compulsory notifiable disease and individual cases are reported to the national epidemiological surveillance network. Incidence rates show variations in different regions. The aim of this study was to analyse the space-time pattern of hepatitis A risk at municipal level in Spain and at global and local levels during the period 1997-2007. At global level we used two estimates of risk: the standardized incidence ratio (SIR) and the posterior probability that the smoothed relative risk is >1 (PP). At local level we used the scan statistic method to analyse the space-time clusters. The SIR and significant PP (>0.8) showed the highest risk concentrated in areas of the Mediterranean coast. The most likely cluster gave a relative risk of 53.530. These spatial statistics methodologies can be complementary tools in the epidemiological surveillance of infectious diseases. PMID- 21676359 TI - Haemophilus influenzae type b infection, vaccination, and H. influenzae carriage in children in Minnesota, 2008-2009. AB - An increase in invasive Haemophilus influenzae type b (Hib) cases occurred in Minnesota in 2008 after the recommended deferral of the 12-15 months Hib vaccine boosters during a US vaccine shortage. Five invasive Hib cases (one death) occurred in children; four had incomplete Hib vaccination (three refused/delayed); one was immunodeficient. Subsequently, we evaluated Hib carriage and vaccination. From 18 clinics near Hib cases, children (aged 4 weeks 60 months) were surveyed for pharyngeal Hib carriage. Records were compared for Hib, diphtheria-tetanus-acellular pertussis (DTaP), and pneumococcal (PCV-7) vaccination. Parents completed questionnaires on carriage risk factors and vaccination beliefs. In 1631 children (February-March 2009), no Hib carriage was detected; Hib vaccination was less likely to be completed than DTaP and PCV-7. Non-type b H. influenzae, detected in 245 (15%) children, was associated with: male sex, age 24-60 months, daycare attendance >15 h/week, a household smoker, and Asian/Pacific Islander race/ethnicity. In 2009, invasive Hib disease occurred in two children caused by the same strain that circulated in 2008. Hib remains a risk for vulnerable/unvaccinated children, although Hib carriage is not widespread in young children. PMID- 21676360 TI - Effectiveness of environmental decontamination as an infection control measure. AB - The effectiveness of environmental decontamination (ED) as a measure in the control of infectious diseases is controversial. This work quantifies the effectiveness of ED by analysing the transmission of pathogens from the environment to susceptible hosts in a Susceptible-Infected-Susceptible model. Analysis of the model shows that ED can render a population disease-free only when the duration of infection (D) is within a certain range. As host-to-host transmission rate is increased, D falls outside this range and the higher levels of ED have a diminishing return in reducing the number of infected hosts at endemic equilibrium. To avoid this, ED can be combined with other control measures, such as treating infected individuals to push the duration of infection into the specified range. We propose decision criteria and minimum ED efforts required for control policies to be effective. PMID- 21676361 TI - Transmission of Streptococcus pneumoniae in adults may occur through saliva. AB - Of 742 army recruits tested for pneumococcal nasopharyngeal/oropharyngeal carriage, 6.6% were positive. Frequent sharing of a drinking glass/bottle was a common, strong and independent risk factor for pneumococcal carriage. Our findings strongly suggest, for the first time, that in young adults, transmission of pneumococci may occur via saliva and this should be considered when conducting an outbreak investigation and carriage studies. PMID- 21676362 TI - Multi-pathogen waterborne disease outbreak associated with a dinner cruise on Lake Michigan. AB - We report an outbreak associated with a dinner cruise on Lake Michigan. This took place on the same day as heavy rainfall, which resulted in 42.4 billion liters of rainwater and storm runoff containing highly diluted sewage being released into the lake. Of 72 cruise participants, 41 (57%) reported gastroenteritis. Stool specimens were positive for Shigella sonnei (n=3), Giardia (n=3), and Cryptosporidium (n=2). Ice consumption was associated with illness (risk ratio 2.2, P=0.011). S. sonnei was isolated from a swab obtained from the one of the boat's ice bins. Environmental inspection revealed conditions and equipment that could have contributed to lake water contaminating the hose used to load potable water onto the boat. Knowledge of water holding and distribution systems on boats, and of potential risks associated with flooding and the release of diluted sewage into large bodies of water, is crucial for public health guidance regarding recreational cruises. PMID- 21676363 TI - Porcine bocaviruses: genetic analysis and prevalence in Chinese swine population. AB - In members of the Bocavirus genus, that contain three open reading frames (ORFs) of the Parvovirinae subfamily, porcine bocaviruses (PoBoVs) exhibit the most genetic diversity. Based on the ORF2-encoded viral protein (VP1) classification, the six reported porcine bocaviruses were grouped into four species: PoBoV1 (porcine boca-like virus or PBoLV), PoBoV2 (porcine parvovirus 4 or PPV4), PoBoV3 (PBoV1/PBoV2) and PoBoV4 (6V/7V), with PoBoV3 and PoBoV4 each having two genotype viruses. All four PoBoV species were detected in the 166 samples collected in 2010 from swine herds located in ten provinces of China. The detection rates for PoBoV1-4 were 28.9%, 6.6%, 19.3% and 39.7%, respectively. The co-infection combinations involving these six porcine bocaviruses in the collected samples were very complex. Furthermore, mixed infections with viruses from other families (porcine reproductive and respiratory syndrome virus, classic swine fever virus and porcine circovirus type 2) were also detected. PMID- 21676365 TI - Volume completion in 4.5-month-old infants. AB - In this study, we examined 4.5-month-old infants' visual completion of self occluding three-dimensional objects. A previous study on this topic reported that 6-month-old, but not 4-month-old infants extrapolate a convex, symmetric prism from a limited view of its surfaces (Soska & Johnson, 2008). As of yet, studies on the development of amodal completion of three-dimensional, self-occluding objects are scarce. Given 4-month-old infants' abilities to derive three dimensional shape from a variety of visual cues, three-dimensional amodal completion may well depend on the perceptual strength of three-dimensionality in the stimulus displays. The first experiments (1A and 1B) tested this hypothesis by means of a habituation paradigm and showed that 4.5-month-old infants are indeed able to amodally complete the back of a self-occluding object when sufficient three-dimensional cues are available. Further support for volume completion in 4.5-month-old infants was found in a second experiment, again using a habituation paradigm, that measured perceived connectedness between two visually separated, self-occluding, three-dimensional objects. PMID- 21676364 TI - Increased electronegative LDL and decreased antibodies against electronegative LDL levels correlate with inflammatory markers and adhesion molecules in hemodialysed patients. AB - BACKGROUND: Chronic Kidney Disease (CKD) patients present high levels of electronegative LDL (LDL-) that can modulate the expression of molecules involved in inflammation and it is closely linked to atherosclerosis. We investigated the association between LDL(-) and inflammatory markers in patients undergoing hemodialysis (HD). METHODS: Forty-seven HD patients from a private clinic in Rio de Janeiro, Brazil were studied and compared with 20 age matched healthy individuals. Serum LDL(-) and anti-LDL(-) autoantibody levels were measured by ELISA; TNF-alpha, IL-6, VCAM-1 and ICAM-1 were determined by a multiplex assay kit. RESULTS: HD patients presented higher IL-6 and TNF-alpha concentrations (4.1 +/- 1.6 and 5.5 +/- 2.1 pg/ml, respectively) than healthy subjects (2.6 +/- 0.2 and 2.4 +/- 1.1 pg/ml, respectively) (p=0.0001). In addition, they presented higher VCAM-1 and ICAM-1 levels and, LDL(-) concentrations were also increased (0.18 +/- 0.12 U/l) when compared to healthy individuals (0.10 +/- 0.08 U/l) (p<0.02). In contrast, the anti-LDL(-) autoantibody levels were lower in HD patients (0.02 +/- 0.01 mg/l) than in healthy subjects (0.05 +/- 0.03 mg/l) (p<0.001). There was a positive correlation between LDL(-) and IL-6 (r=0.25, p=0.004) and ICAM-1 (r=0.36; p=0.003). There was also a negative correlation between anti-LDL(-) autoantibodies and TNF-alpha (r=-0.37; p=0.003) and VCAM-1 (r=-0.50; p=0.0001). CONCLUSIONS: The association between LDL(-) and inflammation and the lower levels of anti-LDL(-) autoantibodies are important risk factors related to atherosclerosis in CKD. PMID- 21676366 TI - Reactive wetting, evolution of interfacial and bulk IMCs and their effect on mechanical properties of eutectic Sn-Cu solder alloy. AB - Lead free solders are increasingly being used in electronic applications. Eutectic Sn-Cu solder alloy is one of the most favored lead free alloys used for soldering in electronic applications. It is inexpensive and principally used in wave soldering. Wetting of liquid solder on a substrate is a case of reactive wetting and is accompanied by the formation of intermetallic compounds (IMCs) at the interface. Wettability of Sn-0.7Cu solder on metallic substrates is significantly affected by the temperature and the type of flux. The wettability and microstructural evolution of IMCs at the Sn-0.7Cu solder/substrate interfaces are reviewed in the present paper. The reliability of solder joints in electronic packaging is controlled by the type and morphology of interfacial IMCs formed between Sn-0.7Cu solder and substrates. The formation and growth mechanisms of interfacial IMCs are highlighted. Mechanical behavior of bulk solder alloy and solder joint interfaces are analyzed. The characteristics of the IMCs which have marked effect on the mechanical properties and fracture behavior as well as reliability of solder joints of the alloy are discussed. An attempt has also been made to discuss the effect of cooling rate and strain rate on shear strength, tensile properties and creep resistance of the solder alloy. It is recommended that future work should focus on evolving a standard procedure involving sequential assessment of wetting behavior, evolution of IMCs and mechanical properties. PMID- 21676367 TI - Angiographic characteristics of coronary disease and postresuscitation electrocardiograms in patients with aborted cardiac arrest outside a hospital. AB - Postresuscitation electrocardiogram (ECG) in patients with aborted cardiac death may demonstrate ST-elevation myocardial infarction (STEMI), ST-T changes, intraventricular conduction delay, or other nonspecific findings. In the present study, we compared ECG to urgent coronary angiogram in 158 consecutive patients with STEMI and 54 patients not fulfilling criteria for STEMI admitted to our hospital from January 1, 2003 through December 31, 2008. At least 1 obstructive lesion was present in 97% of patients with STEMI and in 59% of patients without STEMI with >=1 occlusion in 82% and 39%, respectively (p <0.001). Obstructive lesion was considered acute in 89% of patients with STEMI and in 24% of patients without STEMI (p <0.001). An acute lesion in STEMI had a higher thrombus score (2.6 vs 1.3, p = 0.05) and more often presented with Thrombolysis In Myocardial Infarction grade 0 to 1 flow (75% vs 36%, p <0.01). Percutaneous coronary intervention, which was attempted in 148 lesions in patients with STEMI and in 17 lesions in patients without STEMI, resulted in final Thrombolysis In Myocardial Infarction grade 3 flow in 87% and 71%, respectively (p = 0.34). In conclusion, STEMI on postresuscitation ECG is usually associated with the presence of an acute culprit lesion. However, in the absence of STEMI, an acute culprit lesion is still present in 1/4 of patients. An acute lesion in STEMI is more thrombotic and more often leads to complete occlusion. Urgent percutaneous coronary intervention is feasible and successful regardless of postresuscitation ECG. PMID- 21676368 TI - Systemic hypothermia to prevent radiocontrast nephropathy (from the COOL-RCN Randomized Trial). AB - Radiocontrast nephropathy (RCN) develops in a substantial proportion of patients with chronic kidney disease (CKD) after invasive cardiology procedures and is strongly associated with subsequent mortality and adverse outcomes. We sought to determine whether systemic hypothermia is effective in preventing RCN in patients with CKD. Patients at risk for RCN (baseline estimated creatinine clearance 20 to 50 ml/min) undergoing cardiac catheterization with iodinated contrast >=50 ml were randomized 1:1 to hydration (control arm) versus hydration plus establishment of systemic hypothermia (33 degrees C to 34 degrees C) before first contrast injection and for 3 hours after the procedure. Serum creatinine levels at baseline, 24 hours, 48 hours, and 72 to 96 hours were measured at a central core laboratory. The primary efficacy end point was development of RCN, defined as an increase in serum creatinine by >=25% from baseline. The primary safety end point was 30-day composite rate of adverse events consisting of death, myocardial infarction, dialysis, ventricular fibrillation, venous complication requiring surgery, major bleeding requiring transfusion >=2 U, or rehospitalization. In total 128 evaluable patients (mean creatinine clearance 36.6 ml/min) were prospectively randomized at 25 medical centers. RCN developed in 18.6% of normothermic patients and in 22.4% of hypothermic patients (odds ratio 1.27, 95% confidence interval 0.53 to 3.00, p = 0.59). The primary 30-day safety end point occurred in 37.1% versus 37.9% of normothermic and hypothermic patients, respectively (odds ratio 0.97, 95% confidence interval 0.47 to 1.98, p = 0.93). In conclusion, in patients with CKD undergoing invasive cardiology procedures, systemic hypothermia is safe but is unlikely to prevent RCN. PMID- 21676369 TI - High-sensitivity troponin T level and angiographic severity of coronary artery disease. AB - The association between circulating levels of cardiac troponins and angiographic severity of coronary artery disease (CAD) has not been studied. We investigated whether there is an association between the level of high-sensitivity troponin T (hs-TnT) and angiographic severity of CAD and whether this association is independent of conventional risk factors, N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and C-reactive protein (CRP). This case-control study included 904 patients with stable CAD (cases) and 412 patients with chest pain but without significant CAD on coronary angiogram (controls). Diagnosis of CAD was confirmed or excluded by coronary angiography. Cardiac TnT was measured with conventional and high-sensitivity assays in parallel using the same plasma sample. In patients with no CAD and in those with 1-, 2-, or 3-vessel disease, hs TnT levels (median, twenty-fifth to seventy-fifth percentiles) were 0.005 MUg/L (<0.003 to 0.009), 0.006 MUg/L (0.003 to 0.011), 0.008 MUg/L (0.004 to 0.013), and 0.010 MUg/L (0.006 to 0.017), respectively (p <0.001). In multivariable analysis adjusting for cardiovascular risk factors and clinical variables including NT-pro-BNP and CRP, hs-TnT was an independent predictor of presence of CAD (adjusted odds ratio 1.30, 95% confidence interval 1.07 to 1.59, p = 0.009). In conclusion, in patients with stable and angiographically proved CAD, hs-TnT level is increased compared to subjects without CAD and correlates with angiographic atherosclerotic extent and burden. The association between increased levels of hs-TnT and presence of CAD was independent of traditional cardiovascular risk factors, NT-pro-BNP, and CRP. PMID- 21676370 TI - Comparison of frequency of atrial fibrillation after coronary artery bypass grafting in African Americans versus European Americans. AB - In the general population, African Americans experience atrial fibrillation (AF) less frequently than European Americans. This difference could also exist in the incidence of this arrhythmia after cardiac surgery, but this possibility has been insufficiently examined. To test the association of such an ethnic difference, we compared the incidence of postoperative AF in a consecutive series of 2,312 African Americans and 6,054 European Americans who underwent isolated coronary artery bypass grafting from July 2000 to June 2007. Raw differences between the cohorts in the incidence of new AF were adjusted to take into account the baseline differences. Postoperatively, new-onset AF developed in 504 (22%) of 2,312 African-American patients and in 1,838 (30%) of 6,054 European-American patients (p <0.01). After adjustment with logistic regression analysis for numerous baseline differences, African Americans remained less likely to develop AF (odds ratio 0.63, 95% confidence interval 0.55 to 0.72; p <0.001). Risk was also adjusted using propensity matching. In that analysis, 457 (22%) of 2,059 African-American patients had postoperative AF, as did 597 (29%) of 2,059 matched European-American patients (p <0.01). In conclusion, AF was significantly less common among African-American patients than among European-American patients after coronary artery bypass grafting. PMID- 21676371 TI - A new electrocardiographic criterion to differentiate between Takotsubo cardiomyopathy and anterior wall ST-segment elevation acute myocardial infarction. AB - Several studies have examined the ability of electrocardiography to differentiate between takotsubo cardiomyopathy (TC) and anterior wall acute ST-segment elevation myocardial infarction (AA-STEMI). In those studies, the magnitude of ST segment elevation was not measured at the J point. The American Heart Association, American College of Cardiology Foundation, and Heart Rhythm Society guidelines recommend that the magnitude of ST-segment elevation should be measured at the J point. Accordingly, the aim of this study was to retrospectively examine whether electrocardiography, using the magnitude of ST segment elevation measured at the J point, could differentiate 62 patients with TC from 280 with AA-STEMI. Patients with AA-STEMI were divided into following subgroups: 140 with left anterior descending coronary artery occlusions proximal to the first diagonal branch (AA-STEMI-P), 120 with left anterior descending occlusions distal to the first diagonal branch and proximal to the second diagonal branch (AA-STEMI-M), and 20 with left anterior descending occlusions distal to the second diagonal branch (AA-STEMI-D). TC had a much lower prevalence of ST-segment elevation >=1 mm in lead V(1) (19.4%) compared to AA-STEMI (80.4%, p <0.01), AA-STEMI-P (80.7%, p <0.01), AA-STEMI-M (80%, p <0.01), and AA-STEMI-D (80%, p <0.01). ST-segment elevation >=1 mm in >=1 of leads V(3) to V(5) without ST-segment elevation >=1 mm in lead V(1) identified TC with sensitivity of 74.2% and specificity of 80.6%. Furthermore, this criterion could differentiate TC from each AA-STEMI subgroup, with similar diagnostic values. In conclusion, using the magnitude of ST-segment elevation measured at the J point, a new electrocardiographic criterion is proposed with an acceptable ability to differentiate TC from AA-STEMI. PMID- 21676372 TI - ST-segment deviation in lead aVR on admission is not associated with left ventricular function at predischarge in first anterior wall ST-segment elevation acute myocardial infarction. AB - Previous studies have shown that the analysis of ST-segment deviation in lead aVR on admission provides useful information on angiographic coronary anatomy and risk stratification in acute coronary syndromes. However, the association between ST-segment deviation in lead aVR on admission and left ventricular (LV) function has not been fully investigated in anterior wall acute ST-segment elevation myocardial infarction. In this study, 237 patients with first anterior wall acute ST-segment elevation myocardial infarction were examined. The patients were divided into the following 3 groups according to ST-segment deviation in lead aVR on admission: 85 with ST-segment elevation >=0.5 mm (group A), 106 without ST segment deviation (group B), and 46 with ST-segment depression >=0.5 mm (group C). LV ejection fractions at predischarge were compared among the 3 groups. Among the 3 groups, there were significant differences in the prevalences of proximal left anterior descending coronary artery (LAD) occlusion (group A 75.3%, group B 56.6%, group C 45.7%, p = 0.002), long LAD (group A 27.1%, group B 31.1%, group C 56.5%, p = 0.002), and good collaterals to the LAD (group A 40.0%, group B 25.4%, group C 17.4%, p = 0.01). LV ejection fractions at predischarge did not differ among the 3 groups (group A 56.4 +/- 12.5%, group B 56.9 +/- 12.7%, group C 53.3 +/- 12.2%, p = 0.26). On a multiple regression analysis, establishment of Thrombolysis In Myocardial Infarction grade 3 flow, proximal LAD occlusion, and long LAD were associated with the LV ejection fraction at predischarge. In conclusion, ST-segment deviation in lead aVR on admission is not associated with LV function at predischarge in first anterior wall acute ST-segment elevation myocardial infarction. PMID- 21676373 TI - Immune ring formation associated with cytomegalovirus endotheliitis. AB - PURPOSE: To describe immune ring (IR) formation as a manifestation of cytomegalovirus (CMV) endotheliitis. DESIGN: Retrospective observational case series. METHODS: Review of all consecutive CMV anterior uveitis and endotheliitis patients seen at the Singapore National Eye Centre for the occurrence of an IR. CMV infection was diagnosed by polymerase chain reaction analysis of the aqueous. RESULTS: None of the 72 eyes with CMV anterior uveitis had an IR formation. Four episodes of IR formation were seen in 3 eyes (14.3%) of 21 cases of CMV-positive endotheliitis. All were unilateral and all 3 patients were human immunodeficiency virus negative middle-aged Chinese males. The IR developed 2 to 7 months after occurrence of the endotheliitis and the aqueous was positive for CMV during 2 of the episodes of IR formation. In 2 eyes, the IR occurred at the completion of a course of systemic ganciclovir when the aqueous was negative for CMV. The immune rings resolved with combination therapy of topical prednisolone acetate 0.12% and ganciclovir. Patient 1 had a recurrence of the IR 4 months after stopping treatment but again resolved following treatment with ganciclovir and topical corticosteroids. CONCLUSION: Corneal immune rings can occur as a result of CMV infection. Hence CMV infection may have to be considered in such cases. PMID- 21676374 TI - Quality of life in a german graves orbitopathy population. AB - PURPOSE: To evaluate the validity and responsiveness of a German-language version of the disease-specific Graves orbitopathy quality-of-life questionnaire (GO QOL). DESIGN: Prospective cross-sectional study. METHODS: At a multidisciplinary university orbital center, 310 consecutive unselected Graves orbitopathy outpatients answered the GO-QOL before undergoing complete ophthalmic and endocrine assessment. The main outcome measures were the GO-QOL and its 2 subscales, Visual Functioning and Appearance. RESULTS: The QOL scores for the subscales Visual Functioning and Appearance were (mean +/- SE) 72.5 +/- 1.4 and 71.3 +/- 1.5, respectively. Visual Functioning and Appearance were higher in mild (82.2 +/- 2.2 and 86.0 +/- 17.6) than in moderate to severe (66.6 +/- 1.8, p < .001, 95% CI 15.6-2.9 and 65.5 +/- 25.5, P < .001, 95% CI 15.1-26.0) and in sight threatening Graves orbitopathy (41.9 +/- 9.9, P < .001, 95% CI 25.4-55.3 and 58.5 +/- 9.0, P < .001, 95% CI 15.0-39.4). Visual Functioning and Appearance were also lower in active (63.3 +/- 2.2 and 64.5 +/- 2.2) than in inactive stages (77.0 +/- 1.9; P < .001, 95% CI 7.9-19.3 and 78.3 +/- 1.8, P < .001, 95% CI 8.2-19.2). Visual Functioning was 81.6 +/- 1.8 in patients without and 62.4 +/- 2.0 in patients with diplopia (P < .001, 95% CI 13.8-24.6). Appearance was lower in those receiving psychotherapy (64.7 +/- 3.2) than in those without psychotherapy (74.6 +/- 1.6, P = .005, 95% CI 3.0-16.7). Significant ceiling effects (>=15% at the highest value of the subscale) were observed for Appearance in 59 patients (19%) and for Visual Functioning in 85 patients (27%). CONCLUSION: The German language version of the GO-QOL shows evidence of validity in Graves orbitopathy and it usefully complements ophthalmic assessment in these patients. PMID- 21676375 TI - Blindness and long-term progression of visual field defects in chinese patients with primary angle-closure glaucoma. AB - PURPOSE: To investigate the long-term rates of blindness and visual field (VF) progression in treated primary angle-closure glaucoma (PACG) patients. DESIGN: Retrospective observational case series. METHODS: PACG patients with >=10 years of follow-up were analyzed. All VFs (static automated perimetry, central 24-2 threshold test) performed were reviewed and reliable VFs (fixation losses <20%, false positives and false negatives <33%) were scored using the Advanced Glaucoma Intervention Study (AGIS) system. Progression of a VF defect was defined as a change of >=4 from baseline on 2 consecutive VF tests. RESULTS: From the 137 eyes of 87 patients with PACG with >=10 years of follow-up identified, 6% and 30.1% were blind based on initial visual acuity (VA) and VF criteria respectively and 12.0% had an initial AGIS score of 20; these were excluded. Eighty-three eyes from 57 patients (all Chinese, mean age 59.9 +/- 8.2 years, 67.5% female) were analyzed. The mean AGIS score was 5.14 +/- 4.37 at baseline. VF deterioration was detected in 27 eyes (32.5%) of 21 patients, with 4.8% and 7.2% of eyes progressing to blindness based on VA and VF criteria respectively. On Cox regression, eyes with VF progression had higher mean overall IOP (P < .001), and higher prevalence of previous acute angle closure (AAC, P = .008). CONCLUSIONS: Over 10 years, a third of PACG patients were found to have VF progression, with 7% progressing to blindness while on treatment. Eyes with higher mean overall IOP and a history of previous AAC were more likely to have VF progression. PMID- 21676376 TI - [Family form of isolated left ventricular noncompaction; case of a mother and her son observed in Gabon]. AB - We describe a case report of a young Gabonese lady who presented an acute pulmonary oedema and we suspected a paripartum cardiomyopathy. Subsequent investigations showed isolated left ventricular noncompaction. A few months later, the same disease was disclosed at her 9 year-old son who presented a cardiac insufficiency. Therefore, we suspect a family form of left ventricular noncompaction. And it is the first description in subsaharan Africa. The hereditary character of this new form of cardiomyopathy linked to a genetic mutation on the X chromosome is well known. This disease is associated with heart failure, high incidence of systemic thromboembolism complications or ventricular arrhythmia. The echocardiography and the cardiac magnetic resonance imaging has been reported to be tools for diagnosis. In Africa, access to these techniques remains a privilege. So the discovery of illness is often late and the family screening are special. In our area, the therapeutic management is the medical treatment of heart failure. Implatable cardioverter defibrillator or heart transplantation are not available. So long-term prognosis of our patients with congestive heart failure stays poor. With best equipment in our hospitals and good training of African cardiologists, we should improve the management of our patients. PMID- 21676377 TI - New antimicrobial therapies used against fungi present in subgingival sites--a brief review. AB - Although the main reservoir of Candida spp. is believed to be the buccal mucosa, these microorganisms can coaggregate with bacteria in subgingival biofilm and adhere to epithelial cells. The treatment of periodontal disease includes scaling and root planning (SRP) associated with proper oral hygiene. However, some patients may have negative responses to different therapeutic procedures, with a continuous loss of insertion, so the use of antimicrobials is needed as an adjuvant to SRP treatment. The use of a broad-spectrum antibiotic, such as tetracycline and metronidazole, as an aid in periodontal treatment has also been a factor for the development of superinfections by resistant bacteria and Candida species, even in patients with HIV. In the dental practice, the most commonly used antifungals are nystatin and fluconazole. However, the introduction of new drugs like the next generation of azoles is essential before the onset of emergent species in periodontal disease. Plants are good options for obtaining a wide variety of drugs. This alternative could benefit a large population that uses plants as a first treatment option. Plants have been used in medicine for a long time and are extensively used in folk medicine, because they represent an economic alternative, are easily accessible and are applicable to various diseases. Herein, we briefly review the literature pertaining the presence of Candida sp. in periodontal pockets, the conventional antifungal resistance and new therapies that include natural antifungal agents are reviewed. PMID- 21676378 TI - Can you hear a difference? Neuronal correlates of melodic deviance processing in children. AB - Many studies investigating music processing in adult musicians and nonmusicians point towards pronounced behavioral and neurophysiological differences between the two groups. Recent studies indicate that these differences can already be found in early childhood. Further, electro-encephalography studies using musical discrimination tasks have demonstrated that differences in music processing become more pronounced when explicitly rather than implicitly trained musical abilities are required. Exploring the functional neuroanatomy underlying the processing of different expectation violations in children and its association with musical training, we investigated neural responses to different melodic deviances in musically trained and untrained children. Using functional magnetic resonance imaging, children (aged 11-14 years) were examined while comparing pairs of short melodies that were either identical or differed with respect to four notes. The implemented deviances were either subtle (by inserting plausible in-key notes) or obvious (by inserting implausible out-of-key notes). Our results indicate a strong association between musical training and functional neuroanatomy of the brain. Similar to research on music processing in adults, the processing of obvious melodic deviances activated a network involving inferior frontal, premotor and anterior insula regions in musically trained and untrained children. By contrast, subtle deviances led to activation in the inferior frontal and premotor cortex, the anterior insula, the superior temporal gyrus, and the supramarginal gyrus in musically trained children only. Our work provides further insights into the functional neuroanatomy of melody processing and its association with musical training in children, providing the basis for further studies specifying distinct musical processes (e.g. contour and interval processing). PMID- 21676380 TI - D-serine: the right or wrong isoform? AB - Only recently, d-amino acids have been identified in mammals. Of these, d-serine has been most extensively studied. d-Serine was found to play an important role as a neurotransmitter in the human central nervous system (CNS) by binding to the N-methyl-d-aspartate receptor (NMDAr), similar to glycine. Therefore, d-serine may well play a role in all physiological and pathological processes in which NMDArs have been implied. In this review, we discuss the findings implying an important role for d-serine in human physiology (CNS development and memory and learning) and pathology (excitotoxicity, perinatal asphyxia, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, epilepsy, schizophrenia and bipolar disorder). We will debate on the relative contribution of d-serine versus glycine and conclude with clinical applications derived from these results and future directions to progress in this field. In general, adequate concentrations of d serine are required for normal CNS development and function, while both decreased and increased concentrations can lead to CNS pathology. Therefore, d-serine appears to be the right isoform when present in the right concentrations. PMID- 21676381 TI - Arginine vasotocin neuronal phenotypes and their relationship to aggressive behavior in the territorial monogamous multiband butterflyfish, Chaetodon multicinctus. AB - Intra and interspecific comparisons of arginine vasotocin (AVT) and its mammalian homolog arginine vasopressin (AVP) demonstrate several relationships between these neuropeptides and aggression/dominance behaviors. Prior studies in coral reef butterflyfishes and other fishes indicate that features of AVT neurons in the gigantocellular preoptic area (gPOA) and axon varicosities within the ventral nucleus of the ventral telencephalon should have a positive relationship with aggressive behavior, whereas AVT-ir neuronal features in the parvocellular preoptic area (pPOA) should have a negative relationship. We measured the offensive aggression of wild caught territorial monogamous multiband butterflyfish, Chaetodon multicinctus, in a simple lab paradigm that controlled for social context and variations in social stimuli. Offensive aggression did not follow a clear stereotyped pattern, but rather a complex sequence that includes five action patterns and two approach behaviors. We then used immunohistochemistry to test for associations between AVT immunoreactive features and projections with overall offensive aggression. Our results indicate that gPOA cell number was positively related to aggression while both the size and number of pPOA cells were negatively related to aggression. No association between aggression and the number of axon varicosities in the telencephalic region proposed to be associated with aggression was found. This study provides further support for the relationship between AVT neuronal features and aggression in fishes, and provides preliminary evidence that this relationship may relate to the motivation to produce aggressive behaviors in the immediate future. PMID- 21676382 TI - [Oesophageal leiomyoma using minimally invasive treatment (laparoscopy thoracoscopy)]. PMID- 21676379 TI - The functional neuroanatomy of decision making: prefrontal control of thought and action. AB - Humans exhibit a remarkable capacity for flexible thought and action. Despite changing internal needs and external context, individuals maintain stable goals and pursue purposeful action. Functional neuroimaging research examining the neural underpinnings of such behavioral flexibility has progressed within several distinct traditions, as evident in the largely separate literatures on "cognitive control" and on "decision making." Both topics investigate the formulation of desires and intentions, the integration of knowledge and context, and the resolution of conflict and uncertainty. Additionally, each recognizes the fundamental role of the prefrontal cortex in supporting flexible selection of behavior. But despite this notable overlap, neuroimaging studies in cognitive control and decision making have exerted only limited influence on each other, in part due to differences in their theoretical and experimental groundings. Additionally, the precise organization of control processing within prefrontal cortex has remained unclear, fostering an acceptance of vague descriptions of decision making in terms of canonical cognitive control functions such as "inhibition" or "self-control." We suggest a unifying role for models of the hierarchical organization of action selection within prefrontal cortex. These models provide an important conceptual link between decision-making phenomena and cognitive-control processes, potentially facilitating cross-fertilization between these topics. PMID- 21676383 TI - [Laparoscopic endoluminal intragastric resection of a submucosal leiomyoma near the gastroesophageal joint]. PMID- 21676384 TI - Meticillin-resistant Staphylococcus aureus (MRSA) environmental contamination in a radiology department. AB - AIM: To explore the potential risk to patients and healthcare workers of acquiring meticillin-resistant Staphylococcus aureus (MRSA) in clinical and non clinical areas within a radiology department. MATERIALS AND METHODS: High-risk sites in clinical and non-clinical areas within the Department of Radiology were identified and 125 environmental swabs were obtained by an infection control nurse specialist. Decontamination methods and protocols were reviewed and compared against international decontamination best practice. RESULTS: One of 125 samples was culture positive for MRSA. The positive sample was isolated from the surface of the bore of the magnetic resonance imaging (MRI) unit. A hypochlorite cleaning agent was applied using a long-handled brush to clean the bore of the MRI unit. A repeat environmental screen found the MRI unit to be culture negative for MRSA. CONCLUSION: This study has demonstrated that standard decontamination measures are adequate to prevent environmental contamination with MRSA in a radiology department. However, the MRI unit requires special attention because of its long bore and difficult access. PMID- 21676385 TI - The role of the motor system in discriminating normal and degraded speech sounds. AB - Listening to speech recruits a network of fronto-temporo-parietal cortical areas. Classical models consider anterior, motor, sites involved in speech production whereas posterior sites involved in comprehension. This functional segregation is more and more challenged by action-perception theories suggesting that brain circuits for speech articulation and speech perception are functionally interdependent. Recent studies report that speech listening elicits motor activities analogous to production. However, the motor system could be crucially recruited only under certain conditions that make speech discrimination hard. Here, by using event-related double-pulse transcranial magnetic stimulation (TMS) on lips and tongue motor areas, we show data suggesting that the motor system may play a role in noisy, but crucially not in noise-free environments, for the discrimination of speech signals. PMID- 21676386 TI - Reading minds with neuroscience--possibilities for the law. PMID- 21676388 TI - Urinary bisphenol A and obesity: NHANES 2003-2006. AB - BACKGROUND: Bisphenol A (BPA) is a chemical suspected of causing endocrine and metabolic disruption in animals and humans. In rodents, in utero exposure to low dose BPA is associated with weight gain. Detectable levels of BPA are found in most Americans due to its widespread use in the manufacture of food and drink packaging. We hypothesized that urinary BPA concentrations would be positively associated with general and central obesity. METHODS: Cross-sectional analysis of urinary BPA concentrations, body mass index, and waist circumference in 2747 adults (aged 18-74), using pooled data from the 2003/04 and 2005/06 National Health and Nutrition Examination Surveys. RESULTS: The creatinine-adjusted geometric mean urinary BPA concentration was 2.05MUg/g creatinine (25th percentile: 1.18, 75% percentile: 3.33). Relative to those in the lowest BPA quartile, participants in the upper BPA quartiles were more likely to be classified as obese (quartile 2 odds ratio (OR): 1.85, 95% confidence interval (CI): 1.22, 2.79; quartile 3 OR: 1.60, 95% CI: 1.05-2.44; quartile 4 OR: 1.76, 95% CI: 1.06-2.94). Higher BPA concentration was also associated with abdominal obesity (quartile 2 OR: 1.62, 95% CI: 1.11, 2.36; quartile 3 OR: 1.39, 95% CI: 1.02-1.90; quartile 4 OR: 1.58, 95% CI: 1.03-2.42). CONCLUSIONS: Higher BPA exposure is associated with general and central obesity in the general adult population of the United States. Reverse causation is of concern due to the cross sectional nature of this study; longitudinal studies are needed to clarify the direction of the association. PMID- 21676389 TI - [Dressler's syndrome secondary to acute pulmonary embolism]. PMID- 21676387 TI - Females and males are highly similar in language performance and cortical activation patterns during verb generation. AB - OBJECTIVE: To test the existence of sex differences in cortical activation during verb generation when performance is controlled for. METHODS: Twenty male and 20 female healthy adults underwent functional magnetic resonance imaging (fMRI) using a covert block-design verb generation task (BD-VGT) and its event-related version (ER-VGT) that allowed for intra-scanner recordings of overt responses. Task-specific activations were determined using the following contrasts: BD-VGT covert generation>finger-tapping; ER-VGT overt generation>repetition; ER-VGT overt>covert generation. Lateral cortical regions activated during each contrast were used for calculating language lateralization index scores. Voxelwise regressions were used to determine sex differences in activation, with and without controlling for performance. Each brain region showing male/female activation differences for ER-VGT overt generation>repetition (isolating noun verb association) was defined as a region of interest (ROI). For each subject, the signal change in each ROI was extracted, and the association between ER-VGT activation related to noun-verb association and performance was assessed separately for each sex. RESULTS: Males and females performed similarly on language assessments, had similar patterns of language lateralization, and exhibited similar activation patterns for each fMRI task contrast. Regression analysis controlling for overt intra-scanner performance either abolished (BD VGT) or reduced (ER-VGT) the observed differences in activation between sexes. The main difference between sexes occurred during ER-VGT processing of noun-verb associations, where males showed greater activation than females in the right middle/superior frontal gyrus (MFG/SFG) and the right caudate/anterior cingulate gyrus (aCG) after controlling for performance. Better verb generation performance was associated with increased right caudate/aCG activation in males and with increased right MFG/SFG activation in females. CONCLUSIONS: Males and females exhibit similar activation patterns during verb generation fMRI, and controlling for intra-scanner performance reduces or even abolishes sex differences in language-related activation. These results suggest that previous findings of sex differences in neuroimaging studies that did not control for task performance may reflect false positives. PMID- 21676390 TI - [Atypical pneumonia with "atypical traits". Analysis of a Legionella outbreak]. PMID- 21676391 TI - [Transient ischemic attack due to paradoxical embolism of poldocanol foam]. PMID- 21676392 TI - Heat shock factor Y chromosome (HSFY) mRNA level predicts the presence of retrievable testicular sperm in men with nonobstructive azoospermia. AB - OBJECTIVE: To evaluate heat shock factor Y chromosome (HSFY) mRNA as a biomarker for the presence of retrievable testicular sperm. DESIGN: Case-control study. SETTING: Academic medical center. PATIENT(S): Men with nonobstructive azoospermia (NOA). INTERVENTION(S): Testicular tissue from men with successful or failed testicular sperm extraction was evaluated with qunatitative real-time polymerase chain reaction (qRT-PCR) for expression of HSFY mRNA. MAIN OUTCOME MEASURE(S): Area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and probability of sperm retrieval based on HSFY testing. RESULT(S): We found higher HSFY mRNA expression in testicular tissue from NOA patients in whom sperm were successfully retrieved compared with those in whom sperm were not found, with good discrimination between the groups in all histologic variants of NOA (AUC 0.89 overall, 0.98 for patients with Sertoli cell only [SCO] histology, 0.90 for patients with maturation arrest [MA] histology). Sensitivity and specificity were, respectively, 67% and 93% overall, 92% and 100% for SCO patients, and 67% and 92% for MA patients. The probabilities of sperm retrieval for HSFY-positive and -negative patients were, respectively, 93% and 31% overall, 100% and 7% for SCO patients, and 91% and 32% for MA patients. CONCLUSION(S): Detection of HSFY mRNA expression by qRT-PCR has promising application in the evaluation and counseling of men with NOA before attempted sperm retrieval surgery. PMID- 21676393 TI - Identification of apolipoprotein A1 in the human embryonic secretome. AB - OBJECTIVE: To identify factors secreted by the human embryo and correlate levels with embryo morphology and pregnancy outcome. DESIGN: A laboratory-based study of human embryo protein synthesis and secretion and a retrospective analysis of spent embryo culture media as it relates to pregnancy outcome. SETTING: University-based academic IVF program. PATIENT(S): IVF patients who had donated cryopreserved human pronuclear-stage embryos. Patients undergoing fresh IVF cycles resulting in a blastocyst transfer who donated spent media drops. INTERVENTION(S): In vitro embryo culture and collection of spent media. MAIN OUTCOME MEASURE(S): Protein analysis and identification by two-dimensional gel electrophoresis and mass spectrometry, ApoA1 quantification by ELISA, and mRNA analysis by quantitative reverse transcriptase-polymerase chain reaction. RESULT(S): By protein gel electrophoresis, apolipoprotein A1 (ApoA1) was increased in the culture media from good-quality blastocysts (n = 6 embryos) compared to either cleavage-arrested embryos (n = 6 embryos) or poor-quality blastocysts (n = 6 embryos) using spent media from culture days 4 and 5, respectively. Apolipoprotein A1 concentrations were 23.1% greater in day 5 spent culture media from good-grade blastocysts (n = 30) when compared to poor-grade embryos (n = 30). However, in a group of patients (n = 20) with transfer of two good-quality blastocysts, ApoA1 levels from day 5 spent media did not correlate with embryo implantation and pregnancy. Quantitative reverse transcriptase polymerase chain reaction confirmed the presence of ApoA1 mRNA transcripts in human blastocysts. CONCLUSION(S): Apolipoprotein A1 is produced by human preimplantation embryos, and increased levels are present in spent culture media containing blastocysts of higher morphologic grade. These results suggest a role for lipoproteins in early embryologic development. PMID- 21676394 TI - Divergent effects of a combined hormonal oral contraceptive on insulin sensitivity in lean versus obese women. AB - OBJECTIVE: To evaluate the effects of a commonly used combined hormonal oral contraceptive (OC) on carbohydrate metabolism in obese as compared with lean women. DESIGN: 6-month prospective study. SETTING: Clinical research center at an academic medical center. PATIENT(S): Premenopausal nondiabetic women with body mass index <25 kg/m(2) (n = 15) or >30 kg/m(2) (n = 14). INTERVENTION(S): Ethinyl estradiol (35 MUg) and norgestimate (0.18/0.215/0.25 mg) for 6 cycles. MAIN OUTCOME MEASURE(S): Insulin sensitivity by frequent sampling intravenous glucose tolerance test; other indices of insulin sensitivity (homeostatic model assessment of insulin sensitivity index [ISI HOMA], the Matsuda index); fasting lipid panel. RESULT(S): Insulin sensitivity changed from 6.62 +/- 3.69 min( 1)/mIU/L (baseline) to 8.23 +/- 3.30 min(-1)/mIU/L (6 months) in lean women, and from 4.36 +/- 2.32 to 3.82 +/- 2.32 min(-1)/mIU/L in obese women. Divergent effects on insulin sensitivity were also observed with ISI HOMA and the Matsuda index. Low-density lipoprotein increased by approximately 20 mg/dL in both the lean and obese groups. CONCLUSION(S): Lean and obese women exhibit differential changes in insulin sensitivity when given 6 months of a commonly used oral contraceptive. The mechanisms of these differences and whether these divergent effects persist in the long term require further investigation. PMID- 21676395 TI - Idiopathic hirsutism: local and peripheral expression of aromatase (CYP19A) and 5alpha-reductase genes (SRD5A1 and SRD5A2). AB - OBJECTIVE: To evaluate idiopathic hirsutism etiology via molecular studies testing peripheral and local aromatase and 5alpha-reductase expression. DESIGN: Assessment of the expression of messenger RNA (mRNA) for type 1 and 2,5alpha reductase isoenzyme gene (SDR5A1, SDR5A2) and aromatase (CYP19A) in dermal papillae cells and peripheral blood mononuclear cells. SETTING: University hospital. PATIENT(S): 28 untreated idiopathic hirsute patients and 20 healthy women (controls). INTERVENTION(S): Human skin biopsies and peripheral venous blood. MAIN OUTCOME MEASURE(S): SDR5A1, SDR5A2, CYP19A gene expression in skin biopsies and peripheral blood. RESULT(S): A statistically significant reduction of SRD5A1, SRD5A2, and CYP19A gene expression was found in the dermal papillae cells and peripheral blood mononuclear cell between the study and control group. CONCLUSION(S): Further study, including protein expression and enzyme activity assays, are warranted to characterize the paradoxically low gene expression levels of local 5alpha-reductase and aromatase in women with idiopathic hirsutism. PMID- 21676396 TI - The 981C>T polymorphism in protein tyrosine phosphatase 1B is associated with decreased risk of coronary artery disease in Chinese Han population. AB - OBJECTIVE: The present study was designed to investigate the potential association between the 981C>T polymorphism in protein tyrosine phosphatase 1B (PTP-1B) and coronary artery disease (CAD). METHODS: We conducted a hospital based case-control study with 864 CAD patients and 1008 controls to explore the association between the PTP-1B 981C>T polymorphism and risk of CAD in Chinese Han population. RESULTS: Subjects with the variant genotypes (CT+TT) had a 52% decreased risk of CAD relative to CC carriers (adjusted odds ratio, 0.48; 95% confidence interval, 0.39-0.60). The 981C>T polymorphism was associated with a higher body mass index and serum triglyceride levels in both CAD patients and controls. Moreover, this polymorphism was found to be associated with a lower serum glucose levels in cases, but not in controls. CONCLUSION: Our study demonstrates that the PTP-1B 981C>T polymorphism is associated with decreased risk of CAD in Chinese Han population. PMID- 21676397 TI - Associations between vitamin D and cardiovascular outcomes; Tehran Lipid and Glucose Study. AB - BACKGROUND: Vitamin D status seems to have an association with cardiometabolic risk factors and its deficiency may negatively affect the cardiovascular outcomes. The aim of this study was to determine the possible association between vitamin D status and cardiovascular outcomes. METHOD: We performed a nested case control study within the Tehran Lipid and Glucose Study (TLGS), which followed a representative sample of Tehranian adults. A total of 251 matched pairs, aged>30 years, were selected. Cases were TLGS individuals that were free of cardiovascular disease (CVD) at the beginning of study and developed CVD during assessments of 5.7 year follow up. Each case was matched by age, sex and the month of entry to study with a randomly selected control (risk-set sampling). Prespecified cut points were used to characterize varying degrees of 25-OH D deficiency (<10, between 10 and 14.9, and >= 15 ng/ml). Conditional logistic regression was used to investigate the association between 25-OH-D concentration and the incident cardiovascular outcomes. RESULTS: The mean age of participants was 56.84 +/- 11.17 years and 244 (48.6%) were women. The median (IQ: 25-75) of serum 25-OH-D was 14.1 ng/ml (9.6-29 ng/ml) and 306 (61%) of participants had serum 25-OH-D<15 g/ml. Median serum 25-OH-D was lower in cases (12.5 vs. 18.1, P<0.001). After adjustment for potential confounders, the odds ratio of serum 25 OH-D<10 ng/ml for having CVD outcomes was 2.90 compared with 25-OH-D >= 15 (95% confidence interval (CI): 1.67-5.12, P<0.001). CONCLUSION: Our results indicate that serum 25-OH-D concentration has an independent association with cardiovascular outcomes in adult Tehranians. PMID- 21676398 TI - A mathematical model of force transmission from intrafascicularly terminating muscle fibers. AB - Many long skeletal muscles are comprised of fibers that terminate intrafascicularly. Force from terminating fibers can be transmitted through shear within the endomysium that surrounds fibers or through tension within the endomysium that extends from fibers to the tendon; however, it is unclear which pathway dominates in force transmission from terminating fibers. The purpose of this work was to develop mathematical models to (i) compare the efficacy of lateral (through shear) and longitudinal (through tension) force transmission in intrafascicularly terminating fibers, and (ii) determine how force transmission is affected by variations in the structure and properties of fibers and the endomysium. The models demonstrated that even though the amount of force that can be transmitted from an intrafascicularly terminating fiber is dependent on fiber resting length (the unstretched length at which passive stress is zero), endomysium shear modulus, and fiber volume fraction (the fraction of the muscle cross-sectional area that is occupied by fibers), fibers that have values of resting length, shear modulus, and volume fraction within physiologic ranges can transmit nearly all of their peak isometric force laterally through shearing of the endomysium. By contrast, the models predicted only limited force transmission ability through tension within the endomysium that extends from the fiber to the tendon. Moreover, when fiber volume fraction decreases to unhealthy ranges (less than 50%), the force-transmitting potential of terminating fibers through shearing of the endomysium decreases significantly. The models presented here support the hypothesis that lateral force transmission through shearing of the endomysium is an effective mode of force transmission in terminating fibers. PMID- 21676399 TI - Technique for chestband contour shape-mapping in lateral impact. AB - The chestband transducer permits noninvasive measurement of transverse plane biomechanical response during blunt thorax impact. Although experiments may reveal complex two-dimensional (2D) deformation response to boundary conditions, biomechanical studies have heretofore employed only uniaxial chestband contour quantifying measurements. The present study described and evaluated an algorithm by which source subject-specific contour data may be systematically mapped to a target generalized anthropometry for computational studies of biomechanical response or anthropomorphic test dummy development. Algorithm performance was evaluated using chestband contour datasets from two rigid lateral impact boundary conditions: Flat wall and anterior-oblique wall. Comparing source and target anthropometry contours, peak deflections and deformation-time traces deviated by less than 4%. These results suggest that the algorithm is appropriate for 2D deformation response to lateral impact boundary conditions. PMID- 21676400 TI - A rapid and environmental friendly determination of the dithiocarbamate metabolites ethylenethiourea and propylenethiourea in fruit and vegetables by ultra high performance liquid chromatography tandem mass spectrometry. AB - Previous published methods for the analysis of ETU and PTU are time-consuming and furthermore use dichloromethane (DCM) for extraction or clean-up. This study details the development and validation of a rapid method that combines a simple extraction step with UHPLC-ESI(+)-MS/MS. This is the first application of UHPLC MS/MS to analyse these compounds. Besides that, we replaced DCM with a more environmental-friendly solvent. The analytical performance was evaluated with the analysis of spiked celery samples at 50 MUg kg(-1) (LOQ) and 300 MUg kg(-1). The recoveries were between 65% and 90% for ETU and between 71% and 127% for PTU with RSDs in repeatability and reproducibility conditions below 10% for ETU. This method is rapid (a chromatographic run time of 2 min) and can easily be performed (no laborious clean-up). The presented method is environmental friendly with significant reduction in solvent consumption. PMID- 21676401 TI - Efficient refolding of a hydrophobic protein with multiple S-S bonds by on-resin immobilized metal affinity chromatography. AB - The efficient refolding of recombinant proteins produced in the form of inclusion bodies (IBs) in Escherichia coli still is a complicated experimental problem especially for large hydrophobic highly disulfide-bonded proteins. The aim of this work was to develop highly efficient and simple refolding procedure for such a protein. The recombinant C-terminal fragment of human alpha-fetoprotein (rAFP Cterm), which has molecular weight of 26 kDa and possesses 6 S-S bonds, was expressed in the form of IBs in E. coli. The C-terminal 7* His tag was introduced to facilitate protein purification and refolding. The refolding procedure of the immobilized protein by immobilized metal chelating chromatography (IMAC) was developed. Such hydrophobic highly disulfide-bonded proteins tend to irreversibly bind to traditionally used agarose-based matrices upon attempted refolding of the immobilized protein. Indeed, the yield of rAFP-Cterm upon its refolding by IMAC on agarose-based matrix was negligible with bulk of the protein irreversibly stacked to the resin. The key has occurred to be using IMAC based on silica matrix. This increased on-resin refolding yield of the target protein from almost 0 to 60% with purity 98%. Compared to dilution refolding of the same protein, the productivity of the developed procedure was two orders higher. There was no need for further purification or concentration of the renatured protein. The usage of silica-based matrix for the refolding of immobilized proteins by IMAC can improve and facilitate the experimental work for difficult-to-refold proteins. PMID- 21676402 TI - An improved high-performance liquid chromatographic method for simultaneous determination of tocopherols, tocotrienols and gamma-oryzanol in rice. AB - An improved normal phase high performance liquid chromatographic (NP-HPLC) method was developed for simultaneous quantification of eight vitamin E isomers (alpha-, beta-, gamma- and delta-tocopherols and alpha-, beta-, gamma- and delta tocotrienols) and gamma-oryzanol in rice. A complete separation of all compounds was achieved within 25 min using an Inertsil CN-3, SIL-100A 5 MUM (4.6 mm * 250 mm) column and an isocratic elution system of hexane/isopropanol/ethylacetate/acetic acid (97.6:0.8:0.8:0.8, v/v/v/v) at a flow rate varying from 0.7 to 1.5 mL min(-1). A linear correlation coefficient (r(2)>0.99) and high reproducibility were obtained at concentrations ranging 0.05 10 MUg mL(-1) for vitamin E isomers and 0.5-500 MUg mL(-1) for gamma-oryzanol. This method proved to be rapid, accurate and reproducible. PMID- 21676403 TI - Low-density solvent-based solvent demulsification dispersive liquid-liquid microextraction for the fast determination of trace levels of sixteen priority polycyclic aromatic hydrocarbons in environmental water samples. AB - For the first time, the low-density solvent-based solvent demulsification dispersive liquid-liquid microextraction was developed for the fast, simple, and efficient determination of 16 priority polycyclic aromatic hydrocarbons (PAHs) in environmental samples followed by gas chromatography-mass spectrometric (GC-MS) analysis. In the extraction procedure, a mixture of extraction solvent (n-hexane) and dispersive solvent (acetone) was injected into the aqueous sample solution to form an emulsion. A demulsification solvent was then injected into the aqueous solution to break up the emulsion, which turned clear and was separated into two layers. The upper layer (n-hexane) was collected and analyzed by GC-MS. No centrifugation was required in this procedure. Significantly, the extraction needed only 2-3 min, faster than conventional DLLME or similar techniques. Another feature of the procedure was the use of a flexible and disposable polyethylene pipette as the extraction device, which permitted a solvent with a density lighter than water to be used as extraction solvent. This novel method expands the applicability of DLLME to a wider range of solvents. Furthermore, the method was simple and easy to use, and some additional steps usually required in conventional DLLME or similar techniques, such as the aforementioned centrifugation, ultrasonication or agitation of the sample solution, or refrigeration of the extraction solvent were not necessary. Important parameters affecting the extraction efficiency were investigated in detail. Under the optimized conditions, the proposed method provided a good linearity in the range of 0.05-50 MUg/L, low limits of detection (3.7-39.1 ng/L), and good repeatability of the extractions (RSDs below 11%, n=5). The proposed method was successfully applied to the extraction of PAHs in rainwater samples, and was demonstrated to be fast, efficient, and convenient. PMID- 21676404 TI - Application of multiwall carbon nanotubes-based matrix solid phase dispersion extraction for determination of hormones in butter by gas chromatography mass spectrometry. AB - The multiwall carbon nanotubes (MWCNTs)-based matrix solid phase dispersion (MSPD) was applied for the extraction of hormones, including 17-alpha ethinylestradiol, 17-alpha-estradiol, estriol, 17-beta-estradiol, estrone, medroxyprogesterone, progesterone and norethisterone acetate in butter samples. The method includes MSPD extraction of the target analytes from butter samples, derivatization of hormones with heptafluorobutyric acid anhydride-acetonitrile mixture, and determination by gas chromatography-mass spectrometry. The mixture containing 0.30 g graphitized MWCNTs and 0.10 g MWCNTs was selected as absorbent. Ethyl acetate was used as elution solvent. The elution solvent volume and flow rate were 12 mL and 0.9 mL min(-1), respectively. The recoveries of hormones obtained by analyzing the five spiked butter samples were from 84.5 to 111.2% and relative standard deviations from 1.9 to 8.9%. Limits of detection and quantification for determining the analytes were in the range of 0.2-1.3 and 0.8 4.5 MUg kg(-1), respectively. Compared with other traditional methods, the proposed method is simpler in the operation and shorter in the sample pretreatment time. PMID- 21676405 TI - Identification of novel circulating coffee metabolites in human plasma by liquid chromatography-mass spectrometry. AB - This study reports a liquid chromatography-mass spectrometry method for the detection of polyphenol-derived metabolites in human plasma without enzymatic treatment after coffee consumption. Separation of available standards was achieved by reversed-phase ultra performance liquid chromatography and detection was performed by high resolution mass spectrometry in negative electrospray ionization mode. This analytical method was then applied for the identification and relative quantification of circulating coffee metabolites. A total of 34 coffee metabolites (mainly reduced, sulfated and methylated forms of caffeic acid, coumaric acid, caffeoylquinic acid and caffeoylquinic acid lactone) were identified based on mass accuracy (<4 ppm for most metabolites), specific fragmentation pattern and co-chromatography (when standard available). Among them, 19 circulating coffee metabolites were identified for the first time in human plasma such as feruloylquinic acid lactone, sulfated and glucuronidated forms of feruloylquinic acid lactone and sulfated forms of coumaric acid. Phenolic acid derivatives such as dihydroferulic acid, dihydroferulic acid 4'-O sulfate, caffeic acid 3'-O-sulfate, dimethoxycinnamic acid, dihydrocaffeic acid and coumaric acid O-sulfate appeared to be the main metabolites circulating in human plasma after coffee consumption. The described method is a sensitive and reliable approach for the identification of coffee metabolites in biological fluids. In future, this analytical method will give more confidence in compound identification to provide a more comprehensive assessment of coffee polyphenol bioavailability studies in humans. PMID- 21676406 TI - Morphological and chemical features of nano and macroscale carbons affecting hydrogen peroxide decomposition in aqueous media. AB - Chemical and structural factors of carbon materials affect their activity in adsorption and surface reactions in aqueous media. Decomposition of hydrogen peroxide studied is a probe reaction for exploring parameters of carbons that might be involved, such as specific surface area, nitrogen and oxygen doping and conformational changes. To date, a detailed comparison of the behavior of carbon nanoscale (Carbon Nanotubes, CNT, Single Layer Graphene Oxide, SLGO) with macroscale (Activated carbons, AC) materials in this reaction has not been forthcoming. Herein, we demonstrate that on their first cycle, ACs in doped and undoped forms outperform all nanoscale carbons tested in the H(2)O(2) decomposition. Among the nanocarbons, nitrogen-doped CNT exhibited the highest activity in this reaction. However, subsequent recycling of each carbon, without chemical regeneration between uses, reveals SLGO exhibits greater reaction rate stability over an extended number of cycles (n>8) than other carbons including nitrogen-doped CNT and ACs. The effects of pH, temperature and concentration on the reaction were analyzed. Quantum-chemical modeling and reaction kinetics analysis reveal key processes likely involved in hydrogen peroxide decomposition and show evidence that the reaction rate is linked to active sites with N-and O containing functionalities. PMID- 21676407 TI - Mesoporous zirconosilicate doughnuts with high performance in liquid oxidative dehydrogenation of hydroquinone to quinone. AB - Unusual partially crystalline ordered mesoporous zirconosilicate doughnuts with Si/Zr ratio as low as 1.5 were synthesized from the aqueous polymerisation of a single source molecular precursor Zr[OSi(Ot-BuO)(3)](4) without the use of any templating agent. A radial homogenous mesoporosity (4 nm) was observed inside these very regular sub-micrometric (600 nm) doughnuts. These structures were partially crystallized in hydrothermal conditions (100 degrees C) into an analogous zircon (ZrSiO(4)) framework. The formation mechanism has been investigated. It is evidenced that chlorine anions Cl(-) concentration and pH value are essential to achieve the process, even if their role is still a matter of investigations. The obtained materials demonstrated even higher catalytic activity, selectivity and stability in the liquid oxidative dehydrogenation of hydroquinone to 1,4-benzoquinone compared to TS-1 zeolite catalysts and amorphous highly ordered mesoporous zirconosilicate materials. PMID- 21676408 TI - Impact of pulsed electric field on electrodialysis process performance and membrane fouling during consecutive demineralization of a model salt solution containing a high magnesium/calcium ratio. AB - Pulsed electric fields (PEFs), hashed modes of current consisting in the application of a constant current density during a fixed time (Ton) followed by a pause lapse (Toff), were recently demonstrated as an effective alternative for mineral fouling mitigation and process intensification during electrodialysis (ED) treatments. Recent ED studies have continuously reported a considerable mineral fouling formation on ion-exchange membranes, especially during the demineralization of solutions containing a high Mg/Ca ratio and a basified concentrate solution. The aim of this study was to evaluate the process performance under two different PEF conditions on a mineral solution containing a mineral mixture giving a high Mg(2+)/Ca(2+) ratio of 2/5. Two different pause lapse durations (PEF ratio 1 (Ton/Toff 10s/10s); PEF ratio 0.3 (Ton/Toff 10s/33.3 s)) during consecutive ED treatments and their comparison with dc current were evaluated at a current density of 40 mA/cm(2). Our results showed that PEFs resulted in an intensification of ED process, enhancing the demineralization rates (DRs), reducing the system resistance (SR), and reducing the fouling and energy consumption (EC). PEF ratio 1 was the most optimal condition among the current regimes applied, leading to faster and higher demineralization rates due to a lower fouling and with low energy consumption during all consecutive runs. PMID- 21676409 TI - Synthesis, characterization and comparative evaluation of phenoxy ring containing long chain gemini imidazolium and pyridinium amphiphiles. AB - Two series of phenoxy ring containing long chain imidazolium and pyridinium based gemini amphiphiles have been synthesized from renewable cardanol oil having different spacers (i. e. -S-(CH(2))(n)-S-, where n is 2, 3, 4 & 6). Critical micelle concentration (cmc) of these new gemini amphiphiles has been determined by conductivity method. Further, these new cationic amphiphiles have been evaluated for their DNA binding capability by agarose gel electrophoresis, ethidium bromide exclusion experiments and transmission electron microscopy (TEM). The cytotoxicity of these new amphiphiles have been evaluated by MTT (3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Comparative studies of these phenoxy ring containing long chain gemini imidazolium amphiphiles and their pyridinium analogues depicted low cmc values of the later but greater DNA interaction capability and low cytotoxicity of the former series of amphiphiles. PMID- 21676410 TI - A molecular simulation of interactions between graphene nanosheets and supercritical CO2. AB - The colloidal dispersion stability of nano-sized graphene sheets in supercritical fluid (SCF) media is very important for developing SCF-based exfoliation and dispersion technologies for stabilization and solubilization of graphenes. We carried out molecular dynamics simulations to elucidate the stability mechanism of graphene in supercritical CO(2) (scCO(2)). The potential of mean force (PMF) between two graphene nanosheets in scCO(2) was simulated, and the effect of scCO(2) density and temperature on the PMF behavior has been investigated. The simulation results demonstrate that there exists a free energy barrier between graphenes in the scCO(2) fluid, possibly obstructing the aggregation of graphenes. The single-layer confined CO(2) molecules between the graphene sheets can induce a dominating repulsion interaction between graphene sheets. At higher scCO(2) fluid density, there are more confined CO(2) molecules within the interplate regions, resulting in a stronger repulsive free energy barrier. The effect of temperature on the PMF is relatively minor. The scCO(2) solvent structure shows layered confined arrangement in the interfacial region near the graphene nanosheets, which is correlated well with the PMF profile curve. PMID- 21676411 TI - Congenital heart disease infant death rates decrease as gestational age advances from 34 to 40 weeks. AB - OBJECTIVES: To describe congenital heart disease death rates in infants born between 34 and 40 weeks, estimate the relationship between gestational age and congenital heart disease infant death rates, and compare congenital heart disease death rates across 1- and 2-week intervals in gestational age. STUDY DESIGN: The 2000 to 2003 national linked birth/infant death cohort datasets were obtained. Congenital heart disease deaths were identified by using International Statistical Classification of Diseases, 10th Revision codes. Proportional death rates were calculated by using congenital heart disease deaths and all live births. The relationship between congenital heart disease death rates and gestational age was determined. Death rates were compared across intervals. RESULTS: A total of 14.9 million records were analyzed. Congenital heart disease deaths occurred in 4736 infants (0.04%) born between 34 and 40 weeks. There was a significant, negative linear relationship between congenital heart disease death rate and gestational age (R(2) = 0.97). Comparisons across 1-week intervals varied (P = .02-.23). All 2-week intervals were statistically significant (P < .01). CONCLUSIONS: Congenital heart disease death rates decrease as gestational age approaches 40 weeks. These results should be considered before elective delivery for the sole indication of prenatally diagnosed congenital heart disease. PMID- 21676412 TI - [Fibroblastic rheumatism. Case report]. PMID- 21676413 TI - [When abstract conclusions have no sense: a case of British Medical Journal's exemplary actuation]. PMID- 21676414 TI - [Preexposure prophylaxis in the prevention of HIV infection]. PMID- 21676416 TI - [Role of calcium-rich mineral waters in osteoporosis]. PMID- 21676417 TI - [Age of patients admitted to Internal Medicine departments in Spain: a twenty years perspective]. AB - BACKGROUND AND OBJECTIVE: To analyze the age of patients admitted to Spanish General Internal Medicine (IM) departments over the past 20 years with the hypothesis that patients' age has increased significantly. PATIENTS AND METHODS: On one hand, we analyzed the age of patients admitted in the department of the authors. Secondly we analyzed data provided by the Ministry of Health. Finally we compared a number of different articles from the late eighties with a recent series. RESULTS: Mean age of patients in our department has increased in 19.3 years in 20 years. According to CMBD, the patients >= 75 years increased 4.4% from 2005 to 2009. When comparing the historical and recent series, the average age of the patients increased 8.3 years. CONCLUSIONS: All three sources confirm the hypothesis that patients admitted to IM are significantly older than some years ago, and that this increase in age is greater than the expected by aging of the general population. PMID- 21676418 TI - Triglyceride-high-density lipoprotein cholesterol is associated with microvascular complications in type 2 diabetes mellitus. AB - The purpose of this study was to evaluate whether a high triglyceride/high density lipoprotein cholesterol (TG/HDL-C) ratio is associated with an increased incidence of retinopathy and chronic kidney disease (CKD) in type 2 diabetes mellitus. Individuals with type 2 diabetes mellitus (n = 979) with an estimated glomerular filtration rate greater than 60 mL/min and without retinopathy and cardiovascular disease at baseline were followed up for the incidence of diabetic retinopathy (diagnosed by retinography) and CKD (diagnosed by estimated glomerular filtration rate <=60 mL/min/1.73 m(2)). On follow-up (mean, 4.9 years), 217 (22.2% of total) subjects experienced CKD and/or diabetic-specific retinal lesions (microvascular complication). Of these, 111 subjects developed isolated retinopathy, 85 developed CKD alone, and 21 developed both complications. The TG/HDL-C ratio was positively associated with an increased risk of incident retinopathy and/or CKD (composite microvascular end point) independently of age, sex, body mass index, diabetes duration, hemoglobin A(1c), hypertension, smoking history, low-density lipoprotein cholesterol, albuminuria, and current use of hypoglycemic, antihypertensive, lipid-lowering, or antiplatelet drugs (multivariable-adjusted odds ratio, 2.15; 95% confidence intervals, 1.10-4.25; P = .04). These findings suggested that the TG/HDL-C ratio was associated with an increased incidence of microvascular complications in individuals with type 2 diabetes mellitus without prior cardiovascular disease, independently of several potential confounders. PMID- 21676419 TI - Mitochondrial DNA copy number in peripheral blood in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is associated with insulin resistance and various metabolic diseases; and recently, elevated oxidative stress has been detected in PCOS. Mitochondria are highly susceptible to oxidative damage; and disordered mitochondrial function at the cellular level can impact whole-body metabolic homeostasis, leading to the hypothesis that abnormalities in markers of mitochondrial metabolism are related to PCOS. We compared mitochondrial DNA (mtDNA) copy number in women with and without PCOS and investigated the independent relationship between mtDNA copy number and PCOS after adjustment for metabolic parameters. Fifty women with PCOS and 60 age- and body mass index matched healthy women were studied. Mitochondrial DNA copy numbers as well as metabolic parameters and indices of insulin resistance were assessed. Mitochondrial DNA copy numbers were significantly lower in women with PCOS (P < .01). In the PCOS group, mtDNA copy number was negatively correlated with indices of insulin resistance, waist circumference, and triglyceride levels and positively correlated with sex hormone-binding globulin levels. In multiple logistic regression, the corresponding odds ratios (95% confidence interval) for PCOS by log-transformed mtDNA copy number and homeostasis model assessment of insulin resistance were 0.15 (0.04-0.56) and 4.26 (1.43-12.68), respectively, after adjustment for age, body mass index, and other metabolic factors. We report decreased mtDNA copy numbers in PCOS patients in relation to controls independently of insulin resistance or other metabolic factors. The pathophysiological and clinical significance of this finding requires further investigation. PMID- 21676420 TI - [Narcolepsy with cataplexy associated with H1N1 vaccination]. AB - INTRODUCTION: It has been suggested that the H1N1 vaccine may be a trigger for the onset of narcolepsy-cataplexy, a rare disease whose autoimmune origin is suspected. OBSERVATIONS: We report two patients (a 9-year-old boy and an 18-year old man) with severe narcolepsy-cataplexy, in whom the illness appeared within 3 4 weeks after H1N1 vaccination. In both cases, symptoms developed unusually abruptly and they presented with severe daytime sleepiness and multiple daily cataplexy attacks. Other similar cases have been recently reported associated with H1N1 vaccine. CONCLUSION: Although no formal link can be established, the unusual characteristics of the reported cases and the striking temporal relationship suggests that narcolepsy may be the result of an autoimmune reaction triggered by H1N1 vaccination in susceptible individuals. PMID- 21676421 TI - [Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases]. AB - INTRODUCTION: The childhood ataxia with central nervous system hypomyelination vanishing white matter syndrome (CACH-VWM) was first characterized in children (2 5 years) on clinical and MRI criteria: cerebellospastic signs associated with episodes of rapid deterioration following stress and extensive cavitatingleucoencephalopathy. Causative mutations were found in the five genes encoding the subunits of the eukaryotic initiation factor 2B (eIF2B), involved in protein synthesis and its regulation under cellular stresses. A broad clinical spectrum has been subsequently described from congenital to adult-onset forms leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders. METHODS: The inclusion criteria were based on the presence of EIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis was also included. Clinical and MRI findings were retrospectively recorded in all patients. This multicentric study included 24 patients from 22 families. RESULTS: A sex-ratio imbalance was noted (male/female=5/19). The mean age of onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20), psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years, range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients. Magnetic resonance imaging findings consisted of cerebral atrophy (92%), extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found at a homozygous state in 58% of the 24 eIF2B-mutated patients. CONCLUSION: eIF2B related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by screening for the recurrent p.Arg113His-eIF2Be mutation. PMID- 21676423 TI - Prevalence and incidence of longer term pain in survivors of polytrauma. AB - BACKGROUND: Little is known about the longer term status of pain or the factors associated with pain-related outcome in patients after polytrauma. The current study evaluated the prevalence and severity of pain at least 2 years after injury compared with preinjury status using several pain scores in a Swiss cohort of survivors of blunt polytrauma. METHODS: Pearson correlation testing was used for the comparison of different measures of pain. Uni and multivariate analyses of patient, trauma, and treatment characteristics, as well as parameters of self reported, health-related quality of life and functional outcome, were undertaken to determine associations with pain after polytrauma. RESULTS: Depending on the measure used, 46% to 85% of polytrauma survivors indicated the presence of pain at longer term follow-up. Both the prevalence and the severity of pain were increased compared with the preinjury status (P < .001) and varied importantly depending on scoring. The Trauma Outcome Profile was the most sensitive pain measure and showed the greatest correlation with objective, longer term outcomes (R = .5). Pain measured by the SF-36 was found to have the best internal criterion validity among the scores investigated (R = .6-.8). Patients' longer term pain status had greater associations with health-related quality-of-life scores (R = .6-.8) than with capacity to work or income (R = .4-.5). CONCLUSION: Our study shows a high rate of longer term pain in survivors of polytrauma and important differences in the type and sensitivity of the standard pain measures investigated. Given the potential impact of these findings, international guidelines for the assessment of pain in polytraumatized patients are needed. PMID- 21676422 TI - Propofol's effects on phagocytosis, proliferation, nitrate production, and cytokine secretion in pressure-stimulated microglial cells. AB - BACKGROUND: Intracranial hypertension complicates severe traumatic brain injury frequently and might be associated with poor outcomes. Traumatic brain injury induces a neuroinflammatory response by microglial activation and upregulation of proinflammatory cytokines, such as interleukin-1beta, tumor necrosis factor alpha, and interleukin-6. To elucidate the effect of increased intracranial pressure on microglial function, we studied the effects of increased extracellular pressure on primary human microglial cell phagocytosis, proliferation, cytokine secretion, and total nitrate production. In addition, because many patients receive propofol during anesthesia or intensive care unit sedation, we evaluated whether propofol alters the effects of pressure. METHODS: Human microglial cells were pretreated with (2.5-20 MUg/mL) propofol or Intralipid as a vehicle control were incubated at ambient atmospheric pressure or at 15 or 30 mm Hg increased pressure for 2 h for phagocytosis assays or 24 h for proliferation, cytokine secretion, and total nitrate production studies. Phagocytosis was determined by incorporation of intracellular fluorescent latex beads. Tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 were assayed by sandwich enzyme-linked immunosorbent assay and total nitrate by Greiss reagent. RESULTS: Increased extracellular pressure stimulated phagocytosis versus untreated microglial cells or cells treated with an Intralipid vehicle control. Propofol also stimulated microglial phagocytosis at ambient pressure. Increased pressure, however, decreased phagocytosis in the presence of propofol. Pressure also increased microglial tumor necrosis factor-alpha and interleukin-1beta secretion and propofol pretreatment blocked the pressure-stimulated effect. Interleukin-6 production was not altered either by pressure or by propofol. Pressure also induced total nitrate secretion, and propofol pretreatment decreased basal as well as pressure-induced microglial nitrate production. CONCLUSION: Extracellular pressures consistent with increased intracranial pressure after a head injury activate inflammatory signals in human primary microglial cells in vitro, stimulating phagocytosis, proliferation, tumor necrosis factor-alpha, interleukin-1beta, and total nitrate secretion but not affecting interleukin-6. Such inflammatory events may contribute to the worsened prognosis of traumatic brain injury after increased intracranial pressure. Because propofol alleviated these potentially proinflammatory effects, these results suggest that the inflammatory cascade activated by intracranial pressure might be targeted by propofol in patients with increased intracranial pressure after traumatic brain injury. PMID- 21676424 TI - Hospital costs associated with surgical site infections in general and vascular surgery patients. AB - BACKGROUND: Although much has been written about excess cost and duration of stay (DOS) associated with surgical site infections (SSIs) after cardiothoracic surgery, less has been reported after vascular and general surgery. We used data from the National Surgical Quality Improvement Program (NSQIP) to estimate the total cost and DOS associated with SSIs in patients undergoing general and vascular surgery. METHODS: Using standard NSQIP practices, data were collected on patients undergoing general and vascular surgery at a single academic center between 2007 and 2009 and were merged with fully loaded operating costs obtained from the hospital accounting database. Logistic regression was used to determine which patient and preoperative variables influenced the occurrence of SSIs. After adjusting for patient characteristics, costs and DOS were fit to linear regression models to determine the effect of SSIs. RESULTS: Of the 2,250 general and vascular surgery patients sampled, SSIs were observed in 186 inpatients. Predisposing factors of SSIs were male sex, insulin-dependent diabetes, steroid use, wound classification, and operative time (P < .05). After adjusting for those characteristics, the total excess cost and DOS attributable to SSIs were $10,497 (P < .0001) and 4.3 days (P < .0001), respectively. CONCLUSION: SSIs complicating general and vascular surgical procedures share many risk factors with SSIs after cardiothoracic surgery. Although the excess costs and DOS associated with SSIs after general and vascular surgery are somewhat less, they still represent substantial financial and opportunity costs to hospitals and suggest, along with the implications for patient care, a continuing need for cost effective quality improvement and programs of infection prevention. PMID- 21676425 TI - Optimal ultrasonic array focusing in attenuative media. AB - This paper presents a parametric study on the efficiency of ultrasound focusing in an attenuative medium, using phased arrays. Specifically, an analytical model of ultrasound wave focusing in a homogeneous, isotropic and attenuative fluid with point sources is presented. Calculations based on the model have shown that in an attenuative medium, an optimum frequency exists for the best focusing performance for a particular size of aperture and focal distance. The effect of different f numbers on the focusing performance in the attenuative medium is further investigated. The information obtained from the analytical model provides insights into the design and installation of a phased transducer array for energy efficient wave focusing. PMID- 21676426 TI - Determinants of the HIV-1 core assembly pathway. AB - Based on structural information, we have analyzed the mechanism of mature HIV-1 core assembly and the contributions of structural elements to the assembly process. Through the use of several in vitro assembly assay systems, we have examined details of how capsid (CA) protein helix 1, beta-hairpin and cyclophilin loop elements impact assembly-dependent protein interactions, and we present evidence for a contribution of CA helix 6 to the mature assembly-competent conformation of CA. Additional experiments with mixtures of proteins in assembly reactions provide novel analyses of the mature core assembly mechanism. Our results support a model in which initial assembly products serve as scaffolds for further assembly by converting incoming subunits to assembly proficient conformations, while mutant subunits increase the probability of assembly termination events. PMID- 21676427 TI - Rescue of wild-type mumps virus from a strain associated with recent outbreaks helps to define the role of the SH ORF in the pathogenesis of mumps virus. AB - Mumps virus (MuV) causes acute infections in humans. In recent years, MuV has caused epidemics among highly vaccinated populations. The largest outbreak in the U.S. in the past 20 years occurred in 2005-2006 with over 5000 reported cases in which the majority of the cases was in vaccinated young adults. We sequenced the complete genome of a representative strain from the epidemic (MuV-IA). MuV-IA is a member of genotype G, the same genotype of MuV that was associated with the outbreak in the UK in 2004-2005. We constructed a reverse genetics system for MuV IA (rMuV-IA), and rescued a virus lacking the open reading frame (ORF) of the SH gene (rMuV?SH). rMuV?SH infection in L929 cells induced increased NF-kappaB activation, TNF-alpha production and apoptosis compared to rMuV-IA. rMuV?SH was attenuated in an animal model. These results indicated that the SH ORF of MuV plays a significant role in interfering with TNF-alpha signaling and viral pathogenesis during virus infection. PMID- 21676428 TI - Copper tolerance in the macrolichens Cladonia furcata and Cladina arbuscula subsp. mitis is constitutive rather than inducible. AB - In this study we assessed the degree of copper (Cu) tolerance in two common lichen species (Cladonia furcata and Cladina arbuscula subsp. mitis) that grow on both uncontaminated substrata and the surface of waste heaps from abandoned old Cu-mines. Regardless of their locality, populations of these lichens contain identical strains of photobionts (Asterochloris clade A in C. arbuscula subsp. mitis and clade D in C. furcata). Therefore, it was expected that if there were differences in Cu toxicity or tolerance between populations, that the photobiont could not be a key element of Cu tolerance in these two lichen species. In laboratory experiments samples of both lichen species (from contaminated and control sites) were incubated in Cu solutions (500 MUM) for 24 h. We attempted to determine whether Cu tolerance in these lichens was constitutive, or inducible form. Based on measurements of Cu accumulation, chlorophyll a integrity, chlorophyll a fluorescence, photosynthesis, respiration, measurements of the content of thiobarbituric acid reactive substances (TBARS), the content of soluble proteins, reactive oxygen species (ROS) and the amount of extracellular secondary metabolites of both lichens we found that there were no significant differences in the response of all selected populations of both lichen species to short-term exposure to these high levels of Cu. As a result, we conclude that Cu tolerance in these two lichen species is the constitutive rather than the inducible. PMID- 21676429 TI - The effects of dietary nickel on the detoxification enzymes, innate immunity and resistance to the fungus Beauveria bassiana in the larvae of the greater wax moth Galleria mellonella. AB - In this study, we tested the effects of dietary nickel on the activity of glutathione S-transferase (GST), esterases, phenoloxidase, and encapsulation in the haemolymph of larvae of the greater wax moth Galleria mellonella. We also explored the effects of dietary nickel on larval resistance to infection by the fungus Beauveria bassiana. Larvae fed a low dose of nickel (10 MUg g(-1)) had significantly higher GST, phenoloxidase activity and encapsulation responses than controls fed on a nickel-free diet. We also found that larvae fed a sublethal dose of nickel (50 MUg g(-1)) had increased GST, esterase activity and encapsulation rates but decreased phenoloxidase activity. Although, a sublethal dose of dietary nickel enhanced innate immunity, we found that this reduced resistance against the real pathogen. Our results suggest that enhanced immunity and detoxification enzyme activity of insects may not be beneficial to resistance to fungal infection. It appears that there is a trade off between different resistance mechanisms in insects under different metal treatments. PMID- 21676430 TI - Bioaccumulation, maternal transfer and elimination of polybrominated diphenyl ethers in wild frogs. AB - To investigate bioaccumulation, maternal transfer and elimination of polybrominated diphenyl ethers (PBDEs) in amphibians, we collected adult frogs (Rana limnocharis) from a rice field in an e-waste recycling site in China. We found that ?PBDEs in the whole frogs and various tissues (brain, liver, testis and egg) ranged from 17.10 to 141.11 ng g(-1) wet weight. Various tissues exhibited a similar PBDE congener profile, which was characterized by intermediate brominated congeners (BDE-99 and BDE-153) as the largest contributors, with less lower brominated congeners (BDE-28 and BDE-47) and higher brominated congeners (BDE-209). The maternal transfer capacity of PBDEs declined with the increase in bromine numbers of PBDE congeners. We suggest that the bromine atom number (the molecular size, to some degree) might be a determining factor for the maternal transport of a PBDE congener rather than K(ow) (Octanol Water partition coefficient), which expresses a compound's lipophilicity. ?PBDEs concentrations in frogs decreased over time during a depuration period of 54 days when these wild frogs were brought to the lab from the e-waste recycling site. The half-life of ?PBDEs was 35 days, with about 14 days for BDE-47, and 36 and 81 days for BDE-99 and BDE-153, respectively. The data shows that the elimination of PBDEs has no essential difference from aquatic and terrestrial species. PMID- 21676431 TI - Immunohistochemical expression of prostate tumor overexpressed 1 in cystoprostatectomies with incidental and insignificant prostate cancer. Further evidence for field effect in prostatic carcinogenesis. AB - Prostate tumor overexpressed 1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. It has been suggested that overexpression of prostate tumor overexpressed 1 can contribute to the proliferative status of prostate tumor cells and, thus, to their biologic behavior. Prostate tumor overexpressed 1 and Ki-67 were immunohistochemically evaluated in prostate cancer, high-grade prostatic intraepithelial neoplasia, and normal-looking epithelium in 20 cystoprostatectomies and 20 radical prostatectomies with pT2a Gleason score 6 prostate cancer. The aim was to see whether there were differences in marker expression between cystoprostatectomies and radical prostatectomies. The proportions of prostate tumor overexpressed 1- and Ki-67-positive cells in the cystoprostatectomies and radical prostatectomies increased from normal-looking epithelium through high-grade prostatic intraepithelial neoplasia, away from and adjacent to prostate cancer, to prostate cancer. Prostate tumor overexpressed 1 expression in prostate cancer in cystoprostatectomies was lower than in radical prostatectomies, the differences being significant; there were significant differences in Ki-67 indices. In conclusion, our findings related to prostate tumor overexpressed 1 expression in high-grade prostatic intraepithelial neoplasia, evaluated adjacent and away from prostate cancer, and in incidental and clinical cancers give further support to the concept of field effect in prostatic carcinogenesis as well as to differences in the process of prostatic carcinogenesis between cystoprostatectomies and radical prostatectomies. PMID- 21676432 TI - Medulloepithelioma of the optic disc. AB - A 6-year-old boy with a history of an amblyopic, occasionally red left eye was found to have a solid white mass overlying the optic disc on dilated ocular fundus examination. Transvitreal endoincisional biopsy of the mass yielded neoplastic tissue consistent with intraocular medulloepithelioma. The eye was removed subsequently because of concern that the tumor may invade the retrobulbar optic nerve. Histopathologic and immunohistochemical analysis of the tumor confirmed nonteratoid medulloepithelioma of the optic disc. The child has been followed up for over 36 months without any signs of orbital tumor recurrence or metastasis. PMID- 21676433 TI - Correlation between genomic alterations assessed by array comparative genomic hybridization, prognostically informative histologic subtype, stage, and patient survival in gastric cancer. AB - It is difficult to evaluate the prognostic value of histologic criteria in gastric cancer because of the high variability of morphologic patterns. Recently, histologic subtypes of low, intermediate, or high malignant potential have been identified, providing the basis for a prognostically informative grading system. Because array comparative genomic hybridization systems allow systematic analysis of chromosome alterations, which may be prognostically and pathogenetically informative, we applied high-resolution genome-wide array comparative genomic hybridization to archival material from 81 gastric cancer cases followed for a median of 150 months after surgery. The DNA extracted from paraffin sections gave useful results in 49 tumors, 18 of which were of low-grade, 24 of intermediate, and 7 of high-grade histotypes. Based on the number of chromosome aberrations and the presence/absence of amplifications, 3 tumor clusters of increasing genomic lesion severity were constructed, which proved to correlate significantly with histologic grade and stage as well as with patient survival. Further investigation documented the lower number and severity of genomic alterations in tumors with microsatellite DNA instability and high CD8-rich lymphoid response; the close association of 8p23.1 amplification with cardial cancer; the frequent amplification of genes involved in cell renewal (CDC6, HER2, GRB7, IGFBP4) at 17q12-q21.1, with close histochemical correlation with HER2 membranous expression; and more sporadic amplification of chromosome regions harboring important oncogenes like MYC, KRAS, NRAS, CRKL, CCNE1, or ZNF217. We conclude that genome-wide array comparative genomic hybridization of gastric cancer contributes prognostically relevant information providing a genetic background for histologic grading. PMID- 21676435 TI - Association between natural killer cells and regression in melanocytic lesions. AB - Mortality from melanoma, the deadliest of skin cancers, continues to increase in all age groups. A small number of melanomas spontaneously regress. In vitro studies suggest a role for the natural killer cell in effecting regression. In this study, the goal was to determine if natural killer cells are preferentially involved in the cytotoxic response in regressing lesions. Forty-two cases were selected: nevi with regression, nonregressing melanoma with brisk inflammation, and regressing melanoma. Sections were stained with hematoxylin and eosin and immunostained for CD8, CD56, and T-cell intracytoplasmic antigen 1. Numbers of total lymphocytes, CD8-positive lymphocytes, and T-cell intracytoplasmic antigen 1-positive lymphocytes did not differ among the 3 populations or based on location. CD56 positivity was significantly different among the 3 populations. Regressing melanomas showed the greatest CD56 activity, followed by regressing nevi, whereas inflamed, nonregressing melanomas showed the least. CD56(+) lymphocytes were mostly counted in areas of early regression. The natural killer cell could plausibly play a role in the occurrence of regression as a cytotoxic effector cell or as a mediator of the cytotoxic mechanism. PMID- 21676434 TI - Oncocytic mucoepidermoid carcinoma of the parotid gland with CRTC1-MAML2 fusion transcript: report of a case with review of literature. AB - Oncocytic mucoepidermoid carcinoma is a very rare variant of mucoepidermoid carcinoma, composed predominantly of oncocytic cells. Most previously reported cases described the difficulty in histologic differentiation from other oncocytic tumors. Here we report a case of oncocytic mucoepidermoid carcinoma of parotid gland diagnosed by the detection of CRTC1-MAML2 fusion. A 53-year-old man had a left superficial parotidectomy conducted for 3-cm-sized mass. The resected tumor was composed almost exclusively of oncocytic tumor cells. With detailed histologic evaluation, scarce vacuolated tumor cells, suggestive of mucous cell of mucoepidermoid carcinoma, and one focus of tumor embolism in a vein were found, suggesting the possibility of oncocytic mucoepidermoid carcinoma. Immunohistochemically, oncocytic cells were diffusely positive for p63. Reverse transcriptase polymerase chain reaction and direct sequencing revealed CRTC1 MAML2 translocation of this tumor. To our knowledge, this report describes the first case of oncocytic mucoepidermoid carcinoma confirmed with CRTC1-MAML2 fusion. Identification of this fusion gene may help in distinguishing oncocytic mucoepidermoid carcinoma from its mimics. PMID- 21676436 TI - Genetic alterations and protein expression of HER2 and chromosome 17 polysomy in breast cancer. AB - HER2/neu alteration detection in breast cancer is important for decision making of the HER2-targeted therapy. We retrospectively analyzed the HER2/neu status by fluorescence in situ hybridization and HER2 protein expression by immunohistochemistry in a cohort of 481 patients with invasive breast cancer. Fluorescence in situ hybridization showed that 57.4% of cases exhibited HER2 amplification but 41.4% did not, and 1.2% exhibited an equivocal status. Immunohistochemistry showed that 10.4%, 16.8%, 38.3%, and 34.5% of cases had scores of 0, 1+, 2+, and 3+, respectively. The HER2 status showed a moderate agreement with HER2 expression with a score of 0, 1+, and 3+ (kappa = 0.576, P < .05), and the concordance rate was 90%, 61.7%, and 83.1%, respectively. The HER2 amplification occurred more likely in cases with higher immunohistochemistry scores (P < .001), and polysomy 17 was observed in 28.3% of cases, but more frequently in the HER2 amplification subgroup (33.3%) than in the HER2 nonamplification subgroup (20.1%) (P < .05). There was no significant correlation between the frequency of polysomy 17 and immunohistochemistry scores (P > .05). In the immunohistochemistry 2+ group, 56.5% cases showed HER2/neu amplification, and polysomy 17 occurred more likely in the HER2 amplification subgroup (34.6%) than in the HER2 nonamplification group (13.0%) (P < .001). We concluded that the HER2 status was correlated with HER2 protein expression levels, and it is necessary to determine the HER2 status for cases with immunohistochemistry 2+. The frequency of polysomy 17 was correlated with the HER2 copy number and partially contributed to HER2/neu amplification but not HER2 protein expression. PMID- 21676437 TI - t(4;22)(q12;q11.2) involving presumptive platelet-derived growth factor receptor A and break cluster region in a patient with mixed phenotype acute leukemia. AB - The patient is a 45-year-old woman with a history of breast cancer who had been treated 1 year ago with radiation and chemotherapy. Flow cytometric analysis of bone marrow aspirate revealed 81% blasts positive for CD4, CD11c (partial), CD13, CD19 (partial), cytoplasmic CD22, CD34, CD36, CD45, cytoplasmic CD79a, CD117 (partial), HLA-DR, and terminal deoxynucleotide transferase, consistent with a mixed phenotype acute leukemia (B/myeloid lineage). Conventional karyotypic analysis revealed a t(4;22)(q12;q11.2) in 12 of 13 cells analyzed. Fluorescence in situ hybridization analysis using a dual-color, dual-fusion break cluster region/ABL probe set showed no break cluster region/ABL translocation but an extra break cluster region signal in 85% (170/200) of cells, consistent with a translocation involving the break cluster region gene at 22q11.2. A FIP1L1/CHIC2/platelet-derived growth factor receptor alpha deletion/fusion probe showed signal separation in 96.5% (193/200) of interphase nuclei. Reverse transcriptase-polymerase chain reaction using sense break cluster region primers and an antisense platelet-derived growth factor receptor alpha primer resulted in a product of approximately 590 base pairs, consistent with the presence of a break cluster region/platelet-derived growth factor receptor alpha fusion gene. Because of the presumptive platelet-derived growth factor receptor alpha translocation and its sensitivity to tyrosine-kinase inhibitor, the patient was treated with imatinib mesylate, cytarabine, and idarubicin as induction and maintenance therapy; and she has remained free of disease for 5 months since the initial diagnosis. PMID- 21676438 TI - Risk of in-stent thrombus formation at one year after drug-eluting stent implantation. AB - INTRODUCTION: Although very late stent thrombosis is an important problem with drug-eluting stents, risks for in-stent thrombus formation have not been clarified. Therefore, we examined the risks among patient and lesion characteristics by direct visualization of the stented lesion by angioscopy. MATERIALS AND METHODS: Consecutive patients (n=118) who received successful angioscopic examination of drug-eluting (sirolimus- or paclitaxel-eluting) stents at 1-year after implantation were included. Presence or absence of thrombus directly on the area of each condition determined by the combination of lesion color (white or yellow) and neointima coverage (grade 0-2) was evaluated for each stent; and the factors associated with the presence of thrombus were analyzed. RESULTS: Multivariate logistic regression analysis revealed lesion color (=yellow; odds ratio [OR] 5.5, 95% confidence interval [CI] 3.0-10, p<0.001), neointima coverage (=grade 0 or 1; OR 5.5, 95% CI 2.4-13, p<0.001), and stent type (=paclitaxel-eluting stent; OR 7.6, 95% CI 3.9-15, p<0.001) as independent contributors for in-stent thrombus formation. CONCLUSION: Yellow color of the lesion, poor neointima coverage, and use of paclitaxel-eluting stent were the risks of in-stent thrombus formation at 1 year after DES implantation. PMID- 21676439 TI - Dramatic reduction in tumor burden with neoadjuvant sunitinib prior to bilateral nephron-sparing surgery. AB - Neoadjuvant sunitinib has recently been described for the management of renal cell carcinoma. We present the pre and posttreatment images of a 49-year-old male with bilateral biopsy-proven clear cell renal cell carcinoma who underwent treatment with sunitinib prior to nephron-sparing surgery. After four four-week cycles of daily 50 mg sunitinib, the patient demonstrated a dramatic reduction in tumor burden allowing for successful bilateral partial nephrectomy. PMID- 21676440 TI - Solifenacin may improve sleep quality in patients with overactive bladder and sleep disturbance. AB - OBJECTIVE: To examine the effect of solifenacin for not only overactive bladder symptoms but also sleep disturbance. Nocturia and urgency are independent factors for sleep disturbance. METHODS: Fifteen male patients with overactive bladder symptoms and sleep disturbance were enrolled in this study. The overactive bladder symptoms score (OABSS) and Athens insomnia scale (AIS) were used as a subjective questionnaire for overactive bladder symptoms and insomnia. The Actiwatch-16 (Mini-Mitter-Respironics, Inc., Bend, OR) was used as an objective measurement tool for insomnia. Total sleep time, sleep efficiency, sleep latency, wake-after-sleep onset, and number of awakenings were measured by the Actiwatch. We evaluated the changes of each parameter before and 8 weeks after the administration of solifenacin. Statistical comparisons before and after the administration were made using the Wilcoxon signed-rank test. To examine the relation between OABSS and AIS, Spearman's testing was used for correlations between independent variables and P<.05 was considered statistically significant. RESULTS: Total OABSS and total AIS were significantly improved after administration of solifenacin. The categories of urgency and nocturia in OABSS and the categories of awakening during the night and sleep quality in AIS were also significantly improved. The Actiwatch study showed that total sleep time and sleep efficiency were significantly improved. The decrease of AIS was significantly correlated with the decrease of urgency (rho=0.635, P=.0175) but not with nocturia. CONCLUSION: The treatment of urgency by solifenacin may improve not only overactive bladder symptoms but also sleep disturbance. PMID- 21676441 TI - The relationship of obesity and gender prevalence changes in United States inpatient nephrolithiasis. AB - OBJECTIVE: To review the Nationwide Inpatient Sample database to examine the relationships between obesity, gender, and nephrolithiasis. Recent reports indicate that the prevalence of nephrolithiasis has been increasing, especially among women. METHODS: The Nationwide Inpatient Sample contains data on approximately 20% of hospital stays in the United States. Included in this analysis were discharges with primary diagnosis ICD-9 codes 592.0 (renal calculus) or 592.1 (ureteral calculus), from 1998 through 2003. All raw data were weighted to produce national estimates. Descriptive and inferential statistics were performed to determine changes in nephrolithiasis prevalence and associations of obesity and other comorbidities with nephrolithiasis. RESULTS: We reviewed 181,092,957 hospital stays (weighted data). The prevalence of nephrolithiasis was relatively stable: 0.52% (149,302) in 1998 and 0.47% (147,541) in 2003. The prevalence of obesity increased from 3.06% (878,155) to 4.99% (1,575,247). The male:female ratio of patients with stones decreased from 1.6:1 to 1.2:1. Multivariate analysis revealed a statistically significant relationship (OR = 1.22, 95% CI 1.20-1.23, P <.001) between obesity and urinary stones. Obese females were more likely to develop stones than nonobese females (OR = 1.35, 95% CI 1.33-1.37, P <.001). The association between obesity and stones was weaker in males (OR = 1.04, 95% CI 1.02-1.06, P <.001). CONCLUSION: In this sample of inpatients, obesity was associated with a significantly increased prevalence of urinary stones. This relationship was stronger in females than in males. Further studies are needed to determine whether weight reduction in obese patients affects urinary stone disease. PMID- 21676442 TI - Does pelvicaliceal system anatomy affect success of percutaneous nephrolithotomy? AB - OBJECTIVE: To investigate the effect of the pelvicaliceal system (PCS) anatomy on the percutaneous nephrolithotomy (PCNL) success rate. Although the caliceal anatomy is effective for stone clearance after shock wave lithotripsy and retrograde intrarenal lithotripsy, the effect of the caliceal anatomy after PCNL has not been evaluated to date. METHODS: A total of 498 patients who had undergone PCNL and preoperative intravenous urography were enrolled in our study. Kidney-related anatomic factors, such as the PCS surface area and type, degree of hydronephrosis, infundibulopelvic angle, upper-lower calix angle, infundibular length, and infundibular width were calculated using intravenous urography. The association between the PCNL success rate and kidney-related anatomic factors was retrospectively analyzed using chi-square tests, Fisher's exact test, Mann Whitney U test, and forward stepwise regression analysis. RESULTS: A success rate of 78.1% was achieved. No difference was seen the success rates among the PCS types. The mean PCS surface area was 20.1 +/- 9.7 cm(2) in patients with successful outcomes and 24.5 +/- 10.2 cm(2) in patients with remaining stones (P = .001). The mean infundibulopelvic angle, upper-lower calix angle, infundibular length, and infundibular width were similar in both groups. Multivariate binary logistic regression analysis showed that stone configuration and PCS surface area were independent factors affecting the PCNL success rates. CONCLUSION: The results of our study have shown that the PCS surface area is the only anatomic factor that affects the PCNL success rate and patients with a PCS surface area <20.5 cm(2) have greater PCNL success. PMID- 21676443 TI - Associations between modest weight changes and onset and progression of lower urinary tract symptoms in two population-based cohorts. AB - OBJECTIVES: To conduct a study to determine whether weight changes were associated with the risk of developing lower urinary tract symptoms (LUTS). Obesity has been associated with LUTS in aging men. METHODS: The study population consisted of men participating in the Olmsted County Study of Urinary Symptoms and Health Status among Men and the Flint Men's Health Study. Weight loss and weight gain were defined as a change of >=5% of the baseline weight. LUTS progression was measured by calculating the American Urological Association Symptom Index (AUASI) score slopes for 4 years of follow-up in both cohorts. Additional Cox proportional hazard models were constructed to determine whether the weight changes were associated with the later development of moderate-to severe symptoms or with a >=4-point increase in the AUASI score (Olmsted County Study of Urinary Symptoms and Health Status among Men cohort only). RESULTS: Weight changes were not associated with LUTS progression (all P > .05). Additionally, the rate at which the AUASI scores changed did not vary by the weight change. Finally, in the Olmsted County Study of Urinary Symptoms and Health Status among Men cohort, the weight changes were not associated with risk of having a moderate-to-severe AUASI score or a >=4-point increase in the AUASI score. CONCLUSIONS: Modest weight loss might not prevent the onset or progression of LUTS. However, modest weight gain also might not contribute to changes in LUTS. PMID- 21676444 TI - Green tea extract (epigallocatechin-3-gallate) reduces efficacy of radiotherapy on prostate cancer cells. AB - OBJECTIVES: To assess the influence of epigallocatechin-3-gallate (EGCG) on the efficacy of ionizing radiation on prostate cancer cells because of the increased use of dietary interventions, especially by patients with prostate cancer. Radiotherapy is used to treat localized prostate cancer. Some people consume green tea (EGCG) as a chemopreventive agent against prostate cancer. Green tea can act as an antioxidant and induce superoxide dismutase enzymes, which could scavenge the free oxygen radicals generated by radiotherapy. METHODS: Prostate cancer cell line DU145 cells were treated with EGCG or radiotherapy, or both. Cell death was assessed using trypan blue cell counting, and apoptosis was confirmed by assessing poly (adenosine phosphate ribose) polymerase cleavage. The antioxidant potential was assessed using Western immunoblotting for manganese superoxide dismutase and copper zinc superoxide dismutase enzymes. Radiotherapy was delivered using a linear accelerator. Cell cycle analysis was performed using flow cytometry. RESULTS: Radiotherapy at 3.5 Gy induced a 5.9-fold increase in apoptosis of DU145 cells. Subapoptotic doses of EGCG (1.5-7.5 MUM) significantly reduced ionizing radiation-induced apoptosis (P < .001), with the inhibitory effect of EGCG on ionizing radiation being most effective when added 30 minutes before radiotherapy (P < .001). In addition, when radiotherapy and EGCG were used together, an approximate 1.5-fold increase in manganese superoxide dismutase levels was seen compared with the control and a 2-fold increase compared with radiotherapy alone. CONCLUSIONS: Radiotherapy is effective in inducing apoptosis in DU145 cells, but its effect was significantly reduced in the presence of EGCG, and this was associated with an increase in the induction of manganese superoxide dismutase. PMID- 21676445 TI - Transplant nephrectomy after allograft failure is associated with allosensitization. AB - OBJECTIVES: To evaluate the effect of transplant nephrectomy (TN) on the percentage of panel reactive antibody (%PRA) and donor-specific antibody (DSA) levels in patients with renal allograft failure. METHODS: The records of patients with failed kidney transplants, who had undergone TN from 2000 to 2007, were reviewed. The pre- and post-TN serum samples were available for analysis from 31 patients. Human leukocyte antigen typing and the %PRA was measured in these patients using standard serologic techniques. The pre- and post-TN patient serum samples were evaluated for DSA levels using solid phase assays and single antigen beads. The pre- and post-TN measurements of the %PRA and DSA levels were compared using the Wilcoxon signed rank test, and the associated clinical variables were identified on multivariate regression analysis. RESULTS: The mean %PRA increased from 33.4 to 75.6 for class I antigens (P < .001) and from 38.9 to 60.6 (P = .002) for class II antigens in patients before and after TN, respectively. This increase was associated with an increase in the mean human leukocyte antigen class I and class II DSA levels from 33,518 molecular equivalents of soluble fluorochrome (MESF) to 121,457 MESF (P < .001) and from 45,459 MESF to 126,968 MESF (P < .001), respectively. Regression analysis showed that rejection episodes and an interval from graft failure to TN of <10 months were associated with greater increases in the mean %PRA (P < .001) and mean DSA levels (P = .02). CONCLUSIONS: The results of the present study have confirmed that the %PRA increases after TN in patients with renal allograft failure, and sensitization occurs after TN, with an increase in DSA levels. Rejection episodes and early TN after graft failure might result in a greater degree of sensitization. PMID- 21676446 TI - Polymorphisms in the P450 c17 (17-hydroxylase/17, 20-Lyase) gene: association with estradiol and testosterone concentration in hypospadias. AB - OBJECTIVE: To investigate the association of CYP17 polymorphism with 17beta estradiol (E2) and testosterone (T) concentration in hypospadias. METHODS: Two hundred twenty-three boys (91 with hypospadias and 132 age-matched controls) were included in the study. CYP17 polymorphism was evaluated using the polymerase chain reaction-restriction fragment length polymorphism method, whereas T and E2 levels were estimated in serum by enzyme-linked immunosorbent assay. Association between CYP17 genotypes and 17beta-E2, T, and their ratio (E2/T) was analyzed by analysis of variance followed by Tukey's test. 17beta-E2, T, and E2/T ratio was also compared among the different degrees of hypospadias, as well as in controls, by unpaired Student's t-test. RESULTS: Significantly low levels of T were observed in severe-degree hypospadias (n = 14; mean +/- SD = 1.01 +/- 0.57) compared with mild cases (n = 77; mean +/- SD = 1.93 +/- 1.40) and controls (mean +/- SD = 3.32 +/- 2.06) (P <.05). E2/T ratio was also significantly higher in hypospadias cases (5.36 +/- 3.55) compared with controls (2.21 +/- 2.52). Heterozygous variants (A1/A2) of CYP17 were present in higher frequency (OR = 0.96; 95% CI = .518-1.770) and homozygous (A2) variants were less frequently found in hypospadias (OR = 0.87; 95% CI = .363-2.077), but results were insignificant. No association between 17beta-E2 and T with different CYP17 genotypes was observed. CONCLUSION: Our study suggests that, although polymorphism in CYP17 gene may not be associated with 17beta-E2 and T concentrations in hypospadias cases, low levels of T and higher E2/T ratio might possibly act as risk factors for hypospadias. PMID- 21676447 TI - The activation of peripheral 5-HT1A receptors can inhibit seminal vesicle contraction: an in vivo animal study. AB - OBJECTIVES: To elucidate the differential effects of stimulating various peripheral 5-HT receptor subtypes on the contractile response of seminal vesicles (SVs) induced by electrical stimulation (ES). METHODS: Male Wistar rats (aged 12 14 weeks) were prepared as our previously established model, which allows an intraarterial injection of test agents to directly act on SV. Four selective 5-HT agonists-8-OH-DPAT (5-HT1A), 5-nonyloxytryptamine (5-HT1B), BW723C86 (5-HT2B), and MK-212 (5-HT2C)-were injected at various concentrations (from 10(-8) to 10( 4) mmol/kg). After an injection, the SV contractile response was recorded after ES of lesser splanchnic nerve was applied. Relationships between the concentration of an agonist and its effect on SV contraction were plotted and analyzed. RESULTS: The peripheral injection of 5-HT1A agonist had a dose dependent inhibitory effect on SV contraction and could achieve an inhibition of >50%; the IC50 was 3.16x10(-6) mmol/kg. No significant effects were observed with the peripheral injection of 5-HT1B, 5-HT2B, or 5-HT2C agonist. CONCLUSIONS: Our in vivo animal study shows that the activation of peripheral 5-HT1A receptors can inhibit ES-induced SV contraction, whereas the activation of peripheral 5-HT1B, 5 HT2B, or 5-HT2C receptors has no significant effect. The results suggest that the peripheral 5-HT pathway is a potential therapeutic target of the treatment for premature ejaculation. PMID- 21676448 TI - Technique for preservation of penile skin in genital reconstruction: free graft to the scrotum. AB - OBJECTIVE: To describe a new technique to preserve the penile epithelium with good cosmetic results when additional surgery is a significant possibility. Complex genital reconstruction can require multiple procedures. METHODS: Seven patients underwent grafting of the penile epithelium to the scrotum during genital reconstruction to bank the tissue for potential future use. The graft size was 8-40 mm in the maximal length. RESULTS: The median age at surgery was 8.1 months. The median interval to the last follow-up examination after surgery was 13.5 months. All 7 patients demonstrated excellent wound healing with good cosmetic results. CONCLUSION: In patients with complex genital anomalies, nonhair bearing epithelium is a valuable asset. At times, the paucity of available local tissue necessitates autografting with nongenital epithelium. The need for nongenital tissue can be reduced if excess penile skin is banked for potential use at a later date. We describe a technique in which the penile skin is preserved for potential future reconstruction using free grafting to the scrotum. PMID- 21676449 TI - Oxalate and sucralose absorption in idiopathic calcium oxalate stone formers. AB - OBJECTIVES: To better understand intestinal oxalate transport by correlating oxalate and sucralose absorption in idiopathic calcium oxalate stone formers. Oxalate has been hypothesized to undergo absorption in the large and small intestine by both paracellular and transepithelial transport. Sucralose is a chlorinated sugar that is absorbed by paracellular mechanisms. METHODS: Idiopathic calcium oxalate stone formers were recruited to provide urine specimens on both a self-selected diet and after a meal containing 90 mg of (13)C(2-)oxalate and 5 g of sucralose, and a stool sample for determination of Oxalobacter formigenes colonization. The 24-hour urine collections were fractionated into the first 6 hours and the subsequent 18 hours. Sucralose and oxalate excretion were measured during these periods and used to estimate absorption. RESULTS: Thirty-eight subjects were evaluated. The majority of both the (13)C(2-)oxalate and sucralose absorption occurred within the 0-6-hour collection. The (13)C(2-)oxalate and sucralose absorptions were significantly correlated at the 0-6 hour, the 6-24 hour, and the total 24-hour time periods (P <.04). All 5 oxalate hyperabsorbers(>15% absorption) also absorbed significantly more sucralose during the 0-6 hour and whole 24-hour time points (P <.04). Oxalobacter formigenes colonization did not significantly alter oxalate absorption. CONCLUSIONS: The results suggest that most oxalate is absorbed in the proximal portion of the gastrointestinal tract and that paracellular transport is involved. Augmented paracellular transport, as evidenced by increased sucralose absorption, may also influence oxalate absorption. PMID- 21676451 TI - Unusual presentation of a Mullerian remnant in an infant with recurrent epididymo orchitis. AB - Mullerian duct remnants result from incomplete regression, a defect that occurs during sexual differentiation. Ninety percent of patients with mullerian remnants also have an associated disorder of sexual differentiation such as hypospadias. Presenting signs and symptoms are recurrent bladder infection, perineal pain, dysuria, or infertility. The purpose of this case report is to recount an unusual presentation of a mullerian duct remnant with recurrent epididymo-orchitis and to discuss the embryology, diagnosis, and management of this condition. PMID- 21676450 TI - Internet search trends analysis tools can provide real-time data on kidney stone disease in the United States. AB - OBJECTIVES: To evaluate the utility of using Internet search trends data to estimate kidney stone occurrence and understand the priorities of patients with kidney stones. Internet search trends data represent a unique resource for monitoring population self-reported illness and health information-seeking behavior. METHODS: The Google Insights for Search analysis tool was used to study searches related to kidney stones, with each search term returning a search volume index (SVI) according to the search frequency relative to the total search volume. SVIs for the term, "kidney stones," were compiled by location and time parameters and compared with the published weather and stone prevalence data. Linear regression analysis was performed to determine the association of the search interest score with known epidemiologic variations in kidney stone disease, including latitude, temperature, season, and state. The frequency of the related search terms was categorized by theme and qualitatively analyzed. RESULTS: The SVI correlated significantly with established kidney stone epidemiologic predictors. The SVI correlated with the state latitude (R squared=0.25; P<.001), the state mean annual temperature (R-squared=0.24; P<.001), and state combined sex prevalence (R-squared=0.25; P<.001). Female prevalence correlated more strongly than did male prevalence (R-squared=0.37; P<.001, and R-squared=0.17; P=.003, respectively). The national SVI correlated strongly with the average U.S. temperature by month (R-squared=0.54; P=.007). The search term ranking suggested that Internet users are most interested in the diagnosis, followed by etiology, infections, and treatment. CONCLUSIONS: Geographic and temporal variability in kidney stone disease appear to be accurately reflected in Internet search trends data. Internet search trends data might have broader applications for epidemiologic and urologic research. PMID- 21676452 TI - Paracrine SLPI secretion upregulates MMP-9 transcription and secretion in ovarian cancer cells. AB - OBJECTIVES: Secretory leukocyte protease inhibitor (SLPI) is amplified in serous ovarian cancer. We have dissected its function, showing it is a survival factor for ovarian cancer and promotes tumorigenesis and paclitaxel-resistance. We hypothesized that the protease inhibitory function was responsible for modulating SLPI's invasive capacity. METHODS: Stable HEYA8 ovarian cancer transfectants expressing vector, wild type SLPI, and protease inhibitor null (F-)SLPI were examined in vitro and in xenografts. Invasion, enzyme activity, and MMP production and function assays were applied. SLPI and MMP immunoexpression was graded on tissue microarray and clinical samples. Statistical comparisons used unpaired t test and ANOVA, where appropriate. RESULTS: SLPI and F-SLPI cells caused greater parenchymal and peritoneal dissemination over control cells in xenografts and invasion assays (p<0.001). MMP-9 protease activity was increased in SLPI and F-SLPI cells over control. SLPI, but not F-SLPI, inhibited plasmin activity, necessary for MMP-9 activation and release, and inhibited activation of MMP-9. However, paradoxically, both induced quantitative MMP-9 transcription (p<0.05) and protein (p<0.008), yielding an increased net MMP-9 activity in the face of plasmin inhibition. SLPI and MMP-9 expression were strongly correlated in serous ovarian cancers (r(2)=0.986) and a set of ovarian cancers (p<0.02). SLPI expression was greater in serous than endometrioid ovarian cancers (p=0.04). CONCLUSIONS: SLPI stimulates ovarian cancer invasion, modulated in part by its serine protease inhibitory activity attenuating MMP-9 release. However, SLPI induction of MMP-9, independent of protease inhibition activity, is greater yielding a net pro-invasive behavior. These findings further support SLPI as a molecular target for ovarian cancer. PMID- 21676453 TI - Inhibition of MMPs by alcohols. AB - OBJECTIVES: While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. METHODS: The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 mol/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC(50)). RESULTS: Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3 heptanol and 1-octanol gave the strongest inhibition. SIGNIFICANCE: The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID- 21676454 TI - Influence of cooling rate on residual stress profile in veneering ceramic: measurement by hole-drilling. AB - OBJECTIVES: The manufacture of dental crowns and bridges generates residual stresses within the veneering ceramic and framework during the cooling process. Residual stress is an important factor that control the mechanical behavior of restorations. Knowing the stress distribution within the veneering ceramic as a function of depth can help the understanding of failures, particularly chipping, a well-known problem with Yttria-tetragonal-zirconia-polycrystal based fixed partial dentures. The objective of this study is to investigate the cooling rate dependence of the stress profile in veneering ceramic layered on metal and zirconia frameworks. METHODS: The hole-drilling method, often used for engineering measurements, was adapted for use with veneering ceramic. The stress profile was measured in bilayered disc samples 20 mm in diameter, with a 0.7 mm thick metal or Yttria-tetragonal-zirconia-polycrystal framework and a 1.5mm thick veneering ceramic. Three different cooling procedures were investigated. RESULTS: The magnitude of the stresses in the surface of the veneering ceramic was found to increase with cooling rate, while the interior stresses decreased. At the surface, compressive stresses were observed in all samples. In the interior, compressive stresses were observed in metal samples and tensile in zirconia samples. SIGNIFICANCE: Cooling rate influences the magnitude of residual stresses. These can significantly influence the mechanical behavior of metal-and zirconia-based bilayered systems. The framework material influenced the nature of the interior stresses, with zirconia samples showing a less favorable stress profile than metal. PMID- 21676455 TI - Extreme health inequalities: mortality in homeless people. PMID- 21676456 TI - Psychiatric disorders and mortality among people in homeless shelters in Denmark: a nationwide register-based cohort study. AB - BACKGROUND: The increased mortality of homeless people compared with non-homeless people might be linked to psychiatric disorders. However, homeless people are, because of their insufficient accommodation, difficult to sample and monitor, which has limited previous studies. We aimed to assess registered psychiatric disorders, mortality, and predictors of mortality in the homeless shelter population in Denmark. METHODS: We did a nationwide, prospective, register-based cohort study of homeless people aged 16 years and older who were registered in the Danish Homeless Register between Jan 1, 1999, and Dec 31, 2009. We calculated the proportion of registered psychiatric disorders, overall and cause-specific standardised mortality ratio (SMR), and life expectancy. Hazard ratios (HRs) were used to assess predictors of death. FINDINGS: 32,711 homeless people (23,040 men and 9671 women) were included in the study population. 14,381 men (62.4%) and 5632 women (58.2%) had registered psychiatric disorders, and 11,286 men (49.0%) and 3564 women (36.9%) had a substance abuse diagnosis. During the study period, 3839 men (16.7%) and 951 women (9.8%) died. The overall SMR for men was 5.6 (95% CI 5.4-5.8) and for women was 6.7 (6.2-7.1), and external causes accounted for 1161 (27.9%) of 4161 deaths for which information on the cause was available. Remaining life expectancy at age 15-24 years was 21.6 years (95% CI 21.2-22.1) and 17.4 years (16.4-18.5) lower for homeless men and women, respectively, than the general population. Registered substance abuse disorder was associated with the highest mortality risk compared with no psychiatric contact registered (adjusted HR 1.4, 95% CI 1.3-1.5 for men; 1.7, 1.4-2.1 for women). INTERPRETATION: Health problems are extensive in the homeless shelter population and there is an urgent need for more sustained efforts to reduce the high morbidity and mortality, especially from external causes. Register data is an important resource to supplement existing knowledge on homeless people with more valid and detailed information. FUNDING: The Danish Council for Independent Research. PMID- 21676457 TI - The effect of stress and tissue fluid microenvironment on allogeneic chondrocytes in vivo and the immunological properties of engineered cartilage. AB - Engineered implants derived from neonatal rabbit chondrocytes and collagen type I hydrogel, were loaded in dialyzer pockets and implanted in muscle and articular cavity of rabbits to simulate different stress and tissue fluid micro environments. After 4 and 12 weeks, the expressions of main histocompatibility complex (MHC) molecules as well as the mixed lymphocyte chondrocytes reactions (MLChR) levels of the seeded cells were detected. The results indicated that with stress and synovial fluid microenvironment, the formation of chondroid tissue was prominently promoted in articular cavity. It gave the seeded chondrocytes lower and gradually decreasing levels of allogeneic lymphocytes activation, however, with the higher cell mortality, the MHC molecules expression, especially MHC-I were up-regulated obviously in early stage. These results are very different to those seen in muscle and prove that stress and tissue fluid micro-environments can greatly impact the differentiation and immunological properties of the engineered cartilage. From the perspective of avoiding severe rejection, to promote the formation of the matrix as fast and select scaffold with higher "isolation" ability may be meaningful. Furthermore, the suitably treated dialyzer pockets model can be used for the study of the differentiation and immunological properties of the tissue engineered cartilage. PMID- 21676458 TI - The modulation of platelet adhesion and activation by chitosan through plasma and extracellular matrix proteins. AB - Chitosan has been shown to promote initial wound closure events to prevent blood loss. Platelet adhesion and activation are crucial early events in these processes after traumatic bleeding leading to thrombus formation. Platelet adhesion to chitosan was found to be enhanced in the presence of adsorbed plasma and extracellular matrix proteins and was found to be primarily mediated by alpha(IIb)beta(3) integrins, while alpha(2)beta(1) integrins were found to be involved in platelet adhesion to collagen and perlecan. Platelets were found to be activated by chitosan, as shown by an increase in the expression of alpha(IIb)beta(3) integrins and P-selectin, while the extent of activation was modulated by the presence of proteins including perlecan and fibrinogen. Collagen coated chitosan was found to activate platelets to the same extent as either chitosan or collagen alone. These data support the role of plasma and extracellular matrix proteins in promoting chitosan mediated platelet adhesion and activation supporting the hypothesis that chitosan promotes wound healing via these interactions. PMID- 21676459 TI - The impact of hyperglycemia and the presence of encapsulated islets on oxygenation within a bioartificial pancreas in the presence of mesenchymal stem cells in a diabetic Wistar rat model. AB - This study investigates the potential of bone marrow (BM-MSCs) versus adipose mesenchymal stem cells (AMSCs) to potentiate the oxygenation of encapsulated islets in a subcutaneous bioartificial pancreas. Oxygen pressures (inside subcutaneous implants) were followed in vivo (by electronic paramagnetic resonance) in non-diabetic/diabetic rats transplanted with encapsulated porcine islets or empty implants up to 4 weeks post-transplantation. After graft explantation, neoangiogenesis surrounding the implants was assessed by histomorphometry. Angiogenic properties of BM-MSCs and AMSCs were first assessed in vitro by incubation of the cells in hypoxia chambers, under normoxic/hypoxic and hypo-/hyperglycemic conditions, followed by quantification of vascular endothelial growth factor (VEGF) release. Second, the in vivo aspect was studied by subcutaneous transplantation of encapsulated BM-MSCs and AMSCs in diabetic rats and assessment of the cells' angiogenic properties as described above. Diabetic state and islet encapsulation induced a significant decrease of oxygenation of the subcutaneous implant and an increased number of cells expressing VEGF. AMSCs demonstrated a significantly higher VEGF secretion than BM MSCs in vitro. In vivo, AMSCs improved the implant's oxygenation and vascularization. Diabetes and islet encapsulation significantly reduced the oxygenation of a subcutaneous bioartificial pancreas. AMSCs can improve oxygenation by VEGF release in hypoxia and hyperglycemia states. PMID- 21676460 TI - Concentrations of trace elements [corrected] and organochlorines in Mutton bird (Puffinus griseus). AB - The Sooty Shearwater (Puffinus griseus, commonly known as Mutton bird) is a migratory wild seabird, annually harvested for food by certain native groups in New Zealand and Australia and in many parts of the world. The concentrations of 22 elements and several organochlorine pesticides [2,2-bis(chlorophenyl)-1,1,1 trichloroethane (DDT), its derivatives dichlorodiphenyldichloroethene (DDE) and dichlorodiphenyldichloroethane (DDD), aldrin, chlordane, dicofol, lindane, and methoxychlor] in Mutton bird were determined over two consecutive years to evaluate its safety for human consumption. Twenty bird carcasses were purchased in each of 2007 and 2008 from a local source. No significant year effect (P>0.05) was found in the following nine trace elements: Al, As, Cd, Co, Cr, Cu, Ni, Pb and Se. The concentrations of Hg, Li and Na were higher (P<0.05) in 2008 samples compared to 2007. The toxic trace elements (mg/kg wet weight) in all the samples were below the maximum residual level (MRL). The concentration of Fe, Ca and Se in Mutton bird was higher than that in domestic land animal meats reported in literature. The residual organochlorine concentrations were all below the recommended MRL. Thus Mutton bird meat is high in essential nutrient elements and of low toxicological risk. Due to active use of agrochemical in New Zealand, a monitoring program for contaminants in Mutton birds is recommended. PMID- 21676461 TI - Quantitative immunodetection of metallothioneins in relation to metals concentration in spiders from variously polluted areas. AB - Spiders inhabiting post industrial environments, such as waste heaps or ore bearing areas, are exposed to high concentrations of metals, accumulated in the body of their prey and transferred along food chains. Therefore spiders are pressed to develop metal-neutralization strategies. Low-molecular, multifunction proteins: metallothioneins (MTs), often postulated as biomarkers of metal exposure, are known to bind metals and thus protect organisms against their toxic effects. Yet the proteins are still not well recognized in spiders. The aim of this study was to assess, by immunodetection method, ELISA, the concentration of metallothioneins in adult females of three web building spider species: Araneus diadematus (Araneidae), Agelena labyrinthica (Agelenidae) and Linyphia triangularis (Linyphiidae) from three variously polluted areas in southern Poland: Olkusz, ore-bearing post industrial site; Katowice-WeLnowiec: post metallurgic waste heap, Pilica: the reference, rural, area. The concentration of metallothioneins has been analyzed in relation to the metal concentration in spiders body. The study gives the evidence that metallothioneins are reliably detectable by means of ELISA technique. The analysis of results obtained shows a strong species-dependence of the MTs level. Positive correlations between MTs concentration and metal body burden (mainly Zn and Pb) were found. This suggests that the proteins play an important role in the neutralization and regulation of metal ions in spiders. The same correlation indicate the possibility to consider MTs in spiders as biomarkers of metal exposure and effects. However, the species specificity as well as metal characteristics should be taken under account. PMID- 21676462 TI - Small molecule modulators of MHC class II antigen presentation: mechanistic insights and implications for therapeutic application. AB - Antigen presenting cells express MHC class II molecules bound to peptide fragments and are responsible for activating CD4(+) T cells that then broadly influence many branches of the immune response. A growing interest in developing strategies to therapeutically influence the peptides to which naive CD4(+) T cells are exposed has led to the hunt for small molecules that modulate peptide presentation through the MHC class II pathway. Over the past decade a number of small molecules have been discovered that show surprising diversity in both structure and putative mechanisms. This review discusses how these small molecules were identified and compares the mechanisms by which they may act with what is known about the endogenous peptide exchanger, HLA-DM. PMID- 21676463 TI - A novel mutation in the C3 gene and recurrent invasive pneumococcal infection: a clue for vaccine development. AB - BACKGROUND: We identified a 4 year-old boy born to a consanguineous marriage with C3 deficiency after three episodes of invasive pneumococcal disease. The efficacy of anti-pneumococcal vaccination in C3 deficient patients is not clear. OBJECTIVES: Our objective was to identify the genetic defect resulting in his C3 deficiency and measure his ability to mount an adaptive immune response. METHODS: Fibroblast cell lines were generated from the patient and parents. DNA was isolated and the C3 gene sequenced. Quantitation of C3 expression was performed by immunoprecipitation of (35)S-methionine labeled protein. Isotype specific anti pneumococcal antibodies present in the patients sera was quantitated after administration of Prevnar-7 and Pneumovax vaccines. RESULTS: Pneumococcal types 14, 10B and 29 were identified from the blood on three separate occasions over a period of 20 months. C3 levels in the blood was <10, 71, and 66 for the patient, mother and father, respectively (90-180mg/dl, normal). Sequencing revealed a homozygous deletion of one nucleotide located in exon 31 (delA in position 3997 of cDNA) which resulted in a transcriptional stop signal thirteen codons later. The parents were heterozygous for the mutation. No detectable C3 was noted by immunoprecipitation. The patient mounted adequate antibody responses to the protein-conjugated Prevnar and tetanus vaccines but not to the polysaccharide antigen based Pneumovax vaccine. Major immunoglobulin class levels were normal. CONCLUSION: C3 deficiency results in the selective impairment to mount a response against polysaccharide-based antigens. Protein-conjugated vaccines are likely to be efficacious in immunizing against encapsulated organisms in these patients. PMID- 21676464 TI - Asymmetry of 24-hour intraocular pressure reduction by topical ocular hypotensive medications in fellow eyes. AB - PURPOSE: A core assumption for the 1-eye therapeutic trial of ocular hypotensive medications is the symmetrical reduction of intraocular pressure (IOP) in paired eyes. This assumption was evaluated for 24-hour IOP reduction in patients who underwent monotherapy or adjunctive therapy. DESIGN: Database study. PARTICIPANTS: Patients 41 to 79 years of age with primary open-angle glaucoma or ocular hypertension. METHODS: Twenty-four-hour IOP data from the paired eyes of patients undergoing bilateral monotherapy (n = 66) of latanoprost, travoprost, timolol, or brimonidine or bilateral adjunctive therapy (n = 52) with brinzolamide or timolol added to latanoprost monotherapy were analyzed retrospectively. Measurements of IOP were obtained every 2 hours in a sleep laboratory before and after at least 4-week drug treatments. Strengths of association for single-pair IOP reductions and average IOP reductions in the paired eyes during the office-hour, diurnal, nocturnal, and 24-hour periods and in different body positions were analyzed. MAIN OUTCOME MEASURES: Variance for the difference, percentage distribution of large absolute difference, and coefficient of determination (r(2)) in the paired IOP reductions. RESULTS: The standard deviations for the differences in single-pair IOP reductions from the means were larger than 2.5 mmHg for all periods and body positions under monotherapy and adjunctive therapy. Absolute differences in single-pair IOP reductions of the cutoff thresholds of 3 and 2 mmHg or more occurred in more than 20% and 36% cases, respectively. Corresponding coefficients of determination were 0.240 to 0.374 with monotherapy and 0.215 to 0.381 with adjunctive therapy. When the average differences in the paired IOP reductions were analyzed for a specific period and posture, the standard deviations for the differences in the paired IOP reductions and the percentage distributions of large absolute differences were reduced, and most coefficients of determination were improved. CONCLUSIONS: There is only a weak association between the right- and left-eye responses to IOP lowering monotherapy or adjunctive therapy during a 24-hour period when single pair IOP data are considered. Considering the averages of multiple paired IOP responses can improve the strength of the association. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21676465 TI - Clinical differences between early and late remission in depressive patients. AB - OBJECTIVE: Predicting treatment outcome at an early stage is clinically relevant. The main objectives are: to compare rates of remission after acute and continuation phase treatment and to determine the most common residual symptoms among remitted patients; to compare the residual symptoms in early and late remitted and to identify factors that predict early or faster remission. METHOD: It is a prospective, naturalistic, multicenter, and nationwide epidemiological study of 1595 depressive outpatients. Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS) and the Self Rated Inventory of Depressive Symptomatology (IDS-SR(30)). Assessments were carried out after 6-8 weeks of antidepressant treatment and after 14-20 weeks of continuation treatment. Early remitters were defined with an IDS-SR(30) score <= 14 at first and second assessment. Late remitters were defined as those scoring IDS-SR(30) >14 at first and IDS-SR(30) score <= 14 at second assessment. RESULTS: 140 subjects (8.8%) were in remission after 6-8 weeks of antidepressant treatment and 862 remitted (59%) after 16-20 weeks of treatment. The mean number of residual symptoms is significantly higher among patients who remit later. Greater differences between early and late remitters were found in the following symptoms: feeling sad, reactivity of mood, interpersonal sensitivity and pleasure/enjoyment. Multivariate analysis showed that only comorbid anxiety disorder is significantly associated with late remission. CONCLUSIONS: Early remitted patients have a better "quality" of remission. Late remission is associated with residual symptoms more related to core depressive symptoms. Residual symptoms in early remitted patients may constitute a new target for the treatment of depression. PMID- 21676466 TI - Prevalence and risk factors for recurrence of depression five years after short term psychodynamic therapy. AB - BACKGROUND: Follow-up research concerning the efficacy of treatment for depression is scarce and varies widely in clinical and methodological terms. Aim was to conduct a five-year follow-up study of recurrence of depression after short supportive Psychodynamic Treatment (PDT) alone or in combination with pharmacotherapy. METHODS: Patients who had been treated five years previously for major depressive disorder in a randomised control trial comparing short supportive PDT alone or in combination with pharmacotherapy, were traced. Patients who completed treatment were included. Recurrent episodes in the past five years were identified using CIDI. Severity of symptoms after five years was measured with the Hamilton Rating Scale for Depression and sub-scales Depression, Anxiety and Somatisation of the self-report Symptom Checklist 90. RESULTS: 52 (37%) patients of the original sample were localised. 42% had suffered from one or more recurrences during the follow-up period. There was no significant difference between the group who had received psychotherapy and the group who had received combined therapy during the acute phase. Young women and patients with more residual depressive symptoms and less somatic symptoms directly after treatment, were more at risk for recurrence. LIMITATIONS: Relatively small study population. Furthermore it was not known if patients received other treatment during the follow-up period. CONCLUSIONS: The long-term efficacy of PDT (with or without antidepressants) seemed to be comparable with other psychotherapies for depression. But the high recurrence rate urges us to shift the focus of depression treatment to improving long-term outcome and to the prevention of recurrence, in particular for young women and patients with residual symptoms of depression. PMID- 21676467 TI - Intra-individual changes in anxiety and depression during 12-month follow-up in percutaneous coronary intervention patients. AB - BACKGROUND: Only a paucity of studies focused on intra-individual changes in anxiety and depression over time and its correlates in cardiac patients, which may contribute to the identification of high-risk patients and point to targets for intervention. We examined changes in anxiety and depression over a 12-month period and the demographic and clinical correlates of change scores using an intra-individual approach in patients treated with percutaneous coronary intervention (PCI). METHODS: Consecutive PCI patients (N=715) completed the Hospital Anxiety and Depression Scale (HADS) at baseline and at 12 months post PCI. Individual change scores were calculated and in secondary analysis, three categories of change were identified (i.e., stable, improved, and deteriorated anxiety or depression). RESULTS: The mean individual change was -.16 (+/- 3.0) for anxiety and -.02 (+/- 2.8) for depression. In linear regression analysis, baseline anxiety levels (B = -.25, 95%CI[-.30 to -.20], p = <.001) and baseline depression levels (B = -.28, 95%CI[-.33 to -.22], p =< .001) were significant correlates of individual change scores. Secondary analysis showed that anxiety remained stable in 76.4% (546/715) of patients, while depression remained stable in 81.4% (582/715) of patients. CONCLUSIONS: The findings of the current study showed that levels of anxiety and depression remained stable in the majority of PCI patients from the index PCI to 12 months post-PCI. Future studies using an intra-individual approach are warranted to further examine individual changes in anxiety and depression over time in CAD, and PCI in particular, as a means to bridge the gap between research and clinical practice. PMID- 21676468 TI - Clinical manifestations of geriatric depression in a memory clinic: toward a proposed subtyping of geriatric depression. AB - BACKGROUND: As the older population increases so does the number of older psychiatric patients. Elderly psychiatric patients manifest certain specific and unique characteristics. Different subtypes of depressive syndromes exist in late life depression, and many of these are associated with cognitive impairment. MATERIALS AND METHODS: A total of 109 depressive patients and 30 normal subjects matched by age and educational level were evaluated using a neuropsychiatric interview and an extensive neuropsychological battery. Depressive patients were classified into four different groups by SCAN 2.1 (schedules for clinical assessment in Neuropsychiatry): major depression disorder (n: 34), dysthymia disorder (n: 29), subsyndromal depression (n: 28), and depression due to mild dementia of Alzheimer's type (n: 18). RESULTS: We found significant associations (p<.05) between depressive status and demographic or clinical factors that include marital status (OR: 3.4, CI: 1.2-9.6), level of daily activity (OR: 5.3, CI: 2-14), heart disease (OR: 12.5, CI: 1.6-96.3), and high blood cholesterol levels (p:.032). Neuropsychological differences were observed among the four depressive groups and also between depressive patients and controls. Significant differences were observed in daily life activities and caregivers' burden between depressive patients and normal subjects. CONCLUSION: Geriatric depression is associated with heart disease, high cholesterol blood levels, marital status, and daily inactivity. Different subtypes of geriatric depression have particular clinical features, such as cognitive profiles, daily life activities, and caregivers' burden, that can help to differentiate among them. LIMITATIONS: The cohort referred to a memory clinic with memory complaints is a biased sample, and the results cannot be generalized to other non-memory symptomatic cohorts. PMID- 21676469 TI - Explanations of educational differences in major depression and generalised anxiety disorder in the Irish population. AB - BACKGROUND: Social inequalities in mental disorders have been described, but studies that explain these inequalities are lacking, especially those using diagnostic interviews. This study investigates the contribution of various explanatory factors to the association between educational level and major depression and generalised anxiety disorder in Irish men and women. METHODS: The study population comprised a national random sample of 5771 women and 4207 men aged 18 or more in Ireland (SLAN 2007 survey). Major depression and generalised anxiety disorder were measured using a standardised diagnostic interview (CIDI SF). Four groups of explanatory factors were explored: material, psychosocial, and behavioural factors, and chronic disease. RESULTS: For both genders, low educational level increased the risk of both mental disorders. Material factors, especially no private health insurance, but also no car, housing tenure, insufficient food budget, and unemployment (for men), made the highest contribution (stronger for men than for women) in explaining the association between education and both mental disorders. Psychosocial (especially formal social participation, social support and marital status) and behavioural factors (smoking and physical activity for both genders, and alcohol and drug use for men) and chronic disease made low independent contributions in explaining the association between education and both mental disorders. LIMITATIONS: Given the cross-sectional study design, no causal conclusion could be drawn. CONCLUSIONS: Targeting various material, psychosocial, and behavioural factors, as well as chronic diseases may help to reduce educational differences in depression and anxiety in the general population. PMID- 21676470 TI - Risk of suicide in medical and related occupational groups: a national study based on Danish case population-based registers. AB - BACKGROUND: Suicide risk may be elevated in 'medical' occupational groups, although results of studies are inconsistent. National data are required to examine this issue. It is also important to investigate the possible contribution of psychiatric disorder and access to specific suicide methods. METHODS: In a nested case-control design we used data from Danish national registers for 1981 2006 to examine risk of suicide in nurses, physicians, dentists, pharmacists and veterinary surgeons compared to teachers and the general population, and associations with psychiatric service contact and suicide methods. RESULTS: Crude age- and gender-adjusted rate ratios for suicide compared to teachers were significantly elevated in nurses (RR 1.90, 95% CI 1.63-2.21), physicians (RR 1.87, 95% CI 1.55-2.26), dentists (RR 2.10, 95% CI 1.58-2.79) and pharmacists (RR 1.91, 95% CI 1.26-2.87), but not veterinary surgeons. Risk was also elevated in nurses, physicians and dentists compared with the rest of the general population, the relative risk increasing following adjustments for psychiatric service contact, marital status, gross income and labour market status. Results were similar in both genders. The elevated risk in nurses and dentists decreased during the study period. Elevated risks were not associated with greater psychiatric service contact. Medicinal drugs were commonly used for suicide by nurses, physicians and pharmacists. LIMITATIONS: The study was based in one country. CONCLUSIONS: Risk of suicide is increased in nurses, physicians, dentists and pharmacists in Denmark. This is not reflected in excess psychiatric service contact. Ready access to medicinal drugs may influence risk in nurses, physicians and pharmacists. PMID- 21676471 TI - Delayed transition from ambiguous to risky decision making in alcohol dependence during Iowa Gambling Task. AB - It has been demonstrated that alcohol-dependent patients exhibit decision-making deficits, particularly, hypersensitivity to reward and executive dysfunction. Yet, how the impaired motivational process and executive dysfunction in the patients affect decisions under ambiguity and risk with different degrees of uncertainty is little known. To investigate the neuropsychological origin of the impaired decision making under uncertainty in alcohol dependence, we administered the Iowa Gambling Task (IGT), Game of Dice Task (GDT) and Wisconsin Card Sorting Test (WCST) to 23 alcohol-dependent patients and 21 healthy subjects, and calculated the correlations between the task performances. We found that the patients showed poor performance in all three tasks compared with the healthy subjects. Moreover, correlations between performances on the GDT and the later trials of the IGT were delayed in alcohol-dependent patients when compared with healthy subjects. There is also a significant correlation between performances of earlier trials of the IGT and the WCST in the patients. These findings suggest that executive dysfunction in alcohol-dependent patients hampers appropriate estimation of probability distributions of possible alternatives, leading to a delayed transition from ambiguous to risky conditions in the Iowa Gambling Task. PMID- 21676472 TI - Oral administration of bovine lactoferrin upregulates neutrophil functions in a dog with familial beta2-integrin-related neutrophil dysfunction. AB - Lactoferrin, a glycoprotein present in neutrophils and exocrine secretions, plays important roles in host defense. Administration of bovine lactoferrin has been reported to modulate various neutrophil functions. We found a mixed-breed male dog with novel familial neutrophil dysfunction. The disorder was caused by a decrease of beta2-integrin expression encoding CD18 without mutation. Antibiotics therapy alone did not influence a series of neutrophil functions in the same dog. We examined the effects of oral administration of bovine lactoferrin on the neutrophil function and clinical symptoms in the same dog. Oral chronic administration of bovine lactoferrin increased neutrophilic beta2-integrin gene expression comparable to normal dogs, followed by the upregulation of surface CD18 expression. Concurrently, the superoxide production, phagocytic activity and adherence that were beta2-integrin-related neutrophil functions increased to normal canine levels. The chronic inflammation from bacterial upper respiratory infections and pneumonia was also alleviated in the dog. Our results indicate that oral treatment with bovine lactoferrin increases neutrophil beta2-integrin transcript level, leading to the upregulation of neutrophil functions and improvement of clinical symptoms in the dog with familial neutrophil dysfunction. PMID- 21676473 TI - The pathology of visible blood vessels on the nasal septum in children with epistaxis. AB - OBJECTIVE: Epistaxis is common in children, but its cause remains unknown. About half the children who present with epistaxis have prominent vessels on the nasal septum. The aim of this study was to determine the pathological nature of the prominent septal vessels in children with recurrent epistaxis. METHODS: 4mm punch biopsies of the nasal septal mucosa were taken from 5 children undergoing nasal cautery under general anaesthesia. RESULTS: Histology showed that the prominent vessels were thin-walled arterioles and capillaries with a surrounding inflammatory infiltrate. There was no evidence of venous varicosities or arterial microaneurysms. CONCLUSION: We postulate a mechanism for septal neovascularisation due to chronic low-grade inflammation as a cause for recurrent epistaxis in children. PMID- 21676474 TI - Relationships between measures of muscular performance, proprioceptive acuity, and aging in elderly women with knee osteoarthritis. AB - INTRODUCTION: OA is a multifactorial condition, which predisposes elderly individuals to disabilities. Therefore, aging, especially in women, is considered to be a risk factor for the development and progression of this disease. The aging process and the presence of degenerative diseases lead to losses of strength and proprioceptive acuity. However, studies have reported conflicting results regarding the relationships between these variables. Moreover, it is unclear whether age remains an aggravating factor of these variables in individuals with knee OA. OBJECTIVES: To analyze the relationships between measures of muscular performance, proprioceptive acuity, and age in community dwelling elderly women with knee OA. METHODS: This cross-sectional study involved 35 elderly women aged 65 years and over, who had a clinical diagnosis of unilateral or bilateral knee OA and were able to walk independently. The volunteers were tested for proprioceptive acuity (joint position sense and kinesthesia) and isokinetic muscular performance of the quadriceps and hamstrings on the isokinetic dynamometer Biodex System 3 Pro(r). Descriptive statistics were carried out for all outcome variables and correlation coefficients were calculated with a significance level of alpha < 0.05. RESULTS: No significant correlations were found between the measures of muscular performance and proprioceptive acuity. Furthermore, no significant correlations were found between age and measures of strength and proprioception. CONCLUSIONS: The results suggested no significant relationships between measures of proprioceptive acuity and muscular performance of the quadriceps and hamstring muscles and, especially, no influences of age on these variables in elderly women with knee OA. PMID- 21676475 TI - Cardiovascular involvement in Erdheim-Chester disease. PMID- 21676476 TI - Analysis of the diagnostic accuracy of the gamma interferon assay for detection of bovine tuberculosis in U.S. herds. AB - The goal of this study was to evaluate the test sensitivity (SE) and specificity (SP) of the gamma interferon (G-IFN) assay used for the detection of bovine tuberculosis (bTB) in U.S. cattle herds. In addition, the study assessed the association between G-IFN test results and bTB status of cattle, and explored different cut off values for classification of test results in adult cattle using receiver operating characteristics (ROC) curve analysis. Test SE was estimated using a population of 87 confirmed infected cattle from 14 herds distributed in 6 states. Test SP was estimated using a population of 4123 cattle representing 3000 premises in 3 states. These animals were from bTB free areas, accredited bTB free herds, or herds that were historically bTB free based on the absence of lesions found at slaughter and historical records of negative tests performed for bTB surveillance. The distribution of G-IFN results and its association with bTB infection status was also explored in a group of 914 exposed cattle in which infection was not confirmed. The results showed that the SE of the G-IFN for a cut-off value >=0.1 was 83.9% (76.1, 91.6). The SP of the G-IFN was 90.7% (95% CI: 89.8, 91.6), 97% (95% CI: 96.5, 97.5), and 98.6%(95% CI: 98.2, 98.9), for cut off values of 0.1, 0.3, and 0.5, respectively. For a cut off value >=0.1, the likelihood ratio of a positive G-IFN test was 9.03 (95% CI: 7.90, 10.31), and the likelihood ratio of a negative G-IFN test was 0.18 (95% CI: 0.11, 0.29). The area under the ROC curve was 0.976 (95% CI: 0.97, 0.98), characteristic of a highly accurate test. ROC analysis also showed that lower cut-off values, such as 0.1, have high SE with suitable SP for use in parallel testing, while cut-off values ranging between 0.3 and 0.6 provide the high SP desired in series-testing protocols with lower SE values. Findings from this study indicated that the G-IFN performs with high accuracy in the field, yielding SE and SP estimates comparable to those reported in previous evaluations (Ryan et al., 2000; Ameni et al., 2000; de la Rua-Domenech et al., 2006; Gormley et al., 2006). PMID- 21676477 TI - A side effect of decreased fertility associated with vaccination against bluetongue virus serotype 8 in Holstein dairy cows. AB - Inactivated virus vaccines have been widely used to control bluetongue after introduction of serotype 8 of the bluetongue virus (BTV) in northern Europe in 2006. To evaluate vaccination, quantitative knowledge of its possible side effects is needed. One current adverse reaction with inactivated vaccines is a rise in body temperature, which could reduce cow reproductive performance. The objective of this study was to quantify a possible side effect of vaccination on fertility before the implantation of the embryo of dairy cows under field conditions. The study was performed on herds that were not exposed to BTV. Fertility was assessed by return-to-service following artificial insemination (AI). Biological assumptions for a possible side effect of vaccination were conception failure and embryonic death. Associations between return-to-service rates and vaccine injections were assessed using mixed-logistic regression models and survival analysis. Two models were considered: a 3-week-return-to-service model comparing cows vaccinated between 3 days before and 16 days after AI and unvaccinated cows (assuming an effect on conception failure or early embryonic death), and a 90-day-return-to-service model comparing cows vaccinated between 3 days before and 42 days after AI and unvaccinated cows (assuming an effect on conception failure, early or late embryonic death). Only cows receiving a second vaccine injection between 2 and 7 days after AI had a significantly higher risk of 3-week-return-to-service (RR=1.19 [1.07-1.33]). This corresponds to an increase of return-to-service by 4 percentage points. A side effect of vaccination could be due to early embryonic death. The slight side effect on fertility associated with vaccination was low compared to effects of BTV-8 exposure on fertility. PMID- 21676478 TI - microRNA-7 increases radiosensitivity of human cancer cells with activated EGFR associated signaling. AB - Many microRNAs (miRNAs) play crucial roles in regulating expression of oncogenes or tumor suppressor genes. The epidermal growth factor receptor (EGFR) is frequently overexpressed in a wide range of solid tumors and is an important therapeutic target; however, the therapeutic outcome of currently available anti EGFR agents is often limited due to diverse molecular resistance mechanisms. In this study, we evaluated the potential of targeting miRNA-7 for overcoming radio resistance of cancer cells with activated EGFR-associated signaling. A panel of human cancer cell lines with increased EGFR-PI3K-Akt signaling was transfected with pre-miR-7 or control miRNA. Ectopic overexpression of miR-7 attenuated EGFR and Akt expression and radiosensitized SQ20B squamous cell carcinoma of the larynx, MDA-MB-468 breast cancer cells, A549 lung carcinoma cells, and U251 and U87 malignant glioma cells. In contrast, antisense-mediated inhibition of mature miR-7 expression led up-regulation of EGFR and its downstream effectors, and increased radio-resistance of U251 glioma cells. Overexpression of miR-7 prolonged radiation-induced gammaH2AX foci formation and downregulation of DNA dependent protein kinases (DNA-PKcs). miR-7 may be a useful therapeutic target for overcoming the radio-resistance of human cancers with activated EGFR-PI3K-AKT signaling. PMID- 21676479 TI - Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. AB - BACKGROUND AND PURPOSE: Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. The aim of this study was to evaluate the antitumor activity of a high CAIX-affinity indanesulfonamide (11c) combined with irradiation, compared with the general CA inhibitor acetazolamide (AZA). MATERIAL AND METHODS: HT-29 carcinoma cells with or without (genetic knockdown, KD) CAIX expression were incubated with 11c/AZA under different oxygen levels and proliferation, apoptosis and radiosensitivity were evaluated. 11c/AZA was administered intravenously (1*/day; 5 days) to tumor bearing mice and tumor irradiation (10 Gy) was performed at day 3 of the injection period. Tumor growth and potential treatment toxicity were monitored (3*/week). RESULTS: Treatment with 11c/AZA alone resulted in tumor regression, which was further increased in CAIX expressing cells by combining 11c with irradiation. AZA demonstrated also an additional effect in the KD tumors when combined with irradiation. CAIX inhibition in vitro significantly reduced proliferation and increased apoptosis upon hypoxia exposure without affecting intrinsic radiosensitivity. CONCLUSIONS: Specific inhibition of CAIX activity enhanced the effect of tumor irradiation and might, therefore, be an attractive strategy to improve overall cancer treatment. PMID- 21676480 TI - Optimal range of HbA1c for the prediction of future diabetes: a 4-year longitudinal study. AB - AIM: A glycated hemoglobin (HbA1c) range of 5.7-6.4% has been included as a category of increased risk for diabetes. We evaluated whether or not it is reasonable to apply this HbA1c range to Koreans. METHODS: A retrospective analysis was conducted among subjects who participated in comprehensive health check-ups annually for 5 years. A total of 9723 subjects were classified into 12 categories based on the baseline HbA1c level. RESULTS: During 4 years, 601 of the 9723 subjects (6.2%) developed diabetes. Based on ROC analysis, a HbA1c of 5.7% gave an optimal sensitivity of 62% and specificity of 85% to predict diabetes. The point showing a substantial difference in the Kaplan-Meier curves was a HbA1c of 5.7%. The incidence of diabetes was 20.8% among subjects with a baseline HbA1c of 5.7-6.4%. The hazard ratio of developing diabetes was 6.5 (95% CI, 3.7-10.2) in the subjects with a HbA1c of 5.7% compared with the bottom category of HbA1c (<5.0%). CONCLUSIONS: A HbA1c cut-point of 5.7% is a suitable value for predicting future diabetes. It is reasonable to consider a HbA1c range of 5.7 6.4% as a category of increased risk for diabetes in Korean, similar to an IFG or IGT. PMID- 21676481 TI - The ambiguity of ethnicity as risk factor of vitamin D deficiency--a case study of Danish vitamin D policy documents. AB - OBJECTIVES: To explore how ethnic minorities at risk of vitamin D deficiency are constructed in Danish policy documents (current as of April 2009), regarding vitamin D supplementation. METHODS: Ten policy documents were analysed through content analysis, focusing on definitions and explanations of ethnic minorities being at risk of vitamin D deficiency. This formed the basis for an analysis of constructions of ethnic minorities at risk which was undertaken using the Social Construction of Technology (SCOT) theory as an organising framework. RESULTS: The analysis showed a high degree of interpretative flexibility regarding how ethnic minorities are constructed as a risk group for vitamin D deficiency. The ten documents analysed revealed eight different constructions of the ethnic minorities groups at risk. A low degree of interpretative flexibility was found regarding the importance of skin colour and skin covering. Major disagreements were found regarding the importance attributed to the Islamic religion, other traditions, immigration, gender and age, and use of an evolutionary explanation for the increased risk. CONCLUSIONS: Ethnic minorities at risk of vitamin D deficiency are constructed very differently in Danish policies current as of April 2009. A more precise definition of ethnic minorities in policies and research may be helpful in seeking to identify which ethnic minorities are and are not at risk of vitamin D deficiency. PMID- 21676482 TI - Healthcare access and burden of care for patients with Lyme disease: a large United States survey. AB - OBJECTIVE: To evaluate the challenges faced by Lyme disease patients in obtaining adequate healthcare. METHODS: A web-based survey conducted over nine months was analyzed for the study. The survey focused on medical status, access to healthcare, and burden of illness. For inclusion in the study, survey respondents had to reside in the United States, be more than 10 years old, and have clinically diagnosed Lyme disease with chronic symptoms and positive laboratory testing. RESULTS: Responses from 2424 patients were included in the study. Half of the respondents reported seeing at least seven physicians before the diagnosis of Lyme disease was made. Nearly half had Lyme disease for more than 10 years and traveled over 50 miles to obtain treatment. Most respondents experienced symptoms lasting six months or more despite receiving at least 21 days of antibiotic treatment. A quarter of respondents had been on public support or received disability benefits due to Lyme disease symptoms, and over half had visited an emergency room at least once as a result of these symptoms. CONCLUSIONS: Lyme disease patients frequently endure extensive delays in obtaining an initial diagnosis, have poor access to healthcare and suffer a severe burden of illness. PMID- 21676483 TI - Association between polymorphisms of DNA repair genes and survival of advanced NSCLC patients treated with platinum-based chemotherapy. AB - BACKGROUND: Single nucleotide polymorphism (SNP) in DNA repair genes can be used to explain the differences in survival of platinum-treated non-small cell lung cancer (NSCLC) patients regardless of their performance status. To define the role of DNA repair gene SNPs in NSCLC patients, we investigated the association between survival and 12 different SNPs of 9 DNA repair genes. METHODS: 340 patients were treated with platinum-based chemotherapy. Polymorphisms were detected by real time PCR with TaqMan probe, using genomic DNA extracted from peripheral blood samples. Multivariate logistic or Cox regression analyses were used to adjust for possible confounding variables. RESULTS: The median overall survival time was 15 months and it was significantly longer in patients harboring ERCC1 118 C/T or T/T allele: 18 months as compared to 13.8 months for the C/C allele (P=0.014). Subgroup analysis revealed that ERCC1 118 C/T or T/T was associated with increased survival in elderly patients (P=0.018), male (P=0.022), squamous carcinoma (P=0.003), smoker (P=0.076) and those treated with non gemcitabine/cisplatin or carboplatin (non-GP/GC) regimen (P=0.023). XRCC3C/C was associated with better survival in non-gemcitabine/cisplatin treated patients (P=0.014). Both of CCNH-V270A C/C or C/T and XPD 751 A/A showed a significant longer survival in the squamous cell carcinoma subgroup (P=0.047 and P=0.034 respectively). CONCLUSION: Present data indicates that ERCC1 118 C/T or T/T might provide a better prognostic predictive marker of NSCLC patients treated with platinum-based chemotherapy, mainly in elderly subgroup, male, squamous carcinoma, smoker and those treated with non-GP/GC regimen. PMID- 21676484 TI - Pathologic response rates following definitive dose image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer. AB - INTRODUCTION: Treatment of technically operable, medically fit locoregionally advanced non-small cell lung cancer (NSCLC) patients is a controversial therapeutic challenge. Our group routinely uses a trimodality approach. Recent advances in radiotherapy allow for improved tumor targeting and daily patient positioning. We hypothesized that these technologies would improve pathologic response rates. We analyzed consecutively treated stage IIIA/IIIB NSCLC patients undergoing chemoradiotherapy before major lung resection, with particular attention paid to the impact of advanced technologies. METHODS: Locoregionally advanced NSCLC patients (N2) staged in a multidisciplinary forum with mediastinoscopy were planned to receive platinum-based chemotherapy and 60Gy and major lung resection. Four-dimensional CT (4DCT) and image-guided radiotherapy (IGRT) were used as available. Survival endpoints were estimated using the Kaplan Meier method and compared using the log-rank test. Multivariate analysis was performed using Cox proportional hazards models. RESULTS: We identified 53 patients from 2/1999 to 2/2010. Median RT dose was 59Gy. 68% underwent lobectomy. Forty-three patients were downstaged pathologically (81%), 38 experienced mediastinal sterilization (72%), and 21 (40%) had complete pathologic response (pCR). 1 and 2 year OS were 85.5% and 61.6%. Superior OS and DFS were associated with nodal downstaging and mediastinal sterilization (pN0). Treatment with IGRT/4DCT in 10 patients resulted in high rates of nodal downstaging (100% vs 77%, p=0.0452), mediastinal sterilization (90% vs 67%, p=0.0769), and pCR (60% vs 35%, p=0.0728). CONCLUSIONS: In selected patients, definitive dose CRT followed by major lung resection results in promising DFS and OS. The use of advanced radiotherapy techniques (4DCT and IGRT) appears to result in promising pathologic response rates. PMID- 21676485 TI - Aging correlates with reduction in regulatory-type cytokines and T cells in the gut mucosa. AB - Aging is reported to be associated with decline in oral tolerance induction, which is initiated at the intestinal mucosal surface. Herein, we examined the effect of aging in T cells and cytokines at the intestinal mucosa that might be involved in oral tolerance induction. Frequencies of regulatory-type IEL subsets such as TCRgammadelta(+) and TCRalphabeta(+)CD8alphaalpha(+) were lower in aged mice. Mucosal CD4(+)CD25(+)Foxp3(+) and CD4(+)LAP(+) T cells increased with aging but activated CD44(+)CD4(+) mucosal T cells also augmented. Production of TGF beta and IL-10 in the small intestine of old mice was reduced. Moreover, the ability of mucosal dendritic cells of aged mice to stimulate TGF-beta secretion and differentiation of CD4(+)LAP(+) T cells in co-culture studies also declined with aging. Reduction in these regulatory-type cytokines and T cells may help to explain the decline in susceptibility to oral induction during aging. However, not all mucosal regulatory elements were altered by aging and CD4(+)CD25(+)Foxp3(+) T cells were especially resistant to changes. Persistence of some mechanisms of regulation may play a critical role in maintaining mucosal homeostasis during aging. PMID- 21676486 TI - Expression and function of retinoblastoma binding protein 6 (RBBP6) in human lung cancer. AB - Retinoblastoma binding protein 6 (RBBP6) interacts with both p53 and pRb, and has been identified as an E3 ubiquitin ligase due to the presence of a RING finger domain. RBBP6 promotes the degradation of p53, thereby increasing cell proliferation. However it is not known whether RBBP6 is expressed in lung cancer, or interacts with p53 and pRB to modulate the proliferation or apoptosis of lung cancer cells. As assessed by immunohistochemistry, RBBP6 and p53 proteins were overexpressed in lung adenocarcinomas and lung squamous cell carcinomas. Expression of RBBP6 mRNA in lung tumor tissue was demonstrated by quantitative RT PCR and fluorescence in situ hybridization. Expression of RBBP6 mRNA was low in poorly differentiated tumors but high in well-differentiated tumors. Bronchoalveolar carcinomas showed intense RBBP6 mRNA hybridization in the cytoplasm of cells undergoing mitosis, supporting the association between RBBP6 expression and cell proliferation. By qRT-PCR, RBBP6 mRNA expression was 1.6 fold higher, whereas p53 mRNA expression was 2.9 fold lower in lung tumors compared with normal lung tissue. Transfection of lung adenocarcinoma and squamous cell carcinoma cells with RBBP6 siRNA decreased RBBP6 mRNA expression, whereas transfection with p53 siRNA increased RBBP6 mRNA expression. Treatment with RBBP6 siRNA increased the ratio of Bax/Bcl2 mRNA, suggesting that RBBP6 may have an anti-apoptotic function in lung cancer cells. This is the first report that RBBP6 mRNA and "its protein products" are expressed in subtypes of human lung cancer. RBBP6 may be involved in the degradation of p53, thereby enhancing cell proliferation and inhibiting apoptosis in lung cancer. PMID- 21676487 TI - Generation of antitumor response by IL-2-transduced JAWS II dendritic cells. AB - Antigen-loaded dendritic cells (DCs) are a promising tool for inducing a tumor specific immune response. It seems probable that co-administration of those cells together with cytokine-transduced DCs can further increase effectiveness of the antitumor vaccine. The local production of IL-2 by genetically modified DCs may result in alteration of the unfavorable tumor environment causing immune response dysfunction. In the presented study murine DCs of an established JAWS II cell line were transduced with a retroviral vector carrying murine IL-2 gene (JAWS II/IL-2). JAWS II/IL-2 cells demonstrated slightly decreased tumor antigen (TAg) uptake capacities. However, this modification resulted in enhanced ability of the cells to migrate in vivo. The multiple injection of vaccines containing JAWS II/IL-2 cells caused MC38 tumor growth delay and prolonged mice survival. The immunological response was manifested as cytotoxic natural killer (NK) and T cell activation and tumor tissue infiltration by CD8(+) and CD4(+) cells, accompanied by increased IFN-gamma production by spleen cells. These observations suggest that repeated peritumoral administration of IL-2-producing dendritic cells can inhibit tumor growth by intensification of CD8(+) and CD4(+) cells' influx into tumor tissue and further activation of the systemic antitumor response. It can be concluded that IL-2 transduced dendritic cells may be used as a potent adjuvant in antitumor immunotherapy. PMID- 21676488 TI - Influence of over-expression of cytosolic aspartate aminotransferase on amino acid metabolism and defence responses against Botrytis cinerea infection in Arabidopsis thaliana. AB - Arabidopsis possesses several genes encoding aspartate aminotransferase, which catalyzes the bidirectional conversion of aspartate into glutamate. These amino acids together with asparagine and glutamine play an important role in N storage and distribution. In addition, they act as precursors for other amino acids. The gene encoding cytosolic aspartate aminotransferase, Asp2, was found to be induced upon infection with the necrotrophic pathogen Botrytis cinerea in Arabidopsis. Asp2 over-expression lines and a T-DNA insertion mutant were used to study the role of aspartate aminotransferase in Arabidopsis defence responses. Over expression of Asp2 led to changes in aspartate content and aspartate-derived amino acids. The Asp2 knockout mutant was also slightly affected in its amino acid composition. Under standard growth conditions, the Asp2 transgenic lines did not show morphological changes in comparison with the wild-type. However, transgenic lines with the highest Asp2 expression displayed more spreading lesions when infected with B. cinerea. We discuss how this gene involved in amino acid metabolism might interact with plant defence responses. PMID- 21676489 TI - Elevated CO2 increases water use efficiency by sustaining photosynthesis of water limited maize and sorghum. AB - Maize and grain sorghum seeds were sown in pots and grown for 39 days in sunlit controlled-environment chambers at 360 (ambient) and 720 (double-ambient, elevated)MUmol mol(-1) carbon dioxide concentrations [CO(2)]. Canopy net photosynthesis (PS) and evapotranspiration (TR) was measured throughout and summarized daily from 08:00 to 17:00h Eastern Standard Time. Irrigation was withheld from matched pairs of treatments starting on 26 days after sowing (DAS). By 35 DAS, cumulative PS of drought-stress maize, compared to well-watered plants, was 41% lower under ambient [CO(2)] but only 13% lower under elevated [CO(2)]. In contrast, by 35 DAS, cumulative PS of drought-stress grain sorghum, compared to well-watered plants, was only 9% lower under ambient [CO(2)] and 7% lower under elevated [CO(2)]. During the 27-35 DAS drought period, water use efficiency (WUE, mol CO(2)Kmol(-1)H(2)O), was 3.99, 3.88, 5.50, and 8.65 for maize and 3.75, 4.43, 5.26, and 9.94 for grain sorghum, for ambient-[CO(2)] well watered, ambient-[CO(2)] stressed, elevated-[CO(2)] well-watered and elevated [CO(2)] stressed plants, respectively. Young plants of maize and sorghum used water more efficiently at elevated [CO(2)] than at ambient [CO(2)], especially under drought. Reductions in biomass by drought for young maize and grain sorghum plants were 42 and 36% at ambient [CO(2)], compared to 18 and 14% at elevated [CO(2)], respectively. Results of our water stress experiment demonstrated that maintenance of relatively high canopy photosynthetic rates in the face of decreased transpiration rates enhanced WUE in plants grown at elevated [CO(2)]. This confirms experimental evidence and conceptual models that suggest that an increase of intercellular [CO(2)] (or a sustained intercellular [CO(2)]) in the face of decreased stomatal conductance results in relative increases of growth of C(4) plants. In short, drought stress in C(4) crop plants can be ameliorated at elevated [CO(2)] as a result of lower stomatal conductance and sustaining intercellular [CO(2)]. Furthermore, less water might be required for C(4) crops in future higher CO(2) atmospheres, assuming weather and climate similar to present conditions. PMID- 21676490 TI - Improving knowledge of plant tissue culture and media formulation by neurofuzzy logic: a practical case of data mining using apricot databases. AB - Plant tissue growth can be regulated and controlled via culture media composition. A number of different laborious and time-consuming approaches have been used to attempt development of optimized media for a wide range of species and applications. However, plant tissue culture is a very complex task, and the identification of the influences of process factors such as mineral nutrients or plant growth regulators on a wide spectrum of growth responses cannot always well comprehended. This study employs a new approach, data mining, to uncover and integrate knowledge hidden in multiple data from plant tissue culture media formulations using apricot micropropagation databases as an example. Neurofuzzy logic technology made it possible to identify relationships among several factors (cultivars, mineral nutrients and plant growth regulators) and growth parameters (shoots number, shoots length and productivity), extracting biologically useful information from each database and combining them to create a model. The IF-THEN rule sets generated by neurofuzzy logic were completely in agreement with previous findings based on statistical analysis, but advantageously generated understandable and reusable knowledge that can be applied in future plant tissue culture media optimization. PMID- 21676491 TI - Temperature stress effects in Quercus suber leaf metabolism. AB - Based on projections that climate changes are will intensify in the near future, it is important to understand how plants respond to climate. Consequently, we have been studying the effect of contrasting temperatures on leaf metabolism of Quercus suber, an important Mediterranean oak. Potted plants were grown under controlled conditions for 53 days at 28 degrees C or 10 degrees C. The accumulation of major soluble metabolites was analyzed by NMR. The relative levels of transcripts of genes encoding key enzymes of the shikimate and phenylpropanoid pathway (CS, PAL, CAD and ChS) were examined by means of quantitative, real-time RT-PCR. At 10 degrees C, in the pre-existing leaves, the concentrations of sucrose, quercitol and catechin were higher, as were PAL and ChS transcripts. At 28 degrees C, however, it was the concentration of quinic acid that was higher, as were the concentrations of CS and CAD transcripts. We conclude that contrasting temperatures greatly influence Q. suber metabolism and that a deeper analysis of the effects of more extreme temperatures is needed to understand the possible effects of temperature changes on Q. suber metabolism and physiology. PMID- 21676492 TI - Phytochelatin synthesis in response to elevated CO2 under cadmium stress in Lolium perenne L. AB - The increasing atmospheric CO(2) and heavy metal contamination in soil are two of the major environmental problems. Knowledge of the Cd stress coping mechanisms is needed to understand the regulation of the plants' metabolism under the increasing atmospheric CO(2) levels. Lolium perenne L. was grown hydroponically under two concentrations of atmospheric CO(2) (360 and 1000MULL(-1)) and six concentrations of cadmium (0-160MUmolL(-1)) to investigate Cd uptake, Cd transportation, and variations in phytochelatin (PC) concentration. Cd concentrations in roots and shoots were decreased, but transport index (Ti) was increased under elevated CO(2) compared to ambient CO(2). Regardless of CO(2) concentrations, Cd and PC concentrations, especially the concentrations of high molecular weight PCs (PC(4), PC(5), PC(6)) were higher with increasing Cd concentration in growth media and longer Cd exposure time. Under the elevated CO(2), more high molecular weight PCs (PC(4), PC(5), PC(6)) in shoots and roots were synthesized compared to ambient CO(2), with higher SH:Cd ratio in roots as well. These results indicate that under elevated CO(2), L. perenne may be better protected against Cd stress with higher biomass, lower Cd concentration and better detoxification by phytochelatins. PMID- 21676494 TI - [Clinical ocular signs characteristic of type 2b multiple endocrine neoplasia]. PMID- 21676493 TI - [Comparison of Lasik with femtosecond laser versus Lasik with mechanical microkeratome: predictability of flap depth, corneal biomechanical effects and optical aberrations]. AB - OBJECTIVES: To compare the predictability of flap thickness, high-order optic aberrations (HOAs), and biomechanical properties of cornea between patients treated by Lasik with mechanical microkeratome versus patients treated by FemtoLasik. SETTING: Department of ophthalmology, Pellegrin University Hospital, Bordeaux, France. PATIENTS AND METHODS: We conducted a retrospective study on 53 myopic patients who underwent Lasik with either mechanical microkeratome (MK group) or femtosecond laser (FS group). Refraction, central corneal thickness, high-order optic aberrations (HOAs), corneal hysteresis (CH), and corneal resistance factor (CRF), were analysed pre- and postoperatively in both groups. The central corneal thickness was measured with OCT-Visante((r)) (Carl-Zeiss, Meditec), biomechanical parameters with ORA((r)) (Reichert), and optical aberrations with the Wave Scan((r)) (AMO) aberrometer. RESULTS: We included 44 eyes of 22 patients in the MK group and 62 eyes of 31 patients in the FS group. Preoperatively, the mean best-corrected visual acuity was 0.95 in both groups. In the MK group, the flap was significantly thicker than expected (162/130 MUm), but in the FS group, there was no significant difference (117/120 MUm). The biomechanical properties of the cornea were lower in both groups independently of the flap cutting technique. The HOAs increased after Lasik and were not influenced by the flap cutting technique. CONCLUSION: Neither mechanical microkeratome, nor femtosecond laser for flap creation, increases HOAs and the biomechanical changes of the cornea, according to ORA((r)), significantly after Lasik. PMID- 21676495 TI - Burden of healthcare-associated infections in a paediatric intensive care unit of a developing country: a single centre experience using active surveillance. AB - Healthcare-associated infections (HAIs) are an important cause of morbidity and mortality among critically ill patients of all age groups. This prospective surveillance study was performed to estimate the burden of HAIs in a paediatric intensive care unit (PICU) of a developing country. During the 12-month study, 187 patients were treated in the PICU for >=48h, of whom 36 patients had 44 episodes of HAIs. The crude infection rate and incidence density (ID) of HAI were 19.3/100 patients and 21/1,000 patient-days, respectively. Of the 44 episodes of HAI, 27 (61%) were healthcare-associated pneumonia (HAP), 12 (27%) were bloodstream infections (HA-BSI) and four (9%) were urinary tract infections. Mean length of stay and mortality were significantly higher in patients who developed an HAI [25 vs 7 days (P<0.0001) and 50% vs 27.8% (P<0.005), respectively]. Acinetobacter spp. were the commonest infecting bacteria in both HAP and HA-BSI. For developing countries, active surveillance is essential to reduce the burden of HAIs in high risk groups. PMID- 21676496 TI - The challenges of implantable cardiac device infection due to Helcococcus kunzii. PMID- 21676497 TI - Hospital identity badges: a possible source of healthcare-acquired infection? PMID- 21676498 TI - Association of ApoE and LRP mRNA levels with dementia and AD neuropathology. AB - Inheritance of the epsilon4 allele of apolipoprotein E (ApoE) is the only confirmed and consistently replicated risk factor for late onset Alzheimer's disease (AD). ApoE is also a key ligand for low-density lipoprotein (LDL) receptor-related protein (LRP), a major neuronal low-density lipoprotein receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by quantitative polymerase chain reaction (qPCR) and Western blotting analyses. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indexes of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared with those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in amyloid beta (Abeta) and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition. PMID- 21676499 TI - Changes in the physiology of CA1 hippocampal pyramidal neurons in preplaque CRND8 mice. AB - Amyloid-beta protein (Abeta) is thought to play a central pathogenic role in Alzheimer's disease. Abeta can impair synaptic transmission, but little is known about the effects of Abeta on intrinsic cellular properties. Here we compared the cellular properties of CA1 hippocampal pyramidal neurons in acute slices from preplaque transgenic (Tg+) CRND8 mice and wild-type (Tg-) littermates. CA1 pyramidal neurons from Tg+ mice had narrower action potentials with faster decays than neurons from Tg- littermates. Action potential-evoked intracellular Ca(2+) transients in the apical dendrite were smaller in Tg+ than in Tg- neurons. Resting calcium concentration was higher in Tg+ than in Tg- neurons. The difference in action potential waveform was eliminated by low concentrations of tetraethylammonium ions and of 4-aminopyridine, implicating a fast delayed rectifier potassium current. Consistent with this suggestion, there was a small increase in immunoreactivity for Kv3.1b in stratum radiatum in Tg+ mice. These changes in intrinsic properties may affect information flow through the hippocampus and contribute to the behavioral deficits observed in mouse models and patients with early-stage Alzheimer's disease. PMID- 21676500 TI - [Complication of the intraosseous route in a newborn infant]. PMID- 21676501 TI - [Brain magnetic resonance imaging in heat stroke]. PMID- 21676502 TI - [Bilateral cerebral infarction secondary to traumatic carotid artery dissection]. PMID- 21676503 TI - [Towards the future in pediatric intensive care]. PMID- 21676504 TI - Sentinel lymph node biopsy in patients with operable breast cancer treated with neoadjuvant chemotherapy. AB - AIM: To evaluate the accuracy of sentinel lymph node biopsy (SLNB) in operable breast cancer patients treated with neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Between January 2008-2011, 88 women, mean age 49.4 years, with infiltrating breast carcinoma, were studied prospectively. Patients were T1-3, N0 1, M0. Prior to surgery, the patients received chemotherapy (epirubicin/cyclophosphamide, docetaxel), and trastuzumab in Her2/neu-positive patients. Axillary status was established by physical examination, ultrasound guided core needle biopsy of any suspicious lymph node. The day before surgery, 74-111 MBq of (99m)Tc-albumin nanocolloid was injected periareolarly. All patients underwent breast surgery, with SLNB, followed by complete axillary lymph node dissection (ALND). Sentinel lymph node (SLN) were examined by frozen sections, hematoxylin-eosin staining and immunohistochemical analysis or One Step Nucleic Acid Amplification (OSNA). RESULTS: Mean tumor size: 3.5 cm. Histologic type: 69 invasive ductal, 16 invasive lobular and 3 others. Thirty seven patients had clinical/ultrasound node-positive at presentation. Clinical response of primary tumor to NAC: complete in 38, partial in 45, and stable disease in 5 patients. A pathological complete response was achieved in 25. All patients were clinically node-negative after NAC. SLN identification rate was 92.0%. Six of 7 patients in whom SLN was not found had clinical/ultrasound positive axilla before NAC. SLN accurately determined the axillary status in 96.5%. False negative rate was 8.3%. In 69.4% of patients, SLN was the only positive node. The mean number of SLN removed was 1.7 and nodes resected from the ALND were 13.2. CONCLUSION: SLN biopsy after NAC can predict the axillary status with a high accuracy in patients with breast cancer, avoiding unnecessary ALND. PMID- 21676505 TI - Isomalyngamide A, A-1 and their analogs suppress cancer cell migration in vitro. AB - Isomalyngamide A (1) and A-1 (2) were isolated from the Taiwanese Lyngbya majuscule and the latter structure was elucidated by a combination of NMR spectroscopic analysis and HRESIMS measurement. We report the isolation of isomalyngamide A (1), discovery of isomalyngamide A-1 (2) and their synthetic analogs (3-9), which are further demonstrated to have therapeutic potential against tumor cell migration at the level of nanomolar to micromolar ranges, perhaps, by inactivating the expression of p-FAK, FAK, p-Akt and Akt through beta1 integrin-mediated antimetastatic pathway. PMID- 21676506 TI - Synthesis and anticancer activity of chalcone-pyrrolobenzodiazepine conjugates linked via 1,2,3-triazole ring side-armed with alkane spacers. AB - Aiming to develop multitarget drugs for the anticancer treatment, a new class of chalcone-pyrrolo[2,1-c] [1,4]benzodiazepine (PBD) conjugates linked through a 1,2,3-triazole moiety containing alkane spacers has been designed and synthesized. Combining these two core pharmacophore structures with modifications at A-C8/C-C2-position of PBD ring system yielded analogs with improved efficacy and have shown promising in vitro anticancer activity ranging from <0.1-2.92 MUM. These PBD-conjugates caused G1 cell cycle arrest with effect on G1 cell cycle regulatory proteins such as Cyclin D1 and Cdk4. These conjugates also exhibited inhibitory effect on NF-kB, Bcl-XL proteins that play a vital role in breast cancer cell proliferation. These findings suggest that one of the compound 4d among this series is most effective and has potential for detailed investigations. PMID- 21676507 TI - Ban happy sheets!--Understanding and using evaluation. AB - Evaluating learning in the complex environments of health and education can be fraught with difficulties. Teaching sessions are customarily 'qualitatively' evaluated by participants filling in simple forms which indicate how they found a course--colloquially called 'happy sheets'. These forms place an emphasis on whether participants enjoyed their training rather than benefitted from it; and respondent's comments can focus more on the quality of the catering and whether they liked the facilitator rather than formally measuring educational effectiveness or what behaviours, skills or attitudes will be different as a result of the input. Part of an educator's role is to present a rationale for the value of their work, and to continuously review and improve it. An understanding of evaluation itself and an awareness of the politics and pressures that can be associated with the act of evaluating are vital to support the measurement of quality and the improvement of teaching. This article calls for an end to superficial measurements and for Educationalists to make evaluation a meaningful and integral part of their educational output. It also raises the importance of involving participants in the process of evaluation and making them aware of its potential worth and provides some practical suggestions for nurse educators. PMID- 21676508 TI - Case of tuberculosis of the temporomandibular joint. AB - Tuberculosis (TB) of the temporomandibular joint (TMJ) is rare and misdiagnosis is common. We describe an unusual case of the disease in a 27-year-old Zimbabwean woman. PMID- 21676509 TI - Will PM control undermine China's efforts to reduce soil acidification? AB - China's strategies to control acidifying pollutants and particulate matter (PM) may be in conflict for soil acidification abatement. Acidifying pollutant emissions are estimated for 2005 and 2020 with anticipated control policies. PM emissions including base cations (BCs) are evaluated with two scenarios, a base case applying existing policy to 2020, and a control case including anticipated tightened measures. Depositions of sulfur (S), nitrogen (N) and BCs are simulated and their acidification risks are evaluated with critical load (CL). In 2005, the area exceeding CL covered 15.6% of mainland China, with total exceedance of 2.2 Mt S. These values decrease in the base scenario 2020, implying partial recovery from acidification. Under more realistic PM control, the respective estimates are 17.9% and 2.4 Mt S, indicating increased acidification risks due to abatement of acid-neutralizing BCs. China's anthropogenic PM abatement will have potentially stronger chemical implications for acidification than developed countries. PMID- 21676510 TI - Violence against women is strongly associated with suicide attempts: evidence from the WHO multi-country study on women's health and domestic violence against women. AB - Suicidal behaviours are one of the most important contributors to the global burden of disease among women, but little is known about prevalence and modifiable risk factors in low and middle income countries. We use data from the WHO multi-country study on women's health and domestic violence against women to examine the prevalence of suicidal thoughts and attempts, and relationships between suicide attempts and mental health status, child sexual abuse, partner violence and other variables. Population representative cross-sectional household surveys were conducted from 2000-2003 in 13 provincial (more rural) and city (urban) sites in Brazil, Ethiopia, Japan, Namibia, Peru, Samoa, Serbia, Thailand and Tanzania. 20967 women aged 15-49 years participated. Prevalence of lifetime suicide attempts, lifetime suicidal thoughts, and suicidal thoughts in the past four weeks were calculated, and multivariate logistic regression models were fit to examine factors associated with suicide attempts in each site. Prevalence of lifetime suicide attempts ranged from 0.8% (Tanzania) to 12.0% (Peru city); lifetime thoughts of suicide from 7.2% (Tanzania province) to 29.0% (Peru province), and thoughts in the past four weeks from 1.9% (Serbia) to 13.6% (Peru province). 25-50% of women with suicidal thoughts in the past four weeks had also visited a health worker in that time. The most consistent risk factors for suicide attempts after adjusting for probable common mental health disorders were: intimate partner violence, non-partner physical violence, ever being divorced, separated or widowed, childhood sexual abuse and having a mother who had experienced intimate partner violence. Mental health policies and services must recognise the consistent relationship between violence and suicidality in women in low and middle income countries. Training health sector workers to recognize and respond to the consequences of violence may substantially reduce the health burden associated with suicidal behaviour. PMID- 21676511 TI - Long-term follow-up of mandibular condylar fractures in children. AB - PURPOSE: The aim of this prospective study was to evaluate the long-term clinical and radiographic outcomes of nonsurgically treated mandibular condylar fractures in children. MATERIALS AND METHODS: This study includes 42 children (23 girls and 19 boys) with 54 mandibular condylar fractures. All patients were younger than 18 years at the time of injury and were followed for at least 2 years (mean follow up 4 years). Treatment was either observation or intermaxillary fixation (rigid and/or guiding elastics). Clinical outcome was categorized as favorable or unfavorable. Condylar remodeling was defined as complete, moderate, or poor on the basis of radiographic findings. RESULTS: Thirty-one patients (74%) presented with favorable and 11 (26%) with unfavorable clinical long-term outcome. Unilateral fractures showed a statistically significant increase of unfavorable clinical outcomes compared with bilateral fractures (P = .018). The radiologic examinations showed complete remodeling in 47 (87%), moderate remodeling in 5 (9%), and poor remodeling in 2 (4%) of the condylar fractures. One patient developed condylar overgrowth. No statistically significant relationship between clinical and radiologic outcome was found. Thirty-five patients (83%) had no subjective symptoms, and 41 (98%) described normal chewing function at the last follow-up examination. CONCLUSIONS: Nonsurgical treatment of mandibular condylar fractures leads to acceptable remodeling of the condylar process, good clinical long-term outcome, and minimal subjective symptoms in most children. Unilateral fractures significantly increase the risk for unfavorable clinical outcome. PMID- 21676512 TI - Do perioperative antibiotics decrease implant failure? AB - PURPOSE: To execute an evidence-based review answering the following question: "Among patients receiving dental implants, do those who receive perioperative antibiotic therapy, compared with those who do not, have a decreased likelihood of implant failure?" MATERIALS AND METHODS: We performed a literature review. The primary predictor variable was an antibiotic regimen, which was grouped into 3 categories: a single preoperative dose, a single preoperative dose and multiday postoperative therapy, and no antibiotic therapy. The primary and secondary outcome variables were implant failure and postoperative infection, respectively. RESULTS: Eight studies meeting the inclusion criteria were reviewed. Two studies assessed the effect of a single preoperative antibiotic dose and reported a reduction in implant failure by 1.3% to 2% compared with no antibiotics use. Two studies compared the effect of pre- and postoperative antibiotics and no antibiotic use and found a 4.2% decrease to 1.1% increase in the failure rates when antibiotics were used. Four studies considered the effect of different antibiotic regimens. Only 2 studies found a statistically significant reduction in implant failure (2.5% to 5.4%) when a single preoperative antibiotic dose was used in conjunction with multiday treatment, compared with postoperative multiday treatment only. Four studies analyzed the rate of postoperative infection, which was 0.6% to 3% when no antibiotics were used, 0.6% when preoperative antibiotics alone were used, and 0.8% to 1% when preoperative and postoperative antibiotics were given. CONCLUSION: A single dose of preoperative antibiotic therapy may slightly decrease the failure rate of dental implants. However, the current data do not support the routine use of postoperative antibiotics, which can be tailored by the clinician to the patient's specific needs. PMID- 21676513 TI - Postoperative complications in smoking patients treated with implants: a retrospective study. AB - PURPOSE: To identify the risk of complications (eg, implant loss, infection, peri implantitis, and mucositis) in a group of patients treated with osseointegrated implants and to assess the effect of smoking on this risk. MATERIALS AND METHODS: A retrospective cohort study of patients treated in the Unit of Implantology, University of Barcelona Faculty of Dentistry was performed. All patients had already undergone prosthetic treatment, and the minimal follow-up time after implant surgery was 6 months. RESULTS: A total of 295 patients fulfilled the inclusion criteria; 56.9% were women and 43.1% were men. They received a total of 1,033 implants. There were 209 complications (32 cases of implant loss, 2 cases of infection, 70 cases of peri-implantitis, and 105 cases of mucositis). The smoking habit was associated with an increased risk of complications (P = .008). CONCLUSION: Smokers had an increased risk of complications, including infection, implant loss, mucositis, and peri-implantitis, compared with nonsmoking patients. PMID- 21676514 TI - Automated continuous mandibular distraction osteogenesis: review of the literature. AB - PURPOSE: Current devices for mandibular distraction osteogenesis (DO) are complex and require significant patient or family skill during active distraction. Successful development of an automated, continuous distraction device would eliminate the need for patient participation in this process. The purpose of this study was to comprehensively review devices currently in development for continuous DO and to identify and evaluate the achieved successes and remaining problems. MATERIALS AND METHODS: A PubMed search of the English language literature in October 2008 using the keywords automatic or automated or continuous or hydraulic or motor or magnetic or spring and distraction osteogenesis was performed. The search included all technical notes, animal studies, and human studies describing the use of any automated continuous distraction device for the mandible. Excluded were studies using distraction devices employing hydraulics, motors, or springs that did not distract automatically and continuously and devices used for bones other than the mandible. RESULTS: The search returned 97 matches. Of these, 12 articles were selected as relevant to this review based on the inclusion and exclusion criteria detailed above. Eight distinct devices for automated, continuous DO were described in these reports and evaluated in this review. These included motor driven, spring-mediated, and hydraulically powered distractors. CONCLUSIONS: The abundance of research currently underway to develop a continuous distractor highlights the clinical demand for, and usefulness, of such a device. Despite many advances and promising results, significant problems remain to be overcome before any of these devices gain widespread clinical acceptance. PMID- 21676516 TI - Multicenter analysis of survival and prognostic factors in pathologic stage I non small-cell lung cancer according to the new 2009 TNM classification. AB - INTRODUCTION: The new 2009 TNM classification introduced important modifications in lung cancer staging. The aim of this study is to validate our series of patients with pathologic stage I non-small-cell lung cancer according to the 7th edition of the TNM classification of malignant tumors and to the factors related with prognosis. PATIENTS AND METHODS: A multicenter retrospective study was performed. Survival rates were calculated by the Kaplan-Meier method, and for multivariate analyses, Cox proportional hazards regression model was used. The following variables were analyzed: age, sex, pathologic stage, T category, histology, type of resection and tumor size. RESULTS: A total of 402 patients were included. Mean follow-up was 70.18 months. Overall 5-year survival was 68%. Males and patients over 70 had lower survival. Prognosis worsened with increasing pathologic stage, T category and tumor size. We found no statistically significant differences in prognosis for histology or type of resection. Multivariate analysis showed age, sex and pathologic stage to be independent prognostic factors. CONCLUSIONS: Survival results and the analysis of prognostic factors in our series are similar to those published in the new 2009 TNM classification. The most important prognostic factor is pathologic stage. Other adverse prognostic factors include male sex and age over 70. PMID- 21676515 TI - Fixation of atrophic edentulous mandible fractures by bone plating at the inferior border. AB - PURPOSE: No consensus has been reached regarding the best treatment for repair of fractures of the severely atrophic mandible (<10 mm vertical height). The most complete Cochrane review of the published data could not substantiate a single best practice recommendation for treating these fractures. The present study reports the results of such treatment by placing miniplates at the inferior border of the mandible of 23 fractures of the mandibular body in 16 patients. MATERIALS AND METHODS: This was a consecutive case series during a 30-year period performed by a single surgeon at several practice locations using the technique of extraoral plating at the inferior border. All patients were prospectively monitored clinically and radiographically for achievement of bony union and for complications of sensory disturbances of the lower lip, delayed healing, and hardware removal. The mean observation time was 23.1 months (range 1 to 60), with only 2 cases observed for less than 6 months. RESULTS: All the patients achieved clinical union of their fractures. Two cases of fibrous union did not reach ossification until 5 months after surgery. The hardware removal rate was 13.6%, and the infection/prolonged inflammation rate was 13.6%. There was 1 case of malunion. Those patients who had dentures were able to return to denture wearing postoperatively. CONCLUSIONS: Miniplate fixation of fractures of the severely atrophic mandible at the inferior border is safe and effective. PMID- 21676517 TI - Hypersensitivity pneumonitis related to medium-density fiberboard. AB - Pneumonitis due to hypersensitivity to wood fiber is mainly associated with the fungus that colonizes it. We present the case of a male affected with hypersensitivity pneumonitis in which the agent implicated was medium-density fiberboard, an engineered product whose main component is pine wood fiber. The causal agent was identified by means of a specific bronchial provocation test. PMID- 21676518 TI - A study of the effect of proinflammatory cytokines on the epithelial cells of smokers, with or without COPD. AB - INTRODUCTION: Cigarette smoke is the main cause of inflammation in COPD. The mechanisms that differentiate smokers who develop COPD are diverse. In this study, we analyzed the presence of cytokines in the respiratory secretions of smokers with or without COPD and the secretory properties of the differentiated bronchial epithelium obtained from the individuals themselves after exposure to tobacco smoke. MATERIAL AND METHODS: Twenty-seven smokers were studied, 12 of whom had COPD that had not been previously treated with steroids. In 11, samples were obtained by means of induced sputum, and the remaining samples were collected from bronchial aspiration after bronchoscopy. Concentrations of IL-8, IL-13 and TNFalpha in the supernatant were determined. The results obtained were compared between individuals with and without COPD, and we studied their relationship with the severity of COPD as expressed by the degree of obstruction, dyspnea, presence of hypersecretion and intensity of smoking. Bronchial epithelial cell cultures were obtained by air-liquid interface in 4 smokers. The samples were exposed to increasing concentrations of cigarette smoke (5-20%) and the epithelial mRNA expressions of MUC5AC, IL8 and TNFalpha were determined. RESULTS: COPD patients had significantly higher values of IL-8 than healthy smokers (41 [22] vs. 21 [12] pM). The values of IL-8 correlated significantly with the severity of the obstruction (r=0.6; p<0.05), dyspnea (r=0.45; p<0.05) and the presence of hypersecretion. There was no relationship between cytokines and the intensity or duration of the tobacco habit. Cigarette smoke produced a dose-dependent increase in the expression of RNAm for Muc5AC, IL8 and TNFalpha. CONCLUSIONS: There are differences in cytokine production (fundamentally IL8) between smokers and smokers with COPD which could be explained by the direct action of cigarette smoke on epithelial cells. PMID- 21676519 TI - [Skeletal muscle metastasis as initial presentation of non-small-cell lung carcinoma]. PMID- 21676521 TI - [Recurrent ventricular fibrillation and ST segment elevation in the right precordial leads due to acute occlusion of the conus branch]. PMID- 21676522 TI - [Transcatheter aortic valve implantation in patients with a mechanical mitral valve]. AB - Many patients with severe aortic stenosis never undergo surgical treatment for various reasons. Apart from the standard risks, some patients face an additional problem: their carrying of a mechanical mitral valve. In these patients, transcatheter aortic valve implantation is a therapeutic option. The literature contains only few reports of this procedure being performed (usually transapically) in such patients. This paper reports the cases of 3 patients with severe aortic stenosis, all carrying a mechanical mitral valve and at high surgical risk, all of whom were implanted by transcatheter aortic valve implantation with an Edwards aortic valve prosthesis. All procedures were successful with no complications encountered. PMID- 21676523 TI - Inequalities for which we have no explanation, a reproducible phenomenon in different local health districts. PMID- 21676524 TI - Is Airtraq(r) optical laryngoscope a high-efficiency device for emergent tracheal intubation during infant chest compression? PMID- 21676525 TI - Airway compromise caused by the spontaneous thyroid hemorrhage. PMID- 21676526 TI - Is food anaphylaxis a cause of antiphospholipid syndrome and thrombosis or a coincidence? PMID- 21676527 TI - Heterogeneity in patients and methods. A problem for hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in ovarian carcinoma. PMID- 21676528 TI - Recurrent ischiorectal abscess secondary to transobturator tape erosion: an unusual chronic complication. PMID- 21676529 TI - The relation between pregnancy and stress in rats: considering corticosterone level, hippocampal caspase-3 and MAPK activation. AB - OBJECTIVES: There are some evidences indicating that stress can affect hippocampal survival and function. During pregnancy mother is exposed to more stress and anxiety; also adrenal gland response to ACTH and glucocorticoid secretion is increased. Hence this study was done to assess the effect of restraint stress on corticosterone level, hippocampal caspase-3 and MAPK activation during pregnancy. STUDY DESIGN: The restraint stress was applied in day 14 or days 14-20 (single and repeated stress) of rats' pregnancy. The hippocampi were isolated after last stress episode and western blot analysis was done to assess caspase-3 and MAPK activation. Data were analyzed by one-way ANOVA followed by Student-Newman-Keuls for multiple comparison. RESULTS: Our study showed that single and repeated stress both increase corticosterone level compared to non-stressed pregnant rats, but do not induce hippocampal apoptosis. Single stress increases transient JNK activation but not P38 and ERK. Repeated stress activated none of the MAPKs. CONCLUSION: It seems that pregnancy protects mother's hippocampus against stress-induced damages. PMID- 21676530 TI - Thermodynamic properties and characterization of proteoliposomes rich in microdomains carrying alkaline phosphatase. AB - Tissue-nonspecific alkaline phosphatase (TNAP) is associated to the plasma membrane via a GPI-anchor and plays a key role in the biomineralization process. In plasma membranes, most GPI-anchored proteins are associated with "lipid rafts", ordered microdomains enriched in sphingolipids, glycosphingolipids and cholesterol. In order to better understand the role of lipids present in rafts and their interactions with GPI-anchored proteins, the insertion of TNAP into different lipid raft models was studied using dipalmitoylphosphatidylcholine (DPPC), cholesterol (Chol), sphingomyelin (SM) and ganglioside (GM1). Thus, the membrane models studied were binary systems (9:1 molar ratio) containing DPPC:Chol, DPPC:SM and DPPC:GM1, ternary systems (8:1:1 molar ratio) containing DPPC:Chol:SM, DPPC:Chol:GM1 and DPPC:SM:GM1 and finally, a quaternary system (7:1:1:1 molar ratio) containing DPPC:Chol:SM:GM1. Calorimetry analysis of the liposomes and proteoliposomes indicate that lateral phase segregation could be noted only in the presence of cholesterol, with the formation of cholesterol-rich microdomains centered above Tc=41.5 degrees C. The presence of GM1 and SM into DPPC-liposomes influenced mainly DeltaH and Deltat(1/2) values. The gradual increase in the complexity of the systems decreased the activity of the enzyme incorporated. The presence of the enzyme also fluidifies the systems, as seen by the intense reduction in ?H values, but do not alter Tc values significantly. Therefore, the study of different microdomains and its biophysical characterization may contribute to the knowledge of the interactions between the lipids present in MVs and its interactions with TNAP. PMID- 21676531 TI - Sequence and epigenetic determinants in the regulation of the Math6 gene by Neurogenin3. AB - The bHLH factor Neurogenin3 initiates the differentiation program that leads to formation of pancreatic endocrine cells. Math6 is a closely related bHLH factor transiently activated downstream of Neurogenin3 in endocrine progenitors. Here we characterize the Math6 promoter and locate the Neurogenin3 binding site, thus confirming that Math6 is a genuine Neurogenin3 target. We also show that Math6 activation rates are largely controlled by epigenetic mechanisms involving the balance between activating H3K4 and repressive H3K27 methylation marks. High Math6 expression in the embryonic pancreas associates with an H3K4me3-only state, whereas low Math6 expression in differentiated endocrine cells correlates with chromatin dually marked with H3K4me3/H3K27me3, a feature originally associated with developmental genes that are repressed but poised for activation in ES cells. Importantly, we show that Neurogenin3 can trigger the conversion of Math6 from a poorly transcribed bivalent to an active monovalent state in vitro, hence providing a mechanism whereby Neurogenin3 may activate Math6 in endocrine progenitors. Finally, because Neurogenin3-induced changes in histone methylation are observed at other endocrine gene promoters, we propose that this mechanism may contribute to the determination of endocrine cell fate by Neurogenin3 in the pancreas. PMID- 21676532 TI - Papilloedema as a non-invasive marker for raised intra-cranial pressure following decompressive craniectomy for severe head injury. AB - BACKGROUND: Decompressive craniectomy is an extremely useful surgical procedure for decreasing intra cranial pressure following severe head injury. However, there is anecdotal evidence to suggest that some of these patients may continue to have raised intracranial pressure in spite of an apparently adequate Decompressive craniectomy. AIMS AND OBJECTIVES: (1) To assess whether fundoscopic findings accurately reflect changes in ICP in severe head injury. (2) To study the temporal course of fundoscopic findings in patients with severe head injury following decompressive craniectomy and to correlate fundoscopy findings with ventriculomegaly (if any) on serial Computerized tomography in these patients. MATERIALS AND METHODS: In this prospective study from November 2008 to March 2009, 32 patients severe head injury (GCS <=8) admitted at the Department of Neurosurgery, JPN Apex Trauma Center, All India Institute of Medical Sciences, New Delhi who underwent a wide (>80 cubic cm) decompressive craniectomy with a lax duraplasty for severe head injury were subjected to fundoscopic examinations on the 1st, 3rd, 5th, 7th and 14th post operative days along with serial C.T. imaging studies to check for ventriculomegaly. Ventriculomegaly was defined as dilatation of temporal horn >2mm along with ballooning of III ventricle and/or presence of peri-ventricular lucency. Seven severe head injury patients who were conservatively managed with continuous ICP monitoring were also subjected to serial fundoscopic examinations. RESULTS: 32 patients who underwent decompressive craniectomy for severe head injury were evaluated during the study period. The age group of the patients ranged from 12 to 75 years. The mean GCS on admission was 6/15 (range 3/15-8/15). There were 12 cases of acute traumatic subdural hemorrhage and 20 cases of intracerebral contusion (frontal/temporal regions). Fundoscopic examination showed papilloedema in 81% (n=26) on the first post operative day, 66% (n=21) on the third post operative day, 28% (n=9) on the fifth post operative day, 13% (n=4) on the seventh post operative day and 6% (n=2) at 14 days post-operatively. In 4 (13%) patients papilloedema reappeared on fundoscopy after one week of surgery. Of these, only 1 (3%) patient had ventriculomegaly on CT scans. Lumbar drain was placed in 2 of these patients and resulted in prompt resolution of papilloedema. In the 7 patients who were managed conservatively and had ICP monitoring, serial fundoscopic examination were found to accurately reflect the ICP readings in all cases. No papilloedema was seen in any of the patients when ICP was below 20mm of Hg and papilloedema appeared in all cases where the ICP was >=20mm of Hg. CONCLUSION: Fundoscopy is an extremely useful non-invasive tool to assess changes in intracranial pressure in severe head injury. Reappearance of papilloedema in the postoperative period even in the absence of ventriculomegaly indicates raised ICP and should be treated aggressively. PMID- 21676533 TI - A simple technique to prevent and correct graft vessel kinking in the subcutaneous tunnel: technical note. AB - OBJECT: A simple method for preventing and correcting graft kinking for vascular reconstructive surgery through a subcutaneous tunnel is described. PATIENTS AND METHODS: Using a chest tube, 1-0 silk suture and cerebral aneurysmal clips, the problem of postoperative ischemic complications due to kinking can be solved. CONCLUSION: The main advantages of this method are its simplicity and low cost. Using this method does not require any special equipment and the problem of postoperative ischemic complications due to vascular injury, kinking and vasospasms can be addressed. PMID- 21676534 TI - Characteristics of first ever ischemic stroke in the very elderly: profile of vascular risk factors and clinical outcome. AB - PURPOSE: Age is the most significant non-modifiable risk factor for ischemic stroke (IS). With increasing expectancy of life, the majority of IS patients will be elderly subjects. We studied the epidemiological, clinical and rehabilitation features of patients aged >=85 years with first-ever IS. METHODS: Demographic data, prevalence of risk factors, etiology of stroke, severity of neurological deficit, major complications and mortality rates were collected from a hospital based stroke registry and compared between patients at the age of 65-84 and >=85. Clinical assessment was performed by means of the National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS). RESULTS: Among 216 patients aged >=85 years there was significantly higher proportion of a history of atrial fibrillation than in 128 patients at the age of 65-84 years and lower prevalence of hypertension, diabetes mellitus, hyperlipidemia and smoking. Large artery atherosclerosis was more frequently identified in the older patients (49% vs. 32%, p=0.002). Although NIHSS scores on admission were lower in the older patients they were more disabled at discharge. CONCLUSIONS: With respect to the patients aged <85 years very old IS patients showed different vascular risk factors profile, clinical and rehabilitation course. These findings suggest specializing stroke care in the very elderly. PMID- 21676535 TI - Acute reversible neurotoxicity associated with inhalation of ethyl chloride: a case report. PMID- 21676536 TI - Improvement of sleep architecture in the follow up of a patient with bilateral paramedian thalamic stroke. AB - Normal sleep architecture and arousal require an intact thalamus. Thalamic vascular lesions, particularly in the paramedian region may cause arousal disturbances and hypersomnolence. Although hypersomnolence is one of the main characteristics of acute bilateral paramedian thalamic infarcts, there are only scarce reports in literature concerning polysomnographic follow-up of these patients. The few reported cases in literature show that sleep stages do not significantly change from the acute to chronic phase. We present a case report of a patient with a bilateral paramedian thalamic infarct in which a polysomnographic evaluation of sleep was performed four days and five months after stroke. In the acute phase, polysomnography showed an impairment of phase 2 NREM and absence of phase 3 and 4 NREM with absent sleep spindles. After the acute stroke phase, hypersomnolence improved and sleep spindles reappeared as well as phase 3 and 4 of NREM sleep. Our patient clear clinical and polysomnographic improvement makes us suppose that in this case the initial impairment could have been essentially due to a functional transitory impairment of the thalamocortical and corticothalamic connections. This case report is peculiar because it discloses a marked improvement of sleep architecture which to the best of our knowledge has not been clearly described before. PMID- 21676537 TI - Differentially expressed genes associated with cisplatin resistance in human ovarian adenocarcinoma cell line A2780. AB - Ovarian cancer cells are usually initially sensitive to platinum-based chemotherapy, such as cisplatin (CDDP), but typically become resistant over time. Such drug resistance is a serious impediment to successful disease treatment, and the molecular mechanisms responsible for resistance are not fully understood. In search of novel mechanisms that may lead to the development of CDDP chemoresistance, we used subtractive hybridization to identify differentially expressed genes in CDDP resistant CP70 and C200 cells vs. CDDP sensitive A2780 human ovarian adenocarcinoma cells. We analyzed 256 randomly selected clones. Subtraction efficiency was determined by dot blot and DNA sequencing. Confirmation of differentially expressed cDNAs was done by virtual northern blot analysis, and 17 genes that were differentially expressed in CDDP resistant cell lines vs. CDDP sensitive A2780 cells were identified. The expression of 10 of these genes was low or undetectable in sensitive A2780 cells in comparison to resistant cells and an additional seven genes were more highly expressed in resistant CP70 and C200 vs. A2780 cells. Our identified genes are involved in numerous and diverse cellular processes, such as inhibition of apoptosis (ARHGDIB), stress response (HSPCA, TRA1), chromatin condensation (CNAP1, RanBP2), invasiveness of cells (MMP10), alteration of Ca(2+) homeostasis (ASPH, ATP2B1) and others. Further characterization of these genes and gene products should yield important insights into the biology of CDDP resistance in ovarian carcinoma. PMID- 21676538 TI - Down-regulation of GnT-V inhibits nasopharyngeal carcinoma cell CNE-2 malignancy in vitro and in vivo. AB - To investigate the role of N-acetylglucosaminyltransferases V (GnT-V) in the development of human nasopharyngeal carcinoma (NPC) both in vitro and in vivo, the GnT-V stably suppressed cell line CNE-2 GnT-V/2224 was constructed from CNE 2. The studies indicated that down-regulation of GnT-V inhibited the proliferation, migration and invasion abilities of the NPC cell line CNE-2. The radio sensitivity of CNE-2 was enhanced after down-regulation of GnT-V, which may be associated with the decreased expression of bcl-2. PMID- 21676539 TI - Myricetin induces pancreatic cancer cell death via the induction of apoptosis and inhibition of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. AB - Pancreatic cancer is the fourth leading cause of cancer related deaths and is a disease with poor prognosis. It is refractory to standard chemotherapeutic drugs or to novel treatment modalities, making it imperative to find new treatments. In this study, using both primary and metastatic pancreatic cancer cell lines, we have demonstrated that the flavonoid myricetin induced pancreatic cancer cell death in vitro via apoptosis, and caused a decrease in PI3 kinase activity. In vivo, treatment of orthotopic pancreatic tumors with myricetin resulted in tumor regression and decreased metastatic spread. Importantly, myricetin was non-toxic, both in vitro and in vivo, underscoring its use as a therapeutic agent against pancreatic cancer. PMID- 21676540 TI - Modeling of membrane bioreactor treating hypersaline oily wastewater by artificial neural network. AB - A membrane sequencing batch reactor (MSBR) treating hypersaline oily wastewater was modeled by artificial neural network (ANN). The MSBR operated at different total dissolved solids (TDSs) (35,000; 50,000; 100,000; 150,000; 200,000; 250,000mg/L), various organic loading rates (OLRs) (0.281, 0.563, 1.124, 2.248, and 3.372kg COD/(m(3)day)) and cyclic time (12, 24, and 48h). A feed-forward neural network trained by batch back propagation algorithm was employed to model the MSBR. A set of 193 operational data from the wastewater treatment with the MSBR was used to train the network. The training, validating and testing procedures for the effluent COD, total organic carbon (TOC) and oil and grease (O&G) concentrations were successful and a good correlation was observed between the measured and predicted values. The results showed that at OLR of 2.44kg COD/(m(3)day), TDS of 78,000mg/L and reaction time (RT) of 40h, the average removal rate of COD was 98%. In these conditions, the average effluent COD concentration was less than 100mg/L and met the discharge limits. PMID- 21676541 TI - Photoelectrochemical performance of multi-layered BiOx-TiO2/Ti electrodes for degradation of phenol and production of molecular hydrogen in water. AB - Multi-layered BiO(x)-TiO(2) electrodes were used for the oxidation of chemical contaminants coupled with the production of H(2) characterized by a synergistic enhancement. The BiO(x)-TiO(2) electrodes were composed of a mixed-metal oxide array involving an under layer of TaO(x)-IrO(x), a middle layer of BiO(x)-SnO(2), and a top layer of BiO(x)-TiO(2) deposited in a series on both sides of Ti foil. Cyclic voltammograms showed that the BiO(x)-TiO(2) electrodes had an electrocatalytic activity for oxidation of phenol that was enhanced by 70% under illumination with AM 1.5 light. When the BiO(x)-TiO(2) anode was coupled with a stainless steel cathode in a Na(2)SO(4) electrolyte with phenol and irradiated with UV light at an applied DC voltage, the anodic phenol oxidation rate and the cathodic H(2) production rates were enhanced by factors of four and three, respectively, as compared to the sum of each light irradiation and direct DC electrolysis. These synergistic effects depend on the specific electrode composition and decrease on TaO(x)-IrO(x) and BiO(x)-SnO(2) anodes in the absence of a top layer of BiO(x)-TiO(2). These results indicate that the BiO(x)-TiO(2) layer functions as the key photo-electrocatalyst. The heavy doping level of Bi (25 mol%) in TiO(2) increases the electric conductivity of the parent TiO(2). PMID- 21676542 TI - Synthesis of mesoporous BiOBr 3D microspheres and their photodecomposition for toluene. AB - In this article, a facile solvothermal method was introduced to synthesize mesoporous BiOBr microspheres with Bi(NO(3))(3) as Bi source. The synthesized catalysts were characterized by XRD, SEM, TEM, XPS, UV-vis, TG-DTA, and N(2) adsorption-desorption, and their photoactivity was evaluated by gaseous toluene both under UV and UV-vis irradiation with Degussa TiO(2) P(25) as reference. The prepared BiOBr catalysts were of pure tetragonal phase and its band gap energy was calculated to be about 2.64eV. Comparing with P(25), BiOBr showed promoted photocatalytic activity under UV-vis irradiation, during which more than 90% of toluene was eliminated after 5h irradiation. Kinetic analysis further demonstrated the enhanced activity of BiOBr under UV-vis irradiation and the reaction rate constant k of BiOBr was nearly 2 times higher than that of P(25). The superior activity of BiOBr under UV-vis irradiation can be attributed to its hierarchical structure and suitable band gap energy. Moreover, the reacted intermediates under different light source were identified by GC-MS. Fifteen main intermediates were identified and a tentative pathway of toluene degradation by BiOBr was proposed. PMID- 21676543 TI - Preparation of adsorbent for phosphate recovery from aqueous solutions based on condensed tannin gel. AB - We have synthesized an iron-loaded tannin gel as an adsorbent for phosphate recovery in aqueous solutions. The use of the tannin gel prepared from condensed tannin, which is a ubiquitous and inexpensive natural polymer, is not only cost effective and environment-friendly, but interesting because the phosphate adsorbed gel can be expected to use directly as a fertilizer. The amount of iron loaded into the tannin gel oxidized by nitric acid was much larger than that into the non-oxidized tannin gel. This increase in the amount of the loaded iron resulted in the significant increase in the adsorption amount of phosphate onto the gel. Mossbauer spectroscopy indicated that the morphology of iron in the gel is a mono-type complex, which is formed as a result of the reaction between Fe(III) and the oxidized tannin gel with carbonyl groups. The iron-loaded tannin gel showed the adsorption selectivity for phosphate over other anions and the pH independence of phosphate adsorption in the wide range of initial pH 3-12. The phosphate adsorption isotherm for the iron-loaded tannin gel followed the Freundlich equation with constants of K(F)=2.66 and 1/n=0.31, rather than the Langmuir equation. The adsorption amount of phosphate on iron weight basis for the iron-loaded tannin gel is 31.3mg-P/g-Fe, which indicates that iron in the gel was efficiently used for the phosphate adsorption compared with other phosphate adsorbents, such as iron hydroxides. PMID- 21676544 TI - Adsorptive separation and photocatalytic degradation of methylene blue dye on titanate nanotube powders prepared by hydrothermal process using metal Ti particles as a precursor. AB - Titanate nanotube powders (TNTPs) with the twofold removal ability, i.e. adsorptive separation and photocatalytic degradation, are synthesized under hydrothermal conditions using metal Ti particles as a precursor in the concentrated alkaline solution, and their morphology, structure, adsorptive and photocatalytic properties are investigated. Under hydrothermal conditions, the titanate nanotubes (TNTs) with pore diameter of 3-4nm are produced on the surface of metal Ti particles, and stacked together to form three-dimensional (3D) network with porous structure. The TNTPs synthesized in the autoclave at 130 degrees C for 24h exhibits a maximum adsorption capability of about 197mg g(-1) in the neutral methylene blue (MB) solution (40mg L(-1)) within 90min, the adsorption process can be described by pseudo second-order kinetics model. Especially, in comparison with the adsorptive and the photocatalytic processes are performed in turn, about 50min can be saved through synchronously utilizing the double removal ability of TNTPs when the removal ratio of MB approaches 95% in MB solution (40mg L(-1)) at a solid-liquid (S/L) ratio of 1:8 under ultraviolet (UV) light irradiation. These 3D TNTPs with the twofold removal properties and easier separation ability for recycling use show promising prospect for the treatment of dye pollutants from wastewaters in future industrial application. PMID- 21676545 TI - Synthesis of granular activated carbon/zero valent iron composites for simultaneous adsorption/dechlorination of trichloroethylene. AB - The coupling adsorption and degradation of trichloroethylene (TCE) through dechlorination using synthetic granular activated carbon and zerovalent iron (GAC ZVI) composites was studied. The GAC-ZVI composites were prepared from aqueous Fe(2+) solutions by impregnation with and without the use of a PEG dispersant and then heated at 105 degrees C or 700 degrees C under a stream of N(2). Pseudo first-order rate constant data on the removal of TCE demonstrates that the adsorption kinetics of GAC is similar to those of GAC-ZVI composites. However, the usage of GAC-ZVI composites liberated a greater amount of Cl than when ZVI was used alone. The highest degree of reductive dechlorination of TCE was achieved using a GAC-ZVI700P composite (synthesized using PEG under 700 degrees C). A modified Langmuir-Hinshelwood rate law was employed to depict the behavior of Cl liberation. As a result, a zero-order Cl liberation reaction was observed and the desorption limited TCE degradation rate constant decreased as the composite dosage was increased. The GAC-ZVI composites can be employed as a reactive GAC that is not subject to the limitations of using GAC and ZVI separately. PMID- 21676546 TI - Seroprevalence of Neospora caninum in free-range chickens (Gallus domesticus) from the Americas. AB - Neospora caninum and Toxoplasma gondii are biologically and morphologically similar coccidians with canids as definitive hosts for N. caninum and felids for T. gondii. Feral chickens have been used as indicators of soil contamination with T. gondii oocysts because they feed from ground. In the present study we studied seroprevalence of N. caninum in free range chickens from different countries in America as an indicator of soil contamination due to N. caninum oocysts. Antibodies to N. caninum were found in sera of 524 (39.5%) of 1324 chickens using indirect fluorescent antibody test (IFAT, titer 1:25 or higher). Seropositive chickens from different countries were: 18.5% of 97 from Mexico, 7.2% of 97 from USA, 39.5% of 144 from Costa Rica, 71.5% of 102 from Grenada, 44% of 50 from Guatemala, 83.6% of 98 from Nicaragua, 58.1% of 55 from Argentina, 34.3% of 358 from Brazil, 62.3% of 85 from Chile, 11.2% of 62 from Colombia, 38.7% of 80 from Guyana, 18% of 50 from Peru and 21.7% of 46 from Venezuela. The results indicate widespread exposure of chickens to N. caninum. PMID- 21676547 TI - Effects of dietary supplementation with phytonutrients on vaccine-stimulated immunity against infection with Eimeria tenella. AB - Two phytonutrient mixtures, VAC (carvacrol, cinnamaldehyde, and Capsicum oleoresin), and MC (Capsicum oleoresin and turmeric oleoresin), were evaluated for their effects on chicken immune responses following immunization with an Eimeria profilin protein. Chickens were fed with a non-supplemented diet, or with VAC- or MC-supplemented diets, immunized with profilin, and orally challenged with virulent oocysts of Eimeria tenella. Immunity against infection was evaluated by body weight, fecal oocyst shedding, profilin antibody levels, lymphocyte recall responses, cytokine expression, and lymphocyte subpopulations. Following immunization and infection, chickens fed the VAC- or MC-supplemented diets showed increased body weights, greater profilin antibody levels, and/or greater lymphocyte proliferation compared with non-supplemented controls. Prior to Eimeria infection, immunized chickens on the MC-supplemented diet showed reduced IFN-gamma and IL-6 levels, but increased expression of TNFSF15, compared with non-supplemented controls. Post-infection levels of IFN-gamma and IL-6 were increased, while IL-17F transcripts were decreased, with MC-supplementation. For VAC-supplemented diets, decreased IL-17F and TNFSF15 levels were observed only in infected chickens. Finally, immunized chickens fed the MC-supplemented diet exhibited increased MHC class II(+), CD4(+), CD8(+), TCR1+, or TCR2(+) T cells compared with nonsupplemented controls. Animals on the VAC-containing diet only displayed an increase in K1(+) macrophages. In conclusion, dietary supplementation with VAC or MC alters immune parameters following recombinant protein vaccination against avian coccidiosis. PMID- 21676548 TI - Seroprevalence and risk factors associated with neosporosis in sheep and dogs from farms. AB - This study aimed to establish the seroprevalence and risk factors associated with neosporosis in sheep and dogs from rural properties. 1497 blood samples were collected from sheep and 42 from dogs that cohabited with sheep from 16 farms located in the central region of Sao Paulo State, Brazil. For the detection of N. caninum antibodies it was performed the indirect fluorescent antibody test (IFAT >= 25). For the epidemiological study it was applied a questionnaire for the owners or responsible from the sheep and dogs regarding informations related to neosporosis. The seroprevalence obtained out of the 1497 sheep sera tested was 8.0% (CI95%=6.7-9.2%) and out of the 42 dogs 4.8% (CI95%=0-7.2%). Variables statistically related to seropositivity for N. caninum in sheep were: dams well as water supply (P=0.0004; OR=2.15), presence of other domestic canids (P=0.0013; OR=2.38) and presence of reproductive problems (P=0.0031; OR=1.75). PMID- 21676549 TI - Molecularly targeted therapies in unresectable-metastatic gastric cancer: a systematic review. AB - Gastric cancer is the second leading cause of cancer related-death. Most patients present with an advanced stage of disease that has a dismal outcome. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in the treatment of this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, such as angiogenesis inhibitors and agents targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic gastric cancer. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the stomach, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable. PMID- 21676550 TI - Alterations in the neuroendocrinological stress response to acute psychosocial stress in adolescents engaging in nonsuicidal self-injury. AB - OBJECTIVE: To investigate the neuroendocrinological stress response to acute psychosocial stress in a clinical sample of female adolescents engaging in nonsuicidal self-injury (NSSI). METHODS: The Trier Social Stress Test (TSST), a standardized psychosocial stress protocol, was performed in 14 female patients who engaged in NSSI and 14 healthy control subjects. NSSI was assessed by the Functional Assessment of Self-Mutilation (FASM). Salivary cortisol, heart rate, and affective states, assessed by the Positive and Negative Affect Schedule (PANAS), were measured during the TSST. RESULTS: We found an attenuated cortisol response to acute psychosocial stress in female adolescents with NSSI, whereas no group differences were observed in heart rate and emotional response to the TSST. CONCLUSIONS: These findings indicate that the HPA axis is hyporesponsive in adolescents with NSSI. Therefore, reduced secretion of cortisol could play a role in promoting vulnerability of these individuals to acute stress and maladaptive stress responses. PMID- 21676551 TI - Amorphous cellulose gel as a fat substitute in fermented sausages. AB - Fermented sausages were produced with 25%, 50%, 75% or 100% of their pork back fat content replaced by amorphous cellulose gel. The sausage production was monitored with physical, chemical and microbiological analyses. The final products were submitted to a consumer study, and the volatile compounds of the final products were extracted by solid-phase microextraction and analyzed by GC/MS. The reformulated fermented sausages had significant reductions in fat and cholesterol, and the volatile compounds derived from lipid oxidation were also reduced in the final products. These results suggest that the substitution of up to 50% of the pork back fat content by amorphous cellulose gel can be accomplished without a loss of product quality, enabling the production of fermented sausages with the levels of fat and cholesterol decreased by approximately 45% and 15%, respectively. PMID- 21676552 TI - RTOG sarcoma radiation oncologists reach consensus on gross tumor volume and clinical target volume on computed tomographic images for preoperative radiotherapy of primary soft tissue sarcoma of extremity in Radiation Therapy Oncology Group studies. AB - OBJECTIVE: To develop a Radiation Therapy Oncology Group (RTOG) atlas delineating gross tumor volume (GTV) and clinical target volume (CTV) to be used for preoperative radiotherapy of primary extremity soft tissue sarcoma (STS). METHODS AND MATERIALS: A consensus meeting was held during the RTOG meeting in January 2010 to reach agreement about GTV and CTV delineation on computed tomography (CT) images for preoperative radiotherapy of high-grade large extremity STS. Data were presented to address the local extension of STS. Extensive discussion ensued to develop optimal criteria for GTV and CTV delineation on CT images. RESULTS: A consensus was reached on appropriate CT-based GTV and CTV. The GTV is gross tumor defined by T1 contrast-enhanced magnetic resonance images. Fusion of magnetic resonance and images is recommended to delineate the GTV. The CTV for high-grade large STS typically includes the GTV plus 3-cm margins in the longitudinal directions. If this causes the field to extend beyond the compartment, the field can be shortened to include the end of a compartment. The radial margin from the lesion should be 1.5 cm, including any portion of the tumor not confined by an intact fascial barrier, bone, or skin surface. CONCLUSION: The consensus on GTV and CTV for preoperative radiotherapy of high-grade large extremity STS is available as web-based images and in a descriptive format through the RTOG. This is expected to improve target volume consistency and allow for rigorous evaluation of the benefits and risks of such treatment. PMID- 21676553 TI - Esthesioneuroblastoma: is there a need for elective neck treatment? AB - PURPOSE: To assess the risk of cervical lymph node metastases after definitive treatment for esthesioneuroblastoma (ENB) that did not include elective neck therapy. METHODS AND MATERIALS: This was a retrospective analysis of 26 ENB patients treated at the University of Michigan between 1995 and 2007. Tumor stage was Kadish A in 1 patient, B in 19, C in 5, and unknown in 1. Craniofacial or subcranial resection was performed in 24 patients (92%), with negative margins in 22 (92%). Postoperative radiotherapy (RT) to the primary site was given in 12 patients (46%), and 14 patients (54%) had surgery alone. All patients had clinically N0 disease, and no patient underwent elective neck dissection or radiation. Median follow-up was 72 months. RESULTS: Local relapse-free survival was significantly better for patients who received postoperative RT compared with those who had surgery alone: 100% vs. 29% at 5 years, respectively (p = 0.005). Five-year disease-free survival was 87.5% in the RT group vs. 31% in the surgery alone group (p = 0.05). Regional failure was observed in 7 patients (27%), 6 with Kadish Stage B and 1 with Stage C disease. The most common site of nodal failure was Level II, and 3 patients failed in the contralateral neck. Only 3 patients with regional failure were successfully salvaged. CONCLUSION: The high rate of regional failures when the neck is not electively treated justifies elective nodal RT in patients with both Kadish Stages B and C. In addition, our experience confirms the beneficial effect on local control of adjuvant RT to the tumor bed. PMID- 21676554 TI - External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma--a prospective randomized study. AB - PURPOSE: To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity. METHODS AND MATERIALS: Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity. RESULTS: Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone. CONCLUSIONS: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases. PMID- 21676555 TI - Comparison of radiographic stress views for scapholunate dynamic instability in a cadaver model. AB - PURPOSE: Many different stress views for the diagnosis of scapholunate (SL) instability have been described in the literature. The purpose of this study is to compare these stress views and determine which view has the greatest utility for demonstrating SL gap radiographically. METHODS: We performed a literature search for articles describing SL radiographic stress views. We created SL instability in 9 cadaveric wrists by ligamentous sectioning and imaged each specimen using all radiographic views found in the literature. These included the "clenched pencil" view, clenched fist views in varying positions, and traction views. Scapholunate gaps were measured using digital calipers. RESULTS: We found 8 different SL radiographic stress views specifically described in the literature. In order to further characterize the best stress views, we studied additional parameters, including varied ulnar deviation and degree of obliquity. The clenched pencil view resulted in the most consistent views with the widest SL gaps. With clenched fist views, SL gap trended to a peak at 30 degrees of ulnar deviation. CONCLUSIONS: The clenched pencil view was the best stress view to demonstrate dynamic SL instability. It also allows for a contralateral comparison on 1 radiograph. We recommend this view when evaluating for SL pathology. CLINICAL RELEVANCE: This assessment of relative diagnostic utility might assist clinicians in the creation and use of protocols for the diagnosis of dynamic SL instability. PMID- 21676556 TI - [Reflections on the "feasibility of chorionic villus sampling outside referral prenatal diagnosis centers"]. PMID- 21676557 TI - Injection methamphetamine use is associated with an increased risk of attempted suicide: a prospective cohort study. AB - BACKGROUND: Methamphetamine (MA) use is a growing public health concern in many settings around the world. While some physical and mental health effects associated with injection MA use have been well described, little is known about the relationship between injecting MA and suicidal behavior. We sought to determine whether MA injection was associated with an increased risk of attempting suicide among a prospective cohort of injection drug users (IDUs) in Vancouver, Canada. METHODS: Between 2001 and 2008, eligible participants enrolled in the Vancouver Injection Drug Users Study (VIDUS) completed semi-annual questionnaires that elicited information regarding sociodemographics, drug use patterns, and mental health problems including suicidal behavior. We used Cox proportional hazards models with time-dependent covariates to determine whether self-reported MA injection was an independent predictor of attempting suicide at subsequent time points. RESULTS: Of 1873 eligible participants, 149 (8.0%) reported a suicide attempt, resulting in an incidence density of 2.5 per 100 person-years. Participants who attempted suicide were more likely to be younger (median: 35 vs. 40, p<0.01), female (48.3% vs. 35.1%, p<0.01), and of Aboriginal ancestry (43.6% vs. 31.3%, p<0.01). In a Cox proportional hazards model, MA injection was associated with an 80% increase in the risk of attempting suicide (adjusted hazard ratio=1.80, 95% CI: 1.08-2.99, p=0.02). CONCLUSIONS: These findings suggest that IDUs who inject MA should be monitored for suicidal behavior. Improved integration of mental health and suicide prevention interventions within harm reduction and drug treatment programs may be fruitful. PMID- 21676558 TI - Associations among types of impulsivity, substance use problems and neurexin-3 polymorphisms. AB - BACKGROUND: Some of the genetic vulnerability for addiction may be mediated by impulsivity. This study investigated relationships among impulsivity, substance use problems and six neurexin-3 (NRXN3) polymorphisms. Neurexins (NRXNs) are presynaptic transmembrane proteins that play a role in the development and function of synapses. METHODS: Impulsivity was assessed with the Barratt Impulsiveness Scale Version 11 (BIS-11), the Boredom Proneness Scale (BPS) and the TIME paradigm; alcohol problems with the Michigan Alcoholism Screening Test (MAST); drug problems with the Drug Abuse Screening Test (DAST-20); and regular tobacco use with a single question. Participants (n=439 Caucasians, 64.7% female) donated buccal cells for genotyping. Six NRXN3 polymorphisms were genotyped: rs983795, rs11624704, rs917906, rs1004212, rs10146997 and rs8019381. A dual luciferase assay was conducted to determine whether allelic variation at rs917906 regulated gene expression. RESULTS: In general, impulsivity was significantly higher in those who regularly used tobacco and/or had alcohol or drug problems. In men, there were modest associations between rs11624704 and attentional impulsivity (p=0.005) and between rs1004212 and alcohol problems (p=0.009). In women, there were weak associations between rs10146997 and TIME estimation (p=0.03); and between rs1004212 and drug problems (p=0.03). The dual luciferase assay indicated that C and T alleles of rs917906 did not differentially regulate gene expression in vitro. CONCLUSIONS: Associations between impulsivity, substance use problems and polymorphisms in NRXN3 may be gender specific. Impulsivity is associated with substance use problems and may provide a useful intermediate phenotype for addiction. PMID- 21676559 TI - Kinetics of the response of four positive acute phase proteins in pigs experimentally infected with toxigenic Pasteurella multocida. AB - In the present study, acute phase proteins (APP) responses in pigs after infection with toxigenic strain of Pasteurella multocida (Pm) were evaluated. Twelve piglets from a herd free from toxigenic Pm were used. Six of them were infected intranasally with Pm. CRP, Hp, SAA and Pig-MAP concentrations were measured using commercial ELISA tests. CRP and Hp were significantly induced from 2 days post inoculation (dpi). The concentration of Hp in inoculated pigs remained elevated until the end of the study. The concentrations of SAA and Pig MAP increased significantly from 3 dpi, and remained elevated to 5 or 7 dpi, respectively. Strong correlations were observed between concentration of Hp or SAA and changes in the lungs. No correlations were found between levels of APP in serum and changes observed in the turbinates. On the basis of our investigation, we cannot state that evaluation of APP concentrations in serum may provide useful information about severity of atrophic rhinitis. However, the concentration of all investigated APP increased after inoculation. Thus, APP-measurements may reveal ongoing infection. Monitoring of APP concentrations in the pig herds may help to pinpoint infected animals even before clinical signs are present. If found, these "APP-high" animals may be chosen next for pathogen-specific diagnostics. Early diagnosis and therapy may prevent the infection from spreading in the herd. Moreover, monitoring of APP concentrations in serum may be useful for selecting clinically healthy pigs before integration into an uninfected herd. Future studies should focus on the possibility of distinguishing infected and non infected pigs under field conditions. PMID- 21676561 TI - The role of nutritional supplementation on the outcome of superovulation in cattle. AB - Since the 1990s nutritional supplements including protein, fatty acids, vitamins, and minerals have been used to try and improve the superovulatory response of embryo donors in cattle. However, the accumulated information indicates that nutritional supplementation with protein, fatty acids, or minerals does not increase the number of viable embryos from superovulated cattle. Most of the evidence has shown that vitamin supplementation may increase the mean production of transferable embryos, but only in cows, as a detrimental effect on embryo viability has been reported in young heifers. Nevertheless, vitamin supplementation seems to be effective only when compared with control cows displaying a poor mean embryo production (i.e. less than four viable embryos), questioning the economical significance of such approach. Detrimental effects on embryo development have been reported in superovulated cattle supplemented with protein or fatty acids as well. New approaches to investigate the role of nutritional supplementation on superovulatory outcome in cattle are suggested in the present review. Overall, the available evidence indicates that nutritional supplementation strategies tested are not an effective approach to enhance the superovulatory outcome of well-fed cattle donors. PMID- 21676560 TI - Antibiotic resistance in faecal bacteria isolated from horses receiving virginiamycin for the prevention of pasture-associated laminitis. AB - Enterococcus faecium, a major cause of potentially life-threatening hospital acquired human infections, can be resistant to several antimicrobials, such that streptogramin quinupristin-dalfopristin (Q/D) is one of the few antibiotics still effective. Consequently use of the streptogramin virginiamycin as an animal growth promoter was banned in the EU in 1999 as some believed this contributed to the emergence of Q/D resistant E. faecium. Virginiamycin is advocated for preventing equine pasture-associated laminitis, but its effect on equine faecal bacterial Q/D resistance has not been determined. Faecal samples were obtained from horses receiving virginiamycin, horses co-grazing and horses not exposed to virginiamycin. Streptogramin resistant E. faecium were cultured from 70% (21/30) of animals treated with virginiamycin, 75% (18/24) of co-grazing animals and 69% (11/16) of animals not exposed. ermB and vatD genes were detected using real time PCR in 63% and 66% of animals treated with virginiamycin, 75% and 71% of co grazing animals and 63% and 69% of animals not exposed. Antimicrobial resistance genes were present only in samples which had cultured Q/D resistant E. faecium. There was no significant difference between groups with respect to antimicrobial resistance. The gene load of vatD was significantly (p=0.04) greater in unexposed animals compared to those treated with virginiamycin. The use of virginiamycin to prevent pasture-associated laminitis does not appear to be related to an increased Q/D resistance frequency. However, in view of the high frequency of resistance within all groups, the horse is a reservoir of Q/D resistant genes and clones that potentially could be transferred transiently to humans. PMID- 21676562 TI - A synergistic effect of insulin-like growth factor (IGF-I) on equine luteinizing hormone (eLH)-induced testosterone production from cultured Leydig cells of horses. AB - Localization of IGF-I and IGF-IR were observed in Leydig cells of horses using immunohistochemistry (IHC), suggesting IGF-I may play a role in equine Leydig cell steroidogenesis. Previous studies in other species have indicated that IGF-I increases basal and/or LH/hCG-induced testosterone production. The objectives of this study were to (1) test the synergistic effect of IGF-I on eLH-induced testosterone production in cultured equine Leydig cells and (2) determine if this effect is reproductive stage-dependent. Testes were collected from five pubertal (1.1+/-0.1 year; 1-1.5 year) and eight post-pubertal (2.88+/-0.35 years; 2-4 years) stallions during routine castrations at the UC Davis Veterinary Hospital. Leydig cells were isolated using validated enzymatic and mechanical procedures. Leydig cells were treated without (control) or with increasing concentrations of purified pituitary-derived eLH and/or recombinant human IGF-I (rhIGF-I) and incubated under 95% air: 5% CO(2) at 32 degrees C for 24h. After 24h, culture media was collected and frozen at -20 degrees C until analyzed for testosterone by a validated radioimmunoassay (RIA). In pubertal stallions, treatment with both increasing concentrations of rhIGF-I and 5ng/ml of eLH failed to demonstrate a significant difference in testosterone production compared with 5ng/ml of eLH only. However, in post-pubertal stallions, a significant increase in the concentration of testosterone in culture media was observed from Leydig cells treated with various concentrations of rhIGF-I and 1 or 5ng/ml of eLH compared with 1 or 5ng/ml of eLH only. In conclusion, IGF-I has a synergistic effect on eLH-induced testosterone production in cultured equine Leydig cells from post pubertal but not pubertal stallions. PMID- 21676563 TI - Evaluation of ACE, SP17, and FSHB as candidates for stallion fertility in Hanoverian warmblood horses. AB - The research of fertility in humans and other mammals has strongly advanced in the recent years. The examination of molecular mechanisms influencing horse fertility is relatively recent. We chose the angiotensin converting enzyme (ACE), the sperm autoantigenic protein 17 (SP17) and the follicle stimulating hormone (FSHB) as candidates for determining stallion fertility and to analyze associations of intragenic single nucleotide polymorphisms (SNPs), flanking microsatellites and candidate-gene linked haplotypes with the pregnancy rate per oestrus (PRO) in 179 Hanoverian stallions. Fertility traits analyzed were the least square means of PRO for stallions (LSMs) and the paternal and embryonic component of breeding values for PRO (BVs). We detected nine SNPs and two flanking microsatellites in ACE, eight SNPs and two flanking microsatellites in SP17 and four SNPs and one flanking microsatellite in FSHB. Three SP17-associated SNPs and the two flanking microsatellites showed significant association with the embryonic component of BVs and one SP17-associated microsatellite was also significantly associated with the paternal component of BVs. Two ACE-associated SNPs were significantly associated with the embryonic component of BVs. Significantly associated haplotypes were shown for all three candidate genes and the tested fertility parameters. The final regression analysis model indicated that haplotypes of all three candidate genes significantly contributed to the paternal and embryonic fertility components of PRO. This is the first report of associations of ACE, SP17 and FSHB with fertility traits of stallions. PMID- 21676564 TI - Clinical, hematological, and biochemical findings of uterine torsion in buffaloes (Bubalus bubalis). AB - The aim of this study was to investigate uterine torsion in buffaloes, examine factors influencing the outcome of the disease, and to characterize the related alterations in blood constituents. A total of 126 buffaloes with uterine torsion were examined for stage of gestation, duration, degree, site and direction of torsion, as well as the location of the pregnant horn. Methods of correction were documented along with dam and calf survival. Blood samples were obtained from 20 buffaloes with uterine torsion and 10 healthy buffaloes for hematological and biochemical comparisons. Results showed that uterine torsion in buffaloes occurred in multi- (81.7%) and primiparous (18.3%), during late pregnancy (58.4%) and at full term (41.6%), clockwise (96%) and counter- clockwise (4%), at post- (98.4%) and precervical (1.6%), and was of high (52.3%), moderate (31%) and mild (16.7%) degrees. Torsion was predominantly (P=0.01) on same direction of the pregnant horn. Fetal and maternal mortalities occurred in 78.6% and 23.8% of the cases, respectively. The stage of pregnancy, and degree and duration of uterine torsion were major risk factors for fetal mortality (P=0.0001), while the stage of pregnancy and fetal viability were important risk factors for maternal mortality (P<0.05). There were significant (P<0.05) increases in monocytes, albumin, aspartate aminotransferase, creatine phosphokinase, blood urea nitrogen, and phosphorus and decreases in mean corpuscular hemoglobin concentration and globulin in the affected buffaloes. Time of occurrence and duration of torsion affected some of these parameters. Uterine torsion appears to be a serious problem in buffaloes that has certain peculiarities including time of occurrence, site and direction of torsion, and the high mortality rates. Uterine torsion adversely affects liver and kidney functions. Multiparous might be at greater risk of uterine torsion. The stage of pregnancy, as well as degree and duration of uterine torsion are risk factors for fetal and maternal mortalities. PMID- 21676565 TI - Association of obesity with osteoarthritis in elderly Korean women. AB - OBJECTIVE: Osteoarthritis (OA) is one of the most common sources of pain and disability among elderly people. Many genetic, demographic, and personal characteristics are involved in the risk of OA, of which obesity is one of the most important. This study evaluated the association between obesity and the prevalence of OA in elderly Korean women. METHODS: We recruited participants (n=3750) aged 50 years or older using stratified random sampling of Korean census blocks. Demographic and personal characteristics and a medical history of OA were collected from the participants by questionnaire. RESULTS: We found that demographic variables, including age, education level, income, and personal characteristics (such as regular exercise), were important covariates associated with the prevalence of OA. In this study, body mass index (BMI) was an important demographic variable affecting the prevalence of OA. After adjusting for age, BMI was positively associated with the prevalence of OA [odds ratio (OR), obese vs. normal=2.15; 95% confidence interval (CI), 1.82-2.54; p for trend <0.001]. This association persisted after adjusting for other demographic covariates (OR, obese vs. normal=2.09; 95% CI, 1.76-2.47; p for trend <0.001). CONCLUSIONS: The results indicated that obesity and OA prevalence vary across groups with different demographic characteristics, and increased BMI was related to the risk of OA in elderly women. PMID- 21676566 TI - Close monitoring of initial enzyme replacement therapy in a patient with childhood-onset Pompe disease. AB - Pompe disease is classified into infantile and late-onset (childhood and adult) forms based on onset age and degree of organ involvement. While benefits of enzyme replacement therapy (ERT) for the infantile form have been confirmed, efficacy for late-onset forms reportedly varies. We report close monitoring of initial ERT, focusing especially on the first year, in a 12-year-old boy with childhood-onset Pompe disease. At age 10, he started ERT at 20 mg/kg every other week. Respiratory and motor functions were evaluated at each infusion, and by skeletal muscle computed tomography (CT) and cardiac echography every 4 months. He gained the ability to climb stairs without a rail and % vital capacity improved just 1.5 months after starting ERT. Grip power, manual muscle testing (MMT) and the timed and 6-min walking distance tests (6MWT) improved promptly, paralleling improvements in clinical symptoms. However, this steady improvement stopped around 8 months, with deterioration to the initial level by about 24 months. Antibody against recombinant human alpha-glucosidase was very low at 15 months; therefore, the lack of treatment response did not completely correspond to antibody production. On the other hand, cardiac wall thickening worsened after 4 months, then improved to better than baseline after 8 months, and this improvement was well maintained. Among our set parameters, the timed test results corresponded better to his changing clinical course than did grip power, MMT or 6 min walking test results. PMID- 21676567 TI - Effects of oxcarbazepine treatment on serum lipids and carotid intima media thickness in children. AB - The aim of this study is to evaluate the carotid intima media thickness and serum lipids in pediatric patients with epilepsy treated with oxcarbazepine. The study included 21 pediatric epileptic and 22 healthy children. Intima media thickness and fasting lipid profile were assessed. Although the median value of total cholesterol was in normal limits in the oxcarbazepine group, it was significantly higher when compared with the control group. We did not observe any differences regarding triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and carotid intima media thickness. We suggest that oxcarbazepine treatment in children has a minor effect on serum lipids and it does not seem to have an atherogenic effect. PMID- 21676568 TI - US-CT 3D dual imaging by mutual display of the same sections for depicting minor changes in hepatocellular carcinoma. AB - The purpose of this study was to evaluate the usefulness of ultrasound-computed tomography (US-CT) 3D dual imaging for the detection of small extranodular growths of hepatocellular carcinoma (HCC). The clinical and pathological profiles of 10 patients with single nodular type HCC with extranodular growth (extranodular growth) who underwent a hepatectomy were evaluated using two dimensional (2D) ultrasonography (US), three-dimensional (3D) US, 3D computed tomography (CT) and 3D US-CT dual images. Raw 3D data was converted to DICOM (Digital Imaging and Communication in Medicine) data using Echo to CT (Toshiba Medical Systems Corp., Tokyo, Japan), and the 3D DICOM data was directly transferred to the image analysis system (ZioM900, ZIOSOFT Inc., Tokyo, Japan). By inputting the angle number (x, y, z) of the 3D CT volume data into the ZioM900, multiplanar reconstruction (MPR) images of the 3D CT data were displayed in a manner such that they resembled the conventional US images. Eleven extranodular growths were detected pathologically in 10 cases. 2D US was capable of depicting only 2 of the 11 extranodular growths. 3D CT was capable of depicting 4 of the 11 extranodular growths. On the other hand, 3D US was capable of depicting 10 of the 11 extranodular growths, and 3D US-CT dual images, which enable the dual analysis of the CT and US planes, revealed all 11 extranodular growths. In conclusion, US-CT 3D dual imaging may be useful for the detection of small extranodular growths. PMID- 21676569 TI - Analysis of 23S rRNA genes in metagenomes - a case study from the Global Ocean Sampling Expedition. AB - As an evolutionary marker, 23S ribosomal RNA (rRNA) offers more diagnostic sequence stretches and greater sequence variation than 16S rRNA. However, 23S rRNA is still not as widely used. Based on 80 metagenome samples from the Global Ocean Sampling (GOS) Expedition, the usefulness and taxonomic resolution of 23S rRNA were compared to those of 16S rRNA. Since 23S rRNA is approximately twice as large as 16S rRNA, twice as many 23S rRNA gene fragments were retrieved from the GOS reads than 16S rRNA gene fragments, with 23S rRNA gene fragments being generally about 100bp longer. Datasets for 16S and 23S rRNA sequences revealed similar relative abundances for major marine bacterial and archaeal taxa. However, 16S rRNA sequences had a better taxonomic resolution due to their significantly larger reference database. Reevaluation of the specificity of previously published PCR amplification primers and group specific fluorescence in situ hybridization probes on this metagenomic set of non-amplified 23S rRNA sequences revealed that out of 16 primers investigated, only two had more than 90% target group coverage. Evaluations of two probes, BET42a and GAM42a, were in accordance with previous evaluations, with a discrepancy in the target group coverage of the GAM42a probe when evaluated against the GOS metagenomic dataset. PMID- 21676570 TI - Effective separation and analysis of E- and Z-guggulsterones in Commiphora mukul resin, guggulipid and their pharmaceutical product by high performance thin-layer chromatography-densitometric method. AB - A high performance thin-layer chromatographic (HPTLC) method for the simultaneous determination of the hypolipidemic agents, E- and Z-isomers of guggulsterone in Commiphora mukul resin, guggulipid (ethyl acetate extract of resin), and its pharmaceutical formulation, was developed. The developed system was efficient enough to separate both isomers from their conger, 17,20-dihydroguggulsterone. HPTLC glass plates, pre-coated with silica gel 60F-254, were used as a stationary phase. The mobile phase consisted of toluene:acetone (9.3:0.7, v/v) which gave well resolved spots for E- and Z-guggulsterones (R(f): 0.52+/-0.01, and 0.67+/ 0.01, respectively) following double development of chromatoplate with the same mobile phase under unsaturated conditions. The analyte stability towards the developed chromatographic procedure was also investigated by two-dimensional (2D) HPTLC analysis. 17,20-Dihydroguggulsterone (3) was identified by the electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) analysis. PMID- 21676571 TI - Identification and structural elucidation of an unknown impurity in carbamazepine active pharmaceutical ingredient by liquid chromatography-tandem mass spectrometry and semi-preparative chromatographic isolation. AB - Two impurities were detected in the HPLC analysis of crude carbamazepine active pharmaceutical ingredient. One of the impurities of the order of 0.5% was found to be unknown and has not been reported previously. A LC-MS compatible reverse phase isocratic method was developed and tandem mass spectrometry was performed using electrospray ionization source and ion trap mass analyzer. Isolation of unknown impurity was performed by semi-preparative HPLC followed by characterization using nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (FT-IR) and elemental analysis (CHNS) confirmed its structure as tetrabenzo[b,f,b'f']azepino[4',5':4,5]thieno[2,3-d]azepine-3,9-dicarboxamide. A plausible mechanism for the formation of this impurity is proposed. PMID- 21676573 TI - Bacterial growth on ED ultrasound machines. PMID- 21676572 TI - ACCF/AHA/AMA-PCPI 2011 performance measures for adults with coronary artery disease and hypertension: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures and the American Medical Association-Physician Consortium for Performance Improvement. PMID- 21676574 TI - Emergency cricothyrotomy for trismus caused by instantaneous rigor in cardiac arrest patients. AB - Instantaneous rigor as muscle stiffening occurring in the moment of death (or cardiac arrest) can be confused with rigor mortis. If trismus is caused by instantaneous rigor, orotracheal intubation is impossible and a surgical airway should be secured. Here, we report 2 patients who had emergency cricothyrotomy for trismus caused by instantaneous rigor. This case report aims to help physicians understand instantaneous rigor and to emphasize the importance of securing a surgical airway quickly on the occurrence of trismus. PMID- 21676575 TI - The psychophysiology of medical communication. Linking two worlds of research. AB - OBJECTIVE: Medical communication is goal oriented behavior. As such, it can be modeled as a chain of decisions, resulting from cognitive and emotional processes each potentially associated with psychophysiological reactions. Psychophysiological may be helpful to detect small changes in affect or arousal in the course of a consultation that would be difficult to detect by other evaluations of the process, like self-reports. The question is how psychophysiological communication research should be modeled for unraveling in more detail the cognitive, emotional and interpersonal processes which underlie physician and patient behavior. METHODS: In the world of medical communication research the six-function model of medical communication reveals a number of fundamental perceptual, cognitive and emotional processes which may evoke psychophysiological responses. The world of psychophysiological research encompasses domains of perception, mental imagery, anticipation and action which all have close connections with fundamental tasks in communication. CONCLUSION: This paper discusses ten methodological issues in linking continuous psychophysiological data to verbal and nonverbal events in a medical consultation observed with the Verona coding system. PRACTICE IMPLICATIONS: When linking the two worlds of research, the methodological challenges discussed need to be solved to obtain a valid and reliable application of psychophysiological measures in medical communication research. PMID- 21676576 TI - [Improving the level of understanding of English of medical students is possible. Results of a systematic assessment policy]. AB - OBJECTIVES: To describe the level of English of a population of medical students and the improvement after the implementation of systematic assessment that all students achieve a minimal level. POPULATION AND METHODS: For the past 5 years, all medical students in our medical school have been taking the Test of English for International Communication (TOEIC). The baseline population (students entering second year in 2004) had no specific obligation. After 2004, a score above 600 was mandatory for graduation. Teaching was oriented towards training for the TOEIC and the number of hours was more important for low-level students. RESULTS: The mean score has increased from 618 +/- 146 in 2004, to 687 +/- 94, 717 +/- 97, 733 +/- 96 and 731 +/- 104 for the next four years. The proportion of students who do not achieve a score of 550 (B1 level of the European framework) has decreased from 30 to 0%. DISCUSSION: Improving the level of English of French medical students is possible, if this is made a priority. The objective, as set in engineering studies, that all medical students reach a B2 level would require national guidelines. PMID- 21676577 TI - Preoperative fluoroscopic imaging reduces variability of acetabular component positioning. AB - We evaluated the preoperative errors in the pelvic tilt of 249 hips before total hip arthroplasty using fluoroscopic imaging while the patients were in the lateral decubitus position. The mean absolute value errors of the pelvic tilt were 2.94 degrees (SD, 2.92 degrees ), 2.49 degrees (SD, 2.68 degrees ), and 5.92 degrees (SD, 5.20 degrees ) in the coronal, transverse, and sagittal planes, respectively. Such preoperative errors in the pelvic tilt contribute to malpositioning of the acetabular component, as is frequently observed on postoperative radiographs. We reduced the incidence of malpositioning by correcting the errors in the pelvic tilt through repositioning of the operating table using fluoroscopic imaging before surgery. The new technique using fluoroscopic imaging described in this article can be performed within a short time without a navigation system. PMID- 21676578 TI - Postoperative complication rates in the "super-obese" hip and knee arthroplasty population. AB - The effect of obesity on the outcomes of total joint arthroplasties is an ongoing concern. As obesity becomes more endemic, new categories emerge, such as the "super-obese." We conducted a retrospective study to determine the difference in outcomes among the super-obese. When categorized according to body mass index (BMI), the overall rate of complications was higher for patients with BMI of 45 or higher. Super-obese patients had an odds ratio (OR) of 8.44 for developing inhospital complications. Most importantly, each incremental 5-U increase in BMI above 45 was associated with an increased risk of inhospital (OR, 1.69) and outpatient complications (OR, 2.71), and readmission (OR, 2.0), compared with patients with BMI of 45 to 50. Length of stay was increased by 13.8% for each 5-U increase in BMI above 45. There is a significant increased risk for complications in the super-obese population, and this continues to increase with BMI increases above 45. These data are important when counseling super-obese patients and should be accounted for in reporting quality outcome measures in this population. PMID- 21676579 TI - Load dispersion effects of acetabular reinforcement devices used in revision total hip arthroplasty: a simulation study using finite element analysis. AB - Several types of acetabular reinforcement devices are used to prevent the collapse of grafted bone in revision total hip arthroplasty. However, it remains unclear how the stress is reduced by different devices. We used finite element analysis to evaluate 4 types of acetabular reinforcement devices: Kerboull-type device, Burch-Schneider anti-protrusio cage, Mueller ring, and Ganz ring. The control was a socket fixed with bone cement without any reinforcement devices. The stress distribution on the inner surface of each socket was calculated by binarization image processing. For all 4 reinforcement devices, the stress was reduced to less than one-half of that in the control. All the devices were useful for preventing the collapse of bulk bone grafts applied to load-bearing defects. PMID- 21676580 TI - Squeaking in third- and fourth-generation ceramic-on-ceramic total hip arthroplasty: meta-analysis and systematic review. AB - Postoperative squeaking in ceramic-on-ceramic total hip arthroplasty is a recently emerging phenomenon. We performed a meta-analysis of published data to examine patient and procedural risk factors. Twelve studies (6137 patients, total) were analyzed, with 150 patients (2.4%) complaining of squeaking. The only significant patient risk factor was increasing body mass index (P = .03, n = 2957). There was no significance found with patient age, sex, height, weight, or procedural laterality for squeak incidence. For implant type, the presence of a Stryker Accolade femoral stem (beta-titanium; Stryker Orthopedics, Mahwah, NJ) was significantly found to increase squeak (P < .0001, n = 4654). The presence of a raised metallic lip on the acetabular component was not found to be associated with squeak. Acetabular cup position was also not found to have a significant bearing on the incidence of squeaking. PMID- 21676581 TI - Secondary resurfacing of the patella after primary total knee arthroplasty does the anterior knee pain resolve? AB - Although it has been shown that the risk of anterior knee pain is greater in patients with nonresurfaced patellae, it is not exactly clear whether the pain would resolve with secondary resurfacing of the patella. Thirty-nine patients (41 knees) underwent secondary patellar resurfacing between January 2001 and January 2007. The mean age was 66 years. The mean body mass index was 29.2 kg/m(2). The average time from primary total knee arthroplasty to resurfacing procedure was 29 months. The mean follow-up was 54 months. Anterior knee pain was the indication for secondary resurfacing in all patients. Although the clinical and functional knee scores improved significantly for whole cohort, 8 patients (8 knees) were dissatisfied with the outcome of surgery. This study highlights that secondary resurfacing is not an always rewarding procedure and patients need to be consulted appropriately with regard to the outcome. PMID- 21676582 TI - Re: patients prefer a bicruciate-retaining or the medial pivot total knee prosthesis. PMID- 21676583 TI - Relationship between demographic variables and preoperative pain and disability in 5945 total joint arthroplasties at a single institution. AB - Using a prospective institutional registry, 5945 total joint arthroplasty patients were evaluated for the following preoperative variables: sex, age, living situation, pain (visual analog scale), and activity level (lower extremity activity scale). Univariate analysis was performed with chi(2), t test, and Pearson correlation coefficient. Patient age was inversely correlated with visual analog scale and lower extremity activity scale scores (P < .0001). Whereas total hip arthroplasty was performed as equally in women and men, total knee arthroplasty was more frequent in women. Women were more likely to live alone, experience severe pain, and have limited activity (P < .0001). Patients who lived alone were more likely to experience severe pain or limited activity (P < .0001). Women and patients who live alone experience more pain and disability before surgery, potentially placing them at risk for inferior surgical outcomes. PMID- 21676584 TI - Cost-effectiveness analysis of custom total knee cutting blocks. AB - The purposes of this study were to examine the cost-effectiveness of this technology and to determine improvements in patient outcome needed to make custom total knee cutting blocks cost-effective. A Markov decision model was used to evaluate the cost-effectiveness of custom cutting blocks compared with traditional instrumentation in total knee arthroplasty. The analysis demonstrates routine use of custom cutting blocks for total knee arthroplasty will not be cost effective unless it results in a significantly reduced revision rate. The reduction necessary increases with increasing costs for the custom blocks. Further research will be necessary to determine if this can be achieved using custom cutting blocks. Patients, surgeons, payers, and institutions should consider this when determining their support of this technology in the absence of supportive data. PMID- 21676585 TI - Dislocation and infection after revision total hip arthroplasty: comparison between the first and multiply revised total hip arthroplasty. AB - Dislocation and infection are common complications of total hip arthroplasty (THA). This study evaluated the correlation between the number of revision THAs and the incidence of these complications. Data were obtained from 749 revision THAs. Average follow-up was 13.2 +/- 5.9 years. Patients were grouped as first, second, third, and fourth or greater revision THA. Dislocation rates (5.68%, 7.69%, 8.33%, and 27.45%) and infection rates (1.35%, 1.92%, 2.5%, and 7.84%) in the first, second, third, and fourth or greater groups, respectively, correlated directly with the revision number and were highest (P < .001) in the fourth or greater group. Dislocation and infection are exponentially correlated with the number of revision THA. From the fourth revision onward, those risks are multiplied. PMID- 21676586 TI - Anxiety, social skills, friendship quality, and peer victimization: an integrated model. AB - This cross-sectional study investigated whether anxiety and social functioning interact in their prediction of peer victimization. A structural equation model linking anxiety, social skills, and friendship quality to victimization was tested separately for children with anxiety disorders and normal comparison children to explore whether the processes involved in victimization differ for these groups. Participants were 8-14 year old children: 55 (34 boys, 21 girls) diagnosed with an anxiety disorder and 85 (37 boys, 48 girls) normal comparison children. The final models for both groups yielded two independent pathways to victimization: (a) anxiety independently predicted being victimized; and (b) poor social skills predicted lower friendship quality, which in turn, placed a child at risk for victimization. These findings have important implications for the treatment of childhood anxiety disorders and for school-based anti-bullying interventions, but replication with larger samples is indicated. PMID- 21676587 TI - Danger of proposing a new technique in intermaxillary fixation. PMID- 21676588 TI - A case of destructive calcium pyrophosphate dihydrate crystal deposition disease of the temporomandibular joint: a diagnostic challenge. AB - The authors present the case of a 64-year-old woman with a destructive calcium pyrophosphate dihydrate (CPPD) crystal deposition disease of the temporomandibular joint. Progressive pain, swelling and a malocclusion were her chief complaints. A few granular calcified masses surrounding the left condylar head and extending to the infratemporal fossa and middle cranial base were presented in CT images. It occurred alone without other joints being affected. A provisional diagnosis of occupying lesion with invasion was made preoperatively, but histologically, the mass contained numerous deposits of rod-shaped or rhomboid crystals, which were positively birefringent under a polarising microscope, suggesting a CPPD deposition disease. The histopathological diagnosis was further supported by scanning electron microscopy with energy dispersive X ray spectroscopy. The diagnosis, differential diagnosis and treatment of this disease are discussed. PMID- 21676589 TI - Piezosurgery prevents brain tissue damage: an experimental study on a new rat model. AB - Piezosurgery is a promising meticulous system for bone cutting, based on ultrasound microvibrations. It is thought that the impact of piezosurgery on the integrity of soft tissue is generally low, but it has not been examined critically. The authors undertook an experimental study to evaluate the brain tissue response to skull bone removal using piezosurgery compared with a conventional drilling method. In Wistar male rats, a circular bone window was drilled to the parietal bone using piezosurgery on one side and a conventional bone drill on the other side. The behavioural performance of animals was evaluated using the motor BBB test and sensory plantar test. The brains of animals were evaluated by magnetic resonance imaging (MRI) and histology. The results of MRI showed significantly increased depth and width of the brain lesion in the region of conventional drilling compared with the region where piezosurgery was used. Cresylviolet and NF 160 staining confirmed these findings. There was no significant difference in any of the behavioural tests between the two groups. In conclusion, piezosurgery is a safe method for the performance of osteotomy in close relation to soft tissue, including an extremely injury sensitive tissue such as brain. PMID- 21676590 TI - Elevated concentrations of pentraxin 3 are associated with coronary plaque vulnerability. AB - BACKGROUND: Inflammation is a critical contributing factor to the development and progression of atherosclerosis. Pentraxin 3 (PTX3) is produced abundantly in atherosclerotic lesions while C-reactive protein (CRP) is mainly produced in the liver. In this study, we investigated whether plasma levels of PTX3 might be a sensitive marker both for the severity of coronary artery disease and vulnerable plaques. Next, we determined whether assays for inflammatory molecules can be used to monitor the therapeutic effects of telmisartan on stabilization of vulnerable atherosclerotic plaques. METHODS AND RESULTS: We measured PTX3 concentrations in the peripheral and coronary sinus plasma of 40 patients with angina pectoris (AP) and 20 control subjects. Next, in 28 patients with AP, we determined the correlation between levels of inflammatory molecules and the computed tomography (CT) density of plaques as a quantitative index of plaque vulnerability. There was no significant difference in peripheral plasma PTX3 concentrations between patients with AP and control subjects, while coronary sinus plasma PTX3 concentrations were significantly higher in AP patients than control subjects. The concentrations of PTX3 in coronary sinus and peripheral plasma correlated with Gensini scores as an index of severity of coronary atherosclerosis. Interestingly, there was a significantly negative correlation between plasma PTX3 concentrations and CT density (r=-0.67, p<0.01). On the other hand, CT density did not correlate with the peripheral plasma concentrations of monocyte chemoattractant protein-1 (MCP-1) or high-sensitivity CRP (hsCRP). Furthermore, telmisartan treatment for 6 months decreased plasma concentrations of PTX3 but not those of MCP-1 or hsCRP in 12 patients with essential hypertension. Multivariate regression analysis revealed that changes in PTX3 levels were independent of blood pressure changes. CONCLUSIONS: PTX3 is likely more specific than hsCRP as an indicator of coronary plaque vulnerability that could lead to plaque rupture. PMID- 21676592 TI - High prevalence of nonconvulsive and subtle status epilepticus in an ICU of a tertiary care center: a three-year observational cohort study. AB - BACKGROUND: Status epilepticus is one of the most important neurological emergencies and requires immediate therapy and admission to the intensive care unit. We hypothesized that nonconvulsive and subtle status epilepticus are more frequent than reported. METHODS: This observational cohort study describes types, courses, duration, length of hospital stay, outcome and case fatality rate of status epilepticus in adults in relation to demographic and clinical variables. It was conducted in an intensive care unit of a tertiary care center over three years. RESULTS: 111 status epilepticus episodes had a median duration of 48h. Hospitalization length was 18+/-15.3 days. 81% of the status epilepticus episodes were nonconvulsive and subtle. Case fatality rate was 17%. Age over 70 years had independent positive influence on status epilepticus course (OR: 5.135; p=0.0029). Hospital stay increased by 1.13h with each additional hour of status epilepticus (p=0.02). Subtle status epilepticus was a risk factor for refractoriness (p=0.0065). CONCLUSIONS: Prevalence of nonconvulsive and subtle status epilepticus was higher than reported, emphasising the importance of clinical awareness. Older age was associated with more favorable course. This unexpected and contradictory result has to be taken into account during therapeutic interventions in the elderly and should warn from early resignation regarding treatment. PMID- 21676591 TI - A novel implanted device to wirelessly record and analyze continuous intracranial canine EEG. AB - We present results from continuous intracranial electroencephalographic (iEEG) monitoring in 6 dogs with naturally occurring epilepsy, a disorder similar to the human condition in its clinical presentation, epidemiology, electrophysiology and response to therapy. Recordings were obtained using a novel implantable device wirelessly linked to an external, portable real-time processing unit. We demonstrate previously uncharacterized intracranial seizure onset patterns in these animals that are strikingly similar in appearance to human partial onset epilepsy. We propose: (1) canine epilepsy as an appropriate model for testing human antiepileptic devices and new approaches to epilepsy surgery, and (2) this new technology as a versatile platform for evaluating seizures and response to therapy in the natural, ambulatory setting. PMID- 21676593 TI - LEDGF/DFS70 activates the MK2/IL6/STAT3 pathway in HaCaT. PMID- 21676594 TI - A recombinant antimicrobial peptide inhibits the growth of oxacillin-induced L forms of Staphylococcus aureus. PMID- 21676595 TI - Research planning for the future of psychiatric diagnosis. AB - More than 10 years prior to the anticipated 2013 publication of DSM-5, processes were set in motion to assess the research and clinical issues that would best inform future diagnostic classification of mental disorders. These efforts intended to identify the clinical and research needs within various populations, examine the current state of the science to determine the empirical evidence for improving criteria within and across disorders, and stimulate research in areas that could potentially provide evidence for change. In the second phase of the revision process, the American Psychiatric Institute for Research and Education (APIRE) recently completed the 5-year international series of 13 diagnostic conferences convened by APA/APIRE in collaboration with the World Health Organization and the National Institutes of Health (NIH), under a cooperative grant funded by the NIH. From these conferences, the DSM-5 Task Force and Work Groups have developed plans for potential revisions for DSM-5, including the incorporation of dimensional approaches within and across diagnostic groups to clarify heterogeneity, improve diagnostic validity, and enhance clinical case conceptualization. Use of dimensions for measurement-based care has been shown to be feasible in psychiatric and primary care settings and may inform monitoring of disorder threshold, severity, and treatment outcomes. The integration of dimensions with diagnostic categories represents an exciting and potentially transformative approach for DSM-5 to simultaneously address DSM-IV's clinical short-comings and create novel pathways for research in neurobiology, genetics, and psychiatric epidemiology. PMID- 21676596 TI - Toward a functional neuroanatomical signature of bipolar disorder: quantitative evidence from the neuroimaging literature. AB - The present meta-analysis quantitatively reviewed the functional neuroimaging literature on bipolar disorder (BPD) to better characterize its neuroanatomical signature with respect to the influence of mood state, test conditions, and clinical demographics on regional brain activation. Fifty-five functional neuroimaging studies published between 1987 and 2010 met criteria for inclusion, encompassing a total of 774 adult patients with BPD and 810 healthy adult controls. A meta-analysis was conducted comparing the activation states of multiple brain regions in BPD patients and control subjects. Despite heterogeneity across studies, our findings support the view that limbic hyperactivity and frontal hypoactivity are neurobiological correlates of BPD. Our findings also highlight the involvement of many brain regions and circuits, as well as the critical role of mood state and test conditions in the functional impairments of BPD. This review represents the first attempt to quantitatively articulate the magnitude of functional brain abnormality in BPD, and, in so doing, provides a synthesis of evidence in line with current network models of the disorder. Overall, this review offers support for, and seeks to help guide, the continued use of functional neuroimaging as an informative probe into the complex neurobiology of BPD. PMID- 21676597 TI - Cortex and amygdala morphology in psychopathy. AB - Psychopathy is characterized by abnormal emotional processes, but only recent neuroimaging studies have investigated its cerebral correlates. The study aim was to map local differences of cortical and amygdalar morphology. Cortical pattern matching and radial distance mapping techniques were used to analyze the magnetic resonance images of 26 violent male offenders (age: 32+/-8) with psychopathy diagnosed using the Psychopathy Checklist-Revised (PCL-R) and no schizophrenia spectrum disorders, and in matched controls (age: 35+/- sp="0.12"/>11). The cortex displayed up to 20% reduction in the orbitofrontal and midline structures (corrected p<0.001 bilaterally). Up to 30% tissue reduction in the basolateral nucleus, and 10-30% enlargement effects in the central and lateral nuclei indicated abnormal structure of the amygdala (corrected p=0.05 on the right; and symmetrical pattern on the left). Psychopathy features specific morphology of the main cerebral structures involved in cognitive and emotional processing, consistent with clinical and functional data, and with a hypothesis of an alternative evolutionary brain development. PMID- 21676598 TI - Electroactive SWNT/PEGDA hybrid hydrogel coating for bio-electrode interface. AB - Electric interface between neural tissue and electrode plays a significant role in the development of implanted devices for continuous monitoring and functional stimulation of central nervous system in terms of electroactivity, biocompatibility and long-term stability. To engineer an interface that possesses these merits, a polymeric hydrogel based on poly(ethylene glycol) diacrylate (PEGDA) and single-walled carbon nanotubes (SWNTs) were employed to fabricate a hybrid hydrogel via covalent anchoring strategy, i.e., self-assembly of cysteamine (Cys) followed by Michael addition between Cys and PEGDA. XPS characterization proves that the Cys molecules are linked to gold surface via the strong S-Au bond and that the PEGDA macromers are covalently bonded to Cys. FTIR spectra indicate the formation of hybrid hydrogel coating during photopolymerization. Electrochemical measurements using cyclic voltammetry (CV) and impedance spectrum clearly show the enhancement of electric properties to the hydrogel by the SWNTs. The charge transfer of the hybrid hydrogel-based electrode is quasi-reversible and charge transfer resistance decreases to the tenth of that of the pure hydrogel due to electron hopping along the SWNTs. Additionally, this hybrid hydrogel provides a favorable biomimetic microenvironment for cell attachment and growth due to its inherent biocompatibility. Combination of these merits yields hybrid hydrogels that can be good candidates for application to biosensors and biomedical devices. More importantly, the hybrid hydrogel coatings fabricated via the current strategy have good adhesion to the electrode substrate which is highly desired for chronically implantable devices. PMID- 21676599 TI - Oridonin nanosuspension enhances anti-tumor efficacy in SMMC-7721 cells and H22 tumor bearing mice. AB - PURPOSE: The aim of the present study was to evaluate both the in vitro and in vivo antitumor activity of an oridonin nanosuspension (ORI-N) relative to efficacy of bulk oridonin delivery. METHODS: ORI-N with a particle size of 897.2+/-14.2 nm and a zeta potential of -21.8+/-0.8 mV was prepared by the high pressure homogenization (HPH) technique. The in vitro cytotoxicity of ORI-N against SMMC-7721 cells was evaluated by MTT[3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] assay, the effects of ORI-N on cell cycle and cell apoptosis was analyzed by flow cytometry; the in vivo anti-tumor activity was observed in H22 tumor bearing mice. RESULTS: ORI-N effectively inhibited the proliferation of SMMC-7721 cells. Flow cytometric analysis demonstrated that ORI N arrested SMMC-7721 cells in the G2/M cycle, and furthermore, that ORI-N induced a higher apoptotic rate than the bulk ORI solution. In vivo studies ORI-N also showed higher antitumor efficacy as measured by reduced tumor volume and tumor weight, as well as lower toxicity in H22 solid tumor bearing mice compared to free ORI at the same concentration. CONCLUSIONS: These results suggest that the delivery of ORI-N as a nanosuspension is a promising approach for treating tumors. PMID- 21676600 TI - Dead Sea Minerals loaded polymeric nanoparticles. AB - Therapeutic properties of Dead Sea Water (DSW) in the treatment of skin diseases such as atopic dermatitis, psoriasis and photo aging UV damaged skin have been well established. DSW is in fact rich in minerals such as calcium, magnesium, sodium, potassium, zinc and strontium which are known to exploit anti inflammatory effects and to promote skin barrier recovery. In order to develop a Dead Sea Minerals (DSM) based drug delivery system for topical therapy of skin diseases, polymeric nanoparticles based on Poly (maleic anhydride-alt-butyl vinyl ether) 5% grafted with monomethoxy poly(ethyleneglycol) 2000 MW (PEG) and 95% grafted with 2-methoxyethanol (VAM41-PEG) loaded with DSM were prepared by means of a combined miniemulsion/solvent evaporation process. The resulting nanoparticles were characterized in terms of dimension, morphology, biocompatibility, salt content and release. Cytocompatible spherical nanoparticles possessing an average diameter of about 300 nm, a time controlled drug release profile and a high formulation yield were obtained. PMID- 21676601 TI - Adsorption of chlorhexidine on synthetic hydroxyapatite and in vitro biological activity. AB - The kinetic of chlorhexidine digluconate (CHXDG) uptake from aqueous solution by hydroxyapatite (HA) was investigated by ultraviolet (UV) analysis performed in HA powder (UV-solid) after the CHX adsorption. Adsorption isotherm of chlorhexidine (CHX) uptake was modeled by a combination of Languimir and Langmuir-Freundlich mechanisms. Strong molecule-molecule interactions and positive cooperativity predominated in the surface when CHX concentration was above 8.6 MUg(CHX)/mg(HA). UV-solid spectra (shape, intensity and band position) of CHX bound to HA revealed that long-range molecular structures, such as aggregates or micelles, started to be formed at low CHX concentrations (1.52 MUg(CHX)/mg(HA)) and predominated at high concentrations. Grazing-incidence X-ray diffraction (GIXRD) analysis from synchrotron radiation discarded the formation of crystalline structures on HA surface or precipitation of CHX crystalline salts, as suggested in previous works. The effect of the HA/CHX association on HA in vitro bioactivity, cytotoxicity and CHX antimicrobial activity was evaluated. It was shown that CHX did not inhibit the precipitation of a poorly crystalline apatite at HA/CHX surface after soaking in simulating body fluid (SBF). Cell viability studies after exposure to extracts of HA and HA/CHX showed that both biomaterials did not present significant in vitro toxicity. Moreover, HA/CHX inhibited Enterococcus faecalis growth for up to 6 days, revealing that binding to HA did not affect antimicrobial activity of CHX and reduced bacterial adhesion. These results suggested that HA/CHX association could result in a potential adjuvant antimicrobial system for clinical use. PMID- 21676602 TI - [New antituberculosis vaccines]. AB - Today, only one type of vaccine is available to protect against tuberculosis. This vaccine, called Bacille Calmette-Guerin (BCG) was developed approximately 100 years ago and has been administered at least 3 billion times. Initial multicenter studies have indicated an up to 93% efficacy against childhood tuberculosis mortality. Subsequently, many studies on BCG efficacy have been carried out, with highly variable results, ranging from 0 to 90% efficacy. The reasons for this heterogeneity are not well understood. Large clinical studies have shown that booster vaccinations with BCG do not improve the BCG efficacy. Therefore, new vaccines are urgently needed. Today, there are essentially two lines of efforts being pursued in several laboratories. One of them aims at replacing BCG with superior vaccines. This strategy focuses either on improving existing BCG by constructing strains that overproduce certain protective antigens and/or by improving its immunogenicity, or on starting anew by genetically attenuating virulent Mycobacterium tuberculosis. The second line of research aims at adding onto BCG vaccination, such as a heterologous prime-boost strategy. For this strategy BCG is used as a first vaccine, followed by individual antigens as a booster. These antigens can be presented in several different ways, and preference is currently given to the so-called latency antigens. Both approaches have yielded encouraging results in animal models, and some of them have now entered clinical trials. Although still far from human applications, it is hoped that these strategies will ultimately help to reduce the enormous burden that is caused by tuberculosis. PMID- 21676603 TI - Toxicity of hypofractionated accelerated radiotherapy concurrent with chemotherapy for non-small cell carcinoma of the lung. PMID- 21676604 TI - Response letter from Clinical Pathology Interest Group of the Society of Toxicologic Pathology (STP) for manuscript entitled International recommendations for training future toxicologic pathologists participating in regulatory-type, nonclinical toxicity studies by Bolon et al. PMID- 21676605 TI - Vascular damage mediates neuronal and non-neuronal pathology following short and long-term rotenone administration in Sprague-Dawley rats. AB - Even though rotenone has been used extensively in recent years to produce a model of Parkinson disease in rats, its systemic effects either on neurons apart from dopaminergic structures or non-neuronal tissues have not been elucidated well. In our present study, 30 adult Sprague-Dawley rats were divided into three even groups. A short-term rotenone-treated group received 10 mg/kg b.w. rotenone daily for 7 days. The long-term rotenone-treated group received 3 mg/kg b.w. rotenone daily for 30 days. The control group received vehicle only and were kept 5 rats each in parallel to both short- and long-term rotenone treated groups. It was found that short-term rotenone treatment produced marked vascular damages associated with ischemic neuronal degeneration particularly in the thalamus, cerebellum and nucleus dentatus. In long-term rotenone-treated group, vascular changes were less severe and neuronal degeneration was associated with mild microglial proliferation and astrocytosis. Non-neuronal pathology as the result of short-term rotenone exposure consisted of degeneration and necrosis of seminiferous tubular epithelia with formation of spermatide multinucleate giant cells. On the other hand, long-term rotenone treatment did not affect testicles and only caused sinusoidal dilatation in the liver, myocardial degeneration in the heart and interstitial hemorrhages in the kidneys and lungs. In conclusions, damage to blood vasculature by rotenone appeared mediating neuronal and non neuronal pathology in Sprague-Dawley rats. This effect might provide new insights for ethiopathogenesis of neurodegenerative diseases and contributes to the understanding of hemorrhagic stroke. PMID- 21676606 TI - Computerized lung sound analysis as diagnostic aid for the detection of abnormal lung sounds: a systematic review and meta-analysis. AB - RATIONALE: The standardized use of a stethoscope for chest auscultation in clinical research is limited by its inherent inter-listener variability. Electronic auscultation and automated classification of recorded lung sounds may help prevent some of these shortcomings. OBJECTIVE: We sought to perform a systematic review and meta-analysis of studies implementing computerized lung sound analysis (CLSA) to aid in the detection of abnormal lung sounds for specific respiratory disorders. METHODS: We searched for articles on CLSA in MEDLINE, EMBASE, Cochrane Library and ISI Web of Knowledge through July 31, 2010. Following qualitative review, we conducted a meta-analysis to estimate the sensitivity and specificity of CLSA for the detection of abnormal lung sounds. MEASUREMENTS AND MAIN RESULTS: Of 208 articles identified, we selected eight studies for review. Most studies employed either electret microphones or piezoelectric sensors for auscultation, and Fourier Transform and Neural Network algorithms for analysis and automated classification of lung sounds. Overall sensitivity for the detection of wheezes or crackles using CLSA was 80% (95% CI 72-86%) and specificity was 85% (95% CI 78-91%). CONCLUSIONS: While quality data on CLSA are relatively limited, analysis of existing information suggests that CLSA can provide a relatively high specificity for detecting abnormal lung sounds such as crackles and wheezes. Further research and product development could promote the value of CLSA in research studies or its diagnostic utility in clinical settings. PMID- 21676607 TI - Carbon nanotube supported MnO2 catalysts for oxygen reduction reaction and their applications in microbial fuel cells. AB - Three types of manganese dioxide, alpha-MnO(2), beta-MnO(2), gamma-MnO(2) were tested as alternative cathode catalysts for oxygen reduction reaction (ORR) in air-cathode microbial fuel cells (MFCs). Prepared by solution-based methods, the MnO(2) nanomaterials were comprehensively characterized, and their electrocatalytic activities in neutral electrolyte were investigated with the supporting material of carbon nanotubes (CNTs) by cyclic voltammetry (CV). The CV results showed that all MnO(2) species could catalyze ORR in neutral NaCl solution with different catalytic activities. beta-MnO(2) had the highest catalytic activity due to its intrinsic structure and better interaction with CNTs. Three MnO(2) species were further used as cathode catalysts under optimized conditions in air-cathode cubic MFCs, in which mixed culture was inoculated as biocatalysts and domestic wastewater was used as the substrate in the anode chamber. It was also found that beta-MnO(2) based MFC yielded the best performance with a power density of 97.8 mWm(-2) which was 64.1% that of the Pt based MFC, and a lower internal resistance of 165 Omega. Furthermore, the COD removal efficiency of beta-MnO(2) based MFC was estimated as 84.8%, higher than that of the Pt-based MFC. This study demonstrated that using beta-MnO(2) on CNT support instead of Pt could potentially improve the feasibility of scaling up air cathode MFCs for practical applications by lowering the material cost. PMID- 21676608 TI - Validation of a mobile phone-assisted microarray decoding platform for signal enhanced mutation detection. AB - We have established a mobile phone-assisted microarray decoding platform for signal-enhanced mutation detection. A large amount of single-stranded DNA (ssDNA) was obtained by combining symmetric PCR and magnetic isolation, and ssDNA prepared with magnetic bead as label was further allowed to hybridize against the tag-array for decoding purpose. High sensitivity and specificity was achieved with the detection of genomic DNA. When simultaneously genotyping nine common mutations associated with hereditary hearing loss, the detection limit of 1 ng genomic DNA was achieved. Significantly, a mobile phone was also used to record and decode the genotyping results through a custom-designed imaging adaptor and a dedicated mobile phone software. A total of 51 buccal swabs from patients probably with deafness-related mutations were collected and analyzed. The genotyping results were all confirmed by fluorescence-based laser confocal scanning and direct DNA sequencing. This mobile phone-assisted decoding platform provides an effective but economic mutation detection alternative for the future quicker and sensitive detection of virtually any mutation-related diseases in developing and underdeveloped countries. PMID- 21676609 TI - Polymer therapeutics as nanomedicines: new perspectives. AB - A growing number of polymer therapeutics have entered routine clinical use as nano-sized medicines. Early products were developed as anticancer agents, but treatments for a range of diseases and different routes of administration have followed--recently the PEGylated-anti-TNF Fab Cimzia(r) for rheumatoid arthritis and the PEG-aptamer Macugen(r) for age related macular degeneration. New polymer therapeutic concepts continue to emerge with a growing number of conjugates entering clinical development, for example PEGylated-aptamers and a polymer-based siRNA delivery system. 'Hot' topics of the past 2 years include; emerging issues relating to polymer safety, the increasing use of biodegradable polymers, design of technologies for combination therapy, potential biomarkers for patient individualisation of treatment and Regulatory challenges for 'follow-on/generic' polymer therapeutics. PMID- 21676610 TI - Colorectal cancer survival in socioeconomic groups in England: variation is mainly in the short term after diagnosis. AB - The objective of this study was to examine differences in cancer survival between socioeconomic groups in England, with particular attention to survival in the short term of follow-up. PATIENTS AND METHODS: Individuals diagnosed with colorectal cancer between 1996 and 2004 in England were identified from cancer registry records. Five-year cumulative relative survival and excess death rates were computed. RESULTS: For colon cancer there was a very high excess death rate in the first month of follow-up, and the excess death rate was highest in the socioeconomically deprived groups. In subsequent periods, excess mortality rates were much lower and there was less socioeconomic variation. The pattern of variation in excess death rates was generally similar in rectal cancer but the socioeconomic difference in death rates persisted several years longer. If the excess death rates in the entire colorectal cancer patient population were the same as those observed in the most affluent socioeconomic quintile, the annual reduction would be 360 deaths in colon cancer and 336 deaths in rectal cancer patients. These deaths occurred almost entirely in the first month and the first year after diagnosis. CONCLUSION: Recent developments in the national cancer control agenda have included an increasing emphasis on outcome measures, with short-term cancer survival an operational measure of variation and progress in cancer control. In providing clues to the nature of the survival differences between socioeconomic groups, the results presented here give strong support for this strategy. PMID- 21676611 TI - Vermicomposting of tannery sludge mixed with cattle dung into valuable manure using earthworm Eisenia fetida (Savigny). AB - The present study revealed the role of earthworm in converting tannery sludge into a valuable product. Tannery sludge was toxic to earthworm, therefore it was mixed with cattle dung in different proportions viz. 0:100 (T(0)), 10:90 (T(10)), 25:75 (T(25)), 50:50 (T(50)) and 75:25 (T(75)) on dry weight basis. The minimum mortality and highest population buildup of worms was in T(0) mixture. Nitrogen, sodium, phosphorus and pH increased from initial in the range of 7.3-66.6%, 16.90 70.58%, 8.57-44.8% and 2.8-13.65%, respectively. On the other hand potassium, organic carbon and electrical conductivity decreased in the range of 4.34-28.5%, 7.54-22.35% and 32.35-53.12%, respectively. C:N ratio decreased from 20.53% to 47.36% in the final products. Transition metals increased significantly from the initial value and within the permissible limit. The result indicated that vermicomposting with Eisenia fetida is better for changing this sludge into nutrient rich manure in a short period of time. PMID- 21676612 TI - Discovery of a novel series of nonacidic benzofuran EP1 receptor antagonists. AB - We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain. PMID- 21676613 TI - Native N-glycopeptide thioester synthesis through N->S acyl transfer. AB - Peptide thioesters are important tools for the total synthesis of proteins using native chemical ligation (NCL). Preparation of glycopeptide thioesters, that enable the assembly of homogeneously glycosylated proteins, is complicated by the perceived fragile nature of the sugar moiety. Herein, we demonstrate the compatibility of thioester formation via N->S acyl transfer with native N glycopeptides and report observations that will aid in their preparation. PMID- 21676614 TI - Metabolic labeling of fucosylated glycoproteins in Bacteroidales species. AB - Members of the Bacteroidales order are among the most abundant gram-negative bacteria of the human colonic microbiota. These species decorate their cell surface glycoproteins with fucosylated glycans, which are believed to play important roles in host intestinal colonization. Currently, there is no method for the enrichment of these glycoproteins for their identification. Here, we describe a chemical approach directed toward labeling and detecting fucosylated glycoproteins from cultured Bacteroidales species, namely Bacteroides fragilis and Parabacteroides distasonis. We treated these bacteria with an alkyne-bearing fucose analog, which is metabolically integrated into the bacterial surface fucosylated glycoproteins. The alkyne-tagged glycoproteins can then react with azide-bearing biophysical probes via bioorthogonal click chemistry for detection or glycoproteomic analysis. PMID- 21676615 TI - Efficient synthesis of 3-O-thia-cPA and preliminary analysis of its biological activity toward autotaxin. AB - The efficient synthesis of 3-O-thia-cPAs (4a-d), sulfur analogues of cyclic phosphatidic acid (cPA), has been achieved. The key step of the synthesis is an intramolecular Arbuzov reaction to construct the cyclic thiophosphate moiety. The present synthetic route enables the synthesis of 4a-d in only four steps from the commercially available glycidol. Preliminary biological experiments showed that 4a-d exhibited a similar inhibitory effect on autotaxin (ATX) as original cPA. PMID- 21676616 TI - Side chain SAR of bicyclic beta-lactamase inhibitors (BLIs). 2. N-Alkylated and open chain analogs of MK-8712. AB - The bridged monobactam beta-lactamase inhibitor MK-8712 (1) effectively inhibits class C beta-lactamases. Side chain N-alkylated and ring-opened analogs of 1 were prepared and evaluated for combination with imipenem to overcome class C beta lactamase mediated resistance. Although some analogs were more potent inhibitors of AmpC, none exhibited better synergy with imipenem than 1. PMID- 21676618 TI - Simple verbal instruction improves knee biomechanics during landing in female athletes. AB - Knee injuries are highly prevalent in athletic populations, particularly among female athletes. Many of these injuries occur during landing from a jump. Various comprehensive knee injury prevention programs have been developed to date. However, there is a need to determine which components of these programs contribute directly to changes in knee biomechanics. Therefore, the purpose of this study was to investigate the immediate effect of three different simple verbal instructions on knee biomechanics during landing in adult female recreational athletes. Three-dimensional kinematic and kinetic analysis of landing from a countermovement jump was conducted in a counterbalanced cross-over repeated measures design. Results indicated that the instruction to land with equal weight distribution reduced the asymmetry of peak vertical ground reaction force compared to the control condition. The instruction to land softly reduced peak vertical ground reaction force and increased peak knee flexion compared to the control condition. The instruction to land with knees over toes increased peak knee flexion compared to the control condition. These findings indicate that verbal instruction may be a key component of the effects seen in previous research studies that have investigated the benefits of more complex training programs designed to reduce knee injury risk in female athletes. PMID- 21676617 TI - Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy. AB - Myofibrillar myopathies (MFM) are a group of disorders associated with mutations in DES, CRYAB, MYOT, ZASP, FLNC, or BAG3 genes and characterized by disintegration of myofibrils and accumulation of degradation products into intracellular inclusions. We retrospectively evaluated 53 MFM patients from 35 Spanish families. Studies included neurologic exam, muscle imaging, light and electron microscopic analysis of muscle biopsy, respiratory function testing and cardiologic work-up. Search for pathogenic mutations was accomplished by sequencing of coding regions of the six genes known to cause MFM. Mutations in MYOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined. Comparative analysis of DES, MYOT and ZASP associated phenotypes demonstrates substantial phenotypic distinctions that should be considered in studies of disease pathogenesis, for optimization of subtype-specific treatments and management, and directing molecular analysis. PMID- 21676619 TI - Novel terpenoids of the fungus Aspergillus insuetus isolated from the Mediterranean sponge Psammocinia sp. collected along the coast of Israel. AB - Three novel meroterpenoids, insuetolides A-C (1-3) and four drimane sesquiterpenes, the new (E)-6-(4'-hydroxy-2'-butenoyl)-strobilactone A (4) and the known 2alpha, 9alpha, 11-trihydroxy-6-oxodrim-7-ene (5), strobilactone A (6) and (E,E)-6-(6',7'-dihydroxy-2',4'-octadienoyl)-strobilactone A (7), were isolated from the EtOAc extract of the culture medium of the marine-derived fungus Aspergillus insuetus (OY-207), which was isolated from the Mediterranean sponge Psammocinia sp. The structures of the compounds were determined by spectroscopic methods. Insuetolides A-C reveal a new carbon skeleton derived from the cyclization of farnesyl and 3, 5-dimethylorsellinic acid. Compounds 1, 6, and 7 exhibited anti-fungal activity towards Neurospora crassa with MIC values of 140, 242, and 162 MUM, respectively; and compounds 3, 4, and 7 exhibited mild cytotoxicity towards MOLT-4 human leukemia cells. PMID- 21676620 TI - Disparity in formulations used for fluorescent X-ray intensity measurements. AB - The paper presents a problem in computations of X-ray fluorescence cross sections, shell/sub-shell fluorescence yields, Coster-Kronig yields, vacancy alignment, etc. from X-ray fluorescence (XRF) studies. While using barn/atom as a unit for cross-sections if the atomic masses are not considered it causes a discrepancy in the measured cross-section, yield and alignment values. Most of the earlier publications are being quoted where such an oversight has occurred and discrepancy is evident. PMID- 21676621 TI - Cloning and molecular characterization of an ethylene receptor gene, MiERS1, expressed during mango fruitlet abscission and fruit ripening. AB - We isolated and characterized a mango (Mangifera indica L.) cDNA homolog of the ethylene receptor gene ERS1, designated MiERS1. Genomic Southern blot analysis suggested the existence of a second gene with homology to MiERS1. Spatial and temporal expression patterns of MiERS1 were first studied during fruitlet drop and compared with those of a previously identified MiETR1 gene that encodes an ETR1-type ethylene receptor. Experiments were conducted on developing fruitlet explants in which fruitlet abscission was induced by ethephon treatment. Northern analysis revealed a notable increase in MiERS1 mRNA levels in the fruitlet's activated abscission zone within 24 h of ethephon application, followed by a decreasing pattern 48 h post-treatment. A transient, albeit lesser, increase in MiERS1 mRNA levels was also observed in treated fruitlet seed and mesocarp tissues. In contrast, in the abscission zone, accumulation of MiETR1 transcript remained unchanged; a temporal increase in MiETR1 transcript level was observed in the fruitlet mesocarp, whereas in the seed, MiETR1 expression had already dropped by 24 h. Expression profiles of MiERS1 and MiETR1 were then studied during fruit ripening. In agreement with a previous study and coinciding with the climacteric rise in ethylene production, RNA blot analysis revealed that during fruit ripening, MiETR1 mRNA level increases in both mesocarp and seed tissues. Unexpectedly, however, in those same tissues, MiERS1 transcript accumulation was barely detected. Collectively, our data highlight MiERS1's possible specific function in regulating fruitlet abscission rather than fruit ripening. PMID- 21676623 TI - The surgical and orthodontic management of cherubism in a growing child. AB - Cherubism is a rare non-neoplastic disease that affects the jaws causing significant destruction and disfigurement. The disease also affects the normal eruption, occlusion and function of the dento-alveolar complex. Cherubism may radiographically and histologically resemble central giant cell granuloma, fibrous dysplasia and other giant cell lesions. The case of a 15-year 4-month-old girl with no obvious facial swelling or signs of cherubism is described in this report. The patient presented with a dental malocclusion that included the ectopic eruption and displacement of teeth caused by the lesion. The radiographic findings derived from Cone Beam Computed Tomography (CBCT) technology are described. This case report details the orthodontic and surgical diagnosis and management of a teenager during the post growth period. PMID- 21676622 TI - Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. AB - INTRODUCTION: Osteonecrosis of the jaw (ONJ) is a serious side-effect of intravenous nitrogen-containing bisphosphonate therapy frequently used in the treatment of malignant diseases. Despite numerous case series published so far studies with detailed investigations into risk factors, the precise localization of ONJ and impact of ONJ on the oncological treatment remain sparse. PATIENTS AND METHODS: This single-centre study collated medical records (2003-2009) of all patients that suffered from ONJ within the Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University of Munich, Germany. In total, 126 patients fulfilled the case criteria of ONJ and were examined clinically. The complete medical history including detailed questionnaires was collected of 66 patients, focussing in particular on the identification of underlying risk factors, clinical features, ONJ localization as well as the impact on the oncological treatment. RESULTS: The majority of ONJ cases occurred in patients suffering from malignant diseases (n=117; 92.8%), in particular breast cancer (n=57; 45.2%), multiple myeloma (n=37; 29.4%) and prostate cancer (n=13; 10.3%), all received nitrogen-containing bisphosphonates intravenously. ONJ was also diagnosed in 9 patients (7.1%) suffering from osteoporosis or rheumatoid arthritis. The most prevalent clinical feature was exposed necrotic bone (93.9%) in the oral cavity which was accompanied in 78.8% of cases by pain. A predilection for the mandible and in particular for molar and premolar regions in both jaws was shown. Although no recommendation concerning the oncologic treatment was made, the manifestation of ONJ resulted (in a significant proportion of the patients) in a change of medication and schedule. The most frequent co-medications were steroids and anti angiogenetic drugs, such as thalidomide. DISCUSSION: The predilection for mandibular molar and premolar regions, and the infectious conditions that often precede the onset of ONJ support recent pathogenesis theories stating that local inflammation and associated pH-changes may trigger the release and activation of nitrogen-containing bisphosphonates ultimately resulting in necrosis. CONCLUSION: The development of ONJ has a multi-factorial aetiology and the clinical presentation can vary markedly. ONJ cannot only impair the quality of life but also the treatment of the underlying disease. PMID- 21676624 TI - Noninvasive diagnosis of an adult patient with double-outlet left ventricle. PMID- 21676625 TI - Is retraction of leaflets the principal pathology in rheumatic mitral stenosis? PMID- 21676626 TI - Significance of off-pump coronary artery bypass grafting compared with percutaneous coronary intervention: a propensity score analysis. AB - OBJECTIVE: Although there have been several studies that compared the efficacy of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), the impact of off-pump CABG (OPCAB) has not been well elucidated. The objective of the present study was to compare the outcomes after PCI, on-pump CABG (ONCAB), and OPCAB in patients with multivessel and/or left main disease. METHODS: Among the 9877 patients undergoing first PCI using bare-metal stents or CABG who were enrolled in the CREDO-Kyoto Registry, 6327 patients with multivessel and/or left main disease were enrolled into the present study (67.9+/ 9.8 years old). Among them, 3877 patients received PCI, 1388 ONCAB, and 1069 OPCAB. Median follow-up was 3.5 years. RESULTS: Comparing PCI with all CABG (ONCAB and OPCAB), propensity-score-adjusted all-cause mortality after PCI was higher than that CABG (hazard ratio (95% confidence interval): 1.37 (1.15-1.63), p<0.01). The incidence of stroke was lower after PCI than that after CABG (0.75 (0.59-0.96), p=0.02). CABG was associated with better survival outcomes than PCI in the elderly (interaction p=0.04). Comparing OPCAB with PCI or ONCAB, propensity-score-adjusted all-cause mortality after PCI was higher than that after OPCAB (1.50 (1.20-1.86), p<0.01). Adjusted mortality was similar between ONCAB and OPCAB (1.18 (0.93-1.51), p=0.33). The incidence of stroke after OPCAB was similar to that after PCI (0.98 (0.71-1.34), p>0.99), but incidence of stroke after ONCAB was higher than that after OPCAB (1.59 (1.16-2.18), p<0.01). CONCLUSIONS: In patients with multivessel and/or left main disease, CABG, particularly OPCAB, is associated with better survival outcomes than PCI using bare-metal stents. Survival outcomes are similar between ONCAB and OPCAB. PMID- 21676627 TI - Implantable cardiac defibrillators and end-of-life care--time for reflection, deliberation and debate? AB - Heart failure (HF) is a common condition associated with high rates of morbidity and mortality. Implantable cardiac defibrillators (ICDs) are an important management strategy in HF management and decrease mortality for both primary and secondary prevention. An emerging body of literature identifies the challenges of managing ICDs at the end of life. This report discusses a critical incident experienced by a HF team in a referral centre and outlines the issues to be considered in advancing discussion and debate of managing ICDs at the end of life. Engaging in debate, discussion and consensus guidelines is likely to be crucial in minimising distress and burden for clinicians, patients and their families alike. PMID- 21676628 TI - Association of graft ischemic time with survival after heart transplant among children in the United States. AB - BACKGROUND: Previous studies have found no association between graft ischemic time (IT) and survival in pediatric heart transplant (HTx) recipients. However, previous studies were small or analyzed risk only at the extremes of IT, where observations are few. We sought to determine whether graft IT is independently associated with graft survival in a large cohort of children with no a priori assumptions about where the risk threshold may lie. METHODS: All children aged <18 years in the U.S. undergoing primary HTx (1987 to 2008) were included. The primary end point was graft loss (death or retransplant) within 6 months. Multivariate analysis was performed to analyze the association between graft IT and graft loss within 6 months after transplant. A secondary end point of longer term graft loss was assessed among recipients who survived the first 6 months after transplant. RESULTS: Of 4,716 pediatric HTxs performed, the median IT was 3.5 hours (interquartile range, 2.7-4.3 hours). Adjusted analysis showed that children with an IT > 3.5 hours were at increased risk of graft loss within 6 months after transplant (hazard ratio, 1.3; 95% confidence interval, 1.1-1.5; p = 0.002). Among 6-month survivors, IT was not associated with longer-term graft loss. CONCLUSIONS: IT beyond 3.5 hours is associated with a 30% increase in risk of graft loss within 6 months in pediatric HT recipients. Although the magnitude of risk associated with IT is small compared with the risk associated with recipient factors, these findings may be important during donor assessment for high-risk transplant candidates. PMID- 21676629 TI - Heart transplant recipients supported with extracorporeal membrane oxygenation: outcomes from a single-center experience. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) provides hemodynamic support in refractory cardiogenic shock and may be used after heart transplantation for primary graft dysfunction or rejection. We hypothesized that survival after ECMO support is contingent upon patient selection. METHODS: We examined consecutive adult heart transplant recipients at a single center who underwent transplantation between 1997 and 2009 and required ECMO support. Patients were divided by clinical presentation: pre-emptive therapy, escalating inotropic requirements despite support by intra-aortic balloon pump (IABP); and salvage therapy, cardiac arrest undergoing cardiopulmonary resuscitation with chest compressions. RESULTS: Between 1997 and 2009, there were 37 instances of ECMO use in 32 patients: 23 episodes (19 patients) for pre-emptive therapy and 14 episodes (14 patients) for salvage therapy; 1 patient had both pre-emptive and salvage therapy. Patients did not differ in age, gender or ischemic time. ECMO support was for a median 6 days in both groups, and the incidence of serious vascular complications was comparable (35% and 36%). In the pre-emptive therapy group, 15 episodes (79%) were associated with survival to hospital discharge and 5 patients (26%) were alive at 1 year. In the salvage therapy group, 2 episodes (14%) were associated with survival to hospital discharge and 1 patient (7%) was alive at 1 year. CONCLUSIONS: ECMO support is a viable option for adult heart transplant recipients with severe rejection and refractory cardiogenic shock. To maximize the benefit of this aggressive approach in heart transplant recipients requires early intervention, with a heightened awareness of this option to facilitate expedited use. PMID- 21676630 TI - Stable patients on left ventricular assist device support have a disproportionate advantage: time to re-evaluate the current UNOS policy. AB - Over the years, policies adopted by United Network of Organ Sharing (UNOS) have directed allocation of donor hearts in the USA. These policies have been based on algorithms that allocate a higher priority status to those patients who are the most infirm, and would thereby benefit patients in the most dire of circumstances. Over the last 2 decades, the increased use of LVADs as a bridge to transplantation has had a major impact on lowering the mortality among those on the heart transplant waiting list. Given the constant risk of potential complications related to these devices, early UNOS policies were implemented to specifically allocate higher priority status to patients on LVADs. However, recent advances in LVAD technology coupled with refinements in patient selection and management have dramatically improved patient survival and led to a reduction in complications. It is inevitable that favorable experiences with the current generation of LVADs coupled with continued improvements in technology will lead to increased use of these devices as a bridge to transplantation or to candidacy. PMID- 21676631 TI - Metformin inhibits renal cell carcinoma in vitro and in vivo xenograft. AB - OBJECTIVE: To evaluate the effects of metformin on renal cell carcinoma (RCC) and its underlying mechanisms. MATERIALS AND METHODS: We used 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and colony formation assays to investigate the effects of metformin on RCC cell growth. Flow cytometry was used to evaluate the cell cycle changes after metformin treatment. We further determined the possible signaling molecules involved in this process by immunoblot analysis of various proteins. Furthermore, a xenograft model was used to study the effects of metformin on RCC tumor growth. RESULTS: We demonstrated that metformin effectively inhibits cell proliferation in 786-O and OS-RC-2 RCC cell lines. Moreover, metformin down-regulated cyclin D1 expression and induced G0/G1 cell cycle arrest in these cells. Further study revealed metformin induced the activation of AMP-activated protein kinase (AMPK), and inhibited mammalian target of rapamycin (mTOR), which is a central regulator of protein synthesis and cell growth, and negatively regulated by AMPK. Most importantly, daily treatment of mice with metformin prevented RCC tumor growth in a xenograft model. CONCLUSIONS: Metformin was able to induce G0/G1 cell cycle arrest and inhibit RCC growth in vitro and in vivo. These results suggest that metformin may be a potential therapeutic agent for the treatment of RCC. PMID- 21676633 TI - Sleep, emotional and behavioral difficulties in children and adolescents. AB - Links between sleep and psychopathology are complex and likely bidirectional. Sleep problems and alteration of normal sleep patterns have been identified in major forms of child psychopathology including anxiety, depression and attention disorders as well as symptoms of difficulties in the full range. This review summarizes some key findings with regard to the links between sleep and associated difficulties in childhood and adolescence. It then proposes a selection of possible mechanisms underlying some of these associations. Suggestions for future research include the need to 1) use multi-methods to assess sleep; 2) measure sleep in large-scale studies; 3) conduct controlled experiments to further establish the effects of sleep variations on emotional and behavioral difficulties; 4) take an interdisciplinary approach to further understand the links between sleep and associated difficulties. PMID- 21676634 TI - Endoneurial pathology of the needlestick-nerve-injury model of Complex Regional Pain Syndrome, including rats with and without pain behaviors. AB - Current rodent models of neuropathic pain produce pain hypersensitivity in almost all lesioned animals and not all identified experimental effects are pain specific. 18G needlestick-nerve-injury (NNI) to one tibial nerve of outbred Sprague-Dawley rats models the phenotype of Complex Regional Pain Syndrome (CRPS), a post-traumatic neuropathic pain syndrome, leaving roughly half of NNI rats with hyperalgesia. We compared endoneurial data from these divergent endophenotypes searching for pathological changes specifically associated with pain-behaviors. Tibial, sural, and common sciatic nerves from 12 NNI rats plus 10 nerves from sham-operated controls were removed 14 days post-surgery for morphometric analysis. PGP9.5(+) unmyelinated-fibers were quantitated in plantar hindpaw skin. Distal tibial nerves of NNI rats had endoneurial edema, 30% fewer axons, twice as many mast cells, and thicker blood-vessel walls than uninjured tibial nerves. However the only significant difference between nerves from hyperalgesic versus non-hyperalgesic NNI rats was greater endoneurial edema in hyperalgesic rats (p < 0.01). We also discovered significant axonal losses in uninjured ipsilateral sural nerves of NNI rats, demonstrating spread of neuropathy to nearby nerves formerly thought spared. Tibial and sural nerves contralateral to NNI had significant changes in endoneurial blood-vessels. Similar pathological changes have been identified in CRPS-I patients. The current findings suggest that severity of endoneurial vasculopathy and inflammation may correlate better with neuropathic pain behaviors than degree of axonal loss. Spread of pathological changes to nearby ipsilateral and contralateral nerves might potentially contribute to extraterritorial pain in CRPS. PMID- 21676635 TI - Renal epithelioid angiomyolipoma with epithelial cysts: demonstration of Melan A and HMB45 positivity in the cystic epithelial lining. AB - Renal angiomyolipoma (AML) may present as rare variants such as epithelioid and AML with epithelial cysts posing difficulties for the diagnosis to the surgical pathologist. We report a case of a 46-year-old male patient presenting a 5-cm solid tumor in the lower pole of the left kidney, with cystic changes at cut surface. The tumor exhibited 95% of epithelioid cells with atypical nuclei. A small focus of typical AML was observed. The immunoprofile of tumor cells was classical of AML including expression of melanocytic markers such as HMB45 and Melan A. We report the immunohistochemical study of the cystic component in an epithelioid AML. In contrast to the immunoreactivity reported in typical AML, the present case shows obvious expression of melanocytic markers in the cystic epithelial lining. This is strong evidence that these cysts are neoplastic and derived from AML, rather than entrapped native collecting duct epithelium. PMID- 21676636 TI - PKU: high plasma phenylalanine concentrations are associated with increased prevalence of mood swings. AB - In phenylketonuria, knowledge about the relation between behavior and plasma phenylalanine is scarce. The aim of this study was to determine whether high phenylalanine is associated with disturbed behavior noticed by the patient and or close environment (parents or partners). 48 early treated PKU patients (median age 8.5, range 0-35 years) participated (median phenylalanine concentration in total sample 277 (range 89-1171) MUmol/l; and in patients <12 years 238 (range 89 521) MUmol/l). After sending blood samples, patients or close environment were interviewed with a standardized questionnaire whether they noticed hyperactivity, annoying behavior, mood swings and introvert or extravert behavior. The interviewer as well as the respondents were blinded with regard to the phenylalanine concentration. RESULTS: Patients reported less deviant behavior compared to close environment. Mood swings were positively associated with phenylalanine concentrations in the total group (P=0.039) and patients <12 years (P=0.042). The relationships between temporary high phenylalanine concentrations and hyperactivity, annoying behavior, introvert and extravert behavior were not statistically significant. CONCLUSION: there is a positive association between phenylalanine concentrations and mood swings. PMID- 21676637 TI - [The training in transfusion medicine remains deficient in the centres of Francophone sub-Saharan Africa: results of a preliminary study]. AB - PURPOSE OF THE STUDY: To evaluate the needs in staff training in transfusion centres of Sub-Saharan Africa. MATERIAL AND METHODS: This preliminary study analyzed the training level of each personnel of four blood banks of Sub-Saharan Africa, their training fields, duration and training structures. RESULTS: The needs remain high in all the fields and are critical regarding the administration of blood transfusion services, equipment maintenance and clinical use of blood. PMID- 21676638 TI - Post-bypass hypoglycaemia: a review of current findings. AB - Gastric bypass is one of the most efficient strategies for long-term weight loss and reduction of the comorbidities associated with morbid obesity. Of the complications secondary to gastric bypass, hypoglycaemic episodes have so far been poorly studied. The present study is a comprehensive report of the fewer than 100 cases described in the literature. It shows that strict diagnostic criteria should be applied to differentiate true intense neuroglucopenic symptoms associated with low glucose values (<2.8 mmol/L) from the more frequent symptoms of the dumping syndrome and those occurring in the context of lower-than-normal plasma glucose concentrations. The pancreatic beta-cell hyperfunction initially deemed responsible for hypoglycaemic episodes because of frequent islet abnormalities is described and reappraised in this report. The few validated therapeutic options are also discussed. PMID- 21676639 TI - [Interest of blood markers in predicting radiation-induced toxicity]. AB - The oncologic outcome and the total dose are highly correlated with the treatment by ionizing radiation. The dose increase (total or per fraction) may provoke late side effects that are potentially irreversible. The radiation-induced CD8 lymphocyte apoptotic value and the molecular modifications within the lymphocyte are capable of predicting the level of risk of developing late-side effects after curative intent radiotherapy. In this review, we present the different blood assays in this setting and discuss the current possibilities of researches, namely those involving the proteomic process. PMID- 21676640 TI - [Intensity modulation in breast radiotherapy: development of an innovative field in-field technique at Institut Gustave-Roussy]. AB - PURPOSE: To assess the potential dosimetric gain of presegmentation modulated radiotherapy (OAPS, DosiSoftTM) of breast, compared to routine 3D conformal radiotherapy. PATIENTS AND METHODS: Twenty patients treated with conservative surgery for breast cancer (9 right and 11 left sided) with various breast volume (median 537 cm(3); range [100-1049 cm(3)]) have been selected. For each patient, we have delineated a breast volume and a compensation volume (target volumes), as well as organs at risk (lungs and heart). Two treatment plans have been generated: one using the routine 3D conformal technique and the other with the presegmentation algorithm of DosiSoftTM (OAPS). The dose distribution were analyzed using the conformity index for target volumes, mean dose and V30 Gy for the heart, and mean dose, V20 Gy and V30 Gy for lungs. RESULTS: Over the 20 patients, the conformity index increased from 0.897 with routine technique to 0.978 with OAPS (P<0,0001). For heart and lung, OAPS decreased irradiation (mean cardiac dose 1,3 vs 1,6 Gy [P<0,0001] and pulmonary V20 Gy 6,6 vs 7,1 [P<0,0001]). CONCLUSION: OAPS (DosiSoftTM) is an original method of segmentation of breast. It is automatic, fast and easy, and is able to increase the conformity index, while sparing organ at risk. PMID- 21676641 TI - Upregulation of BNIP3 and translocation to mitochondria in nutrition deprivation induced apoptosis in nucleus pulposus cells. AB - OBJECTIVE: This study was to detect the expression of Bcl-2/adenovirus E1B19-kDa interacting protein 3 in apoptosis induced by nutrition deprivation in nucleus pulposus cells, so as to further understand the mechanism of apoptosis in nucleus pulposus cells. METHODS: Cells isolated from rat caudal disc were cultured under two different oxygen, glucose and serum concentrations for up to 3 days. Interactions between two different concentrations were examined by cell vitality assay mitochondrial membrane potential (Deltapsim) test and apoptosis detect. The expression and location of Bcl-2/adenovirus E1B19-kDa-interacting protein 3 were tested by real-time polymerase chain reaction and immunofluorescence staining. RESULT: Cell vitality and mitochondrial membrane potential (Deltapsim) were significantly reduced in absence of oxygen, glucose and serum while the cell apoptosis percent was significantly increased, as compared with the cells in normal oxygen, glucose and serum concentration. The expression of Bcl 2/adenovirus E1B 19-kDa-interacting protein 3 showed a significant increase in absence of oxygen, glucose and serum, especially in 72 h. Furthermore, the protein was found to translocate to mitochondria. CONCLUSION: Upregulation of Bcl 2/adenovirus E1B 19-kDa-interacting protein 3 and translocation to mitochondria may be involved in apoptosis of nucleus pulposus cells in nutrition deprivation. PMID- 21676642 TI - Finite element modeling of a 3D coupled foot-boot model. AB - Increasingly, musculoskeletal models of the human body are used as powerful tools to study biological structures. The lower limb, and in particular the foot, is of interest because it is the primary physical interaction between the body and the environment during locomotion. The goal of this paper is to adopt the finite element (FE) modeling and analysis approaches to create a state-of-the-art 3D coupled foot-boot model for future studies on biomechanical investigation of stress injury mechanism, foot wear design and parachute landing fall simulation. In the modeling process, the foot-ankle model with lower leg was developed based on Computed Tomography (CT) images using ScanIP, Surfacer and ANSYS. Then, the boot was represented by assembling the FE models of upper, insole, midsole and outsole built based on the FE model of the foot-ankle, and finally the coupled foot-boot model was generated by putting together the models of the lower limb and boot. In this study, the FE model of foot and ankle was validated during balance standing. There was a good agreement in the overall patterns of predicted and measured plantar pressure distribution published in literature. The coupled foot-boot model will be fully validated in the subsequent works under both static and dynamic loading conditions for further studies on injuries investigation in military and sports, foot wear design and characteristics of parachute landing impact in military. PMID- 21676643 TI - Influence of age, gender and severity of tremor on outcome after thalamic and subthalamic DBS for essential tremor. AB - Deep brain stimulation (DBS) is an established treatment for essential tremor (ET). The nucleus ventralis intermedius thalami (Vim) is the target of choice, but promising results have been presented regarding DBS in the posterior subthalamic area (PSA). The aim of this study was to evaluate the possible influence of gender, age and severity of disease on the outcome of these procedures. Sixty eight patients (34 Vim, 34 PSA) with ET were included in this non-randomised study. Evaluation using the Essential Tremor Rating Scale (ETRS) was performed before, and one year after surgery concerning PSA DBS, and at a mean of 28 +/- 24 months concerning Vim DBS. Items 5/6 and 11-14 (hand tremor and hand function) were selected for analysis of tremor outcome. The efficacy of DBS on essential tremor was not related to age or gender. Nor was it associated with the severity of tremor when the percentual reduction of tremor on stimulation was taken into account. However, patients with a more severe tremor at baseline had a higher degree of residual tremor on stimulation. Tremor in the treated hand and hand function were improved with 70% in the Vim group and 89% in the PSA group. PMID- 21676644 TI - Falls in Parkinson's disease: evidence for altered stepping strategies on compliant surfaces. AB - BACKGROUND: Real-world environments comprise surfaces of different textures, densities and gradients, which can threaten postural stability and increase falls risk. However, there has been limited research that has examined how walking on compliant surfaces influences gait and postural stability in older people and PD patients. METHODS: PD patients (n = 49) and age-matched controls (n = 32) were assessed using three-dimensional motion analysis during self-paced walking on both firm and foam walkways. Falls were recorded prospectively over 12 months using daily falls calendars. RESULTS: Walking on a foam surface influenced the temporospatial characteristics for all groups, but PD fallers adopted very different joint kinematics compared with controls. PD fallers also demonstrated reduced toe clearance and had increased mediolateral head motion (relative to walking velocity) compared with control participants. CONCLUSIONS: Postural control deficits in PD fallers may impair their capacity to attenuate surface related perturbations and control head motion. The risk of falling for PD patients may be increased on less stable surfaces. PMID- 21676645 TI - A fluorescent probe for both pH and Zn2+ based on 2-(1-phenyl-1H-benzo[d]imidazol 2-yl)phenol. AB - A sensitive fluorescent probe 2-(1-phenyl-1H-benzo[d]imidazol-2-yl)phenol (HBIZ) for pH and Zn2+ has been developed. Great changes have taken place in the UV-vis absorption and fluorescence spectra for HBIZ upon increasing pH of its aqueous solution, acting as a pH-induced emission "off-on-off" switch with large enhancement factors of ~290 and ~75 over the pH range of 1.00-5.40 and 5.20 10.40. A over 100-fold fluorescence enhancement was also observed after complexation of HBIZ to Zn2+ in N,N-dimethylformamide. PMID- 21676646 TI - Synthesis, spectral and thermal studies of some transition metal mixed ligand complexes: modeling of equilibrium composition and biological activity. AB - Several mixed ligand Ni(II), Cu(II) and Zn(II) complexes of 2-amino-3 hydroxypyridine (AHP) and imidazoles viz., imidazole (him), benzimidazole (bim), histamine (hist) and L-histidine (his) have been synthesized and characterized by elemental and spectral (vibrational, electronic, 1H NMR and EPR) data as well as by magnetic moment values. On the basis of elemental analysis and molar conductance values, all the complexes can be formulated as [MAB]Cl except histidine complexes as MAB. Thermogravimetric studies reveal the presence of coordinated water molecules in most of the complexes. From the magnetic measurements and electronic spectral data, octahedral structure was proposed for Ni(II) and Cu(II)-AHP-his, tetrahedral for Cu(II)-AHP-him/bim/hist, but square planar for the Cu(II)-AHP complex. The g?/A? calculated supports tetrahedral environment around the Cu(II) in Cu(II)-AHP-him/bim/hist and distorted octahedral for Cu(II)-AHP-his complexes. The morphology of the reported metal complexes was investigated by scanning electron micrographs (SEM). The potentiometric study has been performed in aqueous solution at 37 degrees C and I=0.15 mol dm(-3) NaClO4. MABH, MAB and MAB2 species has been identified in the present systems. Proton dissociation constants of AHP and stability constants of metal complexes were determined using MINIQUAD-75. The most probable structure of the mixed ligand species is discussed based upon their stability constants. The in vitro biological activity of the complexes was tested against the Gram positive and Gram negative bacteria, fungus and yeast. The oxidative DNA cleavage studies of the complexes were performed using gel electrophoresis method. Cu(II) complexes have been found to promote DNA cleavage in presence of biological reductant such as ascorbate and oxidant like hydrogen peroxide. PMID- 21676647 TI - Exploiting the quasi-invariance of atomic displacements. AB - The quasi-invariance of the magnitude of atomic displacements is briefly introduced and demonstrated for the case of indole. The usefulness of this property for the assignment of neutron vibrational spectra is underlined. PMID- 21676648 TI - Vibrational assignments, normal coordinate analysis, B3LYP calculations and conformational analysis of methyl-5-amino-4-cyano-3-(methylthio)-1H-pyrazole-1 carbodithioate. AB - The Raman and infrared spectra of solid methyl-5-amino-4-cyano-3-(methylthio)-1H pyrazole-1-carbodithioate (MAMPC, C7H8N4S3) were measured in the spectral range of 3700-100 cm(-1) and 4000-200 cm(-1) with a resolution of 4 and 0.5 cm(-1), respectively. Room temperature 13C NMR and (1)H NMR spectra from room temperature down to -60 degrees C were also recorded. As a result of internal rotation around C-N and/or C-S bonds, eighteen rotational isomers are suggested for the MAMPC molecule (Cs symmetry). DFT/B3LYP and MP2 calculations were carried out up to 6-311++G(d,p) basis sets to include polarization and diffusion functions. The results favor conformer 1 in the solid (experimentally) and gaseous (theoretically) phases. For conformer 1, the two -CH3 groups are directed towards the nitrogen atoms (pyrazole ring) and CS, while the -NH2 group retains sp2 hybridization and C-CN bond is quasi linear. To support NMR spectral assignments, chemical shifts (delta) were predicted at the B3LYP/6-311+G(2d,p) level using the method of Gauge-Invariant Atomic Orbital (GIAO) method. Moreover, the solvent effect was included via the Polarizable Continuum Model (PCM). Additionally, both infrared and Raman spectra were predicted using B3LYP/6-31G(d) calculations. The recorded vibrational, 1H and 13C NMR spectral data favors conformer 1 in both the solid phase and in solution. Aided by normal coordinate analysis and potential energy distributions, confident vibrational assignments for observed bands have been proposed. Moreover, the CH3 barriers to internal rotations were investigated. The results are discussed herein are compared with similar molecules whenever appropriate. PMID- 21676649 TI - Raman spectral study of metal-cytosine complexes: a density functional theoretical (DFT) approach. AB - The fluctuation of surface-enhanced Raman scattering (SERS) spectra has been an obstacle to the analysis of the adsorbate on the metal surface. In this paper, we aim at using the density functional theory (DFT) to study the fluctuant Raman spectra of the cytosine molecule which interacts with a coinage metal atom or cation via N1 and N3 sites. The results show that the adsorption site strongly influences the Raman spectral property of cytosine molecule, especially the relative intensity of some bands. In addition, the SERS spectra of cytosine which is adsorbed on the gold, silver, and copper electrodes are measured, and the possible orientation and adsorption site of the cytosine molecule adsorbed on metal electrodes surface are proposed with the help of DFT simulations. PMID- 21676650 TI - Design and implementation of I2Vote--an interactive image-based voting system using windows mobile devices. AB - PURPOSE: To develop, implement and test a novel audience response system (ARS) that allows image based interaction for radiology education. METHODS: The ARS developed in this project is based on standard Personal Digital Assistants (PDAs) (HP iPAQ 114 classic handheld) running Microsoft(r) Windows Mobile(r) 6 Classic with a large 3.5 in. TFT touch screen (320*240 pixel resolution), high luminance and integrated IEEE 802.11b/g wireless. For software development Visual Studio 2008 professional (Microsoft) was used and all components were written in C#. Two test sessions were conducted to test the software technically followed by two real classroom tests in a radiology class for medical students on thoracic radiology. RESULTS: The novel ARS, called I2Vote, was successfully implemented and provided an easy to use, stable setup. The acceptance of both students and teachers was very high and the interaction with the students improved because of the anonymous interaction possibility. CONCLUSION: An easy to use handheld based ARS that enables interactive, image-based, teaching is achieved. The system effectively adds an extra dimension to the use of an ARS. PMID- 21676651 TI - Characterization of Pseudomonas stutzeri NT-I capable of removing soluble selenium from the aqueous phase under aerobic conditions. AB - Pseudomonas stutzeri strain NT-I was isolated from the drainage wastewater of a selenium refinery plant. This bacterium efficiently reduced selenate to elemental selenium without prolonged accumulation of selenite under aerobic conditions. Strain NT-I was able to reduce selenate completely at high concentrations (up to 10 mM) and selenite almost completely (up to 9 mM). In addition, higher concentrations of selenate and selenite were substantially reduced. Activity was observed under the following experimental conditions: 20-50 degrees C, pH 7-9, and 0.05-20 g L(-1) NaCl for selenate reduction, and 20-50 degrees C, pH 6-9, and 0.05-50 g L(-1) NaCl for selenite reduction. Under anaerobic conditions, selenate was reduced more rapidly, whereas selenite was not reduced at all. The high selenate- and selenite-reducing capability at high concentrations suggested that strain NT-I is suitable for the removal of selenium from high-strength industrial wastewater. PMID- 21676652 TI - Impacts of two perfluorinated compounds (PFOS and PFOA) on human hepatoma cells: cytotoxicity but no genotoxicity? AB - Perfluorinated compounds (PFCs) and particularly two of them, perfluoroctanoate (PFOA) and perfluorooctanesulfonate (PFOS), have been widely produced and used since 1950. They both persist in the environment and accumulate in wildlife and humans. The toxicity of PFOS and PFOA has been studied extensively in rodents with several adverse effects mainly a hepatocarcinogenic potential. Carcinogenic effects are not highlighted in humans' studies. In this study, we investigated the cytotoxic and genotoxic effects of PFOA and PFOS using human HepG2 cells after 1 or 24h of exposure. The cytotoxic and genotoxic potential was evaluated by MTT assay, single cell gel electrophoresis (SCGE) assay and micronucleus assay respectively. We measured the intracellular generation of reactive oxygen species (ROS) using dichlorofluorescein diacetate to identify a potential mechanism of toxicity. We observed a cytotoxic effect of PFOA and PFOS after 24h of exposure starting from a concentration of 200 MUM (MTT: -14.6%) and 300 MUM (MTT: -51.2%) respectively. We did not observe an increase of DNA damage with the comet assay or micronucleus with the micronucleus assay after exposure to the two PFCs. After 24h of exposure, both PFOA and PFOS highlight a decrease of ROS generation (-5.9% to -23%). We did not find an effect after an hour of exposure. Our findings show that PFOA and PFOS exert a cytotoxic effect on the human cells line HepG2 but nor PFOA or PFOS could induce an increase of DNA damage (DNA strand breaks and micronucleus) or reactive oxygen species at the range concentration tested. Our results do not support that oxidative stress and DNA damage are relevant for potential adverse effects of PFOA and PFOS. These results tend to support epidemiological studies that do not show evidence of carcinogenicity. PMID- 21676653 TI - Vitrification as an alternative means of cryopreserving ovarian tissue. AB - Because of the simplicity of vitrification, many authors have investigated it as an alternative to slow freezing for cryopreserving ovarian tissue. In the last decade, numerous studies have evaluated vitrification of ovarian tissue from both humans and animals.Different vitrification solutions and protocols, mostly adapted from embryo and oocyte vitrification, have been applied. The results have been discrepant from species to species and even within the same species, but lately they appear to indicate that vitrification can achieve similar or even superior results to conventional freezing. Despite the encouraging results obtained with vitrification of ovarian tissue from humans and different animal species, it is necessary to understand how vitrification solutions and protocols can affect ovarian tissue, notably preantral follicles. In addition, it is important to bear in mind that the utilization of different approaches to assess tissue functionality and oocyte quality is essential in order to validate the promising results already obtained with vitrification procedures. This review summarizes the principles of vitrification, discusses the advantages of vitrification protocols for ovarian tissue cryopreservation and describes different studies conducted on the vitrification of ovarian tissue in humans and animal species. PMID- 21676654 TI - Development and implementation of a critical pathway for patients with chest pain through action research. AB - AIMS AND BACKGROUND: We report on the development and implementation of a critical pathway for patients with chest pain making use of action research. METHODS: Firstly the population to be included in the pathway was defined and a coordinator was assigned. Secondly a multidisciplinary workgroup for the development of the pathway was instated. The actual development of the pathway consisted of four major steps: (1) evaluation of the current process of care for the chest pain unit (CPU) patients, (2) evaluation of medical evidence and practice in other hospitals, (3) optimization of the process and (4) actual drafting of the pathway. Finally the pathway development was followed by the implementation of the pathway. RESULTS: A chest pain critical pathway could be successfully developed, leading to (1) a triage flowchart based on the European Society of Cardiology guidelines categorizing patients in different risk groups; (2) CPU and hospital standing orders and protocols for the management of the different risk groups; (3) revision of physician and nursing medical records; and (4) development of admission and discharge brochures for patients and family admitted to the CPU. CONCLUSION: To our best knowledge this paper is the first to report on the use of action research to develop a critical pathway for patients with symptoms suggestive of an acute coronary syndrome admitted to a chest pain unit. Our experience suggests that it can serve as a means to reach the objective of conceiving and implementing an evidence-based pathway into everyday clinical practice. PMID- 21676655 TI - Preface: issue 25.5. PMID- 21676656 TI - Postoperative acute appendicitis after laparoscopic gastric band placement. PMID- 21676657 TI - Evaluation of nurse's attitudes toward adult patients of size. AB - BACKGROUND: Obesity is a growing epidemic in the United States, with waistlines expanding (overweight) for almost 66% of the population (National Health and Nutrition Examination Survey 1999-2004). The attitude of society, which includes healthcare providers, toward people of size has traditionally been negative, regardless of their own gender, age, experience, and occupation. The purpose of the present study was to determine whether bariatric sensitivity training could improve nursing attitudes and beliefs toward adult obese patients and whether nurses' own body mass index (BMI) affected their attitude and belief scores. METHODS: An on-line survey was conducted of nursing attitudes and beliefs regarding adult obese patients. The responses were compared between 1 hospital that offered bariatric sensitivity training and 1 that did not. The primary study measures were 2 scales that have been validated to assess weight bias: Attitudes Toward Obese Persons (ATOP) and Beliefs Against Obese Persons (BAOP). The primary outcome measures were the scores derived from the ATOP and BAOP scales. RESULTS: Data were obtained from 332 on-line surveys, to which 266 nurses responded with complete data, 145 from hospital 1 (intervention) and 121 from hospital 2 (control). The mean ATOP scores for hospital 1 were modestly greater than those for hospital 2 (18.0 versus 16.1, P = .03). However, no differences were found between the 2 hospitals for the mean BAOP scores (67.1 versus 67.1, P = .86). No statistically significant differences were found between the 2 hospitals among the BMI groups for either ATOP or BAOP. Within each hospital, no statistically significant trend was found among the BMI groups for either ATOP or BAOP. The association of BMI with the overall ATOP (r = .13, P = .04) and BOAP (r = .12, P = .05) scores was very weak, although marginally significant. The association of the overall ATOP score with the BAOP score was weak, although significant (r = .26, P < .001). CONCLUSION: Annual bariatric sensitivity training might improve nursing attitudes toward obese patients, but it does not improve nursing beliefs, regardless of the respondent's BMI. PMID- 21676658 TI - Differential contribution of XPC, RAD23A, RAD23B and CENTRIN 2 to the UV-response in human cells. AB - Several genes in human cells are activated by physical genotoxic agents in order to regenerate cell homeostasis. Among the pathways contributing to this response, nucleotide excision repair (NER) is unique in restoring the nucleotide sequence of the DNA molecule without generating mutations. The first step of NER is mediated by a protein complex composed of XPC, RAD23B, an ubiquitin receptor and CENTRIN 2, an EF-hand calcium binding protein. These three proteins are multifunctional and participate in other important biochemical pathways. We silenced the XPC, RAD23A or RAD23B genes in HeLa cells for a long period of time by using Epstein Barr Virus-derived plasmids carrying sequences coding for small interfering RNA. XPC silencing confirms an essential role for XPC in DNA repair and cell survival after ultraviolet light irradiation. RAD23A and RAD23B participate in DNA repair and cell survival with diverging functions. Our data also indicate that CENTRIN 2 is recruited onto nuclear damaged areas quickly after irradiation and that XPC plays an important role during its internalization into the nucleus of human cells. Furthermore, the inhibition of XPC expression correlates with a decreased amount of CENTRIN 2 transcript and protein, indicating that XPC is required for the fine tuning of CENTRIN 2 gene expression. Moreover, XPC-silenced cells present a reduced concentration of CENTRIN 2 that affects both its centrosomal and nuclear localization suggesting that XPC deficiency may indirectly slow down cell division. PMID- 21676659 TI - 3-Methyl-3-deazaadenine, a stable isostere of N3-methyl-adenine, is efficiently bypassed by replication in vivo and by transcription in vitro. AB - The goal of the present work was to determine the impact of N3-methyladenine (3 mA), an important lesion generated by many environmental agents and anticancer drugs, on in vivo DNA replication and in vitro RNA transcription. Due to 3-mA chemical instability, the stable isostere 3-methyl-3-deazaadenine (3-m-c(3)A) was site specifically positioned into an oligodeoxynucleotide. The oligomer was, then incorporated into a vector system that is rapidly converted to ssDNA inside yeast cells and requires DNA replication opposite the lesion for plasmid clonal selection. For control purposes, an adenine or a stable apurinic/apyrimidinic (AP)-lesion was placed at the same site. The presence of each lesion in the oligonucleotide was confirmed by MALDI-TOF analysis. Plasmids were then transfected into yeast cells. While the AP-site dramatically reduced plasmid replication in all strains, the 3-m-c(3)A had a slight effect in the rad30 background which significantly increased only in a rev3rad30 background. Considering TLS events opposite 3-m-c(3)A, the lack of Poleta was associated with a substantial increase in AT>GC transitions (p=0.0011), while in the absence of Polzeta only events derived from an error free bypass were detected. The 3-m c(3)A also did not affect in vitro transcription, while the AP-site was a strong block to T7 RNA progression when located in the transcribed strand. We conclude that, in these experimental systems, 3-m-c(3)A is efficiently bypassed by replication in vivo and by transcription in vitro. PMID- 21676660 TI - Development and validation of a liquid chromatography/tandem mass spectrometry method for quantitative determination of amoxicillin in bovine muscle. AB - A simple, quick and economical liquid chromatographic/tandem mass spectrometry (LC-MS/MS) method for the quantitative determination of amoxicillin in bovine muscle was developed and validated. The sample preparation procedure involved a liquid extraction with water, followed by a protein precipitation step with acetonitrile. The extract was purified by a liquid-liquid partition with dichloromethane and the upper aqueous layer was directly injected into the LC MS/MS system. Chromatographic separation was achieved on a reversed phase column, using a mixture of acetonitrile, water and 0.005% formic acid in water as mobile phase. Gradient elution was performed at a flow rate of 0.2 mL min-1. Amoxicillin was detected using positive electrospray ionization in selected reaction monitoring (SRM) mode and was quantified using terbutaline as internal standard. The responses for standards prepared in solvent and in matrix were equivalent and additionally the absence of signal suppression was confirmed by the post column infusion technique. Amoxicillin stability in standard solution and in matrix was investigated at different times and storage conditions. Amoxicillin standards prepared in water were stable on storage up to 20 days at -20 degrees C. Amoxicillin stability in matrix (spiked bovine muscle samples) was assessed up to 15 days at -20 degrees C. The method was validated according to the parameters requested by European Commission Decision 2002/657/EC in terms of specificity, linearity, trueness, precision, decision limit (CCalpha) and detection capability (CCbeta). All the trueness values fell within a range between 14.5% and 6.3%. Precision values for all levels of concentration tested were lower than the relative limit calculated by the Horwitz equation. The amoxicillin MRL is set at 50 MUg kg-1 and the CCalpha and CCbeta of the method were 61.2 MUg kg-1 and 72.4 MUg kg-1, respectively. PMID- 21676661 TI - Investigation of competitive binding of ibuprofen and salicylic acid with serum albumin by affinity capillary electrophoresis. AB - Ibuprofen and salicylic acid, two typical non-steroidal anti-inflammatory drugs, are used commonly as analgesic drug in clinical medicine and sometimes are co administered. When the drugs are co-administered, the drug-drug interactions may occur, and can lead to alter the safety and efficacy of drugs, resulting in variations in drug response of the co-administered drugs. Affinity capillary electrophoresis (ACE) was employed to investigate the competitive binding of ibuprofen and salicylic acid on serum albumin. Mobility ratio, derivatives from mobility shift method, was used to deduce the binding constant (K(b)). The binding constants of ibuprofen with HSA are 2.97*106 M-1 and 7.07*104 M-1, respectively; while for salicylic acid, the binding constant is 5.99*104 M-1. The competitive binding of the two drugs was investigated by addition of excessive ibuprofen into the solutions containing constant concentrations of salicylic acid and serum albumin. The results confirmed that ibuprofen and salicylic acid have different high-affinity binding site, but share some low-affinity binding sites on the serum albumin; and ibuprofen is able to partially replace salicylic acid from the preformed binary complexes of serum albumin and salicylic acid. PMID- 21676662 TI - An asymptomatic case with multiple intrahepatic portosystemic venous shunts. PMID- 21676663 TI - Refinement of ERCP by using the Olympus V-scope system with a 0.025 in. compatible and complete fixable Visiglide((r)) guidewire. AB - AIM: Prospective evaluation of the new 0.025 in. Visiglide((r)) guidewire to facilitate endoscopic retrograde cholangiopancreaticography using the Olympus V scope. MATERIALS AND METHODS: Interventional endoscopic retrograde cholangiopancreaticography was performed in 9 patients with the Olympus V-scope and the 0.025 in. Visiglide((r)) guidewire (VS group), whilst 9 other patients underwent endoscopic retrograde cholangiopancreaticography with a conventional Olympus duodenoscope using 0.035 in. conventional guidewires (controls). Exchange time of accessories, X-ray time, dose and endoscopic retrograde cholangiopancreaticography examination time were investigated. RESULTS: The VS group showed a significantly lower exchange time of endoscopic retrograde cholangiopancreaticography accessories (9; 4-10s, p<0.0001) than controls (29; 19 44s). The Visiglide((r)) guidewire was complete fixable by the elevator in 35/36 instrument exchanges (97%) compared to 16/31 exchanges (52%) using conventional guidewires. LIMITATIONS: Single-centre study, small patient numbers, two investigators. CONCLUSIONS: Endoscopic retrograde cholangiopancreaticography using the Olympus V-scope with the new 0.025 in. Visiglide((r)) guidewire enables a 3-fold faster exchange of accessories due to a nearly complete fixation of the guidewire. PMID- 21676664 TI - [Infantile bullous pemphigoid developing after hexavalent, meningococcal and pneumococcal vaccinations]. AB - Bullous pemphigoid is an acquired autoimmune blistering disorder extremely uncommon in children, characterized by circulating IgG antibodies to antigens of the epidermal basement membrane zone. In general, the clinical course of this condition is good and relapses are rare. The early diagnosis and treatment are fundamental. We present a 3-month-old girl with a blistering eruption on her palms and soles, and urticarial plaques on trunk, and face, 3 weeks after vaccine at two months (hepatitis B, diphtheria, tetanus, pertussis, polio, Haemophilus influenzae B, meningococcal C, pneumococcus). The clinical course worsened with vaccinations at 4 and 6 months. The control of lesions was achieved with oral deflazacort 1 mg/kg/day, with a gradual decrease until 3 months of therapy. The patient is still in remission after 8 months of follow-up. Bullous pemphigoid has been connected with some drugs and vaccinations, 1 day to 4 weeks after receiving immunization. Although the exact mechanism of induction is unclear, this case report has a visible relationship with vaccinations. PMID- 21676665 TI - [Neonatal meningococcal disease]. PMID- 21676666 TI - [Why don't parents vaccinate their children? Reflections on a measles outbreak in a neighbourhood of Granada]. PMID- 21676667 TI - [Coumel tachycardia. A rare arrhythmia in neonates]. PMID- 21676668 TI - Therapy for mitochondrial disorders: little proof, high research activity, some promise. AB - Mitochondrial disorders are a common group of metabolic diseases, the largest subgroup being the respiratory chain deficiencies. The most severe forms of mitochondrial dysfunction manifest in the neonatal period, rendering this group of patients the most challenging for therapy development. Heterogeneity of molecular backgrounds in the whole mitochondrial disease group has hindered therapy trials, but promising results are being gained from studies on animal models. Here I review strategies that have been tested or that can be proposed to be feasible as intervention. Many of these strategies aim to slow down the disease progression or are palliative in nature. However, currently very little evidence for any kind of therapeutic tools is available from double-blind controlled studies. PMID- 21676669 TI - [Disconnection of arteriovenous fistula: standardize the coverage of the hemorragic risk]. AB - During the disconnection of the arteriovenous fistulas, the nursing staff manages a hemorrhagic risk function of various factors requiring the use of an adapted haemostatic treatment. In front of numerous available references, it seemed interesting to us to standardize the coverage of this risk within the service of hemodialysis. We realized an audit to analyze the practices of disconnections and estimate the context of use of the haemostatic agents. A review of the consumptions as well as a medical economic study were realized on the haemostatic agents used in dialysis. A revaluation of the practices after 6 months was programmed to validate the institution of the protocol. Fifty observed disconnections brought to light numerous critical points. A decision tree was established to direct the choice of the haemostatic method. The importance of the direct compression in first intention was reminded and data sheets were realized. Two absorbable bandages were deleted by the allocation and an alginate of class III was subjected to name specific prescription. The assessment in 6 months proves the support of the teams to this new protocol by the impact on the consumptions and the follow-up of the decision tree during the disconnections. This study allowed us to harmonize a common act and to put at the disposal of the nursing only bandage haemostatics indicated in the disconnection of the arteriovenous fistulas. The spread good use was a major axis of improvement of the practices as well as a help for the integration of the new procedure. PMID- 21676670 TI - The tumor ecosystem regulates the roads for invasion and metastasis. AB - Invasive cancer cells traffic from the primary tumor ecosystem to distant metastatic sites. Experimental data are reviewed with a focus on cross-signaling between cancer cells and host cells such as myofibroblasts and mesenchymal stem cells. Invasion-associated cellular activities, namely vesicle exocytosis and epithelial to mesenchymal transition, depend on complex networks of signal transduction pathways including activation of tyrosine kinases, the Rab, Rac and Rho family of small GTPases and cadherin signaling. As clinical validation, some cell types or molecules implicated in invasion-associated activities may serve as prognostic/predictive biomarker or as target for patient-tailored therapy. PMID- 21676671 TI - Contextual influence of highly valued rewards and penalties on delay decisions in children with ADHD. AB - In this study, we examined the influence of both reward and penalty on delay decisions in subjects with ADHD. Eighteen 6- to 13-year-old boys with ADHD (combined or hyperactive-impulsive subtype) along with age- and IQ-matched control participants performed a memory game. If the children were successful at the game, they could choose between a small immediate reward (one white chip in exchange for 5 s of waiting) or a large delayed reward (two white chips in exchange for 60 s of waiting). If they failed, they could choose between a large immediate penalty (two black chips in exchange for 5 s of waiting) or a small delayed penalty (one black chip in exchange for 60 s of waiting). Subsequent to task completion, white chips were exchanged for video time and black chips were exchanged with completion of a written task. All of the participants, regardless of ADHD diagnosis, were motivated to complete the task and chose the delayed alternative most often. We conclude that under highly motivating conditions, children with ADHD are not more delay averse than children from the control group with respect to anticipation of reward and penalty. PMID- 21676672 TI - [Gram-negative bacteremia in neutropenic patients with hematologic disorders. Experiences with prophylactic use of fluoroquinolones]. AB - Gram-negative bacteremia remains a severe complication of neutropenia with a high mortality rate. For high-risk patients prophylactic use of fluoroquinolones is recommended as a preventive strategy. AIMS: To study the effect of fluoroquinolone prophylaxis on Gram-negative bacteremia. METHODS: In the retrospective survey Gram-negative bacteremic episodes occurring in a centre for hematology and stem cell transplantation were studied. Data from the year before and after instituting prophylaxis were compared with regard to the incidence of blood stream infections, spectrum of pathogens, rate of fluoroquinolone resistance and all cause mortality of affected patient population. RESULTS: Only a slight decrease in the incidence of Gram-negative bacteremia was seen (ARR: 0.024) after the introduction of fluoroquinolone prophylaxis. Spectrum of pathogens remained unchanged. However, the proportion of fluoroquinolone resistant Gram-negative isolates increased markedly (from 24% to 59%, p = 0.001), especially fluoroquinolone resistant E. coli strains became more prevalent (from 16% to 75%, p<0.001). All cause mortality at 7 and 30 days remained the same or increased insignificantly. CONCLUSIONS: With the current epidemiological background none of the expected benefits from the fluoroquinolone prophylaxis could be proven, whereas, the rate of fluoroquinolone resistance increased markedly. A reconsideration of present prophylactic strategies is suggested. PMID- 21676673 TI - [Correlation between insulin resistance and puberty in children with increased cardiometabolic risk]. AB - Epidemiologic data provide evidence that the frequency of obesity and cardiometabolic risk factors shows an increasing tendency in childhood. Insulin resistance plays a central role in the pathogenesis of cardiovascular and metabolic consequences of obesity. Transient decrease in the insulin sensitivity during puberty is a well-known physiological process; however, the feature of this phenomenon is not clear in obese children with increased cardiometabolic risk. AIM: The aim of the present study was to assess the effect of puberty on insulin resistance and metabolic parameters in obese children with and without increased cardiometabolic risk. MATERIALS AND METHODS: Anthropometric data, insulin levels during oral glucose tolerance test and lipid status were analyzed of 161 obese children aged 4-18 years. Sigmainsulin/Sigmaglucose ratio was obtained during glucose load and HOMA index was used to assess insulin resistance. Children were sorted into prepubertal (T1), pubertal (T2-4) and postpubertal (T5) cohorts according to Tanner staging criteria and metabolic and insulin resistance parameters were evaluated. Increased cardiometabolic risk was defined as the presence of any two risk factors (elevated fasting plasma glucose, blood pressure, triglyceride or decreased HDL-cholesterol) in addition to obesity. RESULTS: Out of 161 obese subjects, 43 (26.7%) had increased cardiometabolic risk. Decreased HDL-cholesterol and/or elevated triglyceride was observed in 101 (56.5%) cases. Impaired glucose tolerance and/or impaired fasting glucose was found in 23 (14.4%) cases. In subjects without increased cardiometabolic risk, the Sigmainsulin/Sigmaglucose ratio in T1 stage was significantly lower than in T2-4 and T5 stages (p = 0.01). In children with increased cardiometabolic risk, the insulin/glucose ratio was similar in T1, T2-4 and T5 stages, however, it was significantly higher in T1 stage as compared to subjects without increased cardiometabolic risk (p = 0.04). In T2-4 and T5 stages, Sigmainsulin/Sigmaglucose ratio did not differ between children with and without increased cardiometabolic risk. No difference was found in HOMA index between groups with and without increased cardiometabolic risk in T1 stage, however significantly higher levels were observed in subjects with increased cardiometabolic risk at T2-4 stages (p = 0.01), indicating the presence of fasting hyperinsulinemia in this cohort. Elevated HbA1c (>=6.0%) was found in 13 (16%) out of the 81 children investigated, of whom only two cases had abnormal oral glucose tolerance test. In cases having normal HbA1c, oral glucose tolerance test showed impaired glucose tolerance in 5 cases, impaired fasting glucose in 2 cases, both impaired glucose tolerance and impaired fasting glucose in 2 cases, and type 2 diabetes in 2 cases. CONCLUSION: Increased insulin resistance can be observed in obese children without increased cardiometabolic risk. In obese children with increased cardiometabolic risk, substantial insulin resistance occurs in prepuberty and it is present at similar level throughout puberty. Fasting insulin levels are elevated in obese subjects with increased cardiometabolic risk as compared to those without increased cardiometabolic risk. To reveal type 2 diabetes cases, HbA1c and oral glucose tolerance test results should be assessed parallel. PMID- 21676674 TI - [Effects of magnesium supplementation on calcium and magnesium levels, and redox homeostasis in normolipidemic and food-induced hyperlipidemic rats]. AB - Magnesium supplementation is quite popular because of intention of health and healthy lifestyle. However, there is no information on the metabolic effects of magnesium supplementation in healthy people and in different diseases. AIMS: Authors examined the effects of magnesium-malate on calcium, magnesium levels, and antioxidant parameters in normolipidemic and hyperlipidemic rats. METHODS: Male Wistar rats (n = 40; 150-200 g) were divided into 4 groups (control, control treated, hyperlipidemic, hyperlipidemic-treated). Rats in the control and control treated groups were fed with normal diet, while hyperlipidemic and hyperlipidemic treated groups were fed with fat rich diet (2% cholesterol, 20% sunflower oil, 0.5% cholic acid). After the 9-day-long diet the following parameters were measured: routine laboratory parameters with automatic analysator, metal content using ICP-OES, and redox-parameters using spectrophotometric and luminometric methods. RESULTS: Magnesium-malate failed to produce significant changes in the measured parameters in control animals in most cases. Magnesium-malate decreased significantly serum glucose concentration, alkaline phosphatase and amylase activities in the hyperlipidemic group. Significantly low induced chemiluminescent activity was measured in the plasma and erythrocytes of hyperlipidemic group. The magnesium supplementation did not increase significantly magnesium concentration in different organs although the calcium/magnesium concentration ratio was decreased. CONCLUSIONS: In control animals there was no significant change in the measured parameters in most cases after dietary supplementation with a large amount of magnesium for a short period of time, but magnesium supplementation affected the metal homeostasis, routine laboratory parameters and redox system in hyperlipidemic animals. Although several changes were favorable, it should be emphasized that magnesium supplementation must be applied watchfully particularly in metabolic diseases. PMID- 21676675 TI - [Important aspects of end-of-life care. Survey of patients visiting the primary care office]. AB - INTRODUCTION: Death and dying are still taboo topics in Hungary. The care of the dying, the adequate relief of their symptoms and the psychosocial support of both patients and their caregivers are not yet well addressed. AIMS: Authors obtained information about the feelings and thoughts of patients on death and dying, and about their expectations for end-of-life care. METHODS: Mailed questionnaire was send to a convenience sample of 29 adult primary care offices where a total of 845 unselected patients completed the questionnaire. RESULTS: More than two thirds (69%) of respondents would like to receive end of life care in their home. Only 19% of respondents would prefer to die in a hospital. Respondents' greatest fear was to lose their autonomy (55%). The second most noted concern was fear from pain (38%). According to 93% of the participants, truth telling is very important in the event of terminal illness. CONCLUSIONS: Hungarian patients prefer to receive end of life care in their home. Our data support the need for improvement in three primary areas, physician communication skills, pain and symptom management, and expansion of home hospice care. PMID- 21676676 TI - [Johann Misch Astrophilus' book "Medicina Pauperum" in Hungarian. Copy of a lost or hidden book from 1660]. AB - Doctors and pharmacies in the 15th Century only used handwritten copies of the prescription collections available in their time. At the beginning of book printing the publishing of prescription collections immediately became popular. They could be found on the pages of medical and pharmaceutical books of many various editions with different structure and origin, as the forerunner of the official pharmacopoeias. From the 16th Century onwards books with the title "Medicina Pauperum" were published which helped the educated people to tend to themselves, the household, the servants and their immediate surroundings case of an illness. The first work specifically on the topic or of genre of the "Medicina Pauperum" according to our knowledge appeared in Hungarian in the year 1660 and currently seems to survived only in fragments under the title of "Medicina Pauperum", from an unknown author. A rare incident occurred in the present days as a "book" believed to be lost for us turned up from thin air. It is a "copied" manuscript in the size of 97*139 mm attached to the ribs with hemp cord, cropped around and in an unbound state. The book known before only in fractions is now available entirety handwritten on 318 pages, distributed to seven distinct parts. The research of its origin suggests that the author lived and worked in Nagyszombat and was called Johann Misch Astrophilus. The identification of the printing office was possible thanks to the examination of the initials and the gaudily, as well as the fonts and the watermark. By these results the printing very likely occurred in the Brewer Printing Press in Locse. For the possibility of more extensive research and value preservation the manuscript was bounded. The facsimile edition contains the magnified and digitalized pages of the original one and is published in numbered issues. PMID- 21676678 TI - Why choose cardiothoracic surgery as a career? AB - The future of cardiothoracic surgery faces a lofty challenge with the advancement of percutaneous technology and minimally invasive approaches. Coronary artery bypass grafting (CABG) surgery, once a lucrative operation and the driving force of our specialty, faces challenges with competitive stenting and poor reimbursements, contributing to a drop in applicants to our specialty that is further fueled by the negative information that members of other specialties impart to trainees. In the current era of explosive technological progress, the great diversity of our field should be viewed as a source of excitement, rather than confusion, for the upcoming generation. The ideal future cardiac surgeon must be a "surgeon-innovator," a reincarnation of the pioneering cardiac surgeons of the "golden age" of medicine. Equipped with the right skills, new graduates will land high-quality jobs that will help them to mature and excel. Mentorship is a key component at all stages of cardiothoracic training and career development. We review the main challenges facing our specialty--length of training, long hours, financial hardship, and uncertainty about the future, mentorship, and jobs--and we present individual perspectives from both residents and faculty members. PMID- 21676679 TI - Sources of thromboembolism in patients with correctly functioning mechanical valves: a single-center transesophageal echocardiographic study. AB - BACKGROUND: In patients with mechanical prostheses (MP), thromboembolism is one of the most serious complications. The study aim was to assess the incidence of sources of thromboembolism in patients with correctly functioning MP with and without a history of thromboembolism. METHODS: Two hundred ninety-seven patients with correctly functioning MP were enrolled in this single-center, transesophageal echocardiographic (TEE), retrospective, observational study. Two groups were analyzed: Group A, 183 patients with a history of thromboembolism, and Group B, 114 patients with no history of thromboembolism. RESULTS: Definite sources of thromboembolism were revealed in 59% of patients in Group A, and sources of potential thromboembolism were revealed in 13% of patients in Group B (P < .001). Multiple sources of thromboembolism were present in 9% of patients in Group A and 1% of patients in Group B. Localization of sources of thromboembolism included MP ring (59% and 53% of patients in Groups A and B, respectively); left atrium/left atrium appendage (24%/21% and 13%/40% of patients in Groups A and B, respectively); and aorta (12% and 13% of patients in Groups A and B, respectively). Patients with multiple sources of thromboembolism were older (P < .001) and in a higher New York Heart Association (NYHA) class (P = .004). Patients with sources of thromboembolism in the aorta were older than the rest of the group (P < .01). CONCLUSIONS: In patients with correctly functioning MP, sources of thromboembolism are observed 4 times more often in case of the positive history of thromboembolism. The most common source of thromboembolism is thrombosis of MP ring. Age and heart failure predispose multiple sources of thromboembolism. One might consider control TEE after mechanical valve implantation, but only in selected group of patients without embolic events but with a higher risk of thromboembolism. PMID- 21676680 TI - Temporary extracorporeal circulatory support and pulmonary embolectomy for catastrophic amniotic fluid embolism. AB - Amniotic fluid embolism is usually a life-threatening complication of an otherwise healthy pregnancy. Medical management of the coagulopathy and cardiovascular collapse is challenging and is often unsuccessful. We present a case and advocate the use of temporary circulatory support and pulmonary embolectomy in what would otherwise have been a fatal scenario. PMID- 21676681 TI - Long-term results after Carpentier-Edwards pericardial aortic valve implantation, with attention to the impact of age. AB - BACKGROUND: The purpose of this study was to determine long-term patient survival and valve durability for Carpentier-Edwards pericardial valves (Edwards Lifesciences) implanted in the aortic position, with specific attention to the impact of patient age. METHODS: We performed a retrospective cohort study of 2168 patients who underwent implantation of a Carpentier-Edwards pericardial aortic valve between 1991 and 2008. The mean follow-up time was 4.5 years. Primary outcomes of interest were mortality and valve explantation. Survival curves and event-free curves were obtained with the Kaplan-Meier method and compared with the log-rank test. RESULTS: Survival was 92% at 1 year, 73% at 5 years, 38% at 10 years, and 18% at 15 years. Although the mortality rate of younger patients was worse than in the general population, older patients had significantly better survival than their contemporaries. Age was the independent variable most significantly associated with explantation. There was an early hazard phase for patients between 21 and 49 years of age, such that the freedom from explantation was 89% at 3 years. By 10 years, the freedom from explantation was 58% for patients 21 to 49 years of age, compared with 68% for patients 50 to 64 years, 93% for patients 65 to 74 years, and 99% for patients 75 years of age and older. CONCLUSION: We found good long-term survival and durability. Older patients had excellent freedom from explantation, whereas younger patients fared worse. As our population ages, this information becomes increasingly important. Assessing the durability of this pericardial aortic valve may aid in predicting the durability of the transcatheter aortic valves that share the same leaflets. PMID- 21676682 TI - Transcatheter aortic valve implantation after previous mechanical mitral valve replacement: expanding indications? AB - BACKGROUND: Cardiac operation for severe aortic stenosis after previous mitral valve replacement is a surgical challenge in older patients with multiple morbidities. Transcatheter aortic valve implantation (TAVI) after previous mechanical mitral valve replacement has been considered a high-risk procedure, owing to possible interference with the mitral valve prosthesis. METHODS: Since August 2008, 5 female high-risk patients with severe aortic stenosis and previous mitral valve replacement (mean +/- SD age, 80 +/- 5.1 years; logistic EuroSCORE, 39.3% +/- 20.5%) underwent TAVI with a pericardial xenograft valve that was fixed with a stainless steel, balloon-expandable stent (Edwards Lifesciences SAPIEN). We used a transapical approach in 4 patients and a transfemoral approach in 1 patient. Transesophageal echocardiography and multidetector computed tomography were used for preoperative planning and assessment of operation feasibility. The mean distance between the aortic annulus and the mitral valve prosthesis was 10 +/- 1 mm (range, 9-11 mm). RESULTS: TAVI was performed successfully in all 5 patients. There was no direct or functional interference with the mechanical mitral valve prostheses. Echocardiography revealed good valve function with no more than mild paravalvular incompetence early in the postoperative period and during routine follow-up. There were no neurologic events. After an initially uneventful course with good aortic valve function at the most recent echocardiography evaluation, however, 2 of the patients died from fulminant pneumonia on postoperative days 4 and 48. CONCLUSION: TAVI is technically feasible in high-risk patients after previous mechanical mitral valve replacement; however, careful patient selection is mandatory with respect to preoperative clinical status and anatomic dimensions regarding the distance between aortic annulus and mitral valve prosthesis. PMID- 21676683 TI - Cilostazol, a type III phosphodiesterase inhibitor, reduces ischemia/reperfusion induced spinal cord injury. AB - BACKGROUND: Spinal cord injury is still a devastating complication after surgical repair of thoracoabdominal aortic pathologies. In this study, we investigated the protective effect of cilostazol, a type III phosphodiesterase inhibitor, against ischemia/reperfusion (I/R)-induced spinal cord injury in rats. METHODS: Twenty four rats were assigned to 3 experimental study groups: the control group (sham operation, n = 8); the ischemia group (nontreated, n = 8), which underwent aortic occlusion without pharmacologic intervention; and the cilostazol-treated group (n = 8), which received 20 mg/kg cilostazol per day orally for 3 days before spinal ischemia. All animals underwent a 45-minute period of spinal cord ischemia via clamping of the abdominal aorta between the left renal artery and the aortic bifurcation; removal of the aortic clamp was followed by reperfusion. Neurologic status was assessed before spinal ischemia and at 48 hours after the operation. All animals were sacrificed at 48 hours after the operation. Spinal cords were harvested for histopathologic examination and biochemical analyses for the malondialdehyde (MDA) level and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. RESULTS: Tarlov scores at postoperative hour 48 tended to be higher in the cilostazol-treated group than in the nontreated ischemia group (mean +/- SD, 3.66 +/- 0.40 versus 2.32 +/- 0.80; P = .08). Spinal cord tissue MDA levels (per gram protein) were lower in the cilostazol-treated group than in the nontreated ischemia group (0.27 +/- 0.01 mmol/g versus 0.33 +/- 0.04 mmol/g, P = .026), and the cilostazol-treated group had higher activities of tissue SOD (519.6 +/- 56.3 U/g versus 438.9 +/- 67.4 U/g, P = .016) and GSH-Px (4.07 +/- 1.37 U/g versus 3.21 +/- 1.02 U/g, P = .47) than the nontreated ischemia group. Histopathologic analyses demonstrated that cilostazol treatment attenuated I/R-induced cellular damage. CONCLUSION: Administration of cilostazol before spinal cord ischemia reduced neurologic injury and produced clinical improvement by attenuating oxidative stress in this rat spinal cord I/R model. PMID- 21676684 TI - Do patients in congestive cardiac failure undergoing cardiac surgery demonstrate worse outcomes compared with those with a history of cardiac failure? AB - OBJECTIVES: Cardiac surgery in patients with symptoms of congestive cardiac failure (CCF) carries a significant risk of mortality and morbidity. Except for emergencies and in unstable cases, the recommendation has been to delay the operation until the patient is fully recovered. The objective of this study was to determine the consequences of cardiac surgery in patients with acute decompensated heart failure and to compare their outcomes with the results of the operation in patients with previous CCF. METHODS: We compared the outcomes of patients with CCF (n = 707) at the time of cardiac surgery (valve replacement or coronary artery bypass grafting [CABG]) with those with a history of CCF (n = 1583). The EuroSCORE was significantly higher in CCF patients (P < .001). Impaired renal function was also more commonly observed in patients with CCF (P < .001). After adjusting for preoperative characteristics, we compared the 2 groups with respect to postoperative complications, postoperative creatine kinase MB values, and in-hospital mortality. RESULTS: Before adjusting for preoperative characteristics, we found that in-hospital mortality (15.5%) and postoperative complications, such as arrhythmias (31%), renal failure (19%), stroke (4.7%), and myocardial infarction (MI) (3%), were significantly higher in the CCF group than in those with a previous history of CCF. When the patients were matched for preoperative characteristics, the rates of postoperative MI and arrhythmia were the main complications that were significantly higher in the CCF group, compared with the patients with previous CCF. The 2 groups were not significantly different with respect to in-hospital mortality. The results were not affected by the type of procedure (valve or CABG), and the main factor influencing mortality was the EuroSCORE. CONCLUSION: Despite the significant risk of mortality and morbidity in patients with current CCF, cardiac surgery to reverse the cause should not be delayed in these patients, because doing so may lead to further deterioration. Other risk factors, however, should be taken into consideration on an individual basis. PMID- 21676685 TI - Calling the heart by name: distinguished eponyms in the history of cardiac anatomy. AB - Many outstanding scientists have given their names to anatomic structures through time. Recently the use of eponyms has been at the center of a very interesting debate in the columns of prestigious medical journals. Even if some authors have questioned their adoption, not only do the names of great figures in the history of medicine appear inextricably linked to human body structures but they also have been widely adopted. Eponyms enliven medical study and practice by representing major mnemonic aids for students and learners and opening intriguing scenarios on the history of health. Given that physicians frequently are unaware of exactly "who stands behind" a name, this article presents a reconstruction of how eponyms for cardiac structures have developed through time and provides scientific profiles of the personages after whom heart districts have been named. The article is offered in the awareness that scientists of different countries and different ages have contributed to the elaboration of the knowledge of cardiac anatomy, according to their personal skills and to the health technology available in their particular times and places. PMID- 21676686 TI - Interrupted aortic arch or extreme coarctation? A case report and review of the literature. AB - The hallmark feature of aortic interruption that is useful in differentiating it from aortic coarctation is the "complete absence" of continuity between both parts of the interrupted segment. In this study, we reviewed the 28 patients diagnosed with isolated interrupted aortic arch (IAA) who reached adult age (> 20 years), aimed to review the validity of the Celoria-Patton classification in the literature, and reported the first microscopic pathology of the IAA in an adult. PMID- 21676687 TI - One-stage surgical removal of intravenous leiomyomatosis with right heart extension is safe. AB - Intravenous leiomyomatosis is a rare smooth muscle tumor. We report the case of a 42-year-old woman with both intravenous and intracardiac extension of leiomyomatosis who underwent 3 operations within 9 years. During the last admission, she underwent a successful single-stage surgical approach while under cardiopulmonary bypass with circulatory arrest. A postoperative histopathologic examination of the resected specimen confirmed the diagnosis. PMID- 21676688 TI - Late cardiac tamponade by chylous pericardial effusion after coronary artery bypass surgery: case report. AB - Chylopericardium is an uncommon but serious complication after open heart surgery that often necessitates surgical treatment. We describe a case of continuous and severely symptomatic chylous pericardial effusion after coronary artery bypass grafting in which the diagnosis was established by lipid electrophoresis. Initial conservative management failed, and ligation of the thoracic duct and pericardial fenestration were finally required for a successful outcome. PMID- 21676689 TI - Transient bilateral blindness in a patient after cardiac surgery. AB - Our report describes a case of temporary bilateral blindness in a patient after undergoing mitral valve replacement with a mechanical prosthesis and coronary artery bypass grafting. PMID- 21676690 TI - An uncommon cause of myocardial ischemia after coronary artery bypass grafting: "the dangerous drainage". AB - The most common causes of myocardial ischemia and myocardial infarction early after coronary artery bypass grafting surgery are early graft occlusion/thrombosis or occlusion/ thrombosis of coronary arteries due to advanced coronary heart disease. We describe a case of postoperative myocardial ischemia due to an uncommon and quickly reversible cause: mechanical compression of a vein graft by a 19F flexible silicone mediastinal drainage tube. PMID- 21676691 TI - Natural internal banding in adult patients with a large ventricular septal defect and a preserved pulmonary vascular system. AB - OBJECTIVE: Hypertrophied anomalous muscle bands (AMBs) in the right ventricular outflow tract (RVOT) may develop in the context of ventricular septal defects (VSDs) and limit persistent pulmonary overflow. In adult patients with a large VSD, persistent AMBs in the RVOT therefore can simulate the role of an externally placed pulmonary artery band. We termed such alterations natural internal bands (NIBs). Our goal was to establish the morphologic nature of the obstructive muscular lesions of the RVOT in patients with a large VSD. METHODS: Patients who underwent operations for a large VSD in our center, which has a high volume of adult patients with congenital defects, were retrospectively reviewed, and the nature of the NIBs in these patients was documented. All patients underwent transthoracic echocardiography and cardiac catheterization evaluations preoperatively and at postoperative month 3. Histopathologic examination of the AMBs was performed. RESULTS: Of 96 adult patients who underwent operations for a large isolated VSD (mean defect size, 16.9 +/- 3.5 mm), 16 patients had a hemodynamically significant NIB. Two different patterns of obstruction were found. Ten of the 16 patients revealed an os infundibulum morphology, and 6 patients revealed systolic bulging of the conal septum. Four of the patients with os infundibulum also had classic tetralogy-type septal malalignment. The mean peak systolic gradient on the RVOT was 56.5 +/- 17.2 mm Hg and 53.6 +/- 12.3 mm Hg in the patients with os infundibulum and in the patients with systolic bulging of the conal septum, respectively. Surgical repair of the VSD was completed successfully in all patients. Resection of the os infundibulum was performed concomitantly in patients with os infundibulum. At the third postoperative month, the mean peak systolic gradient was 16.8 +/- 3.5 mm Hg in patients with os infundibulum and 26 +/- 5.9 mm Hg (range, 20-35 mm Hg) in patients with systolic septal bulging. CONCLUSIONS: Some mechanisms in adult type VSDs are essential for protecting the pulmonary vasculature. We tried to review these protective mechanisms: hypertrophied AMBs and NIBs. PMID- 21676692 TI - Left ventricular hemangioma. AB - Cardiac hemangiomas are quite rare benign tumors of vascular origin often detected incidentally during routine examinations. Here we present the diagnostic evaluation and excisional biopsy of such a cardiac tumor in a 20-year-old man. PMID- 21676693 TI - Aneurysm of coronary sinus of Valsalva can rupture anytime! AB - An aneurysm of the sinus of Valsalva ruptures in about 35% of all cases and only leads to acute symptoms in 25% of all patients. This paper illustrates a case of a patient who was scheduled for an elective operation due to an aneurysm of the right coronary sinus of Valsalva, which ruptured and led to the necessity of an emergency surgery. PMID- 21676695 TI - [In Process Citation] PMID- 21676694 TI - A 5-Year follow-up of internet-based cognitive behavior therapy for social anxiety disorder. AB - BACKGROUND: Internet-based cognitive behavior therapy (CBT) has been shown to be a promising method to disseminate cognitive behavior therapy for social anxiety disorder (SAD). Several trials have demonstrated that Internet-based CBT can be effective for SAD in the shorter term. However, the long-term effects of Internet based CBT for SAD are less well known. OBJECTIVE: Our objective was to investigate the effect of Internet-based CBT for SAD 5 years after completed treatment. METHOD: We conducted a 5-year follow-up study of 80 persons with SAD who had undergone Internet-based CBT. The assessment comprised a diagnostic interview and self-report questionnaires. The main outcome measure was the Liebowitz Social Anxiety Scale-Self-Report (LSAS-SR). Additional measures of social anxiety were the Social Interaction Anxiety Scale (SIAS) and the Social Phobia Scale (SPS). Attrition rates were low: 89% (71/80) of the participants completed the diagnostic interview and 80% (64/80) responded to the questionnaires. RESULTS: Mixed-effect models analysis showed a significant effect of time on the three social anxiety measures, LSAS-SR, SIAS, and SPS (F(3,98-102) = 16.05 - 29.20, P < .001) indicating improvement. From baseline to 5-year follow up, participants' mean scores on the LSAS-SR were reduced from 71.3 (95% confidence interval [CI] 66.1-76.5) to 40.3 (95% CI 35.2 - 45.3). The effect sizes of the LSAS-SR were large (Cohen's d range 1.30 - 1.40, 95% CI 0.77 - 1.90). Improvements gained at the 1-year follow-up were sustained 5 years after completed treatment. CONCLUSIONS: Internet-based CBT for SAD is a treatment that can result in large and enduring effects. TRIAL REGISTRATION: Clinicaltrials.gov NCT01145690; http://clinicaltrials.gov/ct2/show/NCT01145690 (Archived by WebCite at http://www.webcitation.org/5ygRxDLfK). PMID- 21676696 TI - The luminous world of john and elisabeth buck. AB - Highlights of the research careers of John and Elisabeth Buck are presented, illustrating their importance as investigators of firefly biology including taxonomy, morphology, physiology and behavior, and as catalysts of collegial exchanges advancing progress among investigators of bioluminescence in its widest aspects over the past 50 years. PMID- 21676697 TI - Fireflies at one hundred plus: a new look at flash control. AB - The mysterious process by which fireflies can control their flashing has inspired over a century of careful observation but has remained elusive. Many studies have implicated oxygen as the controlling element in the photochemical reaction, and the discovery of nitric oxide synthetase (NOS) in the lantern has suggested that nitric oxide (NO) may control oxygen access to the light-emitting photocytes, thereby triggering the flash. However, there are several drawbacks to oxygen as a controlling agent, and in view of the prominence of peroxisomes in lantern morphology and biochemistry, we suggest that it is hydrogen peroxide that triggers the flash, and we present a model by which this may take place. PMID- 21676698 TI - Role of nitric oxide and mitochondria in control of firefly flash. AB - In light-producing cells (photocytes) of the firefly light organ, mitochondria are clustered in the cell periphery, positioned between the tracheolar air supply and the oxygen-requiring bioluminescent reactants which are sequestered in more centrally-localized peroxisomes. This relative positioning suggests that mitochondria could control oxygen availability for the light reaction. We hypothesized that active cellular respiration would make the interior regions of the photocytes relatively hypoxic, and that the "on" signal for production of bioluminescence might depend on inhibition of mitochondrial oxygen consumption, which would allow delivered oxygen to pass through the peripheral mitochondrial zone to reach peroxisomes deep in the cell interior. We published recently that exogenous NO induces bioluminescence in the intact firefly; that NO mediates octopamine-induced bioluminescence in the dissected lantern, and that nitric oxide synthase is abundant in cells of the tracheolar system of the light organ. Additional experiments showed that nitric oxide gas (NO) inhibits respiration in isolated lantern mitochondria. Inhibition is reversed by bright light, and this inhibition is relieved when the light is turned off. Altogether, the results support the idea that NO triggers light production by reversible inhibition of mitochondrial respiration in lantern cells, and probably in tracheolar cells as well. The data also suggest that the light of bioluminescence itself relieves NO inhibition thus contributing to rapid on/off switching. While other mechanisms may be in play, NO production that is directly related to neural input appears to have a key role in the oxygen gating that controls flash communication signals. PMID- 21676699 TI - Is the firefly flash regulated by calcium? AB - The very different courtship flashes of Photuris versicolor and Photuris lucicrescens males mirror the pattern of neural impulses produced by their brain. Their lanterns luminescence very differently, however, in response to direct, electrical stimulation. Whereas P. lucicrescens lanterns glow in response to high frequency, continuous electrical stimulation, those of P. versicolor produce only rapid, triple-pulsed flashlettes that resemble, but are not identical to, their courtship flashes. In addition, the exposed lantern tissue of P. versicolor males, when immersed in firefly saline high in potassium and calcium ions, scintillates with hundreds of photocytes flashing in random fashion. P. lucicrescens male lanterns, so treated, only glow. Tests of P. versicolor lanterns with salines of different composition suggest that calcium ions are essential in producing this intense, long lasting scintillation response and are therefore possibly implicated in the final stages of flash control in this species. PMID- 21676700 TI - Flash communication systems of Japanese fireflies. AB - Japanese fireflies range from nocturnal luminescent species to diurnal non luminescent species. Their communication systems are classified into 6 types based on the following criteria: 1) Female responds to male's flashes after a fixed delay; 2) Male is directly attracted by female's light signal, the male perches on a leaf near the female, then the male changes his flashes with twinkling, and copulation behavior is released. However, the female may not respond to the male; 3) Male seeks female calling signal during the male's flying and synchronous flashing, then the male approaches the female, emitting flashes with various patterns, displaying walking-luminescing, sedentary signaling, chasing, and copulating; 4) Male is attracted by continuous luminescent signals of the female, and male perches near the female, then the male distinguishes the female's light organs shape. Thereafter, the male copulation behavior is released by her sex pheromone; 5) Male and female flight occurs in the daytime; when the male approaches the female, copulation is released by the female's pheromone; weak luminescent signals may be fulfilling the function of supplementary communication signals; 6) Luminescent signals have nothing to do with communication between male and female, and copulation is released by a sex pheromone. PMID- 21676701 TI - Nuptial gifts and sexual selection in photinus fireflies. AB - The phenomenon of nuptial gift transfer during mating occurs across a remarkably wide range of taxa, and such male donations are likely to influence both pre copulatory and post-copulatory sexual selection. This paper reviews what is known about nuptial gifts in Photinus fireflies (Coleoptera: Lampyridae), and discusses the adaptive significance of spermatophores in firefly mating systems. During copulation Photinus males transfer a spiral, gelatinous spermatophore to the female: sperm are released into the female's spermatheca for storage, while the remainder of the spermatophore disintegrates within a specialized gland. Radiolabelling studies indicate that male-derived protein is used to help provision the female's developing oocytes, and multiply-mated females show increased fecundity. As most Photinus adults do not feed, these studies suggest that females should continue to forage for matings to supplement their diminishing larval reserves, even after they have gained sufficient sperm to fertilize their eggs. Male spermatophore mass declines across sequential matings, and smaller spermatophores are associated with lower paternity success in situations where males compete for fertilizations. Declining spermatophore size across sequential matings may thus lead to diminishing reproductive returns for firefly males. Taken together, these results suggest that seasonal changes in nuptial gift availability may contribute to reversals of traditional courtship roles, with male choice and female-female competition occurring as spermatophore availability declines. PMID- 21676702 TI - Flash signals, nuptial gifts and female preference in photinus fireflies. AB - The evolution of male courtship signals such as the bioluminescent flashes of fireflies may be shaped, at least in part, by female preference for particular characteristics of the male signal. These female preferences for male courtship signals may arise as a result of the benefits of choosing males with particular traits. One possible benefit of mate choice occurs if females can use male courtship signals as an honest indicator of male nutritional contributions at mating, nuptial gifts. This paper reviews female preference for male flash characteristics in Photinus fireflies (Coleoptera: Lampyridae), and the potential for females to use male flash characteristics to predict nuptial gift quality. In Photinus firefly species with single pulse flashes females preferentially respond to flashes of greater intensity and duration. Male Photinus provide a nuptial gift to females at mating in the form of a spermatophore and flash duration serves as a good predictor of spermatophore mass for males collected early in the season. However, Photinus fireflies do not feed as adults, so spermatophore mass decreases with subsequent matings. In response, nutrient-limited females may stop preferentially responding to longer duration flashes, increasing their overall responsiveness later in the mating season as they forage for spermatophores. Therefore, the evolution of male courtship signals in Photinus fireflies is the product not only of female preference for male flash characteristics, but also the costs and benefits of female choice that shape these preferences. PMID- 21676703 TI - Allometry and proximate mechanisms of sexual selection in photinus fireflies, and some other beetles. AB - Ever since Darwin identified it as the force responsible for the evolution of exaggerated male characters, sexual selection has been the focus of research aimed at understanding the most bizarre and intriguing morphologies and behaviors in Nature. Two congeneric species in the firefly genus Photinus, P. pyralis and P. macdermotti, afford a unique opportunity to examine the interaction between sexual and countervailing natural selection that act to shape the evolution of mating behavior and body size in closely related species with very different courtship strategies. Photinus pyralis males emit very bright flashes during their extended patrolling flights and form 'love knots' of competing suitors, while P. macdermotti males, whose courtships seldom exceed two competing males, produce weaker flashes during a shorter patrolling period.Possibly as a consequence of their scramble competition and long flights, not only is there an extremely wide range of body sizes in P. pyralis males, but they also exhibit wing allometric slopes greater than one, and lantern allometries less than one. In contrast, P. macdermotti males do not have allometric slopes significantly different from one. Small males, when tested in an artificial scramble situation move faster than large males, an advantage in the intense competition that ensues once a female is located. Females answer several males in alternation and fail to respond to all male flashes, with the evident consequence that love knots frequently develop around such fickle females. Allometric relationships in two non-luminescent beetle species with non-visual courtship protocols are compared. Visual, sexually selected characters showed positive allometric slopes, while non visual characters showed isometry or negative slopes. Data presented here support the existence of distinct patterns in modality-specific sexual selection. PMID- 21676704 TI - Flight Studies on Photic Communication by the Firefly Photinus pyralis. AB - Flash communication by the firefly Photinus pyralis was studied in a stationary, simulated flight apparatus in which an individual of either sex could be "flown" and its flashing behavior and flight orientation recorded in response to photic stimulation. Males made long "flights" showing many of the characteristics of their natural, female-seeking patrol flights. Males oriented their flight vectors towards light emitting diode (LED) flashes that mimicked the responses of females to their patrol flashes. Females flew and responded to male-emulating LED flashes, making a previously unknown early response followed by the typical 2 sec delayed response characteristic of the dialoging perched female, including abdominal aiming of the flash. Pairs consisting of males, in tethered flight, and females, perched, were run in an integrating sphere photometer, permitting the first determinations of flash intensities of both sexes during courtship dialog. The implications of this work on thought about evolution of photic behavior in fireflies are considered. PMID- 21676705 TI - Flash Precision at the Start of Synchrony in Photuris frontalis. AB - Synchronous flashing occurs in certain species of Southeast Asian and North American fireflies. Most Southeast Asian synchrony involves stationary congregating fireflies, but North American synchrony occurs in flying fireflies that do not congregate. Southeast Asian synchrony is usually continuous, but North American synchrony is interrupted. Photuris frontalis, the only member of the North American genus Photuris to synchronize, shows an intermittent synchrony. This involves synchronization and repeated re-synchronizations while in flight. The precision that occurs at the start of synchrony was studied in Ph. frontalis using caged fireflies and photometry. Barrier experiments (using two fireflies) or flash entrainment experiments (using one LED and one firefly) were performed to measure the temporal precision of the first entrained flash. In both cases, the first entrained flash was close to unison synchrony (phase = 1.0) and showed little variability. The behavioral implications of the ability to synchronize with the first entrained flash are not known, but it might facilitate male-male interactions during brief, transient encounters such as maintaining distance between closely flying males in search of females. PMID- 21676707 TI - Chronobiology: biological timekeeping. PMID- 21676706 TI - Fireflies as a catalyst for science education. AB - The study of fireflies makes an ideal subject for introducing students of all ages to the world of science, conservation biology, field studies and the importance of observation and understanding connections in the natural world.The synchronous fireflies, Photinus carolinus of the Great Smoky Mountains National Park's Elkmont Historic District can be used as a basis for classroom and field activities in subjects as diverse as conservation biology, economics, geography, ecology, governmental policy, zoology, history, taxonomy and animal behavior.Having been fascinated with the synchronous fireflies for over two decades, I will use the life cycle of the Elkmont Phontinus carolinus found in the Great Smoky Mountains National Park as an example. PMID- 21676708 TI - The comparative biology of ethanol consumption: an introduction to the symposium. PMID- 21676709 TI - Molecular Genetic Analysis of Ethanol Intoxication in Drosophila melanogaster. AB - Recently, the fruit fly Drosophila melanogaster has been introduced as a model system to study the molecular bases of a variety of ethanol-induced behaviors. It became immediately apparent that the behavioral changes elicited by acute ethanol exposure are remarkably similar in flies and mammals. Flies show signs of acute intoxication, which range from locomotor stimulation at low doses to complete sedation at higher doses and they develop tolerance upon intermittent ethanol exposure. Genetic screens for mutants with altered responsiveness to ethanol have been carried out and a few of the disrupted genes have been identified. This analysis, while still in its early stages, has already revealed some surprising molecular parallels with mammals. The availability of powerful tools for genetic manipulation in Drosophila, together with the high degree of conservation at the genomic level, make Drosophila a promising model organism to study the mechanism by which ethanol regulates behavior and the mechanisms underlying the organism's adaptation to long-term ethanol exposure. PMID- 21676710 TI - Dietary Ethanol Mediates Selection on Aldehyde Dehydrogenase Activity in Drosophila melanogaster. AB - Ethanol is an important environmental variable for fruit-breeding Drosophila species, serving as a resource at low levels and a toxin at high levels. The first step of ethanol metabolism, the conversion of ethanol to acetaldehyde, is catalyzed primarily by the enzyme alcohol dehydrogenase (ADH). The second step, the oxidation of acetaldehyde to acetate, has been a source of controversy, with some authors arguing that it is carried out primarily by ADH itself, rather than a separate aldehyde dehydrogenase (ALDH) as in mammals. We review recent evidence that ALDH plays an important role in ethanol metabolism in Drosophila. In support of this view, we report that D. melanogaster populations maintained on ethanol supplemented media evolved higher activity of ALDH, as well as of ADH. We have also tentatively identified the structural gene responsible for the majority of ALDH activity in D. melanogaster. We hypothesize that variation in ALDH activity may make an important contribution to the observed wide variation in ethanol tolerance within and among Drosophila species. PMID- 21676711 TI - The evolutionary ecology of ethanol production and alcoholism. AB - Understanding the evolutionary ecology of ethanol production may yield insights into why humans are prone to excessive consumption of ethanol. In particular, Dudley (2000) suggested that human ancestors developed a genetically based attraction to ethanol because they could use its odor plume to locate fruiting trees and because of health benefits from its consumption. If so, ethanol should be common in wild fruits and frugivores should prefer fruits with higher ethanol content. A literature review reveals that ethanol is indeed common in wild fruits but that it typically occurs in very low concentrations. Furthermore, frugivores strongly prefer ripe over rotting fruits, even though the latter may contain more ethanol. (Data on ethanol content of ripe and rotting wild fruit are lacking.) These results cast doubt on Dudley's hypothesis and raise the question of how humans became exposed to sufficiently high concentrations of ethanol to allow its excessive consumption. Because fermentation is an ancient and widespread practice, I suggest that humans "discovered" ethanol while using fermentation as a food preservation technique. They may have been predisposed to consume ethanol from previous and beneficial exposure to much lower doses or they may have become addicted to it at high concentrations because of fortuitous physiological responses. PMID- 21676712 TI - The possible roles of ethanol in the relationship between plants and frugivores: first experiments with egyptian fruit bats. AB - In this paper we discuss how yeast, fungi ubiquitously present in sugar-rich fruit, can influence the interaction between frugivores and fleshy-fruited plants via ethanol. We suggest that plants, the seeds of which are mostly dispersed by vertebrates, exploit the ethanol from alcoholic fermentation by yeast in their seed dispersal strategy. Moderate consumption of ethanol, i.e., at concentrations close to those in naturally ripening fruit, by frugivores may have beneficial short- and long-term effects for these potential dispersers, whereas consumption of larger quantities may have negative short- and long-term effects. Ethanol vapor emanating from palatable fruit may act as an odor cue, guiding bats and other frugivores to the fruit, and aiding them to assess its quality. In addition, we suggest that ingested ethanol may be an appetitive stimulant. We also evaluate the possibility that ethanol within fruit may be used as a source of energy by frugivorous vertebrates. Our preliminary data indicate that Egyptian fruit bats (Rousettus aegyptiacus) can use the odor of ethanol to assess food suitability, but also that it may not serve as an attractant over short distances (i.e., <1 m). Instead, ethanol is avoided at concentrations greater than 1%, a value which might typically characterize overripe and otherwise unpalatable fruit. Our initial results further indicate that Egyptian fruit bats significantly decrease their food consumption if it contains 1 or 2% ethanol. Overall, ethanol may play diverse roles in the nutritional ecology and behavior of fruit-eating bats, and in the interaction between frugivores and plants, in general. PMID- 21676713 TI - Fruits, fingers, and fermentation: the sensory cues available to foraging primates. AB - Survival and reproductive success hinge on the perception of environmental stimuli. In this regard, foraging efficiency depends on discerning predictive signals in food. A widespread occurrence of ethanol in fruits indicates a sustained historical exposure of frugivores to this compound. Accordingly, Dudley (2000, Quart. Rev. Biol. 75:3-15) proposed that ethanol could represent a prominent sensory cue to primates because of direct and indirectly associated caloric and physiological rewards. However, little is known regarding the extent to which ethanol correlates with such parameters. This information is essential to estimating the importance of detecting and detoxifying ethanol in fruits. Here I present a preliminary analysis of fruits from Southeast Asia; low levels of ethanol were present in fruits of all developmental stages (range: 0.005-0.48%). Moreover, ethanol correlated positively with concentrations of soluble sugars, suggesting that it could be a valuable foraging cue. Recent findings on the sensitivity of primate olfaction and gustation to ethanol are consistent with this notion. However, when primates smell fruits deliberately, it often occurs together with digital and/or dental evaluation of texture. Here I show that softening texture also characterizes the fruit ripening process, and that color is of ambiguous importance to primates possessing trichromatic vision. I discuss the relevance of these findings to the origins of primates and the ecology of key sensory systems and deduce that detecting and selecting fruits on the basis of cues other than color is a persistent theme in primate evolution. Ethanol has likely played a significant and underestimated role in the regulation of primate foraging behavior. PMID- 21676714 TI - Ferment in the family tree: does a frugivorous dietary heritage influence contemporary patterns of human ethanol use? AB - Humans and apes are placed together in the superfamily Hominoidea. The evolutionary trajectory of hominoids is intimately bound up with the exploitation of ripe, fleshy fruits. Fermentation of fruit sugars by yeasts produces a number of alcohols, particularly ethanol. Because of their pre-human frugivorous dietary heritage, it has been hypothesized that humans may show pre-existing sensory biases associating ethanol with nutritional rewards. This factor, in turn, could influence contemporary patterns of human ethanol use. At present, there seems little evidence to support a view of selection specifically for ethanol detection or its utilization over the course of hominoid evolution. Ethanol concentration in wild fruits consumed by monkeys and apes is predicted to be low. Wild monkeys and apes avoid consumption of over-ripe fruits, the class showing notable ethanol concentrations, and for this reason, ethanol plumes may act as deterrents rather than attractants. Any energetic benefits to wild primates from ingested ethanol appear negligible, at best. Mice and rats show patterns of ethanol self administration similar to humans, indicating that a frugivorous dietary heritage is not necessary for such behaviors. In the natural environment, ethanol is predicted to be just one of many alcohols, esters and related compounds routinely encountered by frugivorous primates and of no particular significance. The strong attraction ethanol holds for some individuals could be due to a broad range of genetic and environmental factors. In some humans, the appetite for ethanol appears related to the appetite for sugar. The predisposition some individuals display toward excessive ethanol consumption could involve features of their genetics and biochemical similarities of ethanol and carbohydrate. Regular low ethanol intake is hypothesized to lower the incidence of cardiovascular disease in humans, perhaps through its effects on body fat distribution. Such a benefit, if confirmed, would appear to relate to features of the contemporary human rather than pre-human diet. PMID- 21676715 TI - Ethanol, fruit ripening, and the historical origins of human alcoholism in primate frugivory. AB - Ethanol is a naturally occurring substance resulting from the fermentation by yeast of fruit sugars. The association between yeasts and angiosperms dates to the Cretaceous, and dietary exposure of diverse frugivorous taxa to ethanol is similarly ancient. Ethanol plumes can potentially be used to localize ripe fruit, and consumption of low-concentration ethanol within fruit may act as a feeding stimulant. Ripe and over-ripe fruits of the Neotropical palm Astrocaryum standleyanum contained ethanol within the pulp at concentrations averaging 0.9% and 4.5%, respectively. Fruit ripening was associated with significant changes in color, puncture resistance, sugar, and ethanol content. Natural consumption rates of ethanol via frugivory and associated blood levels are not known for any animal taxon. However, behavioral responses to ethanol may have been the target of natural selection for all frugivorous species, including many primates and the hominoid lineages ancestral to modern humans. Pre-existing sensory biases associating this ancient psychoactive compound with nutritional reward might accordingly underlie contemporary patterns of alcohol consumption and abuse. PMID- 21676716 TI - Alcohol and cardiovascular health. AB - The substantial medical risks of heavy alcohol drinking as well as the existence of a safe drinking limit have been evident for centuries. Modern epidemiologic studies also show lower risk of both morbidity and mortality among lighter drinkers. Defining "heavy" as >=3 standard drinks per day, the alcohol-mortality relationship is a J-curve with risk highest for heavy drinkers, lowest for light drinkers and intermediate for abstainers. A number of non-cardiovascular and cardiovascular problems contribute to the increased mortality risk of heavier drinkers. The lower risk of light drinkers is due mostly to lower risk of the most common cardiovascular condition, coronary heart disease (CHD). Thus, disparate relationships of alcoholic drinking to various cardiovascular and non cardiovascular conditions constitute a modern concept of alcohol and health. Increased cardiovascular risks of heavy drinking include: 1) alcoholic cardiomyopathy, 2) systemic hypertension (high blood pressure), 3) heart rhythm disturbances in binge drinkers, and 4) hemorrhagic stroke. Lighter drinking is unrelated to increased risk of any cardiovascular condition and, in observational studies, is consistently related to lower risk of CHD and ischemic stroke. A protective hypothesis for CHD is robustly supported by evidence for plausible biological mechanisms attributable to ethyl alcohol. International comparisons and some prospective study data suggest that wine is more protective against CHD than liquor or beer. Possible non-alcohol beneficial components in wine (especially red) support possible extra protection by wine, but a healthier pattern of drinking or more favorable risk traits in wine drinkers may also be involved. PMID- 21676717 TI - In memoriam. PMID- 21676718 TI - Patterns and processes in the evolution of fishes: an introduction to the symposium. PMID- 21676719 TI - Evolution and phylogeny of gonad morphology in bony fishes. AB - Gonad morphology at the gross anatomical or histological levels has long been studied by fisheries biologists to identify annual reproductive cycles and length of breeding season, among other goals. Comparative surveys across vertebrate taxa have not been detailed enough, however, to describe fully the differences and similarities among gonads of bony fishes and other vertebrates, and to use gonad morphology in phylogenetic systematic analyses. An emerging constant among vertebrates is the presence of a germinal epithelium composed of somatic and germ cells in both males and females. In females, the germinal epithelium lines the ovarian lamellae. In males, arrangement of the germinal epithelium into compartments varies among osteichthyans: basal taxa have an anastomosing tubular testis, whereas derived taxa have a lobular testis. The lobular testis is proposed as a synapomorphy of the Neoteleostei. The annual reproductive cycle is hypothesized to be the source of morphological variation among testis types. Elongation of germinal compartments during early maturation may result in a transition from anastomosing tubular to lobular testes. In all male atherinomorphs surveyed, spermatogonia are restricted to the distal termini of lobules rather than being distributed along the lobule; there is an epithelioid arrangement of Sertoli and germ cells rather than a germinal epithelium. Arrest of the maturation-regression phases is hypothesized to lead to formation of the atherinomorph testis. Atherinomorphs also have a distinctive egg with fluid, rather than granular, yolk. Variation among germinal epithelia is interpreted in a developing phylogenetic framework to understand evolution of gonad morphology and to propose gonad characters for phylogenetic analyses. PMID- 21676720 TI - The importance of even highly incomplete fossil taxa in reconstructing the phylogenetic relationships of the tetraodontiformes (acanthomorpha: pisces). AB - The use of fossils in the phylogenetics of extant clades traditionally has been a contentious issue. Fossils usually are relatively incomplete, and their use commonly leads to an increase in the number of equally most parsimonious trees and a decrease in the resolution of phylogenies. Fossils alone, however, provide certain kinds of information about the biological history of a clade, and computer simulations have shown that even highly incomplete material can, under certain circumstances, increase the accuracy of a phylogeny, rather than decrease it.Because empirical data are still scarce on the effects of the inclusion of fossils on phylogenetic reconstructions, we attempted to investigate this problem by using a relatively well-known group of acanthomorph fishes, the Tetraodontiformes (triggerfishes, pufferfishes, and ocean sunfishes), for which robust phylogenies using extant taxa already exist and that has a well-studied fossil record. Adding incomplete fossil taxa of tetraodontiforms usually increases the number of equally most parsimonious trees and often decreases the resolution of consensus trees. However, adding fossil taxa may help to correctly establish relationships among lineages that have experienced high degrees of morphological diversification by allowing for a reinterpretation of homologous and homoplastic features, increasing the resolution rather than decreasing it. Furthermore, taxa that were scored for 25% or more of their characters did not cause a significant loss of resolution, while providing unique biological information. PMID- 21676721 TI - Are genome evolution, organism complexity and species diversity linked? AB - Fishes represent an extremely diverse group of vertebrates with a deeply rooted evolutionary history. An understanding of their biology is being enriched by advancements in phylogenetic analysis and genomics, which are providing the framework for deciphering their evolutionary relationships and the molecular details that govern their evolution. Recent discoveries about the structure and function of fish genomes suggest the occurrence of large-scale genome level duplications within the stem lineage of the Actinopterygii (ray-finned fishes). However, little is understood about the effects, if any, of this event in relation to organismal complexity or species diversity. In this manuscript, I propose a hypothesis to test whether there is a likely relationship linking vertebrate genomes, organisms and species diversity. In so doing, I discuss the problems inherent in defining the complexity of genomes and organisms and provide simplifying assumptions that enable a preliminary test of the hypothesis. Results of this test suggest the likelihood of linkage between large-scale genome changes and organismal complexity early in vertebrate evolution but not in the evolution of the ray-finned fishes. A particularly interesting implication of the results is that there may be a limit to the effects of genome level duplications on organismal complexity and species diversity. PMID- 21676722 TI - Phylogeny and jaw ontogeny of beloniform fishes. AB - To investigate jaw evolution in beloniform fishes, we reconstructed the phylogeny of 54 species using fragments of two nuclear (RAG2 and Tmo-4C4) and two mitochondrial (cytochrome b and 16S rRNA) genes. Our total molecular evidence topology refutes the monophyly of needlefishes (Belonidae) and halfbeaks (Hemiramphidae), but supports the monophyly of flyingfishes (Exocoetidae) and sauries (Scomberesocidae). Flyingfishes are nested within halfbeaks, and sauries are nested within needlefishes. Optimization of jaw characters on the tree reveals a diverse array of evolutionary changes in ontogeny. During their development, needlefishes pass through a "halfbeak" stage that closely resembles the adult condition in the hemiramphid halfbeaks. The reconstruction of jaw transitions falsifies the hypothesis that halfbeaks are paedomorphic derivatives of needlefishes. Instead, halfbeaks make up a basal paraphyletic grade within beloniforms, and the needlefish jaw morphology is relatively derived. The parallel between needlefish ontogeny and beloniform phylogeny is discussed, and clades amenable to future morphological analysis are proposed. PMID- 21676723 TI - Evolution of levers and linkages in the feeding mechanisms of fishes. AB - The evolution of feeding mechanisms in the ray-finned fishes (Actinopterygii) is a compelling example of transformation in a musculoskeletal complex involving multiple skeletal elements and numerous muscles that power skull motion. Biomechanical models of jaw force and skull kinetics aid our understanding of these complex systems and enable broad comparison of feeding mechanics across taxa. Mechanical models characterize how muscles move skeletal elements by pulling bones around points of rotation in lever mechanisms, or by transmitting force through skeletal elements connected in a linkage. Previous work has focused on the feeding biomechanics of several lineages of fishes, but a broader survey of skull function in the context of quantitative models has not been attempted. This study begins such a survey by examining the diversity of mechanical design of the oral jaws in 35 species of ray-finned fishes with three main objectives: (1) analyze lower jaw lever models in a broad phylogenetic range of taxa, (2) identify the origin and evolutionary patterns of change in the linkage systems that power maxillary rotation and upper jaw protrusion, and (3) analyze patterns of change in feeding design in the context of actinopterygian phylogeny. The mandibular lever is present in virtually all actinopterygians, and the diversity in lower jaw closing force transmission capacity, with mechanical advantage ranging from 0.04 to 0.68, has important functional consequences. A four-bar linkage for maxillary rotation arose in the Amiiformes and persists in various forms in many teleost species. Novel mechanisms for upper jaw protrusion based on this linkage for maxillary rotation have evolved independently at least five times in teleosts. The widespread anterior jaws linkage for jaw protrusion in percomorph fishes arose initially in Zeiformes and subsequently radiated into a wide range of premaxillary protrusion capabilities. PMID- 21676724 TI - Connectivity, recruitment variation, and the structure of reef fish communities. AB - Coral reefs contain the most speciose communities of fishes on this planet, so it is appropriate to use these to explore how fish species are organized into communities. While descriptive data suggest that the diverse communities of fish on coral reefs are equilibrial assemblages of species, all finely adapted to specific and unique ecological roles, these are highly dynamic, non-equilibrial assemblages with structure driven more by patterns of recruitment and loss of individual fishes, than by patterns of resource allocation among differently adapted phenotypes. As a consequence, local assemblages differ in structure, and structure wanders through time. Individual fish are confronted by different mixes of species in different times and places. The recruitment process that drives these dynamics is complex, being governed by several mechanisms, and local populations receive some portion of their recruitment from distant sources. Information on this connectivity among local populations is critically important for management which is based increasingly on use of marine protected areas (no take zones) both to conserve, and to provide sustainable fisheries. At present, however, we do not know the spatial scale or the extent of this connectivity, and this critical knowledge gap impedes both management, and fundamental understanding. PMID- 21676725 TI - Evolution of thermal reaction norms for growth rate and body size in ectotherms: an introduction to the symposium. PMID- 21676726 TI - Sensitivity of intraspecific latitudinal clines of body size for tetrapods to sampling, latitude and body size. AB - Recent studies have shown that most tetrapod groups (mammals, birds, chelonians, amphibians) show general intraspecific tendencies for increasing body size with latitude, whereas squamates (lizards and snakes) show an intraspecific tendency towards decreasing body size with latitude. Here I evaluate whether these size trends are general by using independent contrasts analysis to investigate the dependence of intraspecific size-latitude relationships (r), and the magnitude alone of size-latitude relationships ([r]), for tetrapod vertebrates, on sample size, range of latitudes sampled, average latitude sampled, and body size. Range of latitudes sampled, average latitude sampled, and body size did not influence body size-latitude relationships (r) or the magnitude alone of body size-latitude relationship ([r]). Sample size did not influence size-latitude relationships (r), but did influence the magnitude alone of size-latitude relationships ([r]), possibly indicating increased precision of estimating size-latitude relationships with increased sampling. In short, intraspecific size-latitude relationships are similar for species of different sizes, occurring at different latitudes, sampled over different latitudinal ranges, and differing in number of populations sampled (though magnitude alone is influenced by sample size). These results suggest that intraspecific size-latitude trends are general, and biologically significant (i.e., are not artifacts of sampling), thus deserving explanation. PMID- 21676727 TI - Bergmann and converse bergmann latitudinal clines in arthropods: two ends of a continuum? AB - Two seemingly opposite evolutionary patterns of clinal variation in body size and associated life history traits exist in nature. According to Bergmann's rule, body size increases with latitude, a temperature effect. According to the converse Bergmann rule, body size decreases with latitude, a season length effect. A third pattern causally related to the latter is countergradient variation, whereby populations of a given species compensate seasonal limitations at higher latitudes by evolving faster growth and larger body sizes compared to their low latitude conspecifics. We discuss these patterns and argue that they are not mutually exclusive because they are driven by different environmental causes and proximate mechanisms; they therefore can act in conjunction, resulting in any intermediate pattern. Alternatively, Bergmann and converse Bergmann clines can be interpreted as over- and undercompensating countergradient variation, respectively. We illustrate this with data for the wide-spread yellow dung fly, Scathophaga stercoraria (Diptera: Scathophagidae), which in Europe shows a Bergmann cline for size and a converse Bergmann cline (i.e., countergradient variation) for development time. A literature review of the available evidence on arthropod latitudinal clines further shows a patterned continuum of responses. Converse Bergmann clines due to end-of-season time limitations are more common in larger species with longer development times. Our study thus provides a synthesis to the controversy about the importance of Bergmann's rule and the converse Bergmann rule in nature. PMID- 21676728 TI - Phenotypic flexibility and physiological tradeoffs in the feeding and growth of marine bivalve molluscs. AB - Bivalve molluscs have a highly plastic feeding and growth physiology. The increasing availability of families artificially selected for faster growth has enabled physiological experiments to investigate the genetic basis for variable rates of growth. Fast growth is achieved by a combination of increased rates of feeding, reduced metabolic rates and lower metabolic costs of growth. In at least one species there is a trade-off between growth in protein and the storage of lipids that are utilized in gametogenesis. Energy requirements for maintenance are also higher in slow-growing individuals. Reduced costs of growth are due in part to increased efficiencies of protein turnover. Nevertheless, high protein turnover (and therefore high metabolic cost) may benefit fitness in the later stages of gametogenesis. Faster feeding rates do not impair flexibility in feeding behavior which compensates for changes in the food environment. Both inter- and intra-species differences in feeding behavior are evident and suggest possible constraints imposed by faster feeding on the efficiency of selection between food particles of different nutritional value. PMID- 21676729 TI - Body size clines in sceloporus lizards: proximate mechanisms and demographic constraints. AB - Although most species of animals examined to date exhibit Bergmann's clines in body size, squamates tend to exhibit opposing patterns. Squamates might exhibit reversed Bergmann's clines because they tend to behaviorally regulate their body temperature effectively; the outcome of this thermoregulation is that warmer environments enable longer daily and annual durations of activity than cooler environments. Lizards of the genus Sceloporus provide an opportunity to understand the factors that give rise to contrasting thermal clines in body size because S. undulatus exhibits a standard Bergmann's cline whereas S. graciosus exhibits a reverse Bergmann's cline. Interestingly, rapid growth by individuals of both species involves adjustments of physiological processes that enable more efficient use of food. Patterns of adult body size are likely the evolutionary consequence of variation in juvenile survivorship among populations. In S. undulatus, delayed maturation at a relatively large body size is exhibited in cooler environments where juveniles experience higher survivorship, resulting in a Bergmann's cline. In S. graciosus, high juvenile survivorship is not consistently found in cooler environments, resulting in no cline or a reversed Bergmann's cline, i.e., geographic patterns in body size aren't necessarily produced by natural selection. Thus, discerning the mechanistic links between the thermal physiology of an organism and environment-specific rates of mortality will be critical to understanding the evolution of body size in relation to environmental temperature. PMID- 21676730 TI - The physiological basis of reaction norms: the interaction among growth rate, the duration of growth and body size. AB - The general effects of temperature and nutritional quality on growth rate and body size are well known. We know little, however, about the physiological mechanisms by which an organism translates variation in diet and temperature into reaction norms of body size or development time. We outline an endocrine-based physiological mechanism that helps explain how this translation occurs in the holometabolous insect Manduca sexta (Sphingidae). Body size and development time are controlled by three factors: (i) growth rate, (ii) the timing of the cessation of juvenile hormone secretion (measured by the critical weight) and (iii) the timing of ecdysteroid secretion leading to pupation (the interval to cessation of growth [ICG] after reaching the critical weight). Thermal reaction norms of body size and development time are a function of how these three factors interact with temperature. Body size is smaller at higher temperatures, because the higher growth rate decreases the ICG, thereby reducing the amount of mass that can accumulate. Development time is shorter at higher temperatures because the higher growth rate decreases the time required to attain the critical weight and, independently, controls the duration of the ICG. Life history evolution along altitudinal, latitudinal and seasonal gradients may occur through differential selection on growth rate and the duration of the two independently controlled determinants of the growth period. PMID- 21676731 TI - Plasticity of size and growth in fluctuating thermal environments: comparing reaction norms and performance curves. AB - Ectothermic animals exhibit two distinct kinds of plasticity in response to temperature: Thermal performance curves (TPCs), in which an individual's performance (e.g., growth rate) varies in response to current temperature; and developmental reaction norms (DRNs), in which the trait value (e.g., adult body size or development time) of a genotype varies in response to developmental temperatures experienced over some time period during development. Here we explore patterns of genetic variation and selection on TPCs and DRNs for insects in fluctuating thermal environments. First, we describe two statistical methods for partitioning total genetic variation into variation for overall size or performance and variation in plasticity, and apply these methods to available datasets on DRNs and TPCs for insect growth and size. Our results indicate that for the datasets we considered, genetic variation in plasticity represents a larger proportion of the total genetic variation in TPCs compared to DRNs, for the available datasets. Simulations suggest that estimates of the genetic variation in plasticity are strongly affected by the number and range of temperatures considered, and by the degree of nonlinearity in the TPC or DRN. Second, we review a recent analysis of field selection studies which indicates that directional selection favoring increased overall size is common in many systems-that bigger is frequently fitter. Third, we use a recent theoretical model to examine how selection on thermal performance curves relates to environmental temperatures during selection. The model predicts that if selection acts primarily on adult size or development time, then selection on thermal performance curves for larval growth or development rates is directly related to the frequency distribution of temperatures experienced during larval development. Using data on caterpillar temperatures in the field, we show that the strength of directional selection on growth rate is predicted to be greater at the modal (most frequent) temperatures, not at the mean temperature or at temperatures at which growth rate is maximized. Our results illustrate some of the differences in genetic architecture and patterns of selection between thermal performance curves and developmental reaction norms. PMID- 21676732 TI - Plastic and Genetic Variation in Wing Loading as a Function of Temperature Within and Among Parallel Clines in Drosophila subobscura. AB - Drosophila subobscura is a European (EU) species that was introduced into South America (SA) approximately 25 years ago. Previous studies have found rapid clinal evolution in wing size and in chromosome inversion frequency in the SA colonists, and these clines parallel those found among the ancestral EU populations. Here we examine thermoplastic changes in wing length in flies reared at 15, 20, and 25 degrees C from 10 populations on each continent. Wings are plastically largest in flies reared at 15 degrees C (the coldest temperature) and genetically largest from populations that experience cooler temperatures on both continents. We hypothesize that flies living in cold temperatures benefit from reduced wing loading: ectotherms with cold muscles generate less power per wing beat, and hence larger wings and/or a smaller mass would facilitate fight. We develop a simple null model, based on isometric growth, to test our hypothesis. We find that both EU and SA flies exhibit adaptive plasticity in wing loading: flies reared at 15 degrees C generally have lower wing loadings than do flies reared at 20 degrees C or 25 degrees C. Clinal patterns, however, are strikingly different. The ancestral EU populations show adaptive clinal variation at rearing a temperature of 15 degrees C: flies from cool climates have lower wing loadings. In the colonizing populations from SA, however, we cannot reject the null model: wing loading increases with decreasing clinal temperatures. Our data suggest that selective factors other than flight have favored the rapid evolution of large overall size at low environmental temperatures. However, selection for increased flight ability in such environments may secondarily favor reduced body mass. PMID- 21676733 TI - Growth strategies and optimal body size in temperate pararginii butterflies. AB - In temperate insects the evolution of growth strategies and the optimal age and size at maturity will depend strongly on seasonal variation in temperature and other resources. However, compared to photoperiod, temperature itself is a relatively poor predictor of seasonal change and timing decisions in insects are often most strongly influenced by the photoperiod. Here I review the evolution of seasonal growth strategies in the butterfly tribe Pararginii (Satyrinae: Nymphalidae) and relate it to life history theory. The results indicate that individual larvae may adjust their growth trajectories in relation to information on time horizons obtained from the photoperiod. The growth strategies can be characterized by a set of state-dependent decision rules that specify how an individual should respond to its internal state and external circumstances. These decision rules may also influence how individual growth change with a rise in temperature, showing that the standard expectation of increased growth rates with increasing temperatures may not always be true. With less time available individual larvae increase growth rates and thereby achieve shorter development times, most often without any effects on final sizes. One reason for the apparent optimization of growth rate seems to be that growing fast may incur costs that larvae developing under lower time limitations chose to avoid. The patterns of growth found in these and many other studies are difficult to reconcile with common assumptions of what typically determines optimal body size in insects. In particular it seems as if there should be some costs of a large body size that, so far, have been poorly documented. PMID- 21676734 TI - Can optimal resource allocation models explain why ectotherms grow larger in cold? AB - Basically all organisms can be classified as determinate growers if their growth stops or almost stops at maturation, or indeterminate growers if growth is still intense after maturation. Adult size for determinate growers is relatively well defined, whereas in indeterminate growers usually two measures are used: size at maturation and asymptotic size. The latter term is in fact not a direct measure but a parameter of a specific growth equation, most often Bertalanffy's growth curve. At a given food level, the growth rate in determinate growers depends under given food level on physiological constraints as well as on investments in repair and other mechanisms that improve future survival. The growth rate in indeterminate growers consists of two phases: juvenile and adult. The mechanisms determining the juvenile growth rate are similar to those in determinate growers, whereas allocation to reproduction (dependent on external mortality rate) seems to be the main factor limiting adult growth. Optimal resource allocation models can explain the temperature-size rule (stating that usually ectotherms grow slower in cold but attain larger size) if the exponents of functions describing the size-dependence of the resource acquisition and metabolic rates change with temperature or mortality increases with temperature. Emerging data support both assumptions. The results obtained with the aid of optimization models represent just a rule and not a law: it is possible to find the ranges of production parameters and mortality rates for which the temperature-size rule does not hold. PMID- 21676735 TI - Size and temperature in the evolution of fish life histories. AB - Body size and temperature are the two most important variables affecting nearly all biological rates and times, especially individual growth or production rates. By favoring an optimal maturation age and reproductive allocation, natural selection links individual growth to the mortality schedule. A recent model for evolution of life histories for species with indeterminate growth, which includes most fish, successfully predicts the numeric values of two key dimensionless numbers and the allometry of the average reproductive allocation versus maturation size across species. Here we use this new model to predict the relationships of age-at-maturity, adult mortality and reproductive effort to environmental temperature and maturation size across species. Age-at-maturity, adult mortality and the proportion of the body mass given to reproduction per year are predicted to show +/-0.25 power allometries with mass at maturity, and an exponential (Boltzmann) temperature dependence. Temperature is assumed to affect only body size growth, so the temperature linkages of maturation, mortality and reproductive effort are indirect via life history optimization; this is briefly contrasted with the idea that (for example) temperature directly affects mortality. PMID- 21676736 TI - Temperature, growth rate, and body size in ectotherms: fitting pieces of a life history puzzle. AB - The majority of ectotherms grow slower but mature at a larger body size in colder environments. This phenomenon has puzzled biologists because classic theories of life-history evolution predict smaller sizes at maturity in environments that retard growth. During the last decade, intensive theoretical and empirical research has generated some plausible explanations based on nonadaptive or adaptive plasticity. Nonadaptive plasticity of body size is hypothesized to result from thermal constraints on cellular growth that cause smaller cells at higher temperatures, but the generality of this theory is poorly supported. Adaptive plasticity is hypothesized to result from greater benefits or lesser costs of delayed maturation in colder environments. These theories seem to apply well to some species but not others. Thus, no single theory has been able to explain the generality of temperature-size relationships in ectotherms. We recommend a multivariate theory that focuses on the coevolution of thermal reaction norms for growth rate and size at maturity. Such a theory should incorporate functional constraints on thermal reaction norms, as well as the natural covariation between temperature and other environmental variables. PMID- 21676737 TI - EcoPhysiology and Conservation: The Contribution of Endocrinology and Immunology- Introduction to the Symposium. PMID- 21676738 TI - How physiological methods and concepts can be useful in conservation biology. AB - The single and synergistic effects of man-made changes to the environment, such as habitat destruction, climate change, introduction of novel, long-lived chemicals into the environment, transport of exotic species and pathogens into new geographical areas, and other factors are predicted to cause widespread population declines and species extinctions of plants and animals in this century. From its inception, physiology has dealt with organismal capacities to deal with environmental change. This essay argues that physiologists, their methods and concepts can make more substantial contributions to Conservation Biology than they have to date. A few of the many ways in which physiologists can participate in Conservation Biology include formulating standards for proof of cause-and-effect relations and providing information about how environmental change could affect organismal energetics, host-pathogen relations, immune defenses, and others. PMID- 21676739 TI - Field endocrinology and conservation biology. AB - Field endocrinology techniques allow the collection of samples (i.e., blood, urine, feces, tissues) from free-living animals for analysis of hormones, receptors, enzymes, etc. These data reveal mechanisms by which individuals respond to environmental challenges, breed, migrate and regulate all aspects of their life cycles. Field endocrinology techniques can also be used to address many issues in conservation biology. We briefly review past and current ways in which endocrine methods are used to monitor threatened species, identify potential stressors and record responses to environmental disturbance. We then focus on one important aspect of conservation: how free-living populations respond to human disturbance, particularly in relation to ecotourism. Breeding adult Magellanic penguins, Spheniscus magellanicus, appear to habituate well to tourists, and breed in an area where about 70,000 people visit during the season. Baseline levels of corticosterone return to normal after exposure of naive birds to humans. However, penguin chicks appear to show a heightened adrenocortical response to handling stress in nests exposed to tourists, compared to chicks living in areas isolated from human intrusions. Given that developmental exposure to stress can have profound influences on how individuals cope with stress as adults, this potential effect of tourists on chicks could have long-term consequences. This field endocrine approach identified a stressor not observed through monitoring behavior alone. PMID- 21676740 TI - Is nitrate an ecologically relevant endocrine disruptor in vertebrates? AB - The last three decades have brought clear recognition that many populations of animals are experiencing severe declines or local and global extinctions. Many examples have become common knowledge to the general public, such as worldwide declines in amphibian populations and extensive loss of coral reefs. The mechanisms underlying these and other changes are poorly understood. However, a growing literature indicates that a wide array of chemical contaminants have the potential to disrupt normal cell-to-cell signaling mechanisms. A global pollutant of most aquatic systems, nitrate has the potential to be an endocrine disrupting contaminant. This paper reviews studies performed on vertebrates demonstrating that nitrate and/or nitrite have the potential to alter endocrine function. Further, a retrospective study of our work on alligators from various lakes in Florida suggests that nitrate could contribute to some of the altered endocrine parameters previously reported in juvenile animals. We propose hypotheses suggesting that nitrate could alter steroidogenesis by 1) conversion to nitrite and nitric oxide in the mitochondria, the site of initial steroid synthesis, 2) altering Cl(-) ion concentrations in the cell by substituting for Cl(-) in the membrane transport pump or 3) binding to the heme region of various P450 enzymes associated with steroidogenesis and altering enzymatic action. Future studies are needed to examine the endocrine disruptive action of this ubiquitous pollutant. A growing literature indicates that all biologists studying natural systems, whether they choose to or not, must now consider contaminant exposure as a direct influence on their studies. That is, ubiquitous global contamination has the potential to alter the endocrine, nervous and immune systems of all organisms with resulting changes in gene expression and phenotypes. PMID- 21676741 TI - The Neuropeptide APGWamide as a Penis Morphogenic Factor (PMF) in Gastropod Mollusks. AB - The goal of this study was to further investigate the role of endogenous APGWamide levels in imposex induction in snails. APGWamide is a common neurotransmittor/neuromodulator peptide found in many species of molluscs, and is often related to sex organ growth or reproductive behavior. Mud snails (Ilyanassa obsoleta) were collected from the Rachel Carson Estuarine Reserve near Beaufort, NC, and were dosed with the environmental contaminant tributyltin (TBT), testosterone (T), or solvent vehicle (EtOH/ saline) controls. Both TBT and T have been shown previously to induce female snails to grow penises (a condition termed imposex), and to increase male penis size. Male normalized penis length was correlated to endogenous APGWamide levels (as measured by Western blotting of whole animal homogenates, r(2) = 0.475), and control males had significantly higher APGWamide levels than control females. All TBT-treated animals, (male, female, and imposex) had levels of APGWamide similar to control males and significantly higher than control females. In testosterone treated animals, APGWamide levels were the same as controls and it is likely that testosterone interferes with a downstream signaling event to induce imposex. In addition, immunohistochemistry for APGWamide expression in abdominal areas was done on female, male and imposex snails collected from the wild. The pattern of APGWamide in imposex snails was similar to male snails, showing large patches of immuno reactive areas in the top portion of the visceral mass. In female snails, no areas of cross-reactivity were found. PMID- 21676742 TI - Impacts of xenobiotics on crustacean molting: the invisible endocrine disruption. AB - Aquatic pollution has led to the accumulation of various xenobiotics in crustaceans. A number of these environmental chemicals have been found to interfere with molting of crustaceans. Results of initial mechanistic studies with Uca pugilator suggest that the disruption of molting results from the disturbance to the Y-organ-ecdysteroid receptor (EcR) axis by xenobiotics. Such disturbance to the Y-organ-EcR axis can be caused by interference with epidermal ecdysteroid signaling and/or alterations in ecdysteroidogenesis and/or ecdysteroid disposition. Because the adverse impacts on crustacean molting cannot be readily seen in the wild, the disruption of molting represents an invisible form of endocrine disruption. PMID- 21676743 TI - Sexual Disruption in the Freshwater Crab (Geothelphusa dehaani). AB - To clarify the effect of environmental endocrine disruptors on the induction of secondary sexual characteristics in wild animals, we observed 1,527 male and 1,847 female specimens of sexually mature Japanese freshwater crabs, Geothelphusa dehaani, collected at 12 sample points from 10 rivers in Sasebo City, Nagasaki Prefecture, Japan. The results obtained were as follows: Abnormal males, with external appearance of a complete male, but having female genital openings, were observed at frequencies of 8-32% of males collected at all sample points. In contrast to this, all females collected were normal.The frequency of abnormal males increased significantly with the increase in individual carapace width.This species inhabits mountain streams in Japan, which are free from tributyltin that is known to induce the sexual mosaic phenomenon in mollusks. The streams are most likely polluted by some agricultural chemicals and chemicals present in waste gases from cars and especially particulate materials from diesel engines. The clear relationship of the frequencies of abnormal males to size (or age) suggests that the sexual mosaic phenomenon is induced not only at early stages of male development but after sexual maturation, in response to long-term exposure to chemical(s) during the whole life cycle of males. The definitive causal factors and mechanisms inducing sexual mosaics in this species are still unclear. PMID- 21676744 TI - Stressed-out lobsters: crustacean hyperglycemic hormone and stress proteins. AB - Organisms in natural habitats must frequently respond to changes in their environments through various physiological mechanisms. My laboratory has developed several methods for the quantification of stress in crustaceans. An ELISA was developed for the crustacean hyperglycemic hormone (CHH) from the American lobster (Homarus americanus). It is sensitive to as little as 0.2 fmol of peptide. Increases in hemolymph CHH were observed under conditions of acute hypoxia, elevated temperature, and altered salinity. In addition, elevated CHH concentrations were observed in Norway lobsters (Nephrops norvegicus) that were parasitized with the dinoflagellate Hematodinium sp.Stress proteins, also known as heat-shock proteins (HSPs), comprise a highly conserved class of proteins that display elevated transcription during periods of stress. Using homologous molecular probes, my collaborators and I have examined the influence of heat shock, osmotic stress, and the molt cycle upon HSP expression at the protein and mRNA levels. We observed a significant elevation in HSP mRNA expression after 1 hr of heat-shock or after 0.5 hr of osmotic stress. When comparing claw and abdominal muscles during molting, we observed a tissue-specific HSP response. Quantification of these different stress responses may serve as early indicators of the degradation of environmental health. PMID- 21676745 TI - Larval Development and Vitellin-like Protein Expression in Palaemon elegans Larvae Following Xeno-oestrogen Exposure. AB - Certain anthropogenic chemicals, most notably xeno-oestrogens, are known to have the potential to disrupt vertebrate endocrine systems. For example, induction of the female-specific protein, vitellogenin, in male fish is a well-known effect of exposure to xeno-oestrogens and serves as a biomarker of such exposure. There have been few comparable studies of putative biomarkers of endocrine disruption in invertebrates. An exception is the upregulation of vitellin-like larval storage protein (LSP) expression in the barnacle cypris larva following exposure to oestrogenic chemicals. The current study aimed to establish whether larvae of the glass prawn, Palaemon elegans, are likewise susceptible to xeno-oestrogen exposure. Using a polyclonal antiserum to P. elegans apolipovitellin, an 86 kDa polypeptide was detected by western blotting in the larval and early postlarval stages of this species. An indirect ELISA applied to the soluble protein fraction of larval homogenates determined that the titre of this putative LSP ranged, depending on larval stage, from 0.48-0.67 ng MUg(-1). Exposure of P. elegans larvae to the xeno-oestrogen 4-n-nonylphenol (4-NP), at 0.2-20 MUg L(-1), resulted in a significant, concentration-independent increase in putative LSP levels of 5-18%. Conversely, exposure to the natural oestrogen, 17beta-oestradiol (E(2)), at 0.2 and 20 MUg L(-1), led to a significant concentration-independent decline (up to 11%) in LSP levels. Whether the effect of 4-NP results from endocrine disruption is not known, however, an oestrogen receptor-mediated effect is unlikely. Other than a slight increase in larval mortality when exposed to 4 NP at 2 MUg L(-1), neither 4-NP nor E(2) significantly affected development, growth or survival of P. elegans larvae. PMID- 21676746 TI - Changes in Nuclear Receptor and Vitellogenin Gene Expression in Response to Steroids and Heavy Metal in Caenorhabditis elegans. AB - To gain basic understanding of the reproductive and developmental effects of endocrine disrupting chemicals in invertebrates, we have used C. elegans as an animal model. The completion of the C. elegans genome sequence brings to bear microarray analysis as a tool for these studies. We previously showed that the C. elegans genome was responsive to vertebrate steroid hormones, and changes in gene expression of traditional biomarkers used in environmental studies were detected; i.e., vitellogenin (vtg), cytochrome P450 (cyp450), glutathione-S-transferase (gst) and heat shock proteins (hsp). The data were interpreted to suggest that exogenous lipophilic compounds can be metabolized via cytochrome P450 proteins, and that the resulting metabolites can bind to members of the Nuclear Receptor (NR) class of proteins and regulate gene expression. In the present study, using DNA microarrays, we examined the pattern of gene expression after progesterone (10(-5), 10(-7) M), estradiol (10(-5) M), cholesterol (10(-9) M) and cadmium (0.1, 1 and 10 MUM) exposure, with special attention to the members of NRs. Of approximately 284 NRs in C. elegans, expression of 25 NR genes (representing 9% of the total NRs in C. elegans) was altered after exposure to steroids. Of note, each steroid activated or inhibited different subsets of NR genes, and only estradiol regulated NR genes implicated in neurogenesis. These results suggest that NRs respond to a variety of exogenous steroids, which regulate important metabolic and developmental pathways. The response of the C. elegans genome to cholesterol and cadmium was analyzed in more detail. Cholesterol is a probable precursor to signaling molecules that may interact with NRs and we focused on expression of genes related to lipid metabolism (cyp450), transport and storage (i.e., vitellogenin). Worms exposed to cadmium respond principally by activating the expression of genes encoding stress-responsive proteins, such as mtl-2 and cdr-1, and no significant changes in expression of NRs or vtg genes were observed. The possible implications of these results with regard to the evolution of steroid receptors, endocrine disruption and the role of vitellogenin as a lipid transporter are discussed. PMID- 21676747 TI - The Freshwater Mussel (Elliptio complanata) as a Sentinel Species: Vitellogenin and Steroid Receptors. AB - Freshwater mussels, Elliptio complanata were collected from a reference and pollutant-impacted pond on Cape Cod, MA. Glutathione-S-transferase (GST) activity was measured in gill, hepatopancreas and foot. In addition, content of seven heavy metals were measured in whole bodies. GST activity was significantly elevated in hepatopancreas and foot, as was whole body cadmium level in animals from the contaminated site suggesting that these animals have been exposed to organic and inorganic contaminants. Sodium dodecyl acrylamide gel electrophoresis (SDS-PAGE) analysis showed putative vitellogenins with molecular weight 180 and 205 kDa bands only in the ovary. In non-denatured gel electrophoresis ovarian extracts revealed two higher molecular weight bands at 550 and 700 kDa, which were reproductive stage specific. Western blotting of SDS-PAGE and non-denatured gels using the anti-scallop yolk-protein antibody confirmed the presence of cross reacting bands of the same molecular weights in the ovary but not other tissues. Although several experiments involving steroid hormone exposure were done, no significant changes in vitellogenin protein levels were observed. However, using an anti-human ERbeta antibody, ERbeta positive bands were observed both in female foot, and the ovary. No cross reactivity with the antibody was observed in hepatopancreas. Additional studies are required to resolve questions of vitellogenin regulation and the role of (xeno)estrogens in bivalve molluscs. PMID- 21676748 TI - Testosterone-Fatty Acid esterification: a unique target for the endocrine toxicity of tributyltin to gastropods. AB - Over the past thirty years, a global occurrence of sexual aberration has occurred whereby females among populations of prosobranch snails exhibit male sex characteristics. This condition, called imposex, has been causally associated with exposure to the biocide tributyltin. Tributyltin-exposed, imposex snails typically have elevated levels of testosterone which have led to the postulate that this endocrine dysfunction is responsible for imposex. This overview describes recent evidence that supports this postulate. Gastropods maintain circulating testosterone levels and administration of testosterone to females or castrates stimulates male sex differentiation in several snail species. Studies in the mud snail (Ilyanassa obsoleta) have shown that gastropods utilize a unique strategy for regulating free testosterone levels. Excess testosterone is converted to fatty acid esters by the action of a testosterone-inducible, high capacity/low affinity enzyme, acyl-CoA:testosterone acyl transferase, and stored within the organisms. Free testosterone levels are regulated during the reproductive cycle apparently due to changes in esterification/desterification suggesting that testosterone functions in the reproductive cycle of the organisms. Testosterone esterification provides a unique target in the testosterone regulatory machinery of snails that is altered by tributyltin. Indeed, imposex and free testosterone levels were elevated in field collected snails containing high tin levels, while testosterone-fatty acid ester pools were reduced in these organisms. These observations indicate that tributyltin elevates free testosterone by reducing the retention of testosterone as fatty acid-esters. This endocrine effect of tributyltin may be responsible for imposex. PMID- 21676749 TI - Annelid Endocrine Disruptors and a Survey of Invertebrate FMRFamide-Related Peptides. AB - There is a growing body of literature describing the actions of endocrine disruptors on annelids. These pollutants cause decreases in growth and reproductive output, delay sexual maturation, and inhibit the immune system in annelids. More studies are needed to determine the mechanisms that underlie these responses. Most invertebrate endocrine disruptor research focuses on steroids. In recent years many new invertebrate peptide hormones including those related to the molluscan peptide FMRFamide have been identified. Since the storage of these peptides can be inhibited by steroids during insect metamorphosis, they may be affected by endocrine disruptors. Therefore, it is worthwhile to give a brief overview of this peptide family to those studying endocrine disruption in invertebrates with the hope that they may begin to consider these peptides in their future research. In 1977 Price and Greenberg isolated FMRFamide from the cerebral ganglia of the clam, Macrocallista nimbosa. Since then researchers have used bioassays and immunoassays to identify a large number of FMRFamide-related peptides (FaRPs) from many invertebrate phyla. Even more peptides are predicted by the FaRP genes that have been sequenced. FaRPs have a variety of functions and act as neurotransmitters, neuromodulators, or neurohormones. Each function is species and tissue specific. Most FaRP receptors are linked to a second messenger system. However, at least one is a ligand gated sodium channel. On going studies are examining FaRPs from the molecular to organismal level. PMID- 21676750 TI - The influence of insect juvenile hormone agonists on metamorphosis and reproduction in estuarine crustaceans. AB - Comparative developmental and reproductive studies were performed on several species of estuarine crustaceans in response to three juvenile hormone agonists (pyriproxyfen, methoprene and fenoxycarb). Larval development of the grass shrimp, Palaemonetes pugio, was greater than two orders of magnitude more sensitive to disruption by methoprene and fenoxycarb than was embryonic development. Developing larvae of the mud crab, Rhithropanopeus harrisii, exhibited reduced metamorphic success at lower concentrations of methoprene and pyriproxyfen than grass shrimp larvae. These responses suggest that the more rigidly controlled metamorphic process in crabs is more sensitive to compounds acting as endocrine disruptors than is the more flexible metamorphic pattern in shrimp. The final crab larval stage, the megalopa, was more sensitive to methoprene and fenoxycarb exposure than earlier zoeal stages. Mud crab larvae exposed to fenoxycarb had reduced biomass and lipid content, particularly triglycerides and sterols. Concentrations of fenoxycarb which reduced the reproductive capacity in single life-cycle exposures of the estuarine mysid, Americamysis bahia, were similar to those concentrations which inhibited metamorphosis in grass shrimp. Juvenile mysids released by exposed adults and reared through maturation without further exposure produced fewer young and had altered sex ratios (lower percentages of males) at lower parental-exposure concentrations than directly affected parental reproduction. These transgenerational responses may well be a product of irreversible effects during developmental exposures which become apparent following maturation and initiation of reproduction. These findings support using a functional approach as an appropriate screening procedure to evaluate potential environmental endocrine disrupting chemicals in aquatic environments. PMID- 21676751 TI - Ecdysteroid responses of estuarine crustaceans exposed through complete larval development to juvenile hormone agonist insecticides. AB - Fenoxycarb and pyriproxyfen are insecticides that gain their toxicity by specifically acting as insect juvenile hormone agonists (JHA), and so are endocrine disruptors by design and effectively prevent larvae from maturing into adults. Efforts to assess the environmental effects of JHAs on nontarget populations of invertebrates have resulted in the utilization of several established estuarine crustacean models. This work was conducted to test the hypothesis that the mortality, inhibition of development and decreased fecundity reported previously in these animals from JHA exposure coincides with abnormal circulating titers of ecdysteroids. Gravid female grass shrimp (Palaemonetes pugio) and mud crabs (Rhithropanopeus harrisii), species with different developmental plasticity and JHA tolerances, were collected and held at wet lab conditions (20 ppt salinity, 25 degrees C) until larval release. Larvae were collected <12 hr after hatch and exposed to JHAs during a static renewal test through end of development with seawater or nominal concentrations of JHA previously shown to induce significant developmental delays and/or decreased body weights. Larvae were subsampled (10 larvae/sample, n = 2 to 8) at each developmental stage, lyophilized, and ecdysteroids extracted by homogenization in 80% methanol and elution from C18 Sep-Pak cartridges with 25%, 60% and 100% methanol to capture the polar, free, and apolar conjugates, respectively, and then quantified by ELISA. As was expected significant differences in successful completion of development (larval survival), developmental duration, and growth (dry weight) were observed. These physiological perturbations were linked with significantly altered ecdysteroid titers, supporting a newly emerging theory that juvenoids possibly act as anti-ecdysteroids through a novel molecular mechanism involving inhibition of ecdysteroid signaling. PMID- 21676752 TI - Bioaccumulation and Metabolic Effects of the Endocrine Disruptor Methoprene in the Lobster, Homarus americanus. AB - Methoprene is a pesticide that acts as a juvenile hormone agonist. Although developed initially against insects, it has since been shown to have toxic effects on larval and adult crustaceans. Methoprene was one of several pesticides applied to the Western Long Island Sound (WLIS) watershed area during the summer of 1999; the other pesticides were malathion, resmethrin, and sumethrin. These pesticides were applied as part of a county-by-county effort to control the mosquito vector of West Nile Virus. Subsequently, the seasonal lobster catches from the WLIS have decreased dramatically. The lethality of the pesticides to lobsters had been unknown. We studied the effects of methoprene while other investigators studied effects of the other pesticides. We questioned whether methoprene, through its effects on larvae, adults or both, could have contributed to this decline. We found that low levels of methoprene had adverse effects on lobster larvae. It was toxic to stage II larvae at 1 ppb. Stage IV larvae were more resistant, but did exhibit significant increases in molt frequency beginning at exposures of 5 ppb. Juvenile lobsters exhibited variations in tissue susceptibility to methoprene: hepatopancreas appeared to be the most vulnerable, reflected by environmental concentrations of methoprene inhibiting almost all protein synthesis in this organ.Our results indicated that methoprene concentrates in the hepatopancreas, nervous tissue and epidermal cells of the adult lobster. Methoprene altered the synthesis and incorporation of chitoproteins (cuticle proteins) into adult postmolt lobster explant shells. SDS PAGE analyses of adult post-molt shell extracts revealed changes in the synthesis of chitoproteins in the methoprene-treated specimens, suggesting that methoprene affects the normal pathway of lobster cuticle synthesis and the quality of the post-molt shell. Although it is likely that a combination of factors led to the reduced lobster population in WLIS, methoprene may have contributed both by direct toxic effects and by disrupting homeostatic events under endocrine control. PMID- 21676753 TI - Drosophila: sentinels of environmental toxicants. AB - Synthetic insecticides have been used intensively for the past 50 years in many parts of the world. Insect populations, both target and nontarget, have responded by evolving resistance. One of the nontarget insects is Drosophila melanogaster, which is well-suited for genetic analysis and has been particularly well-studied in both laboratory and field populations. Resistance to several insecticides, including two for which significant resistance in field populations has not been found, has been generated in susceptible laboratory strains following mutagenesis, allowing comprehensive study of the resistance genes. Field populations of D. melanogaster have evolved resistance to many, but not all, insecticides in use today. Both the genetic and biochemical mechanisms that underlie resistance in this insect are similar to those in other insects. Therefore, D. melanogaster can be a sentinel organism for long-term release of toxicants into the environment. While it remains useful for genetic analysis of resistance, a better understanding of the movement and population structures of this insect will be a prerequisite for its sentinel utilization at specific locales. PMID- 21676754 TI - Antimicrobial Peptide defenses in amphibian skin. AB - One of the most urgent problems in conservation biology today is the continuing loss of amphibian populations on a global scale. Recent amphibian population declines in Australia, Central America, the western United States, Europe, and Africa have been linked to a pathogenic chytrid fungus, Batrachochytrium dendrobatidis, which infects the skin. The skin of amphibians is critical for fluid balance, respiration, and transport of essential ions; and the immune defense of the skin must be integrated with these physiological responses. One of the natural defenses of the skin is production of antimicrobial peptides in granular glands. Discharge of the granular glands is initiated by stimulation of sympathetic nerves. To determine whether antimicrobial skin peptides play a role in protection from invasive pathogens, purified antimicrobial peptides and natural peptide mixtures recovered from the skin secretions of a number of species have been assayed for growth inhibition of the chytrid fungus. The general findings are that most species tested have one or more antimicrobial peptides with potent activity against the chytrid fungus, and natural mixtures of peptides are also effective inhibitors of chytrid growth. This supports the hypothesis that antimicrobial peptides produced in the skin are an important defense against skin pathogens and may affect survival of populations. We also report on initial studies of peptide depletion using norepinephrine and the kinetics of peptide recovery following induction. Approximately 80 nmoles/g of norepinephrine is required to deplete peptides, and peptide stores are not fully recovered at three weeks following this treatment. Because many species have defensive peptides and yet suffer chytrid-associated population declines, it is likely that other factors (temperature, conditions of hydration, "stress," or pesticides) may alter normal defenses and allow for uncontrolled infection. PMID- 21676755 TI - Long Term Monitoring of Grass Shrimp Palaemonetes spp. Population Metrics at Sites with Agricultural Runoff Influences. AB - Rising concern over pesticide usage near estuarine systems and evidence of physical and physiological impacts on estuarine organisms have strengthened the need to better identify the ecological effects of nonpoint source runoff. Grass shrimp, Palaemonetes spp., are ecologically important and abundant marsh inhabitants that may be impacted by anthropogenic contamination. Populations of grass shrimp were sampled monthly, over a period of ten years, at four sites in South Carolina with varying upland land use characteristics. Spatial and temporal trends in grass shrimp densities were noted over time and between sites. Agricultural and golf course land usage corresponded with decreased grass shrimp population levels, overall shrimp size, and percentage of gravid females. Conservation methods, such as the use of best management practices (BMPs) and integrated pesticide management (IPM) at agricultural fields, corresponded with increased grass shrimp population density. PMID- 21676756 TI - Projecting population-level responses of mysids exposed to an endocrine disrupting chemical. AB - To fully understand the implications of a chemical's effect on the conservation of a species, effects observed at the physiological or individual level must be expressed in terms of the population. Since long-term field experiments are typically not feasible, vital rates such as survival and reproduction of individual organisms are measured in life table response experiments (LTRE) and employed to extrapolate the effects of a pollutant on the population. The population-level response of the mysid, Americamysis bahia, to varying concentrations of methoprene (0, 4, 8, 16, 31, 62 MUg/L) was determined using age structured population models. Models were parameterized from the results of an LTRE conducted throughout the entire mysid life cycle. A density-independent matrix model with time invariant demographic parameters was developed to measure the change in population growth rate, lambda, with change in methoprene concentration. The values of lambda were greater than one for all methoprene concentrations, indicating that populations exposed to the concentrations reported here would not become extinct. However, a general decrease in lambda occurred with increasing methoprene concentration and would result in reduced population sizes. Sensitivity and decomposition analyses were conducted to determined the relative roles of the vital rates on altered population growth rates and determined that impaired reproduction was the primary influence on the observed decrease in lambda. The model constructed was a useful tool for linking the individual-level effects to the population-level consequences of methoprene exposure on mysids, as well as defining the mechanism (reduced reproduction) responsible for the observed effects on population. PMID- 21676757 TI - Current knowledge of hagfish reproduction: implications for fisheries management. AB - This review briefly summarizes the latest findings on reproductive endocrinology of Atlantic hagfish (Myxine glutinosa) and implications for fisheries management. In response to a major decline or collapse of the fisheries (groundfish and anadromous species) industry in the Northeast, species that were once considered alternative or underutilized have and are being identified that may be suitable for commercial harvest, one such example is the hagfish. Hagfish in recent years have been sought after as valuable fish not only for their flesh, but also their skin. Currently, there are no regulations governing the harvesting of hagfish along the East Coast. There has been little to no information of the life history of hagfish including growth rate, age determination, reproductive biology, life span, and larval size at hatching. Thus, the level at which a sustainable fisheries for this species can be maintained is unknown. In some parts of the world, hagfish stocks are being depleted due to overfishing. In order for fisheries management to manage its hagfish stocks and develop a sustainable commercial hagfish fishery, critical information is needed to assist in determining the optimal use of this valuable resource.Key elements of the reproductive system have not been elucidated in hagfish. However, there is new evidence from recent reproductive studies that Atlantic hagfish may have a seasonal reproductive cycle. These data include seasonal changes in gonadotropin releasing hormone (GnRH), gonadal steroids, estradiol and progesterone, corresponding to gonadal reproductive stages along with the putative identity of a functional corpus luteum. This newly acquired data may provide important information to fisheries managers of the East Coast. PMID- 21676758 TI - Effect of Eyestalk-Ablation on Circulating Ecdysteroids in Hemolymph of Snow Crabs, Chionoecetes opilio: Physiological Evidence for a Terminal Molt. AB - Bering Sea snow crabs (Chionoecetes opilio) are a commercially important crab harvested in the Bering Sea. Optimal management of this species requires an understanding of the biology of this crab that is currently incomplete. Fisheries managers apply a continuous growth model in their management of snow crab, which assumes that male crabs increase in size throughout their lifespan. Male snow crabs undergo a morphometric molt that leads to a disproportionate increase in chelae size and it is still debated whether this molt is associated with a terminal molt. This study was conducted to determine whether adult male C. opilio are anecdysic. Using current knowledge of the hormonal regulation of crustacean growth, snow crab physiology was manipulated to induce an increase in molting hormones (ecdysteroids). Since female snow crabs are known to undergo a terminal molt after attaining reproductive maturity, we compared ecdysteroid levels in eyestalk-ablated terminally molted females, small-clawed males and large-clawed males. Snow crabs were collected from the Bering Sea and maintained in circulating seawater at approximately 6 degrees C. Animals were either eyestalk ablated or left intact. Ecdysteroid levels in hemolymph were quantified using an enzyme-linked immunosorbant assay (ELISA). Circulating ecdysteroids were significantly higher in small-clawed male crabs when compared to large-clawed males or terminally molted females. Eyestalk-ablation increased circulating ecdysteroids in small-clawed males, but had no significant effect on circulating ecdysteroids in large-clawed males or in terminally molted females. PMID- 21676759 TI - Xenobiotics and the evolution of multicellular animals: emergence and diversification of ligand-activated transcription factors. AB - Multicellular animals, which evolved about 700 to 1,000 myr ago, contain many of the genes found in yeast. Important for the evolution of multicellular animals were new pathways for intercellular signaling that regulated more complex physiological responses. Here we focus on the contribution to this process of lipophilic molecules that interact with nuclear receptors and the aryl hydrocarbon receptor, as well as enzymes that regulate the concentrations of these molecules. Both nuclear receptors and the aryl hydrocarbon receptor are found in invertebrates and vertebrates. We propose that environmental chemicals (xenobiotics) have been an important influence on the evolution of multicellular animals through a process involving the co-evolution of ligand-activated transcription factors and enzymes that detoxify xenobiotics. Indeed, this conversion of "xenobiotic swords" into "adaptive plowshares" contributed to the diverse physiology found in multicelluar animals. An important implication of this analysis is that enzymes as well as hormone receptors are vulnerable targets for endocrine disruptors. That is, some toxic chemicals act by inhibiting the enzymes that catalyze the formation or degradation of lipophilic signals, such as steroids, thus, disrupting hormone action. PMID- 21676760 TI - Non-traditional targets of endocrine disrupting chemicals: the roots of hormone signaling. AB - The topic of endocrine disruption and the broad range of physiological effects caused by endocrine disrupting chemicals (EDCs) can only be meaningfully framed within an ecological and evolutionary context. Environmental pollutants and EDCs operate by disrupting the "chemical communication" that coordinates signaling within an organism. Here we discuss how EDCs are also able to disrupt the chemical communication between plants and soil bacteria necessary for initiating nitrogen-fixing symbiosis. We also examine, through examples of pollutant-related impacts on a wide range of invertebrates, the need for identifying emerging targets of EDCs. We suggest broadening the defined field of endocrine disruption to encompass the effects of synthetic chemicals that interfere with signaling and communication, not only within an organism, but also between organisms and linking ecosystems. The ecological consequences of failing to recognize novel targets of chemical pollutants and EDCs may be a net loss of biological diversity and a further imbalance of the global nitrogen cycle. PMID- 21676761 TI - Pheromonal communication in nereids and the likely intervention by petroleum derived pollutants. AB - Nereis succinea and Platynereis dumerilii (Annelida, Polychaeta) are broadcast spawners and reproduce semelparously. The final events in reproduction, swarming and spawning are co-ordinated by sex pheromones.A water-soluble fraction of crude oil, the volatile fraction (C9-C16) of EKO FISK crude oil was found to induce release of gametes in male nereids at levels <0.3 ppm.Using vacuum distillation, column chromatography, preparative GC and GC-MS analysis we showed that C(5) alkylated benzenes were most potent in inducing sperm release, of those n-butyl-4 methylbenzene and 1,4-diethyl-2-methylbenzene were found to induce release of gametes at concentrations >=4 nM. This threshold is lower than those reported for natural pheromones (nereithione: 60 nM, uric acid: 600 nM) but higher than background levels of aromatic compounds of 0.05 nM and below.Other oil fractions showed additional effects, blocking pheromone reception or narcotising and intoxicating animals. Part of these effects could be assigned to naphthalenes at levels down to approx. 320 nM. In the original mixtures, their action was modified or compensated by the presence of gamete release inducing alkylated benzenes. Other highly paralysing substances remained elusive. PMID- 21676762 TI - The study of endocrine-disrupting compounds: past approaches and new directions. AB - Over the last decade, evidence has mounted demonstrating that human-made compounds released into the environment are disrupting endocrine systems of animals. Research has centered largely on direct steroidogenic or antisteroidogenic effects of these compounds with a recent focus on development of rapid in vitro assays employing estrogen receptors. A literature search and analysis confirms attention placed on estrogen and anti-estrogen-like aspects of endocrine disruption at the receptor level. Non-steroidal components of the hypothalamic-pituitary-end gland axes have received much less attention in the published endocrine disruption literature. Furthermore, aspects of endocrine physiology, such as the ability of animals to cope with stress or communicate chemically, have also received relatively less literature attention when compared to disruption of development and reproduction. As researchers continue to investigate complex mixes of human-synthesized compounds in the environment, it is critical to broaden the spectrum of hormonal disruption investigated beyond estrogenic and androgenic actions and to determine how exposure to mixes affects physiological function beyond reproduction. Last, in the field of endocrine disruption, it also important to begin to use data on individuals for development of hypotheses regarding fitness risks, changes in population dynamics, and the potential for ecosystem level disruption. PMID- 21676763 TI - Endocrine-like Signaling in Cnidarians: Current Understanding and Implications for Ecophysiology. AB - The vertebrate endocrine system is well-characterized, with many reports of disruption by environmental chemicals. In contrast, cnidarians are less compartmentalized, physiological regulation is poorly understood, and the potential for disruption is unknown. Endocrine-like activity has not been systematically studied in cnidarians, but several classical vertebrate hormones (e.g., steroids, iodinated organic compounds, neuropeptides, and indoleamines) have been identified in cnidarian tissues. Investigators have made progress in identifying putative bioregulatory molecules in cnidarians, and testing the effects of these individual compounds. Less progress has been made in elucidating signaling pathways. For example, putative gonadotropin-releasing hormone and sex steroids have been identified in cnidarian tissues, but it is unknown whether these compounds are components of a larger signal cascade comparable to the vertebrate hypothalamic-pituitary-gonadal axis. Further, while sex steroids and iodinated organic compounds may help to regulate cnidarian physiology, the mechanisms of action are unknown. Homologs to the vertebrate steroid and thyroid receptors have not been identified in cnidarians, so more research is needed to understand the mechanisms of endocrine-like signaling in cnidarians. Elucidation of cnidarian regulatory pathways will provide insight into evolution of hormonal signaling. These studies will also improve understanding of how cnidarians respond to environmental cues and will provide a basis to investigate disruption of physiological processes by physical and chemical stressors. PMID- 21676764 TI - Introduction: a symposium honoring george a. Bartholomew. PMID- 21676765 TI - George A. Bartholomew's Contributions to Integrative and Comparative Biology. AB - The Bartholomew Award has now completed a decade of recognizing outstanding young investigators in comparative physiology and biochemistry or in related fields of functional and integrative biology. It honors Professor George A. Bartholomew (Bart to his many students and other friends), whose research contributions continue to be important in shaping these fields. Bart's influence reflects a steadfast adherence to a set of basic precepts: the inherent unity of biology; the need for an evolutionary perspective in functional studies; the value of modern natural history in guiding research investigations; the focus on the organism and its function in nature, even in highly reductionist studies; the importance of biological variability within and between species; and the crucial interactions of physiology and behavior in allowing animals to deal with environmental challenges. Were he to have done nothing else in his career, he would remain an important figure in the fields with which the Society of Integrative and Comparative Biology's (SICB) Division of Comparative Physiology and Biochemistry is concerned. However, his influence is also felt through his inspirational performance as an undergraduate teacher, his skill and wisdom as a graduate mentor, his many services to the University of California, his insightful contributions to scientific committees and policy boards at the national level, and his presidency of the American Society of Zoologists (now SICB). This symposium offers the opportunity for honoring Bart for all his accomplishments and fine personal qualities, while illustrating the contributions of the impressive set of younger investigators who are recipients of the George A. Bartholomew Award. PMID- 21676766 TI - The academic genealogy of george a. Bartholomew. PMID- 21676767 TI - The red and the black: bioluminescence and the color of animals in the deep sea. AB - The colors of deep-sea species are generally assumed to be cryptic, but it is not known how cryptic they are and under what conditions. This study measured the color of approximately 70 deep-sea species, both pelagic and benthic, and compared the results with two sets of predictions: 1) optimal crypsis under ambient light, 2) optimal crypsis when viewed by bioluminescent "searchlights." The reflectances of the pelagic species at the blue-green wavelengths important for deep-sea vision were far lower than the predicted reflectances for crypsis under ambient light and closer to the zero reflectance prediction for crypsis under searchlights. This suggests that bioluminescence is more important than ambient light for the visual detection of pelagic species at mesopelagic depths. The reflectances of the benthic species were highly variable and a relatively poor match to the substrates on which they were found. However, estimates of the contrast sensitivity of deep-sea visual systems suggest that even approximate matches may be sufficient for crypsis in visually complex benthic habitats. Body coloration was generally uniform, but many crabs had striking patterns that may serve to disrupt the outlines of their bodies. PMID- 21676768 TI - Patterns of Hsp gene expression in ectothermic marine organisms on small to large biogeographic scales. AB - The goal of my research program is to employ biochemical and molecular techniques to gain ecological insight into the role of temperature in setting species' distribution patterns in the marine environment. Our central focus is the study of the environmental regulation of gene expression, where we are particularly interested in a set of inducible molecular chaperones, the heat-shock proteins (Hsps), and how the expression of these genes varies with the thermal history of organisms in natural populations. The primary study organisms are intertidal invertebrates and marine fish that experience dramatic changes in body temperature on varying temporal and spatial scales. In this review, I present studies that address the variable expression of Hsps, how these genes are differentially regulated in ectothermic animals in response to ecologically relevant temperature conditions, and how such plasticity in gene expression contributes to physiological plasticity in the environment. PMID- 21676769 TI - Many-to-One Mapping of Form to Function: A General Principle in Organismal Design? AB - We introduce the concept of many-to-one mapping of form to function and suggest that this emergent property of complex systems promotes the evolution of physiological diversity. Our work has focused on a 4-bar linkage found in labrid fish jaws that transmits muscular force and motion from the lower jaw to skeletal elements in the upper jaws. Many different 4-bar shapes produce the same amount of output rotation in the upper jaw per degree of lower jaw rotation, a mechanical property termed Maxillary KT. We illustrate three consequences of many to-one mapping of 4-bar shape to Maxillary KT. First, many-to-one mapping can partially decouple morphological and mechanical diversity within clades. We found with simulations of 4-bars evolving on phylogenies of 500 taxa that morphological and mechanical diversity were only loosely correlated (R(2) = 0.25). Second, redundant mapping permits the simultaneous optimization of more than one mechanical property of the 4-bar. Labrid fishes have capitalized on this flexibility, as illustrated by several species that have Maxillary KT = 0.8 but have different values of a second property, Nasal KT. Finally, many-to-one mapping may increase the influence of historical factors in determining the evolution of morphology. Using a genetic model of 4-bar evolution we exerted convergent selection on three different starting 4-bar shapes and found that mechanical convergence only created morphological convergence in simulations where the starting forms were similar. Many-to-one mapping is widespread in physiological systems and operates at levels ranging from the redundant mapping of genotypes to phenotypes, up to the morphological basis of whole-organism performance. This phenomenon may be involved in the uneven distribution of functional diversity seen among animal lineages. PMID- 21676770 TI - Physiological causes and consequences of social status in salmonid fish. AB - Social interactions in small groups of juvenile rainbow trout (Oncorhynchus mykiss) lead to the formation of dominance hierarchies. Dominant fish hold better positions in the environment, gain a larger share of the available food and exhibit aggression towards fish lower in the hierarchy. By contrast, subordinate fish exhibit behavioural inhibition, including reduced activity and feeding. The behavioural characteristics associated with social status are likely the result of changes in brain monoamines resulting from social interactions. Whereas substantial physiological benefits, including higher growth rates and condition factor, are experienced by dominant trout, low social status appears to be a chronic stress, as indicated by sustained elevation of circulating cortisol concentrations in subordinate fish. High cortisol levels, in turn, may be responsible for many of the deleterious physiological consequences of low social status, including lower growth rates and condition factor, immunosuppression and increased mortality. Circulating cortisol levels may also be a factor in determining the outcome of social interactions in pairs of rainbow trout, and hence in determining social status. Rainbow trout treated with cortisol were significantly more likely to become subordinate in paired encounters with smaller untreated conspecifics. PMID- 21676771 TI - The initiation and control of rapid flight maneuvers in fruit flies. AB - Fruit flies alter flight direction by generating rapid, stereotyped turns, called saccades. The successful implementation of these quick turns requires a well tuned orchestration of neural circuits, musculo-skeletal mechanics, and aerodynamic forces. The changes in wing motion required to accomplish a saccade are quite subtle, as dictated by the inertial dynamics of the fly's body. A fly first generates torque to begin accelerating in the intended direction, but then must quickly create counter-torque to decelerate. Several lines of evidence suggest that the initial turn is initiated by visual expansion, whereas the subsequent counter-turn is triggered by the gyroscopic halteres. This integrated analysis indicates how the functional organization of neural circuits controlling behavior is rigidly constrained by the physical interaction between an animal and the external world. PMID- 21676772 TI - Evolutionary and cellular mechanisms regulating intestinal performance of amphibians and reptiles. AB - Vertebrate intestinal tracts possess an array of structural and functional adaptations to the wide diversity of food and feeding habits. In addition to well described differences in form and function between herbivores and carnivores, the intestine exhibits adaptive plasticity to variation in digestive demand. The capacity to which intestinal performance responds to changes in digestive demands is a product of evolutionary and cellular mechanisms. In this report, I have taken an integrative approach to exploring the mechanisms responsible for the regulation of intestinal performance with feeding and fasting among amphibians and reptiles. Intestinal performance is presented as the total small intestinal capacity to absorb nutrients, quantified as a product of small intestinal mass and mass-specific rates of nutrient uptake. For sit-and-wait foraging snakes and estivating anurans, both of which naturally experience long episodes of fasting, the dramatic downregulation of intestinal morphology and function with fasting reduces energy expenditure during extended fasts. In contrast, frequently-feeding species modestly regulate intestinal performance with fasting and feeding, trading higher basal rates of metabolism during fasting for the frequent expense of upregulating the gut with feeding. Surveying the magnitude by which intestinal uptake capacity is regulated among 26 families of amphibians and reptiles has revealed potentially five lineages that have independently evolved the capacity to widely regulate intestinal performance. The extent to which intestinal performance is downregulated with fasting among amphibians and reptiles, ranging from 0 to 90%, is largely a function of the degree by which mass-specific rates of nutrient transport are depressed, given that loss of intestinal mass with fasting is a common characteristic of vertebrates. In exploring the underlying mechanisms regulating intestinal nutrient uptake, use of the Burmese python has revealed a temporal match between microvillus surface area and intestinal nutrient transport. With feeding, pythons experience a five-fold lengthening of intestinal microvilli, with subsequent reduction after completing digestion. Identifying for the python the cellular processes responsible for the dramatic remodeling of the microvilli would assist in elucidating the mechanisms by which intestinal performance is regulated, as well as identify whether similar steps are employed by other species to regulate their intestines. In finishing, I propose three studies of digestive response: (1) investigate the responses of the ectotherm intestine to hibernation; (2) evaluate whether functional capacities of tissues are matched to digestive demands; and, (3) apply microarray technology to explore the functional genomics of intestinal adaptation. PMID- 21676773 TI - Biotelemetry of New World thrushes during migration: Physiology, energetics and orientation in the wild. AB - Billions of songbirds migrate between continents each year, but we have yet to obtain enough information on in-flight physiology and energetics to fully understand the migratory behavior of any one species. New World Catharus thrushes are common nocturnal migrants amenable to biotelemetry, allowing us to measure physiological parameters during migratory flight in the wild. Here, we review work by the authors on Catharus thrush in-flight physiology during spring migration in continental North America and present new data on individual variation in energy use during migratory flight. Previous work demonstrated that (1) a number of simple behavioral rules are sufficient to explain the initiation of individual migratory flights made by Catharus thrushes, (2) the thrushes used a magnetic compass to orient during the night rather than celestial cues and that they calibrated this magnetic compass each day using cues associated with the setting sun, (3) in total, Catharus thrushes used approximately twice as much energy during stopovers than they used during migratory flight, and (4) thrushes may use more energy when thermoregulating on cold days than on days when they make short migratory flights. Recently, we built upon this work and used newly developed transmitters to measure heart rate, wingbeat frequency and respiration rate of free-flying Swainson's Thrushes (C. ustulatus). We found a large amount of between-individual variation in average heart rate after ascent (range 12.06 14.81 Hz, mean +/- SD, 13.48 +/- 0.75, n = 10), average wingbeat frequency after ascent (10.25-11.75 Hz, 10.82 +/- 0.49, n = 10), and the difference between the two variables (1.5-3.84 Hz, 2.53 +/- 0.76, n = 8). Both heart rate and wingbeat frequency were significantly higher during ascent than later in the flight. We propose biotelemetry as a means to understand energetic trade-offs and decisions during natural migratory flight in songbirds. To further our knowledge of intercontinental songbird migration and the connectivity between wintering and breeding sites, we outline plans for a satellite-based global tracking system for <1 g transmitters. PMID- 21676774 TI - Physiological ecology in the 21st century: advancements in biologging science. AB - Top pelagic predators such as tunas, sharks, marine turtles and mammals have historically been difficult to study due to their large body size and vast range over the oceanic habitat. In recent years the development of small microprocessor based data storage tags that are surgically implanted or satellite-linked provide marine researchers a novel avenue for examining the movements, physiology and behaviors of pelagic animals in the wild. When biological and physical data obtained from the tags are combined with satellite derived sea surface temperature and ocean color data, the relationships between the movements, behaviors and physical ocean environment can be examined. Tag-bearing marine animals can function as autonomous ocean profilers providing oceanographic data wherever their long migrations take them. The biologging science is providing ecological physiologists with new insights into the seasonal movements, habitat utilization, breeding behaviors and population structures in of marine vertebrates. In addition, the data are revealing migration corridors, hot spots and physical oceanographic patterns that are key to understanding how organisms such as bluefin tunas use the open ocean environment. In the 21st century as ecosystem degradation and global warming continue to threaten the existence of species on Earth, the field of physiological ecology will play a more pivotal role in conservation biology. PMID- 21676775 TI - Welcome to the revolution: integrative biology and assessing the impact of endocrine disruptors on environmental and public health. AB - Concern continues to grow over the negative impact of endocrine disrupting chemicals on environmental and public health. The number of identified endocrine disrupting chemicals is increasing, but biological endpoints, experimental design, and approaches for examining and assessing the impact of these chemicals are still debated. Although some workers consider endocrine disruption an "emerging science," I argue here that it is equally, a "merging science" developing in the tradition of integrative biology. Understanding the impact of endocrine disruptors on humans and wildlife is an examination of "context dependent development" and one that Scott Gilbert predicted would require a "new synthesis" or a "revolution" in the biological sciences. Here, I use atrazine as an example to demonstrate the importance of an integrative approach in understanding endocrine disruptors.Atrazine is a potent endocrine disruptor that chemically castrates and feminizes amphibians and other wildlife. These effects are the result of the induction of aromatase, the enzyme that converts androgens to estrogens, and this mechanism has been confirmed in all vertebrate classes examined (fish, amphibians, reptiles, birds, and mammals, including humans). To truly assess the impact of atrazine on amphibians in the wild, diverse fields of study including endocrinology, developmental biology, molecular biology, cellular biology, ecology, and evolutionary biology need to be invoked. To understand fully the long-term impacts on the environment, meteorology, geology, hydrology, chemistry, statistics, mathematics and other disciplines well outside of the biological sciences are required. PMID- 21676776 TI - Integrative Biology, an Organismic Biologist's Point of View. PMID- 21676777 TI - Sponges: new views of old animals. PMID- 21676778 TI - Sponge development and antiquity of animal pattern formation. AB - The last common ancestor to all extant animals possessed features shared between the most basal metazoan lineage-Porifera-and the rest of the animal kingdom. To identify ancient and conserved developmental processes, we have been investigating embryogenesis and metamorphosis in the demosponge Reniera. Many of the cardinal features of eumetazoan development are displayed during Reniera embryogenesis. Specifically, after fertilization there is a period of cell division with little to no cell growth that results in two obvious cell populations distinguished by size as micromeres and macromeres, and by fate: the small cells differentiate into ciliated cells. This is followed by a period of differential cell activities that produces an embryo consisting of two then three layers, where at least 11 populations of differentiated cells are allocated into the different layers and patterned within these layers. This organization yields a swimming larva with the capacity to sense and respond to the surrounding environment, despite a lack of neurons and a coordinating system. During Reniera embryogenesis, the clearest example of cell patterning is the formation of a ring of pigment cells at the future posterior pole of the larva. Pigment cell pattern formation has two phases, both of which may require the movement of a large number of cells apparently in response to a morphogen gradient. First, pigmented cells, which initially cover the surface of the embryo, migrate to the future posterior end and form a dark spot. Second, the cells move outwards from the spot and rearrange into a ring. Numerous and diverse transcription factor genes are expressed during Reniera embryogenesis, most of which belong to metazoan-specific families and include members of POU, LIMHD, Pax, Bar, Prox2, NK-2, T-box, MEF-2, Fox, Sox, Ets, and nuclear hormone receptor families. In combination, these observations suggest that the last common ancestor to all extant metazoan lineages already possessed the basic regulatory genetic architecture to direct the specification, patterning and differentiation of multiple cell types. Some of these differentiated cells may have been arranged into localised functional units i.e., simple tissues. PMID- 21676779 TI - Gastrulation in Calcareous Sponges: In Search of Haeckel's Gastraea. AB - Haeckel's studies of development in calcareous sponges (1872) led him to develop the "Gastraea Theory," which proposes that the ancestral mode of germ layer formation, or gastrulation, was by invagination to produce a functional gut. His observations that gastrulation in the Calcarea occurs by invagination of a ciliated larva upon settlement and metamorphosis were supported by remarkable photomicrographs of the stage by Hammer in 1908. Although no later work found the same stage, these concepts are repeated in texts today. We have re-examined embryogenesis and metamorphosis in Sycon sp. cf. S. raphanus in order to understand when gastrulation occurs. Almost all larvae settle on their ciliated anterior pole and metamorphose into a bilayered juvenile whose interior cells rapidly differentiate into choanocytes and other cells of the young sponge. After a four-year search we have found the transitory stage shown by Hammer in which the anterior cells invaginate into the posterior half of the larva. The hole closes and it is not until some days later that the sponge forms an osculum at its apical pole. To understand whether invagination comprises gastrulation and if the hole can be considered to be a blastopore we have carried out a review of the literature dealing with this brief moment in calcaronean sponge development. Despite the intrigue of this type of metamorphosis, we conclude that gastrulation occurs earlier, during formation of the two cellular regions of the larva, and that metamorphosis involves the reorganization of these already differentiated regions. Considering the pivotal position occupied by the Calcarea as the possible sister-group to all other Metazoa, these results call for a reassessment of germ layer formation and of the relationships of the primary germ layers among basal metazoan phyla. PMID- 21676780 TI - Is there a trade-off between wound-healing and chemical defenses among Caribbean reef sponges? AB - On Caribbean coral reefs, some sponge species produce chemical defenses, while others do not and are non-fatally grazed by predatory fishes. It has been hypothesized that the latter may compensate for fish grazing by growing faster or rapidly healing wounds. Rates of wound-healing were measured for chemically defended and undefended tubular and vase-shaped sponges on patch reefs in the Florida Keys and Bahamas in 2002. Healing rates were significantly faster during the first few days of the experiment, with rates leveling off after the third day. Chemically undefended sponges healed at significantly faster rates (Callyspongia plicifera, 8% area regenerated per day; Callyspongia vaginalis, 6%; Niphates digitalis, 6%; Xestospongia muta, 6.5%) than chemically defended sponges (Cribrochalina vasculum, 2%; Ircinia campana, 2%; Verongula gigantea, 0%). Orientation of wounds relative to the tidal current had no influence on healing rates. Specimens of Niphates digitalis growing in tubular form had faster healing rates than individuals with vasiform shapes. Our results suggest that Caribbean reef sponges followed two different evolutionary trajectories: chemically defended species deter fish predation and have slow healing rates, while chemically undefended species allocate resources to rapid wound-healing in response to grazing. PMID- 21676781 TI - Ecology of antarctic marine sponges: an overview. AB - Sponges are important components of marine benthic communities of Antarctica. Numbers of species are high, within the lower range for tropical latitudes, similar to those in the Arctic, and comparable or higher than those of temperate marine environments. Many have circumpolar distributions and in some habitats hexactinellids dominate benthic biomass. Antarctic sponge assemblages contribute considerable structural heterogeneity for colonizing epibionts. They also represent a significant source of nutrients to prospective predators, including a suite of spongivorous sea stars whose selective foraging behaviors have important ramifications upon community structure. The highly seasonal plankton blooms that typify the Antarctic continental shelf are paradoxical when considering the planktivorous diets of sponges. Throughout much of the year Antarctic sponges must either exploit alternate sources of nutrition such as dissolved organic carbon or be physiologically adapted to withstand resource constraints. In contrast to predictions that global patterns of predation should select for an inverse correlation between latitude and chemical defenses in marine sponges, such defenses are not uncommon in Antarctic sponges. Some species sequester their defensive metabolites in the outermost layers where they are optimally effective against sea star predation. Secondary metabolites have also been shown to short circuit molting in sponge-feeding amphipods and prevent fouling by diatoms. Coloration in Antarctic sponges may be the result of relict pigments originally selected for aposematism or UV screens yet conserved because of their defensive properties. This hypothesis is supported by the bioactive properties of pigments examined to date in a suite of common Antarctic sponges. PMID- 21676782 TI - Impacts of Shading on Sponge-Cyanobacteria Symbioses: A Comparison between Host Specific and Generalist Associations. AB - The marine sponge Lamellodysidea chlorea contains large populations of the host specific, filamentous cyanobacterium Oscillatoria spongeliae. Other marine sponges, including Xestospongia exigua, contain the generalist, unicellular cyanobacterium Synechococcus spongiarum. The impact of cyanobacterial photosynthesis on host sponges was manipulated by shading these sponge cyanobacteria associations. If cyanobacteria benefit their hosts, shading should reduce this benefit. Chlorophyll a concentrations were measured as an index of cyanobacterial abundance. After two weeks, shaded L. chlorea lost more mass than controls, while shaded and control X. exigua did not lose a significant amount of mass. Chlorophyll a concentrations in shaded X. exigua were lower than in controls, but were not significantly different between shaded and control L. chlorea. In addition, L. chlorea shaded in situ lost over 40% of their initial area, but did not differ in chlorophyll a concentrations from controls. These results suggest that Oscillatoria symbionts benefit their host sponges in a mutualistic association. Synechococcus symbionts may be commensals that exploit the resources provided by their sponge hosts without significantly affecting sponge mass. When shaded, Synechococcus symbionts may be consumed by their hosts or may be able to disperse from this unfavorable environment. These data support the hypothesis that more specialized symbionts provide a greater benefit to their hosts, but hypotheses concerning the dispersal abilities of these symbionts remain to be explored. Sponge-cyanobacteria symbioses provide model systems for investigating the costs and benefits of symbiosis and the roles of dispersal, environmental conditions, and phylogenetic history in determining the specificity of endosymbionts for their hosts. PMID- 21676783 TI - Biodiversity, molecular ecology and phylogeography of marine sponges: patterns, implications and outlooks. AB - Marine sponges are an ecologically important and highly diverse component of marine benthic communities, found in all the world's oceans, at all depths. Although their commercial potential and evolutionary importance is increasingly recognized, many pivotal aspects of their basic biology remain enigmatic. Knowledge of historical biogeographic affinities and biodiversity patterns is rudimentary, and there are still few data about genetic variation among sponge populations and spatial patterns of this variation. Biodiversity analyses of tropical Australasian sponges revealed spatial trends not universally reflected in the distributions of other marine phyla within the Indo-West Pacific region. At smaller spatial scales sponges frequently form heterogeneous, spatially patchy assemblages, with some empirical evidence suggesting that environmental variables such as light and/or turbidity strongly contribute to local distributions. There are no apparent latitudinal diversity gradients at larger spatial scales but stochastic processes, such as changing current patterns, the presence or absence of major carbonate platforms and historical biogeography, may determine modern day distributions. Studies on Caribbean oceanic reefs have revealed similar patterns, only weakly correlated with environmental factors. However, several questions remain where molecular approaches promise great potential, e.g., concerning connectivity and biogeographic relationships. Studies to date have helped to reveal that sponge populations are genetically highly structured and that historical processes might play an important role in determining such structure. Increasingly sophisticated molecular tools are now being applied, with results contributing significantly to a better understanding of poriferan microevolutionary processes and molecular ecology. PMID- 21676784 TI - Selection Experiments as a Tool in Evolutionary and Comparative Physiology: Insights into Complex Traits--an Introduction to the Symposium. PMID- 21676785 TI - How and When Selection Experiments Might Actually be Useful. AB - Laboratory natural selection and artificial selection are vital tools for addressing specific questions about evolutionary patterns of variation. Laboratory natural selection can illuminate whether a putative selective agent is capable of generating long-term, sustained changes in individual traits and suites of traits. Artificial selection is the essential tool for understanding the general evolvability of traits and the extent to which genetic correlations constrain evolution. We review the contexts in which each type of experiment seems capable of offering key insights into important evolutionary issues. We also discuss theoretical and methodological considerations that play critical roles in designing selection experiments that are relevant to evolutionary patterns of trait variation. In particular, we focus on the critical role of selection intensity and the consequences of experiments with different intensities. While selection experiments are not practical in many cases, sophisticated selection experiments-designed with careful consideration of the theory of selection-should be taken beyond model organisms and used in well chosen natural systems to understand natural patterns of variation. PMID- 21676786 TI - Divergent selection for aerobic capacity in rats as a model for complex disease. AB - Based upon ideas about evolution, we put forth the argument that the capacity to transfer energy via aerobic metabolism is such a central feature of mammalian biology, that it must also be the primary determinant of complex disease. From this, we hypothesized that artificial selection on low and high capacity for aerobic exercise would create lines that can be used to define the divide between health and disease. In 1996 we began large-scale divergent selection for aerobic treadmill running capacity in a widely heterogeneous stock of rats (N:NIH). By ten generations we developed lines of low capacity runners (LCR) and high capacity runners (HCR) that on average differed by 317%. As a correlated trait, body mass increased at each generation in the LCR while the body mass decreased in the HCR. The lines also separated for key factors of systemic oxygen transport capacity such as maximal oxygen consumption (VO(2)max), tissue perfusion, capillary density, and oxidative enzyme activity (citrate synthase and B-HAD). We also tested our hypothesis that differences in aerobic energy transfer would produce rats that contrast for risk factors associated with complex disease. Indeed, the lines separated for cardiovascular risk factors including differences in blood pressure, cardiac contractility, visceral adiposity, plasma free fatty acids, and triglycerides. The decrease in aerobic capacity was also associated with low amounts of several proteins required for mitochondrial function. PMID- 21676787 TI - Artificial selection on metabolic rates and related traits in rodents. AB - Artificial selection experiments are potentially powerful, yet under-utilized tool of evolutionary and physiological ecology. Here we analyze and review three important aspects of such experiments. First, we consider the effects of instrumental measurement errors and random fluctuations of body mass on the total phenotypic variation. We illustrate this with the analysis of measurements of oxygen consumption in an open-flow respirometry set-ups. We conclude that measurement errors and fluctuations of body mass are likely to reduce the repeatability of oxygen consumption by about one third. Using published estimates of repeatability of metabolic rates we also showed that it does not tend to decline with increasing time between measurements. Second, we review data on narrow sense heritability (h(2)) of metabolic rates in mammals. The results are equivocal: many studies report very low (~0.1) h(2), whereas some recent studies (including our own estimates of h(2) in laboratory mice, obtained by means of parent-offspring regression) report significant h(2) >= 0.4. Finally, we discuss consequences of the lack of replicated lines in artificial selection experiments. We focus on the confounding effect of genetic drift on statistical inferences related to primary (selected) and secondary (correlated) traits, in the absence of replications. We review literature data and analyze them following the guidelines formulated by Henderson (1989, 1997). We conclude that most results obtained in unreplicated experiments are probably robust enough to ascribe them to the effect of selection, rather than genetic drift. However, Henderson's guidelines by no means should be treated as a legitimate substitute of the analysis of variance, based on replicated lines. PMID- 21676788 TI - Phenotypic and evolutionary plasticity of organ masses in response to voluntary exercise in house mice. AB - We used a novel mouse model to study the effects of selective breeding for high locomotor activity (14 generations) on relative organ sizes, hematocrit (Hct), and blood hemoglobin (Hb) concentration. We also examined effects of exercise training and genotype-by-environment interactions by housing animals for 8 weeks with wheels that were either free to rotate or locked. Mice from the four replicate High-Runner (HR) lines were smaller in total body mass but had larger body mass-adjusted kidneys relative to the four Control lines (P < 0.05). Control and HR lines did not differ significantly for mass-adjusted tail length or masses of the "triceps surae" hindlimb muscle group, heart (ventricle), spleen, liver, adrenal glands or gonads. Wheel access caused a reduction in body mass and an increase in relative heart mass. In females only, wheel access caused a reduction in relative spleen mass. Wheel access did not affect relative tail length or relative mass of the triceps surae, liver, adrenal gland or gonads. Significant interactions between selection history and wheel access were observed in females for spleen, liver, and gonad mass as well as Hct and Hb. Wheel access caused increases in both Hct and Hb, mainly in the HR lines. The mini-muscle phenotype, caused by a Mendelian recessive allele that halves hindlimb muscle mass, was significantly associated with several other body composition traits, including reduced body mass, increased tail length, increased heart mass, increased liver mass (females only), increased mean adrenal gland mass (females only), increased mean kidney mass (males only), and reduced Hct (wheel-access females only). Results are discussed in context of the beneficial acclimation hypothesis, genotype-by-environment interactions, and the potential for "nurture" to be self reinforcing of "nature" in some complex behavioral-physiological phenotypes. PMID- 21676789 TI - Neurobiology of Mice Selected for High Voluntary Wheel-running Activity. AB - Selective breeding of house mice has been used to study the evolution of locomotor behavior. Our model consists of 4 replicate lines selectively bred for high voluntary wheel running (High-Runner) and 4 bred randomly (Control). The major changes in High-Runner lines appear to have taken place in the brain rather than in capacities for exercise. Their neurobiological profile resembles features of human Attention Deficit Hyperactivity Disorder (ADHD) and is also consistent with high motivation for exercise as a natural reward. Both ADHD and motivation for natural rewards (such as food and sex), as well as drugs of abuse, have been associated with alterations in function of the neuromodulator dopamine, and High Runner mice respond differently to dopamine drugs. In particular, drugs that block the dopamine transporter protein (such as Ritalin and cocaine) reduce the high-intensity running of High-Runner mice but have little effect on Control mice. In preliminary studies of mice exercised on a treadmill, brain dopamine concentrations did not differ, suggesting that changes in the dopamine system may have occurred downstream of dopamine production (e.g., receptor expression or transduction). Brain imaging by immunohistochemical detection of c-Fos identified several key regions (prefrontal cortex, nucleus accumbens, caudate-putamen, lateral hypothalamus) that appear to play a role in the differential response to Ritalin and in the increased motivation for running in High-Runner mice. The activation of other brain regions, such as the hippocampus, was closely associated with wheel running itself. Chronic wheel running (several weeks) also increased the production of new neurons to apparently maximal levels in the hippocampus, but impaired learning in High-Runner mice. We discuss the biomedical implications of these findings. PMID- 21676790 TI - Selection in nature: experimental manipulations of natural populations. AB - Numerous studies have documented evolution by natural selection in natural populations, but few are genuine selection experiments that are designed and then executed in nature. We will focus on these few cases to illustrate what can be learned from field selection experiments alone or field and laboratory selection experiments together that cannot be learned from laboratory experiments alone. Both types of study allow us to evaluate cause and effect relationships because a planned experiment can be accompanied by a more direct evaluation of the factors that cause evolution. A unique benefit of field experiments is that they give us the opportunity to measure the rate and magnitude of selection in nature. We have found that this rate is far greater than one might imagine based on observations of the fossil record. A combination of field and laboratory selection experiments has revealed the importance of population size and structure in shaping the genetics of adaptation. For example, laboratory selection experiments on insecticide resistance tend to attain resistance though polygenic inheritance. The evolution of insecticide resistance in nature often eventually yields to single genes of large effect that are rare but, once they arise, represent a higher fitness solution to resistance and spread among populations. Finally, field studies enable us to test evolutionary theory in a context in which all of the tradeoffs associated with a trait are realized; in the laboratory, organisms may be shielded from the fitness tradeoffs associated with the evolution of a trait. For example, we have compared the patterns of senescence in guppies from high and low mortality rate environments in the laboratory and in the field. In the laboratory, guppies from high predation environments had delayed senescence relative to those from low predation environments. In the field the apparent relationship is the opposite. One hypothesis for this difference is that a tradeoff associated with the evolution of the high predation life history is a decrease in the investment in the immune system. Such a sacrifice would be evident in nature where there is exposure to disease and parasites but less so in the laboratory, which is relatively disease and parasite free. PMID- 21676791 TI - Behavioral and Neuroendocrine Correlates of Selection for Stress Responsiveness in Rainbow Trout--a Review. AB - In rainbow trout the magnitude of the cortisol response to stress shows both consistency over time and a moderate to high degree of heritability, and high responding (HR) and low responding (LR) lines of rainbow trout have been generated by individual selection for consistently high or low post-stress cortisol values. Using 2nd and 3rd generation fish, we tested the hypothesis that differential stress responsiveness is associated with behavioral alterations in the HR-LR trout model. LR fish showed a tendency to become socially dominant, a rapid recovery of food intake after transfer to a novel environment, and a reduced locomotor response in a territorial intrusion test. Furthermore, stress induced elevation of brain stem and optic tectum concentrations of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine and their metabolites suggests that both synthesis and metabolism of these transmitters were elevated after stress to a larger degree in HR than in LR trout. A divergent pattern was seen in the hypothalamus, where LR fish displayed elevated levels of 5 hydroxyindoleacetic acid (a serotonin metabolite) and 3-methoxy-4 hydroxyphenylglycol (a norepinephrine metabolite). Thus, selection for a single trait, cortisol responsiveness, in rainbow trout is associated with concurrent changes in both behavior and central signaling systems. The apparent parallel to genetically determined stress coping styles in mammals, and the existence of similar trait associations in unselected populations of rainbow trout, suggests an evolutionarily conserved correlation between multiple traits. Continuing studies on the HR and LR trout lines are aimed at providing the physiological and genetic basis for new marker-assisted selection strategies in the rapidly developing finfish aquaculture industry, as well as increased knowledge of the function and evolution of central neuroendocrine signaling systems. PMID- 21676792 TI - Using artificial selection to understand plastic plant phenotypes. AB - The plasticity of any given trait, which has a genetic basis and which may or may not be adaptive, can intensify or attenuate evolved responses, and can itself evolve in response to selection depending on the scale of spatial or temporal heterogeneity. To investigate the complex function and evolution of plastic traits, an appealing yet challenging approach is assessing responses to artificial selection. Here, I review how artificial selection has been employed to explore four botanical research themes: (1) relationships between plastic and evolved responses to multiple stresses, (2) integration of cellular, leaf-level, and whole-plant responses to altered CO(2) concentrations, (3) photomorphogenic and photoperiodic development, both mediated by phytochrome photoreceptors, and (4) the evolution of the pest-induced myrosinase-glucosinolate system in cruciferous plants. These diverse topics are unified not only because they have been studied using artificial selection experiments, but also because they have considered variability in multiple traits affected by multiple factors in the external environment. Limitations of such research include a dearth of long-term studies; a surprising but often logistically necessary omission of control or replicate lines; and numerous issues relating to assessing impacts of inbreeding and drift. In addition to discussing options for circumventing such limitations, I draw attention to strategies for integrating the results of artificial selection studies with progress in functional and evolutionary genomics. PMID- 21676793 TI - The Effects of Evolution are Local: Evidence from Experimental Evolution in Drosophila. AB - One of the enduring temptations of evolutionary theory is the extrapolation from short-term to long-term, from a few species to all species. Unfortunately, the study of experimental evolution reveals that extrapolation from local to general patterns of evolution is not usually successful. The present article supports this conclusion using evidence from the experimental evolution of life-history in Drosophila. The following factors demonstrably undermine evolutionary correlations between functional characters: inbreeding, genotype-by-environment interaction, novel foci of selection, long-term selection, and alternative genetic backgrounds. The virtual certainty that at least one of these factors will arise during evolution shreds the prospects for global theories of the effects of adaptation. The effects of evolution apparently don't generalize, even though evolution is a global process. PMID- 21676794 TI - Adaptive evolution in the lab: unique phenotypes in fruit flies comprise a fertile field of study. AB - Laboratory selection for desiccation resistance, which has been imposed on five replicate populations of Drosophila melanogaster for >200 generations, has resulted in enhanced survivability during periods of extreme water stress. The ability of these populations to persistently resist the fatal effects of desiccation is correlated with evolved physiological traits, namely preferential storage of carbohydrates (associated with reduced lipid reserves) and a dramatic increase in blood volume, which has led to a significant increase in extracellular sodium and chloride content, as well as body mass. When compared to other populations of this drosophilid species, these adaptive traits are unique. While some may argue against the value of evolved traits that have not been found in natural populations, we counter that such traits are of considerable value to the analyses of physiological functions, as well as the underlying mechanisms and evolutionary trajectories of these functions. We propose that multiple physiological consequences almost certainly derive from the evolution of these singular traits; and, furthermore, we discuss future directions for the elucidation of such consequences. PMID- 21676795 TI - Sex-linked Correlated Responses in Female Reproductive Traits to Selection on Male Eye Span in Stalk-eyed Flies. AB - Coevolution between male and female traits can result from correlated responses to selection or correlated selection on genetically independent traits. This study examines the possibility that traits involved in precopulatory sexual selection may influence the evolution of traits involved in postcopulatory sexual selection due to the existence of correlated selection or correlated responses to selection. Artificial selection on male eye span in Cyrtodiopsis dalmanni, a sexually dimorphic stalk-eyed fly, is used to test for correlated changes in reproductive traits of male and female flies. Flies from replicate lines that had been under selection for 57 generations were matched for age and genotyped at four X-linked microsatellite loci. Egg number and testis size increased with age, but did not differ among lines. Spermathecal areas and duct lengths differed among replicates, but not among selection treatments. Female relative eye span, size of the ventral receptacle and egg size exhibited significant correlated responses to selection on male relative eye span. The absence of any change in sperm length or testis size between lines indicates that changes in female traits are unlikely due to correlated selection mediated by sperm competition. Significant effects of X-linked microsatellite genotypes indicate instead that the correlated responses to selection were due, in part, to X-linked genes in linkage disequilibrium or that exhibit pleiotropy. The presence of nonadditive allelic effects on genetically correlated female traits combined with additive allelic effects on a male ornament provides a previously unrecognized mechanism by which genetic variation could be maintained despite strong sexual selection. PMID- 21676796 TI - Intermediary Metabolism and Life History Trade-offs: Lipid Metabolism in Lines of the Wing-polymorphic Cricket, Gryllus firmus, Selected for Flight Capability vs. Early Age Reproduction. AB - The extent to which modifications in intermediary metabolism contribute to life history variation and trade-offs is an important but poorly understood aspect of life history evolution. Artificial selection was used to produce replicate genetic stocks of the wing-polymorphic cricket, Gryllus firmus, that were nearly pure-breeding for either the flight-capable (LW[f]) morph, which delays ovarian growth, or the flightless (SW) morph, which exhibits enhanced early-age fecundity. LW(f) lines accumulated substantially more triglyceride, the main flight fuel in Gryllus, compared with SW-selected lines, and enhanced accumulation of triglyceride was strongly associated with reduced ovarian growth. Increased triglyceride accumulation in LW(f) lines resulted from elevated de novo biosynthesis of fatty acid and two morph-specific trade-offs: (1) greater proportional utilization of fatty acid for glyceride biosynthesis vs. oxidation, and (2) a greater diversion of fatty acids into triglyceride vs. phospholipid biosynthesis. Even though SW lines produced less total lipid and triglyceride, they produced more phospholipid (important in egg development) than did LW(f) lines. Differences between LW(f) and SW morphs in lipid biosynthesis resulted from substantial alterations in the activities of all studied lipogenic enzymes, a result that is consistent with expectations of Metabolic Control Theory. Finally, application of a juvenile hormone analogue to LW(f) females produced a striking SW phenocopy with respect to all aspects of lipid metabolism studied. Global alterations of lipid metabolism, most likely produced by alterations in endocrine regulation, underlie morph specializations for flight vs. early-age fecundity in G. firmus. Modification of the endocrine control of intermediary metabolism is likely to be an important mechanism by which intermediary metabolism evolves and contributes to life history evolution. PMID- 21676797 TI - A physiological perspective on the response of body size and development time to simultaneous directional selection. AB - Natural selection typically acts on multiple traits simultaneously. Quantitative genetics provides the theory for predicting the response to selection of multiple traits and predicts symmetrical responses to selection (the response to upward selection on both traits is equal to their response to downward selection). In reality, however, the response to simultaneous selection on two traits is often asymmetrical. We provide a physiology-based framework to explain the asymmetrical response to simultaneous selection on two important life history traits: body size and development time. The tobacco hornworm, Manduca sexta, is particularly well suited for such a study, as the physiological control of body size and development time is well known in this species. Three physiological factors control both life history traits in M. sexta: growth rate, the critical weight that measures the timing of the onset of the cessation of juvenile hormone secretion (which initiates the processes leading to pupation) and the time interval between the critical weight and secretion of the molting hormone 20 hydroxyecdysteroid (the interval to cessation of growth, ICG). Asymmetry in the response to simultaneous selection on the two life history traits is due to the different types of selection acting on the three physiological factors. The critical weight and ICG are always under synergistic selection when both focal traits are selected in the same direction and under antagonistic selection when the focal traits are selected in opposite directions. Growth rate follows the opposite pattern. We propose a general model to explain the asymmetric response to simultaneous selection. This model emphasizes the importance of physiological processes in understanding evolutionary responses to selection and the control of complex traits. PMID- 21676798 TI - Differential Patterns of Gene Expression and Gene Complement in Laboratory Evolved Lines of E. coli. AB - Laboratory selection experiments play a prominent role in understanding organismal adaptation. Although bacteria are not yet commonly used for such experiments, they are well suited for analyses of both the organismic and the genetic basis of adaptation. Bacteria can be maintained in large populations while occupying limited laboratory space, have short generation times, are well characterized physiologically, biochemically, and genetically, and are readily frozen and revived from the freezer. In addition, the genomes of many species are completely sequenced and knowledge of gene function is unparalleled. Here we review general aspects of selection experiments, the history of using selection experiments in combination with thermal biology and genomics, and highlight findings from six lines of Escherichia coli adapted to high temperature (41.5 degrees C), including changes in organismal fitness, physiological performance, gene complement and gene expression. Our results are an example of the powerful insights that can be discovered by combining the tools and analyses of many biological disciplines including genomics, evolutionary biology, genetics, and evolutionary physiology. PMID- 21676799 TI - Magnetic orientation and navigation in marine turtles, lobsters, and molluscs: concepts and conundrums. AB - The Earth's magnetic field provides a pervasive source of directional information used by phylogenetically diverse marine animals. Behavioral experiments with sea turtles, spiny lobsters, and sea slugs have revealed that all have a magnetic compass sense, despite vast differences in the environment each inhabits and the spatial scale over which each moves. For two of these animals, the Earth's field also serves as a source of positional information. Hatchling loggerhead sea turtles from Florida responded to the magnetic fields found in three widely separated regions of the Atlantic Ocean by swimming in directions that would, in each case, facilitate movement along the migratory route. Thus, for young loggerheads, regional magnetic fields function as navigational markers and elicit changes in swimming direction at crucial geographic boundaries. Older turtles, as well as spiny lobsters, apparently acquire a "magnetic map" that enables them to use magnetic topography to determine their position relative to specific goals. Relatively little is known about the neural mechanisms that underlie magnetic orientation and navigation. A promising model system is the marine mollusc Tritonia diomedea, which possesses both a magnetic compass and a relatively simple nervous system. Six neurons in the brain of T. diomedea have been identified that respond to changes in magnetic fields. At least some of these appear to be ciliary motor neurons that generate or modulate the final behavioral output of the orientation circuitry. These findings represent an encouraging step toward a holistic understanding of the cells and circuitry that underlie magnetic orientation behavior in one model organism. PMID- 21676800 TI - Parallel and interrelated neural systems underlying adaptive navigation. AB - The ability to process in parallel multiple forms of sensory information, and link sensory-sensory associations to behavior, presumably allows for the opportunistic use of the most reliable and predictive sensory modalities in diverse behavioral contexts. Evolutionary considerations indicate that such processing may represent a fundamental operating principle underlying complex sensory associations and sensory-motor integration. Here, we suggest that animal navigation is a particularly useful model of such opportunistic use of sensory and motor information because it is possible to study directly the effects of memory on neural system functions. First, comparative evidence for parallel processing across multiple brain structures during navigation is provided from the literatures on fish and rodent navigation. Then, based on neurophysiological evidence of coordinated, multiregional processing, we provide a neurobiological explanation of learning and memory effects on neural circuitry mediating navigation. PMID- 21676801 TI - The avian hippocampus, homing in pigeons and the memory representation of large scale space. AB - The extraordinary navigational ability of homing pigeons provides a unique spatial cognitive system to investigate how the brain is able to represent past experiences as memory. In this paper, we first summarize a large body of lesion data in an attempt to characterize the role of the avian hippocampal formation (HF) in homing. What emerges from this analysis is the critical importance of HF for the learning of map-like, spatial representations of environmental stimuli used for navigation. We then explore some interesting properties of the homing pigeon HF, using for discussion the notion that the homing pigeon HF likely displays some anatomical or physiological specialization(s), compared to the laboratory rat, that account for its participation in homing and the representation of large-scale, environmental space. Discussed are the internal connectivity among HF subdivisions, the occurrence of neurogenesis, the presence of rhythmic theta activity and the electrophysiological profile of HF neurons. Comparing the characteristics of the homing pigeon HF with the hippocampus of the laboratory rat, two opposing perspectives can be supported. On the one hand, one could emphasize the subtle differences in the properties of the homing pigeon HF as possible departure points for exploring how the homing pigeon HF may be adapted for homing and the representation of large-scale space. Alternatively, one could emphasize the similarities with the rat hippocampus and suggest that, if homing pigeons represent space in a way different from rats, then the neural specializations that would account for the difference must lie outside HF. Only future research will determine which of these two perspectives offers a better approximation of the truth. PMID- 21676802 TI - Mechanisms of magnetic orientation in birds. AB - Behavior and electrophysiological studies have demonstrated a sensitivity to characteristics of the Geomagnetic field that can be used for navigation, both for direction finding (compass) and position finding (map). The avian magnetic compass receptor appears to be a light-dependent, wavelength-sensitive system that functions as a polarity compass (i.e., it distinguishes poleward from equatorward rather than north from south) and is relatively insensitive to changes in magnetic field intensity. The receptor is within the retina and is based on one or more photopigments, perhaps cryptochromes. A second receptor system appears to be based on magnetite and might serve to transduce location information independent of the compass system. This receptor is associated with the ophthalmic branch of the trigeminal nerve and is sensitive to very small (<50 nanotesla) changes in the intensity of the magnetic field. In neither case has a neuron that responded to changes in the magnetic field been traced to a structure that can be identified to be a receptor. Almost nothing is known about how magnetic information is processed within the brain or how it is combined with other sensory information and used for navigation. These remain areas of future research. PMID- 21676803 TI - Multi-modal Orientation Cues in Homing Pigeons. AB - How homing pigeons displaced into unfamiliar territory find their way home has been the subject of extensive experimentation and debate. One reason for the controversy is that pigeons seem to use multiple cues. Clock-shifting experiments show that experienced pigeons use the sun as a preferred compass; when it is not available they rely on magnetic cues. That pigeons can home successfully while wearing frosted lenses suggests that landmarks, while not an essential navigational cue, are important in the final stages. The sensory basis of the "map" or position finding system is probably equally or even more complicated. When conditions around the loft are suitable, pigeons may use olfactory cues to find their way or might use some feature of the earth's magnetic field for their navigation. The Wiltschkos (1989) showed that pigeons raised without free access to ambient odors are not disoriented when anosmic while their siblings raised with free access to the prevailing wind were disoriented. Similarly, sibling pigeons from two lofts in Lincoln, Massachusetts. were well oriented or totally disoriented when released at magnetic anomalies under sunny skies depending upon which of the two lofts they had been reared in. All of these experiments and many more suggest that pigeons use multiple and redundant cues to find their way home. Further, there is the suggestion that which cues they adopt may well be influenced by the characteristics of the area around the home loft in which they were reared. PMID- 21676804 TI - Introduction to the symposium. PMID- 21676805 TI - Phylogenetic context and Basal metazoan model systems. AB - In comparative studies using model organisms, extant taxa are often referred to as basal. The term suggests that such taxa are descendants of lineages that diverged early in the history of some larger taxon. By this usage, the basal metazoans comprise just four phyla (Placozoa, Porifera, Cnidaria, and Ctenophora) and the large clade Bilateria. We advise against this practice because basal refers to a region at the base or root of a phylogenetic tree. Thus, referring to an extant taxon or species as basal, or as more basal than another, can be misleading. While much progress has been made toward understanding some of the phylogenetic relationships within these groups, the relationships among them are still largely not known with certainty. Thus, sound inferences from comparative studies of model organisms demand continued illumination of phylogeny. Hypotheses about the mechanisms underlying metazoan evolution can be drawn from the study of model organisms in Cnidaria, Ctenophora, Placozoa, and Porifera, but it is clear that these model organisms are likely to be derived in many respects. Therefore, testing these hypotheses requires the study of yet additional model organisms. The most effective tests are those that investigate model organisms with phylogenetic positions among two sister groups comprising a larger clade of interest. PMID- 21676806 TI - The Symbiotic Anthozoan: A Physiological Chimera between Alga and Animal. AB - The symbiotic life style involves mutual ecological, physiological, structural, and molecular adaptations between the partners. In the symbiotic association between anthozoans and photosynthetic dinoflagellates (Symbiodinium spp., also called zooxanthellae), the presence of the endosymbiont in the animal cells has constrained the host in several ways. It adopts behaviors that optimize photosynthesis of the zooxanthellae. The animal partner has had to evolve the ability to absorb and concentrate dissolved inorganic carbon from seawater in order to supply the symbiont's photosynthesis. Exposing itself to sunlight to illuminate its symbionts sufficiently also subjects the host to damaging solar ultraviolet radiation. Protection against this is provided by biochemical sunscreens, including mycosporine-like amino acids, themselves produced by the symbiont and translocated to the host. Moreover, to protect itself against oxygen produced during algal photosynthesis, the cnidarian host has developed certain antioxidant defenses that are unique among animals. Finally, living in nutrient poor waters, the animal partner has developed several mechanisms for nitrogen assimilation and conservation such as the ability to absorb inorganic nitrogen, highly unusual for a metazoan. These facts suggest a parallel evolution of symbiotic cnidarians and plants, in which the animal host has adopted characteristics usually associated with phototrophic organisms. PMID- 21676807 TI - Model systems for environmental signaling. AB - Studies of environmental signaling in animals have focused primarily on organisms with relatively constrained responses, both temporally and phenotypically. In this regard, existing model animals (e.g., "worms and flies") are particularly extreme. Such animals have relatively little capacity to alter their morphology in response to environmental signals. Hence, they exhibit little phenotypic plasticity. On the other hand, basal metazoans exhibit relatively unconstrained responses to environmental signals and may thus provide more general insight, insofar as these constraints are likely traits derived during animal evolution. Such enhanced phenotypic plasticity may result from greater sensitivity to environmental signals, or greater abundance of suitable target cells, or both. Examination of what is known of the components of environmental signaling pathways in cnidarians reveals many similarities to well-studied model animals. In addition to these elements, however, macroscopic basal metazoans (e.g., sponges and cnidarians) typically exhibit a system-level capability for integrating environmental information. In cnidarians, the gastrovascular system acts in this fashion, generating local patterns of signaling (e.g., pressure, shear, and reactive oxygen species) via its organism-wide functioning. Contractile regions of tissue containing concentrations of mitochondrion-rich, epitheliomuscular cells may be particularly important in this regard, serving in both a functional and a signaling context. While the evolution of animal circulatory systems is usually considered in terms of alleviating surface-to volume constraints, such systems also have the advantage of enhancing the capacity of larger organisms to respond quickly and efficiently to environmental signals. More general features of animals that correlate with relatively unconstrained responses to environmental signals (e.g., active stem cells at all stages of the life cycle) are also enumerated and discussed. PMID- 21676808 TI - Fission in sea anemones: integrative studies of life cycle evolution. AB - Sea anemones (Phylum Cnidaria; Class Anthozoa, Order Actiniaria) exhibit a diversity of developmental patterns that include cloning by fission. Because natural histories of clonal and aclonal sea anemones are quite different, the gain and loss of fission is an important feature of actiniarian lineages. We have used mitochondrial DNA and nuclear intron DNA phylogenies to investigate the evolution of longitudinal fission in sixteen species in the genus Anthopleura, and reconstructed an aclonal ancestor that has given rise at least four times to clonal descendents. For A. elegantissima from the northeastern Pacific Ocean, a transition to clonality by fission was associated with an up-shore habitat shift, supporting prior hypotheses that clonal growth is an adaptation to the upper shore. Fission in Actiniaria likely precedes its advent in Anthopleura, and its repeated loss and gain is perplexing. Field studies of the acontiate sea anemone Aiptasia californica provided insight to the mechanisms that regulate fission: subtidal Aiptasia responded to experimentally destabilized substrata by increasing rates of pedal laceration. We put forth a general hypothesis for actiniarian fission in which sustained tissue stretch (a consequence of substratum instability or intrinsic behavior) induces tissue degradation, which in turn induces regeneration. The gain and loss of fission in Anthopleura lineages may only require the gain and loss of some form of stretching behavior. In this view, tissue stretch initiates a cascade of developmental events without requiring complex gene regulatory linkages. PMID- 21676809 TI - Self/non-self Discrimination in Basal Metazoa: Genetics of Allorecognition in the Hydroid Hydractinia. AB - Colonial basal metazoans often encounter members of their own species as they grow on hard substrata, with the encounters typically resulting in either fusion of close relatives or rejection between unrelated colonies. These allorecognition responses play a critical role in maintaining the genetic and physiological integrity of the colony. Allorecognition responses in basal metazoans are controlled by highly variable genetic systems. The molecular nature of such systems, however, remains to be determined. Current efforts to identify the genes and molecules controlling allorecognition in basal metazoans have followed two pathways: identification of molecules differentially expressed in incompatible interactions, and positional or map-based cloning of allorecognition genes. Most studies following the first approach have been performed with marine demosponges, while those following the second approach have centered on the cnidarian of the genus Hydractinia. Here, I discuss the latter, focusing primarily on the genetic control of allorecognition responses. PMID- 21676810 TI - Hydra and the evolution of apoptosis. AB - Programmed cell death occurs in most, if not all life forms. It is used to sculpt tissue during embryogenesis, to remove damaged cells, to protect against pathogen infection and to regulate cell numbers and tissue homeostasis. In animals cell death often occurs by a morphologically and biochemically conserved process called apoptosis. A novel group of cysteine proteases, referred to as caspases, constitute the central component of this process. Caspases are activated following the induction of apoptosis and cleave a variety of cellular substrates, thus giving rise to the characteristic morphological events of apoptosis. Apoptosis is rapid and cell corpses are removed by phagocytosis. Recent work has shown that apoptosis also occurs in Cnidaria and Porifera, thus extending the origin of this evolutionary innovation down to the first metazoan animal phyla. Here, we review several examples of the role of apoptosis in cnidarians and then summarize new results on the subcellular localization of caspases and the control of apoptosis in Hydra. We show by immuncytochemistry that caspases in Hydra are localized in mitochondria. Following induction of apoptosis caspases are released from mitochondria as proenzymes and then activated by proteolytic cleavage in the cytoplasm. We also present evidence that apoptosis in Hydra is dramatically stimulated by inhibitors of PI3-kinase. Since PI3-kinase is a central component of growth factor signaling cascades in higher metazoans, this result suggests that control of apoptosis by growth factors is also evolutionarily conserved. We speculate on the role of growth factors in the evolution of apoptosis. PMID- 21676811 TI - Genomics of Basal metazoans. AB - An in-depth understanding of the biology of animals will require the generation of genomics resources from organisms from all phyla in the metazoan phylogenetic tree. Such resources will ideally include complete genome sequences and comprehensive EST (expressed sequence tag) datasets for each species of interest. Of particular interest in this regard are animals in the early diverging non bilaterian phyla Porifera, Placozoa, Cnidaria, and Ctenophora. Publications describing the results from the use of genomics approaches in these phyla have only recently begun to appear (Kortschak et al., 2003; Yang et al., 2003; Steele et al., 2004). Issues to be considered here include choosing the basal metazoan species to examine with genomics approaches, the relative advantages and disadvantages of genome sequencing versus EST projects, and the resources and infrastructure required to carry out such projects successfully. PMID- 21676812 TI - Recent developments in neurobiology: introduction to the symposium. PMID- 21676813 TI - The smell of success and failure: the role of intrinsic and extrinsic chemical signals on the social behavior of crayfish. AB - Animals commonly modify their behavior in the presence of a conspecific or in response to signals. This is particularly true in the context of aggressive exchanges, which animals use to form networks of social relationships and to communicate social status associated with those relationships. Although hierarchical structures are a widespread phenomenon that has been studied extensively, the dynamic communication processes, specifically chemical communication in this review, is relatively overlooked. In particular, it is the exchange of information during agonistic interactions that mediates hierarchies and/or alters the outcomes of agonistic interactions. Given the theoretical appeal of these interactions, and the evolutionary importance and taxonomic diversity associated with social hierarchies, it is not surprising that the sensory mechanisms involved in the formation and maintenance of hierarchical structures have received recent attention. In crayfish, dominance is thought to be largely determined by physical superiority, where encounters are largely dyadic and fighting behavior is highly stereotyped. However, recent evidence has shown that the outcome of dyadic encounters are dependent upon a number of factors other than physical size, that include the exchange of chemical information during encounters, previous social history, and the intrinsic neurochemical state of opponents. We have attempted to provide a comprehensive analysis of the extrinsic chemical processes (previous history, sensory communication, etc.) and intrinsic chemical processes (neurochemical state) that produce and maintain dominance relations and social hierarchies in crayfish. We hope that this review will bring together a global picture of the processes that determine a crayfish's social standing and how intrinsic and extrinsic chemicals have substantial effects on aggressive states and agonistic bouts. PMID- 21676814 TI - Modulation of synaptic function in retinal amacrine cells. AB - Amacrine cells are interneurons that have diverse functions in retinal signal processing. In order to study signaling and modulation in retinal amacrine cells, we employ a simplified culture system containing identifiable GABAergic amacrine cells. Immunocytochemistry experiments indicate that GABAergic amacrine cells express metabotropic glutamate receptor 5 (mGluR5), a group I mGluR usually linked to the IP3 signaling pathway. Ca(2+) imaging experiments using an mGluR5 specific agonist indicate that these receptors are functional and when activated, can stimulate temporally diverse Ca(2+) elevations. To begin to establish the role of these receptors in modulating amacrine cell function, we have used electrophysiological methods to ask whether ion channels are the targets of mGluR5-dependent modulation. Here we discuss our results indicating that activation of mGluR5 leads to enhancement of currents through GABA(A) receptors. This enhancement is dependent upon elevations in cytosolic Ca(2+) and activation of protein kinase C (PKC). To explore the consequences of Ca(2+) elevations in another context, we have used nitric oxide (NO) donors to mimic the effects of activating the Ca(2+)-dependent synthetic enzyme for NO, neuronal nitric oxide synthase. We find that exposure to NO donors also enhances the amplitude of currents through GABA(A) receptors. Together, these results indicate that glutamate from presynaptic bipolar cells has the potential to work through multiple mechanisms to regulate the function of amacrine-to-amacrine cell GABAergic synapses. PMID- 21676815 TI - Rapid central corticosteroid effects: evidence for membrane glucocorticoid receptors in the brain. AB - Glucocorticoid secretion occurs in a circadian pattern and in response to stress. Among the broad array of glucocorticoid actions are multiple effects in the brain, including negative feedback regulation of hypothalamic hormone secretion. The negative feedback of glucocorticoids occurs on both rapid and delayed time scales, reflecting different regulatory mechanisms. While the slow glucocorticoid effects are widely held to involve regulation of gene transcription, the rapid effects are too fast to invoke genomic mechanisms. We provide a brief overview of multiple lines of evidence for membrane-associated glucocorticoid receptors in the brain, with an emphasis on our recent findings of a rapid, G protein dependent glucocorticoid action in the rat hypothalamus. We have observed a novel mechanism of rapid glucocorticoid inhibition of parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) mediated by the retrograde release of endocannabinoids and suppression of synaptic glutamate release. This acute glucocorticoid action may underlie the rapid inhibitory effect of glucocorticoids on hypothalamic neuroendocrine function, and provides a potential model for the rapid glucocorticoid effects that occur in several areas of the brain. PMID- 21676816 TI - Contrasting tactics in motor control by vertebrates and arthropods. AB - Vertebrates and arthropods share the common problem of controlling a rigid, articulated skeleton using neurally-controlled, striated muscle. Since this condition has arisen independently in the two groups, there is no reason to assume, a priori, that the control mechanisms used by the two groups will be the same. Indeed, there appear to be fundamental differences in the tactics used by the two groups. Insects and crustaceans use small numbers of heterogeneous motoneurons, while vertebrates (mammals especially) use many, more homogeneous, motor axons. In particular, arthropods make extensive use of peripheral neuromodulation to alter the properties of both neuromuscular junctions and muscle fibers. There has been little consideration of the functional consequences of these differences. I suggest that, faced with a size constraint on the number of motor units available, arthropods use peripheral modulation of muscle properties to achieve the flexibility and dynamic range that vertebrates achieve through recruitment of motor units. PMID- 21676817 TI - Sharing the secrets of life without water. PMID- 21676818 TI - The limits and frontiers of desiccation-tolerant life. AB - Drying to equilibrium with the air is lethal to most species of animals and plants, making drought (i.e., low external water potential) a central problem for terrestrial life and a major cause of agronomic failure and human famine. Surprisingly, a wide taxonomic variety of animals, microbes, and plants do tolerate complete desiccation, defined as water content below 0.1 g H(2)O g(-1) dry mass. Species in five phyla of animals and four divisions of plants contain desiccation-tolerant adults, juveniles, seeds, or spores. There seem to be few inherent limits on desiccation tolerance, since tolerant organisms can survive extremely intense and prolonged desiccation. There seems to be little phylogenetic limitation of tolerance in plants but may be more in animals. Physical constraints may restrict tolerance of animals without rigid skeletons and to plants shorter than 3 m. Physiological constraints on tolerance in plants may include control by hormones with multiple effects that could link tolerance to slow growth. Tolerance tends to be lower in organisms from wetter habitats, and there may be selection against tolerance when water availability is high. Our current knowledge of limits to tolerance suggests that they pose few obstacles to engineering tolerance in prokaryotes and in isolated cells and tissues, and there has already been much success on this scientific frontier of desiccation tolerance. However, physical and physiological constraints and perhaps other limits may explain the lack of success in extending tolerance to whole, desiccation-sensitive, multicellular animals and plants. Deeper understanding of the limits to desiccation tolerance in living things may be needed to cross this next frontier. PMID- 21676819 TI - Desiccation Tolerance Studied in the Resurrection Plant Craterostigma plantagineum. AB - This review will focus on the acquisition of desiccation tolerance in the resurrection plant Craterostigma plantagineum. Molecular aspects of desiccation tolerance in this plant will be compared with the response of non-tolerant plants to dehydration. Unique features of C. plantagineum are described like the CDT-1 (Craterostigma desiccation tolerance gene-1) gene and the carbohydrate metabolism. Abundant proteins which are associated with the desiccation tolerance phenomenon are the late embryogenesis abundant (=LEA) proteins. These proteins are very hydrophilic and occur in several other species which have acquired desiccation tolerance. PMID- 21676820 TI - Molecular anhydrobiology: identifying molecules implicated in invertebrate anhydrobiosis. AB - Studies in anhydrobiotic plants have defined many genes which are upregulated during desiccation, but comparable studies in invertebrates are at an early stage. To develop a better understanding of invertebrate anhydrobiosis, we have begun to characterise dehydration-inducible genes and their proteins in anhydrobiotic nematodes and bdelloid rotifers; this review emphasises recent findings with a hydrophilic nematode protein. Initial work with the fungivorous nematode Aphelenchus avenae led to the identification of two genes, both of which were markedly induced on slow drying (90-98% relative humidity, 24 hr) and also by osmotic stress, but not by heat or cold or oxidative stresses. The first of these genes encodes a novel protein we have named anhydrin; it is a small, basic polypeptide, with no counterparts in sequence databases, which is predicted to be natively unstructured and highly hydrophilic. The second is a member of the Group 3 LEA protein family; this and other families of LEA proteins are widely described in plants, where they are most commonly associated with the acquisition of desiccation tolerance in maturing seeds. Like anhydrin, the nematode LEA protein, Aav-LEA-1, is highly hydrophilic and a recombinant form has been shown to be unstructured in solution. In vitro functional studies suggest that Aav-LEA 1 is able to stabilise other proteins against desiccation-induced aggregation, which is in keeping with a role of LEA proteins in anhydrobiosis. In vivo, however, Aav-LEA-1 is apparently processed into smaller forms during desiccation. A processing activity was found in protein extracts of dehydrated, but not hydrated, nematodes; these shorter polypeptides are also active anti-aggregants and we hypothesise that processing LEA protein serves to increase the number of active molecules available to the dehydrating animal. Other LEA-like proteins are being identified in nematodes and it seems likely therefore that they will play a major role in the molecular anhydrobiology of invertebrates, as they are thought to do in plants. PMID- 21676821 TI - Factors Inducing Successful Anhydrobiosis in the African Chironomid Polypedilum vanderplanki: Significance of the Larval Tubular Nest. AB - The African chironomid Polypedilum vanderplanki exhibits anhydrobiosis, i.e., the larvae can survive complete desiccation. Recovery rate and trehalose content were investigated in larvae desiccated slowly or at a rate more than 3 times faster. Upon slow desiccation (evaporation rate 0.22 ml day(-1)) larvae synthesized 38 MUg trehalose/individual before complete desiccation, and all of them recovered after rehydration, whereas larvae that were dehydrated quickly (evaporation rate 0.75 ml day(-1)) accumulated only 6.8 MUg trehalose/individual and none of them revived after rehydration. In the pools that are their natural habitat P. vanderplanki larvae make tubes by incorporating detritus or soil with their sticky saliva. This tubular structure is a physical barrier not only to protect the larva from natural enemies but also induces successful anhydrobiosis by reducing the dehydration rate. When larvae were dehydrated with 100 MUl distilled water (DW) in soil tubes, they accumulated 37 MUg trehalose/individual and more than half of them could revive after rehydration, whereas larvae without tubes accumulated lower level of trehalose and none recovered after rehydration. PMID- 21676822 TI - Desiccation tolerance in encysted embryos of the animal extremophile, artemia. AB - Encysted embryos (cysts) of the primitive crustacean, Artemia franciscana, are among the most resistant of all animal life history stages to extremes of environmental stress. These embryos, extremophiles of the animal kingdom, are the main focus of this paper. Previous work has revealed the importance of biochemical and biophysical adaptations that provide a significant part of the basis of their resistance, and I consider some of these here. In the present paper the critical role played by the outer layer of the shell in desiccation tolerance will be one focus. Another involves studies on the response of dried cysts to high temperatures that, among other things, implicate one or more volatile factors released from the cysts that determines the extent of thermotolerance under a given heating regime. A hypothetical scheme is given to account for these peculiar results. Based on western immunoblotting analysis, and data from the literature, the scheme also implicates the heat-induced translocation of the stress protein p26 to nuclei as a potential cause of the reduction in hatching level. PMID- 21676823 TI - Differential longevities in desiccated anhydrobiotic plant systems. AB - Desiccation tolerance is a wide-spread phenomenon in the plant kingdom, particularly in small propagules lacking own root or rhizome system, such as seeds, pollen, spores of spore plants, and whole moss plants, but rare in whole, vascular plants. Longevities in the desiccated state vary from a few days in some pollen and spore types to many decades in some seeds and moss spores, green vegetative tissues being intermediate in that respect. Therefore, small size of a propagule does not appear to be a factor limiting life span. The formation of a glassy state in the cytoplasm upon water loss considerably increases viscosity and slows deteriorative chemical reactions. Intermolecular hydrogen bonding strength and length in the glassy cytoplasm have been suggested to play a role in desiccation tolerance and longevity. To further explore this, a comparative Fourier transform IR study among dried anhydrobiotic plant propagules belonging to different phyla was conducted. This study indicated that strong hydrogen bonding does not correlate with long life span, but rather depends on the composition of the glass forming compounds. By contrast, a large number of double bonds in the acyl chains of the polar lipids correlated with short life span. This result suggests that deteriorative processes in membranes rather than in the glassy cytoplasm determine the rate of aging of dried anhydrobiotic propagules. This would agree with the view that lipids form the only fluid or semi-fluid phase in the dried propagules, which renders them comparatively susceptible to free radical attack. PMID- 21676824 TI - A modulating role for antioxidants in desiccation tolerance. AB - Most organisms depend on the availability of water. However, some life-forms, among them plants and fungi, but very few animals, can survive in the desiccated state. Here we discuss biochemical mechanisms that confer tolerance to desiccation in photosynthetic and non-photosynthetic organisms. We first consider damage caused by water removal and point out that free radicals are a major cause of death in intolerant tissue. Free radicals impair metabolism and necessitate protection and repair during desiccation and rehydration, respectively. As a consequence, desiccation tolerance and prolonged longevity in the desiccated state depend on the ability to scavenge free radicals, using antioxidants such as glutathione, ascorbate, tocopherols and free radical-processing enzymes. Some 'classic' antioxidants may be absent in lower plants and fungi. On the other hand, lichens and seeds often contain secondary phenolic products with antioxidant properties. The major intracellular antioxidant consistently found in all life forms is glutathione, making it essential to survive desiccation. We finally discuss the role of glutathione to act as a signal that initiates programmed cell death. The failure of the antioxidant system during long-term desiccation appears to trigger programmed cell death, causing ageing and eventual death of the organism. In turn, this suggests that a potent antioxidant machinery is one of the underlying mechanisms of desiccation tolerance. PMID- 21676825 TI - Soil nematodes and desiccation survival in the extreme arid environment of the antarctic dry valleys. AB - Soil nematodes are capable of employing an anhydrobiotic survival strategy in response to adverse environmental conditions. The McMurdo Dry Valleys of Antarctica represent a unique environment for the study of anhydrobiosis because extremes of cold, salinity, and aridity combine to limit biological water availability. We studied nematode anhydrobiosis in Taylor Valley, Antarctica, using natural variation in soil properties. The coiled morphology of nematodes extracted from dry valley soils suggests that they employ anhydrobiosis, and these coiled nematodes showed enhanced revival when re-hydrated in water as compared to vermiform nematodes. Nematode coiling was correlated with soil moisture content, salinity, and water potential. In the driest soils studied (gravimetric water content <2%), 20-80% of nematodes were coiled. Soil water potential measurements also showed a high degree of variability. These measurements reflect microsite variation in soil properties that occurs at the scale of the nematode. We studied nematode anhydrobiosis during the austral summer, and found that the proportion of nematodes coiled can vary diurnally, with more nematodes vermiform and presumably active at the warmest time of day. However, dry valley nematodes uncoiled rapidly in response to soil wetting from snowmelt, and most nematode activity in the Dry Valleys may be confined to periods following rare snowfall and melting events. Anhydrobiosis represents an important temporal component of a dry valley nematode's life span. The ability to utilize anhydrobiosis plays a significant role in the widespread distribution and success of these organisms in the Antarctic Dry Valleys and beyond. PMID- 21676826 TI - Dying while Dry: Kinetics and Mechanisms of Deterioration in Desiccated Organisms. AB - Persistence of anhydrous organisms in nature may depend on how long they remain viable in dry environments. Longevity is determined by interactions of humidity, temperature, and unknown cellular factors that affect the propensity for damaging reactions. Here we describe our research to elucidate those cellular factors and to ultimately predict how long a population can survive under extreme conditions. Loss of viability typically follows a sigmoidal pattern, where a period of small changes precedes a cataclysmic decline. The time for viability to decrease to 50% (P50) varied among seed species and among 10 phylogenetically diverse organisms. When stored at elevated temperatures of 35 degrees C and 32% relative humidity (RH), P50 ranged from about a week for spores of Serratia marcescens to several years for fronds of Selaginella lepidophylla. Most of the species studied survived longest at low humidity (10-20% RH), but suffered under complete dryness. Temperature dependencies of aging kinetics appeared similar among diverse organisms despite the disparate longevities. The effect of temperature on seed aging rates was consistent with the temperature dependency of molecular mobility of aqueous glasses, with both showing a reduction by several orders of magnitude when seeds were cooled from 60 degrees C to 0 degrees C. Longevity is an inherited trait in seeds, but its complex expression among widely divergent taxa suggests that it developed through multiple pathways. PMID- 21676827 TI - Anhydrobiosis in bdelloid species, populations and individuals. AB - Bdelloid rotifers are aquatic microinvertebrates common in water bodies and in unstable "terrestrial" habitats, such as mosses and lichens. The key to the adaptability to live in unstable habitats is their capacity to tolerate habitat desiccation through anhydrobiosis, that is assumed apomorphic to the taxon. The life history traits of some "moss" and "water" species of bdelloid are compared, showing that the water species have shorter life span, higher fecundity and earlier age at first reproduction than the moss species. These traits are discussed in the light of current life history theories. Contrary to the assumptions of the models, anhydrobiosis of bdelloids does not appear to imply energy demand. Past research on bdelloid anhydrobiosis is briefly reviewed, focusing on the factors that affect anhydrobiosis success, like morphological and physiological adjustments, and on the effect of events of anhydrobiosis during life time. Desiccation produces a time shift on the age of the bdelloid, which disregards the time spent as anhydrobiotic, following the so-called "Sleeping Beauty" model. Average fecundity is never found to decrease as a consequence of anhydrobiosis, but is either equal or even higher than that of a hydrated rotifer. Bdelloid populations seem to benefit from anhydrobiosis; fitness of a bdelloid is found to decline, if populations are maintained hydrated for several generations, but not if populations are cyclically desiccated. We hypothesize that anhydrobiosis can be an essential event for long-term survival of bdelloid populations. PMID- 21676828 TI - The Evolution of Life Histories in Holo-anhydrobiotic Animals: A First Approach. AB - The life histories of holo-anhydrobiotic animals differ from those of all other organisms by a regular or irregular entrance into an ametabolic state induced by desiccation. Such ametabolic periods will arrest growth and reproduction completely and thus affect primary life history parameters dramatically. The selective forces and the genetic and physiological trade-offs acting on anhydrobiotic animals are to a large extent unknown. Assuming low growth rates and low juvenile to adult survival, general theoretical models on life history responses to stress predict that anhydrobiotic animals will be selected for a high degree of iteroparity, with low fecundity, large egg size, and low total reproductive investment. A high degree of variability in growth and reproduction should create a selective force in the same direction. Although basic empirical data on life history parameters are very scarce, available observations seem to be consistent with this prediction. PMID- 21676829 TI - The signature of seeds in resurrection plants: a molecular and physiological comparison of desiccation tolerance in seeds and vegetative tissues. AB - Desiccation-tolerance in vegetative tissues of angiosperms has a polyphyletic origin and could be due to 1) appropriation of the seed-specific program of gene expression that protects orthodox seeds against desiccation, and/or 2) a sustainable version of the abiotic stress response. We tested these hypotheses by comparing molecular and physiological data from the development of orthodox seeds, the response of desiccation-sensitive plants to abiotic stress, and the response of desiccation-tolerant plants to extreme water loss. Analysis of publicly-available gene expression data of 35 LEA proteins and 68 anti-oxidant enzymes in the desiccation-sensitive Arabidopsis thaliana identified 13 LEAs and 4 anti-oxidants exclusively expressed in seeds. Two (a LEA6 and 1-cys peroxiredoxin) are not expressed in vegetative tissues in A. thaliana, but have orthologues that are specifically activated in desiccating leaves of Xerophyta humilis. A comparison of antioxidant enzyme activity in two desiccation-sensitive species of Eragrostis with the desiccation-tolerant E. nindensis showed equivalent responses upon initial dehydration, but activity was retained at low water content in E. nindensis only. We propose that these antioxidants are housekeeping enzymes and that they are protected from damage in the desiccation tolerant species. Sucrose is considered an important protectant against desiccation in orthodox seeds, and we show that sucrose accumulates in drying leaves of E. nindensis, but not in the desiccation-sensitive Eragrostis species. The activation of "seed-specific" desiccation protection mechanisms (sucrose accumulation and expression of LEA6 and 1-cys-peroxiredoxin genes) in the vegetative tissues of desiccation-tolerant plants points towards acquisition of desiccation tolerance from seeds. PMID- 21676830 TI - Desiccation tolerance in bryophytes: a reflection of the primitive strategy for plant survival in dehydrating habitats? AB - Bryophytes are a non-monophyletic group of three major lineages (liverworts, hornworts, and mosses) that descend from the earliest branching events in the phylogeny of land plants. We postulate that desiccation tolerance is a primitive trait, thus mechanisms by which the first land plants achieved tolerance may be reflected in how extant desiccation-tolerant bryophytes survive drying. Evidence is consistent with extant bryophytes employing a tolerance strategy of constitutive cellular protection coupled with induction of a recovery/repair mechanism upon rehydration. Cellular structures appear intact in the desiccated state but are disrupted by rapid uptake of water upon rehydration, but cellular integrity is rapidly regained. The photosynthetic machinery appears to be protected such that photosynthetic activity recovers quickly. Gene expression responds following rehydration and not during drying. Gene expression is translationally controlled and results in the synthesis of a number of proteins, collectively called rehydrins. Some prominent rehydrins are similar to Late Embryogenesis Abundant (LEA) proteins, classically ascribed a protection function during desiccation. The role of LEA proteins in a rehydrating system is unknown but data indicates a function in stabilization and reconstitution of membranes. Phylogenetic studies using a Tortula ruralis LEA-like rehydrin led to a re examination of the evolution of desiccation tolerance. A new phylogenetic analysis suggests that: (i) the basic mechanisms of tolerance seen in modern day bryophytes have changed little from the earliest manifestations of desiccation tolerance in land plants, and (ii) vegetative desiccation tolerance in the early land plants may have evolved from a mechanism present first in spores. PMID- 21676831 TI - Desiccation tolerance of prokaryotes: application of principles to human cells. AB - The loss of water from cells is a stress that was likely imposed very early in evolution. An understanding of the sensitivity or tolerance of cells to depletion of intracellular water is relevant to the study of quiescence, longevity and aging, because one consequence of air-drying is full metabolic arrest, sometimes for extended periods. When considering the adaptation of cells to physiological extremes of pH, temperature or pressure, it is generally assumed that evolution is driven toward optimum function rather than maximum stability. However, adaptation to desiccation has the singular and crucial distinction that dried cells do not grow, and the time the cell is dried may represent the greater part of the life (the time the cell remains viable) of that cell and its component macromolecules. Is a consideration of "function" relevant in the context of desiccated cells? The response of prokaryotic cells to desiccation, and the mechanisms they employ to tolerate this stress at the level of the cell, genome and proteome are considered. Fundamental principles were then implemented in the design of strategies to achieve air-dry stabilization of sensitive eukaryotic (human) cells. The responses of the transcriptomes and proteomes of prokaryotic cells and eukaryotic cells (yeast and human) to drying in air are compared and contrasted to achieve an evolutionary context. The concept of the "desiccome" is developed to question whether there is common set of structural, physiological and molecular mechanisms that constitute desiccation tolerance. PMID- 21676832 TI - Stabilization of dry Mammalian cells: lessons from nature. AB - The Center for Biostabilization at UC Davis is attempting to stabilize mammalian cells in the dry state. We review here some of the lessons from nature that we have been applying to this enterprise, including the use of trehalose, a disaccharide found at high concentrations in many anhydrobiotic organisms, to stabilize biological structures, both in vitro and in vivo. Trehalose has useful properties for this purpose and in at least in one case-human blood platelets introducing this sugar may be sufficient to achieve useful stabilization. Nucleated cells, however, are stabilized by trehalose only during the initial stages of dehydration. Introduction of a stress protein obtained from an anhydrobiotic organism, Artemia, improves the stability markedly, both during the dehydration event and following rehydration. Thus, it appears that the stabilization will require multiple adaptations, many of which we propose to apply from studies on anhydrobiosis. PMID- 21676833 TI - The Problem with Paradigms: Bateman's Worldview as a Case Study. AB - Bateman's principles, their corollaries and predictions constitute a paradigm for the study of sexual selection theory, evolution of mating systems, parental investment theory, and sexual dimorphism in male and female behavior. Some aspects of this paradigm have been challenged in recent years, while others have been supported by empirical and theoretical research. We re-examine Bateman's 1948 paper in detail, including some methodological problems. Additionally, we review three areas in which an over-reliance on Bateman's predictions about sexual dynamics hindered our ability to understand the potential importance of certain behaviors: 1) male mate choice and sperm allocation; 2) the role of females in initiating and soliciting extra-pair copulations and fertilizations; and 3) the role of females in lekking systems, in which recent evidence suggests that copulations with multiple males (polyandrous behavior) may be common. We conclude this introduction to the symposium by emphasizing the heuristic value of Bateman's contributions, as well as the problems that arise when Bateman's paradigm is viewed through the lens of modern behavioral ecology and evolutionary theory. PMID- 21676834 TI - The darwin-bateman paradigm in historical context. AB - I introduce the term "Darwin-Bateman Paradigm" to include several proposals stemming from the writings of Charles Darwin and A. J. Bateman, including the notions that (a) male reproductive success is more variable than that of females, (b) males gain more in reproductive success from repeated matings than do females, and (c) males are generally eager to mate and relatively indiscriminate whereas females are more discriminating and less eager. I trace this paradigm from Darwin's The Descent of Man through Bateman's research and beyond. I try to clarify the terminology used in applying Bateman's results and discuss both the impact and the criticisms the paradigm has engendered. I then broaden the context of the Darwin-Bateman Paradigm to show related conceptions in disparate fields that evolved in parallel with it. I conclude that gender stereotypes appear to have influenced these conceptions. The paradigm has been of great heuristic value but is in need of further empirical investigation in view of numerous exceptions to these general rules. PMID- 21676835 TI - Terminal Investment Strategies and Male Mate choice: Extreme Tests of Bateman. AB - Bateman's principle predicts the intensity of sexual selection depends on rates of increase of fecundity with mating success for each sex (Bateman slopes). The sex with the steeper increase (usually males) is under more intense sexual selection and is expected to compete for access to the sex under less intense sexual selection (usually females). Under Bateman and modern refinements of his ideas, differences in parental investment are key to defining Bateman slopes and thus sex roles. Other theories predict sex differences in mating investment, or any expenditures that reduce male potential reproductive rate, can also control sex roles. We focus on sexual behaviour in systems where males have low paternal investment but frequently mate only once in their lifetimes, after which they are often killed by the female. Mating effort (=terminal investment) is high for these males, and many forms of investment theory might predict sex role reversal. We find no qualitative evidence for sex role reversal in a sample of spiders that show this extreme male investment pattern. We also present new data for terminally-investing redback spiders (Latrodectus hasselti). Bateman slopes are relatively steep for male redbacks, and, as predicted by Bateman, there is little evidence for role reversal. Instead, males are competitive and show limited choosiness despite wide variation in female reproductive value. This study supports the proposal that high male mating investment coupled with low parental investment may predispose males to choosiness but will not lead to role reversal. We support the utility of using Bateman slopes to predict sex roles, even in systems with extreme male mating investment. PMID- 21676836 TI - The distribution of male and female reproductive success in a broadcast spawning marine invertebrate. AB - Many studies have addressed sexual selection in animals, but few data are available on animals that release eggs and sperm into the environment for external fertilization. Although this reproductive mode represents the ancestral condition and is still a very common reproductive strategy, it is underrepresented in empirical studies and theoretical treatments. Here I present data on the pattern of reproductive success in male and female sea urchins. The results suggest that the strength of sexual selection and the differences between the sexes in the intensity of sexual selection depend on mate density. In general, despite the high degree of multiple paternity, the variance in reproductive success appears to be lower in males and higher in females than it is in polygamous species with internal fertilization. These results may provide insight into the patterns of effective population size in marine invertebrates and also more generally the evolutionary transition from sexual monomorphism to polymorphism in adult traits. PMID- 21676837 TI - Bateman's Principle and Simultaneous Hermaphrodites: A Paradox. AB - Bateman's principle states that reproductive success is limited a) in females by the resources available for egg production; and b) in males, only by access to females and/or eggs. The principle has been used to generate predictions for two aspects of hermaphroditism; a) the advantage of hermaphroditism and b) sexual conflict. Comparing these predictions to the empirical data offers tests of Bateman's principle. Charnov's prediction that hermaphroditism would occur under circumstances where Bateman's principle does not apply is found to be largely correct. However, the prediction as to the association of hermaphroditism and low fixed costs is inconsistent with the data. Alternative explanations that predict that hermaphroditism is a strategy for reducing variance in reproductive success may better explain the data. Probability theory demonstrates that where two strategies have equal mean fitness, which must be the case for male and female function, the strategy with the lower variance in reproductive success must have higher fitness (Gillespie's principle). Bateman's principle predicts that this will be the female role in hermaphrodites. However, Charnov, assuming Bateman's principle, predicted that sexual conflict stemming from a preference for the male role would be important in hermaphrodite mating systems, creating a paradox. Many hermaphrodite mating systems are based on conditional reciprocity with a preferred sexual role indicating sexual conflict. The data demonstrate that the preferred role varies among taxa, contrary to the predictions of Bateman's principle. It has been suggested that Bateman's principle can explain cases in which the female role is preferred (sperm-trading) as involving energy rather than gamete trading. However, energetic considerations suggest that energy trading would only be adaptive if Bateman's principle does not apply, paradoxically. The gamete trading model, based on the prediction that the role that offers control of fertilization will be preferred, is more consistent with the data. Application of Bateman's principle to hermaphrodites leads to contradictory predictions and does not offer the basis for a coherent theory of sexual selection, as Bateman proposed. PMID- 21676838 TI - The Measurement of Sexual Selection Using Bateman's Principles: An Experimental Test in the Sex-Role-Reversed Pipefish Syngnathus typhle. AB - Angus J. Bateman's classic study of sexual selection in Drosophila melanogaster has had a major influence on the development of sexual selection theory. In some ways, Bateman's study has served a catalytic role by stimulating debate on sex roles, sexual conflict and other topics in sexual selection. However, there is still considerable disagreement regarding whether or not "Bateman's principles" are helpful in the study of sexual selection. Here, we test the idea that Bateman's principles provide the basis for a useful method to quantify and compare mating systems. In this study, we focus on the sex-role-reversed pipefish Syngnathus typhle as a model system to study the measurement of sexual selection. We set up artificial breeding assemblages of pipefish in the laboratory and used microsatellite markers to resolve parentage. Three different sex-ratio treatments (female-biased, even and male-biased) were used to manipulate the expected intensity of sexual selection. Measures of the mating system based on Bateman's principles were calculated and compared to the expected changes in the intensity of sexual selection. We also compare the results of this study to the results of a similar study of Bateman's principles in the rough-skinned newt, a species with conventional sex roles. The results of this experiment show that measures of the mating system based on Bateman's principles do accurately capture the relative intensities of sexual selection in the different treatments and species. Thus, widespread use of Bateman's principles to quantify mating systems in nature would facilitate comparative studies of sexual selection and mating system evolution. PMID- 21676839 TI - Patterns of Parental Investment and Sexual Selection in Teleost Fishes: Do They Support Bateman's Principles? AB - Bateman demonstrated differences in variance for fertility and mating success between the sexes, with males usually having a greater variance than females. Thus in general, male reproductive success increases with number of mates acquired. These results have been referred to as "Bateman's principles" and taken together with other parameters (e.g., relative parental investment) have been proposed to estimate a component of sexual selection. For this review I examine patterns of parental care and sexual selection in teleost fishes (substrate brooding and with internal fertilization). I present data for the pumpkinseed sunfish Lepomis gibbosus, in which I estimated cost of paternal care and compared direct measures of the intensity of selection on possible sexually selected traits to measures of sexual selection based on Bateman's principles.Despite high levels of paternal care in substrate brooding fishes, sexual selection tends to act more strongly on males than on females, which suggests that maternal investment is higher than paternal investment and that parental care does not limit the reproductive rate for males. In pumpkinseed sunfish, selection favors parents with high levels of defense that may exclude predators more effectively and, as suggested by Bateman's measures, alternative reproductive strategies may decrease the opportunity for sexual selection within the parental strategy. In teleost fishes with internal fertilization, patterns of parental investment and intensity of sexual selection seem to support Bateman's principles, but further studies using these systems and these measures of selection will improve the understanding of factors affecting the intensity of sexual selection and its relation to mating systems. PMID- 21676840 TI - Bateman gradients in field and laboratory studies: a cautionary tale. AB - Since tools of molecular genetics became readily available, our understanding of bird mating systems has undergone a revolution. The majority of passerine species investigated are socially monogamous, but have been shown to be genetically polygamous. Data sets from natural populations of juncos suggest that multiple mating by females results in a sexual selection gradient as steep for females as for males (a result that does not support Bateman's predictions). However, in males, fitness is enhanced directly through fertilization success with multiple matings; in females fitness benefits may be enhanced immediately through direct access to food, protection against predators, or other resources received from males, or they may be delayed through improvement in offspring quality (e.g., through good genes, or greater genetic compatibility between the female and the extra-pair male). But a steep sexual selection gradient for females can be difficult to interpret. If all females copulate with multiple partners that are equally likely to fertilize eggs, then females that produce larger clutch sizes, for any reason, will appear to have copulated with more males. That is, multiple sires have a higher probability of detection in larger clutches than in smaller ones, giving the impression that females that mate with multiple males increase their reproductive success. Yet, in most studies in which there is a correlation between number of offspring produced by females and number of extra-pair males, causation has not been clearly established and other factors may explain the results. Additional complications in understanding male and female reproductive strategies are: (1) Molecular studies cannot detect extra-pair copulations that did not result in fertilizations; yet if a female acquires food or other resources from extra-pair males, such extra-pair matings may have significant effects on female fitness. Thus, molecular studies provide only a conservative estimate of the number of extra-pair copulations or "mates" that a female has. (2) Clutch size affects the probability that any given male will be successful in fertilizing a female's eggs. Specifically, at any given point, a male's chances of fertilizing at least one egg in the female's clutch will be greater as clutch size increases. We predict that in avian species with small clutch sizes, males may be selected to be choosy and avoid extra-pair copulations, while females should be selected to be less discriminating. Moreover, if extra-pair males provide resources that increase female fitness, the females should seek extra pair copulations, whether or not the males are likely to fertilize any of her eggs.Laboratory studies with insects have yielded clearer evidence of the causal relationship between multiple mating and increased female fitness. We review studies on a tenebrionid beetle in which female fecundity increases directly with number of mates. In these experiments, the nutritive value of the spermatophores does not fully explain the increase in female reproductive success. PMID- 21676841 TI - Bateman's Principle in Cooperatively Breeding Vertebrates: The Effects of Non breeding Alloparents on Variability in Female and Male Reproductive Success. AB - The sex-specific slopes of Bateman's gradients have important implications for understanding animal mating systems, including patterns of sexual selection and reproductive competition. Intersexual differences in the fitness benefits derived from mating with multiple partners are expected to yield distinct patterns of reproductive success for males and females, with variance in direct fitness predicted to be greater among males. These analyses assume that typically all adults are reproductive and that failure to produce offspring is non-adaptive. Among some species of cooperatively breeding birds and mammals, however, non breeding adult alloparents are common and may comprise the majority of individuals in social groups. The presence of a large number of non-breeding adults, particularly when coupled with greater social suppression of reproduction among females, may alter the relative variance in direct fitness between the sexes, thereby generating an apparent contradiction to Bateman's Paradigm. To explore quantitatively the effects of non-breeding alloparents on variance in reproductive success, we used genetic estimates of parentage and reproductive success drawn from the literature to calculate the relative variability in direct fitness for females and males in alloparental and "other" societies of birds and mammals. Our analyses indicate that in mammals and, to a lesser extent, in birds, variability in direct fitness is greater among females in species characterized by the presence of non-breeding alloparents. These data suggest that social interactions, including social suppression of reproduction, are powerful determinants of individual direct fitness that may modify sex-specific patterns of reproductive variance from those described by Bateman. PMID- 21676842 TI - Bateman revisited: the reproductive tactics of female primates. AB - The breeding system of an animal population is thought to depend on the ability of one sex (usually the male) to acquire mates, either directly through association with females or indirectly through defense of the resources desired by females. The sex that contributes most to infant care (usually the female) is constrained by parental involvement and thereby limits reproduction of the opposite sex. Accordingly, males, but not females, enhance their reproductive success by acquiring additional mates. This classical view has emphasized the role of male-male competition in sexual selection, at the expense of fully exploring the potential for female choice. A more recent shift in focus has revealed substantial variation in female reproductive success and increasingly accentuates the importance of female intrasexual competition and male mate choice. A comparative review of primate reproduction, therefore, challenges expectations of male control and female compliance, and calls for a comprehensive treatment of costs and benefits that extends beyond conventional mention of heavy female investment versus male negligence or absenteeism. For individuals that manipulate their social environment or reproductive output, consideration of more subtle, even cryptic, aspects of female behavior and physiology (e.g., social strategizing, sexual solicitation or rejection, sexual advertisement or concealed ovulation, multiple mating, and reproductive failure) raises the question of whether females can be effectively 'monopolized.' Widespread patterns that counter Bateman's paradigm call for a reexamination of the predictions generated by dichotomizing gametes into 'expensive eggs' and 'cheap sperm,' and encourage continued mechanistic research focused on conception quality rather than quantity. PMID- 21676843 TI - Using upper limits of "bateman gradients" to estimate the opportunity for sexual selection. AB - The widespread use of molecular markers to estimate parentage makes possible a new index of the opportunity for sexual selection. After demonstrating the need for a new measure, I develop one based on the upper limit on sexual selection. I describe what sets the upper limit for each sex by showing how maximum fecundity increases with number of mates, accounting for the amount of energy (or critical resources) available for reproduction and levels of parental care. For females the upper limit on sexual selection is set by the value of paternal investment that comes with each mating. For males, the upper limit on sexual selection is set by the fecundity of their mates (including any boost to female fecundity from paternal investment). Sex-roles are most likely to reverse (making males choosy and females competitive) when the amount of reproductive energy investment made by each sex is low, irrespective of the level of paternal investment. Finally, I propose that we use the difference between male and female upper limits on sexual selection to quantify sex differences in the opportunity for sexual selection. Using upper limits to estimate the opportunity for sexual selection is more intuitive than older methods (e.g., standardized variance in mating success), it is experimentally measurable, and it is valuable in understanding the evolution of mating systems. PMID- 21676844 TI - Chance, time allocation, and the evolution of adaptively flexible sex role behavior. AB - An alternative to classic sexual selection hypotheses for sex differentiated pre mating behavior is that time available for mating-as individuals experience it along with fitness differences among alternative potential mates, induces choosy versus indiscriminate mating behavior. This alternative hypothesis says that selection has acted so that all individuals flexibly express fitness-enhancing choosy, indiscriminate, and competitive mating behavior, induced by time-varying life histories, environmental and social cues. Key predictions of DYNAMATE, the formal model of adaptively flexible sex role behavior of individuals of both sexes within dynamically changing populations, include: (1) All individuals regardless of sex assess likely fitness outcomes from mating with alternative potential mates before expressing choosy or indiscriminate behavior. (2) Males and females express adaptively flexible, choosy and indiscriminate behavior so that individuals may change their behavior-from moment to moment-to fit dynamically changing circumstances. (3) Indiscriminate behavior of males and (4) choosy behavior of females would often be maladaptive even in species with greater female than male parental investment, when females have longer latencies to receptivity to re-mating than males, and when the relative reproductive rate of males is greater than in females. (5) Whether or not females show choosy behavior will not affect whether or not males exhibit choosy or indiscriminate behavior, and vice versa. (6) When other model parameters are equal, the proportion of individuals of a given sex expressing choosy or indiscriminate mating behavior is a function of the distribution of fitness ratios (a distribution of all fitness differences that would be conferred on an individual by mating with any two sequentially or simultaneously encountered alternative potential mates). (7) Whether same-sex individuals behaviorally compete is a function of the fitness that would be conferred if the strategist won access to a potential mate, but not a function of relative reproductive rate or its proxy, the operational sex ratio. We call for re-evaluation of sex differences in choosy, indiscriminate, and competitive behavior under strong experimental controls that level the ecological playing fields of males and females, i.e., under experimental conditions informing the mechanisms of phenotypic expression. We end with comments on the classic question of questions: why are the sexes as they are? PMID- 21676845 TI - Don'T throw bateman out with the bathwater! AB - Bateman identified two aspects of sexual selection. The first, called Bateman's principle, is that sexual selection favors increased promiscuity of males but not of females as a result of differences in parental investment in gametes. The second is that the variance in mate number of males is the fundamental cause of a sex difference in fitness variance. We argue that Bateman's insight about the source of sexual selection is more fundamental than his speculation about patterns of parental investment. We show that, when the sex ratio is 1:1, the average female must be as promiscuous as the average male, because each copulation involves one male and one female. Because mean male and female promiscuity are tied together in the same manner as mean male and female fitness, a sex difference in mating propensity must be the result of either (1) a sex difference in the covariance between matings and number offspring, or (2) Fisherian run-away sexual selection, wherein female reluctance to mate is a weak form of female choice. We show how female promiscuity can limit the evolution of male promiscuity, turning the central argument of parental investment theory on its head. PMID- 21676847 TI - Development and implementation of a piperacillin-tazobactam extended infusion guideline. AB - Administration of beta-lactam antibiotics by extended infusion optimizes the pharmacodynamic properties and bactericidal activity of these agents resulting in a potential improvement in patient outcomes and reduction in drug expenditure. Consequently, a pharmacist-led piperacillin-tazobactam extended 4-hour infusion guideline was implemented hospital-wide at a 500-bed academic medical center. Each piperacillin-tazobactam infusion was prospectively monitored for 5 weeks to ensure accurate administration and identify barriers to guideline adherence. Overall, a total of 103 patients received 1215 doses of piperacillin-tazobactam by extended infusions. In all, 98% of the doses were administered at the correct extended infusion rate and 94% of the doses were given at the scheduled time. There were a total of 20 missed doses and 53 delayed doses, accounting for 2% and 4% of the total administered doses, respectively. The primary barrier to adherence was the patient not being on the unit at the time of the scheduled dose followed by the piperacillin-tazobactam dose not being available on the floor. While insufficient power prevented meaningful evaluation of clinical outcomes, we anticipate a conservative annual estimated cost savings of $108,529. Key elements contributing to our success included consistent pharmacy leadership, multidisciplinary involvement, thorough inservicing to health care professionals, hospital-wide implementation, and extensive quality assurance monitoring. PMID- 21676848 TI - Fish oil: what is the role in cardiovascular health? AB - Fish and fish oil supplements are often used to lower triglycerides; however, recent studies suggest the beneficial use of fish oil for other cardiovascular reasons. Studies have shown that in addition to decreasing triglycerides, fish oil has shown benefit in providing antiplatelet activity, improving heart failure, and improving vascular function in diabetes. Fish oil was shown to improve triglycerides in combination with other lipid-lowering therapy such as a statin or fibrate. Fish oil also had effects on lowering total cholesterol, very low-density lipoprotein (VLDL), and increasing high-density lipoprotein (HDL). In terms of its antiplatelet activity, fish oil was shown to lower platelet aggregation when given in combination with clopidogrel and aspirin therapy during PCI, thus fish oil appears to enhance platelet response to clopidogrel. Fish oil has a role in heart failure as well.Fish oil was shown to slightly decrease morbidity and mortality in patients with class II-IV heart failure compared to placebo.Finally, fish oil showed benefit in patients with type II diabetes in terms of improving micro- and macrovascular function. PMID- 21676849 TI - Hypertensive Urgency Associated With Xenadrine EFX Use. AB - Several supplements and herbal products have been shown to increase catecholamines and subsequently mean arterial pressure and systemic vascular resistance. Since ephedra-containing products have been removed from the market, manufacturers of weight loss herbal supplements must produce ephedra-free formulations. Xenadrine EFX is an ephedra-free weight loss product containing a mixture of caffeine, guarana, and bitter orange (standardized to synephrine). Synephrine has been shown in animals and humans to increase systemic vascular resistance and mean arterial pressure. We present a case of a patient who took Xendarine EFX for 2 weeks prior to her presentation to an emergency department with headaches and hypertensive urgency (blood pressure [BP] 234/130 mm Hg). Her BP was controlled after discontinuation of Xenadrine and initiation a nitroprusside drip and oral clonidine. A Naranjo probability score of 6 indicates the adverse drug reaction was probable. Clinicians should be aware of potential cardiovascular changes in patients on Xenadrine EFX or other synephrine containing products. PMID- 21676850 TI - Possible angiotensin-converting enzyme inhibitor (ACEI)-induced small bowel angioedema. AB - OBJECTIVE: To report a case of possible lisinopril-induced angioedema of the small bowel. CASE SUMMARY: A 67-year-old female was admitted to the hospital with abdominal pain, nausea, vomiting, and diarrhea. A computed tomography (CT) scan of the abdomen/pelvis was obtained which showed wall thickening around the area of the jejunum and scant ascites consistent with several diagnoses, including small bowel angioedema. She was treated with intravenous fluids and nasogastric decompression. Stool studies were negative. Her lisinopril was held due to the possibility of small bowel angioedema. A CT enterography obtained 5 days after the discontinuation of lisinopril showed complete resolution of the inflammatory changes and perihepatic fluid. It was felt that angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema of the small bowel was the most likely etiology of her symptoms. DISCUSSION: Angiotensin-converting enzyme inhibitor small bowel angioedema is an uncommon cause of abdominal symptoms. In several cases, patients had been taking ACEIs for years before symptoms occur. Treatment includes cessation of the ACEI and supportive care. CONCLUSIONS: Angiotensin converting enzyme inhibitor-related small bowel angioedema should be considered in the differential diagnosis of unexplained abdominal pain. PMID- 21676851 TI - Evaluation of the Implementation of an Anticoagulation Management Protocol at a Community Hospital. AB - Purpose: The objective of this study was to evaluate the impact of implementation of an anticoagulation protocol involving dosing and monitoring of unfractionated heparin (UFH) and low-molecular-weight heparin, specifically enoxaparin, for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and/or acute coronary syndromes (ACS). Methods: Patients with a primary diagnosis of DVT, PE, and/or ACS treated with UFH and/or enoxaparin were included. Data were collected on patients admitted to a community hospital during February 2008 (preimplementation) and February 2009 (postimplementation). Results: Forty-six patients were included in the preimplementation group and 25 patients in the postimplementation group. Forty-six percent of patients were dosed properly in the preimplementation group (UFH 38% and enoxaparin 50%) compared to 76% in the postimplementation group (UFH 56% and enoxaparin 88%; P = .023). Fifty-four percent of patients were monitored properly in the preimplementation group (UFH 31% and enoxaparin 67%) compared to 68% in the postimplementation group (UFH 56% and enoxaparin 75%; P = .318). Conclusion: Standardized dosing with a multidisciplinary-managed anticoagulation protocol significantly increased proper dosing of anticoagulation therapy; however, the protocol did not significantly improve proper monitoring. A lack of understanding of the need for baseline laboratory data contributes to improper monitoring. An approach which includes significant educational strategies is necessary to optimize patient care. PMID- 21676852 TI - Introduction: men's health. PMID- 21676853 TI - Testosterone replacement therapy in males with erectile dysfunction. AB - Erectile dysfunction (ED) is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Endogenous testosterone is critical for normal libido; however, studies have also demonstrated a potentially important role with respect to the erectile process. The prevalence of testosterone deficiency ranges from 1.7% to 35% in patients with ED, and age is a common factor linking ED and testosterone deficiency. By 2025, global estimates are that there will be 356 million men >65 years. Age-associated testosterone deficiency is characterized by symptoms such as ED, and low serum testosterone. Randomized, placebo controlled studies have established the utility of testosterone replacement therapy (TRT) for the restoration of serum testosterone levels to the normal range in hypogonadal males; however, well designed studies are limited with respect to specific evaluation of the role of TRT as monotherapy in improving erectile function. In addition, recent literature suggests a possible role for TRT in combination with phosphodiesterase-5 (PDE-5) inhibitors for men with ED. The following review describes the potential roles of testosterone in erectile physiology, examines the relationship between testosterone deficiency and ED, and reviews published literature evaluating the use of TRT in hypogonadal males with a diagnosis of ED. PMID- 21676854 TI - Osteoporosis in men: a review of endogenous sex hormones and testosterone replacement therapy. AB - The prevalence of osteoporosis is estimated to be 18% in men, but 30% of all fractures occur in men. With age, men experience a gradual decline in testosterone production and bone density. The rate of trabecular bone loss in the lumbar spine in men over age 50 can be double the rate of loss in men under age 50. Endogenous testosterone, estradiol, and their metabolites play a role in maintaining bone health, but their specific effects on bone turnover have been difficult to elucidate. Recently, large cohort studies have provided more detailed information confirming estrogen's associations and further characterizing the effect of endogenous testosterone and its metabolites on bone mineral density and fractures. Very few clinical trials have assessed the impact of testosterone replacement therapy (TRT) on bone density and fractures in men. The few studies that have been conducted are generally small and not robust enough to show the true treatment effect of TRT and adequately determine its safety. In the absence of data on patient outcomes, it is important for pharmacists to understand the impact of drug therapy on biomarkers and surrogate markers of disease for optimal pharmacotherapy selection and monitoring. PMID- 21676855 TI - Age-related androgen deficiency and type 2 diabetes. AB - There is a higher prevalence of low testosterone levels in males with type 2 diabetes compared to those without. Additionally, there is evidence that low testosterone levels may predict the development of type 2 diabetes. Symptoms of hypogonadism include decreased libido, decreased bone mineral density (BMD), and decreased lean muscle mass. The majority of the published cases in men with diabetes were attributed to age-related idiopathic hypogonadotropic hypogonadism. This paper reviews the link between type 2 diabetes and age-related hypogonadism and the treatment options for hypogonadism. Pharmacists who provide care for males with diabetes should be aware of the increased incidence of hypogonadism, know how to screen for it, and be able to recommend appropriate therapy. PMID- 21676856 TI - Natural therapies used by adult men for the treatment of erectile dysfunction, benign prostatic hyperplasia, and for augmenting exercise performance. AB - It is estimated that over 15% of men use natural biologic-based therapies, which includes herbal products and supplements. There are certain conditions that are specific to men, such as erectile dysfunction and benign prostatic hypertrophy, for which there is some evidence of the efficacy and safety of herbal medications. Furthermore, men may also be more likely to use supplements for energy improvement, muscle gain, and exercise tolerance, and there are a number of supplements proven to aid in these. Practitioners must understand the safety and efficacy of these agents, as well as the patient's full history and goals, prior to recommending any of the therapies discussed herein. PMID- 21676857 TI - An evaluation of diabetes-related measures of control after 6 months of clinical pharmacy specialist intervention. AB - PURPOSE: To evaluate the effectiveness of a pharmacist management regarding the percentages of patients meeting American Diabetes Association (ADA) treatment goals for diabetes and specific Veterans Health Administration (VA) performance measures individually and in combination after 6 months of intervention. METHODS: We retrospectively evaluated the electronic medical record of all new patients seen between October 1, 2007 and March 31, 2009, with an A1c >7%. Primary objectives included the percentages of patients meeting ADA treatment goals individually and in combination after 6 months in addition to the percentage meeting the 3 VA performance goals individually and in combination. RESULTS: One hundred and ninety-seven patients met inclusion criteria. There were 6% of patients who met all ADA goals and 79% who met all VA performance measure goals at study end. Individual goal analyses revealed 43% of patients at a goal A1c of <7%, 55% of patients were at low-density lipoprotein (LDL) goal, 45% of patients at systolic blood pressure (SBP) goal, and 51% of patients at diastolic blood pressure (DBP) goal. Evaluation for VA performance measures showed that 91% patients at goal for A1c, 55% at LDL goal, 70% at systolic BP goal, and 87% met diastolic BP goal. CONCLUSIONS: Six months of pharmacist intervention resulted in improvement in patients achieving ADA and VA performance measure goals individually and in combination. PMID- 21676858 TI - A needs assessment for development and provision of medication therapy management services in New York City. AB - OBJECTIVES: To (1) assess the current extent of medication therapy management (MTM) provision in NYC; (2) investigate New York City pharmacists' attitudes, efforts, interest, and challenges in providing MTM; and 3) examine factors influencing pharmacist interest in providing MTM. METHODS: A cross-sectional design was utilized to survey New York City pharmacists attending a continuing education program. The survey questionnaire contained items pertaining to the extent of MTM currently provided by the pharmacists, attitudes, efforts, and interest in providing MTM and challenges to provision of MTM. RESULTS: A total of 93 out of 123 attendees (73.81%) completed the survey. Pharmacists provided an average of 1.65 (+/- 0.36) MTM services as defined by the APhA and NACDS framework. Pharmacists had slightly positive attitudes toward provision of MTM and were very interested in providing some MTM services. There was a positive correlation between pharmacist attitude toward MTM and interest in providing MTM (r = .31, P = .016). Of all the 6 challenges to provision of MTM listed in the survey, respondents indicated that additional time to be spent with patients and additional pharmacists would be the most difficult to overcome. CONCLUSIONS: This study serves as an assessment of the needs of New York City pharmacists with regard to provision of MTM services. PMID- 21676859 TI - Can we reduce the cost of illness with more compliant patients? An estimation of the effect of 100% compliance with hypertension treatment. AB - INTRODUCTION: The current study was designed to calculate the direct cost of noncompliance of hypertensive patients to the US health system. Understanding these expenses can inform screening and education budget policy regarding expenditure levels that can be calculated to be cost-beneficial. METHOD: The study was conducted in 3 parts. First, a computer search of National Institutes of Health Web sites and professional society Web sites for organizations with members that treat hypertension, and a PubMed search were performed to obtain the numbers required for calculations. Second, formulas were developed to estimate the risk of noncompliance and undiagnosed hypertension. Third, risk calculations were performed using the information obtained in part 1 and the formulas developed in part 2. RESULTS: Direct risk reduction for stroke caused by hypertension, heart attack, kidney disease, and heart disease was calculated for a 100% compliant strategy. Risk, case, and cost reduction for a 100% compliant strategy for hypertension were 32%, 8.5 million and US$ 72 billion, respectively. DISCUSSION: Our analysis means that the society can spend up to the cost of noncompliance in screening, education, and prevention efforts in an attempt to reduce these costly and traumatic sequelae of poorly controlled hypertension in the light of published analysis. PMID- 21676860 TI - The benefits of working together. PMID- 21676862 TI - Structural and biochemical characterization of two binding sites for nucleation promoting factor WASp-VCA on Arp2/3 complex. AB - Actin-related protein (Arp) 2/3 complex mediates the formation of actin filament branches during endocytosis and at the leading edge of motile cells. The pathway of branch formation is ambiguous owing to uncertainty regarding the stoichiometry and location of VCA binding sites on Arp2/3 complex. Isothermal titration calorimetry showed that the CA motif from the C terminus of fission yeast WASP (Wsp1p) bound to fission yeast and bovine Arp2/3 complex with a stoichiometry of 2 to 1 and very different affinities for the two sites (K(d)s of 0.13 and 1.6 MUM for fission yeast Arp2/3 complex). Equilibrium binding, kinetic, and cross linking experiments showed that (i) CA at high-affinity site 1 inhibited Arp2/3 complex binding to actin filaments, (ii) low-affinity site 2 had a higher affinity for CA when Arp2/3 complex was bound to actin filaments, and (iii) Arp2/3 complex had a much higher affinity for free CA than VCA cross-linked to an actin monomer. Crystal structures showed the C terminus of CA bound to the low affinity site 2 on Arp3 of bovine Arp2/3 complex. The C helix is likely to bind to the barbed end groove of Arp3 in a position for VCA to deliver the first actin subunit to the daughter filament. PMID- 21676863 TI - Arp2/3 complex is bound and activated by two WASP proteins. AB - Actin related protein 2/actin related protein 3 (Arp2/3) complex nucleates new actin filaments in eukaryotic cells in response to signals from proteins in the Wiskott-Aldrich syndrome protein (WASP) family. The conserved VCA domain of WASP proteins activates Arp2/3 complex by inducing conformational changes and delivering the first actin monomer of the daughter filament. Previous models of activation have invoked a single VCA acting at a single site on Arp2/3 complex. Here we show that activation most likely involves engagement of two distinct sites on Arp2/3 complex by two VCA molecules, each delivering an actin monomer. One site is on Arp3 and the second is on ARPC1 and Arp2. The VCAs at these sites have distinct roles in activation. Our findings reconcile apparently conflicting literature on VCA activation of Arp2/3 complex and lead to a new model for this process. PMID- 21676864 TI - Solution structure of tandem SH2 domains from Spt6 protein and their binding to the phosphorylated RNA polymerase II C-terminal domain. AB - Spt6 is a highly conserved transcription elongation factor and histone chaperone. It binds directly to the RNA polymerase II C-terminal domain (RNAPII CTD) through its C-terminal region that recognizes RNAPII CTD phosphorylation. In this study, we determined the solution structure of the C-terminal region of Saccharomyces cerevisiae Spt6, and we discovered that Spt6 has two SH2 domains in tandem. Structural and phylogenetic analysis revealed that the second SH2 domain was evolutionarily distant from canonical SH2 domains and represented a novel SH2 subfamily with a novel binding site for phosphoserine. In addition, NMR chemical shift perturbation experiments demonstrated that the tandem SH2 domains recognized Tyr(1), Ser(2), Ser(5), and Ser(7) phosphorylation of RNAPII CTD with millimolar binding affinities. The structural basis for the binding of the tandem SH2 domains to different forms of phosphorylated RNAPII CTD and its physiological relevance are discussed. Our results also suggest that Spt6 may use the tandem SH2 domain module to sense the phosphorylation level of RNAPII CTD. PMID- 21676865 TI - Molecular basis for the interaction of low density lipoprotein receptor-related protein 1 (LRP1) with integrin alphaMbeta2: identification of binding sites within alphaMbeta2 for LRP1. AB - The LDL receptor-related protein 1 (LRP1) is a large endocytic receptor that controls macrophage migration in part by interacting with beta(2) integrin receptors. However, the molecular mechanism underlying LRP1 integrin recognition is poorly understood. Here, we report that LRP1 specifically recognizes alpha(M)beta(2) but not its homologous receptor alpha(L)beta(2). The interaction between these two cellular receptors in macrophages is significantly enhanced upon alpha(M)beta(2) activation by LPS and is mediated by multiple regions in both LRP1 and alpha(M)beta(2). Specifically, we find that both the heavy and light chains of LRP1 are involved in alpha(M)beta(2) binding. Within the heavy chain, the binding is mediated primarily via the second and fourth ligand binding repeats. For alpha(M)beta(2), we find that the alpha(M)-I domain represents a major LRP1 recognition site. Indeed, substitution of the I domain of the alpha(L)beta(2) receptor with that of alpha(M) confers the alpha(L)beta(2) receptor with the ability to interact with LRP1. Furthermore, we show that residues (160)EQLKKSKTL(170) within the alpha(M)-I domain represent a major LRP1 recognition site. Given that perturbation of this specific sequence leads to altered adhesive activity of alpha(M)beta(2), our finding suggests that binding of LRP1 to alpha(M)beta(2) could alter integrin function. Indeed, we further demonstrate that the soluble form of LRP1 (sLRP1) inhibits alpha(M)beta(2) mediated adhesion of cells to fibrinogen. These studies suggest that sLRP1 may attenuate inflammation by modulating integrin function. PMID- 21676866 TI - Structure of the 30-kDa Sin3-associated protein (SAP30) in complex with the mammalian Sin3A corepressor and its role in nucleic acid binding. AB - The ~2-megadalton evolutionarily conserved histone deacetylase-associated Rpd3L/Sin3L complex plays critical roles in altering the histone code and repressing transcription of a broad range of genes involved in many aspects of cellular physiology. Targeting of this complex to specific regions of the genome is presumed to rely on interactions involving one or more of at least 10 distinct subunits in the complex. Here we describe the solution structure of the complex formed by the interacting domains of two constitutively associated subunits, mSin3A and SAP30. The mSin3A paired amphipathic helix 3 (PAH3) domain in the complex adopts the left-handed four-helix bundle structure characteristic of PAH domains. The SAP30 Sin3 interaction domain (SID) binds to PAH3 via a tripartite structural motif, including a C-terminal helix that targets the canonical PAH hydrophobic cleft while two other helices and an N-terminal extension target a discrete surface formed largely by the PAH3 alpha2, alpha3, and alpha3' helices. The protein-protein interface is extensive (~1400 A(2)), accounting for the high affinity of the interaction and the constitutive association of the SAP30 subunit with the Rpd3L/Sin3L complex. We further show using NMR that the mSin3A PAH3 SAP30 SID complex can bind to nucleic acids, hinting at a role for a nucleolar localization sequence in the SID alphaA helix in targeting the Rpd3L/Sin3L complex for silencing ribosomal RNA genes. PMID- 21676867 TI - Monoubiquitination of H2AX protein regulates DNA damage response signaling. AB - Double strand breaks (DSBs) are the most deleterious of the DNA lesions that initiate genomic instability and promote tumorigenesis. Cells have evolved a complex protein network to detect, signal, and repair DSBs. In mammalian cells, a key component in this network is H2AX, which becomes rapidly phosphorylated at Ser(139) (gamma-H2AX) at DSBs. Here we show that monoubiquitination of H2AX mediated by the RNF2-BMI1 complex is critical for the efficient formation of gamma-H2AX and functions as a proximal regulator in DDR (DNA damage response). RNF2-BMI1 interacts with H2AX in a DNA damage-dependent manner and is required for monoubiquitination of H2AX at Lys(119)/Lys(120). As a functional consequence, we show that the H2AX K120R mutant abolishes H2AX monoubiquitination, impairs the recruitment of p-ATM (Ser(1981)) to DSBs, and thereby reduces the formation of gamma-H2AX and the recruitment of MDC1 to DNA damage sites. These data suggest that monoubiquitination of H2AX plays a critical role in initiating DNA damage signaling. Consistent with these observations, impairment of RNF2-BMI1 function by siRNA knockdown or overexpression of the ligase-dead RNF2 mutant all leads to significant defects both in accumulation of gamma-H2AX, p-ATM, and MDC1 at DSBs and in activation of NBS1 and CHK2. Additionally, the regulatory effect of RNF2 BMI1 on gamma-H2AX formation is dependent on ATM. Lacking their ability to properly activate the DNA damage signaling pathway, RNF2-BMI1 complex-depleted cells exhibit impaired DNA repair and increased sensitivity to ionizing radiation. Together, our findings demonstrate a distinct monoubiquitination dependent mechanism that is required for H2AX phosphorylation and the initiation of DDR. PMID- 21676868 TI - Unfolded protein response is required in nu/nu mice microvasculature for treating breast tumor with tunicamycin. AB - Up-regulation of the dolichol pathway, a "hallmark" of asparagine-linked protein glycosylation, enhances angiogenesis in vitro. The dynamic relationship between these two processes is now evaluated with tunicamycin. Capillary endothelial cells treated with tunicamycin were growth inhibited and could not be reversed with exogenous VEGF(165). Inhibition of angiogenesis is supported by down regulation of (i) phosphorylated VEGFR1 and VEGFR2 receptors; (ii) VEGF(165) specific phosphotyrosine kinase activity; and (iii) Matrigel(TM) invasion and chemotaxis. In vivo, tunicamycin prevented the vessel development in Matrigel(TM) implants in athymic Balb/c (nu/nu) mice. Immunohistochemical analysis of CD34 (p < 0.001) and CD144 (p < 0.001) exhibited reduced vascularization. A 3.8-fold increased expression of TSP-1, an endogenous angiogenesis inhibitor in Matrigel(TM) implants correlated with that in tunicamycin (32 h)-treated capillary endothelial cells. Intravenous injection of tunicamycin (0.5 mg/kg to 1.0 mg/kg) per week slowed down a double negative (MDA-MB-435) grade III breast adenocarcinoma growth by ~50-60% in 3 weeks. Histopathological analysis of the paraffin sections indicated significant reduction in vessel size, the microvascular density and tumor mitotic index. Ki-67 and VEGF expression in tumor tissue were also reduced. A significant reduction of N-glycan expression in tumor microvessel was also observed. High expression of GRP-78 in CD144-positive cells supported unfolded protein response-mediated ER stress in tumor microvasculature. ~65% reduction of a triple negative (MDA-MB-231) breast tumor xenograft in 1 week with tunicamycin (0.25 mg/kg) given orally and the absence of systemic and/or organ failure strongly supported tunicamycin's potential for a powerful glycotherapeutic treatment of breast cancer in the clinic. PMID- 21676869 TI - Runx2 protein expression utilizes the Runx2 P1 promoter to establish osteoprogenitor cell number for normal bone formation. AB - The Runt-related transcription factor, Runx2, is essential for osteogenesis and is controlled by both distal (P1) and proximal (P2) promoters. To understand Runx2 function requires determination of the spatiotemporal activity of P1 and P2 to Runx2 protein production. We generated a mouse model in which the P1-derived transcript was replaced with a lacZ reporter allele, resulting in loss of P1 derived protein while simultaneously allowing discrimination between the activities of the two promoters. Loss of P1-driven expression causes developmental defects with cleidocranial dysplasia-like syndromes that persist in the postnatal skeleton. P1 activity is robust in preosteogenic mesenchyme and at the onset of bone formation but decreases as bone matures. Homozygous Runx2 P1(lacZ/lacZ) mice have a normal life span but exhibit severe osteopenia and compromised bone repair in adult mice because of osteoblastic defects and not increased osteoclastic resorption. Gene expression profiles of bone, immunohistochemical studies, and ex vivo differentiation using calvarial osteoblasts and marrow stromal cells identified mechanisms for the skeletal phenotype. The findings indicate that P1 promoter activity is necessary for generating a threshold level of Runx2 protein to commit sufficient osteoprogenitor numbers for normal bone formation. P1 promoter function is not compensated via the P2 promoter. However, the P2 transcript with compensatory mechanisms from bone morphogenetic protein (BMP) and Wnt signaling is adequate for mineralization of the bone tissue that does form. We conclude that selective utilization of the P1 and P2 promoters enables the precise spatiotemporal expression of Runx2 necessary for normal skeletogenesis and the maintenance of bone mass in the adult. PMID- 21676870 TI - Crystal structure of uronate dehydrogenase from Agrobacterium tumefaciens. AB - Uronate dehydrogenase from Agrobacterium tumefaciens (AtUdh) belongs to the short chain dehydrogenase/reductase superfamily and catalyzes the oxidation of D galacturonic acid and D-glucuronic acid with NAD(+) as a cofactor. We have determined the crystal structures of an apo-form of AtUdh, a ternary form in complex with NADH and product (substrate-soaked structure), and an inactive Y136A mutant in complex with NAD(+). The crystal structures suggest AtUdh to be a homohexamer, which has also been observed to be the major form in solution. The monomer contains a Rossmann fold, essential for nucleotide binding and a common feature of the short-chain dehydrogenase/reductase family enzymes. The ternary complex structure reveals a product, D-galactaro-1,5-lactone, which is bound above the nicotinamide ring. This product rearranges in solution to D-galactaro 1,4-lactone as verified by mass spectrometry analysis, which agrees with our previous NMR study. The crystal structure of the mutant with the catalytic residue Tyr-136 substituted with alanine shows changes in the position of Ile-74 and Ser-75. This probably altered the binding of the nicotinamide end of NAD(+), which was not visible in the electron density map. The structures presented provide novel insights into cofactor and substrate binding and the reaction mechanism of AtUdh. This information can be applied to the design of efficient microbial conversion of D-galacturonic acid-based waste materials. PMID- 21676871 TI - Constitutive regulatory activity of an evolutionarily excluded riboswitch variant. AB - The exquisite specificity of the adenine-responsive riboswitch toward its cognate metabolite has been shown to arise from the formation of a Watson-Crick interaction between the adenine ligand and residue U65. A recent crystal structure of a U65C adenine aptamer variant has provided a rationale for the phylogenetic conservation observed at position 39 for purine aptamers. The G39 C65 variant adopts a compact ligand-free structure in which G39 is accommodated by the ligand binding site and is base-paired to the cytosine at position 65. Here, we demonstrate using a combination of biochemical and biophysical techniques that the G39-C65 base pair not only severely impairs ligand binding but also disrupts the functioning of the riboswitch in vivo by constitutively activating gene expression. Folding studies using single-molecule FRET revealed that the G39-C65 variant displays a low level of dynamic heterogeneity, a feature reminiscent of ligand-bound wild-type complexes. A restricted conformational freedom together with an ability to significantly fold in monovalent ions are exclusive to the G39-C65 variant. This work provides a mechanistic framework to rationalize the evolutionary exclusion of certain nucleotide combinations in favor of sequences that preserve ligand binding and gene regulation functionalities. PMID- 21676872 TI - Activity and protein kinase C regulate synaptic accumulation of N-methyl-D aspartate (NMDA) receptors independently of GluN1 splice variant. AB - NMDA receptors are calcium-permeable ionotropic receptors that detect coincident glutamate binding and membrane depolarization and are essential for many forms of synaptic plasticity in the mammalian brain. The obligatory GluN1 subunit of NMDA receptors is alternatively spliced at multiple sites, generating forms that vary in N-terminal N1 and C-terminal C1, C2, and C2' cassettes. Based on expression of GluN1 constructs in heterologous cells and in wild type neurons, the prevalent view is that the C-terminal cassettes regulate synaptic accumulation and its modulation by homeostatic activity blockade and by protein kinase C (PKC). Here, we tested the role of GluN1 splicing in regulated synaptic accumulation of NMDA receptors by lentiviral expression of individual GluN1 splice variants in hippocampal neurons cultured from GluN1 (-/-) mice. High efficiency transduction of GluN1 at levels similar to endogenous was achieved. Under control conditions, the C2' cassette mediated enhanced synaptic accumulation relative to the alternate C2 cassette, whereas the presence or absence of N1 or C1 had no effect. Surprisingly all GluN1 splice variants showed >2-fold increased synaptic accumulation with chronic blockade of NMDA receptor activity. Furthermore, in this neuronal rescue system, all GluN1 splice variants were equally rapidly dispersed upon activation of PKC. These results indicate that the major mechanisms mediating homeostatic synaptic accumulation and PKC dispersal of NMDA receptors occur independently of GluN1 splice isoform. PMID- 21676873 TI - Telomerase is required to protect chromosomes with vertebrate-type T2AG3 3' ends in Saccharomyces cerevisiae. AB - Telomeres containing vertebrate-type DNA repeats can be stably maintained in Saccharomyces cerevisiae cells. We show here that telomerase is required for growth of yeast cells containing these vertebrate-type telomeres. When present at the chromosome termini, these heterologous repeats elicit a DNA damage response and a certain deprotection of telomeres. The data also show that these phenotypes are due only to the terminal localization of the vertebrate repeats because if they are sandwiched between native yeast repeats, no phenotype is observed. Indeed and quite surprisingly, in this latter situation, telomeres are of virtually normal lengths, despite the presence of up to 50% of heterologous repeats. Furthermore, the presence of the distal vertebrate-type repeats can cause increased problems of the replication fork. These results show that in budding yeast the integrity of the 3' overhang is required for proper termination of telomere replication as well as protection. PMID- 21676874 TI - Pseudomonas aeruginosa D-arabinofuranose biosynthetic pathway and its role in type IV pilus assembly. AB - Pseudomonas aeruginosa strains PA7 and Pa5196 glycosylate their type IVa pilins with alpha1,5-linked D-arabinofuranose (d-Araf), a rare sugar configuration identical to that found in cell wall polymers of the Corynebacterineae. Despite this chemical identity, the pathway for biosynthesis of alpha1,5-D-Araf in Gram negative bacteria is unknown. Bioinformatics analyses pointed to a cluster of seven P. aeruginosa genes, including homologues of the Mycobacterium tuberculosis genes Rv3806c, Rv3790, and Rv3791, required for synthesis of a polyprenyl-linked d-ribose precursor and its epimerization to D-Araf. Pa5196 mutants lacking the orthologues of those genes had non-arabinosylated pilins, poor twitching motility, and significantly fewer surface pili than the wild type even in a retraction-deficient (pilT) background. The Pa5196 pilus system assembled heterologous non-glycosylated pilins efficiently, demonstrating that it does not require post-translationally modified subunits. Together the data suggest that pilins of group IV strains need to be glycosylated for productive subunit-subunit interactions. A recombinant P. aeruginosa PAO1 strain co-expressing the genes for d-Araf biosynthesis, the pilin modification enzyme TfpW, and the acceptor PilA(IV) produced arabinosylated pili, confirming that the Pa5196 genes identified are both necessary and sufficient. A P. aeruginosa epimerase knock-out could be complemented with the corresponding Mycobacterium smegmatis gene, demonstrating conservation between the systems of the Corynebacterineae and Pseudomonas. This work describes a novel Gram-negative pathway for biosynthesis of d-Araf, a key therapeutic target in Corynebacterineae. PMID- 21676875 TI - Structure and mechanism of the saposin-like domain of a plant aspartic protease. AB - Many plant aspartic proteases contain an additional sequence of ~100 amino acids termed the plant-specific insert, which is involved in host defense and vacuolar targeting. Similar to all saposin-like proteins, the plant-specific insert functions via protein-membrane interactions; however, the structural basis for such interactions has not been studied, and the nature of plant-specific insert mediated membrane disruption has not been characterized. In the present study, the crystal structure of the saposin-like domain of potato aspartic protease was resolved at a resolution of 1.9 A, revealing an open V-shaped configuration similar to the open structure of human saposin C. Notably, vesicle disruption activity followed Michaelis-Menten-like kinetics, a finding not previously reported for saposin-like proteins including plant-specific inserts. Circular dichroism data suggested that secondary structure was pH-dependent in a fashion similar to influenza A hemagglutinin fusion peptide. Membrane effects characterized by atomic force microscopy and light scattering indicated bilayer solubilization as well as fusogenic activity. Taken together, the present study is the first report to elucidate the membrane interaction mechanism of plant saposin-like domains whereby pH-dependent membrane interactions resulted in bilayer fusogenic activity that probably arose from a viral type pH-dependent helix-kink-helix motif at the plant-specific insert N terminus. PMID- 21676877 TI - Crystal structure of a zinc-dependent D-serine dehydratase from chicken kidney. AB - D-serine is a physiological co-agonist of the N-methyl-D-aspartate receptor. It regulates excitatory neurotransmission, which is important for higher brain functions in vertebrates. In mammalian brains, D-amino acid oxidase degrades D serine. However, we have found recently that in chicken brains the oxidase is not expressed and instead a D-serine dehydratase degrades D-serine. The primary structure of the enzyme shows significant similarities to those of metal activated D-threonine aldolases, which are fold-type III pyridoxal 5'-phosphate (PLP)-dependent enzymes, suggesting that it is a novel class of D-serine dehydratase. In the present study, we characterized the chicken enzyme biochemically and also by x-ray crystallography. The enzyme activity on D-serine decreased 20-fold by EDTA treatment and recovered nearly completely by the addition of Zn(2+). None of the reaction products that would be expected from side reactions of the PLP-D-serine Schiff base were detected during the >6000 catalytic cycles of dehydration, indicating high reaction specificity. We have determined the first crystal structure of the D-serine dehydratase at 1.9 A resolution. In the active site pocket, a zinc ion that coordinates His(347) and Cys(349) is located near the PLP-Lys(45) Schiff base. A theoretical model of the enzyme-D-serine complex suggested that the hydroxyl group of D-serine directly coordinates the zinc ion, and that the epsilon-NH(2) group of Lys(45) is a short distance from the substrate Calpha atom. The alpha-proton abstraction from D serine by Lys(45) and the elimination of the hydroxyl group seem to occur with the assistance of the zinc ion, resulting in the strict reaction specificity. PMID- 21676878 TI - Kinetics and phospholipid specificity of apolipoprotein N-acyltransferase. AB - The enzyme apolipoprotein N-acyltransferase (Lnt) is an integral membrane protein that catalyzes the last step in the post-translational modification of bacterial lipoproteins. Lnt undergoes covalent modification in the presence of phospholipids resulting in a thioester acyl-enzyme intermediate. It then transfers the acyl chain to the alpha-amino group of the N-terminal diacylglyceryl-modified cysteine of apolipoprotein, leading to the formation of mature triacylated lipoprotein. To gain insight into the catalytic mechanism of this two-step reaction, we overproduced and purified the enzyme of Escherichia coli and studied its N-acyltransferase activity using a novel in vitro assay. The purified enzyme was fully active, as judged by its ability to form a stable thioester acyl-enzyme intermediate and N-acylate the apo-form of the murein lipoprotein Lpp in vitro. Incorporation of [(3)H]palmitate and mass spectrometry analysis demonstrated that Lnt recognized the synthetic diacylglyceryl-modified lipopeptide FSL-1 as a substrate in a mixed micelle assay. Kinetics of Lnt using phosphatidylethanolamine as an acyl donor and FSL-1 as a substrate were consistent with a ping-pong type mechanism, demonstrating slow acyl-enzyme intermediate formation and rapid N-acyl transfer to the apolipopeptide in vitro. In contrast to earlier in vitro observations, the N-acyltransferase activity was strongly affected by the phospholipid headgroup and acyl chain composition. PMID- 21676879 TI - Missense mutation in APOC3 within the C-terminal lipid binding domain of human ApoC-III results in impaired assembly and secretion of triacylglycerol-rich very low density lipoproteins: evidence that ApoC-III plays a major role in the formation of lipid precursors within the microsomal lumen. AB - Hepatic assembly of triacylglycerol (TAG)-rich very low density lipoproteins (VLDL) is achieved through recruitment of bulk TAG (presumably in the form of lipid droplets within the microsomal lumen) into VLDL precursor containing apolipoprotein (apo) B-100. We determined protein/lipid components of lumenal lipid droplets (LLD) in cells expressing recombinant human apoC-III (C3wt) or a mutant form (K58E, C3KE) initially identified in humans that displayed hypotriglyceridemia. Although expression of C3wt markedly stimulated secretion of TAG and apoB-100 as VLDL(1), the K58E mutation (located at the C-terminal lipid binding domain) abolished the effect in transfected McA-RH7777 cells and in apoc3 null mice. Metabolic labeling studies revealed that accumulation of TAG in LLD was decreased (by 50%) in cells expressing C3KE. A Fat Western lipid protein overlay assay showed drastically reduced lipid binding of the mutant protein. Substituting Lys(58) with Arg demonstrated that the positive charge at position 58 is crucial for apoC-III binding to lipid and for promoting TAG secretion. On the other hand, substituting both Lys(58) and Lys(60) with Glu resulted in almost entire elimination of lipid binding and loss of function in promoting TAG secretion. Thus, the lipid binding domain of apoC-III plays a key role in the formation of LLD for hepatic VLDL assembly and secretion. PMID- 21676880 TI - Post-translational N-glycosylation of type I transmembrane KCNE1 peptides: implications for membrane protein biogenesis and disease. AB - N-Glycosylation of membrane proteins is critical for their proper folding, co assembly and subsequent matriculation through the secretory pathway. Here, we examine the kinetics of N-glycan addition to type I transmembrane KCNE1 K(+) channel beta-subunits, where point mutations that prevent N-glycosylation at one consensus site give rise to disorders of the cardiac rhythm and congenital deafness. We show that KCNE1 has two distinct N-glycosylation sites: a typical co translational site and a consensus site ~20 residues away that unexpectedly acquires N-glycans after protein synthesis (post-translational). Mutations that ablate the co-translational site concomitantly reduce glycosylation at the post translational site, resulting in unglycosylated KCNE1 subunits that cannot reach the cell surface with their cognate K(+) channel. This long range inhibition is highly specific for post-translational N-glycosylation because mutagenic conversion of the KCNE1 post-translational site into a co-translational site restored both monoglycosylation and anterograde trafficking. These results directly explain how a single point mutation can prevent N-glycan attachment at multiple sites, providing a new biogenic mechanism for human disease. PMID- 21676881 TI - Integrated human physiology: breathing, blood pressure and blood flow to the brain. PMID- 21676882 TI - Calcium controls cardiac function--by all means! PMID- 21676883 TI - A new angle on the role of feedfoward inputs in the generation of orientation selectivity in primary visual cortex. PMID- 21676884 TI - Ageing uncompensated: exercise, nitric oxide and hypoxia. PMID- 21676885 TI - Genetic variation in an miRNA-1827 binding site in MYCL1 alters susceptibility to small-cell lung cancer. AB - Genetic variations in microRNAs (miRNA) that affect control of their target genes may alter individual susceptibilities to cancer. In this study, we took an in silico approach to identify single-nucleotide polymorphisms (SNP) within the 3' untranslated region (UTR) of miRNA genes deregulated in human small-cell lung cancer (SCLC), and then investigated their associations with SCLC susceptibility in 666 SCLC patients and 758 controls. Odds ratios (OR) were estimated by multivariate logistic regression, and biochemical assays were conducted to investigate SNP functions. We identified 2 SNPs, rs3134615 and rs2291854, which were located in the 3'-UTR of the L-MYC gene MYCL1 and the neuronal development Achaete-Scute Complex homolog ASCL1. Case-control analyses showed that the rs3134615T allele was associated with a significantly increased risk of SCLC, with the OR for carrying the GT or TT genotype being 2.08 (95% confidence interval, 1.39-3.21; P = 0.0004) compared with the GG genotype. In support of the likelihood that these 3'-UTR SNPs may directly affect miRNA-binding sites, reporter gene assays indicated MYCL1 as the target of hsa-miR-1827 and the rs3134615 G>T change resulted in altered regulation of MYCL1 expression. Our findings define a 3'-UTR SNP in the human L-MYC oncogene that may increase susceptibility to SCLC, possibly resulting from attenuated interaction with the miRNA hsa-miR-1827. PMID- 21676886 TI - Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. AB - Resistance to platinum-based chemotherapy develops in the majority of patients with epithelial ovarian cancer (EOC). Platinum compounds form electrophilic intermediates that mediate DNA cross-linking and induce double-strand DNA breaks. Because the cellular response to electrophilic xenobiotics is partly mediated by Keap1-Nrf2 pathway, we evaluated the presence of Kelch-like ECH-associated protein 1 (Keap1) mutations and NF-E2-related factor 2 (Nrf2) pathway activation in EOC and correlated these with platinum resistance and clinical outcome. Nrf2 immunohistochemistry revealed nuclear localization (a surrogate of pathway activation) in over half of EOC patient specimens examined, with more common occurrence in the clear cell EOC subtype. Quantitative real-time PCR revealed that Nrf2 target genes were upregulated in tumors with nuclear positivity for Nrf2. Microarray analysis also showed upregulation of Nrf2 target genes in clear cell EOCs compared with other EOC subtypes. In addition, Keap1 sequence analysis revealed genetic mutations in 29% of clear cell samples and 8% of nonclear cell tumors. RNAi-mediated knockdown of Keap1 was associated with Nrf2 pathway activation and resistance to carboplatin in vitro. Importantly, patients with evidence of Nrf2 pathway activation had fewer complete clinical responses to platinum-based therapy, were enriched for platinum resistance, and had shorter median overall survival compared with those who did not show evidence of Nrf2 pathway activation. Our findings identify Keap1 mutations in EOC and they suggest a previously unrecognized role for the Keap1-Nrf2 pathway in mediating chemotherapeutic responses in this disease. PMID- 21676887 TI - TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers. AB - Recurrent gene fusions involving ETS family genes are a distinguishing feature of human prostate cancers, with TMPRSS2-ERG fusions representing the most common subtype. The TMPRSS2-ERG fusion transcript and its splice variants are well characterized in prostate cancers; however, not much is known about the levels and regulation of wild-type ERG. By employing an integrative approach, we show that the TMPRSS2-ERG gene fusion product binds to the ERG locus and drives the overexpression of wild-type ERG in prostate cancers. Knockdown of TMPRSS2-ERG in VCaP cells resulted in the downregulation of wild-type ERG transcription, whereas stable overexpression of TMPRSS2-ERG in the gene fusion-negative PC3 cells was associated with the upregulation of wild-type ERG transcript. Further, androgen signaling-mediated upregulation of TMPRSS2-ERG resulted in the concomitant upregulation of wild-type ERG transcription in VCaP cells. The loss of wild-type ERG expression was associated with a decrease in the invasive potential of VCaP cells. Importantly, 38% of clinically localized prostate cancers and 27% of metastatic prostate cancers harboring the TMPRSS2-ERG gene fusions exhibited overexpression of wild-type ERG. Taken together, these results provide novel insights into the regulation of ERG in human prostate cancers. PMID- 21676888 TI - A novel recombinant Mycobacterium bovis bacillus Calmette-Guerin strain expressing human granulocyte macrophage colony-stimulating factor and Mycobacterium tuberculosis early secretory antigenic target 6 complex augments Th1 immunity. AB - Since Mycobacterium bovis bacillus Calmette-Guerin strain (BCG) fails to protect adults from pulmonary tuberculosis (TB), there is an urgent need for developing a new vaccine. In this study, we constructed a novel recombinant BCG strain (rBCG) expressing human granulocyte macrophage colony-stimulating factor (GM-CSF) and the 6 kDa early secretory antigenic target (ESAT6) of Mycobacterium tuberculosis, named rBCG:GE (expressing GMCSF-ESAT6 complex), and evaluated the immunogenicity of the construct in BALB/c mice. Our results indicated that the rBCG:GE was able to induce higher titer of antibody than the conventional BCG, the rBCG:G (expressing GM-CSF) and the rBCG:E (expressing ESAT6). Moreover, the rBCG:GE also elicited a longer-lasting and stronger Th1 cellular immune responses than the other groups, which was confirmed by the incremental proliferation of splenocytes, the increased percentages of CD4(+) and CD8(+) T cells of spleen, the elevated level of interferon-gamma in splenocyte culture after tuberculin purified protein derivative stimulation, and the increased concentration of GM CSF in serum. The data presented here suggested the possibility that the recombinant BCG:GE might be a good vaccine candidate to TB. PMID- 21676891 TI - Perceptions, attitudes, and beliefs of staff anaesthetists related to multi source feedback used for their performance appraisal. AB - BACKGROUND: The aim of this study was to explore anaesthetists' perceptions and experience of the implementation of multi-source feedback (MSF) for their performance review. METHODS: Twelve semi-structured thematic interviews were conducted with staff anaesthetists and their director to explore the perceptions of, and responses to, the MSF system, the feedback given, and their work context. An inductive thematic cross-comparative analysis of the interview data was conducted. RESULTS: The themes that emerged clustered around the anaesthetists' understanding of MSF, the facilitation process, and the value anaesthetists placed on feedback from the different professional groups available as actual and potential sources of feedback data. CONCLUSIONS: The anaesthetists interviewed in this study accepted performance review and the role of MSF in it. Anaesthetists thought anonymity an important feature of MSF, and viewed the process as an opportunity for self-improvement. To the extent that MSF was viewed by the anaesthetists as surveillance by management, this was seen as being largely benign. Rather a view of the acceptance of self-responsibility for using the information gathered to improve their own performance was held by the majority of those interviewed. While broad sampling of sources within and outside anaesthesia was desired, most value was placed on feedback from both nurses and trainees within anaesthesia. The value of feedback from surgeons was contentious, and this may reflect underlying issues with this important relationship that are yet to be explored. PMID- 21676892 TI - Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. AB - BACKGROUND: Pain after shoulder surgery is often treated with interscalene nerve blocks. Single-injection blocks are effective, but time-limited. Adjuncts such as dexamethasone may help. We thus tested the hypothesis that adding dexamethasone significantly prolongs the duration of ropivacaine and bupivacaine analgesia and that the magnitude of the effect differs among the two local anaesthetics. METHODS: In a double-blinded trial utilizing single-injection interscalene block, patients were randomized to one of four groups: (i) ropivacaine: 0.5% ropivacaine; (ii) bupivacaine: 0.5% bupivacaine; (iii) ropivacaine and steroid: 0.5% ropivacaine mixed with dexamethasone 8 mg; and (iv) bupivacaine and steroid: 0.5% bupivacaine mixed with dexamethasone 8 mg. The primary outcome was time to first analgesic request after post-anaesthesia care unit discharge. The Kaplan Meier survival density estimation and stratified Cox's proportional hazard regression were used to compare groups. RESULTS: Dexamethasone significantly prolonged the duration of analgesia of both ropivacaine [median (inter-quartile range) 11.8 (9.7, 13.8) vs 22.2 (18.0, 28.6) h, log-rank P<0.001] and bupivacaine [14.8 (11.8, 18.1) and 22.4 (20.5, 29.3) h, log-rank P<0.001]. Dexamethasone prolonged analgesia more with ropivacaine than bupivacaine (Cox's model interaction term P=0.0029). CONCLUSIONS: Dexamethasone prolongs analgesia from interscalene blocks using ropivacaine or bupivacaine, with the effect being stronger with ropivacaine. However, block duration was longer with plain bupivacaine than ropivacaine. Thus, although dexamethasone prolonged the action of ropivacaine more than that of bupivacaine, the combined effect of dexamethasone and either drug produced nearly the same 22 h of analgesia. PMID- 21676893 TI - Gastric emptying after overnight fasting and clear fluid intake: a prospective investigation using serial magnetic resonance imaging in healthy children. AB - BACKGROUND: Current guidelines recommend preoperative fasting of 2 h for clear fluids, which is often exceeded in routine clinical practice. Existing data on residual gastric volumes in children do not consider fluid intake within <2 h and rely on the aspiration of gastric contents via a gastric tube. This study evaluated the emptying of clear fluids from the stomach using magnetic resonance imaging (MRI). METHODS: Healthy volunteers aged 6-14 years were asked to fast overnight. MRI scans to assess gastric volumes were obtained before and immediately after drinking 7 ml kg(-1) of diluted raspberry syrup and then every 30 min up to 120 min. Volumes were determined by a blinded investigator and indexed gastric fluid/air volumes (GFV(w)/GAV(w)) and half-life (t(1/2)) of GFV(w) course after clear fluid intake were calculated. RESULTS: Sixteen children, median age 9.2 (range 6.4-12.8) years, were investigated. Median (range) GFV(w) was 0.62 (0.15-0.97) ml kg(-1) before and 6.68 (4.77-7.78) ml kg( 1) immediately after fluid intake, and 2.92 (0.43-5.04), 1.27 (0.28-3.62), 0.42 (0.07-2.49), and 0.32 (0.04-1.13) ml kg(-1) 30, 60, 90, and 120 min thereafter. Median GFV(w) declined exponentially (t(1/2)=26.1 min). Median individual t(1/2) was 23.6 (range 17.9-47.8) min. GAV(w) showed considerable intra- and inter individual variation. CONCLUSIONS: In healthy school children, gastric emptying after ingestion of clear fluid occurs with a median half-life time of <30 min but with considerable inter-individual variation. PMID- 21676894 TI - Intraoperative cell salvaged blood as part of a blood conservation strategy in Caesarean section: is fetal red cell contamination important? AB - BACKGROUND: Cell salvage is used in obstetric surgery as part of a blood conservation strategy in our Trust. This carries a theoretical risk of amniotic fluid embolism and also a risk of fetal red cells being present in the re infusion, resulting in alloimmunization. In this study, we attempted to quantify the risk of antibody formation from re-infusion of autologous blood after Caesarean section. METHODS: Women presenting for elective Caesarean section were routinely requested to consent for collection of blood by cell salvage, using one suction device. If an adequate volume of blood was collected, it was processed and, if clinically appropriate, re-infused via a leucodepletion filter. Women who received a re-infusion were followed up to test for antibody formation. RESULTS: Seventy women consented for re-infusion and follow-up. The median volume re infused was 324 ml (range 118-1690 ml). The median fetal red cell contamination was 0.8 ml (range 0.2-12.9 ml). All re-infusions were given without adverse clinical signs. No antibodies were detected in 48 follow-up samples. One positive anti-S antibody was detected. CONCLUSIONS: The implementation of a blood conservation strategy which includes the use of intraoperative cell salvage appears safe and can contribute to a reduction in the number of blood transfusions to the obstetric population. We remain uncertain of the significance of fetal red cell contamination. PMID- 21676896 TI - Global map of physical interactions among differentially expressed genes in multiple sclerosis relapses and remissions. AB - Multiple sclerosis (MS) is a central nervous system autoimmune inflammatory T cell-mediated disease with a relapsing-remitting course in the majority of patients. In this study, we performed a high-resolution systems biology analysis of gene expression and physical interactions in MS relapse and remission. To this end, we integrated 164 large-scale measurements of gene expression in peripheral blood mononuclear cells of MS patients in relapse or remission and healthy subjects, with large-scale information about the physical interactions between these genes obtained from public databases. These data were analyzed with a variety of computational methods. We find that there is a clear and significant global network-level signal that is related to the changes in gene expression of MS patients in comparison to healthy subjects. However, despite the clear differences in the clinical symptoms of MS patients in relapse versus remission, the network level signal is weaker when comparing patients in these two stages of the disease. This result suggests that most of the genes have relatively similar expression levels in the two stages of the disease. In accordance with previous studies, we found that the pathways related to regulation of cell death, chemotaxis and inflammatory response are differentially expressed in the disease in comparison to healthy subjects, while pathways related to cell adhesion, cell migration and cell-cell signaling are activated in relapse in comparison to remission. However, the current study includes a detailed report of the exact set of genes involved in these pathways and the interactions between them. For example, we found that the genes TP53 and IL1 are 'network-hub' that interacts with many of the differentially expressed genes in MS patients versus healthy subjects, and the epidermal growth factor receptor is a 'network-hub' in the case of MS patients with relapse versus remission. The statistical approaches employed in this study enabled us to report new sets of genes that according to their gene expression and physical interactions are predicted to be differentially expressed in MS versus healthy subjects, and in MS patients in relapse versus remission. Some of these genes may be useful biomarkers for diagnosing MS and predicting relapses in MS patients. PMID- 21676895 TI - A gene-centric association scan for Coagulation Factor VII levels in European and African Americans: the Candidate Gene Association Resource (CARe) Consortium. AB - Polymorphisms in several distinct genomic regions, including the F7 gene, were recently associated with factor VII (FVII) levels in European Americans (EAs). The genetic determinants of FVII in African Americans (AAs) are unknown. We used a 50,000 single nucleotide polymorphism (SNP) gene-centric array having dense coverage of over 2,000 candidate genes for cardiovascular disease (CVD) pathways in a community-based sample of 16,324 EA and 3898 AA participants from the Candidate Gene Association Resource (CARe) consortium. Our aim was the discovery of new genomic loci and more detailed characterization of existing loci associated with FVII levels. In EAs, we identified three new loci associated with FVII, of which APOA5 on chromosome 11q23 and HNF4A on chromosome 20q12-13 were replicated in a sample of 4289 participants from the Whitehall II study. We confirmed four previously reported FVII-associated loci (GCKR, MS4A6A, F7 and PROCR) in CARe EA samples. In AAs, the F7 and PROCR regions were significantly associated with FVII. Several of the FVII-associated regions are known to be associated with lipids and other cardiovascular-related traits. At the F7 locus, there was evidence of at least five independently associated SNPs in EAs and three independent signals in AAs. Though the variance in FVII explained by the existing loci is substantial (20% in EA and 10% in AA), larger sample sizes and investigation of lower frequency variants may be required to identify additional FVII-associated loci in EAs and AAs and further clarify the relationship between FVII and other CVD risk factors. PMID- 21676897 TI - Applications of particle accelerators in medicine. AB - There are nearly 20,000 particle accelerators in operation worldwide, about half of them employed for biomedical uses. This paper focuses on some recent advances in the two main medical domains where accelerators find their use, radionuclide production and radiation therapy. The paper first discusses the use of high energy electron and proton accelerators for the potential, future production of (99)Mo, which is presently provided by fission reactors. Next, it reviews the rationale for the use of protons and carbon ions in cancer therapy, discussing the requirements imposed on accelerator technology and looking at some recent developments. PMID- 21676899 TI - Transient protein-protein interactions. AB - Transient complexes are crucial for diverse biological processes such as biochemical pathways and signaling cascades in the cell. Here, we give an overview of the transient interactions; the importance of transient interactions as drug targets; and the structural characterization of transient protein-protein complexes based on the geometrical and physicochemical features of the transient complexes' interfaces. To better understand and eventually design transient protein-protein interactions (TPPIs), a molecular perspective of the protein protein interfaces is necessary. Obtaining high-quality structures of protein protein interactions could be one way of achieving this goal. After introducing the association kinetics of TPPIs, we elaborate on the experimental techniques detecting TPPIs in combination with the computational methods which classify transient and/or non-obligate complexes. In this review, currently available databases and servers that can be used to identify and predict TPPIs are also compiled. PMID- 21676898 TI - Evolutionary bridges to new protein folds: design of C-terminal Cro protein chameleon sequences. AB - Regions of amino-acid sequence that are compatible with multiple folds may facilitate evolutionary transitions in protein structure. In a previous study, we described a heuristically designed chameleon sequence (SASF1, structurally ambivalent sequence fragment 1) that could adopt either of two naturally occurring conformations (alpha-helical or beta-sheet) when incorporated as part of the C-terminal dimerization subdomain of two structurally divergent transcription factors, P22 Cro and lambda Cro. Here we describe longer chameleon designs (SASF2 and SASF3) that in the case of SASF3 correspond to the full C terminal half of the ordered region of a P22 Cro/lambda Cro sequence alignment (residues 34-57). P22-SASF2 and lambda(WDD)-SASF2 show moderate thermal stability in denaturation curves monitored by circular dichroism (T(m) values of 46 and 55 degrees C, respectively), while P22-SASF3 and lambda(WDD)-SASF3 have somewhat reduced stability (T(m) values of 33 and 49 degrees C, respectively). (13)C and (1)H NMR secondary chemical shift analysis confirms two C-terminal alpha-helices for P22-SASF2 (residues 36-45 and 54-57) and two C-terminal beta-strands for lambda(WDD)-SASF2 (residues 40-45 and 50-52), corresponding to secondary structure locations in the two parent sequences. Backbone relaxation data show that both chameleon sequences have a relatively well-ordered structure. Comparisons of (15)N-(1)H correlation spectra for SASF2 and SASF3-containing proteins strongly suggest that SASF3 retains the chameleonism of SASF2. Both Cro C-terminal conformations can be encoded in a single sequence, showing the plausibility of linking different Cro folds by smooth evolutionary transitions. The N-terminal subdomain, though largely conserved in structure, also exerts an important contextual influence on the structure of the C-terminal region. PMID- 21676900 TI - Gastrokine 1 induces senescence through p16/Rb pathway activation in gastric cancer cells. AB - BACKGROUND AND AIMS: Gastrokine 1 (GKN1) is a stomach-specific protein that is normally expressed in gastric mucosa but not in primary tumours and cell lines. Based on this evidence, it was presumed that GKN1 might play a role in gastric cancer development; however, its function and molecular mechanism are not clear. A systematic study was initiated that combined multiple approaches to define the molecular mechanism of GKN1 in gastric cancer cells. METHOD: Proteomics, western blotting and immunohistochemistry were used to measure the expression level of GKN1. Western blotting combined with immunofluorescence was used to monitor the secretory process of this protein. Subsequently, the function and molecular mechanism of GKN1 was explored in vitro and in vivo. RESULTS: It was shown that GKN1 is an autocrine/paracrine protein and inhibits cell growth due to senescence, which resulted from activation of p16/Rb and p21(waf) pathways. Furthermore, sustained activation of Ras/Raf/MEK/ERK signalling was characterised in gastric cancer cells and a xenograft nude mouse model following GKN1 treatment. CONCLUSION: These results provide comprehensive molecular evidence of GKN1 in inducing senescence of gastric cancer cells, and indicate that GKN1 might be a potential novel target for gastric cancer therapeutics. PMID- 21676901 TI - Vitamin E supplementation in old mice induces antimicrobial activity and improves the efficacy of daptomycin in an animal model of wounds infected with methicillin resistant Staphylococcus aureus. PMID- 21676903 TI - Mechanism of trifluoromethionine resistance in Entamoeba histolytica. AB - OBJECTIVES: To determine the mechanism of trifluoromethionine resistance in Entamoeba histolytica and evaluate the impact of acquired drug resistance on virulence. METHODS: Trifluoromethionine-resistant amoebae were selected in vitro and examined for cross-resistance to antiamoebic drugs, stability of resistance, methionine gamma-lyase (MGL) activity, cell adhesion and virulence. Targeted gene silencing was performed to confirm the role of EhMGL. RESULTS: Trophozoites with a resistance index of 154 were obtained. The cells were susceptible to chloroquine, metronidazole, paromomycin and tinidazole, but remained resistant to trifluoromethionine in the absence of drug pressure. A complete lack of EhMGL activity accompanied by increased adhesion and decreased cytolysis were also observed. Silencing of the EhMGL genes resulted in trifluoromethionine resistance. CONCLUSIONS: This study provides the first demonstration of trifluoromethionine resistance in a parasitic protozoon. Repression of gene expression of drug targets represents a novel mechanism of resistance in E. histolytica. The information obtained from this work should help further development of trifluoromethionine derivatives that have lower chances of inducing resistance. PMID- 21676902 TI - Increasing prevalence and dissemination of NDM-1 metallo-beta-lactamase in India: data from the SMART study (2009). AB - OBJECTIVES: To investigate the beta-lactamase background of ertapenem non susceptible isolates for the presence of the most commonly detected carbapenemase genes, bla(KPC), bla(OXA-48) and bla(VIM), and the newly described bla(NDM-1). METHODS: Two hundred and thirty-five ertapenem-non-susceptible (MIC >= 0.5 mg/L) isolates of Enterobacteriaceae from the worldwide Study for Monitoring Antimicrobial Resistance Trends (SMART) 2009 programme were screened using a multiplex PCR for the presence of bla(KPC), bla(OXA-48), bla(VIM) and bla(NDM-1) genes. Extended-spectrum beta-lactamase (ESBL) and AmpC genes (bla(ESBL) and bla(AmpC)) were identified using the Check-MDR CT101 microarray. DNA sequencing was performed to identify the bla(ESBL), bla(KPC) and bla(NDM-1) genes. Molecular typing was also performed to genetically characterize these isolates. RESULTS: Sixty-six isolates (28%) had a carbapenemase gene, with bla(NDM-1) identified in 33 isolates including 2 isolates carrying both bla(NDM-1) and bla(OXA-48); other carbapenemase genes found included bla(KPC) (n = 23), bla(VIM) (n = 7) and bla(OXA-48) (n = 3). All bla(NDM-1)-carrying isolates were from patients in India and comprised five different species. With the exception of one isolate carrying only bla(NDM-1), all bla(NDM-1) carbapenemase-possessing isolates carried additional beta-lactamases in various combinations: bla(ESBL) and bla(AmpC) (n = 18); bla(ESBL) (n = 10); bla(ESBL), bla(AmpC) and bla(OXA-48) (n = 2); and bla(AmpC) (n = 2). Except for bla(OXA-48)-carrying isolates, novel multilocus sequence types or enterobacterial repetitive intergenic consensus PCR patterns were observed along with clonal dissemination within and among sites. CONCLUSIONS: A range of carbapenemase genes, associated with diverse ESBLs and/or AmpC backgrounds, were found among Enterobacteriaceae isolated during the study. Many of these ertapenem non-susceptible strains were clonally related and carried various combinations of beta-lactamases. PMID- 21676904 TI - Impact of guidelines and enhanced antibiotic stewardship on reducing broad spectrum antibiotic usage and its effect on incidence of Clostridium difficile infection. AB - OBJECTIVES: To evaluate the impact of an 'intervention' consisting of revised antibiotic guidelines for empirical treatment of common infections and enhanced stewardship on reducing broad-spectrum antibiotic usage and its effect on incidence of Clostridium difficile infection (CDI). METHODS: This was a retrospective, quasi-experimental study using interrupted time series (ITS) over 12 months before and after the intervention. The setting was adult medical and surgical wards in University Hospital Lewisham, an acute general hospital in London. The intervention was introduced in April 2006. Revised guidelines avoided broad-spectrum antibiotics, e.g. fluoroquinolones, cephalosporins, clindamycin, amoxicillin and co-amoxiclav, as they were considered to be 'high risk' for CDI. Instead, 'low risk' antibiotics such as penicillin, clarithromycin, doxycycline, gentamicin, vancomycin, trimethoprim and nitrofurantoin were recommended. Changes in antibiotic usage and incidence of CDI before and after the intervention were compared using segmented regression analysis. The negative binomial model was used to analyse the time series to estimate the CDI incidence rate ratio (IRR) following the intervention. RESULTS: The intervention was associated with a significant reduction in the use of fluoroquinolones by 105.33 defined daily doses (DDDs)/1000 occupied bed-days (OBDs) per month [95% confidence interval (CI) 34.18-176.48, P < 0.001] and cephalosporins by 45.93 DDDs/1000 OBDs/month (95% CI 24.11-67.74, P < 0.0001). There was no significant change in total antibiotic, clindamycin, amoxicillin or co-amoxiclav use. There was a significant decrease in CDI following the intervention [IRR 0.34 (0.20-0.58), P < 0.0001]. CONCLUSIONS: Revised antibiotic guidelines and enhanced stewardship was associated with a significant stepwise reduction in the use of cephalosporins and fluoroquinolones and a significant decrease in the incidence of CDI. PMID- 21676905 TI - Improved V3 genotyping with duplicate PCR amplification for determining HIV-1 tropism. AB - OBJECTIVES: To determine whether genotyping of HIV-1 by duplicate PCR amplification of the region encoding the V3 loop is more sensitive than single PCR for detecting CXCR4-using viruses. PATIENTS AND METHODS: The V3 genotypes of the HIV-1 infecting 152 patients enrolled in the multicentre GenoTropism ANRS study were determined by all the participating laboratories using a single PCR and V3 bulk sequencing. In parallel, one laboratory determined the V3 genotype using duplicate PCR and bulk sequencing of pooled amplicons. HIV tropism was predicted with the geno2pheno10 algorithm. The phenotypes of all samples were determined with the Trofile assay and the Toulouse tropism test (TTT) recombinant virus assay. RESULTS: Geno2pheno10 was 56.8% sensitive and 75.9% specific when compared with the Trofile assay for detecting CXCR4-using viruses after a single PCR. Duplicate amplification and bulk sequencing of the pooled PCR amplicons increased the sensitivity to 68.2% and specificity to 79.6%. Geno2pheno10 was 64.1% sensitive and 77.0% specific when compared with the TTT assay for detecting CXCR4-using viruses after a single PCR. Duplicate amplification and sequencing of the pooled PCR amplicons increased sensitivity to 76.9% and specificity to 80.5%. CONCLUSIONS: The genotypic determination of HIV-1 tropism can be improved by duplicate amplifications and sequencing the pooled PCR products. This is a good compromise between improved sensitivity and reasonable cost for the genotype based determination of tropism. PMID- 21676906 TI - Co-occurrence of aminoglycoside resistance gene armA in non-Typhi Salmonella isolates producing CTX-M-15 in Algeria. PMID- 21676907 TI - Early onset and differential temporospatial expression of melanopsin isoforms in the developing chicken retina. AB - PURPOSE: Retinal ganglion cells (RGCs) expressing the photopigment melanopsin (Opn4) display intrinsic photosensitivity. In this study, the presence of nonvisual phototransduction cascade components in the developing chicken retina and primary RGCs cultures was investigated, focusing on the two Opn4 genes: the Xenopus (Opn4x) and the mammalian (Opn4m) orthologs. METHODS: Retinas were dissected at different embryonic (E) and postnatal (P) days, and primary RGC cultures were obtained at E8 and kept for 1 hour to 5 days. Samples were processed for RT-PCR and immunochemistry. RESULTS: Embryonic retinas expressed the master eye gene Pax6, the prospective RGC specification gene Brn3, and components of the nonvisual phototransduction cascade, such as Opn4m and the G protein q (Gq) mRNAs at very early stages (E4-E5). By contrast, expression of photoreceptor cell markers (CRX, red-opsin, rhodopsin, and alpha-transducin) was observed from E7 to E12. Opn4m protein was visualized in the whole retina as early as E4 and remained elevated from E6 to the postnatal days, whereas Opn4x was weakly detected at E8 and highly expressed after E11. RGC cultures expressed Gq mRNA, as well as both Opn4 mRNAs and proteins. Opn4m was restricted exclusively to the GC layer at all ages, whereas Opn4x was limited to the forming GC layer and optic nerve at E8, but by E15, its expression was mostly in Prox1(+) horizontal cells. CONCLUSIONS: The early expression onset of nonvisual phototransduction molecules could confer premature photosensitivity to RGCs, while the appearance of Opn4x expression in horizontal cells suggests the identification of a novel type of photosensitive cell in birds. PMID- 21676909 TI - Subscale assessment of the NEI-RQL-42 questionnaire with Rasch analysis. AB - PURPOSE: To explore the psychometric properties of the 13 subscales of the NEI RQL-42 questionnaire using Rasch analysis. METHODS: The NEI-RQL-42 is a refractive error-related quality of life (QoL) questionnaire with a complex design; its 13 subscales contain 42 questions, which include 16 different question/response category formats. It was completed by 100 laser refractive surgery subjects (spectacle and contact lens wearers) pre- and postoperatively. Rasch analysis was used to assess the use of response categories, success in measuring a single trait per subscale (unidimensionality), ability to discriminate persons (precision), and targeting of the questions to person QoL. RESULTS: Response categories were misused in four subscales (clarity of vision, diurnal fluctuation, symptoms, and appearance), which required repair before further analyses. Six subscales contained items that did not contribute to a single trait measurement (multidimensional). All subscales were found to be inadequate at distinguishing between persons (person separation >2.0), and targeting of the questions to QoL was poor for six subscales. CONCLUSIONS: The NEI-RQL-42 questionnaire is deficient for all psychometric properties tested. Clinicians or researchers wishing to measure QoL related to refractive error correction should consider other questionnaires that have been rigorously developed and meet standard psychometric properties. PMID- 21676908 TI - Blockade of NADPH oxidase restores vasoreparative function in diabetic CD34+ cells. AB - PURPOSE: The vasodegenerative phase of diabetic retinopathy is likely caused by endothelial dysfunction and reduced endothelial repair. Migration of endothelial progenitor cells (EPCs) into areas of vascular injury is critical to vascular repair. This key function, often defective in diabetes, is largely mediated by nitric oxide (NO), which is known to be inactivated by superoxide produced by NADPH oxidase. The authors tested the hypothesis that either increasing eNOS expression or inhibiting NADPH oxidase would restore the reparative function in diabetic EPCs. METHODS: Peripheral blood was obtained from healthy (n = 27) and diabetic (n = 31) persons, and CD34(+) cells were isolated. Expression and activation of eNOS and NADPH oxidase and intracellular levels of NO, superoxide, and peroxynitrite were evaluated. cGMP production and migration to SDF-1alpha were also determined. Reparative function was evaluated in a mouse model of retinal ischemia-reperfusion injury. RESULTS: Diabetic EPCs demonstrate reduced eNOS expression and decreased NO bioavailability and migration in response to SDF 1alpha. Increasing eNOS expression in diabetic cells by AVE3085 resulted in increased peroxynitrite levels and, therefore, did not enhance NO-mediated functions in vitro and in vivo. Expression of Nox2, NADPH oxidase activity, and superoxide levels were higher in diabetic than in nondiabetic EPCs. Pretreatment with apocynin or gp91ds-tat increased NO bioavailability without increasing eNOS activity in response to SDF-1alpha. Ex vivo NADPH oxidase inhibition in diabetic cells restored migratory function in vitro and enhanced their homing to ischemic retinal vasculature in vivo. CONCLUSIONS: The NADPH oxidase system is a promising target for correcting vasoreparative dysfunction in diabetic EPCs. PMID- 21676910 TI - Comparative transcriptome and network biology analyses demonstrate antiproliferative and hyperapoptotic phenotypes in human keratoconus corneas. AB - PURPOSE: To decipher the biological pathways involved in keratoconus pathophysiology by determining the patterns of differential gene expression between keratoconus and control corneas. METHODS: RNA was extracted from surgically removed corneas of 10 keratoconus patients and from normal corneas of 10 control patients who had undergone enucleation of an eye for ocular melanoma. Several hundred thousand RNA transcripts were assessed using exon microarrays. Statistical comparison and identification of differentially regulated and differentially spliced RNA transcripts was performed by comparing keratoconus cases and controls. In addition, relevant biological pathways were identified by information extraction using network biology. RESULTS: Eighty-seven genes showed significant differences in expression levels. Among these, 69 were downregulated in keratoconus patients, particularly partners of the transcription factor AP-1. The 18 overexpressed genes include mucins, keratins, and genes involved in fibroblast proliferation. In addition, 36 genes were shown to be differentially spliced, including 9 among those that were differentially expressed. Network biology and analysis using Gene Ontology descriptors suggest that many members of both groups belong to pathways of apoptosis and regulation of the balance between cellular differentiation and proliferation. CONCLUSIONS: This work constitutes the first genome-wide transcriptome analysis of keratoconus patient corneas that include all currently known genes and exons. Differential expression suggests that mechanisms of cell loss resulting from antiproliferative and hyperapoptotic phenotypes may be responsible for the pathogenesis of keratoconus. Array information, experimental design, raw intensities, and processed log(2) ratios were deposited at the European Bioinformatic Institute's ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/). The accession number is E-MEXP-2777. PMID- 21676911 TI - Functional interconnections of Arabidopsis exon junction complex proteins and genes at multiple steps of gene expression. AB - The exon junction complex (EJC) is deposited on mRNA after splicing and participates in several aspects of RNA metabolism, from intracellular transport to translation. In this work, the functional and molecular interactions of Arabidopsis homologues of Mago, Y14, and PYM, three EJC components that participate in intron-mediated enhancement of gene expression in animals, have been analysed. AtMago, AtY14, and AtPYM are encoded by single genes that show similar expression patterns and contain common regulatory elements, known as site II, that are required for expression. AtPYM and AtY14 are phosphorylated by plant extracts and this modification regulates complex formation between both proteins. In addition, overexpression of AtMago and AtY14 in plants produces an increase in AtPYM protein levels, while overexpression of AtPYM results in increased formation of a complex that contains the three proteins. The effect of AtMago and AtY14 on AtPYM expression is most likely to be due to intron-mediated enhacement of AtPYM expression, since the AtPYM gene contains a leader intron that is required for expression. Indeed, transient transformation asssays indicated that the three proteins are able to increase expression from reporter constructs that contain leader introns required for the expression of different genes. The results indicate that the plant homologues of Mago, Y14, and PYM are closely interconnected, not only through their function as EJC components but also at different steps of their own gene expression mechanisms, probably reflecting the importance of their interaction for the correct expression of plant genes. PMID- 21676912 TI - The equations of life and death: tales told by motor unit number estimation. PMID- 21676913 TI - Olive oil: pertinent to neurologic diseases too? PMID- 21676914 TI - Olive oil consumption, plasma oleic acid, and stroke incidence: the Three-City Study. AB - OBJECTIVE: To determine whether high olive oil consumption, and high plasma oleic acid as an indirect biological marker of olive oil intake, are associated with lower incidence of stroke in older subjects. METHODS: Among participants from the Three-City Study with no history of stroke at baseline, we examined the association between olive oil consumption (main sample, n = 7,625) or plasma oleic acid (secondary sample, n = 1,245) and incidence of stroke (median follow up 5.25 years), ascertained according to a diagnosis validated by an expert committee. RESULTS: In the main sample, 148 incident strokes occurred. After adjustment for sociodemographic and dietary variables, physical activity, body mass index, and risk factors for stroke, a lower incidence for stroke with higher olive oil use was observed (p for trend = 0.02). Compared to those who never used olive oil, those with intensive use had a 41%(95% confidence interval 6%-63%, p = 0.03) lower risk of stroke. In the secondary sample, 27 incident strokes occurred. After full adjustment, higher plasma oleic acid was associated with lower stroke incidence (p for trend = 0.03). Compared to those in the first tertile, participants in the third tertile of plasma oleic acid had a 73% (95% confidence interval 10%-92%, p = 0.03) reduction of stroke risk. CONCLUSIONS: These results suggest a protective role for high olive oil consumption on the risk of stroke in older subjects. PMID- 21676915 TI - Multipoint incremental motor unit number estimation as an outcome measure in ALS. AB - BACKGROUND: Improved outcome measures are necessary to reduce sample size and increase power in amyotrophic lateral sclerosis (ALS) clinical trials. Motor unit number estimation (MUNE) is a potentially attractive tool. MUNE methods previously employed in multicenter trials exhibited excessive variability and were prone to artifact. OBJECTIVE: To evaluate a modification of standard incremental MUNE in a multicenter natural history study of subjects with ALS. METHODS: Fifty healthy subjects were evaluated twice and 71 subjects with ALS were studied repeatedly for up to 500 days. Side and nerve studied was based on clinical examination findings. Nerves were stimulated at 3 specified locations and 3 increments were obtained at each location. Average single motor unit action potential (SMUP) amplitude was calculated by adding the amplitude of the third increment at each location and dividing by 9; SMUP was divided into maximum CMAP amplitude to determine the MUNE. RESULTS: Test-retest variability was 9% in normal subjects. Average MUNE for normal subjects was 225 (+/-87), and was 41.9 (+/-39) among subjects with ALS at baseline. Subjects with ALS showed clear decrements over time, with an overage rate of decline of approximately 9% per month. SMUP amplitude increased with time in a fashion consistent with the known pathophysiology of ALS. CONCLUSION: Multipoint incremental MUNE has a number of attributes that make it attractive as an outcome measure in ALS and other diseases characterized by motor unit loss. It can be rapidly performed on any EMG machine and has repeatability and rates of decline that favorably compare to other previously described methods. PMID- 21676916 TI - Healthy, hunger-free kids act of 2010: an opportunity for school nurses to make a difference. AB - Implementation of the Healthy Hunger-Free Kids Act of 2010 will provide an opportunity for school nurses to intervene in the serious childhood obesity problem in the United States. Major changes in the management of the National School Lunch Program (NSLP) will likely challenge schools yet may provide the impetus for a collaborative effort by the interdisciplinary school staff and parents to make a real difference for children. School nurses must use this occasion for a change to promote healthy eating habits and increased physical activity levels for students to carry into adulthood. PMID- 21676917 TI - The short-term role of corticosteroid therapy for pulmonary arterial hypertension associated with connective tissue diseases: report of five cases and a literature review. AB - Pulmonary arterial hypertension (PAH) is a life-threatening complication in connective tissue diseases (CTD). It remains controversial whether immunosuppressive therapy is useful for PAH associated with CTD (PAH-CTD). The Dana Point algorithm does not refer such treatments in patients with PAH-CTD due to the lack of evidence. However, some case reports have shown the potential efficacy of immunosuppression for PAH-CTD. Here we report five cases of PAH-CTD treated with corticosteroids and discuss the current management of PAH-CTD with immunosuppressive agents. Our cases consisted of three active systemic lupus erythematosus (SLE), a quiescent SLE and an active polymyositis. WHO functional classes at baseline were class III in three cases and class II in two. Median follow-up period was 44 (28-92) weeks. PAH was diagnosed by right heart catheterization in all cases (median pulmonary arterial pressure was 45 (29-49) mmHg). All patients received 1 mg/kg of prednisolone (PSL) for 2-4 weeks, followed by appropriate dose reduction. Methylprednisolone pulse therapy was performed in patients resistant to the high dosage of PSL. Four patients received vasodilators in combination. The therapy as above improved WHO functional class 4 weeks after the initiation of PSL in all the patients. Two patients required dose increase or additional administration of vasodilators due to the dose reduction of PSL. Corticosteroid therapy may be effective for PAH-CTD at least in the short term, even in low general activity of CTD or moderate PAH. Our experience suggests that corticosteroid therapy, by itself or in conjunction with standard vasodilators, is effective for PAH-CTD patients. PMID- 21676918 TI - Early versus later onset childhood-onset systemic lupus erythematosus: Clinical features, treatment and outcome. AB - The objective of the study was to compare clinical features, treatment and disease outcome in patients with early versus later onset of childhood-onset systemic lupus erythematosus (cSLE). A retrospective matched cohort study of cSLE patients diagnosed between 1988 and 2008 and followed for a minimum of one year was conducted. Thirty-four pre-pubertal cSLE patients with disease onset prior to their 12th birthday were matched by ethnicity and year of diagnosis to 34 pubertal cSLE patients. The most common criteria at diagnosis in both groups were malar rash, arthritis, hematologic manifestations, and renal disease. After a mean follow-up of more than six years, a similar proportion of patients in the two groups were still prescribed corticosteroids (47% and 41%); patients in the early onset group required a significantly higher daily dose (0.6 mg/kg prednisone-equivalent versus 0.2 mg/kg, p < 0.05). There were no significant differences in organ involvement, disease activity and disease damage between the two groups, and severe complications occurred at similar rates. There were a greater number of admissions to the pediatric intensive care unit (PICU) in the early onset group (18 versus 5, p = 0.01), with time-to-event analysis demonstrating a significantly shorter disease duration from diagnosis to first PICU admission in the early onset group (p < 0.001). While a similar proportion of patients in the early and later onset groups required treatment with cyclophosphamide, patients in the early onset group received treatment earlier in their disease course (mean 13.7 versus 19.9 months, p < 0.001). Early onset cSLE leads to earlier and more frequent PICU admission, earlier use of cyclophosphamide, and higher corticosteroid dose at long-term follow-up. PMID- 21676919 TI - Systemic lupus erythematosus and cardiac risk factors: medical record documentation and patient adherence. AB - This study explores patients' knowledge of cardiac risk factors (CRFs), analyses how information and advice about CRFs are documented in clinical practice, and assesses patient adherence to received instructions to decrease CRFs. Systemic lupus erythematosus (SLE) patients with >= 4 ACR criteria participated through completing a validated cardiovascular health questionnaire (CHQ). Kappa statistics were used to compare medical records with the self-reported CHQ (agreement) and to evaluate adherence. Two hundred and eleven (72%) of the known patients with SLE participated. The mean age of the patients was 55 years. More than 70% of the SLE patients considered hypertension, obesity, smoking and hypercholesterolaemia to be very important CRFs. The agreement between medical record documentation and patients' reports was moderate for hypertension, overweight and hypercholesterolaemia (kappa 0.42-0.60) but substantial for diabetes (kappa 0.66). Patients' self-reported adherence to advice they had received regarding medication was substantial to perfect (kappa 0.65-1.0). For lifestyle changes in patients with hypertension and overweight, adherence was only fair to moderate (kappa 0.13-0.47). Swedish SLE patients' awareness of traditional CRFs was good in this study. However, the agreement between patients' self-reports and medical record documentation of CRF profiles, and patients' adherence to medical advice to CRF profiles, could be improved. PMID- 21676920 TI - Cognitive dysfunction in SLE: development of a screening tool. AB - BACKGROUND: Cognitive dysfunction (CD) is among the most common neuropsychiatric manifestations of systemic lupus erythematosus (SLE). There are two methods which have been used to detect CD in patients with SLE: traditional neuropsychological tests (NPT) and the Automated Neuropsychological Assessment Metrics (ANAM). Both are time-consuming and neither is readily available for screening purposes. PURPOSE: The aim of our study was to evaluate the Montreal Cognitive Assessment (MoCA) test as a screening tool for detection of CD in SLE. Methods. SLE patients fulfilling ACR criteria were administered the ANAM, a computerized test battery which measures various cognitive domains and the MoCA, a one-page, performance based screening test designed to detect mild cognitive impairment in the elderly. With the ANAM as the gold standard, the performance characteristics of the MoCA were assessed. RESULTS: In total, 44 patients were evaluated. Of these, 11 (25%) were identified by the ANAM as being impaired in comparison with 13 (29.5%) by the MoCA. The scores were significantly correlated (r = 0.57, p < 0.001). Using the standard cutoff of 26, the sensitivity of MoCA was 83% and specificity 73%. CONCLUSION: The MoCA appears to be a promising screening tool for the detection of CD in SLE both for epidemiologic studies and for routine clinical care. PMID- 21676921 TI - Genome-wide analysis reveals the active roles of keratinocytes in oral mucosal adaptive immune response. AB - To elucidate the roles of oral keratinocytes in the adaptive immune response of oral mucosa, global gene expression analysis was performed by microarray technique and integrating computational methods, including hierarchical clustering, biological process Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, self-organizing maps (SOMs) and biological association network analysis (BAN). Raw data from microarray experiments were uploaded to the Gene Expression Omnibus Database, http://www.ncbi.nlm.nih.gov/geo/ (GEO accession GSE28035). We identified 666 differentially expressed genes in the early stage (48 h) and 993 in the late stage (96 h) of the oral mucosal adaptive immune response. The analysis revealed that oral keratinocytes exerted diverse biological functions in different stages of immune response. Specifically, in 48 h the differentially expressed genes encompassed an array of biological ontology associated with immune response, such as antigen processing and presentation, and positive regulation of T-cell mediated cytotoxicity. Several pathways which have been reported to be critical in inflammation, including mitogen-activated protein kinase pathway, were activated. Furthermore, after BAN construction, some putative hub genes and networks such as interleukin-1alpha and its subnetwork were recognized. Taken together, these results give substantial evidence to support the active roles of keratinocytes in the oral mucosal adaptive immune response. PMID- 21676922 TI - Effects of berberine on human rheumatoid arthritis fibroblast-like synoviocytes. AB - Activated rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) play an important role in the initiation and progression of rheumatoid arthritis (RA). Rapid proliferation and defective apoptosis of RAFLSs are two main mechanisms contributing to synovial hyperplasia. Berberine, the major constituent of Coptidis Rhizoma, has been widely used as an antitumor and anti-inflammation agent. Here we show that berberine significantly inhibited cell proliferation of serum-starved human RAFLSs in a dose-dependent manner. Cell cycle analysis of berberine-treated RAFLSs indicated a cell cycle arrest at the G0/G1 phase. The inhibitory effects of berberine correlated with an induction of cyclin-dependent kinase (CDK) inhibitors Cip1/p21 and Kip1/p27 and a reduction of CDK2, CDK4 and CDK6, and cyclins D1, D2 and E. Furthermore, an apoptosis assay showed that berberine treatment increased apoptotic death of RAFLSs, which was associated with an increased expression of proapoptotic protein Bax and decreased expression of antiapoptotic proteins Bcl-2 and Bcl-xl, disruption of mitochondrial membrane potential, and activation of caspase-3, caspase-9 and poly (ADP-ribose) polymerase. Taken together, these results demonstrate that berberine exerts antiproliferative effects against RAFLSs, likely through deregulation of numerous cell cycle and apoptosis regulators, thus having potential therapeutic implications in the treatment of RA. PMID- 21676923 TI - Availability and use of Naswar: an exploratory study. AB - BACKGROUND: Naswar is a niche smokeless tobacco product from Pakistan. There is little information about its availability and user characteristics. METHODS: This cross-sectional survey identified outlets selling Naswar in two wards of one London borough and interviewed a purposively recruited sample of 73 Naswar purchasers. Data were analysed using descriptive and chi-square tests (significance, P <= 0.05). RESULTS: Of 65 outlets identified 15 sold Naswar. The purchasers' mean (SD) age was 32 (+/- 10) years and 63% had completed only secondary education. Naswar consumption was significantly associated with tobacco dependency, whilst starting Naswar use at a younger age, having lower education levels, using Naswar more frequently and being of Pakhtunkhwa origin was associated with high monthly consumption (P <= 0.05). CONCLUSIONS: Naswar was widely available. Naswar purchasers of Pakistani origin were employed and young, but with limited education and little knowledge of Naswar's health impacts. Naswar dependency and consumption was linked to behavioural and socio-demographic factors. Further evidence is needed to support policy development. PMID- 21676924 TI - Direct evidence for concurrent morphological and genetic heterogeneity in an invasive ductal carcinoma of triple-negative phenotype. AB - Triple-negative breast cancers account for 12-17% of all invasive breast carcinomas and comprise a heterogeneous group of tumours, with varying histological features and clinical behaviours. Focal apocrine differentiation can be associated with a subset of these lesions. To establish whether morphological diversity is associated with divergent genetic aberrations the genomic profiles of microdissected, morphologically distinct components from an invasive ductal carcinoma of no special type with triple-negative phenotype and a region of apocrine differentiation were determined by high-resolution microarray-based comparative genomic hybridisation and validated by fluorescence in-situ hybridisation. Morphologically distinct components were found to harbour differing genetic aberrations, with the region of apocrine differentiation demonstrating genomic gains and losses on chromosome arms 9p and 9q, respectively, not present in non-apocrine areas. The results provide additional direct evidence of intra-tumour genetic heterogeneity in breast cancer and demonstrate that morphologically distinct regions can be associated with distinct genetic aberrations. PMID- 21676925 TI - Role of Smac in determining the chemotherapeutic response of esophageal squamous cell carcinoma. AB - PURPOSE: Second mitochondria-derived activator of caspase (Smac) regulates chemotherapy-induced apoptosis. Smac mimetics have been tested in clinical trials as chemosensitizers. We determined the role of Smac in modulating the chemosensitivity of esophageal squamous cell carcinoma (ESCC). EXPERIMENTAL DESIGN: Smac expression was evaluated in tissues from ESCC patients with differential chemotherapeutic responses. The effects of Smac knockdown and Smac mimetics on the chemosensitivity of ESCC cells and the molecular mechanisms by which Smac and Smac mimetics modulate chemosensitivity were determined. The therapeutic responses of ESCC cells with different Smac statuses were compared using xenograft models. RESULTS: We found that Smac was significantly downregulated in most ESCC samples (36.8%, 25/68, P = 0.001), and Smac expression differed significantly (P < 0.05) between chemosensitive and chemoresistant tumors. The associations of tested factors and their responses were examined using logistic regression analysis. In ESCC cells treated with cisplatin, a common chemotherapeutic drug, Smac and cytochrome c were released from mitochondria, and caspase-3 and caspase-9 were activated. Knockdown of Smac abrogated cisplatin-induced apoptosis, mitochondrial dysfunction, cytochrome c release, and caspase activation. Smac deficiency also reduced the effect of cisplatin on long-term cell viability, and led to cisplatin resistance in xenograft tumors in vivo. LBW242, a small molecule Smac mimetic, enhanced cisplatin-induced apoptosis and caspase activation and restored cisplatin sensitivity in Smac-deficient cells. CONCLUSION: Our data suggested that downregulation of Smac may be a chemoresistance mechanism in ESCC. Combinations of Smac mimetics with chemotherapeutic agents may have therapeutic benefits for the treatment of esophageal cancer. PMID- 21676926 TI - Hematopoietic stem cell niche is a potential therapeutic target for bone metastatic tumors. AB - Despite significant improvements in therapy, the prognosis for cancer with bone metastasis is generally poor. Therefore, there is a great need for new therapeutic approaches for metastatic disease. It has been appreciated that tumor cells metastasize to bone using mechanisms similar to those of hematopoietic stem cells (HSC) homing to bone marrow (e.g., CXCL12/CXCR4). It was recently found that prostate cancer cells target the bone marrow microenvironment for HSCs, or the HSC niche, during metastasis. Of importance, these disseminated prostate cancer cells can be mobilized out of the niche with the use of HSC mobilizing agents. These findings suggest that the bone marrow HSC niche is a potential therapeutic target for metastatic disease. Therefore, a hypothesis worth considering is that agents that can disrupt the interactions between tumor cells and the HSC niche may be efficacious when used in conjunction with standard chemotherapeutic agents. Although further understanding of the tumor-niche interactions is needed, the concept of targeting the niche in conjunction with chemotherapy could open up new possibilities to eradicate incurable metastatic diseases. PMID- 21676927 TI - Unpredictable elbow joint perturbation during reaching results in multijoint motor equivalence. AB - Motor equivalence expresses the idea that movement components reorganize in the face of perturbations to preserve the value of important performance variables, such as the hand's position in reaching. A formal method is introduced to evaluate this concept quantitatively: changes in joint configuration due to unpredictable elbow perturbation lead to a smaller change in performance variables than expected given the magnitude of joint configuration change. This study investigated whether motor equivalence was present during the entire movement trajectory and how magnitude of motor equivalence was affected by constraints imposed by two different target types. Subjects pointed to spherical and cylindrical targets both with and without an elbow joint perturbation produced by a low- or high-stiffness elastic band. Subjects' view of their arm was blocked in the initial position, and the perturbation condition was randomized to avoid prediction of the perturbation or its magnitude. A modification of the uncontrolled manifold method variance analysis was used to investigate how changes in joint configuration on perturbed vs. nonperturbed trials (joint deviation vector) affected the hand's position or orientation. Evidence for motor equivalence induced by the perturbation was present from the reach onset and increased with the strength of the perturbation after 40% of the reach, becoming more prominent as the reach progressed. Hand orientation was stabilized more strongly by motor equivalent changes in joint configuration than was three-dimensional position regardless of the target condition. Results are consistent with a recent model of neural control that allows for flexible patterns of joint coordination while resisting joint configuration deviations in directions that affect salient performance variables. The observations also fit a general scheme of synergic control with referent configurations defined across different levels of the motor hierarchy. PMID- 21676928 TI - A watertight acrylic-free titanium recording chamber for electrophysiology in behaving monkeys. AB - Neurophysiological recording in alert monkeys requires the creation of a permanent aperture in the skull for repeated insertion of microelectrodes. Most laboratories use polymethyl methacrylate to attach a recording chamber over the skull opening. Here, we describe a titanium chamber that fastens to the skull with screws, using no polymethyl methacrylate. The gap between the base of the chamber and the skull is filled with hydroxyapatite, forming a watertight gasket. As the chamber base osseointegates with the skull, the hydroxyapatite is replaced with bone. Rather than having a finite lifetime, the recording chamber becomes more firmly anchored the longer it is in place. It has a small footprint, low profile, and needs little maintenance to control infection. Toilette consists of occasional application of betadine to clean the scalp margin, followed by application of neomycin, polymyxin, and bacitracin ointment. Antibiotic is also placed inside the chamber to suppress bacterial proliferation. Thickening of the dura within the chamber can be prevented by regular application of mitocycin C and/or bevacizumab, an antibody against vascular endothelial growth factor. By conducting an e-mail survey, this protocol for chamber maintenance was compared with procedures used in 37 other vision research laboratories. Refinement of appliances and techniques used for recordings in awake monkeys promises to increase the pace of scientific discovery and to benefit animal welfare. PMID- 21676929 TI - Dopamine-induced oscillations of the pyloric pacemaker neuron rely on release of calcium from intracellular stores. AB - Endogenously bursting neurons play central roles in many aspects of nervous system function, ranging from motor control to perception. The properties and bursting patterns generated by these neurons are subject to neuromodulation, which can alter cycle frequency and amplitude by modifying the properties of the neuron's ionic currents. In the stomatogastric ganglion (STG) of the spiny lobster, Panulirus interruptus, the anterior burster (AB) neuron is a conditional oscillator in the presence of dopamine (DA) and other neuromodulators and serves as the pacemaker to drive rhythmic output from the pyloric network. We analyzed the mechanisms by which DA evokes bursting in the AB neuron. Previous work showed that DA-evoked bursting is critically dependent on external calcium (Harris Warrick RM, Flamm RE. J Neurosci 7: 2113-2128, 1987). Using two-photon microscopy and calcium imaging, we show that DA evokes the release of calcium from intracellular stores well before the emergence of voltage oscillations. When this release from intracellular stores is blocked by antagonists of ryanodine or inositol trisphosphate (IP(3)) receptor channels, DA fails to evoke AB bursting. We further demonstrate that DA enhances the calcium-activated inward current, I(CAN), despite the fact that it significantly reduces voltage-activated calcium currents. This suggests that DA-induced release of calcium from intracellular stores activates I(CAN), which provides a depolarizing ramp current that underlies endogenous bursting in the AB neuron. PMID- 21676930 TI - Object-level visual information gets through the bottleneck of crowding. AB - Natural visual scenes are cluttered. In such scenes, many objects in the periphery can be crowded, blocked from identification, simply because of the dense array of clutter. Outside of the fovea, crowding constitutes the fundamental limitation on object recognition and is thought to arise from the limited resolution of the neural mechanisms that select and bind visual features into coherent objects. Thus it is widely believed that in the visual processing stream, a crowded object is reduced to a collection of dismantled features with no surviving holistic properties. Here, we show that this is not so: an entire face can survive crowding and contribute its holistic attributes to the perceived average of the set, despite being blocked from recognition. Our results show that crowding does not dismantle high-level object representations to their component features. PMID- 21676933 TI - Differences in intersaccadic adaptation transfer between inward and outward adaptation. AB - Saccadic adaptation is a mechanism to increase or decrease the amplitude gain of subsequent saccades, if a saccade is not on target. Recent research has shown that the mechanism of gain increasing, or outward adaptation, and the mechanism of gain decreasing, or inward adaptation, rely on partly different processes. We investigate how outward and inward adaptation of reactive saccades transfer to other types of saccades, namely scanning, overlap, memory-guided, and gap saccades. Previous research has shown that inward adaptation of reactive saccades transfers only partially to these other saccade types, suggesting differences in the control mechanisms between these saccade categories. We show that outward adaptation transfers stronger to scanning and overlap saccades than inward adaptation, and that the strength of transfer depends on the duration for which the saccade target is visible before saccade onset. Furthermore, we show that this transfer is mainly driven by an increase in saccade duration, which is apparent for all saccade categories. Inward adaptation, in contrast, is accompanied by a decrease in duration and in peak velocity, but only the peak velocity decrease transfers from reactive saccades to other saccade categories, i.e., saccadic duration remains constant or even increases for test saccades of the other categories. Our results, therefore, show that duration and peak velocity are independent parameters of saccadic adaptation and that they are differently involved in the transfer of adaptation between saccade categories. Furthermore, our results add evidence that inward and outward adaptation are different processes. PMID- 21676931 TI - Cholinergic microvillous cells in the mouse main olfactory epithelium and effect of acetylcholine on olfactory sensory neurons and supporting cells. AB - The mammalian olfactory epithelium is made up of ciliated olfactory sensory neurons (OSNs), supporting cells, basal cells, and microvillous cells. Previously, we reported that a population of nonneuronal microvillous cells expresses transient receptor potential channel M5 (TRPM5). Using transgenic mice and immunocytochemical labeling, we identify that these cells are cholinergic, expressing the signature markers of choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter. This result suggests that acetylcholine (ACh) can be synthesized and released locally to modulate activities of neighboring supporting cells and OSNs. In Ca(2+) imaging experiments, ACh induced increases in intracellular Ca(2+) levels in 78% of isolated supporting cells tested in a concentration-dependent manner. Atropine, a muscarinic ACh receptor (mAChR) antagonist suppressed the ACh responses. In contrast, ACh did not induce or potentiate Ca(2+) increases in OSNs. Instead ACh suppressed the Ca(2+) increases induced by the adenylyl cyclase activator forskolin in some OSNs. Supporting these results, we found differential expression of mAChR subtypes in supporting cells and OSNs using subtype-specific antibodies against M(1) through M(5) mAChRs. Furthermore, we found that various chemicals, bacterial lysate, and cold saline induced Ca(2+) increases in TRPM5/ChAT-expressing microvillous cells. Taken together, our data suggest that TRPM5/ChAT-expressing microvillous cells react to certain chemical or thermal stimuli and release ACh to modulate activities of neighboring supporting cells and OSNs via mAChRs. Our studies reveal an intrinsic and potentially potent mechanism linking external stimulation to cholinergic modulation of activities in the olfactory epithelium. PMID- 21676932 TI - Representation of comparison signals in cortical area MT during a delayed direction discrimination task. AB - Visually guided behavior often involves decisions that are based on evaluating stimuli in the context of those observed previously. Such decisions are made by monkeys comparing two consecutive stimuli, sample and test, moving in the same or opposite directions. We examined whether responses in the motion processing area MT during the comparison phase of this task (test) are modulated by the direction of the preceding stimulus (sample). This modulation, termed comparison signal, was measured by comparing responses to identical test stimuli on trials when it was preceded by sample moving in the same direction (S-trials) with trials when it was preceded by sample moving in a different direction (D-trials). The test always appeared in the neuron's receptive field (RF), whereas sample could appear in the RF or in the contralateral visual field (remote sample). With sample in RF, we found three types of modulation carried by different sets of neurons: early suppression on S-trials and late enhancement, one on S-trials, and the other on D-trials. Under these conditions, many neurons with and without comparison effects exhibited significant, choice-related activity. Response modulation was also present following the remote sample, even though the information about its direction could only reach MT indirectly via top-down influences. However, unlike on trials with in-RF sample, these signals were dominated by response suppression, shedding light on the contribution of top-down influences to the comparison effects. These results demonstrate that during the task requiring monkeys to compare two directions of motion, MT responses during the comparison phase of this task reflect similarities and differences between the two stimuli, suggesting participation in sensory comparisons. The nature of these signals provides insights into the operation of bottom-up and top-down influences involved in this process. PMID- 21676934 TI - Order of operations for decoding superior colliculus activity for saccade generation. AB - To help understand the order of events that occurs when generating saccades, we simulated and tested two commonly stated decoding models that are believed to occur in the oculomotor system: vector averaging (VA) and center-of-mass. To generate accurate saccades, each model incorporates two required criteria: 1) a decoding mechanism that deciphers a population response of the superior colliculus (SC) and 2) an exponential transformation that converts the saccade vector into visual coordinates. The order of these two criteria is used differently within each model, yet the significance of the sequence has not been quantified. To distinguish between each decoding sequence and hence, to determine the order of events necessary to generate accurate saccades, we simulated the two models. Distinguishable predictions were obtained when two simultaneous motor commands are processed by each model. Experimental tests of the models were performed by observing the distribution of endpoints of saccades evoked by weighted, simultaneous microstimulation of two SC sites. The data were consistent with the predictions of the VA model, in which exponential transformation precedes the decoding computation. PMID- 21676935 TI - Changes in action potential features during focal seizure discharges in the entorhinal cortex of the in vitro isolated guinea pig brain. AB - Temporal lobe seizures in humans correlate with stereotyped electrophysiological patterns that can be reproduced in animal models to study the cellular and network changes responsible for ictogenesis. Seizure-like discharges that mimic seizure patterns in humans were induced in the entorhinal cortex of the in vitro isolated guinea pig brain by 3-min arterial applications of the GABA(A) receptor antagonist bicuculline. The onset of seizure is characterized by a paradoxical interruption of firing for several seconds in principal neurons coupled with both enhanced interneuronal firing and increased extracellular potassium (Gnatkovsky et al. 2008). The evolution of action potential features from firing break to excessive and synchronous activity associated with the progression of seizure itself is analyzed here. We utilized phase plot analysis to characterize action potential features of entorhinal cortex neurons in different phases of a seizure. Compared with preictal action potentials, resumed spikes in layer II-III neurons (n = 17) during the early phase of the seizure-like discharge displayed 1) depolarized threshold, 2) lower peak amplitude, 3) depolarized voltage of repolarization and 4) decelerated depolarizing phase, and 5) spike doublettes. Action potentials in deep-layer principal cells (n = 8) during seizure did not show the marked feature changes observed in superficial layer neurons. Action potential reappearance correlated with an increase in extracellular potassium. High-threshold, slow-action potentials similar to those observed in the irregular firing phase of a seizure were reproduced in layer II-III neurons by direct cortical application of a highly concentrated potassium solution (12-24 mM). We propose that the generation of possibly nonsomatic action potentials by increased extracellular potassium represents a crucial step toward reestablish firing after an initial depression in an acute model of temporal lobe seizures. Resumed firing reengages principal neurons into seizure discharge and promotes the transition toward the synchronized burst firing that characterizes the late phase of a seizure. PMID- 21676936 TI - Distinct functions for direct and transthalamic corticocortical connections. AB - Essentially all cortical areas receive thalamic inputs and send outputs to lower motor centers. Cortical areas communicate with each other by means of direct corticocortical and corticothalamocortical pathways, often organized in parallel. We distinguish these functionally, stressing that the transthalamic pathways are class 1 (formerly known as "driver") pathways capable of transmitting information, whereas the direct pathways vary, being either class 2 (formerly known as "modulator") or class 1. The transthalamic pathways provide a thalamic gate that can be open or closed (and otherwise more subtly modulated), and these inputs to the thalamus are generally branches of axons with motor functions. Thus the transthalamic corticocortical pathways that can be gated carry information about the cortical processing in one cortical area and also about the motor instructions currently being issued from that area and copied to other cortical areas. PMID- 21676937 TI - Organisational merger and psychiatric morbidity: a prospective study in a changing work organisation. AB - BACKGROUND: Prospective studies on the relationship between organisational merger and mental health have been conducted using subjective health indicators. The objective of this prospective occupational cohort study was to examine whether a negative change during an organisational merger is an independent predictive factor of psychiatric morbidity. METHOD: Survey data on organisational characteristics, health and other factors were collected prior to (1996) and after the merger (2000); register data on psychiatric morbidity were collected at baseline (1/1/1994-30/9/2000) and during the follow-up (1/10/2000-31/12/2005). Participants were 6511 (77% men) industrial employees aged 21-65 years with no register-based diagnosed psychiatric events prior to the follow-up (the Still Working Study). During the follow-up, 252 participants were admitted to the hospital due to psychiatric disorders, were prescribed a psychotropic drug or attempted or committed suicide. RESULTS: A negative self-reported change in the work organisation during the merger was associated with increased risk of postmerger psychiatric event (HR 1.60, 95% CI 1.19 to 2.14). This association was independent of mental health-related factors measured before the merger announcement, such as demographic characteristics, occupational status, personal orientation to life, self-rated health, self-reported psychiatric morbidity or chronic disease. CONCLUSION: A negative change in work organisation during an organisational merger may elevate the risk for postmerger psychiatric morbidity. PMID- 21676938 TI - A novel signal detection algorithm for identifying hidden drug-drug interactions in adverse event reports. AB - OBJECTIVE: Adverse drug events (ADEs) are common and account for 770 000 injuries and deaths each year and drug interactions account for as much as 30% of these ADEs. Spontaneous reporting systems routinely collect ADEs from patients on complex combinations of medications and provide an opportunity to discover unexpected drug interactions. Unfortunately, current algorithms for such "signal detection" are limited by underreporting of interactions that are not expected. We present a novel method to identify latent drug interaction signals in the case of underreporting. MATERIALS AND METHODS: We identified eight clinically significant adverse events. We used the FDA's Adverse Event Reporting System to build profiles for these adverse events based on the side effects of drugs known to produce them. We then looked for pairs of drugs that match these single-drug profiles in order to predict potential interactions. We evaluated these interactions in two independent data sets and also through a retrospective analysis of the Stanford Hospital electronic medical records. RESULTS: We identified 171 novel drug interactions (for eight adverse event categories) that are significantly enriched for known drug interactions (p=0.0009) and used the electronic medical record for independently testing drug interaction hypotheses using multivariate statistical models with covariates. CONCLUSION: Our method provides an option for detecting hidden interactions in spontaneous reporting systems by using side effect profiles to infer the presence of unreported adverse events. PMID- 21676939 TI - The influence of computerized decision support on prescribing during ward-rounds: are the decision-makers targeted? AB - OBJECTIVE: To assess whether a low level of decision support within a hospital computerized provider order entry system has an observable influence on the medication ordering process on ward-rounds and to assess prescribers' views of the decision support features. METHODS: 14 specialty teams (46 doctors) were shadowed by the investigator while on their ward-rounds and 16 prescribers from these teams were interviewed. RESULTS: Senior doctors were highly influential in prescribing decisions during ward-rounds but rarely used the computerized provider order entry system. Junior doctors entered the majority of medication orders into the system, nearly always ignored computerized alerts and never raised their occurrence with other doctors on ward-rounds. Interviews with doctors revealed that some decision support features were valued but most were not perceived to be useful. DISCUSSION AND CONCLUSION: The computerized alerts failed to target the doctors who were making the prescribing decisions on ward rounds. Senior doctors were the decision makers, yet the junior doctors who used the system received the alerts. As a result, the alert information was generally ignored and not incorporated into the decision-making processes on ward-rounds. The greatest value of decision support in this setting may be in non-ward-round situations where senior doctors are less influential. Identifying how prescribing systems are used during different clinical activities can guide the design of decision support that effectively supports users in different situations. If confirmed, the findings reported here present a specific focus and user group for designers of medication decision support. PMID- 21676940 TI - Health-information exchange: why are we doing it, and what are we doing? AB - Health-information exchange, that is, enabling the interoperability of automated health data, can facilitate important improvements in healthcare quality and efficiency. A vision of interoperability and its benefits was articulated more than a decade ago. Since then, important advances toward the goal have been made. The advent of the Health Information Technology for Economic and Clinical Health Act and the meaningful use program is already having a significant impact on the direction that health-information exchange will take. This paper describes how interoperability activities have unfolded over the last decade and explores how recent initiatives are likely to affect the directions and benefits of health information exchange. PMID- 21676941 TI - Handling anticipated exceptions in clinical care: investigating clinician use of 'exit strategies' in an electronic health records system. AB - Unpredictable yet frequently occurring exception situations pervade clinical care. Handling them properly often requires aberrant actions temporarily departing from normal practice. In this study, the authors investigated several exception-handling procedures provided in an electronic health records system for facilitating clinical documentation, which the authors refer to as 'data entry exit strategies.' Through a longitudinal analysis of computer-recorded usage data, the authors found that (1) utilization of the exit strategies was not affected by postimplementation system maturity or patient visit volume, suggesting clinicians' needs to 'exit' unwanted situations are persistent; and (2) clinician type and gender are strong predictors of exit-strategy usage. Drilldown analyses further revealed that the exit strategies were judiciously used and enabled actions that would be otherwise difficult or impossible. However, many data entries recorded via them could have been 'properly' documented, yet were not, and a considerable proportion containing temporary or incomplete information was never subsequently amended. These findings may have significant implications for the design of safer and more user-friendly point-of care information systems for healthcare. PMID- 21676942 TI - Unicameral bone cyst of the hyoid. PMID- 21676943 TI - Tympanostomy tube placement and vestibular function in children. AB - OBJECTIVE: To determine the effect of bilateral myringotomy with tube placement (BMT) on balance in children 4 to 7 years old. STUDY DESIGN: Case-control study. SETTING: Tertiary-care academic hospital. SUBJECTS AND METHODS: Children with otitis media with effusion (OME) who were scheduled for BMT underwent rotational chair testing (RCT) and computerized dynamic posturography (CDP) preoperatively and at 1, 3, and 6 months postoperatively. Control children without a significant history of middle ear disease were tested at the same intervals. Analysis of covariance was performed to evaluate the effect of BMT on RCT and CDP outcomes with age as a covariate. RESULTS: Seventy-two cases and 56 controls were enrolled. Mean (SD) age was 69 (12) months for cases and 72 (15) months for controls. No difference was seen between groups on RCT outcomes or sensory organization test (SOT) scores. Higher sway velocity during CDP was observed in the OME group both preoperatively and 1 month postoperatively. This difference was not statistically significant. There was no difference between groups 3 months postoperatively. At 6 months, the BMT group had a statistically significant decrease in sway velocity compared with the control group. CONCLUSION: No difference was observed between children with OME and controls in RCT or SOT scores. Gradual improvement in sway velocity was observed after BMT. At the final time point, the groups did significantly differ in speed of sway, although the preoperative baseline difference failed to reach statistical significance. The authors suggest that physicians continue to inquire about balance development in patients with OME. PMID- 21676944 TI - Clinical practice guideline: Polysomnography for sleep-disordered breathing prior to tonsillectomy in children. AB - OBJECTIVE: This guideline provides otolaryngologists with evidence-based recommendations for using polysomnography in assessing children, aged 2 to 18 years, with sleep-disordered breathing and are candidates for tonsillectomy, with or without adenoidectomy. Polysomnography is the electrographic recording of simultaneous physiologic variables during sleep and is currently considered the gold standard for objectively assessing sleep disorders. PURPOSE: There is no current consensus or guideline on when children 2 to 18 years of age, who are candidates for tonsillectomy, are recommended to have polysomnography. The primary purpose of this guideline is to improve referral patterns for polysomnography among these patients. In creating this guideline, the American Academy of Otolaryngology--Head and Neck Surgery Foundation selected a panel representing the fields of anesthesiology, pulmonology medicine, otolaryngology head and neck surgery, pediatrics, and sleep medicine. RESULTS: The committee made the following recommendations: (1) before determining the need for tonsillectomy, the clinician should refer children with sleep-disordered breathing for polysomnography if they exhibit certain complex medical conditions such as obesity, Down syndrome, craniofacial abnormalities, neuromuscular disorders, sickle cell disease, or mucopolysaccharidoses. (2) The clinician should advocate for polysomnography prior to tonsillectomy for sleep-disordered breathing in children without any of the comorbidities listed in statement 1 for whom the need for surgery is uncertain or when there is discordance between tonsillar size on physical examination and the reported severity of sleep disordered breathing. (3) Clinicians should communicate polysomnography results to the anesthesiologist prior to the induction of anesthesia for tonsillectomy in a child with sleep-disordered breathing. (4) Clinicians should admit children with obstructive sleep apnea documented on polysomnography for inpatient, overnight monitoring after tonsillectomy if they are younger than age 3 or have severe obstructive sleep apnea (apnea-hypopnea index of 10 or more obstructive events/hour, oxygen saturation nadir less than 80%, or both). (5) In children for whom polysomnography is indicated to assess sleep-disordered breathing prior to tonsillectomy, clinicians should obtain laboratory-based polysomnography, when available. PMID- 21676945 TI - miR-483-3p controls proliferation in wounded epithelial cells. AB - The mechanisms that regulate keratinocyte migration and proliferation in wound healing remain largely unraveled, notably regarding possible involvements of microRNAs (miRNAs). Here we disclose up-regulation of miR-483-3p in 2 distinct models of wound healing: scratch-injured cultures of human keratinocytes and wounded skin in mice. miR-483-3p accumulation peaks at the final stage of the wound closure process, consistent with a role in the arrest of "healing" progression. Using an in vitro wound-healing model, videomicroscopy, and 5-bromo 2'-uridine incorporation, we observed that overexpression of miR-483-3p inhibits keratinocyte migration and proliferation, whereas delivery of anti-miR-483-3p oligonucleotides sustains keratinocyte proliferation beyond the closure of the wound, compared with irrelevant anti-miR treatment. Expression profiling of keratinocytes transfected with miR-483-3p identified 39 transcripts that were both predicted targets of miR-483-3p and down-regulated after miR-483-3p overexpression. Luciferase reporter assays, Western blot analyses, and silencing by specific siRNAs finally established that kinase MK2, cell proliferation marker MKI67, and transcription factor YAP1 are direct targets of miR-483-3p that control keratinocyte proliferation. miR-483-3p-mediated down-regulation of MK2, MKI67, and YAP1 thus represents a novel mechanism controlling keratinocyte growth arrest at the final steps of reepithelialization. PMID- 21676946 TI - The SUMO E3-ligase PIAS1 couples reactive oxygen species-dependent JNK activation to oxidative cell death. AB - Human endometrial stromal cells (HESCs) exposed to reactive oxygen species (ROS) mount a hypersumoylation response in a c-Jun N-terminal kinase (JNK)-dependent manner. The mechanism that couples JNK signaling to the small ubiquitin-related modifier (SUMO) pathway and its functional consequences are not understood. We show that ROS-dependent JNK activation converges on the SUMO pathway via PIAS1 (protein inhibitor of activated STAT1). Unexpectedly, PIAS1 knockdown not only prevented ROS-dependent hypersumoylation but also enhanced JNK signaling in HESCs. Conversely, PIAS overexpression increased sumoylation of various substrates, including c-Jun, yet inhibited basal and ROS-dependent JNK activity independently of its SUMO ligase function. Expression profiling demonstrated that PIAS1 knockdown enhances and profoundly modifies the transcriptional response to oxidative stress signals. Using a cutoff of 2-fold change or more, a total of 250 ROS-sensitive genes were identified, 97 of which were not dependent on PIAS1. PIAS1 knockdown abolished the regulation of 43 genes but also sensitized 110 other genes to ROS. Importantly, PIAS1 silencing was obligatory for the induction of several cellular defense genes in response to oxidative stress. In agreement, PIAS1 knockdown attenuated ROS-dependent caspase-3/7 activation and subsequent apoptosis. Thus, PIAS1 determines the level of JNK activity in HESCs, couples ROS signaling to the SUMO pathway, and promotes oxidative cell death. PMID- 21676947 TI - Functional studies of cochleate assemblies of an oligo-acyl-lysyl with lipid mixtures for combating bacterial multidrug resistance. AB - The cationic antimicrobial oligo-acyl-lysyls (OAKs) interact with lipid mixtures mimicking the composition of bacterial cytoplasmic membranes. We have reported the ability of one such OAK, C(12)K-7alpha(8), to cluster anionic lipids and to promote a structural change with lipid bilayers to form rolled cylindrical structures or cochleates, without requiring divalent cations for their assembly. These assemblies can be exploited for drug delivery, permitting their synergistic use with antibiotics in systemic therapy to increase efficacy and reduce toxicity. Our previous studies of the biophysical properties of these systems led us to select mixtures with the goal of optimizing their potential for enhancing effectiveness in combating bacterial multidrug resistance. Here, we further investigate the properties of such mixtures that result in enhanced in vivo activity. The role of erythromycin in the assembly of cochleates with OAK in the gel and the liquid crystalline states were assessed, as well as the encapsulation efficiency of the systems chosen. In addition, we found that erythromycin did not undermine the ability of OAKs to induce fusion of vesicles, fusion being an essential component of cochleate formation. The in vivo activity of the new assemblies tested resulted in higher survival rates of animals infected with multidrug resistant bacteria. PMID- 21676948 TI - Pre-surgery briefings and safety climate in the operating theatre. AB - BACKGROUND: In 2008, the WHO produced a surgical safety checklist against a background of a poor patient safety record in operating theatres. Formal team briefings are now standard practice in high-risk settings such as the aviation industry and improve safety, but are resisted in surgery. Research evidence is needed to persuade the surgical workforce to adopt safety procedures such as briefings. OBJECTIVE: To investigate whether exposure to pre-surgery briefings is related to perception of safety climate. METHODS: Three Safety Attitude Questionnaires, completed by operating theatre staff in 2003, 2004 and 2006, were used to evaluate the effects of an educational intervention introducing pre surgery briefings. RESULTS: Individual practitioners who agree with the statement 'briefings are common in the operating theatre' also report a better 'safety climate' in operating theatres. CONCLUSIONS: The study reports a powerful link between briefing practices and attitudes towards safety. Findings build on previous work by reporting on the relationship between briefings and safety climate within a 4-year period. Briefings, however, remain difficult to establish in local contexts without appropriate team-based patient safety education. Success in establishing a safety culture, with associated practices, may depend on first establishing unidirectional, positive change in attitudes to create a safety climate. PMID- 21676949 TI - Occupational health impact of the 2009 H1N1 flu pandemic: surveillance of sickness absence. AB - OBJECTIVES: Workplace absences due to illness can disrupt usual operations and increase costs for businesses. This study of sickness absence due to influenza and influenza-related illness presents a unique opportunity to characterise and measure the impact of the 2009 (H1N1) pandemic, by comparing trends during the pandemic to those of previous years, and adding this information to that obtained by traditional epidemiological surveillance systems. METHODS: We compared the numbers of cases of sickness absence due to illness caused by influenza and influenza-related illness in 2007-2009, and in the first 3 months of 2010 in Catalonia (n=811 940) using a time series approach. Trends were examined by economic activity, age and gender. The weekly endemic-epidemic index (EEI) was calculated and its 95% CI obtained with the delta method, with observed and expected cases considered as independent random variables. RESULTS: Influenza activity peaked earlier in 2009 and yielded more cases than in previous years. Week 46 (in November 2009) had the highest number of new cases resulting in sickness absence (EEI 20.99; 95% CI 9.44 to 46.69). Women and the 'education, health and other social activities' sector were the most affected. CONCLUSIONS: Results indicate that the new H1N1 pandemic had a significant impact on business, with shifts in the timing of peak incidence, a doubling in the number of cases, and changes in the distribution of cases by economic activity sector and gender. Traditional epidemiological surveillance systems could benefit from the addition of information based on sickness absence data. PMID- 21676950 TI - Mortality from ischaemic heart disease in textile workers. PMID- 21676951 TI - Exempting casinos from the Smoke-free Illinois Act will not bring patrons back: they never left. AB - OBJECTIVE: The Smoke-free Illinois Act was implemented in January 2008, one month after the beginning of a national recession. In December 2010, the Illinois legislature proposed new legislation that would provide an exemption for casinos from the act until neighbouring states also implement smoke-free casino policies. Lobbyists and gaming commission representatives argued that Illinois casinos were losing patrons to casinos in neighbouring states that allow smoking. This study examined the influence of the act on casino admissions in Illinois and neighbouring states in light of the economy. METHODS: A multilevel model was developed to examine monthly casino admissions from January 2007 to December 2008. RESULTS: There was no difference in changes in admissions across the four states over time after accounting for the economic downturn. CONCLUSIONS: The Smoke-Free Illinois Act did not have a detectable effect on Illinois casino admissions. PMID- 21676952 TI - Conflict of interest and FCTC implementation in China. AB - OBJECTIVE: To critically review the structure of tobacco control policy making in China, examine conflicts of interest within this structure, and consider how these affected the introduction of on-pack warnings. METHODS: Government policy documents and warning labels were obtained and critically reviewed. RESULTS: Few differences exist between the on-pack warnings formerly used in China and those introduced ostensibly to meet Framework Convention on Tobacco Control (FCTC) obligations. Comparison with tobacco manufactured for export or overseas consumption shows the new Chinese domestic on-pack warnings are demonstrably inferior to those required internationally. The inherent conflict of interest in the Chinese tobacco control agency structure, which must meet commercial and public health objectives, undermined the introduction of new health warnings. CONCLUSIONS: To promote more effective tobacco control policies, the conflict of interest inhibiting the public health function of the State Tobacco Monopoly Administration (STMA) must be removed. Specifically, the public health function must be separated from oversight of commercial production, and packaging must be redesigned with pictorial warnings and messages compliant with Article 11 of the FCTC. PMID- 21676953 TI - Economic and public health impact of 2007-2010 tobacco tax increases in Ukraine. AB - OBJECTIVE: To evaluate the impact of the dynamic 2007-2010 tobacco tax policy in Ukraine on cigarette prices, cigarette consumption, tobacco tax revenue and the tobacco industry's price strategy. METHODS: Using data on cigarette sales, cigarette prices, income and tobacco control policies, price elasticities of cigarette demand in Ukraine were estimated using two methods. Annual data were used to generate point price elasticity estimates, while monthly data were used in a two-step Engle-Granger procedure. RESULTS: The point price elasticity estimate is data sensitive and ranges from -0.11 to -0.62, centring around -0.32. The regression model estimates a long-run price elasticity of -0.28. Cigarette consumption fell by 13% in 2009 and 15% in 2010 while the tax revenue increased by US$700 million and by US$500 million in 2009 and 2010, respectively, compared to the previous year. Tax increases have changed the tobacco industry's price strategy from one of shielding consumers from the impact of smaller tax hikes in 2007-2008, to one of increasing industry net-of-tax prices, after recent, larger tax increases. CONCLUSIONS: The higher real tobacco excise taxes of 2009 and 2010 have significantly reduced tobacco consumption in Ukraine, resulting in encouraging public health and fiscal gains. It will be important for cigarette prices/taxes to keep pace with inflation and income growth for this impact to be sustained. PMID- 21676954 TI - Neurological picture. Traumatic upper limb weakness in a man with type 1 neurofibromatosis. PMID- 21676955 TI - Reducing the risk of venous thromboembolism in patients with acute stroke: more evidence from the CLOTS Trial Collaboration. PMID- 21676956 TI - Early treatment does not seem to affect the risk of mortality in epilepsy but the presence of comorbidity may. PMID- 21676957 TI - Cigarette smoke extract induces prolonged endoplasmic reticulum stress and autophagic cell death in human umbilical vein endothelial cells. AB - AIMS: Consumption of cigarette smoke (CS) is a well-known risk factor for early atherosclerosis; yet, the underlying mechanisms of smoking-associated atherosclerosis are poorly understood. Based on the previous results indicating that CS-induced endothelial cell death neither shows typical features of apoptosis nor of necrosis, we investigated the role of autophagy in CS extract (CSE)-induced cell death of human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: Here, we demonstrate that overexpression of the classical apoptosis inhibitor BCL-XL had no protective effect on CSE-induced cell death, whereas the autophagy inhibitor 3-methyladenin and an shRNAi-mediated knockdown of the autophagy mediator ATG5 significantly delayed cell death. Our results indicate that CSE induces an excess accumulation of misfolded proteins in the endoplasmic reticulum (ER) and consequently the onset of the unfolded protein response. We provide evidence that the ER-resident kinase PERK is a major transducer of ER stress leading to phosphorylation of eIF2alpha and attenuation of protein synthesis. Finally, we show that prolonged ER stress in cells subjected to CS is followed by activation of an autophagic programme. CSE-induced autophagy is characterized by an increase in LC3 II/I ratio and activation ATG12. The autophagic signalling pathway via energy depletion and consequent activation AMP-activated protein kinase could be excluded. CONCLUSION: Our results confirm and extend previous findings reporting on the induction of autophagy by CSE in the lung. We show that protein damage caused by CSE activates autophagy, ultimately resulting in necrotic death of HUVECs. Via this mechanism, cigarette smoking may contribute to the deterioration of vascular endothelial function and the initiation of atherosclerosis. PMID- 21676958 TI - A role for coagulation factor Xa in experimental pulmonary arterial hypertension. AB - AIMS: Anticoagulation with warfarin is recommended for the treatment of patients with pulmonary arterial hypertension (PAH). However, the therapeutic benefit of anticoagulation has not yet been demonstrated experimentally or clinically. Here, rivaroxaban, an oral, direct factor Xa (FXa) inhibitor, was compared with warfarin and enoxaparin in the prevention of right ventricular (RV) dysfunction and hypertrophy in the monocrotaline (MCT) model of pulmonary hypertension. METHODS AND RESULTS: Sprague-Dawley rats (n = 10 per group) were randomized to receive rivaroxaban, warfarin, enoxaparin, or placebo before receiving a subcutaneous injection of MCT 60 mg/kg or saline. Rivaroxaban and enoxaparin were administered for 28 days starting 4 h before MCT injection; warfarin was given for 35 days initiated 7 days before MCT injection. RV haemodynamics and hypertrophy were assessed 28 days after MCT administration. Rivaroxaban dose dependently reduced systolic and end-diastolic RV pressure increase and RV hypertrophy. Warfarin reduced RV pressure increase only. Enoxaparin had no effect on either parameter. Severe bleeding occurred in four and five rats treated with warfarin and enoxaparin, respectively, whereas no overt bleeding was observed in rats treated with rivaroxaban. CONCLUSION: Selective, direct inhibition of FXa by rivaroxaban effectively prevented RV dysfunction and hypertrophy in MCT-injected rats, indicating a role for coagulation factors in experimental pulmonary hypertension. Clinical investigation of the impact of early and continued administration of a specific FXa inhibitor such as rivaroxaban on the course of PAH should be considered. PMID- 21676959 TI - Injury mortality indicators: recommendations from the International Collaborative Effort on Injury Statistics. AB - BACKGROUND: The International Collaborative Effort (ICE) on Injury Statistics called for an effort 'to reach consensus on what are the 10 most important indicators of injury incidence that offer the potential for international comparisons and for regional or global monitoring.' OBJECTIVES: To describe the process of developing the ICE indicators and to present the specifications of selected injury mortality indicators, along with comparisons between selected countries for those specified indicators. METHODS: Participants on the ICE list had been asked to send to one of the authors what they considered the most important five indicators of injury incidence. These were synthesised and presented under six themes: mortality indicators (general); mortality indicators (motor vehicle); mortality indicators (other); hospital data-based (overall); hospital data-based (traumatic brain injury (TBI)); long-term disability (overall). Following two work group discussions and after drafting and revising indicator specifications, agreement was reached on mortality indicators and specifications. Specifications for those mortality indicators are presented. Morbidity indicators are still to be agreed. RESULTS: The mortality indicators proposed were age-adjusted rates of injury death; motor vehicle traffic crash related death; self-harm/suicide; assault/homicide; and TBI death. The empirical work highlighted difficulties in identifying TBI in countries where mortality data do not capture multiple injuries, prompting us to drop the mortality indicator related to TBI and moving us instead to introduce an indicator to monitor the use of undetermined intent in the classification of injury mortality. CONCLUSION: The ICE has reached a consensus on what injury mortality indicators should be used for comparison between countries. Specifications for each of these have been applied successfully to the mortality data of seven countries. PMID- 21676960 TI - Developing a function impairment measure for children affected by political violence: a mixed methods approach in Indonesia. AB - OBJECTIVE: Practitioners in political violence-affected settings would benefit from rating scales that assess child function impairment in a reliable and valid manner when designing and evaluating interventions. We developed a procedure to construct child function impairment rating scales using resources available in low- and middle-income countries. DESIGN: We applied a mixed methods approach. First, rapid ethnographic methods (brief participant observation, collection of diaries and a focus group with children) were used to select daily activities that best represented children's functioning. Second, rating scales based on these activities were examined for their psychometric properties. Construct validity was assessed through a confirmatory factor analysis procedure. SETTING: Central Sulawesi, Indonesia. PARTICIPANTS: Qualitative data were collected for 53 children and psychometric testing was done with 403 children [average age: 9.9 (SD = 1.21), 49% girls] and 385 parents. RESULTS: Using locally available resources, we developed separate child-rated and parent-rated scales, both containing 11 items. The child-rated scale evidenced good internal, test-retest and inter-rater reliability and acceptable convergent and discriminant validity. Construct validity was confirmed by fit of the theorized factor structure-a social-ecological clustering of daily activities. CONCLUSIONS: The procedure resulted in a reliable and valid rating scale to assess child function impairment in the context of political violence. Practitioners can apply this procedure to develop new locally adequate rating scales to strengthen epidemiological surveys, baseline assessments, monitoring and evaluation and eventually, interventions. Further research should address the importance of gender differences and criterion-related validity. PMID- 21676961 TI - Patient and hospital characteristics associated with variation in guideline adherence in intrauterine insemination care. AB - OBJECTIVE: To assess the association of patient and hospital characteristics with adherence to guidelines for intrauterine insemination (IUI) care. DESIGN: Retrospective cohort study using multilevel regression analysis. Characteristics studied at the patient level were female age, type and duration of subfertility, diagnosis and number of started IUI cycles. At the hospital level, the characteristics studied were hospital size, teaching hospital, in vitro fertilization (IVF) licence and number of physicians involved in the IUI programme. Data were obtained from medical records and questionnaires for gynaecologists. SETTING AND PARTICIPANTS: Five hundred and fifty-eight subfertile couples who underwent IUI treatment at 10 Dutch hospitals. MAIN OUTCOME MEASURES: Adherence to systematically developed guideline-based performance indicators describing 20 processes of IUI care. RESULTS: A total of 558 couples who started 2,334 IUI cycles participated. Guideline adherence in IUI care was often substandard and varied considerably between hospitals. Variation in guideline adherence in IUI care was associated with the patient characteristics 'diagnosis' and 'female age'. Only adherence to the guideline recommendation regarding 'screening for tubal occlusion' was associated with hospital characteristics ('hospital size' and 'IVF licence'). Large explained variances up to 39% were found for the different models. CONCLUSIONS: A number of patient and hospital characteristics were associated with variation in guideline adherence in IUI care, particularly the patient characteristics 'diagnosis' and 'female age'. The identification of different subgroups in the patient population and different types of hospitals with regard to the extent of guideline adherence in IUI care is important for the tailoring of interventions to improve IUI care. PMID- 21676962 TI - Three-dimensional simultaneous strain-volume analysis describes left ventricular remodelling and its progression: a pilot study. AB - AIMS: Three-dimensional (3D)-echocardiography speckle imaging allows the evaluation of frame-by-frame strain and volume changes simultaneously. The aim of the present investigation was to describe the strain-volume combined assessment in different patterns of cardiac remodelling. METHODS AND RESULTS: Fifty patients received a 3D acquisition. Patients were classified as follows: healthy subjects (CNT), previous AMI, and normal ejection fraction (EF; group A); ischaemic cardiomyopathy with reduced EF (group B); hypertrophic/infiltrative cardiomyopathy (group C). Values of 3D strain were plotted vs. volume for each frame to build a strain-volume curve for each case. Peak of radial, longitudinal, and circumferential systolic strain (Repsilonp, Lepsilonp, and Cepsilonp, respectively), slopes of the curves (RepsilonSl, LepsilonSl, CepsilonSl), and strain to end-diastolic volume (EDV) ratio (Repsilon/V, Lepsilon/V, Cepsilon/V) were computed for the analysis. Strain-volume curves of the CNT group were steep and clustered, whereas, due to progressive dilatation and reduction of strains, progressive flattening could be demonstrated in groups A and B. Quantitative data supported visual assessment with progressive lower slopes (P< 0.05 for RepsilonSl, CepsilonSl, P= 0.06 for LepsilonSl) and significantly lower ratios (P< 0.01 for Repsilon/V, Lepsilon/V, and Cepsilon/V). Group C showed an opposite behaviour with slopes and ratios close to those of normal subjects. Correlation coefficients between EDV and slopes of the curves were significant for all the directions of strain (CepsilonSl: r = 0.891; ReSl: r = 0.704; LeSl: r = 0.833; P< 0.0001 for all). CONCLUSION: We measured left ventricular volumes and strain by 3D-echo and obtained strain-volume curve to evaluate their behaviour in remodelling. A distinctive and progressive pattern consistent with pathophysiology was observed. The analysis here shown could represent a new non invasive method to assess myocardial mechanics and its relationship with volumes. PMID- 21676963 TI - Subclinical left ventricular dysfunction in Behcet's disease assessed by two dimensional speckle tracking echocardiography. AB - AIMS: The aim of this study was to evaluate the left ventricular (LV) systolic strain by speckle tracking echocardiography (STE) in order to provide the early detection of myocardial dysfunction in patients with Behcet's disease (BD). We also aimed to examine the relationship between LV systolic strain and N-terminal pro-B type natriuretic peptide (NT-proBNP), which is a cardiac biomarker of ventricular dysfunction. METHODS AND RESULTS: Longitudinal and circumferential systolic strain assessed by STE was obtained in 32 BD patients and 27 age-matched controls. NT-proBNP levels were also measured in all subjects. Regional and mean longitudinal strain (-17.8 +/- 2.7 vs. -20.5 +/- 1.8%; P < 0.0001) was significantly lower in BD patients when compared with the healthy controls. Whereas regional and mean circumferential strain values (-22.0 +/- 1.6 vs. -22.2 +/- 2.3%; P = 0.62) did not reveal a significant difference between the patients and the controls. NT-proBNP was significantly higher in the patients than in the controls (65.18 +/- 84.51 vs. 30.84 +/- 14.75 pg/mL; P = 0.003). Linear regression analyses revealed only NT-proBNP as the independent correlate of mean LV longitudinal strain (R = 0.603, P = 0.001). CONCLUSION: Longitudinal myocardial systolic function assessed by STE, which is a sensitive marker of subclinical ventricular dysfunction is impaired in BD. Increased NT-proBNP levels may be a sign of subclinical ventricular dysfunction in these patients. PMID- 21676964 TI - Prevalence and risk distribution of residual dyslipidemia in statin-treated patients in Greece. AB - Many statin-treated patients are not achieving treatment goals and are at risk of cardiovascular (CV) disease. We report the results of patients enrolled in an observational study in Greece, which estimated the residual lipid abnormalities in statin-treated patients. Low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), and triglyceride concentrations were recorded in patients receiving statin therapy for >= 3 months, classified by CV risk according to European Society of Cardiology guidelines. Sixty-three percent of statin-treated patients had an LDL-c not at goal. Low-risk patients were more likely to have an LDL-c not at goal compared with high-risk patients (67.3% vs 61.0%, respectively). They were also less likely to have low HDL-c levels and elevated triglyceride levels compared with high-risk patients. Smoking and sedentary lifestyle were not associated with dyslipidemia in this population. Approximately two thirds of statin-treated patients in Greece are not reaching target/normal lipid levels and could benefit from improved lipid management. PMID- 21676965 TI - C-reactive protein predicts the severity of coronary artery disease beyond low density lipoprotein cholesterol. AB - Prospective studies and clinical trials have shown that C-reactive protein (CRP) independently predicts the occurrence of cardiovascular events, even in individuals without hypercholesterolemia. We evaluated whether CRP can predict the severity of coronary artery stenosis in patients with lower low-density lipoprotein cholesterol (LDL-C) levels. A total of 418 patients with lower LDL-C (<3.37 mmol/L) who underwent coronary angiography were recruited. The median levels of CRP increased according to the number of stenotic vessels. Multivariable adjustment model indicated that CRP was associated with the severity of coronary artery disease (CAD) in the top to the bottom third comparison of CRP levels, yielding an odds ratio of 1.72 (95% confidence interval: 1.08-2.74); this trend was preserved after excluding the confounding effect of statin treatment. C-reactive protein may serve as a useful biomarker for improving the risk assessment and secondary prevention of CAD patients without hypercholesterolemia. PMID- 21676966 TI - Ankle-brachial index as an indicator of arterial stiffness in patients without peripheral artery disease. AB - We tested the hypothesis that the Ankle-Brachial Index (ABI) in patients without peripheral arterial disease ([PAD] ABI > 1.0) is an indicator of arterial stiffness. Fifty-five patients had measurement of carotid pulse wave contour, pulse wave velocity (PWV), and ABI. Vascular stiffness as assessed by augmentation index (AIx) showed a significant (P = .002) inverse correlation with ABI. Dichotomizing ABI into groups above and below the median showed that persons with a lower ABI, >1.0 to 1.5 (n = 27) had a significantly (P < .01) higher AIx than those with a higher ABI > 1.5 (n = 28). In contrast, vascular stiffness assessed by brachial-ankle or carotid femoral PWV did not correlate with ABI. In summary, ABI is an indicator of arterial stiffness assessed by AIx. Vascular changes detected by AIx are not the same as those detected by PWV. Assessment of ABI may have utility in cardiovascular risk assessment in patients without PAD. PMID- 21676967 TI - A composite computational model of liver glucose homeostasis. I. Building the composite model. AB - A computational model of the glucagon/insulin-driven liver glucohomeostasis function, focusing on the buffering of glucose into glycogen, has been developed. The model exemplifies an 'engineering' approach to modelling in systems biology, and was produced by linking together seven component models of separate aspects of the physiology. The component models use a variety of modelling paradigms and degrees of simplification. Model parameters were determined by an iterative hybrid of fitting to high-scale physiological data, and determination from small scale in vitro experiments or molecular biological techniques. The component models were not originally designed for inclusion within such a composite model, but were integrated, with modification, using our published modelling software and computational frameworks. This approach facilitates the development of large and complex composite models, although, inevitably, some compromises must be made when composing the individual models. Composite models of this form have not previously been demonstrated. PMID- 21676968 TI - Decoding GnRH neurohormone pulse frequency by convergent signalling modules. AB - Gonadotropin-releasing hormone (GnRH) mediates control of reproduction. It is secreted in pulses and acts via intracellular effectors to activate gonadotrophin secretion and gene expression. Sub-maximal GnRH pulse frequency can elicit maximal responses, yielding bell-shaped frequency-response curves characteristic of genuine frequency decoders. GnRH frequency decoding is therapeutically important (pulsatile GnRH can drive ovulation in assisted reproduction whereas sustained activation can treat breast and prostate cancers), but the mechanisms are unknown. Here, we consider the possibility that it is due to convergence of distinct pulsatile signals at the transcriptome. We develop a model that mirrors wet-laboratory data for activation and nuclear translocation of GnRH effectors (extracellular signal regulated kinase and nuclear factors of activated T-cells) and incorporates transcription. The model predicts genuine frequency decoding when two transcription factors (TFs) converge at a cooperative gate, and shows how optimal pulse frequency could reflect TF activation kinetics and affinities. Importantly, this behaviour is revealed as an emergent feature of the network, rather than an intrinsic feature of a given protein or pathway, and since such network topology is extremely common, may well be widespread in biological systems. PMID- 21676969 TI - In situ chemichromic studies of interactions between a lutetium bis-octaalkyl substituted phthalocyanine and selected biological cofactors. AB - Spin-coated films, approximately 100 nm thick, of a newly synthesized bis[octakis(octyl)phthalocyaninato] lutetium(III) complex on ultrasonically cleaned glass substrates exhibit pronounced chemichromic behaviour with potential application in healthcare. In situ kinetic optical absorption spectroscopic measurements show that the phthalocyanine Q-band is red shifted by 60 nm upon oxidation arising from exposure to bromine vapour. Recovery to the original state is achieved by the treatment of the oxidized films with nicotinamide adenine dinucleotide and l-ascorbic acid (vitamin C) in an aqueous solution containing 1.5 M lithium perchlorate. The neutralization process is found to be governed by first-order kinetics. The linear increase of the reduction rate with increasing concentration of cofactors provides a basis for calibration of analyte concentrations ranging from 3.5 mM down to 0.03 mM. PMID- 21676970 TI - Intraspecific scaling laws of vascular trees. AB - A fundamental physics-based derivation of intraspecific scaling laws of vascular trees has not been previously realized. Here, we provide such a theoretical derivation for the volume-diameter and flow-length scaling laws of intraspecific vascular trees. In conjunction with the minimum energy hypothesis, this formulation also results in diameter-length, flow-diameter and flow-volume scaling laws. The intraspecific scaling predicts the volume-diameter power relation with a theoretical exponent of 3, which is validated by the experimental measurements for the three major coronary arterial trees in swine (where a least squares fit of these measurements has exponents of 2.96, 3 and 2.98 for the left anterior descending artery, left circumflex artery and right coronary artery trees, respectively). This scaling law as well as others agrees very well with the measured morphometric data of vascular trees in various other organs and species. This study is fundamental to the understanding of morphological and haemodynamic features in a biological vascular tree and has implications for vascular disease. PMID- 21676971 TI - Vortex wake, downwash distribution, aerodynamic performance and wingbeat kinematics in slow-flying pied flycatchers. AB - Many small passerines regularly fly slowly when catching prey, flying in cluttered environments or landing on a perch or nest. While flying slowly, passerines generate most of the flight forces during the downstroke, and have a 'feathered upstroke' during which they make their wing inactive by retracting it close to the body and by spreading the primary wing feathers. How this flight mode relates aerodynamically to the cruising flight and so-called 'normal hovering' as used in hummingbirds is not yet known. Here, we present time resolved fluid dynamics data in combination with wingbeat kinematics data for three pied flycatchers flying across a range of speeds from near hovering to their calculated minimum power speed. Flycatchers are adapted to low speed flight, which they habitually use when catching insects on the wing. From the wake dynamics data, we constructed average wingbeat wakes and determined the time resolved flight forces, the time-resolved downwash distributions and the resulting lift-to-drag ratios, span efficiencies and flap efficiencies. During the downstroke, slow-flying flycatchers generate a single-vortex loop wake, which is much more similar to that generated by birds at cruising flight speeds than it is to the double loop vortex wake in hovering hummingbirds. This wake structure results in a relatively high downwash behind the body, which can be explained by the relatively active tail in flycatchers. As a result of this, slow-flying flycatchers have a span efficiency which is similar to that of the birds in cruising flight and which can be assumed to be higher than in hovering hummingbirds. During the upstroke, the wings of slowly flying flycatchers generated no significant forces, but the body-tail configuration added 23 per cent to weight support. This is strikingly similar to the 25 per cent weight support generated by the wing upstroke in hovering hummingbirds. Thus, for slow flying passerines, the upstroke cannot be regarded as inactive, and the tail may be of importance for flight efficiency and possibly manoeuvrability. PMID- 21676972 TI - Transcriptome analysis of sarracenia, an insectivorous plant. AB - Sarracenia species (pitcher plants) are carnivorous plants which obtain a portion of their nutrients from insects captured in the pitchers. To investigate these plants, we sequenced the transcriptome of two species, Sarracenia psittacina and Sarracenia purpurea, using Roche 454 pyrosequencing technology. We obtained 46 275 and 36 681 contigs by de novo assembly methods for S. psittacina and S. purpurea, respectively, and further identified 16 163 orthologous contigs between them. Estimation of synonymous substitution rates between orthologous and paralogous contigs indicates the events of genome duplication and speciation within the Sarracenia genus both occurred ~2 million years ago. The ratios of synonymous and non-synonymous substitution rates indicated that 491 contigs have been under positive selection (K(a)/K(s) > 1). Significant proportions of these contigs were involved in functions related to binding activity. We also found that the greatest sequence similarity for both of these species was to Vitis vinifera, which is most consistent with a non-current classification of the order Ericales as an asterid. This study has provided new insights into pitcher plants and will contribute greatly to future research on this genus and its distinctive ecological adaptations. PMID- 21676973 TI - Strong influence of regional species pools on continent-wide structuring of local communities. AB - There is a long tradition in ecology of evaluating the relative contribution of the regional species pool and local interactions on the structure of local communities. Similarly, a growing number of studies assess the phylogenetic structure of communities, relative to that in the regional species pool, to examine the interplay between broad-scale evolutionary and fine-scale ecological processes. Finally, a renewed interest in the influence of species source pools on communities has shown that the definition of the source pool influences interpretations of patterns of community structure. We use a continent-wide dataset of local ant communities and implement ecologically explicit source pool definitions to examine the relative importance of regional species pools and local interactions for shaping community structure. Then we assess which factors underlie systematic variation in the structure of communities along climatic gradients. We find that the average phylogenetic relatedness of species in ant communities decreases from tropical to temperate regions, but the strength of this relationship depends on the level of ecological realism in the definition of source pools. We conclude that the evolution of climatic niches influences the phylogenetic structure of regional source pools and that the influence of regional source pools on local community structure is strong. PMID- 21676974 TI - A stem-deuterostome origin of the vertebrate pharyngeal transcriptional network. AB - Hemichordate worms possess ciliated gills on their trunk, and the homology of these structures with the pharyngeal gill slits of chordates has long been a topic of debate in the fields of evolutionary biology and comparative anatomy. Here, we show conservation of transcription factor expression between the developing pharyngeal gill pores of the hemichordate Saccoglossus kowalevskii and the pharyngeal gill slit precursors (i.e. pharyngeal endodermal outpockets) of vertebrates. Transcription factors that are expressed in the pharyngeal endoderm, ectoderm and mesenchyme of vertebrates are expressed exclusively in the pharyngeal endoderm of S. kowalevskii. The pharyngeal arches and tongue bars of S. kowalevskii lack Tbx1-expressing mesoderm, and are supported solely by an acellular collagenous endoskeleton and by compartments of the trunk coelom. Our findings suggest that hemichordate and vertebrate gills are homologous as simple endodermal outpockets from the foregut, and that much vertebrate pharyngeal complexity arose coincident with the incorporation of cranial paraxial mesoderm and neural crest-derived mesenchyme within pharyngeal arches along the chordate and vertebrate stems, respectively. PMID- 21676975 TI - Return to Beringia: parasites reveal cryptic biogeographic history of North American pikas. AB - Traditional concepts of the Bering Land Bridge as a zone of predominantly eastward expansion from Eurasia and a staging area for subsequent colonization of lower latitudes in North America led to early inferences regarding biogeographic histories of North American faunas, many of which remain untested. Here we apply a host-parasite comparative phylogeographical (HPCP) approach to evaluate one such history, by testing competing biogeographic hypotheses for five lineages of host-specific parasites shared by the collared pika (Ochotona collaris) and American pika (Ochotona princeps) of North America. We determine whether the southern host species (O. princeps) was descended from a northern ancestor or vice versa. Three parasite phylogenies revealed patterns consistent with the hypothesis of a southern origin, which is corroborated by four additional parasite lineages restricted to O. princeps. This finding reverses the traditional narrative for the origins of North American pikas and highlights the role of dispersal from temperate North America into Beringia in structuring northern diversity considerably prior to the Holocene. By evaluating multiple parasite lineages simultaneously, the study demonstrates the power of HPCP for resolving complex biogeographic histories that are not revealed by characteristics of the host alone. PMID- 21676976 TI - Evolution of a mimicry supergene from a multilocus architecture. AB - The origin and evolution of supergenes have long fascinated evolutionary biologists. In the polymorphic butterfly Heliconius numata, a supergene controls the switch between multiple different forms, and results in near-perfect mimicry of model species. Here, we use a morphometric analysis to quantify the variation in wing pattern observed in two broods of H. numata with different alleles at the supergene locus, 'P'. Further, we genotype the broods to associate the variation we capture with genetic differences. This allows us to begin mapping the quantitative trait loci that have minor effects on wing pattern. In addition to finding loci on novel chromosomes, our data, to our knowledge, suggest for the first time that ancestral colour-pattern loci, known to have major effects in closely related species, may contribute to the wing patterns displayed by H. numata, despite the large transfer of effects to the supergene. PMID- 21676977 TI - The role of developmental plasticity in evolutionary innovation. AB - Explaining the origins of novel traits is central to evolutionary biology. Longstanding theory suggests that developmental plasticity, the ability of an individual to modify its development in response to environmental conditions, might facilitate the evolution of novel traits. Yet whether and how such developmental flexibility promotes innovations that persist over evolutionary time remains unclear. Here, we examine three distinct ways by which developmental plasticity can promote evolutionary innovation. First, we show how the process of genetic accommodation provides a feasible and possibly common avenue by which environmentally induced phenotypes can become subject to heritable modification. Second, we posit that the developmental underpinnings of plasticity increase the degrees of freedom by which environmental and genetic factors influence ontogeny, thereby diversifying targets for evolutionary processes to act on and increasing opportunities for the construction of novel, functional and potentially adaptive phenotypes. Finally, we examine the developmental genetic architectures of environment-dependent trait expression, and highlight their specific implications for the evolutionary origin of novel traits. We critically review the empirical evidence supporting each of these processes, and propose future experiments and tests that would further illuminate the interplay between environmental factors, condition-dependent development, and the initiation and elaboration of novel phenotypes. PMID- 21676978 TI - A combination of hydrodynamical and statistical modelling reveals non-stationary climate effects on fish larvae distributions. AB - Biological processes and physical oceanography are often integrated in numerical modelling of marine fish larvae, but rarely in statistical analyses of spatio temporal observation data. Here, we examine the relative contribution of inter annual variability in spawner distribution, advection by ocean currents, hydrography and climate in modifying observed distribution patterns of cod larvae in the Lofoten-Barents Sea. By integrating predictions from a particle-tracking model into a spatially explicit statistical analysis, the effects of advection and the timing and locations of spawning are accounted for. The analysis also includes other environmental factors: temperature, salinity, a convergence index and a climate threshold determined by the North Atlantic Oscillation (NAO). We found that the spatial pattern of larvae changed over the two climate periods, being more upstream in low NAO years. We also demonstrate that spawning distribution and ocean circulation are the main factors shaping this distribution, while temperature effects are different between climate periods, probably due to a different spatial overlap of the fish larvae and their prey, and the consequent effect on the spatial pattern of larval survival. Our new methodological approach combines numerical and statistical modelling to draw robust inferences from observed distributions and will be of general interest for studies of many marine fish species. PMID- 21676979 TI - Drastic historic shifts in bumble-bee community composition in Sweden. AB - The species richness of flower-visiting insects has declined in past decades, raising concerns that the ecosystem service they provide by pollinating crops and wild plants is threatened. The relative commonness of different species with shared ecological traits can play a pervasive role in determining ecosystem functioning, but information on changes in abundances of pollinators over time is lacking. We gathered data on relative abundances of bumble-bee species in Swedish red clover fields during three periods in the last 70 years (1940s, 1960s and present), and on clover seed yields since 1921. We found drastic decreases in bumble-bee community evenness, with potential consequences for level and stability of red clover seed yield. The relative abundances of two short-tongued bumble-bees have increased from 40 per cent in the 1940s to entirely dominate present communities with 89 per cent. Average seed yield declined in recent years and variation in yield doubled, suggesting that the current dependence on few species for pollination has been especially detrimental to stability in seed yield. Our results suggest a need to develop management schemes that promote not only species-rich but also more evenly composed communities of service-providing organisms. PMID- 21676980 TI - Male cleaner wrasses adjust punishment of female partners according to the stakes. AB - Punishment is an important deterrent against cheating in cooperative interactions. In humans, the severity of cheating affects the strength of punishment which, in turn, affects the punished individual's future behaviour. Here, we show such flexible adjustments for the first time in a non-human species, the cleaner wrasse (Labroides dimidiatus), where males are known to punish female partners. We exposed pairs of cleaners to a model client offering two types of food, preferred 'prawn' items and less-preferred 'flake' items. Analogous to interactions with real clients, eating a preferred prawn item ('cheating') led to model client removal. We varied the extent to which female cheating caused pay-off reduction to the male and measured the corresponding severity of male punishment. Males punished females more severely when females cheated during interactions with high value, rather than low value, model clients; and when females were similar in size to the male. This pattern may arise because, in this protogynous hermaphrodite, cheating by similar-sized females may reduce size differences to the extent that females change sex and become reproductive competitors. In response to more severe punishment from males, females behaved more cooperatively. Our results show that punishment can be adjusted to circumstances and that such subtleties can have an important bearing on the outcome of cooperative interactions. PMID- 21676981 TI - Blindness following visceral leishmaniasis: a neglected post-kala-azar complication. AB - Visceral leishmaniasis (VL) is an important cause of morbidity and mortality that affects multiple organs. Post-kala-azar ocular involvement is a serious complication that can manifest as blepharo-conjuctivitis or pan-uveitis. Failure of prompt diagnosis and treatment can result in blindness. We report five cases with pan-uveitis that followed the successful treatment of VL and consequent post kala-azar dermal leishmaniasis were presented. Two patients lost their sight permanently but the rest were successfully treated. A high index of suspicion and prompt treatment are of paramount importance in order to avoid blindness following post-kala-azar ocular uveitis. PMID- 21676982 TI - Benign tertian malaria--a misnomer? AB - Plasmodium vivax usually causes an acute self-limiting febrile illness with fever spikes on every third day and no complications or death. Therefore the illness caused by this parasite was termed benign tertian malaria. However, many complications associated with Plasmodium falciparum have been seen with increasing frequency with Plasmodium vivax in recent times. The present study highlights the various complications associated with Plasmodium vivax malaria. PMID- 21676983 TI - Co-infection with hepatitis viruses among HIV-infected individuals at a tertiary care centre in South India. AB - We studied the occurrence of hepatitis B (HBV) and hepatitis C (HCV) virus co infections in human immunodeficiency virus (HIV)-infected individuals in a tertiary care centre. The occurrence of co-infections in our study was less than in the literature reported from the West. However, routine screening of these co infections in HIV patients is recommended to avoid possible liver-related morbidity and mortality as a part of improving their quality of life. PMID- 21676984 TI - Intimate partner violence against deaf female college students. AB - It has been estimated that roughly 25% of all Deaf women in the United States are victims of intimate partner violence (Abused Deaf Women's Advocacy Services [ADWAS]), a figure similar to annual prevalence rates of 16% to 30% for intimate partners in the general population. One goal of the present study was to ascertain the prevalence of intimate partner violence victimization in a sample of Deaf female college students. When comparing the prevalence of physical assault, psychological aggression, and sexual coercion victimization to hearing female undergraduates, the current sample was approximately two times as likely to have experienced victimization in the past year. PMID- 21676985 TI - The pattern of antimicrobial use for palliative care in-patients during the last week of life. AB - BACKGROUND: In terminally ill cancer patients approaching the dying phase, liberal use of antimicrobials is often viewed by palliative care experts as irrational. No previous reports have reviewed current antimicrobial use in palliative care settings in Saudi Arabia. OBJECTIVE: The objective of this study was to explore the pattern of antimicrobial use in a tertiary palliative care unit (TPCU) during the last week of patients' life. METHODS: Medical records of all patients who died in the TPCU over a 14-month period were reviewed for demographics as well as the frequency and rationale of antimicrobial use during the patients' last week of life. Information on antimicrobial use was obtained from a computerized pharmacy database. RESULTS: Of 138 patients who died with advanced cancer in the TPCU, 87 (63%) were on one or more antimicrobials during their last week of life. Antibiotics were more frequently used as compared to antifungal and antiviral agents, 64 (46.4%); 45 (32.6%); and 2 (1.5%), respectively. About one third (31.3%) of patients who received antibiotics during their last week of life were prescribed more than one antibiotic. Antimicrobials were mostly given systemically (79%) rather than topically (21%). The most common rationales for antimicrobial prescribing were oral thrush in 36 patients (25.4%), wound care in 29 patients (20.4%), and on empirical basis in 29 patients (20.4%). CONCLUSIONS: The current practice of antimicrobial prescribing, especially for patients who are eminently dying, may need to be reviewed. Initiation of antimicrobial treatment in this group of patients should be based on clear treatment goals and desired outcomes, considering views of patients and families. PMID- 21676986 TI - Surveillance programme for important equine infectious respiratory pathogens in the USA. AB - The prevalence and epidemiology of important viral (equine influenza virus [EIV], equine herpesvirus type 1 [EHV-1] and EHV-4) and bacterial (Streptococcus equi subspecies equi) respiratory pathogens shed by horses presented to equine veterinarians with upper respiratory tract signs and/or acute febrile neurological disease were studied. Veterinarians from throughout the USA were enrolled in a surveillance programme and were asked to collect blood and nasal secretions from equine cases with acute infectious upper respiratory tract disease and/or acute onset of neurological disease. A questionnaire was used to collect information pertaining to each case and its clinical signs. Samples were tested by real-time PCR for the presence of EHV-1, EHV-4, EIV and S equi subspecies equi. A total of 761 horses, mules and donkeys were enrolled in the surveillance programme over a 24-month study period. In total, 201 (26.4 per cent) index cases tested PCR-positive for one or more of the four pathogens. The highest detection rate was for EHV-4 (82 cases), followed by EIV (60 cases), S equi subspecies equi (49 cases) and EHV-1 (23 cases). There were 15 horses with double infections and one horse with a triple infection. The detection rate by PCR for the different pathogens varied with season and with the age, breed, sex and use of the animal. PMID- 21676987 TI - Infection with Brucella ceti and high levels of polychlorinated biphenyls in bottlenose dolphins (Tursiops truncatus) stranded in south-west England. AB - Eight bottlenose dolphins (Tursiops truncatus) that stranded in Cornwall, south west England, between June 2004 and December 2007 were examined using standardised postmortem examination and bacteriological methods. Evidence of Brucella species infection was found in four of these dolphins on culture. In addition, of the eight dolphins, four were positive and two were weakly positive for antibodies to Brucella species on serological analyses of pericardial and other fluids using a competitive ELISA and two indirect ELISAs. High or very high levels of the sum of 25 individual chlorobiphenyl congeners (?25CBs) were also determined in blubber samples from two of the dolphins (45.5 and 446.6 mg/kg lipid weight). PMID- 21676988 TI - Renal calculi in wild Eurasian otters (Lutra lutra) in England. AB - Macroscopic renal calculi were seen in 50 of 492 (10.2 per cent) wild Eurasian otters found dead in England from 1988 to 2007. Forty-eight adults and two subadults were affected. Calculi were present in 15.7 per cent (31 of 197) of adult males and 12.7 per cent (17 of 134) of adult females. There was an increase in prevalence in the study population over time; no calculi were found in 73 otters examined between 1988 and 1996, but in most subsequent years they were observed with increased frequency. Calculi occurred in both kidneys but were more common in the right kidney. They varied greatly in shape and size; larger calculi were mostly seen in the calyces while the smallest ones were commonly found in the renal medulla. Calculi from 45 cases were examined by x-ray diffraction analysis; in 43 (96 per cent), they were composed solely of ammonium acid urate. Affected otters had heavier adrenal glands relative to their body size than unaffected otters (P<0.001). There was no significant association between body condition index and the presence of calculi (P>0.05). Many otters had fresh bite wounds consistent with intraspecific aggression. The proportion bitten increased over time and this coincided with the increased prevalence of renal calculi. PMID- 21676989 TI - Comparative study of experienced and anticipated stigma in Serbia and the world. AB - AIM: The presented study is part of the International Study of Discrimination and Stigma Outcomes (INDIGO) conducted in 28 countries. The aim of this study was to compare the degree of experienced and anticipated stigma of patients with schizophrenia in Serbia with world results. METHOD: The Discrimination and Stigma Scale (DISC) was applied in individual interviews. The sample comprised 732 subjects of the main study and 50 subjects from Serbia. RESULTS: The amount of negative experienced discrimination in Serbia is the same as in other participating countries. The Serbian sample shows more negative discrimination in intimate relationships, personal safety and general harm due to the diagnosis, but more positive discrimination within the family, privileges during treatment of somatic illnesses, and benefits enjoyed in social and retirement insurance. The Serbian sample shows less anticipated discrimination in looking for a close relationship and in stopping self from applying for work. The results show that socio-demographic variables could not predict negative experienced and anticipated discrimination, while those same variables enable the prediction of 34% of positive discrimination. CONCLUSION: Compared to other investigated countries, stigmatization processes for persons with schizophrenia do not differ considerably in Serbia, which justifies the implementation of unique anti-stigma programmes and joint upgrading of legal regulations. PMID- 21676990 TI - Cognitive-behavioral therapy for depression in Parkinson's disease: a randomized, controlled trial. AB - OBJECTIVE: Despite the negative effects of depression in Parkinson's disease, there is currently no evidence-based standard of care. The purpose of this study was to examine the efficacy of individually administered cognitive-behavioral therapy (CBT), relative to clinical monitoring (with no new treatment), for depression in this medical population. METHOD: Eighty depressed (based on DSM-IV criteria) patients with Parkinson's disease participated in a randomized, controlled trial of CBT relative to clinical monitoring (1:1 ratio) in an academic medical center from April 2007 to July 2010. All patients continued to maintain stable medication regimens under the care of their personal physicians. The 17-item Hamilton Depression Rating Scale (HAM-D) total score was the primary outcome. CBT was modified to meet the unique needs of the Parkinson's disease population and provided for 10 weeks. Assessments were completed by blind raters at baseline and 5 (midpoint), 10 (end of treatment), and 14 weeks (follow-up evaluation) postrandomization. RESULTS: The CBT group reported greater reductions in depression (change in HAM-D score) than the clinical monitoring group. At week 10, the mean HAM-D score change was 7.35 for CBT relative to 0.05 for clinical monitoring. CBT was also superior to clinical monitoring on several secondary outcomes (i.e., Beck Depression Inventory scores, anxiety, quality of life, coping, Parkinson's disease symptom ratings). There were more treatment responders in the CBT group than the clinical monitoring group (56% versus 8%, respectively). CONCLUSIONS: CBT may be a viable approach for the treatment of depression in Parkinson's disease. Further research is needed to replicate and extend these findings. PMID- 21676991 TI - An FMRI study of self-regulatory control and conflict resolution in adolescents with bulimia nervosa. AB - OBJECTIVE: The authors examined functional activity in the frontostriatal systems that mediate self-regulatory capacities and conflict resolution in adolescents with bulimia nervosa. METHOD: Functional magnetic resonance imaging was used to compare blood-oxygen-level-dependent response in 18 female adolescents with bulimia nervosa and 18 healthy female age-matched subjects during performance on a Simon spatial incompatibility task. Bayesian analyses were used to compare the two groups on patterns of brain activation during correct responses to conflict stimuli and to explore the effects of antecedent stimulus context on group differences in self-regulation and conflict resolution. RESULTS: Adolescents with and without bulimia nervosa performed similarly on the task. During correct responses in conflict trials, frontostriatal circuits-including the right inferolateral and dorsolateral prefrontal cortices and putamen-failed to activate to the same degree in adolescents with bulimia nervosa as in healthy comparison subjects. Instead, deactivation was seen in the left inferior frontal gyrus as well as a neural system encompassing the posterior cingulate cortex and superior frontal gyrus. Group differences in cortical and striatal regions were driven by the differential responses to stimuli preceded by conflict and nonconflict stimuli, respectively. CONCLUSIONS: When engaging the self-regulatory control processes necessary to resolve conflict, adolescents with bulimia nervosa displayed abnormal patterns of activation in frontostriatal and default-mode systems. Their abnormal processing of the antecedent stimulus context conditioned their brain response to conflict differently from that of healthy comparison subjects, specifically in frontal regions. It is suspected that functional disturbances in frontal portions of frontostriatal systems may release feeding behaviors from regulatory control, thereby perpetuating the conflicting desires to consume fattening foods and avoid weight gain that characterize bulimia nervosa. PMID- 21676992 TI - Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo and olanzapine-controlled study. AB - OBJECTIVE: The study was designed to evaluate the short-term efficacy and safety of lurasidone in the treatment of acute schizophrenia. METHOD: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of double-blind treatment with 40 mg of lurasidone, 120 mg of lurasidone, 15 mg of olanzapine (included to test for assay sensitivity), or placebo, dosed once daily. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (as the primary efficacy measure) and Clinical Global Impressions severity (CGI S) score (as the key secondary efficacy measure). RESULTS: Treatment with both doses of lurasidone or with olanzapine was associated with significantly greater improvement at week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. There was no statistically significant difference in mean PANSS total or CGI-S change scores for the lurasidone groups compared with the olanzapine group. With responders defined as those with an improvement of at least 20% on the PANSS, endpoint responder rates were significant compared with placebo for olanzapine only. The incidence of akathisia was higher with 120 mg of lurasidone (22.9%) than with 40 mg of lurasidone (11.8%), olanzapine (7.4%), or placebo (0.9%). The proportion of patients experiencing >= 7% weight gain was 5.9% for the lurasidone groups combined, 34.4% for the olanzapine group, and 7.0% for the placebo group. CONCLUSIONS: Lurasidone was an effective treatment for patients with acute schizophrenia. Safety assessments indicated a higher frequency of adverse events associated with 120 mg/day of lurasidone compared with 40 mg/day. PMID- 21676993 TI - Budget impact and sustainability of medical care management for persons with serious mental illnesses. AB - OBJECTIVE: The authors assessed the 2-year outcomes, costs, and financial sustainability of a medical care management intervention for community mental health settings. METHOD: A total of 407 psychiatric outpatients with serious mental illnesses were randomly assigned to usual care or to a medical care manager who provided care coordination and education. Two-year follow-up chart reviews and interviews assessed quality and outcomes of care, as well as costs from both the health system and managerial perspectives. RESULTS: Sustained improvements were observed in the intervention group in quality of primary care preventive services, quality of cardiometabolic care, and mental health-related quality of life. From a health system perspective, by year 2, the mean per patient total costs for the intervention group were $932 (95% CI=-1,973 to 102) less than for the usual care group, with a 92.3% probability that the program was associated with lower costs than usual care. From the community mental health center perspective, the program would break even (i.e., revenues would cover setup costs) if 58% or more of clients had Medicaid or another form of insurance. Given that only 40.5% of clients in this study had Medicaid, the program was not sustainable after grant funding ended. CONCLUSIONS: The positive long-term outcomes and favorable cost profile provide evidence of the potential value of this model. However, the discrepancy between health system and managerial cost perspectives limited the program's financial sustainability. With anticipated insurance expansions under health reform, there is likely to be a stronger business case for safety net organizations considering implementing evidence based interventions such as the one examined in this study. PMID- 21676995 TI - Newly lesioned tissue in multiple sclerosis--a role for oxidative damage? PMID- 21676994 TI - Diagnostic shifts during the decade following first admission for psychosis. AB - OBJECTIVE: Diagnostic shifts have been prospectively examined in the short term, but the long-term stability of diagnoses has rarely been evaluated. The authors examined diagnostic shifts over a 10-year follow-up period. METHOD: A cohort of 470 first-admission patients with psychotic disorders was systematically assessed at baseline and at 6-month, 2-year, and 10-year follow-ups. Longitudinal best estimate consensus diagnoses were formulated after each assessment. RESULTS: At baseline, the diagnostic distribution was 29.6% schizophrenia spectrum disorders, 21.1% bipolar disorder with psychotic features, 17.0% major depression with psychotic features, 2.4% substance-induced psychosis, and 27.9% other psychoses. At year 10, the distribution changed to 49.8%, 24.0%, 11.1%, 7.0%, and 8.1%, respectively. Overall, diagnoses were changed for 50.7% of study participants at some point during the study. Most participants who were initially diagnosed with schizophrenia or bipolar disorder retained the diagnosis at year 10 (89.2% and 77.8%, respectively). However, 32.0% of participants (N=98) originally given a non-schizophrenia diagnosis had gradually shifted to a schizophrenia diagnosis by year 10. The second largest shift was to bipolar disorder (10.7% of those not given this diagnosis at baseline). Changes in the clinical picture explained many diagnostic shifts. In particular, poorer functioning and greater negative and psychotic symptom ratings predicted a subsequent shift to schizophrenia. Better functioning and lower negative and depressive symptom ratings predicted the shift to bipolar disorder. CONCLUSIONS: First-admission patients with psychotic disorders run the risk of being misclassified at early stages in the illness course, including more than 2 years after first hospitalization. Diagnosis should be reassessed at all follow-up points. PMID- 21676996 TI - The Danish religious societies health study. PMID- 21676998 TI - Development and validation of the coping with terror scale. AB - Terrorism creates lingering anxiety about future attacks. In prior terror research, the conceptualization and measurement of coping behaviors were constrained by the use of existing coping scales that index reactions to daily hassles and demands. The authors created and validated the Coping with Terror Scale to fill the measurement gap. The authors emphasized content validity, leveraging the knowledge of terror experts and groups of Israelis. A multistep approach involved construct definition and item generation, trimming and refining the measure, exploring the factor structure underlying item responses, and garnering evidence for reliability and validity. The final scale comprised six factors that were generally consistent with the authors' original construct specifications. Scores on items linked to these factors demonstrate good reliability and validity. Future studies using the Coping with Terror Scale with other populations facing terrorist threats are needed to test its ability to predict resilience, functional impairment, and psychological distress. PMID- 21676997 TI - A reverse transcriptase-related protein mediates phage resistance and polymerizes untemplated DNA in vitro. AB - Reverse transcriptases (RTs) are RNA-dependent DNA polymerases that usually function in the replication of selfish DNAs such as retrotransposons and retroviruses. Here, we have biochemically characterized a RT-related protein, AbiK, which is required for abortive phage infection in the Gram-positive bacterium Lactococcus lactis. In vitro, AbiK does not exhibit the properties expected for an RT, but polymerizes long DNAs of 'random' sequence, analogous to a terminal transferase. Moreover, the polymerized DNAs appear to be covalently attached to the AbiK protein, presumably because an amino acid serves as a primer. Mutagenesis experiments indicate that the polymerase activity resides in the RT motifs and is essential for phage resistance in vivo. These results establish a novel biochemical property and a non-replicative biological role for a polymerase. PMID- 21676999 TI - Sound fields in complex listening environments. AB - The conditions of sound fields used in research, especially testing and fitting of hearing aids, are usually simplified or reduced to fundamental physical fields, such as the free or the diffuse sound field. The concepts of such ideal conditions are easily introduced in theoretical and experimental investigations and in models for directional microphones, for example. When it comes to real world application of hearing aids, however, the field conditions are more complex with regard to specific stationary and transient properties in room transfer functions and the corresponding impulse responses and binaural parameters. Sound fields can be categorized in outdoor rural and urban and indoor environments. Furthermore, sound fields in closed spaces of various sizes and shapes and in situations of transport in vehicles, trains, and aircrafts are compared with regard to the binaural signals. In laboratory tests, sources of uncertainties are individual differences in binaural cues and too less controlled sound field conditions. Furthermore, laboratory sound fields do not cover the variety of complex sound environments. Spatial audio formats such as higher-order ambisonics are candidates for sound field references not only in room acoustics and audio engineering but also in audiology. PMID- 21677000 TI - The effect of osteoarthritis of the hip or knee on work participation. AB - In our systematic literature search, we included studies involving patients with hip or knee osteoarthritis (OA) and outcome measures of work participation. Methodological quality was assessed using 11 criteria; a qualitative data analysis was performed. Fifty-three full-text articles were selected out of 1861 abstracts; finally, data were extracted from 14 articles. Design, populations, definitions, and measurements in the studies showed large variations; work outcomes were often only secondary objectives. The outcomes were summarized as showing a mild negative effect of OA on work participation. Many patients had paid work and managed to stay at work despite limitations. However, research on the effect of OA on work participation is scarce and the methodological quality is often insufficient. The longitudinal course of work participation in individuals with OA has not been described completely. PMID- 21677001 TI - Raynaud's phenomenon in medical laboratory workers who work with solvents. AB - OBJECTIVE: To investigate whether there is an association between Raynaud's phenomenon (RP) and exposure to organic solvents in laboratory workers. METHODS: Technicians, scientists, and laboratory assistants working in histology, cytology, and transfusion medicine were surveyed about their use of solvents, particularly xylene and toluene, and about symptoms of RP. There were 341 responses. OR for having worked with solvents were calculated with logistic regression adjusted for age and sex. RESULTS: Laboratory workers who had worked with solvents had higher rates of severe RP, particularly those who had worked with xylene or toluene and either acetone (OR 8.8, 95% CI 1.9-41.1), or chlorinated solvents (OR 8.9, 95% CI 1.9-41.6), xylene or toluene and acetone compared to those who had worked with xylene or toluene but not acetone (OR 4.5, 95% CI 1.2-16.2), and similarly for chlorinated solvents (OR 4.5, 95% CI 1.2 16.3). RP symptoms occurring in the absence of cold exposure were more frequent for those who had worked with any solvent (OR 3.6, 95% CI 1.2-10.5) and just xylene or toluene (OR 2.8, 95% CI 1.1-7.3). Associations were also seen between increasing exposure to xylene or toluene and severe RP (OR 1.7, 95% CI 1.1-2.7, per 10 years) and with symptoms occurring in the absence of cold exposure (OR 1.7, 95% CI 1.2-2.5, per 10 years). CONCLUSION: We found that exposure to solvents may be associated with the development of RP, supporting previous work indicating that solvent exposure may be an etiological factor in systemic sclerosis. PMID- 21677002 TI - Care partnerships between family physicians and rheumatologists. AB - OBJECTIVE: To describe care partnerships between family physicians and rheumatologists. METHODS: A random sample (20%, n = 478) of family physicians was mailed a questionnaire, asking if there was at least 1 particular rheumatologist to whom the physician tended to refer patients. If the answer was affirmative, the physician would be considered as having a "care partnership" with that rheumatologist. The family physician then rated, on a 5-point scale, factors of importance regarding the relationship with that rheumatologist. RESULTS: The questionnaire was completed by 84/462 (18.2%) of family physicians; 52/84 (61.9%) reported having rheumatology care partnerships according to our definition. Regarding interactions with rheumatologists, most respondents rated the following as important (score >= 4): adequate communication and information exchange (44/50, 88.0%); waiting time for new patients (40/50, 80.0%); clear and appropriate balance of responsibilities (39/49, 79.6%); and patient feedback and preferences (34/50, 68%). Male family physicians were more likely than females to accord high importance to personal knowledge of the rheumatologist, and to physical proximity of the rheumatologist's practice. Regarding relationships with rheumatologists, 30/50 (60.0%) of respondents felt communication and information exchange were adequate, and 35/50 (70.0%) felt they had a clear balance of responsibilities. CONCLUSION: Almost two-thirds of family physicians have rheumatology care partnerships, according to our definition. In this partnership, establishing adequate communication and shorter waiting time seem of paramount importance to family physicians. A balanced sharing of responsibilities and patients' preferences are also valued. Although many physicians reported adequate communication and clear and appropriate balance of responsibilities in their current interactions with rheumatologists, there appears to be room for improvement. PMID- 21677003 TI - Safety and efficacy of rituximab in severe juvenile dermatomyositis: results from 9 patients from the French Autoimmunity and Rituximab registry. AB - OBJECTIVE: To evaluate the safety and efficacy of rituximab (RTX) in juvenile dermatomyositis (JDM) in off-trial patients. METHODS: We conducted a multicenter prospective study of patients with JDM included in the French Autoimmunity and Rituximab (AIR) registry. RESULTS: Nine patients with severe JDM were studied. The main indication for RTX treatment was severe and/or refractory muscle involvement (7 patients), severe calcinosis (1 patient), or severe chronic abdominal pain associated with abdominal lipomatosis (1 patient). RTX was associated with corticosteroids, immunosuppressive drugs, and plasma exchange therapy in 9/9, 5/9, and 2/9 patients, respectively. Mild infections of the calcinosis sites occurred in 2 patients and an infusion-related event in 1. Complete clinical response was achieved in 3/6 patients treated with RTX for muscle involvement. In these responders steroid therapy was stopped or tapered to < 15% of the baseline dosage, with no relapse, with a followup ranging from 1.3 to 3 years. Calcinosis did not improve in the 6 affected patients. CONCLUSION: This small series suggests that rituximab may be effective for treating muscle and skin involvement in a small subset of children with severe JDM, and that its safety profile was satisfactory. Further studies are needed to identify predictive factors of response to RTX in patients with severe JDM. PMID- 21677004 TI - Bone health in adult men and women with a history of juvenile idiopathic arthritis. AB - OBJECTIVE: Our aim was to determine areal bone mineral density (BMD(a)) and disease-related factors linked with BMD(a) in adults with a history of juvenile idiopathic arthritis (JIA). METHODS: Men and women with a history of JIA attending a young adult rheumatology clinic in Newcastle, UK, underwent dual energy x-ray absorptiometry (DEXA) of the lumbar spine and total hip. Information was obtained about disease duration and subtype, previous treatment including corticosteroid and methotrexate therapy, and large-joint replacement. Subjects completed the modified Health Assessment Questionnaire (HAQ). Blood was taken for assessment of C-reactive protein, erythrocyte sedimentation rate, and rheumatoid factor (RF). RESULTS: Seventy-one women and 16 men, mean age 28.7 and 31.4 years, and mean disease duration 20.6 and 24.0 years, respectively, were studied. Mean BMD(a) was 0.982 (Z-score = -0.328; 95% CI -0.657, 0.001) and 1.028 g/cm(2) (Z score = -0.251; 95% CI -1.266, 0.764) in women and men, respectively, at the spine and 0.817 (Z-score = -0.542; 95% CI -0.975, -0.109) and 0.857 g/cm(2) (Z score = -0.176; 95% CI -2.323, 1.971) at the hip. After adjusting for age and sex, increasing HAQ score was associated with both lower spine BMD(a) and hip BMD(a). Compared with patients with oligoarticular disease, those with enthesitis related arthritis had higher BMD(a) at the spine, while those with extended oligoarticular and polyarticular RF-negative disease had lower hip BMD(a). Oral corticosteroids and the presence of a large-joint replacement were associated with lower BMD(a) at both the spine and hip. CONCLUSION: There was a trend toward low BMD(a) in women with a history of JIA. These patients may be at risk of the complications of osteoporosis including fragility fractures and should be considered for targeted preventive measures. PMID- 21677006 TI - The truth hurts. PMID- 21677005 TI - Effect of the application of trial inclusion criteria on the efficacy of adalimumab therapy in a rheumatoid arthritis cohort. AB - OBJECTIVE: To evaluate the influence of inclusion criteria used in rheumatoid arthritis (RA) trials with adalimumab on clinical outcome and response. METHODS: The different inclusion criteria of published trials of adalimumab in RA were separately applied to a large prospective cohort of patients with RA treated with adalimumab (AdRA cohort), thereby mimicking patient selection for a clinical trial. Clinical response and outcome in the resulting 11 projection groups were compared using the 28-joint Disease Activity Score (DAS28) and time-averaged DAS28 as outcome measures of efficacy. RESULTS: Thirteen trials (n = 54-799) with 11 different sets of entry criteria were identified, resulting in 11 projection groups (n = 22-168). The DAS28 at baseline was similar in the original trial and each projection group based on this trial (5.1-6.4, total AdRA cohort 5.1). After 28 weeks, the efficacy varied substantially among the 11 projected groups (change from baseline DAS28: -1.65 to -2.65, time-averaged DAS28 3.67-4.53). Expressed as outcome (DAS28 at 28 weeks), the efficacy was much more similar for almost all projection groups (3.5-4.0) and thus appeared to be mostly independent of disease activity at baseline. CONCLUSION: We observed that different inclusion criteria for clinical trials can have a marked effect on the expected response, i.e., improvement from baseline. A novel finding is that final disease activity appeared much less dependent on initial disease activity. Our study suggests that for daily practice, one can assume that adalimumab treatment will on average result in a DAS28 between 3.5 and 4.0 after 28 weeks of treatment, regardless of baseline disease activity. PMID- 21677007 TI - Health experts brief US congressional staff members on ways to reduce chronic disease. PMID- 21677008 TI - Measles outbreak in Europe. PMID- 21677009 TI - South Sudan: a nation born in crisis. PMID- 21677010 TI - Undoing diagnoses. PMID- 21677011 TI - For-profit companies will strip NHS assets under proposed reforms. PMID- 21677012 TI - Defamation threat leaves people "terrified" to publish articles. PMID- 21677013 TI - Crouching tiger, hidden surgeon. PMID- 21677014 TI - The college of medicine. PMID- 21677015 TI - An early warning for Alzheimer's disease? PMID- 21677016 TI - Doctors involved at Winterbourne View hospital may face GMC hearing. PMID- 21677017 TI - Department of Health is not interested in improving quality, inquiry is told. PMID- 21677019 TI - Computed tomography through the aortic root. PMID- 21677018 TI - A woman with raised alkaline phosphatase and forearm deformity. PMID- 21677020 TI - 'That's part of everybody's job': the perspectives of health care staff in England and New Zealand on the meaning and remit of palliative care. AB - BACKGROUND: the right for patients of all diagnoses to be in receipt of palliative care from an early point in the diagnosis of a life-limiting condition is now enshrined in policy in a number of countries and increased emphasis is placed upon the role of generalist palliative care. However, little is known as to how this policy is enacted on the ground. AIM: to explore understandings of, and perceived roles in relation to, palliative care provision amongst generalist and specialist health care providers in England and New Zealand. DESIGN: qualitative data were collected via individual interviews and focus groups. SETTING/PARTICIPANTS: participants comprised generalist and specialist palliative care providers working in a variety of settings in England (n = 58) and New Zealand (n = 80). RESULTS: the following issues with significant implications for this new phase of development for palliative care were identified: (1) difficulties with terminology and perceived roles/responsibilities; (2) problems of integrating palliative care into a generalist workload; (3) challenges in generalist/specialist partnership working; and (4) the potential negative consequences of specialization. CONCLUSIONS: these data indicate that, within England and New Zealand, the policy rhetoric of universal palliative care provision is not being straightforwardly translated into service delivery and individual clinical practice. Further research is required to explore and evaluate different models of organization and service provision that empower 'generalists' to provide palliative care, without resulting in deskilling. Finally, definitional clarity at an academic/policy level is also needed. PMID- 21677021 TI - Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial. AB - BACKGROUND: Few high-quality trials have examined the effects of progressive resistance training (PRT) on people with multiple sclerosis (MS). OBJECTIVE: To determine the effectiveness of PRT for people with MS, focusing on improving the gait deficits common in this population. METHODS: Using a single blind randomized controlled trial, people with relapsing-remitting MS were randomly allocated to either a PRT program targeting the lower limb muscles twice a week for 10 weeks (n = 36), or usual care plus an attention and social program conducted once a week for 10 weeks (n = 35). Outcomes were recorded at baseline, week 10 and week 22. RESULTS: Participants attended 92% of training sessions, with no serious adverse events. At 10 weeks, no differences were detected in walking performance. However, compared with the comparison group PRT demonstrated increased leg press strength (16.8%, SD 4.5), increased reverse leg press strength (29.8%, SD 12.7), and increased muscle endurance of the reverse leg press (38.7%, SD 32.8). Improvements in favor of PRT were also found for physical fatigue (Mean difference -3.9 units, 95%CI -6.6 to -1.3), and the physical health domain of quality of life (Mean difference 1.5 units, 95%CI 0.1 to 2.9). At week 22 almost no between-group differences remained. CONCLUSION: PRT is a relatively safe intervention that can have short-term effects on reducing physical fatigue, increasing muscle endurance and can lead to small improvements in muscle strength and quality of life in people with relapsing-remitting MS. However, no improvements in walking performance were observed and benefits do not appear to persist if training is completely stopped. PMID- 21677022 TI - Impaired cortical deactivation during hand movement in the relapsing phase of multiple sclerosis: a cross-sectional and longitudinal fMRI study. AB - BACKGROUND: Little is known about the cortical activation changes during clinical relapses in multiple sclerosis (MS). OBJECTIVE: To assess cross-sectional and longitudinal differences in functional magnetic resonance imaging (fMRI) cortical patterns between the relapsing and stable phases of MS. METHODS: We studied 32 patients with relapsing-remitting MS with mild disability: 19 within 48 h of symptom onset of a new relapse (G1) and 13 in the stable phase, relapse-free for at least 6 months (G2). All patients underwent fMRI twice, upon entry (time 1) and 30-50 days later (time 2), during right-hand movement. RESULTS: No between group differences were observed in age, disability or T2 lesion load. Between group analysis showed a significant difference in the ipsilateral precentral gyrus (IPG) activation at time 1. Activity differences in the IPG expressed reduced deactivation in G1 compared with G2. Longitudinal changes in brain activity in the IPG were significantly greater in G1 than G2. G1 patients with a slow clinical recovery (n = 8) showed different activity at baseline and greater activity changes over time in the IPG than patients with a fast recovery (n = 11). CONCLUSION: This study shows that the relapsing phase is associated with reduced brain deactivation in the IPG, which is more marked in patients with a slow clinical recovery. Increased cortical excitability associated with inflammation may determine functional modifications within the ipsilateral motor area. PMID- 21677023 TI - The psychosocial and cognitive impact of longstanding 'benign' multiple sclerosis. AB - BACKGROUND: Benign multiple sclerosis (BMS) is typically defined using the Expanded Disability Status Scale (EDSS), which relies heavily on ambulation. We set out to examine important psychosocial and cognitive outcomes in patients with longstanding BMS compared with patients who had recently progressed to 'no longer benign' (NLB). METHODS: A previously reported cohort of BMS (EDSS <=3 at 20 years disease duration) were re-assessed 25-30 years post-onset. Patients remaining benign (EDSS <=3 at re-assessment) were compared with those NLB for: depression (Beck Depression Inventory), fatigue (Modified Fatigue Impact Scale), health related quality of life (MSQoL-54), cognition (Rao's Neuropsychological Screening Battery), and employment status. RESULTS: A total of 75% (66/88) of the original cohort were located. A total of 61 patients were re-assessed. Twenty-five patients (41%) had progressed in EDSS and were NLB. Compared with benign patients, those NLB were more likely to have: significant fatigue (15/36 [42%] vs. 18/25 [72%], p = 0.019); poorer physical functioning (mean MSQoL-54 = 67.30 vs. 50.89, p = 0.002); an MS-related negative change in employment status (13/36 [36%] vs. 21/25 [84%], p < 0.0001) and cognitive impairment (3/28 [11%] vs. 5/19 [26%]; trend only, p = 0.317). Depression and mental health quality if life differed little between the benign and NLB patients (p > 0.6). CONCLUSIONS: Despite remaining benign for 20 years, a significant proportion of patients progressed with further follow up. While neither depression nor patient-reported mental health quality of life was associated with EDSS progression, patients with longstanding 'benign' MS (EDSS <=3 for 25+ years) had less fatigue, better physical quality of life and employment outcomes and infrequent cognitive impairment. Remaining benign over the long term, as defined by the EDSS, carried some advantages beyond ambulation. PMID- 21677024 TI - Potential role of IL-13 in neuroprotection and cortical excitability regulation in multiple sclerosis. AB - BACKGROUND: Inflammation triggers secondary neurodegeneration in multiple sclerosis (MS). OBJECTIVES: It is unclear whether classical anti-inflammatory cytokines have the potential to interfere with synaptic transmission and neuronal survival in MS. METHODS: Correlation analyses between cerebrospinal fluid (CSF) contents of anti-inflammatory cytokines and molecular, imaging, clinical, and neurophysiological measures of neuronal alterations were performed. RESULTS: Our data suggest that interleukin-13 (IL-13) plays a neuroprotective role in MS brains. We found, in fact, that the levels of IL-13 in the CSF of MS patients were correlated with the contents of amyloid-beta(1-42). Correlations were also found between IL-13 and imaging indexes of axonal and neuronal integrity, such as the retinal nerve fibre layer thickness and the macular volume evaluated by optical coherence tomography. Furthermore, the levels of IL-13 were related to better performance in the low-contrast acuity test and Multiple Sclerosis Functional Composite scoring. Finally, by means of transcranial magnetic stimulation, we have shown that GABAA-mediated cortical inhibition was more pronounced in patients with high IL-13 levels in the CSF, as expected for a neuroprotective, anti-excitotoxic effect. CONCLUSIONS: The present correlation study provides some evidence for the involvement of IL-13 in the modulation of neuronal integrity and synaptic function in patients with MS. PMID- 21677025 TI - Nonsteroidal anti-inflammatory drugs-induced generalized fixed drug eruption: two cases. AB - Fixed drug eruption (FDE) is a drug-induced cutaneous reaction that occurs at the same site with each exposure to a specific medication and usually manifests as round or oval, sharply demarcated erythematous or edematous plaques. The exact mechanism is unknown. The most common causative agent is co-trimoxazole. Other major categories of causative agents of FDE include antibiotics, antiepileptics, and nonsteroidal anti-inflammatory drugs (NSAIDs). FDE usually causes localized eruptions and very rarely generalized lesions. We report two cases of developing generalized FDEs after exposure to diclofenac and naproxen. PMID- 21677026 TI - Novel insights into the mechanisms of pregnancy establishment: regulation of prostaglandin synthesis and signaling in the pig. AB - Ovarian progesterone induces essential changes leading to a temporary state of uterine receptivity for conceptus implantation. Estrogens secreted by the porcine conceptus on days 11 and 12 of pregnancy provide the initial signal for maternal recognition of pregnancy and maintenance of a functional corpus luteum (CL) for continued production of progesterone. As prostaglandins F(2)(alpha) (PGF(2)(alpha)) and E(2) (PGE(2)) exert opposing actions on the CL, a tight control over their synthesis and secretion is critical either for the initiation of luteolysis or maintenance of pregnancy. One of the supportive mechanisms by which conceptus inhibits luteolysis is changing PG synthesis in favor of luteoprotective PGE(2). Conceptus PGE(2) could be amplified by PGE(2) feedback loop in the endometrium. In pigs, as in other species, implantation and establishment of pregnancy is associated with upregulation of expression of proinflammatory factors, which include cytokines, growth factors, and lipid mediators. The conceptus produces inflammatory mediators: interferon gamma and interferon delta, interleukins IL1B and IL6, and PGs, which probably activate inflammatory pathways in the endometrium. The endometrium responds to these embryonic signals by enhancing further progesterone-induced uterine receptivity. Understanding the mechanisms of pregnancy establishment is required for translational research to increase reproductive efficiencies and fertility in humans and animals. PMID- 21677027 TI - Abnormal cortical synaptic plasticity in primary motor area in progressive supranuclear palsy. AB - No study has yet investigated whether cortical plasticity in primary motor area (M1) is abnormal in patients with progressive supranuclear palsy (PSP). We studied M1 plasticity in 15 PSP patients and 15 age-matched healthy subjects. We used intermittent theta-burst stimulation (iTBS) to investigate long-term potentiation (LTP) and continuous TBS (cTBS) to investigate long-term depression (LTD)-like cortical plasticity in M1. Ten patients underwent iTBS again 1 year later. We also investigated short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in M1 with paired-pulse transcranial magnetic stimulation, tested H reflex from upper limb flexor muscles before and after iTBS, and measured motor evoked potential (MEP) input-output (I/O) curves before and after iTBS. iTBS elicited a significantly larger MEP facilitation after iTBS in patients than in healthy subjects. Whereas in healthy subjects, cTBS inhibited MEP, in patients it significantly facilitated MEPs. In patients, SICI was reduced, whereas ICF was normal. H reflex size remained unchanged after iTBS. Patients had steeper MEP I/O slopes than healthy subjects at baseline and became even more steeper after iTBS only in patients. The iTBS-induced abnormal MEP facilitation in PSP persisted at 1-year follow-up. In conclusion, patients with PSP have abnormal M1 LTP/LTD-like plasticity. The enhanced LTP-like cortical synaptic plasticity parallels disease progression. PMID- 21677028 TI - Activation of group II metabotropic glutamate receptors inhibits glutamatergic transmission in the rat entorhinal cortex via reduction of glutamate release probability. AB - Glutamate interacts with ionotropic and metabotropic glutamate receptors (mGluRs). Whereas the entorhinal cortex (EC) is a principal structure involved in learning and memory, the roles of mGluRs in synaptic transmission in the EC have not been completely determined. Here, we show that activation of group II mGluRs (mGluR II) induced robust depression of glutamatergic transmission in the EC. The mGluR II-induced depression was due to a selective reduction of presynaptic release probability without alterations of the quantal size and the number of release sites. The mechanisms underlying mGluR II-mediated suppression of glutamate release included the inhibition of presynaptic release machinery and the depression of presynaptic P/Q-type Ca(2+) channels. Whereas mGluR II-induced depression required the function of Galpha(i/o) proteins, protein kinase A (PKA) pathway was only involved in mGluR II-mediated inhibition of release machinery and thereby partially required for mGluR II-induced inhibition of glutamate release. Presynaptic stimulation at 5 Hz for 10 min also induced depression of glutamatergic transmission via activation of presynaptic mGluR II suggesting an endogenous role for mGluR II in modulating glutamatergic transmission. PMID- 21677029 TI - Maintaining force control despite changes in emotional context engages dorsomedial prefrontal and premotor cortex. AB - Viewing emotional as compared with neutral images results in an increase in force production. An emotion-driven increase in force production has been associated with increased brain activity in ventrolateral prefrontal cortex and primary motor cortex (M1). In many instances, however, force production must be held constant despite changes in emotional state and the neural circuits underlying this form of control are not well understood. To address this issue, we designed a task in which subjects viewed pleasant, unpleasant, and neutral images during a force production task. We measured brain activity using functional magnetic resonance imaging and examined functional connectivity between emotion and motor circuits. Despite similar force performance across conditions, increased brain activity was evidenced in dorsomedial prefrontal cortex (dmPFC) and left ventral premotor cortex (PMv) when force was produced during emotional as compared with neutral conditions. Connectivity analyses extended these findings by demonstrating a task-dependent functional circuit between dmPFC and ventral and dorsal portions of premotor cortex. Our findings show that when force production has to be consistent despite changes in emotional context, a functional circuit between dmPFC and PMv and dorsal premotor cortex is engaged. PMID- 21677030 TI - Subunit contributions to insect olfactory receptor function: channel block and odorant recognition. AB - Insect olfactory receptors are heteromeric ligand-gated ion channels composed of at least one common subunit (Orco) and at least one subunit that confers odorant specificity. Little is known about how individual subunits contribute to the structure and function of the olfactory receptor complex. We expressed insect olfactory receptors in Xenopus oocytes to investigate 2 functional features, ion channel block and odorant recognition. The sensitivity of Drosophila olfactory receptors to inhibition by ruthenium red, a cation channel blocker, varied widely when different specificity subunits were present, suggesting that the specificity subunits contribute to the structure of the ion pore. Olfactory receptors formed by Dmel?Or35a and Orco subunits from several different species displayed highly similar odorant response profiles, suggesting that the Orco subunit does not contribute to the structure of the odorant-binding site. We further explored odorant recognition by conducting a detailed examination of the odorant specificity Dmel?Or67a + Dmel?Orco, a receptor that responds to aromatic structures. This screen identified agonists, partial agonists, and an antagonist of Dmel?Or67a + Dmel?Orco. Our findings favor specific subunit arrangements within the olfactory receptor complex and provide a preliminary odorophore for an olfactory receptor, offering a useful foundation for future exploration of insect olfactory receptor structure. PMID- 21677031 TI - Expression and distribution of facilitative glucose (GLUTs) and monocarboxylate/H+ (MCTs) transporters in rat olfactory epithelia. AB - Cell-to-cell metabolic interactions are crucial for the functioning of the nervous system and depend on the differential expression of glucose transporters (GLUTs) and monocarboxylate transporters (MCTs). The olfactory receptor neurons (ORNs) and supporting cells (SCs) of the olfactory epithelium exhibit a marked polarization and a tight morphological interrelationship, suggesting an active metabolic interaction. We examined the expression and localization of MCTs and GLUTs in the olfactory mucosa and found a stereotyped pattern of expression. ORNs exhibited GLUT1 labeling in soma, dendrites, and axon. SCs displayed GLUT1 labeling throughout their cell length, whereas MCT1 and GLUT3 localize to their apical portion, possibly including the microvilli. Additionally, GLUT1 and MCT1 were detected in endothelial cells and GLUT1, GLUT3, and MCT2 in the cells of the Bowman's gland. Our observations suggest an energetic coupling between SCs and Bowman's gland cells, where glucose crossing the blood-mucosa barrier through GLUT1 is incorporated by these epithelial cells. Once in the SCs, glucose can be metabolized to lactate, which could be transported by MCTs into the Bowman's gland duct, where it can be used as metabolic fuel. Furthermore, SCs may export glucose and lactate to the mucous layer, where they may serve as possible energy supply to the cilia. PMID- 21677032 TI - Combining literature text mining with microarray data: advances for system biology modeling. AB - A huge amount of important biomedical information is hidden in the bulk of research articles in biomedical fields. At the same time, the publication of databases of biological information and of experimental datasets generated by high-throughput methods is in great expansion, and a wealth of annotated gene databases, chemical, genomic (including microarray datasets), clinical and other types of data repositories are now available on the Web. Thus a current challenge of bioinformatics is to develop targeted methods and tools that integrate scientific literature, biological databases and experimental data for reducing the time of database curation and for accessing evidence, either in the literature or in the datasets, useful for the analysis at hand. Under this scenario, this article reviews the knowledge discovery systems that fuse information from the literature, gathered by text mining, with microarray data for enriching the lists of down and upregulated genes with elements for biological understanding and for generating and validating new biological hypothesis. Finally, an easy to use and freely accessible tool, GeneWizard, that exploits text mining and microarray data fusion for supporting researchers in discovering gene-disease relationships is described. PMID- 21677033 TI - When orthologs diverge between human and mouse. AB - Despite the common assumption that orthologs usually share the same function, there have been various reports of divergence between orthologs, even among species as close as mammals. The comparison of mouse and human is of special interest, because mouse is often used as a model organism to understand human biology. We review the literature on evidence for divergence between human and mouse orthologous genes, and discuss it in the context of biomedical research. PMID- 21677034 TI - Premature ovarian failure in patients with autoimmune Addison's disease: clinical, genetic, and immunological evaluation. AB - DESIGN: The design of the study was to investigate the prevalence of the following: 1) premature ovarian failure (POF) in patients with autoimmune Addison's disease (AD); 2) steroid-producing cell antibodies (StCA) and steroidogenic enzymes (17alpha-hydroxylase autoantibodies and P450 side-chain cleavage enzyme autoantibodies) in patients with or without POF; and 3) the value of these autoantibodies to predict POF. PATIENTS: The study included 258 women: 163 with autoimmune polyendocrine syndrome type 2 (APS-2), 49 with APS-1, 18 with APS-4, and 28 with isolated AD. METHODS: StCA were measured by an immunofluorescence technique and 17alpha-hydroxylase autoantibodies and P450 side chain cleavage enzyme autoantibodies by immunoprecipitation assays. RESULTS: Fifty-two of 258 women with AD (20.2%) had POF. POF was diagnosed in 20 of 49 (40.8%) with APS-1, six of 18 (33.3%) with APS-4, 26 of 163 (16%) with APS-2, and none of 28 with isolated AD. In patients with APS-1 and APS-4, POF developed after AD, whereas it preceded AD in patients with APS-2. StCA were detected in 31 of 43 with POF (72%) and 51 of 198 without POF (25.7%). StCA were present in 22 of 38 with APS-1 (57.9%) (11 of 13 with POF); in five of 13 with APS-4 (38.5%) (three of four with POF); in 53 of 162 with APS-2 (32.7%) (17 of 26 with POF), and in one of 28 isolated AD patients (3.6%). Twelve of 13 patients with POF with a duration less than 5 yr (92.3%) and 18 of 25 with duration longer than 5 yr (72%) were StCA positive. Twenty-eight of 31 with POF (90.3%) were positive for at least one steroidogenic antibody. Forty-one women with AD less than 40 yr were followed up for a mean period of 9 yr. Eight of 21 women (38%) positive or seroconverted for steroidogenic autoantibodies developed POF at a mean age of 23 yr (six with APS-1, one with APS-2, and one with APS-4), and none of the 20 patients negative for steroidogenic autoantibodies developed POF. CONCLUSIONS: This study indicates that AD is frequently associated with POF and that steroidogenic antibodies are markers of patients with POF. Steroidogenic autoantibodies are predictive markers of POF in patients with AD. PMID- 21677035 TI - The regulation of vascular endothelial growth factor by hypoxia and prostaglandin F2alpha during human endometrial repair. AB - CONTEXT: The human endometrium has an exceptional capacity for repeated repair after menses, but its regulation remains undefined. Premenstrually, progesterone levels fall and prostaglandin (PG) F2alpha synthesis increases, causing spiral arteriole constriction. We hypothesized that progesterone withdrawal, PGF2alpha, and hypoxia increase vascular endothelial growth factor (VEGF), an endometrial repair factor. DESIGN AND RESULTS: Endometrial biopsies were collected (n = 47) with ethical approval and consent. VEGF mRNA, quantified by quantitative RT-PCR, was increased during menstruation (P < 0.01).VEGF protein was maximally secreted from proliferative endometrial explants. Treatment of an endometrial epithelial cell line and primary human endometrial stromal cells with 100 nm PGF2alpha or hypoxia (0.5% O2) resulted in significant increases in VEGF mRNA and protein. VEGF was maximal when cells were cotreated with PGF(2alpha) and hypoxia simultaneously (P < 0.05-0.001). Secretory-phase endometrial explants also showed an increase in VEGF with cotreatment (P < 0.05). However, proliferative-phase explants showed no increase in VEGF on treatment with PGF2alpha and/or hypoxia. Proliferative tissue was induced to increase VEGF mRNA expression when exposed to progesterone and its withdrawal in vitro but only in the presence of hypoxia and PG. Hypoxia-inducible factor-1alpha (HIF-1alpha) silencing with RNA interference suppressed hypoxia-induced VEGF expression in endometrial cells but did not alter PGF2alpha-induced VEGF expression. CONCLUSIONS: Endometrial VEGF is increased at the time of endometrial repair. Progesterone withdrawal, PGF2alpha, and hypoxia are necessary for this perimenstrual VEGF expression. Hypoxia acts via HIF-1alpha to increase VEGF, whereas PGF2alpha acts in a HIF-1alpha-independent manner. Hence, two pathways regulate the expression of VEGF during endometrial repair. PMID- 21677036 TI - Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors? AB - CONTEXT: The immunopathogenesis of Graves' ophthalmopathy (GO) is still incompletely understood. Attention has shifted from the TSH receptor (TSHR) to the IGF-I receptor (IGF-1R) as a major autoantigen. This review on the pathophysiology of GO focused on orbital fibroblasts and the question whether autoimmunity against TSHR or IGF-1R is primarily involved. EVIDENCE ACQUISITION: Relevant papers on GO were identified by a search on PubMed and scrutiny of their reference lists. In addition, abstracts presented on GO at the 14th International Thyroid Congress in 2010 in Paris, France, were read. EVIDENCE SYNTHESIS: Orbital fibroblasts (OF) are recognized as the prime target cells of the autoimmune attack in GO. In early stages OF are undifferentiated with low TSHR expression and are stimulated to produce hyaluronan by cytokines (released by activated infiltrating T cells) and not by Graves' IgG. OF lacking the surface glycoprotein Thy-1 (not present in the muscle compartment) may differentiate into adipocytes, associated with increased TSHR expression. Graves IgG stimulate hyaluronan in differentiated OF mostly via non-cAMP signaling pathways for growth, which can also be activated via TSHR. The existence of IGF-1R stimulating antibodies in serum remains dubious. Autoimmunity against IGF-1R is also observed in rheumatoid arthritis and is not specific for Graves' disease. Expression of IGF-1R on T and B lymphocytes may contribute to autoimmunity against fibroblasts. CONCLUSION: Autoimmunity against TSHR is most likely initiating the immune response in GO. Autoimmunity against IGF-1R is not specific for Graves' DISEASE but may contribute to ongoing immune reactions. PMID- 21677037 TI - Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. AB - CONTEXT: Several studies found association between vitamin D levels and hypertension, coronary artery calcification, and heart disease. OBJECTIVE: The aim of this study was to summarize the evidence on the effect of vitamin D on cardiovascular outcomes. DESIGN AND METHODS: We searched electronic databases from inception through August 2010 for randomized trials. Reviewers working in duplicate and independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RR) and the weighted mean differences across trials. RESULTS: We found 51 eligible trials with moderate quality. Vitamin D was associated with nonsignificant effects on the patient-important outcomes of death [RR, 0.96; 95% confidence interval (CI), 0.93, 1.00; P = 0.08], myocardial infarction (RR, 1.02; 95% CI, 0.93, 1.13; P = 0.64), and stroke (RR, 1.05; 95% CI, 0.88, 1.25; P = 0.59). These analyses were associated with minimal heterogeneity. There were no significant changes in the surrogate outcomes of lipid fractions, glucose, or diastolic or systolic blood pressure. The latter analyses were associated with significant heterogeneity, and the pooled estimates were trivial in absolute terms. CONCLUSIONS: Trial data available to date are unable to demonstrate a statistically significant reduction in mortality and cardiovascular risk associated with vitamin D. The quality of the available evidence is low to moderate at best. PMID- 21677038 TI - Risk factors for nonvertebral fracture in obese older women. AB - CONTEXT: A high prevalence of obesity has recently been reported in postmenopausal women with low trauma fracture, suggesting that higher bone mineral density (BMD) in obese individuals may not be protective against fracture. OBJECTIVE: The aim of this study was to compare BMD and other risk factors for nonvertebral fracture in 1377 obese postmenopausal women. DESIGN: Characteristics of obese women with and without incident nonvertebral fracture were investigated among the prospective cohort in the Study of Osteoporotic Fractures. SETTING: The Study of Osteoporotic Fractures is a multicenter study of 9704 women (>99% Caucasian) aged 65 yr and over who were recruited between September 1986 and October 1988 from population-based listings at four U.S. clinical centers. MAIN OUTCOME MEASURE: The main outcome measure was nonvertebral fracture. RESULTS: BMD T-scores in the spine, femoral neck, and total hip were significantly lower in obese women who experienced fractures than in obese women without fracture: mean differences, -0.56 [95% confidence interval (CI) = -0.73 to -0.39], -0.46 (95% CI = -0.57 to -0.36), and -0.51 (95% CI = -0.62 to -0.39), respectively (P < 0.0001 for all). A previous history of fracture [odds ratio = 1.69 (95% CI = 1.33-2.14); P < 0.0001] and femoral neck BMD [1.62 (95% CI = 1.42 1.85) per sd decrease in BMD; P < 0.0001] were independently associated with incident nonvertebral fracture. CONCLUSIONS: Obese postmenopausal women who sustain nonvertebral fractures have significantly lower BMD on average than obese women without fracture and are more likely to have a past history of fracture. Fractures in obese postmenopausal women thus exhibit some characteristics of fragility fractures. PMID- 21677039 TI - Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene. AB - CONTEXT: The diagnosis of maturity-onset diabetes of the young type 3 (MODY3), associated with HNF1A molecular abnormalities, is often missed. OBJECTIVE: The objective of the study was to describe the phenotypes of a large series of MODY3 patients and to reassess parameters that may improve its diagnosis. DESIGN, SETTING, AND PATIENTS: This retrospective multicenter study included 487 unrelated patients referred because of suspicion of MODY3. Genetic analysis identified 196 MODY3 and 283 non-MODY3 cases. Criteria associated with MODY3 were assessed by multivariate analysis. The capacity of the model to predict MODY3 diagnosis was assessed by the area under the receiver-operating characteristic curve and was further validated in an independent sample of 851 patients (165 MODY3 and 686 non-MODY3). RESULTS: In the MODY3 patients, diabetes was revealed by clinical symptoms in 25% of the cases and was diagnosed by screening in the others. Age at diagnosis of diabetes was more than 25 yr in 40% of the MODY3 patients. There was considerable variability and overlap of all assessed parameters in MODY3 and non-MODY3 patients. The best predictive model was based on criteria available at diagnosis of diabetes, including age, body mass index, number of affected generations, presence of diabetes symptoms, and geographical origin. The area under the curve of the receiver-operating characteristic analysis was 0.81. When sensitivity was set to 90%, specificity was 49%. CONCLUSIONS: Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations. PMID- 21677040 TI - Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: implications for insulin resistance, inflammation, and atherosclerosis. AB - CONTEXT AND OBJECTIVE: The dysregulation of hepatokines may be associated with the pathogenesis of insulin resistance and type 2 diabetes. A recent study has suggested that selenoprotein P (SeP), a novel hepatokine, may play a role in the regulation of glucose metabolism and insulin sensitivity. We examined the relationship between circulating SeP levels and clinical parameters associated with insulin resistance in humans. PARTICIPANTS AND METHODS: We compared serum SeP concentrations in 100 subjects with diverse glucose tolerance statuses. Furthermore, we evaluated the relationship between SeP and cardiometabolic risk factors including insulin resistance, high-sensitivity C-reactive protein, and carotid intima-media thickness. RESULTS: Serum SeP concentrations were significantly higher in patients with type 2 diabetes or prediabetes than those with normal glucose tolerance (all P < 0.01) and decreased in a stepwise manner [1032.4 (495.9-2149.4) vs. 867.3 (516.3-1582.7) vs. 362.0 (252.5-694.5), P = 0.004]. In addition, overweight and obese subjects had significantly increased SeP levels compared with lean subjects (P = 0.002). Spearman's partial correlation analysis adjusted for age and gender showed a significant relationship between SeP and cardiometabolic factors including body mass index, waist circumference, systolic blood pressure, triglycerides, glucose, hemoglobin A1c, aspartate aminotransferase, and insulin resistance. Furthermore, in multiple regression analyses, SeP showed an independent association with carotid intima media thickness as well as high-sensitivity C-reactive protein, even after adjustment for other confounding factors. CONCLUSIONS: Circulating SeP concentrations were elevated in patients with glucose metabolism dysregulation and were related to various cardiometabolic parameters including insulin resistance, inflammation, and atherosclerosis. PMID- 21677041 TI - Changes in reproductive hormone concentrations predict the prevalence and progression of the frailty syndrome in older men: the concord health and ageing in men project. AB - CONTEXT: Frailty, a syndrome of multiple morbidity, weakness, and immobility in aging, is an increasingly urgent threat to public health. Single measures of low serum androgen have been associated with frailty in men, but the contributory role of hormonal changes with time is unassessed. OBJECTIVE: The objective of the study was to examine, using longitudinal measurements, the relations of serum androgens, estrogens, gonadotropins, and SHBG to the prevalence and progression of frailty in older men. DESIGN: Concord Health and Ageing in Men Project is an observational cohort study of 1705 men (aged 70 yr or older) living in the suburb of Concord, Sydney, Australia. Measurements were obtained at baseline (2005-2007) and 2-yr follow-up (2007-2009). Testosterone (T), dihydrotestosterone, estradiol, and estrone were obtained by liquid chromatography-tandem mass spectrometry, whereas SHBG, LH, and FSH were measured by immunoassay. SETTING: Subjects from the general community were sampled. PARTICIPANTS: A total of 1645 subjects constituting a representative sample of community-dwelling men aged 70 yr old or older participated in the study. OUTCOME MEASURES: The frailty syndrome was measured according to the Cardiovascular Health Study (CHS) and Study of Osteoporotic Fractures (SOF) indices. RESULTS: Androgens and estrogens showed significant age-adjusted associations with concurrent frailty. Subjects in the lowest T quintile had 2.2-fold odds of exhibiting greater CHS frailty as compared with the highest T quintile (P < 0.001); results for dihydrotestosterone, estradiol, estrone, and calculated free T were similar, and were unchanged when the SOF frailty index was substituted for the CHS frailty index. A 1 sd, 2-yr decrease in T, calculated free T, or LH was associated with a 1.2- to 1.3-fold increase in the odds of progression (increase in severity) of frailty. The control for comorbid medical conditions did not affect results. CONCLUSIONS: Age related changes in blood androgens and estrogens may contribute to the development or progression of frailty in men. PMID- 21677042 TI - Impaired delivery of insulin to adipose tissue and skeletal muscle in obese women with postprandial hyperglycemia. AB - CONTEXT: An impaired transfer of insulin from the circulation to the interstitial fluid has been suggested to contribute to insulin resistance. OBJECTIVE: The objective of the study was to address whether the delivery of insulin from the circulation to adipose tissue and skeletal muscle is impaired in obese women with postprandial hyperglycemia compared with lean healthy controls. DESIGN, SETTING, AND PARTICIPANTS: Seven obese nondiabetic women with postprandial hyperglycemia and nine lean healthy women were recruited. The interstitial insulin concentration in adipose tissue and muscle tissue was measured by the microdialysis technique during an oral glucose tolerance test (75 g). In parallel, arterial insulin levels were measured. We used 133Xe clearance and plethysmography to monitor blood flow. Subcutaneous needle biopsies were taken to obtain fat cell size. RESULTS: After oral glucose ingestion, mean arterial insulin levels were higher in obese women than in the lean group. However, interstitial insulin levels in sc adipose tissue and forearm muscle were similar in both groups. Accordingly, the proportion of circulating insulin being transported across the vascular endothelium to the interstitial fluid in adipose tissue and in muscle tissue was significantly lower in the obese compared with the lean group. CONCLUSIONS: Obese subjects with postprandial hyperglycemia need higher circulating insulin levels than lean controls to attain similar interstitial insulin levels in adipose tissue and skeletal muscle, indicating an impaired transfer of insulin across the endothelium. PMID- 21677043 TI - Nonclassic TSH resistance: TSHR mutation carriers with discrepantly high thyroidal iodine uptake. AB - CONTEXT: Inactivating mutations in the TSH receptor gene (TSHR) cause TSH resistance. Most patients with TSH resistance have low to normal thyroidal radioiodine uptake (RAIU), which is consistent with the physiological knowledge that TSH stimulates iodine uptake. To date, only one TSHR mutation-carrying family with discrepantly high RAIU has been reported. OBJECTIVE: We aimed to test whether TSHR mutation carriers with high RAIU are observed in a cohort of Japanese patients with congenital hypothyroidism (CH). SUBJECTS AND METHODS: Twenty-four Japanese CH patients with high RAIU were screened for TSHR mutations. The capacities of mutant TSHR to activate Gs- and Gq-coupled signaling pathways were evaluated in vitro. RESULTS: Two patients were found to have biallelic TSHR mutations: p.[T145I]+[R450H] in one and p.[R450H]+[I661fs] in the other. The two subjects had permanent CH with slightly high RAIU (41.8 and 43.0%, reference 8 40) but did not have goiter. One had a slightly high perchlorate discharge rate (10%, reference <10). Expression experiments revealed that T145I-TSHR retained partial ability to transduce both Gs- and Gq-coupled pathways, whereas I661fs TSHR could transduce neither of them. R450H-TSHR had partial ability to transduce Gs-coupled signaling but had abrogated ability to transduce Gq-coupled signaling, indicating that coupling to Gq was dominantly affected. CONCLUSIONS: We show that 8% of Japanese CH patients with high RAIU (two in 24) has inactivating TSHR mutations. Expression of this apparently discrepant phenotype, which we term nonclassic TSH resistance, is presumably associated with the characteristic signaling property of the mutant TSHR, namely the Gq-dominant coupling defect. PMID- 21677044 TI - In vivo suppression of visfatin by oral glucose uptake: evidence for a novel incretin-like effect by glucagon-like peptide-1 (GLP-1). AB - BACKGROUND: Visfatin represents an adipokine of the visceral adipose tissue exerting pleiotropic effects. The aim of the study was to characterize the physiological regulation of visfatin release in vivo in healthy, nondiabetic probands and in adipocytes in vitro. SUBJECTS AND METHODS: One hundred healthy subjects (64 females and 36 males) underwent an oral glucose tolerance test (75 g). Probands were characterized by anthropometric and laboratory parameters. Fasting and postprandial (1 and 2 h) serum concentrations of glucose, insulin, and visfatin were measured. Stimulation experiments using glucose, insulin, mannitol, and glucagon-like peptide-1 (GLP-1) were performed on 3T3-L1 adipocytes including Western blot analysis. RESULTS: Fasting visfatin levels were not different between males/females or lean/obese individuals but were negatively (r = -0.5; P < 0.001) correlated with fasting glucose levels. Visfatin levels were rapidly and significantly suppressed (P < 0.001) upon an oral glucose intake, and this suppression was more pronounced in overweight and female probands. In vitro experiments demonstrated that hyperglycemia, osmotic stress, and sex steroids did not influence visfatin release. In contrast, insulin strongly (P = 0.002) inhibited visfatin release in vitro by approximately 50%, and this suppression was more pronounced under hyperglycemia. Importantly, GLP-1 strongly (P < 0.001) inhibited adipocytic visfatin release by approximately 50%. CONCLUSIONS: Insulin and GLP-1 are responsible for the rapid suppression of visfatin levels upon an oral glucose uptake in healthy probands. The inhibitory effect of GLP-1 on adipocytic visfatin release together with the absence of direct glucose effects on visfatin release suggests the existence of a novel incretin-like effect represented by a GLP-1/visfatin/axis. PMID- 21677045 TI - NFkappaB and JNK/MAPK activation mediates the production of major macrophage- or dendritic cell-recruiting chemokine in human first trimester decidual cells in response to proinflammatory stimuli. AB - CONTEXT: Preeclampsia is associated with elevated levels of proinflammatory cytokines, excess decidual macrophages, and dendritic cells. IL-1beta- or TNF alpha-stimulated leukocyte-free first trimester decidual cells produced abundant macrophage- and dendritic cell-recruiting chemokines identified in preeclamptic decidua. OBJECTIVE: The relative potency of IL-1beta- or TNF-alpha-induced first trimester decidual cell-secreted chemokines in chemoattracting macrophages or dendritic cells and the signaling pathways involved in the expression of these chemokines were evaluated. INTERVENTIONS AND MAIN OUTCOME MEASURES: First trimester decidual cells were treated with estradiol + medroxyprogesterone acetate +/- IL-1beta or TNF-alpha. The chemotaxis assay was performed by incubating conditioned medium from first trimester decidual cells with neutralizing antibody for six chemokines. The activation of each signaling pathway was examined by Western blotting, flow cytometry, confocal microscopy, and ELISA with or without kinase and nuclear factor kappaB (NFkappaB) inhibitors. RESULTS: Neutralization of CCL2 and CCL5 significantly reduced chemotaxis of monocyte and dendritic cells up to 50 and 36%, respectively. NFkappaB and MAPK (MAPK kinase, JUN NH2-terminal kinase, p38 kinase) pathways were activated by IL 1beta or TNF-alpha in first trimester decidual cells. In IL-1beta- or TNF-alpha stimulated first trimester decidual cells, NFkappaB inhibitor suppressed production of all six chemokines; JUN NH2-terminal kinase inhibitor inhibited secretion of CCL2, CCL4, and CCL5; and MAPK kinase and p38 inhibitor decreased production of CXCL8. CONCLUSIONS: Up-regulation of CCL2 and CCL5 by first trimester decidual cells in response to proinflammatory stimuli may account for the accumulation of macrophages and dendritic cells in preeclamptic decidua. These chemokines and underlying IL-1beta- or TNF-alpha-induced signaling molecules are potential diagnostic and therapeutic targets for preeclampsia. PMID- 21677046 TI - Arabidopsis cell-free extract, ACE, a new in vitro translation system derived from Arabidopsis callus cultures. AB - The analysis of post-transcriptional regulatory mechanisms in plants has benefited greatly from the use of cell-free extract systems. Arabidopsis as a model system provides extensive genetic resources; however, to date a suitable cell-free translation system from Arabidopsis has not been available. In this study, we devised an Arabidopsis cell-free extract (ACE) to be used for in vitro translation studies. Protoplasts were prepared from callus cultures derived from Arabidopsis seedlings, and cell-free extracts were prepared after evacuolation of the protoplasts by Percoll gradient centrifugation. The new ACE system exhibits translation activity comparable with that of the wheat germ extract system. We demonstrated that ACE prepared from the 5'-3' exoribonuclease-deficient mutant of Arabidopsis, xrn4-5, exhibited increased stability of an uncapped mRNA as compared with that from wild-type Arabidopsis. We applied the ACE system to study post-transcriptional regulation of AtCGS1. AtCGS1 codes for cystathionine gamma synthase (CGS) that catalyzes the first committed step of methionine and S adenosyl-l-methionine (AdoMet) biosynthesis in plants, and is feedback regulated by mRNA degradation coupled with translation elongation arrest. The ACE system was capable of reproducing translation elongation arrest and subsequent AtCGS1 mRNA degradation that are induced by AdoMet. The ACE system described here can be prepared in a month after seed sowing and will make it possible to study post transcriptional regulation of plant genes while taking advantage of the genetics of Arabidopsis. PMID- 21677047 TI - Recruiting end-of-life cancer patients in the Netherlands for a study on suffering and euthanasia requests. AB - BACKGROUND: In the Netherlands, GPs performed euthanasia or physician-assisted suicide (EAS) in ~1 of 10 end-of-life cancer patients in their care. Of all explicit requests for EAS directed at GPs, ~44% resulted in EAS. However, the suffering of patients who do and do not request EAS has never been studied. An important barrier for such research is the low prevalence of end-of-life cancer patients per practice (on average two/year). We studied whether it is possible to recruit end-of-life cancer patients, following-up for requests for EAS (if any), in an interview study in general practice, whether selection occurred and which were the threats and opportunities to recruitment. Our target was to recruit at least 50 patients. METHODS: Characteristics of all eligible patients were monitored. RESULTS: One in every three eligible patients were recruited by 44 GPs in a 3-year inclusion period, resulting in 64 patients in the interview study with follow-up until death. The prevalence of explicit requests for EAS was higher (27%; P = 0.026) in the interview sample, and the presence of a depressed mood according to the GP was lower (5%; P = 0.013) than in the sample with eligible but not participating patients. CONCLUSIONS: Recruitment of slightly more than the minimal target number of end-of-life cancer patients in this study in general practice was realized. Monitoring of all eligible patients permitted to evaluate the selection which occurred. Recruitment through GPs who were direct professional colleagues of one of the researchers was a positive recruitment factor. PMID- 21677048 TI - Infliximab alleviates inflammation and ex vivo airway hyperreactivity in asthmatic E3 rats. AB - Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of asthma, and neutralization of TNF-alpha is an effective therapy for inflammatory diseases. The present study tested the idea that a TNF-alpha antibody, infliximab, may be useful in the management of asthma. E3 rats were immunized with ovalbumin (OVA)/alum and received infliximab intra-peritoneally. Two weeks later, OVA-PBS was instilled intranasally daily for 7 days. Bronchoalveolar lavage fluids (BALFs), serum and lung homogenates were collected for analysis of cells and inflammatory mediators. Contractile responses of lobar bronchus segments to agonists were functionally tested. Pulmonary tissues were investigated using histological examination. The results showed that the sensitized 'model E3 rats' exhibited an increase in the total amount of inflammatory cells, primarily eosinophils, in BALF and pulmonary tissue, as well as epithelial damage. Serum levels of IgE increased and so did the levels of nitric oxide, inducible nitric oxide synthase, TNF-alpha and IL-4, IL-5 and IL-13 in lung homogenate and serum. Furthermore, the contractile responses in bronchi induced by endothelin-1, sarafotoxin 6c and bradykinin increased and isoprenaline induced relaxations decreased. All these changes induced by the sensitization procedure were reduced by the infliximab treatment. The results suggest that infliximab prevents the development of local airway inflammation and antagonizes changes of the bronchial smooth muscle receptor phenotype, thereby blocking the development of airway smooth muscle hyperreactivity of asthmatic rats. PMID- 21677049 TI - Dectin-1 and Dectin-2 in innate immunity against fungi. AB - Dectin-1 and Dectin-2 are type II transmembrane proteins of the C-type lectin family with single carbohydrate recognition domains (CRDs) in their extracellular region. They are expressed mainly in dendritic cells and macrophages. Dectin-1 recognizes beta-glucans with its CRD and transduces signals through its immunoreceptor tyrosine-based activation motif (ITAM)-like motif in the cytoplasmic domain, whereas Dectin-2 recognizes alpha-mannans and transduces its signal through association with the ITAM-containing Fc receptor gamma chain. Upon ligand binding, spleen tyrosine kinase is recruited to the ITAM and activates the caspase recruitment domain family member 9 (CARD9)-nuclear factor-kappaB axis, resulting in the activation of various genes including those encoding pro inflammatory cytokines. Both beta-glucans and alpha-mannans are major cell wall components of fungi including Candida albicans and Pneumocystis carinii. Recently, it was reported that Dectin-1 is important in protection against P. carinii by inducing reactive oxygen species, whereas both Dectin-1 and Dectin-2 play important roles in defense against C. albicans by preferentially inducing T(h)17 cell differentiation. In this review, we briefly revisit the structures, ligands, signal transduction and functional roles of Dectin-1 and Dectin-2 in host defense against fungal infection. PMID- 21677050 TI - Effect of somatostatin infusion on peptide YY secretion: studies in the acute and recovery phase of anorexia nervosa and in obesity. AB - OBJECTIVE: Changes in many gastrointestinal peptides, including the anorexigenic peptide YY (PYY), which is produced by L cells, occur in both anorexia nervosa (AN) and obesity (OB). High PYY levels are present in AN, whereas in morbid OB fasting and postprandial PYY secretion is blunted. Somatostatin (somatotropin release-inhibiting factor (SRIF)) reportedly inhibits plasma PYY concentrations in animals and healthy humans, but the effect of a SRIF infusion on spontaneous PYY secretion in AN and OB is unknown. METHODS: A total of 18 young women, seven with acute AN (A-AN), four with AN in the recovery phase (R-AN), and seven with morbid OB, were studied. All subjects underwent an infusion of SRIF (9 MUg/kg i.v./h, over 60 min), with blood samples drawn before and at different time intervals after SRIF administration. Plasma PYY levels were measured at each time point. RESULTS: SRIF significantly inhibited plasma PYY concentrations in R-AN and OB, without affecting PYY titers in A-AN. In OB, the inhibitory effect of SRIF also persisted at 90 min. Withdrawal of SRIF infusion in R-AN resulted in a prompt restoration of basal plasma PYY levels, whereas termination of SRIF infusion in OB was followed by a slower increase of PYY titers toward baseline levels. After infusion, PYY Delta area under the curve (DeltaAUC) in R-AN was significantly higher than those in A-AN and OB patients. A significant difference in PYY DeltaAUC between A-AN and OB was present. CONCLUSIONS: These results suggest the existence of a hypo- and hyper-sensitivity of L cells to the inhibitory effect of SRIF in A-AN and OB respectively. PMID- 21677051 TI - Monitoring of vitamin B-12 nutritional status in the United States by using plasma methylmalonic acid and serum vitamin B-12. AB - BACKGROUND: Various definitions, criteria, tests, and cutoffs have been used to define vitamin B-12 status; however, a need exists for the systematic study of vitamin B-12 status in the United States because of concerns about high folic acid intakes and the potential for associated adverse effects. OBJECTIVE: The objective was to determine the effect of different cutoff choices on outcomes and of the different degrees of serum vitamin B-12 status, definable by the concurrent use of a functional and circulating marker as the first steps to developing a data-based consensus on the biochemical diagnosis of vitamin B-12 deficiency. DESIGN: Data from NHANES, a nationally representative cross-sectional survey, were examined for adults aged >19 y (mean +/- SD age: 45 +/- 1 y) from 1999 to 2004 (n = 12,612). RESULTS: Commonly used cutoffs had a greater effect on prevalence estimates of low vitamin B-12 status with the use of vitamin B-12 than with the use of methylmalonic acid (MMA; 3-26% and 2-6%, respectively). A cutoff of >148 pmol/L for vitamin B-12 and of <=210 nmol/L for MMA resulted in significant misclassifications. Approximately 1% of adults had a clear vitamin B 12 deficiency (low vitamin B-12 and elevated MMA); 92% of adults had adequate vitamin B-12 status. A high percentage of younger women characterized the group with low vitamin B-12 and normal MMA (2% of adults) and may have falsely reflected low vitamin B-12. Adults with elevated MMA (5%) only were demographically similar (ie, by age and race) to the deficient group and may have included some individuals with early vitamin B-12 deficiency. CONCLUSIONS: These analyses indicate the challenges of assessing vitamin B-12 status when uncertainties exist about the appropriate cutoffs. Future studies should determine definable endpoints to achieve this goal. PMID- 21677052 TI - Low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism and promotes inflammation in healthy young men: a randomized controlled trial. AB - BACKGROUND: Sugar-sweetened beverages (SSBs) have unfavorable effects on glucose and lipid metabolism if consumed in high quantities by obese subjects, but the effect of lower doses in normal-weight subjects is less clear. OBJECTIVE: The aim was to investigate the effects of SSBs consumed in small to moderate quantities for 3 wk on LDL particle distribution and on other parameters of glucose and lipid metabolism as well as on inflammatory markers in healthy young men. DESIGN: Twenty-nine subjects were studied in a prospective, randomized, controlled crossover trial. Six 3-wk interventions were assigned in random order as follows: 600 mL SSBs containing 1)40 g fructose/d [medium fructose (MF)], 2) 80 g fructose/d [high fructose (HF)], 3) 40 g glucose/d [medium glucose (MG)], 4) 80 g glucose/d [high glucose (HG)], 5) 80 g sucrose/d [high sucrose (HS)], or 6) dietary advice to consume low amounts of fructose. Outcome parameters were measured at baseline and after each intervention. RESULTS: LDL particle size was reduced after HF by -0.51 nm (95% CI: -0.19, -0.82 nm) and after HS by -0.43 nm (95% CI: -0.12, -0.74; P < 0.05 for both). Similarly, a more atherogenic LDL subclass distribution was seen when fructose-containing SSBs were consumed (MF, HF, and HS: P < 0.05). Fasting glucose and high-sensitivity C-reactive protein (hs-CRP) increased significantly after all interventions (by 4-9% and 60-109%, respectively; P < 0.05); leptin increased during interventions with SSBs containing glucose only (MG and HG: P < 0.05). CONCLUSION: The present data show potentially harmful effects of low to moderate consumption of SSBs on markers of cardiovascular risk such as LDL particles, fasting glucose, and hs-CRP within just 3 wk in healthy young men, which is of particular significance for young consumers. This trial was registered at clinicaltrials.gov as NCT01021969. PMID- 21677053 TI - Defining the process of Dietary Reference Intakes: framework for the United States and Canada. AB - The pioneering project of the harmonization of Dietary Reference Intakes (DRIs) for the United States and Canada resulted in the production of 13 reports from 1997 to 2006 that included 6 reports on specific nutrient groups, 3 reports in preparation for setting recommendations for fiber and antioxidants, 2 reports on applications of DRIs, a report of the synthesis of identified research gaps, and a summary report, Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. This bicountry collaborative effort to harmonize values of reference nutrient intakes has continued through meetings to evaluate the strengths and weaknesses of the first harmonized DRI process in North America and to refine the framework for future revisions of DRIs. PMID- 21677054 TI - Nutritional supplementation during pregnancy and offspring cardiovascular disease risk in The Gambia. AB - BACKGROUND: Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring. OBJECTIVE: The objective was to follow up the offspring in 2 randomized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease (CVD) risk in offspring. DESIGN: We recruited offspring born during 2 trials in The Gambia, West Africa. One trial provided protein-energy-dense food supplements (1015 kcal and 22 g protein/d) to pregnant (intervention, from 20 wk gestation until delivery) or lactating (control, for 20 wk from birth) women and was randomized at the village level. The second was a double-blind, individually randomized, placebo-controlled trial of calcium supplementation (1.5 g/d), which was also provided from 20 wk gestation until delivery. RESULTS: Sixty-two percent (n = 1267) of children (aged 11-17 y) born during the protein-energy trial were recruited and included in the analysis, and 64% (n = 350) of children (aged 5-10 y) born during the calcium trial were recruited and included in the analysis. Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group (adjusted mean difference: -0.05 mmol/L; 95% CI: -0.10, -0.001 mmol/L). There were no other differences in CVD risk factors, including blood pressure, body composition, and cholesterol, between children born to intervention and control women from the protein-energy trial. Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure. CONCLUSION: These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring, at least in this setting and at the ages studied here. This trial was registered at www.controlled-trials.com as ISRCTN96502494. PMID- 21677055 TI - Field-friendly techniques for assessment of biomarkers of nutrition for development. AB - Whereas cost-effective interventions exist for the control of micronutrient malnutrition (MN), in low-resource settings field-friendly tools to assess the effect of these interventions are underutilized or not readily available where they are most needed. Conventional approaches for MN measurement are expensive and require relatively sophisticated laboratory instrumentation, skilled technicians, good infrastructure, and reliable sources of clean water and electricity. Consequently, there is a need to develop and introduce innovative tools that are appropriate for MN assessment in low-resource settings. These diagnostics should be cost-effective, simple to perform, robust, accurate, and capable of being performed with basic laboratory equipment. Currently, such technologies either do not exist or have been applied to the assessment of a few micronutrients. In the Demographic and Health Surveys (DHS), a few such examples for which "biomarkers" of nutrition development have been assessed in low resource settings using field-friendly approaches are hemoglobin (anemia), retinol-binding protein (vitamin A), and iron (transferrin receptor). In all of these examples, samples were collected mainly by nonmedical staff and analyses were conducted in the survey country by technicians from the local health or research facilities. This article provides information on how the DHS has been able to successfully adapt field-friendly techniques in challenging environments in population-based surveys for the assessment of micronutrient deficiencies. Special emphasis is placed on sample collection, processing, and testing in relation to the availability of local technology, resources, and capacity. PMID- 21677056 TI - Effects of social contact and zygosity on 21-y weight change in male twins. AB - BACKGROUND: Recent evidence indicates that social contact is related to similarities in weight gain over time. However, no studies have examined this effect in a twin design, in which genetic and other environmental effects can also be estimated. OBJECTIVE: We determined whether the frequency of social contact is associated with similarity in weight change from young adulthood (mean age: 20 y) to middle age (mean age: 41 y) in twins and quantified the percentage of variance in weight change attributable to social contact, genetic factors, and other environmental influences. DESIGN: Participants were 1966 monozygotic and 1529 dizygotic male twin pairs from the Vietnam-Era Twin Registry. Regression models tested whether frequency of social contact and zygosity predicted twin pair similarity in body mass index (BMI) change and weight change. Twin modeling was used to partition the percentage variance attributable to social contact, genetic, and other environmental effects. RESULTS: Twins gained an average of 3.99 BMI units, or 13.23 kg (29.11 lb), over 21 y. In regression models, both zygosity (P < 0.001) and degree of social contact (P < 0.02) significantly predicted twin pair similarity in BMI change. In twin modeling, social contact between twins contributed 16% of the variance in BMI change (P < 0.001), whereas genetic factors contributed 42%, with no effect of additional shared environmental factors (1%). Similar results were obtained for weight change. CONCLUSION: Frequency of social contact significantly predicted twin pair similarity in BMI and weight change over 21 y, independent of zygosity and other shared environmental influences. PMID- 21677057 TI - Variations in circulating inflammatory factors are related to changes in calorie and carbohydrate intakes early in the course of surgery-induced weight reduction. AB - BACKGROUND: Obesity is considered a low-grade inflammatory state that improves with weight loss. In addition to acute-phase proteins, other cytokines might contribute to systemic inflammation. OBJECTIVE: Our objective was to compare serum concentrations of a large panel of inflammation-related factors in obese and normal-weight subjects and to determine kinetic changes induced by caloric restriction. DESIGN: The cohort comprised 14 normal-weight women and 51 obese women who were followed over 2 y after Roux-en-Y gastric bypass. Multiplexed proteomics were used to simultaneously assay 27 cytokines and growth factors in serum. RESULTS: Concentrations of interleukin (IL)-9, IL-1-receptor antagonist, IL-10, interferon-gamma-inducible protein 10, macrophage inflammatory protein 1beta, monocyte chemoattractant protein 1, IL-8, RANTES (regulated upon activation, normal T cell expressed and secreted), monokine induced by interferon gamma, and vascular endothelial growth factor were found to be elevated in obesity. IL-10 was further elevated in diabetic obese patients, whereas eotaxin was found to be higher only in diabetic subjects. After surgery, many factors showed a biphasic pattern of variation, decreasing sharply at month 3 before rising back to presurgical values at month 6; these changes closely tracked similar kinetic changes in calorie and carbohydrate intake. After 1 y, an overall reduction in cytokines accompanied the reduction in body mass index and an amelioration in metabolic status. CONCLUSIONS: Obesity is associated with elevated circulating concentrations of a large panel of cytokines. Coordinated kinetic changes during weight loss suggest an early influence of calorie and carbohydrate intakes, whereas a longer-term reduction in corpulence might prevail in regulating circulating cytokine concentrations. This trial is registered at clincaltrials.gov as NCT00476658. PMID- 21677058 TI - Fish, shellfish, and long-chain n-3 fatty acid consumption and risk of incident type 2 diabetes in middle-aged Chinese men and women. AB - BACKGROUND: Long-chain polyunsaturated n-3 (omega-3) fatty acids, found mainly in fish, have been postulated to reduce type 2 diabetes (T2D) risk. However, the role of long-chain n-3 fatty acids and fish intake in the development of T2D remains unresolved. OBJECTIVE: We examined associations between fish, shellfish, and long-chain n-3 fatty acids and the risk of T2D in a middle-aged Chinese population. DESIGN: This was a prospective population-based cohort study in 51,963 men and 64,193 women free of T2D, cardiovascular disease, and cancer at baseline with valid dietary information. Dietary intake, physical activity, and anthropometric measurements were collected. A Cox regression model was used to evaluate the association of fish, shellfish, and long-chain n-3 fatty acid (in g/d) with risk of T2D. RESULTS: Fish, shellfish, and long-chain n-3 fatty acid intakes were inversely associated with T2D in women. The relative risks [RRs (95% CI)] for quintiles of fish intake were 1.00, 0.96 (0.86, 1.06), 0.84 (0.75, 0.94), 0.80 (0.71, 0.90), and 0.89 (0.78, 1.01) (P for trend = 0.003) and for shellfish were 1.00, 0.91 (0.82, 1.01), 0.79 (0.71, 0.89), 0.80 (0.71, 0.91), and 0.86 (0.76, 0.99) (P for trend = 0.006). In men, only the association between shellfish intake and T2D was significant. The RRs (95% CI) for quintiles of fish intake were 1.00, 0.92 (0.75, 1.13), 0.80 (0.65, 1.00), 0.89 (0.72, 1.11), and 0.94 (0.74, 1.17) (P for trend = 0.50) and for shellfish intake were 1.00, 0.93 (0.76, 1.12), 0.70 (0.56, 086), 0.66 (0.53, 0.82), and 0.82 (0.65, 1.02) (P for trend = 0.003). CONCLUSIONS: An inverse association between fish and shellfish intake and T2D in women was found. No evidence of a detrimental effect of fish intake in this population was observed. PMID- 21677059 TI - The effects of L-arabinose on intestinal sucrase activity: dose-response studies in vitro and in humans. AB - BACKGROUND: On the basis of results in cell cultures, rodents, and pigs, l arabinose may inhibit intestinal sucrase activity and thereby delay sucrose digestion. OBJECTIVE: The objective was to investigate the dose-response effects of l-arabinose on intestinal sucrase activity in vitro and glucose tolerance, appetite, and energy intake in humans. DESIGN: In vitro, Caco-2 cells were cultured for 21 d, homogenized, and used as an enzyme preparation with sucrose as substrate in concentrations from 7 to 280 mmol/L with 0.84, 1.4, and 2.8 mmol l arabinose/L as inhibitor. Released glucose was measured after 30 min. In the human studies, 15 healthy men participated in a randomized, double-blind, crossover study. Sucrose beverages (75 g in 300 mL) supplemented with 0%, 1.3%, 2.7%, and 4% by weight of l-arabinose were tested at breakfast. Blood for the measurement of glucose, insulin, C-peptide, incretin hormones, and triacylglycerol was collected under fasting conditions and for 3 h postprandially. Postprandial appetite sensations and energy intake at lunch were registered. RESULTS: In vitro, the addition of l-arabinose resulted in uncompetitive inhibition of sucrase activity. In the human studies, supplementation with 4% l-arabinose produced an 11% lower glucose peak, a 33% lower and delayed insulin peak, a 23% reduction in the incremental area under the curve (iAUC) for insulin, a 23% lower and delayed C-peptide peak, a 9% reduction in the iAUC for C-peptide, a 53% increase in the iAUC for glucagon-like peptide-1 (GLP-1), and a 28% reduction in the iAUC for glucose-dependent insulinotropic polypeptide. No effects on triacylglycerol, gastrointestinal symptoms, appetite ratings, or energy intake were observed. CONCLUSIONS: l-Arabinose inhibits sucrase activity from Caco-2 cells; 4% l-arabinose in sucrose beverages reduces postprandial glucose, insulin, and C-peptide responses and enhances the GLP-1 response in humans without gastrointestinal adverse effects. This trial is registered at clinicaltrials.gov as NCT00302302. PMID- 21677060 TI - Posting point-of-purchase nutrition information in university canteens does not influence meal choice and nutrient intake. AB - BACKGROUND: Growing concern over the relation between out-of-home eating and overweight has triggered the use of point-of-purchase (POP) nutrition information when eating out of the home. In canteens that offer various unhealthy choices, the posting of POP nutrition information has the potential to improve meal choices and dietary intakes. OBJECTIVE: The objective of this study was to increase the proportion of consumed meals that comply with recommendations for energy, saturated fat, sodium, and vegetable content by 5%. DESIGN: A one-group pretest-posttest design was used. A total of 224 customers of 2 university canteens completed a questionnaire used for consumer profiling and 3-d food records to assess their meal choices and nutrient intakes. The 12 best meal combinations received star ratings and descriptors for nutrients or food groups that did not comply. RESULTS: Reported meal choices in canteens and nutrient intakes did not improve after the intervention (P > 0.05). The nutritional profile of the meal choice, obtained from a qualitative and quantitative nutritional assessment of meals, mirrored the nutritional profile of all meals offered (P > 0.05) and not that of the recommended meals offered (P < 0.001). Meal choices were not compensated for later in the day (P > 0.05). The healthiest choices were made by participants with greater objective nutrition knowledge, stronger health and weight-control motives, and a greater openness to change meal choices at baseline (P < 0.05). CONCLUSIONS: The posting of nutrition information in university canteens did not effectively change meal choices and nutrient intakes. Despite the intervention, meal choices were largely determined by meals offered. Therefore, nutrition-information interventions in canteens may be more effective with a healthier meal supply. This trial was registered at clinicaltrials.gov as NCT01249508. PMID- 21677061 TI - First assessment of menstrual cycle function and reproductive endocrine status in Samoan women. AB - BACKGROUND: American Samoa and Samoa are now characterized by one of the world's highest levels of adult overweight and obesity. Our objective was to investigate patterns of menstrual cyclicity reported by Samoan women and examine the relationship to adiposity and select hormone levels. METHODS: A cross-sectional analysis was performed among Samoan women, aged 18-39 years (n = 322), using anthropometric and biomarker measures of adiposity and reproductive health, including insulin, adiponectin, testosterone, sex hormone-binding globulin, free androgen index (FAI) and mullerian-inhibiting substance (MIS). Menstrual regularity was assessed from self-reported responses. Multivariable models were estimated to adjust for potential confounding of the associations between menstrual patterns and other measures. RESULTS: A high proportion of the women (13.7%) reported oligomenorrhea or amenorrhea (OM/AM). More than three-quarters, 80.7%, of women were either overweight or obese, using Polynesian-specific criteria, and OM/AM was significantly associated with higher BMI. Abdominal circumference and insulin levels were significantly higher, and adiponectin levels were lower, in those who reported OM/AM versus regular menstruation. The FAI was higher in women with increased BMI. MIS levels declined with age, more slowly in those reporting OM/AM. CONCLUSIONS: Self-reported OM/AM was associated with an elevated BMI, abdominal adiposity and serum insulin, and with reduced adiponectin levels. These findings support a high rate of metabolic syndrome, and perhaps PCOS and reproductive dysfunction, among Samoan women. PMID- 21677062 TI - 1-Aminobenzotriazole, a known cytochrome P450 inhibitor, is a substrate and inhibitor of N-acetyltransferase. AB - 1-Aminobenzotriazole (ABT) has been used widely as a nonselective in vitro and in vivo inhibitor of cytochrome P450 enzymes. To date, however, it has not been evaluated as an inhibitor of UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and N-acetyltransferase (NAT). In the present study, ABT was shown not to inhibit UGT and SULT activity (acetaminophen and 7-hydroxycoumarin as substrates) in rat liver microsomes and rat liver 9000 g supernatant fraction (RLS9), respectively. However, it did inhibit the RLS9-catalyzed N-acetylation of procainamide (IC(50) ~ 30 MUM), and no preincubation time dependence was evident. In agreement, oral ABT (100 mg/kg, 2 h predose) decreased the clearance of intravenous procainamide (45%) in rats, accompanied by a decreased N acetylprocainamide-to-procainamide ratio in urine (0.74 versus 0.21) and plasma (area under the curve ratio 0.59 versus 0.11). Additional studies with human forms of NAT (hNAT1 and hNAT2) revealed that ABT is a more potent inhibitor of hNAT2 compared with hNAT1 (IC(50) 158 MUM versus > 1 mM). Consistent with the IC(50) estimate, formal inhibition studies revealed that inhibition of hNAT2 was competitive with an inhibition constant of 67 MUM. In accordance with the competitive inhibition, ABT was shown to undergo N-acetylation in the presence of both human NAT forms, with hNAT1 exhibiting less activity under the same assay conditions (~40% of hNAT2). In summary, the results described herein indicate that ABT is a substrate and inhibitor of NAT. Such an interaction should be considered when using ABT as a nonselective inhibitor of P450, especially when NAT-dependent metabolism is also involved. PMID- 21677064 TI - Emerging severe and fatal infections due to Klebsiella pneumoniae in two university hospitals in France. AB - Severe infections caused by hypermucoviscous Klebsiella pneumoniae have been reported in Southeast Asian countries over the past several decades. This report shows their emergence in France, with 12 cases observed during a 2-year period in two university hospitals. Two clones (sequence type 86 [ST86] and ST380) of serotype K2 caused five rapidly fatal bacteremia cases, three of which were associated with pneumonia, whereas seven liver abscess cases were caused by K1 strains of ST23. PMID- 21677063 TI - Production of 22-hydroxy metabolites of vitamin d3 by cytochrome p450scc (CYP11A1) and analysis of their biological activities on skin cells. AB - Cytochrome P450scc (CYP11A1) can hydroxylate vitamin D(3), producing 20S hydroxyvitamin D(3) [20(OH)D(3)] and 20S,23-dihydroxyvitamin D(3) [20,23(OH)(2)D(3)] as the major metabolites. These are biologically active, acting as partial vitamin D receptor (VDR) agonists. Minor products include 17 hydroxyvitamin D(3), 17,20-dihydroxyvitamin D(3), and 17,20,23-trihydroxyvitamin D(3). In the current study, we have further analyzed the reaction products from cytochrome P450scc (P450scc) action on vitamin D(3) and have identified two 22 hydroxy derivatives as products, 22-hydroxyvitamin D(3) [22(OH)D(3)] and 20S,22 dihydroxyvitamin D(3) [20,22(OH)(2)D(3)]. The structures of both of these derivatives were determined by NMR. P450scc could convert purified 22(OH)D(3) to 20,22(OH)(2)D(3). The 20,22(OH)(2)D(3) could also be produced from 20(OH)D(3) and was metabolized to a trihydroxyvitamin D(3) product. We compared the biological activities of these new derivatives with those of 20(OH)D(3), 20,23(OH)(2)D(3), and 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. 1,25(OH)(2)D(3), 20(OH)D(3), 22(OH)D(3), 20,23(OH)(2)D(3), and 20,22(OH)(2)D(3) significantly inhibited keratinocyte proliferation in a dose-dependent manner. The strongest inducers of involucrin expression (a marker of keratinocyte differentiation) were 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), 20(OH)D(3), and 1,25(OH)(2)D(3), with 22(OH)D(3) having a heterogeneous effect. Little or no stimulation of CYP24 mRNA expression was observed for all the analogs tested except for 1,25(OH)(2)D(3). All the compounds stimulated VDR translocation from the cytoplasm to the nucleus with 22(OH)D(3) and 20,22(OH)(2)D(3) having less effect than 1,25(OH)(2)D(3) and 20(OH)D(3). Thus, we have identified 22(OH)D(3) and 20,22(OH)(2)D(3) as products of CYP11A1 action on vitamin D(3) and shown that, like 20(OH)D(3) and 20,23(OH)(2)D(3), they are active on keratinocytes via the VDR, however, showing a degree of phenotypic heterogeneity in comparison with other P450scc-derived hydroxy metabolites of vitamin D(3). PMID- 21677065 TI - Quantitation of Candida CFU in initial positive blood cultures. AB - One potential limitation of DNA-based molecular diagnostic tests for Candida bloodstream infection (BSI) is organism burden, which is not sufficiently characterized. We hypothesized that the number of CFU per milliliter (CFU/ml) present in an episode of Candida BSI is too low for reliable DNA-based diagnostics. In this study, we determined Candida burden in the first positive blood culture and explored factors that affect organism numbers and patient outcomes. We reviewed records of consecutive patients with a positive blood culture for Candida in the lysis-centrifugation blood culture system (Isolator, Wampole Laboratories, Cranbury, NJ) from 1987 to 1991. Descriptive statistics and logistic regression analyses were performed. One hundred fifty-two episodes of Candida BSI were analyzed. Patient characteristics included adult age (72%), indwelling central venous catheters (83%), recent surgery (29%), neutropenia (24%), transplant (14%), and other immune suppression (21%). Rates of treatment success and 30-day mortality for candidemia were each 51%. The median CFU/ml was 1 (mode 0.1, range 0.1 to >1,000). In the multivariate analysis, pediatric patients were more likely than adults to have high organism burdens (odds ratio [OR], 10.7; 95% confidence interval [95% CI], 4.3 to 26.5). Initial organism density did not affect patient outcome. Candida CFU/ml in the first positive blood culture of a BSI episode varies greatly; >50% of cultures had <=1 CFU/ml, a concentration below the experimental yeast cell threshold for reliable DNA-based diagnostics. DNA-based diagnostics for Candida BSI will be challenged by low organism density and the need for sufficient specimen volume; future research on alternate targets is warranted. PMID- 21677066 TI - Prevalence and genetic relatedness of methicillin-susceptible Staphylococcus aureus isolates detected by the Xpert MRSA nasal assay. AB - Methicillin-susceptible Staphylococcus aureus (MSSA) isolates lacking mecA yet testing positive on the Xpert MRSA assay were recovered from culture for 7.7% of 248 Xpert-positive nasal samples. These "false-positive" Xpert results may be attributed to staphylococcal cassette chromosome (SCC) elements without the mecA gene. Pulsed-field gel electrophoresis (PFGE) analysis revealed a diverse population of MSSA strains. PMID- 21677067 TI - Four independent molecular prion protein parameters for discriminating new cases of C, L, and h bovine spongiform encephalopathy in cattle. AB - In anticipation of the emergence of more variants of bovine spongiform encephalopathy (BSE), a semiquantitative display of the following four independent molecular diagnostic prion parameters was designed: N terminus, proteinase K (PK) resistance, glycoprofile, and mixed population. One H BSE case, three L BSE cases, six C BSE cases, and one unusual classical BSE (C BSE) case are reported. PMID- 21677068 TI - Reduced sensitivity of oxacillin-screening agar for detection of MRSA ST398 from colonized pigs. PMID- 21677069 TI - Cepheid GeneXpert MTB/RIF assay for Mycobacterium tuberculosis detection and rifampin resistance identification in patients with substantial clinical indications of tuberculosis and smear-negative microscopy results. AB - The GeneXpert MTB/RIF assay was evaluated with microscopically negative and positive pulmonary and extrapulmonary specimens from patients with substantial clinical indications for tuberculosis. For the pulmonary samples, the sensitivity, specificity, and positive and negative predictive values were 90.6%, 94.3%, 93.5%, and 91.7%, and for the extrapulmonary samples, they were 100%, 91.6%, 50%, and 100%, respectively. For microscopically negative specimens, the respective values were 86.3%, 93%, 79%, and 95.6%. The assay correctly detected rifampin resistance in all but one specimen, which harbored a mixed population. The GeneXpert assay was highly effective for tuberculosis diagnosis and identification of rifampin-resistant strains in smear-negative samples. PMID- 21677070 TI - Evaluation of oral antiseptic rinsing before sputum collection to reduce contamination of mycobacterial cultures. AB - To assess whether rinsing with oral antiseptics before sputum collection would reduce contamination of mycobacterial cultures, 120 patients with suspected tuberculosis were randomly assigned to rinse with chlorhexidine or cetylpyridinium mouthwash before collection. The culture contamination rate was significantly lower after rinsing with chlorhexidine before collection, especially for cultures grown in MGIT medium. PMID- 21677072 TI - Tryptophan from human milk induces oxidative stress and upregulates the Nrf-2 mediated stress response in human intestinal cell lines. AB - Chemical screening of digested human milk protein using the oxygen radical absorbance capacity (ORAC(FL)) antioxidant assay confirmed the presence of a peptide fraction (PF23) with high antioxidant activity [5.53 mmol Trolox equivalents (TE)/g] that contained tryptophan as a main component. We evaluated the effects of both PF23 and tryptophan alone on the modulation of oxidative stress in cultured intestinal cells using a dichlorofluorescein diacetate probe. Despite the high ORAC(FL) value, PF23 enhanced (P < 0.05) 2, 2'-azobis (2 amidinopropane) dihydrochloride (peroxyl radical generator)-induced intracellular oxidation in the Caco-2 human adenocarcinoma cell line, suggesting prooxidant activity. Compared to selected peptide fractions with relatively lower ORAC(FL) values, PF23 induced oxidative stress more than all other peptide fractions tested (P < 0.05) and contained more tryptophan than the others (P < 0.05). Similar prooxidant activity was observed for tryptophan when it was added to culture medium for both the Caco-2 cells and FHs 74 Int primary fetal enterocytes, while also exhibiting a high ORAC(FL) value (9.69 mmol TE/g). The effect of tryptophan that involves activation of the Nrf-2 pathway and transcription of antioxidant enzymes was therefore investigated in FHs 74 Int cells. Exposure of infant intestinal cells to tryptophan resulted in Nrf-2 activation and an increase in the gene transcript level of glutathione peroxidase 2. We conclude that tryptophan-induced oxidative stress associated with tryptophan-containing milk peptides induces an adaptive response that involves the activation of the antioxidant responsive signaling pathway in intestinal cells. PMID- 21677071 TI - Refractory chronic pleurisy caused by Helicobacter equorum-like bacterium in a patient with X-linked agammaglobulinemia. AB - We describe a 35-year-old man with X-linked agammaglobulinemia who had refractory chronic pleurisy caused by a Helicobacter equorum-like bacterium. Broad-range bacterial PCR targeting the 16S and 23S rRNA genes and in situ hybridization targeting the 16S rRNA gene of H. equorum confirmed the presence of this pathogen in a human for the first time. PMID- 21677073 TI - A multi-micronutrient beverage enhances the vitamin A and zinc status of Nigerian primary schoolchildren. AB - Schoolchildren in Nigeria are rarely targeted by micronutrient interventions. We completed a 6-mo, double-blind, placebo-controlled trial to determine the effects of a multi-micronutrient beverage on biochemical and anthropometric indicators of nutritional status among schoolchildren participating in a pilot school feeding program in Nasarawa State, Nigeria. Children received 1 of 2 interventions 5 d/wk during school hours: 1) 250 mL/d of a multi-micronutrient beverage that included vitamin A, iron, and zinc (micronutrient); or 2) an isoenergetic control beverage (control). At baseline, 566 children 5-13 y old were randomized to groups (micronutrient: n = 288; control: n = 278). Height, weight, hemoglobin, and serum concentrations of C-reactive protein, ferritin, retinol, and zinc were measured at baseline and at the end of the study. A total of 270 children in the micronutrient group and 264 children in the control group completed the study. Self-reports of vomiting increased in both groups at 6 mo; however, the prevalence tended to be greater in the micronutrient group (21%) compared to the control group (14%) (P = 0.06). Biochemical changes were greater in the micronutrient group compared to control for serum retinol (0.10 +/- 0.02 MUmol/L vs. 0.02 +/- 0.02 MUmol/L; P = 0.016) and zinc (1.0 +/- 0.2 MUmol/L vs. 0.6 +/- 0.2 MUmol/L; P = 0.031). The intervention did not significantly affect hemoglobin or serum ferritin concentrations. The cost effectiveness of the intervention needs to be further evaluated, as does the efficacy of the beverage on anemia and indicators of iron status. PMID- 21677074 TI - Arginine can be synthesized from enteral proline in healthy adult humans. AB - There is considerable controversy recently in identifying dietary precursors for arginine synthesis. We have previously shown in human neonates and piglets that proline is the sole dietary precursor for arginine synthesis. It is unclear in adult humans whether proline is a dietary precursor for arginine. We performed a multi-tracer stable isotope study in adults using (15)N(2)-ureido arginine and (15)N proline to elucidate synthesis of citrulline and arginine and determine whether proline is a precursor for arginine. Primed, intermittent infusions of the labeled amino acids were given enterally to 5 healthy men consuming a standardized milkshake diet. Blood was sampled during plateau enrichment between 1.5 and 3 h. Plasma enrichment occurred for both tracers, giving enteral turnover estimates of 93 MUmol . kg(-1) . h(-1) for arginine and 154 MUmol . kg(-1) . h( 1) for proline. Appearance of the label from proline in arginine and the intermediaries, ornithine and citrulline, was measured in all participants. The rate of synthesis of arginine from proline was 3.7 MUmol . kg(-1) . h(-1), which is estimated to be ~40% of newly synthesized arginine. In this first study in adult humans using an enteral proline tracer, we have demonstrated synthesis of arginine from this dietary amino acid. Therefore, as in newborns, proline must now be considered a dietary precursor for arginine in healthy adults. PMID- 21677075 TI - A sulfur amino acid-free meal increases plasma lipids in humans. AB - The content of sulfur amino acid (SAA) in a meal affects postprandial plasma cysteine concentrations and the redox potential of cysteine/cystine. Because such changes can affect enzyme, transporter, and receptor activities, meal content of SAA could have unrecognized effects on metabolism during the postprandial period. This pilot study used proton NMR ((1)H-NMR) spectroscopy of human plasma to test the hypothesis that dietary SAA content changes macronutrient metabolism. Healthy participants (18-36 y, 5 males and 3 females) were equilibrated for 3 d to adequate SAA, fed chemically defined meals without SAA for 5 d (depletion), and then fed isoenergetic, isonitrogenous meals containing 56 mg.kg(-1).d(-1) SAA for 4.5 d (repletion). On the first and last day of consuming the chemically defined meals, a morning meal containing 60% of the daily food intake was given and plasma samples were collected over an 8-h postprandial time course for characterization of metabolic changes by (1)H-NMR spectroscopy. SAA-free food increased peak intensity in the plasma (1)H-NMR spectra in the postprandial period. Orthogonal signal correction/partial least squares-discriminant analysis showed changes in signals associated with lipids, some amino acids, and lactate, with notable increases in plasma lipid signals (TG, unsaturated lipid, cholesterol). Conventional lipid analyses confirmed higher plasma TG and showed an increase in plasma concentration of the lipoprotein lipase inhibitor, apoC III. The results show that plasma (1)H-NMR spectra can provide useful macronutrient profiling following a meal challenge protocol and that a single meal with imbalanced SAA content alters postprandial lipid metabolism. PMID- 21677076 TI - Whey protein but not soy protein supplementation alters body weight and composition in free-living overweight and obese adults. AB - A double-blind, randomized clinical trial was conducted to determine the effect of consumption of supplemental whey protein (WP), soy protein (SP), and an isoenergetic amount of carbohydrate (CHO) on body weight and composition in free living overweight and obese but otherwise healthy participants. Ninety overweight and obese participants were randomly assigned to 1 of 3 treatment groups for 23 wk: 1) WP; 2) SP (each providing ~56 g/d of protein and 1670 kJ/d); or 3) an isoenergetic amount of CHO. Supplements were consumed as a beverage twice daily. Participants were provided no dietary advice and continued to consume their free choice diets. Participants' body weight and composition data were obtained monthly. Dietary intake was determined by 24-h dietary recalls collected every 10 d. After 23 wk, body weight and composition did not differ between the groups consuming the SP and WP or between SP and CHO; however, body weight and fat mass of the group consuming the WP were lower by 1.8 kg (P < 0.006) and 2.3 kg (P < 0.005), respectively, than the group consuming CHO. Lean body mass did not differ among any of the groups. Waist circumference was smaller in the participants consuming WP than in the other groups (P < 0.05). Fasting ghrelin was lower in participants consuming WP compared with SP or CHO. Through yet-unknown mechanisms, different sources of dietary protein may differentially facilitate weight loss and affect body composition. Dietary recommendations, especially those that emphasize the role of dietary protein in facilitating weight change, should also address the demonstrated clinical potential of supplemental WP. PMID- 21677077 TI - Pulp healing and regeneration: more questions than answers. AB - Differences between pulp repair and regeneration guide different strategic options. After mild carious dentin lesions, odontoblasts and Hoehl's cells are implicated in the formation of reactionary dentin. Reparative dentin formation and/or pulp regeneration after partial degradation is under the control of pulp progenitors. A series of questions arise from recent researches on tissue engineering. In this series of questions, we compare the therapeutic potential of pluripotent embryonic and adult stem cells, both being used in cell-based dental therapies. Crucial questions arise on the origin of stem cells and the localization of niches of progenitors in adult teeth. Circulating progenitor cells may also be candidate for promoting pulp regeneration. Then, we focus on strategies allowing efficient progenitors recruitment. Along this line, we compare the potential of embryonic stem cells versus adult stem cells. Re programming adult pulp cells to become induced pluripotent stem cells constitute another option. Genes, transcription factors and growth factors may be used to stimulate the differentiation cascade. Extracellular matrix molecules or some bioactive specific domains after enzymatic cleavage may also contribute to the formation of an artificial pulp and ultimately to its mineralization. PMID- 21677078 TI - Dental pulp stem cells, niches, and notch signaling in tooth injury. AB - Stem cells guarantee tissue repair and regeneration throughout life. The decision between cell self-renewal and differentiation is influenced by a specialized microenvironment called the 'stem cell niche'. In the tooth, stem cell niches are formed at specific anatomic locations of the dental pulp. The microenvironment of these niches regulates how dental pulp stem cell populations participate in tissue maintenance, repair, and regeneration. Signaling molecules such as Notch proteins are important regulators of stem cell function, with various capacities to induce proliferation or differentiation. Dental injuries often lead to odontoblast apoptosis, which triggers activation of dental pulp stem cells followed by their proliferation, migration, and differentiation into odontoblast like cells, which elaborate a reparative dentin. Better knowledge of the regulation of dental pulp stem cells within their niches in pathological conditions will aid in the development of novel treatments for dental tissue repair and regeneration. PMID- 21677079 TI - TWIST1 promotes the odontoblast-like differentiation of dental stem cells. AB - Stem cells derived from the dental pulp of extracted human third molars (DPSCs) have the potential to differentiate into odontoblasts, osteoblasts, adipocytes, and neural cells when provided with the appropriate conditions. To advance the use of DPSCs for dentin regeneration, it is important to replicate the permissive signals that drive terminal events in odontoblast differentiation during tooth development. Such a strategy is likely to restore a dentin matrix that more resembles the tubular nature of primary dentin. Due to the limitations of culture conditions, the use of ex vivo gene therapy to drive the terminal differentiation of mineralizing cells holds considerable promise. In these studies, we asked whether the forced expression of TWIST1 in DPSCs could alter the potential of these cells to differentiate into odontoblast-like cells. Since the partnership between Runx2 and Twist1 proteins is known to control the onset of osteoblast terminal differentiation, we hypothesized that these genes act to control lineage determination of DPSCs. For the first time, our results showed that Twist1 overexpression in DPSCs enhanced the expression of DSPP, a gene that marks odontoblast terminal differentiation. Furthermore, co-transfection assays showed that Twist1 stimulates Dspp promoter activity by antagonizing Runx2 function in 293FT cells. Analysis of our in vitro data, taken together, suggests that lineage specification of DPSCs can be modulated through ex vivo gene modifications. PMID- 21677080 TI - The microbial challenge to pulp regeneration. AB - Pulp regeneration is considered in cases where the dental pulp has been destroyed because of microbial irritation. Diverse oral and food-borne micro-organisms are able to invade the pulp space, form biofilm on canal walls, and infiltrate dentinal tubules. Prior to pulp regeneration procedures, the pulp space and dentinal walls need to be sufficiently disinfected to allow for and promote regeneration. The necessary level of disinfection is likely higher than that accepted for traditional endodontic therapy, because in traditional techniques the mere lowering of bacterial loads and prevention of bacterial access to periapical tissues is conducive to healing. Moreover, several of the non-specific antimicrobials used in traditional endodontic therapy may cause significant changes in remaining dentin that interfere with its inherent potential to mediate regeneration. Non-specific antimicrobials also suppress all microbial taxa, which may allow residual virulent micro-organisms to preferentially repopulate the pulp space. Therefore, it is important for endodontic pathogens to be studied by molecular methods that allow for a broad depth of coverage. It is then essential to determine the most effective protocols to disinfect the pulp space, with minimal disruption of remaining dentin. These protocols include the topical use of effective antibiotics, including newer agents that have demonstrated efficacy against endodontic pathogens. PMID- 21677081 TI - Mediators of inflammation and regeneration. AB - Characterization of the molecular response under caries lesions requires a robust and reliable transcript isolation system, and analysis of data indicated that collection of extracted teeth in either liquid nitrogen/RNA-stabilizing solution facilitated this. Subsequent transcriptional analysis indicated higher general activity in carious pulps, while characterization of inflammatory mediators, including cytokines and S100 proteins, highlighted increasing expression levels associated with both microbial front progression and elevated cellular immune response. Analysis of the pleiotropic hormone adrenomedullin (ADM) indicated that transcript and protein levels are increased in pulpal tissue during caries, and that protein levels sequestered in dentin due to primary dentinogenesis are comparable with those of TGF-beta1. Expression analysis of a leucine-rich-repeat containing protein (LRRC15/Lib) indicated that this highly conserved molecule was up-regulated during caries, is transcriptionally regulated by pro-inflammatory stimuli, and is relatively abundant in mineralized tissues. PMID- 21677082 TI - Pattern-recognition receptors in pulp defense. AB - Initial sensing of infection is mediated by germline-encoded pattern-recognition receptors (PRRs), the activation of which leads to the expression of inflammatory mediators responsible for the elimination of pathogens and infected cells. PRRs act as immune sensors that provide immediate cell responses to pathogen invasion or tissue injury. Here, we review the expression of PRRs in human dental pulp cells, namely, receptors from the Toll-like (TLR) and Nod-like NLR families, by which cells recognize bacteria. Particular attention is given to odontoblasts, which are the first cells encountered by pathogens and represent, in the tooth, the first line of defense for the host. Understanding cellular and molecular mechanisms associated with the recognition of bacterial pathogens by odontoblasts is critical for the development of therapeutic strategies that aim at preventing excessive pulp inflammation and related deleterious effects. PMID- 21677083 TI - Toll-like receptors, LPS, and dental monomers. AB - Unreacted monomers released from dental resin-based composites at non-cytotoxic concentrations cause a depletion of glutathione and an increase of reactive oxygen species (ROS), leading to, e.g., DNA damage and apoptosis. ROS-sensitive MAP-kinases are activated by HEMA and TEGDMA. MAP-kinases are also involved in the bacteria-triggered cell responses of the innate immune system, e.g., after bacterial lipopolysaccharide (LPS) binding to the Toll-like receptor (TLR) 4. Therefore, both bacteria and monomers imply environmental stress to pulp tissue, and they may influence the target cell reactions in a combined way. In macrophages, cell-surface antigens and cytokines were up-regulated after exposure to LPS, but TEGDMA caused a significant down-regulation. Regulation was dependent on exposure time, indicating that LPS and TEGDMA act differently on MAP-kinases. Furthermore, the cell type played a decisive role. Inhibition of the immune response may result in a decrease in inflammatory symptoms and/or a reduced defense capacity against bacteria. PMID- 21677084 TI - Pulpal progenitors and dentin repair. AB - Mesenchymal stem cells are present in the dental pulp. They have been shown to contribute to dentin-like tissue formation in vitro and to participate in bone repair after a mandibular lesion. However, their capacity to contribute efficiently to reparative dentin formation after pulp lesion has never been explored. After pulp exposure, we have identified proliferative cells within 3 zones. In the crown, zone I is near the cavity, and zone II corresponds to the isthmus between the mesial and central pulp. In the root, zone III, near the apex, at a distance from the inflammatory site, contains mitotic stromal cells which may represent a source of progenitor cells. Stem-cell-based strategies are promising treatments for tissue injury in dentistry. Our experiments focused on (1) location of stem cells induced to leave their quiescent state early after pulp injury and (2) implantation of pulp progenitors, a substitute for classic endodontic treatments, paving the way for pulp stem-cell-based therapies. PMID- 21677085 TI - Regeneration of dental pulp by stem cells. AB - Angiogenesis/vasculogenesis and neurogenesis are essential for pulp regeneration. Two subfractions of side-population (SP) cells, CD31(-)/CD146(-) SP cells and CD105(+) cells with angiogenic and neurogenic potential, were isolated by flow cytometry from canine dental pulp. In an experimental model of mouse hindlimb ischemia, transplantation of these cell populations resulted in an increase in blood flow, including high-density capillary formation. In a model of rat cerebral ischemia, stem cell transplantations enhanced neuronal regeneration and recovery from motor disability. Autologous transplantation of the CD31(-)/CD146( ) SP cells into an in vivo model of amputated pulp resulted in complete regeneration of pulp tissue with vascular and neuronal processes within 14 days. The transplanted cells expressed pro-angiogenic factors, implying trophic action on endothelial cells. Autologous transplantation of CD31(-)/CD146(-) SP cells or CD105(+) cells with stromal-cell-derived factor-1 (SDF-1) into root canals after whole pulp removal of mature teeth resulted in complete regeneration of pulp replete with nerves and vasculature by day 14, followed by dentin formation along the dentinal wall by day 35. Therefore, the potential utility of fractionated SP cells and CD105(+) cells in angiogenesis and neurogenesis was demonstrated by treatment of limb and cerebral ischemia following pulpotomy and pulpectomy. PMID- 21677086 TI - Dentin regeneration in vitro: the pivotal role of supportive cells. AB - The elaboration of dentin-pulp engineering strategies requires the investigation of not only progenitor cell potentials but also their interactions with other non progenitor "supportive" cells. Under severe caries lesions, progenitor cells may be activated by growth factors released after the acidic dissolution of carious dentin. However, dentin regeneration has also been observed after traumatic injuries without any significant dentin dissolution. This raises questions about the origin of signals involved in progenitor cell activation, migration, and differentiation. Study models such as the entire tooth culture and co-cultures of pulp and endothelial cells highlighted the role of interactions between the different pulp cell types and the pivotal role they play in dentin regeneration. Injured pulp fibroblasts secrete growth factors involved in progenitor cell activation and differentiation as well as neoangiogenesis which may pave the pathways for progenitor cell migration. This appears to be the first paper to focus on this very important field in dental pulp biology. PMID- 21677087 TI - Tooth slice/scaffold model of dental pulp tissue engineering. AB - Multipotency is a defining characteristic of post-natal stem cells. The human dental pulp contains a small subpopulation of stem cells that exhibit multipotency, as demonstrated by their ability to differentiate into odontoblasts, neural cells, and vascular endothelial cells. These discoveries highlight the fundamental role of stem cells in the biology of the dental pulp and suggest that these cells are uniquely suited for dental pulp tissue engineering purposes. The availability of experimental approaches specifically designed for studies of the differentiation potential of dental pulp stem cells has played an important role in these discoveries. The objective of this review is to describe the development and characterization of the Tooth Slice/Scaffold Model of Dental Pulp Tissue Engineering. In addition, we discuss the multipotency of dental pulp stem cells, focusing on the differentiation of these cells into functional odontoblasts and into vascular endothelial cells. PMID- 21677088 TI - Scaffolds for dental pulp tissue engineering. AB - For tissue engineering strategies, the choice of an appropriate scaffold is the first and certainly a crucial step. A vast variety of biomaterials is available: natural or synthetic polymers, extracellular matrix, self-assembling systems, hydrogels, or bioceramics. Each material offers a unique chemistry, composition and structure, degradation profile, and possibility for modification. The role of the scaffold has changed from passive carrier toward a bioactive matrix, which can induce a desired cellular behavior. Tailor-made materials for specific applications can be created. Recent approaches to generate dental pulp rely on established materials, such as collagen, polyester, chitosan, or hydroxyapatite. Results after transplantation show soft connective tissue formation and newly generated dentin. For dentin-pulp-complex engineering, aspects including vascularization, cell-matrix interactions, growth-factor incorporation, matrix degradation, mineralization, and contamination control should be considered. Self assembling peptide hydrogels are an example of a smart material that can be modified to create customized matrices. Rational design of the peptide sequence allows for control of material stiffness, induction of mineral nucleation, or introduction of antibacterial activity. Cellular responses can be evoked by the incorporation of cell adhesion motifs, enzyme-cleavable sites, and suitable growth factors. The combination of inductive scaffold materials with stem cells might optimize the approaches for dentin-pulp complex regeneration. PMID- 21677089 TI - Dentin-pulp complex regeneration: from lab to clinic. AB - Dentistry is entering an exciting era in which many of the advances in biotechnology offer opportunities for exploitation in novel and more effective therapies. Pulp healing is complex and dependent on the extent of injury, among many other factors. Many of the molecular and cellular processes involved in these healing events recapitulate developmental processes. The regulation of odontoblast activity is clearly central to pulp healing, and an understanding of the mechanisms involved in these processes is necessary to enable laboratory studies to be translated to clinic application. Transcriptome analysis has identified changes in many odontoblast genes during the life-cycle of this cell and its responses to injurious challenge. The p38 MAPKinase pathway appears to be central to the transcriptional control of odontoblasts and may provide a key target for therapeutic intervention. The many recent advances in knowledge of pulpal stem cells and molecular signaling molecules within the tooth, now provide exciting opportunities for clinical translation to novel therapies. Such translation will require the partnership of researchers and skilled clinicians who can effectively apply advances in knowledge to appropriate clinical cases and develop novel therapies which can be realistically introduced into the clinic. PMID- 21677090 TI - A naturally occurring human adenovirus type 7 variant with a 1743 bp deletion in the E3 cassette. AB - Human adenovirus type 7 (HAdV-7) is an important cause of acute respiratory disease (ARD). Different genomic variants of HAdV-7 have been described, designated 7a-7l. In a previous study to investigate risk factors for ARD and wheezing, nasopharyngeal samples were collected from 90 ill children seeking medical attention in Ribeirao Preto, Sao Paulo, Brazil. HAdVs were identified in 31 samples and were characterized by serum neutralization and genome restriction analysis. Eleven HAdVs were identified as being HAdV-7, five of which were classified as being of genome type 7p (Gomen). Six other HAdV-7 isolates gave new restriction profiles with all enzymes used and were classified as being a new genomic variant, 7m. These isolates were further characterized by sequencing. The hexon and fiber genes of the 7m variant were nearly identical to the prototype, 7p. However, nucleotide sequences from the E3 cassette revealed a 1743 bp deletion affecting the 16.1K, 19K, 20.1K and 20.5K ORFs. PMID- 21677091 TI - A single amino acid change, Q114R, in the cleavage-site sequence of Newcastle disease virus fusion protein attenuates viral replication and pathogenicity. AB - A key determinant of Newcastle disease virus (NDV) virulence is the amino acid sequence at the fusion (F) protein cleavage site. The NDV F protein is synthesized as an inactive precursor, F(0), and is activated by proteolytic cleavage between amino acids 116 and 117 to produce two disulfide-linked subunits, F(1) and F(2). The consensus sequence of the F protein cleavage site of virulent [(112)(R/K)-R-Q-(R/K)-R?F-I(118)] and avirulent [(112)(G/E)-(K/R)-Q (G/E)-R?L-I(118)] strains contains a conserved glutamine residue at position 114. Recently, some NDV strains from Africa and Madagascar were isolated from healthy birds and have been reported to contain five basic residues (R-R-R-K-R?F-I/V or R R-R-R-R?F-I/V) at the F protein cleavage site. In this study, we have evaluated the role of this conserved glutamine residue in the replication and pathogenicity of NDV by using the moderately pathogenic Beaudette C strain and by making Q114R, K115R and I118V mutants of the F protein in this strain. Our results showed that changing the glutamine to a basic arginine residue reduced viral replication and attenuated the pathogenicity of the virus in chickens. The pathogenicity was further reduced when the isoleucine at position 118 was substituted for valine. PMID- 21677092 TI - Roadmap for harmonization of clinical laboratory measurement procedures. AB - Results between different clinical laboratory measurement procedures (CLMP) should be equivalent, within clinically meaningful limits, to enable optimal use of clinical guidelines for disease diagnosis and patient management. When laboratory test results are neither standardized nor harmonized, a different numeric result may be obtained for the same clinical sample. Unfortunately, some guidelines are based on test results from a specific laboratory measurement procedure without consideration of the possibility or likelihood of differences between various procedures. When this happens, aggregation of data from different clinical research investigations and development of appropriate clinical practice guidelines will be flawed. A lack of recognition that results are neither standardized nor harmonized may lead to erroneous clinical, financial, regulatory, or technical decisions. Standardization of CLMPs has been accomplished for several measurands for which primary (pure substance) reference materials exist and/or reference measurement procedures (RMPs) have been developed. However, the harmonization of clinical laboratory procedures for measurands that do not have RMPs has been problematic owing to inadequate definition of the measurand, inadequate analytical specificity for the measurand, inadequate attention to the commutability of reference materials, and lack of a systematic approach for harmonization. To address these problems, an infrastructure must be developed to enable a systematic approach for identification and prioritization of measurands to be harmonized on the basis of clinical importance and technical feasibility, and for management of the technical implementation of a harmonization process for a specific measurand. PMID- 21677093 TI - Accurate single-nucleotide polymorphism allele assignment in trisomic or duplicated regions by using a single base-extension assay with MALDI-TOF mass spectrometry. AB - BACKGROUND: The accurate assignment of alleles embedded within trisomic or duplicated regions is an essential prerequisite for assessing the combined effects of single-nucleotide polymorphisms (SNPs) and genomic copy number. Such an integrated analysis is challenging because heterozygotes for such a SNP may be one of 2 genotypes-AAB or ABB. Established methods for SNP genotyping, however, can have difficulty discriminating between the 2 heterozygous trisomic genotypes. We developed a method for assigning heterozygous trisomic genotypes that uses the ratio of the height of the 2 allele peaks obtained by mass spectrometry after a single-base extension assay. METHODS: Eighteen COL6A2 (collagen, type VI, alpha 2) SNPs were analyzed in euploid and trisomic individuals by means of a multiplexed single-base extension assay that generated allele-specific oligonucleotides of differing M(r) values for detection by MALDI-TOF mass spectrometry. Reference data (mean and SD) for the allele peak height ratios were determined from heterozygous euploid samples. The heterozygous trisomic genotypes were assigned by calculating the z score for each trisomic allele peak height ratio and by considering the sign (+/-) of the z score. RESULTS: Heterozygous trisomic genotypes were assigned in 96.1% (range, 89.9%-100%) of the samples for each SNP analyzed. The genotypes obtained were reproduced in 95 (97.5%) of 97 loci retested in a second assay. Subsequently, the origin of nondisjunction was determined in 108 (82%) of 132 family trios with a Down syndrome child. CONCLUSIONS: This approach enabled reliable genotyping of heterozygous trisomic samples and the determination of the origin of nondisjunction in Down syndrome family trios. PMID- 21677094 TI - Oral fluid cannabinoids in chronic, daily Cannabis smokers during sustained, monitored abstinence. AB - BACKGROUND: Oral fluid (OF) is an accepted alternative biological matrix for drug treatment, workplace, and DUID (driving under the influence of drugs) investigations, but establishing the cannabinoid OF detection window and concentration cutoff criteria are important. METHODS: Cannabinoid concentrations were quantified in OF from chronic, daily cannabis smokers during monitored abstinence. Delta(9)-tetrahydrocannabinol (THC)(3), cannabidiol (CBD), cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH) were determined in daily OF samples collected with the QuantisalTM device. GC-MS limits of quantification (LOQ) were 0.5 MUg/L for THC and CBD, 1 MUg/L for CBN, and 7.5 ng/L for THCCOOH. RESULTS: After providing written informed consent for this institutional review board approved study, 28 participants resided from 4 to 33 days on the secure research unit and provided 577 OF specimens. At the LOQ, THC was generally quantifiable for 48 h, whereas CBD and CBN were detected only at admission. Median THCCOOH detection time was 13 days (CI 6.4-19.6 days). Mean THC detection rates decreased from 89.3% at admission to 17.9% after 48 h, whereas THCCOOH gradually decreased from 89.3% to 64.3% within 4 days. Criteria of THC >=2 MUg/L and THCCOOH >=20 ng/L reduced detection to <48 h in chronic cannabis smokers. An OF THCCOOH/THC ratio <=4 ng/MUg or presence of CBD or CBN may indicate more recent smoking. CONCLUSIONS: THC, THCCOOH, CBD, and CBN quantification in confirmatory OF cannabinoid testing is recommended. Inclusion of multiple cannabinoid cutoffs accounted for residual cannabinoid excretion in OF from chronic, daily cannabis smokers and could reduce the potential for positive test results from passive cannabis smoke exposure and lead to greatly improved test interpretation. PMID- 21677095 TI - Conserved and divergent rhythms of crassulacean acid metabolism-related and core clock gene expression in the cactus Opuntia ficus-indica. AB - The cactus Opuntia ficus-indica is a constitutive Crassulacean acid metabolism (CAM) species. Current knowledge of CAM metabolism suggests that the enzyme phosphoenolpyruvate carboxylase kinase (PPCK) is circadian regulated at the transcriptional level, whereas phosphoenolpyruvate carboxylase (PEPC), malate dehydrogenase (MDH), NADP-malic enzyme (NADP-ME), and pyruvate phosphate dikinase (PPDK) are posttranslationally controlled. As little transcriptomic data are available from obligate CAM plants, we created an expressed sequence tag database derived from different organs and developmental stages. Sequences were assembled, compared with sequences in the National Center for Biotechnology Information nonredundant database for identification of putative orthologs, and mapped using Kyoto Encyclopedia of Genes and Genomes Orthology and Gene Ontology. We identified genes involved in circadian regulation and CAM metabolism for transcriptomic analysis in plants grown in long days. We identified stable reference genes for quantitative polymerase chain reaction and found that OfiSAND, like its counterpart in Arabidopsis (Arabidopsis thaliana), and OfiTUB are generally appropriate standards for use in the quantification of gene expression in O. ficus-indica. Three kinds of expression profiles were found: transcripts of OfiPPCK oscillated with a 24-h periodicity; transcripts of the light-active OfiNADP-ME and OfiPPDK genes adapted to 12-h cycles, while transcript accumulation patterns of OfiPEPC and OfiMDH were arrhythmic. Expression of the circadian clock gene OfiTOC1, similar to Arabidopsis, oscillated with a 24-h periodicity, peaking at night. Expression of OfiCCA1 and OfiPRR9, unlike in Arabidopsis, adapted best to a 12-h rhythm, suggesting that circadian clock gene interactions differ from those of Arabidopsis. Our results indicate that the evolution of CAM metabolism could be the result of modified circadian regulation at both the transcriptional and posttranscriptional levels. PMID- 21677096 TI - Inositol polyphosphate 5-phosphatase7 regulates the production of reactive oxygen species and salt tolerance in Arabidopsis. AB - Plants possess remarkable ability to adapt to adverse environmental conditions. The adaptation process involves the removal of many molecules from organelles, especially membranes, and replacing them with new ones. The process is mediated by an intracellular vesicle-trafficking system regulated by phosphatidylinositol (PtdIns) kinases and phosphatases. Although PtdIns comprise a fraction of membrane lipids, they function as major regulators of stress signaling. We analyzed the role of PtdIns 5-phosphatases (5PTases) in plant salt tolerance. The Arabidopsis (Arabidopsis thaliana) genome contains 15 At5PTases. We analyzed salt sensitivity in nine At5ptase mutants and identified one (At5ptase7) that showed increased sensitivity, which was improved by overexpression. At5ptase7 mutants demonstrated reduced production of reactive oxygen species (ROS). Supplementation of mutants with exogenous PtdIns dephosphorylated at the D5' position restored ROS production, while PtdIns(4,5)P(2), PtdIns(3,5)P(2), or PtdIns(3,4,5)P(3) were ineffective. Compromised salt tolerance was also observed in mutant NADPH Oxidase, in agreement with the low ROS production and salt sensitivity of PtdIns 3-kinase mutants and with the inhibition of NADPH oxidase activity in wild-type plants. Localization of green fluorescent protein-labeled At5PTase7 occurred in the plasma membrane and nucleus, places that coincided with ROS production. Analysis of salt-responsive gene expression showed that mutants failed to induce the RD29A and RD22 genes, which contain several ROS-dependent elements in their promoters. Inhibition of ROS production by diphenylene iodonium suppressed gene induction. In summary, our results show a nonredundant function of At5PTase7 in salt stress response by regulating ROS production and gene expression. PMID- 21677097 TI - Are natural deep eutectic solvents the missing link in understanding cellular metabolism and physiology? PMID- 21677098 TI - Registration of clinical trials. PMID- 21677099 TI - Banding versus bonding of first permanent molars: a multi-centre randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of banding versus bonding of first permanent molars during fixed appliance treatment; in terms of attachment failure, patient discomfort and post-treatment enamel demineralization. DESIGN: Multi-centre randomized clinical trial. SETTING: One District General Hospital Orthodontic Department and two Specialist Orthodontic Practices. PARTICIPANTS: Orthodontic patients aged between 10 and 18 years old, randomly allocated to either receive molar bands (n=40) or molar bonds (n=40). METHOD: Bands were cemented with a conventional glass ionomer cement and tubes were bonded with light-cured composite to all four first permanent molar teeth for each subject. Attachments were reviewed at each recall appointment to assess loosening or loss. The clinical end point of the trial was the day of appliance debond. Enamel demineralization at debond was assessed using the modified International Caries Assessment and Detection System (ICDAS). RESULTS: The first time failure rate for molar bonds was 18.4% and 2.6% for molar bands (P=0.0002). Survival analysis demonstrated molar bonds were more likely to fail compared with molar bands. First permanent molars with bonded tubes experienced more demineralization than those with cemented bands (P=0.027). There was no statistically significant difference in discomfort experienced by patients after banding or bonding first permanent molars (P>0.05). CONCLUSION: This study shows that as part of fixed appliance therapy, American Orthodontics photoetched first permanent molar bands cemented with 3M ESPE Ketac-Cem perform better than American Orthodontics low profile photo-etched and mesh-based first permanent molar tubes bonded with 3M Unitek Transbond XT in terms of failure behaviour and molar enamel demineralization. PMID- 21677100 TI - Level of knowledge and understanding of informed consent amongst the training grade group orthodontists in England, Wales and Northern Ireland. AB - OBJECTIVE: To assess the level of knowledge and understanding of informed consent in UK orthodontic trainees. DESIGN AND SETTING: A cross-sectional, written questionnaire-based study. SETTING: Hospital orthodontic departments in England, Wales and Northern Ireland. SUBJECTS AND METHOD: A one page questionnaire which covered a range of legal issues pertinent to informed consent was circulated to 207 members of the Training Grades Group (TGG) of the British Orthodontic Society (BOS). The questionnaire consisted of four open questions with 11 responses, which the investigators considered to be ideal, seven closed questions requiring yes/no responses and one question requiring a yes/no response followed by two open responses. Following the initial circulation, a second posting to non responders was conducted. RESULTS: The response rate was 61% (N=126). The mean number of complete answers to the 21 questions was 13 (62%; median 13; mode 14). There were a low number of complete responses to specific questions in the following areas - explanations patients need from clinicians prior to obtaining consent; how to fully judge if a patient is capable of consenting; how to manage a patient incapable of giving consent; the legal status of fathers consenting on behalf of their children; whether consent forms have to be re-signed if the start of treatment is delayed by six months or more and responsibility for obtaining consent for dental treatment under general anaesthesia. CONCLUSIONS: There was a disappointingly high proportion of incomplete answers to questions testing the knowledge and understanding of the law as it pertains to informed consent exists amongst members of the TGG of BOS. PMID- 21677101 TI - A method of assessing facial profile attractiveness and its application in comparing the aesthetic preferences of two samples of South Africans. AB - OBJECTIVE: Numerous studies have evaluated the perception of facial attractiveness. However, many of the instruments previously used have limitations. This study introduces an improved tool and describes its application in the assessment of the preferred facial profile in two sample groups. DESIGN: Cross-sectional study. SETTING: Two sites were involved: a rural healthcare facility (Winterveldt, Northwest Province) and the campus of the University of the Witwatersrand (Johannesburg, Gauteng Province). PARTICIPANTS: Adult females and males selected from amongst first, attendees at the healthcare facility, and second, staff of the University of the Witwatersrand. METHODS: Eight androgynous lateral facial profile images were created using a morphing software programme representing six transitions between two anchoring extremes in terms of lip retrusion/protrusion vs protrusion/retrusion. These images were presented to, and rated by, two mixed male/female groups of rural and of urban habitat using a pre piloted form. Statistical analysis of the responses obtained established the preferred facial profile by gender in each group. RESULTS: The perception of facial attractiveness varied marginally between rural and urban black South Africans. There was no statistically significant difference between females and males in the rural group (P=0.2353) and those in the urban sample (P=0.1318) with respect to their choice of ideal facial profile. Females and males in both the rural and urban groups found extreme profile convexity unappealing. By contrast, a larger proportion of rural females, rural males and urban females demonstrated a preference for extreme profile concavity. CONCLUSIONS: The research tool described is a useful instrument in the assessment of facial profile attractiveness. PMID- 21677102 TI - Extraction of four premolars in Black patients with bi-protrusion: aesthetic perceptions of professionals and lay people. AB - OBJECTIVE: To assess the aesthetic perceptions and expectations regarding the results of orthodontic treatment for alterations in the profile of Black patients with bi-protrusion through the extraction of four premolars and maximal anchorage. DESIGN: Cross-sectional. SETTING: Offices of plastic surgeons and orthodontists in the city of Belo Horizonte, Brazil. SUBJECTS AND METHODS: 152 individuals participated in the study and were divided into four groups: Group 1, 38 orthodontists; Group 2, 38 plastic surgeons; Group 3, 38 White laypersons; and Group 4, 38 Black laypersons. The patient sample was composed of six Black individuals (three males and three females) with varying degrees of bi protrusion. Each participant was shown altered photographs of the profile of the final result of treatment, simulating three different bi-protrusion reduction options (2, 4 and 6 mm), which were united with the original initial and final photographs. OUTCOMES: Aesthetic preferences and expectations regarding the true result of treatment. DATA ANALYSIS: The chi-square test for linear trend with Bonferroni correction (a=P<0.008). RESULTS: The aesthetic preference for the majority of participants was for a straighter profile than those provided by the orthodontic treatment. Moreover, the actual profile resulting from the orthodontic treatment was correctly identified by just 22% of the Black laypersons, 22% of the White laypersons, 21% of the orthodontists and 17% of the plastic surgeons. There were significant differences between groups. CONCLUSIONS: This study supports the view that society perceives straight profiles as aesthetically more pleasing in comparison to protruding or slightly protruding profiles. PMID- 21677103 TI - Conjoint Membership in Orthodontics examination of the Royal College of Surgeons of Edinburgh and the College of Dental Surgeons of Hong Kong 2007 Gold Medal -- report of two cases. AB - This article describes the treatment of two orthodontic patients by the recipient of the Gold Medal for the Conjoint Membership in Orthodontics of the Royal College of Surgeons of Edinburgh and the College of Dental Surgeons of Hong Kong in November 2007. PMID- 21677104 TI - A new style of orthognathic clinic. AB - The Orthognathic Team at the Eastman Dental Hospital has developed a new style of multidisciplinary clinic to supplement the traditional orthognathic consultation. The aim of the new clinic is to increase patient satisfaction and involvement in the consent and decision making process, as well as optimizing the information given to prospective patients regarding all aspects of this complex elective treatment. Results of a survey of patients attending the clinic found that 80% thought that the information given was 'just the right amount' and 96% were satisfied with the new structure. They particularly found it useful to meet a patient who had completed treatment. All of those who attended said that they understood the information given to them and would recommend the clinic to those considering orthognathic treatment. They also liked having other patients there with them on the clinic. PMID- 21677105 TI - Northcroft lecture: how has the spectrum of orthodontics changed over the past decades? AB - Three aspects have had a significant impact on orthodontics during the last few decades: the appliances being used, the anchorage being used and finally the distribution of patients being treated. Firstly, the marketing of appliances is increasingly leading the orthodontist to outsource important aspects of treatment such as wirebending and bracket positioning. Brackets and wires are being presented as the solution to all problems and metaphysical terms such as 'intelligent design,' 'working brackets' and 'intelligent wires' are dominating advertising and reducing the impact of evidence-based treatment approaches. Secondly, the introduction of skeletal anchorage has potentially widened the spectrum of orthodontics, allowing for treatments that could not be done with conventional appliances. Biomechanical knowledge is, however, mandatory if we agree that the system should not be abused. Thirdly, the orthodontic population comprises an increasing number of adult patients, many of whom are characterized by a degenerated dentition. The treatment of these patients requires a thorough knowledge not only of biomechanics but also of the reaction of the periodontal tissues to various types of loading. They can be treated only with custom-made appliances adapting the force systems and magnitude to the patient-specific treatment goal. In summary, the orthodontic world is being split between 'appliance-driven fast-food orthodontics' where the results to a large extent are dependent on both growth and function and 'orthodontist-driven' 'slow-food' treatments attempting to push the limits of the possible in relation to complicated problems and reversal of degeneration in adult patients. The latter treatments are performed with individualized appliances adapting the force system to the patient. This paper will attempt to summarize the bearing of these factors on present orthodontics. PMID- 21677108 TI - New horizons in orthodontics. PMID- 21677109 TI - Immunization of teenagers with a fifth dose of reduced DTaP-IPV induces high levels of pertussis antibodies with a significant increase in opsonophagocytic activity. AB - Waning vaccine-induced immunity against Bordetella pertussis is observed among adolescents and adults. A high incidence of pertussis has been reported in this population, which serves as a reservoir for B. pertussis. A fifth dose of reduced antigen of diphtheria-tetanus-acellular-pertussis and inactivated polio vaccine was given as a booster dose to healthy teenagers. The antibody activity against B. pertussis antigens was measured prior to and 4 to 8 weeks after the booster by different assays: enzyme-linked immunosorbent assays (ELISAs) of IgG and IgA against pertussis toxin (PT) and filamentous hemagglutinin (FHA), IgG against pertactin (PRN), opsonophagocytic activity (OPA), and IgG binding to live B. pertussis. There was a significant increase in the IgG activity against PT, FHA, and PRN following the booster immunization (P < 0.001). The prebooster sera showed a geometric mean OPA titer of 65.1 and IgG binding to live bacteria at a geometric mean concentration of 164.9 arbitrary units (AU)/ml. Following the fifth dose, the OPA increased to a titer of 360.4, and the IgG concentration against live bacteria increased to 833.4 AU/ml (P < 0.001 for both). The correlation analyses between the different assays suggest that antibodies against FHA and PRN contribute the most to the OPA and IgG binding. PMID- 21677110 TI - Distinctive immunomodulatory and inflammatory properties of the Escherichia coli type II heat-labile enterotoxin LT-IIa and its B pentamer following intradermal administration. AB - The type I and type II heat-labile enterotoxins (LT-I and LT-II) are strong mucosal adjuvants when they are coadministered with soluble antigens. Nonetheless, data on the parenteral adjuvant activities of LT-II are still limited. Particularly, no previous study has evaluated the adjuvant effects and induced inflammatory reactions of LT-II holotoxins or their B pentameric subunits after delivery via the intradermal (i.d.) route to mice. In the present report, the adjuvant and local skin inflammatory effects of LT-IIa and its B subunit pentamer (LT-IIaB(5)) were determined. When coadministered with ovalbumin (OVA), LT-IIa and, to a lesser extent, LT-IIaB(5) exhibited serum IgG adjuvant effects. In addition, LT-IIa but not LT-IIaB(5) induced T cell-specific anti-OVA responses, particularly in respect to induction of antigen-specific cytotoxic CD8(+) T cell responses. LT-IIa and LT-IIaB(5) induced differential tissue permeability and local inflammatory reactions after i.d. injection. Of particular interest was the reduced or complete lack of local reactions, such as edema and tissue induration, in mice i.d. inoculated with LT-IIa and LT-IIaB(5,) respectively, compared with mice immunized with LT-I. In conclusion, the present results show that LT-IIa and, to a lesser extent, LT-IIaB(5) exert adjuvant effects when they are delivered via the i.d. route. In addition, the low inflammatory effects of LT-IIa and LT-IIaB(5) in comparison to those of LT-I support the usefulness of LT-IIa and LT-IIaB(5) as parenterally delivered vaccine adjuvants. PMID- 21677111 TI - Evidence of Burkholderia pseudomallei-specific immunity in patient sera persistently nonreactive by the indirect hemagglutination assay. AB - The indirect hemagglutination assay (IHA) is the most frequently used serological test to confirm exposure to Burkholderia pseudomallei. Patients with culture confirmed disease often have a nonreactive IHA at presentation and occasionally fail to seroconvert on serial testing. We investigated whether using antigens derived from the cultured isolates of persistently IHA-nonreactive patient sera improved the sensitivity of the IHA. In addition, we assessed the antigen specific lymphocyte response in this group of patients to a panel of B. pseudomallei antigens, including those derived from their own cultured isolates. Eleven patients with culture-proven melioidosis were identified as having persistently IHA-nonreactive sera. A modified IHA using erythrocytes sensitized with patient isolate-derived antigen tested against convalescent-phase serum was performed. The majority (82%) of sera showed a negative (<= 1:5) result, one was borderline (1:20), and one was positive at the cutoff value (1:40). IHA nonreactive sera were also tested by enzyme immunoassay (EIA), with 73% (8/11) demonstrating IgG positivity. In addition, lymphocytes isolated from persistently IHA-nonreactive patient sera demonstrated significantly increased proliferation in response to B. pseudomallei antigens compared to controls. These studies demonstrate the presence of B. pseudomallei-specific antibody by EIA and B. pseudomallei-specific lymphocytes in patient sera categorized as persistently nonreactive according to the IHA. New immunoassays are required and should incorporate B. pseudomallei antigens that are immunoreactive for this subset of IHA-nonreactive patient sera. PMID- 21677112 TI - Using a qualitative approach to develop an evaluation data set for community based health promotion programs addressing racial and ethnic health disparities. AB - Racial and ethnic disparities in health have increasingly become a central focus of health promotion efforts. At the community level, however, collecting data and evaluating these programs has been a challenge because of the diversity of populations, community contexts, and health issues as well as a range of capacities for conducting evaluation. This article outlines a qualitative research process used to develop a Web-based standard program performance data reporting system for programs funded by the U.S. Office of Minority Health (OMH), but generally applicable to community-based health promotion programs addressing health disparities. The "core-and-module" data set, known as the Uniform Data Set (UDS), is a Web-based system and is used as the programwide reporting system for OMH. The process for developing the UDS can be used by any agency, locality, or organization to develop a tailored data collection system allowing comparison across projects via an activity-based typology around which data reporting is structured. The UDS model enables the collection of grounded data reflecting community-level steps necessary to address disparities as well as a reporting structure that can guide data collection based on broader frameworks now emerging that specify criteria for measuring progress toward the elimination of health disparities. PMID- 21677113 TI - CBPR with service providers: arguing a case for engaging practitioners in all phases of research. AB - This review synthesizes the literature on CBPR with service providers to identify the benefits to, unique contributions of, and challenges experienced by professional service providers engaged in collaborative research. Service providers benefited by obtaining research-based knowledge to help the communities they serve, gaining research skills, professional relationships, professional development, and new programs. They contributed by informing research aims, designing interventions, conducting recruitment, informing overall study design, and dissemination. Challenges include time, resources, organizational factors, and disconnects between researchers and service providers. Policy and practice implications are explored. PMID- 21677114 TI - The difficult balance between entertainment and education: a qualitative evaluation of a Dutch health-promoting documentary series. AB - The development, content and potential health promoting effect of the Dutch documentary series, Voor dik & dun ("For thick and thin") were investigated. This series was based on the entertainment-education (EE) strategy and designed to prevent overweight. Qualitative data were collected from three perspectives: those involved in the program development (in-depth interviews), health communication scientists (in-depth interviews), and viewers (focus groups). In addition, viewing figures and website statistics were collected. Results show that finding a proper balance between entertainment and education is difficult for those involved. Voor dik & dun was not very successful in creating this balance and did not reach its priority audience. Findings suggest that, to achieve the desired health-promoting effects, EE programs should focus first extensively on narrative engagement by means of entertainment and later on, when the viewer is engaged, try to educate by means of positive identification with transitional role models. PMID- 21677115 TI - Methodological tips for overcoming formative evaluation challenges: the case of the Arthritis Foundation Walk With Ease program. AB - Formative evaluation is an effective first step in guiding program improvement by identifying participant preferences and yielding information pertinent to making program decisions. As program evaluators working with service providers are increasingly encouraged to adopt evidence-based health promotion programs, a discrete set of real-world recommendations may help extend the use of this methodology to respond to community-specific contexts and improve health impact. This article describes the authors' step-by-step process of conducting a formative evaluation of the Arthritis Foundation Walk With Ease (WWE) program. Data collection targets (leaders, coordinators, and participants in the original program and leaders and participants in the revised piloted program) as well as methods (written surveys, focus groups, structured telephone interviews, and expert reviews) were triangulated. The authors describe the challenges they faced and conclude with practical methodological recommendations about managing time and resources, communications with respondents, and accountability systems for organizing triangulated data. PMID- 21677116 TI - Becoming visible: assessing the availability of online sexual health information for lesbians. AB - Research suggests that lesbians turn to the Internet for information regarding their sexual health. However, limited research has examined the availability of online sexual health resources for this population. This study evaluated the volume, scope, and readability of sexual health information available to lesbians on the Internet. The top three Nielsen-rated search engines were used to identify websites generated using the search term "lesbian sexual health." A content analysis was conducted of 25 unique, functioning websites (46 webpages total) and Flesch Reading Ease and Flesch-Kincaid grade levels were calculated. Nearly one third of the websites were located outside the United States; two were U.S. government sites. Although most sites provided information about sexually transmitted infections and HIV/AIDS (52% to 72%), fewer provided information about safer sex practices (12% to 56%), reproductive cancers (24% to 36%), intimate partner violence (16%), family planning issues (0% to 12%), or other preventive health practices, such as mammograms and gynecological exams (4% to 44%) for lesbians. Readability of websites was much higher than recommended for health materials. Lesbians are in need of comprehensive and reliable sexual health information on the Internet. In particular, sexual health messages written in plain language are needed to encourage safer sex and other preventive practices among lesbians. PMID- 21677117 TI - Exploring a public health perspective on pedestrian planning. AB - A pedestrian plan is a public document that explains a community's vision and goals for future pedestrian activity. This study explored whether involvement by public health professionals in the development of pedestrian plans was associated with certain characteristics of the plan (vision, goals, identified programs, and evaluation). This study identified, collected, and analyzed content of all pedestrian plans in North Carolina through 2008. Among the 46 plans, 39% reported involvement by public health professionals in their development. Overall, 72% of pedestrian plans included a vision statement; health was mentioned four times and quality of life was mentioned five times. Slightly more than half (52%) of the plans included goals to improve public health. Plans that involved public health professionals more often included the type of physical activity, safety, or education program. Only 22% of all pedestrian plans included a proposal to evaluate their implementation. Plans that included public health professionals were less likely to include an evaluation proposal (11%) compared with those that did not involve public health professionals (21%). Public health professionals are encouraged to seek involvement in the pedestrian planning process, particularly in the areas of health program development, implementation, and evaluation. PMID- 21677119 TI - Cod liver oil, young children, and upper respiratory tract infections. AB - Cod liver oil contains long-chain omega-3 fatty acids, as well as vitamins D and A. It was a traditional source of vitamin D in the United States and was used to prevent and treat rickets. In our clinical research, we used liquid cod liver oil of adequate purity and acceptable taste for infants and young children, as well as a children's multivitamin/mineral supplement with selenium and other trace metals. In a cluster-randomized study of pediatric visits for upper respiratory illness during the winter and early spring, these nutritional supplements decreased mean visits/subject/month by 36%-58%. Cod liver oil is culturally valued and has been used as a folk remedy by many low-income minorities in the United States. Nutritional supplements cannot be purchased with SNAP benefits (formerly called food stamps). Inclusion of cod liver oil in state Medicaid formularies would make it available to low-income children, whose families may not be able to pay for it out-of-pocket. PMID- 21677120 TI - Stressor states and the cation crossroads. AB - Neurohormonal activation involving the hypothalamic-pituitary-adrenal axis and adrenergic nervous and renin-angiotensin-aldosterone systems is integral to stressor state-mediated homeostatic responses. The levels of effector hormones, depending upon the degree of stress, orchestrate the concordant appearance of hypokalemia, ionized hypocalcemia and hypomagnesemia, hypozincemia, and hyposelenemia. Seemingly contradictory to homeostatic responses wherein the constancy of extracellular fluid would be preserved, upregulation of cognate binding proteins promotes coordinated translocation of cations to injured tissues, where they participate in wound healing. Associated catecholamine mediated intracellular cation shifts regulate the equilibrium between pro oxidants and antioxidant defenses, a critical determinant of cell survival. These acute and chronic stressor-induced iterations in extracellular and intracellular cations are collectively referred to as the cation crossroads. Intracellular cation shifts, particularly excessive accumulation of Ca2+, converge on mitochondria to induce oxidative stress and raise the opening potential of their inner membrane permeability transition pores (mPTPs). The ensuing loss of cationic homeostasis and adenosine triphosphate (ATP) production, together with osmotic swelling, leads to organellar degeneration and cellular necrosis. The overall impact of iterations in extracellular and intracellular cations and their influence on cardiac redox state, cardiomyocyte survival, and myocardial structure and function are addressed herein. PMID- 21677121 TI - Serum lutein response is greater from free lutein than from esterified lutein during 4 weeks of supplementation in healthy adults. AB - BACKGROUND: Current data suggest great variability in serum response following lutein ingestion from various sources. OBJECTIVE: To compare the relative serum response during supplementation with free lutein (fL) and lutein esters (Le). METHODS: 72 volunteers (23-52 years; body mass index [BMI] >20 and <30 kg/m2; baseline serum lutein <20 ug/dL [<352 nmol/L]) were identified. Subjects, matched for gender, age, and BMI, were randomly assigned to the fL or Le group. fL and Le capsules contained 12.2 mg of free lutein or 27 mg of lutein ester (equivalent to 13.5 mg free lutein), respectively. Fasting blood was obtained at baseline and after 7, 14, 21, and 28 days of supplementation. Supplements were consumed with standard portions of dry, ready-to-eat cereal and 2% cow's milk. RESULTS: Absolute changes in serum lutein, per mg daily dose, were significantly greater in fL vs. Le after 21 days (p = 0.0012) and remained so after 28 days (p = 0.0011) of supplementation. Serum lutein Area Under the Curve [AUC((day 0-28))] response was 17% greater for fL vs. Le (p = 0.0187). Regression models were used and determined that (1) baseline serum lutein levels and (2) the form of lutein ingested (fL > Le) influence the serum lutein response during supplementation, while subject age, gender, BMI, and serum lipids do not affect serum response. CONCLUSIONS: These results suggest that the relative serum lutein response will be significantly greater from supplements containing free lutein than from supplements containing lutein esters. These findings should be useful for future clinical trials exploring the effectiveness of lutein supplementation in the prevention of or protection against age-related macular degeneration and/or cataracts. PMID- 21677122 TI - Fatty acids intake and depressive symptomatology in a Greek sample: an epidemiological analysis. AB - BACKGROUND: Depression is associated with an increased risk of cardiovascular disease, but the association with dietary habits is not well understood. The aim of this work was to statistically model the association of depressive symptoms with fatty acids intake in persons free of cardiovascular disease. METHOD: A random multistage sampling, stratified by gender and age, was performed during 2001-2002. In the present work, psychological and dietary data from 453 men (19 89 years) and 400 women (18-84 years) were analyzed. Depression was assessed with the Zung's Self-rating Depression Scale (ZDRS). After a validation for the investigated population, plasma fatty acids in the form of their methyl esters were determined by gas chromatography, while dietary fatty acids were determined through a semiquantitative food frequency questionnaire and local food composition tables. RESULTS: Women had significantly higher scores on the ZDRS as compared with men (47 +/- 9 vs. 43 +/- 10, p < 0.001). Multiadjusted data analysis after adjusting for age, gender, lifestyle, and dietary habits revealed that increased polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid (MUFA) concentrations, and, more specifically, high concentrations of plasma total n-3 fatty acids (b +/- SE: -1.9 +/- 0.5, p = 0.03), docosahexaenoic acid (-2.91 +/- 1.04, p = 0.02), eicosapentaenoic acid (-2.54 +/- 0.84, p = 0.03), alpha-linoleic acid (-16.8 +/- 7.3, p = 0.01), and linoleic acid (-3.97 +/- 0.21, p = 0.03), were associated with lower scores in the depression scale used. CONCLUSION: These results indicate that increased PUFA and MUFA concentrations are associated with diminished depressive symptomatology among apparently healthy adults. PMID- 21677124 TI - Effects of calcium and resistance exercise on body composition in overweight premenopausal women. AB - OBJECTIVE: To examine the combined treatment effect of a mild energy restriction, high dairy calcium intake, and resistance exercise on promoting favorable body composition changes in overweight women with a low dairy intake. Combined treatment strategies may produce synergistic effects on increasing fat loss and preserving bone in a population at risk for obesity and osteoporosis. METHODS: Overweight, sedentary women consuming a diet low in dairy calcium (<=1 serving of dairy per day) were randomized either (1) to maintain a low-calcium diet (LOW; <= 500 mg; n = 15) or (2) to increase dairy calcium (HIGH; >=1200 mg; n = 14) for 16 weeks. Both groups began resistance training 3 days per week and received dietary counseling to reduce energy intake by 250 kcal per day. Body composition was measured at the beginning and at the end of the study with dual energy x-ray absorptiometry. Two 24-hour dietary recalls were measured at baseline, midpoint, and end of study with Nutrition Data System for Research software. RESULTS: Participants were 36.8 +/- 4.8 years of age, with an average body mass index of 29.1 +/- 2.1 kg/m2. Fat mass decreased significantly over time (LOW = 3.8 +/- 4.1 kg and HIGH = 1.8 +/- 2.1 kg) but was not significantly different by group. Mean energy reduction from baseline was 382 kcal (LOW) and 214 kcal (HIGH; p = 0.14). When change in energy intake was included as a covariate, there was still no significant difference in fat loss between groups. Change in lumbar spine bone mineral density (LOW = -1.5% and HIGH = 0.8%) was significant between groups (p = 0.02). The prescribed mean calcium intake was achieved for each study group (LOW = 454 +/- 143 mg and HIGH = 1312 +/- 183 mg), with no significant changes in protein intake over time (LOW = 0.9 g/kg and HIGH = 1.0 g/kg, p = 0.08). CONCLUSION: These results suggest that increasing dairy calcium offers no added benefit in reducing body fat when combined with resistance training and energy restriction. However, increasing dairy calcium improves bone mineral density in premenopausal overweight women. PMID- 21677125 TI - Type 1 diabetes mellitus and components in drinking water and diet: a population based, case-control study in Prince Edward Island, Canada. AB - OBJECTIVE: To determine the relationship between the risk of type 1 diabetes (T1D) and daily intake of drinking water and dietary components, including nitrate, nitrite, and nitrosamines, during the year prior to diagnosis. METHODS: Controls (n = 105) were matched by age at diagnosis and sex to T1D cases (n = 57) newly diagnosed during 2001-2004. Food consumption was assessed using a food frequency questionnaire. Locally available samples of foods were tested for nitrate, nitrite, and nitrosamine concentrations. Water consumption was determined through an additional questionnaire, and water samples were taken from homes and tested for routine chemical components, including nitrate. RESULTS: After controlling for age, age, sex, and daily energy intake, nitrate intake from food sources showed a non-significant positive trend (odds ratios and 95% confidence intervals for quartiles = 1.00, 1.63 (0.58, 4.63), 1.71 (0.54, 5.40), 3.02 (0.78, 11.74); p for trend = 0.13). Nitrite and nitrosamine intake were not related to T1D risk (p for trend = 0.77 and 0.81, respectively). When food and water components were combined, zinc and calcium intakes were marginally and inversely related to T1D risk (p for trend = 0.07 and 0.06, respectively). After further model adjustment of possible confounders and significant risk factors, an increased intake of caffeine marginally increased the risk of T1D (p = 0.07). CONCLUSION: Dietary components from both food and water sources may influence the risk of developing T1D in young persons. PMID- 21677123 TI - Effects of diets high in walnuts and flax oil on hemodynamic responses to stress and vascular endothelial function. AB - BACKGROUND: Polyunsaturated fatty acids (PUFA) have beneficial effects on cardiovascular risk, although the mechanisms are incompletely understood. In a previous article, we showed significant reductions in low-density lipoprotein cholesterol and several markers of inflammation with increasing intake of alpha linolenic acid (ALA) from walnuts and flax. OBJECTIVE: To examine effects of ALA on cardiovascular responses to acute stress, flow-mediated dilation (FMD) of the brachial artery, and blood concentrations of endothelin-1 and arginine vasopressin (AVP). DESIGN: Using a randomized, crossover study design, cardiovascular responses to acute stress were assessed in 20 hypercholesterolemic subjects, a subset of whom also underwent FMD testing (n = 12). Participants were fed an average American diet (AAD) and 2 experimental diets that varied in the amount of ALA and linoleic acid (LA) that they contained. The AAD provided 8.7% energy from PUFA (7.7% LA, 0.8% ALA). On the LA diet, saturated fat was reduced, and PUFA from walnuts and walnut oil provided 16.4% of energy (12.6% LA, 3.6% ALA). On the ALA diet, walnuts, walnut oil, and flax oil provided 17% energy from PUFA (10.5% LA, 6.5% ALA). RESULTS: The ALA and LA diets significantly reduced diastolic blood pressure (-2 to -3 mm Hg) and total peripheral resistance (-4%), and this effect was evident at rest and during stress (main effect of diet, p < 0.02). FMD increased (+34%) on the diet containing additional ALA. AVP also increased by 20%, and endothelin-1 was unchanged. CONCLUSIONS: These results suggest novel mechanisms for the cardioprotective effects of walnuts and flax, and further work is needed to identify the bioactives responsible for these effects. PMID- 21677126 TI - Consumption of 100% fruit juice and risk of obesity and metabolic syndrome: findings from the national health and nutrition examination survey 1999-2004. AB - OBJECTIVES: The health effects of added sugars have received much attention, but few studies have examined the association between foods that naturally contain sugar, such as 100% fruit juice, and risk of obesity and related conditions. Therefore, our purpose was to study the association between 100% fruit juice intake and risk of obesity and metabolic syndrome in a representative sample of the U.S. population. METHODS: Cross-sectional analysis of a multiethnic sample of U.S. adults from the National Health and Nutrition Examination Survey 1999-2004 was undertaken to examine the association between 100% fruit juice consumption and the odds of obesity (body mass index [BMI] >= 30 kg/m2) and metabolic syndrome (Adult Treatment Panel [ATP] III definition). We used logistic regression analysis to estimate the odds of obesity and metabolic syndrome per category of fruit juice consumption exposure, while adjusting for covariates that may be confounders of this association. RESULTS: Of 14,196 adults included in the sample, 3961 were consumers of fruit juice. Consumers of 100% fruit juice, relative to nonconsumers, had lower mean BMI, lower waist circumference, and lower homeostasis model assessment (HOMA) insulin resistance (p < 0.001). Level of intake (oz/d) had a linear inverse association with HOMA (p < 0.001), whereas the association with BMI and waist circumference was U-shaped (p < 0.001). Consumers relative to nonconsumers had 22% (95% confidence interval [CI] = 13% 30%) lower odds of obesity and 15% (95% CI = 10%-28%) lower odds of metabolic syndrome. After adjustment for demographics and lifestyle factors, the lower odds of obesity remained statistically significant, but a statistically significant reduction in odds of metabolic syndrome was no longer noted. CONCLUSIONS: Compared with nonconsumers, those who consumed 100% fruit juice were leaner, were more insulin sensitive, and had lower odds of obesity and metabolic syndrome. The association with metabolic syndrome was explained primarily by other lifestyle factors, while the association with obesity remained independent. Experimental studies are needed to determine whether any direct physiologic link exists between consumption of 100% fruit juice and lower risks for obesity and metabolic syndrome. PMID- 21677127 TI - Associations between dietary patterns and LDL peak particle diameter: a cross sectional study. AB - OBJECTIVE: Dietary patterns are used to evaluate the effects of overall nutritional habits on health status, and low-density lipoprotein-peak particle diameter (LDL-PPD) has been recognized as an emerging risk factor for cardiovascular disease (CVD). The aim of this study is to verify whether an association exists between dietary patterns and LDL-PPD. METHODS: A total of 635 participants aged between 18 and 55 years were included in this cross-sectional study. Nutritional information was collected with a validated food frequency questionnaire. To establish dietary patterns, factor analysis was performed, which led to characterization of the Western and Prudent dietary patterns. Nondenaturing 2%-16% polyacrylamide gradient gel electrophoresis was used to characterize LDL-PPD. RESULTS: The Western pattern was characterized by high consumption of food such as refined grains, French fries, and red meats, and the Prudent pattern by nonhydrogenated fat, vegetables, eggs, and fish. For the Western profile, a negative correlation was found between score value and LDL-PPD before (r = -0.082, p = 0.039) and after adjustment for age (r = -0.080, p = 0.043). A negative correlation between scores for the Prudent profile and the LDL PPD adjusted for age, sex, plasma triglycerides, and energy was observed (r = 0.12204, p = 0.0021). After division by tertiles and adjustment for the confounding effects of age, sex, plasma triglyceride levels, and energy, a significant difference (p = 0.0015) in LDL-PPD was noted between the highest tertile (255.21 +/- 3.61 A) and the lowest tertile (255.79 +/- 3.68 A) of the Prudent pattern. CONCLUSIONS: Dietary patterns, such as the Western and the Prudent, are associated with LDL-PPD. Dietary patterns can be used to assess the effects of nutritional habits on health status. PMID- 21677129 TI - Regulation of the estrous cycle by neutrophils via opioid peptides. AB - We found previously that neutrophil-depleted mice exhibited significant blockading of both the regular estrous cycle and cyclic changes of steroid hormone levels. In this study, we aimed at elucidation of the underlying mechanism. To examine the possibility that an increase in bacteria in the vaginal vault of neutrophil-depleted mice causes blockading of the estrous cycle, we treated neutrophil-depleted mice with antibiotics but failed to restore the estrous cycle. We then examined another possibility that neutrophils regulate the estrous cycle via opioid peptides, because opioid peptides regulate steroidogenesis in theca and granulosa cells in the ovaries, and because neutrophils contain opioid peptides. In support of this possibility, naloxone, an opioid antagonist, blocked the estrous cycle and a MU opioid receptor agonist restored the estrous cycle in neutrophil-depleted mice. Pro-opiomelanocortin was immunohistochemically detected in peripheral blood neutrophils but not in ones that had infiltrated into the ovaries. i.v. injection of anti-MIP-2 polyclonal Ab caused blockading of the estrous cycle, whereas MIP-2 was detected in the ovaries, suggesting a role of MIP-2 in the regulation of the estrous cycle. Moreover, i.v. injection of MIP-2 decreased the pro-opiomelanocortin signal in peripheral blood neutrophils and caused blockading of the estrous cycle. Together, these results suggest that neutrophils maintain the estrous cycle via opioid peptides. PMID- 21677128 TI - The brain's default network and its adaptive role in internal mentation. AB - During the many idle moments that comprise daily life, the human brain increases its activity across a set of midline and lateral cortical brain regions known as the "default network." Despite the robustness with which the brain defaults to this pattern of activity, surprisingly little is known about the network's precise anatomical organization and adaptive functions. To provide insight into these questions, this article synthesizes recent literature from structural and functional imaging with a growing behavioral literature on mind wandering. Results characterize the default network as a set of interacting hubs and subsystems that play an important role in "internal mentation"-the introspective and adaptive mental activities in which humans spontaneously and deliberately engage in every day. PMID- 21677130 TI - Cyclosporine-resistant, Rab27a-independent mobilization of intracellular preformed CD40 ligand mediates antigen-specific T cell help in vitro. AB - CD40L is critically important for the initiation and maintenance of adaptive immune responses. It is generally thought that CD40L expression in CD4(+) T cells is regulated transcriptionally and made from new mRNA following Ag recognition. However, recent studies with two-photon microscopy revealed that most cognate interactions between effector CD4(+) T cells and APCs are too short for de novo synthesis of CD40L. Given that effector and memory CD4(+) T cells store preformed CD40L (pCD40L) in lysosomal compartments and that pCD40L comes to the cell surface within minutes of antigenic stimulation, we and others have proposed that pCD40L might mediate T cell-dependent activation of cognate APCs during brief encounters in vivo. However, it has not been shown that this relatively small amount of pCD40L is sufficient to activate APCs, owing to the difficulty of separating the effects of pCD40L from those of de novo CD40L and other cytokines in vitro. In this study, we show that pCD40L surface mobilization is resistant to cyclosporine or FK506 treatment, while de novo CD40L and cytokine expression are completely inhibited. These drugs thus provide a tool to dissect the role of pCD40L in APC activation. We find that pCD40L mediates selective activation of cognate but not bystander APCs in vitro and that mobilization of pCD40L does not depend on Rab27a, which is required for mobilization of lytic granules. Therefore, effector CD4(+) T cells deliver pCD40L specifically to APCs on the same time scale as the lethal hit of CTLs but with distinct molecular machinery. PMID- 21677131 TI - Cecal ligation and puncture-induced impairment of innate immune function does not occur in the absence of caspase-1. AB - Mice that have been subjected to cecal ligation and puncture (CLP) have an impaired ability to clear a subsequent Pseudomonas aeruginosa challenge compared with that of sham CLP controls. We hypothesized that this outcome is dependent upon a caspase-1 mechanism and tested this hypothesis by measuring caspase-1 after CLP and by measuring clearance of a bacterial challenge in caspase-1 deficient mice after CLP. Wild-type mice subjected to CLP had increased caspase-1 activity as well as increased IL-1beta and increased IL-18 production in splenocytes stimulated with heat-killed Pseudomonas and had increased plasma concentrations of IL-1beta and IL-18 and impaired clearance of a P. aeruginosa challenge compared with sham controls. Healthy, uninjured caspase-1(-?-) mice did not differ from wild-type mice in their ability to clear a Pseudomonas challenge. However, unlike wild-type mice, caspase-1(-/-) mice subjected to CLP had no impairment of bacterial clearance of the Pseudomonas challenge, suggesting that caspase-1 induction after CLP played a role in impairment of bacterial clearance. This was further substantiated by the use of a specific caspase-1 inhibitor, Ac YVAD-CMK. Wild-type mice treated with Ac-YVAD-CMK (10 mg/kg s.c. twice daily, initiated at time of CLP) did not have impaired clearance of a Pseudomonas challenge compared with that of sham mice and had significantly improved bacterial clearance compared with that of untreated CLP mice. Increased caspase-1 expression and activity after CLP injury appears to contribute to diminished innate immune function. PMID- 21677132 TI - Bruton's tyrosine kinase is required for TLR-dependent heme oxygenase-1 gene activation via Nrf2 in macrophages. AB - Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation and provides cytoprotection against oxidative stress by its products carbon monoxide and biliverdin. More recently, HO-1 has also been shown to exert immunomodulatory functions via cell type-specific anti-inflammatory effects in myeloid/macrophage cells. In the current study, it is demonstrated that Bruton's tyrosine kinase (Btk), the gene of which is mutated in the human immunodeficiency X-linked agammaglobulinemia, is involved in the upregulation of HO-1 gene expression via TLR signaling in macrophages. The specific Btk inhibitor LFM-A13 blocked HO-1 induction by the classical TLR4 ligand LPS in cell cultures of RAW264.7 monocytic cells and primary mouse alveolar macrophages. Moreover, upregulation of HO-1 gene expression was abrogated in LPS-stimulated alveolar macrophages from Btk(-/-) mice. Transfection studies with luciferase reporter gene constructs demonstrated that LPS-dependent induction of HO-1 promoter activity was attenuated by pharmacological Btk inhibition and by an overexpressed dominant-negative mutant of Btk. This induction was mediated by the transcription factor Nrf2, which is a master regulator of the antioxidant cellular defense. Accordingly, nuclear translocation of Nrf2 in LPS-treated macrophages was reduced by Btk inhibition. The generation of reactive oxygen species, but not that of NO, was involved in this regulatory pathway. Btk-dependent induction of HO-1 gene expression was also observed upon macrophage stimulation with ligands of TLR2, TLR6, TLR7, and TLR9, suggesting that Btk is required for HO-1 gene activation by major TLR pathways. PMID- 21677133 TI - Limiting CDR-H3 diversity abrogates the antibody response to the bacterial polysaccharide alpha 1->3 dextran. AB - Anti-polysaccharide Ab responses in mice are often oligoclonal, and the mechanisms involved in Ag-specific clone production and selection remain poorly understood. We evaluated the relative contribution of D(H) germline content versus N nucleotide addition in a classic oligoclonal, T-independent Ab response (alpha 1->3 dextran [DEX]) by challenging adult TdT-sufficient (TdT(+/+)) and TdT deficient (TdT(-/-)) gene-targeted mice, limited to the use of a single D(H) gene segment (D-limited mice), with Enterobacter cloacae. D-limited mice achieved anti DEX-specific levels of Abs that were broadly comparable to those of wild-type (WT) BALB/c mice. Sequence analysis of the third CDR of the H chain intervals obtained by PCR amplification of V(H) domain DNA from DEX-specific plasmablasts revealed the near universal presence of an aspartic acid residue (D99) at the V-D junction, irrespective of the composition of the D(H) locus. Although WT mice were able to use germline D(H) (DQ52, DSP, or DST) gene segment sequence, TdT activity, or both to produce D99, all three D-limited mouse strains relied exclusively on N addition. Additionally, in the absence of TdT, D-limited mice failed to produce a DEX response. Coupled with previous studies demonstrating a reduced response to DEX in TdT(-/-) mice with a WT D(H) locus, we concluded that in the case of the anti-DEX repertoire, which uses a short third CDR of the H chain, the anti-DEX response relies more intensely on sequences created by postnatal N nucleotide addition than on the germline sequence of the D(H). PMID- 21677134 TI - Lenalidomide enhances antigen-specific activity and decreases CD45RA expression of T cells from patients with multiple myeloma. AB - The aim of this study was to investigate whether the specific T cell response against the multiple myeloma Ag HM1.24 is enhanced by the immunomodulatory drug lenalidomide (Revlimid). Ag-specific CD3(+)CD8(+) T cells against the HM1.24 Ag were expanded in vitro by dendritic cells in 29 healthy donors and 26 patients with plasma cell dyscrasias. Ag-specific activation was analyzed by IFN-gamma, granzyme B, and perforin secretion using ELISA, ELISPOT assay, and intracellular staining, and generation of Ag-specific T cells was analyzed by tetramer staining. Expression of T cell maturation markers (CD45RA, CD45R0, CCR7, and CD28) was investigated by flow cytometry. We found that activation of HM1.24 specific T cells from healthy donors and patients with plasma cell dyscrasias was enhanced significantly by lenalidomide and furthermore that the impact of lenalidomide on T cells depends on the duration of the exposure. Notably, lenalidomide supports the downregulation of CD45RA on T cells upon activation, observed in healthy donors and in patients in vitro and also in patients during lenalidomide therapy in vivo. We showed for the first time, to our knowledge, that lenalidomide enhances the Ag-specific activation of T cells and the subsequent downregulation of CD45RA expression of T cells in vitro and in vivo. PMID- 21677135 TI - Anti-CD8 antibodies can trigger CD8+ T cell effector function in the absence of TCR engagement and improve peptide-MHCI tetramer staining. AB - CD8(+) T cells recognize immunogenic peptides presented at the cell surface bound to MHCI molecules. Ag recognition involves the binding of both TCR and CD8 coreceptor to the same peptide-MHCI (pMHCI) ligand. Specificity is determined by the TCR, whereas CD8 mediates effects on Ag sensitivity. Anti-CD8 Abs have been used extensively to examine the role of CD8 in CD8(+) T cell activation. However, as previous studies have yielded conflicting results, it is unclear from the literature whether anti-CD8 Abs per se are capable of inducing effector function. In this article, we report on the ability of seven monoclonal anti-human CD8 Abs to activate six human CD8(+) T cell clones with a total of five different specificities. Six of seven anti-human CD8 Abs tested did not activate CD8(+) T cells. In contrast, one anti-human CD8 Ab, OKT8, induced effector function in all CD8(+) T cells examined. Moreover, OKT8 was found to enhance TCR/pMHCI on-rates and, as a consequence, could be used to improve pMHCI tetramer staining and the visualization of Ag-specific CD8(+) T cells. The anti-mouse CD8 Abs, CT-CD8a and CT-CD8b, also activated CD8(+) T cells despite opposing effects on pMHCI tetramer staining. The observed heterogeneity in the ability of anti-CD8 Abs to trigger T cell effector function provides an explanation for the apparent incongruity observed in previous studies and should be taken into consideration when interpreting results generated with these reagents. Furthermore, the ability of Ab-mediated CD8 engagement to deliver an activation signal underscores the importance of CD8 in CD8(+) T cell signaling. PMID- 21677136 TI - Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. AB - A common denominator among the multiple damage-inducing agents that ultimately lead to activation of NLRP3 has not yet been identified. Recently, production of reactive oxygen species (ROS) has been suggested to act as a common event upstream of the NLRP3 inflammasome machinery. Because de novo translation of NLRP3 is an essential step in the activation of NLRP3, we investigated the role of substances that inhibit either ROS production or its oxidative activity. Although we observe that NLRP3 inflammasome activation is unique among other known inflammasomes in its sensitivity to ROS inhibition, we have found that this phenomenon is attributable to the fact that NLRP3 strictly requires priming by a proinflammatory signal, a step that is blocked by ROS inhibitors. Although these data do not exclude a general role for ROS production in the process of NLRP3 triggered inflammation, they would put ROS upstream of NLRP3 induction, but not activation. PMID- 21677137 TI - Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor. AB - There is a strong association between infection and prematurity; however, the underlying mechanisms remain largely unknown. Nod1 and Nod2 are intracellular pattern recognition receptors that are activated by bacterial peptides and mediate innate immunity. We previously demonstrated that human first-trimester trophoblasts express Nod1 and Nod2, which trigger inflammation upon stimulation. This study sought to determine the expression and function of Nod1 and Nod2 in third-trimester trophoblasts, and to characterize the in vivo effects of Nod1 activation on pregnancy outcome. Human term placental tissues and isolated term trophoblast expressed Nod1, but not Nod2. Activation of Nod1 by its agonist, bacterial gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), in term trophoblast cultures induced a proinflammatory cytokine profile, characterized by elevated levels of secreted IL-6, GRO-alpha, and MCP-1, when compared with the control. However, these cytokines were not upregulated in response to Nod2 stimulation with bacterial MDP. Administration of high-dose bacterial iE-DAP to pregnant C57BL/6J mice on embryonic day 14.5 triggered preterm delivery within 24 h. iE DAP at a lower dose that did not induce prematurity, reduced fetal weight, altered the cytokine profile at the maternal-fetal interface, and induced fetal inflammation. Thus, functional Nod1 is expressed by trophoblast cells across gestation and may have a role in mediating infection-associated inflammation and prematurity. This study demonstrates that pattern recognition receptors, other than the TLRs, may be implicated or involved in infection-associated preterm labor. PMID- 21677138 TI - Early and transient release of leukocyte pentraxin 3 during acute myocardial infarction. AB - Pentraxin 3 (PTX3) plays cardioprotective and anti-atherogenic roles in murine models. PTX3 blood levels raise during early acute myocardial infarction (AMI). Neutrophils from healthy subjects physiologically contain PTX3 in secondary (also called specific) granules. In this study, we report that circulating neutrophils release preformed PTX3 in the early phase of AMI (within 6 h from the onset of clinical symptoms). Depletion of intracellular PTX3 correlates with increased plasma levels and with platelet-neutrophil heterotypic aggregates. Neutrophil PTX3 returns to normal values 48 h after the onset of symptoms; concentration does not vary in matched healthy controls or in patients with chronic stable angina. In vitro, recognition of activated P-selectin(+) platelets causes the formation of neutrophil-platelet heteroaggregates and the release of neutrophil PTX3. Purified or membrane-bound P-selectin triggers PTX3 release from resting neutrophils. Released PTX3 binds to activated platelets in vitro. Moreover, PTX3 binds to a substantial fraction of platelets from patients in the circulating blood. PTX3-bound activated platelets have a reduced ability to 1) form heterotypic aggregates with neutrophils and monocytes; 2) activate neutrophils, as evaluated assessing the upregulation of leukocyte beta(2) integrins; 3) aggregate with other platelets; and 4) bind to fibrinogen. Our results suggest that neutrophils early release prestored PTX3 in patients undergoing AMI. PTX3 binds to activated circulating platelets and dampens their proinflammatory and prothrombotic action, thus possibly contributing to its cardioprotective effects. PMID- 21677139 TI - Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. AB - Extracellular adenosine is elevated in cancer tissue, and it negatively regulates local immune responses. Adenosine production from extracellular ATP has attracted attention as a mechanism of regulatory T cell-mediated immune regulation. In this study, we examined whether small vesicles secreted by cancer cells, called exosomes, contribute to extracellular adenosine production and hence modulate immune effector cells indirectly. We found exosomes from diverse cancer cell types exhibit potent ATP- and 5'AMP-phosphohydrolytic activity, partly attributed to exosomally expressed CD39 and CD73, respectively. Comparable levels of activity were seen with exosomes from pleural effusions of mesothelioma patients. In such fluids, exosomes accounted for 20% of the total ATP-hydrolytic activity. Exosomes can perform both hydrolytic steps sequentially to form adenosine from ATP. This exosome-generated adenosine can trigger a cAMP response in adenosine A(2A) receptor-positive but not A(2A) receptor-negative cells. Similarly, significantly elevated cAMP was also triggered in Jurkat cells by adding exosomes with ATP but not by adding exosomes or ATP alone. A proportion of healthy donor T cells constitutively express CD39 and/or CD73. Activation of T cells by CD3/CD28 cross-linking could be inhibited by exogenously added 5'AMP in a CD73-dependent manner. However, 5'AMP converted to adenosine by exosomes inhibits T cell activation independently of T cell CD73 expression. This T cell inhibition was mediated through the adenosine A(2A) receptor. In summary, the data highlight exosome enzymic activity in the production of extracellular adenosine, and this may play a contributory role in negative modulation of T cells in the tumor environment. PMID- 21677140 TI - Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis. AB - We sought to delineate further the immunological significance of T lymphocytes infiltrating the valve leaflets in calcific aortic stenosis (CAS) and determine whether there were associated alterations in circulating T cells. Using clonotypic TCR beta-chain length and sequence analysis we confirmed that the repertoire of tricuspid CAS valves contains numerous expanded T cell clones with varying degrees of additional polyclonality, which was greatest in cases with severe calcification. We now report a similar proportion of clonal expansions in the much younger bicuspid valve CAS cases. Peripheral blood flow cytometry revealed elevations in HLA-DR(+) activated CD8 cells and in the CD8(+)CD28(null)CD57(+) memory-effector subset that were significantly greater in both bicuspid and tricuspid CAS cases with more severe valve calcification. Lesser increases of CD4(+)CD28(null) T cells were identified, principally in cases with concurrent atherosclerotic disease. Upon immunostaining the CD8 T cells in all valves were mainly CD28(null), and CD8 T cell percentages were greatest in valves with oligoclonal repertoires. T cell clones identified by their clonotypic sequence as expanded in the valve were also found expanded in the circulating blood CD28(null)CD8(+) T cells and to a lesser degree in the CD8(+)CD28(+) subset, directly supporting the relationship between immunologic events in the blood and the valve. The results suggest that an ongoing systemic adaptive immune response is occurring in cases with bicuspid and tricuspid CAS, involving circulating CD8 T cell activation, clonal expansion, and differentiation to a memory-effector phenotype, with trafficking of T cells in expanded clones between blood and the valve. PMID- 21677141 TI - Targeting antigen to mouse dendritic cells via Clec9A induces potent CD4 T cell responses biased toward a follicular helper phenotype. AB - Three surface molecules of mouse CD8(+) dendritic cells (DCs), also found on the equivalent human DC subpopulation, were compared as targets for Ab-mediated delivery of Ags, a developing strategy for vaccination. For the production of cytotoxic T cells, DEC-205 and Clec9A, but not Clec12A, were effective targets, although only in the presence of adjuvants. For Ab production, however, Clec9A excelled as a target, even in the absence of adjuvant. Potent humoral immunity was a result of the highly specific expression of Clec9A on DCs, which allowed longer residence of targeting Abs in the bloodstream, prolonged DC Ag presentation, and extended CD4 T cell proliferation, all of which drove highly efficient development of follicular helper T cells. Because Clec9A shows a similar expression pattern on human DCs, it has particular promise as a target for vaccines of human application. PMID- 21677142 TI - Absence of vasoactive intestinal peptide expression in hematopoietic cells enhances Th1 polarization and antiviral immunity in mice. AB - Vasoactive intestinal peptide (VIP) induces regulatory dendritic cells (DC) in vitro that inhibit cellular immune responses. We tested the role of physiological levels of VIP on immune responses to murine CMV (mCMV) using VIP-knockout (VIP KO) mice and radiation chimeras engrafted with syngenic VIP-KO hematopoietic cells. VIP-KO mice had less weight loss and better survival following mCMV infection compared with wild-type (WT) littermates. mCMV-infected VIP-KO mice had lower viral loads, faster clearance of virus, with increased numbers of IFN gamma(+) NK and NKT cells, and enhanced cytolytic activity of NK cells. Adaptive antiviral cellular immunity was increased in mCMV-infected VIP-KO mice compared with WT mice, with more Th1/Tc1-polarized T cells, fewer IL-10(+) T cells, and more mCMV-M45 epitope peptide MHC class I tetramer(+) CD8(+) T cells (tetramer(+) CD8 T cells). mCMV-immune VIP-KO mice had enhanced ability to clear mCMV peptide pulsed target cells in vivo. Enhanced antiviral immunity was also seen in WT transplant recipients engrafted with VIP-KO hematopoietic cells, indicating that VIP synthesized by neuronal cells did not suppress immune responses. Following mCMV infection there was a marked upregulation of MHC-II and CD80 costimulatory molecule expression on DC from VIP-KO mice compared with DC from WT mice, whereas programmed death-1 and programmed death ligand-1 expression were upregulated in activated CD8(+) T cells and DC, respectively, in WT mice, but not in VIP-KO mice. Because the absence of VIP in immune cells increased innate and adaptive antiviral immunity by altering costimulatory and coinhibitory pathways, selective targeting of VIP signaling represents an attractive therapeutic target to enhance antiviral immunity. PMID- 21677143 TI - Anticardiac myosin immunity and chronic allograft vasculopathy in heart transplant recipients. AB - Chronic allograft vasculopathy (CAV) contributes to heart transplant failure, yet its pathogenesis is incompletely understood. Although cellular and humoral alloimmunity are accepted pathogenic mediators, animal models suggest that T cells and Abs reactive to graft-expressed autoantigens, including cardiac myosin (CM), could participate. To test the relationship between CAV and anti-CM autoimmunity in humans, we performed a cross-sectional study of 72 heart transplant recipients: 40 with CAV and 32 without. Sera from 65% of patients with CAV contained anti-CM Abs, whereas <10% contained Abs to other autoantigens (p < 0.05), and only 18% contained anti-HLA Abs (p < 0.05 versus anti-CM). In contrast, 13% of sera from patients without CAV contained anti-CM Abs (p < 0.05; odds ratio [OR], associating CAV with anti-CM Ab = 13, 95% confidence interval [CI] 3.79-44.6). Multivariable analysis confirmed the association to be independent of time posttransplant and the presence of anti-HLA Abs (OR = 28, 95% CI 5.77-133.56). PBMCs from patients with CAV responded more frequently to, and to a broader array of, CM-derived peptides than those without CAV (p = 0.01). Detection of either CM-peptide-reactive T cells or anti-CM Abs was highly and independently indicative of CAV (OR = 45, 95% CI 4.04-500.69). Our data suggest detection of anti-CM immunity could be used as a biomarker for outcome in heart transplantation recipients and support the need for further studies to assess whether anti-CM immunity is a pathogenic mediator of CAV. PMID- 21677144 TI - Galectin-7 modulates the length of the primary cilia and wound repair in polarized kidney epithelial cells. AB - Galectins (Gal) are beta-galactoside-binding proteins that function in epithelial development and homeostasis. An overlapping role for Gal-3 and Gal-7 in wound repair was reported in stratified epithelia. Although Gal-7 was thought absent in simple epithelia, it was reported in a proteomic analysis of cilia isolated from cultured human airway, and we recently identified Gal-7 transcripts in Madin Darby canine kidney (MDCK) cells (Poland PA, Rondanino C, Kinlough CL, Heimburg Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. J Biol Chem 286: 6780 6790, 2011). We now report that Gal-7 is localized exclusively on the primary cilium of MDCK, LLC-PK(1) (pig kidney), and mpkCCD(c14) (mouse kidney) cells as well as on cilia in the rat renal proximal tubule. Gal-7 is also present on most cilia of multiciliated cells in human airway epithelia primary cultures. Interestingly, exogenous glutathione S-transferase (GST)-Gal-7 bound the MDCK apical plasma membrane as well as the cilium, while the lectin Ulex europeaus agglutinin, with glycan preferences similar to Gal-7, bound the basolateral plasma membrane as well as the cilium. In pull-down assays, beta1-integrin isolated from either the basolateral or apical/cilia membranes of MDCK cells was similarly bound by GST-Gal-7. Selective localization of Gal-7 to cilia despite the presence of binding sites on all cell surfaces suggests that intracellular Gal-7 is specifically delivered to cilia rather than simply binding to surface glycoconjugates after generalized secretion. Moreover, depletion of Gal-7 using tetracycline-induced short-hairpin RNA in mpkCCD(c14) cells significantly reduced cilia length and slowed wound healing in a scratch assay. We conclude that Gal-7 is selectively targeted to cilia and plays a key role in surface stabilization of glycoconjugates responsible for integrating cilia function with epithelial repair. PMID- 21677145 TI - Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice. AB - Patients with acute kidney injury (AKI) have increased serum proinflammatory cytokines and an increased occurrence of respiratory complications. The aim of the present study was to examine the effect of renal and extrarenal cytokine production on AKI-mediated lung injury in mice. C57Bl/6 mice underwent sham surgery, splenectomy, ischemic AKI, or ischemic AKI with splenectomy and kidney, spleen, and liver cytokine mRNA, serum cytokines, and lung injury were examined. The proinflammatory cytokines IL-6, CXCL1, IL-1beta, and TNF-alpha were increased in the kidney, spleen, and liver within 6 h of ischemic AKI. Since splenic proinflammatory cytokines were increased, we hypothesized that splenectomy would protect against AKI-mediated lung injury. On the contrary, splenectomy with AKI resulted in increased serum IL-6 and worse lung injury as judged by increased lung capillary leak, higher lung myeloperoxidase activity, and higher lung CXCL1 vs. AKI alone. Splenectomy itself was not associated with increased serum IL-6 or lung injury vs. sham. To investigate the mechanism of the increased proinflammatory response, splenic production of the anti-inflammatory cytokine IL 10 was determined and was markedly upregulated. To confirm that splenic IL-10 downregulates the proinflammatory response of AKI, IL-10 was administered to splenectomized mice with AKI, which reduced serum IL-6 and improved lung injury. Our data demonstrate that AKI in the absence of a counter anti-inflammatory response by splenic IL-10 production results in an exuberant proinflammatory response and lung injury. PMID- 21677146 TI - Therapeutic potential of DCB-SLE1, an extract of a mixture of Chinese medicinal herbs, for severe lupus nephritis. AB - The pathogenesis of lupus nephritis is mainly attributable to a complex interaction between the innate and adaptive immune systems, including T and B cell function abnormalities. In addition to autoantibody production and immune complex deposition, Th1 and Th17 cytokines may play key roles in the development and progression of lupus nephritis. Acute onset of severe lupus nephritis remains a challenge in terms of prevention and treatment. In the present study, we evaluated the therapeutic effects of DCB-SLE1, an extract of a mixture of four traditional Chinese medicinal herbs (Atractylodis macrocephalae Rhizoma, Eucommiae cortex, Lonicerae caulis, and Hedyotidis diffusae Herba), on an accelerated severe lupus nephritis model, characterized by acute onset of proteinuria, azotemia, autoantibody production, and development of severe nephritis, induced by twice weekly injection of New Zealand black/white F1 mice with Salmonella-type lipopolysaccharide. DCB-SLE1 was administered daily by gavage starting 2 days after the first dose of induction of lipopolysaccharide, and the mice were euthanized at week 1 or week 5. The results showed that DCB SLE1 significantly ameliorated the hematuria, proteinuria, renal dysfunction, and severe renal lesions by 1) suppression of B cell activation and decreased autoantibody production; 2) negative regulation of T cell activation/proliferation and natural killer cell activity; 3) suppression of IL 18, IL-6, and IL-17 production and blocking of NF-kappaB activation in the kidney; and 4) prevention of lymphoid and renal apoptosis. These results show that DCB-SLE1 can protect the kidney from autoimmune response-mediated acute and severe damage through systemic immune modulation and anti-inflammation pathways. PMID- 21677147 TI - Antecedent acute kidney injury worsens subsequent endotoxin-induced lung inflammation in a two-hit mouse model. AB - Acute kidney injury (AKI) contributes greatly to morbidity and mortality in critically ill adults and children. Patients with AKI who subsequently develop lung injury are known to suffer worse outcomes compared with patients with lung injury alone. Isolated experimental kidney ischemia alters distal lung water balance and capillary permeability, but the effects of such an aberration on subsequent lung injury are unknown. We present a clinically relevant two-hit murine model wherein a proximal AKI through bilateral renal ischemia (30 min) is followed by a subsequent acute lung injury (ALI) via intratracheal LPS endotoxin (50 MUg at 24 h after surgery). Mice demonstrated AKI by elevation of serum creatinine and renal histopathological damage. Mice with ALI and preexisting AKI had increased lung neutrophilia in bronchoalveolar lavage fluid and by myeloperoxidase activity over Sham-ALI mice. Additionally, lung histopathological damage was greater in ALI mice with preexisting AKI than Sham-ALI mice. There was uniform elevation of monocyte chemoattractant protein-1 in kidney, serum, and lung tissue in animals with both AKI and ALI over those with either injury alone. The additive lung inflammation after ALI with antecedent AKI was abrogated in MCP 1-deficient mice. Taken together, our two-hit model demonstrates that kidney injury may prime the lung for a heightened inflammatory response to subsequent injury and MCP-1 may be involved in this model of kidney-lung cross talk. The model holds clinical relevance for patients at risk of lung injury after ischemic injury to the kidney. PMID- 21677148 TI - Anti-VEGF antibody treatment accelerates polycystic kidney disease. AB - Polycystic kidney growth implies expansion of the vasculature, suggesting that vascular endothelial growth factor (VEGF)-dependent processes play a critical role and that VEGF is a putative therapeutic target. Whether an anti-VEGF antibody improves renal cystic disease has not been determined. We administrated 5 mg/kg B20.4.1, an anti-VEGF-A antibody, or vehicle intraperitoneally twice weekly to 4-wk-old male normal (+/+) and cystic (Cy/+) Han:SPRD rats for 6 wk. Renal function, urinary protein excretion, organ/body weight ratios, cyst volume, tubular epithelial cell (TEC) proliferation, renal VEGF, hypoxia-inducible factor (HIF)-1alpha and -2alpha expression, renal histology, and kidney hypoxia visualized by [(18)F]fluoromisonidazole positron emission tomography were assessed. The treated compared with untreated +/+ rats had lower TEC proliferation rates, whereas Cy/+ rats receiving B20.4.1 displayed an increased proximal TEC proliferation rate, causing enhanced cyst and kidney growth. The +/+ and Cy/+ rats receiving B20.4.1 had severe renal failure and extensive glomerular damage. Proteinuria, which was highest in anti-VEGF-treated Cy/+ and lowest in untreated normal littermates, was positively correlated with renal HIF-1alpha and negatively correlated with VEGF expression. The untreated Cy/+ vs. +/+ rats had higher overall [(18)F]fluoromisonidazole uptake. The +/+ rats receiving B20.4.1 vs. untreated had increased [(18)F]fluoromisonidazole uptake, whereas the uptake was unchanged among treated vs. untreated Cy/+ animals. In conclusion, B20.4.1 caused an exaggerated cystic response of the proximal tubules in cystic rats and severe kidney injury that was associated with low renal VEGF and high HIF-1alpha levels. Anti-VEGF drug therapy may therefore not be a treatment option for polycystic kidney disease. PMID- 21677149 TI - Activity of the Ste20-like kinase, SLK, is enhanced by homodimerization. AB - The expression and activation of the Ste20-like kinase, SLK, is increased during renal development and recovery from ischemic acute renal failure. SLK promotes apoptosis, and during renal injury and repair, transcriptional induction or posttranscriptional control of SLK may, therefore, regulate cell survival. SLK contains protein interaction (coiled-coil) domains, suggesting that posttranslational homodimerization may also modulate SLK activity. We therefore expressed coiled-coil regions in the C-terminal domain of SLK as fusion proteins and demonstrated their homodimerization. By gel-filtration chromatography, endogenous and heterologously expressed SLK were detected in a macromolecular protein complex. To test the role of homodimerization in kinase activation, we constructed a fusion protein consisting of the SLK catalytic domain (amino acids 1-373) and a modified FK506 binding protein, Fv (Fv-SLK 1-373). Addition of AP20187 (an analog of FK506) enhanced the homodimerization of Fv-SLK 1-373. In an in vitro kinase assay, the dimeric Fv-SLK 1-373 displayed greater kinase activity than the monomeric form. In cells expressing Fv-SLK 1-373, homodimerization increased activation-specific phosphorylation of the proapoptotic kinases, c-Jun N-terminal kinase and p38 kinase. Compared with the monomer, dimeric Fv-SLK 1-373 enhanced the activation of a Bax promoter-luciferase reporter. Finally, expression of Fv-SLK 1-373 induced apoptosis, and the effect was increased by homodimerization. Thus the activity, downstream signaling, and functional effects of SLK are enhanced by dimerization of the kinase domain. PMID- 21677150 TI - ERK pathway mediates P2X7 expression and cell death in renal interstitial fibroblasts exposed to necrotic renal epithelial cells. AB - We recently reported that necrotic renal proximal epithelial cells (RPTC) stimulate the expression of P2X7 receptor in renal fibroblasts and that P2X7 receptor mediates deleterious epithelial-fibroblast cross talk. The present study was carried out to investigate the signaling mechanism of necrotic RPTC-induced P2X7 expression in cultured renal interstitial fibroblasts (NRK-49F). Exposure of NRK-49F to necrotic RPTC supernatant (RPTC-Sup) induced a time- and dose dependent phosphorylation of several signaling pathways including extracellular signal-regulated kinases (ERK1/2), p38, c-Jun N-terminal kinases (JNKs), and AKT in NRK-49F. Pharmacological inhibition of ERK1/2, but not p38, JNK, and AKT pathways, blocked RPTC-Sup-induced P2X7 expression and renal interstitial fibroblast death. Knockdown of ERK1/2 or MEK1, a direct upstream activator of ERK1/2, also reduced RPTC-Sup-induced P2X7 expression and cell death of renal fibroblasts. Conversely, overexpression of MEK1 enhanced these responses. Upon necrotic RPTC exposure, phosphorylation of Elk1, a transcriptional factor targeted by ERK1/2, was increased in NRK-49F, and knockdown of Elk1 by siRNA remarkably reduced RPTC-Sup-induced P2X7 expression as well as renal fibroblast death. Furthermore, silencing of MEK1 inhibited Elk1 phosphorylation in response to necrotic RPTC, whereas overexpression of MEK1 increased Elk1 phosphorylation. Taken together, these data reveal that necrotic RPTC induces P2X7 expression in renal fibroblasts through activation of the MEK1-ERK1/2-Elk1 signaling pathway. PMID- 21677151 TI - Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells. AB - Cancer stem cells are responsible for tumor initiation and chemoresistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the ovarian cancer stem cells are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase independent cell death in a panel of ovarian cancer stem cells. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and by increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of cellular starvation that activates two independent pathways: (i) AMPKalpha1 pathway leading to mTOR inhibition; and (ii) mitochondrial MAP/ERK kinase/extracellular signal-regulated kinase pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemoresistant cell population opens a new venue for treating ovarian cancer patients. PMID- 21677152 TI - Quality metrics to accompany spike sorting of extracellular signals. PMID- 21677153 TI - When does the visual system need to look back? PMID- 21677154 TI - Cerebellar-dependent learning in larval zebrafish. AB - Understanding how neuronal network activity contributes to memory formation is challenged by the complexity of most brain circuits and the restricted ability to monitor the activity of neuronal populations in vivo. The developing zebrafish (Danio rerio) is an animal model that circumvents these problems, because zebrafish larvae possess a rich behavioral repertoire and an accessible brain. Here, we developed a classical conditioning paradigm in which 6- to 8-d-old larvae develop an enhanced motor response to a visual stimulus (conditioned stimulus, CS) when it is paired with touch (unconditioned stimulus, US). Using in vivo calcium imaging we demonstrate that CS and US activate different subsets of neurons in the cerebellum; their activity, modulated by learning two-photon laser ablation, revealed that the cerebellum is involved in acquisition and extinction, but not the retention, of this memory. PMID- 21677155 TI - Spatial and temporal properties of tic-related neuronal activity in the cortico basal ganglia loop. AB - Motor tics are involuntary brief muscle contractions that interfere with ongoing behavior and appear as a symptom in several human disorders. While the pathophysiology of tics is still largely unknown, multiple lines of evidence suggest the involvement of the corticobasal ganglia loop in tic disorders. We administered local microinjections of bicuculline into the putamen of Macaca fascicularis monkeys to induce motor tics, while simultaneously recording neuronal activity from the primary motor cortex, putamen, and globus pallidus. These data were used to explore the spatial and temporal properties of tic related neuronal activity within the cortico-basal ganglia system. In the putamen, tics were associated with brief bursts of activity of phasically active neurons (presumably the projection neurons) and complex excitation-inhibition patterns of tonically active neurons. Tic-related activity within the putamen was spatially focused and somatotopically organized. In the globus pallidus, tic related activity was diffusely distributed throughout the motor territory. Tic related activity in the putamen usually preceded the tic-related activations in the cortex, but in the globus pallidus, tic-related activity was mostly later than the cortex. These findings shed new light on the role of the different basal ganglia nuclei in the generation of motor tics. Despite the early and somatotopically focused nature of tic-related activity in the input stage of the basal ganglia, tic-related activity in the output nucleus is temporally late and diffusely distributed, making it incompatible with a role in tic initiation. Instead, abnormal basal ganglia activity may serve to modulate motor patterns or activate learning mechanisms, thus augmenting further tic expression. PMID- 21677156 TI - Monosynaptic and polysynaptic feed-forward inputs to mitral cells from olfactory sensory neurons. AB - Olfactory sensory neurons (OSNs) expressing the same odorant receptor converge in specific glomeruli where they transmit olfactory information to mitral cells. Surprisingly, synaptic mechanisms underlying mitral cell activation are still controversial. Using patch-clamp recordings in mouse olfactory bulb slices, we demonstrate that stimulation of OSNs produces a biphasic postsynaptic excitatory response in mitral cells. The response was initiated by a fast and graded monosynaptic input from OSNs and followed by a slower component of feedforward excitation, involving dendro-dendritic interactions between external tufted, tufted and other mitral cells. The mitral cell response occasionally lacked the fast OSN input when few afferent fibers were stimulated. We also show that OSN stimulation triggers a strong and slow feedforward inhibition that shapes the feedforward excitation but leaves unaffected the monosynaptic component. These results confirm the existence of direct OSN to mitral cells synapses but also emphasize the prominence of intraglomerular feedforward pathways in the mitral cell response. PMID- 21677157 TI - Cerebral regulation of facial expressions of pain. AB - Facial expression of affective states plays a key role in social interactions. Interestingly, however, individuals differ substantially in their level of expressiveness, ranging from high expressive to stoic individuals. Here, we investigate which brain mechanisms underlie the regulation of facial expressiveness to acute pain. Facial responses, pain ratings, and brain activity (BOLD-fMRI) evoked by noxious heat and warm (control) stimuli were recorded in 34 human volunteers with different degrees of facial expressiveness. Within-subject and between-subject variations in blood oxygenation level-dependent (BOLD) responses were examined specifically in relation to facial responses. Pain expression was inversely related to frontostriatal activity, consistent with a role in downregulating facial displays. More detailed analyses of the peak activity in medial prefrontal cortex revealed negative BOLD responses to thermal stimuli, an effect generally associated with the default mode network. Given that this negative BOLD response was weaker in low expressive individuals during pain, it could reflect stronger engagement in, or reduced disengagement from, self reflective processes in stoic individuals. The occurrence of facial expressions during pain was coupled with stronger primary motor activity in the face area and interestingly-in areas involved in pain processing. In conclusion, these results indicate that spontaneous pain expression reflects activity within nociceptive pathways while stoicism involves the active suppression of expression, a manifestation of learned display rules governing emotional communication and possibly related to an increased self-reflective or introspective focus. PMID- 21677158 TI - Perirhinal and parahippocampal cortices differentially contribute to later recollection of object- and scene-related event details. AB - How the different elements of our experiences are encoded into episodic memories has remained one of the major questions in memory research. Although the pivotal role of the medial temporal lobe as a whole for memory formation is well established, much controversy surrounds the precise contributions of the subregions in the medial temporal lobe cortex (MTLC), most notably the perirhinal cortex (PrC) and the parahippocampal cortex (PhC). Although one prominent view links PrC processes with familiarity-based memory and PhC with recollection, an alternative organizing principle is the representational domain critical for successful memory performance (e.g., object- versus scene-related information). In this functional magnetic resonance imaging study, we directly compared successful source encoding during object versus scene imagery, holding perceptual input constant across the two representational domains. Although the hippocampus contributed to associative encoding of both object and scene information, our results revealed a clear double dissociation between PrC and PhC for object- versus scene-related source encoding. In particular, PrC, but not PhC, encoding activation predicted later source memory for the object imagery task, whereas PhC, but not PrC, encoding activation predicted later source memory for the scene imagery task. Interestingly, the transitional zone between PrC and posterior PhC contributed to both object and scene source encoding, possibly reflecting a gradient in domain preference along MTLC. In sum, these results strongly point to representational domain as a key factor determining the involvement of different MTLC subregions during successful episodic memory formation. PMID- 21677159 TI - DeltaNp63 regulates stem cell dynamics in the mammalian olfactory epithelium. AB - The ability of the olfactory epithelium (OE) to regenerate after injury is mediated by at least two populations of presumed stem cells-globose basal cells (GBCs) and horizontal basal cells (HBCs). Of the two, GBCs are molecularly and phenotypically analogous to the olfactory progenitors of the embryonic placode (OPPs). In contrast, HBCs are a reserve stem cell population that appears later in development and requires activation by severe epithelial damage before contributing to epithelial reconstitution. Neither HBC emergence nor the mechanism of activation after injury is understood. Here we show that the transcription factor p63 (Trp63), which is expressed selectively by adult HBCs, is required for HBC differentiation. The first evidence of HBC differentiation is the expression of p63 by cells that closely resemble embryonic OPPs and adult GBCs by morphology and expression of the transcription factors Sox2, Ascl1, and Hes1. HBC formation is delayed in Ascl1 knock-out OE and is completely abrogated in p63-null mice. Strikingly, other cell types of the OE form normally in the p63 knock-out OE. The role of p63 in HBC differentiation appears to be conserved in the regenerating rat OE, where HBCs disappear and then reappear after tissue lesion. Finally, p63 protein is downregulated in HBCs activated by lesion to become multipotent progenitor cells. Together, our data identify a novel mechanism for the generation of a reserve stem cell population and suggest that a p63-dependent molecular switch is responsible for activating reserve stem cells when they are needed. PMID- 21677160 TI - Transgenic mice reveal unexpected diversity of on-off direction-selective retinal ganglion cell subtypes and brain structures involved in motion processing. AB - On-Off direction-selective retinal ganglion cells (DSGCs) encode the axis of visual motion. They respond strongly to an object moving in a preferred direction and weakly to an object moving in the opposite, "null," direction. Historically, On-Off DSGCs were classified into four subtypes according to their directional preference (anterior, posterior, superior, or inferior). Here, we compare two genetically identified populations of On-Off DSGCs: dopamine receptor 4 (DRD4) DSGCs and thyrotropin-releasing hormone receptor (TRHR)-DSGCs. We find that although both populations are tuned for posterior motion, they can be distinguished by a variety of physiological and anatomical criteria. First, the directional tuning of TRHR-DSGCs is broader than that of DRD4-DSGCs. Second, whereas both populations project similarly to the dorsal lateral geniculate nucleus, they project differently to the ventral lateral geniculate nucleus and the superior colliculus. Moreover, TRHR-DSGCs, but not DRD4-DSGCs, also project to the zona incerta, a thalamic area not previously known to receive direction tuned visual information. Our findings reveal unexpected diversity among mouse On Off DSGC subtypes that uniquely process and convey image motion to the brain. PMID- 21677161 TI - Complex propagation patterns characterize human cortical activity during slow wave sleep. AB - Cortical electrical activity during nonrapid eye movement (non-REM) sleep is dominated by slow-wave activity (SWA). At larger spatial scales (~2-30 cm), investigated by scalp EEG recordings, SWA has been shown to propagate globally over wide cortical regions as traveling waves, which has been proposed to serve as a temporal framework for neural plasticity. However, whether SWA dynamics at finer spatial scales also reflects the orderly propagation has not previously been investigated in humans. To reveal the local, finer spatial scale (~1-6 cm) patterns of SWA propagation during non-REM sleep, electrocorticographic (ECoG) recordings were conducted from subdurally implanted electrode grids and a nonlinear correlation technique [mutual information (MI)] was implemented. MI analysis revealed spatial maps of correlations between cortical areas demonstrating SWA propagation directions, speed, and association strength. Highest correlations, indicating significant coupling, were detected during the initial positive-going deflection of slow waves. SWA propagated predominantly between adjacent cortical areas, albeit spatial noncontinuities were also frequently observed. MI analysis further uncovered significant convergence and divergence patterns. Areas receiving the most convergent activity were similar to those with high divergence rate, while reciprocal and circular propagation of SWA was also frequent. We hypothesize that SWA is characterized by distinct attributes depending on the spatial scale observed. At larger spatial scales, the orderly SWA propagation dominates; at the finer scale of the ECoG recordings, non REM sleep is characterized by complex SWA propagation patterns. PMID- 21677162 TI - White matter anisotropy in the ventral language pathway predicts sound-to-word learning success. AB - According to the dual stream model of auditory language processing, the dorsal stream is responsible for mapping sound to articulation and the ventral stream plays the role of mapping sound to meaning. Most researchers agree that the arcuate fasciculus (AF) is the neuroanatomical correlate of the dorsal steam; however, less is known about what constitutes the ventral one. Nevertheless, two hypotheses exist: one suggests that the segment of the AF that terminates in middle temporal gyrus corresponds to the ventral stream, and the other suggests that it is the extreme capsule that underlies this sound-to-meaning pathway. The goal of this study was to evaluate these two competing hypotheses. We trained participants with a sound-to-word learning paradigm in which they learned to use a foreign phonetic contrast for signaling word meaning. Using diffusion tensor imaging, a brain-imaging tool to investigate white matter connectivity in humans, we found that fractional anisotropy in the left parietal-temporal region positively correlated with the performance in sound-to-word learning. In addition, fiber tracking revealed a ventral pathway, composed of the extreme capsule and the inferior longitudinal fasciculus, that mediated auditory comprehension. Our findings provide converging evidence supporting the importance of the ventral steam, an extreme capsule system, in the frontal-temporal language network. Implications for current models of speech processing are also discussed. PMID- 21677163 TI - Upregulation of CREB-mediated transcription enhances both short- and long-term memory. AB - Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression. PMID- 21677164 TI - A novel positron emission tomography imaging protocol identifies seizure-induced regional overactivity of P-glycoprotein at the blood-brain barrier. AB - Approximately one-third of epilepsy patients are pharmacoresistant. Overexpression of P-glycoprotein and other multidrug transporters at the blood brain barrier is thought to play an important role in drug-refractory epilepsy. Thus, quantification of regionally different P-glycoprotein activity in the brain in vivo is essential to identify P-glycoprotein overactivity as the relevant mechanism for drug resistance in an individual patient. Using the radiolabeled P glycoprotein substrate (R)-[(11)C]verapamil and different doses of coadministered tariquidar, which is an inhibitor of P-glycoprotein, we evaluated whether small animal positron emission tomography can quantify regional changes in transporter function in the rat brain at baseline and 48 h after a pilocarpine-induced status epilepticus. P-glycoprotein expression was additionally quantified by immunohistochemistry. To reveal putative seizure-induced changes in blood-brain barrier integrity, we performed gadolinium-enhanced magnetic resonance scans on a 7.0 tesla small-animal scanner. Before P-glycoprotein modulation, brain uptake of (R)-[(11)C]verapamil was low in all regions investigated in control and post status epilepticus rats. After administration of 3 mg/kg tariquidar, which inhibits P-glycoprotein only partially, we observed increased regional differentiation in brain activity uptake in post-status epilepticus versus control rats, which diminished after maximal P-glycoprotein inhibition. Regional increases in the efflux rate constant k(2), but not in distribution volume V(T) or influx rate constant K(1), correlated significantly with increases in P glycoprotein expression measured by immunohistochemistry. This imaging protocol proves to be suitable to detect seizure-induced regional changes in P glycoprotein activity and is readily applicable to humans, with the aim to detect relevant mechanisms of pharmacoresistance in epilepsy in vivo. PMID- 21677165 TI - Ventral premotor-motor cortex interactions in the macaque monkey during grasp: response of single neurons to intracortical microstimulation. AB - Recent stimulation studies in monkeys and humans have shown strong interactions between ventral premotor cortex (area F5) and the hand area of primary motor cortex (M1). These short-latency interactions usually involve facilitation from F5 of M1 outputs to hand muscles, although suppression has also been reported. This study, performed in three awake macaque monkeys, sought evidence that these interactions could be mediated by short-latency excitatory and inhibitory responses of single M1 neurons active during grasping tasks. We recorded responses of these M1 neurons to single low-threshold (<=40 MUA) intracortical microstimuli delivered to F5 sites at which grasp-related neurons were recorded. In 29 sessions, we tested 232 M1 neurons with stimuli delivered to between one and four sites in F5. Of the 415 responses recorded, 142 (34%) showed significant effects. The most common type of response was pure excitation (53% of responses), with short latency (1.8-3.0 ms) and brief duration (~1 ms); purely inhibitory responses had slightly longer latencies (2-5 ms) and were of small amplitude and longer duration (5-7 ms). They accounted for 13% of responses, whereas mixed excitation then inhibition was seen in 34%. Remarkably, a rather similar set of findings applied to 280 responses of 138 F5 neurons to M1 stimulation; 109 (34%) responses showed significant effects. Thus, with low-intensity stimuli, the dominant interaction between these two cortical areas is one of short-latency, brief excitation, most likely mediated by reciprocal F5-M1 connections. Some neurons were tested with stimuli at both 20 and 40 MUA; inhibition tended to dominate at the higher intensity. PMID- 21677166 TI - The neural correlates of subjective utility of monetary outcome and probability weight in economic and in motor decision under risk. AB - In decision under risk, people choose between lotteries that contain a list of potential outcomes paired with their probabilities of occurrence. We previously developed a method for translating such lotteries to mathematically equivalent "motor lotteries." The probability of each outcome in a motor lottery is determined by the subject's noise in executing a movement. In this study, we used functional magnetic resonance imaging in humans to compare the neural correlates of monetary outcome and probability in classical lottery tasks in which information about probability was explicitly communicated to the subjects and in mathematically equivalent motor lottery tasks in which probability was implicit in the subjects' own motor noise. We found that activity in the medial prefrontal cortex (mPFC) and the posterior cingulate cortex quantitatively represent the subjective utility of monetary outcome in both tasks. For probability, we found that the mPFC significantly tracked the distortion of such information in both tasks. Specifically, activity in mPFC represents probability information but not the physical properties of the stimuli correlated with this information. Together, the results demonstrate that mPFC represents probability from two distinct forms of decision under risk. PMID- 21677167 TI - Artificial CSF motion ensures rhythmic activity in the developing CNS ex vivo: a mechanical source of rhythmogenesis? AB - Spontaneous rhythmic activity is a ubiquitous feature of developing neural structures that has been shown to be essential for the establishment of functional CNS connectivity. However, the primordial origin of these rhythms remains unknown. Here, we describe two types of rhythmic activity in distinct parts of the developing CNS isolated ex vivo on microelectrode arrays, the expression of which was found to be strictly dependent upon the movement of the artificial CSF (aCSF) flowing over the inner wall of the ventricles or over the outer surface of the CNS. First, whole embryonic mouse hindbrain-spinal cord preparations (stages E12.5-E15.5) rhythmically expressed waves of activity originating in the hindbrain and propagating in the spinal cord. Interestingly enough, the frequency of this rhythm was completely determined by the speed of the aCSF flow. In particular, at all stages considered, hindbrain activity was abolished when the perfusion was stopped. Immature rhythmic activity was also recorded in the isolated newborn (P0-P8) mouse cortex under normal aCSF perfusion. Again, this rhythm was abolished when the perfusion flow was stopped. In both structures, this phenomenon was not due to changes in temperature, oxygen level, or pH of the bath, but to the movement itself of the aCSF. These observations challenge the so-called "spontaneous" nature of rhythmic activity in immature neural networks and suggest that the movement of CSF in the ventricles and around the brain in vivo may mechanically drive rhythmogenesis in the developing CNS. PMID- 21677168 TI - Persistent long-term synaptic plasticity requires activation of a new signaling pathway by additional stimuli. AB - Most memories are strengthened by additional stimuli, but it is unclear how additional stimulation or training reinforces long-term memory. To address this we examined whether long-term facilitation (LTF) of Aplysia sensorimotor synapses in cell culture-a cellular correlate of long-term sensitization of defensive withdrawal reflexes in Aplysia californica-can be prolonged by additional stimulation. We found that 1 d treatment with serotonin (5-HT; five brief applications at 20 min intervals) produced LTF lasting ~3 d, whereas 2 d of such 5-HT treatments induced a persistent LTF lasting >7 d. Incubation with the protein synthesis inhibitor rapamycin during the second set of 5-HT treatments abolished all facilitation, and synapse strength returned prematurely to baseline. Persistent LTF required more persistent elevation in the expression of the neurotrophin-like peptide sensorin and its secretion. Activation of protein kinase C (PKC) during the second day of 5-HT treatments, not required for LTF or changes in sensorin expression during the first set of 5-HT treatments, is critical for persistent LTF and replaces phosphoinositide 3 kinase (PI3K) activity in mediating the increase in sensorin expression. In contrast, activations of PKC during the first day of 5-HT treatments and PI3K during the second day of 5-HT treatments are unnecessary for persistent LTF or the increases in sensorin expression. Thus, additional stimuli make preexisting plasticity labile as they recruit a new signaling cascade to regulate the synthesis of a neurotrophin-like peptide required for persistent alterations in synaptic efficacy. PMID- 21677169 TI - GABAA receptor endocytosis in the basolateral amygdala is critical to the reinstatement of fear memory measured by fear-potentiated startle. AB - Reinstatement represents a phenomenon that may be used to model the effects of retraumatization observed in patients with posttraumatic stress disorder (PTSD). In this study, we found intraperitoneal injection of the beta-adrenergic receptor antagonist propranolol (10 mg/kg) 1 h before reinstatement training attenuated reinstatement of fear memory in rats. Conversely, reinstatement was facilitated by intra-amygdalar administration of beta-adrenergic receptor agonist isoproterenol (Iso; 2 MUg per side) 30 min before reinstatement training. The frequency and amplitude of the miniature IPSC (mIPSC) and the surface expression of the beta3 and gamma2 subunits of the GABA(A) receptor (GABA(A)R) were significantly lower in reinstated than in extinction rats, whereas the AMPA/NMDA ratio and the surface expression of GluR1 and GluR2 in the amygdala did not differ between groups. In amygdala slices, Iso-induced decrease in the surface beta3 subunit of GABA(A) receptor was blocked by a Tat-conjugated dynamin function-blocking peptide (Tat-P4) pretreatment (10 MUm for 30 min). By contrast, Tat-scramble peptide had no effect. Intravenous injection (3 MUmol/kg) or intra amygdalar infusion (30 pmol per side) of Tat-P4 interfered with reinstatement. Reinstatement increased the association between protein phosphatase 2A (PP2A) and the beta3 subunit of the GABA(A)R, which was abolished by PP1/PP2A inhibitors okadaic acid and calyculin A. These results suggest the involvement of beta adrenergic receptor activation and GABA(A) receptor endocytosis in the amygdala for the reinstatement in fear memory. PMID- 21677170 TI - Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. AB - The autism spectrum disorder tuberous sclerosis complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes, whose protein products form a heterodimeric complex that negatively regulates mammalian target of rapamycin-dependent protein translation. Although several forms of synaptic plasticity, including metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), depend on protein translation at the time of induction, it is unknown whether these forms of plasticity require signaling through the Tsc1/2 complex. To examine this possibility, we postnatally deleted Tsc1 in vivo in a subset of hippocampal CA1 neurons using viral delivery of Cre recombinase in mice. We found that hippocampal mGluR-LTD was abolished by loss of Tsc1, whereas a protein synthesis-independent form of NMDA receptor-dependent LTD was preserved. Additionally, AMPA and NMDA receptor-mediated EPSCs and miniature spontaneous EPSC frequency were enhanced in Tsc1 KO neurons. These changes in synaptic function occurred in the absence of alterations in spine density, morphology, or presynaptic release probability. Our findings indicate that signaling through Tsc1/2 is required for the expression of specific forms of hippocampal synaptic plasticity as well as the maintenance of normal excitatory synaptic strength. Furthermore, these data suggest that perturbations of synaptic signaling may contribute to the pathogenesis of TSC. PMID- 21677171 TI - Ionic dynamics mediate spontaneous termination of seizures and postictal depression state. AB - Epileptic seizures are characterized by periods of recurrent, highly synchronized activity that spontaneously terminates, followed by postictal state when neuronal activity is generally depressed. The mechanisms for spontaneous seizure termination and postictal depression remain poorly understood. Using a realistic computational model, we demonstrate that termination of seizure and postictal depression state may be mediated by dynamics of the intracellular and extracellular ion concentrations. Spontaneous termination was linked to progressive increase of intracellular sodium concentration mediated by activation of sodium channels during highly active epileptic state. In contrast, an increase of intracellular chloride concentration extended seizure duration making possible long-lasting epileptic activity characterized by multiple transitions between tonic and clonic states. After seizure termination, the extracellular potassium was reduced below baseline, resulting in postictal depression. Our study suggests that the coupled dynamics of sodium, potassium, and chloride ions play a critical role in the development and termination of seizures. Findings from this study could help identify novel therapeutics for seizure disorder. PMID- 21677172 TI - Mature mice lacking Rbl2/p130 gene have supernumerary inner ear hair cells and supporting cells. AB - Adult mammalian auditory hair cells (HCs) and their associated supporting cells (SCs) do not proliferate, and HC death leads to irreversible neurosensory hearing loss and balance impairment. In nonmammalian vertebrates, loss of HCs induces mitotic proliferation of adjacent nonsensory SCs and/or direct SC transdifferentiation to generate replacement cells. This results in the structural and functional recovery of the nonmammalian sensory systems. Potential replacement of mammalian auditory HCs, either by transplanting cells or by transforming existing cells through molecular therapy, has long been proposed. However, HC replacement strategies with clear therapeutic potential remain elusive. The retinoblastoma (pRB) family of cell cycle regulators, Rb1, Rbl1 (p107), and Rbl2 (p130), regulate the G(1)- to S-phase transition in proliferating cells. In the inner ear, the biochemical and molecular pathways involving pRBs, particularly p107 and p130, are relatively unexplored and their therapeutic suitability is yet to be determined. In this study, we analyzed the cochleae of adult p130 knock-out (p130(-/-)) mice and showed that lack of the p130 gene results in extra rows of HCs and SCs in the more apical regions of the cochlea. No evidence of transdifferentiation of these supernumerary SCs into HCs was observed in the p130(-/-) mouse. Nevertheless, unscheduled proliferation of SCs in the adult p130(-/-) cochlea coupled to downregulation of bona fide cell cycle inhibitors provides a mechanistic basis for the role of p130 as a regulator of SC and HC mitotic quiescence in the more apical regions of the cochlea. Interestingly, p130(-/-) mice exhibited nearly normal peripheral auditory sensitivity. PMID- 21677173 TI - Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. AB - Despite extensive research to develop an effective neuroprotective strategy for the treatment of ischemic stroke, therapeutic options remain limited. Although caspase-dependent death is thought to play a prominent role in neuronal injury, direct evidence of active initiator caspases in stroke and the functional relevance of this activity have not previously been shown. Using an unbiased caspase-trapping technique in vivo, we isolated active caspase-9 from ischemic rat brain within 1 h of reperfusion. Pathogenic relevance of active caspase-9 was shown by intranasal delivery of a novel cell membrane-penetrating highly specific inhibitor for active caspase-9 at 4 h postreperfusion (hpr). Caspase-9 inhibition provided neurofunctional protection and established caspase-6 as its downstream target. The temporal and spatial pattern of expression demonstrates that neuronal caspase-9 activity induces caspase-6 activation, mediating axonal loss by 12 hpr followed by neuronal death within 24 hpr. Collectively, these results support selective inhibition of these specific caspases as an effective therapeutic strategy for stroke. PMID- 21677174 TI - Astrocytes display complex and localized calcium responses to single-neuron stimulation in the hippocampus. AB - Astrocytes show a complex structural and physiological interplay with neurons and respond to neuronal activation in vitro and in vivo with intracellular calcium elevations. These calcium changes enable astrocytes to modulate synaptic transmission and plasticity through various mechanisms. However, the response pattern of astrocytes to single neuronal depolarization events still remains unresolved. This information is critical for fully understanding the coordinated network of neuron-glial signaling in the brain. To address this, we developed a system to map astrocyte calcium responses along apical dendrites of CA1 pyramidal neurons in hippocampal slices using single-neuron stimulation with channelrhodopsin-2. This technique allowed selective neuronal depolarization without invasive manipulations known to alter calcium levels in astrocytes. Light evoked neuronal depolarization was elicited and calcium events in surrounding astrocytes were monitored using the calcium-sensitive dye Calcium Orange. Stimulation of single neurons caused calcium responses in populations of astrocytes along the apical axis of CA1 cell dendrites. Calcium responses included single events that were synchronized with neuronal stimulation and poststimulus changes in calcium event frequency, both of which were modulated by glutamatergic and purinergic signaling. Individual astrocytes near CA1 cells showed low ability to respond to repeated neuronal depolarization events. However, the response of the surrounding astrocyte population was remarkably accurate. Interestingly, the reliability of responses was graded with respect to astrocyte location along the CA1 cell dendrite, with astrocytes residing in the primary dendrite subregion being most responsive. This study provides a new perspective on the dynamic response property of astrocyte ensembles to neuronal activity. PMID- 21677175 TI - Subjective sense of memory strength and the objective amount of information accurately remembered are related to distinct neural correlates at encoding. AB - Although commonly used, the term memory strength is not well defined in humans. Besides durability, it has been conceptualized by retrieval characteristics, such as subjective confidence associated with retrieval, or objectively, by the amount of information accurately retrieved. Behaviorally, these measures are not necessarily correlated, indicating that distinct neural processes may underlie them. Thus, we aimed at disentangling neural activity at encoding associated with either a subsequent subjective sense of memory strength or with a subsequent objective amount of information remembered. Using functional magnetic resonance imaging (fMRI), participants were scanned while incidentally encoding a series of photographs of complex scenes. The next day, they underwent two memory tests, quantifying memory strength either subjectively (confidence on remembering the gist of a scene) or objectively (the number of details accurately remembered within a scene). Correlations between these measurements were mutually partialed out in subsequent memory analyses of fMRI data. Results revealed that activation in left ventral lateral prefrontal cortex and temporoparietal junction predicted subsequent confidence ratings. In contrast, parahippocampal and hippocampal activity predicted the number of details remembered. Our findings suggest that memory strength may reflect a functionally heterogeneous set of (at least two) phenomena. One phenomenon appears related to prefrontal and temporoparietal top down modulations, resulting in the subjective sense of memory strength that is potentially based on gist memory. The other phenomenon is likely related to medial-temporal binding processes, determining the amount of information accurately encoded into memory. Thus, our study dissociated two distinct phenomena that are usually described as memory strength. PMID- 21677176 TI - A switch in the neuromodulatory effects of dopamine in the oval bed nucleus of the stria terminalis associated with cocaine self-administration in rats. AB - Chronic exposure to drugs of abuse alters brain reward circuits and produces functional changes in the dopamine (DA) system. However, it is not known whether these changes are directly related to drug-driven behaviors or whether they simply are adaptive responses to long-term drug exposure. Here, we combined the rat model of cocaine self-administration with brain slice electrophysiology to identify drug-use related alterations in the neuromodulatory effects of DA in the oval bed nucleus of the stria terminalis (ovBST), a robust DA terminal field. Long-Evans rats self-administered cocaine intravenously (0.75 mg/kg/injection) for an average of 15 d, on reward-lean or -rich schedules of reinforcement. Brain slice recordings conducted 20 h after the last self-administration session revealed a reversal of the neuromodulatory effect of DA on GABA(A)-IPSCs. Specifically, the effect of DA switched from a D2-mediated decrease in drug-naive rats to a D1-receptor-mediated increase in GABA(A)-IPSC in cocaine self administering rats. Furthermore, the switch in DA modulation of GABA(A)-IPSC remained after a 30 d withdrawal period. In contrast, this switch was not observed after the acquisition phase of cocaine self-administration, when rats received cocaine passively, or in rats maintaining sucrose self-administration. Therefore, our study reveals a reversal in the effects of DA on inhibitory transmission, from reduction to enhancement, in the ovBST of cocaine self administering rats. This change was unique to voluntary intake of cocaine and maintained after a withdrawal period, suggesting a mechanism underlying the maintenance of cocaine self-administration and perhaps craving during drug-free periods. PMID- 21677177 TI - Dynamic interaction of Ih and IK-LVA during trains of synaptic potentials in principal neurons of the medial superior olive. AB - In neurons of the medial superior olive (MSO), voltage-gated ion channels control the submillisecond time resolution of binaural coincidence detection, but little is known about their interplay during trains of synaptic activity that would be experienced during auditory stimuli. Here, using modeling and patch-clamp recordings from MSO principal neurons in gerbil brainstem slices, we examined interactions between two major currents controlling subthreshold synaptic integration: a low-voltage-activated potassium current (I(K-LVA)) and a hyperpolarization-activated cation current (I(h)). Both I(h) and I(K-LVA) contributed strongly to the resting membrane conductance and, during trains of simulated EPSPs, exhibited cumulative deactivation and inactivation, respectively. In current-clamp recordings, regular and irregular trains of simulated EPSCs increased input resistance up to 60%, effects that accumulated and decayed (after train) over hundreds of milliseconds. Surprisingly, the mean voltage and peaks of EPSPs increased by only a few millivolts during trains. Using a model of an MSO cell, we demonstrated that the nearly uniform response during modest depolarizing stimuli relied on changes in I(h) and I(K-LVA), such that their sum remained nearly constant over time. Experiments and modeling showed that, for simplified binaural stimuli (EPSC pairs in a noisy background), spike probability gradually increased in parallel with the increasing input resistance. Nevertheless, the interplay between I(h) and I(K-LVA) helps to maintain a nearly uniform shape of individual synaptic responses, and we show that the time resolution of synaptic coincidence detection can be maintained during trains if EPSC size gradually decreases (as in synaptic depression), counteracting slow increases in excitability. PMID- 21677179 TI - Role of cerebellar cortical protein synthesis in transfer of memory trace of cerebellum-dependent motor learning. AB - We developed a new protocol that induces long-term adaptation of horizontal optokinetic response (HOKR) eye movement by hours of spaced training and examined the role of protein synthesis in the cerebellar cortex in the formation of memory of adaptation. Mice were trained to view 800 cycles of screen oscillation either by 1 h of massed training or by 2.5 h to 8 d of training with 0.5 h to 1 d space intervals. The HOKR gains increased similarly by 20-30% at the end of training; however, the gains increased by 1 h of massed training recovered within 24 h, whereas the gains increased by spaced training were sustained over 24 h. Bilateral floccular lidocaine microinfusions immediately after the end of training recovered the gains increased by 1 h of massed training but did not affect the gains increased by 4 h of spaced training, suggesting that the memory trace of adaptation was transferred from the flocculus to the vestibular nuclei within 4 h of spaced training. Blockade of floccular protein synthesis, examined by bilateral floccular microinfusions of anisomycin or actinomycin D 1-4 h before the training, impaired the gains increased by 4 h of spaced training but did not affect the gains increased by 1 h of massed training. These findings suggest that the transfer of the memory trace of adaptation occurs within 4 h of spaced training, and proteins synthesized in the flocculus during training period may play an important role in memory transfer. PMID- 21677178 TI - Regulation of extrasynaptic 5-HT by serotonin reuptake transporter function in 5 HT-absorbing neurons underscores adaptation behavior in Caenorhabditis elegans. AB - Serotonin [5-hydroxytryptamine (5-HT)]-absorbing neurons use serotonin reuptake transporter (SERT) to uptake 5-HT from extracellular space but do not synthesize it. While 5-HT-absorbing neurons have been identified in diverse organisms from Caenorhabditis elegans to humans, their function has not been elucidated. Here, we show that SERT in 5-HT-absorbing neurons controls behavioral response to food deprivation in C. elegans. The AIM and RIH interneurons uptake 5-HT released from chemosensory neurons and secretory neurons. Genetic analyses suggest that 5-HT secreted by both synaptic vesicles and dense core vesicles diffuse readily to the extrasynaptic space adjacent to the AIM and RIH neurons. Loss of mod-5/SERT function blocks the 5-HT absorption. mod-5/SERT mutants have been shown to exhibit exaggerated locomotor response to food deprivation. We found that transgenic expression of MOD-5/SERT in the 5-HT-absorbing neurons fully corrected the exaggerated behavior. Experiments of cell-specific inhibition of synaptic transmission suggest that the synaptic release of 5-HT from the 5-HT-absorbing neurons is not required for this behavioral modulation. Our data point to the role of 5-HT-absorbing neurons as temporal-spatial regulators of extrasynaptic 5 HT. Regulation of extrasynaptic 5-HT levels by 5-HT-absorbing neurons may represent a fundamental mechanism of 5-HT homeostasis, integrating the activity of 5-HT-producing neurons with distant targets in the neural circuits, and could be relevant to some actions of selective serotonin reuptake inhibitors in humans. PMID- 21677180 TI - Asymmetry of parietal interhemispheric connections in humans. AB - Visuospatial abilities are preferentially mediated by the right hemisphere. Although this asymmetry of function is thought to be due to an unbalanced interaction between cerebral hemispheres, the underlying neurophysiological substrate is still largely unknown. Here, using a method of trifocal transcranial magnetic stimulation, we show that the right, but not left, human posterior parietal cortex exerts a strong inhibitory activity over the contralateral homologous area by a short-latency connection. We also clarify, using diffusion tensor magnetic resonance imaging, that such an interaction is mediated by direct transcallosal projections located in the posterior corpus callosum. We argue that this anatomo-functional network may represent a possible neurophysiological basis for the ongoing functional asymmetry between parietal cortices, and that its damage could contribute to the clinical manifestations of neglect. PMID- 21677181 TI - Parallel processing of nociceptive and non-nociceptive somatosensory information in the human primary and secondary somatosensory cortices: evidence from dynamic causal modeling of functional magnetic resonance imaging data. AB - Several studies have suggested that, in higher primates, nociceptive somatosensory information is processed in parallel in the primary (S1) and secondary (S2) somatosensory cortices, whereas non-nociceptive somatosensory input is processed serially from S1 to S2. However, evidence suggesting that both nociceptive and non-nociceptive somatosensory inputs are processed in parallel in S1 and S2 also exists. Here, we aimed to clarify whether or not the hierarchical organization of nociceptive and non-nociceptive somatosensory processing in S1 and S2 differs in humans. To address this question, we applied dynamic causal modeling and Bayesian model selection to functional magnetic resonance imaging (fMRI) data collected during the selective stimulation of nociceptive and non nociceptive somatosensory afferents in humans. This novel approach allowed us to explore how nociceptive and non-nociceptive somatosensory information flows within the somatosensory system. We found that the neural activities elicited by both nociceptive and non-nociceptive somatosensory stimuli are best explained by models in which the fMRI responses in both S1 and S2 depend on direct thalamocortical projections. These observations indicate that, in humans, both nociceptive and non-nociceptive information are processed in parallel in S1 and S2. PMID- 21677182 TI - Behavioral and in vivo electrophysiological evidence for presymptomatic alteration of prefrontostriatal processing in the transgenic rat model for huntington disease. AB - Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD. PMID- 21677185 TI - FMRI adaptation reveals a cortical mechanism for the coding of space near the hand. AB - Behavioral studies in humans and electrophysiological recordings in nonhuman primates have suggested the existence of a specific representation of the space immediately surrounding the body. In macaques, neurons that have visual receptive fields limited to a region of space close around a body part have been found in premotor and parietal areas. These cells are hypothesized to encode the location of external objects in coordinate systems that are centered on individual body parts. In the present study, we used an fMRI adaptation paradigm on healthy participants to reveal areas in the anterior part of the intraparietal sulcus, the inferior parietal lobe (supramarginal gyrus), and the dorsal and ventral portions of the premotor cortex that exhibit selective BOLD adaptation to an object moving near the right hand. Crucially, these areas did not manifest adaptation if the stimulus was presented in far space (100 cm) or when the hand was retracted from the object. This hand-centered selectivity could not be detected when a traditional fMRI analysis approach was used. These findings are important as they provide the most conclusive neuroimaging evidence to date for a representation of near-personal space in the human brain. They also demonstrate a selective mechanism implemented by human perihand neurons in the premotor and posterior parietal areas and add to earlier findings from humans and nonhuman primates. PMID- 21677184 TI - Pacemaker neurons within newborn spinal pain circuits. AB - Spontaneous activity driven by "pacemaker" neurons, defined by their intrinsic ability to generate rhythmic burst firing, contributes to the development of sensory circuits in many regions of the immature CNS. However, it is unknown whether pacemaker-like neurons are present within central pain pathways in the neonate. Here, we provide evidence that a subpopulation of glutamatergic interneurons within lamina I of the rat spinal cord exhibits oscillatory burst firing during early life, which occurs independently of fast synaptic transmission. Pacemaker neurons were distinguished by a higher ratio of persistent, voltage-gated Na(+) conductance to leak membrane conductance (g(Na,P)/g(leak)) compared with adjacent, nonbursting lamina I neurons. The activation of high-threshold (N-type and L-type) voltage-gated Ca(2+) channels also facilitated rhythmic burst firing by triggering intracellular Ca(2+) signaling. Bursting neurons received direct projections from high-threshold sensory afferents but transmitted nociceptive signals with poor fidelity while in the bursting mode. The observation that pacemaker neurons send axon collaterals throughout the neonatal spinal cord raises the possibility that intrinsic burst firing could provide an endogenous drive to the developing sensorimotor networks that mediate spinal pain reflexes. PMID- 21677183 TI - Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. AB - The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5 HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (TPH1) in EC cells and on TPH2 in neurons; therefore, mice lacking TPH1 and/or TPH2 distinguish EC-derived from neuronal 5-HT. Deletion of TPH2, but not TPH1, decreased myenteric neuronal density and proportions of dopaminergic and GABAergic neurons but did not affect the extrinsic sympathetic innervation of the gut; intestinal transit slowed in mice lacking TPH2 mice, but gastric emptying accelerated. Isolated enteric crest-derived cells (ENCDCs) expressed the serotonin reuptake transporter (SERT) and 15 subtypes of 5-HT receptor. Addition of 5-HT to cultures of isolated ENCDCs promoted total and dopaminergic neuronal development. Rings of SERT-immunoreactive terminal axons surrounded myenteric dopaminergic neurons and SERT knock-out increased intestinal levels of dopamine metabolites, implying that enteric dopaminergic neurons receive a serotonergic innervation. Observations suggest that constitutive gastrointestinal motility depends more on neuronal than EC cell serotonin; moreover, serotonergic neurons promote development/survival of some classes of late-born enteric neurons, including dopaminergic neurons, which appear to innervate and activate in the adult ENS. PMID- 21677186 TI - Constructing realistic engrams: poststimulus activity of hippocampus and dorsal striatum predicts subsequent episodic memory. AB - Encoding of real-life episodic memory commonly involves integration of information as the episode unfolds. Offline processing immediately following event offset is expected to play a role in encoding the episode into memory. In this study, we examined whether distinct human brain activity time-locked to the offset of short narrative audiovisual episodes could predict subsequent memory for the gist of the episodes. We found that a set of brain regions, most prominently the bilateral hippocampus and the bilateral caudate nucleus, exhibit memory-predictive activity time-locked to the stimulus offset. We propose that offline activity in these regions reflects registration to memory of integrated episodes. PMID- 21677188 TI - Munc18-1 tuning of vesicle merger and fusion pore properties. AB - The release of hormones and neurotransmitters, mediated by regulated exocytosis, can be modified by regulation of the fusion pore. The fusion pore is considered stable and narrow initially, eventually leading to the complete merger of the vesicle and the plasma membranes. By using the high-resolution patch-clamp capacitance technique, we studied single vesicles and asked whether the Sec1/Munc18 proteins, interacting with the membrane fusion-mediating SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, affect fusion pore properties. Munc18-1 mutants were transfected into lactotrophs to affect the interaction of Munc18-1 with syntaxin1 (Synt1) (R39C), Rab3A (E466K), and Mints (P242S). Compared with wild-type, Munc18-1 E466K increased the frequency of the fusion event. The latter two mutants increased the fusion pore dwell-time. All the mutants stabilized narrow fusion pores and increased the amplitude of fusion events, likely via preferential fusion of larger vesicles, since overexpression of Munc18-1 R39C did not affect the average size of vesicles, as determined by stimulated emission depletion (STED) microscopy. Single-molecule atomic force microscopy experiments revealed that wild-type Munc18-1, but not Munc18-1 R39C, abrogates the interaction between synaptobrevin2 (Syb2) and Synt1 binary trans-complexes. However, neither form of Munc18-1 affected the interaction of Syb2 with the preformed binary cis-Synt1A-SNAP25B complexes. This indicates that Munc18-1 performs a proofing function by inhibiting tethering of Syb2-containing vesicles solely to Synt1 at the plasmalemma and favoring vesicular tethering to the preformed binary cis-complex of Synt1A-SNAP25B. The association of Munc18-1 with the ternary SNARE complex leads to tuning of fusion pores via multiple and converging mechanisms involving Munc18-1 interactions with Synt1A, Rab3A, and Mints. PMID- 21677187 TI - PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. AB - Nuclear distribution factor E-homolog 1 (NDE1), Lissencephaly 1 (LIS1), and NDE like 1 (NDEL1) together participate in essential neurodevelopmental processes, including neuronal precursor proliferation and differentiation, neuronal migration, and neurite outgrowth. NDE1/LIS1/NDEL1 interacts with Disrupted in Schizophrenia 1 (DISC1) and the cAMP-hydrolyzing enzyme phosphodiesterase 4 (PDE4). DISC1, PDE4, NDE1, and NDEL1 have each been implicated as genetic risk factors for major mental illness. Here, we demonstrate that DISC1 and PDE4 modulate NDE1 phosphorylation by cAMP-dependent protein kinase A (PKA) and identify a novel PKA substrate site on NDE1 at threonine-131 (T131). Homology modeling predicts that phosphorylation at T131 modulates NDE1-LIS1 and NDE1-NDEL1 interactions, which we confirm experimentally. DISC1-PDE4 interaction thus modulates organization of the NDE1/NDEL1/LIS1 complex. T131-phosphorylated NDE1 is present at the postsynaptic density, in proximal axons, within the nucleus, and at the centrosome where it becomes substantially enriched during mitosis. Mutation of the NDE1 T131 site to mimic PKA phosphorylation inhibits neurite outgrowth. Thus PKA-dependent phosphorylation of the NDE1/LIS1/NDEL1 complex is DISC1-PDE4 modulated and likely to regulate its neural functions. PMID- 21677189 TI - Accumbens shell AMPA receptors mediate expression of extinguished reward seeking through interactions with basolateral amygdala. AB - Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B). Rats were subsequently tested in the training context, A (ABA), or the extinction context, B (ABB). Pre-test injections of the glutamate AMPA receptor antagonist, NBQX (1 ug) into AcbSh had no effect on renewal of alcoholic beer seeking when rats were returned to the training context (ABA). However, NBQX increased responding when rats were tested in the extinction context (ABB). In a second experiment, rats received training, extinction, and test in the same context. Pre-test injections of NBQX (0, 0.3, and 1 ug) into the AcbSh dose-dependently attenuated expression of extinction. We also found that NBQX in the AcbSh had no effect on initial acquisition of extinction or the motivation to respond for reward as measured by break point on a progressive ratio schedule. Finally, we show that pharmacological disconnection of a basolateral amygdala (BLA) -> AcbSh pathway via NBQX in AcbSh combined with reversible inactivation of the contralateral BLA attenuates expression of extinction. Together, these results suggest that AcbSh AMPA receptors mediate expression of extinguished reward seeking through glutamatergic inputs from the BLA. PMID- 21677190 TI - Spatial and reversal learning in the Morris water maze are largely resistant to six hours of REM sleep deprivation following training. AB - This first test of the role of REM (rapid eye movement) sleep in reversal spatial learning is also the first attempt to replicate a much cited pair of papers reporting that REM sleep deprivation impairs the consolidation of initial spatial learning in the Morris water maze. We hypothesized that REM sleep deprivation following training would impair both hippocampus-dependent spatial learning and learning a new target location within a familiar environment: reversal learning. A 6-d protocol was divided into the initial spatial learning phase (3.5 d) immediately followed by the reversal phase (2.5 d). During the 6 h following four or 12 training trials/day of initial or reversal learning phases, REM sleep was eliminated and non-REM sleep left intact using the multiple inverted flowerpot method. Contrary to our hypotheses, REM sleep deprivation during four or 12 trials/day of initial spatial or reversal learning did not affect training performance. However, some probe trial measures indicated REM sleep-deprivation associated impairment in initial spatial learning with four trials/day and enhancement of subsequent reversal learning. In naive animals, REM sleep deprivation during normal initial spatial learning was followed by a lack of preference for the subsequent reversal platform location during the probe. Our findings contradict reports that REM sleep is essential for spatial learning in the Morris water maze and newly reveal that short periods of REM sleep deprivation do not impair concurrent reversal learning. Effects on subsequent reversal learning are consistent with the idea that REM sleep serves the consolidation of incompletely learned items. PMID- 21677192 TI - A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin. AB - Tunicamycin (TM) inhibits eukaryotic asparagine-linked glycosylation, protein palmitoylation, ganglioside production, proteoglycan synthesis, 3-hydroxy-3 methylglutaryl coenzyme-A reductase activity, and cell wall biosynthesis in bacteria. Treatment of cells with TM elicits endoplasmic reticulum stress and activates the unfolded protein response. Although widely used in laboratory settings for many years, it is unknown how TM enters cells. Here, we identify in an unbiased genetic screen a transporter of the major facilitator superfamily, major facilitator domain containing 2A (MFSD2A), as a critical mediator of TM toxicity. Cells without MFSD2A are TM-resistant, whereas MFSD2A-overexpressing cells are hypersensitive. Hypersensitivity is associated with increased cellular TM uptake concomitant with an enhanced endoplasmic reticulum stress response. Furthermore, MFSD2A mutant analysis reveals an important function of the C terminus for correct intracellular localization and protein stability, and it identifies transmembrane helical amino acid residues essential for mediating TM sensitivity. Overall, our data uncover a critical role for MFSD2A by acting as a putative TM transporter at the plasma membrane. PMID- 21677194 TI - Did early Homo migrate "out of" or "in to" Africa? PMID- 21677195 TI - Northern Africa could also have housed the source population for living humans. PMID- 21677196 TI - Deep sequencing of patient genomes for disease diagnosis: when will it become routine? AB - Next-generation sequencing technologies have greatly lowered the cost of whole genome sequencing (WGS) and related approaches. Thus, comprehensive sequencing for diagnostic purposes may clear this financial hurdle in the near future. The report by Bainbridge and colleagues in this issue of Science Translational Medicine illustrates the diagnostic power of WGS. In this Perspective, we discuss whether and how genome sequencing might become routine for clinical diagnosis. PMID- 21677197 TI - Breaking free of sample size dogma to perform innovative translational research. AB - Innovative clinical and translational research is often delayed or prevented by reviewers' expectations that any study performed in humans must be shown in advance to have high statistical power. This supposed requirement is not justifiable and is contradicted by the reality that increasing sample size produces diminishing marginal returns. Studies of new ideas often must start small (sometimes even with an n of 1) because of cost and feasibility concerns, and recent statistical work shows that small sample sizes for such research can produce more projected scientific value per dollar spent than larger sample sizes. Renouncing false dogma about sample size would remove a serious barrier to innovation and translation. PMID- 21677198 TI - Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation. AB - The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (T(regs)); thymectomy or T(reg) depletion abrogated tolerance restoration. The aging of the immune system ("immune senescence") is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics. PMID- 21677199 TI - The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive, dysregulated response to alveolar injury that culminates in compromised lung function from excess extracellular matrix production. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. We examined fibrotic lungs from mice and from patients with IPF and detected increased expression of dimethylarginine dimethylaminohydrolases (DDAHs)--key enzymes that metabolize asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase, to form l-citrulline and dimethylamine. DDAHs are up regulated in primary alveolar epithelial type II cells from these mice and patients where they are colocalized with inducible nitric oxide synthase. In cultured alveolar epithelial type II cells from bleomycin-induced fibrotic mouse lungs, inhibition of DDAH suppressed proliferation and induced apoptosis in an ADMA-dependent manner. In addition, DDAH inhibition reduced collagen production by fibroblasts in an ADMA-independent but transforming growth factor/SMAD dependent manner. In mice with bleomycin-induced pulmonary fibrosis, the DDAH inhibitor L-291 reduced collagen deposition and normalized lung function. In bleomycin-induced fibrosis, inducible nitric oxide synthase inhibition decreased fibrosis, but an even stronger reduction was observed after inhibition of DDAH. Thus, DDAH inhibition reduces fibroblast-induced collagen deposition in an ADMA independent manner and reduces abnormal epithelial proliferation in an ADMA dependent manner, offering a possible therapeutic avenue for attenuation of pulmonary fibrosis. PMID- 21677200 TI - Whole-genome sequencing for optimized patient management. AB - Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins. PMID- 21677201 TI - The cerebral palsy research registry: development and progress toward national collaboration in the United States. AB - Cerebral palsy is the most common neurodevelopmental motor disability in children. The condition requires medical, educational, social, and rehabilitative resources throughout the life span. Several countries have developed population based registries that serve the purpose of prospective longitudinal collection of etiologic, demographic, and functional severity. The United States has not created a comprehensive program to develop such a registry. Barriers have been large population size, poor interinstitution collaboration, and decentralized medical and social systems. The Cerebral Palsy Research Registry was created to fill the gap between population and clinical-based cerebral palsy registries and promote research in the field. This is accomplished by connecting persons with cerebral palsy, as well as their families, to a network of regional researchers. This article describes the development of an expandable cerebral palsy research registry, its current status, and the potential it has to affect families and persons with cerebral palsy in the United States and abroad. PMID- 21677202 TI - Streptococcus pneumoniae meningoencephalitis with bilateral basal ganglia necrosis: an unusual complication due to vasculitis. AB - Streptococcus pneumoniae (S pneumoniae) is a common cause of bacterial meningitis, frequently leading to death or severe neurological impairment. We report an exceptional case of a 4-month-old boy with meningitis caused by S pneumoniae. Computed tomography (CT) and magnetic resonance imaging (MRI) examinations of the brain showed bilateral symmetrical necrosis involving the lentiform and caudate nuclei, as well as the thalamus. T1-weighted MR images showed patchy areas of increased signal intensity, consistent with hemorrhagic transformation of the lesions. Autopsy revealed widespread necrosis of the basal ganglia with clear signs of vasculitis. Severe complications of S pneumoniae meningoencephalitis are known in infants but to our knowledge, such lesions in the basal ganglia have only been reported thrice in adults and never in children. PMID- 21677204 TI - EMDR treatment for posttraumatic stress disorder, with focus on hippocampal volumes: a pilot study. PMID- 21677205 TI - Is the functional state of schizophrenic patients located in the vicinity of a bifurcation point? PMID- 21677206 TI - Use of transcranial magnetic stimulation in bipolar disorder. PMID- 21677207 TI - Personality changes in brain injury. PMID- 21677208 TI - Subacute sclerosing panencephalitis presenting as mania. PMID- 21677209 TI - Repetitive transcranial magnetic stimulation or venlafaxine-induced mania? PMID- 21677210 TI - Atypical migraine manifesting as mania. PMID- 21677211 TI - Blepharospasm as an obsessive-compulsive phenomenon. PMID- 21677212 TI - Prosodic impairment in Alzheimer's disease: assessment and clinical relevance. PMID- 21677213 TI - The effect of riluzole augmentation in a patient with treatment-resistant obsessive-compulsive disorder, taking two other glutaminergic agents. PMID- 21677214 TI - Passivity phenomena in nocturnal frontal-lobe epilepsy. PMID- 21677215 TI - A case of marchiafava bignami disease: complete recovery with thiamine. PMID- 21677216 TI - Decision-making impairment may precede limb apraxia in corticobasal degeneration. PMID- 21677217 TI - Internet pornography and frontotemporal dementia. PMID- 21677218 TI - Further evidence of the usefulness of MRI-based neuronavigation for the treatment of depression by rTMS. PMID- 21677219 TI - Voltage-gated, potassium-channel antibody-associated limbic encephalitis presenting as acute psychosis. PMID- 21677220 TI - Feature-selection based cognitive control. PMID- 21677221 TI - Myasthenic crisis may mimic antipsychotic-induced extrapyramidal syndromes. PMID- 21677222 TI - Escitalopram and ischemic stroke: causal or chance association? PMID- 21677223 TI - DBS, Parkinson's disease, and suicide. PMID- 21677224 TI - Duloxetine-related growth of putamen and brainstem in first-onset drug-naive major depressive disorder with panic disorder: a case series. PMID- 21677225 TI - Duloxetine-induced subcortical growth in a patient with major depressive disorder and panic disorder. PMID- 21677226 TI - Aripiprazole-related body-weight gain and nutritional counseling. PMID- 21677227 TI - Paliperidone-induced obsessive symptoms. PMID- 21677228 TI - Bupropion and panic disorder: case report and review of the literature. PMID- 21677229 TI - Intranasal oxytocin as an adjunct to escitalopram in major depression. PMID- 21677230 TI - Bupropion-induced mania and hypomania: a report of two cases. PMID- 21677231 TI - Gustatory and olfactory hallucinations under therapeutic dosing of bupropion. PMID- 21677232 TI - Delirium associated with olanzapine therapy in an elderly man with bipolar affective disorder. PMID- 21677233 TI - Venlafaxine and excessive yawning: is there any link? PMID- 21677234 TI - Psychiatric onset of multiple sclerosis: description of two cases. PMID- 21677235 TI - Acute and subacute neuropsychiatric presentations in H1N1 viral encephalitis. PMID- 21677236 TI - Thyroid function and oppositional defiant disorder: more than a coincidence in prepubertal boys with attention-deficit hyperactivity disorder? PMID- 21677237 TI - Anterior cingulate cortex: unique role in cognition and emotion. PMID- 21677238 TI - FDA Perspective on the DSM-5 approach to classification of "cognitive" disorders. AB - Primary "cognitive" disorders (e.g., Alzheimer's disease) often have behavioral features, just as primary behavioral disorders (e.g., schizophrenia) often have cognitive features. Drug research in recent years has expanded into targeting the full range of symptoms of both types of disorders. DSM-5 should include these associated features of each type of disorder, because acknowledging the full range of symptoms for each type of disorder has important research and treatment implications. PMID- 21677241 TI - Transcutaneous electrical stimulation (TENS) for psychogenic movement disorders. AB - Psychogenic movement disorders (PMDs) often result in disability and diminished quality of life, yet medical therapies are presently limited and largely ineffective. On the basis of previous reports that transcutaneous electrical nerve stimulation (TENS) is helpful for certain patients with organic movement disorders, the authors studied the effects of TENS in 19 patients with PMDs, utilizing the Psychogenic Movement Disorder Rating Scale (PMDRS) as well as patient-rated assessments of PMD magnitude, persistence, and disability. The PMDRS Severity score significantly improved after a mean follow-up of 6.9 months, and short duration of PMD was found to be the only identifiable predictor of a favorable outcome. Although the tingling sensation produced by TENS makes it poorly suited for a controlled clinical trial, the device has a favorable side effect profile and is an acceptable palliative treatment for a subset of PMD patients. PMID- 21677240 TI - The spectrum of sociopathy in dementia. AB - Although well-known from head trauma and acute strokes, sociopathic behavior from dementia is less known and understood. This study reviewed 33 dementia patients who had been in trouble with the law. They were divided into two groups: 22 who committed impulsive sociopathic acts and 11 who committed non-impulsive acts. The impulsive patients demonstrated nonviolent acts, such as disinhibited sexual behavior or pathological stealing, and had disproportionate frontal-caudate atrophy on neuroimaging. The majority of non-impulsive patients demonstrated agitation-paranoia, sometimes with reactive aggression, delusional beliefs, or aphasic paranoia, and had advanced memory and other cognitive impairment. The impulsive patients tended to have frontally predominant illnesses such as frontotemporal dementia or Huntington's disease, whereas the non-impulsive group tended to have Alzheimer's disease or prominent aphasia. Sociopathy has different causes in dementia. Two common mechanisms are disinhibition, with frontally predominant disease, and agitation-paranoia, with greater cognitive impairment. These forms of sociopathy differ significantly from the antisocial/psychopathic personality. PMID- 21677242 TI - Engaging in cognitive activities, aging, and mild cognitive impairment: a population-based study. AB - The authors investigated whether engaging in cognitive activities is associated with aging and mild cognitive impairment (MCI) in a cross-sectional study derived from an ongoing population-based study of normal cognitive aging and MCI in Olmsted County, MN. A random sample of 1,321 study participants ages 70 to 89 (N=1,124 cognitively normal persons, and N=197 subjects with MCI) were interviewed about the frequency of cognitive activities carried out in late life (within 1 year of the date of interview). Computer activities; craft activities, such as knitting, quilting, etc.; playing games; and reading books were associated with decreased odds of having MCI. Social activities, such as traveling, were marginally significant. Even though the point-estimates for reading magazines, playing music, artistic activities, and group activities were associated with reduced odds of having MCI, none of these reached statistical significance. The equally high prevalence of reading newspapers in both groups yielded no significant between-group difference. PMID- 21677243 TI - Relationship between corpus callosum abnormalities and schneiderian first-rank symptoms in antipsychotic-naive schizophrenia patients. AB - The corpus callosum (CC), has been hypothesized to be implicated in the pathogenesis of schizophrenia; however, the findings from magnetic resonance imaging studies are conflicting. Moreover, the relationship between first-rank symptoms (FRS) and CC abnormalities in schizophrenia is yet to be examined. The authors examined CC morphometry, based on Witelson's method, in antipsychotic naive-schizophrenia patients in comparison with matched healthy-control subjects. Patients had significantly smaller CC, splenium, and isthmus areas than control subjects. A novel finding of the study is that only those without FRS differed from control subjects, but not those with FRS. Study findings support a neuro developmental hypothesis and possible connectivity abnormalities in symptom genesis. PMID- 21677244 TI - Neuroendocrinal study of depression in male epileptic patients. AB - Endocrine changes are reported in both epilepsy and depression. The interrelationships between mood, epilepsy, and endocrine changes are not well characterized. The authors included 40 epileptic patients (20 depressed, 20 nondepressed) and 20 healthy subjects. All patients had an electroencephalogram, and were given the Hamilton Rating Scale for Depression. All subjects were tested for serum levels of cortisol, prolactin, testosterone, and thyroid hormones. Patients were medication-free. Patients had elevated prolactin and cortisol and reduced serum testosterone relative to control subjects. Depressed patients had higher cortisol levels than nondepressed. Data suggest that the effects of epilepsy and depression on cortisol, but not other hormones, may be additive. PMID- 21677245 TI - Neuropsychiatric aspects of primary progressive aphasia. AB - Few studies have reported neuropsychiatric symptoms (NPS) in primary progressive aphasia (PPA), a neurodegenerative disorder that primarily affects the left hemisphere. Depression is associated with left-sided stroke, but it remains unclear whether depression and other NPS are also associated with PPA. The authors compared the frequency of neuropsychiatric symptoms in 55 cases of PPA with 110 cognitively normal persons matched for age, sex, and education. Depression, apathy, agitation, anxiety, appetite change, and irritability are associated with PPA. Hallucinations, delusions, and night-time behavior were not associated with PPA. PMID- 21677246 TI - Differential effects of executive functioning on suicide attempts. AB - Suicide is common among individuals with psychiatric illness; executive functioning may be associated with suicide risk. The authors examined demographic, clinical, and executive-functioning variables in suicide ideators and suicide attempters, hypothesizing that attempters would demonstrate poorer executive-functioning skills. Seventy-seven participants with psychiatric illness completed a neuropsychological battery while hospitalized or residing in crisis houses after expressing suicidal ideation (N=40) or making a suicide attempt (N=37). Logistic regression predicted suicide Ideator versus suicide Attempter status; suicide Attempters exhibited poorer inhibition but better problem-solving ability than suicide Ideators. Suicide attempt risk may be associated with better problem-solving skills, but worse inhibitory control. PMID- 21677247 TI - Phenomenological and neuropsychological profile across motor variants of delirium in a palliative-care unit. AB - Studies using composite measurement of cognition suggest that cognitive performance is similar across motor variants of delirium. The authors assessed neuropsychological and symptom profiles in 100 consecutive cases of DSM-IV delirium allocated to motor subtypes in a palliative-care unit: Hypoactive (N=33), Hyperactive (N=18), Mixed (N=26), and No-Alteration motor groups (N=23). The Mixed group had more severe delirium, with highest scores for DRS-R-98 sleep wake cycle disturbance, hallucinations, delusions, and language abnormalities. Neither the total Cognitive Test for Delirium nor its five neuropsychological domains differed across Hyperactive, Mixed, and Hypoactive motor groups. Most patients (70%) with no motor alteration had DRS-R-98 scores in the mild or subsyndromal range even though they met DSM-IV criteria. Motor variants in delirium have similar cognitive profiles, but mixed cases differ in expression of several noncognitive features. PMID- 21677248 TI - Recognition of self-generated facial emotions is impaired in schizophrenia. AB - Individuals with schizophrenia have difficulties in recognizing facial emotions in others. This study investigated whether this impairment also exists for self generated expressions. Nineteen patients with schizophrenia and 19 comparison subjects were filmed while producing facial expressions in response to a visual model or a written sentence. After 2 months, all subjects were asked to rate their own emotional expressions. These ratings were compared with the evaluations of 12 healthy independent raters. With respect to the comparison subjects, the patients produced less expressive responses and were less able to recognize their own expressions. Moreover, patients were totally unaware of these impairments. PMID- 21677249 TI - Temporary interruption of deep brain stimulation for Parkinson's disease during outpatient electroconvulsive therapy for major depression: a novel treatment strategy. AB - The safety of electroconvulsive therapy (ECT) in patients with deep brain stimulation (DBS) has not been established. Cases reported had no adverse events, but DBS was withheld throughout the weeks of the ECT course. The authors report the first case of temporary interruption of DBS only during the minutes of each outpatient ECT. PMID- 21677250 TI - Relationships between multiple sclerosis and depression. AB - The authors' findings suggest that major depressive disorder (MDD) may occur as a prodrome to and may delay diagnosis of multiple sclerosis (MS). Lifetime prevalence of MDD was 59%; 14% of subjects reported MDD as a prodrome to MS, and 10% reported a resulting delay in MS diagnosis. PMID- 21677251 TI - Sleep disturbance after mild traumatic brain injury: indicator of injury? AB - Mild traumatic brain injury (mTBI) is a complex entity with no known objective diagnostic markers. To test the hypothesis that sleep disturbances in the acute mTBI period can serve as an indicator of brain injury, the authors compared sleep polysomnograms (PSG) and sleep EEG power spectra (PS) data in seven mTBI subjects with seven age- and race-matched healthy-control subjects. The two groups differed significantly on PS measures, suggesting that mTBI can result in a disruption of sleep microarchitecture and, in theory, could be of use as a marker for brain injury. These pilot findings need to be replicated on larger samples. PMID- 21677252 TI - Huntington's disease: effect of memantine on FDG-PET brain metabolism? AB - In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient choosing to continue treatment over the 18-month follow-up period). The treatment regimen was well tolerated. No significant differences on neuropsychological parameters before and after treatment were detected; but the patient who continued treatment did not deteriorate at 18 months' reevaluation, whereas the three patients who had stopped treatment after 3 to 4 months had minor progression in all cognitive domains on re-evaluation 12 months after the end of treatment. PMID- 21677253 TI - Inferential-reasoning impairment in schizophrenia-spectrum disorders. AB - The performance of 15 participants with schizophrenia-spectrum disorders (SCZ) on an inferential-reasoning task was compared with that of 15 healthy-control participants (HC). The SCZ group showed poorer inferential reasoning than HCs, independent of their negative or positive symptoms. These findings are consistent with previous research showing deficits of reasoning in schizophrenia, and indicate that this deficit is independent of severity of delusions. PMID- 21677254 TI - Elevated plasma ceramides in depression. AB - The authors did a preliminary examination asking whether plasma ceramides were elevated in depression, and whether the elevation was more pronounced in Alzheimer's disease patients than in control subjects. Results suggest that plasma ceramides are elevated in persons with a diagnosis of major depression, regardless of dementia status. PMID- 21677255 TI - The influence of thyroid function on cognition in a sample of ethnically diverse, rural-dwelling women: a project FRONTIER study. AB - This study examined the influence of thyroid markers (TSH and FT4) on cognition in a sample of rural-dwelling women. Data were analyzed from 81 women who were enrolled in an ongoing study of rural health, Project FRONTIER. Cognition was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). TSH levels were significantly related to the RBANS Attention Index, and FT4 levels were significantly related to the RBANS Language Index. The current study found that TSH and FT4 were differentially related to neurocognitive domains, with TSH being related only to measures of attention and FT4 to measures of language. PMID- 21677256 TI - Catatonia in psychotic patients: clinical features and treatment response. AB - The authors report clinical features and treatment response in 25 patients with catatonia admitted to an inpatient psychiatric unit specializing in psychotic disorders. Electroconvulsive therapy, benzodiazepines, and clozapine had beneficial effects on catatonic features, whereas typical antipsychotics resulted in clinical worsening. PMID- 21677258 TI - Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: a meta-analysis of eleven randomized clinical trials. AB - An independent reanalysis of 11 randomized clinical trials shows that oseltamivir treatment reduces the risk of lower respiratory tract complications requiring antibiotic treatment by 28% overall (95% confidence interval [CI], 11%-42%) and by 37% among patients with confirmed influenza infections (95% CI, 18%-52%). PMID- 21677260 TI - Gap junctions favor normal rat kidney epithelial cell adaptation to chronic hypertonicity. AB - Upon hypertonic stress most often resulting from high salinity, cells need to balance their osmotic pressure by accumulating neutral osmolytes called compatible osmolytes like betaine, myo-inositol, and taurine. However, the massive uptake of compatible osmolytes is a slow process compared with other defense mechanisms related to oxidative or heat stress. This is especially critical for cycling cells as they have to double their volume while keeping a hospitable intracellular environment for the molecular machineries. Here we propose that clustered cells can accelerate the supply of compatible osmolytes to cycling cells via the transit, mediated by gap junctions, of compatible osmolytes from arrested to cycling cells. Both experimental results in epithelial normal rat kidney cells and theoretical estimations show that gap junctions indeed play a key role in cell adaptation to chronic hypertonicity. These results can provide basis for a better understanding of the functions of gap junctions in osmoregulation not only for the kidney but also for many other epithelia. In addition to this, we suggest that cancer cells that do not communicate via gap junctions poorly cope with hypertonic environments thus explaining the rare occurrence of cancer coming from the kidney medulla. PMID- 21677259 TI - Deficiency of Prdx6 in lens epithelial cells induces ER stress response-mediated impaired homeostasis and apoptosis. AB - The multifunctional cytoprotective protein peroxiredoxin 6 (Prdx6) maintains cellular homeostasis and membrane integrity by regulating expression of intracellular reactive oxygen species (ROS) and phospholipid turnover. Using cells derived from targeted inactivation of Prdx6 gene or its depletion by RNA interference or aging, we showed that Prdx6 deficiency in cells evoked unfolded protein response (UPR), evidenced by increased expression or activation of proapoptotic factors, CHOP, ATF4, PERK, IRE-alpha and eIF2-alpha and by increased caspases 3 and 12 processing. Those cells displayed enhanced and sustained expression of endoplasmic reticulum (ER) stress-related chaperon proteins, Bip/glucose-regulated protein 78, calnexin, and calreticulin. Under cellular stress induced by hypoxia (1% O(2) or CoCl(2) treatment) or tunicamycin, Prdx6 deficient cells exhibited aberrant activation of ER stress-responsive genes/protein with higher expression of ROS, and died with apoptosis. Wild-type cells exposed to tunicamycin or hypoxia remained relatively insensitive with lower expression of ROS and ER-responsive genes than did Prdx6-deficient cells, but upregulation of ER stress responsive proteins or chaperones mimicked the UPR response of Prdx6-deficient or aging cells. Expression of Prdx6 blocked ER stress induced deleterious signaling by optimizing physiologically aberrant expression of ER stress responsive genes/proteins in Prdx6-deficient cells or cells facing stressors, and rescued the cells from apoptosis. These findings demonstrate that impaired homeostasis and progression of pathogenesis in Prdx6-deficient lens epithelial cells or in aging cells should be blocked by a supply of Prdx6. The results provide a new molecular basis for understanding the etiology of several age-associated degenerative disorders, and potentially for developing antioxidant Prdx6-based therapeutics. PMID- 21677261 TI - Hypoxia. Cross talk between oxygen sensing and the cell cycle machinery. AB - A fundamental physiological property of mammalian cells is the regulation of proliferation according to O(2) availability. Progression through the cell cycle is inhibited under hypoxic conditions in many, but not all, cell types, and this G1 arrest is dependent on hypoxia-inducible factor (HIF) 1alpha. Components of the hexameric MCM helicase, which binds to replication origins before the onset of DNA synthesis, are present in large excess in mammalian cells relative to origins, suggesting that they may have additional functions. Screens for HIF 1alpha interacting proteins revealed that MCM7 binds to the amino-terminal PER SIM-ARNT (PAS) domain of HIF-1alpha and stimulates prolyl hydroxylation-dependent ubiquitination and degradation of HIF-1alpha, whereas MCM3 binds to the carboxyl terminus of HIF-1alpha and enhances asparaginyl hydroxylation-dependent inhibition of HIF-1alpha transactivation domain function. Thus MCM proteins inhibit HIF activity via two distinct O(2)-dependent mechanisms. Under prolonged hypoxic conditions, MCM mRNA expression is inhibited in a HIF-1alpha-dependent manner. Thus HIF and MCM proteins act in a mutually antagonistic manner, providing a novel molecular mechanism for homeostatic regulation of cell proliferation based on the relative levels of these proteins. PMID- 21677262 TI - A molecular formula for heart failure and sudden cardiac death. Focus on "Nav1.5 dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice". PMID- 21677263 TI - Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. AB - Late Na(+) current (I(NaL)) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) are both increased in the diseased heart. Recently, CaMKII was found to phosphorylate the Na(+) channel 1.5 (Na(v)1.5), resulting in enhanced I(NaL). Conversely, an increase of I(NaL) would be expected to cause elevation of intracellular Ca(2+) and activation of CaMKII. However, a relationship between enhancement of I(NaL) and activation of CaMKII has yet to be demonstrated. We investigated whether Na(+) influx via Na(v)1.5 leads to CaMKII activation and explored the functional significance of this pathway. In neonatal rat ventricular myocytes (NRVM), treatment with the I(NaL) activators anemone toxin II (ATX-II) or veratridine increased CaMKII autophosphorylation and increased phosphorylation of CaMKII substrates phospholamban and ryanodine receptor 2. Knockdown of Na(v)1.5 (but not Na(v)1.1 or Na(v)1.2) prevented ATX-II-induced CaMKII phosphorylation, providing evidence for a specific role of Na(v)1.5 in CaMKII activation. In support of this view, CaMKII activity was also increased in hearts of transgenic mice overexpressing a gain-of-function Na(v)1.5 mutant (N(1325)S). The effects of both ATX-II and the N(1325)S mutation were reversed by either I(NaL) inhibition (with ranolazine or tetrodotoxin) or CaMKII inhibition (with KN93 or autocamtide 2-related inhibitory peptide). Furthermore, ATX-II treatment also induced CaMKII-Na(v)1.5 coimmunoprecipitation. The same association between CaMKII and Na(v)1.5 was also found in N(1325)S mice, suggesting a direct protein protein interaction. Pharmacological inhibitions of either CaMKII or I(NaL) also prevented ATX-II-induced cell death in NRVM and reduced the incidence of polymorphic ventricular tachycardia induced by ATX-II in rat perfused hearts. Taken together, these results suggest that a Na(v)1.5-dependent increase in Na(+) influx leads to activation of CaMKII, which in turn phosphorylates Na(v)1.5, further promoting Na(+) influx. Pharmacological inhibition of either CaMKII or Na(v)1.5 can ameliorate cardiac dysfunction caused by excessive Na(+) influx. PMID- 21677264 TI - Aging and exercise training reduce testes microvascular PO2 and alter vasoconstrictor responsiveness in testicular arterioles. AB - Testicular function and associated testosterone concentration decline with advancing age, and an impaired O2 supply may contribute, in part, to this reduction. We hypothesized that there would be a reduced microvascular Po2 (Po2(m)) in the testes from aged rats, and this reduced Po2(m) would be associated with impaired vasomotor control in isolated resistance arterioles. In addition, given the positive effect of exercise on microvascular Po2 and arteriolar function, we further hypothesized that there would be an enhanced Po2(m) in the testes from aged animals after aerobic exercise training. Testicular Po2(m) was measured in vivo via phosphorescence quenching in young and aged sedentary (SED) and exercise-trained (ET; 15 m/min treadmill walking, 15 degree incline, 5 days/wk for 10 wk) male Fischer-344 rats. Vasoconstriction to alpha-adrenergic [norepinephrine (NE) and phenylephrine (PE)] and myogenic stimuli in testicular arterioles was assessed in vitro. In the SED animals, testicular Po2(m) was reduced by ~50% with old age (aged SED 11.8 +/- 1.9 vs. young SED 22.1 +/- 1.1 mmHg; P = 0.0001). Contrary to our hypothesis, exercise training did not alter Po2(m) in the aged group and reduced testicular Po2(m) in the young animals, abolishing age-related differences (young ET, 10.0 +/- 0.8 vs. aged ET, 10.7 +/- 0.9 mmHg; P = 0.37). Vasoconstrictor responsiveness to NE and PE was diminished in aged compared with young (NE: young SED, 58 +/- 2 vs. aged SED, 47 +/- 2%; P = 0.001) (PE: young SED, 51 +/- 3 vs. aged SED, 36 +/- 5%; P = 0.008). Exercise training did not alter maximal vasoconstriction to NE in young or aged groups. In summary, advancing age is associated with a reduced testis Po2(m) and impaired adrenergic vasoconstriction. The diminished testicular microvascular driving pressure of O2 and associated vascular dysfunction provides mechanistic insight into the old age-related decrease in testicular function, and a reduced Po2(m) may contribute, in part, to reduced fertility markers after exercise training. PMID- 21677266 TI - Brain IL-6- and PG-dependent actions of IL-1beta and lipopolysaccharide in avian fever. AB - There is no persuasive evidence of a correlation between proinflammatory cytokines and avian fever. In this study, for the first time, we use avian cytokines to investigate a role for proinflammatory cytokines in the central component of avian fever. IL-1beta and IL-6 injected intracerebroventricularly into Pekin ducks (n = 8) initiated robust fevers of equal magnitude and duration, although there was a significant difference in the latency to a febrile response. In addition, the IL-1beta-induced fever could be abolished with an intracerebroventricular injection of antibodies to avian IL-6 or an oral administration of a PG synthesis inhibitor. Our findings indicate the following sequence of events within the central component of the avian febrile mechanism: IL-1beta gives rise to bioactive IL-6, which stimulates an accelerated synthesis of PGs, and these PGs then adjust the sensitivity of warm-sensitive neurons in the avian brain stem to mediate fever. Yet PGE2 was not upregulated in the cerebrospinal fluid of ducks made febrile with LPS. We conclude that IL-1beta and IL-6 may well mediate fever by instigating an accelerated synthesis of brain derived PG, of a class other than PGE2, or that IL-6 serves as one of the terminal mediators of the avian febrile response. PMID- 21677267 TI - Cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in conscious rats. AB - The response to myocardial ischemia is complex and involves the cardio-cardiac sympathetic reflex. Specifically, cardiac spinal (sympathetic) afferents are excited by ischemic metabolites and elicit an excitatory sympathetic reflex, which plays a major role in the genesis of ventricular arrhythmias. For example, brief myocardial ischemia leads to ATP release, which activates cardiac spinal afferents through stimulation of P2 receptors. Clinical work with patients and preclinical work with animals document that disruption of this reflex protects against ischemia-induced ventricular arrhythmias. However, the role of afferent signals in the initiation of sustained ventricular tachycardia has not been investigated. Therefore, we tested the hypothesis that cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in adult (12-15 wk of age), conscious, male Sprague-Dawley rats. To test this hypothesis, the susceptibility to ventricular tachyarrhythmias produced by occlusion of the left main coronary artery was determined in two groups of conscious rats: 1) deafferentation (bilateral excision of the T1-T5 dorsal root ganglia) and 2) control (sham deafferentation). The ventricular arrhythmia threshold (VAT) was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Results document a significantly higher VAT in the deafferentation group (7.0 +/- 0.7 min) relative to control (4.3 +/- 0.3 min) rats. The decreased susceptibility to tachyarrhythmias with deafferentation was associated with a reduced cardiac metabolic demand (lower rate-pressure product and ST segment elevation) during ischemia. PMID- 21677268 TI - Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate. AB - In patients with acute ischemic stroke, diabetes and hyperglycemia are associated with increased infarct size, more profound neurologic deficits and higher mortality. Notwithstanding extensive clinical and experimental data, treatment of stroke-associated hyperglycemia with insulin is controversial. In addition to hyperglycemia, diabetes and even early prediabetic insulin resistance are associated with increased levels of amino acids, including the neurotoxic glutamate, in the circulation. The pleiotropic metabolic effects of insulin include a reduction in the concentration of amino acids in the circulation. In this article, we show that in diabetic rats exposed to transient middle cerebral artery occlusion, a decrease of plasma glutamate by insulin or glucagon reduces CSF glutamate, improves brain histology, and preserves neurologic function. The neuroprotective effect of insulin and glucagon was similar, notwithstanding their opposite effects on blood glucose. The therapeutic window of both hormones overlapped with the short duration (~30 min) of elevated brain glutamate following brain trauma in rodents. Similar neuroprotective effects were found after administration of the glutamate scavenger oxaloacetate, which does not affect glucose metabolism. These data indicate that insulin and glucagon exert a neuroprotective effect within a very brief therapeutic window that correlates with their capacity to reduce glutamate, rather than by modifying glucose levels. PMID- 21677265 TI - Adenosine A2a receptors and O2 sensing in development. AB - Reduced mitochondrial oxidative phosphorylation, via activation of adenylate kinase and the resulting exponential rise in the cellular AMP/ATP ratio, appears to be a critical factor underlying O2 sensing in many chemoreceptive tissues in mammals. The elevated AMP/ATP ratio, in turn, activates key enzymes that are involved in physiologic adjustments that tend to balance ATP supply and demand. An example is the conversion of AMP to adenosine via 5'-nucleotidase and the resulting activation of adenosine A(2A) receptors, which are involved in acute oxygen sensing by both carotid bodies and the brain. In fetal sheep, A(2A) receptors associated with carotid bodies trigger hypoxic cardiovascular chemoreflexes, while central A(2A) receptors mediate hypoxic inhibition of breathing and rapid eye movements. A(2A) receptors are also involved in hypoxic regulation of fetal endocrine systems, metabolism, and vascular tone. In developing lambs, A(2A) receptors play virtually no role in O2 sensing by the carotid bodies, but brain A(2A) receptors remain critically involved in the roll off ventilatory response to hypoxia. In adult mammals, A(2A) receptors have been implicated in O2 sensing by carotid glomus cells, while central A(2A) receptors likely blunt hypoxic hyperventilation. In conclusion, A(2A) receptors are crucially involved in the transduction mechanisms of O2 sensing in fetal carotid bodies and brains. Postnatally, central A(2A) receptors remain key mediators of hypoxic respiratory depression, but they are less critical for O2 sensing in carotid chemoreceptors, particularly in developing lambs. PMID- 21677269 TI - Adrenergic control of vascular resistance varies in muscles composed of different fiber types: influence of the vascular endothelium. AB - The influence of the sympathetic nervous system (SNS) upon vascular resistance is more profound in muscles comprised predominately of low-oxidative type IIB vs. high-oxidative type I fiber types. However, within muscles containing high oxidative type IIA and IIX fibers, the role of the SNS on vasomotor tone is not well established. The purpose of this study was to examine the influence of sympathetic neural vasoconstrictor tone in muscles composed of different fiber types. In adult male rats, blood flow to the red and white portions of the gastrocnemius (Gast(Red) and Gast(White), respectively) and the soleus muscle was measured pre- and postdenervation. Resistance arterioles from these muscles were removed, and dose responses to alpha1-phenylephrine or alpha2-clonidine adrenoreceptor agonists were determined with and without the vascular endothelium. Denervation resulted in a 2.7-fold increase in blood flow to the soleus and Gast(Red) and an 8.7-fold increase in flow to the Gast(White). In isolated arterioles, alpha2-mediated vasoconstriction was greatest in Gast(White) (~50%) and less in Gast(Red) (~31%) and soleus (~17%); differences among arterioles were abolished with the removal of the endothelium. There was greater sensitivity to alpha(1)-mediated vasoconstriction in the Gast(White) and Gast(Red) vs. the soleus, which was independent of whether the endothelium was present. These data indicate that 1) control of vascular resistance by the SNS in high-oxidative, fast-twitch muscle is intermediate to that of low-oxidative, fast twitch and high-oxidative, slow-twitch muscles; and 2) the ability of the SNS to control blood flow to low-oxidative type IIB muscle appears to be mediated through postsynaptic alpha1- and alpha2-adrenoreceptors on the vascular smooth muscle. PMID- 21677270 TI - Sry, more than testis determination? AB - The Sry locus on the mammalian Y chromosome is the developmental switch responsible for testis determination. Inconsistent with this important function, the Sry locus is transcribed in adult males at times and in tissues not involved with testis determination. Sry is expressed in multiple tissues of the peripheral and central nervous system. Sry is derived from Sox3 and is similar to other SOXB family loci. The SOXB loci are responsible for nervous system development. Sry has been demonstrated to modulate the catecholamine pathway, so it should have functional consequences in the central and peripheral nervous system. The nervous system expression and potential function are consistent with Sry as a SOXB family member. In mammals, Sox3 is X-linked and undergoes dosage compensation in females. The expression of Sry in adult males allows for a type of sexual differentiation independent of circulating gonadal hormones. A quantitative difference in Sox3 plus Sry expression in males vs. females could drive changes in the transcriptome of these cells, differentiating male and female cells. Sry expression and its transcriptional effects should be considered when investigating sexual dimorphic phenotypes. PMID- 21677271 TI - Transpulmonary pyruvate kinetics. AB - Shuttling of intermediary metabolites, such as pyruvate, contributes to the dynamic energy and biosynthetic needs of tissues. Tracer kinetic studies offer a powerful tool to measure the metabolism of substrates like pyruvate that are simultaneously taken up from and released into the circulation by organs. However, we understood that during each circulatory passage, the entire cardiac output transits the pulmonary circulation. Therefore, we examined the transpulmonary pyruvate kinetics in an anesthetized rat model during an unstimulated (Con), lactate clamp (LC), and epinephrine infusion (Epi) conditions using a primed-continuous infusion of [U-13C]pyruvate. Compared with Con and Epi stimulation, LC significantly increased mixed central venous ([v]) and arterial ([a]) pyruvate concentrations (P < 0.05). We hypothesized that the lungs, specifically the pulmonary capillary beds are sites of simultaneous production and removal of pyruvate and contributes significantly to whole body carbohydrate intermediary metabolism. Transpulmonary net pyruvate balances were positive during all three conditions, indicating net pyruvate uptake. Net balance was significantly greater during epinephrine stimulation compared with the unstimulated control (P < 0.05). Tracer-measured pyruvate fractional extraction averaged 42.8 +/- 5.8% for all three conditions and was significantly higher during epinephrine stimulation (P < 0.05) than during either Con or LC conditions, that did not differ from each other. Pyruvate total release (tracer measured uptake - net balance) was significantly higher during epinephrine stimulation (400 +/- 100 MUg/min) vs. Con (30 +/- 20 MUg/min) (P < 0.05). These data are interpreted to mean that significant pyruvate extraction occurs during circulatory transport across lung parenchyma. The extent of pulmonary parenchymal pyruvate extraction predicts high expression of monocarboxylate (lactate/pyruvate) transporters (MCTs) in the tissue. Western blot analysis of whole lung homogenates detected three isoforms, MCT1, MCT2, and MCT4. We conclude that a major site of circulating pyruvate extraction resides with the lungs and that during times of elevated circulating lactate, pyruvate, or epinephrine stimulation, pyruvate extraction is increased. PMID- 21677273 TI - Mre11 is expressed in mammalian mitochondria where it binds to mitochondrial DNA. AB - Mre11 is a critical participant in upkeep of nuclear DNA, its repair, replication, meiosis, and maintenance of telomeres. The upkeep of mitochondrial DNA (mtDNA) is less well characterized, and whether Mre11 participates has been unknown. We previously found that high NaCl causes some of the Mre11 to leave the nucleus, but we did not then attempt to localize it within the cytoplasm. In the present studies, we find Mre11 in mitochondria isolated from primary renal cells and show that the amount of Mre11 in mitochondria increases with elevation of extracellular NaCl. We confirm the presence of Mre11 in the mitochondria of cells by confocal microscopy and show that some of the Mre11 colocalizes with mtDNA. Furthermore, crosslinking of Mre11 to DNA followed by Mre11 immunoprecipitation directly demonstrates that some Mre11 binds to mtDNA. Abundant Mre11 is also present in tissue sections from normal mouse kidneys, colocalized with mitochondria of proximal tubule and thick ascending limb cells. To explore whether distribution of Mre11 changes with cell differentiation, we used an experimental model of tubule formation by culturing primary kidney cells in Matrigel matrix. In nondifferentiated cells, Mre11 is mostly in the nucleus, but it becomes mostly cytoplasmic upon cell differentiation. We conclude that Mre11 is present in mitochondria where it binds to mtDNA and that the amount in mitochondria varies depending on cellular stress and differentiation. Our results suggest a role for Mre11 in the maintenance of genome integrity in mitochondria in addition to its previously known role in maintenance of nuclear DNA. PMID- 21677274 TI - Systemic oxytocin induces a prolactin secretory rhythm via the pelvic nerve in ovariectomized rats. AB - We have shown previously that an intravenous injection of oxytocin (OT) in ovariectomized (OVX) rats initiates a circadian rhythm of prolactin (PRL) secretion similar to that observed after cervical stimulation (CS). In this study, we investigated the pathway through which OT triggers the PRL rhythm. We first tested whether an intracerebroventricular injection of OT could trigger the PRL secretory rhythm. As it did not, we injected OT intravenously while an OT receptor antagonist was infused intravenously. This antagonist completely abolished the PRL surges, suggesting that a peripheral target of OT is necessary for triggering the PRL rhythm. We hypothesized that OT may induce PRL release, which would be transported into the brain and trigger the rhythm. In agreement with this, OT injection increased circulating PRL by 5 min. To test whether this acute increase in PRL release would induce the PRL rhythm, we compared the effect of intravenously administered thyrotropin-releasing hormone (TRH) and OT. Although TRH injection also increased PRL to a comparable level after 5 min, only OT-injected animals expressed the PRL secretory rhythm. Motivated by prior findings that bilateral resection of the pelvic nerve blocks CS-induced pseudopregnancy and OT-induced facilitation of lordosis, we then hypothesized that the OT signal may be transmitted through the pelvic nerve. In fact, OT injection failed to induce a PRL secretory rhythm in pelvic-neurectomized animals, suggesting that the integrity of the pelvic nerve is necessary for the systemic OT induction of the PRL secretory rhythm in OVX rats. PMID- 21677272 TI - Biology's response to dieting: the impetus for weight regain. AB - Dieting is the most common approach to losing weight for the majority of obese and overweight individuals. Restricting intake leads to weight loss in the short term, but, by itself, dieting has a relatively poor success rate for long-term weight reduction. Most obese people eventually regain the weight they have worked so hard to lose. Weight regain has emerged as one of the most significant obstacles for obesity therapeutics, undoubtedly perpetuating the epidemic of excess weight that now affects more than 60% of U.S. adults. In this review, we summarize the evidence of biology's role in the problem of weight regain. Biology's impact is first placed in context with other pressures known to affect body weight. Then, the biological adaptations to an energy-restricted, low-fat diet that are known to occur in the overweight and obese are reviewed, and an integrative picture of energy homeostasis after long-term weight reduction and during weight regain is presented. Finally, a novel model is proposed to explain the persistence of the "energy depletion" signal during the dynamic metabolic state of weight regain, when traditional adiposity signals no longer reflect stored energy in the periphery. The preponderance of evidence would suggest that the biological response to weight loss involves comprehensive, persistent, and redundant adaptations in energy homeostasis and that these adaptations underlie the high recidivism rate in obesity therapeutics. To be successful in the long term, our strategies for preventing weight regain may need to be just as comprehensive, persistent, and redundant, as the biological adaptations they are attempting to counter. PMID- 21677275 TI - Cortical activation and lamina terminalis functional connectivity during thirst and drinking in humans. AB - The pattern of regional brain activation in humans during thirst associated with dehydration, increased blood osmolality, and decreased blood volume is not known. Furthermore, there is little information available about associations between activation in osmoreceptive brain regions such as the organum vasculosum of the lamina terminalis and the brain regions implicated in thirst and its satiation in humans. With the objective of investigating the neuroanatomical correlates of dehydration and activation in the ventral lamina terminalis, this study involved exercise-induced sweating in 15 people and measures of regional cerebral blood flow (rCBF) using a functional magnetic resonance imaging technique called pulsed arterial spin labeling. Regional brain activations during dehydration, thirst, and postdrinking were consistent with the network previously identified during systemic hypertonic infusions, thus providing further evidence that the network is involved in monitoring body fluid and the experience of thirst. rCBF measurements in the ventral lamina terminalis were correlated with whole brain rCBF measures to identify regions that correlated with the osmoreceptive region. Regions implicated in the experience of thirst were identified including cingulate cortex, prefrontal cortex, striatum, parahippocampus, and cerebellum. Furthermore, the correlation of rCBF between the ventral lamina terminalis and the cingulate cortex and insula was different for the states of thirst and recent drinking, suggesting that functional connectivity of the ventral lamina terminalis is a dynamic process influenced by hydration status and ingestive behavior. PMID- 21677277 TI - Antibody-directed myostatin inhibition enhances muscle mass and function in tumor bearing mice. AB - Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12; LLC, n = 9) or a mouse chimera of anti human myostatin antibody (PF-354, 10 mg.kg-1.wk-1, LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8-10% (P < 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment (P > 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection (P < 0.05) but was not improved with PF-354 treatment (P > 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively (P < 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice (P < 0.05) but was not different in PF 354-treated tumor-bearing mice (P > 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia. PMID- 21677276 TI - Identification of a neuronal gene expression signature: role of cell cycle arrest in murine neuronal differentiation in vitro. AB - Stem cells are a potential key strategy for treating neurodegenerative diseases in which the generation of new neurons is critical. A better understanding of the characteristics and molecular properties of neural stem cells (NSCs) and differentiated neurons can help with assessing neuronal maturity and, possibly, in devising better therapeutic strategies. We have performed an in-depth gene expression profiling study of murine NSCs and primary neurons derived from embryonic mouse brains. Microarray analysis revealed a neuron-specific gene expression signature that distinguishes primary neurons from NSCs, with elevated levels of transcripts involved in neuronal functions, such as neurite development and axon guidance in primary neurons and decreased levels of multiple cytokine transcripts. Among the differentially expressed genes, we found a statistically significant enrichment of genes in the ephrin, neurotrophin, CDK5, and actin pathways, which control multiple neuronal-specific functions. We then artificially blocked the cell cycle of NSCs with mitomycin C (MMC) and examined cellular morphology and gene expression signatures. Although these MMC-treated NSCs displayed a neuronal morphology and expressed some neuronal differentiation marker genes, their gene expression patterns were very different from primary neurons. We conclude that 1) fully differentiated mouse primary neurons display a specific neuronal gene expression signature; 2) cell cycle block at the S phase in NSCs with MMC does not induce the formation of fully differentiated neurons; 3) cytokines change their expression pattern during differentiation of NSCs into neurons; and 4) signaling pathways of ephrin, neurotrophin, CDK5, and actin, related to major neuronal features, are dynamically enriched in genes showing changes in expression level. PMID- 21677279 TI - Management of twin-to-twin transfusion syndrome. PMID- 21677280 TI - Reduction in reactive oxygen species production by mitochondria from elderly subjects with normal and impaired glucose tolerance. AB - OBJECTIVE: Aging increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes. It has been proposed that increased reactive oxygen species (ROS) generation by dysfunctional mitochondria could play a role in the pathogenesis of these metabolic abnormalities. We examined whether aging per se (in subjects with normal glucose tolerance [NGT]) impairs mitochondrial function and how this relates to ROS generation, whether older subjects with IGT have a further worsening of mitochondrial function (lower ATP production and elevated ROS generation), and whether exercise reverses age-related changes in mitochondrial function. RESEARCH DESIGN AND METHODS: Mitochondrial ATP and ROS production were measured in muscle from younger individuals with NGT, older individuals with NGT, and older individuals with IGT. Measurements were performed before and after 16 weeks of aerobic exercise. RESULTS: ATP synthesis was lower in older subjects with NGT and older subjects with IGT versus younger subjects. Notably, mitochondria from older subjects (with NGT and IGT) displayed reduced ROS production versus the younger group. ATP and ROS production were similar between older groups. Exercise increased ATP synthesis in the three groups. Mitochondrial ROS production also increased after training. Proteomic analysis revealed downregulation of several electron transport chain proteins with aging, and this was reversed by exercise. CONCLUSIONS: Old mitochondria from subjects with NGT and IGT display mitochondrial dysfunction as manifested by reduced ATP production but not with respect to increased ROS production. When adjusted to age, the development of IGT in elderly individuals does not involve changes in mitochondrial ATP and ROS production. Lastly, exercise reverses the mitochondrial phenotype (proteome and function) of old mitochondria. PMID- 21677281 TI - In vivo misfolding of proinsulin below the threshold of frank diabetes. AB - OBJECTIVE: Endoplasmic reticulum (ER) stress has been described in pancreatic beta-cells after onset of diabetes-a situation in which failing beta-cells have exhausted available compensatory mechanisms. Herein we have compared two mouse models expressing equally small amounts of transgenic proinsulin in pancreatic beta-cells. RESEARCH DESIGN AND METHODS: In hProCpepGFP mice, human proinsulin (tagged with green fluorescent protein [GFP] within the connecting [C]-peptide) is folded in the ER, exported, converted to human insulin, and secreted. In hProC(A7)Y-CpepGFP mice, misfolding of transgenic mutant proinsulin causes its retention in the ER. Analysis of neonatal pancreas in both transgenic animals shows each beta-cell stained positively for endogenous insulin and transgenic protein. RESULTS: At this transgene expression level, most male hProC(A7)Y CpepGFP mice do not develop frank diabetes, yet the misfolded proinsulin perturbs insulin production from endogenous proinsulin and activates ER stress response. In nondiabetic adult hProC(A7)Y-CpepGFP males, all beta-cells continue to abundantly express transgene mRNA. Remarkably, however, a subset of beta-cells in each islet becomes largely devoid of endogenous insulin, with some of these cells accumulating large quantities of misfolded mutant proinsulin, whereas another subset of beta-cells has much less accumulated misfolded mutant proinsulin, with some of these cells containing abundant endogenous insulin. CONCLUSIONS: The results indicate a source of pancreatic compensation before the development of diabetes caused by proinsulin misfolding with ER stress, i.e., the existence of an important subset of beta-cells with relatively limited accumulation of misfolded proinsulin protein and maintenance of endogenous insulin production. Generation and maintenance of such a subset of beta-cells may have implications in the avoidance of type 2 diabetes. PMID- 21677282 TI - Endothelin-1 reduces glucose uptake in human skeletal muscle in vivo and in vitro. AB - OBJECTIVE: Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may interfere with glucose uptake. Our objective was to investigate whether exogenous ET-1 affects glucose uptake in the forearm of individuals with insulin resistance and in cultured human skeletal muscle cells. RESEARCH DESIGN AND METHODS: Nine male subjects (aged 61 +/- 3 years) with insulin resistance (M value <5.5 mg/kg/min or a homeostasis model assessment of insulin resistance index >2.5) participated in a protocol using saline infusion followed by ET-1 infusion (20 pmol/min) for 2 h into the brachial artery. Forearm blood flow (FBF), endothelium-dependent vasodilatation, and endothelium-independent vasodilatation were assessed. Molecular signaling and glucose uptake were determined in cultured skeletal muscle cells. RESULTS: ET-1 decreased forearm glucose uptake (FGU) by 39% (P < 0.05) after the 2-h infusion. ET-1 reduced basal FBF by 36% after the 2-h infusion (P < 0.05) and impaired both endothelium dependent vasodilatation (P < 0.01) and endothelium-independent vasodilatation (P < 0.05). ET(A) and ET(B) receptor expression was detected on cultured skeletal muscle cells. One-hour ET-1 incubation increased glucose uptake in cells from healthy control subjects but not from type 2 diabetic patients. Incubation with ET-1 for 24 h reduced glucose uptake in cells from healthy subjects. ET-1 decreased insulin-stimulated Akt phosphorylation and increased phosphorylation of insulin receptor substrate-1 serine 636. CONCLUSIONS: ET-1 not only induces vascular dysfunction but also acutely impairs FGU in individuals with insulin resistance and in skeletal muscle cells from type 2 diabetic subjects. These findings suggest that ET-1 may contribute to the development of insulin resistance in skeletal muscle in humans. PMID- 21677283 TI - Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes. AB - OBJECTIVE: In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known. RESEARCH DESIGN AND METHODS: Twelve patients with type 2 diabetes and 13 nondiabetic individuals were examined in the fasting state and after mixed meal ingestion. Deconvolution analyses were performed on insulin and glucagon concentration time series sampled at 1-min intervals. RESULTS: Both insulin and glucagon were secreted in distinct pulses, occurring at ~5-min intervals. In patients with diabetes, postprandial insulin pulse mass was reduced by 74% (P < 0.001). Glucagon concentrations were increased in the patients during fasting and after meal ingestion (P < 0.05), specifically through an increased glucagon pulse mass (P < 0.01). In healthy subjects, the increase in postprandial insulin levels was inversely related to respective glucagon levels (P < 0.05). This relationship was absent in the fasting state and in patients with diabetes. CONCLUSIONS: Glucagon and insulin are secreted in a coordinated, pulsatile manner. A plausible model is that the postprandial increase in insulin burst mass represses the corresponding glucagon pulses. Disruption of the insulin-glucagon interaction in patients with type 2 diabetes could potentially contribute to hyperglucagonemia. PMID- 21677285 TI - The editor in chief position in transition. PMID- 21677284 TI - The insulin-like growth factor-1 receptor is a negative regulator of nitric oxide bioavailability and insulin sensitivity in the endothelium. AB - OBJECTIVE: In mice, haploinsufficiency of the IGF-1 receptor (IGF-1R(+/-)), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin resistant heterodimers composed of one IGF-1Ralphabeta and one insulin receptor (IR), IRalphabeta complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti inflammatory signaling radical nitric oxide (NO). RESEARCH DESIGN AND METHODS: Using a number of complementary gene-modified mice with reduced IGF-1R at a whole body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability. RESULTS: IGF-1R(+/-) mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity. CONCLUSIONS: These data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium. PMID- 21677287 TI - Interleukin-17 and atherosclerotic vascular disease. PMID- 21677286 TI - DDAH says NO to ADMA. PMID- 21677288 TI - Vascular cell lineage determination and differentiation. PMID- 21677289 TI - Key transcriptional regulators of early vascular development. AB - The formation of the vasculature depends on the precise spatial and temporal control of gene expression to define endothelial cell identity and to ensure the correct distribution and structure of the forming vessel network. This review provides an overview of the establishment of the vascular system, accompanied by a detailed discussion of the transcription factors involved in regulating endothelial gene expression during vasculogenesis and early vessel formation in both fish and mammalian systems. We also review the transcriptional pathways lying both upstream and downstream of key vascular transcription factors. PMID- 21677290 TI - Endothelial differentiation: molecular mechanisms of specification and heterogeneity. AB - A complex and diverse vascular system is requisite for the survival of higher organisms. The process of vascular development is highly regulated, involving the de novo formation of vessels (vasculogenesis), followed by expansion and remodeling of the primitive vasculature (angiogenesis), culminating in differentiation of endothelial phenotypes, as found in the mature vascular system. Over the last decade, significant advances have been made in understanding the molecular regulation of endothelial cell development and differentiation. Endothelial development, in particular the mechanisms in play during vasculogenesis and angiogenesis, is discussed in a sister review to this article. This review highlights the key pathways governing in endothelial differentiation, with a focus on the major molecular mechanisms of endothelial specification and heterogeneity. PMID- 21677291 TI - Smooth muscle cell differentiation in vitro: models and underlying molecular mechanisms. AB - Development of in vitro models by which to study smooth muscle cell (SMC) differentiation has been hindered by some peculiarities intrinsic to these cells, namely their different embryological origins and their ability to undergo phenotypic modulation in cell culture. Although many in vitro models are available for studying SMC differentiation, careful consideration should be taken so that the model chosen fits the questions being posed. In this review, we summarize several well-established in vitro models available to study SMC differentiation from stem cells and outline novel mechanisms recently identified as underlying SMC differentiation programs. PMID- 21677292 TI - Signaling mechanisms that regulate smooth muscle cell differentiation. AB - Extensive studies over the last 30 years have demonstrated that vascular smooth muscle cell (SMC) differentiation and phenotypic modulation is controlled by a dynamic array of environmental cues. The identification of the signaling mechanisms by which these environmental cues regulate SMC phenotype has been more difficult because of our incomplete knowledge of the transcription mechanisms that regulate SMC-specific gene expression. However, recent advances in this area have provided significant insight, and the goal of this review is to summarize the signaling mechanisms by which extrinsic cues control SMC differentiation. PMID- 21677294 TI - The spatial and developmental relationships in the macrophage family. AB - A classic study in 1968 proposed that bone marrow-dwelling promonocytes differentiate to monocytes, which then intravasate, circulate, and, on tissue entry, differentiate to sessile macrophages. Since then, understanding of the macrophage family relationship has undergone substantial enhancement and occasional revision. It is currently recognized that in addition to their role in the bone marrow, hematopoietic progenitors circulate and give rise to their descendants in extramedullary niches. Monocytes, of which there are several subsets, are not merely circulating macrophage precursors but participate in the immune response in their own right. Macrophages are highly heterogeneous and, as recent studies indicate, can arise in the absence of a monocyte intermediate. These spatial and developmental relationships reveal a complex interactive network and underscore the importance of context in evaluating biological systems. The observations have significant implications for how we image, target, and treat disease. PMID- 21677295 TI - Adventitial biology: differentiation and function. AB - Recent evidence indicates that stem/progenitor cells are present in the adventitia and participate in vascular repair and the formation of neointimal lesions in severely damaged vessels. Data have also demonstrated that these resident stem/progenitor cells could differentiate into endothelial or smooth muscle cells in response to different stimuli. Under pathological conditions, adventitial inflammation results in releasing a panel of cytokines, such as stromal cell-derived factor-1 and tumor necrosis factor-alpha, that may lead to local stem/progenitor mobilization and differentiation. Overall, these data support the impact of the adventitial progenitors in pathophysiological processes of lesion development in the arterial wall. In the present review, we aim to summarize the data concerning the presence of the resident stem cells and discuss the pathological impact of the adventitia in vascular diseases. We will also discuss the possible signal pathways orchestrating stem cell differentiation toward vascular lineage and highlight controversial issues related to the role of adventitial progenitors. PMID- 21677293 TI - Monocyte and macrophage dynamics during atherogenesis. AB - Vascular inflammation is associated with and in large part driven by changes in the leukocyte compartment of the vessel wall. Here, we focus on monocyte influx during atherosclerosis, the most common form of vascular inflammation. Although the arterial wall contains a large number of resident macrophages and some resident dendritic cells, atherosclerosis drives a rapid influx of inflammatory monocytes (Ly-6C(+) in mice) and other monocytes (Ly-6C(-) in mice, also known as patrolling monocytes). Once in the vessel wall, Ly-6C(+) monocytes differentiate to a phenotype consistent with inflammatory macrophages and inflammatory dendritic cells. The phenotype of these cells is modulated by lipid uptake, Toll like receptor ligands, hematopoietic growth factors, cytokines, and chemokines. In addition to newly recruited macrophages, it is likely that resident macrophages also change their phenotype. Monocyte-derived inflammatory macrophages have a short half-life. After undergoing apoptosis, they may be taken up by surrounding macrophages or, if the phagocytic capacity is overwhelmed, can undergo secondary necrosis, a key event in forming the necrotic core of atherosclerotic lesions. In this review, we discuss these and other processes associated with monocytic cell dynamics in the vascular wall and their role in the initiation and progression of atherosclerosis. PMID- 21677297 TI - Quality achievement and disease prevalence in primary care predicts regional variation in renal replacement therapy (RRT) incidence: an ecological study. AB - BACKGROUND: Diabetes Meillitus (DM) and hypertension (HT) are important causes of end-stage renal disease (ESRD) and renal replacement therapy (RRT) is the standard active treatment. Financially, incentivized quality initiatives for primary care include pay-for-performance (P4P) in DM and HT. Our aim was to examine any effect of disease prevalence and P4P on RRT incidence and regional variation. METHODS: The incidence of RRT, sex and ethnicity data and P4P disease register and achievement data were obtained for each NHS locality. We calculated correlation coefficients for P4P indicators since 2004/05 and socio-demographic data for these 152 localities. We then developed a regression model and regression coefficient (R(2)) to assess to what extent these variables might predict RRT incidence. RESULTS: Many of the P4P indicators were weakly but highly significantly correlated with RRT incidence. The strongest correlation was 2004/05 for DM prevalence and 2006/07 for HT quality. DM prevalence and the percentage with blood pressure control in HT target (HT quality) were the most predictive in our regression model R(2) = 0.096 and R(2) = 0.085, respectively (P < 0.001). Combined they predicted a fifth of RRT incidence (R(2) = 0.2, P < 0.001) while ethnicity and deprivation a quarter (R(2) = 0.25, P < 0.001). Our final model contained proportion of population >75 years, DM prevalence, HT quality, ethnicity and deprivation index and predicted 40% of variation (R(2) = 0.4, P < 0.001). CONCLUSION: Our findings add prevalence of DM and quality of HT management to the known predictors of variation in RRT, ethnicity and deprivation. They raise the possibility that interventions in primary care might influence later events in specialist care. PMID- 21677296 TI - The adventitia: a dynamic interface containing resident progenitor cells. AB - Conventional views of the tunica adventitia as a poorly organized layer of vessel wall composed of fibroblasts, connective tissue, and perivascular nerves are undergoing revision. Recent studies suggest that the adventitia has properties of a stem/progenitor cell niche in the artery wall that may be poised to respond to arterial injury. It is also a major site of immune surveillance and inflammatory cell trafficking and harbors a dynamic microvasculature, the vasa vasorum, that maintains the medial layer and provides an important gateway for macrophage and leukocyte migration into the intima. In addition, the adventitia is in contact with tissue that surrounds the vessel and may actively participate in exchange of signals and cells between the vessel wall and the tissue in which it resides. This brief review highlights recent advances in our understanding of the adventitia and its resident progenitor cells and discusses progress toward an integrated view of adventitial function in vascular development, repair, and disease. PMID- 21677298 TI - Evaluation of a new immunoassay for cystatin C, based on a double monoclonal principle, in men with normal and impaired renal function. AB - BACKGROUND: Elevated cystatin C in blood reflects impaired glomerular filtration rate (GFR), but current cystatin C assays, based on polyclonal antibodies and immunoturbidimetric or nephelometric detection, have several limitations. We evaluated a new immunoassay based on monoclonal antibodies in samples from patients with and without chronic kidney disease (CKD). METHODS: The study enrolled 170 men without known CKD (Group A) and 104 men with CKD (Group B). All patients were assessed with iohexol clearance, plasma creatinine and plasma cystatin C by a conventional particle-enhanced immunoturbidimetric assay (PETIA) and by the new double monoclonal assay. In Group A, three serial blood draws were performed at median intervals of 4 h and 12 days between samples, to also allow assessments of the variability in cystatin C values with the new assay. Concordance correlation coefficients and the 95% limits of agreement were used to estimate the agreement of reciprocal cystatin C and reciprocal creatinine with iohexol clearance. RESULTS: Median iohexol clearance (mL/min/1.73 m(2)) was 81 [interquartile range (IQR) 70, 92] in Group A and 23 (IQR 16, 34) in Group B. The concordance correlation with GFR for the new cystatin C assay compared to the established assay was similar in Group A (0.441 versus 0.465) but higher in Group B (0.680 versus 0.593). Cystatin C measured by both assays exhibited closer agreement with GFR than creatinine. The agreement between the two cystatin C assays was high, with concordance correlations of 0.815 in Group A and 0.935 in Group B. Compared to the conventional assay, the new assay tended to yield lower values of cystatin C at the low end of the range in Group A. The new cystatin C assay exhibited small intraindividual variability across serial samples (coefficient of variation <= 6%). CONCLUSIONS: In this first clinical evaluation, the new cystatin C assay performed similarly to the established PETIA in patients with normal GFR and better in patients with CKD. The new assay may offer an alternative to current commercial assays to detect and monitor impaired kidney function. PMID- 21677300 TI - CYP3A5 and ABCB1 polymorphisms in donor and recipient: impact on Tacrolimus dose requirements and clinical outcome after renal transplantation. AB - BACKGROUND: The effect of potentially relevant genetic polymorphisms, CYP3A5 6986A>G and ABCB1 3435C>T, on Tacrolimus pharmacokinetics and graft clinical outcome was investigated in donor and recipient DNA samples from 209 kidney transplant patients. METHODOLOGY/PRINCIPAL FINDINGS: The mean follow-up was 21.8 +/- 9 months. The Tacrolimus dose, trough blood concentrations (C0) and C0/dose ratio were only statistically correlated with the recipient CYP3A5 genotype. CYP3A5 and ABCB1 genotypes appeared to have no influence on the incidence of Biopsy Proven Acute Rejection and Delayed Graft Function. Renal function was not affected by CYP3A5 and ABCB1 genotypes. Histological evaluation of biopsies revealed also no significant association between Tacrolimus toxicity features and donor or recipient CYP3A5 and ABCB1 polymorphisms. Tacrolimus sparing appeared to be independent of CYP3A5 and ABCB1 genotypes. CONCLUSIONS/SIGNIFICANCE: Recipient CYP3A5 6986A>G polymorphism explains part of the interindividual variability of the pharmacokinetics of Tacrolimus. The clinical outcome at 2-year follow-up does not appear to be related to the donor or recipient CYP3A5 6986A>G and/or ABCB1 3435C>T polymorphisms. PMID- 21677301 TI - Epidemiology and prognostic significance of chronic kidney disease in the elderly -the Three-City prospective cohort study. AB - BACKGROUND: Little is known about normal kidney function level and the prognostic significance of low estimated glomerular filtration rate (eGFR) in the elderly. METHODS: We determined age and sex distribution of eGFR with both the Modification of Diet in Renal Disease (MDRD) study and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 8705 community-dwelling elderly aged >= 65 years and studied its relation to 6-year mortality. In a subsample of 1298 subjects examined at 4 years, we assessed annual eGFR decline and clinically relevant markers including microalbuminuria (3-30 mg/mmol creatinine) with diabetes, proteinuria >= 50 mg/mmol, haemoglobin <11 g/L or resistant hypertension despite three drugs. RESULTS: Median (interquartile range) MDRD eGFR was 78 (68-89) mL/min/1.73 m(2) in men and 74 (65-83) in women; there were 79 (68 87) and 77 (67-85) for CKD-EPI eGFR, respectively. Prevalence of MDRD eGFR <60 mL/min/1.73 m(2) was 13.7% and of CKD-EPI eGFR was 12.9%. After adjustment for several confounders, only those with an eGFR <45 mL/min/1.73 m(2) had significantly higher all-cause and cardiovascular mortality than those with an eGFR of 75-89 mL/min/1.73 m(2) whatever the equation. In the subsample men and women with an MDRD eGFR of 45-59 mL/min/1.73 m(2), 15 and 13% had at least one clinical marker and 15 and 3% had microalbuminuria without diabetes, respectively; these percentages were 41 and 21% and 23 and 10% in men and women with eGFR <45, respectively. Mean MDRD eGFR decline rate was steeper in men than in women, 1.75 versus 1.41 mL/min/1.73 m(2)/year. CONCLUSIONS: Moderately decreased eGFR is more often associated with clinical markers in men than in women. In both sexes, eGFR <45 mL/min/1.73 m(2) is related to poor outcomes. The CKD-EPI and the MDRD equations provide very similar prevalence and long-term risk estimates in this elderly population. PMID- 21677302 TI - Effect of mean arterial pressure, haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is a common and serious condition carrying significant costs. During cardiopulmonary bypass (CPB) surgery, modifiable factors may contribute to post-operative AKI. Their avoidance might be a potential target for nephroprotection. METHODS: The objective of the present study was to identify and determine whether intraoperative hypotension, anaemia, or their combination, red blood cell transfusion or vasopressor use are independent risk factors for post-operative AKI defined by the RIFLE (renal Risk, Injury, Failure, Loss of renal function and End-stage renal disease) classification and other thresholds using a mixed logistic multivariate model. RESULTS: We analysed 381 468 mean arterial pressure (MAP) measurements from 920 consecutive on-pump cardiac surgery patients. Overall, 19.5% developed AKI which was associated with an 8.2-fold increase in-hospital mortality. Haemoglobin concentration was an independent risk factor for AKI {odds ratio [OR] 1.16 per g/dL decrease [95% confidence interval (CI) 1.05-1.31]; P = 0.018} with systemic arterial oxygen saturation and pressure values not adding further strength to such an association. MAP alone or vasopressor administration was not independently associated with AKI but volume of red blood cell transfusion was, with its effect being apparent at a haemoglobin level of >8 g/dL (>5 mmol/L). In patients with severe anaemia (<25th percentile of lowest haemoglobin), the independent effect of hypotension (>75th percentile of area under the curve MAP <50 mmHg) on AKI was more pronounced [OR 3.36 (95% CI 1.34-8.41); P = 0.010]. CONCLUSION: Intraoperative avoidance of the extremes of anaemia, especially during severe hypotension and avoidance of transfusion in patients with haemoglobin levels >8 g/dL (>5 mmol/L) may help decrease AKI in patients undergoing cardiac surgery and represent targets for future controlled interventions. PMID- 21677303 TI - Intensive home hemodialysis: the best treatment in the best system. PMID- 21677304 TI - De novo lipogenesis in the differentiating human adipocyte can provide all fatty acids necessary for maturation. AB - The primary products of de novo lipogenesis (DNL) are saturated fatty acids, which confer adverse cellular effects. Human adipocytes differentiated with no exogenous fat accumulated triacylglycerol (TG) in lipid droplets and differentiated normally. TG composition showed the products of DNL (saturated fatty acids from 12:0 to 18:0) together with unsaturated fatty acids (particularly 16:1n-7 and 18:1n-9) produced by elongation/desaturation. There was parallel upregulation of expression of genes involved in DNL and in fatty acid elongation and desaturation, suggesting coordinated control of expression. Enzyme products (desaturation ratios, elongation ratios, and total pathway flux) were also correlated with mRNA levels. We used (13)C-labeled substrates to study the pathway of DNL. Glucose (5 mM or 17.5 mM in the medium) provided less than half the carbon used for DNL (42% and 47%, respectively). Glutamine (2 mM) provided 9 10%, depending upon glucose concentration. In contrast, glucose provided most (72%) of the carbon of TG-glycerol. Pathway analysis using mass isotopomer distribution analysis (MIDA) revealed that the pathway for conversion of glucose to palmitate is complex. DNL in human fat cells is tightly coupled with further modification of fatty acids to produce a range of saturated and unsaturated fatty acids consistent with normal maturation. PMID- 21677305 TI - Pathway for the movement of water and cryoprotectants in bovine oocytes and embryos. AB - The permeability of cells is important for cryopreservation. Previously, we showed in mice that the permeability to water and cryoprotectants of oocytes and embryos at early cleavage stages (early embryos) is low because these molecules move across the plasma membrane predominantly by simple diffusion through the lipid bilayer, whereas permeability of morulae and blastocysts is high because of a water channel, aquaporin 3 (AQP3). In this study, we examined the pathways for the movement of water and cryoprotectants in bovine oocytes/embryos and the role of AQP3 in the movement by determining permeability, first in intact bovine oocytes/embryos, then in bovine morulae with suppressed AQP3 expression, and finally in mouse oocytes expressing bovine AQP3. Results suggest that water moves through bovine oocytes and early embryos slowly by simple diffusion, as is the case in mice, although channel processes are also involved in the movement. On the other hand, water appears to move through morulae and blastocysts predominantly by facilitated diffusion via channels, as in mice. Like water, cryoprotectants appear to move through bovine oocytes/early embryos mostly by simple diffusion, but channel processes could also be involved in the movement of glycerol and ethylene glycol, unlike that in mice. In bovine morulae, although glycerol and ethylene glycol would move predominantly by facilitated diffusion, mostly through AQP3, as in mice, dimethylsulfoxide appears to move predominantly by simple diffusion, unlike in mice. These results indicate that permeability related properties of bovine oocytes/embryos are similar to those of mouse oocytes/embryos, but species-specific differences do exist. PMID- 21677306 TI - Inhibition of ovarian KIT phosphorylation by the ovotoxicant 4-vinylcyclohexene diepoxide in rats. AB - In vitro exposure of Postnatal Day 4 (PND4) rat ovaries to the occupational chemical 4-vinylcyclohexene diepoxide (VCD) destroys specifically primordial and primary follicles via acceleration of atresia. Because oocyte-expressed c-kit (KIT) plays a critical role in follicle survival and activation, a direct interaction of VCD with KIT as its mechanism of ovotoxicity was investigated. PND4 rat ovaries were cultured with and without VCD (30 MUM) for 2 days. When assessed by Western analysis or mobility shift detection, phosphorylated KIT (pKIT) was decreased (P < 0.05) by VCD exposure, while total KIT protein was unaffected. Anti-mouse KIT2 (ACK2) antibody binds KIT and blocks its signaling pathways, whereas anti-mouse KIT 4 (ACK4) antibody binds KIT but does not block its activity. PND4 rat ovaries were incubated for 2 days with and without VCD with and without ACK2 (80 MUg/ml) or ACK4 (80 MUg/ml). ACK2 decreased pKIT; however, ACK4 had no effect. Conversely, ACK2 did not affect a VCD-induced decrease in pKIT, whereas ACK4 further reduced it. Because ACK2 and ACK4 (known to directly bind KIT) affect VCD responses, these results support the fact that VCD interacts directly with KIT. The effect of these antibodies on VCD-induced follicle loss was measured after 8 days of incubation. ACK2 further reduced (P < 0.05) VCD-induced follicle loss, whereas ACK4 did not affect it. These findings demonstrate that VCD induces ovotoxicity by direct inhibition of KIT autophosphorylation of the oocyte. The data also further support the vital function of KIT and its signaling pathway in primordial follicle survival and activation, as well as its role in VCD-induced ovotoxicity. PMID- 21677307 TI - Kisspeptins in reproductive biology: consensus knowledge and recent developments. AB - Kisspeptins, a family of neuropeptides encoded by the Kiss1 gene that are mainly expressed in discrete neuronal populations of the hypothalamus, have recently emerged as essential upstream regulatory elements of GnRH (gonadotropin-releasing hormone) neurons and, thereby, potent elicitors of gonadotropin secretion. Indeed, kisspeptins are now recognized as important regulators of key aspects of the maturation and function of the reproductive axis, including the sexual differentiation of the brain, the timing of puberty, the adult regulation of gonadotropin secretion by gonadal hormones, and the control of fertility by metabolic and environmental (e.g., photoperiod) cues. Appreciation of these fundamental biological features has led to the contention that kisspeptins are indispensable elements of the reproductive brain whose relevance goes beyond their crucial physiological roles and may pose potential pathophysiological and therapeutic interest. In spite of such a consensus, recent developments in the field have helped to expand, and somewhat challenged, our current understanding of the neuroendocrine and molecular mechanisms whereby some of the effects of kisspeptins are conducted. This review aims to provide a synoptic and balanced account of the consensus knowledge and recent findings in the field of kisspeptin physiology, which we predict will be crucial in shaping the progress of our understanding of the roles played by this family of neuropeptides in reproductive biology. PMID- 21677308 TI - The differential effect of atrazine on luteinizing hormone release in adrenalectomized adult female Wistar rats. AB - High doses of atrazine (ATR), administered for 4 days, suppress luteinizing hormone (LH) release and increase adrenal hormones levels. Considering the known inhibitory effects of adrenal hormones on the hypothalamo-pituitary-gonadal axis, we investigated the possible role the adrenal gland has in mediating ATR inhibition of LH release. To determine the extant and duration of adrenal activation, ovariectomized Wistar rats were given a single dose of ATR (0, 50, or 200 mg/kg), and corticosterone (CORT) levels were assayed at multiple time points posttreatment. CORT levels were increased within 20 min and remained elevated over 12 h postgavage in 200-mg/kg animals. To determine the effects of adrenalectomy on ATR inhibition of the LH surge and pulsatile LH release, adrenalectomized (ADX) or sham-operated ovariectomized rats were treated for 4 days with ATR (0, 10, 100, or 200 mg/kg), and an LH surge was induced with hormone priming. In the afternoon following the last dose of ATR, blood was sampled hourly for 9 h. Another cohort of ovariectomized rats was examined for pulsatile patterns of LH secretion after ATR (0, 50, or 200 mg/kg) and sampled every 5 min for 3 h. ADX had no effect on ATR inhibition of the LH surge but prevented the ATR disruption of pulsatile LH release. These data indicate that ATR selectively affects the LH pulse generator through alterations in adrenal hormone secretion. Adrenal activation does not play a role in ATR's suppression of the LH surge, and therefore ATR may work centrally to alter the preovulatory LH surge in female rats. PMID- 21677309 TI - When an egg is not an egg: compromised maternal mRNA storage and stabilization. PMID- 21677310 TI - Role of the double luteinizing hormone peak, luteinizing follicles, and the secretion of inhibin for dominant follicle selection in Asian elephants (Elephas maximus). AB - Elephants express two luteinizing hormone (LH) peaks timed 3 wk apart during the follicular phase. This is in marked contrast with the classic mammalian estrous cycle model with its single, ovulation-inducing LH peak. It is not clear why ovulation and a rise in progesterone only occur after the second LH peak in elephants. However, by combining ovarian ultrasound and hormone measurements in five Asian elephants (Elephas maximus), we have found a novel strategy for dominant follicle selection and luteal tissue accumulation. Two distinct waves of follicles develop during the follicular phase, each of which is terminated by an LH peak. At the first (anovulatory) LH surge, the largest follicles measure between 10 and 19.0 mm. At 7 +/- 2.4 days before the second (ovulatory) LH surge, luteinization of these large follicles occurs. Simultaneously with luteinized follicle (LUF) formation, immunoreactive (ir) inhibin concentrations rise and stay elevated for 41.8 +/- 5.8 days after ovulation and the subsequent rise in progesterone. We have found a significant relationship between LUF diameter and serum ir-inhibin level (r(2) = 0.82, P < 0.001). The results indicate that circulating ir-inhibin concentrations are derived from the luteinized granulosa cells of LUFs. Therefore, it appears that the development of LUFs is a precondition for inhibin secretion, which in turn impacts the selection of the ovulatory follicle. Only now, a single dominant follicle may deviate from the second follicular wave and ovulate after the second LH peak. Thus, elephants have evolved a different strategy for corpus luteum formation and selection of the ovulatory follicle as compared with other mammals. PMID- 21677311 TI - Association of body mass index in early adulthood and middle age with future site specific cancer mortality: the Harvard Alumni Health Study. AB - BACKGROUND: The association between adiposity in early adulthood and subsequent development of specific malignancies is unclear. Further, the potential for mediation by adiposity in middle age has not been well examined. In a rare study, we investigated the association of body mass index (BMI) in early adulthood with mortality from several site-specific cancers. DESIGN: In the Harvard Alumni Health Study cohort, 19 593 males had a physical examination at the university between 1914 and 1952 (mean age: 18.4 years) and returned a questionnaire in 1962 or 1966 (mean age = 45.1 years). BMI was computed using weight (kg)/height(2) (m(2)) at both time points. Vital status follow up continued for a maximum of 82 years. RESULTS: Positive early adulthood cancer mortality gradients by BMI were found for all malignancies combined (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI]: 1.05-1.17 for a one standard deviation increase in early adulthood BMI), and for lung (HR = 1.24; 95% CI = 1.10-1.40) and skin (HR = 1.29; 95% CI = 0.96-1.75) cancers. There were also apparent associations for cancers of the oesophagus and urogenital sites. Mediation by BMI in middle age was found to be minimal. CONCLUSION: Higher BMI in early adulthood appears to be a direct risk factor for selected malignancies several decades later. PMID- 21677312 TI - Effect of stem cell source on outcomes after unrelated donor transplantation in severe aplastic anemia. AB - Outcome after unrelated donor bone marrow (BM) transplantation for severe aplastic anemia (SAA) has improved, with survival rates now approximately 75%. Increasing use of peripheral blood stem and progenitor cells (PBPCs) instead of BM as a graft source prompted us to compare outcomes of PBPC and BM transplantation for SAA. We studied 296 patients receiving either BM (n = 225) or PBPC (n = 71) from unrelated donors matched at human leukocyte antigen-A, -B, -C, -DRB1. Hematopoietic recovery was similar after PBPC and BM transplantation. Grade 2 to 4 acute graft-versus-host disease risks were higher after transplantation of PBPC compared with BM (hazard ratio = 1.68, P = .02; 48% vs 31%). Chronic graft-versus-host disease risks were not significantly different after adjusting for age at transplantation (hazard ratio = 1.39, P = .14). Mortality risks, independent of age, were higher after PBPC compared with BM transplantation (hazard ratio = 1.62, P = .04; 76% vs 61%). These data indicate that BM is the preferred graft source for unrelated donor transplantation in SAA. PMID- 21677313 TI - CD81 is essential for the formation of membrane protrusions and regulates Rac1 activation in adhesion-dependent immune cell migration. AB - CD81 (TAPA-1) is a member of the widely expressed and evolutionary conserved tetraspanin family that forms complexes with a variety of other cell surface receptors and facilitates hepatitis C virus entry. Here, we show that CD81 is specifically required for the formation of lamellipodia in migrating dendritic cells (DCs). Mouse CD81(-/-) DCs, or murine and human CD81 RNA interference knockdown DCs lacked the ability to form actin protrusions, thereby impairing their motility dramatically. Moreover, we observed a selective loss of Rac1 activity in the absence of CD81, the latter of which is exclusively required for integrin-dependent migration on 2-dimensional substrates. Neither integrin affinity for substrate nor the size of basal integrin clusters was affected by CD81 deficiency in adherent DCs. However, the use of total internal reflection fluorescence microscopy revealed an accumulation of integrin clusters above the basal layer in CD81 knockdown cells. Furthermore, beta1- or beta2-integrins, actin, and Rac are strongly colocalized at the leading edge of DCs, but the very fronts of these cells protrude CD81-containing membranes that project outward from the actin-integrin area. Taken together, these data suggest a thus far unappreciated role for CD81 in the mobilization of preformed integrin clusters into the leading edge of migratory DCs on 2-dimensional surfaces. PMID- 21677315 TI - Raf inhibition causes extensive multiple tissue hyperplasia and urinary bladder neoplasia in the rat. AB - Seven novel and potent Raf small molecule kinase inhibitors (C1-7) were evaluated in seven-day oral repeat dose rat toxicity studies. All compounds tested induced hyperplasia in multiple tissues. Consistently affected was stratified squamous epithelium at a number of sites and transitional epithelium of urinary bladder and kidney. A seven-day time course study in rats showed morphologic evidence of epithelial proliferation in the nonglandular stomach within four to five hours after a single dose of C-1. Similar indications of cellular proliferation were observed in the urinary bladder by day 2 and in the heart, kidney, and liver by day 3. Transcriptional evidence of proliferation in the urinary bladder was detected within four to five hours after a single dose consistent with activation of the PI3K/AKT and ERK/MAPK pathways. In a twenty-eight-day rat toxicity study of C-1, hyperplasia was observed in the esophagus, nonglandular stomach, skin, urinary bladder, kidney, and heart. Hyperplasia of transitional epithelium of the urinary bladder was particularly severe and in one female rat was accompanied by the presence of a transitional cell carcinoma. These results suggest that these Raf inhibitors induce early transcriptional changes driving unchecked cell proliferation, resulting in marked tissue hyperplasia that can progress to carcinoma within a short time frame. PMID- 21677314 TI - Suppression of HTLV-1 replication by Tax-mediated rerouting of the p13 viral protein to nuclear speckles. AB - Disease development in human T-cell leukemia virus type 1 (HTLV-1)-infected individuals is positively correlated with the level of integrated viral DNA in T cells. HTLV-1 replication is positively regulated by Tax and Rex and negatively regulated by the p30 and HBZ proteins. In the present study, we demonstrate that HTLV-1 encodes another negative regulator of virus expression, the p13 protein. Expressed separately, p13 localizes to the mitochondria, whereas in the presence of Tax, part of it is ubiquitinated, stabilized, and rerouted to the nuclear speckles. The p13 protein directly binds Tax, decreases Tax binding to the CBP/p300 transcriptional coactivator, and, by reducing Tax transcriptional activity, suppresses viral expression. Because Tax stabilizes its own repressor, these findings suggest that HTLV-1 has evolved a complex mechanism to control its own replication. Further, these results highlight the importance of studying the function of the HTLV-1 viral proteins, not only in isolation, but also in the context of full viral replication. PMID- 21677316 TI - Health and fitness of young people: what is the role of sport? PMID- 21677317 TI - Cooling an acute muscle injury: can basic scientific theory translate into the clinical setting? AB - Ice is commonly used after acute muscle strains but there are no clinical studies of its effectiveness. By comparison, there are a number of basic scientific studies on animals which show that applying ice after muscle injury has a consistent effect on a number of important cellular and physiological events relating to recovery. Some of these effects may be temperature dependant; most animal studies induce significant reductions in muscle temperature at the injury site. The aim of this short report was to consider the cooling magnitudes likely in human models of muscle injury and to discuss its relevance to the clinical setting. Current best evidence shows that muscle temperature reductions in humans are moderate in comparison to most animal models, limiting direct translation to the clinical setting. Further important clinical questions arise when we consider the heterogenous nature of muscle injury in terms of injury type, depth and insulating adipose thickness. Contrary to current practice, it is unlikely that a 'panacea' cooling dose or duration exists in the clinical setting. Clinicians should consider that in extreme circumstances of muscle strain (eg, deep injury with high levels of adipose thickness around the injury site), the clinical effectiveness of cooling may be significantly reduced. PMID- 21677318 TI - Hamstring strain injuries: are we heading in the right direction? PMID- 21677319 TI - [Correlation of suicide and antidepressant prescriptions (N06A) by gender and age groups in Hungary and Bacs-Kiskun County between 1999-2006]. AB - INTRODUCTION: The author examines and determines the effect of antidepressant prescription and consumption on suicides by gender and age group in Hungary and Bacs-Kiskun County. Despite the significant decrease in the number of suicides both in Hungary and Bacs-Kiskun County since 1984, the figure is still very high. Behind the generally decreasing statistical figures, between 2007 and 2009 the number of suicide victims increased by 0.5%, and the number of male suicide victims increased by 2.2% in Hungary. There are several new hypotheses to explain the decrease, among which the most controversial is the one looking for connections between the decreasing number of suicide victims and the increasing consumption of antidepressants (N06A). METHODS: The connections between suicides and the consumption of antidepressants was examined and analyzed in the population in 1999-2006, in Hungary and Bacs-Kiskun County on the basis of the data of the Hungarian Central Statistical Office and National Health Insurance Company. Four indicators were used in the analysis of antidepressant consumption and suicides: 1. The number of patients using antidepressants. 2. The days of treatment: DOT. 3. The amount of the selected antidepressant. 4. DHD: DDD/1000 inhabitant/day. (DDD: Defined daily dose by the WHO). The connections were identified with correlation coefficients. RESULTS: The results of the analysis supported the hypothesis that in spite of some contradictions there is a connection between the increase in antidepressant use and the decrease in the number of suicides. The increased use of antidepressants is one of the factors contributing to the decrease of suicides. CONCLUSION: Although the complex diagnostics and treatment of depression will lead to the decrease of the risk of suicide in depressed patients, there is an underlying question to be explained in future research: considering the fact that depressive disorders can be treated, why this cannot lead to a more intense decrease in the number of suicides. In future suicide prevention programs higher attention must be paid to high risk populations, especially depressed patients. PMID- 21677320 TI - Psychometric properties of the Hungarian version of the original and the short form of the Positive and Negative Affect Schedule (PANAS). AB - AIM: Psychometric properties of the Hungarian version of the original and the short form of the Positive and Negative Affect Schedule (PANAS) were investigated in the present study. METHODS: Participants were undergraduate university students (N=1163) and patients visiting their General Practitioners (GPs) for various somatic complaints (N=466). RESULTS: According to the confirmatory factor analysis, both versions showed adequate fit to the theoretical one-and-one (positive and negative affect) factor model. Internal consistency coefficients (Cronbach-alpha values) were above .8 for the original positive and negative scales, .73 and .79 for the short positive scale, and .65 and .67 for the short negative scale in the student and the patient groups, respectively. The correlations between the original 10-item subscales and their 5-item counterparts were above .9 in both groups. CONCLUSION: The short PANAS scale represents a good and practical alternative for the original version, with lower but still acceptable internal consistency values. PMID- 21677321 TI - [Effect of dopaminergic and serotonergic gene variants on cognitive performance]. AB - According to twin studies heritability of cognitive skills is substantial, however, little is known about the gene variants responsible for coding individual variability. Results of candidate gene studies implicate an important role of the dopaminergic system in coding individual differences in reaction time performance, and the possible role of the function of the serotonergic system has also emerged. GOALS: The aim of our study was to carry out association analyses between performance on the Stroop-task and selected gene polymorphisms of the dopaminergic and serotonergic system. RESULTS: In this study we examined 179 young adult's Stroop-performance measuring the attentional inhibition. The number of mistakes showed remarkable individual variability which can be related to the polymorphisms of the dopamine D4 receptor gene according to several previous studies. The short and long variations of the variable number tandem repeat polymorphism in the promoter region of the serotonin transporter gene was also studied based on the hypothesis of dopamine-serotonin balance. CONCLUSION: Our results demonstrate that the performance in the Stroop task is related to the genetic variants of the dopaminergic, as well as the serotonergic system. PMID- 21677322 TI - [Change in platelet aggregation and ATP secretion: is there an early prediction of antidepressive therapy? (preliminary report)]. AB - The number of biomarkers has increased to a great extent in the last years, but we have no marker in practice to help in the diagnosis of depression or to estimate the effectiveness of therapy. In depression we can measure the activation and aggregation of platelets, and the parallel secretion of ATP. Antidepressive therapy decreases aggregation and leads to changes in the release of ATP as well. The aim of our study was to determine whether the change in ATP release in early stages can predict the effectiveness of antidepressive treatment. PMID- 21677323 TI - Candidate gene studies of dopaminergic and serotonergic polymorphisms. AB - The most researched candidate genes of psychiatric genetic association studies are the components of the monoamine neurotransmitter systems, out of which serotonin and dopamine transmitter systems gained particular attention due to their major role in regulating emotional functions and cognitive processes. The paper reviews association studies focusing on the polymorphisms of receptors, transporters and enzymes that belong to these two transmitter systems. Numerous studies demonstrated significant associations between serotonergic and dopaminergic polymorphisms and diagnostic categories, personality traits and cognitive functions, however, results of monoamine gene variants and psychological properties are often contradictory. The contradictions can partially be explained with relatively small sample sizes of earlier studies, heterogeneity of methods across the studies and our expanding knowledge of the function of polymorphisms. On the whole, however, it can be declared that psychogenetic research plays an important role in the development of personalized pharmacotherapy. PMID- 21677324 TI - Prodrugs and active metabolites among antidepressive compounds. AB - Clinical effect of drugs is influenced by the composition of the pharmaceutical preparation but substantially by the fate of the drug in the body. Metabolism of the xenobiotic drug compounds may result in pharmacologically inactive metabolites, however, metabolites with higher pharmacological activity can also be produced. These active metabolites may have different pharmacokinetic properties than the parent drug. Co-existence of the parent drug and the active metabolite in the body may significantly modify the therapeutic effect. Knowledge based system of pharmacokinetics and metabolism of the drugs has a high impact in understanding both the pharmacokinetic and the pharmacodynamic interactions. Cytochrome P450 isoenzymes taking part in the metabolic activity of the central nervous system is a developing area in metabolic studies. In the present study CYP isoenzymes with significant activity in the brain and the clinically important pharmacokinetic and metabolic data of antidepressive compounds are summarized. PMID- 21677326 TI - Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications. AB - Herb induced liver injury (HILI) is a particular challenge that also applies to purported cases presumably caused by black cohosh (BC), an herb commonly used to treat menopausal symptoms. We analyzed and reviewed all published case reports and spontaneous reports of initially alleged BC hepatotoxicity regarding quality of case details and causality assessments. Shortcomings of data quality were more evident in spontaneous reports of regulatory agencies compared to published case reports, but assessments with the scale of CIOMS (Council for the International Organizations of Sciences) or its updated version revealed lack of causality for BC in all cases. The applied causality methods are structured, quantitative, and liver specific with clear preference over an ad hoc causality method or the liver unspecific Naranjo scale. Reviewing the case data and the reports dealing with quality specifications of herbal BC products, there is general lack of analysis with respect to authentication of BC in the BC products used by the patients. However, in one single regulatory study, there was a problem of BC authentication in the analysed BC products, and other reports addressed the question of impurities and adulterants in a few BC products. It is concluded that the use of BC may not exert an overt hepatotoxicity risk, but quality problems in a few BC products were evident that require additional regulatory quality specifications. PMID- 21677327 TI - Is pre-treatment liver biopsy necessary for all hepatitis C genotypes? AB - BACKGROUND: Current practice guidelines recommend liver biopsy prior to treatment of hepatitis C genotype-1 but not for genotype-2/3; this is based on expert opinion, not on published evidence. METHODS: In retrospective analysis of a large trial database prior to the publication of recent guidelines, we compared outcomes in 985 treatment-naive patients with hepatitis C who did or did not undergo liver biopsy before starting peginterferon alfa-2a plus ribavirin. RESULTS: Physicians elected to treat 141/654 (21.6%) genotype-1 patients and 126/331 (38.1%) genotype-2/3 patients without liver biopsy. There were no differences in baseline characteristics among those with or without pre-treatment liver biopsy, except for female preponderance in genotype-1 patients with liver biopsy. The sustained viral response (SVR) rate was no different amongst genotype 2/3 patients who had a biopsy before treatment with 66.3% SVR vs. 69.8% of those treated without biopsy (p = 0.546), but significantly higher among genotype-1 patients with pre-treatment liver biopsy at 54.6 vs. 44.0% for those treated without a liver biopsy (p = 0.029). In genotype-1 patients with liver biopsy, more patients with cirrhosis had dose adjustments (p = 0.0057) rather than drug discontinuation. There was tendency for earlier discontinuation among patients without pre-treatment liver biopsy. CONCLUSIONS: Pre-treatment liver biopsy was associated with better SVR amongst genotype-1 patients. This improvement may reflect ongoing commitment to completing the treatment course by both patient and physician. In genotype-2/3 patients, pre-treatment liver biopsy may not be essential to maximize SVR rates. This study validates the recommendations of the most recent treatment guidelines for hepatitis C. PMID- 21677328 TI - Sirolimus may be associated with early recurrence of biliary obstruction in liver transplant patients undergoing endoscopic stenting of biliary strictures. AB - INTRODUCTION: Recurrent biliary obstruction necessitating premature repeat endoscopic retrograde pancreatography (ERCP) remains a costly and morbid problem in patients undergoing treatment of post-orthotopic liver transplantation (OLT) biliary strictures. We evaluated the relationship between prednisone or sirolimus use and early recurrence of biliary obstruction given their negative effects on collagen production and cholangiocyte regeneration. METHODS: Medical records of adult patients who underwent OLT from 1998-2008 and developed anastomotic (ABS) and/or nonanastomotic (NABS) biliary strictures requiring endoscopic plastic stent therapy were reviewed. Outcome was early recurrence of biliary obstruction requiring repeat ERCP. Univariate and multivariable logistic regression analysis, adjusting for age, sex, and time from OLT to ERCP, were performed. RESULTS: 35 patients with ABS and 9 patients with NABS underwent a total of 157 ERCPs. Median patient age was 56 years, 68% were male, and hepatitis C was the most common OLT indication (52%). Early recurrence of biliary obstruction ocurred following 17.1% of ERCPs. In univariate analysis, neither prednisone nor sirolimus was associated with early recurrence of biliary obstruction. In multivariate analysis, however, sirolimus use was associated with increased incidence of early recurrent biliary obstruction (OR = 2.53; 95% CI: 0.77-8.32; p = 0.12); this was more pronounced at doses > 3 (OR = 4.27; 95% CI: 0.62-29.3; p = 0.14) than at <= 3 mg/day (OR = 2.24; 95% CI: 0.62-8.13; p = 0.22) and statistically significant in patients with ABS only (OR = 1.44 per mg increase in sirolimus dose; 95% CI 1.02-2.03; p = 0.037). CONCLUSIONS: Sirolimus use, particularly at higher doses and patients with ABS, may be associated with an increased risk of early recurrence of biliary obstruction requiring repeat ERCP for post-OLT biliary strictures. Additional studies are needed to further investigate these findings and elucidate other risk factors. PMID- 21677329 TI - Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. AB - INTRODUCTION: The burden of non-alcoholic steatohepatitis (NASH) is growing and current pharmacologic treatments are limited by side effects and inconsistent efficacy. Pilot studies suggest that pentoxifylline (PTX) can reduce liver injury in patients with NASH. OBJECTIVE: We sought to determine the tolerability of PTX and its effect on aminotransferases and liver histology in patients with NASH. MATERIAL AND METHODS: Thirty patients with biopsy proven NASH were randomized in a 2:1 fashion to receive 1,200 mg PTX or placebo for 12 months. Metabolic parameters, aminotransferases, liver histology and hepatic gene expression changes were compared. RESULTS: At baseline the groups were similar. Adverse events were mild, most frequently headache and abdominal cramps, and did not differ between groups (p = NS). After 12 months, ALT and AST decreased from 92 +/ 12 IU/L to 67 +/- 13 IU/L and 67 +/- 6 IU/L to 47 +/- 6 IU/L (p < 0.05), respectively in patients treated with PTX. No significant effect was seen with placebo. Steatosis and cellular ballooning improved in the PTX group (p < 0.05), whereas no histological feature of steatohepatitis improved with placebo. However, between groups comparison of both biochemical and histological features were nonsignificant. CONCLUSION: Pentoxifylline is safe, well tolerated and improves transaminases and histology in patients with NASH when compared to baseline and may be a reasonable therapeutic modality for the treatment of NASH. However PTX failed to reduce transaminases compared to placebo and did not positively affect any of the metabolic markers postulated to contribute to NASH. Although animal data and small pilot studies in humans have suggested that PTX may be effective as a treatment for NASH, translating this therapy to clinical practice may prove challenging. PMID- 21677330 TI - Nonvariceal upper gastrointestinal bleeding in patients with liver cirrhosis. Clinical features, outcomes and predictors of in-hospital mortality. A prospective study. AB - BACKGROUND: Clinical and endoscopic features of cirrhotic patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) have been rarely reported and clinical outcomes and predictors of mortality have not been evaluated. AIMS: 1) To describe the clinical features; 2) To define the clinical outcomes; and 3) To identify the predictors of in-hospital mortality of cirrhotic patients with NVUGIB. METHODS: One hundred sixty cirrhotic patients with NVUGIB were prospectively studied. Clinical features, endoscopic findings, clinical outcomes and in-hospital mortality rate were studied. Predictors of death were identified by means of univariate and multiple logistic regression analysis. RESULTS: The mean age was 56.5 +/- 14.4, male gender prevailed. Alcohol was the most frequent etiology. Hemodynamic instability was reported in 29.4%. Mean serum hemoglobin was 9.5 +/- 3.3 g/dL and blood transfusions were required in 59.4%. Gastroduodenal ulcers were the most frequent source of bleeding (50.6%). In endoscopy "high-risk" bleeding stigmata (HRBS) at the ulcer base were found in 53.1%. All patients with HRBS received endoscopic treatment. Rebleeding occurred in 3 patients (1.9%) and mortality was of 13.8%. By univariate analysis: Cryptogenic etiology, BUN, hypoalbuminemia, active bleeding at ulcer base, and endoscopic treatment were predictors of mortality. However, only cryptogenic etiology, hypoalbuminemia and active bleeding at ulcer base were independent predictors of death in multivariate analysis. CONCLUSIONS: Gastroduodenal ulcers as a source of NVUGIB are frequent in cirrhotic patients. They were severe; half of them had HRBS, and required frequently endoscopic treatment. In-hospital mortality of these patients seemed to be greater than that of non-cirrhotic patients, and it was significantly related to cryptogenic etiology of cirrhosis, renal dysfunction, severe hepatic failure, and active bleeding ulcers on admission to the hospital. PMID- 21677331 TI - Diagnostic significance of plasma osteopontin in hepatitis C virus-related hepatocellular carcinoma. AB - BACKGROUND AND AIM: Outcome of hepatocellular carcinoma (HCC) depends mainly on its early diagnosis. The performance of traditional biomarkers is not satisfactory. Osteopontin (OPN) is of potential importance. This study aim to assess the diagnostic value of plasma OPN compared with alpha-fetoprotein (AFP) for the diagnosis of HCV- related HCC. METHODS: We recruited 113 HCC patients compared with 120 matched cirrhotic patients and 120 Controls. The plasma level of OPN and serum AFP for all participants were assessed. RESULTS: The median plasma OPN level was significantly higher in the HCC group than in the cirrhotic patient group or in the normal control group (p-value < 0.001), while OPN levels were not differed significantly in correlation with the degree of liver function deterioration in terms of advanced Child-Pugh class (p-value < 0.9). The diagnostic efficacy of OPN were superior to AFP in terms of AUC, sensitivity, specificity, PPV and NPV either in diagnosis of early or late stages of HCC (0.88 vs. 0.56; P = 0.0001, 0.991vs. 0.899; p = 0.01; respectively). CONCLUSION: Plasma OPN level is a potential diagnostic marker for HCC, especially among high-risk group of patients. These values extend beyond the traditional tumor biomarkers as AFP, as it possesses good prognostic value. PMID- 21677332 TI - Is gallbladder cancer decreasing in view of increasing laparoscopic cholecystectomy? AB - BACKGROUND: Gallstone disease affects over 20 million people in the U.S. and is a major risk factor for gallbladder cancer (GBC). In 1988, a less invasive, low cost procedure, laparoscopic cholecystectomy (LC), was introduced and became the standard of care for management of gallstones. METHODS: GBC incidence (1973-2007) and mortality rates (1969-2006) were calculated using SEER Program data. LC rates (1993-2008) were obtained from NAMCS, NHAMCS, and HCUP. Annual percent change was estimated by gender, age, and race, and the statistical significance was assessed at p < 0.05. Correlation analysis was performed on GBC and LC trends. RESULTS: Since the early 1970s, GBC incidence and mortality rate have declined. Women and older age groups continue to have the highest risk for GBC, despite having greater declines. Incidence significantly decreased among whites, but did not among blacks. The number of inpatient LC procedures increased by 15% between 1994 and 2008; however, inpatient and outpatient LC rates remained stable. LC rate was not significantly correlated with either GBC incidence or mortality. CONCLUSIONS: The decline in incidence and mortality of GBC began decades before the introduction of LC and apparently has stabilized in the past decade. No temporal relationship existed between LC rate and the incidence and mortality rates of GBC. Our study suggests that prevention of a rare tumor may be extremely difficult if the surgical removal of a risk factor is involved. PMID- 21677333 TI - Hepatitis B virus infection has no significant role on lymphoproliferative disorders post liver transplantation: PTLD. int survey. AB - INTRODUCTION: Based on very limited data, it has been recently suggested that hepatitis B virus infection can play significant roles in post transplantation lymphoproliferative disorders. In the current study pooling data of PTLD in HBV positive liver recipients gathered from the existing literature, we sought to analyze and compare characteristics, behavior and prognosis of PTLD arising in HBV positive liver graft recipients. METHODS: A comprehensive search for the available data though PubMed and Google Scholar for reports of PTLD and HBV infection in liver recipients was conducted. Data of 18 different studies were pooled and analyzed. RESULTS: Liver recipients with HBV positive-PTLD were comparable to their HBV negative counterparts in gender, age at transplantation, time from transplantation to PTLD development, lymphoma cell type, histopathology of lesions, remission episodes, mortality rate, multi-organ involvement, and disseminated PTLD (p > 0.1 for all). HBV positive PTLD patients were significantly less likely to complicate spleen (0 vs. 23%, respectively; p = 0.015). Survival of the two patient groups were comparable (p = 0.8). CONCLUSION: HBV infection has no significant impact on inducing some distinct types of PTLD and represents no survival effect in PTLD setting. Future prospective studies are needed for confirming our findings. PMID- 21677334 TI - Anatomical cardiac alterations in liver cirrhosis: an autopsy study. AB - BACKGROUND: It has been suggested that liver cirrhosis (LC), regardless of etiology, may be associated with anatomical cardiac alterations. OBJECTIVE: To describe the frequency and type of macroscopical anatomic cardiac abnormalities present in alcoholic and non-alcoholic cirrhotic patients in an autopsy series. MATERIAL AND METHODS: The autopsy records performed at our institution during a 12-year period (1990-2002) were reviewed. All cases with final diagnosis of LC were included, their demographic characteristics as well as cirrhosis etiology and macroscopic anatomical cardiac abnormalities (MACA) analyzed. Patients with any known history of heart disease prior to diagnosis of cirrhosis were excluded. RESULTS: A total of 1,176 autopsies were performed, of which 135 cases (11.5%) were patients with LC. Two patients with cardiac cirrhosis were excluded. Chronic alcohol abuse (29%) and chronic hepatitis due to hepatitis C virus (HCV) infection (20%) were the most common causes of cirrhosis. The etiology was not identified in 35% of the cases, even after exhaustive clinical, serological and/or radiological assessment. In the postmortem analysis, 43% of the cases were informed to have MACA (47% in the group of patients with alcoholic cirrhosis and 41% in other types of cirrhosis); this rate increased to 62% in patients with ascites. The most frequent alterations were cardiomegaly and left ventricular hypertrophy (LVH). CONCLUSION: The results confirm the high frequency of cardiac abnormalities in patients with cirrhosis, regardless of cirrhosis etiology. PMID- 21677335 TI - Novel cytochrome P450-2D6 promoter sequence variations in hepatitis C positive and negative subjects. AB - INTRODUCTION: CYP2D6 is a liver enzyme that metabolizes more that 25% of drugs and thus may play a pivotal role in drug-drug interactions. The promoter sequences of cytochrome P450 2D6 (CYP2D6) gene could impact metabolic activity. METHODS: We analyzed genetic variations in the promoter sequence of CYP2D6 gene for 71 hepatitis C negative and 15 hepatitis C positive subjects. RESULTS: We found two novel genetic variants -1822A->G; -1740C->T, only in two patients with hepatitis C. Also, two linked new promoter sequence variations at -2060 G->A and 2053 T->G nucleotide positions that present in both hepatitis C negative and positive subjects are identified. The -2060 and -2053 variations are confirmed to be in linkage disequilibrium. The individuals with -2060A/A, and -2053G/G variation appeared to be associated with significantly lower levels of liver CYP2D6 mRNA. Analysis of CYP2D6 enzymatic activity in *1/*1 (wild type) subjects revealed that hepatitis C positive subjects expressed about 2.6-fold lower activity (24.0 +/- 1.5 vs. 62.6 +/- 3.7 pmol/min/mg; p = 0.0061) relative to hepatitis C negative. CONCLUSION: These data suggest that promoter variations 1822A->G and -1740C->T are present only in hepatitis C infected subjects. Hepatitis C positive individuals were associated with a lower liver CYP2D6 enzyme activity. PMID- 21677336 TI - Hepatoprotective effect of stem of Musa sapientum Linn in rats intoxicated with carbon tetrachloride. AB - METHODS: The study was designed to evaluate the hepatoprotective activity of aqueous extract of central stem of Musa sapientum (AqMS) against carbon tetrachloride induced hepatotoxicity in rats. Animals were divided into six groups. Group I served as normal control. Group II, III, IV, V & VI were administered CCl(4) mixed with olive oil 1:1 (1.5 mL/kg) I.P., twice a week for 5 weeks. Group II was maintained as CCl(4) intoxicated control. Group III, IV and V received AqMS at a dose of 25, 50 and 100 mg/kg. Group VI received silymarin 100 mg/kg for 5 weeks orally once daily. Marker enzymes of hepatic functions estimated in serum were AST, ALT and ALP. Antioxidant parameters estimated were MDA and GSH in blood and liver and SOD in blood, after fifth week, animals were sacrificed, livers dissected out and evaluated for histomorphological changes. RESULTS: There was significant rise in AST, ALT and ALP in CCl(4) intoxicated control group II. Treatment with AqMS prevented rise in levels of these enzymes. There was significant rise in MDA and fall in GSH in blood and liver in group II, indicating increased lipid peroxidation and oxidative stress upon CCl(4) administration. Treatment with AqMS prevented rise in MDA & increased GSH in treated group. SOD levels were decreased in group II while groups treated with AqMS showed significant rise (p < 0.05). Maximum hepatoprotective effect was observed with 50 mg/kg dose. Hepatoprotective effect observed with this dose was comparable to standard hepatoprotective drug silymarin. The results of pathological study also support the results of biochemical findings. CONCLUSION: the results of the present study indicate that stem of Musa sapientum possess hepatoprotective effect and probably it is due to it's antioxidant property. PMID- 21677337 TI - Prophylactic and curative effects of purslane on bile duct ligation-induced hepatic fibrosis in albino rats. AB - INTRODUCTION: Hepatic fibrosis is a common pathological process of chronic liver injury. Oxidative stress and inflammation may have prognostic value in disease progression. OBJECTIVE: To examine the implication of both aforementioned factors in hepatic fibrosis progression and whether, the antioxidant effect of various biological active constituents such as phenolic, flavonoids and fatty acids of purslane hydro-ethanolic extract can represent a potential target for therapy. METHODS: Purslane exhibited a considerable antioxidant potential in DPPH assay compared to alpha-tocopherol. Consequently, the current study was designed to examine the prophylactic and curative effects of purslane extract on bile duct ligation (BDL)-induced liver fibrosis in rats in comparison with silymarin as a reference hepatoprotective agent. Purslane (400 mg/kg/day) or silymarin (50 mg/kg/day) were administered orally for 4 weeks, immediately after surgery in order to evaluate the prophylactic effect and for 3 weeks starting 3 weeks after BDL in order to evaluate the curative effect. BDL significantly increased liver enzymes, total bilirubin (TB) and tumor necrosis factor-alpha (TNF-alpha) in serum along with malondialdehyde (MDA) in liver tissues. RESULTS: Significant decrease in hepatic antioxidant defense system was noted in BDL-rats. Conversely, administration of purslane reversed all these biochemical parameters which were previously induced by BDL. Considerably, purslane effect was more pronounced in the prophylactic study than that in the curative one. CONCLUSION: The present work suggested that purslane had prophylactic and curative value on cholestasis induced liver fibrosis through inhibition of oxidative stress, decreasing the expression of profibrogenic cytokines, collagenolytic activity and activation of hepatic stellate cells. PMID- 21677338 TI - Hepatic endometriosis. PMID- 21677339 TI - Trans-arterial (90)yttrium radioembolization for patients with unresectable tumors originating from the biliary tree. AB - Patients with malignant tumors originating from the biliary tree have a poor prognosis, since only a minority of tumors can be resected and most palliative regimens have shown only limited success. We present two patients with unresectable tumors, who were treated with trans-arterial (90)yttrium radioembolization: a patient with an infiltrating gallbladder carcinoma and a patient with an extensive intrahepatic cholangiocarcinoma. In both cases the treatment was technically feasible, effective in controlling tumor growth, and without significant side effects. In conclusion, the presented cases demonstrate the potential of (90)yttrium radioembolization as a palliative treatment option for malignant tumors of the biliary tree. PMID- 21677340 TI - Course of a HBsAg positive liver transplantation in a hepatitis B and D virus coinfected recipient. AB - The increasing demand for transplantation has led to consideration of liver grafts from donors exposed to hepatitis B virus (HBV). Six transplantations of liver grafts from hepatitis B surface antigen (HBsAg) positive donors have been reported; two recipients suffered from HBV/HDV (hepatitis Delta virus) coinfection and were followed up for 10-12 months. Here, we report a 56 months follow-up of a HBV/HDV-coinfected recipient of a HBsAg positive liver graft. Posttransplant combination prophylaxis consisted of hepatitis immunoglobulin, lamivudine and adefovir dipivoxil. HBsAg remained positive during stable posttransplant follow-up and subclinical HDV reinfection with low replication rate was detected at 1 month. Pegylated interferon therapy was introduced after documentation of histological evidence of mild chronic hepatitis, but without virological response after 48 weeks. Finally, antiviral treatment was switched to tenofovir disoproxil fumarate. More than 50 months posttransplant the recipient revealed clinical symptoms of decompensated liver cirrhosis and has been relisted for liver transplantation. In conclusion HBsAg positive liver grafts in HBsAg positive recipients with HDV coinfection may result in virological recurrence and rapid development of liver cirrhosis. PMID- 21677341 TI - Operational tolerance after liver transplantation, more common than we think: a case report. AB - Operational tolerance after liver transplantation has been described in around 20% of the recipients. These patients are able to maintain a normal graft function in the absence of immunosuppressive drugs, thus being free of adverse effects that are common and frequently severe. Here we present a well-documented case of operational tolerance after liver transplantation and discuss current concepts on this topic with emphasis on recent findings that will potentially allow for identifying graft-tolerant patients. PMID- 21677342 TI - Multiple venous and arterial thromboses of the gallbladder causing acute cholecystitis. A previously undescribed complication of essential thrombocythemia. AB - Well established complications of essential thrombocythemia are multiple thrombohemorrhagic phenomena in various abdominal organs. We describe the case of a 22 year old man with essential thrombocythemia and thrombosis of the mesenteric and splenic veins as well as cavernomatous transformation of the portal vein. The patient also had a splenic infarction and a subphrenic hematoma. Additionally, he developed signs and symptoms of acute cholecystitis which in turn led to an open cholecystectomy. The gallbladder had a markedly thickened wall due to multiple recent and recanalized thrombi predominantly in subserosal veins. Only a few arteries were occluded by thrombi. A marked vascular proliferation in the subserosal connective tissue mimicking a hemangioma was most likely the result of collateral circulation. There was also a mild acute and chronic inflammatory infiltrate and edema in the lamina propria of the gallbladder. Hyperplasia of interstitial cells of Cajal in the lamina propria and between smooth muscle cells and proliferation of nerve trunks in the subserosal connective tissue adjacent to the thrombosed veins and arteries was also noted. To our knowledge this unique gallbladder thrombotic complication of essential thrombocythemia has not been previously reported. PMID- 21677343 TI - Salmonella enteritidis liver abscess. PMID- 21677344 TI - Tenofovir as a first line option for prophylaxis in a patient with hepatitis B virus associated nephrotic syndrome. PMID- 21677345 TI - Clathrin heavy chain (CHC) staining for the diagnosis of small hepatocellular carcinoma. PMID- 21677346 TI - [The brain and cytokines - the mutual origin of depression, obesity and cardiovascular diseases?]. AB - Accumulating evidence points to a pivotal role of the brain in the regulation of the circulatory system and energy balance. It has also been found that common civilization diseases such as depression, obesity, hypertension, myocardial infarction or heart failure are accompanied by an increase in concentration of inflammatory mediators in the blood, cerebrospinal fluid and various tissues. Recent studies have revealed that inflammatory mediators that are synthesized peripherally or in the brain may affect the nervous regulation of animal body systems. For example, it has been found that non-specific pro-inflammatory stimuli as well as treatment with several cytokines may cause depressive behavior, disturbances in energy balance and alterations in the circulatory system. On the other hand, knockout of genes for pro-inflammatory cytokines or administration of anti-inflammatory mediators may normalize the pathological changes. In the present manuscript we will review studies that imply the common neuroinflammatory pathogenesis of cardiovascular diseases, depression and energy balance disorders. PMID- 21677347 TI - [Acridines as antitumor drugs]. AB - Acridines belong to a group of polycyclic heteroaromatic compounds and exhibit a broad spectrum of biological activity including antiprotozoal, antibacterial, antiviral and antitumor activity. Acridine derivatives with antitumor activity have different mechanisms of action at the molecular level. The data obtained so far indicate that one of the main steps is the formation of physico-chemical complexes with DNA. Among acridine derivatives with anticancer activity we can distinguish five main classes of compounds: nitroacridines, 9-anilinoacridines, pyrazoloacridines, imidazoacridines, and triazoloacridines. Compounds from different classes differ both in mechanism of action and spectrum of antitumor activity. PMID- 21677348 TI - [The role of hepatic lipid accumulation in the development of insulin resistance in the liver]. AB - Insulin resistance (IR) is commonly defined as a lack of insulin effects on target tissues, due to impaired post-receptor signaling pathways. Generally, liver IR is manifested by uncontrolled glucose release to the blood stream (hyperglycemia). However, metabolic consequences of hepatic insulin resistance are more profound, involving also lipid imbalances. Accumulation of intracellular lipids such as diacylglycerols (DAG) and ceramides (CER) was found to interfere directly with the insulin signaling cascade, inducing hepatic IR. Molecular targets of elevated DAG and/ or CER levels include activation of protein kinase C (PKC) and/or protein phosphatase that dephosphorylates Akt/PKB. In either case as a result insulin resistance develops, enhancing hyperglycemia and subsequent hyperinsulinemia, which in turn aggravate liver lipogenesis and fatty acid accumulation. PMID- 21677349 TI - [The influence of hepatitis B virus polymorphism on the progression of chronic liver disease]. AB - Hepatitis B virus (HBV) infection is one of the major human health problems worldwide. It is estimated that chronic HBV infection affects more than 350 million people globally. It is one of the leading causes of liver cirrhosis and hepatocellular carcinoma. High genetic variability is a characteristic feature of HBV as the viral polymerase lacks proofreading activity. The nucleotide substitution rate for HBV is 10-fold higher than for other DNA viruses. Genetic variations of HBV influence the clinical outcome of HBV infection. There are eight genotypes of hepatitis B virus (A-H) that have a distinct geographical distribution. There is clinical significance of HBV genotype in terms of disease activity, risk of progression to cirrhosis, the development of hepatocellular carcinoma and response to antiviral treatments. Moreover, polymorphism in HBV viral polymerase influences the development of HBV mutants resistant to nucleotide analogue treatment that is a consequence of treatment failure. PMID- 21677350 TI - [Role of leptin in the regulation of lipid and carbohydrate metabolism]. AB - Leptin is a hormone secreted primarily by adipose tissue and its blood levels depend on the amount of fat stored in adipocytes. Leptin has a wide range of physiological effects. Acting directly or through the sympathetic nervous system it participates in the regulation of energy metabolism. Leptin inhibits synthesis of triacylglycerols in the liver, adipose tissue and skeletal muscles, thus reducing the intracellular lipid content in these tissues. In adipocytes, leptin down-regulates the expression of genes encoding fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), the major enzymes of fatty acid synthesis, while it up-regulates the expression of the hormone-sensitive lipase (HSL) encoding gene, thus stimulating hydrolysis of triacylglycerols in adipose tissue. Moreover, leptin enhances fatty acid oxidation in adipocytes, and skeletal and cardiac muscle by increasing the expression of genes encoding key enzymes involved in this process, carnitine palmitoyltransferase 1 (CPT1) and medium chain acyl-CoA dehydrogenase (MCAD). It has also been demonstrated that this hormone improves insulin sensitivity and glucose tolerance by stimulating glucose transport and metabolism in many tissues. It is known that leptin is involved in the long-term regulation of food intake. However, increasing evidence suggests that it may also influence energy substrate utilization in peripheral tissues. Therefore, leptin can effectively control whole-body energy homeostasis by altering lipid and carbohydrate metabolism, especially in adipose tissue and muscles. PMID- 21677352 TI - [The role of protein AS160/TBC1D4 in the transport of glucose into skeletal muscles]. AB - Skeletal muscle plays an essential role in the regulation of whole-body glucose homeostasis. Glucose is transported into the muscle cells via protein-mediated transport that requires sarcolemmal glucose transporters (GLUT). Translocation of GLUT-4 to the plasma membranes is the most potent factor stimulating glucose uptake by myocytes. Relocation of GLUT-4 from an intracellular pool(s) to the plasma membranes is activated by either insulin (associated with activation of kinase PI3K), or physical activity (associated with activation of kinase AMPK). Recent studies have shown that the signaling protein known as AS160 is involved in the directed GLUT-4 intramyocellular redistribution. AS160 protein appears to be activated by the insulin pathway as well as by AMPK. Moreover, in human skeletal muscles that are insulin-resistant, insulin-stimulated phosphorylation of AS160 is significantly impaired. Therefore, decreased insulin-induced AS160 phosphorylation that results in diminished GLUT-4 redistribution to the plasma membrane may play an important role in insulin resistance in vivo. PMID- 21677353 TI - [Metformin - mechanisms of action and use for the treatment of type 2 diabetes mellitus]. AB - Metformin is widely used for the treatment of type 2 diabetes mellitus. Although this biguanide derivative has been used for more than 50 years, its mechanism of action has not been fully elucidated. In this article we describe the latest achievements concerning the mechanisms of antihyperglycemic action of metformin. They include: decrease of glucose absorption in the small intestine, increase of glucose transport into cells, decrease in the plasma free fatty acid concentrations and inhibition of gluconeogenesis. Activation of AMP-activated protein kinase (AMPK) plays an important role in these processes. The latest discoveries have revealed mechanisms of anti-atherosclerotic, hypotensive and anticancer action of metformin and its impact on vein endothelial function. The pleiotropic actions of metformin include impact on plasma lipid profile, decrease of oxidative stress, and increase in plasma fibrinolytic activity. Although metformin is not metabolized, the latest research has shown that it is actively transported into hepatocytes and renal tubular epithelium, by OCT1 (organic cation transporter 1, encoded by the SLC22A1 gene) and OCT2 (organic cation transporter 2, encoded by the SLC22A2 gene), respectively. However, MATE1 transporter (multidrug and toxin extrusion 1 protein) is encoded by the SLC47A1 gene and facilitates metformin excretion from these cells into bile and urine. Metformin transporter gene polymorphisms may contribute to significant variation in drug response. Further studies of mechanisms of metformin action could contribute to its wider use for the prevention of type 2 diabetes mellitus, cancer, and Alzheimer's disease, and for the treatment of type 1 diabetes mellitus, and polycystic ovary syndrome (PCOS). PMID- 21677354 TI - [Epstein-Barr virus infection - life cycle, methods of diagnosis, associated diseases]. AB - Epstein-Barr virus (EBV) is a ubiquitous virus that infects about 90-95% of the adult population. EBV establishes life-long latent persistence. The virus is found to be the major cause of infectious mononucleosis but it has also been associated with development of endemic Burkitt's lymphoma. Result of EBV infection is the most common complication in patients after transplantation which is a post-transplant lymphoproliferative disease. Strong associations between EBV infection and Hodgkin's lymphoma, nasopharyngeal carcinoma, gastric carcinoma and carcinomas derived from smooth muscle tissue also exist. There is a hypothesis that there is an association between EBV infection and autoimmune and allergic diseases. EBV is a Herpesvirus family member; its genetic material has dsDNA form. There are two strains of EBV: A and B. The only host for EBV is human with target cells: B cells and epithelial cells. The life cycle of EBV consists of lytic and latent phases. In the latent phase three different patterns of gene expression are possible. Due to some circumstances EBV can undergo reactivation, which is an important issue in transplantology. The main methods of diagnosis of EBV infections are serological methods that detect certain specific antibodies and recently more popular molecular biological methods such as PCR or in situ hybridization. PMID- 21677355 TI - [Molecular recognition of viral infections - immune response stimulation]. AB - The mammalian immune system has evolved several mechanisms that allow bacterial and viral infections to be successfully fought. Animal cells are able to recognize viral infection and this recognition is dependent on the presence of intracellular sensors that instantly identify danger signals and initiate signal cascades leading to an effective antiviral response. Several host proteins have been identified as intracellular sensors, namely: Toll-like receptors, RIG-I-like receptors, AIM2-like receptors and DAI, DNA-dependent activator of IFN regulatory factor. They recognize and bind viral genomic nucleic acids and all their replicative intermediates. Receptor-ligand interaction leads to activation of specific metabolic pathways that include synthesis and release of type I interferons and proinflammatory cytokines. These mediators are in turn responsible for synchronizing mechanisms of innate and adaptive antiviral immunity. They are crucial for blocking viral replication, preventing the spread of infection and eventually eliminating the virus from the host. Signaling pathways dependent on RIG-I, independent of TLR and other viral ligand(s) identification mechanisms leading to antiviral immune response stimulation, are discussed in this review. PMID- 21677356 TI - [The role of docosahexaenoic acid in neuronal function]. AB - Docosahexaenoic acid (DHA, C22: 6n-3) is the most abundant polyunsaturated fatty acid in neuronal phospholipids, particularly in the cortex. The main source of DHA for neural cells is food, and hepatic and astroglia DHA synthesis from essential a-linolenic acid (C18: 3n-3). Accretion of DHA in the brain is most intensive during fetal life and the first two years of life. An adequate level of DHA in cell membranes is important for many functions of neural cells and this is presumably the reason for DHA saving in the adult mammalian brain during dietary a-linolenic acid deficiency. DHA-containing phospholipids in membranes are flexible and membranes possessing a high content of them are quite thin, more permeable to ions and small molecules, have looser lipid packing, and finally are more "dynamic" than membranes composed of other fatty acid containing phospholipids. Furthermore, these membranes create an appropriate environment for integral proteins highly condensed in neurons, such as receptors, ion channels, enzymes, and peripheral proteins. The quantity of phosphatidylserine in the inner membrane lipid layer depends on the availability of DHA to neurons. Phosphatidylserine promotes neuronal survival by translocation/activation of kinase Akt and Raf-1/MEK. DHA present in membrane phospholipids facilitates v SNARE/t-SNARE complex formation, which is necessary for fusion of synaptic vesicles and plasma membranes necessary for transmitter exocytosis, and neurite outgrowth-dependent plasticity. DHA plays an important neuroprotective role. DHA has been shown to inhibit PGE2 synthesis and COX-1 expression in astrocytes, and DHA derivatives, especially neuroprotectins D, can suppress inflammatory responses, preventing neuronal damage or apoptosis. The results of high DHA content in neuronal membranes and formation of DHA derivates, as well as the function of DHA-dependent phosphatidylserine, may explain the promising results supporting beneficial DHA supplementation in neurodegenerative diseases and improvement of brain function. PMID- 21677357 TI - [Yeast as a model for studying neurodegeneration]. AB - At the level of genetics and physiology the yeast Saccharomyces cerevisiae is are the best characterized eukaryotic cells. The yeast cells can be used as a model to study the mechanisms involved in human disease. Yeast shares conserved cellular mechanisms with all eukaryotes including mammals and human. Nowadays, despite the lack of a neural system, yeasts are successfully used in the study of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease and Parkinson's disease. Exquisite genetics and molecular tools used in biology allow examination of the role of yeast homologues of human genes as well as heterologous expression of human genes in yeast. Yeasts have become a suitable model to study the causes of pathological changes in protein folding, mutations and formation of aggregates. PMID- 21677358 TI - Glutamate NMDA receptors in pathophysiology and pharmacotherapy of selected nervous system diseases. AB - Glutamate is the basic excitatory neurotransmitter acting via N-methyl-D aspartate receptors (NMDARs). It co-regulates many important physiological functions, including learning, memory, and behaviour. An excess of glutamate, as well as NMDAR over-activity, produce pathological effects. Glutamate-related neurotoxicity is involved in the pathogenesis of many neurological conditions. This article briefly describes the role of the glutamate system in the pathophysiology of brain ischemia, selected neurodegenerative disorders, and schizophrenia. It also reviews the current and potential future status of agents targeting NMDARs in neuropsychopharmacology. PMID- 21677359 TI - [Congenital myopathies - skeletal muscle diseases related to disorder of actin filament structure and functions]. AB - Congenital myopathies are clinically and genetically heterogeneous disorders characterized by muscle structural abnormalities, muscle weakness and deformities. The clinical spectrum of the disease ranges from severe cases with early death to adult-onset cases with slow progression. In the skeletal muscle fibers, the specific structural changes are rod-shaped structures present in the sarcoplasm (nemaline myopathy - NM) or nuclei (intranuclear rod myopathy - IRM), cap-like structures peripherally located within muscle fibers (cap disease - CD), accumulations of actin filaments (actin myopathy - AM), changes in the fiber type proportion and size (congenital fiber type disproportion - CFTD), irregularity of Z-lines and abnormal localization of myofiber nuclei. Mutations in several genes encoding muscle proteins have been linked to congenital myopathy. These genes include a-skeletal actin (ACTA1), tropomyosin (TPM2 and TPM3), troponin (TNNT1) and nebulin (NEB). In vitro and in vivo studies show that mutations identified within these genes have varying impacts on thin filament protein structure, which affect polymerization and stabilization of actin filament, actin cellular localization and regulation of actin-myosin activity. Many lines of evidence suggest that mutated proteins have "toxic" effects. Unfortunately, there is no existing simple correlation between the degree of protein disruption, muscle pathologies and disease severity. PMID- 21677360 TI - Effects of isoflurane anesthesia on the cardiovascular function of the C57BL/6 mouse. AB - Isoflurane (ISO) is the most commonly used inhalational anesthetic for experimental interventions in mice and is preferred for imaging technologies that require the mouse to remain anesthetized for relatively long time periods. This study compares the stability of mean arterial pressure (MAP), heart rate (HR), and body temperature under ISO concentrations of 1%, 1.5%, and 2% (volume-to volume, v/v) for up to 90 minutes postinduction. At all three levels of anesthesia, we examined evoked physiological responses to fractional inspiratory ratio variations of oxygen (FiO2) and nitrous oxide (N2O). In addition, we determined the hemodynamic effects of anesthesia on pH, glucose, insulin, glucocorticoids, and partial pressure of oxygen and of carbon dioxide in the blood (paO2, paCO2). The results indicate that the most appropriate ISO dose level was 1.5% v/v, yielding stable MAP and HR values comparable to those observed in the animal's conscious state, with a minute-to-minute variability in MAP and HR of .11%. Based on such recordings, the optimal FiO2 appeared to be 50%. The additional use of N2O was associated with higher and more stable values of MAP and HR. Arterial pH values were within the physiological range and varied between 7.20 and 7.43. ISO anesthesia at 1.5% v/v was also associated with mild hyperglycemia (+47%), whereas insulin levels and corticosteroids remained unaltered. We conclude that the application of isoflurane as an inhalational anesthetic in the mouse can be optimized to attain stable hemodynamics by administering it at 1.5% v/v and by supplementing it with N2O. PMID- 21677361 TI - Heat shock proteins and cancer therapy: the trail grows hotter! PMID- 21677362 TI - Is nanomedicine still promising? PMID- 21677363 TI - Predicting EEG complexity from sleep macro and microstructure. AB - This work investigates the relation between the complexity of electroencephalography (EEG) signal, as measured by fractal dimension (FD), and normal sleep structure in terms of its macrostructure and microstructure. Sleep features are defined, encoding sleep stage and cyclic alternating pattern (CAP) related information, both in short and long term. The relevance of each sleep feature to the EEG FD is investigated, and the most informative ones are depicted. In order to quantitatively assess the relation between sleep characteristics and EEG dynamics, a modeling approach is proposed which employs subsets of the sleep macrostructure and microstructure features as input variables and predicts EEG FD based on these features of sleep micro/macrostructure. Different sleep feature sets are investigated along with linear and nonlinear models. Findings suggest that the EEG FD time series is best predicted by a nonlinear support vector machine (SVM) model, employing both sleep stage/transitions and CAP features at different time scales depending on the EEG activation subtype. This combination of features suggests that short-term and long-term history of macro and micro sleep events interact in a complex manner toward generating the dynamics of sleep. PMID- 21677364 TI - A retunable surface coil for high field 31P and 1H magnetic resonance evaluations of the living mouse leg. AB - This study presents a retunable surface coil that can be adjusted to at least two Larmor frequencies sequentially without the need to remove the coil from the magnet and while avoiding interference between channels. A prototype (1)H/(31)P surface coil for the analysis of the in vivo mouse leg under electrical stimulation was designed for operation at 11.75 T. The coil has a high-quality factor of over 100 for both operational frequencies. To demonstrate the capabilities of this simple design, in vivo experiments were conducted to acquire high-resolution (1)H images and (31)P spectra of the C57BL/6 mouse leg, both with high temporal resolution. Proton diffusion tensor imaging was also performed to evaluate rodent skeletal muscle architecture. This design makes the acquisition of physiological data about both muscle structure and energetics (PCr, ATP and Pi) possible in a single experimental session. PMID- 21677365 TI - An integral test of FLUKA nuclear models with 160 MeV proton beams in multi-layer Faraday cups. AB - Monte Carlo (MC) codes are useful tools to simulate the complex processes of proton beam interactions with matter. In proton therapy, nuclear reactions influence the dose distribution. Therefore, the validation of nuclear models adopted in MC codes is a critical requisite for their use in this field. A simple integral test can be performed using a multi-layer Faraday cup (MLFC). This method allows separation of the nuclear and atomic interaction processes, which are responsible for secondary particle emission and the finite primary proton range, respectively. In this work, the propagation of 160 MeV protons stopping in two MLFCs made of polyethylene and copper has been simulated by the FLUKA MC code. The calculations have been performed with and without secondary electron emission and transport, as well as charge sharing in the dielectric layers. Previous results with other codes neglected those two effects. The impact of this approximation has been investigated and found to be relevant only in the proximity of the Bragg peak. Longitudinal charge distributions computed with FLUKA with both approaches have been compared with experimental data from the literature. Moreover, the contribution of different processes to the measurable signal has been addressed. A thorough analysis of the results has demonstrated that the nuclear and electromagnetic models of FLUKA reproduce the two sets of experimental data reasonably well. PMID- 21677366 TI - Monitoring proton radiation therapy with in-room PET imaging. AB - We used a mobile positron emission tomography (PET) scanner positioned within the proton therapy treatment room to study the feasibility of proton range verification with an in-room, stand-alone PET system, and compared with off-line equivalent studies. Two subjects with adenoid cystic carcinoma were enrolled into a pilot study in which in-room PET scans were acquired in list-mode after a routine fractionated treatment session. The list-mode PET data were reconstructed with different time schemes to generate in-room short, in-room long and off-line equivalent (by skipping coincidences from the first 15 min during the list-mode reconstruction) PET images for comparison in activity distribution patterns. A phantom study was followed to evaluate the accuracy of range verification for different reconstruction time schemes quantitatively. The in-room PET has a higher sensitivity compared to the off-line modality so that the PET acquisition time can be greatly reduced from 30 to <5 min. Features in deep-site, soft-tissue regions were better retained with in-room short PET acquisitions because of the collection of (15)O component and lower biological washout. For soft tissue equivalent material, the distal fall-off edge of an in-room short acquisition is deeper compared to an off-line equivalent scan, indicating a better coverage of the high-dose end of the beam. In-room PET is a promising low cost, high sensitivity modality for the in vivo verification of proton therapy. Better accuracy in Monte Carlo predictions, especially for biological decay modeling, is necessary. PMID- 21677367 TI - Online detector response calculations for high-resolution PET image reconstruction. AB - Positron emission tomography systems are best described by a linear shift-varying model. However, image reconstruction often assumes simplified shift-invariant models to the detriment of image quality and quantitative accuracy. We investigated a shift-varying model of the geometrical system response based on an analytical formulation. The model was incorporated within a list-mode, fully 3D iterative reconstruction process in which the system response coefficients are calculated online on a graphics processing unit (GPU). The implementation requires less than 512 Mb of GPU memory and can process two million events per minute (forward and backprojection). For small detector volume elements, the analytical model compared well to reference calculations. Images reconstructed with the shift-varying model achieved higher quality and quantitative accuracy than those that used a simpler shift-invariant model. For an 8 mm sphere in a warm background, the contrast recovery was 95.8% for the shift-varying model versus 85.9% for the shift-invariant model. In addition, the spatial resolution was more uniform across the field-of-view: for an array of 1.75 mm hot spheres in air, the variation in reconstructed sphere size was 0.5 mm RMS for the shift invariant model, compared to 0.07 mm RMS for the shift-varying model. PMID- 21677368 TI - The refractive index of human hemoglobin in the visible range. AB - Because the refractive index of hemoglobin in the visible range is sensitive to the hemoglobin concentration, optical investigations of hemoglobin are important for medical diagnostics and treatment. Direct measurements of the refractive index are, however, challenging; few such measurements have previously been reported, especially in a wide wavelength range. We directly measured the refractive index of human deoxygenated and oxygenated hemoglobin for nine wavelengths between 400 and 700 nm for the hemoglobin concentrations up to 140 g l(-1). This paper analyzes the results and suggests a set of model functions to calculate the refractive index depending on the concentration. At all wavelengths, the measured values of the refractive index depended on the concentration linearly. Analyzing the slope of the lines, we determined the specific refraction increments, derived a set of model functions for the refractive index depending on the concentration, and compared our results with those available in the literature. Based on the model functions, we further calculated the refractive index at the physiological concentration within the erythrocytes of 320 g l(-1). The results can be used to calculate the refractive index in the visible range for arbitrary concentrations provided that the refractive indices depend on the concentration linearly. PMID- 21677370 TI - Patterned nanoporous gold as an effective SERS template. AB - We demonstrate large area two-dimensional arrays of patterned nanoporous gold for use as easy-to-fabricate, cost-effective, and stable surface enhanced Raman scattering (SERS) templates. Using a simple one-step direct imprinting process, subwavelength nanoporous gold (NPG) gratings are defined by densifying appropriate regions of a NPG film. Both the densified NPG and the two-dimensional grating pattern are shown to contribute to the SERS enhancement. The resulting substrates exhibit uniform SERS enhancement factors of at least 10(7) for a monolayer of adsorbed benzenethiol molecules. PMID- 21677371 TI - ZnO nanorod array/CuAlO2 nanofiber heterojunction on Ni substrate: synthesis and photoelectrochemical properties. AB - A novel ZnO nanorod array (NR)/CuAlO(2) nanofiber (NF) heterojunction nanostructure was grown on a substrate of Ni plates using sol-gel synthesis for the NFs and hydrothermal reaction for the NRs. Compared with a traditional ZnO/CuAlO(2) laminar film nanostructure, the photocurrent of this fibrous network heterojunction is significantly increased. A significant blue-shift of the absorption edge and a favorable forward current to reverse current ratio at applied voltages of -2 to +2 V were observed in this heterojunction with the increase of Zn(2+) ion concentration in the hydrothermal reaction. Furthermore, the photoelectrochemical properties were investigated and the highest photocurrent of 3.1 mA cm(-2) was obtained under AM 1.5 illumination with 100 mW cm(-2) light intensity at 0.71 V (versus Ag/AgCl). This novel 3D fibrous network nanostructure plays an important role in the optoelectronic field and can be extended to other binary or ternary oxide compositions for various applications. PMID- 21677369 TI - A cortical neural prosthesis for restoring and enhancing memory. AB - A primary objective in developing a neural prosthesis is to replace neural circuitry in the brain that no longer functions appropriately. Such a goal requires artificial reconstruction of neuron-to-neuron connections in a way that can be recognized by the remaining normal circuitry, and that promotes appropriate interaction. In this study, the application of a specially designed neural prosthesis using a multi-input/multi-output (MIMO) nonlinear model is demonstrated by using trains of electrical stimulation pulses to substitute for MIMO model derived ensemble firing patterns. Ensembles of CA3 and CA1 hippocampal neurons, recorded from rats performing a delayed-nonmatch-to-sample (DNMS) memory task, exhibited successful encoding of trial-specific sample lever information in the form of different spatiotemporal firing patterns. MIMO patterns, identified online and in real-time, were employed within a closed-loop behavioral paradigm. Results showed that the model was able to predict successful performance on the same trial. Also, MIMO model-derived patterns, delivered as electrical stimulation to the same electrodes, improved performance under normal testing conditions and, more importantly, were capable of recovering performance when delivered to animals with ensemble hippocampal activity compromised by pharmacologic blockade of synaptic transmission. These integrated experimental modeling studies show for the first time that, with sufficient information about the neural coding of memories, a neural prosthesis capable of real-time diagnosis and manipulation of the encoding process can restore and even enhance cognitive, mnemonic processes. PMID- 21677372 TI - Scanning gate microscopy on graphene: charge inhomogeneity and extrinsic doping. AB - We have performed scanning gate microscopy (SGM) on graphene field effect transistors (GFET) using a biased metallic nanowire coated with a dielectric layer as a contact mode tip and local top gate. Electrical transport through graphene at various back gate voltages is monitored as a function of tip voltage and tip position. Near the Dirac point, the response of graphene resistance to the tip voltage shows significant variation with tip position, and SGM imaging displays mesoscopic domains of electron-doped and hole-doped regions. Our measurements reveal substantial spatial fluctuation in the carrier density in graphene due to extrinsic local doping from sources such as metal contacts, graphene edges, structural defects and resist residues. Our scanning gate measurements also demonstrate graphene's excellent capability to sense the local electric field and charges. PMID- 21677373 TI - Thermoelectric properties of individual single-crystalline PbTe nanowires grown by a vapor transport method. AB - We report the thermoelectric performance of individual PbTe nanowires with sizes ranging from 76 to 436 nm grown from a vapor transport method that synthesizes high-quality, single-crystalline PbTe nanowires. Independent measurements of temperature-dependent Seebeck coefficient (S), thermal conductivity (kappa) and electrical conductivity (sigma) of individual PbTe nanowires were investigated. By varying the nanowire size, the simultaneous increase and decrease of S (-130 uV K(-1)) and kappa (1.2 W m(-1) K(-1)), respectively, are achieved at room temperature. Our results demonstrate the enhanced thermoelectric properties of individual single-crystalline PbTe nanowires, compared to that of bulk PbTe, and can provide guidelines for future work on nanostructured thermoelectrics based on PbTe. PMID- 21677374 TI - Breath analysis system based on phase-shifting interferometric microscopy readout of microcantilever arrays. AB - Microcantilever (MC) sensors can provide ultrasensitive bio-chemical detection. Monitoring the bending response of large arrays of MC sensors coated with a library of receptors will produce a characteristic 'breath-print' corresponding to the breath composition; this promises to be suitable for non-invasive medical diagnostics. While MC arrays with hundreds of individual sensors can be produced readily, conventional MC readout methods are not suitable for the parallel readout of tens or hundreds of individual sensors. We have developed a MC sensor array readout method based on phase-shifting interferometric microscopy (PSIM) which allows for the simultaneous monitoring of the response of all MCs within the field of view of the readout microscope optics. Based on this sensor technology, we have built an exhaled breath-analysis research instrument for the Point of Care Diagnostics Development Unit at the University of Leicester, UK. In this paper, we describe the PSIM readout system and the breath-analysis instrument that will be used to test sensor surface coatings and develop sensor sets with response patterns suitable for clear correlation to patients' health condition. PMID- 21677375 TI - Abnormal tau phosphorylation in the thorny excrescences of CA3 hippocampal neurons in patients with Alzheimer's disease. AB - A key symptom in the early stages of Alzheimer's disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients. PMID- 21677376 TI - GLT-1 loss accelerates cognitive deficit onset in an Alzheimer's disease animal model. AB - Glutamate transporters regulate normal synaptic network interactions and prevent neurotoxicity by rapidly clearing extracellular glutamate. GLT-1, the dominant glutamate transporter in the cerebral cortex and hippocampus, is significantly reduced in Alzheimer's disease (AD). However, the role GLT-1 loss plays in the cognitive dysfunction and pathology of AD is unknown. To determine the significance of GLT-1 dysfunction on AD-related pathological processes, mice lacking one allele for GLT-1(+/-) were crossed with transgenic mice expressing mutations of the amyloid-beta protein precursor and presenilin-1 (AbetaPPswe/PS1DeltaE9) and investigated at 6 or 9 months of age. Partial loss of GLT-1 unmasked spatial memory deficits in 6-month-old mice expressing AbetaPPswe/PS1DeltaE9, with these mice also exhibiting an increase in the ratio of detergent-insoluble Abeta42/Abeta40. At 9 months both behavioral performance and insoluble Abeta42/Abeta40 ratios among GLT-1(+/+)/AbetaPPswe/PS1DeltaE9 and GLT-1(+/-)/AbetaPPswe/PS1DeltaE9 mice were comparable. These results suggest that deficits in glutamate transporter function compound the effects of familial AD AbetaPP/PS1 mutant transgenes in younger animals and thus may contribute to early occurring pathogenic processes associated with AD. PMID- 21677377 TI - Potentiation of tau aggregation by cdk5 and GSK3beta. AB - Hyperphosphorylation of tau is closely associated with its aggregation by as yet undefined mechanisms. We attempted herein to further investigate the interrelationships between tau aggregation and phosphorylation by inhibition and activation of cdk5 and GSK3beta in cells expressing normal tau and a mutant form of tau (3PO-tau), which generates intracellular aggregates while retaining microtubule-binding capacity). Aggregates were routinely observed in cells expressing 3PO-tau, but never in cells expressing normal tau, whether or not cdk5 or GSK3beta was overexpressed. In addition, in cells expressing 3PO-tau, both the percentage of cells with aggregates, as well as the size of aggregates, was increased following overexpression of cdk5 or GSK3beta, decreased following treatment with pharmacological agents (roscovitine and lithium) active against these kinases, and increased following treatment with the phosphatase inhibitor okadaic acid. These findings collectively indicate that phosphorylation potentiates aggregation in the presence of one or more key tau mutations. These findings confirm and extend prior studies in which overexpression of the cdk5 activator p35, or GSK3beta, induced phosphorylation, mislocalization and/or aggregation of tau. PMID- 21677378 TI - Variability of the clinical phenotype in an Italian family with dementia associated with an intronic deletion in the GRN gene. AB - Mutations in the progranulin gene (GRN) were recently identified as an important cause of familial frontotemporal dementia (FTD). More than 60 pathogenic mutations have been reported up to now and prominent phenotypic variability within and among affected kindreds has been described. We have studied an Italian family with clinical evidence of dementia, and here we report detailed clinical records, imaging, sequential neurological examinations, cognitive assessments, and genetic analysis of three affected members of the same generation. Genetic analysis revealed the presence of the null mutation IVS6 + 5_8delGTGA in GRN, leading to haploinsufficiency, as documented by mRNA analysis. The mutation is associated with wide variation of the clinical phenotype, ranging from FTD to Alzheimer's disease and to a rapidly-progressive dementia. In summary, the patients of this kindred showed highly variable clinical features that do not have a close correspondence with the pattern of the cerebral atrophy. Our data extend the phenotypic spectrum and the complexity of neurodegenerative diseases linked to GRN mutations. PMID- 21677379 TI - BDNF gene polymorphisms are associated with Alzheimer's disease-related depression and antidepressant response. AB - Brain-derived neurotrophic factor (BDNF) is needed to support neuronal survival and differentiation. It also promotes synaptic remodeling and modulates the function of many other neurotransmitters. The current study examined potential association between single nucleotide polymorphisms (SNPs) of the BDNF gene (G11757 C, C270T, G196A, G-712A) and Alzheimer's disease-related depression (AD D). Participants included 336 patients with AD; 128 of these patients had AD-D. Response to 8-week paroxetine treatment was also assessed. The frequency of the 11757 C allele was significantly higher in AD-D than in the Alzheimer's disease without depression (AD-nD) patients (p = 0.003 after Bonferroni correction). The 196A allele occurred with significantly higher frequency in AD-D patients (p = 0.001 after Bonferroni correction versus AD-nD). Carriers of the A allele of G196A responded better to paroxetine treatment. These findings support an important role of BDNF polymorphism in AD-D. PMID- 21677380 TI - Anti-ATP synthase autoantibodies from patients with Alzheimer's disease reduce extracellular HDL level. AB - Aside from being an integral protein involved in the synthesis and hydrolysis of ATP, Ecto-F1-ATPase plays a role in cholesterol homeostasis. We demonstrated the presence of autoantibodies to ecto-F1-ATPase (ASabs) in sera and cerebrospinal fluids from patients with Alzheimer's disease (AD). Herein we show that ASabs, unlike irrelevant antibodies, can increase cellular uptake of HDL, a risk factor for the development of AD, via a mechanism involving the prototypical function of ecto-F1-ATPase: the generation of ADP due to the hydrolysis of ATP. Piceatannol, a specific inhibitor ecto-F1-ATPase, completely hindered these effects. We hypothesize that ASabs could exert a pathogenetic role in AD. PMID- 21677381 TI - Strategies for H-score normalization of preanalytical technical variables with potential utility to immunohistochemical-based biomarker quantitation in therapeutic response diagnostics. AB - Digital quantitative immunohistochemical analysis of protein biomarker expression offers a broad dynamic range against which clinical outcomes may be measured. Semi-quantitative expression data represented as an H-score is produced by computer generated average intensity of positive staining given weight by the percentage of cells showing positive staining. While patient H-scores vary for biological reasons, variation may also arise from preanalytic technical issues, such as differences in fixation protocols. In this study, we present data on two candidate calibrator nuclear-localized proteins, SNRPA and SnRNP70, with robust and consistent expression levels across breast cancers. Quantitative expression measurement of these two candidate biomarkers may potentially be used to eliminate the effect of differences in preanalytic processing of specimens by normalizing H-scores derived from test biomarkers of interest. To examine the effects of preanalytical fixation variation on biomarker quantitation and potential utility of candidate calibrators to address such issues, 6 surgically resected human breast cancer patient specimens were divided into 6 portions and fixed under distinct conditions (fixation following resection in formalin for 2 hr, 8 hr or 48 hr, or held overnight at 4 degrees C in buffered saline prior to formalin fixation for 2 hr, 8 hr, or 48 hr). We find H-score variation between fixation conditions within individual patient's tumors that were stained for XPF, ATM, BRCA1, pMK2 and PARP1. Most interestingly, detectable expression of SNRPA and SnRNP70 is covariant to test biomarkers under distinct fixation conditions and so these hold the potential for serving as calibration standards for general antigen preservation and reactivity. PMID- 21677382 TI - Mapping of shoot fly tolerance loci in sorghum using SSR markers. AB - Sorghum (Sorghum bicolor (L.) Moench) is one of the most important crops in the semiarid regions of the world. One of the important biotic constraints to sorghum production in India is the shoot fly which attacks sorghum at the seedling stage. Identification of the genomic regions containing quantitative trait loci (QTLs) for resistance to shoot fly and the linked markers can facilitate sorghum improvement programmes through marker-assisted selection. A simple sequence repeat (SSR) markerbased skeleton linkage map of two linkage groups of sorghum was constructed in a population of 135 recombinant inbred lines (RIL) derived from a cross between IS18551 (resistant to shoot fly) and 296B (susceptible to shoot fly). A total of 14 SSR markers, seven each on linkage groups A and C were mapped. Using data of different shoot fly resistance component traits, one QTL which is common for glossiness, oviposition and dead hearts was detected following composite interval mapping (CIM) on linkage group A. The phenotypic variation explained by this QTL ranged from 3.8%-6.3%. Besides the QTL detected by CIM, two more QTLs were detected following multi-trait composite interval mapping (MCIM), one each on linkage groups A and C for the combinations of traits which were correlated with each other. Results of the present study are novel as we could find out the QTLs governing more than one trait (pleiotropic QTLs). The identification of pleiotropic QTLs will help in improvement of more than one trait at a time with the help of the same linked markers. For all the QTLs, the resistant parent IS18551 contributed resistant alleles. PMID- 21677384 TI - Determination of genetic relationships among elite thermosensitive genic male sterile lines (TGMS) of rice (Oryza sativa L.) employing morphological and simple sequence repeat (SSR) markers. AB - A set of morphological traits and SSR markers were used to determine the genetic relationship among 12 elite thermosensitive genic male sterile (TGMS) lines developed at three different research institutions of India. Agro-morphological data recorded on 20 morphological traits revealed a wide base of genetic variation and a set of four morphological traits could distinguish most of the TGMS lines. Analysis with 30 SSR markers (20 EST-SSRs and 10 genomic SSRs) revealed 27 markers to be polymorphic, amplifying a total of 83 alleles. Each SSR marker amplified 2-6 alleles with an average of 2.76 alleles per marker and a PIC value varying from 0.54 to 0.96. Cluster analysis based on SSR and morphological data clearly differentiated the lines according to their source of origin. Correlation analysis between morphological and molecular data revealed a very poor association (r = 0.06), which could be attributed to selection pressure, genetic drift, sampling error and unknown relationship among related lines. The SSR markers discriminated the genotypes distinctly and quantified the genetic diversity precisely among the TGMS lines. Data on the yield per plant indicated that the genotypes grouping under a similar cluster showed same heterotic behaviour as compared to the genotypes from different clusters when crossed to similar pollinators. PMID- 21677383 TI - Correlations between genetic variance and adiposity measures, and gene x gene interactions for obesity in postmenopausal Vietnamese women. AB - Although environmental factors are important, there is considerable evidence that genes also have a significant role in the pathogenesis of obesity. We conducted a population-based study to investigate the relationship between candidate genes for obesity (UCP1, UCP2, ADRA2B, ADRB3, LEPR, VDR and ESR1) and adiposity measures (body mass index, body fat percentage, weight, waist circumference and waist-hip ratio) in terms of individual gene and gene x gene interaction in models unadjusted and adjusted for covariates (age, years since menopause, educational level and total energy intake). Postmenopausal women with TC genotype of ESR1 gene had higher body fat percentage than those with TT genotype in the models unadjusted and adjusted for the covariates (P = 0.006 in adjusted model). In multiple logistic regression analysis, BsmI and ApaI SNPs of VDR genes were significantly associated with overweight and obesity. The UCP2-VDR ApaI interaction to susceptibility of overweight and obesity was first observed from logistic regression analysis, and then confirmed in the multifactor dimensionality reduction method unadjusted and adjusted for the covariates. This interaction had 69.09% prediction accuracy for overweight and obesity (P = 0.001, sign test). In conclusion, the study suggests the significant association of ESR1 and VDR genes with adiposity measures and the UCP2-VDR ApaI interaction to susceptibility to being overweight and obesity in postmenopausal Vietnamese women. PMID- 21677385 TI - Cytotaxonomical analysis of Momordica L. (Cucurbitaceae) species of Indian occurrence. AB - Somatic chromosome number and detailed karyotype analysis were carried out in six Indian Momordica species viz. M. balsamina, M. charantia, M. cochinchinensis, M. dioica, M. sahyadrica and M. cymbalaria (syn. Luffa cymbalaria; a taxon of controversial taxonomic identity). The somatic chromosome number 2n = 22 was reconfirmed in monoecious species (M. balsamina and M. charantia). Out of four dioecious species, the chromosome number was reconfirmed in M. cochinchinensis (2n = 28), M. dioica (2n = 28) and M. subangulata subsp. renigera (2n = 56), while in M. sahyadrica (2n = 28) somatic chromosome number was reported for the first time. A new chromosome number of 2n = 18 was reported in M. cymbalaria against its previous reports of 2n = 16, 22. The karyotype analysis of all the species revealed significant numerical and structural variations of chromosomes. It was possible to distinguish chromosomes of M. cymbalaria from other Momordica species and also between monoecious and dioecious taxa of the genus. Morphology and crossability among the dioecious species was also studied. Evidence from morphology, crossability, pollen viability and chromosome synapsis suggests a segmental allopolyploid origin for M. subangulata subsp. renigera. The taxonomic status of the controversial taxon M. cymbalaria was also discussed using morphological, karyological and crossability data. PMID- 21677386 TI - Chromosome analysis of five Brazilian species of poison frogs (Anura: Dendrobatidae). AB - Dendrobatid frogs have undergone an extensive systematic reorganization based on recent molecular findings. The present work describes karyotypes of the Brazilian species Adelphobates castaneoticus, A. quinquevittatus, Ameerega picta, A. galactonotus and Dendrobates tinctorius which were compared to each other and with previously described related species. All karyotypes consisted of 2n = 18 chromosomes, except for A. picta which had 2n = 24. The karyotypes of the Adelphobates and D. tinctorius species were highly similar to each other and to the other 2n = 18 previously studied species, revealing conserved karyotypic characteristics in both genera. In recent phylogenetic studies, all Adelphobates species were grouped in a clade separated from the Dendrobates species. Thus, we hypothesized that their common karyotypic traits may have a distinct origin by chromosome rearrangements and mutations. In A. picta, with 2n = 24, chromosome features of pairs from 1 to 8 are shared with other previously karyotyped species within this genus. Hence, the A. picta data reinforced that the C-banding pattern and the NOR location are species-specific traits in the genus Ameerega. Moreover, the Ameerega monophyletism proposed by previous phylogenetic studies indicates that the karyotypic differences among species in this genus result from a long divergence time. PMID- 21677387 TI - Validation and dissection of quantitative trait loci for leaf traits in interval RM4923-RM402 on the short arm of rice chromosome 6. AB - Validation and dissection of a QTL region for leaf traits in rice which has been reported in a number of independent studies were conducted. Three sets of near isogenic lines (NILs) were originated from a residual heterozygous line derived the indica cross Zhenshan 97B/Milyang 46. They were overlapping and totally covered a 4.2-Mb heterogenous region extending from RM4923 to RM402 on the short arm of rice chromosome 6. Each NIL set consisted of 10 maternal lines and 10 paternal lines. They were measured for the length, width, perimeter and area of the top three leaves and the number of spikelets per panicle, number of grains per panicle and grain weight per panicle. In NIL sets 6-4 and 6-7, differing in intervals RM4923-RM225 and RM19410-RM6119, respectively, significant variations with the enhancing alleles from the female parent ZS97 were shown for the length, perimeter and area except for the area of the third leaf from top in 6-4, but the effects were lower in 6-4 than in 6-7. No significant effects were detected for the three traits in the remaining NIL set. It was shown that flag leaf length (FLL) is the primary target of the QTLs detected. Two QTLs for FLL linked in repulsion phase were resolved, of which qFLL6.2 located in the 1.19-Mb interval RM3414-RM6917 had a major effect with the enhancing allele from Zhenshan 97B, and qFLL6.1 located in the 946.8-kb interval RM19350-RM19410 had a smaller effect with the enhancing allele from Milyang 46. The two QTLs also exerted pleiotropic effects on the yield traits. PMID- 21677388 TI - Occurrence of differential meiotic associations and additional chromosomes in the embryo-sac mother cells of Allium roylei Stearn. AB - A small population of complex translocation heterozygote plants of Allium roylei from the Bani region of Jammu Province was studied for meiosis in the female track. This study resulted in identification of two variants, having embryo-sac mother cells (EMCs) with more than 16 chromosomes. EMCs of the remaining plants invariably had diploid (2n = 16) chromosome complement. Female meiosis, in general, was found to be abnormal, with nearly 23% and 11% chromosomes associating as quadrivalents or trivalents at prophase I and at metaphase I, respectively. This was followed by irregular segregation of chromosomes at anaphase I. Amongst the variants; one had 38% EMCs with eight bivalents plus two small sized chromosomes. Their small size, dispensable nature and tendency to affect the pairing behaviour of normal complement are some of the features that latter chromosomes share with the B chromosomes. Seventeen to nineteen chromosomes were observed in 35% EMCs of other variant; the remaining cells had 16 chromosomes. Chromosomal behaviour in both kind of cells (euploid and aneuploid) was more or less similar. Unlike female meiocytes, male meiocytes analysed earlier of this strain always had 16 chromosomes which paired to form extremely complex associations involving 3-16 chromosomes. The most likely cause of this asynchrony with regards to number of chromosomes involved in multivalent formation seems to be interaction of genes controlling chiasma formation with the different physiological conditions of male and female meiocytes. PMID- 21677389 TI - Estimating genetic correlations based on phenotypic data: a simulation-based method. AB - Knowledge of genetic correlations is essential to understand the joint evolution of traits through correlated responses to selection, a difficult and seldom, very precise task even with easy-to-breed species. Here, a simulation-based method to estimate genetic correlations and genetic covariances that relies only on phenotypic measurements is proposed. The method does not require any degree of relatedness in the sampled individuals. Extensive numerical results suggest that the propose method may provide relatively efficient estimates regardless of sample sizes and contributions from common environmental effects. PMID- 21677390 TI - Analysis of embryo, cytoplasmic and maternal genetic correlations for seven essential amino acids in rapeseed meal (Brassica napus L.). AB - Genetic correlations of nutrient quality traits including lysine, methionine, leucine, isoleucine, phenylalanine, valine and threonine contents in rapeseed meal were analysed by the genetic model for quantitative traits of diploid plants using a diallel design with nine parents of Brassica napus L. These results indicated that the genetic correlations of embryo, cytoplasm and/or maternal plant havemade different contribution to total genetic correlations of most pairwise nutrient quality traits. The genetic correlations among the amino acids in rapeseed meal were simultaneously controlled by genetic main correlations and genotype x environment (GE) interaction correlations, especially for the maternal dominance correlations. Most components of genetic main correlations and GE interaction correlations for the pairwise traits studied were significantly positive. Some of the pairwise traits had negative genetic correlations, especially between valine and other amino acid contents. Indirect selection for improving the quality traits of rapeseed meal could be expected in rape breeding according to the magnitude and direction of genetic correlation components. PMID- 21677391 TI - QTL mapping for test weight by using F(2:3) population in maize. AB - Test weight is an important trait in maize breeding. Understanding the genetic mechanism of test weight is important for effective selection of maize test weight improvement. In this study, quantitative trait loci (QTL) for maize test weight were identified. In the years 2007 and 2008, a F(2:3) population along with the parents Chang7-2 and Zheng58 were planted in Zhengzhou, People's Republic of China. Significant genotypic variation for maize test weight was observed in both years. Based on the genetic map containing 180 polymorphic SSR markers with an average linkage distance of 11.0 cM, QTL for maize test weight were analysed by mixed-model composite interval mapping. Five QTL, including four QTL with only additive effects, were identified on chromosomes 1, 2, 3, 4 and 5, and together explained 25.2% of the phenotypic variation. Seven pairs of epistatic interactions were also detected, involving 11 loci distributed on chromosomes 1, 2, 3, 4, 5 and 7, respectively, which totally contributed 18.2% of the phenotypic variation. However, no significant QTL x environment (QxE) interaction and epistasis x environment interaction effects were detected. The results showed that besides the additive QTL, epistatic interactions also formed an important genetic basis for test weight in maize. PMID- 21677392 TI - MicroRNA expression profiling in neurogenesis of adipose tissue-derived stem cells. AB - Adipose tissue-derived stem cells (ADSCs) are one population of adult stem cells that can self renew and differentiate into multiple lineages. Because of advantages in method and quantity of acquisition, ADSCs are gaining attention as an alternative source of bone marrow mesenchymal stem cells. In this study, we performed microRNA profiling of undifferentiated and of neurally-differentiated ADSCs to identify the responsible microRNAs in neurogenesis using this type of stem cell. MicroRNAs from four different donors were analysed by microarray. Compared to the undifferentiation control, we identified 39-101 microRNAs with more than two-fold higher expression and 3-9 microRNAs with two-fold lower expression. The identified microRNAs were further analysed in terms of gene ontology (GO) in relation with neurogenesis, based on their target mRNAs predicted by computational analysis. This study revealed the specific microRNAs involved in neurogenesis via microRNA microarray, and may provide the basic information for genetic induction of adult stem cell differentiation using microRNAs. PMID- 21677393 TI - Physical localization of NORs and ITS length variants in old Portuguese durum wheat cultivars. AB - The variation at the internal transcribed spacer (ITS) region of the ribosomal DNA has been correlated with the number of nucleolar organizer regions (NORs) in some plant species. Besides, the number of NORs might influence the rate of homogenization of the rDNA repeats. In recent studies, ITS length variants were detected in bread wheat cultivars but no reports about their presence in durum wheat were found. In the present study, we localized and identified the NORs of 51 old Portuguese durum wheat cultivars by using sequential silver staining and fluorescence in situ hybridization performed with the pTa71 rDNA probe. We also detected ITS length variants by PCR-RFLP. No variation at the number of Ag-NORs per metaphase was found among the 51 durum wheat cultivars, but the PCR-RFLP technique carried out with the restriction enzyme HpaII, allowed the detection of ITS length variants among them. The molecular data was used in order to establish the genetic relationships among cultivars and botanical varieties of durum wheat. The knowledge of this feature could be useful for future design of breeding strategies, involving this collection that constitutes an excellent repository of germplasm in Portugal. PMID- 21677394 TI - The first genetic map of pigeon pea based on diversity arrays technology (DArT) markers. AB - With an objective to develop a genetic map in pigeon pea (Cajanus spp.), a total of 554 diversity arrays technology (DArT) markers showed polymorphism in a pigeon pea F(2) mapping population of 72 progenies derived from an interspecific cross of ICP 28 (Cajanus cajan) and ICPW 94 (Cajanus scarabaeoides). Approximately 13% of markers did not conform to expected segregation ratio. The total number of DArT marker loci segregating in Mendelian manner was 405 with 73.1% (P > 0.001) of DArT markers having unique segregation patterns. Two groups of genetic maps were generated using DArT markers. While the maternal genetic linkage map had 122 unique DArT maternal marker loci, the paternal genetic linkage map has a total of 172 unique DArT paternal marker loci. The length of these two maps covered 270.0 cM and 451.6 cM, respectively. These are the first genetic linkage maps developed for pigeon pea, and this is the first report of genetic mapping in any grain legume using diversity arrays technology. PMID- 21677395 TI - Analysis of the heterochromatin of Cebus (Primates, Platyrrhini) by micro-FISH and banding pattern comparisons. AB - The karyotype of the neotropical primate genus Cebus (Platyrrhini: Cebidae), considered the most ancestral one, shows the greatest amount of heterochromatin described among Platyrrhini genera. Banding techniques and restriction enzyme digestion have previously revealed great variability of quantity and composition of heterochromatin in this genus. In this context, we use fluorescence in situ hybridization (FISH) to analyse this genomic region and discuss its possible role in the diversification of Cebus.We used a heterochromatin probe for chromosome 11 of Cebus libidinosus (11qHe+ CLI probe), obtained by chromosome microdissection. Twenty-six specimens belonging to the families Atelidae, Cebidae, Callitrichidae and Pithecidae (Platyrrhini) were studied. Fourteen out of 26 specimens were Cebus (Cebidae) individuals of C. libidinosus, C. xanthosternos, C. apella, C. nigritus, C. albifrons, C. kaapori and C. olivaceus. In Cebus specimens, we found 6 to 22 positive signals located in interstitial and telomeric positions along the different species. No hybridization signal was observed among the remaining Ceboidea species, thus reinforcing the idea of a Cebus-specific heterochromatin composed of a complex system of repetitive sequences. PMID- 21677396 TI - Deletion of NSD1 exon 14 in Sotos syndrome: first description. PMID- 21677397 TI - Variation in the PTEN-induced putative kinase 1 gene associated with the increase risk of type 2 diabetes in northern Chinese. PMID- 21677398 TI - Association of ATP-binding cassette transporter-A1 polymorphism with apolipoprotein AI level in Tehranian population. PMID- 21677399 TI - Determination of exon 7 SMN1 deletion in Iranian patients and heterozygous carriers by quantitative real-time PCR. PMID- 21677400 TI - Molecular cloning and variation of omega-gliadin genes from a somatic hybrid introgression line II-12 and parents (Triticum aestivum cv. Jinan 177 and Agropyron elongatum). PMID- 21677401 TI - Molecular identification of G6PD Chatham (G1003A) in Khuzestan province of Iran. PMID- 21677402 TI - Novel missense mutation (L1917P) involving sac-domain of NSD1 gene in a patient with Sotos syndrome. PMID- 21677403 TI - Association of CTLA4, CD28 and ICOS gene polymorphisms with clinicopathologic characteristics of childhood IgA nephropathy in Korean population. PMID- 21677404 TI - Cystinuria AA (B): digenic inheritance with three mutations in two cystinuria genes. PMID- 21677405 TI - Association of DDAH2 gene polymorphism with cardiovascular disease in Egyptian patients. PMID- 21677406 TI - Identification of possible genetic polymorphisms involved in cancer cachexia: a systematic review. AB - Cancer cachexia is a polygenic and complex syndrome. Genetic variations in regulation of the inflammatory response, muscle and fat metabolic pathways, and pathways in appetite regulation are likely to contribute to the susceptibility or resistance to developing cancer cachexia. A systematic search of Medline and EmBase databases, covering 1986-2008 was performed for potential candidate genes/genetic polymorphisms relating to cancer cachexia. Related genes were then identified using pathway functional analysis software. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Genes with variants which had functional or clinical associations with cachexia and replicated in at least one study were entered into pathway analysis software to reveal possible network associations between genes. A total of 184 polymorphisms with functional or clinical relevance to cancer cachexia were identified in 92 candidate genes. Of these, 42 polymorphisms (in 33 genes) were replicated in more than one study with 13 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Thirty-three genes were found to be significantly interconnected in two major networks with four genes (ADIPOQ, IL6, NFKB1 and TLR4) interlinking both networks. Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides an initial framework to select genes/polymorphisms for further study in cancer cachexia, and to develop their potential as susceptibility biomarkers of developing cachexia. PMID- 21677407 TI - Genetic polymorphism of serotonin transporter 5-HTTLPR: involvement in smoking behaviour. AB - Data suggest that the serotonin (5-hydroxytryptamine, 5-HT) system is implicated in the pathogenesis of multiple neuropsychiatric disorders and may also be involved in smoking behaviour since nicotine increases brain serotonin secretion. It is known that smoking behaviour is influenced by both genetic and environmental factors. The present review examines the role of the serotonin transporter gene (5-HTT) in smoking behaviour and investigating studies that showed association of 5-HTT gene with smoking. This study discusses a polymorphism which has been investigated by many researchers, as the bi-allelic insertion/deletion polymorphism in the 5'- flanking promoter region (5-HTTLPR). This gene has received considerable attention in attempts to understand the molecular determinants of smoking. Therefore, in the present study, the relationship between genetic polymorphism of serotonin transporter in smoking behaviour is reviewed considering the interactive effect of genetic factors. PMID- 21677408 TI - Genotyping of the k-casein and beta-lactoglobulin genes in Chinese Holstein, Jersey and water buffalo by PCR-RFLP. PMID- 21677409 TI - Identification and characterization of the pig ABIN-1 gene and investigation of its association with reproduction traits. PMID- 21677410 TI - Genetic diversity and population structure of the marbled rockfish, Sebastiscus marmoratus, revealed by SSR markers. PMID- 21677411 TI - Isolation of microsatellite loci in Akodon azarae (Muridae, Sigmodontinae) and cross-amplification in other Akodontini species. PMID- 21677412 TI - Characterization of 10 polymorphic microsatellite markers for Mediterranean blue mussel Mytilus galloprovincialis by EST database mining and cross-species amplification. PMID- 21677413 TI - Cross-species amplification of human microsatellite markers in pig-tailed and stump-tailed macaques. PMID- 21677415 TI - The positive correlation between cord serum retinol-binding protein 4 concentrations and fetal growth. AB - BACKGROUND/AIMS: Retinol-binding protein 4 (RBP4) has been shown to be associated with insulin resistance and fatty acid metabolism. We hypothesize that RBP4 might play a role in fetal growth and that cord serum RBP4 may act as a marker of fetal growth, independent of fetal insulin levels. METHODS: Twenty-one women having fetuses in the top quartile (>75th percentile) of birth weights for gestational age were enrolled into the trial, along with 21 women having fetuses in the bottom quartile (<25th percentile) of birth weights for gestational age. Serum RBP4 and insulin levels were analyzed. RESULTS: Cord serum RBP4 and insulin concentrations were significantly higher in the top quartile group (14.3 +/- 3.7 ng/ml, 3.8 +/- 5.2 MUIU/ml) than in the bottom quartile group (11.3 +/- 2.6 ng/ml, 0.9 +/- 1.4 MUIU/ml; p = 0.004, p = 0.017). Cord serum RBP4 and insulin as well as gestational age (r = 0.744, r(2) = 0.553, p < 0.001) were significantly correlated with fetal birth weights. CONCLUSION: Cord serum RBP4 concentrations were higher in subjects with top quartile fetuses than in those with bottom quartile fetuses. Cord serum RBP4 concentrations were significantly correlated with fetal birth weight. These findings may indicate that cord serum RBP4 plays a regulatory role in fetal growth. PMID- 21677414 TI - Regulation of aquaporins and sodium transporter proteins in the solitary kidney in response to partial ureteral obstruction in neonatal rats. AB - Unilateral ureteral obstruction (UUO) impairs function of the obstructed kidney, and the contralateral nonobstructed kidney compensates depending on the degree and duration of UUO. This study aimed to determine the hemodynamic and molecular changes in the solitary kidney in response to partial ureteral obstruction (PUO) where any compensation from the contralateral kidney was eliminated so that all observed changes in the kidney tissue occurred in the kidney with PUO. Newborn rats were subjected to unilateral left nephrectomy (UNX) within the first 48 h of life and a subset of UNX rats was subjected to severe PUO of the right kidney at day 14. Renal blood flow and whole kidney volume were measured with MRI at week 10. The renal protein abundance of aquaporin 1 (AQP1), AQP2 and AQP3 as well as Na,K-ATPase, NaPi-2 (type 2 sodium-phosphate cotransporter) and NHE3 (type 3 sodium-proton exchanger) were examined by immunoblotting and immunocytochemistry. At 10 weeks of age, the protein abundance of AQP2, AQP3, Na,K-ATPase, NaPi-2 and NHE3 were increased in response to PUO. In contrast, AQP1 expression was markedly decreased compared to sham-operated rats. These findings were confirmed by immunohistochemistry. GFR, urine osmolality and urine sodium excretion were reduced and kidney weight increased in response to PUO. In conclusion, the present study demonstrated major changes in the protein abundance of renal AQP1, AQP2 and AQP3 and sodium transporters in the solitary PUO kidney. These changes were paralleled by decreased urinary sodium excretion and a significant reduction in urinary osmolality from the obstructed kidney, suggesting a functional association between the molecular changes and the ability of the obstructed kidney to handle sodium and water in this solitary kidney model. PMID- 21677416 TI - Kidney transplant for autosomal dominant polycystic kidney disease: the superiority of concurrent bilateral nephrectomy. AB - OBJECTIVE: To assess the transplant outcome of patients who underwent concurrent bilateral nephrectomies (CBN) during kidney transplantation (KT) owing to autosomal dominant polycystic kidney disease (ADPKD). METHODS: The study included 67 ADPKD patients, 4 of whom were excluded, and the rest, 63 patients, were divided into two groups: KT with CBN (group A, n = 31) and KT without CBN (group B, n = 32). Demographic factors, transplant-related factors, posttransplant complications and patient survival were compared. RESULTS: There was no statistical difference in demographic or transplant-related factors between the two groups, though group A patients required more operation time (300 +/- 30.85 vs. 120 +/- 20.78 min, p < 0.01), needed more blood transfusion (4.31 +/- 1.05 vs. 1.35 +/- 0.23 U, p < 0.01) and had more adjacent organ injury during operation (22.58 vs. 0%, p < 0.01) compared with group B. However, group A patients had better relief from arterial hypertension persistence and lower urinary tract infection postoperation than group B (16/24 vs. 22/24, 6.45 vs. 31.25%, p < 0.05). Patient survival in the two groups was similar at 1 and 5 years (p > 0.05). CONCLUSION: CBN could be safely performed during KT for patients with ADPKD. The patients could benefit from reduction of the operative procedures, better relief from arterial hypertension persistence and lower urinary tract infection posttransplantation. PMID- 21677417 TI - Lack of association of the genotype in the GNAS Fok I polymorphism and prostate cancer. AB - BACKGROUND: G proteins are ubiquitously expressed signal transduction proteins playing a key role in multiple signal transduction pathways. The Galphas subunit has been considered as an apoptosis factor. In this study the role of GNAS T393C genotypes of the GNAS gene encoding Galphas was analyzed for its influence on the development and progression of prostate cancer. METHODS: Genotyping of the GNAS T393C polymorphism in 196 prostate cancer patients and 200 healthy controls was performed by DNA extraction followed by PCR and restriction analysis. RESULTS: We observed no evidence of effects related to GNAS T393C genotype as demonstrated by a comparison of the genotype distribution in prostate cancer patients and healthy controls, the genotype distribution dependent on grade of the primary diagnosis or data on clinical follow-up. CONCLUSIONS: In conclusion, this study did not demonstrate an association between the GNAS T393C genotype and prostate cancer though such a relationship has been described for other cancer entities. PMID- 21677418 TI - Impact of sleep position on stone clearance after shock wave lithotripsy in renal calculi. AB - OBJECTIVES: We evaluated the impact of sleep position on the effectiveness of shock wave lithotripsy (SWL) in renal calculi. PATIENTS AND METHODS: Patients (n = 120) with a single radiopaque renal stone who were candidates for SWL were enrolled. For studying patients' position during sleep, a novel sleep position recorder was designed. Group 1 (n = 60) consisted of patients who slept preferentially on the ipsilateral side of the stone; group 2 (n = 60) comprised patients who slept preferentially on the contralateral side. Treatment effectiveness was defined as the absence of residual stones >3 mm up to 3 months after SWL. RESULTS: The mean (range) percent of sleep on the ipsilateral side of the stone was 61.5% (51-78) and on the contralateral side it was 62.4% (51-81) in groups 1 and 2, respectively (p > 0.05). The overall success rate of SWL was 88.3% (77.4-95.2) and 70.0% (56.8-81.2) in groups 1 and 2, respectively (p = 0.01). Stone clearance increased with an increasing percent of total sleep time on the ipsilateral side of the kidney stone (p = 0.045). CONCLUSIONS: The percent of stone-free patients was higher in the group of patients who slept ipsilaterally relative to the kidney stone compared with patients who slept on the contralateral side. PMID- 21677419 TI - Ileocystoplasty in rats: metabolic, renal and enteropatch changes in a mid- and long-term follow-up. AB - INTRODUCTION: Bladder augmentation predisposes humans to many metabolic, renal and enteropatch changes. Our aim was to evaluate in a rat model of ileocystoplasty mid- and long-term urinary, metabolic, renal and graft changes. MATERIALS AND METHODS: We performed an ileocystoplasty and a sham operation in 30 rats. Seven augmented rats and 3 sham-operated animals were euthanized after 1, 3 and 6 months. We performed urinalysis, urine culture and blood sampling for serum electrolytes and urea. Histopathological changes of the ileal patch and kidneys were also evaluated. RESULTS: The urine cultures were positive in 14.3, 57 and 71%, respectively, 1, 3 and 6 months after surgery. Urinary pH, serum chloride and urea of the augmented group were significantly higher. Bladder calculi were formed in 23.8% of ileocystoplasty. Histopathological examination showed urothelialization of the graft with hyperplastic/metaplastic changes. The kidneys showed glomerular depletion and a marked distal tubular ectasia. CONCLUSIONS: Our data showed that, in a mid- and long-term follow-up, rat bladders subjected to ileocystoplasty displayed hyperchloremic metabolic acidosis, electrolyte imbalance, enhanced serum blood urea levels and glomerular/tubular changes. Hyperplastic and/or metaplastic changes at the junctional zone were observed. Our experimental results suggest that frequent monitoring of renal function and surveillance of humans who have undergone ileocystoplasty are recommended. PMID- 21677420 TI - Anaesthesia in transrectal prostate biopsy: which is the most effective technique? AB - BACKGROUND: Prostate biopsy (PBx) techniques have changed significantly since the original Hodge's scheme, with an increase in the number and location of cores. These improvements have been realized in part because of the introduction of different local anaesthesia techniques. We critically analysed the literature discussing the role of anaesthesia techniques for use during PBx to find which technique provides the best pain relief for the patient and safety for the urologist. METHODS: We performed a literature review by searching the Medline database for articles published between January 2000 and March 2010. Electronic searches were limited to the keywords 'transrectal prostate biopsy' and 'anaesthesia'. RESULTS: Pain and discomfort perceived during PBx are the result of different anatomic factors: the introduction to and movement of the transrectal ultrasound probe in the rectum and the needle piercing the rectum and the prostate capsule. The anaesthesia techniques currently available can be divided into two groups: local (i.e. intrarectal lubricant agents, periprostatic nerve blocks, caudal blocks, pudendal nerve blocks, and their different combinations) and systemic (i.e. oral/intravenous drug administration and sedoanalgesia). CONCLUSIONS: The most effective anaesthesia technique for transrectal PBx performed in outpatient settings is the periprostatic nerve blocks with 1 or 2% lidocaine 10 ml, which is associated with intrarectal lubricant agents, especially in younger people. Nevertheless, the current choice of the anaesthesia technique still depends both on patient characteristics (age, prostate size, number and location of cores, anxious personality, need for re biopsy) and, above all, the urologist's experience and habits. PMID- 21677421 TI - The honeybee antimicrobial peptide apidaecin differentially immunomodulates human macrophages, monocytes and dendritic cells. AB - We show that apidaecin binds to human macrophages, monocytes and dendritic cells, displaying different intracellular distributions and inducing diversified effects. An apidaecin-cell association was detectable at concentrations as low as 5 MUM and increased without saturation until 60 MUM, was receptor independent and required a physiological temperature (37 degrees C). For apidaecin, cytosolic localization was prevalent in macrophages and endosomal localization in monocytes, and associations with the plasma membrane were predominant in dendritic cells. Apidaecin upregulated T-lymphocyte co-stimulatory molecule CD80 and cytokine/chemokine production in macrophages, but not in monocytes and dendritic cells. Suboptimal stimulatory doses (5-10 MUM) of apidaecin partially inhibited the lipopolysaccharide (LPS)-induced increase in major histocompatibility complex class II (MHCII) and CD86 in macrophages, and the release of selected cytokines/chemokines by both macrophages [interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha] and monocytes [IL-6, TNF-alpha, basic fibroblast growth factor (FGF) and eotaxin]. Apidaecin had a double-edged effect: at low concentrations it partially antagonized LPS-stimulatory effects on both macrophages and monocytes while it stimulated pro-inflammatory and pro-immune functions of macrophages at higher concentrations. PMID- 21677422 TI - Pulmonary hypertension in idiopathic pulmonary fibrosis: a review. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive diffuse parenchymal disease with a poor prognosis. Pulmonary hypertension (PH) often complicates the course of IPF and may even be found in patients with preserved lung function. Possible pathogenetic mechanisms of PH in IPF include vascular destruction, pulmonary hypoxic vasoconstriction and vascular remodeling due to overexpression of cytokines and growth factors. PH in IPF patients is associated with decreased exercise capacity and a worse prognosis. Due to its prognostic significance, it seems important to investigate for PH in these patients. As the symptoms of PH in IPF are nonspecific, the development of PH in a patient with known IPF can be easily overlooked. Noninvasive methods provide clues for the diagnosis, but their sensitivity is limited. Doppler echocardiography is a useful tool for the detection of PH which also provides additional information regarding associated cardiac abnormalities. However, right heart catheterization remains the gold standard diagnostic test. Therapeutic options for PH in IPF are limited. Long term oxygen administration for the correction of hypoxemia should be recommended. The availability of new pharmacological agents in the treatment of PH has raised the possibility of therapy in patients with IPF and associated PH. Whether these PH-targeted therapies may be of benefit in this patient group, in terms of improving functional outcomes and survival, remains uncertain. PMID- 21677423 TI - Effects of somatostatin and octreotide on the interactions between neoplastic gastroenteropancreatic endocrine cells and endothelial cells: a comparison between in vitro and in vivo properties. AB - BACKGROUND/AIMS: Experimental studies in vitro suggest that somatostatin and some of its analogues used in clinical practice, such as octreotide, may have potent antiangiogenic properties. However, the clinical transposition of these data is difficult. METHODS: To address this issue, we designed a comparative study of the effects of somatostatin and octreotide on the interactions between neoplastic endocrine cells and endothelial cells in several in vitro and in vivo experimental models, including primary cultures of human umbilical vein endothelial cells (HUVEC), indirect cocultures between HUVEC and the somatostatin producing endocrine cell line STC-1, and an animal model of intrahepatic dissemination of STC-1 cells. RESULTS: 10(-8)M octreotide markedly inhibited both basal and VEGF-stimulated HUVEC proliferation, had no effect on endothelial cell migration, but inhibited endothelial tubule formation. HUVEC cocultured with the somatostatin- and VEGF-producing STC-1 cells presented a markedly decreased proliferation, a slightly increased motility and an increased capacity of tubule formation; in this system, the inhibition of endothelial cell proliferation was abolished by neutralizing anti-somatostatin but was restored in the presence of anti-VEGF antibodies. This suggests that somatostatin is able to antagonize the effects of VEGF on endothelial cell proliferation but not on endothelial cell sprouting. Finally, no significant effect of octreotide on tumor growth and intratumoral microvascular density was detected in an experimental model of intrahepatic dissemination of STC-1 cells. CONCLUSION: The in vitro antiangiogenic effects of somatostatin and its analogues are likely to be efficiently counterbalanced in the tumor microenvironment by the concomitant release of proangiogenic factors like VEGF. PMID- 21677425 TI - Altered phenotype of blood dendritic cells in patients with acute pneumonia. AB - BACKGROUND: Dendritic cells (DCs) play a key role in the host defence against inhaled pathogens. However, the phenotype of blood DCs in patients with acute respiratory infections is unknown. OBJECTIVE: To investigate the number and the expression of function-associated molecules of blood DCs in patients with acute infectious pneumonia. METHODS: Sixteen patients with acute pneumonia and 19 controls without pneumonia were included in the study. The number as well as the expression of function-associated molecules of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) were analysed in peripheral blood using four-colour flow cytometry. RESULTS: Elevated concentrations of procalcitonin (median: 0.55 ng/ml) and the rapid response to antibiotic treatment suggested a bacterial origin of the pneumonia in the patients. Total mDC (median: 27% of the controls) and pDC counts (median: 53% of the controls) were markedly reduced in patients with pneumonia, as compared to the controls. Percentages of blood mDCs, but not pDCs, were negatively correlated with serum concentrations of C-reactive protein. Patients with pneumonia were characterised by a significantly increased expression of Fc gamma receptors (CD32 and CD64) on mDCs and the Toll-like receptor 9 (TLR9) on pDCs. CONCLUSIONS: Circulating DCs are markedly reduced in patients with pneumonia, and characterised by an up-regulation of molecules recognising pathogen-associated molecular patterns and opsonised antigens. PMID- 21677424 TI - Brain transcriptomic response of threespine sticklebacks to cues of a predator. AB - Predation pressure represents a strong selective force that influences the development and evolution of living organisms. An increasing number of studies have shown that both environmental and social factors, including exposure to predators, substantially shape the structure and function of the brain. However, our knowledge about the molecular mechanisms underlying the response of the brain to environmental stimuli is limited. In this study, we used whole-genome comparative oligonucleotide microarrays to investigate the brain transcriptomic response to cues of a predator in the threespine stickleback, Gasterosteus aculeatus. We found that repeated exposure to olfactory, visual and tactile cues of a predator (rainbow trout, Oncorrhynchus mykiss) for 6 days resulted in subtle but significant transcriptomic changes in the brain of sticklebacks. Gene functional analysis and gene ontology enrichment revealed that the majority of the transcripts differentially expressed between the fish exposed to cues of a predator and the control group were related to antigen processing and presentation involving the major histocompatibility complex, transmission of synaptic signals, brain metabolic processes, gene regulation and visual perception. The top four identified pathways were synaptic long-term depression, RAN signaling, relaxin signaling and phototransduction. Our study demonstrates that exposure of sticklebacks to cues of a predator results in the activation of a wide range of biological and molecular processes and lays the foundation for future investigations on the molecular factors that modulate the function and evolution of the brain in response to stressors. PMID- 21677426 TI - Evolution of leptin structure and function. AB - Leptin, the protein product of the obese(ob or Lep) gene, is a hormone synthesized by adipocytes that signals available energy reserves to the brain, and thereby influences development, growth, metabolism and reproduction. In mammals, leptin functions as an adiposity signal: circulating leptin fluctuates in proportion to fat mass, and it acts on the hypothalamus to suppress food intake. Orthologs of mammalian Lep genes were recently isolated from several fish and two amphibian species, and here we report the identification of two Lep genes in a reptile, the lizard Anolis carolinensis. While vertebrate leptins show large divergence in their primary amino acid sequence, they form similar tertiary structures, and may have similar potencies when tested in vitro on heterologous leptin receptors (LepRs). Leptin binds to LepRs on the plasma membrane, activating several intracellular signaling pathways. Vertebrate LepRs signal via the Janus kinase (Jak) and signal transducer and activator of transcription (STAT) pathway. Three tyrosine residues located within the LepR cytoplasmic domain are phosphorylated by Jak2 and are required for activation of SH2 containing tyrosine phosphatase-2, STAT5 and STAT3 signaling. These tyrosines are conserved from fishes to mammals, demonstrating their critical role in signaling by the LepR. Leptin is anorexigenic in representatives of all vertebrate classes, suggesting that its role in energy balance is ancient and has been evolutionarily conserved. In addition to its integral role as a regulator of appetite and energy balance, leptin exerts pleiotropic actions in development, physiology and behavior. PMID- 21677427 TI - What is the safe and accurate procedure for thyroid nodules in childhood? PMID- 21677428 TI - Outpatient versus inpatient observation after percutaneous native kidney biopsy: a cost minimization study. AB - BACKGROUND/AIMS: Percutaneous kidney biopsy (PKB) is the primary diagnostic tool for kidney disease. Outpatient 'day surgery' (ODS) following PKB in low-risk patients has previously been described as a safe alternative to inpatient observation (IO). This study aims to determine if ODS is less costly compared to IO while accounting for all institutional costs (IC) associated with post-PKB complications, including death. METHODS: A cost minimization study was performed using decision analysis methodology which models relative costs in relation to outcome probabilities yielding an optimum decision. The potential outcomes included major complications (bleeding requiring blood transfusion or advanced intervention), minor complications (bleeding or pain requiring additional observation), and death. Probabilities were obtained from the published literature and a base case was selected. IC were obtained for all complications from institutional activity-based cost estimates. The base case assumed a complication rate of 10% with major bleeding occurring in 2.5% of patients (for both arms) and death in 0.1 and 0.15% of IO and ODS patients, respectively. RESULTS: ODS costs USD 1,394 per biopsy compared to USD 1,800 for IO inclusive of all complications. IC for ODS remain less when overall complications <20%, major complications <5.5%, and IC per death 500 umol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD. RESULTS: Women had significantly lower urate concentrations than did men [316.8 umol/l (SD 88.0) vs. 367.4 umol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 umol/l (OR 1.69, 95% CI 1.03-2.78) but not for urate >500 umol/l (OR 1.55, 95% CI 0.72-3.32) in men. A negative linear term was significant for urate <500 umol/l, and across the entire range a convex quadratic term was significant. CONCLUSIONS: Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk. PMID- 21677448 TI - Serum vitamins and heavy metals in blood and urine, and the correlations among them in Parkinson's disease patients in China. AB - BACKGROUND: Some heavy metals are suspected to be pathogenic and some vitamins protective against Parkinson's disease (PD), and the interaction between heavy metals and vitamins could be associated with the pathophysiology of PD. METHODS: Subjects comprised PD patients and sex- and age-matched controls recruited from an outpatient clinic in China. Morning blood and urine samples were used to measure concentrations of metals and vitamins. RESULTS: The serum iron, whole blood manganese, urine iron and copper levels were significantly higher in the PD patients than in the controls. The correlation coefficient between serum and urine concentrations of iron in the PD patients was significant. The serum vitamin E/urine copper ratio was significantly lower in the PD patients than in the controls. Serum vitamin E was negatively correlated with serum copper and was positively correlated with urine copper in the PD patients. Serum vitamin B(12) was positively correlated with serum zinc in the PD patients and was negatively correlated with urine zinc in the controls. CONCLUSIONS: Excessive intake of iron and copper, accumulation of manganese, vitamin E/copper imbalance in intake, and vitamin B(12) decrease by zinc deficiency in the body might be involved in the etiology of PD. PMID- 21677449 TI - Prevalence of dementia among elderly people living in Cotonou, an urban area of Benin (West Africa). AB - BACKGROUND/AIMS: The population of Benin is, like those of most developing countries, aging; dementia is therefore a major concern. Our goal was to estimate the prevalence of dementia in an elderly population living in urban Benin. METHODS: In a cross-sectional community-based study, people aged 65 years and above were screened using the Community Screening Interview for Dementia and the Five-Word Test. RESULTS: The prevalence of dementia was 3.7% (95% CI 2.6-4.8) overall. The figure increased with age and was higher among women than men. CONCLUSION: Dementia was slightly more prevalent than previously reported in a rural area of Benin, but the rate was similar to that recorded in other cities in developing countries. PMID- 21677450 TI - Increased brachial-ankle pulse wave velocity is independently associated with white matter hyperintensities. AB - BACKGROUND: White matter hyperintensities (WMHs) are a risk factor for stroke. Their etiology is considered to be cerebral microvascular abnormality. However, the association between WMHs and arteriosclerosis is not yet clear. The aim of this hospital-based cohort study was to identify the arteriosclerotic characteristics associated with WMHs. METHODS: We cross-sectionally included 240 consecutive patients with no history of stroke. We measured the brachial-ankle pulse wave velocity (baPWV), ankle brachial pressure index, and intima-media thickness of the common carotid artery, and we performed magnetic resonance brain imaging. WMHs were defined as periventricular hyperintensity (Fazekas grade >=3) and/or separate deep white matter hyperintense signals (Fazekas grade >=2). We determined the prevalence of WMHs, silent brain infarction (SBI), hypertension, hypercholesterolemia, diabetes mellitus, ischemic heart disease, and smoking. We compared 2 groups of patients, defined by the presence or absence of WMHs, using multiple logistic regression analyses. RESULTS: In multivariable analysis, SBI (OR 3.38; 95% CI 1.52-7.72), hypertension (OR 2.23; 95% CI 1.03-5.15), female sex (OR 1.95; 95% CI 1.03-3.76), baPWV (OR 1.12; 95% CI 1.02-1.23), and age (OR 1.09; 95% CI 1.04-1.14) were independently associated with WMHs. CONCLUSIONS: An increased baPWV is associated with WMHs. Management of increased baPWV may help to prevent the progression of WMHs and stroke. PMID- 21677451 TI - FOLFOX as adjuvant chemotherapy after curative resection of distant metastases in patients with colorectal cancer. AB - OBJECTIVES: The prophylactic effect of FOLFOX regimen, a standard regimen for unresectable colorectal cancer (CRC), was investigated in the adjuvant setting of CRC cases with distant metastases. METHODS: The study population included 116 CRC patients with synchronous metastases and 91 patients with metachronous metastases who had undergone curative operation in our hospital between 2000 and 2009. Clinicopathological parameters of CRC, postoperative chemotherapeutic regimen, recurrence rate, and relapse-free survival (RFS) were analyzed retrospectively. RESULTS: After resection of CRC and synchronous metastases, 53 (84%) out of 63 patients without chemotherapy, and 38 (83%) out of 46 that received 5 fluorouracil (5-FU) alone or with leucovorin (LV) developed recurrent tumors. By contrast, only 1 (17%) among 6 patients who underwent FOLFOX treatment showed recurrence. The FOLFOX group exhibited significantly improved RFS as compared to the 5-FU (+ LV) or surgery-alone group (p = 0.03, p = 0.007, respectively). On the other hand, in patients with metachronous metastases, tumor-relapse rate and RFS were not significantly influenced by post-metastasectomy therapies. CONCLUSIONS: In this retrospective analysis, the adjuvant administration of FOLFOX appeared to reduce the risk of relapse in a small group of CRC patients with synchronous metastases. Prospective randomized trials will be required to confirm the benefits of this management strategy. PMID- 21677452 TI - Time-course studies of implanted rabbit VX2 liver tumors to identify the appropriate time for starting hepatic arterial embolization in animal models. AB - PURPOSE: We followed the 4-week course of implanted VX2 tumors in rabbits and compared MRI and pathological findings to determine the appropriate time for starting therapy in animal liver tumor models. MATERIALS AND METHODS: We used 18 Japanese white rabbits. The VX2 liver tumor was harvested from one tumor-bearing rabbit and implanted in the liver of the other 17 rabbits. They were then sacrificed at 1 (n = 5), 2 (n = 3), 3 (n = 4), and 4 weeks (n = 5) after implantation and MRI study. Using MRI scans and/or pathological specimens of individual rabbits, we evaluated the tumor survival ratio, the major tumor axes, intrahepatic metastases, and peritoneal dissemination. RESULTS: All tumor transplantations were successful. At 1 week, 56.25% of the implanted tumors were visualized on MRI scans. At 2 weeks or later, all transplanted rabbits were confirmed to be tumor-bearing on MRI scans. At 3 weeks after implantation, the tumor size was similar on MRI scans and in pathological specimens. There were no intra-hepatic metastases or peritoneal disseminations within 2 weeks of tumor transplantation. CONCLUSION: We suggest that in studies of implanted VX2 models addressing the treatment of solid hepatic tumors, it may be prudent to start hepatic arterial embolization at 2 weeks after implantation. PMID- 21677454 TI - Carcinosarcoma of the ovary: analysis of 13 cases and review of the literature. AB - OBJECTIVES: The aim of this study was to evaluate our experience with patients affected by ovarian carcinosarcoma. PATIENTS AND METHODS: During a 16-year period, data on 13 patients with ovarian carcinosarcoma were collected. They were obtained from hospital charts and follow-up visits. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test. All tests were two-tailed with p values < 0.05 considered significant. RESULTS: Our study was conducted on 13 patients with ovarian carcinosarcoma referred to our unit, during an observation time of about 16 years (March 1994 to October 2010). An improved survival was observed in patients treated with optimal cytoreductive surgery with residual tumors <2 cm (30 vs. 5 months; p = 0.042). All patients underwent adjuvant chemotherapy based on the combination of cisplatin, epirubicin and ifosfamide (PEI) and taxol and carboplatin (TAX-CBDCA) regimen. Overall survival of the patient population was 17 months. CONCLUSIONS: Similarly to data published in the literature, we observed that malignant mixed mullerian ovarian tumors are very aggressive and are usually diagnosed at an advanced age and at an advanced stage of disease. Therefore, due to the rarity of the tumor we would like to add our series to those already published in the literature, although our treatment recommendations are actually based upon retrospective studies with a small patient population. PMID- 21677453 TI - Gemcitabine and oxaliplatin combination chemotherapy for patients with refractory pancreatic cancer. AB - OBJECTIVE: The aim of this study was to investigate the effect of gemcitabine and oxaliplatin combination chemotherapy on refractory pancreatic cancer. METHODS: Patients with advanced pancreatic cancer refractory to gemcitabine and S-1 were treated with gemcitabine 1,000 mg/m2 over 30 min and oxaliplatin 85 mg/m2 over 120 min on days 1 and 15. Treatment was repeated every 4 weeks and tumor response was assessed every two cycles by RECIST version 1.0. RESULTS: Twenty-two patients with pathologically confirmed pancreatic cancer were enrolled. The treatment was administered as a second-line chemotherapy in eighteen patients (82%) and as a third-line chemotherapy in four patients (18%). Tumor response did not occur in any of the cases. Thirteen patients demonstrated stable diseases, and the disease control rate was 59%. Median overall survival and time to progression were 6.8 months (95% CI, 2.8-11.5) and 2.6 months (95% CI, 1.5-3.8), respectively. Median overall survival from the first-line chemotherapy was 22.7 months (95% CI, 14.8 24.4). The major grade 3/4 adverse events included neutropenia (14%), anorexia (23%), and peripheral neuropathy (14%). CONCLUSIONS: Gemcitabine and oxaliplatin combination chemotherapy was tolerable but had limited activity in patients with advanced pancreatic cancer in a refractory setting. PMID- 21677455 TI - Comparison of long-term outcome between doublet and triplet neoadjuvant chemotherapy in non-metastatic osteosarcoma of the extremity. AB - OBJECTIVE: This study compared outcomes between doublet (AP) and triplet (IAP) neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremity. METHODS: A total of 124 patients were enrolled. In the AP group, a doublet regimen of intraarterial cisplatin and intravenous doxorubicin was given to 77 patients from 1991 to 1999. In the IAP group, a triplet regimen of additional intravenous ifosfamide was given to 47 patients from 2000 to 2007. After completion of 3 cycles of chemotherapy, patients underwent surgery. We assessed tumor response according to pathologic tumor necrosis, and treated patients with further adjuvant chemotherapy. RESULTS: The overall pathologic response was excellent with more than 90% tumor necrosis in 74.8% of patients. Total necrosis of tumors was also found in 46 (37.4%) patients. There was no difference between the 2 groups in pathologic response (75.3 vs. 72.3%; p = 0.52) or other clinicopathologic parameters. There was no difference between the 2 groups in recurrence rate (31.2 vs. 31.9%; p = 0.17) or lung metastasis (28.6 vs. 23.4%; p = 0.53). Moreover, there were no statistical differences in median disease-free survival and overall survival between the groups. There was more hematologic toxicity in the IAP group (neutropenia, p = 0.002; thrombocytopenia, p = 0.001; febrile neutropenia, p < 0.001). CONCLUSIONS: The addition of ifosfamide to doxorubicin and cisplatin in neoadjuvant chemotherapy did not show improved outcomes in this study. Further trials are required to elucidate optimal neoadjuvant chemotherapy and effective salvage regimens. PMID- 21677456 TI - End-of-life hospital costs in cancer patients: do advance directives or routes of hospital admission make a difference? AB - OBJECTIVE: End-of-life cancer care is costly. The current study explored whether advance directives or route of hospital admission reduced cancer patients' terminal hospitalization costs. METHODS: This single-institution study focused on solid tumor patients who died on an inpatient oncology service in 2008 and 2009. Patients' total costs were compared based on advance directives and route of hospitalization. RESULTS: Among 120 patients, all except 4 had an incurable malignancy. Forty-six (38%) had an advance directive. Sixteen (13%) were admitted after an oncology clinic visit and 6 (5%) from hospice; others were admitted via other routes, most commonly from the emergency department. The median total cost for hospitalization (range) per patient was USD 12,962 (1,244-138,877). Patients with advance directives had no statistically significant difference in cost (p = 0.30), even after adjusting for age and time in the hospital. Those admitted after an oncology clinic or from hospice also had no difference in cost compared to those admitted via another route. Use of cardiopulmonary resuscitation, intensive care unit monitoring and intubation were similar between all compared groups. CONCLUSION: Advance directives and route of admission do not appear to impact the cost of terminal hospitalization for cancer patients. PMID- 21677457 TI - Therapeutic outcomes of papillary thyroid cancer patients in different risk groups. AB - OBJECTIVE: The objective of this study was to determine the therapeutic outcome of papillary thyroid cancer (PTC) patients in different risk groups in one institute. METHODS: A total of 1,759 PTC patients were categorized into low- (n = 1,123), intermediate- (n = 75), and high-risk (n = 561) groups according to tumor node-metastasis (TNM) stage. RESULTS: Of the patients, 15.1% presented with lymph node metastases, and 4.6% presented with distant metastases at the time of thyroid operation. After 8.0 +/- 0.1 years of follow-up, 73 (4.2%) patients died of thyroid cancer. Tumor size, local invasion, and lymph node metastases adversely influenced recurrence and survival. Of the patients in the 3 groups, 9 (0.8%), 8 (10.7%), and 56 (10.0%) died of thyroid cancer, respectively. In addition, 88 (7.8%), 14 (18.7%), and 144 (25.8%) patients showed recurrence during the follow-up period. Patients with highly aggressive histological patterns showed increased recurrence and cancer mortality compared with the low risk group; otherwise, values were not higher than those of the high-risk group. CONCLUSIONS: The cancer-related mortality was nearly 10% in the intermediate- and high-risk groups, and the patients in these groups required aggressive surgical and postoperative adjuvant therapies. PMID- 21677458 TI - Prognostic impact of phosphorylated mitogen-activated protein kinase expression in patients with metastatic gastric cancer. AB - BACKGROUND: This study was designed to investigate the expression of phosphorylated mitogen-activated protein kinase (p-MAPK/Erk1 and Erk2) and its correlation with outcomes in patients with metastatic gastric cancer. METHODS: p MAPK was detected by immunohistochemistry using monoclonal antibodies in a total of 223 formalin-fixed, paraffin-embedded samples obtained from 156 patients who received first-line chemotherapy in a phase III trial. RESULTS: p-MAPK was positive in 93 (59.6%) and negative in 63 (40.4%) of the 156 patients evaluated. Similar rates of p-MAPK positivity were found in primaries (53%) and metastatic lesions (61.4%). Overall survival was significantly shorter in p-MAPK-positive patients (13.7 vs. 8.5 months) in the univariate analysis. However, this prognostic value disappeared as a trend in the multivariate analysis (p = 0.1). There was a strong, positive correlation between p-MAPK and the MIB-1 proliferation index, but MIB-1 did not predict outcomes. CONCLUSION: p-MAPK expression could be a potential negative prognostic parameter in patients with metastatic gastric cancer treated with chemotherapy. PMID- 21677459 TI - Regarding 'Treatment of colorectal cancer with and without bevacizumab: a phase III study'. PMID- 21677460 TI - Comment on 'Treatment of colorectal cancer with and without bevacizumab: a phase III study'. PMID- 21677462 TI - A prognostic model to predict clinical outcome in gastric cancer patients with bone metastasis. AB - BACKGROUND: The clinicopathological manifestations and treatment outcomes of bone metastasis of gastric cancer are largely unknown. We delineated a prognostic model to identify different risk groups on the basis of clinical parameters. METHODS: Patients who had bone metastasis at the time of diagnosis of gastric cancer (synchronous metastasis) or who developed bone metastasis during follow-up (metachronous metastasis) were retrospectively reviewed from January 1998 to May 2008. RESULTS: Bone metastasis was identified in 203 (2.4%) of 8,633 patients: 126 patients (62%) with synchronous metastasis and 77 patients with metachronous metastasis. The median time to event was 16 months (range 4-87). As for treatment, 120 patients (59%) received systemic chemotherapy. The median survival time was 103 days (95% CI 80-126). Poor performance status [Eastern Cooperative Oncology Group 3-4; relative risk (RR) = 1.91, p = 0.011], multiple bone metastasis (RR = 2.593, p = 0.002), and abnormal carcinoembryonic antigen (RR = 1.779, p = 0.004) implied independent factors for survival. For patients who had zero to two of these factors identified, chemotherapy had a beneficial effect (175 vs. 43 days; p < 0.0001). CONCLUSION: We recommend that the therapeutic approach with bone metastasis be customized to facilitate the risk stratification, so as to consequently provide the most appropriate therapy for each patient. PMID- 21677463 TI - Cross-trial comparisons in the oncology arena: when is this justified? PMID- 21677465 TI - Predicting hospital mortality in critically ill cancer patients according to acute kidney injury severity. AB - BACKGROUND: Acute kidney injury (AKI) is a frequent complication in hospitalized patients, especially in those in intensive care units (ICU). The RIFLE classification might be a valid prognostic factor for critically ill cancer patients. The present study aims to evaluate the discriminatory capacity of RIFLE versus other general prognostic scores in predicting hospital mortality in critically ill cancer patients. METHODS: This is a single-center study conducted in a cancer-specialized ICU in Brazil. All of the 288 patients hospitalized from May 2006 to June 2008 were included. RIFLE classification, APACHE II, SOFA, and SAPS II scores were calculated and the area under receiver operating characteristic (AROC) curves and logistic multiple regression were performed using hospital mortality as the outcome. RESULTS: AKI, defined by RIFLE criteria, was observed in 156 (54.2%) patients. The distribution of patients with any degree of AKI was: risk, n = 96 (33.3%); injury, n = 30 (10.4%), and failure, n = 30 (10.4%). Mortality was 13.6% for non-AKI patients, 49% for RIFLE 'R' patients, 62.3% for RIFLE 'I' patients, and 86.8% for RIFLE 'F' patients (p = 0.0006). Logistic regression analysis showed that RIFLE criteria, APACHE II, SOFA, and SAPS II were independent factors for mortality in this population. The discrimination of RIFLE was good (AROC 0.801, 95% CI 0.748-0.854) but inferior compared to those of APACHE II (AROC 0.940, 95% CI 0.915-0.966), SOFA (AROC 0.910, 95% CI 0.876-0.943), and SAPS II (AROC 0.869, 95% CI 0.827-0.912). CONCLUSION: AKI is a frequent complication in ICU patients with cancer. RIFLE was inferior to commonly used prognostic scores for predicting mortality in this cohort of patients. PMID- 21677464 TI - Treating primary liver cancer with hepatic arterial infusion of floxuridine and dexamethasone: does the addition of systemic bevacizumab improve results? AB - OBJECTIVES: This study investigated the efficacy and safety of adding systemic (IV) bevacizumab (Bev) to hepatic arterial infusion (HAI) with floxuridine (FUDR)/dexamethasone (Dex) in unresectable primary liver cancer. METHODS: Patients with unresectable intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC) were treated with HAI FUDR/Dex plus IV Bev. Results were compared to a recent study of HAI without Bev in a similar patient population. RESULTS: Twenty-two patients (18 ICC, 4 HCC) were treated with HAI FUDR/Dex plus Bev; 7 (31.8%) had partial response and 15 (68.2%) had stable disease. Median survival was 31.1 months (CI 14.14-33.59), progression-free survival (PFS) 8.45 months (CI 5.53-11.05), and hepatic PFS 11.3 months (CI 7.93 15.69). In the previous trial with HAI alone (no Bev), the response was 50%; median survival, PFS, and hepatic PFS were 29.5, 7.3, and 10.1 months. In the present trial, bilirubin elevation (>2 mg/dl) was seen in 24% of patients and biliary stents were placed in 13.6%, versus 5.8 and 0%, respectively, in the HAI trial without Bev. Due to increased biliary toxicity, the trial was prematurely terminated. CONCLUSION: Adding Bev to HAI FUDR/Dex appeared to increase biliary toxicity without clear improvement in outcome (median PFS 8.45 vs. 7.3 months, and median survival 31.1 vs. 29.5 months, for HAI + Bev vs. HAI alone groups, respectively). PMID- 21677466 TI - [Clinic for Radiation Therapy and Internal Medicine Oncology, Pius-Hospital Oldenburg, Germany]. PMID- 21677467 TI - [Prevention and early detection]. PMID- 21677468 TI - [Follow-up, complications and their treatment in the surgical, radiotherapeutic and pharmacological treatment of lung cancer]. PMID- 21677469 TI - Changing pathology with changing drugs. PMID- 21677470 TI - Changing pathology with changing drugs: skin cancer. AB - Today skin cancer is mainly treated by surgical interventions. New findings concerning molecular biology and the signaling pathways in epithelial skin cancers such as basal cell carcinoma, squamous cell carcinoma or melanoma, and mesenchymal skin cancers such as angiosarcoma and dermatofibrosarcoma protuberans (DFSP) have identified new molecular targets for a systemic or local treatment approach. For DFSP there is an opportunity already today to reduce the intensity of surgical procedures by pretreatment with targeted therapy. This article highlights important aspects in several skin cancer types. PMID- 21677471 TI - Changing pathology with changing drugs: tumors of the gastrointestinal tract. AB - Gastrointestinal cancer treatment is being based more and more on pathology that yields integrated information leading to targeted therapy, i.e. morphological identification of the histological type of the tumor and its context, staging of the tumor, and identification of various targets. This provides a realistic appraisal of the tumor and allows surgeons and oncologists to choose the best treatment from an increased range of drug options. An accurate diagnosis remains the major determinant of treatment, but new drugs and new insights into molecular pathways acting in carcinogenesis enhance molecular diagnosis in cancer. In most adenocarcinomas, therapy is only organ orientated and staging dependent, and not patient targeted. Currently, the identification and validation of new targets as well as molecular classification of the tumors are inducing the incorporation of new tests into the daily practice of surgical pathology. These new tests require appropriate tissue preservation and selection of the tissue to be analyzed and harmonized to morphological criteria. In colorectal adenocarcinoma, which is the second most common malignant tumor in both genders, the biomarkers that are relevant at the present time are the genetic instability status of the tumor, the KRAS mutation status as a negative predictive marker for the overall rate of response to anti-EGFR treatment in patients with metastatic cancer, and BRAF mutation as an unfavorable prognostic marker. In gastric adenocarcinoma, HER2 overexpression is correlated with poor outcomes and more aggressive disease in a subset of cases with clinical response to trastuzumab. Met mutations have also been evidenced. Hepatocellular carcinoma is a highly chemoresistant tumor with several genetic alterations. Pancreatic adenocarcinoma is a leading cause of cancer death with frequent KRAS mutations. No biomarker has been clearly identified in either of these tumors. Gastrointestinal stromal tumors that constitute less than 3% of all gastrointestinal malignancies have been individualized since 1988. They express the KIT protein, a membrane receptor, and respond to imatinib which is a tyrosine kinase receptor inhibitor, depending on the mutational status of the tumor. PMID- 21677472 TI - Kidney cancer pathology in the new context of targeted therapy. AB - The outcome in metastatic renal cancer remains poor with an overall survival at 5 years of less than 10%. However, molecular pathology in kidney cancer has developed extensively in the few last years, providing a basis for new systemic therapies including antiangiogenic drugs and mTOR inhibitors. Use of these targeted therapies in metastatic disease has improved the prognosis but still in a too-limited range, with a lack of consistent predictive biomarkers. The multiple entities of renal tumors add complexity to the research of biomarkers and the design of clinical trials. This review aims to focus on pathways in renal cancer (VHL/HIF, mTOR, c-MYC, c-MET, and immune response) in the respective tumor subtypes, accounting for the effects of targeted therapies and providing the framework to search for relevant predictive biomarkers and propose new trials. This overview underscores that the pathways are often intermingled and common (at least partially) to the different tumor subtypes. PMID- 21677474 TI - Phosphoproteins and the dawn of functional phenotyping. AB - Phosphorylation is one of the most important processes in cell signal transduction. Detection of phosphorylated proteins in cancer tissue is useful for prognosis and diagnosis, and it might be very helpful in monitoring treatment using targeted therapy. For these reasons, the in situ quantitative measurement and subcellular localization of phosphoproteins will likely be important. However, phosphoproteins are extremely labile, a likely explanation for inconsistent or contradictory reports. Thus, the development of new paradigms for tissue handling, immunostaining, and quality control are needed. PMID- 21677475 TI - [Mechanism and strategy for treatment of cancer metastasis to bone]. AB - Bone, as well as the lung and liver, is among the sites of predilection for cancer metastasis. The bone stores large amounts of growth factors such as insulin-like growth factors and transforming growth factor-b, and provides fertile soil for metastatic cancer cells by continuously releasing these bone stored growth factors, which are a consequence of osteoclastic bone resorption. Metastatic cancer cells in turn produce osteoclast-stimulating cytokines such as parathyroid hormone-related protein( PTH-rP), prostaglandin E2.(PGE2), and various interleukins(ILs). These cancer-produced osteoclast-stimulating cytokines bind to their cognitive receptors and promote the expression of ligands for the receptor activators of nuclear factor kB (RANKL)in osteoblasts. RANKL then binds to its receptor RANK, expressed in pre-osteoclasts, stimulates mature osteoclast formation, and subsequently, osteoclastic bone resorption. This vicious cycle between metastatic cancer cells and osteoclasts is critical to the development and progression of bone metastases. In addition, it is likely that metastatic cancer cells are influenced by bone environments(or niche)and acquire additional capacities such as an epithelial-mesenchymal transition(EMT), allowing them to be resistant to chemotherapy or apoptosis, to survive in a dormant state, or to aggressively spread to distant organs including lung and liver. Thus, the bone can serve as transit port. Disrupting this cycle by inhibiting osteoclastic bone resorption, antagonizing bone-derived growth factors, and neutralizing RANKL or PTH-rP, should be a promising therapeutic intervention for bone metastases. Bisphosphonates(BP)are specific inhibitors of osteoclasts, and have been shown to significantly reduce skeletal-related events(SRE)associated with bone metastasis. Denosumab is a neutralizing monoclonal antibody to RANKL and has recently been found to inhibit SRE more effectively than BP. Further understanding of the crosstalk communication between metastatic cancer cells and bone at the molecular level should lead us to design novel, more effective and specific treatments for cancer patients with bone metastases. PMID- 21677476 TI - [The 9th international conference of the asian clinical oncology society in Japan after a twenty year interval--what is the standpoint of Japan in Asia ?]. AB - The 9th International Conference of the Asia Clinical Oncology Society(ACOS)was held at Gifu Grand Hotel, Gifu Japan on August 25, 26, and 27 2010. The Society was established in Osaka, Japan, in October 1991. Meeting have been held every two years, starting in Osaka, and then to Bangkok, Kunming, Bali, Taipei, Seoul, Beijing, Manila, and now to Gifu. There was a twenty year interval in Japan between meetings in Osaka and Gifu. The main theme of the 9th ACOS was titled "Talk to the Worldwide from Asia," and the sub-theme was titled "Multidisciplinary Treatment for Asian Cancer Patients "For this 9th ACOS, we gathered 42 councilors from Asian countries to serve on the ACOS committee and 365 doctors from Japan to serve on a local organizing committee. For congress program, we scheduled 161 special sessions for the president's lectures, key note lectures, special lectures, educational lectures, symposium, workshop, luncheon seminars, etc. We received about 500 abstracts for oral or poster presentations; among them, 140 abstracts came from Asian countries. As for speakers, 475 were from Japan, 85 from Korea, 34 from Taiwan, 27 from China, over 10 from India, Indonesia, Viet Nam, USA, and other countries. Finally a total of 704 speakers were gathered from 20 countries(from the outside Asia; UK, France, Germany, and Australia). The total number of registered investigators was 1, 136, and the total number of participants, including our congress staffs, volunteers, neighborhood doctors, Gifu citizens, patients, etc., was over 1, 500. In this 9th ACOS we discussed some new ideas, such as Asian cancer statistics, mission, vision and core values of ACOS, new anti-cancer drugs developed from Japan(TS-1 and Xeloda), Inter group clinical trials among Asian countries, less invasive surgery using endoscopic assisted operation, Asian traditional medicine, open workshops with citizens, etc. Moreover, we published a commemorative book entitled" Recent Advances of Cancer in Asian Countries. PMID- 21677477 TI - [Tykerb for breast cancer]. AB - There are four members of the ErbB family: the epidermal growth factor(EGF)receptor(also called HER1 or EGFR), HER2, HER3 and HER4. Dimerization is the process whereby two HER receptor molecules associate to form a noncovalent complex. HER dimers are the active receptor forms required for transmission of external stimuli to the interior of the cell. HER dimerization occurs upon ligand binding and both HER homodimers and heterodimers can be formed in the process. However, HER2 appears to be the preferred dimerization partner of the other HER family members. Fifteen~20% of all breast cancers are HER2 positive and have a poor prognosis. Trastuzumab is an excellent, rationally-designed targeted cancer treatment. It is a recombinant, humanized, anti-HER2 monoclonal antibody that specifically binds to the extracellular area of HER2. However, the overall trastuzumab response rate is low, and the causes of trastuzumab resistance are poorly understood. Thus, there is a need for alternative anti-HER2 strategies for trastuzumab-resistant disease. Lapatinib is an orally administered small molecule, reversible inhibitor of both EGFR and HER2 tyrosine kinase, and its activities include subsequent inhibition of its down- stream MAPK-ERK1/2, and the AKT signaling pathway. Lapatinib is more active when used in combination with capecitabine. For women with trastuzumab pre-treated HER2-positive breast cancer, Here, I will review the basics of EGFR and HER, and the treatment strategy for HER2-positive breast cancer with lapatinib. PMID- 21677473 TI - The changing role of pathology in breast cancer diagnosis and treatment. AB - Pathological examination has been the gold standard for diagnosis in cancer and its role has also included the elucidation of etiology, pathogenesis, clinicopathological correlation, and prognostication. The advent of newer technologies and the realization that breast cancer is heterogeneous has shifted the focus to prognostication, with increased attention being paid to the identification of morphological features and immunohistochemical markers of prognostic relevance. However, despite the massive efforts invested in the identification of immunohistochemical biomarkers in breast cancer the majority have not proven to be of value in multivariate analyses and only estrogen receptor, progesterone receptor, and Her2/neu expression have remained essential components of pathological examination. These 3 markers were initially employed for prognostication but their role in treatment also rendered them of predictive value. Newer molecular methods, especially high-throughput technologies, have shown that even morphologically similar subtypes of breast cancer can show molecular heterogeneity; moreover, infiltrating ductal carcinoma can be separated into at least 4 molecular subtypes designated luminal (ER+, PR+, and Her2/neu-), Her2 overexpressing (ER-, PR-, and Her2/neu+), basal-like (ER-, PR-, Her2/neu-, and CK5/6+, EGFR+), and normal breast-like (ER-, PR-, and Her2/neu-), each with different clinical outcomes. The importance of proliferative gene expression in these subtypes has been demonstrated and surrogate immunohistochemical markers include ER, PR, Her2/neu, and Ki67 for the more expensive molecular tests. Molecular technologies, importantly, have not only provided further insights into the heterogeneity of breast cancer but have also opened new avenues for treatment through the identification of signaling molecules important in the proliferation and survival of the neoplastic cells. The treatment of cancer thus shifts from the conventional approach of 'one size fits all' to one of personalized treatment tailored to the specific characteristics of the tumor. Pathologists continue to play their traditional role in diagnosis but, as purveyors of the excised tissue, pathologists now have the additional role of identifying biomarkers responsive to therapeutic manipulation, thus playing an inextricable role as diagnostic oncologists in the management of breast cancer. PMID- 21677478 TI - [Erlotinib in non-small cell lung cancer]. AB - Erlotinib and gefitinib are quinazoline derivatives that selectively and reversibly inhibit the tyrosine kinase activity of the EGFR. Activating mutations in the EGFR confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. Erlotinib has been developed in EGFR mutation-positive patients as a firstline treatment, and results from recently completed phase III studies have shown superior progression free survival and response rates for erlotinib, compared to chemotherapy. PMID- 21677479 TI - [Colorectal cancer chemotherapy and anti-EGFR therapy]. AB - Anti-EGFR antibodies show benefits for some K-ras wild-type patients. Addinganti VEGF monoclonal antibodies to stateof- the-art adjuvant chemotherapy for stage II or III colon cancer does not improve disease-free survival. Bevacizumab shows an additive effect for FOLFOX/FOLFIRI therapy as a first-line chemotherapy. Anti EGFR therapy has limited adaptation as a first-line chemotherapy based on current evidence and adverse events. When the disease is greatly influenced by tumor regression or has high risk with bevacizumab, anti-EGFR therapy may be used as first-line chemotherapy. Anti-EGFR therapy is recommended as second- or third line chemotherapy. FOLFIRI therapy is recommended as a second-line therapy and IRI+ Cmab therapy is recommended as a third-line therapy in cases when it is possible to treat usingthree or higher lines. Supportive care is especially important to improve the treatment outcome. PMID- 21677480 TI - [Second-line treatment of advanced renal cell carcinoma after first-line targeted therapy]. AB - Cytokines were the only drugs proven to be effective for advanced renal cell carcinoma(RCC). Introducing the targeted drugs prolonged patients' survival. However, limited high-quality evidence is now available for second-line treatment. Everolimus is effective for patients who have experienced progression of disease after sunitinib and/or sorafenib. Further prospective study including the sequencing of targeted drugs is warranted to develop better treatment strategies. PMID- 21677481 TI - [Nilotinib as a second-line treatment for chronic myeloid leukemia]. AB - Chronic myeloid leukemia(CML)is a clonal disease of the hematopoietic stem cells that is characterized by excessive proliferation, but retains of the capacity for differentiation duringthe chronic phase of the disease. This phase is followed after 4-6 years by rapid progression, an accelerated phase, and consequently a fatal acute leukemia a blast crisis. The hallmark abnormality of CML is the Philadelphia chromosome that generates a BCR-ABL fusion gene, resulting in the expression of a leukemia-specific oncoprotein, Bcr-Abl. Bcr-Abl is a potent tyrosine kinase and plays a central role in CML pathogenesis. Recently, the treatment of CML has been revolutionized by the introduction of imatinib mesylate(IM). With daily IM treatment, more than 80% of chronic-phase CML patients achieve a complete cytogenetic response. Nevertheless, a small percentage of CML patients are primarily refractory or acquire secondary resistance against IM. Nilotinib is a highly selective Abl kinase inhibitor that possesses greater potency and selectivity for Abl kinase than IM. In addition to being more potent than IM against wild-type BCR-ABL, nilotinib is significantly active against many IM-resistant BCR-ABL mutants. In preclinical studies, nilotinib has produced hematologic and cytogenetic responses in CML patients, with either IM resistance or IM intolerance. As second-line treatment, both nilotinib and dasatinib may be used in case of suboptimal response or failure, which is defined in the efficacy criteria of the European Leukemia Net Consensus. The choice of second-generation tyrosine kinase inhibitors may be made after the mutation analyses of the kinase domain. It is recommended that nilotinib or dasatinib whichever was shown to be active against the specific mutation, should be chosen for treatment. For patients with no mutations or patients with IM intolerance, it is recommended that either second-generation tyrosine kinase inhibitor be chosen, based on the patient's disease history. PMID- 21677482 TI - [Sunitinib as a second-line therapy for imatinib-resistant gastrointestinal stromal tumors]. AB - Gastrointestinal stromal tumor(GIST)is one ofthe representative diseases for which molecularly targeted therapy is very effective. Imatinib mesylate, a tyrosine kinase inhibitor of KIT and platelet-derived growth factor receptor(PDGFR), has dramatically improved the prognosis ofpatients with advanced, recurrent, and/or metastatic GISTs. Although the rate of response to imatinib therapy is high, the emergence ofimatinib -resistant tumors and the second-line therapy following imatinib therapy have become new clinical problems. Sunitinib malate, a multi-targeted tyrosine kinase inhibitor that shows activity against KIT and other receptor tyrosine kinases, including PDGFR and vascular endothelial growth factor receptor, is the only treatment for imatinib-resistant GISTs that is covered by national health insurance in Japan as ofthis writing. Several clinical trials that evaluated sunitinib as potential second-line therapy in Western countries and Japan found a clinical benefit rate of2 4 to 39% and a median time to progression of7 months. However, it is necessary to adequately manage the adverse events of sunitinib therapy in order to receive the full benefits of the therapy, because various severe adverse events, particularly thrombocytopenia and hand-foot syndrome in Japanese GIST patients, frequently lead to poor tolerability. Further investigation is required to find an appropriate regimen for Japanese GIST patients. PMID- 21677483 TI - [Investigation of gastric cancer chemotherapy in hiroshima prefecture]. AB - AIM: The Hiroshima Oncology Group of Gastric Cancer(HOG-GC)distributed a multiple answer questionnaire to investigate the realities of chemotherapy for gastric cancer. SUBJECTS AND METHOD: Seventy-six hospitals in Hiroshima were surveyed. The Japanese classification was used for the staging criteria. RESULTS: Forty-one hospitals, including 10 centers for cancer treatment, completed and returned the questionnaires. For stage II & III cases requiring adjuvant chemotherapy, S-1 was the most commonly used(84%)regimen. A standard starting dose was used in 79% of these cases, and S-1 was administered for one year continuously in 84% of the cases. For stage I B & II (T1), S-1 and UFT were used in 45%and 20%of the cases, respectively. In cases with non-resectable gastric cancer, S-1 plus CDDP and S-1 alone were used as a first-line therapy in 62% and 26% of the patients under 75 years age, respectively, and in 33% and 46% of the patients older than 75 years of age, respectively. In patients with ascites and peritoneal dissemination, S-1 plus CDDP, S-1, S-1 plus DTX, S-1 plus PTX, and PTX were used in 26%, 15%, 21%, 17%, and 17% of cases, respectively. Some of the patients with peritoneal dissemination underwent gastrectomy. CONCLUSION: S-1 was widely used for gastric cancer chemotherapy in Hiroshima Prefecture. Taxane-containing regimens or palliative gastrectomy were commonly used in cases with peritoneal dissemination. PMID- 21677484 TI - [Clinical efficacy and safety of CPT-11+CDDP therapy as third-line chemotherapy for advanced and recurrent gastric cancer]. AB - The clinical efficacy and safety of CPT-11+CDDP therapy were studied retrospectively in 34 patients with advanced and recurrent gastric cancer. The overall response rate was 5. 9%; MST was 209 days. The adverse effects observed were grade 3 in 7 patients(20. 6%). CPT-11+CDDP therapy could be useful and safe as third-line chemotherapy. PMID- 21677485 TI - Efficacy and toxicity of S-1 plus cisplatin combination neoadjuvant chemotherapy in patients with oral cancer. AB - S-1 is a newly developed oral fluoropyrimidine derivative that is now widely used as a chemotherapeutic agent in the treatment of various carcinomas. This study was performed to assess the efficacy and safety profile of the combination of S-1 and cisplatin(S-1/CDDP)in patients with oral cancer as neo-adjuvant chemotherapy. We reviewed our experience of 12 patients diagnosed with oral carcinoma, who were treated with S-1/CDDP. S-1 was administered orally at a dose of 50mg twice a day for 21 consecutive days, followed by a 14-day rest period. CDDP(60mg/m2)in 500 mL physiological saline was administered by intravenous drip as a 120-min infusion on day 8, together with standard premedications and hydration. Seven partial responders were obtained. The median follow-up duration was 54. 8 months, and all patients were alive excluding one case. This regimen was well tolerated, with only one case of grade 3 thrombocytopenia, and no grade 4 patient. No treatment related death was observed. Moreover, we evaluated immunohistochemical expressions of thymidylate synthase (TS), dihydropyrimidine dehydrogenase(DPD), and orotate phosphoribosyl transferase(OPRT)which are associated with chemosensitivity to 5-FU-based therapies. We investigated the relation between the immunohistochemical score and clinicopathological factors, however we could not clarify the relationship between the efficacy of chemotherapy and results of immunohistochemistry. PMID- 21677486 TI - [A retrospective study of oral adverse events with colorectal cancer chemotherapy using bevacizumab]. AB - PURPOSE: We encountered serious oral mucositis in some patients undergoing colorectal chemotherapy with bevacizumab. We retrospectively investigated the role bevacizumab plays in the occurrence of oral mucositis. SUBJECTS AND METHODS: Between January 2008 and December 2009, we encountered 11 patients for whom chemotherapy with bevacizumab had resulted in oral mucositis. The patients included 5 men and 6 women, with a mean age of 67. 9 years(range, 62-76 years). Among the patients, 5 had grade 1 oral mucositis, 3 had grade 2, and 3 had grade 3. We analyzed the risk factors, grades, symptoms, and treatments of oral mucositis in these patients. RESULTS: In 6 patients, bevacizumab was administered in combination with mFOLFOX6, and in 5 patients, bevacizumab was administered in combination with FOLFIRI. Seven patients had undergone prior treatment without the occurrence of serious oral mucositis. With respect to oral health, 8 patients had periodontal disease, 7 had dental caries, 3 wore dentures, 3 exhibited poor oral self-care, and 2 had diabetes; in addition, 2 patients were smokers. Symptoms of oral mucositis included mucosal reddening in 11 patients, oral mucosal erosion or ulcer in 7, fungus infection in 6, aphtha in 7, pseudomembrane formation in 3, and poor oral intake in 2. All the patients had oral mucositis at the occlusal line of the buccal mucosa. The treatment for oral mucositis included polaprezinc. CONCLUSION: Because many factors influence the development of oral mucositis, determining the specific cause of oral mucositis is difficult. Bevacizumabmay possibly decrease the VEGF levels in saliva and delay wound healing in oral mucositis. Therefore, oral mucositis may be caused not only by diabetes and poor oral self-care but by bevacizumab. PMID- 21677487 TI - [Incidence of infusion reactions induced by cetuximab chemotherapy]. AB - We retrospectively investigated the incidence of infusion reactions following cetuximab chemotherapy in 93 patients with colorectal cancer. Patients received chemotherapy treatment from September 2008 to February 2010 at Aichi Cancer Center Hospital. The initial cetuximab dose was 400 mg/m(2), followed weekly by an additional 250 mg/m(2), and biweekly by 500 mg/m(2). Infusion reactions were observed in 12 patients (13%), with grade 1 reactions in 6 patients and grade 2 reactions in 6 patients. Eleven of the 12 patients (92%) experienced infusion reactions during the first treatment. Typical grade 1 adverse events were fever and chills, nausea, vomiting and pruritus. Non-steroidal anti-inflammatory drugs were given for fever and chills. Grade 2 adverse events included dyspnea and wheezing, eruption, facial flushing and convulsions. Steroids were given for these symptoms. Infusion reactions were observed in 3 of the 12 patients (25%) <15 min after intravenous injection, 16-60 min after injection in 3 more patients (25%), and 61-120 min after injection in the remaining 6 patients (50%). PMID- 21677488 TI - [Effect of local cooling at injection site of goserelin acetate for pain relief]. AB - OBJECTIVE: The objective of this study was to assess the usefulness of ice cubes and vapocoolant spray for relieving pain induced by goserelin acetate injections. MATERIAL AND METHOD: Fourty-seven patients with prostate cancer receiving hormonal manipulation by goserelin acetate were enrolled in this study. They received goserelin acetate injections after analgesic pretreatments with ice cubes until March 2009, and with vapocoolant spray and ethyl chroride after April 2009. We had them fill out a questionnaire asking whether they preferred to continue cooling pretreatments. We assessed the pricking pain using the face scale(FS)and the numerical rating scale(NRS). RESULT: The median FS and NRS scores at the first pretreatment(ice cube or vapocoolant spray)were lower than those at no pretreatment(p<0. 01 in both scores). Thirty-nine patients(83. 0%)preferred cooling pretreatment. Only 5 patients preferred no pretreatment. The differences in the median FS score and NRS score between ice cubes and vapocoolant spray were not significant(p=0. 353 in FS, p=0. 120 in NRS). No adverse events associated with the cooling pretreatment occurred except for late onset subcutaneous hemorrhages in 2 cases. CONCLUSION: The local cooling at the injection site of goserelin acetate was effective irrespective of the method(ice cube or vapocoolant spray)for the relief of pricking pain without causing serious complications. PMID- 21677489 TI - [Side effects analyses in consideration of renal function for S-1-administered patients]. AB - Although many analyses of S-1 side effects are reported, there are no reports where the analyses of side effects were performed in consideration of renal function, which is an important index of medication dose. Therefore, we investigated side effects in consideration of renal function. The subjects were 163 patients administered S-1 at the Department of Surgery of Ogaki Municipal Hospital, between October 2008 and December 2009. The frequency and severity of side effects were high and serious in the groupwhose creatinine clearance was low. A significant difference was observed among 3 groups with regard to thrombocytopenia and dehydration. In conclusion, we think that pharmacists must take renal function into consideration when administering medication, to keepclose medicinal guidance, and to actively observe progress. PMID- 21677490 TI - [Clinical efficacy of oxycodone against cancer-related pain with a wide variety of pathophysiologies]. AB - Cancer-related pain has a wide variety of pathophysiologies. It is well known that many cancer patients suffer from visceral pain, neuropathic pain and bone pain, not only during the terminal phase but also in the active treatment phase. In general, opioids are highly effective against cancer-related pain. It is essential that opioids be selected appropriately based on the pathophysiology of pain, since the analgesic properties of opioids are not homogeneous;the sensitivities of each opioid on neuropathic pain and bone pain differ markedly. In clinical practice, it is also important that potential adverse effects of opioids are taken into account carefully. It has been demonstrated that oxycodone has favorable analgesic potency against neuropathic pain of both malignant and non-malignant origin, such as chemotherapy-induced peripheral neuropathic pain;however, we should be extremely cautious so as to avoid abuse and addiction to opioids when they are prescribed in the active treatment phase. Oxycodone could be effective on refractory bone pain that has a complicated pathophysiological mechanism. Furthermore, it has been reported that oxycodone may have a superior safety profile compared to morphine. Taking these characteristics into consideration, it appears that oxycodone is suitable as a first-line medication for the management of cancer-related pain that comes in a wide variety of pathophysiologies. PMID- 21677491 TI - [Effect of S-1 in a patient with metastatic eyelid sebaceous carcinoma]. AB - We report a 68-year-old female with a history of repeated right cervical lymph node metastasis secondary to eyelid sebaceous carcinoma. She had undergone right neck dissection due to lymph node metastasis at the department of surgery in an other local hospital. After the orbital exenteration, she underwent multiple operations, including 2 right partial parotidectomy and then total parotidectomy, 4 right cervical lymph node excisions and 1 left upper neck dissection due to lymph node metastasis. Adjuvant chemotherapy with S-1(at a dose of 80 mg per day)alone was applied as tumor dormancy therapy on an outpatient basis. Any adverse events during S-1 medication were observed. New metastatic lesions were not found until 29 months after the beginning of chemotherapy with S-1 alone. Although the effectiveness of S-1 for eyelid sebaceous carcinoma has not been demonstrated, S-1 might be useful in patients with recurrent eyelid sebaceous carcinoma based on our patient's recurrence-free survival. PMID- 21677492 TI - [Retrospective analysis of immediate cause of death in lung cancer-two case reports of lung cancer deaths due to bowel necrosis]. AB - The immediate cause of death of 313 patients who died of lung cancer during 5 years in this center was analyzed. The specific, immediate causes of the 313 deaths were respiratory failure 34. 8%, pneumonia 19. 0%, cachexia 12. 0%, and brain metastasis 8. 3%. Digestive organ disease deaths were 7. 0%(22 patients), being the 5th-ranking immediate cause of death. Of these 22 cases, hepatic insufficiency death by liver metastasis was in 10 out of 22 cases, and gastrointestinal bleeding was in 8 cases. Two patients died of intestinal tract necrosis, but the direct causal relationship between the cause of death and the tumor was unconfirmed from the autopsy result. However, we speculated that an elderly, tumor-bearing condition combined with chemotherapy led to prolonged immobility, a poor nutritional state, and rapid weight loss, which could be influential on the bowel necrosis. PMID- 21677493 TI - [A radical resection of non-small cell lung cancer invading chest wall with ipsilateral axillary lymph node metastases]. AB - A 41-year-old man who had non-small cell lung cancer invading his right 3rd, 4th and 5th ribs with hilum lymph node swelling(cT3N1M0, cStage III A), received chemoradiation therapy, cisplatin(CDDP)/docetaxel, and 2 Gy/Fr of irradiation prior to surgery. But the therapy was discontinued due to interstitial pneumonitis on day 24, during 28 Gy of radiation. At that time, a PET-CT scan revealed the accumulation of FDG in the primary tumor, hilar lymph node, and one of the ipsilateral axillar lymph nodes, in which cancer cell presence was proven by aspiration needle cytology. We organized a radical operation even though the node status was classified to cStage IV, because ipsilateral axillary lymph nodes may be regarded as regional nodes for tumors invading the chest wall. Right upper lobectomy and chest wall resection were performed, and the ipsilateral hilar, mediastinal, and axillary lymphnode were dissected. Pathological findings showed no active cancer cell in the primary lesion and hilar lymph nodes(Ef. 3), but obvious metastasis in one of the axillary lymph nodes(pT0N0M1b, pStage IV). The patient received adjuvant chemotherapy(CDDP/vinorelbine), and is alive and tumor free 10months after the resection. PMID- 21677494 TI - [A case of intractable hepatic encephalopathy successfully treated by oral administration of vancomycin hydrochloride, with subsequent improvement of hepatic function reserve enabling transcatheter arterial chemoembolization against hepatocellular carcinoma]. AB - We report a case of an 80-year-old male who suffered from intractable hepatic encephalopathy and hepatocellular carcinoma( HCC), associated with hepatitis type C-related liver cirrhosis. He was unable to receive HCC treatment due to the deterioration of his liver. His hepatic encephalopathy was resistant to oral administration of laxatives, lactulose, and kanamycin sulfate, etc. His blood ammonia concentration averaged about 130 mg/dL, and often exceeded 200 mg/dL(normal range: <80 mg/dL). Later, an oral administration of vancomycin hydrochloride, 0. 5 g once every 3 days, was initiated. Soon after ward, his blood ammonia concentration declined to the normal range(about 50 mg/dL), and the clinical symptoms of hepatic encephalopathy showed a remarkable improvement. By the continuation of vancomycin administration, the normalization of his state of consciousness was achieved, improving his quality of life, and his activities of daily living. Three months after beginning treatment, he was able to receive transcatheter arterial chemoembolization for the treatment of HCC, because his liver function reserve improved(Child-Pugh score decreased from 10 to 7). PMID- 21677495 TI - [A case of gastric cancer accompanied by disseminated carcinomatosis of bone marrow with DIC, and subdural hematoma successfully treated with sequential methotrexate and 5-fluorouracil therapy]. AB - A 44-year-old man visited a nearby hospital because of severe headache. Brain MRI revealed a subdural hematoma, and he was transferred to the Department of Neurosurgery of our hospital. Burr hole surgery was performed on the second day of hospitalization because of an enlargement of the hematoma. Laboratory data on admission showed the presence of a disseminated intravascular coagulation(DIC). Bone marrow aspiration revealed metastases of signet ring cell carcinoma, and abdominalCT showed gastric cancer. He was diagnosed as having DIC with bone marrow metastases of advanced gastric cancer. Despite anti-DIC therapy and blood transfusion, his systemic bleeding tendency was not improved. The neurosurgeon therefore consulted with a palliative care team. Since the patient was still young, we considered that he should be treated with anti-cancer drugs. At first, his family did not accept chemotherapy because they were pessimistic about his prognosis. However, after he regained his consciousness, we were able to perform sequential MTX and 5-FU therapy with the consent of the patient and his family. The therapy was successful, and he recovered from DIC and was discharged on the 57th hospital day. PMID- 21677496 TI - Phenytoin toxicity in a patient receiving concomitant use of phenytoin and S-1 plus cisplatin chemotherapy for advanced gastric cancer. AB - A 61-year-old man had been receiving phenytoin(225mg/day)and valproate(600mg/day)for several years as the treatment for seizures. He was diagnosed with advanced gastric cancer,and S-1 plus cisplatin treatment was administered as neoadjuvant chemotherapy because bulky lymph node metastases were found at the time of the initial diagnosis. He complained of weakness of the lower extremities,light -headedness,and trembling of the upper extremities 2 months after the start of concomitant treatment with S-1 plus cisplatin. The serum phenytoin concentration increased to 21. 2mg/mL. Head computed tomography and magnetic resonance imaging did not reveal any intracranial lesion such as brain metastasis. Therefore, we diagnosed phenytoin toxicity due to concomitant use of S-1 and phenytoin,and the dose of phenytoin was then decreased to 150 mg. Although the weakness of the lower extremities improved,light -headedness remained. Phenytoin and valproate treatments were stopped,and he was able to walk 7 days after the termination of therapy. It is important to predict the timing of phenytoin toxicity due to S-1,and therapeutic drug monitoring should be performed in patients receiving S-1 plus cisplatin and phenytoin. PMID- 21677497 TI - [Primary adenocarcinoma of small intestine with peritoneal dissemination treated with S-1 and CPT-11 combination chemotherapy]. AB - A 62-year-old woman was admitted for epigastralgia, nausea and tarry stool.Abdominal CT showed a tumor to the jejunum from the duodenum, and peritoneal dissemination.Gastroduodenoscopy showed a type 2 tumor, and the histopathological examination revealed a well-to moderately-differentiated adenocarcinoma.Accordingly, she was diagnosed with primary adenocarcinoma of the small intestines and underwent surgery.The first-line chemotherapy with S-1/CPT 11 was started after surgery, and the tumor marker returned to normal.The treatment of 14 courses was continued until PD due to the enlargement of the peritoneal dissemination.Second - and third-line chemotherapy were performed; however, she died 20 months after the initial treatment.Although the incidence of primary adenocarinoma of the small intestines is relative- ly low, and there is no established chemotherapy at present, this case suggested that S-1/CPT-11may be an effective regimen for advanced primary adenocarcinoma of the small intestines. PMID- 21677498 TI - Abdominal wall infiltration by small bowel adenocarcinoma in a patient with Crohn's disease--a case report. AB - A 46-year-old man with Crohn's disease was referred to our hospital. In 2007, abdominal pain accompanied by redness and swelling of the right lower quadrant developed. A small bowel series and computed tomography of the abdomen revealed a stricture in the terminal ileum, suggesting a penetration of the abdominal wall. He was transferred to the department of surgery, and the affected portion of the bowel was resected to eliminate the stricture. At laparotomy, the ileum 35 cm proximal to the ileocecal valve adhered to the abdominal wall in the right lower quadrant. The involved site of the ileal wall and a portion of the abdominal wall were resected. Postoperative microscopic examination revealed an invasion of the abdominal wall by an ileal adenocarcinoma; reoperation was therefore performed. Histopathological examination revealed an adenocarcinoma at the previously sutured site of the ileal wall, against a backdrop of Crohn's disease. The postoperative recovery was good, and the patient received chemotherapy. During follow-up, computed tomography and positron emission tomography demonstrated abnormal changes of the abdominal wall, suggesting a recurrence. He received radiotherapy of the abdominal wall. Although he had tentative regression, the patient died 1 year and 9 months after the first operation. PMID- 21677499 TI - [A case report of conversion therapy for initially unresectable colorectal cancer liver metastases after cetuximab as third-line treatment]. AB - The introduction of monoclonal antibodies into the treatment protocols for metastatic colorectal cancer(mCRC)has significantly improved outcomes. There are some patients with mCRC, initially judged unresectable, who become resectable after chemotherapy. For patients with isolated liver metastases, surgical resection is recommended when feasible. We experienced a case in which an initially unresectable mCRC liver metastases converted into a resectable one after cetuximab monotherapy as third-line treatment. The sample from hepatectomy was a pathologically complete response; no remnants were detected. The management of liver metastases contributes to improvements in the clinical setting. For conducting a multimodal treatment of mCRC, the participation of various specialists such as medical oncologists, colorectal/hepaticsurgeons and diagnostic/therapeutic radiologists is indispensable. Furthermore, it is necessary to construct an evidence-based consensus on potentially resectable CRC liver metastases in each hospital. PMID- 21677500 TI - [A case of effective neoadjuvant chemoradiotherapy with capecitabine for locally advanced sigmoid colon cancer]. AB - A 60-year-old man was hospitalized for urodynia. Clinical examinations demonstrated a locally advanced sigmoid colon cancer with direct extension to the bladder, rectum, and pelvic wall. We considered that curative resection was not possible and performed temporary colostomy for fecal diversion. After colostomy, he was treated with neoadjuvant chemoradiotherapy(NACRT)for down staging. The radiation therapy was delivered with 45 Gy(1. 8 Gy/fraction; 5 days/week*5 weeks), and the concurrent chemotherapy was performed with capecitabine(825mg/m2 twice daily on radiotherapy days). CT scan confirmed a dramatic response with downstaging of the tumor following NA-CRT(clinical response, PR in the RECIST criteria). Invasion of the tumor to pelvic wall disappeared on CT scan, and[18F]fluorodeoxyglucose positron emission tomography( FDG-PET)failed to demonstrate any distant metastasis. We considered that the tumor was hence resectable and performed total pelvic exenteration(TPE)1 month after NACRT. A pathological examination of surgical specimens confirmed a R0 resection. The patient made an unremarkable postoperative recovery. He went on to receive adjuvant capecitabine chemotherapy, completing four cycles. He remains well and disease-free 10 months following surgery. NACRT with capecitabine appears effective even for unresectable locally advanced sigmoid colon cancer. PMID- 21677501 TI - [A case of drug-induced interstitial pneumonitis after chemotherapy with UFT and leucovorin for multiple lung metastases of rectal cancer]. AB - The patient was a 70-year-old male who had multiple lung metastases of rectal cancer. He was administered UFT(300mg/ day)and LV(75mg/day)after Hartmann operation for rectal cancer. He complained of fever and difficulty breathing after 2 courses of these medicines, and was admitted for UFT-and LV-induced interstitial pneumonitis. Treatment with methylpredni- solone(30mg/day)improved his symptoms and revealed radical findings. He was ready for discharge on the 10th day after treatment. Interstitial pneumonitis-induced UFT and LV is rare, but can lead to severe complications, which should be diagnosed and treated by corticosteroid as soon as possible. PMID- 21677502 TI - [A case of marked efficacy of low-dose UFT against metastatic bladder cancer]. AB - The two regimens of treatment consisted of either cisplatin and gemcitabine or methotrexate, vinblastine, doxorubicin and cisplatin(M-VAC), which has been widely adopted for muscle-invasive bladder cancer. But because of its potential toxicity, its tolerability has been troublesome, especially for very elderly patients. Herein, we report a bladder cancer case with multiple metastases which were controlled by low-dose UFT. At the same time, the chemosensitivity of 5-FU combined with uracylor 5-chloro-2, 4-dihydroxypyridine(CDHP). Four invasive bladder cancer cell lines were evaluated with a collagen gel droplet embedded drug sensitivity test(CD-DST). Three of four cell lines showed an increasing sensitivity to 5-FU with the combination of uracilor CDHP. Examinations with CD DST may provide important scientific evidence for determining suitable chemotherapy for patients with advanced bladder cancer. PMID- 21677503 TI - [A case of recurrent endometrial cancer metastasis successfully treated with zoledronic Acid]. AB - Although metastasis to the bone is common in solid tumors, it seldom occurs in endometrial cancer. A rare case of endometrial carcinoma that presented wth symptoms of bone metastasis in the right ischium and treated successfully by zoledronic acid is described. A 57-year-old woman presented with pain of the right ischium. Computed tomography and magnetic resonance imaging revealed bone metastasis and enlargement of the uterus. Endometrial biopsy confirmed endometrial adenocarcinoma. The patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and biopsy of the ischium. Postoperatively, the patient received six courses of chemotherapy using paclitaxel and carboplatin. However, pain of the right-ischium reappeared 9 months after surgery. The patient was treated with 4 mg of zoledronic acid every 4 weeks. After 4 cycles of treatment, the visual analogue scale regressed from 70 to 10. Zoledronic acid can palliate bone pain caused by a variety of endometrial cancers. PMID- 21677504 TI - [A case of multiple bone metastasis of gastric carcinoma accompanying DIC successfully controlled with combination of S-1 and low-dose CDDP]. AB - The patient was a 50-year-old man who underwent total gastrectomy twelve years ago. Ahigh level of ALP was found in the patient in April 2008. Based on various examinations, the diagnosis of multiple bone metastasis of gastric carcinoma accompanying disseminated intravascular coagulation(DIC)was made. The patient was treated with S-1/CDDP. S-1(80mg/ m / / 2day)was administered for 14 days followed by a 7-day rest period, and a CDDP(20mg/m2)infusion was administered on days 1 and 8. After one course of treatment, the DIC was controlled, and the patient was given a one-year prognosis. The combination of S-1 and low-dose CDDP may be considered effective even for multiple bone metastases of gastric carcinoma with DIC. PMID- 21677505 TI - [A case of pancreatic well-differentiated neuroendocrine carcinoma surviving 8 years and 5 months with treatments for multiple liver tumors diagnosed as carcinoid tumor]. AB - The case was a 58-year-old woman who visited our hospital for a thorough examination after multiple liver tumors were found in her at a nearby hospital. By liver tumor biopsy, we diagnosed them as carcinoid. Bone scintigraphy showed an abnormal accumulation in the external left scapula and in both of her hip joints, but the primary lesion was unclear. She died 8 years and 5 months after disease onset from deterioration of liver lesions, inspite of our treatments, such as gemcitabine administration of systemic chemotherapy, transcatheter arterial chemoembolization for liver lesions, and radiation therapy for bone lesions. Pathological anatomy suggested a pancreatic, well-differentiated neuroendocrine carcinoma. PMID- 21677506 TI - TiO2 nanotube stimulate chondrogenic differentiation of limb mesenchymal cells by modulating focal activity. AB - Vertically aligned, laterally spaced nanoscale titanium nanotubes were grown on a titanium surface by anodization, and the growth of chondroprogenitors on the resulting surfaces was investigated. Surfaces bearing nanotubes of 70 to 100 nm in diameter were found to trigger the morphological transition to a cortical actin pattern and rounded cell shape (both indicative of chondrocytic differentiation), as well as the up-regulation of type II collagen and integrin beta4 protein expression through the down-regulation of Erk activity. Inhibition of Erk signaling reduced stress fiber formation and induced the transition to the cortical actin pattern in cells cultured on 30-nm-diameter nanotubes, which maintained their fibroblastoid morphologies in the absence of Erk inhibition. Collectively, these results indicate that a titanium-based nanotube surface can support chondrocytic functions among chondroprogenitors, and may therefore be useful for future cartilaginous applications. PMID- 21677508 TI - A case of thyroiditis during natalizumab therapy for multiple sclerosis. PMID- 21677507 TI - Steroid myopathy: some unresolved issues. AB - Steroid myopathy is a non-inflammatory toxic myopathy that occurs as side effect of exogenous and endogenous glucocorticoid excess. The purpose of this review is to examine issues that limit our understanding of this myopathy with respect to nosology, etiopathogenesis, conditioning factors, and muscle fiber selectivity. We suggest that if more data were available on these issues, the understanding of steroid myopathy would be enhanced substantially, thus allowing an early detection of its occurrence (before the appearance of clinical or laboratory signs) and a proper treatment of the patients. PMID- 21677509 TI - Endocrinology and art. The hermaphroditos asleep. PMID- 21677510 TI - Autophagy and proteotoxicity in cardiomyocytes. AB - Increasing evidence suggests that misfolded proteins and intracellular aggregates contribute to cardiac disease and heart failure. We wished to determine if autophagic induction by Atg7 is sufficient to reduce misfolded protein and aggregate content in protein misfolding-stressed cardiomyocytes. We used loss- and gain-of-function approaches in cultured cardiomyocytes to determine the effects of ATG7 knockdown and Atg7 overexpression in protein conformation-based toxicity induced by expression of a mutant aB crystallin (CryAB (R120G) ) known to cause human heart disease. We show that Atg7 induces basal autophagy and rescues the CryAB accumulation of misfolded proteins and aggregates in cardiomyocytes. PMID- 21677512 TI - Notes from the Editor-in-Chief. PMID- 21677511 TI - Tuba and N-WASP function cooperatively to position the central lumen during epithelial cyst morphogenesis. AB - The process of epithelial lumenogenesis requires coordination of a network of signaling machinery communicated to each cell through subsequent cell divisions. Formation of a single hollow lumen has previously been shown to require Tuba, a Cdc42 GEF, for Cdc42 activation and correct spindle orientation. Using a Caco-2 model of lumenogenesis, we show that knockdown (KD) of the actin regulator N WASP, causes a multilumen phenotype similar to Tuba KD. Defects in lumenogenesis in Tuba KD and N-WASP KD cells are observed at the two cell stage with inappropriate marking of the pre-apical patch (PAP) - the precursor to lumen formation. Strikingly, both Tuba and N-WASP depend on each other for localization to the PAP. We conclude that N-WASP functions cooperatively with Tuba to facilitate lumenogenesis and this requires the polyproline region of N-WASP. PMID- 21677513 TI - Twisting the lion's tail: Collaborative health policy making in British Columbia. AB - The respective roles of government, academia and health authorities in supporting health systems and service delivery research in the context of health policy making have often been unclear. A new strategy is necessary, one that encompasses the interdependence of research and practice and respects different kinds of knowledge and the needs and capacity of all stakeholders. Reform efforts to date have focused mainly on structural change and genuine collaboration has been pushed to the back seat. A major challenge in the health policy making process is expressing not just what we think but how we think, which requires us to be self aware and critically reflective on how we make sense of our day-to-day realities. Using an analogy with philosophical roots, this essay explores health services research in the context of the BC health system and examines how such research and related activities can be contextualized, understood and applied in health policy making. PMID- 21677514 TI - Playing to our strengths in evidence and policy. AB - Lindstrom, MacLeod and Levy provide an interesting and challenging perspective on collaborative policy making. In this commentary, we argue that effective policy making will require playing to our strengths as policy makers and researchers, rather than the creation of new roles and vehicles. We also argue that we need greater value placed on evidence and intellectual capital across all institutions in our health system. PMID- 21677515 TI - It's a matter of values: partnership for innovative change. AB - We need new ways of thinking and of working in order to accommodate the complexity of the challenges in and urgent need for health system innovation and change. Solution seeking must begin with the convergence of two driving imperatives: the need to ground partnership in shared values and the need for systems thinking. The authors see three core value perspectives as central to partnerships for change: a patient- and family-centred social responsibility and equity paradigm, a commitment to changing outcomes and an evidence-informed strategy that integrates needs for research and knowledge translation. These imperatives can be expressed as a simple value stream: (1) articulate the shared values foundation of key partners; (2) express a common vision for changes needed; (3) develop a governance framework articulating roles, accountability and decision-making; (4) collaborate on an integrated intervention plan that takes complexity into account; and (5) ensure continuous improvement based on measured outcomes. The authors link this value stream to a six-point framework of guiding principles for innovation and implementation and discuss these six principles: values, systems, thinking, leadership, governance, learning networks and innovation research. Working partnerships among government, health services researchers and academic health science networks are essential if innovative change is to be implemented and sustained. PMID- 21677516 TI - Lion king or Aslan: a tale from Narnia! AB - In the Chronicles of Narnia series by C.S. Lewis, Aslan the all-powerful but benevolent lion does not need to have his tail twisted; rather, he twists tails to create convergence and harmony in his dream world. In this issue's lead article, "Twisting the Lion's Tail: Collaborative Health Policy Making in British Columbia," the authors discuss the problems regarding better coordination of health services research, knowledge translation and policy making. The roles of academia, health authorities and government are presently unclear, with leadership differences, power discrepancies, conflicting agendas, lag times and systemic structural complexity. Exploring these issues in British Columbia, Lindstrom, MacLeod and Levy advocate a change in perspective from practice gaps to bridging knowledge boundaries. Recommendations include networking of academia, action research and strengthening of relationships between stakeholders. However, a key cohesive element seems missing. Health technology assessment (HTA) is a formidable, dynamic driving force. With over 20 years' experience in HTA, Canada has a number of world-class innovative agencies federally and provincially that actively involve academia to generate evidence for informed policy making. Increased use of evidence-based medicine in research and the clinic may be achieved by augmenting HTA's scientific capacity through the creation of pan Canadian exchange forums and by boosting the demand for knowledge translation. PMID- 21677517 TI - Are we in a pickle? Rethinking the world of research and user interaction. AB - The lion's tail and knowledge boundaries are two analogies referred to in the lead essay by Lindstrom, MacLeod and Levy. These may be helpful but require slight readjustment. Grabbing onto the lion's tail implies one reality and one intersection point, whereas the old analogy of the blind men and the elephant shows that various perspectives are required. Integrated knowledge translation refers to user involvement throughout the research process. Participatory models are one form of integrated knowledge translation, but caution is required to help maintain the knowledge boundaries. There is the real danger of one group becoming "pickled," or having unbalanced osmotic pressure from another group, resulting in destroyed "cell wall" boundaries. Neither researchers nor users should morph into each other but should, rather, fulfill unique roles within a respectful, trusted research relationship. Lessons learned at the Manitoba Centre for Health Policy teach us that collaborative health services research takes time, money, mutual understanding and respect (including respect from academic institutions for this paradigm of research). This requires a dedicated centre of core group scientists willing to devote the necessary time. Diffused networks may not be stable enough to maintain the long-term relationship building required for the intersection of researchers and decision-makers. PMID- 21677518 TI - Musings on collaborative health policy - 15 years on. AB - Strategies to facilitate an understanding of successful collaborations between researchers and policy makers in the article "Twisting the Lion's Tail: Collaborative Health Policy Making in British Columbia" have relatively good face validity and fairly good construct validity. It's been my experience, however, that strategies that work for one project don't necessarily work for others and strategies that work for parts of one project don't always work for other parts of the same project. What seems important is that health policy collaborators establish clarity on roles, responsibilities and rules of engagement for specific projects, knowing prospectively that these will vary across time and depending on the nature of a project. PMID- 21677519 TI - A call for a new connectivity. AB - "Twisting the Lion's Tail" is a valuable and timely contribution to the literature on the need to break down silo thinking and acting. If we stay within a narrow silo by suggesting that researchers generate knowledge, practitioners use the knowledge and then researchers evaluate the results, we will not get to the system thinking view articulated in the lead paper. The author hopes his observations presented in this commentary add to the conversation. PMID- 21677520 TI - Evidence over barriers: important but not enough. AB - Overcoming the boundary conditions that impede the flow of evidence derived from research from academia to healthcare decision-makers in government and their agencies continues to be a challenge. But even the reduction/elimination of all such barriers and perfect collaboration are unlikely to yield what those of us in the "real world" yearn for, doing the right things right - policy and other decisions perfectly informed by evidence of what works and what doesn't to achieve a defined outcome. For that to happen, the calculus of decision-makers would have to exclude or evidence would have to trump political considerations, both large P and small p, an unlikely accomplishment in British Columbia or anywhere in our so-called healthcare system. That's reality! PMID- 21677523 TI - From the Editor-in-Chief. AB - This issue of World Health & Population presents papers that have been published online by WHP and are selected here as representative of recent interesting contributions to the journal. Three of the five articles originate from Nigeria, and two of these focus on malaria. The other two articles report on healthcare in South Asian settings - slums in Calcutta (Kolkata) and health facilities planning in the city of Khulna in Bangladesh. PMID- 21677524 TI - The potential for transmission of hospital-acquired infections by non-critical medical devices: the role of thermometers and blood pressure cuffs. AB - Healthcare-associated infection (HAI) is a major but often neglected public health problem. Most attention to HAI prevention is given to high-risk invasive diagnostic and therapeutic healthcare tools, while the importance of less critical tools tends to be underestimated. This study was designed to assess the potential contributory role played by thermometers and blood pressure cuffs in HAI transmission in a Nigerian teaching hospital. Analysis of swabs from thermometers and blood pressure cuffs used in the teaching hospital was conducted using standard microbiological techniques. PMID- 21677525 TI - Knowledge of malaria and preventive measures among pregnant women attending antenatal clinics in a rural local government area in Southwestern Nigeria. AB - OBJECTIVE: This study determined the level of knowledge of malaria and preventive measures among pregnant women and its influence on the uptake of preventive measures. METHODS: A cross-sectional survey was carried out among 209 participants selected from pregnant women attending antenatal clinics in primary healthcare centres in Irepodun/Ifelodun, a local government area in Ekiti state, Nigeria. RESULTS: Knowledge of malaria was found to be very good, average and poor among two (1.0%), 165 (78.9%) and 42 (20.1%) respondents, respectively. Of the 109 (52.2%) respondents who had heard about intermittent preventive treatment, eight (7.3%) scored "very good" on knowledge, while 53 (48.6%) and 48 (44.1%) scored "average" and "poor," respectively. Of the 144 (68.9%) respondents who had heard about insecticide-treated nets, 95 (66.0%) scored "good" on knowledge, while 49 (34.0%) scored "poor." Factors that significantly influenced knowledge about malaria were occupation, level of education, months at first appearance at antenatal clinic and transportation cost. Knowledge significantly influenced uptake of insecticide-treated nets and intermittent preventive treatment in pregnancy ( p < .05). CONCLUSION: There is a need to intensify efforts to provide health education on malaria and preventive measures as well as to encourage preventive practices among pregnant women. PMID- 21677526 TI - Balancing the present and the future: a study of contraceptive use in Calcutta's slums. AB - Calcutta, an important metropolitan city in eastern India, has a large slum population. Despite the poor economic status of this population, analysis of DHS data (2004-2005) reveals that contraceptive use levels in Calcutta slums is quite high, with a large proportion preferring terminal methods. Econometric analysis reveals that cultural factors are important determinants of contraceptive use. Results also indicate that respondents attempt to balance current needs (by trying to limit family size through use of contraceptives) but also try to provide for the future (by having at least one son before adopting family planning methods). PMID- 21677527 TI - Measuring physical accessibility to health facilities--a case study on Khulna City. AB - Improving health services is a crucial issue and an immense challenge for the government of any Third World country. Bangladesh lacks healthcare services, one of the basic necessities of life. This paper demonstrates a method for estimating the geographical accessibility of health facilities by population coverage, average travel time and distance to the closest hospital. This analysis was applied to community units in the research area, allowing geographical access to be linked to people. The study area was divided into hexagons of equal size, and accessibility was measured from the centre of each hexagon. Despite the abundance of evidence on the inadequacy of health services in Khulna City, this study has given us a diverse dimension of possibilities. The study found that even with existing health facilities, discontent about the unavailability of health services can be mitigated in most areas. Exceptions are some peripheral areas, where average travel time to reach the city centre and distance from hospital services is greater. PMID- 21677528 TI - Assessing the progress of malaria control in Nigeria. AB - One third of the world's malaria deaths occur in Nigeria. It is doubtful whether Nigeria will meet the malaria control target of the Millennium Development Goals by 2015, having failed to meet the Abuja target to halve the burden of malaria by 2010. This paper assesses the current malaria burden and progress toward malaria control. Substantial data were obtained from the 2008 Nigeria Demographic and Health Survey and other secondary sources. Data showed that the malaria burden is still enormous because of inadequate control efforts. In 2008, only 17% of Nigerians owned at least one net, compared with 12% in 2003. Eight percent owned an insecticide-treated mosquito net (ITN), but only 6% of under-five children and 5% of pregnant women slept under an ITN. Only one third of under-five children with fever received antimalarial drugs, while one fifth of pregnant women took antimalarial drugs for prevention. Chloroquine is still the most common drug used in malaria treatment, despite its ban in first-line treatment since 2005. The paper concludes that scaling up home management of malaria and a community centred approach to ITN and artemisinin-based combination therapy provisioning should be prioritized. PMID- 21677529 TI - World health & population. PMID- 21677530 TI - Engaging informal providers in TB control: what is the potential in the implementation of the WHO Stop TB Strategy? A discussion paper. AB - The World Health Organization (WHO) Stop TB Strategy calls for involvement of all healthcare providers in tuberculosis (TB) control. There is evidence that many people with TB seek care from informal providers before or after diagnosis, but very little has been done to engage these informal providers. Their involvement is often discussed with regard to DOTS (directly observed treatment - short course), rather than to the implementation of the comprehensive Stop TB Strategy. This paper discusses the potential contribution of informal providers to all components of the WHO Stop TB Strategy, including DOTS, programmatic management of multi-drug-resistant TB (MDR-TB), TB/HIV collaborative activities, health systems strengthening, engaging people with TB and their communities, and enabling research.The conclusion is that with increased stewardship by the national TB program (NTP), informal providers might contribute to implementation of the Stop TB Strategy. NTPs need practical guidelines to set up and scale up initiatives, including tools to assess the implications of these initiatives on complex dimensions like health systems strengthening. PMID- 21677531 TI - Privatization and management development in the healthcare sector of Georgia. AB - Healthcare reforms in Georgia parallel some of the major changes made by other Central and Eastern European countries. This is especially true of efforts to privatize the health sector and secure capital investments from Western Europe. Privatization of Georgian healthcare requires an understanding of the Soviet-era healthcare system and ideological orientation. Many of the issues and problems of privatization in Georgia require new knowledge to enhance equity outcomes, improve financial performance, increase access to care and encourage healthcare competition. Training existing and future healthcare leaders in modern management theory and practice is paramount. A university based health-management education partnership model was developed and implemented between several universities in the United States and Europe, along with two Georgian universities, to address workforce demands, changing market conditions, management knowledge and leadership competencies. Health-management education concentrations were developed and implemented along with several short courses to meet market demand for trained leaders and managers. PMID- 21677532 TI - Treating common illnesses among children under five years: a portrayal of health seeking behaviours and practices in the northern areas of Pakistan. AB - BACKGROUND: Inappropriate practices and behaviours while treating a child's illness impede correct medical consultation. We studied the health seeking behaviours of people engaging with healthcare systems for the treatment of under five children. METHODOLOGY: In the Ghizer District of the Northern Areas of Pakistan, a descriptive cross-sectional household survey was conducted in a random sample of 25 communities. Respondents were either a parent or caregiver of the child. RESULTS: Malaria, fever and diarrhea were found in almost one third of the children under five. One third of respondents did not know the cause of the child's illness. For seeking quality care, the majority visit private clinics, but home remedies, traditional practices and consultation with a faith healer were also common. Lack of knowledge about the child's illness and not making it a priority, lack of money and restricted women's social mobility are factors behind the delayed consultation (median delay: 2 to 3 days). CONCLUSION: Health education and health promotion programs must address the knowledge gaps about children's illnesses and advocate appropriate health-seeking behaviours. Issues around quality of care in government centres and affordability in the private health sector must be addressed in order to improve health service utilization. PMID- 21677533 TI - Religion, condom use acceptability and use within marriage among rural women in Malawi. AB - INTRODUCTION: Correct and consistent condom use within an HIV-discordant partnership could prevent sexual transmission of human immunodeficiency virus (HIV). METHODS: Data on ever-married women from rural Malawi were obtained from the Malawi Diffusion and Ideational Change Project (MDICP) of 2006. We assessed the strength of association between religion and acceptability of condom use within marriage in general and also when one of the partners is suspected or known to be HIV infected. RESULTS: A total of 1,664 ever-married women participated in the MDICP 2006. Of these, 66.7% believed condom use was acceptable within marriage when one partner suspects or knows that the other was HIV infected; 38.2% believed condoms were acceptable within marriage generally. Only 13.8% reported ever having used condoms within the current or most recent marriage. Multivariate analysis found no difference in acceptability of condoms within marriage between Christians and Muslims, or between Catholics and all but one of the individual denominations assessed. CONCLUSION: Christian women in rural Malawi were no more or no less likely to accept condom use than Muslim women; there was also no difference in attitude toward condom use within marriage among Malawian women. PMID- 21677534 TI - SATB2 in combination with cytokeratin 20 identifies over 95% of all colorectal carcinomas. AB - The special AT-rich sequence-binding protein 2 (SATB2), a nuclear matrix associated transcription factor and epigenetic regulator, was identified as a tissue type-specific protein when screening protein expression patterns in human normal and cancer tissues using an antibody-based proteomics approach. In this respect, the SATB2 protein shows a selective pattern of expression and, within cells of epithelial lineages, SATB2 expression is restricted to glandular cells lining the lower gastrointestinal tract. The expression of SATB2 protein is primarily preserved in cancer cells of colorectal origin, indicating that SATB2 could function as a clinically useful diagnostic marker to distinguish colorectal cancer (CRC) from other types of cancer. The aim of this study was to further explore and validate the specific expression pattern of SATB2 as a clinical biomarker and to compare SATB2 with the well-known cytokeratin 20 (CK20). Immunohistochemistry was used to analyze the extent of SATB2 expression in tissue microarrays with tumors from 9 independent cohorts of patients with primary and metastatic CRCs (n=1882). Our results show that SATB2 is a sensitive and highly specific marker for CRC with distinct positivity in 85% of all CRCs, and that SATB2 and/or CK20 was positive in 97% of CRCs. In conclusion, the specific expression of SATB2 in a large majority of CRCs suggests that SATB2 can be used as an important complementary tool for the differential diagnosis of carcinoma of unknown primary origin. PMID- 21677535 TI - Role of immunohistochemistry in the evaluation of needle core biopsies in adult renal cortical tumors: an ex vivo study. AB - Multiple therapeutic options for renal tumors that are now available have put pathologists under increasing pressure to render diagnosis on limited material. Results on biopsies by hematoxylin and eosin (H&E) have historically not been encouraging. Currently, multiple immunohistochemical markers with differential expression in these renal tumors are available. We studied the utility of such markers on needle biopsies that were obtained ex vivo. After nephrectomy, two 18 guage cores were obtained and processed routinely. Expressions of carbonic anhydrase (CA) IX, CD117, alpha-methylacyl-CoA racemase (AMACR), cytokeratin 7 (CK7), and CD10 were evaluated. Results, with or without immunostaining, were compared with the final nephrectomy diagnosis. We studied 145 tumors, including 119 renal cell carcinomas (83 clear cell, 18 papillary, 14 chromophobe, and 4 type unclassified), 11 oncocytomas, and 15 miscellaneous tumors. Adequate evaluable material was present in 123 (85%) cases. In such biopsies, 81% of cases were correctly classified by H&E alone, with correct diagnosis in 90% of cases in the most common tumor subtypes (clear cell, papillary and chromophobe renal cell carcinoma, and oncocytoma). By adding immunostains, the accuracy was 90% overall and 99% among the 4 most common subtypes. The following extent and patterns of immuneexpression were highly useful in the diagnoses: diffuse, membranous CAIX expression in clear cell renal cell carcinoma, diffuse positivity for AMACR in papillary renal cell carcinoma, distinct peripheral cytoplasmic accentuation for CD117 in chromophobe renal cell carcinoma, widespread and intense positivity for CK7 in chromophobe and papillary renal cell carcinoma, and diffuse membranous reactivity in clear cell and patchy/luminal in papillary renal cell carcinoma for CD10. In conclusion, utilizing immunostains improves classification of renal tumors on needle biopsy, which may be of particular help for pathologists with limited experience. Both extent and patterns must be considered for a definitive diagnosis. PMID- 21677536 TI - A histologic and immunohistochemical study describing the diversity of tumors classified as sinonasal high-grade nonintestinal adenocarcinomas. AB - Nonintestinal sinonasal adenocarcinomas (SNACs) are somewhat poorly characterized and high-grade nonintestinal SNACs have been only rarely reported. Here, we review our experience with these tumors. Twenty-seven cases of high-grade nonintestinal SNACs were identified from 22 men and 5 women. Ages ranged from 22 to 83 years (mean+/-1 standard deviation=54.7+/-18.6 y; median=60 y). Thirteen cases involved the nasal cavity and sinuses, 10 involved the nasal cavity only, and 4 involved sinuses only. Most cases had marked cytologic and nuclear pleomorphism, abundant mitotic activity, and necrosis; however, these features were not uniform. Although histologically heterogeneous, recurrent growth patterns were seen that resembled other neoplasms of the area. Tumors lacked CDX2 and CK20 immunoreactivity (aside from rare CK20 immunoreactive cells). High-grade nonintestinal SNACs are more common in men and, although they occur over a wide age range, they are much more common in older individuals. Histologically, they show a great deal of heterogeneity. PMID- 21677538 TI - Primary schwannoma of the bone: a clinicopathologic and radiologic study of 17 cases. AB - Primary schwannoma of the bone, defined as arising within the medullary cavity and radiologically mimicking more common primary bone tumors, is rare. We present 17 tumors, 13 conventional schwannomas, and 4 melanotic type. Collectively, they represented <1% of all primary bone tumors seen at Mayo Clinic over a 33-year period. Most tumors affected long bones. There was a slight female predilection. Fifteen tumors were sporadic, and 2 were syndrome associated (Carney complex). Pain was the most common symptom. Given their rarity, schwannomas of the bone are not usually included in the differential diagnosis of primary osseous spindle cell tumors. Thus, they are prone to misdiagnosis and overtreatment. Similar to their more common extraosseous counterparts, primary schwannomas of the bone behave in a benign manner and are successfully treated by local excision alone. PMID- 21677537 TI - Hyaline globules in neuroendocrine and solid-pseudopapillary neoplasms of the pancreas: a clue to the diagnosis. AB - Distinguishing between solid-pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine tumors (PanNETs) may pose a diagnostic dilemma. Both can demonstrate solid growth patterns, and both can be immunoreactive with neuroendocrine markers such as synaptophysin and CD56. One well-established feature of SPNs is the presence of hyaline globules, which in contrast has only rarely been reported in PanNETs. Clinicopathologic features of 361 cases originally classified as PanNETs were examined. Of these, 24 tumors (6.6%) had hyaline globules, raising the possibility of SPN. Immunohistochemistry for beta catenin was performed on these 24 neoplasms, and showed nuclear labeling in 6 cases. These 6 cases, which also demonstrated cytoplasmic CD10 staining, were reclassified as SPNs. The remaining 18 cases maintained their original diagnosis as PanNETs, and the hyaline globules in these cases were periodic acid-Schiff (PAS) positive, diastase resistant, and immunoreactive with alpha-1-antitrypsin. All 24 cases were histologically re-evaluated, and the pattern of invasion, presence of clear cells, and nuclear grooves were found to be helpful in distinguishing SPNs from PanNETs. We conclude that the presence of hyaline globules should raise SPNs in the differential diagnosis of a solid cellular neoplasm of the pancreas. However, this should not be used as the sole criterion in the diagnosis of SPNs, as hyaline globules may also be seen in 5% of PanNETs. Immunohistochemical and histologic features supporting the diagnosis of SPNs over PanNETs include CD10 and nuclear beta-catenin labeling, an insidious pattern of invasion, clear cells, and nuclear grooves. PMID- 21677539 TI - Immunohistochemistry for ERG expression as a surrogate for TMPRSS2-ERG fusion detection in prostatic adenocarcinomas. AB - BACKGROUND: TMPRSS2-ERG fusions have been identified in about one-half of all prostatic adenocarcinomas (PCas). Fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction have been the most commonly used techniques in this setting. The aim of this study was to evaluate the utility of ERG immunoexpression as a surrogate for TMPRSS2-ERG fusion in a large series of PCa cases. MATERIALS AND METHODS: Four hundred twenty-seven radical retropubic prostatectomy tissue samples were used to construct 10 tissue microarrays (TMAs). FISH analysis was previously conducted using dual-color interphase break-apart probes for the 5' and 3' regions of the ERG gene. ERG expression was evaluated using a commercial rabbit anti-ERG monoclonal antibody (clone EPR3864; Epitomics, Burlingame, CA). Each TMA spot was independently assessed, and any nuclear staining positivity was considered as indicative of ERG expression. RESULTS: TMPRSS2-ERG fusions were detected by FISH in 195 (45.7%) of the PCa cases. ERG immunoexpression was found in 192 (45.0%) of the PCa cases and in none of the nontumoral tissue samples. Mean ERG H-scores were significantly higher in tumors harboring FISH-detected TMPRSS2-ERG fusions (P<0.00001), and there was a strong association between ERG immunohistochemical expression and the TMPRSS2-ERG status defined by FISH (P<0.00001), with a sensitivity of 86% (95% CI, 80%-90%) and a specificity of 89% (95% CI, 84%-93%). Receiver-operating characteristic curve analysis showed that ERG immunoexpression had a high accuracy for identifying TMPRSS2-ERG fusions detected by FISH, with an area under the curve of 0.87 (95% CI, 0.84%-0.91; P<0.00001). CONCLUSIONS: We found that ERG immunohistochemical expression has a high accuracy for defining the TMPRSS-ERG fusion status. ERG immunohistochemistry may offer an accurate, simpler, and less costly alternative for evaluation of ERG fusion status in PCa than FISH. PMID- 21677540 TI - Gastric pit dysplasia in adjacent gastric mucosa in 414 gastric cancers: prevalence and characteristics. AB - Despite wide acceptance of the chronic gastritis-intestinal metaplasia-dysplasia carcinoma sequence, especially for intestinal-type gastric adenocarcinoma, the precise nature of the subtle precursor lesions of gastric cancer remains to be delineated. For example, pit dysplasia with surface foveolar maturation is not well defined, nor is its prevalence and biological characteristics well characterized. We have evaluated the surrounding gastric mucosa of 414 gastric cancers for the presence of gastric pit dysplasia. We investigated its relationship with various clinicopathological and immunophenotypic features of gastric adenocarcinoma, as well as the severity and extent of any surrounding gastritis and intestinal metaplasia. p53 expression and Ki-67 proliferation index were also evaluated. We have found that 21.0% (n=87) of gastric cancer cases showed pit dysplasia in adjacent gastric mucosa. Gastric cancers with pit dysplasia were significantly associated with older age, male sex, body/fundic location, and intestinal histologic type (P<0.05). Interestingly, gastric mucin containing intestinal metaplasia (incomplete intestinal metaplasia) was highly associated with adenocarcinoma with pit dysplasia (P=0.000). In addition, MUC6 expression in gastric adenocarcinoma was associated with pit dysplasia (P=0.036). p53 overexpression and increased Ki-67 proliferation index were more evident in gastric pit dysplasia compared with adjacent gastric mucosa. We suggest that gastric pit dysplasia is an important candidate precursor of gastric adenocarcinoma and may represent another morphologic step in the pathogenesis of gastric adenocarcinoma, especially of intestinal type. More detailed prospective studies are needed to determine the precise significance of these findings. PMID- 21677541 TI - Low-grade fibromyxoid sarcoma of the small intestine: report of 4 cases with molecular cytogenetic confirmation. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue tumor that typically involves the deep soft tissues of the extremities. However, LGFMS has been described in other locations including the head and neck, retroperitoneum, and mesentery. Translocations involving the FUS gene located at 16p are considered to be highly specific for the diagnosis of this tumor when present in conjunction with the appropriate morphologic appearance. We report 4 cases of LGFMS arising in the small bowel. The patients' ages (3 female, 1 male) ranged from 52 to 71 years (median, 61 y). None of the patients had a history of soft tissue sarcoma. An intramural tumor was presented in all cases, ranging from 4.5 to 14.5 cm in greatest diameter (mean, 10 cm). Microscopically, the tumors consisted of an admixture of hypocellular, heavily collagenized zones and more cellular myxoid nodules, containing a greater number of neoplastic cells arranged around characteristic curvilinear vessels. By immunohistochemistry, all tumors were positive for vimentin and negative for smooth muscle actin, CD117, CD34, and S100 protein. Fluorescence in situ hybridization for rearrangement of the FUS locus at 16p11 was positive in 3 informative cases. Follow-up information was available in 3 cases; 2 patients are alive without disease and another patient died of disease. We conclude that LGFMS should be included in the differential diagnosis of fibrous or myxoid spindle cell tumors of the gastrointestinal tract. On the basis of limited follow-up, the natural history of enteric LGFMS seems to be similar to that of LGFMS in other locations, with potential for late metastases. PMID- 21677542 TI - Thymic carcinoma associated with multilocular thymic cyst: a clinicopathologic study of 7 cases. AB - We present 7 cases of thymic carcinoma associated with a multilocular thymic cyst (MTC). The patients were 5 men and 2 women aged 22 to 71 years (mean, 49.3 y). Clinically, 6 patients presented with chest, sternal, or upper extremity pain, and in 1 patient the tumor was an incidental finding. Grossly, 4 tumors were described as multilobulated solid-cystic masses, whereas 3 cases were described as solid tumors with a white-yellow cut surface and areas of hemorrhage and necrosis. The tumor size ranged from 7.0 to 10.0 cm (mean, 8.1 cm). Histologically, 4 cases were classified as squamous cell carcinoma, and 1 each as sarcomatoid (spindle) cell carcinoma, papillary carcinoma, and basaloid carcinoma. In addition to the tumor component, prominent MTC changes were observed in the adjacent remnant thymic tissue. Immunohistochemical studies were conducted in 2 cases of squamous cell carcinoma. The neoplastic cells were positive for cytokeratin (CK), CK5/6, and p63, and showed variable reactivity for CK7 and CD5. Clinical follow-up showed that 4 patients were alive and well, 2 to 63 months after diagnosis, and 3 patients were alive with disease, 13 to 33 months after diagnosis. This study expands the morphologic spectrum of thymic carcinoma associated with MTC, detects a higher incidence than previously believed, and highlights the importance of adequate sampling and proper evaluation of all cystic lesions of the anterior mediastinum so as not to mistake malignancy for a benign cystic process. PMID- 21677543 TI - A case of hairy cell leukemia with CCND1-IGH@ translocation: indolent non-nodal mantle cell lymphoma revisited. AB - CCND1-IGH@ translocation is considered pathognomonic of mantle cell lymphoma (MCL), as this distinct chromosomal abnormality has not been reported in any other subtypes of mature B-cell lymphoma. Despite this unifying cytogenetic feature, MCL encompasses 2 distinct groups: the usual MCLs with an overall survival of 3 to 5 years and the so-called "indolent non-nodal mantle cell lymphomas (INNMCLs)." The latter group of MCLs has quite distinctive clinical features, including frequent neoplastic lymphocytosis, absent peripheral lymphadenopathy, and indolent clinical courses. The clinical, biological, and molecular characteristics of INNMCL are still not well understood. Herein, we report a patient with clinical and cytogenetic features of INNMCL with overlapping morphologic and immunophenotypic features resembling hairy cell leukemia (HCL). After failing the chemotherapeutic regimen for MCL, he received a HCL-directed therapy and achieved durable response. This case suggests that CCND1 IGH@ may rarely occur in other mature B-cell neoplasms such as HCL. Further clinicopathologic studies of the so-called "INNMCL" are warranted. PMID- 21677544 TI - Diagnosis of "Fetal lung interstitial tumor" requires a FISH negative for trisomies 8 and 2. PMID- 21677546 TI - TTF-1 expression in breast carcinoma-the chosen clone matters. PMID- 21677548 TI - Epithelioid Sarcoma-like hemangioendothelioma (pseudomyogenic hemangioendothelioma). PMID- 21677549 TI - Why and when should we conduct collaborative international oncology nursing research? PMID- 21677550 TI - A purposeful career path to make a difference in cancer care. PMID- 21677551 TI - Patients' stories provide insights. PMID- 21677556 TI - What's new in Shock, July 2011? PMID- 21677557 TI - The anti-inflammatory potential of selective cholinergic agonists. PMID- 21677558 TI - Sepsis, kidney, and tissue oxygenation: new methods, new insights, new perspectives? PMID- 21677559 TI - Participatory dreaming: a unitary appreciative inquiry into healing with women abused as children. AB - Unitary appreciative inquiry was used to explore healing in the lives of 11 women abused as children using a model of participatory dreaming. Aesthetics, imagery, and journaling were used in a participatory design aimed at the appreciation of healing in the lives of the participants as it related to the abuse. Using Cowling's theory of unitary healing, research and practice were combined within a unitary-transformative framework. Participatory dreaming was useful in illuminating the life patterning in the lives of the women and promoted the development of new knowledge and skills that led to change and transformation, both individually and collectively. PMID- 21677560 TI - The challenges of improving survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma. PMID- 21677561 TI - Use of mesh during ventral hernia repair in clean-contaminated and contaminated cases: outcomes of 33,832 cases. AB - OBJECTIVE: To analyze and compare postoperative occurrences following ventral hernia repairs (VHRs) using mesh in clean-contaminated and contaminated wounds. BACKGROUND: Ventral hernia repairs using mesh is one of the most common surgical procedures performed. However, guidelines and outcomes of repairs in clean contaminated or grossly contaminated ventral hernias have not been established. METHODS: Patients who underwent VHR with mesh between the dates January 1, 2005 and April 4, 2010 at all hospitals in the United States participating in the National Surgical Quality Improvement Program (NSQIP) were reviewed. Data from 33,832 patients were analyzed by field contamination level and then compared with data from patients who underwent VHR without mesh. Data were analyzed using the odds ratio test with a 95% confidence interval. RESULTS: The odds of having one or more postoperative occurrences were significantly greater in clean contaminated and contaminated cases using mesh when compared with clean cases, with odds ratios of 3.56 (3.25-3.89) and 5.05 (1.78-12.41), respectively. There was a significantly increased risk of superficial surgical site infections (SSI) (2.53), deep SSI (3.09) and organ/space SSI (6.16), wound disruption (4.41), pneumonia (4.43), and sepsis (4.90) for clean-contaminated cases. Both clean contaminated and contaminated cases had an increased risk of septic shock (5.82 and 26.74, respectively), and need for ventilator for more than 48 hours (5.59 and 26.76, respectively). In addition, there was a significantly increased odds ratio of complications in patients who underwent VHR with mesh (3.56) to nonmesh (2.52) in clean-contaminated cases. CONCLUSION: There is a significant increase in risk of postoperative occurrences following VHRs using mesh in clean contaminated and contaminated cases relative to clean cases. We recommend avoiding the use of mesh in any level of contamination. PMID- 21677562 TI - Nomogram to predict risk of 30-day morbidity and mortality for patients with disseminated malignancy undergoing surgical intervention. AB - OBJECTIVE: To estimate individual risk of 30-day surgical morbidity and mortality after surgical intervention for patients with disseminated malignancy (DMa). BACKGROUND: Patients with DMa frequently require surgical consultation for palliative operations. Although these patients are at high risk for surgical morbidity and mortality, limited data exist allowing individual risk stratification. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2005 to 2007, we identified 7447 patients with DMa. Each of the 53 preoperative ACS NSQIP variables was analyzed to assess risk of morbidity and mortality. Logistic regression models were developed using stepwise model selection and generalized additive models. Covariates were evaluated for nonlinearity and interactions among variables. We constructed nomograms utilizing clinically and statistically significant covariates to predict 30-day risk of morbidity and mortality. RESULTS: Overall 30 day unadjusted morbidity and mortality rates were 28.3% and 8.9%, respectively. Mortality rates reached 18.4% for vascular procedures and 27.9% for emergent operations. Increasing age, impaired functional status, Do-Not-Resuscitate status, impaired respiratory function, ascites, hypoalbuminema, elevated creatinine, and abnormal WBC were all significant predictors (P < 0.0001) of increased morbidity and mortality on multivariate analysis. Nomograms to predict individual 30-day risk of complications and death based on preoperative factors were developed and validated by bootstrapping. Concordance indices were 0.704 and 0.861 for morbidity and mortality, respectively. CONCLUSIONS: Surgical intervention among patients with DMa is associated with substantial morbidity and mortality. We have constructed nomograms to predict individual risk of 30-day morbidity and mortality. These have significant implications for surgical decision-making in this group of patients. PMID- 21677563 TI - Prevalence of painful musculoskeletal conditions in female and male veterans in 7 years after return from deployment in Operation Enduring Freedom/Operation Iraqi Freedom. AB - BACKGROUND: We sought to describe sex differences in the prevalence of painful musculoskeletal conditions in men and women Veterans after deployment in Operation Enduring Freedom (Afghanistan) and Operation Iraqi Freedom (Iraq) (OEF OIF). METHODS: This is an observational study using Veterans Affairs (VA) administrative and clinical databases of OEF-OIF Veterans who had enrolled in and used VA care. The prevalence of back problems, musculoskeletal conditions, and joint disorders was determined at years 1 through 7 after deployment for female and male Veterans using ICD-9 code groupings for these conditions. RESULTS: Female Veterans were younger (mean age 29 vs. 30, P<0.0001), more likely to be African American (26% vs. 13%, P<0.0001), and less likely to be married (34% vs. 47%, P<0.0001). For both female and male Veterans, the prevalence of painful musculoskeletal conditions increased each year after deployment. After adjustment for significant demographic differences, women were more likely than men to have back problems [year 1 odds ratio (OR) 1.06 (1.01, 1.11)], musculoskeletal problems [year 1 OR 1.32 (1.24, 1.40)], and joint problems [year 1 OR 1.36 (1.21, 1.53)] and the odds of having these conditions increased each year for women compared with men in years 1 to 7 after deployment. DISCUSSION: To provide quality care to female Veterans, the VA must understand the impact of deployment on women's health. Our findings provide an important picture of the increasing prevalence of musculoskeletal conditions in the female Veteran population and highlight the importance of the VA targeting treatment programs that focus on issues of particular importance to women with musculoskeletal pain. PMID- 21677564 TI - Persistent hiccups with continuous intrathecal morphine infusion. AB - OBJECTIVE: To report a case of hiccups secondary to intrathecal (IT) morphine infusion. METHODS: Case report and discussion. RESULTS: The hiccups in our patient resolved on substitution of IT morphine infusion with hydromorphone. DISCUSSION: We report a case of a 44-year-old man who developed persistent hiccups with IT morphine infusion pump therapy. The hiccups persisted despite various nonpharmacological and pharmacological measures. The untoward symptom resolved after substitution of IT hydromorphone for IT morphine. PMID- 21677565 TI - Analysis of shortened versions of the tampa scale for kinesiophobia and pain catastrophizing scale for patients after anterior cruciate ligament reconstruction. AB - OBJECTIVE: Recent work suggests that psychological influence on pain intensity and knee function should be considered for patients after anterior cruciate ligament reconstruction (ACLR). The Tampa Scale for Kinesiophobia (TSK) and Pain Catastrophizing Scale (PCS) have been used to determine psychological influence in these patients. However, TSK and PCS factor structures have not been described for patients with ACLR. This study investigated 2 groups of patients post-ACLR to determine if the use of shortened questionnaires is warranted. METHODS: Cross sectional study in which patients completed measures during early (n=105, median days from surgery=56.0) and late (n=184, median days from surgery=195.0) postoperative phases of ACLR rehabilitation. RESULTS: Shortened questionnaires for fear of pain, fear of injury, and somatic focus were generated for the TSK 11. A shortened questionnaire for magnification/helplessness and rumination was generated for the PCS in the late group only. There were minimal differences in the shortened questionnaires for clinical subgroups based on sex, ACLR graft type, method of injury, or nature of injury. Correlation and regression analyses suggested a shortened version of the TSK-11 for fear of injury was appropriate for use in the early postoperative phase, whereas the original TSK-11 scale may be appropriate for use in the late postoperative phase. There were no shortened versions of the PCS for consideration in the early postoperative phase, but a shortened version for magnification/helplessness was appropriate for use in the late postoperative phase. DISCUSSION: Shortened versions of the TSK-11 and PCS may be appropriate for ACLR populations, depending on the postoperative phase. These data may guide future research of psychological factors in ACLR populations so that levels predictive of risk for developing chronic pain and/or inability to return to pre-injury activity levels can be determined. PMID- 21677566 TI - Is physiotherapy effective for children with complex regional pain syndrome type 1? AB - OBJECTIVES: This study synthesized current research evidence on the effectiveness of physiotherapy for the management of children diagnosed with complex regional pain syndrome type 1 (CRPS-1), to provide up-to-date physiotherapy treatment recommendations, and to identify areas that require further investigation. METHODS: Nine electronic databases were searched for quantitative studies that evaluated the effect of physiotherapy on children with CRPS-1. The methodological quality of the studies was evaluated using the Critical Review Form. Data were extracted regarding the study design, participant characteristics, types of outcome measures used, and physiotherapy technique used and its effectiveness. RESULTS: The search strategy identified 303 potential studies, of which 12 met the inclusion criteria (1 randomized controlled trial, 1 comparative study, 10 case series). The methodological quality of all studies was rated as poor to fair. The "stand-alone" value of physiotherapy could not be determined as physiotherapy was prescribed in conjunction with psychological and medical interventions. There is low volume and poor-to-fair quality evidence which suggests that physiotherapy prescribed with other interventions may lead to short term improvement in the signs and symptoms of CRPS-1 or functional ability in children with CRPS-1, and the relapse rate may be moderately high. DISCUSSION: High-quality studies are required in this area. These studies should evaluate a package of care (which includes physiotherapy); they should investigate the effects of physiotherapy treatments that have proven effectiveness in adults with CRPS-1; they should use psychometrically sound measures to evaluate outcome; and the nature of physiotherapy should be detailed in future publications to enable replication in the clinical setting. PMID- 21677567 TI - Prevalence and characteristics of widespread pain in female primary health care patients with chronic low back pain. AB - OBJECTIVES: To estimate the prevalence of widespread pain (WP) according to the American College of Rheumatology, 1990, in women with chronic low back pain (CLBP) consulting primary health care and to evaluate the differences in body function, activity, participation, environmental factors, health-related quality of life, and other health-related aspects between patients having CLBP with or without WP. METHODS: A cross-sectional study of women with CLBP including clinical assessment and questionnaires was conducted. Patients were categorized as having CLBP with or without WP and differences between these groups were evaluated. RESULTS: One hundred thirty patients were assessed. Twenty-eight percent (n=37) had WP. Patients with CLBP+WP showed more impaired physical performance (6-min walk test, handgrip strength), higher numbers of tender points, more severe pain, fatigue, and depression compared with CLBP (P<0.05). The CLBP+WP showed greater activity limitation (P=0.00047). Work disability was 35% (n=13/37) in CLBP+WP compared with 16% (n=15/93) in CLBP (P=0.032). Private social support was negatively impacted in CLBP+WP (P=0.010). The CLBP+WP showed lower health-related quality of life (SF-36) in the physical function, bodily pain, and vitality dimension (P<0.05). More severe clinical stress symptoms and risk for future disability were registered for the CLBP+WP (P<0.001). DISCUSSION: Twenty-eight percent fulfilled the American College of Rheumatology 1990 criteria for WP. When WP was present, patients reported significantly more impaired body functions, more severe activity limitations, and participation restrictions. Environmental factors, health-related quality of life, and other health-related aspects were also negatively impacted. It is suggested that the presence of WP should be evaluated in female patients with CLBP. PMID- 21677568 TI - Prescription long-term opioid use in HIV-infected patients. AB - OBJECTIVES: To examine changes the in use of prescription opioids for the management of chronic noncancer pain in human immunodeficiency virus (HIV) infected patients and to identify patient characteristics associated with long term use. METHODS: Long-term prescription opioid use (ie, 120+ days supply or 10+ prescriptions during a year) was assessed between 1997 and 2005 among 6939 HIV infected Kaiser Permanente members and HIV-uninfected persons in the general health plan memberships. RESULTS: In 2005, 8% of HIV individuals had prevalent long-term opioid use, more than double the prevalence among HIV-uninfected individuals. However, the large increases in use from 1997 to 2005 in the general population were not observed for HIV-infected individuals. The strongest associations with prevalent use among HIV-infected individuals were female sex with a prevalence ratio (PR) of 1.8 (95% CI=1.3, 2.5); Charlson comorbidity score of 2 or more (compared with a score of 0) with a PR of 1.9 (95% CI=1.4, 2.8); injection drug use history with a PR of 1.8 (95% CI=1.3, 2.6); and substance use disorders with a PR of 1.8 (95% CI=1.3, 2.5). CD4, HIV viral load, and acquired immunodeficiency syndrome diagnoses were associated with prevalent opioid use early in the antiretroviral therapy era (1997), but not in 2005. CONCLUSIONS: Long-term opioid use for chronic pain has remained stable over time for HIV patients, whereas its use increased in the general population. The prevalence of prescribed opioids in HIV patients was highest for certain subgroups, including women, and those with a comorbidity and substance abuse history. PMID- 21677569 TI - Patients with temporomandibular disorders have increased fatigability of the cervical extensor muscles. AB - OBJECTIVES: To determine whether patients with myogenous and mixed temporomandibular disorders (TMD) have greater fatigability of the cervical extensor muscles while performing a neck extensor muscle endurance test (NEMET) when compared with healthy controls. METHODS: A total of 151 individuals participated in this study. Of these 47 were healthy controls, 57 patients had myogenous TMD, and 47 patients had mixed TMD. All patients performed the NEMET. The patients were instructed to maintain a prone lying position with the neck unsupported as long as possible, stopping at signs of fatigue or any discomfort. Electromyographic activity of the cervical extensor muscles during the NEMET and the holding time were collected for all patients and were compared across groups. A 1-way analysis of variance was used to evaluate the differences in holding time between patients with TMD and healthy controls. A mixed model analysis was used to evaluate the differences in normalized median frequency at different times (fatigue index) for the cervical extensor muscles while performing the NEMET between patients with TMD and controls. RESULTS: There were statistically significant differences (P<0.05) in the slopes of the normalized median frequency between patients with TMD and healthy controls at 10, 30, 40, 50, 60, 70, 80, 90, and 100 seconds of the NEMET. Holding time was significantly reduced in both patients with myogenous TMD and mixed TMD when compared with healthy controls (P<0.05). DISCUSSION: These results highlight the fact that alterations of endurance capacity of the extensor cervical muscles could be implicated in the neck-shoulder disturbances presented in patients with TMD. PMID- 21677570 TI - Identification of patients with chronic low back pain who might benefit from additional psychological assessment. AB - OBJECTIVES: To identify signs and symptoms that should alert clinicians to the need for additional psychological assessment in patients with chronic low back pain (CLBP). METHODS: In this prospective cohort study, 229 consecutive patients with CLBP who attended an outpatient rehabilitation center were assessed by psychologists and physical therapists before their treatment started. The signs and symptoms assessed by the physical therapists were compared with the assessments made by the psychologists, which were considered to be the reference standard (relevant psychological disturbances, yes or no). Univariable and multivariable regression methods were applied to investigate which signs and symptoms were associated with the reference standard. A receiver operator characteristic (ROC) curve was constructed to assess the overall accuracy of the final model. RESULTS: The psychologists classified 53% of the patients as having relevant psychological disturbances. Univariable analysis revealed statistically significant differences (P<0.05) between the 2 patient groups (relevant psychological disturbances, yes or no) for 10 of the 17 signs and symptoms. Multivariate analysis yielded a screening instrument consisting of the following 4 signs and symptoms: presence of Waddell signs, elevated scores on the pain drawing, absence of a directional preference, and daily use of analgesic medication for CLBP [area under the ROC curve, 0.81 (95% confidence interval: 0.75, 0.87)]. DISCUSSION: This study established a clinically useful screening instrument for the identification of patients with CLBP who might benefit from additional psychological assessment in an outpatient rehabilitation setting. Further research is needed to confirm our preliminary results. PMID- 21677571 TI - Pain has a strong negative impact on the fluoxetine response in hospitalized patients with major depressive disorder. AB - OBJECTIVES: Response to an antidepressant is frequently the main goal in treating depression. The purpose of this study was to identify predictor(s) of response to the antidepressant, fluoxetine. METHODS: One hundred thirty-one newly hospitalized patients with major depressive disorder received fluoxetine (20 mg/d) for 6 weeks. Symptom severity was assessed using the 17-item Hamilton Depression Rating Scale at weeks 0, 1, 2, 3, 4, and 6. Response was defined as a reduction of >=50% of the 17-item Hamilton Depression Rating Scale score. We compared the responders and nonresponders in terms of baseline variables. Pain measures included the Short-Form-36 (SF-36) pain severity score and pain interference score. Univariate logistic regression was used to identify variables associated with fluoxetine response. RESULTS: A total of 66 (58.9%) of the 112 completers were classified as responders after a 6-week treatment. The responders and nonresponders did not differ in baseline variables, except melancholic features (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) and pain measures (SF-36). SF-36 pain severity score had the smallest P value (P=0.015). Its odds ratio (0.70) means that each point increase in the score of pain severity is expected to decrease the chance of response by approximately 30%. CONCLUSIONS: These findings from newly hospitalized patients with multiple pain measures support the previous studies, which enrolled mainly outpatients and found that a higher level of pain can have a strong negative impact on the antidepressant response. These data require confirmation and extension to outpatients and other antidepressants. PMID- 21677572 TI - The metabolism of opioid agents and the clinical impact of their active metabolites. AB - BACKGROUND: The metabolism of opioids is critical to consider for multiple reasons. The most commonly prescribed opioid agents often have metabolites that are active and are the source of both analgesic activity and an increased incidence of adverse events. Many opioids are metabolized by cytochrome P450 enzymes. Polymorphisms in cytochrome P450 genes and inhibition or induction of cytochrome P450 enzymes by coadministered drugs may significantly impact the systemic concentration of opioids and their metabolites and the associated efficacy or adverse events. METHODS: This is a narrative review of the metabolism of various opioids that will highlight the impact of their active metabolites, and the potential impact of cytochrome P450 activity on analgesic activity. RESULTS: An understanding of "opioid metabolic machinery," cytochrome P450 activity, and drug-drug interactions in the context of opioid selection may benefit clinicians and patients alike. CONCLUSIONS: A greater appreciation of the metabolism of commonly prescribed opioid analgesics and the impact of their active metabolites on efficacy and safety may aid prescribers in tailoring care for optimal outcomes. PMID- 21677573 TI - Experienced acetaldehyde reaction does not improve treatment response in outpatients treated with supervised disulfiram. AB - AIM: The major mode of action of disulfiram is assumed to be a psychological deterrence of an acetaldehyde reaction after alcohol consumption. However, it is still unclear whether patients need to experience an acetaldehyde reaction with the help of a "test drink" at the beginning of the therapy to achieve a better efficacy. Therefore, in this study, we test the hypothesis if an experienced acetaldehyde reaction during the therapy with disulfiram predicts better treatment outcome in alcohol-dependent patients. METHOD: We evaluated outcome data of 46 patients treated with supervised disulfiram with experienced versus not experienced acetaldehyde reaction. RESULTS: Alcohol consumption during outpatient disulfiram treatment was reported by 46% of the patients. Ninety percent of these patients reported typical symptoms of an acetaldehyde reaction. Comparing the course of abstinence rates, our results suggest that the experience of an acetaldehyde reaction was not associated with any differences in treatment outcome but with a significant earlier discontinuation of the therapy. CONCLUSIONS: This study supports the position that the experience of an acetaldehyde reaction is not necessary for disulfiram's action and does not lead to a better treatment outcome. Hence, there is no evidence for the necessity of a test drink before the initiation of a supervised disulfiram therapy. PMID- 21677574 TI - The atorvastatin during ischemic stroke study: a pilot randomized controlled trial. AB - OBJECTIVES: Statins have antioxidant, anti-inflammatory, anticoagulant, and profibrinolytic properties that might play a useful role in the acute phase of ischemic stroke. This pilot study assessed the possible neuroprotective action of high-dose atorvastatin administration during the first week after an ischemic stroke, to obtain data for planning a wider multicenter study. METHODS: Sixty-two patients with ischemic stroke, aged 75.3 (SD, +/-11.9) years (68% women), were randomized into a placebo (n = 31) and an atorvastatin 80 mg/d (n = 31) group. The double-blind treatment lasted 7 days. The primary end point was a decrease of National Institutes of Health Stroke Scale score of 4 points or higher after 7 days. Infarct volume measured on computed tomographic scan after 3 days and a modified Rankin Scale of less than 2 at 3 months were secondary end points. RESULTS: There was no difference in the primary end point between the 2 groups (odds ratio, atorvastatin vs placebo, 0.74; 95% confidence interval, 0.26-2.17). Infarct volume also was similar in the 2 groups. Instead, there were more patients with modified Rankin Scale of less than 2 at 3 months in the atorvastatin than in the placebo group (adjusted odds ratio, 6.7; 95% confidence interval, 1.0-45.0; P = 0.05). This prevalence concerned only the subgroup with mild strokes (National Institutes of Health Stroke Scale, <=10; 53.8% vs 15.4%, respectively; P = 0.04). Atorvastatin was well tolerated. CONCLUSIONS: This pilot study was unable to show any short-term benefit of atorvastatin during the acute phase of ischemic stroke. However, it suggested a possible favorable functional effect at 3 months in the least severe strokes, which could be the primary end point for a future multicenter trial. PMID- 21677575 TI - Spontaneously resolving seronegative autoimmune limbic encephalitis. AB - OBJECTIVE: We describe a patient with seronegative autoimmune limbic encephalitis (SNALE) masquerading as glioma. Brain magnetic resonance imaging (MRI) abnormalities, distinctive pathological findings, and spontaneous remission are highlighted. BACKGROUND: There are 15 previously reported SNALE cases, 1 with pathology. MATERIALS AND METHODS: A 66-year-old man presented with prominent amnestic syndrome, progressive cognitive decline, and refractory complex partial seizures. RESULTS: Initial brain MRI suggested herpes limbic encephalitis. A 3 week course of intravenous acyclovir was ineffective. Cerebrospinal fluid analysis revealed no pleocytosis. Repeat brain MRI showed a left uncal hippocampal, contrast-enhancing lesion with mass effect, which was resected. Pathology revealed perivascular and parenchymal mixed lymphocytic inflammatory infiltrates, microglial nodules, neuronophagia, microglial activation, astrocytosis, and lymphocyte emperipolesis within neurons. Thorough searches for infectious pathogens and autoantibodies were negative. Six weeks later, a new enhancing right mesial temporal lesion appeared, with increased seizure activity and further cognitive impairment. Although immune therapy was declined, spontaneous resolution of the new enhancing lesion, with full seizure control and significant cognitive improvement, occurred. CONCLUSIONS: SNALE may masquerade as glioma. Pathologic changes in our case of SNALE are distinctive. Spontaneous resolution of a focal SNALE lesion may potentially occur without immune therapy. PMID- 21677576 TI - Higher autonomic activation predicts better performance in iowa gambling task. AB - OBJECTIVE: To evaluate the relationship between the autonomic nervous system basal state and performance in decision-making tasks. BACKGROUND: The link between performance in decision-making tasks and acute changes in autonomic parameters during their execution has been extensively investigated. However, there is lacking evidence regarding the relationship between decision making and basal autonomic state. METHODS: Resting autonomic nervous system activity in 18 healthy individuals was assessed by means of heart rate variability (HRV) analysis before conducting 3 different decision-making tasks: an ambiguous one, the Iowa Gambling Task; a test that assesses risk-taking behavior, the Game of Dice Task; and a test that assesses reversal learning behavior, the Reversal Learning Task. The tasks were administered in a random manner. RESULTS: There was a direct correlation between the Iowa Gambling Task net score and the resting low frequency HRV (r = 0.73; P < 0.001), which is strongly influenced by sympathetic activity. No correlations were found between HRV and the Game of Dice Task net score or the Reversal Learning Task last error trial. CONCLUSIONS: The results are compatible with the idea that a higher basal activation of autonomic nervous system is beneficial for subsequent decision-making process. PMID- 21677577 TI - Perioperative cardiac evaluation, monitoring, and risk reduction strategies in noncardiac surgery patients. AB - PURPOSE OF REVIEW: Cardiac complications after noncardiac surgery cause significant morbidity and mortality. This review will discuss recent developments in risk stratification, monitoring, and risk reduction strategies. RECENT FINDINGS: The addition of biomarkers for ischemia, left ventricular function, and atherosclerosis to classic cardiac risk factors improves the prediction of both short-term and long-term outcome after noncardiac surgery. Intraoperative monitoring, using continuous 12-lead ECG assessment and transesophageal echocardiography, may timely identify treatable myocardial ischemia and arrhythmias. A prudent perioperative beta-blocker and statin regimen can reduce cardiac complications and mortality without increasing the risk of stroke in intermediate to high-risk patients. The use of circulatory assist devices might improve outcomes after major surgery in patients with severely reduced left ventricular function. SUMMARY: Systematic preoperative assessment can identify patients at high risk of cardiac complications and guide the application of appropriate risk reduction strategies. PMID- 21677578 TI - Procedural sedation and analgesia in the emergency department. AB - PURPOSE OF REVIEW: Procedural sedation and analgesia is frequently administered outside of the operating room in emergency departments (EDs) and ICUs. Evidence was sought concerning patients' safety in the ED. RECENT FINDINGS: Procedural sedation, when administered in the ED by trained personnel, is safe. Extensive literature demonstrates that propofol, ketamine, midazalam, and fentanyl are appropriate medications with proper monitoring and the presence of appropriate personnel. Preprocedural fasting may not be necessary in many cases. SUMMARY: With appropriately trained personnel, proper equipment, and the studied drugs ED sedation and analgesia is safe and an appropriate procedure. PMID- 21677579 TI - Cardiovascular and renal complications in patients receiving a solid-organ transplant. AB - PURPOSE OF REVIEW: Cardiovascular and renal complications among solid-organ transplant recipients are a frequent source of morbidity. Appropriate management of these complications throughout the perioperative period significantly affects long-term recipient survival. This review details the identification, management, and potential preventive strategies for perioperative cardiovascular and renal complications among solid-organ transplant recipients. RECENT FINDINGS: Abdominal transplant candidates have a significantly higher prevalence of risk factors for obstructive coronary artery disease than the general population. There is no consensus on pretransplant screening for coronary artery disease or determination of perioperative risk in candidates awaiting transplantation. Limitations of noninvasive cardiac screening tests such as dobutamine stress echocardiography and myocardial perfusion scintigraphy complicate preoperative evaluation and cardiac risk stratification. Coronary angiography remains the definitive mechanism for determining the presence and severity of coronary artery disease prior to transplantation; however, the relationship between angiographically documented coronary artery disease and cardiovascular morbidity after transplantation is inconsistent. This has raised speculation that perioperative adverse cardiac events are not principally caused by obstructive coronary artery disease but other acute events related to surgical intervention and allograft function. Current data indicate coronary angiography is safe even with patients demonstrating renal insufficiency. A cardiac screening program should reflect the patient population, dynamics of the transplant program, and institutional expertise. The development of classification schemes for defining and categorizing acute kidney injury reflects the importance of preserved renal function in long-term recipient survival. The potential of serum markers as indicators of acute kidney injury has provided a foundation for understanding the global influence of surgical intervention and allograft function upon recipient survival. SUMMARY: Meticulous attention to all aspects of the transplant process, including operative events and early allograft function, is necessary to minimize morbidity. Further research is necessary to identify mechanisms that support and improve early allograft function to optimize recipient long-term survival. PMID- 21677580 TI - Postoperative sepsis. AB - PURPOSE OF REVIEW: Postoperative sepsis is a major cause of surgical associated morbidity and mortality. Our goal is to describe its incidence, pathophysiology, and contributing factors. In addition, we will review preventive measures and treatment options that may possibly reduce its healthcare burden. RECENT FINDINGS: We review epidemiologic data and clinical tools presented in multiple current studies, which may help lower incidence and improve outcome of postoperative sepsis. SUMMARY: The incidence of postoperative sepsis has not declined over the past years, although mortality is trending downwards. Several biochemical and genetic markers may allow early diagnosis. Prevention and prompt treatment may lower mortality. PMID- 21677581 TI - From molecules to mind and back.... PMID- 21677582 TI - POEMS syndrome: the matter-of-fact approach. AB - PURPOSE OF REVIEW: The aim is to provide an up-to-date overview of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome with special regard to the available therapy options. RECENT FINDINGS: In the past 20 years this rare plasmaproliferative disorder has been extensively characterized from a clinical point of view with complete description of the typical features as well as of other organ involvement not considered in the acronym as nephropathy or pachimeningitis. In this syndrome, the serum levels of vascular endothelial growth factor (VEGF) are abnormally elevated and now this is considered one of the major criteria for making the diagnosis. VEGF has also a prognostic value, as it decreases in response to therapy and definitely has a pathogenetic role in the multisystem involvement of POEMS. Recently great advance occurred in the treatment of POEMS syndrome with new immunomodulatory drugs such as lenalidomide, autologous peripheral blood stem cell transplantation or bevacizumab, an anti-VEGF monoclonal antibody. SUMMARY: Although many aspects of POEMS syndrome remain unclear, a valid biomarker of disease, VEGF, is available for diagnosis as well as a wide range of therapeutic options. PMID- 21677583 TI - New light from the dark: what blindness can teach us about brain function. AB - PURPOSE OF REVIEW: In this review, we discuss findings from some recent brain imaging studies that shed new light on our understanding of the role of visual experience on the development of the brain morphological and functional architecture in humans. To what extent is vision truly necessary to 'see' the world around us? RECENT FINDINGS: Congenitally blind and sighted individuals present analogous cognitive and social performances. Findings from structural and functional brain studies in both sighted and congenitally blind individuals have shown the existence of supramodal brain regions able to process external information regardless of the sensory modality through which such an information has been acquired. This more abstract nature of functional cortical organization may enable congenitally blind individuals to acquire knowledge, form mental representations of and interact effectively with an external world that they have never seen. SUMMARY: Altogether, findings from both behavioural and imaging studies indicate that the brain functional organization is to a large extent independent from visual experience and able to process information in a supramodal fashion. The study of the blind brain is a very powerful approach to understanding not only the cross-modal plastic, adaptative modifications that occur in the 'visual' regions but primarily the functional architecture of the human brain itself. PMID- 21677584 TI - Update on treatment rationale and options for the ageing face. AB - PURPOSE OF REVIEW: Techniques for rejuvenation of the ageing face continue to evolve rapidly as we gain further understanding of the ageing face. This article reviews various noninvasive, nonsurgical and surgical options in light of the recent clinical research and provides some pointers for management. RECENT FINDINGS: The ageing of facial structures depends on genetic, anatomic, chronologic, and environmental factors. For optimal rejuvenation various anatomical structures should be treated in combination using appropriate modalities. This involves management of the skin envelope, subcutaneous tissues including facial fat compartments, muscles and bony skeleton. Treatment outcome may be measured using a validated, objective, quantitative facial grading scale. SUMMARY: A brief overview of the facial ageing process is presented, based on which a treatment plan is suggested in order to target specific anatomic structures. Recent literature pertaining to cosmoceuticals, injectables, lasers and surgical options is briefly discussed. It should be stressed that a thorough analysis of the ageing face is mandatory for planning appropriate treatment, monitoring, achieving optimal outcome, and furthering our knowledge. PMID- 21677585 TI - Bisphosphonate-related osteonecrosis of the jaws. AB - PURPOSE OF REVIEW: The purpose of this article is to review a new pathologic entity named bisphosphonate-related osteonecrosis of the jaws (BRONJ). RECENT FINDINGS: BRONJ was observed and first reported in 2001-2002 when clinicians noticed cases of refractory osteomyelitis after simple dental procedures such as dental extractions in patients who had received bisphosphonate therapy. The condition was initially seen in patients who received i.v. bisphosphonates for malignancies such as multiple myeloma and metastatic breast cancer. However, with the use of bisphosphonate therapy for osteoporosis, BRONJ is seen in patients without a cancer diagnosis. SUMMARY: The incidence of BRONJ remains unclear. Treatment recommendations based on sound scientific data are sparse. The management of BRONJ remains a difficult and controversial situation that continues to challenge the clinician. PMID- 21677586 TI - Alveolar distraction osteogenesis for oral rehabilitation in reconstructed jaws. AB - PURPOSE OF REVIEW: To present a literature review of alveolar distraction osteogenesis (ADO) for reconstructed jaws, with emphasis on indications, critical surgical factors, protocols and complications for oral rehabilitation of reconstructed jaws. RECENT FINDINGS: The defects in jaw result mostly from malignancy, benign tumor or gunshot injury. Jaw reconstructions were performed mostly by vascularized fibula graft. Alveolar distraction was primarily indicated to correct vertical discrepancy between the reconstructed region and residual ridge in order to achieve adequate height of the transplanted bone prior to implant placement. The vertical bone height gained ranged from 6 to 15 mm. The most common complications reported were infections and distractor malalignment. SUMMARY: This review reveals few numbers of case series on this topic. However, ADO in reconstructed jaws can produce consistent evidence of bone regeneration, with stable augmentation results clinically, histologically and radiographically, thus making it a predictable surgical procedure prior to oral implant rehabilitation. PMID- 21677587 TI - Bone tissue substitutes and replacements. AB - PURPOSE OF REVIEW: A host of synthetically engineered materials have come to market in the past three decades, changing the way surgical reconstruction is performed. Although tissue engineering holds the promise of true tissue replacement, this technology is years away from true clinical use. In the interim, understanding of the current synthetic bone substitutes will be reviewed to provide the clinician with an updated understanding of the different classes along with advantages, disadvantages and novel applications. RECENT FINDINGS: A discussion of currently used bone cements, scaffolds, bone matrices and growth factors will be included. In addition, a sampling of exciting basic science experiments and preliminary treatments for synthetic bone reconstruction is covered. SUMMARY: Each reconstructive surgeon should have a comprehensive understanding of the current technologies to optimize reconstruction of bony defects. As this field is rapidly changing, new iterations arrive yearly, which possess improved osteoconductive, osteoinductive, osteointegrative and osteogenic properties. A better understanding of these new products and material will allow each reconstructive surgeon the ability to provide patients with the safest and most successful reconstruction. PMID- 21677588 TI - Value of fecal occult blood test as a screening test before capsule endoscopy. AB - BACKGROUND: The primary aim was to assess the value of immunochemical and guaiac fecal occult blood test (FOBT) as a screening test before capsule endoscopy (CE) in the setting of obscure gastrointestinal bleeding (OGIB). METHODS: A prospective study from the St Vincent's Hospital, a tertiary referral hospital in Melbourne, Australia. Sixty-eight patients referred for CE to investigate OGIB underwent two immunochemical/guaiac FOBTs within 2 weeks preceding CE. The correlation between a positive FOBT before CE and clinically significant findings (CSFs) on CE was assessed. RESULTS: Thirty of 68 (44%) patients with OGIB had significant findings on CE. The accuracy of a combined immunochemical and guaiac FOBT for predicting clinically significant findings on CE was 62% [95% confidence interval (CI): 0.50-0.72]. The sensitivity and specificity were low at 63% (95% CI: 0.50-0.75) and 61% (95% CI: 0.50-0.70), respectively. CONCLUSION: FOBT has low accuracy as a screening test before CE and thus cannot be recommended for this purpose. PMID- 21677589 TI - Nonpopulation-based glaucoma screening exercise in an osteoporosis patient organization: can elderly persons with advanced health awareness identify their risk for glaucoma? AB - PURPOSE: To investigate whether osteoporosis patient organization members with advanced health awareness can identify their risk for glaucoma. METHODS: Members of an osteoporosis patient organization group were provided with structured written information on risk factors for glaucoma. Later, the participants completed questionnaires on their risk for glaucoma (average vs. increased), demographics, trait anxiety (Trait Anxiety Inventory), health anxiety (Shortened Health Anxiety Inventory), and underwent a detailed screening for glaucoma. Participants classified as possible glaucoma cases later underwent a detailed glaucoma investigation. RESULTS: The average age of 114 self-recruited White attendees (107 female and 7 male) was 70.9 years (range, 41 to 88 y). The final prevalence of glaucoma was 7.9%. Forty-three participants indicated an increased risk for glaucoma and 71 participants did not estimate his/her risk to be increased. No relationship was found between the participants' response on the glaucoma risk assessment questionnaire and presence of glaucoma (Fisher exact test, P=0.725), presence of any risk factor of glaucoma (P>0.473 for all risk factors), various sociodemographic parameters (chi test, P>0.05 for all parameters), trait anxiety (Mann-Whitney test, P=0.178), or health anxiety (P=0.204). CONCLUSIONS: Our results suggest that even when general health information and awareness training sessions are regularly given to elderly members of a nonglaucoma patient organization, self-assessment of risk for glaucoma may remain poor among the members. PMID- 21677590 TI - Long-term medical management of primary open-angle glaucoma and ocular hypertension in the UK: optimizing cost-effectiveness and clinic resources by minimizing therapy switches. AB - PURPOSE: The objective was to assess the long-term economic consequences of the medical management of glaucoma in the UK. METHODS: The economic evaluation was conducted using the results from a 10-year Markov model based around 3 key triggers for a switch in medical therapy for glaucoma, namely: lack of tolerance (using hyperemia as a proxy); intraocular pressure (IOP) not meeting treatment benchmark; and glaucoma progression. Clinical data from a comprehensive systematic literature review and meta-analysis were used. Direct costs associated with glaucoma treatment are considered (at 2008/9 prices) from the perspective of the UK NHS as payer (outpatient/secondary care setting). Using this model, the economic consequences of 3 prostaglandin-based treatment sequences were compared. RESULTS: Drug acquisition costs account for around 8% to 13% of the total cost of glaucoma and, if ophthalmologist visits are included, amount to approximately L0.80 to L0.90 per day of medical therapy. The total long-term costs of all prostaglandin strategies are similar because of a shift in resources: increased drug costs are offset by fewer clinic visits to instigate treatment switches, and by avoiding surgery or costs associated with managing low vision. Under the latanoprost-based strategy, patients would have longer intervals between the need to switch therapies, which is largely due to a reduction in hyperemia, seen as a proxy for tolerance. This leads to a delay in glaucoma progression of 12 to 13 months. For every 1000 clinic appointments, 719 patients can be managed for 1 year with a latanoprost-based strategy compared with 586 or 568 with a bimatoprost or travoprost-based strategy. CONCLUSIONS: Drug acquisition costs are not a key driver of the total cost of glaucoma management and the cost of medical therapy is offset by avoiding the cost of managing low vision. Economic models of glaucoma should include the long-term consequences of treatment as these will affect cost-effectiveness. This analysis supports the hypothesis that the economic and clinical benefits can be optimized by minimizing therapy switches. PMID- 21677591 TI - Relationship between morphological characteristics and etiology of pressure ulcers in intensive care unit patients. AB - PURPOSE: Pressure ulcer (PU) prevention is crucial for critically ill patients in the intensive care unit, but etiologic factors leading to their development have not yet been completely elucidated. This study explores the relationships among etiologic factors, interventional nursing care, and morphological characteristics of PUs in intensive care unit patients. DESIGN: We used a qualitative exploratory method to link morphological characteristics of specific PUs to etiologic factors. METHODS: Details of individual PUs were described by sketching the PU photograph and categorized to characterize the morphology of PUs. After identification of characteristics, the development process was evaluated by in depth review of medical records. RESULTS: The morphological characteristics of 30 PUs were organized into 4 categories. This process revealed a type of PU not previously described, which we labeled "leaf-type." These PUs were located on the lower sacrum, rhombic-oval in shape, and characterized by purpura and PU wrinkles. Possible etiologic factors for the specific PUs were divided into 4 categories: (1) the occurrence of PU risk episodes, (2) failure of the peripheral circulation, (3) periods of critical immobility, and (4) position change techniques inducing skin deformation. CONCLUSION: PU can be categorized into 4 morphological types, including a new category of leaf-shaped PU. We found that frequently repeated position changes such as lateral tilt and repeated head elevation caused deformation of the sacral skin that may play a role in PU development. PMID- 21677593 TI - Meningococcal disease: early recognition is vital to patient outcomes. AB - Since the development of vaccines to prevent Haemophilus influenzae type b and Streptococcus pneumoniae, Neisseria meningitidis is the leading cause of bacterial meningitis in the United States. Education of healthcare professionals to improve identification and provide immediate treatment of patients with symptoms consistent with meningococcal disease will result in improved outcomes. PMID- 21677594 TI - Planning for the future. PMID- 21677592 TI - Race and timeliness of transfer for revascularization in patients with acute myocardial infarction. AB - OBJECTIVES: Patients with acute myocardial infarction (AMI) who are admitted to hospitals without coronary revascularization are frequently transferred to hospitals with this capability. We sought to determine whether the timeliness of hospital transfer and quality of destination hospitals differed between black and white patients. METHODS: We evaluated all white and black Medicare beneficiaries admitted with AMI at nonrevascularization hospitals in 2006 who were transferred to a revascularization hospital. We compared hospital length of stay before transfer and the transfer destination's 30-day risk-standardized mortality rate for AMI between black and white patients. We used hierarchical regression to adjust for patient characteristics and examine within and across-hospital effects of race on 30-day mortality and length of stay before transfer. RESULTS: A total of 25,947 (42%) white and 2345 (37%) black patients with AMI were transferred from 857 urban and 774 rural nonrevascularization hospitals to 928 revascularization hospitals. Median (interquartile range) length of stay before transfer was 1 day (1 to 3 d) for white patients and 2 days (1 to 4 d) for black patients (P<0.001). In adjusted models, black patients tended to be transferred more slowly than white patients, a finding because of both across and within hospital effects. For example, within a given urban hospital, black patients were transferred an additional 0.24 days (95% confidence interval 0.03-0.44 d) later than white patients. In addition, the lengths of stay before transfer for all patients at urban hospitals increased by 0.37 days (95% confidence interval 0.28 0.47 d) for every 20% increase in the proportion of AMI patients who were black. These results were attenuated in rural hospitals. The risk-standardized mortality rate of the revascularization hospital to which patients were ultimately sent did not differ between black and white patients. CONCLUSIONS: Black patients are transferred more slowly to revascularization hospitals after AMI than white patients, resulting from both less timely transfers within hospitals and admission to hospitals with greater delays in transfer; however, 30-day mortality of the revascularization hospital to which both groups were sent to appeared similar. Race-based delays in transfer may contribute to known racial disparities in outcomes of AMI. PMID- 21677595 TI - Psychometric validation of a short acculturation scale for Korean immigrants. AB - BACKGROUND: Acculturation has been identified as a determinant of health behavior and outcome among ethnic minorities. The high prevalence of lifestyle-related chronic diseases and risk factors among Korean immigrants calls for a valid short acculturation scale to use in clinical practice and health research settings. OBJECTIVES: The aim of this study was to validate the psychometric properties of a short acculturation scale originally developed for Hispanics after translating the scale to Korean (SAS-K) to determine its suitability for use with Korean immigrants. METHODS: A self-administered questionnaire was completed by 143 Korean immigrants with Type 2 diabetes aged 30-80 years from a Korean community in Southern California. Confirmatory factor analysis, criterion validity, and internal reliability were utilized to evaluate the psychometric properties of the SAS-K. RESULTS: Using a second-order confirmatory factor analysis, a 3-factor structure, chi(51) = 121.49, p < .001 (comparative fit index = .950, standardized root mean squared residual = .055, root mean square error of approximation = .099), was confirmed. The SAS-K was associated positively with length of residence, age of arrival, and English proficiency. Reliability for the total SAS K was .93. Cronbach's alpha coefficients for each subscale of the SAS-K ranged from .80 (Ethnic Social Relations) to .95 (Media). DISCUSSION: The 12-item, easy to-use SAS-K showed satisfactory reliability and validity and, thus, is an appropriate instrument for measuring acculturation in Korean immigrants. The short nature and ease of administration of the SAS-K make it an ideal choice for healthcare providers and researchers to assess acculturation levels quickly and easily and to further the development and use of more culture-appropriate interventions. PMID- 21677596 TI - Acculturation and the Center For Epidemiological Studies-Depression Scale for Hispanic women. AB - BACKGROUND: Culturally valid measures of depression for Spanish-speaking Hispanic women are important for developing and implementing effective interventions to reduce health disparities. The Center for Epidemiological Studies-Depression Scale (CES-D) is a widely used measure of depression. Differential item functioning has been studied using language preference as a proxy for acculturation, but it is unknown if the results were due to acculturation or the language of administration. OBJECTIVE: The aim of this study was to evaluate the relationship of acculturation, defined with a dimensional measure, to Spanish CES D item responses. METHODS: Spanish-speaking Hispanic women (n = 504) were recruited for a randomized controlled trial of Salud, Educacion, Prevencion y Autocuidado (Health, Education, Prevention, and Self-Care). Acculturation, an important dimension of variation within the diverse U.S. Hispanic community, was defined by high or low scores on the Americanism subscale of the Bidimensional Acculturation Scale. Differential item functioning for each of the 20 CES-D items between more acculturated and less acculturated women was tested using ordinal logistic regression. RESULTS: No items on the Depressed Affect, Somatic Activity, or Positive Affect subscales showed meaningful differential item functioning, but 1 item ("People were unfriendly") on the Interpersonal subscale had small results (R = 1.1%). DISCUSSION: The majority of CES-D items performed similarly for Spanish-speaking Hispanic women with high and low acculturation. Less acculturated women responded more positively to "People were unfriendly," despite having an equivalent level of depression, than did more acculturated women. Possibilities for improving this item are proposed. PMID- 21677597 TI - Assessing fidelity to an intervention in a randomized controlled trial to improve medication adherence. AB - BACKGROUND: Behavioral intervention effectiveness in randomized controlled trials requires fidelity to the protocol. Fidelity assessment tools tailored to the intervention may strengthen intervention research. OBJECTIVE: The aim of this study was to describe the assessment of fidelity to the structured intervention protocol in an examination of a nurse-delivered telephone intervention designed to improve medication adherence. METHODS: Fidelity assessment included random selection and review of approximately 10% of the audiorecorded intervention sessions, stratified by interventionist and intervention session. Audiotapes were reviewed along with field notes for percentage of agreement, addressing whether key components were covered during the sessions. Visual analog scales were used to provide summary scores (0 = low to 5 = high) of interaction characteristics of the interventionists and participants with respect to engagement, demeanor, listening skills, attentiveness, and openness. RESULTS: Four nurse interventionists delivered 871 structured intervention sessions to 113 participants. Three trained graduate student researchers assessed 131 intervention sessions. The mean percentage of agreement was 92.0% (+/-10.5%), meeting the criteria of 90% congruence with the intervention protocol. The mean interventionist interaction summary score was 4.5 +/- 0.4, and the mean participant interaction summary score was 4.5 +/- 0.4. DISCUSSION: Overall, the interventionists successfully delivered the structured intervention content, with some variability in both the percentage of agreement and quality of interaction scores. Ongoing assessment aids in ensuring fidelity to study protocol and having reliable study results. PMID- 21677598 TI - Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone. AB - BACKGROUND: The optimal graft-versus-host disease (GVHD) prophylaxis after umbilical cord blood transplantation has not been established. Our previous observation using single calcineurin inhibitors revealed a high incidence and severity of early immune-mediated complications, especially for older patients or those with poor performance status. METHODS: We conducted a single institute pilot study assessing the safety and effectiveness of mycophenolate mofetil (MMF) and tacrolimus (FK) combination as a GVHD prophylaxis for 29 patients (FK+MMF), and the results were compared with matched-pairs extracted from our historical database who received FK alone as GVHD prophylaxis (control). RESULTS: FK+MMF group showed superior engraftment rate compared with control group (cumulative incidence until day 60 posttransplant; 90%+/-0% vs. 69%+/-1%, P=0.02). A cumulative incidence of severe type preengraftment immune reactions was significantly decreased in FK+MMF group (16%+/-1%) compared with that of control group (52%+/-2%, P=0.03), and, remarkably, there was no nonrelapse mortality (NRM) observed up to day 30 posttransplant in FK+MMF group, whereas 21%+/-1% of NRM was observed in the control group. However, the incidences of acute and chronic GVHD, estimated overall and progression-free survivals were comparable between two groups. CONCLUSIONS: MMF and FK in combination was well tolerated and decreased early NRM possibly by better control of preengraftment immune reactions. Subsequent NRM or disease progression needs to be overcome to further improve survival. PMID- 21677599 TI - Systemic complement activation in deceased donors is associated with acute rejection after renal transplantation in the recipient. AB - BACKGROUND: Acute rejection after renal transplantation has been shown to be negatively associated with long-term graft survival. Identifying donor factors that are associated with acute rejection in the recipient could help to a better understanding of the relevant underlying processes that lead to graft injury. Complement activation has been shown to be an important mediator of renal transplant related injury. In this study, we analyzed the effect of systemic complement activation in deceased donors before transplantation of their kidneys on posttransplant outcome in the recipient. METHODS: Plasma from 232 deceased brain-dead and deceased cardiac-dead donors were analyzed for the complement activation markers C5b-9, C4d, Bb, and complement component mannan binding lectin by ELISA. The association of these parameters with posttransplant outcome in recipients was analyzed in a multivariate regression model. RESULTS: It was found that C5b-9 level in donor plasma is associated with biopsy-proven acute rejection in the recipient during the first year after renal transplantation (P = 0.035). Both in deceased brain-dead and deceased cardiac-dead donors increased complement activation was found. CONCLUSIONS: In conclusion, we found C5b-9 in the donor to be associated with acute rejection of renal transplants in the recipient. Whether targeting complement activation in the donor may ameliorate acute rejection in the recipient needs to be studied. PMID- 21677600 TI - Effect of everolimus introduction on cardiac allograft vasculopathy--results of a randomized, multicenter trial. AB - BACKGROUND: Everolimus reduces the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant (HTx) recipients, but the influence on established CAV is unknown. METHODS: In this Nordic Certican Trial in Heart and lung Transplantation substudy, 111 maintenance HTx recipients (time post-HTx 5.8 +/- 4.3 years) randomized to everolimus+reduced calcineurin inhibitor (CNI) or standard CNI had matching (intravascular ultrasound) examinations at baseline and 12 months allowing accurate assessment of CAV progression. RESULTS: No significant difference in CAV progression was evident between the treatment groups (P = 0.30). When considering patients receiving concomitant azathioprine (AZA) therapy (n = 39), CAV progression was attenuated with everolimus versus standard CNI (Deltamaximal intimal thickness 0.00 +/- 0.04 and 0.04 +/- 0.04 mm, Deltapercent atheroma volume 0.2% +/- 3.0% and 2.6% +/- 2.5%, and Deltatotal atheroma volume 0.25 +/- 14.1 and 19.8 +/- 20.4 mm(3), respectively [P < 0.05]). When considering patients receiving mycophenolate mofetil (MMF), accelerated CAV progression occurred with everolimus versus standard CNI (Deltamaximal intimal thickness 0.06 +/- 0.12 vs. 0.02 +/- 0.06 mm and Deltapercent atheroma volume 4.0% +/- 6.3% vs. 1.4% +/- 3.1%, respectively; P < 0.05). The levels of C reactive protein and vascular cell adhesion molecule-1 declined significantly with AZA+everolimus, whereas MMF+everolimus patients demonstrated a significant increase in levels of C-reactive protein, vascular cell adhesion molecule-1, and von Willebrand factor. CONCLUSIONS: Conversion to everolimus and reduced CNI does not influence CAV progression among maintenance HTx recipients. However, background immunosuppressive therapy is important as AZA+everolimus patients demonstrated attenuated CAV progression and a decline in inflammatory markers, whereas the opposite pattern was seen with everolimus+MMF. The different effect of everolimus when combined with AZA versus MMF could potentially reflect hitherto unknown interactions. PMID- 21677601 TI - Recent advances in the studies on luotonins. AB - Luotonins are alkaloids from the aerial parts of Peganum nigellastrum Bunge. that display three major skeleton types. Luotonins A, B, and E are pyrroloquinazolino quinoline alkaloids, luotonins C and D are canthin-6-one alkaloids, and luotonin F is a 4(3H)-quinazolinone alkaloid. All six luotonins have shown promising cytotoxicities towards selected human cancer cell lines, especially against leukemia P-388 cells. Luotonin A is the most active one, with its activity stemming from topoisomerase I-dependent DNA-cleavage. Such intriguing biological activities and unique structures have led not only to the development of synthetic methods for the efficient synthesis of these compounds, but also to interest in structural modifications for improving the biological properties. Recent progress in the study of luotonins is covered. PMID- 21677602 TI - Comparison of compositions and antimicrobial activities of essential oils from chemically stimulated agarwood, wild agarwood and healthy Aquilaria sinensis (Lour.) gilg trees. AB - The composition and antimicrobial activity of the essential oils which were obtained from agarwood originated from Aquilaria sinensis (Lour.) Gilg stimulated by the chemical method (S1) were characterized, taking wild agarwood (S2) and healthy trees (S3) respectively as the positive and negative controls. The chemical composition of S1 was investigated by gas chromatography-mass spectrometry (GC-MS). The essential oil of S1 showed a similar composition to that of S2, being rich in sesquiterpenes and aromatic constituents. However, the essential oil of S3 was abundant in fatty acids and alkanes. Essential oils of S1 and S2 had better inhibition activities towards Bacillus subtilis and Staphyloccus aureus, compared with essential oil of S3. Escherichia coli was not sensitive to any of them. PMID- 21677603 TI - Synthesis and in vitro protein tyrosine kinase inhibitory activity of furan-2 yl(phenyl)methanone derivatives. AB - A series of novel furan-2-yl(phenyl)methanone derivatives were synthesized, and their structures were established on the basis of 1H-NMR, 13C-NMR and mass spectral data. All the prepared compounds were screened for their in vitro protein tyrosine kinase inhibitory activity and several new derivatives exhibited promising activity, which, in some cases, was identical to, or even better than that of genistein, a positive reference compound. The preliminary structure activity relationships of these compounds were investigated and are discussed. PMID- 21677604 TI - Directed formation of DNA nanoarrays through orthogonal self-assembly. AB - We describe the synthesis of terpyridine modified DNA strands which selectively form DNA nanotubes through orthogonal hydrogen bonding and metal complexation interactions. The short DNA strands are designed to self-assemble into long duplexes through a sticky-end approach. Addition of weakly binding metals such as Zn(II) and Ni(II) induces the formation of tubular arrays consisting of DNA bundles which are 50-200 nm wide and 2-50 nm high. TEM shows additional long distance ordering of the terpy-DNA complexes into fibers. PMID- 21677605 TI - Derivatives of 10,16-dihydroxyhexadecanoic acid isolated from tomato (Solanum lycopersicum) as potential material for aliphatic polyesters. AB - The main monomer of tomato cuticle, 10,16-dihydroxyhexadecanoic acid (or 10,16 dihydroxypalmitic acid; 10,16-DHPA), was isolated and used to efficiently synthesize two different monomers (16-hydroxy-10-oxo-hexadecanoic and 7-oxohexa decanedioic acids) in addition to a dimer and linear and branched trimers. These compounds were fully characterized using NMR and MS techniques and could be used as starting materials for the synthesis of a wide range of chemicals and bio polyesters, particularly the latter due to their physical properties, non toxicity, and relative abundance among raw materials. PMID- 21677606 TI - Microwave assisted synthesis of some new fused 1,2,4-triazines bearing thiophene moieties with expected pharmacological activity. AB - Rapid and efficient solvent-free synthesis of 4-amino-3-mercapto-6-[2-(2 thienyl)vinyl]-1,2,4-triazin-5(4H)-one 1 under microwave irradiation is described. Some new fused heterobicyclic nitrogen systems such as 1,2,4 triazino[3,4-b][1,3,4]thiadiazinones, 1,3,4-thiadiazolo[2,3-c][1,2,4]triazinone and pyrazolo[5,1-c]-[1,2,4]triazine-7-carbonitrile, have been synthesized by treatment of 1 with bifunctional oxygen and halogen compounds, CS2/KOH and malononitrile via heterocyclization reactions, in addition to some uncondensed triazines. Structures of the products have been deduced from their elemental analysis and spectral data (IR, 1H-NMR, 13C-NMR). Select new synthesized compounds were screened as anticancer agents, with some showing activity as cytotoxic agents against different cancer cell lines. PMID- 21677607 TI - Peripheral lymphocyte DNA damage and oxidative stress in patients with ulcerative colitis. AB - INTRODUCTION: Ulcerative colitis (UC) is a fairly common chronic inflammatory disorder. Chronic inflammation may contribute to the risk of colorectal cancer through the accumulation of specific products resulting from DNA damage. Previous studies reported that DNA damage and oxidative stress play a significant role in the pathophysiology of UC, but the results are inconsistent. OBJECTIVES: In the present study, we investigated peripheral DNA damage and oxidative stress in patients with UC. PATIENTS AND METHODS: The study included 20 patients with UC and 20 controls. Peripheral lymphocyte DNA damage was measured using the alkaline comet assay. Plasma total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) were determined. RESULTS: DNA damage levels, TOS, and OSI were significantly higher in patients with UC than in controls (P <0.001 for all parameters), while TAC was significantly lower (P <0.001). DNA damage was significantly correlated with TOS, TAC, and OSI (r = 0.604, P <0.001; r = -0.593, P <0.001; and r = 0.716, P <0.001, respectively). Moreover, TAC levels were significantly correlated with TOS and OSI (r = 0.604, P <0.001; r = 0.399, P <0.05; and r = -0.513, P <0.05, respectively). CONCLUSIONS: Our results show that increased peripheral DNA damage and oxidative stress seem to be associated with decreased antioxidant levels and thus may in part contribute to the development of colorectal cancer associated with UC. PMID- 21677608 TI - Update and review on the basics of pain management. AB - This article reviews the major findings of research related to pharmacological pain therapies used in treating acute and chronic pain, it compares advantages and disadvantages of certain drugs used mainly in pain management (for example, opioids and non steroidal anti-inflammatory drugs), and others that have a secondary use in pain management (for example, skeletal muscle relaxants, antidepressants, and anticonvulsants) and their intended indications. Our goal is to present accurate up-to-date applicable data on these pharmacological choices. PMID- 21677609 TI - Swine flu (H1N1) infection among patients with neurologic disorders. A review of published evidence. AB - Although the 2009 Swine flu (H1N1) pandemic has apparently been abolished, there are still lessons to be learnt. We reviewed the clinical and pathological manifestations of CNS involvement of influenza A virus infection. Neurologic disorders were most commonly seen as underlying medical conditions in swine flu, and neurological complications of the H1N1 vaccination. The major point with regard to the H1N1 pandemic is a mild disease with high contagiosity, which can have severe outcomes in those with underlying diseases including neurological ones. PMID- 21677610 TI - The acute effects of mirtazapine on pain related behavior in healthy animals. AB - OBJECTIVE: To investigate whether the tetracyclic antidepressant mirtazapine has a pain-suppressing effect in healthy animals. METHODS: In the first step, Swiss albino female mice weighing 25-35 g were used. Eight groups each containing 8 mice were established as follows:- Control (saline), mirtazapine 5 mg/kg, 10 mg/kg, and 20 mg/kg, mirtazapine 10mg/kg and its combinations L-Nitro-L-Arginine Methyl Ester (L-NAME) 100 mg/kg, L-Arginine 100 mg/kg, naloxone 1 mg/kg, and cyproheptadine 50 ug/kg. This study was performed in the Department of Pharmacology, Faculty of Medicine, Eskisehir Osmangazi University, Eskisehir, Turkey during March, April, and May 2009. One hour after the drugs were given intraperitoneally, hot plate, tail clip, tail flick, and writhing tests were used for evaluating antinociceptive effects. In the second step, the brain hippocampus of Sprague Dawley type male rats weighing 250+/-20 g were isolated and 0.6 um hippocampus slices were obtained. In vitro groups were established as control, mirtazapine 3x10(-3)M, 4x10(-3)M, 5x10(-3)M, mirtazapine 4x10(-3)M and its combinations L-NAME, L-Arginine, naloxone, and cyproheptadine 4x10(-3)M. RESULTS: Mirtazapine did not show central spinal analgesic activity, but had significant peripheral and biphasic central analgesic effects at the supraspinal level. In addition, there were no significant differences between the different groups in nitric oxide synthase levels on the brain slices. CONCLUSION: The nitrergic pathway does not have an effect on the central antinociceptive activity of mirtazapine, while opiatergic and serotonergic pathways have a significant role. PMID- 21677611 TI - Evaluation of viral antibodies in Iranian multiple sclerosis patients. AB - OBJECTIVE: To evaluate the viral antibodies in new Iranian multiple sclerosis (MS) patients. METHODS: In a cross-sectional study, sera from 61 MS patients and 60 healthy individuals were collected from January 2009 to March 2010 in the Immunology Department of Arak University of Medical Sciences, Arak, Iran, and examined for the presence of the anti-Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), measles, mumps, and para-influenza viruses IgG and IgM using an enzyme-linked immunosorbent assay or immunofluorescence. RESULTS: There were significant differences between the MS patients and the healthy individuals (controls) in the seroprevalence of anti-HHV-6 IgM (odds ratio [OR]=4.3, 95% confidence interval [CI]=2-9.3, p=0.001); anti-HHV-6 IgG (OR=2, 95% CI=1-4, p=0.04); anti-measles IgM (OR=3.2, 95% CI=1.5-6.9, p=0.002); and the anti-mumps IgM (OR=4.1, 95% CI=1.9-8.8, p=0.0001) and IgG (OR=9.5, 95% CI=3-29.6, p=0.0001). Almost all MS patients and the control individuals were negative to EBV and parainfluenza IgM. CONCLUSION: These results confirm an association between the incidence of MS and the antibodies to HHV-6 and the measles and mumps viruses, and show induction of a primary immune response (IgM), or virus reactivation, in MS patients. These viruses may have an important role in development of MS as an initial trigger in this geographical area. PMID- 21677612 TI - Clinical and radiological study of Iraqi multiple sclerosis patients with childhood onset. AB - OBJECTIVE: To study the clinical and radiological characteristics of multiple sclerosis (MS) with onset below 18 years. METHODS: This retrospective study was carried out at the MS Clinic in the Medical City Hospital in Baghdad, Iraq between March 2008 and March 2009. The records of the center were surveyed, and 77 patients with the onset of MS below 18 years were identified. Their clinical and radiological data were then analyzed. RESULTS: The female:male ratio was 1.6:1, and the mean age at onset was 14.95 years. Seven (9.1%) patients where children (age below 10 years), and 70 (90.9%) patients where adolescents (age 10 18 years) at onset. Seventy patients (90.9%) had an initial course of relapsing remitting MS, 9 (11.7% of the total) of them progressed to secondary progressive MS after a mean duration of 9.87+/-4.135 years. Seven patients had primary progressive MS as the initial course. The most common presenting symptom was optic neuritis (35.8%). Fifty-nine (76.6%) patients had monofocal presentation, and 18 (23.4%) had polyfocal presentation. Fifty-one (63%) patients had periventricular MRI lesions. The percentage of supratentorial lesions was higher than infratentorial lesions, children had a higher incidence of basal ganglionic lesions than adolescents (p=0.002), and males had a higher incidence of infratentorial lesion than females (p=0.033). CONCLUSION: Male patients have a higher incidence of infratentorial MRI lesions than female patients. Children had a higher incidence of MRI lesions in the basal ganglia than adolescents. PMID- 21677613 TI - Disability and prognosis of relapsing remitting multiple sclerosis, is it different in Iraqi patients? AB - OBJECTIVE: To assess the prognostic factors of relapsing remitting multiple sclerosis (RR-MS) in Iraqi patients. METHODS: This retrospective study of patients with RR-MS was carried out at the MS Clinic in Baghdad Teaching Hospital, Baghdad, Iraq between March 2008 and January 2010. Patients history and extended disability status scale scores were reviewed using the clinic database. RESULTS: Five hundred patients (270 female, and 230 male) fulfilled the McDonald criteria for RR-MS, their mean age was 45.58 years. Mono symptoms were found in 70% of patients. Hemiplegia (48%) was the most common clinical feature followed by optic neuritis (24%). Poor prognostic indicators were older age at onset, pyramidal and sphincter involvement at the beginning of the illness, and more relapses in the first 2 years of the illness. There were no significant effects of gender or symptom type as prognostic indicators on the residual disability of the studied patient. CONCLUSION: Older age at onset, pyramidal and sphincter involvement at the beginning of the illness, and more relapses in the first 2 years of the illness were poor prognostic indicators. PMID- 21677614 TI - Clinical utility of F wave parameters in unilateral S1 radiculopathy. AB - OBJECTIVE: To investigate the F wave parameters (F duration, F minimum latency, F maximum latency, F mean latency, F chronodispersion, and F persistence) of the tibial nerve with unilateral S1 radiculopathy. We evaluated the differences of these parameters between the affected and unaffected sides and also with the control group. METHODS: The study was performed from September 2007 to January 2008 in the Electrophysiology Laboratory of Marmara University Medical Faculty, Istanbul, Turkey. Bilateral tibial F waves were obtained from 20 normal control subjects (control group) and 20 patients with unilateral S1 radiculopathy (patient group). Minimum, maximum, and mean F latency values were corrected by the subject's height (F min/H, F max/H, F mean/H). Needle electromyography was performed in the patient group. The patients with a history of diabetes, alcoholism, or other abnormality known to affect peripheral nerves were excluded. RESULTS: In the control group, no significant differences were found in any of the F-wave parameters between the 2 sides. In the patient group, there were significant prolongations of F duration, F min/H, F max/H, F mean/H, and F chronodispersion on the lesion side. Patients' F durations of the affected and unaffected side were significantly longer than the control group. The F chronodispersion also showed significant prolongation on the affected side in the patient group compared with the control group. Among 20 patients, 15 had evidence of denervation or polyphasic potentials on needle electromyography. CONCLUSION: The F wave study can be clinically useful in the evaluation of S1 radiculopathies, especially in patients with mild and early stage of the disease. Both F duration and F chronodispersion have a higher diagnostic value as compared to F min in the diagnosis of lumbosacral radiculopathy, especially in cases with normal findings on needle electromyography. PMID- 21677615 TI - Brain magnetic resonance image segmentation using novel improvement for expectation maximizing. AB - OBJECTIVE: To improve the quality of expectation maximizing (EM) for brain image segmentation, and to evaluate the accuracy of segmentation results. METHODS: This brain segmentation study was conducted in Universiti Putra Malaysia in Serdong, Malaysia between February and November 2010 on simulated and real images using novel improvement for EM. The EM-1 (proposed algorithm) was compared with neighborhood based extensions for fuzzy C-mean (FCM). The EM-1 was also applied to all 20 normal real MRI volumes and compared with reported results from the Internet Brain Segmentation Repository. RESULTS: In simulated images, the EM-1 outperforms neighborhood based extensions for FCM. The average similarity index value of the proposed algorithm for all 20 normal images is 0.802. The EM-1 produces the average Jaccard indices rho higher than other algorithms and near to manual results. The average similarity indices rho for EM-1 and FCM extensions (FCM with spatial information [FCM-S], Fast Generalized FCM [FGFCM]) for all 20 normal images are: EM-1=0.802, FCM-S=0.7517, enhanced FCM=0.7581, and FGFCM=0.7597. CONCLUSION: Experimental results show that the proposed algorithm performs better than other studied algorithms on various noise levels in terms of similarity index, rho. PMID- 21677617 TI - The effect of hemiplegia/hemiparesis, diabetes mellitus, and hypertension on hospital length of stay after stroke. AB - OBJECTIVE: To determine and analyze the variables of age, hemiplegia/hemiparesis, diabetes mellitus (DM), and hypertension (HTN) on the hospital length of stay (LoS) in the stroke rehabilitation unit. METHODS: We conducted a retrospective cross-sectional study of all patients who completed the stroke rehabilitation program at Sultan Bin Abdulaziz Humanitarian City, Riyadh, Kingdom of Saudi Arabia between January 2007 and October 2010. Admission records of 687 patients were identified with the mean age of 61.7 +/- 14.7 (mean +/- SD) years, and were included in this study. The patients were divided into 5 groups based on their age (30-80 years). Patients aged <= 29 and >= 81 years were excluded due to small sample sizes. Mixed hemispheric patients were also excluded. RESULTS: The frequency of the stroke occurrence was highest in the 61-70 age group, and lowest in the 30-40 age group. Compared with left hemiplegia/hemiparesis (43.5 days), patients with right hemiplegia/hemiparesis (47.3 days) had significantly higher LoS (p=0.042). Compared with stroke alone, in patients with stroke combined with DM and HTN the LoS was significantly higher in right (p=0.003) and left hemiplegia/hemiparesis (p=0.046) patients. CONCLUSION: Right hemiplegia/hemiparesis and combined comorbidity (DM + HTN) has a significant effect on LoS stroke patients; age also had a similar effect. PMID- 21677616 TI - Posterior cervical decompressive laminectomy and lateral mass screw fixation. AB - OBJECTIVE: To review the results and complications of cervical decompressive laminectomy and lateral mass screw fixation. METHODS: This retrospective study was carried out between October 2006 and January 2010 at King Abdullah University Hospital, Irbid, Jordan. Over 40 months, 405 lateral mass screws were placed in 50 patients aged 22-65 years (17 females, and 33 males) for variable cervical pathologies including degenerative disease, trauma, and neoplasm. All cases were performed with a polyaxial screw/rod construct. Most patients had 14 mm length and 3.5 mm diameter screws placed. The screw location was evaluated by postoperative plain x-ray and CT. The facet joint, foraminal and foramen transversarium violation were also assessed. RESULTS: All screws were placed using the Anderson or Sekhon methods. No patients experienced neural or vascular injury as a result of screw position. One patient needed screw repositioning. Three patients experienced superficial wound infection. Five patients experienced pain around the shoulder of C5 distribution that subsided over time. No patients had screw pullouts or symptomatic adjacent segment disease. Postoperative CT scanning showed no compromise of the foramen transversarium or neural foramen in the vast majority of the patients. CONCLUSION: Lateral mass screw stabilization is a safe and effective surgical technique. This study exhibits the safety and effectiveness of lateral mass fixation for a variety of subaxial cervical spine disease. PMID- 21677618 TI - Fluoxetine as a treatment for post-traumatic stress disorder. AB - OBJECTIVE: To assess the effectiveness of fluoxetine in the treatment of post traumatic stress disorder (PTSD) in adults. METHODS: A meta-analysis was conducted between April 2008 and December 2010 at West China Hospital, Chengdu, China. Any randomized controlled trials (RCTs) in which fluoxetine were used for PTSD were considered through computerized databases up to September 2010 such as MEDLINE, EBSCO, EMBASE, and ELSEVIER. The RCTs were strictly assessed by investigators for inclusion in the study, collated trial data, and trial quality. The results of 7 RCTs included were combined in this meta-analysis to determine the effectiveness of fluoxetine on PTSD. RESULTS: Significant findings from the randomized and placebo-controlled trials suggest that fluoxetine could be an effective medication for PTSD (Respond: relative risk=1.21, 95% confidence interval [CI]: 1.03-1.43; Davidson Trauma Scale total score: weighted mean differences=-7.73, 95% CI: -11.69-3.76). In addition, fluoxetine can cause fairly mild adverse effects for those PTSD patients. CONCLUSION: Findings suggest that fluoxetine is an effective treatment for PTSD, with mild adverse effects on individuals. PMID- 21677619 TI - Atypical radiological findings in cerebral hydatid disease. AB - Cerebral hydatid disease is very rare, representing only 2% of all cerebral space occupying lesions. The diagnosis is usually based on a pathognomonic CT pattern. Exceptionally, the image is atypical raising suspicion of many differential diagnoses such as intracerebral infectious, vascular lesions, or tumors. We report 2 atypical cases of cerebral hydatid cysts diagnosed in a 21, and a 24 year-old woman. The CT scan results suggest oligodendroglioma in the first case and brain abscess in the second. An MRI was helpful in the diagnosis of the 2 cases. Both patients underwent successful surgery with a good outcome. The hydatid nature of the cyst was confirmed by histology in both cases. PMID- 21677620 TI - An unusual cause of cerebral venous sinus thrombosis. Paroxysmal nocturnal hemoglobinuria. AB - Cerebral venous sinus thrombosis caused by paroxysmal nocturnal hemoglobinuria is uncommon. Our case is a 44-year-old woman who presented with a 2 day history of headaches, nausea, and seizures followed by a Todd's paresis; she had been diagnosed as paroxysmal nocturnal hemoglobinuria for 4 years. A magnetic resonance venography revealed extensive thrombosis of the cerebral venous sinus. She received antithrombotic treatment with a good outcome. We highlight paroxysmal nocturnal hemoglobinuria as the reason for the cerebral venous sinus thrombosis. The treatment of cerebral venous sinus thrombosis caused by paroxysmal nocturnal hemoglobinuria should be individualized. PMID- 21677621 TI - Paraganglioma of the sacral spinal canal. AB - Paragangliomas are tumors arising in the paraganglia. Involvement of the spine is less common, and usually takes the form of intradural compression of the cauda equina. We report here a case of a 60-year-old man with recurrent and progressive pain of his sacral and perineal area, accompanied by occasional rod and perineal hypoesthesia on admission. He underwent laminectomies of the vertebral bodies S1 and S2, and an en bloc resection of the tumor. Postoperative histopathological examination revealed a paraganglioma. Postoperative staging showed no pathological abnormalities, and no tumor recurrence after one year. Even though rare, the paraganglioma of the sacral spinal canal should be considered in the differential diagnosis of tumors occurring in the spine. PMID- 21677622 TI - Zoster myelitis in sickle cell anemia. AB - A 17-year-old female patient, known case of sickle cell anemia was admitted to our hospital with 10 days history of fever, vomiting, and epigastric pain. On examination, her temperature was 38 degrees C. There was a vesicular type of rash below the nipple and over the left chest involving the back. She was diagnosed as herpes zoster and was started on acyclovir with good hydration and analgesia. Three days later, she developed weakness and decreased sensation of the right leg. On the fifth day, examination revealed power of 1/5 on the right leg, and 4/5 on the left leg, there was proximal and distal increased tone and brisk reflexes and up going toe on the right side with sensory level at T4-T6. An MRI of the thoracolumbar spine showed high signal intensity at T4-T6. The CSF analysis revealed positive polymerase chain reaction for varicella zoster. She was treated with intravenous (IV) dexamethasone 4 mg, 4 times per day. After 3 days she developed left leg weakness, urine incontinence, and power in the left leg was 3/5. Reflex plantar was up going bilaterally with sensory level at the nipple, T4-T6. She was then stared on IV methylprednisolone one gm for 3 days followed by a tapering dose of prednisolone 50 mg for 2 weeks, after a week of starting medication she was able to walk. This case of transverse myelitis is related to varicella zoster infection, with sickle cell anemia, and was successfully treated with high dose IV methylprednisolone, IV acyclovir, and physiotherapy. PMID- 21677623 TI - Primary frontoparietal lobe convexity germinoma with dural invasion mimics meningioma. AB - Intracranial germinomas are rare and account for only 0.4-3.4% of primary intracranial tumors. They develop mainly in the midline structures in adolescents. The pineal gland is the most common site of this tumor. Here, we describe an unusual case of a giant primary intracranial germinoma located in the intracranial hemisphere with radiological findings that mimicked a meningioma. The clinical diagnosis of the intracranial germinoma was difficult because of its unusual clinical presentation, the location of the lesion, and atypical imaging findings. Based on this case study, we suggest that germinoma might be a possible diagnosis when a tumor of the hemispheres with dura invasion mimics meningioma, especially in young patients. Furthermore, we recommend that frozen biopsy sections should be taken routinely during surgery to aid in rapid diagnosis and effective therapy. PMID- 21677624 TI - Septo-optic dysplasia syndrome with schizencephaly and sudden visual loss. A new observation. PMID- 21677625 TI - Pediatric electroencephalography. Parent's knowledge and experience. PMID- 21677626 TI - Can propofol cause seizures? an experimental study. PMID- 21677627 TI - An innovative new method to diagnose enuresis objectively. PMID- 21677628 TI - West syndrome, can topiramate be on top? PMID- 21677629 TI - A young woman with recurring seizures. PMID- 21677630 TI - A woman with seizures and papilledema. PMID- 21677632 TI - Hepcidin: clinical utility as a diagnostic tool and therapeutic target. AB - Iron is essential for life, yet excessive iron can damage tissues and organs. To prevent iron deficiency and overload, iron balance is regulated by the hormone hepcidin. Hepcidin levels increase in response to iron sufficiency, decreasing intestinal iron absorption and inhibiting release of iron from stores and macrophages. Iron deficiency lowers hepcidin, leading to enhanced iron absorption and mobilization of iron from stores. Hepcidin is also increased by inflammation, and has a major role in the anemia of chronic disease. Chronic kidney disease (CKD) is associated with increased hepcidin levels, and this likely contributes to the incidence and severity of anemia, and resistance to erythropoiesis stimulating agents (ESAs). Elevated hepcidin contributes to the dysregulation of iron homeostasis in CKD. In patients with CKD, although parenteral iron in CKD can bypass some of the iron-blocking effects of hepcidin, free iron and iron stores increase, anemia is only partially corrected, and ESA dose requirements remain significantly higher than physiological replacement. Agents that lower hepcidin or inhibit its actions may be effective strategies to restore normal iron homeostasis, and overcome anemia of chronic kidney disease. We review the regulation of hepcidin, its role in CKD-related anemia, and discuss the potential for hepcidin as a clinical marker, and several investigational methods to lower hepcidin for treatment of anemia in CKD. PMID- 21677633 TI - Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. AB - Acute kidney injury, a common complication of cardiac surgery with cardiopulmonary bypass, is associated with increased morbidity and mortality. Ischemic preconditioning at a remote site mitigates ischemia-reperfusion injury and may prevent acute kidney injury after cardiac surgery, thus providing clinical benefit. To further study this, we enrolled 120 adult patients undergoing elective cardiac surgery for whom cardiopulmonary bypass was anticipated in a randomized, single-blind, and controlled pilot trial. Patients were stratified for the type of surgery and equally assigned to a control group or to receive remote ischemic preconditioning by an automated thigh tourniquet consisting of three 5-min intervals of lower extremity ischemia separated by 5 min intervals of reperfusion. The primary end point was acute kidney injury defined as an elevation of serum creatinine of >=0.3 mg/dl or >=50% within 48 h after surgery. Fifty-nine patients in each group were analyzed on an intention-to treat basis. Acute kidney injury occurred in 12 remote ischemic preconditioned and 28 control patients, reflecting an absolute risk reduction of 0.27 and a significantly reduced relative risk due to preconditioning of 0.43. Hence, remote ischemic preconditioning prevents acute kidney injury in patients undergoing cardiopulmonary bypass-assisted cardiac surgery. PMID- 21677635 TI - Smoking is a risk factor in the progression to kidney failure. AB - To study the role of smoking in renal damage, we measured gender-specific effects, dose-response relationships, and whether cessation reduced the risk of smoking on future kidney failure. During a median follow-up of 10.3 years, 124 of 65,589 participants of the HUNT II study, a Norwegian population, progressed to stage 5 chronic kidney disease. Former- and current-smokers less than 70 years of age at inclusion had significant multi-adjusted hazard ratios of 3.32 and 4.01 for kidney failure compared to those who never smoked. In men, the risk increased with a significantly higher trend for cumulative smoking (pack-years); however, the risk significantly decreased with increased elapsed years since smoking cessation. Although the prevalence of current smoking did not differ between genders, females had smoked less (10.2 compared to 15.8 pack-years) and the number of kidney failure cases was lower in females than in men (46 compared to 78). The effect of smoking on the risk of kidney failure was similar (hazard ratios of 2.94 and 4.30 in current-smoking women and men, respectively), but did not reach statistical significance in women. Thus, in this large population-based sample, we found that smoking is a significant risk factor for future kidney failure. Smoking cessation decreased this risk, at least in men. PMID- 21677636 TI - Factor H-related protein 1 neutralizes anti-factor H autoantibodies in autoimmune hemolytic uremic syndrome. AB - The autoimmune form of atypical hemolytic uremic syndrome (HUS) is characterized by circulating autoantibodies against the complement regulator factor H, and is often associated with deficiency of the factor H-related proteins CFHR1 and CFHR3. Here we studied whether anti-factor H autoantibodies crossreact with CFHR1, and determined functional consequences of this. In ELISA, anti-factor H immunoglobulin G (IgG) autoantibodies from 24 atypical HUS patients bound to the short consensus repeat 20 domain of factor H, 21 antibodies also recognized CFHR1, but none CFHR3. Three patients also had anti-factor H IgA autoantibodies crossreacting with CFHR1. Analysis of the IgG fractions in CFHR1-deficient patients found that CFHR1-IgG complexes were formed during plasma exchange treatment, indicating that autoantibodies recognize CFHR1 in vivo. Recombinant CFHR1 prevented hemolysis of sheep erythrocytes caused by patient plasma containing anti-factor H IgG, but it did not inhibit red cell lysis caused by a factor H mutation (W1183 L) in the short consensus repeat 20 domain. Thus, exogenous CFHR1 provided during plasma exchange therapy may neutralize anti factor H autoantibodies and help in the treatment of autoimmune atypical HUS. PMID- 21677634 TI - Plasma neutrophil gelatinase-associated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia. AB - Although plasma neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker for early detection of acute kidney injury, its ability to predict recovery is unknown. Using RIFLE criteria to define kidney injury, we tested whether higher plasma NGAL concentrations on the first day of RIFLE-F would predict failure to recover in a post hoc analysis of a multicenter, prospective, cohort study of patients with community-acquired pneumonia. Recovery was defined as alive and not requiring renal replacement therapy during hospitalization or having a persistent RIFLE-F classification at hospital discharge. Median plasma NGAL concentrations were significantly lower among the 93 of 181 patients who recovered. Plasma NGAL alone predicted failure to recover with an area under the receiver operating characteristic curve of 0.74. A clinical model using age, serum creatinine, pneumonia severity, and nonrenal organ failure predicted failure to recover with area under the curve of 0.78. Combining this clinical model with plasma NGAL concentrations did not improve prediction. The reclassification of risk of renal recovery, however, significantly improved by 17% when plasma NGAL was combined with the clinical model. Thus, in this cohort of patients with pneumonia-induced severe acute kidney injury, plasma NGAL appears to be a useful biomarker for predicting renal recovery. PMID- 21677637 TI - Distinct roles for C3a and C5a in complement-induced tubulointerstitial injury. AB - To prevent injury to host tissues, complement activation is regulated by a number of plasma and membrane-associated proteins, most of which limit C3 and C5 activation. An influx of circulating C3 from a syngeneic host into donor kidneys deficient in Crry (a membrane protein that reduces C3 convertase activity) causes spontaneous complement activation, primarily in the tubulointerstitum, leading to renal failure. To determine the roles of the C3a and C5a anaphylatoxins in tubulointerstitial inflammation and fibrosis, kidneys from Crry-/-C3-/- mice were transplanted into hosts lacking the C3a and/or C5a receptor. While unrestricted complement activation in the tubules was not affected by receptor status in the transplant recipient, C3a receptor deficiency in the recipients led to significantly reduced renal leukocyte infiltration and the extent of tubulointerstitial inflammation and fibrosis, all of which led to preserved renal function. The absence of C5a receptors in recipients was not only inconsequential, but the protective effect of C3a receptor deficiency was also eliminated, suggesting distinct roles of C3a and C5a receptor signaling in this model. There was significant infiltration of the tubulointerstitum with 7/4+F4/80+CD11b+ myelomonocytic cells and Thy1.2+ T cells along injured tubules, and interstitial collagen I and III deposition, all of which were C3a receptor dependent. Thus, blockade of C3a receptor signaling is a possible treatment to reduce renal inflammation and preserve renal function associated with complement activation. PMID- 21677638 TI - Liver X receptor-activating ligands modulate renal and intestinal sodium phosphate transporters. AB - Cholesterol is pumped out of the cells in different tissues, including the vasculature, intestine, liver, and kidney, by the ATP-binding cassette transporters. Ligands that activate the liver X receptor (LXR) modulate this efflux. Here we determined the effects of LXR agonists on the regulation of phosphate transporters. Phosphate homeostasis is regulated by the coordinated action of the intestinal and renal sodium-phosphate (NaPi) transporters, and the loss of this regulation causes hyperphosphatemia. Mice treated with DMHCA or TO901317, two LXR agonists that prevent atherosclerosis in ApoE or LDLR knockout mice, significantly decreased the activity of intestinal and kidney proximal tubular brush border membrane sodium gradient-dependent phosphate uptake, decreased serum phosphate, and increased urine phosphate excretion. The effects of DMHCA were due to a significant decrease in the abundance of the intestinal and renal NaPi transport proteins. The same effect was also found in opossum kidney cells in culture after treatment with either agonist. There was increased nuclear expression of the endogenous LXR receptor, a reduction in NaPi4 protein abundance (the main type II NaPi transporter in the opossum cells), and a reduction in NaPi co-transport activity. Thus, LXR agonists modulate intestinal and renal NaPi transporters and, in turn, serum phosphate levels. PMID- 21677639 TI - The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA ("ecstasy") in humans. AB - This study assessed the pharmacodynamic and pharmacokinetic effects of the interaction between the selective norepinephrine (NE) transporter inhibitor reboxetine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") in 16 healthy subjects. The study used a double-blind, placebo-controlled crossover design. Reboxetine reduced the effects of MDMA including elevations in plasma levels of NE, increases in blood pressure and heart rate, subjective drug high, stimulation, and emotional excitation. These effects were evident despite an increase in the concentrations of MDMA and its active metabolite 3,4 methylenedioxyamphetamine (MDA) in plasma. The results demonstrate that transporter-mediated NE release has a critical role in the cardiovascular and stimulant-like effects of MDMA in humans. PMID- 21677640 TI - Can network analysis improve pattern recognition among adverse events following immunization reported to VAERS? AB - Current methods of statistical data mining are limited in their ability to facilitate the identification of patterns of potential clinical interest from spontaneous reporting systems of medical product adverse events (AEs). Network analysis (NA) allows for simultaneous representation of complex connections among the key elements of such a system. The Vaccine Adverse Event Reporting System (VAERS) can be represented as a network of 6,428 nodes (74 vaccines and 6,354 AEs) with more than 1.4 million interlinkages. VAERS has the characteristics of a "scale-free" network, with certain vaccines and AEs acting as "hubs" in the network. Known safety signals were visualized using NA methods, including hub identification. NA offers a complementary approach to current statistical data mining techniques for visualizing multidimensional patterns, providing a structural framework for evaluating AE data. PMID- 21677641 TI - NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. AB - Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants. PMID- 21677644 TI - Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. AB - Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-beta-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers. PMID- 21677646 TI - Earthquakes: The lessons of Tohoku-Oki. PMID- 21677647 TI - Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. AB - Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge. Neurotransmission mediated by NMDA receptors is essential for basic brain development and function. These receptors form heteromeric ion channels and become activated after concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion-channel activity is allosterically regulated by binding of small compounds to the amino-terminal domain (ATD) in a subtype-specific manner. Ifenprodil and related phenylethanolamine compounds, which specifically inhibit GluN1 and GluN2B NMDA receptors, have been intensely studied for their potential use in the treatment of various neurological disorders and diseases, including depression, Alzheimer's disease and Parkinson's disease. Despite considerable enthusiasm, mechanisms underlying the recognition of phenylethanolamines and ATD mediated allosteric inhibition remain limited owing to a lack of structural information. Here we report that the GluN1 and GluN2B ATDs form a heterodimer and that phenylethanolamine binds at the interface between GluN1 and GluN2B, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b ATD from Xenopus laevis and the GluN2B ATD from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B ATD, by engineering of an inter-subunit disulphide bond, markedly decreases sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B ATD is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. These findings pave the way for improving the design of subtype-specific compounds with therapeutic value for neurological disorders and diseases. PMID- 21677648 TI - Coseismic and postseismic slip of the 2011 magnitude-9 Tohoku-Oki earthquake. AB - Most large earthquakes occur along an oceanic trench, where an oceanic plate subducts beneath a continental plate. Massive earthquakes with a moment magnitude, M(w), of nine have been known to occur in only a few areas, including Chile, Alaska, Kamchatka and Sumatra. No historical records exist of a M(w) = 9 earthquake along the Japan trench, where the Pacific plate subducts beneath the Okhotsk plate, with the possible exception of the ad 869 Jogan earthquake, the magnitude of which has not been well constrained. However, the strain accumulation rate estimated there from recent geodetic observations is much higher than the average strain rate released in previous interplate earthquakes. This finding raises the question of how such areas release the accumulated strain. A megathrust earthquake with M(w) = 9.0 (hereafter referred to as the Tohoku-Oki earthquake) occurred on 11 March 2011, rupturing the plate boundary off the Pacific coast of northeastern Japan. Here we report the distributions of the coseismic slip and postseismic slip as determined from ground displacement detected using a network based on the Global Positioning System. The coseismic slip area extends approximately 400 km along the Japan trench, matching the area of the pre-seismic locked zone. The afterslip has begun to overlap the coseismic slip area and extends into the surrounding region. In particular, the afterslip area reached a depth of approximately 100 km, with M(w) = 8.3, on 25 March 2011. Because the Tohoku-Oki earthquake released the strain accumulated for several hundred years, the paradox of the strain budget imbalance may be partly resolved. This earthquake reminds us of the potential for M(w) ~ 9 earthquakes to occur along other trench systems, even if no past evidence of such events exists. Therefore, it is imperative that strain accumulation be monitored using a space geodetic technique to assess earthquake potential. PMID- 21677649 TI - Identifying neurobiological phenotypes associated with alcohol use disorder severity. AB - Although numerous studies provide general support for the importance of genetic factors in the risk for alcohol use disorders (AUDs), candidate gene and genome wide studies have yet to identify a set of genetic variations that explain a significant portion of the variance in AUDs. One reason is that alcohol-related phenotypes used in genetic studies are typically based on highly heterogeneous diagnostic categories. Therefore, identifying neurobiological phenotypes related to neuroadaptations that drive the development of AUDs is critical for the future success of genetic and epigenetic studies. One such neurobiological phenotype is the degree to which exposure to alcohol taste cues recruits the basal ganglia, prefrontal cortex, and motor areas, all of which have been shown to have a critical role in addictive behaviors in animal studies. To that end, this study was designed to examine whether cue-elicited responses of these structures are associated with AUD severity in a large sample (n=326) using voxelwise and functional connectivity measures. Results suggested that alcohol cues significantly activated dorsal striatum, insula/orbitofrontal cortex, anterior cingulate cortex, and ventral tegmental area. AUD severity was moderately correlated with regions involved in incentive salience such as the nucleus accumbens and amygdala, and stronger relationships with precuneus, insula, and dorsal striatum. The findings indicate that AUDs are related to neuroadaptations in these regions and that these measures may represent important neurobiological phenotypes for subsequent genetic studies. PMID- 21677650 TI - The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. AB - Social avoidance and social phobia are core symptoms of various psychopathologies but their underlying etiology remains poorly understood. Therefore, this study aims to reveal pro-social effects of the neuropeptide oxytocin (OT), under both basal and stress-induced social avoidance conditions in rodents using a social preference paradigm. We initially show that intracerebroventricular (i.c.v.) application of an OT receptor antagonist (OTR-A) in naive male rats (0.75 MUg/5 MUl), or mice (20 MUg/2 MUl), reduced social exploration of a novel con-specific indicative of attenuated social preference. Previous exposure of male rats to a single social defeat resulted in loss of their social preference and social avoidance, which could be restored by i.c.v. infusion of synthetic OT (0.1 MUg/5 MUl) 20 min before the social preference test. Although the amygdala has been implicated in both social and OT-mediated actions, bilateral OTR-A (0.1 MUg/1 MUl) or OT (0.01 MUg/1 MUl) administration into various subnuclei of the amygdala did not affect basal or stress-induced social preference behavior, respectively. Finally, we demonstrate the social specificity of these OT-mediated effects by showing that neither an arginine vasopressin V1a receptor antagonist (0.75 MUg/5 MUl, i.c.v.) nor the anxiogenic drug pentylenetetrazol (15 mg/kg, i.p.) altered social preference, with OTR-A not affecting non-social anxiety on the elevated plus-maze. Overall, the data indicate that the basal activity of the endogenous brain OT system is sufficient to promote natural occurring social preference in rodents while synthetic OT shows potential to reverse stress-induced social avoidance and might thus be of use for treating social phobia and social dysfunction in humans. PMID- 21677651 TI - Persistent increase in hypothalamic arginine vasopressin gene expression during protracted withdrawal from chronic escalating-dose cocaine in rodents. AB - Arginine vasopressin (AVP) from the paraventricular nucleus (PVN) of hypothalamus has important roles in regulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress-related behaviors during chronic stress. It is unknown, however, whether AVP in the PVN is involved in the modulation of HPA activity after chronic cocaine exposure. Here, we examined the gene expression alterations of AVP in the hypothalamus, and V1b receptor and pro-opiomelanocortin (POMC) in the anterior pituitary, as well as HPA hormonal changes, in Fischer rats after chronic cocaine and withdrawal, using two different chronic (14-day) 'binge' pattern administration regimens: steady-dose cocaine (SDC, 45 mg/kg/day) and escalating-dose cocaine (EDC, 45 up to 90 mg/kg/day). There was a significant (7 fold) plasma adrenocorticotropic hormone (ACTH) elevation after chronic EDC (but not SDC), coupled with increased V1b and POMC mRNA levels in the anterior pituitary. From acute (1-day) to protracted (14-day) withdrawal from chronic EDC (but not from SDC), we found persistent elevations of both plasma ACTH and corticosterone levels and AVP mRNA levels in the PVN. Selective V1b antagonist SSR149415 (5 mg/kg) attenuated acute withdrawal-induced HPA activation after EDC. To study potential roles of endogenous opioids in modulating the AVP gene, we administered naloxone (1 mg/kg); we found that opioid receptor antagonism increased AVP mRNA levels in cocaine-naive rats, but not in cocaine-withdrawn rats, suggesting less tonic opioid inhibition of PVN AVP neurons after chronic EDC. To assess the effects of cocaine withdrawal on sub-populations of PVN AVP neurons, we utilized AVP-enhanced green fluorescent protein (EGFP) promoter transgenic mice and found that acute withdrawal following chronic EDC increased the number of AVP-EGFP neurons in the parvocellular PVN (pPVN). These results suggest that during protracted withdrawal, enhanced pPVN AVP gene expression is associated with persistent elevations of basal HPA activity; a hyposensitivity of PVN AVP gene expression to naloxone is indicative of reduced opioidergic tone. Our studies indicate that the AVP and its V1b receptor system may be a potential therapeutic target for treating anxiety and depressive symptoms associated with cocaine addiction. PMID- 21677653 TI - Selective pyramidal cell reduction of GABA(A) receptor alpha1 subunit messenger RNA expression in schizophrenia. AB - Levels of messenger RNA (mRNA) for the alpha1 subunit of the GABA(A) receptor, which is present in 60% of cortical GABA(A) receptors, have been reported to be lower in layer 3 of the prefrontal cortex (PFC) in subjects with schizophrenia. This subunit is expressed in both pyramidal cells and interneurons, and thus lower alpha1 subunit levels in each cell population would have opposite effects on net cortical excitation. We used dual-label in situ hybridization to quantify GABA(A) alpha1 subunit mRNA expression in calcium/calmodulin-dependent kinase II alpha (CaMKIIalpha)-containing pyramidal cells and glutamic acid decarboxylase 65 kDa (GAD65)-containing interneurons in layer 3 of the PFC from matched schizophrenia and healthy comparison subjects. In subjects with schizophrenia, mean GABA(A) alpha1 subunit mRNA expression was significantly 40% lower in pyramidal cells, but was not altered in interneurons. Lower alpha1 subunit mRNA expression in pyramidal cells was not attributable to potential confounding factors, and thus appeared to reflect the disease process of schizophrenia. These results suggest that pyramidal cell inhibition is reduced in schizophrenia, whereas inhibition of GABA neurons is maintained. The cell type specificity of these findings may reflect a compensatory response to enhance layer 3 pyramidal cell activity in the face of the diminished excitatory drive associated with the lower dendritic spine density on these neurons. PMID- 21677652 TI - Phencyclidine-induced loss of asymmetric spine synapses in rodent prefrontal cortex is reversed by acute and chronic treatment with olanzapine. AB - Enduring cognitive deficits exist in schizophrenic patients, long-term abusers of phencyclidine (PCP), as well as in animal PCP models of schizophrenia. It has been suggested that cognitive performance and memory processes are coupled with remodeling of pyramidal dendritic spine synapses in prefrontal cortex (PFC), and that reduced spine density and number of spine synapses in the medial PFC of PCP treated rats may potentially underlie, at least partially, the cognitive dysfunction previously observed in this animal model. The present data show that the decrease in number of asymmetric (excitatory) spine synapses in layer II/III of PFC, previously noted at 1-week post PCP treatment also occurs, to a lesser degree, in layer V. The decrease in the number of spine synapses in layer II/III was sustained and persisted for at least 4 weeks, paralleling the observed cognitive deficits. Both acute and chronic treatment with the atypical antipsychotic drug, olanzapine, starting at 1 week after PCP treatment at doses that restore cognitive function, reversed the asymmetric spine synapse loss in PFC of PCP-treated rats. Olanzapine had no significant effect on spine synapse number in saline-treated controls. These studies demonstrate that the effect of PCP on asymmetric spine synapse number in PFC lasts at least 4 weeks in this model. This spine synapse loss in PFC is reversed by acute treatment with olanzapine, and this reversal is maintained by chronic oral treatment, paralleling the time course of the restoration of the dopamine deficit, and normalization of cognitive function produced by olanzapine. PMID- 21677654 TI - Retraction. Androgen activates PEG10 to promote carcinogenesis in hepatic cancer cells. PMID- 21677655 TI - Retraction. Selectively frequent expression of CXCR5 enhances resistance to apoptosis in CD8(+)CD34(+) T cells from patients with T-cell-lineage acute lymphocytic leukemia. PMID- 21677656 TI - Angiotensin II induces microtubule reorganization mediated by a deacetylase SIRT2 in endothelial cells. AB - Angiotensin II has been implicated in vascular remodeling. Microtubule composed of tubulins regulates cell shape, migration and survival. Tubulin acetylation has an important role in the control of microtubule structure and microtubule-based cellular functions. In this study, angiotensin II induced disassembly and deacetylation of alpha-tubulin, which were blocked by pretreatment with an angiotensin II type 1 receptor blocker losartan and a sirtuin class deacetylase inhibitor sirtinol, and by depletion of a deacetylase SIRT2 using RNA interference. We investigated the involvement of SIRT2 in angiotensin II-induced endothelial cell migration using the Boyden chamber method. Angiotensin II caused a significant increase in cell migration, which was blocked by pretreatment with sirtinol and SIRT2 depletion. It has been reported that angiotensin II is involved in cytoskeletal reorganization stimulated by mechanical stretch in endothelial cells. We also demonstrated that endothelial cells subjected to a 10% uniaxial stretch showed vertical alignment to the direction of tension and tubulin deacetylation in the peripheral side of cells, in comparison with control static cells. The mechanical stretch-induced changes of microtubules were blocked by pretreatment with sirtinol and SIRT2 depletion. Immunofluorescence microscopy showed that acetylated tubulin was decreased in platelet-endothelial cell adhesion molecule-1-positive cells in the intima of the aortic walls in mice loaded with angiotensin II, in comparison with mice loaded with control vehicle. These data show that angiotensin II and mechanical stretch stimulate microtubule redistribution and deacetylation via SIRT2 in endothelial cells, suggesting the emerging role of SIRT2 in hypertension-induced vascular remodeling. PMID- 21677657 TI - The associations between G972R polymorphism of the IRS-1 gene, insulin resistance, salt sensitivity and non-dipper hypertension. AB - The aim of this study was to assess the association between G972R polymorphism of the insulin receptor substrate-1 (IRS-1) gene and the circadian variation in blood pressure, insulin sensitivity and salt sensitivity in subjects with uncomplicated, never-treated essential hypertension receiving low-, normal- and high-salt diets. The study was performed on 115 subjects aged 27.48+/-5.1 years with never-treated, uncomplicated hypertension. In the 7-day consecutive period of time, subjects received a normal-, low- and high-salt diet. At the end of each dietary regimen, the following parameters were recorded: 24-h blood pressure monitoring, lipid profile, insulin level, glucose level, aldosterone level and plasma renin activity. Insulin resistance was evaluated by the homeostasis model assessment (HOMA). In comparison with Gly/Gly carriers, subjects with the G972R polymorphism had higher concentrations of total and LDL cholesterol and triglycerides and HOMA but lower HDL cholesterol. On a high-salt diet, patients with the G972R polymorphism had an increased risk for insulin resistance (odds ratio (OR)=11.42, 95% confidence interval (CI) 7.68-28.44), salt sensitivity (OR=5.38, 95% CI 1.14-25.34) and non-dipper hypertension (OR=3.6, 95% CI 1.07 12.09). Regardless of the dietary salt intake, blood pressure values were similar between G972R and Gly/Gly carriers. In conclusion, the results of our study suggest that the G972R polymorphism of the IRS-1 gene is associated with insulin resistance, salt sensitivity and non-dipper hypertension. PMID- 21677658 TI - Epigenetic regulation of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is diagnosed as a sustained elevation of pulmonary arterial pressure to more than 25 mm Hg at rest or to more than 30 mm Hg with exercise. PAH is an intrinsic disease of the pulmonary vascular smooth muscle and endothelial cells in association with plexiform lesions, medial thickening, concentric laminar intimal fibrosis and thrombotic lesions. Pulmonary vascular remodeling is the characteristic pathological change of PAH. The pathogenesis of PAH has been studied at the level of smooth muscle and endothelial cells. Existing research does not adequately explain susceptibility to the disease, and recent evidence reveals that epigenetic alterations may be involved in PAH. Epigenetics refers to all heritable changes in phenotype or in gene expression states, including chromatin remodeling, DNA methylation, histone modification and RNA interference, which are not involved in the DNA sequence itself. This review will focus on recent advances in epigenetics related to PAH, including epigenetic changes of superoxide dismutase, endothelial nitric oxide synthase and the bone morphogenetic protein signaling pathway. This will provide new insight for improved treatment and prevention of PAH. Future work aimed at specific epigenetic treatments may prove to be an effective therapy for patients with PAH. PMID- 21677659 TI - The dismal fat, kidney and brain connection: what to do? PMID- 21677660 TI - Significance of measuring oxidative stress in lifestyle-related diseases from the viewpoint of correlation between d-ROMs and BAP in Japanese subjects. AB - In recent years, oxidative stress has been postulated to be an important factor in the pathogenesis and development of lifestyle-related diseases. In this study, we investigated the association between the derivatives of reactive oxygen metabolites (d-ROMs), as an index of products of reactive oxygen species (ROS), and biological antioxidant potential (BAP), as an index of antioxidant potential. We also investigated the associations between d-ROMs or BAP and the risk factors for lifestyle-related diseases or metabolic syndrome-associated factors to evaluate their usefulness in preventive medicine. There were 442 subjects who underwent health checkup examination in our facilities. In addition to standard medical checkup items, we analyzed d-ROMs, BAP, brachial-ankle pulse wave velocity, high-sensitivity C-reactive protein level and visceral fat area (VFA) visualized on a computed tomography scan. The mean d-ROM value in females was significantly higher than that in males. There was a positive correlation between the d-ROM and VFA levels. On correlation analysis, there was a negative correlation between the d-ROM and creatinine levels. As factors that influence d ROMs, the level of VFA was selected, suggesting the significance of oxidative stress measurement with d-ROMs. In addition, there was a positive correlation between d-ROMs and BAP values. Further research is required to resolve whether increased production of ROS or the antioxidant potential that can compensate for such an increase of ROS is more important in vivo. PMID- 21677661 TI - Ventricular repolarization before and after treatment in patients with secondary hypertension due to renal-artery stenosis and primary aldosteronism. AB - A prolonged QT interval is a risk factor for ischemic heart disease in hypertensive subjects. Patients with renal-artery stenosis and primary aldosteronism (PA) are at increased risk of cardiovascular events. The objective of the present study was to evaluate the QT interval in patients with renovascular hypertension (RV) and PA before and after treatment. A total of 24 patients with RV and 38 with PA were studied; 89 patients with essential hypertension (EH) served as control group. Corrected QT intervals (QTcH) were measured from a 12-lead ECG. Basal QTcH was longer in RV (429+/-30 ms) and PA (423+/-23 ms) compared with EH controls (407+/-18 ms; P<0.001). The prevalence of QTcH >440 ms was higher in RV (29%) and PA patients (29%) compared with EH controls (4%; P<0.001). QTcH interval was evaluated after treatment in 19 RV and 15 PA patients. QTcH was reduced after renal-artery angioplasty in RV patients (419+/-14 ms; P=0.02), and after spironolactone or adrenalectomy in PA (403+/-12 ms; P=0.01). In conclusion, QT interval was prolonged in patients with RV and PA compared with controls with EH. After angioplasty of renal-artery stenosis in RV, and treatment with spironolactone or adrenalectomy in PA, the cardiovascular risk of such patients may be reduced by concomitant blood pressure lowering and QT duration shortening. PMID- 21677662 TI - Copy number polymorphisms in new HapMap III and Singapore populations. AB - Copy number variations can be identified using newer genotyping arrays with higher single nucleotide polymorphisms (SNPs) density and copy number probes accompanied by newer algorithms. McCarroll et al. (2008) applied these to the HapMap II samples and identified 1316 copy number polymorphisms (CNPs). In our study, we applied the same approach to 859 samples from three Singapore populations and seven HapMap III populations. Approximately 50% of the 1291 autosomal CNPs were found to be polymorphic only in populations of non-African ancestry. Pairwise comparisons among the 10 populations showed substantial differences in the CNPs frequencies. Additionally, 698 CNPs showed significant differences with false discovery rate (FDR)<0.01 among the 10 populations and these loci overlap with known disease-associated or pharmacogenetic-related genes such as CFHR3 and CFHR1 (age related macular degeneration), GSTTI (metabolism of various carcinogenic compounds and cancers) and UGT2B17 (prostate cancer and graft-versus-host disease). The correlations between CNPs and genome-wide association studies-SNPs were investigated and several loci, which were previously unreported, that may potentially be implicated in complex diseases and traits were found; for example, childhood acute lymphoblastic leukaemia, age related macular degeneration, breast cancer, response to antipsychotic treatment, rheumatoid arthritis and type-1 diabetes. Additionally, we also found 5014 novel copy number loci that have not been reported previously by McCarroll et al. (2008) in the 10 populations. PMID- 21677663 TI - Ancient links between Siberians and Native Americans revealed by subtyping the Y chromosome haplogroup Q1a. AB - To investigate the structure of Y chromosome haplogroups R-M207 and Q-M242 in human populations of North Asia, we have performed high-resolution genotyping using both single nucleotide polymorphisms and short tandem repeat (STR)-based approaches of 121 M207- and M242-derived samples from 885 males of 16 ethnic groups of Siberia and East Asia. As a result, the following Y chromosome haplogroups were revealed: R1b1b1-M73 (2.0%), R1b1b2-M269 (0.7%), R2-M124 (1.1%), Q1a*-MEH2 (0.5%), Q1a2-M25 (0.1%), Q1a3*-M346 (9.2%) and Q1a3a-M3 (0.2%). Despite the low coalescence age of haplogroup Q1a3*-M346, which is estimated in South Siberia as about 4.5+/-1.5 thousand years ago (Ka), divergence time between these Q1a3*-M346 haplotypes and Amerindian-specific haplogroup Q1a3a-M3 is equal to 13.8+/-3.9 Ka, pointing to a relatively recent entry date to America. In addition, unique cluster of haplotypes belonging to Q1a*-MEH2 was found in Koryaks inhabiting the Sea of Okhotsk coast (at a frequency of 10.3%). Although the level of STR diversity associated with Q1a*-MEH2 is very low, this lineage appears to be closest to the extinct Palaeo-Eskimo individuals belonging to the Saqqaq culture arisen in the New World Arctic about 5.5 Ka. This finding suggests that Q1a*-MEH2 likely traces a population migration originating in Northeast Siberia across the Bering Strait. PMID- 21677664 TI - WITHDRAWN: Evaluation of next-generation sequencing software in mapping and assembly. AB - Next-generation high-throughput DNA sequencing technologies have advanced progressively in sequence-based genomic research and novel biological applications with the promise of sequencing DNA at unprecedented speed. These new non-Sanger-based technologies feature several advantages, when compared with traditional sequencing methods in terms of higher sequencing speed, lower per run cost and higher accuracy. However, reads from next-generation sequencing (NGS) platforms, such as 454/Roche, ABI/SOLiD and Illumina/Solexa, are usually short, thereby restricting the applications of NGS platforms in genome assembly and annotation. We presented an overview of the challenges that these novel technologies meet and particularly illustrated various bioinformatics attempts on mapping and assembly for problem solving. We then compared the performance of several programs in these two fields and further provided advices on selecting suitable tools for specific biological applications.Journal of Human Genetics advance online publication, 16 June 2011; doi:10.1038/jhg.2011.62. PMID- 21677665 TI - Endothelial apoptosis decrease following tadalafil administration in patients with arterial ED does not last after its discontinuation. AB - Although it is well known that phosphodiesterase V inhibitors, used to treat patients with ED, can improve the endothelial dysfunction in organic vascular forms, few studies have explored the duration of their effect on the endothelium after discontinuation. Therefore, the purpose of this study was to evaluate the serum concentrations of apoptotic endothelial microparticles (EMPa), selected as a marker of endothelial damage, in patients with arterial ED at baseline, during tadalafil administration and 3 and 6 months after its discontinuation. In all, 50 patients with arterial ED were evaluated at baseline and 1 week after administration of tadalafil 5 mg once daily for 90 days. Clinical (International Index of Erectile Function-5 score), instrumental (dynamic penile echo color Doppler) and flow-cytometric (serum EMPa concentrations) analyses were performed before (T0) and 1 week (T1), 3 months (T2) and 6 months (T3) after tadalafil discontinuation. The events CD45(neg)/CD144(pos)/annexinV(pos) were defined as EMPa. At T0, patients with arterial ED had serum EMPa concentration significantly higher than 20 healthy men (controls). At T1, patients with arterial ED showed a serum EMPa concentration significantly lower than T0. The significant difference was maintained, though reduced, at T2 and completely lost at T3. In conclusion, the administration of tadalafil decreased serum EMPa concentration in patients with arterial ED. This positive effect on the endothelial dysfunction disappeared 6 months after tadalafil discontinuation. PMID- 21677666 TI - Satisfaction with sex and erection hardness: results of the Asia-Pacific sexual health and overall wellness survey. AB - The Asia-Pacific Sexual Health and Overall Wellness (AP SHOW) survey assessed sexual satisfaction and health and the association with erection hardness in 13 Asia-Pacific countries/regions. Adults aged 25-74 years who had sexual intercourse > 1 time in the past 12 months answered Internet surveys or participated in street-intercept interviews. Data were weighted by demographics and country/region size. Of 3957 (men, n=2016 and women, n=1941) respondents, 41% of men and 34% of women were completely or very satisfied with sex. Satisfaction with sex was linked to satisfaction with life priorities and overall health. Few respondents (men, 38% and women, 26%) were very or completely satisfied with erection hardness. Optimal erection hardness was reported by 45% of men (48% of women regarding their partners' erections). Erection hardness was associated with increased frequency of sex and importance of and satisfaction with erection related elements of men's sexual performance. Approximately half of respondents (men, 57% and women, 47%) were at least moderately interested in improving the sexual experience. Most Asia-Pacific respondents were less than very satisfied with sex. Satisfaction with sex was associated with satisfaction with life priorities. Erection hardness was associated with sexual satisfaction and activity, satisfaction with life priorities and overall health. PMID- 21677668 TI - Identification of TROP2 (TACSTD2), an EpCAM-like molecule, as a specific marker for TGF-beta1-dependent human epidermal Langerhans cells. AB - Langerin (CD207) expression is a hallmark of epidermal Langerhans cells (LCs); however, CD207(+) cells comprise several functional subsets. Murine studies showed that epidermal, but not dermal, CD207(+) cells require transforming growth factor-beta 1 (TGF-beta1) for development, whereas human data are lacking. Using gene profiling, we found that the surface molecule TROP2 (TACSTD2) is strongly and rapidly induced during TGF-beta1-dependent LC commitment of human CD34(+) hematopoietic progenitor cells or monocytes. TROP2 is conserved between mouse and human, and shares substantial amino-acid identity with EpCAM, a marker for murine epidermal LCs. To our knowledge, neither TROP2 nor EpCAM expression has been analyzed in human dendritic cell (DC) subsets. We found that (i) all human epidermal LCs are TROP2(+)EpCAM(+); (ii) human dermis lacks CD207(+)EpCAM(-) or CD207(+)TROP2(-) DCs, i.e., equivalents of murine dermal CD207(+) DCs; and (iii) pulmonary CD207(+) cells are TROP2(-)EpCAM(-). Moreover, although EpCAM was broadly expressed by pulmonary and intestinal epithelial cells, as well as by bone marrow erythroid progenitor cells, these cells lacked TROP2. However, although TROP2 is expressed by human LCs as well as by human and murine keratinocytes, most murine LCs, except of a small subset, lacked TROP2. Therefore, TROP2 is a marker for human TGF-beta1-dependent epidermal LCs. PMID- 21677667 TI - Homozygosity mapping and whole-exome sequencing to detect SLC45A2 and G6PC3 mutations in a single patient with oculocutaneous albinism and neutropenia. AB - We evaluated a 32-year-old woman whose oculocutaneous albinism (OCA), bleeding diathesis, neutropenia, and history of recurrent infections prompted consideration of the diagnosis of Hermansky-Pudlak syndrome type 2. This was ruled out because of the presence of platelet delta-granules and absence of AP3B1 mutations. As parental consanguinity suggested an autosomal recessive mode of inheritance, we employed homozygosity mapping, followed by whole-exome sequencing, to identify two candidate disease-causing genes, SLC45A2 and G6PC3. Conventional dideoxy sequencing confirmed pathogenic mutations in SLC45A2, associated with OCA type 4 (OCA-4), and G6PC3, associated with neutropenia. The substantial reduction of SLC45A2 protein in the patient's melanocytes caused the mislocalization of tyrosinase from melanosomes to the plasma membrane and also led to the incorporation of tyrosinase into exosomes and secretion into the culture medium, explaining the hypopigmentation in OCA-4. Our patient's G6PC3 mRNA expression level was also reduced, leading to increased apoptosis of her fibroblasts under endoplasmic reticulum stress. To our knowledge, this report describes the first North American patient with OCA-4, the first culture of human OCA-4 melanocytes, and the use of homozygosity mapping, followed by whole-exome sequencing, to identify disease-causing mutations in multiple genes in a single affected individual. PMID- 21677669 TI - T-cell receptor gene therapy: critical parameters for clinical success. AB - T-cell receptor (TCR) gene therapy aims to induce immune reactivity against tumors by introducing genes encoding a tumor-reactive TCR into patient T cells. This approach has been extensively tested in preclinical mouse models, and initial clinical trials have demonstrated the feasibility and potential of TCR gene therapy as a cancer treatment. However, data obtained from preclinical and clinical studies suggest that both the therapeutic efficacy and the safety of TCR gene therapy can be and needs to be further enhanced. This review highlights those strategies that can be followed to develop TCR gene therapy into a clinically relevant treatment option for cancer patients. PMID- 21677670 TI - Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. AB - JAKs are required for signaling initiated by several cytokines (e.g., IL-4, IL 12, IL-23, thymic stromal lymphopoietin (TSLP), and IFNgamma) implicated in the pathogenesis of inflammatory skin diseases such as psoriasis and atopic dermatitis (AD). Direct antagonism of cytokines, such as IL-12 and IL-23 using ustekinumab, has proven effective in randomized studies in psoriasis patients. We hypothesized that local inhibition of cytokine signaling using topical administration of INCB018424, a small molecule inhibitor of JAK1 and JAK2, would provide benefit similar to systemic cytokine neutralization. In cellular assays, INCB018424 inhibits cytokine-induced JAK/signal transducers and activators of transcription (STAT) signaling and the resultant production of inflammatory proteins (e.g., IL-17, monocyte chemotactic protein-1, and IL-22) in lymphocytes and monocytes, with half-maximal inhibitory concentration values <100 nM. In vivo, topical application of INCB018424 resulted in suppression of STAT3 phosphorylation, edema, lymphocyte infiltration, and keratinocyte proliferation in a murine contact hypersensitivity model and inhibited tissue inflammation induced by either intradermal IL-23 or TSLP. Topical INCB018424 was also well tolerated in a 28-day safety study in Gottingen minipigs. These results suggest that localized JAK1/JAK2 inhibition may be therapeutic in a range of inflammatory skin disorders such as psoriasis and AD. Clinical evaluation of topical INCB018424 is ongoing. PMID- 21677671 TI - Upregulation of Toll-like receptors (TLRs) 6, 7, and 8 in keloid scars. PMID- 21677672 TI - Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue. AB - Interleukin-7 (IL-7) and the IL-7 receptor (IL-7R) have been shown to be alternatively spliced in infectious diseases. We tested IL-7 and IL-7R splicing in a tuberculosis (TB)-vaccine/Mycobacterium tuberculosis (Mtb)-challenge model in non-human primates (NHPs). Differential IL-7 splicing was detected in peripheral blood mononuclear cells (PBMCs) from 15/15 NHPs showing 6 different IL 7 spliced isoforms. This pattern did not change after infection with virulent Mtb. We demonstrated increased IL-7 (6 exon) and IL-17 protein production in lung tissue along with concomitant decreased transforming growth factor-beta (TGF beta) from NHPs (vaccinated with a recombinant BCG (rBCG)) who showed increased survival after Mtb challenge. IL-7 increased IL-17 and interferon-gamma (IFN gamma) gene and protein expression in PBMCs. Mtb-infected NHPs showed differential IL-7R splicing associated with the anatomical location and tissue origin, that is, in lung tissue, hilus, axillary lymph nodes (LNs) and spleen. Differential splicing of the IL-7R was typical for healthy (non-Mtb infected) and for Mtb-infected lung tissue with a dominant expression of soluble IL-7R (sIL-7R) receptor lacking exon 6 (9:1 ratio of sIL-7R/cell-bound IL-7R). Differential ratios of cell-bound vs sIL-7R could be observed in hilus and axillary LNs from Mtb-infected NHPs with an inversed ratio of 1:9 (sIL-7R/cell-bound IL-7R) in spleen and PBMCs. Soluble IL-7R is exclusively present in lung tissue. PMID- 21677675 TI - Signalling: location, location, location. PMID- 21677673 TI - Long-term effects of aldosterone blockade in resistant hypertension associated with chronic kidney disease. AB - Hypertension is a major risk factor for the development and progression of chronic kidney disease (CKD). Mineralocorticoid receptor antagonists (MRAs) are effective in the management of resistant hypertension but are not widely used in CKD because of the risk of hyperkalemia. We retrospectively evaluated the long term effects and safety of MRAs added to a pre-existing antihypertensive regimen in subjects with resistant hypertension associated with stage 3 CKD. In all, 32 patients were treated with spironolactone and 4 with eplerenone for a median follow-up of 312 days. MRAs induced a significant decrease in systolic blood pressure from 162+/-22 to 138+/-14 mm Hg (P<0.0001) and in diastolic blood pressure from 87+/-17 to 74+/-12 mm Hg (P<0.0001). Serum potassium increased from 4.0+/-0.5 to 4.4+/-0.5 mEq l(-1) (P=0.0001), with the highest value being 5.8 mEq l(-1). The serum creatinine increased from 1.5+/-0.3 to 1.8+/-0.5 mg dl(-1) (P=0.0004) and the estimated glomerular filtration rate decreased from 48.6+/-8.7 to 41.2+/-11.5 ml min(-1) per 1.73 m(2) (P=0.0002). One case of acute renal failure and three cases of significant hyperkalemia occurred. MRAs significantly reduced blood pressure in subjects with resistant hypertension associated with stage 3 CKD, although close biochemical monitoring is recommended because of an increased risk of hyperkalemia and worsening of renal function. PMID- 21677678 TI - Leukaemia: targeted therapy re-enABLed? PMID- 21677677 TI - Dynamic modelling of oestrogen signalling and cell fate in breast cancer cells. AB - Cancers of the breast and other tissues arise from aberrant decision-making by cells regarding their survival or death, proliferation or quiescence, damage repair or bypass. These decisions are made by molecular signalling networks that process information from outside and from within the breast cancer cell and initiate responses that determine the cell's survival and reproduction. Because the molecular logic of these circuits is difficult to comprehend by intuitive reasoning alone, we present some preliminary mathematical models of the basic decision circuits in breast cancer cells that may aid our understanding of their susceptibility or resistance to endocrine therapy. PMID- 21677681 TI - Antimicrobials: Killing persisters while they sleep. PMID- 21677682 TI - Parasitology: The malaria food channel. PMID- 21677683 TI - Genome watch: Singled out. PMID- 21677684 TI - Bacterial protein toxins that modify host regulatory GTPases. AB - Many bacterial pathogens produce protein toxins to outmanoeuvre the immune system of the host. Some of these proteins target regulatory GTPases such as those belonging to the RHO family, which control the actin cytoskeleton of the host cell. In this Review, I discuss a diversity of mechanisms that are used by bacterial effectors and toxins to modulate the activity of host GTPases, with a focus on covalent modifications such as ADP-ribosylation, glucosylation, adenylylation, proteolysis, deamidation and transglutamination. PMID- 21677685 TI - Emerging patterns of marine nitrogen fixation. AB - Biological N(2) fixation is an important part of the marine nitrogen cycle as it provides a source of new nitrogen that can support biological carbon export and sequestration. Research in the past decade has focused on determining the patterns of distribution and abundance of diazotrophs, defining the environmental features leading to these patterns and characterizing the factors that constrain marine N(2) fixation overall. In this Review, we describe how variations in the deposition of iron from dust to different ocean basins affects the limiting nutrient for N(2) fixation and the distribution of different diazotrophic species. However, many questions remain about marine N(2) fixation, including the role of temperature, fixed nitrogen species, CO(2) and physical forcing in controlling N(2) fixation, as well as the potential for heterotrophic N(2) fixation. PMID- 21677687 TI - WW domain interactions regulate the Hippo tumor suppressor pathway. AB - The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis in Drosophila and mammalians. Although the signaling of the core kinases is relatively well understood, less is known about the upstream inputs, downstream outputs and regulation of the whole cascade. Enrichment of the Hippo pathway components with WW domains and their cognate proline-rich interacting motifs provides a versatile platform for further understanding the mechanisms that regulate organ growth and tumorigenesis. Here, we review recently discovered mechanisms of WW domain-mediated interactions that contribute to the regulation of the Hippo signaling pathway in tumorigenesis. We further discuss new insights and future directions on the emerging role of such regulation. PMID- 21677689 TI - SIRT1 RNAi knockdown induces apoptosis and senescence, inhibits invasion and enhances chemosensitivity in pancreatic cancer cells. AB - The NAD(+)-dependent deacetylase, sirtuin 1 (SIRT1), has been recently been suspected to have a role in tumorigenesis. We investigated the expression of SIRT1 in pancreatic cancer and the effect of SIRT1-targeted RNA interference (RNAi) on cell proliferation and tumor formation in a pancreatic cancer cell line, PANC1. The expression of SIRT1 was investigated in 49 specimens of pancreatic cancer and adjacent normal pancreatic tissues. SIRT1 was overexpressed in pancreatic cancer tissues at both the mRNA and protein levels, with increased SIRT1 positivity associated with tumors from patients over 60 years old, tumors larger than 4 cm, higher TNM (extent of tumor (T), the extent of spread to lymph nodes (N), and presence of distant metastasis (M)) stage or the presence of lymph node or hepatic metastases. The PANC-1 was stably transfected with a SIRT1 small hairpin RNA (shRNA) expression plasmid and compared with untransfected and PANC-1 negative RNAi cells. Proliferation of PANC-1-SIRT1-RNAi cells was significantly reduced, accompanied by increased rates of apoptosis, G1 arrest and senescence. Furthermore, FOXO3a expression was markedly upregulated in PANC-1-SIRT1-RNAi cells, but no significant difference in p53 expression was observed. The invasive ability of PANC-1-SIRT1-RNAi cells was markedly reduced in vitro, which was linked to increased E-cadherin and reduced-MMP expression. Additionally, PANC-1 SIRT1-RNAi cells had a significantly reduced capacity to form tumors in vivo compared with untransfected and PANC-1-negative RNAi cells. These results suggest that SIRT1 may promote cell proliferation and tumor formation in pancreatic cancer, and downregulation of SIRT1 using shRNA could provide a novel therapeutic treatment. PMID- 21677686 TI - Host factors involved in retroviral budding and release. AB - The plasma membrane is the final barrier that enveloped viruses must cross during their egress from the infected cell. Here, we review recent insights into the cell biology of retroviral assembly and release; these insights have driven a new understanding of the host proteins, such as the ESCRT machinery, that are used by retroviruses to promote their final separation from the host cell. We also review antiviral host factors such as tetherin, which can directly inhibit the release of retroviral particles. These studies have illuminated the role of the lipid bilayer as the unexpected target for virus restriction by the innate immune response. PMID- 21677688 TI - Ocular neuroprotection by siRNA targeting caspase-2. AB - Retinal ganglion cell (RGC) loss after optic nerve damage is a hallmark of certain human ophthalmic diseases including ischemic optic neuropathy (ION) and glaucoma. In a rat model of optic nerve transection, in which 80% of RGCs are eliminated within 14 days, caspase-2 was found to be expressed and cleaved (activated) predominantly in RGC. Inhibition of caspase-2 expression by a chemically modified synthetic short interfering ribonucleic acid (siRNA) delivered by intravitreal administration significantly enhanced RGC survival over a period of at least 30 days. This exogenously delivered siRNA could be found in RGC and other types of retinal cells, persisted inside the retina for at least 1 month and mediated sequence-specific RNA interference without inducing an interferon response. Our results indicate that RGC apoptosis induced by optic nerve injury involves activation of caspase-2, and that synthetic siRNAs designed to inhibit expression of caspase-2 represent potential neuroprotective agents for intervention in human diseases involving RGC loss. PMID- 21677690 TI - Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus). AB - Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and FX-binding-ablated Ad5 vectors in non-human primates. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. In addition, we show that Ad5 binding to hepatocytes may be due to the presence of heparan sulfate proteoglycans (HSPGs) on the cell membrane. Therefore, the Ad5-FX-HSPG pathway mediating liver gene transfer in rodents is also the mechanism underlying Ad5 hepatocyte transduction in Microcebus murinus. PMID- 21677692 TI - Illumina-based analysis of microbial community diversity. AB - Microbes commonly exist in milieus of varying complexity and diversity. Although cultivation-based techniques have been unable to accurately capture the true diversity within microbial communities, these deficiencies have been overcome by applying molecular approaches that target the universally conserved 16S ribosomal RNA gene. The recent application of 454 pyrosequencing to simultaneously sequence thousands of 16S rDNA sequences (pyrotags) has revolutionized the characterization of complex microbial communities. To date, studies based on 454 pyrotags have dominated the field, but sequencing platforms that generate many more sequence reads at much lower costs have been developed. Here, we use the Illumina sequencing platform to design a strategy for 16S amplicon analysis (iTags), and assess its generality, practicality and potential complications. We fabricated and sequenced paired-end libraries of amplified hyper-variable 16S rDNA fragments from sets of samples that varied in their contents, ranging from a single bacterium to highly complex communities. We adopted an approach that allowed us to evaluate several potential sources of errors, including sequencing artifacts, amplification biases, non-corresponding paired-end reads and mistakes in taxonomic classification. By considering each source of error, we delineate ways to make biologically relevant and robust conclusions from the millions of sequencing reads that can be readily generated by this technology. PMID- 21677691 TI - Identification and isolation of active N2O reducers in rice paddy soil. AB - Dissolved N(2)O is occasionally detected in surface and ground water in rice paddy fields, whereas little or no N(2)O is emitted to the atmosphere above these fields. This indicates the occurrence of N(2)O reduction in rice paddy fields; however, identity of the N(2)O reducers is largely unknown. In this study, we employed both culture-dependent and culture-independent approaches to identify N(2)O reducers in rice paddy soil. In a soil microcosm, N(2)O and succinate were added as the electron acceptor and donor, respectively, for N(2)O reduction. For the stable isotope probing (SIP) experiment, (13)C-labeled succinate was used to identify succinate-assimilating microbes under N(2)O-reducing conditions. DNA was extracted 24 h after incubation, and heavy and light DNA fractions were separated by density gradient ultracentrifugation. Denaturing gradient gel electrophoresis and clone library analysis targeting the 16S rRNA and the N(2)O reductase gene were performed. For culture-dependent analysis, the microbes that elongated under N(2)O-reducing conditions in the presence of cell-division inhibitors were individually captured by a micromanipulator and transferred to a low-nutrient medium. The N(2)O-reducing ability of these strains was examined by gas chromatography/mass spectrometry. Results of the SIP analysis suggested that Burkholderiales and Rhodospirillales bacteria dominated the population under N(2)O-reducing conditions, in contrast to the control sample (soil incubated with only (13)C-succinate). Results of the single-cell isolation technique also indicated that the majority of the N(2)O-reducing strains belonged to the genera Herbaspirillum (Burkholderiales) and Azospirillum (Rhodospirillales). In addition, Herbaspirillum strains reduced N(2)O faster than Azospirillum strains. These results suggest that Herbaspirillum spp. may have an important role in N(2)O reduction in rice paddy soils. PMID- 21677693 TI - DddW, a third DMSP lyase in a model Roseobacter marine bacterium, Ruegeria pomeroyi DSS-3. AB - Ruegeria pomeroyi DSS-3 is a model Roseobacter marine bacterium, particularly regarding its catabolism of dimethylsulfoniopropionate (DMSP), an abundant anti stress molecule made by marine phytoplankton. We found a novel gene, dddW, which encodes a DMSP lyase that cleaves DMSP into acrylate plus the environmentally important volatile dimethyl sulfide (DMS). Mutations in dddW reduced, but did not abolish DMS production. Transcription of dddW was greatly enhanced by pre-growth of cells with DMSP, via a LysR-type regulator. Close DddW homologs occur in only one other Roseobacter species, and there are no close homologs and only a few related sequences in metagenomes of marine bacteria. In addition to DddW, R. pomeroyi DSS-3 had been shown to have two other, different, DMSP lyases, DddP and DddQ, plus an enzyme that demethylates DMSP, emphasizing the importance of this substrate for this model bacterium. PMID- 21677694 TI - Sharing of quorum-sensing signals and role of interspecies communities in a bacterial plant disease. AB - Pathogenic bacteria interact not only with the host organism but most probably also with the resident microbial flora. In the knot disease of the olive tree (Olea europaea), the causative agent is the bacterium Pseudomonas savastanoi pv. savastanoi (Psv). Two bacterial species, namely Pantoea agglomerans and Erwinia toletana, which are not pathogenic and are olive plant epiphytes and endophytes, have been found very often to be associated with the olive knot. We identified the chemical signals that are produced by strains of the three species isolated from olive knot and found that they belong to the N-acyl-homoserine lactone family of QS signals. The luxI/R family genes responsible for the production and response to these signals in all three bacterial species have been identified and characterized. Genomic knockout mutagenesis and in planta experiments showed that virulence of Psv critically depends on QS; however, the lack of signal production can be complemented by wild-type E. toletana or P. agglomerans. It is also apparent that the disease caused by Psv is aggravated by the presence of the two other bacterial species. In this paper we discuss the potential role of QS in establishing a stable consortia leading to a poly-bacterial disease. PMID- 21677696 TI - Antecubital transmission of mechanical aortic valve closure sounds: recognition of a potential source of error during blood pressure measurement. PMID- 21677695 TI - Arterial-cardiac destiffening following long-term antihypertensive treatment. AB - BACKGROUND: We examined whether in addition to producing a greater degree of improvement of the arterial stiffness, long-term angiotensin II receptor blocker (ARB) treatment might also have a more beneficial effect on the cardiac diastolic dysfunction than long-term calcium-channel blocker (CCB) treatment; we also evaluated the association between the improvements of the two variables brought about by ARB treatment in subjects with stage I or II hypertension. METHODS: One hundred and thirteen patients were randomly allocated to treatment with an ARB (candesartan) or a CCB (amlodipine). Echocardiography and measurement of the brachial-ankle pulse wave velocity (PWV) were conducted in both groups at the start of the treatment and at the end of 2-3-years' treatment. RESULTS: After adjustments for covariates, the extent of reduction of the brachial-ankle PWV ( 200 +/- 18 cm/s vs. -141 +/- 18 cm/s, P = 0.03) and that of the increase of the E/A ratio (0.08 +/- 0.03 vs. 0.01 +/- 0.03, P = 0.04) were significantly greater in the candesartan group than in the amlodipine group. A significant relationship was identified between the delta changes of the brachial-ankle PWV and delta changes of the E/A ratio observed following long-term candesartan treatment. CONCLUSION: Long-term candesartan treatment may have a more beneficial effect on the stiffness of the large- to- middle-sized arteries than long-term amlodipine treatment, and this treatment may also concomitantly improve the cardiac diastolic dysfunction; a significant association appeared to exist between the improvements of the two variables observed following long-term candesartan treatment. PMID- 21677697 TI - SNPs in microRNA binding sites in 3'-UTRs of RAAS genes influence arterial blood pressure and risk of myocardial infarction. AB - BACKGROUND: We hypothesized that single nucleotide polymorphisms (SNPs) located in microRNA (miR) binding sites in genes of the renin angiotensin aldosterone system (RAAS) can influence blood pressure and risk of myocardial infarction. METHODS: Using online databases dbSNP and TargetScan, we identified 10 SNPs in potential miR binding sites in eight RAAS-related genes, common in Caucasians. We genotyped a large case-control study on myocardial infarctions, the Study of Myocardial Infarctions LEiden (SMILE) for these 10 SNPs and found nine SNPs, in seven genes, to be prevalent. Functionality of each SNP in interfering with mRNA/miR binding was tested using a dual luciferase reporter gene system. RESULTS: Of these nine SNPs, four SNPs, located in the arginine vasopressin 1A receptor (AVPR1A), bradykinin 2 receptor (BDKRB2), and thromboxane A2 receptor (TBXA2R) genes were associated with blood pressure. The rare allele of the AVPR1A SNP rs11174811, was associated with increased blood pressure whereas the rare alleles of the two linked BDKRB2 SNPs rs5225 and rs2069591 and of the TBXA2R SNP rs13306046 were associated with decreased blood pressure. Although not associated with blood pressure, the rare allele of the mineralocorticoid receptor (NR3C2) SNP rs5534, was associated with a twofold increased risk of myocardial infarction in men younger than 50 years. For all of these five SNPs, except rs2069591, we could demonstrate a reduction in miR-induced repression of gene expression. CONCLUSIONS: Common SNPs in miR binding sites of RAAS-related genes can influence both blood pressure and risk of myocardial infarction. These results may imply an important role for SNPs in miR target sites in human disease. PMID- 21677698 TI - Redefining blood pressure targets in high-risk patients?: lessons from coronary endpoints in recent randomized clinical trials. AB - The benefits of lowering blood pressure (BP) in hypertension, as well as in patients with diabetes, chronic renal disease or with a high cardiovascular (CV) risk profile, have been consistently demonstrated. Further clinical trials have explored the influence of BP levels in the lower range on the incidence of CV events, while some others have designed to evaluate the potential benefits obtained with an intensive antihypertensive therapy, aimed at achieving a target systolic BP levels below 120 mm Hg on major CV events among high-risk individuals with type 2 diabetes, as compared to that obtained from a standard therapy. Taken together, the results of several recent randomized clinical trials (RCTs) have challenged the currently prevailing paradigm "the lower, the better" in the hypertension management and have somehow revitalized the concept of the J-curve with respect to relations between BP levels and coronary events. In fact, detailed analyses showed an increased risk of coronary events, mostly myocardial infarction, in those patients who achieved the lowest BP levels, particularly in high-risk subsets of hypertensive patients. The same trials, however, confirmed the benefits of BP reductions even below 120 mm Hg on stroke incidence. In the present article, we revisited the main findings of some recent large clinical trials performed in hypertension and in high-risk individuals. Our conclusions highlight the importance of a closer scrutiny for coronary artery disease and suggest caution in lowering BP levels aggressively in patients with high-risk profile or diabetes. PMID- 21677699 TI - Differences in blood pressure by body position (supine, Fowler's, and sitting) in hypertensive subjects. AB - BACKGROUND: Although blood pressure (BP) differences from supine to sitting position have long been recognized, limited data are available on other commonly used body positions. We performed a cross-sectional study to compare BP values obtained in supine, sitting, and Fowler's positions in essential hypertensive subjects. METHODS: Systolic BP (SBP) and diastolic BP (DBP) were recorded using an automatic oscillometric device. Nine measurements were taken: three measurements, in random order, in supine, Fowler's, and sitting position. Two generalized estimating equations models were used to evaluate potential predictors of SBP and DBP adjusting for heart rate and measurement order. RESULTS: The sample consisted of 250 subjects (mean age 66.3 +/- 13.4 years; 44.4% males). Measured in supine, Fowler's, and sitting position, mean SBPs were 139.3 +/- 14.0; 138.1 +/- 13.8; 137.2 +/- 13.7 mm Hg, respectively, and mean DBPs 80.1 +/- 9.1; 81.9 +/- 9.4; 83.0 +/- 9.6 mm Hg, respectively. At multivariate analysis, mean SBP significantly decreased if measured in Fowler's and sitting positions, as compared to supine. In contrast, DBP significantly increased. A relevant proportion of subjects showed large differences (<= or >=10 mm Hg) in mean SBP across positions: i.e., 30.0% comparing supine vs. sitting SBP. An even higher prevalence of large differences was observed according to the measurement order within the same positions, with no univocal direction (random variation). CONCLUSIONS: Fowler's position may represent a valid alternative to sitting and supine positions for BP measurement in clinical practice. BP random variability was found to be large regardless of body position, reinforcing the need for operators to closely follow current guidelines that recommend >=2 recordings at each measurement. PMID- 21677702 TI - Full transparency. PMID- 21677700 TI - Endothelin: key mediator of hypertension in preeclampsia. AB - Preeclampsia is a pregnancy-induced hypertensive disorder characterized by proteinuria and widespread maternal endothelial dysfunction. It remains one of the most common disorders in pregnancy and remains one of the leading causes of maternal and fetal morbidity. Recent research has revealed that placental insufficiency, resulting in hypoxia and ischemia, is a central causative pathway in the development of the disorder. In response, the placenta secretes soluble substances into the maternal circulation which are responsible for the symptomatic phase of the disease. Among the most well characterized factors in the disease pathology are the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), inflammatory cytokines, and agonistic angiotensin II type-1 receptor autoantibodies. Each of these factors has been shown to induce hypertension experimentally through the production of endothelin-1 (ET-1), a powerful vasoconstrictor. Antagonism of the endothelin-A receptor has proved beneficial in numerous animal models of gestational hypertension, and it remains an intriguing target for pharmacological intervention in preeclampsia. PMID- 21677701 TI - Endothelial-dependent flow-mediated dilation in African Americans with masked hypertension. AB - BACKGROUND: Office-blood pressure (BP) measurements alone overlook a significant number of individuals with masked-hypertension (office-BP: 120/80-139/89 mm Hg and 24-h ambulatory BP monitoring (ABPM) daytime >=135/85 mm Hg or night-time >=120/70 mm Hg). Diminished endothelial function contributes to the pathogenesis of hypertension. To better understand the pathophysiology involved in the increased cardiovascular (CV) disease risk associated with masked-hypertension, we estimated the occurrence, assessed the endothelial function, compared plasma levels of inflammatory markers, white blood cell count (WBC count), tumor necrosis factor-alpha (TNF-alpha), and high sensitivity C-reactive protein (hsCRP) and examined the possible relationship between endothelial function and inflammatory markers in apparently healthy prehypertensive (office-BP: 120/80 139/89 mm Hg) African Americans. METHODS: Fifty African Americans who were sedentary, nondiabetic, nonsmoking, devoid of CV disease were recruited. Office BP was measured according to JNC-7 guidelines to identify prehypertensives in whom ABPM was then assessed. Fasting plasma samples were assayed for inflammatory markers. Brachial artery flow-mediated dilation (FMD) at rest and during reactive hyperemia was measured in a subset of prehypertensives. RESULTS: Subjects in the masked-hypertension sub-group had a higher hsCRP (P = 0.04) and diminished endothelial function (P = 0.03) compared to the true-prehypertensive sub-group (office-BP: 120/80-139/89 mm Hg and ABPM: daytime <135/85 mm Hg or night-time <120/70 mm Hg). Regression analysis showed that endothelial function was inversely related to hsCRP amongst the masked-hypertensive sub-group (R(2) = 0.160; P = 0.04). CONCLUSIONS: Masked-hypertension was identified in 58% of African Americans which suggests that a masking phenomenon may exist in a sub group of prehypertensives who also seem to have a diminished endothelial function that could be mediated by an elevated subclinical inflammation leading to the increased CV disease. PMID- 21677703 TI - Contaminated food for thought. PMID- 21677704 TI - Great ape debate. PMID- 21677716 TI - Studies spy on a river's rage. PMID- 21677705 TI - Poison in party pills is too much to swallow. PMID- 21677717 TI - Life hackers seek new tools. PMID- 21677718 TI - Mouse library set to be knockout. PMID- 21677719 TI - Species spellchecker fixes plant glitches. PMID- 21677720 TI - Europe tackles huge fraud. PMID- 21677721 TI - Egypt invests in its science. PMID- 21677722 TI - Animal rights: Chimpanzee research on trial. PMID- 21677723 TI - Physics of life: The dawn of quantum biology. PMID- 21677724 TI - Buried by bad decisions. PMID- 21677725 TI - Democratizing clinical research. PMID- 21677730 TI - Extinctions: consider all species. PMID- 21677731 TI - Making society more resilient. PMID- 21677732 TI - Extinctions: conserve not collate. PMID- 21677733 TI - Population decline is a long way off. PMID- 21677734 TI - Peer reviews: some are already public. PMID- 21677735 TI - Brazilian soya: the argument against. PMID- 21677736 TI - Worm scientist's identity revealed. PMID- 21677737 TI - Change Chinese returnee rules. PMID- 21677738 TI - Brazilian soya: the argument for. PMID- 21677739 TI - Animal behaviour: Born leaders. PMID- 21677741 TI - Condensed-matter physics: Microscopy of the macroscopic. PMID- 21677740 TI - Protein synthesis: Stop the nonsense. PMID- 21677742 TI - Structural biology: Porthole to catalysis. PMID- 21677743 TI - Astrophysics: Early black holes uncovered. PMID- 21677744 TI - Gene expression: The autism disconnect. PMID- 21677745 TI - Intestinal networks in health and disease. PMID- 21677746 TI - Intestinal homeostasis and its breakdown in inflammatory bowel disease. AB - Intestinal homeostasis depends on complex interactions between the microbiota, the intestinal epithelium and the host immune system. Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and a breakdown in these pathways may precipitate the chronic inflammatory pathology found in inflammatory bowel disease. It is now evident that immune effector modules that drive intestinal inflammation are conserved across innate and adaptive leukocytes and can be controlled by host regulatory cells. Recent evidence suggests that several factors may tip the balance between homeostasis and intestinal inflammation, presenting future challenges for the development of new therapies for inflammatory bowel disease. PMID- 21677747 TI - Genetics and pathogenesis of inflammatory bowel disease. AB - Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease. Cellular programs responsible for intestinal homeostasis use diverse intracellular and intercellular networks to promote immune tolerance, inflammation or epithelial restitution. Complex interfaces integrate local host and microbial signals to activate appropriate effector programs selectively and even drive plasticity between these programs. In addition, genetic studies and mouse models have emphasized the role of genetic predispositions and how they affect interactions with microbial and environmental factors, leading to pro-colitogenic perturbations of the host-commensal relationship. PMID- 21677748 TI - Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. AB - The identification of intestinal stem cells as well as their malignant counterparts, colon cancer stem cells, has undergone rapid development in recent years. Under physiological conditions, intestinal homeostasis is a carefully balanced and efficient interplay between stem cells, their progeny and the microenvironment. These interactions regulate the astonishingly rapid renewal of the intestinal epithelial layer, which consequently puts us at serious risk of developing cancer. Here we highlight the microenvironment-derived signals that regulate stem-cell fate and epithelial differentiation. As our understanding of normal intestinal crypt homeostasis grows, these developments may point towards new insights into the origin of cancer and the maintenance and regulation of cancer stem cells. PMID- 21677750 TI - A conditional knockout resource for the genome-wide study of mouse gene function. AB - Gene targeting in embryonic stem cells has become the principal technology for manipulation of the mouse genome, offering unrivalled accuracy in allele design and access to conditional mutagenesis. To bring these advantages to the wider research community, large-scale mouse knockout programmes are producing a permanent resource of targeted mutations in all protein-coding genes. Here we report the establishment of a high-throughput gene-targeting pipeline for the generation of reporter-tagged, conditional alleles. Computational allele design, 96-well modular vector construction and high-efficiency gene-targeting strategies have been combined to mutate genes on an unprecedented scale. So far, more than 12,000 vectors and 9,000 conditional targeted alleles have been produced in highly germline-competent C57BL/6N embryonic stem cells. High-throughput genome engineering highlighted by this study is broadly applicable to rat and human stem cells and provides a foundation for future genome-wide efforts aimed at deciphering the function of all genes encoded by the mammalian genome. PMID- 21677749 TI - Human nutrition, the gut microbiome and the immune system. AB - Marked changes in socio-economic status, cultural traditions, population growth and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help to address several pressing global health problems. PMID- 21677751 TI - Latent TGF-beta structure and activation. AB - Transforming growth factor (TGF)-beta is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-beta1 requires the binding of alpha(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-beta binding proteins. Crystals of dimeric porcine proTGF-beta1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between alpha(v)beta(6) integrin and the prodomain is insufficient for TGF-beta1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-beta family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis. PMID- 21677753 TI - Black hole growth in the early Universe is self-regulated and largely hidden from view. AB - The formation of the first massive objects in the infant Universe remains impossible to observe directly and yet it sets the stage for the subsequent evolution of galaxies. Although some black holes with masses more than 10(9) times that of the Sun have been detected in luminous quasars less than one billion years after the Big Bang, these individual extreme objects have limited utility in constraining the channels of formation of the earliest black holes; this is because the initial conditions of black hole seed properties are quickly erased during the growth process. Here we report a measurement of the amount of black hole growth in galaxies at redshift z = 6-8 (0.95-0.7 billion years after the Big Bang), based on optimally stacked, archival X-ray observations. Our results imply that black holes grow in tandem with their host galaxies throughout cosmic history, starting from the earliest times. We find that most copiously accreting black holes at these epochs are buried in significant amounts of gas and dust that absorb most radiation except for the highest-energy X-rays. This suggests that black holes grew significantly more during these early bursts than was previously thought, but because of the obscuration of their ultraviolet emission they did not contribute to the re-ionization of the Universe. PMID- 21677754 TI - Zero outward flow velocity for plasma in a heliosheath transition layer. AB - Voyager 1 has been in the reservoir of energetic ions and electrons that constitutes the heliosheath since it crossed the solar wind termination shock on 16 December 2004 at a distance from the Sun of 94 astronomical units (1 AU = 1.5 * 10(8) km). It is now ~22 AU past the termination shock crossing. The bulk velocity of the plasma in the radial-transverse plane has been determined using measurements of the anisotropy of the convected energetic ion distribution. Here we report that the radial component of the velocity has been decreasing almost linearly over the past three years, from ~70 km s(-1) to ~0 km s(-1), where it has remained for the past eight months. It now seems that Voyager 1 has entered a finite transition layer of zero-radial-velocity plasma flow, indicating that the spacecraft may be close to the heliopause, the border between the heliosheath and the interstellar plasma. The existence of a flow transition layer in the heliosheath contradicts current predictions--generally assumed by conceptual models--of a sharp discontinuity at the heliopause. PMID- 21677752 TI - X-ray structure of a bacterial oligosaccharyltransferase. AB - Asparagine-linked glycosylation is a post-translational modification of proteins containing the conserved sequence motif Asn-X-Ser/Thr. The attachment of oligosaccharides is implicated in diverse processes such as protein folding and quality control, organism development or host-pathogen interactions. The reaction is catalysed by oligosaccharyltransferase (OST), a membrane protein complex located in the endoplasmic reticulum. The central, catalytic enzyme of OST is the STT3 subunit, which has homologues in bacteria and archaea. Here we report the X ray structure of a bacterial OST, the PglB protein of Campylobacter lari, in complex with an acceptor peptide. The structure defines the fold of STT3 proteins and provides insight into glycosylation sequon recognition and amide nitrogen activation, both of which are prerequisites for the formation of the N-glycosidic linkage. We also identified and validated catalytically important, acidic amino acid residues. Our results provide the molecular basis for understanding the mechanism of N-linked glycosylation. PMID- 21677755 TI - Emerging local Kondo screening and spatial coherence in the heavy-fermion metal YbRh2Si2. AB - The entanglement of quantum states is both a central concept in fundamental physics and a potential tool for realizing advanced materials and applications. The quantum superpositions underlying entanglement are at the heart of the intricate interplay of localized spin states and itinerant electronic states that gives rise to the Kondo effect in certain dilute magnetic alloys. In systems where the density of localized spin states is sufficiently high, they can no longer be treated as non-interacting; if they form a dense periodic array, a Kondo lattice may be established. Such a Kondo lattice gives rise to the emergence of charge carriers with enhanced effective masses, but the precise nature of the coherent Kondo state responsible for the generation of these heavy fermions remains highly debated. Here we use atomic-resolution tunnelling spectroscopy to investigate the low-energy excitations of a generic Kondo lattice system, YbRh(2)Si(2). We find that the hybridization of the conduction electrons with the localized 4f electrons results in a decrease in the tunnelling conductance at the Fermi energy. In addition, we observe unambiguously the crystal-field excitations of the Yb(3+) ions. A strongly temperature-dependent peak in the tunnelling conductance is attributed to the Fano resonance resulting from tunnelling into the coherent heavy-fermion states that emerge at low temperature. Taken together, these features reveal how quantum coherence develops in heavy 4f-electron Kondo lattices. Our results demonstrate the efficiency of real-space electronic structure imaging for the investigation of strong electronic correlations, specifically with respect to coherence phenomena, phase coexistence and quantum criticality. PMID- 21677756 TI - Modular and predictable assembly of porous organic molecular crystals. AB - Nanoporous molecular frameworks are important in applications such as separation, storage and catalysis. Empirical rules exist for their assembly but it is still challenging to place and segregate functionality in three-dimensional porous solids in a predictable way. Indeed, recent studies of mixed crystalline frameworks suggest a preference for the statistical distribution of functionalities throughout the pores rather than, for example, the functional group localization found in the reactive sites of enzymes. This is a potential limitation for 'one-pot' chemical syntheses of porous frameworks from simple starting materials. An alternative strategy is to prepare porous solids from synthetically preorganized molecular pores. In principle, functional organic pore modules could be covalently prefabricated and then assembled to produce materials with specific properties. However, this vision of mix-and-match assembly is far from being realized, not least because of the challenge in reliably predicting three-dimensional structures for molecular crystals, which lack the strong directional bonding found in networks. Here we show that highly porous crystalline solids can be produced by mixing different organic cage modules that self-assemble by means of chiral recognition. The structures of the resulting materials can be predicted computationally, allowing in silico materials design strategies. The constituent pore modules are synthesized in high yields on gram scales in a one-step reaction. Assembly of the porous co-crystals is as simple as combining the modules in solution and removing the solvent. In some cases, the chiral recognition between modules can be exploited to produce porous organic nanoparticles. We show that the method is valid for four different cage modules and can in principle be generalized in a computationally predictable manner based on a lock-and-key assembly between modules. PMID- 21677759 TI - To the readers. PMID- 21677757 TI - Converting nonsense codons into sense codons by targeted pseudouridylation. AB - All three translation termination codons, or nonsense codons, contain a uridine residue at the first position of the codon. Here, we demonstrate that pseudouridylation (conversion of uridine into pseudouridine (Psi), ref. 4) of nonsense codons suppresses translation termination both in vitro and in vivo. In vivo targeting of nonsense codons is accomplished by the expression of an H/ACA RNA capable of directing the isomerization of uridine to Psi within the nonsense codon. Thus, targeted pseudouridylation represents a novel approach for promoting nonsense suppression in vivo. Remarkably, we also show that pseudouridylated nonsense codons code for amino acids with similar properties. Specifically, PsiAA and PsiAG code for serine and threonine, whereas PsiGA codes for tyrosine and phenylalanine, thus suggesting a new mode of decoding. Our results also suggest that RNA modification, as a naturally occurring mechanism, may offer a new way to expand the genetic code. PMID- 21677760 TI - How can primary health care system and community-based participatory research be complementary? AB - Health statistics leave little doubt that the current health system in Iran, which is mainly based on primary health care (PHC), is a functioning one, and that health in Iran has improved far beyond where it was 40 years ago. However, this system has its limitations too. While PHC is very effective in reducing morbidity and mortality from infectious diseases and other acute conditions, it is far less effective in addressing chronic and multifactorial conditions which are now emerging in Iran. In this article, we review some of the salient features of the current health system in Iran, its strengths and limitations, and then introduce community-based participatory research (CBPR) as a method that could potentially fill some of the gaps in the system. We will discuss the definition and steps needed to implement CBPR, provide some important references, and discuss how this approach may not only improve the health system but it could also lead to improvement in other fields in the society too. PMID- 21677761 TI - How much importance do we give to target audiences in article writing? AB - OBJECTIVES: Writing papers can be used as a means to convey a message. Knowledge transfer is also about conveying the right message to the right target audience. The aim of this study was to determine the proportion of articles that had mentioned a clear message and the target audience in the abstract and the article as a whole, and also to examine their association with different determinant factors. METHODS: Articles published from 2001 to 2006 that were based on clinical and health system research conducted on Iranian populations and on maternal care, diabetes and tuberculosis were searched systematically in domestic and international databases. Eventually checklists (Additional file 1) were completed for 795 articles. RESULTS: Overall, 98.5% of articles had a clear message, whereas 12.5% had addressed the direct target audience. Presence of a clear message in formatted abstracts were seen 3.6 times more (CI95%: 1.5-8.7) than in articles without formatted abstracts (p = 0.005). Addressing of the direct target audience was seen twice as much in health system research articles as compared to clinical studies, odds ratio was 2.3 (CI95%: 1.47-3.48, p<0.001). CONCLUSIONS: Creating a format for journal abstracts seems to be an effective intervention for presenting the message in articles. PMID- 21677762 TI - Prevalence of Cardiovascular Disease Risk Factors in Migrants Participating in the PEP Family Heart Study, Nuremberg. AB - OBJECTIVES: The aim of this study was to assess the prevalence of cardiovascular risk factors in adults and their children from the 3 major groups of migrants participating in the PEP Family Heart Study11 and to compare the cardio-metabolic risk profiles between migrants and German participants. METHODS: In this community-based cross-sectional study, anthropometric data, blood pressure and lipid profiles of migrants (480 children, 363 adults) from Turkey (TUR), Eastern Europe (EEU) and German immigrants from the former Soviet Union (GFSU) were compared with age and gender adjusted German (GER) residents (3253 children, 2491 adults). RESULTS: The profile of risk factors differed considerably regarding specificity and frequency. The prevalence of >=3 risk factors was as follows: in GFSU men 62%, women 36%, boys 19% and girls 17%; in TUR men 57%, women 30%, 15% boys and 6% girls; in GER men 48%, women 19%, boys 4% and girls 6%; for EEU men 38%, women 25% and 0% in children. No risk factor was present in GFSU men 13%, women 25%, boys 38% and girls 42%; TUR men 13%, women 28%, boys 27% and girls 22 %; GER men16%, women 45%, boys 46% and girls 41%; EEU men 17%, women 42 %, boys 29% and girls 27%. About 50% of the adults from Turkey and Eastern Europe were current smokers and one third of women and half of men from these two countries were overweight. CONCLUSIONS: The implementation of primary care measures for the prevention of cardiovascular disease in migrants is necessary, and it should consider the ethnic differences and the heterogeneous risk profiles. PMID- 21677763 TI - Birth weight, cord blood lipoprotein and apolipoprotein levels in Indian newborns. AB - OBJECTIVES: Primordial prevention of chronic disease is of clinical and public health importance. Considering the fetal onset of atherosclerosis, we aimed to determine the cord blood level of lipoproteins and apolipoproteins as well as their correlation with birth weight and gestational age. METHODS: This cross sectional study comprised 100 healthy Indian newborns. Ten ml. of cord blood was collected from placental end of umbilical vein. Serum was separated by centrifugation and analyzed on the same day for lipid profile including total cholesterol (TC), triglycerides (TG), high density lipoprotein- cholesterol (HDL C), very low density lipoproteincholesterol (VLDL) and low density lipoprotein cholesterol (LDL-C), apolipoproteins A-I and B (ApoA-I, ApoB). Atherogenic index (AI) was calculated as the ratio of ApoB to ApoA-I. RESULTS: Cord blood of female newborns had higher TC, HDL-C, LDL-C, Apo A-I, Apo B and AI as compared to male newborns, whereas TG and VLDL-C were higher in male than in female newborns. Significant positive correlation was observed between cord blood Apo A-I and HDL C (r= 0.45, p<0.01), and between cord blood Apo-B and LDL-C (r= 0.44, p<0.01). Non-significant inverse correlation was observed between Apo A-I and ApoB with gestational age. There was a significant inverse correlation between TG and gestational age (r= -0.197, p <0.05). Positive non-significant correlation was observed between AI and birth weight (r=0.046, p>0.05). CONCLUSIONS: These findings are another confirmatory evidence for the association of prenatal factors with cord blood lipid profile, and can serve as starting point for studying lipid transport system changes during early life. PMID- 21677764 TI - A Comparison of Adaptive Behaviors among Mentally Retarded and Normal Individuals: A guide to Prevention and Treatment. AB - OBJECTIVES: Because of the importance of adaptive behaviors in social and domestic lives, this study aimed at a comparison of various domains of adaptive behaviors, between mentally retarded and normal individuals. METHODS: A number of 246 normal and 74 mentally retarded individuals (7-18 years of age, mean: 12+/ 3.5 years), participated this study in Tehran, Iran. Their adaptive behaviors scores, were obtained using "Adaptive Behavioral Scale, Residential & Community" (ABS-RC: 2), consisting of 18 domains of behavior. The scale was first translated into Persian by the professionals and then retranslated into English by another translator, to ensure content non-distortion. RESULTS: THE FOLLOWING DOMAINS WERE SIGNIFICANTLY LOWER IN MENTALLY RETARDED THAN IN NORMAL INDIVIDUALS: independent functioning, economic activity, language development, number & time, prevocational/vocational activity, self-direction, responsibility, socialization, disturbing interpersonal behavior, domestic activity, social engagement, conformity and trustworthiness. No significant difference was documented in the physical development, stereotype & hyperactive behaviors, sexual behavior as well as self abuse behavior domains, between the two groups. CONCLUSIONS: As mentally deficient subjects did worse than normal ones in terms of many adaptive behavioral domains, it implies that the adaptive behavioral issues in such people might need a great deal of attention and intervention. For these retarded people to function better in their social and residential environment, it would be necessary to develop their adaptive behaviors. This study may shed light on the importance of attention to the adaptive behavioral domains of mentally retarded people and also indicates the necessity of preventive measures, even for normal individuals. PMID- 21677765 TI - Association of the Waist-to-Height Ratio with Cardiovascular Risk Factors in Children and Adolescents: The Three Cities Heart Study. AB - OBJECTIVES: To determine the best anthropometric index in relation to cardiovascular disease risk factors among children and adolescents. METHODS: This cross-sectional school-based study was conducted among a random sample of 3179 students, aged 6 to 18 years, in three large cities in Brazil. RESULTS: The prevalence of overweight and obesity was 10% and 5%, respectively. In relation to the students in the lower quartile (Q1) of the distribution of subscapular skinfold, the students in the upper quartile (Q4) presented a 2.0 times higher risk (odds ratio) of having elevated total cholesterol levels. Overweight and obese students had a 3.3 times higher risk of having elevated systolic blood pressure, and a 1.9 times higher risk of elevated diastolic blood pressure than other students. The less active students presented a 1.58 times higher risk of having waist-to-height ratio (WHtR) above the upper tertile (Q3). WHtR mean values was 0.46 (SE 0.00) presented the largest area under the curve (AUC) [0.613 (CI995%:0.578-0.647)] for high total cholesterol levels, [0.546 (CI995%: 0.515 0.578)] for low HDL-C levels, and [0.614 (CI95%: 0.577-0.651)] for high LDL-C levels, while body mass index presented the largest AUC [0.669 (CI95%: 0.64 0.699)] for increased diastolic blood pressure followed by the waist circumference for increased systolic blood pressure [0.761 (CI95%: 0.735-0.787)]. CONCLUSIONS: WHtR is considered as a simple and accurate anthropometric parameter that identifies youth with cardiovascular risk factors. In this study, WHtR above 0.44 was indicative of risk factors in children and adolescents. These findings can be applied in future preventive strategies against CVDs, and screening programs. PMID- 21677766 TI - Secondary prevention by enhancing adherence in diabetic patients. AB - OBJECTIVES: Adherence to prescribed medications is a key dimension of healthcare quality. Poor medication adherence might be a significant barrier to achievement of positive clinical outcomes. This study aimed to compare the adherence to oral hypoglycemic agents in patients with type 2 diabetes by using two methods of completing diary checklist and collecting drug shells. METHODS: This randomized clinical trial was conducted in Isfahan Diabetes Institute. A number of 100 type 2-diabetic patients were selected through systematic sampling method and then were randomly allocated to two groups of equal number. Each group was invited to attend our 12-week educational program. We asked one group to complete diary checklist about how they took their drugs during the study period. The other group was asked to collect the shells of oral hypoglycemic agents after taking in a pocket. Medication adherence ratio was calculated for both groups. RESULTS: Overall, 87 patients completed the study, of which 30 cases (34.5%) were in the check list group and 57 (65.5%) in the reference group. In the check list group, the adherence ratio was good in 96.7% and moderate in 3.3%, with no case of poor adherence. In the reference group, the corresponding figures were 55.2%, %6.9 and 37.9%, respectively (p<0.05 between groups). CONCLUSIONS: Although the adherence ratio was greater than 80% in both groups, it was significantly higher in the check list group. Therefore, we suggest that by increasing adherence to prescribed medications, diary checklist can be an effective method of secondary prevention of chronic diseases, as diabetes mellitus. PMID- 21677767 TI - Lifestyle, Cardiovascular Drugs and Risk Factors in Younger and Elder Adults: The PEP Family Heart Study. AB - OBJECTIVES: This study aimed to compare cardiovascular disease (CVD) risk factors, lifestyle habits and pharmacological treatment in two groups of elder adults with 20 years difference in their mean age. METHODS: This study comprised 590 women including two groups with mean age of 42.4+/-5.5 vs. 66.5+/-4.0 years, and 486 men of two groups with mean age of 44.1+/-5.6 vs. 63.9+/-7.0 years. Data on physical examination, fasting blood analyses, 7-day dietary records, physical activity, smoking and actual medication use were recorded. RESULTS: Compared with younger individuals, seniors had a more adverse risk factor profile in terms of abdominal obesity, overweight, hyperglycemia, hypertension, dyslipoproteinemia without differences in HDL-C. But this is not reflected by lifestyle behavior. Less than 2% of the elderly and 17% of the younger adults were current smoker. Furthermore, the pattern of physical activity was different in terms of more continuous sports in seniors contrasting with extremes between no sports and more than twice a week in the younger group. Seniors consumed significantly less carbohydrates including more monosaccharide and less polysaccharides, more alcohol and water. The intake of fat and protein was higher in elder women than in all other groups. One third of seniors took antihypertensive medications and 12% used lipid modifying drugs. CONCLUSIONS: Different levels of prevention against CVDs and their risk factors shall be considered for various age groups of population. The findings of this study emphasize on the necessity of preventive measures against smoking and physical inactivity in younger adults and dietary habits in seniors. PMID- 21677768 TI - Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart. AB - BACKGROUND: Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is associated with severe cardiac complications including cardiomyopathy and cardiac arrhythmias. Recent research suggests that impaired voltage-gated ion channels in dystrophic cardiomyocytes accompany cardiac pathology. It is, however, unknown if the ion channel defects are primary effects of dystrophic gene mutations, or secondary effects of the developing cardiac pathology. METHODOLOGY/PRINCIPAL FINDINGS: To address this question, we first investigated sodium channel impairments in cardiomyocytes derived from dystrophic neonatal mice prior to cardiomyopahty development, by using the whole cell patch clamp technique. Besides the most common model for DMD, the dystrophin-deficient mdx mouse, we also used mice additionally carrying an utrophin mutation. In neonatal cardiomyocytes, dystrophin-deficiency generated a 25% reduction in sodium current density. In addition, extra utrophin-deficiency significantly altered sodium channel gating parameters. Moreover, also calcium channel inactivation was considerably reduced in dystrophic neonatal cardiomyocytes, suggesting that ion channel abnormalities are universal primary effects of dystrophic gene mutations. To assess developmental changes, we also studied sodium channel impairments in cardiomyocytes derived from dystrophic adult mice, and compared them with the respective abnormalities in dystrophic neonatal cells. Here, we found a much stronger sodium current reduction in adult cardiomyocytes. The described sodium channel impairments slowed the upstroke of the action potential in adult cardiomyocytes, and only in dystrophic adult mice, the QRS interval of the electrocardiogram was prolonged. CONCLUSIONS/SIGNIFICANCE: Ion channel impairments precede pathology development in the dystrophic heart, and may thus be considered potential cardiomyopathy triggers. PMID- 21677769 TI - Under pressure: response urgency modulates striatal and insula activity during decision-making under risk. AB - When deciding whether to bet in situations that involve potential monetary loss or gain (mixed gambles), a subjective sense of pressure can influence the evaluation of the expected utility associated with each choice option. Here, we explored how gambling decisions, their psychophysiological and neural counterparts are modulated by an induced sense of urgency to respond. Urgency influenced decision times and evoked heart rate responses, interacting with the expected value of each gamble. Using functional MRI, we observed that this interaction was associated with changes in the activity of the striatum, a critical region for both reward and choice selection, and within the insula, a region implicated as the substrate of affective feelings arising from interoceptive signals which influence motivational behavior. Our findings bridge current psychophysiological and neurobiological models of value representation and action-programming, identifying the striatum and insular cortex as the key substrates of decision-making under risk and urgency. PMID- 21677770 TI - CD34+/M-cadherin+ bone marrow progenitor cells promote arteriogenesis in ischemic hindlimbs of ApoE-/- mice. AB - BACKGROUND: Cell-based therapy shows promise in treating peripheral arterial disease (PAD); however, the optimal cell type and long-term efficacy are unknown. In this study, we identified a novel subpopulation of adult progenitor cells positive for CD34 and M-cadherin (CD34+/M-cad+ BMCs) in mouse and human bone marrow. We also examined the long-lasting therapeutic efficacy of mouse CD34+/M cad+ BMCs in restoring blood flow and promoting vascularization in an atherosclerotic mouse model of PAD. METHODS AND FINDINGS: Colony-forming cell assays and flow cytometry analysis showed that CD34+/M-cad+ BMCs have hematopoietic progenitor properties. When delivered intra-arterially into the ischemic hindlimbs of ApoE-/- mice, CD34+/M-cad+ BMCs alleviated ischemia and significantly improved blood flow compared with CD34+/M-cad- BMCs, CD34-/M-cad+ BMCs, or unselected BMCs. Significantly more arterioles were seen in CD34+/M-cad+ cell-treated limbs than in any other treatment group 60 days after cell therapy. Furthermore, histologic assessment and morphometric analyses of hindlimbs treated with GFP+ CD34+/M-cad+ cells showed that injected cells incorporated into solid tissue structures at 21 days. Confocal microscopic examination of GFP+ CD34+/M cad+ cell-treated ischemic legs followed by immunostaining indicated the vascular differentiation of CD34+/M-cad+ progenitor cells. A cytokine antibody array revealed that CD34+/M-cad+ cell-conditioned medium contained higher levels of cytokines in a unique pattern, including bFGF, CRG-2, EGF, Flt-3 ligand, IGF-1, SDF-1, and VEGFR-3, than did CD34+/M-cad- cell-conditioned medium. The proangiogenic cytokines secreted by CD34+/M-cad+ cells induced oxygen- and nutrient-depleted endothelial cell sprouting significantly better than CD34+/M cad- cells during hypoxia. CONCLUSION: CD34+/M-cad+ BMCs represent a new progenitor cell type that effectively alleviates hindlimb ischemia in ApoE-/- mice by consistently improving blood flow and promoting arteriogenesis. Additionally, CD34+/M-cad+ BMCs contribute to microvascular remodeling by differentiating into vascular cells and releasing proangiogenic cytokines and growth factors. PMID- 21677772 TI - Deactivation of signal transducer and activator of transcription 3 reverses chemotherapeutics resistance of leukemia cells via down-regulating P-gp. AB - Multidrug resistance (MDR) caused by overexpression of p-glycoprotein is a major obstacle in chemotherapy of malignant cancer, which usually is characterized by constitutive activation of signal transducer and activator of transcription 3 (STAT3), but their relation between MDR and STAT3 remains unclear. Here, we showed that STAT3 was overexpressed and highly activated in adriamycin-resistant K562/A02 cells compared with its parental K562 cells. Blockade of activation of STAT3 by STAT3 decoy oligodeoxynucleotide (ODN) promoted the accumulation and increased their sensitivity to adriamycin by down-regulating transcription of mdr1 and expression of P-gp, which were further confirmed by using STAT3-specific inhibitor JSI-124. Inhibition of STAT3 could also decrease mdr1 promoter mediated luciferase expression by using mdr1 promoter luciferase reporter construct. Otherwise, activation of STAT3 by STAT3C improved mdr1 transcription and P-gp expression. The ChIP results demonstrated that STAT3 could bind to the potential promoter region of mdr1, and STAT3 decoy depressed the binding. Further mutation assay show +64~+72 region could be the STAT3 binding site. Our data demonstrate a role of STAT3 in regulation of mdr1 gene expression in myeloid leukemia and suggest that STAT3 may be a promising therapeutic target for overcoming MDR resistance in myeloid leukemia. PMID- 21677771 TI - Design of targeted B cell killing agents. AB - B cells play an important role in the pathogenesis of both systemic and organ specific autoimmune diseases. Autoreactive B cells not only produce autoantibodies, but also are capable to efficiently present specific autoantigens to T cells. Furthermore, B cells can secrete proinflammatory cytokines and amplify the vicious process of self-destruction. B cell-directed therapy is a potentially important approach for treatment of various autoimmune diseases. The depletion of B cells by anti-CD20/19 monoclonal antibody Retuximab(r) used in autoimmune diseases therapy leads to systemic side effects and should be significantly improved. In this study we designed a repertoire of genetically engineered B cell killers that specifically affected one kind of cells carrying a respective B cell receptor. We constructed immunotoxins (ITs), fused with c-myc epitope as a model targeting sequence, based on barnase, Pseudomonas toxin, Shiga like toxin E.coli and Fc domain of human antibody IgGgamma1. C-MYC hybridoma cell line producing anti-c-myc IgG was chosen as a model for targeted cell depletion. C-myc sequence fused with toxins provided addressed delivery of the toxic agent to the target cells. We demonstrated functional activity of designed ITs in vitro and showed recognition of the fusion molecules by antibodies produced by targeted hybridoma. To study specificity of the proposed B cells killing molecules, we tested a set of created ITs ex vivo, using C-MYC and irrelevant hybridoma cell lines. Pseudomonas-containing IT showed one of the highest cytotoxic effects on the model cells, however, possessed promiscuous specificity. Shiga-like toxin construct demonstrated mild both cytotoxicity and specificity. Barnase and Fc containing ITs revealed excellent balance between their legibility and toxic properties. Moreover, barnase and Fc molecules fused with c-myc epitope were able to selectively deplete c-myc-specific B cells and decrease production of anti-c myc antibodies in culture of native splenocytes, suggesting their highest therapeutic potential as targeted B cell killing agents. PMID- 21677773 TI - Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington's disease. AB - Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD. PMID- 21677774 TI - Shortcomings of vitamin D-based model simulations of seasonal influenza. AB - Seasonal variation in serum concentration of the vitamin D metabolite 25(OH) vitamin D [25(OH)D], which contributes to host immune function, has been hypothesized to be the underlying source of observed influenza seasonality in temperate regions. The objective of this study was to determine whether observed 25(OH)D levels could be used to simulate observed influenza infection rates. Data of mean and variance in 25(OH)D serum levels by month were obtained from the Health Professionals Follow-up Study and used to parameterize an individual-based model of influenza transmission dynamics in two regions of the United States. Simulations were compared with observed daily influenza excess mortality data. Best-fitting simulations could reproduce the observed seasonal cycle of influenza; however, these best-fit simulations were shown to be highly sensitive to stochastic processes within the model and were unable consistently to reproduce observed seasonal patterns. In this respect the simulations with the vitamin D forced model were inferior to similar modeling efforts using absolute humidity and the school calendar as seasonal forcing variables. These model results indicate it is unlikely that seasonal variations in vitamin D levels principally determine the seasonality of influenza in temperate regions. PMID- 21677775 TI - Microstructure abnormalities in adolescents with internet addiction disorder. AB - BACKGROUND: Recent studies suggest that internet addiction disorder (IAD) is associated with structural abnormalities in brain gray matter. However, few studies have investigated the effects of internet addiction on the microstructural integrity of major neuronal fiber pathways, and almost no studies have assessed the microstructural changes with the duration of internet addiction. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the morphology of the brain in adolescents with IAD (N = 18) using an optimized voxel-based morphometry (VBM) technique, and studied the white matter fractional anisotropy (FA) changes using the diffusion tensor imaging (DTI) method, linking these brain structural measures to the duration of IAD. We provided evidences demonstrating the multiple structural changes of the brain in IAD subjects. VBM results indicated the decreased gray matter volume in the bilateral dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), the orbitofrontal cortex (OFC), the cerebellum and the left rostral ACC (rACC). DTI analysis revealed the enhanced FA value of the left posterior limb of the internal capsule (PLIC) and reduced FA value in the white matter within the right parahippocampal gyrus (PHG). Gray matter volumes of the DLPFC, rACC, SMA, and white matter FA changes of the PLIC were significantly correlated with the duration of internet addiction in the adolescents with IAD. CONCLUSIONS: Our results suggested that long-term internet addiction would result in brain structural alterations, which probably contributed to chronic dysfunction in subjects with IAD. The current study may shed further light on the potential brain effects of IAD. PMID- 21677776 TI - Prevalence of the Cryptosporidium pig genotype II in pigs from the Yangtze River Delta, China. AB - BACKGROUND: Cryptosporidium spp. is prevalent globally, pigs are an important Cryptosporidium reservoir. In China, little data regarding rates of Cryptosporidium infections in pigs are available. The present study was therefore aimed at characterizing the distribution of Cryptosporidium species in pigs from two different cities, Shaoxing and Shanghai, from the Yangtze River delta. METHODOLOGY/PRINCIPAL FINDINGS: Nested PCR to amplify the 18S rRNA locus on DNA extracted from fecal samples (n = 94) revealed the positive rate of Cryptosporidium in pigs from two cities was approximately 17.0%. The positive rates in Shanghai and Shaoxing were 14.3% and 25.0% respectively. Amplified sequences were verified by sequencing. The identified strain belonged to the C. pig genotype II using BLAST analysis in the NCBI database. CONCLUSION/SIGNIFICANCE: Our finding of Cryptosporidium pig genotype II in pigs in the Yangtze River delta area suggests that pig farms in this region must be considered a public health threat and proper control measures be introduced. PMID- 21677777 TI - Edaravone guards dopamine neurons in a rotenone model for Parkinson's disease. AB - 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at least partly to edaravone's inhibition of rotenone-induced reactive oxygen species production or apoptotic promoter Bax expression and its up-regulation of the vesicular monoamine transporter 2 (VMAT2) expression. Collectively, edaravone may provide novel clinical therapeutics for PD. PMID- 21677778 TI - Helios is associated with CD4 T cells differentiating to T helper 2 and follicular helper T cells in vivo independently of Foxp3 expression. AB - BACKGROUND: Although in vitro IL-4 directs CD4 T cells to produce T helper 2 (Th2)-cytokines, these cytokines can be induced in vivo in the absence of IL-4 signalling. Thus, mechanism(s), different from the in vitro pathway for Th2 induction, contribute to in vivo Th2-differentiation. The pathway for in vivo IL 4-independent Th2-differentiation has yet to be characterized. FINDINGS: Helios (ikzf2), a member of the Ikaros transcription regulator family, is expressed in thymocytes and some antigen-matured T cells as well as in regulatory T cells. It has been proposed that Helios is a specific marker for thymus-derived regulatory T cells. Here, we show that mouse ovalbumin-specific CD4 (OTII) cells responding to alum-precipitated ovalbumin (alumOVA) upregulate Th2 features - GATA-3 and IL 4 - as well as Helios mRNA and protein. Helios is also upregulated in follicular helper T (TFh) cells in this response. By contrast, OTII cells responding to the Th1 antigen - live attenuated ovalbumin-expressing Salmonella - upregulate Th1 features - T-bet and IFN-gamma - but not Helios. In addition, CD4 T cells induced to produce Th2 cytokines in vitro do not express Helios. The kinetics of Helios mRNA and protein induction mirrors that of GATA-3. The induction of IL-4, IL-13 and CXCR5 by alumOVA requires NF-kappaB1 and this is also needed for Helios upregulation. Importantly, Helios is induced in Th2 and TFh cells without parallel upregulation of Foxp3. These findings suggested a key role for Helios in Th2 and TFh development in response to alum-protein vaccines. We tested this possibility using Helios-deficient OTII cells and found this deficiency had no discernable impact on Th2 and TFh differentiation in response to alumOVA. CONCLUSIONS: Helios is selectively upregulated in CD4 T cells during Th2 and TFh responses to alum-protein vaccines in vivo, but the functional significance of this upregulation remains uncertain. PMID- 21677779 TI - Prevalence and incidence of HIV in a rural community-based HIV vaccine preparedness cohort in Masaka, Uganda. AB - BACKGROUND: Local HIV epidemiology data are critical in determining the suitability of a population for HIV vaccine efficacy trials. The objective of this study was to estimate the prevalence and incidence of, and determine risk factors for HIV transmission in a rural community-based HIV vaccine preparedness cohort in Masaka, Uganda. METHODS: Between February and July 2004, we conducted a house-to-house HIV sero-prevalence survey among consenting individuals aged 18-60 years. Participants were interviewed, counseled and asked to provide blood for HIV testing. We then enrolled the HIV uninfected participants in a 2-year HIV sero-incidence study. Medical evaluations, HIV counseling and testing, and sample collection for laboratory analysis were done quarterly. Sexual risk behaviour data was collected every 6 months. RESULTS: The HIV point prevalence was 11.2%, and was higher among women than men (12.9% vs. 8.6%, P = 0.007). Risk factors associated with prevalent HIV infection for men were age <25 years (aOR = 0.05, 95% CI 0.01-0.35) and reported genital ulcer disease in the past year (aOR = 2.17, 95% CI 1.23-3.83). Among women, being unmarried (aOR = 2.59, 95% CI 1.75 3.83) and reported genital ulcer disease in the past year (aOR = 2.40, 95% CI 1.64-3.51) were associated with prevalent HIV infection. Twenty-one seroconversions were recorded over 2025.8 person-years, an annual HIV incidence of 1.04% (95% CI: 0.68-1.59). The only significant risk factor for incident HIV infection was being unmarried (aRR = 3.44, 95% CI 1.43-8.28). Cohort retention after 2 years was 87%. CONCLUSIONS: We found a high prevalence but low incidence of HIV in this cohort. HIV vaccine efficacy trials in this population may not be feasible due to the large sample sizes that would be required. HIV vaccine preparatory efforts in this setting should include identification of higher risk populations. PMID- 21677780 TI - Trypanosomatid RACK1 orthologs show functional differences associated with translation despite similar roles in Leishmania pathogenesis. AB - RACK1 proteins belong to the eukaryote WD40-repeat protein family and function as spatial regulators of multiple cellular events, including signaling pathways, the cell cycle and translation. For this latter role, structural and genetic studies indicate that RACK1 associates with the ribosome through two conserved positively charged amino acids in its first WD40 domain. Unlike RACK1s, including Trypanosoma brucei RACK1 (TbRACK1), only one of these two positively-charged residues is conserved in the first WD40 domain of the Leishmania major RACK1 ortholog, LACK. We compared virulence-attenuated LACK single copy (LACK/-) L. major, with L. major expressing either two LACK copies (LACK/LACK), or one copy each of LACK and TbRACK1 (LACK/TbRACK1), to evaluate the function of these structurally distinct RACK1 orthologs with respect to translation, viability at host temperatures and pathogenesis. Our results indicate that although the ribosome-binding residues are not fully conserved in LACK, both LACK and TbRACK1 co-sedimented with monosomes and polysomes in LACK/LACK and LACK/TbRACK1 L. major, respectively. LACK/LACK and LACK/TbRACK1 strains differed in their sensitivity to translation inhibitors implying that minor sequence differences between the RACK1 proteins can alter their functional properties. While biochemically distinguishable, both LACK/LACK and LACK/TbRACK1 lines were more tolerant of elevated temperatures, resistant to translation inhibitors, and displayed robust pathogenesis in vivo, contrasting to LACK/- parasites. PMID- 21677782 TI - HOXB5 cooperates with NKX2-1 in the transcription of human RET. AB - The enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5' upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype. PMID- 21677781 TI - Negative regulation of interferon-beta gene expression during acute and persistent virus infections. AB - The production of type I interferons (IFNs) in response to viral infections is critical for antiviral immunity. However, IFN production is transient, and continued expression can lead to inflammatory or autoimmune diseases. Thus, understanding the mechanisms underlying the negative regulation of IFN expression could lead to the development of novel therapeutic approaches to the treatment of these diseases. We report that the transcription factor IRF3 plays a central role in the negative regulation of interferon-beta (IFNbeta) expression during both acute and persistent (chronic) virus infections. We show that the degradation of IRF3 during acute infections, rather than the activation of transcriptional repressors, leads to the down regulation of IFNbeta expression. We also show that the block to IFNbeta expression in mouse embryonic fibroblasts that are persistently infected with Sendai virus (SeV) correlates with the absence of transcriptionally active IRF3. Remarkably, ongoing protein synthesis and viral replication are required to maintain repression of the IFNbeta gene in persistently infected cells, as the gene can be activated by the protein synthesis inhibitor cycloheximide, or by the antiviral drug ribavirin. Finally, we show that the SeV V protein inhibits IRF3 activity in persistently infected cells. Thus, in conjunction with the known interference with STAT1 by the SeV C protein, both IFN activation and its signaling pathways are blocked in persistently infected cells. We conclude that the transcription factor IRF3 is targeted for turnover and inactivation through distinct mechanisms from both the host cells and virus, leading to the inhibition of IFNbeta gene expression during acute and persistent viral infections. These observations show that IRF3 plays a critical role, not only in the activation of the IFNbeta gene, but also in the controlling the duration of its expression. (284 words). PMID- 21677783 TI - Expression of sumoylation deficient Nkx2.5 mutant in Nkx2.5 haploinsufficient mice leads to congenital heart defects. AB - Nkx2.5 is a cardiac specific homeobox gene critical for normal heart development. We previously identified Nkx2.5 as a target of sumoylation, a posttranslational modification implicated in a variety of cellular activities. Sumoylation enhanced Nkx2.5 activity via covalent attachment to the lysine residue 51, the primary SUMO acceptor site. However, how sumoylation regulates the activity of Nkx2.5 in vivo remains unknown. We generated transgenic mice overexpressing sumoylation deficient mutant K51R (conversion of lysine 51 to arginine) specifically in mouse hearts under the control of cardiac alpha-myosin heavy chain (alpha-MHC) promoter (K51R-Tg). Expression of the Nkx2.5 mutant transgene in the wild type murine hearts did not result in any overt cardiac phenotype. However, in the presence of Nkx2.5 haploinsufficiency, cardiomyocyte-specific expression of the Nkx2.5 K51R mutant led to congenital heart diseases (CHDs), accompanied with decreased cardiomyocyte proliferation. Also, a number of human CHDs-associated Nkx2.5 mutants exhibited aberrant sumoylation. Our work demonstrates that altered sumoylation status may underlie the development of human CHDs associated with Nkx2.5 mutants. PMID- 21677784 TI - Biological responses to perfluorododecanoic acid exposure in rat kidneys as determined by integrated proteomic and metabonomic studies. AB - BACKGROUND: Perfluorododecanoic acid (PFDoA) is a perfluorinated carboxylic chemical (PFC) that has broad applications and distribution in the environment. While many studies have focused on hepatotoxicity, immunotoxicity, and reproductive toxicity of PFCAs, few have investigated renal toxicity. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used comparative proteomic and metabonomic technologies to provide a global perspective on renal response to PFDoA. Male rats were exposed to 0, 0.05, 0.2, and 0.5 mg/kg/day of PFDoA for 110 days. After 2-D DIGE and MALDI TOF/TOF analysis, 79 differentially expressed proteins between the control and the PFDoA treated rats (0.2 and 0.5 mg-dosed groups) were successfully identified. These proteins were mainly involved in amino acid metabolism, the tricarboxylic acid cycle, gluconeogenesis, glycolysis, electron transport, and stress response. Nuclear magnetic resonance-based metabonomic analysis showed an increase in pyruvate, lactate, acetate, choline, and a variety of amino acids in the highest dose group. Furthermore, the profiles of free amino acids in the PFDoA treated groups were investigated quantitatively by high-coverage quantitative iTRAQ-LC MS/MS, which showed levels of sarcosine, asparagine, histidine, 1-methylhistidine, Ile, Leu, Val, Trp, Tyr, Phe, Cys, and Met increased markedly in the 0.5 mg dosed group, while homocitrulline, alpha aminoadipic acid, beta-alanine, and cystathionine decreased. CONCLUSION/SIGNIFICANCE: These observations provide evidence that disorders in glucose and amino acid metabolism may contribute to PFDoA nephrotoxicity. Additionally, alpha(2u) globulin may play an important role in protecting the kidneys from PFDoA toxicity. PMID- 21677785 TI - NGF and proNGF regulate functionally distinct mRNAs in PC12 cells: an early gene expression profiling. AB - The biological activities of NGF and of its precursor proNGF are quite distinct, due to different receptor binding profiles, but little is known about how proNGF regulates gene expression. Whether proNGF is a purely pro-apoptotic molecule and/or simply a "less potent NGF" is still a matter of debate. We performed experiments to address this question, by verifying whether a proNGF specific transcriptional signature, distinct from that of NGF, could be identified. To this aim, we studied gene expression regulation by proNGF and NGF in PC12 cells incubated for 1 and 4 hours with recombinant NGF and proNGF, in its wild-type or in a furin-cleavage resistant form. mRNA expression profiles were analyzed by whole genome microarrays at early time points, in order to identify specific profiles of NGF and proNGF. Clear differences between the mRNA profiles modulated by the three neurotrophin forms were identified. NGF and proNGF modulate remarkably distinct mRNA expression patterns, with the gene expression profile regulated by NGF being significantly more complex than that by proNGF, both in terms of the total number of differentially expressed mRNAs and of the gene families involved. Moreover, while the total number of genes modulated by NGF increases dramatically with time, that by proNGFs is unchanged or reduced. We identified a subset of regulated genes that could be ascribed to a "pure proNGF" signalling, distinct from the "pure NGF" one. We also conclude that the composition of mixed NGF and proNGF samples, when the two proteins coexist, influences the profile of gene expression. Based on this comparison of the gene expression profiles regulated by NGF and its proNGF precursor, we conclude that the two proteins activate largely distinct transcriptional programs and that the ratio of NGF to proNGF in vivo can profoundly influence the pattern of regulated mRNAs. PMID- 21677786 TI - Perceptual rivalry: reflexes reveal the gradual nature of visual awareness. AB - Rivalry is a common tool to probe visual awareness: a constant physical stimulus evokes multiple, distinct perceptual interpretations ("percepts") that alternate over time. Percepts are typically described as mutually exclusive, suggesting that a discrete (all-or-none) process underlies changes in visual awareness. Here we follow two strategies to address whether rivalry is an all-or-none process: first, we introduce two reflexes as objective measures of rivalry, pupil dilation and optokinetic nystagmus (OKN); second, we use a continuous input device (analog joystick) to allow observers a gradual subjective report. We find that the "reflexes" reflect the percept rather than the physical stimulus. Both reflexes show a gradual dependence on the time relative to perceptual transitions. Similarly, observers' joystick deflections, which are highly correlated with the reflex measures, indicate gradual transitions. Physically simulating wave-like transitions between percepts suggest piece-meal rivalry (i.e., different regions of space belonging to distinct percepts) as one possible explanation for the gradual transitions. Furthermore, the reflexes show that dominance durations depend on whether or not the percept is actively reported. In addition, reflexes respond to transitions with shorter latencies than the subjective report and show an abundance of short dominance durations. This failure to report fast changes in dominance may result from limited access of introspection to rivalry dynamics. In sum, reflexes reveal that rivalry is a gradual process, rivalry's dynamics is modulated by the required action (response mode), and that rapid transitions in perceptual dominance can slip away from awareness. PMID- 21677787 TI - Efficacy and safety of abciximab in diabetic patients who underwent percutaneous coronary intervention with thienopyridines loading: a meta-analysis. AB - BACKGROUND: It has been controversial whether abciximab offered additional benefits for diabetic patients who underwent percutaneous coronary intervention (PCI) with thienopyridines loading. METHODS: MEDLINE, EMBASE, the Cochrane library clinical trials registry, ISI Science Citation Index, ISI Web of Knowledge and China National Knowledge Infrastructure (CNKI) were searched, supplemented with manual-screening for relevant publications. Quantitative meta analyses were performed to assess differences between abciximab groups and controls with respect to post-PCI risk of major cardiac events (MACEs), angiographic restenosis and bleeding complications. RESULTS: 9 trials were identified, involving 2,607 diabetic patients receiving PCI for coronary artery diseases. Among those patients who underwent elective PCI or primary PCI, pooling results showed that abciximab did not significantly reduce risks of MACEs (for elective-PCI patients: RR(1-month): 0.93, 95% CI: 0.60-1.44; RR(1-year): 0.95, 95% CI: 0.81-1.11; for primary-PCI patients: RR(1-month): 1.05, 95% CI: 0.70 1.57; RR(1-year): 0.98, 95% CI: 0.80-1.21), nor all-cause mortality, re infarction and angiographic restenosis in either group. The only beneficial effect by abciximab appeared to be a decrease 1-year TLR (target lesion revascularization) risk in elective-PCI patients (RR1-year: 0.83, 95% CI: 0.70 0.99). Moreover, occurrence of minor bleeding complications increased in elective PCI patients treated with abciximab (RR: 2.94, 95% CI: 1.68-5.13, P<0.001), whereas major bleedings rate was similar (RR: 0.83, 95% CI: 0.27-2.57). CONCLUSIONS: Concomitant dosing of abciximab and thienopyridines provides no additional benefit among diabetic patients who underwent PCI; this conclusion, though, needs further confirmation in larger studies. PMID- 21677788 TI - Reduction of severe acute maternal morbidity and maternal mortality in Thyolo District, Malawi: the impact of obstetric audit. AB - BACKGROUND: Critical incident audit and feedback are recommended interventions to improve the quality of obstetric care. To evaluate the effect of audit at district level in Thyolo, Malawi, we assessed the incidence of facility-based severe maternal complications (severe acute maternal morbidity (SAMM) and maternal mortality) during two years of audit and feedback. METHODOLOGY/PRINCIPAL FINDINGS: Between September 2007 and September 2009, we included all cases of maternal mortality and SAMM that occurred in Thyolo District Hospital, the main referral facility in the area, using validated disease-specific criteria. During two- to three-weekly audit sessions, health workers and managers identified substandard care factors. Resulting recommendations were implemented and followed up. Feedback was given during subsequent sessions. A linear regression analysis was performed on facility-based severe maternal complications. During the two year study period, 386 women were included: 46 died and 340 sustained SAMM, giving a case fatality rate of 11.9%. Forty-five cases out of the 386 inclusions were audited in plenary with hospital staff. There was a reduction of 3.1 women with severe maternal complications per 1000 deliveries in the district health facilities, from 13.5 per 1000 deliveries in the beginning to 10.4 per 1000 deliveries at the end of the study period. The incidence of uterine rupture and major obstetric hemorrhage reduced considerably (from 3.5 to 0.2 and from 5.9 to 2.6 per 1000 facility deliveries respectively). CONCLUSIONS: Our findings indicate that audit and feedback have the potential to reduce serious maternal complications including maternal mortality. Complications like major hemorrhage and uterine rupture that require relatively straightforward intrapartum emergency management are easier to reduce than those which require uptake of improved antenatal care (eclampsia) or timely intravenous medication or HIV-treatment (peripartum infections). PMID- 21677789 TI - Mitochondrial DNA lineages of African origin confer susceptibility to primary open-angle glaucoma in Saudi patients. AB - PURPOSE: We previously reported that certain mitochondrial DNA (mtDNA) polymorphisms in the coding region may be involved in the pathogenesis for primary open-angle-glaucoma (POAG). This encouraged us to extend our work and assess whether mtDNA diagnostic polymorphisms, defining geographically structured haplogroups, could be associated with the development of POAG. METHODS: We sequenced the mtDNA regulatory hypervariable region-I (HVS-I) region and coding regions, comprising haplogroup diagnostic polymorphisms, in 176 POAG patients and 186 matched healthy controls (free of glaucoma by examination) of Saudi Arabia ascendancy. A large sample of 810 healthy Saudi Arabs representing the general Saudi population has also been included in the analysis. Assigning individuals into various mitochondrial haplogroups was performed using the nomenclature previously described for African and for Eurasian sequences. RESULTS: African mtDNA haplotypes belonging to L haplogroups, excluding L2, confer susceptibility to POAG whereas the Eurasian haplogroup N1 was associated with reduced risk of developing POAG in Saudi Arabian population. CONCLUSIONS: Saudi individuals with mtDNA of African origin are at higher risk of developing POAG. In addition, the mtDNA Eurasian haplogroup N1 may play a mild protective effect to this illness. PMID- 21677790 TI - Age-related changes in the water-soluble lens protein composition of Wistar and accelerated-senescence OXYS rats. AB - PURPOSE: To determine the age-related and the cataract-specific changes in the crystallin composition in lenses of accelerated-senescence OXYS (cataract model) and Wistar (control) rats. METHODS: The water soluble (WS) and insoluble (WIS) fractions of the lens proteins were separated; the identity and relative abundance of each crystallin in WS fraction were determined with the use of two dimensional electrophoresis (2-DE) and Matrix-Assisted Laser Desorption Ionization-Time Of Flight (MALDI-TOF) mass spectrometry. All statistical calculations were performed using the software package Statistica 6.0 by factor dispersion analysis (ANOVA/MANOVA) and Newman-Keuls post-hoc test for comparison of group mean values. RESULTS: The WIS protein content increased significantly in the aged animal lenses; the WIS/WS ratio increases in approximately 8 times to the age of 62 weeks. The interstrain difference was insignificant in this experiment. 2-DE maps of the young rat lenses (3 weeks) showed single spots for each lens protein while in older lenses (12 and 62 weeks) each crystallin was presented by several spots. The abundance of gammaA-gammaF-crystallins in WS fraction significantly decreases with age. A significant increase in the percentage abundance was also found for alpha-crystallins and betaB2-crystallin from 3 to 12 weeks. The major differences between Wistar and OXYS lenses are the faster decay of the content of gammaA-gammaF-crystallins in OXYS lenses, and the significant decrease of unmodified alphaA-crystallin abundance in old OXYS lenses. CONCLUSIONS: The presented results demonstrate that the increase of the water-insoluble (WIS) protein fraction is rather age-specific than cataract specific phenomenon. The major age-related changes in WS protein composition are the fast insolubilization of gamma-crystallins, and the increase of alphaB- and betaB2-crystallin abundance. The main interstrain differences, which could be attributed to the cataract-specific processes, are the faster decay of the content of gamma-crystallins and the significant decrease of unmodified alphaA crystallin abundance in the OXYS lenses. PMID- 21677791 TI - Gene-specific differential response to anti-apoptotic therapies in zebrafish models of ocular coloboma. AB - PURPOSE: We recently demonstrated that molecular therapy using aminoglycosides can overcome the underlying genetic defect in two zebrafish models of ocular coloboma and showed abnormal cell death to be a key feature associated with the optic fissure closure defects. In further studies to identify molecular therapies for this common congenital malformation, we now examine the effects of anti apoptotic compounds in zebrafish models of ocular coloboma in vivo. METHODS: Two ocular coloboma zebrafish lines (pax2.1/noi(tu29a) and lamb1/gup(m189)) were exposed to diferuloylmethane (curcumin) or benzyloxycarbonyl-Val-Ala-Asp(Ome) fluoromethylketone (zVAD-fmk; a pan-caspase inhibitor) for up to 8 days post fertilization. The effects of these compounds were assessed by morphology, histology, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and western blot analysis. RESULTS: The size of the coloboma in gup zebrafish mutants treated with diferuloylmethane was greatly reduced. In treated mutants a reduction in TUNEL staining and a 67% decrease in activated caspase-3 protein were observed. The release of cytochrome c from the mitochondria into the cytosol was reduced fourfold by in vivo diferuloylmethane treatment, suggesting that the drug was acting to inhibit the intrinsic apoptotic pathway. Inhibition of caspases directly with zVAD-fmk also resulted in a similar reduction in coloboma phenotype. Treatment with either diferuloylmethane or zVAD-fmk resulted in a statistically significant 1.4 fold increase in length of survival of these mutant zebrafish (p<0.001), which normally succumb to the lethal genetic mutation. In contrast, the coloboma phenotype in noi zebrafish mutants did not respond to either diferuloylmethane or zVAD-fmk exposure, even though inhibition of apoptotic cell death was observed by a reduction in TUNEL staining. CONCLUSIONS: The differential sensitivity to anti-apoptotic agents in lamb1 deficient and pax2.1-deficient zebrafish models, suggests that apoptotic cell death is not a final common pathway in all ocular coloboma genotypes. When considering anti-cell death therapies for ocular colobomatous defects attention should be paid to the genotype under investigation. PMID- 21677792 TI - A novel MERTK deletion is a common founder mutation in the Faroe Islands and is responsible for a high proportion of retinitis pigmentosa cases. AB - PURPOSE: The aim of the study was to elucidate the genetic background of retinitis pigmentosa (RP) in a Faroe Islands population, a genetic isolate in the North Atlantic Ocean. METHODS: Blood samples were collected from subjects diagnosed with RP and their families. DNA from affected individuals underwent single nucleotide polymorphism microarray analysis and homozygosity mapping followed by sequence analysis of candidate genes. RESULTS: We identified 25 cases of nonsyndromic RP corresponding to a prevalence of 1 in 1,900. Single nucleotide polymorphism analysis revealed a homozygous region on chromosome 2q, common to patients in four families, which harbored the RP gene MER tyrosine kinase protooncogene (MERTK). A deletion of 91 kb was identified in seven patients, representing 30% of the analyzed Faroese cases of nonsyndromic RP. The clinical course of six patients who were homozygous for the deletion showed onset in the first decade followed by a rapid deterioration of both rod and cone photoreceptor function. Early macular involvement was present, in accordance with that of other reported patients with MERTK mutations. CONCLUSIONS: Previous studies have shown a frequency of less than 1% of MERTK mutations in RP patients. The 91-kb deletion encompassing exons 1-7 of MERTK is a common founder mutation in the Faroe Islands, responsible for around 30% of RP, and together with mutations in protocadherin 21 (PCDH21) accounts for more than half of the retinal dystrophy cases. PMID- 21677793 TI - Pro370Leu myocilin mutation in a Chinese pedigree with juvenile-onset open angle glaucoma. AB - PURPOSE: To investigate the genotype and phenotype of juvenile-onset open angle glaucoma (JOAG) in a Chinese family (PN pedigree). METHODS: Each family member was comprehensively examined by an experienced ophthalmologist. The clinical characteristics of the family patients with JOAG were documented. Blood samples were obtained from 22 available participants from the PN pedigree. Linkage analysis was performed to identify the possible chromosome loci. The presence of gene mutation was ascertained by polymerase chain reaction amplification and subsequent direct sequencing. RESULTS: The affected members in the PN pedigree are characterized by early age of onset (mean age at diagnosis is 17 years old), severe clinical presentations, high intraocular pressure (mean IOP of 34.18+/ 2.97 mmHg), and poor response to pharmacological treatment (87.5% of the patients required filtering surgery). The region on chromosome 1 between D1S3464 and D1S1619 was identified in this pedigree by linkage analysis. A Pro370Leu myocilin mutation resulting from a heterozygous C->T transition at the 1,109th nucleotide in exon 3 was detected by gene sequencing. The Pro370Leu mutation co-segregated among all affected individuals of PN pedigree. CONCLUSIONS: The GLC1A Pro370Leu mutation is firmly correlated with a severe POAG phenotype. These data provide clues for the severe disease-causing nature of the Pro370Leu allele. Gene screening may be a useful method for pre-symptom diagnosis and a forewarning to detect the at-risk individuals in familial open-angle glaucoma patients, especially in pedigrees of early-onset. PMID- 21677794 TI - Spectrum of rhodopsin mutations in Korean patients with retinitis pigmentosa. AB - PURPOSE: To determine the spectrum and frequency of rhodopsin gene (RHO) mutations in Korean patients with retinitis pigmentosa (RP) and to characterize genotype-phenotype correlations in patients with mutations. METHODS: The RHO mutations were screened by direct sequencing, and mutation prevalence was measured in patients and controls. The impact of missense mutations to RP was predicted by segregation analysis, peptide sequence alignment, and in silico analysis. The severity of disease in patients with the missense mutations was compared by visual acuity, electroretinography, optical coherence tomography, and kinetic visual field testing. RESULTS: Five heterozygous mutations were identified in six of 302 probands with RP, including a novel mutation (c.893C>A, p.A298D) and four known mutations (c.50C>T, p.T17M; c.533A>G, p.Y178C; c.888G>T, p.K296N; and c.1040C>T, p.P347L). The allele frequency of missense mutations was measured in 114 ethnically matched controls. p.A298D, newly identified in a sporadic patient, had never been found in controls and was predicted to be pathogenic. Among the patients with the missense mutations, we observed the most severe phenotype in patients with p.P347L, less severe phenotypes in patients with p.Y178C or p.A298D, and a relatively moderate phenotype in a patient with p.T17M. CONCLUSIONS: The results reveal the spectrum of RHO mutations in Korean RP patients and clinical features that vary according to mutations. Our findings will be useful for understanding these genetic spectra and the genotype-phenotype correlations and will therefore help with predicting disease prognosis and facilitating the development of gene therapy. PMID- 21677796 TI - A 'sense' of history and pediatric cardiology. PMID- 21677795 TI - The in vitro toxicity of venoms from South Asian hump-nosed pit vipers (Viperidae: Hypnale). AB - Hump-nosed pit vipers (Genus Hypnale) are venomous snakes from South India and Sri Lanka. Envenoming by Hypnale species may cause significant morbidity and is characterized by local envenoming and less commonly coagulopathy and acute renal failure. Currently there are three nominal species of this genus: H. hypnale, H. zara and H. nepa. This study investigates the biochemical and pharmacological properties of the venoms from the three Hypnale species in Sri Lanka. The three Hypnale venoms had similar chromatographic profiles using reverse phase high performance liquid chromatography and fractions with procoagulant activity were identified. Hypnale venoms had potent cytotoxicity in cultured rat aorta smooth muscle cells with similar IC(50) values. The venoms had weak neurotoxic and myotoxic activity in the isolated chick biventer muscle preparation. They had mild procoagulant activity with close MCC(5) values and also phospholipase activity. Locally available polyvalent antivenom did not neutralise any venom effects. The study demonstrates that the three Hypnale venoms are similar and cytotoxicity appears to be the most potent effect, although they have mild procoagulant activity. These findings are consistent with clinical reports. PMID- 21677797 TI - Message from the editor. PMID- 21677798 TI - Global research priorities in rheumatic fever and rheumatic heart disease. AB - We now stand at a critical juncture for rheumatic fever (RF) and rheumatic heart disease (RHD) control. In recent years, we have seen a surge of interest in these diseases in regions of the world where RF/RHD mostly occur. This brings real opportunities to make dramatic progress in the next few years, but also real risks if we miss these opportunities. Most public health and clinical approaches in RF/RHD arose directly from programmes of research. Many unanswered questions remain, including those around how to implement what we know will work, so research will continue to be essential in our efforts to bring a global solution to this disease. Here we outline our proposed research priorities in RF/RHD for the coming decade, grouped under the following four challenges: Translating what we know already into practical RHD control; How to identify people with RHD earlier, so that preventive measures have a higher chance of success; Better understanding of disease pathogenesis, with a view to improved diagnosis and treatment of ARF and RHD; and Finding an effective approach to primary prevention. We propose a mixture of basic, applied, and implementation science. With concerted efforts, strong links to clinical and public health infrastructure, and advocacy and funding support from the international community, there are good prospects for controlling these RF and RHD over the next decade. PMID- 21677799 TI - Genes, autoimmunity and pathogenesis of rheumatic heart disease. AB - Pathogenesis of rheumatic heart disease (RHD) remains incompletely understood. Several genes associated with RHD have been described; most of these are involved with immune responses. Single nucleotide polymorphisms in a number of genes affect patients with RHD compared to controls. Molecular mimicry between streptococcal antigens and human proteins, including cardiac myosin epitopes, vimentin and other intracellular proteins is central to the pathogenesis of RHD. Autoreactive T cells migrate from the peripheral blood to the heart and proliferate in the valves in response to stimulation with specific cytokines. The types of cells involved in the inflammation as well as different cytokine profiles in these patients are being investigated. High TNF alpha, interferon gamma, and low IL4 are found in the rheumatic valve suggesting an imbalance between Th1 and Th2 cytokines and probably contributing to the progressive and permanent valve damage. Animal model of ARF in the Lewis rat may further contribute towards understanding the ARF. PMID- 21677800 TI - Intermediate and long-term followup of percutaneous device closure of fossa ovalis atrial septal defect by the Amplatzer septal occluder in a cohort of 529 patients. AB - OBJECTIVES: The aim of present study is to analyze the intermediate and long-term follow up results of percutaneous closure of fossa ovalis atrial septal defect (ASD) with Amplatzer septal occluder (ASO) in a large cohort of patients including children and adults. METHODS: Between May 1998 and July 2008, 529 patients (age group 2-77 years, median 28 years) underwent successful device closure with an ASO at single tertiary referral cardiac center in India.. This was out of an attempted 543 cases. The procedure was carried out in catheterization laboratory under transesophageal echocardiographic and fluoroscopy guidance. The mean size of ASD was 20 mm (7-40 mm) while size of septal occluder was 10-40 mm (mean 24 mm). Two devices were deployed in four patients. Three patients developed transitory pulmonary edema in immediate postprocedure period requiring ICU care for 48 hrs. All patients were advised for Aspirin (3-5 mg/kg, maximum 150 mg) once daily for 6 months. In patients with device 30 mm or larger, Clopidogril ( 75 mg once daily) was given for 3 months in addition to Aspirin. Clinical evaluation, echocardiogram were done on 3 months, 6 months and then at 1, 3, 5, 7 and 10 years of follow up. Transesophageal echocardiography (TEE) was performed in case of any doubt on clinical evaluation or on transthoracic echocardiography (n=10). RESULTS: Followup data is available for 496 patients (93.7%). Followup period is from 12 months to 120 months (median 56 months). On followup, device was in position in all patients, no residual shunt and no evidence of thrombosis. Interventricular septal motion normalized on day of procedure in 89% patients, in 6% over 3 months while flat septal motion persisted in 5% (n=25, all in age group > 40 years) of cases, though right ventricular dilatation persisted in 10% (n=50, age more than 40 years) of patients. Symptom-free survival was 96.7 % (480/496) in patients who came for followup. Only one 68 year old patient with preexistent tricuspid regurgitation developed congestive heart failure, and one patient (58 years old) had a history of hemiparesis after 1 year of device on telephonic interview. Ten patients were in atrial fibrillation (AF) before the procedure and remained in AF on followup. CONCLUSIONS: Our study showed that percutaneous closure of fossa ovalis ASD is a safe and effective procedure on intermediate and long-term followup in both the children as well as adults.both. Technical factors during the procedure and proper follow up are important. Our single centre intermediate and long term experience in a large number of patients support the use of device closure as an alternative to surgery. PMID- 21677802 TI - Device closure of secundum atrial septal defects: To balloon size or not to balloon size. PMID- 21677801 TI - Trans-catheter closure of atrial septal defect: Balloon sizing or no Balloon sizing - single centre experience. AB - BACKGROUND: Selecting the device size using a sizing balloon could oversize the ostium secundum atrial septal defect (OSASD) with floppy margins and at times may lead to complications. Identifying the firm margins using trans-esophageal echocardiography (TEE) and selecting appropriate-sized device optimizes ASD device closure. This retrospective study was undertaken to document the safety and feasibility of device closure without balloon sizing the defect. METHODS: Sixty-one consecutive patients who underwent trans-catheter closure of OSASD guided by balloon sizing of the defect and intra procedural fluoroscopy (group I) and 67 consecutive patients in whom TEE was used for defect sizing and as intraprocedural imaging during device deployment (group II) were compared. The procedural success rate, device characteristics, and complications were compared between the two groups. RESULTS: The procedure was successful in 79.7 % patients. The success rate in group II (60 of 67, 89.6%) was significantly higher than in group I (41 of 61, 67.2 %) (P = 0.002). Mean upsizing of ASD device was significantly lower in group II (P < 0.001). TEE also provided better success rate with smaller device in subjects with large ASD (>25 mm) and in those who were younger than 14 years of age. There were four cases of device embolization (two in each group); of which one died in group II despite successful surgical retrieval. CONCLUSION: Balloon sizing may not be essential for successful ASD device closure. TEE-guided sizing of ASD and device deployment provides better success rate with relatively smaller sized device. PMID- 21677803 TI - Comparison of contrast and noncontrast magnetic resonance angiography for quantitative analysis of thoracic arteries in young patients with congenital heart defects. AB - BACKGROUND: Contrast MRA (C-MRA) is the standard for quantitative analysis of thoracic vessels. We evaluated a noncontrast MRA (NC-MRA) sequence (3-D EKG and navigator-gated SSFP) for quantitative evaluation of the thoracic aorta and branch pulmonary arteries in young patients with congenital heart disease. OBJECTIVE: To compare contrast and noncontrast magnetic resonance angiography for quantitative analysis of thoracic arteries in young patients with congenital heart defects. METHODS: Measurements of thoracic aorta and branch pulmonary arteries were obtained from C-MRA and NC-MRA images in 51 patients, ages 2-35 years. Vessel diameters were compared using correlation and Bland-Altman analysis. Interobserver variability was assessed using percent variation. RESULTS: C-MRA and NC-MRA measurements were highly correlated (r = 0.91-0.98) except for the right pulmonary artery (r = 0.74, 0.78). Agreement of measurements was excellent (mean difference -0.07 to -0.53 mm; mean % difference -1.8 to 4.9%) except for the right pulmonary artery which was less good (mean difference 0.73, -1.38 mm; -3, -10%). Interobserver variability ranged from 5% to 8% for aortic and from 10% to 16% for pulmonary artery measures. The worse agreement and greater variability of the pulmonary artery measures appears due to difficulty standardizing the measurements in patients with abnormal and irregular vessels. CONCLUSION: These data indicate that C-MRA and NC-MRA measures are comparable and could be used interchangeably, avoiding administration of contrast in selected patients. PMID- 21677804 TI - Assessment of operability in d-transposition of great arteries with ventricular septal defect: A practical method. AB - INTRODUCTION: Pulmonary vascular disease is a risk factor in the surgical management of patients with d-transposition of great arteries (d-TGA) and a ventricular septal defect (VSD). In older infants or children with this physiology, the question of operability often arises. Cardiac catheterization in this condition can be fallacious. It is well known that oxygen reduces pulmonary arterial pressure and pulmonary vascular resistance especially where irreversible pulmonary vascular obstructive disease has still not set in. We tried to implement this effect of oxygen in correlation with echocardiography in patients with TGA-VSD physiology where operability was in question. METHODS: Patients with d-TGA and a large post tricuspid shunt in whom operability was considered doubtful were selected for the study. We administered humidified oxygen at the rate of 10 litres/minute by mask for 48 hours in the ward or intensive care unit. After administration of oxygen we reassessed the child echocardiographically looking for signs of lowering of pulmonary vascular resistance which included increased pulmonary venous blood flow to the left atrium (LA) and right to left shunting across the VSD. OBSERVATION: We studied 1 patient with d-TGA and aortopulmonary window (APW), 4 patients with TGA / large VSD and 1 patient with Taussig-Bing anomaly. The age of the studied children ranged from 4 months to 3 years with a mean age of 1.1 years. After administering oxygen as described, echocardiogram showed an increase in pulmonary venous blood flow to the LA and right to left shunting across the VSD in 5 patients and increased flow reversal in aorta in presence of the APW. CONCLUSION: Patients with TGA/VSD physiology with doubtful operability can be subjected to this method of determining operability using echocardiography after administering oxygen. Although not 100% accurate in predicting long term postoperative pulmonary hypertension, this is a simple, noninvasive method that can aid in decision making in such a situation. PMID- 21677805 TI - Operability in transposition of great arteries with ventricular septal defect: A difficult question - is the answer really so simple? PMID- 21677806 TI - Repair of rheumatic mitral regurgitation in children. PMID- 21677807 TI - Admixture lesions in congenital cyanotic heart disease. PMID- 21677808 TI - Acquired origin of the left anterior descending coronary artery from the pulmonary artery: A complication of the arterial switch operation. AB - The prevalence of coronary anomalies in the transposition of the great arteries is high. Transfer of the coronary arteries during arterial switch operation is the principle step and incomplete transport of the coronary arteries to the neoaortic root results into iatrogenic coronary problems. We present a case with the residual left anterior descending coronary artery originating from the pulmonary artery as a complication of the failure of transfer during the arterial switch operation. PMID- 21677809 TI - Occult anomalous origin of the left coronary artery from the pulmonary artery with ventricular septal defect. AB - Manifestations of anomalous left coronary artery from the pulmonary trunk may be masked in the presence of an associated shunt lesion that prevents fall of pulmonary artery pressures and allows perfusion of the anomalous coronary artery. We present such a patient with a large ventricular septal defect associated with the anomalous coronary artery from the pulmonary artery. PMID- 21677810 TI - Imaging of pericardial lymphangioma. AB - Pericardial cystic lymphangioma is a developmental malformation of the lymphatic system. We report a case of cystic pericardial lymphangioma in the anterior mediastinum in a 1-year-old male child. The lesion was diagnosed with multidetector computed tomography and magnetic resonance imaging (MRI). Histopathological examination showed features of cystic lymphangioma. PMID- 21677811 TI - Giant pericardial cyst in a 5-year-old child: A rare anomaly. AB - Pericardial cysts are uncommon congenital abnormalities that occur in the middle mediastinum. Most of these are found incidentally on chest x-rays. The occurrence of pericardial cyst in children is quite rare. It needs to be differentiated from other cystic mediastinal masses. A rare case of pericardial cyst in a 5 year old male child is reported. The child presented with chest pain, cough and fever. The preoperative diagnosis of pericardial cyst was suggestive on echocardiography and CT scan. It was confirmed on histopathology after successful surgical excision. The rarity of this benign mediastinal lesion in children prompted us to report this case. PMID- 21677812 TI - Reninoma presenting as cardiac syncope. AB - Reninoma, a renin-secreting tumor of the juxta-glomerular cells of the kidney, is a rare but surgically treatable cause of secondary hypertension in children. We report a case of reninoma presenting as cardiac syncope with long QTc on electrocardiogram due to hypokalemia. PMID- 21677813 TI - LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation. AB - In LEOPARD syndrome, mutations affecting exon 13 of the PTPN11 gene have been correlated with a rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy (HCM). This is a report of early onset severe HCM in an infant with LEOPARD syndrome and an unusual mutation in exon 13, showing genotype-phenotype correlation. PMID- 21677814 TI - Kodamaea ohmeri tricuspid valve endocarditis with right ventricular inflow obstruction in a neonate with structurally normal heart. AB - The yeast Kodamaea (Pichia) ohmeri is a rare human pathogen with infrequent report of neonatal infection. Native valve endocarditis by Kodamaea ohmeri is extremely rare. The current case report describes a case of fatal nosocomial native valve endocarditis without any structural heart defects in a 40dayold baby. The patient was referred to our institute after having ICU stay of 18 days in another hospital for necrotizing enterocolitis and was found to have obstructive tricuspid valve mass and fungemia with Kodamaea ohmeri. In spite of the treatment, patient developed sepsis with disseminated intravascular coagulation and could not be revived. PMID- 21677815 TI - Myocardial infarction in children: Two interesting cases. AB - Myocardial infarction in children is extremely rare and can have various etiologies. The following two case reports highlight rare but important causes of myocardial infarction in children. PMID- 21677816 TI - Technology and healthcare costs. AB - Medicine in the 21(st) century is increasingly dependent on technology. Unlike in many other areas, the cost of medical technology is not declining and its increasing use contributes to the spiraling healthcare costs. Many medical professionals equate progress in medicine to increasing use of sophisticated technology that is often expensive and beyond the reach of the average citizen. Pediatric heart care is very technology-intensive and therefore very expensive and beyond the reach of the vast majority of children in the developing world. There is an urgent need to address this situation through development and use of appropriate technology in accordance with the needs and priorities of the society. A number of simple and inexpensive quality measures that have the potential of improving outcomes substantially without the need for expensive equipment should be instituted before embracing high-end technology. Innovations to reduce costs that are commonly used in limited resource environments should be tested systematically. PMID- 21677817 TI - Diffuse infiltrative cardiac tuberculosis. AB - We present the cardiac magnetic resonance images of an unusual form of cardiac tuberculosis. Nodular masses in a sheet-like distribution were seen to infiltrate the outer myocardium and pericardium along most of the cardiac chambers. The lesions showed significant resolution on antitubercular therapy. PMID- 21677818 TI - Current form of randomized controlled trials. PMID- 21677819 TI - Organic anion transporting polypeptide 1B3 (OATP1B3) is overexpressed in colorectal tumors and is a predictor of clinical outcome. AB - BACKGROUND AND AIMS: OATP1B3 is an organic anion transporting polypeptide (OATP) that functions as a multispecific transporter in the normal liver. We examined the expression and clinical significance of OATP1B3 in colon cancers in tissue microarrays. METHODS: Immunohistochemistry was used to assess OATP1B3 protein expression in paraffinized colon tumor tissue microarrays. OATP1B3 immunostaining was evaluated by location and intensity. Relationships between OATP1B3 expression, known prognostic variables and clinical outcomes were examined. RESULTS: 278 colon tumor samples of all stages were evaluated for OATP1B3 expression. OATP1B3 immunostaining was detectable in the majority (56%) of the tumor samples. Higher OATP1B3 expression was seen in lower stage tumors (p = 0.003) and lower grade (p = 0.004) tumors, but was not predictive of 5-year survival or tumor recurrence as an independent variable. Within individual tumor grades, OATP1B3 expression was associated with improved 5-year survival, but not recurrence in patients with poorly differentiated tumors. CONCLUSION: OATP1B3 expression was seen in the majority of colon tumors and may be a marker of lower grade and lower stage tumors and may predict for improved outcome in certain tumors. PMID- 21677820 TI - Epidemiology of viral hepatitis in Sudan. AB - Hepatitis virus infections are the most common cause of liver disease worldwide. Sudan is classified among the countries with high hepatitis B virus seroprevalence. Exposure to the virus varied from 47%-78%, with a hepatitis B surface antigen prevalence ranging from 6.8% in central Sudan to 26% in southern Sudan. Studies pointed to infection in early childhood in southern Sudan while there was a trend of increasing infection rate with increasing age in northern Sudan. Hepatitis B virus was the commonest cause of chronic liver disease and hepatocellular carcinoma and was the second commonest cause of acute liver failure in the Sudan. Studies of hepatitis C virus showed a low seroprevalence of 2.2%-4.8% and there was no association with schistosomiasis or with parenteral antischistosomal therapy. Hepatitis E virus was the commonest cause of acute hepatitis among pediatric, adult, and displaced populations. Recent introduction of screening of blood and blood products for hepatitis B virus and hepatitis C virus infections and the introduction of hepatitis B virus vaccine as part of the extended program of immunization is expected to reduce the infection rate of these viruses in the Sudan. PMID- 21677821 TI - Oropharyngeal Crohn's disease. AB - Crohn's disease is a chronic inflammatory disease that can affect any part of the gastrointestinal tract. Classically the disease has a predilection for the distal small bowel and colon and presents with dominant symptoms of abdominal pain and diarrhea. This case report describes a 38-year-old woman with Crohn's disease who presented with odynophagia. Direct visualization of the oropharynx revealed a large serpiginous Crohn's disease ulcer. A precipitous drop in hemoglobin prompted a series of gastroenterologic investigations that confirmed both ileal and oropharyngeal Crohn's disease. This manuscript describes the presentation of oropharyngeal Crohn's and reviews previous reports and management options. PMID- 21677823 TI - Methylnaltrexone in the treatment of opioid-induced constipation. AB - Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a MU opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (RelistorTM; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, MU opioid receptor antagonist that accelerates oral-cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies. PMID- 21677824 TI - Helicobacter pylori neutrophil activating protein as target for new drugs against H. pylori inflammation. AB - Helicobacter pylori (H. pylori) infection is among the most common human infections and the major risk factor for peptic ulcer disease and gastric cancer. Within this work we present the implication of C-terminal region of H. pylori neutrophil activating protein in the stimulation of neutrophil activation as well as the evidence that the C-terminal region of H. pylori activating protein is indispensable for neutrophil adhesion to endothelial cells, a step necessary to H. pylori inflammation. In addition we show that arabino galactan proteins derived from chios mastic gum, the natural resin of the plant Pistacia lentiscus var. Chia inhibit neutrophil activation in vitro. PMID- 21677825 TI - Current status of endoscopic submucosal dissection for the management of early gastric cancer: a Korean perspective. AB - The early diagnosis of gastric cancer allows patients and physicians to pursue the option of endoscopic resection, which is significantly less invasive than conventional surgical resection. In Korea, the use of endoscopic submucosal dissection (ESD) has been increasing, and many reports on ESD have been published. In addition, Korean gastroenterologists from several hospitals performing ESD have conducted formal meetings to discuss useful information regarding ESD. Here, we discuss the Korean experience with ESD, including outcomes and prospects of endoscopic treatments. PMID- 21677822 TI - Hydrophobic bile acids, genomic instability, Darwinian selection, and colon carcinogenesis. AB - Sporadic colon cancer is caused predominantly by dietary factors. We have selected bile acids as a focus of this review since high levels of hydrophobic bile acids accompany a Western-style diet, and play a key role in colon carcinogenesis. We describe how bile acid-induced stresses cause cell death in susceptible cells, contribute to genomic instability in surviving cells, impose Darwinian selection on survivors and enhance initiation and progression to colon cancer. The most likely major mechanisms by which hydrophobic bile acids induce stresses on cells (DNA damage, endoplasmic reticulum stress, mitochondrial damage) are described. Persistent exposure of colon epithelial cells to hydrophobic bile acids can result in the activation of pro-survival stress response pathways, and the modulation of numerous genes/proteins associated with chromosome maintenance and mitosis. The multiple mechanisms by which hydrophobic bile acids contribute to genomic instability are discussed, and include oxidative DNA damage, p53 and other mutations, micronuclei formation and aneuploidy. Since bile acids and oxidative stress decrease DNA repair proteins, an increase in DNA damage and increased genomic instability through this mechanism is also described. This review provides a mechanistic explanation for the important link between a Western-style diet and associated increased levels of colon cancer. PMID- 21677826 TI - Do we have enough evidence for expanding the indications of ESD for EGC? AB - Endoscopic submucosal dissection (ESD) is the most advanced and representative technique in the field of therapeutic endoscopy and has been used for the treatment of gastrointestinal neoplasms, including early gastric cancer. The major difference and advantage of ESD compared to existing endoscopic resection techniques, such as endoscopic mucosal resection (EMR) and polypectomy, are the width and depth of the resection. Newly developed cutting devices, distal attachable endoscopic accessories, and an advanced electrosurgical unit have helped to overcome the limitations of therapeutic endoscopy in terms of lesion size, location, presence of fibrotic scarring, and accompanying ulcers. As a result, the indications for ESD have been expanded from the classical indication for EMR and polypectomy, and there is now support for a further expansion of ESD indications. At present, the most critical factor to consider in the decision of whether to perform ESD is the probability of unexpected lymph node metastasis. The guidelines for ESD are continually being updated and debated. In this review, we discuss the strengths and weaknesses of the expanded guidelines, based on evidence found in the literature. PMID- 21677827 TI - Diagnosis of gastric epithelial neoplasia: Dilemma for Korean pathologists. AB - The histopathological diagnosis of gastric mucosal biopsy and endoscopic mucosal resection/endoscopic submucosal dissection specimens is important, but the diagnostic criteria, terminology, and grading system are not the same in the East and West. A structurally invasive focus is necessary to diagnose carcinoma for most Western pathologists, but Japanese pathologists make a diagnosis of cancer based on severe dysplastic cytologic atypia irrespective of the presence of invasion. Although the Vienna classification was introduced to reduce diagnostic discrepancies, it has been difficult to adopt due to different concepts for gastric epithelial neoplastic lesions. Korean pathologists experience much difficulty making a diagnosis because we are influenced by Japanese pathologists as well as Western medicine. Japan is geographically close to Korea, and academic exchanges are active. Additionally, Korean doctors are familiar with Western style medical terminology. As a result, the terminology, definitions, and diagnostic criteria for gastric intraepithelial neoplasia are very heterogeneous in Korea. To solve this problem, the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists has made an effort and has suggested guidelines for differential diagnosis: (1) a diagnosis of carcinoma is based on invasion; (2) the most important characteristic of low grade dysplasia is the architectural pattern such as regular distribution of crypts without severe branching, budding, or marked glandular crowding; (3) if nuclear pseudostratification occupies more than the basal half of the cryptal cells in three or more adjacent crypts, the lesion is considered high grade dysplasia; (4) if severe cytologic atypia is present, careful inspection for invasive foci is necessary, because the risk for invasion is very high; and (5) other structural or nuclear atypia should be evaluated to make a final decision such as cribriform pattern, papillae, ridges, vesicular nuclei, high nuclear/cytoplasmic ratio, loss of nuclear polarity, thick and irregular nuclear membrane, and nucleoli. PMID- 21677828 TI - Worldwide experiences of endoscopic submucosal dissection: not just Eastern acrobatics. AB - The high incidence of gastric cancer has led to the initiation of cancer screening programs. As a result, the number of early gastric cancer cases has increased and consequentially, the cancer mortality rate has decreased. Moreover, the development of minimally invasive endoscopic treatment has been introduced for these early lesions. Endoscopic submucosal dissection (ESD) is now recognized as one of the preferred treatment modalities for premalignant gastrointestinal epithelial lesions and early gastric cancer without lymph node metastasis. We review the results of ESD including experiences in Japan and Korea, as well as western countries. PMID- 21677829 TI - Chicken soup for teaching and learning ESD. AB - Endoscopic submucosal dissection (ESD) is becoming a popular procedure for the diagnosis and treatment of superficial mucosal lesions, and has the advantage of en bloc resection which yields a higher complete resection and remission rate compared to endoscopic mucosal resection (EMR). However, the learning process of this advanced endoscopic procedure requires a lengthy training period and considerable experience to be proficient. A well framed training protocol which is safe, effective, easily reproducible and cost-effective is desirable to teach ESD. In addition, the training course may need to be tailored around settings such as ethnicity, culture, workload, and disease incidence. In Asian countries with a large volume of early gastric lesions which need endoscopic treatment, endoscopists would be able to learn ESD expanding their skills from EMR to ESD under the supervision of experts. Whereas, in Western countries due to the low incidence of superficial gastric tumors, trials have utilized simulator models to improve learning. In Korea, the Korean Society of Gastrointestinal Endoscopy (KSGE) is playing an important role in training many gastroenterologists who have shown an interest in performing ESD by providing an annual live demonstration and a nationwide tutoring program. The purpose of this article is to introduce our ESD tutoring experience, review the published papers related to this topic, and propose several suggestions for future directions in teaching and learning ESD. PMID- 21677830 TI - Endoscopic submucosal dissection for early gastric cancer: quo vadis? AB - The diagnosis of early gastric cancer (EGC) is of great interest because its endoscopic and surgical treatment presents the best chance for a cure. With technical development, endoscopic submucosal dissection (ESD) has been widely performed for the curative treatment of EGC in Korea. Multinational studies of ESD for EGC will be the next missions that overcome these limitations and global guidelines will be processed for ESD for EGC. PMID- 21677831 TI - Hepatobiliary scintigraphy for detecting biliary strictures after living donor liver transplantation. AB - AIM: To investigate the diagnostic accuracy of hepatobiliary scintigraphy (HBS) in detecting biliary strictures in living donor liver transplantation (LDLT) patients. METHODS: We retrospectively reviewed 104 adult LDLT recipients of the right hepatic lobe with duct-to-duct anastomosis, who underwent HBS and cholangiography. The HBS results were categorized as normal, parenchymal dysfunction, biliary obstruction, or bile leakage without re-interpretation. The presence of biliary strictures was determined by percutaneous cholangiography or endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: In 89 patients with biliary strictures, HBS showed biliary obstruction in 50 and no obstruction in 39, for a sensitivity of 56.2%. Of 15 patients with no biliary strictures, HBS showed no obstruction in 11, for a specificity of 73.3%. The positive predictive value (PPV) was 92.6% (50/54) and the negative predictive value (NPV) was 22% (11/50). We also analyzed the diagnostic accuracy of the change in bile duct size. The sensitivity, NPV, specificity, and PPV were 65.2%, 27.9%, 80% and 95%, respectively. CONCLUSION: The absence of biliary obstruction on HBS is not reliable. Thus, when post-LDLT biliary strictures are suspected, early ERCP may be considered. PMID- 21677832 TI - Keratinocyte growth factor gene therapy ameliorates ulcerative colitis in rats. AB - AIM: To investigate the effect of keratinocyte growth factor (KGF) gene therapy in acetic acid-induced ulcerative colitis in rat model. METHODS: The colitis of Sprague-Dawley rats was induced by intrarectal infusion of 1 mL 5% (v/v) acetic acid. Twenty-four hours after exposed to acetic acid, rats were divided into three experimental groups: control group, attenuated Salmonella typhimurium Ty21a strain (SP) group and SP strain carrying human KGF gene (SPK) group, and they were separately administered orally with 10% NaHCO(3), SP or SPK. Animals were sacrificed and colonic tissues were harvested respectively on day 3, 5, 7 and 10 after administration. Weights of rats, colonic weight/length ratio and stool score were evaluated. Histological changes of colonic tissues were examined by hematoxylin and eosin (HE) staining method. The expression of KGF, KGF receptor (KGFR) and TNF-alpha were measured either by enzyme-linked immunosorbent assay or Western blotting. Immunohistochemistry was used to detect the cellular localization of KGFR and Ki67. In addition, superoxide dismutase (SOD) activity and malondialdehyde (MDA) contents in the homogenate were measured. RESULTS: Body weight and colonic weight/length ratio were declined in SPK group compared with SP and control groups (body weight: 272.78 +/- 17.92 g vs 243.72 +/- 14.02 g and 240.68 +/- 12.63 g, P < 0.01; colonic weight/length ratio: 115.76 +/- 7.47 vs 150.32 +/- 5.99 and 153.67 +/- 5.50 mg/cm, P < 0.01). Moreover, pathological changes of damaged colon were improved in SPK group as well. After administration of SPK strain, KGF expression increased markedly from the 3rd d, and remained at a high level till the 10th d. Furthermore, KGFR expression and Ki67 expression elevated, whereas TNF-alpha expression was inhibited in SPK group. In the group administered with SPK, SOD activity increased significantly (d 5: 26.18 +/- 5.84 vs 18.12 +/- 3.30 and 18.79 +/- 4.74 U/mg, P < 0.01; d 7: 35.48 +/- 3.35 vs 22.57 +/- 3.44 and 21.69 +/- 3.94 U/mg, P < 0.01; d 10: 46.10 +/- 6.23 vs 25.35 +/- 4.76 and 27.82 +/- 6.42 U/mg, P < 0.01) and MDA contents decreased accordingly (d 7: 7.40 +/- 0.88 vs 9.81 +/- 1.21 and 10.45 +/- 1.40 nmol/mg, P < 0.01; d 10: 4.36 +/- 0.62 vs 8.41 +/- 0.92 and 8.71 +/- 1.27 nmol/mg, P < 0.01), compared with SP and control groups. CONCLUSION: KGF gene therapy mediated by attenuated Salmonella ameliorates ulcerative colitis induced by acetic acids, and it may be a safe and effective treatment for ulcerative colitis. PMID- 21677833 TI - Chronic constipation: facilitator factor for development of varicocele. AB - AIM: To evaluate the possible relationship between varicocele and chronic constipation. METHODS: Between April 2009 and May 2010, a total of 135 patients with varicocele or constipation and 120 healthy controls were evaluated. Patients were divided into two groups. In both groups detailed medical history was taken and all patients were examined physically by the same urologist and gastroenterologist. All of them were evaluated by color Doppler ultrasonography. All patients with constipation, except for the healthy controls of the second group, underwent a colonoscopy to identify the etiology of the constipation. In the first group, we determined the rate of chronic constipation in patients with varicocele and in the second group, the rate of varicocele in patients with chronic constipation. In both groups, the rate of the disease was compared with age-matched healthy controls. In the second group, the results of colonoscopies in the patients with chronic constipations were also evaluated. RESULTS: In the first group, mean age of the study and control groups were 22.9 +/- 4.47 and 21.8 +/- 7.21 years, respectively (P < 0.05). In the second group, mean age of the study and control groups were 52.8 +/- 33.3 and 51.7 +/- 54.3 years, respectively (P < 0.05). In the first group, chronic constipation was observed in 8 of the 69 patients with varicocele (11.6%) and 3 out of 60 in healthy controls (5%), respectively. In this regard, there was no statistical significance between varicocele patients and the healthy control (P = 0.37). In the second group, varicocele was observed in 16 of the 66 patients with chronic constipation (24.24%) and 12 out of 60 in healthy controls (20%) respectively. Similarly, there was no statistical significance between chronic constipation and healthy controls (P = 0.72). Internal/external hemorrhoids were detected in 4 of the 16 patients with chronic constipation and varicocele, in the second group. In the remaining 50 patients with chronic constipation 9 had internal/external hemorrhoids. In this regard, there was no statistical significance between chronic constipation and healthy controls (P = 0.80). CONCLUSION: Chronic constipation may not be a major predictive factor for the development of varicocele, but it may be a facilitator factor for varicocele. PMID- 21677834 TI - Secretion of melatonin and 6-sulfatoxymelatonin urinary excretion in functional dyspepsia. AB - AIM: To evaluate blood concentration of melatonin and urinary excretion of its metabolite, 6-sulfatoxymelatonin (6-OHMS), in functional dyspepsia (FD). METHODS: Ninety individuals were enrolled in the study: 30 in each study group: patients with postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and controls. Blood samples were drawn at 02:00 and 09:00 h and 24-h urine collection was performed. Serum melatonin and urinary 6-OHMS concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: Serum melatonin concentration at night and in the morning was significantly (P < 0.001) higher in PDS patients [at 02:00 h-93.3 pg/mL, quartile range (QR): 79.8-116.2; at 09.00 h-14.3 pg/mL, QR: 7.06-19.0] than in EPS (57.2 pg/mL, QR: 42.6-73.1; 8.1 pg/mL, QR: 4.1-9.3) and control patients (57.7 pg/mL, QR: 51.2-62.5; 8.1 pg/mL, QR: 5.4-10.3). A similar relationship was observed for urinary 6-OHMS excretion. Patients with severe PDS symptoms had a higher melatonin concentration than these with moderate syndromes, whereas patients with severe EPS had a lower urinary 6-OHMS excretion than patients with moderate symptoms. CONCLUSION: Evaluation of melatonin serum concentrations and 24-h urinary 6-OHMS excretion are useful methods for differential diagnosis of various clinical forms of FD. PMID- 21677835 TI - Endoscopic removal and trimming of distal self-expandable metallic biliary stents. AB - AIM: To evaluate the efficacy and safety of endoscopic removal and trimming of self-expandable metallic stents (SEMS). METHODS: All SEMS had been placed for distal biliary strictures. Twenty-seven endoscopic procedures were performed in 19 patients in whom SEMS (one uncovered and 18 covered) removal had been attempted, and 8 patients in whom stent trimming using argon plasma coagulation (APC) had been attempted at Tokyo Medical University Hospital. The APC settings were: voltage 60-80 W and gas flow at 1.5 L/min. RESULTS: The mean stent indwelling period for all patients in whom stent removal had been attempted was 113.7 +/- 77.6 d (range, 8-280 d). Of the 19 patients in whom removal of the SEMS had been attempted, the procedure was successful in 14 (73.7%) without procedure related adverse events. The indwelling period in the stent removable group was shorter than that in the unremovable group (94.9 +/- 71.5 d vs 166.2 +/- 76.2 d, P = 0.08). Stent trimming was successful for all patients with one minor adverse event consisting of self-limited hemorrhage. Trimming time ranged from 11 to 16 min. CONCLUSION: Although further investigations on larger numbers of cases are necessary to accumulate evidence, the present data suggested that stent removal and stent trimming is feasible and effective for stent-related complications. PMID- 21677836 TI - Clinical significance of serum expression of GRObeta in esophageal squamous cell carcinoma. AB - AIM: To determine the association between serum levels of growth-related gene product beta (GRObeta) and clinical parameters in esophageal squamous cell carcinoma (ESCC). METHODS: Using enzyme-linked immunosorbent assay, serum GRObeta levels were measured in ESCC patients (n = 72) and healthy volunteers (n = 83). The association between serum levels of GRObeta and clinical parameters of ESCC was analyzed statistically. RESULTS: The serum GRObeta levels were much higher in ESCC patients than in healthy controls (median: 645 ng/L vs 269 ng/L, P < 0.05). Serum GRObeta levels were correlated positively with tumor size, lymph node metastasis, and tumor-node-metastasis (TNM) staging, but not with gender or the histological grade of tumors in ESCC patients. The sensitivity and specificity of the assay for serum GRObeta were 73.61% and 56.63%, respectively. CONCLUSION: GRObeta may function as an oncogene product and contribute to tumorigenesis and metastasis of ESCC. PMID- 21677837 TI - Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice. AB - AIM: To examine the effects of 2,4-dihydroxybenzophenone (BP-1), a benzophenone derivative used as an ultraviolet light absorbent, on acetaminophen (APAP) induced hepatotoxicity in C57BL/6J mice. METHODS: Mice were administered orally with BP-1 at doses of 200, 400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP (350 mg/kg body weight) was given subcutaneously. Twenty four hours after APAP intoxication, the serum enzyme including serum alaine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) were measured and liver histopathologic changes were examined. RESULTS: BP-1 administration dramatically reduced serum ALT, AST and LDH levels. Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner. Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment, and glutathione depletion was ameliorated obviously. CONCLUSION: BP-1 can effectively protect C57BL/6J mice from APAP induced hepatotoxicity, and reduction of oxidative stress might be part of the protection mechanism. PMID- 21677838 TI - PAd-shRNA-PTN reduces pleiotrophin of pancreatic cancer cells and inhibits neurite outgrowth of DRG. AB - AIM: To investigate the silencing effects of pAd-shRNA-pleiotrophin (PTN) on PTN in pancreatic cancer cells, and to observe the inhibition of pAd-shRNA-PTN on neurite outgrowth from dorsal root ganglion (DRG) neurons in vitro. METHODS: PAd shRNA-PTN was used to infect pancreatic cancer BxPC-3 cells; assays were conducted for knockdown of the PTN gene on the 0th, 1st, 3rd, 5th, 7th and 9th d after infection using immunocytochemistry, real-time quantitative polymerase chain reaction (PCR), and Western blotting analysis. The morphologic changes of cultured DRG neurons were observed by mono-culture of DRG neurons and co-culture with BXPC-3 cells in vitro. RESULTS: The real-time quantitative PCR showed that the inhibition rates of PTN mRNA expression in the BxPC-3 cells were 20%, 80%, 50% and 25% on the 1st, 3rd, 5th and 7th d after infection. Immunocytochemistry and Western blotting analysis also revealed the same tendency. In contrast to the control, the DRG neurons co-cultured with the infected BxPC-3 cells shrunk; the number and length of neurites were significantly decreased. CONCLUSION: Efficient and specific knockdown of PTN in pancreatic cancer cells and the reduction in PTN expression resulted in the inhibition of neurite outgrowth from DRG neurons. PMID- 21677839 TI - Enhanced proliferation, invasion, and epithelial-mesenchymal transition of nicotine-promoted gastric cancer by periostin. AB - AIM: To investigate the contribution of periostin in nicotine-promoted gastric cancer cell proliferation, survival, invasion, drug resistance, and epithelial mesenchymal transition (EMT). METHODS: Gastric cancer cells were treated with nicotine and periostin protein expression was determined by immunoblotting. Periostin mRNA in gastric cancer cells was silenced using small interfering RNA (siRNA) techniques and periostin gene expression was evaluated by quantitative reverse transcription-polymerase chain reaction. Gastric cancer cells transfected with control or periostin siRNA plasmid were compared in terms of cell proliferation using the methylthiazolyldiphenyl-tetrazolium bromide assay. Cell apoptosis was compared using annexin V-fluoresceine isothiocyanate and propidium iodine double staining. Tumor invasion was determined using the Boyden chamber invasion assay, and the EMT marker Snail expression was evaluated by immunoblotting. RESULTS: Nicotine upregulated periostin in gastric cancer cells through a COX-2 dependent pathway, which was blocked by the COX-2-specific inhibitor NS398. Periostin mRNA expression was decreased by ~87.2% by siRNA in gastric cancer cells, and stable periostin-silenced cells were obtained by G418 screening. Periostin-silenced gastric cancer cells exhibited reduced cell proliferation, elevated sensitivity to chemotherapy with 5-fluorouracil, and decreased cell invasion and Snail expression (P < 0.05). CONCLUSION: Periostin is a nicotine target gene in gastric cancer and plays a role in gastric cancer cell growth, invasion, drug resistance, and EMT facilitated by nicotine. PMID- 21677840 TI - Lower body weight and female gender: hyperphosphatemia risk factors after sodium phosphate preparations. AB - Casais et al have reported an inverse correlation between serum phosphate and body weight after administration of sodium phosphate at a dose of 60 g. Our group has already described the relationship between body weight and hyperphosphatemia with these preparations, although our study was not quoted by Casais. We performed a pharmacokinetic study involving 13 volunteers who were divided into two groups on the basis of body weight: group I consisting of seven women with a median weight of 60 kg and group II consisting of five men and one woman with a median weight of 119.2 kg. Group I developed higher peak phosphate levels and maintained these levels above the subjects in Group II for a prolonged time period despite adequate hydration being ensured with frequent monitoring of weight, fluid intake and total body weight. Our study demonstrated that adequate hydration does not protect against the secondary effects of hyperphosphatemia. In the study by Casais et al, 66% of the study subjects were women, the correlation between serum phosphate and gender in their data also appears to be important. Women are at higher risk of acute phosphate nephropathy due to a diminished volume of distribution of the high dose of ingested phosphate. Decreased volume of distribution in women is due to diminished body weight. This is further compounded by decreased creatinine clearance in females. PMID- 21677841 TI - Partnership working in England-where we are now and where we've come from. AB - INTRODUCTION: Joint working between health and social care has long been a policy priority in England, with growing interest by the previous New Labour government in achieving 'joined-up solutions to joined-up problems'. POLICY/PRACTICE: Against this background, this paper reviews lessons from current and previous partnership initiatives, summarising some of the key approaches adopted and exploring key underlying concepts and frameworks. CONCLUSION: Despite a tendency to focus on structural 'solutions', evidence and experience suggests a series of more important processes, approaches and concepts that might help to promote more effective inter-agency working-including a focus on outcomes, consideration of the depth and breadth of relationship required and the need to work together on different levels. PMID- 21677842 TI - Ten years of integrated care: backwards and forwards. The case of the province of Quebec, Canada. AB - INTRODUCTION: Quebec's rapidly growing elderly and chronically ill population represents a major challenge to its healthcare delivery system, attributable in part to the system's focus on acute care and fragmented delivery. DESCRIPTION OF POLICY PRACTICE: Over the past few years, reforms have been implemented at the provincial policy level to integrate hospital-based, nursing home, homecare and social services in 95 catchment areas. Recent organizational changes in primary care have also resulted in the implementation of family medicine groups and network clinics. Several localized initiatives were also developed to improve integration of care for older persons or persons with chronic diseases. CONCLUSION AND DISCUSSION: Quebec has a history of integration of health and social services at the structural level. Recent evaluations of the current reform show that the care provided by various institutions in the healthcare system is becoming better integrated. The Quebec health care system nevertheless continues to face three important challenges in its management of chronic diseases: implementing the reorganization of primary care, successfully integrating primary and secondary care at the clinical level, and developing effective governance and change management. Efforts should focus on strengthening primary care by implementing nurse practitioners, developing a shared information system, and achieving better collaboration between primary and secondary care. PMID- 21677843 TI - Ten years of jointly commissioning health and social care in England. AB - INTRODUCTION: Over the past two decades, the service delivery landscape across health and social care in England has been reshaped in order to separate the commissioning of services from their delivery. POLICY/PRACTICE: The market ethic that underpinned this move has depicted the previously roles as unresponsive to the needs of service users and dominated by provider interests. As well as seeming to offer commissioners the chance to change the nature of provision and type of provider, this policy model also created a further new opportunity-for joint commissioning across organisational boundaries. The logic here is that if two or more commissioners can jointly shape their programmes then they will be better able to secure integrated provision across a range of separate agencies and professions. CONCLUSION: This article reviews the experience of joint commissioning across health and social care over the past decade in England. It contrasts the proliferation of policies against the paucity of achievements, seeks explanations for this situation, and offers pointers for future development. PMID- 21677844 TI - A decade of integration and collaboration: the development of integrated health care in Sweden 2000-2010. AB - INTRODUCTION: The recent history of integrated health care in Sweden is explored in this article, focusing on the first decade of the 2000s. In addition, there are some reflections about successes and setbacks in this development and challenges for the next decade. DESCRIPTION OF POLICY AND PRACTICE: The first efforts to integrate health care in Sweden appeared in the beginning of the 1990s. The focus was on integration of intra-organisational processes, aiming at a more cost-effective health care provision. Partly as a reaction to the increasing economism at that time, there was also a growing interest in quality improvement. Out of this work emerged the 'chains of care', integrating all health care providers involved in the care of specific patient groups. During the 2000s, many county councils have also introduced inter-organisational systems of 'local health care'. There has also been increasing collaboration between health professionals and other professional groups in different health and welfare services. DISCUSSION AND CONCLUSION: Local health care meant that the chains of care and other forms of integration and collaboration became embedded in a more integrative context. At the same time, however, policy makers have promoted free patient choice in primary health care and also mergers of hospitals and clinical departments. These policies tend to fragment the provision of health care and have an adverse effect on the development of integrated care. As a counterbalance, more efforts should be put into evaluation of integrated health care, in order to replace political convictions with evidence concerning the benefits of such health care provision. PMID- 21677845 TI - Integrated care organizations in Switzerland. AB - INTRODUCTION: The Swiss health care system is characterized by its decentralized structure and high degree of local autonomy. Ambulatory care is provided by physicians working mainly independently in individual private practices. However, a growing part of primary care is provided by networks of physicians and health maintenance organizations (HMOs) acting on the principles of gatekeeping. TOWARDS INTEGRATED CARE IN SWITZERLAND: The share of insured choosing an alternative (managed care) type of basic health insurance and therefore restrict their choice of doctors in return for lower premiums increased continuously since 1990. To date, an average of one out of eight insured person in Switzerland, and one out of three in the regions in north-eastern Switzerland, opted for the provision of care by general practitioners in one of the 86 physician networks or HMOs. About 50% of all general practitioners and more than 400 other specialists have joined a physician networks. Seventy-three of the 86 networks (84%) have contracts with the healthcare insurance companies in which they agree to assume budgetary co responsibility, i.e., to adhere to set cost targets for particular groups of patients. Within and outside the physician networks, at regional and/or cantonal levels, several initiatives targeting chronic diseases have been developed, such as clinical pathways for heart failure and breast cancer patients or chronic disease management programs for patients with diabetes. CONCLUSION AND IMPLICATIONS: Swiss physician networks and HMOs were all established solely by initiatives of physicians and health insurance companies on the sole basis of a healthcare legislation (Swiss Health Insurance Law, KVG) which allows for such initiatives and developments. The relevance of these developments towards more integration of healthcare as well as their implications for the future are discussed. PMID- 21677846 TI - Ten years of integrated care for mental disorders in the Netherlands. AB - BACKGROUND AND PROBLEM STATEMENT: Integrated care for mental disorders aims to encompass forms of collaboration between different health care settings for the treatment of mental disorders. To this end, it requires integration at several levels, i.e. integration of psychiatry in medicine, of the psychiatric discourse in the medical discourse; of localization of mental health care and general health care facilities; and of reimbursement systems. DESCRIPTION OF POLICY PRACTICE: Steps have been taken in the last decade to meet these requirements, enabling psychiatry to move on towards integrated treatment of mental disorder as such, by development of a collaborative care model that includes structural psychiatric consultation that was found to be applicable and effective in several Dutch health care settings. This collaborative care model is a feasible and effective model for integrated care in several health care settings. The Bio Psycho Social System has been developed as a feasible instrument for assessment in integrated care as well. DISCUSSION: The discipline of psychiatry has moved from anti-psychiatry in the last century, towards an emancipated medical discipline. This enabled big advances towards integrated care for mental disorder, in collaboration with other medical disciplines, in the last decade. CONCLUSION: Now is the time to further expand this concept of care towards other mental disorders, and towards integrated care for medical and mental co morbidity. Integrated care for mental disorder should be readily available to the patient, according to his/her preference, taking somatic co-morbidity into account, and with a focus on rehabilitation of the patient in his or her social roles. PMID- 21677847 TI - Progress toward integrating care for seniors in Canada: "We have to skate toward where the puck is going to be, not to where it has been.". AB - INTRODUCTION: Integrating care is a developing feature of provincial health delivery in Canada for those with chronic conditions. The purposes of this project were to review the conceptual understandings underlying integrated care, examine the features of models of cost-effective care for the elderly, and then ascertain to what extent Canadian provinces were implementing these features. METHOD: These goals were accomplished through a review of the integrated care literature followed by a survey of the Canadian provinces. A pretested questionnaire was sent to each of the 10 provincial Ministries of Health in 2008. The questionnaire collected basic background information and then asked a series of open- and close-ended questions about each of the best practice features of integrated care as found in the literature review. RESULTS: System improvements in integrating care for the elderly are being implemented in Canadian provincial health care systems. There has been substantial improvement in the delivery of case management services but the supply of some community services could be improved. As well, the linkages amongst primary, acute and community care remain weak. DISCUSSION AND CONCLUSION: Providing an adequate supply of services is an ongoing issue in many provinces and could be the result of either inadequate funding and/or poor targeting of scarce resources. While it is promising that so many provinces are starting to break down the silos amongst types of health care service providers, much remains to be accomplished. These issues are at the core of integrating care and are among the challenges being faced by other countries. PMID- 21677848 TI - Genome Sequence of Campylobacter jejuni strain 327, a strain isolated from a turkey slaughterhouse. AB - Campylobacter is one of the leading causes of food-borne gastroenteritis and has a high prevalence in poultry. Campylobacter jejuni subsp. jejuni 327 is a subspecies of the genus Campylobacter of the family Campylobacteraceae in the phylum Proteobacteria. The microaerophilic, spiral shaped, catalase positive bacterium obtains energy from the metabolism of amino acids and Krebs cycle intermediates. Strain 327 was isolated from a turkey slaughter production line and is considered environmentally sensitive to food processing (cold, heat, drying) and storage conditions. The 327 whole genome shotgun sequence of 1,618,613 bp long consists of 1,740 protein-coding genes, 46 tRNA genes and 3 rRNA operons. A protein based BLAST analysis places the turkey isolate 327 close to the human clinical strain 81116 (NCTC 11828). PMID- 21677849 TI - Complete genome sequence of Arthrobacter phenanthrenivorans type strain (Sphe3). AB - Arthrobacter phenanthrenivorans is the type species of the genus, and is able to metabolize phenanthrene as a sole source of carbon and energy. A. phenanthrenivorans is an aerobic, non-motile, and Gram-positive bacterium, exhibiting a rod-coccus growth cycle which was originally isolated from a creosote polluted site in Epirus, Greece. Here we describe the features of this organism, together with the complete genome sequence, and annotation. PMID- 21677850 TI - Complete genome sequence of Hydrogenobacter thermophilus type strain (TK-6). AB - Hydrogenobacter thermophilus Kawasumi et al. 1984 is the type species of the genus Hydrogenobacter. H. thermophilus was the first obligate autotrophic organism reported among aerobic hydrogen-oxidizing bacteria. Strain TK-6(T) is of interest because of the unusually efficient hydrogen-oxidizing ability of this strain, which results in a faster generation time compared to other autotrophs. It is also able to grow anaerobically using nitrate as an electron acceptor when molecular hydrogen is used as the energy source, and able to aerobically fix CO(2)via the reductive tricarboxylic acid cycle. This is the fifth completed genome sequence in the family Aquificaceae, and the second genome sequence determined from a strain derived from the original isolate. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 1,742,932 bp long genome with its 1,899 protein-coding and 49 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677851 TI - Complete genome sequence of Riemerella anatipestifer type strain (ATCC 11845). AB - Riemerella anatipestifer (Hendrickson and Hilbert 1932) Segers et al. 1993 is the type species of the genus Riemerella, which belongs to the family Flavobacteriaceae. The species is of interest because of the position of the genus in the phylogenetic tree and because of its role as a pathogen of commercially important avian species worldwide. This is the first completed genome sequence of a member of the genus Riemerella. The 2,155,121 bp long genome with its 2,001 protein-coding and 51 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677852 TI - Complete genome sequence of Marivirga tractuosa type strain (H-43). AB - Marivirga tractuosa (Lewin 1969) Nedashkovskaya et al. 2010 is the type species of the genus Marivirga, which belongs to the family Flammeovirgaceae. Members of this genus are of interest because of their gliding motility. The species is of interest because representative strains show resistance to several antibiotics, including gentamicin, kanamycin, neomycin, polymixin and streptomycin. This is the first complete genome sequence of a member of the family Flammeovirgaceae. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 4,511,574 bp long chromosome and the 4,916 bp plasmid with their 3,808 protein-coding and 49 RNA genes are a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677853 TI - Complete genome sequence of Deinococcus maricopensis type strain (LB-34). AB - Deinococcus maricopensis (Rainey and da Costa 2005) is a member of the genus Deinococcus, which is comprised of 44 validly named species and is located within the deeply branching bacterial phylum Deinococcus-Thermus. Strain LB-34(T) was isolated from a soil sample from the Sonoran Desert in Arizona. Various species of the genus Deinococcus are characterized by extreme radiation resistance, with D. maricopensis being resistant in excess of 10 kGy. Even though the genomes of three Deinococcus species, D. radiodurans, D. geothermalis and D. deserti, have already been published, no special physiological characteristic is currently known that is unique to this group. It is therefore of special interest to analyze the genomes of additional species of the genus Deinococcus to better understand how these species adapted to gamma- or UV ionizing-radiation. The 3,498,530 bp long genome of D. maricopensis with its 3,301 protein-coding and 66 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677854 TI - Complete genome sequence of Desulfurococcus mucosus type strain (O7/1). AB - Desulfurococcus mucosus Zillig and Stetter 1983 is the type species of the genus Desulfurococcus, which belongs to the crenarchaeal family Desulfurococcaceae. The species is of interest because of its position in the tree of life, its ability for sulfur respiration, and several biotechnologically relevant thermostable and thermoactive extracellular enzymes. This is the third completed genome sequence of a member of the genus Desulfurococcus and already the 8(th) sequence from a member the family Desulfurococcaceae. The 1,314,639 bp long genome with its 1,371 protein-coding and 50 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677855 TI - Permanent draft genome sequence of Vibrio tubiashii strain NCIMB 1337 (ATCC19106). AB - Vibrio tubiashii NCIMB 1337 is a major and increasingly prevalent pathogen of bivalve mollusks, and shares a close phylogenetic relationship with both V. orientalis and V. coralliilyticus. It is a Gram-negative, curved rod-shaped bacterium, originally isolated from a moribund juvenile oyster, and is both oxidase and catalase positive. It is capable of growth under both aerobic and anaerobic conditions. Here we describe the features of this organism, together with the draft genome and annotation. The genome is 5,353,266 bp long, consisting of two chromosomes, and contains 4,864 protein-coding and 86 RNA genes. PMID- 21677856 TI - Complete genome sequence of Bacteroides salanitronis type strain (BL78). AB - Bacteroides salanitronis Lan et al. 2006 is a species of the genus Bacteroides, which belongs to the family Bacteroidaceae. The species is of interest because it was isolated from the gut of a chicken and the growing awareness that the anaerobic microflora of the cecum is of benefit for the host and may impact poultry farming. The 4,308,663 bp long genome consists of a 4.24 Mbp chromosome and three plasmids (6 kbp, 19 kbp, 40 kbp) containing 3,737 protein-coding and 101 RNA genes and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677857 TI - Complete genome sequence of Odoribacter splanchnicus type strain (1651/6). AB - Odoribacter splanchnicus (Werner et al. 1975) Hardham et al. 2008 is the type species of the genus Odoribacter, which belongs to the family Porphyromonadaceae in the order 'Bacteroidales'. The species is of interest because members of the Odoribacter form an isolated cluster within the Porphyromonadaceae. This is the first completed genome sequence of a member of the genus Odoribacter and the fourth sequence from the family Porphyromonadaceae. The 4,392,288 bp long genome with its 3,672 protein-coding and 74 RNA genes and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677858 TI - Complete genome sequence of Oceanithermus profundus type strain (506). AB - Oceanithermus profundus Miroshnichenko et al. 2003 is the type species of the genus Oceanithermus, which belongs to the family Thermaceae. The genus currently comprises two species whose members are thermophilic and are able to reduce sulfur compounds and nitrite. The organism is adapted to the salinity of sea water, is able to utilize a broad range of carbohydrates, some proteinaceous substrates, organic acids and alcohols. This is the first completed genome sequence of a member of the genus Oceanithermus and the fourth sequence from the family Thermaceae. The 2,439,291 bp long genome with its 2,391 protein-coding and 54 RNA genes consists of one chromosome and a 135,351 bp long plasmid, and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677859 TI - Complete genome sequence of Cellulophaga lytica type strain (LIM-21). AB - Cellulophaga lytica (Lewin 1969) Johansen et al. 1999 is the type species of the genus Cellulophaga, which belongs to the family Flavobacteriaceae within the phylum 'Bacteroidetes' and was isolated from marine beach mud in Limon, Costa Rica. The species is of biotechnological interest because its members produce a wide range of extracellular enzymes capable of degrading proteins and polysaccharides. After the genome sequence of Cellulophaga algicola this is the second completed genome sequence of a member of the genus Cellulophaga. The 3,765,936 bp long genome with its 3,303 protein-coding and 55 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677860 TI - Non-contiguous finished genome sequence of Bacteroides coprosuis type strain (PC139). AB - Bacteroides coprosuis Whitehead et al. 2005 belongs to the genus Bacteroides, which is a member of the family Bacteroidaceae. Members of the genus Bacteroides in general are known as beneficial protectors of animal guts against pathogenic microorganisms, and as contributors to the degradation of complex molecules such as polysaccharides. B. coprosuis itself was isolated from a manure storage pit of a swine facility, but has not yet been found in an animal host. The species is of interest solely because of its isolated phylogenetic location. The genome of B. coprosuis is already the 5(th) sequenced type strain genome from the genus Bacteroides. The 2,991,798 bp long genome with its 2,461 protein-coding and 78 RNA genes and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. PMID- 21677861 TI - The IGS Standard Operating Procedure for Automated Prokaryotic Annotation. AB - The Institute for Genome Sciences (IGS) has developed a prokaryotic annotation pipeline that is used for coding gene/RNA prediction and functional annotation of Bacteria and Archaea. The fully automated pipeline accepts one or many genomic sequences as input and produces output in a variety of standard formats. Functional annotation is primarily based on similarity searches and motif finding combined with a hierarchical rule based annotation system. The output annotations can also be loaded into a relational database and accessed through visualization tools. PMID- 21677862 TI - Meeting report of the RNA Ontology Consortium January 8-9, 2011. AB - This report summarizes the proceedings of the structure mapping working group meeting of the RNA Ontology Consortium (ROC), held in Kona, Hawaii on January 8 9, 2011. The ROC hosted this workshop to facilitate collaborations among those researchers formalizing concepts in RNA, those developing RNA-related software, and those performing genome annotation and standardization. The workshop included three software presentations, extended round-table discussions, and the constitution of two new working groups, the first to address the need for better software integration and the second to discuss standardization and benchmarking of existing RNA annotation pipelines. These working groups have subsequently pursued concrete implementation of actions suggested during the discussion. Further information about the ROC and its activities can be found at http://roc.bgsu.edu/. PMID- 21677863 TI - A proposal to sequence the genome of a garter snake (Thamnophis sirtalis). AB - Here we develop an argument in support of sequencing a garter snake (Thamnophis sirtalis) genome, and outline a plan to accomplish this. This snake is a common, widespread, nonvenomous North American species that has served as a model for diverse studies in evolutionary biology, physiology, genomics, behavior and coevolution. The anole lizard is currently the only genome sequence available for a non-avian reptile. Thus, the garter snake at this time would be the first available snake genome sequence and as such would provide much needed comparative representation of non-avian reptilian genomes, and would also allow critical new insights for vertebrate comparative genomic studies. We outline the major areas of discovery that the availability of the garter snake genome would enable, and describe a plan for whole-genome sequencing. PMID- 21677864 TI - Enriching public descriptions of marine phages using the Genomic Standards Consortium MIGS standard. AB - In any sequencing project, the possible depth of comparative analysis is determined largely by the amount and quality of the accompanying contextual data. The structure, content, and storage of this contextual data should be standardized to ensure consistent coverage of all sequenced entities and facilitate comparisons. The Genomic Standards Consortium (GSC) has developed the "Minimum Information about Genome/Metagenome Sequences (MIGS/MIMS)" checklist for the description of genomes and here we annotate all 30 publicly available marine bacteriophage sequences to the MIGS standard. These annotations build on existing International Nucleotide Sequence Database Collaboration (INSDC) records, and confirm, as expected that current submissions lack most MIGS fields. MIGS fields were manually curated from the literature and placed in XML format as specified by the Genomic Contextual Data Markup Language (GCDML). These "machine-readable" reports were then analyzed to highlight patterns describing this collection of genomes. Completed reports are provided in GCDML. This work represents one step towards the annotation of our complete collection of genome sequences and shows the utility of capturing richer metadata along with raw sequences. PMID- 21677866 TI - Twenty-five years of service. PMID- 21677865 TI - Data shopping in an open marketplace: Introducing the Ontogrator web application for marking up data using ontologies and browsing using facets. AB - In the future, we hope to see an open and thriving data market in which users can find and select data from a wide range of data providers. In such an open access market, data are products that must be packaged accordingly. Increasingly, eCommerce sellers present heterogeneous product lines to buyers using faceted browsing. Using this approach we have developed the Ontogrator platform, which allows for rapid retrieval of data in a way that would be familiar to any online shopper. Using Knowledge Organization Systems (KOS), especially ontologies, Ontogrator uses text mining to mark up data and faceted browsing to help users navigate, query and retrieve data. Ontogrator offers the potential to impact scientific research in two major ways: 1) by significantly improving the retrieval of relevant information; and 2) by significantly reducing the time required to compose standard database queries and assemble information for further research. Here we present a pilot implementation developed in collaboration with the Genomic Standards Consortium (GSC) that includes content from the StrainInfo, GOLD, CAMERA, Silva and Pubmed databases. This implementation demonstrates the power of ontogration and highlights that the usefulness of this approach is fully dependent on both the quality of data and the KOS (ontologies) used. Ideally, the use and further expansion of this collaborative system will help to surface issues associated with the underlying quality of annotation and could lead to a systematic means for accessing integrated data resources. PMID- 21677867 TI - Differences in learning and study strategies inventory scores between chiropractic students with lower and higher grade point averages. AB - PURPOSE: This pilot study was designed to investigate the relationship between chiropractic students' learning and study strategies and academic performance. Differences in strategic learning between chiropractic students with higher grade points averages (GPAs) and those with lower GPAs have not been previously reported. METHODS: Fifty-seven consenting first-trimester chiropractic students self-administered the Learning and Study Strategies Inventory (LASSI). Differences between high and low GPA groups were evaluated for 10 subtests and three factors using independent samples t-tests. RESULTS: The high GPA group scored significantly higher (p < .05) on LASSI subtests Anxiety, Attitude, Concentration, Motivation, Test Strategies, and Selecting Main Ideas, and on factors Effort-Related Activities and Goal Orientation. No differences between groups were found for subtests Information Processing, Self-Testing, Study Aids, and Time Management or for the Cognitive Activities factor. CONCLUSIONS: The results of this study show that differences in LASSI subtest and factor scores are associated with academic performance. For the participants studied, motivational and affective aspects of strategic learning contributed to higher academic performance, whereas cognitive strategies did not. Higher performing students utilized Effort-Related and Goal Orientation learning strategies at significantly higher levels than lower performing students. The LASSI may be useful in identifying students who could benefit from learning and study skills development. Longitudinal study is recommended to investigate the effects of students' learning and study strategies on different academic content domains as well as the effects of strategic study and learning skills training on academic performance. PMID- 21677868 TI - Collaborative testing: the effect of group formation process on overall student performance. AB - PURPOSE: With increased focus on student preparation for high-stakes licensure exams, there is more interest in alternate forms of content delivery and assessment. This interest has focused on factors within the learning environment that may impact student's course performance and program progress. In this project, the impact of the method of group determination (random assignment vs. student selection) on student performance in a neuroanatomy course within a collaborative testing environment is examined. METHODS: THE COURSE PERFORMANCE OF TWO COHORTS (COHORT ONE: randomized grouping = 80; cohort two: student-selected grouping = 82) were compared. All students completed weekly quizzes within collaborative groups, while completing unit exams individually. The mean sum of both the quiz scores and examination scores were compared. RESULTS: While the two groups differed (Wilks' lambda = 0.211; F = 53.541; df = 10,143; p < .05), no pattern was evident among the assessments (ie, one group did not differ significantly on all quizzes or examinations). In overall quiz performance, the randomized groupings scored significantly higher than the student-selected groups (F = 112.252; df = 1152; p < .05) while no difference was noted relative to overall exam scores (F = 2.672; df = 1152; p > .05). CONCLUSIONS: While the collaborative testing paradigm has been shown to be a valuable learning tool, no differences are apparent in the course performance between students in randomly assigned groups compared to those in student-selected groups. The very nature of random groups may have encouraged students to be proficient in all of the material, whereas students who were allowed to choose their groups may have divided the material among themselves and not become individually proficient in all concepts. PMID- 21677869 TI - Laboratory pre-participation screening examination in a chiropractic college: development, implementation, and results. AB - INTRODUCTION: Chiropractic students often serve as subjects in laboratories where they and their classmates practice examinations, various soft tissue techniques, physiological therapeutic modalities, and active rehabilitation. There are contraindications and risks associated with these procedures. This article describes how a procedure was developed to identify potential health concerns and risks that students may face while serving as subjects or performing procedures in clinical skills laboratories. METHODS: Screening questions and examination procedures were developed through a consensus process. Findings from the screening process determine whether students may engage in full participation or limited participation (precautions) or are prohibited from receiving certain procedures (contraindications). Skills laboratory students and their instructors are informed of any identifiable precautions or contraindications to participation. RESULTS: Since its implementation, precautions regarding delivery of manual therapies were found in 4% of those examined and precautions regarding receiving manual therapies in 11.5%. Contraindications to receiving specified manual therapies were found in 8%, and 4% had contraindications to certain physiological therapeutic modalities. DISCUSSION: Further work is necessary to improve compliance with follow-up regarding diagnosis of conditions revealed or suspected. Future efforts should address how well students adhered to precautions and contraindications, the nature and frequency of injuries sustained within the laboratories, and what specific measures were taken by faculty to help students with special needs. CONCLUSION: This chiropractic college now has a method to describe potential risks, explain rules of laboratory participation, and obtain consent from each student. PMID- 21677870 TI - Training the evidence-based practitioner: university of Western States document on standards and competencies. AB - An important goal of chiropractic clinical education should be to teach specific evidence-based practice (EBP) skills to chiropractic students, interns, and doctors. Using a nominal group process, the authors produced a document similar to the Council of Chiropractic Education standards for clinical competencies that can be used to drive an EBP curriculum. Standard texts and journal articles were consulted to create the standards for this program and each standard and corresponding learning objective was discussed in detail and was then graded by the committee in terms of importance and the level of competency that should be attained. Six standards and 31 learning objectives were generated with the learning objectives being further divided into lists of specific competencies. It is the hope of these authors that by sharing this document it can serve as a comprehensive and detailed seed document for other institutions. PMID- 21677871 TI - Building interprofessional frameworks through educational reform. AB - The North American health care sector is being reformed to enhance collaboration among health care professionals to render patient care and improve outcomes. Changing educational frameworks will play a key role in achieving this goal. It is therefore important to gain an understanding of the application of interprofessional health care education and collaborative models of education. Chiropractic and other health care faculties would need to have an effective understanding and clarification of the characteristics of interprofessional care and its foundation in education from which appropriate educational and curricular models could be developed. PMID- 21677872 TI - World Federation of chiropractic/consortium of European chiropractic educators/association of chiropractic colleges education conference 2010. PMID- 21677873 TI - PDGF-B Can sustain self-renewal and tumorigenicity of experimental glioma-derived cancer-initiating cells by preventing oligodendrocyte differentiation. AB - According to the cancer stem cell (CSC)/cancer-initiating cell hypothesis, glioma development is driven by a subpopulation of cells with unique tumor-regenerating capacity. We have characterized sphere-cultured glioma-derived cancer-initiating cells (GICs) from experimental gliomas induced by platelet-derived growth factor B (PDGF-B) in neonatal Gtv-a Arf(-/-) mice. We found that the GICs can maintain their stem cell-like characteristics in absence of exogenous epidermal growth factor and fibroblast growth factor 2 and that this culture condition was highly selective for tumor-initiating cells where as few as five GICs could induce secondary tumor formation after orthotopic transplantation. Addition of FBS to the medium caused the GICs to differentiate into cells coexpressing glial fibrillary acidic protein and Tuj1, and this differentiation process was reversible, suggesting that the GICs are highly plastic and able to adapt to different environments without losing their tumorigenic properties. On inhibition of virally transduced PDGF-B by small interfering RNA treatment, the GICs stopped proliferating, lost their self-renewal ability, and started to uniformly express CNPase, a marker of oligodendrocyte precursor cells and mature oligodendrocytes. Most importantly, PDGF-B depletion completely abrogated the tumor-initiating capacity of the GICs. Our findings suggest that interfering with PDGF-controlled differentiation could be a therapeutic avenue for patients diagnosed with the PDGF-driven proneural subtype of human glioblastoma. PMID- 21677874 TI - Insulin-like growth factor-dependent proliferation and survival of triple negative breast cancer cells: implications for therapy. AB - Triple-negative breast cancers have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The prevailing view is that targeting the insulin-like growth factor (IGF) signal transduction pathway will not be beneficial for triple-negative breast cancers because their growth is not IGF responsive. The present study investigates the importance of IGFs in the proliferation and survival of triple-negative breast cancer cells. Estrogen and progesterone receptors, HER2, type I IGF, and insulin receptors were measured by Western transfer analysis. The effects of IGF-1 on proliferation were assessed by DNA quantitation and on cell survival by poly (ADP-ribose) polymerase cleavage. The effect of IGF-1 on phosphorylation of the IGF receptors, Akt and mitogen activated protein kinase, was measured by Western transfer analysis. Seven cell lines were identified as models of triple-negative breast cancer and shown to express IGF receptors at levels similar to those present in estrogen-responsive cell lines known to respond to IGFs. IGF-1 increased the proliferation and cell survival of all triple-negative cell lines. Proliferation was attenuated after reduction of type I IGF receptor expression. Cells that express higher levels of receptor were more sensitive to subnanomolar IGF-1 concentrations, but the magnitude of the effects was not correlated simply with the absolute amount or phosphorylation of the IGF receptors, Akt or mitogen-activated protein kinase. These results show that IGFs stimulate cell proliferation and promote cell survival in triple-negative breast cancer cells and warrant investigation of the IGF signal transduction pathway as a therapeutic target for the treatment of triple-negative breast cancer. PMID- 21677875 TI - Targeting of alpha(v)-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer. AB - Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide alpha(v)-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that alpha(v)-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking alpha(v)-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms. PMID- 21677876 TI - Androgen depletion induces senescence in prostate cancer cells through down regulation of Skp2. AB - Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated beta-galactosidase activity, heterochromatin protein 1beta foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells. PMID- 21677877 TI - Trimodal glioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-beta receptor I kinase inhibitor LY2109761. AB - Here we investigate the effects of the novel transforming growth factor-beta receptor I (TGF-betaRI) serine/threonine kinase inhibitor LY2109761 on glioblastoma when combined with the present clinical standard combination regimen radiotherapy and temozolomide (TMZ). Human GBM U87 (methylated MGMT promoter), T98 (unmethylated MGMT promoter), and endothelial cells (HUVECs) were treated with combinations of LY2109761, TMZ, and radiation. We found that LY2109761 reduced clonogenic survival of U87 and T98 cells and further enhanced the radiation-induced anticlonogenicity. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ. Interestingly, as expected, the methylated U87 model was more sensitive to TMZ than the unmethylated T98 model in all experiments, whereas the opposite was found for LY2109761. Moreover, with respect to tumor angiogenesis, while LY2109761 decreased the glioblastoma proliferation index (Ki-67) and the microvessel density (CD31 count), the relative pericyte coverage (alpha-SMA/CD31 ratio) increased in particular after triple therapy, suggesting a vascular normalization effect induced by LY2109761. This normalization could be attributed in part to a decrease in the Ang-2/Ang-1 messenger RNA ratio. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast enhanced magnetic resonance imaging. Together, the data indicate that the addition of a TGF-betaRI kinase inhibitor to the present clinical standard (radiation plus TMZ) has the potential to improve clinical outcome in human glioblastoma, especially in patients with unmethylated MGMT promoter status. PMID- 21677878 TI - Chromosome arm-specific long telomeres: a new clonal event in primary chronic myelogenous leukemia cells. AB - Previous studies demonstrated that critically shortened telomere lengths correlate with the chromosome instability in carcinogenesis. However, little has been noticed regarding the correlation of long telomeres at specific chromosomes with malignant disorders. We studied relative telomere lengths (RTLs) for individual chromosomes using the quantitative fluorescence in situ hybridization technique in a cohort of 32 patients with chronic myeloid leukemia (CML) and 32 normal samples. We found that telomeres at some specific chromosome arms remain well maintained or even lengthened in a high frequency (27/32) of leukemia cases. In particular, 10 chromosome arms, 4q, 5p, 7q, 11p, 13p, 13q, 14p, 15p, 18p, and Xp, with long telomeres were consistently identified in different samples, and six of them (4q, 5p, 13p, 13q, 14p, and Xp) with relatively long telomeres were also observed in normal samples, but they appeared in lower occurrence rate and shorter RTL than in CML samples. Our results strongly indicate the presence of a special leukemia cell population, or a clone, originated from a common progenitor that is characterized with chromosome arm-specific long telomeres. We suggest that relatively long telomeres located at key chromosomes could be preferentially maintained or further elongated during the early stage of malignant transformation. PMID- 21677880 TI - Combined Striatum, Brain Stem, and Optic Nerve Involvement due to Mycoplasma pneumoniae in an Ambulatory Child. AB - In children, Mycoplasma pneumoniae encephalitis has been characterized by acute onset of an encephalopathy associated with extrapyramidal symptoms and symmetric basal ganglia with or without brain stem involvement on magnetic resonance imaging. Our case, showing unilateral optic neuritis, ophthalmoplegia, no extrapyramidal symptoms, and typical striatal involvement on magnetic resonance imaging, broadens the spectrum of varying clinical manifestations of childhood M. pneumoniae-associated encephalopathy. PMID- 21677881 TI - Identification of the occipito-pontine tract using diffusion-tensor fiber tracking in adult-onset adrenoleukodystrophy with topographic disorientation. AB - X-linked adrenoleukodystrophy is a severe and progressive neurodegenerative disease caused by the peroxisomal transporter ATP-binding cassette, subfamily D, member 1 gene mutations. The defect of this gene product results in accumulation of very-long-chain fatty acids in organs and serum, central demyelination, and peripheral axonopathy. Although there are different magnetic resonance (MR) findings which reflect various phenotypes in adrenoleukodystrophy, some cases present with specific symmetrical occipital white-matter lesions. We describe a patient with adult-onset X-linked adrenoleukodystrophy with topographic disorientation, whose brain MR images revealed T2-signal hyperintensity along the occipito-pontine tract and lateral lemnisci, but not in the cortico-spinal tract in the brainstem. The occipito-pontine tract and lateral lemnisci were clearly detected using diffusion-tensor fiber tracking, suggesting that the topographic disorientation of this patient might be related to the occipito-pontine tract. MR tractography can effectively identify the occipito-pontine tract and may help to localize the fibers associated with clinical symptoms. PMID- 21677879 TI - Induction of p21-dependent senescence by an NAE inhibitor, MLN4924, as a mechanism of growth suppression. AB - Cullin-RING ubiquitin ligase (CRL), with its founding member of SKP1-Cullins-F box proteins (SCF) E3 ubiquitin ligase, is the largest family of E3 ligases, which requires cullin neddylation for its activation. Recently, an inhibitor of NEDD8 activating enzyme (NAE), MLN4924, was reported to block cullin neddylation and inactivate CRL/SCF E3, resulting in apoptosis induction and tumor suppression both in vitro and in vivo. We report here that apoptosis is not the sole mechanism by which MLN4924 suppresses tumor cell growth because apoptosis is moderately induced by the drug in some cancer cell lines and drug-induced growth suppression is only partially blocked by a pan-caspase inhibitor, z-VAD. MLN4924 treatment induces the characteristics of senescence phenotypes as evidenced by enlarged and flattened cellular morphology and positive staining of senescence associated beta-Gal. MLN4924-induced senescence is associated with cellular response to DNA damage, triggered by accumulation of DNA-licensing proteins CDT1 and ORC1, as a result of inactivation of CRL/SCF E3s. The senescence occurs in the manner independent of pRB/p16 and p53, but dependent on p21, a known substrate of CRL/SCF E3s and a mediator of senescence, which accumulates on CRL/SCF inactivation by MLN4924. Furthermore, MLN4924-induced senescence is irreversible and coupled with persistent accumulation of p21 and sustained activation of DNA damage response. Our study reveals a novel mechanism of MLN4924 action and showed that MLN4924 could be further developed as an effective anticancer agent by inducing apoptosis and irreversible senescence. PMID- 21677882 TI - Intraoperative changes in idiopathic macular holes by spectral-domain optical coherence tomography. AB - PURPOSE: To examine anatomical changes in idiopathic macular holes during surgery using handheld spectral-domain optical coherence tomography (SD-OCT). METHODS: Five eyes of 5 patients who underwent surgery for the repair of idiopathic macular holes were examined. The surgery included standard 25-gauge, 3-port pars plana vitrectomy, removal of the internal limiting membrane (ILM), fluid-air exchange, and 20% sulfur hexafluoride tamponade. Intraoperative SD-OCT images of the macular holes were obtained after ILM removal and under fluid-air exchange using a handheld SD-OCT. From SD-OCT images, the macular hole base diameter (MHBD) was measured and compared. RESULTS: All macular holes were successfully closed after the primary surgery. The mean MHBD under fluid-air exchange was significantly smaller than the mean MHBD after ILM removal and the preoperative mean MHBD. In 1 eye with a stage 3 macular hole, SD-OCT images revealed that the inner edges of the macular hole touched each other under fluid-air exchange. CONCLUSION: Fluid-air exchange significantly reduced MHBD during surgery to repair macular holes. Fluid-air exchange may be an important step for macular hole closure as it reduces the base diameter of the macular hole. PMID- 21677883 TI - Chronic refractory uveitis in a patient with childhood-onset cyclic neutropenia. AB - We report a rare case of chronic refractory uveitis in a patient with childhood onset cyclic neutropenia (CN). A 19-year-old woman, who had a history of CN beginning at age 2, presented with bilateral chronic nongranulomatous uveitis, complicated cataract, retinal vasculitis, cystoids macular edema, and vitreous hemorrhage. She had recurrent episodes of oral ulcers, tonsillitis, genital ulcers, and folliculitis during neutropenic nadir. After the resumption of granulocyte colony-stimulating factor therapy for her CN, vitreous hemorrhage in both eyes followed. Her eyes were treated with topical corticosteroids, retinal photocoagulation, and cataract surgery. Blood and bone marrow test results confirmed the diagnosis of CN. She also fulfilled the diagnostic criteria of Behcet's disease, though clinical features of her uveitis were dissimilar to those found in that disease. PMID- 21677884 TI - Ultrabiomicroscopic-histopathologic correlations in individuals with autosomal dominant congenital microcoria: three-generation family report. AB - BACKGROUND: Congenital microcoria (CMC) is due to a maldevelopment of the dilator pupillae muscle of the iris, with a pupil diameter of less than 2 mm. It is associated with juvenile open angle glaucoma and myopia. We report on a three generation Mexican-Mestizo family with CMC. The eldest member's iris biopsy proved muscle anomalies. Further, we analyzed novel ultrasound biomicroscopy findings in the family members who did not require surgery. PATIENTS AND METHODS: A 62-year-old woman, her 41-year-old son and her 9-year-old grandson affected with microcoria since birth, documented by clinical examination and ultrasound biomicroscopy. The eldest member underwent phacoemulsification, and a biopsy of the iris and the anterior capsule of the lens was taken. RESULTS: Ultrasound biomicroscopy confirmed the CMC diagnosis showing iris thinning and a pupil diameter of less than 2 mm. Histopathology of the iris showed a significant reduction of smooth muscle cells, but no alterations of the anterior lens capsule. DISCUSSION: Although CMC is a rare disorder, which is due to a maldevelopment of the dilator pupillae muscle of the iris, it could be associated with juvenile open angle glaucoma and myopia; therefore, precise diagnosis is required. Ultrasound biomicroscopy could be a great option to confirm the disorder. PMID- 21677885 TI - Full Thickness Macular Hole Closure after Exchanging Silicone-Oil Tamponade with C(3)F(8) without Posturing. AB - PURPOSE: To report a case of macular hole closure after the exchange of a silicone-oil tamponade with gas C(3)F(8) 14%. METHOD: A 64-year-old female patient with a stage IV macular hole underwent a three-port pars-plana vitrectomy and internal limiting membrane peeling. Due to the patient's chronic illness (respiratory problems), a silicone-oil tamponade was preferred. However, the macula hole was still flat opened four months postoperatively. Therefore, the patient underwent an exchange of silicone oil with gas C(3)F(8) 14%. No face-down position was advised postoperatively due to her health problems. RESULTS: Macular hole closure was confirmed with optical coherence tomography six weeks after exchanging the silicone oil with gas. CONCLUSIONS: Macular hole surgery using a silicone-oil tamponade has been proposed as treatment of choice for patients unable to posture. In our case, the use of a long-acting gas (C(3)F(8) 14%), even without posturing, proved to be more effective. PMID- 21677886 TI - Frosted branch angiitis diagnosed as neuro-behcet: a diagnostic and etiologic dilemma. AB - PURPOSE: To report a case of frosted branch angiitis (FBA) secondary to neuro Behcet. METHODS: Description, diagnosis, angiogram imaging and follow-up of a 28 year-old female with FBA. RESULTS: 'Frosted branch angiitis' is a clinical term applied to three conditions: infiltration of vessels by malignant cells, and sheathing of vessels either secondary to an active disorder or subsequently to a previous inflammatory disease. Our patient's history of two optic neuropathies and the lack of demyelinating signs in neuroimaging made us consider FBA in the context of neuro-Behcet. CONCLUSION: Recognition of the category of FBA from the clinical signs is essential to establish the correct diagnosis and prescribe the appropriate treatment. PMID- 21677887 TI - Disfiguring annular sarcoidosis improved by adalimumab. AB - Depending on the location, dermatoses can produce blemishes that severely impair quality of life and require highly effective treatment that is otherwise used for extensive skin involvement. We report the case of a 39-year-old, otherwise healthy male disfigured by an 8 * 7-cm hypopigmented and centrally atrophic annular plaque with erythematous indurated borders in an area of scar tissue on his forehead. Skin biopsies revealed non-caseating granulomas, and hilar involvement was identified, leading to the diagnosis of systemic sarcoidosis stage II with cutaneous involvement. The lesions proved resistant to multiple therapies, but responded within 4 months to adalimumab with regression of the lesion and inflammatory infiltrate. The visual analogue scale of disease activity decreased from 7/10 to 3.5/10, and the Dermatology Life Quality Index from 16/30 to 3/30 points. In conclusion, TNF-alpha inhibition can control inflammation and disfigurement by cutaneous sarcoidosis and restore quality of life. PMID- 21677888 TI - Peculiar distribution of tumorous xanthomas in an adult case of erdheim-chester disease complicated by atopic dermatitis. AB - Erdheim-Chester disease is a rare non-Langerhans form of histiocytosis with multiple organ involvement. Approximately 20% of patients have xanthoma-like lesions, usually on the eyelids. We report a case of Erdheim-Chester disease in a 32-year-old male who showed peculiar xanthomatous skin lesions and also had atopic dermatitis. His skin manifestations included ring-like yellowish tumors on his periorbital regions, rope necklace-like tumors on his neck, and spindle shaped tumors on his right preauricular region and cubital fossas. He also had exophthalmos and diabetes insipidus. Chronic eczematous lesions were present on the flexor aspect of his extremities, and his serum eosinophil numbers and immunoglobulin E levels were elevated. A histological examination of his right neck tumor showed foamy macrophages and touton-type giant cells, which were positive for CD68 and CD163 and negative for S-100 and CD1a. We suggest that the complication of atopic dermatitis may have contributed to the uncommon clinical features in this case. PMID- 21677889 TI - Rapid Growth of Dermatofibrosarcoma Protuberans Associated with Bilateral Adrenalectomy for Cushing's Syndrome. AB - We describe a 50-year-old Japanese patient with dermatofibrosarcoma protuberans (DFSP) rapidly growing after bilateral adrenalectomy for Cushing's syndrome that reduced the serum level of cortisol from 17.1 to 0.8 mg/dl. It is known that glucocorticoids decrease the transcriptions of the COL1A1 gene and the PDGFB gene, which is under the direct control of the COL1A1 gene in most DFSP. Therefore, the hypersecretion of glucocorticoids in Cushing's syndrome might suppress the development of DFSP. To the best of our knowledge, this is the first case of rapid growth of DFSP that may be associated with bilateral adrenalectomy for Cushing's syndrome. PMID- 21677890 TI - Early start of chemotherapy after resection of primary colon cancer with synchronous multiple liver metastases: a case report. AB - The start of chemotherapy treatment usually requires a delay of about 4 weeks after surgical resection in patients with primary colorectal cancer and synchronous distant metastasis. However, there is no evidence to indicate the required length of this delay interval. In addition, there is a chance that a patient may die because postoperative chemotherapy was not started soon enough and a metastatic tumor was able to develop rapidly. Here, we present a case in which combination chemotherapy with capecitabine and oxaliplatin (XELOX) was started within 1 week after a right hemicolectomy for synchronous multiple liver metastases. To our knowledge, this is the first report of the start of chemotherapy, involving treatments such as folinic acid, fluorouracil, and oxaliplatin (FOLFOX); folinic acid, fluorouracil, and irinotecan (FOLFIRI); and XELOX, within 1 week after a colorectal cancer operation with anastomosis. The findings suggest possible changes in the start time of chemotherapy after surgery in the future. PMID- 21677891 TI - Return from the darkside--Sleep Medicine fellowship training: past, present and future. PMID- 21677892 TI - Truckers drive their own assessment for obstructive sleep apnea: a collaborative approach to online self-assessment for obstructive sleep apnea. AB - BACKGROUND: Commercial motor vehicle drivers are at an increased risk for obstructive sleep apnea (OSA). The Federal Motor Carrier Safety Administration (FMCSA) Medical Review Board has recommended that commercial motor vehicle drivers undergo testing for OSA if they have a positive Berlin Questionnaire or a BMI >= 30 kg/m(2). We developed an online screening tool based on the Berlin Questionnaire for anonymous use by commercial drivers to assess their risk of OSA prior to their required FMCSA physicals. METHODS: We based the survey on the Berlin Sleep Questionnaire. The survey was hosted on the Truckers for a Cause Chapter of Alert Well and Keeping Energetic of the American Sleep Apnea Association (TFAC-AWAKE) organization website, and was promoted through the TFAC's XM radio, word of mouth, and trucking industry press contacts. RESULTS: A total of 595 individuals completed the survey. Of these, 55.9% were positive on the Berlin, 78.3% had either hypertension or obesity, 69.6% were obese, 47.6% had a BMI > 33 kg/m(2), and 20.5% reported falling asleep at stoplights. CONCLUSIONS: Some commercial drivers willingly assess their OSA risk anonymously online, and a majority of those who do so are obese, have positive Berlin screening questionnaires, and would be required to undergo polysomnography if recommendations made to the FMCSA became regulation. In contrast to reported behavior during actual Commercial Driver Medical Examinations physicals, some commercial drivers will report OSA symptoms if it is "safe" to do so. Sleep health professionals need expedient, non-punitive methods to keep commercial motor vehicle drivers healthy and driving and to raise drivers' awareness of the dangers of drowsy driving and unhealthy lifestyles. PMID- 21677893 TI - Driving simulator performance remains impaired in patients with severe OSA after CPAP treatment. AB - STUDY OBJECTIVES: To assess the effectiveness of CPAP treatment in improving 90 minute driving simulator performance in severe OSA patients compared to age/gender matched controls. DESIGN: Driving simulator performance was assessed at baseline and 3 months later, with OSA patients treated with CPAP during the interval. SETTING: University Teaching Hospital. PARTICIPANTS: Patients with severe OSA (n = 11) and control subjects without OSA (n = 9). INTERVENTIONS: CPAP MEASUREMENTS AND RESULTS: Simulator driving parameters of steering deviation, braking reaction time and crashes were measured at baseline and ~3 months follow up. At baseline, OSA subjects demonstrated significantly greater steering deviation compared to controls (mean [95% CI], OSA group, 49.9 cm [43.7 to 56.0 cm] vs control group, 34.9 cm [28.1 to 41.7 cm], p = 0.003). Following ~3 months of CPAP treatment (mean +/- SD 6.0 +/- 1.4 h/night), steering deviation in OSA subjects improved by an average of 3.1 cm (CI, 1.4 to 4.9), p < 0.001, while no significant steering changes were observed in the control group. Despite the improvement, steering deviation in the OSA group remained significantly higher than in controls (OSA group, 46.7 cm [CI, 40.6 to 52.8 cm] vs control group, 36.1 cm [CI, 29.3 to 42.9 cm], p = 0.025). CONCLUSIONS: While driving simulator performance improved after ~3 months of CPAP treatment with high adherence in patients with severe OSA, performance remained impaired compared to control subjects. These results add to the growing body of evidence that some neurobehavioral deficits in patients with severe OSA are not fully reversed by treatment. Further studies are needed to assess causes of residual driving simulator impairment and to determine whether this is associated with persistent elevated real-life accident risk. TRIAL REGISTRATION: Data presented in this manuscript was collected as part of a clinical trial "Experimental Investigations of Driving Impairment in Obstructive Sleep Apnoea" ACTRN12610000009011, http://www.anzctr.org.au/trial_view.aspx?ID=334979 PMID- 21677894 TI - The Relationship between psychomotor vigilance performance and quality of life in obstructive sleep apnea. AB - OBJECTIVE: Patients with obstructive sleep apnea (OSA) commonly have cognitive complaints, particularly in attention, and report decreased quality of life. We examined how vigilance and sustained attention, as assessed by the Psychomotor Vigilance Task (PVT), were related to quality of life after controlling for apnea severity and depression in subjects with OSA. SUBJECTS AND METHODS: Fifty-seven patients with newly diagnosed and untreated OSA had their sleep monitored with polysomnography. Quality of life was assessed by the Short Form-36 health survey questionnaire (SF-36). Mood was assessed by the Center for Epidemiologic Studies Depression (CES-D) Scale. After sleep monitoring and psychological assessments were performed, the 10-minute PVT was administered. The main outcome variables were PVT lapse count and average response time (RT). Simple correlations and multiple linear regression were used to examine the association between PVT performance and age, body mass index, sleep variables, apnea hypopnea index, oxygen desaturation index, and CES-D. RESULTS AND CONCLUSION: Both the PVT lapse count and RT were significantly associated with the SF-36 physical component summary score (PCS). In multiple linear regression, PVT RT was an independent predictor of the SF-36 PCS (full model R(2) = 0.331, p = 0.003). PVT lapse was also an independent predictor of the SF-36 PCS (full model R(2) = 0.320, p = 0.004). However, neither PVT RT nor lapse was a significant independent predictor of the SF-36 mental component summary score (MCS). Only CES-D was an individual predictor of the SF-36 MCS (beta = -0.676, p < 0.001). Impairments in sustained attention and vigilance may underlie the limitations in physical health-related quality of life reported by people with OSA, even after controlling for demographic variables, apnea severity, and depression. PMID- 21677895 TI - A randomized crossover trial of the effect of a novel method of pressure control (SensAwake) in automatic continuous positive airway pressure therapy to treat sleep disordered breathing. AB - OBJECTIVES: To study the acute effect of the new SensAwake CPAP modality (reducing pressure on awakenings) on wake after sleep onset (WASO) and other polysomnographic measures in patients with obstructive sleep apnea (OSA). STUDY DESIGN: Randomized crossover trial comparing an automatic continuous positive airway pressure device (AutoCPAP) with and without SensAwake on sleep architecture. CPAP naive patients received each therapy for a single night in the laboratory with at least 1-week washout. Both patients' and technicians' subjective satisfaction was assessed. Pressure data measured and stored by the AutoCPAP device were also analyzed. RESULTS: OSA was controlled adequately by both modes (SensAwake ON apnea hypopnea index +/- SD, AHI = 5.3 +/- 5.6/h vs. SensAwake OFF = 5.4 +/- 5.8, p = 0.9) in the 42 patients who completed the protocol. Mean and 90% pressures were significantly lower with SensAwake (mean ON = 6.9 +/- 1.9 vs. OFF = 7.7 +/- 2.5 cm H(2)O, p < 0.05; 90% pressure ON = 9.6 +/- 2.7 vs. OFF = 10.6 +/- 2.7 cm H(2)O, p < 0.02). SensAwake did not improve WASO (ON = 74 +/- 54 min vs. OFF = 78 +/- 51 min, p = 0.6). There were no differences in other sleep architecture measures or patient satisfaction between the 2 modalities. AutoCPAP-measured AHI closely approximated PSG-derived (ROC AUC = 0.81 [95% CI 0.71-0.92], p = 0.0001). CONCLUSIONS: SensAwake provides similar control of the AHI to the standard AutoCPAP mode but does so at lower mean and 90% pressures. However, no measure of sleep architecture was significantly improved by the SensAwake mode during this initial acute exposure. The internal AutoCPAP AHI detection and calculation was similar to PSG-derived AHI measures. Longer term studies are needed to evaluate any long-term influence of SensAwake on WASO. PMID- 21677896 TI - Relationship between sleep apnea, fat distribution, and insulin resistance in obese children. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with obesity, inflammation, and insulin resistance. The role of fat distribution in OSA pathogenesis has not been established in children. The objective of the study is to examine the relationship between fat distribution, OSA, and insulin resistance in an unselected population of obese children. METHODS: All obese (BMI > 95th percentile) children (ages 5-18 y) seen at a pediatric obesity clinic were invited to participate. Subjects underwent polysomnography, and were tested for dyslipidemia, inflammation, and insulin resistance measured by the homeostasis model assessment (HOMA). In a subset of subjects, magnetic resonance (MRI) imaging was used to determine the abdominal visceral and subcutaneous adipose tissue areas and magnetic resonance spectroscopy (MRS) spectroscopy was used to intramyocellular lipids in leg muscles. MEASUREMENTS AND MAIN RESULTS: 31 obese subjects enrolled and completed polysomnography and serum testing, and 19 subjects underwent MRI/MRS. The mean age was 12.6 +/- 3.0 y and the mean body mass index (BMI) was 39.5 +/- 11.2 kg/m(2). Forty-eight percent had OSA (mean apnea hypopnea index [AHI] 6.26 +/- 6.77 events/h) Subjects with OSA had significantly increased BMI, log HOMA, triglycerides, and leptin compared to those without OSA. In regression analysis, only BMI z-score was associated with log HOMA. In the subset of patients with imaging data, visceral fat area was strongly predictive of AHI (p = 0.003, r(2) = 0.556). BMI z-score, gender, and age were not predictive. CONCLUSIONS: Visceral fat distribution is independently predictive of OSA severity in obese children. PMID- 21677897 TI - Ramelteon and improved insomnia in alcohol-dependent patients: a case series. AB - In this case series of 5 alcohol-dependent patients with insomnia who had initiated abstinence, a 4-week course of ramelteon 8 mg nightly was associated with markedly improved insomnia scores, increased total sleep time, and decreased time to fall asleep. Given its lack of abuse potential and evidence of low melatonin levels in alcoholism, ramelteon deserves further study as a treatment for insomnia in this group of patients. PMID- 21677898 TI - An e-mail delivered CBT for sleep-health program for college students: effects on sleep quality and depression symptoms. AB - STUDY OBJECTIVES: We examined the effects of a cognitive behavioral self-help program (Refresh) to improve sleep, on sleep quality and symptoms of depression among first-year college students. METHODS: Students in one residence hall (n = 48) participated in Refresh and students in another residence hall (n = 53) participated in a program of equal length (Breathe) designed to improve mood and increase resilience to stress. Both programs were delivered by e-mail in 8 weekly PDF files. Of these, 19 Refresh program participants and 15 Breathe program participants reported poor sleep quality at baseline (scores >= 5 on the Pittsburgh Sleep Quality Index [PSQI]). Participants completed the PSQI and the Center for Epidemiological Studies-Depression Scale (CES-D) at baseline and post intervention. RESULTS: Among students with poor sleep (PSQI > 5) at baseline, participation in Refresh was associated with greater improvements in sleep quality and greater reduction in depressive symptoms than participation in Breathe. Among students with high sleep quality at baseline there was no difference in baseline to post-intervention changes in sleep (PSQI) or depressive symptom severity (CES-D). CONCLUSIONS: A cognitive behavioral sleep improvement program delivered by e-mail may be a cost effective way for students with poor sleep quality to improve their sleep and reduce depressive symptoms. An important remaining question is whether improving sleep will also reduce risk for future depression. PMID- 21677899 TI - A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome. AB - STUDY OBJECTIVE: To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate to-severe primary restless legs syndrome (RLS). METHODS: This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as "very much" or "much" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo. Secondary endpoints included GEn 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF and subjective measures for sleep. Safety and tolerability assessments included adverse events. RESULTS: 325 subjects were randomized (GEn 1200 mg = 113; 600 mg = 115; placebo = 97). GEn 1200 mg significantly improved mean [SD] IRLS total score at Week 12 LOCF (baseline: 23.2 [5.32]; Week 12: 10.2 [8.03]) compared with placebo (baseline: 23.8 [4.58]; Week 12: 14.0 [7.87]; adjusted mean treatment difference [AMTD]: 3.5; p = 0.0015), and significantly more GEn 1200 mg-treated (77.5%) than placebo treated (44.8%) subjects were CGI-I responders (p < 0.0001). Similar significant results were observed with GEn 600 mg for IRLS (AMTD: -4.3; p < 0.0001) and CGI-I (72.8% compared with 44.8%; p < 0.0001). GEn also significantly improved sleep outcomes (Post-Sleep Questionnaire, Pittsburgh Sleep Diary and Medical Outcomes Sleep Scale) compared with placebo. The most commonly reported adverse events were somnolence (GEn 1200 mg = 18.0%; 600 mg = 21.7%; placebo = 2.1%) and dizziness (GEn 1200 mg = 24.3%; 600 mg = 10.4%; placebo = 5.2%). Dizziness increased with increased dose and led to discontinuation in 2 subjects (GEn 1200 mg, n = 1; GEn 600 mg, n = 1). Somnolence led to discontinuation in 3 subjects (GEn 600 mg). CONCLUSIONS: GEn 1200 mg and 600 mg significantly improve RLS symptoms and sleep disturbance compared with placebo and are generally well tolerated. PMID- 21677900 TI - Reward-seeking behavior in human narcolepsy. AB - STUDY OBJECTIVES: The hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing and addiction. Because individuals with narcolepsy with cataplexy have low hypocretin levels, we hypothesized that they may be less prone to risk- and reward-seeking behaviors, including substance abuse. DESIGN: Endpoints were performance on an array of psychometric tests (including the Eysenck Impulsiveness Scale, the Zuckerman Sensation Seeking Scale, the Gormally Binge Eating Scale, and the Beck Depression and Anxiety Inventory) and on the Balloon Analogue Risk Task (BART). SETTING: Tertiary narcolepsy referral centers in Leiden (The Netherlands) and Boston (USA). PATIENTS: Subjects with narcolepsy with cataplexy (n = 30), narcolepsy without cataplexy (n = 15), and controls (n = 32) matched for age, sex, and smoking behavior. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: There was no difference in risk-taking behavior between narcolepsy with or without cataplexy and the control group, as measured using the BART and the array of questionnaires. However, subjects in the narcolepsy with cataplexy group had significantly higher scores on the Eysenck Impulsiveness Scale (p < 0.05), with 10.0% categorized as impulsive, compared to 6.7% of the narcolepsy without cataplexy group and none of the controls. Narcoleptics with cataplexy also scored significantly higher than controls on the Binge Eating Scale (p < 0.05), with moderate or severe binge eating in 23%. On the depression and anxiety scales, all narcolepsy patients, especially those with cataplexy, scored significantly higher than controls. CONCLUSIONS: We found that narcoleptics with or without cataplexy generally have normal risk-taking behavior, but narcoleptics with cataplexy were more impulsive and more prone to binge eating than patients without cataplexy and controls. Our findings shed new light on the relation between sleepiness and impulsiveness. Furthermore, rates of depression and anxiety were higher in all narcoleptic subjects. However, using the current methods, no evidence could be found to support the hypothesis that hypocretin deficiency would affect reward-processing in humans. PMID- 21677902 TI - Compulsion or chronobiology? A case of severe obsessive-compulsive disorder treated with cognitive-behavioral therapy augmented with chronotherapy. AB - OBJECTIVES: Individuals with treatment-resistant obsessive compulsive disorder (OCD) have elevated rates of delayed sleep phase. This report describes a patient with severe OCD who had failed prior trials of pharmacotherapy and psychotherapy, and whose symptoms were associated with delayed bedtimes and delays in the time she initiated her nighttime compulsions. METHODS: Case report. RESULTS: A 54 year old woman with OCD kept sleep/symptom logs as an adjunct to traditional cognitive behavioral therapy for OCD. At presentation, she reported habitual bedtime = 06:00, wake time = 13:00, sleep latency ' 5 min, and total sleep time = 6.5-7.5 h. Later time of initiating her compulsions was associated with longer time performing the compulsions (r = 0.86, p < 0.001). Cognitive-behavioral therapy with adjunctive chronotherapy was associated with substantial improvement. CONCLUSIONS: OCD patients with nighttime compulsions may receive light exposure that results in delayed sleep times/circadian phase. Chronotherapy may enhance outcomes for refractory OCD patients, particularly those who perform compulsions at night. PMID- 21677901 TI - Sleep staging based on autonomic signals: a multi-center validation study. AB - STUDY OBJECTIVES: One of the most important caveats of ambulatory devices is the inability to record and stage sleep. We assessed an algorithm determining 4 different stages: wake, light sleep, deep sleep, and REM sleep using signals derived from the portable monitor Watch-PAT100 (PAT recorder). METHODS: Participants (38 normal subjects and 189 patients with obstructive sleep apnea [OSA]) underwent simultaneous overnight recordings with polysomnography (PSG) and the PAT recorder in a study originally designed to assess the accuracy of the PAT recorder in diagnosing OSA. Light/deep sleep and REM sleep from the PAT recorder recording were automatically scored based on features extracted from time series of peripheral arterial tone amplitudes and inter pulse periods. The PSG scored sleep stages 1 and 2 were classified as light sleep for epoch-by-epoch comparisons. RESULTS: The overall agreement in detecting light/deep and REM sleep were 88.6% +/- 5.9% and 88.7% +/- 5.5%, respectively. There was a good agreement between PSG and the PAT recorder in quantifying sleep efficiency (78.4% +/- 9.9% vs. 78.8% +/- 13.4%), REM latency (237 +/- 148 vs. 225 +/- 159 epochs), and REM percentage (14.4% +/- 6.5% vs. 19.3% +/- 8.7%). OSA severity did not affect the sensitivity and specificity of the algorithm. The Cohen kappa coefficient for detecting all sleep stages: sleep from wake, REM from NREM sleep, and deep from light sleep were 0.48, 0.55, 0.59, and 0.46, respectively. CONCLUSIONS: Analysis of autonomic signals from the PAT recorder can detect sleep stages with moderate agreement to more standard techniques in normal subjects and OSA patients. This novel algorithm may provide insights on sleep and sleep architecture when applying the PAT recorder for OSA diagnosis. PMID- 21677903 TI - Sodium oxybate-induced sleep driving and sleep-related eating disorder. AB - Hypnosedative-induced complex behaviors have gained increased attention in recent years as a potential complication of benzodiazepines and benzodiazepine-receptor agonist use. Sodium oxybate (SO), the sodium salt of gamma-hydroxybutyrate, an inhibitory neurotransmitter, has been associated with dose-dependent rates of somnambulism; however, there is limited information about complex motor behaviors with SO. We describe a patient with narcolepsy-cataplexy who experienced one episode of sleep-driving and at least two sleep-related eating episodes with therapeutic doses of SO. PMID- 21677904 TI - The child's rumbling slumber. PMID- 21677905 TI - Which is the greater sin? Continuing to smoke or non-compliance with CPAP therapy? PMID- 21677906 TI - Smoking is not better for you than sleep apnea. PMID- 21677908 TI - Multimodal coherent anti-Stokes Raman spectroscopic imaging with a fiber optical parametric oscillator. AB - We report on multimodal coherent anti-Stokes Raman scattering (CARS) imaging with a source composed of a femtosecond fiber laser and a photonic crystal fiber (PCF) based optical parametric oscillator (FOPO). By switching between two PCFs with different zero dispersion wavelengths, a tunable signal beam from the FOPO covering the range from 840 to 930 nm was produced. By combining the femtosecond fiber laser and the FOPO output, simultaneous CARS imaging of a myelin sheath and two-photon excitation fluorescence imaging of a labeled axons in rat spinal cord have been demonstrated at the speed of 20 MUs per pixel. PMID- 21677909 TI - Physical fitness training after stroke: time to translate evidence into practice. PMID- 21677910 TI - Service implications of implementing guidance for oral bowel cleansing agents in colonoscopy. AB - INTRODUCTION: Bowel preparation has led to serious adverse events. Consequently, regulatory and advisory bodies have issued guidance,including a risk stratification of patients,aiming to minimise this risk. AIMS: To determine the impact of the new guidance on our current practice of Picolax used in colonoscopy with regard to patient stratification,compliance and service implementation. METHODS: Patients listed for day case colonoscopy during October 2009 were audited using data from the hospital and endoscopy databases. A follow-up, structured patient telephone interview evaluated side effects, the assessment process and patient experience. RESULTS: Of the participating 112 patients, 97.4% were clinically reviewed before colonoscopy,98.3% received written instructions and 70% verbal instructions. None had their preparation dispensed by a regulated professional. Although 62% of patients were retrospectively identified as 'at risk' (elderly, with congestive cardiac failure, cirrhosis or chronic kidney disease or on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics or non-steroidal anti-inflammatory drugs), none were identified before their procedure. Significant events (postural hypotension, collapse, dizziness, palpitations, faint) were seen in 4.4%, all of whom could potentially be identified as 'at risk' using a stratification of low epidermal growth factor receptor with relevant co-morbidity (congestive cardiac failure or cirrhosis). CONCLUSIONS: Given the difficulties with compliance and the high prevalence of 'at risk' patients, the implementation will be challenging and require significant service redesign. PMID- 21677911 TI - Physician involvement enhances coding accuracy to ensure national standards: an initiative to improve awareness among new junior trainees. AB - Record Keeping Standards is a development led by the Royal College of Physicians of London (RCP) Health Informatics Unit and funded by the National Health Service (NHS) Connecting for Health. A supplementary report produced by the RCP makes a number of recommendations based on a study held at an acute hospital trust. We audited the medical notes and coding to assess the accuracy, documentation by the junior doctors and also to correlate our findings with the RCP audit. Northern Lincolnshire & Goole Hospitals NHS Foundation Trust has 114,000 'finished consultant episodes' per year. A total of 100 consecutive medical (50) and rheumatology (50) discharges from Diana Princess of Wales Hospital from August October 2009 were reviewed. The results showed an improvement in coding accuracy (10% errors), comparable to the RCP audit but with 5% documentation errors. Physician involvement needs enhancing to improve the effectiveness and to ensure clinical safety. PMID- 21677912 TI - Endoscopic retrograde cholangio-pancreatography practice in district general hospitals in North East England: a Northern Regional Endoscopy Group (NREG) study. AB - AIM: Endoscopic retrograde cholangio-pancreatography (ERCP) is an important tool for the management of pancreato-biliary disease. The aim of this study was to compare the current practice of ERCP in North East England against the key 2004 National Confidential Enquiry Report into Patient Outcome and Death (NCEPOD) recommendations and the standards set by the Joint Advisory Group on Gastrointestinal Endoscopy (JAG). METHODS: This was a prospective multicentre study involving all hospitals in North East England, coordinated through the Northern Regional Endoscopy Group (NREG). RESULTS: Fourteen endoscopy units submitted data for 481 ERCPs. Mean dose of midazolam was 3.24 mg (standard deviation 1.35; range 1-8 mg). Coagulation profile results were available on 469 patients (97%). Radiological investigations were documented in 96% of the procedures (463 of 481) prior to ERCP. The most common indication for ERCP was related to choledocholithiasis and its complications. All procedures were performed with a therapeutic intent. A total of 84% of all patients were either American Society of Anesthesiologists grade I or II. The selective biliary cannulation rate was 87.3%. The total completion rate of all procedures was 80.2% (381 of 475) and completion of therapy was 89.5% (425 of 475). The 30-day mortality rate was 2% (ten patients) and procedure-related complications occurred in 5% of patients. There were no deaths directly as a result of ERCP; all deaths were related to underlying medical conditions. CONCLUSIONS: The practice of ERCP in North East England adheres to the key recommendations of the NCEPOD and the standards set by JAG. The rates of complications compare favourably with those reported internationally. PMID- 21677914 TI - Monomorphic ventricular tachycardia caused by arsenic trioxide therapy for acute promyelocytic leukaemia. AB - Arsenic trioxide has become the treatment of choice for patients with acute promyelocytic leukaemia. Cardiovascular toxicity is known to occur with this therapy, in particular heart rhythm disorders due to QT interval prolongation. We present a case of ventricular arrhythmia with no QT prolongation in a patient receiving arsenic trioxide therapy. PMID- 21677913 TI - Mycotic aneurysm of the aorta as a complication of Bacillus Calmette-Guerin instillation. AB - Bacillus Calmette-Guerin (BCG) is a live attenuated strain of Mycobacterium bovis that has been widely used for the treatment of superficial transitional cell carcinoma of the bladder. We describe a rare case of supra-renal mycotic aortic aneurysm secondary to BCG instillation in a 75-year-old male. Patients presenting with systemic symptoms post-instillation, possibly with an aneurysm, should raise suspicion of BCG dissemination, which requires early instigation of anti mycobacterial drugs. PMID- 21677915 TI - Diagnosis in diabetes: does it matter? AB - The diagnosis of diabetes subtypes in a busy clinic is usually based on the age at onset, phenotype and biochemical diagnostic criteria. Not surprisingly, the focus is predominantly on diagnosing type 1 and type 2 diabetes. More challenging for the physician is to think of monogenic diabetes, which results from gene mutations that reduce beta cell function. Often misdiagnosed as type 1 or type 2 diabetes, maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, accounting for 1-2% of all diabetes cases. A diagnosis of monogenic diabetes has important implications in treatment, the prediction of disease progression and screening of family members. We highlight two cases of monogenic diabetes, where the diagnosis had significant implications in all the above parameters. This is followed by a discussion on the glucokinase and hepatocyte nuclear factor-1 alpha MODY, which together constitute the most frequent cause of MODY syndromes in all populations. PMID- 21677917 TI - Colon capsule endoscopy for detection of polyps and cancers: a step closer to non invasive colon screening? PMID- 21677916 TI - Boceprevir for previously treated chronic hepatitis C virus genotype 1 infection. PMID- 21677918 TI - Randomised controlled trials: important but overrated? AB - Practising physicians individualise treatments, hoping to achieve optimal outcomes by tackling relevant patient variables. The randomised controlled trial (RCT) is universally accepted as the best means of comparison. Yet doctors sometimes wonder if particular patients might benefit more from treatments that fared worse in the RCT comparisons. Such clinicians may even feel ostracised by their peers for stepping outside treatments based on RCTs and guidelines. Are RCTs the only acceptable evaluations of how patient care can be assessed and delivered? In this controversy we explore the interpretation of RCT data for practising clinicians facing individualised patient choices. First, critical care anaesthetists John Boylan and Brian Kavanagh emphasise the dangers of bias and show how Bayesian approaches utilise prior probabilities to improve posterior (combined) probability estimates. Secondly, Jane Armitage, of the Clinical Trial Service Unit in Oxford, argues why RCTs remain essential and explores how the quality of randomisation can be improved through systematic reviews and by avoiding selective reporting. PMID- 21677919 TI - Non-cystic fibrosis bronchiectasis. AB - Bronchiectasis is a chronic debilitating condition. Pathologically, a vicious cycle of infection and inflammation exists in the permanently damaged airways with patients suffering a persistent cough, chronic daily sputum production and recurrent chest infections. Once termed an 'orphan disease', the prevalence of bronchiectasis has become increasingly recognised over the past few decades. The associated burden of disease in terms of respiratory morbidity, effect on patients' health-related quality of life and the economic cost of long term management is significant and it has become apparent that more research into its causes and management is urgently needed. This article reviews what is currently known about bronchiectasis, its pathophysiology, aetiology and management strategies. PMID- 21677920 TI - Advances in the prevention and treatment of lung cancer. AB - Lung cancer remains the most common fatal malignancy in the Western world. Survival rates have only improved modestly over the past three decades and new approaches are urgently required. It is clear that a concerted effort to reduce cigarette smoking is required. However, about 10% of patients with lung cancer are never smokers, indicating genetic or other predisposition. Lung cancer screening programmes are being trialled to target high-risk populations. Genetic strategies will provide new methods for screening and predicting response to treatment. Current therapy for lung cancer has reached a plateau and novel agents have shown modest clinical efficacy. Understanding the mechanisms by which chronic inflammatory disorders such as chronic obstructive pulmonary disease contribute to lung cancer development will help to identify new biological targets and biomarkers of early disease. This review focuses on recent advances in lung cancer prevention and treatment. PMID- 21677921 TI - Identifying blood biomarkers to improve the diagnosis of stroke. AB - Blood biomarkers are useful for the management of many diseases and could be useful for doctors caring for stroke patients, if they accurately predicted a diagnosis or recurrence of stroke. In a series of studies, we systematically reviewed the blood biomarker literature in stroke, determined the performance of existing blood biomarkers for the diagnosis of stroke and examined the value of markers of inflammation to predict recurrent stroke and myocardial infarction. PMID- 21677922 TI - Better clinical decision making and reducing diagnostic error. AB - A major amount of our time working in clinical practice involves thinking and decision making. Perhaps it is because decision making is such a commonplace activity that it is assumed we can all make effective decisions. However, this is not the case and the example of diagnostic error supports this assertion. Until quite recently there has been a general nihilism about the ability to change the way that we think, but it is now becoming accepted that if we can think about, and understand, our thinking processes we can improve our decision making, including diagnosis. In this paper we review the dual process model of decision making and highlight ways in which decision making can be improved through the application of this model to our day-to-day practice and by the adoption of de biasing strategies and critical thinking. PMID- 21677923 TI - Scottish Intercollegiate Guidelines Network: the first 15 years (1993-2008). AB - The Scottish Intercollegiate Guidelines Network (SIGN) was established in 1993. One of the first national programmes of evidence-based clinical practice guidelines, it has played a lead role internationally in many of the developments in guideline methodology. The challenges faced from the beginning of the organisation up to its integration into the National Health Service and how they were addressed are set out and related to SIGN's contribution to the Scottish tradition of medical education. PMID- 21677924 TI - Egill Skallagrimsson: the first case of Van Buchem disease? AB - Egill Skallagrimsson, a tenth-century Viking, was a colourful warrior poet and an early anti-hero. The thickness and strength of his skull and his very ugly facial features with a prominent mandible have suggested to some authorities that Egill suffered from Paget's disease of bone. However, Paget's bone, while thickened, lacks structural integrity, infrequently involves the mandible and is prone to fractures. The more recent discoveries of sclerosing bone diseases, the elucidation of their pathophysiological abnormalities in intracellular signalling in bones and current research on the sclerostin or LRP5 genes suggest Van Buchem disease as a more probable diagnosis, although the hypothesis remains conjecture in the absence of any of his remains. PMID- 21677925 TI - Scientific surgeon of the Enlightenment or 'plagiarist in everything': a reappraisal of Benjamin Bell (1749-1806). AB - The Edinburgh surgeon Benjamin Bell has been regarded as a scientific thinker in the Enlightenment tradition, despite being accused during his lifetime of both plagiarism and a failure to be innovative. Yet subsequent historical accounts regard him much more favourably. A review of his life and work discusses possible explanations for this apparent lack of concordance. PMID- 21677926 TI - A Venetian edition of Avicenna's works owned by Lonicer: Part I. PMID- 21677927 TI - Antiphospholipid syndrome as cause of cognitive decline or dementia in the elderly. PMID- 21677928 TI - Inherited cancer syndromes should be considered in young patients with newly diagnosed head and neck cancer. PMID- 21677929 TI - Circadian rhythm sleep disorders--a historical perspective. PMID- 21677930 TI - Lord Moran as a biographer of Churchill. PMID- 21677931 TI - Salivary cortisol in the evaluation of incidentalomas. PMID- 21677932 TI - Conformational aspects in the studies of organic compounds by electronic circular dichroism. AB - The electronic circular dichroism (ECD) spectra of flexible molecules include the contributions of all conformers populated at the working temperature. ECD spectra of chiral substrates depend on their stereochemistry in terms of both absolute configuration, as reflected in the sign of the spectrum, and molecular conformation, which dictates the overall spectral shape (possibly including the sign) in a very sensitive manner. The unique high sensitivity of ECD towards conformation, as well as of other chiroptical spectroscopies, renders these techniques a useful alternative or complement to standard spectroscopic tools for conformational investigations, such as NMR. This tutorial review provides first a brief discussion of the main principles of ECD spectroscopy and related methods for interpretation of spectra, with special reference to conformational aspects. The review focuses on the common problems encountered in the application of ECD for assignments of absolute configuration of flexible molecules. These problems can be handled either by taking into account the whole conformational ensemble or by considering rigid derivatives prepared ad hoc. Finally, the review presents the relatively less common but very interesting application of ECD spectroscopy for conformational analyses of organic compounds. PMID- 21677933 TI - Palladium(II)- and platinum(II)phenyl-2,6-bis(oxazole) pincer complexes: syntheses, crystal structures, and photophysical properties. AB - Phenyl-2,6-bis(oxazole) ligands have been explored for the synthesis of novel palladium(II) and platinum(II) pincer complexes. The materials were characterized by spectroscopic methods and by X-ray crystallography. Investigations of the photophysical properties revealed that the lowest triplet states of the materials are largely centred at the bis(oxazole) ligands. The platinum(II) compounds are moderately emissive in fluid solution at ambient temperature. Introduction of both strong donors and strong acceptors leads to a significant red shift of the emission. Due to the facile synthesis of bis(oxazole) based complexes with electronically tuneable oxazole moieties, these materials might be promising alternatives to the well-established phenyl-2,6-bipyridyl systems. PMID- 21677934 TI - The asymmetric Heck and related reactions. AB - The asymmetric inter- and intramolecular Heck and related reactions are comprehensively reviewed, from their original development to recent advances in terms of substrate scope, reactivity, regio- and enantioselectivity. Their reaction mechanisms/catalytic cycles are discussed in order to understand the concepts underpinning the significant recent developments of these processes. The design and application of new chiral ligands has been pivotal to reaction enhancements and, for each Heck and related process, we classify ligands by the nature of the denticity, chirality and donor atoms involved. In this manner, the continued development of ligand architectural design and application can be more easily monitored for each process. Significant improvements in reaction times, a disadvantage in many Heck reactions, have been addressed through a combination the use of microwave-assisted protocols and ligand design. The asymmetric Fujiwara-Moritani and oxidative boron Heck-type reactions, recent additions to Heck type processes, will also be discussed in this critical review (149 references). PMID- 21677935 TI - Mechanochromism of Ag(I) complexes with iPrNHC(S)NHP(S)(OiPr)2. AB - Reaction of the potassium salt of iPrNHC(S)NHP(S)(OiPr)(2) (HL) with AgPF(6) leads to the hexanuclear [{Ag(3)(iPrNHC(S)NP(S)(OiPr)(2)-S,S')(3)}(2)] ([(Ag(3)L(3))(2)]) complex. The reversible conversion between yellow-emitting ([(Ag(3)L(3))(2)]) and blue-emitting ([Ag(3)L(3)]) materials on grinding and recrystallization was established. [Ag(3)L(3)] was also prepared by a mechanically induced solid-state reaction. PMID- 21677936 TI - Tracing sources of coal combustion using stable sulfur isotope ratios in epilithic mosses and coals from China. AB - In China, coal combustion is the most important source of atmospheric sulfur pollution. Moss sulfur isotopic signatures have been believed to hold source specific information that can serve as a fingerprint to identify atmospheric sulfur sources. In cities where only local coals were combusted, we observed a good correspondence of average sulfur isotope ratios in urban mosses (Haplocladium microphyllum) to the values of local coals (delta(coals) = 1.455delta(mosses)- 3.945, R(2) = 0.975, p = 0.01). But if different types of coals were combusted, we did not know whether moss sulfur isotope ratios can indicate mixed coals. To confirm this, using a mixing model we estimated the ratios of imported coal to local coals at cities where both coals were used. We found that the estimated ratios at large cities (>1 million people) where both coals were used were similar to the reported ratios in their respective provinces. For small cities (<0.5 million people) in Jiangxi Province and other provinces, the estimated ratios were higher than the reported ratios because the relatively cheaper local coals were less used in all the small cities except in cities where local coal deposits were found nearby. The comparison results showed that moss sulfur isotope is a useful tool for indicating coal-derived sulfur even in cities where mixed coals were combusted. PMID- 21677937 TI - Microfluidic immunomagnetic multi-target sorting--a model for controlling deflection of paramagnetic beads. AB - We describe a microfluidic system that uses a magnetic field to sort paramagnetic beads by deflecting them in the direction normal to the flow. In the experiments we systematically study the dependence of the beads' deflection on bead size and susceptibility, magnet strength, fluid speed and viscosity, and device geometry. We also develop a design parameter that can aid in the design of microfluidic devices for immunomagnetic multi-target sorting. PMID- 21677938 TI - Improved selectivity in discriminating handedness and diameter of single-walled carbon nanotubes with N-substituted 3,6-carbazolylene-bridged chiral diporphyrin nanotweezers. AB - Chiral diporphyrin nanotweezers 1 consisting of two chiral porphyrins with N substituted 3,6-carbazolylene in between have been studied for the separation of single-walled carbon nanotubes (SWNTs). As compared to the analogous nanotweezers 2 without an N-substitutent, nanotweezers 1 with the N-octylcarbazolylene spacer exhibit much higher extraction ability and better selectivity for SWNTs. A narrower diameter range of SWNTs, from 0.88 to 0.92 nm, was selectively extracted with nanotweezers 1. In addition, only (7,6)-SWNTs of 0.90 nm diameter were optically enriched through extraction with 1, while SWNTs extracted with 2 showed lower optical purity of (7,6)-SWNTs. These enhanced extraction and discrimination abilities of 1 can be attributed to the formation of a more stable SWNT complex of 1 than of 2 in methanol. PMID- 21677939 TI - Recent progress on surface pattern fabrications based on monolayer colloidal crystal templates and related applications. AB - This review summarizes the recent progress toward the fabrication of surface patterns depending on the monolayer colloidal crystal templates. Based on the structural differences of the acquired surface patterns, various synthesis routes are introduced in detail. The diverse device applications of the synthesized surface patterns are also summarized, including sensors, energy-related devices, field emissions, wettability control, and so on. Future research should focus on surface patterns composed of multiple-layered structures and hybrid materials, and the widening of their application explorations. PMID- 21677940 TI - Pd-carbene catalyzed carbonylation reactions of aryl iodides. AB - A series of carbene complexes [PdBr(2)((i)Pr(2)-bimy)L] (C2-C13) with different types of co-ligands (L) have been tested for their catalytic activities in the carbonylative annulation of 2-iodophenol with phenylacetylene in DMF to afford the respective flavone 2a. Complex C12 with an N-phenylimidazole co-ligand showed the best activity and also afforded high yields when the substrate scope was extended to other aryl or pyridyl acetylenes. In addition, catalyst C12 was also efficient in the carbonylative annulation of 2-iodoaniline with acid chlorides giving the desirable 2-substituted 4H-3,1-benzoxazin-4-ones (4) in good yields. Additionally, this Pd-NHC complex also proved to be a very efficient catalyst for the hydroxycarbonylation of iodobenzene derivatives at low catalyst loading and under low CO pressure. These results demonstrate the versatility and efficiency of this phosphine-free Pd(II)-NHC complex in different types of carbonylations of aryl iodides under mild conditions. PMID- 21677941 TI - A statistical approach for the assessment and redesign of the Nile Delta drainage system water-quality-monitoring locations. AB - There are several deficiencies in the statistical approaches proposed in the literature for the assessment and redesign of surface water-quality-monitoring locations. These deficiencies vary from one approach to another, but generally include: (i) ignoring the attributes of the basin being monitored; (ii) handling multivariate water quality data sequentially rather than simultaneously; (iii) focusing mainly on locations to be discontinued; and (iv) ignoring the reconstitution of information at discontinued locations. In this paper, a methodology that overcomes these deficiencies is proposed. In the proposed methodology, the basin being monitored is divided into sub-basins, and a hybrid cluster analysis is employed to identify groups of sub-basins with similar attributes. A stratified optimum sampling strategy is then employed to identify the optimum number of monitoring locations at each of the sub-basin groups. An aggregate information index is employed to identify the optimal combination of locations to be discontinued. The proposed approach is applied for the assessment and redesign of the Nile Delta drainage water quality monitoring locations in Egypt. Results indicate that the proposed methodology allows the identification of (i) the optimal combination of locations to be discontinued, (ii) the locations to be continuously measured and (iii) the sub-basins where monitoring locations should be added. To reconstitute information about the water quality variables at discontinued locations, regression, artificial neural network (ANN) and maintenance of variance extension (MOVE) techniques are employed. The MOVE record extension technique is shown to result in a better performance than regression or ANN for the estimation of information about water quality variables at discontinued locations. PMID- 21677942 TI - Infrared spectromicroscopy of biochemistry in functional single cells. AB - Over the years Fourier-Transform Infrared (FTIR) spectroscopy has been widely employed in the structural and functional characterization of biomolecules. The introduction of infrared (IR) microscopes and of synchrotron light sources has created expectations that FTIR could become a generally viable technique to study both structure and reactivity in vivo, inside single cells, by performing measurements that up to a few years ago were the preserve of in vitro experiments on purified macromolecules. In this review we present the state-of-the-art in the application of FTIR spectromicroscopy as a technique for the study of structure and dynamics in single cells, we discuss the performance requirements for this application and review developments in sample handling methods. PMID- 21677943 TI - Aerosol size distribution and mass concentration measurements in various cities of Pakistan. AB - During March and April 2010 aerosol inventories from four large cities in Pakistan were assessed in terms of particle size distributions (N), mass (M) concentrations, and particulate matter (PM) concentrations. These M and PM concentrations were obtained for Karachi, Lahore, Rawalpindi, and Peshawar from N concentrations using a native algorithm based on the Grimm model 1.109 dust monitor. The results have confirmed high N, M and PM concentrations in all four cities. They also revealed major contributions to the aerosol concentrations from the re-suspension of road dust, from sea salt aerosols, and from vehicular and industrial emissions. During the study period the 24 hour average PM(10) concentrations for three sites in Karachi were found to be 461 MUg m(-3), 270 MUg m(-3), and 88 MUg m(-3), while the average values for Lahore, Rawalpindi and Peshawar were 198 MUg m(-3), 448 MUg m(-3), and 540 MUg m(-3), respectively. The corresponding 24 hour average PM(2.5) concentrations were 185 MUg m(-3), 151 MUg m(-3), and 60 MUg m(-3) for the three sites in Karachi, and 91 MUg m(-3), 140 MUg m(-3), and 160 MUg m(-3) for Lahore, Rawalpindi and Peshawar, respectively. The low PM(2.5)/PM(10) ratios revealed a high proportion of coarser particles, which are likely to have originated from (a) traffic, (b) other combustion sources, and (c) the re-suspension of road dust. Our calculated 24 hour averaged PM(10) and PM(2.5) concentrations at all sampling points were between 2 and 10 times higher than the maximum PM concentrations recommended by the WHO guidelines. The aerosol samples collected were analyzed for crustal elements (Al, Fe, Si, Mg, Ca) and trace elements (B, Ba, Cr, Cu, K, Na, Mn, Ni, P, Pb, S, Sr, Cd, Ti, Zn and Zr). The averaged concentrations for crustal elements ranged from 1.02 +/- 0.76 MUg m( 3) for Si at the Sea View location in Karachi to 74.96 +/- 7.39 MUg m(-3) for Ca in Rawalpindi, and averaged concentrations for trace elements varied from 7.0 +/- 0.75 ng m(-3) for B from the SUPARCO location in Karachi to 17.84 +/- 0.30 MUg m( 3) for Na at the M. A. Jinnah Road location, also in Karachi. PMID- 21677944 TI - A low-voltage electrokinetic nanochannel drug delivery system. AB - Recent work has elucidated the potential of important new therapeutic paradigms, including metronomic delivery and chronotherapy, in which the precise timing and location of therapeutic administration has a significant impact on efficacy and toxicity. New drug delivery architectures are needed to not only release drug continuously at precise rates, but also synchronize their release with circadian cycles. We present an actively controlled nanofluidic membrane that exploits electrophoresis to control the magnitude, duration, and timing of drug release. The membrane, produced using high precision silicon fabrication techniques, has platinum electrodes integrated at the inlet and outlet that allow both amplification and reversal of analyte delivery with low applied voltage (at or below 2 VDC). Device operation was demonstrated with solutions of both fluorescein isothiocyanate conjugated bovine serum albumin and lysozyme using fluorescence spectroscopy, fluorescence microscopy, and a lysozyme specific bio assay and has been characterized for long-term molecular release and release reversibility. Through a combination of theoretical and experimental analysis, the relative contributions of electrophoresis and electroosmosis have been investigated. The membrane's clinically relevant electrophoretic release rate at 2 VDC exceeds the passive release by nearly one order of magnitude, demonstrating the potential to realize the therapeutic paradigm goal. PMID- 21677945 TI - Microfluidics made of yarns and knots: from fundamental properties to simple networks and operations. AB - We present and characterize cotton yarn and knots as building blocks for making microfluidic circuits from the bottom up. The yarn used is made up of 200-300 fibres, each with a lumen. Liquid applied at the extremity of the yarn spontaneously wets the yarn, and the wetted length increases linearly over time in untreated yarn, but progresses according to a square root relationship as described by Washburn's equation upon plasma activation of the yarn. Knots are proposed for combining, mixing and splitting streams of fluids. Interestingly, the topology of the knot controls the mixing ratio of two inlet streams into two outlet yarns, and thus the ratio can be adjusted by choosing a specific knot. The flow resistance of a knot is shown to depend on the force used to tighten it and the flow resistance rapidly increases for single-stranded knots, but remains low for double-stranded knots. Finally, a serial dilutor is made with a web made of yarns and double-stranded overhand knots. These results suggest that yarn and knots may be used to build low cost microfluidic circuits. PMID- 21677970 TI - Silicon-doped hematite nanosheets with superlattice structure. AB - We report a universal strategy for doping hematite photoanode materials. Si-doped hematite nanosheets with a superlattice structure were first synthesised by hydrothermal treatment of a mixture of FeCl(3) agent and liquid phase laser ablation-derived-silicon colloids. The dopant site in Si-doped hematite was clarified at the atomic scale. PMID- 21677946 TI - DNA manipulation with elastomeric nanostructures fabricated by soft-moulding of a FIB-patterned stamp. AB - A Focused Ion Beam (FIB)-patterned silicon mould is used to fabricate elastomeric nanostructures, whose cross-section can be dynamically and reversibly tuned by applying a controlled mechanical stress. Direct-write, based on FIB milling, allows the fabrication of nanostructures with a variety of different geometries, aspect ratio, spacing and distribution offering a higher flexibility compared to other nanopatterning approaches. Moreover, a simple double replication process based on poly(dimethylsiloxane) permits a strong reduction of the fabrication costs that makes this approach well-suited for the production of low cost nanofluidic devices. DNA stretching and single molecule manipulation capabilities of these platforms have been successfully demonstrated. PMID- 21677971 TI - A strategy to design highly efficient porphyrin sensitizers for dye-sensitized solar cells. AB - We designed highly efficient porphyrin sensitizers with two phenyl groups at meso positions of the macrocycle bearing two ortho-substituted long alkoxyl chains for dye-sensitized solar cells; the ortho-substituted devices exhibit significantly enhanced photovoltaic performances with the best porphyrin, LD14, showing J(SC) = 19.167 mA cm(-2), V(OC) = 0.736 V, FF = 0.711, and overall power conversion efficiency eta = 10.17%. PMID- 21677972 TI - Hydrogen bonding and chemical shift assignments in carbazole functionalized isocyanides from solid-state NMR and first-principles calculations. AB - Carbazole functionalized polyisocyanides are known to exhibit excellent electronic properties (E. Schwartz, et al., Chemistry of Materials, 2010, 22, 2597). The functionalities and properties of such materials crucially depend on the organization and stability of the polymer structure. We combine solid-state Nuclear Magnetic Resonance (NMR) experiments with first-principles calculations of isotropic chemical shifts, within the recently developed converse approach, to rationalize the origin of isotropic chemical shifts in the crystalline monomer l isocyanoalanine 2-(9H-carbazol-9-yl) ethyl amide (monomer 1) and thereby gain insight into the structural organization of its polymer (polymer 2). The use of state-of-the-art solid-state NMR experiments combined with Density Functional Theory (DFT) based calculations allows an unambiguous assignment of all proton and carbon resonances of the monomer. We were able to identify the structure stabilising interactions in the crystal and understand the influence of the molecular packing in the crystal structure on the chemical shift data observed in the NMR spectra. Here the Nuclear Independent Chemical Shift (NICS) approach allows discriminating between 'physical' interactions amongst neighboring molecules such as ring-current effects and 'chemical' interactions such as hydrogen bonding. This analysis reveals that the isocyanide monomer is stabilized by multiple hydrogen bonds such as a bifurcated hydrogen bond involving -N-H, -C H and O=C- moieties and Ar-H...C=N- hydrogen bonding (Ar = aromatic group). Based on the geometrical arrangement it is postulated that the carbazole units are involved in the weak sigma-pi interactions giving rise to a Herringbone packing of the molecules. The chemical shift analysis of the polymer spectra readily establishes the existence of N-H...O=C hydrogen bonds despite the limited resolution exhibited by the polymer spectra. It is also elucidated that the relative arrangement of the carbazole units in the polymer differs significantly from that of the monomer. PMID- 21677974 TI - Beyond the Forster formulation for resonance energy transfer: the role of dark states. AB - Resonance Energy Transfer (RET) is investigated in pairs of charge-transfer (CT) chromophores. CT chromophores are an interesting class of pi conjugated chromophores decorated with one or more electron-donor and acceptor groups in polar (D-pi-A), quadrupolar (D-pi-A-pi-D or A-pi-D-pi-A) or octupolar (D(-pi A)(3) or A(-pi-D)(3)) structures. Essential-state models accurately describe low energy linear and nonlinear spectra of CT-chromophores and proved very useful to describe spectroscopic effects of electrostatic interchromophore interactions in multichromophoric assemblies. Here we apply the same approach to describe RET between CT-chromophores. The results are quantitatively validated by an extensive comparison with time-dependent density functional theory (TDDFT) calculations, confirming that essential-state models offer a simple and reliable approach for the calculation of electrostatic interchromophore interactions. This is an important result since it sets the basis for more refined treatments of RET: essential-state models are in fact easily extended to account for molecular vibrations in truly non-adiabatic approaches and to account for inhomogeneous broadening effects due to polar solvation. Optically forbidden (dark) states of quadrupolar and octupolar chromophores offer an interesting opportunity to verify the reliability of the dipolar approximation. In striking contrast with the dipolar approximation that strictly forbids RET towards or from dark states, our results demonstrate that dark states can take an active role in RET with interaction energies that, depending on the relative orientation of the chromophores, can be even larger than those relevant to allowed states. Essential state models, whose predictions are quantitatively confirmed by TDDFT results, allow us to relate RET interaction energies towards allowed and dark states to the supramolecular symmetry of the RET-pair, offering reliable design strategies to optimize RET-interactions. PMID- 21677973 TI - Quantifying the breakdown of the Born-Oppenheimer approximation in surface chemistry. AB - The Born-Oppenheimer Approximation (BOA) forms the basis for calculating electronically adiabatic potential energy surfaces, thus providing the framework for developing a molecular level understanding of a variety of important chemical problems. For surface chemistry at metal surfaces, it is now clear that for some processes electronically nonadiabatic effects can be important, even dominant; however, the magnitude of BOA breakdown may vary widely from one chemical system to another. In this paper we show that molecular-beam surface scattering experiments can be used to derive quantitative information about the magnitude of BOA breakdown. A state-to-state rate model is used to interpret the pre exponential factor of the well-known Arrhenius surface temperature dependence of the electronically nonadiabatic vibrational excitation. We also show that reference to a "thermal limit" provides a quick and simple rule of thumb for quantifying BOA breakdown. We demonstrate this approach by comparing electronically nonadiabatic vibrational inelasticity for NO(nu = 0 -> 1) to NO(nu = 15 ->nu'? 15) and show that the electronically nonadiabatic coupling strengths are of a similar magnitude. We compare experiments for NO and HCl scattering from Au(111) and derive the quantitative relative magnitude for the electronically nonadiabatic influences in each system. The electronically nonadiabatic influences are 300-400 times larger for NO than for HCl, for incidence energies near 0.9 eV. PMID- 21677975 TI - Stabilization of organic field-effect transistors by tert-butyl groups in dibenzotetrathiafulvalene derivatives. AB - For a material for organic thin-film transistors, not only high mobility but also low threshold voltage and long-term stability are important requirements. In order to realize these properties, materials with relatively large oxidation potentials, namely weak donors, have been designed as p-channel organic semiconductors. Here we propose a different strategy; transistor properties of dibenzotetrathiafulvalene (DBTTF) are significantly improved by the introduction of tert-butyl groups. Although this chemical modification does not much change the ionization potential, small threshold voltage and stability over several months are attained together with the improved mobility, probably due to some kind of passivation effect of the bulky tert-butyl groups. In contrast, the systematic fluorine substitution rapidly diminishes the transistor performance. There are two kinds of herringbone structures with much different dihedral angles of about 50 degrees and 130 degrees , and the tert-butyl compound falls into the former category. PMID- 21677976 TI - Do protein-protein interaction databases identify moonlighting proteins? AB - One of the most striking results of the human (and mammalian) genomes is the low number of protein-coding genes. To-date, the main molecular mechanism to increase the number of different protein isoforms and functions is alternative splicing. However, a less-known way to increase the number of protein functions is the existence of multifunctional, multitask, or "moonlighting", proteins. By and large, moonlighting proteins are experimentally disclosed by serendipity. Proteomics is becoming one of the very active areas of biomedical research, which permits researchers to identify previously unseen connections among proteins and pathways. In principle, protein-protein interaction (PPI) databases should contain information on moonlighting proteins and could provide suggestions to further analysis in order to prove the multifunctionality. As far as we know, nobody has verified whether PPI databases actually disclose moonlighting proteins. In the present work we check whether well-established moonlighting proteins present in PPI databases connect with their known partners and, therefore, a careful inspection of these databases could help to suggest their different functions. The results of our research suggest that PPI databases could be a valuable tool to suggest multifunctionality. PMID- 21677977 TI - Catalysis of aptamer-modified AuPd nanoalloy probe and its application to resonance scattering detection of trace UO(2)2+. AB - AuPd nanoalloy and nanopalladium with a diameter of 5 nm were prepared, using sodium citrate as the stabilizing agent and NaBH(4) as the reductant. The nanocatalyst containing palladium on the surface exhibited a strong catalytic effect on the slow NiP particle reaction between NiCl(2) and NaH(2)PO(2), and the NiP particle system showed a resonance scattering (RS) peak at 508 nm. The RS results showed that the Pd atom on AuPd nanoalloy surface is the catalytic center. Combining the aptamer cracking reaction of double-stranded DNA (dsDNA) UO(2)(2+), AuPd nanoalloy aggregation, and AuPd nanoalloy catalysis, both AuPd nanoalloy RS probe and AuPd nanoalloy catalytic RS assays were developed for the determination of 40-250 pmol L(-1) UO(2)(2+) and 5.0-50 pmol L(-1) UO(2)(2+), respectively. PMID- 21677978 TI - pH-controlled reversible drug binding and release using a cytosine-rich hairpin DNA. AB - Here we report that a cytosine-rich DNA carrier, that oscillates between a hairpin and an i-motif structure in its response to pH variation, can be used as a drug binding and release device. PMID- 21677979 TI - Synthesis of non-symmetrically sulphonated phosphine sulphonate based Pd(II) catalyst salts for olefin polymerisation reactions. AB - Direct sulphonation of 2-(diphenylphosphino)benzenesulphonic acid was extensively studied. The non-symmetrically functionalised reaction products obtained, related to the widely applied water soluble phosphine ligands m,m,m-TPPTS and m,m-TPPDS, display chelating kappa(2)-(P,O)-coordination to Pd(II) metal centres. Phase transfer reaction of rac-o,m-TPPDS as the potassium salt with 18-crown-6 and complexation to Pd(II) gives the novel anionic catalyst precursor [K(18-crown 6)](2)[kappa(2)(P,O){rac-o,m-TPPDS}PdMeCl] suitable for olefin polymerisation reactions. Ethene homo- and co-polymerisation reactions with polar functionalised olefins were investigated with this anionic phosphine sulphonate Pd(II)-based pre catalyst salt. PMID- 21677980 TI - Light-controlled smart nanotubes based on the orthogonal assembly of two homopolymers. AB - Two homopolymers can orthogonally self-assemble into pseudo-copolymer based on terminal host-guest interactions, and these supramolecular copolymers further fabricate one-dimensional nanotubes in water. By applying alternate UV/visible light, the aggregates can reversibly assemble and disassemble by means of the association and disassociation of active connection. PMID- 21677981 TI - Non-linear and linear enhancement of enzymatic reaction kinetics using a biomolecule concentrator. AB - In this work we investigate concentration-enhanced enzyme activity assays in nanofluidic biomolecule concentrator chips which can be used to detect and study very low abundance enzymes from cell lysates and other low volume, low concentration samples. A mathematical model is developed for a mode of operation of the assay (J. H. Lee, B. D. Cosgrove, D. A. Lauffenburger and J. Han, J. Am. Chem. Soc., 2009, 131, 10340-10341) in which enzyme and substrate are concentrated together into a plug on chip which results in a non-linear enhancement of the reaction rate. Two reaction phases, an initial quadratic enzyme-limited phase and a later, linear substrate-limited phase, are predicted and then verified with experiments. It is determined that, in most practical situations, the reaction eventually enters a substrate-limited phase, therefore mitigating the concern for non-specific reactions of biosensor substrates with off-target enzymes in such assays. We also use this mode to demonstrate a multiplexed concentration-enhanced enzyme activity assay. We then propose and demonstrate a new device and mode of operation, in which only the enzyme is concentrated and then mixed with a fixed amount of substrate in an adjacent picolitre-scale reaction chamber. This mode results in a linear enhancement of the reaction rate and can be used to perform mechanistic studies on low abundance enzymes after concentrating them into a plug on chip. PMID- 21677982 TI - Health risk assessment of organochlorine pesticides with emphasis on DDTs and HCHs in abandoned agricultural soils. AB - The aim of this study was to evaluate the consequence of changing land use from agriculture land to other use purposes with respect to OCPs non-cancer and cancer risk on human health, based on concentrations of DDTs and HCHs in soils collected from 55 locations representing 12 different land use types. There were no non cancer risks of DDTs and gamma-HCHs on adults and children, and there were very low cancer risks of DDD, o,p'-DDE, DDT, alpha-HCH, beta-HCH, gamma-HCH based on their total concentrations in all samples. Nonetheless, there were significant correlations of DDT to its metabolites (DDE and DDD) (r = 0.506 and r = 0.648) and DDE to DDD (r = 0.438) both at p < 0.01. OCP levels should be routinely monitored in different environmental media and food in order to verify whether there is fresh input. Their potential risks on human health should also be assessed. PMID- 21677983 TI - Kopsihainanines A and B, two unusual alkaloids from Kopsia hainanensis. AB - Kopsihainanine A (1), an unprecedented skeleton with a 6/5/6/6/6 pentacyclic rearranged ring system, together with a new biogenetically related compound, kopsihainanine B (2), were isolated from Kopsia hainanensis. Their structures were elucidated by means of spectroscopic methods. The absolute configuration of 1 was determined by ECD calculation. PMID- 21677984 TI - N-Fmoc-alpha-sulfo-beta-alanine: a versatile building block for the water solubilisation of chromophores and fluorophores by solid-phase strategy. AB - An easy and efficient solid-phase synthesis strategy to obtain rapidly water soluble chromophores/fluorophores in highly pure form has been developed. This first successful use of N-Fmoc-alpha-sulfo-beta-alanine as a SPPS building block opens the way to the future development of promising direct "on-resin" peptide labelling and water-solubilising methods. PMID- 21677985 TI - Investigation of self-immolative linkers in the design of hydrogen peroxide activated metalloprotein inhibitors. AB - A series of self-immolative boronic ester protected methyl salicylates and metal binding groups with various linking strategies have been investigated for their use in the design of matrix metalloproteinase proinhibitors. PMID- 21677987 TI - New environmentally friendly catalysts containing Pd-interstitial carbon made from Pd-glucose precursors for ultraselective hydrogenations in the liquid phase. AB - We report a novel preparation of a Pd nanocatalyst modified with subsurface C via blending a glucose precursor at the molecular level: the catalyst is demonstrated for the first time to be stereoselective in the hydrogenation of alkynes to cis alkenes in the liquid phase. PMID- 21677986 TI - A practical synthesis of Rho-Kinase inhibitor Y-27632 and fluoro derivatives and their evaluation in human pluripotent stem cells. AB - A practical synthesis of the Rho-Kinase inhibitor Y-27632 and two new fluoro derivatives was achieved in seven steps and with a good overall yield of 45% starting from commercially available (R)-1-phenylethylamine. Compared to Y-27632 the new fluoro derivatives showed reduced or no effect on hPSC vitality and expansion after dissociation in human pluripotent stem cells. PMID- 21677988 TI - UV promoted phenanthridine syntheses from oxime carbonate derived iminyl radicals. AB - Oxime carbonates were found to be excellent precursors for the clean and direct generation of iminyl radicals under UV irradiation. Suitably functionalised iminyls underwent cyclisations yielding various phenanthridines and also substituted quinolines and isoquinolines. EPR and X-ray analyses of oxime carbonates provided insight into the mechanism. PMID- 21677989 TI - An enantiopure Fe(III)4 single-molecule magnet. AB - A pair of enantiopure star-shaped Fe(III)(4) clusters were constructed from simple chiral ligands. AC field frequency dependence and a hysteresis loop, which are very important features of SMMs, were observed. Circular dichroism (CD) spectra demonstrated that the chirality was successfully transferred from the ligand to the coordination environment of Fe(3+) ions. PMID- 21677990 TI - Existence of both blue-shifting hydrogen bond and Lewis acid-base interaction in the complexes of carbonyls and thiocarbonyls with carbon dioxide. AB - In this study, 16 gas phase complexes of the pairs of XCHZ and CO(2) (X = F, Cl, Br; Z = O, S) have been identified. Interaction energies calculated at the CCSD(T)/aug-cc-pVTZ//MP2/aug-cc-pVTZ level including both BSSE and ZPE corrections range from -5.6 to -10.5 kJ mol(-1) for XCHOCO(2) and from -5.7 to 9.1 kJ mol(-1) for XCHS...CO(2). Substitution of one H atom by one halogen in formaldehyde and thioformaldehyde reduces the interaction energy of XCHZ...CO(2), while a CH(3) substitution increases the interaction energy of both CH(3)CHO...CO(2) and CH(3)CHS...CO(2). NBO and AIM analyses also point out that the strength of Lewis acid-base interactions decreases going from >C1=S3...C6 to >C1=O3C6 and to >C1-X4...C6. This result suggests the higher capacity of solubility of thiocarbonyl compounds in scCO(2), providing an enormous potential application for designing CO(2)-philic materials based on the >C=S functional group in competition with >C=O. The Lewis acid-base interaction of the types >C=S...C, >C-Cl...C and >C-Br...C is demonstrated for the first time. The contribution of the hydrogen bonding interaction to the total interaction energy is larger for XCHS...CO(2) than for XCHO...CO(2). Upon complexation, a contraction of the C1-H2 bond length and a blue shift of its stretching frequency have been observed, as compared to the isolated monomer, indicating the existence of a blue-shifting hydrogen bond in all complexes examined. Calculated results also lend further support for the viewpoint that when acting as proton donor, a C H bond having a weaker polarization will induce a stronger distance contraction and frequency blue shift upon complexation, and vice versa. PMID- 21677991 TI - Tunable single-site ruthenium catalysts for efficient water oxidation. AB - The catalytic water oxidation activity of mononuclear ruthenium complexes comprising a pyridine-functionalized abnormal triazolylidene ligand can be adjusted by modification of the triazolylidene substituents, which is readily achieved through click-type cycloaddition chemistry, affording some of the most active ruthenium catalysts known thus far for water oxidation (TONs > 400, TOFs close to 7000 h(-1)). PMID- 21677992 TI - Pyrazolinofullerenes: a less known type of highly versatile fullerene derivatives. AB - The cycloaddition of readily available nitrile imines to [60]fullerene affording 2-pyrazolino[60]fullerenes is a versatile procedure for the functionalization of fullerenes. In contrast to other functionalization methods these cycloadducts are obtained generally in good yields as single isomers, thus avoiding the formation of undesired stereoisomers. This tutorial review discusses these less known fullerene compounds that display, however, interesting electrochemical and photophysical properties. Owing to their outstanding electron acceptor character, similar to pristine C(60), and their remarkable thermal stability, these cycloadducts are good candidates for incorporation in photovoltaic devices. However, more work is needed in order to design better pyrazolinofullerenes exhibiting improved performances for PV applications. PMID- 21677993 TI - Lensless imaging for simultaneous microfluidic sperm monitoring and sorting. AB - 5.3 million American couples of reproductive age (9%) are affected by infertility, among which male factors account for up to 50% of cases, which necessitates the identification of parameters defining sperm quality, including sperm count and motility. In vitro fertilization (IVF) with or without intra cytoplasmic sperm injection (ICSI) has become the most widely used assisted reproductive technology (ART) in modern clinical practice to overcome male infertility challenges. One of the obstacles of IVF and ICSI lies in identifying and isolating the most motile and presumably healthiest sperm from semen samples that have low sperm counts (oligozoospermia) and/or low sperm motility (oligospermaesthenia). Microfluidic systems have shown potential to sort sperm with flow systems. However, the small field of view (FOV) of conventional microscopes commonly used to image sperm motion presents challenges in tracking a large number of sperm cells simultaneously. To address this challenge, we have integrated a lensless charge-coupled device (CCD) with a microfluidic chip to enable wide FOV and automatic recording as the sperm move inside a microfluidic channel. The integrated system enables the sorting and tracking of a population of sperm that have been placed in a microfluidic channel. This channel can be monitored in both horizontal and vertical configuration similar to a swim-up column method used clinically. Sperm motilities can be quantified by tracing the shadow paths for individual sperm. Moreover, as the sperm are sorted by swimming from the inlet towards the outlet of a microfluidic channel, motile sperm that reach the outlet can be extracted from the channel at the end of the process. This technology can lead to methods to evaluate each sperm individually in terms of motility response in a wide field of view, which could prove especially useful, when working with oligozoospermic or oligospermaesthenic samples, in which the most motile sperm need to be isolated from a pool of small number of sperm. PMID- 21677994 TI - Complement component C4A and apolipoprotein A-I in plasmas as biomarkers of the severe, early-onset preeclampsia. AB - Preeclampsia is a common pregnancy complication that is associated with maternal perinatal morbidity and mortality. Because of its early onset (before 34 weeks) and the potential for serious outcomes, severe, early-onset preeclampsia (sePE) should be regarded as a different form of preeclampsia. It is an important cause of preterm birth and fetal growth restriction and adverse maternal and neonatal outcomes. As there is no diagnostic test yet available for this disease, we used a proteomic approach to identify novel plasma biomarkers for developing severe, early-onset preeclampsia. We conducted case-control studies comparing nulliparous women with severe preeclampsia requiring delivery prior to 34 weeks of gestation with healthy nulliparous women matched by gestational age at sampling. Plasma was depleted of albumin and IgG and analyzed by two-dimensional gel electrophoresis (2DE). Seven specific plasma proteins for early-onset preeclampsia were detected by mass spectrometry had statistically significant expression differences when compared to controls. The expression of complement component C4A and apolipoprotein A-I were validated by immunoblotting. The complement component C4A in the plasmas of sePE women is lower than the severe, late-onset PE (slPE) women [mean +/- SD; 3.05 +/- 0.14 times reference level (normal/sePE) in sePE women vs. 2.73 +/- 0.10 times reference level (normal/slPE) in slPE women, P < 0.05]. Apolipoprotein A-I is higher in sePE women than slPE women [mean +/- SD; 1.58 +/- 0.14 times reference level (sePE/normal) in sePE women vs. 1.04 +/- 0.16 times reference level (slPE/normal) in slPE women, P < 0.05]. Furthermore, C4A can accurately distinguish severe PE (sePE and slPE) from mild PE (mePE and mlPE) and was proved by the results of ELISA. Further studies have been done to determine the relation between PE and hypoxia. JAR cells were cultured under hypoxia for 72 h. Total cellular proteins were gathered and lysed. Lower C4A and higher apolipoprotein A-I had been observed in JAR of hypoxia conditions than normoxia conditions through western blotting. The result proved that PE is correlated with hypoxia. In summary, C4A and apolipoprotein A-I are able to function as markers to distinguish ePE women from lPE women, and severe PE from mild PE, or perhaps even as disease predictors that might become relevant for diagnostics. PMID- 21677995 TI - Chemical composition, sources, solubility, and transport of aerosol trace elements in a tropical region. AB - Aerosol particle samples (PM10) were collected at urban, industrial and rural sites located in Rio de Janeiro, Brazil, between October 2008 and September 2009. Aerosol samples for each site were analyzed for total and soluble metals, water soluble ions, carboxylic acids, and water-soluble organic carbon (WSOC). The results showed that the mean PM10 concentrations were 34 MUg m(-3); 47 MUg m(-3) and 71 MUg m(-3) at the rural, urban and industrial sites, respectively. An increase in the average concentration of these particles due to air stagnation was observed during the period from May to September for all sites, and an increase in hospitalization for respiratory problems was also reported. On average, the anions species represented 4 to 14% of total content, while cations species corresponded to 1 to 11% and 7.5% for WSOC. The overall metal content at the industrial site was nearly the double that at the rural site. The concentrations of the studied species are influenced mainly by site location and the specific characteristics present at each site. However, higher concentrations of some species were observed on particular dates and were probably due to biomass burning and African dust events. The acid/aqueous percentiles showed that the most efficiently extracted metals from the aqueous phase were V and Ni (40%), while Al and Fe represented a lower percentage (<3%). Analysis of the aqueous fraction provides important information about the bioavailability of metals that is associated with the inflammatory process in the lungs. PMID- 21677996 TI - Striped nanowires and nanorods from mixed SAMS. AB - We investigate the use of mixed self-assembled monolayers (SAMs) for creating nanoscale striped patterns on nanowires and nanorods. Our simulations predict that SAMs comprised of an equal composition of length-mismatched, thermodynamically incompatible surfactants adsorbed on nanowire surfaces self organize into equilibrium stripes of alternating composition always perpendicular, rather than parallel, to the nanowire axis. We support the simulation results with preliminary experimental investigations of gold nanorods coated with binary mixtures of ligand molecules, which show stripes roughly perpendicular to the rod axis in all cases. PMID- 21677997 TI - Eu3+ doped KYF4 nanocrystals: synthesis, electronic structure, and optical properties. AB - Monodisperse cubic-phase KYF(4) : Eu(3+) nanocrystals (NCs) were synthesized via a modified thermal decomposition method. The optical properties of Eu(3+) in KYF(4) NCs including multiple luminescence centers, site symmetry, luminescence dynamics, as well as crystal-field levels of Eu(3+) were investigated in detail based on high-resolution photoluminescence (PL) spectroscopy at low temperature (10 K). Different from Eu(3+) in bulk counterparts, multiple sites of Eu(3+) in KYF(4) NCs were revealed by using the luminescence of Eu(3+) as a sensitive structural probe. The highest site symmetry of Eu(3+) at new near-surface site was deduced to be distorted from O(h) to D(2) (or C(2v)). Due to a small filling factor (0.45) of NCs, the PL lifetime of (5)D(0) of Eu(3+) in KYF(4) NCs was much longer than that in bulk counterparts, which was found to be significantly affected by the surrounding medium around the NCs. PMID- 21677998 TI - Novel alpha-arylnitriles synthesis via Ni-catalyzed cross-coupling of alpha bromonitriles with arylboronic acids under mild conditions. AB - An applicable and easy-handling Ni-catalyst can be used to promote direct arylation of alpha-bromonitriles with various arylboronic acids to construct alpha-arylnitriles under mild conditions. The methodology tolerates beta hydrogens and functional groups in the substrates. PMID- 21677999 TI - World health day 2011: antimicrobial resistance and practical solutions. PMID- 21678000 TI - Putting health risks from radiation exposure into context: lessons from past accidents. PMID- 21678001 TI - Incidence and risk factors for development of new-onset diabetes after kidney transplantation. AB - INTRODUCTION: New-onset diabetes after transplantation (NODAT) is an increasingly recognised metabolic complication of kidney transplantation that is associated with increased morbidity and mortality. This study aimed to determine the incidence of NODAT and identify risk factors for development of NODAT among kidney allograft recipients in a single centre. MATERIALS AND METHODS: We retrospectively reviewed all kidney allograft recipients in our centre between 1998 and 2007. NODAT were determined using criteria as per American Diabetes Association guidelines. Logistic regression analyses were performed to identify predictors of NODAT. RESULTS: Among 388 patients included in the analysis, NODAT was reported in 94 patients (24.2%) after a median follow-up time of 52.1 months. The cumulative incidence of NODAT was 15.8%, 22.8% and 24.5% at 1, 3, and 5 years following transplantation. Seven clinical factors were independent predictors of NODAT: older age, HLA B13 and B15 phenotypes, use of sirolimus, acute rejections, higher pre-transplant and post-transplant (day 1) plasma glucose levels. Patients with NODAT had poorer outcomes in both graft and patient survival. CONCLUSION: Our study demonstrates a significant risk and burden of NODAT in an Asian transplant population. Risk stratification and aggressive monitoring of blood glucose early post-transplantation is necessary to identify high-risk patients so that appropriate tailoring of immunosuppression and early institution of lifestyle modifications can be implemented. PMID- 21678002 TI - Validation of the comprehensive ICF core sets for diabetes mellitus:a Malaysian perspective. AB - INTRODUCTION: Diabetes mellitus (DM) is a chronic disease that is prevalent in many countries. The prevalence of DM is on the rise, and its complications pose a heavy burden on the healthcare systems and on the patients' quality of life worldwide. MATERIALS AND METHODS: This is a multicentre, cross-sectional study involving 5 Health Clinics conducted by Family Medicine Specialists in Malaysia. Convenience sampling of 100 respondents with DM were selected. The International Classifi cation of Functioning, Disability and Health (ICF) based measures were collected using the Comprehensive Core Set for DM. SF-36 and self-administered forms and comorbidity questionnaire (SCQ) were also used. RESULTS: Ninety-seven percent had Type 2 DM and 3% had Type 1 DM. The mean period of having DM was 6 years. Body functions related to physical health including exercise tolerance (b455), general physical endurance (b4550), aerobic capacity (b4551) and fatiguability (b4552) were the most affected. For body structures, the structure of pancreas (s550) was the most affected. In the ICF component of activities and participation, limitation in sports (d9201) was the highest most affected followed by driving (d475), intimate relationships (d770), handling stress and other psychological demands (d240) and moving around (d455). Only 7% (e355 and e450) in the environmental category were documented as being a relevant factor by more than 90% of the patients. CONCLUSION: The content validity of the comprehensive ICF Core set DM for Malaysian population were identified and the results show that physical and mental functioning were impaired in contrast to what the respondents perceived as leading healthy lifestyles. PMID- 21678003 TI - Attenuation of stress-based ventricular contractility in patients with heart failure and normal ejection fraction. AB - INTRODUCTION: The maximal rate of change of pressure-normalised wall stress dsigma*/dtmax has been proposed as cardiac index of left ventricular (LV) contractility. In this study, we assessed the capacity of dsigma*/dtmax to diagnose heart failure with normal ejection fraction (HFNEF). MATERIALS AND METHODS: One hundred healthy normal controls and 140 patients admitted with heart failure (100, HFREF and 40, HFNEF) underwent echocardiography for stress-based contractility dsigma*/dtmax. Patients with signifi cant valvular heart disease were excluded. Tissue Doppler indices were also measured. RESULTS: dsigma*/dtmax was 4.43 +/- 1.27 s-1 in control subjects; reduced in HFNEF, 3.02 +/- 0.98 s-1; and HFREF, 2.00 +/- 0.67 s-1 (P <0.001). In comparison with age- and sex-matched groups (n = 26 each), we found similar trend on reduction of dsigma*/dtmax (normal control; 3.91 +/- 0.87 s-1; HFNEF, 2.90 +/- 0.84 s-1; HFREF, 1.84 +/- 0.59 s-1, P <0.001). On multivariate analysis, dsigma*/dtmax was found to be the independent predictor of HFNEF and HFREF. The area under the curve of the receiver operating characteristics (ROC) in detecting HFNEF compared with normal controls (dsigma*/dtmax>3.2 s-1) was 0.84 (P <0.0001), and in detecting HFREF compared with HFNEF (dsigma*/dtmax>2.32 s-1) was 0.88 (P <0.0001). CONCLUSION: This data confi rms that dsigma*/dtmax on echocardiography is a powerful independent predictor in patients with HFNEF. In a population with a high suspicion of HFNEF, dsigma*/dtmax may significantly contribute to early diagnosis and hence be useful in the triage and management of HFNEF patients. PMID- 21678004 TI - TT genotype of the methylenetetrahydrofolate reductase C677T polymorphism is an important determinant for homocysteine levels in multi-ethnic Malaysian ischaemic stroke patients. AB - INTRODUCTION: The functional point mutation C677T in the methylenetetrahydrofolate reductase (MTHFR) gene, has been reported to contribute to hyperhomocysteinaemia which is a risk factor for atherothrombotic ischaemic strokes. This study evaluated the prevalence of the C677T polymorphism of the gene in Malaysian ischaemic stroke subjects of Malay, Chinese and Indian ethnicities, and its association with homocysteine levels (tHcy). MATERIALS AND METHODS: A total of 292 subjects were recruited, comprising 150 ischaemic stroke patients and 142 control subjects who were age and sex matched. Plasma homocysteine, serum folate and vitamin B12 were measured in all subjects. Genotyping was carried out using PCR-RFLP. RESULTS: The homocysteine levels were significantly higher (P = 0.001) in the stroke group (11.35 +/- 2.75 MUmol/L) compared to the control group (10.38 +/- 2.79 MUmol/L). The MTHFR C677T genotype distribution for the stroke group was 46%, 40% and 14%, respectively for CC, CT and TT genotypes and 59.9%, 33.8% and 6.3%, respectively for the control group. The genotype and allelic frequencies were significantly different between the 2 groups, with P = 0.02 and P = 0.004 respectively. No significant difference was seen in the genotype distribution inter-ethnically. An increasing tHcy was seen with every additional T allele, and the differences in the tHcy for the different genotypes were significant in both the control (P <0.001) and stroke groups (P <0.001). CONCLUSION: This study shows that TT genotype of the methylenetetrahydrofolate reductase C677T polymorphic gene is an important determinant for homocysteine levels in Malaysian ischaemic stroke patients. PMID- 21678005 TI - Solitary fibrous tumour of the rectosigmoid wall: report of a case and review of the literature. PMID- 21678006 TI - Acute subclavian vein thrombosis in a healthy young male. PMID- 21678008 TI - 7th College of Physicians lecture: the changing face of medicine, medicine: past, present and future. PMID- 21678007 TI - A case of biopsy proven acute demyelinating encephalomyelitis (ADEM) with haemorrhagic leucoencephalitis. PMID- 21678009 TI - Burden of end-stage organ failures on quality of life and impact on society. PMID- 21678010 TI - Robotics in gynaecology: a very brief history. PMID- 21678011 TI - Gynaecologic robot-assisted cancer and endoscopic surgery (GRACES) in a tertiary referral centre. AB - INTRODUCTION: Robotic-assisted gynaecologic surgery is gaining popularity and it offers the advantages of laparoscopic surgery whilst overcoming the limitations of operative dexterity. We describe our experience with the fi rst 40 cases operated under the GRACES (Gynaecologic Robot- Assisted Cancer and Endoscopic Surgery) programme at the Department of Obstetrics & Gynecology, National University Hospital, Singapore. MATERIALS AND METHODS: A review was performed for the fi rst 40 women who had undergone robotic surgery, analysing patient characteristics, surgical timings and surgery-related complications. All cases were performed utilising the da Vinci(r) surgical system (Intuitive Surgical, Sunnyvale, CA) with 3 arms and 4 ports. Standardised instrumentation and similar cuff closure techniques were used. RESULTS: Seventeen (56%) were for endometrial cancer and the rest, for benign gynaecological disease. The mean age of the patients was 52.3 years. The average docking time was 11 minutes (SD 0.08). The docking and operative times were analysed in tertiles. Data for patients with endometrial cancer and benign cases were analysed separately. There were 3 cases of complications- cuff dehiscence, bleeding from vaginal cuff and tumour recurrence at vaginal vault. CONCLUSION: Our caseload has enabled us to replicate the learning curve reported by other centres. We advocate the use of a standard instrument set for the fi rst 20 cases. We propose the following sequence for successful introduction of robot-assisted gynaecologic surgery - basic systems training, followed shortly with a clinical case, and progressive development of clinical competence through a proctoring programme. PMID- 21678012 TI - Biomimetic nanostructured materials: potential regulators for osteogenesis? AB - Nanostructured materials are gaining new impetus owing to the advancements in material fabrication techniques and their unique properties (their nanosize, high surface area-to-volume ratio, and high porosity). Such nanostructured materials mimic the subtleties of extracellular matrix (ECM) proteins, creating artifi cial microenvironments which resemble the native niches in the body. On the other hand, the isolation of mesenchymal stem cells (MSCs) from various tissue sources has resulted in the interest to study the multiple differentiation lineages for various therapeutic treatments. In this review, our focus is tailored towards the potential of biomimetic nanostructured materials as osteoinductive scaffolds for bone regeneration to differentiate MSCs towards osteoblastic cell types without the presence of soluble factors. In addition to mimicking the nanostructure of native bone, the supplement of collagen and hydroxyapatite which mimic the main components of the ECM also brings signifi cant advantages to these materials. PMID- 21678013 TI - Enhancement of a master-slave robotic system for natural orifice transluminal endoscopic surgery. AB - INTRODUCTION: A novel robotic platform for Natural Orifice Transluminal Endoscopic Surgery (NOTES) is presented in this paper. It aims to tackle two crucial technical barriers which hinder its smooth transition from animal studies to clinical trials: providing effective instrumentations to perform complex NOTES procedures and maintaining the spatial orientation for endoscopic navigation. MATERIALS AND METHODS: The technical barriers are overcome by the design of the robotic system considering size, triangulation, dexterity, maneuverability and complexity. It is also shown that haptic feedback and interventional navigation system could solve the problem of off-axis manipulation of the camera angle and loss of spatial orientation upon entering the peritoneal cavity in transgastric NOTES procedure, respectively. RESULTS: Successful ESD (endoscopic submucosal dissection) and wedge hepatic resection have been performed on live pigs with our Master And Slave Transluminal Endoscopic Robot (MASTER) system, showing its capability to perform advanced endoscopic surgical and NOTES procedures. It is found that the MASTER exhibited good grasping and cutting efficiency. And the lesion resection time could be significantly reduced with more practice between the endoscopist and the robot operator. CONCLUSION: This study evaluates the feasibility of MASTER system as a platform overcoming the barriers to NOTES. It is also demonstrated that the MASTER could effectively mitigate the technical constraints normally encountered in NOTES procedures. PMID- 21678014 TI - Current technology in navigation and robotics for liver tumours ablation. AB - Radiofrequecy ablation is the most widely used local ablative therapy for both primary and metastatic liver tumours. However, it has limited application in the treatment of large tumours (tumours >3cm) and multicentric tumours. In recent years, many strategies have been developed to extend the application of radiofrequency ablation to large tumours. A promising approach is to take advantage of the rapid advancement in imaging and robotic technologies to construct an integrated surgical navigation and medical robotic system. This paper presents a review of existing surgical navigation methods and medical robots. We also introduce our current developed model - Transcutaneous Robot assisted Ablation-device Insertion Navigation System (TRAINS). The clinical viability of this prototyped integrated navigation and robotic system for large and multicentric tumors is demonstrated using animal experiments. PMID- 21678015 TI - Orthopaedic implant technology: biomaterials from past to future. AB - Orthopaedic implant technology is heavily based on the development and use of biomaterials. These are non-living materials (e.g. metals, polymers and ceramics) that are introduced into the human body as constituents of implants that fulfill or replace some important function. Examples would be prosthetic joint replacements and fracture fixation implants. For orthopaedic biomaterials to succeed in their desired functions and outcomes in the body, a number of factors need to be considered. The most obvious mechanical properties of the implants are that they need to suit their intended function, and various classes and types of biomaterials have been developed and characterised for use in different implant components depending on their demands. Less well understood but no less important are the interactions that occur between the constituent biomaterials and the living cells and tissues, both of the human host as well as pathogens such as bacteria. Biomaterials used for orthopaedic applications are generally considered to be biocompatible. However, adverse effects arising from interactions at the implant interface can result in various modes of implant failure, such as aseptic loosening and implant infection. This review paper uses the illustrative example of total hip replacement (which has been called the operation of the century) to highlight key points in the evolution of orthopaedic biomaterials. It will also examine research strategies that seek to address some of the major problems that orthopaedic implant surgery are facing today. PMID- 21678016 TI - Interface tissue engineering: next phase in musculoskeletal tissue repair. AB - Increasing incidence of musculoskeletal injuries coupled with limitations in the current treatment options have necessitated tissue engineering and regenerative medicine- based approaches. Moving forward from engineering isolated musculoskeletal tissues, research strategies are now being increasingly focused on repairing and regenerating the interfaces between dissimilar musculoskeletal tissues with the aim to achieve seamless integration of engineered musculoskeletal tissues. This article reviews the state-of-the-art in the tissue engineering of musculoskeletal tissue interfaces with a focus on Singapore's contribution in this emerging field. Various biomimetic scaffold and cellbased strategies, the use of growth factors, gene therapy and mechanical loading, as well as animal models for functional validation of the tissue engineering strategies are discussed. PMID- 21678017 TI - Engineering a trans-tibial prosthetic socket for the lower limb amputee. AB - INTRODUCTION: This review addresses the different prosthetic socket designs for trans-tibial amputees, the biomechanics behind the designs and the current state of the field. Of particular focus is the classic patella-tendon bearing (PTB) socket and the more recent sockets manufactured using pressure casting techniques and the theory, biomechanics and clinical implications of the two designs. Methods to examine and compare these designs are also addressed. MATERIALS AND METHODS: Journal papers by various investigators which have clinical significance/impact on the field of trans-tibial socket design were chosen for this review. Articles were chosen over a period of over 50 years to demonstrate the evolution of knowledge. RESULTS: The engineering of the trans-tibial socket has been largely subjected to empirical derivations and biomechanical theory that remains, for the most part, unproven. The fundamental principles of the PTB socket have been widely refuted. Hydrostatic theory based on pressure casting techniques, on the other hand, provides an optimal scenario to produce a more uniform stump/socket interface pressure. CONCLUSION: Preliminary studies indicate the pressure casting technique has the potential to produce comfortable sockets, providing an alternative to the PTB design. Various studies have been attempted to quantitatively compare the 2 types of socket designs. However, further quantitative biomechanical studies are needed to explain the fundamental theory surrounding the pressure cast technique. Methods that could help further understand the pressure cast concept include amputee gait analysis, stump/socket interface pressure measurements, computer aided socket design and finite element modelling techniques. PMID- 21678018 TI - Pregnancy outcomes among female dental personnel--a registry-based retrospective cohort study. AB - OBJECTIVES: The aim of this study was to investigate whether women who have worked as dental personnel in Norway, a group with possible previous exposure to mercury vapor, have had an excess risk of having children with congenital malformations or other adverse pregnancy outcomes compared to the general population. METHODS: A cohort of female dental personnel was identified from the archives of the public dental healthcare and the national trade unions in Norway. Data on births and pregnancy outcomes during 1967-2006 were obtained from the Medical Birth Registry of Norway (MBRN). The final cohort of dental personnel consisted of 4482 dental assistants and 1011 dentists. All other women registered in the MBRN were assigned to the control group, in total 1,124,758. Excess risks of several adverse pregnancy outcomes for dental personnel compared to the general population were estimated. Analyses were conducted for the whole time period as well as stratified by 10-year periods. RESULTS: Female dental personnel had no observed increased occurrence of congenital malformations (including malformations of the central nervous system, dysplasia of the hip, clubfoot, malformations of the heart and great vessels), low birth weight, preterm birth, small for gestational age, changed gender ratio, multiple birth, stillbirth, or prenatal death. CONCLUSION: On a group level, we did not observe any excess risks of congenital malformations or other adverse pregnancy outcomes among female dental personnel in Norway during 1967-2006 compared to the general population. PMID- 21678020 TI - Effects of spatial compatibility on integration processes in graph comprehension. AB - A precondition for efficiently understanding and memorizing graphs is the integration of all relevant graph elements and their meaning. In the present study, we analyzed integration processes by manipulating the spatial compatibility between elements in the data region and the legend. In Experiment 1, participants judged whether bar graphs depicting either statistical main effects or interactions correspond to previously presented statements. In Experiments 2 and 3, the same was tested with line graphs of varying complexity. In Experiment 4, participants memorized line graphs for a subsequent validation task. Throughout the experiments, eye movements were recorded. The results indicated that data-legend compatibility reduced the time needed to understand graphs, as well as the time needed to retrieve relevant graph information from memory. These advantages went hand in hand with a decrease of gaze transitions between the data region and the legend, indicating that data-legend compatibility decreases the difficulty of integration processes. PMID- 21678019 TI - Surface substance loss of subsurface bovine enamel lesions after different steps of the resinous infiltration technique: a 3D topography analysis. AB - Surface substance loss of subsurface enamel lesions before (baseline/demineralization) and after each step of the infiltration technique was evaluated by means of a three-dimensional focus variation. Eighty enamel specimens were prepared and partially varnished (control). Non-varnished areas were demineralized (pH 4.95; 28 days), and etched with phosphoric acid gel (20%; 5 s). Specimens were randomly assigned to eight groups (n = 10), and were infiltrated using four resinous materials. In subgroups 1, polymerization and finishing with abrasive polishing strips followed. In subgroups 2, excess material was removed before polymerization (E1/E2-Excite, Vivadent; F1/F2 Fortify, Bisco; G1/G2-Glaze & Bond, DMG; I1/I2-Icon, DMG). Topometrical evaluation revealed a negligible substance loss of demineralized enamel. After etching, mean (+/-SD) differences of height decreased uniformly (-6.6 +/- 2.0 MUm; p = 0.089; ANOVA). For infiltrated lesions, DH of subgroups 1 was comparable to the etched lesions, with a significant increase (compared to etched lesions) in subgroups 2 (1.1 +/- 0.1 MUm; p < 0.001; t test). Within the limitations of this study, it is concluded that etching of initial subsurface lesions will result in significant surface substance loss; removal of excess material before light-curing should simplify the infiltration procedure, and this will avoid any abrasion resulting from polishing procedures. PMID- 21678021 TI - Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family. AB - To describe the coexistence of mutations of both the multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) genes in a large Italian family and evaluate if it could be associated with more aggressive clinical manifestations of the two syndromes. Blood samples were obtained for genetic and biochemical analyses. The RET gene exons (8, 10, 11, 13, 14, 15, 16, 18) and the MEN1 coding regions, including the exon-intron boundaries, were amplified by PCR and directly sequenced. We identified two germline mutations in the proband: the first one, K666M, located at the exon 11 of RET proto-oncogene and the second one, IVS4+1G>T, located in the MEN1 gene. The functional characterization of IVS4+1G>T variation, located in the splicing donor site of exon 4 of MEN1 gene, caused the in-frame junction of exon 3 to exon 5, thus obtaining a shorter protein. The same proband's germline mutations were found in 16 relatives out of 21 screened subjects: 8 carried IVS4+1G>T, 4 RET K666M, and 4 both the mutations. This is the second report in literature of coexistence in the same family of germline mutations of both RET proto-oncogene and MEN1 gene. The simultaneous presence of the two mutations was not apparently associated with more aggressive diseases, since at last follow-up all patients appeared to be disease-free or well compensated by medical therapy; finally, no one exhibited metastatic diseases. PMID- 21678022 TI - Effect of the silk protein sericin on cryopreserved rat islets. AB - BACKGROUND/PURPOSE: Cryopreservation is necessary for the long-term storage of islet cells and to increase the practicality of clinical islet transplantation. Fetal bovine serum (FBS) supplemented with 10% dimethyl sulfoxide (DMSO) is generally used as a freezing medium for islet cells. However, FBS should ideally be avoided in cell culture and transplantation because of recent animal health problems, such as bovine spongiform encephalopathy and viral infections. The aim of this study was to develop a new serum-free freezing medium by examining the effectiveness of the silk protein sericin, which is produced by Bombyx mori. METHODS: Islets prepared from Lewis rats by collagenase digestion and Histopaque gradient centrifugation, followed by culture in medium containing 0.1% sericin for 3 days, were cryopreserved using 0.1, 0.5, 1, 2, and 5% sericin or FBS. DMSO (1, 4, 7, 10, and 15%) was added to the medium as a cryoprotectant. After thawing, on days 1, 4, 7, and 14, viable islets were counted in order to evaluate their survival. Insulin secretion was measured in vitro by a static incubation test on day 4. The in vivo function of cultured islets was tested by syngeneic transplantation. Islets were evaluated histologically and immunohistochemically after transplantation. RESULTS: There were no significant differences between freezing medium containing 1% sericin and that containing 10% FBS with regard to the survival rate of islets and stimulated insulin secretion. Following transplantation, islets rapidly reversed hyperglycemia and maintained normal glycemic control. In addition, the use of 7% DMSO as a cryoprotectant with sericin showed the same results as higher DMSO concentrations with FBS. CONCLUSION: The present results showed that serum-free medium containing sericin is useful for both cryopreservation and cell culture. PMID- 21678023 TI - Effect of lithium on the electrical properties of polycystin-2 (TRPP2). AB - Polycystin-2 (PC2, TRPP2) is a TRP-type, non-selective cation channel whose dysfunction is implicated in changes in primary cilium structure and genesis of autosomal dominant polycystic kidney disease (ADPKD). Lithium (Li(+)) is a potent pharmaceutical agent whose effect on cell function is largely unknown. In this work, we explored the effect of Li(+) on PC2 channel function. In vitro translated PC2 was studied in a lipid bilayer reconstitution system exposed to different chemical conditions such as Li(+) or K(+) chemical gradients and different symmetrical concentrations of either cation. Li(+) inhibited PC2 function only from the external side, by decreasing the single-channel conductance and modifying the reversal potential consistent with both permeability to and blockage of the channel. When a chemical gradient was imposed, the PC2 single-channel conductance was 144 pS and 107 pS for either K(+) or Li(+), respectively. Data were analysed in terms of the Goldman-Hodgkin-Katz approximation and energy models based on absolute rate theory to understand the mechanism(s) of Li(+) transport and blockage of PC2. The 2S3B model better explained the findings, including saturation, anomalous mole fraction, non linearity of the current-voltage curves under bi-ionic conditions and concentration dependence of permeability ratios. The data indicate that Li(+) modifies PC2 channel function, whose effect unmasks a high-affinity binding site for this ion, and an intrinsic asymmetry in the pore structure of the channel. The findings provide insights into possible mechanism(s) of Li(+) regulation of ciliary length and dysfunction mediated by this cation. PMID- 21678024 TI - Major forest types and the evolution of sustainable forestry in China. AB - In this article, we introduce China's major forest types and discuss the historical development of forest management in China, including actions taken over the last decade toward achieving SMF. Major challenges are identified, and a strategy for SFM implementation in China is presented. China's forests consist of a wide variety of types with distinctive distributional patterns shaped by complex topography and multiple climate regimes. How to manage this wide array of forest resources has challenged forest managers and policy-makers since the founding of the country. Excessive exploitation of China's forest resources from the 1950s to the late 1990s contributed to environmental problems and calamities, such as floods, soil erosion, and desertification. At the start of the new millennium, the Chinese government decided to shift its emphasis from timber production towards the achievement of sustainable forest management (SFM). With a series of endeavors such as the implementation of the "Six Key Forestry Projects" and the reform of forest tenure policies, and the adoption of a classification system for China's forests, a beginning has been made at reversing the trend of environmental degradation that occurred throughout the latter half of the last century. At the same time, huge challenges remain to be tackled for the development of forestry in China. PMID- 21678025 TI - Gender differences in lung cancer mortality trends in Andalusia 1975-2008: a joinpoint regression analysis. AB - Death rates from lung cancer in men are higher in Andalusia than in other Spanish regions. This study describes lung cancer mortality rates and their trends in Andalusia from 1975 through 2008. Data on lung cancer mortality were obtained from the Death Registry of Andalusia. For each gender, age group-specific and standardized (overall and truncated) rates were calculated by the direct method using the world standard population. Joinpoint regression analysis was used to identify points where a significant change in trends occurred. In men, short-term trends for age-standardized mortality rates (ASMRs) declined significantly from 2004 through 2008 for each age group < 80 years old. In women, the segmented joinpoint analysis showed a decrease from 1975 through 1998 in ASMRs (overall) ( 0.6%, P < 0.05), followed by a marked increase (4.6%, P < 0.05). A decrease in male versus female mortality due to lung cancer is evident in Andalusia (Spain). PMID- 21678026 TI - Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection. AB - Tumor-infiltrating lymphocytes (TILs) represent the host immune response to cancer. CD8(+) cytotoxic T cells (CTLs) have a central role in the elimination of tumors, while regulatory T cells (Tregs) can suppress the immune reaction. The aim of this study was to investigate the prognostic value of TILs, especially Tregs and CTLs, in hepatocellular carcinoma (HCC) patients after resection. CD3(+), CD4(+), CD8(+), and FoxP3(+) TILs were assessed by immunohistochemistry in tumor tissue from 141 randomly selected HCC patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Kaplan-Meier and Cox regression analysis using the median values as cutoff. The density of intratumoral Tregs (P = 0.040) and peritumoral CTLs (P = 0.004) were an independent factor for overall survival (OS), but not for disease-free survival (DFS). The density of CD3(+) and CD4(+) TILs, and the prevalence of Tregs and CTLs were associated with neither OS nor DFS. The presence of low intratumoral Tregs with high intratumoral CTLs was a negative independent prognostic factor for OS (P = 0.001), while that of low intratumoral Tregs and low peritumoral CTLs independently correlated with improved DFS (P = 0.008). Moreover, the combined analysis of Tregs and CTLs displayed better prognostic performances than any of them alone. Additionally, higher density of intratumoral Tregs correlated with both the presence of liver cirrhosis (P = 0.025) and increased tumor size (P = 0.050). Tregs within tumor environment are promising prognostic parameters for HCC patients, and their combination with CTLs can predict prognosis more effectively. PMID- 21678027 TI - Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. AB - Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a long non-coding RNA (lncRNA), is up-regulated in many solid tumors and associated with cancer metastasis and recurrence. However, its role in hepatocellular carcinoma (HCC) remains poorly understood. In the present study, we evaluated the expression of MALAT1 by quantitative real-time PCR in 9 liver cancer cell lines and 112 HCC cases including 60 cases who received liver transplantation (LT) with complete follow-up data. Moreover, small interfering RNA (siRNA) was used to inhibit MALAT1 expression to investigate its biological role in tumor progression. We found that MALAT1 was up-regulated in both cell lines and clinical tissue samples. Patients with high expression level of MALAT1 had a significantly increased risk of tumor recurrence after LT, particularly in patients who exceeded the Milan criteria. On multivariate analysis, MALAT1 was an independent prognostic factor for predicting HCC recurrence (hazard ratio, 3.280, P = 0.003).In addition, inhibition of MALAT1 in HepG2 cells could effectively reduce cell viability, motility, invasiveness, and increase the sensitivity to apoptosis. Our data suggest that lncRNA MALAT1 play an important role in tumor progression and could be a novel biomarker for predicting tumor recurrence after LT and serve as a promising therapeutic target. PMID- 21678028 TI - The advent and evolution of QSAR at Pomona College. PMID- 21678029 TI - The effects of priming on a public health campaign targeting cardiovascular risks. AB - Public health interventions are cost-effective methods to reduce heart disease. The present study investigated the impact of a low-cost priming technique on a public health campaign targeting cardiovascular risk. Participants were 415 individuals (66% female) ages 18 and older recruited through clinics and churches. The study consisted of three phases. In Phase I, participants completed a brief survey to assess knowledge of the cardiovascular health indicators. The survey served as the prime (intervention) for the study. At Phase II, participants were provided with access to a public health campaign consisting of an education brochure on cardiovascular health. Following the educational campaign, all participants completed a post-campaign survey in Phase III of the study. Participants who completed the surveys in both Phase I and III were placed in the intervention condition (26%) and those who only completed the Phase III survey were placed in the control condition (74%). Participants who were primed reported greater awareness of the public health campaign. Additionally, more intervention participants reported they had knowledge of their own and the normal ranges for cholesterol, glucose, and body mass index. For participants who were aware of the health promotion campaign, more participants in the primed group indicated they had knowledge of their own cholesterol and glucose levels and had made positive lifestyle changes as a result of the campaign. Results suggest the presence of a priming effect. Public health campaigns may benefit from the inclusion of a low-cost prime prior to intervention. PMID- 21678030 TI - Association of a common variant in TCF7L2 gene with type 2 diabetes mellitus in a Persian population. AB - Diabetes is one of the most common and challenging health problems. Studies in several nations show that polymorphisms within the transcription factor 7-like 2 genes could be associated with type 2 diabetes (T2D). Therefore, a case-control study was conducted to find the association between SNP rs7903146 and T2D in our population. The study consists of 110 patients referring to clinic and 80 healthy controls randomly selected based on WHO guideline. DNA was extracted from blood and genotyped by PCR-RFLP with specific primers to amplify a fragment for restriction enzyme (RsaI). A chi-square test was calculated to compare the proportions of genotypes or alleles. Using a logistic regression model, the odds ratio for risk of developing T2D was calculated with and without adjustment for age, sex, and BMI. The frequency of the T allele of rs7903146 (C/T) polymorphism was significantly higher in diabetic subjects (47.3%) compared to that in normal subjects (34.4%). Logistic regression analysis of the rs7903146 polymorphism showed that the odds ratio was 3.71(95% CI: 1.43-9.56; P: 0.008) for the TT genotype and 1.26 (95% CI: 0.67-2.39; P: 0.516) for the CT genotype when compared with the CC genotype. Odds ratio adjusted for age, sex, and BMI have shown similar results. The results show that rs7903146 of TCF7L2 gene is an important susceptibility gene for T2D mellitus in the province of Isfahan, Iran. Our results support the recent findings that rs7903146 of TCF7L2 gene is an important genetic risk factor for the development of T2D in multiple ethnic groups. PMID- 21678031 TI - Molecular dissection of TDP-43 proteinopathies. AB - TDP-43 has been identified as a major component of ubiquitin-positive tau negative cytoplasmic inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). We raised antibodies to phosphopeptides representing 36 out of 64 candidate phosphorylation sites of human TDP-43 and showed that the antibodies to pS379, pS403/404, pS409, pS410 and pS409/410 labeled the inclusions, but not the nuclei. Immunoblot analyses demonstrated that the antibodies recognized TDP-43 at ~45 kDa, smearing substances and 18-26 kDa C-terminal fragments. Furthermore, the band patterns of the C-terminal fragments differed between neuropathological subtypes, but were indistinguishable between brain regions and spinal cord in each individual patient. Protease treatment of Sarkosyl-insoluble TDP-43 suggests that the different band patterns of the C-terminal fragments reflect different conformations of abnormal TDP-43 molecules between the diseases. These results suggest that molecular species of abnormal TDP-43 are different between the diseases and that they propagate from affected cells to other cells during disease progression and determine the clinicopathological phenotypes of the diseases. PMID- 21678032 TI - Alternative approaches to assessing intervention effectiveness in randomized trials: application in a colorectal cancer screening study. AB - BACKGROUND: Previous analysis of a randomized community-based trial of a multi component intervention to increase colorectal cancer (CRC) screening among Filipino Americans (n = 548) found significantly higher screening rates in the two intervention groups compared to the control group, when using intent-to-treat analysis and self-reported screening as the outcome. This report describes more nuanced findings obtained from alternative approaches to assessing intervention effectiveness to inform future intervention implementation. METHODS: The effect of the intervention on CRC screening receipt during follow-up was estimated using methods that adjusted for biases due to missing data and self-report and for different combinations of intervention components. Adjustment for self-report used data from a validation substudy. Effectiveness within demographic subgroups was also examined. RESULTS: Analyses accounting for self-report bias and missing data supported the effectiveness of the intervention. The intervention was also broadly effective across the demographic characteristics of the sample. Estimates of the intervention effect were highest among participants whose providers received a letter as part of the intervention. CONCLUSIONS: The findings increase confidence that the intervention could be broadly effective at increasing CRC screening in this population. Subgroup analyses and attempts to deconstruct multi component interventions can provide important information for future intervention development, implementation, and dissemination. PMID- 21678033 TI - Body fatness and sex steroid hormone concentrations in US men: results from NHANES III. AB - OBJECTIVE: Obesity is associated with a variety of chronic diseases, including cancer, which may partly be explained by its influence on sex steroid hormone concentrations. Whether different measures of obesity, i.e., body mass index (BMI), waist circumference, and percent body fat were differentially associated with circulating levels of sex steroid hormones was examined in 1,265 men, aged 20-90+ years old, attending the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III). MATERIALS AND METHODS: Serum hormones were measured by immunoassay. Weight, height, and waist circumference were measured by trained staff. Percent body fat was estimated from bioelectrical impedance. Multivariate linear regression was used to estimate associations between body fatness measures and hormone levels. RESULTS: Total and free testosterone and sex hormone binding globulin concentrations decreased, whereas total and free estradiol increased with increasing BMI, waist circumference, and percent body fat (all p trend < 0.05). The magnitude of change in these hormones was similar for a one-quartile increase in each body fatness measure. CONCLUSION: Measured BMI, waist circumference, and percent body fat led to similar inferences about their association with hormone levels in men. PMID- 21678035 TI - From PACS to Web-based ePR system with image distribution for enterprise-level filmless healthcare delivery. AB - The concept of PACS (picture archiving and communication system) was initiated in 1982 during the SPIE medical imaging conference in New Port Beach, CA. Since then PACS has been matured to become an everyday clinical tool for image archiving, communication, display, and review. This paper follows the continuous development of PACS technology including Web-based PACS, PACS and ePR (electronic patient record), enterprise PACS to ePR with image distribution (ID). The concept of large-scale Web-based enterprise PACS and ePR with image distribution is presented along with its implementation, clinical deployment, and operation. The Hong Kong Hospital Authority's (HKHA) integration of its home-grown clinical management system (CMS) with PACS and ePR with image distribution is used as a case study. The current concept and design criteria of the HKHA enterprise integration of the CMS, PACS, and ePR-ID for filmless healthcare delivery are discussed, followed by its work-in-progress and current status. PMID- 21678036 TI - In vitro modelling of cortical neurogenesis by sequential induction of human umbilical cord blood stem cells. AB - Neurogenesis of excitatory neurons in the developing human cerebral neocortex is a complex and dynamic set of processes and the exact mechanisms controlling the specification of human neocortical neuron subtypes are poorly understood due to lack of relevant cell models available. It has been shown that the transcription factors Pax6, Tbr2 and Tbr1, which are sequentially expressed in the rodent neocortex, regulate and define corticogenesis of glutamatergic neocortical neurons. In humans the homologues of these genes are generally expressed in a similar pattern, but with some differences. In this study, we used purified human umbilical cord blood stem cells, expressing pluripotency marker genes (OCT4, SOX2 and NANOG), to model human neocortical neurogenesis in vitro. We analyzed the expression patterns of PAX6, TBR2 and TBR1, at both protein and mRNA levels, throughout the 24 days of a sequential neuronal induction protocol. Their expression patterns correlated with those found in the developing human neocortex where they define different developmental stages of neocortical neurons. The derived cord blood neuron-like cells expressed a number of neuronal markers. They also expressed components of glutamatergic neurotransmission including glutamate receptor subunits and transporters, and generated calcium influxes upon stimulation with glutamate. Thus we have demonstrated that it is possible to model neocortical neurogenesis using cord blood stem cells in vitro. This may allow detailed analysis of the molecular mechanisms regulating neocortical neuronal specification, thus aiding the development of potential therapeutic tools for diseases and injuries of the cerebral cortex. PMID- 21678037 TI - Defective neuromuscular transmission in the SOD1 G93A transgenic mouse improves after administration of human umbilical cord blood cells. AB - To assess the effect of human umbilical cord blood (hUCB) transplantation on neuromuscular transmission in SOD1(G93A) transgenic mice, we studied the probability of neuromuscular transmission (PNMT), a relevant physiological indicator of motor nerve function, in 3 SOD1(G93A) mice transplanted with hUCB and compared to PNMT in 4 SOD1(G93A) mice without cell transplantation and 3 non mutant SOD1 transgenic mice. For preparations isolated from non-mutant SOD1 transgenic mice, PNMT was 0.93 and 0.84 during the first 5 s of 70 and 90 Hz trains, respectively. PNMT gradually declined to 0.77 and 0.42 at the end of the trains. In striking contrast, PNMT for preparations from non-treated mutant SOD1(G93A) mice was 0.52 and 0.36 in the first 5 s of 70 and 90 Hz trains, respectively (p<0.05). Treatment with hUCB significantly (p<0.05) improved PNMT in SOD1(G93A) preparations. That is, the initial 5 s PNMT was 0.88 and 0.68 for the 70 and 90 Hz stimuli, respectively. We concluded that hUCB transplantation significantly improved PNMT for muscles removed from SOD1(G93A) mice. Testing PNMT in the SOD1(G93A) mouse model could be used as a simple in vitro protocol to detect a positive cellular response to therapeutic interventions in ALS. PMID- 21678038 TI - Hantavirus infection--hemorrhagic fever with renal syndrome: the first case series reported in Romania and review of the literature. AB - Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic infectious disease caused by Hantaviruses, a group of RNA viruses belonging to the Bunyaviridae family. Humans may get the disease by contamination with excreta of carrier rodents. The disease typically manifests with the triad fever-thrombocytopenia acute kidney injury (AKI). Although its global prevalence seems to be increasing, Hantavirus infection is still commonly overlooked, because of its clinical polymorphism and non-specific symptoms, particularly in mild cases. Until recently, the disease was virtually unknown in Romania, due to lack of physicians' awareness and of adequate laboratory diagnostic techniques. In this article, we present the first six cases of HFRS diagnosed in our country, based on serology testing. We review the existing literature on HFRS and discuss our findings in comparison with other reports. All our patients presented with fever, flu syndrome, bleeding, gastrointestinal symptoms, and oliguria. Among laboratory abnormalities, elevated serum creatinine and liver enzymes, high C-reactive protein, leukocytosis, low platelet count, and hematuria were constantly seen. Five patients required hemodialysis. All patients survived and five of them completely recovered their renal function, while only one patient retained a mild impairment of the glomerular filtration rate. From a clinical viewpoint, we believe that Hantavirus infection should be considered in all patients presenting with fever, thrombocytopenia, and AKI, when specific serology testing would be indicated. From a public health perspective, we suggest that future efforts in our country should be directed toward (1) increasing the understanding and the awareness of this disease among health care professionals, (2) educating the population at risk on the application of prophylactic measures, (3) expanding the availability of diagnostic laboratory tools, and (4) developing research on national zoonotic virus reservoirs. PMID- 21678039 TI - A PACS archive architecture supported on cloud services. AB - PURPOSE: Diagnostic imaging procedures have continuously increased over the last decade and this trend may continue in coming years, creating a great impact on storage and retrieval capabilities of current PACS. Moreover, many smaller centers do not have financial resources or requirements that justify the acquisition of a traditional infrastructure. Alternative solutions, such as cloud computing, may help address this emerging need. METHODS: A tremendous amount of ubiquitous computational power, such as that provided by Google and Amazon, are used every day as a normal commodity. Taking advantage of this new paradigm, an architecture for a Cloud-based PACS archive that provides data privacy, integrity, and availability is proposed. The solution is independent from the cloud provider and the core modules were successfully instantiated in examples of two cloud computing providers. Operational metrics for several medical imaging modalities were tabulated and compared for Google Storage, Amazon S3, and LAN PACS. RESULTS: A PACS-as-a-Service archive that provides storage of medical studies using the Cloud was developed. The results show that the solution is robust and that it is possible to store, query, and retrieve all desired studies in a similar way as in a local PACS approach. CONCLUSION: Cloud computing is an emerging solution that promises high scalability of infrastructures, software, and applications, according to a "pay-as-you-go" business model. The presented architecture uses the cloud to setup medical data repositories and can have a significant impact on healthcare institutions by reducing IT infrastructures. PMID- 21678040 TI - Adverse drug reaction reporting in the Czech Republic 2005-2009. AB - OBJECTIVE: The aim of this study was to assess the situation regarding spontaneous adverse drug reaction reporting in the Czech Republic during a 5-year period (2005-2009). SETTING: Descriptive study was conducted using the data from the Czech State Institute for Drug Control pharmacovigilance database. METHODS: The data referring to all spontaneous adverse drug reaction reports received, by the pharmacovigilance department of the Czech State Institute for Drug Control during 2005-2009 were collected, analysed and compared with data from the Slovak Republic, Denmark, and the United Kingdom. MAIN OUTCOME MEASURES: The number of received spontaneous adverse drug reactions reports by year per 10,000 inhabitants, the seriousness and outcome of reactions, the reporting groups, and the top ten molecules which contributed to the highest number of reports. RESULTS: During the study period 2005-2009, the pharmacovigilance department of the State Institute for Drug Control received 7,708 spontaneous adverse drug reactions reports of which 73.6% were serious and 2.1% resulted in death. The number of spontaneous adverse drug reactions reports per 10,000 inhabitants ranged from 1.3 to 1.7, which was lower when compared with the number of reports from three other EU countries. The healthcare professionals contributed to 64.2% of the adverse drug reactions reports, whilst marketing authorization holders provided 35.5%, and finally patients with 0.3%. Vaccines, ketoprofen, amoxicillin, statins, and estradiol were amongst the top ten molecules that gave the highest number of spontaneous adverse drug reactions reports. CONCLUSIONS: Our assessment of adverse drug reactions spontaneous reports received by the Czech Institute for Drug Control during 2005-2009 showed that the reporting rate is relatively low and remains constant over the 5 year period. More emphasis on academic/professional training is needed to educate all potential reporters on the mechanism of reporting of adverse drug reactions and to also emphasize the importance of the whole pharmacovigilance process. PMID- 21678041 TI - Biochemical outcome of small-volume or insignificant prostate cancer treated with radical prostatectomy in Japanese population. AB - BACKGROUND: We investigated the biochemical outcome of small-volume prostate cancers [tumor volume (TV) < 0.5 mL, SVCa] and insignificant prostate cancers (TV <0.5 mL without any Gleason pattern 4/5 elements, InsigCa) treated with radical prostatectomy. METHODS: Between April 2000 and May 2010, 609 patients with prostate cancer underwent radical prostatectomy at Hirosaki University Graduate School of Medicine. Of these, 237 were excluded from the study because of preoperative adjuvant therapy. The remaining 372 patients underwent routine histopathological and TV evaluations. Biochemical recurrence (BCR) was defined as the presence of prostate-specific antigen (PSA) levels greater than 0.2 ng/mL after prostatectomy. RESULTS: The median patient age was 68 years (range 48-78 years) and the median preoperative PSA level was 7.50 ng/mL. The mean follow-up period was 45.9 months and the mean TV was 2.16 mL. Sixty patients (16.3%) had SVCa and 14 (3.7%) had InsigCa. The 5-year BCR-free survival rate for patients with SVCa was 67.3% and that for patients with a TV of 0.5 or greater was 87.1%. A significant difference was seen between the groups using the log-rank test (P = 0.008). We could not identify any BCR in patients with InsigCa. CONCLUSION: Despite the limited number of cases, patients with InsigCa did not develop BCR whereas 12.9% of those with SVCa developed BCR after radical prostatectomy within 5 years. Accurate prediction of the biochemical outcome of SVCa remains difficult and further studies are needed. PMID- 21678042 TI - The mechanism of a nuclear pore assembly: a molecular biophysics view. AB - The basic problem of nuclear pore assembly is the big perinuclear space that must be overcome for nuclear membrane fusion and pore creation. Our investigations of ternary complexes: DNA-PC liposomes-Mg2+, and modern conceptions of nuclear pore structure allowed us to introduce a new mechanism of nuclear pore assembly. DNA induced fusion of liposomes (membrane vesicles) with a single-lipid bilayer or two closely located nuclear membranes is considered. After such fusion on the lipid bilayer surface, traces of a complex of ssDNA with lipids were revealed. At fusion of two identical small liposomes (membrane vesicles) < 100 nm in diameter, a "big" liposome (vesicle) with ssDNA on the vesicle equator is formed. ssDNA occurrence on liposome surface gives a biphasic character to the fusion kinetics. The "big" membrane vesicle surrounded by ssDNA is the base of nuclear pore assembly. Its contact with the nuclear envelope leads to fast fusion of half of the vesicles with one nuclear membrane; then ensues a fusion delay when ssDNA reaches the membrane. The next step is to turn inside out the second vesicle half and its fusion to other nuclear membrane. A hole is formed between the two membranes, and nucleoporins begin pore complex assembly around the ssDNA. The surface tension of vesicles and nuclear membranes along with the kinetic energy of a liquid inside a vesicle play the main roles in this process. Special cases of nuclear pore formation are considered: pore formation on both nuclear envelope sides, the difference of pores formed in various cell-cycle phases and linear nuclear pore clusters. PMID- 21678043 TI - [Standardized and structured histopathological evaluation of colorectal polyps: a practical checklist against the background of the new WHO classification]. AB - Gastroenterologists removing colorectal polyps expect standardized and well structured pathological reports, providing them with all relevant data for the further clinical management of the patient. Over the last year, a task force of clinicians and pathologists has developed a checklist to improve and harmonize endoscopic and pathological reporting of colorectal polyps. This checklist concentrates more on concrete recommendations from evidence-based guidelines and established international classifications for daily practice rather than detailed molecular pathological pathways of carcinogenesis. These recommendations are based on the current S3 guidelines for colorectal cancer (the chapter entitled "Management of colorectal polyps"), the histomorphological consensus manuscript of the GI working group of the German Society for Pathology, as well as the current WHO classification for tumors of the digestive system. PMID- 21678044 TI - Mathematical modeling of Fe(II), Cu(II), Ni(II) and Zn(II) removal in a horizontal rotating tubular bioreactor. AB - Industrial wastewaters polluted with toxic heavy metals are serious ecological and environmental problem. Therefore, in this study multi-heavy metals (Fe(2+), Cu(2+), Ni(2+) and Zn(2+)) removal process with mixed microbial culture was examined in the horizontal rotating tubular bioreactor (HRTB) by different combinations of process parameters. Hydrodynamic conditions and biomass sorption capacity have main impact on the removal efficiency of heavy metals: Fe(2+) 95.5 79.0%, Ni(2+) 92.7-54.8%, Cu(2+) 87.7-54.9% and Zn(2+) 81.8-38.1%, respectively. On the basis of experimental results, integral mathematical model of removal heavy metals in the HRTB was established. It combines hydrodynamics (mixing), mass transfer and kinetics to define bioprocess conduction in the HRTB. Mixing in the HRTB was described by structured cascade model and metal ion removal by two combined diffusion-adsorption models, respectively. For Langmuir model, average variances between experimental and simulated concentrations of metal ions were in the range of 1.22-10.99 * 10(-3) and for the Freundlich model 0.12-3.98 * 10(-3), respectively. On the basis of previous facts, it is clear that developed integral bioprocess model with Freundlich model is more efficient in the prediction of concentration of metal ions in the HRTB. Furthermore, the results obtained also pointed out that the established model is at the same time accurate and robust and therefore it has great potential for use in the scale-up procedure. PMID- 21678045 TI - Risk of nonlower respiratory serious adverse events following COPD exacerbations in the 4-year UPLIFT(r) trial. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with systemic consequences. Data from a 4-year trial (Understanding Potential Long-term Impacts on Function with Tiotropium [UPLIFT((r))], n = 5,992) were used to determine risk for nonlower respiratory serious adverse events (NRSAEs) following an exacerbation. METHODS: Patients with >= 1 exacerbation were analyzed. NRSAE incidence rates (incidence rate [IR], per 100 patient-years) were calculated for the 30 and 180 days before and after the first exacerbation. NRSAEs were classified by diagnostic terms and organ classes. Maentel-Haenszel rate ratios (RR) (pre- and postexacerbation onset) along with 95% confidence intervals (CI) were computed. RESULTS: A total of 3,960 patients had an exacerbation. The mean age was 65 years, forced expiratory volume in 1 s (FEV(1)) was 38% predicted, and 74% were men. For all NRSAEs, the IRs 30 days before and after an exacerbation were 20.2 and 65.2 with RR (95% CI) = 3.22 (2.40-4.33). The IRs for the 180-day periods were 13.2 and 31.0 with RR (95% CI) = 2.36 (1.93 2.87). The most common NRSAEs by organ class for both time periods were cardiac, respiratory system (other), and gastrointestinal. All NRSAEs as well as cardiac events were more common after the first exacerbation, irrespective of whether the patient had cardiac disease at baseline. CONCLUSIONS: The findings confirm that, after exacerbations, serious adverse events in other organ systems are more frequent, particularly those that are cardiac in nature. PMID- 21678047 TI - Intervening at the entry point: differences in how CIT trained and non-CIT trained officers describe responding to mental health-related calls. AB - In response to challenges officers face with mental health-related calls, police departments are implementing specialized response programs like Crisis Intervention Teams (CIT). CIT is gaining support for its promise to promote safe, respectful interactions with police and individuals with mental illnesses. This paper outlines the results of a qualitative study investigating the impact of CIT. We found difference in CIT and non-CIT officers' response tactics to mental health-related calls and assessments of danger. CIT officers described a broader understanding of exhibited behaviors and considered more options when deciding the outcomes of calls. Implications and directions for future research are discussed. PMID- 21678049 TI - Membrane attachment of Slr0006 in Synechocystis sp. PCC 6803 is determined by divalent ions. AB - Slr0006 is one of the Synechocystis sp. PCC 6803 proteins strongly induced under carbon limiting conditions. Slr0006 has no predicted transmembrane helices or signal peptide sequence, yet it was exclusively recovered in the membrane fraction of Synechocystis, when the cells were broken in isolation buffers which contain divalent cations and are generally used for photosynthesis studies. Even subsequent washing of the membranes with high salt or various detergents did not release Slr0006, indicating strong binding of the Slr0006 protein to the membranes. Further, DNAse or RNAse treatment did not disturb the tight binding of Slr0006 protein to the membranes. Nevertheless, when the cells were broken in the absence of divalent cations, Slr0006 remained completely soluble. Binding of the Slr0006 to the membrane could not be properly reconstituted if the cations were added after breaking the cells in the absence of divalent ions. This unusual phenomenon has to be considered in identification and localization of other yet uncharacterized cyanobacterial proteins. PMID- 21678048 TI - Physiological characterization and light response of the CO2-concentrating mechanism in the filamentous cyanobacterium Leptolyngbya sp. CPCC 696. AB - We studied the interactions of the CO(2)-concentrating mechanism and variable light in the filamentous cyanobacterium Leptolyngbya sp. CPCC 696 acclimated to low light (15 MUmol m(-2) s(-1) PPFD) and low inorganic carbon (50 MUM Ci). Mass spectrometric and polarographic analysis revealed that mediated CO(2) uptake along with both active Na(+)-independent and Na(+)-dependent HCO(3)(-) transport, likely through Na(+)/HCO(3)(-) symport, were employed to concentrate Ci internally. Combined transport of CO(2) and HCO(3)(-) required about 30 kJ mol( 1) of energy from photosynthetic electron transport to support an intracellular Ci accumulation 550-fold greater than the external Ci. Initially, Leptolyngbya rapidly induced oxygen evolution and Ci transport to reach 40-50% of maximum values by 50 MUmol m(-2) s(-1) PPFD. Thereafter, photosynthesis and Ci transport increased gradually to saturation around 1,800 MUmol m(-2) s(-1) PPFD. Leptolyngbya showed a low intrinsic susceptibility to photoinhibition of oxygen evolution up to PPFD of 3,000 MUmol m(-2) s(-1). Intracellular Ci accumulation showed a lag under low light but then peaked at about 500 MUmol photons m(-2) s( 1) and remained high thereafter. Ci influx was accompanied by a simultaneous, light-dependent, outward flux of CO(2) and by internal CO(2)/HCO(3)(-) cycling. The high-affinity and high-capacity CCM of Leptolyngbya responded dynamically to fluctuating PPFD and used excitation energy in excess of the needs of CO(2) fixation by increasing Ci transport, accumulation and Ci cycling. This capacity may allow Leptolyngbya to tolerate periodic exposure to excess high light by consuming electron equivalents and keeping PSII open. PMID- 21678050 TI - Intussusception in adults with cystic fibrosis: a case series with review of the literature. PMID- 21678051 TI - Th1 responses are more susceptible to infliximab-mediated immunosuppression than Th17 responses. AB - BACKGROUND: Treatment with infliximab, a chimeric anti-tumor necrosis factor (TNF)-alpha antibody, is highly efficient in patients with inflammatory bowel disease (IBD). It neutralizes soluble TNF-alpha and induces the apoptosis of transmembrane TNF-alpha-positive macrophages and T cells in the gut. Recently, T helper (Th)17, as well as Th1, responses have been implicated in the pathogenesis of IBD. AIMS: To clarify the effects of infliximab on Th1 and Th17 responses in vitro. METHODS: Naive CD4(+) T cells isolated from the peripheral blood of healthy volunteers were stimulated under Th1- or Th17-inducing conditions in the presence of 10 MUg/ml of infliximab or control immunoglobulin (Ig)G1. The concentrations of interferon (IFN)-gamma, interleukin (IL)-17, and TNF-alpha in the culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Th1 and Th17 cells were immunostained with infliximab or control IgG1 and transmembrane TNF-alpha-positive cells were analyzed by flow cytometry. Annexin V staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assays were conducted in order to analyze the percentage of apoptotic cells. RESULTS: Both Th1 and Th17 cells expressed soluble and transmembrane TNF-alpha abundantly. Although infliximab suppressed IFN-gamma secretion by Th1 cells and IL-17 secretion by Th17 cells, the level of the former was more profound than the latter. Infliximab increased annexin V- and TUNEL-positive apoptotic cells under Th1-inducing conditions, but not under Th17-inducing conditions. CONCLUSIONS: Infliximab suppressed Th1 and Th17 differentiation in vitro; however, IFN-gamma production by Th1 cells was more profoundly suppressed than IL-17 secretion by Th17 cells. Th1 responses were more susceptible to infliximab-mediated apoptosis than Th17 responses. Our results clarify a new mechanism of action of infliximab. PMID- 21678052 TI - Understanding the differential nitrogen sensing mechanism in rice genotypes through expression analysis of high and low affinity ammonium transporter genes. AB - Two rice genotypes, Kalanamak 3119 (KN3119) and Pusa Basmati 1(PB1) differing in their optimum nitrogen requirements (30 and 120 kg/ha, respectively) were undertaken to study the expression of both high and low affinity ammonium transporter genes responsible for ammonium uptake. Exposing the roots of the seedlings of both the genotypes to increasing (NH(4))(2)SO(4) concentrations revealed that all the three families of rice AMT genes are expressed, some of which get altered in a genotype and concentration specific manner. This indicates that individual ammonium transporter genes have defined contributions for ammonium uptake and plant growth. Interestingly, in response to increasing nitrogen concentrations, a root specific high affinity gene, AMT1;3, was repressed in the roots of KN3119 but not in PB1 indicating the existence of a differential ammonium sensing mechanism. This also indicates that not only AMT1;3 is involved not only in ammonium uptake but may also in ammonium sensing. Further, if it can differentiate and could be used as a biomarker for nitrogen responsiveness. Expression analysis of low affinity AMT genes showed that, both AMT2;1 and AMT2;2 have high levels of expression in both roots and shoots and in KN3119 are induced at low ammonium concentrations. Expressions of AMT3 family genes were higher shoots than in the roots indicating that these genes are probably involved in the translocation and distribution of ammonium ions in leaves. The expression of the only high affinity AMT gene, AMT1;1, along with six low affinity AMT genes in the shoots suggests that low affinity AMTs in the shoots leaves are involved in supporting AMT1;1 to carry out its activities/function efficiently. PMID- 21678053 TI - Down-regulation of beta3-integrin inhibits bone metastasis of small cell lung cancer. AB - Bone is one of the most frequent targets of small cell lung cancer (SCLC) metastasis, but the molecular mechanism remains unclear. beta3-integrin plays an important role in invasion of various kinds of tumors. Yet, its role in bone metastasis of SCLC is still unknown. In this study, we first examined the expression of beta3-integrin in SBC-5 and SBC-3 cells by real-time PCR, western blot and immunofluorescence. We found that, compared to none bone-metastatic SBC 3 cells, beta3-integrin was highly expressed in SBC-5 cells, a specific bone metastatic SCLC cells line characterized in our previous study. We next constructed beta3-integrin siRNA and transfected SBC-5 cell line, and found that beta3-integrin siRNA significantly down-regulated the beta3-integrin mRNA level and protein expression in SBC-5 cell line. We further found that inhibition of beta3-integrin significantly reduced tumor cell proliferation and induced apoptosis. In addition, the beta3-integrin down-regulated cells presented significant decrease in cell adhesion, migration and invasion activity. Our results suggest the beta3-integrin has an essential effect on tumor cell proliferation and progression, and may be a potential therapeutic target for the prevention of skeletal metastases of lung cancer. PMID- 21678054 TI - Molecular characterization and identification of a novel polymorphism of 200 bp indel associated with age at first egg of the promoter region in chicken follicle stimulating hormone receptor (FSHR) gene. AB - Follicle-stimulating hormone receptor (FSHR) plays an important role in animal follicular development. Polymorphisms in FSHR promoter region likely impact transcription and follicle growth and maturation. In this study, a fragment of ~1.9 kb of cFSHR promoter for Zang, Xianju, Lohmann Brown, Jining Bairi and Wenchang breeds (line) was obtained. Totally 49 variations were revealed, of which 39 are single nucleotide substitutions, one is nucleotide substitution of (TTG) to (CAC) and nine are indels. Polymorphism at -874 site (a 200 bp indel mutation) was identified, and their effects on egg production traits as well as gene expression were analyzed. At this site, allele I(+) was dominant in Lohmann Brown and Xinyang Brown (a synthetic egg-laying line) lines, but very rare in three Chinese indigenous chicken breeds, namely Jining Bairi, Wenchang, Zang and one synthetic boiler line (Luqin). In Xinyang Brown population, the polymorphism was associated with age at first egg (AFE) (P < 0.05) and its effect on egg number at 37 weeks of age (E37) and egg number at 57 weeks of age (E57) was not significantly different (P > 0.05). The cFSHR mRNA level was not significantly different between three genotypes in small white and small yellow follicles of Xinyang Brown hens, however, allele I(+) tends to increase cFSHR transcription. PMID- 21678055 TI - Induction of cell differentiation and promotion of endocan gene expression in stomach cancer by melatonin. AB - The pineal hormone melatonin has been shown to have anticancer therapeutic properties in patients with gastric cancer, the mechanisms, however, remain largely unknown. The present study examined the effects of melatonin on cell differentiation related factors, namely, endocan, alkaline phosphatase, and lactate dehydrogenase, in gastric adenocarcinoma cell line SGC7901. Expression of endocan was significantly decreased in tissue of gastric cancer as compared to normal stomach tissue, as determined by immunohistochemical staining, and there is correlation between the degree of the decrease of endocan expression and the degree of differentiation of the cancer. Treatment of cultured gastric adenocarcinoma cells with 10(-4) mol/l melatonin significantly increased the gene expression of endocan and down-regulated the activity of alkaline phosphatase and lactate dehydrogenase, two enzymes that promote de-differentiation in gastric tissue; and there was a negative correlation between the level of endocan expression and the activities of differentiation marker enzymes in the melatonin treated cancer cells. Gastric cancer cells treated with melatonin show more differentiated morphologic phenotype as compared the untreated cells. The findings indicate that melatonin may play its anticancer role in gastric adenocarcinoma by acting as a differentiation inducer. PMID- 21678056 TI - Characterization of a thermostable lipase showing loss of secondary structure at ambient temperature. AB - A gene encoding extracellular lipase was cloned and characterized from metagenomic DNA extracted from hot spring soil. The recombinant gene was expressed in E. coli and expressed protein was purified to homogeneity using hydrophobic interactions chromatography. The mature polypeptide consists of 388 amino acids with apparent molecular weight of 43 kDa. The enzyme displayed maximum activity at 50 degrees C and pH 9.0. It showed thermal stability up to 40 degrees C without any loss of enzyme activity. Nearly 80% enzyme activity was retained at 50 degrees C even after incubation for 75 min. However above 50 degrees C the enzyme displayed thermal instability. The half life of the enzyme was determined to be 5 min at 60 degrees C. Interestingly the CD spectroscopic study carried out in the temperature range of 25-95 degrees C revealed distortion in solution structure above 35 degrees C. However the intrinsic tryptophan fluorescence spectroscopic study revealed that even with the loss of secondary structure at 35 degrees C and above the tertiary structure was retained. With p-nitrophenyl laurate as a substrate, the enzyme exhibited a K ( m ), V ( max ) and K ( cat ) of 0.73 +/- 0.18 MUM, 239 +/- 16 MUmol/ml/min and 569 s(-1) respectively. Enzyme activity was strongly inhibited by CuCl(2), HgCl(2) and DEPC but not by PMSF, eserine and SDS. The protein retained significant activity (~70%) with Triton X-100. The enzyme displayed 100% activity in presence of 30% n-Hexane and acetone. PMID- 21678057 TI - miR-29a and miR-142-3p downregulation and diagnostic implication in human acute myeloid leukemia. AB - Expression profiling of microRNAs (miRNAs) in most diseases might be popular and provide the possibility for diagnostic implication, but few studies have accurately quantified the expression level of dysregulated miRNAs in acute myeloid leukemia (AML). In this study, we analyzed the peripheral blood mononuclear cells (PBMCs) from 10 AML patients (subtypes M1 to M5) and six normal controls by miRNA microarray and identified several differentially expressed miRNAs. Among them miR-29a and miR-142-3p were selectively encountered in Northern blot analysis and their significantly decreased expression in AML was further confirmed. Quantitative real-time PCR in 52 primarily diagnosed AML patients and 100 normal controls not only verified the expression properties of these 2 miRNAs, but also established that the expression level of miR-142-3p and miR-29a in PBMCs could be used as novel diagnostic markers. A better diagnostic outcome was achieved by combining miR-29a and miR-142-3p with about 90% sensitivity, 100% specificity, and an area under the ROC curve (AUC) of 0.97. Our results provide insights into the involvement of miRNAs in leukemogenesis, and offer candidates for AML diagnosis and therapeutic strategy. PMID- 21678058 TI - In silico characterization of the neural alpha tubulin gene promoter of the sea urchin embryo Paracentrotus lividus by phylogenetic footprinting. AB - During Paracentrotus lividus sea urchin embryo development one alpha and one beta tubulin genes are expressed specifically in the neural cells and they are early end output of the gene regulatory network that specifies the neural commitment. In this paper we have used a comparative genomics approach to identify conserved regulatory elements in the P. lividus neural alpha tubulin gene. To this purpose, we have first isolated a genomic clone containing the entire gene plus 4.5 Kb of 5' upstream sequences. Then, we have shown by gene transfer experiments that its non-coding region drives the spatio-temporal gene expression corresponding substantially to that of the endogenous gene. In addition, we have identified by genome and EST sequence analysis the S. purpuratus alpha tubulin orthologous gene and we propose a revised annotation of some tubulin family members. Moreover, by computational techniques we delineate at least three putative regulatory regions located both in the upstream region and in the first intron containing putative binding sites for Forkhead and Nkx transcription factor families. PMID- 21678059 TI - Perceived neighborhood environment affecting physical and mental health: a study with Korean American older adults in New York City. AB - This study examined how subjective perceptions of the neighborhood environment (e.g., perceived ethnic density, safety, social cohesion, and satisfaction) influenced the physical and mental health of Korean American older adults. Using data from 420 residents of the New York City metropolitan area (M(age) = 71.6, SD = 7.59), health perceptions and depressive symptoms were estimated with hierarchical regression models entered in the order of (1) demographics and acculturation, (2) health-related variables, and (3) perceived neighborhood environment. After controlling for the effects of the individual-level variables, perceived neighborhood environment was found to make a significant contribution to both outcomes. Individuals less satisfied with their overall neighborhood environment were more likely to have negative perceptions of health and depressive symptoms. A strong linkage between perceived neighborhood safety and depressive symptoms was also observed. Findings from the study highlight the importance of subjective evaluations of neighborhood environment and provide implications for health promotion. PMID- 21678061 TI - Improving surgical outcome following the Norwood procedure. AB - BACKGROUND: The Norwood procedure consists of three palliative operations, performed in neonates with hypoplastic left heart syndrome. Especially the first stage (Norwood I) is associated with the highest mortality rates in paediatric cardiac surgery (up to 25%). During surgery, the aorta is reconstructed and a systemic-to-pulmonary shunt is applied. Originally the modified Blalock-Taussig shunt was used, but recently the right-ventricle-to-pulmonary-artery shunt is increasingly being employed. We reviewed the results of our operative strategy, where an individualised choice of shunt is made. Furthermore, attempts to reduce interstage mortality (between Norwood I and II) were assessed. METHODS: All neonates who underwent Norwood stage I palliation from August 2004 until November 2010 were included in this retrospective analysis. Mortality rates and management strategies were compared. RESULTS: Thirty-six patients were available for analysis. Overall 30-day mortality was 5.6% (2 patients) and interstage mortality after discharge was 14% (5 patients). In 2006, a novel clinical protocol was introduced, aimed at reduction of mortality during the interstage period. This resulted in reduction of interstage mortality from 23% to 9% (3 of 13 infants, versus 2 of 23), with a cumulative survival of 82% (maximum follow-up 4 years). CONCLUSION: Early surgical results following the Norwood procedure using an individualised shunt choice are favourable. PMID- 21678060 TI - Small heat shock protein LimHSP16.45 protects pollen mother cells and tapetal cells against extreme temperatures during late zygotene to pachytene stages of meiotic prophase I in David Lily. AB - Plant meiotic prophase I is a complicated process involving the late zygotene and pachytene stages, both crucial for completing synapsis and recombination. Using David Lily (Lilium davidii var. Willmottiae) as our research material, we performed suppression subtractive hybridization to construct EST library of anthers at various stages of development by the pollen mother cells. From this library, we identified small heat shock protein LimHSP16.45 was highly expressed during the late zygotene to pachytene stages. Our results also showed that LimHSP16.45 was almost specifically expressed in the anther compared with the root, stem, or leaf, and in situ expression of LimHSP16.45 mRNAs showed strong signals in the pollen mother cells and tapetal cells. LimHSP16.45 could be induced by heat and cold in lily anthers, and its ectopic expression enhanced the viability of E. coli cells under both high and low temperatures. In vitro, it acted as molecular chaperone and could help luciferase refolding after heat shock stress. All of these data suggest that LimHSP16.45, working as molecular chaperone, possibly protects pollen mother cells and tapetal cells against extreme temperatures during late zygotene to pachytene stages of meiotic prophase I in David Lily. PMID- 21678062 TI - A young man with near-syncope. PMID- 21678063 TI - Influence of chromosome 22q11.2 microdeletion on postoperative calcium level after cardiac-correction surgery. AB - One of the most common constitutional chromosomal abnormalities, 22q11.2 microdeletion (del22q11.2) syndrome has diverse medical complications, such as congenital heart defect, hypocalcaemia, and immune deficiency, which require coordinated multidisciplinary care. Until now, the natural history of hypocalcaemia in chromosome del22q11.2 syndrome had been only partly documented, but there has been limited recognition of the importance of calcium status during the postoperative period when altered calcium status may be associated with serious complications. The goals of our study were (1) to delineate the clinical characteristics of serum calcium in patients with del22q11.2 during the postoperative period and (2) to make recommendations for the investigation and management of del22q11.2 patients after cardiac correction. This study included 22 children diagnosed with del22q11.2 syndrome and 110 children without del22q11.2 syndrome from Nanjing Children's Hospital. Clinical examinations and blood ionized calcium testing were reviewed retrospectively. A comparative study of postoperative calcium levels and complications of del22q11.2 patients with nondeletion patients was performed. Association between postoperative hypocalcaemia and adverse incidents after cardiac correction was also examined. Postoperative hypocalcaemia was observed among 86.4% of del22q11.2 patients and among only 47.3% of nondeletion subjects. The difference was statistically significant (P = 0.0017). Patients with del22q11.2 syndrome also had a much sharper decrease in serum calcium levels during the first 6 h after surgery than nondeletion patients. Postoperative clinical analysis showed that del22q11.2 patients with hypocalcaemia experience more postoperative complications (18 of 19) and greater mortality (5 of 19) after cardiac correction than del22q11.2 patients without normal calcium levels and nondeletion patients. Del22q11.2 children have high susceptibility of hypocalcaemia during the postoperative period, and this low calcium status after cardiac correction may be associated with significant risk of postoperative complications and mortality in patients with del22q11.2. PMID- 21678064 TI - X chromosome inactivation in human and mouse pluripotent stem cells. AB - Since the groundbreaking hypothesis of X chromosome inactivation (XCI) proposed by Mary Lyon over 50 years ago, a great amount of knowledge has been gained regarding this essential dosage compensation mechanism in female cells. For the mammalian system, most of the mechanistic studies of XCI have so far been investigated in the mouse model system, but recently, a number of interesting XCI studies have been extended to human pluripotent stem cells, including both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Emerging data indicate that XCI in hESCs and hiPSCs is much more complicated than that of their mouse counterparts. XCI in human pluripotent stem cells is not as stable and is subject to environmental influences and epigenetic regulation in vitro. This mini-review highlights the key differences in XCI between mouse and human stem cells with a greater emphasis placed on the understanding of the epigenetic regulation of XCI in human stem cells. PMID- 21678066 TI - Does mild hypothermia protect against reperfusion injury? The debate continues. AB - Mild hypothermia (32-35 degrees C) salvages ischemic myocardium and reduces infarct size in hearts undergoing ischemia/reperfusion. It is clear that a cardioprotective effect is evident when the heart is cooled during ischemia, and the protection is greater as the duration of normothermic ischemia is increasingly limited. The effect of cooling just before and at reperfusion is more controversial. Multiple experimental studies have revealed no effect of mild hypothermia on myocardial infarction when cooling was initiated in the waning minutes of ischemia. But Gotberg et al. have demonstrated a small effect in pigs cooled with cold intravenous saline and a venous thermode, although the effect of cooling during ischemia continued to be more prominent. Clinical studies have been disappointing, and possible explanations are offered. Gotberg's new data are encouraging, but it is questioned whether this is the correct time to conduct a new large-scale clinical trial. PMID- 21678065 TI - Current status of genome-wide association studies in cancer. AB - Genome-wide association studies in cancer have already identified over 150 regions associated with two dozen specific cancers. Already, a handful of multi cancer susceptibility regions have been uncovered, providing new insights into perhaps common mechanisms of carcinogenesis. For each new susceptibility allele, investigators now face the arduous task of interrogating each region beginning with fine mapping prior to pursuing the biological basis for the direct association of one or more variants. It appears that there may be a significant number of common alleles that contribute to the heritability of a specific cancer. Since each region confers a small contribution to the risk for cancer, it is daunting to consider any single nucleotide polymorphism (SNP) as a clinical test. Since the complex genomic architecture of each cancer differs, additional genotyping and sequence analysis will be required to comprehensively catalog susceptibility alleles followed by the formidable task of understanding the interactions between genetic regions as well as the environment. It will be critical to assess the applicability of genetic tests in specific clinical settings, such as when to perform screening tests with calculable risks (e.g., biopsies or chemoprevention), before incorporating SNPs into clinical practice. To advance the current genomic observations to the clinical venue, new studies will need to be designed to validate the utility of known genetic variants in assessing risk for cancer as well as its outcomes. PMID- 21678067 TI - Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. AB - Cellular functions accompanying establishment of premature senescence in methotrexate-treated human colon cancer C85 cells are deciphered in the present study from validated competitive expression microarray data, analyzed with the use of Ingenuity Pathways Analysis (IPA) software. The nitrosative/oxidative stress, inferred from upregulated expression of inducible nitric oxide synthase (iNOS) and mitochondrial dysfunction-associated genes, including monoamine oxidases MAOA and MAOB, beta-amyloid precursor protein (APP) and presenilin 1 (PSEN1), is identified as the main determinant of signaling pathways operating during senescence establishment. Activation of p53-signaling pathway is found associated with both apoptotic and autophagic components contributing to this process. Activation of nuclear factor kappaB (NF-kappaB), resulting from interferon gamma (IFNgamma), integrin, interleukin 1beta (IL-1beta), IL-4, IL-13, IL-22, Toll-like receptors (TLRs) 1, 2 and 3, growth factors and tumor necrosis factor (TNF) superfamily members signaling, is found to underpin inflammatory properties of senescent C85 cells. Upregulation of p21-activated kinases (PAK2 and PAK6), several Rho molecules and myosin regulatory light chains MYL12A and MYL12B, indicates acquisition of motility by those cells. Mitogen-activated protein kinase p38 MAPK beta, extracellular signal-regulated kinases ERK2 and ERK5, protein kinase B AKT1, as well as calcium, are identified as factors coordinating signaling pathways in senescent C85 cells. PMID- 21678068 TI - Outcome of stapled hemorrhoidopexy versus doppler-guided hemorrhoidal artery ligation for grade III hemorrhoids. AB - PURPOSE: To evaluate the long-term results, early and late complication rates, and overall satisfaction of patients with grade III hemorrhoids treated by stapled hemorrhoidopexy (SH) or Doppler-guided hemorrhoidal artery ligation (DGHAL). METHODS: Operative and follow-up patients' data were prospectively collected for patients undergoing either SH or DGHAL by a single surgeon during a 2-year period. A retrospective comparison between patients' outcome operated by one of the two methods was made based on this data. Clinical data on postoperative pain, analgesic requirements, time to first bowel movement and functional recovery were collected at five postoperative follow-up visits (1 and 6 weeks, 6, 12, and 18 months). Data on patient satisfaction, recurrence of hemorrhoidal symptoms and further treatments were obtained by a standardized questionnaire that was conducted during the last visit 18 months postoperatively. RESULTS: A total of 63 patients underwent SH (aged 52 +/- 3.2 years) and 51 patients underwent DGHAL (aged 50 +/- 7.3 years). DGHAL patients experienced less postoperative pain as scored by pain during bowel movement (2.1 +/- 1.4 vs. 5.5 +/- 1.9 for SH), and required fewer analgesics postoperatively. Hospital stay, time to first bowel movement, and complete functional recovery were also significantly shorter for the DGHAL patients. Nine DGHAL patients (18%) suffered from persistent bleeding or prolapses and required additional treatment compared with 2 (3%) patients in the SH group. SH patients reported greater satisfaction compared with DGHAL patients at 1 year postoperatively. CONCLUSION: Both SH and DGHAL are safe procedures and have similar effectiveness for treating grade III hemorrhoids. DGHAL is less painful and provides earlier functional recovery, but is associated with higher recurrence rates and lower satisfaction rates compared with SH. PMID- 21678069 TI - Technique for constructing an incisionless laparoscopic stoma. AB - Minimally invasive surgery continues to evolve, and with the advent of single port laparoscopic access incisionless stoma, creation is possible. Outlined below is the technical approach to the incisionless stoma. It can be applied to the construction of ileostomies as well as colostomies, end, or loop stomas. Our early experience reveals favorable outcomes. This is perhaps one of the least technically demanding procedures that can be performed through a single incision laparoscopic port. PMID- 21678070 TI - Sigmoid intramural hematoma and hemoperitoneum: an early severe complication after stapled hemorrhoidopexy. AB - Stapled hemorrhoidopexy is a widely used surgical technique for treating hemorrhoids, although severe complications have been reported. The authors report a rare case of extensive ascending intramural hematoma of the sigmoid colon complicating stapled hemorrhoidopexy, with perforation and hemoperitoneum. Diagnosis was established at CT scan and treatment consisted of drainage, suturing, and diverting colostomy. This reported case is the ninth described in the literature, but, so far, it is not known what preventive measures to use in order to avoid such a rare complication. Adoption of a correct surgical technique remains the step of utmost importance in order to prevent such a severe postoperative complication. PMID- 21678071 TI - Basilar migraine mistaken for encephalitis. PMID- 21678072 TI - Spinal cord stimulation for recurrent painful neuromas of the foot. AB - The authors report the case of a patient affected by recurrent neuromas of the interdigital nerves of the left foot that appeared after surgery for Morton's disease. Implantation of spinal cord stimulation (SCS) system was performed after three unsuccessful surgical revisions, which demonstrated the presence of multiple neuromas growing at endings of the stumps of the nerves and fasciculi. The patient developed chronic neuropathic pain localized within the third metatarsal region of the left foot. Conservative treatments failed and autonomous gait became impossible. SCS immediately abolished pain and the patient was able to perform her normal daily activities within 1 month. At our knowledge, this is the first report in literature of SCS successfully employed for recurrent and refractory pain due to Morton's neuroma. PMID- 21678073 TI - VGCC antibody-positive paraneoplastic cerebellar degeneration presenting with positioning vertigo. AB - A 70-year-old woman developed paraneoplastic cerebellar degeneration (PCD) due to P/Q-type and N-type voltage-gated calcium channel antibodies and small cell lung cancer, the main clinical manifestations of which were severe positioning vertigo and vomiting. Loss of the visual suppression of caloric nystagmus, spontaneous downbeat nystagmus, periodic alternating nystagmus, and positioning vertigo in our patient most probably corresponds to the cerebellar flocculus/paraflocculus lesion caused by PCD. PMID- 21678074 TI - Bone marrow mesenchymal stem cells can be mobilized into peripheral blood by G CSF in vivo and integrate into traumatically injured cerebral tissue. AB - The efficacy of granulocyte colony-stimulating factor (G-CSF) in mobilizing mesenchymal stem cells (MSCs) into peripheral blood (PB) and the ability of PB MSCs incorporated into injured brain were tested. Colony forming, cell phenotype and differentiation potential of mouse MSCs mobilized by G-CSF (40 MUg/kg) were evaluated. Mortality and pathological changes in mice with serious craniocerebral trauma plus G-CSF treatment (40 MUg/kg) were investigated. Bone marrow (BM) cells derived from GFP mice were fractionated into MSCs, hematopoietic stem cells (HSCs), and non-MSC/HSCs using magnetic beads and adherent culture. The resultant cell populations were transplanted into injured mice. The in vivo integration and differentiation of the transplanted cells were detected immunocytochemically. The expression of SDF-1 in injured area of brain was tested by Western blot. G-CSF was able to mobilize MSCs into PB (fourfold increase). PB-MSCs possessed similar characteristics as BM-MSCs in terms of colony formation, the expression pattern of CD73, 44, 90, 106, 31 and 45, and multipotential of differentiation. Accumulative total mice mortality was lower in TG group (5/14) than that in T group (7/14). It was MSCs, not HSCs or non-MSC/HSC cells integrated into the damaged cerebral tissue and differentiated into cells expressing neural markers. Increased SDF-1 expression in injured area of brain was confirmed, which could facilitate the homing of MSCs to brain. G-CSF can mobilize MSCs into PB and MSCs in PB can integrate into injured cerebral tissue and transdifferentiated into neural cells and may benefit the repair of trauma. PMID- 21678075 TI - Neurovascular centers--a need for a change. PMID- 21678077 TI - Fire accidents in neonatal nursery: prevention and management. PMID- 21678078 TI - Anisotropies of linear and curvilinear completions at the blind spot. AB - Previous studies have shown anisotropies of perceptual completion of the line at the blind spot. The present study examined anisotropies of collinear and noncollinear completions at the blind spot. A physically aligned or misaligned pair of horizontal or vertical line segments was presented on opposite sides of the blind spot. Observers reported the appearance of the line segments. In Experiment 1, the range of noncollinear completion in the vertical line segments was significantly larger than that in the horizontal line segments, whereas an anisotropy of the range of collinear completion was not observed. In Experiment 2, linear and curvilinear completions predominantly occurred in the horizontal and vertical line segments, respectively. In Experiment 3, the tolerance of collinear completion was not significantly larger than vernier acuity. These results suggest that linear and curvilinear completions at the blind spot have different anisotropic tendencies. These different anisotropic processes might bring about anisotropies of perceptual completion of the line at the blind spot. PMID- 21678079 TI - Metallothionein and brain inflammation. AB - Since the seminal discoveries of Bert Vallee regarding zinc and metallothioneins (MTs) more than 50 years ago, thousands of studies have been published concerning this fascinating story. One of the most active areas of research is the involvement of these proteins in the inflammatory response in general, and in neuroinflammation in particular. We describe the general aspects of the inflammatory response, highlighting the essential role of the major cytokine interleukin-6, and review briefly the expression and function of MTs in the central nervous system in the context of neuroinflammation. Particular attention is paid to the Tg2576 Alzheimer disease mouse model and the preliminary results obtained in mice into which human Zn(7)MT-2A was injected, which suggest a reversal of the behavioral deficits while enhancing amyloid plaque load and gliosis. PMID- 21678080 TI - Competitive binding of Fe3+, Cr3+, and Ni2+ to transferrin. AB - Competitive binding of Fe(3+), Cr(3+), and Ni(2+) to transferrin (Tf) was investigated at various physiological iron to Tf concentration ratios. Loading percentages for these metal ions are based on a two M(n+) to one Tf (i.e., 100% loading) stoichiometry and were determined using a particle beam/hollow cathode optical emission spectroscopy (PB/HC-OES) method. Serum iron concentrations typically found in normal, iron-deficient, iron-deficient from chronic disease, iron-deficient from inflammation, and iron-overload conditions were used to determine the effects of iron concentration on iron loading into Tf. The PB/HC OES method allows the monitoring of metal ions in competition with Fe(3+) for Tf binding. Iron-overload concentrations impeded the ability of chromium (15.0 MUM) or nickel (10.3 MUM) to load completely into Tf. Low Fe(3+) uptake by Tf under iron-deficient or chronic disease iron concentrations limited Ni(2+) loading into Tf. Competitive binding kinetic studies were performed with Fe(3+), Cr(3+), and Ni(2+) to determine percentages of metal ion uptake into Tf as a function of time. The initial rates of Fe(3+) loading increased in the presence of nickel or chromium, with maximal Fe(3+) loading into Tf in all cases reaching approximately 24%. Addition of Cr(3+) to 50% preloaded Fe(3+)-Tf showed that excess chromium (15.0 MUM) displaced roughly 13% of Fe(3+) from Tf, resulting in 7.6 +/- 1.3% Cr(3+) loading of Tf. The PB/HC-OES method provides the ability to monitor multiple metal ions competing for Tf binding and will help to understand metal competition for Tf binding. PMID- 21678081 TI - Involvement of c-Src/STAT3 signal in EGF-induced proliferation of rat spermatogonial stem cells. AB - Epidermal growth factor (EGF) plays a role in male germ cell development, but the precise function is yet to be defined. This study shows that EGF stimulates rat spermatogonial proliferation in a dose-dependent manner and significantly increased the protein levels of phosphated c-Src (p-c-Src) and phosphated signal transducer and activator of transcription 3 (p-STAT3). Moreover, overexpression of c-Src tagged with enhanced green fluorescence protein (EGFP) in rat spermatogonial stem cells enhances the cell viability. In contrast, knockdown or inhibition of c-Src inhibits rat spermatogonial stem cell proliferation; EGF could not abrogate the inhibitory effect. Evidently, the content of p-STAT3 protein was increased in c-Src-expressing cells and decreased in c-Src suppressing cells. Furthermore, knockdown or inhibition of STAT3 also suppressed cell viability; neither EGF nor increased c-Src could reverse the inhibitory effect. These results are the first evidence that EGF induces proliferation of rat spermatogonial stem cells through c-Src/STAT3 signal. PMID- 21678082 TI - Nuclear translocation of beta-catenin correlates with CD44 upregulation in Helicobacter pylori-infected gastric carcinoma. AB - Infection with Helicobacter pylori CagA-positive strains is associated with gastric adenocarcinoma. CagA H. pylori activates the beta-catenin signal by translocation into nucleus which promotes carcinogenesis. Deregulated accumulation of nuclear beta-catenin enhances transcription of beta-catenin target genes including CD44 and promotes malignant transformation. The aim of this study was to investigate whether nuclear translocation of beta-catenin correlates with CD44 expression in CagA H. pylori-infected gastric carcinoma. To address these issues, we examined 140 gastric biopsy specimens by using immunohistochemical and immunofluorescence staining, Western blot, and mutational analysis of the exon 3 beta-catenin gene. The nuclear localization of beta catenin was significantly (chi(2) = 21.175; P < 0.001) increased in advanced gastric carcinoma and also correlated (chi(2) = 22.857; P < 0.001) with the CagA H. pylori positive specimens. We also observed that tyrosine-phosphorylated beta catenin was significantly (chi(2) = 14.207; P < 0.001) increased in samples showing nuclear localization of beta-catenin and also it correlated (chi(2) = 43.69; P < 0.03) with the CagA H. pylori positive specimens. Exon 3 beta-catenin gene mutation was not detected in H. pylori-infected gastric carcinoma. CD44 up regulation was significantly associated with tyrosine-phosphorylated beta-catenin (chi(2) = 22.5; P < 0.001), and this change was closely associated with nuclear translocation of beta-catenin (chi(2) = 13.393; P < 0.001) in CagA H. pylori infected gastric carcinoma. In conclusion, our data suggest that CagA H. pylori infection is responsible for the tyrosine phosphorylation of beta-catenin and its nuclear translocation, which upregulates beta-catenin target gene CD44 in gastric carcinoma. PMID- 21678083 TI - Comparative phylogeography of four component species of deciduous broad-leaved forests in Japan based on chloroplast DNA variation. AB - A phylogeographic study of four tree species (Padus grayana, Euonymus oxyphyllus, Magnolia hypoleuca, and Carpinus laxiflora) growing in Japanese deciduous broad leaved forests was conducted based on chloroplast DNA (cpDNA) variations. Using nucleotide sequences of 702-1,059 bp of intergenic spacers of cpDNA, 20, 27, eight, and eight haplotypes were detected among 251, 251, 226, and 262 individuals sampled from 67, 79, 75, and 71 populations of the above species, respectively. The geographical pattern of the cpDNA variations was highly structured in each species, and the following three regional populations were genetically highly differentiated among all four species: (1) the Sea of Japan side area, (2) the Kanto region, and (3) southwestern Japan. Based on some interspecific similarities among the phylogeographic patterns, the following migration scenario of Japanese deciduous broad-leaved forests was postulated. During the last glacial maximum (LGM), the forests were separately distributed in six regions. After LGM, as the climate warmed, the forests in eastern Japan separately expanded from each of the refugia along the Sea of Japan-side or along the Pacific Ocean-side. In contrast, those in southwestern Japan retreated and moved to high altitudes from each of the continuous forests. PMID- 21678084 TI - A neglected case of rare palsy of the descending branch of the posterior interosseous nerve due to penetrating injury. PMID- 21678085 TI - Prevalence and characteristics of chronic musculoskeletal pain in Japan. AB - BACKGROUND: This cross-sectional study was conducted to obtain epidemiologic data on chronic musculoskeletal pain in the Japanese people, and with it a better understanding of the actual conditions and problems involved. METHODS: A questionnaire covering basic information, chronic musculoskeletal pain, daily life, quality of life, and social loss was prepared and mailed to 11507 individuals aged 18 years or older. Subjects were selected randomly nationwide in accordance with the demographic composition of Japan. RESULTS: The prevalence of chronic musculoskeletal pain was 15.4%. The prevalence was highest in people in their 30s to 50s. Pain occurred most frequently in the low back, neck, shoulder, and knee. Among symptomatic subjects, 42% sought treatment, by visiting a medical institution (19%), taking folk remedies (20%), or both (3%). Treatment was generally prolonged, with 70% of those treated reporting treatment durations of more than a year. Although 69% reported that their symptoms had improved, 30% reported unchanged or aggravated symptoms and dissatisfaction with treatment. Among symptomatic subjects, a high percentage of both men and women had lost jobs, left school, been absent from work or school, or had changed jobs. Basic activities of daily living (ADL) were disturbed in men, and the instrumental ADL (IADL) score was low in women. SF-36 scale scores were significantly lower in every area for subjects with chronic pain. CONCLUSIONS: Chronic musculoskeletal pain does not necessarily improve even with prolonged treatment. It adversely affects daily life and both physical and mental health. Because those suffering pain often increasingly need assistance in daily activities, people around them are also affected. The therapeutic system and treatment procedures for chronic musculoskeletal pain merit prompt review. PMID- 21678086 TI - [Learning from mistakes - a standard process even in science]. PMID- 21678087 TI - [Association between allergy to benzoyl peroxide, vitiligo and implantation of a cemented total knee joint prosthesis: Is there a connection?]. AB - Allergies against bone cement or bone cement components have been well-described. We report on a 63-year-old patient who presented with progressive vitiligo all over the body after implantation of a cemented total knee replacement. A dermatological examination was performed and an allergy to benzoyl peroxide was found. A low-grade infection was diagnosed 5 months after implantation of the total knee replacement and the prosthesis was replaced with a cement spacer. After treating the infection of the knee replacement non-cemented arthrodesis of the knee was performed. In cases of new, unknown skin efflorescence, urticaria and periprosthetic loosening of cemented joint replacement, the differential diagnosis should include not only infections but also possible allergies against bone-cement and components such as benzoyl peroxide or metal components. PMID- 21678088 TI - [Biphosphonate-induced femoral stress fractures : A new problem and knowledge so far - case report]. AB - During the last several years the treatment of osteoporosis with bisphosphonates has become accepted as a safe and effective procedure. However, recently there have been increasing numbers of reports of rare complications in the literature. Particularly the occurrence of atypical fractures of the femur has become a focus of interest but the problem is insufficiently known and only rarely addressed in the scientific discussion. The case illustrated here and a survey of the important facts in the recent literature highlight essential aspects of long-term bisphosphonate therapy. PMID- 21678089 TI - Audiovisual material as educational innovation strategy to reduce anxiety response in students of human anatomy. AB - This study presents the design, effect and utility of using audiovisual material containing real images of dissected human cadavers as an innovative educational strategy (IES) in the teaching of Human Anatomy. The goal is to familiarize students with the practice of dissection and to transmit the importance and necessity of this discipline, while modulating their anxiety. The study included 303 first-year Human Anatomy students, randomly assigned to two groups (Traditional and Educational Innovation). Their state of anxiety was measured using the State-Trait-Anxiety Inventory. Repeated measures ANOVA with between subject factors was applied. The between-subject factor was Educational Innovation (EI). Two levels were established for this factor. The within-subject factor was Time, four levels being considered here. The results show that the effects of the Educational Innovation factor, Time factor and EI * Time interaction were statistically significant. These results provide an additional element of efficacy to the use of videos as an IES. That is, the use of video material as an introduction into an anxiety-provoking situation which resembles real-life viewing and interaction with human cadavers for the first time significantly diminishes the anticipatory reaction of dread against which novel students have not had the opportunity to develop any cognitive strategy of emotional control. PMID- 21678090 TI - Hypertensive choroidopathy in Castleman's disease. PMID- 21678091 TI - Experimental studies and modeling of drug release from a tunable affinity-based drug delivery platform. AB - An affinity-based drug delivery platform for controlling drug release is analyzed by a combination of experimental studies and mathematical modeling. This platform has the ability to form selective interactions between a therapeutic agent and host matrix that yields advantages over systems that employ nonselective methods. The incorporation of molecular interactions in drug delivery can increase the therapeutic lifetime of drug delivery implants and limit the need for multiple implants in treatment of chronic illnesses. To analyze this complex system for rational design of drug delivery implants, we developed a mechanistic mathematical model to quantify the molecular events and processes. With a beta cyclodextrin hydrogel host matrix, defined release rates were obtained using a fluorescent model drug. The key processes were the complexation between the drug and cyclodextrin and diffusion of the drug in the hydrogel. Optimal estimates of the model parameters were obtained by minimizing the difference between model simulation and experimentally measured drug release kinetics. Model simulations could predict the drug release dynamics under a wide range of experimental conditions. PMID- 21678092 TI - Aperture fixation instead of transverse tunnels at the patella for medial patellofemoral ligament reconstruction. AB - PURPOSE: Medial patellofemoral ligament (MPFL) reconstruction is an effective option for the treatment of recurrent patellar instability. Most techniques utilize the passage of a tendon graft through tunnels at the patella with the risk of patellar fracture. The purpose of this study was to investigate the strength of the recent MPFL reconstruction techniques (transverse tunnel, interference screw, anchor, and docking technique). METHODS: Thirty-six saw bones were divided into four groups (transverse tunnel, interference screw, anchor fixation, and docking technique) with nine patellae in each. Patella-tendon constructs were pre-loaded to 10 N and cyclically loaded for 20 cycles from 2 to 30 N under load control at a rate of 5 N/sec. The construct was then tested to failure at a constant displacement rate of 6 mm/sec. Ultimate load (N), stiffness (N/mm), and failure mode were recorded for each specimen. RESULTS: The docking group had lower ultimate load [106 (SD 41) N] and stiffness [14 (SD 2) N/mm] values than the other groups tested (P = 0.007). The anchor group had lower stiffness [21 (SD 6) N/mm] values than the tunnel group [28 (SD 3) N/mm (P = 0.01)] and the interference screw group [31 (SD 6) N/mm, (P = 0.004)]. There was no significant difference in the ultimate load between anchor [299 (SD 116) N], tunnel [304 (SD 140) N], and interference screw groups [241 (SD 103) N] (n.s.). CONCLUSION: Aperture fixation techniques, especially interference screw fixation, were as strong as the technique utilizing tunnels in the patella for MPFL reconstruction. PMID- 21678093 TI - Retro-trochanteric sciatica-like pain: current concept. AB - The aim of this manuscript is to review the current knowledge in terms of retro trochanteric pain syndrome, make recommendations for diagnosis and differential diagnosis and offer suggestions for treatment options. The terminology in the literature is confusing and these symptoms can be referred to as 'greater trochanteric pain syndrome', 'trochanteric bursitis' and 'trochanteritis', among other denominations. The authors focus on a special type of sciatica, i.e. retro trochanteric pain radiating down to the lower extremity. The impact of different radiographic assessments is discussed. The authors recommend excluding pathology in the spine and pelvic area before following their suggested treatment algorithm for sciatica-like retro-trochanteric pain. PMID- 21678094 TI - Meniscal allograft transplantation in isolated and combined surgery. AB - PURPOSE: The purpose of this study was to report the initial results of meniscus allograft transplantation after a 2-year follow-up period with second-look arthroscopy of 18 patients. METHODS: Seven medial and 11 lateral meniscus allografts were evaluated with a median follow-up of 24.9 months (range, 18-41 months). The clinical outcome and failure rate were evaluated by use of second look arthroscopy in all patients, magnetic resonance imaging (MRI) analysis in 17 patients, and standardized outcome scores assessment, including Lysholm score, Knee Injury, and Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS) on pain and satisfaction and International Knee Documentation Committee (IKDC) objective ratings in all patients. Patients were grouped into medial and lateral subgroups as well as those with isolated or combined procedures. RESULTS: For the second-look arthroscopic findings, 6 meniscus transplants (33%) had normal characteristics, 10 (56%) had altered characteristics, and 2 (11%) failed. On MRI, two grafts had grade III signals and 11 showed partially extruded. Patients demonstrated statistically significant improvements in standardized outcome scores and VAS pain scales. Overall, 67% of the patients reported that they were completely or mostly satisfied with the procedure. There were no significant differences in the medial and lateral subgroups and no significant differences were noted in the isolated and combined subgroups. CONCLUSIONS: Arthroscopic meniscus transplantation can achieve satisfying subjective and objective clinical outcomes, with a failure rate of 11% after 1-3 years of follow-up, as documented by second-look arthroscopy. PMID- 21678095 TI - Autologous platelet-rich plasma gel to reduce donor-site morbidity after patellar tendon graft harvesting for anterior cruciate ligament reconstruction: a randomized, controlled clinical study. AB - PURPOSE: Bone-patellar tendon-bone technique (BPTB) for anterior cruciate ligament injuries is associated with a higher risk of donor-site morbidity. To evaluate whether platelet-rich plasma (PRP), due to its anti-inflammatory properties and capacity to stimulate tissue regeneration, was able to reduce the anterior knee pain, the kneeling pain, and donor-site morbidity, as evidenced by evaluation of VISA and VAS scoring scales and MRI analysis of the tendon and bone defect, we performed a clinical randomized controlled study where PRP gel was applied to donor site after ACL reconstruction with BPTB. METHODS: Forty young athletes with the indication of ACL reconstruction with patellar tendon grafts were randomly assigned to group A (n = 20 patients, control group) or group B (n = 20 patients, PRP group). The autologous PRP gel was applied to both the patellar and tendon bone plug harvest site and stabilized by the peritenon suture. At 12-month follow-up, all patients underwent clinical examination and VAS and VISA questionnaires, respectively, evaluating the average daily pain of the knee and the pain during particular activities involving the knee, were filled. MRI at the same time point was also performed. RESULTS: VISA scores were significantly higher in the patients treated with PRP (84.5 +/- 11.8 and 97.8 +/- 2.5 for group A and for group B; P = 0.041), whereas no significant difference in postoperative VAS scores between the two groups was observed (1 +/- 1.4 and 0.6 +/- 0.9 for group A and group B, n.s.). In 85% of PRP group patients, the tibial and patellar bone defect was satisfactorily filled by new bony tissue (>70% of bone gap filled), whereas this percentage was just of 60% in control group patients, but this difference was not statistically significant. CONCLUSIONS: The study shows the usefulness of PRP in reducing subjective pain at the donor-site level after ACL reconstruction with BPTB. However, this approach deserves further investigations to confirm PRP efficacy and to elucidate its mechanism of action. LEVEL OF EVIDENCE: Prospective randomized controlled study, Level I. PMID- 21678097 TI - Osteosarcoma cells differentiate into phenotypes from all three dermal layers. AB - BACKGROUND: Osteosarcomas are the most common solid malignant bone tumors, but little is known of their origin. The embryonal rest hypothesis views cancer cells as arising from committed progenitor stem cells in each tissue. Adult tissue contains primitive stem cells that retain the ability to differentiate across dermal lines, raising the possibility that the stem cell of origin of cancers may be from a more primitive stem cell than a progenitor. QUESTIONS/PURPOSES: Can osteosarcoma cells, when cultured under conditions used for multipotent stem cells, be induced to differentiate into multiple phenotypes, including those of the three different dermal lineages: mesodermal, ectodermal, and endodermal? METHODS: One rat and one human osteosarcoma cell line were cultured and treated with concentrations of 0, 10(-10), 10(-9), 10(-8), 10(-7), and 10(-6) mol/L dexamethasone for 5 weeks. Seventeen phenotypes were assayed either by tissue specific histochemical stains or antibodies to tissue-specific proteins. Each phenotype was tested across all dexamethasone concentrations for each cell line and each phenotype was tested in three separate experiments with induction by dexamethasone RESULTS: Rat osteosarcoma (ROS) 17/2.8 and human osteosarcoma cell line U-2 show the appearance of cells that have markers for (1) mesodermal phenotypes such as bone, cartilage, skeletal muscle, and endothelial cells, (2) ectodermal phenotypes such as astrocytes, oligodendrocytes, neurons, and keratinocytes, and (3) an endodermal phenotype, hepatocytes. This indicates osteosarcomas are composed, at least in part, of primitive stem cells capable of differentiating into tissues from all three dermal lineages. CLINICAL RELEVANCE: If osteosarcomas arise from primitive stem cells, then treatment of osteosarcomas with exogenous differentiation agents may cause the stem cells to differentiate, thus halting their proliferation and stopping tumor growth. PMID- 21678098 TI - Cementless revision TKA with bone grafting of osseous defects restores bone stock with a low revision rate at 4 to 10 years. AB - BACKGROUND: Addressing bone loss in revision TKA is challenging despite the array of options to reconstruct the deficient bone. Biologic reconstruction using morselized loosely-packed bone graft potentially allows for augmentation of residual bone stock while offering physiologic load transfer. However it is unclear whether the reconstructions are durable. QUESTIONS/PURPOSES: We therefore sought to determine (1) survivorship and complications, (2) function, and (3) radiographic findings of cementless revision TKA in combination with loosely packed morselized bone graft to reconstruct osseous defects at revision TKA. PATIENTS AND METHODS: We retrospectively reviewed 56 patients who had undergone revision TKAs using cementless long-stemmed components in combination with morselized loose bone graft at our institution. There were 26 men and 30 women with a mean age of 68.3 years (range, 56-89 years). Patients were followed to assess symptoms and function and to detect radiographic loosening, component migration, and graft incorporation. The minimum followup was 4 years (mean, 7.3 years; range, 4-10 years). RESULTS: Cumulative prosthesis survival, with revision as an end point, was 98% at 10 years. The mean Oxford Knee Scores improved from 21 (36%) preoperatively to 41 (68%) at final followup. Five patients (9%) had reoperations for complications. CONCLUSIONS: Our observations suggest this technique is reproducible and obviates the need for excessive bone resection, use of large metal augments, mass allografts, or custom prostheses. It allows for bone stock to be reconstructed reliably with durable midterm component fixation. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21678099 TI - Sufficient release of antibiotic by a spacer 6 weeks after implantation in two stage revision of infected hip prostheses. AB - BACKGROUND: Although antibiotic-loaded spacers are commonly used to treat periprosthetic infections, it is unclear whether spacers continue to release bactericidal levels of antibiotic 6 weeks after implantation. QUESTIONS/PURPOSES: We asked whether an antibiotic can be detected in the tissue surrounding the spacer 6 weeks after implantation and whether the concentration is higher than the minimal inhibition concentration (MIC) previously determined for pathogens that are responsible for most periprosthetic infections. METHODS: We removed 14 spacers used in two-stage septic revisions of infected hip prostheses 6 weeks after the primary implantations and determined the concentration of the antibiotics in the membrane formed between the spacer and the neighboring bone on the acetabular and the femoral sides. In seven cases Copal cement with gentamicin and clindamycin were used, and in seven other cases vancomycin was added to the Copal cement. Concentrations of the spacer antibiotics in the neighboring tissue were determined by tandem mass spectroscopy. RESULTS: All three antibiotics were detected in concentrations higher than their MIC. There were no differences between the groups regardless whether vancomycin was added to the cement, or whether the cement was applied with the acetabular cup spacer or with the stem spacer. CONCLUSIONS: We concluded that, using the spacer technique described in this study, 6 weeks after spacer implantation, the concentrations of antibiotic are sufficient to treat a periprosthetic infection. PMID- 21678101 TI - Identification of directed interactions in networks. AB - Multichannel data collection in the neurosciences is routine and has necessitated the development of methods to identify the direction of interactions among processes. The most widely used approach for detecting these interactions in such data is based on autoregressive models of stochastic processes, although some work has raised the possibility of serious difficulties with this approach. This article demonstrates that these difficulties are present and that they are intrinsic features of the autoregressive method. Here, we introduce a new method taking into account unobserved processes and based on coherence. Two examples of three-process networks are used to demonstrate that although coherence measures are intrinsically non-directional, a particular network configuration will be associated with a particular set of coherences. These coherences may not specify the network uniquely, but in principle will specify all network configurations consistent with their values and will also specify the relationships among the unobserved processes. Moreover, when new information becomes available, the values of the measures of association already in place do not change, but the relationships among the unobserved processes may become further resolved. PMID- 21678100 TI - Advanced hemodynamic monitoring: principles and practice in neurocritical care. AB - Advanced hemodynamic monitoring is necessary for many patients with acute brain and/or spinal cord injury. Optimizing cerebral and systemic physiology requires multi-organ system function monitoring. Hemodynamic manipulations are cardinal among interventions to regulate cerebral perfusion pressure and cerebral blood flow. The pulmonary artery catheter is not any more the sole tool available; less invasive and potentially more accurate methodologies have been developed and employed in the operating room and among diverse critically ill populations. These include transpulmonary thermodilution, arterial pressure pulse contour, and waveform analysis and bedside critical care ultrasound. A thorough understanding of hemodynamics and of the available monitoring modalities is an essential skill for the neurointensivist. PMID- 21678102 TI - A hybrid radiation detector for simultaneous spatial and temporal dosimetry. AB - In this feasibility study an organic plastic scintillator is calibrated against ionisation chamber measurements and then embedded in a polymer gel dosimeter to obtain a quasi-4D radiation detector. This hybrid dosimeter was irradiated with megavoltage x-rays from a linear accelerator, with temporal measurements of the dose rate being acquired by the scintillator and spatial measurements acquired with the gel dosimeter. The detectors employed in this study are radiologically equivalent; and we show that neither detector perturbs the intensity of the radiation field of the other. By employing these detectors in concert, spatial and temporal variations in the radiation intensity can now be detected and gel dosimeters can be calibrated for absolute dose from a single irradiation. PMID- 21678103 TI - [In-hospital emergencies at a surgical university hospital]. AB - BACKGROUND: Emergency treatment and resuscitation within hospitals are managed by so-called medical emergency teams (MET). The present study examined the circumstances, number, initial treatment and further hospital course of in hospital emergency cases at a level 1 university hospital. METHODS: A retrospective study of in-hospital emergencies on the surgical wards of a university hospital including all non-intensive care areas from January 2007 to June 2010 was carried out. A self-developed documentation protocol which was introduced in 2006 was used by the MET to document general patient characteristics and details of the emergency treatment. These data included the place where the emergency situation arose, the patient's assignment to a surgical discipline, a detailed description of the emergency situation, the effectiveness of basic life support measures as well as the further hospital course of the patient. RESULTS: A total of 235 emergency cases were documented within the study period of 3.5 years. The frequency of in-hospital emergencies was 4/1,000 admitted patients per year. Cardiac arrest was encountered in 31,5%. Out of all patients 54,5% were admitted to an intensive care unit. CONCLUSION: The tasks of a MET at a surgical university hospital go beyond mere cardiopulmonary resuscitation. Emergency cases within the full spectrum of perioperative complications are encountered. Further multicenter studies with standardized protocols are required to analyze the management of German in-hospital emergencies. PMID- 21678104 TI - [The anterolateral thigh flap: its versatility in oncological soft tissue reconstruction of the head and neck region]. AB - The anterolateral thigh flap (ATL) has become a standard procedure in reconstructive microsurgery. In this study the results with the ALT for reconstruction in the head and neck area after tumor resection in 33 patients were retrospectively analyzed. Patients included 28 men and 5 women aged 47-70 years who suffered from intraoral and extraoral tumors. Satisfactory soft tissue coverage could be achieved in all patients and no flaps were lost. The ALT is a versatile free flap enabling reliable soft tissue reconstruction of complex defects in the head and neck region. Flap dissection and preparation of the recipient area can usually be performed simultaneously. Additional advantages include the long and strong caliber vascular pedicle, the low donor site morbidity and the different possibilities of tissue composition, making the ALT a workhorse flap in modern reconstructive microsurgery. PMID- 21678106 TI - [18th Annual Congress of the Renal Transplantation Working Group of the German Society of Urology: Wurzburg, 18-20 November 2010]. PMID- 21678105 TI - [Extent of resection for neuroendocrine tumors of the small intestine]. AB - Neuroendocrine tumors of the small intestine have been diagnosed with increasing frequency over the past 35 years and presently account for approximately 2% of all gastrointestinal neoplasms. While most of these tumors are discovered incidentally during emergency laparotomy or in the clinical setting of unknown primary cancer with hepatic metastases, the growing awareness of this rare entity and improved diagnostic methods promote earlier diagnosis. The classical carcinoid syndrome with flush, diarrhea and cardiac strain is observed only in 20 30% of patients. The clinical symptoms necessitate a special preoperative preparation of the patient including evaluation of cardiac function.Prospective studies assessing the efficacy of surgical treatment strategies for neuroendocrine neoplasms of the small intestine do not exist. However, retrospective studies have demonstrated that curative as well as palliative resection of the primary tumor improves the prognosis and the quality of life of patients. Besides limited resection of the small bowel in order to avoid postoperative short bowel syndrome an effective clearance of the regional lymph nodes is essential. A primary tumor site in the terminal ileum requires dissection of the lymph nodes on the right side of the ileocolic artery which usually implies an additional resection of the right colon. In cases of a primary tumor site located in the lower ileum up to the distal jejunum, a cone-shaped resection of the mesenterium of the small bowel with extension of lymphadenectomy into adjacent segments with preservation of vascularization is performed. PMID- 21678107 TI - [Metastatic renal cell carcinoma: therapeutic concepts for non-medicinal treatment]. AB - Metastatic renal cell carcinoma has a poor prognosis with a median overall survival rate of approximately 2 years. The current standard medicinal therapy includes the use of tyrosine kinase inhibitors or antiangiogenic substances, such as VEGF receptor antagonists. Improvement in clinical response is to be expected when surgical tumor debulking by nephrectomy or metastasectomy is performed before medicinal therapy is started and should be considered especially in patients with a good performance status. Additionally, complete resection of solitary or at least a limited number of metastases can potentially be done with curative intent. Radiotherapy remains the standard procedure for palliative therapy of brain metastases to reduce clinical symptoms and to improve intracerebral tumor control. PMID- 21678108 TI - The behavior of matrix metalloproteinase-9 in lymphocytic colitis, collagenous colitis and ulcerative colitis. AB - Matrix metalloproteinases play an important role in extracellular matrix remodelling. It has been proposed that matrix metalloproteinase-9 (MMP-9) is involved in epithelial damage in ulcerative colitis (UC). However, to our knowledge, no data are available in terms of MMP-9 expression in microscopic colitis. Determination of mucosal protein expression levels of MMP-9 in lymphocytic colitis (LC), collagenous colitis (CC) and UC. MMP-9 immunohistochemical expressions were analyzed in paraffin-embedded tissue samples by immunohistochemistry including patients with LC, CC, UC, active diverticulitis, inactive diverticular disease and healthy control subjects. UC was also subgrouped according to the severity of inflammation. Immunostaining was determined semiquantitatively. Independent colonic biopsies from healthy and severe UC cases were used for gene expression analyses. For further comparison MMP-9 serum antigen levels were also determined in patients with UC and control patients without macroscopic or microscopic changes during colonoscopy. MMP-9 mucosal expression was significantly higher in UC (26.7 +/- 19.5%) compared to LC (6.6 +/- 9.3%), CC (6.4 +/- 7.6%), active diverticulitis (5.33 +/- 2.4%), inactive diverticular disease (5.0 +/- 2.2%) and controls (6.3 +/- 2.6%) (P < 0.001). The immunohistochemical expression of MMP-9 in LC and CC was similar as compared to controls. MMP-9 expression was significantly higher in each inflammatory group of UC compared to controls (mild: 11.0 +/- 2.8%, moderate: 23.9 +/- 3.7%, severe UC: 52.6 +/- 3.9% and 6.3 +/- 2.6%, respectively, P < 0.005). The gene expression microarray data and RT-PCR results demonstrated a significantly higher expression of MMP-9 in severely active UC compared to healthy controls (P < 0.001). Significantly higher MMP-9 serum antigen concentrations were observed in UC patients compared with the control group (P < 0.05). MMP-9 seems to play no role in the inflammatory process of LC and CC. In contrast, the mucosal up-regulation of MMP-9 correlated with the severity of inflammation in UC. The increased MMP-9 expression could contribute to the severity of mucosal damage in active UC. PMID- 21678109 TI - Prognostic significance of Wnt-1, beta-catenin and E-cadherin expression in advanced colorectal carcinoma. AB - Wnt/beta-catenin pathway plays an important role in initiation and progression of colorectal oncogenesis. The aim of this study was to determine expression and localization of E-cadherin, beta-catenin and Wnt-1 proteins in colorectal tumors. Expression of beta-catenin, E-cadherin and Wnt-1 was determined by immunohistochemistry on advanced colorectal cancers. Abnormal expression of E cadherin, beta-catenin, Wnt-1 was observed. Additionally, we revealed correlations between levels of studied proteins and histoclinical data. In multivariate analysis nuclear beta-catenin, higher carcinoembryonic antigen serum level before treatment, female sex and tumor localized in colon or rectum were independent unfavorable prognostic factors. These findings support the hypothesis that Wnt/beta-catenin pathway plays an important role in advanced colorectal carcinoma. PMID- 21678110 TI - Breast tumor characteristics in hormone replacement therapy users. AB - The aim of this study was to further elucidate the influence of HRT use, regarding duration, regimen and route of administration, on breast tumor characteristics. We evaluated the associations between HRT use and breast tumor characteristics in 530 postmenopausal women diagnosed with invasive breast cancer. Detailed information on HRT use and mammographic attendance were collected through a postal questionnaire. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression. Tumors in HRT users were significantly smaller, more often of ductal histologic type and with lower grade and lower mitotic index compared to tumors in nonusers. Tumor characteristics did not vary significantly by HRT duration, regimen and route of administration, except for mitotic index, which was more often of score 2 in long-term users, and of score 3 in short-term users. Higher mammographic surveillance among HRT users did not explain our results. We conclude that tumors in HRT users have a more favorable prognostic profile regardless of duration, regimen and route of administration. These effects seem to be due to the influence of HRT on preexisting tumors causing their greater differentiation rather than earlier detection due to mammographic surveillance. PMID- 21678111 TI - A mathematical model of cell cycle effects in gastric cancer chemotherapy. AB - A mathematical model is presented to investigate the relationship between drug order and treatment response in gastric cancer chemotherapy involving a taxane (either paclitaxel or docetaxel) coupled with flavopiridol. To model treatment effects, we simulate treatment by bolus injection and employ a pulsing condition to indicate cell kill as well as instantaneous changes to the cell's transition rates. Cell population growth is described using an ordinary differential equation model whereby we examine the treatment effects upon cells in various stages of the cell cycle. Ultimately, the results generated support prior clinical investigations which indicate that for an enhanced synergistic effect, flavopiridol must be administered following taxane therapy. PMID- 21678112 TI - Imaging of vulnerable plaques: will it affect patient management and influence outcomes? PMID- 21678113 TI - Paediatric MRI under sedation: is it necessary? What is the evidence for the alternatives? AB - To achieve diagnostic images during MRI examinations, small children need to lie still to avoid movement artefact. To reduce patient motion, obviate the need for voluntary immobilisation or breath-holding and therefore obtain high-quality images, MRI of infants is frequently carried out under sedation or general anaesthesia, but this is not without risk and expense. However, many other techniques are available for preparing children for MRI, which have not been fully evaluated. Here, we evaluate the advantages and disadvantage of sedation and anaesthesia for MRI. We then evaluate the alternatives, which include neonatal comforting techniques, sleep manipulation, and appropriate adaptation of the physical environment. We summarize the evidence for their use according to an established hierarchy. Lastly, we discuss several factors that will influence the choice of imaging preparation, including patient factors, imaging factors and service provision. The choice of approach to paediatric MRI is multi-factorial, with limited scientific evidence for many of the current approaches. These considerations may enable others to image children using MRI under different circumstances. PMID- 21678114 TI - Transient elastography for assessment of fibrosis in paediatric liver disease. AB - The prognosis and management of chronic liver diseases in children largely depend on the extent and progression of liver fibrosis, which is often the most important predictor of disease outcome, and thus influences the indication for potential therapy. Unfortunately, liver biopsy continues to be the gold standard for the staging and grading of fibrosis. Liver biopsy is an invasive and painful technique with several limitations. These limitations have led to the development of alternative noninvasive methods for the accurate assessment of fibrosis and for the maintenance of an acceptable risk/benefit ratio. In the last decades, transient elastography (TE) has received increasing consideration as a means of evaluating disease progression in paediatric chronic liver disease. TE is an accurate and reproducible methodology for identifying subjects without fibrosis or significant fibrosis, or with advanced fibrosis. In this review, we provide an outline of liver fibrosis in paediatric liver diseases, including fibrogenesis, and noninvasive techniques for the diagnosis and follow-up of fibrosis, and then focus on the characteristics of TE and on its strength in the assessment of liver fibrosis, paying particular attention to studies conducted in children. PMID- 21678116 TI - XXV Triennial World Congress--SICOT 2011. PMID- 21678115 TI - Influence of the right- versus left-sided sleeping position on the apnea-hypopnea index in patients with sleep apnea. AB - PURPOSE: Sleep and sleep position have a significant impact on physical, cardiac and mental health, and have been evaluated in numerous studies particularly in terms of lateral sleeping positions and their association with diseases. We retrospectively examined the relationship between the sleeping position and position-specific apnea-hypopnea index (AHI) in obstructive sleep apnea-hypopnea (OSA) patients. METHODS: We assessed the sleeping body position and the body position-specific AHI score in patients who were referred for suspected OSA and underwent diagnostic nocturnal polysomnography. In order to eliminate inter individual differences, only those who had a similar percentage of time spent in the LSSP and RSSP for each patient were enrolled. To provide this validity, only subjects that had a similar percentage of left and right lateral sleep time (+/ 10%) were included in the analysis. RESULTS: A total of 864 patients had nocturnal diagnostic PSG. Of them, 131 patients met the inclusion criteria. The percent rate spent in the supine sleeping position (SSP) was 31.3 +/- 18.7%, in the LSSP was 31.8 +/- 10% and in the RSSP was 32.6 +/- 10.8%. Whereas the SSP specific AHI score was the highest with 60.4 +/- 36.2/h among all the sleeping position-specific AHI scores (p < 0.001), the LSSP-specific AHI score was statistically higher than that for RSSP (30.2 +/- 32.6/h vs. 23.6 +/- 30.1/h; p < 0.001). When comparing individuals sub-grouped based on OSA severity, there was a statistically significant difference between the LSSP-specific AHI score and RSSP specific AHI score in patients with severe (p = 0.002) and moderate (p = 0.026), but not mild (p = 0.130) OSA. CONCLUSION: We found that the sleeping position had a significant influence on apneic events and RSSP decreased the frequency of obstructive respiratory events in patients with moderate and severe disease. PMID- 21678117 TI - Autophagy suppression promotes apoptotic cell death in response to inhibition of the PI3K-mTOR pathway in pancreatic adenocarcinoma. AB - Targeting of pathways downstream of RAS represents a promising therapeutic strategy for pancreatic cancer, the fourth leading cause of cancer-related death in the USA, since activation of the Raf-MEK-ERK and PI3K-AKT pathways is found frequently in this disease and is associated with poor prognosis. Taking advantage of a panel of human PDAC cell lines and specific inhibitors of PI3K and/or mTOR, we systematically address the question whether dual-targeted inhibition of the PI3K and mTOR pathways offers advantages over single-targeted inhibition of PI3K in PDAC. We observe greater overall susceptibility of cell lines to dual inhibition compared to targeting PI3K alone. However, we find that dual inhibition of PI3K and mTOR induces autophagy to a greater extent than inhibition of each target alone. In agreement with this, we show that combined administration of PI3K/mTOR and autophagy inhibitors results in increased anti tumor activity in vitro and in vivo in models of pancreatic adenocarcinoma. XL765, a PI3K/mTOR inhibitor used in our in vivo studies, is currently undergoing clinical evaluation in a variety of cancer types, while the autophagy inhibitor chloroquine is a widely used anti-malaria compound. Thus, our studies provide rationale for clinical development of combinations of these compounds for the treatment of pancreatic adenocarcinoma. PMID- 21678118 TI - Identification of heparin samples that contain impurities or contaminants by chemometric pattern recognition analysis of proton NMR spectral data. AB - Chemometric analysis of a set of one-dimensional (1D) (1)H nuclear magnetic resonance (NMR) spectral data for heparin sodium active pharmaceutical ingredient (API) samples was employed to distinguish USP-grade heparin samples from those containing oversulfated chondroitin sulfate (OSCS) contaminant and/or unacceptable levels of dermatan sulfate (DS) impurity. Three chemometric pattern recognition approaches were implemented: classification and regression tree (CART), artificial neural network (ANN), and support vector machine (SVM). Heparin sodium samples from various manufacturers were analyzed in 2008 and 2009 by 1D (1)H NMR, strong anion-exchange high-performance liquid chromatography, and percent galactosamine in total hexosamine tests. Based on these data, the samples were divided into three groups: Heparin, DS <= 1.0% and OSCS = 0%; DS, DS > 1.0% and OSCS = 0%; and OSCS, OSCS > 0% with any content of DS. Three data sets corresponding to different chemical shift regions (1.95-2.20, 3.10-5.70, and 1.95 5.70 ppm) were evaluated. While all three chemometric approaches were able to effectively model the data in the 1.95-2.20 ppm region, SVM was found to substantially outperform CART and ANN for data in the 3.10-5.70 ppm region in terms of classification success rate. A 100% prediction rate was frequently achieved for discrimination between heparin and OSCS samples. The majority of classification errors between heparin and DS involved cases where the DS content was close to the 1.0% DS borderline between the two classes. When these borderline samples were removed, nearly perfect classification results were attained. Satisfactory results were achieved when the resulting models were challenged by test samples containing blends of heparin APIs spiked with non-, partially, or fully oversulfated chondroitin sulfate A, heparan sulfate, or DS at the 1.0%, 5.0%, and 10.0% (w/w) levels. This study demonstrated that the combination of 1D (1)H NMR spectroscopy with multivariate chemometric methods is a nonsubjective, statistics-based approach for heparin quality control and purity assessment that, once standardized, minimizes the need for expert analysts. PMID- 21678119 TI - Striking presence of Egyptian blue identified in a painting by Giovanni Battista Benvenuto from 1524. AB - Egyptian blue has been identified in a painting from 1524 by the Italian artist Ortolano Ferrarese (Giovanni Battista Benvenuto). Egyptian blue is the oldest known synthetic pigment, invented by the Egyptians in the fourth dynasty (2613 2494 BC) of the Old Kingdom and extensively used throughout Antiquity. From about 1000 A.D., it disappeared from the historical record and was only reinvented in the late nineteenth and early twentieth century. The discovery of Egyptian blue in Ortolano Ferrarese's painting from 1524 shows that Egyptian blue was in fact available in the period from which it is normally considered not to exist. The identification of Egyptian blue is based on optical microscopy supported by energy-dispersive spectroscopy and visual light photon-induced spectroscopy, and finally confirmed by Raman microspectroscopy. PMID- 21678121 TI - Parents' reading-related knowledge and children's reading acquisition. AB - Teacher reading-related knowledge (phonological awareness and phonics knowledge) predicts student reading, however little is known about the reading-related knowledge of parents. Participants comprised 70 dyads (children from kindergarten and grade 1 and their parents). Parents were administered a questionnaire tapping into reading-related knowledge, print exposure, storybook reading, and general cultural knowledge. Children were tested on measures of letter-word knowledge, sound awareness, receptive vocabulary, oral expression, and mathematical skill. Parent reading-related knowledge showed significant positive links with child letter-word knowledge and sound awareness, but showed no correlations with child measures of mathematical skill or vocabulary. Furthermore, parent reading-related knowledge was not associated with parents' own print exposure or cultural knowledge, indicating that knowledge about English word structure may be separate from other cognitive skills. Implications are discussed in terms of improving parent reading-related knowledge to promote child literacy. PMID- 21678122 TI - Effect of baicalin on matrix metalloproteinase-9 expression and blood-brain barrier permeability following focal cerebral ischemia in rats. AB - Focal cerebral ischemia results in an increased expression of matrix metalloproteinase-9 (MMP-9), which induces vasogenic brain edema via disrupting the blood-brain barrier (BBB) integrity. Recent studies from our laboratory showed that baicalin reduces ischemic brain damage by inhibiting inflammatory reaction and neuronal apoptosis in a rat model of focal cerebral ischemia. In the present study, we first explored the effect of baicalin on the neuronal damage, brain edema and BBB permeability, then further investigated its potential mechanisms. Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO). Baicalin was administrated by intraperitoneally injected twice at 2 and 12 h after the onset of MCAO. Neuronal damage, brain edema and BBB permeability were measured 24 h following MCAO. Expression of MMP-9 protein and mRNA were determined by western blot and RT-PCR, respectively. Expression of tight junction protein (TJP) occludin was detected by western blot. Neuronal damage, brain edema and BBB permeability were significantly reduced by baicalin administration following focal cerebral ischemia. Elevated expression of MMP-9 protein and mRNA were significantly down-regulated by baicalin administration. In addition, MCAO caused the decreased expression of occludin, which was significantly up-regulated by baicalin administration. Our study suggested that baicalin reduces MCAO-induced neuronal damage, brain edema and BBB permeability, which might be associated with the inhibition of MMP-9 expression and MMP-9 mediated occludin degradation. PMID- 21678123 TI - Japanese encephalitis (JE). Part I: clinical profile of 1,282 adult acute cases of four epidemics. AB - Japanese encephalitis (JE) is numerically the most important global cause of encephalitis and so far confirmed to have caused major epidemics in India. Most of the reported studies have been in children. This largest study involving only adults, belonging to four epidemics, is being reported from Gorakhpur. The aim of this study is to detail the acute clinical profile (not viral) outcome and to classify the sequelae at discharge. This prospective study involved 1,282 adult patients initially diagnosed as JE admitted during the epidemics of 1978, 1980, 1988, and 1989, on identical clinical presentation and CSF examination. In the meantime, the diagnosis of JE was confirmed by serological and/or virological studies in only a representative number of samples (649 of 1,282 cases). Eighty three left against medical advice (LAMA) at various stages, so 1,199 of 1,282 were available for the study. Peak incidence of [1,061 of 1,282 (83%)] of clinically suspected cases was from September 15 to November 2. Serum IgM and IgG were positive in high titers in 50.87% (330 of 649) and IgM positive in CSF in 88.75% (109 of 123) of the cases. JE virus could be isolated from CSF and brain tissue in 5 of 5 and 4 of 5 samples, respectively. Altered sensorium (AS) in (96%), convulsions (86%), and headache (85%) were the main symptoms for hospitalization by the third day of the onset. Other neurological features included hyperkinetic movements in 593 of 1,282 (46%)-choreoathetoid in 490 (83%) and bizarre, ill-defined in 103 (17%). The features of brain stem involvement consisted of opsoclonus (20%), gaze palsies (16%), and pupillary changes (48%) with waxing and waning character. Cerebellar signs were distinctly absent. Dystonia and decerebrate rigidity was observed in 43 and 6%, respectively, paralytic features in 17% and seizures in 30%. Many non-neurological features of prognostic importance included abnormal breathing patterns (ABP) (45%), pulmonary edema (PO) (33%), and upper gastrointestinal hemorrhage (UGIH) (16%). Injection dexamethasone was used in 1978 in all 208 cases, including 21 of PO. Patients were later randomized alternately in dexa and non-dexa groups. Forty-six cases of PO from the non-dexa group were transferred to the dexa group as an ultimate life saving measure. Thus, it was administered in 737 of 1,199 patients including 529 patients from the later epidemics in doses of 4 mg IV every 8 h for 7 days. Of 1,199, 462 did not receive it. There was no significant difference in mortality (p > 0.05) between the dexa (42.47%) and the non-dexa group (42.86%). All PO cases expired; so after the exclusion of the PO cases from dexa group, the difference of 6.14% (42.86 and 36.72) became significant (p < 0.01) (511 of 1,199 (43%) expired, [320 of 511 (63%) died within 3 days of hospitalization]). Out of a total of 1,199 patients treated, 688 (57%) were discharged; 23 of 688 (3%) without any sequelae and 665 of 688 (97%) with neuropsychiatric deficits classified into nine groups. During the four epidemics, the diagnosis of JE was basically on identical clinical presentation of acute encephalitic syndrome (AES) consisting of (1) abrupt onset of fever, headache, and AS, (2) dystonias and various movement disorders, (3) opsoclonus and gaze palsies, (4) CSF findings, and (5) the presence of residual neuropsychiatric and neurological features in the survivors. PMID- 21678124 TI - The importance of a proper aetiological diagnosis in the management of patients with invasive mycoses: a case report of a brain abscess by Scedosporium apiospermum. AB - Scedosporium apiospermum is a saprobic fungus responsible for many different clinical manifestations. Although it affects mostly immunocompromised patients, pulmonary and disseminated scedosporiosis have also been reported in immunocompetent subjects. It often causes subcutaneous mycetoma, despite its preferential tropism to CNS. The authors describe a fatal case of a S. apiospermum brain abscess in a 58-year-old female. She was affected by chronic liver disease and idiopathic pulmonary fibrosis and had been treated with corticosteroid therapy for a long time. She recovered in a neurosurgery unit, wherein TC scan and cerebral MRI revealed an expansive left temporo-parietal process with vasogenic oedema. A stereotactic puncture of the lesion was carried out, and pus of brain abscess was evacuated. Empirical antifungal therapy was initiated with liposomal amphotericine B based on the clinical suspicion of Zygomycetes infection; after 3 days, posaconazole was added. The correct aetiological diagnosis arrived too late and the patient was treated with no specific therapy. This fatal case confirms the necessity of having a fast and correct aetiological diagnosis to improve the patient's outcome. PMID- 21678125 TI - Adherence, shared decision-making and patient autonomy. AB - In recent years the formerly quite strong interest in patient compliance has been questioned for being too paternalistic and oriented towards overly narrow biomedical goals as the basis for treatment recommendations. In line with this there has been a shift towards using the notion of adherence to signal an increased weight for patients' preferences and autonomy in decision making around treatments. This 'adherence-paradigm' thus encompasses shared decision-making as an ideal and patient perspective and autonomy as guiding goals of care. What this implies in terms of the importance that we have reason to attach to (non )adherence and how has, however, not been explained. In this article, we explore the relationship between different forms of shared decision-making, patient autonomy and adherence. Distinguishing between dynamically and statically framed adherence we show how the version of shared decision-making advocated will have consequences for whether one should be interested in a dynamically or statically framed adherence and in what way patient adherence should be assessed. In contrast to the former compliance paradigm (where non-compliance was necessarily seen as a problem), using observations about (non-)adherence to assess the success of health care decision making and professional-patient interaction turns out to be a much less straightforward matter. PMID- 21678126 TI - Giant coronary artery aneurysm with coronary arteriovenous fistula draining into the coronary sinus. AB - A 77-year-old patient suffering from a giant right coronary artery aneurysm with coronary arteriovenous fistula was admitted to our hospital. The fistula could not be documented preoperatively by computed tomography or coronary angiography but was documented intraoperatively by transesophageal echocardiography (TEE). However, TEE was unable to visualize the draining site of the fistula. Direct palpation by the surgeon ultimately confirmed that the fistula was draining into the coronary sinus. The fistula was closed and the volume of the aneurysm reduced by partial resection. The postoperative course of the patient was uneventful. Giant aneurysms occasionally displace cardiac structures. In such cases, combined imaging technologies, including TEE, may be needed for precise assessment of the giant aneurysm and fistula. PMID- 21678127 TI - FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation. AB - To examine the roles of FGF and ERK MAPK signaling in osteocyte differentiation and function, we performed microarray analyses using the osteocyte cell line MLO Y4. This experiment identified a number of mineralization-related genes that were regulated by FGF2 in an ERK MAPK-dependent manner. Real-time PCR analysis indicated that FGF2 upregulates Ank, Enpp1, Mgp, Slc20a1, and Dmp1 in MLO-Y4 cells. Consistent with this observation, the selective FGF receptor inhibitor PD173074 decreased Ank, Enpp1, Slc20a1, and Dmp1 mRNA expression in mouse calvaria in organ culture. Since Dmp1 plays a central role in osteocyte differentiation and mineral homeostasis, we further analyzed FGF regulation of Dmp1. Similar to FGF2, FGF23 upregulated Dmp1 expression in MLO-Y4 cells in the presence of Klotho. Furthermore, increased extracellular phosphate levels partially inhibited FGF2-induced upregulation of Dmp1 mRNA expression, suggesting a coordinated regulation of Dmp1 expression by FGF signaling and extracellular phosphate. In MLO-Y4 osteocytes and in MC3T3E1 and primary calvaria osteoblasts, U0126 strongly inhibited both basal expression of Dmp1 mRNA and FGF2-induced upregulation. Consistent with the in vitro observations, real-time PCR and immunohistochemical analysis showed a strong decrease in Dmp1 expression in the skeletal elements of ERK1(-/-); ERK2(flox/flox); Prx1-Cre mice. Furthermore, scanning electron microscopic analysis revealed that no osteocytes with characteristic dendritic processes develop in the limbs of ERK1(-/-); ERK2 (flox/flox); Prx1-Cre mice. Collectively, our observations indicate that FGF signaling coordinately regulates mineralization-related genes in the osteoblast lineage and that ERK signaling is essential for Dmp1 expression and osteocyte differentiation. PMID- 21678128 TI - Prospective versus retrospective ECG-gated 64-detector coronary CT angiography for evaluation of coronary artery bypass graft patency: comparison of image quality, radiation dose and diagnostic accuracy. AB - We aimed to evaluate image quality, radiation dose and diagnostic accuracy of coronary CT angiography (CCTA) with a prospectively gated transverse-axial scan (PGT) compared with a retrospectively gated helical scan (RGH), using a 64-slice scanner in patients who underwent coronary artery bypass graft (CABG). Of the 131 consecutive patients that underwent CABG using 64-slice multidetector row computed tomography during 2008, patients with heart rate (HR) of <75 beats/minute (bpm), and HR variation <10 bpm were included in the study. PGT was performed on 39 patients with 93 grafts, with RGH performed on 43 patients with 102 grafts. Image quality (1: excellent-4: poor) and estimated radiation dose were compared between the two groups. Of these, a total of 64 segments in 26 patients were subjected to invasive coronary angiography (ICA) for clinical reasons. Diagnostic accuracy of CCTA for evaluation of graft was performed between the two groups with ICA as a reference standard in terms of significant stenosis (>= 50% of luminal stenosis). The image quality was not statistically different in the two groups. Mean effective radiation dose was 6.5 mSv in PGT group, which was significantly lower than that in the RGH-group (21.2 mSv; P < 0.001). There was no statistically significant difference in diagnostic accuracy between the two groups (PGT-group versus RGH-group; 93.1% versus 91.4%). PGT can achieve dose reductions of up to 70% compared to RGH while maintaining image quality and high diagnostic accuracy in patients undergoing CABG. PMID- 21678129 TI - Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia. AB - Due to the poor prognosis and limited therapeutic options for adult patients with acute lymphoblastic leukemia (ALL), development of novel therapies is much needed to prolong patient survival and increase the efficacy of their treatment. Malignant T cells need high levels of nutrients to maintain their proliferation rate. Borrelidin, a small molecule nitrile-containing macrolide, is an inhibitor of bacterial and eukaryal threonyl-tRNA synthetase. Borrelidin-mediated inhibition of aminoacyl-tRNA synthesis, leads to an induction in the levels of uncharged tRNA, nutritional stress and ultimately inhibition of protein synthesis. The aim of the present study was to investigate whether borrelidin treatment inhibits the proliferation of malignant ALL cell lines, Jurkat and CEM cells, and study the mechanism by which this drug acts. Our results show that borrelidin was able to potently inhibit the proliferation of ALL cell lines with a half maximal inhibitory concentration of 50 ng/ml. Borrelidin showed a greater inhibitory effect on ALL cell lines compared to primary fibroblasts. Flow cytometry and western blot analysis indicated that borrelidin was able to increase the level of apoptosis and cause G(1) arrest in ALL cell lines. Activation of the general control nonderepressible-2 (GCN2) kinase stress responsive pathway and induction of CHOP protein was significantly higher in ALL cell lines treated with borrelidin. These findings collectively suggest for the first time that borrelidin targets ALL cell lines by inducing apoptosis and mediating G(1) arrest and that borrelidin treatment in ALL cell lines is correlated with activation of the GCN2 kinase pathway. PMID- 21678131 TI - [Vessel aging. The role of oxidative stress and protein glycation]. AB - The slow procession of the primary mechanisms of aging leads, at first, to unnoticed changes in the vascular system. Endothelial dysfunction is one of the earliest markers in aging vessels, caused by oxidative stress via the reduction of the availability of NO, on the one hand, and the nitrosylation of proteins, on the other hand. At the same time, glycation of the proteins of the extracellular matrix leads to stiffening of the vessel wall. Together with the loss of elastic fibers, e.g., elastin, this leads to the age-related changes of the vessels. Knowledge of these primary mechanisms of aging may lead to the development of new drugs. PMID- 21678132 TI - [Diabetes and cardiovascular diseases in old age]. AB - The treatment of cardiovascular diseases in diabetic geriatric patients needs an individual risk-benefit analysis. The overtreatment of hyperglycemia in the sense of metabolic control that is too tight (HbA(1)c level <6%) may lead to increased mortality. As a rule, the target HbA(1)c level in geriatric patients with diabetes mellitus should be between 7 and 8%. PMID- 21678135 TI - Prion seeded conversion and amplification assays. AB - The conversion of the normal prion protein (PrP(C)) into its misfolded, aggregation-prone and infectious (prion) isoform is central to the progression of transmissible spongiform encephalopathies (TSEs) or prion diseases. Since the initial development of a cell free PrP conversion reaction, striking progress has been made in the development of much more continuous prion-induced conversion and amplification reactions. These studies have provided major insights into the molecular underpinnings of prion propagation and enabled the development of ultra sensitive tests for prions and prion disease diagnosis. This chapter will provide an overview of such reactions and the practical and fundamental consequences of their development. PMID- 21678136 TI - Fragment screening using X-ray crystallography. AB - The fragment-based approach is now well established as an important component of modern drug discovery. A key part in establishing its position as a viable technique has been the development of a range of biophysical methodologies with sufficient sensitivity to detect the binding of very weakly binding molecules. X ray crystallography was one of the first techniques demonstrated to be capable of detecting such weak binding, but historically its potential for screening was under-appreciated and impractical due to its relatively low throughput. In this chapter we discuss the various benefits associated with fragment-screening by X ray crystallography, and describe the technical developments we have implemented to allow its routine use in drug discovery. We emphasize how this approach has allowed a much greater exploitation of crystallography than has traditionally been the case within the pharmaceutical industry, with the rapid and timely provision of structural information having maximum impact on project direction. PMID- 21678137 TI - Thermodynamic properties for applications in chemical industry via classical force fields. AB - Thermodynamic properties of fluids are of key importance for the chemical industry. Presently, the fluid property models used in process design and optimization are mostly equations of state or G (E) models, which are parameterized using experimental data. Molecular modeling and simulation based on classical force fields is a promising alternative route, which in many cases reasonably complements the well established methods. This chapter gives an introduction to the state-of-the-art in this field regarding molecular models, simulation methods, and tools. Attention is given to the way modeling and simulation on the scale of molecular force fields interact with other scales, which is mainly by parameter inheritance. Parameters for molecular force fields are determined both bottom-up from quantum chemistry and top-down from experimental data. Commonly used functional forms for describing the intra- and intermolecular interactions are presented. Several approaches for ab initio to empirical force field parameterization are discussed. Some transferable force field families, which are frequently used in chemical engineering applications, are described. Furthermore, some examples of force fields that were parameterized for specific molecules are given. Molecular dynamics and Monte Carlo methods for the calculation of transport properties and vapor-liquid equilibria are introduced. Two case studies are presented. First, using liquid ammonia as an example, the capabilities of semi-empirical force fields, parameterized on the basis of quantum chemical information and experimental data, are discussed with respect to thermodynamic properties that are relevant for the chemical industry. Second, the ability of molecular simulation methods to describe accurately vapor liquid equilibrium properties of binary mixtures containing CO(2) is shown. PMID- 21678138 TI - Integrated multifunctional microfluidics for automated proteome analyses. AB - Proteomics is a challenging field for realizing totally integrated microfluidic systems for complete proteome processing due to several considerations, including the sheer number of different protein types that exist within most proteomes, the large dynamic range associated with these various protein types, and the diverse chemical nature of the proteins comprising a typical proteome. For example, the human proteome is estimated to have >10(6) different components with a dynamic range of >10(10). The typical processing pipeline for proteomics involves the following steps: (1) selection and/or extraction of the particular proteins to be analyzed; (2) multidimensional separation; (3) proteolytic digestion of the protein sample; and (4) mass spectral identification of either intact proteins (top-down proteomics) or peptide fragments generated from proteolytic digestions (bottom-up proteomics). Although a number of intriguing microfluidic devices have been designed, fabricated and evaluated for carrying out the individual processing steps listed above, work toward building fully integrated microfluidic systems for protein analysis has yet to be realized. In this chapter, information will be provided on the nature of proteomic analysis in terms of the challenges associated with the sample type and the microfluidic devices that have been tested to carry out individual processing steps. These include devices such as those for multidimensional electrophoretic separations, solid-phase enzymatic digestions, and solid-phase extractions, all of which have used microfluidics as the functional platform for their implementation. This will be followed by an in depth review of microfluidic systems, which are defined as units possessing two or more devices assembled into autonomous systems for proteome processing. In addition, information will be provided on the challenges involved in integrating processing steps into a functional system and the approaches adopted for device integration. In this chapter, we will focus exclusively on the front-end processing microfluidic devices and systems for proteome processing, and not on the interface technology of these platforms to mass spectrometry due to the extensive reviews that already exist on these types of interfaces. PMID- 21678139 TI - PTOV1 is associated with UCH-L1 and in response to estrogen stimuli during the mouse oocyte development. AB - To investigate the biological significance of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) involvement in oocyte maturation, we screened for proteins that bound to UCH-L1 in mouse ovaries, and we found that the prostate tumor overexpressed-1 (PTOV1) protein was able to bind to UCH-L1. PTOV1 is highly expressed in prostate cancers and considered as a potential marker for carcinogenesis and the progress of prostate cancer. It was reported that PTOV1 plays an important role in cell cycle regulation, but its role in mammalian oocyte development and meiosis is still unclear. In this paper, it was found that the expression levels of PTOV1 in mouse ovaries progressively increased from prepubescence to adulthood. And we found by immunohistochemistry that PTOV1 spreaded in both the cytoplasm and nuclei of oocytes during prepuberty, but in normal adult mouse oocytes, it concentrated not only in nuclei but also on the plasma membrane, though in some oocytes with abnormal shapes, PTOV1 did not display the typical distribution patterns. In granulosa cells, however, it was found to locate in the cytoplasm at all the selected ages. In postnatal mouse ovaries (28 days), estradiol treatment induced the adult-specific distribution pattern of PTOV1 in oocytes. In addition, UCH-L1 was shown to be associated with CDK1, which participated in the regulation of cell cycle and oocyte maturation. Therefore, we propose that the distribution changes of PTOV1 are age-dependent, and significant for mouse oocyte development and maturation. Moreover, the discovery that PTOV1 is associated with UCH-L1 in mouse oocytes supports the explanations for that UCH-L1 is involved in oocyte development and maturation, especially under the regulation of estrogen. PMID- 21678140 TI - Heart rate variability is related to training load variables in interval running exercises. AB - Overload principle of training states that training load (TL) must be sufficient to threaten the homeostasis of cells, tissues, organs and/or body. However, there is no "golden standard" for TL measurement. The aim of the present study was to investigate if post-exercise heart rate variability (HRV) could be used to evaluate TL of interval running exercises with different intensities and durations. Thirteen endurance-trained men (35 +/- 5 years) performed MO(250) [moderate intensity, 2 * 6 * 250 m/rec 30 s/5 min at 85% of the maximal velocity of the graded maximal test (V (max))], MO(500) (2 * 3 * 500 m/rec 1 min/5 min at 85% V (max)) and HI(250) (high intensity, 2 * 6 * 250 m/rec 30 s/5 min at 105% V (max)) interval exercises on a treadmill. HRV was analyzed during rest, exercise and immediate 15 min recovery. Fast recovery of LFP (P < 0.001), HFP (P < 0.01) and TP (P < 0.01) occurred during the first two recovery minutes after each exercise. Strong negative correlations (P < 0.01) were found between post exercise HRV and perceived exertion as well as excess post-exercise oxygen consumption. Post-exercise HRV differentiated interval exercises of equal work, but varying intensity or distance of running bout. The results of the present study suggest that immediate post-exercise HRV may offer objective information on TL of interval exercises with different bout durations and intensities. PMID- 21678141 TI - Evaluating efficiency of training: an application in primary health centers using multiple comparison techniques. AB - The purpose of this research is to measure the efficiency of training in the general principles of vaccine applications, the cold chain, and the adverse effects after vaccination for 51 employees (31 midwives and 20 nurses) working at primary health centers in Tuzla Health Group Region via test and retest method. The data collected through measurement of test scores before and after training is analyzed via multiple comparison techniques such as general test scores, the scores of each training, the scores of previously trained subjects, and difference scores. Achievement scores after training were significantly high. Previous training did not reveal significant effects on the results. Having been trained before did not cause permanent influence. PMID- 21678142 TI - Introducing the health coach at a primary care practice: a pilot study (part 2). AB - It is well known that the cost of healthcare in the United States is a poor value proposition. One of the primary goals of the healthcare reform act is to reduce cost while improving healthcare quality. The authors believe that adding a health coach helps to achieve this goal. In part I, the authors discuss the role of a health coach in the healthcare field. They present the findings from a pilot study at a primary care practice managing diabetes of patients using a health coach. The findings from the study suggest that adding a health coach helps in cost savings as well as improved health for the patients. PMID- 21678143 TI - Is nursing a profession in Turkey? AB - Nursing has been a dynamic process since the existence of humanity on Earth. As a part of this process, whether nursing is an occupation or a profession has been a long-lasting question. There exist different sets of criteria and schemes of classification that are used to define professions. In this article the authors inquire into the professionalism of nursing in Turkey in view of the criteria for nursing professionalism first set by B. K. Miller et al. (1993). PMID- 21678144 TI - Social capital influence in illicit drug use among racial/ethnic groups in the United States. AB - Data from the 2003 National Survey on Drug Use and Health was utilized to elucidate the relationship between individual-level social capital and illicit drug use among racial/ethnic groups. Analysis of variance indicated that Whites had different perceptions of social capital compared to other groups, in measures of social participation, neighborhood cohesion, trust, and norms of reciprocity. Logistic regression analysis showed that individual-level social capital, measured by trust and norms of reciprocity, was weakly associated with illicit drug use. However, individuals with higher social participation were less likely to have used illicit drugs ever or during the month prior to the interview. The association between social capital and illicit drug use is discussed, as well as the role of social participation in illicit drug use. Rather than an individual level measure of social capital, future research should employ a neighborhood level measure of social capital that aggregates neighborhood cohesion, trust, norms of reciprocity, and social participation. PMID- 21678145 TI - Ecstasy use and associated risk factors among Asian-American youth: findings from a national survey. AB - This study examined ecstasy use and associated risk and protective factors among Asian American youth. Data from 996 Asian American adolescents and 1,108 Asian American young adults were used. Ecstasy use was relatively common among Asian American youth. Among adolescents, it was associated with older age, poor parent child communication, having been approached by drug sellers, living in a metropolitan area, and positive attitudes toward substance use. Among Asian American young adults, it was associated with having been born in the United States, having been approached by drug sellers, criminal justice system involvement, and positive attitudes toward substance use. Implications for designing substance use prevention/intervention programs for this minority group are discussed. PMID- 21678146 TI - The use of coca: prehistory, history, and ethnography. AB - The purpose of this article is to review the use of the natural mild stimulant coca, which is a story that originates with the prehistory of coca, evolves through its following historical uses, and leads up to the eventual development of cocaine. This discussion will begin with the botanical background of the coca plant, followed by a review of some of the prehistoric, historic and ethnographic evidence of coca use, which indicates the extensive antiquity and pervasiveness of coca use in South and Central America. The diverse roles that coca played among the Inca and other indigenous peoples led to the early adoption of coca in the West and, in turn, to the resultant discovery of cocaine and its assorted early applications, particularly for medicinal purposes. PMID- 21678147 TI - Academics and substance use among Latino adolescents: results from a national study. AB - This study investigated the relationship between academic factors and past-year alcohol, cigarette, and marijuana use in an adolescent sample of Latinos. Secondary data analysis was conducted using a subsample of Latino adolescents (N=2,593) from the 2006 National Survey on Drug Use and Health. School connectedness and parental involvement in school were protective across all substances. Fighting in school increased the risk for use of all substances, and failing grades increased the risk for alcohol and marijuana use. Implications for prevention include the development of prevention programs that aim to increase students' connection to school and increase parental involvement. PMID- 21678148 TI - Predictors of relapse in Filipino male methamphetamine users: a mixed methods approach. AB - Using a simultaneous mixed methods design, this article studies the relapse predictors of Filipino methamphetamine abusers. Results of the quantitative study, with 32 relapsed and 19 abstaining individuals, indicate that self efficacy, negative affect, motivation, coping, and craving were found to predict relapse and functional social support did not. In-depth interviews with 11 relapse and 10 abstaining individuals supported the quantitative study. Although the results mirror existing literature, the issue of social support was given emphasis in the discussion. Implications for treatment, limitations, and recommendations for future study are also discussed. PMID- 21678149 TI - Analysis of the 5 iron golf swing when hitting for maximum distance. AB - Most previous research on golf swing mechanics has focused on the driver club. The aim of this study was to identify the kinematic factors that contribute to greater hitting distance when using the 5 iron club. Three-dimensional marker coordinate data were collected (250 Hz) to calculate joint kinematics at eight key swing events, while a swing analyser measured club swing and ball launch characteristics. Thirty male participants were assigned to one of two groups, based on their ball launch speed (high: 52.9 +/- 2.1 m . s(-1); low: 39.9 +/- 5.2 m . s(-1)). Statistical analyses were used to identify variables that differed significantly between the two groups. Results showed significant differences were evident between the two groups for club face impact point and a number of joint angles and angular velocities, with greater shoulder flexion and less left shoulder internal rotation in the backswing, greater extension angular velocity in both shoulders at early downswing, greater left shoulder adduction angular velocity at ball contact, greater hip joint movement and X Factor angle during the downswing, and greater left elbow extension early in the downswing appearing to contribute to greater hitting distance with the 5 iron club. PMID- 21678150 TI - Ground reaction forces, kinematics, and muscle activations during the windmill softball pitch. AB - The aims of the present study were to examine quantitatively ground reaction forces, kinematics, and muscle activations during the windmill softball pitch, and to determine relationships between knee valgus and muscle activations, ball velocity and muscle activation as well as ball velocity and ground reaction forces. It was hypothesized that there would be an inverse relationship between degree of knee valgus and muscle activation, a direct relationship between ground reaction forces and ball velocity, and non-stride leg muscle activations and ball velocity. Ten female windmill softball pitchers (age 17.6 +/- 3.47 years, stature 1.67 +/- 0.07 m, weight 67.4 +/- 12.2 kg) participated. Dependent variables were ball velocity, surface electromyographic (sEMG), kinematic, and kinetic data while the participant was the independent variable. Stride foot contact reported peak vertical forces of 179% body weight. There were positive relationships between ball velocity and ground reaction force (r = 0.758, n = 10, P = 0.029) as well as ball velocity and non-stride leg gluteus maximus (r = 0.851, n = 10, P = 0.007) and medius (r = 0.760, n = 10, P = 0.029) muscle activity, while there was no notable relationship between knee valgus and muscle activation. As the windmill softball pitcher increased ball velocity, her vertical ground reaction forces also increased. Proper conditioning of the lumbopelvic-hip complex, including the gluteals, is essential for injury prevention. From the data presented, it is evident that bilateral strength and conditioning of the gluteal muscle group is salient in the windmill softball pitch as an attempt to decrease incidence of injury. PMID- 21678151 TI - Age-related differences in guessing on free and forced recall tests. AB - This study examined possible age-related differences in recall, guessing, and metacognition on free recall tests and forced recall tests. Participants studied categorised and unrelated word lists and were asked to recall the items under one of the following test conditions: standard free recall, free recall with a penalty for guessing, free recall with no penalty for guessing, or forced recall. The results demonstrated interesting age differences regarding the impact of liberal test instructions (i.e., forced recall and no penalty) relative to more conservative test instructions (i.e., standard free recall and penalty) on memory performance. Specifically, once guessing was controlled, younger adults' recall of categorised lists varied in accordance with test instructions while older adults' recall of categorised lists did not differ between conservative and liberal test instructions, presumably because older adults approach standard free recall tests of categorised lists with a greater propensity towards guessing than young adults. PMID- 21678152 TI - Involuntary autobiographical memories in dysphoric mood: a laboratory study. AB - The frequency and characteristics of involuntary autobiographical memories were compared in 25 stable dysphoric and 28 non-dysphoric participants, using a new laboratory-based task (Schlagman & Kvavilashvili, 2008). Participants detected infrequent target stimuli (vertical lines) in a simple vigilance task and recorded any involuntary autobiographical memories that came to mind, mostly in response to irrelevant words presented on the screen. Dysphoric participants reported involuntary memories as frequently and as quickly as non-dysphoric participants and their memories were not repetitive intrusive memories of negative or traumatic events. Additional content analysis showed that dysphoric participants did not recall more memories of objectively negative events (e.g., accidents, illnesses, deaths) than non-dysphoric participants. However, significant group differences emerged in terms of a mood congruency effect whereby dysphoric participants rated their memories as more negative than non dysphoric participants. Moreover, the proportion of negatively rated involuntary memories was related to lower mood ratings at the end of the session in the dysphoric but not in the non-dysphoric group. Finally, groups did not differ on several memory characteristics such as vividness, specificity (high in both groups) and rates of rehearsal (low in both groups). Theoretical and practical implications of these findings for research on depression and autobiographical memory are discussed. PMID- 21678153 TI - The costs and benefits of testing text materials. AB - Tests have been shown to improve the later recall of tested information, a result known as the testing effect. Tests, however, can also impair the later recall of related information, an effect known as retrieval-induced forgetting. Although retrieval-induced forgetting has been demonstrated using a wide variety of materials, recent work suggests that learning information in the context of a coherent text passage may afford protection from retrieval-induced forgetting. In four experiments we explored the conditions under which retrieval-induced forgetting does and does not occur with such materials. We found that two factors the coherence of the to-be-learned material and the competitiveness of retrieval practice-are important in determining whether retrieval-induced forgetting does or does not occur. Furthermore, even if retrieval-induced forgetting does occur, having the opportunity to restudy the forgotten information can prevent that forgetting from persisting. Taken together, these findings provide greater understanding of the costs and benefits of testing text materials, with possible implications for the optimisation of testing as a tool for learning in educational contexts. PMID- 21678154 TI - Distinct and shared cognitive functions mediate event- and time-based prospective memory impairment in normal ageing. AB - Prospective memory (PM) is the ability to remember to perform an action at a specific point in the future. Regarded as multidimensional, PM involves several cognitive functions that are known to be impaired in normal ageing. In the present study we set out to investigate the cognitive correlates of PM impairment in normal ageing. Manipulating cognitive load, we assessed event- and time-based PM, as well as several cognitive functions, including executive functions, working memory, and retrospective episodic memory, in healthy participants covering the entire adulthood. We found that normal ageing was characterised by PM decline in all conditions and that event-based PM was more sensitive to the effects of ageing than time-based PM. Whatever the conditions, PM was linked to inhibition and processing speed. However, while event-based PM was mainly mediated by binding and retrospective memory processes, time-based PM was mainly related to inhibition. The only distinction between high- and low-load PM cognitive correlates lies in an additional, but marginal, correlation between updating and the high-load PM condition. The association of distinct cognitive functions, as well as shared mechanisms with event- and time-based PM, confirm that each type of PM relies on a different set of processes. PMID- 21678155 TI - Collaborative memory and part-set cueing impairments: the role of executive depletion in modulating retrieval disruption. AB - When people are exposed to a subset of previously studied list items they recall fewer of the remaining items compared to a condition where none of the studied items is provided during recall. This occurs both when the subset of items is provided by the experimenter (i.e., the part-set cueing deficit in individual recall) and when they are provided during the course of a collaborative discussion (i.e., the collaborative inhibition effect in group recall). Previous research has identified retrieval disruption as a common mechanism underlying both effects; however, less is known about the factors that may make individuals susceptible to such retrieval disruption. In the current studies we tested one candidate factor: executive control. Using an executive depletion paradigm we directly manipulated an individual's level of executive control during retrieval. Results revealed no direct role of executive depletion in modulating retrieval disruption. In contrast, executive control abilities were indirectly related to retrieval disruption through their influence at encoding. Together these results suggest that executive control des not directly affect retrieval disruption at the retrieval stage, and that the role of this putative mechanism may be limited to the encoding stage. PMID- 21678156 TI - Keeping an eye on the truth? Pupil size changes associated with recognition memory. AB - During recognition memory tests participants' pupils dilate more when they view old items compared to novel items. We sought to replicate this "pupil old/new effect" and to determine its relationship to participants' responses. We compared changes in pupil size during recognition when participants were given standard recognition memory instructions, instructions to feign amnesia, and instructions to report all items as new. Participants' pupils dilated more to old items compared to new items under all three instruction conditions. This finding suggests that the increase in pupil size that occurs when participants encounter previously studied items is not under conscious control. Given that pupil size can be reliably and simply measured, the pupil old/new effect may have potential in clinical settings as a means for determining whether patients are feigning memory loss. PMID- 21678157 TI - Remembering all that and then some: recollection of autobiographical memories after a 1-year delay. AB - We have previously shown that repeated retrievals of remote autobiographical memories over the course of one month led to an overall increase in reported detail (Nadel, Campbell, & Ryan, 2007). The current study examined the retrieval of those same memories 1 year later in order to determine whether the level of detail remained stable or whether the memories returned to their original state. Participants reported even more details than they had recalled at least 1 year earlier, including new details that were reported for the first time. This finding was consistent across both multiple and single retrieval conditions, suggesting that the critical factor leading to the increase in recall was the passage of time. These findings provide evidence for long-term effects of repeated retrieval on memory content. PMID- 21678158 TI - Antimicrobial sesquiterpenoids from Laurus nobilis L. AB - Activity-guided fractionations of leaf extracts from Laurus nobilis L. led to the isolation of a known sesquiterpene lactone, deacetyl laurenobiolide (1). Compound 1 showed antimicrobial activity against periopathic pathogens (Actinomyces viscosus, Porphyromonas gingivalis, Prevotella intermedia and Actinobacillus actinomycetemcomitans), opportunistic Gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes) and fungi (Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus). Furthermore, acetylation and cyclisation of deacetyl laurenobiolide (1) yielded laurenobiolide (2) and a new compound, (5S,6R,7S,8S,10R)-6,8-dihydroxyeudesma-4(15),11(13)-dien-12-oic acid 12,8-lactone (3), respectively. Compounds 2 and 3 also showed antimicrobial activities. All compounds 1-3 demonstrated growth inhibitory effects with minimum inhibitory concentrations ranging from 31 to 1000 ug mL(-1). This is the first report of compounds 1-3 showing antimicrobial activities. PMID- 21678159 TI - Polyoxygenated ergostane-type sterols from the liquid culture of Ganoderma applanatum. AB - A new polyoxygenated ergostane-type sterol, 3beta,5alpha,6beta,8beta,14alpha pentahydroxy-(22E,24R)-ergost-22-en-7-one (1), has been isolated from the liquid culture of the basidiomycete Ganoderma applanatum together with four known sterols, 3beta,5alpha,9alpha-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (2), ergosterol peroxide (3), 6-dehydrocerevisterol (4) and cerevisterol (5). Two of these sterols (2, 4) are reported to have been isolated from this species for the first time. The structures of these compounds were determined by chemical and spectroscopic analyses, including 1D- and 2D-NMR, as well as by comparison of their spectroscopic data with those reported in the literature. PMID- 21678160 TI - Synthesis and antimicrobial studies of hydroxylated chalcone derivatives with variable chain length. AB - A series of (E)-1-(4-alkyloxyphenyl)-3-(hydroxyphenyl)-prop-2-en-1-one have been successfully synthesised via Claisen-Schmidt condensation. The synthesised chalcone derivatives consisted of hydroxyl groups at either ortho, meta or para position and differed in the length of the alkyl groups, C (n) H(2) (n) (+1,) where n = 6, 10, 12 and 14. The structures of all compounds were defined by elemental analysis, IR, (1)H- and (13)C-NMR. The antimicrobial studies were carried out against wild-type Escherichia coli American Type Culture Collection 8739 to evaluate the effect of the hydroxyl and the alkyl groups of the synthesised chalcones. All the synthesised compounds have shown significant antimicrobial activities. The optimum inhibition was dependent on the position of the hydroxyl group as well as the length of the alkyl chains. PMID- 21678161 TI - Effect of Tridax procumbens (Linn.) on bile duct ligation-induced liver fibrosis in rats. AB - The present study was undertaken to clarify whether methanolic extract of Tridax procumbens prevents liver fibrosis in rat. The hepatic fibrosis was induced by 28 days of bile duct ligation in rats. The 4-week treatment with Tridex procumbens reduced the serum aspartate aminotransferase (U L-1), glutamate pyruvate transaminase (U L-1), alkaline phosphatase (IU L-1), lactate dehydrogenase (IU L 1), total bilirubin (mg dL-1), direct bilirubin (mg dL-1) and hydroxyproline (mg gm-1) content in liver and improved the histological appearance of liver section. The results of this study led us to conclude that T. procumbens can reduce the degree of hepatocellular damage and may become antifibrotic agent for liver fibrosis. PMID- 21678162 TI - Family relations, mental health and adherence to nutritional guidelines in patients facing dialysis initiation. AB - This study investigated the effect of family relations on patients' adjustment to dialysis. The two main aims were to develop a family typology, and to explore the influence of family profile on the patient's anxiety, depression and adherence to nutritional guidelines. The sample consisted of 120 patients (mean age 63 years; 67.5% of men). They completed several measures 1, 6 and 12 months after dialysis initiation. The scales used were the Family Relationship Index and the Hospital Anxiety and Depression Scale. Perceived adherence to nutritional guidelines was assessed using two visual analogical scales. Results showed that family relations remained stable over time. Cluster analysis yielded three family profiles, which were named conflict, communicative and supportive families. Patients belonging to conflict families perceived themselves as less adhering to nutritional guidelines. For these patients, anxiety and depressive moods increased significantly over time, whereas mental health remained stable over time for communicative and supportive families. This research underlines that family relations are essential in global consideration of the care of patients treated by dialysis. Conflict families seem especially at risk. They should be identified early to help them adapt to this stressful treatment. PMID- 21678163 TI - Mood as a resource in dealing with health recommendations: how mood affects information processing and acceptance of quit-smoking messages. AB - OBJECTIVE: An experimental study tested the effects of positive and negative mood on the processing and acceptance of health recommendations about smoking in an online experiment. It was hypothesised that positive mood would provide smokers with the resources to systematically process self-relevant health recommendations. DESIGN: One hundred and twenty-seven participants (smokers and non-smokers) read a message in which a quit smoking programme was recommended. Participants were randomly assigned to one of four conditions: positive versus negative mood, and strong versus weak arguments for the recommended action. MAIN OUTCOME MEASURES: Systematic message processing was inferred when participants were able to distinguish between high- and low-quality arguments, and by congruence between attitudes and behavioural intentions. Persuasion was measured by participant's attitudes towards smoking and the recommended action, and by their intentions to follow the action recommendation. RESULTS: As predicted, smokers systematically processed the health message only under positive mood conditions; non-smokers systematically processed the health message only under negative mood conditions. Moreover, smokers' attitudes towards the health message predicted intentions to quit smoking only under positive mood conditions. CONCLUSION: Findings suggest that positive mood may decrease defensive processing of self-relevant health information. PMID- 21678164 TI - Perceptions of treatment control moderate the daily association between negative affect and diabetes problems among adolescents with type 1 diabetes. AB - Perceived control over diabetes may serve to buffer the relationship between adolescents' experience of daily negative affect and daily problems with diabetes. In a daily diary study including 209 adolescents (ages 10.5-15.5) with type 1 diabetes, we examined how daily affect related to daily fluctuations in experience of diabetes problems, and whether perceptions of control moderated these daily associations. Using hierarchical linear modelling, we found that day to-day experiences of negative affect were associated with more frequent daily diabetes problems. Perceptions of treatment control moderated associations between negative affect and number of problems; negative affect was more strongly associated with number of problems among teens perceiving lower versus higher treatment control over their illness. The same pattern of association was not apparent for personal control. Results suggest that perceived treatment control may help to buffer detrimental associations between negative affect and adolescents' ability to successfully manage their diabetes. PMID- 21678165 TI - How does a vacation from work affect employee health and well-being? AB - Health and well-being (H&W) improve during vacation. However, it is unclear whether this general development applies to all employees, while also little is known about the underlying processes causing such an improvement. Our research questions were: (1) Does every worker experience a positive effect of vacation on H&W? and (2) Can vacation activities and experiences explain changes in H&W during vacation? In a 7-week longitudinal field study, 96 workers reported their H&W 2 weeks before, during, 1 week, 2 and 4 weeks after a winter sports vacation on 6 indicators (health status, mood, fatigue, tension, energy level and satisfaction). Sixty percent of the sample experienced substantial improvement of H&W during and after vacation. Yet, a small group experienced no (23%) or a negative effect of vacation (17%). Spending limited time on passive activities, pleasure derived from vacation activities, and the absence of negative incidents during vacation explained 38% of the variance in the vacation effect. Although vacation has a positive, longer lasting effect for many, it is not invariably positive for all employees. Choosing especially pleasant vacation activities and avoiding negative incidents as well as passive activities during active vacations apparently contributes to the positive effect of vacation on H&W. PMID- 21678166 TI - Integration of five health behaviour models: common strengths and unique contributions to understanding condom use. AB - The purpose of this research was to select from the health belief model (HBM), theories of reasoned action (TRA) and planned behaviour (TPB), information motivation-behavioural skills model (IMB) and social cognitive theory (SCT) the strongest longitudinal predictors of women's condom use and to combine these constructs into a single integrated model of condom use. The integrated model was evaluated for prediction of condom use among young women who had steady versus casual partners. At Time 1, all constructs of the five models and condom use were assessed in an initial and a replication sample (n = 193, n = 161). Condom use reassessed 8 weeks later (Time 2) served as the main outcome. Information from IMB, perceived susceptibility, benefits, and barriers from HBM, self-efficacy and self-evaluative expectancies from SCT, and partner norm and attitudes from TPB served as indirect or direct predictors of condom use. All paths replicated across samples. Direct predictors of behaviour varied with relationship status: self-efficacy significantly predicted condom use for women with casual partners, while attitude and partner norm predicted for those with steady partners. Integrated psychosocial models, rich in constructs and relationships drawn from multiple theories of behaviour, may provide a more complete characterisation of health protective behaviour. PMID- 21678167 TI - The benefits of expressive writing on sleep difficulty and appearance concerns for college women. AB - The college years represent an important developmental period in the lives of young women, who report health-related difficulties such as sleep disturbance and body/eating concerns. This study explored whether expressive writing (EW) can decrease health-relevant complaints among college women. College females (n = 111) were randomised into an EW condition (writing about body concerns) or a control writing condition and completed three 15-min writing sessions. Results indicate that participants in the EW condition reported less sleep difficulty and less body-focused upward social comparison at 8-week follow-up, relative to control participants. For individuals who reported higher perceived stress at baseline, the EW condition resulted in less eating disturbance and less social comparison, relative to the control condition. The effect of EW on eating disturbance for those who were high in stress was partially mediated by the change in upward social comparisons focused on one's body. These findings suggest that EW about body image and appearance concerns may positively influence the trajectory of risk for, or resilience against, future complications as a result of sleep difficulty, eating disturbance and body dissatisfaction. PMID- 21678168 TI - A qualitative analysis of attitudes to face transplants: contrasting views of the general public and medical professionals. AB - While there has been a considerable criticism and debate about face transplantation from ethicists, surgeons and psychologists, little is known about the attitudes of medical professionals and the general public whose support will be necessary if face transplants are to be accepted. This study therefore conducted in-depth, semi-structured interviews with medical professionals (8) and the general public (8) to explore their understanding of and attitudes to face transplants. A thematic analysis was used to analyse these data. Five overarching themes were identified including agreement in principal, caveats and conditions, medical and technical difficulties, function and appearance, and the significance of the human face. The analysis revealed overwhelming support in principle for face transplants, but with important caveats and conditions. Both groups shared clear representations of deserving and undeserving candidates, and concerns about psychological adjustment. The general public sample demonstrated little understanding of medical implications or the consequences of a failed graft, which did concern the medical professionals. Neither group showed a clear understanding of the psychological or social factors required to predict best outcomes and identify suitable candidates. Analyses revealed a stereotypical belief from both groups that the life of a severely disfigured recipient is intolerable without this operation. PMID- 21678169 TI - The impact of self-efficacy and implementation intentions-based interventions on fruit and vegetable intake among adults. AB - This study tested the effect of interventions designed for people who do not eat yet the recommended daily fruit and vegetable intake (FVI) but have a positive intention to do so. Adults (N = 163) aged 20-65 were randomised into four groups: implementation intentions (II group), self-efficacy (SE group), combination of II + SE group) and a control group receiving written information on nutrition. Study variables were measured at baseline, post-intervention and at 3-month follow-up. At follow-up, compared to the control group, FVI increased significantly in the II and II + SE groups (1.5 and 1.9 servings per day, respectively). Most psychosocial variables significantly increased compared to the control group, with the exception of SE for vegetable intake (VI). Moreover, at 3-month follow up, change in FVI was mediated by changes in fruit intake (FI) intention and VI action planning. In conclusion, II interventions were efficient to increase FVI, with or without consideration for the development of SE. Thus, future studies should favour the adoption of this approach to bridge the intention-behaviour gap for FVI. PMID- 21678170 TI - Sleep hygiene behaviours: an application of the theory of planned behaviour and the investigation of perceived autonomy support, past behaviour and response inhibition. AB - This study investigated the sleep hygiene behaviour of university students within the framework of the Theory of Planned Behaviour (TPB [Ajzen, I. (1991). The theory of planned behavior. Organizational Behavior and Human Decision Processes, 50, 179-211.]), and examined the predictive validity of additional variables including perceived autonomy support, past behaviour and response inhibition. A total of 257 undergraduate students from an Australian university were administered two online questionnaires at two time points. At time 1, participants completed the TPB questionnaire and the Go/NoGo task as a measure of response inhibition. A week later at time 2, participants completed a questionnaire measuring the performance of sleep hygiene behaviours. Multiple and hierarchical regression analyses showed that the TPB model significantly predicted intention and behaviour. Although intention and perceived behavioural control were statistically significant in predicting behaviour, past behaviour and response inhibition accounted for more variance when added to the TPB model. Subjective norm was found to be the strongest predictor of intention implying the importance of normative influences in sleep hygiene behaviours. Response inhibition was the strongest predictor of behaviour, reinforcing the argument that the performance of health protective behaviours requires self-regulatory ability. Therefore, interventions should be targeted at enhancing self-regulatory capacity. PMID- 21678171 TI - The nature of caregiving in children of a parent with multiple sclerosis from multiple sources and the associations between caregiving activities and youth adjustment overtime. AB - This study explored youth caregiving for a parent with multiple sclerosis (MS) from multiple perspectives, and examined associations between caregiving and child negative (behavioural emotional difficulties, somatisation) and positive (life satisfaction, positive affect, prosocial behaviour) adjustment outcomes overtime. A total of 88 families participated; 85 parents with MS, 55 partners and 130 children completed questionnaires at Time 1. Child caregiving was assessed by the Youth Activities of Caregiving Scale (YACS). Child and parent questionnaire data were collected at Time 1 and child data were collected 12 months later (Time 2). Factor analysis of the child and parent YACS data replicated the four factors (instrumental, social-emotional, personal-intimate, domestic-household care), all of which were psychometrically sound. The YACS factors were related to parental illness and caregiving context variables that reflected increased caregiving demands. The Time 1 instrumental and social emotional care domains were associated with poorer Time 2 adjustment, whereas personal-intimate was related to better adjustment and domestic-household care was unrelated to adjustment. Children and their parents exhibited highest agreement on personal-intimate, instrumental and total caregiving, and least on domestic-household and social-emotional care. Findings delineate the key dimensions of young caregiving in MS and the differential links between caregiving activities and youth adjustment. PMID- 21678172 TI - Do distant foods decrease intake? The effect of food accessibility on consumption. AB - OBJECTIVE: Two studies examined the hypothesis that making snacks less accessible contributes to the regulation of food intake. Study 1 examined whether decreasing the accessibility of snacks reduces probability and amount of snack intake. The aim of Study 2 was to replicate the results and explore the underlying mechanism in terms of perceived effort to obtain the snack and perceived salience of the snack. METHODS: In Study 1 (N = 77) and Study 2 (N = 54) distance to a bowl of snacks was randomly varied at 20, 70 or 140 cm in an experimental between subjects design. Main outcome measures were the number of people who ate any snacks (probability of snack intake), the amount of snacks consumed and risk of compensatory behaviour as measured by food craving. In Study 2, self-report ratings of salience and effort were examined to explore potential underlying mechanisms. RESULTS: Study 1 showed lower probability and amount of intake in either of more distant conditions (70 and 140 cm) compared to the proximal condition (20 cm), with no unintended effects in terms of increased craving. Study 2 replicated the results of Study 1 and showed that distance affected perceived effort but not salience. CONCLUSIONS: Making snacks less accessible by putting them further away is a potentially effective strategy to decrease snack intake, without risk of compensatory behaviour. PMID- 21678173 TI - A contextual approach on sex-related biases in pain judgements: the moderator effects of evidence of pathology and patients' distress cues on nurses' judgements of chronic low-back pain. AB - Although women report feeling more pain than men, their pain is often underdiagnosed and undertreated. By proposing a gender-based theoretical conceptualisation, we argue that such sex-related biases may be enhanced or suppressed by contextual variables pertaining to the clinical situation, the perceiver or the patient. Consequently, we aimed to explore the moderator role of two clinically relevant variables in a chronic low-back pain (CLBP) scenario: diagnostic evidence of pathology (EP) and pain behaviours conveying distress. One hundred and twenty-six female nurses (M = 35.33, SD = 7.64) participated in an experimental between-subjects design, 2 (patient's sex) * 2 (EP: present vs. absent) * 2 (pain behaviours: with vs. without distress). Independent variables were operationalised by vignettes depicting a patient with CLBP. Nurses judged the patient's pain on several dimensions: (1) credibility; (2) disability; (3) severity of the clinical situation; (4) psychological attributions and (5) willingness to offer support. Main findings showed that judgements of women's pain were influenced by EP, while judgements of men's pain were not. Moreover, nurses showed biases against men, but only in the presence of EP. The influence of distress cues was less consistent. Theoretical and practical implications are drawn. PMID- 21678174 TI - Self-efficacy and multiple illness representations in older adults: a multilevel approach. AB - OBJECTIVES: The Common-Sense Model assumes that individuals form subjective representations about their illnesses, which in turn guide cognitive and behavioural responses. This assumption is complicated in individuals with multimorbidity, and it is an open question to which degree illness-specific and person-level factors determine the representations of specific illnesses. This study examines the structure and interrelations of illness representations in multimorbidity employing a hierarchical framework based on Cognitive Theory. METHODS: Multiple illness representations were assessed in 305 people aged 65 and older using two Brief Illness Perception Questionnaires. Multilevel modelling was used to explore the relations between illness representations and to explain how two illness-specific representations--personal control and treatment control- were determined by a person-level factor, self-efficacy. RESULTS: Self-efficacy had significant main (B = 0.29; p < 0.01 for personal control; B = 0.19; p < 0.05 for treatment control) and interaction effects (B = 0.38; p < 0.01 personal control on self-efficacy * timeline; B = -0.31; p < 0.05 treatment control on self-efficacy * coherence). CONCLUSIONS: This study suggests that illness specific representations of older people with multimorbidity are a product of both illness-specific and person-level factors, such as self-efficacy. Strengthening individual self-efficacy may improve illness controllability regardless and on top of illness-specific information. PMID- 21678175 TI - Are smokers interested in genetic testing for smoking addiction? A socio cognitive approach. AB - Genetic advances have made genetically tailored smoking cessation treatments possible. In this study, we examined whether smokers are interested in undergoing a genetic test to identify their genetic susceptibility to nicotine addiction. In addition, we aimed to identify socio-cognitive determinants of smokers' intention to undergo genetic testing. Following the protection motivation theory (PMT), we assessed the following constructs using an online survey among 587 smokers: threat appraisal (i.e. susceptibility and severity), fear, coping appraisal (i.e. response efficacy and self-efficacy), response costs and intention. In addition, knowledge, social norms and information-seeking behaviour were measured. Mean intention rates were 2.57 on a 5-point scale. Intention was significantly associated with threat appraisal and coping appraisal, as predicted by the PMT. Fear of the outcome was negatively associated with the intention to undergo genetic testing, but response costs, knowledge and social influence were not. Intention to undergo genetic testing in turn was positively related to seeking information about genetic testing and genetically tailored smoking cessation treatments. Smokers seem ambivalent or 'on the fence' with regard to undergoing a genetic test for smoking addiction. Socio-cognitive concepts such as susceptibility, severity, response efficacy and self-efficacy may be used to inform or educate smokers about the value of genetically tailored smoking cessation treatments. PMID- 21678176 TI - Autonomy and defensiveness: experimentally increasing adaptive responses to health-risk information via priming and self-affirmation. AB - Health information is often ineffective in motivating health-behaviour change. One way to improve information effectiveness might be to highlight autonomy, which is associated with less defensiveness and more adaptive psychological functioning. Three studies assessed whether experimentally elevating autonomy led to adaptive responses to risk information about alcohol consumption. In Study 1 (N = 104), participants completed either an autonomy prime or a neutral prime task and read either risk information about the dangers of alcohol consumption or neutral information. Among high-risk participants in the autonomy prime condition, those who read risk information reported greater autonomous motivation towards moderate alcohol consumption than did those in the neutral information condition. Study 2 (N = 157) compared two types of autonomy prime tasks with a neutral condition. For high-risk participants who read risk information, the autonomy prime tasks elicited greater autonomous motivation, more positive attitudes and greater intentions to drink in moderation than did the neutral prime task. Study 3 (N = 130) found that for high-risk participants who read risk information, autonomy prime participants reported less subsequent alcohol consumption than did neutral prime participants. The results are discussed in terms of the benefits of autonomy for adaptive responses to risk information. PMID- 21678177 TI - Posttraumatic growth after childbirth: a prospective study. AB - A growing body of research has examined the potential for positive change following challenging and traumatic events, this is known as posttraumatic growth (PTG). Childbirth is a valuable opportunity to extend previous work on PTG as it allows the role of different variables to be considered prospectively. The aim of this study was to prospectively examine correlates of PTG after birth, including sociodemographic and obstetric variables, social support and psychological distress, using a prospective, longitudinal design. A total of 125 women completed questionnaires during their third trimester of pregnancy and 8 weeks after birth. At least a small degree of positive change following childbirth was reported by 47.9% of women; however, average levels of growth were lower than generally reported in other studies. A regression model of age, type of delivery, posttraumatic stress symptoms during pregnancy and general distress after birth significantly predicted 32% of the variance in growth after childbirth. The strongest predictors of growth were operative delivery (beta 0.23-0.30) and posttraumatic stress symptoms in pregnancy (beta 0.32). These findings emphasise the importance of assessing pre-event characteristics when considering the development of PTG after a challenging event. PMID- 21678178 TI - Neuroticism and self-reported somatic health: a twin study. AB - Using a twin sample (N = 188; 53 monozygotic and 39 dizygotic twin pairs, and 4 single twins whose co-twin did not participate), this study sought (1) to estimate heritabilities of neuroticism and of somatic complaints rated on the basis of two different time frames ('the last week' vs. 'in general'); (2) to estimate the genetic association between neuroticism and the complaints indices and (3) to examine to what extent somatic complaints are aetiologically distinct from neuroticism. Using models with common additive genetic (A) and individual specific environmental (E) factors, the heritabilities for neuroticism and complaints 'in general' and during 'the last week' were 0.46 (0.20-0.65), 0.44 (0.22-0.62), and 0.45 (0.22-0.63), respectively. Nearly 60% of the phenotypic correlation between neuroticism and somatic complaints were accounted for by A. Furthermore, a substantial part of the variance in somatic complaints was due to unique genetic and individual-specific environmental influences unrelated to neuroticism. These results suggest that somatic complaints are moderately heritable and that a considerable portion of the covariance between neuroticism and complaints measures is due to genetic factors. Yet, the findings also suggest that these two attributes are distinct entities with overlapping, but not identical, underlying genetic and environmental influences. PMID- 21678179 TI - Changing eating behaviour vs. losing weight: the role of goal focus for weight loss in overweight women. AB - A 6-week longitudinal study with N = 126 overweight women participating in a weight-loss programme investigated the hypothesis that focusing on the process (dietary behaviours) rather than on the outcome of dieting (weight loss) is associated with more successful goal pursuit and achievement. As expected, process focus was related positively to subjective daily success in dieting as well as to actual weight loss, and negatively to deviations from the diet. In contrast, outcome focus had a negative impact on successful dieting: focusing on weight loss was marginally negatively related to actual weight loss and was associated with more disinhibition after lapses. Confirming hypotheses, self regulation failure (i.e. deviations from the diet, disinhibition) was negatively related to daily affective well-being. Contrary to hypotheses, however, goal focus was not directly associated with affective well-being but only indirectly through self-regulation. Focusing on the process rather than on the outcome of dieting, then, might help achieving difficult health-related goals and support self-regulation but does not contribute directly to affective well-being. PMID- 21678180 TI - A longitudinal study of psychosocial distress in breast cancer: prevalence and risk factors. AB - This longitudinal study was conducted among 102 women with non-metastasic breast cancer to identify the time evolution and prevalence of distress at specific times through diagnosis and treatment of disease: preliminary diagnosis, surgery, definitive diagnosis and chemotherapy. Additionally, the study aimed to examine the role of demographic, medical and psychosocial factors on distress. The results indicated that prevalence of distress was higher at initial diagnosis (25%) than the following time points (approximately 17%). The differences inter individuals in the levels of distress were observed over the four assessments. No relation between distress and demographic and medical factors was found. However, psychosocial aspects were significant risk factors. Patterns of emotional suppression and specific coping responses like helplessness/hopelessness, anxious preoccupation, cognitive avoidance and fatalism were positively related to distress, whereas fighting spirit and perceived social support showed a protective role. Moreover, helplessness/hopelessness and anxious preoccupation jointly predicted 75% of cases and 98% non-cases of distress. Finally, a mediational model between emotional suppression and distress through helplessness/hopelessness was tested. Results support the necessity of routine distress screening all through the illness. Implications of data for psychosocial interventions with breast cancer patients are highlighted. PMID- 21678182 TI - Emotional inhibition: a discourse analysis of disclosure. AB - Evidence generated within the emotional disclosure paradigm (EDP) suggests that talking or writing about emotional experiences produces health benefits, but recent meta-analyses have questioned its efficacy. Studies within the EDP typically rely upon a unidimensional and relatively unsophisticated notion of emotional inhibition, and tend to use quantitative forms of content analysis to identify associations between percentages of word types and positive or negative health outcomes. In this article, we use a case study to show how a qualitative discourse analysis has the potential to identify more of the complexity linking the disclosure practices and styles that may be associated with emotional inhibition. This may illuminate the apparent lack of evidence for efficacy of the EDP by enabling more comprehensive theorisations of the variations within it. PMID- 21678181 TI - Randomised trial of expressive writing for distressed metastatic breast cancer patients. AB - Women with metastatic breast cancer and significant psychological distress (N = 87) were assigned randomly to engage in four home-based sessions of expressive writing or neutral writing. Women in the expressive writing group wrote about their deepest thoughts and feelings regarding their cancer, whereas women in the neutral writing group wrote about their daily activities in a factual manner. No statistically significant group differences in existential and psychological well being, fatigue and sleep quality were found at 8-weeks post-writing. However, the expressive writing group reported significantly greater use of mental health services during the study than the neutral writing group (55% vs. 26%, respectively; p < 0.05). Findings suggest that expressive writing may improve the uptake of mental health services among distressed cancer patients, but is not broadly effective as a psychotherapeutic intervention. PMID- 21678183 TI - Distress and emotional well-being in breast cancer patients prior to radiotherapy: an expectancy-based model. AB - Understanding precursors to distress and emotional well-being (EWB) experienced in anticipation of radiotherapy would facilitate the ability to intervene with this emotional upset (i.e. higher distress, lower EWB). Thus, this study tested an expectancy-based model for explaining emotional upset in breast cancer patients prior to radiotherapy. Women affected by breast cancer (N = 106) were recruited and participants completed questionnaires prior to commencing radiotherapy. Structural equation modelling was used to test a cross-sectional model, which assessed the ability of dispositional optimism (Life Orientation Test-Revised - two factors), response expectancies (Visual Analog Scale items), medical (type of surgery, cancer stage and chemotherapy history) and demographic (age, race, ethnicity, education and marital status) variables to predict both EWB (Functional Assessment of Chronic Illness Therapy - Emotional Well-being Subscale) and distress (Profile of Mood States - short version). The model represented a good fit to the data accounting for 65% of the variance in EWB and 69% in distress. Significant predictors of emotional upset were pessimism, response expectancies, Latina ethnicity, cancer stage and having had a mastectomy. These variables explained a large portion of emotional upset experienced prior to radiotherapy for breast cancer and are important to consider when aiming to reduce distress and improve EWB in this context. PMID- 21678184 TI - HIV-related stigma in African and Afro-Caribbean communities in the Netherlands: manifestations, consequences and coping. AB - HIV-related stigma in African and Afro-Caribbean diaspora communities in the Netherlands was investigated. Interviews with HIV-positive and HIV-negative community members demonstrated that HIV-related stigma manifests as social distance, physical distance, words and silence. The psychological consequences of HIV-related stigma among those diagnosed with HIV reported were emotional pain, sadness, loneliness, anger, frustration and internalised stigma. The social consequences included decreased social network size, limited social support and social isolation, and resulted from not only enacted stigma but also self-imposed social withdrawal. Also, poor treatment adherence was a health-related consequence. People living with HIV employed both problem-focused and emotion focused coping strategies to mitigate the negative consequences of stigma. Problem-focused coping strategies included selective disclosure, disengagement, affiliating with similar others, seeking social support and, to a lesser extent, activism. Emotion-focused strategies included distraction, positive reappraisal, religious coping, external attributions, disidentification and acceptance. HIV related stigma clearly permeates African and Afro-Caribbean communities in the Netherlands, and should be targeted for intervention. PMID- 21678185 TI - A refined taxonomy of behaviour change techniques to help people change their physical activity and healthy eating behaviours: the CALO-RE taxonomy. AB - BACKGROUND: Current reporting of intervention content in published research articles and protocols is generally poor, with great diversity of terminology, resulting in low replicability. This study aimed to extend the scope and improve the reliability of a 26-item taxonomy of behaviour change techniques developed by Abraham and Michie [Abraham, C. and Michie, S. (2008). A taxonomy of behaviour change techniques used in interventions. Health Psychology, 27(3), 379-387.] in order to optimise the reporting and scientific study of behaviour change interventions. METHODS: Three UK study centres collaborated in applying this existing taxonomy to two systematic reviews of interventions to increase physical activity and healthy eating. The taxonomy was refined in iterative steps of (1) coding intervention descriptions, and assessing inter-rater reliability, (2) identifying gaps and problems across study centres and (3) refining the labels and definitions based on consensus discussions. RESULTS: Labels and definitions were improved for all techniques, conceptual overlap between categories was resolved, some categories were split and 14 techniques were added, resulting in a 40-item taxonomy. Inter-rater reliability, assessed on 50 published intervention descriptions, was good (kappa = 0.79). CONCLUSIONS: This taxonomy can be used to improve the specification of interventions in published reports, thus improving replication, implementation and evidence syntheses. This will strengthen the scientific study of behaviour change and intervention development. PMID- 21678186 TI - The role of context and timeframe in moderating relationships within the theory of planned behaviour. AB - This study examined the moderating effect of context and timeframe on the predictive ability of Theory of Planned Behaviour (TPB) constructs. Three hundred and eighty-three students completed TPB measures either in a campus bar or a library and were randomly allocated to one of three timeframe conditions: tonight, tomorrow or next week. There was a three-way interaction such that the subjective norms of participants in a bar were more predictive of their intentions to binge drink that night, whereas the subjective norms of participants in a library were less predictive of intentions to binge drink that night. This research provides empirical evidence that ignoring context may result in underestimation of the importance of normative factors in binge drinking. It also suggests that other research utilising the TPB needs to take greater account of the impact of context of data collection, which has been neglected to date. PMID- 21678187 TI - Listening to music and physiological and psychological functioning: the mediating role of emotion regulation and stress reactivity. AB - Music listening has been suggested to have short-term beneficial effects. The aim of this study was to investigate the association and potential mediating mechanisms between various aspects of habitual music-listening behaviour and physiological and psychological functioning. An internet-based survey was conducted in university students, measuring habitual music-listening behaviour, emotion regulation, stress reactivity, as well as physiological and psychological functioning. A total of 1230 individuals (mean = 24.89 +/- 5.34 years, 55.3% women) completed the questionnaire. Quantitative aspects of habitual music listening behaviour, i.e. average duration of music listening and subjective relevance of music, were not associated with physiological and psychological functioning. In contrast, qualitative aspects, i.e. reasons for listening (especially 'reducing loneliness and aggression', and 'arousing or intensifying specific emotions') were significantly related to physiological and psychological functioning (all p = 0.001). These direct effects were mediated by distress augmenting emotion regulation and individual stress reactivity. The habitual music-listening behaviour appears to be a multifaceted behaviour that is further influenced by dispositions that are usually not related to music listening. Consequently, habitual music-listening behaviour is not obviously linked to physiological and psychological functioning. PMID- 21678188 TI - 'It's as if PBC didn't exist': the illness experience of women affected by primary biliary cirrhosis. AB - This study investigates the illness experience of women who are affected by primary biliary cirrhosis (PBC), a rare chronic liver disease which mostly affects women. Despite the fact that PBC is medically recognised, it shares many characteristics with other chronic and controversial conditions which may lead to delegitimation of the patient's experience of illness, impacting on the construction of the patient's self-identity. Twenty three women took part in semi structured interviews. Data were analysed using interpretative phenomenological analysis and the analysis identified three themes that are interrelated and characterised by a dynamic of normalisation. The first theme, the delegitimation of women's experience, implies denial of patients' sick-role, trivialisation of fatigue and lack of consideration of patients' needs. The second theme, PBC as a challenge to women's social identity refers to how patients face delegitimation and manage the illness's consequences for relationships and social roles. The third theme, the need for biographical continuity, focuses on how patients construct their ill identities as a consequence of both the delegitimation and the challenges posed by PBC. Results are discussed in a gender perspective, highlighting how delegitimation and identity construction processes are influenced by women's social roles and conditions. PMID- 21678189 TI - Motives and health-related behaviour: incremental prediction by implicit motives. AB - The study assessed whether implicit motives, which operate largely outside of conscious awareness, can provide any incremental prediction of health-related behaviour over that provided by explicit motives. In a cross-sectional survey study, 251 young adults completed measures of sun exposure behaviour, sun protection behaviour and risk-related sexual behaviour, participatory motives for these behaviours, life goals (representing explicit dispositional motives), and the Single Category Implicit Association Test adapted to measure implicit motives. Analysis was by structural equation modelling. Power life goal (the goal of asserting oneself and seeking social status) predicted sun exposure behaviour and risk-related sexual behaviour. Altruism life goal (acting for the welfare of others) predicted sun protection behaviour and inversely predicted risk-related sexual behaviour. These effects of life goals were mediated by participatory motives. Implicit dispositional achievement motive (the largely unconscious need to succeed at challenging tasks) inversely predicted sun exposure behaviour, this effect being mediated by a reduction in appearance-related participatory motive for sun exposure. Implicit dispositional achievement motive also inversely predicted risk-related sexual behaviour, this effect being direct. It is concluded that implicit dispositional motives can provide some incremental prediction of health-related behaviour. Possibilities for further research, including the experimental manipulation of motive engagement, are discussed. PMID- 21678190 TI - A longitudinal application of three health behaviour models in the context of skin protection behaviour in individuals with occupational skin disease. AB - Occupational skin disease (OSD) is common, associated with poor prognosis and poses a significant burden to the individual and society. We applied the theory of planned behaviour (TPB), the prototype-willingness model (PWM) and the health action process approach (HAPA) to the prediction and explanation of occupationally relevant skin protection behaviour in individuals with OSD. We used a longitudinal design. In this study, 150 individuals participating in a 3 week inpatient tertiary prevention programme completed measures assessing the constructs of the TPB, PWM and HAPA at admission (T 0), discharge (T 1) and once the individual had returned to work and worked for 4 consecutive weeks (T 2) (n = 117). Intention was measured at T 0 and skin protection behaviour at T 2. Path analysis was used to assess the longitudinal associations of the models' constructs with intention and skin protection behaviour. TPB as well as PWM variables accounted for 30% of variance in behaviour, HAPA variables for 33%. While not all predictions were confirmed by the data, all three models are able to inform us about the formation of skin protection intention and behaviour in individuals with OSD. The findings are discussed in light of future interventions and research. PMID- 21678191 TI - Getting one's thoughts straight: a dialogical analysis of women's accounts of poorly controlled type 2 diabetes. AB - Type 2 diabetes is a metabolic disorder characterised by chronically elevated blood glucose and a high risk of cardiovascular and other complications. Self management is central to diabetes care and includes taking regular exercise, low fat/sugar diet and blood glucose monitoring. However, little is understood about how people with diabetes make sense of self-management. Our aim, therefore, is to explore the process of 'getting one's thoughts straight' in relation to illness self-management for women with poorly controlled type 2 diabetes. Eight women were recruited from two hospitals in the North of England. Each was interviewed using a biographic-narrative method. Narratives were analysed using a dialogical approach. We use Bakhtin's concepts of voice, official and unofficial truth, and internally persuasive discourse to explore how participants considered, struggled with, and, sometimes, acted upon self-management. We demonstrate how the truth by which participants lived shifted as they encountered new perspectives and experiences. The accounts revealed tension between official, authoritative voices, typically concerned with optimal illness control and unofficial voices that speak at a lived, embodied level. In conclusion, we suggest moving beyond the notion of self-management towards a conceptualisation of life with chronic illness that includes personal goals, values and embodied experience in context. PMID- 21678192 TI - Emotional competence and quality of life of children with asthma: The mediating effect of coping strategies. AB - This study explored the mediating effect of coping strategies on the relationship between emotional competence (EC) and quality of life (QOL) among children with asthma. Participants were 87 children (M age = 11.72, SD = 2.58) with controlled and partially controlled asthma, undergoing everyday treatment. They filled in questionnaires assessing EC, coping strategies and QOL. Results showed that the association between some ECs and the QOL of children with asthma was fully mediated by two maladaptive cognitive coping strategies. Among children with asthma, a greater ability to differentiate their emotions, a reduced attention to bodily signals of emotions and a reduced analysis of their current emotional state were related to decreased engagement in two coping strategies ('Ignoring Asthma' and 'Worrying about Asthma'), which in turn increased their QOL. These findings show that EC has an indirect effect on QOL through very specific coping strategies. They also emphasise the importance of screening EC in children with asthma and the importance of developing and using multidisciplinary interventions for them. PMID- 21678193 TI - An explanatory model of adjustment to type I diabetes based on attachment, coping, and self-regulation theories. AB - The aim of this study was to develop and test a model of adjustment to type I diabetes. Three hundred young adults (172 females and 128 males) with type I diabetes were asked to complete the Adult Attachment Inventory (AAI), the Brief Illness Perception Questionnaire (Brief IPQ), Task-oriented subscale of the Coping Inventory for Stressful Situations (CISS), D-39, and well-being subscale of the Mental Health Inventory (MHI). HbA1c was obtained from laboratory examination. Results from structural equation analysis partly supported the hypothesized model. Secure and avoidant attachment styles were found to have effects on illness perception, ambivalent attachment style did not have significant effect on illness perception. Three attachment styles had significant effect on task-oriented coping strategy. Avoidant attachment had negative direct effect on adjustment too. Regression effects of illness perception and task oriented coping strategy on adjustment were positive. Therefore, positive illness perception and more usage of task-oriented coping strategy predict better adjustment to diabetes. So, the results confirmed the theoretical bases and empirical evidence of effectiveness of attachment styles in adjustment to chronic disease and can be helpful in devising preventive policies, determining high-risk maladjusted patients, and planning special psychological treatment. PMID- 21678194 TI - Targeting those in need: baseline data from the first English National Health Service (NHS) health trainer service. AB - As part of a wider strategy to reduce health inequalities, England's National Health Service has introduced health trainers (HTs) to facilitate healthier behaviour among disadvantaged groups. This study reports baseline data from the first English HT service: assessing whether the HTs reached socially disadvantaged clients engaging in unhealthy behaviours and describing client belief characteristics relevant to the delivery of the service. Data from 864 clients show that the service reached disadvantaged groups and that those groups were engaging in risky health behaviours. Self-efficacy about changing behaviour was not strong and clients were unlikely to have made explicit behaviour-change plans prior to attending the service. Implications for HT services around targeting those most in need and supporting psychological triggers for change are discussed. PMID- 21678195 TI - Motivation in Italian whole blood donors and the role of commitment. AB - The literature contains numerous reports on motivation in blood donors, although none of these are specific to blood donation in Italy and almost all of them focus on altruism and the desire to help others. Altruism is important, but a comprehensive analysis of donor motivation should examine all the factors affecting the decision to donate, including commitment to voluntary blood donor organizations. The aims of this paper are to verify if the motivational factors that influence the choice to donate blood in Italy are generally consistent with the findings from other countries reported in the literature and to focus on commitment to donor organizations as an additional factor. A sample of 895 whole blood donors completed a self-report questionnaire containing questions about: reasons for beginning to donate, people who influenced this choice, and level of commitment to voluntary blood donor organizations. The most frequently reported reasons for giving blood for the first time were "to help others" (56%), "influence of family/friends" (22%), and "social/moral obligation" (11.2%); commitment did not vary as a function of the leading motivation reported. Differences emerged between males, who more frequently reported having been influenced by parents and friends, and females, who referred more often to altruistic motives. The opportunity to check one's own state of health also played an important role (6.9%), especially for male donors. Overall, however, the decision to donate was primarily a personal choice (41.3%), although influence was also attributed to relatives (21.8%), friends (22.3%), and voluntary blood donor organizations (21.8%). The reported level of commitment to the donor organization was positively correlated with the number of total and annual donations made and number of new donors recruited. PMID- 21678196 TI - A Protection Motivation Theory application to date rape education. AB - Date rape risk communication is a key component of education-based Date Rape Prevention Programs, common across colleges. In such programs, risk assessment in date rape is approached cautiously in order to avoid a tone of "victim blaming." Since it is important in the assessment of any risk to understand the surrounding social context of the risky situation and the individual's unique relationship with that social context, this study examines Protection Motivation Theory as it applies to handling the risk of date rape without victim blaming. The paper links individual personality and social contexts with risk communication. The study sample comprised 367 undergraduate women enrolled in a large Southern Public University. The study examines the relationships between dating activity, social competency, and type of information provided with the dependents variables of date rape related protection behavior (intent), belief, and knowledge. A factorial multiple analysis of covariance analysis found that the dependent variables had a significant relationship with aspects of social competency and dating activity. The exposure to varying information about date rape was not significantly related to the dependent variables of date rape-related protection behavior (intent), belief, and knowledge. The identification of social competency and dating activity status as protective factors in this study makes a significant contribution to the practice and research efforts in date rape education. PMID- 21678197 TI - The effects of perceived social support on quality of life in patients awaiting coronary artery bypass grafting and their partners: testing dyadic dynamics using the Actor-Partner Interdependence Model. AB - Patients awaiting coronary artery bypass grafting (CABG) need support from their partners or family caregivers to manage their self care successfully and to maximise quality of life. Partners need social support to help overcome the stressful tasks of an unexpected caregiving role. It is not known whether the individual's perceived social support contributes to their own, as well as their partner's quality of life. The aims of this study were to assess differences in social support and quality of life in patients and partners awaiting CABG, and to examine whether patients' and partners' perceived social support predicted their own, as well as their partner's quality of life before CABG. This cross-sectional study recruited 84 dyads (patients 84% males, aged 64.5 years and partners 94% females, aged 61.05 years). Perceived social support was assessed using the Medical Outcomes Study Social Support survey, with sub-scales for informational/emotional support, affectionate support, tangible support and positive social interaction. Quality of life was assessed using the Short-Form 12 Health Survey. Dyadic data were analysed using the Actor-Partner Interdependence Model, with distinguishable dyad regression. Results revealed the patients' informational/emotional support exhibited an actor effect on their own mental health (beta = 0.19, p = 0.001); indicating those with low informational/emotional support had poorer mental health. There was a partner effect of the patients' informational/emotional support on their partner's mental health (beta = 0.14, p = 0.024), indicating the patients' informational/emotional support was associated with the partner's mental health. None of the other types of social support exhibited an actor effect or a partner effect on the patient's or the partner's mental or physical health. More research into the relationship between social support and mental health is needed to help inform the design of interventions that target the dyad. PMID- 21678198 TI - Increasing organ donor registration rates by providing an immediate and complete registration opportunity: an experimental assessment of the IIFF model. AB - The IIFF model of organ donation holds that the simultaneous presence of four factors directly influence donor registration: (1) immediate and complete registration opportunity (ICRO), (2) information, (3) focused engagement, and (4) favorable activation. Two field experiments examined the impact of an ICRO on organ donation registration. In Study 1, participants were at town halls where they knew organ donation was to be discussed. Registration cards were distributed and then collected at the end of the session in half of the town halls. For the other half, participants were asked to mail in completed cards. In three US cities, participants given an ICRO registered at a significantly greater rate (z = 4.865, p < 0.05). Study 2, targeting Hispanics at a swap meet, differed in that the registration impact of awareness of the availability of an ICRO was investigated. Participants made aware of an ICRO registered at a significantly greater rate (z = 4.1, p = 0.000). PMID- 21678199 TI - Who deserves to be sick? An exploration of the relationships between belief in a just world, illness causal attributions and their fairness judgements. AB - This research explored relationships between beliefs about justice, illness causal attributions and fairness judgements of those causes. Participants (n = 200) completed questionnaires assessing their belief in a just world (BJW) and measuring causal attributions and fairness judgements for 42 illness causes classified into behavioural, environmental and hidden (genetic, mystic, psychosocial) categories. As predicted, BJW was correlated positively with all fairness judgements, but with none of the illness causal attributions. Behavioural causes of illness were judged to be fairer than environmental causes, which were judged fairer than hidden causes. Finally, for environmental and hidden causes (uncontrollable illness attributions), positive correlations between causal attributions and their corresponding fairness judgements were found only among participants with high BJW. Implications of these findings for decision makers and health professionals are discussed, with emphasis on the need to consider the combined effect of causal attributions and BJW on illness fairness judgements. PMID- 21678200 TI - An exploration of cognitive appraisals following spinal cord injury. AB - This study explored the cognitive appraisals that people make following spinal cord injury (SCI) about their situation and their ability to cope with it. Appraisals are thought to be important in determining individual responses to different events and have been shown to predict psychological well-being following injury. A cross-sectional interview study was used. Ten individuals who had recently started rehabilitation at the National Spinal Injuries Centre following an SCI were interviewed. Eight men and two women with a variety of injury level and completeness participated. Interviews were semi-structured and aimed to elicit participants' appraisals of their experiences and their ability to cope. Interviews were analysed qualitatively using interpretative phenomenological analysis. Four super-ordinate themes emerged from the interviews. These were making sense of a traumatic experience, impact of the SCI, coping and altered view of self and life. The interviews revealed that appraisals following SCI are complex and relate not only to the individual but also to their context, life stage, roles and relationships. The study adds to the theoretical understanding of the appraisal process following SCI. Ideas for further research are generated and clinical implications for improving patient experiences and developing appraisal-focused interventions are considered. PMID- 21678201 TI - Traditional versus modern values and interpersonal factors predicting stress response syndromes in a Swiss elderly population. AB - Stress response syndromes like adjustment disorders or complicated grief are assumed to be shaped by social-cultural factors in addition to biological and psychological factors. In previous research, value orientations and interpersonal factors were found to jointly predict those syndromes (Maercker, A., Mohiyeddini, C., Muller, M., Xie, W., Hui Yang, Z., Wang, J., & Muller, J. ( 2009 ). Traditional versus modern values, self-perceived interpersonal factors, and posttraumatic stress in Chinese and German crime victims. Psychology and Psychotherapy, 82(Pt 2), 219-232.). In addition to the previous finding, the current study using Swiss elderly (65-97 years) aimed to replicate patterns of predictors leading to stress responses in people with recent bereavement or severe life events. Traditional (conformity, tradition and benevolence) and modern values (stimulation, hedonism and achievement) and two self-perceived interpersonal mediator processes (disclosure intentions and social acknowledgement as a victim) were assessed. The current study confirms the previous model in parts, that is, the indirect path from social acknowledgment to stress response syndrome is mediated by disclosure intentions. Traditional values and not modern values explained substantial variance for disclosure intentions and are therefore indirectly linked to worse mental health outcomes whereas the direct association appears somewhat controversial in light of previous findings. PMID- 21678202 TI - Response to Open Peer Commentaries on "Relative versus absolute standards for everyday risk in adolescent HIV prevention trials: expanding the debate". PMID- 21678203 TI - Fat chance getting an obstetrician in South Florida? Ethics and discrimination in obstetrics and gynecology. PMID- 21678204 TI - It's time for bioethics to see chronic pain as an ethical issue. PMID- 21678205 TI - Relative versus absolute standards for everyday risk in adolescent HIV prevention trials: expanding the debate. AB - The concept of minimal risk has been used to regulate and limit participation by adolescents in clinical trials. It can be understood as setting an absolute standard of what risks are considered minimal or it can be interpreted as relative to the actual risks faced by members of the host community for the trial. While commentators have almost universally opposed a relative interpretation of the environmental risks faced by potential adolescent trial participants, we argue that the ethical concerns against the relative standard may not be as convincing as these commentators believe. Our aim is to present the case for a relative standard of environmental risk in order to open a debate on this subject. We conclude by discussing how a relative standard of environmental risk could be defended in the specific case of an HIV vaccine trial among adolescents in South Africa. PMID- 21678206 TI - A relative standard for minimal risk is unnecessary and potentially harmful to children: lessons from the Phambili trial. PMID- 21678207 TI - (Un)risky business: adolescents and HIV prevention trials. PMID- 21678208 TI - Reopening old divisions. PMID- 21678209 TI - Why we don't need a relative risk standard for adolescent HIV vaccine trials in South Africa. PMID- 21678210 TI - The dangers of using a relative risk standard for minimal risk. PMID- 21678211 TI - Uniqueness, exploitation, and relative risk standards in adolescent research. PMID- 21678212 TI - Minimal risk remains an open question. PMID- 21678213 TI - The concept of minimal risk: the need for better guidance on the ethics review process. PMID- 21678214 TI - Regulating "higher risk, no direct benefit" studies in minors. PMID- 21678215 TI - Is continuous sedation at the end of life an ethically preferable alternative to physician-assisted suicide? AB - The relatively new practice of continuous sedation at the end of life (CS) is increasingly being debated in the clinical and ethical literature. This practice received much attention when a U.S. Supreme Court ruling noted that the availability of CS made legalization of physician-assisted suicide (PAS) unnecessary, as CS could alleviate even the most severe suffering. This view has been widely adopted. In this article, we perform an in-depth analysis of four versions of this "argument of preferable alternative." Our goal is to determine the extent to which CS can be considered to be an alternative to PAS and to identify the grounds, if any, on which CS may be ethically preferable to PAS. PMID- 21678216 TI - Palliative sedation: it's not a panacea. PMID- 21678217 TI - Additional reasons for not viewing continuous sedation as preferable alternative for physician-assisted suicide. PMID- 21678218 TI - Elimination of pain versus elimination of suffering: Why CDS is ethically preferable to PAS. PMID- 21678219 TI - Clarifying the ethics of continuous sedation. PMID- 21678220 TI - The lacking of moral equivalency for continuous sedation and PAS. PMID- 21678221 TI - Continuous deep sedation: consistent with physician's role as healer. PMID- 21678222 TI - A death of one's own: the perils and pitfalls of continuous sedation as the ethical alternative to lethal prescription. PMID- 21678223 TI - If suicide is painless, is painlessness suicide? PMID- 21678224 TI - Assisted suicide is compatible with medical ethos. PMID- 21678225 TI - Ethically preferable alternative practice: "no"; a preferable, head-to-head analytical approach: "maybe". PMID- 21678226 TI - Continuous deep sedation in end-of-life care: disentangling palliation from physician-assisted death. PMID- 21678227 TI - Palliative sedation, physician-assisted suicide, and euthanasia: "same, same but different"? PMID- 21678228 TI - The community speaks: continuous deep sedation as caregiving versus physician assisted suicide as killing. PMID- 21678229 TI - Determinants of central processing order in psychological refractory period paradigms: central arrival times, detection times, or preparation? AB - Three psychological refractory period (PRP) experiments were conducted to assess the effect of central arrival times at the bottleneck on task order scheduling. In Experiment 1, a visual first task (plus-minus symbol discrimination) was combined with an auditory second task (left-right tone judgement) in a standard PRP paradigm with constant task order. In Experiment 2, the order of the tasks varied unpredictably. In Experiment 3, visual-auditory dual-task trials were randomly mixed with single-task trials. To dissociate central arrival times from stimulus detection times, the perceptual stage of the visual task was extended using stimulus degradation. Most importantly, no evidence for a first-come, first served principle at the central bottleneck was found with the employed paradigms. Instead, the results indicated that preparation (Experiment 1) and the detection times of the stimuli (Experiments 2 and 3) were the main determinants of central processing order in the present study. In the light of previous research, the results indicate that central processing order can be influenced by various factors. The interplay between these factors seems to depend highly on the conditions and requirements of the employed experimental paradigm. PMID- 21678230 TI - Processing of indexical information requires time: Evidence from change deafness. AB - Studies of change detection have increased our understanding of attention, perception, and memory. In two innovative experiments we showed that the change detection phenomenon can be used to examine other areas of cognition specifically, the processing of linguistic and indexical information in spoken words. One hypothesis suggests that cognitive resources must be used to process indexical information, whereas an alternative suggests that it is processed more slowly than linguistic information. Participants performed a lexical decision task and were asked whether the voice presenting the stimuli changed. Nonwords varying in their likeness to real words were used in the lexical decision task to encourage participants to vary the amount of cognitive resources/processing time. More cognitive resources/processing time are required to make a lexical decision with word-like nonwords. Participants who heard word-like nonwords were more likely to detect the change when it occurred (Experiment 1) and were more confident that the voice was the same when it did not change (Experiment 2). These results suggest that indexical information is processed more slowly than linguistic information and demonstrate how change detection can provide insight to other areas of cognition. PMID- 21678231 TI - [Crime-related amnesia: real or feigned?]. AB - In the context of criminal forensic evaluations, experts are often confronted with the problem of offenders' claims of crime-related amnesia. Because of the far-reaching legal consequences of the expert opinion, the nature of the suspected memory disorder has to be investigated with special care and due consideration of differential diagnoses. While the diagnosis of organic amnesia is comparatively easy to make, the same is not true for dissociative amnesia. Despite existing theoretical explanations such as stress, peritraumatic dissociation or repression, to date there is no sound, scientifically based and empirically supported explanation for the occurrence of genuine, non-organic crime-related amnesia. In the criminal context of claimed amnesia, secondary gain is usually obvious; thus, possible malingering of memory loss has to be carefully investigated by the forensic expert. To test this hypothesis, the expert has to resort to methods based on a high methodological level. The diagnosis of dissociative amnesia cannot be made by mere exclusion of evidence for organic amnesia; instead, malingering has to be ruled out on an explicit basis. PMID- 21678232 TI - [Electroconvulsive therapy for major depression in borderline personality disorder]. AB - Depressive disorder is a serious and frequent complication in borderline personality disorder (BPD), however, its severity tends to be neglected particularly if symptoms are short-lived or inconsistent as is common in patients with BPD. Yet the high frequency in these patients requires especially rapid and effective therapy to reduce the risks of vital endangerment, chronification and psychosocial impairment. Efficient crisis intervention is essential for continuity of the disease-specific multimodal therapy enabling lasting remission and social and vocational rehabilitation in BPD. In particular with regard to the high incidence of poor or failed pharmacological responses in patients with BPD, electroconvulsive therapy (ECT) is of significant relevance among antidepressant treatment options. Despite the wide consensus on its efficacy, there are only few selected trials on ECT for major depression (MD) in BPD. This review summarises the published original studies on this issue, and critically scrutinises indication, benefits and risks of ECT for MD in BPD. It contributes to a focused, discriminating view on ECT and thus enables an optimised patient-oriented, efficient indication for MD in BPD. PMID- 21678233 TI - Flavonoids from the roots of Campylotropis hirtella. AB - Eight new flavonoids, including three pterocarpene derivatives, hirtellanines C E, two flavanones, hirtellanines F and G, three isoflavanones, hirtellanines H-J, as well as four known compounds were isolated from the roots of Campylotropis hirtella. The structures of the new compounds were elucidated by spectroscopic analyses, including 2D-NMR techniques. Pharmacological investigation indicated that the new compounds, particularly hirtellanines D and G, possessed potent immunosuppressive activities and low relative cytotoxicities. PMID- 21678234 TI - Carlina oxide--a natural polyacetylene from Carlina acaulis (Asteraceae) with potent antitrypanosomal and antimicrobial properties. AB - Carlina acaulis (Asteraceae) has a long history of medicinal use in Europe due to its antimicrobial properties. The strong activity of Carlina oxide, themain compound of the essential oil of C. acaulis against two MRSA strains, Streptococcus pyogenes, Pseudomonas aeruginosa, Candida albicans, and C. glabrata was confirmed. A strong and selective activity against Trypanosoma brucei brucei with an IC50 of 1.0 MUg/mL and a SI of 446 compared to human HeLa cells was recorded. The selective toxicity of Carlina oxide makes it a promising lead compound for the development of drugs to treat African trypanosomiasis and multiresistant gram-positive bacteria. PMID- 21678235 TI - Acridanone alkaloid in Baliospermum montanum--evaluation of its effect against anaphylaxis. AB - Baliospermum montanum leaves yielded 3-hydroxy-2,4-dimethoxy-10-methyl-9 acridanone (1), an alkaloid from the CHCl3 fraction. Spectroscopic analysis was performed to assign the structure of the new compound (1) and its absolute configuration. The compound was evaluated for its effect in anaphylaxis by estimation of the release of histamine in systemic anaphylaxis model. The acridanone alkaloid significantly inhibited the degranulation of mast cells up to 65.22 % and 75.12 % at a dose of 50 and 75 mg/kg, respectively. PMID- 21678236 TI - Profiling of phenolics from Tephrosia cinerea. AB - An HPLC-ESIMS(n) method, based on high-performance liquid chromatography coupled to electrospray positive ionization multistage ion trap mass spectrometry, has been used to rapidly identify and guide the isolation of phenolic constituents from the methanol extract of the aerial parts of T. cinerea. On the basis of the results of the online screening by HPLC-ESIMS (n), 17 phenolic constituents, including two new compounds, namely demethylapollinin 7- O- beta-D glucopyranoside (1) and cineroside A (17), were isolated, and their structures were unambiguously assigned by the extensive use of 1D- and 2D-NMR experiments. PMID- 21678237 TI - Umbilical cord as temporary coverage in gastroschisis. AB - INTRODUCTION: Although the early definitive closure of gastroschisis is possible in many cases, there is an ongoing discussion about the advantages of staged reduction. Different strategies and materials have been described to wrap the bowel for protection and reduce heat and fluid loss. The variety of devices ranges from prosthetic patches to biomaterials. We present use of the umbilical cord for temporary coverage in primarily irreducible gastroschisis. METHOD: After revision and reduction of as much gut as possible under constant monitoring of the bladder pressure, the remaining eviscerated intestine is covered by the longitudinally split umbilical cord. Over the following days the continued reduction of the bowel relies on gravity, assisted by progressive compression by the shrinking umbilical cord tissue. At 10 days after performing the umbilical cord flap, it is possible to close the fascia without complications using gentle pressure. RESULTS: Since 1991 we have used this umbilical cord flap for staged reduction in 17 infants (10 females, 7 males) with giant gastroschisis. There were no complications related to use of the umbilical cord flap, no infections or NEC episodes, and no mortality. Length of hospital stay was 5 weeks on average. In 3 patients the course was complicated by associated defects or an underlying malformation. CONCLUSION: Our experience confirms the advantage of a staged reduction in giant gastroschisis. The use of autogenic material such as the umbilical cord has advantages such as low infection rates and easy availability. PMID- 21678238 TI - A new intraperitoneal technique for safe repair of incarcerated inguinal hernias: a novel technique to consider. AB - INTRODUCTION: Inguinal herniotomy is one of the most common operations performed by paediatric surgeons. Most procedures are elective operations but occasionally the hernia is incarcerated. Complications after emergency repair of an incarcerated hernia repair are higher than those associated with elective surgery because of congestion of the sac. Operative techniques described so far include low, high, preperitoneal and laparoscopic approaches. We describe here an open intraperitoneal technique. METHODS: 6 boys aged between 4-40 weeks were taken urgently to the operating room for incarcerated inguinal hernia repair. All boys were operated on using an open intraperitoneal technique. In this technique, the congested sac does not need to be separated from the adherent vas and vessels within the inguinal canal, the reduced bowel can be inspected with 3D visualisation and resected if necessary, and the peritoneum can be easily incised and sutured through a single skin incision, reducing the risk of complications and providing superior cosmesis. RESULTS: All patients had very good postoperative outcomes with no complications. CONCLUSIONS: The technique can be used not only for incarcerated inguinal hernia repair but also for problematic repairs of recurrent hernias. Disadvantages include postoperative hydrocele formation and failure to inspect the testicle. PMID- 21678239 TI - Experience with the NICE guidelines for imaging studies in children with first pyelonephritis. AB - PURPOSE: This retrospective study evaluates the applicability of a selective approach for imaging in children aged 0-15 years with a first episode of pyelonephritis, based on the UTI guidelines of the National Institute for Health and Clinical Excellence (NICE). MATERIAL AND METHODS: A total of 96 consecutive patients were included (age range: 0.1-14.9 years, median age: 0.7 years), treated for a first episode of confirmed culture-positive pyelonephritis. At initial hospitalization all patients underwent ultrasound examination of the kidneys and urinary tract (US) and technetium-99m mercaptoacetyltriglycine scinti and renography ( (99m)Tc MAG3). If vesicoureteral reflux (VUR) was suspected, then prophylactic antimicrobial therapy was prescribed and the patients were referred to a surgeon for further evaluation including voiding cystoureterography (VCU). Patients with known urological anomalies including antenatally diagnosed anomalies were excluded. All patients were followed up for a median of 5.2 years (3.5-8.6 years). RESULTS: Initially, US findings were abnormal in 29 (30%) patients and (99m)Tc MAG3 findings were abnormal in 20 (21%) cases. At follow up, prophylactic antimicrobial therapy was prescribed for 19 (20%), and VUR was diagnosed by VCU in 9 patients. Surgery was carried out in 7 (7%) patients, primarily for VUR. If the NICE guidelines had been initially followed, 5 of our 9 patients with VUR would not have been identified. VUR surgery was performed in 4 of these cases. Moreover, 9 cases with urological anomalies subsequently prescribed prophylactic antimicrobial therapy would have been missed. CONCLUSION: We do not recommend following the imaging strategies of the NICE guidelines for children with a first episode of pyelonephritis. Our most important argument is that at follow-up, after a minimum of 3.5 years, the initial diagnosis of VUR would have been missed in 4 out of the 5 patients who underwent VUR surgery. PMID- 21678240 TI - Effect of stent placement, balloon or cutting balloon dilatation on stricture formation after caustic esophageal burn in rats. AB - INTRODUCTION: This study aimed to evaluate the effects of stent placement prior to stricture development following caustic esophageal burn (CEB) in an animal model. The outcomes after stent placement were also compared with those after balloon dilatation and cutting balloon dilatation performed after stricture development. Groups were compared with regard to stricture development and weight loss. MATERIALS AND METHODS: 40 rats were divided into 5 groups. CEB was created as described by Gehanno et al. In Group A (control) no CEB was performed and the esophagus was only rinsed with saline. Group B rats underwent CEB with no subsequent treatment. Group C rats underwent CEB followed by balloon dilatation in the 3 (rd) and 4 (th) week. Group D rats underwent CEB followed by cutting balloon dilatation in the 3 (rd) week. Group E rats underwent CEB with subsequent placement of a silicon stent in the same session. The animals were sacrificed in the 6 (th) week, and the stenosis index (SI), collagen deposition, and hydroxyproline (HP) levels were determined in the esophageal segments and statistically compared. RESULTS: Although weight loss occurred in Group C and Group B rats (238.87+/-15.95 g vs. 233.83+/-19.01 g), weight loss in Group C rats was less marked compared to Group B. Similarly, the SI in Group C was lower compared to that of Group B and the difference was statistically significant. Although there was no difference in weight between the rats in Group C and Group B before the procedure (p=0.318), there was statistically significant difference thereafter (p=0.002). The SI of Group D was also lower compared with that of Group B, and the difference was statistically significant. Weight gain in Group E rats was similar to that noted in Group A rats and was higher compared to Group B; this difference was statistically significant. The SI for Group E was lower compared to that of Group B. CONCLUSION: Stenting performed at the time of corrosive injury and cutting balloon dilatation performed after stricture formation had a positive effect with regard to SI and weight gain in an animal model. PMID- 21678241 TI - When is a scrotal swelling not a scrotal swelling? PMID- 21678242 TI - Congenital bladder diverticula as a cause of bladder outlet obstruction in children. PMID- 21678243 TI - Fetal extraperitoneal rectal perforation in a preterm baby. PMID- 21678245 TI - [Personal health record - still in an experimental stage]. PMID- 21678247 TI - [The opportunities and challenges of nursing professional development: celebrating 100 years of nursing in Taiwan]. AB - This article used both retrospective and prospective perspectives to rethink and reflect upon the opportunities and challenges of nursing professional development in Taiwan. The authors conducted a literature review on the 2011-2015 Strategic Directions for Strengthening Nursing and Midwifery Services (SDNM) initiated by the World Health Organization (WHO) and on analyses of nursing related polices and programs from done by Taiwan health administrative offices. It is important to record the contribution of nursing to Taiwan's healthcare delivery system. Such is especially in light of the Taiwan's centenary celebrations in 2011 and of the Department of Health's consolidation into the Ministry of Health and Welfare in 2012 due to central government reforms. PMID- 21678246 TI - Outcomes of bronchial artery embolization for life-threatening hemoptysis due to tuberculosis and post-tuberculosis sequelae. AB - PURPOSE: To determine the long-term outcomes of bronchial artery embolization in patients with massive hemoptysis due to pulmonary tuberculosis and post tuberculosis sequelae and to study the factors influencing success. MATERIALS AND METHODS: In this study, 58 patients underwent 64 bronchial artery embolizations for massive hemoptysis due to tuberculosis or its sequelae between 1998 and 2008. Their images and procedure details were reviewed. Medical records and direct contact were used to obtain information on outcome. The cumulative hemoptysis control rate per follow-up interval was calculated. RESULTS: The data showed that 25 patients presented with acute massive hemoptysis and 33 presented with chronic recurrent hemoptysis. The median quantity of blood was 400 mL (range, 70-2000 mL). The median follow-up period was 432 days (range, 11-1789 days). Twenty-seven patients had recurrence after a median period of 110 days after the procedure (range, 1-959 days). The hemoptysis control rate was 93% at 2 weeks, 86% at one month, 79.5% at 3 months, 63% at 6 months, 51% at one year and 39% at 2 years. Six patients underwent repeat procedures. Chest pain was the most common procedure-related complication (n=20, 34.5%); there was no spinal cord complication or mortality. There were seven deaths, five of which were related to hemoptysis. Nine patients were lost to follow-up. Lung cavities (P = 0.08), nonbronchial systemic artery collaterals (P = 0.081) and systemicto- pulmonary venous shunts (P = 0.053) were more common in those who experienced recurrence. CONCLUSION: Bronchial artery embolization is a relatively safe procedure that is lifesaving in patients who are not suitable for surgery. However, the associated long-term outcome is less satisfactory. PMID- 21678248 TI - [The nurse administrator in transition: reflections and future perspectives]. AB - The growing complexity of Taiwan's healthcare system increasingly challenges nurse administrators. Multifaceted competencies and skills are essential for nurse administrators to manage organizational resources, ensure patient safety and maintain care quality. The author designed this paper to explore from a broad historical perspective the current challenges nurse administrators face. The paper provides recommendations to prepare and train future nurse administrators to fulfill their management roles confidently and competently. PMID- 21678249 TI - [The assertive nursing administrator]. AB - This article explains assertive behavior in nursing administrators. This is an important quality that helps safeguard the interests of nursing staff and enhances the dignity of the nursing profession. Assertive behavior differs from non-assertive behavior and aggressive behavior. It is a learned interpersonal communications skill that communicates one's professional position and feelings, confirms one's needs, expressess opinions clearly at the right time and place, provides appropriate facts to illustrate problems and avoid judgment errors, and politely and firmly sustains an appropriate degree of independent authority necessary to upholding the rights and dignity of nurses. PMID- 21678250 TI - [Reformation of the nursing administration and management system]. AB - In today's rapidly changing healthcare environment, nursing administrators and managers must enhance their abilities to anticipate and manage change in order to minimize the impact of such on healthcare delivery systems. To maintain patient care quality, nursing leaders should be familiar with change trends and implement innovative strategies that improve the work environment for nurses. This paper describes current major challenges faced by nursing administrators and introduces the concept of change and related strategies and available change management tools. This paper used five core competencies proposed by the Institute of Medicine (IOM) to illustrate and share experiences of managing change in clinical settings. PMID- 21678251 TI - [Critical research issues in nursing policy and management: a healthcare system perspective]. AB - This study explores critical research issues in nursing policy and management in Taiwan from a healthcare system perspective that considers resources, programmes and organisations, service delivery, policy and management, and economic support. Findings suggest the following: In terms of resources, priority issues include quantity planning, active surveillance, planning methodology, and estimation of work life expectancies for nursing manpower. In terms of programmes / organisations and delivery, priority issues include skill mix, task shifting, nationwide nursing work surveys, and nursing manpower structure and utilization. In terms of policy/management and economic support, priority issues included minimum nursing manpower requirements by law or medical institution standards and the relationship between the social insurance payment system and development of the nursing profession. The last section of this paper makes suggestions on practical ways to improve nursing policy and management research in Taiwan. PMID- 21678252 TI - [Thyroidectomies: surgical site infection risk factors of using prophylactic antibiotics]. AB - BACKGROUND: Surgical site infection is one of the most common types of nosocomial infection and an important factor in increased mortality and medical costs. The effectiveness of prophylactic antibiotics use on thyroidectomy wound sites merits further examination. PURPOSE: This study compared the influence of prophylactic antibiotics use or non-use on surgical site infection risk, average hospital stay length and average medical costs in thyroidectomy patients. METHODS: This cross sectional study targeted patients undergoing thyroidectomies at the general surgery ward of a medical center during the period 2007 to 2008. Subjects were divided into two groups. The first comprised patients who received prophylactic antibiotics thirty minutes before receiving a thyroidectomy between January 1, 2007 and October 31, 2007. A retrospective review of patient charts and reports was conducted for this group. The second consisted of patients that did not receive prophylactic antibiotics 30 minutes before receiving a thyroidectomy between November 1, 2007 and October 31, 2008 in line with a new antibiotics policy enforced at the research hospital. RESULTS: A total of 310 subjects were enrolled in the study. All subjects were free of surgical site infection. Fifteen patients (4.8%) received a course in antibiotics after surgery and six (40.0%) of these showed surgical site swelling (x2 = 120.33; p < .01). Statistically significant risk factors of post-surgery antibiotics use included diabetes mellitus (x2 = 6.39; p = .03), a surgery duration in excess of 2 hours (x2 = 4.40; p = .04), drainage tube remaining in place at the surgical site (x2 = 4.58; p = .03) and drainage tube insertion for more than 2 days (x2 = 6.24; p = .03). Significant reductions in average hospital stay length (3.65 days +/- 1.04; p < .01) and medical costs (p < .01) were observed when prophylactic antibiotics were not used before surgery. The cost of post-operative antibiotics increased by $5,851 and medical costs increased from $32,436 to $63,895 when hospital stay length exceeded four days. If hospital stay length was kept within four days and post-operative antibiotics were used, this study found no significant difference in drug or medical costs. CONCLUSION: Not using prophylactic antibiotics before thyroidectomy does not increase surgical site infection risk. PMID- 21678253 TI - [Relationships between stress perception and stress biomarkers in family caregivers]. AB - BACKGROUND: Family caregivers (FCGs) of persons with dementia (PWDs) face chronic stress. However, their stress has often been assessed by their distress in the absence of physiological indicators. Studies to date have rarely documented the relationships between distress and various stress biomarkers. PURPOSE: The aim of this study was to explore the relationships between distress and stress biomarkers in FCGs. METHODS: This was a secondary data analysis study that used data collected by two projects funded by the National Science Council. Samples included 113 dyads of PWDs and their FCGs willing to donate blood samples. Original study data sites comprised two teaching hospitals (memory clinics and psychiatric outpatients), two regional hospitals (neurology clinics), and two dementia daycare centers for community-dwelling PWDs in northern Taiwan. FCG distress was assessed using the Chinese Neuropsychological Inventory-Caregiver Distress Scale (CNPI-CD); Stress biomarkers included interleukin (IL)-1beta, IL 6, IL-10, cortisol, and C-reactive protein (CRP). RESULTS: Stress biomarker levels did not correlate with overall FCG distress related to PWD neuropsychological problems. However, IL-1beta, IL-6, and IL-10 levels did correlate with specific FCG distress toward specific PWD neuropsychological symptoms. CONCLUSIONS: This study found certain stress biomarkers (IL-1beta, IL 6, IL-10) associated with specific PWDs' neuropsychological symptoms (p < .05). Further longitudinal research is needed to clarify causal relationships between subjective distress and objective stress biomarkers to evaluate FCG stress levels more comprehensively. PMID- 21678254 TI - [Pediatric nurses: cognition of young child development and attitudes and behaviors toward developmental care]. AB - BACKGROUND: The effectiveness of early detection and intervention is emphasized in child development. The knowledge and attitudes of pediatric nurses related to child development is a factor critical to identifying and helping disabled children. PURPOSE: The purpose of this study was to explore general pediatric nurse knowledge of young child development and attitudes and behavior toward child developmental care. METHODS: Researchers collected data for this descriptive study using a structured questionnaire and recruited a sample of 112 pediatric nurses from hospitals in Central Taiwan. Data was analyzed by Mean, Pearson correlation, ANOVA, and Logistic regression. RESULTS: The study revealed pediatric nurses have a good level of knowledge related to children development. Although most participants held positive attitudes toward early intervention and child developmental care, their related behaviors were inadequately reported. Predictive factors of child developmental care behavior in nurses included attending related courses and number of children that has. CONCLUSION: Child development-related programs are an important factor affecting nurse child developmental care behavior. The authors recommend establishing developmental care programs and encouraging nurse participation. Early intervention concepts and models should be introduced in nursing and continued education programs. PMID- 21678255 TI - [An investigation of the diet preferences of patients with metabolic syndrome who underwent coronary artery bypass graft surgery]. AB - BACKGROUND: The coronary artery disease (CAD) patients are not free of disease recurrence following coronary artery bypass graft (CABG) surgery. There may be risk of restenosis or occlusion in coronary blood flow. Risk reduction, such as diet control, is needed for long-term vascular patency. PURPOSE: The purpose of this study was to explore the diet preferences of post coronary artery bypass graft surgery patients with metabolic syndrome. METHODS: A cross-section research design and purposive sampling were conducted in this study. The study was conducted at a general hospital in northern Taiwan. A total of 104 samples recruited. And given a respondent demographics questionnaire and Chinese food frequency questionnaire. Eata were managed and analyzed using SPSS 17.0 software. RESULTS: We found that postoperative patients ate less vegetables and milk and more fried food. They also used cooking oil more frequently. CONCLUSION: We recommend that patients after CABG surgery take more vegetables with less fried food and cooking oil. They should improve their diet preferences and eating habit. More than half of the patients have meals prepared by their spouses. More emphasis should be focused on improving the health knowledge of those who prepare food. We hope this result can provide more information about postoperative diet education for medical staff and help patients and their families consume a diet richer in healthy foods. PMID- 21678256 TI - [New opportunities for nursing in the future of intermediate care]. AB - Intermediate care is an important focus of the Taiwan Government, domestic diagnosis groups, and the Ten-Year Long-Term Care Project. The objective of intermediate care is to bridge acute and long-term care in order to deliver more comprehensive healthcare to the population. It is an emerging healthcare service model. Intermediate care and a supportive environment should facilitate the functional recovery of patients and their successful return to the community. This article first describes the origins of intermediate care, its definitions and components, service models and related research. It then proposes the role of nursing in intermediate care and implications for nursing in the future of domestic intermediate care policy. We hope that academia, the government and health industry can work together to facilitate intermediate care in order to extend and expand nursing roles. PMID- 21678257 TI - [Opportunities and challenges for community healthcare center psychiatric care]. AB - Public health nurses are the largest manpower component in community-based psychiatric care in Taiwan. However, controversies related to primary responsibility for such have erupted and must be addressed in order to ensure patients receive the most appropriate care and healthcare professionals are adequately trained and supported. This article used the STEP (social technological-economical-political assessment) method to assess the macro-level contextual changes that have affected healthcare centers and public health nurses providing community psychiatric care as well as their role function and development. This study recommends several policy changes based on findings. PMID- 21678258 TI - [Pregnancy and the struggle to quit smoking]. AB - The negative effects of smoking during pregnancy are well documented. Health care providers typically advise pregnant women who smoke usually to quit for their health as well as for the health of their fetus. Most women are familiar with the need to stop smoking while pregnant. Hospitals offer various smoking cessation services. However, the literatures reveals a low uptake of smoking cessation services among pregnant women. The purpose of this paper is to explore the smoking cessation experience and feelings amongst women during pregnancy and assess smoking cessation intervention in antenatal care. Findings may provide health care providers a better understanding of this issue and help women overcome related challenges. PMID- 21678259 TI - [High-quality nursing health care environment: the patient safety perspective]. AB - Patient safety is regarded as an important indicator of nursing care quality, and nurses hold frontline responsibility to maintain patient safety. Many countries now face healthcare provider shortfalls, and recognize a close correlation between adequate manpower and patient safety. Many healthcare organizations work to foster positive work environments in order to improve health service quality. The active participation and "buy in" of nurses, patients and policymakers are critical to maximize healthcare environment quality and improve patient safety. This article adopts Donabedian's theoretical "Structure-Process-Outcome" model of quality (Donabedian, 1988) and presumes all high-quality healthcare environment indicators to be linked to patient safety. In addition to raising public awareness regarding the influence of healthcare environment quality on patient safety, this research suggests certain indicators for tracking and assessing healthcare environment quality. Future research may design an empirical study based on these indicators to help further enhance healthcare environment quality and the professional development of nurses. PMID- 21678260 TI - [The internationalization of the nursing profession in Taiwan]. AB - Globalization, nursing manpower migration, and the multinational nature of the medical industry have increased the level of internationalization in Taiwan's nursing profession. In nursing practice, competencies for the general nursing list (Taiwan version) and ICNP (International Classification for Nursing Practice) have been clinically tested and revised. In academic nursing, significant effort is invested toward achieving the three general objectives of internationalized teaching, internationalized campuses, and international academic exchanges. We should further test and revise Taiwan's competencies for the general nursing list, and the ICNP should be continually tested and revised. Additionally, nursing personnel should strengthen foreign language competencies, appreciate different nursing practice cultures, participate in international exchange activities, and place increasing emphasis on international cooperation in research and nursing education accreditation. Such should further enhance and strengthen international cooperation, which should further encourage internationalization in the domestic nursing profession. PMID- 21678261 TI - [Applying mencian's "mind of compassion" to real life situations in nursing practice]. AB - "Mind of Compassion", as elaborated by Mencius, emphasizes practice in life. It is a concept also highly valued in Confucian. The moral practice stressed by Confucian is a categorical imperative. Because the main concern is on life itself, moral actions should be taken "as is," without the need to refer to any other conditions. Nursing practice deals with patient diseases and death. Such is precisely the environment in which moral practice should take place. Professional healthcare workers may make very good use of the values and meanings of this moral practice and employ such to its fullest. As Mencius' "Mind of Compassion" reflects the main essence of nursing practice, its elaboration can be highly beneficial in nursing care. This article uses Mencius' concept as well as relevant Western theories and concepts (e.g., caring, empathy and sympathy) to clarify the main values and ways to practice a meaningful life. PMID- 21678262 TI - [Project to improve abdominal obesity in day care ward psychiatric patients]. AB - BACKGROUND & PROBLEMS: Over half (57.14%) of patients in our ward suffer from abdominal obesity. This rate is on a continuing upward trend. Reasons for such obesity include lack of physical activity classes, inadequate physical activity, high calorie diets and unhealthy eating habits, chronic diseases and drug side effects, poor motivation to reduce weight, and lack of crisis awareness of abdominal obesity. PURPOSE: This project was designed to lessen the problem of abdominal obesity among psychiatric day care inpatients. RESOLUTION: Resolution measures implemented included: (1) arranging aerobic exercise classes; (2) scheduling classes to teach patients healthy diet habits and knowledge regarding diseases and drugs; (3) holding a waistline reduction competition; (4) displaying health education bulletin boards; (5) holding a quiz contest with prizes for correct answers. RESULTS: The eight abdominally obese patients in the ward achieved an average waist circumference reduction of 2.9 cm and the overall abdominal obesity rate in the ward fell to 35.7%. BMI, eating habits, and awareness of weight loss importance and motivation all improved. The outcome achieved targeted project objectives. CONCLUSIONS: We recommend the integration of obesity prevention into routine ward activities and quality control indicators. Nurses should provide patients with weight loss concepts, regularly monitor risk factors, and encourage patient family cooperation to maintain medical care quality. PMID- 21678263 TI - [Improving patient safety: acupuncture therapy administered in the rehabilitation department]. AB - BACKGROUND: Therapies that combine Chinese and western medicine is applied particularly often on patients in rehabilitation departments to reduce disease and illness recovery times. Acupuncture (fine needle piercing) is a widely applied traditional Chinese therapeutic approach. However, accidents including leaving needles in the patient's body and patient fainting due to carelessness or inadequate nursing training have raised concerns about the efficacy of acupuncture. PURPOSE: This article was written to recommend ways to improve the safety of acupuncture applied to patients in rehabilitation departments. RESOLUTION: The authors developed standard operating procedures, nursing records, double-checking requirements, and on-the-job training courses. RESULT: After implementation of recommended resolutions, nursing staff cognition rose from 9.6 (63.8%) to 14.5 points (96.6%); the Traditional Chinese Medicine (TCM) nursing skill accuracy rate rose from 93 (58.1%) to 144 points (90.0%); and accident incidents fell from 6 (0.9%; 2008.1-2009.1) to 0 (2009.4.1-4.30). CONCLUSION: Implementing resolution recommendations effectively enhance patient safety. PMID- 21678264 TI - [Enhancing nurse implementation of oral healthcare in an intensive care unit]. AB - BACKGROUND: Oral health professionals identified inadequate levels of patient oral health in our intensive care unit (ICU). A post-review analysis of collected data and field observation notes concluded that this problem resulted from several factors including: (1) Failure of ICU nurses to follow mouth care standards; (2) lack of oral injury care procedures; (3) lack of oral injury consultation procedures; (4) lack of oral care monitoring; (5) substandard oral care assistive devices. PURPOSE: The authors designed this project to raise general nursing staff knowledge of oral hygiene standards and increase the ability of nurses to implement proper oral healthcare. RESOLUTION: After discussions with oral health professionals and reviewing articles in the literature, the authors implemented Critical Patient Oral Care Standards and Oral Injury Consultation Procedures and purchased new assistive care devices. The authors also conducted regular on-the-job training sessions for hospital staff that were reinforced by regular monitoring. RESULTS: Training significantly increased nursing staff recognition of oral health care. Oral health care test scores rose from an initial average of 16% correct to a final average of 90% correct. Accurate implementation of oral health care in the ICU rose from an initial 19.69% to 78.66% of cases. CONCLUSION: This project significantly enhanced the accuracy and appropriateness of nurse oral health care delivery and quality health care promotion in the ICU. PMID- 21678265 TI - [Project to ameliorate cognitive function deterioration in day care dementia patients]. AB - BACKGROUND & PROBLEMS: Deterioration of cognitive functions, including disorientation related to people, time and place, loss of memory, and deterioration in interpersonal skills, is very common in dementia patients. Expense of care rises as conditions worsen. PURPOSE: The authors designed this project to ameliorate the deterioration of cognitive functions and enhance cognition in daily life. SOLUTION: The project was carried out between Jan 1, 2007 and June 30, 2007. The three strategies used included: (1) educating staff and establishing care guidelines; (2) introducing environmental keys such as a reality-oriented board, clock information, photo labels, and image signs; (3) redesigning and implementing daily activities. RESULTS: Following the intervention, average cognitive functions improved from 6.58 +/- 3.19 to 5.11 +/- 3.20 (total: 10). The mistaken recognition rate for items including the toilet, personal bed, clothes closet, meal seating position and time decreased from 38% to 13%. CONCLUSION: This project significantly improved cognitive function and recognition in dementia patients. The experience described within may serve as a reference for dementia institutions and healthcare workers. PMID- 21678266 TI - [Measures to reduce lighting-related energy use and costs at hospital nursing stations]. AB - BACKGROUND: Hospitals have long been expected to deliver medical services in an environment that is comfortable and bright. This expectation keeps hospital energy demand stubbornly high and energy costs spiraling due to escalating utility fees. Hospitals must identify appropriate strategies to control electricity usage in order to control operating costs effectively. PURPOSE: This paper proposes several electricity saving measures that both support government policies aimed at reducing global warming and help reduce energy consumption at the authors' hospital. PROJECT: The authors held educational seminars, established a website teaching energy saving methods, maximized facility and equipment use effectiveness (e.g., adjusting lamp placements, power switch and computer saving modes), posted signs promoting electricity saving, and established a regularized energy saving review mechanism. RESULT: After implementation, average nursing staff energy saving knowledge had risen from 71.8% to 100% and total nursing station electricity costs fell from NT$16,456 to NT$10,208 per month, representing an effective monthly savings of 37.9% (NT$6,248). CONCLUSION: This project demonstrated the ability of a program designed to slightly modify nursing staff behavior to achieve effective and meaningful results in reducing overall electricity use. PMID- 21678267 TI - [Project to enhance accuracy of nursing assessments performed by medical and surgical ICU nursing staffs]. AB - BACKGROUND: Some nurses do not have the skills necessary to evaluate general ICU patient condition and the meaning of laboratory data adequately. This can influence nursing care quality and patient safety. Between October 16th and 29th, 2009, this project employed a checklist to evaluate nursing assessment accuracy in medical and surgical ICUs. The unexpectedly low accuracy rate of two-thirds (63.4 percent) was caused by factors including poor nursing assessment cognizance, lack of experience performing nursing assessments, nursing assessment skills taught only to experienced nursing staff, and a lack of nursing assessment guidelines. PURPOSE: This project was designed to improve nursing assessment cognizance and accuracy among nursing staff. RESOLUTION: The authors: 1. Established formal nursing assessment guidelines; 2. made a CD-ROM to introduce nursing assessment basics; and 3. employed lectures and simulation exercises to teach nursing assessment skills. RESULTS: Nursing assessment accuracy improved significantly to 85.8 percent and actual nursing assessment cognizance scores ranged between 68.7 and 83.1. CONCLUSIONS: This project effectively improved nursing assessment accuracy and may be considered and referenced by relevant medical organizations. PMID- 21678268 TI - [Reducing patient pressure sore incidence in the surgical intensive care unit]. AB - BACKGROUND: Pressure ulcers were an increasingly significant problem among patients in the authors' ward. The eight patients diagnosed with pressure ulcers (0.42% of all inpatients) during the first half of 2009 represented a 140% increase over the first half of 2008 (0.28% of all inpatients). PURPOSE: This project was designed to reduce pressure ulcer incidence in the surgical intensive care unit (ICU) to 0.05%. METHODS: Intervention measures included: 1) holding professional training on preventing pressure ulcers; 2) specifying appropriate patient turnover tools; 3) creating and distributing to nurses a proper turnover technique and positioning manual; 4) creating and distributing to nurses a comprehensive patient skin inspection checklist; and 5) organizing a permanent pressure ulcer care quality and audit committee. RESULTS: Pressure ulcer incidence fell from 0.42% to 0.04% following implementation of the methods. CONCLUSION: Results demonstrate the effectiveness of using the proposed methods to reduce pressure ulcer incidence and enhance nursing care quality. PMID- 21678270 TI - [The experience using the ADOPT problem-solving training protocol in a hemodialysis patient with poor IDWG control]. AB - The health problems of hemodialysis patient are complex, involving physical, mental and social aspects. Those with chronic conditions must be able to resolve disease and treatment problems on their own expectation in order to maintain life quality. This case report describes how the authors applied the ADOPT (Attitude, Definition, Open mind, Planning, Try it out) problem-solving training model to care for a hemodialysis patient with poor interdialytic weight gain (IDWG) control. Nursing care was provided to this patient from November 3rd to December 8th, 2008. This case demonstrated ADOPT model efficacy at improving the patient's problem solving abilities in various daily life situations. The authors hope this theory-based intervention can help establish an innovative and effective care model for patients with chronic conditions. PMID- 21678269 TI - [Hematology-oncology port-A: improving nursing care quality]. AB - BACKGROUND: Hospitalized hematology-oncology patients undergoing chemotherapy face a significant risk of port-A related bloodstream infections. Nurses are uniquely positioned to help adjust clinical practices necessary to prevent port-A related bloodstream infections and improve patient outcomes. Between July 1st, 2008 and June 30th, 2009, twelve patients in our ward were stricken with port-A related bloodstream infections (an infection rate of .318%). Data analysis indicated inadequate nursing competency in all aspects of port-A care. Nurses did not have adequate knowledge of port-A modified standard care protocols and did not provide dressings suited to hematology-oncology patient needs. Also, both patients and caregivers lacked adequate skin care knowledge. Our team developed a project to address and minimize port-A related bloodstream infection issues in our hospital. OBJECTS: The authors designed this project to enhance integration of both the central line insertion care and maintenance practice bundles in order to reduce port-A related bloodstream infection incidence. RESOLUTION: The plan was implemented from August 15, 2009 to December 20, 2009. It included establishing a standardization port-A care protocol, implementing a more appropriate dressing type, performing an irregular audit of port-A care techniques, holding educational training, and establishing skin care instructions for patients and their families. RESULTS: Hematology-oncology patient port-A related bloodstream infections fell from .318% pre-implementation to .099% post implementation. The effective rate of improvement was 68.87%. CONCLUSION: Standardization of Port-A care under this project achieved infection reduction results that achieved our anticipated goals. This project furthermore enhanced the delivery and quality of patient nursing services. This experience can serve as a reference to medical organizations involved in hematology-oncology patient care. PMID- 21678271 TI - [Therapeutic play in nursing care: one experience with a school-age liver transplant recipient]. AB - This case report described an experience using therapeutic play in the care of a school-age living donor liver transplant recipient. A first intervention employed playing the patient's favorite game in order to create a therapeutic relationship. The author then introduced therapeutic play elements into the game to observe the patient's personal health behaviors, evaluate patient perception of hospitalization and assess the knowledge of self-care protocols. Therapeutic play was then used to raise patient familiarity with daily care specifics. The author found therapeutic play also helpful in persuading the patient to share deep feelings on the anxiety of separation from her parents while in the ICU. During the nursing process, the author recognized therapeutic play as an effective tool to communicate with children and improve treatment protocol compliance. The author recommends that nurses incorporate therapeutic play in clinical practice to reduce children's stress during hospitalization. PMID- 21678272 TI - [Culturally competent care: helping an immigrant mother's child with cancer return to elementary school]. AB - In bicultural families in Taiwan, women who have immigrated to Taiwan and married a Taiwanese husband are often obligated to be the primary caregiver for their sick children. Thus, in Taiwan's transcultural healthcare environment these mothers are an important communication bridge between healthcare professionals and families. As mothers consider the education and development of their children while the latter recover from illness, they bear primary responsibility for communicating and coordinating amongst the family, hospital and school. Active and comprehensive nursing plans are needed to assist immigrant mothers and their children to complete treatment plans. The author is a primary nurse who helped the mother to understand care methods and how to integrate medical professional, teacher, and family member resources to make her child's reentry school successful. This article described the process of school reentry, follow-ups, specific nursing intervention, and evaluation that contributed to the child achieving his developmental tasks. The author hopes this article can be a reference for clinical care and future research. PMID- 21678273 TI - [A nurse's experience caring for a patient with breast cancer who had been previously reported dead by her family]. AB - This article describes the author's experience caring for a female with breast cancer who was reported dead by her family four years earlier due to a long-term disappearance. She had been transferred multiple times hospital to hospital due to inability to afford medical care. Data were collected via observations, interviews, and physical assessments. The author identified four primary problems, including impaired tissue integrity, pain, being compelled to abandon treatment due to financial status, desire for familial support, and sense of guilt toward her family. The author used Watson's Caring Theory to build trust with the patient and provided guidance on wound treatment, pain relief, and rebuilding family relationships in order to help restore the patient's identity and financial aid. As a result, the patient was able to transfer to a public hospital where she received free medical assistance and regained hope in her therapy. However, the palliative-care coordinator misinterpreted the referral and, as a result, experienced moral distress. After clarifying and explaining the meaning and importance of the patient referral, the coordinator accepted her and continued care. This case report can provide a reference for nurses caring for patients without personal identity or financial aid. Nurses should be aware of the presence of moral distress in other medical team members. Early recognition and timely management of team members' moral distress is fundamental to providing the best quality of care for patients and their families. PMID- 21678274 TI - [Self-regulation effect in dietary control of obesity]. AB - Problems associated with excess bodyweight and obesity are increasing worldwide. These problems increase risks of metabolic syndrome, cardiovascular disorders and hypertension. Improving diet and exercise control and self-monitoring, self evaluating and self-adjusting are critical to modify risky lifestyles. In this paper, the author's designed a diet control protocol and then applied it to an obese adult. The project ran from Feb 2nd to July 30th, 2009, and used the principles and concepts of self-regulation theory, a daily diet plan, and body weight chart to guide the patient to consider and appreciate the gaps between his behavior and the standard in order to encourage improvement. The processes related to the goal and effect are significant. By learning self-regulation skills the patient's weight declined from 106.1kg to 84.4kg. Self-efficacy also improved. The author predict the efficacy of the approach in helping prevent chronic disease. The author wishes to share their experience with nursing colleagues and propose this protocol as an effective diet control approach for obese patients. PMID- 21678275 TI - [Interferon gamma based tests as a new tool in diagnosis of latent tuberculosis]. PMID- 21678276 TI - [Interferon-gamma assays T-SPOT.TB for the diagnosis of latent tuberculosis infection]. AB - INTRODUCTION: The diagnosis of latent tuberculosis infection (LTBI) is currently based on the century-old tuberculin skin test (TST). However a positive reaction can result from infection by Mycobacterium tuberculosis, BCG vaccination or cross reaction with nontuberculous mycobacteria. T-SPOT.TB assay is a new test to diagnose tuberculosis infection by measuring in vitro T-cell interferon gamma release in response to two Mycobacterium tuberculosis-specific antigens: ESAT-6 and CFP 10. MATERIAL AND METHODS: T-SPOT.TB assay has been performed on whole blood samples (n = 137) from March to September 2010. A tuberculin skin test result was available for 96 of participants. A positive TST result was considered if the induration was 10 mm or more. RESULTS: Of the 137 patients tested, T SPOT.TB assay results were positive in 37 (27%), negative in 98 (71.5%) and indeterminate in only 2 (1.5%) persons. We analyzed T-SPOT.TB and TST results in the 96 patients for whom both test were available. Concordance between T-SPOT.TB and TST results (10 mm skin reaction interpreted as positive) was 79%. Fifteen (15.6%) patients had a positive TST result and a negative T-SPOT.TB and 5 (5.2%) patients had a negative TST result and a positive T-SPOT.TB. We observed good correlation between positive T-SPOT.TB results and the size of induration >= 15 mm in TST results. CONCLUSIONS: T-SPOT.TB offers a more accurate approach than TST for identification tuberculosis infection. The study shows that the test T SPOT.TB is a good diagnostic tool in identifying persons with tuberculosis infection. For full confirmation of this assessment, it is necessary to examine more cases. PMID- 21678277 TI - [Exhaled nitric oxide in patients with esophagitis]. AB - INTRODUCTION: Assessment of nitric oxide (NO) concentration in exhaled air is broadly used to monitor the airway inflammation in asthma. High level of NO are also observed in paranasal sinuses and gastrointestinal tract (GT). The intact esopahageal sphincters are responsible for maintain the NO within the GT. It is not known how much the GT and especially esophageal motility disorders can affect the FeNO measurements. The aim of the study was to assess if the gastroesophageal reflux disease has any impact on level of NO in exhaled air in patients who do not suffer from any airway disease. MATERIAL AND METHODS: In 51 patients, in whom asthma, nasal polyps or atopy were excluded, gastroscopy with biopsy was performed. In 13 of them no esophageal pathology was found and they were considered as the control group. In the other 38 patients the esophagitis was diagnosed based on Los Angeles classification. RESULTS: The concentration of NO in exhaled air in patients with endoscopical gastro-esophageal changes did not differ significantly from the NO concentration in patients without inflammatory changes in stomach and esophagus (p = 0.68). Moreover, the presence of hiatal hernia did not affect the FeNO (p = 0.67). There was also no significant dependence between NO level and infection with Helicobacter pylori (p = 0.18). CONCLUSIONS: The gastroesophageal pathologies did not significantly affect NO concentration in exhaled air. PMID- 21678278 TI - [MDR, pre-XDR and XDR drug-resistant tuberculosis in Poland in 2000-2009]. AB - INTRODUCTION: Tuberculosis (TB) is a curable disease and its spread can be prevented by using appropriate diagnostic methods and effective treatment. The obstacle to the rapid eradication of the disease from a population may be strains resistant to essential and most effective antibiotics. In many places in the world MDR, pre-XDR and XDR-TB was reported. These forms of TB do not respond to the standard six-month treatment with first-line anti-TB drugs and the therapy should be conducted two years or more with drugs that are less potent, more toxic and much more expensive. MATERIAL AND METHODS: This study included MDR-TB strains isolated from 297 patients in 2000-2009. To determine the XDR-TB population structure, the 19 isolates were genotyped by spoligotyping and MIRU-VNTR (mycobacterial interspersed repetitive units-variable number of tandem repeats) method. RESULTS: Among 297 MDR-TB cases, 36 (12.1%) were pre-extensively drug resistant (pre-XDR), 19 (6.4%) were XDR and 1 (0.3%) was pre-totally drug resistant (pre-TDR). Four of the 19 XDR isolates exhibit a unique spoligopattern, while the rest 15 belonged to one of 5 clusters. The MIRU-VNTR analysis reduced the number of clustered isolates to 11. CONCLUSIONS: The study documented the emergence of pre-extensively and extensively drug-resistant tuberculosis in Poland among patients with multidrug-resistant TB. Genotyping methods showed clonal similarity among XDR strains and may suggest the possible transmission among patients with newly diagnosed and with recurrent TB. PMID- 21678279 TI - [Role of biomarkers in making the diagnosis of tuberculous pleurisy]. AB - Although tuberculosis is one of the most common causes of pleural effusion, diagnosis of tuberculous pleuritis still remains a challenge. This is due to paucity of M. tuberculosis organisms in pleural effusion which results in a relatively low sensitivity of the routinely used diagnostic methods. Thus, different biomarkers in pleural effusion have been extensively studied in order to improve the diagnostic accuracy. Pleural fluid deaminase adenosine activity (ADA) and interferon gamma (IFN-gamma) concentration have been shown to be the most reliable and cost-effective markers of tuberculous pleurisy. Hence, these markers have been included in different diagnostic algorithms for patients suspected of tuberculous pleurisy. A high variability of the diagnostic performance and/or more advanced technical demands significantly limit the use of other relatively new diagnostic methods, such as nucleic acid amplification tests (NAATs) and IFN-gamma releasing assays (IGRAs). The article presents a current data on the potential use of different biomarkers in the diagnosis of tuberculous pleurisy. PMID- 21678280 TI - [Respiratory tract burn injuries]. AB - Respiratory tract burns are one of the most serious injuries of human organism. They often accompany severe skin burns, increasing morbidity and mortality. Pathologic events happening in the lungs in the course of inhalation injury consist of: edema and necrosis of bronchial mucosa, increase of bronchial blood flow and vascular permeability, recruitment of inflammatory mediators, and obturation of bronchial tract with the casts composed of mucus, tissue debris, neutrophils and fibrin. The above mentioned processes lead to progressive disturbances of pulmonary gas exchange and tissue hypoxia. Introduction of standardized bronchoscopic procedures resulted in the possibility of early diagnosis and treatment of inhalation injuries. There are many treatment options, some of them combined with early and late complications, the optimal treatment protocol is still lacking. Early hyperbaric oxygen therapy is one of the most promising methods of treatment leading to decrease of mortality due to inhalation injury. PMID- 21678281 TI - [Granuloma of epididymis of patient treated with intravesical BCG therapy- complication of BCG therapy or tuberculosis?]. AB - We present a case of 72-year old man treated from 2007 for superficial bladder carcinoma. Patient had undergone surgical intervention for transitional cell carcinoma of the bladder, followed by BCG therapy. Two years later enlarged right testis and epididymis was observed. A resection was carried out. Histologic examination revealed in epididymis cauda granulomatous infiltration with eosinophilic necrosis. No bacteriologic tests of resected material were performed. Suspecting BCG infection or TB patient was referred to the Institute of Tuberculosis and Lung Diseases in Warsaw for pulmonary evaluation. Chest X ray, chest CT scan and bronchoscopy were performed but beside revealing scars in bronchi suggesting a history of TB did not contribute to the diagnosis. Tuberculin skin test was 21 mm. Diagnosis was determinated by spoligotyping which found bacille of Mycobacterium tuberculosis in specimen preserved in paraffin block. Tuberculosis of right epididymis and past pulmonary tuberculosis was diagnosed. Patient was treated with rifampin, isoniazid and pirazynamide. PMID- 21678282 TI - [Bacteriologically confirmed pulmonary tuberculosis in a patient with lymphangioleiomyomatosis accompanying tuberous sclerosis syndrome]. AB - Lymphangioleiomyomatosis (LAM) is a rare disease of unknown origin, that may be sporadic or develop in the course of tuberous sclerosis (TS). Patients do not present immune deficiency, but structural changes in the lung parenchyma (cysts) may encourage various infections, for example tuberculosis. Radiologic findings are often difficult to interpret, because of changes related to LAM itself. We present a young women with a history of TS and LAM, in whom protracting respiratory tract infection was finally diagnosed as tuberculosis. Initial diagnosis was based primarily on clinical signs and symptoms and treatment was started despite the negative result of the sputum microscopy for acid fast bacilli. In the course of treatment the diagnosis was supported by positive tuberculin skin test, interferon-gamma release assay and genetic test for M. tuberculosis in bronchoalveolar lavage fluid, and finally, positive sputum culture in liquid medium. PMID- 21678283 TI - [Fifth Polish-French Pneumonological Conference, Cracow, 8-9 October 2010]. PMID- 21678284 TI - Effects of platelet and inflammatory system activation on outcomes in diabetic patients with ST segment elevation myocardial infarction treated with primary percutaneous coronary intervention. AB - BACKGROUND: Recurrent myocardial ischaemia and restenosis are more common in diabetic patients treated with primary percutaneous coronary intervention (PCI) due to an acute coronary syndrome (ACS) compared to patients without diabetes. Diabetes is also associated with increased residual platelet activity during dual antiplatelet treatment. In recent reports, platelet reactivity has been linked to outcomes after ACS. Appropriate platelet inhibition might lead to improved outcomes in this patient population. To this end, newest methods to evaluate platelet function may prove helpful. AIM: To evaluate 6-month outcomes in diabetic patients treated with primary PCI due to ST segment elevation myocardial infarction (STEMI) in relation to platelet reactivity evaluated at discharge. METHODS: The study included 120 diabetic patients treated with primary PCI due to STEMI. Patients received loading doses of acetylsalicylic acid (ASA, 300 mg) and clopidogrel (600 mg) on admission, and later were treated with maintenance doses of 75 mg of ASA and clopidogrel. Blood for platelet aggregation testing was collected at discharge. We used whole blood impedance aggregometry using the Multiplate aggregometer with arachidonic acid (AA), adenosine diphosphate (ADP), collagen, and thrombin receptor peptide agonist (TRAP) as agonists. Six-month follow-up was based on telephone contact and hospital discharge summaries if hospitalisation occurred. The primary combined endpoint included recurrent ACS and restenosis. RESULTS: The primary combined endpoint occurred in 28 (23%) patients. Among patients with the primary endpoint, we found significantly higher platelet reactivity as evaluated by aggregation testing using AA and TRAP at discharge following the initial infarction compared to patients without the primary endpoint (area under aggregation curve 1137.4 +/- 198.5 vs 833.5 +/- 253.4; p = 0.013 for TRAP-induced aggregation, and 333.0 +/- 263.8 vs 186.9 +/- 105.4; p = 0.019 for AA-induced aggregation). We found no relationship between ADP- and collagen-induced aggregation at discharge and the occurrence of the primary endpoint. CONCLUSIONS: Increased platelet reactivity evaluated by TRAP induced aggregation is related to a higher rate of restenosis and recurrent ACS during a 6-month follow-up of diabetic STEMI patients treated with PCI. PMID- 21678285 TI - [Diabetes, increased platelet reactivity despite treatment and cardiovascular incidents after heart attack]. PMID- 21678286 TI - The prevalence of risk factors for atherosclerosis among middle school students in Sopot, Poland: results of the SOPKARD 15 programme. AB - BACKGROUND: SOPKARD 15 is a comprehensive programme to assess the health status of a population of teenagers. The aspects assessed in the study are: physical development, nutritional status, arterial blood pressure, lipid and carbohydrate metabolism, oral hygiene, and psychological parameters. AIM: To assess the prevalence of cardiovascular risk factors in the study population. METHODS: We examined 372 children (185 girls) at the age of 14. The cut-off values for normal lipid blood levels were based on the NCEP-Peds guidelines. Body mass index was assessed on the basis of the Polish centile charts. Blood pressure values assessed against the centile charts were the mean values calculated on the basis of the second and third measurements. RESULTS: Systolic and diastolic blood pressure values were elevated in 15.81% and 10.90% of the subjects, respectively. Abnormal blood glucose was detected in fewer than 6% of the children. Total cholesterol was elevated in 8% and borderline in 24% of the subjects; 8.5% of children were overweight and 7.4% were obese; 5.0% of the subjects took very little physical exercise; 16.4% of boys and 23.4% of girls admitted smoking. Dental examination revealed inflamed gums in 77.6% of the subjects. The diagnosis of a depressive episode was confirmed in 4.2% of the teenagers. CONCLUSIONS: 1. Due to the high prevalence of the risk factors there is a need to launch a comprehensive cardiovascular prevention programme among the teenagers. 2. A considerable proportion of children with lipid abnormalities indicate the need for more frequent lipid profile testing in children. PMID- 21678287 TI - [Not Available]. PMID- 21678288 TI - Is haemodynamic evaluation with impedance cardiography in patients with heart failure undergoing testing of the implanted cardioverter-defibrillator of clinical importance? AB - BACKGROUND: Identification of individual factors associated with high defibrillation threshold (DFT) seems to be of high clinical importance. Impedance cardiography (ICG) may be used for non-invasive evaluation of the haemodynamic status. Whether ICG parameters may improve identification of patients with high DFT has not yet been examined. AIM: To evaluate clinical risk factors of high DFT including ICG parameters. METHODS: The study group included 69 patients with heart failure (aged 62.7 +/- 9.5 years, NYHA class: I-III) selected for implantation of a cardioverter-defibrillator (ICD). Clinical assessment included physical examination, echocardiography and ICG monitoring before and after defibrillation. RESULTS: Initial defibrillation was unsuccessful in 17 (36.6%) patients. High DFT group was characterised by higher left ventricular end diastolic diameter (LVEDD >= 5.6 cm: 100.0% vs 70.2%; p = 0.01), lower left ventricular ejection fraction (LVEF < 30%: 76.5% vs 44.7%; p = 0.024), higher baseline thoracic fluid content (one of ICG parameters) (TFC >= 35 1/kOhm: 29.4% vs 6.4%; p = 0.014) and more frequent amiodarone treatment (41.2% vs 14.9%; p = 0.025). A proposed algorithm based on predefined values of TFC, LVEF and LVEDD was shown to be effective in predicting high DFT (area under curve: 0.771). CONCLUSIONS: Risk factors of high DFT include left ventricular enlargement, low LVEF, high TFC and amiodarone treatment. An algorithm including TFC measurement by ICG increases the efficacy of identification of patients with high DFT. PMID- 21678289 TI - [Not Available]. PMID- 21678290 TI - Early and long-term outcome of surgery for cardiac myxoma: experience of a single cardiac surgical centre. AB - BACKGROUND: Outcome after surgery for cardiac myxoma is very good, although due to relatively low prevalence in general population there are only a few reports with long-term follow-up that involved large number of patients. AIM: To evaluate short- and long-term outcome after myxoma removal in a single cardiac surgical centre. METHODS: The study involved 64 patients (42 women and 22 men) at the age ranging from 21 to 79 (mean 54.1 +/- 18.8) years who were treated between 1981 2009 in our institution. All patients were operated on from median sternotomy and cardiopulmonary bypass. Additionally, in 6 (9.4%) patients coronary artery bypass grafting was performed (1 to 3 grafts were implanted) and in other 2 (3.1%) ostium secundum atrial septal defect was closed. Patient survival and complications rate were assessed using the Kaplan-Meier curves. Moreover, functional status at the last follow-up examination was evaluated. RESULTS: Two patients died in the perioperative period (in-hospital mortality 3.1%) and 4 during follow-up ranging from 5 to 320 months (median 81 months, cumulated follow up period 5376 patient-months). Four other patients were lost from follow-up. One year survival probability was 0.95 +/- 0.03, 5-year - 0.88 +/- 0.04 and 10-year - 0.84 +/- 0.06. Estimated 10-year freedom from cardiac complications was 0.72 +/- 0.08, hospital readmission 0.80 +/- 0.07 and cardiac surgical reintervention 0.96 +/- 0.03. None of the patients had tumour recurrence. At the last follow-up examination, 90.7% of patients were in functional NYHA classes I or II. CONCLUSIONS: Surgery for cardiac myxoma is associated with low long-term mortality and morbidity. Functional status following operation improved significantly after surgery. PMID- 21678291 TI - [Not Available]. PMID- 21678292 TI - Prolonged P wave dispersion in pre-diabetic patients. AB - BACKGROUND: It is known that overt diabetes as well as chronic hyperglycaemia can lead to atrial fibrillation. A P wave dispersion (PWD) represents heterogeneity in atrial refractoriness. AIM: To investigate PWDs in patients with pre-diabetes. METHOD: Based on the results of examinations, 84 pre-diabetic patients (the pre DM group; 50 female, 34 male; mean age 54 +/- 8.6 years) who had no overt diabetes, coronary artery disease or hypertension, whose fasting blood glucose was higher than 100 mg/dL and/or whose 2 h glucose concentrations on an oral glucose tolerance test was in the range of 140 to 199 mg/dL, and 48 healthy volunteers (the non-DM group, 30 female, 18 male; mean age 51.7 +/- 7.3 years) with no illnesses, were enrolled in this study. Standard 12-lead electrocardiograms of all patients were taken at 50 mm/s and 20 mm/mV standardisation. Maximum (P(max)) and minimum (P(min)) P-wave durations were measured. The PWD was defined as the difference between P(max) and P(min). RESULTS: The P(max) and PWD values were significantly higher in pre-DM compared to non-DM (104 +/- 13 ms vs 98 +/- 12 ms; p < 0.05, 42 +/- 13 ms vs 34 +/- 11 ms; p <0.01 respectively). A positive correlation was found between PWD and fasting blood glucose (r = 0.32; p < 0.01). There was no correlation between PWD and HbA(1c) levels (r = 19; p > 0.05). Multivariate regression analysis showed no relationship between PWD and age, left atrial diameter, E, A, E/A or HbA(1c). However, there was a relationship between PWD and fasting blood glucose. CONCLUSIONS: The P(max) and PWD are increased in pre-diabetic patients who have no coronary artery disease, hypertension or left ventricular hypertrophy PMID- 21678293 TI - [Hyperglycemia and P wave]. PMID- 21678294 TI - The effects of osteoprotegerin (OPG) gene polymorphism in patients with ischaemic heart disease on the morphology of coronary arteries and bone mineral density. AB - BACKGROUND: The incidence of coronary artery disease (CAD) and osteoporosis increases with age, especially in the elderly. Many studies have shown that vessel calcification is associated with low bone mineral density (BMD) and an increased risk of bone fractures. Experimental studies have shown that osteoprotegerin (OPG) gene knockout mice have aortic calcification and osteoporosis at the same time. AIM: To assess the frequency of OPG gene polymorphisms in patients with CAD and to analyse the relationship between the severity of CAD and BMD. METHODS: The study group comprised 31 postmenopausal women (mean age 65.6, range 39-82 years) undergoing elective coronary angiography for CAD symptoms. The BMD was measured at the hip by dual X-ray absorptiometry (DEXA). Clinical data were collected using a questionnaire developed by the authors which addressed CAD risk factors, treatment, previous diagnosis of osteoporosis and the risk factors of osteoporosis. The control group consisted of 30 postmenopausal women attending the osteoporosis clinic without the history of CAD (mean age 70.5, range 56-84 years). Written informed consent was obtained from all the patients. Genotyping of two polymorphisms 209, 245 in the promoter region and 1181 in the exon of the OPG gene was performed in both groups. RESULTS: Coronary angiography in study group revealed normal coronary arteries in 35% (n = 11) of the women. The analysis of 209 C/T polymorphism showed no presence of TT homozygotes in either group. Also, no significant differences between the 209 C/T polymorphic variants, BMD and progression of atherosclerosis in coronary arteries were found. In both groups no CC homozygous variants for 245 A/C were revealed. However, a statistically significant relationship between 245 A/C polymorphism and BMD was shown. The AC carriers had osteoporosis more frequently (57%) than AA carriers (12%) of the OPG gene (p = 0.0382). There were no significant differences in the OPG gene 245 A/C polymorphisms and CAD progression. Homozygotes for CC 1181 were shown to have normal coronary arteries more frequently (60%) than heterozygotes for CG 1181 (29%; p = 0.0023). We failed to show significant differences between 1181 C/G polymorphism and BMD in both groups. CONCLUSIONS: 1. This study revealed a significant association between homozygotes for AA 245 and normal BMD in study group. 2. The analysis of 209 C/T and 245 C/T C polymorphisms has shown no presence of homozygotes for TT 209 OPG or CC 245 OPG in both groups. 3. Carriers of the homozygous CC 1181 OPG gene were shown to have normal coronary arteries more frequently when compared to heterozygotes for CG or homozygotes for GG. PMID- 21678295 TI - [Decalcified bones, calcified heart?]. PMID- 21678297 TI - [Analysis of T-wave alternansu - hopes and failures]. PMID- 21678296 TI - Microvolt T-wave alternans for the risk stratification of dangerous ventricular arrhythmias in patients with previously implanted automatic cardioverter defibrillator. AB - BACKGROUND: Sudden cardiac death (SCD) is the main cause of death in patients with reduced left ventricular ejection fraction (LVEF). Implantation of an automatic cardioverter-defibrillator (ICD) significantly reduces mortality of these patients. T-wave alternans (TWA) analysis is a relatively new method of SCD risk stratification. However, it's prognostic role in patients with ICD has not yet been fully established. AIM: To assess the predictive value of TWA in patients with previously implanted ICD. METHODS: The study included 67 patients with properly functioning ICD (54 men and 13 women, aged 62.2 +/- 8.4 years). All patients underwent TWA analysis on the treadmill using the Cambridge Heart 2000 system. Results were considered as positive, negative or indeterminate. Each patient had at least 1 clinical control visit with ICD interrogation during the 12 +/- +/- 6 months of follow-up. The recurrence of sustained ventricular arrhythmias: ventricular tachycardia (VT) or ventricular fibrillation (VF) was analysed. RESULTS: No significant relationship was found between previous infarction (p = 0.810), aetiology (p = 0.768), LVEF (p = 0.413) or age (p = 0.562) and the incidence of arrhythmia during follow-up. The results of TWA were not significantly different between patients with or without VT or VF. The TWA analysis identified patients with arrhythmia recurrences with a sensitivity of 62%, specificity of 49%, negative predictive value of 81%, and positive predictive value of 28%. The TWA performance was better in patients with non ischaemic than ischaemic cardiomyopathy (negative predictive value: 100%, positive predictive value: 75%). CONCLUSIONS: The TWA alternans was moderately effective for identification of patients with ICD and ventricular arrhythmia recurrences. The test was most useful for identification of patients with non ischaemic cardiomyopathy who are of low arrhythmic risk. PMID- 21678298 TI - Giant right ventricular mural vegetation mimicking a cardiac tumour. AB - Mural vegetations in the course of infective endocarditis are very rare. We report the case of a patient with an extremely large right ventricular free wall vegetation. Establishing diagnosis in the presence of only mural vegetations on echocardiography scan without valve involvement in the inflammatory process was difficult. In a differential diagnosis, benign and malignant tumours, metastases and thrombi were taken into account. The patient was operated upon and the tumour was removed successfully. A histopathological examination revealed an inflammatory character of the tumour. The patient was treated according to antibiogram and discharged home in stable condition. PMID- 21678299 TI - [Acute pulmonary embolism following cardiac arrest in a 31 year-old female with long QT syndrome]. AB - A case of a young female with acute pulmonary embolism following cardiac arrest due to ventricular fibrillation as a result of long QT syndrome is presented. A differential diagnosis has been discussed. PMID- 21678300 TI - [Successful therapy and rehabilitation following stroke in a pregnant woman with prosthetic aortic valve]. AB - This report describes a case of a 40 year-old woman with implanted aortic prosthetic valve, who experienced thrombo-embolic complication in a form of ischaemic stroke in 15 week of pregnancy. At the beginning of the event, the patient suffered from mixed aphasia, right-side paresis and depressive syndrome. Thanks to cooperation of many specialists, especially rehabilitation team, she restored overall physical efficiency, speaking ability, delivered a healthy child, and returned to normal family and social activity. Problems of anti thrombotic therapy during pregnancy in patients with prosthetic valves are discussed. PMID- 21678302 TI - [Depression, its therapy and venous thromboembolism: three cases of pulmonary embolism]. AB - The associations between depression and coronary heart disease, especially via platelet hyperactivity, have been widely described. The relationships between depression and venous thromboembolism are less clear. We present three cases of pulmonary embolism (PE) in patients with previously diagnosed depression and discuss possible, depression-related prothrombotic factors, including the impact of psychotropic drugs. A 69 year-old woman, treated with different antidepressants and also antipsychotics, died two months after recurrent PE. Another woman, at the same age, on mirtazapine therapy, developed segmental PE. In a 39 year-old man, taking paroxetine, severe PE required thrombolysis. PMID- 21678304 TI - [Stem cells in cardiological clinical trials]. AB - Stem cell-based therapy is a novel therapeutic strategy introduced into cardiology, although there are not any established standards within the stem/progenitor cell type employed, their preparation, rout of administration as well as methods controlling the pathophysiological and clinical parameters after the cell application. The aim of the present work was a complex meta-analysis of the clinical trials carried out in this field. Over 1000 patients with myocardial infarction as well as circulatory failure have been treated with stem cell-based therapy so far, but the obtained results are not concordant. Progress within cell biology and biotechnology give hopes for development of more effective therapeutic approaches. Identification and isolation of cardiac- -specific stem/progenitor cells may deliver new perspectives for such therapy in the nearest future. PMID- 21678305 TI - [Clinical significance of interactions between clopidogrel and proton pump inhibitors]. PMID- 21678306 TI - [Wide QRS ectopic beats without sinus code resseting ventricular or supraventricular with aberration?]. PMID- 21678308 TI - [Fibrotic tissue reflecting lead course after percutaneous leads extraction]. AB - We present a case report of fibrotic tissue reflecting lead course after percutaneous pacemaker lead extraction. PMID- 21678309 TI - [A case of recurrent stent thrombosis in a drug-eluting stent following antiplateled therapy discontinuation]. AB - Stent thrombosis is one of the major complications that occur in percutaneous coronary interventions with stents. Various factors have been attributed to the development of stent thrombosis and several strategies have been recommended for its management. We report a case of 45 year-old patient with recurrent subacute and late stent thrombosis following antiplateled therapy discontinuation on the 6th day and 11th month after he discharging from hospital. PMID- 21678311 TI - Transvenous extraction of a five year-old ventricular lead inadvertently implanted in the left ventricle. AB - Inadvertent lead implantation into the left ventricle (LV) is a rare but serious complication of permanent pacing and should be diagnosed as soon as possible. We report a case of a patient with a pacemaker pocket infection with sepsis and two ventricular leads - one old electrode abandoned in the right ventricle and another one unintentionally implanted via patent foramen ovale into the LV. Both leads were extracted percutaneously, although the procedure was complicated by a minor ischaemic stroke. PMID- 21678312 TI - [Remove the electrodes properly located - whether it's time for percutaneous extraction?]. PMID- 21678313 TI - [Summary of the article: Zannad F, McMurray JJV, Krum H et al.; for the EMPHASIS HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med, 2011; 364: 11-21]. PMID- 21678314 TI - [Not Available]. PMID- 21678315 TI - Presidential letter: from Turin (1951) to Moscow (2011). The past, present and future of cardiovascular surgery--reflections at the time of the Diamond Jubilee of the ESCVS. PMID- 21678316 TI - [Report on the XV Scientific and Training Symposium of Working Group of Cardiac Rehabilitation and Exercise Physiology of the Polish Cardiac Society]. PMID- 21678317 TI - [Recommendations of the Echocardiography Working Group of the Polish Cardiac Society for stress echocardiography use in clinical practice 2011]. PMID- 21678318 TI - [Landscape test for assessing visual memory in Alzheimer's disease]. AB - INTRODUCTION: Visual episodic memory is affected in the early phases of Alzheimer's disease (AD). AIMS: To design a visual memory test free of any verbal content, to offer its normative values in the elderly population in Spain, to validate the test in a group of patients with mild AD and to determine its capacity to discriminate between subjects with AD and controls. SUBJECTS AND METHODS: The study involved a sample of 263 subjects (137 controls and 126 patients with AD) over 50 years of age. The landscape test consists of a first part in which participants are shown 25 photographs of landscapes. Five minutes later, the previous 25 photos are shown again together with 25 new pictures, and the subject must recognise the ones that have already been seen. The statistical analysis was performed using the Student t test for independent measures, ANCOVA, linear regression, Pearson's correlation and the ROC curve. RESULTS: In the control group, sex and schooling did not have any significant effect on the results, although differences were found between the youngest group (50-59 years) and the oldest age group (equal to or above 80 years). Findings show that there is a significant difference between the mean scores on the landscape test obtained by the two groups (control: 44.06 +/- 3.2; AD: 34.25 +/- 6.6; p < 0.001). The area under the curve from the landscape test was 0.904, with a sensitivity of 0.82 and a specificity of 0.85. CONCLUSIONS: The landscapes test is a simple, sensitive and novel instrument for assessing visual memory in early AD. PMID- 21678319 TI - Effects of functional electro-stimulation in the theta-band coherence: a quantitative electroencephalograph study. AB - INTRODUCTION: Functional electrical stimulation (FES) is a technique used for rehabilitation of motor and sensory dysfunction and consisted in the application of neuromuscular electrical stimulation concurrently with a functional activity. Previous studies suggest that sensory motor processing during FES stimulation of hand is similar to that of voluntary hand movement. AIM: To examine the changes in theta band (4-8 Hz) coherence in the centro-parietal and temporo-parietal junction during a FES task. Our hypothesis is that different conditions of electro-stimulation can produce changes in the theta band coherence in the sensory-motor and multisensory integration. SUBJECTS AND METHODS: The sample was composed of 24 students, male (n =14) and female (n =10), between 25 and 40 years old. Subjects were randomly distributed in three groups: control group (n = 8), G24 (n = 8) and G36 (n = 8). The control group simulated four blocks without electrostimulation been applied. The G24 group was exposed to four blocks of electrostimulation. The G36 group was exposed to six blocks of electrostimulation. We employed FES equipment to stimulate the extension of the right index finger and the electroencephalographic signal was simultaneously recorded. RESULTS: A main effect was found for the condition, block and electrode in the centro-parietal junction, although we only found a main effect for condition and electrode in the temporo-parietal junction. CONCLUSION. Our results suggest that the functional coupling between the central and parietal areas is directly connected to the priming memory function, although the coupling between temporal and parietal areas is related to the working memory. PMID- 21678320 TI - [Memory and metamemory during transient global amnesia: a comparative study about long-term follow up]. AB - INTRODUCTION: Diagnostic criteria of transient global amnesia (TGA) establishes that memory functioning has to be recovered in 24 hours. However, there are contradictory data about the existence of long-term sequelae. Furthermore, there is no consensus about which is the most suitable tool in order to use in the assessment of the follow up of these patients. AIMS: To assess episodic memory of TGA patients during amnesic episode and 7, 30 and 90 days after with free recall and Mini-Mental tasks. Moreover, it has been measured patient's metamemory. SUBJECTS AND METHODS: 17 TGA patients and 17 healthy volunteers, matched by age, sex, and educational level were assessed. A longitudinal (four assessments) and factorial (patients and control group) study was carried out. RESULTS: During TGA, free recall and Mini-Mental tasks were significantly affected. However, only free recall task showed improvement along time and impairment after three months. It has been also detected that metamemory of TGA patients is imprecise. CONCLUSIONS: Comparing with control group, both free recall and Mini-Mental tasks have significant lower levels during TGA, but only the first one is sensitive enough to show long-term disturbance associated with this amnesia. PMID- 21678321 TI - [Multiple mononeuritis in a patient with Churg-Strauss syndrome. Pseudo conduction block as an early electroclinical expression]. AB - INTRODUCTION: Multiple mononeuritis is one of the most frequent manifestations of Churg-Strauss syndrome. CASE REPORT: We describe a case of acute sensory-motor multiple mononeuritis in all four limbs of a 53-year-old male with Churg-Strauss syndrome. Electrodiagnosis performed within the first seven days revealed conduction blocks in several nerves. Follow-up studies showed diffuse bilateral sensory-motor axonal polyneuropathy with symmetries, but without blocks. Electrophysiological and histological analyses, together with experimental studies, showed it to be an axonopathy secondary to acute ischaemia. CONCLUSIONS: In only a few cases, such as this one and in a small number of incipient studies, have there been reports of conduction blocks that, owing to the fact that they are commonly related with demyelination, give rise to confusion when it comes to diagnoses and prognoses. The condition usually displays axonopathy due to Wallerian degeneration. It therefore seems recommendable in these cases to proceed with caution and to perform neurophysiological studies in the following weeks in order to prevent inappropriate diagnostic and prognostic judgements from being formed. PMID- 21678322 TI - [Pharmacological targets in multiple sclerosis]. AB - Multiple sclerosis is the most frequent chronic inflammatory, demyelinating and neurodegenerative disease in young adults, but has no definitive pharmacological treatment. It is a heterogeneous disease from the immunological, neuropathological and clinical point of view, as well as in terms of its response to different therapies. Over the last two decades, pharmacology has focused on developing drugs that are capable of modifying the course of this disease, with the aim of reducing the frequency of the outbreaks and the speed at which the disability produced by the disease progresses. Nevertheless, today, there are no drugs that are capable of offering a curative effect that can fully stabilise the disease, and neuroprotective and neuroreparative strategies are still in their early stages. In this work we carry out a critical review of the different pathogenic paths involved in multiple sclerosis and we discuss the different pharmacological approaches that have been followed, based on the clinical trials that are currently being conducted. In the near future it is to be expected that, first, we will manage to stabilise the disease completely and, later, recover some of the functions altered by this disease. Research is being conducted at such a rate that we have to be optimistic and think that soon we will be able to improve the situation of those who suffer from the disease. PMID- 21678323 TI - [N200: an electrophysiological signal associated with inhibitory control, as an endophenotype candidate in attention deficit hyperactivity disorder]. AB - INTRODUCTION: N200 (N2) is an electrophysiological component related with the analysis of perceptual disruptions and with the recognition of a stop signal (inhibitory control); neuroanatomically, it has been associated with right-hand orbitofrontal structures. Its modulation has been studied with go/no go-type tasks and the Stop Signal Task (SST). DEVELOPMENT: While the SST is being carried out in subjects with attention deficit hyperactivity disorder (ADHD), differences in the amplitude of the N2 have been observed in comparison to control subjects. Moreover, a number of studies have reported that ADHD has a high degree of inheritability, with linkages to several susceptibility loci. From all this, it is acknowledged that inhibitory control, and more particularly N2 modulation, is a quantitative trait that may be expressed in different ways in the members of families with and without ADHD, as well as in unaffected subjects from the general population, while also being a candidate as an endophenotype of the disorder. This hypothesis has been confirmed in 141 families with the genetic isolate of Antioquia, in which differences have been identified in this electrical signal on comparing the members of affected and unaffected families and these two groups with unaffected members of the general population. CONCLUSIONS: These findings suggest that N2 is an electrophysiological signal that is modulated by faulty inhibitory control in subjects with ADHD and, in this respect, could be used as a candidate in the search for endophenotypes in the familial form of this disorder. PMID- 21678324 TI - [POEMS syndrome: a review of the literature]. AB - POEMS syndrome is a rare multisystemic paraneoplastic disorder. That is associated with a plasma cell dyscrasia. It is characterized by peripheral neuropathy, organomegaly, endocrinopathy, M protein, skin changes and other systemic features. The pathogenesis of POEMS is not well understood, but overproduction of vascular endothelial growth factor is likely to be responsible for most of characteristic symptoms. There are no randomized controlled trials in patients with POEMS syndrome but are therapies which benefit these patients, including radiation therapy, chemotherapy, cortico-steroids and stem cell transplant. PMID- 21678326 TI - [Anti-NMDA receptor encephalitis in a four-year-old male]. PMID- 21678327 TI - [Chagas disease and stroke code: an imported case]. PMID- 21678328 TI - [Intravenous lacosamide in monotherapy in a case of complex partial epileptic status]. PMID- 21678330 TI - Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery. AB - BACKGROUND: Peripheral arterial disease (PAD) is frequently treated by either an infrainguinal autologous (using the patient's own veins) or synthetic graft bypass. The rate of occlusion of the graft after one year is between 12% and 60%. To prevent occlusion, patients are treated with an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion. This is an update of a Cochrane review first published in 2003. OBJECTIVES: To evaluate whether antithrombotic treatment improves graft patency, limb salvage and survival in patients with chronic PAD undergoing infrainguinal bypass surgery. SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3). SELECTION CRITERIA: Randomised, controlled trials; two review authors independently assessed the methodological quality of each trial using a standardised checklist. DATA COLLECTION AND ANALYSIS: Data collected included patient details, inclusion and exclusion criteria, type of graft, antithrombotic therapy, outcomes, and side effects. MAIN RESULTS: A total of 14 trials were included in this review; 4970 patient results were analysed. Four trials evaluating vitamin K antagonists (VKA) versus no VKA suggested that oral anticoagulation may favour autologous venous, but not artificial, graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin (ASA) or aspirin and dipyridamole provided evidence to support a positive effect of VKA on the patency of venous but not artificial grafts. Three trials comparing low molecular weight heparin (LMWH) to unfractionated heparin (UFH) failed to demonstrate a significant difference on patency. One trial comparing LMWH with placebo found no significant improvement in graft patency over the first postoperative year in a population receiving aspirin. One trial showed an advantage for LMWH versus aspirin and dipyridamol at one year for patients undergoing limb salvage procedures. Perioperative administration of ancrod showed no greater benefit when compared to unfractionated heparin. Dextran 70 showed similar graft patency rates to LMWH but a significantly higher proportion of patients developed heart failure with dextran. AUTHORS' CONCLUSIONS: Patients undergoing infrainguinal venous graft are more likely to benefit from treatment with VKA than platelet inhibitors. Patients receiving an artificial graft benefit from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers are needed in the future to compare antithrombotic therapies with either placebo or antiplatelet therapies. PMID- 21678331 TI - Adjuvant progestagens for endometrial cancer. AB - BACKGROUND: Endometrial cancer is the most common genital tract carcinoma among women in developed countries, with most women presenting with stage 1 disease. Adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of recurrence of disease. OBJECTIVES: To evaluate the effectiveness and safety of adjuvant progestagen therapy for the treatment of endometrial cancer. SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Group Trials Specilaised Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. MEDLINE and EMBASE up to April 2009. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestagen therapy in women who have had surgery for endometrial cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Risk ratios (RRs) comparing survival in women who did and did not receive progestagen were pooled in random effects meta-analyses. . MAIN RESULTS: Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). AUTHORS' CONCLUSIONS: There is no evidence to support the use of adjuvant progestagen therapy in the primary treatment of endometrial cancer. PMID- 21678332 TI - Therapeutic ultrasound for acute ankle sprains. AB - BACKGROUND: Ultrasound is used in the treatment of a wide variety of musculoskeletal disorders, which include acute ankle sprains. This is an update of a Cochrane review first published in 1999, and previously updated in 2004. OBJECTIVES: To evaluate the effects of ultrasound therapy in the treatment of acute ankle sprains. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (September 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (1966 to September 2010), EMBASE (1983 to September 2010), CINAHL (1982 to 2004), and PEDro - the Physiotherapy Evidence Database (accessed 01/06/09). We also searched the Cochrane Rehabilitation and Related Therapies Field database, reference lists of articles, and contacted colleagues.The WHO International Clinical Trials Registry Platform was searched for ongoing trials. SELECTION CRITERIA: Randomised or quasi-randomised trials were included if the following conditions were met: at least one study group was treated with therapeutic ultrasound; participants had acute lateral ankle sprains; and outcome measures included general improvement, pain, swelling, functional disability, or range of motion. DATA COLLECTION AND ANALYSIS: Two authors independently performed study selection, and assessed the risk of bias and extracted data. Risk ratios and risk differences together with 95% confidence intervals were calculated for dichotomous outcomes and mean differences together with 95% confidence intervals for continuous outcome measures. Limited pooling of data was undertaken where there was clinical homogeneity in terms of participants, treatments, outcomes, and follow-up time points. MAIN RESULTS: Six trials were included, involving 606 participants. Five trials included comparisons of ultrasound therapy with sham ultrasound; and three trials included single comparisons of ultrasound with three other treatments. The assessment of risk of bias was hampered by poor reporting of trial methods and results. None of the five placebo-controlled trials (sham ultrasound) demonstrated statistically significant differences between true and sham ultrasound therapy for any outcome measure at one to four weeks of follow-up. The pooled risk ratio for general improvement at one week was 1.04 (random-effects model, 95% confidence interval 0.92 to 1.17) for active versus sham ultrasound. The differences between intervention groups were generally small, between zero and six per cent, for most dichotomous outcomes. AUTHORS' CONCLUSIONS: The evidence from the five small placebo-controlled trials included in this review does not support the use of ultrasound in the treatment of acute ankle sprains. The potential treatment effects of ultrasound appear to be generally small and of probably of limited clinical importance, especially in the context of the usually short-term recovery period for these injuries. However, the available evidence is insufficient to rule out the possibility that there is an optimal dosage schedule for ultrasound therapy that may be of benefit. PMID- 21678333 TI - WITHDRAWN: Neoadjuvant cisplatin for advanced bladder cancer. AB - BACKGROUND: Bladder cancer is the second most common malignancy of the genito urinary system. During the past 20 years many phase II clinical trials have investigated the role of chemotherapy in patients with locally advanced bladder cancer. These studies have identified a number of active single-agent cytotoxic drugs such as cisplatin. Although promising results have also been achieved with various combinations of drugs there is no conclusive evidence that chemotherapy improves survival, irrespective of whether it is given before (neoadjuvant or pre emptive), with (concurrent) or after (adjuvant) local treatment. Despite this, many clinicians now use neoadjuvant chemotherapy in the routine treatment of locally advanced bladder cancer. OBJECTIVES: The main objective of this review was to investigate whether platinum-based chemotherapy given either before or during local treatment, improves the survival of patients with locally advanced bladder cancer. A further objective was to determine whether there is any evidence that such chemotherapy is more or less effective within well defined subgroups of patients. SEARCH STRATEGY: MEDLINE and CANCERLIT bibliographic searches were supplemented by information obtained from trial registers and, by hand searching relevant meeting proceedings, and by discussion with relevant trialists and organisations. SELECTION CRITERIA: Trials were included in the meta analysis provided they were properly randomised, included patients with advanced bladder cancer and compared local treatment versus the same local treatment plus neoadjuvant or concurrent chemotherapy. DATA COLLECTION AND ANALYSIS: Updated individual patient data were sought from the trialists responsible for all eligible randomised controlled trials (all were unpublished at outset of meta analysis). Time-to-event analyses of survival were done on intention to treat basis. A sensitivity analysis including summary data from the single trial for which individual patient data were not available was also done. Pre-defined subgroup analyses by age, sex, tumour stage and grade were also carried out. MAIN RESULTS: Individual data on 479 patients from 4 randomised trials were available. Data extracted from a published report was used for 1 further trial (325 patients) in a supplementary analysis. Analysis of the individual patient data gave an overall hazard ratio of 1.02 in favour of local therapy alone (P = 0.845, 95% confidence interval (CI) = 0.81 to 1.26). When this analysis was supplemented by data from the only trial for which individual patient information was not available, the hazard ratio was 0.91 in favour of chemotherapy (P = 0.328, 95% confidence interval = 0.75 to 1.10). Neither analysis was conventionally significant. The only prognostic factor for which the evidence suggested a differential treatment effect (interaction) across groups was age (chi(2) test for trend = 3.833, P = 0.05), with younger age groups (< 60 years) showing a possible effect in favour or chemotherapy. AUTHORS' CONCLUSIONS: There is insufficient information currently included in this meta-analysis to obtain a definitive answer to the question of whether neoadjuvant cisplatin-based chemotherapy improves the survival of patients with locally advanced bladder cancer. Since the publication of this review by the collaborative group in 1995, 4 additional trials have been completed, although none of these has yet been published in full. The next update of the meta-analysis (planned for 1999/2000) will aim to include source data from these trials and should therefore provide more definitive results. PMID- 21678334 TI - Interventions for primary vesicoureteric reflux. AB - BACKGROUND: Vesicoureteric reflux (VUR) results in urine passing retrograde up the ureter. Urinary tract infections (UTI) associated with VUR have been considered a cause of permanent renal parenchymal damage in children with VUR. Management of these children has been directed at preventing UTI by antibiotic prophylaxis and/or surgical correction of VUR. The optimum strategy is not clear. OBJECTIVES: To evaluate the benefits and harms of different treatment options for primary VUR. SEARCH STRATEGY: In August 2010 we searched CENTRAL, MEDLINE and EMBASE and screened reference lists of papers and abstracts from conference proceedings. SELECTION CRITERIA: RCTs in any language comparing any treatment of VUR including surgical or endoscopic correction, antibiotic prophylaxis, non invasive non-pharmacological techniques and any combination of therapies. DATA COLLECTION AND ANALYSIS: Two authors independently searched the literature, determined study eligibility, assessed quality, extracted and entered data. We expressed dichotomous outcomes as risk ratios (RR) and their 95% confidence intervals (CI) and continuous data as mean differences (MD) and their 95% CI's Data were pooled using the random effects model. MAIN RESULTS: Twenty RCTs (2324 children) were included. Long-term low-dose antibiotic prophylaxis compared to no treatment/placebo did not significantly reduce repeat symptomatic UTI (846 children: RR 0.68, 95% CI 0.39 to 1.17) or febrile UTI (946 children: RR 0.77, 95% CI 0.47 to 1.24) at two years. There was considerable heterogeneity in the analyses and only one study was adequately blinded. At one to three years, antibiotic prophylaxis reduced the risk of new or progressive renal damage on DMSA scan (446 children: RR 0.35, 95% CI 0.15 to 0.80). Side effects were infrequent when reported, but antibiotics increased the likelihood of bacterial drug resistance threefold (132 UTIs: RR 2.94, 95% CI 1.39 to 6.25).When long-term antibiotic prophylaxis was compared with surgical or endoscopic correction of VUR plus antibiotics for one to 24 months (10 studies, 1141 children), the risk of symptomatic UTI was not significantly different at any time point. Combined surgical and antibiotic treatment caused a 57% reduction in febrile UTI by five years (2 studies, 449 children: RR 0.43, 95% CI 0.27 to 0.70) but did not decrease the risk of new or progressive renal damage at any time point. Postoperative obstruction was seen in 0% and 7% of children in two surgical studies and 0% in one endoscopic study. AUTHORS' CONCLUSIONS: Compared with no treatment, use of long-term, low-dose antibiotics did not significantly reduce the number of repeat symptomatic and febrile UTIs in children with VUR. Considerable heterogeneity in the analyses and inclusion of only one adequately blinded study, made drawing firm conclusions challenging. Antibiotic prophylaxis significantly reduced the risk of developing new or progressive renal damage, but assuming an 8% baseline risk, 33 children would need long-term antibiotic prophylaxis to prevent one more child developing kidney damage over the course of two to three years.The added benefit of surgical or endoscopic correction of VUR over antibiotic treatment alone remains unclear. Eight children would require combined surgical and antibiotic treatment to prevent one additional child developing febrile UTI by five years, but it would not cause fewer children developing renal damage. PMID- 21678335 TI - Propylthiouracil for alcoholic liver disease. AB - BACKGROUND: Randomised clinical trials have addressed the question whether propylthiouracil has any beneficial effects in patients with alcoholic liver disease. OBJECTIVES: To assess the beneficial and harmful effects of propylthiouracil for patients with alcoholic liver disease. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (April 2011), The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (April 2011), MEDLINE (1948 to April 2011), EMBASE (1980 to April 2011), and Science Citation Index Expanded (1900 to April 2011). These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included irrespective of blinding, publication status, or language. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method in RevMan Analyses. The risk of bias of the randomised clinical trials was evaluated by bias risk domains such as generation of allocation sequence, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, academic bias, and source of funding. MAIN RESULTS: Combining the results of six randomised clinical trials with high risk of bias which included 710 patients demonstrated no significant effects of propylthiouracil versus placebo on all-cause mortality (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30), liver-related mortality (RR 0.90, 95% CI 0.58 to 1.40), or complications of the liver disease. Although propylthiouracil was not associated with a significant increased risk of non-serious adverse events, there were occasional instances of serious adverse events such as leukopenia and generalised bullous eruption. AUTHORS' CONCLUSIONS: We could not demonstrate any significant beneficial effect of propylthiouracil on all-cause mortality, liver-related mortality, liver complications, or liver histology of patients with alcoholic liver disease. Propylthiouracil was associated with adverse events. Confidence intervals were wide. Thus, the risk of random errors and systematic errors was high. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials. PMID- 21678336 TI - Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. AB - BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life threatening condition resulting from excessive ovarian stimulation. Reported incidence varies from 1% to 10% of in vitro fertilization (IVF) cycles. The factors contributing to OHSS have not been completely explained. The release of vasoactive substances secreted by the ovaries under human chorionic gonadotrophin (hCG) stimulation may play a key role in triggering this syndrome. This condition is characterised by a massive shift of fluid from the intra-vascular compartment to the third space resulting in profound intra vascular depletion and haemoconcentration. OBJECTIVES: To assess the effect of withholding gonadotrophins (coasting) on the prevention of ovarian hyperstimulation syndrome in assisted reproduction cycles. SEARCH STRATEGY: For the update of this review we searched the Cochrane Menstrual Disorders and Subfertility Review Group Trials Register (July 2010), CENTRAL (inception to July 2010), MEDLINE (PubMed) (inception to July 2010), and EMBASE (inception to July 2010) for randomised controlled trials (RCTs) in which coasting was used to prevent OHSS. SELECTION CRITERIA: Only randomised controlled trials (RCTs) in which coasting was used to prevent OHSS were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. Disagreements were resolved by discussion. Study authors were contacted to request additional information or missing data. The intervention comparisons were coasting versus early unilateral follicular aspiration (EUFA), no coasting or other interventions. Statistical analysis was performed in accordance with the Cochrane Menstrual Disorders and Subfertility Group guidelines. MAIN RESULTS: This updated review identified 16 studies of which four met the inclusion criteria. There was no evidence of a difference in the incidence of moderate and severe OHSS (odds ratio (OR) 0.53, 95% CI 0.23 to 1.23), live birth (OR 0.48, 95% CI 0.14 to 1.62; P = 0.24) or in the clinical pregnancy rate (OR 0.69, 95% CI 0.44 to 1.08) between the groups. Significantly fewer oocytes were retrieved in coasting groups compared with GnRHa (OR -2.44, 95% CI -4.30 to -0.58; P = 0.01) or no coasting (OR -3.92, 95% CI -4.47 to -3.37; P < 0.0001). Data for coasting versus EUFA were not pooled for number of oocytes retrieved due to heterogeneity (I(2) = 87%). AUTHORS' CONCLUSIONS: There was no evidence to suggest a benefit of using coasting to prevent OHSS compared with no coasting or other interventions. PMID- 21678338 TI - Scopolamine (hyoscine) for preventing and treating motion sickness. AB - BACKGROUND: This is an update of a Cochrane Review first published in The Cochrane Library in Issue 3, 2004 and previously updated in 2007 and 2009.Motion sickness, the discomfort experienced when perceived motion disturbs the organs of balance, may include symptoms such as nausea, vomiting, pallor, cold sweats, hypersalivation, hyperventilation and headaches. The control and prevention of these symptoms has included pharmacological, behavioural and complementary therapies. Although scopolamine (hyoscine) has been used in the treatment and prevention of motion sickness for decades, there have been no systematic reviews of its effectiveness. OBJECTIVES: To assess the effectiveness of scopolamine versus no therapy, placebo, other drugs, behavioural and complementary therapy or two or more of the above therapies in combination for motion sickness in persons (both adults and children) without known vestibular, visual or central nervous system pathology. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 14 April 2011. SELECTION CRITERIA: All parallel-arm, randomised controlled trials (RCTs) focusing on scopolamine versus no therapy, placebo, other drugs, behavioural and complementary therapy or two or more of the above therapies in combination. We considered outcomes relating to the prevention of onset or treatment of clinically-defined motion sickness, task ability and psychological tests, changes in physiological parameters and adverse effects. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data from the studies using standardised forms. We assessed study quality. We expressed dichotomous data as odds ratio (OR) and calculated a pooled OR using the random-effects model. MAIN RESULTS: Of 35 studies considered potentially relevant, 14 studies enrolling 1025 subjects met the entry criteria. Scopolamine was administered via transdermal patches, tablets or capsules, oral solutions or intravenously. Scopolamine was compared against placebo, calcium channel antagonists, antihistamine, methscopolamine or a combination of scopolamine and ephedrine. Studies were generally small in size and of varying quality.Scopolamine was more effective than placebo in the prevention of symptoms. Comparisons between scopolamine and other agents were few and suggested that scopolamine was superior (versus methscopolamine) or equivalent (versus antihistamines) as a preventative agent. Evidence comparing scopolamine to cinnarizine or combinations of scopolamine and ephedrine is equivocal or minimal.Although sample sizes were small, scopolamine was no more likely to induce drowsiness, blurring of vision or dizziness compared to other agents. Dry mouth was more likely with scopolamine than with methscopolamine or cinnarizine.No studies were available relating to the therapeutic effectiveness of scopolamine in the management of established symptoms of motion sickness. AUTHORS' CONCLUSIONS: The use of scopolamine versus placebo in preventing motion sickness has been shown to be effective. No conclusions can be made on the comparative effectiveness of scopolamine and other agents such as antihistamines and calcium channel antagonists. In addition, we identified no randomised controlled trials that examined the effectiveness of scopolamine in the treatment of established symptoms of motion sickness. PMID- 21678337 TI - Psychoeducation for schizophrenia. AB - BACKGROUND: Schizophrenia can be a severe and chronic illness characterised by lack of insight and poor compliance with treatment. Psychoeducational approaches have been developed to increase patients' knowledge of, and insight into, their illness and its treatment. It is supposed that this increased knowledge and insight will enable people with schizophrenia to cope in a more effective way with their illness, thereby improving prognosis. OBJECTIVES: To assess the effects of psychoeducational interventions compared with standard levels of knowledge provision. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (February 2010). SELECTION CRITERIA: All relevant randomised controlled trials focusing on psychoeducation for schizophrenia and/or related serious mental illnesses involving individuals or groups. We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: At least two review authors extracted data independently from included papers. We contacted authors of trials for additional and missing data. We calculated risk ratios (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data. We used a fixed effects model for heterogeneous dichotomous data. Where possible we also calculated the numbers needed to treat (NNT), as well as weighted means for continuous data. MAIN RESULTS: This review includes a total of 5142 participants (mostly inpatients) from 44 trials conducted between 1988 and 2009 (median study duration ~ 12 weeks, risk of bias - moderate). We found that incidences of non compliance were lower in the psychoeducation group in the short term (n = 1400, RR 0.52 CI 0.40 to 0.67, NNT 11 CI 9 to 16). This finding holds for the medium and long term. Relapse appeared to be lower in psychoeducation group (n = 1214, RR 0.70 CI 0.61 to 0.81, NNT 9 CI 7 to 14) and this also applied to readmission (n = 206, RR 0.71 CI 0.56 to 0.89, NNT 5 CI 4 to 13). Scale-derived data also suggested that psychoeducation promotes better social and global functioning. In the medium term, treating four people with schizophrenia with psychoeducation instead of standard care resulted in one additional person showing a clinical improvement. Evidence suggests that participants receiving psychoeducation are more likely to be satisfied with mental health services (n = 236, RR 0.24 CI 0.12 to 0.50, NNT 5 CI 5 to 8) and have improved quality of life. AUTHORS' CONCLUSIONS: Psychoeducation does seem to reduce relapse, readmission and encourage medication compliance, as well as reduce the length of hospital stay in these hospital-based studies of limited quality. The true size of effect is likely to be less than demonstrated in this review - but, nevertheless, some sort of psychoeducation could be clinically effective and potentially cost beneficial. It is not difficult to justify better, more applicable, research in this area aimed at fully investigating the effects of this promising approach. PMID- 21678339 TI - WITHDRAWN: Humidified air inhalation for treating croup. AB - BACKGROUND: Croup (laryngotracheobronchitis) is a common cause of upper airway obstruction in children with a peak incidence of 60 per 1000 child years in those aged between one and two years. It is characterised by hoarseness, a barking cough, and inspiratory stridor. These symptoms are thought to occur as a result of oedema of the larynx and trachea, which have been triggered by a recent viral infection. Para influenza virus type 1 is the agent most commonly identified in cases of croup. Severe cases are admitted to hospital and steroid treatment is established to reduce disease severity. Treatment with humidified air was previously widely used and is still commonly recommended as home treatment. OBJECTIVES: To assess the efficacy of humidified air in the treatment of croup. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2005), MEDLINE (1966 to January 2006) and EMBASE (1990 to January 2006). SELECTION CRITERIA: Randomised controlled trials (RCTs) involving children suffering from croup treated with humidified air. DATA COLLECTION AND ANALYSIS: Two authors independently identified potentially relevant abstracts identified from the search and then assessed the full papers for inclusion and methodological quality. Outcome measures included mortality, ventilation, admission to hospital, re-contact with medical services, number of days off school and relief of symptoms; these were separately analysed for the week following treatment. Data extraction was performed by the two authors then entered by one and checked by the second author. Missing data were obtained from trial authors where possible. Data were analysed using Review Manager version 4.2. Sensitivity and sub-group analysis were not possible due to the paucity of trials. MAIN RESULTS: Three studies in emergency settings provided data on 135 patients with moderate croup for the main outcome (croup score). The combined results from 20 to 60 minutes in the three studies marginally favoured the treatment group with a weighted standardised mean difference of -0.14 (95% confidence interval (CI) -0.75 to 0.47). No other outcomes were significantly different between the groups. AUTHORS' CONCLUSIONS: The croup score of children managed in an emergency setting with mild to moderate croup probably does not improve greatly with inhalation of humidified air. Further research is needed in primary care settings, using a wider range of more sensitive outcome measures. PMID- 21678340 TI - Epinephrine for bronchiolitis. AB - BACKGROUND: Bronchodilators are commonly used for acute bronchiolitis, despite uncertain effectiveness. OBJECTIVES: To examine the efficacy and safety of epinephrine in children less than two with acute viral bronchiolitis. SEARCH STRATEGY: We searched CENTRAL (2010, Issue 3) which contains the Acute Respiratory Infections Group's Specialized Register, MEDLINE (1950 to September Week 2, 2010), EMBASE (1980 to September 2010), Scopus (1823 to September 2010), PubMed (March 2010), LILACS (1985 to September 2010) and Iran MedEx (1998 to September 2010). SELECTION CRITERIA: We included randomized controlled trials comparing epinephrine to placebo or another intervention involving children less than two years with acute viral bronchiolitis. Studies were included if the trials presented data for at least one quantitative outcome of interest.We selected primary outcomes a priori, based on clinical relevance: rate of admission by days one and seven of presentation for outpatients, and length of stay (LOS) for inpatients. Secondary outcomes included clinical severity scores, pulmonary function, symptoms, quality of life and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the searches, applied inclusion criteria, assessed risk of bias and graded the evidence. We conducted separate analyses for different comparison groups (placebo, non-epinephrine bronchodilators, glucocorticoids) and for clinical setting (inpatient, outpatient). MAIN RESULTS: We included 19 studies (2256 participants). Epinephrine versus placebo among outpatients showed a significant reduction in admissions at Day 1 (risk ratio (RR) 0.67; 95% confidence interval (CI) 0.50 to 0.89) but not at Day 7 post-emergency department visit. There was no difference in LOS for inpatients. Epinephrine versus salbutamol showed no differences among outpatients for admissions at Day 1 or 7. Inpatients receiving epinephrine had a significantly shorter LOS compared to salbutamol (mean difference -0.28; 95% CI 0.46 to -0.09). One large RCT showed a significantly shorter admission rate at Day 7 for epinephrine and steroid combined versus placebo (RR 0.65; 95% CI 0.44 to 0.95). There were no important differences in adverse events. AUTHORS' CONCLUSIONS: This review demonstrates the superiority of epinephrine compared to placebo for short-term outcomes for outpatients, particularly in the first 24 hours of care. Exploratory evidence from a single study suggests benefits of epinephrine and steroid combined for later time points. More research is required to confirm the benefits of combined epinephrine and steroids among outpatients. There is no evidence of effectiveness for repeated dose or prolonged use of epinephrine or epinephrine and dexamethasone combined among inpatients. PMID- 21678341 TI - Weight reduction for non-alcoholic fatty liver disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming a wide spread liver disease. The present recommendations for treatment are not evidence-based. Some of them are various weight reduction measures with diet, exercise, drug, or surgical therapy. OBJECTIVES: To assess the benefits and harms of intended weight reduction for patients with NAFLD. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, PubMed, EMBASE, Science Citation Index Expanded, Chinese Biomedicine Database, and ClinicalTrials.gov until February 2011. SELECTION CRITERIA: We included randomised clinical trials evaluating weight reduction with different measures versus no intervention or placebo in NAFLD patients. DATA COLLECTION AND ANALYSIS: We extracted data independently. We calculated the odds ratio (OR) for dichotomous data and calculated the mean difference (MD) for continuous data, both with 95% confidence intervals (CI). MAIN RESULTS: The review includes seven trials; five on aspects of lifestyle changes (eg, diet, physical exercise) and two on treatment with a weight reduction drug 'orlistat'. In total, 373 participants were enrolled, and the duration of the trials ranged from 1 month to 1 year. Only one trial on lifestyle programme was judged to be of low risk of bias. We could not perform meta-analyses for the main outcomes as they were either not reported or there were insufficient number of trials for each outcome to be meta-analysed. We could meta-analyse the available data for body weight and body mass index only. Adverse events were poorly reported. AUTHORS' CONCLUSIONS: The sparse data and high risk of bias preclude us from drawing any definite conclusion on lifestyle programme or orlistat for treatment of NAFLD. Further randomised clinical trials with low risk of bias are needed to test the beneficial and harmful effects of weight reduction for NAFLD patients. The long-term prognosis of development of fibrosis, mortality, and quality of life should be studied. PMID- 21678342 TI - Cardioprotective interventions for cancer patients receiving anthracyclines. AB - BACKGROUND: Anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous malignancies. Unfortunately, their use is limited by a dose-dependent cardiotoxicity. In an effort to prevent this cardiotoxicity, different cardioprotective agents have been studied. OBJECTIVES: The objective of this review was to assess the efficacy of different cardioprotective agents in preventing heart damage in cancer patients treated with anthracyclines. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010) and EMBASE (1980 to November 2010) databases. In addition, we handsearched reference lists, conference proceedings of the International Society of Paediatric Oncology (SIOP) and American Society of Clinical Oncology (ASCO) meetings (1998 to 2010) and ongoing trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which any cardioprotective agent was compared to no additional therapy or placebo in cancer patients (children and adults) receiving anthracyclines. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and data extraction including adverse effects. MAIN RESULTS: We identified RCTs for the eight cardioprotective agents N-acetylcysteine, phenethylamines, coenzyme Q10, a combination of vitamins E and C and N-acetylcysteine, L-carnitine, carvedilol, amifostine and dexrazoxane (mostly for adults with advanced breast cancer). All studies had methodological limitations and for the first seven agents there were too few studies to allow pooling of results. None of the individual studies showed a cardioprotective effect. The 10 included studies on dexrazoxane enrolled 1619 patients. The meta-analysis for dexrazoxane showed a statistically significant benefit in favour of dexrazoxane for the occurrence of heart failure (risk ratio (RR) 0.29, 95% CI 0.20 to 0.41). No evidence was found for a difference in response rate or survival between the dexrazoxane and control groups. The results for adverse effects were ambiguous. No significant difference in the occurrence of secondary malignancies was identified. AUTHORS' CONCLUSIONS: No definitive conclusions can be made about the efficacy of cardioprotective agents for which pooling of results was impossible. Dexrazoxane prevents heart damage and no evidence for a difference in response rate or survival between the dexrazoxane and control groups was identified. The evidence available did not allow us to reach any definite conclusions about adverse effects. We conclude that if the risk of cardiac damage is expected to be high, it might be justified to use dexrazoxane in patients with cancer treated with anthracyclines. However, clinicians should weigh the cardioprotective effect of dexrazoxane against the possible risk of adverse effects for each individual patient. PMID- 21678343 TI - Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. AB - BACKGROUND: It has been unclear whether repeat dose(s) of prenatal corticosteroids are beneficial. OBJECTIVES: To assess the effectiveness and safety of repeat dose(s) of prenatal corticosteroids. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2011), searched reference lists of retrieved studies and contacted authors for further data. SELECTION CRITERIA: Randomised controlled trials of women who had already received a single course of corticosteroids seven or more days previously and considered still at risk of preterm birth. DATA COLLECTION AND ANALYSIS: We assessed trial quality and extracted data independently. MAIN RESULTS: We included 10 trials (more than 4730 women and 5650 babies) with low to moderate risk of bias. Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary outcomes respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91, eight trials, 3206 infants, numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNT 30, 95% CI 19 to 79).Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference (MD) -75.79 g, 95% CI 117.63 to -33.96, nine trials, 5626 infants). However, outcomes that adjusted birthweight for gestational age (birthweight Z scores, birthweight multiples of the median and small-for-gestational age) did not differ between treatment groups.At early childhood follow-up no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or serious outcome) or in the secondary outcome growth assessments. AUTHORS' CONCLUSIONS: The short-term benefits for babies of less respiratory distress and fewer serious health problems in the first few weeks after birth support the use of repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. These benefits were associated with a small reduction in size at birth. The current available evidence reassuringly shows no significant harm in early childhood, although no benefit.Further research is needed on the long-term benefits and risks for the woman and baby. Individual patient data meta-analysis may clarify how to maximise benefit and minimise harm. PMID- 21678344 TI - Provider training and experience for people living with HIV/AIDS. AB - BACKGROUND: The complexity of HIV/AIDS raises challenges for the effective delivery of care. It is important to ensure that the expertise and experience of care providers is of high quality. Training and experience of HIV/AIDS providers may impact not only individual patient outcomes but increasingly on health care costs as well. OBJECTIVES: The objective of this review is to assess the effects of provider training and experience on people living with HIV/AIDS on the following outcomes: immunological (ie. viral load, CD4 count), medical (ie. mortality, proportion on antiretrovirals), psychosocial (ie. quality of life measures) and economic outcomes (ie health care costs). SEARCH STRATEGY: We searched MEDLINE, EMBASE, Dissertation Abstracts International (DAI), CINAHL, HealthStar, PsycInfo, PsycLit, Social Sciences Abstracts, and Sociological Abstracts from January 1, 1980 through May 29, 2009. Electronic searches were performed for abstracts from major international AIDS conferences. Reference lists from pertinent articles, books and review articles were retrieved and reviewed. SELECTION CRITERIA: Randomized controlled trials (RCTs), controlled clinical trials, cohort, case control, cross-sectional studies and controlled before and after designs that examined the qualifications/training and patient volume of HIV/AIDS care of providers caring for persons known to be infected with HIV/AIDS were included. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed trial quality and extracted data. Study authors were contacted for further information as required. Assessment of confounding factors was undertaken independently by two reviewers. MAIN RESULTS: A total of four studies (one randomized controlled trial, three non- randomized studies) involving 8488 people living with HIV/AIDS were included. The main findings of this review demonstrated a trend to improved outcomes when treated by a provider with more training/expertise in HIV/AIDS care in the outpatient (clinic) setting. Due to the heterogeneity of the included studies, we could not perform a meta analysis. We present a descriptive review of the results. AUTHORS' CONCLUSIONS: The results demonstrate improved medical outcomes when treated by a provider with more training/expertise in HIV/AIDS care in the outpatient (clinic) setting. Since all of these studies were conducted in North America, this does not address any issues regarding the level of training/expertise required by providers working in countries with more limited resources. Practitioners who do not consider themselves 'experts' in HIV/AIDS care and care for few of these patients need to seriously consider this review which demonstrates a trend towards worse patient outcomes when receiving care by those with low caseloads/training in HIV/AIDS care. PMID- 21678346 TI - Antibiotics for bronchiolitis in children. AB - BACKGROUND: Bronchiolitis is a serious, potentially life-threatening respiratory illness commonly affecting babies. It is often caused by respiratory syncytial virus (RSV). Antibiotics are not recommended for bronchiolitis unless there is concern about complications such as secondary bacterial pneumonia or respiratory failure. Nevertheless, they are used at rates of 34% to 99% in uncomplicated cases. OBJECTIVES: To evaluate the effectiveness of antibiotics for bronchiolitis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2010, issue 4), which includes the Cochrane Acute Respiratory Infection Group's Specialised Register, and the Database of Abstracts of Reviews of Effects, MEDLINE (January 1966 to November 2010), EMBASE (1990 to December 2010) and Current Contents (2001 to December 2010). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing antibiotics to placebo in children under two years diagnosed with bronchiolitis, using clinical criteria (including respiratory distress preceded by coryzal symptoms with or without fever). Primary clinical outcomes included time to resolution of signs or symptoms (pulmonary markers included respiratory distress, wheeze, crepitations, oxygen saturation and fever). Secondary outcomes included hospital admissions, length of hospital stay, re-admissions, complications or adverse events and radiological findings. DATA COLLECTION AND ANALYSIS: Two review authors independently analysed the search results. MAIN RESULTS: Five studies (543 participants) met our inclusion criteria. One study randomised 52 children to either ampicillin or placebo and found no significant difference between the two groups for length of illness. A small study (21 children) with higher risk of potential bias randomised children with proven RSV infection to clarithromycin or placebo and found clarithromycin may reduce hospital re-admission (8% antibiotics versus 44% placebo; Fishers exact; P = 0.081). The two studies (267 children) providing adequate data for length of hospital stay showed no difference between antibiotics and control (pooled mean difference 0.34; 95% CI -0.71 to 1.38). Two studies randomised children to intravenous ampicillin, oral erythromycin and control and found no difference for most symptom measures. None of the trials reported deaths. AUTHORS' CONCLUSIONS: This review found minimal evidence to support the use of antibiotics for bronchiolitis. Research to identify a possible small subgroup of patients who have complications from bronchiolitis such as respiratory failure and who may benefit from antibiotics is justified. PMID- 21678347 TI - Topical anaesthetics for repair of dermal laceration. AB - BACKGROUND: Topical local anaesthetics are recognized as providing effective analgesia for numerous superficial procedures, including repair of dermal lacerations. The need for cocaine in topical anaesthetic formulations has been questioned due to concern about adverse effects, and so novel preparations of cocaine-free anaesthetics have been developed. OBJECTIVES: To compare the efficacy and safety of infiltrated local anaesthetics with those of topical local anaesthetics for repair of dermal lacerations and to evaluate the efficacy and safety of various single or multi-component topical anaesthetics to identify cocaine-free topically applied local anaesthetics that may provide equivalent analgesia to those containing cocaine. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10); MEDLINE (1966 to November 2010); EMBASE (1980 to November 2010); CINAHL (1982 to November 2010); and reference lists of articles. We also handsearched selected journals, reviewed abstracts presented at international society meetings, reviewed metaregisters of ongoing trials and contacted manufacturers and researchers in the field. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated the efficacy and safety of topical anaesthetics for repair of torn skin in adult and paediatric patients. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse event information from the trials. MAIN RESULTS: We included 23 RCTs involving 3128 patients. The small number of trials in each comparison group and the heterogeneity of outcome measures precluded quantitative analysis of data in all but one outcome, pain scores using a visual analogue scale. The majority of trials that compared infiltrated and topical anaesthetics are at high risk of bias, which is likely to affect the interpretation of the results. Several cocaine-free topical anaesthetics were found to provide effective analgesic efficacy. However, the data regarding the efficacy of each topical agent is mostly based upon single comparisons, in trials that have unclear or high risk of bias. Mild, self-limited erythematous skin induration occurred in one case after application of topical tetracaine-adrenaline-cocaine (TAC) where a total of 1042 patients were exposed. No serious complications were reported in any of the patients treated with either cocaine-based or cocaine-free topical anaesthetics. AUTHORS' CONCLUSIONS: Based on mostly descriptive analysis, topical anaesthetics are possibly an efficacious, non-invasive means of providing analgesia prior to suturing of dermal lacerations. However, additional well designed RCTs with low risk of bias are necessary before definitive conclusions can be made. PMID- 21678345 TI - Early intervention for psychosis. AB - BACKGROUND: Proponents of early intervention have argued that outcomes might be improved if more therapeutic efforts were focused on the early stages of schizophrenia or on people with prodromal symptoms. Early intervention in schizophrenia has two elements that are distinct from standard care: early detection, and phase-specific treatment (phase-specific treatment is a psychological, social or physical treatment developed, or modified, specifically for use with people at an early stage of the illness).Early detection and phase specific treatment may both be offered as supplements to standard care, or may be provided through a specialised early intervention team. Early intervention is now well established as a therapeutic approach in America, Europe and Australasia. OBJECTIVES: To evaluate the effects of: (a) early detection; (b) phase-specific treatments; and (c) specialised early intervention teams in the treatment of people with prodromal symptoms or first-episode psychosis. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (March 2009), inspected reference lists of all identified trials and reviews and contacted experts in the field. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) designed to prevent progression to psychosis in people showing prodromal symptoms, or to improve outcome for people with first-episode psychosis. Eligible interventions, alone and in combination, included: early detection, phase specific treatments, and care from specialised early intervention teams. We accepted cluster-randomised trials but excluded non-randomised trials. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality rated them and extracted data. For dichotomous data, we estimated relative risks (RR), with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat/harm statistic (NNT/H) and used intention-to-treat analysis (ITT). MAIN RESULTS: Studies were diverse, mostly small, undertaken by pioneering researchers and with many methodological limitations (18 RCTs, total n=1808). Mostly, meta analyses were inappropriate. For the six studies addressing prevention of psychosis for people with prodromal symptoms, olanzapine seemed of little benefit (n=60, 1 RCT, RR conversion to psychosis 0.58 CI 0.3 to 1.2), and cognitive behavioural therapy (CBT) equally so (n=60, 1 RCT, RR conversion to psychosis 0.50 CI 0.2 to 1.7). A risperidone plus CBT plus specialised team did have benefit over specialist team alone at six months (n=59, 1 RCT, RR conversion to psychosis 0.27 CI 0.1 to 0.9, NNT 4 CI 2 to 20), but this was not seen by 12 months (n=59, 1 RCT, RR 0.54 CI 0.2 to 1.3). Omega 3 fatty acids (EPA) had advantage over placebo (n=76, 1 RCT, RR transition to psychosis 0.13 CI 0.02 to 1.0, NNT 6 CI 5 to 96). We know of no replications of this finding.The remaining trials aimed to improve outcome in first-episode psychosis. Phase-specific CBT for suicidality seemed to have little effect, but the single study was small (n=56, 1 RCT, RR suicide 0.81 CI 0.05 to 12.26). Family therapy plus a specialised team in the Netherlands did not clearly affect relapse (n=76, RR 1.05 CI 0.4 to 3.0), but without the specialised team in China it may (n=83, 1 RCT, RR admitted to hospital 0.28 CI 0.1 to 0.6, NNT 3 CI 2 to 6). The largest and highest quality study compared specialised team with standard care. Leaving the study early was reduced (n=547, 1 RCT, RR 0.59 CI 0.4 to 0.8, NNT 9 CI 6 to 18) and compliance with treatment improved (n=507, RR stopped treatment 0.20 CI 0.1 to 0.4, NNT 9 CI 8 to 12). The mean number of days spent in hospital at one year were not significantly different (n=507, WMD, -1.39 CI -2.8 to 0.1), neither were data for 'Not hospitalised' by five years (n=547, RR 1.05 CI 0.90 to 1.2). There were no significant differences in numbers 'not living independently' by one year (n=507, RR 0.55 CI 0.3 to 1.2). At five years significantly fewer participants in the treatment group were 'not living independently' (n=547, RR 0.42 CI 0.21 to 0.8, NNT 19 CI 14 to 62). When phase-specific treatment (CBT) was compared with befriending no significant differences emerged in the number of participants being hospitalised over the 12 months (n=62, 1 RCT, RR 1.08 CI 0.59 to 1.99).Phase-specific treatment E-EPA oils suggested no benefit (n=80, 1 RCT, RR no response 0.90 CI 0.6 to 1.4) as did phase-specific treatment brief intervention (n=106, 1 RCT, RR admission 0.86 CI 0.4 to 1.7). Phase-specific ACE found no benefit but participants given vocational intervention were more likely to be employed (n=41, 1 RCT, RR 0.39 CI 0.21 to 0.7, NNT 2 CI 2 to 4). Phase specific cannabis and psychosis therapy did not show benefit (n=47, RR cannabis use 1.30 CI 0.8 to 2.2) and crisis assessment did not reduce hospitalisation (n=98, RR 0.85 CI 0.6 to 1.3). Weight was unaffected by early behavioural intervention. AUTHORS' CONCLUSIONS: There is emerging, but as yet inconclusive evidence, to suggest that people in the prodrome of psychosis can be helped by some interventions. There is some support for specialised early intervention services, but further trials would be desirable, and there is a question of whether gains are maintained. There is some support for phase-specific treatment focused on employment and family therapy, but again, this needs replicating with larger and longer trials. PMID- 21678348 TI - Non-clinical interventions for reducing unnecessary caesarean section. AB - BACKGROUND: Caesarean section rates are steadily increasing globally. The factors contributing to these observed increases are complex. Non-clinical interventions, those applied independent of patient care in a clinical encounter, may have a role in reducing unnecessary caesarean sections. OBJECTIVES: To evaluate the effectiveness and safety of non-clinical interventions for reducing unnecessary caesarean sections. SEARCH STRATEGY: We searched the following electronic databases: the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register (29 March 2010), the Cochrane Pregnancy and Childbirth Group Specialised Register (29 March 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2); MEDLINE (1950 to March 2010); EMBASE (1947 to March 2010) and CINAHL (1982 to March 2010). SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-experimental studies, controlled clinical trials (CCTs), controlled before and after studies (CBAs) with at least two intervention and control sites, and interrupted time series analyses (ITS) where the intervention time was clearly defined and there were at least three data points before and three after the intervention. Studies evaluated non-clinical interventions to reduce unnecessary caesarean section rates. Participants included pregnant women and their families, healthcare providers who work with expectant mothers, communities and advocacy groups. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the quality and abstracted data of all eligible studies using a standardised data extraction form, modified from the Cochrane EPOC checklists. We contacted study authors for additional information. MAIN RESULTS: We included 16 studies in this review.Six studies specifically targeted pregnant women. Two RCTs were shown to be effective in reducing caesarean section rates: a nurse-led relaxation training programme for women with a fear or anxiety of childbirth and birth preparation sessions. However, both RCTs were small in size and targeted younger mothers with their first pregnancies. There is insufficient evidence that prenatal education and support programmes, computer patient decision-aids, decision-aid booklets and intensive group therapy are effective.Ten studies targeted health professionals. Three of these studies were effective in reducing caesarean section rates. A cluster-RCT of guideline implementation with mandatory second opinion resulted in a small, statistically significant reduction in total caesarean section rates (adjusted risk difference (RD) -1.9; 95% confidence interval (CI) -3.8 to -0.1); this reduction was predominately in intrapartum sections. An ITS study of mandatory second opinion and peer review feedback at department meetings found statistically significant results at 48 months for reducing repeat caesarean section rates (change in level was -6.4%; 95% CI -9.7% to -3.1% and change in slope -1.14%; 95% CI -1.9% to -0.3%) but not for total caesarean section rates. A cluster-RCT of guideline implementation with support from local opinion leaders increased the proportion of women with a previous caesarean section being offered a trial of labour (absolute difference 16.8%) and the number who had a vaginal birth (VBAC rates) (absolute difference 13.5%). The P values are, however, not reported due to unit of analysis errors. There was insufficient evidence that audit and feedback, training of public health nurses, insurance reform, external peer review and legislative changes are effective. AUTHORS' CONCLUSIONS: Implementation of guidelines with mandatory second opinion can lead to a small reduction in caesarean section rates, predominately in intrapartum sections. Peer review, including pre-caesarean consultation, mandatory secondary opinion and postcaesarean surveillance can lead to a reduction in repeat caesarean section rates. Guidelines disseminated with endorsement and support from local opinion leaders may increase the proportion of women with previous caesarean sections being offered a trial of labour in certain settings. Nurse-led relaxation classes and birth preparation classes may reduce caesarean section rates in low-risk pregnancies. PMID- 21678349 TI - Manual material handling advice and assistive devices for preventing and treating back pain in workers. AB - BACKGROUND: Training and the provision of assistive devices are considered major interventions to prevent back pain and its related disability among workers exposed to manual material handling (MMH). OBJECTIVES: To determine the effectiveness of MMH advice and training and the provision of assistive devices in preventing and treating back pain. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2011, issue 1), MEDLINE, EMBASE, CINAHL, Nioshtic, CISdoc, Science Citation Index, and PsychLIT to February 2011. SELECTION CRITERIA: We included randomised controlled trials (RCT) and cohort studies with a concurrent control group that were aimed at changing human behaviour in MMH and measured back pain, back pain-related disability or sickness absence. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed the risk of bias using the criteria recommended by the Cochrane Back Review Group for RCTs and MINORS for the cohort studies.We based the results and conclusions on the analysis of RCTs only. We compared these with the results from cohort studies. MAIN RESULTS: We included nine RCTs (20,101 employees) and nine cohort studies (1280 employees) on the prevention of back pain in this updated review. Studies compared training to no intervention (4), professional education (2), a video (3), use of a back belt (3) or exercise (2). Other studies compared training plus lifting aids to no intervention (3) and to training only (1). The intensity of training ranged from a single educational session to very extensive personal biofeedback.Six RCTs had a high risk of bias.None of the included studies showed evidence of a preventive effect of training on back pain.There was moderate quality evidence from seven RCTs (19,317 employees) that those who received training reported levels of back pain similar to those who received no intervention, with an odds ratio of 1.17 (95% confidence intervals (CI) 0.68 to 2.02) or minor advice (video), with a relative risk of 0.93 (95% CI 0.69 to 1.25). Confidence intervals around the effect estimates were still wide due to the adjustment for the design effect of clustered studies.The results of the cohort studies were similar to those of the randomised studies. AUTHORS' CONCLUSIONS: There is moderate quality evidence that MMH advice and training with or without assistive devices does not prevent back pain or back pain-related disability when compared to no intervention or alternative interventions. There is no evidence available from RCTs for the effectiveness of MMH advice and training or MMH assistive devices for treating back pain. More high quality studies could further reduce the remaining uncertainty. PMID- 21678350 TI - Dynamic compression plating versus locked intramedullary nailing for humeral shaft fractures in adults. AB - BACKGROUND: Surgical fixation of fractures of the shaft of the humerus generally involves plating or nailing. It is unclear whether one method is more effective than the other. OBJECTIVES: To compare compression plating and locked intramedullary nailing for primary surgical fixation (surgical fixation of an acute fracture or early fixation following failure of conservative treatment) of humeral shaft fractures in adults. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (February 2011), The Cochrane Library 2011, Issue 1, MEDLINE and EMBASE (both to February 2011) and trial registries for ongoing trials. SELECTION CRITERIA: Randomised and quasi randomised controlled trials comparing compression plates and locked intramedullary nail fixation for humeral shaft fractures in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial methodology and extracted data. Disagreement was resolved by discussion, or third party adjudication. Treatment effects were assessed using risk ratios for dichotomous data and mean differences for continuous data, together with 95% confidence intervals. Where appropriate, data were pooled using a fixed-effect model. MAIN RESULTS: Five small trials comparing dynamic compression plates with locked intramedullary nailing were included in this review. These involved a total of 260 participants undergoing surgery for either acute fractures or after early failure of conservative treatment. All five trials had methodological flaws, such as the lack of assessor blinding, that could have influenced their findings. There was no significant difference in fracture union between plating and nailing (five trials, RR 1.05; 95% CI 0.97 to 1.13). There was a statistically significant increase in shoulder impingement following nailing when compared with plating (five trials, RR 0.12; 95% CI 0.04 to 0.38). Intramedullary nails were removed significantly more frequently than plates (three trials, RR 0.17; 95% CI 0.04 to 0.76). There was no statistically significant difference between plating and nailing in operating time, blood loss during surgery, iatrogenic radial nerve injury, return to pre-injury occupation by six months or American Shoulder and Elbow Surgeons (ASES) scores.Two further small trials are awaiting classification. AUTHORS' CONCLUSIONS: The available evidence shows that intramedullary nailing is associated with an increased risk of shoulder impingement, with a related increase in restriction of shoulder movement and need for removal of metalwork. There was insufficient evidence to determine if there were any other important differences, including in functional outcome, between dynamic compression plating and locked intramedullary nailing for humeral shaft fractures. PMID- 21678351 TI - Evaluation of follow-up strategies for patients with epithelial ovarian cancer following completion of primary treatment. AB - BACKGROUND: Ovarian cancer is the sixth most common cancer and seventh cause of cancer death in women worldwide. Traditionally, many patients who have been treated for cancer undergo long-term follow up in secondary care. Recently however it has been suggested that the use of routine review may not be effective in improving survival, quality of life (QoL), and relieving anxiety. In addition, it may not be cost effective. OBJECTIVES: To compare the potential benefits of different strategies of follow up in women with epithelial ovarian cancer following completion of primary treatment. SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2010, Issue 4), MEDLINE and EMBASE (to November 2010). We also searched CINAHL, PsycLIT, registers of clinical trials, abstracts of scientific meetings, reference lists of review articles, and contacted experts in the field. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) that evaluated follow-up strategies for patients with epithelial ovarian cancer following completion of primary treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. MAIN RESULTS: We found only one RCT (Rustin 2010) that met our inclusion criteria. This trial included 529 women and reported data on immediate treatment versus delayed treatment in women with confirmation of remission and with normal CA125 concentration and no radiological evidence of disease after surgery and first-line chemotherapy.Overall survival showed no significant difference between the immediate and delayed arms after a median follow up of 56.9 months (unadjusted hazard ratio (HR) = 0.98, 95% confidence interval (CI) 0.80 to 1.20; P = 0.85). Time from randomisation to first deterioration in global health score or death was significantly shorter in the early group compared with the delayed group (HR 0.71, 95% CI 0.58 to 0.88; P < 0.01). The trial was at low risk of bias. AUTHORS' CONCLUSIONS: There is a lack of randomised studies on most aspects of follow-up care after treatment for epithelial ovarian cancers. Limited evidence from a single trial suggests that routine surveillance with CA125 in asymptomatic patients, with treatment at CA125 relapse, does not seem to offer survival advantage when compared to treatment at symptomatic relapse. Randomised controlled trials are needed to compare different types of follow up on the outcomes of survival, quality of Life, cost and psychological effects. PMID- 21678352 TI - Interventions for Mooren's ulcer. AB - BACKGROUND: Mooren's ulcer is a chronic, painful peripheral ulcer of the cornea. Its cause is unknown but it can or will lead to loss of vision if untreated. Severe pain is common in patients with Mooren's ulcer and the eye(s) may be intensely reddened, inflamed and photophobic, with tearing. The disease is rare in the northern hemisphere but more common in southern and central Africa, China and the Indian subcontinent. There are a number of treatments used such as anti inflammatory drugs (steroidal and non-steroidal), cytotoxic drugs (topical and systemic), conjunctivectomy and cornea debridement (superficial keratectomy). There is no evidence to show which is the most effective amongst these treatment modalities. OBJECTIVES: The aim of this systematic review is to assess the effectiveness of the various interventions (medical and surgical) for Mooren's ulcer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2011, Issue 4), MEDLINE (January 1950 to April 2011), EMBASE (January 1980 to April 2011), Latin American and Caribbean Health Sciences Literature Database (LILACS), (January 1982 to April 2011), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrial.gov). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 16 April 2011. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) or discuss any prospective non-RCTs in the absence of any RCTs. The trials included would be of people of any age or gender diagnosed with Mooren's ulcer and all interventions (medical and surgical) would be considered. DATA COLLECTION AND ANALYSIS: Two authors screened the search results independently; we found no studies that met our inclusion criteria. MAIN RESULTS: As we found no studies that met our inclusion criteria, we highlighted important considerations for conducting RCTs in the future in this area. AUTHORS' CONCLUSIONS: We found no evidence in the form of RCTs to assess the treatment effect for the various interventions for Mooren's ulcer. High quality RCTs that compare medical or surgical interventions across different demographics are needed. Such studies should make use of various outcome measures, (i.e. healed versus not healed, percentage of area healed, speed of healing etc.) as well as ensuring high quality randomisation and data analysis, as highlighted in this review . PMID- 21678353 TI - Biofeedback for pain management during labour. AB - BACKGROUND: Labour is often associated with pain and discomfort caused by a complex and subjective interaction of multiple factors, and should be understood within a multi-dimensional and multi-disciplinary framework. Within the non pharmacological approach, biofeedback has focused on the acquisition of control over some physiological responses with the aid of electronic devices, allowing individuals to regulate some physical processes (such as pain) which are not usually under conscious control. The role of this behavioural approach for the management of pain during labour, as an addition to the standard prenatal care, has been never assessed systematically. This review is one in a series of Cochrane reviews examining pain relief in labour, which will contribute to an overview of systematic reviews of pain relief for women in labour (in preparation). OBJECTIVES: To examine the effectiveness of the use of biofeedback in prenatal lessons for managing pain during labour. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2011), CENTRAL (The Cochrane Library 2011, Issue 1), PubMed (1950 to 20 March 2011), EMBASE (via OVID) (1980 to 24 March 2011), CINAHL (EBSCOhost) (1982 to 24 March 2011), and PsycINFO (via Ovid) (1806 to 24 March 2011). We searched for further studies in the reference lists of identified articles. SELECTION CRITERIA: Randomised controlled trials of any form of prenatal classes which included biofeedback, in any modality, in women with low-risk pregnancies. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: The review included four trials (186 women) that hugely differed in terms of the diversity of the intervention modalities and outcomes measured. Most trials assessed the effects of electromyographic biofeedback in women who were pregnant for the first time. The trials were judged to be at a high risk of bias due to the lack of data describing the sources of bias assessed. There was no significant evidence of a difference between biofeedback and control groups in terms of assisted vaginal birth, caesarean section, augmentation of labour and the use of pharmacological pain relief. The results of the included trials showed that the use of biofeedback to reduce the pain in women during labour is unproven. Electromyographic biofeedback may have some positive effects early in labour, but as labour progresses there is a need for additional pharmacological analgesia. AUTHORS' CONCLUSIONS: Despite some positive results shown in the included trials, there is insufficient evidence that biofeedback is effective for the management of pain during labour. PMID- 21678354 TI - Peritoneal drainage versus laparotomy as initial surgical treatment for perforated necrotizing enterocolitis or spontaneous intestinal perforation in preterm low birth weight infants. AB - BACKGROUND: Standard surgical management of infants with perforated necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) is laparotomy with the resection of the necrotic or perforated segments of the intestine. Peritoneal drainage is an alternative approach to the management of such infants. OBJECTIVES: To evaluate the benefits and risks of peritoneal drainage compared to laparotomy as the initial surgical treatment for perforated NEC or SIP in preterm infants. SEARCH STRATEGY: Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2010, Issue 3), MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL (1982 to July 2010), previous reviews and cross-references were searched. Abstracts of paediatric academic society meetings were also searched (online: 2000 to 2009; handsearching Pediatric Research: 1995 to 2000). SELECTION CRITERIA: All randomised or quasi-randomised controlled trials in preterm (< 37 weeks gestation), low birth weight (< 2500 g) infants with perforated NEC or SIP allocated to peritoneal drainage or laparotomy as initial surgical treatment. DATA COLLECTION AND ANALYSIS: Data were excerpted from the trial reports and analysed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Only two randomised controlled trials (RCT) met the eligibility criteria. Overall, no significant differences were seen between the peritoneal drainage and laparotomy groups regarding the incidence of mortality within 28 days of the primary procedure (28/90 versus 30/95; typical relative risk (RR) 0.99, 95% CI 0.64 to 1.52; N = 185, two trials); mortality by 90 days after the primary procedure (typical RR 1.05, 95% CI 0.71 to 1.55; N = 185, two trials) and the number of infants needing total parenteral nutrition for more than 90 days (typical RR 1.18, 95% CI 0.72 to 1.95; N = 116, two trials). Nearly 50% of the infants in the peritoneal drainage group could avoid the need for laparotomy during the study period (44/90 versus 95/96; typical RR 0.49, 95% CI 0.39 to 0.61; N = 186, two trials). One study found that the time to attain full enteral feeds in infants <= 1000 g was prolonged in the peritoneal drainage group (mean difference (MD) 20.77, 95% CI 3.62 to 37.92). AUTHORS' CONCLUSIONS: Evidence from two RCTs suggests no significant benefits or harms of peritoneal drainage over laparotomy. However, due to the very small sample size, clinically significant differences may have easily been missed. No firm recommendations can be made for clinicians. Large multicentre randomised controlled trials are needed to address this question definitively. PMID- 21678356 TI - Symptomatic oxygen for non-hypoxaemic chronic obstructive pulmonary disease. AB - BACKGROUND: Dyspnoea is a common symptom in chronic obstructive pulmonary disease (COPD). People who are hypoxaemic may be given long-term oxygen relief therapy (LTOT) to improve their life expectancy and quality of life. However, the symptomatic benefit of home oxygen therapy in mildly or non-hypoxaemic people with COPD with dyspnoea who do not meet international funding criteria for LTOT (PaO(2)< 55 mmHg or other special cases) is unknown. OBJECTIVES: To determine the efficacy of oxygen versus medical air for relief of subjective dyspnoea in mildly or non-hypoxaemic people with COPD who would not otherwise qualify for home oxygen therapy. The main outcome was patient-reported dyspnoea and secondary outcome was exercise tolerance. SEARCH STRATEGY: We searched the Cochrane Airways Group Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, to November 2009, to identify randomised controlled trials. We handsearched reference lists of included articles. SELECTION CRITERIA: We only included randomised controlled trials of oxygen versus medical air in mildly or non-hypoxaemic people with COPD. Two review authors independently assessed articles for inclusion. DATA COLLECTION AND ANALYSIS: One review author completed data extraction and methodological quality assessment. A second review author then over-read evidence tables to assess for accuracy. MAIN RESULTS: Twenty-eight trials on 702 patients met the criteria for inclusion; 18 trials (431 participants) were included in the meta-analysis. Oxygen reduced dyspnoea with a standardised mean difference (SMD) of -0.37 (95% confidence interval (CI) -0.50 to -0.24, P < 0.00001). We observed significant heterogeneity. AUTHORS' CONCLUSIONS: Oxygen can relieve dyspnoea in mildly and non-hypoxaemic people with COPD who would not otherwise qualify for home oxygen therapy. Given the significant heterogeneity among the included studies, clinicians should continue to evaluate patients on an individual basis until supporting data from ongoing, large randomised controlled trials are available. PMID- 21678357 TI - Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. AB - BACKGROUND: A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including (1) a February 2010 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism. DATA COLLECTION AND ANALYSIS: Using a standardized data form we extracted data on risk of bias, participants, interventions and outcomes of interest that included all cause mortality, venous thromboembolism, major bleeding and minor bleeding. MAIN RESULTS: Of 8187 identified citations, five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The quality of evidence was moderate for all outcomes. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.94; 95% CI 0.8 to 1.03) at two years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (P = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74). AUTHORS' CONCLUSIONS: Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while increasing the risk for bleeding. PMID- 21678358 TI - Effectiveness of staffing models in residential, subacute, extended aged care settings on patient and staff outcomes. AB - BACKGROUND: A key concern for managers and nurse administrators of healthcare settings is staffing. Determining and maintaining an appropriate level and mix of staff is especially problematic for those working in the long-term aged-care sector, where resident needs are complex and recruitment and retention of staff is challenging. OBJECTIVES: To identify which staffing models are associated with the best patient and staff outcomes. SEARCH STRATEGY: We searched the Effective Practice and Organisation of Care (EPOC) Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effectiveness (DARE) in The Cochrane Library and the databases MEDLINE, EMBASE, Ageline, CINAHL, and Dissertation abstracts. We also handsearched the reference lists and bibliographies of all retrieved articles. SELECTION CRITERIA: This review considered interrupted time series studies and studies with concurrent control designs of care staff or residents of residential or subacute or extended aged-care settings that evaluated the effectiveness of staffing models and skill mixes on resident and care staff outcomes. DATA COLLECTION AND ANALYSIS: Two review authors critically appraised all studies that were retrieved based on the screening of titles and abstracts according to the EPOC Group's data collection checklist.The same two review authors independently extracted and summarised details of eligible studies using the data abstraction form developed by EPOC. MAIN RESULTS: We included two studies (one interrupted time series and one controlled before-and-after study); both evaluated a primary care model compared with a either a team-nursing model or a usual-care model. The primary-care model was found to provide slightly better results than the comparator for some outcomes such as resident well-being or behaviour. While nursing staff favoured the primary-care model in one study, neither study found significant improvements in staff outcomes using the primary model compared with the comparator. One study evaluated the uptake of the primary-care model within their facilities and found incorporation of this model into their practice was limited. AUTHORS' CONCLUSIONS: Apart from two small studies evaluating primary care, no evidence in the form of concurrently controlled trials could be identified. While these two studies generally favour the use of primary care, the research designs of both ITS and CBA studies are considered prone to bias, specifically selection and blinding of participants and assessors. Therefore, these studies should be regarded with caution and there is little clear evidence for the effective use of any specific model of care in residential aged care to benefit either residents or care staff. Research in this area is clearly needed. PMID- 21678355 TI - Antipsychotic medication for early episode schizophrenia. AB - BACKGROUND: Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are unclear. There have been numerous suggestions that people with early episodes of schizophrenia appear to respond differently than those with multiple prior episodes. The number of episodes may moderate response to drug treatment. OBJECTIVES: To assess the effects of antipsychotic medication treatment on people with early episode schizophrenia spectrum disorders. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group register (July 2007) as well as references of included studies. We contacted authors of studies for further data. SELECTION CRITERIA: Studies with a majority of first and second episode schizophrenia spectrum disorders comparing initial antipsychotic medication treatment with placebo, milieu, or psychosocial treatment. DATA COLLECTION AND ANALYSIS: Working independently, we critically appraised records from 681studies, of which five studies met inclusion criteria. John Rathbone from the Schizophrenia Group supported us with the data extraction. We calculated risk ratios (RR) and their 95% confidence intervals (CI) where possible. For continuous data, we calculated mean difference (MD). We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. MAIN RESULTS: Five studies with a combined N = 998 met inclusion criteria. Four studies (N = 724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs N = 353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT N = 240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT N = 236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT N = 94, RR 0.96 CI 0.3 to 3.6). Two studies (Cole 1964; May 1976) contributed data to assessment of side effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications compared to placebo. Rappaport 1978 suggested a higher rehospitalisation rate for those receiving chlorpromazine compared to placebo (N = 80, RR 2.29 CI 1.3 to 4.0, NNH 2.9). However, a higher attrition in the placebo group is likely to have introduced a survivor bias into this comparison, as this difference becomes non significant in a sensitivity analysis on intent-to-treat participants (N = 127, RR 1.69 CI 0.9 to 3.0). One study (May 1976) contributes data to a comparison of trifluoperazine to psychotherapy on long-term health in favour of the trifluoperazine group (N = 92, MD 5.8 CI 1.6 to 0.0); however, data from this study are also likely to contain biases due to selection and attrition. One study (Mosher 1995) contributes data to a comparison of typical antipsychotic medication to psychosocial treatment on six-week outcome measures of global psychopathology (N = 89, MD 0.01 CI -0.6 to 0.6) and global improvement (N = 89, MD -0.03 CI -0.5 to 0.4), indicating no between-group differences. On the whole, there is very little useable data in the few studies meeting inclusion criteria. AUTHORS' CONCLUSIONS: With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia. PMID- 21678359 TI - Hands-on therapy interventions for upper limb motor dysfunction following stroke. AB - BACKGROUND: Recent studies have attempted to disaggregate therapeutic intervention packages by looking at the impact of structure and process characteristics of environment upon outcome. However, what is commonly referred to as the 'black box' of therapy has yet to be comprehensively unpacked. This failure to analyse the components of therapy means that it remains unclear how much therapy should be provided, who should provide it, and which patients should be targeted to ensure that functional outcomes are maximized. This review, therefore, seeks to assess the effectiveness of specific therapeutic interventions in the rehabilitation of the paretic upper limb post stroke. OBJECTIVES: To identify if specific hands-on therapeutic interventions enhance motor activity and function of the upper limb post stroke. SEARCH STRATEGY: We searched the trials registers of the Cochrane Stroke Group (March 2010), the Cochrane Complementary Medicine Field (March 2010) and the Cochrane Rehabilitation and Related Therapies Field (March 2010); MEDLINE (1966 to March 2010); AMED (1985 to March 2010); EMBASE (1980 to March 2010); CINAHL (1982 to March 2010); the Physiotherapy Evidence Database (PEDro) (March 2010); and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1). In an effort to identify other published, unpublished and ongoing trials we planned to handsearch journals, searched ongoing trials registers, reviewed reference lists, and contacted relevant professional organizations. SELECTION CRITERIA: Randomized controlled trials (RCTs) involving adults aged 18 years or over and including descriptions of specific hands-on interventions and techniques, rather than packages or approaches to treatment. DATA COLLECTION AND ANALYSIS: Following completion of the searches, two review authors independently assessed the trials and extracted data using a data extraction pro forma. The same two review authors independently recorded and documented the methodological quality of the trials. MAIN RESULTS: Three studies, involving a total of 86 participants, met all the selection criteria and were included in the review. However, extreme levels of heterogeneity were evident. Therefore, we could not undertake a meta-analysis of the results and completed a narrative synthesis instead. AUTHORS' CONCLUSIONS: Overall, the review demonstrated that the limited evidence of benefit of stretching, passive exercises and mobilization, when applied to the hemiplegic upper limb following stroke, merits further research. PMID- 21678360 TI - Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. AB - BACKGROUND: Compared to patients without cancer, patients with cancer who receive anticoagulant treatment for venous thromboembolism are more likely to develop recurrent venous thromboembolism (VTE). OBJECTIVES: To compare the efficacy and safety of three types of parenteral anticoagulants for the initial treatment of VTE in patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science. SELECTION CRITERIA: Randomized clinical trials (RCTs) comparing low molecular weight heparin (LMWH), unfractionated heparin (UFH), and fondaparinux in patients with cancer and objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form, data was extracted in duplicate on methodological quality, participants, interventions, and outcomes of interest that included mortality, recurrent VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. MAIN RESULTS: Of 3986 identified citations, 16 RCTs were eligible: 13 compared LMWH to UFH, two compared fondaparinux to heparin, and one compared dalteparin to tinzaparin. Meta analysis of 11 studies showed a statistically significant reduction in mortality at three months of follow up with LMWH compared with UFH (relative risk (RR) 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the effect estimate after excluding studies of lower methodological quality (RR 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH showed no statistically significant reduction in VTE recurrence (RR 0.78; 95% CI 0.29 to 2.08). The overall quality of evidence was low for LMWH versus UFH due to imprecision and likely publication bias. There were no statistically significant differences between heparin and fondaparinux for the outcomes of death (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63) or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59). The one study comparing dalteparin to tinzaparin did not find a statistically significant difference in mortality (RR 0.86; 95% CI 0.43 to 1.73). AUTHORS' CONCLUSIONS: LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer. Additional trials focusing on patient important outcomes will further inform the questions addressed in this review. PMID- 21678361 TI - Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. AB - BACKGROUND: Cancer increases the risk of thromboembolic events even while on anticoagulation. OBJECTIVES: To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including a February 2010 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI Web of Science. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively-confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach. MAIN RESULTS: Of 8187 identified citations, nine RCTs were eligible and reported data for 1908 patients with cancer. Meta-analysis of seven RCTs showed that LMWH, compared to VKA provided no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). Other results did not exclude a beneficial or harmful effect of LMWH compared to VKA for the outcomes of major bleeding (RR 1.05; 95% CI 0.53 to 2.10) or thrombocytopenia (RR 1.02; 95% CI 0.60 to 1.74). The quality of evidence was low for mortality, major bleeding and minor bleeding and moderate for recurrent VTE. One RCT comparing six months extension of anticoagulation with 18 months ximelagatran 24 mg twice daily versus placebo found a reduction in VTE (HR 0.16; 95% CI 0.09 to 0.30) but did not exclude beneficial or harmful effects for the outcomes of mortality and bleeding. One RCT, comparing dabigatran to VKA, did not exclude beneficial or harmful effect of one agent over the other. AUTHORS' CONCLUSIONS: For the long-term treatment of VTE in patients with cancer, LMWH compared to VKA reduces venous thromboembolic events but not death. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and downsides and integrate the patient's values and preferences for the important outcomes and alternative management strategies. PMID- 21678362 TI - Statins for acute coronary syndrome. AB - BACKGROUND: The early period following the onset of acute coronary syndromes (ACS) represents a critical stage of coronary heart disease with a high risk for recurrent events and deaths. The short-term effects of early treatment with statins in patients suffering from ACS on patient-relevant outcomes are unclear. OBJECTIVES: To assess the benefits and harms of early administered statins in patients with ACS from randomized controlled trials (RCTs). SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (to 1 February 2010). No language restrictions were applied. We supplemented the search by contacting experts in the field, by reviewing reference lists of reviews and editorials on the topic, and by searching trial registries. SELECTION CRITERIA: RCTs comparing statins with placebo or usual care, initiation of statin therapy within 14 days following the onset of ACS, and follow-up of at least 30 days reporting at least one clinical outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. We pooled treatment effects and calculated risk ratios (RRs) for all outcomes in the treatment and control groups using a random effects model. MAIN RESULTS: Eighteen studies (14,303 patients) compared early statin treatment versus placebo or usual care in patients with ACS. Compared to placebo or usual care, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction (MI), and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) and four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month and at four months, although there were favorable trends related to statin use for each of these endpoints. The incidence of episodes of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels > 10 times the upper limit of normal) in statin treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. AUTHORS' CONCLUSIONS: Based on available evidence, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS. PMID- 21678363 TI - Nitric oxide donors for cervical ripening and induction of labour. AB - BACKGROUND: Sometimes it is necessary to bring on labour artificially because of safety concerns for the mother or baby. This review is one of a series of reviews of methods of labour induction using a standardised protocol.Induction of labour occurs in approximately 20% of pregnancies in the UK. The ideal agent for induction of labour would induce cervical ripening without causing uterine contractions. Currently most commonly used cervical ripening or induction agents result in uterine activity or contractions, or both. Cervical ripening without uterine contractility could occur safely in an outpatient setting and it may be expected that this would result in greater maternal satisfaction and lower costs. OBJECTIVES: To determine the effects of nitric oxide (NO) donors for third trimester cervical ripening or induction of labour, in comparison with placebo or no treatment or other treatments from a predefined hierarchy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2010) and the reference lists of trial reports and reviews. SELECTION CRITERIA: Clinical trials comparing NO donors for cervical ripening or labour induction to other methods listed above it on a predefined list of methods of labour induction. The trials include some form of random allocation to either group; and report one or more of the prestated outcomes. NO donors (isosorbide mononitrate, nitroglycerin and sodium nitroprusside) are compared to other methods listed above it on a predefined list of methods of labour induction. DATA COLLECTION AND ANALYSIS: This review is part of a series of reviews focusing on methods of induction of labour. Three review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. MAIN RESULTS: We considered 19 trials; we included 10 (including a total of 1889 women) trials, excluded eight trials and one trial report is awaiting classification. Included studies compared NO donors to placebo, vaginal prostaglandin E2, intracervical PGE2 and vaginal misoprostol. All included studies were of a generally high standard with a low risk of bias.There are very limited data available to compare nitric oxide donors to any other induction agent. There is no evidence of any difference between any of the prespecified outcomes when comparing NO donors to other induction agents, with the exception of an increase in maternal side effects. AUTHORS' CONCLUSIONS: NO donors do not appear currently to be a useful tool in the process of induction of labour. More studies are required to examine how NO donors may work alongside established induction of labour protocols, especially those based in outpatient settings. PMID- 21678364 TI - Interventions for enhancing consumers' online health literacy. AB - BACKGROUND: Access to health information is critical to enable consumers to participate in decisions on health. Increasingly, such information is accessed via the internet, but a number of barriers prevent consumers making effective use of it. These barriers include inadequate skills to search, evaluate and use the information. It has not yet been demonstrated whether training consumers to use the internet for health information can result in positive health outcomes. OBJECTIVES: To assess the effects of interventions for enhancing consumers' online health literacy (skills to search, evaluate and use online health information). SEARCH STRATEGY: We searched: the Cochrane Consumers and Communication Review Group Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1 2008); MEDLINE (Ovid); EMBASE (Ovid); CINAHL (Dialog); ERIC (CSA Illumina); LISA (CSA Illumina); PsycINFO (Ovid); Index to scientific and technical proceedings; SIGLE; ASLIB Index to Theses; ProQuest Dissertation Abstracts; National Research Register/UK CRN Portfolio database; Current Controlled Trials - MetaRegister of Controlled Trials. We searched all databases for the period January 1990 to March 2008. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster RCTs and associated economic evaluations, quasi-RCTs, interrupted time series analyses, and controlled before and after (CBA) studies assessing interventions to enhance consumers' online health literacy, in any language. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, assessed their quality and extracted data. We contacted study authors for clarification and to seek missing data. We presented results as a narrative and tabular summary, and calculated mean differences where appropriate. MAIN RESULTS: We included two studies: one randomised controlled trial (RCT) and one controlled before and after (CBA) study with a combined total of 470 participants. The RCT compared internet health information classes with patient education classes for participants with HIV infection. Only the RCT, which we rated as having a moderate risk of bias, reported statistically significant positive effects for primary outcomes related to online health literacy in the intervention group, for the following outcomes: 'Self-efficacy for health information seeking', 'health information evaluation skills' and the 'number of times the patient discussed online information with a health provider'. The CBA, which we rated as having a high risk of bias, compared internet health information classes with a control group receiving no intervention among healthy adults aged 50+. It showed significant positive changes only in a secondary (behavioural) outcome in the intervention group, regarding the readiness to adopt the internet as a tool for preventive health information. No adverse effects were reported.There is low quality evidence that such interventions may improve some outcomes relevant to online health literacy in certain populations. AUTHORS' CONCLUSIONS: Due to the small number of studies and their variable methodological quality, the evidence is too weak to draw any conclusions about implications for the design and delivery of interventions for online health literacy. There is a need for well designed RCTs to investigate the effects of such interventions. These should involve different participants (in terms of disease status, age, socio-economic group and gender) to analyse the extent to which online health literacy reduces a barrier to using the internet for health information. Trials should be conducted in different settings and should examine interventions to enhance consumers' online health literacy (search, appraisal and use of online health information) like internet training courses, measuring outcomes up to at least one year after the intervention to estimate the sustainability of the intervention effects. PMID- 21678365 TI - Education programmes for people with diabetic kidney disease. AB - BACKGROUND: Adherence to complex regimens for patients with diabetic kidney disease (DKD) is often poor. Interventions to enhance adherence require intensive education and behavioural counselling. However, whether the existing evidence is scientifically rigorous and can support recommendations for routine use of educational programmes in DKD is still unknown. OBJECTIVES: To evaluate the benefits and harms of education programmes for people with DKD. SEARCH STRATEGY: In January 2010 we searched the Cochrane Renal Group's Specialised Register, CENTRAL, MEDLINE, EMBASE and four Chinese medicine databases (CBM-disc, Chinese Science and Technique Journals Database, China National Infrastructure and WanFang). SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi RCTs studying the benefits and harms of educational programmes for people with DKD. DATA COLLECTION AND ANALYSIS: Two authors independently searched the literature, determined study eligibility, assessed quality, extracted and entered data. We expressed dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI) and continuous data as mean difference (MD) or standardised mean differences (SMD). Data were pooled using the random effects model. MAIN RESULTS: Two studies (207 patients) were eligible. The methodological quality was not high. Compared with no educational programmes, educational programmes for patients with diabetes on dialysis improved patients' knowledge for the following outcomes: diagnosis (SMD 1.14, 95% CI 0.93 to 1.90); monitoring (SMD 1.51, 95% CI 1.0 to 2.01); hypoglycaemia (SMD 1.67, 95% CI 1.16 to 2.17), hyperglycaemia (SMD 0.80, 95% CI 0.35 to 1.25); medication with insulin (SMD 1.21, 95% CI 0.74 to 1.68); oral medication (SMD 0.98, 95% CI 0.52 to1.43); personal health habits (SMD 1.84, 95% CI 1.33 to 2.36); diet (SMD 0.53, 95% CI 0.09 to 0.97); exercise (SMD 1.13, 95% CI 0.67 to 1.60); chronic complications (SMD 1.28, 95% CI 0.80 to1.75) and living with diabetes and coping with stress (SMD 0.71, 95% CI 0.26 to 1.15). For patients with diabetes and microalbuminuria, educational programmes improved general knowledge for the following outcomes: diabetes (SMD 0.84, 95% CI 0.43 to 1.26); patients' total self-efficacy (MD 19.00, 95% CI 12.58 to 25.42) and patients' changes in beliefs on treatment effectiveness (MD 0.25, 95% CI 0.07 to 0.43) at the end of treatment, and general knowledge (MD 14.39, 95% CI 7.45 to 21.33); specific self-efficacy in home blood glucose monitoring (HBGM) (MD 11.28, 95% CI 1.92 to 20.64) and changes of beliefs on personal control (MD 0.31, 95% CI 0.01 to 0.61) at the end of three-months follow-up. For patients with diabetes on dialysis, educational programmes also showed improvement in the following self management behaviours: checking feet (RR 1.63, 95% CI 1.01 to 2.63); using lotion (RR 9.71, 95% CI 2.45 to 38.56) and wearing appropriate shoes and socks (RR 4.39, 95% CI 1.87 to 10.32). For patients with diabetes and microalbuminuria, educational programmes improved the following behaviours: general diet (MD 0.73, 95% CI 0.10 to 1.36), specific diet (MD 1.02, 95% CI 0.42 to1.62) and HBGM (MD 2.13, 95% CI 1.18 to 3.08) at the end of treatment; and specific diet (MD 0.62, 95% CI 0.18 to 1.06) and HBGM (MD 1.48, 95% CI 0.48 to 2.48) at the end of three months follow-up. No data were available on changes in kidney function, incidence of cardiovascular events, change of patients' attitude or adverse events. AUTHORS' CONCLUSIONS: Education programmes appear to have beneficial effects on improving patients' knowledge of diabetes and some self-management behavioural changes for patients with diabetes on dialysis or with microalbuminuria. Educational programmes appear to have beneficial effects on improving patients' self-efficacy and result in some beliefs changes for patients with diabetes and microalbuminuria. However, only two studies with small sample sizes and inadequate quality were included in this review. There is, therefore, inadequate evidence to support the beneficial effects of education programmes for people with DKD. PMID- 21678366 TI - Male circumcision for prevention of homosexual acquisition of HIV in men. AB - BACKGROUND: Previous systematic reviews found inconsistent effects of male circumcision on HIV acquisition in men who have sex with men (MSM). However, a number of new studies have become available in the three years since the last systematic review. OBJECTIVES: To assess the effects of male circumcision for preventing HIV acquisition by men through sex with men. SEARCH STRATEGY: In June 2010 we electronically searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, AIDS Education Global Information System, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform; hand searched reference lists of relevant articles; and contacted relevant organisations and experts. We updated the search in March 2011. SELECTION CRITERIA: We looked for randomised controlled trials (RCTs) and observational studies that assessed the effects of male circumcision on HIV acquisition in MSM. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility and methodological quality, and extracted data. We expressed study results as odds ratios (OR) with 95% confidence intervals (CI), and conducted random-effects meta-analysis. MAIN RESULTS: We found no completed RCT and included 21 observational studies with 71,693 participants. The only eligible RCT is currently ongoing among MSM in China. The pooled effect estimate for HIV acquisition was not statistically significant (20 studies; 65,784 participants; OR 0.86, 95% CI 0.70 to 1.06) and showed significant heterogeneity (I2=53%). In a subgroup analysis, the results were statistically significant in studies of men reporting an insertive role (7 studies, 3465 participants; OR 0.27, 95% CI 0.17 to 0.44; I2=0%) but not in studies of men reporting a receptive role (3 studies, 1792 participants; OR 1.20, 95% CI 0.63 to 2.29; I2 = 0%). There was no significant association between male circumcision and syphilis (8 studies; 34,999 participants: OR 0.96, 95% CI 0.82 to 1.13; I2 = 0%), herpes simplex virus 1 (2 studies, 2740 participants; OR 0.90, 95% CI 0.53 to 1.52; I2=0%), or herpes simplex virus 2 (5 studies;10,285 participants; OR 0.86, 95% CI 0.62 to 1.21; I2=0%). The overall GRADE quality of evidence was low. None of the included studies assessed adverse effects associated with male circumcision. AUTHORS' CONCLUSIONS: Current evidence suggests that male circumcision may be protective among MSM who practice primarily insertive anal sex, but the role of male circumcision overall in the prevention of HIV and other sexually transmitted infections among MSM remains to be determined. Therefore, there is not enough evidence to recommend male circumcision for HIV prevention among MSM at present. Further research should be of high quality and further explore interaction with the predominant sexual role. PMID- 21678367 TI - Computer assisted surgery for knee ligament reconstruction. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction is one of the most frequently performed orthopaedic procedures. The most common technical cause of reconstruction failure is graft malpositioning. Computer assisted surgery aims to aid graft placement. OBJECTIVES: To assess the effects of computer assisted reconstruction surgery versus conventional operating techniques for ACL or posterior cruciate ligament (PCL) deficient knees in adults. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3), MEDLINE (1966 to March 2010), EMBASE (1980 to March 2010), CINAHL (1937 to March 2010), article references and prospective trial registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised controlled trials that compared computer assisted surgery (CAS) of the ACL and PCL with conventional operating techniques not involving CAS, were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, assessed risk of bias and extracted data. Where appropriate, data were pooled using risk ratios or mean differences, both with 95% confidence intervals. MAIN RESULTS: Four randomised controlled trials were included (266 participants). All involved ACL reconstructions performed by experienced surgeons. Risk of bias assessment was hampered by poor reporting of trial methods. Pooled data from two trials showed no statistically or clinically significant differences at two years or more follow-up in self-reported quality of life outcomes: International Knee Documentation Committee (IKDC) subjective scores (mean difference 2.05, 95% CI 2.16 to 6.25) and Lysholm scores (mean difference 2.05, 95% CI -2.16 to 6.25). A third trial also found a minimal difference in IKDC subjective scores (mean difference = 0.2). Pooled data from three trials for normal or nearly normal IKDC knee examination grades at final follow-up showed no significant differences between the two groups (risk ratio 1.01, 95% CI 0.96 to 1.06). No significant differences were found for other objective measures of knee function. The only adverse effects reported were some loss in range of motion in two versus three participants in one trial. CAS use was associated with longer operating times (range 9.3 to 26 minutes). AUTHORS' CONCLUSIONS: A favourable effect of computer assisted surgery for cruciate ligament reconstructions of the knee compared with conventional reconstructions could neither be demonstrated nor refuted. There is insufficient evidence to advise for or against the use of CAS. There is a need for improved reporting of future studies of this technology. PMID- 21678368 TI - Interventions for supporting informal caregivers of patients in the terminal phase of a disease. AB - BACKGROUND: Patients in the terminal phase of a disease may have complex needs. It is often family and friends who play a central role in providing support, despite health professional input and regardless of whether the patient is at home or elsewhere. Such informal caring may involve considerable physical, psychological, and economic stresses. A range of supportive programmes for caregivers is being developed including psychological support and practical assistance. OBJECTIVES: To assess the effects of supportive interventions that aim to improve the psychological and physical health of informal caregivers of patients in the terminal phase of their illness. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2 2010); MEDLINE (1950 to May 2010); EMBASE (1980 to May 2010); PsycINFO (1872 to May 2010); CINAHL (1937 to May 2010); National Health Service Research Register (2000 to November 2008) and Dissertation Abstracts (1716 to May 2010). We searched the reference lists of relevant studies; contacted experts; and handsearched journals. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions to support adults who were caring for a friend or relative with a disease in the terminal phase. Interventions could include practical and emotional support and/or the facilitation of coping skills. Interventions could support caregivers indirectly via patient care. DATA COLLECTION AND ANALYSIS: Two authors independently screened citations against the selection criteria. Data were extracted by one author and checked by another. This included extraction of any adverse effects. Risk of bias assessment was undertaken by two authors. We contacted trial authors to obtain missing information. Trial data were combined, where appropriate, on the review's primary outcomes. MAIN RESULTS: We included eleven RCTs involving 1836 caregiver participants. Nine interventions were delivered directly to the caregiver. Seven of these provided support in the caring role, another involved a family life review, and one grief therapy. None provided practical support. The other two interventions aimed to support caregivers indirectly via patient care. Overall the risk of bias is unclear, as all trials under-reported methods.There is low quality evidence that interventions directly supporting the caregiver significantly reduce psychological distress in the short term (8 trials: standardised mean difference (SMD) -0.15; 95% confidence interval (CI) -0.28 to -0.02). There is also low quality evidence that these interventions in the short term may marginally improve coping skills and quality of life, but neither results were statistically significant (7 trials: SMD -0.05; 95% CI -0.24 to 0.14; 6 trials: SMD 0.08; 95% CI -0.11 to 0.26, respectively). One study assessed physical outcomes, specifically sleep improvement, and found no difference (median effect 0.00). No study measured health service use or adverse outcomes. In one study, however, a subgroup of intervention participants had higher levels of family conflict.Evidence was less clear on the indirect interventions. While both trials in this category found that supporting the patient may reduce psychological distress, none of the four assessments were statistically significant. There were no evaluations of coping with the caring role, quality of life, service use or adverse outcomes. In one trial there was no difference between trial arms in the proportion of caregivers reporting good physical health. AUTHORS' CONCLUSIONS: There is evidence that supportive interventions may help reduce caregivers' psychological distress. These findings suggest that practitioners should enquire about the concerns of caregivers and should consider that they may benefit from additional support. There is, however, a need for further research to explore the benefits identified, and to assess the interventions' effects on physical health, and potential harms. Trials need to report their methods fully. PMID- 21678369 TI - Chinese herbal medicine for diabetic peripheral neuropathy. AB - BACKGROUND: Chinese herbal medicine is frequently used for treating diabetic peripheral neuropathy in China. Many controlled trials have been undertaken to investigate its efficacy. OBJECTIVES: To assess the beneficial effects and harms of Chinese herbal medicine for people with diabetic peripheral neuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (15 June 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2010 in The Cochrane Library), MEDLINE (January 1966 to June 2010), EMBASE (January 1980 to June 2010), AMED (January 1985 to June 2010), Chinese Biomedical Database (CBM) (1979 to June 2010), Chinese National Knowledge Infrastructure Database (CNKI) (1979 to June 2010), and VIP Chinese Science and Technique Journals Database (1989 to June 2010). We searched for unpublished literature in the Chinese Conference Papers Database and Chinese Dissertation Database (from inception to March 2010). No language or publication restrictions were used. SELECTION CRITERIA: We included randomized controlled trials of Chinese herbal medicine (with a minimum of four weeks treatment duration) for people with diabetic peripheral neuropathy compared with placebo, no intervention, or conventional interventions. Trials of herbal medicine plus a conventional drug versus the drug alone were also included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and evaluated trial quality. We contacted study authors for additional information. The data analyses were carried out using Review Manager 5.1 (Cochrane software). MAIN RESULTS: Thirty nine randomized trials involving 2890 participants were included. All trials were conducted and published in China. Thirty different herbal medicines were tested in these trials, including four single herbs (extracts from a single herb), eight traditional Chinese patent medicines, and 18 self-concocted Chinese herbal compound prescriptions. The trials reported on global symptom improvement (including improvement in numbness or pain) and changes in nerve conduction velocity. There was inadequate reporting on adverse events in the included trials. Most of the trials did not mention whether they monitored adverse effects at all. Only two trials reported adverse events: one occurred in the control group in one trial and in which group was unclear in the other trial . Conclusions cannot be drawn from this review about the safety of herbal medicines due to inadequate reporting. Most of the trials were of low methodological quality and therefore the interpretation of any positive findings for the efficacy of the included Chinese herbal medicines for treating diabetic peripheral neuropathy should be made with caution. AUTHORS' CONCLUSIONS: Based on this systematic review, there is no evidence to support the objective effectiveness and safety of Chinese herbal medicines for diabetic peripheral neuropathy. No well designed, randomized placebo controlled trial with objective outcome measures has been conducted. PMID- 21678370 TI - Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults. AB - BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a childhood onset disorder that can persist into adulthood. Amphetamines are used to treat adult ADHD, but uncertainties persist about their efficacy and safety. OBJECTIVES: To examine the efficacy and safety of amphetamines for adults with ADHD, as well as the influence of dose, drug type and release formulation type. SEARCH STRATEGY: We searched CENTRAL, PubMed, EMBASE, CINAHL, PsycINFO, clinicaltrials.gov, UK Clinical Trials Gateway and references obtained from articles and experts in the field. We conducted the electronic searches on 25 February 2010. SELECTION CRITERIA: Randomized controlled trials comparing the efficacy of amphetamine derivatives against placebo or an active intervention. DATA COLLECTION AND ANALYSIS: Two authors extracted data from each included study. We used the standardized mean difference (SMD) and the risk ratio (RR) to assess continuous and dichotomous outcomes, respectively. We conducted a stratified analysis to determine the influence of moderating variables. We assessed the trials for risk of bias and drew a funnel plot to investigate the possibility of publication bias. MAIN RESULTS: We included seven studies, which enrolled 1091 participants. All studies were placebo-controlled and three included an active comparator: guanfacine, modafinil and paroxetine. Most studies had short-term follow-up, with a mean study length of 8.1 weeks. Amphetamines improved ADHD symptom severity (SMD = -0.72; 95% CI -0.87 to -0.57) but did not improve retention in treatment overall and were associated with increased dropout due to adverse events (RR 3.03; 95% CI 1.52 to 6.05). The three amphetamine derivatives investigated (dextroamphetamine, lisdexamphetamine and mixed amphetamine salts (MAS)) were all efficacious for reducing ADHD symptoms, but MAS also increased retention in treatment. Different doses did not appear associated with differences in efficacy. We investigated immediate and sustained drug release formulations but found no difference between them on any outcome. When amphetamines were compared to other drug interventions, no differences were found. We did not find any study to be at low risk of bias overall, mainly because amphetamines have powerful subjective effects that may reveal the assigned treatment. AUTHORS' CONCLUSIONS: Amphetamines improved short-term ADHD symptom severity. MAS also increased retention in treatment. Amphetamines were associated with higher attrition due to adverse events. The short study length and the restrictive inclusion criteria limit the external validity of these findings. Furthermore, the possibility that the results of the included studies were biased was high, which could have led to an overestimation of amphetamine efficacy. PMID- 21678371 TI - Collaboration between local health and local government agencies for health improvement. AB - BACKGROUND: In many countries, national, regional and local inter- and intra agency collaborations have been introduced in order to improve health outcomes. Evidence is needed on the effectiveness of locally-developed partnerships which target changes in individual health outcomes and behaviours. OBJECTIVES: To evaluate the effects of interagency collaboration between local health and local government agencies on health outcomes. SEARCH STRATEGY: Twenty-five databases were searched using a highly sensitive search strategy. 'Snowballing' methods were also used, including expert contact, website searching and reference list follow up. SELECTION CRITERIA: Randomized controlled trials (RCTs), controlled clinical trials (CCTs), controlled before-and-after studies (CBAs) and interrupted time series (ITS) where the study reported on interagency collaboration between health and local government agencies. Studies were selected independently in duplicate by two of five authors. DATA COLLECTION AND ANALYSIS: From the team of five review authors, two authors independently conducted data extraction and assessed risk of bias for each study. MAIN RESULTS: Eleven studies were identified, presenting information on a total of 26,686 participants. Owing to the heterogeneity between studies a narrative synthesis was undertaken. The included studies covered a range of topics. Six studies examined mental health initiatives, of which one study showed health benefit; four showed modest improvement in one or more of the outcomes measured, but no clear overall health gain; and one study showed no evidence of health gain. Two studies were related to lifestyle improvements of which one failed to show health gains for the intervention population, while the other showed more unhealthy lifestyle behaviours persisting in the intervention population. Three studies were related to chronic disease management and all three failed to demonstrate health gains. AUTHORS' CONCLUSIONS: Collaboration between local health and local government is commonly considered best practice. However, the review did not identify any reliable evidence that inter-agency collaboration, compared to standard services, leads to health improvement. A few studies identified component benefits but these were not reflected in overall outcome scores and could have resulted from the use of significant additional resources. Although agencies appear enthusiastic about collaboration, methodological flaws in the primary studies and incomplete implementation of initiatives have prevented the development of a strong evidence base. If these flaws are addressed in future studies (for example by providing greater detail on the implementation of programs, using more robust designs, with integrated process evaluations and measurement of health outcomes) it could provide a better understanding of what might work and why.When updating this review, we will analyse any partnership or process evaluations of our included studies to try to identify markers of success in local collaborative partnerships that could inform policy developments in the future. PMID- 21678372 TI - Secondary bone grafting for alveolar cleft in children with cleft lip or cleft lip and palate. AB - BACKGROUND: Secondary alveolar bone grafting has been widely used to reconstruct alveolar cleft. However, there is still some controversy. OBJECTIVES: To compare the effectiveness and safety of different secondary bone grafting methods. SEARCH STRATEGY: The final electronic and handsearches were carried out on 11 February 2011, and included the Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Chinese Biomedical Literature Database and WHO International Clinical Trials Registry Platform. All the Chinese professional journals in the oral and dental field were handsearched and conference proceedings consulted. There was no language or time restriction. SELECTION CRITERIA: Only randomized clinical trials were selected. Patients with the diagnosis of cleft lip and alveolar process only, unilateral cleft lip and palate and bilateral cleft lip and palate involving the alveolar process and greater than 5 years of age were included. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed the quality of included studies independently. Disagreement between the two review authors was resolved by discussion in the review team. The first authors of the included studies were contacted for additional information, if necessary. MAIN RESULTS: Two of 582 potential studies met the inclusion criteria and were included. One trial compared alveolar bone grafting using artificial materials (InFuse bone graft substitute impregnated with BMP-2) with a traditional iliac graft. The other trial investigated the application of fibrin glue to the bone graft. Both trials were small with 21 and 27 patients and were assessed as being at high risk of bias. Any apparent differences between the interventions for outcomes in either study must therefore be treated with great caution and are not highlighted here. AUTHORS' CONCLUSIONS: Due to the high level of risk of bias in the two included trials there is insufficient evidence to conclude that one intervention is superior to another. PMID- 21678373 TI - Early mobilisation for elbow fractures in adults. AB - BACKGROUND: A fall on the outstretched arm can result in an elbow fracture. Loss of elbow function is a common problem with these fractures and can have major implications for functional capabilities. It is unknown whether early mobilisation can improve functional outcome without increasing complications. OBJECTIVES: To compare the effects (benefits and harms) of early mobilisation versus delayed mobilisation of the elbow after elbow fractures in adults. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (August 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE (1950 to August 2010), EMBASE (1980 to August 2010), CINAHL (1982 to June 2010), PEDro (31 May 2010), and ongoing trials registers (April 2010). SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials evaluating early mobilisation of the elbow joint after elbow fracture in adults. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed risk of bias and extracted data. There was no pooling of data. MAIN RESULTS: We included one trial reporting outcome at follow-up times ranging between two and 47 months for 81 participants with Mason type 1 and 2 radial head fractures. This poorly-reported trial was at particular high risk of detection and reporting biases. The trial found no significant differences between early and delayed mobilisation in the numbers of participants with pain or limitations in their range of elbow motion. All participants were reported as being able to use their arms for full activities of daily living and none had changed their occupation or lifestyle. There was no mention of fracture complications. AUTHORS' CONCLUSIONS: There is a lack of robust evidence to inform on the timing of mobilisation, and specifically on the use of early mobilisation, after non-surgical or surgical treatment for adults with elbow fractures.There is a need for high quality, well-reported, adequately powered, randomised controlled trials that compare early versus delayed mobilisation in people with commonly-occurring elbow fractures, treated with or without surgery. Trials should use validated upper limb function scales, and assessment should be both short-term (to monitor recovery and early complications) and long-term (at least one year). PMID- 21678374 TI - Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2D) exhibit an increased risk of cardiovascular disease and mortality compared to the background population. Observational studies report a relationship between reduced blood glucose and reduced risk of both micro- and macrovascular complications in patients with T2D. OBJECTIVES: To assess the effects of targeting intensive versus conventional glycaemic control in T2D patients. SEARCH STRATEGY: Trials were obtained from searches of CENTRAL (The Cochrane Library), MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL (until December 2010). SELECTION CRITERIA: We included randomised clinical trials that prespecified different targets of glycaemic control in adults with T2D. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Dichotomous outcomes were assessed by risk ratios (RR) and 95% confidence intervals (CI). MAIN RESULTS: Twenty trials randomised 16,106 T2D participants to intensive control and 13,880 T2D participants to conventional glycaemic control. The mean age of the participants was 62.1 years. The duration of the intervention ranged from three days to 12.5 years. The number of participants in the included trials ranged from 20 to 11,140. There was no significant difference between targeting intensive and conventional glycaemic control for all-cause mortality (RR 1.01, 95% CI 0.90 to 1.13; 29,731 participants, 18 trials) or cardiovascular mortality (RR 1.06, 95% CI 0.90 to 1.26; 29,731 participants, 18 trials). Trial sequential analysis (TSA) showed that a 10% RR reduction could be refuted for all cause mortality. Targeting intensive glycaemic control did not show a significant effect on the risk of non-fatal myocardial infarction in the random-effects model but decreased the risk in the fixed-effect model (RR 0.86, 95% CI 0.78 to 0.96; P = 0.006; 29,174 participants, 12 trials). Targeting intensive glycaemic control reduced the risk of amputation (RR 0.64, 95% CI 0.43 to 0.95; P = 0.03; 6960 participants, 8 trials), the composite risk of microvascular disease (RR 0.89, 95% CI 0.83 to 0.95; P = 0.0006; 25,760 participants, 4 trials), retinopathy (RR 0.79, 95% CI 0.68 to 0.92; P = 0.002; 10,986 participants, 8 trials), retinal photocoagulation (RR 0.77, 95% CI 0.61 to 0.97; P = 0.03; 11,142 participants, 7 trials), and nephropathy (RR 0.78, 95% CI 0.61 to 0.99; P = 0.04; 27,929 participants, 9 trials). The risks of both mild and severe hypoglycaemia were increased with targeting intensive glycaemic control but substantial heterogeneity was present. The definition of severe hypoglycaemia varied among the included trials; severe hypoglycaemia was reported in 12 trials that included 28,127 participants. TSA showed that firm evidence was reached for a 30% RR increase in severe hypoglycaemic when targeting intensive glycaemic control. Subgroup analysis of trials exclusively dealing with glycaemic control in usual care settings showed a significant effect in favour of targeting intensive glycaemic control for non-fatal myocardial infarction. However, TSA showed more trials are needed before firm evidence is established. AUTHORS' CONCLUSIONS: The included trials did not show significant differences for all-cause mortality and cardiovascular mortality when targeting intensive glycaemic control compared with conventional glycaemic control. Targeting intensive glycaemic control reduced the risk of microvascular complications while increasing the risk of hypoglycaemia. Furthermore, intensive glycaemic control might reduce the risk of non-fatal myocardial infarction in trials exclusively dealing with glycaemic control in usual care settings. PMID- 21678375 TI - Adhesives for bonded molar tubes during fixed brace treatment. AB - BACKGROUND: Orthodontic treatment involves using fixed or removable appliances (dental braces) to correct the positions of teeth. The success of a fixed appliance depends partly on the metal attachments (brackets and bands) being glued to the teeth so that they do not become detached during treatment. Brackets (metal squares) are usually attached to teeth other than molars, where bands (metal rings that go round each tooth) are more commonly used. Orthodontic tubes (stainless steel tubes that allow wires to pass through them), are typically welded to bands but they may also be glued directly (bonded) to molars. Failure of brackets, bands and bonded molar tubes slows down the progress of treatment with a fixed appliance. It can also be costly in terms of clinical time, materials and time lost from education/work for the patient. OBJECTIVES: To evaluate the effectiveness of the adhesives used to attach bonded molar tubes, and the relative effectiveness of the adhesives used to attach bonded molar tubes versus adhesives used to attach bands, during fixed appliance treatment, in terms of: (1) how often the tubes (or bands) come off during treatment; and (2) whether they protect the bonded (or banded) teeth against decay. SEARCH STRATEGY: The following electronic databases were searched: the Cochrane Oral Health Group Trials Register (to 16 December 2010), the Cochrane Central Register of Controlled Clinical Trials (CENTRAL) (The Cochrane Library 2010, Issue 3), MEDLINE via OVID (1950 to 16 December 2010) and EMBASE via OVID (1980 to 16 December 2010). There were no restrictions regarding language or date of publication. SELECTION CRITERIA: Randomised controlled trials of participants with full arch fixed orthodontic appliance(s) with molar tubes, bonded to first or second permanent molars. Trials which compared any type of adhesive used to bond molar tubes (stainless steel or titanium) with any other adhesive, are included.Trials are also included where:(1) a tube is bonded to a molar tooth on one side of an arch and a band cemented to the same tooth type on the opposite side of the same arch; (2) molar tubes have been allocated to one tooth type in one patient group and molar bands to the same tooth type in another patient group. DATA COLLECTION AND ANALYSIS: The selection of papers, decision about eligibility and data extraction were carried out independently and in duplicate without blinding to the authors, adhesives used or results obtained. All disagreements were resolved by discussion. MAIN RESULTS: Two trials (n = 190), at low risk of bias, were included in the review and both presented data on first time failure at the tooth level. Pooling of the data showed a statistically significant difference in favour of molar bands, with a hazard ratio of 2.92 (95% confidence intervals (CI) 1.80 to 4.72). No statistically significant heterogeneity was shown between the two studies. Data on first time failure at the patient level were also available and showed statistically different difference in favour of molar bands (risk ratio 2.30; 95% CI 1.56 to 3.41) (risk of event for molar tubes = 57%; risk of event for molar bands 25%).One trial presented data on decalcification again showing a statistically significant difference in favour of molar bands. No other adverse events identified. AUTHORS' CONCLUSIONS: From the two well-designed and low risk of bias trials included in this review it was shown that the failure of molar tubes bonded with either a chemically-cured or light-cured adhesive was considerably higher than that of molar bands cemented with glass ionomer cement. One trial indicated that there was less decalcification with molar bands cemented with glass ionomer cement than with bonded molar tubes cemented with a light-cured adhesive. However, given there are limited data for this outcome, further evidence is required to draw more robust conclusions. PMID- 21678376 TI - Routine drainage for orthotopic liver transplantation. AB - BACKGROUND: Routine use of abdominal drainage in patients undergoing liver transplantation is controversial. OBJECTIVES: To assess the benefits and harms of routine abdominal drainage after orthotopic liver transplantation versus no drainage and to address different drain types. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and the MetaRegister of Controlled Trials until March 2011 to identify the randomised trials. SELECTION CRITERIA: We planned to include only randomised clinical trials (irrespective of language, blinding, or publication status) addressing this issue. DATA COLLECTION AND ANALYSIS: Two authors identified the trials for inclusion independently. Two authors planned to collect the data independently. We planned to analyse the data with both the fixed-effect and the random-effects model using RevMan Analysis. For each outcome we planned to calculate the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) based on intention-to-treat analysis whenever possible. MAIN RESULTS: We did not identify any randomised clinical trials addressing this issue. AUTHORS' CONCLUSIONS: There is currently no evidence to conclude whether routine abdominal drainage is useful or harmful in patients undergoing orthotopic liver transplantation. Evidence from non randomised studies of high risk of bias showed conflicting results on the impact of routine drainage in orthotopic liver transplantation on serious adverse events, showing that this question is an important clinical research question. Well-designed randomised clinical trials with adequate sample size to decrease systematic errors and to decrease random errors are necessary. PMID- 21678377 TI - Admission tests other than cardiotocography for fetal assessment during labour. AB - BACKGROUND: Evidence on the benefits of admission tests other than cardiotocography in preventing adverse perinatal outcomes has not been established. OBJECTIVES: To assess the effectiveness of admission tests other than cardiotocography in preventing adverse perinatal outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2011). SELECTION CRITERIA: Randomised (individual and cluster) controlled trials, comparing labour admission tests other than CTG for the prevention of adverse perinatal outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, quality and extracted data. MAIN RESULTS: We included one study involving 883 women.Comparison of sonographic assessment of amniotic fluid index (AFI) on admission versus no sonographic assessment of AFI on admission. The incidence of cesarean section for fetal distress in the intervention group (29 of 447) was significantly higher than those of controls (14 of 436) (risk ratio (RR) 2.02; 95% confidence interval (CI) 1.08 to 3.77).The incidence of Apgar score less than seven at five minutes in the intervention group (10 of 447) was not significantly different from controls (seven of 436) (RR 1.39, 95% CI 0.54 to 3.63).The incidence of artificial oxytocin for augmentation of labour in the intervention group (213 of 447) was significantly higher than controls (132 of 436) (RR 1.57; 95% CI 1.32 to 1.87).The incidence of neonatal NICU admission in the intervention group (35 of 447) was not significantly different from the controls (33 of 436) (RR 1.03; 95% CI 0.66 to 1.63) AUTHORS' CONCLUSIONS: There is not enough evidence to support the use of admission tests other than cardiotocography for fetal assessment during labour. Appropriate randomised controlled trials with adequate sample size of admission tests other than cardiotocography for fetal assessment during labour are required. PMID- 21678378 TI - Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. AB - BACKGROUND: Alcohol abuse and dependence represents a very serious health problem worldwide with major social, interpersonal and legal interpolations. Pharmacological treatments presently used are of uncertain effectiveness and there is even more doubt on the comparative effects and value for money. OBJECTIVES: To summarize Cochrane reviews that assess the effectiveness and safety of pharmacological interventions in the treatment of alcohol withdrawal. METHODS: We searched the Cochrane Database of Systematic Reviews (30 November 2010). Two authors independently screened, extracted data, summarised key characteristics of the included reviews and assessed their quality using AMSTAR; the quality of the evidence was summarised according to the GRADE methodology. MAIN RESULTS: Five reviews, 114 studies, 7333 participants, satisfied criteria for inclusions. The outcomes considered were alcohol withdrawal seizures, adverse events and dropouts. Comparing the five treatments with placebo, benzodiazepines performed better for seizures, three studies, 324 participants, RR 0.16 (95% CI 0.04 to 0.69), moderate quality of evidence. Comparing each of the five treatments versus specific class of drugs, benzodiazepines performed better than antipsychotics for seizures, 4 studies, 633 participants, RR 0.24 (95% CI 0.07 to 0.88) high quality of the evidence. Comparing different benzodiazepines and anticonvulsants among themselves, 28 comparisons, results never reached statistical significance but chlordiazepoxide performed better. The quality of evidence was high for 3% of the results, moderate for 28%, low for 48% and very low for 20%. AUTHORS' CONCLUSIONS: Among the treatments considered, benzodiazepines showed a protective benefit against seizures, when compared to placebo and a potentially protective benefit for many outcomes when compared with antipsychotics. Nevertheless, no definite conclusions about the effectiveness and safety of benzodiazepines were possible, because of the heterogeneity of the trials both in interventions and in the assessment of outcomes. Data on potential harms are sparse and fragmented. Results do not provide sufficient evidence in favour of anticonvulsants for the treatment of AWS, but anticonvulsants seem to have limited side effects. There is also not enough evidence of effectiveness and safety of baclofen, because only one study consider this treatment and of GHB for which no strong differences were observed in the comparisons with placebo, benzodiazepines and anticonvulsants. PMID- 21678379 TI - Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic intravascular activation of coagulation, leading to deposition of fibrin in the bloodstream, that may occur in patients with acute and chronic leukemia. OBJECTIVES: To assess the clinical effectiveness and safety of any pharmacological intervention for treating DIC in acute or chronic leukemia. SEARCH STRATEGY: The search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 12), MEDLINE (1950 to 28 October 2010), EMBASE (1980 to 10 October 2010), LILACS (1982 to 19 August 2010) and African Index Medicus (1993 to 19 August 2010). There was no language restriction. We sought additional randomized controlled trials (RCTs) from the World Health Organization (WHO) Clinical Trials Registry Platform and by using the reference lists of primary studies found. SELECTION CRITERIA: RCTs assessing the effectiveness of interventions for treating disseminated intravascular coagulation (DIC) in patients with acute and chronic leukemia. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: Four RCTs (126 participants) met the inclusion criteria. These trials evaluated the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate. Included RCTs reported data on mortality and bleeding. The included RCTs were classified as: 1) including patients with or without leukemia, and 2) only including patients with leukemia. However, data were not reported for the leukemia subgroup. We were not able to pool results from studies due to the inconsistency in the measurement and reporting of mortality and bleeding data. The included studies were at high risk of bias. AUTHORS' CONCLUSIONS: We found four RCTs which reported mortality and bleeding data. It is not possible to determine whether human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are effective or harmful for patients presenting with DIC related to acute or chronic leukemia. The effects of these interventions need to be tested in sufficiently powered RCTs. Outcome measures should include in-hospital mortality from any cause, overall mortality, incidence of resolution of respiratory failure, renal failure, shock and safety. The definition of bleeding should be standardized in these patients. PMID- 21678380 TI - Metroplasty versus expectant management for women with recurrent miscarriage and a septate uterus. AB - BACKGROUND: The prevalence of recurrent miscarriage in women with a septate uterus has increased. Restoration of the morphology of the uterus can hypothetically increase live birth rate and subsequent pregnancies in women with a septate uterus and recurrent miscarriage. OBJECTIVES: To determine whether hysteroscopic metroplasty in women with a septate uterus and two or more preceding miscarriages improves pregnancy outcomes. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register (inception to August 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (inception to August 2010), MEDLINE (1950 to August 2010), EMBASE (1980 to August 2010). PSYCHINFO (1806 to August 2010). In addition we searched trial registers for ongoing and registered trials, conference abstracts and OpenSigle and sources of Grey literature. SELECTION CRITERIA: Only randomised controlled trials (RCTs) that assess the effect on reproductive outcome of hysteroscopic metroplasty in women with a history of two or more preceding miscarriages and a septate uterus were eligible for inclusion. DATA COLLECTION AND ANALYSIS: If there had been data to include, two authors would have independently assessed trial quality and extracted data. They would have also contacted study authors for additional information. We collected adverse effects information from the trials. MAIN RESULTS: No randomised controlled trials were identified for inclusion. AUTHORS' CONCLUSIONS: Hysteroscopic metroplasty in women with recurrent miscarriage and a septate uterus is being performed in many countries to improve reproductive outcomes in women.This treatment has been assessed in non-controlled studies, which suggested a positive effect on pregnancy outcomes. However, these studies are biased due to the fact that the participants with recurrent miscarriage treated by hysteroscopic metroplasty served as their own controls. Until now, the effectiveness and possible complications of hysteroscopic metroplasty have never been considered in a randomised controlled trial.Taking this into account there is insufficient evidence to support this treatment in these women. A randomised controlled trial is urgently needed and currently underway (www.studies-obsgyn.nl/trust NTR 1676). PMID- 21678381 TI - Short courses of antibiotics for children and adults with bronchiectasis. AB - BACKGROUND: Bronchiectasis is an important cause of respiratory morbidity in both developing and developed countries. Antibiotics are considered standard therapy in the treatment of this condition but it is unknown whether short courses (four weeks or less) are efficacious. OBJECTIVES: To determine whether short courses of antibiotics (i.e. less than or equal to four weeks) for treatment of acute and stable state bronchiectasis, in adults and children, are efficacious when compared to placebo or usual care. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, OLDMEDLINE, CINAHL, AMED and PsycINFO and handsearching of respiratory journals and meeting abstracts were performed by the Cochrane Airways Group up to February 2011. SELECTION CRITERIA: Only randomised controlled trials were considered. Adults and children with bronchiectasis (defined clinically or radiologically) were included. Patients with cystic fibrosis were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the titles, abstracts and citations to assess eligibility for inclusion. Only one study fulfilled the inclusion criteria and thus meta-analysis could not be performed. MAIN RESULTS: The single eligible study showed a small benefit, when compared to placebo, of four weeks of inhaled antibiotic therapy in adults with bronchiectasis and pseudomonas in their sputum. There were no studies in children and no studies on oral or intravenous antibiotics. AUTHORS' CONCLUSIONS: There is insufficient evidence in the current literature to make reasonable conclusions about the efficacy of short course antibiotics in the management of adults and children with bronchiectasis. Until further evidence is available, adherence to current treatment guidelines is recommended. PMID- 21678382 TI - Integrating prevention of mother-to-child HIV transmission (PMTCT) programmes with other health services for preventing HIV infection and improving HIV outcomes in developing countries. AB - BACKGROUND: Every year nearly 400,000 children are infected with HIV through mother-to-child transmission (MTCT), which is responsible for more than 90% of HIV infections in children. In high-income countries, the MTCT rate is less than 1% through perinatal prevention of mother-to-child HIV transmission (PMTCT) interventions. In low- and middle-income countries, PMTCT programme coverage remains low and consequently transmission rate high. The World Health Organisation recommends integration of PMTCT programmes with other healthcare services to increase access and improve uptake of these interventions. OBJECTIVES: To assess the effect of integration of perinatal PMTCT measures with other health care services on coverage and service uptake compared to stand-alone PMTCT programmes and healthcare services or partially integrated PMTCT interventions. SEARCH STRATEGY: We searched the following databases, for the time period of January 1990 to August 2010: MEDLINE, EMBASE, the WHO Global Health Library, CAB abstracts, CINAHL, POPLINE, PsycINFO, Sociological Abstracts, ERIC, AEGIS, Google Scholar, New York Academy of Medicine Grey Literature, Open SIGLE, British Library Catalogue, ProQuest Dissertation & Theses Database and U.S. National Library of Medicine Gateway system. We also searched the Cochrane Database of Systematic Reviews (the Cochrane Library 2010, Issue 7), the Cochrane Central Register of Controlled Trials (the Cochrane Library 2010, Issue 7), Database of Abstracts of Reviews on Effects (the Cochrane Library 2010, Issue 7). We also searched for ongoing trials in the WHO International Clinical Trials Registry and Controlled clinical trials (January 1990 to July 2010). We performed ISI Web of Knowledge Cited Reference Search and scanned the reference lists of the included articles for additional relevant studies. We contacted authors to locate additional eligible studies. To maximise sensitivity we did not employ any methodological filters. SELECTION CRITERIA: Randomised controlled trials (RCT), cluster-randomised controlled trials (cluster RCT), controlled clinical trials (CCT), controlled before and after (CBA) studies and interrupted time series (ITS) studies comparing integrated PMTCT interventions to non-integrated or partially integrated care for pregnant women, mothers and their infants in low- and middle-income countries. DATA COLLECTION AND ANALYSIS: Two review authors independently ran the searches, selected studies, assessed methodological quality, and extracted data. The third review author resolved any disagreements. MAIN RESULTS: Only one study met the inclusion criteria. A cluster-randomised trial (12 clusters, n=7664), compared mother-infant nevirapine coverage at labour ward between intervention clinics implementing rapid HIV testing with structured nevirapine assessment and control clinics implementing informal assessment of nevirapine adherence. The authors measured nevirapine coverage in all clinics at baseline and after the implementation of the intervention. An increase of 10% (range of difference in coverage from -10% to +33%) was observed in the intervention sites compared to 10% decline in mother-infant coverage in the control sites (range of difference in coverage from -13% to 0%). The study showed that the probability of nevirapine coverage of mothers and their infants in the intervention arm compared to control arm increased from 0.89 at baseline to 1.22 during the intervention period, representing a multiplicative effect of 1.37 upon the ratio of relative risks at baseline (RR 1.37, bootstrapped 95% CI, 1.041.77). The study had a low risk of bias. No studies were found that evaluated the effectiveness of integrating other perinatal PMTCT interventions with healthcare services. AUTHORS' CONCLUSIONS: We found only one study suggesting that integrating perinatal PMTCT interventions with other healthcare services in low- and middle-income countries increases the proportion of pregnant women, mothers and infants receiving PMTCT intervention. The weak evidence base does not enable making any inferences for other countries or contexts. The study that met the inclusion criteria assessed only the impact of integrating PMTCT intervention in labour ward on the proportion of mothers and their infants receiving nevirapine. The study showed significant improvement in intervention coverage but it only addressed the labour ward aspect of PMTCT programme. We did not find sufficient evidence to make definitive conclusions about the effectiveness of integration of these interventions with other health services rather than providing them as stand-alone services. Further research is urgently needed to assess the effect of integrating perinatal prevention of mother-to-child HIV transmission interventions with other health services on intervention coverage, service uptake, quality of care and health outcomes and the optimal integration modality. PMID- 21678383 TI - Nutritional advice for improving outcomes in multiple pregnancies. AB - BACKGROUND: Multiple pregnancies are associated with higher rates of perinatal mortality and morbidity than singleton pregnancies, mainly due to an increased risk of preterm birth. Because fetal outcome is best at a particular range of maternal weight gain, it has been suggested that women with multiple pregnancies should take special diets (particularly high-calorie diets) designed to boost weight gain. However, 'optimal weight gain' in the mother in retrospective studies may merely reflect good growth of her babies and delivery at or near term (both associated with good outcome) and artificially boosting weight gain by nutritional input may confer no advantage. Indeed, a high-calorie diet may be unpleasant to consume, and could lead to long-term problems of being overweight. It is therefore important to establish if specialised diets are actually of benefit to women with multiple pregnancies and their babies. OBJECTIVES: To assess the effects of specialised diets or nutritional advice for women with multiple pregnancies (two or more fetuses). SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2011). SELECTION CRITERIA: Randomised controlled trials, 'quasi-random' studies, and cluster-randomised trials of women with multiple pregnancies (two or more fetuses) either nulliparous or multiparous and their babies. Crossover trials and studies reported only as abstracts were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: We identified no trials for inclusion in this review. MAIN RESULTS: A comprehensive search of the Cochrane Pregnancy and Childbirth Group's Trials Register found no potentially eligible trial reports. AUTHORS' CONCLUSIONS: There is no robust evidence from randomised trials to indicate whether specialised diets or nutritional advice for women with multiple pregnancies do more good than harm. There is a clear need to undertake a randomised controlled trial. PMID- 21678389 TI - From environmental enrichment to Fragile X: the retirement of William Greenough introduction to a special issue. PMID- 21678390 TI - Understanding the social brain in autism. AB - Autism is an early onset neurodevelopmental disorder characterized by disruption of early social interaction. Although the social disability of autism remains the central defining feature of the condition, mechanisms that might account for this disability remain poorly understood. This paper briefly reviews some aspects of the social deficit in autism focusing on new approaches to characterizing social information processing problems, potential brain mechanisms, and theoretical models of the disorder. It will touch on aspects of specific social processes that appear to develop in unusual ways in autism including facial perception, joint attention, and social information processing. The importance of adopting more ecologically valid methods and for integrating the various approaches in deriving new models for social deficits in autism will be highlighted. Future research should build on the emerging synergy of different aspects of social neuroscience. PMID- 21678391 TI - Evidence that angiogenesis lags behind neuron and astrocyte growth in experience dependent plasticity. AB - Bill Greenough's work on the cell biology of information storage suggests that we cannot understand the mechanism of long-term memory without understanding the series of cellular transactions that drive coordinated structural changes in neurons, glia, and blood vessels. Here, we show that after 4 days of differential housing, neuropil of EC cortex has expanded significantly, but the vasculature has not, resulting in a dilution of the blood supply. Significant growth of neurons and astrocytes has been reported within this time period, suggesting expression of synaptic plasticity might involve temporally coordinated genomic responses by both neurons and glia. Given that astrocytes appear to couple neuronal and vascular growth during development, we hypothesize that they may also mediate the onset of angiogenesis in response to neural demand in the EC brain. Further, these results may imply that a neuron's capacity for plasticity could be constrained by the rate of vascular expansion. PMID- 21678392 TI - Synapses on demand require dendrites at the ready: how defining stages of dendritic development in vitro could inform studies of behaviorally driven information storage in the brain. AB - Bill Greenough's work provides a framework for thinking about synaptogenesis not only as a key step in the initial wiring of neural systems according to a species typical plan (i.e., experience-expectant development), but also as a mechanism for storing information based an individual's unique experience over its lifetime (i.e., experience-dependent plasticity). Analysis of synaptic development in vitro brings a new opportunity to test the limits of expectant-expectant development at the level of the individual neuron. We analyzed dendritic growth, synapse formation, and the development of specialized cytoplasmic microdomains during development in cultured hippocampal neurons, to determine if the timing of each of these events is correlated. Taken together, the findings reported here support the hypotheses that (1) dendritic development is rate limiting in synapse formation and (2) synaptic circuits are assembled in a step-wise fashion consistent with a stage-specific shift from genomically pre-programmed to activity-dependent mechanisms. PMID- 21678393 TI - Plasticity of gray matter volume: the cellular and synaptic plasticity that underlies volumetric change. AB - Fifty years ago, Mark Rosenzweig and coworkers described environmental effects on brain chemistry and gross brain weight. William Greenough then used stereological tools, electron microscopy, and the Golgi stain to demonstrate that enrichment led to dendritic growth and synapse addition. Together these forms of plasticity accounted for cortical expansion and a reduction in cell density. In parallel with other investigators, Greenough demonstrated that these effects were not limited to the rodent, the cortex, or development, but instead generalize to many species, brain regions, and life stages. Studies of the anatomical effects of enrichment foreshadowed the recent empirical evidence for cortical volumetric increases after environmental experience and training in humans. Since research in humans is limited to regional effects, the analysis of the cellular and synaptic effects of enrichment, and their contribution to volumetric increases can inform us of the potential cellular and subcellular plasticity the leads to volume change in humans. PMID- 21678394 TI - Reflections of experience-expectant development in repair of the adult damaged brain. AB - Behavioral experience has long been known to influence functional outcome after brain injury, but only recently has its pervasive role in the reorganization of the adult brain after damage become appreciated. We briefly review findings from animal models on the role of experience in shaping neuronal events after stroke like injury. Experience-dependent neural plasticity can be enhanced or impaired by brain damage, depending upon injury parameters and timing. The neuronal growth response to some experiences is heightened due to interactions with denervation induced plasticity. This includes compensatory behavioral strategies developed in response to functional impairments. Early behavioral experiences can constrain later experience-dependent plasticity, leading to suboptimal functional outcome. Time dependencies and facets of neural growth patterns are reminiscent of experience-expectant processes that shape brain development. As with sensitive periods in brain development, this process may establish behavioral patterns early after brain injury which are relatively resistant to later change. PMID- 21678395 TI - Descartins, the memory molecules. AB - Investigation of protein translation at the synapse, using functioning synaptic particles termed synaptoneurosomes, has led to identification of Fragile X protein as a key synaptic component. In its absence, some key mRNAs are translated more diffusely in the cell, and more slowly. Recent studies have implicated ERK (extracellular receptor regulated kinase) as a central factor in regulating the kinetics of translation at the synapse. PMID- 21678396 TI - The role of glutamate in my professional life: from molecular neuroplasticity to the relief of suffering. AB - This invited address is offered in celebration of the career of Dr. William T. Greenough, especially the mentorship aspect of this illustrious career. It details how glutamate has been a thread throughout my professional career, including in my training with Bill. Our investigations of the role of metabotropic glutamate receptors in synaptic plasticity, specifically in relation to the fragile-X mental retardation protein, are described. I then discuss how glutamate has played a role in my current professional life as a psychiatrist working in palliative care. Finally, I end with some words about how the training I received from Bill has had, and continues to have, an impact on my professional development. PMID- 21678397 TI - Physiological and anatomical studies of associative learning: Convergence with learning studies of W.T. Greenough. AB - The quest to understand how the brain is able to store information for later retrieval has been pursued by many scientists through the years. Although many have made very significant contributions to the field and our current understanding of the process, few have played as pivotal a role in advancing our understanding as William T. Greenough. The current report will utilize associative learning, a training paradigm that has greatly assisted in our understanding of memory consolidation, to demonstrate how findings emerging from the Greenough laboratory helped to not only shape our current understanding of learning induced anatomical plasticity, but to also launch future analyses into the molecular players involved in this process, especially the Fragile X Mental Retardation Protein. PMID- 21678398 TI - Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study. AB - New data regarding a positive association between smoking and risk of epithelial ovarian cancer (EOC), especially the mucinous tumor type, has started to emerge. The purpose of this study was to examine the association between different measures of smoking exposures and subtypes of EOC in a large cohort of women from 10 European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort is a multicenter prospective study initiated in 1992. The questionnaires included data about dietary, lifestyle, and health factors. Information about cigarette smoking was collected from individuals in all participating countries. We used Cox proportional hazard regression models to estimate hazard ratio (HR) of EOC overall and serous, mucinous, and endometroid histological subtypes, with 95% confidence intervals (CIs) associated with different measures of smoking exposures adjusting for confounding variables. Altogether 836 incident EOC cases were identified among 326,831 women. The tumors were classified as 400 serous, 83 mucinous, 80 endometroid, 35 clear cell, and 238 unspecified. Compared with never smokers, current smokers had a significantly increased risk for mucinous tumors [HR = 1.85 (95% CI 1.08-3.16)] and those smoking more than 10 cigarettes per day had a doubling in risk [HR = 2.25(95% CI 1.26-4.03)] as did those who had smoked less than 15 pack-years of cigarettes [HR = 2.18 (95% CI 1.07-4.43)]. The results from the EPIC study add further evidence that smoking increases risk of mucinous ovarian cancer and support the notion that the effect of smoking varies according to histological subtype. PMID- 21678399 TI - Hair dye use and risk of bladder cancer in the New England bladder cancer study. AB - Aromatic amine components in hair dyes and polymorphisms in genes that encode enzymes responsible for hair dye metabolism may be related to bladder cancer risk. We evaluated the association between hair dye use and bladder cancer risk and effect modification by N-acetyltransferase-1 (NAT1), NAT2, glutathione S transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) genotypes in a population-based case-control study of 1193 incident cases and 1418 controls from Maine, Vermont and New Hampshire enrolled between 2001 and 2004. Individuals were interviewed in person using a computer-assisted personal interview to assess hair dye use and information on potential confounders and effect modifiers. No overall association between age at first use, year of first use, type of product, color, duration or number of applications of hair dyes and bladder cancer among women or men was apparent, but increased risks were observed in certain subgroups. Women who used permanent dyes and had a college degree, a marker of socioeconomic status, had an increased risk of bladder cancer [odds ratio (OR) = 3.3, 95% confidence interval (CI): 1.2-8.9]. Among these women, we found an increased risk of bladder cancer among exclusive users of permanent hair dyes who had NAT2 slow acetylation phenotype (OR = 7.3, 95% CI: 1.6-32.6) compared to never users of dye with NAT2 rapid/intermediate acetylation phenotype. Although we found no relation between hair dye use and bladder cancer risk in women overall, we detected evidence of associations and gene-environment interaction with permanent hair dye use; however, this was limited to educated women. These results need confirmation with larger numbers, requiring pooling data from multiple studies. PMID- 21678400 TI - Resveratrol-induced apoptosis is enhanced in low pH environments associated with cancer. AB - Many critical factors such as hypoxia, nutrient deficiency, activation of glycolytic pathway/Warburg effect contribute to the observed low pH in tumors compared to normal tissue. Studies suggest that such tumor specific acidic environment can be exploited for the development of therapeutic strategies against cancer. Independent observations show reduction in pH of mammalian cells undergoing internucleosomal DNA fragmentation and apoptosis. As such, our group has extensively demonstrated that anticancer mechanisms of different plant polyphenols involve mobilization of endogenous copper and consequent internucleosomal DNA breakage. Copper is redox active metal, an essential component of chromatin and is sensitive to subtle pH changes in its microenvironment. Here we explored whether, acidic pH promotes growth inhibition, apoptosis, and DNA damaging capacity of chemopreventive agent resveratrol. Our results reveal that growth inhibition and internucleosomal DNA fragmentation induced apoptosis in Capan-2 and Panc-28 pancreatic cancer cell lines (and not in normal HPDE cells) by resveratrol is enhanced at lower pH. Using comet assay, we further demonstrate that DNA breakage by resveratrol is enhanced with acidification. Membrane permeable copper specific chelator neocuproine (and not iron chelator orthophenanthroline) abrogated growth inhibition and apoptosis by resveratrol. Western blot results show enhanced activation of DNA laddering marker H2.aX by resveratrol at acidic pH that was reversed by neocuproine and not by orthophenanthroline. Our findings provide irrevocable proof that low pH environment can be turned into tumor weakness and assist in eradication of cancer cells by resveratrol. PMID- 21678401 TI - Role of SF-1 and DAX-1 during differentiation of P19 cells by retinoic acid. AB - Retinoic acid (RA) is critical for embryonic development and cellular differentiation. Previous work in our laboratory has shown that blocking the RA dependent increase in pre-beta cell leukemia transcription factors (PBX) mRNA and protein levels in P19 cells prevents endodermal and neuronal differentiation. Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1) and steroidogenic factor (SF-1) were found by microarray analysis to be regulated by PBX in P19 cells. To determine the roles of DAX-1 and SF-1 during RA-dependent differentiation, P19 cells that inducibly express either FLAG-DAX-1 or FLAG-SF-1 were prepared. Unexpectedly, overexpression of DAX-1 had no effect on the RA-induced differentiation of P19 cells to either endodermal or neuronal cells. However, SF-1 overexpression prevented the RA-dependent loss of OCT-4, DAX-1 and the increase in COUP-TFI, COUP-TFII, and ETS-1 mRNA levels during the commitment stages of both endodermal and neuronal differentiation. Surprisingly, continued expression of SF-1 for 7 days caused the RA-independent loss of OCT-4 protein and RA-dependent loss of SSEA-1 expression. Despite the loss of well-characterized pluripotency markers, these cells did not terminally differentiate into either endodermal or neuronal cells. Instead, the cells gained the expression of many steroidogenic enzymes with a pattern consistent with adrenal cells. Finally, we found evidence for a feedback loop in which PBX reduces SF-1 mRNA levels while continued SF-1 expression blocks the RA-dependent increase in PBX levels. Taken together, these data demonstrate that SF-1 plays a dynamic role during the differentiation of P19 cells and potentially during early embryogenesis. PMID- 21678402 TI - Lactoferricin mediates anabolic and anti-catabolic effects in the intervertebral disc. AB - Lactoferricin (LfcinB) antagonizes biological effects mediated by angiogenic and catabolic growth factors, in addition to pro-inflammatory cytokines and chemokines in human endothelial cells and tumor cells. However, the effect of LfcinB on intervertebral disc (IVD) cell metabolism has not yet been investigated. Using bovine nucleus pulposus (NP) cells, we analyzed the effect of LfcinB on proteoglycan (PG) accumulation, PG synthesis, and anabolic gene expression. We assessed expression of genes for matrix-degrading enzymes such as matrix metalloproteases (MMPs) and a disintegrin-like and metalloprotease with thrombospondin motifs (ADAMTS family), as well as their endogenous inhibitors, tissue inhibitor of metalloproteases (TIMPs). In order to understand the specific molecular mechanisms by which LfcinB exerts its biological effects, we investigated intracellular signaling pathways in NP cells. LfcinB increased PG accumulation mainly via PG synthesis in a dose-dependent manner. Simultaneously, LfcinB dose-dependently downregulated catabolic enzymes. LfcinB's anti-catabolic effects were further demonstrated by a dose-dependent increase in multiple TIMP family members. Our results demonstrate that ERK and/or p38 mitogen-activated protein kinase pathways are the key signaling cascades that exert the biological effects of LfcinB in NP cells, regulating transcription of aggrecan, SOX-9, TIMP 1, TIMP-2, TIMP-3, and iNOS. Our results suggest that LfcinB has anabolic and potent anti-catabolic biological effects on bovine IVD cells that may have considerable promise in the treatment of disc degeneration in the future. PMID- 21678403 TI - Hsp22 (HspB8/H11) knockdown induces Sam68 expression and stimulates proliferation of glioblastoma cells. AB - Sam68 (Src-associated protein in mitosis 68 kDa) is a multifunctional protein, known to govern cellular signal transduction, transcription, RNA metabolism, proliferation, apoptosis, and HIV-1 replication. Although intrinsic mechanisms that modulate Sam68 function are beginning to emerge, the regulatory events contributing to its expression remain elusive. We previously reported that heat shock protein-22 (Hsp22) antagonizes Sam68 function in rev-response element (RRE) mediated gene expression. We now demonstrate that Sam68 levels correlate inversely with Hsp22 in a variety of cells, including U87, Jurkat, 293T, and U 937. In U87 glioblastoma cells, which contained high levels of Hsp22 than other cell lines tested, Hsp22 knockdown dramatically increased both Sam68 mRNA and protein, altered cellular morphology, and enhanced cell proliferation. This heightened proliferation was associated with a sharp decrease in G(0) /G(1) and a corresponding increase in S and G(2) /M phases in exponentially growing cultures. The increased S phase population in turn correlated with enhanced expression of cell cycle regulatory proteins such as cyclin E, cyclin A, ribonucleotide reductase (RNR), and proliferating cell nuclear antigen (PCNA), which are required for the transition of cells from G(1) to S phase. Collectively, our results demonstrate for the first time that Hsp22 regulates Sam68 expression and the ratio of Sam68 to Hsp22 may determine the proliferative potential of glioblastoma cells. PMID- 21678404 TI - New role of the human equilibrative nucleoside transporter 1 (hENT1) in epithelial-to-mesenchymal transition in renal tubular cells. AB - Epithelial-to-mesenchymal transition (EMT) is an important pro-fibrotic event in which tubular epithelial cells are transformed into myofibroblasts. Nucleoside transporters (NT) are regulated by many factors and processes, some of which are involved in fibrosis, such as cytokines, inflammation, and proliferation. Equilibrative nucleoside transporter 1 (ENT1) has been proved to be the most widely expressed adenosine transporter. In that sense, ENT1 may be a key player in cell damage signaling. Here we analyze the role of human ENT1 (hENT1) in the EMT process in proximal tubular cells. Addition of the main inducer of EMT, the transforming growth factor-beta1, to HK-2 cells increased hENT1 mRNA and protein level expression. ENT1-mediated adenosine uptake was also enhanced. When cells were incubated with dipyridamole to evaluate the potential contribution of ENT1 to EMT by blocking its transport activity, EMT was induced. Moreover, the knock down of hENT1 with siRNA induced EMT and collagen production in HK-2 cells. Kidneys isolated from ENT1 knockout mice showed higher levels of interstitial collagen and alpha-SMA positive cells than wild-type mice. Our results point to a new potential role of hENT1 as a modulator of EMT in proximal tubular cells. In this sense, hENT1 could be involved in renal protection processes, and the loss or reduced expression of hENT1 would lead to an increased vulnerability of cells to the onset and/or progression of renal fibrosis. PMID- 21678405 TI - Two mutations impair the stability and function of ubiquitin-activating enzyme (E1). AB - Protein ubiquitination plays critical roles in the regulation of multiple cellular processes including cell proliferation, signal transduction, oncogenesis, and hypoxic response. TS20 is a Balb3T3-derived cell line in which ubiquitination is inhibited by restrictive temperature. While TS20 has been used to elucidate the degradation of many important proteins including p53, p27, HIF 1alpha, and ornithine decarboxylase, the molecular basis of its temperature sensitivity has not been fully determined. We cloned full-length E1 cDNA from TS20. Sequencing analysis revealed two point mutations (nt736G to A and nt2313G to C) that lead to substitution of aa189A to T and aa714W to C, respectively. Transient transfection assays revealed that mutant E1 was less stable than its wild-type counterpart, and restrictive temperature (39 degrees C) accelerated its degradation. Under permissive temperature, reverting aa714C to W significantly improved E1 stability and activity. Under restrictive temperature, reverting of both substitutions was required to fully restore E1 stability. Similar results were observed when the mutants were expressed in non-TS20 cells, indicating the mutations are sufficient for its temperature sensitive degradation observed in TS20 cells. Functionally, reverting aa714C to W was sufficient to facilitate the monoubiquitination of H2A and to support TS20 growth at 39 degrees C. It also significantly improved the ubiquitination-dependent disposal of HIF-1alpha. Our data conclusively demonstrate that mutations introgenic to UVBE1 cause E1 instability, which leads to deficiency of E1 function. Our data establish the molecular basis for unambiguous interpretation of experimental data based on TS20 cells, and provide new insight into the structural determinants of E1 stability. PMID- 21678406 TI - Reduction of ribosome biogenesis with activation of the mTOR pathway in denervated atrophic muscle. AB - Mammalian target of rapamycin (mTOR) pathway positively regulates the cell growth through ribosome biogenesis in many cell type. In general, myostatin is understood to repress skeletal muscle hypertrophy through inhibition of mTOR pathway and myogenesis. However, these relationships have not been clarified in skeletal muscle undergoing atrophy. Here, we observed a significant decrease of skeletal muscle mass at 2 weeks after denervation. Unexpectedly, however, mTOR pathway and the expression of genes related to myogenesis were markedly increased, and that of myostatin was decreased. However, de novo ribosomal RNA synthesis and the levels of ribosomal RNAs were dramatically decreased in denervated muscle. These results indicate that ribosome biogenesis is strongly controlled by factors other than the mTOR pathway in denervated atrophic muscle. Finally, we assessed rRNA transcription factors expression and observed that TAFIa was the only factor decreased. TAFIa might be a one of the limiting factor for rRNA synthesis in denervated muscle. PMID- 21678407 TI - Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2). AB - Certain environmental factors including drugs exacerbate or precipitate psoriasis. Lithium is the commonest cause of drug-induced psoriasis but underlying mechanisms are currently unknown. Lithium inhibits glycogen synthase kinase 3 (GSK-3). As lithium does not exacerbate other T-cell-mediated chronic inflammatory diseases, we investigated whether lithium may be acting directly on epidermal keratinocytes by inhibiting GSK-3. We report that lithium-induced keratinocyte proliferation at therapeutically relevant doses (1-2 mM) and increased the proportion of cells in S phase of the cell cycle. Inhibition of GSK 3 in keratinocytes by retroviral transduction of GSK-binding protein (an endogenous inhibitory protein) or through a highly selective pharmacological inhibitor also resulted in increased keratinocyte proliferation. Nuclear factor of activated T cells (NFAT) is an important substrate for GSK-3 and for cyclosporin, an effective treatment for psoriasis that inhibits NFAT activation in keratinocytes as well as in lymphocytes. Both lithium and genetic/pharmacological inhibition of GSK-3 resulted in increased nuclear localization of NFAT2 (NFATc1) and increased NFAT transcriptional activation. Finally, retroviral transduction of NFAT2 increased keratinocyte proliferation whereas siRNA-mediated knockdown of NFAT2 reduced keratinocyte proliferation and decreased epidermal thickness in an organotypic skin equivalent model. Taken together, these data identify GSK-3 and NFAT2 as key regulators of keratinocyte proliferation and as potential molecular targets relevant to lithium-provoked psoriasis. PMID- 21678408 TI - Human peripheral blood CD34-positive cells enhance therapeutic regeneration of chronically injured liver in nude rats. AB - We investigated whether transplantation of purified human peripheral blood CD34(+) cells could reduce established liver fibrosis and up-regulate therapeutic regeneration. Human peripheral blood CD34(+) cells were isolated from total mononuclear cells of healthy volunteers by magnetic cell sorting. Recipient nude rats were injected intraperitoneally with carbon tetrachloride (CCl(4)) twice weekly for 3 weeks before single administration of CD34(+) cells. CCl(4) was then re-administered twice weekly for 3 more weeks, and the nude rats were sacrificed. Saline (control group), 1 * 10(5) (low-dose group), 5 * 10(5) (middle-dose group), or 2 * 10(6) (high-dose group) CD34(+) cells/kg body weight were intrasplenically transplanted after CCl(4) treatment for 3 weeks. Reverse transcriptase-polymerase chain reaction analysis of the freshly isolated CD34(+) cells revealed the expression of CD31, keratin19, alpha-smooth muscle actin (alpha-SMA), and epithelial growth factor, but not other liver related markers. The transplanted cells differentiated into vascular and sinusoidal endothelial cells, and vascular smooth muscle cells. CD34(+) cell transplantation reduced liver fibrosis in a dose-dependent fashion, with decreased collagen type-I and alpha-SMA-positive cells after 6 weeks of CCl(4) treatment by Mallory's Azan and immunohistochemical staining. Gelatin zymography showed that the expression levels of active matrix metalloproteinase-2 and -9 in CD34(+) cell transplanted livers were significantly stronger than those in saline-infused livers. In recipients of high-doses of CD34(+) cells, the number of PCNA-positive hepatocyte increased 6 weeks after CCl(4) treatment compared with saline-infused livers. We conclude that human peripheral blood CD34(+) cell transplantation halts established liver fibrosis and promotes hepatic regeneration in CCl(4)-induced chronic liver injury. PMID- 21678409 TI - Interplay between membrane lipid peroxidation, transglutaminase activity, and cyclooxygenase 2 expression in the tissue adjoining to breast cancer. AB - Breast cancer, a leading cause of cancer related deaths worldwide, is one of the most common neoplasms in women. The increased generation of reactive oxygen species (ROS) in breast lesion is critically involved in the mutagenic processes that drive to breast carcinoma initiation and progression. To date, the molecular events occurring in the tissue adjoin the cancer lesion have not been elucidated. Here, we investigated the role of excess ROS generation during human breast carcinogenesis by evaluating oxidative stress biomarkers, tissue transglutaminase (t-TGase) activity, and expression levels of ubiquitin and cyclooxygenase-2 (COX 2) in the normal tissue adjoin to fibroadenoma (nFA), atypical ductal hyperplasia (nADH), and invasive ductal carcinoma (nIDC) from 45 breast cancer patients. We found that lipid peroxidation and nitric oxide production significantly increased in nIDC respect to nFA and nADH (P < 0.005) whereas the 4-hydroxy-2-nonenal (HNE) protein-adducts increased only in nADH (P < 0.005). The increased lipid damage observed in nIDC correlates with estrogen receptor exposure in IDC (R(2) = 0.89). Moreover, nIDC and invasive ductal carcinoma (IDC) showed a 10-fold higher t TGase activity compared to nFA and nADH. Contrary, COX-2 expression levels significantly decreased nIDC and IDC respect to the nFA and nADH (P < 0.001). The analysis of the free ubiquitin expression revealed equal levels in nADH and nIDC samples whereas high molecular weight-ubiquitin conjugate increased about fivefold only in nIDC (P < 0.01 vs. nADH). These novel findings reveal an interplay between membrane lipid peroxidation, t-TGase activity, and COX-2 expression levels in the tissue adjoining to neoplastic lesion during breast cancer progression. PMID- 21678410 TI - Inhibition of human methionine adenosyltransferase 1A transcription by coding region methylation. AB - Two genes (MAT1A and MAT2A) encode for the essential enzyme methionine adenosyltransferase (MAT). MAT1A is silenced in hepatocellular carcinoma (HCC), and absence of MAT1A leads to spontaneous development of HCC in mice. Previous report correlated promoter methylation to silencing of MAT1A but definitive proof was lacking. Here we investigated the role of methylation in regulating MAT1A expression. There are three MspI/HpaII sites from -1,913 to +160 of the human MAT1A gene (numbered relative to the translational start site) at position -977, +10, and +88. Bisulfite treatment and DNA sequencing, and Southern blot analysis showed that methylation at +10 and +88, but not -977, correlated with lack of MAT1A expression. MAT1A promoter construct methylated at -977, +10 or +88 position has 0.7-fold, 3-fold, and 1.6-fold lower promoter activity, respectively. Methylation at -977 and +10 did not inhibit the promoter more than methylation at +10 alone; while methylation at +10 and +88 reduced promoter activity by 60%. Mutation of +10 and +88 sites also resulted in 40% reduction of promoter activity. Reactivation of MAT1A correlated with demethylation of +10 and +88. In vitro transcription assay showed that methylation or mutation of +10 and +88 sites reduced transcription. In conclusion, our data support the novel finding that methylation of the MAT1A coding region can inhibit gene transcription. This represents a key mechanism for decreased MAT1A expression in HCC and a target for therapy. To our knowledge, this is the first example of coding region methylation inhibiting transcription of a mammalian gene. PMID- 21678411 TI - Essential role of maternal UCHL1 and UCHL3 in fertilization and preimplantation embryo development. AB - Post-translational protein modification by ubiquitination, a signal for lysosomal or proteasomal proteolysis, can be regulated and reversed by deubiquitinating enzymes (DUBs). This study examined the roles of UCHL1 and UCHL3, two members of ubiquitin C-terminal hydrolase (UCH) family of DUBs, in murine fertilization and preimplantation development. Before fertilization, these proteins were associated with the oocyte cortex (UCHL1) and meiotic spindle (UCHL3). Intracytoplasmic injection of the general UCH-family inhibitor ubiquitin-aldehyde (UBAL) or antibodies against UCHL3 into mature metaphase II oocytes blocked fertilization by reducing sperm penetration of the zona pellucida and incorporation into the ooplasm, suggesting a role for cortical UCHL1 in sperm incorporation. Both UBAL and antibodies against UCHL1 injected at the onset of oocyte maturation (germinal vesicle stage) reduced the fertilizing ability of oocytes. The subfertile Uchl1(gad-/-) mutant mice showed an intriguing pattern of switched UCH localization, with UCHL3 replacing UCHL1 in the oocyte cortex. While fertilization defects were not observed, the embryos from homozygous Uchl1(gad-/ ) mutant females failed to undergo morula compaction and did not form blastocysts in vivo, indicating a maternal effect related to UCHL1 deficiency. We conclude that the activity of oocyte UCHs contributes to fertilization and embryogenesis by regulating the physiology of the oocyte and blastomere cortex. PMID- 21678412 TI - Strong expression association between matriptase and its substrate prostasin in breast cancer. AB - Breast cancer tumorigenesis is accompanied by increased levels of extracellular proteases that are capable of remodeling the extracellular matrix as well as cleaving and activating growth factors and signaling receptors that are critically involved in neoplastic progression. Multiple studies implicate the membrane anchored serine protease matriptase (also known as MT-SP1 and epithin) in breast cancer. The pro-form of the GPI-anchored serine protease prostasin has recently been identified as a physiological substrate of matriptase and the two proteases are co-expressed in multiple healthy tissues. In this study, the inter relationship between the two membrane-anchored serine proteases in breast cancer was investigated using breast cancer cell lines and breast cancer patient samples to delineate the association between matriptase and prostasin. We used Western blotting to determine the expression of matriptase and prostasin proteins in a panel of breast cancer cell lines and immunohistochemistry to assess the expression in serial sections from breast cancer tissue arrays. We demonstrate that the expression of matriptase and prostasin is closely correlated in breast cancer cell lines as well as in breast cancer tissue samples. Furthermore, matriptase and prostasin display a near identical spatial expression pattern in the epithelial compartment of breast cancer tissue. These data suggest that the matriptase-prostasin cascade might play a critical role in breast cancer. PMID- 21678413 TI - Potential effect of resistin on the ET-1-increased reactions of blood pressure in rats and Ca2+ signaling in vascular smooth muscle cells. AB - Resistin and endothelin-1 (ET-1) are upregulated in people with type II diabetes mellitus, central obesity, and hypertension. ET-1 signaling is involved in Ca(2+) contraction coupling and related to blood pressure regulation. The aim of this study is to investigate the role of resistin on ET-1-increased blood pressure and Ca(2+) signaling. The blood pressure and cytosolic Ca(2+) of vascular smooth muscle cells (VSMCs) of Sprague-Dawley rats were detected. The data demonstrated that resistin accelerated and prolonged ET-1-induced increases in blood pressure and had significant effects on ET-1-increased Ca(2+) reactions. Resistin-enhanced ET-1-increased Ca(2+) reactions were reversed by blockers of store-operated Ca(2+) entry (SOCE) and extracellular-signal-regulated kinase (ERK). The endogenous expression of Orai and stromal interaction molecular (STIM) were characterized in the VSMCs. Furthermore, resistin-enhanced ET-1 Ca(2+) reactions and the resistin-dependent activation of SOCE were abolished under STIM1-siRNA treatment, indicating that STIM1 plays an important role in resistin-enhanced ET 1 Ca(2+) reactions in VSMCs. Resistin appears to exert effects on ET-1-induced Ca(2+) increases by enhancing the activity of ERK-dependent SOCE (STIM1 partcipated), and may accelerate and prolong ET-1-increased blood pressure via the same pathway. PMID- 21678414 TI - Absence of MCP-1 leads to elevated bone mass via impaired actin ring formation. AB - Monocyte chemoattractant protein-1 (MCP-1) is associated with various inflammatory diseases involving bone loss, and is expressed along with its receptor by bone marrow-derived macrophages (BMM), which are osteoclast (OC) precursors. To investigate the role of MCP-1 in bone remodeling, we compared MCP 1-knockout (KO) mice with wild-type (WT) mice. The absence of MCP-1 increased bone mass and lowered serum collagen type I fragments (CTX-1) and TRACP 5b, but had no significant effect on the N-terminal propeptide of type I procollagen, suggesting that OCs are primarily responsible for the bone phenotype observed in the absence of MCP-1. MCP-1 deficiency resulted in reduced numbers and activity of OCs in vitro. It also led to a reduced level of c-Fms and receptor activator of nuclear factor-kappaB receptor and impaired actin ring formation. Activation of ERK, Akt, Rac1, and Rho upon M-CSF stimulation was also reduced and our evidence suggests that the aberrant actin ring formation was partly due to reduced activation of these molecules. Our findings point to a role of osteoclast MCP-1 in regulating bone remodeling. The higher bone mass in the femurs of MCP-1 KO mice could be, at least in part, due to decreased osteoclastogenesis and bone resorption resulting from aberrant M-CSF signaling in OCs. PMID- 21678415 TI - Transactivation of EGFR/PI3K/Akt involved in ATP-induced inflammatory protein expression and cell motility. AB - Phenotype transition of vascular smooth muscle cells (VSMCs) is important in vascular diseases, such as atherosclerosis and restenosis. Once released, ATP may promote activation of VSMCs by stimulating cyclooxygenase-2 (COX-2), cytosolic phospholipase A(2) (cPLA(2)) expression and prostaglandin (PG)E(2) synthesis via activation of MAPKs and NF-kappaB. However, whether alternative signaling pathways participated in regulating COX-2 and cPLA(2) expression associated with cell migration were investigated in rat VSMCs. Western blot analysis, RT-PCR, promoter assay and PGE(2) ELISA were used to determine expression of COX-2, cPLA(2) and PGE(2). Specific inhibitors and siRNAs against various protein kinases or transcription factors were used to investigate the related signaling components in inflammatory protein induction by ATPgammaS. We found that ATPgammaS-induced COX-2 and cPLA(2) expression and PGE(2) release was attenuated by the pharmacological inhibitors or transfection with siRNA against PKCdelta, c Src, EGFR, PI3-K, Akt, p44/p42 MAPK or Elk-1. Moreover, ATPgammaS-stimulated phosphorylation of PKCdelta, c-Src, EGFR, Akt, p42/p44 MAPK and Elk-1, suggesting the participation of PKCdelta/c-Src/EGFR/PI3-K/Akt/p42/p44 MAPK cascade in mediating Elk-1 activities in VSMCs. In addition, migration assay revealed that ATPgammaS promoted cell mobility through up-regulation of COX-2 and cPLA(2) expression and PGE(2) release, which was attenuated by pretreatment with PGE(2) receptor antagonists. Taken together, these data showed that ATPgammaS up regulated the expression of COX-2 and cPLA(2) through transactivation of PKCdelta/c-Src/EGFR/PI3K/Akt/Elk-1 pathway. Newly synthesized PGE(2) acted on its receptors to promote cell motility of ATPgammaS-stimulated VSMCs. PMID- 21678417 TI - Runx1 and C/EBPbeta transcription factors directly up-regulate P2X3 gene transcription. AB - Recent evidence indicates that transcription factor Runx1 modulates the expression of several phenotypic markers in dorsal root ganglia (DRGs) neurons, including the pain-related P2X3 receptor. In several cell lineages C/EBP transcription factors interact with the Runx factor family members to jointly bind and activate transcription of target genes. Here, we examine whether these two transcription factors directly regulate P2X3 gene expression. Through in silico analyses of the first 2 kb of the P2X3 gene promoter we identified putative consensus-binding sites for both Runx1 and C/EBPbeta transcription factors. Transient over-expression in PC12 cells of either Runx1 or C/EBPbeta increases P2X3 gene promoter activity and co-expression of both factors results in an additive stimulatory effect on the promoter function. Accordingly, chromatin immunoprecipitation assays demonstrate that both Runx1 and C/EBPbeta bind to the P2X3 promoter in PC12 cells expressing this gene. Site-directed mutagenesis of the proximal Runx1 and C/EBPbeta consensus elements in the P2X3 promoter decrease Runx1- and C/EBPbeta-mediated transcriptional activity. Moreover, C/EBPbeta-mediated enhancement of the P2X3 promoter requires a functional Runx1 binding site. Altogether our results support a functional and coordinated role for Runx1 and C/EBPbeta transcription factors during activation of P2X3 gene transcription. PMID- 21678416 TI - Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2 dependent manner. AB - Loss-of-function mutations in angiogenin (ANG) gene were discovered in amyotrophic lateral sclerosis (ALS) patients and ANG has been shown to prevent neuronal death both in vitro and in vivo. The neuro-protective activity of ANG was brought about partially by inhibiting stress-induced apoptosis. ANG attenuates both the extrinsic and the intrinsic apoptotic signals by activating Nf-kappab-mediated cell survival pathway and Bcl-2-mediated anti-apoptotic pathway. Here we report that ANG inhibits nuclear translocation of apoptosis inducing factor (AIF), an important cell death-executing molecule known to play a dominant role in neurodegenerative diseases. ANG inhibits serum withdrawal induced apoptosis by attenuating a series of Bcl-2-dependent events including caspase-3 activation, poly ADP-ribose polymerase-1 (PARP-1) cleavage, and AIF nuclear translocation. PMID- 21678418 TI - The RhoA-Rok-myosin II pathway is involved in extracellular matrix-mediated regulation of prolactin signaling in mammary epithelial cells. AB - In mammary epithelial cells (MECs), prolactin-induced signaling and gene expression requires integrin-mediated cell adhesion to basement membrane (BM). In the absence of proper cell-BM interactions, for example, culturing cells on collagen-coated plastic dishes, signal propagation is substantially impaired. Here we demonstrate that the RhoA-Rok-myosin II pathway accounts for the ineffectiveness of prolactin signaling in MECs cultured on collagen I. Under these culture conditions, the RhoA pathway is activated, leading to downregulation of prolactin receptor expression and reduced prolactin signaling. Enforced activation of RhoA in MECs cultured on BM suppresses prolactin receptor levels, and prevents prolactin-induced Stat5 tyrosine phosphorylation and beta casein expression. Overexpression of dominant negative RhoA in MECs cultured on collagen I, or inhibiting Rok activity, increases prolactin receptor expression, and enhances prolactin signaling. In addition, inhibition of myosin II ATPase activity by blebbistatin also exerts a beneficial effect on prolactin receptor expression and prolactin signaling, suggesting that tension exerted by the collagen substratum, in collaboration with the RhoA-Rok-myosin II pathway, contributes to the failure of prolactin signaling. Furthermore, MECs cultured on laminin-coated plastic have similar morphology and response to prolactin as those cultured on collagen I. They display high levels of RhoA activity and are inefficient in prolactin signaling, stressing the importance of matrix stiffness in signal transduction. Our results reveal that RhoA has a central role in determining the fate decisions of MECs in response to cell-matrix interactions. PMID- 21678420 TI - Embryologic origin of endometriosis: analysis of 101 human female fetuses. AB - The etiology of endometriosis, a gynecological disease characterized by the presence of endometrial glands and stroma outside the uterine cavity, is still unknown. Our research group has recently demonstrated the presence of ectopic endometrium in human female fetuses at different gestational ages. In this manuscript we describe four new cases of fetal endometriosis found among a series of 52 female fetuses analyzed at autopsy. The anatomical localization of this ectopic endometrium, and its histological and immunohistochemical characteristics are depicted. We suggest that endometriosis is caused by dislocation of primitive endometrial tissue outside the uterine cavity during organogenesis. The clinical and pathological implications of these findings are discussed. PMID- 21678419 TI - Identification of RUNX3 as a component of the MST/Hpo signaling pathway. AB - Recent genetic screens of fly mutants and molecular analysis have revealed that the Hippo (Hpo) pathway controls both cell proliferation and cell death. Deregulation of its human counterpart (the MST pathway) has been implicated in human cancers. However, how this pathway is linked with the known tumor suppressor network remains to be established. RUNX3 functions as a tumor suppressor of gastric cancer, lung cancer, bladder cancer, and colon cancer. Here, we show that RUNX3 is a principal and evolutionarily conserved component of the MST pathway. SAV1/WW45 facilitates the close association between MST2 and RUNX3. MST2, in turn, stimulates the SAV1-RUNX3 interaction. In addition, we show that siRNA-mediated RUNX3 knockdown abolishes MST/Hpo-mediated cell death. By establishing that RUNX3 is an endpoint effector of the MST pathway and that RUNX3 is capable of inducing cell death in cooperation with MST and SAV1, we define an evolutionarily conserved novel regulatory mechanism loop for tumor suppression in human cancers. PMID- 21678421 TI - PML expression in soft tissue sarcoma: prognostic and predictive value in alkylating agents/antracycline-based first line therapy. AB - Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our study was to evaluate promyelocytic leukemia gene expression value as prognostic factor and as a factor predicting response to alkylating agents/antracycline-based first line therapy. One hundred eleven patients affected by locally advanced and metastatic soft tissue sarcoma were selected. PML expression was evaluated by immunohistochemical analysis in pathological samples and in the corresponding normal tissue from each case. PML immunohistochemical results were correlated with prognosis and with radiological response to alkylating agents/antracycline-based first line therapy. PML expression was significantly reduced in synovial sarcomas (P < 0.0001), in myofibroblastic sarcomas (P < 0.0001), angiosarcomas (P < 0.0001), in leiomyosarcomas (P = 0.003), in mixoid liposarcomas (P < 0.0001), and in dedifferentiated liposarcomas (P < 0.0001). No significant difference was found for pleomorphic sarcoma [31.8 (95% CI: 16.7-41.0); P = 0.21]. and pleomorphic liposarcomas (P = 0.51). Loss of PML expression was found to be statistically correlated with TTP (P < 0.0001), median duration of response (P = 0.007), and OS (P = 0.02). No correlation was observed between PML expression and treatment efficacy. PML IHC expression is down-regulated in synovial sarcomas, myofibroblastic sarcomas, angiosarcomas, liposarcoma, and leiomyosarcomas and its expression correlated with prognosis. PMID- 21678422 TI - Pharmacokinetic analysis of plasma curves obtained after i.v. injection of the PET radioligand [11C] raclopride provides a likely explanation for rapid radioligand metabolism. AB - Positron emission tomography (PET) is an imaging technique that provides direct measurements of receptor binding in neurons. The present study was performed to find reasons for the common observation of rapid metabolism of receptor radioligands during time of a brain PET scan. To this aim, the 1-h phase during which imaging-data are acquired was evaluated by using a pharmacokinetic approach. The values of half-lives, volumes of distribution, and dilution calculated for a set of metabolite corrected plasma curves of D2-receptor radioligand [(11)C]raclopride (PETc) during 50 min after radioligand injection in tracer dose were compared with the reference values obtained from a set of plasma curves (REFc) during 30 h after i.v. infusion of unlabelled raclopride in pharmacological doses. We found that the half-life of PETc correspond to the distribution half-life of REFc. Accordingly, the distribution volume during the terminal phase of PETc (13.6 +/- 10.8 L) was significantly lower than that during the terminal phase (82.2 +/- 30.5 L) and at steady state (59.4 +/- 20 L) for REFc, and the dilution of raclopride in body for PETc at 50 min was 38 L, whereas it was 1015 L for REFc at 30 h. The [(11)C]raclopride in plasma at 50 min was higher (10% of dose) than the value for unlabelled raclopride at 30 h (4%). We concluded that the kinetic behavior of the radiolabelled drug [(11)C]raclopride during the 1 h time of a PET corresponds to the distribution phase. The high percentage of [(11)C]raclopride in plasma during this phase is a likely reason for the observed rapid radioligand metabolism. PMID- 21678423 TI - The phenotype and functional alterations of macrophages in mice with hyperglycemia for long term. AB - Abnormal immunity and its related complications are the major causes of mortality and morbidity in diabetes patients. Macrophages, as one of the important innate cells, play pivotal roles in controlling immune homeostasis, immunity, and tolerance. The effects of hyperglycemia on the function of macrophages in hosts remain to be determined. Here we used mice with streptozotocin (STZ)-induced diabetes for long term to study the changes of macrophages. We found that F4/80(+) peritoneal exudate macrophages (PEMs) from mice with diabetes for 4 months displayed significantly reduced CD86 and CD54 expression and tumor necrosis factor (TNF)-alpha and IL-6 production but enhanced nitric oxide (NO) secretion compared with control mice when treated with interferon (IFN)-gamma and lipopolysaccharide (LPS), while the activity of arginase in PEMs from diabetic mice was significantly higher than control mice when stimulating with IL-4. These dysfunctions of macrophages could be efficiently reversed by insulin treatment. Importantly, in vitro bone marrow-derived macrophages showed similar functional changes, indicating the epigenetic alteration of macrophage precursors in these mice. In an in vitro culture system, high glucose and insulin significantly altered TNF-alpha, IL-6, and NO production and arginase activity of macrophages, which was reversed by the treatment with AKT and ERK inhibitors. Therefore, hyperglycemia and insulin deficiency can modify macrophage function through AKT mTOR and ERK pathways and through epigenetic effects on macrophage precursors. To further identify different components of diabetes on the dysfunction of macrophages is important for efficient prevention of diabetic complications. PMID- 21678424 TI - Human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by AMP-activated protein kinase. AB - AMP-activated protein kinase (AMPK) is an energy-sensing kinase that has recently been shown to regulate the differentiation of preadipocytes and osteoblasts. However, the role of AMPK in stem cell differentiation is largely unknown. Using in vitro culture models, the present study demonstrates that AMPK is a critical regulatory factor for osteogenic differentiation. We observed that expression and phosphorylation of AMPK were increased during osteogenesis in human adipose tissue-derived mesenchymal stem cells (hAMSC). To elucidate the role of AMPK in osteogenic differentiation, we investigated the effect of AMPK inhibition or knockdown on mineralization of hAMSC. Compound C, an AMPK inhibitor, reduced mineralized matrix deposition and suppressed the expression of osteoblast specific genes, including alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), and osteocalcin (OCN). Knockdown of AMPK by shRNA-lentivirus infection also reduced osteogenesis. In addition, inhibition or knockdown of AMPK during osteogenesis inhibited ERK phosphorylation, which is required for osteogenesis. Interestingly, inhibition of AMPK induced adipogenic differentiation of hAMSC, even in osteogenic induction medium (OIM). These results provide a potential mechanism involving AMPK activation in osteogenic differentiation of hAMSC and suggest that commitment of hAMSC to osteogenic or adipogenic lineage is governed by activation or inhibition of AMPK, respectively. PMID- 21678425 TI - Cellular and molecular large-scale features of fetal adipose tissue: is bovine perirenal adipose tissue brown?. AB - Epidemiological and fetal programming studies point to the role of fetal growth in adult adipose tissue (AT) mass in large mammals. Despite the incidence of fetal AT growth for human health and animal production outcomes, there is still a lack of relevant studies. We determined the cellular and large-scale-molecular features of bovine fetal perirenal AT sampled at 110, 180, 210, and 260 days post conception (dpc) with the aim of identifying key cellular and molecular events in AT growth. The increase in AT weight from 110 to 260 dpc resulted from an increase in adipocyte volume and particularly adipocyte number that were concomitant with temporal changes in the abundance of 142 proteins revealed by proteomics. At 110 and 180 dpc, we identified proteins such as TCP1, FKBP4, or HSPD1 that may regulate adipocyte precursor proliferation by controlling cell cycle progression and/or apoptosis or delaying PPARgamma-induced differentiation. From 180 dpc, the up-regulation of PPARgamma-induced proteins, lipogenic and lipolytic enzymes, and adipokine expression may underpin the differentiation and increase in adipocyte volume. Also from 180 dpc, we unexpectedly observed up regulations in the beta-subunit of ATP synthase, which is normally bypassed in brown AT, as well as in aldehyde dehydrogenases ALDH2 and ALDH9A1, which were predominantly expressed in mouse white AT. These results, together with the observed abundant unilocular adipocytes at 180 and 260 dpc, strongly suggest that fetal bovine perirenal AT has much more in common with white than with brown AT. PMID- 21678426 TI - Molecular characterization of myosin phosphatase in endothelium. AB - The phosphorylation status of myosin light chain (MLC) is regulated by both MLC kinases and type 1 Ser/Thr phosphatase (PPase 1), MLC phosphatase (MLCP) activities. The activity of the catalytic subunit of MLCP (CS1beta) towards myosin depends on its associated regulatory subunit, namely myosin PPase targeting subunit 1 (MYPT1). Our previously published data strongly suggested the involvement of MLCP in endothelial cell (EC) barrier regulation. In this study, our new data demonstrate that inhibition of MLCP by either CS1beta or MYPT1 siRNA based depletion results in significant attenuation of purine nucleotide (ATP and adenosine)-induced EC barrier enhancement. Consistent with the data, thrombin induced EC F-actin stress fiber formation and permeability increase were attenuated by the ectopic expression of constitutively active (C/A) MYPT1. The data demonstrated for the first time direct involvement of MLCP in EC barrier enhancement/protection. Cloning of MYPT1 in human pulmonary artery EC (HPAEC) revealed the presence of two MYPT1 isoforms, long and variant 2 (V2) lacking 56 amino acids from 553 to 609 of human MYPT1 long, which were previously identified in HeLa and HEK 293 cells. Our data demonstrated that in Cos-7 cells ectopically expressed EC MYPT1 isoforms co-immunoprecipitated with intact CS1beta suggesting the importance of PPase 1 activity for the formation of functional complex of MYPT1/CS1beta. Interestingly, MYPT1 V2 shows decreased binding affinity compared to MYPT1 long for radixin (novel MLCP substrate and a member of ERM family proteins). These results suggest functional difference between EC MYPT1 isoforms in the regulation of MLCP activity and cytoskeleton. PMID- 21678427 TI - Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage. AB - The decision tree to determine whether the P-glycoprotein (P-gp)/multidrug resistance protein 1 (MDR1)-mediated drug-drug interaction (DDI) study is recommended has been proposed by the International Transporter Consortium. We, therefore, designed an in vitro P-gp inhibition assay and determined the appropriate risk criteria for P-gp-mediated DDI at the drug discovery stage. Effects of P-gp inhibitors on digoxin transport across a monolayer of MDR1 expressing cells were examined. The IC(50) (half-maximal inhibitory concentration) values generated from the efflux ratio (ER) were smaller than those generated from basolateral-to-apical directional apparent permeability. The difference in IC(50) values was kinetically described in a compartment model analysis. This analysis indicated that ER is a highly sensitive parameter that can be used for the degree of P-gp inhibition. Considering IC(50) values and the increase in digoxin exposure in clinical DDI studies, the risk criteria of [I(2)]/IC(50) = 30 ([I(2)], theoretically maximal gastrointestinal concentration) was the optimal cutoff value to predict a clinically relevant DDI. We also investigated whether the IC(50) value itself is applicable to assess the DDI risk. In conclusion, compounds with IC(50) values less than 2 MUM exhibit high risk for P-gp-mediated DDIs. However, compounds with IC(50) values greater than or equal to 2 MUM are inconclusive because clinical doses should be considered for the precise DDI risk assessment. PMID- 21678428 TI - Calcium binding to a factor ix Fc fusion protein and effects on higher-order structure. AB - There is significant scope for more meaningful evaluation of higher-order structure in defining the quality of biopharmaceutical products [Bush L. 2010. Biopharm Int 23(4):14]. We have used isothermal titration calorimetry (ITC) to characterize the Ca(2+) -binding isotherm of a recombinant human factor IX Fc fusion protein (rFIXFc) and the parent recombinant human factor IX molecule (rFIX). Circular dichroism, intrinsic fluorescence, and Fourier transform infrared spectroscopies detected characteristic spectral changes that appear qualitatively consistent with the previously characterized behavior of the factor IX molecule. Sedimentation velocity and dynamic light scattering measurements were recorded in the presence and absence of Ca(2+) over the protein concentration range 1-10 mg/mL. ITC of Ca(2+) binding to rFIXFc reveals a distinctive exothermic-binding isotherm, which is interpreted as consistent with two high-affinity and approximately 14 lower-affinity Ca(2+) sites reported in the literature for human factor IX (Schmidt AE, Bajaj SP. 2003. Trends Cardiovasc Med 13(1):39-45). Analysis of accelerated degradation samples showed significant alterations in Ca(2+) binding, which correlates with significant loss of biopotency and fragmentation by gel chip capillary electrophoresis. Collectively, these data establish a close correspondence in the Ca(2+) -binding characteristics of rFIXFc and its parent rFIX molecule. The utility of ITC to provide a highly pertinent and selective biophysical signature of structure function for a therapeutic factor protein is discussed. PMID- 21678429 TI - Risk factors for sexual aggression in young men: an expansion of the confluence model. AB - There are many explanations for high rates of sexual aggression, with no one theory dominating the field. This study extends past research by evaluating an expanded version of the confluence model with a community sample. One-hour audio computer-assisted self-interviews were completed by 470 young single men. Using structural equation analyses, delinquency, hostile masculinity, impersonal sex, and misperception of women's sexual cues were positively and directly associated with the number of sexually aggressive acts committed. There were also indirect effects of childhood victimization, personality traits associated with subclinical levels of psychopathy, and alcohol consumption. These findings demonstrate the usefulness of the confluence model, as well as the importance of broadening this theory to include additional constructs. PMID- 21678430 TI - Implicit alcohol-aggression scripts and alcohol-related aggression on a laboratory task in 11- to 14-year-old adolescents. AB - Social scripts are commonly shared representations of behavior in social contexts, which are seen to be partly transmitted through social and cultural media. Research suggests that people hold scripts associated with alcohol-related aggression, but, unlike general aggression scripts, there is little evidence of social transmission. To demonstrate social transmission of alcohol-related aggression scripts, learning mechanisms based on personal experience should be minimized. We used a lexical decision task to examine implicit links between alcohol and aggression in alcohol-naive adolescents who have limited personal or vicarious experience of alcohol-related aggression. One hundred and four 11-14 year old adolescents made lexical decisions on aggressive or nonaggressive words preceded by 40-ms alcohol or nonalcohol word primes. Repeated measures analyses of group data showed that alcohol word primes did not lead to faster responses to aggressive words than to nonaggressive words, nor were responses to aggressive words faster when they were preceded by alcohol word primes than by nonalcohol word primes. However, at an individual level, faster recognition times to the alcohol prime/aggression target word combination predicted aggression on a competitive laboratory task in 14 year olds only. This occurred only when the competitive aggression task was preceded by a visual presentation of alcoholic, but not nonalcoholic beverage, images. We concluded that alcohol-related aggression scripts are not strongly developed in this age group, but individual differences in script strength are linked to alcohol-related laboratory aggression. PMID- 21678431 TI - Do scientific theories affect men's evaluations of sex crimes? AB - Evolutionary psychology accounts of gender differences in sexual behaviors in general and men's sexual aggression, in particular, has been criticized for legitimizing males' sexual misconduct. To empirically assess such critiques, two studies examined how men's judgments of male sex crimes (solicitation of sex from a prostitute; rape) are influenced by exposure to (a) evolutionary psychological theories and (b) social-constructivist theories. Across two studies, a consistent pattern emerged compared with a control condition (a) exposure to evolutionary psychology theories had no observable impact on male judgments of men's criminal sexual behavior, whereas (b) exposure to social-constructivist theories did affect judgments, leading men to evaluate sex crimes more harshly. Additional results (from Study 2) indicate that this effect is mediated by perceptions of male control over sexual urges. These results have implications for journalists, educators, and scientists. Aggr. Behav. 37:440-449, 2011. (c) 2011 Wiley-Liss, Inc. PMID- 21678432 TI - Differential pharmacokinetic analysis of in vivo erythropoietin receptor interaction with erythropoietin and continuous erythropoietin receptor activator in sheep. AB - The two erythropoiesis stimulating agents (ESAs), short acting recombinant human erythropoietin (EPO) and long acting continuous erythropoietin receptor activator (CERA), have been hypothesized to share an in vivo elimination pathway that involves binding to erythropoietin receptor (EPOR) and subsequent internalization. A physiologically based recirculation model and a pharmacokinetic tracer interaction methodology (TIM) were used to compare the in vivo interaction kinetics with EPOR between the two ESAs in adult sheep. Animals treated with EPO experienced a greater EPOR up-regulation than those treated with CERA, as evidenced by an eightfold-higher initial EPOR normalized production rate constant, k(syn) /R(0) , versus a twofold-larger EPOR degradation rate constant, k(deg) . In agreement with in vitro studies, EPO had a lower in vivo equilibrium dissociation constant from EPOR than CERA (K(D) = 6 versus 88.4 pmol/l, respectively, p < 0.01). The internalization and/or degradation of the EPO-EPOR complex was faster than that of the CERA-EPOR complex (k(int) = 24 versus 2.41 h( 1) , respectively, p < 0.01). The adopted model enables a mechanism-based explanation for CERA's slower elimination and greater erythropoietic activity in vivo. As predicted by the model, the slower elimination of CERA is due to: (1) less EPOR up-regulation induced by CERA administration; (2) slower binding of CERA to EPOR; and (3) reduced internalization and/or degradation rate of surface bound CERA. Slower CERA/EPOR complex elimination explains the greater in vivo erythropoiesis reported for CERA, despite its lower affinity to EPOR. A sensitivity analysis showed that the model parameters were reliably estimated using the TIM methodology. PMID- 21678433 TI - Moderate prevalence of transmitted drug resistance and high HIV-1 genetic diversity in patients from Mato Grosso State, Central Western Brazil. AB - Few reports have described the molecular characteristics of the AIDS epidemic within the interior regions of Brazil, a country of continental dimensions. To help fill this gap, the prevalence of transmitted antiretroviral drug resistance and human immunodeficiency virus type 1 (HIV-1) diversity in Mato Grosso State, central western Brazil are reported. Drug-naive patients (n = 105) were recruited at a reference center in Cuiaba/Mato Grosso State located across the border with Bolivia and considered a southern gate to the Amazon forest. For 92 HIV-1 isolates, the protease and partial reverse transcriptase fragments were amplified by nested-PCR and sequenced. Drug resistance was analyzed by the Calibrated Population Resistance tool and the International AIDS Society-USA database. HIV-1 subtypes were determined by REGA and phylogenetic analyses. Recombinant viruses were analyzed by SIMPLOT. Drug resistance mutations were observed in 5.4%: nucleoside reverse transcriptase inhibitor mutations M41L (n = 1), D67N (n = 1), and K219E (n = 1), the non-nucleoside reverse transcriptase inhibitor mutation K103N (n = 1) and the protease inhibitor mutation L90M (n = 1). Around 20% of the isolates were recombinants: different patterns of B/F1 mosaics (n = 11), four B/C, one F1/C/B, one F1/C, and one D/F1. Subtype B(PR) B(RT) represented 71.7%, 5.4% were of subtype C(PR) C(RT) and 3.3% were of subtype F1(PR) F1(RT) . A moderate prevalence of transmitted resistance and the co-circulation of subtypes B, F1, C, different recombinants, including the first report of subtype D, were found in Mato Grosso State, far from the epicenter of the epidemic. These results highlight the importance of monitoring transmitted drug resistance and HIV-1 genetic diversity in the interior regions of Brazil. PMID- 21678434 TI - Comparative analysis of disease severity between genotypes IA and IIIA of hepatitis A virus. AB - Although hepatitis A is a major health problem worldwide, it has not yet been clarified whether or not viral factors affect the clinical characteristics. This study aimed to investigate if a genotype of hepatitis A virus (HAV) affects disease severity among adolescent and adult populations. Clinical data and specimens were collected from patients >=16-years-of-age with acute hepatitis A at two university hospitals in Korea during the two study periods: 1998 and 1999 (n = 45), and 2009 (n = 66). Nucleotide sequencing of the complete VP1 region of the HAV isolates was performed for phylogenetic analysis and genotyping. Clinical parameters related to disease severity were compared by HAV genotype to determine its clinical relevance. Of the 87 patients, 47 were male and the mean age was 29.8 +/- 8.1 years. The genotype IIIA (93.0%, 53/57) was predominant in the year 2009, whereas IA (93.3%, 28/30) was the major genotype in 1998 and 1999. When comparing disease severity between the two HAV genotypes, the patients with genotype IIIA were older and had higher alanine aminotransferase (ALT) levels, prolonged prothrombin times and lower serum albumin levels. In a multivariate logistic regression model, higher ALT levels >= 1,000 IU/L (odds ratio [OR] 11.7, 95% confidence interval [CI] 2.5-54.0) and longer hospitalization (OR 22.49, 95%CI 4.6-132.5) were associated independently with genotype IIIA. In conclusion, this study indicates that HAV genotype might be one of the viral factors responsible for the disease severity of hepatitis A. PMID- 21678435 TI - Characterization of hepatitis B virus in Turkish blood donors, and the prevalence of the SP1 splice variant. AB - Hepatitis B is a disease of the liver that can manifest acutely, or persist chronically as a result of infection with the hepatitis B virus (HBV). Turkey has a moderate endemicity level of HBV infection, and all data published to date has shown this to be of genotype D, predominantly of subgenotype D1. However the sequences of very few full genomes have been published. The aim of this study was to characterize the molecular profile of hepatitis B virus in asymptomatic, first time Turkish blood donors. The results confirm that genotype D, subgenotype D1 is the most prevalent HBV strain in Turkey, accounting for 94% of cases. Subgenotypes D2 and D3 were present as minority strains (4% and 2%, respectively). A singly spliced HBV variant that is capable of forming defective HBV particles and has been associated with apoptosis and activation of T-cell responses was also detected in 52.5% of samples screened, co-circulating with wild type genomes. PMID- 21678436 TI - Aboriginal Taiwanese hepatitis B carriers have more favorable viral factors than Han Chinese carriers. AB - Several viral factors are associated with disease progression in hepatitis B virus (HBV) carriers. Compared with Taiwanese Han Chinese, Taiwanese aborigines have a higher prevalence of chronic HBV infection and a higher standardized mortality rate of chronic liver diseases but a lower standardized mortality rate of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether aboriginal Taiwanese HBV carriers have more favorable viral factors which reduce the risk for HCC than Han Chinese carriers. Blood samples from 3,488 HBV carriers (1,527 aborigines and 1,961 Han Chinese) were assayed for aminotransferases, hepatitis B e antigen (HBeAg), HBV DNA, and HBV genotype. Aboriginal HBV carriers had a lower HBeAg-positive rate (5.3% vs. 10.2%, P < 0.0001) and a lower viral load of HBV DNA > 2,000 IU/ml (27.4% vs. 36.7%, P < 0.0001) but a higher rate of alcohol consumption (40.0% vs. 19.3%, P < 0.0001) than Han Chinese carriers. The prevalence of HBV genotype B in aboriginal carriers (92.7%) was significantly higher than that in Han Chinese carriers (72.7%) in all age groups (P < 0.05). In addition, patients with rare genotype D infections were clustered in a township in southern Taiwan. In conclusion, aboriginal Taiwanese HBV carriers have more favorable viral factors than Han Chinese carriers, which may be partly responsible for the lower standardized mortality rate of HCC in Taiwanese aborigines. PMID- 21678437 TI - Mutations in the E2 and NS5A regions in patients infected with hepatitis C virus genotype 1a and their correlation with response to treatment. AB - Heterogeneity of subgenomic regions of hepatitis C virus (HCV) may be associated with response to interferon (IFN) therapy. The amino acid sequences of the PKR/eIF-2alpha phosphorylation homology domain (pePHD), IFN sensitivity determining region (ISDR), PKR binding domain (PKRBD), and variable region 3 (V3) were studied in 19 patients before and after 4 weeks of treatment. All patients were infected with HCV genotype 1a and were treated with pegylated-IFN and ribavirin. Thirteen patients achieved sustained viral response (responders) and six failed to clear viral RNA (nonresponders). The amino acid sequences in the pePHD and ISDR were identical in responders and nonresponders. However, amino acid substitution at position 2252 of PKRBD was significantly different between responders and nonresponders (P = 0.044). A larger number of mutations were observed in the V3 region of responders (P < 0.001). In this region, the amino acid in position 2364 differed between responders and nonresponders (responders: aspartic acid and serine, nonresponders: asparagine, P = 0.018). The amino acid sequences in the regions which were studied did not change after 4 weeks of treatment. It is concluded that the presence of specific amino acids in position 2252 of PKRBD and position 2364 of V3 might be associated with clinical response to IFN. PMID- 21678438 TI - Analyses of human papillomavirus genotypes and viral loads in anogenital warts. AB - Condylomata acuminata (genital warts) are the most common sexually transmitted viral diseases. These lesions are caused by infection with mucosal human papillomaviruses (HPVs). However, there is limited information on HPV strain distribution involved in the molecular pathogenesis of these lesions. To address this, the strain prevalence and the frequency of multiple HPV infections were determined in wart tissue obtained from 31 patients attending a wart clinic. These lesions were bisected and subjected to parallel DNA and mRNA extractions. HPV-type prevalence and incidence of multiple infections were determined by the Roche Linear Array assay. qPCR compared HPV 6, 11, 16, and 18 viral loads and RT qPCR measured HPV 6 and 11 E6 genomic expression levels. Seventy-one percent of these samples were infected with multiple HPVs. Only one sample was negative for HPV 6 or 11 DNA. Forty-eight percent of samples were positive for a high risk (oncogenic) HPV. The results show that multiple infections in tissue are frequent and the subsequent analysis of HPV 6 and 11 E6 DNA viral loads suggested that other HPVs could be causing lesions. Further analysis of HPV 6/11 E6 mRNA levels showed that there was no discernable relationship between HPV 6 E6 DNA viral load and relative HPV 6 or 11 E6 mRNA levels thereby questioning the relevance of viral load to lesion causality. PMID- 21678439 TI - Low-level persistence of human papillomavirus 16 DNA in a cohort of closely followed adolescent women. AB - Most human papillomavirus (HPV) infections in young women become undetectable by standard assays after a few months. It is possible that many HPV infections do not actually clear, but persist at very low levels for years, becoming detected again later in life. The purpose of this study is to describe HPV 16 clearance, reappearance, and low-level persistence in a cohort of adolescent women. Adolescent women (N = 66), not vaccinated against HPV, were recruited from 1998 to 2008 into a longitudinal study. Self-collected vaginal samples were obtained quarterly and tested for HPV by Linear Array HPV Genotyping Test (LA-HPV). To explore low-level persistence, a type-specific nested PCR for HPV 16 (TSN-PCR-16) was developed. Women with HPV 16 detected by LA-HPV had their negative swabs retested with TSN-PCR-16. Forty-two participants with HPV 16, followed for a mean of 6.3 years, were analyzed. Using LA-HPV, the median duration of HPV 16 detection was 428 days (SD 852.5 days). TSN-PCR-16 detected HPV 16 during periods of LA-HPV non-detection in samples from many women. Using a combination of LA-HPV and TSN-PCR-16 results, the median duration of HPV 16 detection was 1,022.5 days (SD 943.7 days). The durations of detection differed significantly between the two methods (P = 0.0042) with a mean difference of 434.5 days. In adolescent females, duration of HPV 16 detection was significantly longer when TSN-PCR-16 was combined with LA-HPV. Some apparently cleared HPV 16 could be shown to persist at low levels using nested PCR. PMID- 21678440 TI - Human papillomavirus infection among women with cytological abnormalities in Switzerland investigated by an automated linear array genotyping test. AB - Limited data are available describing human papillomavirus (HPV) genotype distribution among females with cytological abnormalities in Switzerland. Cervical cell specimens obtained from 5,318 women were screened routinely by liquid-based Pap smear. All specimens with cellular abnormalities were analyzed subsequently for HPV DNA by the Linear Array HPV genotyping test. Cellular abnormalities were found in 202 (3.8%) specimens, of which 150 (74.3%) were positive for high-risk (HR) HPV. HR-HPV was detected in 20 (60.6%; 95% CI, 43.7 75.4%) of 33 specimens with atypical squamous cells of undetermined significance compared to 98 (72.1%; 95% CI, 64-78.9%) of 136 low-grade squamous intraepithelial lesions and 32 (97%; 95% CI, 83.4-99.9%) of 33 high-grade squamous intraepithelial lesions. The cumulative prevalence of HR-HPV other than HPV 16 and 18 was significantly higher than HPV 16 and/or 18 lesions with atypical squamous cells and low-grade lesions and was comparable in high-grade squamous intraepithelial lesions. The most common HR-HPV genotypes were HPV 16 (15.2%), HPV 31 (12.1%), HPV 58 (12.1%), HPV 51 (9.1%), and HPV 59 (9.1%) in women with atypical squamous cells, HPV 16 (25%), HPV 51 (16.9%), HPV 52 (11.8%), HPV 31 (9.6%), and HPV 56 (8.1%) in women with low-grade lesions (LSIL) and HPV 16 (57.6%), HPV 18 (18.2%), HPV 31 (15.2%), HPV 52 (12.1%), and HPV 58 (6.1%) in women with high-grade lesions (HSIL). PMID- 21678441 TI - Comparison of the PapilloCheck(r) assay with the digene HC2 HPV DNA assay for the detection of 13 high-risk human papillomaviruses in cervical and anal scrapes. AB - The PapilloCheck(r) assay was compared with the Digene HC2 HPV DNA assay for the detection of 13 high-risk human papillomaviruses (HPV) in 240 samples, including 181 cervical scrapes and 59 anal scrapes. Overall, 75 (30.5%) samples were positive by the Digene HC2 HPV DNA assay: 34 (18.8%) cervical scrapes and 41 (69.5%) anal scrapes. By considering only the 13 high-risk HPV types detected by the Digene HC2 HPV DNA assay, 66 (27.5%) samples were positive by the PapilloCheck(r) assay: 27 (14.9%) cervical scrapes and 39 (66.1%) anal scrapes. Concordant results between the two assays were obtained for 225 (93.8%) samples with a Kappa coefficient value of 0.85, indicating an excellent agreement. By considering all the HPV types detectable by the PapilloCheck(r) assay, the overall prevalence of HPV was 34.2% (82/240): 21.0% (38/181) in cervical scrapes and 74.6% (44/59) in anal scrapes. Among the samples positive by the PapilloCheck(r) assay, a multiple HPV infection (2-9 HPV types) was identified in 43 of 82 (52.4%) samples, including 7 of 38 (18.4%) cervical samples, and 36 of 44 (81.8%) anal samples. The prevalence of high-risk HPV, as determined by the PapilloCheck(r) assay, was 17.6% (36/205) in samples with normal cytology, 83.9% (26/31) in samples with low-grade squamous intraepithelial lesions or atypical squamous cells of undetermined significance, and 100% (4/4) in samples with high grade squamous intraepithelial lesions. The results obtained indicate that the PapilloCheck(r) assay may be considered as a reliable screening test for HPV detection and typing. PMID- 21678442 TI - Human papillomavirus infection in lung and esophageal cancers: analysis of 485 Asian cases. AB - The role of human papillomavirus (HPV) in the development of lung and esophageal cancer remains inconclusive, which is in contrast to the established role HPV plays in the development of uterine cervical cancer. One of the reasons for this is the difference among reported HPV infection rates in these cancers. An analysis of 485 lung and esophageal cancers (176 lung squamous cell carcinoma, 128 lung adenocarcinoma, 181 esophageal carcinoma) in eight institutions in Asia (Tokyo, Kochi, Kagoshima, and Okinawa, Japan; Seoul and Daegu, Korea; Changhua, Republic of China (Taiwan); Singapore, Singapore) was carried out in order to clarify infection rates with HPV. Samples were examined in one laboratory of the Department of Pathology, the University of Tokyo, Japan in order to avoid inter laboratory variation using a combination of polymerase chain reaction and in situ hybridization (ISH). HPV was found in 6.3%, 7%, and 9.4% of patients with lung squamous cell carcinoma, lung adenocarcinoma, and esophageal cancer, respectively. Among the geographic areas surveyed, Kagoshima exhibited a significantly higher prevalence of HPV infection in cases of esophageal carcinoma (24.1%). There was no geographical difference in the infection rates of HPV in lung carcinomas. Subtype-specific ISH was also performed, which identified the high-risk HPV types 16/18 in the majority (75.7%) of the patients with lung and esophageal cancer positive for HPV. PMID- 21678443 TI - Effect of antiretroviral drugs on the quality of semen. AB - The aim of this cross-sectional study was to determine which antiretroviral drugs (ARVs) are associated with changes in the characteristics of semen and the impact of these ARVs according to their score penetration into the male genital compartment. Data from 144 men infected with HIV-1 enrolled in an Assisted Reproductive Technology program were analyzed retrospectively. A seminal penetration score of ARV was based on the available literature. The nonparametric Kruskal-Wallis test and chi-square test were used. There was no difference on sperm parameters between NRTI, NNRTI, or PI regimen. In patients receiving NRTIs or PIs no differences were observed between antiretrovirals of these classes. However, in patients receiving NNRTIs, nevirapine (n = 22) was associated with a higher percentage of progressively motile spermatozoa (P < 0.0001) versus efavirenz (n = 38) as well as vitality (P = 0.0004). No relationship was observed between semen quality and the penetration score. NRTIs and PIs were not associated with any semen changes. Nevirapine was associated with a better quality of semen versus efavirenz. It would be of interest to validate, improve and test our penetration score in a prospective study. PMID- 21678444 TI - Molecular characterization of BK polyomavirus subtypes in renal transplant recipients in Brazil. AB - BK polyomavirus (BKV) is highly prevalent in the world population. Different reports indicate that BKV subtypes and subgroups present an uneven geographical distribution which might be correlated with human migration. However, there is a lack of data on the BKV subtype distribution in the South American population. The occurrence of BKV subtypes and subgroups detected in 51 kidney transplant recipients in Rio de Janeiro, Brazil is described. According to genetic studies, the population in this region descends mainly from European or African immigrants, with a relatively low genetic background from the Amerindians. By sequencing the VP1 region of BKV, subgroups Ib1 and Ia of subtype I were found in 34 (67%) and 15 (29%), respectively, of samples, while subtype II was present in 2 (4%) of the samples. Subtypes III and IV were not detected. Phylogenetic analysis indicated similarities between Brazilian BKV subgroup Ia and East African lineages; and subgroup Ib-1 with Asian and North American lineages, while subtype II samples were similar to sequences from Japan and the UK. This is the first report that describes distribution of BKV subtypes in South America. The high prevalence of BKV subgroup Ia probably reflects the high proportion of African descendants in this population. On the other hand, the predominance of subgroup Ib-1 and the absence of Ib-2 in an area with a high proportion of European ancestry was unexpected. Further studies in South American populations are needed to provide a better understanding of the epidemiology of BKV in this region. PMID- 21678445 TI - Positive Epstein-Barr virus and cytomegalovirus IgM assays in primary HIV infection. AB - We report three cases with misleading cytomegalovirus (CMV) or Epstein-Barr virus (EBV) immunoglobulin M (IgM) results during primary human immunodeficiency virus (HIV) infection. We determined the rate of positive anti-CMV IgM assays or anti EBV capsid antigen IgM assays in sera from a group of well-characterized subjects with primary HIV infection as 2.9% (1/35; 95%CI: 0.15-16.6%) for each infection. The rate of positive anti-EBV capsid antigen IgM assays in subjects with positive hepatitis A virus IgM assays was 30% (6/20; 95%CI: 14.6-51.9%). Clinicians need to consider the limitations of IgM assays for diagnosis of herpesvirus infections, and consider testing for other infections with overlapping clinical manifestations. PMID- 21678446 TI - Decreased expression of surfactant protein D mRNA in human lungs in fatal cases of H5N1 avian influenza. AB - Microarray analysis of gene expression profile of lungs from two fatal H5N1 influenza cases identified 3,435 genes with higher than twofold changes in mRNA levels as compared to those of normal lung. One thousand nineteen genes and 2,416 genes were up-regulated and down-regulated commonly, respectively. Gene ontology analysis identified several ontology terms with significant association with these genes, most of which are related to cellular metabolism and regulation of cellular process including apoptosis and chemotaxis. Pulmonary surfactant protein D (SP-D) was found to be down-regulated. Quantitative RT-PCR confirmed the levels of SP-D mRNA in the lungs infected with H5N1 to be lower than those of normal lungs and lungs from patients with acute respiratory distress syndrome. SP-D plays multiple roles in respiratory innate defense against various pathogens, regulation of inflammatory responses, and maintenance of alveolar integrity. Reduction of SP-D in H5N1 influenza may play important roles in the pathogenesis of the disease. PMID- 21678447 TI - Viral load of the highly pathogenic avian influenza H5N1 virus in infected human tissues. AB - The highly pathogenic avian influenza A (H5N1) virus is a virulent virus that causes an acute febrile respiratory disease with high mortality in humans. To gain a better insight of H5N1 viral distributions in infected human tissues, the levels of viral RNA were determined in the autopsy tissues from two patients who were infected with H5N1 virus by using real-time reverse transcription-polymerase chain reaction. In one patient who died on day 6 of the illness, the viral load in the lung was extremely high, whereas the levels of viral RNA in the other organs were more than 6 log lower. In the other patient who died on day 17 of the illness, the viral load was similar in the lung and other organs, and was comparable to the viral load in the extra-pulmonary tissues of the first patient. These results suggested that while the H5N1 virus can cause disseminated infection in humans, the lung is still the major site of viral replication, and viral replication in the lung in the later stages may decrease as a result of the depletion of the available target cells. In addition, the mRNA levels of the tumor necrosis factor-alpha (TNF-alpha) were found to be associated with the viral titers. PMID- 21678448 TI - WU polyomavirus infection among children in South China. AB - This study aimed at investigating the prevalence and clinical characteristics of children with respiratory infection by WU polyomavirus (WUPyV) in Southern China. Nasopharyngeal aspirate samples were collected from 771 children with acute respiratory tract infection admitted to hospital and 82 samples from healthy subjects for routine examination at the outpatient service at the Second Affiliated Hospital of Shantou University, Medical College from July 2008 to June 2009. WUPyV was detected by the polymerase chain reaction (PCR) and DNA sequencing. All WUPyV-positive specimens were characterized further for nine viruses causing common respiratory infections, including influenza A and B, respiratory syncytial virus (RSV), parainfluenza virus (PIV) 1 and 3, human metapneumovirus, human bocavirus, adenovirus, and rhinovirus by PCR or real time (RT)-PCR. Fifteen out of 771 specimens from patients with acute respiratory tract infection, but none from healthy subjects, were positive for WUPyV and the positivity rate was 2%. Patients with WUPyV infection were between 2 and 48 months of age, and nine of the patients were male while six female. Four out of 15 patients were co-infected with RSV, one with adenovirus or rhinovirus, respectively. Patients with WUPyV infection displayed predominantly cough, moderate fever, and wheezing, and were diagnosed with pneumonia (n = 8), bronchiolitis (n = 4), upper respiratory tract infections (n = 2) and bronchitis (n = 1). One patient developed encephalitis. Therefore, WUPyV infection can cause acute respiratory tract infection with atypical symptoms, including severe complications, in children. PMID- 21678449 TI - Secondary lymphoid tissue as an important site for WU polyomavirus infection in immunocompetent children. AB - The polyomaviruses KI and WU (KIPyV and WUPyV) have been identified in respiratory specimens from children with acute respiratory infections, which suggests the respiratory tract as a possible site of infection. However, the persistence of infection in the lymphoid system is unknown. Fresh samples (n = 211) of tonsils, adenoids, and peripheral blood mononuclear cells (PBMCs) from 83 immunocompetent children (mean age 4.8 years) were tested for amplification of the KIPyV VP1 and WUPyV VP2 genes. The known BK and JC polyomaviruses and the lymphotropic human herpesvirus (HHV)-6 were also investigated by quantitative real-time PCR and direct sequencing. In addition, 98 nasopharyngeal swabs collected from children (mean age 6.2 years) affected by seasonal influenza-like illness were tested. Of the lymphoid tissues, 34.9% were positive for WUPyV, 4.8% for BK virus, and 33.8% for HHV-6. KIPyV and JC virus were not detected in these specimens. None of the polyomaviruses were detected in PBMCs. Among the nasopharyngeal samples, the prevalence of WUPyV was 27.5%, although 70% of the positive samples were co-infected with at least one of the following respiratory viruses: influenza virus, adenovirus, and respiratory syncytial virus. Phylogenetic analysis revealed high sequence homology (99%) between lymphoid- and nasopharynx-derived WUPyV strains. These results suggest that the tonsils and adenoids of immunocompetent children are a reservoir for WUPyV infection; probably due to the respiratory route of transmission. In addition, the prevalence of WUPyV was high among the children, and the virus was identified more frequently in older children than during the first years of life. PMID- 21678450 TI - Contribution of common and recently described respiratory viruses to annual hospitalizations in children in South Africa. AB - The contribution of viruses to lower respiratory tract disease in sub-Saharan Africa where human immunodeficiency virus may exacerbate respiratory infections is not well defined. No data exist on some of these viruses for Southern Africa. Comprehensive molecular screening may define the role of these viruses as single and co-infections in a population with a high HIV-AIDS burden. To address this, children less than 5 years of age with respiratory infections from 3 public sector hospitals, Pretoria South Africa were screened for 14 respiratory viruses, by PCR over 2 years. Healthy control children from the same region were included. Rhinovirus was identified in 33% of patients, RSV (30.1%), PIV-3 (7.8%), hBoV (6.1%), adenovirus (5.7%), hMPV (4.8%), influenza A (3.4%), coronavirus NL63 (2.1%), and OC43 (1.8%). PIV-1, PIV-2, CoV-229E, -HKU1, and influenza B occurred in <1.5% of patients. Most cases with adenovirus, influenza A, hMPV, hBoV, coronaviruses, and WU virus occurred as co-infections while RSV, PIV-3, and rhinovirus were identified most frequently as the only respiratory pathogen. Rhinovirus but not RSV or PIV-3 was also frequently identified in healthy controls. A higher HIV sero-prevalence was noticed in patients with co-infections although co-infections were not associated with more severe disease. RSV, hPMV, PIV-3, and influenza viruses had defined seasons while rhinovirus, adenovirus, and coronavirus infections occurred year round in this temporal region of sub Saharan Africa. PMID- 21678451 TI - Comparative evaluation of the Seegene Seeplex RV15 and real-time PCR for respiratory virus detection. AB - Respiratory virus infections contribute substantially both to hospitalizations of young children, and to morbidity in immunocompromised patients such as those with hematological malignancies. Their rapid and accurate diagnosis is essential to patient management. To evaluate the prospective utility of Seeplex(r) DPO technology in respiratory virus diagnosis, a panel of 99 respiratory samples positive by real-time RT-PCR for one or more viruses was assayed by the Seegene Seeplex(r) RV12 system. As well as being able to detect all 10 viruses in the real-time RT-PCR system with the exception of enteroviruses, RV12 can also distinguish between the two subgroups of RSV and detect two subgroups of coronaviruses. Seven of the nine viruses in common with the RT-PCR were detected reliably by RV12. Eleven samples RT-PCR-positive for Metapneumovirus and five samples positive for influenza B were not detected by RV12. Seegene developed a second-generation system, RV15, which not only allowed detection of three additional viruses, but also addressed the potential problems with RV12 specificity. To address these concerns, 84 respiratory samples positive for a range of viruses by real-time PCR were assayed with RV15. The results of this evaluation improved significantly upon those seen with RV12. The high throughput capabilities and potential lower technical requirements afforded by the Seeplex(r) system may offer an alternative to real-time RT-PCR systems. PMID- 21678452 TI - Genotype diversity of group A rotavirus strains in children with acute diarrhea in urban Burkina Faso, 2008-2010. AB - In this study, the diversity of G and P genotypes of rotavirus strains in Burkinabe children were examined. Between November 2008 and February 2010, 447 stool samples were collected from children <5 years of age with acute diarrhea visiting hospital in Ouagadougou. Group A rotavirus was previously detected in 151/447 (33.8%) of the samples tested by an immunochromatographic test and these samples were now tested further for rotavirus G and P genotypes by RT-PCR. Of these, the rotavirus type genes were amplified by RT-PCR for 140/151 (92.7%) samples and G and P genotypes were successfully determined for 81 (57.9%) and 130 (92.9%) samples, respectively. The most prevalent G genotypes were G1, 34/140 (24.3%), and G9, 21/140 (15%), while the predominant P genotypes were P[6], 56/140 (40%), and P[8], 54/140 (38.6%). Among the single infections, 63/140 (45%), the predominant G/P combinations were: G1P[8] (33%), G9P[8] (29%), and G2P[6] (14%). The unusual strains G1P[9] (3%), G12P[6] (3%), G10P[6] (2%), and G2P[8] (2%) were also detected. In a high number of strains 61/140 (43.6%), the G genotype could not be determined and mixed infections were determined in 17/140 (12.1%) of strains identified. This study highlights the high diversity and presence of unusual rotavirus strains in children in Burkina Faso. PMID- 21678453 TI - Plasma osteoprotegerin levels and long-term prognosis in patients with intermediate coronary artery lesions. AB - BACKGROUND: Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily and plays an important regulatory role in the skeletal, immune, and vascular systems. Intermediate coronary artery lesions that have a diameter stenosis of approximately 20%-70% might cause serious consequences. However, the prognostic value of plasma OPG levels in patients with intermediate coronary artery lesions has been less reported. HYPOTHESIS: We hypothesized that OPG is a predictive marker of prognosis of intermediate coronary artery lesions. METHODS: A prospective study was performed on 890 patients with intermediate (20%-70%) coronary lesions. The median age was 62 years (25th and 75th percentiles, 55 and 70 years, respectively) and 67.2% were male. Fasting blood was sampled at baseline. The primary clinical endpoint was a composite of readmission due to angina pectoris, nonfatal myocardial infarction, revascularization, and cardiovascular death. RESULTS: During a median follow-up of 24 months, events occurred in 11.1% of the patients. Of these patients, 7.9% were readmitted for angina pectoris, 1.5% received revascularization, 0.7% suffered nonfatal myocardial infarction, and 1.0% died. The plasma levels of OPG (median, 5304.7 pg/mL vs 2993.4 pg/mL, P<0.001) and high-sensitivity C-reactive protein (median, 4.8 mg/L vs 2.6 mg/L, P<0.001) were higher in patients with events than those without events. After adjusting for traditional risk factors such as age, gender, smoking, hypertension, diabetes, dyslipidemia, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein, percent area stenosis, and drug administration, a multivariate Cox proportional hazard analysis showed that higher OPG levels were an independent predictive factor of the composite clinical endpoint (hazard ratio: 2.49, 95% confidence interval: 1.26-4.89, fourth quartile vs first quartile). CONCLUSIONS: The higher level of OPG is an independent predictive factor of prognosis in patients with intermediate coronary lesions. PMID- 21678454 TI - Appropriate therapy but not inappropriate shocks predict survival in implantable cardioverter defibrillator patients. AB - BACKGROUND: Inappropriate implantable cardioverter defibrillator (ICD) shocks have been linked to a worse clinical outcome due to direct myocardial injury. HYPOTHESIS: The occurrence of ventricular tachyarrhythmia indicating progression of the underlying heart disease, but not the ICD shock itself, has prognostic impact in clinical routine. METHODS: In a retrospective study, 1117 recipients of an ICD were analyzed with respect to appropriate and inappropriate therapies and survival. RESULTS: During a mean follow-up of 2.92 years, appropriate therapy occurred in 27.7% and 54.0% of patients who had received an ICD for primary and secondary prevention of sudden cardiac death (SCD), respectively (P<0.0001). Inappropriate shock therapy occurred in 15.0% and 25.4% of patients who had received an ICD for primary and secondary prevention of SCD, respectively (P = 0.122). Appropriate ICD therapy had a strong impact on overall survival (P<0.0001), and this association was found both in primary (P<0.0001) and secondary (P = 0.002) prevention of SCD. Inappropriate ICD shocks had no impact on total mortality, neither in primary nor secondary prevention of SCD. CONCLUSIONS: Inappropriate shocks do not affect survival, in strong contrast to appropriate ICD therapy. Our study does not support the hypothesis that shock therapy in itself worsens clinical outcome. However, it confirms that appropriate ICD therapy is a warning sign and should prompt physicians to consider additional treatment strategies. PMID- 21678455 TI - The efficacy and safety of sildenafil in patients with pulmonary arterial hypertension associated with the different types of congenital heart disease. AB - BACKGROUND: The difference in underlying pathophysiology in different congenital heart disease (CHD) may have an influence on clinical outcome. It remains unclear whether the effect of sildenafil on pulmonary arterial hypertension (PAH) varies in different types of CHD. HYPOTHESIS: The potential effect of sildenafil on pulmonary arterial hypertension related to CHD may be associated with shunt location. METHODS: In this 12-week, prospective, open label, multicenter trial, 55 patients with CHD were divided into the 3 groups: atrial septal defects group (ASD, n = 15), ventricular septal defects group (VSD, n = 24), and patent ductus arteriosus group (PDA, n = 16). Exercise capacity, hemodynamic parameters, and arterial oxygen saturation were assessed at baseline and after sildenafil therapy (25 mg, 3 times daily). RESULTS: Six-minute walk distance significantly increased from 377.2 +/- 68.7 m to 436.0 +/- 70.4 m in patients with ASD, from 371.2 +/- 66.0 m to 413.7 +/- 83.1 m in VSD, and from 384.3 +/- 90.2 m to 440.9 +/- 71.8 m in PDA (P<0.01, respectively). Moreover, sildenafil also improved the pulmonary vascular resistance and pulmonary blood flow index in the 3 groups, whereas no significant changes in systemic vascular resistance and systemic arterial pressure were observed. However, arterial oxygen saturation was significantly improved in the ASD group only. The incidence of adverse events was similar among the 3 groups. CONCLUSIONS: Sildenafil therapy seems to be effective and safe for PAH secondary to ASD, VSD, and PDA, although some clinical and hemodynamic parameters were changed in a different manner among the 3 groups. PMID- 21678456 TI - Enantioresolution of five beta-blockers by reversed-phase high-performance liquid chromatography using fifteen chiral derivatizing reagents having amino acids or their amides as chiral auxiliaries on a cyanuric chloride platform. AB - Enantioseparation of five beta-blockers, namely, (R,S)-atenolol, (R,S) propranolol, (R,S)-bisoprolol, (R,S)-metoprolol and (R,S)-carvedilol, was achieved as their diastereomers prepared with chiral derivatizing reagents (CDRs) synthesized on a cyanuric chloride platform. Fifteen CDRs were synthesized by nucleophilic substitution of the Cl atom in cyanuric chloride or its 6-methoxy derivative with amino acids (namely, L-Leu, L-Val, D-Phg, L-Met and L-Ala) or their amides as chiral auxiliaries. The diastereomers were synthesized under microwave irradiation for 70 or 100 s at 85% power. Separation of diastereomers was carried out on a C(18) column and gradient eluting mixtures of methanol with aqueous trifluoroacetic acid with UV detection at 230 nm. Separation efficiencies of the reagents were compared on the basis of effect of chiral auxiliaries (i.e. amino acids or amino acid amides) and achiral substituents (i.e. chlorine or methoxy group) in the CDRs. The method was validated for detection limit, linearity, accuracy and precision. PMID- 21678457 TI - Simple HPLC method for detection of trace ephedrine and pseudoephedrine in high purity methamphetamine. AB - A simple and sensitive HPLC technique was developed for the qualitative determination of ephedrine and pseudoephedrine (ephedrines), used as precursors of clandestine d-methamphetamine hydrochloride of high purity. Good separation of ephedrines from bulk d-methamphetamine was achieved, without any extraction or derivatization procedure on a CAPCELLPACK C18 MGII (250 * 4.6 mm) column. The mobile phase consisted of 50 mM KH2 PO4-acetonitrile (94:6 v/v %) using an isocratic pump system within 20 min for detecting two analytes. One run took about 50 min as it was necessary to wash out overloaded methamphetamine for column conditioning. The analytes were detected by UV absorbance measurement at 210 nm. A sample (20 mg) was simply dissolved in 1 mL of water, and a 50 MUL aliquot of the solution was injected into the HPLC. The detection limits for ephedrine and pseudoephedrine in bulk d-methamphetamine were as low as 3 ppm each. This analytical separation technique made it possible to detect ephedrine and/or pseudoephedrine in seven samples of high-purity d-methamphetamine hydrochloride seized in Japan. The presence of trace ephedrines in illicit methamphetamine may strongly indicate a synthetic route via ephedrine in methamphetamine profiling. This method is simple and sensitive, requiring only commonly available equipment, and should be useful for high-purity methamphetamine profiling. PMID- 21678458 TI - Use of an automated capillary DNA sequencer to investigate the interaction of cisplatin with telomeric DNA sequences. AB - The determination of the sequence selectivity of DNA-damaging agents is very important in elucidating the mechanism of action of anti-tumour drugs. The development of automated capillary DNA sequencers with fluorescent labelling has enabled a more precise method for DNA sequence specificity analysis. In this work we utilized the ABI 3730 capillary sequencer with laser-induced fluorescence to examine the sequence selectivity of cisplatin with purified DNA sequences. The use of this automated machine enabled a higher degree of precision of both position and intensity of cisplatin-DNA adducts than previously possible with manual and automated slab gel procedures. A problem with artefact bands was overcome by ethanol precipitation. It was found that cisplatin strongly formed adducts with telomeric DNA sequences. PMID- 21678459 TI - Isolation and characterization of free haem from the shell gland of quail and hen. AB - Free haem was isolated from the shell gland of the quail, Coturnix coturnix japonica, and of the fowl, Galinus domesticus, and characterized by HPLC-ESI MS/MS. Quantification by HPLC gave values of 1.17-1.40 nmol/mg quail shell gland protein for haem, 1.66-2.17 nmol/mg protein for protoporphyrin and 0.25-0.40 nmol/mg protein for biliverdin. Possible implications of this previously unreported finding are discussed but they are not considered incompatible with the conclusion that all eggshell pigments are endogenously synthesized in the oviduct system. PMID- 21678460 TI - Biselyngbyaside, isolated from marine cyanobacteria, inhibits osteoclastogenesis and induces apoptosis in mature osteoclasts. AB - The mass and function of bones depend on the maintenance of a complicated balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An inhibitor of osteoclast differentiation and/or function is expected to be useful for treatment of bone lytic diseases such as osteoporosis, rheumatoid arthritis, and tumor metastasis into bone. Biselyngbyaside is a recently isolated macrolide compound from marine cyanobacteria Lyngbya sp. that shows wide-spectrum cytotoxicity toward human tumor cell lines. In this study, we investigated the effects of biselyngbyaside on osteoclast differentiation and function. Biselyngbyaside inhibited receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis in mouse monocytic RAW264 cells and primary bone marrow-derived macrophages at a low concentration. Similarly, biselyngbyaside suppressed osteoblastic cell-mediated osteoclast differentiation in cocultures. In the RANKL-induced signaling pathway, biselyngbyaside inhibited the expression of c-Fos and NFATc1, which are important transcription factors in osteoclast differentiation. In mature osteoclasts, biselyngbyaside decreased resorption-pit formation. Biselyngbyaside also induced apoptosis accompanied by the induction of caspase-3 activation and nuclear condensation, and these effects were negated by the pancaspase inhibitor z-VAD-FMK. Taken together, the present findings indicate that biselyngbyaside suppresses bone resorption via inhibition of osteoclastogenesis and induction of apoptosis. Thus, biselyngbyaside may be useful for the prevention of bone lytic diseases. PMID- 21678461 TI - Demography of squirrel monkeys (Saimiri sciureus) in captive environments and its effect on population growth. AB - Understanding which life-history variables have the greatest influence on population growth rate has great ecological and conservation importance. Applying models of population regulation and demographic mechanisms can aid management and conservation of both wild and captive populations. By comparisons of sensitivity, elasticity, and life-table response analyses, we identified demographic processes that were most likely to produce changes in population size (via prospective analyses) and the traits that actually influenced population changes (via retrospective analyses) among sexes, zoological facilities, and generations of captive squirrel monkey populations (Saimiri sciureus). Variation in life-history traits occurs within each group analyzed. Those traits that vary the most include age at maturity, age at last reproduction, and fertility. Zoos with increasing population growth rates maintain earlier ages of maturity, later ages of last reproduction, high rates of juvenile and adult survival, and most importantly greater fertility, reflecting shorter inter-birth intervals. Using prospective analyses, juvenile and adult survivals were predicted to be demographic traits with the greatest effect on population growth. Surprisingly, and despite predictions, retrospective analyses revealed that fertility was the life-history characteristic trait that contributed the most to changes in population size. PMID- 21678463 TI - Genome-wide mapping of ZNF652 promoter binding sites in breast cancer cells. AB - A significant proportion of transcription factors encoded by the human genome are classical C(2) H(2) zinc finger proteins that regulate gene expression by directly interacting with their cognate DNA binding motifs. We previously showed that one such C(2) H(2) zinc finger DNA binding protein, ZNF652 (zinc finger protein 652), specifically and functionally interacts with CBFA2T3 to repress transcription of genes involved in breast oncogenesis. To identify potential targets by which ZNF652 exerts its putative tumour suppressive function, its promoter-specific cistrome was mapped by ChIP-chip. De novo motif scanning of the ZNF652 binding sites identified a novel ZNF652 recognition motif that closely resembles the previously characterised in vitro binding site, being a 10 nucleotide core of that 13 nucleotide sequence. Genes with ZNF652 binding sites function in diverse cellular pathways, and many are involved in cancer development and progression. Characterisation of the in vivo ZNF652 DNA binding motif and identification of potential ZNF652 target genes are key steps towards elucidating the function(s) of this transcription factor in the normal and malignant breast cell. PMID- 21678462 TI - Ethanol differentially regulates snail family of transcription factors and invasion of premalignant and malignant pancreatic ductal cells. AB - Pancreatic cancer is one of the deadliest of cancers with a dismal 5-year survival rate. Epidemiological studies have identified chronic pancreatitis as a risk factor for pancreatic cancer. Pancreatic cancer cells also demonstrate increased expression of the transcription factor Snail, a key regulator of epithelial-mesenchymal transition. As ethanol is one of the major causes of pancreatitis, we examined the effect of ethanol on Snail family members in immortalized human pancreatic ductal epithelial (HPDE) cells and in pancreatic cancer cells. Ethanol induced Snail mRNA levels 2.5-fold in HPDE cells, with only 1.5-fold mRNA induction of the Snail-related protein slug. In contrast, ethanol increased Slug mRNA levels 1.5- to 2-fold in pancreatic cancer cells, with minimal effect on Snail. Because Snail increases invasion of cancer cells, we examined the effect of ethanol on invasion of HPDE and pancreatic cancer cells. Surprisingly, ethanol decreased invasion of HPDE cells, but had no effect on invasion of pancreatic cancer cells. Mechanistically, ethanol increased adhesion of HPDE cells to collagen and increased expression of the collagen binding alpha2 and beta1-integrins. In contrast, ethanol did not affect collagen adhesion or integrin expression in pancreatic cancer cells. Also in contrast to HPDE cells, ethanol did not attenuate ERK1/2 phosphorylation in pancreatic cancer cells; however, inhibiting ERK1/2 decreased pancreatic cancer cell invasion. Overall, our results identify the differential effects of ethanol on premalignant and malignant pancreatic cells, and demonstrate the pleiotropic effects of ethanol on pancreatic cancer progression. PMID- 21678464 TI - The therapeutic potential of bone marrow-derived stromal cells. AB - Since the replacement of the hematopoietic system became feasible through bone marrow (BM) transplantation, the idea of how to replace other organs of the body has been in the forefront of medical research. Scientists have been searching for the ideal stem cell that could be manipulated to differentiate into any tissue. Although the embryonal stem cells seemed to have the ability to do this, the difficulties surrounding their use prevented them from becoming therapeutically useful. Thus, the field turned to adult stem cells, particularly stem cells of BM origin. We have learnt a lot during the last decade about the potential of the BM derived stromal (also called mesenchymal stem) cells (BMSCs). The first studies suggested them as cell replacement tools, but later it turned out that their usefulness is more likely due to paracrine effects due to a large variety of secreted factors that induce growth and differentiation of the tissue-specific stem cells as well as prevent injured cells from apoptotic death. Finally, a whole new field emerged when many groups confirmed that these cells are also capable of regulating immune function in a so far unknown, dynamic manner. When BMSCs are injected they seem to be able to sense the environment and respond according to the actual need of the organism in order to survive. This plasticity can never be done by the use of any drugs and such a "live" cell therapy could open a whole new chapter in clinical care in the future. PMID- 21678465 TI - Effects of a glycogen synthase kinase-3beta inhibitor (LiCl) on c-myc protein in intervertebral disc cells. AB - Wnt/beta-catenin (hereafter called Wnt) signaling is a key inducer and regulator of joint development, and is involved in the formation of bone and cartilage. We previously reported that Wnt signaling plays an essential role in the control of cell proliferation and cell senescence in intervertebral disc cells. In the present study, we provide evidence that the expression of c-myc, a key protein required for cell proliferation, is regulated by Wnt signaling. Our data also show that activation of Wnt signaling by LiCl, a Wnt signaling activator, leads to the suppression of c-myc promoter activity and expression. To ascertain whether Wnt signaling regulates the expression of c-myc, we measured both its transcript and protein expression. Following treatment with LiCl, c-myc expression was suppressed at both the mRNA and protein levels. In nucleus pulposus cells treated with c-myc, cell viability increased significantly, whereas treatment with a c-myc inhibitor decreased cell viability. Taken together, these results suggest that c-myc is an important factor that promotes the proliferation of nucleus pulposus cells. These findings provide new insight into the regulation and maintenance of cell proliferation in nucleus pulposus cells. PMID- 21678466 TI - Role of mycobacteria effectors in phagosome maturation blockage and new drug targets discovery. AB - Tuberculosis remains a serious global health threat with nearly 10 million new cases and 1.7 million deaths every year. The emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) further complicates this problem. It is pressing to find new ways to combat Mtb. The success of Mtb is largely attributed to its ability to persist within macrophages by arresting phagosomal maturation. The bacterial proteins and lipids play important roles in this inhibition which involves several aspects of phagosomal maturation, including both fusion and fission events and recruitment of V-ATPases allowing acidification. Understanding the interaction between the pathogen and host macrophage is essential to eradicate or control tuberculosis. This review focuses on the mechanism of phagolysosome formation, the pivotal event for the fates of infection participants and abundance of novel drug targets. PMID- 21678467 TI - Role and regulation of bacterial LuxR-like regulators. AB - LuxR transcriptional regulator is a key player in Quorum Sensing (QS), coordinates the expression of a variety of genes, including those encoding virulence factors and antibiotics biosynthesis, motility, nodulation, plasmid transfer, bioluminescence, and biofilm formation. The characteristics and roles of this family, especially those of Mycobacterium, are summarized in this paper to give clues for drug target discovery. PMID- 21678468 TI - The role of Lrp5/6 in cardiac valve disease: experimental hypercholesterolemia in the ApoE-/- /Lrp5-/- mice. AB - Lrp5/6 co-receptor is known to play a role in bone formation and lipid metabolism. This gene encodes a member of the low-density lipoprotein (LDL) receptor gene family. This study tests the hypothesis that Lrp5/6 is necessary for the development of valve calcification in experimental hypercholesterolemia. Experimental hypercholesterolemia mouse models were tested: Lrp5(-/-) /ApoE(-/ ):Lrp5(-/-) /ApoE(-/-) mice (n = 180). Group I (n = 60) normal diet, Group II (n = 60) 0.25% chol diet (w/w), and Group III (n = 60) 0.25% (w/w) chol diet + atorv for the development of calcification by MicroCT and Synchrotron MicroCT Scan and by Masson trichrome stain. Finally gene expression for Lrp5, Lrp6, and Runx2 PCR was performed to evaluate the expression in the control and the cholesterol valves. The ApoE(-/-) cholesterol treated mice developed calcification and increase in Lrp5, Runx2 (P < 0.05) as compared to control. The Lrp5(-/-) mice developed no calcification by MicroCT and Synchrotron and positive gene expression for Lrp5/6 or Runx2. The double knockout ApoE(-/-):Lrp5(-/-) developed mild mineralization in the cholesterol treated valves with an increase in Lrp6 and Runx2 expression(P < 0.05). There was no mineralization in the right sided hearts valves. In conclusion Lrp5/6 is necessary for calcification in the aortic valve in the presence of experimental hypercholesterolemia. These data demonstrate the first mouse genetic evidence for the LDL-Density-Pressure theory in cardiac valves. PMID- 21678469 TI - Identification of a novel effector domain of BIN1 for cancer suppression. AB - Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein with tumor suppressor properties. The protein interacts with and inhibits the c-MYC transcription factor through the BIN1 MYC-binding domain (MBD). However, in vitro colony formation assays have clearly demonstrated that the MBD is not essential for BIN1-mediated growth arrest. We hypothesized that BIN1 contains a MYC independent effector domain (MID) for cancer suppression. Because a functionally unique domain frequently contains a distinct structure, the human full-length BIN1 protein was subjected to limited trypsin digestion and the digested peptides were analyzed with Edman sequencing and mass spectrometry. We identified a trypsin-resistant peptide that corresponds to amino acids 146-268 of BIN1. It encompassed part of the BAR region, a putative effector region of BIN1. Computational analysis predicted that the peptide is very likely to exhibit coiled-coil motifs, implying a potential role for this region in sustaining the BIN1 structure and function. Like MBD-deleted BIN1, the trypsin-resistant peptide of BIN1 was predominantly present in the cytoplasm and was sufficient to inhibit cancer growth, regardless of dysregulated c-MYC activity. Our results suggest that the coiled-coil BIN1 BAR peptide encodes a novel BIN1 MID domain, through which BIN1 acts as a MYC-independent cancer suppressor. PMID- 21678470 TI - Comparative proteome analysis of 3T3-L1 adipocyte differentiation using iTRAQ coupled 2D LC-MS/MS. AB - Adipose tissue is critical in obesity and type II diabetes. Blocking of adipocyte differentiation is one of the anti-obesity strategies targeting on strong rise in fat storage and secretion of adipokine(s). However, the molecular basis of adipocyte differentiation and its regulation remains obscure. Therefore, we exposed 3T3-L1 cell line to appropriate hormonal inducers as adipocyte differentiation model. Using iTRAQ-coupled 2D LC-MS/MS, a successfully exploited high-throughput proteomic technology, we nearly quantitated 1,000 protein species and found 106 significantly altered proteins during adipocyte differentiation. The great majority of differentially expressed proteins were related to metabolism enzymes, structural molecules, and proteins involved in signal transduction. In addition to previously reported differentially expressed molecules, more than 20 altered proteins previously unknown to be involved with adipogenic process were firstly revealed (e.g., HEXB, DPP7, PTTG1IP, PRDX5, EPDR1, SPNB2, STEAP3, TPP1, etc.). The partially differential proteins were verified by Western blot and/or real-time PCR analysis. Furthermore, the association of PCX and VDAC2, two altered proteins, with adipocyte conversion was analyzed using siRNA method, and the results showed that they could contribute considerably to adipogenesis. In conclusion, our data provide valuable information for further understanding of adipogenesis. PMID- 21678471 TI - Multi-biomarker pattern for tumor identification and prognosis. AB - In last decades, the basic, clinical, and translational research efforts have been directed to the identification of standard biomarkers associated with the degree of malignancy. There is an increasingly public health concern for earlier detection of cancer development at stages in which successful treatments can be achieved. To meet this urgent clinical demand, early stage cancer biomarkers supported by reliable and robust experimental data that can be readily applicable in the clinical practice, are required. In the current standard protocols, when one or two of the canonical proliferating index biomarkers are analyzed, contradictory results are frequently reached leading to incorrect cancer diagnostic and unsuccessful therapies. Therefore, the identification of other cellular characteristics or signatures present in the tumor cells either alone or in combination with the well-established proliferation markers emerge as an alternative strategy in the improvement of cancer diagnosis and treatment. Because it is well known that several pathways and processes are altered in tumor cells, the concept of "single marker" in cancer results incorrect. Therefore, this review aims to analyze and discuss the proposal that the molecular profile of different genes or proteins in different altered tumor pathways must be established to provide a better global clinical pattern for cancer detection and prognosis. PMID- 21678473 TI - Overexpression of cyclooxygenase-2 in NCI-H292 human alveolar epithelial carcinoma cells: roles of p38 MAPK, ERK-1/2, and PI3K/PKB signaling proteins. AB - Evidence suggests overexpression of COX-2 and its role in many human cancers, including lung. However, the regulatory mechanism underlying COX-2 overexpression in lung cancer is not fully understood. We herein investigated whether COX-2 is overexpressed in human airway cancer cell lines, including A549 (lung), Hep-2 (bronchial), and NCI-H292 (alveolar). When grown in cell culture medium containing 10% FBS (serum), of note, there was strong and transient induction of COX-2 protein and mRNA in NCI-H292 cells, but little or low COX-2 expression is seen in A549 or Hep-2 cells. Interestingly, strong and sustained activities of ERK-1/2, JNK-1/2, p38 MAPK, and PKB were also shown in NCI-H292 cells grown in presence of serum. Profoundly, results of pharmacological inhibition studies demonstrated that the serum-dependent COX-2 up-regulation in NCI-H292 cells is attributed to not only the p38 MAPK-, PI3K/PKB-, and ERK-1/2-mediated COX-2 transcriptional up-regulation but also the p38 MAPK- and ERK-1/2-mediated post transcriptional COX-2 mRNA stabilization. Of further note, it was shown that the ERK-1/2 and PI3K/PKB (but not COX-2, p38 MAPK, and JNK-1/2) activities are necessary for growth of NCI-H292 cells. These findings collectively demonstrate for the first time that COX-2 expression is transiently up-regulated by serum addition in NCI-H292 cells and the serum-induced COX-2 expression is closely linked to the p38 MAPK-, ERK-1/2-, and PI3K/PKB-mediated COX-2 transcriptional and post-transcriptional up-regulation. PMID- 21678474 TI - alpha1 -Adrenergic receptor-induced cytoskeletal organization and cell motility in CCL39 fibroblasts requires phospholipase D1. AB - The role of phospholipase D (PLD) in cytoskeletal reorganization, ERK activation, and migration is well established. Both isoforms of PLD (PLD1 and PLD2) can independently activate stress fiber formation and increase ERK phosphorylation. However, the isoform's specificity, upstream activators, and downstream targets of PLD that coordinate this process are less well understood. This study explores the role of alpha(1) -adrenergic receptor stimulation and its effect on PLD activity. We demonstrate that PLD1 activators, RhoA, and PKCalpha are critical for stress fiber formation and ERK activation, and enhance the production of phosphatidic acid (PA) upon phenylephrine addition. Ectopic expression of dominant negative PLD1 and not PLD2 blocks ERK activation, inhibits stress fiber formation, and reduces cell motility in CCL39 fibroblasts. Furthermore, we demonstrate the mechanism for PLD1 activation of ERK involves Ras. This work indicates that PLD1 plays a novel role mediating growth factor and cell motility events in alpha(1) -adrenergic receptor-activated cells. PMID- 21678475 TI - Photodynamic therapy boosts anti-glioma immunity in mice: a dependence on the activities of T cells and complement C3. AB - Photodynamic therapy (PDT) involves the systemic administration of a tumor specific photosensitizer and local irradiation of visible light, can generate highly cytotoxic molecular species in the tumor and kill malignant cells directly or by shutting down the tumor microvasculature. Collectively data show that anti tumor immunity is an important mechanism that mediates the PDT-induced tumor destroying effects in many types of cancers. However, it is unknown whether PDT also promotes anti-tumor immunity in gliomas in the central nervous system (CNS). Here we show that the PDT generates regional and systemic anti-tumor immunity in mice with G422 gliomas in the brain. The infiltration of immune cells and the release of inflammatory factors, such as TNF-alpha and IFN-gamma, are increased in animals with G422 gliomas following PDT when compared with those without receiving PDT. The lymphocytes that are isolated from PDT-treated mice are able to induce anti-tumor immunity in nude mice. The anti-glioma immunity fostered by PDT is inhibited in complement C3 knockout mice and the nude mice indicate the requirement of the activities of complement C3 and T cells. Thus, T cells that produce cytokines, along with complement C3, may play crucial roles in mediating PDT-induced anti-glioma responses. PMID- 21678472 TI - Sensory nerve induced inflammation contributes to heterotopic ossification. AB - Heterotopic ossification (HO), or bone formation in soft tissues, is often the result of traumatic injury. Much evidence has linked the release of BMPs (bone morphogenetic proteins) upon injury to this process. HO was once thought to be a rare occurrence, but recent statistics from the military suggest that as many as 60% of traumatic injuries, resulting from bomb blasts, have associated HO. In this study, we attempt to define the role of peripheral nerves in this process. Since BMP2 has been shown previously to induce release of the neuroinflammatory molecules, substance P (SP) and calcitonin gene related peptide (CGRP), from peripheral, sensory neurons, we examined this process in vivo. SP and CGRP are rapidly expressed upon delivery of BMP2 and remain elevated throughout bone formation. In animals lacking functional sensory neurons (TRPV1(-/-) ), BMP2 mediated increases in SP and CGRP were suppressed as compared to the normal animals, and HO was dramatically inhibited in these deficient mice, suggesting that neuroinflammation plays a functional role. Mast cells, known to be recruited by SP and CGRP, were elevated after BMP2 induction. These mast cells were localized to the nerve structures and underwent degranulation. When degranulation was inhibited using cromolyn, HO was again reduced significantly. Immunohistochemical analysis revealed nerves expressing the stem cell markers nanog and Klf4, as well as the osteoblast marker osterix, after BMP2 induction, in mice treated with cromolyn. The data collectively suggest that BMP2 can act directly on sensory neurons to induce neurogenic inflammation, resulting in nerve remodeling and the migration/release of osteogenic and other stem cells from the nerve. Further, blocking this process significantly reduces HO, suggesting that the stem cell population contributes to bone formation. PMID- 21678476 TI - Recombinant BMP 4/7 fusion protein induces differentiation of bone marrow stem cells. AB - Bone morphogenetic proteins (BMPs) induce differentiation of mesenchymal cells to cartilage and bone. We cloned BMP4 and BMP7 cDNAs from human placenta and fetal cartilage cells, respectively, and used an Escherichia coli expression system to produce recombinant BMP4 and BMP4/7 proteins. Differentiation of primary cultures of bone marrow stem cells (BMSC) treated with BMP4 or BMP4/7 was evaluated by Von Kossa staining and by determining alkaline phosphatase activity and osteocalcin level. BMP4/7-induced BMSC differentiation more potently than BMP4. We showed that BMP4/7 fusion protein expressed in E. coli is biologically active and is a novel strategy to treat bone injury in a clinical setting. PMID- 21678477 TI - Vorinostat, SAHA, represses telomerase activity via epigenetic regulation of telomerase reverse transcriptase in non-small cell lung cancer cells. AB - Vorinostat (suberoylanilide hydroxamic acid), a class of histone deacetylase inhibitors, represents an emerging class of anticancer agents currently progressing in clinical trials. It causes cell growth inhibition, differentiation, and apoptosis of many tumor types in vitro and in vivo. Recently, it was reported that hTERT is one of the targets for cancer therapy in cancer cells. Telomerase repeat amplification protocol assay was used to analyze the expression of hTERT after vorinostat treatment in the A549 lung cancer cells. Vorinostat inhibited telomerase activity by reducing the expression of human telomerase reverse transcriptase (hTERT) in A549 human lung cancer cells. The epigenetic regulation mechanism is responsible for the repression of hTERT by vorinostat, analyzed through the methylation-specific PCR and bisulfite sequencing of the hTERT promoter. Vorinostat induced the demethylation of site specific CpGs on the promoter region of hTERT, which was caused by the down regulation of DNA methyltransferases. DNA methyltransferases (DNMT1 and DNMT3b) were also decreased in vorinostat-treated A549 cancer cells. Furthermore, chromatin immunoprecipitation analysis of the hTERT promoter revealed that vorinostat decreased the level of inactive chromatin markers dimethyl-H3K9, and the declined binding of DNMT1 and DNMT3b were associated. The novel insights showed that vorinostat down-regulated telomerase via epigenetic alteration in lung cancer to vorinostat-mediated cancer-specific therapies. PMID- 21678478 TI - Differential cytotoxic responses to low- and high-dose photodynamic therapy in human gastric and bladder cancer cells. AB - Here, we present differential cytotoxic responses to two different doses of photodynamic therapies (PDTs; low-dose PDT [LDP] and high-dose PDT [HDP]) using a chlorin-based photosensitizer, DH-II-24, in human gastric and bladder cancer cells. Fluorescence-activated cell sorting analysis using Annexin V and propidium iodide (PI) showed that LDP induced apoptotic cell death, whereas HDP predominantly caused necrotic cell death. The differential cytotoxic responses to the two PDTs were further confirmed by a DiOC(6) and PI double-staining assay via confocal microscopy. LDP, but not HDP, activated caspase-3, which was inhibited by Z-VAD, Trolox, and BAPTA-AM. LDP and HDP demonstrated opposite effects on intracellular reactive oxygen species (ROS)/Ca(2+) signals; LDP stimulated intracellular ROS production, contributing to a transient increase of intracellular Ca(2+) , whereas HDP induced a massive and prolonged elevation of intracellular Ca(2+) responsible for the transient production of intracellular ROS. In addition, the two PDTs also increased in situ transglutaminase 2 (TG2) activity, with a higher stimulation by HDP, and this increase in activity was prevented by Trolox, BAPTA-AM, and TG2-siRNA. LDP-induced apoptotic cell death was strongly inhibited by Trolox and TG2-siRNA and moderately suppressed by BAPTA AM. However, HDP-mediated necrotic cell death was partially inhibited by BAPTA-AM but not by TG2-siRNA. Thus, these results demonstrate that LDP and HDP induced apoptotic and necrotic cell death by differential signaling mechanisms involving intracellular Ca(2+) , ROS, and TG2. PMID- 21678479 TI - The interaction topology of Mycobacterium tuberculosis genes response to capreomycin and novel clues for more drug targets. AB - The resurgence of tuberculosis (TB) and emergence of multidrug-resistant TB (MDR TB) are significant obstacles to stop TB treatment. Capreomycin (CPM) is regarded as an ideal second-line treatment for TB as well as for MDR-TB. However, the inexorable emergence of capreomycin resistant TB cases accentuates the urgent need for more detailed characterization of CPM targets. Most of these are single gene mutation, such as those involved in the complex formation of ribosomal 30S initiation, inhibit protein synthesis, affect 50S ribosomal protein L10, control transcription and translation of operon rpIJL-rpoBC. A new paradigm integrating gene, small metabolites, protein and underlying signaling pathway to shed light on the physiology, pathogenesis, and network of pathogen response is emerging. This model holds great promise to unravel the intricacy of drug action. However, to our knowledge, no such work regarding Mycobacterium tuberculosis response to capreomycin exposure was ever reported. We employed the data mining to construct an interaction topology of M. tuberculosis genes response to capreomycin. Most valuable genes were summarized for further experimental validation based on this topology. Dampening the virulence factors and respiratory of M. tuberculosis might be the new targets of CPM beyond Rv1364c, pe_pgrs38, pe_pgrs51 which are the salient nodes of the network and represent most promising new capreomycin targets meriting further exploration. This work will facilitate further investigation of capreomycin targets against M. tuberculosis and be conducive to novel TB drug discovery. PMID- 21678480 TI - Molybdenum enzymes and molybdenum cofactor in mycobacteria. AB - When intracelluar pathogens enter the host macrophages where in addition to oxidative and antibiotic mechanisms of antimicrobial activity, nutrients are deprived. Human pathogen Mycobacterium tuberculosis is one of macrophage parasitisms, which can replicate and persist for decades in dormancy state in virulent environments. It is very successful in escaping the killing mechanisms of macrophage. Molybdenum (Mo) enzymes involve in the global carbon, sulfur, and nitrogen cycles by catalyzing important redox reactions. There are several Mo enzymes in mycobacteria and they exert several important physiological functions, such as dormancy regulation, the metabolism of energy sources, and nitrogen source. Pterin-based Mo cofactor (Moco) is the common cofactor of the Mo enzymes in mycobacteria but the cofactor biosynthesis is nearly an untapped area. The present article discusses the physiological function of Mo enzymes and the structural feature of the genes coding for Moco biosynthesis enzymes in mycobacteria. PMID- 21678481 TI - BMI1 as a novel target for drug discovery in cancer. AB - Growing evidence has demonstrated that clonogenic cancer stem (initiating) cells are responsible for tumor regrowth and disease relapse. Bmi-1 plays a critical role in the self-renewal of adult stem cells. The Bmi-1 protein is elevated in many types of cancers, and experimental reduction of Bmi-1 protein levels by small interfering RNA (siRNA) causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. The Bmi-1 protein has no known enzymatic activity, but serves as the key regulatory component of the PRC1 complex (polycomb repressive complex-1). This complex influences chromatin structure and regulates transcriptional activity of a number of important loci including the Ink4a locus which encodes the tumor suppressor proteins p16(Ink4a) and p14(Arf) . In this prospective study, we will discuss the implication of BMI1 in cancers, the biology of BMI1, and the regulatory control of BMI1 expression. The target validation and the future prospects of targeting BMI1 in cancer therapy are also discussed. PMID- 21678482 TI - Identification of a quantitative trait locus for spontaneous osteoarthritis in STR/ort mice. AB - Osteoarthritis (OA) is the most common joint disorder in humans. Most of the animal models of OA were developed by surgical destabilization of joints or through transgenic approaches, and information from naturally occurring models of OA is very limited. The mouse strain STR/ort is recognized as a spontaneous model of OA. This mouse is unique in that it develops late onset cartilage degeneration of the tibio-femoral joint, similar to human OA. The purpose of this study was to identify quantitative trait loci (QTL) for the OA phenotype in STR/ort. Whereas the trait had been reported to be recessive, a significant population of the F1 generation exhibited OA phenotype. Thus, backcrossed (BC) mice generated by crossing F1 male to C57BL/6N female mice were used for genetic analysis. Degeneration of articular cartilage in BC mice was evaluated by scanning electron microscopy. Linkage analysis was carried out using microsatellite markers covering the entire genome. Cartilage degeneration in STR/ort mice was a polygenic trait. A QTL for the OA phenotype was mapped to a region 20 centimorgans proximal to the centromere of chromosome 4 (LOD = 3.37, p = 0.0065). A QTL associated with the onset of cartilage degeneration in C57BL/6N mice was also identified on chromosome 5 (LOD = 3.04, p = 0.0147). These results suggest that multiple loci are involved in the OA phenotype in mice. PMID- 21678484 TI - Microarray expression profiling of Spodoptera litura in response to oxidative stress. AB - To examine the expression profile of oxidative stress responsive genes in Spodoptera litura, we constructed a cDNA library from S. litura injected with hydrogen peroxide (H(2)O(2)). Using a microarray chip composed of 2,964 cDNAs, we screened gene expression at 1, 3, 5, 7, and 9 h post H(2)O(2) injection. Data were clustered into 15 groups of genes that behave similarly across each time course. Seventy-three genes were identified as being at least twofold up- or downregulated after treatment with H(2)O(2) in S. litura. We constructed expressed sequence tags (ESTs) for genes that changed at least twofold after treatment with H(2)O(2) . The functional classification of these ESTs based on Gene Ontology showed that the ESTs are rich in genes involved in oxidoreductase activity (5.7%), defense (14.3%), cellular process (22.9%), and development (17.1%). PMID- 21678485 TI - Immunohistological localization of serotonin in the CNS and feeding system of the stable fly Stomoxys calcitrans L. (Diptera: Muscidae). AB - Serotonin, or 5-hydroxytryptamine (5-HT), plays critical roles as a neurotransmitter and neuromodulator that control or modulate many behaviors in insects, such as feeding. Neurons immunoreactive (IR) to 5-HT were detected in the central nervous system (CNS) of the larval and adult stages of the stable fly, Stomoxys calcitrans, using an immunohistological technique. The location and pattern of the 5-HT IR neurons are described and compared for these two different developmental stages. Anatomical features of the fly feeding system were analyzed in third instar larvae and adult flies using a combination of histological and immunohistological techniques. In third instar larvae, the cibarial dilator muscles were observed within the cibarial pump skeleton and innervated by 5-HT IR neurons in nerves arising from the brain. There were four pairs of nerves arising from the frontal surface of the larval brain that innervate the cibarial pump muscles, pharynx, and muscles controlling the mouth hooks. A strong serotoninergic innervation of the anterior stomatogastric system was observed, which suggests 5-HT may play a role in the coordination of different phases of food ingestion by larvae. Similarly, many 5-HT IR neurons were found in both the brain and the thoracico-abdominal ganglia in the adult, some of which innervate the cibarial pump dilator muscles and the stomatogastric muscles. This is tnhe first report describing neuromuscular structures of the stable fly feeding system. The results reported here suggest 5-HT may play a critical role in feeding behaviors of stable fly larvae and adults. PMID- 21678486 TI - A trypsin-like protease in rice green semi-looper, Naranga aenescens Moore (Lepidoptera: Noctuidae): purification and characterization. AB - The rice green semi looper, Naranga aenescens Moore (Lepidoptera: Noctuidae) causes severe damage to rice fields in Eastern Asia and Middle East. We demonstrate that two types of serine proteases are active in the midgut of the third instar larvae of N. aenescens, but trypsin-like proteases are considerably more active than chymotrypsin-like proteases. To develop better control strategies, purification and biochemical characterization of a major trypsin-like digestive protease from the midgut of the third instar larvae of N. aenescens was achieved by gel filtration and anion exchange chromatography. After the final purification step, the enzyme was purified 9.62-fold with a recovery of 16.1% and a specific activity of 4.12 U/mg protein and a molecular mass of approximately 88.5 kDa. Biochemical characterization indicated that the purified protease had highest activity at pH 10 and 30 degrees C and was stable for up to 6 h under those conditions. Divalent cations, especially Ca2+, Mg2+, and Cu2+, increased the enzyme activity and synthetic inhibitors that target trypsin-like activity caused a significant reduction in caseinolytic activity. These data may be used to develop inhibitors that decrease the damage of N. aenescens to rice cultivars in the field. PMID- 21678487 TI - Cloning and characterization of the Bombyx mori ecdysone oxidase. AB - The physiological titer of molting hormones in insects depends on relative activities of synthesis and degradation pathways. Ecdysone oxidase (EO) is a key enzyme in the inactivation of ecdysteroid. However, there are only a few reports on ecdysteroid inactivation and its enzymes in silkworm. In this study, we cloned and characterized the Bombyx mori EO (BmEO). The BmEO cDNA contains an ORF of 1,695 bp and the deduced protein sequence contains 564 amino acid residues. The deduced protein sequence contains two functional domains of glucose-methanol choline oxidoreductase in N-terminal and C-terminal. Comparing the expression levels of BmEO in different tissues, high transcription was mainly present in hemocytes. Reduced expression of this enzyme is expected to lead to pathological accumulation of ecdysone in the hemolymph of silkworm larvae or pupae. Our data show that RNA inference of BmEO transcripts resulted in the accumulation of ecdysteroid and death of larvae or pupae. We infer that EO is a crucial element in the physiology of insect development. PMID- 21678488 TI - Cloning and expression analysis of a muscarinic cholinergic receptor from the brain of ant, Polyrhachis vicina. AB - Muscarinic acetylcholine receptors (mAchRs) are the predominant cholinergic receptors in the central and peripheral nervous systems of animals. They also have been found in various insect nervous systems. In this article, a full-length cDNA of a pupative mAchR (PmAchR) was obtained from the brains of ant Polyrhachis vicina by homology cloning in combination with rapid amplification of cDNA ends. PmAchR encodes a 599-amino acid protein that exhibits a high degree of homology with other mAchRs. Real-time quantitative RT-PCR analysis showed that PmAchR is differentially expressed in the brains of workers, males, and females. By in situ hybridization, it is revealed that PmAchR is widely expressed in different soma clusters of the brain, including the mushroom bodies, the antennal lobes, as well as the optic lobes (OL), and the most intensely staining is found in Kenyon cells. Nonetheless, there are more positive nerve fibers in the OL of males' brains than in females' and workers' brains. PMID- 21678489 TI - Generalized double-acquisition imaging for radiofrequency inhomogeneity mitigation in high-field MRI: experimental proof and performance analysis. AB - Transmit arrays have been developed to compensate for radiofrequency inhomogeneities in high-field MRI using different excitation schemes. They can be classified into static or dynamic shimmings depending on the target: homogenizing the radiofrequency field directly or homogenizing the flip angle distribution using the Bloch equation. We have developed an intermediate solution to compare shimming performances between different transmit arrays. This solution, called generalized double-acquisition imaging, is easier to implement than most dynamic shimming methods and offers more degrees of freedom than static shimmings. It uses two acquisitions so that the second acquisition complements the excitation of the first one to obtain by superposition an image that minimizes radiofrequency artefacts. For validation, the method is demonstrated experimentally for a gradient echo sequence on a spherical homogeneous phantom and by simulation on a human head model. PMID- 21678490 TI - Regional and temporal variations in tissue sodium concentration during the acute stroke phase. AB - A technique for noninvasively quantifying the concentration of sodium ((23) Na) ions was applied to the study of ischemic stroke. (23) Na-magnetic resonance imaging techniques have shown considerable potential for measuring subtle changes in ischemic tissue, although studies to date have suffered primarily from poor signal/noise ratio. In this study, accurate quantification of tissue sodium concentration (TSC) was achieved in (23) Na images with voxel sizes of 1.2 MUL acquired in 10 min. The evolution of TSC was investigated from 0.5 to 8 h in focal cortical and subcortical ischemic tissue following permanent middle cerebral artery occlusion in the rat (n = 5). Infarct volumes determined from TSC measurements correlated significantly with histology (P = 0.0006). A delayed linear model was fitted to the TSC time course data in each voxel, which revealed that the TSC increase was more immediate (0.2 +/- 0.1 h delay time) in subcortical ischemic tissue, whereas it was delayed by 1.6 +/- 0.5 h in ischemic cortex (P = 0.0002). No significant differences (P = 0.5) were measured between TSC slope rates in cortical (10.2 +/- 1.1 mM/h) and subcortical (9.7 +/- 1.1 mM/h) ischemic tissue. The data suggest that any TSC increase measured in ischemic tissue indicates infarction (core) and regions exhibiting a delay to TSC increase indicate potentially salvageable tissue (penumbra). PMID- 21678491 TI - Identification of association between disease and multiple markers via sparse partial least-squares regression. AB - Although genome-wide association studies have led to the identifications of hundreds of genes underlying dozens of traits in recent years, most published studies have primarily used single marker-based analysis. Intuitively, more information may be utilized when multiple markers are jointly analyzed. Therefore, many methods have been proposed in the literature for association analysis between traits and multiple markers. Among these methods, simulation and real data analyses have shown that it is often more effective to reduce the dimensionality of the markers in a region through principal components analysis of all the markers first, and then to perform association analysis between traits and those principal components that account for most of the genetic variations in the region. However, one major limitation of this approach is that the principal components are derived purely from marker genotypes, without consideration of their relevance to traits. Furthermore, these components are constructed as linear combinations of all the markers even when only a limited number are potentially relevant to traits. In this manuscript, we propose the use of sparse partial least-squares regression to derive the components that are linear combinations of only relevant markers. This approach is able to use information from both traits and marker genotypes. Extensive simulations and real data analyses on a Crohn's disease data set suggest the superiority of this approach over existing methods. PMID- 21678492 TI - The inter-rater reliability of the Japanese version of the Inventory of Depressive Symptomatology, clinician version. AB - The Inventory of Depressive Symptomatology, clinician version (IDS-C), was developed by Rush et al. to evaluate the severity of major depressive episodes. The aim of the present study was to establish the inter-rater reliability of the Japanese version of the IDS-C. A total of 16 subjects with DSM-IV major depressive episode were evaluated. Two psychiatrists, who had completed a training session for evaluating the IDS-C before starting this reliability study, attended systematic interview sessions with each subject to evaluate the IDS-C independently, using the Japanese version of the structured interview guide for combined rating of the IDS-C and the Hamilton Depression Rating Scale. The severity of the 30 IDS-C items assessed by the two raters ranged from 0 to 4 for 27 items and from 0 to 3 for 3 items. The analysis of variance intra-class correlation inter-rater reliability values for the individual scale items ranged from 0.874 to 1.000. The present results suggest that the Japanese version of the IDS-C is a potentially useful rating instrument with high inter-rater reliability for measuring the severity of depressive symptoms in the hands of psychiatrists with sufficient evaluation training. PMID- 21678493 TI - No association between BDNF Val66Met polymorphism and emergence of psychiatric symptoms in systemic lupus erythematosus patients. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in the regulation of synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent studies have suggested that BDNF plays a role in the pathogenesis of psychiatric symptoms in patients with systemic lupus erythematosus (SLE). OBJECTIVES: We hypothesized that the polymorphism of BDNF Val66Met is associated with the emergence of psychiatric symptoms (PS) and serum BDNF levels in SLE patients. To examine the hypothesis, we compared the BDNF Val66Met polymorphism and serum BDNF levels in patients with SLE with or without PS. METHODS: Psychiatric symptoms were assessed in 54 patients with SLE. PS were evaluated using the Brief Psychiatric Rating Scale. Genotyping was carried out using a 54-nuclease assay. Serum BDNF levels were measured by using enzyme-linked immunosorbent assay. RESULTS: The presence of the Met allele was not significantly associated with the presence of PS or with serum BDNF levels in patients with SLE. CONCLUSION: Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor in the various forms of PS and serum BDNF levels in SLE. PMID- 21678495 TI - AnatomicalTerms.info: heading for an online solution to the anatomical synonym problem hurdles in data-reuse from the Terminologia Anatomica and the foundational model of anatomy and potentials for future development. AB - The many synonyms for anatomical structures confuse medical students and complicate medical communication. Easily accessible translations would alleviate this problem. None of the presently available resources-Terminologia Anatomica (TA), digital terminologies such as the Foundational Model of Anatomy (FMA), and websites-are fully satisfactory to this aim. Internet technologies offer new possibilities to solve the problem. Several authors have called for an online TA. An online translation resource should be easily accessible, user-friendly, comprehensive, expandable, and its quality determinable. As first step towards this goal, we built a translation website that we named www.AnatomicalTerms.info, based on the database of the FMA. It translates between English, Latin, eponyms, and to a lesser extent other languages, and presently contains over 31,000 terms for 7,250 structures, covering 95% of TA. In addition, it automatically presents searches for images, documents and anatomical variations regarding the sought structure. Several terminological and conceptual issues were encountered in transferring data from TA and FMA into AnatomicalTerms.info, resultant from these resources' different set-ups (paper versus digital) and targets (machine versus human-user). To the best of our knowledge, AnatomicalTerms.info is unique in its combination of user-friendliness and comprehensiveness. As next step, wiki-like expandability will be added to enable open contribution of clinical synonyms and terms in different languages. Specific quality measures will be taken to strike a balance between open contribution and quality assurance. AnatomicalTerms.info's mechanism that "translates" terms to structures furthermore may enhance targeted searching by linking images, descriptions, and other anatomical resources to the structures. PMID- 21678494 TI - Predictors of relapse in a study of duloxetine treatment for patients with generalized anxiety disorder. AB - OBJECTIVE: Data from a relapse prevention study of duloxetine treatment for adults with generalized anxiety disorder (GAD) were examined to identify predictors of relapse. METHODS: Patients responding to 6 months of open-label duloxetine treatment were randomized to continuation with duloxetine or withdrawal to placebo for a 6-month double-blind continuation phase (duloxetine, N= 216; placebo, N= 213). Post hoc analyses compared time to GAD relapse during continuation phase by using predictor variables that included patient demographics, symptom severity measures (Hamilton Anxiety Scale Scores [HAMA], Hospital Anxiety and Depression Scale), functional outcomes, and visual analogue scale (VAS) pain measures. Univariate and multivariate analyses were performed using predictor variables from time of randomization into the continuation, withdrawal phase. RESULTS: Severity of anxiety symptoms, degree of functional impairment, and severity of pain at time of randomization were significantly predictive of likelihood of relapse during the continuation phase. Multivariate backwards elimination analysis of significant univariate predictors identified HAMA item one (anxious mood) >= 1 and severity of pain while awake (>= 30 on VAS) as the strongest predictors of GAD relapse. CONCLUSIONS: For patients with GAD responding to open-label treatment with duloxetine, residual symptoms related to anxious mood, pain severity, and psychosocial function were associated with increased relapse risk, although the greatest risk was associated with anxious mood and increased severity of pain while awake. PMID- 21678496 TI - XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification. AB - The role of X chromosome-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) in mediating apoptosis has been reported but the underlying mechanism remains unclear. The present study was designed to examine the putative interaction between XAF1 and p53 and the functional importance of this interaction in regulation of apoptosis in human gastric and colon cancer cells. We first identified XAF1 as a novel target gene of p53 by the chromatin immunoprecipitation (CHIP) assay and demonstrated that wild-type p53, but not mutant p53, down-regulated XAF1 at both mRNA and protein levels, which acted mostly under the condition of high expression of XAF1 and was associated with the physical interaction between p53 and the XAF1 promoter. We also found that the over-expression of XAF1 led to activation of wild-type p53 via post-translational modification in cells with or without DNA damage, which resulting in p53 nuclear accumulation and its increased transcriptional activity and enhancing p53 dependent apoptosis. These findings suggest that a potential novel feedback loop exists between XAF1 and wild-type p53. PMID- 21678497 TI - Constitutive AhR activation leads to concomitant ABCG2-mediated multidrug resistance in cisplatin-resistant esophageal carcinoma cells. AB - Esophageal squamous cell carcinoma (ESCC) is a highly malignant disease that is generally not responding to chemotherapy. It is particularly predominant in China. Although ESCC is significantly associated with cigarette smoking, the relationship between its molecular pathogenesis and responsiveness to chemotherapy and cigarette smoke remains elusive. This study reported the constitutive activation of aryl hydrocarbon receptor (AhR), leading to ABCG2 upregulation and the multidrug resistance (MDR) phenotype, in ESCC cell lines with acquired cisplatin resistance. Reporter gene assay, chromatin immunoprecipitation analysis and specific gene knockdown confirmed that the enhanced AhR binding to a xenobiotic response element (XRE) within the ABCG2 promoter is responsible for ABCG2 overexpression. A HSP90 inhibitor (17-AAG) and two AhR antagonists (kaempferol and salicylamide) were shown to inhibit ABCG2 upregulation, thereby reversing the ABCG2-mediated MDR. Our data therefore advocate the use of these inhibitors as novel chemosensitizers for the treatment of esophageal cancer. PMID- 21678498 TI - Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP-2/9 expression via inhibiting ERK1/2 and reducing DNA-binding activity of NF-kappaB in colon cancer cells. AB - Nimbolide, a plant-derived limonoid has been shown to exert its antiproliferative effects in various cell lines. We demonstrate that nimbolide effectively inhibited proliferation of WiDr colon cancer cells through inhibition of cyclin A leading to S phase arrest. It also caused activation of caspase-mediated apoptosis through the inhibition of ERK1/2 and activation of p38 and JNK1/2. Further nimbolide effectively retarded tumor cell migration and invasion through inhibition of metalloproteinase-2/9 (MMP-2/9) expression, both at the mRNA and protein level. It was also a strong inhibitor of VEGF expression, promoter activity, and in vitro angiogenesis. Finally, nimbolide suppressed the nuclear translocation of p65/p50 and DNA binding of NF-kappaB, which is an important transcription factor for controlling MMP-2/9 and VEGF gene expression. PMID- 21678499 TI - Reversible switching of the emission of diphenyldibenzofulvenes by thermal and mechanical stimuli. PMID- 21678500 TI - An unexpected and easy way of freezing the configuration of a triaryl phosphane oxide. AB - Configurationally stable triaryl phosphane oxides are important for reactions with transfer of chiral information. Apart from introducing bulky substituents to suppress fast inversion of helicity at room temperature, the use of a second chiral element which induces chirality in the triaryl phosphane oxide, so that it adopts only one configuration, is suitable. With regard to chirality transfer, C(2)-symmetric imidazole cyclopeptides were tested for obtaining a configurationally stable phosphane oxide. Density functional calculations showed almost equal energies of the three possible triaryl phosphane oxides (MMM)-1, (PPP)-1, and (MP)-1. Surprisingly, after synthesis only the MMM conformer is present in solution, and its configurational stability was proved by variable temperature and 2D NMR experiments as well as CD measurements. In view of the results of the DFT calculations, formation of stable (MMM)-1 cannot be explained thermodynamically but by kinetic reaction control. This concept of freezing the conformation of a triaryl phosphane oxide can in future be used to easily prepare configurationally stable stereoisomeric propellerlike compounds. PMID- 21678502 TI - Chemical synthesis, structural characterization, optical properties, and photocatalytic activity of ultrathin ZnSe nanorods. AB - Ultrathin ZnSe nanorods in the cubic phase have been synthesized by the reaction of selenium and zinc oleate for 30 min at 240 degrees C. These nanorods showed an average diameter of 2.4 nm, which is much smaller than the Bohr size of bulk ZnSe. Thus, they exhibited a remarkable quantum size effect in terms of their optical properties. The formation of the ultrathin nanorods could be attributed to the oriented attachment mechanism, which was supported by the structure of the nanorods and the control experiments. The ultrathin nanorods were transferred into an aqueous solution by ligand exchange. The performance of these nanorods as a catalyst was examined, using the photodegradation of methyl orange as a model reaction. It was found that the ultrathin nanorods possessed better photocatalytic activities than conventional ones. PMID- 21678501 TI - Preparation of Pt@Fe2O3 nanowires and their catalysis of selective oxidation of olefins and alcohols. AB - Iron oxide coated platinum nanowires (Pt@Fe(2)O(3)NWs) with a diameter of 2.8 nm have been prepared by the oxygen oxidation of FePt NWs in oleylamine. These "cable"-like NWs were characterised by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy and X-ray absorption fine structure analysis. These Pt@Fe(2)O(3) NWs were used as "non-support" heterogeneous catalysts in oxidation of olefins and alcohols. The results revealed that it is an active and highly selective catalyst. Styrene derivatives were tested with molecular oxygen as the sole oxidant, with benzaldehyde successfully obtained from styrene in an absolute yield of 31%, whereas the use of tert-butyl hydroperoxide as the sole oxidant in the oxidation of alcohols led to yields of more than 80% of the corresponding ketone or aldehyde. This unsupported catalyst was found to be more active (TOF=96.5 h(-1)) than other reported Fe(2)O(3) nanoparticle catalysts and could be recycled multiple times without any notable decrease in activity. Our findings will extend the use of such nanomaterial catalysts to new catalytic systems. PMID- 21678503 TI - Ruthenium bidentate phosphine complexes for the coordination and catalytic dehydrogenation of amine- and phosphine-boranes. AB - Addition of the amine-boranes H(3)B?NH(2)tBu, H(3)B?NHMe(2) and H(3)B?NH(3) to the cationic ruthenium fragment [Ru(xantphos)(PPh(3))(OH(2))H][BAr(F)(4)] (2; xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; BAr(F)(4)=[B{3,5 (CF(3))(2)C(6)H(3)}(4)](-)) affords the eta(1)-B-H bound amine-borane complexes [Ru(xantphos)(PPh(3))(H(3)B?NH(2)tBu)H][BAr(F)(4)] (5), [Ru(xantphos)(PPh(3))(H(3) B?NHMe(2))H][BAr(F)(4)] (6) and [Ru(xantphos)(PPh(3))(H(3)B?NH(3))H][BAr(F)(4)] (7). The X-ray crystal structures of 5 and 7 have been determined with [BAr(F)(4)] and [BPh(4)] anions, respectively. Treatment of 2 with H(3)B?PHPh(2) resulted in quite different behaviour, with cleavage of the B-P interaction taking place to generate the structurally characterised bis-secondary phosphine complex [Ru(xantphos)(PHPh(2))(2)H][BPh(4)] (9). The xantphos complexes 2, 5 and 9 proved to be poor precursors for the catalytic dehydrogenation of H(3)B?NHMe(2). While the dppf species (dppf=1,1'-bis(diphenylphosphino)ferrocene) [Ru(dppf)(PPh(3))HCl] (3) and [Ru(dppf)(eta(6)-C(6)H(5)PPh(2))H][BAr(F)(4)] (4) showed better, but still moderate activity, the agostic-stabilised N-heterocyclic carbene derivative [Ru(dppf)(ICy)HCl] (12; ICy=1,3-dicyclohexylimidazol-2 ylidene) proved to be the most efficient catalyst with a turnover number of 76 h( 1) at room temperature. PMID- 21678504 TI - Crown ether complex cation ionic liquids: preparation and applications in organic reactions. AB - A series of crown ether complex cation ionic liquids (CECILs) were designed, synthesised and characterised by NMR spectroscopy, HRMS, thermogravimetric differential thermal analysis (TG-DTA) and elemental analysis. Their applications in various organic reactions were investigated: [15-C-5Na][OH], [15-C-5Na][OAc], [18-C-6K][OH] and [18-C-6K][OAc] (15-C-5=[15]crown-5; 18-C-6=[18]crown-6) efficiently catalysed the Michael addition of alkenes and relevant nucleophiles; [18-C-6K][OH] and [15-C-5Na][OH] effectively catalysed the Henry reaction of nitromethane and aromatic aldehydes; [18-C-6K][OH] has excellent catalytic efficiency for Knoevenagel condensation of aromatic aldehydes and malononitrile; PdCl(2) /[18-C-6K](3)[PO(4)]/K(2)CO(3) efficaciously catalysed the Heck reaction of olefins and aromatic halides; [18-C-6K][BrO(3)] can be used as both oxidant and solvent in the oxidation reaction of aromatic alcohols. The CECIL catalysts [15-C-5Na][OH] (Michael addition) and [18-C-6K][OH] (Henry reaction) can be recycled and reused several times without obvious loss of activity and their recovery is very simple. PMID- 21678505 TI - Rational design of zinc-organic coordination polymers directed by N-donor co ligands. AB - A family of Zn(II) -based metal-organic coordination polymers (MOCPs) [Zn(L)(imid)(2)] (1), [Zn(L)(2,2'-bpy)] (2), [Zn(2)(L)(2)(Py)(3)] (3), [Zn(L)(DPP)]?DMF (4), [Zn(L)(DPEA)] (5), [Zn(2)(L)(2)(4,4'-bpy)] (6), [Zn(L)(3,4' DPEE)]?DMF (7), and [Zn(3)(L)(3)(3,4'-DPEE)(2)]?DMF (8) (L=dithieno[3,2-b:2',3' e]benzene-2,6-dicarboxylic acid, imid=imidazole, bpy=bipyridine, Py=pyridine, DPP=1,3-di(pyridin-4-yl)propane, DPEA=1,2-di(pyridin-4-yl)ethane, and DPEE=(E) 3,4'-(ethene-1,2-diyl)dipyridine) have been rationally designed and generated in the solvothermal reaction systems of the new conjugated thiophene derivative L, Zn(ClO(4))(2)?6H(2)O, and seven different aromatic N-donor co-ligands separately. These N-donor compounds were carefully selected and employed in the crystal preparation of the eight MOCPs as structure-directing co-ligands owing to their structural specialties and habitual coordination fashions. Among these MOCPs, compounds 1-3 are 1D polymers with different chain structures. Compounds 4, 7, and 8 are 2D structures, in which 4 has two sets of twofold interpenetrating layers, whereas 7 and 8 are both built from three independent sheets. Compounds 5 and 6 are 3D frameworks, in which 5 exhibits a fivefold interpenetrating diamondoid network, whereas 6 shows a typical twofold interpenetrating pillared layer structure with nanoscale channels. The photoluminescent properties of these MOCPs, including excitation, emission, and radiactive lifetime, have also been investigated to help us tentatively understand their structure-property relationships. PMID- 21678506 TI - cyclo-Bis(urea-3,6-dichlorocarbazole) as a chromogenic and fluorogenic receptor for anions and a selective sensor of zinc and copper cations. PMID- 21678507 TI - Processing nanomaterials in molten salts: partially electrometallized TiO2 as Pt support for enhanced catalytic oxidation of CO and CH3OH. PMID- 21678508 TI - "Deconvoluted fullerene" derivatives: synthesis and characterization. AB - We have designed the synthesis of "deconvoluted fullerene" derivatives that present an ordered pattern of hexagons and pentagons in the backbone of the molecule. We not only mimicked the fullerene structure in dihedral planes, but also preserved its electron accepting behavior and enlarged its optical absorption. Moreover, very preliminary photoluminescence (PL) quenching experiments also confirmed the potentiality of these materials as acceptors in the field of organic photovoltaics (OPV)s. A brief discussion of the surface morphology, based on AFM analysis, is also presented. PMID- 21678509 TI - The pivotal role of symmetry in the ruthenium-catalyzed ring-closing metathesis of olefins. AB - The synthesis of Ru-based precatalysts with N-heterocyclic carbene (NHC) ligands bearing syn- and anti-methyl groups on the NHC backbone and aryl N-substituents with differing steric bulk was carried out. The catalytic behavior of the monophospine Ru precatalysts (7a, 7b, 8a, and 8b) was compared to the corresponding family of phosphine-free catalysts (9a, 9b, 10a and 10b) in the ring-closing metathesis (RCM) of olefins. These catalysts showed high efficiency in RCM reactions and the syn-isomers 7a and 9a, in particular, proved to be among the most active catalysts in the formation of tetrasubstituted olefins through RCM. DFT studies on the entire RCM catalytic cycle of hindered olefins were performed to rationalize the different behaviors of catalysts with syn- and anti methyl groups on the NHC backbone. Theoretical results not only disclosed how NHC symmetry influences the overall activity of the catalyst, but also gave relevant and more general indications on the crucial steps of the RCM of olefins. PMID- 21678510 TI - Photoelectrochemistry of free-base-porphyrin-functionalized zinc oxide nanoparticles and their applications in biosensing. AB - The photoelectrochemical properties of free-base-porphyrin-functionalized zinc oxide nanoparticles were studied. A universal photoelectrochemical biosensing platform was constructed on indium tin oxide (ITO) by using the functional nanohybrid. The nanohybrid was synthesized by means of dentate binding of ZnO nanoparticles with carboxylic groups of 4,4',4'',4'''-(21H,23H-porphine 5,10,15,20-tetrayl)tetrakis(benzoic acid) (TCPP), and characterized with scanning electron microscopy, contact angle measurement, and spectral techniques. The nanohybrid-coated ITO electrode showed an efficient photocurrent response under irradiation at a wavelength of 360 nm, which could be greatly improved upon addition of cysteine by its oxidation at +0.3 V. The possible mechanism was that cysteine acts as a sacrificial electron donor to scavenge the photogenerated holes that locate on the excited state of TCPP, which then injects the photoexcitation electrons into the conduction band of ZnO nanoparticles, thereby transferring photoinduced electrons to the ITO electrode. Based on this enhanced photocurrent signal, a novel method for photoelectrochemical detection of cysteine was developed with a linear range of 0.6 to 157 MUmol L(-1) in physiological media. The detection limit was 0.2 MUmol L(-1) at a signal-to-noise ratio of 3. The novel strategy of cysteine analysis could provide an alternative method for monitoring biomolecules and extend the application of porphyrin functionalized semiconductor nanoparticles. PMID- 21678511 TI - Expanding the utility of Bronsted base catalysis: biomimetic enantioselective decarboxylative reactions. AB - As a result of the low reactivity of simple esters, the use of them as nucleophiles in direct asymmetric transformations is a long-standing challenge in synthetic organic chemistry. Nature approaches this difficulty through a decarboxylative mechanism, which is used for polyketide synthesis. Inspired by nature, we report guanidine-catalyzed biomimetic decarboxylative C-C and C-N bond formation reactions. These highly enantioselective decarboxylative Mannich and amination reactions utilized malonic acid half thioesters as simple ester surrogates. It is proposed that nucleophilic addition precedes decarboxylation in the mechanism, which has been investigated in detail through the identification of intermediates by using electrospray ionization (ESI) mass-spectrometric analysis and DFT calculations. PMID- 21678512 TI - A biomimetic principle for the chemical modification of metal surfaces: synthesis of tripodal catecholates as analogues of siderophores and mussel adhesion proteins. AB - By following a biomimetic design principle, tetravalent scaffolds based on an adamantyl and trisalkylmethyl core structure have been synthesized. These scaffolds have been coupled to three catecholamines, thus resembling the characteristic tripodal recognition motif of many natural metal binders, such as mussel adhesion proteins and siderophores, for example, enterobactin. Besides this tripodal recognition element, our scaffolds provide a fourth position for the conjugation of effector molecules. These effectors can be conjugated through biocompatible conjugation techniques to the scaffold and can be used to tailor the properties of different metal surfaces for a range of applications, for example, in implant engineering. Herein, we describe the synthesis of several tripodal metal binders and their immobilization on TiO(2) surfaces by using a simple dip-coating procedure. Furthermore, we demonstrate the conjugation of our surface binders to the dye eosin Y as an effector molecule by peptide coupling. The resulting surfaces have been analyzed by using ellipsometry, time-of-flight secondary ion mass spectrometry, IR spectroscopy, and contact-angle measurements to confirm the specific loading on TiO(2) films and nanoparticles with our trivalent surface binders. As a proof of concept, we have demonstrated the functionalization of TiO(2) nanoparticles with the eosin Y dye. PMID- 21678513 TI - Au(I) /Au(III) catalysis: an alternative approach for C-C oxidative coupling. AB - When reacted in the presence of external oxidants, gold complexes are capable of catalyzing oxidative homo- and cross-coupling reactions involving the formation of new C-C bonds. Over the last few years, several cascade processes have been reported in which coupling is preceded by a gold-mediated aryl C-H functionalization or nucleophilic addition. These reactions combine the unique reactivity of gold with oxidative coupling, enabling the construction of C-C bonds between coupling partners that are not easily accessed using alternative catalysts. In this Concept paper, the development of gold-catalyzed oxidative coupling reactions is discussed focusing on C-C bond-forming reactions of broad synthetic appeal. PMID- 21678514 TI - The role of chirality in directing the formation of cup-shaped porphyrins and the coordination characteristics of such hosts. AB - Cup-shaped porphyrin 1a has four norbornane rings for encircling space and this type of host could be of interest in supramolecular and catalytic chemistry. We used (1)H NMR spectroscopy to investigate the acid-catalyzed (pTsOH in CHCl(3) and TFA in CH(3)CN) condensation of racemic, enantioenriched (80-85 % enantiomeric excess (ee)), and enantiopure (99 % ee) pyrromethanecarbinol 7 into 1a. We found that the oligomerization of racemic 7(rac) would give 1a-d in the ratio different from the statistical one, though a minuscule quantity of 1a (<5 %) formed. The oligomerization of enantioenriched 7 (80-85 % ee), however, led to the formation of greater amounts of 1a (31-47 %) along with other stereoisomers 1b-d. Importantly, pTsOH catalyzed the conversion of enantiopure 7 (99 % ee) into 1a (>95 % diastereomeric excess (de), 25 % overall yield) in CHCl(3) although prolonged reaction times or greater concentration of the catalytic acid gave rise to 1b-d at the expense of 1a. The metallation of 1 a with Zn(OAc)(2) led to the formation of Zn(II) -1 a and we used computational (DFT: RI-BP86/SV(P),TZVP) and experimental ((1)H NMR spectroscopy) methods to study the partitioning of smaller N-methylimidazole 13 (94 A(3) ) and bigger 1,5-dicyclohexylimidazole 14 (268 A(3)) between the inner and outer side of the host. We found that bigger 14 was mostly encapsulated (90 %) inside Zn(II) -1 a at 298.0 K, whereas smaller 13 would equally partition between the two sides of the host. Furthermore, the out/in equilibrium was, in the case of 14-Zn(II) -1a, favored by entropy (TDeltaS degrees (out/in) =3.5+/-0.1 kcal mol(-1)) indicating that perhaps differential solvation of the coordinated ligand assisted the encapsulation. PMID- 21678515 TI - Selective palladium-loaded MIL-101 catalysts. AB - Palladium nanoparticles (NPs) of different mean particle size have been synthesized in the host structure of the porous coordination polymer (or metal organic framework: MOF) MIL-101. The metal-organic chemical vapor deposition method was used to load MIL-101 with the Pd precursor complex [(eta(5) C(5)H(5))Pd(eta(3)-C(3)H(5))]. Loadings higher than 50 wt.% could be accomplished. Reduction of the Pd precursor complex with H(2) gave rise to Pd NPs inside the MIL-101 (Pd@MIL-101). The reduction conditions, especially the temperature, allows us to make size-conform (size of the Pd NPs correlates with the size of the cavities of the host structure of MIL-101) and undersized Pd NPs. The Pd@MIL-101 samples were characterized by X-ray diffraction, IR spectroscopy, Brauner-Emmett-Teller (BET) analysis, elemental analysis, and transmission electron microscopy (TEM). Catalytic studies, hydrogenation of ketones, were performed with selected Pd@MIL-101 catalysts. Activity, selectivity, and recyclability of the catalyst family are discussed. PMID- 21678516 TI - Stabilizing low-valent refractory metals in a strongly oxidizing medium: the first molybdenum(V) sulfate--MoO(HSO4)(SO4)--from Mo(CO)6 in oleum. PMID- 21678517 TI - Lanthanide-doped multicolor GdF3 nanocrystals for time-resolved photoluminescent biodetection. PMID- 21678518 TI - A luminescent host-guest hybrid between a Eu(III) complex and MWCNTs. PMID- 21678519 TI - In vitro cytotoxic activity and structure activity relationships of iridoid glucosides derived from Veronica species. AB - This study was an investigation of the cytotoxic activity of iridoid glucosides, including aucubin, catalpol, 6-O-acetylcatalpol, veronicoside, catalposide, verproside, amphicoside, veratroylcatalposide, verminoside, aquaticosides B and C isolated from different Veronica species. The cytotoxic activity was determined against Hep-2 (human epidermoid carcinoma), RD (human rhabdomyosarcoma), L-20B (transgenic murine L-cells) cancer cell lines and Vero (African green monkey kidney cells) non-cancerous cell line using the MTT method. While verminoside, amphicoside and veronicoside were found to exhibit cytotoxic activity in the concentration range of 70-355 uM, acetylcatalpol, aquaticosides B and C, catalposide, veratroylcatalposide and verproside showed cytostatic activity. Apoptotic cell death was observed as the effect of verminoside in the histological analysis of the tested cell lines. In conclusion, iridoid glucosides are considered to show a biphasic effect on cancer cells that is both cytostatic and cytotoxic, depending on the chemical structure and the type of cancer cell. PMID- 21678520 TI - An extract of Withania somnifera attenuates endothelin-1-stimulated pigmentation in human epidermal equivalents through the interruption of PKC activity within melanocytes. AB - Redox imbalances have been shown to be closely linked to a variety of altered cellular responses and profoundly affect intracellular signaling pathways, especially the PKC/MAPK pathway which is a major pathway involved in regulating melanogenesis within human melanocytes. To elucidate the effects of redox balance regulation on epidermal hyperpigmentary disorders, an antioxidant-rich herb extract of Withania somnifera was used to assess its effect on endothelin-1 (EDN1)-stimulated pigmentation in human epidermis equivalents and its biological mechanisms analysed. Addition of the Withania somnifera extract (10 ug/mL) elicited a marked depigmenting effect on EDN1 (10 nm)-stimulated pigmentation which was accompanied by a significant decrease in eumelanin content. Real-time RT-PCR and western blotting revealed that the stimulated expression of melanocyte specific mRNAs and proteins, including microphthalmia associated transcription factor (MITF), was significantly suppressed at days 7-10 of culture by the Withania somnifera extract (10 ug/mL), suggesting an impairment in intracellular signaling upstream of gene expression. Signaling analysis revealed that in Withania somnifera extract (10 ug/mL)-treated human melanoma cells in culture, there was a marked deficiency in EDN1 (10 nm)-stimulated phosphorylation of Raf 1, MEK, ERK, MITF and Cyclic AMP responsive element binding protein (CREB) at 15 min after EDN1 treatment. Consistently, treatment with withaferin A, a major component of the Withania somnifera extract, at concentrations of 10-50 um also significantly down-regulated the EDN1 stimulated phosphorylation of Raf-1, MEK, ERK, MITF and CREB at 15 min after EDN1 treatment. Since Raf-1 is phosphorylated by protein kinase C (PKC) activity, these findings indicate that the Withania somnifera extract attenuates EDN1-stimulated pigmentation by preferentially inhibiting EDN1-triggered PKC activity. PMID- 21678521 TI - The in vitro inhibition of human CYP1A2, CYP2D6 and CYP3A4 by tetrahydropalmatine, neferine and berberine. AB - The purpose of this study was to investigate the in vitro inhibition potential of the three purified herbal constituents tetrahydropalmatine (Tet), neferine (Nef) and berberine (Ber) towards recombinant human CYP1A2, CYP2D6 and CYP3A4 metabolic activities. In vitro incubations were performed with phenacetin, dextromethorphan and testosterone, respectively, as CYP substrates and their metabolites were determined by validated HPLC methods. Positive control inhibitors were run for each CYP in all incubation series. Inhibition was expressed by IC50 values. All herbal constituents demonstrated some, but variable, inhibition potencies towards the investigated CYP enzymes. CYP2D6 was the most sensitive for inhibition and then mainly by Tet and Ber with IC50 values of 3.04 +/- 0.26 uM and 7.40 +/- 0.36 uM, respectively. CYP3A4 and especially CYP1A2 were inhibited to a much smaller extent by all constituents. Neferine showed the lowest overall interaction potential towards the CYP enzymes investigated. The CYP inhibition potential for the purified constituents could be related to their chemical structures. No clinical significant metabolic interaction seems likely to occur between the CYP enzymes and herbal constituents tested, with a possible exception for the CYP2D6 inhibition by Tet and Ber. PMID- 21678523 TI - Topography of four different endodontic rotary systems, before and after being used for the 12th time. AB - Root canal preparation may damage NiTi instruments resulting in wear and deformation. The aim of this study was to make a comparative evaluation of the surface topography of the cervical third of four different rotary systems, before and after being used twelve times, in 1.440 resin blocks with simulated root canals with standardized 45 degrees curvatures, and analyzed by atomic force microscopy AFM. The blocks were divided into four groups and prepared according to the manufacturers recommendations: Group 1--K3(r); Group 2--Protaper Universal(r); Group 3--Twisted Files(r) and Group 4--Biorace(r). After each preparation, the instruments were washed and autoclaved. A total of 240 instruments were selected, being 30 new instruments and 30 after having been used for the 12th time, from each group. These instruments were analyzed by AFM and for quantitative evaluation, the mean RMS (Root mean square) values of the cervical third of the specimens from the four groups were used. The result showed that all the rotary files used for the 12th time suffered wear with change in the topography of the cervical region of the active portion of the file (ANOVA p < 0.01). Classifying the specimens in increasing order, from the least to the greatest wear suffered, Group 3 (2.8993 nm) presented the least wear, followed by Group 4 (12.2520 nm), Group 1 (36.0043 nm) and lastly, Group 2 (59.8750 nm) with the largest amount of cervical surface wear. PMID- 21678524 TI - MRT letter: Nanoscopy of protein colocalization in living cells by STED and GSDIM. AB - We report the use of superresolution fluorescence microscopy for studying the nanoscale distribution of protein colocalization in living mammalian cells. Nanoscale imaging is attained both by a targeted and a stochastic fluorescence on off switching superresolution method, namely by stimulated emission depletion (STED) and ground state depletion microscopy followed by individual molecular return (GSDIM), respectively. Analysis of protein colocalization is performed by bimolecular fluorescence complementation (BiFC). Specifically, a nonfluorescent fragment of the yellow fluorescent protein Citrine is fused to tubulin while a counterpart nonfluorescent fragment is fused to the microtubulin-associated protein MAP2 such that fluorescence is reconstituted on contact of the fragment carrying proteins. Images with resolution down to 65 nm prove a powerful new way for studying protein colocalization in living cells at the nanoscale. PMID- 21678525 TI - Neurotrophin Trk receptors in the brain of a teleost fish, Nothobranchius furzeri. AB - Trk neurotrophin receptors are transmembrane tyrosine kinase proteins known as TrkA, TrkB, and TrkC. TrkA is the high affinity receptor for nerve growth factor, TrkB is the one for both brain-derived neurotrophic factor and neurotrophin-4, and TrkC is the preferred receptor for neurotrophin-3. In the adult mammalian brain, neurotrophins are important regulators of neuronal function and plasticity. This study is based on Nothobranchius furzeri, a teleost fish that is becoming an ideal candidate as animal model for aging studies because its life expectancy in captivity is of just 3 months. In adult N. furzeri, all three investigated neurotrophin Trk receptors were immunohistochemically detected in each brain region. TrkA positive neuronal perikarya were localized in the dorsal and ventral areas of the telencephalon and in the cortical nucleus; TrkB immunoreactivity was observed in neuronal perikarya of the dorsal and ventral areas of the telencephalon, the diffuse inferior lobe of the hypothalamus, and Purkinje cells; TrkC positive neuronal perikarya were detected in the most aboral region of the telencephalon, in the magnocellular preoptic nucleus and in few neurons dispersed in the hypothalamus. Numerous positive fibers were widely distributed throughout the brain. Radial glial cells lining the mesencephalic and rhombencephalic ventricles showed immunoreactivity to all three Trks. These findings suggest an involvement of neurotrophins in many aspects of biology of adult N. furzeri. PMID- 21678526 TI - TRPV4 in the sensory organs of adult zebrafish. AB - TRPV4 is a nonselective cation channel that belongs to the vanilloid (V) subfamily of transient receptor potential (TRP) ion channels. While TRP channels have been found to be involved in sensing temperature, light, pressure, and chemical stimuli, TPRV4 is believed to be primarily a mechanosensor although it can also respond to warm temperatures, acidic pH, and several chemical compounds. In zebrafish, the expression of trpv4 has been studied during embryonic development, whereas its pattern of TPRV4 expression during the adult life has not been thoroughly analyzed. In this study, the occurrence of TRPV4 was addressed in the zebrafish sensory organs at the mRNA (RT-PCR) and protein (Westernblot) levels. Once the occurrence of TRPV4 was demonstrated, the TRPV4 positive cells were identified by using immunohistochemistry. TPRV4 was detected in mantle and sensory cells of neuromasts, in a subpopulation of hair sensory cells in the macula and in the cristae ampullaris of the inner ear, in sensory cells in the taste buds, in crypt neurons and ciliated sensory neurons of the olfactory epithelium, and in cells of the retina. These results demonstrate the presence of TRPV4 in all sensory organs of adult zebrafish and are consistent with the multiple physiological functions suspected for TRPV4 in mammals (mechanosensation, hearing, and temperature sensing), but furthermore suggest potential roles in olfaction and vision in zebrafish. PMID- 21678527 TI - Transmission electron microscopy as a tool to image bioinorganic nanohybrids: the case of phage-gold nanocomposites. AB - In recent years, bioinorganic nanohybrids composed of biological macromolecules and functional inorganic nanomaterials have revealed many unique properties that show promise for the future. Transmission electron microscopy (TEM) is a popular and relatively simple tool that can offer a direct visualization of the nanomaterials with high resolutions. When TEM is applied to visualize bioinorganic nanohybrids, a treatment of negative staining is necessary due to the presence of biological molecules in the nanohybrids except for those with densely packed inorganic materials. However, the conventional negative-staining procedure for regular biological samples cannot be directly applied to such bioinorganic nanohybrids. To image a specific bioinorganic nanohybrid, negative staining factors such as negative stain type, working pH, staining time, and drying method, should be identified. Currently, no detailed studies have been done to investigate how to adjust negative-staining factors based on specific bioinorganic nanohybrids. In this study, bacteriophage-gold nanoparticle hybrids were chosen as a model to systematically study the effects of each factor on the negative staining of the nanohybrids. The best staining conditions for gold nanoparticle-phage nanohybrids were obtained and the effects of each factor on the negative staining of general nanohybrids were discussed. This work indicates that with proper staining it is possible to use TEM to visualize directly both biological and inorganic components without introducing any artifact. PMID- 21678531 TI - Modulating the acidity: highly acidic Bronsted acids in asymmetric catalysis. AB - Recently, chiral highly acidic Bronsted acids have emerged as powerful catalysts for enantioselective C-C and C-X bond-forming reactions. Their strong acidity renders them valuable tools for the activation of imines, carbonyl compounds, and other weakly basic substrates. As a result, new perspectives are opened and highly stereoselective transformations based on the concept of chiral contact-ion pair catalysis can be realized. This Minireview gives an overview of the design and application of these new organocatalysts and presents recent results in this rapidly growing field. PMID- 21678532 TI - A. M. Zaitsev: lasting contributions of a synthetic virtuoso a century after his death. PMID- 21678528 TI - Optic vesicle-like structures derived from human pluripotent stem cells facilitate a customized approach to retinal disease treatment. AB - Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine. PMID- 21678533 TI - Facile conversion of CO/H2 into methoxide at a uranium(III) center. PMID- 21678534 TI - Indeno[2,1-a]fluorene: an air-stable ortho-quinodimethane derivative. PMID- 21678535 TI - Enantioselective C-C bond formation as a result of the oriented prochirality of an achiral aldehyde at the single-crystal face upon treatment with a dialkyl zinc vapor. PMID- 21678536 TI - Branching cascades: a concise synthetic strategy targeting diverse and complex molecular frameworks. PMID- 21678537 TI - Dynamic monitoring of newly synthesized proteomes: up-regulation of myristoylated protein kinase A during butyric acid induced apoptosis. PMID- 21678538 TI - A ribonucleotide reductase-like electron transfer system in the nitroaryl-forming N-oxygenase AurF. PMID- 21678539 TI - Isopenicillin N synthase binds delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-thia allo-isoleucine through both sulfur atoms. AB - Isopenicillin N synthase (IPNS) catalyses the synthesis of isopenicillin N (IPN), the biosynthetic precursor to penicillin and cephalosporin antibiotics. IPNS is a non-heme iron(II) oxidase that mediates the oxidative cyclisation of the tripeptide delta-L-alpha-aminoadipoyl-L-cysteinyl-D-valine (ACV) to IPN with a concomitant reduction of molecular oxygen to water. Solution-phase incubation experiments have shown that, although IPNS can turn over analogues with a diverse range of hydrocarbon side chains in the third (valinyl) position of its substrate, the enzyme is much less tolerant of polar residues in this position. Thus, although IPNS converts delta-L-alpha-aminoadipoyl-L-cysteinyl-D-isoleucine (ACI) and AC-D-allo-isoleucine (ACaI) to penam products, the isosteric sulfur containing peptides AC-D-thiaisoleucine (ACtI) and AC-D-thia-allo-isoleucine (ACtaI) are not turned over. To determine why these peptides are not substrates, we crystallized ACtaI with IPNS. We report the synthesis of ACtaI and the crystal structure of the IPNS:Fe(II) :ACtaI complex to 1.79 A resolution. This structure reveals direct ligation of the thioether side chain to iron: the sulfide sulfur sits 2.66 A from the metal, squarely in the oxygen binding site. This result articulates a structural basis for the failure of IPNS to turn over these substrates. PMID- 21678540 TI - Probing protein-protein interactions with a genetically encoded photo crosslinking amino acid. PMID- 21678541 TI - An MD2 hot-spot-mimicking peptide that suppresses TLR4-mediated inflammatory response in vitro and in vivo. PMID- 21678542 TI - Robotic-assisted bariatric surgery: a systematic review. AB - BACKGROUND: Bariatric laparoscopic surgery has been shown to lead to sustainable weight-loss in obese individuals. Robotic-assisted laparoscopic surgery is proposed as the next major evolution in minimally invasive surgery. This study systematically reviews the literature regarding the feasibility and safety of robotic-assisted bariatric surgery in obese patients. METHODS: A comprehensive search of electronic databases was completed for the period 2003 to 2010. Two independent reviewers assessed the studies for relevance, inclusion, and extracted data. RESULTS: After an initial screen of 297 titles, 22 studies met the inclusion criteria. A total of 1253 patients with a mean preoperative body mass index of 46.6 kg/m(2) were obtained from 13 included studies. Major complications of malabsorptive procedures included eight anastomotic leaks (2.4%), bleeding (7/349 patients = 2%) and strictures/stenosis (13/430 patients = 3%). There were no reported deaths. CONCLUSIONS: This systematic review demonstrates that robotic-assisted bariatric surgery is both a safe and feasible option for severely obese patients. PMID- 21678543 TI - Totally robotic right colectomy: a preliminary case series and an overview of the literature. AB - BACKGROUND: Since the introduction of robotics, relatively few series have been published evaluating its role for right colectomy. The aim of this study was to report our preliminary experience with totally robotic right colectomy (TRRC). METHODS: Between 2009 and 2010 we performed three TRRCs, using a hand-sewn intracorporeal anastomosis. Data were retrospectively reviewed. RESULTS: Two women and one man underwent a TRRC. Mean operative time was 270 min. Mean blood loss was 30 ml. There was no conversion. Mean number of lymph nodes harvested was 18. There were no complications. Median hospital stay was 10 days. After a median follow-up of 10 months, there was no tumoural recurrence. CONCLUSION: TRRC is not only safe and feasible but also oncologically effective. Although preliminary and small, this experience confirmed the results from previous series using a hand sewn intracorporeal anastomosis. Larger series are required to draw firm conclusions concerning the possible indications for TRRC. PMID- 21678544 TI - Determination of dipyrone in pharmaceutical preparations based on the chemiluminescent reaction of the quinolinic hydrazide-H2O2-vanadium(IV) system and flow-injection analysis. AB - A rapid, economic and sensitive chemiluminescent method involving flow-injection analysis was developed for the determination of dipyrone in pharmaceutical preparations. The method is based on the chemiluminescent reaction between quinolinic hydrazide and hydrogen peroxide in a strongly alkaline medium, in which vanadium(IV) acts as a catalyst. Principal chemical and physical variables involved in the flow-injection system were optimized using a modified simplex method. The variations in the quantum yield observed when dipyrone was present in the reaction medium were used to determine the concentration of this compound. The proposed method requires no preconcentration steps and reliably quantifies dipyrone over the linear range 1-50 ug/mL. In addition, a sample throughput of 85 samples/h is possible. PMID- 21678545 TI - Pathogenesis of cleft lip and its relation to embryonic face shape in A/J and C57BL mice. 1968. PMID- 21678546 TI - Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. AB - BACKGROUND: The purpose of this study was to investigate the effect of chronic uptake of bhang, prepared from the Cannabis sativa, on male reproductive physiology in adult male Parkes strain (P) mice. An attempt was also made to investigate the presence of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors, and fatty acid amide hydrolase (FAAH) in the testis and to evaluate any changes in it resulting from chronic intake of bhang in mice. METHODS AND RESULTS: Adult male mice were given bhang (3 or 6 mg/kg body weight/day) orally for 36 consecutive days. Chronic intake of bhang caused regressive changes in the testes and suppressed sperm count, viability and motility. Bhang intake also caused significant decline in circulating testosterone level due to decline in testicular 3beta HSD enzyme activity. An immunohistochemical study demonstrated the presence of CB1, CB2 and FAAH in the testis of mice. The present study also showed significant variation in the CB1 and CB2 receptors and FAAH protein levels in testes of mice exposed to bhang. These suppressive effects may be due to inhibitory effect of bhang on pituitary expression of gonadotrophin releasing hormone (GnRH) I receptor protein. Treatment of testes with bhang in vitro significantly decreased testicular luteinizing hormone receptor (LHR) and FAAH expression suggesting direct action of bhang on testicular activity. CONCLUSIONS: The findings of this study thus suggest that bhang may impair fertility in male mice through alteration in the testicular endocannabinoid system and that chronic bhang exposure in humans would be predicted to alter male fertility. PMID- 21678547 TI - Impaired reproduction in adult male, but not female, rats following juvenile treatment with the aromatase inhibitor, exemestane. AB - BACKGROUND: Exemestane is an irreversible steroidal inhibitor of cytochrome-P450 aromatase required for estrogen synthesis. The safety of the drug in the pediatric population, particularly in males, has not previously been evaluated. Given the increased interest in treating children with aromatase inhibitors, we undertook a study in rats to assess the potential for exemestane to alter reproductive development and function when administered to juveniles. METHODS: Male and female rats were treated with exemestane at doses anticipated to produce exposures approximately 2- and 35-fold the expected clinical plasma exposure in young adult males during the period of reproductive maturation. After maturation, treated rats were mated to evaluate the potential impact on reproductive function. RESULTS AND CONCLUSION: There were no effects on sexual maturation in either sex or on female reproductive function. Treatment of juvenile male rats caused increased cohabitation time and decreased copulation rates; pregnancy rates and litter size were not affected in rats that mated. Decreased testis (10 15%) and epididymis (20-30%) weights, and decreased Sertoli cell numbers were noted at all doses. This indicates that exemestane can reduce Sertoli cell proliferation during maturation. The sensitive window for this effect is expected to be limited to the period of Sertoli cell proliferation, which is completed by around postnatal day 15 in rats and before puberty in humans. Treatment beginning at a later time relative to the window for Sertoli cell proliferation or for a longer duration is not expected to have additional adverse effect as the effect was not shown to be degenerative. PMID- 21678548 TI - Essential fatty acid supplementation of DHA and ARA and effects on neurodevelopment across animal species: a review of the literature. AB - Docosahexanoic acid (DHA) and arachidonic acid (ARA) are long chain essential fatty acids used as supplements in commercial infant formula. DHA/ARA deficient states are associated with adverse neurological outcomes in animals and humans. Preterm infants are at risk for DHA/ARA deficiency. A few clinical reports on the effects of fatty acid supplementation have shown benefit in preterm, low birth weight, and normal infants in the first year of life, whereas others did not. Studies in animals have reported shortened gestation, fetal growth retardation, reduced infant body mass, and increased fetal mortality with consumption of fatty acids during pregnancy. To understand the data that support fatty acid supplementation in infant formula, a review of the animal model literature was undertaken, to examine the effects of DHA/ARA on neurodevelopment, including the effects on visual acuity. Several points emerged from this review. (1) Animal studies indicate that requirements for DHA/ARA vary depending on developmental age. Alterations of the ratio of DHA/ARA can impact developmental outcome. (2) The available studies suggest that while supplementation of DHA/ARA in an appropriate ratio can increase tissue levels of these fatty acids in the brain and retina, tissues sensitive to depletion of fatty acids, the benefit of routine supplementation remains unclear. Few studies measure functional outcome relative to changes in physiologic pools of DHA/ARA after supplementation. (3) Animal literature does not support a clear long-term benefit of replenishing DHA/ARA tissue levels and administration of these fatty acids at concentrations above those in human milk suggests adverse effects on growth, survival, and neurodevelopment. PMID- 21678549 TI - Chemically functionalized surface patterning. AB - Patterning substrates with versatile chemical functionalities from micro- to nanometer scale is a long-standing and interesting topic. This review provides an overview of a range of techniques commonly used for surface patterning. The first section briefly introduces conventional micropatterning tools, such as photolithography and microcontact printing. The second section focuses on the currently used nanolithographic techniques, for example, scanning probe lithography (SPL), and their applications in surface patterning. Their advantages and disadvantages are also demonstrated. In the last section, dip-pen nanolithography (DPN) is emphatically illustrated, with a particular stress on the patterning and applications of biomolecules. PMID- 21678550 TI - Scanning tunneling luminescence of individual CdSe nanowires. AB - The local luminescence properties of individual CdSe nanowires composed of segments of zinc blende and wurtzite crystal structures are investigated by low temperature scanning tunneling luminescence spectroscopy. Light emission from the wires is achieved by the direct injection of holes and electrons, without the need for coupling to tip-induced plasmons in the underlying metal substrate. The photon energy is found to increase with decreasing wire diameter due to exciton confinement. The bulk bandgap extrapolated from the energy versus diameter dependence is consistent with photon emission from the zinc blende-type CdSe sections. PMID- 21678552 TI - Influence of nanostructure morphology on host capacity and kinetics of guest release. PMID- 21678551 TI - Anodic deposition of colloidal iridium oxide thin films from hexahydroxyiridate(IV) solutions. AB - A facile, in-situ deposition route to stable iridium oxide (IrO(x).nH(2)O) nanoparticle thin films from [Ir(OH)(6)](2-) solutions is reported. The [Ir(OH)(6)](2-) solution, made by alkaline hydrolysis of [IrCl(6)](2-), is colorless and stable near neutral pH, and forms blue IrO(x).nH(2)O nanoparticle suspensions once it is adjusted to acidic or basic conditions. IrO(x).nH(2)O nanoparticle thin films are grown anodically on glassy carbon, fluorine-doped tin oxide, and gold electrodes by electrolyzing [Ir(OH)(6)](2-) solutions at +1.0-1.3 V versus Ag/AgCl. The thickness of the IrO(x).nH(2)O films can be controlled by varying the concentration of [Ir(OH)(6)](2-) , the deposition potential, and/or the deposition time. These thin films are stable between pH 1 and 13 and have the lowest overpotential (eta) for the oxygen evolution reaction (OER) of any yet reported. Near neutral pH, the Tafel slope for the OER at a IrO(x).nH(2)O film/Au rotating disk electrode was 37-39 mV per decade. The exchange current density for the OER was 4-8 * 10(-10) A cm(-2) at a 4 mC cm(-2) coverage of electroactive Ir. PMID- 21678553 TI - Plasmonic nickel nanoantennas. AB - The fundamental optical properties of pure nickel nanostructures are studied by far-field extinction spectroscopy and optical near-field microscopy, providing direct experimental evidence of the existence of particle plasmon resonances predicted by theory. Experimental and calculated near-field maps allow for unambiguous identification of dipolar plasmon modes. By comparing calculated near field and far-field spectra, dramatic shifts are found between the near-field and far-field plasmon resonances, which are much stronger than in gold nanoantennas. Based on a simple damped harmonic oscillator model to describe plasmonic resonances, it is possible to explain these shifts as due to plasmon damping. PMID- 21678554 TI - A morphology-dependent bio-organic template for inorganic nanowire synthesis. PMID- 21678555 TI - Design, synthesis, and biological evaluation of ring-opened bengamide analogues. PMID- 21678556 TI - Development of antitrypanosomal and antiplasmodial nonpeptidic cysteine protease inhibitors based on N-protected-guanidino-furan and -pyrrole building blocks. PMID- 21678557 TI - Synthesis, structure, and reactivity of hydridoiridium complexes bearing a pincer type PSiP ligand. AB - A series of iridium tetrahydride complexes [Ir(H)(4)(PSiP-R)] bearing a tridentate pincer-type bis(phosphino)silyl ligand ([{2-(R(2)P)C(6)H(4)}(2)MeSi]( ), PSiP-R, R=Cy, iPr, or tBu) were synthesized by the reduction of [IrCl(H)(PSiP R)] with Me(4)N.BH(4) under argon. The same reaction under a nitrogen atmosphere afforded a rare example of thermally stable iridium(III)-dinitrogen complexes, [Ir(H)(2)(N(2))(PSiP-R)]. Two isomeric dinitrogen complexes were produced, in which the PSiP ligand coordinated to the iridium center in meridional and facial orientations, respectively. Attempted substitution of the dinitrogen ligand in [Ir(H)(2)(N(2))(PSiP-Cy)] with PMe(3) required heating at 150 degrees C to give the expected [Ir(H)(2)(PMe(3))(PSiP-Cy)] and a trigonal bipyramidal iridium(I) dinitrogen complex, [Ir(N(2))(PMe(3))(PSiP-Cy)]. The reaction of [Ir(H)(4)(PSiP Cy)] with three equivalents of 2-norbornene (nbe) in benzene afforded [Ir(I)(nbe)(PSiP-Cy)] in a high yield, while a similar reaction of [Ir(H)(4)(PSiP R)] with an excess of 3,3-dimethylbutene (tbe) in benzene gave the C-H bond activation product, [Ir(III)(H)(Ph)(PSiP-R)], in high yield. The oxidative addition of benzene is reversible; heating [Ir(III)(H)(Ph)(PSiP-Cy)] in the presence of PPh(3) in benzene resulted in reductive elimination of benzene, coordination of PPh(3), and activation of the C-H bond of one aromatic ring in PPh(3). [Ir(III)(H)(Ph)(PSiP-R)] catalyzed a direct borylation reaction of the benzene C-H bond with bis(pinacolato)diboron. Molecular structures of most of the new complexes in this study were determined by a single-crystal X-ray analysis. PMID- 21678558 TI - Dispersible shortened boron nitride nanotubes with improved molecule-loading capacity. AB - The oxidation process of boron nitride nanotubes was thoroughly investigated, and a slow oxidation characteristic was clearly revealed. Subsequently, the controllable oxidation process was utilized to break the sturdy structure of the boron nitride nanotubes to fabricate shortened nanotubes. The shortened boron nitride nanotubes were found to possess good solubility in water and many organic solvents. Further experiments demonstrated remarkably improved molecule-loading capacity of the shortened boron nitride nanotubes. These dispersible shortened boron nitride nanotubes might have the potential to be developed as effective delivery systems for various molecules, which may find applications in bio related fields. PMID- 21678559 TI - Adsorption of N719 dye on anatase TiO2 nanoparticles and nanosheets with exposed (001) facets: equilibrium, kinetic, and thermodynamic studies. AB - Anatase TiO(2) nanosheets (TiO(2) NS) with dominant (001) facets and TiO(2) nanoparticles (TiO(2) NP) with dominant (101) facets are fabricated by hydrothermal hydrolysis of Ti(OC(4)H(9))(4) in the presence and absence of hydrogen fluoride (HF), respectively. Adsorption of N719 onto the as-prepared samples from ethanol solutions is investigated and discussed. The adsorption kinetic data are modeled using the pseudo-first-order, pseudo-second-order, and intraparticle diffusion kinetics equations, and indicate that the pseudo-second order kinetic equation and intraparticle diffusion model can better describe the adsorption kinetics. Furthermore, adsorption equilibrium data of N719 on the as prepared samples are analyzed by Langmuir and Freundlich models; this suggests that the Langmuir model provides a better correlation of the experimental data. The adsorption capacities (q(max)) of N719 on TiO(2) NS at various temperatures, determined using the Langmuir equation, are 65.2 (30 degrees C), 68.2 (40 degrees C), and 76.6 (50 degrees C) mg g(-1), which are smaller than those on TiO(2) NP, 92.4 (30 degrees C), 100.0 (40 degrees C), and 108.2 (50 degrees C) mg g(-1), respectively. The larger adsorption capacities of N719 for TiO(2) NP versus NS are attributed to its higher specific surface areas. However, the specific adsorption capacities (q(max)/S(BET)) at various temperatures are 1.5 (30 degrees C), 1.6 (40 degrees C), and 1.7 (50 degrees C) mg m(-2) for TiO(2) NS, which are otherwise higher than those for NP, 0.9 (30 degrees C), 1.0 (40 degrees C), and 1.1 (50 degrees C) mg m(-2), respectively. The larger specific adsorption capacities of N719 for TiO(2) NS versus NP are because the (001) surface is more reactive for dissociative adsorption of reactant molecules compared with (101) facets. Notably, the q(max) and q(max)/S(BET) for both TiO(2) samples increase with increasing temperature, suggesting that adsorption of N719 on the TiO(2) surface is an endothermic process, which is further confirmed by the calculated thermodynamic parameters including free energy, enthalpy, and entropy of adsorption process. The present work will provide a new understanding on the adsorption process and mechanism of N719 molecules onto TiO(2) NS and NP, and this should be of great importance for enhancing the performance of dye sensitized solar cells. PMID- 21678560 TI - Internal chelation-guided regio- and stereoselective Pauson-Khand-type reaction by chiral rhodium(I) catalysis. PMID- 21678561 TI - One-pot construction of multi-substituted spiro-cycloalkanediones by an organocatalytic asymmetric epoxidation/semipinacol rearrangement. PMID- 21678562 TI - Degranulation of mast cells due to compound 48/80 induces concentration-dependent intestinal contraction in rainbow trout (Oncorhynchus mykiss Walbaum) ex vivo. AB - Rainbow trout (Oncorhynchus mykiss) intestinal strips (n = 10) were mounted in an isolated organ bath and the effect of incremental doses of compound 48/80 was recorded. Compound 48/80 induced concentration-related contraction in all the examined strips following a sigmoidal dose-response curve fit. Values for maximal contraction (E(max) , g cm(-2)), negative logarithm of the EC(50) (pD(2)), and hill slope were, respectively (mean+/-standard error), 12.88 +/- 0.51, 1.88 +/- 0.05, 1.49 +/- 0.27. The histological modification induced on mast cells (MCs) due to compound 48/80 was characterized by mean of gray-levels and texture analysis. Significant differences were observed between gray-levels values (Linear mixed model, P<0.01), contrast, and entropy (Linear mixed model, P<0.05) of MCs from compound 48/80-treated strips compared with MCs from untreated strips. Moreover, maximal intestinal contraction (due to compound 48/80) correlates positively and significantly (Pearson and Spearman correlations, P<0.05) with degranulation intensity determined by means of gray-levels analysis. Four antisera were tested on intestinal sections and no MCs positive to serotonin, substance P, met-enkephalin, and bombesin were found. This study demonstrates that compound 48/80 induces the degranulation of trout intestinal MCs ex vivo, and that the aforementioned degranulation promotes a concentration dependent intestinal contraction. PMID- 21678564 TI - Development of a vision-related quality of life instrument for children ages 8-18 years for use in juvenile idiopathic arthritis-associated uveitis. AB - OBJECTIVE: To determine the validity and reliability of a novel questionnaire to measure vision-related quality of life (VRQOL) in children ages 8-18 years for use in juvenile idiopathic arthritis (JIA)-associated uveitis: the Effects of Youngsters' Eyesight on Quality of Life (EYE-Q). METHODS: Several steps validated the EYE-Q. We interviewed experts and children on how vision affects a child's activities. We developed new items and selected relevant items from existing instruments. We administered initial versions of the EYE-Q to normal-sighted children and those with JIA-associated uveitis. For this study, children with various (or no) ocular conditions were recruited from a clinical population. Visual acuity and contrast sensitivity were performed, and the EYE-Q and Pediatric Quality of Life Inventory (PedsQL) were administered. The EYE-Q was repeated 10 days later. Patients, parents, and physicians rated vision severity. RESULTS: Of 120 patients, 48% were female, 46.7% had no visual impairment, and 53.3% had bilateral eye involvement. The mean age was 11.3 years. There were significant differences in the measures based on visual acuity (P < 0.001). Children with more severe visual acuity and bilateral eye involvement had worse EYE-Q scores (P < 0.001). There were significant associations between the EYE-Q and PedsQL (r = 0.375), repeat EYE-Q (r = 0.864), and clinical measures of ocular disease (r = -0.620). CONCLUSIONS: Our study provides evidence of the validity and reliability of the EYE-Q in the measurement of VRQOL. The EYE-Q may complement clinical measures of visual impairment and overall QOL and become an important tool in the assessment of QOL in JIA-associated uveitis. PMID- 21678565 TI - [Dermatomycoses]. PMID- 21678566 TI - Communicating about chemical body burden, with Tracey Woodruff and Rachel Morello Frosch. PMID- 21678567 TI - Proceedings from the Breast Health Global Initiative (BHGI) 2010 Global Summit. PMID- 21678568 TI - Biomedical research: Growing with the flow. PMID- 21678569 TI - Experiencing an injury at work. PMID- 21678571 TI - Research. Using HIV-positive organ donations could save lives, researchers say. PMID- 21678570 TI - [Analysis of clinical feature and treatment outcome in 42 patients with lymphoblastic lymphoma]. AB - OBJECTIVE: To investigate the clinical features and treatment outcomes of different regimens in Chinese patients with lymphoblastic lymphoma (LBL). METHODS: Forty-three patients with LBL were retrospectively analysed, of which 30 were T-LBL, and 13 B-LBL. RESULTS: (1) Most patients were young men with a median age of 21, and 63.0% of the T-LBL patients had mediastinal masses. (2) Treatment outcome could be assessed in 37 cases, of which the response rate (RR) was 81.1% and complete remission (CR) rate was 67.6%. The RR and CR rates in patients treated with regimens for ALL (ALL-like group) and those treated with regimens for NHL (NHL-like group) were 94.4%, 68.4% and 83.3%, 52.6%, respectively. (3) The estimated median overall survival (OS) and progression free survival (PFS) of hematopoietic stem cell transplantation (HSCT) group were significant longer than those of ALL-like group (P=0.018, P=0.025) and NHL-like group (P=0.016, P=0.011). The OS at 5 years in NHL-like group, ALL-like group and HSCT group were (14.4+/ 9.4)%, (20.2+/-12.7)% and (79.5+/-13.1 )%, respectively. CONCLUSION: (1) LBL is more common in young men, with less involvement of peripheral blood. Compared with B-LBL, T-LBL often has a mediastinal mass and serious cavity effusion. (2) Intensive treatment regimens for ALL should be used in LBL. HSCT at CR1 can improve outcome obviously. PMID- 21678572 TI - Guidance targets HIV testing in U.K.'s gay community. PMID- 21678573 TI - Prisons. Brief delay in receiving medicine not deliberate indifference. PMID- 21678574 TI - SSI. HIV-positive not entitled to disability benefits, court says. PMID- 21678575 TI - After high school, youths with autism spectrum disorders lose access to services. PMID- 21678576 TI - [Bipolar and monopolar affective disorders of juvenile age]. AB - Results of clinico-psychopathological and clinico-catamnestic studies are presented based on the examination of 174 patients with affective disorders that manifested themselves at the age of 15-25 years. The main psychopathological features of juvenile phase-affective conditions are described (subtle vital manifestations of the thymic component, polymodality of the affect with simultaneous presentation of two varieties of affective disorders, instability of the affect changing within a single phase, high occurrence of overvalued ideas reflecting specific emotions of the juvenile age with concomitant manifestations of pubertal psychological crisis underlain by common pathogenetic mechanisms). High frequency of mixed affective conditions and the predominance of the bipolar type of the disease are emphasized, clinical features of mono- and bipolar pathology are described. It is concluded that a special algorithm of psychopharmacological and psychotherapeutic therapy adapted to the juvenile age is needed for the treatment of the above disorders. PMID- 21678577 TI - [Vascular depressions]. AB - The notion of vascular depression (VD) includes depressive disorders resulting from organic cerebral lesions of vascular genesis. Two types of VD are distinguished: post-stroke VD (PSD) and VD proper (SDP). VD develops in case of clinically manifest (neurologic) lesions in cerebral vessels that simultaneously act as psychogenic (nosogenic) factors. SDP is associated with clinically latent vascular disorders ("silent" infarctions and white matter ischemia). VD is characterized by multiple phenomenological convergence of vascular signs and symptoms inherent in both PSD and SDP. Whatever the type of VDs, they are associated with frequent cognitive problems with a variety of dynamic patterns, viz. reversible, relatively stable, and progressing. PMID- 21678578 TI - Bibliography. Current world literature. Androgens. PMID- 21678579 TI - What blood pressure do we target in dialysis patients? PMID- 21678580 TI - [Which factors allow to anticipate the diagnosis of prostate cancer in pin patients? A study on 546 patients]. AB - AIM OF THE STUDY: To analyze which factors allow to assess the risk of finding a prostate cancer (PCa) at repeated biopsies in patients with diagnosis of prostatic intraepithelial neoplasia (PIN). PATIENTS AND METHODS: At our institute all patients with a diagnosis of PIN undergo a 6-monthly control biopsy until the achievement of a benign histology or up to a maximum of 4 consecutive biopsies. For this study a retrospective review of clinical and bioptic data of patients with a diagnosis of isolated PIN (i.e. without associated atypical small acinar proliferation or small cancer foci) was carried out. The correlation between these features and the probability to find PCa at the first re-biopsy or at a further re-biopsy was independently analyzed. RESULTS: The data of 546 patients subjected to a median number of 3 biopsies, (mean: 10.8 and 12.9 cores at initial biopsy and at first re-biopsy, respectively), and with a mean "bioptic" follow-up time of 14.8 months, were analyzed. PCa was found in 174 cases (31.8%): for 116 of them it took place at the first re-biopsy, with a mean latency of 7.8 months from PIN diagnosis, whereas for 58 at a further re-biopsy, with a mean latency of 21.6 months. The risk of diagnosing PCa at the first re-biopsy was statistically correlated with the PSA value--for which a cut-off value of 7 ng/mL was identified--and with an anomalous rectal prostatic examination at the time of the initial biopsy. Differently, the risk of diagnosing PCa after the first re-biopsy correlated with the number of cores positive for PIN at the initial biopsy--for which a cut-off of 4 was identified--and to the ratio between these and the total number of cores, defined as PIN density--for which a cut-off of 50% was determined. DISCUSSION AND CONCLUSIONS. It is possible to suggest a tailored protocol of controls in patients with a diagnosis of PIN on the basis of the data available at the initial biopsy: a) high PSA value and/or an anomalous prostatic rectal examination: the diagnosis of PCa is probably just unacknowledged by the initial sampling and it is advisable to carry out an early re-biopsy; b) number of cores with PIN equal to or higher than 4 and/or PIN density equal to or higher than 50%: a true transition from PIN to PCa is likely to happen with time and it is advisable to carry out a delayed re-biopsy; c) no risk factors: just clinical and PSA monitoring to establish the indication to re-biopsy. PMID- 21678581 TI - A study of out-of-plane cation dynamics in a bis-thiourea pyridinium chloride inclusion compound. AB - The out-of-plane motion of the pyridinium cation in the bis-thiourea pyridinium chloride inclusion compound has been studied in a wide temperature range using (1)H NMR, dielectric spectroscopy and quasielastic neutron scattering. The geometry of this motion is obtained from the Q-dependence of the elastic incoherent structure factor determined from the quasielastic neutron scattering measurements. We find that the pyridinium cation performs out-of-plane reorientations around the axis passing through two opposite atoms of the ring. The correlation times as a function of temperature were measured in the three known crystallographic phases, finding a good agreement between the three techniques employed. The activation energy for this motion changes from 5 +/- 1 kJ mol(-1) in the low-temperature phase to 1.2 +/- 0.2 kJ mol(-1) in the intermediate and high-temperature phases. PMID- 21678582 TI - Preparation and enhanced visible-light photocatalytic H2-production activity of CdS-sensitized Pt/TiO2 nanosheets with exposed (001) facets. AB - CdS-sensitized Pt/TiO(2) nanosheets with exposed (001) facets were prepared by hydrothermal treatment of a Ti(OC(4)H(9))(4)-HF-H(2)O mixed solution followed by photochemical reduction deposition of Pt nanoparticles (NPs) on TiO(2) nanosheets (TiO(2) NSs) and chemical bath deposition of CdS NPs on Pt/TiO(2) NSs, successively. The UV and visible-light driven photocatalytic activity of the as prepared samples was evaluated by photocatalytic H(2) production from lactic acid aqueous solution under UV and visible-light (lambda >= 420 nm) irradiation. It was shown that no photocatalytic H(2)-production activity was observed on the pure TiO(2) NSs under UV and/or visible-light irradiation. Deposition of CdS NPs on Pt/TiO(2) NSs caused significant enhancement of the UV and visible-light photocatalytic H(2)-production rates. The morphology of TiO(2) particles had also significant influence on the visible-light H(2)-production activity. Among TiO(2) NSs, P25 and the NPs studied, the CdS-sensitized Pt/TiO(2) NSs show the highest photocatalytic activity (13.9% apparent quantum efficiency obtained at 420 nm), exceeding that of CdS-sensitized Pt/P25 by 10.3% and that of Pt/NPs by 1.21%, which can be attributed to the combined effect of several factors including the presence of exposed (001) facets, surface fluorination and high specific surface area. After many replication experiments of the photocatalytic hydrogen production in the presence of lactic acid, the CdS-sensitized Pt/TiO(2) NSs did not show great loss in the photocatalytic activity, confirming that the CdS/Pt/TiO(2) NSs system is stable and not photocorroded. PMID- 21678583 TI - For what it's worth: watch your girth. PMID- 21678584 TI - A case of ameloblastic fibroma treated with surgery and orthodontic therapy. PMID- 21678585 TI - The 10 habits of highly successful optometrists. PMID- 21678587 TI - Medical identity theft. PMID- 21678586 TI - Effects of electrode surface modification with chlorotoxin on patterning single glioma cells. AB - A microchip patterned with arrays of single cancer cells can be an effective platform for the study of tumor biology, medical diagnostics, and drug screening. However, patterning and retaining viable single cancer cells on defined sites of the microarray can be challenging. In this study we used a tumor cell-specific peptide, chlorotoxin (CTX), to mediate glioma cell adhesion on arrays of gold microelectrodes and investigated the effects of three surface modification schemes for conjugation of CTX to the microelectrodes on single cell patterning, which include physical adsorption, covalent bonding mediated by N hydroxysuccinimide (NHS), and covalent bonding via crosslinking succinimidyl iodoacetate and Traut's (SIA-Traut) reagents. The CTX immobilization to microelectrodes was confirmed by high-resolution X-ray photoelectron spectroscopy. Physically adsorbed CTX showed better support for cell adhesion and is more effective in confining adhered cells on the electrodes than covalently bound CTX. Furthermore, cell adhesion and spreading on microelectrodes were quantified in real-time by impedance measurements, which revealed an impedance signal from physically adsorbed CTX electrodes four times greater than the signal from covalently-bound CTX electrodes. PMID- 21678588 TI - Codes and values for ophthalmic imaging. PMID- 21678589 TI - Medicare appeals. PMID- 21678590 TI - What if "what if" actually happens. PMID- 21678592 TI - NC: Workers comp. insurer denied RN's claim: court affirmed commission's decision for nurse. Steelman v. Select Medical Corporation, COA10-521 (4/19/2011)-NC. PMID- 21678591 TI - Commander's introduction. PMID- 21678593 TI - The use of sugammadex to reverse rocuronium in a patient with myotonic dystrophy. PMID- 21678594 TI - There are still some positive mental health stories out there. PMID- 21678595 TI - The government's mental health strategy could reinforce inequalities in mental health services for black and minority ethnic people. PMID- 21678596 TI - Suburban sanctuary. PMID- 21678597 TI - Inside edge. PMID- 21678598 TI - Healthy debate. PMID- 21678599 TI - Making the connection. PMID- 21678600 TI - Welfare writes. PMID- 21678601 TI - Outside the box. PMID- 21678602 TI - The bigger picture. PMID- 21678603 TI - Mental health and art. PMID- 21678604 TI - Doctor's orders. PMID- 21678605 TI - Perspectives. PMID- 21678606 TI - Robert Goemans, in his article in the March issue of Mental health today, raised important questions about 21st century mental health services, and the roles and responsibilities of different professionals. PMID- 21678608 TI - Go your own way. PMID- 21678607 TI - More to it than stigma: the multiple ways young people make sense of mental illness. PMID- 21678609 TI - On the record. Interview by Alita Howe. PMID- 21678610 TI - Special Issue dedicated to Pietro di Prampero. PMID- 21678611 TI - Immune markers in breast milk and fetal and maternal body fluids: a systematic review of perinatal concentrations. AB - Breastfeeding represents the continued exposure of the infant to the maternal immune environment.Uterine, perinatal, and postnatal exposure to immune factors may contribute to an infant's risk of developing immune-mediated disorders, including allergies. A PubMed search was conducted to review studies in humans and analyze concentrations of immune markers (TGF-beta, IFN-gamma, eotaxin, CCL5, CXCL10, TNF-alpha, MCP-1, IL-1beta, IL-4, IL-5, IL-6,IL-8, IL-10, IL-12, IL-13, sCD14, sIgA, IgG4, IgM) found in maternal serum, amniotic fluid, cord serum, colostrum, transition and mature milk. Concentrations of immune markers showed large variations across samples and studies. Reports documented conflicting results. Small sample sizes, differences in population characteristics, inconsistent sample collection times, and various sample collection and measurement methods may have led to wide variations in the concentrations of immune markers. Studies analyzing the associations between immune markers in maternal fluids and infant allergies remain inconclusive because of gaps in knowledge and a lack of standardized methods. PMID- 21678612 TI - ILCA's INSIDI TRACK: a resource for breastfeeding mothers: putting your premature or ill baby to breast. PMID- 21678613 TI - SAC C VS disease surveillance report: Early cases of Streptococcus dysgalactiae arthritis seen in lambs. PMID- 21678614 TI - Analyze this. PMID- 21678615 TI - The author file: Rohit Bhargava and Carol Hirschmug. Interview by Monya Baker. PMID- 21678616 TI - Points of view: the overview figure. PMID- 21678617 TI - Brain function marries anatomy. PMID- 21678618 TI - Understanding sleeping sickness. PMID- 21678620 TI - Highlighting enhancers. PMID- 21678619 TI - One particle to rule them all? PMID- 21678621 TI - Speeding up RNAi. PMID- 21678622 TI - A fountain of youth (for worms). PMID- 21678623 TI - Early implementation of pre-existing condition insurance plans: providing an interim safety net for the uninsurable. AB - The Pre-Existing Condition Insurance Plan (PCIP) is a temporary program implemented under the Patient Protection and Affordable Care Act to make health insurance coverage available to uninsured individuals with preexisting conditions until 2014, when exchange-based health insurance becomes available to all. The PCIP program began enrolling applicants in July 2010. This issue brief examines enrollment trends, early changes to plan structures and premiums, and estimates of out-of-pocket costs by utilization pattern and type of plan. It also provides information about the age and medical conditions of early PCIP enrollees. Although PCIP enrollment has been lower than expected due to affordability issues, a lack of public awareness, and the requirement that applicants be uninsured for six months, the plans are nonetheless playing an important role in making coverage available to otherwise uninsurable Americans with preexisting conditions. PMID- 21678635 TI - [Mitigating the moral risks of private medicine in public hospitals (SHARAP) through regulation and accountability]. AB - BACKGROUND: SHARAP (the Hebrew acronym for private medical service) is an arrangement that allows patients in certain Israeli hospitals to choose their physicians in return for a fee paid, either privately or through some form of parallel insurance. At present, SHARAP is legally precluded from government hospitals but the issue is a source of public debate and the introduction of SHARAP into public hospitals owned by the government and health funds is supported by the Israel Medical Association and MK Yakov Litzman. While advantages to patients, hospitals and medical practitioners are acknowledged, these arrangements carry moral risks related to justice and fair allocation of resources, problems relating to conflicts of interests, the potential for exploitation of patients by physicians with private privileges and the potential for corrupt behaviors. AIM: To address the questions: Do the advantages of these arrangements justify the moral risks involved in the introduction of private medicine into public hospitals? Secondly, can these moral risks be mitigated through regulation without undermining the advantages accrued? METHOD: Ethical and public health policy evaluation based on empiric data and international experience. RESULTS: The potential advantages to patients, providers, hospitals and government of a SHARAP program in public hospitals may be undermined if the implementation does not incorporate regulatory structures. Appropriate regulatory precautions may mitigate most of these concerns adequately to allow all parties to enjoy benefits whilst diminishing actual harm incurred though injustice, conflicts of interest and exploitation. PMID- 21678636 TI - [Eosinophilic esophagitis--the experience in a tertiary pediatric center]. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is an inflammatory disorder with increasing prevalence. It typically presents with swallowing difficulties, heartburn or dyspepsia, and in toddlers, failure to thrive. EoE is characterized by eosinophilic infiltrates of the esophageal mucosa, and endoscopies with tissue diagnosis are mandatory. Hypersensitivity has been implicated in the pathogenesis, therefore, most treatment options include steroids and allergen avoidance. AIMS: To summarize a tertiary pediatric clinic's experience with EoE in children and adolescents, describe the spectrum of clinical presentations and treatment options, and raise awareness of this disorder among medical personnel. METHODS: A retrospective, descriptive study of patients diagnosed with EoE at our institute over the past 5 years. Demographic details, presenting symptoms, laboratory studies, endoscopic and pathologic findings were analyzed. Information regarding medical and nutritional therapies and response to treatment were summarized. RESULTS: Fifteen cases of EoE in children and adolescents are described. Average age at diagnosis was 9 years (range 0.7-161. The most common complaint was dysphagia (60%e. The majority demonstrated food allergies 19/121. Most of the patients were treated with topical ingested steroids, while others had either elemental formula or allergen elimination. Favorable responses were seen in most patients treated with steroids (8/11). Long-term results of nutritional therapy are insufficient to draw conclusions on its efficacy. CONCLUSIONS: EoE causes major eating difficulties and affects quality of life in children, sometimes accompanied by failure to thrive. There is a clear association with food allergies, and positive responses to steroids are common. A high index of suspicion and referral to a gastroenterologist for definite diagnosis are required. Combining medical with nutritional treatment seems promising but further studies regarding the long-term outcome are needed. PMID- 21678637 TI - [Frequency of respiratory symptoms in workers in traditional Arab bakeries]. AB - BACKGROUND: Respiratory complaints are quite common among workers exposed to flour dust. As a rule, such symptoms are not recognized as work-related. METHODS: A cross-sectional survey of 111 male workers from about 20 traditional Arab bakeries in northern Israel was conducted during 2008. Data collection was performed utilizing a dedicated questionnaire with special emphasis on respiratory symptomatology. RESULTS: The main findings were: as a rule, this is a relatively young group of workers. Most bakeries employ 3-5 workers who perform all the jobs involved (family business). The bakeries are usually a single room where all processes, including selling of the pitahs are performed in one common space. Over 50% of the workers are current smokers. About 45% of the workers indicate respiratory symptoms, moreso among current smokers. About 2/3 of the symptomatic workers believe that occupational exposure to flour dust is causally related to their symptoms, OR =14.9 [95% CI = 5.69-38.84). CONCLUSIONS: These findings attest to the need to perform a large scale (and more quantitative) evaluation of this occupational sector, in order to better identify the major risk factors involved. PMID- 21678638 TI - [Cutaneous metastases from epithelial ovarian cancer]. AB - Cutaneous involvement is a rare presentation of ovarian cancer. There are only a few such case reports in the literature, most of them in surgical scars or subcutaneous nodules. This is a rare case of a patient presenting with skin metastases originating from primary ovarian carcinoma, which appeared 8 months following a disease-free interval. Based on this case report and a review of the literature, it is concluded that cutaneous involvement in ovarian cancer is a poor prognostic sign. Life expectancy of these patients is only a few months from the time of diagnosis of skin metastases. Thus, one should consider merely a palliative approach in these cases. PMID- 21678639 TI - [Chronic asthma, depressive symptoms and risk behaviors: results from a national health survey]. AB - BACKGROUND: Previous research suggests that depression is common in individuals with asthma. Research on the association between depressive symptoms and health related risk behaviors in persons with respiratory disorders is scarce. OBJECTIVE: To assess the association between asthma and depressive symptoms; and to evaluate the relationship between depressive symptoms and risk behaviors (smoking, physical inactivity and obesity) in individuals with asthma. METHODS: We analyzed data from the Israeli National Health Interview Survey [INHIS-1), conducted on a large sample (N = 9,509) of the adult Israeli population (age > or = 21 years) in 2003-4. Data on socio-demographic factors, chronic respiratory conditions, depressive symptoms and risk behaviors were obtained through telephone interviews. Analyses were performed using adjusted Logistic regression models. RESULTS: A total of 381 participants (4.0%) reported chronic asthma in the year previous to the interview. Of those, 15.5% had moderate depressive symptoms compared with 7.2% of participants with no respiratory conditions (odds ratio, 1.95; 95% CI, 1.40-2.72; P < .0001). Depressive symptoms in individuals with asthma were significantly associated with smoking (adjusted odds ratio (AOR) 3.31; 95% CI, 1.58-6.91; P = .001 for moderate depressive symptoms; AOR 1.91; 95% CI, 1.05-3.45; P = .03 for mild depressive symptoms); moderate but not mild depressive symptoms were significantly associated with physical inactivity (AOR, 3.05; 95% CI, 1.52-6.12; P = .002). These associations were stronger in females. Depressive symptoms were not associated with obesity. CONCLUSIONS: Among Israelis with chronic asthma, depressive symptoms are associated with important differences in health behaviors (higher rates of smoking and lack of physical activity) which may impact on the course of respiratory illness and on overall health. PMID- 21678640 TI - [Identification of K-RAS mutations in colorectal cancer patients in Israel]. AB - BACKGROUND: Activating mutations of the oncogene K-RAS are a common finding within cells of malignant, sporadic colorectal cancer. The existence of such mutations endows the tumor with proliferation potential which is independent of external stimuli by growth factors such as the epidermal growth factor of upstream receptor (EGFR]. Hence, anticancer, novel biologic drugs, aimed at inhibiting the EGFR, such as cetuximab, are rendered ineffective in cases of colorectal cancer harboring activated K-RAS. AIMS: Quantification and characterization of activating mutations in a large cohort of sporadic colorectal tumors in the Israeli population. METHODS: The results of a mutation analysis kit application in 419 tumor samples collected in Israel during the years 2007-2009 by the diagnostic unit of Teva in Israel--Oncotest-Advantest Ltd. RESULTS: The utilization of a direct, pre-specified mutation kit analysis (TheraScreen: K-ras Mutation Kit) has identified a total rate of 44.8% mutations. Most mutations (82.4%) were identified within codon 12 and the minority on codon 13. These results are in concordance with modern series conducted worldwide. PMID- 21678641 TI - [Personalized medicine--the future is already here]. AB - Personalized medicine is pharmaceuticals or biological treatments paired with diagnostic tests (companion tests) that personalized the medicine in question with genetics or genetic signatures. Target-specific cancer therapeutics has remarkably improved the outcomes of patients and represents the frontline approach to treatments in oncology today. The molecular basis governing the deveLopment of colorectal cancer is well established. K-ras is one of the early key components in the development of colorectal cancer (CRC) and is involved in many signal transduction pathways of the epidermal growth factor receptor--EGFR. Both cetuximab and panitumumab, EGFR monoclonal antibodies, are approved for the treatment of colorectal cancer. Patients with mutations in oncogene K-ras are not considered candidates for those treatments. Therefore, identifying patients with K-ras mutations is critical prior to treatment selection. In Israel, cetuximab is approved as third line therapy in CRC patients and K-ras testing is required before choosing therapy. The study by Segal et at, pubLished in this issue, assessed the prevalence of molecular types of K-ras mutations in stage IV CRC patients who failed two lines of treatment. Those results revealed a pattern similar to that seen in other studies. This editorial discusses the results of this study in the context of personalized medicine and presents the need for promoting the understanding and use of personalized medicine within the Israeli healthcare system. Use of personalized medicine Leads to better health outcomes and may result in saving healthcare costs. PMID- 21678642 TI - [Platelet rich plasma--a new biotechnology for treatment of sports injuries]. AB - Autologous platelet-rich plasma (PRP) is a relatively new biotechnology backed by over two decades of research in diverse areas. With its growing use for the treatment of musculoskeletal injuries, Orthopaedic Sports Medicine may be the discipline in which translational use of PRP has progressed most rapidly. PRP therapy involves the injection of a small volume of plasma or the application of PRP gel foam directly to the site of injury. It is composed of numerous growth factors (GF) secreted from large numbers of 'activated' platelets, directed at facilitating and enhancing physiological wound healing and rapid tissue regeneration. With wide variations in preparation protocols, kits, activation methods, platelet concentrations and growth factors, many questions are still unanswered. Similarly, application methods, timing of treatment and volume of injection are inconsistent, emphasizing the need for appropriately powered level 1 and 2 studies with adequate and relevant outcome measures and clinically appropriate follow-up in order to assess the efficacy and effectiveness of all elements of PRP therapy. Clinical interventions in sports and musculoskeletal medicine aim to achieve predictable, rapid tissue repair and enhance wound heating and to restore the high mechanical performance and functional levels of non-injured tissue in the shortest possible time. PRP may be a remarkable step forward in this quest. This review will evaluate the evolution and most recent contributions of PRP treatment. PMID- 21678643 TI - [The new anticoagulants]. AB - Anticoagulant therapy is based on two veteran drugs, which have been in use for over 60 years: heparin and warfarin. Due to the limitations of these agents, new parenteral anticoagulants have been introduced, mainly the low molecular weight heparins, fondaparinux and direct thrombin inhibitors. The need to develop new drugs has led to major efforts by the pharmaceutical industry and many promising anticoagulant oral agents are being tested. Ximelgatran has been withdrawn from the market after several cases of hepatotoxicity have been observed. Two oral agents, dabigatran and rivaroxaban, have recently been approved in Europe. Dabigatran inhibits thrombin, while rivaroxaban is factor X inhibitor. Other drugs include apixaban, idraparinux and are in Phase III studies. PMID- 21678644 TI - [Benign multiple sclerosis]. AB - Multiple sclerosis is a demyelinating disease of the central nervous system affecting young adults and leading to significant disability over time. The disease subtype, which results in minimal disability over time, has been defined as benign multiple sclerosis. This review will discuss the various features of benign multiple sclerosis, including cognitive and motor criteria for defining the disability, the disease duration, magnetic resonance imaging characteristics, disease progression and criteria for treatment. PMID- 21678645 TI - [proPSA: a precursor of prostate-specific antigen, may improve the early diagnosis of prostate cancer]. AB - Since its introduction as a mass-screen parameter for early detection of prostate cancer, PSA was credited for a significant revolution in the management of prostate disease. But over 2 decades of global experience with this marker have emphasized that the recommended threshold value of 4.0 ng/ml may not be valid in distinguishing tumor growth from benign proliferation of the prostate in over 30% of the cases. Hence, more advanced tools of PSA evaluation have been introduced such as "PSA velocity", "PSA density" or age-related PSA". Recently, precursor molecules of PSA were identified, which are assumed to be zymogen structures devoid of proteolytic activity. These precursor species known as pro-PSAs possess an additional "tail" ranging in size from 2 to 7 extra amino acids at the N terminus of PSA, and represent a fraction of the non-complex or "free PSA", that has usually been identified as a marker for non-cancerous proliferation of the prostate. Interestingly, one of these proPSA structures in particular, [ 2]proPSA, has demonstrated to be more specifically indicative of prostate tumor growth in numerous clinical studies. Lately, a chemiluminescence kit has been approved by the European Health Agency as a more specific marker for diagnosis of prostate malignancy, mostly in men with PSA levels ranging from 2-10 ng/ml. PMID- 21678646 TI - [Ethics in obstetrics and gynecology]. AB - The immense progress in diagnostic and therapeutic modalities in medicine has forced a parallel development of ethical considerations in applying them. This is especially true with regard to obstetrics and gynecology, as this discipline encompasses within it the power to bestow life through fertility treatment, as well as the ability to deny them as a result of a discovery of genetic or structural malformation during pregnancy. In this review some of the issues in obstetrics and gynecology that mandate ethical guidance, as reflected from the current relevant literature, are presented. Furthermore, ethical issues of a more general nature, such as inter-colleague and teacher-student relationships are elaborated. The medical establishment recognizes the importance of ethics. However, its recommendations in various themes seem to be detached from the de facto conditions in clinical practice, considering the terms in which the medical system actually functions. Therefore, an adaptation of ethical recommendations to the true nature of clinical "field" medicine is required. PMID- 21678647 TI - [Female urethral diverticula--clinical and surgical aspects]. AB - Urethral diverticula are a common cause of chronic genitourinary symptoms in women. They occur in 5% of women overall, with higher frequencies in selected populations of symptomatic women. The classical presentation is with recurrent urinary tract infections and post-micturition dribbling but almost any urinary symptom may be a presenting feature. Newer imaging modalities such as magnetic resonance imaging and perineal ultrasound are now widely available and urethral diverticula, that were previously unrecognized, can now be more easily detected. However, despite the availability of effective diagnostic techniques, diagnosis is often delayed. This is due to a lack of awareness among clinicians. These patients are often inappropriately treated for other conditions, significantly delaying the proper management of their condition. A high index of suspicion, a careful examination and referral for appropriate investigation will improve the number correctly diagnosed and lead to considerable benefit since most symptomatic cases can be cured by appropriate surgery. This review aims to summarize the presentation, investigation and management of female urethral diverticulum. Hopefully, greater awareness will lead to more timely diagnosis and appropriate treatment. PMID- 21678648 TI - [Treatment for Pott's disease with neurological complication]. AB - Tuberculosis of the spine (Pott's disease) is the most common skeletal involvement in tuberculosis, and is often accompanied with neurological deficiency. Surgical treatment was previously the mainstay of therapy in cases of Pott's disease with neurological deficiency, but since clinical recovery was found in patients awaiting surgery, conservative management with antibiotic treatment as a first Line treatment has been advocated. This conservative approach may improve the patients' neurological status while avoiding the morbidity and mortality of surgical treatment. PMID- 21678649 TI - [The human microbiome]. AB - The complex microbial populations that colonize the human body form the human microbiome. The human microbiota may contain 1014) cells, an order of magnitude greater than the number of the human cells, and can express 100 times more genes than the human genome. The metagenome is the collective genomes of the human and its microbial flora. Major international colLaborative efforts currently explore the diverse human microbiomes from five different body areas: the nasopharyngeal, gastrointestinal and female urogenital tracts, the oral cavity and the skin. Defining the complexity of the human microbiome in health and disease will enhance the understanding of multiple pathological mechanisms and facilitate the development of novel diagnostic tools and therapeutic interventions. PMID- 21678650 TI - [Influence of fluoxetine and paroxetine on anxiety-like behavior in young and adult prenatally stressed male rats]. AB - We present the results of a comparative analysis of the effects of the chronic administration of the selective serotonin reuptake inhibitors fluoxetine (5.0 mg/kg, p.o.) and paroxetine (5.0 mg/kg, p.o.) for 14 days of the postnatal period on anxiety-like behavior in the prenatally stressed male rats as studied during pubertal period (1.5 month) and in the adult age (3 month). The chronic administration of paroxetine in male rats did not change the anxiety-like behavior in male rates of any age. On the contrary, the administration of fluoxetine modulated the anxiety-like behavior of prenatally stressed rats depending on the age: the anxiolytic effect was observed in young males, while the anxiogenic effect was observed in adult male rats. PMID- 21678651 TI - [Edema in nervous tissue studied on model of hemorrhagic stroke in vitro]. AB - The development of edema in the survival olfactory cortex slices under the long term action of autoblood has been studied by monitoring the bioelectric activity of nervous cells. The level of disorder in electrogenesis of cells was revealed by comparing the focal potentials with their control values; the degree of the nervous tissue swelling in various periods of autoblood action was determined by weighing. In the model of hemorrhagic stroke, the dependence of edema growth on the level of activity of ionotropic glutamate receptors has been determined using the pharmacological blockade technique. PMID- 21678652 TI - [Endothelium-protective effects of vinpocetine, pentoxifylline and enalapril in patients with chronic brain ischemia]. AB - The influence of vinpocetine, pentoxifylline and enalapril on endothelium functions has been studied in a group of in 172 patients with chronic brain ischemia. The endothelium-protective effect of drugs was manifested as the inhibition of the Willebrand factor output during arteriovenous occlusion test and as the renewal of endothelium-depended vasodilation. The extent of neurologic deficit reduction correlated with decrease in the activated endothelium-depended output of the Willebrand factor. PMID- 21678653 TI - [Correction of aldosterone level as marker of RAAS dysfunction in patients with arterial hypertension degree II-III and chronic kidney diseases]. AB - The hyperactivation of renin-angiotensin-aldosterone system (RAAS) underlies the development and the progression of arterial hypertension and chronic kidney diseases. Aldosterone is the main unit of RAAS and self-sufficient predictor of the development of cardiovascular events. In this study, the angiotensin receptor blocker valsartan, ACE inhibitor enalapril, and direct renin inhibitor aliskiren were used for the correction of blood pressure and aldosterone levels in patients with hypertension and chronic kidney diseases. The data obtained suggest that the proposed complex therapy provides the most complete blood pressure reduction and aldosterone level correction (as evidence of RAAS activity recovery), greatly improves the prognoses, and ensures maximum nephroprotection in the patients with arterial hypertension and chronic kidney diseases. PMID- 21678654 TI - [Hemorheological disorders in Epstein-Barr virus mononucleosis in children and methods of their correction]. AB - The results of observations in a group of 80 young patients aged 1-14 years with diagnosis of primary Epstein-Barr virus (EBV) infection are presented. Hemorheological disorders arising from the EBV mononucleosis were identified. The results of using reamberin in the infusion therapy for the correction of hemorheological disorders have been analyzed. It is established that reamberine infusion reduces the plasma viscosity and blood viscosity, rapidly improves the condition of children, and restores hemodynamic indices. The use of reamberine helped to reduce the duration of hospital treatment for patients with severe EBV mononucleosis. PMID- 21678655 TI - [Overcoming resistance of tuberculosis infectious agent by isoniazid-silver nanocomposite]. AB - The antituberculous activity of a nanocomposite based on nanoparticulate silver and isoniazid has been studied on the model of drug-resistant tuberculosis in a group of 65 white mice. The possibility of overcoming the resistance of the tuberculosis activator by the proposed nanocomposite of isoniazid and nanoparticulate silver is demonstrated in terms of the survival index, biometric data, bacteriological and pathomorphological parameters. Dose-dependent parameters of the presence of nanoparticulate silver in the composite structure are established. The results of preclinical research scientifically prove good prospects for using nanoparticulate silver in the treatment of drug-resistant tuberculosis. PMID- 21678657 TI - [Biogenic stimulants of metabolism in articular cartilage]. AB - The review considers issues of pharmacodynamics and clinical applications of drugs with the metabolic type of action, which stimulate regeneration and provide the protective action on articular cartilage in cases of osteoarthritis. Published data of the experimental and clinical trials of the main chondroprotective agents are analyzed. PMID- 21678656 TI - [Antioxidant and membranoprotector treatment of chronic pyelonephritis]. AB - The results of investigation of the clinical efficiency of using the antioxidant drug cytoflavin in a complex therapy of patients with chronic pyelonephritis prior to development of azotemia are presented. It is shown that cytoflavin in combination with basic therapy reduces the intensity of lipid peroxidation processes (as monitored using diene conjugates, malonic dialdehyde, and Schiffbase metabolites) with retention of the antioxidant status. The proposed treatment normalizes the ratio of blood plasma phospholipid fractions and erythrocytes membranes. PMID- 21678658 TI - [Molecular mechanisms of gestagen action]. PMID- 21678659 TI - [Imaging diagnosis Q & A. A solitary fibrous tumor]. PMID- 21678661 TI - [Emergency resection of the upper right lobe together with the thoracic wall for chronic necrotic pulmonary aspergillosis with sudden development of pulmonary congestion during pneumonectomy]. PMID- 21678662 TI - [Professor Doctor Docent Gioconda Dobrescu (September 8, 1926-May 17 2009)]. PMID- 21678663 TI - [Professor Doctor Constantin Eremia Cotrutz (May 1, 1935-May 15, 2009)]. PMID- 21678664 TI - ZOE paste pulpectomies outcome in primary teeth: a systematic review. AB - OBJECTIVE: To perform a systematic review in which the clinical research question for primary teeth with irreversible pulpal pathosis was "how pulpectomies with zinc oxide eugenol (ZOE) paste performed compared to other materials in their clinical and radiographic outcomes after twelve months or more follow-up period. STUDY DESIGN: A literature survey of the electronic database (1950-2010) used the Medical Subject Headings and free text terms. Forty three references were retrieved and inclusion criteria were applied; 15 articles remained for full-text evaluation. From these, two were selected for data extraction regarding quality characteristics and results. RESULTS: Selected studies showed moderate or high risk of bias. The overall success of pulpectomy was 80.0% (Calcicur), 60.0% (Sealapex) and varied from 85.0% to 100.0% (ZOE) and 89.0% to 100.0% (Vitapex). Solely Calcicur presented success rate significantly lower when compared to ZOE and Vitapex. These pastes lead to overfilled canals and particles of extruded ZOE were still evident even after the evaluation period. Resorption of Vitapex, Calcicur and Sealapex within the root canal was also reported. CONCLUSIONS: In primary teeth with irreversible pulpal changes ZOE pulpectomies yielded similar outcome than Vitapex and Sealapex, although there was no agreement with regard to filling materials' resorption. PMID- 21678665 TI - Clinical and radiographic study of chemical-mechanical removal of caries using Papacarie: 24-month follow up. AB - BACKGROUND: The chemical-mechanical removal of caries involves the chemical softening of the infected dentin, following by the mechanical removal of the softened tissue using non-cutting manual instruments. Papacarie (Formula&Acao, Sao Paulo, Brazil) is a product in gel form used for the chemical-mechanical softening of the affected tissue. OBJECTIVE: The purpose of the present study was to evaluate the effectiveness of Papacarie. METHODS: Clinical and radiographic evaluations were performed on 14 young permanent molars treated with Papacarie and restored with glass ionomer cement (VitroMolar DFL Ind. Com LTDA, Rio de Janeiro, Brazil) 24 months following intervention. RESULTS: Success was achieved in 13 of the 14 cases. CONCLUSION: Papacarie was effective in the treatment of carious lesions and constitutes a conservative alternative that offers benefits to patients. PMID- 21678666 TI - Accuracy of an electronic apex locator: a clinical evaluation in primary molars with and without resorption. AB - OBJECTIVE: The aim of this study was to evaluate the accuracy of electronic apex locator (Root ZX) in primary teeth with and without apical root resorption in vivo. STUDY DESIGN: The electronic working length was determined in 28 primary teeth (A total of 46 primary molar root canals with 24 roots without resorption and 22 roots with resorption) from twenty-eight healthy children using Root ZX. The teeth were then extracted. The actual length of each root was measured placing a K-File until the tip was visible at the apical foramen or the apical resorption level and approved with digital microscopic evaluation under 20x magnification and then withdrawn 1 mm. The distances from the file tip to the base of the rubber stop were measured and compared with the measurement obtained from apex locator. The data were evaluated with t test using standard statistical software (SPSS 13.0). The critical value of statistical significance was 5%. RESULTS: For root canals without resorption, the accuracy of Root ZX was 79.16% and 95.82% within +/- 0.5 and +/- 1 mm, respectively. For root canals with resorption, the accuracy of Root ZX was 63.63% and 86.35% within +/- 0.5 and +/- 1 mm, respectively. No statistically significant differences were detect between the electronically determined lengths and the actual lengths regardless of whether or not resorption. CONCLUSION: Using a Root ZX Electronic Apex Locator in primary teeth with or without resorption is recommended for the determination of working length. PMID- 21678667 TI - Prevalence and risk indicators of temporomandibular disorder signs and symptoms in a pediatric population with spastic cerebral palsy. AB - OBJECTIVE: To determine risk indicators for signs and symptoms of temporomandibular disorders (TMD) in children with cerebral palsy (n = 60) and control subjects (n = 60). STUDY DESIGN: The subjects were assessed by means of questionnaire and clinical exam: 1) signs and symptoms of TMD; 2) malocclusions [Dental Aesthetic Index (DAI)]; 3) harmful habits; and 4) bio-psychosocial characteristics. Statistical analysis involved the chi-square, Fisher's exact tests (p < or = 0.05) and multivariate logistic regression (forward stepwise procedure). Variables that achieved a p-value < or = 0.20 were used as potential predictors of signs and symptoms of TMD and applied as co-variables in the multivariate analysis. RESULTS: The prevalence of at least one sign and/or symptom of TMD in the present sample was 1.7% (n = 1) among the individuals in the control group and 13.3% (n = 8) among the individuals with cerebral palsy. The presence of cerebral palsy (Odds Ratio: 9.08; p = 0.041), male gender (OR: 6.21; p = 0.027), severity of the malocclusion (OR: 4.75; p = 0.031), mouth breathing (OR: 5.40; p = 0.022) and mixed dentition (OR: 4.73; p = 0.035) were identified as risk indicators for signs and symptoms of TMD. CONCLUSIONS: It was concluded that children with cerebral palsy had a significantly greater chance of developing signs and symptoms of TMD. PMID- 21678668 TI - Reduction in bacterial loading using 2% chlorhexidine gluconate as an irrigant in pulpectomized primary teeth: a preliminary report. AB - OBJECTIVE: The aim of this study was to evaluate the reduction in bacterial loading using 2% chlorhexidine gluconate as an irrigating solution in pulpectomized primary teeth. STUDY DESIGN: A randomized, controlled clinical trial was performed that included primary teeth with pulp necrosis. Forty necrotic teeth were included, 20 irrigated with 2% chlorhexidine gluconate (experimental group) and 20 with sterile saline solution (control group); in all cases, 2 microbiological samples from within the canals were taken with sterile paper points, the first after the canal opening and before the first irrigation, and the second after instrumentation and final irrigation, before filling. All samples were evaluated by McFarlands scale. RESULTS: The results were statistically analyzed by the Mann-Whitney U test. After analyzing samples before and after irrigation in the control group (saline), we found a significant decrease of bacterial load (P < 0.0002). The same occurred in the chlorhexidine group samples (P < 0.0001). When both groups were compared post-irrigation, a statistically significant difference was observed in favor of 2% chlorhexidine gluconate. CONCLUSION: Two percent chlorhexidine gluconate showed a greater reduction of intracanal bacterial loading compared with that observed with sterile saline solution. This irrigating solution is suggested as an alternative for pulpectomy of necrotic primary teeth. PMID- 21678669 TI - Early response of mechanically exposed dental pulps of swine to antibacterial hemostatic agents or diode laser irradiation. AB - OBJECTIVES: The purpose of this study was to compare the effectiveness of an antibacterial and hemostatic agent to diode laser irradiation in the healing of mechanically exposed porcine pulps. MATERIALS AND METHOD: The experiment required three adult swine (Sus scrofa domestica, Yorkshire) with 36 teeth prepared with occlusal penetrations into the pulpal tissues. The preparations were performed under general anesthesia and the pulps were exposed using high speed instrumentation with rubber dam isolation and a disinfected field. Following instrumentation the coronal pulpal tissue was amputated and immediately treated with ferric sulfate and chlorhexidine semi-gel (12), diluted Buckley' formocresol solution (12) for 5 minutes or laser irradiation with a diode laser (12). After treatment, hemostasis was obtained and a ZOE base applied to the treated pulps (36). The pulpal bases were all covered with a RMGI (Fuji II LC). The tissue samples were collected at 4 weeks (28 days). Following fixation, the samples were de-mineralized, sectioned, stained and histologically graded with a scale of 0-4. RESULTS: The treatment groups were statistically different with the Laser Treated Group demonstrating the least inflammation. CONCLUSION: Pulpotomy treatment with the KaVo Gentle Ray Diode Laser demonstrated significantly less inflammation than the other two pulpal therapy modalities. The ferric sulfate and chlorhexidine mixture demonstrated the greatest inflammation as histologically graded. Also, the histological sections of pulpotomized swine teeth treated with the ferric sulfate and chlorhexidine mixture presented with black pigmented areas in the pulp and surrounding tissue. The formocresol group (clinical standard) and the diode laser group did not present with the black precipitate. PMID- 21678670 TI - Microleakage and SEM analysis of flowable resin used as a sealant following three fissure preparation techniques--an in vitro study. AB - OBJECTIVE: Preventive procedures using pit and fissure sealants are one of the important aspects of pediatric dental practice. The objectives of this in vitro study were to comparatively evaluate microleakage and resin tag penetration of a flowable resin used as a sealant on molars after preparation with Conventional, Enameloplasty and Fissurotomy techniques. METHOD: A total of 48 teeth were divided into 3 groups (n-16). Group A (CST), Group B (EST), and Group C (FT). Following the fissure preparation sealant was applied as per manufacturer's instructions. 8 samples in each group were used for Microleakage and Resin tag analysis. Microleakage analysis was done under Stereomicroscope after Methylene blue dye immersion by using scoring system. The resin tag analysis was done by measuring the length of resin tags on scanning electron microscope (SEM) images consisting of 10 microm scale taken under optical zoom of 2000 X. RESULTS: Significantly lesser microleakage score (P < 0.01) and longer resin tag penetration (P < 0.001) observed in EST (mean score 0.5 +/- 0.53) & (12.19 +/- 1.93 microm) when compared to CST (mean score 1.75 +/- 0.89) & (5.96 +/- 1.84 microm) and FT (mean score 1.5 +/- 0.53) & (6.76 +/- 1.82 microm) which showed more microleakage and short resin tags. No statistical significance between CST and FT was found. CONCLUSION: EST has proven to be an excellent method for preparation of pits and fissures when Flowable composite is used as a sealant because of its lesser microleakage and longer resin tag penetration. PMID- 21678671 TI - Microleakage evaluation using acetate peel technique. AB - OBJECTIVES: To evaluate and measure the interfacial space or the restoration cavity integrity for probable microleakage using acetate film; acetate peel technique under different magnifications. STUDY DESIGN: Premolar tooth was obtained and standardized class V restoration with Z-350 done both buccally and lingually. The tooth was hemisectioned buccolingually and embedded in epoxy resin, polished, acid etched, washed and dried. The sectioned sample was flooded with acetone and a pre-cut acetate film placed over it. As the acetone evaporated, the film took the shape of the micro relief produced by etching and dried in 10-15 mins. It was pulled off the tooth surface and mounted between two glass slides for examination under research microscope with different magnifications. RESULTS: This enabled us to measure the interfacial space that might lead to leakage of restoration and also could detect the intricate details of tooth. CONCLUSION: The acetate peel technique is an efficient way to study the interfacial space/restoration-cavity marginal integrity at a higher magnification and was a fast and reliable tool for assessing the microleakage of a restorative material. PMID- 21678672 TI - An in vitro evaluation of radicular penetration of hydrogen peroxide from bleaching agents during intra-coronal tooth bleaching with an insight of biologic response. AB - OBJECTIVES: External root resorption is the complication of intra-coronal bleaching done with 30% H2O2 alone or mixed with sodium perborate but not with sodium perborate mixed with water. The study was done to comparatively evaluate the H2O2 leakage from three H2O2 liberating bleaching agents. STUDY DESIGN: Fifty one single rooted human teeth were used. After root canal therapy gutta percha was removed below cemento-enamel junction. Three bleaching agents: sodium perborate mixed with water, sodium perborate mixed with 30% H2O2 and 30% H2O2 alone were used. Teeth without defect, with cervical root defect and with mid root defect constituted group A, group B and group C. According to various bleaching agents groups were subdivided into subgroup 1, 2 and 3. H2O2 leakage was measured with the help of spectrophotometer RESULTS: Almost all teeth showed H2O2 leakage. It was maximum in B1 followed by C1, B2, A1, A2, C2, B3, A3 and C3. CONCLUSION: Sodium perborate mixed with water was found to be the best bleaching agent. PMID- 21678673 TI - Microstructure of mineralized tissues in human primary teeth. AB - The aim of this study was to analyze the structural characteristics of the mineralized dental tissues--enamel, dentin and cementum--in primary teeth and to correlate the histological aspects observed in function of the dental type- single-rooted or multi-rooted. METHOD: Eighteen human primary noncarious teeth were sectioned in facial-lingual (single-rooted) and mesio-distal direction (multi-rooted). One to three samples from each tooth were obtained. The samples were prepared by the ground technique and analyzed under light microscopy at different magnifications. A quantitative and descriptive analysis of the morphology of the mineralized tissues was performed. RESULTS: Spindles, tufts and lamellae were consistently observed mainly in the occlusal surface of the primary molars. The scalloped pattern of the dentinoenamel junction was not always present. The same was seen for zones of interglobular dentin. Dead tracts in dentin and tertiary dentin were observed mainly in single-rooted teeth below areas of dental attrition. Areas of cellular and acellular cementum were observed in the two dental types. CONCLUSIONS: Primary teeth have some structural peculiarities and these should be investigated concerning the clinical repercussion. PMID- 21678674 TI - Micro-shear bond strength of different adhesives to human dental enamel. AB - The aim of this study was to evaluate the micro-shear bond strength of 5 adhesive systems to enamel, one single-bottle acid-etch adhesive (O), two self-etching primers (P) and two all-in-one self-etching adhesives (S). METHOD: Sixty premolar enamel surfaces (buccal or lingual) were ground flat with 400- and 600-grit SiC papers and randomly divided into 5 groups (n = 12), according to the adhesive system: SB2--Single Bond 2 (O); CSE--Clearfil SE Bond (P); ADS--AdheSE (P); PLP- Adper Prompt L-Pop (S); XE3--Xeno III (S). Tygon tubing (inner diameter of 0.8 mm) restricted the bonding area to obtain the resin composite (Z250) cylinders. After storage in distilled water at 37 degrees C for 24h and thermocycling, micro shear testing was performed (crosshead speed of 0.5 mm/min). Data were submitted to one-way ANOVA and Tukey test (a = 5%). Samples were also subjected to stereomicroscopic and SEM evaluations after micro-shear testing. Mean bond strength values (MPa +/- SD) and the results of Tukey test were: SB2: 36.36 (+/- 3.34)a; ADS: 33.03 (17.83)a; XE3: 32.76 (+/- 5.61)a; CSE: 30.61 (+/- 6.68)a; PLP: 22.17 (+/- 6.05)b. Groups with the same letter were not statistically different. It can be concluded that no significant difference was there between SB2, ADS, XE3 and CSE, in spite of different etching patterns of these adhesives. Only PLP presented statistically lower bond strengths compared with others. PMID- 21678675 TI - A rare case of gingival fibromatosis associated with hypertrichosis and a dysmorphic face. AB - Several forms of hypertrichosis have been described with and without gingival hyperplasia; some of them are recognized as genetic disorder and associated with syndromes. In all reported cases the most striking differences from other are the craniofacial features. We present a case of a 6-year-old boy with hypertrichosis associated with gingival hyperplasia and a characteristic, coarse face and we consider this case to be a distinctive entity. PMID- 21678676 TI - Developmental dental defects linked with chemoradiotherapy: a case report. AB - Developmental orofacial dentoalveolar complications associated with chemoradiotherapy in an 8 year old child with a history of rhabdomyosarcoma are reported. This report details, clinically and radiographically, these effects in a child diagnosed at 3 years of age with a lesion primary to the left buccinator. Early evaluation is vital to determine potential dentoalveolar complications and long-term consequences. PMID- 21678677 TI - Oral health status of normal children and those affiliated with cardiac diseases. AB - If a child's general health is compromised, care for his/her oral and dental health becomes an absolute necessity. Children with heart diseases require special dental care because of the risk of developing infective endocarditis. AIMS AND OBJECTIVES: Was to evaluate the oral health status, parental oral health care knowledge of the pediatric cardiac patients and non cardiac group and infective endocarditis awareness among the parents of the cardiac group. MATERIALS AND METHODS: Include a total of 50 children with heart diseases and 50 non-cardiac children aged 2-12 years were examined for dental caries index and simplified debris index. A structured, administered questionnaire for parents/caregivers about knowledge of infective endocarditis and oral health were used for data collection. RESULTS: Showed no statistically significant differences between the caries experience score for the two groups and oral health knowledge. Knowledge about Infective Endocarditis in parents of study group was very poor. Simplified Debris Index of age group 6-12 years was higher in study groups compared to the controls. CONCLUSION: Improvements should be made in educating parents and children on the importance of caries prevention and maintaining a good oral hygiene in prevention of infective endocarditis. PMID- 21678678 TI - Evaluation of oral hygiene status, salivary characteristics and dental caries experience in acute lymphoblastic leukemic (ALL) children. AB - Leukemia constitutes approximately 30% of all childhood cancers and Acute Lymphoblastic Leukemia (ALL) is the most common type of malignancy. Oral dryness, ulceration, increased dental decay seen is due to altered salivary flow rate and buffering capacity in these children. Oxidative stress may play an important role in the malignancies resulting in onset of inflammatory oral pathologies. Saliva constitutes first line of defense against free radical-mediated oxidative stress. The present study attempted to relate the oral health status, salivary flow rate, salivary pH, gingival health status, dental caries experience and total salivary antioxidant levels in ALL children. A total of 120 children aged 4-10 years (90 leukemic children, study group and 30 normal healthy siblings, control group) were divided into 4 groups of 30 each. Oral health status, gingival status and dental caries experience was recorded followed by un-stimulated saliva collection. Total antioxidant capacity of un-stimulated saliva was evaluated. The results depicted deterioration in oral health status, gingival status and increased dental caries experience in leukemic children. Salivary flow rate, salivary pH and total salivary antioxidant levels were lowered in leukemic children when compared with control group. PMID- 21678679 TI - Oral health status and practices of 5 and 12 year old Indian tribal children. AB - OBJECTIVES: To assess oral health status and practices of 5- and 12-year-old Tribal school children. METHODS: A total of 418, 5-year-old children and 327, 12 year-old children were enrolled Information on demographic characteristics of participants along with oral health behavior was collected. Clinical data were collected on dental fluorosis, periodontal status, dental caries and treatment needs. Dean's index criterion was used to assess dental fluorosis. Community Periodontal Index (CPI) for periodontal conditions and Dentition status and treatment needs for dental caries were recorded. RESULTS: Between meal sugar consumption was high (100%). None of the children in both the age groups had visited trained health personnel for dental treatment. Dental fluorosis prevalence in 5- and 12-year olds was 11.9% and 22.9% respectively. Bleeding on probing and calculus was common between both the age groups. A low mean number of healthy sextants were found and this decreased with age. Mean dmft/DMFT values for 5- and 12-year olds were 4.13 +/- 3.90 and 1.15 +/- 1.62. Significant caries index (SIC) scores for 5- and 12-year olds were 7.17 +/- 4.30 and 3.78 +/- 3.21 respectively. CONCLUSION: The present study reveals high sugar consumption, dental fluorosis, poor oral hygiene, and untreated dental disease of tribal children. Under these circumstances, the implementation of preventive programs including restriction of sweets in school premises for the tribal children is the key to good oral health. PMID- 21678680 TI - Muscle response during treatment of Class II Division 1 malocclusion with Forsus Fatigue Resistant Device. AB - PURPOSE: To evaluate the muscle response in order to determine the mechanism of neuromuscular adaptations with Forsus Fatigue Resistant Device which has greater elasticity and flexibility; allows greater range of movement of mandible; is available in prefabricated assembly of springs, tubes and rods and is a simple, effective and reliable corrective appliance that benefits not only growing patients but also malocclusions that previously required extractions, headgears and surgery. METHOD: Bilateral EMG activity from anterior temporalis and masseter muscles was monitored longitudinally on 10 young growing females with Class II Division 1 malocclusion to determine changes in postural, swallowing, and maximal voluntary clenching over an observation period of 6 months. RESULTS: There was a significant decrease in the muscle activity at one month after Forsus Fatigue Resistant Device insertion during swallowing of saliva and maximal voluntary clenching which gradually returned to pre treatment levels at the end of six months. CONCLUSION: This study suggests that Forsus Fatigue Resistant Device should be given for at least six months to allow for adequate neuromuscular adaptations to occur for long-term stability of the result. PMID- 21678681 TI - Soft tissue profiles of 3-5 year old preschool children. AB - OBJECTIVE: Identifying the characteristics of soft-tissue profiles in 3-5 year old children. METHODS: Children that participated in the study were selected from the 6 major districts of Ankara. In the selected schools, 3-5 year old 1513 children with primary dentition were examined and profile photographs were obtained. Facial convexity angle (FCA) and Total facial convexity angle (TFCA) were measured from profile photographs. RESULTS: The mean values for the total facial convexity (145.9 degrees +/- 4.2) and facial convexity (165.3 degrees +/- 4.5) angles were determined. FCA and TFCA were significantly influenced by primary second molar terminal plane relationship. CONCLUSION: Finding of this study may be used as clinical references for pediatric dental patients and also, the significant relationship between soft tissue profile and primary occlusion is important for orthodontic diagnosis and treatment of pediatric dental patients. PMID- 21678682 TI - Wei Li Fang. Tar heel footprints in health care. PMID- 21678683 TI - Medical costs of secondhand-smoke exposure in North Carolina. AB - BACKGROUND: The health hazards of exposure to secondhand smoke (SHS) are well defined. Less is known about the economic costs. We performed an analysis of the medical costs of SHS in North Carolina that was based on a similar study conducted in Minnesota. METHODS: We used 2006 Blue Cross and Blue Shield of North Carolina claims data and national and state surveillance data to calculate the treated prevalence of medical conditions that have been found to be related to exposure to SHS, as established by a 2006 report from the US surgeon general. We used the population attributable risk for these conditions to calculate the number of individuals whose episodes of illness could be attributed to exposure to SHS. We adjusted these treatment costs for other types of insurance provided in the state, using Medical Expenditure Panel Survey data. RESULTS: The total annual cost of treatment for conditions related to SHS exposure in North Carolina was estimated to be $293,304,430, in 2009 inflation-adjusted dollars. Sensitivity analysis showed a range of $208.2 million to $386.3 million. The majority of individuals affected were children, but the greatest costs were for cardiovascular conditions. CONCLUSION: These cost data provide additional rationale for regulating smoking in all work sites and public places. PMID- 21678684 TI - Variables associated with use and susceptibility to use of cigarettes among North Carolina adolescents: results from the 2007 statewide survey of high school students. AB - BACKGROUND: As North Carolina works to sustain recent reductions in smoking among adolescents, more knowledge is needed to design effective prevention programs. This study examined the variables associated with use and susceptibility to use of cigarettes use among North Carolina students in high school (ie, grades 9-12). METHODS: Data were collected from the 2007 North Carolina Youth Tobacco Survey (NCYTS). The NCYTS is a biannual public school- and charter school-based survey of North Carolina students in grades 6-12. Seventy-four of 115 school districts from 3 distinct geographic regions of the state were selected for participation in the 2007 NCYTS. The survey was completed by 3,364 students (81.6%) at participating high schools, for an overall completion rate of 78.3% among all North Carolina high school students. Logistic regression models examined variables associated with current use of cigarettes, ever having used cigarettes (also referred to as "ever use"), and susceptibility to use of cigarettes. All analyses included sampling weights, which enabled results to be generalized to all high school students in North Carolina. RESULTS: A total of 48.9% of students reported ever use, 19.0% were classified as current users, and 33.5% were classified as susceptible to use. Females, nonminorities, and older students had higher odds than males, minorities, and younger students, respectively, of being a current smoker. Minorities, however, had higher odds than nonminorities of ever smoking. Use of other forms of tobacco increased the odds of current use and ever use of cigarettes. Agreement with the statement that smoking makes one look cool or fit in increased the odds of being susceptible to smoking. Having a willingness to wear an item promoting a tobacco company and having close friends who smoked individually increased the odds of each of the 3 outcomes. LIMITATIONS: Data are from a cross-sectional survey conducted every other year, in which students self-report use of, attitudes about, and perceptions about tobacco products. CONCLUSIONS: Many variables should be taken into account to optimize efforts to prevent tobacco use, countermarket campaigns, and policy initiatives in North Carolina. PMID- 21678685 TI - Use of 2001-2002 Behavioral Risk Factor Surveillance System data to characterize cancer survivors in North Carolina. AB - OBJECTIVE: We used Behavioral Risk Factor Surveillance System (BRFSS) data to examine demographic characteristics, health status, quality of life, and preventive health behaviors among adult cancer survivors in North Carolina. METHODS: We analyzed responses to state-added questions on cancer survivorship and to standard BRFSS questions concerning health status, quality of life, and health behaviors, including access of preventive services associated with cancer prevention and early detection, from the 2001 and 2002 North Carolina BRFSS. RESULTS: Cancer survivors were more likely than individuals with no self-reported history of cancer to be women (62.7% vs 51.3%), white (80.8% vs 70.3%), aged 65 years or older (48.7% vs 13.8%), and up to date with colorectal cancer screening (66.4% vs 52.4%); as likely to be current smokers (28.0% vs 26.2%); and more likely to report poor or fair health status (28.2% vs 17.2%). Cancer survivors reported lower quality of life, measured as the number of physically and mentally unhealthy days in the previous 30 days. LIMITATIONS: This was a cross-sectional survey that relied on self-reported history of cancer, healthy behaviors, and use of preventive services. CONCLUSIONS: Data from a statewide, population-based survey can be used to assess unmet needs of cancer survivors. Comprehensive cancer-control programs should be able to design interventions and monitor progress of state cancer-survivorship goals. PMID- 21678686 TI - Honoring their service: behavioral health services in North Carolina for military service members, veterans, and their families. AB - The North Carolina Institute of Medicine Task Force on Behavioral Health Services for the Military and Their Families examined the adequacy of Medicaid- and state funded services for mental health conditions, developmental disabilities (including traumatic brain injury), and substance abuse that are currently available in North Carolina to military service members, veterans, and their families. The task force determined that there are several gaps in services and made 13 recommendations related to federal, state, and local community resources. This article reviews the work of the task force and current efforts to improve services in North Carolina. PMID- 21678687 TI - A congressional look at postdeployment behavioral health care. AB - As the 2 US senators from North Carolina, it is our job to support veterans and active-duty personnel as they work to keep our country safe. Because of the physical and psychological stresses of repeated deployments, it is critically important that we make significant strides to improve the behavioral health services available to these individuals and their families. PMID- 21678688 TI - Initiatives to improve access to behavioral health services in the Veterans Affairs Health System. AB - In response to veterans' needs in the context of recent deployments, the Veterans Affairs (VA) health system has increased the number of its facilities and caregivers and has pioneered changes in policy and programs. We review significant recent initiatives to improve access to behavioral health services in the VA health system. PMID- 21678689 TI - North Carolina National Guard Integrated Behavioral Health System. AB - The North Carolina National Guard (NCNG) Integrated Behavioral Health System is designed to systematically bring the best internal and external military resources together to function collaboratively for the betterment of behavioral health assessment, crisis intervention, referral, and case management services available to NCNG service members and their families. PMID- 21678690 TI - The Governor's Focus on Servicemembers, Veterans, and Their Families. AB - The Governor's Focus on Servicemembers, Veterans, and Their Families is a coalition of federal, state, and local agencies and professional and consumer organizations. Its goal is to develop and maximize public and private services and supports for service members in active and reserve components of the armed forces, veterans, and their families. PMID- 21678691 TI - Co-location of behavioral health and primary care services: Community Care of North Carolina and the Center of Excellence for Integrated Care. AB - The North Carolina Division of Mental Health, Developmental Disabilities, and Substance Abuse Services works with partners to reduce the impact of behavioral health conditions in communities throughout the state. We review state-funded behavioral health initiatives that provide support to military personnel and their families, with special attention to public services and co-location efforts. PMID- 21678692 TI - Challenges to providing services to North Carolina Veterans who have traumatic brain injury. PMID- 21678693 TI - Behavioral health conditions among military personnel and veterans: prevalence and best practices for treatment. AB - The Department of Defense and the Department of Veterans Affairs place a high priority on behavioral health assessment, treatment, and research. We present the national and regional prevalence of the most-common behavioral health problems experienced by Operation Enduring Freedom and Operation Iraqi Freedom veterans and offer resources for best practices for treatment. PMID- 21678694 TI - The Citizen Soldier Support Program: a case study. PMID- 21678660 TI - Evaluation of the Faraday angle by numerical methods and comparison with the Tore Supra and JET polarimeter electronics. AB - On the Tore Supra tokamak, a far infrared polarimeter diagnostic has been routinely used for diagnosing the current density by measuring the Faraday rotation angle. A high precision of measurement is needed to correctly reconstruct the current profile. To reach this precision, electronics used to compute the phase and the amplitude of the detected signals must have a good resilience to the noise in the measurement. In this article, the analogue card's response to the noise coming from the detectors and their impact on the Faraday angle measurements are analyzed, and we present numerical methods to calculate the phase and the amplitude. These validations have been done using real signals acquired by Tore Supra and JET experiments. These methods have been developed to be used in real-time in the future numerical cards that will replace the Tore Supra present analogue ones. PMID- 21678695 TI - Behavioral health services, projects, and programs available to North Carolina military personnel and their families. PMID- 21678696 TI - North Carolina National Guard Family Assistant Centers. PMID- 21678697 TI - The National Organization on Disability's Wounded Warrior Career Demonstration Program. PMID- 21678698 TI - The Affordable Care Act and the Triple Solution for a Healthier America. AB - GlaxoSmithKline promotes improvement in the health of Americans through the Triple Solution for a Healthier America, which focuses on prevention, intervention, and innovation. The Affordable Care Act includes provisions that embody the Triple Solution and provides unprecedented funding to further develop comparative effectiveness research, health information technology, and quality standards. PMID- 21678699 TI - The sledgehammer. PMID- 21678700 TI - Denosumab. Limited efficacy in fracture prevention, too many adverse effects. AB - The standard drug for postmenopausal osteoporotic women with a high risk of fracture is alendronic acid, used in conjunction with non-drug measures. There are no drugs with demonstrated efficacy on the risk of fracture in castrated men with prostate cancer. Denosumab, a monoclonal antibody that inhibits a cytokine acting mainly on bone cells and lymphocytes, has been authorised in the European Union for use in both these settings. There are no trials comparing denosumab versus alendronic acid for symptomatic fracture prevention. In two trials involving 1189 and 504 women, the incidence of clinical fractures, recorded as simple adverse effects, did not differ significantly between the groups. In a placebo-controlled trial in about 7900 elderly osteoporotic women, denosumab significantly reduced the incidence of symptomatic vertebral fractures (0.8% versus 2.6% after 3 years) and hip fractures (0.7% versus 1.2%). An indirect comparison, providing weak evidence, suggests that denosumab is less effective than alendronic acid. In a placebo-controlled trial in 1468 castrated men with prostate cancer, denosumab did not reduce the incidence of symptomatic fractures after 3 years. Only the incidence of vertebral fractures, detected on routine radiographs, showed a statistically significant decline (1.5% versus 3.5%). Denosumab has numerous adverse effects. In placebo-controlled trials, this monoclonal antibody was associated with a higher incidence of deep-seated infections such as endocarditis, cancer, and skin rash. More data are needed on the risk of pancreatitis, long-term bone disorders (atypical fractures, delayed fracture healing, osteonecrosis of the jaw), hypocalcaemia and cataracts, all of which were reported in clinical trials. In practice, denosumab is not sufficiently effective to outweigh its established and potential risks in postmenopausal osteoporotic women or in castrated men with prostate cancer. PMID- 21678701 TI - Docetaxel and adjuvant treatment of breast cancer. AB - In women with node-negative breast cancer, replacing fluorouracil with docetaxel in the adjuvant chemotherapy protocol did not improve efficacy but in one trial led to a 5-fold increase in serious adverse effects. PMID- 21678702 TI - Telmisartan in high-risk cardiovascular patients. No need to change standard practice. AB - No more effective than ramipril in a trial including 25620 patients; two unconvincing placebo-controlled trials in a total of about 26 200 patients. PMID- 21678703 TI - Intravenous moxifloxacin. Even more harmful than the oral form. PMID- 21678704 TI - To treat or not to treat cancer patients with chemotherapy at the end of life? AB - An interesting prospective British study examined clinical and laboratory data from about 600 patients who died within 30 days of receiving cytotoxic cancer chemotherapy. The vast majority of patients had been treated with palliative rather than curative intent. For about one-quarter of the patients who received palliative chemotherapy, the therapy was considered to have caused or hastened their death. 40% of the patients who died within 30 days following chemotherapy had experienced a serious adverse effect related to the cytotoxic treatment, sometimes requiring hospitalisation. These adverse effects included infections, coagulation disorders, gastrointestinal disorders and renal impairment. Nearly one-quarter of the patients had a poor performance status when chemotherapy was instituted. In particular, more than half of them already had a cancer-related complication when they started the cycle, such as impaired kidney or liver function, hypoalbuminaemia, ascites or pleural effusion. Only 16% of the deaths were discussed with the medical team in a morbidity and mortality meeting. In practice, not administering cytotoxic chemotherapy is sometimes the best solution for patients. Healthcare teams would be well advised to prepare for the (ideally shared) decision on whether or not to treat a terminally ill cancer patient with cytotoxic drugs; by conducting a systematic analysis of the causes of death of other patients treated in the same manner. PMID- 21678705 TI - Somatropin: increased mortality? PMID- 21678706 TI - Adjuvant-containing H1N1 influenza vaccine pandemrix: narcolepsy in children. PMID- 21678707 TI - Fluoxetine in early pregnancy: cardiac birth defects. PMID- 21678708 TI - Acute heart failure with dyspnoea: initial treatment. Furosemide and trinitrine, despite the lack of a proven survival benefit. AB - For patients with acute heart failure and dyspnoea due to pulmonary congestion, the risk of death in the short term is high. To determine how best to manage these patients, we reviewed the relevant literature using the standard Prescrire methodology. There are few reliable clinical trial data. None of the available drugs has been shown to improve survival. Loop diuretics such as furosemide improve some haemodynamic parameters and dyspnoea due to congestion, i.e., water and salt retention. The dose is adjusted on the basis of clinical response, renal status and previous use of a loop diuretic, especially in chronic heart failure. The main adverse effects of loop diuretics are hypotension, hyponatraemia, hypokalaemia, renal failure and ototoxicity. Compared with repeated injections, continuous infusion seems to carry a lower risk of death and ototoxicity. High doses are associated with excess mortality. Nitrate derivatives such as trinitrine and isosorbide dinitrate are vasodilators. Only intravenous administration has been assessed in acute heart failure. These drugs improve certain haemodynamic parameters, reduce blood pressure and increase coronary flow.Their effect declines rapidly above a certain dose in about 20% of patients. They seem to improve dyspnoea and, according to a difficult-to-interpret trial of isosorbide dinitrate, may reduce the risk of myocardial infarction. There is no firm evidence that nitrate derivatives improve survival in patients with acute heart failure, but they reduce mortality in patients with myocardial infarction, a frequent cause of acute heart failure. The main adverse effect of nitrate derivatives is hypotension, meaning that these drugs should not be used when blood pressure is low and that blood pressure should be closely monitored during treatment. Randomised trials of another vasodilator, nesiritide, showed excess mortality at 30 days. There are no such trials of nitrate derivatives. In patients with cardiogenic shock, inotropes (mainly dopamine, dobutamine and milrinone) improve symptoms and haemodynamic parameters but may increase mortality.These drugs carry a risk of ventricular and supraventricular arrhythmias and tachycardia. Their use requires continuous monitoring in an intensive care unit. Cardiac glycosides, including digoxin, have been used empirically in acute heart failure. The use of digoxin is mentioned in only one clinical practice guideline, in patients with atrial fibrillation and a rapid heart rate. Its narrow therapeutic margin and its frequent interactions with other drugs make digoxin difficult to use. Oxygen is usually recommended in case of hypoxaemia but its clinical value has not been assessed comparatively in acute heart failure. In some trials, routine oxygen delivery, without taking into account the degree of hypoxia, appeared to be harmful in patients with myocardial infarction. Non-invasive ventilation has been assessed in several comparative randomised trials, in which it was found to improve some physiological parameters. In a trial in 1069 patients, it had no impact on mortality at 30 days, or on the need for endotracheal intubation. It is not appropriate for patients with respiratory distress necessitating intubation, or with altered consciousness, severe dementia, major anxiety. It is often poorly tolerated. Its main adverse effects are aggravation of right heart failure, pneumothorax, and aspiration of gastric contents. Early treatment probably improves outcome. Clinical practice guidelines recommend urgent hospitalisation of patients with acute heart failure. In summary, the choice of initial treatment for patients with acute heart failure and dyspnoea depends largely on blood pressure.Treatment is mainly based on loop diuretics, nitrate derivatives (when blood pressure is not too low) and non-invasive ventilation. It should be emphasised that these patients are highly unstable and that there is a narrow margin between beneficial and harmful effects of available treatments. Patients receiving treatment should always be closely monitored. PMID- 21678709 TI - Lambert-Eaton myasthenic syndrome in brief. AB - Lambert-Eaton myasthenic syndrome is a rare neurological syndrome of autoimmune origin. It is usually associated with small-cell lung cancer but may be idiopathic. The main clinical feature is potentially disabling limb muscle weakness. Clinical signs of autonomic nervous system involvement are frequent. The muscle weakness often improves with physical exercise, which distinguishes this syndrome from myasthenia. Tendon reflexes are reduced or absent but reappear temporarily after brief muscle contraction. Diagnosis is confirmed by electromyographic findings. Management is generally based on treatment of the underlying malignancy. Immunosuppressants are used in severe disease and in cases not associated with cancer, but they have limited efficacy. Symptomatic treatments are available but their efficacy is poorly documented. PMID- 21678710 TI - 2010 drug packaging review: identifying problems to prevent errors. AB - Prescrire's analyses showed that the quality of drug packaging in 2010 still left much to be desired. Potentially dangerous packaging remains a significant problem: unclear labelling is source of medication errors; dosing devices for some psychotropic drugs create a risk of overdose; child-proof caps are often lacking; and too many patient information leaflets are misleading or difficult to understand. Everything that is needed for safe drug packaging is available; it is now up to regulatory agencies and drug companies to act responsibly. In the meantime, health professionals can help their patients by learning to identify the pitfalls of drug packaging and providing safe information to help prevent medication errors. PMID- 21678711 TI - Control of drug advertising in France: opaque and ineffective. AB - The French authorities frequently require drug companies to modify advertisements aimed at healthcare professionals, but it is impossible to know which advertisements are concerned. Prepublication screening of direct-to-consumer drug advertisements does not prevent these ads from trivialising drug consumption. PMID- 21678712 TI - Nurses to lead on last offices. PMID- 21678713 TI - NHS evidence supports you in your drive to deliver quality". PMID- 21678714 TI - "Admitting to suffering from depression is just not cricket'. PMID- 21678715 TI - "Nutritious meals count for nothing if they are cold". PMID- 21678716 TI - Why do patients fail to follow long term treatment? AB - To enhance their understanding of issues around adherence to treatment, eight health professionals adhered to a randomly selected six-week treatment regimen suitable for patients with type 1 diabetes. These regimens are designed to promote optimal diabetes control and promote patients' health and wellbeing. The participants were expected to undertake a number of invasive tasks, including blood-glucose monitoring and the administration of placebo injections. The extent to which members of the team felt able to manage their care was measured using self-reported questionnaires and their reflections were documented throughout the trial. The trial forced the team to question their expectations of children and young people with diabetes, and those of their parents. It also gave them an insight into factors that influence adherence to treatment. PMID- 21678718 TI - How to manage the diabetic foot. PMID- 21678717 TI - Using A&E data to prevent violence in communities. AB - The majority of violent assaults are not reported to the police but many people present to emergency departments with their injuries. A significant number of these incidents are alcohol-related. Assault data can be collected by reception staff using the Cardiff model, then used by the Community Safety Partnership to identify problem licensed premises and crime hotspots to reduce the incidence of violence and attendances at emergency departments. PMID- 21678719 TI - Adverse reactions: know the risks. PMID- 21678720 TI - Using the skills of public volunteers to steer services. AB - This article explains how to achieve accreditation for a practice development unit, focusing on the demand for public-patient representation on its steering group. It maps the unit's development and how public-patient input has evolved, with decisions being made jointly by health professionals and public representatives about the selection, management and progression of current and future practice development. PMID- 21678721 TI - Behind bars. PMID- 21678722 TI - Look to the future to create an effective vision. PMID- 21678723 TI - Time to decriminalise drug. PMID- 21678724 TI - Bacteria isolated from bloodstream infections at a tertiary care hospital in Dar es Salaam, Tanzania--antimicrobial resistance of isolates. PMID- 21678725 TI - Cultural safety and family medicine in Africa. PMID- 21678726 TI - Doctor IPT ignorance contributing to TB epidemic--study. PMID- 21678728 TI - Life on the inside; coming out--Lex's story. PMID- 21678727 TI - Transgender patients sidelined by attitudes and labelling. PMID- 21678729 TI - Recommendations pertaining to the use of viral vaccines: influenza 2011. PMID- 21678730 TI - Heart transplantation: research that led to the first human transplant in 1967. PMID- 21678731 TI - Vascular cause for stridor in infants. PMID- 21678732 TI - MRI of a twin pregnancy in a uterus bicornis unicollis. PMID- 21678733 TI - Paediatric cardiac services in South Africa. PMID- 21678734 TI - Tuberculosis in prisons in sub-Saharan Africa--a potential time bomb. PMID- 21678735 TI - Referral steps in district health system are side-stepped. PMID- 21678736 TI - Relationships of heredity and dry eye with pterygia in black African patients. PMID- 21678737 TI - Tuberculosis control has failed in South Africa--time to reappraise strategy. AB - South Africa's rate of tuberculosis (TB) has increased over the last 20 years, to now having the third-highest TB burden in the world. The TB control programme has primarily focused on effective case management of passively presenting TB cases, and progress has been recorded towards international treatment targets. While outcomes for notified TB cases have improved, this strategy failed to contain the TB epidemic. South Africa has the highest per capita annual risk of TB disease of comparably sized countries globally, and its communities have extremely high TB transmission rates. The rates of TB infection of children and adolescents are now similar to those reported 100 years ago in Europe long before chemotherapy became available. High rates of HIV testing of TB patients in Cape Town allows analysis of TB notification data stratified by age, type of TB and HIV status, and a better understanding of TB epidemiology. TB infection prevalence data from Cape Town communities allow estimation of the prevailing force of TB infection and, together with TB notification and prevalence data, the effective number of secondary infections and case finding proportions can be estimated. This better understanding of the major drivers of the TB epidemic allows reasons to be identified for failure of the present strategy. New control strategies can also be identified, that must be accompanied by novel TB control targets. PMID- 21678738 TI - The influence of burnout on skills retention of junior doctors at Red Cross War Memorial Children's Hospital: a case study. AB - This study used the Maslach Burnout Inventory to evaluate the degree of burnout among junior doctors at Red Cross War Memorial Children's Hospital (RXH), Cape Town, and the influence thereof on the retention of valuable skills in the hospital. It further considered measures that could be taken to mitigate the causes of burnout, by means of qualitative methods. BACKGROUND: The research explores the significance of burnout and the role it plays in the retention of junior doctors at RXH. There has been an increase in the migration of medical doctors worldwide, with an exodus of doctors from South Africa. Along with the effects of HIV/AIDS, this places extra strain on those who remain. METHODOLOGY: A two-part, mixed quantitative and qualitative study consisting of a validated measure, the Maslach Burnout Inventory, was sent to 39 junior doctors at RXH. Responses were received from 23 doctors (one of which was invalid), constituting a 60% response rate. The second part consisted of four semistructured interviews. RESULTS: Of the 22 respondents, 100% experienced a high degree of burnout on one of the three scales of burnout, namely emotional exhaustion, depersonalisation and reduced accomplishment. Of those surveyed, 95% expressed an intention to leave RXH. CONCLUSION: The degree of emotional exhaustion and depersonalisation experienced by the junior doctors at RXH was significantly higher than that in a normative sample of 1 104 doctors. Recruitment, improved management and planning, increased support, mentorship and a more empathetic administration were some of the factors suggested to mitigate the burnout experienced by the junior doctors. PMID- 21678739 TI - A lower body mass index is associated with cardiomyopathy in people with HIV infection: evidence from a case comparison study. AB - The cause of cardiomyopathy in patients infected with the human immunodeficiency virus (HIV) remains largely unknown, although a number of predisposing factors have been identified. Malnutrition has been postulated to be a contributory factor, but the association of anthropometric measures of nutritional status with HIV-associated cardiomyopathy has not been established. METHOD: We investigated the association between anthropometric measures of nutritional status and cardiomyopathy in HIV-positive individuals in a cross-sectional case comparison study. RESULTS: Seventeen cases of HIV-associated cardiomyopathy and a comparison group of 18 HIV-positive individuals without cardiomyopathy were studied. There was no significant difference between the two groups in age, gender, CD4 cell count, HIV RNA viral load or World Health Organization (WHO) clinical stage of HIV disease. Patients with HIV-associated cardiomyopathy had evidence of undernutrition compared with HIV-infected people without cardiomyopathy, as evidenced by a significantly lower body mass index (BMI) (20.9 kg/m2 v. 27.0 kg/m2, p = 0.02), mid-upper arm circumference (26.2 cm v. 27.3 cm, p = 0.02), and bone-free arm muscle area (26.7 cm2 v. 32.8 cm2, p = 0.02). However, in a multivariate stepwise logistic regression model, a lower BMI was the only independent anthropometric risk factor for cardiomyopathy (odds ratio 0.76, 95% confidence interval 0.64 - 0.97, p = 0.02). CONCLUSION: A lower BMI is associated with cardiomyopathy in people who are living with HIV. PMID- 21678740 TI - A bird's eye view of PMTCT coverage at two regional hospitals and their referral clinics in a resource-limited setting. AB - BACKGROUND: While countries strengthen their health information systems, local health managers require alternative strategies to monitor their prevention of mother-to-child transmission (PMTCT) programmes to improve coverage and service delivery. OBJECTIVE: To demonstrate the use of a postpartum audit to establish PMTCT coverage and programme deficiencies at hospitals and multiple primary health care facilities. METHODS: A cross-sectional hospital-based medical chart audit of pregnant women admitted in labour to their regional hospital. Their antenatal hand-held medical records were added to a hospital-issued maternity chart that was used to record further obstetric and perinatal management during their hospital stay. Women recuperating in the postnatal wards up to 48 hours after delivery at two hospitals in KwaZulu-Natal participated. Data included their antenatal attendance, access to HIV counselling and testing (HCT), and access to nevirapine (NVP) for PMTCT. RESULTS: Fifty-three clinics were indirectly evaluated as a result of the postpartum audit. All clinics provided HCT and the average HIV testing rate was 91% (range 40 - 100); 15% (N = 8) of these clinics with HIV testing rates of < 80% were identified. The median frequency of NVP dispensing at 53 clinics was 87% (interquartile range 67 - 100); among these 30% (N = 16) with NVP dispensing frequencies of < 80% were identified. CONCLUSION: An exit survey by trained nurses at a maternity hospital can provide health services management with a quick estimate of antenatal and PMTCT coverage of multiple primary health facilities in a specified catchment area. Challenges in the PMTCT programme at primary health clinic and hospital levels were highlighted. PMID- 21678741 TI - Immunogenicity and safety of an acellular pertussis, diphtheria, tetanus, inactivated poliovirus, Hib-conjugate combined vaccine (Pentaxim) and monovalent hepatitis B vaccine at 6, 10 and 14 weeks of age in infants in South Africa. AB - OBJECTIVE: To assess the immunogenicity and safety data for a pentavalent combination vaccine containing acellular pertussis, inactivated poliovirus, and Haemophilus influenzae (Hib) polysaccharide-conjugate antigens. METHODS: A DTaP IPV//PRP T vaccine (Pentaxim) was given at 6, 10 and 14 weeks of age to 212 infants in South Africa. Monovalent hepatitis B vaccine was given concomitantly. Immunogenicity was assessed using seroprotection and seroconversion rates; safety was assessed by monitoring for solicited injection site and systemic adverse events, and follow-up monitoring for unsolicited adverse events and serious adverse events. RESULTS: Immunogenicity was high for each vaccine antigen, and similar to a reference study done in France using a similar (2, 3 and 4 months of age) administration schedule. After the third dose, 94.6% of participants had anti-PRP > or = 0.15 microg/ml. The anti-PRP geometric mean antibody titre (GMT) was 2.0 microg/ml. The seroprotection rates for diphtheria and tetanus (> or = 0.01 IU/ml), poliovirus types 1, 2 and 3 (> or = 8 1/dil U) and hepatitis B were all 100%. Anti-polio GMTs were very high, 1 453, 1 699 and 2 398 (1/dil U) for types 1, 2 and 3, respectively. The seroconversion/vaccine response rates to pertussis antigens (4-fold increase in antibody concentration) were 97.5% for PT and 83.9% for FHA. CONCLUSIONS: The DTaP-IPV//PRP T vaccine was highly immunogenic at 6, 10 and 14 weeks of age in infants in South Africa, was compatible with the monovalent hepatitis B vaccine, and was well tolerated. PMID- 21678742 TI - Assessing menopausal status in women aged 40 - 49 using depot-medroxyprogesterone acetate, norethisterone enanthate or combined oral contraception. AB - BACKGROUND: Determining symptoms of menopause in older users of hormonal injectable contraceptives may be challenging, owing to method-induced amenorrhoea, suppression of follicle-stimulating hormone (FSH) and vasomotor symptoms. OBJECTIVE: To investigate menopausal symptoms in women aged 40 - 49 using injectable contraceptives depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN) or combined oral contraceptives (COCs), compared with non-users of hormonal contraception. METHODS: Women using DMPA (N = 127), NET-EN (N = 102), COCs (N = 106) and 161 non-hormonal contraceptive user controls were recruited. Baseline visit serum FSH was measured and information was collected on vasomotor symptoms and menstrual regularity. RESULTS: There was no difference in reporting of vasomotor symptoms between the groups. There was no evidence of a difference in FSH level between non-users (mean FSH 26.7 IU/ml, SD 28.7) and DMPA users (mean FSH 23.1 IU/ml, SD 27.8) (p = 0.64). However, the NET EN (mean FSH 11.0 IU/ml, SD 10.9) (p = 0.003) and COC groups (mean FSH 12.5 IU/ml, SD 18.7) (p = 0.001) had significantly lower FSH levels compared with the non-user group. CONCLUSION: The lower FSH levels found in the NET-EN and COC users compared with controls may indicate a greater degree of suppression of FSH levels in these two methods, compared with DMPA. Measuring FSH levels may therefore be informative of menopausal status in DMPA users but not in NET-EN or COC users. Vasomotor symptoms may assist in assessing menopausal status in DMPA, NET-EN and COC users. PMID- 21678743 TI - Huge cuts ahead for front line staff. PMID- 21678744 TI - "Collaboration is crucial when caring for terminally ill children". PMID- 21678745 TI - "When I grow up I want to make everyone agree with me". PMID- 21678746 TI - "Regrets of the dying should influence end of life care". PMID- 21678747 TI - Think about it: a prompt to discuss end of life choices. AB - A team of nurses in East Lancashire developed a communication tool to help initiate end-of-life discussions and support advance care planning. This article describes the development, implementation and evaluation of the "Think about it" communication prompt. PMID- 21678748 TI - How effective is the preferred priorities of care document? AB - BACKGROUND: Growing recognition that people nearing the end of life should have greater control over their care has increased the use of the preferred priorities for care (PPC) document. AIM: To explore district nurses' experiences of using PPCs in practice. METHOD: A literature review and qualitative, unstructured interviews with 11 district nurses were carried out. RESULTS: The study identified five key themes associated with the use of the PPC document: communication skills; hopelessness; empowerment; admission avoidance; and multiprofessional working. CONCLUSION: The PPC document was seen as a valuable end-of-life care tool by district nurses. Protocols and guidelines governing the use of the PPC, and the support required by health professionals using the document, would maximise its benefits. This could ensure a wider range of health professionals would use the document, rather than its use being confined to district nurses. PMID- 21678750 TI - Community midwives have more time to spend on care and carry out more home visits thanks to digital pens linked to Blackberry mobile phones. PMID- 21678749 TI - Sedation for infants and children. PMID- 21678751 TI - Mind mapping in qualitative research. AB - BACKGROUND: We tested a theory that mind mapping could be used as a tool in qualitative research to transcribe and analyse an interview. METHOD: We compared results derived from mind mapping with those from interpretive phenomenological analysis by examining patients' and carers' perceptions of a new nurse-led service. RESULTS: Mind mapping could be used to rapidly analyse simple qualitative audio-recorded interviews. CONCLUSION: More research is needed to establish the extent to which mind mapping can assist qualitative researchers. PMID- 21678752 TI - The call to cure. PMID- 21678754 TI - Reaching out. PMID- 21678753 TI - Complaints need correct response. PMID- 21678755 TI - Control of obesity--a call for collective action. PMID- 21678756 TI - Meaningful use incentive or unsound business practice. PMID- 21678757 TI - Primary Ewing's sarcoma of the kidney with caval involvement: a case report. AB - Ewing sarcoma, also referred to as primitive neuroectodermal tumor (PNET), is a malignancy, histologically characterized by Homer-Wright rosettes and small round cells, that presents most commonly in bone or soft tissue in the pediatric and adolescent populations. We report the case of a patient that presents with intermittent gross hematuria, abdominal mass and elevated blood pressure. After surgical excision of the renal mass, the rare finding of a primary renal Ewing's sarcoma was discovered. After surgery the patient was additionally treated with chemotherapy. After presenting this case, we briefly discuss the unique case of isolated renal Ewing's sarcoma, including incidence and treatment. PMID- 21678758 TI - Does atenolol reduce adverse cardiovascular outcomes in adult patients with hypertension? PMID- 21678759 TI - Fluoride varnish applied during well child checks. PMID- 21678760 TI - Under the big top. Life at the Oklahoma Capitol. PMID- 21678761 TI - Electrically enhanced biofilm removal in a contaminated model dental unit waterline. PMID- 21678762 TI - Fun with photons: selective light induced reactions in solution and in water soluble nano-containers. AB - Two distinct strategies for controlling selectivity, in particular stereoselectivity in photochemical reactions are reviewed. In the first strategy, supramolecular approach using cucurbituril nano-containers in catalytic amounts is employed to control selectivity during photochemical transformations. In the second approach, a generalized methodology for carrying out light-induced transformations in solution at ambient conditions is detailed where axially chiral motifs are employed to enantiospecifically transfer the axial chirality in the reactant to point chirality in the photoproduct(s). PMID- 21678763 TI - E- and P-selectin: differences, similarities and implications for the design of P selectin antagonists. AB - Selectins form a family of Ca2+ -dependent carbohydrate binding proteins that mediate the initial step of leukocyte recruitment in the inflammatory process. Blocking of selectins is therefore considered a promising therapeutic approach to treat acute and chronic inflammatory diseases which are caused by excessive extravasation of leukocytes. This mini-review highlights the major structural differences between E- and P-selectin and summarizes the resulting strategies for the design of selectin antagonists. PMID- 21678764 TI - Hydrogen storage in formic acid amine adducts. AB - Formic acid, containing 4.4 wt% of hydrogen, is a non-toxic liquid at ambient temperature and therefore an ideal candidate as potential hydrogen storage material. Formic acid can be generated via catalytic hydrogenation of CO2 or bicarbonate in the presence of an amine with suitable ruthenium catalysts. In addition selective dehydrogenation of formic acid amine adducts can be carried out at ambient temperatures with either ruthenium phosphine catalyst systems as well as iron-based catalysts. In detail we obtained with the [RuCl2(benzene)]2/dppe catalyst system a remarkable TON of 260,000 at room temperature. Moreover applying Fe3(CO)12 together with tribenzylphosphine and 2,2':6',2"-terpyridine under visible light irradiation a TON of 1266 was obtained, which is the highest activity known to date for selective dehydrogenation of formic acid applying non-precious metal catalysts. PMID- 21678765 TI - From ligand-stabilized gold nanoparticles to hybrid organic-inorganic superstructures. AB - Gold nanoparticles (Au NPs) have many potential applications including nanoelectronics, catalysts and sensors. These future devices depend on stable and monodisperse NPs and their directed assembly. Herein we review our efforts to develop oligomeric thioether ligands able to direct the synthesis of Au NPs and their surface functionalization. A screening of different oligomeric thioethers indicates that the NPs become more stable and monodisperse with increasing length of the thioether oligomer. The heptameric benzylic thioether 4 stabilizes monodisperse NPs with a diameter of 1 nm and excellent long-term stability in solution. It is further monofunctionalized with a central protected acetylene. After NP formation in the presence of the ligands we utilize the peripheral functionality to interlink the NPs. A mild oxidative diacetylene coupling protocol is used to covalently bind these 'artificial molecules'. This wet chemical procedure leads to the formation of hybrid organic-inorganic superstructures. PMID- 21678766 TI - Systematic coarse graining flowing polymer melts: thermodynamically guided simulations and resulting constitutive model. AB - Complex fluids, such as polymers, colloids, liquid-crystals etc., show intriguing viscoelastic properties, due to the complicated interplay between flow-induced structure formation and dynamical behavior. Starting from microscopic models of complex fluids, a systematic coarse-graining method is presented that allows us to derive closed-form and thermodynamically consistent constitutive equations for such fluids. Essential ingredients of the proposed approach are thermodynamically guided simulations within a consistent coarse-graining scheme. In addition to this new type of multiscale simulations, we reconstruct the building blocks that constitute the thermodynamically consistent coarse-grained model. We illustrate the method for low-molecular polymer melts, which are subject to different imposed flow fields like planar shear and different elongational flows. The constitutive equation for general flow conditions we obtain shows rheological behavior including shear thinning, normal stress differences, and elongational viscosities in good agreement with reference results. PMID- 21678767 TI - Excitonic splittings in jet-cooled molecular dimers. AB - In more than 60 years of research on molecular excitons, there has been extensive theoretical work but few experimental investigations have rigorously tested the predictions of exciton coupling theories. In centrosymmetric doubly H-bonded molecular dimers with identical chromophores, the S0-->S1 electronic transition dipole moments of the monomers combine in a parallel and antiparallel fashion, giving the S0-S1 and S0-->S2 transitions of the dimer. One of these is strictly symmetry-forbidden and the other fully allowed. Minimal perturbations such as 12C/13C or H/D isotopic substitution lift the symmetry restrictions sufficiently to render both transitions allowed. The excitonic (Davydov) splitting can then be measured as the energy difference between the respective vibrationless O0(0) bands. We have measured the mass-specific vibronic spectra of the centrosymmetric H-bonded dimers (2-pyridone)2 and (2-aminopyridine)2 that are supersonically cooled to a few K and isolated in molecular beams, using two-color resonant two photon ionization spectroscopy. Comparison of the all-12C- and 13C- isotopomer spectra yield excitonic splittings of delta(exp) = 43.5 and 10.5 cm(-1), respectively. The corresponding splittings calculated by high-level ab initio methods (RI-CC2/aug-cc-pVTZ) are 20 to 50 times larger. These purely electronic ab initio exciton splittings need to be reduced ('quenched') by vibronic coupling to the optically active vibrational modes. Only after quenching are the experimentally observed exciton splittings correctly reproduced. PMID- 21678768 TI - Enantioselective Diels-Alder reactions of unsaturated beta-ketoesters catalyzed by chiral ruthenium PNNP complexes. AB - We report here dicationic ruthenium PNNP complexes that promote the enantioselective Diels-Alder reaction of alpha-methylene beta-ketoesters with various dienes. Complex [Ru(OEt2)2(PNNP)](PF6)2, formed in situ from [RuCl2,(PNNP)] and (Et3O)PF6 (2 equiv.), catalyzes the Diels-Alder reaction of such unsaturated beta-ketoesters to give novel alkoxycarbonyltetrahydro-1 indanone derivatives (nine examples) with up to 93% ee. The crystal structure of the substrate-catalyst adduct shows that the lower face of the substrate is shielded by a phenyl ring of the PNNP ligand, which accounts for the high enantioselectivity. The attack of the diene from the open re enantioface of the unsaturated beta-ketoester is consistent with the absolute configuration of the product. A useful application of this method is the reaction with Dane's diene to give estrone derivatives with up to 99% ee and an ester-exo:endo ratio of up to 145:1 (after recrystallization). Besides the enantioselective formation of all carbon quaternary centers, this methodology is notable because unsaturated beta ketoesters have been rarely used in Diels-Alder reactions. Furthermore, enantiomerically pure estrone derivatives are interesting in view of their potential applications, including the treatment of breast cancer. PMID- 21678769 TI - Chemical imaging on the nanoscale-top-illumination tip-enhanced Raman spectroscopy. AB - A top illumination system for tip-enhanced Raman spectroscopy (TERS) in a gap mode configuration is presented here, which allows chemical analysis of sample surfaces with a lateral resolution beyond the optical diffraction limit and optical detection of very small amounts of analyte molecules (down to single molecule sensitivity). The technique combines the high resolution of an STM with label-free, chemical-rich information of Raman spectra at ambient pressure. In this system, using a special geometry with illumination and detection perpendicular to the sample surface, a lateral resolution of <15 nm was achieved using low laser powers and split second acquisition times per spectrum. This was achieved due to a very high enhancement of the Raman signals in the order of 10(7) by etched metal tips, and allowed the acquisition of 64 x 64 to 200 x 200 pixels chemical Raman maps with full spectral information in every pixel within a reasonable time frame (<25 min for 64 x 64 pixels). The Raman maps give simultaneous information about localization and chemical nature of a sample with high sensitivity and high resolution. PMID- 21678770 TI - A density dependent dispersion correction. AB - Density functional approximations fail to provide an accurate treatment of weak interactions. More recent, but not readily available functionals can lead to significant improvements. A simple alternative to correct for the missing weak interactions is to add, a posteriori, an atom pair-wise dispersion correction. We here present a density dependent dispersion correction, dDXDM, which dramatically improves the performance of popular functionals (e.g., PBE-dDXDM or B3LYP-dDXDM) for a set of 145 systems featuring both inter- and intramolecular interactions. Whereas the highly parameterized M06-2X functional, the long-range corrected LC BLYP and the fully non-local van der Waals density functional rPW86-W09 also lead to improved results as compared to standard DFT methods, the enhanced performance of dDXDM remains the most impressive. PMID- 21678771 TI - Self-reporting materials: protein-mediated visual indication of damage in a bulk polymer. AB - Damage self-reporting materials are able to indicate the presence of microscopic damaged regions by easy to detect signals, such as fluorescence. Therefore, these smart materials can reduce the risk of catastrophic failure of load-bearing components, e.g., in aerospace and construction applications. We highlight here our proof-of-concept paper and we present some additional data, which shows that proteins can be used as mechanophores in solid polymeric materials. Macroscopic mechanical forces were transferred from the polymer to the embedded proteins. The biomolecules act as molecular strain sensor, giving the material the desired self reporting property. Poly(ethylene glycol) and poly(acrylamide) (PAAm) networks were doped with small amounts of thermsosome (THS), a protein cage from the family of chaperonins, that encapsulated a pair of fluorescent proteins. THS acts as a scaffold which brings the two fluorescent proteins into distance suitable for fluorescence resonance energy transfer (FRET). Moreover, THS can be distorted by mechanic forces so that the distance between the fluorescent proteins changes, leading to a change in FRET efficiency. Using the brittle PAAm as a model system, we were able to visualize microcracks in the polymers by FRET microscopy and by fluorescence lifetime imaging. THS also stabilizes the encapsulated guest proteins against thermal denaturation, increasing their half-live at 70 degrees C by a factor of 2.3. PMID- 21678772 TI - Functional group distributions on mesoporous silica. AB - Most applications of mesoporous silica require some degree of functionalization. The surface of porous materials can be divided into external and internal (pore) surfaces, and in many cases, a selective functionalization of these surface subsections is desired. This short review outlines our recent work in this field and focuses on the postsynthetic functionalization of mesoporous silica with aminopropylalkoxysilanes and on the analysis of the respective functional group distributions by confocal laser scanning microscopy. Methods to obtain an amino functionalized external surface and functional group gradients on the pore surface are reported. Arrays of silica nanochannels (ASNCs) serve as a model system for mesoporous silica. PMID- 21678773 TI - On-line reaction monitoring of lithiation of halogen substituted acetanilides via in situ calorimetry, ATR spectroscopy, and endoscopy. AB - Lithiation of N-(4-chlorophenyl)-pivalamide (NCP) and two additional substituted acetanilides: 4-fluoroacetanilide (4-F) and 4-chloroacetanilide (4-Cl) has been monitored by means of calorimetry, on-line ATR-IR and UV/vis spectroscopy and endoscopy. The combined on-line monitoring revealed the differences between the reaction paths of the chosen substrates. Thus the product structure and the reaction times for the individual reaction steps can be determined in situ. PMID- 21678774 TI - Investigation of h-BN/Rh(111) nanomesh interacting with water and atomic hydrogen. AB - Recent STM experiments show that by exposing h-BN/Rh(111) nanomesh to water or atomic hydrogen interesting phenomena can be observed. We investigated by Density Functional Theory (DFT) the structure of bare nanomesh as well as in the presence of water clusters and atomic hydrogen. Our simulations allow the correct interpretation of the observed modifications of the STM topography under different tested conditions. For example, we could determine that the frequently observed three protrusions within the pore appearing in STM images obtained after dosing small amounts of water, are most likely determined by water hexamers. We also could confirm that the flattening of the h-BN overlayer after dosing atomic hydrogen is determined by the intercalation of the latter between BN and metal, which prevents the effective binding between N and Rh. PMID- 21678775 TI - NMR of insensitive nuclei enhanced by dynamic nuclear polarization. AB - Despite the powerful spectroscopic information it provides, Nuclear Magnetic Resonance (NMR) spectroscopy suffers from a lack of sensitivity, especially when dealing with nuclei other than protons. Even though NMR can be applied in a straightforward manner when dealing with abundant protons of organic molecules, it is very challenging to address biomolecules in low concentration and/or many other nuclei of the periodic table that do not provide as intense signals as protons. Dynamic Nuclear Polarization (DNP) is an important technique that provides a way to dramatically increase signal intensities in NMR. It consists in transferring the very high electron spin polarization of paramagnetic centers (usually at low temperature) to the surrounding nuclear spins with appropriate microwave irradiation. DNP can lead to an enhancement of the nuclear spin polarization by up to four orders of magnitude. We present in this article some basic concepts of DNP, describe the DNP apparatus at EPFL, and illustrate the interest of the technique for chemical applications by reporting recent measurements of the kinetics of complexation of 89Y by the DOTAM ligand. PMID- 21678776 TI - Functionalizable oligoprolines as molecular scaffolds. AB - Azidoproline (Azp) containing oligoprolines are conformationally well-defined, helical molecular scaffolds that allow for facile functionalization. Within this article we describe the synthesis of Azp-containing oligoprolines and different strategies to introduce functional moieties. In addition, the influence of factors such as substituents at the y-position of proline as well as functional groups at the termini on the conformational stability of the molecular scaffolds are briefly presented. PMID- 21678777 TI - Asymmetric intramolecular Diels-Alder reactions of trienals catalyzed by chiral ruthenium Lewis acids. AB - Chiral single-point binding ruthenium Lewis acid catalysts [Ru(acetone)((S,S) BIPHOP-F)(Cp)][SbF6] ((S,S)-1a) and [Ru(acetone)((S,S)-BIPHOP-F)(indenyl)][SbF6] ((S,S)-1b) efficiently catalyze intramolecular Diels-Alder (IMDA) reactions of trienals under mild conditions to afford the endo cycloaddition products as the major products in good yields with high diastereo- and enantioselectivities. PMID- 21678778 TI - Highly selective rhodium catalyzed domino C-H activation/cyclizations. AB - The direct functionalization of carbon-hydrogen bonds is an emerging tool to establish more sustainable and efficient synthetic methods. We present its implementation in a cascade reaction that provides a rapid assembly of functionalized indanylamines from simple and readily available starting materials. Careful choice of the ancillary ligand---an electron-rich bidentate phosphine ligand--enables highly diastereoselective rhodium(i)-catalyzed intramolecular allylations of unsubstituted ketimines induced by a directed C-H bond activation and allene carbo-metalation sequence. PMID- 21678779 TI - Diagnostic and sensory polymer brushes. PMID- 21678780 TI - Midwifery SOS... PMID- 21678781 TI - Infantile colic. PMID- 21678782 TI - Specialised milks: a guide to the right choices. AB - Specialist milks are prescribed if a baby is preterm, has faltering growth, a suspected food allergy, or other medical condition that precludes them from having one of the usual formula milks. Because there are many different types of specialist milks available--and their suitability for different conditions and age groups varies--it is vital to refer a child for specialist help. PMID- 21678783 TI - A topic in 10 questions: How to support breastfeeding mothers. PMID- 21678784 TI - Rickets: concerns over the worldwide increase. AB - Rickets is a childhood disease that causes a softening of the bones, potentially leading to fractures and deformity. Eighty years ago it was thought to have largely been eradicated from the U.K. However a recent increase in cases of rickets, not just in Britain but around the world, has proven this isn't the case. Today the disease affects children from all types of socio-economic backgrounds, not just the poorer ones, and it is primarily caused by low levels of vitamin D and certain foods. In January 2011 the government's chief medical officer Dame Sally Davies recommended all children aged six months to five should be given vitamin D supplements, particularly during winter months when natural sunshine is limited. The irony is that the advice in recent years for children to wear a high factor sunscreen and remain covered up while playing outdoors are partly felt to be behind the reason for its re-emergence. Parents and health professionals alike were shocked when it was revealed that a school girl living on the Isle of Wight developed rickets precisely because of her mother's vigilance at following sun safety rules. NICE, in their latest report (Jan 2011) stated that: "Exposure to the sun has a number of benefits. For example, it increases people's sense of wellbeing, allows them to synthesise vitamin D and provides opportunities for physical activity". A tendency for children to stay indoors and watch TV or play on computer games, rather than play outside when the sun is shining, is arguably also another contributing factor. PMID- 21678785 TI - Helping parents with sex education. AB - Health visitors, school nurses and other community nurses are sometimes asked for advice by parents and carers on the emerging sexuality of their children. Parents often lack knowledge about sexual development and are confused about whether to talk to their children about sex. They may have been brought up in a family where sex was not mentioned. They are worried that they do not have the skills or the knowledge to help their children. They do not know whether to leave it all to the school or not allow their children to have any information. All the evidence shows that children who have had their questions answered and who know about sex and relationships start sexual activity later, use contraception more reliably and are less likely to cause or have an unwanted pregnancy. Sex education should be part of the ordinary information and moral guidance that parents normally give and should start as early as possible. The type of advice to give to parents and carers is split into age ranges that they might find helpful. Examples of language and the level of information required are given. A list of resources for further guidance is included. PMID- 21678786 TI - Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance. AB - Sitamaquine is a 8-aminoquinoline in development for the treatment of visceral leishmaniasis by oral route, no activity being observed on the experimental cutaneous leishmaniasis experimental models. Recent data explain how sitamaquine accumulate in Leishmania parasites, however its molecular targets remain to be identified. An advantage of sitamaquine is its short elimination half-life, preventing a rapid resistance emergence. The antileishmanial action of its metabolites is not known. The selection of a sitamaquine-resistant clone of L. donovani in laboratory and the phase II clinical trials pointing out some adverse effects such as methemoglobinemia and nephrotoxicity are considered for a further development decision. PMID- 21678788 TI - The Hippoboscidae (Insecta: Diptera) from Madagascar, with new records from the "Parc National de Midongy Befotaka". AB - The Hippoboscidae or "louse-flies" is a family of pupiparous Diptera, which in their adult stage are ectoparasites of mammals and birds. This paper presents a comprehensive review of Malagasy Hippoboscidae. In total, amongst the 213 species of this family known worldwide, 14 have been reported in Madagascar, among which six are considered as endemic to the Malagasy region. In addition, data are presented from a collection of 17 Hippoboscidae obtained from seven species of forest-dwelling birds in the "Parc National de Midongy Befotaka", southeastern Madagascar, in 2003. The flies in this collection belong to three different species: Icosta malagasii (one), Ornithoica podicipis (ten) and Ornithoctona laticomis (six). The two former species were previously only known from single specimens in museum collections; the later species is distributed across much of the Afrotropical region and the records presented herein are the first for Madagascar. All the seven bird species are new hosts for hippoboscids. We present the first description of the male of Icosta malagasii. An illustrated dichotomous determination key of the 14 Malagasy species, based on morphological criteria only, is presented. PMID- 21678787 TI - Pneumocystis jirovecii colonization in chronic pulmonary disease. AB - Pneumocystis jirovecii causes pneumonia in immunosuppressed individuals. However, it has been reported the detection of low levels of Pneumocystis DNA in patients without signs and symptoms of pneumonia, which likely represents colonization. Several studies performed in animals models and in humans have demonstrated that Pneumocystis induces a local and a systemic response in the host. Since P jirovecii colonization has been found in patients with chronic pulmonary diseases it has been suggested that P jirovecii may play a role in the physiopathology and progression of those diseases. In this report we revise P. jirovecii colonization in different chronic pulmonary diseases such us, chronic obstructive pulmonary disease, interstitial lung diseases, cystic fibrosis and lung cancer. PMID- 21678789 TI - Trapping tsetse flies on water. AB - Riverine tsetse flies such as Glossina palpalis gambiensis and G. tachinoides are the vectors of human and animal trypanosomoses in West Africa. Despite intimate links between tsetse and water, to our knowledge there has never been any attempt to design trapping devices that would catch tsetse on water. In mangrove (Guinea) one challenging issue is the tide, because height above the ground for a trap is a key factor affecting tsetse catches. The trap was mounted on the remains of an old wooden dugout, and attached with rope to nearby branches, thereby allowing it to rise and fall with the tide. Catches showed a very high density of 93.9 flies/"water-trap"/day, which was significantly higher (p < 0.05) than all the catches from other habitats where the classical trap had been used. In savannah, on the Comoe river of South Burkina Faso, the biconical trap was mounted on a small wooden raft anchored to a stone, and catches were compared with the classical biconical trap put on the shores. G. p. gambiensis and G. tachinoides densities were not significantly different from those from the classical biconical one. The adaptations described here have allowed to efficiently catch tsetse on the water, which to our knowledge is reported here for the first time. This represents a great progress and opens new opportunities to undertake studies on the vectors of trypanosomoses in mangrove areas of Guinea, which are currently the areas showing the highest prevalences of sleeping sickness in West Africa. It also has huge potential for tsetse control using insecticide impregnated traps in savannah areas where traps become less efficient in rainy season. The Guinean National control programme has already expressed its willingness to use such modified traps in its control campaigns in Guinea, as has the national PATTEC programme in Burkina Faso during rainy season. PMID- 21678790 TI - Lamellodiscus euzeti n. sp. (Monogenea:Diplectanidae), a parasite from Dentex canariensis and D. gibbosus (Teleostei:Sparidae) in the Atlantic Ocean and Mediterranean Sea. AB - Lamellodiscus euzeti n. sp. (Monogenea:Diplectanidae) is described from the gills of two sparid fishes, Dentex canariensis (Steindachner) off Senegal and Ivory Coast and D. gibbosus (Rafinesque) off Senegal and Tunisia. The new species belongs to the "ignoratus" group, characterized by a lamellodisc with complete lamellae, a "lyre" shaped male copulatory organ type, and the "ignoratus" sensu stricto subgroup, characterized by a haptor with simple lateral dorsal bars. Lamellodiscus euzeti n. sp can be distinguished from all the congeneric species of the "ignoratus" subgroup by the presence of a prominent protuberance at the base of the curved part of the simple piece of the male copulatory organ (MCO), a large bulb at the base of the bifurcated piece of the MCO and the presence of 5-6 spines in the distal portion of the axial branch of the bifurcated piece of the MCO. Specificity and biogeography of Lamellodiscus species from sparid fishes are discussed. PMID- 21678791 TI - Study of types of some species of "Filaria" (Nematoda) parasites of small mammals described by Von Linstow and Molin. AB - Parasitic nematodes from the Berlin (ZMB) and Vienna (NMW) Museum collections referred to the genus Filaria Mueller, 1787 by von Linstow or Molin were studied. Three samples were in good condition and the specimens redescribed. Litomosa hepatica (von Linstow, 1897) n. comb., sample ZMB Vermes Entozoa 3368, from the megachiropteran Pteropus neohibernicus, Bismarck Archipelago, resembles L. maki Tibayrenc, Bain & Ramanchandran, 1979, from Pteropus vampyrus, in Malaysia, but the buccal capsule differs. Both species display particular morphological characters which differ from species of Litomosa parasitic in microchiropterans. The remaining material originates from Brazil. The spicule morphology of Litomosoides circularis (von Linstow, 1899) Chandler, 1931, sample ZMB Vermes Entozoa 1059 from Hesperomys spec. (= Holochilus brasiliensis), Porto Alegre, confirms that it belongs to the sigmodontis group; the microfilaria presents characters of the genus Litomosoides, e.g. body attenuated at both extremities and salient cephalic hook. Taxonomic discussions by others confirm that species of Litomosoides belonging to the sigmodontis group and described subsequently are distinct from L. circularis. Litomosoides serpicula (Molin, 1858) Guerrero, Martin, Gardner & Bain, 2002, is redescribed, sample NMW 6323 from the bat Phyllostoma spiculatum (= Sturnira lilium), Ypanema. It is very close to L. brasiliensis Almeida, 1936, type host Moytis sp., but distinguished by a single ring in the buccal capsule, rather than two, supporting previous conclusions that the taxon L. brasiliensis, as generally regarded, may represent a complex of species. Samples NMW 6322 and NMW 6324, from other bats and also identified by Molin (1858) as Filaria serpicula, contain unidentifiable fragments of Litomosoides incertae sedis. Filaria hyalina von Linstow, 1890, sample ZMB Vermes Entozoa Q 3905 from Sorer vulgaris (= Sorex araneus), is incertae sedis because it contains two unidentifiable posterior parts of male, which might be an acuarid, Stammerinema sp. Filaria vesperuginis von Linstow, 1885, sample ZMB Vermes Entozoa Q 3929, from the bat Vesperugo serotinus (= Eptesicus serotinus), contains encysted nematode larvae and is a nomen dubium. PMID- 21678792 TI - The relationship between MHC-DRB1 gene second exon polymorphism and hydatidosis resistance of Chinese Merino (Sinkiang Junken type), Kazakh and Duolang sheep. AB - The present study aimed at detecting the association of ovine major histocompatibility complex class II (Ovar II) DRB1 gene second exon and susceptibility or resistance to hydatidosis in three sheep breeds of Sinkiang. The MHC-DRB1 second exon was amplified by polymerase chain reaction (PCR) from DNA samples of healthy sheep and sheep with hydatidosis. PCR products were characterized by the restriction fragment length polymorphism (RFLP) technique. Five restriction enzymes, Mval, Haelll, Sacl, Sacll, Hin1l, were used, yielding 14 alleles and 31 restriction patterns. Frequencies of patterns Mvalbc, Hin1lab, Sacllab, Haelllde, Haellldf, Haellldd (P < 0.01) in Kazakh sheep, Saclab (P < 0.05) in Duolang sheep, and Haelllab, Haelllce, Haelllde, Haelllee (P < 0.01) in Chinese Merino (Sinkiang Junken type) sheep, were significantly higher in healthy sheep compared with infected sheep. These results indicated a strong association between these patterns and hydatidosis resistance. In contrast, the frequencies of Mvalbb, Saclaa, Hinl lbb, Haelllef (P < 0.01) and Haelllab (P < 0.05) in Kazakh sheep, Saclbb, Haelllae, Hin1lab (P < 0.05), Haelllaa, Haelllbe, Haelllef (P < 0.01) in Duolang sheep, Sacllaa (P < 0.05) and Haelllbd, Hin1lbb, Haelllcf, Haelllef (P < 0.01) in Chinese Merino sheep (Sinkiang Junken type) were significantly lower in healthy sheep compared with infected sheep. This indicated a strong association between these patterns and hydatidosis susceptibility. In addition, sheep with the pattern of Haelllef demonstrated a high hydatidosis susceptibility (P < 0.01) in all three breeds, while sheep with the pattern Haelllde demonstrated significant hydatidosis resistance (P < 0.01) in Kazakh and Chinese Merino sheep (Sinkiang Junken type). These results suggest that the Ovar DRB1 gene plays a role in resistance to hydatidosis infection in the three sheep breeds. PMID- 21678794 TI - Haplometra cylindracea (Zeder, 1800) (Trematoda:Plagiorchiidae): variation in the dates of cercarial shedding for overwintering Galba truncatula. AB - Natural infections of Galba truncatula with Haplometra cylindracea were followed from 2001 to 2009 to determine if their characteristics were similar when snails came from water collections frequented by Bufo bufo or by frogs and newts for their egg-laying. Snail samples were collected from both types of sites to count shed cercariae for three days and also free cercariae when snails were dissected. In sites only frequented by B. bufo, cercarial shedding occurred earlier than in those colonized by frogs and newts (March instead of April-May). In contrast, the number of cercariae shed during three successive days was significantly higher in May. This variation in the dates of cercarial shedding might be due, either to a synchronism between cercaria-releasing snails and the presence of the definitive host (tadpoles) in water collections, or to an earlier infection of overwintering snails in autumn by H. cylindracea miracidia in the case of toad-frequented sites. PMID- 21678793 TI - Trypanosoma vivax, T. congolense "forest type" and T. simiae: prevalence in domestic animals of sleeping sickness foci of Cameroon. AB - In order to better understand the epidemiology of Human and Animal trypanosomiasis that occur together in sleeping sickness foci, a study of prevalences of animal parasites (Trypanosoma vivax, T. congolense "forest type", and T. simiae) infections was conducted on domestic animals to complete the previous work carried on T. brucei gambiense prevalence using the same animal sample. 875 domestic animals, including 307 pigs, 264 goats, 267 sheep and 37 dogs were sampled in the sleeping sickness foci of Bipindi, Campo, Doume and Fontem in Cameroon. The polymerase chain reaction (PCR) based method was used to identify these trypanosome species. A total of 237 (27.08%) domestic animals were infected by at least one trypanosome species. The prevalence of T. vivax, T. congolense "forest type" and T. simiae were 20.91%, 11.42% and 0.34% respectively. The prevalences of 7 vivax and T. congolense "forest type" differed significantly between the animal species and between the foci (p < 0.0001); however, these two trypanosomes were found in all animal species as well as in all the foci subjected to the study. The high prevalences of 7 vivax and T congolense "forest type" in Bipindi and Fontem-Center indicate their intense transmission in these foci. PMID- 21678795 TI - Zoonotic onchocerciasis in Hiroshima, Japan, and molecular analysis of a paraffin section of the agent for a reliable identification. AB - Japan is a country of high specific diversity of Onchocerca with eight species, the adults of two not yet known. Onchocerca dewittei japonica, a common filarial parasite of wild boar, had been proved to be the agent of five zoonotic onchocerciasis in Kyushu island with morphological and molecular studies. The sixth case, at Hiroshima in the main island, was identified to the same Onchocerca species, based on adult characters observed on histological sections. To consolidate the identification, mitochondrial cytochrome c oxidase subunit 1 (CO1) gene analysis was attempted with the formalin-fixed, paraffin-embedded parasite specimen. The sequence (196 bp) of a CO1 gene fragment of the parasite successfully PCR-amplified agreed well with those of O. dewittei japonica registered in GenBank, confirming the morphological identification. Moreover a comparison with the CO1 gene sequences of six other Onchocerca species in GenBank excluded the possibility that Onchocerca sp. from wild boar and Onchocerca sp. type A from cattle in Japan, were the causative agents in this case. Mitochondrial DNA analysis proved to be a valuable tool to support the morphological method for the discrimination of zoonotic Onchocerca species in a histological specimen. PMID- 21678796 TI - Intestinal helminths infection of rats (Ratus norvegicus) in the Belgrade area (Serbia): the effect of sex, age and habitat. AB - SUMMARY: Gastrointestinal helminths of Norway rat (Rattus norvegicus) from the Belgrade area were studied as a part of a wider ecological research of rats in Serbia (data on the distribution, population ecology, economic and epizoothiological-epidemiological importance, and density control). Rats were captured from May 2005 to July 2009 at both urban and suburban-rural sites. Of a total of 302 trapped rats 48% were males and 52% females, with 36.5% and 38.8% of juvenile-subadult individuals, per sex respectively. Intestinal helminth infection was noted in 68.5% of rats, with a higher prevalence in male hosts and in adult individuals. Higher numbers of infected juveniles-subadults were noted in suburban-rural habitats, while an opposite tendency was noted in adult rats. Seven helminth species were recovered, of which five were nematode (Heterakis spumosa, Nippostrongylus brasiliensis, Capillaria sp., Trichuris muns and Syphacia muris) and two cestode species (Hymenolepis diminuta and Rodentolepis fraterna). The most prevalent parasites were Heterakis spumosa (36.7%) and Hymenolepis diminuta (30.5 %). Sex and habitat-related differences were noted in the prevalence of infection with Capillaria sp. and Trichuris muris, while there were no age-related differences in the prevalence of infection with any individual helminth species. Significantly higher prevalence of infection was noted in summer as compared to spring or winter, with a tendency to be higher in autumn as compared to spring. The only significant difference in the prevalence of infection between habitat-related was noted during spring. H. spumosa was most prevalent in summer, while H. diminuta and N. brasiliensis in autumn. The mean intensity of infection with H. spumosa, R. fraterna, S. muris and T muris was higher in autumn than in the other seasons, while N. brasiliensis and Capillaria sp. occured in winter. No more than four helminth species were found in one host. PMID- 21678798 TI - Are there some positions editors just shouldn't publish? PMID- 21678797 TI - Human giardiasis in Serbia: asymptomatic vs symptomatic infection. AB - Despite the public health importance of giardiasis in all of Europe, reliable data on the incidence and prevalence in Western Balkan Countries (Serbia, Bosnia and Herzegovina, Croatia, Montenegro and FYR Macedonia) are scarce, and the relative contribution of waterborne and food-borne, or person-to-person and/or animal-to-person, transmission of human giardiasis is not yet clear. To provide baseline data for the estimation of the public health risk caused by Giardia, we here review the information available on the epidemiological characteristics of asymptomatic and symptomatic human infection in Serbia. Although asymptomatic cases of Giardia represent a major proportion of the total cases of infection, high rates of Giardia infection were found in both asymptomatic and symptomatic populations. No waterborne outbreaks of giardiasis have been reported, and it thus seems that giardiasis mostly occurs sporadically in our milieu. Under such circumstances, control measures to reduce the high prevalence of giardiasis in Serbia have focused on person-to-person transmission, encouraging proper hygiene, but for more targeted intervention measures, studies to identify other risk factors for asymptomatic and symptomatic infections are needed. PMID- 21678799 TI - Are there some things doctors just shouldn't do? PMID- 21678800 TI - That personal touch. PMID- 21678801 TI - That personal touch. PMID- 21678802 TI - That personal touch. PMID- 21678803 TI - That personal touch. PMID- 21678804 TI - Learning from lingering angst. PMID- 21678805 TI - Families and forensic DNA profiles. PMID- 21678806 TI - The dread disease: cancer in the developing world. PMID- 21678807 TI - To tell or not to tell. PMID- 21678808 TI - Case study. To tell or not to tell. Commentary. PMID- 21678809 TI - Growing respect for opposition. PMID- 21678810 TI - In search of a wide-angle lens. PMID- 21678811 TI - Two chicks in a lab with eggs. PMID- 21678812 TI - Surrogate health care decisions and same-sex relationships. PMID- 21678813 TI - Rethinking the ethics of physician participation in lethal injection execution. PMID- 21678814 TI - The tortured patient: A medical dilemma. PMID- 21678815 TI - Conscience rules: implications for care. PMID- 21678816 TI - Human stampedes: a neglected disaster in the developing world. PMID- 21678817 TI - Impact of organizational structure on vaccination of first responders: a case study. AB - The experience of H1N1 vaccine delivery to public safety personnel in a suburban county in Florida suggests a relationship between the degree of hierarchy of an agency and successful implementation of a vaccination program for novel 2009 H1N1 influenza virus. This case study describes the structural organization of the Sheriff's Office and Fire Rescue in County X, provides timelines for vaccine program implementation and numbers of personnel vaccinated, and illustrates the impact of autonomy on the timeliness of vaccine implementation. An "emergency approval pathway" is recommended for organizations or departments that are likely to encounter delays in disaster or pandemic response due to organizational structure. PMID- 21678818 TI - Strengthening hospital preparedness for chemical, biological, radiological, nuclear, and explosive events: clinicians' opinions regarding physician/physician assistant response and training. AB - OBJECTIVES: This research explores the attitudes of physicians and physician assistants (PA) regarding response roles and responsibilities as well as training opinions to understand how best to partner with emergency department physicians and to effectively apply scarce healthcare dollars to ensure successful emergency preparedness. DESIGN: Physicians and PAs representing 21 specialties in two level I trauma public hospitals were surveyed. Participants scored statements within four categories regarding roles and responsibilities of clinicians in a disaster; barriers to participation; implementation of chemical, biological, radiological, nuclear, and explosive training; and training preferences on a Likert scale of 1 (strongly agree) to 5 (strongly disagree). Additional open-ended questions were asked. RESULTS: Respondents strongly feel that they have an ethical responsibility to respond in a disaster situation and that other clinicians would be receptive to their assistance. They feel that they have clinical skills that could be useful in a catastrophic response effort. They are very receptive to additional training to enable them to respond. Respondents are neutral to slightly positive about whether this training should be mandated, yet requiring training as a condition for licensure, board certification, or credentialing was slightly negative. Therefore, it is unclear how the mandate would be encouraged or enforced. Barriers to training include mild concerns about risk and malpractice, the cost of training, the time involved in training, and the cost for the time in training (eg, lost revenue and continuing medical education time). Respondents are not concerned about whether they can learn and retain these skills. Across all questions, there was no statistically significant difference in responses between the medical and surgical subspecialties. CONCLUSIONS: Improving healthcare preparedness to respond to a terrorist or natural disaster requires increased efforts at organization, education and training. Physicians are willing to increase their knowledge base if it is possible to create a mutually positive win-win environment to minimize cost and disruption while maximizing preparedness. There is no clear consensus on the implementation of this training, but to most efficiently and effectively use scare homeland security dollars, a dialogue must begin between the medical profession, medical societies, and US Department of Health and Human Services to determine the best training strategies. PMID- 21678820 TI - Regional public health preparedness teams in North Carolina: an analysis of their structural capacity and impact on services provided. AB - In December 2001, the North Carolina Division of Public Health established Public Health Regional Surveillance Teams (PHRSTs) to build local public health capacity to prevent, prepare for, respond to, and recover from public health incidents and events. Seven PHRSTs are colocated at local health departments (LHDs) around the state. The authors assessed structural capacity of the PHRSTs and analyzed the relationship between structural capacity and the frequency of support and services provided to LHDs by PHRSTs. Five categories of structural capacity were measured: human, fiscal, informational, physical, and organizational resources. In addition, variation in structural capacity among teams was also examined. The most variation was seen in human resources. Although each team was originally designed to include a physician/epidemiologist, industrial hygienist, nurse/epidemiologist, and administrative support technician, team composition varied such that only the administrative support technician is common to all teams. Variation in team composition was associated with differences in the support and services that PHRSTs provide to LHDs. Teams that reported having a medical doctor or a doctor of osteopathic medicine (chi2 = 9.95; p < 0.01) or an epidemiologist (chi2 = 5.35; p < 0.02) had larger budgets and provided more support and services, and teams that housed a pharmacist reported more partners (chi2 = 52.34; p < 0.01). Teams that received directives from more groups (such as LHDs) also provided more support and services in planning (Z = 21.71; p < 0.01), communication and liaison (Z = 12.11; p < 0.01), epidemiology and surveillance (Z = 5.09; p < 0.01), consultation and technical support (Z = 2.25; p = 0.02), H1N1 outbreak assistance (Z = 10.25; p < 0.01), and public health event response (Z = 2.19; p = 0.03). In the last 10 years, significant variation in structural capacity, particularly in human resources, has been introduced among PHRSTs. These differences explain much of the variation in support and services provided to LHDs by PHRSTs. PMID- 21678819 TI - Understanding estimated worker absenteeism rates during an influenza pandemic. AB - OBJECTIVES: Published employee absenteeism estimates during an influenza pandemic range from 10 to 40 percent. The purpose of this study was to estimate daily employee absenteeism through the duration of an influenza pandemic and to determine the relative impact of key variables used to derive the estimates. DESIGN: Using the Centers for Disease Control and Prevention's FluWorkLoss program, the authors estimated the number of absent employees on any given day over the course of a simulated 8-week pandemic wave by using varying attack rates. Employee data from a university with a large academic health system were used. Sensitivity of the program outputs to variation in predictor (inputs) values was assessed. Finally, the authors examined and documented the algorithmic sequence of the program. RESULTS: Using a 35 percent attack rate, a total of 47,270 workdays (or 3.4 percent of all available workdays) would be lost over the course of an 8-week pandemic among a population of 35,026 employees. The highest (peak) daily absenteeism estimate was 5.8 percent (minimum 4.8 percent; maximum 7.4 percent). Sensitivity analysis revealed that varying days missed for nonhospitalized illness had the greatest potential effect on peak absence rate (3.1 to 17.2 percent). Peak absence with 15 and 25 percent attack rates were 2.5 percent and 4.2 percent, respectively. CONCLUSIONS: The impact of an influenza pandemic on employee availability may be less than originally thought, even with a high attack rate. These data are generalizable and are not specific to institutions of higher education or medical centers. Thus, these findings provide realistic and useful estimates for influenza pandemic planning for most organizations. PMID- 21678821 TI - Risk perceptions and preparedness of typhoon disaster on coastal inhabitants in China. AB - China is highly vulnerable to natural disasters. Southeastern China situated on the Pacific Ocean experiences severe and devastating typhoons and hydrogeological disasters every year. Although respondents are highly aware of the typhoon outbreaks, they do not have necessary precautionary actions. This retrospective study evaluates the inhabitants' sociodemographic characteristics with risk perceptions and preparedness. Subjects (434 adults) were recruited from two rural areas in coastal south-eastern China, both with high typhoon exposure. One area (landfall area [LA]) was more severely affected than the other (surrounding area [SA) by the 2006 typhoon "Saomai." Subjects were interviewed using a structured questionnaire with items addressing sociodemographic characteristics and exposure to public education related to emergency preparedness, risk perception, and coping strategies. Overall, most residents (92 percent) were aware that they lived in a high-risk area. About 54.6 percent respondents chose media as the first approach to obtain preparedness education, and 32.4 percent of respondents thought that personal experience is an important tool to defend themselves from typhoon. In LA, residents perceived themselves to be at higher risk than those who lived in the SA. More than 66.5 percent of respondents were terrified by typhoon, and 62.2 percent of respondents were afraid of its recurrence. Respondents emphasized that their life style (61.4 percent), property losses (54.5 percent), and threat to life (52.4 percent) were influenced by typhoon attack. Coping behavior most likely to be adopted was "anticipatory food, water storage and residents in LA is significantly higher than SA (p < 0.01). Risk perception with Spider Map analysis depicted that the item of disaster information is similar in both familiarity or dread associated with the risk axes (p > 0.05). However, in rescue and recovery of typhoon items, the score of familiarity with risk and dread with the risk axes is below 2.5. Regression analyses indicated that poor coping behavior was positively associated with age, risk perception, residential location, and knowledge of preparedness. The results indicated that risk perceptions and precaution activity were strongly related with inhabitants' sociodemographic characteristics and vulnerability of disaster affected zone. PMID- 21678823 TI - Looking to front-line clinicians, staff for lasting improvements. PMID- 21678822 TI - Fatalities of the 2008 Los Angeles train crash: autopsy findings. AB - INTRODUCTION: Train crashes represent a devastating multicasualty event. The purpose of this study was to analyze the injury severity, specific organ injuries, and cause of death in the fatalities of the 2008 Chatsworth, Los Angeles train crash. METHODS: This is a review of the medical examiner records of the 25 fatalities in the train crash. The Injury Severity (ISS) Score, body area with severe injuries (Abbreviated Injury Scale [AIS] > or = 4), specific organ injuries, and causes of death were recorded. The immediate cause of death was determined to be the most severe or most rapidly fatal injury in the opinion of the reviewers. RESULTS: A total of 25 fatalities occurred, including 24 victims who were pronounced dead at the accident scene and one who died 4 days later in the hospital. One victim did not undergo full autopsy. All of the decedents were located in the locomotive or in the passenger car immediately behind the locomotive. Overall, 15/24 decedents (63 percent) sustained unsurvivable injuries to at least one body region rendering an ISS of 75. The chest was the most severely injured body area (AIS > or = 4; 18/24, 75 percent), followed by the head (13/24, 54 percent), the extremities (11/24, 46 percent), and the abdomen (7/24, 29 percent). Spinal fractures were recorded in 17/24 (71 percent), and the cervical spine was the most commonly injured site. Thoracic aortic rupture was found in eight cases (33 percent) and cardiac ruptures in five cases (21 percent). CONCLUSIONS: The Metrolink train crash in 2008 in Chatsworth, Los Angeles, was the worst train crash in the history of California with 25 fatalities. The most common cause of death was due to chest injury (cardiac and aortic laceration) followed by head injury. This review could aid in improving passenger protection from head-on collision and in further development of head protection in train seats, as well as be useful in disaster planning and a benchmark for future rescue and triage operations. PMID- 21678824 TI - Does Medtronic action signal a shift? PMID- 21678825 TI - Hybrid ORs: what's behind the increasing demand? PMID- 21678826 TI - Planning and staffing a hybrid OR. PMID- 21678827 TI - Nurses speak up on new ORs design. PMID- 21678828 TI - Laparoscopic sleeve gastrectomy for obesity. PMID- 21678829 TI - Answering your questions on charging. PMID- 21678830 TI - Coping with state infection reporting. PMID- 21678832 TI - Surviving and thriving: no longer a student: NCSBN's transition to practice initiative. PMID- 21678831 TI - Change! change! change! PMID- 21678833 TI - The nursing list: top 10 weight management tips for nurses. PMID- 21678834 TI - Healthy work environments = healthy nurses. PMID- 21678835 TI - Healthy people 2020: thirty years of moving towards health. PMID- 21678836 TI - Safe staffing summit: the opening of a dialogue. PMID- 21678837 TI - Helmet use in Connecticut motorcycle crashes: a state without a universal helmet law. AB - OBJECTIVES: Assess the association of helmet use with motorcycle crash mortality and identify characteristics of riders who do not wear helmets in Connecticut crashes. METHODS: Police crash data for Connecticut motorcycle crashes 2001-2007 were analyzed. Bivariate analysis and multivariable logistic regressions were performed including age, gender, seating position, road type, season, time of day, and recklessness. RESULTS: Of the 9,214 crashes with helmet use data available, helmets were worn in 4072 (44.2%). Non-helmeted riders, age > or =18, riding interstate or state roads, in the evening or at night, and who were riding recklessly were associated with higher odds of fatality. Predictors of nonhelmet use included males, passengers, age <18 or 30 to 59, and riding in the summer, eveningor at night, and on U.S., state, and localroads. CONCLUSION: Current crash data affirm that helmets reduce fatal crashes in Connecticut. A set of factors help predict nonhelmeted riders to whom safety training could be targeted. PMID- 21678838 TI - Infective endocarditis in two young men with previously undiagnosed bicuspid aortic valves. AB - Infective endocarditis (IE) is an uncommon, potentially life-threatening microbial infection of the endocardial surface of the heart. An increased risk for IE is associated with a variety of pre-existing structural intracardiac conditions, including a bicuspid aortic valve, which provide a nidus for infection. A bicuspid aortic valve affects 0.5 to 2% of the population, the majority of patients are male, and patients usuallyremain unaware of their condition until infection or calcific valvular dysfunction occurs. We report two cases of native valve IE in otherwise healthy young men seen within a recent two month period; both cases involved a previously undiagnosed bicuspid aortic valve and required a combination of aggressive antimicrobial therapy and early surgery as definitive treatment. Any patient, especially a young male, presentingwith a febrile illness and a previously or newly diagnosed heart murmur should raise the index of clinical suspicion for this disease. PMID- 21678839 TI - Cerebral mucormycosis in a diabetic man. AB - Cerebral mucormycosis without systemic foci of involvement is a rare life threatening fungal infection that is reported to be more common in intravenous drug abusers. We present a case of isolated cerebral mucormycosis in a diabetic patient diagnosed through excision and biopsy and treated with combination of surgery and amphotericin with posaconazole. PMID- 21678840 TI - Isolated thrombocytopenia: should we routinely screen for antiphospholipid antibodies? AB - BACKGROUND: Antiphospholipid (aPL) antibodies are thought to be present in at least 25% of immune thrombocytopenia patients. Conversely, more than 25% of patients with aPL antibody syndrome (APLAS) present with thrombocytopenia. AIMS: To identify the rate of a PL antibody positivity in patients with isolated thrombocytopenia and correlate this finding with the occurrence ofthromboembolic (TE) events or equivalents. MATERIALS AND METHODS: By performing prospective andretrospective analysis of a series of 64 consecutive patients with moderate persistent thrombocytopenia, we established the serologic evidence of APLAS and performed the existing clinico-laboratory correlations. The presence of aPL antibodies in patients with thromocytopenia was tested for statistical significance using chi2 test of independence for categorical variables (one degree of freedom, 95% confidence) as well as Fisher's exact test for small numbers of observations. RESULTS: We detected the presence of aPL antibodies in nine of 64 (14%) of patients with isolated thrombocytopenia and four of nine APLAS patients (approximately 44%) also tested positive for antiplatelet antibodies. Five of nine APLAS patients (approximately 56%) had a consistently increased mean platelet volume (MPV). Although the numbers are small, the values proved statistically significant. Two of nine APLAS patients (approximately 22%) developed TE events or equivalents, and two patients were subsequently diagnosed with systemic lupus erythematosus. CONCLUSIONS: We believe that patients with isolated thrombocytopenia should be tested for the presence of aPL antibodies, as our findings have shown a correlation between the presence of aPL antibodies and occurrence of TE events. Identification of an APLAS subset in this context appears justified in terms of early institution of antiplatelet therapy, especially in patients with additional cardiovascular risk factors. PMID- 21678841 TI - Stress-ulcer prophylaxis: an overused therapeutic modality. PMID- 21678842 TI - "Change is coming, and we cannot avoid it". PMID- 21678843 TI - "Vroom--vroom". PMID- 21678844 TI - Connecticut's medical profession plays its part in promoting the health of the school-age child. May 1961. PMID- 21678845 TI - Professional ethics--business ethics. PMID- 21678846 TI - How'm I doing? PMID- 21678847 TI - The cookie monster. PMID- 21678848 TI - Comparative effectiveness research. PMID- 21678849 TI - Making your practice "value" able. PMID- 21678850 TI - The doctor as patient. PMID- 21678851 TI - A comparative study of American football helmet removal techniques using a cadaveric model of cervical spine injury. AB - BACKGROUND: American football is the source of a significant number of cervical spine injuries. Removal of the helmets from these individuals is often problematic and presents a potential for exacerbation of the injury. There are two widely recognized helmet removal techniques that are currently in practice. In this study, the two methods are compared for cervical movement and potential for cord injury to determine their relative efficiency and clinical utility. METHODS: A single cadaver with a simulated cervical injury was used to compare the National Athletic Trainers' Association (NATA) and cast saw techniques of helmet removal. Directed lateral fluoroscopy was used to measure the relative changes in angulation, translation, distraction, and space available to the spinal cord during helmet removal using the two techniques as performed by medical personnel with limited training in the methods. RESULTS: By radiologists' reports, there were no detectable changes in disc height, translation or space available for the spinal cord during helmet removal with either of the studied techniques. Operators noted that the noise of the cast saw would probably be significantly uncomfortable for any live subject inside of a helmet. CONCLUSION: Both the NATA and cast saw methods appear effective for the safe removal of a football helmet and with little risk of further injury to the cervical spine. Considering the simplicity and efficiency of the NATA helmet removal technique, the authors conclude that the NATA technique should be the preferred helmet removal method. PMID- 21678852 TI - Sports-related concussion. PMID- 21678854 TI - Children cannot vote, shouldn't we advocate for them? PMID- 21678853 TI - "Stick out your tongue and say 'ahhhh'!". PMID- 21678856 TI - Appropriate prophylactic aspirin use for Mississippi physicians. PMID- 21678855 TI - After all is said and done... PMID- 21678857 TI - Mississippi's complex obesity epidemic. PMID- 21678858 TI - McEachin's poem pops. PMID- 21678859 TI - MSMA leads physician participation in Delta Health Alliance grant program. PMID- 21678860 TI - Do not spill up nose!!! PMID- 21678861 TI - Be an agent for the future. PMID- 21678862 TI - Here today. Gone tomorrow. Disappearing dental practices leave patients in the lurch and legal obligations in their wake. PMID- 21678863 TI - Sharing responsibility. PMID- 21678864 TI - Hard to say good-bye. Bernard P. Tillis Award-winning essay. PMID- 21678865 TI - CAD/CAM lingual bracket systems. The new superior invisible braces? PMID- 21678866 TI - Evaluation of radiation exposure with Tru-Align intraoral rectangular collimation system using OSL dosimeters. AB - A pilot study to compare radiation exposure with the Tru-Align rectangular collimation system to round collimation exposures was undertaken. Radiation exposure at various points within the cross sections of the collimators and entrance, intraoral and exit dose measurements were measured using InLight OSL dosimeters. Overall dose reduction with the use of the rectangular collimation system was estimated by taking into account the ratios of collimator openings and the average radiation exposure at the measurement points. Use of the Tru-Align system resulted in an average radiation exposure within the perimeter of the projected outline of the rectangular collimator of 36.1 mR, compared to 148.5 mR with the round collimator. Our calculations indicate a dose reduction by a factor of approximately 3.2 in the case of the Tru-Align system compared to round collimation. The Tru-Align system was easy to use, but in some situations failed to allow Xray coverage of the entire surface of the image receptor, leading to cone cuts. PMID- 21678867 TI - Numb chin syndrome: dental treatment implications. AB - Numb chin syndrome (NCS) is characterized by facial numbness and lip paresthesia along the distribution of the mental branch of the trigeminal nerve. Most cases of this syndrome that are not dental in origin are usually associated with malignant tumors or diffuse metastatic disease. This case report emphasizes the necessity for the dentist, when confronted with such a case, to gather all diagnostic information before providing dental treatment. PMID- 21678868 TI - Introduction and overview of bone grafting. AB - Implants are becoming the standard of care for the replacement of missing teeth; therefore, an in-depth understanding of bone grafting and bone healing is essential for the modern practitioner. We provide an overview of basic bone biology and graft classifications that are frequently used in these procedures. In it, we present the three different properties of bone grafting materials, including osteoinduction, osteogenesis and osteoconduction. And we describe different types of bone grafting materials, including natural and artificial bone sources. PMID- 21678869 TI - A wake-up call: people with HIV and AIDS live longer. AB - A national survey found that Americans' sense of urgency about HIV/AIDS as a national health problem has fallen dramatically. A review of government and foundation reports is used to emphasize the continuing extent of the epidemic in New York State and the United States. The emphasis is on the need for dentists to consider modifications for dental services, given the reality that many individuals with HIV/AIDS are living longer. PMID- 21678870 TI - Validity of conventional surgical treatment methods for mandibular dentigerous cysts. Two case reports. AB - Dentigerous cysts, which are the most commonly seen odontogenic cysts in the jaws, usually expand asymptomatically and extensively. They are surgically eliminated along with the accompanying impacted tooth, because of their destructive nature to the surrounding vital structures, tissues, bone and teeth. The surgical treatment for removing dentigerous cysts includes decompression, marsupialization, enucleation or curettage of the cyst through an extraoral or intraoral approach. Cysts causing tooth displacement and involving loss of bone are treated by marsupialization or decompression, followed by enucleation. In the cases presented here, both patients had enlarged dentigerous cysts in the left mandibular molar region, with an accompanying impacted tooth. Both cases were treated surgically by the enucleation technique alone, without any need for additional autogenous grafts or alloplastic materials to regain integrity of bone structure. They were rehabilitated with dental implants. The implant-retained fixed prostheses functioned well throughout the 24-month evaluation time; and the functional and psychological needs of the patients were provided successfully. PMID- 21678871 TI - Rehabilitation of geriatric hemiglossectomy patient with implant-supported overdentures. Clinical report. AB - Carcinomas of the tongue constitute approximately 5% to 10% of oral carcinomas. Rehabilitation of these patients postsurgery is challenging because the motor control of the tongue is lost and postsurgical scarring reduces the vestibular depth needed to support and retain a denture. Implant-supported overdentures are a viable option to rehabilitate such patients. The restoration provides enhanced function and wearer comfort. PMID- 21678872 TI - CMS draws mixed reviews with the release of proposed ACO rules. AB - Patient-centered approach should lead to more consistent, efficient care. Timely sharing of data, multiple payment models seen as benefits to hospitals. Greatest concerns center around implementation difficulties. PMID- 21678873 TI - System achieves dramatic improvements. AB - Physicians involved in designing specific solutions. CEO "immerses" himself in system to obtain feedback from physicians. Significant improvements achieved in infections, mortality rates. PMID- 21678875 TI - Why aren't patients in compliance? PMID- 21678874 TI - Protecting workers said integral' to quality care. PMID- 21678876 TI - Home monitoring cuts cardiac readmissions. PMID- 21678877 TI - TJC proposes 90% flu shot goal. PMID- 21678878 TI - Report to Congress gives structure to healthcare reform requirements. PMID- 21678879 TI - MRSA program reaps rewards at VA. PMID- 21678880 TI - Who's at the table for your root-cause analysis? PMID- 21678881 TI - Choosing the right measurements is key. PMID- 21678882 TI - Memorial Hermann takes home Franklin. PMID- 21678883 TI - Victim or initiator? Certified nursing assistants' perceptions of resident characteristics that contribute to resident-to-resident violence in nursing homes. AB - The purpose of this portion of a larger qualitative study was to explore certified nursing assistants' (CNAs) perceptions of the characteristics of both the victims and initiators of resident-to-resident violence (RRV) to identify resident characteristics that influence development of RRV. Findings gained from semi-structured interviews revealed that CNAs perceive initiators of RRV to be "more with it" and to have "strong personalities," a "short fuse," and "life history" that make them prone to inflict harm on other residents. CNAs described victims of RRV using phrases such as, "they don't know," "can't communicate," and "gets around good." The results also revealed that, in some situations, residents who were usually even tempered might strike out with violence if exposed to triggers over time. This study provides the first detailed description of nursing home residents who initiate violence against other residents. Knowledge gained from this study may be useful in generating models of RRV-a precursor to developing interventions for its prevention. PMID- 21678884 TI - Serious behavioral disorders in children and adolescents. PMID- 21678885 TI - Pediatric and adolescent depression. PMID- 21678886 TI - A 7-year-old girl with intermittent vomiting, abdominal pain, and weight loss. PMID- 21678887 TI - A premature girl with pallor and rash. PMID- 21678888 TI - Predictors of treatment response in adolescent depression. PMID- 21678889 TI - Cognitive behavioral treatment of depression in youth. PMID- 21678890 TI - Family intervention strategies for adolescent depression. PMID- 21678891 TI - Assessment and management of suicidal behavior in children and adolescents. PMID- 21678892 TI - Proteomics-based compositional analysis of complex cellulase-hemicellulase mixtures. AB - Efficient deconstruction of cellulosic biomass to fermentable sugars for fuel and chemical production is accomplished by a complex mixture of cellulases, hemicellulases, and accessory enzymes (e.g., >50 extracellular proteins). Cellulolytic enzyme mixtures, produced industrially mostly using fungi like Trichoderma reesei, are poorly characterized in terms of their protein composition and its correlation to hydrolytic activity on cellulosic biomass. The secretomes of commercial glycosyl hydrolase-producing microbes was explored using a proteomics approach with high-throughput quantification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we show that proteomics based spectral counting approach is a reasonably accurate and rapid analytical technique that can be used to determine protein composition of complex glycosyl hydrolase mixtures that also correlates with the specific activity of individual enzymes present within the mixture. For example, a strong linear correlation was seen between Avicelase activity and total cellobiohydrolase content. Reliable, quantitative and cheaper analytical methods that provide insight into the cellulosic biomass degrading fungal and bacterial secretomes would lead to further improvements toward commercialization of plant biomass-derived fuels and chemicals. PMID- 21678893 TI - Broadband electric spectroscopy at high CO2 pressure: dipole moment of CO2 and relaxation phenomena of the CO2-poly(vinyl chloride) system. AB - Broadband electric spectroscopy (BES) is a technique that shows promise in studying the interactions of dense or supercritical gases with polymers, particularly with respect to chain mobility. Polymers that are treated with dense gases show a reduction in the viscosity, glass transition, and melting temperature. A high pressure cell for BES has been constructed that can be used from ambient temperature and pressure to 353 K and 15 MPa and over a frequency range from 20 Hz to 1 MHz. In the past, the dielectric constant of CO(2) was determined by measurements at only one or two frequency values. New instrumentation and technology allow this experiment to be expanded to cover a wider frequency range. BES measurements of CO(2) do not show any relaxation peaks in the permittivity from 20 Hz to 1 MHz and 1 to 6 MPa. By these measurements, the CO(2) dielectric constant was evaluated between 0.1 and 6 MPa. Cell testing with poly(vinyl chloride) (PVC) at 323 K and CO(2) pressures from 0.1 to 13 MPa indicate an increase in the chain segmental motion at high pressures resulting from a reduction in the glass transition temperature of the PVC-CO(2) system due to plasticization by CO(2). PMID- 21678894 TI - Calf thymus DNA-binding ability study of anthocyanins from purple sweet potatoes ( Ipomoea batatas L.). AB - A total of 10 anthocyanin compounds were identified from five purple sweet potato ( Ipomoea batatas L.) varieties, Qunzi, Zishu038, Ji18, Jingshu6, and Ziluolan, by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to assess their calf thymus DNA-binding ability in vitro. The interaction between anthocyanins and calf thymus DNA in Tris-HCl buffer solution (pH 6.9) was evaluated by fluorescence spectroscopy. Using ethidium bromide (EB) as a fluorescence probe, fluorescence quenching of the emission peak was seen in the DNA-EB system when anthocyanins were added, indicating that the anthocyanins bound with DNA. The acylated groups influenced the ability of the interaction with DNA. Anthocyanins from purple sweet potato with more acylated groups in sorphorose have a stronger binding ability with DNA. PMID- 21678896 TI - Biotechnological production of vitamin B2-enriched bread and pasta. AB - Lactic acid bacteria (LAB) were obtained from durum wheat flour samples and screened for roseoflavin-resistant variants to isolate natural riboflavin overproducing strains. Two riboflavin-overproducing strains of Lactobacillus plantarum isolated as described above were used for the preparation of bread (by means of sourdough fermentation) and pasta (using a prefermentation step) to enhance their vitamin B2 content. Pasta was produced from a monovarietal semolina obtained from the durum wheat cultivar PR22D89 and, for experimental purposes, from a commercial remilled semolina. Several samples were collected during the pasta-making process (dough, extruded, dried, and cooked pasta) and tested for their riboflavin content by a high-performance liquid chromatography method. The applied approaches resulted in a considerable increase of vitamin B2 content (about 2- and 3-fold increases in pasta and bread, respectively), thus representing a convenient and efficient food-grade biotechnological application for the production of vitamin B2-enriched bread and pasta. This methodology may be extended to a wide range of cereal-based foods, feed, and beverages. Additionally, this work exemplifies the production of a functional food by a novel biotechnological exploitation of LAB in pasta-making. PMID- 21678897 TI - Differences in mercury bioaccumulation between polar bears (Ursus maritimus) from the Canadian high- and sub-Arctic. AB - Polar bears (Ursus maritimus) are being impacted by climate change and increased exposure to pollutants throughout their northern circumpolar range. In this study, we quantified concentrations of total mercury (THg) in the hair of polar bears from Canadian high- (southern Beaufort Sea, SBS) and sub- (western Hudson Bay, WHB) Arctic populations. Concentrations of THg in polar bears from the SBS population (14.8 +/- 6.6 MUg g(-1)) were significantly higher than in polar bears from WHB (4.1 +/- 1.0 MUg g(-1)). On the basis of delta(15)N signatures in hair, in conjunction with published delta(15)N signatures in particulate organic matter and sediments, we estimated that the pelagic and benthic food webs in the SBS are ~ 4.7 and ~ 4.0 trophic levels long, whereas in WHB they are only ~ 3.6 and ~ 3.3 trophic levels long. Furthermore, the more depleted delta(13)C ratios in hair from SBS polar bears relative to those from WHB suggests that SBS polar bears feed on food webs that are relatively more pelagic (and longer), whereas polar bears from WHB feed on those that are relatively more benthic (and shorter). Food web length and structure accounted for ~ 67% of the variation we found in THg concentrations among all polar bears across both populations. The regional difference in polar bear hair THg concentrations was also likely due to regional differences in water-column concentrations of methyl Hg (the toxic form of Hg that biomagnifies through food webs) available for bioaccumulation at the base of the food webs. For example, concentrations of methylated Hg at mid-depths in the marine water column of the northern Canadian Arctic Archipelago were 79.8 +/- 37.3 pg L(-1), whereas, in HB, they averaged only 38.3 +/- 16.6 pg L(-1). We conclude that a longer food web and higher pelagic concentrations of methylated Hg available to initiate bioaccumulation in the BS resulted in higher concentrations of THg in polar bears from the SBS region compared to those inhabiting the western coast of HB. PMID- 21678899 TI - The Douglas-Kroll-Hess approach. PMID- 21678900 TI - Measurement of N2, N2O, NO, and CO2 emissions from soil with the gas-flow-soil core technique. AB - Here we describe a newly designed system with three stand-alone working incubation vessels for simultaneous measurements of N(2), N(2)O, NO, and CO(2) emissions from soil. Due to the use of a new micro thermal conductivity detector and the redesign of vessels and gas sampling a so-far unmatched sensitivity (0.23 MUg N(2)-N h(-1) kg(-1) ds or 8.1 MUg N(2)-N m(-2) h(-1)) for detecting N(2) gas emissions and repeatability of experiments could be achieved. We further tested different incubation methods to improve the quantification of N(2) emission via denitrification following the initialization of soil anaerobiosis. The best results with regard to the establishment of a full N balance (i.e., the changes in mineral N content being offset by simultaneous emission of N gases) were obtained when the anaerobic soil incubation at 25 degrees C was preceded by soil gas exchange under aerobic conditions at a lower incubation temperature. The ratios of N and C gas emission changed very dynamically following the initialization of anaerobiosis. For soil NO(3)(-) contents of 50 mg N kg(-1) dry soil (ds) and dissolved organic carbon (DOC) concentrations of approximately 300 mg C kg(-1) ds, the cumulative emissions of N(2), N(2)O, and NO were 24.3 +/- 0.1, 12.6 +/- 0.4, and 10.1 +/- 0.3 mg N kg(-1) ds, respectively. Thus, N gas emissions accounted (on average) for 46.2% (N(2)), 24.0% (N(2)O), and 19.2% (NO) of the observed changes in soil NO(3)(-). The maximum N(2) emission reached 1200 MUg N h(-1) kg(-1) ds, whereas the peak emissions of N(2)O and NO were lower by a factor of 2-3. The overall N(2):N(2)O and NO:N(2)O molar ratios were 1.6-10.0 and 1.6-2.3, respectively. The measurement system provides a reliable tool for studying denitrification in soil because it offers insights into the dynamics and magnitude of gaseous N emissions due to denitrification under various incubation conditions. PMID- 21678901 TI - Surface-confined assemblies and polymers for molecular logic. AB - Stimuli responsive materials are capable of mimicking the operation characteristics of logic gates such as AND, OR, NOR, and even flip-flops. Since the development of molecular sensors and the introduction of the first AND gate in solution by de Silva in 1993, Molecular (Boolean) Logic and Computing (MBLC) has become increasingly popular. In this Account, we present recent research activities that focus on MBLC with electrochromic polymers and metal polypyridyl complexes on a solid support. Metal polypyridyl complexes act as useful sensors to a variety of analytes in solution (i.e., H(2)O, Fe(2+/3+), Cr(6+), NO(+)) and in the gas phase (NO(x) in air). This information transfer, whether the analyte is present, is based on the reversible redox chemistry of the metal complexes, which are stable up to 200 degrees C in air. The concurrent changes in the optical properties are nondestructive and fast. In such a setup, the input is directly related to the output and, therefore, can be represented by one-input logic gates. These input-output relationships are extendable for mimicking the diverse functions of essential molecular logic gates and circuits within a set of Boolean algebraic operations. Such a molecular approach towards Boolean logic has yielded a series of proof-of-concept devices: logic gates, multiplexers, half adders, and flip-flop logic circuits. MBLC is a versatile and, potentially, a parallel approach to silicon circuits: assemblies of these molecular gates can perform a wide variety of logic tasks through reconfiguration of their inputs. Although these developments do not require a semiconductor blueprint, similar guidelines such as signal propagation, gate-to-gate communication, propagation delay, and combinatorial and sequential logic will play a critical role in allowing this field to mature. For instance, gate-to-gate communication by chemical wiring of the gates with metal ions as electron carriers results in the integration of stand-alone systems: the output of one gate is used as the input for another gate. Using the same setup, we were able to display both combinatorial and sequential logic. We have demonstrated MBLC by coupling electrochemical inputs with optical readout, which resulted in various logic architectures built on a redox-active, functionalized surface. Electrochemically operated sequential logic systems such as flip-flops, multivalued logic, and multistate memory could enhance computational power without increasing spatial requirements. Applying multivalued digits in data storage could exponentially increase memory capacity. Furthermore, we evaluate the pros and cons of MBLC and identify targets for future research in this Account. PMID- 21678902 TI - The dynamic nature of RNA as key to understanding riboswitch mechanisms. AB - Riboswitches are gene regulation elements within RNA that recognize specific metabolites. They predominantly occur in the untranslated leader regions of bacterial messenger RNA (mRNA). Upon metabolite binding to the aptamer domain, a structural change in the adjoining downstream expression platform signals "on" or "off" for gene expression. Researchers have achieved much progress in characterizing ligand-bound riboswitch states at the molecular level; an impressive number of high-resolution structures of aptamer-ligand complexes is now available. These structures have significantly contributed toward our understanding of how riboswitches interact with their natural ligands and with structurally related analogues. In contrast, relatively little is known about the nature of the unbound (apo) form of riboswitches. Moreover, the details of how changes in the aptamer domain are transduced into conformational changes in the decision-making expression platform remain murky. In this Account, we report on recent efforts aimed at the characterization of free states, ligand recognition, and ligand-induced folding in riboswitches. Riboswitch action is best approached as a cotranscriptional process, which implies sequential folding and release of the aptamer prior to the signaling of the expression platform. Thus, a complex interplay of several factors has to be taken into account, such as speed of transcription, transcriptional pausing, kinetics and thermodynamics of RNA structure formation, and kinetics and thermodynamics of ligand binding. The response mechanism appears to be best described as a process in which ligand recognition critically dictates the folding pathway of the nascent mRNA during its expression; the resulting structures determine the interactions with the transcriptional or translational apparatus. We discuss experimental methods that offer insight into the dynamics of the free riboswitch state. These include probing experiments, such as in-line and selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) techniques, small-angle X-ray scattering (SAXS) analysis, NMR spectroscopy, and fluorescence spectroscopy, including single molecule fluorescence resonance energy transfer (smFRET) imaging. One of our research contributions is an approach, termed 2ApFold, that incorporates noninvasive 2-aminopurine modifications in riboswitches. The fluorescence response of these moieties is used to delineate the order of secondary-tertiary structure formation and rearrangements taking place during ligand-induced folding. This information can be used to explore the kinetics of ligand recognition and to analyze the degree of structure preorganization of the free riboswitch state. Furthermore, we discuss a recent smFRET study on the SAM-II riboswitch; this report underscores the importance of choosing strategic labeling patterns that leave maximal conformational freedom to the regulatory interaction. Finally, we comment on how riboswitch ligand recognition appeals to the concepts of conformational selection and induced fit, and on the question of whether riboswitches act under thermodynamic or kinetic control. This Account highlights the fact that a thorough understanding of RNA dynamics in vitro is required to shed light on cellular riboswitch mechanisms. Elucidating these mechanisms will contribute not only to ongoing efforts to target riboswitches with antibiotics but also to attempts to engineer artificial cell regulation systems. PMID- 21678903 TI - Highly ordered square arrays from a templated ABC triblock terpolymer. AB - Square-symmetry patterns are of interest in nanolithography but are not easily obtained from self-assembly of a diblock copolymer. Instead, we demonstrate highly ordered 44 nm period square patterns formed in a thin film of polyisoprene block-polystyrene-block-polyferrocenylsilane (PI-b-PS-b-PFS) triblock terpolymer blended with 15% PS homopolymer by controlling the film thickness, solvent anneal conditions, the surface chemistry and topography of the substrates. The square patterns consist of PFS pillars that remained after removal of the PI and PS with an oxygen plasma. On an unpatterned smooth substrate, the average grain size of the square pattern was increased dramatically to several micrometers by the use of brush layers and specific solvent anneal conditions. Templated self-assembly of well-ordered square patterns was demonstrated on substrates containing nanoscale topographical sidewalls and posts, written by electron beam lithography, in which the sidewalls and base of the substrate were independently chemically functionalized. PMID- 21678904 TI - A concise asymmetric total synthesis of (+)-brevisamide. AB - A new protecting-group-free synthesis of the marine monocyclic ether (+) brevisamide is reported. The enantioselective synthesis utilizes a key asymmetric Henry reaction and an Achmatowicz rearrangement for the formation of the tetrahydropyran ring. A penultimate Stille cross-coupling allows for an efficient installation of the conjugated (E,E)-diene side chain ultimately delivering (+) brevisamide. PMID- 21678905 TI - An efficient synthesis of the protected carbohydrate moiety of Brasilicardin A. AB - A synthesis of the protected carbohydrate moiety 2 of Brasilicardin A starting from l-rhamnose and d-glucosamine is described. The disaccharide was synthesized using a TMSOTf-mediated glycosylation of the 2-phthalimido-2-deoxyglucose donor 5 and the 3-hydroxyl group of the protected L-rhamnose derivative 4, which already bears the 3-hydroxybenzoate unit. The imidate 2 was coupled via TMSOTf-mediated glycosidation with cholesterol as a model aglycone followed by the selective cleavage of all the acetate groups to give the Brasilicardin A analogue 16. PMID- 21678906 TI - Role of Fe doping in tuning the band gap of TiO2 for the photo-oxidation-induced cytotoxicity paradigm. AB - UV-light-induced electron-hole (e(-)/h(+)) pair generation with free radical production in TiO(2)-based nanoparticles is a major conceptual paradigm for biological injury. However, to date, this hypothesis has been difficult to experimentally verify due to the high energy of UV light that is intrinsically highly toxic to biological systems. Here, a versatile flame spray pyrolysis (FSP) synthetic process has been exploited to synthesize a library of iron-doped (0-10 wt%) TiO(2) nanoparticles. These particles have been tested for photoactivation mediated cytotoxicity using near-visible light exposure. The reduction in TiO(2) band gap energy with incremental levels of Fe loading maintained the nanoparticle crystalline structure in spite of homogeneous Fe distribution (demonstrated by XRD, HRTEM, SAED, EFTEM, and EELS). Photochemical studies showed that band gap energy was reciprocally tuned proportional to the Fe content. The photo-oxidation capability of Fe-doped TiO(2) was found to increase during near-visible light exposure. Use of a macrophage cell line to evaluate cytotoxic and ROS production showed increased oxidant injury and cell death in parallel with a decrease in band gap energy. These findings demonstrate the importance of band gap energy in the phototoxic response of the cell to TiO(2) nanoparticles and reflect the potential of this material to generate adverse effects in humans and the environment during high-intensity light exposure. PMID- 21678907 TI - Design, synthesis, and X-ray crystallographic studies of alpha-aryl substituted fosmidomycin analogues as inhibitors of Mycobacterium tuberculosis 1-deoxy-D xylulose 5-phosphate reductoisomerase. AB - The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5 phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. alpha-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4 dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin-DXR complex. Our best inhibitor has an IC(50) = 0.15 MUM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 MUg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite. PMID- 21678908 TI - S1-state model of the O2-evolving complex of photosystem II. AB - We introduce a quantum mechanics/molecular mechanics model of the oxygen-evolving complex of photosystem II in the S(1) Mn(4)(IV,III,IV,III) state, where Ca(2+) is bridged to manganese centers by the carboxylate moieties of D170 and A344 on the basis of the new X-ray diffraction (XRD) model recently reported at 1.9 A resolution. The model is also consistent with high-resolution spectroscopic data, including polarized extended X-ray absorption fine structure data of oriented single crystals. Our results provide refined intermetallic distances within the Mn cluster and suggest that the XRD model most likely corresponds to a mixture of oxidation states, including species more reduced than those observed in the catalytic cycle of water splitting. PMID- 21678909 TI - Impact of seawater-quality and water treatment procedures on the active bacterial assemblages at two desalination sites. AB - Inorganic and organic compounds, particles and microorganisms in intake waters are mainly responsible for fouling of reverse osmosis membranes, which reduces the efficiency of the desalination process. The characterization of seawater quality to better predict its fouling potential remains a challenge for the desalination field and little is known about the seasonal variability of water quality parameters in the coastal waters used to supply desalination plants. In this study, standard water quality methods were combined with flow cytometry and molecular methods (16S rRNA sequencing and fingerprinting) to assess in parallel, the physicochemical properties, the microbial abundance and the active microbial community composition of the intake waters and their associated pretreated waters at two desalination sites from July 2007 to July 2008. The overall assessment of quality parameters revealed that microfiltration followed by slow sand filtration were the most efficient in removing microorganisms than the conventional dual media filtration routinely used in full-scale desalination plants, and that all treatments were inefficient for organic matter reduction. Temporal variation of the environmental parameters such as temperature, turbidity and silt density index only moderately affected the bacterial community structure in raw waters, but that interestingly, water treatment compartments changed the composition and diversity of the metabolically active bacterial populations and thus create distinct ecological post-treatment niches. PMID- 21678910 TI - Microbially mediated O-methylation of bisphenol A results in metabolites with increased toxicity to the developing zebrafish (Danio rerio) embryo. AB - Bisphenol A (BPA) is used in the manufacture of plastics, and has been identified in various environmental matrices, including human serum and breast milk. The prevalence of BPA in the environment and the potential exposure to humans underscores the need to more fully understand the fate of BPA in the environment and the resulting effects and toxicity to humans and other organisms. Here we demonstrate that Mycobacterium species, including Mycobacterium vanbaalenii strain PYR-1, are able to O-methylate BPA to its mono- and dimethyl ether derivatives (BPA MME and BPA DME, respectively). The O-methylation of BPA results in metabolites with increased toxicity as shown from differences in survival and occurrence of developmental lesions in developing zebrafish embryos exposed to BPA, BPA MME, and BPA DME. The mono- and dimethyl ether derivatives were more toxic than BPA, resulting in increased mortality at 5 (LC(50) = 0.66 and 1.2 mg L(-1)) and 28 (LC(50) = 0.38, <0.5 mg L(-1)) days post fertilization. Furthermore, exposure to either of the O-methylated metabolites resulted in an increase in the incidence of developmental lesions as compared to BPA exposure. These data illustrate a new mechanism for microbial transformation of BPA, producing metabolites warranting further study to understand their prevalence and effects in the environment. PMID- 21678911 TI - Organocatalytic asymmetric conjugate addition and cascade acyl transfer reaction of alpha-nitroketones. AB - Organocatalytic asymmetric conjugate addition of alpha-nitroketones to beta,gamma unsaturated alpha-keto esters has been developed. A pyrrolidine-based thiourea tertiary amine was identified as the best catalyst. The reaction was found to proceed via cascade conjugate addition and acyl transfer reaction. A number of alpha-nitroketones and beta,gamma-unsaturated alpha-keto esters were examined in this transformation. 5-Nitro-2-acyloxypent-2-enoates were obtained in good yields (up to 99%) and enantioselectivities (up to 99% ee). The products could be hydrolyzed to provide 5-nitro-2-oxopentanoates, which are not available from the direct addition of nitromethane to beta,gamma-unsaturated alpha-keto esters. PMID- 21678912 TI - Important role of oxidative stress biomarkers in Huntington's disease. AB - This study examined global oxidative stress (GOS) and antioxidant system and their correlation with disease stage in 19 patients with HD. The results revealed an increase in oxidative stress biomarkers and a reduction in antioxidant systems in HD patients. The effects were more intense in HD1 than in HD2 patients. Additionally, carbonylated proteins and GOS were correlated with disease stage. These findings suggest that oxidative stress plays an important role in the pathogenesis of HD. PMID- 21678913 TI - Sequential reductive and oxidative biodegradation of chloroethenes stimulated in a coupled bioelectro-process. AB - This article for the first time demonstrates successful application of electrochemical processes to stimulate sequential reductive/oxidative microbial degradation of perchloroethene (PCE) in mineral medium and in contaminated groundwater. In a flow-through column system, hydrogen generation at the cathode supported reductive dechlorination of PCE to cis-dichloroethene (cDCE), vinyl chloride (VC), and ethene (ETH). Electrolytically generated oxygen at the anode allowed subsequent oxidative degradation of the lower chlorinated metabolites. Aerobic cometabolic degradation of cDCE proved to be the bottleneck for complete metabolite elimination. Total removal of chloroethenes was demonstrated for a PCE load of approximately 1.5 MUmol/d. In mineral medium, long-term operation with stainless steel electrodes was demonstrated for more than 300 days. In contaminated groundwater, corrosion of the stainless steel anode occurred, whereas DSA (dimensionally stable anodes) proved to be stable. Precipitation of calcareous deposits was observed at the cathode, resulting in a higher voltage demand and reduced dechlorination activity. With DSA and groundwater from a contaminated site, complete degradation of chloroethenes in groundwater was obtained for two months thus demonstrating the feasibility of the sequential bioelectro-approach for field application. PMID- 21678915 TI - Luminescence investigation on ultraviolet-emitting rare-earth-doped phosphors using synchrotron radiation. AB - Three series of new ultraviolet-emitting Ca(9)Y(PO(4))(7):Ln(3+) (Ln = Ce, Gd, Pr) phosphors were synthesized, and their luminescence was investigated. Under vacuum ultraviolet excitation Ca(9)Y(PO(4))(7):Ce(3+) phosphors emit UVA light with one broad emission centered at 346 nm, on account of the 5d(1) -> 4f(1) transition of Ce(3+) ions; the optimal doping concentration of these phosphors is 0.2 mol. Ca(9)Y(PO(4))(7):Gd(3+) phosphors show a strong 4f(7) -> 4f(7) transition and a sharp UVB emission band at 312 nm; the optimal doping concentration of these phosphors is 0.7 mol. The PL spectra of Ca(9)Y(PO(4))(7):Pr(3+) show two broad UVC emission bands centered between 230 and 340 nm, owing to the 4f(1)5d(1) -> 4f(2) transition of Pr(3+) ions; the optimal doping concentration of these phosphors is 0.2 mol. Under 172 nm excitation, we found that the luminescence intensity of the UVA-emitting Ca(9)Y(PO(4))(7):0.2Ce(3+) is 0.3675 times that of BaSi(2)O(5):0.05Pb(2+), that of the UVB-emitting Ca(9)Y(PO(4))(7):0.7Gd(3+) is 1.7 times that of YAl(3)(BO(3))(4):0.25Gd(3+), and that of the UVC-emitting Ca(9)Y(PO(4))(7):0.2Pr(3+) is 1.5 times that of LaPO(4):0.1Pr(3+). The thermal stability investigation indicated that the luminescence decay was only 9.2%, 18.2%, and 10.3% for Ca(9)Y(PO(4))(7):0.2Ce(3+), Ca(9)Y(PO(4))(7):0.7Gd(3+), and Ca(9)Y(PO(4))(7):0.2Pr(3+) at 250 degrees C relative to that at ambient temperature, respectively. The Ca(9)Y(PO(4))(7):Ln(3+) (Ln = Ce, Gd, Pr) phosphors exhibit high emission efficiency and excellent thermal stability. PMID- 21678914 TI - Effectiveness of CID, HCD, and ETD with FT MS/MS for degradomic-peptidomic analysis: comparison of peptide identification methods. AB - We report on the effectiveness of CID, HCD, and ETD for LC-FT MS/MS analysis of peptides using a tandem linear ion trap-Orbitrap mass spectrometer. A range of software tools and analysis parameters were employed to explore the use of CID, HCD, and ETD to identify peptides (isolated from human blood plasma) without the use of specific "enzyme rules". In the evaluation of an FDR-controlled SEQUEST scoring method, the use of accurate masses for fragments increased the number of identified peptides (by ~50%) compared to the use of conventional low accuracy fragment mass information, and CID provided the largest contribution to the identified peptide data sets compared to HCD and ETD. The FDR-controlled Mascot scoring method provided significantly fewer peptide identifications than SEQUEST (by 1.3-2.3 fold) and CID, HCD, and ETD provided similar contributions to identified peptides. Evaluation of de novo sequencing and the UStags method for more intense fragment ions revealed that HCD afforded more contiguous residues (e.g., >= 7 amino acids) than either CID or ETD. Both the FDR-controlled SEQUEST and Mascot scoring methods provided peptide data sets that were affected by the decoy database used and mass tolerances applied (e.g., identical peptides between data sets could be limited to ~70%), while the UStags method provided the most consistent peptide data sets (>90% overlap). The m/z ranges in which CID, HCD, and ETD contributed the largest number of peptide identifications were substantially overlapping. This work suggests that the three peptide ion fragmentation methods are complementary and that maximizing the number of peptide identifications benefits significantly from a careful match with the informatics tools and methods applied. These results also suggest that the decoy strategy may inaccurately estimate identification FDRs. PMID- 21678916 TI - Protein encapsulation by humic substances. AB - Protein encapsulation by natural organic matter is hypothesized to preserve the activity of proteins in terrestrial and aquatic environments. Direct molecular level evidence for encapsulation of net positively charged proteins lysozyme, trypsin, and ribonuclease A by a diverse set of humic substances (HS) in nanostructured films was collected using a combination of optical waveguide lightmode spectroscopy and quartz crystal microbalance measurements. The results suggest that protein-HS electrostatic attraction drives encapsulation of positively charged lysozyme by a soil humic acid at pH 5 to 8 and by six additional humic and fulvic acids from terrestrial and mixed terrestrial aquatic sources at pH 5 and 6. Encapsulation of trypsin and ribonuclease A, which had negatively charged surface patches under the studied conditions, suggested that localized protein-HS electrostatic repulsion is overcompensated by attractive forces, likely including contributions from the hydrophobic effect. Evidence is provided showing that encapsulation of lysozyme at pH 8 and of ribonuclease A at pH 5 and 6 involved partial disassembly of HA supramolecular associations. This work advances a molecular-level picture of protein encapsulation by HS and presents a novel approach to study the effects of encapsulation on protein enzymatic activity and susceptibility to abiotic and biotic transformations. PMID- 21678917 TI - Two-electron oxidation of deoxyguanosine by a Ru(III) complex without involving oxygen molecules through disproportionation. AB - Among the many mechanisms for the oxidation of guanine derivatives (G) assisted by transition metals, Ru(III) and Pt(IV) metal ions share basically the same principle. Both Ru(III)- and Pt(IV)-bound G have highly positively polarized C8 H's that are susceptible to deprotonation by OH(-), and both undergo two-electron redox reactions. The main difference is that, unlike Pt(IV), Ru(III) is thought to require O(2) to undergo such a reaction. In this study, however, we report that [Ru(III)(NH(3))(5)(dGuo)] (dGuo = deoxyguanosine) yields cyclic-5'-O-C8-dGuo (a two-electron G oxidized product, cyclic-dGuo) without O(2). In the presence of O(2), 8-oxo-dGuo and cyclic-dGuo were observed. Both [Ru(II)(NH(3))(5)(dGuo)] and cyclic-dGuo were produced from [Ru(III)(NH(3))(5)(dGuo)] accelerated by [OH(-)]. We propose that [Ru(III)(NH(3))(5)(dGuo)] disproportionates to [Ru(II)(NH(3))(5)(dGuo)] and [Ru(IV)(NH(3))(4)(NH(2)(-))(dGuo)], followed by a 5' OH attack on C8 in [Ru(IV)(NH(3))(4)(NH(2)(-))(dGuo)] to initiate an intramolecular two-electron transfer from dGuo to Ru(IV), generating cyclic-dGuo and Ru(II) without involving O(2). PMID- 21678918 TI - Catalytic asymmetric intermolecular Stetter reaction of enals with nitroalkenes: enhancement of catalytic efficiency through bifunctional additives. AB - An asymmetric intermolecular Stetter reaction of enals with nitroalkenes catalyzed by chiral N-heterocyclic carbenes has been developed. The reaction rate and efficiency are profoundly impacted by the presence of catechol. The reaction proceeds with high selectivities and affords good yields of the Stetter product. Internal redox products were not observed despite of the protic conditions. The impact of catechol has been found to be general, facilitating far lower catalyst loadings than were previously achievable. PMID- 21678919 TI - Electronic structure of 2,2'-bipyridine organotransition-metal complexes. Establishing the ligand oxidation level by density functional theoretical calculations. AB - A density functional theoretical (DFT) study (B3LYP) has been carried out on 20 organometallic complexes containing eta(5)- and/or eta(3)-coordinated cyclopentadienyl anions (Cp(-)) and 2,2'-bipyridine (bpy) ligand(s) at varying oxidation levels, i.e., as the neutral ligand (bpy(0)), as the pi-radical monoanion (bpy(*-))(-), or as the diamagnetic dianion (bpy(2-))(2-). The molecular and electronic structures of these species in their ground states and, in some cases, their first excited states have been calculated using broken symmetry methodology. The results are compared with experimental structural and spectroscopic data (where available) in order to validate the DFT computational approach. The following electron-transfer series and complexes have been studied: [(Cp)(2)V(bpy)](0,+,2+) (1-3), [(Cp)(2)Ti(bpy)](-,0,+,2+) (4-7), [(Cp)(2)Ti(biquinoline)](0,+) (8 and 9), [(Cp*)(2)Ti(bpy)](0) (10) (Cp* = pentamethylcyclopentadienyl anion), [Cp*Co(bpy)](0,+) (11 and 12), [Cp*Co(bpy)Cl](+,0) (13 and 14), [Fe(toluene)(bpy)](0) (15), [Cp*Ru(bpy)](-) (16), [(Cp)(2)Zr(bpy)](0) (17), and [Mn(CO)(3)(bpy)](-) (18). In order to test the predictive power of our computations, we have also calculated the molecular and electronic structures of two complexes, A and B, namely, the diamagnetic dimer [Cp*Sc(bpy)(MU-Cl)](2) (A) and the paramagnetic (at 25 degrees C) mononuclear species [(eta(5)-C(5)H(4)(CH(2))(2)N(CH(3))(2))Sc((m)bpy)(2)] (B). The crystallographically observed intramolecular pi-pi interaction of two N,N' coordinated pi-radical anions in A leading to an S = 0 ground state is reliably reproduced. Similarly, the small singlet-triplet gap of ~600 cm(-1) between two antiferromagnetically coupled (bpy(*-))(-) ligands in B, two ferromagnetically coupled radical anions in the triplet excited state of B, and the structures of A and B is reproduced. Therefore, we are confident that we can present computationally obtained, detailed electronic structures for complexes 1-18. We show that N,N'-coordinated neutral bpy(0) ligands behave as very weak pi acceptors (if at all), whereas the (bpy(2-))(2-) dianions are strong pi-donor ligands. PMID- 21678920 TI - Simple method for preparing poly(ethylene glycol)-surface-conjugated liposome encapsulated hemoglobins: physicochemical properties, long-term storage stability, and their reactions with O2, CO, and NO. AB - During the last few decades, liposome-encapsulated hemoglobin (LEH) dispersions have been investigated for use as red blood cell (RBC) substitutes. However, the process for formulating LEHs is cumbersome, and the composition of the lipid mixture is often complex. This work investigates a simple approach to formulating LEHs from a simple lipid mixture composed of high-phase-transition lipid distearoylphosphatidylcholine (DSPC) and cholesterol. To improve the circulation half-life and colloidal state of LEHs, the surfaces of unmodified LEHs were conjugated with poly(ethylene glycol) (PEG-LEHs). The results of this work show that PEG-LEH dispersions exhibited average diameters ranging from 166 to 195 nm that were colloidally stable for 4 to 5 months, hemoglobin (Hb) concentrations ranging from 9.6 to 14 g/dL, methemoglobin levels of less than 1%, oxygen affinities (i.e., P(50) values) ranging from 20 to 23 mm Hg, and cooperativity coefficients ranging from 1.4 to 2.2. The reactions of PEG-LEHs with physiologically important ligands, such as oxygen (O(2)), carbon monoxide (CO), and nitric oxide (NO), were also measured. It was observed that PEG-LEHs and RBCs exhibited retarded gaseous ligand binding/release kinetics compared to that of acellular Hb's. This result provides important insight into the pivotal role that the intracellular diffusion barrier plays in the transport of gases into and out of these structures. Collectively, our results demonstrate that the PEG-LEH dispersions prepared in this study show good potential as an RBC substitute. PMID- 21678921 TI - Biochemical characterization of human SET and MYND domain-containing protein 2 methyltransferase. AB - SET and MYND domain-containing protein 2 (SMYD2) is a protein lysine methyltransferase that catalyzes the transfer of methyl groups from S adenosylmethionine (AdoMet) to acceptor lysine residues on histones and other proteins. To understand the kinetic mechanism and the function of individual domains, human SMYD2 was overexpressed, purified, and characterized. Substrate specificity and product analysis studies established SMYD2 as a monomethyltransferase that prefers nonmethylated p53 peptide substrate. Steady state kinetic and product inhibition studies showed that SMYD2 operates via a rapid equilibrium random Bi Bi mechanism at a rate of 0.048 +/- 0.001 s(-1), with K(M)s for AdoMet and the p53 peptide of 0.031 +/- 0.01 MUM and 0.68 +/- 0.22 MUM, respectively. Metal analyses revealed that SMYD2 contains three tightly bound zinc ions that are important for maintaining the structural integrity and catalytic activity of SMYD2. Catalytic activity was also shown to be dependent on the GxG motif in the S-sequence of the split SET domain, as a G18A/G20A double mutant and a sequence deletion within the conserved motif impaired AdoMet binding and significantly decreased enzymatic activity. The functional importance of other SMYD2 domains including the MYND domain, the cysteine-rich post-SET domain, and the C-terminal domain (CTD), were also investigated. Taken together, these results demonstrated the functional importance of distinct domains in the SMYD family of proteins and further advanced our understanding of the catalytic mechanism of this family. PMID- 21678922 TI - Effect of colloidal particle size on adsorbed monodisperse and bidisperse monolayers. AB - Coating hydrogel films or microspheres by an adsorbed colloidal shell is one synthesis method for forming colloidosomes. The colloidal shell allows control of the release rate of encapsulated materials, as well as selective transport. Previous studies found that the packing density of self-assembled, adsorbed colloidal monolayers is independent of the colloidal particle size. In this paper we develop an equilibrium model that correlates the packing density of charged colloidal particles in an adsorbed shell to the particle dimensions in monodisperse and bidisperse systems. In systems where the molar concentration in solution is fixed, the increase in adsorption energy with increasing particle size leads to a monotonic increase in the monolayer packing density with particle radius. However, in systems where the mass fraction of the particles in the adsorbing solutions is fixed, increasing particle size also reduces the molar concentration of particles in solution, thereby reducing the probability of adsorption. The result is a nonmonotonic dependence of the packing density in the adsorbed layer on the particle radius. In bidisperse monolayers composed of two particle sizes, the packing density in the layer increases significantly with size asymmetry. These results may be utilized to design the properties of colloidal shells and coatings to achieve specific properties such as transport rate and selectivity. PMID- 21678924 TI - Pyrogenic remobilization of historic industrial lead depositions. AB - Relatively high levels (4.3 to 51 MUg/g) of labile lead (Pb) in ash from the 2009 Jesusita Fire in Santa Barbara County, California attest to the pyrogenic remobilization of historic industrial lead depositions in this relatively pristine area in Southern California, USA. The primarily industrial origin of that lead was evidenced by its poor correlations (simple linear regressions) with lithogenic aluminum (r = 0.18, p = 0.354, n = 30) and iron (r = 0.21, p = 0.270, n = 30) concentrations and by its associated enrichment factors (EFs): EF using aluminum as conservative element (f-Al) vs lead concentration [Pb] (r = 0.79, p < 0.001, n = 30), and EF using iron as conservative element (f-Fe) vs [Pb] (r = 0.83, p < 0.001, n = 30). The industrial origins of much of that lead were corroborated by its isotopic compositions ((206)Pb/(207)Pb and (208)Pb/(207)Pb), which fell between those of natural lead in the Santa Barbara Basin and previous leaded gasoline emissions in Southern California. This apparent pyrogenic remobilization of legacy lead pollution indicates that it-and other persistent pollutants-will increase with the projected increase in the frequency and intensity of forest fires in the Southwest U.S. and elsewhere as a consequence of climate change. PMID- 21678925 TI - Influence of cationic composition and pH on the formation of metal stearates at oil-water interfaces. AB - We study the formation of layers of metal stearates at the interface between a decane solution of stearic acid and aqueous salt solutions of variable composition and pH by monitoring the evolution of their mechanical, optical, and chemical properties as a function of time after formation of the interface. For values of the pH below the pK(a) of stearic acid hardly any interfacial activity is observed. For pH > pK(a), stearic acid deprotonates at the interface and forms metal stearates, eventually leading to the formation of macroscopic solid layers. Dynamic interfacial tension measurements reveal that the process takes place in several stages, which we attribute to the successive formation of dilute and dense monolayers followed by three-dimensional growth. In the presence of divalent ions, the solid layers display a significant increase in the dilatational storage modulus. Experiments performed with an aqueous phase containing multiple cation species (artificial seawater) give rise to particularly pronounced growth of solid layers, which preferentially incorporate Ca(2+) as revealed by X-ray photoelectron and infrared spectroscopy. Our results highlight in particular the importance of the complex synergistic effects of simultaneously present monovalent and divalent cation species on the interfacial adsorption. PMID- 21678923 TI - Structural-functional role of chloride in photosystem II. AB - Chloride binding in photosystem II (PSII) is essential for photosynthetic water oxidation. However, the functional roles of chloride and possible binding sites, during oxygen evolution, remain controversial. This paper examines the functions of chloride based on its binding site revealed in the X-ray crystal structure of PSII at 1.9 A resolution. We find that chloride depletion induces formation of a salt bridge between D2-K317 and D1-D61 that could suppress the transfer of protons to the lumen. PMID- 21678926 TI - Ab initio study of the anomalous solvatochromic behavior of large betaines. AB - The structure and spectroscopic properties of a diluted compound can be deeply affected by its interaction with the neighboring molecules of the solvent, and the associated solvatochromism is an effect that becomes more noticeable with the increase in both the dipole moment of the solute and the polarity of the medium. The correct description of the complex set of interactions that prevail in the solvation process remains a challenge for theoreticians not only when interpreting an observed behavior but also when considering the possible existence of novel properties in untested solute-solvent systems. On the basis of an ab initio study, we examine here how the presence of solvents of different polarities should affect the electronic properties of a family of molecules, formally related to Betaine-30 (aka Reichardt's dye), whose donor (D) and acceptor (A) groups are terminally connected to conjugated chains of different sizes. Because these molecules exhibit elevated ground-state dipole moment that should strongly interact with molecules of a polar solvent, a large hypsochromic shift is predicted for them. However, in a recent gas-phase study of these molecules, we have established the existence of an "inversion" in the spatial localization of their frontier orbitals when the size of the conjugated bridge connecting the D and A groups is progressively increased. This fact has led us to suggest that the increase in size of dissolved betaines should be accompanied by a large variation in their solvatochromic properties. In this work, we first use the self-consistent reaction field approach at the configuration interaction level to estimate the expected bathochromic shift in the absorption spectra (positive solvatochromism) in the largest members of the investigated betaine family when dissolved in different low polarity solvents and then discuss the conformational changes as a consequence of the solute--solvent interactions. We then use these results to interpret the observed solvatochromic properties of push--pull molecules of varying size and discuss the corresponding implications on their photochemical properties. PMID- 21678927 TI - Effect of counterion structure on rates and diastereoselectivities in alpha,beta unsaturated iminium-ion Diels-Alder reactions. AB - The use of cyclic alpha,beta-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity. PMID- 21678928 TI - Pentavalent and tetravalent uranium selenides, Tl3Cu4USe6 and Tl2Ag2USe4: syntheses, characterization, and structural comparison to other layered actinide chalcogenide compounds. AB - The compounds Tl(3)Cu(4)USe(6) and Tl(2)Ag(2)USe(4) were synthesized by the reaction of the elements in excess TlCl at 1123 K. Both compounds crystallize in new structure types, in space groups P2(1)/c and C2/m, respectively, of the monoclinic system. Each compound contains layers of USe(6) octahedra and MSe(4) (M = Cu, Ag) tetrahedra, separated by Tl(+) cations. The packing of the octahedra and the tetrahedra within the layers is compared to the packing arrangements found in other layered actinide chalcogenides. Tl(3)Cu(4)USe(6) displays peaks in its magnetic susceptibility at 5 and 70 K. It exhibits modified Curie-Weiss paramagnetic behavior with an effective magnetic moment of 1.58(1) MU(B) in the temperature range 72-300 K, whereas Tl(2)Ag(2)USe(4) exhibits modified Curie Weiss paramagnetic behavior with MU(eff) = 3.4(1) MU(B) in the temperature range 100-300 K. X-ray absorption near-edge structure (XANES) results from scanning transmission X-ray spectromicroscopy confirm that Tl(3)Cu(4)USe(6) has Se bonding characteristic of discrete Se(2-) units, Cu bonding generally representative of Cu(+), and U bonding consistent with a U(4+) or U(5+) species. On the basis of these measurements, as well as bonding arguments, the formal oxidation states for U may be assigned as +5 in Tl(3)Cu(4)USe(6) and +4 in Tl(2)Ag(2)USe(4). PMID- 21678929 TI - (Li/Ag)CoO2: a new intergrowth cobalt oxide composed of rock salt and delafossite layers. AB - A new ordered (Li/Ag)CoO(2) layered compound with an unusual oxygen packing combining rock salt and delafossite layers is obtained during the (Li(+), Na(+))/Ag(+) ionic exchange from the OP4-(Li/Na)CoO(2) precursor. This compound is actually an intermediate step to the final D4-AgCoO(2) delafossite and can be isolated thanks to the kinetics difference between the Li(+)/Ag(+) and Na(+)/Ag(+) exchange processes. It crystallizes in the P6(3)/mmc space group with cell parameters a(hex.) = 2.848(3) A and c(hex.) = 21.607(7) A. The details of the structure as well as its thermal stability and transport properties are presented and discussed. PMID- 21678931 TI - Molecular nitrides with titanium and rare-earth metals. AB - A series of titanium-group 3/lanthanide metal complexes have been prepared by reaction of [{Ti(eta(5)-C(5)Me(5))(MU-NH)}(3)(MU(3)-N)] (1) with halide, triflate, or amido derivatives of the rare-earth metals. Treatment of 1 with metal halide complexes [MCl(3)(thf)(n)] or metal trifluoromethanesulfonate derivatives [M(O(3)SCF(3))(3)] at room temperature affords the cube-type adducts [X(3)M{(MU(3)-NH)(3)Ti(3)(eta(5)-C(5)Me(5))(3)(MU(3)-N)}] (X = Cl, M = Sc (2), Y (3), La (4), Sm (5), Er (6), Lu (7); X = OTf, M = Y (8), Sm (9), Er (10)). Treatment of yttrium (3) and lanthanum (4) halide complexes with 3 equiv of lithium 2,6-dimethylphenoxido [LiOAr] produces the aryloxido complexes [(ArO)(3)M{(MU(3)-NH)(3)Ti(3)(eta(5)-C(5)Me(5))(3)(MU(3)-N)}] (M = Y (11), La (12)). Complex 1 reacts with 0.5 equiv of rare-earth bis(trimethylsilyl)amido derivatives [M{N(SiMe(3))(2)}(3)] in toluene at 85-180 degrees C to afford the corner-shared double-cube nitrido compounds [M(MU(3)-N)(3)(MU(3) NH)(3){Ti(3)(eta(5)-C(5)Me(5))(3)(MU(3)-N)}(2)] (M = Sc (13), Y (14), La (15), Sm (16), Eu (17), Er (18), Lu (19)) via NH(SiMe(3))(2) elimination. A single-cube intermediate [{(Me(3)Si)(2)N}Sc{(MU(3)-N)(2)(MU(3)-NH)Ti(3)(eta(5) C(5)Me(5))(3)(MU(3)-N)}] (20) was obtained by the treatment of 1 with 1 equiv of the scandium bis(trimethylsilyl)amido derivative [Sc{N(SiMe(3))(2)}(3)]. The X ray crystal structures of 2, 7, 11, 14, 15, and 19 have been determined. The thermal decomposition in the solid state of double-cube nitrido complexes 14, 15, and 18 has been investigated by thermogravimetric analysis (TGA) and differential thermal analysis (DTA) measurements, as well as by pyrolysis experiments at 1100 degrees C under different atmospheres (Ar, H(2)/N(2), NH(3)) for the yttrium complex 14. PMID- 21678930 TI - Theoretical study of the mechanism of oxoiron(IV) formation from H2O2 and a nonheme iron(II) complex: O-O cleavage involving proton-coupled electron transfer. AB - It has recently been shown that the nonheme oxoiron(IV) species supported by the 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane ligand (TMC) can be generated in near-quantitative yield by reacting [Fe(II)(TMC)(OTf)(2)] with a stoichiometric amount of H(2)O(2) in CH(3)CN in the presence of 2,6-lutidine (Li, F.; England, J.; Que, L., Jr. J. Am. Chem. Soc. 2010, 132, 2134-2135). This finding has major implications for O-O bond cleavage events in both Fenton chemistry and nonheme iron enzymes. To understand the mechanism of this process, especially the intimate details of the O-O bond cleavage step, a series of density functional theory (DFT) calculations and analyses have been carried out. Two distinct reaction paths (A and B) were identified. Path A consists of two principal steps: (1) coordination of H(2)O(2) to Fe(II) and (2) a combination of partial homolytic O-O bond cleavage and proton-coupled electron transfer (PCET). The latter combination renders the rate-limiting O-O cleavage effectively a heterolytic process. Path B proceeds via a simultaneous homolytic O-O bond cleavage of H(2)O(2) and Fe-O bond formation. This is followed by H abstraction from the resultant Fe(III)-OH species by an *OH radical. Calculations suggest that path B is plausible in the absence of base. However, once 2,6-lutidine is added to the reacting system, the reaction barrier is lowered and more importantly the mechanistic path switches to path A, where 2,6-lutidine plays an essential role as an acid-base catalyst in a manner similar to how the distal histidine or glutamate residue assists in compound I formation in heme peroxidases. The reaction was found to proceed predominantly on the quintet spin state surface, and a transition to the triplet state, the experimentally known ground state for the TMC-oxoiron(IV) species, occurs in the last stage of the oxoiron(IV) formation process. PMID- 21678932 TI - Electroluminescence from nanoscale materials via field-driven ionization. AB - The high degree of morphological and energetic disorder inherent to many nanosized materials places limitations on charge injection into and transport rates through thin films of these materials. We demonstrate electroluminescence achieved by local generation of charge that eliminates the need for injection of charge carriers from the device electrodes. We show electroluminescence from thin films of nanoscale materials that do not support direct current excitation and suggest a mechanism for the charge generation and electroluminescence that is consistent with our time-averaged and time-resolved observations. PMID- 21678933 TI - Imaging translational and rotational diffusion of single anisotropic nanoparticles with planar illumination microscopy. AB - Here we demonstrated a simple yet powerful method, planar illumination microscopy, to directly track the rotational and translational diffusion dynamics of individual anisotropic nanoparticles in solution and living cells. By illuminating gold nanorods (GNRs) with two orthogonal sheets of light and resolving the polarized scattering signal with a birefringent crystal, we readily achieved three-dimensional angular resolving capability for single GNRs in noisy surroundings. The rotational dynamics of individual GNRs dispersed in glycerol/water mixtures with different chemical modification were tracked, and the measured rotational diffusion coefficient was well fitted to a previously reported theoretical model (Torre, J. G. d. l.; Martinez, M. C. L. Macromolecules 1987, 20, 661-666; Tirado, M. M.; Torre, J. G. d. l. J. Chem. Phys. 1980, 73, 1986-1993). In addition, the translational and rotational movements of individual GNRs transported by kinesin motor protein on microtubules inside living cells were directly imaged. Compared to its motion in free solution, a GNR attached to motor-protein did not rotate significantly while moving forward. Our method can be further generalized to allow determination of three-dimensional orientation of single dipoles using many different illumination modes. PMID- 21678935 TI - Highly efficient decomposition of organic dye by aqueous-solid phase transfer and in situ photocatalysis using hierarchical copper phthalocyanine hollow spheres. AB - The hierarchical tetranitro copper phthalocyanine (TNCuPc) hollow spheres were fabricated by a simple solvothermal method. The formation mechanism was proposed based on the evolution of morphology as a function of solvothermal time, which involved the initial formation of nanoparticles followed by their self aggregation to microspheres and transformation into hierarchical hollow spheres by Ostwald ripening. Furthermore, the hierarchical TNCuPc hollow spheres exhibited high adsorption capacity and excellent simultaneously visible-light driven photocatalytic performance for Rhodamine B (RB) under visible light. A possible mechanism for the "aqueous-solid phase transfer and in situ photocatalysis" was suggested. Repetitive tests showed that the hierarchical TNCuPc hollow spheres maintained high catalytic activity over several cycles, and it had a better regeneration capability under mild conditions. PMID- 21678934 TI - Geometric and electrostatic study of the [4Fe-4S] cluster of adenosine-5' phosphosulfate reductase from broken symmetry density functional calculations and extended X-ray absorption fine structure spectroscopy. AB - Adenosine-5'-phosphosulfate reductase (APSR) is an iron-sulfur protein that catalyzes the reduction of adenosine-5'-phosphosulfate (APS) to sulfite. APSR coordinates to a [4Fe-4S] cluster via a conserved CC-X(~80)-CXXC motif, and the cluster is essential for catalysis. Despite extensive functional, structural, and spectroscopic studies, the exact role of the iron-sulfur cluster in APS reduction remains unknown. To gain an understanding into the role of the cluster, density functional theory (DFT) analysis and extended X-ray fine structure spectroscopy (EXAFS) have been performed to reveal insights into the coordination, geometry, and electrostatics of the [4Fe-4S] cluster. X-ray absorption near-edge structure (XANES) data confirms that the cluster is in the [4Fe-4S](2+) state in both native and substrate-bound APSR while EXAFS data recorded at ~0.1 A resolution indicates that there is no significant change in the structure of the [4Fe-4S] cluster between the native and substrate-bound forms of the protein. On the other hand, DFT calculations provide an insight into the subtle differences between the geometry of the cluster in the native and APS-bound forms of APSR. A comparison between models with and without the tandem cysteine pair coordination of the cluster suggests a role for the unique coordination in facilitating a compact geometric structure and "fine-tuning" the electronic structure to prevent reduction of the cluster. Further, calculations using models in which residue Lys144 is mutated to Ala confirm the finding that Lys144 serves as a crucial link in the interactions involving the [4Fe-4S] cluster and APS. PMID- 21678936 TI - Predicted electronic and thermodynamic properties of a newly discovered Zn8Sb7 phase. AB - A new binary compound, Zn(8)Sb(7), has recently been prepared in nanoparticulate form via solution synthesis. No such phase is known in the bulk phase diagram; instead, one would expect phase separation to the good thermoelectric semiconductors ZnSb and Zn(4)Sb(3). Here, density functional calculations are employed to determine the free energies of formation, including effects from vibrations and configurational disorder, of the relevant phases, yielding insight into the phase stability of Zn(8)Sb(7). Band structure calculations predict Zn(8)Sb(7), much like ZnSb and Zn(4)Sb(3), to be an intermetallic semiconductor with similar thermoelectric properties. If sufficient entropy or surface energy exists to stabilize the bulk material, it would be stable in a limited temperature window at high temperature. PMID- 21678937 TI - Electrostatic and dispersion interactions during protein adsorption on topographic nanostructures. AB - Recently, biomaterials research has focused on developing functional implant surfaces with well-defined topographic nanostructures in order to influence protein adsorption and cellular behavior. To enhance our understanding of how proteins interact with such surfaces, we analyze the adsorption of lysozyme on an oppositely charged nanostructure using a computer simulation. We present an algorithm that combines simulated Brownian dynamics with numerical field calculation methods to predict the preferred adsorption sites for arbitrarily shaped substrates. Either proteins can be immobilized at their initial adsorption sites or surface diffusion can be considered. Interactions are analyzed on the basis of Derjaguin-Landau-Verway-Overbeek (DLVO) theory, including electrostatic and London dispersion forces, and numerical solutions are derived using the Poisson-Boltzmann and Hamaker equations. Our calculations show that for a grooved nanostructure (i.e., groove and plateau width 8 nm, height 4 nm), proteins first contact the substrate primarily near convex edges because of better geometric accessibility and increased electric field strengths. Subsequently, molecules migrate by surface diffusion into grooves and concave corners, where short-range dispersion interactions are maximized. In equilibrium, this mechanism leads to an increased surface protein concentration in the grooves, demonstrating that the total amount of protein per surface area can be increased if substrates have concave nanostructures. PMID- 21678938 TI - Titania-assisted dispersion of carboxylated single-walled carbon nanotubes in a ZnO sol for transparent conducting hybrid films. AB - We report a facile chemical route for stabilizing a dispersion of carboxylated single-walled carbon nanotubes (SWCNTs) in a ZnO sol. The dispersion is stabilized via capping of the carboxyl groups on the SWCNT surface by a titania layer, which was confirmed by Fourier transform infrared spectroscopy and transmission electron microscopy. We also demonstrate that the conductivity of the films prepared from the SWCNT/TiO(x)/ZnO sol is dramatically enhanced by thermal treatment and that the thermal stability of the hybridized films with the ZnO sol is notably improved relative to that of a pristine SWCNT film. The structural and chemical changes of the fabricated films were characterized by Raman spectroscopy. As one application, it was presented that thermally treated SWCNT/TiO(x)/ZnO hybrid thin film sensors showed hydrogen sensing characteristics even at room temperature. PMID- 21678939 TI - Extending the laserspray ionization concept to produce highly charged ions at high vacuum on a time-of-flight mass analyzer. AB - A new matrix compound, 2-nitrophloroglucinol, is reported which not only produces highly charged ions similar to electrospray ionization (ESI) under atmospheric pressure (AP) and intermediate pressure (IP) laserspray ionization (LSI) conditions but also the most highly charged ions so far observed for small proteins in mass spectrometry (MS) under high vacuum (HV) conditions. This new matrix extends the compounds that can successfully be employed as matrixes with LSI, as demonstrated on an LTQ Velos (Thermo) at AP, a matrix-assisted laser desorption/ionization (MALDI)-ion mobility spectrometry (IMS) time-of-flight (TOF) SYNAPT G2 (Waters) at IP, and MALDI-TOF Ultraflex, UltrafleXtreme, and Autoflex Speed (Bruker) mass spectrometers at HV. Measurements show that stable multiple charged molecular ions of proteins are formed under all pressure conditions indicating softer ionization than MALDI, which suffers a high degree of metastable fragmentation when multiply charged ions are produced. An important analytical advantage of this new LSI matrix are the potential for high sensitivity equivalent or better than AP-LSI and vacuum MALDI and the potential for enhanced mass selected fragmentation of the abundant highly charged protein ions. A second new LSI matrix, 4,6-dinitropyrogallol, produces abundant multiply charged ions at AP but not under HV conditions. The differences in these similar compounds ability to produce multiply charged ions under HV conditions is believed to be related to their relative ability to evaporate from charged matrix/analyte clusters. PMID- 21678940 TI - Double-electrochromic coordination polymer network films. AB - Formation and characteristic properties of organized double-electrochromic films consisting of electrochromic poly(4-(2,2':6,2"-terpyridyl)phenyliminofluorene) (P 1)-zinc ion complexes and electrochromic anions are reported. The anions are 2,2' azino-bis(3-ethylbenzo-thiazoline-6-sulfonate) (ABTS) and poly((4 sulfonatophenyl)iminofluorene) (P-2). The films were prepared upon multiple sequential adsorption of P-1 and the zinc salts of ABTS and P-2 on solid supports using coordinative interactions between the Zn ions and the terpyridine (tpy) ligands. The ABTS and P-2 ions are incorporated in the films via electrostatic forces neutralizing the charge of the complexed divalent zinc (Zn(2+)) ions. The optical, electrochemical, and electrochromic properties of the films are described. Films consisting of the Zn ion complex of P-1 and ABTS are yellow in the neutral state and change their color to brownish gray and finally blue, if anodically oxidized at ~640 mV vs FOC. Films containing the Zn ion complex of P 1, with P-2 as a counterion, are yellow in the neutral state and change color to dark red and finally blue, if anodically oxidized at ~450 mV vs FOC. Compared with previously reported films of the Zn ion complex of P-1 with nonelectroactive hexafluorophosphate as the counterion, the new films exhibit faster response times, as well as higher contrast, and the colors in the oxidized state are modified. The films are stable under ambient conditions and might be useful as active layers in electrochromic devices. PMID- 21678941 TI - Accurate determination of plasmonic fields in molecular junctions by current rectification at optical frequencies. AB - Current rectification, i.e., induction of dc current by oscillating electromagnetic fields, is demonstrated in molecular junctions at an optical frequency. The magnitude of rectification is used to accurately determine the effective oscillating potentials in the junctions induced by the irradiating laser. Since the gap size of the junctions used in this study is precisely determined by the length of the embedded molecules, the oscillating potential can be used to calculate the plasmonic enhancement of the electromagnetic field in the junctions. With a set of junctions based on alkyl thiolated molecules with identical HOMO-LUMO gap and different lengths, an exponential dependence of the plasmonic field enhancement on gap size is observed. PMID- 21678942 TI - Copper-catalyzed aerobic oxidation of hydroxamic acids leads to a mild and versatile acylnitroso ene reaction. AB - A mild formation of transient acylnitroso intermediates using a copper chloride catalyst and 1 atm of air as the terminal oxidant is described. The mild reaction conditions enable the inter- and intramolecular acylnitroso ene reaction with a wide range of functionalized alkene partners, as well as the first asymmetric variant. Notably, this transformation provides a practical and operationally simple method for effecting allylic amidation using an environmentally benign oxidant and a readily abundant transition metal. PMID- 21678944 TI - Protein-induced excited-state dynamics of protochlorophyllide. AB - The light-driven NADPH:protochlorophyllide oxidoreductase (POR) is a key enzyme of chlorophyll biosynthesis in angiosperms. POR's unique requirement for light to become catalytically active makes the enzyme an attractive model to study the dynamics of enzymatic reactions in real time. Here, we use picosecond time resolved fluorescence and femtosecond pump-probe spectroscopy to examine the influence of the protein environment on the excited-state dynamics of the substrate, protochlorophyllide (PChlide), in the enzyme/substrate (PChlide/POR) and pseudoternary complex including the nucleotide cofactor NADP(+) (PChlide/NADP(+)/ POR). In comparison with the excited-state processes of unbound PChlide, the lifetime of the thermally equilibrated S(1) excited state is lengthened from 3.4 to 4.4 and 5.4 ns in the PChlide/POR and PChlide/NADP(+)/POR complex, whereas the nonradiative rates are decreased by ~30 and 40%, respectively. This effect is most likely due to the reduced probability of nonradiative decay into the triplet excited state, thus keeping the risk of photosensitized side reactions in the enzyme low. Further, the initial reaction path involves the formation of an intramolecular charge-transfer state (S(ICT)) as an intermediate product. From a strong blue shift in the excited-state absorption, it is concluded that the S(ICT) state is stabilized by local interactions with specific protein sites in the catalytic pocket. The possible relevance of this result for the catalytic reaction in the enzyme POR is discussed. PMID- 21678945 TI - Structures and stabilities of Fe2+/3+ complexes relevant to Alzheimer's disease: an ab initio study. AB - Iron is one of the most abundant metals found in senile plaques of post mortem patients with Alzheimer's disease. However, the interaction mode between iron ions and beta-amyloid peptide as well as their precise affinity is unknown. In this study we apply ab initio computational methodology to calculate binding energies of Fe(2+/3+) with the His13-His14 sequence of Abeta, as well as other important ligands such as His6 and Tyr10. Calculations were carried out at the "MP2/6-311+G(2df,2p)"//B3LYP/6-31+G(d) level of theory and solvent effects included by the IEFPCM procedure. Several reaction paths for the binding of imidazole, phenol, and the His13-His14 fragment (modeled by N-(2-(1H-imidazol-4 yl)ethyl)-3-(1H-imidazol-4-yl)propanamide) were sequentially explored. The results show that the most stable complexes containing His13-His14 and phenolate of Tyr10 are the pentacoordinated [Fe(2+)(O-HisHis)(PhO(-))(H(2)O)](+) and [Fe(3+)(N-HisHis)(PhO(-))(H(2)O)](+) compounds and that simultaneous coordination of tyrosine and His13-His14 to Fe(2+/3+) is thermodynamically favorable in water at physiological pH. Computed Raman spectra confirm the conclusion obtained by Miura et al. ( Biochemistry 2000 , 39 , 7024 ) that tyrosine is coordinated to Fe(3+) but do not exclude coordination of imidazoles. Finally, calculations of standard reduction potentials indicate that phenol coordination reduces the redox activity of the iron/Abeta complexes. PMID- 21678946 TI - Density functional analysis of geometries and electronic structures of gold phosphine clusters. The case of Au4(PR3)42+ and A(u4MU2-I)2(PR3)4. AB - Geometries, ligand binding energies, electronic structure, and excitation spectra are determined for Au(4)(PR(3))(4)(2+) and Au(4)(MU(2)-I)(2)(PR(3))(4) clusters (R = PH(3), PMe(3), and PPh(3)). Density functionals including SVWN5, Xalpha, OPBE, LC-omegaPBE, TPSS, PBE0, CAM-B3LYP, and SAOP are employed with basis sets ranging from LANL2DZ to SDD to TZVP. Metal--metal and metal--ligand bond distances are calculated and compared with experiment. The effect of changing the phosphine ligands is assessed for geometries and excitation spectra. Standard DFT and hybrid ONIOM calculations are employed for geometry optimizations with PPh(3) groups. The electronic structure of the gold--phosphine clusters examined in this work is analyzed in terms of cluster ("superatom") orbitals and d-band orbitals. Transitions out of the d band are significant in the excitation spectra. The use of different basis sets and DFT functionals leads to noticeable variations in the relative intensities of strong transitions, although the overall spectral profile remains qualitatively unchanged. The replacement of PMe(3) with PPh(3) changes the nature of the electronic transitions in the cluster due to low-lying pi* orbitals. To reproduce the experimental geometries of clusters with PPh(3) ligands, computationally less expensive PH(3) or PMe(3) ligands are sufficient for geometry optimizations. However, to predict cluster excitation spectra, the full PPh(3) ligand must be considered. PMID- 21678947 TI - Synthetic application and structural elucidation of axially chiral dicarboxylic acid: asymmetric Mannich-type reaction with diazoacetate, (diazomethyl)phosphonate, and (diazomethyl)sulfone. AB - The past decade has witnessed the burgeoning research fields of chiral Bronsted acid catalysis. However, carboxylic acids, arguably the most general acids in organic chemistry, have rarely been used as chiral Bronsted acid catalysts. In this context, we developed axially chiral dicarboxylic acid and evaluated its catalytic activity in asymmetric Mannich-type reaction of aromatic aldehyde derived N-Boc imines and tert-butyl diazoacetate. To demonstrate the remarkable generality of this catalytic system, tert-butyl diazoacetate was replaced with its phosphorus and sulfur analogues, (diazomethyl)phosphonate and (diazomethyl)sulfone, by which synthetically valuable chiral beta-amino phosphonates and beta-amino sulfones could be obtained with high enantioselectivities under identical reaction conditions. X-ray crystallographic analysis of axially chiral dicarboxylic acid complexed with a pyridine derivative revealed its unique internal hydrogen bonding, a property that serves as a basis for its distinctive acidity and chiral scaffold. PMID- 21678948 TI - Proton NMR relaxometry study of Nafion membranes modified with ionic liquid cations. AB - Proton nuclear magnetic resonance (NMR) relaxometry was used to study the ionic mobility and levels of confinement within Nafion membranes modified by incorporation of selected ionic liquid (IL) cations. These studies were performed aiming at understanding the effect of using different types of ionic liquid cations, and their degree of incorporation, in the values of the spin-lattice relaxation times (T(1)) obtained at different values of frequency and thus detect the influence of confinement level on the ions mobility. The frequency dependence of the proton spin-lattice relaxation rate, R(1) = 1/T(1), for the modified Nafion/IL cation membranes was compared with that obtained for an unmodified Nafion membrane, allowing for distinguishing different contributions of the motions of the molecules depending on the frequency tested. The experimental R(1) results were analyzed in terms of models that consider the sum of the most effective relaxation contributions, to estimate the translational self-diffusion coefficient of the moving molecular species in the modified membranes. The stability of these membranes with temperature in terms of the spin-lattice relaxation was compared with results obtained by thermogravimetric analysis. PMID- 21678950 TI - Effect of graphene Fermi level on the Raman scattering intensity of molecules on graphene. AB - We studied the modulation of Raman scattering intensities of molecules on graphene by tuning the graphene Fermi level with electrical field effect (EFE). A series of metal phthalocyanine (M-Pc) molecules (M = Mn, Fe, Co, Ni, Cu, Zn), which have different molecular energy levels, were used as probe molecules. The Raman intensities of all these M-Pc molecules become weaker when the graphene Fermi level is up-shifted by applying a positive gate voltage, while they become stronger when the graphene Fermi level is down-shifted by applying a negative gate voltage. However, this Raman intensity modulation only occurs when applying the gate voltage with a fast sweep rate, while it is nearly absent when applying the gate voltage with a slow sweep rate, which is likely due to the arising of the hysteresis effect in the graphene EFE. In addition, the Raman modulation ability for M-Pc molecules with smaller energy gaps is larger than that with larger energy gaps due to the difference in the energy alignment between graphene and these M-Pc molecules. Furthermore, this modulation shows the greatest one on single-layer graphene and mainly comes from the first layer of molecules which are in direct contact with graphene. The Raman modulation of molecules in GERS with the EFE suggests that the Raman enhancement for GERS occurs through a chemical enhancement mechanism. PMID- 21678949 TI - Probing autoinducer-2 based quorum sensing: the biological consequences of molecules unable to traverse equilibrium states. AB - Bacteria have developed a cell-to-cell communication system, termed quorum sensing (QS), which allows for the population-dependent coordination of their behavior via the exchange of chemical signals. Autoinducer-2 (AI-2), a class of QS signals derived from 4,5-dihydroxy-2,3-pentandione (DPD), has been revealed as a universal signaling molecule in a variety of bacterial species. In spite of considerable interest, the study of putative AI-2 based QS systems remains a challenging topic in part due to the rapid interconversion between the linear and cyclic forms of DPD. Herein, we report the design and development of efficient syntheses of carbocyclic analogues of DPD, which are locked in the cyclic form. The synthetic analogues were evaluated for the modulation of AI-2-based QS in Vibrio harveyi and Salmonella typhimurium. No agonists were uncovered in either V. harveyi or S. typhimurium assay, whereas weak to moderate antagonists were found against V. harveyi. On the basis of NMR analyses and DFT calculations, the heterocyclic oxygen atom within DPD appears necessary to promote hydration at the C3 position of cyclic DPD to afford the active tetrahydroxy species. These results also shed light on the interaction between the heterocyclic oxygen atom and receptor proteins as well as the importance of the linear form and dynamic equilibrium of DPD as crucial requirements for activation of AI-2 based QS circuits. PMID- 21678951 TI - Polymer-modified Fe0 nanoparticles target entrapped NAPL in two dimensional porous media: effect of particle concentration, NAPL saturation, and injection strategy. AB - Polymer-modified nanoscale zerovalent iron (NZVI) particles are delivered into porous media for in situ remediation of nonaqueous phase liquid (NAPL) source zones. A systematic and quantitative evaluation of NAPL targeting by polymer modified NZVI in two-dimensional (2-D) porous media under field-relevant conditions has not been reported. This work evaluated the importance of NZVI particle concentration, NAPL saturation, and injection strategy on the ability of polymer-modified NZVI (MRNIP2) to target the NAPL/water interface in situ in a 2 D porous media model. Dodecane was used as a NAPL model compound for this first demonstration of source zone targeting in 2-D. A driving force for NAPL targeting, the surface activity of MRNIP2 at the NAPL/water interface was verified ex situ by its ability to emulsify NAPL in water. MRNIP2 at low particle concentration (0.5 g/L) did not accumulate in or near entrapped NAPL, however, MRNIP2 at moderate and high particle concentrations (3 and 15 g/L) did accumulate preferentially at entrapped NAPL, i.e., it was capable of in situ targeting. The amount of MRNIP2 that targets a NAPL source depends on NAPL saturation (S(n)), presumably because the saturation controls the available NAPL/water interfacial area and the flow field through the NAPL source. At effective S(n) close or equal to 100%, MRNIP2 bypassed NAPL and accumulated only at the periphery of the entrapped NAPL region. At lower S(n), flow also carries MRNIP2 to NAPL/water interfaces internal to the entrapped NAPL region. However, the mass of accumulated MRNIP2 per unit available NAPL/water interfacial area is relatively constant (~0.8 g/m(2) for MRNIP2 = 3 g/L) from S(n) = 13 to ~100%, suggesting that NAPL targeting is mostly controlled by MRNIP2 sorption onto the NAPL/water interface. PMID- 21678952 TI - Access to antigens related to anthrose using pivotal cyclic sulfite/sulfate intermediates. AB - Anthrose is the upstream terminal unit of the tetrasaccharide side chain from a major glycoprotein of Bacillus anthracis exosporium and is part of important antigenic determinants. A novel entry to anthrose-containing antigens and precursors is described. The synthetic route, starting from D(+)-fucose, makes use of intermediates featuring a cyclic sulfite or sulfate function which serves successively as a protecting and a leaving group. PMID- 21678953 TI - Bulky, optically active P-stereogenic phosphine-boranes from pure H menthylphosphinates. AB - The transformation of readily available pure-H-menthylphosphinates into chiral phosphinous acid-boranes permits the elaboration of bulky P-stereogenic secondary phosphine-boranes. Taking advantage of the synthetic potential of these compounds, a broad range of hindered P-chiral tertiary phosphine-boranes has been prepared with excellent enantiomeric excesses. The utility of bulky o tolylphosphines was illustrated by the synthesis of a rare enantiopure phosphapalladacycle (S(P),S(P))-12. PMID- 21678955 TI - Room temperature dehydrogenation of ethane to ethylene. AB - The transient titanium alkylidyne, (PNP)Ti=C(t)Bu (PNP = N[2-P(i)Pr(2)-4 methylphenyl](2)(-)), activates a C-H bond of ethane at room temperature, and a beta-hydrogen of the resulting ethyl ligand is subsequently transferred to the adjacent alkylidene ligand to form an ethylene adduct of titanium. Treatment of the ethylene complex with two-electron oxidants such as organic azides results in extrusion of ethene concomitant with formation of a mononuclear titanium imido complex. PMID- 21678956 TI - Fouling of nanofiltration, reverse osmosis, and ultrafiltration membranes by protein mixtures: the role of inter-foulant-species interaction. AB - Protein fouling of nanofiltration (NF), reverse osmosis (RO), and ultrafiltration (UF) membranes by bovine serum albumin (BSA), lysozyme (LYS), and their mixture was investigated under cross-flow conditions. The effect of solution chemistry, membrane properties, and permeate flux level was systematically studied. When the solution pH was within the isoelectric points (IEPs) of the two proteins (i.e., pH 4.7-10.4), the mixed protein system experienced more severe flux decline compared to the respective single protein systems, which may be attributed to the electrostatic attraction between the negatively charged BSA and positively charged LYS molecules. Unlike a typical single protein system, membrane fouling by BSA-LYS mixture was only weakly dependent on solution pH within this pH range, and increased ionic strength was found to enhance the membrane flux as a result of the suppressed BSA-LYS electrostatic attraction. Membrane fouling was likely controlled by foulant-fouled-membrane interaction under severe fouling conditions (elevated flux level and unfavorable solution chemistry that promotes fouling), whereas it was likely dominated by foulant-clean-membrane interaction under mild fouling conditions. Compared to nonporous NF and RO membranes, the porous UF membrane was more susceptible to dramatic flux decline due to the increased risk of membrane pore plugging. This study reveals that membrane fouling by mixed macromolecules may behave very differently from that by typical single foulant system, especially when the inter-foulant-species interaction dominates over the intra-species interaction in the mixed foulant system. PMID- 21678954 TI - Efficient incorporation of protein flexibility and dynamics into molecular docking simulations. AB - Flexibility and dynamics are protein characteristics that are essential for the process of molecular recognition. Conformational changes in the protein that are coupled to ligand binding are described by the biophysical models of induced fit and conformational selection. Different concepts that incorporate protein flexibility into protein-ligand docking within the context of these two models are reviewed. Several computational studies that discuss the validity and possible limitations of such approaches will be presented. Finally, different approaches that incorporate protein dynamics, e.g., configurational entropy, and solvation effects into docking will be highlighted. PMID- 21678957 TI - Highly hydrophilic surfaces from polyglycidol grafts with dual antifouling and specific protein recognition properties. AB - Homopolymer grafts from alpha-tert-butoxy-omega-vinylbenzyl-polyglycidol (PGL) were prepared on gold and stainless steel (SS) substrates modified by 4-benzoyl phenyl (BP) moieties derived from the electroreduction of the parent salt 4 benzoyl benzene diazonium tetrafluoroborate. The grafted BP aryl groups efficiently served to surface-initiate photopolymerization (SIPP) of PGL. In similar conditions, SIPP of hydroxyethyl methacrylate (HEMA) permitted the production of PHEMA grafts as model surfaces. Water contact angles were found to be 66 degrees , 15 degrees , and 0 degrees for SS-BP, SS-PHEMA, and SS-PPGL, respectively. The spontaneous spreading of water drops on SS-PPGL was invariably observed with 1.5 MUL water drops. PPGL thus appears as a superhydrophilic polymer. Resistance to nonspecific adsorption of proteins of PPGL and PHEMA grafts on gold was evaluated by surface plasmon resonance (SPR) using antibovine serum albumin (anti-BSA). The results conclusively show that PPGL-grafts exhibit enhanced resistance to anti-BSA adsorption compared to the well-known hydrophilic PHEMA. PPGL grafts were further modified with BSA through the carbonyldiimidazole activation of the OH groups providing immunosensing surfaces. The so-prepared PPGL-grafted BSA hybrids specifically interacted with anti-BSA in PBS as compared to antimyoglobin. It is clear that the superhydrophilic character of PPGL grafts opens new avenues for biomedical applications where surfaces with dual functionality, namely, specific protein grafting together with resistance to biofouling, are required. PMID- 21678958 TI - Oxidative cycloaddition of 1,1,3,3-tetramethyldisiloxane to alkynes catalyzed by supported gold nanoparticles. AB - Gold nanoparticles supported on TiO(2) (0.1-1% mol) catalyze at room temperature and at extremely mild conditions the unprecedented oxidative cycloaddition of 1,1,3,3-tetramethyldisiloxane to alkynes, forming substituted 2,5-dihydro-1,2,5 oxadisiloles, with concomitant evolution of hydrogen gas. For the majority of the substrates, the yields are exceptional (up to 99%). The reaction proceeds at room temperature, tolerates a variety of functional groups, and can be performed in several solvents. PMID- 21678959 TI - Chemiluminescent and chemiluminescence resonance energy transfer (CRET) detection of DNA, metal ions, and aptamer-substrate complexes using hemin/G-quadruplexes and CdSe/ZnS quantum dots. AB - Nucleic acid subunits consisting of fragments of the horseradish peroxidase (HRP) mimicking DNAzyme and aptamer domains against ATP or sequences recognizing Hg(2+) ions self-assemble, in the presence of ATP or Hg(2+), into the active hemin-G quadruplex DNAzyme structure. The DNAzyme-generated chemiluminescence provides the optical readout for the sensing events. In addition, the DNAzyme-stimulated chemiluminescence resonance energy transfer (CRET) to CdSe/ZnS quantum dots (QDs) is implemented to develop aptamer or DNA sensing platforms. The self-assembly of the ATP-aptamer subunits/hemin-G-quadruplex DNAzyme, where one of the aptamer subunits is functionalized with CdSe/ZnS QDs, leads to the CRET signal. Also, the functionalization of QDs with a hairpin nucleic acid that includes the G quadruplex sequence in a ''caged'' configuration is used to analyze DNA. The opening of the hairpin structure by the target DNA assembles the hemin-G quadruplex DNAzyme that stimulates the CRET signal. By the application of three different sized QDs functionalized with different hairpins, the multiplexed analysis of three different DNA targets is demonstrated by the generation of three different CRET luminescence signals. PMID- 21678960 TI - Crystal structures of antibiotic-bound complexes of aminoglycoside 2'' phosphotransferase IVa highlight the diversity in substrate binding modes among aminoglycoside kinases. AB - Aminoglycoside 2''-phosphotransferase IVa [APH(2'')-IVa] is a member of a family of bacterial enzymes responsible for medically relevant resistance to antibiotics. APH(2'')-IVa confers high-level resistance against several clinically used aminoglycoside antibiotics in various pathogenic Enterococcus species by phosphorylating the drug, thereby preventing it from binding to its ribosomal target and producing a bactericidal effect. We describe here three crystal structures of APH(2'')-IVa, one in its apo form and two in complex with a bound antibiotic, tobramycin and kanamycin A. The apo structure was refined to a resolution of 2.05 A, and the APH(2'')-IVa structures with tobramycin and kanamycin A bound were refined to resolutions of 1.80 and 2.15 A, respectively. Comparison among the structures provides insight concerning the substrate selectivity of this enzyme. In particular, conformational changes upon substrate binding, involving rotational shifts of two distinct segments of the enzyme, are observed. These substrate-induced shifts may also rationalize the altered substrate preference of APH(2'')-IVa in comparison to those of other members of the APH(2'') subfamily, which are structurally closely related. Finally, analysis of the interactions between the enzyme and aminoglycoside reveals a distinct binding mode as compared to the intended ribosomal target. The differences in the pattern of interactions can be utilized as a structural basis for the development of improved aminoglycosides that are not susceptible to these resistance factors. PMID- 21678961 TI - Examination of surface adsorption of cetyltrimethylammonium bromide and sodium dodecyl sulfate. AB - Several pieces of experimental evidence of condensation of soluble surfactant molecules, cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS), into the air/water surface region from the bulk solution are presented at different added salt concentrations in order to substantiate that the concentrated molecules do not locate just at the air/solution interface. The insoluble monolayer just at the air/subphase interface for the two surfactants could be studied by surface pressure (pi) versus molecular surface area (A), surface potential (DeltaV) versus the area (A), infrared absorption of the surface region, and BAM (Brewster angle microscope) image. From surface tension versus concentration curves for the two surfactant solutions, the apparent molecular surface area and the cmc values were determined at different added salt concentrations, and the degree of counterion binding to micelle was found to be 0.70 and 0.73 for CTAB and SDS, respectively. Further examination was made on infrared absorption from the surface region of the surfactant solutions and on BAM images of the surface planes in order to examine the difference between the insoluble monolayer and the condensation in the surface region. Finally, the new concept of bilayer or bilamellar aggregate for soluble surfactant solutions is presented together with the former experimental evidence, which is consistent with several interfacial phenomena of the surfactant solutions. PMID- 21678962 TI - Nanopatterning by molecular polygons. AB - Molecular polygons with three to six sides and binary mixtures thereof form long range ordered patterns at the TCB/HOPG interface. This includes also the 2D crystallization of pentagons. The results provide an insight into how the symmetry of molecules is translated into periodic structures. PMID- 21678963 TI - Graphene nanoribbons from unzipped carbon nanotubes: atomic structures, Raman spectroscopy, and electrical properties. AB - We investigated the atomic structures, Raman spectroscopic and electrical transport properties of individual graphene nanoribbons (GNRs, widths ~10-30 nm) derived from sonochemical unzipping of multiwalled carbon nanotubes (MWNTs). Aberration-corrected transmission electron microscopy (TEM) revealed a high percentage of two-layer (2 L) GNRs and some single-layer ribbons. The layer-layer stacking angles ranged from 0 degrees to 30 degrees including average chiral angles near 30 degrees (armchair orientation) or 0 degrees (zigzag orientation). A large fraction of GNRs with bent and smooth edges was observed, while the rest showed flat and less smooth edges (roughness <=1 nm). Polarized Raman spectroscopy probed individual GNRs to reveal D/G ratios and ratios of D band intensities at parallel and perpendicular laser excitation polarization (D(?)/D(?)). The observed spectroscopic trends were used to infer the average chiral angles and edge smoothness of GNRs. Electrical transport and Raman measurements were carried out for individual ribbons to correlate spectroscopic and electrical properties of GNRs. PMID- 21678964 TI - Intra- and intermolecular interactions in the crystals of 3,4-diamino-1,2,4 triazole and its 5-methyl derivative. Experimental and theoretical investigations of charge density distribution. AB - In this paper intra- and intermolecular interactions in crystals of 3,4-diamino 1,2,4-triazole (DAT) and its 5-methyl derivative (DAMT) were investigated in details by experimental (high-resolution X-ray diffraction) and theoretical (ab initio quantum chemistry (MP2/aug-cc-pvdz), AIM, and NBO) methods. Influence of n pi conjugation and n->sigma* hyperconjugation on the geometry of DAT and DAMT molecules was shown. All intermolecular interactions in crystals of the DAT and DAMT including weak X-H...pi and mixed X-H...N/X-H...pi hydrogen bonds were considered. Comparison of BCP characteristics of these interactions from experimental and theoretical charge density distribution demonstrates systematic increase of bonding in isolated dimers compared with dimers in the crystal phase. The ability of amino groups in both crystals serve as proton acceptors in hydrogen bonding was confirmed. PMID- 21678965 TI - Calculation of configurational entropy with a Boltzmann-quasiharmonic model: the origin of high-affinity protein-ligand binding. AB - Accurate assessment of configurational entropy remains a large challenge in biology. While many methods exist to calculate configurational entropy, there is a balance between accuracy and computational demands. Here we calculate ligand and protein conformational entropies using the Boltzmann-quasiharmonic (BQH) method, which treats the first-order entropy term by the Boltzmann expression for entropy while determining correlations using the quasiharmonic model. This method is tested by comparison with the exact Clausius expression for entropy on a range of test molecules ranging from small ligands to a protein. Using the BQH method, we then analyze the rotational and translational (R/T) entropy change upon ligand binding for five protein complexes to explore the origins of extremely tight affinity. The results suggest that in these systems such affinity is achieved by a combination of simultaneously maintaining good protein-ligand contacts while allowing significant residual R/T motion of the ligand through suitable protein motions. PMID- 21678966 TI - Systematic investigation of the catalytic cycle of a single site ruthenium oxygen evolving complex using density functional theory. AB - The mechanism of water oxidation by a single site ruthenium oxygen evolving complex is investigated using fully unrestricted pseudospectral B3LYP with the effective core potential LACV3P in continuum solvent with some quantum mechanical waters. Guess wave functions have been used that allow greater flexibility in sampling different electronic configurations of the complex. Systematic comparison with experiment is improved using these guesses because they provide a complete analysis of the low energy manifold and help to alleviate the formal disconnect between theory and experiment in assigning Lewis structures for transition metal complexes. In agreement with results from the literature, the challenging 4e(-)and 4H(+) oxidation of water is accomplished using a mechanism that features three proton coupled electron transfers, one electron transfer, one atom proton transfer (APT), and one ligand exchange (LE). Calculations on a large database of ruthenium complexes allows us to benchmark the computation of reduction half potentials and free energies of activation and to investigate systematic ligand variations and their effect on the reaction mechanism. Mean unsigned errors of reduction half potentials in comparison to experiment are generally small (100-200 mV). The APT and LE steps are found to be rate limiting with free energy barriers of 19.27 and 19.53 kcal/mol respectively, which is in excellent agreement with the ~20 kcal/mol barrier obtained from experimental rate constants using classical transition state theory. PMID- 21678967 TI - Ab initio study of the decomposition of 2,5-dimethylfuran. AB - The initial steps in the thermal decomposition of 2,5-dimethylfuran are identified as scission of the C-H bond in the methyl side chain and formation of beta- and alpha-carbenes via 3,2-H and 2,3-methyl shifts, respectively. A variety of channels are explored which prise the aromatic ring open and lead to a number of intermediates whose basic properties are essentially unknown. Once the furan ring is opened demethylation to yield highly unsaturated species such as allenylketenes appears to be a feature of this chemistry. The energetics of H abstraction by the hydroxyl radical (and other abstracting species) from a number of mono- and disubstituted methyl furans has been studied. H-atom addition to 2,5 dimethylfuran followed by methyl elimination is shown to be the most important route to formation of the less reactive 2-methylfuran. Identification of 2 ethenylfuran as an C(6)H(6)O intermediate in 2,5-dimethylfuran flames is probably not correct and is more likely the isomeric 2,5-dimethylene-2,5-dihydrofuran for which credible formation channels exist. PMID- 21678968 TI - Computational study of the deamination of 8-oxoguanine. AB - Oxidation of guanine in DNA yields the nucleobase damage product 8-oxoguanine (8 oxoG), whose further oxidation gives other more stable products. In the present study, the mechanism for the deamination of 8-oxoG with H(2)O, 2H(2)O, H(2)O/OH( ), and 2H(2)O/OH(-) and for protonated 8-oxoG (8-oxoGH(+)) with H(2)O has been investigated using ab initio calculations. All structures were optimized at RHF/6 31G(d), MP2/6-31G(d), and B3LYP with the 6-31G(d), 6-31+G(d), 6-31G(d,p), 6 31+G(d,p), and 6-31++G(d.p) basis sets. Energies were determined at the G3MP2 level of theory, and solvent calculations were performed using both the polarizable continuum model (PCM) and the solvation model on density (SMD). Intrinsic reaction coordinate calculations were performed to characterize the transition states on the potential energy surface. Thermodynamic properties (DeltaE, DeltaH, and DeltaG), activation energies, enthalpies, and Gibbs free energies of activation were also calculated for each reaction investigated. All pathways yield an initial tetrahedral intermediate and, in the final step, an intermediate that dissociates to products via a 1,3-proton shift. At the G3MP2 level of theory, deamination with H(2)O/OH(-) was found to have an overall activation energy of 187, 176, and 156 kJ mol(-1) for the gas phase, PCM, and SMD, respectively, which are ~50 kJ mol(-1) lower than with H(2)O only. These barriers can be compared to those for the reaction of 8-oxoGH(+) with H(2)O of 248 kJ mol(-1) in the gas phase and 238 kJ mol(-1) in aqueous solution (PCM). The lowest overall activation energies (G3MP2) are for the deamination of 8-oxoG with 2H(2)O/OH(-), 134 kJ mol(-1) in the gas phase and 129 kJ mol(-1) with PCM. PMID- 21678969 TI - Fabrication and placement of a ring structure of nanoparticles by a laser-induced micronanobubble on a gold surface. AB - We have developed a new fabrication method for a ring structure of assembled nanoparticles on a gold surface by the use of continuous Nd:YAG laser light. A micronanobubble on a gold surface, created by laser local heating, acts as a template for the formation of the ring structure. Both Marangoni convection flow and capillary flow around the micronanobubble are responsible for the driving force to assemble nanoparticles such as CdSe Q-dots into the ring structure from the solution. Because a single micronanobubble was generated by the Nd:YAG laser focusing point, the precise positioning of the ring structure was feasible directly on the gold surface, which makes it possible to fabricate various patterns of rings such as arrays and letters and even a double-ring structure without any photomasks or any templates. PMID- 21678970 TI - A circumventing role for the non-native intermediate in the folding of beta lactoglobulin. AB - Folding experiments have suggested that some proteins have kinetic intermediates with a non-native structure. A simple G o model does not explain such non-native intermediates. Therefore, the folding energy landscape of proteins with non native intermediates should have characteristic properties. To identify such properties, we investigated the folding of bovine beta-lactoglobulin (betaLG). This protein has an intermediate with a non-native alpha-helical structure, although its native form is predominantly composed of beta-structure. In this study, we prepared mutants whose alpha-helical and beta-sheet propensities are modified and observed their folding using a stopped-flow circular dichroism apparatus. One interesting finding was that E44L, whose beta-sheet propensity was increased, showed a folding intermediate with an amount of beta-structure similar to that of the wild type, though its folding took longer. Thus, the intermediate seems to be a trapped intermediate. The high alpha-helical propensity of the wild type sequence likely causes the folding pathway to circumvent such time-consuming intermediates. We propose that the role of the non-native intermediate is to control the pathway at the beginning of the folding reaction. PMID- 21678971 TI - Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3). AB - We describe a novel method of drug discovery using MLSD and drug repositioning, with cancer target STAT3 being used as a test case. Multiple drug scaffolds were simultaneously docked into hot spots of STAT3 by MLSD, followed by tethering to generate virtual template compounds. Similarity search of virtual hits on drug database identified celecoxib as a novel inhibitor of STAT3. Furthermore, we designed two novel lead inhibitors based on one of the lead templates and celecoxib. PMID- 21678972 TI - Experimental and computational thermochemical study of N-benzylalanines. AB - Calorimetric measurements are expected to provide useful data regarding the relative stability of alpha- versus beta-amino acid isomers, which, in turn, may help us to understand why nature chose alpha- instead of beta-amino acids for the formation of the biomolecules that are essential constituents of life on earth. The present study is a combination of the experimental determination of the enthalpy of formation of N-benzyl-beta-alanine, and high-level ab initio calculations of its molecular structure. The experimentally determined standard molar enthalpy of formation of N-benzyl-beta-alanine in gaseous phase at T = 298.15 K is -(298.8 +/- 4.8) kJ.mol(-1), whereas its G3(MP2)//B3LYP-calculated enthalpy of formation is -303.7 kJ.mol(-1). This value is in very good agreement with the experimental one. Although the combustion experiments of N-benzyl-alpha alanine were unsuccessful, its calculated enthalpy of formation is -310.7 kJ.mol( 1); thus, comparison with the corresponding experimental enthalpy of formation of N-benzyl-beta-alanine, -(298.8 +/- 4.8) kJ/mol, is in line with the concept that the more branched amino acid (alpha-alanine) is intrinsically more stable than the linear beta-amino acid, beta-alanine. PMID- 21678973 TI - Nanospheres of a new intermetallic FeSn5 phase: synthesis, magnetic properties and anode performance in Li-ion batteries. AB - We synthesized monodisperse nanospheres of an intermetallic FeSn(5) phase via a nanocrystal-conversion protocol using preformed Sn nanospheres as templates. This tetragonal phase in P4/mcc space group, along with the defect structure Fe(0.74)Sn(5) of our nanospheres, has been resolved by synchrotron X-ray diffraction and Rietveld refinement. Importantly, FeSn(5), which is not yet established in the Fe-Sn phase diagram, exhibits a quasi-one dimensional crystal structure along the c-axis, thus leading to interesting anisotropic thermal expansion and magnetic properties. Magnetization measurements indicate that nanospheres are superparamagnetic above the blocking temperature T(B) = 300 K, which is associated with the higher magnetocrystalline anisotropy constant K = 3.33 kJ m(-3). The combination of the magnetization measurements and first principles density functional theory calculations reveals the canted antiferromagnetic nature with significant spin fluctuation in lattice a-b plane. The low Fe concentration also leads Fe(0.74)Sn(5) to enhanced capacity as an anode in Li ion batteries. PMID- 21678974 TI - Ionization-enhanced decomposition of 2,4,6-trinitrotoluene (TNT) molecules. AB - The unimolecular decomposition reaction of TNT can in principle be used to design ways to either detect or remove TNT from the environment. Here, we report the results of a density functional theory study of possible ways to lower the reaction barrier for this decomposition process by ionization, so that decomposition and/or detection can occur at room temperature. We find that ionizing TNT lowers the reaction barrier for the initial step of this decomposition. We further show that a similar effect can occur if a positive moiety is bound to the TNT molecule. The positive charge produces a pronounced electron redistribution and dipole formation in TNT with minimal charge transfer from TNT to the positive moiety. PMID- 21678975 TI - Characterization of morphine-glucose-6-phosphate dehydrogenase conjugates by mass spectrometry. AB - A key characteristic of the analyte-reporter enzyme conjugate used in the enzyme multiplied immunoassay technique (EMIT) is the inhibition of the conjugate enzyme upon anti-analyte antibody binding. To improve our understanding of the antibody induced inhibition mechanism, we characterized morphine-glucose-6-phosphate dehydrogenase (G6PDH) conjugates as model EMIT analyte-reporter enzyme conjugates. Morphine-G6PDH conjugates were prepared by acylating predominantly the primary amines on G6PDH with morphine 3-glucuronide NHS ester molecules. In this study, morphine-G6PDH conjugates were characterized using a combination of methods, including tryptic digestion, immunoprecipitation, matrix-assisted laser desorption ionization mass spectrometry, and electrospray ionization tandem mass spectrometry. Twenty-six conjugation sites were identified. The identified sites all were found to be primary amines. The degree of conjugation was determined to be less than the number of conjugation sites, suggesting heterogeneity within the morphine-G6PDH conjugate population. Two catalytically important residues in the active site (K22 and K183) were among the identified conjugation sites, explaining at least partially the cause of loss of activity due to the coupling reaction. PMID- 21678976 TI - Catalytic enantioselective protonation of enol trifluoroacetates by means of hydrogenocarbonates and cinchona alkaloids. AB - Herein is disclosed an efficient catalytic enantioselective protonation of enol acetates by means of a readily implementable transition-metal-free chemical process. By making use of simple hygrogenocarbonates as the proton source and hydroquinine anthraquinone-1,4-diyl diether as the chiral proton shuttle, a series of cyclic enol trifluoroacetates are protonated under mild conditions to yield the corresponding ketones in up to 93% ee. PMID- 21678977 TI - Real time evolution of liquid crystalline nanostructure during the digestion of formulation lipids using synchrotron small-angle X-ray scattering. AB - The role of the digestion of lipids in facilitating absorption of poorly water soluble compounds, such as vitamins, is not only an important nutritional issue but is increasingly being recognized as an important determinant in the effectiveness of lipid-based drug formulations. It has been known for some time that lipids often form complex liquid crystalline structures during digestion and that this may impact drug solubilization and absorption. However, until recently we have been unable to detect and characterize those structures in real time and have been limited in establishing the interplay between composition, digestion, and nanostructure. Here, we establish the use of an in vitro lipid digestion model used in conjunction with synchrotron small-angle X-ray scattering by first confirming its validity using known, nondigestible liquid crystalline systems, and then extend the model to study the real time evolution of nanostructure during the digestion of common formulation lipids. The formation of liquid crystalline structures from unstructured liquid formulations is discovered, and the kinetics of formation and dependence on composition is investigated. PMID- 21678978 TI - Lateral self-sorting on surfaces: a practical approach to double-channel photosystems. AB - We report that self-sorting during self-organizing surface-initiated copolymerization (co-SOSIP) provides facile access to oriented multicomponent architectures. Alternate lateral and uniform axial self-sorting into formal supramolecular n/p-heterojunction photosystems is found to generate up to 40 times more photocurrent. More or less topological matching gives rise to alternate axial self-sorting into inactive charge-transfer complexes or uniform lateral sorting into the less active macrodomains, respectively. Experimental support for self-repair during co-SOSIP is reported. Initiators on the surface are shown to serve as templates for the self-sorting into multichannel architectures of freely variable composition. PMID- 21678980 TI - Visualizing cell extracellular matrix (ECM) deposited by cells cultured on aligned bacteriophage M13 thin films. AB - Topographical features ranging from micro- to nanometers can affect cell orientation and migratory pathways, which are important factors in tissue engineering and tumor migration. In our previous study, a convective assembly of bacteriophage M13 resulted in thin films which could be used to control the alignment of cells. However, several questions regarding its underlying reasons to dictate cell alignment remained unanswered. Here, we further study the nanometer topographical features generated by the bacteriophage M13 crystalline film, which results in the alignment of the cells and extracellular matrix (ECM) proteins. Sequential imaging analyses at micro- and nanoscale levels of aligned cells and fibrillar matrix proteins were documented using scanning electron microscopy and immunofluorescence microscopy. As a result, we observed baby hamster kidney cells with higher degree of alignment on the ordered M13 substrates than NIH-3T3 fibroblasts, a difference which could be attributed to the intrinsic nature of the cells' production of ECM proteins. The results from this study provide a crucial insight into the topographical features of a biological thin film, which can be utilized to control the orientation of cells and surrounding ECM proteins. PMID- 21678979 TI - Multifunctional surface modification of gold-stabilized nanoparticles by bioorthogonal reactions. AB - Nanocarriers that combine multiple properties in an all-in-one system hold great promise for drug delivery. The absence of technology to assemble highly functionalized devices has, however, hindered progress in nanomedicine. To address this deficiency, we have chemically synthesized poly(ethylene oxide)-beta poly(epsilon-caprolactone) (PEO-b-PCL) block polymers modified at the apolar PCL terminus with thioctic acid and at the polar PEO terminus with an acylhydrazide, amine, or azide moiety. The resulting block polymers were employed to prepare nanoparticles that have a gold core, an apolar polyester layer for drug loading, a polar PEO corona to provide biocompatibility, and three different types of surface reactive groups for surface functionalization. The acylhydrazide, amine, or azide moieties of the resulting nanoparticles could be reacted with high efficiencies with modules having a ketone, isocyanate, or active ester and alkyne function, respectively. To demonstrate proof of principle of the potential of multisurface functionalization, we prepared nanoparticles that have various combinations of an oligo-arginine peptide to facilitate cellular uptake, a histidine-rich peptide to escape from lysosomes, and an Alexa Fluor 488 tag for imaging purposes. It has been shown that uptake and subcellular localization of the nanoparticles can be controlled by multisurface modification. It is to be expected that the modular synthetic methodology provides unique opportunities to establish optimal configurations of nanocarriers for disease-specific drug delivery. PMID- 21678981 TI - Structural, optical, and electronic properties of a series of 3,4 propylenedioxythiophene oligomers in neutral and various oxidation States. AB - A series of 3,4-propylenedioxythiophene (ProDOT) oligomers (nP(Hex)) with dihexyl side chains and methylthio end-capping units was synthesized as a model of poly(3,4-alkylenedioxythiophene)s. The slope of the linear relationship between the energy of the absorption maxima of nP(Hex) in the neutral states and the reciprocal of the number of monomer units (1/n) was found to be comparable to that of 3,4-ethylenedioxythiophene (EDOT) oligomers, suggesting that both the ProDOT and the EDOT oligomers have a similar effective conjugation. In cyclic voltammetry measurements, both the first and second oxidation waves and the third and fourth waves were shown to merge into one peak with increasing chain length. The stepwise chemical oxidations of nP(Hex) with SbCl(5) in CH(2)Cl(2) at room temperature gave their stable cationic species in various oxidation states, and it was found that only the radical cations (polarons) have an obvious absorption band in the visible region. Interestingly, when the absorption spectra of tetramer radical cation 4P(Hex)(+.) were measured at low temperatures, reversible disproportionation into dication 4P(Hex)(2+) and neutral species 4P(Hex) was observed in addition to pi-dimer formation. Furthermore, the radical cations of the longer oligomers showed only the disproportionation reaction. From the comparisons of the results of experiments and the theoretical calculations of the dications, 6P(Hex)(2+) was found to have a closed-shell nature, and only a weak singlet biradical character appeared even in longer oligomers 10P(Hex)(2+) and 12P(Hex)(2+). Overall, the electron-donating dioxy substituents are considered to stabilize high p-doping levels with closed-shell dication (bipolaron) structures in poly(3,4-alkylenedioxythiophene)s, which enables the transparency properties of the polymers. PMID- 21678982 TI - Dual silane surface functionalization for the selective attachment of human neuronal cells to porous silicon. AB - Porous silicon (pSi) surfaces were chemically micropatterned through a combination of photolithography and surface silanization reactions. This patterning technique produces discretely defined regions on a pSi surface functionalized with a specific chemical functionality, and the surrounding surface displays a completely different functionality. The generated chemical patterns were characterized by a combination of IR microscopy and the conjugation of two different fluorescent organic dyes. Finally, the chemically patterned pSi surface was used to direct the attachment of neuronal cells to the surface. This patterning strategy will be useful for the development of high-throughput platforms for investigating cell behavior. PMID- 21678983 TI - Applying in-silico retention index and mass spectra matching for identification of unknown metabolites in accurate mass GC-TOF mass spectrometry. AB - One of the major obstacles in metabolomics is the identification of unknown metabolites. We tested constraints for reidentifying the correct structures of 29 known metabolite peaks from GCT premier accurate mass chemical ionization GC-TOF mass spectrometry data without any use of mass spectral libraries. Correct elemental formulas were retrieved within the top-3 hits for most molecular ion adducts using the "Seven Golden Rules" algorithm. An average of 514 potential structures per formula was downloaded from the PubChem chemical database and in silico-derivatized using the ChemAxon software package. After chemical curation, Kovats retention indices (RI) were predicted for up to 747 potential structures per formula using the NIST MS group contribution algorithm and corrected for contribution of trimethylsilyl groups using the Fiehnlib RI library. When matching the range of predicted RI values against the experimentally determined peak retention, all but three incorrect formulas were excluded. For all remaining isomeric structures, accurate mass electron ionization spectra were predicted using the MassFrontier software and scored against experimental spectra. Using a mass error window of 10 ppm for fragment ions, 89% of all isomeric structures were removed and the correct structure was reported in 73% within the top-5 hits of the cases. PMID- 21678984 TI - Flexible and semitransparent strain sensors based on micromolded Pd nanoparticle carbon MU-stripes. AB - Flexible resistive strain sensors have been fabricated by micromolding Pd alkanethiolate on polyimide substrates and subjecting to thermolysis in air. Thus produced stripes were ~1 MUm wide with spacing of ~0.5 MUm and contained Pd nanoparticles in carbon matrix. The nanoparticle size and the nature of carbon are much dependent on the thermolysis temperature as is also the resistance of the microstripes. Generally, lower thermolysis temperatures (<230 degrees C) produced stripes containing small Pd nanoparticles with significant fraction of carbon from the precursor decomposition. The stripes were poorly conducting yet interestingly, exhibited change of resistance under tensile and compressive strain. Particularly noteworthy are the stripes produced from 195 degrees C thermolysis, which showed a high gauge factor of ~390 with strain sensitivity, 0.09%. With molding at 230 degrees C, the stripes obtained were highly conducting, and amazingly did not change the resistance with strain even after several bending cycles. The latter are ideal as flexible conduits and interconnects. Thus, the article reports a method of producing flexible sensitive strain sensors on one hand and on the other, flexible conduits with unchanging resistance, merely by fine-tuning the precursor decomposition under the molding conditions. PMID- 21678985 TI - Self-organizing surface-initiated polymerization: facile access to complex functional systems. AB - Facile access to complex systems is crucial to generate the functional materials of the future. Herein, we report self-organizing surface-initiated polymerization (SOSIP) as a user-friendly method to create ordered as well as oriented functional systems on transparent oxide surfaces. In SOSIP, self-organization of monomers and ring-opening disulfide exchange polymerization are combined to ensure the controlled growth of the polymer from the surface. This approach provides rapid access to thick films with smooth, reactivatable surfaces and long range order with few defects and high precision, including panchromatic photosystems with oriented four-component redox gradients. The activity of SOSIP architectures is clearly better than that of disordered controls. PMID- 21678986 TI - Innovative research at the interface of chemistry and biology. PMID- 21678990 TI - Role of electric field on surface wetting of polystyrene surface. AB - The role of surface charge in fluid flow in micro/nanofluidics systems as well as the role of electric field to create switchable hydrophobic surfaces is of interest. In this work, the contact angle (CA) and contact angle hysteresis (CAH) of a droplet of deionized (DI) water were measured with applied direct current (DC) and alternating current (AC) electric fields. The droplet was deposited on a polystyrene (PS) surface, commonly used in various nanotechnology applications, coated on a doped silicon (Si) wafer. With the DC field, CA decreased with an increase in voltage. Because of the presence of a silicon oxide layer and a space charge layer, the change of the CA was found to be lower than with a metal substrate. The CAH had no obvious change with a DC field. An AC field with a positive value was applied to the droplet to study its effect on CA and CAH. At low frequency (lower than 10 Hz), the droplet was visibly oscillating. The CA was found to increase when the frequency of the applied AC field increased from 1 Hz to 10 kHz. On the other hand, the CA decreased with an increasing peak-peak voltage at or lower than 10 kHz. The CAH in the AC field was found to be lower than in the DC field and had a similar trend to static CA with increasing frequency. A model is presented to explain the data. PMID- 21678991 TI - Proteomics reveals a role for the RNA helicase crhR in the modulation of multiple metabolic pathways during cold acclimation of Synechocystis sp. PCC6803. AB - One of the earliest and largest transcriptional responses that occur during exposure of Synechocystis sp. PCC6803 to cold is the induction of the crhR RNA helicase transcript. We show that crhR deletion results in failure to cold acclimate: there is reduced growth at 24 degrees C and marked impairment of growth at 20 degrees C. 2D-DIGE, using five biological replicates, was used to analyze the proteomic differences between the wild-type and DeltacrhR strains grown at (1) 34 degrees C and (2) following transfer from 34 to 24 degrees C (cold-acclimation). Sixteen significantly differentially expressed proteins were identified between the two strains grown at 34 degrees C. Forty-three distinct proteins were identified that responded to cold-acclimation of the wild-type and 34 proteins for the mutant, with only 26 proteins common to both. A large proportion of the proteomic responses (76.5%) could not be predicted from published transcriptomic data. Only modest similarity is observed between proteomic and transcriptomic responses (r = 0.54-0.70). We propose functions for three previously hypothetical proteins. We suggest molecular targets for CrhR action and identify downstream regulated events in metabolism. PMID- 21678992 TI - On modulating the self-assembly behaviors of poly(styrene-b-4 vinylpyridine)/octyl gallate blends in solution state via hydrogen bonding from different common solvents. AB - We have investigated the complexation-induced phase behavior of the mixtures of poly(styrene-b-4-vinylpyridine) (PS-b-P4VP) and octyl gallate (OG) due to hydrogen bonding in different solvents. The Fourier transform infrared spectroscopic result indicates that the hydrogen-bonding was formed between the P4VP blocks and OG in both THF and DMF, implying the P4VP blocks can bind to OG. For PS-b-P4VP/OG mixture in chloroform, the morphological transitions were induced from the unimer configuration to swollen aggregate and complex-micelles by adding OG. Interestingly, the complex-micelles can lead the formation of the honeycomb structure from chloroform solution. The PS-b-P4VP/OG mixture in THF, behaving an amphiphilic diblock copolymer in solution state, exhibited a series of morphological transitions from sphere, pearl-necklace-liked rod, worm-liked rod, vesicle, to core-shell-corona aggregates by increasing the OG content. In contrast, the PS-b-P4VP/OG mixture in DMF maintained the unimer configuration upon adding OG. Therefore, the complexation-induced morphology of the mixtures of PS-b-P4VP and OG can be mediated by adopting different common solvents to affect the self-assembly behavior. PMID- 21678994 TI - Determination of free and bound phenolic compounds in buckwheat spaghetti by RP HPLC-ESI-TOF-MS: effect of thermal processing from farm to fork. AB - Nowadays there is considerable interest in the consumption of alternative crops as potential recipes for gluten-free products production. Therefore, the use of buckwheat for the production of gluten-free pasta has been investigated in the present study. RP-HPLC-ESI-TOF-MS has been applied for the separation and characterization of free and bound phenolic compounds in buckwheat flour and buckwheat spaghetti. Thus, 32 free and 24 bound phenolic compounds in buckwheat flour and spaghetti have been characterized and quantified. To the authors' knowledge, protochatechuic-4-O-glucoside acid and procyanidin A have been detected in buckwheat for the first time. The results have demonstrated a decrease of total free phenolic compounds from farm to fork (from flour to cooked spaghetti) of about 74.5%, with a range between 55.3 and 100%, for individual compounds. The decrease in bound phenols was 80.9%, with a range between 46.2 and 100%. The spaghetti-making process and the cooking caused losses of 46.1 and 49.4% of total phenolic compounds, respectively. Of the total phenolic compounds present in dried spaghetti, 11.6% were dissolved in water after cooking. PMID- 21678993 TI - Combined pressure-temperature effects on carotenoid retention and bioaccessibility in tomato juice. AB - This study highlights the changes in lycopene and beta-carotene retention in tomato juice subjected to combined pressure-temperature (P-T) treatments ((high pressure processing (HPP; 500-700 MPa, 30 degrees C), pressure-assisted thermal processing (PATP; 500-700 MPa, 100 degrees C), and thermal processing (TP; 0.1 MPa, 100 degrees C)) for up to 10 min. Processing treatments utilized raw (untreated) and hot break (~93 degrees C, 60 s) tomato juice as controls. Changes in bioaccessibility of these carotenoids as a result of processing were also studied. Microscopy was applied to better understand processing-induced microscopic changes. TP did not alter the lycopene content of the tomato juice. HPP and PATP treatments resulted in up to 12% increases in lycopene extractability. all-trans-beta-Carotene showed significant degradation (p < 0.05) as a function of pressure, temperature, and time. Its retention in processed samples varied between 60 and 95% of levels originally present in the control. Regardless of the processing conditions used, <0.5% lycopene appeared in the form of micelles (<0.5% bioaccessibility). Electron microscopy images showed more prominent lycopene crystals in HPP and PATP processed juice than in thermally processed juice. However, lycopene crystals did appear to be enveloped regardless of the processing conditions used. The processed juice (HPP, PATP, TP) showed significantly higher (p < 0.05) all-trans-beta-carotene micellarization as compared to the raw unprocessed juice (control). Interestingly, hot break juice subjected to combined P-T treatments showed 15-30% more all-trans-beta-carotene micellarization than the raw juice subjected to combined P-T treatments. This study demonstrates that combined pressure-heat treatments increase lycopene extractability. However, the in vitro bioaccessibility of carotenoids was not significantly different among the treatments (TP, PATP, HPP) investigated. PMID- 21678995 TI - Enzyme biosensor based on plasma-polymerized film-covered carbon nanotube layer grown directly on a flat substrate. AB - We report a novel approach to fabrication of an amperometric biosensor with an enzyme, a plasma-polymerized film (PPF), and carbon nanotubes (CNTs). The CNTs were grown directly on an island-patterned Co/Ti/Cr layer on a glass substrate by microwave plasma enhanced chemical vapor deposition. The as-grown CNTs were subsequently treated by nitrogen plasma, which changed the surface from hydrophobic to hydrophilic in order to obtain an electrochemical contact between the CNTs and enzymes. A glucose oxidase (GOx) enzyme was then adsorbed onto the CNT surface and directly treated with acetonitrile plasma to overcoat the GOx layer with a PPF. This fabrication process provides a robust design of CNT-based enzyme biosensor, because of all processes are dry except the procedure for enzyme immobilization. The main novelty of the present methodology lies in the PPF and/or plasma processes. The optimized glucose biosensor revealed a high sensitivity of 38 MUA mM(-1) cm(-2), a broad linear dynamic range of 0.25-19 mM (correlation coefficient of 0.994), selectivity toward an interferent (ascorbic acid), and a fast response time of 7 s. The background current was much smaller in magnitude than the current due to 10 mM glucose response. The low limit of detection was 34 MUM (S/N = 3). All results strongly suggest that a plasma polymerized process can provide a new platform for CNT-based biosensor design. PMID- 21678996 TI - A laminar flow electroporation system for efficient DNA and siRNA delivery. AB - By introducing a hydrodynamic mechanism into a microfluidics-based electroporation system, we developed a novel laminar flow electroporation system with high performance. The laminar buffer flow implemented in the system separated the cell suspension flow from the electrodes, thereby excluding many unfavorable effects due to electrode reaction during electroporation, such as hydrolysis, bubble formation, pH change, and heating. Compared to conventional microfluidic electroporation systems, these improvements significantly enhanced transfection efficiency and cell viability. Furthermore, successful electrotransfection of plasmid DNA and, more importantly, synthetic siRNA, was demonstrated in several hard-to-transfect cell types using this system. PMID- 21678997 TI - A 4-week repeated oral dose toxicity study of dairy fat naturally enriched in vaccenic, rumenic and alpha-linolenic acids in rats. AB - Few studies have focused on the toxicological risks of dairy fat intake. A standard dairy fat (SDF) with a 70% SFA content and a naturally enriched dairy fat (EDF) in vaccenic, rumenic and alpha-linolenic acids and low in SFA (54%) have been examined in a 4-week repeated dose oral toxicity study as a daily dose of 2000 mg/kg bw by gavage in rats. Comparisons were established with a third group of rats (control) which did not receive fat administration. Both fats were well tolerated, and no adverse events or mortality were observed during the treatment nor after a 2-week observation period. EDF and SDF did not cause significant differences with respect to a control group in body weight gain, food consumption, clinical observations, organ weight ratios, histopathological findings and most of the hematological and biochemical parameters including total cholesterol and cholesterol fractions in plasma. In rats treated with SDF, a significant increase of triglycerides was observed as compared to the control group. By contrast, in rats treated with EDF, a significant decrease in triglycerides was detected. EDF orally administered to rats was safe, and no treatment-related toxicity was detected. The results also suggest that EDF could protect against the increase of triglyceride concentrations in plasma. PMID- 21678998 TI - Potential-dependent recombination kinetics of photogenerated electrons in n- and p-type GaN photoelectrodes studied by time-resolved IR absorption spectroscopy. AB - Recombination kinetics of photogenerated electrons in n-type and p-type GaN photoelectrodes active for H(2) and O(2) evolution, respectively, from water was examined by time-resolved IR absorption (TR-IR) spectroscopy. Illumination of a GaN film with UV pulse (355 nm and 6 ns in duration) gives transient interference spectra in both transmittance and reflection modes. Simulation shows that the interference spectra are caused by photogenerated electrons. We observed that recombination in the microsecond region is greatly affected by the applied potentials, the lifetime becoming longer at negative and positive potentials for n- and p-type GaN electrodes, respectively. There is a good correlation between potential dependence of the steady-state reaction efficiency and that of the number of surviving electrons in the millisecond region. We also performed potential jump measurement to examine the shift in Fermi level by photogenerated charge carriers. In the case of n-type GaN, the electrode potential jumps to the negative side by accumulation of electrons in the bulk. However, in the case of p type GaN, the electrode potential first jumps to the negative side within 20 MUs and gradually shifts to the positive side in a few milliseconds, while the number of charge carriers is constant at >0.2 ms. This two-step process is ascribed to electron transport from the bulk to the surface of GaN, because the electrode potential is sensitive to the number of electrons in the bulk. The results confirm that TR-IR combined with potential jump measurement provides useful information for understanding the behavior of charge carriers in photoelectrochemical systems. PMID- 21678999 TI - 2,5-Bis(2-octyldodecyl)pyrrolo[3,4-c]pyrrole-1,4-(2H,5H)-dione-based donor acceptor alternating copolymer bearing 5,5'-di(thiophen-2-yl)-2,2'-biselenophene exhibiting 1.5 cm2.V(-1).s(-1) hole mobility in thin-film transistors. AB - A novel diketopyrrolopyrrole-based pi-conjugated copolymer P(DPP-alt-DTBSe), 5, and a known copolymer P(DPP-alt-QT), 4, have been synthesized in 80-90% yield using the Stille coupling reaction. The molecular weights of 4 and 5 are 58,781 and 19,271 g/mol, respectively, with polydispersity values of 3.25-3.35. A relatively small band gap of 1.32-1.39 eV and excellent solubility in organic solvents were achieved in the two polymers. Thin-film transistors made of 5 exhibit outstanding performance (e.g., MU > 1.0-1.5 cm(2).V(-1).s(-1), I(on)/I(off) > 10(5)-10(6)) with a conventional n-octyltrichlorosilane-SiO(2) gate dielectric. PMID- 21679000 TI - Ceric ammonium nitrate-catalyzed azidation of 1,2-anhydro sugars: application in the synthesis of structurally diverse sugar-derived morpholine 1,2,3-triazoles and 1,4-oxazin-2-ones. AB - Azidation of 1,2-anhydro sugars with NaN(3) in CH(3)CN by using a catalytic amount of ceric ammonium nitrate has been accomplished in a regio- and stereoselective manner. Various 1,2-anhydro sugars produced 2-hydroxy-1-azido sugars in good yields which, in turn, were converted to structurally diverse sugar-derived morpholine triazoles and sugar oxazin-2-ones. These sugar derivatives were tested against various commercially available glycosidases, and two of them were found to be active in the micromolar range. PMID- 21679001 TI - Probing into interesting effects of fractal Ge nanoclusters induced by Pd nanoparticles. AB - Metal/semiconductor thin films are a class of unique materials that have widespread technological applications, particularly in the field of microelectronic devices. New strategies of fractal assessment for Pd/Ge bilayer films formed at various annealing temperatures are of fundamental importance in the development of micro/nanodevices. Herein, Pd/Ge bilayer films with interesting fractal nanoclusters were successfully prepared by evaporation techniques. Temperature-dependent properties of resistance and fractal dimensions in Pd/Ge bilayer films with self-similar Ge fractal nanoclusters were investigated in detail. Experimental results indicated that the fractal crystallization behavior and film resistance in Pd/Ge bilayer films are influenced significantly by annealing temperatures and fractal dimensions. The measurements of film resistance confirmed that there is an evident relationship between the film resistance and the fractal dimension. These phenomena were reasonably explained by the random tunneling junction network mechanism. PMID- 21679002 TI - Electronic structure of the two-leg spin ladder (C5H12N)2CuBr4. AB - A density functional theory study of the two-leg spin ladder (C(5)H(12)N)(2)CuBr(4) reveals antiferromagnetic interactions through the rungs and legs, although the latter are significantly smaller. Our work suggests interest in manipulating the physical behavior of this prototypical system by doping or chemical modifications. PMID- 21679003 TI - Use of bevacizumab in metastatic colorectal cancer: report from the Mexican opinion and analysis forum on colorectal cancer treatment with bevacizumab (September 2009). AB - Colorectal cancer is one of the most common cancers worldwide, and although associated mortality rates in South American countries are generally among the lowest in the world, they are on the rise. The prognosis of patients diagnosed with metastatic colorectal cancer has improved markedly over the last 12 years, increasing from 5 months with best supportive care to almost 2 years with combination chemotherapy plus bevacizumab. New prognostic and predictive biomarkers have been identified to guide therapy. Prognostic markers indicate patient survival independent of therapy and include disease stage, mutational status, and carcinoembryonic antigen. More recently, predictive markers of treatment outcomes have been identified. The most studied are mutations of the KRAS and BRAF genes, which are associated with resistance to epidermal growth factor receptor-targeted therapy. Tumor blood vessels have a number of structural and functional abnormalities that result in increased tumor vascularity and growth driven by angiogenesis. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, which binds to and neutralizes VEGF-A, has become a central part of the treatment of metastatic colorectal cancer. The addition of bevacizumab to fluorouracil (5-FU)/leucovorin, irinotecan plus bolus 5-FU/leucovorin, or irinotecan plus infusional 5-FU/leucovorin significantly improves the overall survival of patients with previously untreated metastatic colorectal cancer. In addition, a significant increase in overall survival is seen when bevacizumab is added to oxaliplatin plus infusional 5-FU/leucovorin (FOLFOX) in patients with metastatic colorectal cancer who progressed on a non bevacizumab-containing regimen. Although the majority of studies were performed prior to the identification of KRAS and BRAF as predictive biomarkers, subsequent analysis has shown the benefits of bevacizumab occur independently of the mutational status of these genes. In patients who have progressed on a bevacizumab-containing regimen, continuation of bevacizumab is significantly associated with an improved survival based on observational cohort studies. Surgical resection is recommended in patients with metastatic colorectal cancer where complete removal of tumors can be achieved. Perioperative chemotherapy using FOLFOX for 3 months before and 3 months after surgery is associated with a 9% improvement in 3-year survival. The use of chemotherapy in patients initially deemed unresectable has produced resection rates approaching 40%, and the addition of bevacizumab to chemotherapy in this setting is feasible, safe, and effective. In a study of 219 patients, the addition of bevacizumab to FOLFOX was associated with a significant increase in major or complete pathologic response compared with FOLFOX alone. Improvements in patient survival have changed the treatment paradigm for metastatic colorectal cancer. Newer approaches view treatment not as distinct lines of therapy but as a continuum that includes personalized treatment plans offering maintenance therapy and even drug holidays between aggressive treatment periods. This approach achieves similar efficacy outcomes with reduced toxicity, and investigation of the role of bevacizumab as maintenance therapy is ongoing. PMID- 21679004 TI - Axitinib for the management of metastatic renal cell carcinoma. AB - In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5 mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2-6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advanced RCC previously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable non-cumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95% CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95% CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6). In the three studies, the most common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients. An observed association between diastolic blood pressure >=90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm. PMID- 21679005 TI - Neoadjuvant dose-dense gemcitabine plus docetaxel and vinorelbine plus epirubicin for operable breast cancer: improved prognosis in triple-negative tumors. AB - BACKGROUND: Neoadjuvant anti-tumor activity of an alternating taxane- and anthracycline-based dose-dense regimen in patients with operable, non inflammatory large breast cancer was investigated. OBJECTIVE: The objective is to study the rate of pathological complete response in patients with breast cancer receiving dose-dense chemotherapy sequentially with gemcitabine plus docetaxel and vinorelbine plus epirubicin. METHODS: Women (n = 74) with clinical stage II or III breast cancer were enrolled in this open-label, multicenter study to receive six 2-weekly courses of gemcitabine 1000 mg/m2 plus docetaxel 75 mg/m2 on days 1 and 15, and vinorelbine 25 mg/m2 plus epirubicin 100 mg/m2 on days 29 and 43. Patients with an objective response on day 56 then received another cycle of gemcitabine/docetaxel on day 57 and of vinorelbine/epirubicin on day 71. Conservative surgery was scheduled for all patients. RESULTS: Of the patients enrolled, 30% had triple-negative breast cancer (TNBC). The pathologic complete response (pCR) rate was 22% overall, but was higher in TNBC than patients without TNBC (40.9% vs 14.0%; p = 0.028). Among patients with a pCR, patients with TNBC had similar recurrence-free survival (RFS) and overall survival (OS) to patients without TNBC. Among those without a pCR, RFS rates for patients with TNBC were significantly lower than for patients without TNBC (p = 0.04). The most common severe hematologic toxicity was neutropenia. CONCLUSIONS: Administering four drugs in a dose-dense alternating sequence gave a high pCR in patients with operable, invasive breast cancer. Patients with TNBC with a pCR had similar OS to patients without TNBC, whereas patients with TNBC without a pCR had poorer survival rate than their non-TNBC counterparts. PMID- 21679006 TI - Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel. AB - BACKGROUND: A novel estradiol-based combined oral contraceptive (COC) is currently available in many countries worldwide, including Europe and the US. Based on previous studies, it is expected that this estradiol-based COC will have a reduced hepatic effect compared with COCs containing ethinylestradiol with regard to proteins controlling the hemostatic balance. OBJECTIVE: The aim of this study was to compare the hemostatic effects of the estradiol valerate/dienogest COC with a monophasic low-estrogen dose COC containing ethinylestradiol/levonorgestrel. STUDY DESIGN: Healthy women aged 18-50 years were randomized to receive a COC containing estradiol valerate/dienogest (2 days estradiol valerate 3 mg, 5 days estradiol valerate 2 mg/dienogest 2 mg, 17 days estradiol valerate 2 mg/dienogest 3 mg, 2 days estradiol valerate 1 mg, 2 days placebo) or ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg in a crossover study design. Women received each treatment for three cycles, with two washout cycles between treatments. The primary efficacy variables were the intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three. RESULTS: Data from 29 women were assessed. Intra-individual absolute changes in prothrombin fragment 1 + 2 and D-dimer from baseline to cycle three were less pronounced with estradiol valerate/dienogest than with ethinylestradiol/levonorgestrel. CONCLUSION: The novel COC containing estradiol valerate/dienogest had similar or less pronounced effects on hemostatic parameters than ethinylestradiol/levonorgestrel. PMID- 21679007 TI - Artist(r) tablets (carvedilol) for hypertensive patients in Japan: results of a drug use survey. AB - BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14.4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a drug use survey, which we conducted as a post-marketing survey. OBJECTIVE: This prospective post-marketing drug use survey was conducted to assess the safety and efficacy of the beta adrenergic receptor antagonist (beta-blocker) Artist(r) Tablets (carvedilol) in patients with hypertension in Japan. PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: This was a prospective survey conducted over 3 years from October 1993 to September 1996. The standard observation period for the patients was defined as 12 weeks of treatment with carvedilol. RESULTS: We collected data on 4961 patients at 561 medical institutions who had not been previously treated with carvedilol; 4574 patients were included in the safety analysis and 4422 in the efficacy analysis. The incidence of adverse drug reactions (the proportion of patients with adverse drug reactions) was 4.31% (197 of 4574 patients), which is less than that shown in the pre-approval clinical trial of carvedilol (6.85% [68 of 993]). The most common adverse drug reactions were bradycardia, dizziness, hypotension, headache, and feeling light-headed. After 12 weeks' treatment with carvedilol, systolic/diastolic blood pressure (SBP/DBP) was reduced from 168.2 +/- 18.6/95.7 +/- 11.3 mmHg at baseline to 144.3 +/- 17.3/83.4 +/- 10.8 mmHg. Patients were classified according to which antihypertensive drug they had been using when carvedilol treatment was initiated. Coadministered agents were calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), diuretics, and alpha-adrenergic receptor antagonists (alpha-blockers). At 12 weeks, the change in SBP/DBP in the monotherapy group was -22.7/-12.2 mmHg and that of each combination therapy subgroup, CCB, ACEI, diuretic, and beta-blocker, was -26.1/ 12.7 mmHg, -25.4/-11.9 mmHg, -26.3/-13.0 mmHg, and -24.4/-11.5 mmHg, respectively. The achievement rates for target BP (<140/90 mmHg) were 29.5% in the monotherapy group, 34.8% in the CCB group, 31.3% in the ACEI group, 31.8% in the diuretic group, and 32.4% in the beta-blocker group. There was no significant difference in the achievement of target BP among the four combination therapy subgroups (p = 0.475). These results indicate that carvedilol exerts reasonable BP reduction regardless of whether it is used as monotherapy or in combination therapy, and that the effect is not influenced by the coadministered drug. Moreover, carvedilol was also effective in reducing BP levels in elderly patients (>=65 years) and in patients with diabetes mellitus or renal diseases. CONCLUSIONS: The results of this study reflect the results of clinical trials up to the time of approval and it was confirmed that carvedilol is a highly useful drug in the treatment of hypertension. PMID- 21679008 TI - Artist(r) tablets (carvedilol) for hypertensive patients in Japan: results of a long-term special survey. AB - BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey. OBJECTIVE: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the beta-adrenergic receptor antagonist (beta-blocker) Artist(r) tablets 10 mg, 20 mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months). PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment. RESULTS: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 +/- 46.5 mg/dL) to after carvedilol treatment (114.6 +/- 43.3 mg/dL).[n = 141; p = 0.310]. In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001). CONCLUSIONS: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension. PMID- 21679009 TI - Rvx 208. AB - RVX 208 (RVX-208; RVX000222) is a first-in-class novel small molecule in development by Resverlogix Corporation for acute coronary syndromes, atherosclerosis and Alzheimer disease. It increases the levels of apolipoprotein A1 and high-density lipoprotein cholesterol, thereby potentially reducing the risk for cardiovascular disease. This review discusses the key development milestones and therapeutic trials of this drug. This summary has been extracted from Wolters Kluwer's R&D Insight drug pipeline database. R&D Insight tracks and evaluates drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch. This is an open access article published under the terms of the Creative Commons License "Attribution-NonCommercial-NoDerivative 3.0" (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits non-commercial use, distribution, and reproduction, provided the original work is properly cited and not altered. PMID- 21679010 TI - Identification of the human liver cytochrome P450 isoenzymes responsible for the 5-methylhydroxylation of the novel anti-fibrotic drug AKF-PD. AB - Identification of cytochrome P450 isoforms (CYPs) involved in flourofenidone (5 methyl-1-(3-fluorophenyl)-2-[1H]-pyridone, AKF-PD) 5-methylhydroxylation was carried out using human liver microsomes and cDNA-expressed human CYPs (supersomes). The experiments were performed in the following in vitro models: (A) a study of AKF-PD metabolism in liver microsomes: (a) correlations study between the rate of AKF-PD 5-methylhydroxylation and activity of CYPs; (b) the effect of specific CYPs inhibitors on the rate of AKF-PD 5-methylhydroxylation; (B) AKF-PD biotransformation by cDNA-expressed human CYPs (1A2, 2D6, 2C9, 2C19, 2E1, 3A4). In human liver microsomes, the formation of AKF-PD 5 methylhydroxylation metabolite significantly correlated with the caffeine N3 demethylase (CYP1A2), chlorzoxazone 6-hydroxylase (CYP2E1), midazolam 1'- hydroxylase (CYP3A4), tolbutamide 4-hydroxylase (CYP2C9), and debrisoquin 4 hydroxylase (CYP2D6) activities. The production of AKF-PD 5-methylhydroxylation metabolite was completely inhibited by a-naphthoflavone (a CYP1A2 inhibitor) with the IC50 value of 0.12 MUM in human liver microsomes. The cDNA-expressed human CYPs generated different amounts of AKF-PD 5-methylhydroxylation metabolites, but the preference of CYP isoforms to catalyze AKF-PD metabolism was as follows: 2D6 > 2C19 > 1A2 > 2E1 > 2C9 > 3A4. The results demonstrated that CYP1A2 is the main isoform catalyzing AKF-PD 5-methylhydroxylation while CYP3A4, CYP2C9, CYP2E1, CYP2C19, and CYP2D6 are engaged to a lesser degree. Potential drug-drug interactions involving CYP1A2 may be noticed when AKF-PD is used combined with CYP1A2 inducers or inhibitors. PMID- 21679011 TI - Mean platelet volume could be a promising biomarker to monitor dietary compliance in celiac disease. AB - BACKGROUND: Celiac disease (CD) is an autoimmune disease that develops in patients with a genetic predisposition, incurring a susceptibility to gluten containing foods such as barley, wheat, and rye. The elimination of gluten from the diet is the main therapeutic approach and usually leads to clinical and laboratory improvement. There are no ideal markers that objectively assess dietary compliance in CD patients. MATERIALS AND METHODS: Sixty newly diagnosed CD patients (male/female: 43/17) and 40 healthy subjects (male/female: 23/17) were enrolled in this study. The diagnosis of CD was established by both histological findings of duodenum biopsy (total villous atrophy and lymphocytic infiltration) and positive antibodies against endomysium or gliadin. RESULTS: A significantly higher mean platelet volume (MPV) was observed in the CD group compared with healthy subjects (8.45 +/- 0.96 fL versus 7.93 +/- 0.63 fL; p = 0.004). After introduction of a gluten-free diet, the MPV of CD patients in the dietary adherent group was significantly lower than that of the non-adherent group (8.09 +/- 0.6 fL versus 8.9 +/- 1.08 fL; p = 0.001). Overall dietary adherence rate was 71.6% (43/60 CD patients). In the dietary compliant group, initiation of gluten-free diet was associated with a significant decrease in MPV from base-line values (8.56 fL versus 8.25 fL; p = 0.008). In the non-adherent group, MPV on 3-month follow-up was higher than at base-line (8.05 fL versus 8.91 fL; p = 0.001). CONCLUSION: MPV could be a promising and easily available biomarker for monitoring of dietary adherence in CD patients at a low cost in comparison with other modalities. PMID- 21679012 TI - Systolic and diastolic blood pressure, mean arterial pressure and pulse pressure for prediction of cardiovascular events and mortality in a Middle Eastern population. AB - We compared systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure (PP) as independent predictors of cardiovascular disease (CVD), total and CVD mortality among an Iranian population. The study conducted among 5991 subjects aged >= 30 years without baseline CVD and antihypertensive medication. The mean of two measurements of SBP and DBP, in sitting position, was considered the subject's blood pressure. During a median follow-up of 8.7 years, 346 CVD and 157 deaths, 63 attributed to CVD, occurred. Hazard ratios (HRs) of each outcome were calculated for a one standard deviation (SD) increase in each blood pressure (BP) measures. In multivariate models, all BP measures were associated with increased risk of CVD regardless of age. In those aged < 60 years, SBP, DBP, PP and MAP were associated with total mortality (p < 0.05), but in subjects aged >= 60 years, only SBP and PP increased risk of total mortality significantly. In multivariate analyses, a 1SD increase in SBP, PP and MAP were associated with 35%, 31% and 28% increased risk of CVD mortality (p < 0.05). In terms of fitness and discrimination of models, DBP, PP and MAP were not superior to SBP. In conclusion, our findings provided further evidence from a Middle Eastern population, in support of SBP predictability for CVD events and CVD and all-cause mortality compared with other BP measures. PMID- 21679013 TI - Arterial wave reflection decreases gradually from supine to upright. AB - BACKGROUND. An increase in total peripheral resistance (TPR) usually increases arterial wave reflection. During passive head-up tilt (HUT), however, arterial wave reflection decreases with increasing TPR. This study addressed whether arterial wave reflection gradually decreases during HUT. METHODS. In 10 healthy volunteers (22-39 years, nine males), we recorded finger arterial pressures in supine position (0 degrees ), and 30 degrees and 70 degrees degrees HUT and active standing (90 degrees ). Aortic pressure was constructed from the finger pressure signal and hemodynamics were calculated. Arterial wave reflection was quantified as the augmentation index (AIx) and the reflection magnitude (RM). RESULTS. During HUT, heart rate increased (p < 0.001), stroke volume and cardiac output decreased (p < 0.001 and p < 0.01), diastolic blood pressure increased (p < 0.001), whereas systolic blood pressure did not change. TPR increased from 0.9 dyn s/cm(5) at 0? to 1.2, 1.4 and 1.4 dyn s/cm(5) at 30 degrees , 70 degrees and 90 degrees (p < 0.001). AIx fell gradually from 25% at 0 degrees to 16%, -1% and -10% at 30 degrees , 70 degrees and 90 degrees (p < 0.001). The RM decreased from 0.572 at 0 degrees to 0.456 at 90 degrees (p < 0.001). CONCLUSION. From supine to upright, arterial wave reflection represented as AIx and RM gradually decreases in the presence of increasing TPR. PMID- 21679014 TI - Colonization of rice leaf blades by an African strain of Xanthomonas oryzae pv. oryzae depends on a new TAL effector that induces the rice nodulin-3 Os11N3 gene. AB - African strains of Xanthomonas oryzae pv. oryzae contain fewer TAL effectors than Asian strains, and their contribution to pathogenicity is unknown. Systematic mutagenesis of tal genes was used to decipher the contribution of each of the eight TAL effector paralogs to pathogenicity of African X. oryzae pv. oryzae BAI3. A strain mutated in talC was severely affected in the production of disease symptoms. Analysis of growth in planta upon leaf-clip inoculation showed that mutant bacteria multiplied only at the site of inoculation at the apex of the leaf, suggesting a requirement for talC during colonization of vascular tissues. Such tissue-specific effect of a tal mutant is a novel phenotype, which has not yet been characterized in other xanthomonads. Microarray experiments comparing the host response of rice leaves challenged with BAI3(R) vs. BAI3(R)DeltatalC were performed to identify genes targeted by TalC. A total of 120 upregulated and 21 downregulated genes were identified, among them Os11N3, which is a member of the MtN3/saliva family. Based on semiquantitative reverse transcription polymerase chain reaction and beta-glucuronidase reporter assays, we show that Os11N3 is directly upregulated by TalC and identify a TalC DNA target box within the Os11N3 upstream sequence. PMID- 21679015 TI - At what BMI are parents of pre-schoolers concerned? National cross-sectional study. AB - Many parents do not recognize that their young children are overweight or obese, possibly because epidemiological cutpoints may not reflect parent perceptions of overweight. We determined whether any Body mass index (BMI) cutpoint reliably triggers parent concern, drawing on the first wave (2004) of the Longitudinal Study of Australian Children (LSAC). BMI (kg/m(2)) and parent concern about their child's weight categorized in three different ways (any, moderately or greater, very) were available for 4,983 children aged 4-5. We used logistic regression to assess the relationship between BMI and parent concern, and receiver operating characteristic (ROC) curves to determine BMI cutpoints that best discriminate parent concern. Parent concern about their pre-schoolers' weight related only modestly to body mass and was not triggered by any definable BMI threshold. This may partly explain why current childhood obesity policies are ineffective, as they typically require individual concern leading to family behavioural change. PMID- 21679016 TI - Expression of response gene to complement-32 in renal tissue of children with immunoglobulin A nephropathy. AB - OBJECTIVE: This study aimed to investigate the expression and significance of response gene to complement-32 (RGC-32) in renal tissue of children with immunoglobulin A nephropathy (IgAN). MATERIAL AND METHODS: Forty-five patients diagnosed as having IgAN by renal biopsy were enrolled. The expression of RGC-32, alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta(1) (TGF beta(1)) was observed by immunohistostaining. The relationshis between the expression of RGC-32, alpha-SMA, TGF-beta1, degree of renal pathological lesions in IgAN and clinical index were assessed by Spearman correlation. RESULTS: Immunohistostaining analysis showed that RGC-32 protein was present in epithelial cells of renal tubules in normal and IgAN renal tissues. With more severe renal pathological lesions, the expression of RGC-32 in IgAN was increased. The expression of RGC-32 was positively correlated with that of alpha-SMA, TGF beta(1) and the degree of renal pathological lesions in children with IgAN (p < 0.05), but had no relationship with serum creatinine, urinary N-acetyl-beta-d glucosaminidase/creatinine, urinary microalbuminuria/creatinine, urinary microimmunoglobulin/creatinine or urinary alpha(1)-microglobulin/creatinine ratio (p > 0.05). CONCLUSION: Expression of RGC-32 can reflect the degree of renal pathological lesions in IgAN. RGC-32 may participate in the renal tubulointerstitial lesions in children with IgAN, especially in epithelial mesenchymal transition induced by TGF-beta(1). PMID- 21679017 TI - Febrile reactions after transrectal ultrasound-guided prostatic biopsy: a retrospective study. AB - OBJECTIVE: The aim of this study was to evaluate the incidence and clinical presentation in patients with hospital admission owing to febrile infections after transrectal ultrasound-guided prostate biopsies. MATERIAL AND METHODS: The case histories of the 57 patients (3.5%) who, between January 2006 and December 2009, were admitted owing to a febrile infection secondary to the 1633 transrectal prostate biopsies performed during the period were retrospectively analysed. Norfloxacin 400 mg ? 2 was given for 3 days as prophylaxis starting just before or within 10 min of biopsy. RESULTS: Quinolone-resistant Escherichia coli was isolated from blood cultures in 43% of the patients (n = 15) presenting with fever between 24 and 48 h postbiopsy. The urine culture was positive in 13% and no patient had symptoms suggestive of a urinary tract infection (UTI). In patients presenting after 48 h (n = 42), quinolone-resistant E. coli was never isolated from blood; E. coli was cultured from urine in 45% of the patients and in 48% it was associated with UTI symptoms. CONCLUSIONS: The finding that early postbiopsy fever was often associated with a quinolone-resistant E. coli bacteraemia and never with UTI symptoms, as opposed to late-onset fever, where such symptoms were common and quinolone-resistant E. coli was rarely detected, suggests divergent pathogenic mechanisms underpinning early- and late-onset febrile reactions. These findings have implications for how antibiotic prophylaxis should be given. PMID- 21679018 TI - Impact of tumour size on recurrence and progression in Ta/T1 carcinoma of the urinary bladder. AB - OBJECTIVE: This study aimed to evaluate the impact of tumour size on recurrence and progression in a population-based series of non-muscle-invasive bladder cancers. MATERIAL AND METHODS: Clinical and pathological characteristics of patients with primary Ta/T1 bladder cancer were registered. The patients' tumours were categorized by size into five size groups (1-10, 11-20, 21-30, 31-40 and >40 mm) or three size groups (1-15, 16-30 and >30 mm). RESULTS: The analysis included 768 evaluable patients with a mean follow-up of 60 months. Recurrence was observed in 478 patients (62%) and progression in 71 (9%). Tumour size was associated with recurrence for tumours sized 21?30, 31?40 and >40 mm (p = 0.03, p < 0.001, p < 0.001, respectively) in the five size group and for tumours sized 16?30 and >30 mm (p = 0.003 and p < 0.001) in the three size group. Other factors affecting recurrence were T1 tumour category, multiplicity and surgery performed by residents (p < 0.001, p < 0.001, p = 0.002, respectively). Considering progression, there was no significant association with tumour size, and T1 category and local recurrence were the only significant risk factors (both p < 0.001). CONCLUSION: Tumour size ?15 mm is associated with a lower risk of recurrence but not progression. Dividing tumour size into three size groups gives additional information compared with two size groups with cut-off at 30 mm. PMID- 21679019 TI - Therapy persistence and adherence in patients with chronic obstructive pulmonary disease: multiple versus single long-acting maintenance inhalers. AB - OBJECTIVE: To compare persistence and adherence among patients with chronic obstructive pulmonary disease (COPD) treated with either multiple- or single- long-acting maintenance inhalers. METHODS: Patients with >=2 COPD medical claims and >=2 prescriptions for a long-acting inhaler within 1 year were classified as single- or multiple-inhaler users based on their treatment regimen (MarketScan database; 2004-2008) and matched on demographics and statistically significant baseline characteristics. Persistence, analyzed via time to treatment discontinuation, and treatment adherence, measured by proportion of days covered (PDC), were compared between the two groups over a 12-month period. Sensitivity analyses were conducted in patients with poorly and well-controlled disease. RESULTS: A total of 23,494 patients were grouped into 11,747 matched pairs. After adjusting for confounding factors, multiple-inhaler users had a significantly higher discontinuation rate [Hazard ratio = 1.40, p < 0.0001] compared with single-inhaler users. Multiple-inhaler users were less likely to be adherent than single-inhaler users with an average PDC of 0.51 (SD = 0.272) vs. 0.55 (SD = 0.279), respectively (p < 0.0001). These results were consistent for the poorly- and well-controlled disease groups. CONCLUSIONS: Multiple long-acting inhaler users demonstrated lower treatment persistence and adherence rates than single long-acting inhaler users. Limitations of the study are related to the retrospective, observational design and use of claims data. PMID- 21679020 TI - Oligonucleotide bioanalysis: sensitivity versus specificity. PMID- 21679021 TI - In vivo solid-phase microextraction sampling: a promising future. PMID- 21679023 TI - News & analysis. PMID- 21679022 TI - Generation of multiplicity in immunoassays. PMID- 21679025 TI - Bioanalysis young investigator: Bhagwat Prasad. AB - It gives me immense pleasure to nominate Bhagwat Prasad for the Bioanalysis Young Investigator Award 2011. He was my direct student since he joined the National Institute of Pharmaceutical Education and Research in July 2004 until February 2011. I had been his teacher and later his guide during his Masters and PhD programs. Since March 2011 Bhagwat has been affiliated with the Department of Pharmaceutics, University of Washington, Seattle (WA, USA) as a post-doctoral fellow. His research projects include bioanalysis of transporter proteins in human tissues using modern LC-MS platforms and clinical studies for understanding drug-drug interactions. Under my direct supervision Bhagwat completed his MS (Pharm) and PhD. Bhagwat has used modern qualitative and quantitative LC-MS approaches during his research. He has first-hand experience of using multiple mass spectrometers. He has published several excellent research and review papers in journals such as, European Journal of Pharmaceutical Sciences, Trends in Analytical Chemistry, Journal of Pharmaceutical and Biomedical Analysis and Drug Discovery Today: Therapeutic Strategies. In a nutshell, Bhagwat Prasad is an outstanding bioanalytical researcher. I am deeply impressed by his drive and determination and, therefore, strongly nominate him for the Bioanalysis Young Investigator Award 2011. PMID- 21679026 TI - Recommendations on: internal standard criteria, stability, incurred sample reanalysis and recent 483s by the Global CRO Council for Bioanalysis. AB - "The Global CRO Council (GCC) for Bioanalysis was formed in an effort to bring together many CRO leaders to openly discuss bioanalysis and the regulatory challenges unique to the outsourcing industry" PMID- 21679027 TI - Blood stability testing: European Bioanalysis Forum view on current challenges for regulated bioanalysis. AB - Since 2008, blood stability testing has gained considerable attention in the European Bioanalysis Forum (EBF) with discussions aiming to align processes, timing and reporting of analyte stability testing in blood as part of method development and validation. In this recommendation, EBF summarizes the conclusions reached to date and aims to provide recommendation for the experimental conduct of such assays as well as the inclusion of stability testing into the scope of method development and validation. Besides considering a step wise approach for blood stability testing, recommendation is made to analyze the blood fraction using a qualified assay in order to circumvent important experimental hurdles. This article will provide an increased understanding of the impact of blood stability testing but furthermore invites scientists to share their views in order to refine the thinking to reach a global harmonized view. PMID- 21679028 TI - Determination of palonosetron in human urine by LC-MS/MS. AB - BACKGROUND: Palonosetron is used for the prevention of chemotherapy-induced nausea and vomiting. However, quantification of this drug in human urine has been rare. RESULTS: A one-step dilution method for the analysis of palonosetron in human urine using LC coupled to positive MS/MS has been developed and validated according to US FDA guidelines. The method uses 200 ul of urine and covers a working range from 2.5-1000 ng/ml with a LLOQ of 2.5 ng/ml. CONCLUSION: This new LC-MS/MS assay is sensitive and specific despite using an external standard method. It is suitable for clinical studies of palonosetron. PMID- 21679029 TI - Incurred sample reanalysis: different evaluation approaches on data obtained for spironolactone and its active metabolite canrenone. AB - BACKGROUND: The inherent reproducibility of a bioanalytical approach is usually sustained through incurred sample reanalysis (ISR). Questions relating to the number of ISRs, the right moment for performing reanalysis, the way of performing an appropriate statistical refinement of experimental data and actions to be taken in the case of failure are frequently raised. RESULTS: Data resulting from ISR following a bioequivalence study for spironolactone formulations are discussed. Reanalysis of samples was carried out twice: immediately after the end of the study and after a period that overcame the long-term stability study achieved during method validation. The Bland-Altman approach was used to assess experimental results. ISR was successful over the short reanalysis period for both compounds. Data produced through reanalysis after the long-term period indicated a systematic positive bias for the metabolite canrenone (although results supported reproducibility). The results obtained for spironolactone were affected by a strong negative systematic bias and failed to support reproducibility. The explanation deals with the continuous conversion of spironolactone to canrenone in plasma samples. However, reproducibility of the method may be sustained by comparing original and repeated differences between concentration values in samples by means of a paired t-test, Wilcoxon sign rank sum test and linear regression. CONCLUSIONS: Different statistical approaches for making data comparisons are discussed and may be successfully applied during reanalysis of samples from a bioequivalence study. Results of the evaluations may differ in accordance with the statistical procedure being applied, thus a definitive conclusion requires consideration of all specific experimental circumstances arising during production of the processed data. PMID- 21679030 TI - Quantitative analysis of skeletal symmetric chlorhexidine in rat plasma using doubly charged molecular ions in LC-MS/MS detection. AB - BACKGROUND: The skeletal symmetric structure of chlorhexidine predicts that each doubly charged molecular ion may generate two para-chlorbenzenguanidines daughter ions through bond cleavage at two protonation sites, thus generating better sensitivity in MRM transition than that involving singly charged molecular ions. This unique nature can be used to improve sensitivity of a LC-MS/MS method. RESULTS: High-throughput LC-MS/MS was developed and validated to quantify chlorhexidine in rat plasma as low as 0.500 ng/ml. In the method, a unique chromatographic method on a narrow bore column reduced run time to 2.5 min and successfully minimized high background from accumulation of endogenous compounds in matrix on the column. CONCLUSION: This method was proved to be robust and suitable to support rat dermal toxicology studies. PMID- 21679031 TI - Ultrafast selective quantification of methotrexate in human plasma by high throughput MALDI-isotope dilution mass spectrometry. AB - BACKGROUND: A new analytical MS method using isotope dilution combined with MALDI triple quadrupole MS/MS has been developed and validated for the determination of methotrexate and 7-hydroxymethotrexate in plasma. Methotrexate, methotrexate-d3, 7-hydroxymethotrexate and 7-hydroxymethotrexate-d3 were monitored by selected reaction monitoring using the transitions m/z 455.2->308.2, 458.2->311.2, 471.2 >324.2 and 474.2->327.2 for methotrexate, methotrexate-d3, 7-hydroxymethotrexate and 7-hydroxymethotrexate-d3, respectively. RESULTS: The LLOQ was 1 nmol/l for methotrexate and 7-hydroxymethotrexate while the limit of detection was 0.3 nmol/l for both analytes. The new developed method was cross-validated by a fluorescence polarization immunoassay and tested for its clinical feasibility by measuring plasma samples from patients suffering from acute lymphoblastic leukemia. Plasma methotrexate concentrations ranged between 66.0 and 954 nmol/l and observed 7-hydroxymethotrexate/methotrexate ratios ranged between 0.1 and 32.4, respectively. CONCLUSION: The new method showed comparable analytical performances as the fluorescence polarization immunoassay, but analyte specificity and sensitivity of the newly developed method were significantly better. PMID- 21679032 TI - Bioanalytical approaches to analyzing peptides and proteins by LC--MS/MS. AB - Peptides and proteins have been utilized as therapeutic agents for over 40 years. Traditional approaches to quantify these molecules in biological matrices have utilized immunoassay approaches that can be time inefficient, lack assay specificity and have limited analytical ranges. The advances in sample preparation technologies, chromatographic systems and their chemistries, mass spectrometers and their software over the last decade have meant that LC-MS/MS approaches to peptide and protein quantification are feasible and can overcome the problems associated with quantification by immunoassay. In this article we present an overview of the challenges and approaches to overcome them when performing quantitative bioanalysis of peptides and proteins by LC-MS/MS. PMID- 21679033 TI - MALDI imaging techniques dedicated to drug-distribution studies. AB - Previously, MS was often used to analyze the composition and structure of biological molecules present in solutions. Today, technology developments enable the application of MS for the analysis of localized biomolecules on biological tissue surfaces. This technique is called MS imaging. MALDI imaging MS is a technique whereby thousands of compounds present in a tissue section are detected simultaneously without labeling. Although initially used for the detection of biomolecules such as peptides and proteins, this technology is also used today for drug detection. These characteristics make MS imaging an ideal technology that is perfectly adapted for ADME (absorption, distribution, metabolism and excretion) studies. In fact, this technology facilitates the tracking of one or several administered drugs, as well as the metabolites that result from their assimilations. In this article, we will present the various possibilities that MALDI imaging MS approaches have to offer for the study of drugs and their metabolites using MS, MS/MS, FAST-SRM and MRM modes. In this context, we investigate two studies: the distribution of olanzapine in the kidney and the overall distribution of BDM31343 in mouse whole-body section. PMID- 21679034 TI - Effects of physiologically relevant dynamic shear stress on platelet complement activation. AB - Disturbed shear stress, commonly found in cardiovascular diseases, plays important roles in platelet activation and functions. It has been reported that when activated by elevated shear stress, platelets were able to support complement activation to completion. In this study, through a dynamic cone and plate shearing device, three physiologically relevant shear stresses were applied to platelets, mimicking the shear conditions when platelets pass through a normal left coronary artery (0.05-1 Pa), a 60% stenosis (elevated shear stress at 6.5 Pa for less than 0.1 s), and when platelets are trapped in a recirculation zone past a stenosis (<0.5 Pa). After shear exposure, platelet-surface complement activation (C1q, C4d, iC3b, and SC5b-9 depositions) was measured using a solid phase ELISA approach and flow cytometry. Production of complement regulatory proteins - C1-inhibitor (C1-INH) and complement receptor 1 (CR1), was also measured. Results demonstrated that low-pulsatile shear stress (recirculation) was able to initiate platelet complement activation, by increasing C1q deposition significantly. Both pathological shear stresses triggered significant increases in C1 inhibitor generation and noticeable changes in CR1 production, effectively preventing complement activation from completion. These results suggested that for platelets, low-pulsatile shear stress may be more pro-atherogenic, compared to elevated shear stress, especially when the shear stress exposure time is short. PMID- 21679035 TI - Reduced tumour progression and angiogenesis in 1,2-dimethylhydrazine mice treated with NS-398 is associated with down-regulation of cyclooxygenase-2 and decreased beta-catenin nuclear localisation. AB - Cyclooxygenase (COX)-2 is a key molecular target of colon cancer prevention. However, the mechanisms by which COX-2 inhibitors confer protective effects against tumour development are not completely understood. The aim of this study was to elucidate the effects of NS-398 in the 1,2-dimethylhydrazine (DMH) mouse model with respect to alteration in the expression of COX-2 and E-cadherin catenin complex. Alterations in cell proliferation, apoptosis, and vascular density were investigated. NS-398 showed reduced COX-2 immunoreactivity in adenomas with a decrease in vascular density in non-dysplastic mucosa. Adenomas revealed increased E-cadherin and beta-catenin reactivity. NS-398 reduced the percentages of tumour cells with nuclear localisation of beta-catenin and cyclin D1. Bromodeoxyuridine (BrdUrd) index in adenomas was significantly higher in untreated animals. NS-398 resulted in significant increase in apoptosis in adenomas. Our results suggest a protective role of NS-398 on tumour development associated with reduced COX-2 expression, reduced vascular density and perturbation of beta-catenin signalling pathway. PMID- 21679036 TI - Antibiosis activity of Pantoea agglomerans biocontrol strain E325 against Erwinia amylovora on apple flower stigmas. AB - Pantoea agglomerans E325, the active ingredient in a commercial product for fire blight control, was previously shown in vitro to produce a unique alkaline- and phosphate-sensitive antibiotic specific to Erwinia amylovora. Antibiosis was evaluated as a mode of antagonism on flower stigmas using two antibiosis deficient mutants. On King's medium B, mutants E325ad1 and E325ad2 have stable smooth-butyrous or hypermucoid colony morphologies, respectively, and the parental strain E325 exhibits phenotypic plasticity with predominantly hypermucoid colonies accompanied by slower-growing, smooth-butyrous colonies. Mutants were tested against E. amylovora on stigmas of detached flowers of crab apple (Malus mandshurica) in growth chambers and apple (Malus domestica) in the orchard. Epiphytic fitness of the antibiosis-negative mutants was similar or greater than the parental strain as determined by relative area under the population curve (RAUPC). In laboratory and orchard trials, both mutants had significantly lower inhibitory activity against the pathogen (i.e., less reduction of E. amylovora RAUPC) compared with the parental strain. E325 and the mutants caused similar decreases in pH in a broth medium, indicating that acidification, which was previously reported as a possible mechanism of pathogen inhibition on stigmas, is not directly related to antibiosis. In this study we provide the first evidence for E325 antibiosis involved in E. amylovora growth suppression on apple flower stigmas. PMID- 21679037 TI - Two promoter rearrangements in a drug efflux transporter gene are responsible for the appearance and spread of multidrug resistance phenotype MDR2 in Botrytis cinerea isolates in French and German vineyards. AB - In French and German vineyards, Botrytis cinerea isolates with multiple fungicide resistance phenotypes have been observed with increasing frequencies. Multidrug resistance (MDR) results from mutations that lead to constitutive overexpression of genes encoding drug efflux transporters. In MDR2 and MDR3 strains, overexpression of the major facilitator superfamily transporter gene mfsM2 has been found to result from a rearrangement in the mfsM2 promoter (type A), caused by insertion of a retroelement (RE)-derived sequence. Here, we report the discovery of another, similar RE-induced rearrangement of the mfsM2 promoter (type B) in a subpopulation of French MDR2 isolates. MDR2 isolates harboring either type A or type B mutations in mfsM2 show the same resistance phenotypes and similar levels of mfsM2 overexpression. RE sequences similar to those in mfsM2 were found in low copy numbers in other but not all B. cinerea strains analyzed, including non-MDR2 strains. Population genetic analyses support the hypothesis that the two rearrangement mutations have only occurred once, and are responsible for the appearance and subsequent spread of all known MDR2 and MDR3 strains in French and German wine-growing regions. PMID- 21679038 TI - Delaying selection for fungicide insensitivity by mixing fungicides at a low and high risk of resistance development: a modeling analysis. AB - This study used mathematical modeling to predict whether mixtures of a high resistance-risk and a low-risk fungicide delay selection for resistance against the high-risk fungicide. We used the winter wheat and Mycosphaerella graminicola host-pathogen system as an example, with a quinone outside inhibitor fungicide as the high-risk and chlorothalonil as the low-risk fungicide. The usefulness of the mixing strategy was measured as the "effective life": the number of seasons that the disease-induced reduction of the integral of canopy green area index during the yield forming period could be kept <5%. We determined effective lives for strategies in which the dose rate (i) was constant for both the low-risk and high risk fungicides, (ii) was constant for the low-risk fungicide but could increase for the high-risk fungicide, and (iii) was adjusted for both fungicides but their ratio in the mixture was fixed. The effective life was highest when applying the full label-recommended dose of the low-risk fungicide and adjusting the dose of the high-risk fungicide each season to the level required to maintain effective control. This strategy resulted in a predicted effective life of <= 12 years compared with 3 to 4 years when using the high risk fungicide alone. PMID- 21679039 TI - The cost of learning from our mistakes. PMID- 21679040 TI - Efficacy of anesthetic agents to delay pain onset after periodontal surgery. AB - The aim of this study was to evaluate the influence of 2 anesthetic agents on patients' postoperative pain perception after periodontal surgery. For this parallel-group, double-blinded, randomized clinical trial, 36 open flap debridement surgeries were performed on patients who presented with periodontal disease with clinical signs of inflammation after nonsurgical treatment on at least 1 quadrant. Patients were allocated to 1 of the following groups: group 1, 2% lidocaine with 1 ? 100,000 epinephrine; group 2, 2% mepivacaine with 1 ? 100,000 norepinephrine. Pain intensity was assessed using the visual analog scale during the first 8 hours after surgery. All patients received 750-mg acetaminophen tablets, which they were instructed to take as a rescue medication if necessary. The results demonstrated that postoperative pain intensity was statistically lower in group 2 than in group 1 at the 1-, 2-, and 3-hour periods after surgery, although the pain intensity for all groups could be considered mild. In conclusion, patients in both groups reported similar mild pain after periodontal surgery. PMID- 21679041 TI - Administration of anesthetics using metal syringes. An ex vivo study. AB - The aim of the present study was to assess injection flow rates of metal syringes, with an emphasis on injection speed and the generation of flow pulsations. A cohort of 64 operators (32 practitioners and 32 students) performed 3 consecutive ex vivo simulated injections (SIs) of 1.8-mL cartridges of anesthetic solution. Two needle diameters were tested (27-gauge and 30-gauge). Each SI was filmed and analyzed using a computer. In most cases, the SI lasted longer than 60 seconds with the 30-gauge needle (75%) but not with the 27-gauge needle (47.9%) (P < .0001). Practitioners and men delivered a full cartridge significantly faster than students and women, respectively (P = .0007 in both cases). All operators generated 1 pulse in at least 1 of the 3 SIs with both types of needles, especially during the first 3 seconds (254/384; 66.1%). Pulses occurred more frequently with practitioners (P = .0176) and with the 27-gauge needle (P = .005). Within its methodological limits, the present study showed how difficult it is to control injection pressure when using a metal syringe, especially at the beginning of the injection. Computerized systems may help overcome this problem. PMID- 21679042 TI - Bispectral index monitoring of sedation depth in pediatric dental patients. AB - The bispectral index (BIS) monitor records electroencephalogram waveforms and provides an objective measure of the hypnotic effect of a sedative drug on brain activity. The aim of this pilot study was to use the BIS monitor to evaluate the depth of procedural sedation in pediatric dental patients and to assess if the BIS monitor readings correlate with a validated pediatric sedation scale, the University of Michigan Sedation Scale (UMSS), in determining the level of sedation in these patients. Thirty-five pediatric dental patients requiring sedation were studied prospectively. A baseline BIS reading was obtained and during the procedure an independent observer recorded the BIS every 5 minutes. The operator, who was blinded to the BIS results, determined the UMSS scale at the same 5-minute interval. The patients were monitored postoperatively for 1 hour. There was a significant but moderate correlation between BIS values and UMSS scores (Spearman's rank correlation r = -0.574, P < .0001). Percentage of agreement and kappa coefficient using all the observations were also calculated. The percentage of agreement was 37.8%, the kappa coefficient was 0.18 (P < .0001), and the weighted kappa coefficient 0.26 (P < .0001). A lack of correlation was noted between the deeper levels of UMSS sedation scores and BIS values. This study demonstrated a significant correlation between BIS values and the UMSS score in pediatric dental patients undergoing mild to moderate sedation. Based on our results, it appears that the BIS monitor may be useful during mild or moderate sedations to establish the level of sedation objectively without the need to stimulate the patient. PMID- 21679043 TI - A double-blind placebo-controlled comparison of a novel formulation of intravenous diclofenac and ketorolac for postoperative third molar extraction pain. AB - Dyloject is a novel formulation of diclofenac intended for intravenous (IV) administration. This formulation employs the solubilizing agent hydroxypropyl beta-cyclodextrin to permit bolus IV administration. The efficacy and safety of 5 dose levels of IV diclofenac were compared with IV ketorolac and placebo following third molar extraction. This was a single-dose, randomized, double blind, placebo- and comparator-controlled, parallel-group study. A total of 353 subjects with moderate to severe pain received placebo; ketorolac 30 mg; or IV diclofenac 3.75, 9.4, 18.75, 37.5, or 75 mg (N = 51 for all groups, except N = 47 for ketorolac). The primary endpoint was total pain relief over 6 hours (TOTPAR6) as measured by the visual analog scale (VAS). Secondary endpoints included multiple measures of pain intensity and relief; patient global evaluation; and times to pain relief and rescue medication. Dropouts and adverse effects (AEs) were also monitored. IV diclofenac was superior to placebo as measured by TOTPAR6 (P < .0001 for all doses except 3.75 mg, for which P = .0341). IV diclofenac 3.75 mg was statistically superior to placebo for TOTPAR2 and TOTPAR4. IV diclofenac at both 37.5 and 75 mg was superior to placebo (P < .05) at the earliest (5 minute) assessments of pain intensity and pain relief, but ketorolac was not. The proportion of patients reporting 30% or greater pain relief at 5 minutes was significantly greater after IV diclofenac 37.5 and 75 mg than after ketorolac 30 mg or placebo. Secondary endpoints confirmed the primary findings. Treatment-related AEs were generally mild to moderate and were typical for nonsteroidal anti-inflammatory drugs (NSAIDs). The more rapid onset of action of IV diclofenac compared with the reference injectable NSAID ketorolac suggests additional clinical benefit. If confirmed in larger series, these findings may improve the safety and efficacy of postoperative NSAID analgesia. PMID- 21679044 TI - Recognition and management of complications during moderate and deep sedation part 1: respiratory considerations. AB - The risk for complications while providing any level of sedation or general anesthesia is greatest when caring for patients having significant medical compromise. It is reassuring that significant untoward events can generally be prevented by careful preoperative assessment, along with attentive intraoperative monitoring and support. Nevertheless, we must be prepared to manage untoward events should they arise. This continuing education article will review respiratory considerations and will be followed by a subsequent article addressing cardiovascular considerations. PMID- 21679049 TI - Synthesis and antioxidant, cytotoxicity and antimicrobial activities of novel curcumin mimics. AB - Claisen-Schmidt condensation of 3-(1,2,3,6-tetrahydro-1-methylpyridin-4-yl)-2,4,5 trimethoxybenzaldehyde 3 and various aromatic, heterocyclic and alicyclic amides of 3- aminoacetophenone 6(a-s) afforded novel curcumin mimics. All the synthesized compounds were characterized by IR, (1)H NMR, Mass spectroscopy and evaluated for antioxidant, cytotoxicity and antimicrobial activity. Out of the 20 compounds screened, compounds 7i, 7l, 7q, and 7n have shown excellent radical scavenging activity, compounds 7o, 7t, 7f, and 7r have shown significant xanthine oxidase inhibition, and compounds 7a, 7k and 7l were found to be potent inhibitors of selected cancer cell lines. Compounds 7h, 7t, 7l, 7i, and 7e have shown good antibacterial activity, whereas compounds 7j, 7f, 7o, 7h, and 7t exhibited significant antifungal activity. PMID- 21679050 TI - Luteolin downregulates IL-1beta-induced MMP-9 and -13 expressions in osteoblasts via inhibition of ERK signalling pathway. AB - The inhibitory effect of four structurally related flavonoids, apigenin, baicalein, luteolin and quercetin on the matrix metalloproteinase (MMP)-9 and -13 expressions in osteoblasts was investigated. Treatment with IL-1beta induced both MMP-9 and -13 mRNA expressions as measured by quantitative real-time PCR. Luteolin and apigenin decreased IL-1beta-induced MMP-9 and -13 mRNA expressions, whereas baicalein and quercetin showed little effects. Related to signalling, treatment with IL-1beta induced ERK phosphorylation as measured by Western blotting. Further studies showed that transfection with a constitutively active form of the Ras protein (Ras(V12)) induced stronger ERK phosphorylation and upregulated MMP-9 and -13 mRNA expressions. However, transfection with a dominant negative form of the Ras protein (Ras(N17)) inhibited the ERK activation and MMP 9 and -13 mRNA expressions induced by IL-1beta, which supported the involvement of ERK signalling in IL-1beta-induced MMP-9 and -13 expressions. Treatment with luteolin effectively inhibited the IL-1beta-induced ERK activation in dose dependent manner. Taken together, luteolin might inhibit IL-1beta-induced MMP-9 and -13 expressions, in part, via inhibition of ERK signalling. PMID- 21679051 TI - QSAR of 2-(4-methylsulphonylphenyl)pyrimidine derivatives as cyclooxygenase-2 inhibitors: simple structural fragments as potential modulators of activity. AB - The cyclooxygenase-2 (COX-2) inhibitory activity of 2-(4 methylsulphonylphenyl)pyrimidine derivatives has been quantitatively analyzed in terms of Dragon descriptors. The derived QSAR models have provided rationales to explain the activity of titled derivatives. The descriptors (Me, Mp, GATS1p and GATS5p) identified in CP-MLR analysis have highlighted the role of atomic properties, such as Sanderson electronegativity and polarizability, to explain the inhibitory activity. Additionally, prevalence of aromatic ether functionality (descriptor nRORPh) and certain structural fragments (number of Me groups, C-001; number of H attached to heteroatom, H-050 and number of H attached to alpha-C, H 051) in a molecular structure are helpful to rationalize the COX-2 inhibitory activity of pyrimidine derivatives. The partial least square (PLS) analysis has also confirmed the dominance of information content of CP-MLR-identified descriptors for modelling the activity. PMID- 21679052 TI - Synthesis, characterization and biocidal activity of some transition metal(II) complexes with isatin salicylaldehyde acyldihydrazones. AB - Cobalt(II), nickel(II), copper(II), zinc(II) and cadmium(II) complexes with two new unsymmetrical ligands, isatin salicylaldehyde oxalic acid dihydrazide (isodh) and isatin salicylaldehyde malonic acid dihydrazide (ismdh) were synthesized and characterized by elemental analyses, electrical conductance, magnetic moments, electronic, NMR, ESR and IR spectral studies. The isodh acts as a dibasic tetra dentate ligand bonding through two >C=N-, a deprotonated phenolate and deprotonated indole enolate groups to the metal. The ismdh ligand shows monobasic tetra dentate behaviour in bonding with metal ion through two >C=N-, indole >C=O and a deprotonated phenolate group. The electronic spectral data suggest 4 coordinate square planar geometry for Co(II), Ni(II) and Cu(II) complexes of isodh, whereas, 6-coordinate octahedral structure for the ismdh complexes. The ESR studies also indicate a square planar and distorted octahedral environment around Cu(II) for isodh and ismdh complexes, respectively. Most of the metal complexes show better antifungal activity than the standard and a significant antibacterial activity against various fungi and bacteria. PMID- 21679053 TI - Acetaldehyde-derived modifications on cytosolic human carbonic anhydrases. AB - Acetaldehyde can generate modifications in several proteins, such as carbonic anhydrase (CA) II. In this study, we extended in vitro investigations on acetaldehyde adduct formation by focusing on the other human cytosolic CA enzymes I, III, VII, and XIII. High-resolution mass spectrometric analysis indicated that acetaldehyde most efficiently formed covalent adducts with CA II and XIII. The binding of up to 19 acetaldehydes in CA II is probably attributable to the high number of lysine residues (n = 24) located mainly on the surface of the enzyme molecule. CA XIII formed more adducts (up to 25) than it contains lysine residues (n = 16) in its primary structure. Acetaldehyde treatment induced only minor changes in CA catalytic activity in most cases. The present study provides the first evidence that acetaldehyde can bind to several cytosolic CA isozymes. The functional consequences of such modifications will be further investigated in vivo by using animal models. PMID- 21679055 TI - Disruption of redox homeostasis and induction of apoptosis by suppression of glutathione synthetase expression in a mammalian cell line. AB - The stable HepG2 transfectants anti-sensing expression of the glutathione synthetase (GS) gene exhibited delayed cell growth and increased reactive oxygen species (ROS) level. After the treatment with hydrogen peroxide, the intracellular ROS level was much higher in the stable transfectants than in the vector control cells. However, the GSH levels decreased more significantly in the stable transfectants than in the vector control cells, in the presence of hydrogen peroxide. Hydrogen peroxide-induced apoptosis of the stable transfectants was notably higher than that of the vector control cells. The GS anti-sense RNAs rendered the HepG2 cells more sensitive to growth arrest caused by glucose deprivation. They also sensitized the HepG2 cells to cadmium chloride (Cd) and nitric oxide (NO)-generating sodium nitroprusside (SNP). In brief, the results confirm that GS plays an important role in the defense of the human hepatoma cells against oxidative stress by reducing apoptosis and maintaining redox homeostasis. PMID- 21679056 TI - Association of the metabolic syndrome with age-related, nonatherosclerotic, chronic medical conditions. AB - Abstract In this article we review the association of three principal factors of the metabolic syndrome-- insulin resistance, hypertension, and increased levels of inflammation factors--with several chronic, nonatherosclerotic conditions associated with aging--frailty, cognitive decline, impaired cardiovascular autonomic control, and possibly osteoporosis. We hypothesize that the metabolic syndrome is associated with "accelerated" aging. PMID- 21679057 TI - Depot-specific overexpression of proinflammatory, redox, endothelial cell, and angiogenic genes in epicardial fat adjacent to severe stable coronary atherosclerosis. AB - BACKGROUND: Pro- and antiinflammatory genes are expressed in epicardial adipose tissue (EAT). Our objectives were to characterize genes in EAT that may contribute specifically to coronary atherogenesis and to measure circulating adipokines matched to their messenger RNAs (mRNAs) in EAT. We hypothesized that severe coronary atherosclerosis (CAD) would preferentially affect gene expression in EAT as compared to substernal fat or subcutaneous thoracic adipose tissue (SAT), as well as circulating levels of adipokines. METHODS: Fat mRNA was quantified using reverse transcription polymerase chain reaction (RT-PCR), and circulating adipokines were measured by enzyme-linked immunosorbent assays (ELISAs) in patients with severe stable CAD and controls without severe CAD undergoing open heart surgery. RESULTS: A total of 39 of 70 mRNAs in EAT were significantly increased in CAD. Only 4 and 3 of these mRNAs were increased in substernal fat and SAT, respectively. Of the mRNAs increased in EAT, 17 were either inflammatory adipokines or proteins known to be involved in inflammatory processes, 7 were involved in oxidative stress and or oxygen species regulation, whereas 15 were proteins involved in metabolism and regulation of gene transcription or proteins unique to fat cells. The largest increases, over three fold, were seen in GPX3, gp91 phox, p47phox, heme oxygenase, and interleukin-8 (IL-8). Tpl2 mRNA was uniquely elevated in all three fat depots from CAD patients, and its expression in SAT, but not in EAT or substernal fat, was directly correlated with homeostasis model assessment of insulin resistance (HOMA IR) values. Compared to controls, there were no associations between circulating levels of IL-8, lipocalin-2, nerve growth factor (NGF), RANTES, CD-163, GPX-3, monocyte chemotactic protein-1 (MCP-1)/CCL2, leptin, soluble vascular endothelial growth factor receptor-1 (sFLT1), fatty acid binding protein-4 (FABP-4), and plasminogen activator inhibitor-1 (PAI-1) and increases in their gene expression in EAT adjacent to CAD. CONCLUSIONS: Expression of proinflammatory, redox, endothelial cell, and angiogenic genes in EAT is depot specific and supports the hypothesis that pathophysiologically EAT contributes locally to CAD. CAD links with these fat depots might involve Tpl2 as a primary response indicator. PMID- 21679058 TI - Balanced caloric macronutrient composition downregulates immunological gene expression in human blood cells-adipose tissue diverges. AB - Cardiovascular disease, obesity, and type 2 diabetes are conditions characterized by low-grade systemic inflammation, strongly influenced by lifestyle, but the mechanisms that link these characteristics are poorly understood. Our first objective was to investigate if a normocaloric diet with a calorically balanced macronutrient composition influenced immunological gene expression. Findings regarding the suitability of blood as biological material in nutrigenomics and gene expression profiling have been inconclusive. Our second objective was to compare blood and adipose tissue sample quality in terms of adequacy for DNA microarray analyses, and to determine tissue-specific gene expression patterns. Blood and adipose tissue samples were collected for gene expression profiling from three obese men before, during, and after a 28-day normocaloric diet intervention where each meal contained an approximately equal caloric load of macronutrients. Time series analyses of blood gene expression revealed a cluster of downregulated genes involved in immunological processes. Blood RNA quality and yield were satisfactory, and DNA-microarray analysis reproducibility was similar in blood and adipose tissue. Gene expression correlation between blood and adipose tissue varied according to gene function, and was especially low for genes involved in immunological and metabolic processes. This suggests that diet composition is of importance in inflammatory processes in blood cells. The findings also suggest that a systems biology approach, in which tissues are studied in parallel, should be employed to fully understand the impact of dietary challenges on the human body. PMID- 21679060 TI - Commentary: Minimum reporting standards for endovascular AAA repair: practical, clinically-relevant, and easy to use. PMID- 21679059 TI - Pragmatic minimum reporting standards for endovascular abdominal aortic aneurysm repair. PMID- 21679061 TI - Use of multispectral MRI to monitor aneurysm sac contents after endovascular abdominal aortic aneurysm repair. AB - PURPOSE: To validate a newly developed semi-automatic multispectral magnetic resonance imaging (MRI) tool for quantitatively monitoring aneurysm sac contents in patients after endovascular aneurysm repair (EVAR). METHODS: MRI studies from 24 EVAR patients were retrospectively analyzed. The precontrast T1-weighted and T2-weighted and the postcontrast T1-weighted images were displayed simultaneously. Two independent observers classified the aneurysm sac voxels into categories for endoleak, unorganized thrombus, or organized thrombus by interactively thresholding the multispectral images relative to the signal intensity of fat. Voxel classification was visualized as a color overlay on the MR images; when the observer changed the thresholds, the color overlay was updated immediately. The volumes of the voxels in each category were calculated and expressed in milliliters. The intra- and interobserver variability for measuring the volumes of endoleak and unorganized and organized thrombus were calculated; a Bland and Altman analysis was applied to determine the mean differences and the repeatability coefficient (RC). RESULTS: Mean aneurysm sac volume was 78 +/- 42 mL. The intraobserver mean difference for the endoleak volume was 0.5 +/- 1.9 mL with an RC of 3.7 mL; the interobserver mean difference was -0.8 +/- 3.6 mL (RC 7.1 mL). The intraobserver mean difference for unorganized thrombus volume was -1.2 +/- 4.4 mL (RC 8.6 mL); the interobserver mean difference was 0.3 +/- 6.3 mL with an RC of 12.3 mL. The intraobserver mean difference for organized thrombus volume was 0.8 +/- 5.0 mL (RC 9.7 mL); the interobserver mean difference was 0.4 +/- 6.3 mL (RC 12.4 mL). CONCLUSION: Reproducible monitoring of aneurysm sac contents in EVAR patients is feasible with multispectral MRI in combination with our semi-automatic post-processing tool. PMID- 21679062 TI - CT angiography in stent-graft sizing: impact of using inner vs. outer wall measurements of aortic neck diameters. AB - PURPOSE: To assess the impact of using inner wall vs. outer wall measurements on stent-graft sizing for endovascular repair of abdominal aortic aneurysm (AAA). METHODS: Preoperative static and electrocardiographically-gated 64-slice computed tomographic angiography (CTA) datasets were acquired on 40 consecutive AAA patients (29 men; mean age 78.9 +/- 6 years, range 75-89). On static images, the aortic neck diameters were manually measured twice by 2 readers at 3 clinically relevant levels (supra-, juxta-, and infrarenal). The measurements were obtained from intima-to-intima (inner wall) and from adventitia-to-adventitia (outer wall). Dynamically reconstructed scans were also reviewed in each phase of the cardiac cycle to identify inner and outer minimum/maximum diameters. Using inner and outer wall measurements performed on static images, readers selected the size of a stent-graft that required inner neck diameter measurements and then one that required outer wall diameters. To calculate the relative oversizing, each selected stent-graft size was compared to that obtained using dynamic measurements. Oversizing <4% or >30% was considered inadequate. RESULTS: Mean variations for the inner and outer wall diameters of 9.75% +/- 4.01% and 8.66% +/ 3.71%, respectively, were recorded on static CTAs; the absolute changes in diameters were 1.82 +/- 0.63 mm and 1.91 +/- 0.64 mm, respectively. No statistically significant differences were found relative to aortic pulsatility at the 3 levels in the neck for the inner or outer wall diameters. Significant variability was seen between inner (mean 20.8 +/- 3.4 mm) vs. outer (mean 23.7 +/ 4.3 mm; p < 0.05) wall diameters. Stent-graft sizes significantly changed on the basis of the measurement method and device; for example, using the outer diameter to size a stent-graft that requires an inner diameter reference changed 36% of the selected stent-graft sizes, with ~20% being excessively oversized. Conversely, using the inner diameter to size an outer-diameter-based stent-graft resulted in nearly 40% of the sizes being altered. Based on dynamic measurements, the changes were more dramatic: the oversizing was considered excessive in up to 90% of patients if the measurement method did not match the stent-graft's stipulated reference. CONCLUSIONS: These data suggest that stent-graft sizing should follow the manufacturer's recommendations for using inner or outer diameter references based on dynamic patterns (mean value between diastolic and systolic diameters suggested). PMID- 21679063 TI - Reproducibility of deriving parameters of AAA rupture risk from patient-specific 3D finite element models. AB - PURPOSE: To assess the reproducibility of estimating biomechanical parameters of abdominal aortic aneurysms (AAA) based on finite element (FE) computations derived from a commercially available, semiautomatic vascular analyzer that reconstructs computed tomographic angiography (CTA) data into FE models. METHODS: The CTA data from 10 consecutive male patients (mean age 74 years, range 63-87) with a fusiform infrarenal AAA >5 cm in diameter were used for this study, along with the CTA scans from 4 individuals without aortic disease. Three different observers used semiautomatic reconstruction software to create deformable contour models from axial CT scans. These 3-dimensional FE models captured the aortic wall and thrombus tissue using isotropic finite strain constitutive modeling. Geometric (maximum diameter and volume measurements based on an anatomical centerline) and biomechanical determinants [aneurysm peak wall stress (PWS) and the peak wall rupture risk (PWRR) index] were then calculated from the FE models. The determinations were made 5 times for each anonymized dataset presented for analysis in random order (5-fold measurements for 14 datasets produced 210 measurements from the 3 observers). Inter- and intraobserver variability were assessed by calculating the coefficient of variation of these repeated measures. The methodological variations were expressed with the intraclass correlation coefficient (ICC) and Bland-Altman plots. RESULTS: The median segmentation time was < 1 hour (mean 39.2 minutes, range 25-48) for datasets from the AAA patients; for the healthy individuals, segmentation times were considerably shorter (median 8.7 minutes, range 4-15). Intraobserver reproducibility was high, as represented by a CV <3% for the diameter measurement and < 5.5% for volume, PWS, and the PWRR index. The ICC was 0.97 (range 0.95-0.98) for diameter and 0.98 (range 0.97-0.99) for volume; for PWS and the PWRR index, the ICCs were equal at 0.98 (range 0.97 0.99). CONCLUSION: The reproducibility of volume and maximum diameter measurements in infrarenal AAAs with FE analysis is high. With the model used in this semiautomatic reconstruction software, wall stress analysis can be achieved with high agreement among observers and in serial measurements by a single observer. PMID- 21679064 TI - Predictive factors for the development of type II endoleaks. AB - PURPOSE: To define predictive factors for endoleak type II (EL-II) based on quantifiable factors in the imaging studies of patients undergoing endovascular aneurysm repair (EVAR). METHODS: The data on 208 consecutive patients (137 men; mean age 75.2 years, range 62-84) who underwent EVAR between the years 2003 and 2008 were retrospectively reviewed. The abdominal aortic aneurysm (AAA) diameter ranged from 4.8 to 12.8 cm. Data were collected on the type of AAA; the type of stent-graft (aortomonoiliac versus bifurcated); the performance of hypogastric artery embolization; the presence, number, diameter, and patency of aortoiliac branches identified on the pre and post-EVAR imaging studies; and the presence and type of EL-II (transient vs. persistent) with the goal of identifying any imaging-based predictive factors for the development of EL-II. RESULTS: Among the 208 cases, 11 patients had endoleaks other than type II and were excluded, leaving 195 patients for analysis. In all, 28 (13.4%) patients were diagnosed with EL-II. All had >=4 patent lumbar arteries (mean diameter >2.3 mm). Ten patients with a transient EL-II had a mean of 4.3 patent lumbar arteries, which had diameters <2 mm (mean 1.5 mm). In the 18 patients with persistent EL-II, the mean diameter of the 4 lumbar arteries was 2.7 mm; at least 1 of the lumbar arteries was >2 mm. The presence of at least 4 patent lumbar arteries (p<0.001) and at least 1 patent hypogastric artery (p<0.001) were predictive factors for EL II. At least 1 lumbar artery >2 mm in diameter was a positive predictive factor for the development of persistent EL-II (p<0.001). CONCLUSION: Patent hypogastric and lumbar arteries are significantly associated with a higher risk of developing EL-II. Larger diameter lumbar arteries tend to be associated with persistent EL IIs, while lumbar arteries <2 mm would more likely be seen with a transient EL II. If substantiated in larger studies, these angiographic criteria may guide early treatment of EL-II to avoid aneurysm sac expansion and potential rupture. PMID- 21679065 TI - Commentary: A step closer to identifying patients at risk of developing clinically significant type II endoleaks. PMID- 21679066 TI - The rationale for lowering the size threshold in elective endovascular repair of abdominal aortic aneurysm. AB - The current size threshold for elective abdominal aortic aneurysm (AAA) repair is 5.5 cm. Over this diameter limit, the AAA rupture rate exceeds the perioperative mortality of open surgical repair. Endovascular aneurysm repair (EVAR) is associated with lower perioperative mortality rates, so it seems logical to hypothesize that the size threshold for endovascular AAA repair should be lowered. The arguments supporting this proposal are: (1) the EVAR-associated mortality rises several fold with increasing age, (2) larger AAAs have more complex anatomy that may not be suitable for EVAR, and (3) smaller AAAs treated with EVAR have lower perioperative and long-term mortality and fewer secondary interventions. Future guidelines may need to consider lowering the size threshold for elective AAA repair in the endovascular era in certain patient subgroups. The reduction of the size threshold should be counterbalanced against the cost of the procedures, as well as the age, life expectancy, and general condition of the patient. PMID- 21679067 TI - Safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. AB - PURPOSE: To evaluate the safety of endovascular treatment of chronic cerebrovascular insufficiency (CCSVI) in patients with multiple sclerosis (MS). METHODS: In a 1-year period, 461 MS patients (261 women; mean age 45.4 years, range 21-79) with CCSVI underwent endovascular treatment of 1012 venous lesions during 495 procedures [34 (6.9%) reinterventions]. While balloon angioplasty was preferred, 98 stents were implanted in 76 patients for lesion recoil, restenosis, or suboptimal dilation. The procedures were analyzed for incidences of major adverse events (death, major bleeding, or clinical deterioration of MS), access site complications, procedure-related complications, and procedural safety related variables (fluoroscopy and contrast times). The complication rates were compared to published data for similar endovascular methods. RESULTS: There were no deaths, major bleeding events, or clinical deterioration of MS. Access site complications included limited groin hematoma (5, 1.0%); there were no arteriovenous fistulas or puncture site infections. Systemic complications included only rare cardiac arrhythmias (6, 1.2%). Procedure-related complications included vein rupture (2, 0.4%), vein dissection (15, 3.0%), acute in-stent/in segment thrombosis (8, 1.6%), and acute recoil (1, 0.2%); there was no stent migration or fracture or distal embolization. Mean fluoroscopy time was 22.7 minutes, and mean contrast volume was 136.3 mL. CONCLUSION: Endovascular therapy appears to be a safe and reliable method for treating CCSVI. Innovations such as purpose-specific materials and devices are needed, as are case-controlled and randomized data to establish efficacy in ameliorating MS symptoms. PMID- 21679068 TI - Commentary: Significance of the internal jugular vein in the treatment of cerebrovascular insufficiency. PMID- 21679069 TI - Commentary: Safety of endovascular treatment for CCSVI and future perspectives. PMID- 21679070 TI - Endovenous mechanochemical ablation of great saphenous vein incompetence using the ClariVein device: a safety study. AB - PURPOSE: To evaluate the feasibility and safety of endovenous mechanochemical ablation (MOCA) for the treatment of great saphenous vein (GSV) incompetence. METHODS: The newly developed ClariVein device uses a technique that combines mechanical endothelial damage using a rotating wire with the infusion of a liquid sclerosant. Heating of the vein and tumescent anesthesia are not required; only local anesthesia is utilized at the insertion site. In a pilot study, 30 limbs in 25 patients (18 women; mean age 52 years) with GSV incompetence were treated with MOCA using polidocanol at 2 centers. Initial technical success, complications, patient satisfaction, and classification by venous clinical severity score (VCSS) were assessed 6 weeks after the treatment. RESULTS: Initial technical success of MOCA was 100%. There were no major adverse events. Minor complications consisted of 9 local ecchymoses at the puncture site and superficial phlebitis that resolved within a week in 4 limbs. Duplex ultrasonography at 6 weeks showed 26 (87%) of 30 veins were completely occluded; 3 veins showed partial recanalization in the proximal (n = 2) and distal GSV. One patient had full segment recanalization and was successfully retreated. The VCSS significantly improved at 6 weeks (p < 0.001). Patient satisfaction was high, with a median satisfaction of 8.8 on a 0-10 scale. CONCLUSION: This study showed that endovenous MOCA, using polidocanol, is feasible and safe in the treatment of GSV incompetence. Larger studies with a prolonged follow-up are indicated to prove the efficacy of this technique in terms of obliteration rates. PMID- 21679071 TI - Commentary: Endovenous mechanochemical ablation: how much improvement is good enough? PMID- 21679072 TI - Endovascular exclusion of thoracic aortic aneurysms with the 1- and 2-component Zenith TX2 TAA endovascular grafts: analysis of 2-year data from the TX2 pivotal trial. AB - PURPOSE: To compare the midterm results of endovascular treatment of thoracic aortic aneurysms and ulcers in patients who received either a 1-component or 2 component Zenith TX2 stent-graft. METHODS: Data were gathered from a prospectively maintained registry for the Zenith TX2 pivotal trial. Among 158 patients who underwent thoracic endovascular aortic repair (TEVAR) between March 2004 and July 2006, 64 received a 1-component stent-graft (group 1) and 94 patients a 2-component device (group 2). RESULTS: In group 2, there were more men (79% vs. 63%; p = 0.03), and the patients had more diagnosed (p<0.01) and previously repaired (p<0.01) abdominal aortic aneurysms. Aneurysms in group 2 were significantly larger in both diameter (63 vs. 56 mm, p<0.01) and length (157 vs. 113 mm, p<0.01). Percent of thoracic aorta covered by the stent-graft was greater in group 2 (80% vs. 50%, p<0.01). Patients in group 2 had a significantly longer operation time (124+/-48 vs. 100+/-39 minutes, p<0.01) and significantly increased estimated blood loss during the procedure (248+/-359 vs. 169+/-139 mL, p = 0.05). Procedural success at 30 days was 95% in group 1 and 85% in group 2 (p = 0.06). Postoperative paraplegia and paraparesis were not observed in group 1, but 9 patients in group 2 (p = 0.01) were affected. Treatment success, endoleak, migration, secondary intervention rate, and all-cause and aneurysm-related mortality were not significantly different between the groups at 30 days, 1 year, and 2 years. CONCLUSION: TEVAR using 1 or 2 TX2 components has similar results in terms of mortality and midterm treatment success. Patients treated with 2 components showed increased perioperative morbidity, including paraplegia, which may be related to the greater extent of graft coverage required in this patient group, as well as to male gender, previous aortic repair, longer operating time, and increased blood loss. PMID- 21679073 TI - Transapical wire-assisted endovascular repair of thoracic aortic dissection. AB - PURPOSE: To describe a technique for transapical wire-assisted endograft deployment under rapid ventricular pacing for a type B dissection involving the proximal left subclavian artery and extending to the aortic bifurcation. CASE REPORT: A 58-year-old man presented with a symptomatic thoracic aneurysm as a complication of a chronic type B dissection, with a short proximal neck in zone 1. After arch vessel debranching, the patient underwent endoluminal repair with deployment of a closed web, tapered Valiant thoracic endograft over a through-and through wire from the left groin to the apex of the left ventricle, using rapid ventricular pacing to reduce cardiac output. The remaining dissected aorta was covered with a second Valiant endograft down to the distal third of the descending thoracic aorta and bare Z stents down to the aortic bifurcation to re expand the true lumen. A freeflow Valiant endograft was deployed as a proximal extension to treat a proximal type I endoleak. The recovery was complicated by retrograde type A aortic dissection, considered secondary to the bare stent. The complication was repaired surgically; postoperative computed tomography after recovery was unremarkable. CONCLUSION: Transapical wire-assisted deployment with rapid ventricular pacing is feasible and may provide improved stability for stenting within the aortic arch. The use of a stent-graft with a proximal bare stent is associated with a higher risk of retrograde extension of the dissection and warrants lifelong imaging follow-up. PMID- 21679074 TI - Commentary: Transapical through-and-through wire technique: another addition to the toolbox for difficult arch anatomies. PMID- 21679075 TI - Commentary: Marching closer toward a convergence of technologies for thoracic aortic endografting and percutaneous heart valve therapies. PMID- 21679076 TI - Technique for branched thoracic stent-graft repair of a chronic type a aortic dissection in a patient with multiple prior sternotomies. AB - PURPOSE: To present a technique for endovascular treatment of a type A aortic dissection in a patient with multiple prior sternotomies and multiple medical comorbidities. TECHNIQUE: The method is illustrated in a 76-year-old man with a history of hypertension, hyperlipidemia, coronary artery disease, and open repair of a type A aortic dissection via a median sternotomy. The latter procedure was complicated by a pericardial effusion requiring drainage and sternal re-wiring. The diameter of the residual type A dissection beginning just distal to the aortic root had increased by 1.5 cm over 1 year, indicating the need for further intervention. To avoid redo sternotomy, a hybrid endovascular approach was planned, but it would require landing the stent in the ascending aortic arch, thus mandating branch vessel revascularization. Prior to stent-graft deployment, right-to-left carotid-carotid and left carotid-subclavian artery bypasses were performed with 8-mm polytetrafluoroethylene grafts. Three Talent grafts were deployed from the celiac artery to the left subclavian artery. A pre-wired homemade branched Talent stent-graft (34*34*115 mm) was used to revascularize the innominate artery and secure the arch. Transvenous ventricular pacing was used to improve deployment accuracy. A 10*38-mm iCast stent was placed through the branch and extended into the innominate artery. The subclavian artery was occluded with 2 Amplatzer plugs. Postoperative computed tomography demonstrated excellent proximal fixation, a widely patent branched graft to the innominate artery, and thrombosis of the aneurysmal false lumen. CONCLUSION: Treatment of type A dissections remains a difficult surgical challenge. The approach taken should be tailored for each patient. We successfully employed a combination of available minimally invasive techniques to treat a patient who was not ideally suited to any of the individual strategies. PMID- 21679077 TI - Commentary: Intuition and innovation in aortic arch repairs. PMID- 21679078 TI - Treatment of residual type A aortic dissection with implantation of the Djumbodis system: is purely endovascular treatment becoming a reality? AB - PURPOSE: To evaluate the usefulness of a new transfemoral device to avoid major complications related to residual type A aortic dissection following ascending aortic replacement. CASE REPORTS: Three men (aged 60, 61, and 72 years, respectively) with a residual type A aortic dissection following replacement of the ascending aorta 1, 4, and 5 years prior, respectively, were treated with the Djumbodis Dissection System. The residual dissection developed at the distal anastomosis of the aortic graft and involved all the aortic arch. The Djumbodis Dissection System is an uncovered steel stent, available in 3 lengths (40, 90, 140 mm), pre-mounted on a low pressure (0.3 bars) balloon catheter. The mesh of the device is sufficiently large to bring together the dissected layers without occluding main vital branches. The device was implanted through the femoral artery over a stiff guidewire to exclude the residual false lumen. Satisfactory aortic remodeling was documented in all cases at 1 year. CONCLUSION: The Djumbodis Dissection System might be a purely endovascular treatment to replace open surgery for residual type A aortic dissection. More cases and longer follow up are required. PMID- 21679079 TI - Commentary: Endovascular treatment of residual aortic dissection. PMID- 21679080 TI - A reliable approach to diabetic neuroischemic foot wounds: below-the-knee angiosome-oriented angioplasty. AB - PURPOSE: To evaluate the clinical benefit in wound healing and limb preservation after primary below-the-knee angioplasty guided by an angiosome model of perfusion in diabetic patients with neuroischemic foot ulcers. METHODS: From September 2001 to April 2010, 232 limb-threatening neuroischemic wounds in 208 diabetic patients (147 men; mean age 74.3 years, range 42-97) were treated by below-the-knee endoluminal and/or subintimal angioplasty. There were 19 (8%) TASC II type B, 80 (34%) type C, and 133 (57%) type D infrapopliteal lesions. Patients treated prior to 2005 when the angiosome-targeted revascularization protocol was introduced (89 limbs, group 1) were compared to 134 limbs treated subsequently according to the angiosome model (group 2). The angiosome-oriented group 2 included 25% procedures focusing on the anterior tibial and dorsalis pedis arteries, 68% on the posterior tibial and plantar vessels, and 7% on the peroneal arteries. RESULTS: The global technical success was 80% (187/232): 82% in group 1 and 79% in group 2. The cumulative patient survival rates were 90%, 78%, and 65% in group 1 and 93%, 82%, and 71% in group 2 at 12, 24, and 36 months, respectively (p = 0.545). At the same time points, the freedom from amputation rates were 84%, 79%, and 79% in group 1 versus 90%, 89%, and 89% in group 2 (p = 0.035). Clinical success rates were 76%, 68%, 68% in the group 1 and 85%, 79%, and 79% in group 2 (p = 0.025). Primary and secondary patency rates did not differ between groups (p = 0.813 and p = 0.511). Patients in group 2 treated with angiosome-targeted revascularization had significantly better wound healing (p<0.018) and limb preservation (p<0.030). CONCLUSION: Below-the-knee first-line angioplasty guided by an angiosome model may prove beneficial in terms of better wound healing of diabetic foot ulcers and subsequent limb salvage. Further technical improvements and large comparative studies are necessary to support these observations. PMID- 21679081 TI - Computational biomechanics to simulate the femoropopliteal intersection during knee flexion: a preliminary study. AB - PURPOSE: To assess if finite element (FE) models can be used to predict deformation of the femoropopliteal segment during knee flexion. METHODS: Magnetic resonance angiography (MRA) images were acquired on the lower limbs of 8 healthy volunteers (5 men; mean age 28 +/- 4 years). Images were taken in 2 natural positions, with the lower limb fully extended and with the knee bent at ~ 40 degrees . Patient-specific FE models were developed and used to simulate the experimental situation. The displacements of the artery during knee bending as predicted by the numerical model were compared to the corresponding positions measured on the MRA images. RESULTS: The numerical predictions showed a good overall agreement between the calculated displacements of the motion measures from MRA images. The average position error comparing the calculated vs. actual displacements of the femoropopliteal intersection measured on the MRA was 8 +/- 4 mm. Two of the 8 subjects showed large prediction errors (average 13 +/- 5 mm); these 2 volunteers were the tallest subjects involved in the study and had a low body mass index (20.5 kg/m2). CONCLUSION: The present computational model is able to capture the gross mechanical environment of the femoropopliteal intersection during knee bending and provide a better understanding of the complex biomechanical behavior. However, results suggest that patient-specific mechanical properties and detailed muscle modeling are required to provide accurate patient specific numerical predictions of arterial displacement. Further adaptation of this model is expected to provide an improved ability to predict the multiaxial deformation of this arterial segment during leg movements and to optimize future stent designs. PMID- 21679082 TI - Impact of carotid stent cell design on vessel scaffolding: a case study comparing experimental investigation and numerical simulations. AB - PURPOSE: To quantitatively evaluate the impact of carotid stent cell design on vessel scaffolding by using patient-specific finite element analysis of carotid artery stenting (CAS). METHODS: The study was organized in 2 parts: (1) validation of a patient-specific finite element analysis of CAS and (2) evaluation of vessel scaffolding. Micro-computed tomography (CT) images of an open-cell stent deployed in a patient-specific silicone mock artery were compared with the corresponding finite element analysis results. This simulation was repeated for the closed-cell counterpart. In the second part, the stent strut distribution, as reflected by the inter-strut angles, was evaluated for both cell types in different vessel cross sections as a measure of scaffolding. RESULTS: The results of the patient-specific finite element analysis of CAS matched well with experimental stent deployment both qualitatively and quantitatively, demonstrating the reliability of the numerical approach. The measured inter-strut angles suggested that the closed-cell design provided superior vessel scaffolding compared to the open-cell counterpart. However, the full strut interconnection of the closed-cell design reduced the stent's ability to accommodate to the irregular eccentric profile of the vessel cross section, leading to a gap between the stent surface and the vessel wall. CONCLUSION: Even though this study was limited to a single stent design and one vascular anatomy, the study confirmed the capability of dedicated computer simulations to predict differences in scaffolding by open- and closed-cell carotid artery stents. These simulations have the potential to be used in the design of novel carotid stents or for procedure planning. PMID- 21679083 TI - Enhanced efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents in the prevention of restenosis. AB - PURPOSE: To determine the efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents (SEBMAS) in restenosis prevention. METHODS: A balloon-expandable bioabsorbable magnesium alloy stent (BMAS) was created and coated with biodegradable poly(lactic acid-co-trimethylene carbonate) that contained the antiproliferative drug sirolimus (140 +/- 40 ug/cm2). Both the uncoated BMAS and the coated SEBMAS were deployed 2 cm apart in balloon-injured infrarenal abdominal aortas of 20 New Zealand white rabbits. The stented aortic segments were removed at 30, 60, 90, and 120 days (5 rabbits per interval) after implantation. The average stent strut sectional area of each group was measured to evaluate the degree of magnesium corrosion and to forecast the biodegradation time profile of the magnesium stent. Histology and histopathology of the sectioned stented aortic segments were performed to evaluate neointima formation, endothelialization, and inflammation. RESULTS: The SEBMAS degraded gradually after being implanted into the rabbit aorta, and total biocorrosion occurred after ~120 days. In all groups, the lumen area was significantly greater, but the neointimal area was significantly smaller in SEBMAS segments compared with the uncoated BMAS segments (p < 0.05) at all time points. There was no significant difference in the injury or inflammation scores between the groups. Endothelialization was delayed at 30 days in the SEBMAS segments vs. the uncoated BMAS segments. CONCLUSION: SEBMAS further reduces intimal hyperplasia and improves the lumen area when compared to uncoated BMAS; however, it delays vascular healing and endothelialization. PMID- 21679084 TI - Commentary: Deliver the drug and disappear: is the bioabsorbable magnesium stent growing up or still shrinking? PMID- 21679085 TI - Advancements in catheter-directed ultrasound-accelerated thrombolysis. AB - PURPOSE: To review all available literature on catheter-directed ultrasound accelerated thrombolysis for peripheral artery occlusions, stroke, deep venous thrombosis, and pulmonary embolism. METHODS: A systematic literature search was performed, using MEDLINE, EMBASE and Cochrane databases. A total of 77 reports focusing on catheter-delivered ultrasound-accelerated thrombolysis were identified. RESULTS: Experimental studies show that high intensity ultrasound may induce thrombolysis, with and without the addition of plasminogen activators, mainly by acoustic cavitation and mechanical disruption, while low intensity, high frequency ultrasound waves may actually enhance plasmin-mediated thrombolysis. In a total of 340 clinical cases of various thromboembolic conditions, catheter-directed ultrasound-accelerated thrombolysis was related to rapid revascularization and a reduction in treatment time, drug dosage, hospitalization time, and possibly major bleeding complications compared to standard thrombolysis. Reported complication rates, including bleeding and embolization, were low. CONCLUSION: Ultrasound enhanced thrombolysis seems to be a promising concept in the treatment of various thromboembolic conditions. The technique has shown to be safe and efficacious in vitro, in vivo, and in clinical studies. Randomized controlled trials are warranted and should be awaited before considering catheter-directed ultrasound-accelerated thrombolysis as a new standard treatment. PMID- 21679086 TI - Safety and efficacy of the StarClose vascular closure device in more than 1000 consecutive peripheral angioplasty procedures. AB - PURPOSE: To present a large single-center retrospective study investigating the safety and efficacy of the StarClose extravascular closure device in achieving hemostasis after antegrade or retrograde femoral artery catheterization during peripheral angioplasty procedures. METHODS: Between January 2004 and October 2009, 1213 StarClose devices were implanted in 850 consecutive patients (598 men; mean age 65.8 +/- 12.2 years) who underwent peripheral endovascular procedures. Femoral artery punctures included 625 (51.5%) retrograde and 588 (48.5%) antegrade accesses. The primary endpoints were hemostasis success, device failure, and major and minor complication rates up to 30 days. RESULTS: A 6-F vascular sheath was used in the majority of cases [39 (3.2%) 7-F and 9 (0.7%) 8 F]. The device was applied more than once in the same femoral artery of 124 (10.2%) limbs during different angioplasty sessions. Overall hemostasis success was achieved in 1139 (93.9%) cases. In 237 (20.8%) of those, additional manual compression for <5 minutes was necessary due to immediate vessel oozing. The remaining 74 (6.1%) cases required prolonged standard manual compression because of hemostasis failure, including 13 (1.1%) failures to deliver the clip. Overall major and minor complication rates were 0.3% (4/1213) and 5.3% (64/1213), respectively. CONCLUSION: The StarClose vascular closure device is safe and effective in achieving hemostasis during antegrade and retrograde peripheral angioplasty procedures. PMID- 21679087 TI - Vaccinomics for the major blood feeding helminths of humans. AB - Approximately one billion people are infected with hookworms and/or blood flukes (schistosomes) in developing countries. These two parasites are responsible for more disability adjusted life years lost than most other neglected tropical diseases (NTDs), and together, are second only to malaria. Although anthelmintic drugs are effective and widely available, they do not protect against reinfection, resistant parasites are likely to emerge, and mass drug administration programs are unsustainable. Therefore, there is a pressing need for the development of vaccines against these parasites. In recent years, there have been major advances in our understanding of hookworms and schistosomes at the molecular level through the use of "omics" technologies. The secretomes of these parasites have been characterized using transcriptomics, genomics, proteomics, and newly developed gene manipulation and silencing techniques, and the proteins of interest are now the target of novel antigen discovery approaches, notably immunomics. This research has resulted in the discovery, development, and early stage clinical trials of subunit vaccines against hookworms and schistosomes. PMID- 21679088 TI - Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development. AB - INTRODUCTION: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity. AREAS COVERED: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing. EXPERT OPINION: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC. PMID- 21679089 TI - Drug delivery in soft tissue engineering. AB - INTRODUCTION: Tissue defects, sustained through disease or trauma, present enormous challenges in regenerative medicine. Modern tissue engineering (TE) aims at replacing or repairing these defects through a combined approach of biodegradable scaffolds, suitable cell sources and appropriate environmental cues, such as biomolecules presented on scaffold surfaces or sustainably released from within. AREAS COVERED: This review provides a brief overview of the various drugs and bioactive molecules of interest to TE, as well as a selection of materials that have been proposed for TE scaffolds and matrices in the past. It then proceeds to discuss encapsulation, immobilization and controlled release strategies for bioactive proteins, before discussing recent advances in this area with a special focus on soft TE. EXPERT OPINION: Overall, minimal clinical success has been achieved so far in using growth factor, morphogen, or adhesion factor modified scaffolds and matrices; only one growth factor delivery system (Regranex Gel), has been approved by the FDA for clinical use, with only a handful of other growth factors being approved for human use so far. However, many more growth factors are currently in clinical Phase I - II or preclinical trials and many delivery systems utilize materials already approved by the FDA for other purposes. With respect to drug delivery in soft TE, a combination of increased research efforts in hydrogel and support material development as well as growth factor development is needed before clinical success is realized. PMID- 21679090 TI - From dorzolamide 2%/timolol 0.5% to brinzolamide 1%/timolol 0.5% fixed combination: a 6-month, multicenter, open-label tolerability switch study. AB - PURPOSE: To assess ocular surface status and tolerability after switching glaucoma patients from dorzolamide/timolol to brinzolamide/timolol fixed combination (FC). METHODS: Six-month, multicenter, open-label, prospective study that switched 72 patients from dorzolamide/timolol to brinzolamide/timolol FC. Intraocular pressure (IOP), tear film break-up-time (TF-BUT), fluorescein staining and Glaucoma Symptom Scale (GSS) questionnaire were recorded at baseline and after 6 months. RESULTS: Median interquartile range (IQR) IOP was 16 (IQR 15 18) mmHg at baseline and 16 (15 - 17) mmHg and 6 months. TF-BUT significantly improved (p < 0.0001); the regression analysis found a negative association between TF-BUT changes and age at baseline and at month 6 (r = -0.32; p = 0.0082 and r = -0.31; p = 0.0085). Patients with no corneal fluorescein staining statistically increased after substitution (p = 0.04). Quality of life - as examined by the GSS symptoms (SYMP) score - statistically improved (p < 0.0001), revealing an association between GSS SYMP score and age [coefficient -0.67, 95% confidence interval (CI) -1.13 to -0.21, p = 0.0005), superficial keratitis (coefficient -8.26, 95% CI -15.73 to -0.80, p = 0.031) and TF-BUT (coefficient 4.94, 95% CI 1.71 to 8.17, p = 0.003). CONCLUSION: Brinzolamide/timolol FC is associated with reduced topical discomfort and improved signs of ocular surface disease. The good tolerability and comfort of this FC might contribute to good patient adherence. PMID- 21679091 TI - Sodium oxybate for the treatment of fibromyalgia. AB - INTRODUCTION: Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that is synthesized within the CNS, mostly from its parent compound gamma amino butyric acid (GABA). GHB acts as a neuromodulator/neurotransmitter to affect neuronal activity of other neurotransmitters and so, stimulate the release of growth hormone. Its sodium salt (sodium oxybate: SXB) was approved by the Food and Drug Administration (FDA) for the treatment of narcolepsy. SXB has shown to improve disrupted sleep and increase NR3 (slow-wave restorative) sleep in patients with narcolepsy. It is rapidly absorbed and has a plasma half-life of 30 - 60 min, necessitating twice-nightly dosing. Most of the observed effects of SXB result from binding to GABA-B receptors. AREAS COVERED: Several randomized, controlled trials demonstrated significantly improved fibromyalgia (FM) symptoms with SXB. As seen in narcolepsy trials, SXB improved sleep of FM patients, increased slow wave sleep duration as well as delta power, and reduced frequent night-time awakenings. Furthermore, FM pain and fatigue was consistently reduced with nightly SXB over time. Commonly reported adverse events included headache, nausea, dizziness and somnolence. Despite its proven efficacy, SXB did not receive FDA approval for the management of FM in 2010, mostly because of concerns about abuse. EXPERT OPINION: Insomnia, fatigue and pain are important clinical FM symptoms that showed moderate improvements with SXB in several large, well designed clinical trials. Because of the limited efficacy of currently available FM drugs additional treatment options are needed. In particular, drugs like SXB - which belong to a different drug class than other Food and Drug Administration (FDA)-approved FM medications such as pregabalin, duloxetine and milnacipran - would provide a much-needed addition to presently available treatment options. However, the FDA has set the bar high for future SXB re-submissions, with requirements of superior efficacy and improved risk mitigation strategies. At this time, no future FDA submission of SXB for the fibromyalgia indication is planned. PMID- 21679092 TI - Autoimmune phenomena in untreated and treated marginal zone lymphoma. AB - INTRODUCTION: Current literature suggests an association between various autoimmune conditions and marginal zone lymphoma (MZL). However, these autoimmune conditions have not been comprehensively systematized to date. As a result, their clinical implications remain largely unknown. AREAS COVERED: The authors provide a comprehensive review of the existing literature on various autoimmune abnormalities documented in the course of MZL, as well as on autoimmune alterations induced by certain MZL therapies. EXPERT OPINION: The course of MZL is accompanied by a variety of hematologic and non-hematologic autoimmune disorders. Whereas some of them could be secondary and related to the course of the MZL, others may be primary and might even favor the development of MZL itself. In addition, authentic autoimmune conditions have been documented with the use of rituximab as a single agent and the nucleoside analogs. Therefore, we believe caution should be exerted with the use of these agents in MZL patients with evidence of autoimmune disorders, as exacerbation of autoimmune phenomena can be anticipated. While the heterogeneity of the MZL subtypes represents an inherent limitation, integration of emerging information from immunology research laboratories and clinical practice could translate into improved outcomes of this disease spectrum. PMID- 21679093 TI - A screening method for phosphohistidine phosphatase 1 activity. AB - Abstract Introduction. Research in the field of protein-bound phosphohistidine phosphorylation has been hampered by the difficulties in analysis and detection of phosphohistidine. Therefore a screening method was developed primarily for the analysis of phosphohistidine phosphatase 1 (PHPT1) activity. Methods. A highly positively charged substrate, Ac-Val-Arg-Leu-Lys-His-Arg-Lys-Leu-Arg-pNA, containing the peptide surrounding the phosphorylated histidine in ion channel KCa3.1 was chemically phosphorylated using phosphoramidate. Excess phosphoramidate was removed by anion exchange chromatography using a micro spin column. After incubation of the eluate with PHPT1, the removed phosphate was bound on a consecutive anion exchange spin column. The eluate was assayed in a micro plate format for remaining phosphate in the substrate Ac-Val-Arg-Leu-Lys His(P)-Arg-Lys-Leu-Arg-pNA. Histone H4, also highly positive in charge, was subjected to the same procedure to explore the possibility to use other substrates to PHPT1 in this assay format. Results. It was found that Ac-Val-Arg Leu-Lys-His(P)-Arg-Lys-Leu-Arg-pNA and phosphohistone H4 were dephosphorylated by PHPT1. The apparent K(m) for Ac-Val-Arg-Leu-Lys-His(P)-Arg-Lys-Leu-Arg-pNA was in the order of 10 MUM.Using this method, phosphohistidine phosphatase activity was detected in mouse liver cell sap with Ac-Val-Arg-Leu-Lys-His(P)-Arg-Lys-Leu-Arg pNA as substrate. Discussion. The described method for determination of PHPT1 activity is comparably much easier and faster than presently used methods for detection of phosphohistidine phosphatase activity. It is also sensitive, since the lower activity limit was 5 pmol phosphate released per min. It has the potential to be used both for more rapid screening for inhibitors and activators to phosphohistidine phosphatases and for screening of histidine kinases. PMID- 21679094 TI - Relationship between articular cartilage damage and subchondral bone properties and meniscal ossification in the Dunkin Hartley guinea pig model of osteoarthritis. AB - OBJECTIVES: To describe the age-related changes of articular cartilage, subchondral bone morphology, and stiffness. Furthermore, to investigate whether subchondral bone histological and mechanical properties and meniscal histological properties are related to articular cartilage damage in the Dunkin Hartley guinea pig model of osteoarthritis (OA). METHODS: Forty male Dunkin Hartley guinea pigs aged 2, 6, 9, and 12 months were studied. The right stifle joints and the left menisci were embedded undecalcified and the tibial articular cartilage and subchondral bone and the menisci were examined using histology. The stiffness of the left tibial subchondral bone was determined with indentation testing. RESULTS: The Osteoarthritis Research Society International (OARSI) grade of the osteoarthritic cartilage lesions of the medial (p < 0.001) and lateral (p < 0.001) condyle and the ossification of the medial (p < 0.001) and lateral (p < 0.001) meniscus increased significantly with age and was significantly more pronounced at the medial condyle than at the lateral condyle. The grade of the osteoarthritic cartilage lesions was significantly correlated (r = 0.78, p < 0.001) with the meniscal ossification, weakly correlated (r = 0.34, p < 0.007) with the subchondral bone plate thickness, and not correlated with the subchondral bone density (r = -0.010, p = 0.94) and the subchondral bone stiffness (r = -0.13, p = 0.30). CONCLUSION: The meniscal ossification observed in Dunkin Hartley guinea pigs may play an important role in the pathogenesis of OA in these animals. PMID- 21679096 TI - Reactive arthritis in a population exposed to an extensive waterborne gastroenteritis outbreak after sewage contamination in Pirkanmaa, Finland. AB - OBJECTIVES: To assess the occurrence, clinical picture, and triggering infections of reactive arthritis (ReA) associated with a large waterborne gastroenteritis outbreak. METHODS: After an extensive sewage contamination of the water supply system, an estimated 8453 of the 30 016 inhabitants of the town of Nokia fell ill. General practitioners and occupational physicians were advised to refer any patients with suspicion of new ReA to rheumatological examination including faecal culture, human leucocyte antigen (HLA)-B27 and antibody tests for Campylobacter, Salmonella, and Yersinia. RESULTS: Forty-five patients (33 females, 12 males) aged 16-77 years (median 53) were referred. ReA was diagnosed in 21, postinfectious arthralgia in 13, and other musculoskeletal conditions in 11 patients. HLA-B27 was positive in five out of 44 patients (11%). Of the 21 patients with ReA, possible triggering infections were observed in seven (33%), Campylobacter in four, Yersinia in three, and Salmonella in one, who also had Campylobacter infection. ReA was mild in all but one patient who presented with persistent Salmonella enterica serotype enteritidis infection. CONCLUSIONS: Taking into account the large population contaminated with potentially arthritogenic agents, the occurrence of ReA was rare and mild in character. PMID- 21679097 TI - Vildagliptin in the treatment of type 2 diabetes mellitus. AB - INTRODUCTION: Inhibition of dipeptidyl peptidase IV (DPP-4) augments glucose dependent insulin release and is a new approach to the treatment of type 2 diabetes (T2DM). Vildagliptin is a new DPP-4 inhibitor approved in many countries for the treatment of T2DM. This review provides an overview of vildagliptin with emphasis on its pharmacology and clinical effectiveness. AREAS COVERED: Results of preclinical and several Phase II and III studies from 2004 - 2010 are discussed. EXPERT OPINION: Vildagliptin acts to inhibit the breakdown of glucagon like peptide (GLP)-1, which in turn enhances the beta-cell response to glucose and inhibits glucagon secretion. It is an effective agent alone or in combination in patients with T2DM, resulting in modest improvements in HbA1c usually in the 0.5 - 1% range. Advantages include weight neutrality and a lesser incidence of hypoglycemia. Concerns remain regarding its use in renal disease and potential complications seen in animal models. PMID- 21679098 TI - Gender differences in perception of dyspnea, assessment of control, and quality of life in asthma. AB - BACKGROUND: There is limited information on the inter-relationship between gender, perception of dyspnoea and health-related quality of life (HRQoL) in asthma. METHODS: In a cross-sectional study in an out-patient setting, 85 patients with bronchial asthma, 41 males and 44 females, underwent spirometry and were administered the following instruments to measure asthma control, HRQoL and dyspnoea : (a) Asthma control questionnaire (ACQ), (b) Asthma Quality of Life questionnaire (AQLQ), (c) Baseline dyspnoea index (BDI) questionnaire and Oxygen Cost Diagram (OCD). RESULTS: Overall, male patients had greater airways obstruction but reported similar level of asthma control as females. Among patients with mild persistent asthma, females had a poorer level of control. The BDI and the OCD scores were significantly lower in female patients indicating greater dyspnoea and they also had a poorer quality of life especially in the symptoms and emotional domains of the AQLQ. After adjusting for the severity of airways obstruction in multivariate analysis, female gender and a poorer quality of life were independent predictors of increased perception of dyspnoea. CONCLUSIONS: Female patients with asthma are likely to have a greater perception of dyspnoea, report a poorer control and have a poorer quality of life as compared to males. Female gender and a poorer quality of life are independent predictors of increased perception of dyspnoea in asthmatics. PMID- 21679099 TI - Translational research on prolyl oligopeptidase inhibitors: the long road ahead. AB - Despite the fact that some have passed early phases of clinical trials, no prolyl oligopeptidase inhibitors are currently on the market. Yet, since 2003, there has been a boost in patent applications claiming prolyl oligopeptidase inhibitors for the treatment of Alzheimer's and Parkinson's diseases, and other neurodegenerative and psychiatric disorders. While experts in the field call for innovative scaffolds to develop more potent inhibitors with more favorable properties, they also relate a lack of knowledge of the toxicology, bioavailability, pharmacokinetics and pharmacodynamics of existing compounds that hinders their assessment. Yet, with the current insights, it is difficult to correlate specific inhibitor effects with the postulated functions of prolyl oligopeptidase in the brain. PMID- 21679101 TI - Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease. AB - Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory disorders of the respiratory tract that are characterized by airflow limitation. They are distinct conditions with different causes, structural changes, and immunopathology. The pathophysiology in asthma and COPD involves not only the proximal large airways, but also the distal small airways, and thus the small airways are an important therapeutic target in the treatment of both diseases. The assessment of diseased distal small airways is challenging. Extensive disease can be present in the small airways with little abnormality in conventional pulmonary function tests. Recent advances in imaging technologies have led to better spatial resolution to assess small airways morphology non-invasively. New physiological tests have been developed to detect disease and response to therapy in regional airways. Improving the efficiency of existing aerosolized therapy to direct drug to the appropriate lung regions may improve clinical efficacy. Approaches to target distal lung regions include developing new drug formulations with smaller aerosol particle size or using inhaler devices that emit aerosolized drug at slow inhalation flows. Large studies are needed to determine whether better distal lung deposition leads to improvements in small airways function that are translated into clinically significant patient outcomes. PMID- 21679102 TI - Increased daily sodium intake is an independent dietary indicator of the metabolic syndrome in middle-aged subjects. AB - AIMS: We investigated the association between daily sodium intake and each individual component of the metabolic syndrome (MS) as well as the metabolic cluster per se and clarified which of the combinations of MS features is particularly associated with sodium intake. METHODS: A total of 716 subjects from our OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort were selected to fill in a food follow-up diary for a 1-week period. The MS was determined using the International Diabetes Federation (IDF) criteria. RESULTS: Subjects with the MS used more sodium (P < 0.001), less carbohydrate (P < 0.001), less fibre (P = 0.031), and more alcohol (P < 0.001) than those without the MS. High sodium intake was strongly related to elevated BMI (P = 0.003), waist (P < 0.001), and higher fasting blood glucose (P < 0.001). The subjects with the highest sodium intake suffered more often from type 2 diabetes (P = 0.007). Sodium intake was highest in the group where all the MS criteria were present (P < 0.001). High sodium intake was a statistically significant predictor of the MS in logistic regression analysis (P = 0.009). The highest sodium intake was observed in the IDF criteria combination waist + glucose + blood pressure. CONCLUSIONS: These findings suggest that a reduction in sodium intake may be especially beneficial in the treatment of individuals with the MS. PMID- 21679103 TI - Specific immunotherapy for allergic rhinitis to grass and tree pollens in daily medical practice-symptom load with sublingual immunotherapy compared to subcutaneous immunotherapy. AB - Abstract Background. Despite strong evidence for subcutaneous and sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis, comparative data are scarce. Objectives. We performed an individual patient data meta-analysis of four observational studies to compare the effectiveness of both application routes. Methods. After individual analysis, a subsequent analysis of the total data pool was performed. Descriptive and explorative data analysis methods were used. Results. Altogether 847 patients (382 male, 453 female) aged 3-78 years (mean age 28.3 years) were treated with specific immunotherapy: 665 (78.5%) patients sublingual and 182 (21.5%) subcutaneous. The majority of patients (61.6%) in both treatment groups started specific immunotherapy due to severe rhinitis symptoms which occurred frequently or very frequently. Most patients in both treatment groups had moderate to severe conjunctivitis symptom load which occurred frequently or very frequently. Median rhinitis and conjunctivitis symptom loads decreased during both treatments to the same extent. Similar improvements in the symptom loads were observed in patients stratified for age, disease duration, and presence or absence of mild to moderate asthma. Conclusion. The effectiveness of sublingual and subcutaneous immunotherapy with pollen extracts appeared virtually equal in daily medical routine. Due to the advantageous safety profile, the sublingual application may be favorable. PMID- 21679105 TI - Electrocardiographic presentation of global ischemia in acute coronary syndrome predicts poor outcome. AB - BACKGROUND: Global ischemia (GI) electrocardiogram (ECG), wide-spread ST depression with inverted T waves maximally in leads V(4-5), and lead aVR ST elevation (STE), is a marker of an adverse outcome in patients with non-ST elevation acute coronary syndromes (ACS), perhaps because this pattern is indicative of left main stenosis. The prognostic value of this ECG pattern has not been established. AIMS: The distribution of ECG changes and the prognostic value of the GI ECG were studied. METHODS: ECGs of consecutive patients admitted with suspected ACS (n = 1,188) were classified into seven ECG categories: STE, Q waves without STE, left bundle branch block, left ventricular hypertrophy, GI ECG, other ST depression and/or T wave inversion, and other findings. RESULTS: The GI ECG pattern predicted a high rate (48%) of composite end-points (mortality, re-infarction, unstable angina, resuscitation, or stroke) at 10-month follow-up compared to the other ECG categories (36%) (HR 1.78; CI 95% 1.31-2.41; P < 0.001). In multivariate analysis, the GI ECG pattern was associated with a higher rate of composite end-points (HR 1.40; CI 95% 1.02-1.91; P = 0.035). The multivariate analysis furthermore identified age, creatinine level, and diabetes as independent predictors of prognosis. CONCLUSIONS: The GI ECG pattern predicted an unfavorable outcome, when compared to other ECG patterns in patients with ACS. PMID- 21679104 TI - Diabetic vascular disease and the potential role of macrophage glucose metabolism. AB - Cardiovascular complications remain the leading cause of mortality in adult human subjects with diabetes. Hyperglycemia has long been hypothesized to explain some of the effects of diabetes on cardiovascular complications caused by atherosclerosis, but a clear causative role for hyperglycemia has not been established. Recent studies in animal models indicate that glucose may play a role in diabetes-accelerated atherosclerosis by promoting pro-inflammatory responses in myeloid cells, which are key cell types in atherosclerosis. For example, monocytes and macrophages often take on a more pro-inflammatory phenotype in the setting of diabetes. Moreover, in-vitro studies demonstrate a connection between pro-inflammatory molecules and glucose metabolism in macrophages and dendritic cells. This review concerns the role of glucose metabolism in inflammatory macrophages, and their potential role in diabetic vascular disease. Further in-vivo studies, focusing on myeloid-specific effects of glucose metabolism as it relates to atherosclerosis, are needed to increase our understanding of the relationship between diabetes, myeloid cells, and cardiovascular disease. PMID- 21679106 TI - Platelet kinetics after slow versus standard transfusions: a pilot study. AB - BACKGROUND: Platelet transfusion is required in the acute phase of some thrombocytopenic disorders in order to prevent potentially dangerous hemorrhages.The purpose of this study was to assess the increase in platelet count following a slow platelet transfusion. METHODS: Patients suffering from thrombocytopenia due to various underlying diseases were enrolled in the prospective pilot feasibility trial and were randomly divided into two groups. Standard platelet transfusion was administered in one group, while slow transfusion was used in the other. The platelet count was examined at 1 hour, 24 hours, and 1 week following the transfusions. RESULTS: Although the platelet count was higher following 1 hour after transfusion via the standard method, the count tended to be higher 1 week after the transfusion in the slow transfusion group. This difference, however, only turned out to be statistically significant amongst females. CONCLUSION: A therapy of slow platelet transfusion might be more effective for the prevention of platelet loss. Further studies will be required to strengthen this hypothesis. PMID- 21679108 TI - Neuroproteomics and Parkinson's disease: don't forget human samples. PMID- 21679107 TI - Implementation of HIV early infant diagnosis and HIV type 1 RNA viral load determination on dried blood spots in Cameroon: challenges and propositions. AB - The testing of dried blood spots (DBSs) for human immunodeficiency type 1 (HIV-1) proviral DNA by PCR is a technology that has proven to be particularly valuable in diagnosing exposed infants. We implemented this technology for HIV-1 early infant diagnosis (EID) and HIV-1 RNA viral load determination in infants born of HIV-1-seropositive mothers from remote areas in Cameroon. The samples were collected between December 2007 and September 2010. Fourteen thousand seven hundred and sixty-three (14,763) DBS samples from infants born of HIV-positive mothers in 108 sites nationwide were tested for HIV. Of these, 1452 were positive on first PCR analyses (PCR1), giving an overall infection rate of 12.30%. We received only 475 DBS specimen for a second PCR testing (PCR2); out of these, 145 were positive. The median HIV-1 RNA viral load for 169 infant DBS samples tested was 6.85 log copies/ml, with values ranging from 3.37 to 8 log copies/ml. The determination of the viral load on the same DBS as that used for PCR1 allowed us to bypass the PCR2. The viral load values were high and tend to decrease with age but with a weak slope. The high values of viral load among these infants call for early and effective administration of antiretroviral therapy (ART). The findings from this study indicate that the use of DBS provides a powerful tool for perinatal screening programs, improvement on the testing algorithm, and follow-up during treatment, and thus should be scaled up to the entire nation. PMID- 21679109 TI - Back to the future in bladder cancer research. PMID- 21679111 TI - Latex beads internalization and quantitative proteomics join forces to decipher the endosomal proteome. AB - The proteome analysis of endocytic compartments has been constrained by the limited purity of the organelle fractions obtained by current biochemical methods. Duclos and coworkers have developed a novel method to isolate highly purified endosomal organelles based on small latex beads internalization followed by gradient centrifugation and successfully combined it with a redundant peptide counting method to compare the relative abundance of proteins in organelles. The presence of bona fide markers in their respective subcellular organelles and the identification of several new endosomal-associated proteins, attested the applicability of their combinatory approach. Future applications of this strategy may deliver a comprehensive endosomal proteome chart: from the identification of the key players to the determination of time and signaling-dependent proteome changes. As a long-term perspective, such an approach may unveil new clues to the molecular mechanisms underlining human diseases associated with endosomal biogenesis defects. PMID- 21679112 TI - Searching for biomarkers: humoral response profiling with luciferase immunoprecipitation systems. AB - B-cell-mediated humoral responses are triggered in many human diseases, including autoimmune diseases, cancer, and neurologic and infectious diseases. However, the full exploitation of the information contained within a patient's antibody repertoire for diagnosis, monitoring and even disease prediction has been limited due to the poor diagnostic performance of many immunoassay formats. We have developed luciferase immunoprecipitation systems (LIPS) that harnesses light emitting proteins to generate high-definition antibody profiles that are optimal for both diagnostics and biomarker discovery. Here, we describe the results and implications from a range of LIPS-antibody profiling studies performed in our laboratory. These include highly sensitive diagnostics for domestic and global pathogens, insights into infection-related diseases, discovery of new biomarkers for human diseases, subcategorization of symptoms and identification of pathogenic autoantibodies against self-proteins. These investigations highlight the types of humoral response profiles associated with different diseases, provide new information related to disease pathogenesis and offer a framework for incorporating LIPS antibody profiling into global health initiatives and disease monitoring. PMID- 21679113 TI - Capitalizing on the hydrophobic bias of electrospray ionization through chemical modification in mass spectrometry-based proteomics. AB - Protein chemical derivatization has emerged as an invaluable bioanalytical approach in mass spectrometry-based proteomics with nearly unlimited potential. To date, derivatization strategies in proteomics have primarily focused on improving mass spectral identification and relative quantification of proteins, as well as increasing enrichment yield from complex mixtures. However, there is a great opportunity to develop and exploit front-end chemical processes to enhance the ability to detect low-abundant peptides and proteins for a large number of applications. The content of this article focuses on improvements in targeted, mass spectrometry-based proteomic strategies, achieved by taking advantage of the mechanism of ESI through the use of hydrophobic chemical derivatization. PMID- 21679114 TI - Proteomics moves from expression to turnover: update and future perspective. AB - Proteomics is a rapidly developing discipline that seeks to understand the role of proteins in the wider biological context. In order to take a holistic view of a biological system, it is vital that we can elucidate the dynamics of the proteome. In this article, we have outlined the recent advances in experimental strategies for measuring protein synthesis and degradation on a proteome-wide scale. The application of mass spectrometry and non-mass spectrometric-based approaches in this field of research has been discussed. The article also explores the challenges associated with these types of analyses and the development of appropriate bioinformatic resources for interrogating the complex datasets that are generated. PMID- 21679115 TI - Advantages of mRNA display selections over other selection techniques for investigation of protein-protein interactions. AB - mRNA display is a genotype-phenotype conjugation method that allows for amplification-based, iterative rounds of in vitro selection to be applied to peptides and proteins. mRNA display can be used to display both long natural protein and short synthetic peptide libraries with unusually high diversities for the investigation of protein-protein interactions. Here, we summarize the advantages of mRNA display by comparing it with other widely used peptide or protein-selection techniques, and discuss various applications of this technique in studying protein-protein interactions. PMID- 21679116 TI - Human urine proteomics: building a list of human urine cancer biomarkers. AB - In the last decade, several reports have focused on the identification and characterization of proteins present in urine. In an effort to build a list of proteins of interest as biomarkers, we reviewed the largest urine proteomes and built two updated lists of proteins of interest (available as supplementary tables). The first table includes a consensus list of 443 proteins found in urine by independent laboratories and reported on the top three largest urine proteomes currently published. This consensus list of proteins could serve as biomarkers to diagnose, monitor and manage a number of diseases. Here, we focus on a reduced list of 35 proteins with potential interest as cancer biomarkers in urine following two criteria: first, proteins previously detected in urine using bottom up proteomic experiments, and second, those suggested as cancer protein biomarkers in human plasma. In an effort to standardize the information presented and its use in future studies, here we include the updated International Protein Index (v. 3.80) and primary Swiss-Prot accession numbers, official gene symbols and recommended full names. The main variables that influence urine proteomic experiments are also discussed. PMID- 21679118 TI - Magnetic nanoparticles-based digestion and enrichment methods in proteomics analysis. AB - In proteome research, rapid and effective proteolysis and enrichment strategies are essential for successful protein identification. Functionalized magnetic microspheres of micro- and nano-meter size are gaining increasing attention due to their easy manipulation and recovery, great specific surface areas and high surface activity. The introduction of magnetic nanoparticles into the field of proteomics study has accelerated the development of digestion and enrichment methods. In this article, we mainly focus on recent developments of using different functionalized magnetic nanoparticles for rapid digestion and preconcentration of low-abundance peptides/proteins, including those containing post-translational modifications, such as phosphorylation and glycosylation, prior to mass spectrometric analysis. PMID- 21679117 TI - Proteomic responses of skeletal and cardiac muscle to exercise. AB - Regular exercise is effective in the prevention of chronic diseases and confers a lower risk of death in individuals displaying risk factors such as hypertension and dyslipidemia. Thus, knowledge of the molecular responses to exercise provides a valuable contrast for interpreting investigations of disease and can highlight novel therapeutic targets. While exercise is an everyday experience and can be conceptualized in simple terms, it is also a complex physiological phenomenon and investigation of exercise responses requires sophisticated analytical techniques and careful standardization of the exercise stimulus. Proteomic investigation of exercise is in its infancy but the ability to link changes in function with comprehensive changes in protein expression and post-translational modification holds great promise for advancing physiology. This article highlights recent pioneering work investigating the effects of exercise in skeletal and cardiac muscle that has uncovered novel mechanisms underlying the benefits of physical activity. PMID- 21679119 TI - Recent progress in predicting protein sub-subcellular locations. AB - In the last two decades, the number of the known protein sequences increased very rapidly. However, a knowledge of protein function only exists for a small portion of these sequences. Since the experimental approaches for determining protein functions are costly and time consuming, in silico methods have been introduced to bridge the gap between knowledge of protein sequences and their functions. Knowing the subcellular location of a protein is considered to be a critical step in understanding its biological functions. Many efforts have been undertaken to predict the protein subcellular locations in silico. With the accumulation of available data, the substructures of some subcellular organelles, such as the cell nucleus, mitochondria and chloroplasts, have been taken into consideration by several studies in recent years. These studies create a new research topic, namely 'protein sub-subcellular location prediction', which goes one level deeper than classic protein subcellular location prediction. PMID- 21679120 TI - The SODyssey: superoxide dismutases from biochemistry, through proteomics, to oxidative stress, aging and nutraceuticals. AB - A total of 40 years have already passed since the pioneering work of McCord and Fridovich on erythrocuprein superoxide dismutase (SOD) activity. This modern scientific 'Odyssey' has been accompanied by a series of successes in the fields of biochemistry, biomedicine and proteomics. In this article, we resume the main strides in these fields, mainly aiming at delivering an exhaustive portrait of SOD's involvement in several oxidative stress-triggered threats to human health, including neurodegenerative disorders (amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and Huntington's diseases), cardiovascular diseases, cancer and aging. In parallel, food-derived chemical compounds appear to be intertwined with cellular redox poise modulation, as this increasingly emerges from clinical biochemical and proteomic investigations. Thus, we will also consider the involvement of these nutraceuticals in oxidative stress-triggered diseases and SOD activity modulation. Like a modern Ulysses, researchers know that the journey is not yet over. Nevertheless, much information has been gathered over the last four decades. PMID- 21679123 TI - Patient and tumor characteristics may raise clinicians' awareness of familial colorectal cancer: a Norwegian population-based study. AB - BACKGROUND: The aim of this study was to identify patient and tumor characteristics that may be useful for clinicians in the identification of possible familial colorectal cancer (CRC). METHODS: Among 562 unselected, consecutively diagnosed colorectal cancer patients, 490 patients were included and divided into familial or sporadic CRC based on family history data collected by standardized patient interviews. Clinical data were collected from the patients' medical records. Patients were classified as familial CRC according to currently accepted family history criteria. Each patient was also classified according to Amsterdam II criteria and the 4th and 5th criteria in the Revised Bethesda Guidelines that address information on family history. Tumors were described by location and histopathology; 316 tumors were examined by molecular analyses. RESULTS: Right-sided colonic tumors and synchronous CRC tumors were associated with familial CRC, and patients with metachronous CRC or Lynch syndrome-related tumors were more likely to be classified as familial CRC. The patients' age at diagnosis did not differ between the groups. Other patient or tumor characteristics were not associated with familial CRC. CONCLUSION: CRC patients with right-sided colonic cancers, synchronous cancers and previous CRC and/or LS-related tumors were more likely to have familial CRC, and young age at diagnosis was not associated with familial CRC in these data. A detailed family history of colorectal cancer is essential in the identification of patients and families with familial CRC. PMID- 21679124 TI - New simple and rapid method for purification of mesenchymal stem cells from the human umbilical cord Wharton jelly. AB - We have developed a simple and rapid method for isolation of human umbilical cord matrix stem cells (hUCMS). The umbilical cord contains a virtual inexhaustible source of adult stem cells. We have substantially modified, simplified, and improved previously reported hUCMS isolation procedures in terms of either used enzyme type, or digestion time, and substantially enhanced the final product yield and purity. The isolated hUCMS were positive for CD90, CD117, and SCF, and negative for CD31 and CD45 surface markers. mRNA and related proteins (i.e., Sox2, Oct4a, Nanog, ABCG2, and c-Myc) that coincide with an uncommitted cell status also were detected. hUCMS express genes and proteins for CD90 and Nestin that are associated with mesenchymal stem cells, as well as other genes that specifically relate to different embryonic germ layers, namely, Vimentin, Sox7, Sox17, FoxA2, E-cadherin, and N-cadherin. hUCMS showed multilineage cell differentiation potential into adipogenic, osteogenic, and neural cell phenotypes, under the influence of lineage-specific, differentiation culture media. Moreover, the basal expression of endocrine cell markers makes these cells seemingly suitable for endocrine cell phenotype differentiation. Noteworthy, Activin A induced hUCMS to acquire definitive endoderm cell markers. PMID- 21679125 TI - Perceived food hypersensitivity: a review of 10 years of interdisciplinary research at a reference center. AB - Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years' interdisciplinary research program dealing with such patients. The patients (more than 400) included in our studies were all adults referred to a university hospital because of gastrointestinal complaints self attributed to food hypersensitivity. Despite extensive examinations, food allergy was seldom diagnosed. The majority of the patients fulfilled the diagnostic criteria for irritable bowel syndrome. In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life. However, psychological factors could explain only approximately 10% of the variance in the patients' symptom severity and 90% of the variance thus remained unexplained. Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and "IgE-armed" mast cells. Multiple factors such as immune activation, disturbed intestinal fermentation, enteric dysmotility, post-infectious changes and "local" allergy in the gut as well as psychological disturbances may play a role in the pathophysiology of perceived food hypersensitivity. Hence, our results support the view that management of these patients should be interdisciplinary. PMID- 21679126 TI - LRRK2 Parkinson's disease: from animal models to cellular mechanisms. AB - Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) play a major role in the development of Parkinson's disease. The most frequently defined mutations of LRRK2 are located in the central catalytic region of the LRRK2 protein, suggesting that dysregulations of its enzymatic activities contribute to PD pathogenesis. Herein, we review recent progress in research concerning how LRRK2 mutations affect cellular pathways and lead to neuronal degeneration. We also summarize recent evidence revealing the endogenous function of LRRK2 protein within cells. These concepts can be used to further understand disease pathophysiology and serve as a platform to develop therapeutic strategies for the treatment of Parkinson's disease. PMID- 21679127 TI - Diagnostic utility of a soluble cytokeratin 18 assay for gastrointestinal graft vs.-host disease detection. AB - BACKGROUND: Gastrointestinal/liver graft-vs.-host disease is a frequent complication after allogeneic hematopoietic cell transplantation. Endoscopic biopsies are needed to confirm clinical diagnosis, but this is not always feasible due to concurrent complications after transplantation. Cytokeratin 18 is expressed in epithelial colon cells and hepatocytes. Apoptosis, a hallmark of graft-vs.-host disease, results in the cleavage of cytokeratin 18 and the resulting fragments are released into the circulation. METHODS: The aim of the present study was to assess the general performance and usefulness of a serologic test for soluble cytokeratin 18 for gastrointestinal/liver graft-vs.-host disease detection. Plasmatic concentration of soluble cytokeratin 18 was measured in 38 individuals undergoing hematopoietic cell transplantation. A two-fold increase of sCK18 above the pre-transplant concentration was used as a threshold value. RESULTS: Plasmatic concentration of soluble cytokeratin 18 was significantly elevated in patients with gastrointestinal/liver graft-vs.-host disease. Soluble cytokeratin 18 concentration raised before the onset of clinical symptoms in 69% of the patients with gastrointestinal/liver graft-vs.-host disease. The threshold value used in our study resulted in a high sensitivity and a low false negative rate for gastrointestinal/liver graft-vs.-host disease detection. CONCLUSIONS: Soluble cytokeratin 18 seems to be a suitable biomarker for gastrointestinal/liver graft-vs.-host disease detection, particularly when a biopsy is not feasible. PMID- 21679128 TI - Multicentre comparison of free thyroid hormones immunoassays: the Immunocheck study. AB - BACKGROUND: In order to evaluate whether there is still present a very large variability in measured values and analytical performance among different free thyroid (FT) hormone immunoassays, we considered the results derived from an External Quality Assessment (EQA) scheme, named Immunocheck. METHODS: The EQA Immonocheck study enrolled about 1000 participant laboratories, which measured the 54 quality control samples distributed in the three annual cycles (2007, 2008 and 2009). Participant laboratories produced a total of 30,476 results for FT3 and 31,351 for FT4, respectively. RESULTS: The results recovered during the EQA cycles allowed the estimation of assay imprecision (i.e., within-method and between-laboratories variability). On average, control samples with lower free triiodothyronine (FT3) and free thyroxine (FT4) concentrations showed higher imprecision values (CV%) than those with levels within or above the normal range. The agreement among the results produced by different methods was estimated by computing the percent differences (i.e., percent bias values) between the concentrations measured by the methods and the mean of all collected results (i.e., consensus mean). CONCLUSIONS: The results of our study demonstrate that a large variability in measured values is still present among different free thyroid hormone immunoassays. Indeed, some immunoassays for both FT3 and FT4 measurement showed percent bias values compared to the consensus mean >20%. Laboratories should inform the clinicians about analytical performance and reference limits of the method used. Furthermore, the clinicians should avoid the use of different methods in the follow-up of patients. PMID- 21679129 TI - Genotyping of the hemochromatosis HFE p.H63D and p.C282Y mutations by high resolution melting with the Rotor-Gene 6000(r) instrument. AB - BACKGROUND: The genotyping of HFE p.C282Y and p.H63D mutations is one of the most requested molecular analyses in the laboratorial routine. In this scenario, the main aim was to develop a genotyping assay that has advantages compared to other methods. METHODS: Genotypes for the HFE p.C282Y (c.G845A; rs1800562) and p.H63D (c.C187G, rs1799945) mutations were assessed by polymerase chain reaction (PCR) followed by high resolution melting (HRM) analysis with the Rotor-Gene 6000((r)) instrument. Validation studies were conducted in samples bi-directionally sequenced. RESULTS: The melting assay was developed in a unique procedure and to ensure the result in approximately 112 min (31 min for sample preparation and 81 min for the PCR-HRM step). Genotypes for the HFE p.C282Y mutation were easily distinguished in the region of 80-86 degrees C. For the HFE p.H63D, genotypes were also easily distinguished in the region of 76-82 degrees C, but using the addition of known wild-type genotype DNA in all unknown samples plus a reaction without addition. In validation, genotypes were 100% concordant between methods. CONCLUSIONS: Our genotyping assay with the Rotor-Gene 6000((r)) instrument applies to the laboratorial routine with several advantages, especially in large scale demand. The main advantages were the non-dependence on gel electrophoresis and on mutagenic reagents for visualization of fragments, reduction of the chances for contamination due to sample preparation, the lack of use of probe based methods and cost-effectiveness. PMID- 21679130 TI - Glycated albumin may be a possible alternative to hemoglobin A1c in diabetic patients with anemia. AB - BACKGROUND: We assessed whether glycated albumin (GA) is a useful glycemic indicator in diabetic patients with anemia who did not undergo dialysis. METHODS: Hemoglobin A(1c) (HbA(1c)) and GA were simultaneously measured in 370 diabetic subjects who had not undergone dialysis. The relationship between GA and HbA(1c) was evaluated in patients with and without anemia. RESULTS: GA-to-HbA(1c) ratio was significantly higher (3.3+/-0.7 vs. 2.8+/-0.5, p<0.001) and the regression slope between GA and HbA(1c) was steeper in diabetic patients with than in those without anemia (6.2 vs. 4.2, p<0.001). CONCLUSIONS: HbA(1c) was underestimated in diabetic patients with anemia than in those without anemia, with the degree of underestimation increasing as glycemic control became poorer. GA may more accurately assess glycemic control in diabetic patients with anemia than HbA(1c). PMID- 21679131 TI - Enhanced frequency of CFTR gene variants in couples who are candidates for assisted reproductive technology treatment. AB - BACKGROUND: An increased frequency of (cystic fibrosis transmembrane conductance regulator) CFTR mutations has been detected in some types of male infertility. The aim of this study was to shed light on the link between CFTR mutations and infertility. METHODS: We sequenced the CFTR gene in 294 subjects (190 males) affected by infertility of different origin who underwent assisted reproductive technology (ART). As a control group, we studied 1000 (353 males) unrelated, unselected subjects from the general population of southern Italy. RESULTS: The frequency of CFTR mutations, some of which are detected only by gene sequencing, and of the IVS8 poly(TG)12-poly(T)5-V470 haplotype was significantly higher in obstructive [congenital bilateral absence of vasa defer-entes (CBAVD, five cases)] and secretory (23 cases) azoospermic patients than in the general population. Some patients, primarily those with CBAVD, were compound heterozygous for two mutations. Interestingly, the frequency of the TG12-T5-V470 variant haplotype was significantly higher in severe oligospermic patients (88 cases) and in patients with tubal sterility (74 cases) compared with the general population. Finally, neither the frequency of CFTR mutations nor the frequency of the TG12-T5 variants differed between patients with mild oligospermia (74 cases) and patients with ovulatory sterility (30 cases) compared with the general population. CONCLUSIONS: All subjects affected by obstructive or secretory azoospermia should undergo molecular analysis and counselling for CF using gene scanning which has a high detection rate and also reveals rare CFTR mutations. Molecular analysis seems to be less mandatory in other types of male/female infertility. Furthermore, we found that the CFTR TG12-T5-V470 variant haplotype was associated with both severe oligospermia and tubal infertility, thereby implicating the CFTR protein in both spermatogenesis and tubal functionality. PMID- 21679132 TI - How to obtain DNA from injection drug users? PMID- 21679133 TI - Significant elevation of plasma pentraxin 3 in patients with pelvic inflammatory disease. AB - BACKGROUND: Pentraxin 3 (PTX3) plays an important role in innate immune responses and in inflammation disease. The aim of this study was to investigate the diagnostic and prognostic potential of PTX3 in pelvic inflammatory disease (PID) and correlate it with the severity and outcome of PID. METHODS: Blood specimens were collected from 64 patients with PID before and after treatment and 70 healthy controls and the plasma levels of PTX3 were measured using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: It was found that the plasma level of PTX3 expression was elevated in PID patients compared with healthy controls and decreased significantly after they received treatment. When the cut-off level of plasma PTX3 was set at 2.87 ng/mL, PTX3 had higher sensitivity (84.38%) and lower false-negative rate (15.63%) than CRP (79.69% and 20.31%, respectively) in predicting PID. The level of PTX3 also exhibited a significant correlation with length of hospital stay (r=0.581, p<0.001). CONCLUSIONS: Plasma PTX3 concentration not only predicts the presence of PID with lower false-negative rate than CRP, but plasma PTX3 concentration is also affiliated with the presence of tubo-ovarian abscess (TOA) and the length of hospital stay. PMID- 21679134 TI - Determinants of oxidative stress related to gender: relevance of age and smoking habit. AB - BACKGROUND: Magnitude and major causes of oxidative stress may be different between sexes, although limitedly addressed in clinical studies with controversial results. The present study aimed to determine whether any gender related difference exists concerning oxidative stress in a population of 332 subjects of both sexes, in a wide age range, with and without cigarette smoking habit. METHODS: The Oxidative-INDEX was calculated after evaluation of serum hydroperoxides (ROMs) and total antioxidant capacity (OXY) by means of commercial kits (d-ROMs and Oxy-adsorbent Tests, Diacron, Italy) subtracting the OXY standardized variable from the ROMs standardized variable. RESULTS: The Oxidative INDEX resulted higher in women with respect to men (p<0.001), in smokers (p<0.01) than in non-smokers, and correlated with cigarette number (p<0.01), age (p<0.001), and post-menopausal status (p<0.001). The multivariate analysis identified age, high blood pressure, and smoking habit as factors independently associated with the Oxidative-INDEX in men, whereas cigarette smoking and age represented the independent risk factors for an elevated oxidative stress status in women. CONCLUSIONS: Gender-based differences in oxidative stress levels may provide a biochemical basis for the epidemiologic differences in the disease susceptibility between sexes, and suggest different strategies for risk assessment, diagnosis, and treatment specifically targeted to men and women. PMID- 21679135 TI - Incorporating platelet-rich plasma into electrospun scaffolds for tissue engineering applications. AB - Platelet-rich plasma (PRP) therapy has seen a recent spike in clinical interest due to the potential that the highly concentrated platelet solutions hold for stimulating tissue repair and regeneration. The aim of this study was to incorporate PRP into a number of electrospun materials to determine how growth factors are eluted from the structures, and what effect the presence of these factors has on enhancing electrospun scaffold bioactivity. PRP underwent a freeze thaw-freeze process to lyse platelets, followed by lyophilization to create a powdered preparation rich in growth factors (PRGF), which was subsequently added to the electrospinning process. Release of protein from scaffolds over time was quantified, along with the quantification of human macrophage and adipose-derived stem cell (ADSC) chemotaxis and proliferation. Protein assays demonstrated a sustained release of protein from PRGF-containing scaffolds at up to 35 days in culture. Scaffold bioactivity was enhanced as ADSCs demonstrated increased proliferation in the presence of PRGF, whereas macrophages demonstrated increased chemotaxis to PRGF. In conclusion, the work performed in this study demonstrated that the incorporation of PRGF into electrospun structures has a significant positive influence on the bioactivity of the scaffolds, and may prove beneficial in a number of tissue engineering applications. PMID- 21679136 TI - Caffeic Acid, a versatile pharmacophore: an overview. AB - The caffeic acid scaffold, which is abundant in nature, is extremely versatile and is found in a number of biologically active molecules. The purpose of this review is to provide an overview of the pharmacological activity of synthetic caffeic acid analogs including recent reports of anti-inflammatory, anti-cancer, and antiviral activities of these compounds. PMID- 21679137 TI - Recent progress in therapeutic and diagnostic applications of lanthanides. AB - The biological properties of the lanthanides, primarily based on their similarity to calcium, have been the basis for research into potential therapeutic applications of lanthanides since the early part of the twentieth century. Up to date, cerium nitrate has been used as a topical cream with silver sulfadiazene for the treatment of burn wounds. A lanthanide texaphyrin complex (motexafin gadolinium) has been evaluated through Phase III clinical trials for the treatment of brain metastases in non-small cell lung cancer. Lanthanum carbonate (Fosrenol) as a phosphate binder has been approved for the treatment of hyperphosphatemia in renal dialysis patients in both the USA and Europe. This review will highlight therapeutic applications of the lanthanides for burn wounds, cancer, hyperphosphatemia, immune function, magnetic resonance imaging (MRI) contrast agents and osteoporosis, and discuss their future potential in the medical fields. PMID- 21679138 TI - Synthesis of 2, 3-disubstituted-Quinazolin-4-(3H)-ones. AB - The present review covers a concise account of the synthesis of bioactive 2, 3 disubstituted-quinazoline-4(3H)-ones and the recent developments in the area of versatile quinazolinones with a special emphasis on new synthetic routes and strategies. PMID- 21679139 TI - Microaspiration in intubated critically ill patients: diagnosis and prevention. AB - Microaspiration of contaminated oropharyngeal secretions and gastric contents frequently occurs in intubated critically ill patients, and plays a major role in the pathogenesis of ventilator-associated pneumonia. Risk factors for microaspiration include impossible closure of vocal cords, longitudinal folds in high-volume low-pressure polyvinyl chloride cuffs, and underinflation of tracheal cuff. Zero positive end expiratory pressure, low peak inspiratory pressure, tracheal suctioning, nasogastric tube and enteral nutrition increase the risk for microaspiration. Other patient related factors include supine position, coma, sedation, and hyperglycemia. Technetium 99 labelled enteral feeding is probably the most accurate marker of microaspiration in critically ill patients. However, use of this radioactive marker is restricted to nuclear medicine departments. Blue methylene is a reliable qualitative marker of microaspiration. However, fiberoptic bronchoscopy is required to diagnose microaspiration of blue dye in ICU patients. Quantitative pepsin measurement in tracheal aspirates is accurate in diagnosing microaspiration of gastric contents in critically ill patients. In addition, this marker is easy to use in routine practice. However, pepsin should be detected rapidly after aspiration. In vitro, and clinical studies suggested that semirecumbent position, polyurethane cuffs, positive end expiratory pressure, low-volume low-pressure cuff, and continuous control of cuff pressure were efficient in reducing microaspiration in ICU patients. Other preventive measures such as subglottic aspiration, tapered shape cuff, guayule latex cuff, lateral horizontal patient position, gastrostomy tube, and postpyloric feeding require further investingation. PMID- 21679140 TI - New antibiotics for severe ICU-aquired bacterial infections. AB - Infection is a major cause of morbidity and mortality in intensive care units (ICU). The impact on prognostic of an inadequate antibiotic therapy is well established. The problem is due to the growing spread of resistant microorganisms, including both Gram-negative and Gram-positive pathogens, especially in the case of ICU-acquired infections. In this context, antibiotics with broad spectrum activity are usually required. Moreover, these antibiotics should reach high concentrations in tissues, especially in lungs, and should exert a bactericidal activity for the most severely ill patients, especially those with bloodstream infections. A frequent problem in clinical practice is the lack of data validating their use in the context of critically ill patients. In the present article, we review the newest antibiotics that could be of interest for severe ICU-acquired infections: tigecycline, moxifloxacine, the newer carbapenems, linezolide and daptomycine. We discuss their approved indications and identify the fields in which they could be used to treat infections acquired in the ICU. PMID- 21679141 TI - Adjunctive therapies in severe pneumonia in critical care patients. AB - AIM: To review available evidence for the role of adjunctive therapies in severe pneumonia. METHODS: We focused on therapies that have attracted recently interest such as glucocorticosteroids (GCs), statins and recombinant activated protein-C. RESULTS: Experimental animal and human studies showed that GCs are able to modulate the inflammatory response and may offer a benefit in patients with severe sepsis. Randomized trials in pneumonia are few, mostly limited in septic shock and ARDS patients. Recombinant activated protein C is a potent anticoagulant and profibrinolytic enzyme which can inhibit the systemic inflammatory response. Available data, although limited, showed that activated protein C can reduce mortality in severe sepsis, especially in severe pneumonia due to S. Pneumoniae. Statins have pleiotropic properties which can affect the inflammatory cascade. The use of statins has been found to be associated with decreased mortality in some studies with pneumina whereas the use of statins was associated with increased risk of death in others. However, data come from observational or retrospective studies. CONCLUSION: Treatment with GCs may modulate the inflammatory response in critically ill patients with pneumonia but a clear effect of steroids on survival is debatable. The administration of GCs should be considered in patients with severe pneumonia when vasopressor dependent septic shock. Activated protein-C may be considered in patients with severe CAP or HAP and sepsis or organ failure. The role of statins in the management of severe pneumonia remains controversial until data from clinical trails will be available. PMID- 21679142 TI - Novel therapies for Pseudomonas aeruginosa pneumonia. AB - P. aeruginosa is the bacteria most commonly responsible for hospital-acquired and ventilator-associated pneumonia. Numerous factors are encoded in its genome, and they explain its high virulence. P. aeruginosa also develops a quorum sensing (QS), which coordinates the expression of these factors. The type III secretion system, a needle-complex, allows exotoxin injections into eukaryotic cells and is involved in the pathogenesis of acute pneumonia. This pathogen develops a high level of resistance to all antibiotics, which leads to a shortage of treatment options for many patients. Thus, new preventive or therapeutic approaches are in development. Immunotherapy that uses monoclonal antibodies has been successfully tested in blocking the type III secretion system (anti-PcrV) or helping immune cells phagocytose P. aeruginosa. Inhibiting the quorum sensing has also been efficacious in vitro and in vivo. New antibacterial peptides may enlarge the panel of treatments in the near future. However, current treatment for patients still relies on antibiotics. The development of resistance to all classes of available antibiotics leads to colistin revival with good clinical results. Topical delivery through aerosol could allow for the increase in the antibiotic concentration inside the infection site while limiting its systemic toxicity. Finally, Candida airway colonization has been found to be associated with P. aeruginosa-associated pneumonia in ventilated patients. In addition to targeting the bacteria, reducing Candida airway colonization may also decrease the incidence of such infections. PMID- 21679143 TI - Non-invasive mechanical ventilation to prevent ICU-acquired infection. AB - Several forms of supportive techniques for respiration in intensive care units (ICU) are currently available. The most widely used is invasive mechanical ventilation through the use of an endotracheal tube (ETT). ETTs are proved to be important contributors to the pathogenesis and development of ventilator-acquired pneumonia (VAP) as artificial airways interfere with a number of respiratory tract defence mechanisms and facilitate bacterial colonisation of the tracheobronchial tree. The occurrence of VAP is known to be one of the leading cause of morbidity and mortality in ICUs. On that basis, non-invasive techniques have been developed through the use of patient-ventilator interfaces in the form of facial masks which allow the development of ventilatory modalities working in synchrony with the patient. The purpose of this review is to examine the impact of non-invasive ventilation on the occurrence of ICU-acquired infections, most likely VAP, when used as an alternative for endotracheal intubation or when applied after early extubation. Regarding the reduction of endotracheal intubation, many studies have confirmed the net benefit of using non-invasive ventilation, mostly in chronic obstructive pulmonary diseases with acute hypercapnic ventilatory failure, in cardiogenic pulmonary edema, and in selected populations such as immunocompromised patients. Additionally, some studies have demonstrated a substantial benefit on hospital mortality. Early extubation with immediate application of non-invasive ventilation as a method to wean patients from invasive ventilation has shown a significant effect on hospital mortality. Overall, in our experience, patients with chronic obstructive pulmonary disease with hypercapnic acute respiratory failure are most likely benefiting from non invasive ventilation either in the acute setting or during the immediate post extubation phase. Acute cardiogenic patients must also receive primary respiratory non-invasive support. For immunocompromised patients, given the broad range of immunosuppression settings, the underlying condition should guide the decision of applying non-invasive support or not in a case by case approach. PMID- 21679144 TI - How could we reduce antibiotic use in critically ill patients? AB - The role of antibiotic pressure in the selection of antibiotic-resistant bacteria is still under debate in the scientific community and often confounded by scarce data on antibiotic usage. Several studies demonstrated that prior antibiotic exposure is likely to increase patient's colonization and infection by antimicrobial-resistant bacteria. Of even more concern is the significant mortality associated with these infections, in particular in critically ill patients. Therefore, the control of antibiotic usage in intensive care units (ICUs) is of paramount importance. Antibiotic stewardship programmes (ASP) have been demonstrated to represent a useful intervention to reduce the inappropriate antibiotic usage in hospitalized patients. A few trials were performed in ICU population with positive results. The major risk we foresee for the implementation of ASP for ICU patients is the lack of consideration of local ecology and strict quality indicators. The development of new pattern of antimicrobial resistance might be ascribed to an inappropriate ASP. European networks to define best strategies and antibiotic-care bundles need to be supported at national and international level. To optimize antibiotic use in the ICU and to fight against the spread of resistance, it is extremely important to adopt a multifaceted approach including ASP. PMID- 21679145 TI - New methods to clean ICU rooms. AB - Hospital-acquired infections (HAI) represent the most common adverse event in the intensive care unit (ICU). Their prevalence is high and they are associated with increased morbidity and mortality. The environment plays a central role in the transmission of hospital-acquired pathogens (HAP) and in the pathogenesis of HAI. Many bacteria, especially multidrug resistant ones, can survive for several months in the hospital environment in particular in areas close to the patients. It has been proven that pathogens are transmitted from the environment to the patients. Many studies have concluded that current cleaning methods are microbiologically ineffective. This failure concerns daily cleaning as well as terminal cleaning after patient discharge. It has been demonstrated that improvements in environmental cleaning are associated with a decrease in the rate of HAP and of HAI. New cleaning methods could enhance hospital cleaning efficiency. Three new technologies seem promising because they are microbiologically effective, easy and safe to use: (1) hydrogen peroxide vapor and (2) UV light decontamination are used for terminal cleaning. These techniques are effective even in difficultly accessible areas. (3) ultramicrofibers which can be associated with a copper-based biocide can be used for daily cleaning. Other methods such as ozone, steam or high-efficiency particulate air filtration are not efficient enough to be considered serious contenders for the improvement of the quality of the hospital environment. These new technologies have not been yet linked to a decrease in the prevalence and the incidence in HAP and HAI. It remains difficult to justify the extra-cost associated with these new methods until more studies can confirm their effectiveness in the management of HAI. PMID- 21679146 TI - Cytomegalovirus infections in non-immunocompromised and immunocompromised patients in the intensive care unit. AB - Infection, inflammatory response, activation of coagulation cascade and sepsis are tightly interconnected. In the initial phase, sepsis is characterized by a pro-inflammatory state, while in the late phase, by an anti-inflammatory state which favors cytomegalovirus reactivation. Cytomegalovirus infection would accentuate the sepsis-induced immunologic effects increasing the risk for other infections. The rate of CMV infection is 17% in critically ill nonimmunocompromised patients, up to 30% in hematopoietic stem cell transplant and up to 60% in solid organ transplant recipients. Cytomegalovirus infection in critically ill patients is associated with prolonged ventilator support, nosocomial infections, prolonged hospital and/or ICU stay and increased mortality. In immunocompromised patients, cytomegalovirus causes direct effects (viral syndrome, pneumonia, meningo-encephalitis, and gastro-intestinal tract involvement) and indirect (immunomodulatory) effects. These indirect effects would predispose the patients to secondary infections, delay immune recovery after hematopoietic stem cell transplant, and increase the risk of EBV-related B cell lymphoproliferative disease and allograft rejection. Cytomegalovirus serology is not useful for the diagnosis of active infections. Cytomegalovirus culture is impractical for clinical purposes. The shell vial assay has low sensitivity. pp65 antigen is a sensitive and specific diagnostic method. Real time PCR is more sensitive and specific (earlier detection) than pp65 antigen test and it is a more reliable marker to monitor the clearance of viremia. Ganciclovir and valganciclovir are the first-line antiviral therapies for the treatment of immunocompromised patients, while foscarnet and cidofovir are reserved mainly for treatment of ganciclovir-resistant cytomegalovirus infections. PMID- 21679147 TI - Usefulness of real-time PCR for the diagnosis of sepsis in ICU-acquired infections. AB - Real-time PCR methods are able to rapidly detect a wide panel of microorganisms. These methods are of interest in critically ill patients to determine the presence of bacteria in the blood and other biological samples, especially in those patients with prior antimicrobial treatment. In intensive care unit (ICU), the LightCycler SeptiFast (LC-SF) Test provides 1.5 to 2 fold higher positivity rate compared with conventional blood cultures. Although identification of the bacterium by LC-SF is rapid and sensitive, susceptibility test could not be performed using this technique, except the methicillin- resistance for Staphylococci. The conventional cultures remain necessary for samples in ICU because of the high incidence of multidrug-resistant bacteria and the need for antimicrobial susceptibility of the bacterium to treat the patient correctly. A negative result for a Gram positive or negative bacterium allows deescalating the initial antimicrobial treatment, and decreasing the pressure of selection. Moreover, it is necessary to understand and interpret a DNA signal knowing that a dead bacterial material may be detected in a patient without any infection. What is the clinical relevance of bacterial DNA present in the blood and does the DNAemia found reflect true infection? Cost-effectiveness of the real-time PCR should be determined. Meanwhile, this test should be restricted to severe clinical situations, especially ICU patients with severe sepsis. In the future, real-time PCR tests should include more pathogens and antimicrobial resistant targets. PMID- 21679148 TI - New advances in intensive care unit-acquired infection. PMID- 21679149 TI - Quantitative analysis of UGT2B28 mRNA expression by real-time RT-PCR and application to human tissue distribution study. AB - We recently established a method for quantitative determination of human catalytically active UDP-glucuronosyltransferases (UGTs) other than UGT2A1 and UGT2B28 by real-time reverse transcription-polymerase chain reaction (RT-PCR), and applied the method to an exhaustive analysis of localization in various human tissues. We report here an additional quantitative determination method targeting UGT2B28. To date, there have been no reports on the distribution of UGT2B28 mRNA expression in human tissues based on quantitative determination. Human UGT2B28 was clearly detected in the breast and adipose tissue. UGT2B28 expression in the breast was comparatively low, about 1.6% of GAPDH mRNA levels, and was less than 5% of normalized (against GAPDH) UGT2B7 and 2B10 mRNA expression levels in the liver. Although the UGT2B28 has 97% identity with UGT2B11 at the cDNA sequence level, the primers constructed for UGT2B28 did not detect UGT2B11. In addition, significant expression of UGT2B11 was detected in the liver, breast and kidney, and was clearly different from the distribution of UGT2B28. Therefore, we conclude that the real-time RT-PCR method established here is very specific for human UGT2B28 isozyme. PMID- 21679150 TI - In vitro metabolism of phenstatin: potential pharmacological consequences. AB - Phenstatin and its derivatives are potential anticancer drug candidates according to their inhibitory properties on tubulin polymerization, cell growth and antivascular activity. However, at the present time, neither pharmacological nor metabolic studies have been conducted in order to strengthen the relevance of phenstatine as a drug discovery candidate. In the present work, the metabolic fate of phenstatin in rat and human microsomal preparations was studied to investigate the stability of this tubulin polymerization inhibitor and any effects of the metabolites on polymerization and on PC3 cancer cell proliferation. The metabolites were separated by high-performance liquid chromatography and, after their synthesis, characterized by simultaneous LC-DAD UV and LC-ESI-MS analyses. Thus, eight metabolites were identified. The major biotransformation pathways are carbonyl reduction, O-methylation at C-3', O methylation after aromatic hydroxylation at the position C-2' on phenyl B ring and O-demethylation on A ring. Four of the identified metabolites were as active or more active, than phenstatin in vitro. Moreover, the better stability of phenstatin versus CA-4 and the lack of quinone formation could justify the design of new analogues which could include various substituents on phenyl rings or linker group in order to modulate the metabolism of phenstatin toward even more active metabolites and so up-regulate the pharmacological activity. PMID- 21679151 TI - Inhibition of renal alkaline phosphatase by cimetidine. AB - Alkaline phosphatase (ALP) belongs to hydrolase group of enzymes. It is responsible for removing phosphate groups from many types of molecules, including nucleotides and proteins. Cimetidine (trade name Tagamet) is an antagonist of histamine H2-receptor that inhibits the production of gastric acid. Cimetidine is used for the treatment of gastrointestinal diseases. In this study the inhibitory effect of cimetidine on mouse renal ALP activity was investigated. Our results showed that cimetidine can inhibit ALP by uncompetitive inhibition. In the absence of inhibitor the V(max) and K(m) of the enzyme were found to be 13.7 mmol/mg prot.min and 0.25 mM, respectively. Both the Vmax and Km of the enzyme decreased with increasing cimetidine concentrations (0- 1.2 mM). The Ki and IC(50) of cimetidine were determined to be about 0.5 mM and 0.52 mM, respectively. PMID- 21679152 TI - Alpha-1-adrenergic receptor blockade modifies insulin-regulated aminopeptidase (IRAP) activity in rat prostate and modulates oxytocin functions. AB - BACKGROUND: Oxytocin (OT) is one of the important paracrine factors that prostate synthesizes. OT maintains its resting tone and stimulates its contractile activity. However, the involvement of OT in modulating cell proliferation of the prostate is being investigated. In fact, alterations in OT concentrations accompany both benign prostatic hyperplasia/hypertrophy and carcinoma of the prostate. The enzyme Insulin-regulated aminopeptidase (IRAP) is the main responsible of OT levels regulation through its catabolism. To date, the long acting selective alpha(1)-adrenergic receptor antagonist doxazosin is widely used to the treatment of BPH. Thus, our aim was to analyze the effects of doxazosin on IRAP specific activity and its putative effects on prostate OT regulation and functions. METHODS: Fifteen male Wistar rats were treated subcutaneously with 10 mg/Kg doxazosin during 15 days and fifteen controls were treated with the vehicle only. After the treatment period, prostate was removed to obtain soluble and membrane-bound fractions. Soluble and membrane-bound IRAP specific activities were assayed fluorometrically using leucyl-beta-naphthylamide as substrate. Prostate OT content was assayed by enzyme immunoassay. RESULTS: Doxazosin treatment significantly increased membrane-bound IRAP specific activity in rat prostate by 59.4%, whereas no changes were observed in the soluble fraction. Treatment with doxazosin also significantly increased OT concentration by 26.3%. CONCLUSIONS: In vivo administration of doxazosin to male rats modify both prostatic IRAP activity and OT levels. Because there is now evidence that OT plays a physiological role in the regulation of growth and muscular contractility within the gland, more attention should be paid to IRAP activity, which could represent a new target for the regulation of the functions of OT under physiological or pathological conditions such as BPH and prostate cancer. PMID- 21679153 TI - Human liver enzymes responsible for metabolic elimination of tyramine; a vasopressor agent from daily food. AB - Dietary tyramine is associated with hypertensive crises because of its ability to induce the release of catecholamines. The roles of monoamine oxidase (MAO); flavin-containing monooxygenase (FMO); and cytochrome P450 2D6 (CYP2D6) were studied in terms of the enzymatic elimination of tyramine in vitro at a substrate concentration of 1.0 uM; which is relevant to in vivo serum concentrations. Tyramine elimination by human liver supernatant fractions was decreased by ~70% in the absence of NADPH. Pargyline; an MAO inhibitor; decreased tyramine elimination rates by ~30%. Among recombinant P450 and FMO enzymes; CYP2D6 had a high activity in terms of tyramine elimination. Tyramine elimination rates were inhibited by quinidine and significantly correlated with bufuralol 1' hydroxylation activities (a CYP2D6 marker). Liver microsomes genotyped for CYP2D6*10/*10 and CYP2D6*4/*4 showed low and undetectable activities; respectively; compared with the wild-type CYP2D6*1/*1. The present results suggest that tyramine is eliminated mainly by polymorphic CYP2D6. Tyramine toxicity resulting from differences in individual metabolic elimination is thus genetically determined. PMID- 21679155 TI - Nutrition and Alzheimer's disease: is there any connection? PMID- 21679156 TI - Combination treatment in Alzheimer's disease: results of a randomized, controlled trial with cerebrolysin and donepezil. AB - Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimer's disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n=64), donepezil (10 mg; n=66) and a combination of both treatments (n=67) in mild-to moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinician's Interview-Based Impression of Change plus caregiver input; CIBIC+) and cognition (change from baseline in AD Assessment Scale-cognitive subscale+; ADAS-cog+) at week 28. Changes in functioning (AD Cooperative Study Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean+/-SD for Cerebrolysin: -1.7+/-7.5; donepezil: -1.2+/-6.1; combination: -2.3+/-6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested. PMID- 21679157 TI - HIV-TAT-fused FHIT protein functions as a potential pro-apoptotic molecule in hepatocellular carcinoma cells. AB - Accumulating evidence has demonstrated that FHIT (fragile histidine triad) is a bona fide tumour suppressor gene in a large fraction of human tumours, including hepatocellular cancer. A virus-based delivery system has been developed to transfer the FHIT gene into many types of cancer cells to inhibit growth or even induce apoptosis. However, a protein-based replacement strategy for FHIT has not been performed in cancer cells. Here, we used HIV-TAT (transactivator of transcription)-derived peptide to transfer the purified FHIT protein into HCC (hepatocellular carcinoma) cells and determine the biological effect of this fusion protein in inducing apoptosis. Affinity chromatography was used to purify TAT peptide-fused human FHIT (TAT-FHIT) protein from BL21 Escherichia coli. Immunofluorescence staining and Western blot analysis were performed to identify the expression and internalization of TAT-FHIT in HCC cells compared with the purified FHIT protein. Our study showed that TAT-FHIT protein can translocate into cancer cells in 1 h after incubation at 37 degrees C. Furthermore, the results of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay, Annexin-V staining and Western blotting demonstrated that TAT-FHIT can robustly inhibit growth and induce apoptosis of HCC cells in vitro. In addition, a mechanistic study showed that both exogenous and intrinsic apoptotic pathways were involved in TAT-FHIT-mediated apoptosis and this effect could be attenuated partially by a mitochondrial protector TAT-BH4, indicating that mitochondrion plays a critical role in TAT-FHIT-mediated pro-apoptotic effect in cancer cells. Taken together, our study suggests that TAT-FHIT is a potential pro-apoptotic molecule in HCC cells and strengthen the hypothesis of its therapeutic application against HCC. PMID- 21679158 TI - Characterization and functional analysis of GhRDR6, a novel RDR6 gene from cotton (Gossypium hirsutum L.). AB - RDR6 (RNA-dependent RNA polymerase 6) is not only involved in virus resistance but also plays an important role in natural plant development. In the present study, a novel RDR gene, named GhRDR6 (Gossypium hirsutum RDR6), was isolated from cotton (G. hirsutum L.). Alignment and evolutionary relationship analyses showed that GhRDR6 was more closely related to RDR6 than to other RDRs. Expression analysis indicated that this single-copy gene is constitutively expressed in the roots, stems and leaves. Semi-quantitative RT-PCR (reverse transcription-PCR) showed that GhRDR6 was up-regulated by the application of various phytohormones, including MeJA [methyl JA (jasmonate)], ABA (abscisic acid), JA, alpha-naphthylacetic acid, gibberellins and ET (ethylene). In addition, GhRDR6 expression increased in response to wounding, cold (4 degrees C) and NaCl treatments, but not by drought. Furthermore, overexpression of GhRDR6 in transgenic Nicotiana benthamiana plants resulted in root lengths longer than the wide-type during the seeding stage. Interestingly, the GhRDR6-overexpressing plants displayed reduced tolerance to oxidative damage, resulting in reduced ABA sensitivity, but they tolerated freezing. Moreover, resistance to potato virus Y was enhanced in transgenic N. benthamiana plants. These results suggest that GhRDR6 may play an important role in plant defence responses and a pivotal role in plant development. PMID- 21679154 TI - Tau as a therapeutic target for Alzheimer's disease. AB - Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer's disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained. PMID- 21679159 TI - Adipose stem cells originate from perivascular cells. AB - Recent research has shown that adipose tissues contain abundant MSCs (mesenchymal stem cells). The origin and location of the adipose stem cells, however, remain unknown, presenting an obstacle to the further purification and study of these cells. In the present study, we aimed at investigating the origins of adipose stem cells. alpha-SMA (alpha-smooth muscle actin) is one of the markers of pericytes. We harvested ASCs (adipose stromal cells) from alpha-SMA-GFP (green fluorescent protein) transgenic mice and sorted them into GFP-positive and GFP negative cells by FACS. Multilineage differentiation tests were applied to examine the pluripotent ability of the alpha-SMA-GFP-positive and -negative cells. Immunofluorescent staining for alpha-SMA and PDGF-Rbeta (platelet-derived growth factor receptor beta) were applied to identify the alpha-SMA-GFP-positive cells. Then alpha-SMA-GFP-positive cells were loaded on a collagen-fibronectin gel with endothelial cells to test their vascularization ability both in vitro and in vivo. Results show that, in adipose tissue, all of the alpha-SMA-GFP positive cells congregate around the blood vessels. Only the alpha-SMA-GFP positive cells have multilineage differentiation ability, while the alpha-SMA-GFP negative cells can only differentiate in an adipogenic direction. The alpha-SMA GFP-positive cells maintained expression of alpha-SMA during multilineage differentiation. The alpha-SMA-GFP-positive cells can promote the vascularization of endothelial cells in three-dimensional culture both in vitro and in vivo. We conclude that the adipose stem cells originate from perivascular cells and congregate around blood vessels. PMID- 21679160 TI - A combined action of pulmonary surfactant proteins SP-B and SP-C modulates permeability and dynamics of phospholipid membranes. AB - Proteins SP-B and SP-C are essential to promote formation of surface-active films at the respiratory interface, but their mechanism of action is still under investigation. In the present study we have analysed the effect of the proteins on the accessibility of native, quasi-native and model surfactant membranes to incorporation of the fluorescent probes Nile Red (permeable) and FM 1-43 (impermeable) into membranes. We have also analysed the effect of single or combined proteins on membrane permeation using the soluble fluorescent dye calcein. The fluorescence of FM 1-43 was always higher in membranes containing SP B and/or SP-C than in protein-depleted membranes, in contrast with Nile Red which was very similar in all of the materials tested. SP-B and SP-C promoted probe partition with markedly different kinetics. On the other hand, physiological proportions of SP-B and SP-C caused giant oligolamellar vesicles to incorporate FM 1-43 from the external medium into apparently most of the membranes instantaneously. In contrast, oligolamellar pure lipid vesicles appeared to be mainly labelled in the outermost membrane layer. Pure lipidic vesicles were impermeable to calcein, whereas it permeated through membranes containing SP-B and/or SP-C. Vesicles containing only SP-B were stable, but prone to vesicle vesicle interactions, whereas those containing only SP-C were extremely dynamic, undergoing frequent fluctuations and ruptures. Differential structural effects of proteins on vesicles were confirmed by electron microscopy. These results suggest that SP-B and SP-C have different contributions to inter- and intra-membrane lipid dynamics, and that their combined action could provide unique effects to modulate structure and dynamics of pulmonary surfactant membranes and films. PMID- 21679162 TI - Induction of labor and the risk for emergency cesarean section in nulliparous and multiparous women. AB - OBJECTIVE: To assess the risk for emergency cesarean section among women in whom labor was induced in gestational week >=41 and to evaluate if parity and mode of induction affected this association. DESIGN: Hospital-based retrospective cohort study. POPULATION: Singleton pregnancies delivered after >=41 gestational weeks at Danderyd Hospital, Stockholm, Sweden, during 2002-2006. MATERIAL AND METHODS: Of 23 030 singleton pregnancies meeting the entry criteria, 881 were induced with a Bishop score of <7. Obstetric outcome was assessed through linkage with the Swedish Medical Birth Registry and a local obstetrical database containing information from patients' medical files. Results were adjusted for body mass index, age and the use of epidural analgesia. MAIN OUTCOME MEASURE: Risk for emergency cesarean section. RESULTS: Among women who were induced, the proportions delivered by emergency cesarean section were 42% for nulliparous and 14% for multiparous. Compared to spontaneous onset, this corresponded to a more than threefold increase in risk for nulliparous women (OR 3.34, 95%CI 2.77-4.04) and an almost twofold increase in risk for multiparous women (OR 1.94, 95%CI 1.24 3.02). There was no significant difference in risk for emergency cesarean section between the two methods of induction (PGE(2) and transcervical catheter). CONCLUSIONS: Compared to spontaneous onset of delivery, induction of labor is associated with an increased risk for emergency cesarean section both among nulliparous and multiparous women. When labor is induced, the high risk for emergency cesarean must be kept in mind. PMID- 21679161 TI - Modulation of doxorubicin resistance by the glucose-6-phosphate dehydrogenase activity. AB - How anti-neoplastic agents induce MDR (multidrug resistance) in cancer cells and the role of GSH (glutathione) in the activation of pumps such as the MRPs (MDR associated proteins) are still open questions. In the present paper we illustrate that a doxorubicin-resistant human colon cancer cell line (HT29-DX), exhibiting decreased doxorubicin accumulation, increased intracellular GSH content, and increased MRP1 and MRP2 expression in comparison with doxorubicin-sensitive HT29 cells, shows increased activity of the PPP (pentose phosphate pathway) and of G6PD (glucose-6-phosphate dehydrogenase). We observed the onset of MDR in HT29 cells overexpressing G6PD which was accompanied by an increase in GSH. The G6PD inhibitors DHEA (dehydroepiandrosterone) and 6-AN (6-aminonicotinamide) reversed the increase of G6PD and GSH and inhibited MDR both in HT29-DX cells and in HT29 cells overexpressing G6PD. In our opinion, these results suggest that the activation of the PPP and an increased activity of G6PD are necessary to some MDR cells to keep the GSH content high, which is in turn necessary to extrude anticancer drugs out of the cell. We think that our data provide a new further mechanism for GSH increase and its effects on MDR acquisition. PMID- 21679163 TI - Prevalence of impaired glucose tolerance and diabetes after gestational diabetes mellitus comparing different cut-off criteria for abnormal glucose tolerance during pregnancy. AB - OBJECTIVE: To determine the prevalence of diabetes and impaired glucose tolerance after gestational diabetes mellitus in relation to different categories of glucose tolerance during pregnancy. DESIGN: Prospective study. SETTING: Four delivery departments and three hospitals in southern Sweden took part in recruitment and follow-up. POPULATION: Women undergoing a 75g oral glucose tolerance test during pregnancy delivering in 2003-2005. METHODS: At first follow up, one to two years after delivery, 29% of eligible women with abnormal glucose tolerance during pregnancy had an oral glucose tolerance test - 160 with gestational diabetes and 309 with gestational impaired glucose tolerance - in addition to 167 control women. Cut-off levels defining gestational diabetes and impaired glucose tolerance were two-hour capillary blood glucose levels of 9.0 and 7.8mmol/l or plasma glucose 10.0 and 8.6mmol/l, respectively. MAIN OUTCOME MEASURES: Frequency of abnormal test results at follow-up. RESULTS: Diabetes was diagnosed in 11% and impaired glucose tolerance in 24% of women with gestational diabetes vs. 4 and 23% in those with gestational impaired glucose tolerance, respectively. Combining women with abnormal test results during pregnancy revealed diabetes or impaired glucose tolerance in 29% as compared to 10% among controls; the odds ratio (95% confidence interval) for having abnormal test results was 3.3 (1.8-5.9) in a multivariate logistic regression analysis. CONCLUSIONS: Lowering the cut-off level for gestational diabetes to include the category of impaired glucose tolerance would identify a high percentage of women with diabetes and impaired glucose tolerance postpartum, who constitute target groups for intervention and/or diabetes prevention. PMID- 21679165 TI - Travel letter from Toronto. PMID- 21679164 TI - Extra-membranous pregnancy, prolonged ruptured membranes and circumvallate placenta. PMID- 21679166 TI - Near-tetraploid acute myeloid leukaemia. PMID- 21679167 TI - Molluscum contagiosum in a patient with adult T-cell leukaemia/lymphoma. PMID- 21679168 TI - Does felt gender compatibility mediate influences of self-perceived gender nonconformity on early adolescents' psychosocial adjustment? AB - This study evaluated the hypothesis that self-perceived gender nonconformity is distressing to children because it undermines a confident sense of gender compatibility. Participants were 357 early adolescents (180 boys, M age = 12.68 years) in England who responded to questionnaires measuring friendship styles (preoccupied, avoidant), gender compatibility (typicality, contentedness), and adjustment (self-esteem, peer social competence, depression, narcissism). Sex differences in friendship styles indicated that preoccupied and avoidant styles were typical for girls and boys, respectively. Gender-atypical friendship styles predicted poor adjustment, and their impact on adjustment was partially mediated by felt gender compatibility. Results suggest that perceiving gender-atypical attributes in the self undermines adjustment partly because it leads children to feel incompatible with their gender collective. PMID- 21679169 TI - Theory of mind and social interest in zero-acquaintance play situations. AB - Many studies have examined associations between children's theory of mind and social behavior with familiar peers, but to date none have examined how theory of mind might relate to behavior toward unfamiliar peers in a play setting. Forty four 4-year-olds (21 girls, 23 boys) participated in standard theory-of-mind tasks and in a play session with 3 or 4 other children who were unfamiliar. Children were also tested on general vocabulary ability. No relations were found between theory of mind and social engagement. However, positive associations were found between theory of mind and time spent observing, but not interacting with, other children. Possible explanations of the links between theory of mind, temperament, and social interest are considered. PMID- 21679170 TI - Preschoolers' quarantining of fantasy stories. AB - Preschool-aged children are exposed to fantasy stories with the expectation that they will learn messages in those stories that are applied to real-world situations. We examined children's transfer from fantastical and real stories. Over the course of 2 studies, 31/2- to 51/2-year-old children were less likely to transfer problem solutions from stories about fantasy characters than stories about real people. A combined analysis of the participants in the 2 studies revealed that the factors predicting transfer differed for the fantasy and real stories. These findings are discussed within the context of their implications for preschoolers' developing boundaries between fantasy and real worlds. PMID- 21679171 TI - Effect of foster care on young children's language learning. AB - This report examines 174 young children's language outcomes in the Bucharest Early Intervention Project, the first randomized trial of foster placement after institutional care. Age of foster placement was highly correlated with language outcomes. Placement by 15 months led to similar expressive and receptive language test scores as typical age peers at 30 and 42 months. Placement from 15 to 24 months also led to dramatic language improvement. In contrast, children placed after 24 months had the same severe language delays as children in institutional care. Language samples at 42 months confirmed that placement after 24 months led to lower expressive skill. PMID- 21679172 TI - Why don't smart teens have sex? A behavioral genetic approach. AB - Academic achievement and cognitive ability have been shown to predict later age at first sexual intercourse. Using a sample of 536 same-sex twin pairs who were followed longitudinally from adolescence to early adulthood, this study tested whether relations between intelligence, academic achievement, and age at first sex were due to unmeasured genetic and environmental differences between families. Twins who differed in their intelligence or their academic achievement did not differ in their age at first sex. Rather, the association between intelligence and age at first sex could be attributed entirely to unmeasured environmental differences between families, whereas the association between academic achievement and age at first sex could be attributed entirely to genetic factors. PMID- 21679174 TI - A longitudinal study of religious identity and participation during adolescence. AB - To examine the development of religious identity during the teenage years, adolescents (N = 477) from Latin American, Asian, and European backgrounds completed questionnaires in the 10th, 11th, and 12th grades (10th grade age: M = 15.81, SD = 0.36). Results indicated that religious identity remained stable across high school whereas religious participation declined. Even after controlling for ethnic differences in religious affiliation, socioeconomic background, and generational status, adolescents from Latin American and Asian backgrounds reported higher levels of religious identity and adolescents from Latin American backgrounds reported higher rates of religious participation. Within individual adolescents, changes in religious identity were associated with changes in ethnic and family identities, suggesting important linkages in the development of these social identities during adolescence. PMID- 21679173 TI - Impaired acuity of the approximate number system underlies mathematical learning disability (dyscalculia). AB - Many children have significant mathematical learning disabilities (MLD, or dyscalculia) despite adequate schooling. The current study hypothesizes that MLD partly results from a deficiency in the Approximate Number System (ANS) that supports nonverbal numerical representations across species and throughout development. In this study of 71 ninth graders, it is shown that students with MLD have significantly poorer ANS precision than students in all other mathematics achievement groups (low, typically, and high achieving), as measured by psychophysical assessments of ANS acuity (w) and of the mappings between ANS representations and number words (cv). This relation persists even when controlling for domain-general abilities. Furthermore, this ANS precision does not differentiate low-achieving from typically achieving students, suggesting an ANS deficit that is specific to MLD. PMID- 21679175 TI - Imitation in infancy: rational or motor resonance? AB - The present study investigates the contribution of 2 mechanisms to imitation in infancy. The principle of rational action suggests that infants normatively evaluate the efficiency of observed actions. In contrast, it has been proposed that motor resonance (i.e., the mapping of others' actions onto one's own motor repertoire) plays a central role in imitation. This study tested 14-month-old infants (n = 95) in 5 conditions and manipulated the extent to which the observed actions could be matched onto the infants' own motor repertoire as well as whether the observed behavior appeared to be efficient. The results suggest that motor resonance plays a more central role in imitation in infancy than does a rational evaluation of the observed action. PMID- 21679176 TI - Effects of nonmaternal care in the first 3 years on children's academic skills and behavioral functioning in childhood and early adolescence: a sibling comparison study. AB - Nonmaternal care of infant children is increasingly common, but there is disagreement as to whether it is harmful for children. Using data from 9,185 children (5 years and older) who participated in the Children of the National Longitudinal Survey of Youth, the current study compared 2 groups: those for whom nonmaternal care was initiated in the first 3 years and those for whom it was not. Between-family comparisons showed that early nonmaternal care was associated with higher achievement and lower behavior problem scores in childhood and adolescence. However, within-family comparisons failed to detect differences between siblings who had different early nonmaternal care experiences. The study concludes that the timing of entry to nonmaternal care in the first 3 years has neither positive nor negative effects on children's outcomes. PMID- 21679177 TI - Young children's learning and transfer of biological information from picture books to real animals. AB - Preschool children (N = 104) read a book that described and illustrated color camouflage in animals (frogs and lizards). Children were then asked to indicate and explain which of 2 novel animals would be more likely to fall prey to a predatory bird. In Experiment 1, 3- and 4-year-olds were tested with pictures depicting animals in camouflage and noncamouflage settings; in Experiment 2, 4 year-olds were tested with real animals. The results show that by 4 years of age, children can learn new biological facts from a picture book. Of particular importance, transfer from books to real animals was found. These findings point to the importance that early book exposure can play in framing and increasing children's knowledge about the world. PMID- 21679178 TI - Age differences in strategic planning as indexed by the tower of London. AB - The present study examined age differences in performance on the Tower of London, a measure of strategic planning, in a diverse sample of 890 individuals between the ages of 10 and 30. Although mature performance was attained by age 17 on relatively easy problems, performance on the hardest problems showed improvements into the early 20s. Furthermore, whereas age-related performance gains by children and adolescents (ages 10-17) on the hardest problems were partially mediated by maturational improvements in both working memory and impulse control, improved performance in adulthood (ages 18+) was fully mediated by late gains in impulse control. Findings support an emerging picture of late adolescence as a time of continuing improvement in planned, goal-directed behavior. PMID- 21679179 TI - Trajectories of the home learning environment across the first 5 years: associations with children's vocabulary and literacy skills at prekindergarten. AB - Children's home learning environments were examined in a low-income sample of 1,852 children and families when children were 15, 25, 37, and 63 months. During home visits, children's participation in literacy activities, the quality of mothers' engagements with their children, and the availability of learning materials were assessed, yielding a total learning environment score at each age. At 63 months, children's vocabulary and literacy skills were assessed. Six learning environment trajectories were identified, including environments that were consistently low, environments that were consistently high, and environments characterized by varying patterns of change. The skills of children at the extremes of learning environment trajectories differed by more than 1 SD and the timing of learning experiences related to specific emerging skills. PMID- 21679180 TI - Predominant role of obesity/insulin resistance in oxidative stress development. AB - BACKGROUND: Hyperlipidaemia, hyperglycaemia and hyperinsulinaemia, hallmarks of the postprandial state, have been also associated with increased oxidative stress and lipoprotein oxidation contributing to vascular injury and atherosclerosis. However, the specific links among metabolic disorders, postprandial state, insulin resistance and oxidative stress are still to be clarified. This study aimed at investigating the individual role played by obesity, insulin resistance and type 2 diabetes in the occurrence of fasting and postprandial oxidative stress. DESIGN: Biomarkers of oxidative stress [F2-isoprostanes and circulating oxidized low-density lipoproteins (LDL)], LDL oxidability (conjugated diene kinetic, thiobarbituric acid reactive substances (TBARs) formation and electronegativity increase) and antioxidant vitamins (beta-carotene, alpha tocopherol and retinol) were evaluated at fasting and 6 h after a standard fat rich meal in 10 obese diabetic (ObD), 11 obese and 11 normal-weight control men. Insulin sensitivity was evaluated by euglycaemic hyperinsulinaemic clamp. RESULTS: ObD and obese subjects, characterized by a similar level of adiposity and insulin resistance, showed higher urinary F2-isoprostanes and circulating oxidized LDL, an increased susceptibility to oxidation of plasma LDL (lower lag phase, higher TBARs formation, and higher relative electrophoretic mobility), and lower plasma content of beta-carotene and retinol than control subjects, both at fasting and after the test meal. CONCLUSIONS: Obesity and insulin resistance, more than type 2 diabetes, play the most relevant role in oxidative stress development. The correction of obesity and insulin resistance might be a useful strategy in counteracting systemic oxidative stress. PMID- 21679181 TI - Testosterone, SHBG and risk of type 2 diabetes in the second evaluation of the Pizarra cohort study. AB - AIM: To evaluate the association between serum levels of testosterone, sex hormone-binding globulin (SHBG) and calculated bioavailable testosterone (bioT), and the risk of type 2 diabetes mellitus (T2D) in a prospective cohort from southern Spain (Pizarra study). RESEARCH DESIGN AND METHODS: The study was performed in the Pizarra Cohort Study, a prospective study started in 1995 with a follow-up of 11 years. Anthropometric and metabolic variables were measured at baseline and at 6 and 11 years of follow-up. Total testosterone (TT), SHBG and calculated bioT were determined at the 6-year follow-up. RESULTS: The levels of TT and bioT in men were negatively associated with the risk of obesity, T2D and the metabolic syndrome. In women, the levels of TT and bioT were associated positively with the risk of insulin resistance. The levels of SHBG were associated negatively with the risk of T2D, obesity and insulin resistance in both men and women. For all groups, the association was higher at the 11-year follow-up. CONCLUSIONS: Low levels of testosterone and SHBG increase the risk of T2D in men, and high levels of testosterone increase the risk of insulin resistance in women. The association between TT levels and the risk of T2D is not completely independent of other variables, such as exposure time, adiposity, insulin resistance or SHBG levels. This study also shows that the different responses between men and women are probably because of the protective effect of SHBG, levels of which are higher in women than in men. PMID- 21679182 TI - Oesophageal sensation in response to high PCO(2) and acidic solutions in nonerosive reflux disease. AB - BACKGROUND: Heartburn is commonly associated with the presence of acid in the oesophageal lumen. However, in patients with nonerosive reflux disease (NERD), the mechanism by which acid traverses the mucosa is not clear. We hypothesized that the luminal acid signal traverses the oesophageal epithelium in the form of the highly permeant gas CO(2) , which then is reconverted to H(+) in the submucosa. MATERIALS AND METHODS: Ten patients with heartburn, normal upper endoscopy and increased oesophageal acid exposure (NERD patients) and 10 healthy subjects were enrolled. Perceptual responses to intraoesophageal acid (0.1 N HCl solution) and a high PCO(2) solution were determined using a randomized cross over design. Stimulus-response functions to perfusions were quantified by three parameters: lag time to symptom perception, intensity rating and perfusion sensitivity score. RESULTS: In NERD patients, the difference in lag time to typical symptom perception, intensity rating and perfusion sensitivity score between high PCO(2) and acid perfusions was statistically significant (P = 0.02, 0.01 and 0.02, respectively). However, the difference in the same perfusion parameters between acid and high PCO(2) perfusions was nonsignificant in healthy controls. When NERD and controls were compared, the difference between the different perfusion variables was nonsignificant (adjusted to age). CONCLUSIONS: In NERD subjects, acid perfusion reliably evoked heartburn symptoms of greater intensity than in healthy controls. Nevertheless, a high PCO(2) perfusion failed to produce symptoms in either group. PMID- 21679183 TI - Phenotypes of articular disc cells in the rat temporomandibular joint as demonstrated by immunohistochemistry for nestin and GFAP. AB - The articular disc is a dense collagenous tissue containing disc cells that are phenotypically described as chondrocyte-like cells or fibrochondrocytes. Despite the possible existence of these phenotypes in systemic joints, little is known about the detailed classification of the articular disc cells in the temporomandibular joint. In this immunocytochemical study we examined the localization and distribution patterns of nestin and glial fibrillary acidic protein (GFAP) in the articular disc of the rat temporomandibular joint at postnatal day 1, and weeks 1, 2, 4 and 8, based on the status of tooth eruption and occlusion. Nestin and GFAP are intermediate filament proteins whose expression patterns are closely related to cell differentiation and cell migration. Both types of immunopositive cell greatly increased postnatally to a stable level after postnatal week 4, but they showed different distribution patterns and cell morphologies. Nestin-reactive disc cells, which were characterized by a meagre cytoplasm and thin cytoplasmic processes, were scattered in the articular disc, whereas GFAP-positive cells, characterized by broader processes, existed exclusively in the deeper area. In mature discs, the major proportion of articular disc cells exhibited GFAP immunoreactivity. Furthermore, a double-immunostaining demonstrated that the nestin-negative cells, consisting of GFAP-positive and -negative cells, exhibited immunoreactions for heat shock protein 25. These findings indicate that the articular disc cells comprise at least three types in the rat temporomandibular joint and suggest that their expressions closely relate to mechanical loading forces within the joint, including occlusal force, as observed through postnatal development. PMID- 21679184 TI - Development of human minor salivary glands: expression of mucins according to stage of morphogenesis. AB - The formation of salivary glands entails the proliferation of epithelial cells from the stomatodeum into the underlying ectomesenchyme, culminating in a complex network of ducts and acinar bulbs. The extent to which mucins regulate this process is unknown, but they appear to mediate luminal space formation and maturation. Our aim was to examine mucin expression patterns during the morphogenesis of human salivary glands. Mucin expression - MUC1, 2, 3, 4, 5AC, 5B, 6, and 16 - was analyzed in specimens of developing human salivary glands, obtained from fetuses at 4-24 weeks' gestation, and fully developed salivary glands by immunohistochemistry. Expression patterns were analyzed qualitatively according to the development stage of the salivary glands. Mucins 1, 3, 4, 5B, and 16 were expressed during salivary gland development - being stronger in all ductal segments by the final phases of branching morphogenesis and in mature glands. Acinar cells were negative for most mucins, including MUC1 in mature salivary glands. Mucins 2, 5AC, and 6 were not expressed. Mucins MUC1, 3, 4, 5B, and 16 are expressed in developing human salivary glands and in mature glands, suggesting important roles in the maturation and maintenance of the ductal network. PMID- 21679186 TI - What do 'omic technologies have to offer periodontal clinical practice in the future? AB - BACKGROUND AND OBJECTIVE: Periodontal diseases are the most common chronic inflammatory diseases of humans and a major cause of tooth loss. Inflammatory periodontitis is also a complex multifactorial disease involving many cell types, cell products and interactions. It is associated with a dysregulated inflammatory response, which fails to resolve, and which also fails to re-establish a beneficial periodontal microbiota. There is a rich history of biomarker research within the field of periodontology, but exemplary improvements in analytical platform technologies offer exciting opportunities for discovery. These include the 'omic technologies, such as genomics, transcriptomics, proteomics and metabolomics, which provide information on global scales that can match the complexity of the disease. This narrative review focuses on the recent advances made in in vivo human periodontal research by use of 'omic technologies. MATERIAL AND METHODS: The Medline database was searched to identify articles currently available on 'omic technologies with regard to periodontal research. RESULTS: One hundred and sixty-one articles focusing on biomarkers of and 'omic advances in periodontal research were analysed for their contributions to the understanding of periodontal diseases. CONCLUSION: The data generated by the use of 'omic technologies have huge potential to inform paradigm shifts in our understanding of periodontal diseases, but data management, analysis and interpretation require a thoughtful and systematic bioinformatics approach, to ensure meaningful conclusions can be made. PMID- 21679185 TI - Sleep duration varies as a function of glutamate and GABA in rat pontine reticular formation. AB - The oral part of the pontine reticular formation (PnO) is a component of the ascending reticular activating system and plays a role in the regulation of sleep and wakefulness. The PnO receives glutamatergic and GABAergic projections from many brain regions that regulate behavioral state. Indirect, pharmacological evidence has suggested that glutamatergic and GABAergic signaling within the PnO alters traits that characterize wakefulness and sleep. No previous studies have simultaneously measured endogenous glutamate and GABA from rat PnO in relation to sleep and wakefulness. The present study utilized in vivo microdialysis coupled on-line to capillary electrophoresis with laser-induced fluorescence to test the hypothesis that concentrations of glutamate and GABA in the PnO vary across the sleep/wake cycle. Concentrations of glutamate and GABA were significantly higher during wakefulness than during non-rapid eye movement sleep and rapid eye movement sleep. Regression analysis revealed that decreases in glutamate and GABA accounted for a significant portion of the variance in the duration of non-rapid eye movement sleep and rapid eye movement sleep episodes. These data provide novel support for the hypothesis that endogenous glutamate and GABA in the PnO contribute to the regulation of sleep duration. PMID- 21679187 TI - Do patients with aggressive periodontitis have evidence of diabetes? A pilot study. AB - BACKGROUND AND OBJECTIVE: Complex relationships exist between diabetes and periodontal disease. Diabetes is accepted as a risk factor for periodontal disease, and recent evidence supports the existence of a bidirectional relationship between these two diseases. It has been hypothesized that inflammation, lipids and adipokines may mediate these relationships. However, research regarding the above relationships with respect to aggressive periodontitis is very limited. This pilot study aimed to investigate whether patients with aggressive periodontitis (not previously diagnosed with diabetes) have evidence of diabetes and have altered serum levels of inflammatory mediators, lipids and adipokines. MATERIAL AND METHODS: Glycaemic control markers (random plasma glucose and glycated haemoglobin), inflammatory mediators (high sensitivity C-reactive protein, tumour necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma and interleukin-18), lipids (triglycerides, total cholesterol and high-density lipoprotein-cholesterol) and adipokines (leptin, adiponectin and resistin) were measured in serum samples from 30 patients with aggressive periodontitis and 30 age- and sex-matched periodontally healthy control subjects, none of whom had a previous diagnosis of diabetes. RESULTS: Levels of glycaemic control markers, inflammatory mediators, lipids and adipokines were not significantly different (p > 0.05) between the aggressive periodontitis patients and healthy subjects for unadjusted and adjusted analyses (adjusting for body mass index, smoking, ethnicity, age and sex). The p-value for the adjusted analysis of adiponectin in female aggressive periodontitis patients compared with the female control subjects reached 0.064, the mean adiponectin level being lower in the female aggressive periodontitis patients (4.94 vs. 5.97 MUg/mL). CONCLUSION: This pilot study provided no evidence to suggest that patients with aggressive periodontitis (not previously diagnosed with diabetes) have evidence of diabetes or altered serum levels of inflammatory mediators, lipids and adipokines. PMID- 21679188 TI - The photosynthetic plasticity of crassulacean acid metabolism: an evolutionary innovation for sustainable productivity in a changing world. AB - SUMMARY: The photosynthetic specialization of crassulacean acid metabolism (CAM) has evolved many times in response to selective pressures imposed by water limitation. Integration of circadian and metabolite control over nocturnal C4 and daytime C3 carboxylation processes in CAM plants provides plasticity for optimizing carbon gain and water use by extending or curtailing the period of net CO2 uptake over any 24-h period. Photosynthetic plasticity underpins the ecological diversity of CAM species and contributes to the potential for high biomass production in water-limited habitats. Perceived evolutionary constraints on the dynamic range of CO2 acquisition strategies in CAM species can be reconciled with functional anatomical requirements and the metabolic costs of maintaining the enzymatic machinery required for C3 and C4 carboxylation processes. Succulence is highlighted as a key trait for maximizing biomass productivity in water-limited habitats by serving to buffer water availability, by maximizing the magnitude of nocturnal CO2 uptake and by extending the duration of C4 carboxylation beyond the night period. Examples are discussed where an understanding of the diverse metabolic and ecological manifestations of CAM can be exploited for the sustainable productivity of economically and ecologically important species. PMID- 21679190 TI - Water supply and demand remain balanced during leaf acclimation of Nothofagus cunninghamii trees. AB - Higher leaf vein density (D(vein) ) enables higher rates of photosynthesis because enhanced water transport allows higher leaf conductances to CO(2) and water. If the total cost of leaf venation rises in proportion to the density of minor veins, the most efficient investment in leaf xylem relative to photosynthetic gain should occur when the water transport capacity of the leaf (determined by D(vein) ) matches potential transpirational demand (determined by stomatal size and density). We tested whether environmental plasticity in stomatal density (D(stomata) ) and D(vein) were linked in the evergreen tree Nothofagus cunninghamii to achieve a balance between liquid and gas phase water conductances. Two sources of variation were examined; within-tree light acclimation, and differences in sun leaves among plants from ecologically diverse populations. Strong, linear correlations between D(vein) and D(stomata) were found at all levels of comparison. The correlations between liquid- and vapour phase conductances implied by these patterns of leaf anatomy were confirmed by direct measurement of leaf conductance in sun and shade foliage of an individual tree. * Our results provide strong evidence that the development of veins and stomata are coordinated so that photosynthetic yield is optimized relative to carbon investment in leaf venation. PMID- 21679189 TI - Plant defensin AhPDF1.1 is not secreted in leaves but it accumulates in intracellular compartments. AB - * Apart from their antifungal role, plant defensins have recently been shown to be involved in abiotic stress tolerance or in inhibition of root growth when added in plant culture medium. We studied the subcellular localization of these proteins, which may account for these different roles. * Stable and transient expression of AhPDF1.1::GFP (green fluorescent protein) fusion proteins were analysed in yeast and plants. Functional tests established that the GFP tag did not alter the action of the defensin. Subcellular localization of AhPDF1.1 was characterized: by imaging AhPDF1.1::GFP together with organelle markers; and by immunolabelling AhPDF1.1 in Arabidopsis halleri and Arabidopsis thaliana leaves using a polyclonal serum. * All our independent approaches demonstrated that AhPDF1.1 is retained in intracellular compartments on the way to the lytic vacuole, instead of being addressed to the apoplasm. * These findings challenge the commonly accepted idea of secretion of defensins. The subcellular localization highlighted in this study could partly explain the dual role of plant defensins on plant cells and is of major importance to unravel the mechanisms of action of these proteins at the cellular level. PMID- 21679191 TI - Association of 25-hydroxyvitamin D3)levels in adult New Zealanders with ethnicity, skin color and self-reported skin sensitivity to sun exposure. AB - The study aim was to determine the contribution of ethnicity, objectively measured skin color and skin reaction-to-sun exposure to variations in 25 hydroxyvitamin D(3) [25(OH)D(3) ]. A multiethnic sample (European, Maori, Pacific and Asian) of 503 adult volunteers aged 18-85 years, recruited from Auckland and Dunedin in New Zealand, answered a questionnaire on sun exposure and self-defined ethnicity. Skin color was measured using a spectrophotometer and the Individual Typology Angle (ITA) calculated. A blood sample was collected 4 weeks later to measure 25(OH)D(3). 25(OH)D(3) was associated with ethnicity, but not self reported skin reaction-to-sun exposure. Amongst the ethnic groups, Asians had the lowest mean 25(OH)D level (37.0 nmol L(-1)) and Europeans with lighter colored skin had the highest (57.9 nmol L(-1)). An association also was seen between 25(OH)D(3) and skin color, with an increase of 2-3 nmol L(-1) per 10 degrees increase in ITA value, indicating higher 25(OH)D(3) with lighter skin color; but much of this association disappeared after adjusting for ethnicity. In contrast, ethnicity remained associated with 25(OH)D(3) after adjusting for ITA skin color and skin reaction-to-sun exposure. These results indicate that self-defined ethnicity was a major determinant of variations in serum 25(OH)D(3), while objective measures of skin color explained relatively little additional variation. PMID- 21679192 TI - Evidence against sink limitation by the sucrose-to-starch route in potato plants expressing fructosyltransferases. AB - To investigate whether the route from sucrose to starch limits sink strength of potato tubers, we established an additional storage carbohydrate pool and analyzed allocation of imported assimilates to the different pools. Tuber specific expression of the fructan biosynthetic enzymes of globe artichoke resulted in accumulation of fructans to about 5% of the starch level, but did not increase tuber dry weight per plant. While partial repression of starch synthesis caused yield reduction in wild-type plants, it stimulated fructan accumulation, and yield losses were ameliorated in tubers expressing fructosyltransferases. However, a nearly complete block of the starch pathway by inhibition of sucrose synthase could not be compensated by the fructan pathway. Although fructan concentrations rose, yield reduction was even enhanced, probably because of a futile cycle of fructan synthesis and degradation by invertase, which is induced when sucrose synthase is knocked out. The data do not support a limitation of sink strength by enzyme activities of the starch pathway but point to an energy limitation of storage carbohydrate formation in potato tubers. PMID- 21679193 TI - ABA treatment of germinating maize seeds induces VP1 gene expression and selective promoter-associated histone acetylation. AB - Seed germination commences from a low metabolic state to a bioactive state and is associated with changes in the pattern of gene expression. Recent studies have revealed that epigenetic processes are involved in abscisic acid (ABA)-regulated seed germination processes. In this study, we showed that the expression of both histone acetyltransferases (HATs) and histone deacetylases (HDACs) was increased gradually during seed germination accompanying an increase in overall acetylation level of histone H3. Application of exogenous ABA repressed the expression of HATs as well as HDACs and delayed histone acetylation. Suppressing HDAC by treatment with an HDAC inhibitor, trichostatin A (TSA), led to an increase in global histone acetylation and inhibited seed germination and growth. However, ABA and TSA both delayed the downregulation of the embryogenesis-related gene viviparous1 (VP1) during seed germination. The further chromatin immunoprecipitation experiments showed that the promoter region of the VP1 gene was deacetylated during seed germination, and this deacetylation event was inhibited by both ABA and TSA. These results suggested that a balance of the two enzymes HATs and HDACs affected the acetylation status of the VP1 gene and ABA selectively activated its transcription by an accumulation of acetylated histone H3 associated with the promoter region during seed germination. PMID- 21679195 TI - Contact allergy in the cleaning industry: analysis of contact allergy surveillance data of the Information Network of Departments of Dermatology. AB - BACKGROUND: Occupational contact allergy is a common problem in the cleaning industry. OBJECTIVES: To identify the most frequent occupation-associated allergens and time trends in contact allergy in female cleaners. METHODS: We analysed the patch test data concerning 803 female cleaners, who were evaluated for occupational contact dermatitis in 45 dermatological departments contributing to the Information Network of Departments of Dermatology (IVDK) from 1996 to 2009. Female patients, except cleaners, with occupational dermatitis (n = 14494) and female controls without occupational dermatitis (n = 64736) patch tested during this time period formed the control groups. RESULTS: One hundred and fifty six (19.4%) cleaners had past or present atopic dermatitis. Six hundred and fifty five (81.6%) cleaners suffered from occupational hand dermatitis. Allergic contact dermatitis was diagnosed in 249 (31%) of the cleaners. As compared with the control group without occupational dermatitis, female cleaners were significantly more often sensitized to occupationally relevant allergens such as rubber additives, especially thiurams [11.6%, 95% confidence interval (CI) 9.1 14.1 vs. 1.5%, 95% CI 1.4-1.6], zinc diethyldithiocarbamate (3.4%, 95% CI 2.1-4.7 vs. 0.4, 95% CI 0.3-0.4), and mercaptobenzothiazole (1.8, 95% CI 0.7-2.9 vs. 0.5, 95% CI 0.4-0.6), as well as formaldehyde (3.4, 95% CI 2.0-4.7 vs. 1.4%, 95% CI 1.3-1.5). No differences were seen in patterns of sensitization to occupational allergens in younger (<=40 years of age) and older (>40 years of age) female cleaners. CONCLUSION: Formaldehyde and rubber additives such as thiurams, zinc diethyldithiocarbamate and mercaptobenzothiazole are occupationally relevant allergens in female cleaners. Prevention strategies are needed to address the problem. PMID- 21679194 TI - Allergic contact dermatitis caused by isopropyl alcohol: a missed allergen? AB - BACKGROUND: Isopropyl alcohol is a secondary alcohol, a structural isomer of propanol, that is widely used as an industrial solvent and as a preservative and antiseptic in the clinical environment. It is known to be a mild irritant for the eyes and mucous membranes, but is considered to be a weak and infrequent sensitizer. OBJECTIVES: To show that isopropyl alcohol should be considered as a potential allergen in patients with eczema who have contact with this substance. MATERIALS AND METHODS: We present a series of 1450 patients patch tested with isopropyl alcohol during the period 1992-2011. RESULTS: Forty-four patients showed an allergic response to isopropyl alcohol. Four cases presented as occupational hand eczema. Fourteen cases were seen in patients with leg ulcers. Twenty-six patients presented with eczematous lesions following the use of products containing isopropyl alcohol to disinfect previous skin lesions. Eighty four per cent of the patients showed sensitization to three or more allergens. Relevance was present in 84% of the patients. CONCLUSIONS: We report here the first large case series of contact allergy to isopropyl alcohol, which demonstrates that sensitization to this substance might not be as uncommon as previously thought. PMID- 21679196 TI - Pharmacokinetics of veterinary drugs in laying hens and residues in eggs: a review of the literature. AB - Poultry treated with pharmaceutical products can produce eggs contaminated with drug residues. Such residues could pose a risk to consumer health. The following is a review of the information available in the literature regarding drug pharmacokinetics in laying hens, and the deposition of drugs into eggs of poultry species, primarily chickens. The available data suggest that, when administered to laying hens, a wide variety of drugs leave detectable residues in eggs laid days to weeks after the cessation of treatment. PMID- 21679198 TI - Twelve hours of sustained ventricular fibrillation supported by a continuous-flow left ventricular assist device. AB - Left ventricular assist device (LVAD) therapy improves survival and quality of life by mechanically unloading the left ventricle and maintaining hemodynamics in patients with end-stage heart failure. LVADs can also be lifesaving by maintaining hemodynamics during ventricular arrhythmia. Continuous-flow LVADs have become the preferred LVAD technology. As presented here, a continuous-flow LVAD successfully provided hemodynamic support to a patient in sustained ventricular fibrillation for over 12 hours when the internal defibrillator was unable to terminate the arrhythmia. This case demonstrates that continuous-flow LVADs can be lifesaving in the setting of otherwise certain hemodynamic collapse from sustained ventricular fibrillation. PMID- 21679197 TI - Toltrazuril sulfone sodium salt: synthesis, analytical detection, and pharmacokinetics in the horse. AB - Toltrazuril sulfone (ponazuril) is a triazine-based antiprotozoal agent with clinical application in the treatment of equine protozoal myeloencephalomyelitis (EPM). In this study, we synthesized and determined the bioavailability of a sodium salt formulation of toltrazuril sulfone that can be used for the treatment and prophylaxis of EPM in horses. Toltrazuril sulfone sodium salt was rapidly absorbed, with a mean peak plasma concentration of 2400 +/- 169 (SEM) ng/mL occurring at 8 h after oral-mucosal dosing and was about 56% bioavailable compared with the i.v. administration of toltrazuril sulfone in dimethylsulfoxide (DMSO). The relative bioavailability of toltrazuril sulfone suspended in water compared with toltrazuril sulfone sodium salt was 46%, indicating approximately 54% less oral bioavailability of this compound suspended in water. In this study, we also investigated whether this salt formulation of toltrazuril sulfone can be used as a feed additive formulation without significant reduction in oral bioavailability. Our results indicated that toltrazuril sulfone sodium salt is relatively well absorbed when administered with feed with a mean oral bioavailability of 52%. Based on these data, repeated oral administration of toltrazuril sulfone sodium salt with or without feed will yield effective plasma and cerebrospinal fluid (CSF) concentrations of toltrazuril sulfone for the treatment and prophylaxis of EPM and other protozoal diseases of horses and other species. As such, toltrazuril sulfone sodium salt has the potential to be used as feed additive formulations for both the treatment and prophylaxis of EPM and various other apicomplexan diseases. PMID- 21679199 TI - Exhaustive isolation of diarrhoeagenic Escherichia coli by a colony hybridization method using hydrophobic grid-membrane filters in combination with multiplex real time PCR. AB - AIMS: The present study aimed to develop a colony hybridization method for the exhaustive detection and isolation of diarrhoeagenic Escherichia coli (DEC) from samples containing numerous coliform bacteria. METHODS AND RESULTS: Digoxigenin labelled DNA probes were designed to detect seven pathotypes of DEC based on type specific genes. A total of 615 meat, food and faeces samples identified as DEC positive by multiple real-time PCR for the virulence genes (eae, stx, elt, est, virB, aggR, afaB and astA) were analysed by a colony hybridization method, which involved filtering enrichment cultures through hydrophobic grid-membrane filters. DEC were isolated from 72.5% (446/615) of samples by the colony hybridization method but were only detected in 26.3% (162/615) of samples by a conventional culture method. The hybridization method was particularly effective for isolating low-level contaminants, such as enterotoxigenic and Shiga toxin-producing E. coli, which were isolated from 51.8% (58/112) of samples identified as positive by PCR for the enterotoxin genes, in contrast to only 4.5% (5/112) of samples analysed by the conventional method. CONCLUSIONS: The developed colony hybridization system allows for the efficient and simultaneous isolation of all DEC pathotypes. SIGNIFICANCE AND IMPACT OF THE STUDY: The colony hybridization system described here permits the sensitive isolation of DEC and represents a suitable tool for ecological investigations of DEC. PMID- 21679200 TI - Testing the performance of microbiological safety cabinets used in microbiology laboratories in South Korea. AB - AIMS: To test a performance of the microbiological safety cabinets (MSCs) according to the type of MSCs in microbial laboratories. METHODS AND RESULTS: Tests were carried out to assess the performance of 31 MSCs in 14 different facilities, including six different biological test laboratories in six hospitals and eight different laboratories in three universities. The following tests were performed on the MSCs: the downflow test, intake velocity test, high-efficiency particulate air filter leak test and the airflow smoke pattern test. These performance tests were carried out in accordance with the standard procedures. Only 23% of Class II A1 (8), A2 (19) and unknown MSCs (4) passed these performance tests. The main reasons for the failure of MSCs were inappropriate intake velocity (65%), leakage in the HEPA filter sealing (50%), unbalanced airflow smoke pattern in the cabinets (39%) and inappropriate downflow (27%). CONCLUSIONS: This study showed that routine checks of MSCs are important to detect and strengthen the weak spots that frequently develop, as observed during the evaluation of the MSCs of various institutions. SIGNIFICANCE AND IMPACT OF THE STUDY: Routine evaluation and maintenance of MSCs are critical for optimizing performance. PMID- 21679201 TI - A novel DNA extraction and duplex polymerase chain reaction assay for the rapid detection of Prototheca zopfii genotype 2 in milk. AB - AIMS: To develop a PCR-based assay to detect Prototheca zopfii (P. zopfii) and its mastitis-related subtype (genotype 2) directly from milk samples. METHODS AND RESULTS: The DNA extraction method herein is based on the lysing properties of chemical agents, mechanical grinding and DNA-binding properties of silica particles; this method was developed to rapidly extract DNA directly from P. zopfii in bovine milk. Two pairs of primers specific for P. zopfii and genotype 2 were used in the duplex PCR, and a sensitivity test showed that the detection level was 5 * 10(2) colony-forming units (CFU) ml(-1) for P. zopfii and 5 * 10(3) CFU ml(-1) for genotype 2. Furthermore, a practical survey of 23 milk samples showed that the assay produced results that were in accordance with those obtained by the conventional microbiology method. CONCLUSIONS: The DNA extraction method is effective in isolating sufficient quantities of DNA from P. zopfii in milk for PCR analysis. The PCR assay is economical, sensitive and more rapid than the conventional culture method. SIGNIFICANCE AND IMPACT OF THE STUDY: The assay could be used as an alternative method for the rapid the detection of bovine mastitis resulting from P. zopfii genotype 2. PMID- 21679202 TI - Phenotypic diversity of Edwardsiella tarda isolated from different origins. AB - AIMS: To evaluate the diversity of phenotypic characteristics among isolates of Edwardsiella tarda from various origins. METHODS AND RESULTS: A total of 10 E. tarda strains were investigated on biological characteristics including flagella formation, bacterial motility, biofilm formation, extracellular protein and plasmid profiles. All the E. tarda strains (including two previous recognized as nonflagellation strains) were proven to have an average of 1-7 peritrichous flagella with the precise number positively correlated with motility and biofilm formation. All the E. tarda strains exhibited similar protein profiles except ET2034, LMG2793 and ET080814, which lacked the three major bands of approximately 18, 21 and 55 kDa. E. tarda with the same geographic location shared similar plasmid profiles. CONCLUSIONS: Edwardsiella tarda strains exhibited diversities in phenotypic characteristics that may be linked to differences in geographic location or host origin. In addition, the number of flagella is essential for bacterial motility and biofilm formation. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report demonstrating the difference in flagella formation between E. tarda strains, which may broaden the understanding of flagellation trait at intra-species level. Furthermore, evaluation of virulence-associated characteristics can provide useful information for unveiling the diverse pathogenic mechanisms of E. tarda. PMID- 21679204 TI - Practice patterns for achalasia--room for improvement? PMID- 21679206 TI - Is liver stiffness measurement unreliable in obese patients? PMID- 21679208 TI - Helicobacter pylori eradication and weight gain: has it opened a Pandora's box? PMID- 21679209 TI - Appendicectomy as a potential therapy for refractory ulcerative proctitis. PMID- 21679210 TI - Prunes vs. psyllium for chronic idiopathic constipation. PMID- 21679211 TI - Tolerability and effect of mesalazine in postinfectious irritable bowel syndrome. PMID- 21679212 TI - Tube feeding therapy in paediatric Crohn's disease. PMID- 21679215 TI - Regulations and risk analysis. From the editors. PMID- 21679214 TI - Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome. AB - BACKGROUND: Otilonium bromide (OB) is a spasmolytic agent that blocks L-Type Calcium channels in human colonic smooth muscle. AIM: To study the efficacy of OB in symptom control in irritable bowel syndrome (IBS). METHODS: A total of 356 patients (46.16+/-19years, 71% female) with IBS participated in a double-blind, randomised, parallel placebo-controlled phase IV study. OB (40mg t.d.s.) or placebo was administered for 15weeks, and follow-up was extended 10 additional weeks. RESULTS: Otilonium bromide (n=179) and placebo (n=177) groups had comparable demographics, symptom severity and IBS subtype. Both OB and placebo reduced abdominal pain and IBS symptoms. The effect of OB was significantly greater than placebo in the reduction of weekly frequency of episodes of abdominal pain at the end of treatment period (primary endpoint, -0.90+/-0.88 vs. -0.65+/-0.91, P=0.03), reduction of abdominal bloating (-1.2+/-1.2 vs. -0.9+/ 1.1, P=0.02) and global efficacy by patient assessment (1.3+/-1.1 vs. 1.0+/-1.1, P=0.047). Intensity of abdominal pain, proportion of patient responders, safety and quality of life scores were similarly affected by OB and placebo. During follow-up, the therapeutic effect of OB remained greater than placebo in terms of withdrawal rate due to symptom relapse (10% vs. 27%, P=0.009), global efficacy of treatment and relapse-free probability (P=0.038). CONCLUSIONS: This placebo controlled double-blind study shows that otilonium bromide is safe, well tolerated and superior to placebo in reducing the frequency of abdominal pain, severity of abdominal bloating and protecting from symptom relapse in IBS. These results further confirm that patients with IBS can improve during and following treatment with otilonium bromide. PMID- 21679216 TI - Time to worry: Whither risk analysis and the compression of government funding in the United States? PMID- 21679217 TI - Introduction to part 1 of the special series on risk regulation. PMID- 21679218 TI - The role of analysis on the 17 most political acres on the face of the earth. AB - Benefit-cost and risk analyses associated with agency rule making are required by presidential order and are reviewed by the Office of Management and Budget's (OMB) Office of Information and Regulatory Affairs (OIRA). This White House oversight of agency regulatory analysis means that OIRA's work, though primarily analytic, competes daily with the intense political pressures that characterize all work in the White House. Even in the face of the demands of politics, analysis is respected and utilized. A balance between politics and analysis is maintained in several ways. Several structural characteristics of the White House help protect analysis, such as a strong complement of offices whose role is primarily analytic (for example, the Council of Economic Advisors, the Office of Science and Technology Policy, and OMB). OIRA's ability to successfully coordinate its regulatory review with White House officials ensures that it serves as an agent for presidential regulatory policy at the same time it champions higher quality benefit-cost and risk analysis. This role as intermediary between analytic and political judgment also results from OIRA's expertise in such analysis and its reputation for the discretion necessary to maintain the trust of the president's upper level staff. PMID- 21679219 TI - Defragmenting the regulatory process. AB - The regulatory process is often criticized for being cumbersome and slow, much like a computer whose hard drive is fragmented by files no longer used or useful. Like such a computer, the regulatory process contains many requirements of dubious utility. These include the Paperwork Reduction Act, the Regulatory Flexibility Act, and numerous executive orders. While other parts of the regulatory process such as notice and comment and cost-benefit analysis have received much more academic attention, these other parts of the process deserve examination as well. This article argues that such an examination will reveal that these statutes and executive orders add little of value to the regulatory process while consuming agency resources. An improved requirement for cost benefit analysis with distributional analysis could easily replace virtually all of these requirements and improve regulations while reducing the time needed to promulgate regulations. PMID- 21679220 TI - Cilostazol protects the heart against ischaemia reperfusion injury in a rabbit model of myocardial infarction: focus on adenosine, nitric oxide and mitochondrial ATP-sensitive potassium channels. AB - 1. The present study examined whether or not cilostazol reduces the myocardial infarct size, and investigated its mechanism in a rabbit model of myocardial infarction. 2. Japanese white rabbits underwent 30 min of coronary occlusion, followed by 48 h of reperfusion. Cilostazol (1 and 5 mg/kg) or vehicle was given intravenously 5 min before ischaemia. 8-p-sulfophenyl theophylline (8SPT; an adenosine receptor blocker, 7.5 mg/kg), Nomega-nitro-L-arginine methylester (l NAME; an NOS inhibitor, 10 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD; a mitochondrial ATP-sensitive potassium (KATP) channel blocker, 5 mg/kg) was given intravenously 5 min before cilostazol injection. Infarct size was determined as a percentage of the risk area. 3. The myocardial interstitial levels of adenosine and nitrogen oxide (NOx) during ischaemia and reperfusion, and the intensity of myocardial dihydroethidium staining were determined. 4. Infarct size was significantly reduced in the cilostazol 1 mg/kg (38.4% (2.9%)) and cilostazol 5 mg/kg (30.7% (4.7%)) groups compared with that in the control group (46.5% (4.2%)). The infarct size-reducing effect of cilostazol was completely abolished by 8SPT (46.6% (3.5%)), L-NAME (49.0% (5.5%)), or 5HD (48.5% (5.1%)). 8SPT, L NAME or 5HD alone did not affect the infarct size. Cilostazol treatment significantly increased myocardial levels of adenosine and NOx during ischaemia, and attenuated the intensity of dihydroethidium staining during reperfusion. 5. These findings show that cilostazol reduces the myocardial infarct size by increasing adenosine and NOx levels, attenuating superoxide production and opening the mitochondrial KATP channels. Cilostazol might provide a new strategy for the treatment of coronary heart disease. PMID- 21679222 TI - Faith: a concept analysis. AB - AIM: This paper reports a concept analysis of faith. BACKGROUND: There are numerous scholars who consider spirituality and religiosity as they relate to health and nursing. Faith is often implied as linked to these concepts but deserves distinct exploration. In addition, as nursing practice conducted within communities of faith continues to emerge, concept clarification of faith is warranted. METHOD: Qualitative analysis deliberately considered the concept of faith within the lens of Margaret Newman's health as expanding consciousness. Data sources used included a secondary analysis of stories collected within a study conducted in 2008, two specific reconstructed stories, the identification of attributes noted within these various stories and selected philosophical literature from 1950 to 2009. FINDINGS: A definition was identified from the analysis; faith is an evolving pattern of believing, that grounds and guides authentic living and gives meaning in the present moment of inter-relating. Four key attributes of faith were also identified as focusing on beliefs, foundational meaning for life, living authentically in accordance with beliefs, and interrelating with self, others and/or Divine. CONCLUSION: Although a seemingly universal concept, faith was defined individually. Faith appeared to be broader than spiritual practices and religious ritual and became the very foundation that enabled human beings to make sense of their world and circumstances. More work is needed to understand how faith community nursing can expand the traditional understanding of denominationally defined faith community practices and how nurses can support faith for individuals with whom they encounter within all nursing practice. PMID- 21679221 TI - The association between antipsychotic agents and the risk of myocardial infarction: a systematic review. AB - AIM: Patient populations that are prescribed antipsychotic agents have higher cardiovascular mortality rates. The risk of myocardial infarction is influenced by various factors that are more prevalent in patients with a mental illness. The aim of this review was to determine whether the use of antipsychotic agents is associated with the incidence of myocardial infarction in adults. METHODS: Using multiple sources, all studies of antipsychotic agents using myocardial infarction as primary or secondary outcome measures were considered for inclusion. Study populations were adult subjects who had been prescribed an antipsychotic agent at least once in their medical history. RESULTS: It total, five studies were identified. Four studies with small numbers of events reported a moderate to strong effect of typical antipsychotic agents on the risk of myocardial infarction. The largest study had a favourable internal validity compared with all other studies and reported no association between the risk of myocardial infarction and current use of either atypical (relative risk 0.98, 95% confidence interval [CI] 0.88, 1.09) or typical antipsychotic agents (relative risk 0.99, 95% CI 0.96, 1.03). CONCLUSION: Clinical and methodological heterogeneity between the studies in this review led to an inconclusive answer to the question whether the use of antipsychotics is associated with the incidence of myocardial infarction in adults. Whilst results conflicted, the largest study did not find an association between the use of antipsychotic agents and an increased risk of myocardial infarction. PMID- 21679223 TI - Development and effectiveness of a school programme on improving body image among elementary school students in Taiwan. AB - AIM: The objectives of this study were to develop a programme to improve body image among elementary school students and to evaluate the effectiveness of the programme. BACKGROUND: The idea that a slim body is beautiful has become popular in recent decades, and has negatively impacted body image among school children. There is a need for further development of prevention programmes. METHODS: This study applied a quasi-experimental design. The study participants were 314 5th and 6th graders in two elementary schools in Taipei City, with 112 in the intervention group and 202 in the control group. The intervention group received an 8-week educational programme. The study participants filled out structured questionnaires at preintervention, postintervention and 3 months after intervention between October 2007 and April 2008. The indicators of effectiveness included perceptional (estimation of body size), attitudinal (body satisfaction) and behavioural (diet and vomiting to lose weight) aspects of body image. FINDINGS: Intervention students showed a greater increase in body satisfaction from pretest to posttest relative to controls. At 3 months after intervention, the intervention students still had significantly higher body satisfaction than controls. There were no statistically significant differences in the perceptional and behavioural aspects of body image. CONCLUSION: This study demonstrated that a school programme improved body satisfaction among elementary school students. The findings of this study could serve as a basis for further development of body image programmes for children to prevent a drastically deteriorating body image when they enter puberty. PMID- 21679224 TI - The effect of an educational programme on attitudes of nurses and medical residents towards the benefits of positive communication and collaboration. AB - AIMS: This article is a report of a study to determine the effect of an educational programme and to follow up weekly meetings on nurses and medical resident's attitudes towards positive communication and collaboration. BACKGROUND: Clear and appropriate communication and interdisciplinary collaboration is critical to the delivery of quality care. Collaborative practice among all healthcare professionals creates a positive work environment, decreases costs, improves job satisfaction among nurses and improves patient care, as well as decreasing patient morbidity and mortality. Poor communication and lack of teamwork or collaboration have been cited as persistent problems in healthcare. METHOD: The study was conducted in 2008 - 2009 at a hospital where a new medical residency programme was beginning and nurses had no prior experience working with medical residents. A quasi-experimental pre test, post-test design was used. The Jefferson Scale of Attitudes towards Physician-Nurse Collaboration and the Communication, Collaboration and Critical Thinking for Quality Patient Outcomes Survey tool measured the attitudes of 68 nurses and 47 medical residents in the areas of positive communication and collaboration. RESULTS/FINDINGS: The study demonstrates that a formal educational programme and follow-up discussions improved the attitudes of both nurses and medical residents on the Jefferson scale (medical residents t = 4.68, P = 0.001, nurses t = 4.37, P = 0.001) and on the communication scale (medical residents t = 4.23, P = 0.001, nurses t = 4.13, P = 0.001). CONCLUSION: Continuing education for nurses, medical residents and other healthcare providers may assist in developing positive communication styles and promote collegiality and team work. PMID- 21679225 TI - Family members' perceived meaning of visiting nursing home residents in Taiwan. AB - AIM: The purpose of this article is to report the findings of a study to explore perceived family meaning of visiting older nursing home residents in Taiwan. BACKGROUND: Family involvement in the care of institutionalized elders benefits residents, family and staff. Families have traditionally been involved through in person visits. One factor influencing family visits is motivation, which is a vague concept, creating a need to better understand the meaning families ascribe to visiting nursing home residents. Understanding this meaning is necessary to develop intervention programmes that facilitate the quality of families' nursing home visits. However, little is known about the meaning of family visits to nursing home residents in Asian countries. METHODS: Data were collected April 2009-2010 in audiotaped, individual, in-depth interviews with 15 family members of residents at four nursing homes in Taiwan. These family members included five women and 10 men, predominantly residents' children and spouses. RESULTS: The meaning of family visits to nursing home residents was captured by five major themes: hoping for recovery, honouring filial/karmic responsibility, insuring care quality, maintaining family relationships and making up for guilt. CONCLUSIONS: The findings of this study can be considered by nurses and policy makers when designing interventions and allocating resources to improve the quality of family visits with nursing home residents. These interventions can be tailored to family members' perceived meanings for visiting, e.g. those hoping for residents' recovery may benefit from health-promotion programmes, and those honouring filial/karmic responsibility might be helped by education on different ways to show filial respect. PMID- 21679226 TI - Pain and psychological well-being of older persons living in nursing homes: an exploratory study in planning patient-centred intervention. AB - AIM: This article is a report on a study to examine the pain situation, the use of oral analgesics and non-pharmacological strategies and the psychological well being of older patients living in nursing homes; the relationships between pain and psychological well-being were also explored. BACKGROUND: Pain is common among older adults world-wide, and tends to be under-treated. Indeed, the high prevalence of pain may further hinder the fulfilment of psychological needs in a Maslow hierarchy of needs model. METHOD: It was a quantitative cross-sectional study; older adults from six nursing homes were invited to join the study in 2007 2009, with a response rate of 100%. Pain was measured using the Geriatric Pain Assessment, happiness using the Subjective Happiness Scale, life satisfaction using the Life Satisfaction Index - A Form, loneliness using the Revised UCLA Loneliness Scale and depression was measured using the Geriatric Depression Scale. RESULTS: A convenience sample of 302 older patients (213 females and 89 males aged from 60 to 101, mean age of 84.99) joined the study. The majority of them had experienced pain in the previous 3 months, with a pain intensity of 4.51 on a 10-point scale. Pain sites were mainly the knee, back, shoulder and musculoskeletal areas. Only 50% of them took oral analgesics, and 70% used non pharmacological measures for pain relief. The pain group reported significantly more loneliness and depression when compared with their no-pain counterparts. CONCLUSIONS: As the number of older patients increases, so does the need for alternative accommodation; thus, pain management education is urgently needed for staff and nursing home residents. PMID- 21679227 TI - Is the Community Attitudes towards the Mentally Ill scale valid for use in the investigation of European nurses' attitudes towards the mentally ill? A confirmatory factor analytic approach. AB - AIM: This study aimed to assess the construct validity of the Community Attitudes towards the Mentally Ill scale in the investigation of European nurses' attitudes towards mental illness and mental health patients. BACKGROUND: The harbouring of negative attitudes by nurses towards any patient can have implications for recovery. To gather robust evidence upon which to base information and education aimed at fostering acceptance, support and general positivity towards people with mental health illness, a valid and reliable system of data collection is required. METHOD: A confirmatory factor analysis of both the original Community Attitudes towards the Mentally Ill scale and two modified versions of the scale were carried out during May - June 2007 using a data set representing the responses of 858 European nurses to the scale. Data were subjected to three different confirmatory factor analyses using Maximum Likelihood estimation in the software package, Analysis of Moment Structures 7. A number of absolute, relative and incremental fit statistics were used to assess the fit of the original Community Attitudes towards the Mentally Ill scale and two modified versions to the European nursing data. FINDINGS: A modification of the scale was found to be most suitable for use in the investigation of European nurses' attitudes towards mental illness and people with mental illness. CONCLUSION: Further research is recommended to develop a valid and reliable research tool to specifically measure the attitudes of 'nurses' working across different mental healthcare facilities towards this vulnerable patient group. PMID- 21679228 TI - A structure and process evaluation of an Australian hospital admission avoidance programme for aged care facility residents. AB - AIM: To describe and evaluate the structures and processes involved in a hospital in the Nursing Home programme. BACKGROUND: Older Australians are the largest consumers of healthcare, and as a result of the ageing process are at risk of developing hospital acquired iatrogenic complications. Hospital admission avoidance programmes that aim to provide care for patients in their own environment include Hospital in the Home and, more recently, Hospital in the Nursing Home. METHODS: In 2006, a qualitative evaluation of a nurse-led Hospital in the Nursing Home programme using semi-structured interviews with 19 stakeholders was undertaken. Data analysis involved using start codes and content analysis. FINDINGS: Effective referral and communication strategies were important for Hospital in the Nursing Home implementation. Furthermore, the Hospital in the Nursing Home programme manager had acute care and community experience and worked in an advanced practice role. These elements were integral to the programme's operation. CONCLUSION: As the population ages, reducing hospital admissions for aged-care facility residents has the potential to improve patient outcomes. A structurally and procedurally sound programme is a key element in achieving this aim. PMID- 21679229 TI - English version of the interim report published in 1998 by the members of the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association. AB - The Japanese Dermatological Association established an advisory committee in 1995 to set up severity scoring systems for atopic dermatitis (AD). Its interim report was published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998) by Chairman Hikotaro Yoshida. Because of the strong demand for an English version, we have decided to publish the report in English. This prospective study was designed to evaluate the status of 259 AD patients using Method 1, which involves a simple global evaluation of disease severity; Method 2, which involves global evaluation by summing severity scores obtained from five body regions (i.e. the head and neck, anterior and posterior trunks, and upper and lower limbs); Method 3, which consists of both assessment of the extent of involved areas at each of the five body regions and that of the severity scores of each eruption component observed in the most severely affected body region; and Method 4, which consists of the evaluation of only subjective components (daytime pruritus and sleep disturbance). Employing the results obtained with Method 1 as a tentative benchmark, we analyzed its correlation with those of Methods 2, 3 and 4 to statistically assess the validity and reliability of these methods. Method 2, Method 3 and the portion of Method 4 involving evaluation of only the subjective symptom of daytime pruritus but not the sleep disturbance were considered useful in evaluating AD severity. PMID- 21679230 TI - English version of the concluding report published in 2001 by the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association. AB - The Japanese Dermatological Association established an advisory committee in 1995 to develop a severity scoring system for atopic dermatitis (AD). Its interim and concluding reports were published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998 and 111: 2023-2033, 2001). Because of the strong demand for an English version, we have decided to publish the reports in English. This manuscript is the English version of the concluding report. The interim report suggested that eruption components such as erythema, papule, erosion, crust, excoriation and lichenification with extent of involved areas in five body regions, including the head and neck, anterior and posterior trunks, and upper and lower limbs, were important items for assessing AD severity. Additionally, it was recommended that streamlining of eruption components was mandatory for improving the statistical validity and reliability. The committee members subsequently concentrated their efforts on this task, and finally proposed an Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association. PMID- 21679232 TI - Metformin for gestational diabetes in routine clinical practice. AB - AIMS: To compare maternal and neonatal outcomes in women with gestational diabetes treated with diet, metformin and/or insulin in routine clinical practice in a single centre. METHODS: We analysed prospectively collected data from the National Women's Health database for all women with gestational diabetes who delivered between January 2007 and December 2009. Since June 2007, women requiring medication have been given a choice of either metformin or insulin treatment, except women with a fetal abdominal circumference less than the 10th percentile, who were not offered metformin. RESULTS: There were 1269 women with gestational diabetes; treatment was diet in 371, insulin in 399 and metformin in 465 (249 metformin alone, 216 metformin and insulin). Women treated with metformin and/or insulin had significantly higher BMIs compared with those in the diet group (P < 0.001) and had a higher fasting glucose at diagnosis (p < 0.001). Women treated with insulin had higher rates of Caesarean delivery (45.6% insulin, 37% metformin, 34% diet, P = 0.02) than women treated with metformin or diet. They also had higher rates of preterm births (19.2% insulin, 12.5% metformin, 12.1% diet, P = 0.005), customized large-for-gestational-age infants (18.5% insulin, 12.5% metformin, 12.4% diet, P = 0.02), neonatal admissions (18.7% insulin, 12.7% metformin, 14.0% diet, P = 0.04) and neonatal intravenous dextrose use (11.1% insulin, 5.1% metformin, 7.4% diet, P = 0.004). Neonatal outcomes were similar between diet- and metformin-treated women. CONCLUSIONS: In routine practice, use of metformin in gestational diabetes was associated with fewer adverse outcomes compared with insulin, but baseline differences between treatment groups may have contributed to this. PMID- 21679233 TI - The danger of using inappropriate point-of-care glucose meters in patients on icodextrin dialysis. AB - AIMS: Icodextrin is a glucose polymer used to maintain an osmotic gradient in peritoneal dialysis. Metabolites of icodextrin are known to cause overestimation of blood glucose in glucose meters using glucose dehydrogenase/pyrroloquinolinequinone systems. The aim of this study is to determine the extent of icodextrin interference in glucose meters using the newer glucose dehydrogenase/NAD or glucose oxidase systems. This has not been established previously. METHODS: Fasting blood samples (n = 4) were spiked with either one icodextrin metabolite (maltose, maltotriose or maltotetraose) or a combination, at various blood concentrations expected during dialysis. Samples were tested in triplicate on: five glucose-meters, a Radiometer(r) (glucose oxidase/hydrogen peroxide) and laboratory (hexokinase) analysers. Each meter was also tested on blood from six patients undergoing dialysis. Accuracy was evaluated as % Bias = [(meter glucose - laboratory glucose)/laboratory glucose] * 100. RESULTS: A single icodextrin metabolite affected glucose measurements and, in combination, the interferences were additive in the two Accu-Chek(r) and Optium(r) Xceed meters by > 10%. Amongst these meters, the Optium Xceed 5-s machine was less affected. Meters using glucose oxidase were least affected by interference. A similar trend in interference was observed in vivo. CONCLUSION: While meters using glucose dehydrogenase/NAD are less affected by icodextrin metabolites, interference can still be demonstrated. The degree of interference can vary in different glucose meters using this enzyme/cofactor system, as seen in the Optium Xceed machines. Icodextrin is an important source of interference that sometimes even experienced professionals are unaware of and which leads to clinically significant errors in insulin dose adjustment. Awareness of this interference and selection of the most appropriate glucose meters are crucial to minimize this hazard. PMID- 21679234 TI - Effects of genetic vs. environmental factors on cardiovascular autonomic function: a twin study. AB - AIMS: Cardiovascular autonomic function is often assessed in patients with diabetes by measuring heart rate variability and baroreflex sensitivity, the heritability of which is not fully understood. The present study was aimed to determine the effects of genetic and environmental factors on heart rate variability and baroreflex sensitivity in monozygotic and dizygotic adult healthy twin pairs. METHODS: A total of 101 (63 monozygotic, 38 dizygotic) adult twin pairs (n = 202; mean age 44.3 years) were investigated. Anthropometric variables and serum metabolic markers were measured, while environmental characteristics were evaluated by questionnaires. Linear and spectral indices of heart rate variability and baroreflex sensitivity were determined by non-invasive methods. All measurements were adjusted for age and gender (model 1) and for all significantly relevant covariates (model 2). Heritability A-C-E structural equation models were used for characterizing the proportion of additive genetic, shared and unshared environmental influences. RESULTS: Genetic influence of different cardiovascular autonomic indices was estimated between 10.3 and 39.4%, common environmental influence was found between 0.0 and 33.2%, while unshared environmental influence was observed between 60.6 and 81.4% in model 1 analysis. In multivariable-adjusted heritability estimates (model 2), the magnitude of the genetic effects decreased to 0.0%, common environmental influence was nearly unchanged (values between 4.4 and 14.5%), while unshared environmental influence slightly increased (values between 85.5 and 96.5%). CONCLUSIONS: Unshared environmental but not genetic factors have substantial influence on cardiovascular autonomic function, suggesting that appropriate treatment of all modifiable environmental factors is of importance in order to prevent or ameliorate cardiovascular autonomic neuropathy. PMID- 21679235 TI - Screening for type 2 diabetes. Lessons from the ADDITION-Europe study. AB - AIMS: To describe and compare attendance rates and the proportions of people identified with Type 2 diabetes mellitus in people with previously unknown diabetes who participated in screening programmes undertaken in general practice in the UK, Denmark and the Netherlands as part of the ADDITION-Europe study. METHODS: In Cambridge, routine computer data searches were conducted to identify individuals aged 40-69 years at high risk of Type 2 diabetes using the Cambridge Diabetes Risk Score. In Denmark, the Danish Diabetes Risk Score was mailed to individuals aged 40-69 years, or completed by patients visiting their general practitice. In the Netherlands, the Hoorn Symptom Risk Questionnaire was mailed to individuals aged 50-69 years. In these three centres, high-risk individuals were invited to attend subsequent steps in the screening programme, including random blood glucose, HbA(1c) , fasting blood glucose and/or oral glucose tolerance test. In Leicester, eligible people aged 40-69 years were invited directly for an oral glucose tolerance test. In all centres, Type 2 diabetes was defined according to World Health Organization 1999 diagnostic criteria. RESULTS: Attendance rates ranged from 20.2% (oral glucose tolerance test in Leicester without pre-stratification) to 95.1% (random blood glucose in opportunistic screening in Denmark in high-risk people). The percentage of people with newly detected Type 2 diabetes from the target population ranged from 0.33% (Leicester) to 1.09% (the Netherlands). CONCLUSIONS: Screening for Type 2 diabetes was acceptable and feasible, but relatively few participants were diagnosed in all participating centres. Different strategies may be required to increase initial attendance and ensure completion of screening programmes. PMID- 21679236 TI - Diabetes in pregnancy may differentially affect neonatal outcomes for twins and singletons. AB - AIM: We tested the hypothesis that diabetes in pregnancy may differentially affect neonatal outcomes in twin vs. singleton pregnancies. METHODS: In a retrospective cohort analysis of twins (n = 422 068) and singletons (n = 14 298 367) born in the USA from 1998 to 2001, we evaluated the adjusted odds ratios of adverse neonatal outcomes comparing diabetic vs. non-diabetic pregnancies, controlling for maternal characteristics. Primary outcomes include macrosomia (birthweight for gestational age > 90th percentile), congenital anomalies, low 5 min Apgar score (< 4) and neonatal death. RESULTS: Diabetes in pregnancy was associated with a similarly increased risk of congenital anomalies (adjusted odds ratios 1.52 vs. 1.59) and smaller increased risks of preterm birth (adjusted odds ratios 1.27 vs. 1.49) and macrosomia (adjusted odds ratios 1.38 vs. 2.03) in twins vs. singletons, but reduced risks of low 5-min Apgar score (adjusted odds ratio 0.74) and neonatal death (adjusted odds ratio 0.76) in twins but not singletons. CONCLUSIONS: Diabetes in pregnancy may differentially affect neonatal outcomes in twins and singletons, indicating a need for further studies to differentiate the effects by clinical subtypes of diabetes in pregnancy, and to consider/evaluate differential clinical management protocols of diabetes in multiple vs. singleton pregnancies. PMID- 21679237 TI - Expression of biologically active human insulin-like growth factor 1 in Arabidopsis thaliana seeds via oleosin fusion technology. AB - Novel protein expression in plant-based systems has become an important tool in producing and studying therapeutic proteins. Among many plant-based systems developed so far, oleosin fusion technology is one of the most cost-effective and convenient methods. In this study, an important therapeutic protein, human insulin-like growth factor 1 (hIGF-1), was expressed in Arabidopsis thaliana seeds via this technology. The plant bias codon usage-optimized hIGF-1 gene was fused to the C-terminal of A. thaliana 18.5 kDa oleosin gene, and the fusion gene driven by an oleosin promoter was transferred into A. thaliana ecotype Col-0. The accumulation of oleosin-hIGF-1 fusion protein in transgenic seeds was up to 0.75% of total seed protein (TSP) and the expression level of hIGF-1 was 0.17% of the TSP, which was eight times higher than previously reported using other plant based hIGF-1 production systems. The biological activity of the hIGF-1 as an oleosin-hIGF-1 fusion protein in vitro was demonstrated by using human SH-SY5Y neuroblastoma cells. PMID- 21679239 TI - A continuous cell alkaline lysis, neutralization, and clarification combination process for production of plasmid pUDK-HGF. AB - Plasmid DNA for biopharmaceutical applications is produced easily in Escherichia coli bacteria. The cell lysis is the most crucial step for purification of plasmid DNA. In this paper, we describe a continuous cell alkaline lysis, neutralization, and clarification combination process for production of plasmid pUDK-HGF using hollow fiber ultrafiltration column as a lysis chamber and compare the plasmid DNA yield and homogeneity with the T-connector and manual processes, respectively. The results show that the plasmid pUDK-HGF yield of the combination process is 13% higher than manual lysis, twice higher than using T-connector. When the proportion of lysed cells and neutralization solution is 3:1, the plasmid pUDK-HGF yield can improve by 70%. This process could be easily scaled up to meet the industrial scale for cell lysis. PMID- 21679238 TI - Surface modification of POSS-nanocomposite biomaterials using reactive oxygen plasma treatment for cardiovascular surgical implant applications. AB - In this study, central composite design (CCD) was used to develop predictive models to optimize operating conditions of plasma surface modification. It was concluded that out of the two process variables, power and duration of plasma exposure, the latter was significantly affecting the surface energy (gamma(s) ), chemistry, and topography of polyhedral oligomeric silsesquioxane-poly(carbonate urea)urethane (POSS-PCU) films. On the basis of experimental data, CCD was used to model the gamma(s) using a quadratic modeling of the process variables to achieve optimum surface energy to improve the interaction between endothelial cells (ECs). It was found that optimal water theta for EC adhesion and retention, which was reported 55 degrees from supporting literature (equivalent to gamma(s) = 51 mN/m), was easily achievable using the following experimental conditions: (1) power output at 30 W for 75 Sec, (2) 90 W for 40 Sec, and (3) 90 W for 55 Sec in oxygen. In vitro cell culture and metabolic activity studies on optimized films [as in (1)] demonstrate increased adhesion, coverage, and growth of human umbilical vein endothelial cells that were confluent over a shorter time period (<24 H) than controls. Such materials enhanced the EC response and promoted endothelialization on optimized films, thus demonstrating their use as bypass graft materials. PMID- 21679240 TI - Parameters for effective in vitro production of zinc finger nucleic acid-binding proteins. AB - Immobilized metal affinity chromatography (IMAC) is widely used for the production of recombinant proteins for a variety of applications; however, a number of challenges are typically encountered by researchers depending on the properties of the specific proteins in question. Here, we describe technical issues we have encountered in production of recombinant zinc finger nucleic acid binding proteins by IMAC intended for detailed and accurate in vitro analysis. The process encountered leading to a modified IMAC protocol for effective production of high-purity, native zinc finger nucleic acid-binding proteins is described in detail. The parameters with respect to solubility, lysis and redox conditions, removal of residual metal ions with chelating agents, and renaturation in the presence of divalent metal cations are described. These procedures have been extended to production of a wide array of RNA-binding proteins in our laboratory and would be relevant to a number of protein purification applications. PMID- 21679241 TI - A genetic algorithm for the optimization of the thermoinduction protocol for high level production of recombinant human-like collagen from Escherichia coli. AB - Production of recombinant human-like collagen (RHLC) by thermoinduction of recombinant Escherichia coli BL 21 during high cell density cultivation was investigated in a 30 L bioreactor. The effects of induction temperature (T), pH, and carbon-to-nitrogen molar ratio of the nutrient medium (C/N) were examined. The optimal thermoinduction protocol for RHLC production was determined by using a model coupling genetic algorithm and artificial neural networks. The optimal operating conditions were as follows: maintenance of induction temperature at 42 degrees C for 3 H and then at 39.4 degrees C until the end, induction pH at 7.03, and C/N at 4.8 (mol/mol). The theoretical maximum concentration of RHLC was 12.5 g/L, whereas the experimental value was 12.1 g/L under the optimal induction conditions. PMID- 21679242 TI - Expression, purification, and characterization of protective MPT64 antigen protein and identification of its multimers isolated from nontoxic Mycobacterium tuberculosis H37Ra. AB - MPT64, a secreted protein of Mycobacterium tuberculosis (MTB), stimulates the immune reactions within cells and is a protective antigen that is lost by the bacilli Calmette-Guerin (BCG) vaccine during propagation. To minimize the toxicity caused by MTB, we used the MPT64 gene encoded by nontoxic H37Ra MTB to carry out genetic expansion via polymerase chain reaction and gene clone MPT64. The plasmid DNA encoded MPT64 was expressed at 20 degrees C for 22 H, and a large quantity of MPT64 was obtained. In the absence of urea, MPT64 multimers with subunits being covalently connected via disulfide bonds were detected by Western blot showing strong protein-protein interactions, as evidenced by the formation of MPT64 tetramers. Finally, with urea of decreasing concentrations, we refolded MPT64 purified in the presence of urea and determined its secondary structures using circular dichroism. MPT64 was found to contain 2.2% alpha-helix, 50.9% beta sheet, 19.5% turn, and 27.4% random coil. The molecular weight of MPT64 was determined by a matrix-assisted laser desorption ionization-time of flight mass spectrometer and found to be 23,497 Da, very close to the theoretical molecular weight of MPT64. The results presented here provide a sound basis for future biochemical and biophysical studies of MPT64 or any other proteins encoded by nontoxic H37Ra MTB. PMID- 21679243 TI - In vitro digestive stability of complexes between gliadin and synthetic blocking peptides. AB - Celiac disease is caused by an inappropriate immune response to incompletely digested gluten proteins. We investigated whether synthetic peptides with high affinity to wheat gliadin could be selected with a phage display technique and whether complexes between such peptides and gliadin could sustain gastric and pancreatic digestion. Two synthetic peptides, P61 and P64, were selected because of their high affinity to immobilized gliadin. They were allowed to form complexes with gliadin, whereafter the complexes were subjected to in vitro digestion with gastric and pancreatic enzymes. The digestion products were analyzed with Western blot and RP HPLC. The results showed that both peptides formed stable complexes with intact gliadin and that complexes between gliadin and peptide P64 partly resisted gastrointestinal digestion. The two peptides reduced the binding of serum anti-gliadin IgA antibodies by 12%, and 11.5%, respectively, and the binding of anti-gliadin antibodies of the IgG isotype by 13% and 10%. Thus peptides produced by a phage display technique could interact stably with gliadin partly masking epitopes for antibody binding. A combination of peptides of this kind may be used to block gliadin-immune system interactions. PMID- 21679244 TI - Incorporation of antigens from Mannheimia haemolytica culture supernatant, and recombinant bovine C3d into ISCOM matrix using neutravidin-biotin interaction. AB - The aim of this study was to incorporate antigens from Mannheimia haemolytica culture supernatant, and an immune modulatory molecule, recombinant bovine C3d (rBoC3d), into immune stimulating complexes (ISCOMs) using neutravidin-biotin interaction. Biotinylated ISCOM matrix was generated using a commercial kit. The biotinylated ISCOM matrix was incubated with neutravidin and then centrifuged in a sucrose density gradient. The rBoC3d was expressed as an in vivo biotinylated protein and with a c-Myc tag (EQKLISEEDL) engineered to facilitate detection. The neutravidin-coated ISCOM matrix was incubated with biotinylated antigens from M. haemolytica culture supernatants and rBoC3d. To test the association among the neutravidin-coated ISCOM matrix, biotinylated antigens and rBoC3d, an analytical sucrose density gradient (10-40%, w/w) was performed. The experimental formulations were run in SDS-PAGE gels under reducing conditions. For Western immunoblot analysis, polyclonal bovine antiavidin, monoclonal anti-c-Myc, monoclonal antileukotoxin, and anti-GS60 antibodies were used to detect the presence of neutravidin, rBoC3d, leukotoxin, and GS60 antigens, respectively. By taking advantage of the biotin-neutravidin interaction, not only leukotoxin but also the recombinant immunomodulatory molecule, rBoC3d, was incorporated into ISCOM particles. PMID- 21679245 TI - The effect of carbon source supplementation on the production of poly(3 hydroxybutyrate-co-3-hydroxyvalerate) by Cupriavidus necator. AB - The objective of the present study was to investigate the ability of Cupriavidus necator to produce poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) on various carbon sources in batch cultivation. These results show that C. necator produces poly-3-hydroxybutyrate from single carbon sources. The highest poly-3 hydroxybutyrate (P3HB) content was achieved at growth on fructose in the exponential growth phase. The maximum yield of the P3HV content was obtained when fructose was mixed with acetate. The highest content P3HB-co-3HV was also achieved by C. necator when we supplied C-excess and N- and P-normal conditions. These results indicate that C. necator accumulates high polyhydroxyalkanoates (PHA) content by depleting these elements in the culture medium. Nitrogen and phosphorus limitation has no significant effect on the PHA production, whereas C excess leads to an increase in PHA formation of up to 92% PHAs of cell dry weight after growth on 5 g/L acetate and 40 g/L fructose. PMID- 21679246 TI - Nonlinear pharmacokinetic properties of mildronate capsules: a randomized, open label, single- and multiple-dose study in healthy volunteers. AB - Mildronate has been used as antianginal drug in parts of Europe for many years, but its pharmacokinetic (PK) properties in humans remain unclear. This study was designed to assess and compare the PK properties of mildronate capsules after single escalating oral dose and multiple doses in healthy Chinese volunteers. Volunteers were randomly assigned to receive a single dose of 250, 500, 1000, 1250 or 1500 mg of mildronate capsules. Those who received the 500-mg dose continued on the multiple-dose phase and received 500 mg three times a day for 13 days. Plasma drug concentrations were analysed by ultraperformance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Tolerability was assessed throughout the study. A total of 40 Chinese volunteers were enrolled in the study. No period or sequence effect was observed. Area under the concentration and C(max) were increased proportionally with the dose levels, whereas t(1/2) and V(d)/f were dependent on the dose. Nonlinear PK properties were found at doses of 250-1500 mg. There was an accumulation after multiple-dose administration. No serious adverse events (AEs) were reported in the PK study. The formulation was well tolerated. PMID- 21679247 TI - Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a systematic review. AB - BACKGROUND AND AIM: Surgery is the standard treatment option for hepatocellular carcinoma (HCC) meeting the Milan criteria, defined as single HCC <= 5 cm in maximum diameter or up to three nodules <= 3 cm. However, favorable survival outcomes have also been reported for these HCCs following radiofrequency ablation (RFA). METHODS: We performed a systematic review to compare the results of hepatic resection and percutaneous RFA as a primary treatment option of HCC meeting the Milan criteria. Studies were identified by searching MEDLINE on PubMed, the Cochrane Library database and CANCERLIT using appropriate key words. RESULTS: In all six identified observational studies, there were no statistically significant differences in overall survival rates between the two treatment modalities. The results of two randomized trials are controversial, while the power of these randomized trials is too limited to reach a reliable conclusion. In practice, the choice of treatment between surgery and RFA largely depends on the relationship between the local recurrence and perioperative mortality rates of HCC patients. Following RFA, local recurrence rates are low when a minimal safety margin >= 4-5 mm is achieved. A previous simulation study of overall survival for very early stage HCC, defined as an asymptomatic solitary small HCC <= 2 cm, showed that primary RFA with a 9% local recurrence rate is comparable to surgical resection with a 3% operative mortality rate. CONCLUSION: Acquisition of a sufficient safety margin seems to be a critical factor before recommending wider application of RFA as primary treatment for HCCs that meet the Milan criteria. PMID- 21679248 TI - Health utilities and psychometric quality of life in patients with early- and late-stage hepatitis C virus infection. AB - BACKGROUND AND AIM: Hepatitis C virus (HCV) infection is associated with impairment in health-related quality of life (HRQOL). The purpose of this study was to evaluate HRQOL across the HCV disease spectrum using preference-based (utility) and non-preference-based (psychometric) methods, adjusting for sociodemographic factors and co-morbidity. METHODS: Hepatitis C virus patients (n = 751) were recruited from several tertiary care settings in Vancouver, Canada for this observational, cross-sectional cohort study. Patients completed the Health Utilities Index Mark 2/3, a self-administered time trade-off utility instrument, and the Hepatitis Quality of Life Questionnaire (SF-36 with HCV specific items). We examined the association between HRQOL and disease stage using linear regression adjusting for age, education, marital status, income, and co-morbidities. RESULTS: Utility scores were low across disease stage and instrument, ranging from 0.51 to 0.80. On the SF-36, the mean Physical Component Summary score ranged from 37.2 to 49.2 across disease stage, and the Mental Component Summary score ranged from 39.7 to 45.7 (United States norms = 50). In general, patients with viral clearance had the highest scores, and those with late-stage disease (cirrhosis, liver cancer) had the lowest. Multivariable linear regression showed that the effect of disease stage was modest overall. Increasing age, lower income, unattached marital status, and high comorbidity were strongly associated with impairment in HRQOL. CONCLUSIONS: The effect of stage of disease on HRQOL is modest, although viral clearance is associated with higher HRQOL. HCV patients' HRQOL is strongly associated with concomitant illness and sociodemographic factors. PMID- 21679249 TI - Normal liver elasticity values using acoustic radiation force impulse imaging: a prospective study in healthy living liver and kidney donors. AB - BACKGROUND AND AIM: Although several studies have investigated the normal range of liver elasticity using acoustic radiation force impulse (ARFI) elastography in healthy volunteers, they could not strictly exclude the morphological and functional liver abnormalities. The aim of this study was to identify the normal range of ARFI velocity by recruiting healthy living liver and kidney donors who passed the full laboratory tests and imaging studies. METHODS: The study prospectively enrolled 108 healthy living liver (n = 42) and kidney donors (n = 66) who were admitted for transplantation between July 2010 to April 2011. None of the subjects had abnormal liver function test and imaging findings including conventional ultrasonography, computed tomography or magnetic resonance imaging. RESULTS: The mean age of the study population (58 men and 50 women) was 35.5 years, and the mean ARFI velocity was 1.07 +/- 0.11 m/s (range: 0.79-1.27). ARFI velocity was not significantly different between subjects with body mass index (BMI) < 23.5 kg/m(2) and those with BMI >= 23.5 kg/m(2) (1.05 +/- 0.12 m/s vs 1.07 +/- 0.10 m/s, P = 0.518), nor was it significantly different according to age (P = 0.067) and gender (1.08 +/- 0.12 m/s for men vs 1.05 +/- 0.11 m/s for women, P = 0.085). Using the 5(th) and 95(th) percentiles, we determined the normal range and mean of ARFI velocity to be 0.85-1.25 m/s and 1.07 +/- 0.11 m/s. CONCLUSIONS: We identified the normal range of ARFI velocity as 0.85-1.25 m/s and found that it was not significantly influenced by BMI, gender, and age. PMID- 21679250 TI - Resistance of Helicobacter pylori to quinolones and clarithromycin assessed by genetic testing in Japan. AB - BACKGROUND AND AIM: As bacterial resistance to clarithromycin limits the efficacy of clarithromycin-based regimens for Helicobacter pylori infection, attention has turned to quinolone-based rescue therapies. Resistance of H. pylori to both clarithromycin and quinolone can be predicted by genetic testing. Here, we used this approach to evaluate the prevalence of clarithromycin- and quinolone resistant strains of H. pylori in Japan. METHODS: DNA was extracted from gastric tissue samples obtained from 153 patients infected with H. pylori (103 naive for eradication therapy and 50 with previous eradication failure following triple proton pump inhibitor/amoxicillin/clarithromycin therapy). Mutations in H. pylori 23S rRNA and gyrA genes associated with resistance to clarithromycin and quinolones, respectively, were determined. RESULTS: Of 153 patients, 85 (55.6%) were infected with clarithromycin-resistant strains. The prevalence of clarithromycin-resistant strains in patients with previous eradication failure (90.0%, 45/50) was significantly higher than that (38.8%, 40/103) of those naive for eradication therapy (P < 0.001). Fifty-nine patients (38.6%) were infected with strains resistant to quinolones. The incidence of quinolone-resistant strains also appeared higher in patients with eradication failure (48.0%, 24/50) than in those who had not undergone therapy (34.0%, 35/103); however, the difference was not statistically significant (P = 0.112). The incidence of quinolone-resistance in clarithromycin-resistant strains (44/85, 51.8%) was significantly higher than that in clarithromycin-sensitive strains (15/68, 22.1%) (P < 0.001). CONCLUSIONS: A high incidence of quinolone-resistance was found in clarithromycin-resistant strains of H. pylori, particularly in patients with previous eradication failure. Our results suggest that testing for susceptibility of H. pylori to quinolones is useful for determining the optimal rescue eradication regimen. PMID- 21679251 TI - Colorectal neoplasms in relation to non-alcoholic fatty liver disease in Korean women: a retrospective cohort study. AB - BACKGROUND AND AIM: Metabolic syndrome has been associated with an increased risk for colorectal cancer. Non-alcoholic fatty liver disease (NAFLD) is regarded as a hepatic manifestation of metabolic syndrome. We investigated whether NAFLD is associated with colorectal neoplasms in Korean women. METHODS: This retrospective cohort study included data from 5517 women, aged 35-80 years, who underwent life insurance company health examinations between July 2002 and June 2006. Fatty liver disease was assessed by abdominal ultrasound, with NAFLD defined as fatty liver disease in the absence of alcohol use of > 40 g/week or other secondary causes. The incidence of colorectal neoplasms through December 2008 was obtained through medical certificate codes for insurance claims. The association between NAFLD and the risk of colorectal neoplasms was estimated using standard Cox proportional hazards models. RESULTS: Of the study population, 15.1% were diagnosed with NAFLD. During follow-up, 65 women were verified as having adenomatous polyps and 15 as having colorectal cancer. Adjusted relative risks (95% confidence interval [CI]) for adenomatous polyps by age, low high-density lipoprotein-cholesterol, and NAFLD were 1.12 (95% CI 1.09-1.15), 2.56 (95% CI 1.53-4.28) and 1.94 (95% CI 1.11-3.40). Adjusted relative risks (95% CI) for colorectal cancer by age and NAFLD were 1.23 (95% CI 1.17-1.29) and 3.08 (95% CI 1.02-9.34). CONCLUSIONS: Our findings demonstrate a significant relationship between NAFLD and colorectal neoplasms. Among the various manifestations of metabolic syndrome, NAFLD may predict the development of colorectal neoplasms in Korean women. PMID- 21679252 TI - Helicobacter pylori outer membrane proteins on gastric mucosal interleukin 6 and 11 expression in Mongolian gerbils. AB - BACKGROUND AND AIM: The levels of interleukin (IL)-6 and IL-11 in the gastric mucosa are related to mucosal inflammation; however, the chronological changes in cytokine expression during different phases of Helicobacter pylori infection and the effects of H. pylori virulence factors, particularly those of outer membrane proteins, remain obscure. The aim of this study was to clarify the chronological changes in cytokine levels in relation to several H. pylori outer membrane proteins. METHODS: We studied Mongolian gerbils inoculated with wild-type H. pylori 7.13 for up to 48 weeks and then examined animals infected with oipA, babA, or alpAB isogenic mutants for 12 weeks. Mucosal IL-6 and IL-11 mRNA levels were measured using real-time reverse transcription-polymerase chain reactions. RESULTS: High levels of gastric mucosal IL-6 and IL-11 mRNA in gerbils infected with wild-type H. pylori were observed during the chronic phase of infection, reaching maximums at 12 and 6 months, respectively. Infection with oipA and babA mutants resulted in significantly reduced cytokine levels and inflammatory cell infiltrations compared to gerbils infected with wild-type strains, and this persisted throughout the observation period. The alpAB mutants did not infect gerbils. Mucosal IL-6 and IL-11 levels were significantly associated with the grade of inflammatory cell infiltration. CONCLUSIONS: OipA and BabA result in more severe H. pylori infection and increased IL-6 and IL-11 levels, which in turn may increase the risk of developing H. pylori-induced gastrointestinal diseases. PMID- 21679253 TI - Lenalidomide can be highly effective in chronic lymphocytic leukaemia despite T cell depletion and deletion of chromosome 17p. AB - Lenalidomide is an immunomodulatory agent with activity in a range of haematological cancers including chronic lymphocytic leukaemia (CLL). However, major questions remain concerning its effectiveness in patients with T-cell depletion or deletion of TP53 on chromosome 17p. This case report provides insight into these questions by showing that lenalidomide/dexamethasone in combination can be highly effective as induction therapy for refractory 17p-CLL, that remission quality can be improved by subsequent maintenance with lenalidomide alone and that the anti-leukaemic effects of lenalidomide and its stimulatory effects on non-malignant B cells are preserved despite prolonged T cell depletion resulting from prior alemtuzumab/methylprednisolone. PMID- 21679254 TI - Acute myeloid leukaemia with Pseudo-Chediak-Higashi granules and intracytoplasmic vacuoles. PMID- 21679255 TI - Bone marrow mesenchymal stem cell response to nano-structured oxidized and turned titanium surfaces. AB - OBJECTIVES: The aim of this study was to analyse the topographic features of a novel nano-structured oxidized titanium implant surface and to evaluate its effect on the response of human bone marrow mesenchymal stem cells (BM-MSC) compared with a traditional turned surface. METHODS: The 10 * 10 * 1 mm turned (control) and oxidized (test) titanium samples (P.H.I. s.r.l.) were examined by scanning electron microscopy (SEM) and atomic force microscopy (AFM) and characterized by height, spatial and hybrid roughness parameters at different dimensional ranges of analysis. Primary cultures of BM-MSC were seeded on titanium samples and cell morphology, adhesion, proliferation and osteogenic differentiation, in terms of alkaline phosphatase activity, osteocalcin synthesis and extracellular matrix mineralization, were evaluated. RESULTS: At SEM and AFM analyses turned samples were grooved, whereas oxidized surfaces showed a more complex micro- and nano-scaled texture, with higher values of roughness parameters. Cell adhesion and osteogenic parameters were greater on oxidized (P<0.05 at least) vs. turned surfaces, whereas the cell proliferation rate was similar on both samples. CONCLUSIONS: Although both control and test samples were in the range of average roughness proper of smooth surfaces, they exhibited significantly different topographic properties in terms of height, spatial and, mostly, of hybrid parameters. This different micro- and nano-structure resulted in an enhanced adhesion and differentiation of cells plated onto the oxidized surfaces. PMID- 21679256 TI - Clinical outcomes of prostate cancer patients detected by prostate-specific antigen-based population screening in Kanazawa City, Japan. AB - OBJECTIVES: Most common population screening systems for prostate cancer are administered by municipal governments in Japan. These systems suffer from difficulties in adequate follow up of patients at several urology departments in the region. We analyzed the clinical characteristics and outcomes of prostate cancer patients detected in our prostate-specific antigen (PSA)-based population screen, and examined the efficiency of the system. METHODS: Since 2000, we have carried out PSA-based population screening in men aged 55-69 years. For the present study, primary treatments and clinical outcomes of prostate cancer patients diagnosed by this screening program were obtained from each urology department in the region. RESULTS: A total of 32,769 men participated in this screening program from 2000 to 2006. Overall, 249 cases (0.76%) of prostate cancer were diagnosed. The rate of patients within gray zone levels of serum total PSA on primary screening increased and this was significantly higher in 2003 than in the first 2 years of the program. Clinical T stage was defined in 247 patients (99.2%), and 231 (93.5%) were cases of clinically localized cancer. A total of 75% of these patients underwent radical treatment. Eight-year cause specific and overall survivals were 97.5% and 93.3%, respectively. Four patients, all of them presenting with advanced disease at diagnosis, died from prostate cancer. CONCLUSIONS: The present study showed good clinical outcomes for screening-detected prostate cancer patients and it showed the effectiveness of our screening system. PMID- 21679257 TI - Specifically requesting surgical tattoo removal: are deep personal motivations involved? AB - BACKGROUND: Motivations for tattoo removal include employment reasons, stigmata, changes in lifestyles or partners, incompatibility with present attitudes and values and clothing problems. Most studies on the motivations for tattoo removal have focused on patients seeking laser therapy. We hypothesized that patients seeking surgical tattoo removal would present with different motivations. OBJECTIVE: We analysed the characteristics and motivations of patients specifically requesting surgical tattoo removal. METHODS: We retrospectively reviewed the medical records of 16 patients in Helsinki, Finland, from 2005 to 2011. Demographic, clinical data, number of tattoos, location and size, time elapsed since tattooing, reason(s) for wanting surgical tattoo removal and surgical operations were analysed and compared with the other literature on tattoo removal. RESULTS: Patients were mainly Caucasian females (ratio 3 : 1, median age of 26 years). Tattoos were all done by studio artists, most measured less than 30 cm2, and were quite recent (median 5.3 years). Personal reasons accounted for 42.8% of all reasons, professional/social reasons for 37.5% and miscellaneous for 18.8%. Personal concerns were usually marital status changes, with few expressing dissatisfaction with the actual design of the tattoo. Tattoos were excised during a single procedure in 70% of the cases with only one case producing a hypertrophic scar. CONCLUSIONS: Patients seeking surgical removal were aware of the limits and risks of the technique. They expressed intense personal reasons for wanting radical surgical removal. The possibility of surgical tattoo removal should be accessible to patients if the tattoo is small and discussion reveals strong personal motivation. PMID- 21679258 TI - Developmental changes in hypothalamic Kiss1 expression during activation of the pulsatile release of luteinising hormone in maturing ewe lambs. AB - Onset of puberty is characterised by a marked increase in the frequency of release of gonadotrophin-releasing hormone (GnRH) and luteinising hormone (LH). The Kiss1 gene plays a critical role in pubertal development, and its product, kisspeptin, stimulates GnRH and LH release. In the present study, we tested the hypothesis that Kiss1 gene expression in the preoptic area (POA) and hypothalamus increases during maturation of the reproductive neuroendocrine axis in association with increased LH pulsatility. Ovariectomised, oestradiol-replaced lambs were euthanised at 25, 30 and 35 weeks of age. Blood samples were collected before euthanasia to characterise the pattern of LH release. Kiss1 mRNA was detected in coronal sections of the POA and hypothalamus and Kiss1-expressing cells were identified on the basis of silver grain density. The mean number of Kiss1-expressing cells in the POA/periventricular (PeV) areas increased from 25 to 30 weeks of age. No further increase at 35 weeks of age was observed, and the changes in Kiss1 expression in the POA/PeV were independent of changes in LH pulse frequency. The mean number of Kiss1-expressing cells in the arcuate (ARC) nucleus did not differ among age groups, although it was greater in the middle ARC of lambs exhibiting increased frequency of LH release. The density of silver grains per cell did not differ among groups in any of the areas studied. The results obtained indicate that the Kiss1 gene is activated in the POA/PeV and ARC of ewe lambs during juvenile development, and that kisspeptin neurones in the middle ARC, in particular, are involved in the acceleration of pulsatile LH release during maturation of the reproductive neuroendocrine axis in ewe lambs. PMID- 21679260 TI - Month of birth is not a risk factor for narcolepsy with cataplexy in the Netherlands. AB - The month of birth has been proposed as a risk factor for narcolepsy, suggesting a harmful influence during early development. Several authors have described an excess of births in March in those developing narcolepsy later. Analysis methods in published studies varied, but no study corrected completely for possible changes in seasonal birth pattern over time in the appropriate population. The present study describes changes in seasonal birth pattern of the entire Dutch population over a 79-year span and compared the monthly birth pattern of Dutch narcoleptics with the population data. Month and year of birth were noted for 307 patients with non-familial narcolepsy with cataplexy, born in the Netherlands between 1923 and 2001. The numbers of live births per month and per year from the entire Dutch population for the same period were used to calculate a virtual data set of expected births per month with exactly the number of cataplexy cases, but with the birth pattern of the Dutch population. Observed and expected numbers per month were compared using the chi-square test. In the 1970s the peak of births shifted from spring to autumn, confirming the need to correct for changing seasonal patterns. There was no significant difference between observed and expected birth numbers per month. An effect of birth month on the occurrence of narcolepsy with cataplexy was not found in a study of 307 cases after adjusting for changing birth patterns in the general population. PMID- 21679259 TI - The distribution of messenger RNAs encoding the three isoforms of the transducer of regulated cAMP responsive element binding protein activity in the rat forebrain. AB - Increasing evidence indicates that the cAMP responsive element binding protein (CREB)-dependent transcriptional activation of a number of genes requires the CREB co-activator: transducer of regulated CREB activity (TORC). Because of the central importance of CREB in many brain functions, we examined the topographic distribution of TORC1, 2, and 3 mRNAs in specific regions of the rat forebrain. In situ hybridisation analysis revealed that TORC1 is the most abundant isoform in most forebrain structures, followed by TORC2 and TORC3. All three TORC isoforms were found in a number of brain nuclei, the ventricular ependyma and pia mater. Although high levels of TORC1 were widely distributed in the forebrain, TORC2 was found in discrete nuclei and TORC3 mostly in the ependyma, and pia mater. The relative expression of TORC isoforms was confirmed by quantitative reverse transcriptase-polymerase chain reaction analysis in the hippocampus and hypothalamus. In the paraventricular nucleus of the hypothalamus, TORC1 and 2 mRNAs were abundant in the parvicellular and magnocellular neuroendocrine compartments, whereas TORC3 expression was low. All three isoform mRNAs were found elsewhere in the hypothalamus, with the most prominent expression of TORC1 in the ventromedial nucleus, TORC2 in the dorsomedial and arcuate nuclei, TORCs 1 and 2 in the supraoptic nucleus, and TORC2 in the suprachiasmatic nucleus. These differential distribution patterns are consistent with complex roles for all three TORC isoforms in diverse brain structures, and provide a foundation for further studies on the mechanisms of CREB/TORC signalling on brain function. PMID- 21679261 TI - Gender differences in trauma history and symptoms as predictors of relapse to alcohol and drug use. AB - The objective of this study was to determine whether there are gender-specific associations between trauma exposure and alcohol or drug relapse in alcohol dependent adults. Participants were 51 men (n = 24) and women (n = 27) with alcohol dependence, 22 (43.1%) of whom relapsed during study participation. Severity of childhood trauma; number of lifetime events evoking fear, helplessness, or horror; and current trauma symptoms all predicted relapse in women, but not in men. These findings highlight the importance of assessing trauma history and providing treatment of trauma-related symptoms for individuals with alcohol and drug dependence, and for women in particular. PMID- 21679262 TI - Psychiatric and substance use disorders among methadone maintenance patients with chronic hepatitis C infection: effects on eligibility for hepatitis C treatment. AB - We set out to describe the prevalence and severity of psychiatric and substance use disorders (SUDs) in methadone maintenance treatment (MMT) patients with chronic hepatitis C virus (HCV) infection and to measure the impact on HCV treatment eligibility. Psychiatric disorders, SUDs, and HCV-treatment eligibility were assessed in 111 MMT patients prior to a controlled trial of HCV treatment. Lifetime and current diagnosis rates, respectively, were: any non-SUD Axis I disorder: 82% and 57%, any mood disorder: 67% and 35%, any anxiety disorder: 63% and 22%, any psychotic disorder: 11% and 9%. Antisocial personality disorder was present in 40%. A total of 56% met criteria for current SUDs. A total of 66% received psychiatric medications prior to HCV treatment; over half were receiving antidepressants. Despite psychiatric and substance use comorbidity, only 15% of patients were ineligible for HCV treatment: 10% due to failure to complete the evaluation, and 5% due to psychiatric severity. Substance use did not lead to ineligibility in any participant. Multiple logistic regression showed the Beck Depression Inventory contributed significantly to predicting HCV treatment eligibility. Most MMT patients were eligible [corrected] for HCV treatment despite current SUD and non-SUD diagnoses. Depression severity may be a more significant predictor of HCV treatment eligibility than is substance use. PMID- 21679263 TI - Meta-analysis of supplemental treatment for depressive and anxiety disorders in patients being treated for alcohol dependence. AB - Approximately half of those receiving treatment for an alcohol use disorder (AUD) also suffer with an anxiety or depressive (internalizing) disorder. Because all internalizing disorders mark a poor alcohol treatment outcome, it seems reasonable to supplement AUD treatment with a psychiatric intervention when these disorders co-occur with AUD. However, this conclusion may be faulty given that the various possible interrelationships between AUD and internalizing disorders do not uniformly imply a high therapeutic yield from this approach. Unfortunately, the studies conducted to date have been too few and too small to resolve this important clinical issue with confidence. Therefore, we used a meta analytic method to synthesize the effects from published randomized controlled trials examining the impact of supplementing AUD treatment with a psychiatric treatment for co-occurring internalizing disorder (N = 15). We found a pooled effect size (d) of .32 for internalizing outcomes and .22 for a composite of alcohol outcomes; however, the alcohol outcomes effect sizes were greater than this for some specific outcome domains. Subgroups that differed in terms of internalizing outcomes included treatment type (medication vs. cognitive behavioral therapy) and treatment focus (anxiety vs. depression). There was also a trend for the studies with better internalizing disorder outcomes to have better alcohol outcomes. These results indicate that clinical outcomes (both psychiatric and alcohol-related) could be somewhat improved by supplementing AUD treatment with psychiatric treatment for co-occurring internalizing disorder. PMID- 21679264 TI - Examining naltrexone and alcohol effects in a minority population: results from an initial human laboratory study. AB - Prior clinical findings have indicated a potential lack of naltrexone efficacy among African Americans with alcohol dependence. However, no definitive conclusions have been drawn due to the relatively small numbers of African Americans in most alcohol treatment trials. The purpose of this study was to examine alcohol and naltrexone effects on healthy African-American individuals in a laboratory environment. Nonalcohol-dependent social drinking adults of African descent (n = 43) were recruited for participation. After consenting and completing the baseline assessment, they participated in four separate alcohol challenge sessions each separated by at least 10 days. During each of the sessions, subjects were administered alcohol or sham drinks, after pretreatment with either naltrexone (50 mg/day) or placebo in a double-blind fashion. The order of the four sessions was randomly assigned. During each session, breath alcohol levels and subjective responses were measured. Results indicate an alcohol effect among these subjects for subjective responses, but no naltrexone effect. Similar to the apparent lack of clinical efficacy findings, naltrexone does not appear to impact alcohol effects in African-American social drinkers. Future studies should investigate African-American populations with heavy drinking as well as alcohol-dependent subjects in order to strengthen the parallels to clinical findings. PMID- 21679265 TI - A pilot study of life events and mood disorders: self-report survey in chinese heroin-dependent individuals. AB - An understanding of the relationship among life events, anxiety, depression, and heroin abuse may benefit the prevention and early treatment of heroin dependence. The objective of this study was to assess self-reported life events, anxiety, and depression in patients with heroin dependence. In this survey, Chinese heroin dependent patients (n = 139) were asked to conduct a battery of self-reported questionnaires. A total of 76.26% of heroin-dependent patients reported the occurrence of major lifestyle pattern (dietary and sleep) changes as negative life events. Financial problems from family, unemployment, and poor interpersonal relationships were also frequently reported as negative events. Heroin-dependent patients experienced overwhelmingly more negative life events than positive life events. Those negative life events positively correlated with depression and anxiety. They also exhibited high levels of anxiety (Self-Rating Anxiety Scale, mean 44.42 +/- 8.27) and depression (Self-Rating Depression Scale, mean 47.28 +/- 8.54). Although preliminary, findings from this study suggest the need for further investigation of life events, anxiety, and depression in a generalized large sample, which may benefit community-based psychosocial intervention and prevention of relapse in heroin-dependent subjects. PMID- 21679266 TI - A meta-analysis of the efficacy of nonphysician brief interventions for unhealthy alcohol use: implications for the patient-centered medical home. AB - Brief physician interventions can reduce alcohol consumption. Physicians may not have the time to provide brief interventions, and it is unclear whether nonphysicians can do so effectively. We conducted a systematic review and meta analysis to examine the efficacy of brief interventions by nonphysician clinicians for unhealthy alcohol use. We searched the English-language literature in MEDLINE and other databases covering the domains of alcohol problems, primary care, nonphysician, and brief interventions. Studies of brief interventions delivered at least in part by nonphysicians in primary care and examining drinking outcomes were included. Sensitivity analyses examined the effect of excluding studies that contributed disproportionately to the heterogeneity of results. Thirteen studies, conducted 1996-2008, met our criteria. Seven studies with a total of 2,633 patients were included in the meta-analysis. Nonphysician interventions were associated with 1.7 (95% confidence interval [CI]=-.03 to 3.5) fewer standard drinks per week than control conditions (p = .054). Excluding the one study that increased heterogeneity, the effect was smaller but reached statistical significance; nonphysician counseling was associated with 1.4 (95% CI = .3- 2.4) fewer standard drinks per week compared to control (p = .012). Nonphysician brief interventions are modestly effective at reducing drinking in primary care patients with unhealthy alcohol use. PMID- 21679267 TI - Predictors of treatment retention for substance-dependent adults with co occurring depression. AB - Low attendance in addiction treatment, particularly in cases of comorbidity, has been identified as a pervasive challenge. We examine predictors of treatment retention in a sample of veterans (N = 253) participating in a clinical trial comparing two types of psychotherapy for co-occurring depression and substance use disorders. The study protocol included 24 weeks of outpatient group psychotherapy in either a newly developed Integrated Cognitive Behavioral Therapy (ICBT) or Twelve-Step Facilitation Therapy (TSF). Using a model of treatment utilization developed by Aday and Anderson, we analyzed predictors categorized into predisposing factors, enabling resources, need for treatment, and type of treatment received. Outcome included total number of sessions attended (maximum of 36 sessions). Treatment retention did not differ between the two study interventions. Bivariate analyses indicated that predisposing factors were most predictive, with older participants, Caucasians, and those using only alcohol in the month before treatment attending more sessions, and individuals who had recently experienced a health event remained in treatment longer. Importantly, several factors were not related to treatment retention: marital status, education, neuropsychological functioning, financial stress, chronic health problems, treatment motivation, and psychiatric severity. In the combined model of predisposing, enabling and need factors, age and ethnicity were the only significant predictors. PMID- 21679270 TI - Seroma formation in two cohorts after axillary lymph node dissection in breast cancer surgery: does timing of drain removal matter? AB - The purpose of this study was to compare short-term versus long-term axillary drainage in women treated for lymph node positive breast cancer. A comparative cohort study on differences between short-term or long-term axillary drainage was performed. Primary outcome measures were seroma formation demanding aspiration and wound related complications. Secondary outcome measures were type of operation (modified radical mastectomy (MRM) or wide local excision with axillary lymph node dissection (ALND) or completing ALND after positive sentinel node), length of hospital stay, and visits to the emergency department and outpatient clinic. The short-term drainage group consisted of 37 patients, and the long-term drainage group of 40 patients. Short-term drainage was associated with a shorter hospital stay (1.7 versus 2.6 days, p = 0.01), but more visits to the emergency department (0.3 versus 0.1, p = 0.04) and outpatient clinic (3.6 versus 2.8, p = 0.03). Overall incidence of seroma formation was 40% and more frequently in the short-term drainage group (p = 0.01). The highest incidence of seroma and largest aspirated volumes were found in patients with short-term drainage and MRM. No difference in incidence of wound infection was found between both groups, and overall incidence of wound infection was 32%. Seroma formation itself was associated with a higher risk of wound infection (OR 4.39 95% CI 1.6-12.1). Short term axillary drainage does not lead to an increase in wound-related problems, but is associated with a higher incidence of seroma. This seems especially the case in patients who underwent MRM. Therefore, we propose a differentiated policy: patients treated with MRM should be offered long-term axillary drainage, whereas patients treated with breast conserving therapy and ALND or completing ALND after a positive sentinel node should be offered short-term axillary drainage. PMID- 21679271 TI - Regulation of the angiogenesis inhibitor thrombospondin-1 by the breast cancer susceptibility gene-1 (BRCA1). PMID- 21679272 TI - Single follicular unit hair transplantation to restore eyebrows. PMID- 21679268 TI - Quality of life among treatment seeking methamphetamine-dependent individuals. AB - As the number of men and women entering treatment for substance use disorders continues to increase across the country, it becomes vitally important to understand their quality of life (QOL) or perceived health status, in order to inform treatment efforts for improving such outcomes. To date, QOL assessments among methamphetamine (MA) dependent users are limited. This paper examines QOL health status among a sample of 838 treatment seeking MA users at admission. Using regression analysis, predictors of QOL are examined among MA users. Predictors of poor QOL among MA users at treatment admission included being female, white, high school educated or more, married, experiencing psychosocial dysfunction (lifetime trauma, suicide, social conflict), reporting a high frequency of both MA and polydrugs for 15 days or more in the past month, chronicity of MA and polydrug use, injection use, and having co-morbid medical and psychiatric impairment. Employment status was the only factor related to better health status perceptions. This study expands the scope of scholarly examination of MA-dependent users entering treatment, as there has not been a development of coherent profiles of QOL among representative samples of clinical MA-abusing populations to date. PMID- 21679273 TI - Primary great saphenous vein aneurysm. PMID- 21679274 TI - Correlation between preoperative magnetic resonance imaging and surgical margins with modified Mohs for dermatofibrosarcoma protuberans. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is characterized by asymmetrical and poorly defined growth. Magnetic resonance imaging (MRI) has been proposed for the delimitation of this tumor. OBJECTIVES: To study the utility of MRI in evaluating the depth of infiltration in DFSP and to compare the efficiency of clinical palpation with that of MRI in delimiting the invasiveness of DFSP. METHODS: Observational, prospective study of DFSP cases. The MRI scans for all cases were compared with the exact histological infiltration plane obtained using modified Mohs micrographic surgery (MMS). RESULTS: Forty-three DFSPs were included: 22 primary, nine recurrent, and 12 extirpated with positive margins. Sensitivity for detecting deep invasion was 58% on examination using palpation and 67% using MRI. CONCLUSIONS: We present the largest series of DFSP cases studied using MRI published to date. In primary cases, MRI has greater sensitivity than palpation for detecting depth of infiltration (67% vs 58%). MRI seems to be useful in primary DFSP in locations other than the head, neck, and upper part of the thorax. MRI is not useful for confirming tumor persistence in extirpated DFSP with positive margins or for studying lateral extension in primary DFSP. PMID- 21679275 TI - An unusual case of infiltrating basal cell carcinoma. PMID- 21679276 TI - Effect of temperaments on quality of life and social adaptation in depressive patients with mood disorder. AB - AIMS: The aim of this study was to investigate the effects of temperament on quality of life and social adaptation in depressive patients with mood disorder. METHODS: Forty-six consecutive depressive outpatients were investigated by using the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire version, the Munich Personality Test, the World Health Organization Quality of Life 26 (WHO QOL 26), and the Social Adaptation Self evaluation Scale (SASS). The unpaired t-test, Pearson's r and multiple regression analysis were used to assess three variables (age, the number of temperaments and/or personality types, and Hamilton Depression Rating Scale scores) as independent variables with the scores of WHO QOL 26 and SASS as the dependent variables. RESULTS: The number of temperaments and/or personalities and Hamilton Depression Rating Scale scores were significantly and negatively associated with WHO QOL 26 scores while only the number of temperaments and/or personalities was significantly and negatively associated with SASS scores. CONCLUSIONS: The findings suggest that the combination of temperaments and/or personality types assessed with the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire version and the Munich Personality Test may worsen both quality of life and social adaptation and that some temperaments and/or personality types in combination may be subclinical manifestations of mood disorders. PMID- 21679277 TI - Factors influencing suicidal ideation among Japanese adults: from the national survey by the Cabinet Office. AB - AIM: Suicide prevention is of pressing importance in Japan, and grappling with this problem necessitates clarifying the causes of suicidal ideation. The purpose of the present study was to investigate several factors influencing suicidal ideation. This was done through analyzing factors examined in prior research and accessing suicide sites. METHODS: A total of 1080 randomly selected adults were asked about stress, stress release, social support sources, depression, access of suicides sites, and suicidal ideation. RESULTS: Around 6% of men in their 20s and 30s as well as 7% of people with suicide ideations had accessed suicide sites on the web. Those with suicide ideations were more likely to access suicide sites than those without. There was no sex difference in suicide ideations. The results concerning factors influencing past-year suicide ideations revealed that there were age and sex differences in these factors. CONCLUSION: For men in their 20s through their 50s, accessing suicide sites influenced suicidal ideations through depression, and for women in the same age bracket, emotional support influenced suicidal ideations through depression. For men and women over the age of 60, depression strongly influenced suicidal ideations. PMID- 21679278 TI - Association between deficient mismatch repair system and efficacy to irinotecan containing chemotherapy in metastatic colon cancer. AB - The present study investigated the association between deficient mismatch repair (dMMR) and efficacy outcomes of irinotecan-based first-line chemotherapy in patients with metastatic colorectal cancer (mCRC). Among 297 patients with sporadic mCRC receiving an irinotecan-containing regimen as first-line chemotherapy, 197 with available paraffin-embedded tissues were included in the current analysis. Tumors displaying loss of MMR protein (MLH1 or MSH2) and/or a microsatellite instability-high (MSI-H) genotype by PCR were classified as dMMR. Deficient mismatch repair was found in 23 evaluable tumors, among which eight displayed negativity for MLH1 expression, 11 for MSH2 expression, and four for both. The overall response rate was 47.2% (46.0% in proficient MMR (pMMR) and 56.5% in dMMR), with no significant difference between the two groups (P = 0.569). Median progression-free survival was 8.85 months in patients with dMMR tumors and 6.82 months in patients with pMMR tumors, but this difference did not reach statistical significance (P = 0.089). Median overall survival was not different between the two groups (P = 0.413). Efficacy outcomes of first-line irinotecan-based chemotherapy did not differ significantly between mCRC patients with pMMR and those with dMMR. Our data collectively indicate that MMR status is not effective as a single predictive marker for response to irinotecan-based chemotherapy in mCRC patients. PMID- 21679279 TI - Cost-effectiveness analysis for Pap smear screening and human papillomavirus DNA testing and vaccination. AB - INTRODUCTION: As the effectiveness of cytology-based screening programme for cervical cancer in mortality reduction has reached a plateau, various preventive strategies have been considered, including intensive Pap smear screening and the supplemental use of human papillomavirus (HPV) DNA test or HPV vaccination. Cost and effectiveness of these various preventive strategies are therefore of great concern for health policy makers. OBJECTIVE: We intended to assess whether the combination of HPV DNA testing or HPV vaccination with Pap smear screening programme or the sole annual Pap smear screening is more effective and cost effective in prevention of cervical cancer than the existing triennial Pap smear screening programme. METHODS: A Markov decision model was constructed to compare total costs and effectiveness between different preventive strategies (including annual Pap smear, HPV DNA testing or HPV vaccination together with Pap smear screening programme) as opposed to the triennial Pap smear screening alone (the comparator). Probabilistic cost-effectiveness (C-E) analysis was adopted to plot a series of simulated incremental C-E ratios scattered over C-E plane and also to yield the acceptability curve for different comparisons of strategies. The threshold of vaccine cost and the influence of attendance rate were also investigated. RESULTS: Compared with triennial Pap smear screening programme, most of preventive strategies cost more but gain additional life years (quadrant I of C-E plane) except HPV DNA testing with Pap smear every 5 years dominated by triennial Pap smear screening programme. The most cost-effective strategy was annual Pap smear (incremental C-E ratio = $31 698), followed by HPV DNA testing with Pap smear every 3 years ($36 627), and vaccination programme with triennial Pap smear screening ($44 688) with the corresponding cost-effective probabilities by the acceptability curve being 65.52%, 52.08% and 35.84% given the threshold of $40 000 of willingness to pay. Vaccination combined with triennial Pap smear would be as cost-effective as annual Pap smear provided the cost of vaccination was lowered to $250 per full course of injection. CONCLUSIONS: Among various preventive strategies annual Pap smear screening programme is still the most cost effective and additional HPV DNA testing is a cost-effective choice under a reasonable threshold of willingness to pay. Vaccination programme in combination with triennial screening would be cost-effective if vaccine cost can be greatly reduced in a large economic scale. PMID- 21679280 TI - A P5 cancer medicine approach: why personalized medicine cannot ignore psychology. AB - A system approach termed P4 medicine has recently been proposed in the field of oncology. This approach has been advanced as an extension of what is usually called 'personalized' or 'genomic medicine'. P4 medicine creates effective predictive, personalized, preventive and participatory models to treat patients. In order to give more relevance to the behavioural component that impinges on the way individuals act to prevent, cope and react to illnesses, how they decide between different therapeutic options and interact with physicians and adhere to treatment, we propose that P4 medicine should be transformed into P5 medicine. The fifth P represents the psycho-cognitive aspects to be considered in order to empower the patient, increase his/her quality of life and transform him/her from a passive recipient into an active decision-maker in the treatment process. PMID- 21679281 TI - Survey on physicians' knowledge and attitudes towards clinical practice guidelines at the Mexican Institute of Social Security. AB - OBJECTIVE: A survey was organized to determine the general level of knowledge and attitudes of medical personnel towards clinical practice guidelines (CPG). METHODS: A questionnaire modified from two validated instruments was used. Multi stratified sampling was applied, and 1782 questionnaires were completed. RESULTS: A total of 80.4% of physicians had regular employment contract, 8.6% managerial post and 9.3% temporary work contract. Average age and working time were 43.7 and 15 years respectively; 64.3% were male. It was reported that 47.9% participated in academic activities, 70.8% belonged to a medical association, 40.3% identified CPG as steps towards arriving at a diagnosis and/or treatment and 14.9% thought that CPG were norms. A total of 10.7% of the physicians believed that guidelines are based on scientific evidence, 10% perceived them as supporting tools, 10.8% had no knowledge of them, 65% said that they used them, 76.7% thought that personal experience was as important as CPG recommendations and 57.4% thought that CPG were necessary for good medical practice. Physicians preferred that CPG be produced by personnel from outside the Mexican Institute of Social Security, or who had followed validity criteria. CONCLUSIONS: The majority of physicians considered CPG to be useful tools. It was evident that few knew where to acquire CPG, and this would lead to their limited use. Findings from this study enabled procuring a broader idea of the level of knowledge and attitudes of Mexican Institute of Social Security physicians towards CPG. This information is relevant when planning strategies for the purpose of sharing and implementing CPG. PMID- 21679282 TI - Toward the second stage of recovery from the 3.11 Tohoku Earthquake. AB - Nearly 2 months have passed since the 3.11 Tohoku Earthquake. In central Sendai, where Tohoku University is located, life is slowly returning back to normal, at least on the surface. However, just a few kilometers away, where the tsunami washed away an entire town, wreckage still litters the coast. The second stage of recovering from the disaster has begun. What can we do to revive universities and communities in the affected areas? PMID- 21679284 TI - Acromegaly: presentation, morbidity and treatment outcomes at a single centre. AB - OBJECTIVE: Analysis of patients with acromegaly followed-up at a single centre, focusing on baseline characteristics, morbidity and efficacy of treatment. DESIGN AND METHODS: Retrospective review of electronic medical records of acromegalics from 1987 to 2009. RESULTS: One hundred and fifteen patients (45 men), aged 47 +/ 14 years, with a mean follow-up of 8.8 +/- 0.8 years were studied. Twenty-five per cent had micro- and 75% macroadenomas. Forty-three per cent presented with visual field defects, 49% had hypertension, 25% diabetes mellitus and 35% dyslipidaemia. At follow-up, 50% had myocardial hypertrophy, 55% colon polypodiasis, 74% nodular thyroid disease and 18% adrenal masses. Surgery was performed in 79% (8% twice), followed by conventional radiotherapy in 27%. Fifty two per cent of the patients achieved remission. Disease control was reported in 65% of microadenomas and 41% of macroadenomas. Remission rates with surgery alone were 41%. Improvement of remission rates was achieved with subsequent treatment with somatostatin analogues (SSA) (53%), or conventional radiotherapy (63%). Nevertheless, pituitary reserve was compromised with the latter. SSA significantly improved outcomes in microadenomas, even as a monotherapy (remission in 89%), in contrast to macroadenomas (0%), although these agents were associated with impaired glucose metabolism and cholelithiasis in half of the patients. CONCLUSIONS: Acromegaly is associated with an increased morbidity. About half of the treated patients achieved remission (2/3 of microadenomas). The best outcomes were reported for the combination of surgery with radiotherapy, in spite of a higher risk of hypopituitarism. SSA led to remission in a significant percentage of microadenomas, but was associated with increased rates of cholelithiasis and impaired glucose homeostasis. PMID- 21679283 TI - Production of a novel bioflocculant MNXY1 by Klebsiella pneumoniae strain NY1 and application in precipitation of cyanobacteria and municipal wastewater treatment. AB - AIMS: To isolate and characterize the novel bioflocculant-producing bacteria, to optimize the bioflocculant production and to evaluate its potential applications. METHODS AND RESULTS: Klebsiella pneumoniae strain NY1, a bacterium that produces a novel bioflocculant (MNXY1), was selected on the chemically defined media. It was classified according to the 16S rRNA gene sequence, morphological and microscopic characteristics. MNXY1 was characterized to contain 26% protein and 66% total sugar. The constituent sugar monomers of MNXY1, revealed by NMR analysis, are glucose, galactose and quinovose. Favourable culture conditions for MNXY1 production were determined. Strain NY1 produces a high level (14.9 g l(-1)) of MNXY1. MNXY1 is thermostable and tolerant to the extreme pH. It precipitated 54% of cyanobacteria from laboratory culture and 72% of the total suspended solids from raw wastewater. CONCLUSIONS: Strain NY1 was identified to produce a novel bioflocculant MNXY1. The outstanding performance of MNXY1 in practical applications and its availability in copious amounts make it attractive for further investigation and development for industrial scale applications. SIGNIFICANCE AND IMPACT OF THE STUDY: This is first report for the identification of a quinovose-containing bioflocculant and application of a protein polysaccharide complex bioflocculant in precipitation of cyanobacteria. These findings suggest that MNXY1 holds great potential for use in management of harmful algae and city wastewater treatment. PMID- 21679285 TI - Fabry disease in Spain: description of Spanish patients and a comparison with other European countries using data from the Fabry Outcome Survey (FOS). AB - AIMS: Fabry disease (FD) is an X-chromosome-linked transmitted lysosomal storage disorder as a result of the deficient activity of enzyme alpha-galactosidase A. This leads to accumulation of neutral glycosphingolipids associated with organ involvement and premature death. We report the clinical characteristics of Spanish patients enrolled on the Fabry Outcome Survey (FOS; an international multicentre registry for the disease) and also compare these data with those from the rest of Europe. METHODS: Baseline clinical data of 92 patients (41 males and 51 females) are described and analysed globally and according to gender. We compare the data of Spanish patients with those previously published from the rest of Europe patients in FOS. RESULTS: Mean age of onset of symptoms in men was 20, and 24 years in women, with a mean delay of 11 years to the diagnosis in both genders. The predominant clinical involvement in male patients was renal (69%), cardiac (66%) and neurological (60%), and for female patients, it was neurological (42%), cardiac (33%), keratopathy (30%) and nephropathy (28%). Disease severity was significantly higher in male patients. Compared to the rest of European FOS-patients, Spanish patients were diagnosed at an earlier age with a smaller proportion of disease-related involvement for most organ irrespective of gender, though not its global severity in male patients. CONCLUSIONS: We present the largest cohort of Spanish patients diagnosed with FD. The pattern of involvement (though not its global severity) could be different in Spanish patients in comparison with others from Europe. Expanding the knowledge of FD will permit early diagnosis as well as the possibility of starting the specific treatment. PMID- 21679286 TI - Oral fingolimod for the treatment of patients with relapsing forms of multiple sclerosis. AB - Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral treatment approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis (MS). The aim of this review was to provide a concise, comprehensive overview of the clinically relevant mechanism of action, efficacy and safety information available for fingolimod. Key data were derived from two international, Phase III, double-blind, randomised trials (TRANSFORMS and FREEDOMS) performed over 12 and 24 months, respectively, which evaluated fingolimod 0.5 and 1.25 mg daily in 1703 patients with relapsing forms of MS. In TRANSFORMS, there was a 52% reduction in the annualised relapse rate (ARR) with fingolimod 0.5 mg vs. 30 MUg intramuscular interferon beta-1a (0.16 vs. 0.33; p < 0.001) at 1 year. In FREEDOMS, there was a 55% decrease in ARR at 2 years with fingolimod 0.5 mg vs. placebo (0.18 vs. 0.40; p < 0.001). Risk of disability progression, confirmed at 3 months, was also reduced by 30% over the 2-year study period with fingolimod vs. placebo (p = 0.02). Significantly fewer new or enlarged lesions on T(2) -weighted images were seen in both studies (TRANSFORMS, p = 0.002 vs. interferon beta-1a at 1 year; FREEDOMS, p < 0.001 vs. placebo at 2 years). Overall, fingolimod 0.5 mg was well tolerated by patients. Transient, generally asymptomatic bradycardia and infrequent atrioventricular block were seen with the administration of the first dose. Macular oedema and serious infections occurred infrequently. Reversible, asymptomatic elevations of liver enzymes could also occur. As the first approved oral disease-modifying treatment, fingolimod offers patients a convenient alternative to regular self-injection for the treatment of relapsing forms of MS. In addition to high efficacy with a relatively acceptable safety profile, fingolimod provides a therapy with a new mechanism of action. PMID- 21679287 TI - Do the organizational reforms of general practice care meet users' concerns? The contribution of the Delphi method. AB - CONTEXT: The debate over primary care reform in France, as in most OECD countries, centres on questions about efficacy and accessibility. Do these reforms actually respond to the users' concerns? OBJECTIVE: The objective of this study was to identify the importance that users attribute to different aspects of general practice (GP) care. DESIGN: The method used was a variant of the classical Delphi approach, called Delphi 'ranking-type'. Between May and September 2009, 74 experts aged over 18 were recruited by 'snowballing' sampling. Three iterative rounds were required to identify the core aspects through a consensus-building approach. RESULTS: It is shown that users attribute a very high importance to the 'doctor-patient relationship' dimension. The following aspects 'GP patient information about his/her illness', 'Clarity of communication and explanation', and 'Whether the GP seemed listen to the patient' were evaluated by 96% of the experts as being of high importance. The coordination of GP was also considered as a very important aspect for 85% of the experts. In contrast, the aspects that belong to the organizational dimension appeared to be of relatively low importance for users. CONCLUSIONS: Our results support a comprehensive approach of care and argue in favour of care reorganization following the patient-centred model. To promote organizational care reforms through the prism of the doctor-patient relationship could thus be a fruitful way to insure a better quality of care and the social acceptability of the reforms. PMID- 21679289 TI - Statistical inference for stochastic simulation models--theory and application. AB - Statistical models are the traditional choice to test scientific theories when observations, processes or boundary conditions are subject to stochasticity. Many important systems in ecology and biology, however, are difficult to capture with statistical models. Stochastic simulation models offer an alternative, but they were hitherto associated with a major disadvantage: their likelihood functions can usually not be calculated explicitly, and thus it is difficult to couple them to well-established statistical theory such as maximum likelihood and Bayesian statistics. A number of new methods, among them Approximate Bayesian Computing and Pattern-Oriented Modelling, bypass this limitation. These methods share three main principles: aggregation of simulated and observed data via summary statistics, likelihood approximation based on the summary statistics, and efficient sampling. We discuss principles as well as advantages and caveats of these methods, and demonstrate their potential for integrating stochastic simulation models into a unified framework for statistical modelling. PMID- 21679288 TI - Met or matched expectations: what accounts for a successful back pain consultation in primary care? AB - BACKGROUND: Patients' as well as doctors' expectations might be key elements for improving the quality of health care; however, previous conceptual and theoretical frameworks related to expectations often overlook such complex and complementary relationship between patients' and doctors' expectations. The concept of 'matched patient-doctor expectations' is not properly investigated, and there is lack of literature exploring such aspect of the consultation. AIM: The paper presents a preliminary conceptual model for the relationship between patients' and doctors' expectations with specific reference to back pain management in primary care. METHODS: The methods employed in this study are integrative literature review, examination of previous theoretical frameworks, identification of conceptual issues in existing literature, and synthesis and development of a preliminary pragmatic conceptual framework. OUTCOME: A simple preliminary model explaining the formation of expectations in relation to specific antecedents and consequences was developed; the model incorporates several stages and filters (influencing factors, underlying reactions, judgement, formed reactions, outcome and significance) to explain the development and anticipated influence of expectations on the consultation outcome. CONCLUSION: The newly developed model takes into account several important dynamics that might be key elements for more successful back pain consultation in primary care, mainly the importance of matching patients' and doctors' expectations as well as the importance of addressing unmet expectations. PMID- 21679291 TI - Effects of initiation and titration of a single pre-prandial dose of insulin glulisine while continuing titrated insulin glargine in type 2 diabetes: a 6 month 'proof-of-concept' study. AB - AIM: Stepwise intensification of insulin treatment to match the progressive decline of endogenous insulin secretion has been shown to be an effective management strategy in type 2 diabetes mellitus (T2DM). The efficacy of initiating and titrating a single bolus dose of insulin glulisine to baseline insulin glargine plus oral hypoglycaemic agents (OHAs) was investigated. METHODS: This was a 6-month, parallel-group, randomized, open-label, Phase IV study conducted in the US, UK and Russia. People with T2DM (HbA(1c) 7.5-9.5%) using any basal insulin underwent a 3-month run-in period on insulin glargine titrated to optimize fasting blood glucose (BG) control. Those with HbA(1c) >7.0% were randomized to either continue prior therapy (n = 57) or to add a single dose of insulin glulisine (n = 49) immediately prior to the main meal for a further 3 months. Two different titration algorithms were employed for the bolus dose, targeting 2-h postprandial BG <=135 mg/dL (<=7.5 mmol/l; Russia and UK) or pre meal/bedtime BG 100-120 mg/dl (5.5-6.7 mmol/l; US). RESULTS: HbA(1c) and fasting plasma glucose levels decreased during the run-in period. In the 3 months after randomization, more participants in the basal-plus-bolus group reached HbA(1c) <7.0% than the basal-only control group (22.4 vs. 8.8%; p < 0.05), with significantly greater reduction of HbA(1c) (-0.37 vs. -0.11%; p = 0.0290). Rates of hypoglycaemia and mean weight change were comparable between the treatment groups. CONCLUSIONS: In people with T2DM inadequately controlled on basal insulin plus OHAs, adding a single injection of insulin glulisine prior to the main meal significantly improves glucose control without undesired side effects. PMID- 21679292 TI - Exploiting natural variation to identify insect-resistance genes. AB - Herbivorous insects are widespread and often serious constraints to crop production. The use of insect-resistant crops is a very effective way to control insect pests in agriculture, and the development of such crops can be greatly enhanced by knowledge on plant resistance mechanisms and the genes involved. Plants have evolved diverse ways to cope with insect attack that has resulted in natural variation for resistance towards herbivorous insects. Studying the molecular genetics and transcriptional background of this variation has facilitated the identification of resistance genes and processes that lead to resistance against insects. With the development of new technologies, molecular studies are not restricted to model plants anymore. This review addresses the need to exploit natural variation in resistance towards insects to increase our knowledge on resistance mechanisms and the genes involved. We will discuss how this knowledge can be exploited in breeding programmes to provide sustainable crop protection against insect pests. Additionally, we discuss the current status of genetic research on insect-resistance genes. We conclude that insect resistance mechanisms are still unclear at the molecular level and that exploiting natural variation with novel technologies will contribute greatly to the development of insect-resistant crop varieties. PMID- 21679290 TI - Coiled-coil domains enhance the membrane association of Salmonella type III effectors. AB - Coiled-coil domains in eukaryotic and prokaryotic proteins contribute to diverse structural and regulatory functions. Here we have used in silico analysis to predict which proteins in the proteome of the enteric pathogen, Salmonella enterica serovar Typhimurium, harbour coiled-coil domains. We found that coiled coil domains are especially prevalent in virulence-associated proteins, including type III effectors. Using SopB as a model coiled-coil domain type III effector, we have investigated the role of this motif in various aspects of effector function including chaperone binding, secretion and translocation, protein stability, localization and biological activity. Compared with wild-type SopB, SopB coiled-coil mutants were unstable, both inside bacteria and after translocation into host cells. In addition, the putative coiled-coil domain was required for the efficient membrane association of SopB in host cells. Since many other Salmonella effectors were predicted to contain coiled-coil domains, we also investigated the role of this motif in their intracellular targeting in mammalian cells. Mutation of the predicted coiled-coil domains in PipB2, SseJ and SopD2 also eliminated their membrane localization in mammalian cells. These findings suggest that coiled-coil domains represent a common membrane-targeting determinant for Salmonella type III effectors. PMID- 21679293 TI - 23. Pain in patients with cancer. AB - Pain in patients with cancer can be refractory to pharmacological treatment or intolerable side effects of pharmacological treatment may seriously disturb patients' quality of life. Specific interventional pain management techniques can be an effective alternative for those patients. The appropriate application of these interventional techniques provides better pain control, allows the reduction of analgesics and hence improves quality of life. Until recently, the majority of these techniques are considered to be a fourth consecutive step following the World Health Organization's pain treatment ladder. However, in cancer patients, earlier application of interventional pain management techniques can be recommended even before considering the use of strong opioids. Epidural and intrathecal medication administration allow the reduction of the daily oral or transdermal opioid dose, while maintaining or even improving the pain relief and reducing the side effects. Cervical cordotomy may be considered for patients suffering with unilateral pain at the level below the dermatome C5. This technique should only be applied in patients with a life expectancy of less than 1 year. Plexus coeliacus block or nervus splanchnicus block are recommended for the management of upper abdominal pain due to cancer. Pelvic pain due to cancer can be managed with plexus hypogastricus block and the saddle or lower end block may be a last resort for patients suffering with perineal pain. Back pain due to vertebral compression fractures with or without pathological tumor invasion may be managed with percutaneous vertebroplasty or kyphoplasty. All these interventional techniques should be a part of multidisciplinary patient program. PMID- 21679294 TI - Multiplate whole blood impedance aggregometry: a new tool for von Willebrand disease. PMID- 21679295 TI - Low-carb tissue factor? PMID- 21679298 TI - A genome-wide association study for quantitative traits in schizophrenia in China. AB - Few genome-wide association studies (GWAS) of schizophrenia have included Chinese populations, and verification of positive genetic findings from other ethnic groups is rare in Chinese groups. We used fluid intelligence as the quantitative trait reflecting schizophrenia dysfunction in Chinese populations, and determined the impact of genetic variation on fluid intelligence phenotypic patterns to identify genetic influences in schizophrenia. The study sample comprised 98 patients with schizophrenia and 60 healthy controls. The general fluid intelligence of participants was assessed with Cattell's Culture-Free Intelligence Test (CCFIT). Subjects were genotyped using the Illumina HumanHap 660 beadchip. We identified the methionine sulfoxide reductase A (MSRA) gene on chromosome 8 as having an association with fluid intelligence. However, only CCFIT subtest 1 (series score) demonstrated a significant result for the interaction term using the criteria of the quantitative trait (QT) analysis of 10(-5) for at least three SNPs. There were 15 haplotype blocks of MSRA gene SNPs identified using Haploview 4.2 with solid spine D' > 0.80. The strongest QT interaction was noted in Block 3, with the most common haplotypes being AAACAGCAG and CGCAGAAGA. In conclusion, we report data from a GWAS with quantitative traits design from Chinese first-episode schizophrenia patients and matched controls. Although the gene identified requires confirmation in an independent sample, the MSRA gene located on chromosome 8 was found to be associated with the phenotype of schizophrenia. PMID- 21679296 TI - Inducible hydrogen sulfide synthesis in chondrocytes and mesenchymal progenitor cells: is H2S a novel cytoprotective mediator in the inflamed joint? AB - Hydrogen sulfide (H(2)S) has recently been proposed as an endogenous mediator of inflammation and is present in human synovial fluid. This study determined whether primary human articular chondrocytes (HACs) and mesenchymal progenitor cells (MPCs) could synthesize H(2)S in response to pro-inflammatory cytokines relevant to human arthropathies, and to determine the cellular responses to endogenous and pharmacological H(2)S. HACs and MPCs were exposed to IL-1beta, IL 6, TNF-alpha and lipopolysaccharide (LPS). The expression and enzymatic activity of the H(2)S synthesizing enzymes cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) were determined by Western blot and zinc-trap spectrophotometry, respectively. Cellular oxidative stress was induced by H(2)O(2), the peroxynitrite donor SIN-1 and 4-hydroxynonenal (4-HNE). Cell death was assessed by 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (DCm) was determined in situ by flow cytometry. Endogenous H(2) S synthesis was inhibited by siRNA-mediated knockdown of CSE and CBS and pharmacological inhibitors D,L propargylglycine and aminoxyacetate, respectively. Exogenous H(2)S was generated using GYY4137. Under basal conditions HACs and MPCs expressed CBS and CSE and synthesized H(2)S in a CBS-dependent manner, whereas CSE expression and activity was induced by treatment of cells with IL-1beta, TNF-alpha, IL-6 or LPS. Oxidative stress-induced cell death was significantly inhibited by GYY4137 treatment but increased by pharmacological inhibition of H(2)S synthesis or by CBS/CSE-siRNA treatment. These data suggest CSE is an inducible source of H(2)S in cultured HACs and MPCs. H(2)S may represent a novel endogenous mechanism of cytoprotection in the inflamed joint, suggesting a potential opportunity for therapeutic intervention. PMID- 21679299 TI - Sexual function assessment in postmenopausal women with the 14-item changes in sexual functioning questionnaire. AB - INTRODUCTION: Sexual function assessment is relevant to improve female health care. AIM: Assess sexual function in postmenopausal women and determine predictors related to sociodemographic, lifestyle, and health-related female/partner data and tool measures. METHODS: Cross-sectional study in which 117 sexually active postmenopausal women filled out the 14-item Changes in Sexual Functioning Questionnaire (CSFQ-14), the 10-item Center for Epidemiologic Studies Short Depression Scale (CESD-10), the Menopause Rating Scale (MRS), and a general questionnaire containing female/partner data. Correlations between tool measurements and female/partner data were analyzed. MAIN OUTCOME MEASURES: Primary end point was sexual function predictors. RESULTS: Median age was 57 years, 8.5% had low income, 3.4% had surgical menopause, 17.1% had hypertension, and 66.7% increased body mass index. In addition, 21.4% were current hormone therapy users and 28.2% engaged in regular exercise. According to the MRS, muscle/joint problems (86.3%) and physical/mental exhaustion (81.2%) were the top encountered menopausal symptoms. Also, 48.7% displayed depressed mood (CESD-10 total scores >= 10) and 64.1% displayed total CSFQ-14 scores <=41, suggesting sexual dysfunction. Internal consistency (Cronbach's alpha) was high for all tools: total CSFQ-14 scale (0.87), total MRS (0.80), and the CESD-10 (0.85). CSFQ 14 total scores inversely correlated with MRS scores (total, psychological, and urogenital, P < 0.05). Arousal scale scores inversely correlated with MRS total and urogenital scores whereas orgasm scores only with the total MRS. CESD-10 scores inversely correlated with all CSFQ-14 scores and positively with all MRS scores. Multiple linear regression was used to obtain a reduced best-fit model predicting total CSFQ-14 scores (sexual function). Total CSFQ-14 scores were positively correlated to female education, and education and regular exercising in the partner and inversely correlated to CESD-10 total scores. CONCLUSION: Assessed with the CSFQ-14 tool, sexual function of this postmenopausal sample correlated to female/partner educational, lifestyle, and health factors. More research is warranted in this regard. PMID- 21679300 TI - Comparison of a new length measurement technique for inflatable penile prosthesis implantation to standard techniques: outcomes and patient satisfaction. AB - INTRODUCTION: Within a study evaluating the redesigned AMS 700MS inflatable penile prosthesis (IPP) (American Medical Systems, Minnetonka, MN, USA), one site used new length measurement technique (NLMT), a more aggressive dilation and measurement of the corpora cavernosa on a stretched penis, to address penile shortening. AIM: To compare cylinder size and patient satisfaction, between a NLMT and traditional sizing for IPP implantation. METHODS: Fourteen men received IPPs using NLMT, and 55 with traditional sizing. Nationwide sales data from 2005 to 2008 for AMS 700 IPPs was obtained from AMS for comparison; additional surveys captured patient satisfaction. MAIN OUTCOME MEASURE: Demographic data, cylinder sizes, and patient satisfaction were compared between the NLMT and standard techniques. RESULTS: The Fisher's exact test (P<0.001) showed a significant difference between the cylinder sizes with NLMT as compared with standard techniques. Of the 14 NLMT patients, 71.4% (10) received cylinders>21 cm long and 28.6% (4) received cylinders<21 cm long, as compared with 12.7% (7) and 87.3% (48), respectively, for patients implanted by traditional techniques. There were ethnic differences between the samples: 42.9% (6) NLMT patients were of African American descent, as compared with 10.9% (6) in the standard technique group. However, longer cylinders were utilized more often, with 83.3% (5) of African Americans treated using the NLMT; as compared with 33.3% (2) of the standard technique group. Nationwide data reveal 12.3% of patients routinely receive 21 cm cylinders. At 6 months postimplantation, patient satisfaction with NLMT was no different than standard techniques. There were no distal erosions, complications, infections, or pain concerns reported through 24 months among the NLMT patients. CONCLUSIONS: The NLMT resulted in a larger number of subjects implanted with larger cylinders. Satisfaction with performance and complication rates for NLMT patients was comparable to those implanted using standard techniques. PMID- 21679297 TI - Delayed procedural learning in alpha7-nicotinic acetylcholine receptor knockout mice. AB - The alpha7-nicotinic acetylcholine receptor (nAChR) has long been a procognitive therapeutic target to treat schizophrenia. Evidence on the role of this receptor in cognition has been lacking, however, in part due to the limited availability of suitable ligands. The behavior of alpha7-nAChR knockout (KO) mice has been examined previously, but cognitive assessments using tests with cross-species translatability have been limited to date. Here, we assessed the cognitive performance of alpha7-nAChR KO and wild-type (WT) littermate mice in the attentional set-shifting task of executive functioning, the radial arm maze test of spatial working memory span capacity and the novel object recognition test of short-term memory. The reward motivation of these mutants was assessed using the progressive ratio breakpoint test. In addition, we assessed the exploratory behavior and sensorimotor gating using the behavioral pattern monitor and prepulse inhibition, respectively. alpha7-nAChR KO mice exhibited normal set shifting, but impaired procedural learning (rule acquisition) in multiple paradigms. Spatial span capacity, short-term memory, motivation for food, exploration and sensorimotor gating were all comparable to WT littermates. The data presented here support the notion that this receptor is important for such procedural learning, when patterns in the environment become clear and a rule is learned. In combination with the impaired attention observed previously in these mice, this finding suggests that agonist treatments should be examined in clinical studies of attention and procedural learning, perhaps in combination with cognitive behavioral therapy. PMID- 21679301 TI - Sexual health of Dutch medical students: nothing to worry about. AB - INTRODUCTION: Little is known about the sexual lives and development of medical students because of relatively small sample sizes and, in particular, low response rates in research. Enhancing medical students' awareness and understanding of sexual behavior is imperative, as gaps in knowledge might impede effective sexual health consultations in their later professional practice. AIM: The aim of this study was to provide insight into the sexual lives and development of medical students. MAIN OUTCOME MEASURES: The main outcome measures of this study are demographic, contextual, and sexual data based on validated surveys. METHODS: Preclinical medical students aged under 26 years were approached during scheduled classes and by e-mail to complete a web-based questionnaire. Our results were compared with international and Dutch normative data. Ordinal regression analysis and Pearson's correlation analysis were used to assess relationships between variables. RESULTS: A total of 1,598 questionnaires were returned (response rate 52%: 1,198 by women, 400 by men). There were 719 first-year students (mean age 19.17 years) and 879 third-year students (mean age 21.5 years). Gender distribution differences were seen in all the cohorts and were corrected for. Compared with international and Dutch (88%) normative data, our first- (62.7%; P<0.001) and third-year (79.9%; P=0.018) medical students had less sexual experience and showed different advancements in sexual behavior. However, these differences decreased, which suggests that medical students "catch up" as their age increases. Sexual behavior in our sample did not differ from international data, except for a strikingly high sexual satisfaction (80%). We also confirmed that social and environmental characteristics change with alterations in sexual behavior. Although contraceptive measures were used more frequently (98%; P=0.006), sexually transmitted diseases were more common (4.6%; P=0.008), which suggests inappropriate use of protective measures. Independent predictive determinants for protective sexual behavior were the form of relationship (P<0.001; OR=1.97) and sexual orientation (P=0.009; odds ratio=2.26). CONCLUSION: These data provide insight into the sexuality of medical students. The results of this study reliably clarify previous findings and form a solid basis for further research. PMID- 21679302 TI - Severity of erectile dysfunction could predict left ventricular diastolic dysfunction in patients without overt cardiac complaint. AB - INTRODUCTION: It has been repeatedly demonstrated that presence of erectile dysfunction (ED) may predate the occurrence of overt event of coronary artery disease. However, the association between severity of ED and left ventricular diastolic dysfunction (LVDD) was rarely reported. AIM: The aim of this study was to assess the association between severity of ED and LVDD in patients without overt cardiac complaint. MAIN OUTCOME MEASURES: The International Index of Erectile Function (IIEF) was used to assess erectile function. Diastolic Doppler parameters measurements and tissue Doppler imaging were used to assess left ventricular diastolic function. METHODS: A total of 230 male ED patients without overt cardiac complaint were enrolled in this study. Erectile function was assessed using the IIEF. Patients were also screened for socio demographic data and medical comorbidities that included age, smoking, diabetes, hypertension, and dyslipidemia. All patients were referred to cardiologist for cardiac assessment. Left ventricular diastolic function that included diastolic Doppler parameters measurements and tissue Doppler imaging were also assessed. RESULTS: Mean age+/ standard deviation was 57.5+/-5.6 (range of 42-81). There were significant associations between the following risk factors: age, obesity, smoking, hypertension, dyslipidemia, and increased severity of ED (P<0.05 for each). Of the patients, 77.4%, 74.8%, 80%, and 66.1% had abnormal transmitral E/A (E/A) ratio, deceleration time (DT), isovolumic relaxation time (IVRT), mitral E velocity/tissue Doppler imaging E velocity (E/Em) ratio, respectively. Only the means of IVRT and (E/Em) ratio had significant associations with increased severity of ED (P<0.001 for each). There were significant associations between increased severity of ED and the following categorical echo parameters: grades 1 and 2 of E/A ratio, DT, IVRT, and grades 1, 2, and 3 of (E/Em) ratio (P<0.05 for each). CONCLUSIONS: The current study clearly demonstrated that LVDD is prevalent among patients with ED-associated medical comorbidities without overt cardiac complaint. There were significant associations between increased severity of ED and presence of LVDD in those patients. PMID- 21679231 TI - Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in Europe and Canada: results of the Dyslipidaemia International Study. AB - AIM: To assess the prevalence of persistent lipid abnormalities in statin-treated patients with diabetes with and without the metabolic syndrome. METHODS: This was a cross-sectional study of 22,063 statin-treated outpatients consecutively recruited by clinicians in Canada and 11 European countries. Patient cardiovascular risk factors, risk level, lipid measurements and lipid-modifying medication regimens were recorded. RESULTS: Of the 20,129 subjects who had documented diabetes and/or metabolic syndrome status, 41% had diabetes (of whom 86.8% also had the metabolic syndrome). Of those with diabetes, 48.1% were not at total cholesterol target compared with 58% of those without diabetes. Amongst those with diabetes, 41.6 and 41.3% of those with and without the metabolic syndrome, respectively, were not at their LDL cholesterol goal relative to 54.2% of those with metabolic syndrome and without diabetes, and 52% of those with neither condition. Twenty per cent of people with diabetes but without the metabolic syndrome were not at the optimal HDL cholesterol level compared with 9% of those with neither condition. Of people with diabetes and the metabolic syndrome, 49.9% were not at optimal triglyceride level relative to 13.5% of people with neither diabetes nor the metabolic syndrome. Simvastatin was the most commonly prescribed statin (>45%) and the most common statin potency was 20-40 mg/day (simvastatin equivalent). Approximately 14% of patients were taking ezetimibe alone or in combination with a statin. CONCLUSIONS: Despite evidence supporting the benefits of lipid modification and international guideline recommendations, statin-treated patients with diabetes had a high prevalence of persistent lipid abnormalities. There is frequently room to optimize therapy through statin dose up-titration and/or addition of other lipid-modifying therapies. PMID- 21679303 TI - Radiation-induced erectile dysfunction using prostate-confined modern radiotherapy in a rat model. AB - INTRODUCTION: The mechanisms of radiation-induced erectile dysfunction (ED) are unclear, as clinical studies are limited, and previous animal models were based on wide-field irradiation, which does not model current radiotherapy (RT) techniques. AIMS: To perform functional and morphological analyses of erectile function (EF) utilizing image-guided stereotactic prostate-confined RT in a rat model. METHODS: Sixty young adult male rats aged 10-12 weeks old were divided into age-matched sham and RT groups. A single 20-Gy fraction to the prostate was delivered to RT animals. Penile bulb, shaft, and testes were excluded from treatment fields. MAIN OUTCOME MEASURES: Bioassay and intracavernous pressure (ICP) measurements were conducted at 2, 4, and 9 weeks following RT. Perfusion analysis of the corpora cavernosa (CC) was conducted using Hoechst injected prior to sacrifice. Penile shaft and cavernous nerve (CN) were evaluated by immunohistochemistry. Plasma testosterone level was analyzed using a testosterone enzyme-linked immunosorbent assay (ELISA) assay kit. RESULTS: Irradiated animals demonstrated statistically significant time-dependent functional impairment of EF by bioassay and ICP measurement from 4 weeks. Neuronal nitric oxide synthase (NOS) expression was decreased in CN by 4 weeks. In CC, expression levels of anti alpha smooth muscle actin and endothelial NOS were significantly decreased at 9 weeks. In penile dorsal vessels, smooth muscle/collagen ratio was significantly decreased at 4 and 9 weeks. Additionally, Hoechst perfusion showed time-dependent decrease in CC of RT animals, whereas CD31 expression was not affected. No toxicities were noted; testosterone levels were similar in both groups. CONCLUSION: We demonstrated time-dependent ED following image-guided stereotactic RT. Our results imply that reduction of neuronal NOS expression in cavernous nerve could trigger consecutive reduction of smooth muscle content as well as blood perfusion in CC that resulted in corporal veno-occlusive dysfunction. Present study could be a cornerstone to future research that may bring comprehensive scientific understanding of radiation-induced ED. PMID- 21679305 TI - Hyperthyroidism: a risk factor for female sexual dysfunction. AB - INTRODUCTION: Hyperthyroidism is a common hormonal disorder in women that may cause female sexual dysfunction (FSD). AIM: To assess sexual function in women with hyperthyroidism. METHODS: A total of 40 women with clinical hyperthyroidism and 40 age-matched voluntary healthy women controls were included in the study. All the subjects were evaluated with a detailed medical and sexual history, including a Female Sexual Function Index (FSFI) questionnaire for sexual status and the Beck Depression Inventory (BDI) for psychiatric assessment. MAIN OUTCOMES MEASURES: The levels of serum thyroid-stimulating hormone (TSH), thyroid hormones, sex hormone binding globulin (SHBG), total testosterone (tT), free testosterone (fT), prolactin, estradiol, follicle-stimulating hormone, and luteinizing hormone were measured. RESULTS: The mean total FSFI scores were 24.2 +/- 9.96 in the hyperthyroidic group and 29 +/- 10.4 in the control group (P < 0.0001). Desire (P < 0.040), arousal (P < 0.0001), lubrication (P < 0.0001), orgasm (P < 0.0001), satisfaction (P < 0.0001), and pain (P < 0.007) domain scores were also significantly lower in women with hyperthyroidism. The mean BDI score for hyperthyroidic patients was significantly greater than the score for the control group (P < 0.0001). The mean SHBG level in the hyperthyroidic group was found to be significantly higher than the level in the controls (P < 0.0001), whereas the mean fT level in the hyperthyroidic group was lower than in the control group (P < 0.0001). The FSFI score showed a significant negative correlation with the serum SHBG (r = -0.309, P = 0.005), free triiodothyronine (r = -0.353, P = 0.006) and free tetraiodothyronine (r = -0.305, P = 0.018) levels, BDI scores (r = -0.802, P = 0.0001) and positive correlation with tT (r = 0.284, P = 0.011), fT (r = 0.407, P = 0.001), and TSH (r = 0.615, P = 0.0001) levels. CONCLUSIONS: A significant percentage of women with clinical hyperthyroidism had sexual dysfunction. Increased depressive symptoms, increased SHBG level, and decreased fT levels were all found to be associated with FSD in clinical hyperthyroidism. PMID- 21679304 TI - Improvement in sexual quality of life of the female partner following vardenafil treatment of men with erectile dysfunction: a randomized, double-blind, placebo controlled study. AB - INTRODUCTION: Erectile dysfunction (ED) impacts on both members of the couple. Female partners of men with ED are more likely to report reduced sexual quality of life than women whose partners do not have ED. AIM: To assess vardenafil efficacy in men with ED and determine the effects of treatment on their female partner's sexual quality of life. METHODS: Study participants comprised men aged 18-64 years with ED and their female partners. Eligible men had ED of >=6 months' duration and a female partner who was motivated to support their ED treatment. Eligible women had a total Female Sexual Function Index score >23.55, indicating absence of significant sexual dysfunction. Following a 4-week screening period, men were randomized to treatment with vardenafil 10 mg or placebo, which could be titrated to 20 or 5 mg after 4 weeks. MAIN OUTCOMES MEASURES: Primary efficacy variables were question 3 of the Sexual Encounter Profile questionnaire (SEP3) and the quality-of-life domain of the modified Sexual Life Quality Questionnaire (mSLQQ-QOL). RESULTS: The intent-to-treat population included 343 couples, with 168 and 175 men receiving vardenafil or placebo, respectively. Vardenafil treatment significantly improved both erection maintenance and the female partners' sexual quality of life. Least squares (LS) mean SEP3 overall success rates after 12 weeks of treatment were 9.5 (baseline) vs. 67.2 (week 12) and 12.4 (baseline) vs. 24.2 (week 12) in the vardenafil and placebo groups, respectively (P < 0.0001). In female partners, LS mean mSLQQ-QOL scores were 28.8 (baseline) vs. 68.2 (last observation carried forward [LOCF]) in the vardenafil group and 24.6 (baseline) vs. 40.5 (LOCF) in the placebo group (P < 0.0001). CONCLUSIONS: Vardenafil treatment of men with ED improved both their erectile function and the sexual quality of life of their female partners. PMID- 21679307 TI - Implicit and explicit cognitive sexual processes in survivors of childhood sexual abuse. AB - INTRODUCTION: Women with a history of childhood sexual abuse (CSA) exhibit higher rates of sexual dysfunction than nonabused women. AIM: Because sexual responses are affected by cognitive processes, this study investigated the implicit and explicit cognitive processing of sexual stimuli in women with a history of CSA. METHODS: Women with (CSA; N = 34) and without (no history of abuse [NSA]; N = 22) a history of CSA participated in a quasi-experimental study. MAIN OUTCOME MEASURE: Implicit processes, described as involuntary or unintentional responses to stimuli, were assessed using the Implicit Association Test (IAT). Explicit processes, described as intentional, voluntary, or effortful processing of sexual stimuli, were assessed through a self-reported questionnaire (Sexual Self-Schema Scale). RESULTS: Results showed initial evidence of between group differences in the cognitive processing of sexual stimuli. Regarding the implicit processes, women in the NSA group showed that sexual pictures were more strongly associated with positive valence (pleasure) than nonsexual pictures. For the CSA group, neutral and sexual pictures were similarly associated with pleasure. Conversely, for both groups, romantic pictures were more strongly associated with positive valence than sexual pictures. Moreover, sexual satisfaction was predicted by both implicit and explicit processes, suggesting that the sexuality of women is affected by both processes independently. CONCLUSIONS: These results fit within the larger body of literature suggesting that implicit and explicit processes independently predict different aspects of behavior. PMID- 21679306 TI - Erectile function rehabilitation after radical prostatectomy: practice patterns among AUA members. AB - INTRODUCTION: Despite a growing body of evidence supporting erectile function (EF) rehabilitation after radical prostatectomy (RP), there are no guidelines on this subject. AIM: To explore EF rehabilitation practice patterns of American Urological Association (AUA) urologists. METHODS: A 35-question instrument was constructed assessing physician demographics, training, and EF rehabilitation practices after RP, and was e-mailed to AUA members by the AUA Office of Education. Data were acquired by the AUA and analyzed by the investigators. MAIN OUTCOME MEASURE: Percentage of responders who recommend EF rehabilitation practices following RP, characterization of prevalent rehabilitation practices. RESULTS: Of the 618 urologists who completed the survey, 71% were in private practice, 28% considered themselves as sexual medicine specialists, although only 4% were fellowship-trained, 43% were urologic oncology specialists (14% fellowship-trained), 86% performed RP, and 86% of responders recommended rehabilitation practices. Being a sexual medicine or a urologic oncology specialist was not predictive of rehabilitation employment. Forty-three percent rehabilitate all patients, 57% only selected patients. Selection for rehabilitation was dependent upon preop EF by 66%, nerve-sparing status by 22%, and age by 5%. Eleven percent started rehab immediately after RP, 97% within 4 months. 24%, 45% and 18% ceased rehab at <12, 12-18, and 18-24 months, respectively. Eighty-nine percent of RP surgeons performed rehabilitation vs. only 66% who do not perform RP (P < 0.0001). Eighty-seven percent prefer phosphodiesterase type 5 inhibitors (PDE5i) as their primary strategy followed (in order) by vacuum erection device (VED), intracavernosal injection (ICI), and urethral suppositories. CONCLUSIONS: Among the respondents, penile rehabilitation is a common practice. Urologic oncologists and RP surgeons are more likely to use rehabilitation practices. The most commonly employed strategy is regular PDE5i use for 12-18 months after RP. . PMID- 21679308 TI - International index of erectile function: a misnomer at risk of being misleading from misuse. PMID- 21679309 TI - Left Shift 1+ flag for the detection of band neutrophils: interlaboratory variations and recommendations for the routine laboratory. AB - INTRODUCTION: Microscopic differential analysis of leukocytes is a time-consuming activity for routine diagnostic laboratories. The criteria used to decide whether a manual differential should be performed should therefore be as strict as possible. The goal of this investigation was to give recommendations for the use of the left shift (LS) 1+ flag, which signals the presence of band neutrophils. METHODS: The LS1+ flag of the ADVIA 120 and 2120 hematology analyzers was evaluated in 6 peripheral hospital laboratories in the Netherlands. In 2683 samples with exclusively a LS1+ flag, the percentage of band neutrophils were determined microscopically. A set of photographs of neutrophils were used to examine the differences between laboratories in the assessment of band cells. RESULTS: In 18% of all samples with only a LS1+ flag, 5% or more band neutrophils were found. However, this percentage differed greatly between laboratories, as did the proportion of samples that received a LS1+ flag. Several factors were found to influence the amount and accuracy of the LS1+ alarm, i.e. band neutrophil counting by microscopists, specificity of request for leukocyte differentials, percentage of general practitioners requesting a leukocyte differential, and sample storage. Based on these findings, a number of recommendations were formulated. CONCLUSION: Critical control of the factors influencing the LS1+ flag can significantly decrease the number of microscopic samples to be reviewed and may be valuable for every laboratory performing routine differentials, using any type of hematology analyzer. PMID- 21679311 TI - MRD analysis and treatment outcome in three children with SET-NUP214-positive hematological malignancies. PMID- 21679312 TI - Accurate testing for dysfunctional molecules: the potential for missing the diagnosis. PMID- 21679313 TI - sGD: software for estimating spatially explicit indices of genetic diversity. AB - Anthropogenic landscape changes have greatly reduced the population size, range and migration rates of many terrestrial species. The small local effective population size of remnant populations favours loss of genetic diversity leading to reduced fitness and adaptive potential, and thus ultimately greater extinction risk. Accurately quantifying genetic diversity is therefore crucial to assessing the viability of small populations. Diversity indices are typically calculated from the multilocus genotypes of all individuals sampled within discretely defined habitat patches or larger regional extents. Importantly, discrete population approaches do not capture the clinal nature of populations genetically isolated by distance or landscape resistance. Here, we introduce spatial Genetic Diversity (sGD), a new spatially explicit tool to estimate genetic diversity based on grouping individuals into potentially overlapping genetic neighbourhoods that match the population structure, whether discrete or clinal. We compared the estimates and patterns of genetic diversity using patch or regional sampling and sGD on both simulated and empirical populations. When the population did not meet the assumptions of an island model, we found that patch and regional sampling generally overestimated local heterozygosity, inbreeding and allelic diversity. Moreover, sGD revealed fine-scale spatial heterogeneity in genetic diversity that was not evident with patch or regional sampling. These advantages should provide a more robust means to evaluate the potential for genetic factors to influence the viability of clinal populations and guide appropriate conservation plans. PMID- 21679314 TI - Rise of the machines--recommendations for ecologists when using next generation sequencing for microsatellite development. AB - Next generation sequencing is revolutionizing molecular ecology by simplifying the development of molecular genetic markers, including microsatellites. Here, we summarize the results of the large-scale development of microsatellites for 54 nonmodel species using next generation sequencing and show that there are clear differences amongst plants, invertebrates and vertebrates for the number and proportion of motif types recovered that are able to be utilized as markers. We highlight that the heterogeneity within each group is very large. Despite this variation, we provide an indication of what number of sequences and consequent proportion of a 454 run are required for the development of 40 designable, unique microsatellite loci for a typical molecular ecological study. Finally, to address the challenges of choosing loci from the vast array of microsatellite loci typically available from partial genome runs (average for this study, 2341 loci), we provide a microsatellite development flowchart as a procedural guide for application once the results of a partial genome run are obtained. PMID- 21679316 TI - Do humor styles matter in the relationship between personality and subjective well-being? AB - The primary goal of this research was to examine the role of humor styles in the relationships between personality (extraversion and neuroticism) and two components of subjective well-being: life satisfaction and affective well-being. The sample consisted of 225 young adults, with mean age 23.61 years. Results indicated that the relationship between both extraversion and neuroticism and satisfaction with life could be partially explained by the mediating role of self enhancing humor. Additionally, affiliative humor proved to be a partial mediator of the relationship between neuroticism and affective well-being. The findings of this research suggested that adaptive humor styles might be one of the mechanisms linking personality and subjective well-being. PMID- 21679317 TI - Depressive symptoms and quality of life in people with age- related macular degeneration. AB - PURPOSE: To examine quality of life and associated factors in people with Age Related Macular Degeneration (AMD). METHODS: One hundred and forty-five AMD participants (mean age 78.0 +/- 7.7 years) and 104 age- and gender- matched controls (mean age 78.1 +/- 5.8 years) comprised the study populations for this case-control study. Depressive symptoms were measured with the Goldberg Anxiety and Depression (GAD) scale; general health and daily functioning was assessed with the Medical Outcomes Study Short Form 36 (SF-36) and questions relating to assistance required for daily living activities. RESULTS: People with AMD performed more poorly than controls on the GAD depression scale, and physical functioning subscale of SF-36. 44.4% of people with AMD had clinically significant depressive symptoms compared to 17.5% of controls (p < 0.001). Multiple regression analysis revealed that AMD was independently associated with depressive symptoms and a path model indicated that AMD led to depressive symptoms both directly and indirectly via reduced general health and social functioning. CONCLUSION: Psychological and functional outcome measures are reduced in people with AMD. Earlier recognition and treatment of depressive symptoms in people with AMD may be crucial to maintaining quality of life in this group. PMID- 21679315 TI - MtbHLH1, a bHLH transcription factor involved in Medicago truncatula nodule vascular patterning and nodule to plant metabolic exchanges. AB - This study aimed at defining the role of a basic helix-loop-helix (bHLH) transcription factor gene from Medicago truncatula, MtbHLH1, whose expression is upregulated during the development of root nodules produced upon infection by rhizobia bacteria. We used MtbHLH1 promoter::GUS fusions and quantitative reverse transcription polymerase chain reaction analyses to finely characterize the MtbHLH1 expression pattern. We altered MtbHLH1 function by expressing a dominantly repressed construct (CRES-T approach) and looked for possible MtbHLH1 target genes by transcriptomics. We found that MtbHLH1 is expressed in nodule primordia cells derived from pericycle divisions, in nodule vascular bundles (VBs) and in uninfected cells of the nitrogen (N) fixation zone. MtbHLH1 is also expressed in root tips, lateral root primordia cells and root VBs, and induced upon auxin treatment. Altering MtbHLH1 function led to an unusual phenotype, with a modified patterning of nodule VB development and a reduced growth of aerial parts of the plant, even though the nodules were able to fix atmospheric N. Several putative MtbHLH1 regulated genes were identified, including an asparagine synthase and a LOB (lateral organ boundary) transcription factor. Our results suggest that the MtbHLH1 gene is involved in the control of nodule vasculature patterning and nutrient exchanges between nodules and roots. PMID- 21679318 TI - Salzburg Skiing for the Elderly Study: study design and intervention--health benefit of alpine skiing for elderly. AB - The aim of this study was to monitor the long-term effects of skiing on the health-related parameters of older individuals. This paper describes the overall study design and the intervention phase. The study utilized a randomized control group design consisting of an intervention group (n=27; age: 67.5 +/- 2.8 years) and a control group (n=20; age: 67.3 +/- 4.4 years). Parameters of interest were measured during pre-, post- and retention-test sessions. The intervention phase lasted for 12 weeks, with an average of 28.5 days of guided skiing. Daily heart rate (HR) profiles and global positioning system data throughout the ski day were recorded. Perceived exertion levels as well as mood status of the subjects were recorded regularly. The intervention group completed an average of 4885 vertical meters of downhill skiing, with a total skiing distance of 40.5 km/day. In the skiing phase, the average physiological load was 72.4 +/- 8.9% of HR(max) . The dimension "positive mood" referred to skiing (on scale of 0-10), with an average value of 7.6 +/- 1.7 after skiing. The dimension of "negative mood" was much less pronounced, having a mean of 1.1 +/- 1.5 after skiing. Two subjects suffered injuries while falling during skiing. The effects of the 12-week skiing intervention on the tested parameters will be reported in the following papers of this supplementum. PMID- 21679319 TI - Salzburg Skiing for the Elderly Study: influence of alpine skiing on aerobic capacity, strength, power, and balance. AB - Alpine skiing is a recreational sport with high demands on the cardiovascular and neuromuscular systems. It is assumed that skiing could have positive effects on the decline in aerobic capacity, strength, and balance ability of older individuals. In a 12-week intervention study, 47 elderly subjects (age 60-76 years) were randomized into an intervention group (IG) and a control group (CG). The IG averaged 28.5 days of guided skiing during 12 weeks. Aerobic capacity, leg power, and strength as well as postural stability were tested before, immediately after, and 10 weeks after the intervention phase. VO(2 max) improved by 7.2% from Pre to Post for the IG, without any change in the CG. Jump height increased on average by 6% over the 12 weeks for the IG, while jump height for the CG deteriorated by -11.7%. Dynamic maximal strength measured in both legs increased by 16% in the IG during the 12 weeks of skiing. In the CG, it increased by 7%, without being significant. In postural ability, no differences between groups or over time were noted. It appears that, in older individuals, 12 weeks of skiing leads to a significant increase in aerobic capacity, leg muscle power, and strength. PMID- 21679320 TI - Skeletal muscle remodeling in response to alpine skiing training in older individuals. AB - This study investigated whether regular alpine skiing could reverse sarcopenia and muscle weakness in older individuals. Twenty-two older men and women (67 +/- 2 years) underwent 12 weeks of recreational skiing, two to three times a week, each session lasting ~ 3.5 h. An age-matched, inactive group (n=20, 67 +/- 4 years) served as a control (CTRL). Before and after the training period, knee extensors muscle thickness (T(m) ), pennation angle (theta) and fascicle length (L(f) ) of the vastus lateralis muscle were measured by ultrasound. Maximum isokinetic knee extensor torque (MIT) at an angular velocity of 60 degrees /s was measured by dynamometry. After the training, T(m) increased by 7.1% (P<0.001), L(f) by 5.4% (P<0.02) and theta by 3.4% (P<0.05). The increase in T(m) was matched by a significant gain in MIT (13.3%, P<0.001). No significant changes, except for a decrease in theta (2.1%, P<0.02), were found in the CTRL group. The gain in T(m) in the training group correlated significantly with an increase in the focal adhesion kinase content, pointing to a primary role of this mechano sensitive protein in sarcomere remodeling with muscle hypertrophy. Overall, the results show that alpine skiing is an effective intervention for combating sarcopenia and weakness in old age. PMID- 21679321 TI - Load-sensitive adhesion factor expression in the elderly with skiing: relation to fiber type and muscle strength. AB - We hypothesized that 12 weeks of downhill skiing mitigates the functional deficits of knee extensor muscles in elderly subjects due to the specific recruitment of fast motor units during forceful turns on the slope. Downhill skiing led to a 1.4-fold increase in the mean cross-sectional area of slow (P=0.04)- and fast (P=0.08)-type muscle fibers. Fold changes in the expression of the structural component of focal adhesions, gamma-vinculin, were correlated with alterations in concentric force (r=0.64). Hypertrophy of fast fibers was more pronounced in women than in men (1.7 vs 1.1). Gender-specific structural functional adjustments of knee extensor muscles and attached patellar tendon were reflected by altered expression of pro- vs de-adhesive proteins and a number of correlations. The de-adhesive protein tenascin-C was selectively increased in women compared with men (1.7 vs 1.1) while the content of the adhesive collagen XII was specifically reduced in women. The pro-adhesive focal adhesion kinase showed a specific increase in men compared with women (1.9 vs 1.1). Our findings indicate that quantitatively matched adaptations in slow and fast motor units of extensor muscle underlie the preventive effect of skiing against sarcopenia and support that hypertrophy and reinforcement of fiber adhesion operate in the improvement of muscle strength. PMID- 21679322 TI - Effect of alpine skiing training on tendon mechanical properties in older men and women. AB - Strain is one of the parameters determining tendon adaptation to mechanical stimuli. The aim of this study was to test whether the patellar tendon strain induced during recreational alpine skiing would affect tendon mechanical properties in older individuals. Twenty-two older males and females (67 +/- 2 years) were assigned to a 12-week guided skiing programme (IG) and 20 aged matched volunteers served as controls (CG). Patellar tendon mechanical properties and cross-sectional area (CSA) were measured before and after training, with combined dynamometry and ultrasonography scanning. None of the variables changed significantly in the CG after training. In the IG, tendon stiffness and Young's modulus were increased (respectively, 14% and 12%, P<0.01), without any significant change in tendon CSA. In addition, changes in tendon stiffness were blunted in women (9%) compared with men (19%). Serum IGF-1 concentration tended to be lower in women (-19%, P=0.07). These results demonstrate that the mechanical stimulus induced by alpine skiing is sufficient to elicit adaptive changes in patellar tendon mechanical and material properties in older subjects. Furthermore, the present sex-specific adaptations are consistent with previous reports of lower collagen metabolic responsiveness in women and may be underpinned by anthropometric and metabolic differences. PMID- 21679323 TI - Salzburg Skiing for the Elderly Study: changes in cardiovascular risk factors through skiing in the elderly. AB - Numerous studies have shown that treatment of the modifiable cardiovascular risk factors (CVRF) results in a decreased risk to suffer from stroke or myocardial infarction. Despite the fact that exercise training is a potent treatment choice for CVRF, this is the first randomized study to assess the effects of alpine skiing on CVRF in elderly skiers. Subjects (n=42) were randomized into an intervention group (IG; n=22; 12 males/10 females; age: 66.6 +/- 2.1 years) completing 12 weeks of guided skiing or a control group (CG; n=20; 10 males/10 females; age: 67.3 +/- 4.4 years). CVRF were assessed before and after the intervention period. No cardiovascular event occurred within a total of 795.1 h of skiing. A significant increase in exercise capacity in IG (DeltaVO(2 max) : +2.0 mL/kg/min, P=0.005) but not in CG (DeltaVO(2 max) : -0.1 mL/kg/min, P=0.858; IG vs CG: P=0.008) as well as a decrease in body fat mass [IG: -2.3%, P<0.0001; CG: +/- 0.0%, P=0.866; IG vs CG: P<0.0001] was achieved. Blood pressure, blood lipids, heart rate and everyday physical activity remained essentially unchanged. Alpine skiing in the elderly is safe with respect to cardiovascular events, and improves some, but not all CVRF. PMID- 21679324 TI - Glucose homeostasis and cardiovascular disease biomarkers in older alpine skiers. AB - Alpine skiing and ski training involves elements of static and dynamic training, and may therefore improve insulin sensitivity. Healthy men and women who where beginners/intermediate level of alpine skiing, were studied before (Pre) and immediately after (Post) 12 weeks of alpine ski training. After an additional 8 weeks a third test (retention study, Ret) was performed. The subjects were randomized into an intervention group (IG, n=22, age=66.6 +/- 0.4 years) or a control group (CG, n=20, age=67.0 +/- 1.0 years). Plasma glucose decreased (P<0.05) in CG, but increased (P<0.05) again at Ret, while a continued decrease was seen in IG (Ret vs Post, P<0.05). Plasma insulin decreased (P<0.05) with training in IG, while no effect was seen in CG. HOMA2 index for insulin resistance decreased (P<0.05) from 0.80 +/- 0.08 to 0.71 +/- 0.09 in IG. The value at Ret (0.57 +/- 0.08) tended (P=0.067) to be different from Post. In CG the corresponding values were 0.84 +/- 0.09, 0.81 +/- 0.12 and 0.70 +/- 0.09, respectively. Total cholesterol and LDL decreased in both IC and CG, a result, interpreted as seasonal variation. Biomarkers for endothelial function and low grade inflammation were not elevated and similar in IG and CG, and did not change. Alpine ski training improves glucose homeostasis and insulin sensitivity in healthy, elderly individuals. PMID- 21679325 TI - Spinal reflex plasticity in response to alpine skiing in the elderly. AB - The present study was designed to assess the influence of 12 weeks (28.5 +/- 2.6 skiing days) of alpine skiing on spinal reflex plasticity, strength and postural control in senior citizens. Therefore, soleus H-reflexes and postural stability were measured during bipedal quiet and unstable stance in 22 (12 male and 10 female) elderly subjects aged 66.6 +/- 1 years. Furthermore, the maximal isometric force was determined in a leg press. The results showed an increased H reflex excitability after the training (+39%; P<0.05) while no changes occurred in the background EMG. The postural sway decreased after training (-6.6 cm; P <= 0.05) and the maximal force increased (+16.1%; P<0.05). No adaptations in any parameter could be observed in the control group. The present study demonstrated that skiing training was effective to alter the spinal reflex activity in elderly individuals. The increased H-reflexes correspond to adaptations known from strength training in young subjects. It may be assumed that alpine skiing induced a functional adaptation in that subjects have learned to integrate Ia afferent feedback more efficiently to ensure adequate motoneuron output. PMID- 21679326 TI - Does a skiing intervention influence the psycho-social characteristics of the elderly? AB - The purpose of this study was to assess whether a guided alpine skiing intervention lasting 12 weeks has an impact on psycho-social dimensions, measured by subjective assessments, of individuals who are 60+ years of age. A number of well-established questionnaires were used to measure well-being, life satisfaction, self-concept, health status, depression and self-efficacy. The physical self-concept in the domain "strength" increased significantly in the intervention group from pre- to post-test and remained stable through the retention test, whereas the control group demonstrated nearly no alteration. A similar effect was obtained in life satisfaction for the dimension "friends and relatives." On the contrary, psycho-social aspects of the elderly were not negatively influenced. The subjects of this study had very high pre-test scores that might reflect a ceiling effect which, in turn, can explain the marginal positive impact of the intervention. The findings of this study argue for recommending a guided alpine skiing intervention for individuals who are 60 years of age and older with high values in psycho-social variables. PMID- 21679327 TI - Effect of a skiing intervention on the psycho-physiological reactivity and recovery in the elderly. AB - This study determined the effects of a skiing intervention lasting 12 weeks on the psycho-physiological reactivity to and recovery from mental stressors in individuals who are 60+ years of age. In accordance with the cross-stressor hypothesis, it was assumed that a skiing intervention optimizes psycho physiological pre-conditions for coping with stress. A cognitive task was used to investigate stress-induced changes (reactivity) in the high-frequency (HF) component of the heart rate variability (HRV) and in the skin conductance level (SCL) as well as recovery from this stressor. The intervention group demonstrated a significant increase in maximal oxygen consumption that was not accompanied by alterations in HRV at rest. In comparison with the control group, there was no difference in the alteration of the reactivity and recovery in the HF component and in the SCL after completing the training. The findings indicate that neither the psycho-physiological reactivity nor the recovery was influenced by the skiing intervention. It may be speculated that the intensity of the skiing intervention was too low to induce such adaptations. Therefore, further studies are encouraged to enhance the duration and intensity of the exercises to achieve adaptations of the autonomous nervous system of elderly individuals. PMID- 21679328 TI - Physical self-concept and physical fitness in elderly individuals. AB - This investigation examined the relations between physical self-concept and physical fitness (endurance, balance, muscle strength, muscle power) for gaining knowledge about the interrelationship between subjective ratings and objective fitness scores in the elderly in three steps: (1) detecting correlations and changes in time, (2) clarifying the influence of gender, and (3) of a skiing intervention lasting 12 weeks. Physical self-concept was assessed using a modified version of the Physical Self-Concepts (PSK) scales (Stiller et al., 2004) reflecting three first-order factors (endurance, strength, general sportiness) and one second-order factor (global fitness). Objective fitness scores were obtained by VO(2 max), counter movement jump, concentric muscle strength, and static balance. The results reveal that elderly individuals' global physical self and general sportiness are mainly linked to VO(2 max) and concentric muscle strength. Global physical self is predicted by VO(2 max) in females and by physical strength (concentric muscle strength) in males, indicating gender differences. Over time, correlations between subjective ratings and objective fitness scores become stronger in the sense of convergent validity in the skiing intervention group, whereas convergent and divergent validity cannot be supported by data of the control group. In sum, physical self-concept is an important factor in the context of physical intervention programs in the elderly. PMID- 21679329 TI - Review: a systematic review of quality of life measures for people with intellectual disabilities and challenging behaviours. AB - BACKGROUND: The quality of life (QOL) construct is proposed as a method to assess service outcomes for people utilising disability services. With this in mind, the aim of this study was to conduct a systematic review of available QOL measures for people with intellectual disability (ID) to pinpoint psychometrically sound measures that can be routinely used for service evaluation. METHOD: A systematic search of the disability literature published between 1980 and 2008 was conducted in order to identify appropriate QOL tools for use within an Australian context. Twenty-four QOL instruments were identified and each instrument was then evaluated against a set of psychometric and measurement criteria. RESULTS: Six of the instruments examined were deemed to be psychometrically sound on the available information. No instruments were found that specifically assess QOL for people with ID who exhibit challenging behaviour. Most of the instruments assess QOL from a subjective perspective, use a questionnaire format and measure only some (not all) of the eight theoretically accepted domains of QOL. CONCLUSIONS: More instruments that measure QOL need to be developed and rigorously validated. This is especially the case for high-needs disability populations like those individuals that exhibit challenging behaviour or have severe to profound ID, as it is questionable whether existing measures can be used with these populations. PMID- 21679330 TI - Brief report: the sexual and physical abuse histories of offenders with intellectual disability. AB - BACKGROUND: Some studies have found higher rates of childhood sexual abuse in sex offenders while others have failed to find such relationships. METHOD: This study reviews the sexual and physical abuse histories of 156 male sex offenders with intellectual disability (ID), 126 non-sexual male offenders with ID and 27 female offenders with ID. RESULTS: Sexual offenders reported a higher rate of sexual abuse in childhood than non-sexual male offenders (32.6% vs. 17.8%), while the opposite was true for non-accidental injury (16.0% vs. 32.5%). Female offenders reported the highest rates of sexual abuse in childhood (59.3%). CONCLUSIONS: Some specificity of childhood abuse was evident in the male cohorts suggesting limited evidence of a developmental pathway to offending, while the women were a group highly vulnerable to all forms of abuse. PMID- 21679331 TI - Unsettled infant behaviour and health service use: a cross-sectional community survey in Melbourne, Australia. AB - AIMS: To investigate factors associated with health service use by women and their infants in Victoria, Australia. METHODS: Cross-sectional screening survey of 875 women with 4-month-old infants attending immunisation clinics in five local government areas in Melbourne between May 2007 and August 2008. The self report instrument assessed socio-demographic characteristics, unsettled infant behaviour, maternal mood (Edinburgh Postnatal Depression Scale) and, the outcome, health service use during the first 4 months post-partum. RESULTS: Mothers and their infants used on average 2.8 different health services in the first 4 months post-partum (range 0-8). After adjustment for other factors, high health service use (defined as >3 different services) was more common in mothers whose infants were unsettled with persistent crying, resistance to soothing and poor sleep. A one-point increase on the unsettled infant behaviour measure was associated with an 8% (2-14%) increase in the use of >3 services, 9% (3-16%) in use of emergency departments, 7% (2-13%) in use of telephone helplines and 9% (3-14%) of parenting services. Poorer maternal mental health was also implicated with a one-point increase on the Edinburgh Postnatal Depression Scale associated with a 4% (0.4 8%) increase in the likelihood of using more than three services. CONCLUSIONS: Unsettled infant behaviour is associated with increased use of multiple health services. The high use of emergency departments by families with unsettled infants found in this study suggests that enhancement of primary health-care capacity might be required. PMID- 21679332 TI - Emotional and behavioural adjustment of children born very preterm at early school age. AB - AIMS: This paper describes the emotional and behavioural adjustment of children born very preterm (VPT) at early school age. Of particular interest was the degree of agreement between parents and teachers, and the extent of situational (parent or teacher) and pervasive (parent and teacher reported) adjustment problems. METHODS: A regionally representative cohort of 104 VPT (<=33 weeks gestation) and 108 full-term (FT) children born during 1998-2000 was studied prospectively to age six. At corrected age six, child emotional and behavioural adjustment was assessed using the parent and teacher rated strengths and difficulties questionnaires. RESULTS: According to parents, 6-year-old VPT children had odds of emotional, inattention/hyperactivity and peer problems that were 2.7 to 3.8 times higher than their FT peers. Similar difficulties were identified by teachers, but odds were much lower and nonsignificant (1.1-1.8). Agreement between parents and teachers was lower in the VPT than the FT group (mean alternative chance-correlated coefficient , AC(1) = 0.63 vs. 0.80). Examination of the extent of pervasively identified adjustment problems showed that VPT children had higher rates of emotional (6% vs. 1%) and inattention/hyperactivity problems (12% vs. 6%) than FT children. CONCLUSIONS: Early school age, VPT children are at increased risk of pervasive emotional problems and inattention/hyperactivity, although these risks are relatively modest. The use of multiple informants to assess VPT children's well-being is important to minimise the effects of report source bias and the over identification of adjustment problems in children born VPT. PMID- 21679333 TI - Acute vitamin A toxicity: a report of three paediatric cases. AB - The following report describes three paediatric cases of vitamin A toxicity secondary to carnivorous fish liver ingestion. Further discussion of vitamin A toxicity and management of toxicity is included. PMID- 21679334 TI - Phenotype-directed treatment of pre-school-aged children with recurrent wheeze. AB - Wheeze in childhood may comprise different underlying diseases. Disease-specific treatment could potentially improve treatment efficacy. Various attempts have been made to differentiate between pre-school wheeze phenotypes. In this review, the results of clinical trials evaluating treatment of pre-school wheeze are discussed, with specific emphasis on the characteristics and phenotype of the study populations. Evidence suggests that systemic corticosteroids are not beneficial for the treatment of mild-to-moderate exacerbations of pre-school wheeze, irrespective of phenotype. The use of high-dose intermittent inhaled corticosteroid treatment cannot be recommended because of unacceptable side effects. Treatment with regular inhaled corticosteroids and leukotriene antagonists offer modest benefit, but neither treatment reduces hospitalisation rates. There is currently some evidence for a phenotype-specific effect of treatment. Phenotype-directed treatment of pre-school wheeze is currently limited by our ability to accurately differentiate between clinically useful phenotypes. PMID- 21679335 TI - Anaphylaxis to an ondansetron wafer. PMID- 21679336 TI - Role of food allergy in childhood atopic dermatitis. AB - The interplay between atopic dermatitis (AD) and food allergy is complex and subject to significant misconceptions both by the general public and the medical community. Childhood AD is a very prevalent disorder. In its moderate and severe forms, AD is a challenging disorder to manage from the perspective of the child, parent and treating doctor. As AD is one of the disease manifestations of atopy, it is unsurprising that many children with AD also have a coexisting IgE-mediated food allergy. It is a common misconception that food allergy is causal in the setting of AD. However, in a proportion of sufferers, food allergy does play a role in triggering or exacerbating pre-existing AD by immune-mediated mechanisms and potentially by non-immune mechanisms. It is, therefore, important to differentiate causality, co-existent disease and disease modifiers in this context. This paper seeks to clarify the role of food allergy in childhood AD, and to outline a rational framework for the diagnosis and approach to food allergy in the context of the management of a child with problematic AD. PMID- 21679337 TI - Measuring antibiotic prescribing in hospitalised children in resource-poor countries: a systematic review. AB - Antibiotic resistance represents a significant threat to global health. Widespread exposure to antibiotics drives the development of antibiotic resistance. Little is known about the exposure to antibiotics of hospitalised children, particularly in resource-poor countries where the burden of infectious disease is highest. The review sought to identify original research quantifying antibiotic use in hospitalised children in resource countries. The methods used were: A systematic search of the MEDLINE, CINAHL, EMBASE, LILACS and African Index Medicus databases. Eighteen papers were identified and the methodology varied considerably. Only seven used a recognised defined daily dose (DDD) methodology. The studies reveal a high exposure of hospitalised children to antibiotics. With the exception of data from China, the studies were limited by their design. Limited evidence of the variation in drug, dose and total exposure to antibiotic use in hospitalised children in resource-poor countries exists. An international network of surveillance of both antimicrobial prescribing and resistance using a simple standardised methodology in this context remains an important goal. A simplified paediatric version of the adult DDD methodology is required to allow international comparison between populations. PMID- 21679338 TI - Infant deaths due to heparin overdose: time for a concerted action on prevention. AB - Heparin is one of the most commonly used drugs in tertiary paediatric centres. Across the last decade, targeted research has been directed towards improving the level of evidence supporting paediatric-specific recommendations for the use and management of heparin in infants and children. In contrast, little effort has been directed towards improving the safe use of heparin despite a plethora of fatal and non-fatal heparin-related errors being reported in the lay press. This short report highlights the need for united and concerted action to develop strategies aimed at minimising avoidable infant deaths related to heparin errors. PMID- 21679339 TI - Medical management of paediatric burn injuries: best practice. AB - Burns commonly occur in children and their first aid remains inadequate despite burn prevention programmes. While scald injuries predominate, contact and flame burns remain common. Although typically less severe injuries overall than those in adults, hypertrophic scarring complicating both the burn wound and even donor sites occur more frequently in children. The heterogeneous nature of burn wounds, coupled with the difficulties associated with the early clinical assessment of burn depth, has stimulated the application of novel technologies to predict burn wound outcome. This review explores current best practice in the management of paediatric burns, with a focus on prevention, optimal first aid, resuscitation, burn wound prediction and wound management strategies. PMID- 21679340 TI - Unusual presentation of tubular carcinoma of the breast. PMID- 21679341 TI - An unusual case of scintigraphic mapping in invasive carcinoma of a cancer patient. PMID- 21679342 TI - Hedgehog signaling pathway as a therapeutic target in various types of cancer. AB - Hedgehog (Hh) signaling is an important factor in growth and patterning during embryonic development. A mutation in Patched, Smoothened or Gli1, which regulate the Hh signaling pathway, might lead to the onset of glioblastoma, basal cell carcinoma, medulloblastoma and rhabdomyosarcoma. Recently, Hh signaling has been reported to be activated in a ligand-dependent manner, contributing to carcinogenesis and cancer progression. Hedgehog signaling is reactivated in various types of cancer, and this contributes to cancer progression by facilitating proliferation, invasion and cell survival. Moreover, Hh signaling is associated with several other signaling pathways that contribute to cancer progression. These observations indicate that controlling Hh signaling might become a target for novel molecular targeting therapy. PMID- 21679343 TI - Characterization of a reproducible gastric pain model using oral capsaicin titration in healthy volunteers. AB - BACKGROUND: Sensory sensitization is one of the main pathophysiological hypotheses in functional gastrointestinal disorders (FGIDs). As sensitization may affect various sensory modalities, we aimed to develop a reproducible gastric pain model utilizing polymodal pathways for use in functional and other pain disorders. METHODS: In this double-blind, cross-over study 42 healthy subjects swallowed one capsule containing either capsaicin 0.5mg or nocebo every 15min until moderate pain (intensity >30 on 100mm visual analogue scale) was attained for at least 5min. Pain was rated every minute. Capsaicin titration was repeated thrice for reliability calculation. KEY RESULTS: Moderate pain in the upper abdomen was successfully achieved in 38 of 42 subjects (90%) with capsaicin titration and in one of 42 (2%) with nocebo. The median dosage required to induce moderate pain for at least 5min was two capsules (interquartile range 1-3) and the median gastric pain intensity was 47 (41-53). The median duration of moderate pain was 8min (5-12). Moderate pain was successfully reproduced with capsaicin in all subjects on study days 2 and 3, with an excellent Cronbach reliability coefficient of >0.8. CONCLUSIONS & INFERENCES: Standardized gastric pain can be conveniently achieved in a majority of healthy subjects using a simple oral capsaicin titration, with minimal adverse events. The between-test reproducibility is high and nocebo responses are negligible. This technique stimulating a multimodal physiological pathway will be useful in the investigation of sensory changes in FGIDs, including functional dyspepsia. PMID- 21679344 TI - Detection and signaling of glucose in the intestinal mucosa--vagal pathway. AB - Intestinal luminal exposure to glucose initiates changes in food intake and gastrointestinal (GI) motor and secretory function. It does this by stimulating the release of GI hormones and 5-hydroxytryptamine (5-HT) from enteroendocrine and enterochromaffin cells (EC), respectively, which in turn activate intrinsic and extrinsic neuronal pathways. An article in this issue of the journal provides new insight into the mechanisms involved in luminal glucose sensing. Vincent et al. have used a novel in vivo technique to determine activation of gut epithelial cells and vagal afferent pathways in rats by staining for activated calcium calmodulin kinase II (pCaMKII) along the pathway. In the mucosa, they found that intraluminal glucose activated EC cells and brush cells. At the next stage, pCaMKII was seen in neurons of the myenteric plexus and vagal afferent neurons in the nodose ganglia. In the central nervous system (CNS), activation was seen in second- and higher-order neurons in the dorsal vagal complex and hypothalamus. They found that 5-HT(3) receptors were involved in initiating neural signaling as activation of neurons, but not EC cells, was reduced by 5-HT(3) receptor antagonism. Selectively stimulating the sodium-glucose cotransporter (SGLT-3) had similar effects to glucose. This suggests that SGLT-3 behaves as a glucose sensor, mainly on EC cells, inducing the release of 5-HT, which activates 5-HT(3) receptors on vagal afferent endings nearby and in turn, their connections in the CNS. There is evidence elsewhere that other sensors and transmitter mechanisms are involved in this pathway, so the possibility exists of multiple redundant systems. PMID- 21679347 TI - Small airway disease in asthma: a need for awareness in patients and doctors. PMID- 21679348 TI - Relation between physical capacity, nutritional status and systemic inflammation in COPD. AB - BACKGROUND: Decreased physical capacity, weight loss, fat-free mass depletion and systemic inflammation are frequently observed in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: Our aim was to examine relations between physical capacity, nutritional status, systemic inflammation and disease severity in COPD. METHOD: Forty nine patients with moderate to severe COPD were included in the study. Spirometry was preformed. Physical capacity was determined by a progressive symptom limited cycle ergo meter test, incremental shuttle walking test, 12-minute walk distance and hand grip strength test. Nutritional status was investigated by anthropometric measurements, (weight, height, arm and leg circumferences and skinfold thickness) and bioelectrical impedance assessment was performed. Blood samples were analyzed for C-reactive protein (CRP) and fibrinogen. RESULT: Working capacity was positively related to forced expiratory volume in 1 s (FEV(1) ) (p < 0.001), body mass index and fat free mass index (p = 0.01) and negatively related to CRP (p = 0.02) and fibrinogen (p = 0.03). Incremental shuttle walk test was positively related to FEV(1) (p < 0.001) and negatively to CRP (p = 0.048). Hand grip strength was positively related to fat free mass index, and arm and leg circumferences. Fifty to 76% of the variation in physical capacity was accounted for when age, gender, FEV(1) , fat free mass index and CRP were combined in a multiple regression model. CONCLUSION: Physical capacity in chronic obstructive pulmonary disease is related to lung function, body composition and systemic inflammation. A depiction of all three aspects of the disease might be important when targeting interventions in chronic obstructive pulmonary disease. PMID- 21679349 TI - Short-term prognosis of occupational asthma in a Finnish population. AB - BACKGROUND: Causative agents of occupational asthma (OA) are well described in literature but far less is known about factors affecting the outcome of OA. Short duration of exposure, early diagnosis when symptoms appear and further avoidance of exposure have been suggested as good prognostic factors. This study was designed to investigate a short-term outcome of OA. METHODS: The medical records of 47 Caucasian patients from a Finnish population diagnosed with OA in year 2003 were reviewed retrospectively. Employment status at 6-month follow-up of all patients was determined. We assessed the following potential predictors of unemployment at follow-up: the causative agents of OA, asthma medication, spirometry results, smoking status, gender, age, occupation, atopy status, bronchial hyperresponsiveness and time to diagnosis. We calculated odd ratios (ORs) to predict employment status at follow-up. RESULTS: At the follow-up examination, 23 persons (49%) were not working. At the time of follow-up there were no significant differences in pulmonary function between those employed and those who discontinued to work. Atopy at baseline predicted diminished lung function at the 6-month follow-up. In addition, atopy was the only prognostic factor and was inversely related to the work discontinuation at the follow-up [OR 0.18, 95% confidence interval (CI) 0.04-0.79]. Work continuation as an OA outcome at 6 months could not be predicted by gender, age, occupational status, exposure antigen, smoking habits or duration of symptoms before diagnosis. CONCLUSIONS: The socio-economic short-term prognosis of OA was relatively poor since half of the patients were not at work at the 6 months follow-up. PMID- 21679350 TI - Repeated high-dose inhalation allergen challenge in asthma. AB - INTRODUCTION: Inhalation allergen challenge in humans is used to investigate lung pathophysiology and responses to novel therapies. However, the single high-dose allergen challenges that are commonly performed do not mimic repeated symptomatic environmental allergen exposure. OBJECTIVES: To develop and evaluate the safety of a repeated high-dose symptomatic inhalation allergen challenge model. METHODS: Sixteen subjects with atopic asthma were recruited. Each underwent three inhalation allergen challenges using house dust mite (Dermatophagoides pteronyssinus) antigen at 48-h intervals with a target of symptom induction and an early asthmatic reaction fall in forced expiratory volume in 1 s (FEV(1) ) of 15% from baseline. RESULTS: All of the subjects completed the three-challenge protocol and the target immediate airway bronchoconstrictor response was achieved in all the subjects at all challenges. There were no adverse events recorded. The early asthmatic reaction was similar for the three challenges whether measured as mean maximal fall in FEV(1) or mean area under the curve. The late asthmatic reaction was also similar over the three challenges with no evidence of priming or desensitisation. Symptom scores and reliever medication use significantly increased over the time of the challenges. Baseline lung function and reversibility was unchanged 4 days after the last challenge. CONCLUSION: We demonstrate that repeated high-dose inhaled house dust mite allergen challenge in human volunteers with mild asthma is safe, repeatable and acceptable. This allows the use of this model in further studies focused on understanding the pathophysiology of allergen induced asthma and the impact of therapeutic interventions. PMID- 21679351 TI - Fatigue and plasma cytokine concentrations at rest and during exercise in patients with sarcoidosis. AB - BACKGROUND: Patients with sarcoidosis exhibit exercise intolerance-related fatigue and increased levels of circulating proinflammatory cytokines at rest. Exercise may result in increased plasma cytokine levels (PCLs) in healthy adults, but such a relationship has not been studied in sarcoidosis patients. OBJECTIVES: To assess relationship of fatigue in sarcoidosis with PCLs at rest and with cardiopulmonary exercise testing (CPET). METHODS: We assessed lung function, CPET data, multidimensional fatigue inventory, plasma tumor necrosis factor-alpha (TNF alpha) and interleukin-1beta (IL-1beta) concentrations before, immediately after, and 4-6 h following CPET in 22 sarcoidosis patients (13 receiving immunomodulatory drugs) and 22 controls. RESULTS: Patients exhibited greater fatigue, reduced cardiorespiratory function, higher Medical Research Council (MRC) scores and higher plasma TNF-alpha concentrations than controls at all times. Plasma IL-1beta levels did not differ between cohorts. Patients exhibited a 28% increase (statistically not significant) in TNF-alpha level immediately post exercise. Plasma IL-beta concentrations did not change among cohorts. Treated patients exhibited higher MRC and physical fatigue scores and lower breathing reserve, but no differences in cardiorespiratory function or PCLs compared to untreated patients. In treated patients, pre-exercise plasma IL-1beta correlated with physical fatigue, reduced motivation and total fatigue; TNF-alpha levels only correlated with general fatigue score. CONCLUSION: Treated sarcoidosis patients exhibit a relation between physical fatigue, reduced motivation and total fatigue and pre-exercise plasma IL-1beta concentrations. Acute exercise does not increase PCLs. Whether the reduced MRC score and physical fatigue in treated patients is related to the therapy or to the underlying inflammatory process is difficult to determine. PMID- 21679352 TI - Prevalence of sleep apnoea in diabetic patients. AB - BACKGROUND: Diabetes and obstructive sleep apnoea (OSA) syndrome share a high prevalence in industrialized nations. The presence of OSA seems to promote the development of diabetes mellitus (DM) and vice versa. MATERIALS AND METHODS: In order to assess the prevalence of sleep disordered breathing, we studied 498 patients with DM type 2 and 58 patients with DM type 1 from 15 centres, using a screening device determining airflow and pulse oximetry. Age of the patients was 59.9 +/- 13.1 years, mean body mass index was 31.9 +/- 6.9 kg/m(2) . Duration of diagnosis of DM was 9.3 +/- 7.3 years. RESULTS: Among the patients, 37.4% had an apnoea-hypopnoea index (AHI) >=15/h suggestive of OSA. The prevalence of an AHI >= 15/h among the patients with DM type 1 was 10.3%. One hundred ninety-three (35.2%) patients suffered from neuropathy. We found a higher prevalence for neuropathy, nephropathy, hypertension, cardiovascular disease and heart failure in the group with an AHI >= 15/h. CONCLUSIONS: The prevalence of sleep disordered breathing is increased in patients with DM. Most of these patients had no typical clinical symptoms of OSA and would have been undiagnosed without diagnostic assessment of OSA. PMID- 21679353 TI - Budesonide/formoterol maintenance and reliever therapy versus conventional best standard treatment in asthma in an attempted 'real life' setting. AB - AIMS: The purpose of this study was to compare the efficacy of budesonide/formoterol maintenance and reliever therapy (Symbicort(r) SMART(r), AstraZeneca AB, Sodertalje, Sweden) with conventional best standard treatment (CBST) in patients with persistent asthma in an attempted 'real life' setting. METHODS: In total, 1835 patients from Denmark, Finland and Norway were randomized to 26 weeks treatment with budesonide/formoterol 160/4,5 ug twice daily plus budesonide/formoterol 160/4,5 ug for symptom relief or CBST according to the Global Initiative for Asthma guidelines. The study was randomized, open-label and designed to reflect 'real life' asthma management. Efficacy variables were time to first severe asthma exacerbation, rate of severe asthma exacerbations, asthma control (Asthma Control Questionnaire-5) and use of inhaled glucocorticosteroids (IGCS). RESULTS: Treatment with budesonide/formoterol maintenance and reliever therapy led to a 21% reduction in time to first severe asthma exacerbation compared with CBST, although not statistically significant (hazard ratio 0.794, P = 0.189). A trend towards a reduction in the rate of severe exacerbations in the budesonide/formoterol maintenance and reliever therapy group was observed (16 vs 22 events/100 patient years; P = 0.058). The percentage of patients with well controlled asthma increased significantly among those treated with budesonide/formoterol maintenance and reliever therapy compared with CBST (45% vs 40%; odds ratio 1.39; P < 0.01), in spite of a significant 31% reduction in total mean daily IGCS dose (P < 0.0001). No difference in mean as-needed medication use was seen (P = 0.98). All treatments were well tolerated. CONCLUSION: Budesonide/formoterol maintenance and reliever therapy resulted in a better overall asthma control with a significant lower daily IGCS dose compared with CBST. PMID- 21679354 TI - Palladium-alpha-lipoic acid complex attenuates alloxan-induced hyperglycemia and enhances the declined blood antioxidant status in diabetic rats. AB - BACKGROUND: Palladium alpha-lipoic acid (Pd-LA) complex has unique electronic and redox properties that appear to be the key to its physiological effectiveness. A proprietary liquid blend containing Pd-LA as the major component was demonstrated to be effective in improving the activities of mitochondrial enzymes in aged rats. METHODS: The Pd-LA complex was evaluated for its hypoglycemic effect against the alloxan-induced diabetic model, as well as in the oral glucose tolerance test in rats. The in vitro free radical scavenging activity of Pd-LA was also determined. RESULTS: Administration of Pd-LA (0.5 mL/kg; equivalent to 3.8 mg complexed alpha-lipoic acid/kg, p.o.) daily for 5 days to alloxan-induced diabetic animals significantly reduced the blood glucose level (P < 0.05). The blood antioxidant status in the diabetic animals was significantly improved by the treatment of Pd-LA (P < 0.05). Similarly, Pd-LA showed significant in vitro antioxidant activity in a concentration-dependent manner. CONCLUSIONS: Results of the study conclude that the Pd-LA complex is effective in lowering the blood glucose level and enhancing the declined antioxidant status in diabetic animals. Significant finding(s) of the study include: (i) Pd-LA significantly increased the tolerance of glucose and was also effective in ameliorating hyperglycemia induced by alloxan; (ii) Pd-LA significantly enhanced the activities of blood superoxide dismutase, catalase, glutathione peroxidase and level of glutathione in diabetic animals; and (iii) Pd-LA showed significant in vitro antioxidant activity. This study adds: The therapeutic efficiency of Pd-LA is demonstrated against declined antioxidant status as well as hyperglycemia associated with diabetes. PMID- 21679355 TI - Cerebrospinal fluid B-cell expansion in longitudinally extensive transverse myelitis associated with neuromyelitis optica immunoglobulin G. AB - A first episode of central nervous system (CNS) demyelination may represent heterogeneous entities such as acute disseminated encephalomyelitis, clinically isolated syndrome, neuromyelitis optica (NMO), or multiple sclerosis. As new immune therapies become available, it is increasingly important to make an early diagnosis. Autoantibodies such as NMO immunoglobulin G (IgG) and myelin oligodendrocyte glycoprotein IgG are increasingly being employed to define subgroups of CNS demyelination or guide treatment. Similarly, cerebrospinal fluid (CSF) immunophenotyping can demonstrate B-lymphocyte subpopulation expansion, which has been used to guide therapy in other autoimmune CNS disorders. We present a report on a 15-year-old male with longitudinally extensive transverse myelitis with magnetic resonance imaging findings of oedema, cavitation, and gadolinium enhancement. NMO-IgG and aquaporin 4 IgG were positive; thus, we diagnosed a limited form of NMO. Acute CSF immunophenotyping revealed a 3.6% expansion of CD19 B-cell populations, whereas a comparison group of five children (4 males, age range 2-15y; mean age 7y) with other neurological disorders showed only a 0.51% expansion (SD 0.25%). In view of the diagnosis of a 'limited form of neuromyelitis optica', we therefore elected to treat him aggressively from the outset with a prolonged steroid regimen and mycophenylate mofetil. This case demonstrates a correlation between autoantibody production and CSF B lymphocyte expansion in an individual with CNS demyelination. These approaches could be used in individuals with a first episode of CNS demyelination to help delineate immunological subgroups and guide treatment. PMID- 21679356 TI - Going with the flow: neuroinflammation. PMID- 21679358 TI - 'Causal relation between spasticity, strength, gross motor function, and functional outcome in children with cerebral palsy: a path analysis'. PMID- 21679357 TI - Effects of a supported speed treadmill training exercise program on impairment and function for children with cerebral palsy. AB - AIM: To compare the effects of a supported speed treadmill training exercise program (SSTTEP) with exercise on spasticity, strength, motor control, gait spatiotemporal parameters, gross motor skills, and physical function. METHOD: Twenty-six children (14 males, 12 females; mean age 9y 6mo, SD 2y 2mo) with spastic cerebral palsy (CP; diplegia, n=12; triplegia, n=2; quadriplegia n=12; Gross Motor Function Classification System levels II-IV) were randomly assigned to the SSTTEP or exercise (strengthening) group. After a twice daily, 2-week induction, children continued the intervention at home 5 days a week for 10 weeks. Data collected at baseline, after 12-weeks' intervention, and 4 weeks after the intervention stopped included spasticity, motor control, and strength; gait spatiotemporal parameters; Gross Motor Function Measure (GMFM); and Pediatric Outcomes Data Collection Instrument (PODCI). RESULTS: Gait speed, cadence, and PODCI global scores improved, with no difference between groups. No significant changes were seen in spasticity, strength, motor control, GMFM scores, or PODCI transfers and mobility. Post-hoc testing showed that gains in gait speed and PODCI global scores were maintained in the SSTTEP group after withdrawal of the intervention. INTERPRETATION: Although our hypothesis that the SSTTEP group would have better outcomes was not supported, results are encouraging as children in both groups showed changes in function and gait. Only the SSTTEP group maintained gains after withdrawal of intervention. PMID- 21679359 TI - Functional decline in children undergoing selective dorsal rhizotomy after age 10. AB - AIM: To compare function and gait in a group of children older than most children who received selective dorsal rhizotomy (SDR) with age- and function-matched peers who received either orthopedic surgery or no surgical intervention. METHOD: A retrospective study examined ambulatory children with diplegic cerebral palsy, aged between 10 years and 20 years and categorized in Gross Motor Function Classification System (GMFCS) levels I or II. Three groups were considered: (1) children who had selective dorsal rhizotomy (n=8; two females, six males; mean age 15y 4mo at SDR, 16y 8mo at follow-up); (2) children who had orthopedic surgery (n=9; three females, six males; mean age 14y 6mo at SDR, 15y 1mo at follow-up), and (3) children who had no surgical intervention (n=9; two females, seven males; mean age 15y 6mo at follow-up). Longitudinal measures of gait analysis (velocity, gait deviation index, and gait variable scores) and gross motor function (GMFCS level, Gross Motor Function Measure scores, and centiles) were examined. RESULTS: No significant differences were found between changes in gait comparing rhizotomy with orthopedic surgery; however, the group who received orthopedic surgery demonstrated improved gait compared with the group without surgical intervention. Longitudinal comparisons of gross motor function demonstrated a decrease in the group who received SDR. Between-group analysis of outcomes also demonstrated worse outcomes of the SDR group compared with the orthopedic surgery group and with the no surgical intervention group. INTERPRETATION: Rhizotomy in older children was associated with functional declines compared with similar children who had no surgery and with those who underwent orthopedic surgery. This suggests that age greater than 10 years might be a contraindication for SDR if the goal is to improve motor skills. PMID- 21679360 TI - Sequencing revolution. PMID- 21679361 TI - Predictive validity of Prechtl's Method on the Qualitative Assessment of General Movements: a systematic review of the evidence. AB - AIM: The aim of this systematic review was to examine the evidence for the predictive validity of Prechtl's Method on the Qualitative Assessment of General Movements (GMsA) with respect to neurodevelopmental outcomes. METHOD: Six electronic databases (PsychINFO, Embase, Health and Psychosocial Instruments, PubMed, and AMED) were searched using the following keywords to identify all studies that examined the predictive validity of the GMsA: 'general movements', 'assessment', 'movement', 'child development', 'infant', and 'predictive value of test'. Only English- and French-language studies were included, whereas studies that focused on spontaneous mobility in preterm infants, but not necessarily the GMsA, or which did not report on the predictive value of the GMsA were excluded. A total of 39 studies were included in the final analysis. RESULTS: Studies were separated according to the age at follow-up: 12 to 23 months, 2 to 3, 4 to 11, and 12 to 18 years. All used a longitudinal cohort study design; however, the outcome measures differed greatly amongst the studies. Values for sensitivity, specificity, positive predictive value, and negative predictive value varied amongst studies. The overall trend indicated that the presence of abnormalities in the quality of fidgety movements at 12 weeks adjusted age is more predictive of adverse outcomes than abnormal writhing movements. INTERPRETATION: The GMsA demonstrates potential as a cost-effective, non-intrusive means of infant examination. However, current studies include important sources of bias. Future methodologically rigorous studies with functional outcomes are suggested. PMID- 21679362 TI - The relationship between group A streptococcal infections and Tourette syndrome: a study on a large service-based cohort. AB - AIM: To evaluate the relationship between diagnosis and clinical course of Tourette syndrome and group A Streptococcus (GAS). METHOD: GAS infections, anti streptococcal, and anti-basal ganglia antibodies (ABGA) were compared between 168 patients (136 males, 32 females) with Tourette syndrome; (median [range] age [25th-75th centile] 10y [8-11y]); median Tourette syndrome duration (25th-75th centile), 3y (1y 3mo-5y 9mo) and a comparison group of 177 patients (117 males, 60 females) with epileptic or sleep disorders median age [25th-75th centile], 10y [8y-1y 6mo]). One hundred and forty-four patients with Tourette syndrome were followed up at 3-month intervals; exacerbations of tics, obsessive-compulsive symptoms, and other psychiatric comorbidities were defined by a bootstrap procedure. The effect of new GAS infections and identification of new ABGA upon risk of exacerbation was assessed using logistic regression analysis. RESULTS: Cross-sectionally, patients with Tourette syndrome exhibited a higher frequency of GAS infection (8% vs 2%; p=0.009), higher anti-streptolysin O (ASO) titres (246 [108-432] vs 125 [53-269]; p<0.001), and higher ABGA frequency (25% vs 8%; p<0.001) than the comparison group. On prospective analysis, ASO titres were persistently elevated in 57% of patients with Tourette syndrome; however, new infections or newly identified ABGA did not predict clinical exacerbations (all p>0.05). INTERPRETATION: Patients with Tourette syndrome might be more prone to GAS infections and develop stronger antibody responses to GAS, probably as a result of underlying immune dysregulation. New GAS infections are unlikely to exert, years after their onset, a major effect upon the severity of neuropsychiatric symptoms. PMID- 21679363 TI - Functional decline in children undergoing selective dorsal rhizotomy after age 10. PMID- 21679364 TI - The relationship between group A streptococcal infections and Tourette syndrome. PMID- 21679365 TI - The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders. AB - A group of disorders with disparate symptomatology, including congenital cerebellar ataxia, retinal blindness, liver fibrosis, polycystic kidney disease, and polydactyly, have recently been united under a single disease mechanism called 'ciliopathies'. The ciliopathies are due to defects of the cellular antenna known as the primary cilium, a microtubule-based extension of cellular membranes found in nearly all cell types. Key among these ciliopathies is Joubert syndrome, displaying ataxia, oculomotor apraxia, and mental retardation* with a pathognomonic 'molar tooth sign' on brain magnetic resonance imaging. The importance of ciliary function in neuronal development has been appreciated only in the last decade with the classification of Joubert syndrome as a ciliopathy. This, together with the identification of many of the clinical features of ciliopathies in individuals with Joubert syndrome and the localization of Joubert syndrome's causative gene products at or near the primary cilium, have defined a new class of neurological disease. Cilia are involved in diverse cellular processes including protein trafficking, photoreception, embryonic axis patterning, and cell cycle regulation. Ciliary dysfunction can affect a single tissue or manifest as multi-organ involvement. Ciliary defects have been described in retinopathies such as retinitis pigmentosa and Leber congenital amaurosis (defects in photoreceptor ciliary protein complexes), renal syndromes with nephronophthisis and cystic dysplastic kidneys, and liver conditions such as fibrosis and biliary cirrhosis. Recognizing the diverse presentations of the ciliopathies and screening strategies following diagnosis is an important part of the treatment plan of children with cilia-related disorders. PMID- 21679366 TI - Effects of a home-based treadmill training exercise program on impairment and function. PMID- 21679367 TI - The Deciphering Developmental Disorders (DDD) study. PMID- 21679368 TI - Cross-sectional study on the correlation of serum uric acid with disease severity in Korean patients with psoriasis. AB - BACKGROUND: Hyperuricaemia is a common finding in patients with psoriasis. However, previous studies have reported inconsistent results about the association between serum uric acid concentration (SUAC) and psoriasis severity. Recent studies have also reported that SUAC is associated with metabolic dysregulation. AIM: To assess any association between SUAC and clinical features of psoriasis, and to investigate the characteristics of patients with psoriasis with hyperuricaemia compared with similar patients with normouricaemia. METHODS: Cross-sectional data from 198 Korean patients with psoriasis who visited our clinic were analysed. Association of SUAC with clinical features of psoriasis, body mass index (BMI) and various laboratory values was assessed in both genders separately. RESULTS: The average uric acid concentration of patients with psoriasis was not significantly different from that of the healthy population, for both genders (P > 0.05). There was a positive correlation between SUAC and Psoriasis Area and Severity Index (PASI) and BMI in patients with psoriasis (P < 0.05). There was no association with age of disease onset, family history of psoriasis, or other laboratory values (P > 0.05), in either gender. Of the other factors of disease severity, the extent of body surface involvement was correlated with uric acid concentration (P < 0.05) although there was no significant relationship with activity of individual lesions (P > 0.05). Mean PASI and extent of psoriasis were increased in hyperuricaemic compared with normouricaemic patients (P < 0.05). CONCLUSIONS: SUAC in patients with psoriasis is positively associated with PASI, extent of skin involvement and BMI for both genders independently. PMID- 21679369 TI - Histiocytoid Sweet syndrome. PMID- 21679370 TI - Tender erythematous papules on the elbows, buttocks and knees. PMID- 21679373 TI - Influenza A (H1N1) 2009 pandemic: was there a difference in the two waves in patients requiring admission to the intensive-care unit? AB - Influenza virus is prone to mutations that may alter the intensity of subsequent waves of infection. In this study, we evaluated whether outcomes were different in the two waves of the influenza A (H1N1) 2009 pandemic in patients admitted to the intensive-care unit. Age, gender, lag-time to presentation and APACHE-II scores were similar in both waves. Although ventilatory requirements were similar (36/37 vs. 36/39), non-significant reductions in the durations (days) of ventilation (10.3 +/- 8.0 vs. 7.8 +/- 9.4, p 0.11) and hospitalization (14.9 +/- 10.5 vs. 12.3 +/- 14.1, p 0.20) were observed in the second wave. The clinical profile and outcomes were not significantly different between the two waves among severely ill patients. PMID- 21679374 TI - Structure-based virtual screening of glycogen synthase kinase 3beta inhibitors: analysis of scoring functions applied to large true actives and decoy sets. AB - Comparative assessment of nine different scoring functions (OpenEye and Tripos implementation) applied to structure-based virtual screening based on rigid docking of the pregenerated conformations library of glycogen synthase kinase 3beta (GSK-3beta) inhibitors has been carried out. The functions studied belong to the following types: Gaussian (Chemgauss3, Shapegauss), empirical (Chemscore, OEChemscore, Piecewise Linear Potential, Screenscore), force field-based (D_score and G_score), and potential of mean force (PMF_score). Overall enrichment of the large true inhibitors set against the set of true non-inhibitors, Directory of Useful Decoys (DUD), cyclin-dependent kinase 2 subset, and NCI Diversity Set was evaluated by means of ROC (receiver operating characteristic) method. According to this analysis, scoring function Chemscore leads to the best enrichment of the inhibitors whereas the best early enrichment of the actives may be obtained with the help of Chemgauss3 function as estimated by BEDROC (Boltzmann-enhanced discrimination of ROC) metrics. PMID- 21679375 TI - Discovery of new antifungal leads via pharmacophore modeling and QSAR analysis of fungal N-myristoyl transferase inhibitors followed by in silico screening. AB - N-Myristoyl transferase is an essential enzyme for fungal growth and survival. The continuous interest in the development of new antifungal agents prompted recent interest in developing new potent inhibitors of fungal N-myristoyl transferase. In this context, we combined pharmacophore and QSAR modeling to explore the structural requirements for potent N-myristoyl transferase inhibitors employing 55 known N-myristoyl transferase ligands. Four binding pharmacophore models emerged in the optimal QSAR equations (R(2)(44) = 0.81-0.83, F-statistic = 47.89-58.83, r(2)(L00)= 0.77-0.80, against 11 external test inhibitors = 0.61 0.71). The successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve profiles. The QSAR equations and their associated pharmacophore models were validated by the identification and experimental evaluation of new promising antifungal leads retrieved from the NCI database and our in-house-built database of established drugs and agrochemicals. PMID- 21679376 TI - Foreword: Lesson learning about getting research into policy and practice. AB - FOREWORD: The UK Department for International Development (DFID) is committed to investing in research to combat poverty, reduce high mortality and morbidity in resource poor contexts and support progress towards meeting the Millennium Development Goals. Research helps us to identify what works, what does not work and how to understand the local context when introducing new ways of working. There is no point doing research if the findings do not get into policy and practice. DFID strongly encourages all research programmes to consider research uptake activities as an integral part of the research.This special supplement draws on the work of the Sexual Health HIV Evidence into Practice (SHHEP) initiative. SHHEP is a collaboration across four DFID Research Programme Consortia (RPC) that undertake research and action on HIV and Sexual and Reproductive Health in resource poor contexts. Each consortium consists of 5 or more research, advocacy or service provider institutions from the south and the north working together over a five year period on critical areas of sexual and reproductive health. The essence of SHHEP is to share learning on research uptake and research engagement in Sexual and Reproductive Health, including HIV. The group has formulated a range of targeted mechanisms to communicate health research to different audiences and spearhead change, and were finalists for the British Medical Journal 2010 Getting Research into Practice (GRiP) prize.The papers in this special supplement focus on lesson learning on getting research into policy and practice. They highlight the range of methodologies and approaches researchers and communication specialists have used in different contexts to try to ensure research does not simply gather dust on library shelves but feeds into and is relevant to policy and practice in different contexts (for example South Africa, Swaziland, Tanzania, Uganda, Malawi, Ghana, Bangladesh) and on a diversity of topic areas (Gender based violence, sexualities, orphans and vulnerable children, HIV care and treatment including male circumcision, cotrimoxazole and links with nutrition).The work reported in this supplement provides examples of approaches that have been tried and from which other researchers can learn. They demonstrate that getting research into policy and practice is complex, dynamic and multi-faceted; and a wide range of context and issue specific conceptual and practical approaches have to be used. I hope that the innovative approaches and promising ways forward, presented in these papers, will inspire and motivate others.Professor Christopher WhittyDirector Research and Evidence DivisionDepartment for International DevelopmentDr Sue KinnHead of Health ResearchDepartment for International Development. PMID- 21679377 TI - Using research to influence sexual and reproductive health practice and implementation in Sub-Saharan Africa: a case-study analysis. AB - BACKGROUND: Research institutions and donor organizations are giving growing attention to how research evidence is communicated to influence policy. In the area of sexual and reproductive health (SRH) and HIV there is less weight given to understanding how evidence is successfully translated into practice. Policy issues in SRH can be controversial, influenced by political factors and shaped by context such as religion, ethnicity, gender and sexuality. METHODS: The case studies presented in this paper analyse findings from SRH/HIV research programmes in sub-Saharan Africa: 1) Maternal syphilis screening in Ghana, 2) Legislative change for sexual violence survivors In Ghana, 3) Male circumcision policy in South Africa, and 4) Male circumcision policy in Tanzania. Our analysis draws on two frameworks, Sumner et al's synthesis approach and Nutley's research use continuum. RESULTS: The analysis emphasises the relationships and communications involved in using research to influence policy and practice and recognises a distinction whereby practice is not necessarily influenced as a result of policy change - especially in SRH - where there are complex interactions between policy actors. CONCLUSION: Both frameworks demonstrate how policy networks, partnership and advocacy are critical in shaping the extent to which research is used and the importance of on-going and continuous links between a range of actors to maximize research impact on policy uptake and implementation. The case-studies illustrate the importance of long-term engagement between researchers and policy makers and how to use evidence to develop policies which are sensitive to context: political, cultural and practical. PMID- 21679378 TI - Playing the role of a 'boundary organisation': getting smarter with networking. AB - BACKGROUND: This paper discusses the practices of organisations that cross the boundary between research and politics, to promote evidence-based policies and programmes. METHODS: It uses the experience of a network of organisations in Africa to describe the methodology, challenges and successes of efforts to promote utilisation of research on the inter-connections between HIV/AIDS, food security and nutrition in South Africa. It emphasises that crossing the boundary between science and politics can be done systematically and is inevitable for any attempt that seeks influence policy making. RESULTS: The paper reveals the complexity of the research-policy making interface and identifies key lessons for the practice of networking and engaging policy and decision-makers. CONCLUSION: The concept of boundary organisation is a helpful means to understand the methodological underpinnings of efforts to get research into policy and practice and to understand the 'messy' process of doing so. PMID- 21679379 TI - Creating a public space and dialogue on sexuality and rights: a case study from Bangladesh. AB - This article describes and analyses a research based engagement by a university school of public health in Bangladesh aimed at raising public debate on sexuality and rights and making issues such as discrimination more visible to policy makers and other key stakeholders in a challenging context. The impetus for this work came from participation in an international research programme with a particular interest in bridging international and local understandings of sexual and reproductive rights. The research team worked to create a platform to broaden discussions on sexuality and rights by building on a number of research activities on rural and urban men's and women's sexual health concerns, and on changing concepts of sexuality and understandings of sexual rights among specific population groups in Dhaka city, including sexual minorities. Linked to this on going process of improving the evidence base, there has been a series of learning and capacity building activities over the last four years consisting of training workshops, meetings, conferences and dialogues. These brought together different configurations of stakeholders - members of sexual minorities, academics, service providers, advocacy organisations, media and policy makers. This process contributed to developing more effective advocacy strategies through challenging representations of sexuality and rights in the public domain. Gradually, these efforts brought visibility to hidden or stigmatised sexuality and rights issues through interim outcomes that have created important steps towards changing attitudes and policies. These included creating safe spaces for sexual minorities to meet and strategise, development of learning materials for university students and engagement with legal rights groups on sexual rights. Through this process, it was found to be possible to create a public space and dialogue on sexuality and rights in a conservative and challenging environment like Bangladesh by bringing together a diverse group of stakeholders to successfully challenge representations of sexuality in the public arena. A further challenge for BRAC University has been to assess its role as a teaching and research organisation, and find a balance between the two roles of research and activism in doing work on sexuality issues in a very sensitive political context. PMID- 21679380 TI - Strange bedfellows: bridging the worlds of academia, public health and the sex industry to improve sexual health outcomes. AB - The public health response to sexually transmitted infections, particularly HIV, has been and continues to be overwhelmingly focused on risk, disease and negative outcomes of sex, while avoiding discussion of positive motivations for sex (e.g. pleasure, desire, love). Recent advocacy efforts have challenged this approach and organisations have promoted the eroticisation of safer sex, especially in the context of HIV prevention.This paper is a case study of one of these organizations - The Pleasure Project. It gives a brief background on the public health approach to sex and sexual health, and recommends an alternative approach which incorporates constructs of pleasure and desire into sexual health interventions. The Pleasure Project's aims and unorthodox communications strategies are described, as are the response to and impact of its work, lessons learned and ongoing challenges to its approach.The Pleasure Project combines evidence (rigorous and experimental as well as qualitative and anecdotal) with experiential knowledge from the sex industry and safer-sex promotion to communicate messages about eroticising safer sex to influence researchers, public health practitioners and policymakers, mainstream media and the porn world. There are significant barriers to this work, because it challenges common and entrenched norms and values related to sex and pleasure and their role in the public health sphere. Other barriers include: the limited range of existing rigorous intervention trials which incorporate pleasure constructs; the lack of effective indicators to measure pleasure constructs; limited funding and resources; discomfort among public health practitioners, researchers and donors with concepts of pleasure and sex; and rejection of erotic media as a potential tool for prevention.Despite the backdrop of sex-negative public health practice, there is anecdotal evidence that safer sex, including condom use, can be eroticised and made pleasurable, based on qualitative research by The Pleasure Project and other like-minded organisations. Yet there is a need for more research on the effectiveness of pleasure components in sexual health interventions, particularly in high-risk contexts. This need has become urgent as practitioners look for new ways to promote sexual health and as new prevention technologies (including female condoms and microbicides) are introduced or disseminated. PMID- 21679381 TI - Challenges in linking health research to policy: a commentary on developing a multi-stakeholder response to orphans and vulnerable children in Ghana. AB - The Research and Development Division (RDD) of the Ghana Health Service (GHS) has a remit to build research capacity and conduct policy relevant research. By being situated within the GHS, RDD has good access to directors and programme managers, within and beyond the Ministry of Health. This structure has been facilitating collaboration through research cycles for 20 years, from agenda setting to discussions on policy relevance.This approach has been applied to research activities within the Addressing the Balance of Burden in AIDS (ABBA) Research Programme Consortium to tackle the challenges facing HIV affected orphans and vulnerable children (OVCs). The government strategy on OVCs recommends they should be encouraged to live in their home communities rather than in institutions. We present lessons here on efforts to use research to build a response across different agencies to address the problems that communities and families face in caring for these children in their communities.This approach to building consensus on research priorities points to the value of collaboration and dialogue with multiple stakeholders as a means of fostering ownership of a research process and supporting the relevance of research to different groups. Our experience has shown that if the context within which researchers, policy makers and stakeholders work were better understood, the links between them were improved and research were communicated more effectively, then better policy making which links across different sectors may follow. At the same time, collaboration among these different stakeholders to ensure that research meets social needs, must also satisfy the requirements of scientific rigour. PMID- 21679382 TI - Designing and implementing a communications strategy: lessons learnt from HIV and Sexual and Reproductive Health Research Programme Consortia. AB - In recent years there has been increasing recognition of the importance of strategic research communication. Health research organisations need to be able to communicate their research effectively to increase the probability that the findings influence policy and practice, and benefit those in greatest need. Many research funders are making communications a requirement of research funding. This paper reflects on the experience in developing and implementing communications strategies of several Research Programme Consortia funded by the Department for International Development.Different research topics will require different communications approaches in order to be effective. This is reflected in the diversity of strategies employed by different research programmes. Strategic research communications designed to influence policy and practice require different skills and expertise from those required for carrying out research and writing it up for publication in academic journals. Therefore researchers involved in communicating research should be supported in this work. One of the ways in which research programme consortia have sought to do this is through convening workshops to develop the communications skills of researchers from partner organisations. These have proven invaluable. Another way of providing ongoing support to those involved in communicating research is through a Communications Community of Practice. Where this has been used it has proven a good way to support researchers both with ideas and resources, but also a strong sense of belonging to a community that shares a common concern with communication. Developing strong partnerships with research users, other research organisations, knowledge intermediaries and other stakeholders is vital for effective communication.Embracing the challenges and opportunities presented by communicating research to influence policy practice is vital if research is to have maximum possible impact, and demonstrate its worth at a time when funding for health and development activities is at risk. Sharing lessons learnt in this process between research programmes is important to support this work. PMID- 21679383 TI - Strengthening the research to policy and practice interface: exploring strategies used by research organisations working on sexual and reproductive health and HIV/AIDS. AB - This commentary introduces the HARPS supplement on getting research into policy and practice in sexual and reproductive health (SRH). The papers in this supplement have been produced by the Sexual Health and HIV Evidence into Practice (SHHEP) collaboration of international research, practitioner and advocacy organizations based in research programmes funded by the UK Department for International Development.The commentary describes the increasing interest from research and communication practitioners, policy makers and funders in expanding the impact of research on policy and practice. It notes the need for contextually embedded understanding of ways to engage multiple stakeholders in the politicized, sensitive and often contested arenas of sexual and reproductive health. The commentary then introduces the papers under their respective themes: (1) The theory and practice of research engagement (two global papers); (2) Applying policy analysis to explore the role of research evidence in SRH and HIV/AIDS policy (two papers with examples from Ghana, Malawi, Uganda and Zambia); (3) Strategies and methodologies for engagement (five papers on Kenya, South Africa, Ghana, Tanzania and Swaziland respectively); (4) Advocacy and engagement to influence attitudes on controversial elements of sexual health (two papers, Bangladesh and global); and (5) Institutional approaches to inter-sectoral engagement for action and strengthening research communications (two papers, Ghana and global).The papers illustrate the many forms research impact can take in the field of sexual and reproductive health. This includes discursive changes through carving out legitimate spaces for public debate; content changes such as contributing to changing laws and practices, procedural changes such as influencing how data on SRH are collected, and behavioural changes through partnerships with civil society actors such as advocacy groups and journalists.The contributions to this supplement provide a body of critical analysis of communication and engagement strategies across the spectrum of SRH and HIV/AIDS research through the testing of different models for the research-to policy interface. They provide new insights on how researchers and communication specialists can respond to changing policy climates to create windows of opportunity for influence. PMID- 21679384 TI - What shapes research impact on policy? Understanding research uptake in sexual and reproductive health policy processes in resource poor contexts. AB - Assessing the impact that research evidence has on policy is complex. It involves consideration of conceptual issues of what determines research impact and policy change. There are also a range of methodological issues relating to the question of attribution and the counter-factual. The dynamics of SRH, HIV and AIDS, like many policy arenas, are partly generic and partly issue- and context-specific. Against this background, this article reviews some of the main conceptualisations of research impact on policy, including generic determinants of research impact identified across a range of settings, as well as the specificities of SRH in particular. We find that there is scope for greater cross-fertilisation of concepts, models and experiences between public health researchers and political scientists working in international development and research impact evaluation. We identify aspects of the policy landscape and drivers of policy change commonly occurring across multiple sectors and studies to create a framework that researchers can use to examine the influences on research uptake in specific settings, in order to guide attempts to ensure uptake of their findings. This framework has the advantage that distinguishes between pre-existing factors influencing uptake and the ways in which researchers can actively influence the policy landscape and promote research uptake through their policy engagement actions and strategies. We apply this framework to examples from the case study papers in this supplement, with specific discussion about the dynamics of SRH policy processes in resource poor contexts. We conclude by highlighting the need for continued multi-sectoral work on understanding and measuring research uptake and for prospective approaches to receive greater attention from policy analysts. PMID- 21679385 TI - Strategies and tensions in communicating research on sexual and reproductive health, HIV and AIDS: a qualitative study of the experiences of researchers and communications staff. AB - BACKGROUND: Sexual and Reproductive Health (SRH) and HIV issues are often controversial and neglected, leading to challenges with engaging policy actors. Research evidence is complex, posing further challenges for ensuring that policy and practice are evidence-based. Many health researchers are adopting innovative approaches to engaging stakeholders in their research, yet these experiences are not often shared. This qualitative study focuses on the research communication and policy influencing objectives, strategies and experiences of four research consortia working on SRH, HIV and AIDS. METHODS: We carried out 22 in-depth interviews with researchers and communications specialists (research actors) from the four consortia and their partners, working in nine countries in sub-Saharan Africa and Asia. Using the 'framework' approach to qualitative data analysis, we identified factors that affect the interaction of research evidence with policy and practice. We used the ODI RAPID analytical framework to present these results, adapting this tool by incorporating the actions, strategies and positionality of research actors. RESULTS: The characteristics of researchers and their institutions, policy context, the multiplicity of actors, and the nature of the research evidence all play a role in policy influencing processes. Research actors perceived a trend towards increasingly intensive and varied communication approaches. Effective influencing strategies include making strategic alliances and coalitions and framing research evidence in ways that are most attractive to particular policy audiences. Tensions include the need to identify and avoid unnecessary communication or unintended impacts, challenges in assessing and attributing impact and the need for adequate resources and skills for communications work. CONCLUSIONS: We contend that the adapted RAPID framework can serve as a tool for research actors to use in resolving these tensions, through facilitating a reflexive approach to considering their own combination of attributes, skills, networks and objectives and the ways these relate to policy contexts, actors and processes. PMID- 21679386 TI - Getting research into policy - Herpes simplex virus type-2 (HSV-2) treatment and HIV infection: international guidelines formulation and the case of Ghana. AB - BACKGROUND: Observational epidemiological and biological data indicate clear synergies between Herpes simplex virus type 2 (HSV-2) and HIV, whereby HSV-2 enhances the potential for HIV acquisition or transmission. In 2001, the World Health Organization (WHO) launched a call for research into the possibilities of disrupting this cofactor effect through the use of antiherpetic therapy. A WHO Expert Meeting was convened in 2008 to review the research results. The results of the trials were mostly inconclusive or showed no impact. However, the WHO syndromic management treatment guidelines were modified to include acyclovir as first line therapy to treat genital ulcer disease on the basis of the high prevalence of HSV-2 in most settings, impact and cost-benefit of treatment on ulcer healing and quality of life among patients. METHODS: This paper examines the process through which the evidence related to HIV-HSV-2 interactions influenced policy at the international level and then the mechanism of international to national policy transfer, with Ghana as a case study. To better understand the context within which national policy change occurs, special attention was paid to the relationships between researchers and policy-makers as integral to the process of getting evidence into policy. Data from this study were then collected through interviews conducted with researchers, program managers and policy-makers working in sexual health/STI at the 2008 WHO Expert Meeting in Montreux, Switzerland, and in Accra, Ghana. RESULTS: The major findings of this study indicate that investigations into HSV-2 as a cofactor of HIV generated the political will necessary to reform HSV-2 treatment policy. Playing a pivotal role at both the international level and within the Ghanaian policy context were 'policy networks' formed either formally (WHO) or informally (Ghana) around an issue area. These networks of professionals serve as the primary conduit of information between researchers and policy-makers. Donor influence was cited as the single strongest impetus and impediment to policy change nationally. CONCLUSIONS: Policy networks may serve as the primary driving force of change in both international context and in the case of Ghana. Communication among researchers and policy-makers is critical for uptake of evidence and opportunities may exist to formalize policy networks and engage donors in a productive and ethical way. PMID- 21679387 TI - National policy development for cotrimoxazole prophylaxis in Malawi, Uganda and Zambia: the relationship between Context, Evidence and Links. AB - BACKGROUND: Several frameworks have been constructed to analyse the factors which influence and shape the uptake of evidence into policy processes in resource poor settings, yet empirical analyses of health policy making in these settings are relatively rare. National policy making for cotrimoxazole (trimethoprim sulfamethoxazole) preventive therapy in developing countries offers a pertinent case for the application of a policy analysis lens. The provision of cotrimoxazole as a prophylaxis is an inexpensive and highly efficacious preventative intervention in HIV infected individuals, reducing both morbidity and mortality among adults and children with HIV/AIDS, yet evidence suggests that it has not been quickly or evenly scaled-up in resource poor settings. METHODS: Comparative analysis was conducted in Malawi, Uganda and Zambia, using the case study approach. We applied the 'RAPID' framework developed by the Overseas Development Institute (ODI), and conducted a total of 47 in-depth interviews across the three countries to examine the influence of context (including the influence of donor agencies), evidence (both local and international), and the links between researcher, policy makers and those seeking to influence the policy process. RESULTS: Each area of analysis was found to have an influence on the creation of national policy on cotrimoxazole preventive therapy (CPT) in all three countries. In relation to context, the following were found to be influential: government structures and their focus, donor interest and involvement, healthcare infrastructure and other uses of cotrimoxazole and related drugs in the country. In terms of the nature of the evidence, we found that how policy makers perceived the strength of evidence behind international recommendations was crucial (if evidence was considered weak then the recommendations were rejected). Further, local operational research results seem to have been taken up more quickly, while randomised controlled trials (the gold standard of clinical research) was not necessarily translated into policy so swiftly. Finally the links between different research and policy actors were of critical importance, with overlaps between researcher and policy maker networks crucial to facilitate knowledge transfer. Within these networks, in each country the policy development process relied on a powerful policy entrepreneur who helped get cotrimoxazole preventive therapy onto the policy agenda. CONCLUSIONS: This analysis underscores the importance of considering national level variables in the explanation of the uptake of evidence into national policy settings, and recognising how local policy makers interpret international evidence. Local priorities, the ways in which evidence was interpreted, and the nature of the links between policy makers and researchers could either drive or stall the policy process. Developing the understanding of these processes enables the explanation of the use (or non-use) of evidence in policy making, and potentially may help to shape future strategies to bridge the research-policy gaps and ultimately improve the uptake of evidence in decision making. PMID- 21679388 TI - Engaging media in communicating research on sexual and reproductive health and rights in sub-Saharan Africa: experiences and lessons learned. AB - BACKGROUND: The mass media have excellent potential to promote good sexual and reproductive health outcomes, but around the world, media often fail to prioritize sexual and reproductive health and rights issues or report them in an accurate manner. In sub-Saharan Africa media coverage of reproductive health issues is poor due to the weak capacity and motivation for reporting these issues by media practitioners. This paper describes the experiences of the African Population and Health Research Center and its partners in cultivating the interest and building the capacity of the media in evidence-based reporting of reproductive health issues in sub-Saharan Africa. METHODS: The paper utilizes a case study approach based primarily on the personal experiences and reflections of the authors (who played a central role in developing and implementing the Center's communication and policy engagement strategies), a survey that the Center carried out with science journalists in Kenya, and literature review. RESULTS: The African Population and Health Research Center's media strategy evolved over the years, moving beyond conventional ways of communicating research through the media via news releases and newspaper stories, to varying approaches that sought to inspire and build the capacity of journalists to do evidence-based reporting of reproductive health issues. Specifically, the approach included 1) enhancing journalists' interest in and motivation for reporting on reproductive health issues through training and competitive grants for outstanding reporting ; 2) building the capacity of journalists to report reproductive health research and the capacity of reproductive health researchers to communicate their research to media through training for both parties and providing technical assistance to journalists in obtaining and interpreting evidence; and 3) establishing and maintaining trust and mutual relationships between journalists and researchers through regular informal meetings between journalists and researchers, organizing field visits for journalists, and building formal partnerships with professional media associations and individual journalists. CONCLUSION: Our experiences and reflections, and the experiences of others reviewed in this paper, indicate that a sustained mix of strategies that motivate, strengthen capacity of, and build relationships between journalists and researchers can be effective in enhancing quality and quantity of media coverage of research. PMID- 21679389 TI - Investing in the future: lessons learnt from communicating the results of HSV/ HIV intervention trials in South Africa. AB - BACKGROUND: Communicating the results of randomised controlled trials may present challenges for researchers who have to work with communities and policy-makers to anticipate positive outcomes, while being aware that results may show no effect or harm. METHODS: We present a case study from the perspective of researchers in South Africa about the lessons learnt from communicating the results of four trials evaluating treatment for herpes simplex virus type 2 (HSV-2) as a new strategy for HIV prevention. RESULTS: We show that contextual factors such as misunderstandings and mistrust played an important role in defining the communications response. Use of different approaches in combination was found to be most effective in building understanding, credibility and trust in the research process. During the communication process, researchers acted beyond their traditional role of neutral observers and became agents of social change. This change in role is in keeping with a global trend towards increased communication of research results and presents both opportunities and challenges for the conduct of future research. CONCLUSIONS: Despite disappointing trial results which showed no benefit of HSV-2 treatment for HIV prevention, important lessons were learnt about the value of the communication process in building trust between researchers, community members and policy-makers, and creating an enabling environment for future research partnerships. PMID- 21679390 TI - The impact of HIV and AIDS research: a case study from Swaziland. AB - BACKGROUND: Swaziland is experiencing the world's worst HIV and AIDS epidemic. Prevalence rose from four percent of antenatal clinic attendees in 1992 to 42.6 percent in 2004. The Report 'Reviewing 'Emergencies' for Swaziland: Shifting the Paradigm in a New Era' published in 2007 bought together social and economic indicators. It built a picture of the epidemic as a humanitarian emergency, requiring urgent action from international organisations, donors, and governments. Following a targeted communications effort, the report was believed to have raised the profile of the issue and Swaziland - a success story for HIV and AIDS research. METHODS: Keen to understand how, where and why the report had an impact, Health Economics and HIV/AIDS Research Division commissioned an assessment to track and evaluate the influence of the research. This tapped into literature on the significance of understanding the research-to-policy interface. This paper outlines the report and its impact. It explores key findings from the assessment and suggests lessons for future research projects. RESULTS: The paper demonstrates that, although complex, and not without methodological issues, impact assessment of research can be of real value to researchers in understanding the research-to-policy interface. CONCLUSION: Only by gaining insight into this process can researchers move forward in delivering effective research. PMID- 21679391 TI - Insecticide resistance in malaria vector mosquitoes at four localities in Ghana, West Africa. AB - BACKGROUND: Malaria vector control programmes that rely on insecticide-based interventions such as indoor house spraying with residual insecticides or insecticide treated bed nets, need to base their decision-making process on sound baseline data. More and more commercial entities in Africa, such as mining companies, are realising the value to staff productivity of controlling malaria transmission in their areas of operation.This paper presents baseline entomological data obtained during surveys conducted for four mining operations in Ghana, West Africa. RESULTS: The vast majority of the samples were identified as Anopheles gambiae S form with only a few M form specimens being identified from Tarkwa. Plasmodium falciparum infection rates ranged from 4.5 to 8.6% in An. gambiae and 1.81 to 8.06% in An. funestus. High survival rates on standard WHO bioassay tests were recorded for all insecticide classes except the organophosphates that showed reasonable mortality at all locations (i.e. >90%). The West African kdr mutation was detected and showed high frequencies in all populations. CONCLUSIONS: The data highlight the complexity of the situation prevailing in southern Ghana and the challenges facing the malaria vector control programmes in this region. Vector control programmes in Ghana need to carefully consider the resistance profiles of the local mosquito populations in order to base their resistance management strategies on sound scientific data. PMID- 21679392 TI - New approach to modulate retinal cellular toxic effects of high glucose using marine epa and dha. AB - BACKGROUND: Protective effects of omega-3 fatty acids against cellular damages of high glucose were studied on retinal pigmented epithelial (RPE) cells. METHODS: Retinal epithelial cells were incubated with omega-3 marine oils rich in EPA and DHA and then with high glucose (25 mM) for 48 hours. Cellular responses were compared to normal glucose (5 mM): intracellular redox status, reactive oxygen species (ROS), mitochondrial succinate deshydrogenase activity, inflammatory cytokines release and caveolin-1 expression were evaluated using microplate cytometry, ELISA and flow cytometry techniques. Fatty acids incorporation in retinal cell membranes was analysed using chromatography. RESULTS: Preincubation of the cells with fish oil decreased ROS overproduction, mitochondrial alterations and TNFalpha release. These protective effects could be attributed to an increase in caveolin-1 expression induced by marine oil. CONCLUSION: Marine formulations rich in omega-3 fatty acids represent a promising therapeutic approach for diabetic retinopathy. PMID- 21679393 TI - Patients Referred to a Norwegian Trauma Centre: effect of transfer distance on injury patterns, use of resources and outcomes. AB - BACKGROUND: Triage and interhospital transfer are central to trauma systems. Few studies have addressed transferred trauma patients. This study investigated transfers of variable distances to OUH (Oslo University Hospital, Ulleval), one of the largest trauma centres in Europe. METHODS: Patients included in the OUH trauma registry from 2001 to 2008 were included in the study. Demographic, injury, management and outcome data were abstracted. Patients were grouped according to transfer distance: <=20 km, 21-100 km and > 100 km. RESULTS: Of the 7.353 included patients, 5.803 were admitted directly, and 1.550 were transferred. The number of transfers per year increased, and there was no reduction in injury severity during the study period. Seventy-six per cent of the transferred patients were severely injured. With greater transfer distances, injury severity increased, and there were larger proportions of traffic injuries, polytrauma and hypotensive patients. With shorter distances, patients were older, and head injuries and injuries after falls were more common. The shorter transfers less often activated the trauma team: <=20 km -34%; 21-100 km -51%; > 100 km -61%, compared to 92% of all directly admitted patients. The mortality for all transferred patients was 11%, but was unequally distributed according to transfer distance. CONCLUSION: This study shows heterogeneous characteristics and high injury severity among interhospital transfers. The rate of trauma team assessment was low and should be further examined. The mortality differences should be interpreted with caution as patients were in different phases of management. The descriptive characteristics outlined may be employed in the development of triage protocols and transfer guidelines. PMID- 21679394 TI - Registration accuracy for MR images of the prostate using a subvolume based registration protocol. AB - BACKGROUND: In recent years, there has been a considerable research effort concerning the integration of magnetic resonance imaging (MRI) into the external radiotherapy workflow motivated by the superior soft tissue contrast as compared to computed tomography. Image registration is a necessary step in many applications, e.g. in patient positioning and therapy response assessment with repeated imaging. In this study, we investigate the dependence between the registration accuracy and the size of the registration volume for a subvolume based rigid registration protocol for MR images of the prostate. METHODS: Ten patients were imaged four times each over the course of radiotherapy treatment using a T2 weighted sequence. The images were registered to each other using a mean square distance metric and a step gradient optimizer for registration volumes of different sizes. The precision of the registrations was evaluated using the center of mass distance between the manually defined prostates in the registered images. The optimal size of the registration volume was determined by minimizing the standard deviation of these distances. RESULTS: We found that prostate position was most uncertain in the anterior-posterior (AP) direction using traditional full volume registration. The improvement in standard deviation of the mean center of mass distance between the prostate volumes using a registration volume optimized to the prostate was 3.9 mm (p < 0.001) in the AP direction. The optimum registration volume size was 0 mm margin added to the prostate gland as outlined in the first image series. CONCLUSIONS: Repeated MR imaging of the prostate for therapy set-up or therapy assessment will both require high precision tissue registration. With a subvolume based registration the prostate registration uncertainty can be reduced down to the order of 1 mm (1 SD) compared to several millimeters for registration based on the whole pelvis. PMID- 21679395 TI - A microarray approach to identify genes involved in seed-pericarp cross-talk and development in peach. AB - BACKGROUND: Field observations and a few physiological studies have demonstrated that peach embryogenesis and fruit development are tightly coupled. In fact, attempts to stimulate parthenocarpic fruit development by means of external tools have failed. Moreover, physiological disturbances during early embryo development lead to seed abortion and fruitlet abscission. Later in embryo development, the interactions between seed and fruit development become less strict. As there is limited genetic and molecular information about seed-pericarp cross-talk and development in peach, a massive gene approach based on the use of the MUPEACH 1.0 array platform and quantitative real time RT-PCR (qRT-PCR) was used to study this process. RESULTS: A comparative analysis of the transcription profiles conducted in seed and mesocarp (cv Fantasia) throughout different developmental stages (S1, S2, S3 and S4) evidenced that 455 genes are differentially expressed in seed and fruit. Among differentially expressed genes some were validated as markers in two subsequent years and in three different genotypes. Seed markers were a LTP1 (lipid transfer protein), a PR (pathogenesis-related) protein, a prunin and LEA (Late Embryogenesis Abundant) protein, for S1, S2, S3 and S4, respectively. Mesocarp markers were a RD22-like protein, a serin-carboxypeptidase, a senescence related protein and an Aux/IAA, for S1, S2, S3 and S4, respectively.The microarray data, analyzed by using the HORMONOMETER platform, allowed the identification of hormone-responsive genes, some of them putatively involved in seed-pericarp crosstalk. Results indicated that auxin, cytokinins, and gibberellins are good candidates, acting either directly (auxin) or indirectly as signals during early development, when the cross-talk is more active and vital for fruit set, whereas abscisic acid and ethylene may be involved later on. CONCLUSIONS: In this research, genes were identified marking different phases of seed and mesocarp development. The selected genes behaved as good seed markers, while for mesocarp their reliability appeared to be dependent upon developmental and ripening traits. Regarding the cross-talk between seed and pericarp, possible candidate signals were identified among hormones.Further investigations relying upon the availability of whole genome platforms will allow the enrichment of a marker genes repertoire and the elucidation of players other than hormones that are involved in seed-pericarp cross-talk (i.e. hormone peptides and microRNAs). PMID- 21679396 TI - Why is spirometry underused in the diagnosis of the breathless patient: a qualitative study. AB - BACKGROUND: Use of spirometry is essential for the accurate diagnosis of respiratory disease but it is underused in both primary and specialist care. In the current study, we have explored the reasons for this underuse. METHODS: Five separate focus groups were undertaken with final year medical undergraduates, junior hospital doctors, general practitioners (GPs) and specialist trainees in respiratory medicine. The participants were not told prior to the session that we were specifically interested in their views about spirometry but discussion was moderated to elicit their approaches to the diagnosis of a breathless patient, their use of investigations and their learning preferences. RESULTS: Undergraduates and junior doctors rarely had a systematic approach towards the breathless patient and tended, unless prompted, to focus on the emergency room situation rather than on patients with longer term causes of breathlessness. Whilst their theoretical knowledge embraced the possibility of a non-respiratory cause for breathlessness, neither undergraduates nor junior doctors spontaneously mentioned the use of spirometry in the diagnosis of respiratory disease. When prompted they cited lack of familiarity with the use and location of equipment, and lack of encouragement to use it as being major barriers to utilization. In contrast, GPs and specialist respiratory trainees were enthusiastic about its use and perceived spirometry as a core element of the diagnostic workup. CONCLUSIONS: More explicit training is needed regarding the role of spirometry in the diagnosis and management of those with lung disease and this necessitates both practical experience and training in interpretation of the data. However, formal teaching is likely to be undermined in practice, if the concept is not strongly promoted by the senior staff who act as role models and trainers. PMID- 21679397 TI - Yes, research can inform health policy; but can we bridge the 'Do-Knowing It's Been Done' gap? PMID- 21679398 TI - Ecological factors associated with dengue fever in a Central Highlands province, Vietnam. AB - BACKGROUND: Dengue is a leading cause of severe illness and hospitalization in Vietnam. This study sought to elucidate the linkage between climate factors, mosquito indices and dengue incidence. METHODS: Monthly data on dengue cases and mosquito larval indices were ascertained between 2004 and 2008 in the Dak Lak province (Vietnam). Temperature, sunshine, rainfall and humidity were also recorded as monthly averages. The association between these ecological factors and dengue was assessed by the Poisson regression model with adjustment for seasonality. RESULTS: During the study period, 3,502 cases of dengue fever were reported. Approximately 72% of cases were reported from July to October. After adjusting for seasonality, the incidence of dengue fever was significantly associated with the following factors: higher household index (risk ratio [RR]: 1.66; 95% confidence interval [CI]: 1.62-1.70 per 5% increase), higher container index (RR: 1.78; 95% CI: 1.73-1.83 per 5% increase), and higher Breteau index (RR: 1.57; 95% CI: 1.53-1.60 per 5 unit increase). The risk of dengue was also associated with elevated temperature (RR: 1.39; 95% CI: 1.25-1.55 per 2 degrees C increase), higher humidity (RR: 1.59; 95% CI: 1.51-1.67 per 5% increase), and higher rainfall (RR: 1.13; 95% CI: 1.21-1.74 per 50 mm increase). The risk of dengue was inversely associated with duration of sunshine, the number of dengue cases being lower as the sunshine increases (RR: 0.76; 95% CI: 0.73-0.79 per 50 hours increase). CONCLUSIONS: These data suggest that indices of mosquito and climate factors are main determinants of dengue fever in Vietnam. This finding suggests that the global climate change will likely increase the burden of dengue fever infection in Vietnam, and that intensified surveillance and control of mosquito during high temperature and rainfall seasons may be an important strategy for containing the burden of dengue fever. PMID- 21679399 TI - Physical activity, sedentary behaviors, and estimated insulin sensitivity and secretion in pregnant and non-pregnant women. AB - BACKGROUND: Overweight and obesity during pregnancy raise the risk of gestational diabetes and birth complications. Lifestyle factors like physical activity may decrease these risks through beneficial effects on glucose homeostasis. Here we examined physical activity patterns and their relationships with measures of glucose homeostasis in late pregnancy compared to non-pregnant women. METHODS: Normal weight and overweight women without diabetes (N = 108; aged 25-35 years) were studied; 35 were pregnant (in gestational weeks 28-32) and 73 were non pregnant.Insulin sensitivity and beta-cell response were estimated from an oral glucose tolerance test. Physical activity was measured during 10-days of free living using a combined heart rate sensor and accelerometer. Total (TEE), resting (REE), and physical activity (PAEE) energy expenditure were measured using doubly labeled water and expired gas indirect calorimetry. RESULTS: Total activity was associated with reduced first-phase insulin response in both pregnant (Regression r2 = 0.11; Spearman r = -0.47; p = 0.007) and non-pregnant women (Regression r2 = 0.11 Spearman; r = -0.36; p = 0.002). Relative to non-pregnant women, pregnant women were estimated to have secreted 67% more insulin and had 10% lower fasting glucose than non-pregnant women. Pregnant women spent 13% more time sedentary, 71% less time in moderate-to-vigorous intensity activity, had 44% lower objectively measured total activity, and 12% lower PAEE than non-pregnant women. Correlations did not differ significantly for any comparison between physical activity subcomponents and measures of insulin sensitivity or secretion. CONCLUSIONS: Our findings suggest that physical activity conveys similar benefits on glucose homeostasis in pregnant and non-pregnant women, despite differences in subcomponents of physical activity. PMID- 21679400 TI - Prognostic value of hematogenous dissemination and biological profile of the tumor in early breast cancer patients: a prospective observational study. AB - BACKGROUND: The aim of this study was to investigate the incidence and prognostic value of disseminated tumor cells in bone marrow of breast carcinoma patients with early disease, and to analyze this finding in relation to lymph node involvement, determined by sentinel lymph node (SLN) biopsy analysis, and to prognostic factors of interest. METHODS: 104 patients with operable (T<3 cm) breast cancer and clinically- and sonographically-negative axillary lymph nodes were scheduled for SLN biopsy. Bone marrow aspirates were collected before the start of surgery from both iliac crests, and mononuclear cell layers were separated by density centrifugation (Lymphoprep). Slide preparations were then examined for the presence of disseminated tumor cells by immunocytochemistry with anti-cytokeratin antibodies (A45-B/B3). Lymphoscintigraphy was performed 2 hours after intratumor administration of 2 mCi (74 MBq) of 99mTc colloidal albumin. The SLN was evaluated for the presence of tumor cells by hematoxylin-eosin staining and, when negative, by immunocytochemistry using anti-cytokeratin antibody (CAM 5.2). Survival analyses and comparative analyses were performed on the results of bone marrow determinations, SLN biopsy, and known prognostic factors, including breast cancer subtypes according to the simplified classification based on ER, PR and HER2. RESULTS: Lymph node and hematogenous dissemination occur in one-third of patients with early-stage breast cancer, although not necessarily simultaneously. In our study, disseminated tumor cells were identified in 22% of bone marrow aspirates, whereas 28% of patients had axillary lymph node involvement. Simultaneous lymph node and bone marrow involvement was found in only 5 patients (nonsignificant). In the survival study (60 months), a higher, although nonsignificant rate of disease-related events (13%) was seen in patients with disseminated tumor cells in bone marrow, and a significant association of events was documented with the known, more aggressive tumor subtypes: triple negative receptor status (21%) and positive ERBB2 status (29%). CONCLUSIONS: Tumor cell detection in bone marrow can be considered a valid prognostic parameter in patients with early disease. However, the classic prognostic factors remain highly relevant, and the newer breast cancer subtypes are also useful for this purpose. PMID- 21679401 TI - Sparing the contralateral submandibular gland without compromising PTV coverage by using volumetric modulated arc therapy. AB - BACKGROUND: Salivary gland function decreases after radiation doses of 39 Gy or higher. Currently, submandibular glands are not routinely spared. We implemented a technique for sparing contralateral submandibular glands (CLSM) during contralateral elective neck irradiation without compromising PTV coverage. METHODS: Volumetric modulated arc therapy (RapidArcTM) plans were applied in 31 patients with stage II-IV HNC without contralateral neck metastases, all of whom received elective treatment to contralateral nodal levels II-IV. Group 1 consisted of 21 patients undergoing concurrent chemo-radiotherapy, with elective nodal doses of 57.75 Gy (PTVelect) and 70 Gy to tumor and pathological nodes (PTVboost) in 7 weeks. Group 2 consisted of 10 patients treated with radiotherapy to 54.45 Gy to PTVelect and 70 Gy to PTVboost in 6 weeks. All clinical plans spared the CLSM using individually adapted constraints. For each patient, a second plan was retrospectively generated without CLSM constraints ('non-sparing plan'). RESULTS: PTV coverage was similar for both plans, with 98.7% of PTVelect and 99.2% of PTVboost receiving >=95% of the prescription dose. The mean CLSM dose in group 1 was 33.2 Gy for clinical plans, versus 50.6 Gy in 'non-sparing plans' (p < 0.001). In group 2, mean CLSM dose was 34.4 Gy for clinical plans, and 46.8 Gy for non-sparing plans (p = 0.002). CONCLUSIONS: Elective radiotherapy to contralateral nodal levels II-IV using RapidArc consistently limited CLSM doses well below 39 Gy, without compromising PTV-coverage. Future studies will reveal if this extent of dose reduction can reduce patient symptoms. PMID- 21679402 TI - Morphometrical analysis of transbronchial cryobiopsies. AB - The recent introduction of bronchoscopically recovered cryobiopsy of lung tissue has opened up new possibilities in the diagnosis of neoplastic and non-neoplastic lung diseases in various aspects. Most notably the morphological diagnosis of peripheral lung biopsies promises to achieve a better yield with a high quality of specimens. To better understand this phenomenon, its diagnostic options and perspectives, this study morphometrically compares 15 cryobiopsies and 18 transbronchial forceps biopsies of peripheral lung tissue a priori without considering clinical hit ratio or integration of results in the clinical diagnostic processing. Cryotechnically harvested specimens were significantly larger (mean: 17.1 +/- 10.7 mm2 versus 3.8 +/- 4.0 mm2) and contained alveolar tissue more often. If present, the alveolar part in cryobiopsies exceeded the one of forceps biopsies. The alveolar tissue of crybiopsy specimens did not show any artefacts. Based on these results cryotechnique seems to open up new perspectives in bronchoscopic diagnosis of lung disease. PMID- 21679403 TI - Intraocular nematode with diffuse unilateral subacute neuroretinitis: case report. AB - BACKGROUND: Live intraocular nematode is a rare occurrence. Nematode can migrate actively within the eye, creating visual symptoms and damaging ocular tissue. CASE PRESENTATION: A 26-year old man presented with painless reduced vision of the left eye for one week duration. It was associated with floaters. Visual acuity on the left eye was hand movement. Anterior segment examination was normal with normal intra-ocular pressure. Fundus examination showed a live nematode lying subretinally at the macular area with macular oedema and multifocal chorioretinal lesions at peripheral retina. There was no vitritis, vasculitis or any retinal hemorrhage. Systemic examination revealed normal findings and laboratory studies only showed leucocytosis with normal eosinophil count and negative serum toxocara antibody. The diagnosis of introcular nematode with diffuse unilateral subacute neuroretinitis was made. He was treated with oral anti-helminths and a course of oral steroid at a reducing dose. The nematode had died evidenced by its immobility during the treatment and finally disintegrated, leaving macular oedema with mottling appearance and mild hyperpigmentation. Multifocal chorioretinal lesions had also resolved. However despite treatment his visual acuity during follow-up had remained poor. CONCLUSIONS: Cases of intraocular nematode, though not commonly encountered, continue to present the ophthalmologist with the problem of diagnosis and management and hence poorer prognosis to the patient. PMID- 21679404 TI - Teaching physiotherapy skills in culturally-diverse classes. AB - BACKGROUND: Cultural competence, the ability to work in cross-cultural situations, has been acknowledged as a core skill for physiotherapists and other health professionals. Literature in this area has focused on the rationale for physiotherapists to provide culturally-competent care and the effectiveness of various educational strategies to facilitate the acquisition of knowledge about cultural competence by physiotherapists and physiotherapy students. However, there is a paucity of research on how students with different cultural needs, who are attending one university class, can be accommodated within a framework of learning core physiotherapy skills to achieve professional standards. RESULTS: This paper reports on steps which were taken to resolve the specific needs of a culturally-diverse body of first year physiotherapy students, and the impact this had on teaching in a new physiotherapy program located in Greater Western Sydney, Australia. Physiotherapy legislative, accreditation and registration requirements were considered in addition to anti-discrimination legislation and the four ethical principles of decision making. CONCLUSIONS: Reflection on this issue and the steps taken to resolve it has resulted in the development of a generic framework which focuses on providing quality and equitable physiotherapy education opportunities to all students. This framework is generalizable to other health professions worldwide. PMID- 21679405 TI - Origin and global diversification patterns of tropical rain forests: inferences from a complete genus-level phylogeny of palms. AB - BACKGROUND: Understanding how biodiversity is shaped through time is a fundamental question in biology. Even though tropical rain forests (TRF) represent the most diverse terrestrial biomes on the planet, the timing, location and mechanisms of their diversification remain poorly understood. Molecular phylogenies are valuable tools for exploring these issues, but to date most studies have focused only on recent time scales, which minimises their explanatory potential. In order to provide a long-term view of TRF diversification, we constructed the first complete genus-level dated phylogeny of a largely TRF-restricted plant family with a known history dating back to the Cretaceous. Palms (Arecaceae/Palmae) are one of the most characteristic and ecologically important components of TRF worldwide, and represent a model group for the investigation of TRF evolution. RESULTS: We provide evidence that diversification of extant lineages of palms started during the mid-Cretaceous period about 100 million years ago. Ancestral biome and area reconstructions for the whole family strongly support the hypothesis that palms diversified in a TRF like environment at northern latitudes. Finally, our results suggest that palms conform to a constant diversification model (the 'museum' model or Yule process), at least until the Neogene, with no evidence for any change in diversification rates even through the Cretaceous/Paleogene mass extinction event. CONCLUSIONS: Because palms are restricted to TRF and assuming biome conservatism over time, our results suggest the presence of a TRF-like biome in the mid-Cretaceous period of Laurasia, consistent with controversial fossil evidence of the earliest TRF. Throughout its history, the TRF biome is thought to have been highly dynamic and to have fluctuated greatly in extent, but it has persisted even during climatically unfavourable periods. This may have allowed old lineages to survive and contribute to the steady accumulation of diversity over time. In contrast to other plant studies, our results suggest that ancient and steady evolutionary processes dating back to the mid-Cretaceous period can contribute, at least in part, to present day species richness in TRF. PMID- 21679406 TI - Deep sequencing on genome-wide scale reveals the unique composition and expression patterns of microRNAs in developing pollen of Oryza sativa. AB - BACKGROUND: Pollen development in flowering plants requires strict control of the gene expression program and genetic information stability by mechanisms possibly including the miRNA pathway. However, our understanding of the miRNA pathway in pollen development remains limited, and the dynamic profile of miRNAs in developing pollen is unknown. RESULTS: Using next-generation sequencing technology, we pyrosequenced small RNA populations from rice uninucleate microspores to tricellular pollen and control sporophytic tissues at the genome wide level. We identified 292 known miRNAs, including members of all 20 families conserved in plants, and 75 novel miRNAs. Of the 292 known miRNAs, 202 were expressed, with 103 enriched, in developing pollen. More than half of these novel miRNAs displayed pollen-or stage-specific expression. Furthermore, analyzing the 367 miRNAs and their predicted targets indicated that correlation in expression profiles of pollen-enriched known miRNAs and their targets significantly differs from that of sporophyte-enriched known miRNAs and their targets in some functional terms, while novel miRNAs appeared to negatively regulate their targets. Importantly, gene ontology abundance analysis demonstrated chromatin assembly and disassembly was important in the targets of bicellular pollen expressed novel miRNAs. Principal component analysis revealed pollen of all three stages was discriminated from sporophytes, largely because of the novel and non conserved known miRNAs. CONCLUSIONS: Our study, for the first time, revealed the differences in composition and expression profiles of miRNAs between developing pollen and sporophytes, with novel and non-conserved known miRNAs the main contributors. Our results suggest the important roles of the miRNA pathway in pollen development. PMID- 21679407 TI - Molecular genetic analysis of the PLP1 gene in 38 families with PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. AB - BACKGROUND: The breadth of the clinical spectrum underlying Pelizaeus-Merzbacher disease and spastic paraplegia type 2 is due to the extensive allelic heterogeneity in the X-linked PLP1 gene encoding myelin proteolipid protein (PLP). PLP1 mutations range from gene duplications of variable size found in 60 70% of patients to intragenic lesions present in 15-20% of patients. METHODS: Forty-eight male patients from 38 unrelated families with a PLP1-related disorder were studied. All DNA samples were screened for PLP1 gene duplications using real time PCR. PLP1 gene sequencing analysis was performed on patients negative for the duplication. The mutational status of all 14 potential carrier mothers of the familial PLP1 gene mutation was determined as well as 15/24 potential carrier mothers of the PLP1 duplication. RESULTS AND CONCLUSIONS: PLP1 gene duplications were identified in 24 of the unrelated patients whereas a variety of intragenic PLP1 mutations were found in the remaining 14 patients. Of the 14 different intragenic lesions, 11 were novel; these included one nonsense and 7 missense mutations, a 657-bp deletion, a microdeletion and a microduplication. The functional significance of the novel PLP1 missense mutations, all occurring at evolutionarily conserved residues, was analysed by the MutPred tool whereas their potential effect on splicing was ascertained using the Skippy algorithm and a neural network. Although MutPred predicted that all 7 novel missense mutations would be likely to be deleterious, in silico analysis indicated that four of them (p.Leu146Val, p.Leu159Pro, p.Thr230Ile, p.Ala247Asp) might cause exon skipping by altering exonic splicing elements. These predictions were then investigated in vitro for both p.Leu146Val and p.Thr230Ile by means of RNA or minigene studies and were subsequently confirmed in the case of p.Leu146Val. Peripheral neuropathy was noted in four patients harbouring intragenic mutations that altered RNA processing, but was absent from all PLP1-duplication patients. Unprecedentedly, family studies revealed the de novo occurrence of the PLP1 duplication at a frequency of 20%. PMID- 21679408 TI - Intensity modulated radiotherapy for elderly bladder cancer patients. AB - BACKGROUND: To review our experience and evaluate treatment planning using intensity-modulated radiotherapy (IMRT) and helical tomotherapy (HT) for the treatment of elderly patients with bladder cancer. METHODS: From November 2006 through November 2009, we enrolled 19 elderly patients with histologically confirmed bladder cancer, 9 in the IMRT and 10 in the HT group. The patients received 64.8 Gy to the bladder with or without concurrent chemotherapy. Conventional 4-field "box" pelvic radiation therapy (2DRT) plans were generated for comparison. RESULTS: The median patient age was 80 years old (range, 65-90 years old). The median survival was 21 months (5 to 26 months). The actuarial 2 year overall survival (OS) for the IMRT vs. the HT group was 26.3% vs .37.5%, respectively; the corresponding values for disease-free survival were 58.3% vs. 83.3%, respectively; for locoregional progression-free survival (LRPFS), the values were 87.5% vs. 83.3%, respectively; and for metastases-free survival, the values were 66.7% vs. 60.0%, respectively. The 2-year OS rates for T1, 2 vs. T3, 4 were 66.7% vs. 35.4%, respectively (p = 0.046). The 2-year OS rate was poor for those whose RT completion time greater than 8 weeks when compared with the RT completed within 8 wks (37.9% vs. 0%, p = 0.004). CONCLUSION: IMRT and HT provide good LRPFS with tolerable toxicity for elderly patients with invasive bladder cancer. IMRT and HT dosimetry and organ sparing capability were superior to that of 2DRT, and HT provides better sparing ability than IMRT. The T category and the RT completion time influence OS rate. PMID- 21679410 TI - Pattern of seat belt use by drivers in Trinidad and Tobago, West Indies. AB - BACKGROUND: In Trinidad and Tobago, the law on the mandatory use of seat belts was passed in 1995, but this law is hardly enforced. The objective of this study was to determine the frequency and predictors of seat belt use by motor vehicle drivers in the country. FINDINGS: A cross-sectional study of 959 motor vehicle drivers using a self-administered questionnaire. Data analysis included Pearson Chi square test and multinomial logistic regression analysis in order to determine the possible predictors of seat belt use by the drivers in Trinidad and Tobago. A majority of the drivers sometimes (51.8%) or always (31.6%) use a seat belt. About 16.7%, 29% and 54.2% of the drivers perceived that the other drivers use their seat belts more frequently, with the same frequency and less frequently respectively compared to themselves. The main reason for not using seat belt by the drivers was given as frequent stops (40.7%) and the main motivation to use seat belt by the drivers was given as stiffer penalties for non-compliance with the seat belt law (44.5%). The predictors of seat belt use were male driver, no formal or lower level of education, driving for less than 10 years, and the perception that the other drivers use seat belts with the same or higher frequency compared to the respondents. CONCLUSION: Only a small proportion of the drivers in Trinidad and Tobago always use a seat belt when driving. There is the need to enforce the seat belt legislation in the country. PMID- 21679409 TI - High frequency of chlamydial co-infections in clinically healthy sheep flocks. AB - BACKGROUND: The epidemiological situation of ovine chlamydial infections in continental Europe, especially Germany is poorly characterised. Using the German state of Thuringia as a model example, the chlamydial sero- and antigen prevalence was estimated in thirty-two randomly selected sheep flocks with an average abortion rate lower than 1%. Seven vaccinated flocks were reviewed separately. RESULTS: A wide range of samples from 32 flocks were examined. Assumption of a seroprevalence of 10% (CI 95%) at flock level, revealed that 94% of the tested flocks were serologically positive with ongoing infection (i.e. animals with seroconversion) in nearly half (47%) of the flocks. On the basis of an estimated 25% antigen prevalence (CI 95%), PCR and DNA microarray testing, together with sequencing revealed the presence of chlamydiae in 78% of the flocks. The species most frequently found was Chlamydophila (C.) abortus (50%) followed by C. pecorum (47%) and C. psittaci genotype A (25%). Mixed infections occurred in 25% of the tested flocks. Samples obtained from the vaccinated flocks revealed the presence of C. abortus field samples in 4/7 flocks. C. pecorum was isolated from 2/7 flocks and the presence of seroconversion was determined in 3/7 flocks. CONCLUSIONS: The results imply that chlamydial infections occur frequently in German sheep flocks, even in the absence of elevated abortion rates. The fact that C. pecorum and the potentially zoonotic C. psittaci were found alongside the classical abortifacient agent C. abortus, raise questions about the significance of this reservoir for animal and human health and underline the necessity for regular monitoring. Further studies are needed to identify the possible role of C. psittaci infections in sheep. PMID- 21679411 TI - Photoproduction of iodine with nanoparticulate semiconductors and insulators. AB - The crystal structures of different forms of TiO2 and those of BaTiO3, ZnO, SnO2, WO3, CuO, Fe2O3, Fe3O4, ZrO2 and Al2O3 nanoparticles have been deduced by powder X-ray diffraction. Their optical edges have been obtained by UV-visible diffuse reflectance spectra. The photocatalytic activities of these oxides and also those of SiO2 and SiO2 porous to oxidize iodide ion have been determined and compared. The relationships between the photocatalytic activities of the studied oxides and the illumination time, wavelength of illumination, concentration of iodide ion, airflow rate, photon flux, pH, etc., have been obtained. Use of acetonitrile as medium favors the photogeneration of iodine. PMID- 21679412 TI - Clinical relevance of DNA microarray analyses using archival formalin-fixed paraffin-embedded breast cancer specimens. AB - BACKGROUND: The ability of gene profiling to predict treatment response and prognosis in breast cancers has been demonstrated in many studies using DNA microarray analyses on RNA from fresh frozen tumor specimens. In certain clinical and research situations, performing such analyses on archival formalin fixed paraffin-embedded (FFPE) surgical specimens would be advantageous as large libraries of such specimens with long-term follow-up data are widely available. However, FFPE tissue processing can cause fragmentation and chemical modifications of the RNA. A number of recent technical advances have been reported to overcome these issues. Our current study evaluates whether or not the technology is ready for clinical applications. METHODS: A modified RNA extraction method and a recent DNA microarray technique, cDNA-mediated annealing, selection, extension and ligation (DASL, Illumina Inc) were evaluated. The gene profiles generated from FFPE specimens were compared to those obtained from paired fresh fine needle aspiration biopsies (FNAB) of 25 breast cancers of different clinical subtypes (based on ER and Her2/neu status). Selected RNA levels were validated using RT-qPCR, and two public databases were used to demonstrate the prognostic significance of the gene profiles generated from FFPE specimens. RESULTS: Compared to FNAB, RNA isolated from FFPE samples was relatively more degraded, nonetheless, over 80% of the RNA samples were deemed suitable for subsequent DASL assay. Despite a higher noise level, a set of genes from FFPE specimens correlated very well with the gene profiles obtained from FNAB, and could differentiate breast cancer subtypes. Expression levels of these genes were validated using RT-qPCR. Finally, for the first time we correlated gene expression profiles from FFPE samples to survival using two independent microarray databases. Specifically, over-expression of ANLN and KIF2C, and under expression of MAPT strongly correlated with poor outcomes in breast cancer patients. CONCLUSION: We demonstrated that FFPE specimens retained important prognostic information that could be identified using a recent gene profiling technology. Our study supports the use of FFPE specimens for the development and refinement of prognostic gene signatures for breast cancer. Clinical applications of such prognostic gene profiles await future large-scale validation studies. PMID- 21679413 TI - CD4saurus Rex &HIVelociraptor vs. development of clinically useful immunological markers: a Jurassic tale of frozen evolution. AB - One of the most neglected areas of everyday clinical practice for HIV physicians is unexpectedly represented by CD4 T cell counts when used as an aid to clinical decisions. All who care for HIV patients believe that CD4+ T cell counts are a reliable method to evaluate a patient immune status. There is however a fatalistic acceptance that besides its general usefulness, CD4+ T cell counts have relevant clinical and immunological limits. Shortcomings of CD4 counts appear in certain clinical scenarios including identification of immunological nonresponders, subsequent development of cancer on antiretroviral treatment, failure on treatment simplification. Historical and recently described parameters might be better suited to advise management of patients at certain times during their disease history. Immunogenotypic parameters and innate immune parameters that define progression as well as immune parameters associated with immune recovery are available and have not been introduced into validation processes in larger trials. The scientific and clinical community needs an effort in stimulating clinical evolution of immunological tests beyond "CD4saurus Rex" introducing new parameters in the clinical arena after appropriate validation. PMID- 21679414 TI - 'The girl with her period is the one to hang her head' Reflections on menstrual management among schoolgirls in rural Kenya. AB - BACKGROUND: The onset of menstruation is a landmark event in the life of a young woman. Yet the complications and challenges that can accompany such an event have been understudied, specifically in resource-poor settings. As interventions aim to improve female attendance in schools, it is important to explore how menstruation is perceived and navigated by girls in the school setting. This research conveys rural Kenyan schoolgirls' perceptions and practices related to menstruation METHODS: Data were collected at six rural schools in the Nyanza Province of Western Kenya. Using focus group discussions, in-depth interviews, and field notes from observations, researchers collected information from 48 primary schoolgirls and nine teachers. Systematic analysis began with a reading of transcripts and debriefing notes, followed by manual coding of the narratives. RESULTS: Focus group discussions became opportunities for girls to share thoughts on menstruation, instruct one another on management practices and advise one another on coping mechanisms. Girls expressed fear, shame, distraction and confusion as feelings associated with menstruation. These feelings are largely linked to a sense of embarrassment, concerns about being stigmatized by fellow students and, as teachers explained, a perception that the onset of menstruation signals the advent of a girl's sexual status. Among the many methods for managing their periods, girls most frequently said they folded, bunched up or sewed cloth, including cloth from shirts or dresses, scraps of old cloth, or strips of an old blanket. Cloth was reported to frequently leak and cause chafing, which made school attendance difficult particularly as the day progressed. Attitudes and practices of girls toward menstruation have been arranged into personal, environmental and behavioural factors. CONCLUSION: Further research on menstrual management options that are practical, sustainable and culturally acceptable must be conducted to inform future programs and policies that aim to empower young girls as they transition into womanhood. Stakeholders working within this and similar contexts must consider systematic mechanisms to explain to young girls what menstruation is and how to manage it. Providing sanitary supplies or guiding girls on how to create supplies serve as critical components for future interventions. PMID- 21679415 TI - Cultural aspects of primary healthcare in india: A case- based analysis. AB - Delivering quality primary care to large populations is always challenging, and that is certainly the case in India. While the sheer magnitude of patients can create difficulties, not all challenges are about logistics. Sometimes patient health-seeking behaviour leads to delays in obtaining medical help for reasons that have more to do with culture, social practice and religious belief. When primary care is accessed via busy state-run outpatient departments there is often little time for the physician to investigate causes behind a patient's condition, and these factors can adversely affect patient outcomes. We consider the case of a woman with somatic symptoms seemingly triggered by psychological stresses associated with social norms and familial cultural expectations. These expectations conflict with her personal and professional aspirations, and although she eventually receives psychiatric help and her problems are addressed, initially, psycho-social factors underlying her condition posed a hurdle in terms of accessing appropriate medical care. While for many people culture, belief and social norms exert a stabilising, positive influence, in situations where someone's personal expectations differ significantly from accepted social norms, individual autonomy can be directly challenged, and in which case, something has to give. The result of such challenges can negatively impact on health and well being, and for patients with immature defence mechanisms for dealing with inner conflict, such an experience can be damaging and ensuing somatic disturbances are often difficult to treat. Patients with culture-bound symptoms are not uncommon within primary care in India or in other Asian countries and communities. We argue that such cases need to be properly understood if satisfactory patient outcomes are to be achieved. While some causes are structural, having to do with how healthcare is accessed and delivered, others are about cultural values, social practices and beliefs. We note how some young adult women are adversely affected and discuss some of the ethical issues that arise. PMID- 21679416 TI - Retention in an antiretroviral therapy programme during an era of decreasing drug cost in Limbe, Cameroon. AB - BACKGROUND: In 2002, Cameroon initiated scale up of antiretroviral therapy (ART); on 1 October 2004, a substantial reduction in ART cost occurred. We assessed the impact of this event and other factors on enrolment and retention in care among HIV-infected patients initiating ART from February 2002 to December 2005 at the single ART clinic serving the Southwest Region in Limbe, Cameroon. METHODS: We retrospectively analyzed clinical and pharmacy payment records of HIV-infected patients initiating ART according to national guidelines. We compared two cohorts of patients, enrolled before and after 1 October 2004, to determine if price reduction was associated with enhanced enrolment. We assessed factors associated with retention and survival by Cox proportional hazards models. Retention in care implied patients who had contact with the healthcare system as of 31 December 2005 (including those who were transferred to continue care in other ART centres), although these patients may have interrupted therapy at some time. A patient who was not retained in care may have dropped out (lost to follow up) or died. RESULTS: Mean enrolment rates for 2920 patients who initiated ART before and after the price reduction were 46.5 and 95.5 persons/month, respectively (p < 0.001). The probabilities of remaining alive and in care were 0.66 (95% CI 0.64 0.68) at six months, 0.58 (95% CI 0.56-0.60) at one year, 0.47 (95% CI 0.45-0.49) at two years and 0.35 (95% CI 0.32-0.38) at three years; they were not significantly different between the two cohorts of patients enrolled before and after the price reduction over the first 15 months of comparable follow up (hazard ratio 1.1; 95% CI 0.9-1.2, p = 0.27). In multivariable analysis using multiple imputations to compensate for missing values, factors associated with dropping out of care or dying were male gender (HR 1.33 [1.18-1.50], p = 0.003), treatment paid by self, family or partly by other (HR 3.05 [1.99-4.67], p < 0.001), and, compared with residents of Limbe, living more than 150 km from Limbe (HR 1.41 [1.18-1.69], p < 0.001), or being residents of Douala (HR 1.51 [1.16 1.98], p < 0.001). CONCLUSIONS: Reducing the cost of ART increased enrolment of clients in the programme, but did not change retention in care. In a system where most clients pay for ART, an accessible clinic location may be more important than the cost of medication for retention in care. Decentralizing ART clinics might improve retention and survival among patients on ART. PMID- 21679417 TI - Neutralizing antibody response in the patients with hand, foot and mouth disease to enterovirus 71 and its clinical implications. AB - Enterovirus 71 (EV71) has emerged as a significant pathogen causing large outbreaks in China for the past 3 years. Developing an EV71 vaccine is urgently needed to stop the spread of the disease; however, the adaptive immune response of humans to EV71 infection remains unclear. We examined the neutralizing antibody titers in HFMD patients and compared them to those of asymptomatic healthy children and young adults. We found that 80% of HFMD patients became positive for neutralizing antibodies against EV71 (GMT = 24.3) one day after the onset of illness. The antibody titers in the patients peaked two days (GMT = 79.5) after the illness appeared and were comparable to the level of adults (GMT = 45.2). Noticeably, the antibody response was not correlated with disease severity, suggesting that cellular immune response, besides neutralizing antibodies, could play critical role in controlling the outcome of EV71 infection in humans. PMID- 21679418 TI - Analysis of time-dependent adaptations in whole-body energy balance in obesity induced by high-fat diet in rats. AB - BACKGROUND: High-fat (HF) diet has been extensively used as a model to study metabolic disorders of human obesity in rodents. However, the adaptive whole-body metabolic responses that drive the development of obesity with chronically feeding a HF diet are not fully understood. Therefore, this study investigated the physiological mechanisms by which whole-body energy balance and substrate partitioning are adjusted in the course of HF diet-induced obesity. METHODS: Male Wistar rats were fed ad libitum either a standard or a HF diet for 8 weeks. Food intake (FI) and body weight were monitored daily, while oxygen consumption, respiratory exchange ratio, physical activity, and energy expenditure (EE) were assessed weekly. At week 8, fat mass and lean body mass (LBM), fatty acid oxidation and uncoupling protein-1 (UCP-1) content in brown adipose tissue (BAT), as well as acetyl-CoA carboxylase (ACC) content in liver and epidydimal fat were measured. RESULTS: Within 1 week of ad libitum HF diet, rats were able to spontaneously reduce FI to precisely match energy intake of control rats, indicating that alterations in dietary energy density were rapidly detected and FI was self-regulated accordingly. Oxygen consumption was higher in HF than controls throughout the study as whole-body fat oxidation also progressively increased. In HF rats, EE initially increased, but then reduced as dark cycle ambulatory activity reached values ~38% lower than controls. No differences in LBM were detected; however, epidydimal, inguinal, and retroperitoneal fat pads were 1.85-, 1.89-, and 2.54-fold larger in HF-fed than control rats, respectively. Plasma leptin was higher in HF rats than controls throughout the study, indicating the induction of leptin resistance by HF diet. At week 8, UCP-1 content and palmitate oxidation in BAT were 3.1- and 1.5-fold higher in HF rats than controls, respectively, while ACC content in liver and epididymal fat was markedly reduced. CONCLUSION: The thermogenic response induced by the HF diet was offset by increased energy efficiency and time-dependent reduction in physical activity, favoring fat accumulation. These adaptations were mainly driven by the nutrient composition of the diet, since control and HF animals spontaneously elicited isoenergetic intake. PMID- 21679419 TI - Herpes zoster in Germany: quantifying the burden of disease. AB - BACKGROUND: Herpes zoster (HZ) is caused by a reactivation of the varicella zoster-virus (VZV) and mainly affects individuals aged>=50 years. Vaccines have been licensed or are under development that can protect against HZ and its main complication postherpetic neuralgia (PHN). In Germany, the burden of disease caused by HZ is not well known. To support the decision making process related to a potential vaccination recommendation, we estimated annual HZ disease burden in people aged>=50 years in Germany by utilizing various data sources. METHODS: We assessed for 2007 and 2008 HZ-outpatient incidence (number of cases per 1,000 person-years, PY) by utilizing the Association of Statutory Health Insurance Physicians (ASHIP) database, which contains nationwide routine outpatient data. For the same time period annual number of HZ-inpatients and HZ-associated deaths were identified by using the Federal Health Monitoring System (FHM). PHN incidence and loss of quality-adjusted life years (QALYs) caused by HZ were calculated by multiplying number of identified HZ-patients with upper and lower limit estimates for proportion of HZ-cases developing PHN and HZ-related QALY, respectively. RESULTS: For the study period we identified an annual average of 306,511 HZ-outpatients aged 50+, resulting in a HZ-incidence of 9.6/1,000 PY. A total 14,249 HZ-associated inpatients and 66 deaths were reported in both years on average. HZ-incidence increased by age from 6.21 in people 50-54 years to 13.19 per 1,000 PY in people aged>=90 years. Females were significantly more frequently affected than males in terms of outpatient HZ-incidence (11.12 vs. 7.8 per 1,000 PY), inpatient HZ-incidence (0.51 vs. 0.38 per 1,000 PY) and mortality (0.29 vs. 0.10 per 100,000 PY). PHN-incidence was estimated to range between 0.43 and 1.33 per 1,000 PY. Based on these figures, there were between 3,065 to 24,094 QALYs lost due to HZ in persons aged>=50 years in Germany per annum. CONCLUSION: Our study provides important baseline estimates for HZ-related disease burden in Germany. HZ poses a considerable burden on the health care system in Germany both in terms of outpatient and inpatient services. Follow-up assessments of HZ disease burden are needed to monitor the impact of VZV-vaccinations in Germany. PMID- 21679420 TI - Comparative evaluation of the potential impact of rotavirus versus HPV vaccination in GAVI-eligible countries: a preliminary analysis focused on the relative disease burden. AB - BACKGROUND: Immunization policymakers at global and local levels need to establish priorities among new vaccines competing for limited resources. However, comparison of the potential impact of single vaccination programs is challenging, primarily due to the limited number of vaccine analyses as well as their differing analytic approaches and reporting formats. The purpose of this study is to provide early insight into how the comparative impact of different new vaccines could be assessed in resource-poor settings with respect to affordability, cost-effectiveness, and distributional equity. METHODS: We compared the health, economic, and financial consequences of introducing the two vaccines in 72 GAVI-eligible countries using a number of different outcome measures to evaluate affordability, cost-effectiveness, and distributional equity. We use simple static models to standardize the analytic framework and improve comparability between the two new vaccines. These simple models were validated by leveraging previously developed, more complex models for rotavirus and human papillomavirus (HPV). RESULTS: With 70% coverage of a single-age cohort of infants and pre-adolescent girls, the lives saved with rotavirus (~274,000) and HPV vaccines (~286,000) are similar, although the timing of averted mortality differs; rotavirus-attributable deaths occur in close proximity to infection, while HPV-related cancer deaths occur largely after age 30. Deaths averted per 1000 vaccinated are 5.2 (rotavirus) and 12.6 (HPV). Disability-adjusted life years (DALYs) averted were ~7.15 million (rotavirus) and ~1.30 million (HPV), reflecting the greater influence of discounting on the latter, given the lagtime between vaccination and averted cancer. In most countries (68 for rotavirus and 66 for HPV, at the cost of I$25 per vaccinated individual) the incremental cost per DALY averted was lower than each country's GDP per capita. Financial resources required for vaccination with rotavirus are higher than with HPV since both genders are vaccinated. CONCLUSIONS: While lifesaving benefits of rotavirus and HPV vaccines will be realized at different times, the number of lives saved over each target populations' lifetimes will be similar. Model-based analyses that use a standardized analytic approach and generate comparable outputs can enrich the priority-setting dialogue. Although new vaccines may be deemed cost effective, other factors including affordability and distributional equity need to be considered in different settings. We caution that for priority setting in an individual country, more rigorous comparisons should be performed, using more comprehensive models and considering all relevant vaccines and delivery strategies. PMID- 21679421 TI - P-glycoprotein and breast cancer resistance protein in acute myeloid leukaemia cells treated with the aurora-B kinase inhibitor barasertib-hQPA. AB - BACKGROUND: Aurora kinases play an essential role in orchestrating chromosome alignment, segregation and cytokinesis during mitotic progression, with both aurora-A and B frequently over-expressed in a variety of human malignancies. Over expression of the ABC drug transporter proteins P-glycoprotein (Pgp) and Breast cancer resistance protein (BCRP) is a major obstacle for chemotherapy in many tumour types with Pgp conferring particularly poor prognosis in acute myeloid leukaemia (AML). Barasertib-hQPA is a highly selective inhibitor of aurora-B kinase that has shown tumouricidal activity against a range tumour cell lines including those of leukaemic AML origin. METHODS: Effect of barasertib-hQPA on the pHH3 biomarker and cell viability was measured in a panel of leukaemic cell lines and 37 primary AML samples by flow cytometry. Pgp status was determined by flow cytometry and BCRP status by flow cytometry and real-time PCR. RESULTS: In this study we report the creation of the cell line OCI-AML3DNR, which over expresses Pgp but not BCRP or multidrug resistance-associated protein (MRP), through prolonged treatment of OCI-AML3 cells with daunorubicin. We demonstrate that Pgp (OCI-AML3DNR and KG-1a) and BCRP (OCI-AML6.2) expressing AML cell lines are less sensitive to barasertib-hQPA induced pHH3 inhibition and subsequent loss of viability compared to transporter negative cell lines. We also show that barasertib-hQPA resistance in these cell lines can be reversed using known Pgp and BCRP inhibitors. We report that barasertib-hQPA is not an inhibitor of Pgp or BCRP, but by using 14[C]-barasertib-hQPA that it is effluxed by these transporters. Using phosphoHistone H3 (pHH3) as a biomarker of barasertib-hQPA responsiveness in primary AML blasts we determined that Pgp and BCRP positive primary samples were less sensitive to barasertib-hQPA induced pHH3 inhibition (p = <0.001) than samples without these transporters. However, we demonstrate that IC50 inhibition of pHH3 by barasertib-hQPA was achieved in 94.6% of these samples after 1 hour drug treatment, in contrast to the resistance of the cell lines. CONCLUSION: We conclude that Pgp and BCRP status and pHH3 down-regulation in patients treated with barasertib should be monitored in order to establish whether transporter-mediated efflux is sufficient to adversely impact on the efficacy of the agent. PMID- 21679422 TI - RNA interference in marine and freshwater sponges: actin knockdown in Tethya wilhelma and Ephydatia muelleri by ingested dsRNA expressing bacteria. AB - BACKGROUND: The marine sponge Tethya wilhelma and the freshwater sponge Ephydatia muelleri are emerging model organisms to study evolution, gene regulation, development, and physiology in non-bilaterian animal systems. Thus far, functional methods (i.e., loss or gain of function) for these organisms have not been available. RESULTS: We show that soaking developing freshwater sponges in double-stranded RNA and/or feeding marine and freshwater sponges bacteria expressing double-stranded RNA can lead to RNA interference and reduction of targeted transcript levels. These methods, first utilized in C. elegans, have been adapted for the development and feeding style of easily cultured marine and freshwater poriferans. We demonstrate phenotypic changes result from 'knocking down' expression of the actin gene. CONCLUSION: This technique provides an easy, efficient loss-of-function manipulation for developmental and gene regulatory studies in these important non-bilaterian animals. PMID- 21679423 TI - A novel recombinant pseudorabies virus expressing parvovirus VP2 gene: Immunogenicity and protective efficacy in swine. AB - BACKGROUND: Porcine parvovirus (PPV) VP2 gene has been successfully expressed in many expression systems resulting in self-assembly of virus-like particles (VLPs) with similar morphology to the native capsid. Here, a pseudorabies virus (PRV) system was adopted to express the PPV VP2 gene. METHODS: A recombinant PRV SA215/VP2 was obtained by homologous recombination between the vector PRV viral DNA and a transfer plasmid. Then recombinant virus was purified with plaque purification, and its identity confirmed by PCR amplification, Western blot and indirect immunofluorescence (IFA) analyses. Electronic microscopy of PRV SA215/VP2 confirmed self-assembly of both pseudorabies virus and VLPs from VP2 protein. RESULTS: Immunization of piglets with recombinant virus elicited PRV specific and PPV-specific humoral immune responses and provided complete protection against a lethal dose of PRV challenges. Gilts immunized with recombinant viruses induced PPV-specific antibodies, and significantly reduced the mortality rate of (1 of 28) following virulent PPV challenge compared with the control (7 of 31). Furthermore, PPV virus DNA was not detected in the fetuses of recombinant virus immunized gilts. CONCLUSIONS: In this study, a recombinant PRV SA215/VP2 virus expressing PPV VP2 protein was constructed using PRV SA215 vector. The safety, immunogenicity, and protective efficacy of the recombinant virus were demonstrated in piglets and primiparous gilts. This recombinant PRV SA215/VP2 represents a suitable candidate for the development of a bivalent vaccine against both PRV and PPV infection. PMID- 21679424 TI - Short read Illumina data for the de novo assembly of a non-model snail species transcriptome (Radix balthica, Basommatophora, Pulmonata), and a comparison of assembler performance. AB - BACKGROUND: Until recently, read lengths on the Solexa/Illumina system were too short to reliably assemble transcriptomes without a reference sequence, especially for non-model organisms. However, with read lengths up to 100 nucleotides available in the current version, an assembly without reference genome should be possible. For this study we created an EST data set for the common pond snail Radix balthica by Illumina sequencing of a normalized transcriptome. Performance of three different short read assemblers was compared with respect to: the number of contigs, their length, depth of coverage, their quality in various BLAST searches and the alignment to mitochondrial genes. RESULTS: A single sequencing run of a normalized RNA pool resulted in 16,923,850 paired end reads with median read length of 61 bases. The assemblies generated by VELVET, OASES, and SeqMan NGEN differed in the total number of contigs, contig length, the number and quality of gene hits obtained by BLAST searches against various databases, and contig performance in the mt genome comparison. While VELVET produced the highest overall number of contigs, a large fraction of these were of small size (< 200bp), and gave redundant hits in BLAST searches and the mt genome alignment. The best overall contig performance resulted from the NGEN assembly. It produced the second largest number of contigs, which on average were comparable to the OASES contigs but gave the highest number of gene hits in two out of four BLAST searches against different reference databases. A subsequent meta-assembly of the four contig sets resulted in larger contigs, less redundancy and a higher number of BLAST hits. CONCLUSION: Our results document the first de novo transcriptome assembly of a non-model species using Illumina sequencing data. We show that de novo transcriptome assembly using this approach yields results useful for downstream applications, in particular if a meta-assembly of contig sets is used to increase contig quality. These results highlight the ongoing need for improvements in assembly methodology. PMID- 21679425 TI - Semi-automatic segmentation of multiple mouse embryos in MR images. AB - BACKGROUND: The motivation behind this paper is to aid the automatic phenotyping of mouse embryos, wherein multiple embryos embedded within a single tube were scanned using Magnetic Resonance Imaging (MRI). RESULTS: Our algorithm, a modified version of the simplex deformable model of Delingette, addresses various issues with deformable models including initialization and inability to adapt to boundary concavities. In addition, it proposes a novel technique for automatic collision detection of multiple objects which are being segmented simultaneously, hence avoiding major leaks into adjacent neighbouring structures. We address the initialization problem by introducing balloon forces which expand the initial spherical models close to the true boundaries of the embryos. This results in models which are less sensitive to initial minimum of two fold after each stage of deformation. To determine collision during segmentation, our unique collision detection algorithm finds the intersection between binary masks created from the deformed models after every few iterations of the deformation and modifies the segmentation parameters accordingly hence avoiding collision.We have segmented six tubes of three dimensional MR images of multiple mouse embryos using our modified deformable model algorithm. We have then validated the results of the our semi-automatic segmentation versus manual segmentation of the same embryos. Our Validation shows that except paws and tails we have been able to segment the mouse embryos with minor error. CONCLUSIONS: This paper describes our novel multiple object segmentation technique with collision detection using a modified deformable model algorithm. Further, it presents the results of segmenting magnetic resonance images of up to 32 mouse embryos stacked in one gel filled test tube and creating 32 individual masks. PMID- 21679426 TI - How many days of monitoring predict physical activity and sedentary behaviour in older adults? AB - BACKGROUND: The number of days of pedometer or accelerometer data needed to reliably assess physical activity (PA) is important for research that examines the relationship with health. While this important research has been completed in young to middle-aged adults, data is lacking in older adults. Further, data determining the number of days of self-reports PA data is also void. The purpose of this study was to examine the number of days needed to predict habitual PA and sedentary behaviour across pedometer, accelerometer, and physical activity log (PA log) data in older adults. METHODS: Participants (52 older men and women; age = 69.3 +/- 7.4 years, range= 55-86 years) wore a Yamax Digiwalker SW-200 pedometer and an ActiGraph 7164 accelerometer while completing a PA log for 21 consecutive days. Mean differences each instrument and intensity between days of the week were examined using separate repeated measures analysis of variance for with pairwise comparisons. Spearman-Brown Prophecy Formulae based on Intraclass Correlations of .80, .85, .90 and .95 were used to predict the number of days of accelerometer or pedometer wear or PA log daily records needed to represent total PA, light PA, moderate-to-vigorous PA, and sedentary behaviour. RESULTS: Results of this study showed that three days of accelerometer data, four days of pedometer data, or four days of completing PA logs are needed to accurately predict PA levels in older adults. When examining time spent in specific intensities of PA, fewer days of data are needed for accurate prediction of time spent in that activity for ActiGraph but more for the PA log. To accurately predict average daily time spent in sedentary behaviour, five days of ActiGraph data are needed. CONCLUSIONS: The number days of objective (pedometer and ActiGraph) and subjective (PA log) data needed to accurately estimate daily PA in older adults was relatively consistent. Despite no statistical differences between days for total PA by the pedometer and ActiGraph, the magnitude of differences between days suggests that day of the week cannot be completely ignored in the design and analysis of PA studies that involve < 7-day monitoring protocols for these instruments. More days of accelerometer data were needed to determine typical sedentary behaviour than PA level in this population of older adults. PMID- 21679427 TI - T cell Activation does not drive CD4 decline in longitudinally followed HIV infected Elite Controllers. AB - BACKGROUND: Elite controllers (EC) are a rare subset of HIV infected individuals who control viral load below 50 copies/ml of plasma without treatment. METHODS: Thirty four EC were studied. The slope of CD4 count change was available for 25 of these subjects. We assessed immune activation by measuring the percent of CD38+HLA-DR+CD8+ T cells in the EC group and comparing it with that in 24 treatment-naive HIV disease progressors and 13 HIV uninfected healthy controls. RESULTS: Compared to HIV uninfected subjects, EC had higher percentages of CD38+HLA-DR+CD8+ T cells (p < 0.001) that was lower than that observed in progressors (p < 0.01). Fifteen of 25 EC had a slope of CD4 count change that was not significantly different from 0 while 3 had a positive and 7 a negative CD4 count slope. Immune activation did not distinguish EC subsets with stable/increasing versus declining CD4 counts. CONCLUSIONS: Elevated immune activation in ECs is not associated with a faster rate of CD4 decline. PMID- 21679428 TI - The effect of cardiovascular risk factors on the longitudinal evolution of the carotid intima medial thickness in children with type 1 diabetes mellitus. AB - BACKGROUND: Type 1 diabetes mellitus is a generally accepted atherogenic risk factor. The aim of this prospective longitudinal study was to evaluate changes in carotid intima media thickness (cIMT) in children and adolescents with type 1 diabetes mellitus (T1DM) using standardized methods. METHODS: We re-evaluated cIMT in 70 (38 f) of initial 150 (80 f) patients with T1DM after 4 years. At re evaluation, mean (+/-SD) age was 16.45+/-2.59 y, mean diabetes duration was 9.2+/ 3.24 y and patients had a mean HbA1c of 8.14+/-1.06%. RESULTS: Mean cIMT z-scores increased significantly during 4 years (0.58+/-0.75, p<0.001) as well as BMI-z score (0.41+/-0.81, p<0.01), systolic blood pressure (0.77+/-1.15, p<0.01) and HbA1c (0.90+/-1.07, <0.001). In a linear regression model systolic blood pressure z-score at first measurement (0.02, CI: 0.01, 0.04) was a significant predictor for the mean effect on cIMT z-score. In a logistic regression model significant risk factors for an increase in IMT of >=1.5 z-scores were BMI z-scores (OR: 3.02, CI:1.11, 10.14), diabetes duration (OR:1.32, CI:1.04, 1.77) and systolic blood pressure (OR: 1.14, CI: 1.04, 1.27) at first measurement each. CONCLUSIONS: Longitudinal cIMT measurements revealed progression in subclinical atherosclerosis during a four year period in diabetic children and adolescents. Systolic blood pressure and BMI were related to cIMT increment. Control of these risk factors by lifestyle and medical intervention may prevent progression of cIMT in diabetic children. PMID- 21679429 TI - Application of site and haplotype-frequency based approaches for detecting selection signatures in cattle. AB - BACKGROUND: 'Selection signatures' delimit regions of the genome that are, or have been, functionally important and have therefore been under either natural or artificial selection. In this study, two different and complementary methods- integrated Haplotype Homozygosity Score (|iHS|) and population differentiation index (FST)--were applied to identify traces of decades of intensive artificial selection for traits of economic importance in modern cattle. RESULTS: We scanned the genome of a diverse set of dairy and beef breeds from Germany, Canada and Australia genotyped with a 50 K SNP panel. Across breeds, a total of 109 extreme |iHS| values exceeded the empirical threshold level of 5% with 19, 27, 9, 10 and 17 outliers in Holstein, Brown Swiss, Australian Angus, Hereford and Simmental, respectively. Annotating the regions harboring clustered |iHS| signals revealed a panel of interesting candidate genes like SPATA17, MGAT1, PGRMC2 and ACTC1, COL23A1, MATN2, respectively, in the context of reproduction and muscle formation. In a further step, a new Bayesian FST-based approach was applied with a set of geographically separated populations including Holstein, Brown Swiss, Simmental, North American Angus and Piedmontese for detecting differentiated loci. In total, 127 regions exceeding the 2.5 per cent threshold of the empirical posterior distribution were identified as extremely differentiated. In a substantial number (56 out of 127 cases) the extreme FST values were found to be positioned in poor gene content regions which deviated significantly (p < 0.05) from the expectation assuming a random distribution. However, significant FST values were found in regions of some relevant genes such as SMCP and FGF1. CONCLUSIONS: Overall, 236 regions putatively subject to recent positive selection in the cattle genome were detected. Both |iHS| and FST suggested selection in the vicinity of the Sialic acid binding Ig-like lectin 5 gene on BTA18. This region was recently reported to be a major QTL with strong effects on productive life and fertility traits in Holstein cattle. We conclude that high-resolution genome scans of selection signatures can be used to identify genomic regions contributing to within- and inter-breed phenotypic variation. PMID- 21679430 TI - The ward atmosphere important for the psychosocial work environment of nursing staff in psychiatric in-patient care. AB - BACKGROUND: The nursing staff working in psychiatric care have a demanding work situation, which may be reflected in how they view their psychosocial work environment and the ward atmosphere. The aims of the present study were to investigate in what way different aspects of the ward atmosphere were related to the psychosocial work environment, as perceived by nursing staff working in psychiatric in-patient care, and possible differences between nurses and nurse assistants. METHODS: 93 nursing staff working at 12 general psychiatric in patient wards in Sweden completed two questionnaires, the Ward Atmosphere Scale and the QPSNordic 34+. Data analyses included descriptive statistics, the Mann Whitney U-test, Spearman rank correlations and forward stepwise conditional logistic regression analyses. RESULTS: The data revealed that there were no differences between nurses and nurse assistants concerning perceptions of the psychosocial work environment and the ward atmosphere. The ward atmosphere subscales Personal Problem Orientation and Program Clarity were associated with a psychosocial work environment characterized by Empowering Leadership. Program Clarity was related to the staff's perceived Role Clarity, and Practical Orientation and Order and Organization were positively related to staff perceptions of the Organizational Climate. CONCLUSIONS: The results from the present study indicate that several ward atmosphere subscales were related to the nursing staff's perceptions of the psychosocial work environment in terms of Empowering Leadership, Role Clarity and Organizational Climate. Improvements in the ward atmosphere could be another way to accomplish improvements in the working conditions of the staff, and such improvements would affect nurses and nurse assistants in similar ways. PMID- 21679432 TI - Randomised cluster trial to support informed parental decision-making for the MMR vaccine. AB - BACKGROUND: In the UK public concern about the safety of the combined measles, mumps and rubella [MMR] vaccine continues to impact on MMR coverage. Whilst the sharp decline in uptake has begun to level out, first and second dose uptake rates remain short of that required for population immunity. Furthermore, international research consistently shows that some parents lack confidence in making a decision about MMR vaccination for their children. Together, this work suggests that effective interventions are required to support parents to make informed decisions about MMR. This trial assessed the impact of a parent-centred, multi-component intervention (balanced information, group discussion, coaching exercise) on informed parental decision-making for MMR. METHODS: This was a two arm, cluster randomised trial. One hundred and forty two UK parents of children eligible for MMR vaccination were recruited from six primary healthcare centres and six childcare organisations. The intervention arm received an MMR information leaflet and participated in the intervention (parent meeting). The control arm received the leaflet only. The primary outcome was decisional conflict. Secondary outcomes were actual and intended MMR choice, knowledge, attitude, concern and necessity beliefs about MMR and anxiety. RESULTS: Decisional conflict decreased for both arms to a level where an 'effective' MMR decision could be made one-week (effect estimate = -0.54, p < 0.001) and three-months (effect estimate = -0.60, p < 0.001) post-intervention. There was no significant difference between arms (effect estimate = 0.07, p = 0.215). Heightened decisional conflict was evident for parents making the MMR decision for their first child (effect estimate = 0.25, p = 0.003), who were concerned (effect estimate = 0.07, p < 0.001), had less positive attitudes (effect estimate = -0.20, p < 0.001) yet stronger intentions (effect estimate = 0.09, p = 0.006). Significantly more parents in the intervention arm reported vaccinating their child (93% versus 73%, p = 0.04). CONCLUSIONS: Whilst both the leaflet and the parent meeting reduced parents' decisional conflict, the parent meeting appeared to enable parents to act upon their decision leading to vaccination uptake. PMID- 21679431 TI - Reference gene selection for gene expression studies using RT-qPCR in virus infected planthoppers. AB - BACKGROUND: Planthoppers not only severely affect crops by causing mechanical damage when feeding but are also vectors of several plant virus species. The analysis of gene expression in persistently infected planthoppers might unveil the molecular basis of viral transmission. Quantitative real-time RT-PCR (RT qPCR) is currently the most accurate and sensitive method used for quantitative gene expression analysis. In order to normalize the resulting quantitative data, reference genes with constant expression during the experimental procedures are needed. RESULTS: Partial sequences of the commonly used reference genes actin (ACT), alpha1-tubulin (TUB), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), elongation factor 1 alpha (EF1A), ribosomal protein S18 (RPS18) and polyubiquitin C (UBI) from Delphacodes kuscheli, a planthopper capable of persistently transmitting the plant fijivirus Mal de Rio Cuarto virus (MRCV), were isolated for the first time. Specific RT-qPCR primers were designed and the expression stability of these genes was assayed in MRCV-infective and naive planthoppers using geNorm, Normfinder and BestKeeper tools. The overall analysis showed that UBI, followed by 18S and ACT, are the most suitable genes as internal controls for quantitative gene expression studies in MRCV-infective planthoppers, while TUB and EF1A are the most variable ones. Moreover, EF1A was upregulated by MRCV infection. CONCLUSIONS: A RT-qPCR platform for gene expression analysis in the MRCV-infected planthopper vector Delphacodes kuscheli was developed. Our work is the first report on reference gene selection in virus-infected insects, and might serve as a precedent for future gene expression studies on MRCV and other virus planthopper pathosystems. PMID- 21679433 TI - The UK clinical research network--has it been a success for dermatology clinical trials? AB - BACKGROUND: Following the successful introduction of five topic-specific research networks in the UK, the Comprehensive Local Research Network (CLRN) was established in 2008 in order to provide a blanket level of support across the whole country regardless of the clinical discipline. The role of the CLRN was to facilitate recruitment into clinical trials, and to encourage greater engagement in research throughout the National Health Service (NHS). METHODS: This report evaluates the impact of clinical research networks in supporting clinical trials in the UK, with particular reference to our experiences from two non-commercial dermatology trials. It covers our experience of engaging with the CLRN (and other research networks) using two non-commercial dermatology trials as case studies. We present the circumstances that led to our approach to the research networks for support, and the impact that this support had on the delivery of these trials. RESULTS: In both cases, recruitment was boosted considerably following the provision of additional support, although other factors such as the availability of experienced personnel, and the role of advertising and media coverage in promoting the trials were also important in translating this additional resource into increased recruitment. CONCLUSIONS: Recruitment into clinical trials is a complex task that can be influenced by many factors. A world class clinical research infrastructure is now in place in England (with similar support available in Scotland and Wales), and it is the responsibility of the research community to ensure that this unique resource is used effectively and responsibly. PMID- 21679434 TI - Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain. AB - BACKGROUND: The exact mechanism of knee osteoarthritis (OA)-associated pain is unclear, whereas mixed evidence of inflammatory pain and neuropathic pain has been noted. We aimed to investigate pain-related sensory innervation in a monoiodoacetate (MIA)-induced model of OA. METHODS: Sixty of seventy female Sprague Dawley rats of six week-old underwent intra-articular MIA and fluorogold (FG) retrograde neurotracer injection into their right (ipsilateral) knee, while their left knees were treated with FG in saline as a control (contralateral knee). Other rats were treated with FG only bilaterally, and used as controls. Rats were evaluated for tactile allodynia using von Frey hairs. Proinflammatory mediators in the knee soft tissues, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and nerve growth factor (NGF), were quantified using ELISAs to evaluate inflammation in the knee after 1, 4, 7, 14, 21, and 28 days post injection. Dorsal root ganglia (DRG) were immunostained for three molecules after 7, 14, 21, and 28 days post injection: calcitonin gene-related peptide (CGRP), a marker of inflammatory pain; and activating transcription factor-3 (ATF3) and growth associated protein-43 (GAP43), as markers for nerve injury and regenerating axons. The distribution of microglia in the spinal cord were also evaluated, because they have been reported to increase in neuropathic pain states. These evaluations were performed up to 28 days postinjection. P < 0.05 was considered significant. RESULTS: Progressive tactile allodynia and elevated cytokine concentrations were observed in ipsilateral knees. CGRP-immunoreactive ( ir) ipsilateral DRG neurons significantly increased, peaking at 14 days postinjection, while expression of FG-labeled ATF3-ir or ATF3-ir GAP43-ir DRG neurons significantly increased in a time-dependent manner. Significant proliferation of microglia were found with time in the ipsilateral dorsal horn. CONCLUSIONS: Pain-related characteristics in a MIA-induced rat OA model can originate from an inflammatory pain state induced by the local inflammation initiated by inflammatory cytokines, and that state will be followed by gradual initiation of neuronal injury, which may induce the neuropathic pain state. PMID- 21679435 TI - Early outcome and blood-brain barrier integrity after co-administered thrombolysis and hyperbaric oxygenation in experimental stroke. AB - BACKGROUND: After promising results in experimental stroke, normobaric (NBO) or hyperbaric oxygenation (HBO) have recently been discussed as co-medication with tissue plasminogen activator (tPA) for improving outcome. This study assessed the interactions of hyperoxia and tPA, focusing on survival, early functional outcome and blood-brain barrier (BBB) integrity following experimental stroke. METHODS: Rats (n = 109) underwent embolic middle cerebral artery occlusion or sham surgery. Animals were assigned to: Control, NBO (60-minute pure oxygen), HBO (60 minute pure oxygen at 2.4 absolute atmospheres), tPA, or HBO+tPA. Functional impairment was assessed at 4 and 24 hours using Menzies score, followed by intravenous application of FITC-albumin as a BBB permeability marker, which was allowed to circulate for 1 hour. Further, blood sampling was performed at 5 and 25 hours for MMP-2, MMP-9, TIMP-1 and TIMP-2 concentration. RESULTS: Mortality rates did not differ significantly between groups, whereas functional improvement was found for NBO, tPA and HBO+tPA. NBO and HBO tended to stabilize BBB and to reduce MMP-2. tPA tended to increase BBB permeability with corresponding MMP and TIMP elevation. Co-administered HBO failed to attenuate these early deleterious effects, independent of functional improvement. CONCLUSIONS: The long-term consequences of simultaneously applied tPA and both NBO and HBO need to be addressed by further studies to identify therapeutic potencies in acute stroke, and to avoid unfavorable courses following combined treatment. PMID- 21679436 TI - MotifClick: prediction of cis-regulatory binding sites via merging cliques. AB - BACKGROUND: Although dozens of algorithms and tools have been developed to find a set of cis-regulatory binding sites called a motif in a set of intergenic sequences using various approaches, most of these tools focus on identifying binding sites that are significantly different from their background sequences. However, some motifs may have a similar nucleotide distribution to that of their background sequences. Therefore, such binding sites can be missed by these tools. RESULTS: Here, we present a graph-based polynomial-time algorithm, MotifClick, for the prediction of cis-regulatory binding sites, in particular, those that have a similar nucleotide distribution to that of their background sequences. To find binding sites with length k, we construct a graph using some 2(k-1)-mers in the input sequences as the vertices, and connect two vertices by an edge if the maximum number of matches of the local gapless alignments between the two 2(k-1) mers is greater than a cutoff value. We identify a motif as a set of similar k mers from a merged group of maximum cliques associated with some vertices. CONCLUSIONS: When evaluated on both synthetic and real datasets of prokaryotes and eukaryotes, MotifClick outperforms existing leading motif-finding tools for prediction accuracy and balancing the prediction sensitivity and specificity in general. In particular, when the distribution of nucleotides of binding sites is similar to that of their background sequences, MotifClick is more likely to identify the binding sites than the other tools. PMID- 21679437 TI - Meta-analysis of grain yield QTL identified during agricultural drought in grasses showed consensus. AB - BACKGROUND: In the last few years, efforts have been made to identify large effect QTL for grain yield under drought in rice. However, identification of most precise and consistent QTL across the environments and genetics backgrounds is essential for their successful use in Marker-assisted Selection. In this study, an attempt was made to locate consistent QTL regions associated with yield increase under drought by applying a genome-wide QTL meta-analysis approach. RESULTS: The integration of 15 maps resulted in a consensus map with 531 markers and a total map length of 1821 cM. Fifty-three yield QTL reported in 15 studies were projected on a consensus map and meta-analysis was performed. Fourteen meta QTL were obtained on seven chromosomes. MQTL1.2, MQTL1.3, MQTL1.4, and MQTL12.1 were around 700 kb and corresponded to a reasonably small genetic distance of 1.8 to 5 cM and they are suitable for use in marker-assisted selection (MAS). The meta-QTL for grain yield under drought coincided with at least one of the meta QTL identified for root and leaf morphology traits under drought in earlier reports. Validation of major-effect QTL on a panel of random drought-tolerant lines revealed the presence of at least one major QTL in each line. DTY12.1 was present in 85% of the lines, followed by DTY4.1 in 79% and DTY1.1 in 64% of the lines. Comparative genomics of meta-QTL with other cereals revealed that the homologous regions of MQTL1.4 and MQTL3.2 had QTL for grain yield under drought in maize, wheat, and barley respectively. The genes in the meta-QTL regions were analyzed by a comparative genomics approach and candidate genes were deduced for grain yield under drought. Three groups of genes such as stress-inducible genes, growth and development-related genes, and sugar transport-related genes were found in clusters in most of the meta-QTL. CONCLUSIONS: Meta-QTL with small genetic and physical intervals could be useful in Marker-assisted selection individually and in combinations. Validation and comparative genomics of the major-effect QTL confirmed their consistency within and across the species. The shortlisted candidate genes can be cloned to unravel the molecular mechanism regulating grain yield under drought. PMID- 21679439 TI - Field evaluation of the intermittent preventive treatment of malaria during pregnancy (IPTp) in Benin: evolution of the coverage rate since its implementation. AB - BACKGROUND: Malaria is an important public health problem in Africa. Pregnant women are a vulnerable population and this disease can underlie an increased risk of low-birth weight newborns (< 2500 g); these women therefore need management during pregnancy. This was previously provided by chloroquine treatment, which, because of compliance problems and drug resistance, was replaced by intermittent preventive treatment with sulfadoxine-pyrimethamine (ITPp-SP) with two single doses taken after 16 weeks of amenorrhea, at least 4 weeks apart. This protocol was recommended by the World Health Organization (WHO) in 1998 and was initiated in Benin in 2006 after its political adoption in 2004.A retrospective longitudinal study was conducted in eight maternity hospitals in two geographical areas in Benin (in the south and north). The study investigated 2420 women who gave birth from 2005 to 2009. The antenatal cards of those women were randomly selected over 5 years with the aim of analyzing the IPT coverage in the study's maternity hospitals. RESULTS: The rate of IPT-SP coverage evolved from 3.7% in 2005 to 87.8% in 2009 for women who had received at least one dose and from 2.7% to 68.4% from 2005 to 2009 for those who had received complete ITP (two doses). Variability in the results was observed depending on the geographical area (north/south) and the type of area (rural/urban). CONCLUSIONS: In total, application of IPT-SP 2-doses has rapidly evolved since 2005, but the objective of 80% IPT coverage has not yet been achieved throughout the country. Moreover, problems of drug shortage recurring in the field (reported by health staff) remain to be resolved. PMID- 21679438 TI - Use of the evidence base in substance abuse treatment programs for American Indians and Alaska Natives: pursuing quality in the crucible of practice and policy. AB - BACKGROUND: A variety of forces are now shaping a passionate debate regarding the optimal approaches to improving the quality of substance abuse services for American Indian and Alaska Native communities. While there have been some highly successful efforts to meld the traditions of American Indian and Alaska Native tribes with that of 12-step approaches, some American Indian and Alaska Natives remain profoundly uncomfortable with the dominance of this Euro-American approach to substance abuse treatment in their communities. This longstanding tension has now been complicated by the emergence of a number of evidence-based treatments that, while holding promise for improving treatment for American Indian and Alaska Natives with substance use problems, may conflict with both American Indian and Alaska Native and 12-step healing traditions. DISCUSSION: We convened a panel of experts from American Indian and Alaska Native communities, substance abuse treatment programs serving these communities, and researchers to discuss and analyze these controversies in preparation for a national study of American Indian and Alaska Native substance abuse services. While the panel identified programs that are using evidence-based treatments, members still voiced concerns about the cultural appropriateness of many evidence-based treatments as well as the lack of guidance on how to adapt them for use with American Indians and Alaska Natives. The panel concluded that the efforts of federal and state policymakers to promote the use of evidence-based treatments are further complicating an already-contentious debate within American Indian and Alaska Native communities on how to provide effective substance abuse services. This external pressure to utilize evidence-based treatments is particularly problematic given American Indian and Alaska Native communities' concerns about protecting their sovereign status. SUMMARY: Broadening this conversation beyond its primary focus on the use of evidence-based treatments to other salient issues such as building the necessary research evidence (including incorporating American Indian and Alaska Native cultural values into clinical practice) and developing the human and infrastructural resources to support the use of this evidence may be far more effective for advancing efforts to improve substance abuse services for American Indian and Alaska Native communities. PMID- 21679440 TI - Concordant and opposite roles of DNA-PK and the "facilitator of chromatin transcription" (FACT) in DNA repair, apoptosis and necrosis after cisplatin. AB - BACKGROUND: Platinum-containing chemotherapy produces specific DNA damage and is used to treat several human solid tumors. Tumors initially sensitive to platinum based drugs frequently become resistant. Inhibition of DNA repair is a potential strategy to enhance cisplatin effectiveness. After cisplatin treatment, a balance between repair and apoptosis determines whether cancer cells proliferate or die. DNA-dependent protein kinase (DNA-PK) binds to DNA double strand breaks (DSBs) through its Ku subunits and initiates non-homologous end joining. Inhibition of DNA-PK sensitizes cancer cells to cisplatin killing. The goal of this study is to elucidate the mechanism underlying the effects of DNA-PK on cisplatin sensitivity. RESULTS: Silencing the expression of the catalytic subunit of DNA-PK (DNA-PKcs) increased sensitivity to cisplatin and decreased the appearance of gammaH2AX after cisplatin treatment. We purified DNA-PK by its Ku86 subunit and identified interactors by tandem mass spectrometry before and after cisplatin treatment. The structure specific recognition protein 1 (SSRP1), Spt16 and gammaH2AX appeared in the Ku86 complex 5 hours after cisplatin treatment. SSRP1 and Spt16 form the facilitator of chromatin transcription (FACT). The cisplatin induced association of FACT with Ku86 and gammaH2AX was abrogated by DNase treatment. In living cells, SSRP1 and Ku86 were recruited at sites of DSBs induced by laser beams. Silencing SSRP1 expression increased sensitivity to cisplatin and decreased gammaH2AX appearance. However, while silencing SSRP1 in cisplatin-treated cells increased both apoptosis and necrosis, DNA-PKcs silencing, in contrast, favored necrosis over apoptosis. CONCLUSIONS: DNA-PK and FACT both play roles in DNA repair. Therefore both are putative targets for therapeutic inhibition. Since DNA-PK regulates apoptosis, silencing DNA-PKcs redirects cells treated with cisplatin toward necrosis. Silencing FACT however, allows both apoptosis and necrosis. Targeting DNA repair in cancer patients may have different therapeutic effects depending upon the roles played by factors targeted. PMID- 21679441 TI - Shifting patterns of natural variation in the nuclear genome of caenorhabditis elegans. AB - BACKGROUND: Genome wide analysis of variation within a species can reveal the evolution of fundamental biological processes such as mutation, recombination, and natural selection. We compare genome wide sequence differences between two independent isolates of the nematode Caenorhabditis elegans (CB4856 and CB4858) and the reference genome (N2). RESULTS: The base substitution pattern when comparing N2 against CB4858 reveals a transition over transversion bias (1.32:1) that is not present in CB4856. In CB4856, there is a significant bias in the direction of base substitution. The frequency of A or T bases in N2 that are G or C bases in CB4856 outnumber the opposite frequencies for transitions as well as transversions. These differences were not observed in the N2/CB4858 comparison. Similarly, we observed a strong bias for deletions over insertions in CB4856 (1.44: 1) that is not present in CB4858. In both CB4856 and CB4858, there is a significant correlation between SNP rate and recombination rate on the autosomes but not on the X chromosome. Furthermore, we identified numerous significant hotspots of variation in the CB4856-N2 comparison.In both CB4856 and CB4858, based on a measure of the strength of selection (ka/ks), all the chromosomes are under negative selection and in CB4856, there is no difference in the strength of natural selection in either the autosomes versus X or between any of the chromosomes. By contrast, in CB4858, ka/ks values are smaller in the autosomes than in the X chromosome. In addition, in CB4858, ka/ks values differ between chromosomes. CONCLUSIONS: The clear bias of deletions over insertions in CB4856 suggests that either the CB4856 genome is becoming smaller or the N2 genome is getting larger. We hypothesize the hotspots found represent alleles that are shared between CB4856 and CB4858 but not N2. Because the ka/ks ratio in the X chromosome is higher than the autosomes on average in CB4858, purifying selection is reduced on the X chromosome. PMID- 21679442 TI - Interferon-lambda1 induces peripheral blood mononuclear cell-derived chemokines secretion in patients with systemic lupus erythematosus: its correlation with disease activity. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organ systems. Previous studies have suggested that interferon lambda 1 (IFN-lambda1), a type III interferon, plays an immunomodulatory role. In this study we investigated its role in SLE, including its correlation with disease activity, organ disorder and production of chemokines. METHODS: We determined levels of IFN-lambda1 mRNA in peripheral blood mononuclear cells (PBMC) and serum protein levels in patients with SLE using real-time polymerase chain reaction (real-time PCR) and enzyme-linked immunoassay (ELISA). Further, we detected the concentration of IFN-inducible protein-10 (IP-10), monokine induced by IFN-gamma (MIG) and interleukin-8 (IL-8) secreted by PBMC under the stimulation of IFN-lambda1 using ELISA. RESULTS: IFN-lambda1 mRNA and serum protein levels were higher in patients with SLE compared with healthy controls. Patients with active disease showed higher IFN-lambda1 mRNA and serum protein levels compared with those with inactive disease as well. Serum IFN-lambda1 levels were positively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), anti-dsDNA antibody, C-reactive protein (CRP) and negatively correlated with complement 3. Serum IFN-lambda1 levels were higher in SLE patients with renal involvement and arthritis compared with patients without the above-mentioned manifestations. IFN-lambda1 with different concentrations displayed different effects on the secretion of the chemokines IP-10, MIG and IL 8. CONCLUSIONS: These findings indicate that IFN-lambda1 is probably involved in the renal disorder and arthritis progression of SLE and associated with disease activity. Moreover, it probably plays an important role in the pathogenesis of SLE by stimulating secretion of the chemokines IP-10, MIG and IL-8. Thus, IFN lambda1 may provide a novel research target for the pathogenesis and therapy of SLE. PMID- 21679443 TI - Abnormal networks of immune response-related molecules in bone marrow cells from patients with rheumatoid arthritis as revealed by DNA microarray analysis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis that progresses to destruction of cartilage and bone. Bone marrow (BM) cells have been shown to contribute to this pathogenesis. In this study, we compared differentially expressed molecules in BM cells from RA and osteoarthritis (OA) patients and analyzed abnormal regulatory networks to identify the role of BM cells in RA. METHODS: Gene expression profiles (GEPs) in BM-derived mononuclear cells from 9 RA and 10 OA patients were obtained by DNA microarray. Up- and down-regulated genes were identified by comparing the GEPs from the two patient groups. Bioinformatics was performed by Expression Analysis Systemic Explorer (EASE) 2.0 based on gene ontology, followed by network pathway analysis with Ingenuity Pathways Analysis (IPA) 7.5. RESULTS: The BM mononuclear cells showed 764 up-regulated and 1,910 down-regulated genes in RA patients relative to the OA group. EASE revealed that the gene category response to external stimulus, which included the gene category immune response, was overrepresented by the up-regulated genes. So too were the gene categories signal transduction and phosphate metabolism. Down-regulated genes were dominantly classified in three gene categories: cell proliferation, which included mitotic cell cycle, DNA replication and chromosome cycle, and DNA metabolism. Most genes in these categories overlapped with each other. IPA analysis showed that the up-regulated genes in immune response were highly relevant to the antigen presentation pathway and to interferon signaling. The major histocompatibility complex (MHC) class I molecules, human leukocyte antigen (HLA)-E, HLA-F, and HLA-G, tapasin (TAP) and TAP binding protein, both of which are involved in peptide antigen binding and presentation via MHC class I molecules, are depicted in the immune response molecule networks. Interferon gamma and interleukin 8 were overexpressed and found to play central roles in these networks. CONCLUSIONS: Abnormal regulatory networks in the immune response and cell cycle categories were identified in BM mononuclear cells from RA patients, indicating that the BM is pathologically involved in RA. PMID- 21679444 TI - Characterization of a branched lipopeptide candidate vaccine against influenza A/Puerto Rico 8/34 which is recognized by human B and T-cell immune responses. AB - The use of synthetic peptides as immunogens represents an exciting alternative to traditional vaccines. However, to date most of these synthetic peptides are not highly immunogenic. The lack of immunogenicity might be addressed by conjugation between T or B cell epitopes with universal or immunodominant T-helper epitopes. The construction of lipidated peptides, branched peptides, or designs combining both of these elements might enhance the immunogenicity, as they might target Toll-Like Receptors and/or mimic the 3-dimensional structure of epitopes within the native protein. Herein, a recognized peptide immunogen based on the hemagglutinin protein of A/Puerto Rico/8/34 was chosen as a backbone and modified to evaluate if the construction of branched peptides, lipidation, the addition of cysteine residues, or mutations could indeed alter epitope reactivity. Screening the different designs with various antibody binding and cellular assays revealed that combining a branched design with the addition of lipid moieties greatly enhanced the immunoreactivity. PMID- 21679445 TI - Hyaluronan modulates accumulation of hypoxia-inducible factor-1 alpha, inducible nitric oxide synthase, and matrix metalloproteinase-3 in the synovium of rat adjuvant-induced arthritis model. AB - INTRODUCTION: Hypoxia is a feature of the inflamed synovium in rheumatoid arthritis (RA). Intra-articular injection of hyaluronan (HA) may be considered a potential way to treat RA. However, the exact molecular mechanism of HA on decreased cellular responses to hypoxic environment is unclear. The present study has been designed to use the adjuvant-induced arthritis model to examine the effects of HA on the changes of immunohistochemical expressions of hypoxia inducible factor-1alpha (HIF-1alpha), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-3 (MMP3) in the synovial tissues at the early phase of arthritic inflammation. METHODS: Monoarthritis was induced in adult male Sprague Dawley (250-300 g) via intraarticular injection of complete Freund's adjuvant (CFA) into the tibiotarsal joint. The CFA-induction arthritis animals were divided into three groups: treatment (intraarticular injection of HA), placebo (intraarticular injection of saline) and controls (no treatments). Functional evaluations of edema and pain behavior, histology, and HIF-1alpha, iNOS, and MMP3 immunohistochemistry were performed before, after the first injection, three injections, and on the follow-up injection of the treatments. RESULTS: Intra articular injection of HA also significantly suppressed the mechanical allodynia (p < 0.001) and overexpressions of HIF-1alpha (p < 0.001), iNOS (p = 0.004) and MMP3 (p < 0.001) immunoreactivity in synovium. CONCLUSIONS: This study demonstrated that early intervention of HA is an effective protection against accumulation of inflammation-induced HIF-1alpha, iNOS, and MMP3 to limit erosive damage in CFA-induced model of arthritis. PMID- 21679446 TI - Evaluation of an online interactive Diabetes Needs Assessment Tool (DNAT) versus online self-directed learning: a randomised controlled trial. AB - BACKGROUND: Methods for the dissemination, understanding and implementation of clinical guidelines need to be examined for their effectiveness to help doctors integrate guidelines into practice. The objective of this randomised controlled trial was to evaluate the effectiveness of an interactive online Diabetes Needs Assessment Tool (DNAT) (which constructs an e-learning curriculum based on individually identified knowledge gaps), compared with self-directed e-learning of diabetes guidelines. METHODS: Health professionals were randomised to a 4 month learning period and either given access to diabetes learning modules alone (control group) or DNAT plus learning modules (intervention group). Participants completed knowledge tests before and after learning (primary outcome), and surveys to assess the acceptability of the learning and changes to clinical practice (secondary outcomes). RESULTS: Sixty four percent (677/1054) of participants completed both knowledge tests. The proportion of nurses (5.4%) was too small for meaningful analysis so they were excluded. For the 650 doctors completing both tests, mean (SD) knowledge scores increased from 47.4% (12.6) to 66.8% (11.5) [intervention group (n = 321, 64%)] and 47.3% (12.9) to 67.8% (10.8) [control group (n = 329, 66%)], (ANCOVA p = 0.186). Both groups were satisfied with the usability and usefulness of the learning materials. Seventy seven percent (218/284) of the intervention group reported combining the DNAT with the recommended reading materials was "very useful"/"useful". The majority in both groups (184/287, 64.1% intervention group and 206/299, 68.9% control group) [95% CI for the difference (-2.8 to 12.4)] reported integrating the learning into their clinical practice. CONCLUSIONS: Both groups experienced a similar and significant improvement in knowledge. The learning materials were acceptable and participants incorporated the acquired knowledge into practice. TRIAL REGISTRATION: ISRCTN: ISRCTN67215088. PMID- 21679447 TI - Analysis of nitrogen oxides (NOx) in the exhaled breath condensate (EBC) of subjects with asthma as a complement to exhaled nitric oxide (FeNO) measurements: a cross-sectional study. AB - BACKGROUND: The study of pulmonary biomarkers with noninvasive methods, such as the analysis of exhaled breath condensate (EBC), provides a useful approach to the pathophysiology of asthma. Although many recent publications have applied such methods, numerous methodological pitfalls remain. The first stage of our study consisted of validating methods for the collection, storage and analysis of EBC; we next sought to clarify the utility of analysing nitrogen oxides (NOx) in the EBC of asthmatics, as a complement to measuring exhaled nitric oxide (FeNO). METHODS: This hospital-based cross-sectional study included 23 controls matched with 23 asthmatics. EBC and FeNO were performed and respiratory function measured. Intra-assay and intra-subject reproducibility were assessed for the analysis of NOx in the EBC of 10 healthy subjects. RESULTS: The intraclass correlation coefficient (ICC) was excellent for intra-assay reproducibility and was moderate for intra-subject reproducibility (Fermanian's classification). NOx was significantly higher in asthmatics (geometric mean [IQR] 14.4 MUM [10.4 - 19.7] vs controls 9.9 MUM [7.5 - 15.0]), as was FeNO (29.9 ppb [17.9 - 52.4] vs controls 9.6 ppb [8.4 - 14.2]). FeNO also increased significantly with asthma severity. CONCLUSIONS: We validated the procedures for NOx analysis in EBC and confirmed the need for assays of other biomarkers to further our knowledge of the pathophysiologic processes of asthma and improve its treatment and control. PMID- 21679448 TI - Association of transforming growth factor-beta1 gene C-509T and T869C polymorphisms with atherosclerotic cerebral infarction in the Chinese: a case control study. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine involved in inflammation and pathogenesis of atherosclerosis. There is scant information on the relation between variations within the TGF-beta1 gene polymorphisms and risks of ischemic cerebrovascular diseases. Therefore, this case-controlled study was carried out to investigate the possible association of the TGF-beta1 gene C-509T and T869C polymorphisms, and their combined genotypes with the risk of atherosclerotic cerebral infarction (CI) in the Chinese population. RESULTS: We recruited 164 CI patients and 167 healthy control subjects who were frequency-matched for age and gender. The frequencies of the 509TT genotype and T allele gene were significantly higher in the CI group (P = 0.007, P = 0.006). The frequencies of +869CC genotype and C allele were higher in the CI group (P = 0.002, P = 0.004). In the CI group, the individuals with -509TT genotype had a significantly higher level of plasma triglyceride (TG) (P = 0.017). +869CC genotype correlated significantly with higher level of plasma low density lipoprotein cholesterol (LDL-c) in the CI group (P = 0.015). With haplotype analysis, the frequency of the -509T/+869C combined genotype was significantly higher in the CI group than in controls (P < 0.001). CONCLUSIONS: Our study suggests that C-509T and T869C gene polymorphisms in TGF-beta1 may be a critical risk factor of genetic susceptibility to CI in the Chinese population. PMID- 21679449 TI - Minimal regulatory spaces in yeast genomes. AB - BACKGROUND: The regulatory information encoded in the DNA of promoter regions usually enforces a minimal, non-zero distance between the coding regions of neighboring genes. However, the size of this minimal regulatory space is not generally known. In particular, it is unclear if minimal promoter size differs between species and between uni- and bi-directionally acting regulatory regions. RESULTS: Analyzing the genomes of 11 yeasts, we show that the lower size limit on promoter-containing regions is species-specific within a relatively narrow range (80-255 bp). This size limit applies equally to regions that initiate transcription on one or both strands, indicating that bi-directional promoters and uni-directional promoters are constrained similarly. We further find that young, species-specific regions are on average much longer than older regions, suggesting either a bias towards deletions or selection for genome compactness in yeasts. While the length evolution of promoter-less intergenic regions is well described by a simplistic, purely neutral model, regions containing promoters typically show an excess of unusually long regions. Regions flanked by divergently transcribed genes have a bi-modal length distribution, with short lengths found preferentially among older regions. These old, short regions likely harbor evolutionarily conserved bi-directionally active promoters. Surprisingly, some of the evolutionarily youngest regions in two of the eleven species (S. cerevisiae and K. waltii) are shorter than the lower limit observed in older regions. CONCLUSIONS: The minimal chromosomal space required for transcriptional regulation appears to be relatively similar across yeast species, and is the same for uni-directional and bi-directional promoters. New intergenic regions created by genome rearrangements tend to evolve towards the more narrow size distribution found among older regions. PMID- 21679450 TI - Improving identification and management of partner violence: examining the process of academic detailing: a qualitative study. AB - BACKGROUND: Many physicians do not routinely inquire about intimate partner violence. PURPOSE: This qualitative study explores the process of academic detailing as an intervention to change physician behavior with regard to intimate partner violence (IPV) identification and documentation. METHOD: A non-physician academic detailer provided a seven-session modular curriculum over a two-and-a half month period. The detailer noted written details of each training session. Audiotapes of training sessions and semi-structured exit interviews with each physician were recorded and transcribed. Transcriptions were qualitatively and thematically coded and analyzed using Atlas ti(r). RESULTS: All three study physicians reported increased clarity with regard to the scope of their responsibility to their patients experiencing IPV. They also reported increased levels of comfort in the effective identification and appropriate documentation of IPV and the provision of ongoing support to the patient, including referrals to specialized community services. CONCLUSION: Academic detailing, if presented by a supportive and knowledgeable academic detailer, shows promise to improve physician attitudes and practices with regards to patients in violent relationships. PMID- 21679451 TI - Impact of dizziness on everyday life in older primary care patients: a cross sectional study. AB - BACKGROUND: Dizziness is a common and often disabling symptom, but diagnosis often remains unclear; especially in older persons where dizziness tends to be multicausal. Research on dizziness-related impairment might provide options for a functional oriented approach, with less focus on finding diagnoses. We therefore studied dizziness-related impairment in older primary care patients and aimed to identify indicators related to this impairment. METHODS: In a cross-sectional study we included 417 consecutive patients of 65 years and older presenting with dizziness to 45 general practitioners in the Netherlands from July 2006 to January 2008. We performed tests, including patient history, and physical and additional examination, previously selected by an international expert panel and based on an earlier systematic review. Our primary outcome was impact of dizziness on everyday life measured with the Dutch validated version of the Dizziness Handicap Inventory (DHI). After a bootstrap procedure (1500x) we investigated predictability of DHI-scores with stepwise backward multiple linear and logistic regressions. RESULTS: DHI-scores varied from 0 to 88 (maximum score: 100) and 60% of patients experienced moderate or severe impact on everyday life due to dizziness. Indicators for dizziness-related impairment were: onset of dizziness 6 months ago or more (OR 2.8, 95% CI 1.7-4.7), frequency of dizziness at least daily (OR 3.3, 95% CI 2.0-5.4), duration of dizziness episode one minute or less (OR 2.4, 95% CI 1.5-3.9), presence of anxiety and/or depressive disorder (OR 4.4, 95% CI 2.2-8.8), use of sedative drugs (OR 2.3, 95% CI 1.3-3.8) , and impaired functional mobility (OR 2.6, 95% CI 1.7-4.2). For this model with only 6 indicators the AUC was .80 (95% CI .76-.84). CONCLUSIONS: Dizziness-related impairment in older primary care patients is considerable (60%). With six simple indicators it is possible to identify which patients suffer the most from their dizziness without exactly knowing the cause(s) of their dizziness. Influencing these indicators, if possible, may lead to functional improvement and this might be effective in patients with moderate or severe impact of dizziness on their daily lives. PMID- 21679452 TI - Use of traditional cooking fuels and the risk of young adult cataract in rural Bangladesh: a hospital-based case-control study. AB - BACKGROUND: This study aimed to investigate the independent relationship between the use of various traditional biomass cooking fuels and the occurrence of cataract in young adults in rural Bangladesh. METHODS: A hospital-based age- and sex-matched case-control study incorporating two control groups was conducted. Cases were cataract patients aged 18 and 49 years diagnosed on the basis of any opacity of the crystalline lens or its capsule and visual acuity poorer than 6/18 on the Log Mar Visual Acuity Chart in either eye, or who had a pseudophakic lens as a result of cataract surgery within the previous 5 years. Non-eye-disease (NE) controls were selected from patients from ENT or Orthopaedics departments and non cataract eye-disease (NC) controls from the Ophthalmology department. Data pertaining to history of exposure to various cooking fuels and to established risk factors for cataract were obtained by face-to-face interview and analyzed using conditional logistic regression. RESULTS: Clean fuels were used by only 4% of subjects. A majority of males (64-80% depending on group) had never cooked, while the rest had used biomass cooking fuels, mainly wood/dry leaves, with only 6 having used rice straw and/or cow dung. All females of each group had used wood/dry leaves for cooking. Close to half had also used rice straw and/or cow dung. Among females, after controlling for family history of cataract and education and combining the two control groups, case status was shown to be significantly related to lifetime exposure to rice straw, fitted as a trend variable coded as never, <=median of all exposed, >median of all exposed (OR=1.52, 95%CI 1.04-2.22), but not to lifetime exposure to wood/dry leaves. Case status among females showed an inverse association with ever use of cow dung as a cooking fuel (OR 0.43, 95%CI 0.22-0.81). CONCLUSIONS: In this population, where cooking is almost exclusively done using biomass fuels, cases of young adult cataract among females were more likely to have had an increased lifetime exposure to cooking with rice straw fuel and not to have cooked using cow dung fuel. There is a possibility that these apparent associations could have been the result of uncontrolled founding, for instance by wealth. The nature of the associations, therefore, needs to be further investigated. PMID- 21679453 TI - Specialist involvement and referral patterns in ambulatory medical care for patients with dementia in Germany: results of a claims data based case-control study. AB - BACKGROUND: To analyze the referral processes from general practitioners to specialists and among specialists for dementia patients in the time periods before, during and after the diagnosis in Germany. METHODS: In this case-control study claims data from 1,848 insurants with incident dementia aged 65 years and more and 7,392 matched controls were compared over a two-year period covering the pre-incidence, incidence and post-incidence time periods. RESULTS: We found an increase in referrals of 30% in the incidence quarter, mainly from general practice to neuropsychiatry and from there to radiology. Referrals to clinical chemistry and other disciplines for dementia-specific reasons were negligible in amount. 34% of incident cases had at least one contact with a neuropsychiatrist during the year of incidence, and the majority of them visited this specialist repeatedly during that year. Only a minority (13.5%) of patients was referred to radiology for imaging. Referrals to other specialists declined whereas self referrals did not increase. CONCLUSIONS: The referral rates to relevant specialists (neuropsychiatry, radiology and clinical chemistry) are far less frequent than proposed in German guidelines. More research is needed to explain the gape between guidelines and daily care and to find ways for a better implementation of guidelines in ambulatory care. Guidelines should not only deal with diagnostic procedures and therapeutic options but also consider questions of applicability in daily clinical practice and propose effective organizational models of care provision. PMID- 21679454 TI - Noise reduction in protein-protein interaction graphs by the implementation of a novel weighting scheme. AB - BACKGROUND: Recent technological advances applied to biology such as yeast-two hybrid, phage display and mass spectrometry have enabled us to create a detailed map of protein interaction networks. These interaction networks represent a rich, yet noisy, source of data that could be used to extract meaningful information, such as protein complexes. Several interaction network weighting schemes have been proposed so far in the literature in order to eliminate the noise inherent in interactome data. In this paper, we propose a novel weighting scheme and apply it to the S. cerevisiae interactome. Complex prediction rates are improved by up to 39%, depending on the clustering algorithm applied. RESULTS: We adopt a two step procedure. During the first step, by applying both novel and well established protein-protein interaction (PPI) weighting methods, weights are introduced to the original interactome graph based on the confidence level that a given interaction is a true-positive one. The second step applies clustering using established algorithms in the field of graph theory, as well as two variations of Spectral clustering. The clustered interactome networks are also cross-validated against the confirmed protein complexes present in the MIPS database. CONCLUSIONS: The results of our experimental work demonstrate that interactome graph weighting methods clearly improve the clustering results of several clustering algorithms. Moreover, our proposed weighting scheme outperforms other approaches of PPI graph weighting. PMID- 21679455 TI - The chronic kidney disease model: a general purpose model of disease progression and treatment. AB - BACKGROUND: Chronic kidney disease (CKD) is the focus of recent national policy efforts; however, decision makers must account for multiple therapeutic options, comorbidities and complications. The objective of the Chronic Kidney Disease model is to provide guidance to decision makers. We describe this model and give an example of how it can inform clinical and policy decisions. METHODS: Monte Carlo simulation of CKD natural history and treatment. Health states include myocardial infarction, stroke with and without disability, congestive heart failure, CKD stages 1-5, bone disease, dialysis, transplant and death. Each cycle is 1 month. Projections account for race, age, gender, diabetes, proteinuria, hypertension, cardiac disease, and CKD stage. Treatment strategies include hypertension control, diabetes control, use of HMG-CoA reductase inhibitors, use of angiotensin converting enzyme inhibitors, nephrology specialty care, CKD screening, and a combination of these. The model architecture is flexible permitting updates as new data become available. The primary outcome is quality adjusted life years (QALYs). Secondary outcomes include health state events and CKD progression rate. RESULTS: The model was validated for GFR change/year -3.0 +/- 1.9 vs. -1.7 +/- 3.4 (in the AASK trial), and annual myocardial infarction and mortality rates 3.6 +/- 0.9% and 1.6 +/- 0.5% vs. 4.4% and 1.6% in the Go study. To illustrate the model's utility we estimated lifetime impact of a hypothetical treatment for primary prevention of vascular disease. As vascular risk declined, QALY improved but risk of dialysis increased. At baseline, 20% and 60% reduction: QALYs = 17.6, 18.2, and 19.0 and dialysis = 7.7%, 8.1%, and 10.4%, respectively. CONCLUSIONS: The CKD Model is a valid, general purpose model intended as a resource to inform clinical and policy decisions improving CKD care. Its value as a tool is illustrated in our example which projects a relationship between decreasing cardiac disease and increasing ESRD. PMID- 21679456 TI - Openness in participation, assessment, and policy making upon issues of environment and environmental health: a review of literature and recent project results. AB - Issues of environment and environmental health involve multiple interests regarding e.g. political, societal, economical, and public concerns represented by different kinds of organizations and individuals. Not surprisingly, stakeholder and public participation has become a major issue in environmental and environmental health policy and assessment. The need for participation has been discussed and reasoned by many, including environmental legislators around the world. In principle, participation is generally considered as desirable and the focus of most scholars and practitioners is on carrying out participation, and making participation more effective. In practice also doubts regarding the effectiveness and importance of participation exist among policy makers, assessors, and public, leading even to undermining participatory practices in policy making and assessment.There are many possible purposes for participation, and different possible models of interaction between assessment and policy. A solid conceptual understanding of the interrelations between participation, assessment, and policy making is necessary in order to design and implement effective participatory practices. In this paper we ask, do current common conceptions of assessment, policy making and participation provide a sufficient framework for achieving effective participation? This question is addresses by reviewing the range of approaches to participation in assessment and policy making upon issues of environment and environmental health and some related insights from recent research projects, INTARESE and BENERIS.Openness, considered e.g. in terms of a) scope of participation, b) access to information, c) scope of contribution, d) timing of openness, and e) impact of contribution, provides a new perspective to the relationships between participation, assessment and policy making. Participation, assessment, and policy making form an inherently intertwined complex with interrelated objectives and outcomes. Based on experiences from implementing openness, we suggest complete openness as the new default, deviation from which should be explicitly argued, in assessment and policy making upon issues of environment and environmental health. Openness does not undermine the existing participatory models and techniques, but provides conceptual means for their more effective application, and opens up avenues for developing new kinds of effective participatory practices that aim for societal development through collaborative creation of knowledge. PMID- 21679457 TI - The development of an adaptive upper-limb stroke rehabilitation robotic system. AB - BACKGROUND: Stroke is the primary cause of adult disability. To support this large population in recovery, robotic technologies are being developed to assist in the delivery of rehabilitation. This paper presents an automated system for a rehabilitation robotic device that guides stroke patients through an upper-limb reaching task. The system uses a decision theoretic model (a partially observable Markov decision process, or POMDP) as its primary engine for decision making. The POMDP allows the system to automatically modify exercise parameters to account for the specific needs and abilities of different individuals, and to use these parameters to take appropriate decisions about stroke rehabilitation exercises. METHODS: The performance of the system was evaluated by comparing the decisions made by the system with those of a human therapist. A single patient participant was paired up with a therapist participant for the duration of the study, for a total of six sessions. Each session was an hour long and occurred three times a week for two weeks. During each session, three steps were followed: (A) after the system made a decision, the therapist either agreed or disagreed with the decision made; (B) the researcher had the device execute the decision made by the therapist; (C) the patient then performed the reaching exercise. These parts were repeated in the order of A-B-C until the end of the session. Qualitative and quantitative question were asked at the end of each session and at the completion of the study for both participants. RESULTS: Overall, the therapist agreed with the system decisions approximately 65% of the time. In general, the therapist thought the system decisions were believable and could envision this system being used in both a clinical and home setting. The patient was satisfied with the system and would use this system as his/her primary method of rehabilitation. CONCLUSIONS: The data collected in this study can only be used to provide insight into the performance of the system since the sample size was limited. The next stage for this project is to test the system with a larger sample size to obtain significant results. PMID- 21679458 TI - Do clinical guidelines reduce clinician dependent costs? AB - Clinician dependent costs are the costs of care that are under the discretion of the healthcare provider. These costs include the costs of drugs, tests and investigations, and discretionary outpatient visits and impatient stays. The purpose of this review was to summarize recent evidence, relevant to both developed and developing countries on whether evidence based clinical guidelines can change hospitals variable costs which are clinician dependent, and the degree of financial savings achieved at hospital level. Potential studies for inclusion were identified using structured searches of Econlit, J-Stor, and Pubmed databases. Two reviewers independently evaluated retrieved studies for inclusion. The methodological quality of the selected articles was assessed using the Oxford Centre for Evidence- Based Medicine (CEBM) levels of evidence. The results suggest that 10 of the 11 interventions were successful reducing financial costs. Most of the interventions, either in modeling studies or real interventions generate significant financial saving, although the former reported higher savings because the studies assumed 100 percent compliance. PMID- 21679459 TI - Pattern of malaria transmission along the Rahad River basin, Eastern Sudan. AB - BACKGROUND: Understanding malaria vector mosquitoes and their infectivity dynamics is of importance in setting up intervention and control programmes. Patterns of malaria transmission have been shown to differ between non-irrigated and irrigated semi-arid areas of eastern Sudan. However, very little information is available regarding malaria transmission dynamics along the seasonal river's basin. Such information is required for the design of effective vector control strategies. METHODS: A longitudinal study for mosquito sampling using pyrethrum spray catch (PSC) was conducted in two villages (Koka & Um Salala) along the Rahad River basin from December 2005 to October 2006. The Plasmodium falciparum circumsporozoite (CSP) and human blood index (HBI) were detected by ELISA. Three seasons were considered and the surveys represented cool dry, hot dry and rainy seasons were November - February, March - June, July - October, respectively. The CSP was compared between the seasons and populations using Chi-square test. The differences between the seasons and the populations in the other entomological indices, including Entomological Inoculation Rates (EIR), were measured using Tukey-Kramer HSD and Student T-test, respectively. The association between An. arabiensis density and monthly total rainfall was examined using regression analysis. RESULTS: A total of 1,402 adult female anopheline mosquitoes were sampled, of which 98% were An. gambiae complex; the rest were An. rufipes. All specimens of An. gambiae complex identified by the PCR were An. arabiensis. Bimodal annual peaks of An. arabiensis densities were observed following the peak of rainfall and recess of the Rahad River after a time- lag of two months (Koka r = 0.79, d.f. = 1, P = 0.05; Um Salala, r = 0.88, d.f. = 1, P = 0.02). The CSP differed significantly among the seasons only in Koka (P = 0.0009) where the mean was nine times higher than in Um Salala (P = 0.0014). Active transmission was observed in Koka during the hot, dry season (CSP = 6.25%) and the EIR was observed to be 0.01 ib/p/n during this time. The EIR peaked to 0.71 ib/p/n during the rainy season and decreased to 0.18 ib/p/n during the minor peak of the cool dry season (P = 0.54). The combined annual average of the EIR for both populations was 55.48 ib/p/y and, typically, it would take approximately 192.7 days for an individual to receive an infective bite from An. arabiensis. CONCLUSION: The bimodal annual peaks and the active transmission observed during the hot dry season suggested low to moderate perennial malaria transmission pattern. Infectivity and transmission rates increased with proximity to the river following the peak of rainfall and the subsequent recession in the flow of the Rahad River. Current vector interventions can be integrated with larval control and should be formatted in accordance with targeted according to the time and space. PMID- 21679460 TI - LAVA: an open-source approach to designing LAMP (loop-mediated isothermal amplification) DNA signatures. AB - BACKGROUND: We developed an extendable open-source Loop-mediated isothermal AMPlification (LAMP) signature design program called LAVA (LAMP Assay Versatile Analysis). LAVA was created in response to limitations of existing LAMP signature programs. RESULTS: LAVA identifies combinations of six primer regions for basic LAMP signatures, or combinations of eight primer regions for LAMP signatures with loop primers, which can be used as LAMP signatures. The identified primers are conserved among target organism sequences. Primer combinations are optimized based on lengths, melting temperatures, and spacing among primer sites. We compare LAMP signature candidates for Staphylococcus aureus created both by LAVA and by PrimerExplorer. We also include signatures from a sample run targeting all strains of Mycobacterium tuberculosis. CONCLUSIONS: We have designed and demonstrated new software for identifying signature candidates appropriate for LAMP assays. The software is available for download at http://lava dna.googlecode.com/. PMID- 21679461 TI - Transcriptomic, proteomic and metabolomic analysis of UV-B signaling in maize. AB - BACKGROUND: Under normal solar fluence, UV-B damages macromolecules, but it also elicits physiological acclimation and developmental changes in plants. Excess UV B decreases crop yield. Using a treatment twice solar fluence, we focus on discovering signals produced in UV-B-irradiated maize leaves that translate to systemic changes in shielded leaves and immature ears. RESULTS: Using transcriptome and proteomic profiling, we tracked the kinetics of transcript and protein alterations in exposed and shielded organs over 6 h. In parallel, metabolic profiling identified candidate signaling molecules based on rapid increase in irradiated leaves and increased levels in shielded organs; pathways associated with the synthesis, sequestration, or degradation of some of these potential signal molecules were UV-B-responsive. Exposure of just the top leaf substantially alters the transcriptomes of both irradiated and shielded organs, with greater changes as additional leaves are irradiated. Some phenylpropanoid pathway genes are expressed only in irradiated leaves, reflected in accumulation of pathway sunscreen molecules. Most protein changes detected occur quickly: approximately 92% of the proteins in leaves and 73% in immature ears changed after 4 h UV-B were altered by a 1 h UV-B treatment. CONCLUSIONS: There were significant transcriptome, proteomic, and metabolomic changes under all conditions studied in both shielded and irradiated organs. A dramatic decrease in transcript diversity in irradiated and shielded leaves occurs between 0 h and 1 h, demonstrating the susceptibility of plants to short term UV-B spikes as during ozone depletion. Immature maize ears are highly responsive to canopy leaf exposure to UV-B. PMID- 21679462 TI - The dynamics of vertebrate homeobox gene evolution: gain and loss of genes in mouse and human lineages. AB - BACKGROUND: Homeobox genes are a large and diverse group of genes, many of which play important roles in transcriptional regulation during embryonic development. Comparison of homeobox genes between species may provide insights into the evolution of developmental mechanisms. RESULTS: Here we report an extensive survey of human and mouse homeobox genes based on their most recent genome assemblies, providing the first comprehensive analysis of mouse homeobox genes and updating an earlier survey of human homeobox genes. In total we recognize 333 human homeobox loci comprising 255 probable genes and 78 probable pseudogenes, and 324 mouse homeobox loci comprising 279 probable genes and 45 probable pseudogenes (accessible at http://homeodb.zoo.ox.ac.uk). Comparison to partial genome sequences from other species allows us to resolve which differences are due to gain of genes and which are due to gene losses. CONCLUSIONS: We find there has been much more homeobox gene loss in the rodent evolutionary lineage than in the primate lineage. While humans have lost only the Msx3 gene, mice have lost Ventx, Argfx, Dprx, Shox, Rax2, LOC647589, Tprx1 and Nanognb. This analysis provides insight into the patterns of homeobox gene evolution in the mammals, and a step towards relating genomic evolution to phenotypic evolution. PMID- 21679463 TI - Relatives Education And Coping Toolkit--REACT. Study protocol of a randomised controlled trial to assess the feasibility and effectiveness of a supported self management package for relatives of people with recent onset psychosis. AB - BACKGROUND: Mental health problems commonly begin in adolescence when the majority of people are living with family. This can be a frightening time for relatives who often have little knowledge of what is happening or how to manage it. The UK National Health Service has a commitment to support relatives in order to reduce their distress, but research studies have shown that this can lead to a better outcome for service users as well. Unfortunately, many relatives do not get the kind of support they need. We aim to evaluate the feasibility, acceptability and effectiveness of providing and supporting a Relatives' Education and Coping Toolkit (REACT) for relatives of people with recent onset psychosis. METHODS: The study is a randomised control trial. Trial Registration for Current Controlled Trials ISRCTN69299093. Relatives of people receiving treatment from the Early Intervention Service for psychosis are randomly allocated to receive either Treatment As Usual (TAU) or TAU plus the REACT intervention. The main aims of the study are to: (i) determine the acceptability of a supported self-management intervention; (ii) determine preference for type of support; (iii) assess the feasibility of the design; (iv) identify the barriers and solutions to offering support for self-management approaches within the NHS; (v) estimate the likely effect size of the impact of the intervention on outcome for relatives; (vi) gain detailed feedback about the barriers and solutions to using a self-management approach; (vii) describe the way in which the intervention is used. Outcomes will be assessed from baseline and at 6 month follow-up. DISCUSSION: The intervention is compared to current treatment in a sample of participants highly representative of relatives in routine early intervention services across the UK. The intervention is protocolised, offered within routine practice by existing staff and extensive process data is being collected. Randomisation is independent; all assessments are made by blind raters. The limitations of the study are the lack of control over how the intervention is delivered, the short follow-up period, and the lack of assessment of service user outcomes. Despite these, the findings will inform future effectiveness trials and contribute to the growing evidence base for supported self-mangement interventions in mental health. PMID- 21679464 TI - Prevalence and clinical pattern of paediatric HIV infection at the University College Hospital, Ibadan, Nigeria: a prospective cross-sectional study. AB - BACKGROUND: The prevalence of Paediatric HIV infection is largely unknown in many countries in sub-Saharan Africa. This study was aimed at determining the prevalence, clinical pattern of HIV infection and outcome among new patients aged <15 years using age-specific diagnostic methods. METHODS: A prospective cross sectional study was carried out using the provider initiated HIV testing and counselling (PITC) model. HIV rapid test in parallel was used for screening and confirmation was with HIV DNA PCR in children <18 months and Western Blot in children >= 18 months. RESULTS: A total of 600 children were enrolled with ages ranging between one day and 179 months. Male: female ratio was 1.2:1. HIV seroprevalence was 12.3% and after confirmatory tests, the prevalence was 10%. Fourteen (37.8%) of the children aged less 18 months were exposed but not infected. Mother-to-child transmission accounted for 93.3% of cases. Features predictive of HIV infection were diarrhoea, cough, weight loss, ear discharge generalized lymphadenopathy, presence of skin lesions, parotid swelling and oral thrush. About 75% presented in advanced or severe clinical stages of the disease, 56.8% had severe immunodeficiency while 50% had viral loads more than 100,000 copies/ml. Mortality rate was 14.3% among HIV positive compared with 11.3% in HIV negative children but was not significant. Among the HIV positive children, 26.7% were orphans. CONCLUSIONS: The prevalence rate of HIV infection among new patients screened using the PITC model was high, majority resulting from mother to-child transmission. Most children presented in advanced stages of the disease and mortality rate among them was high. Though, the study site being a referral centre might have contributed to the high prevalence observed in this study, there is a need to expand access to PMTCT services, ensure implementation of PITC in paediatric settings and expand support services for HIV infected children. PMID- 21679465 TI - NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications. AB - INTRODUCTION: Women with triple-negative breast cancer have the worst prognosis, frequently present with metastatic tumors and have few targeted therapy options. Notch-1 and Notch-4 are potent breast oncogenes that are overexpressed in triple negative and other subtypes of breast cancer. PEA3, an ETS transcription factor, is also overexpressed in triple-negative and other breast cancer subtypes. We investigated whether PEA3 could be the critical transcriptional activator of Notch receptors in MDA-MB-231 and other breast cancer cells. METHODS: Real-time PCR and Western blot analysis were performed to detect Notch-1, Notch-2, Notch-3 and Notch-4 receptor expression in breast cancer cells when PEA3 was knocked down by siRNA. Chromatin immunoprecipitation was performed to identify promoter regions for Notch genes that recruited PEA3. TAM-67 and c-Jun siRNA were used to identify that c-Jun was necessary for PEA3 enrichment on the Notch-4 promoter. A Notch-4 luciferase reporter was used to confirm that endogenous PEA3 or AP-1 activated the Notch-4 promoter region. Cell cycle analysis, trypan blue exclusion, annexin V flow cytometry, colony formation assay and an in vivo xenograft study were performed to determine the biological significance of targeting PEA3 via siRNA, Notch signaling via a gamma-secretase inhibitor, or both. RESULTS: Herein we provide new evidence for transcriptional regulation of Notch by PEA3 in breast cancer. PEA3 activates Notch-1 transcription in MCF-7, MDA-MB-231 and SKBr3 breast cancer cells. PEA3 activates Notch-4 transcription in MDA-MB-231 cells where PEA3 levels are endogenously high. In SKBr3 and BT474 breast cancer cells where PEA3 levels are low, overexpression of PEA3 increases Notch-4 transcripts. Chromatin immunoprecipitation confirmed the enrichment of PEA3 on Notch-1 and Notch-4 promoters in MDA-MB-231 cells. PEA3 recruitment to Notch-1 was AP-1-independent, whereas PEA3 recruitment to Notch-4 was c-JUN dependent. Importantly, the combined inhibition of Notch signaling via a gamma secretase inhibitor (MRK-003 GSI) and knockdown of PEA3 arrested growth in the G1 phase, decreased both anchorage-dependent and anchorage-independent growth and significantly increased apoptotic cells in vitro. Moreover, either PEA3 knockdown or MRK-003 GSI treatment significantly reduced tumor growth of MDA-MB-231 xenografts in vivo. CONCLUSIONS: Taken together, the results from this study demonstrate for the first time that Notch-1 and Notch-4 are novel transcriptional targets of PEA3 in breast cancer cells. Targeting of PEA3 and/or Notch pathways might provide a new therapeutic strategy for triple-negative and possibly other breast cancer subtypes. PMID- 21679466 TI - Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma. AB - BACKGROUND: Cladribine or 2-chlorodeoxyadenosine (2-CDA) is a well-known purine nucleoside analog with particular activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL). Its benefits in multiple myeloma (MM) remain unclear. Here we report the inhibitory effects of cladribine on MM cell lines (U266, RPMI8226, MM1.S), and its therapeutic potential in combination with a specific inhibitor of the signal transducer and activator of transcription 3 (STAT3). METHODS: MTS-based proliferation assays were used to determine cell viability in response to cladribine. Cell cycle progression was examined by flow cytometry analysis. Cells undergoing apoptosis were evaluated with Annexin V staining and a specific ELISA to quantitatively measure cytoplasmic histone associated DNA fragments. Western blot analyses were performed to determine the protein expression levels and activation. RESULTS: Cladribine inhibited cell proliferation of MM cells in a dose-dependent manner, although the three MM cell lines exhibited a remarkably different responsiveness to cladribine. The IC50 of cladribine for U266, RPMI8226, or MM1.S cells was approximately 2.43, 0.75, or 0.18 MUmol/L, respectively. Treatment with cladribine resulted in a significant G1 arrest in U266 and RPMI8226 cells, but only a minor increase in the G1 phase for MM1.S cells. Apoptosis assays with Annexin V-FITC/PI double staining indicated that cladribine induced apoptosis of U266 cells in a dose-dependent manner. Similar results were obtained with an apoptotic-ELISA showing that cladribine dramatically promoted MM1.S and RPMA8226 cells undergoing apoptosis. On the molecular level, cladribine induced PARP cleavage and activation of caspase-8 and caspase-3. Meanwhile, treatment with cladribine led to a remarkable reduction of the phosphorylated STAT3 (P-STAT3), but had little effect on STAT3 protein levels. The combinations of cladribine and a specific STAT3 inhibitor as compared to either agent alone significantly induced apoptosis in all three MM cell lines. CONCLUSIONS: Cladribine exhibited inhibitory effects on MM cells in vitro. MM1.S is the only cell line showing significant response to the clinically achievable concentrations of cladribine-induced apoptosis and inactivation of STAT3. Our data suggest that MM patients with the features of MM1.S cells may particularly benefit from cladribine monotherapy, whereas cladribine in combination with STAT3 inhibitor exerts a broader therapeutic potential against MM. PMID- 21679467 TI - Renal kallikrein excretion and epigenetics in human acute kidney injury: expression, mechanisms and consequences. AB - BACKGROUND: Renal kallikrein (KLK1) synthesis and urinary excretion are reportedly diminished during AKI (acute kidney injury) in animal models, and provision of kallikrein abrogates renal injury in this setting, but data in human AKI is limited. Therefore we first examined KLK1 renal excretion in human AKI, and then probed potential endocrine and epigenetic mechanisms for its alterations. METHODS: KLK1 enzymatic activity excretion was evaluated in urine from patients with established or incipient AKI, versus healthy/non-hospital as well as ICU controls. Endocrine control of KLK1 excretion was then probed by catecholamine and aldosterone measurements in established AKI versus healthy controls. To examine epigenetic control of KLK1 synthesis, we tested blood and urine DNA for changes in promoter CpG methylation of the KLK1 gene, as well as LINE-1 elements, by bisulfite sequencing. RESULTS: Patients with early/incipient AKI displayed a modest reduction of KLK1 excretion, but unexpectedly, established AKI displayed substantially elevated urine KLK1 excretion, ~11-fold higher than healthy controls, and ~3-fold greater than ICU controls. We then probed potential mechanisms of the change. Established AKI patients had lower SBP, higher heart rate, and higher epinephrine excretion than healthy controls, though aldosterone excretion was not different. Promoter KLK1 CpG methylation was higher in blood than urine DNA, while KLK1 methylation in blood DNA was significantly higher in established AKI than healthy controls, though KLK1 methylation in urine tended to be higher in AKI, directionally consistent with earlier/incipient but not later/established changes in KLK1 excretion in AKI. On multivariate ANOVA, AKI displayed coordinate changes in KLK1 excretion and promoter methylation, though directionally opposite to expectation. Control (LINE-1 repetitive element) methylation in blood and urine DNA was similar between AKI and controls. CONCLUSIONS: Unexpectedly, increased KLK1 excretion in AKI patients was found; this increase is likely to be due in part to increments in adrenergic tone during BP depression. Epigenetic changes at KLK1 may also play a role in early changes of KLK1 expression and thus AKI susceptibility or recovery. PMID- 21679468 TI - A systematic review of the clinical effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of suspected coronary artery disease. AB - BACKGROUND: This systematic review summarized recent evidence pertaining to the clinical effectiveness of 64-slice or higher computed tomography angiography (CTA) in patients with suspected coronary artery disease (CAD). If CTA proves to be a successful diagnostic performance measure, it could prevent the use of invasive diagnostic procedures in some patients. This would provide multiple health and cost benefits, particularly for under resourced areas where invasive coronary angiography is not always available. METHODS: A systematic method of literature searching and selection was employed with searches limited to December 2006 to March 2009. Included studies were quality assessed using National Health and Medical Research Council (NHMRC) diagnostic levels of evidence and a modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. Individual and pooled diagnostic performance measures were calculated using standard meta analytic techniques at the patient, vessel and segment level. A positive result was defined as greater than or equal to 50% stenosis. RESULTS: Twenty-eight studies were included in the systematic review examining 3,674 patients. The primary meta-analysis at the patient-level indicated a sensitivity of 98.2% and specificity of 81.6%. The median (range) positive predictive value (PPV) was 90.5% (76%-100%) and negative predictive value (NPV) 99.0% (83%-100%). In all vessels, the pooled sensitivity was 94.9%, specificity 89.5%, and median (range) PPV 75.0% (53%-95%) and NPV 99.0% (93%-100%). At the individual artery level, overall diagnostic accuracy appeared to be slightly higher in the left main coronary artery and slightly lower in the left anterior descending and circumflex artery. In all segments, the sensitivity was 91.3%, specificity 94.0% and median (range) PPV 69.0% (44%-86%) and NPV 99.0% (98%-100%). CONCLUSIONS: The high sensitivity indicates that CTA can effectively identify the majority of patients with significant coronary artery stenosis. The high NPV at the patient, vessel and segment level establishes CTA as an effective non-invasive alternative to invasive coronary angiography (ICA) for the exclusion of stenosis. PMID- 21679469 TI - Gbetagamma subunits inhibit Epac-induced melanoma cell migration. AB - BACKGROUND: Recently we reported that activation of Epac1, an exchange protein activated by cAMP, increases melanoma cell migration via Ca 2+ release from the endoplasmic reticulum (ER). G-protein betagamma subunits (Gbetagamma) are known to act as an independent signaling molecule upon activation of G-protein coupled receptor. However, the role of Gbetagamma in cell migration and Ca 2+ signaling in melanoma has not been well studied. Here we report that there is crosstalk of Ca 2+ signaling between Gbetagamma and Epac in melanoma, which plays a role in regulation of cell migration. METHODS: SK-Mel-2 cells, a human metastatic melanoma cell line, were mainly used in this study. Intracellular Ca 2+ was measured with Fluo-4AM fluorescent dyes. Cell migration was examined using the Boyden chambers. RESULTS: The effect of Gbetagamma on Epac-induced cell migration was first examined. Epac-induced cell migration was inhibited by mSIRK, a Gbetagamma -activating peptide, but not its inactive analog, L9A, in SK-Mel-2 cells. Guanosine 5', alpha-beta-methylene triphosphate (Gp(CH2)pp), a constitutively active GTP analogue that activates Gbetagamma, also inhibited Epac induced cell migration. In addition, co-overexpression of beta1 and gamma2, which is the major combination of Gbetagamma, inhibited Epac1-induced cell migration. By contrast, when the C-terminus of beta adrenergic receptor kinase (betaARK-CT), an endogenous inhibitor for Gbetagamma, was overexpressed, mSIRK's inhibitory effect on Epac-induced cell migration was negated, suggesting the specificity of mSIRK for Gbetagamma. We next examined the effect of mSIRK on Epac-induced Ca 2+ response. When cells were pretreated with mSIRK, but not with L9A, 8-(4 Methoxyphenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8-pMeOPT), an Epac-specific agonist, failed to increase Ca 2+ signal. Co-overexpression of beta1 and gamma2 subunits inhibited 8-pMeOPT-induced Ca 2+ elevation. Inhibition of Gbetagamma with betaARK-CT or guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS), a GDP analogue that inactivates Gbetagamma, restored 8-pMeOPT-induced Ca 2+ elevation even in the presence of mSIRK. These data suggested that Gbetagamma inhibits Epac-induced Ca 2+ elevation. Subsequently, the mechanism by which Gbetagamma inhibits Epac-induced Ca 2+ elevation was explored. mSIRK activates Ca 2+ influx from the extracellular space. In addition, W-5, an inhibitor of calmodulin, abolished mSIRK's inhibitory effects on Epac-induced Ca 2+ elevation, and cell migration. These data suggest that, the mSIRK-induced Ca 2+ from the extracellular space inhibits the Epac-induced Ca 2+ release from the ER, resulting suppression of cell migration. CONCLUSION: We found the cross talk of Ca 2+ signaling between Gbetagamma and Epac, which plays a major role in melanoma cell migration. PMID- 21679471 TI - Unplanned readmission rates, length of hospital stay, mortality, and medical costs of ten common medical conditions: a retrospective analysis of Hong Kong hospital data. AB - BACKGROUND: Studies on readmissions attributed to particular medical conditions, especially heart failure, have generally not addressed the factors associated with readmissions and the implications for health outcomes and costs. This study aimed to investigate the factors associated with 30-day unplanned readmission for 10 common conditions and to determine the cost implications. METHODS: This population-based retrospective cohort study included patients admitted to all public hospitals in Hong Kong in 2007. The sample consisted of 337,694 hospitalizations in Internal Medicine. The disease-specific risk-adjusted odd ratio (OR), length of stay (LOS), mortality and attributable medical costs for the year were examined for unplanned readmissions for 10 medical conditions, namely malignant neoplasms, heart diseases, cerebrovascular diseases, pneumonia, injury and poisoning, nephritis and nephrosis, diabetes mellitus, chronic liver disease and cirrhosis, septicaemia, and aortic aneurysm. RESULTS: The overall unplanned readmission rate was 16.7%. Chronic liver disease and cirrhosis had the highest OR (1.62, 95% confidence interval (CI) 1.39-1.87). Patients with cerebrovascular disease had the longest LOS, with mean acute and rehabilitation stays of 6.9 and 3.0 days, respectively. Malignant neoplasms had the highest mortality rate (30.8%) followed by aortic aneurysm and pneumonia. The attributed medical cost of readmission was highest for heart disease (US$3 199 418, 95% CI US$2 579 443-803 393). CONCLUSIONS: Our findings showed variations in readmission rates and mortality for different medical conditions which may suggest differences in the quality of care provided for various medical conditions. In hospital care, comprehensive discharge planning, and post-discharge community support for patients need to be reviewed to improve the quality of care and patient health outcomes. PMID- 21679470 TI - Human and great ape red blood cells differ in plasmalogen levels and composition. AB - BACKGROUND: Plasmalogens are ether phospholipids required for normal mammalian developmental, physiological, and cognitive functions. They have been proposed to act as membrane antioxidants and reservoirs of polyunsaturated fatty acids as well as influence intracellular signaling and membrane dynamics. Plasmalogens are particularly enriched in cells and tissues of the human nervous, immune, and cardiovascular systems. Humans with severely reduced plasmalogen levels have reduced life spans, abnormal neurological development, skeletal dysplasia, impaired respiration, and cataracts. Plasmalogen deficiency is also found in the brain tissue of individuals with Alzheimer disease. RESULTS: In a human and great ape cohort, we measured the red blood cell (RBC) levels of the most abundant types of plasmalogens. Total RBC plasmalogen levels were lower in humans than bonobos, chimpanzees, and gorillas, but higher than orangutans. There were especially pronounced cross-species differences in the levels of plasmalogens with a C16:0 moiety at the sn-1 position. Humans on Western or vegan diets had comparable total RBC plasmalogen levels, but the latter group showed moderately higher levels of plasmalogens with a C18:1 moiety at the sn-1 position. We did not find robust sex-specific differences in human or chimpanzee RBC plasmalogen levels or composition. Furthermore, human and great ape skin fibroblasts showed only modest differences in peroxisomal plasmalogen biosynthetic activity. Human and chimpanzee microarray data indicated that genes involved in plasmalogen biosynthesis show cross-species differential expression in multiple tissues. CONCLUSION: We propose that the observed differences in human and great ape RBC plasmalogens are primarily caused by their rates of biosynthesis and/or turnover. Gene expression data raise the possibility that other human and great ape cells and tissues differ in plasmalogen levels. Based on the phenotypes of humans and rodents with plasmalogen disorders, we propose that cross-species differences in tissue plasmalogen levels could influence organ functions and processes ranging from cognition to reproduction to aging. PMID- 21679472 TI - Mobile phones and head tumours. The discrepancies in cause-effect relationships in the epidemiological studies - how do they arise? AB - BACKGROUND: Whether or not there is a relationship between use of mobile phones (analogue and digital cellulars, and cordless) and head tumour risk (brain tumours, acoustic neuromas, and salivary gland tumours) is still a matter of debate; progress requires a critical analysis of the methodological elements necessary for an impartial evaluation of contradictory studies. METHODS: A close examination of the protocols and results from all case-control and cohort studies, pooled- and meta-analyses on head tumour risk for mobile phone users was carried out, and for each study the elements necessary for evaluating its reliability were identified. In addition, new meta-analyses of the literature data were undertaken. These were limited to subjects with mobile phone latency time compatible with the progression of the examined tumours, and with analysis of the laterality of head tumour localisation corresponding to the habitual laterality of mobile phone use. RESULTS: Blind protocols, free from errors, bias, and financial conditioning factors, give positive results that reveal a cause effect relationship between long-term mobile phone use or latency and statistically significant increase of ipsilateral head tumour risk, with biological plausibility. Non-blind protocols, which instead are affected by errors, bias, and financial conditioning factors, give negative results with systematic underestimate of such risk. However, also in these studies a statistically significant increase in risk of ipsilateral head tumours is quite common after more than 10 years of mobile phone use or latency. The meta analyses, our included, examining only data on ipsilateral tumours in subjects using mobile phones since or for at least 10 years, show large and statistically significant increases in risk of ipsilateral brain gliomas and acoustic neuromas. CONCLUSIONS: Our analysis of the literature studies and of the results from meta analyses of the significant data alone shows an almost doubling of the risk of head tumours induced by long-term mobile phone use or latency. PMID- 21679473 TI - Increase of nitrosative stress in patients with eosinophilic pneumonia. AB - BACKGROUND: Exhaled nitric oxide (NO) production is increased in asthma and reflects the degree of airway inflammation. The alveolar NO concentration (Calv) in interstitial pneumonia is reported to be increased. However, it remains unknown whether NO production is increased and nitrosative stress occurs in eosinophilic pneumonia (EP). We hypothesized that nitrosative stress markers including Calv, inducible type of NO synthase (iNOS), and 3-nitrotyrosine (3-NT), are upregulated in EP. METHODS: Exhaled NO including fractional exhaled NO (FENO) and Calv was measured in ten healthy subjects, 13 patients with idiopathic pulmonary fibrosis (IPF), and 13 patients with EP. iNOS expression and 3-NT formation were assessed by immunocytochemistory in BALf cells. The exhaled NO, lung function, and systemic inflammatory markers of the EP patients were investigated after corticosteroid treatment for 4 weeks. RESULTS: The Calv levels in the EP group (14.4 +/- 2.0 ppb) were significantly higher than those in the healthy subjects (5.1 +/- 0.6 ppb, p < 0.01) and the IPF groups (6.3 +/- 0.6 ppb, p < 0.01) as well as the FENO and the corrected Calv levels (all p < 0.01). More iNOS and 3-NT positive cells were observed in the EP group compared to the healthy subject and IPF patient. The Calv levels had significant positive correlations with both iNOS (r = 0.858, p < 0.05) and 3-NT positive cells (r = 0.924, p < 0.01). Corticosteroid treatment significantly reduced both the FENO (p < 0.05) and the Calv levels (p < 0.01). The magnitude of reduction in the Calv levels had a significant positive correlation with the peripheral blood eosinophil counts (r = 0.802, p < 0.05). CONCLUSIONS: These results suggested that excessive nitrosative stress occurred in EP and that Calv could be a marker of the disease activity. PMID- 21679474 TI - Ovarian endometriomas and IVF: a retrospective case-control study. AB - We performed this retrospective case-control study analyzing 428 first-attempt in vitro fertilization (IVF) cycles, among which 254 involved women with a previous or present diagnosis of ovarian endometriosis. First, the results of these 254 cycles were compared with 174 cycles involving patients with proven non endometriotic tubal infertility having similar age and body mass index. Women with ovarian endometriosis had a significantly higher cancellation rate, but similar pregnancy, implantation and delivery rates as patients with tubal infertility. Second, among the women with ovarian endometriosis, the women with a history of laparoscopic surgery for ovarian endometriomas prior to IVF and no visual endometriosis at ovum pick-up (n = 112) were compared with the non operated women and visual endometriomas at ovum pick-up (n = 142). Patients who underwent ovarian surgery before IVF had significantly shorter period, lower antral follicle count and required higher gonadotropin doses than patients with non-operated endometriomas. The two groups of women with a previous or present ovarian endometriosis did, however, have similar pregnancy, implantation and live birth rates. In conclusion, ovarian endometriosis does not reduce IVF outcome compared with tubal factor. Furthermore, laparoscopic removal of endometriomas does not improve IVF results, but may cause a decrease of ovarian responsiveness to gonadotropins. PMID- 21679475 TI - Improved pregnancy outcome in refugees and migrants despite low literacy on the Thai-Burmese border: results of three cross-sectional surveys. AB - BACKGROUND: Maternal and infant health has been associated with maternal education level, which is highly associated with literacy. We aimed at estimating literacy rates among reproductive age women attending antenatal clinics in camps for refugees and in migrant clinics in Tak province, north-western Thailand, to determine whether illiteracy had an impact on birth outcomes. METHODS: Three reading assessments were conducted using an identical method each time, in 1995 97, 2003 and 2008. Midwives chose at random one of four pre-set sentences. Each woman was asked to read aloud and scoring was based on a "pass/fail" system. Pregnancy outcomes were compared with maternal literacy rate. RESULTS: Overall, 47% (1149/2424) of women were able to read. A significant improvement was observed among migrant (34% in 2003 vs. 46% in 2008, p = 0.01), but not refugee (47% in 1995-97, 49% in 2003, and 51% in 2008) women. Literate women were significantly more likely to be of non-Karen ethnicity, primigravidae, non smokers, to remain free from malaria during pregnancy and to deliver in a health clinic. Significant improvements in pregnancy outcome (reductions in premature births, low birth weight newborns and neonatal death) between 1995-97 and 2003 were unrelated to literacy. CONCLUSIONS: Significant reductions in poor pregnancy outcome over time have not been driven by changes in literacy rates, which have remained low. Access to early diagnosis and treatment of malaria in this population, and delivery with skilled birth attendants, despite ongoing low literacy, appears to have played a significant role. PMID- 21679476 TI - Changes in adolescents' intake of sugar-sweetened beverages and sedentary behaviour: results at 8 month mid-way assessment of the HEIA study--a comprehensive, multi-component school-based randomized trial. AB - BACKGROUND: Inconsistent effects of school-based obesity prevention interventions may be related to how different subgroups receive them. The aim of this study was to evaluate the effect of an intervention program, including fact sheets to parents and classroom components, on intake of sugar-sweetened beverages (SSB) and screen time. Further, to explore whether potential effects and parental involvement varied by adolescents' gender, weight status (WS) and parental educational level. METHODS: In total, 1465 11-year-olds participated at the pre test and the 8 month mid-way assessment of the HEIA study. Parents (n = 349) contributed with process evaluation data. Self-reported intake of SSB was collected from the 11-year-olds assessing frequency and amount, while time used on watching TV/DVD and computer/game-use (weekday and weekend day) were assed by frequency measures. Data on awareness of the intervention and dose received were collected from parents. Covariance analyses (ANCOVA) were conducted testing for effects by gender and for moderation by WS and parental education. RESULTS: Time spent on TV/DVD (week p = 0.001, weekend p = 0.03) and computer/game-use (week p = 0.004, weekend p <.001), and the intake of SSB during weekend days (p = 0.04), were significantly lower among girls in the intervention group compared to the control group girls after 8 months. Girls' WS did not moderate these findings. However, no significant effects of the intervention were found for boys, but moderation effects were found for WS (week days: TV/DVD, p = 0.03 and computer/games, p = 0.02). There were no moderating effects of parental education for neither boys nor girls with respect to intake of SSB, time used for watching TV/DVD and computer/game-use. Parental awareness of the intervention was significantly higher among the parents of girls, while the parents of boys were more satisfied with the fact sheets. CONCLUSIONS: The preventive initiatives appeared to change behaviour in girls only. This study suggests that exploration of potential beneficial or negative effects of intervention in subgroups is important. In formative evaluation of obesity prevention studies it seems warranted to include issues related to gender, WS and parental involvement in order to enhance the effectiveness of preventive initiatives. PMID- 21679477 TI - PeptX: using genetic algorithms to optimize peptides for MHC binding. AB - BACKGROUND: The binding between the major histocompatibility complex and the presented peptide is an indispensable prerequisite for the adaptive immune response. There is a plethora of different in silico techniques for the prediction of the peptide binding affinity to major histocompatibility complexes. Most studies screen a set of peptides for promising candidates to predict possible T cell epitopes. In this study we ask the question vice versa: Which peptides do have highest binding affinities to a given major histocompatibility complex according to certain in silico scoring functions? RESULTS: Since a full screening of all possible peptides is not feasible in reasonable runtime, we introduce a heuristic approach. We developed a framework for Genetic Algorithms to optimize peptides for the binding to major histocompatibility complexes. In an extensive benchmark we tested various operator combinations. We found that (1) selection operators have a strong influence on the convergence of the population while recombination operators have minor influence and (2) that five different binding prediction methods lead to five different sets of "optimal" peptides for the same major histocompatibility complex. The consensus peptides were experimentally verified as high affinity binders. CONCLUSION: We provide a generalized framework to calculate sets of high affinity binders based on different previously published scoring functions in reasonable runtime. Furthermore we give insight into the different behaviours of operators and scoring functions of the Genetic Algorithm. PMID- 21679478 TI - Nutrient intake variability and number of days needed to assess intake in preschool children. AB - The duration of the period of time during which diet should be recorded for sufficiently accurate results on the usual intake of an individual is an especially challenging issue in prospective studies among children. We set out to describe nutrient intake variability in preschoolers and to determine the number of record days required (D) to estimate intake of energy and thirty-two nutrients. The diet and the use of dietary supplements were assessed with three consecutive daily food records including one weekend day in 1639 children participating in the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention Project (DIPP) in Finland. Variance ratios and D stratified by sex and age groups were calculated for 455 (1-year-old), 471 (3 year-old) and 713 (6-year-old) children (born between 1998 and 2003). Within:between variance ratios and D increase with increasing age, and are slightly higher for girls. Vitamin A, cholesterol, n-3 and n-6 fatty acids, beta carotene and folate intakes require the most replicates. Including supplemental intake has an impact on the variance estimates according to the proportion of supplement users. In the DIPP Nutrition Study with 3 d food records, the correlation coefficients between observed and true intakes of energy and thirty two nutrients averaged 0.91 in 1-year-old children, 0.79 in 3-year-old children and 0.74 in 6-year-old children. For providing accurate nutrient intake estimates, three replicates of food records are reasonable in 1-year-old children but must be questioned for several nutrients in 3- and 6-year-old children. The accuracy of ranking boys is greater than that for girls. PMID- 21679479 TI - n-6 Fatty acids and risk for CHD: consider all the evidence. PMID- 21679480 TI - Don't disregard the essential distinction between PUFA species. PMID- 21679482 TI - Importance of early nutritional screening in patients with gastric cancer. AB - In the present study, we evaluated the relationship between nutritional status, disease stage and quality of life (QoL) in 100 patients recently diagnosed with gastric carcinoma. The patients' nutritional status was investigated with anthropometric, biochemical, inflammatory and functional variables; and we also evaluated the nutritional risk with the Nutritional Risk Screening 2002. Oncological staging was standard. QoL was evaluated using the Functional Assessment of Anorexia/Cachexia Therapy questionnaire. The statistical correlation between nutritional risk score (NRS) and oncological characteristics or QoL was evaluated using both univariable and multivariable analyses. Weight loss and reduction of food intake were the most frequent pathological nutritional indicators, while biochemical, inflammatory and functional variables were in the normal range. According to NRS, thirty-six patients were malnourished or at risk for malnutrition. Patients with NRS >= 3 presented a significantly greater percentage of stage IV gastric cancer and pathological values of C-reactive protein, while no correlation was found with the site of tumour. NRS was negatively associated with QoL (P < 0.001) and this relation was independent from oncological and inflammatory variables as confirmed by multivariable analysis. In the present study, we found that in patients with gastric cancer malnutrition is frequent at diagnosis and this is likely due to reduction in food intake. Moreover, NRS is directly correlated with tumour stage and inversely correlated with QoL, which makes it a useful tool to identify patients in need of an early nutritional intervention during oncological treatments. PMID- 21679484 TI - The role of infant feeding practices in the explanation for ethnic differences in infant growth: the Amsterdam Born Children and their Development study. AB - Rapid early growth in infants may influence overweight and CVD in later life. Both rapid growth and these disease outcomes disproportionately affect some ethnic minorities. We determined ethnic differences in growth rate (Delta standard deviation scores, DeltaSDS) during the first 6 months of life and assessed the explanatory role of infant feeding. Data were derived from a multiethnic cohort for the Amsterdam Born Children and their Development study (The Netherlands). Growth data (weight and length) of 2998 term-born singleton infants with no fetal growth restriction were available for five ethnic populations: Dutch (n 1619), African descent (n 174), Turkish (n 167), Moroccan (n 232) and other non-Dutch (n 806). DeltaSDS for weight, length and weight-for length between 4 weeks and 6 months were defined using internal references. Infant feeding pattern (breast-feeding duration, introduction of formula feeding and complementary feeding) in relation to ethnic differences in growth rate was examined by multivariate linear regression. Results showed that the growth rate was higher in almost all ethnic minorities, with beta between 0.07 and 0.41 for DeltaSDS weight and between 0.12 and 0.42 for DeltaSDS length, compared with ethnic Dutch infants. DeltaSDS weight-for-length was similar across groups, except for Moroccan infants (beta 0.25, P < 0.05) after correction for confounders. In general, exclusive breast-feeding for 4 months was associated with slower growth for all three growth measures. Feeding factors explained, to a small degree, the higher weight and length gain in African descent infants, but not the higher DeltaSDS weight-for-length in the Moroccan population. More research is needed to elucidate the underlying mechanisms of the high infant growth rate in Turkish and Moroccan infants. PMID- 21679483 TI - Estimated dietary intakes of flavonols, flavanones and flavones in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24 hour dietary recall cohort. AB - Flavonols, flavanones and flavones (FLAV) are sub-classes of flavonoids that exert cardioprotective and anti-carcinogenic properties in vitro and in vivo. We aimed to estimate the FLAV dietary intake, their food sources and associated lifestyle factors in ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. FLAV intake and their food sources for 36 037 subjects, aged between 35 and 74 years, in twenty seven study centres were obtained using standardised 24 h dietary recall software (EPIC-SOFT). An ad hoc food composition database on FLAV was compiled using data from US Department of Agriculture and Phenol-Explorer databases and was expanded using recipes, estimations and flavonoid retention factors in order to increase its correspondence with the 24 h dietary recall. Our results showed that the highest FLAV-consuming centre was the UK health-conscious group, with 130.9 and 97.0 mg/d for men and women, respectively. The lowest FLAV intakes were 36.8 mg/d in men from Umea and 37.2 mg/d in women from Malmo (Sweden). The flavanone sub class was the main contributor to the total FLAV intake ranging from 46.6 to 52.9 % depending on the region. Flavonols ranged from 38.5 to 47.3 % and flavones from 5.8 to 8.6 %. FLAV intake was higher in women, non-smokers, increased with level of education and physical activity. The major food sources were citrus fruits and citrus-based juices (especially for flavanones), tea, wine, other fruits and some vegetables. We concluded that the present study shows heterogeneity in intake of these three sub-classes of flavonoids across European regions and highlights differences by sex and other sociodemographic and lifestyle factors. PMID- 21679485 TI - Effects of oligofructose on appetite profile, glucagon-like peptide 1 and peptide YY3-36 concentrations and energy intake. AB - In rats, oligofructose has been shown to stimulate satiety hormone secretion, reduce energy intake and promote weight loss. The present study aimed to examine the effect of oligofructose supplementation on appetite profiles, satiety hormone concentrations and energy intake in human subjects. A total of thirty-one healthy subjects (ten men and twenty-one women) aged 28 (SEM 3) years with a BMI of 24.8 (SEM 0.3) kg/m(2) were included in a randomised double-blind, cross-over study. The subjects received 10 g oligofructose, 16 g oligofructose or 16 g placebo (maltodextrin) daily for 13 d, with a 2-week washout period between treatments. Appetite profile, active glucagon-like peptide 1 (GLP-1) and peptide YY3-36 (PYY) concentrations and energy intake were assessed on days 0 and 13 of the treatment period. Time * treatment interaction revealed a trend of reduction in energy intake over days 0-13 by oligofructose (P = 0.068). Energy intake was significantly reduced (11 %) over time on day 13 compared with day 0 with 16 g/d oligofructose (2801 (SEM 301) v. 3217 (SEM 320) kJ, P < 0.05). Moreover, energy intake was significantly lower with 16 g/d oligofructose compared with 10 g/d oligofructose on day 13 (2801 (SEM 301) v. 3177 (SEM 276) kJ, P < 0.05). Area under the curve (AUC) for GLP-1 on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose (45 (SEM 4) v. 41 (SEM 3) pmol/l * h, P < 0.05). In the morning until lunch, AUC(0-230 min) for PYY on day 13 was significantly higher with 16 g/d oligofructose compared with 10 g/d oligofructose and placebo (409 (SEM 35) v. 222 (SEM 19) and 211 (SEM 20) pg/ml * h, P < 0.01). In conclusion, 16 g/d and not 10 g/d oligofructose may be an effective dose to reduce energy intake, possibly supported by higher GLP-1 and PYY concentrations. PMID- 21679486 TI - Geographical distribution of schistosomiasis and soil-transmitted helminths among school children in informal settlements in Kisumu City, Western Kenya. AB - This cross-sectional study determined the prevalence and distribution of schistosome and soil-transmitted helminth (STH) infections among 1,308 children aged 10-18 years in 34 primary schools in 8 informal urban settlements in Kisumu City, western Kenya. Stool samples were collected and examined for eggs of Schistosoma mansoni and STH (Hookworms, Ascaris lumbricoides and Trichuris trichiura) using the Kato-Katz technique. Haematuria was used as a proxy indicator of urinary schistosomiasis. Schools and water bodies were mapped using a geographical information system. Overall, 34% of children were infected with one or more helminth species whereas 16.2% of children were infected with one or more STH species. Schools in closest proximity to Lake Victoria and River Nyamasaria had the highest S. mansoni prevalence while schools with STH were more homogenously distributed. Mean school prevalence of S. mansoni infection was 21% (range=0-69.7%), S. haematobium 3.6% (range=0-12%), hookworms 6.1% (range=0-20%), A. lumbricoides 4.9% (range=0-18.4%), and T. trichiura 7.7% (range=0-18.6%). Helminth-related morbidities were not associated with infection. Our study demonstrates that schistosomiasis and STH are important health priorities among schools in informal settlements of Kisumu City, and highlights the need for routine deworming in similar settings. PMID- 21679487 TI - Towards a new role for vector systematics in parasite control. AB - Vector systematics research is being transformed by the recent development of theoretical, experimental and analytical methods, as well as conceptual insights into speciation and reconstruction of evolutionary history. We review this progress using examples from the mosquito genus Anopheles. The conclusion is that recent progress, particularly in the development of better tools for understanding evolutionary history, makes systematics much more informative for vector control purposes, and has increasing potential to inform and improve targeted vector control programmes. PMID- 21679488 TI - CrATP interferes in the promastigote-macrophage interaction in Leishmania amazonensis infection. AB - Recent have shown the relationship between Ecto-Nucleoside-Triphosphate Diphosphohydrolases (Ecto-NTPDases or ecto-nucleotidases) and virulence and infectivity in trypanosomatids. In this work, the inhibition of the ecto-ATPase activities and promastigote growth of Leishmania amazonensis by CrATP was characterized. Furthermore, this compound was used to investigate the role of ecto-nucleotidase in the interaction of L. amazonensis with resident peritoneal macrophages obtained from BALB/c mice. CrATP partially inhibits the ecto-ATPase activity, presenting Ki values of 575.7+/-199.1 and 383.5+/-79.0 MUm, in the presence or absence of 5 mm MgCl2, respectively. The apparent Kms for ATP (2.9+/ 0.5 mm to Mg2+-dependent ecto-ATPase and 0.4+/-0.2 mm to Mg2+-independent ecto ATPase activities) are not significantly altered by CrATP, suggesting a reversible non-competitive inhibition of both enzymes. When CrATP was added to the cultivation medium at 500 MUm, it drastically inhibited the cellular growth. The interaction of promastigote forms of L. amazonensis with BALB/c peritoneal macrophages is strongly affected by CrATP. When the parasites were treated with 500 MUm CrATP before interacting with macrophages, the adhesion and endocytic indices were strongly reduced to 53.0+/-14.8% and 39.8+/-1.1%, respectively. These results indicate that ecto-nucleotidase plays an important role in the infection process caused by Leishmania amazonensis. PMID- 21679489 TI - Population genetics of Schistosoma haematobium: development of novel microsatellite markers and their application to schistosomiasis control in Mali. AB - The recent implementation of mass drug administration (MDA) for control of uro genital schistosomiasis has identified an urgent need for molecular markers to both directly monitor the impact of MDA, for example to distinguish re-infections from uncleared infections, as well as understand aspects of parasite reproduction and gene flow which might predict evolutionary change, such as the development and spread of drug resistance. We report the development of a novel microsatellite tool-kit allowing, for the first time, robust genetic analysis of individual S. haematobium larvae collected directly from infected human hosts. We genotyped the parasite populations of 47 children from 2 schools in the Segou region of Mali, the first microsatellite study of this highly neglected parasite. There was only limited evidence of population subdivision between individual children or between the two schools, suggesting that few barriers to gene flow exist in this population. Complex relationships between parasite reproductive success, infection intensity and host age and gender were identified. Older children and boys harboured more diverse infections, as measured by the number of unique adult genotypes present. Individual parasite genotypes had variable reproductive success both across hosts, a pre-requisite for evolutionary selection, and, phenotypically, in hosts of different ages and genders. These data serve as a baseline against which to measure the effect of treatment on parasite population genetics in this region of Mali, and the tools developed are suitable to further investigate this important pathogen, and its close relatives, throughout their range. PMID- 21679491 TI - Non echo planar, diffusion-weighted magnetic resonance imaging (periodically rotated overlapping parallel lines with enhanced reconstruction sequence) compared with echo planar imaging for the detection of middle-ear cholesteatoma. PMID- 21679490 TI - Dynamics of Sept4 expression in fibrotic livers of mice infected with Schistosoma japonicum. AB - n order to investigate the dynamics of Septin4 (Sept4) expression and its function in the formation of fibrotic livers in mice infected with Schistosoma japonicum, we constructed the mouse model of S. japonicum egg-induced liver fibrosis for 24 weeks. Immunohistochemical staining, qRT-PCR and Western blot were used to detect the expression of Sept4 and alpha-smooth muscle actin (alpha SMA). We found Sept4 localized in the perisinusoidal space where hepatic stellate cells (HSCs) distribute in the periphery of circumoval granulomas and the portal venule. The expression of Sept4 and alpha-SMA had a similar significant tendency of an up-regulation to a peak at 12 weeks post-infection (p.i.) followed by a down-regulation. At 24 weeks p.i. both were at a low level. These results suggest that Sept4 and alpha-SMA may interact together in HSCs. Based on this evidence, we hypothesize that Sept4 seems to be involved in the formation of inflammatory granulomata and subsequent liver fibrosis by regulating HSCs activation. PMID- 21679492 TI - Triple manifestation of extramedullary plasmacytoma in the upper airway: an unusual clinical entity. AB - OBJECTIVE: We report an extremely rare case of extramedullary plasmacytoma. METHOD: Case report and review of the English-literature concerning extramedullary plasmacytoma and multiple myeloma. RESULT: We present an unusual case of multiple extramedullary plasmacytomas, which, over a protracted course of 30 years, presented on different occasions at three separate sites in the head and neck. The patient was managed surgically on all occasions, and was disease free at the time of writing. CONCLUSION: Following review of the literature, we believe this to be the only case with this extremely unusual presentation. This case is noteworthy, not only because of the rarity of extramedullary plasmacytoma, but also because it highlights a number of important clinical issues. The diagnosis and management of extramedullary plasmacytoma require close cooperation between multiple disciplines. PMID- 21679493 TI - Hypocalcaemia following thyroidectomy for treatment of Graves' disease: implications for patient management and cost-effectiveness. AB - BACKGROUND: No consensus exists on optimal treatment for Graves' disease once anti-thyroid medication fails to induce remission. Total thyroidectomy is a more cost-effective treatment than radioactive iodine or life-long anti-thyroid medication, but hypocalcaemia is an important complication, leading to longer hospital admissions and increased prescription costs. This study aimed to compare the relative risk of hypocalcaemia requiring medical treatment for patients with Graves' disease. METHODS: Prospective cohort study of patients undergoing total thyroidectomy for Graves' disease and for multinodular goitre, calculating serum calcium levels 24-hours post-operatively and prescription rates. RESULTS: Mean corrected calcium concentrations 24 hours post-operatively were 2.05 mmol/l for Graves' disease patients and 2.14 mmol/l for multinodular goitre patients (p = 0.003). Biochemical hypocalcaemia developed in 92 per cent (n = 34) of Graves' disease patients and 71 per cent (n = 43) of multinodular goitre patients (p = 0.012). Graves' disease patients were more likely to be prescribed calcium supplementation pre-discharge (p = 0.037). CONCLUSION: Total thyroidectomy for Graves' disease carries an increased risk of hypocalcaemia at 24 hours, and of calcium supplementation pre-discharge. Graves' disease patients should be informed of the increased risk of hypocalcaemia associated with total thyroidectomy, and this risk must be factored into future cost-effectiveness analysis. PMID- 21679494 TI - Systemic inflammation and its response to treatment in patients with asthma. AB - BACKGROUND: Asthma is an obstructive airway disease characterized by airway inflammation. OBJECTIVE: To measure systemic inflammation in asthma patients, and to assess the effect of treatment on systemic inflammation. METHODS: In 30 newly diagnosed non-randomized adult asthma patients we measured systemic inflammation markers (serum high-sensitivity C-reactive protein, total leukocyte count, and erythrocyte sedimentation rate) before and after a 6-week standard treatment with inhaled steroids and inhaled beta(2) agonist. The comparison group comprised 20 healthy control subjects. All the subjects were non-smokers. RESULTS: The measured systemic inflammation markers were higher in the asthma patients: high sensitivity C-reactive protein 4.8 +/- 6.0 mg/dL vs 1.5 +/- 1.4 mg/dL, P < .001; total leukocyte count 8,936 +/- 2,592 cells/MUL versus 7,741 +/- 1,924 cells/MUL, P < .001; erythrocyte sedimentation rate 24.8 +/- 12.3 mm/h versus 15.3 +/- 6.5 mm/h, P < .001. In the asthma patients, high-sensitivity C-reactive protein negatively correlated with percent-of-predicted FEV(1) (r = -0.64, P = .001), percent-of-predicted forced vital capacity (FVC) (r = -0.39, P = .03), FEV(1)/FVC% (r = -0.71, P < .001), and percent-of-predicted forced expiratory flow during the middle half of the FVC maneuver (FEF(25-75)) (r = -0.51, P = .004). Total leukocyte count negatively correlated with percent-of-predicted FEV(1) (r = -0.64, P = .001), percent-of-predicted FEV(1)/FVC (r = -0.74, P < .001), and percent-of-predicted FEF(25-75) (r = -0.58, P = .001). Body mass index positively correlated with high-sensitivity C-reactive protein (r = 0.65, P < .001). Multiple linear regression showed significant correlation of high sensitivity C-reactive protein (r(2) = 0.75) with age (beta = 0.31, P = .008), body mass index (beta = 0.99, P = .001), family size (beta = 0.33, P = .008), and weight (beta = -0.45, P = .01). The systemic inflammation markers decreased significantly (P < .001 for all comparisons) after 6 weeks of treatment: high sensitivity C-reactive protein decreased from 4.8 +/- 6.0 mg/dL to 2.4 +/- 5.4 mg/dL, total leukocyte count decreased from 8,936 +/- 2,592 cells/MUL to 6,960 +/ 1,785 cells/MUL, and erythrocyte sedimentation rate decreased from 24.8 +/- 12.3 mm/h to 15.8 +/- 10.1 mm/h. CONCLUSIONS: Inhaled steroids plus inhaled beta(2) agonist significantly reduced systemic inflammation in asthma patients. PMID- 21679495 TI - Not to invade: a better strategy? PMID- 21679496 TI - Patient needs should drive ventilator selection for stockpiling: "handy" devices may not "lend a hand". PMID- 21679497 TI - Effective bronchodilator resuscitation of children in the emergency room: device or interface? PMID- 21679498 TI - Hypertonic saline and PEP: is it worth a try? PMID- 21679499 TI - Polymorphisms in the nitric oxide synthase 1 gene are associated with severe chronic rhinosinusitis. AB - BACKGROUND: Nitric oxide (NO), is a biological messenger molecule and a component of innate immunity, with important roles in the regulation of inflammation and in defense against bacterial biofilms. Polymorphisms in genes regulating NO production have the potential for a role in the development of chronic rhinosinusitis (CRS). The purpose of this study was to determine whether polymorphisms in genes regulating NO synthesis are associated with CRS. METHODS: An established population of 206 individuals with severe CRS and 196 postal code matched controls was previously screened using a pooling genome-wide associations study to estimate allelic frequency. Genes regulating NO synthesis with a maximal probability of association were identified. High-probability single nucleotide polymorphisms SNPs from the NO synthase (NOS1) and its ligand NOS1 adaptor protein (NOS1AP) genes were retained for individual genotyping. PLINK software was used to determine association. RESULTS: Sixteen SNPs were genotyped successfully with a genotype distribution in agreement with Hardy-Weinberg equilibrium. Two SNPs for NOS1 (rs1483757 and rs9658281) were significantly associated with CRS, with a protective effect. The severe subphenotype showed stronger associations. Subgroup analysis for the presence of nasal polyps, origin, and gender did not influence strength of associations. CONCLUSION: These data suggest that polymorphisms in the NOS1 gene may play a role in the susceptibility to develop CRS. Study findings apply to patients with severe CRS, unresponsive to surgery. PMID- 21679500 TI - The liquid Panax ginseng inhibits epidermal growth factor-induced metalloproteinase 9 and cyclooxygenase 2 expressions via inhibition of inhibitor factor kappa-B-alpha and extracellular signal-regulated kinase in NCI-H292 human airway epithelial cells. AB - BACKGROUND: Ginseng (Panax ginseng C.A. Meyer) has been used in Asian countries for the treatment of various diseases. However, the mechanisms of liquid Panax ginseng (LG) on allergic inflammatory response in epidermal growth factor (EGF) stimulated human airway epithelial cells remain largely unclear. METHODS: MUC5AC, cyclooxygenase (COX) 2, and matrix metalloproteinase (MMP) 9 expressions were measured using reverse transcription-polymerase chain reaction, Western blotting, and gelatin zymogram analyses in NCI-H292 cells. Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) protein levels were analyzed by Western blotting. RESULTS: To gain insight into the antiallergy effects of LG, we examined its influence on epidermal growth factor (EGF)-induced MMP-9 and COX-2 productions in NCI-H292 cells. LG was treated for 1 hour and then followed by EGF treatment for 24 hours into NCI-H292 cells. The decrease of COX-2 production was correlated with the reduced levels of proteins and mRNAs of inducible MMP-9 and MUC5AC. LG blocked upstream signaling of NF-kappa-B activation via inhibition of phosphorylations of inhibitor factor-kappa- B-alpha (I-kappa-B-alpha) and ERK. These results suggest that LG protects NCI-H292 cells from EGF-induced damage by down-regulation of COX-2, MMP-9, and MUC5AC gene expressions by blocking NF-kappa-B and ERK. CONCLUSION: LG modulates allergic inflammatory response in EGF-stimulated NCI-H292 human airway epithelial cells via inhibition of I-kappa-B-alpha and ERK. PMID- 21679501 TI - M1 and M3 muscarinic receptors mediate relaxation and contraction in canine nasal veins. AB - BACKGROUND: Acetylcholine (ACh) has been shown to induce nasal congestion via vasorelaxation of intranasal posterior collecting veins (PCV) coupled with vasocontraction of extranasal outflow veins (dorsal nasal vein [DNV] and sphenopalatine vein [SPV]). The aim of this study was to characterize the muscarinic receptor subtype(s) involved in ACh-induced relaxation and contraction in canine nasal veins. METHODS: PCV, DNV, and SPV were isolated from the canine nose. In vitro isometric tension of segments from these veins was monitored to reflect vascular reactivity. ACh concentration-response curve was studied in the presence of muscarinic receptor subtype inhibitors. Immunohistochemical localization of M(1)-M(5) receptor subtypes in the veins was performed. RESULTS: ACh-induced relaxation in PVC was inhibited by pertussis toxin (PTX; inhibitor of G-protein that couples M(2)/M(4) receptors), methoctramine (selective M(2) muscarinic receptor inhibitor), muscarinic toxin 7 (MT-7; selective M(1) muscarinic receptor inhibitor), and 4-diphenylacetoxy-methylpiperidine methiodide (4-DAMP; selective M(3) muscarinic receptor inhibitor). ACh-induced contraction in SPV and DNV was potentiated by PTX and methoctramine but was inhibited by MT-7 and 4-DAMP. Immunohistochemistry confirmed the presence of five muscarinic receptor subtypes in the endothelium of nasal veins, with staining of M(3) > M(1) > M(5) > M(2) = M(4) in PVC but M(2) = M(4) > M(3) > M(1) > M(5) in outflow veins. M(1) and M(3) receptor subtypes were localized in the smooth muscles of both types of veins. CONCLUSION: The results show that ACh relaxes intranasal veins and contracts extranasal veins primarily via M(1) and M(3) muscarinic receptor subtypes, implying the therapeutic value of M(1)/M(3)-specific or highly selective anticholinergics on nasal congestion. PMID- 21679502 TI - Allergic rhinitis and secondhand tobacco smoke: a population-based study. AB - BACKGROUND: Allergic rhinitis (AR) is a common disease that affects approximately one-fifth of the U.S. population. Few studies have evaluated the association between secondhand tobacco smoke (SHS) exposure and the impacts on symptom severity in AR. In this study, we evaluated the association of SHS and AR in a community-based study of adult nonsmokers. METHODS: In Washington County, Maryland, 83 subjects with AR (physician diagnosed or reported skin test positive), and 117 nonallergic subjects from the same community were recruited and interviewed. A validated questionnaire was used to assess past and present SHS exposure as well as disease-specific quality of life. RESULTS: SHS was reported in 34/83 allergic subjects. Compared with AR subjects with no SHS exposure, subjects with AR and SHS were more likely to report a family history of chronic sinusitis (p = 0.04) and use nasal decongestants (p = 0.012). There was also a borderline association with reporting more severe nasal obstruction (p = 0.14) and nasal drainage (p = 0.08). Compared with nonallergic subjects, allergic subjects were more likely to report longer SHS exposure currently (adjusted mean difference = 1.6 hours/week; p = 0.01) and 20 years ago (adjusted mean difference = 2.9 hours/week; p = 0.03). CONCLUSION: Past and current SHS may be a risk factor for AR. Allergic subjects with SHS exposure were more likely to use nasal decongestants and to report more severe nasal symptoms such as nasal obstruction and nasal drainage than nonexposed allergic subjects. PMID- 21679503 TI - Heparin inhibits mucus hypersecretion in airway epithelial cells. AB - BACKGROUND: Heparin is one of the most important anticoagulant drugs. It has been known that heparin also possesses anti-inflammatory activities. Mucus hypersecretion is an important characteristic of airway inflammation. However, little is known about the regulatory effects of heparin on mucus hypersecretion in airway epithelial cells. To elucidate the anti-inflammatory function of heparin in airway epithelial cells, we examined the in vivo effects of heparin on mucus hypersecretion and neutrophil infiltration in rat nasal epithelium. We also examined the in vitro effects of heparin on mucin production and IL-8 secretion from cultured human airway epithelial cells. METHODS: We induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. The effects of intranasal instillation with heparin on mucus production and neutrophil infiltration were examined. in vitro effects of heparin on airway epithelial cells were examined using cultured NCI-H292 cells. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using an anti-MUC5AC monoclonal antibody. RESULTS: Intranasal instillation with unfractionated heparin (UFH; 100 IU/0.1 mL) or low molecular weight heparin (LMWH; 100 IU/0.1 mL) at 30 minutes before LPS instillation significantly inhibited LPS-induced mucus production and neutrophil infiltration in rat nasal epithelium. UFH or LMWH inhibited tumor necrosis factor alpha (10 ng/mL)-induced secretion of MUC5AC and IL-8 from NCI-H292 cells in a dose-dependent manner (0.01 10 IU/mL). MUC5AC mRNA expression was also significantly inhibited. CONCLUSION: These results indicate that heparin inhibits airway mucus hypersecretion in airway epithelial cells directly and indirectly through the suppression of IL-8 secretion and neutrophil infiltration. PMID- 21679504 TI - Impact of allergic rhinitis on bronchi: an 8-year follow-up study. AB - BACKGROUND: Allergic rhinitis is considered a strong risk factor for the onset of asthma. However, few studies addressed this issue from a functional point of view. The aim of this study was to follow up a group of patients with allergic rhinitis to investigate the onset of possible spirometric abnormalities and/or bronchial hyperreactivity (BHR). METHODS: Eighty-nine patients with moderate severe persistent allergic rhinitis were prospectively and consecutively evaluated; 940 controls were also included in the study. Clinical examination, skin-prick test, spirometry, and methacholine challenge were performed in all patients every 2 years for 8 years. RESULTS: The number of patients with forced expiratory flow at 25 and 75% of pulmonary volume of <70% of predicted significantly increased during the observation time. At baseline, no subjects had BHR; whereas 34 patients had BHR after 8 years. Sensitization to mites, birch, and Parietaria as well as rhinitis duration are risk factors for these changes. CONCLUSION: This study highlights the close link between upper and lower airways and suggests that spirometry should be performed in patients with allergic rhinitis. PMID- 21679505 TI - Pattern of expression of cell cycle-related proteins in malignant transformation of sinonasal inverted papilloma. AB - BACKGROUND: It has been suggested that sinonasal inverted papilloma (IP) can progress to squamous cell carcinoma (SCC); however, mechanisms of malignant transformation are not fully understood. This study investigated alterations in the expression of cell cycle-related proteins in a multistep process of malignant transformation of IPs. METHODS: The expression of cell cycle-related proteins, including p53, p21, p16, and p63, was evaluated by immunohistochemistry in 21, 56, 7, and 18 cases of nasal polyps, IPs, IPs with dysplasia, and IPs with SCC, respectively. Furthermore, we determined the possible correlation between the expression of these proteins and clinicopathological variables in patients with IPs with SCC. RESULTS: Expression of p53 was found only in 8 of 18 IPs with SCC (44.4%). The frequency of p21 positivity was significantly higher in IPs with dysplasia (71.4%) and IPs with SCC (77.8%) compared with nasal polyps (0%) and IPs (12.5%). A p16 positivity was observed in 82.1% of IPs and 57.1% of IPs with dysplasia, whereas 83.3% of IPs with SCC showed an apparent loss of p16 protein expression. A p63 positivity was found in all specimens, but the percentage of positive cells was significantly increased in IPs with dysplasia and IPs with SCC compared with nasal polyps and IPs. There was no significant correlation between the expression of these proteins and clinicopathological variables, such as tumor stage, histological differentiation, and the proportion of malignant areas in patients with IPs with SCC. CONCLUSION: Alteration of cell cycle-related proteins may contribute importantly to the malignant transformation from IP to SCC. PMID- 21679506 TI - A prospective, randomized, single-blinded controlled trial on biodegradable synthetic polyurethane foam as a packing material after septoplasty. AB - BACKGROUND: We evaluated synthetic polyurethane foam (SPF; Polyganics BV, Groningen, The Netherlands) as a packing material used after septoplasty compared with Merocel (Medtronic Xomed Surgical Products, Jacksonville, FL) in the aspects of clinical efficacy and the subjective severity of symptoms. METHODS: A prospective, randomized, single-blinded controlled study was performed in 64 patients who had undergone septoplasty. The patients were randomized to receive Merocel or SPF after septoplasty. Assessments of clinical efficacy on bleeding and pain were done and subjective symptoms related to packing materials were evaluated using questionnaires quantified by the visual analog scale. RESULTS: There was no difference in repacking or additional packing due to postoperative bleeding, bleeding and/or septal hematoma on the removal of packing, and the mucosal condition after packing removal during postoperative period between the Merocel and SPF groups. Bleeding and pain during packing removal was significantly lower in patients with SPF packing. Also, in the SPF group, patient's general satisfaction and willingness to reuse the material were higher compared with the Merocel group. CONCLUSION: SPF is as suitable as Merocel to be used after septoplasty with beneficial effects on bleeding and pain at packing removal. PMID- 21679507 TI - Bacterial interference in upper respiratory tract infections: a systematic review. AB - BACKGROUND: Published definitions of bacterial interference (BI) differ, some focusing on changes in the normal flora and others on changes in subsequent infection. A need for consensus was identified at a roundtable discussion of BI in upper respiratory tract infections (URTI). We conducted a systematic review of the available data to justify a consensus definition of BI specific to URTI as "a dynamic, antagonistic interaction between at least 2 organisms that affects the life cycle of each, changes the microenvironment, and alters the organisms' colonization, invasiveness, and ability to affect the health of the host." METHODS: Continued communication among the faculty postroundtable was used to identify and refine the search criteria to (1) in vitro and in vivo studies assessing bacterial URTI, (2) BI evaluated by response to treatment of URTI with antimicrobial agents, and (3) bacterial function in relation to interactions between normal (nonpathogenic) and pathological flora. The criteria were applied to systematic searches of MEDLINE (1950 onward), EMBASE (1974 onward), and the Cochrane Library (2007). RESULTS: Twenty-nine studies met the inclusion criteria, most focused on children with recurrent infections. Qualitative analysis supports the consensus definition. Interfering organisms affected the life cycle of test pathogens and inhibited their colonization, invasiveness, and health outcomes. Data were insufficient for statistical analysis. CONCLUSION: Interactions between interfering organisms and potential pathogens isolated from the same host can alter response to infection and treatment. More studies are needed, particularly in adults, to understand the role of interfering organisms, the influence of antibiotics, and the potential for recolonization posttreatment. PMID- 21679508 TI - Diagnostic accuracy evaluation of nasal sound spectral analysis compared with peak nasal inspiratory flow in nasal septal deviation. AB - BACKGROUND: Noninvasive evaluation of nasal airflow has remained a constant challenge for clinicians. A recently developed method for measurement of nasal obstruction has been evaluated. This study was designed to compare results of nasal sound spectral analysis (NSSA) with results of peak nasal inspiratory flow (PNIF) and visual analog scale (VAS) of nasal obstruction. Main outcome measure was diagnostic accuracy evaluation of NSSA compared with PNIF in nasal septal deviation. METHODS: Analysis of original nasal sounds was performed using the ameliorated NSSA system with a software program and evaluation of nasal inspiratory sound and its intensity into spectral and frequency scale was performed using fast Fourier transform. NSSA and PNIF were performed on 43 patients with nasal septal deviations and 40 healthy subjects. We characterized the following frequency spectrum using a series of variables: low frequency (0-1 kHz), medium frequency (1-2 kHz), and high frequency (2-4 kHz). RESULTS: A significant difference was observed between PNIF values and nasal inspiratory sound intensity of the deviated patients and the control group (p < 0.001). A correlation was observed in patients between NSSA results at a frequency range of 2-4 kHz and PNIF results. A cutoff between normal and pathological of 15.2 +/- 2.0 dB (2-4 kHz) for NSSA and 118.0 +/- 15.5 L/min for PNIF was calculated. No significant differences in terms of sensitivity of NSSA and PNIF (86.04% versus 79.07%) and specificity (82.50% versus 77.50%) were computed. CONCLUSION: NSSA and PNIF provide valuable information to aid in support of clinical decision making. PMID- 21679509 TI - The status of the olfactory cleft may predict postoperative olfactory function in chronic rhinosinusitis with nasal polyposis. AB - BACKGROUND: Preoperative inflammation of the olfactory cleft may cause not only the obstruction of this area, but also damage of the olfactory neuroepithelium, resulting in anosmia. Therefore, the evaluation of the affected olfactory cleft by computed tomography (CT) might help predict postoperative olfaction. METHODS: Fifty-two patients who underwent functional endoscopic sinus surgery for chronic rhinosinusitis (CRS) with nasal polyps were examined preoperatively and at 6 months after surgery. OMU CT was obtained preoperatively and olfactory function tests such as the butanol threshold test, the cross-cultural smell identification test, and questionnaires were performed at the initial preoperative visit and at 6 months after surgery. The correlation between the status of the olfactory cleft on CT and the postoperative olfactory results were investigated. RESULTS: The findings of olfactory cleft opacification and the CT scores had a negative correlation with preoperative olfactory results (p < 0.05). The olfactory cleft opacification showed a stronger correlation with the preoperative olfactory results than the CT score. The total olfactory cleft opacification score and anterior olfactory cleft opacification score (AOCS) were more significantly correlated with the postoperative olfactory results than the other parameters (p < 0.05). Among the CT findings, the AOCS was a significant prognostic factor of olfactory results after surgery; these findings were significant on multiple regression analysis (p < 0.05). The postoperative olfactory scores and the improvement of olfactory scores after surgery were increased more in the mild AOCS group than in the moderate and severe AOCS groups (p < 0.05). Recovery and normosmia rates were much better in the mild AOCS group in this study (p < 0.05). CONCLUSION: Preoperative CT findings, especially the anterior portion of the olfactory cleft, had a statistically significant association with the postoperative olfactory results in patients with CRS with nasal polyps. PMID- 21679510 TI - Radiographic distribution of drops and sprays within the sinonasal cavities. AB - BACKGROUND: Topical nasal sprays are commonly prescribed for sinonasal disease. Nasal drops applied in a head-down position are described alternatively to sprays. Multiple research methods have investigated the deposition pattern of intranasal medications, each with limitations. This pilot study analyzed the use of a conebeam computed tomography (CBCT) scanner to study deposition patterns of intranasal sprays and drops using radiopaque contrast solution. METHODS: Nine volunteers participated in this two-trial study. In trial 1, participants instilled 3 sprays of contrast into each nostril. After 3 minutes a CBCT scan was performed. In trial 2, 3 drops of contrast were instilled into the participants' nostrils in the "vertex-to-floor" position. Again, after 3 minutes a CBCT scan was performed. Two otolaryngologists and a neuroradiologist reviewed the images and scored 21 sites within the sinonasal cavity for the presence of contrast. RESULTS: Contrast was detected in the nasal vestibule and inferior nasal vault in nearly every trial with the spray and drops. Nasal spray was more diffusely distributed within the nasal cavity and was detected at a greater proportion on the floor of the nose, inferior meatus, anterior inferior nasal cavity, and nasopharynx. Neither spray nor drops were consistently detected in spaces superior to the middle turbinate. CONCLUSION: Radiopaque contrast delivered by nasal spray and drops were detected by the CBCT scanner, with a significant difference at one subsite. Neither spray nor drops were detected in superior nasal spaces. The CBCT scan provides an alternative to conventional CT scans in future studies using this technique. PMID- 21679511 TI - The effectiveness of steroids for edema, ecchymosis, and intraoperative bleeding in rhinoplasty. AB - BACKGROUND: The aim of this study was to investigate the dose-related effectiveness of steroids on periorbital edema, ecchymosis, and intraoperative bleeding in patients who underwent open rhinoplasty with osteotomy. METHODS: Forty patients were divided into three groups: those in group 1 (n = 15) were given a single dose of 1-mg/kg intravenous (i.v.) methylprednisolone, those in group 2 (n = 15) were given a single dose of 3-mg/kg i.v. methylprednisolone preoperatively, and group 3 (n = 10) was the control group. Eyelid edema and periorbital soft-tissue ecchymosis were evaluated separately using a scale of 0 4. RESULTS: In groups using the steroid preoperatively, periorbital edema and ecchymosis were significantly lower compared with the control group (p < 0.05). No significant differences were seen clinically or statistically in preventing or reducing either the periorbital ecchymosis or the periorbital edema between groups 1 and 2. Also, there was no significant difference among the groups in terms of bleeding (p > 0.05). No complications with regard to the operation or steroid use were observed. CONCLUSION: Our results support that steroids significantly decrease periorbital ecchymosis and periorbital edema in open rhinoplasty with osteotomy. Additionally, our results suggest that if the dose of steroids is adjusted according to body weight, there is no significant benefit in a single dose of 3 mg/kg of methylprednisolone over a lower dose of 1 mg/kg and there is no need for higher doses of methylprednisolone administration. PMID- 21679512 TI - Mucosal cysts in the paranasal sinuses: long-term follow-up and clinical implications. AB - BACKGROUND: Although mucosal cysts in the paranasal sinuses (PSMCs) are commonly detected, the long-term follow-up studies of PSMCs are sparse. This study evaluated the natural course of PSMCs and identified risk factors for the disease progression. METHODS: A total of 133 subjects with PSMCs who underwent health checkup including brain magnetic resonance imaging more than two times with an interval of >=24 months between January 2000 and December 2009 were included. The characteristics of PSMCs were analyzed on the initial and follow-up images. Nasal symptoms, smoking status, and comorbid medical conditions were evaluated using structured questionnaires and medical records. RESULTS: The mean follow-up duration was 40.38 months (range, 24.0-109.8 months). The mean size of PSMCs decreased from 15.07 to 12.73 mm. Only 8.3% of subjects showed an increase in size, whereas the size of cysts was decreased or unchanged in the remaining 91.7% of subjects. Six (4.5%) subjects complained of nasal symptoms during follow-up and subsequent sinusitis was developed in 3% of subjects. An increase in cyst size was associated with development of sinusitis (odds ratio = 45.375). Initial size of cysts >20 mm and bilateral location were significant risk factors for progression (p = 0.019 and p = 0.039, respectively). CONCLUSION: The majority of PSMCs in this follow-up study were decreased or unchanged and most subjects were asymptomatic. Just observation is enough for most PSMCs. However, those who have a large cyst (>20 mm) or bilateral cysts at initial diagnosis were at risk for disease progression and should be regularly followed. PMID- 21679513 TI - Hyaluronic acid gel in the treatment of empty nose syndrome. AB - BACKGROUND: Empty nose syndrome (ENS) along with atrophic rhinitis are disease entities that are bothersome for patients and difficult for their doctors to treat. The purpose of this study was to evaluate the usefulness of intranasal injection of hyaluronic acid (HA) gel in patients with symptoms of ENS. METHODS: Three patients suffering from ENS and atrophic rhinitis underwent trial treatment consisting of submucosal injections of HA preparations into the inferior nasal concha and under the mucous membrane of the septum. RESULT: As a result of treatment, the patients' symptoms improved for several months and no complications were recorded. CONCLUSION: Because of its simplicity, safety, and fairly good, but impermanent clinical effects, HA injections appear to be worth considering in less severe forms of ENS. PMID- 21679514 TI - Use of narrow band imaging in evaluation of possible nasopharyngeal carcinoma. AB - BACKGROUND: This study was designed to evaluate the narrow band imaging (NBI) system for its ability to differentiate between malignant neoplasm and benign neoplasm by real-time image during nasopharyngoscopy, the quality of the visualization, and the limitation of the NBI in nasopharyngeal lesions. METHODS: Between June 2009 and May 2010, 63 patients who had a suspected nasopharyngeal tumor via nasopharyngoscopy at Taipei Veterans General Hospital, Taiwan, were included in this study. All of the patients received nasopharyngoscopy with conventional view and NBI view and nasopharyngeal biopsy. The patients were divided into two groups depending on the pathological results: nasopharyngeal carcinoma (NPC) and lymphoid hyperplasia/chronic inflammation (LH). RESULTS: Forty-one patients were in the NPC group and 22 patients were in the LH group. The pattern of the NBI view showed regular cobblestone in the LH group, except for one patient. The pattern of the NBI view showed an irregular engorged vascular pattern and/or microvascular proliferative pattern in 32 of 41 NPC patients (78.0%). The sensitivity, specificity, positive predictive value, and negative predictive value of NBI in nasopharynx (NP) were 78.0, 95.5, 97.0, and 70.0%, respectively, in NP neoplasm. CONCLUSION: NBI could be helpful in differentiating benign and malignant neoplasm in the NP region. Using NBI in NP regions had some limitations, including bleeding and mucus coating. PMID- 21679515 TI - Impact of nasal polyposis on erectile dysfunction. AB - BACKGROUND: Our male patients with chronic rhinosinusitis with nasal polyposis (NP) declare a better sexual function after functional endoscopic sinus surgery (FESS) with polypectomy. This study was planned to conduct the first prospective, controlled trial evaluating the possible relation between erectile dysfunction (ED) and NP by subjective and objective parameters. METHODS: Thirty-three male patients with NP and thirty randomly selected male control subjects were evaluated. All subjects underwent assessments of nasal endoscopy, rhinomanometry, body mass index (BMI), Epworth Sleepiness Scale, full in-laboratory polysomnograpy and serum levels of glucose, thyroid hormones, lipid profile, and testosterone. ED was evaluated by the erectile function domain of the International Index of Erectile Function (IIEF-EF) subjectively and nocturnal penile tumescence (NPT) objectively. The NP group was reassessed 6 months after FESS. RESULTS: The mean age, BMI, and laboratory tests of the patients and the control subjects had no significant difference. The well-recognized risk factors for ED were eliminated. Preoperative evaluation of the patients revealed that ED was present in 34 and 24% of the patients by IIEF-EF and NPT, respectively, which was significantly higher than the control group (p = 0.009 and p = 0.018, respectively). There was a significant improvement of ED in the assessment of IIEF-EF and NPT postoperatively (p = 0.014 and p = 0.037, respectively). CONCLUSION: ED was determined in a high percentage of patients with NP and significantly ameliorated after FESS. NP might present a risk factor in the development of ED. PMID- 21679516 TI - Nasal eosinophilia can predict bronchial hyperresponsiveness in persistent rhinitis: evidence for united airways disease concept. AB - BACKGROUND: Nasal eosinophils may be indicative of bronchial hyperresponsiveness (BHR) in rhinitis concerning the "united airways disease" theory. This study was designed to evaluate the relationship between nasal eosinophilia and BHR in persistent perennial rhinitis patients. METHODS: Thirty-seven patients (12 males and 25 females, mean age: 33.3 +/- 10.4 years) were included in the study. Skin prick test, nasal symptom score, nasal smears, methacholine bronchial challenge test, and nasal rhinometry were obtained in all patients. Eosinophil count in nasal smears was expressed as a percentage of the total cells. None of the patients had asthma. RESULTS: There was no difference between the number of atopic and nonatopic patients having BHR (4/20 versus 4/17; chi-squared = 0.07; p > 0.05). Total nasal flow was lower and percentage of nasal eosinophils was higher in the patients with BHR than in patients without BHR (p = 0.012 and p = 0.009, respectively). A cutoff point of 68% nasal eosinophils yielded a sensitivity of 100% (63.1-100) and a specificity of 58.6% (38.9-76.5) to determine the presence of BHR. Positive likelihood ratio for the value of eosinophils above cutoff value was 2.42 (1.8-3.3). CONCLUSION: This study shows the relationship between nasal eosinophils and BHR in persistent perennial rhinitis patients. Nasal eosinophil percentage below cutoff value indicates that a patient does not have BHR. PMID- 21679517 TI - Middle turbinate suture conchopexy during endoscopic sinus surgery does not impair olfaction. AB - BACKGROUND: One of the primary goals of endoscopic sinus surgery (ESS) is to create widely patent paranasal sinus ostia, and lateralization of a middle turbinate (MT) after ESS can obstruct otherwise patent ethmoid and maxillary sinuses. Numerous methods have been used to assist in the avoidance of this complication including the use of packing in the ethmoid sinus as a "spacer," controlled creation of synechia between the MT and septum, and suture medialization of the MT to the septum. The latter is an effective technique, but because the olfactory groove lies superior in the groove between the MT and septum, concerns have been raised as to the effect of this maneuver on olfaction. The aim of this pilot study was to objectively evaluate olfaction before and after suture conchopexy, and, secondarily, to evaluate the effectiveness of this technique in preventing lateralization of the MT. This study was designed to assess the effect of suture medialization of the MT during ESS on olfactory sensation. METHODS: Objective assessment of olfactory function using the University of Pennsylvania Smell Identification Test (UPSIT) was performed before and 6 months after ESS in 153 patients between January 2006 and January 2008. Postoperative follow-up exams were also performed to determine the effectiveness of the medialization procedure and the patency of the ethmoid cavities. RESULTS: UPSIT testing showed a small but statistically significant improvement in olfactory function after MT suture medialization to the septum when compared with preoperative assessment. Postoperative endoscopic examination revealed that lateralization of the MT was a rare complication after suture medialization of the MT. CONCLUSION: MT suture medialization during ESS is an effective method for preventing lateralization of the MT and does not impair olfactory function. PMID- 21679518 TI - Septal dislocation for endoscopic access of the anterolateral maxillary sinus and infratemporal fossa. AB - BACKGROUND: Transnasal approaches to the anterolateral maxillary sinus and infratemporal fossa are challenging with traditional endoscopic techniques and instrumentation. Additional access in the anterior and lateral direction can be obtained with modified endoscopic medial maxillectomy (MEMM) or total endoscopic medial maxillectomy (TEMM) or via a transseptal approach. Alternatively, we have used a septal dislocation technique to help access these areas. Access to these areas may be necessary for treatment of inverted papilloma, schwannoma, and juvenile nasopharyngeal angiofibromas. The aim of this study is to examine the effectiveness of septal dislocation for anterolateral reach in extended endoscopic sinus surgery. METHODS: Cadaver dissection was performed on eight sides. MEMM, TEMM, and septal dislocation were sequentially performed according to standard techniques. Image-guided axial screenshots were used to identify the extent of anterolateral reach in each stage by measuring the angle of access from the midline. RESULTS: TEMM adds 12 degrees of anterolateral reach when compared with MEMM. With septal dislocation, an average of 20 additional degrees is provided over TEMM. The anterior maxillary sinus is routinely accessed with straight instruments after septal dislocation. CONCLUSION: The anterolateral maxillary sinus and infratemporal fossa are difficult areas to access with standard endoscopic techniques. Septal dislocation is a straightforward technique to achieve additional visualization and access when combined with TEMM. PMID- 21679519 TI - Immunohistological study of wound healing after submucosal radiofrequency tissue ablation of inferior nasal turbinate in a sheep model. AB - BACKGROUND: Data on the molecular processes involved in nasal mucosa wound healing after radiofrequency tissue ablation (RTA) of the inferior nasal turbinate (INT) are missing. This study was designed to examine tissue expression of fibronectin, collagen III, CD68, and matrix metalloproteinase (MMP) 9 in the INT (ventral) after RTA in sheep. METHODS: An experimental randomized controlled study was performed. Seventeen INTs (ventral) of nine sheep were used. RTA was applied in 12 INTs. Turbinate samples were studied 1, 3, and 8 weeks postoperatively (4 samples/time point) and in five control INTs (without surgery). Besides hematoxylin and eosin staining, immunostaining was done for MMP 9, collagen III, fibronectin, and CD68. A quantitative grading ranging between 0 (no immunoreactivity at all) and 100% (profuse immunoreactivity) was performed by a blinded senior pathologist. Comparisons between groups were performed using Mann-Whitney U test and Kruskal-Wallis one-way ANOVA. Spearman's rho correlation coefficients were calculated between histological and/or immunohistological variables. RESULTS: At week 8, fibronectin (p = 0.025), collagen III (p = 0.004), and MMP-9 (p < 0.001) immunoreactivity was significantly higher than controls, while immunoreactivity for CD68 was higher, although not significantly (p = 0.114) compared with controls. Strong correlations have been found between mucosal vascularization and interstitial space volume (r = 0.776), interstitial space volume and epithelial cell necrosis (r = 0.730), and CD68 immunostaining and epithelial cell necrosis (r = 0.784). CONCLUSION: Given their high tissue concentrations after RTA application, fibronectin, collagen III, CD68, and MMP-9 deserve further study as candidate modulators of the INT wound-healing process. PMID- 21679520 TI - Major symptom score utility index for patients with acute rhinosinusitis. AB - BACKGROUND: Evaluation of acute rhinosinusitis treatment effectiveness is based on patient-reported relief of symptoms. This study was designed to develop a multiattribute utility scoring algorithm for the Major Symptom Score (MSS) and secondarily to evaluate the psychometric characteristics (i.e., validity and responsiveness) of the MSS Utility Index (MSSUI). METHODS: Adult patients with acute rhinosinusitis were recruited for this longitudinal observational study through primary care and specialist physician offices. One hundred ninety patients participated in a preference elicitation exercise for MSS health states. Resulting preference data were used to generate a utility scoring algorithm for the MSS. Participants completed the MSS and 20-Question Sino-Nasal Outcome Test (SNOT-20) at baseline and completed the MSS twice daily for 15 days via daily diary. On days 7 and 15, participants completed the MSS, SNOT-20, and Overall Treatment Effect scale and were evaluated by physicians via the Physician Global Improvement Scale (PGIS). RESULTS: At baseline, the mean +/- SD. MSSUI score was 0.51 +/- 0.17 and was negatively correlated with SNOT-20 scores (r = -0.58; p < 0.001). Days 2-8 average MSSUI scores were negatively correlated with day 7 SNOT 20 (r = -0.46; p < 0.001) and PGIS (r = -0.22; p < 0.001) scores; whereas days 9 15 average MSSUI scores were inversely related to day 15 SNOT-20 (r = -0.40; p < 0.001) and PGIS (r = -0.32, p < 0.001) scores. Mean MSSUI scores improved from baseline with effect sizes at days 7 and 15 of 0.82 and 1.20, respectively. CONCLUSION: The MSSUI represents an acceptable and psychometrically sound patient reported end point for clinical trials comparing treatments for acute rhinosinusitis. PMID- 21679521 TI - Increased expression of a disintegrin and metalloprotease 8 in allergic rhinitis. AB - BACKGROUND: A disintegrin and metalloproteases (ADAMs) constitute a family of cell surface proteins containing disintegrin and metalloprotease domain, which associate features of adhesion molecules and proteases. ADAM8 is a member of the ADAM family and has recently been implicated to have a role in allergic lung inflammation. Therefore, our aims were to determine the expression of ADAM8 mRNA and protein and to localize ADAM8 protein in the nasal mucosa of patients with allergic rhinitis and control subjects. METHODS: Inferior turbinate mucosa samples were obtained from 20 patients with allergic rhinitis and 20 matched healthy normal controls. ADAM8 mRNA was extracted from the inferior turbinate mucosa, and then reverse transcription-polymerase chain reaction was performed. Western blot testing was used to analyze differences in the level of ADAM8 protein expression between patients with allergic rhinitis and normal controls, and the ADAM8 protein was localized with immunohistochemical staining. RESULTS: The level of expression of ADAM8 mRNA and protein in the nasal mucosa was significantly increased in patients with allergic rhinitis compared with normal controls. ADAM8 protein was expressed in the epithelium, infiltrating inflammatory cells, and submucosal glands. CONCLUSION: ADAM8 is expressed in human nasal mucosa and is increased in patients with allergic rhinitis. These results suggest a possible contribution for ADAM8 in chronic inflammation of the nasal mucosa in patients with allergic rhinitis. PMID- 21679522 TI - Effect of dexamethasone on wound healing of the septal mucosa in the rat. AB - BACKGROUND: Postoperative treatment after functional endoscopic sinus surgery (FESS) aims to modulate the wound healing process. Systemic or topically applied corticosteroids have been reported to be beneficial for improving nasal wound healing after FESS. However, few studies have investigated the effects of postoperative systemic steroids on nasal wound healing with regard to histological changes. The aim of this study was to evaluate the effect of systemic dexamethasone on nasal wound healing after mechanical injury in the rat. METHODS: A unilateral wound in the nasal cavity was induced using the brushing technique in 4-week-old, Sprague-Dawley rats (n = 70). Dexamethasone (0.15 mg/kg daily for 7 days) and normal saline were administered i.p. to the experimental and control groups (n = 35 for each) after the injury. The rats (n = 7 for each) were killed on days 2, 5, 14, 28, and 42 after the injury. Histological changes in the nasal mucosa were examined and compared using hematoxylin and eosin and Masson's trichrome staining. RESULTS: The experimental group showed less subepithelial edema formation and epithelial disarray at the early phase of the wound healing period. There were statistically significant differences in the subepithelial thickness and epithelial thickness indices between the experimental and control groups (p < 0.05). Ciliary and goblet cell indices were lower in the experimental group, which means that ciliary and goblet cell regeneration may be delayed by dexamethasone (p < 0.05). There were no differences in the subepithelial fibrosis index between the two groups. Adhesion formation between the nasal septum and turbinate were found only in the control group. CONCLUSION: Systemic dexamethasone after mucosal injury may lessen subepithelial edema, goblet cell hyperplasia, and adhesion formation; however, it may cause delayed mucosal ciliary regeneration. PMID- 21679523 TI - Prevalence and risk factors of chronic rhinosinusitis in Korea. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common inflammatory diseases with multiple etiologies. Despite its high prevalence, risk factors influencing its prevalence have not been thoroughly revealed. Therefore, we investigated the prevalence and risk factors of CRS in Korea. METHODS: The 4098 subjects that participated in the Korea National Health and Nutrition Examination Survey were included in the study. Risk factors were categorized into sociodemographic and personal medical factors. Univariate and multivariate analyses were performed to identify significant risk factors of CRS. In addition, population attributable risks of the significant factors were calculated to estimate the effect on the population level. RESULTS: The prevalence of CRS in Korea was 6.95%. Among sociodemographic factors, male sex, old age, and heavy stress were significantly related with CRS. Influenza vaccination, septal deviation, and persistent allergic rhinitis were significant personal medical risk factors of CRS. Among these risk factors, persistent/moderate to severe allergic rhinitis was proven to be the most significant risk factor for CRS at the population level. CONCLUSION: Although the prevalence and risk factors vary according to time, place, and diagnostic criteria, periodic epidemiological study on CRS is necessary to reduce socioeconomic expenditure and establish an improved national health care policy. PMID- 21679524 TI - A controlled laboratory and clinical evaluation of a three-dimensional endoscope for endonasal sinus and skull base surgery. AB - BACKGROUND: One criticism of current video systems for endoscopic surgery is that two-dimensional (2D) images lack depth perception and may impair surgical dissection. To objectively measure the efficacy of 3D endoscopy, we designed a training model with specific tasks to show potential differences between 2D and 3D endoscopy. Its clinical value was then evaluated during endoscopic sinus and skull base surgical cases. METHODS: Fifteen subjects were grouped according to endoscopic experience: novices and nonnovices. A training model was constructed to include five tasks: incision manipulation; ring transfer; nerve hook; distance estimation, visual only; and distance estimation, visual and tactile. Each participant was assessed with both a standard 2D endoscope and a 3D endoscope. The clinical value of a 3D endoscope (Visionsense, Ltd., Petach Tikva, Israel) was then examined in four endoscopic sinus cases and four skull base cases. RESULTS: Of the subjects, six (40%) were novices. Overall, the errors committed during any one task were not significantly different between systems. Novices trended toward more success during the nerve hook task using the 3D system. With size cueing versus visualization alone, distance estimation was significantly more accurate. Novices tended to prefer the 3D system and experienced surgeons disliked the initial learning curve. Advantages were particularly noticed during skull base surgery; subjectively improved depth perception was beneficial during vascular dissection. CONCLUSION: Three-dimensional endoscopy may improve depth perception and performance for novices. The 3D endoscope is a safe and feasible tool for endoscopic sinus and skull base surgery; it is promising for improving microneurosurgical dissection precision transnasally. PMID- 21679526 TI - Near-infrared spectroscopy of orbitofrontal cortex during odorant stimulation. AB - BACKGROUND: For olfaction, several studies have reported near-infrared spectroscopy (NIRS) signal changes in the orbitofrontal cortex (OFC) during odor stimulation. However, the roles of human OFC in olfactory cognition are less well understood. This study was designed to better understand the roles of OFC for olfaction. METHODS: Hemodynamic responses for phenyl ethyl alcohol or citral in the OFCs were measured with NIRS. After the experiment, participants were asked to describe the characteristics of the odor and to rate odor intensity and hedonic valence. RESULTS: Statistical analysis of all participants' data showed significant changes in the concentration of total hemoglobin in the left OFC during the trial (p = 0.04). The total hemoglobin signal increased significantly in the right OFC (p = 0.0008) of the participants who successfully identified the odorant stimulus. CONCLUSION: Our findings showed that NIRS combined with a questionnaire is a useful method for studying the functional neuroanatomy of OFC in terms of olfaction. PMID- 21679525 TI - Three-dimensional volumetric measurements and analysis of the maxillary sinus. AB - BACKGROUND: Multiple chronic rhinosinusitis (CRS) staging systems have been developed in an attempt to correlate symptoms with radiological imaging results. Currently, no perfect system exists. We sought to analyze the maxillary sinus (MS) using three-dimensional volumetric measurements and advanced high-resolution CT imaging. METHODS: We reviewed MS CT scans from 50 control subjects and 50 subjects with documented CRS involving at least one MS. The following measurements were recorded: (1) volume of MS free air, (2) MS mucosal thickening, and (3) MS lateral wall bony thickness. Average Hounsfield unit (HU) values for mucosal thickening among CRS subjects were also recorded. Values are expressed as mean +/- SD and median. Values from the CRS patients were compared with healthy controls using Student's t-tests. RESULTS: Among controls (n = 50), volumes (mL) of right and left MS were 24.1 +/- 9.7 and 24.7 +/- 9.0, respectively. Among CRS patients (n = 50), the portion of mucosal disease to total sinus volume was 51.8% (right) and 50.7% (left). Mean bony thickness (mm) in controls was 0.98 +/- 0.2 (right) and 1.0 +/- 0.3 (left). CRS patients had significantly greater bony thickness 1.9 +/- 0.8 (right) and 2.0 +/- 0.9 (left; p = 0.0001). HU for diseased MS were 30.1 +/- 18.7 (right) and 35.7 +/- 22.1 (left). CONCLUSION: Three dimensional volumetric analysis combined with HU calculations and bony thickness measurements represents a new and unique way to evaluate CT scans in patients with CRS. Additional studies correlating symptoms with imaging findings as well as analysis of all paranasal sinuses is the next step toward a novel staging system. PMID- 21679527 TI - The nose as a target organ in the diagnosis of severe aspirin-exacerbated respiratory disease. AB - BACKGROUND: The nasal provocation test (NPT) with lysine aspirin is a useful tool in the diagnosis of aspirin-exacerbated respiratory disease (AERD), previously reffered to as Samter's disease. The aim of the present study focuses on methodological interventions to show the usefulness of the NPT with lysine aspirin in differentiating AERD patients from aspirin-tolerant asthma (ATA) patients to improve the diagnostic efficacy and minimize the risk for adverse reactions compared with the gold standard. METHODS: Thirty AERD patients comprised the active study group while the control group consisted of 25 ATA patients. A combination of objective nasal aerodynamic response (i.e., nasal inspiratory flow and nasal inspiratory resistance) was evaluated by active anterior rhinomanometry and the subjective clinical nasal and extranasal symptoms (including forced expiratory volume) were monitored throughout the challenge. RESULTS: Fifty-five NPTs were successfully completed: sensitivity, 87%; specificity, 100%; positive predictive value, 100%; negative predictive value, 86%; global efficacy, 92.72%. No severe adverse reactions were recorded. CONCLUSION: The present NPT with lysine aspirin proved to be a safe, efficient, and a timesaving method in the diagnosis of patients with AERD, even in those with severe rhinitis-rhinosinusitis and/or recurrent nasal polyposis. PMID- 21679528 TI - Postoperative care with Chinese herbal medicine or amoxicillin after functional endoscopic sinus surgery: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: A number of herbal preparations have been reported being used as adjunctive treatment of patients with chronic rhinosinusitis (CRS) after functional endoscopic sinus surgery (FESS). This study was designed to examine the efficacy of Chinese herbal medicine (CHM) in the postoperative care of post FESS patients. METHODS: Patients with CRS who underwent FESS were prospectively enrolled in the study. Before surgery, they were evaluated by various methods, including the Chinese version of the Rhinosinusitis Outcome Measure (CRSOM-31), nasal endoscopy, acoustic rhinometry, and computed tomography (CT). After surgery, they were randomized to take CHM (Tsang-Erh-San extract granules and Houttuynia extract powder) for 8 weeks, amoxicillin for 4 weeks, or placebo. They were revaluated by CRSOM-31, nasal endoscopy, and acoustic rhinometry at 8 weeks and by CT at 12 weeks after surgery. RESULTS: Ninety-seven patients (33 in the CHM group, 34 in the amoxicillin group, and 30 in the placebo group) completed the study. In the CHM group, CRSOM-31 and endoscopic scores significantly decreased, and the second minimal cross-sectional area of the nasal cavity measured by acoustic rhinometry significantly increased after treatment. In the amoxicillin and placebo groups, CRSOM-31, endoscopic, and CT scores significantly decreased after treatment. However, there were no significant differences in subjective and objective treatment outcomes among three groups of patients. CONCLUSION: Our results showed there was no significant benefit of using CHMs (Tsang-Erh-San extract granules and Houttuynia extract powder) or oral amoxicillin in post-FESS care of CRS patients. Additional investigation is necessary for post-FESS care. PMID- 21679529 TI - Repeated intranasal instillation with staphylococcal enterotoxin B induces nasal allergic inflammation in guinea pigs. AB - BACKGROUND: Staphylococcal enterotoxins (SEs) appear to play a role in the pathogenesis of allergic disease. However, no animal models have been reported to show nasal allergic inflammation by repeated inhalation with staphylococcal enterotoxin B (SEB) in the absence of adjuvant. This study was designed to determine whether intranasal instillation of guinea pigs with SEB results in nasal allergic inflammation. METHODS: Guinea pigs were intranasally instilled with 40 MUL of 4-MUg SEB once every 4 days 11 times. For the control group, guinea pigs were prepared with saline instead of SEB. Sneezing and nasal scratching frequency were evaluated after each intranasal instillation. The production of antigen-specific antibodies including IgE, nasal eosinophilia, and cytokines in the nasal cavity lavage fluid (NCLF) were measured after the 11th intranasal immunization. RESULTS: In the model group, symptoms of sneezing and nasal scratching were induced at the 8th to 11th challenges. Intranasal immunization with SEB elicited a local nasal mucosa inflammatory response characterized by apparent eosinophil infiltration. In the NCLF, the expression of IL-4 but not interferon-gamma was increased after challenges. The serum levels of total and SEB-specific IgE and IgG1 were higher in model groups in comparison with the control groups (p < 0.01). CONCLUSION: These results indicate that repeated intranasal instillation with SEB leads to Th2 immune response, allergic nasal inflammation, and increased antigen-specific IgE production that are characteristic of allergic rhinitis (AR). The model in this study could be valuable in analyzing the pathogenesis of AR infected with Staphylococcus aureus. PMID- 21679530 TI - Objective usefulness of thin silastic septal splints after septal surgery. AB - BACKGROUND: Silastic splints have been used as effective tools for septal support, avoiding adhesion, and mucosal healing after septal surgery. Furthermore, although many surgeons insert septal splints, no well-designed trials exist to support their use. A randomized double-blinded controlled trial was performed. METHODS: We recruited 40 subjects who had undergone septoplasty only without sinus surgery or turbinoplasty. A silastic septal splint was inserted in one side of the nasal cavity at the end of each septoplasty, with the other side serving as a control. The splint side and control side were randomly selected. Nasal discomfort score (10-point scale) and mucosal status (grades 1-4) were surveyed in a blinded setting on postoperative days 7 and 14. RESULTS: Forty of 83 subjects fulfilled the enrollment criteria. On the 7th postoperative day there was no significant difference in nasal discomfort between the splint and control sides (6.2 +/- 1.28 and 5.7 +/- 1.27, respectively; p = 0.116), but the mucosal status was better on the splint side than on the control side (1.5 +/- 0.51 and 2.5 +/- 0.85; p < 0.001). At 14 days postoperatively, the symptom score (2.7 +/- 1.06 versus 3.8 +/- 1.25; p < 0.001) and mucosal status (1.5 +/- 0.55 versus 1.9 +/- 0.68; p = 0.013) were significantly better on the splint side compared with the control side. CONCLUSION: Insertion of a silastic septal splint after septal surgery should be accepted as a routine procedure. PMID- 21679531 TI - Mucocele rate after endoscopic skull base reconstruction using vascularized pedicled flaps. AB - BACKGROUND: Postoperative cerebrospinal fluid leak is a significant risk after endoscopic skull base surgery. Recently, novel reconstructive techniques using vascularized pedicled mucosal flaps have been applied to decrease this potential risk. Complete mucosal extirpation in the wound bed is not always feasible and the impact of insetting the flap over intact underlying mucosa is not clear. The purpose of this study was to determine the rate of mucocele formation after nasoseptal flap reconstruction without mucosal stripping. METHODS: This is an Institutional Review Board-approved, retrospective study consisting of 28 patients undergoing skull base reconstruction using a pedicled nasoseptal flap between 2008 and 2010 at a tertiary care hospital. In all cases the sinus or skull base mucosa surrounding the defect was left intact. Patients were followed postoperatively by endoscopy and/or imaging for evidence of mucocele formation in the reconstructive bed. RESULTS: The total rate of mucocele formation was 3.6% (1 of 28, noted on postoperative day 46). The mean follow-up time was 243 +/- 174 days (range, 46-585 days). Eleven patients were followed for over 1 year. All flaps remained viable and well vascularized. CONCLUSION: The pedicled nasoseptal flap is an effective means of reconstruction after endoscopic skull base surgery. Avoidance of extensive stripping of the surrounding mucosa does not result in a significant rate of postoperative mucocele formation in the short term. Long-term follow-up is still indicated. PMID- 21679532 TI - Experiences with a new surgical technique for closure of large perforations of the nasal septum in 55 patients. AB - BACKGROUND: The surgical closure of nasal septal perforation is still an unsolved clinical problem. In this study the experiences with a novel surgical technique for closure of large perforations of the nasal septum are presented. METHODS: A total of 55 patients with symptomatic nasal septal perforation measuring 23 +/- 3 mm (range, 11-38 mm) at the widest point were enrolled in the study. The closure of the nasal septal perforation was performed with a new and simple surgical technique using a nasal mucosal flap consisting of the defect-corresponding mucosa of the floor of the nose, inferior nasal meatus, and inferior turbinate. RESULTS: A symptomatic improvement of nasal symptoms was noted in all treated patients. In only 3 of 55 cases was the perforation closing incomplete. CONCLUSION: Our experience with this flap shows its reliability and safety in repairing large nasal septal perforations, with many advantages compared with other techniques for septal perforation repair. PMID- 21679533 TI - Comparison of outcomes of simple polypectomy plus balloon catheter dilatation versus functional endoscopic sinus surgery in nasal polyposis: a preliminary study. AB - BACKGROUND: The aim of this study was to compare the outcomes of functional endoscopic sinus surgery (FESS) and simple polypectomy plus balloon catheter dilatation (BCD) in nasal polyposis. METHODS: Ten patients (six male and four female subjects) with nasal polyposis who underwent surgical treatment were included in this research. BCD was performed on one side of each patient's paranasal sinuses (after nasal polypectomy by microdebrider) while standard FESS was performed on the other side. Preoperatively, all patients were treated with oral methylprednisolone, 1 mg/kg per day, for 5 days, which was reduced and stopped on the 14th day. Pre- and postoperative endoscopic and radiological findings were compared. Endonasal endoscopic examination results were classified according to MacKay classification. Paranasal sinus computed tomography findings were evaluated according to Lund-MacKay classification. RESULTS: Pre- and postmedical treatment results of the patients were not significantly different according to MacKay classification. There was no significant difference between the results of FESS and BCD during 12-month follow-up period according to Lund MacKay and MacKay classifications. There was significant improvement in the results obtained 1 and 12 months after FESS and BCD, respectively. The improvement was also radiologically evident. CONCLUSION: At 1 year postsurgery, polypectomy plus BCD is as effective as FESS. Longer-term studies are necessary to validate this technique. PMID- 21679534 TI - Activated recombinant factor VIIa and uncontrolled gastrointestinal bleeding. PMID- 21679535 TI - Leiomyosarcoma of the colon: unresolved issues of a rare but highly aggressive malignancy. PMID- 21679536 TI - Recurrent peritoneal hemangiopericytoma. PMID- 21679537 TI - A dilated cystic duct stump as a cause of postcholecystectomy syndrome. PMID- 21679538 TI - Spontaneous hemoperitoneum during pregnancy: a diagnosis pitfall. PMID- 21679539 TI - Vertebral artery injury after blunt trauma without concomitant cervical or neurologic injuries: a screening conundrum. PMID- 21679540 TI - Early definitive closure of abdomen using components separation technique after damage control surgery. PMID- 21679541 TI - Granular cell tumor. PMID- 21679542 TI - Laparoscopic approach to Waugh's syndrome. PMID- 21679543 TI - Small bowel obstruction secondary to pelvic inflammatory disease. PMID- 21679544 TI - Laparoscopic repair of inguinal and incisional hernias. PMID- 21679545 TI - Early laparoscopic cholecystectomy is the appropriate management for acute gangrenous cholecystitis. AB - Treatment of severe acute cholecystitis by laparoscopic cholecystectomy remains controversial because of technical difficulties and high rates of complications. We determined whether early laparoscopic cholecystectomy is appropriate for acute gangrenous cholecystitis. The medical records of 116 patients with acute gangrenous cholecystitis admitted to the Korea University Guro Hospital between January 2005 and December 2009 were reviewed. The early operation group, those patients who had cholecystectomies within 4 days of the diagnosis, was compared with the delayed operation group, who had cholecystectomies 4 days after the diagnosis. Of the 116 patients, 57 were in the early operation group and 59 were in the delayed operation group. There were no statistical differences between the groups with respect to gender, age, body mass index, operative methods, major complications, duration of symptoms, mean operative time (98 vs 107 minutes), or postoperative hospital stay. However, the total hospital stay was significantly longer in the delayed operation group. More patients underwent preoperative percutaneous cholecystostomy in the delayed operation group (3.5 vs 15.3%). Early laparoscopic cholecystectomy for acute gangrenous cholecystitis is safe and feasible. There is no advantage to postponing an urgent operation in patients with acute gangrenous cholecystitis. PMID- 21679546 TI - Early laparoscopic cholecystectomy for gangrenous cholecystitis. PMID- 21679547 TI - Minimally invasive adrenalectomy: a multicenter comparison of transperitoneal and retroperitoneal approaches. AB - Minimally invasive adrenalectomy (MIA) is both feasible and safe with either transperitoneal or retroperitoneal entry. However, only a few studies have rigorously compared these two techniques. The aim of the current study is to compare transperitoneal and retroperitoneal adrenalectomy to detect significant differences in patient selection and perioperative outcomes. Between 1995 and 2009, 171 patients underwent MIA through transperitoneal (n = 127) or retroperitoneal access (n = 44). The respective cohorts were then examined retrospectively through matched and unmatched comparisons. Multivariate analyses of intraoperative blood loss, postoperative morbidity, and length of hospital stay were performed. Surgical indications were benign lesions (70.2%), malignant tumors (11.1%), and pheochromocytomas (18.7%). The postoperative morbidity rate was 15.8 per cent, but mortality was null. The rate of conversion to open surgery was 5.3 per cent. Blood loss and operative time were significantly lower with the transperitoneal approach, whereas time to oral intake was shorter for the retroperitoneal group. Tumor size less than 4.5 cm was associated with less blood loss, shorter hospital stay, and lower postoperative morbidity. Laparoscopic and retroperitoneal routes are both effective and safe for excising adrenal lesions. In the present study, however, laparoscopic adrenalectomy demonstrated shorter operative times with less blood loss. Regardless of this, we remain cautious in recommending one procedure preferentially. Other important measures of clinical outcome such as required pain control, ease of patient recovery, and cost considerations were not included in this analysis. Further randomized trials, with large patient numbers, are therefore desirable for defining an optimal surgical method. PMID- 21679548 TI - Making liver transection even safer: a novel use of microwave technology. AB - Hepatic surgery has evolved significantly in the past decade. The current article describes the largest series of patients in United States undergoing liver resective therapy with the use of microwave technology for liver precoagulation. Glisson's capsule was incised after securing inflow and outflow control. Two antennae, 2 cm apart, connected to a 915-MHz generator, were inserted 5 cm into liver parenchyma at a 130 degrees angle. Once the parenchyma was firm and changed its color to gray, the antennae were advanced along the line of transection. The parenchyma was divided with electrocautery. Intra- and postoperative data were analyzed. Thirty-five patients (24 men) underwent liver resections. Diseases treated were colorectal metastases (n = 9), hepatic adenoma (n = 3), gallbladder cancer (n = 3), hepatocellular carcinoma (n = 4), neuroendocrine tumor (n = 2), cholangiocarcinoma (n = 5), hemangioma (n = 2), focal nodular hyperplasia (n = 2), metastatic gastrointestinal stromal tumor (n = 1), hydatid cyst (n = 1), hepatoid carcinoma (n = 1), hepatolithiasis (n = 1), and suspected metastatic breast cancer (n = 1). Resections done were right hepatectomy (n = 19), segmental resection (n = 5), left hepatectomy (n = 4), extended right hepatectomy (n = 4), Segment IVb and Segment V resections during radical cholecystectomy (n = 2), and left lateral sectionectomy (n = 1). Median operative time for major resection was 188 and 251 minutes for minor resection. There was one postoperative mortality. Bile leak needing stenting occurred in one patient. Median blood loss for major resection was 500 mL and 265 mL for minor resection. Intraoperative transfusion was required in nine major and one minor resections. Other complications were ileus in four, deep vein thrombosis in two, intra-abdominal abscess in one, and cardiac events in two patients. Liver precoagulation with microwave technology is a novel and efficient technique with minimal morbidity and mortality for liver transection. PMID- 21679549 TI - Two-port laparoscopic common bile duct exploration with T-tube choledochostomy for management of choledocholithiasis: an initial clinical report. AB - Laparoscopic common bile duct exploration (LCBDE) is generally performed using a four- or five-port technique. We report a unique technique of two-port transcholedochal LCBDE with T-tube placement. Twelve consecutive patients with common bile duct (CBD) stones underwent LCBDE through two entry ports, one homemade single port (Uen port) inserted in a 2-cm umbilical wound and one 5-mm subxiphoid trocar port. With the assistance of a 1.2-mm needle that was inserted through a right lower intercostal space into the abdominal cavity to facilitate the operation, two-port dome-down laparoscopic cholecystectomy, choledochotomy, choledochoscopic removal of ductal caculi, and T-tube choldochostomy were performed with conventional methods using standard laparoscopic instruments along with manually operated angled shafts. After completion of the operation, the T tube catheter was brought out through the subxiphoid trocar wound. All operations were completed successfully without the need of additional ports. There was no complication and no residual stones. Mean operation time was 120 minutes (range, 90 to 150 minutes), and mean postoperative hospital stay was 3.5 days (range, 3 to 4 days). Scarless wound healing was achieved except one T-tube scar. Two-port transumbilical LCBDE with T-tube choledochostomy is a feasible, safe, and effective technique that allows one-scar abdominal surgery for treatment of CBD stones. Further studies and the development of better instruments are necessary before this can be recommended as a standard procedure. PMID- 21679550 TI - Cervical spinal cord injury associated with near-drowning does not increase pneumonia risk or mortality. AB - Body surfing accidents (BSA) can cause cervical spinal cord injuries (CSCIs) that are associated with near-drowning (ND). The submersion injury from a ND can result in aspiration and predispose to pulmonary complications. We predicted a worse outcome (particularly the development of pneumonia) in patients with CSCIs associated with ND. A retrospective review was performed of patients who were treated at Eastern Virginia Medical School for a CSCI resulting from a blunt mechanism. Data collected included basic demographic data, data regarding injury and in-hospital outcomes, and discharge data, including discharge disposition. Statistics were performed using chi(2) and Student t test. In 2003 to 2008, 141 patients were treated for CSCIs with inclusion criteria. Thirty patients (21%) had an associated ND (BSA) and 111 patients (79%) did not (BLT). The cohorts were similar in mean age (BSA, 45 years; BLT, 50 years; P = 0.16) and male gender distribution (BSA, 93%; BLT, 79%; P = 0.13). The cohorts were similar in injury severity using Injury Severity Score (BSA, 22; BLT, 24; P = 0.65). The cohorts were similar in rates of developing pneumonia (BSA, 3%; BLT, 12%; P = 0.31). The rate of infection was significantly higher in the cohort without an associated near-drowning (BSA, 10%; BLT, 32%; P = 0.033). The mean intensive care unit stay (BSA, 3.5 days; BLT, 11.3 days; P = 0.057) and the rate of mortality were similar (BSA, 10%; BLT, 10% P = 0.99). Those patients with an associated ND had a shorter hospital stay (BSA, 5.7 days; BLT, 22.2 days; P = 0.007) and a better chance of being discharged home (BSA, 57%; BLT, 27%; P = 0.004). CSCIs after a BSA do better than their counterparts without an associated ND. CSCIs associated with ND appear to be isolated injuries with minimal pulmonary involvement despite submersion injuries. PMID- 21679551 TI - Selection criteria for complete cytoreduction after cytoreductive surgery for peritoneal surface malignancy: lessons learned from our first series of patients. AB - The appropriate selection criteria for complete cytoreduction in patients with peritoneal surface malignancies have not been determined. We performed a retrospective analysis of all patients receiving cytoreductive surgery (CRS) during the study period of 2004 to 2008 to determine appropriate selection criteria for successful complete cytoreduction. During the study period, 38 patients underwent attempted CRS. Cytoreduction was scored complete, incomplete, or not reported in 53 per cent (n = 20), 37 per cent (n = 14), and 11 per cent (n = 4), respectively. Median overall survival for compete and incomplete cytoreduction was 56 months versus 5 months (P = 0.011), respectively. Compared with incomplete cytoreduction, patients receiving complete cytoreduction were more likely to have a lower Peritoneal Cancer Index (PCI) and not have received preoperative systemic chemotherapy (CT). Univariate analysis verified PCI greater than 20 (hazard ratio [HR], 0.048; CI, 0.004 to 0.515; P = 0.01) and CT (HR, 0.17; 0.004 to 0.77; P = 0.021) as predictors of incomplete cytoreduction. Small bowel (100%), periportal region (33%), and mesentery (27%) were the most common sites of residual disease. In conclusion, PCI less than 20 and the need for preoperative chemotherapy should be strongly considered when selecting patients with peritoneal surface malignancy for attempted cytoreduction. Early evaluation of the small bowel, mesentery, and periportal region for resectability prevents unnecessary surgery. PMID- 21679552 TI - Lidocaine patches reduce pain in trauma patients with rib fractures. AB - Rib fracture pain is notoriously difficult to manage. The lidocaine patch is effective in other pain scenarios with an excellent safety profile. This study assesses the efficacy of lidocaine patches for treating rib fracture pain. A prospectively gathered cohort of patients with rib fracture was retrospectively analyzed for use of lidocaine patches. Patients treated with lidocaine patches were matched to control subjects treated without patches. Subjective pain reports and narcotic use before and after patch placement, or equivalent time points for control subjects, were gathered from the chart. All patients underwent long-term follow-up, including a McGill Pain Questionnaire (MPQ). Twenty-nine patients with lidocaine patches (LP) and 29 matched control subjects (C) were analyzed. During the 24 hours before patch placement, pain scores and narcotic use were similar (LP 5.3, C 4.6, P = 0.19 and LP 51, C 32 mg morphine, P = 0.17). In the 24 hours after patch placement, LP patients had a greater decrease in pain scores (LP 1.2, C 0.0, P = 0.01) with no change in narcotic use (LP -8.4, C 0.5-mg change in morphine, P = 0.25). At 60 days, LP patients had a lower MPQ pain score (LP 7.7, C 12.2, P < 0.01), although only one patient was still using a patch. There was no difference in time to return to baseline activity (LP 73, C 105 days, P = 0.16) and no adverse events. Lidocaine patches are a safe, effective adjunct for rib fracture pain. Lidocaine patches resulted in a sustained reduction in pain, outlasting the duration of therapy. PMID- 21679553 TI - Operative decision-making for follicular thyroid lesions: a community hospital system experience. AB - Follicular neoplasms of the thyroid are a frequent indication for surgery of the thyroid gland. We evaluated the use of frozen sections on intraoperative decision making, possible avoidance of reoperative surgery, and histologic findings in a retrospective cohort. A database was created of all thyroid operations from 2001 to 2007. Data collected included age, gender, preoperative cytology, indication for surgery, surgeon, intraoperative decision-making, and histologic findings. Of the 723 thyroidectomies, 203 were performed for follicular neoplasms diagnosed by fine needle aspiration. Of these, 135 had cytology reports available within our electronic medical record; 44 per cent (59 of 135) of these patients had an intraoperative frozen section. Only two of 59 (3.4%) were positive for carcinoma, both of which were papillary carcinomas. One was interpreted as "suspicious" for carcinoma by the pathologist. In these three cases, the surgeon proceeded with total thyroidectomy at the time of initial surgery. The results of frozen section altered the operation in only three of 59 cases (5.1%). Intraoperative frozen section rarely impacts the conduct of thyroidectomy for follicular neoplasms. PMID- 21679554 TI - Combined side-to-end anastomosis with temporary end colostomy for the management of selected left-sided colonic emergencies. AB - Management of surgical emergencies of the left colon commonly requires excision of the colonic segment bearing the lesion, creation of an end colostomy, and closure of the rectosigmoid stump. Closure of the end stoma may be technically challenging. During this study, we used a new surgical technique involving the creation of an end-to-side anastomosis of the rectosigmoid stump to the base of the proximal colonic segment in association with an end colostomy. During a 15 year period, 23 patients were offered this type of surgery. Mortality was zero. Complications were observed in seven patients (morbidity, 7/23). Mean hospitalization time was 12.3 days. Closure of the colostomy was performed approximately 1 month after initial surgery and was easily performed using a mechanical stapler, either intraperitoneally or even extraperitoneally. No complications were observed after closure of the colostomy. The described technique is a useful alternative for the management of selected patients with left-sided colonic surgical emergencies. Its main advantage is that it greatly facilitates colostomy closure, which is performed earlier compared with the colostomy closure after a typical Hartmann's procedure. PMID- 21679555 TI - Impacting the problem of inner-city youth violence: "Educating Kids About Gun Violence" program. AB - The Educating Kids Against Gun Violence (EKG) program was developed in response to high levels of gun violence in an urban inner-city county through a partnership between the county prosecutor's office, local law enforcement, and a Level 1 trauma center. This program incorporates short video clips and interactive presentations, which address legal and medical consequences of gun violence. The program was presented to youths varying in age and degree of prior contact with the criminal justice system. Pre and post surveys were used to evaluate the short-term impact of the EKG program on the legal and medical knowledge and attitudes of youth participants. There were 130 pre and post surveys that could be exactly matched. Sixty-three per cent of participants had been arrested and 35 per cent had been convicted of a crime. On the post survey, 79 per cent stated that "the program will help keep me out of trouble" and 69 per cent stated that "in the future because of this program I will be less likely to carry a gun". The EKG program seemed to have positive short-term impacts on youth knowledge of legal and medical consequences and attitudes regarding gun violence. PMID- 21679556 TI - Long-term outcomes with transfascial sutures versus tacks in laparoscopic ventral hernia repair: a review. AB - Although most surgeons report using both transfascial sutures and laparoscopically placed tacks to secure prostheses in laparoscopic ventral hernia repair, a significant minority have reported large series in which sutures were omitted. A systematic review of the available literature was conducted for large case series and controlled trials documenting long-term follow-up. Forty-three articles were identified, including 6015 patients whose prostheses were secured with transfascial sutures (with or without tacks), and 2450 patients receiving tacks or staples alone. The mean follow-up time reported was 30.1 months. No significant difference was found in rates of hernia recurrence, mesh removal, prolonged postoperative pain, patient body mass index, or hernia defect size between the two groups. The suture group did experience a significantly higher rate of surgical site infection. Although suture tensile strength is greater than that of tacks, and despite numerous anecdotal reports of hernia recurrence secondary to suture failure or omission, the existing literature does not show superiority of one mesh fixation technique over the other for recurrence, whereas infection rates increase when transfascial suture is used. PMID- 21679557 TI - Laparoscopic appendectomy provides better outcomes than open appendectomy in elderly patients. AB - The incidence of acute appendicitis in elderly patients is increasing due to prolonged life span. The associated morbidity and mortality related to perforation of acute appendicitis continue to present challenges to physicians. The role of laparoscopic appendectomy is still controversial. This study aimed to compare the postoperative outcomes of elderly patients who received either a laparoscopic or an open appendectomy. We retrospectively reviewed charts of patients with acute appendicitis between January 2005 and February 2009. Elderly patients who received laparoscopic or open appendectomies were enrolled. The demographics, preoperative condition, operating time, intraoperative blood loss, and postoperative course were analyzed. A total of 150 patients were enrolled in this study. On average, patients who received a laparoscopic appendectomy had fewer hospital days and lower rates of postoperative ventilator dependence than patients who received an open appendectomy. In the management of elderly patients with acute appendicitis, laparoscopic appendectomy provides better outcomes than open appendectomy. PMID- 21679558 TI - Appendicitis, body mass index, and CT: is CT more valuable for obese patients than thin patients? AB - The purpose of our study is to determine whether body mass index (BMI = weight in kg/height in meters(2)) was related to the rate of negative appendectomy in patients who underwent preoperative CT. A surgical database search performed using the procedure code for appendectomy identified 925 patients at least 18 years of age who underwent urgent appendectomy between January 1998 and September 2007. BMI was computed for the 703 of these 925 patients for whom height and weight information was available. Patients were stratified based on body mass index (BMI 15-18.49 = underweight; 18.5-24.9 = normal weight; 25-29.9 = overweight; 30-39.9 = obese; >= 40 = morbidly obese). Negative appendectomy rates were computed. Negative appendectomy rates for patients who did and did not undergo preoperative CT were 27 per cent and 50 per cent for underweight patients, 10 per cent and 15 per cent for normal weight patients, 12 per cent and 17 per cent for overweight patients, 7 per cent and 30 per cent for obese patients, and 10 per cent and 100 per cent for morbidly obese patients. The difference in negative appendectomy rates for overweight patients, obese patients, and morbidly obese patients who underwent preoperative CT as compared with patients in the same BMI category who did not undergo preoperative CT was statistically significant (P <= 0.001). The negative appendectomy rates for overweight patients, obese patients, and morbidly obese patients who underwent preoperative CT were significantly lower than for patients in these same BMI categories who did not undergo preoperative CT. PMID- 21679559 TI - Closed midshaft femur fractures: are they only for trauma centers? AB - Trauma centers are limited resources, particularly in rural areas, and availability of emergency care in some parts of the United States may be inadequate. The declining number of orthopedic surgeons willing to care for injured patients has limited access to fracture repair in some communities. We studied the management of closed midshaft femur fractures in both trauma centers (TCs) and nontrauma centers (NTCs) to evaluate outcome for this common orthopedic injury and determine if these issues have affected fracture care in Kentucky. All patients 16-years-old and older who suffered femur fractures in Kentucky from 2004 and 2005 were identified. There were 334 TC patients and 341 NTC patients with closed, midshaft femur fractures. The mean age of TC patients (33 +/- 17 years) was significantly lower than that of NTC patients (59 +/- 25 years). TC patients were more likely men (71% vs 44%), had more associated injuries (2.4 +/- 2.1 vs 0.5 +/- 1.2), and had longer lengths of stay (8.3 +/- 9.8 vs 6.4 +/- 7.1 days) (TCs vs NTCs, all P < 0.005). Although both groups ultimately underwent internal fixation (97% vs 99%, TCs vs NTCs), TC patients were more likely (2.7% vs 0.3%) to receive external fixation than the NTC patients (P < 0.05). There was no significant difference in the percentage of patients that received only a closed reduction. There was no significant difference in hospital mortality (0.3% vs 0.9%, TCs vs NTCs, P = 0.62). Although differences in patient populations exist between TCs and NTCs, both TCs and NTCs manage substantial numbers of patients with closed, midshaft femur fractures with low mortality in this state database. PMID- 21679560 TI - Ultrasound detection of pneumothorax compared with chest X-ray and computed tomography scan. AB - Pneumothorax after trauma can be a life threatening injury and its care requires expeditious and accurate diagnosis and possible intervention. We performed a prospective, single blinded study with convenience sampling at a Level I trauma center comparing thoracic ultrasound with chest X-ray and CT scan in the detection of traumatic pneumothorax. Trauma patients that received a thoracic ultrasound, chest X-ray, and chest CT scan were included in the study. The chest X-rays were read by a radiologist who was blinded to the thoracic ultrasound results. Then both were compared with CT scan results. One hundred and twenty five patients had a thoracic ultrasound performed in the 24-month period. Forty six patients were excluded from the study due to lack of either a chest X-ray or chest CT scan. Of the remaining 79 patients there were 22 positive pneumothorax found by CT and of those 18 (82%) were found on ultrasound and 7 (32%) were found on chest X-ray. The sensitivity of thoracic ultrasound was found to be 81.8 per cent and the specificity was found to be 100 per cent. The sensitivity of chest X ray was found to be 31.8 per cent and again the specificity was found to be 100 per cent. The negative predictive value of thoracic ultrasound for pneumothorax was 0.934 and the negative predictive value for chest X-ray for pneumothorax was found to be 0.792. We advocate the use of chest ultrasound for detection of pneumothorax in trauma patients. PMID- 21679561 TI - Minimally invasive parathyroid surgery, the Norman 20% rule: is it valid? AB - The 20 per cent rule proposed by Norman established a guideline using radioactivity in the minimally invasive radioguided parathyroidectomy (MIRP) technique to localize and confirm removal of an abnormal parathyroid gland in patients with primary hyperparathyroidism. If radioactivity in the resected gland was at least 20 per cent of excision site/background radioactivity, the 20 per cent rule was satisfied. Patients meeting these criteria underwent unilateral MIRP without intraoperative parathyroid hormone assay or intraoperative frozen section. The study aim was to independently evaluate the 20 per cent rule in MIRP patients with primary hyperparathyroidism. Using the University of Louisville Parathyroid Database from January 1, 1999 to December 31, 2007, 216 MIRP patients with complete radioguided and postoperative management data were identified. The average percentage of ex vivo parathyroid gland radioactivity compared with excision site/background radioactivity was 107 per cent with a range from 14 to 388 per cent. For 99 per cent (196/198) radioactivity recorded from the excised gland was at least 20 per cent of radioactivity recorded from the excision site. Normocalcemia was documented in 98.5 per cent (195/198) at 12 month follow-up. Our data supports the 20 per cent rule in that in 99 per cent of MIRP patients the resected gland radioactivity was at least 20 per cent of excision site radioactivity allowing localization and confirmation of an overactive gland without intraoperative parathyroid hormone monitoring or tissue analysis. PMID- 21679562 TI - Is gastrectomy safe in the elderly? A single institution review. AB - The population of the United States is aging. Studies within the last several years have demonstrated that major abdominal operations in elderly patients can be done safely, but with increased rates of complications. We set out to determine the rates of morbidity and mortality in elderly patients undergoing gastric resection at a tertiary care university hospital. A retrospective analysis was performed of 157 consecutive gastric resections between January 1998 and July 2007. Group A (n = 99) consisted of patients < 75-years-old at surgery, whereas group B (n = 58) included patients who were >= 75 years of age at time of surgery. These two groups had their clinical and demographic data analyzed. Postoperative length of hospital stay, perioperative major morbidity, and in hospital mortality were analyzed using analysis of variance, chi(2), and multivariate analyses. The average age of patients in group A was 57 years, compared with 81 years in group B. We found no significant difference in the percentage of gastric resections for malignancy (group A, 49% vs group B, 62%) or emergency surgery (group A, 10% vs group B, 10%) between age groups. There was a significant increase in length of stay in the older patients (11.7 days vs 17.6 days; P = 0.032), as well as major complications (11.1% in group A vs 27.6% in group B; P = 0.008). The in-hospital mortality rates approached significance (group A, 4% vs group B, 12%; P = 0.057). Gastric resection in elderly patients carries with it longer hospital stays, higher risk of complications, and in hospital mortality rates despite similarity in patient disease. This information is imperative to convey to the elderly patients in the preoperative period before gastric resection. PMID- 21679563 TI - Traumatic pneumonectomy: a viable option for patients in extremis. AB - The combination of respiratory insufficiency, right heart failure, and depth of shock is thought to result in mortality approaching 100 per cent after pneumonectomy. We did a retrospective review of patients requiring pneumonectomy over 6 years. Data collected included demographics, emergency department and operating room course, critical care management, complications, and mortality. Seven patients were identified. Mean age was 26.5 years. Five sustained penetrating and two sustained blunt trauma. Mean Injury Severity Score was 26 and Revised Trauma Score was 4.4. Mean admission systolic blood pressure, lactate, and pH were 98 mm Hg, 10.1 mmol/L, and 6.98, respectively. Mean time to operation was 49 minutes. Mean estimated blood loss was 5.4 liters and mean intraoperative transfusion was 13.1 units of packed red blood cells. All seven developed right heart failure. Four required prone ventilation, one oscillating ventilation, four continuous renal replacement, and three extracorporeal membrane oxygenation. Four patients died (57%); two of refractory right heart failure within the first 24 hours and two of multiple organ failure on postoperative days 9 and 138. Mean length of stay in survivors was 71 days. All survivors were neurologically intact and none required mechanical ventilation at discharge. The need for pneumonectomy after trauma is rare. Patients undergoing pneumonectomy who present in extremis require significant intra and postoperative support, with a survival of 42 per cent. PMID- 21679564 TI - Cardiopulmonary resuscitation in the field: a battle worth fighting for? PMID- 21679565 TI - Retrorectal bilobed cyst in a young female, an unusual cause of dyschezia. PMID- 21679566 TI - Ultralow anterior resection for prolapsed giant solitary rectal polyp of Peutz Jeghers type. PMID- 21679567 TI - Late pregnancy should not delay abdominal exploration for internal hernia after gastric bypass surgery. PMID- 21679568 TI - Portal vein aneurysm. PMID- 21679569 TI - Biliary cystadenoma: case series and review of the literature. PMID- 21679570 TI - Laparoscopic management of chylous ascites caused by traumatic injury. PMID- 21679571 TI - Traumatic sigmoid degloving injuries in the pediatric population. PMID- 21679572 TI - Laparoscopic ventral hernia repair with acute perforated cholecystitis and no short- or long-term evidence of prosthesis infection. PMID- 21679573 TI - Postoperative nausea and vomiting in males. PMID- 21679574 TI - Direct cardiac invasion of hepatocellular carcinoma with ball-valve phenomenon. PMID- 21679575 TI - Long-term disease-free postoperative survival after combined vascular resection for hilar cholangiocarcinoma. PMID- 21679576 TI - Western trauma association blunt splenic injury algorithm is useful in spontaneous rupture of a normal spleen. PMID- 21679577 TI - Primary appendiceal lymphoma presenting as acute appendicitis. PMID- 21679578 TI - Surgical management of incidental adrenal schwannomas. PMID- 21679579 TI - Preoperative multidisciplinary management of airway obstruction by huge goiter with papillary thyroid cancer. PMID- 21679580 TI - Post cholecystectomy gossypiboma: a malignant masquerade. PMID- 21679581 TI - Aberrant hepatic arterial anatomy and the whipple procedure: lessons learned. AB - Appreciation and study of hepatic arterial anatomical variability is essential to the performance of a pancreaticoduodenectomy to avoid surgical complications such as bleeding, hepatic ischemia/failure, and anastomotic leak/stricture. Awareness of this variability permits the surgeon to adapt the surgical technique to deal with anomalies identified preoperatively or intraoperatively thereby preventing unnecessary surgical morbidity and mortality. The objective of our study is to provide a comprehensive review of the anatomic arterial anomalies and discuss surgical strategies that will equip the surgeon to deal with all anomalies that may be encountered a priori or en passant during the course of a Whipple procedure. PMID- 21679582 TI - Benefits of laparoscopy: does the disease condition that indicated colectomy matter? AB - The benefits of laparoscopic (LC) over open colectomy (OC) have been well characterized for a variety of conditions. Whether the relative benefits of LC differ for different conditions has not been previously investigated. The aim of this study was to identify whether there are differences in benefits of LC for colon cancer (CC), Crohn's disease (CD), and diverticular disease (DD). Data of patients with CC, CD, and DD undergoing elective colectomy from January 2000 to December 2007 were identified from departmental databases. Patients with CC, CD, and DD undergoing LC were matched 1:1 for diagnosis, gender, body mass index, surgical procedure, American Society of Anesthesiologists scale, and date of surgery to patients undergoing OC. TNM stage was also matched for patients with CC. Two hundred eighty-nine patients undergoing LC (CC, 93; CD, 140; DD, 56) were matched 1:1 to 289 patients undergoing OC. Median age was 49 years (range, 14 to 91 years) in LC and 52 years (range, 14 to 98 years) in OC (P = 0.35). All other matched criteria were also similar in both groups. The conversion rate to OC was 13 per cent (n = 36). Patients undergoing LC had significantly shorter lengths of stay (LOS) (3 days [range, 1 to 70 days] vs 6 days [range, 1 to 37 days], P < 0.001) and lower estimated blood loss (EBL) (100 mL [range, 10 to 1750 mL] vs 200 mL [range, 10 to 1700 mL], P < 0.001). Median operative time was similar in both groups (LC: 145 minutes [range, 35 to 431 minutes] vs OC: 135 minutes [range, 23 to 485 minutes], P = 0.54). The conversion rate was lower for DD (2%) when compared with CC (18.9%) and CD (13.4%). Improvement in EBL with LC was least pronounced in patients with CD and most pronounced in patients with DD (P interaction < 0.001). In the LC group, patients with DD presented less postoperative complications (P = 0.009). LC results in reduced LOS and EBL with similar complications rates when compared with OC. The benefits of LC are more pronounced in DD when compared with CD and CC. PMID- 21679583 TI - Seatbelt triad: severe abdominal wall disruption, hollow viscus injury, and major vascular injury. AB - The triad of seatbelt-related severe abdominal wall disruption, hollow viscus injury, and distal abdominal aortic injury after a motor vehicle collision is uncommon. We present a small case series involving those three clinical features with the goal of preventing a future missed diagnosis of the distal abdominal aortic injury in particular. PMID- 21679585 TI - Feasibility of pancreaticoduodenectomy in a nonuniversity tertiary care center: what are the key elements of success? AB - It is advocated that a favorable outcome for pancreaticoduodenectomy (PD) is related to a high volume at university centers. This article examines the specific elements that allow an equivalent outcome from PD in a nonuniversity tertiary care center (NUTCC). The study was performed to: (1) evaluate the outcome of PDs done at a NUTCC; (2) study the components of the process that are required to attain success in a NUTCC; and (3) provide a new look at the volume outcome relationships in complex surgeries in a novel nonuniversity setting. Medical records of patients who underwent PD by a single surgeon between September 2005 and August 2008 at a high-volume NUTCC were analyzed. The records were reviewed with respect to preoperative and postoperative data, 30-day mortality, morbidity, and histopathology data. A total of 122 patients underwent PD. The mean age was 68.2 years. Jaundice was the most common presenting symptom in 57 per cent (69 patients). Thirty-nine patients (32%) underwent a pylorus preserving PD. The mean operative time was 237 minutes. The mean estimated blood loss was 480 mL. The mean length hospital stay was 13 days. Thirty-day mortality was 3.2 per cent (four patients) and overall morbidity was 49 per cent. The key factors in developing a team dedicated to the care of the patient undergoing PD are discussed. A center of excellence can be developed in a NUTCC resulting in outcomes that meet and indeed may exceed nationally reported benchmarks. The key elements to success include a team approach to the patient undergoing PD. PMID- 21679584 TI - Re-evaluation of the necessity of prophylactic drainage after liver resection. AB - Abdominal drainage after liver resection is considered unnecessary: however, there still exist a number of cases where drain is effective to prevent serious infectious complications. We re-evaluated the necessity of drain placement after liver resection from the retrospective analysis of postoperative complications with special reference to the need for drain insertion of 140 patients undergoing hepatectomy without intraoperative abdominal drainage from 2007 through 2010. Three patients required drain reinsertion in the early postoperative period (before postoperative Day 7); all had undergone extended right hepatectomy for hepatocellular carcinoma with portal vein thrombus followed by postoperative liver failure. Risk factors for postoperative bile leakage included repeated hepatectomy, operative procedure with exposure of the major Glisson's sheath (i.e., central bisegmentectomy and anterior segmentectomy), and intraoperative bile leakage. However, because the onset of this complication was as late as postoperative Day 19.5, prophylactic drainage does not appear useful. Although not required routinely, prophylactic drainage might be useful in patients undergoing extended hepatectomy, a high-risk hepatectomy procedure exposing the major Glisson's sheath, those with positive intraoperative bile leakage, for hepatocellular carcinoma, and especially complicated with portal vein thrombus. PMID- 21679586 TI - Stapled hemorrhoidopexy as a day-surgery procedure. AB - In the last 10 years, stapled hemorrhoidectomy has gained worldwide consensus. We studied a day-surgery stapled hemorrhoidopexy protocol to allow shorter recovery time and cost reduction. From 2003 to 2008, we performed 292 outpatient stapled hemorrhoidopexies under spinal or local anesthesia including symptomatic Grade III and IV hemorrhoid disease. We used PPH 01 to PPH 03 staplers. We assessed early and late postoperative pain with a Visual Analog Scale, whereas clinical postoperative examinations were performed at seven days, 6 months, and 1, 3, and 5 years after surgery. The mean surgery time was approximately 18 minutes (range, 13 to 39 minutes). Of 292 patients, 39 were not dischargeable for urine retention, severe pain, or mild bleeding. Four other patients were rehospitalized within 8 days for bleeding. Twenty-one patients reported transient fecal urgency, whereas nobody reported anal incontinence. We can conclude that stapled hemorrhoidopexy is a safe and effective procedure if performed in a day-surgery unit. The complication rate is comparable to that of inpatient procedures. PMID- 21679587 TI - Transumbilical laparoscopic-assisted appendectomy: an extracorporeal single incision alternative to conventional laparoscopic techniques. AB - Recently the use of a single umbilical incision to perform an appendectomy has been described. The purpose of this study was to review our initial experience with transumbilical laparoscopic-assisted appendectomy (TULAA) in the pediatric population. A retrospective review of all pediatric patients treated for appendicitis over a 10-month period was performed. The surgical technique involved using a standard 3-mm or 5-mm trocar for visualization and insufflation. A dissecting/grasping instrument was used adjacent to the trocar through the same incision. Patient demographics, operative findings and time as well as postoperative course were reviewed. Of 21 patients undergoing laparoscopy appendectomy, 18 patients successfully underwent TULAA. Five patients had advanced appendicitis, four had a retrocecal appendix, and three had appendicoliths. The average total operative time was 51 +/- 15 minutes. Overall, the average length of stay was 1.2 +/- 0.8 days; however, all patients with nonperforated appendicitis were discharged the day after surgery. All patients were followed postoperatively, and none reported postoperative complications of abscess or wound infection. Cost analysis demonstrated a markedly reduced associated cost for TULAA compared with conventional laparoscopy. TULAA is a safe and effective single-incision approach for early appendicitis that incorporates both open and laparoscopic techniques to provide excellent exploration of the abdomen, a short hospital stay, minimal pain, and an excellent cosmetic result. The technique described is cost-effective, because it does not use any special laparoscopes, trocars, or staplers. When performed as described in this study, only a single trocar and a standard laparoscopic setup are required. Cases of advanced appendicitis may require additional trocars or "conversion" to conventional laparoscopic techniques. PMID- 21679588 TI - Randomized objective comparison of live tissue training versus simulators for emergency procedures. AB - There is a lack of objective analysis comparing live tissue and simulator training. This article aims to objectively determine the difference in outcomes. Twenty-four Air Force volunteers without prior experience performing emergency procedures were randomly assigned to receive training in tube thoracostomy (chest tube) and cricothyroidotomy training on either a pig model (Sus scrofa domestica) or on the TraumaMan simulator. One week posttraining, students were tested on human cadavers with objective and subjective results recorded. Average completion time for tube thoracostomy in the animal model group was 2 minutes 4 seconds and 1 minute 51 seconds in the simulator group with a mean difference of 12 seconds (P = 0.74). Average completion time for cricothyroidotomy in the animal model group was 2 minutes 35 seconds and 3 minutes 29 seconds in the simulator group with a mean difference of 53 seconds (P = 0.32). Overall confidence was 9 per cent higher in the animal trained group (P = 0.42). Success rate of cricothyroidotomy was 75 per cent in the animal model group and 58 per cent in the simulator-trained group (P = 0.67). Success rate of chest tube placement was 92 per cent in the animal group and 83 per cent in the simulator group (P = 1.00). There was no statistically significant difference in chest tube and cricothyroidotomy outcomes or confidence in the groups trained with live animal models or simulators at the 95 per cent confidence interval. Trends suggest a possible difference, but the number of cadavers required to reach greater than 95 per cent statistical confidence prohibited continuation of the study. PMID- 21679589 TI - The history of mastectomy. AB - The mastectomy that is performed today is a procedure born from hundreds of years of discoveries, inventions, and amendments to existing surgical techniques. The reasons for performing this extreme surgery have changed as well, ranging from unilateral breast removal to allow greater upper limb functionality to bilateral removal of the breasts or breast tissue in individuals predisposed to breast cancer or in individuals who have already been diagnosed. The additions of surgical tools and anesthetics to the field of medicine further transformed the surgical field in general and had a large impact on the mastectomy. William Halsted's radical mastectomy served as the basis of most future breast removal techniques, and it the method recognized today as the "radical mastectomy." Most radical surgeries are currently used for prophylaxis, whereas less invasive lumpectomies have eclipsed breast removal surgeries as of the latter half of the 20th century. PMID- 21679590 TI - Clinicopathological risk factors for recurrence within one year after initial hepatectomy for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) shows a high rate of recurrence after hepatectomy; predictive factors for early recurrence would help determine optimal therapeutic and management strategies. Among 163 patients with HCC undergoing hepatectomy with curative intent, 46 patients developed recurrence within 1 year. Clinicopathological data were retrospectively analyzed to identify predictive parameters for early recurrence. Survival rates in cases of recurrence within 1 year were worse than those of no recurrence within 1 year or recurrence after 1 year. Protein induced by vitamin K absence/antagonist II (PIVKA-II) greater than 150, positive fucosylated alpha-fetoprotein (L3-AFP), and deviancy from Milan criteria (MC) on preoperative imaging were associated with high risk of early recurrence and total number of these three risk factors predicted the survival. With multivariate analysis, (1) preoperatively, positive factors of two or more among three items of PIVKA-II, L3-AFP, and deviancy from MC; (2) and postoperatively, pathological cancer spread (microscopic vascular invasion and/or intrahepatic metastasis) both represented risks for early recurrence. A combination of three preoperative factors, PIVKA-II, L3-AFP, and MC status, in conjunction with the postoperative factor of cancer spread status represents a significant indicator for recurrence within 1 year. Improving the prognosis of patients with HCC would depend on how to adequately treat those at high risk of early recurrence. PMID- 21679591 TI - Incidence and outcomes of critical illness-related corticosteroid insufficiency in trauma patients. AB - The spectrum of critical illness-related corticosteroid insufficiency (CIRCI) in trauma is not fully defined. This study describes our trauma experience with hydrocortisone-treated patients experiencing CIRCI. We conducted a 5-year retrospective analysis from a Level II trauma center using biochemical and clinical criteria for adrenal insufficiency. Seventy patients met the inclusion criteria for CIRCI. There was a 34 per cent mortality rate despite therapy. Nonsurvivors were older with larger admission base deficits and experienced higher rates of sepsis, bacteremia, and pneumonia. Nonsurvivors had prolonged vent days (mean 53 +/- 64 days) when compared with survivors (mean 30 +/- 22 days; P = 0.029). Renal replacement therapy was a strong predictor of mortality. Spinal cord-injured patients had high Injury Severity Scores (mean 34 +/- 18), elevated baseline cortisol levels (mean 56 +/- 84 vs. 18 +/- 14; P = 0.004), and required prolonged duration of steroid therapy (30 +/- 52 vs. 15 +/- 15 days; P = 0.080) when compared with the nonspinal cord-injured group. Our data suggest that CIRCI in trauma is associated with significant mortality and morbidity even when patients are treated appropriately. PMID- 21679592 TI - Hepatic aneurysm: a review. AB - Originally described over 220 years ago, the clinical scenario of hepatic aneurysms remains incompletely understood. Moreover, its optimal treatment has yet to be defined. The present paper reviews the literature regarding this pathological state of the abdomen and discusses what is known regarding the presentation, diagnosis, and anatomy of hepatic arterial aneurysms. PMID- 21679593 TI - Laparoscopic approach to adrenalectomy: review of perioperative outcomes in a single center. AB - Laparoscopic expertise increases the volume of adrenalectomies at referral centers. We report our 10-year experience with laparoscopic adrenalectomy. All laparoscopic adrenalectomies at a single institution were prospectively recorded in a surgical outcomes database. Patient demographics, operative/perioperative outcomes, and adrenal pathology were reviewed retrospectively. From March 1999 through July 2009, 154 laparoscopic adrenalectomies were performed in 150 patients. Average patient age was 49.9 years (range 15-82); mean body mass index was 31.1 kg/m(2) (range 17-56). Pathologic diagnoses included hyperaldosteronism (n = 69), nonfunctional adenoma (n = 28), pheochromocytoma (n = 23), hypercortisolism (n = 14), malignancy (primary n = 3, metastasis n = 9), and cyst (n = 4). Seventy-three per cent (n = 110) occurred on the left, 23 per cent (n = 35) on the right, 2.6 per cent (n = 4) bilateral, and 0.6 per cent (n = 1) as extra-adrenal. The average tumor measured 3.6 cm (range 0.4-12). The average operative time was 156 minutes (range 62-409), the mean estimated blood loss was 60 mL (range 10-400), and mean American Society of Anesthesiologists score was 2.6 (range 1-4). Three operations (0.2%) were converted to open. Three patients (0.2%) experienced perioperative complications (respiratory failure, urinary tract infection, line sepsis, and readmission within 30 days). The average length of stay was 3.4 days (range 1-44) and mean follow-up was 96.9 days (5-2567). No wound-related complications or deaths occurred. Pathologic diagnosis was not associated with a particular side or development of a complication (P > 0.5). Patients with pheochromocytomas had the longest operative times, highest estimated blood loss, and highest American Society of Anesthesiologists scores (218.2 minutes, 128 mL, 3.0; P < 0.004). Laparoscopic adrenalectomy is safe and effective. Removal of pheochromocytomas is more challenging and may be more appropriate for referral to a specialized center for optimal outcomes. PMID- 21679594 TI - A strategy for reducing surgical backlogs: lessons from a veterans administration hospital. AB - A process was developed to use a nontraditional operative day (Saturday) to increase the number of inguinal herniorrhaphies (IHs) performed. The purpose of this analysis was to compare operating times and outcomes between patients undergoing IH on Saturday versus the weekday. A retrospective review was conducted that included patients who underwent IH from October 2008 to January 2010. This cohort was divided based on the day on which surgery occurred. The outcome measures were operative times, room turnover time, and complication rates. Operative time was shorter for Saturday IHs (50.7 vs. 67.8 min, P <= 0.001). The greatest difference between the two groups occurred in turnover times. We considered Saturday turnover time to be zero, which was possible because of multiple support teams and additional room availability. Turnover times during the week averaged 40.5 +/- 2 minutes. There was no difference in complication rates for the two groups (Saturday IHs 17.6% vs. 20.9% for weekday IHs, P = 0.75). Elective cases can be accomplished more rapidly during nontraditional operating times if there are multiple support teams and rooms available. PMID- 21679595 TI - Lymph nodes ratio is associated with the survival of colorectal cancer patients with peritoneal carcinomatosis. AB - The purpose of this study was to clarify the prognostic factors in patients with peritoneal carcinomatosis from colorectal origin, especially focusing on lymph node status. Between 1998 and 2007, 126 patients who underwent surgical treatment for primary colorectal cancer with peritoneal carcinomatosis were retrospectively assessed concerning prognostic factors. To estimate survival, we formulated a scoring system by numbers of independent poor prognostic factors. According to a multivariate analysis, extent of peritoneal carcinomatosis (hazard ratio, 1.93; 95% confidence interval, 1.19-3.13; P = 0.008) and lymph node ratio (hazard ratio, 1.87; 95% confidence interval, 1.05-3.33; P = 0.034) were found to be independent poor prognostic factors for survival. Furthermore, we demonstrated that score formulated by the number of these criteria was highly predictive of survival (P < 0.001). The 5-year survival rate for patients with score 0 (having no criteria), score 1 (having one criterion), and score 2 (having two criteria) were 25.1 per cent, 6.2 per cent, and 0 per cent, respectively. Lymph node ratio is an important prognostic factor in addition to the extent of peritoneal carcinomatosis after resection of primary colorectal carcinoma. Patients without these criteria have a favorable outcome, and therefore should be considered for further aggressive surgery and intraperitoneal chemotherapy. PMID- 21679596 TI - Hepatic artery aneurysms: evolution from open to endovascular repair techniques. AB - With the development of endovascular therapy, treatment for hepatic artery aneurysm (HAA) has evolved from open excision and repair to include endovascular approaches. We reviewed our recent experience with HAA to help define the treatment of HAA. From 2002 to 2010, five patients underwent treatment of HAA, all men with a median age of 63.2 years (range, 41-75). The median diameter of HAA was 5.8 cm (range, 2.4 cm-11 cm). Four lesions involved the extrahepatic portion of the hepatic artery, and one was an intrahepatic HAA that involved the right hepatic artery. Three were true aneurysms and two were pseudoaneurysms associated with trauma. Four of the five HAA patients were symptomatic, three with nonspecific abdominal pain, and one with free hemorrhage from a ruptured intrahepatic pseudoaneurysm. All five underwent computed tomography and selective arteriography. Two patients underwent open surgical aneurysmectomy and revascularization because of aneurysm location and concerns of the potential lack of collateral flow. Three patients underwent an endovascular coil embolization because obliteration of a saccular aneurysm could be achieved without compromising arterial flow of the native hepatic vessel. Re-embolization was necessary in the intrahepatic aneurysm because of recanalization of a feeding vessel. Endovascular embolization is an important minimally invasive approach in the treatment of HAA. Depending on HAA location and the adequacy of collateral arterial flow around the lesion, open aneurysmectomy and revascularization may be required. PMID- 21679597 TI - Operative intervention for complete pancreatic transection in children sustaining blunt abdominal trauma: revisiting an organ salvage technique. AB - Complete pancreatic transection (CPT) in children is managed commonly with distal pancreatectomy (DP). Alternatively, Roux-en-Y distal pancreaticojejunostomy (RYPJ) may be performed to preserve pancreatic tissue. The purpose of this study was to review our experience using either procedure in the management of children sustaining CPT after blunt abdominal trauma. We retrospectively reviewed the records of all children admitted to our institution during the last 15 years who were confirmed at operation to have CPT after blunt mechanisms. Summary statistics of demographic data were performed to describe children receiving either RYPJ or DP. CPT occurred in 28 children: 15 had DP, 10 had RYPJ, and three had cystogastrostomy. RYPJ children, compared with DP, were younger (7.5 vs. 12.3 years, P = 0.039) and sustained more grade IV pancreatic injuries (70% vs. 14%, P = 0.01). DP patients were 5.63 times more likely to tolerate full enteral feeds (P = 0.009). Nevertheless, when controlling for age, injury severity score, and pancreatic injury grade, procedure type did not statistically affect total and postoperative lengths of stay and postoperative complications. In the operative management algorithm of children sustaining CPT, DP may afford an earlier return to full enteral feeds. RYPJ seems otherwise equivalent to DP and preserves significant pancreatic glandular tissue and the spleen. PMID- 21679598 TI - Risk factors for delirium in trauma patients: the impact of ethanol use and lack of insurance. AB - The purpose of this study was to examine independent risk factors, and in particular the impact of alcohol on the development of delirium, in a cohort of trauma patients screened for ethanol ingestion on admission to hospital. The National Trauma Databank (v. 7.0) was used to identify all patients 18 years or older screened for ethanol on admission. Patients who developed delirium were compared with those who did not. Stepwise logistic regression analysis was used to identify independent risk factors for the development of delirium. A total of 504,839 patients with admission ethanol levels were identified. Of those, 2,909 (0.6%) developed delirium. Patients developing delirium were significantly older, more frequently male, and more likely to sustain thermal injuries and falls. Patients developing delirium had more comorbidities including chronic ethanol use (19.1% vs. 4.5%, P < 0.001) and cardiovascular disease (21.5% vs. 12.2%, P < 0.001). On admission, patients developing delirium were more likely to be intoxicated with ethanol (55.4% vs. 26.5%, P < 0.001) and were more likely to be uninsured (17.8% vs. 0.9%, P < 0.001). A stepwise logistic regression model identified lack of insurance, positive ethanol on admission, chronic ethanol use, Intensive Care Unit admission, age >= 55 years, burns, Medicare insurance, falls, and history of cardiovascular disease as independent risk factors for the development of delirium. The incidence of delirium in this trauma patient cohort was 0.6 per cent. The above risk factors were independently associated with the development of delirium. This data may be helpful in designing interventions to prevent delirium. PMID- 21679599 TI - Resection and drainage of hilar cholangiocarcinoma: an 11-year experience of a single center in mainland China. AB - The purpose of this study is to provide appropriate approaches for resection and drainage of hilar cholangiocarcinomas. Surgical approaches and postoperative survival rates of the patients were analyzed retrospectively. The 1-, 3-, and 5 year cumulative survival rates for patients who underwent resection were 76.6, 36.2, and 10.6 per cent, which was higher than those of 60, 14.3, and 0 per cent, respectively, in palliative operation. Moreover, the 1-, 3-, and 5-year cumulative survival rates for patients who underwent R0 were 88.9, 44.4, and 13.9 per cent, which was improved compared with those of 36.4, 9.1, and 0 per cent, respectively, in nonR0 resection. In addition, the overall survival time of patients who underwent R0 resection combined with hemihepatectomy and caudate lobe resection was longer than of those who underwent R0 without this extra operation, especially within 3 years after operation. After endoscopic metal biliary endoprothesis for patients who were intolerant of resection, liver function was improved at 2 weeks postoperation and the 1-, 3-, and 5-year cumulative survival rates for these patients were 72.7, 18.2, and 0 per cent, respectively. Treatment should be personalized. Resection is the most efficacious therapy, and negative histologic margins should be achieved in radical operation and "skeletonized" surgical operation is the basic requirement of radical treatment of hilar cholangiocarcinoma. Portal vein resection is beneficial to long-term survival and R0 resection combined with caudate lobe resection and hemihepatectomy is more efficacious for patients with Bismuth-Corlette type III hilar cholangiocarcinoma. The preferred approach of drainage in palliative operation is endoscopic metal biliary endoprothesis, which is more appropriate than tumor resection for the patients who suffer from serious comorbidities. PMID- 21679600 TI - Incidence, risk factors, and outcomes for atrial arrhythmias in trauma patients. AB - The purpose of this study is to determine the incidence, risk factors, and outcomes after the development of an atrial arrhythmia (AA) in trauma patients admitted to the intensive care unit (ICU). We performed a retrospective study of more than 7 years of trauma patients admitted to the ICU at an urban, academic Level I trauma center. Patients with AA, defined as atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia, were compared with patients without AA. Groups were compared by univariate and multivariate analysis. Three thousand, four hundred and ninety-nine trauma patients were admitted to the ICU during the study period and 210 (6%) developed an AA. AA patients were more likely to sustain blunt trauma, were older, more often female, more severely injured, and sustained more head injuries. The only independent risk factor for developing an AA was age > 55 years (odds ratio = 4.6, P < 0.01). Mortality was higher in the AA group (33% vs. 14%, P < 0.01) and AA was an independent risk factor for mortality (odds ratio = 1.7, P = 0.01). Twenty-eight per cent (n = 59) of AA patients received beta-blockers in the postinjury period, and these patients had lower mortality (22% vs. 37%, P = 0.04). AA occurs in 6 per cent of trauma patients admitted to the ICU. Developing an AA is an independent risk factor for mortality after trauma. Beta-blocker therapy was associated with decreased mortality in trauma patients with AA. PMID- 21679601 TI - Intraoperative ultrasound can facilitate the wire guided breast procedure for mammographic abnormalities. AB - Wire guided breast procedures are the most commonly used breast conserving operation for nonpalpable cancers. We did a retrospective review of all patients who underwent the wire guided breast procedure at a county hospital with an associated surgical residency program. Twenty-eight patients underwent the procedure with intraoperative ultrasound from June 2009 to March 2010. Breast cancer patients who underwent a wire-guided lumpectomy with intraoperative ultrasound had a lower rate of positive margins (9% vs. 26%, P = 0.28) and a smaller volume of tissue removed (126 cm3 vs. 146 cm3, P = 0.57). For wire guided excisional biopsy, the volume of tissue removed was smaller in the intraoperative ultrasound group (30 cm3 vs. 44 cm3, P = 0.17) and the targeted area was more likely to be removed in one specimen (1.1 vs. 1.5, P = 0.03). Intraoperative ultrasound can improve surgical outcomes of the wire guided breast procedure. PMID- 21679602 TI - The setback pulley dermal suture for skin defects. PMID- 21679603 TI - An unusual presentation of acute abdominal pain: perforation of retroperitoneal Ewing sarcoma. PMID- 21679604 TI - William Williams Keen, MD: 'Marshall' of American surgery and pioneer of neurosurgery. PMID- 21679605 TI - Intestinal obstruction from end-to-side or side-to-side anastomosis made by a circular stapling device. PMID- 21679606 TI - Epiploic appendagitis: a rare, often missed diagnosis. PMID- 21679607 TI - John D. Stewart, M.D. (1903-1983), a grandfather of transplants. PMID- 21679608 TI - A supraclavicular approach to thyroidectomy. PMID- 21679609 TI - Sir William Ernest Miles. PMID- 21679610 TI - Gastric heterotopia in the rectum: a rare cause of rectal bleeding. PMID- 21679611 TI - Thomas Dent Mutter: the humble narrative of a surgeon, teacher, and curious collector. PMID- 21679613 TI - Ethanol intoxication is a confounding factor in traumatic brain injury outcome. PMID- 21679614 TI - Ventral herniation of the left hepatic lobe after sternal reconstruction with a rectus abdominis muscle flap. PMID- 21679615 TI - A rare case of symptomatic celiac artery aneurysm. PMID- 21679616 TI - Clostridium septicum myonecrosis: a destructive and lethal condition. PMID- 21679617 TI - From cylindrical battery ingestion to right hemicolectomy. PMID- 21679618 TI - Cholangiocarcinoma in HIV-positive patients: are these conditions related? PMID- 21679619 TI - Recurrent invasive ductal carcinoma of the breast presenting as a metastasis to the duodenum with long-term survival. PMID- 21679620 TI - Standardized hospital compounded parenteral nutrition formulations do not guarantee safety. PMID- 21679621 TI - The incidence of traumatic brain injury in Tehran, Iran: a population based study. PMID- 21679622 TI - Chest wall reconstruction with porcine acellular dermal matrix (strattice) and a latissimus myocutaneous flap. PMID- 21679623 TI - Primary intrahepatic biliary cystadenocarcinoma. PMID- 21679624 TI - Pneumatosis cystoides intestinalis presenting with portal vein gas and pneumoperitoneum. PMID- 21679625 TI - Leiomyosarcoma of inferior cava vein: en bloc resection and primary repair of vessel. PMID- 21679626 TI - Synchronous appendicitis and umbilical hernial sac metastasis from cecal adenocarcinoma. PMID- 21679627 TI - Aberrant obturator artery: a hidden threat after pelvic fracture. PMID- 21679628 TI - Observed discordance between sonographic and operative findings: a retrospective analysis of test sensitivity. PMID- 21679629 TI - Ileocolic intussusception caused by endometriosis. PMID- 21679630 TI - Perils, pitfalls, and benefits of a surgeon as a health system employee: the contracting process. AB - One would be hard pressed today to find a general surgeon or subspecialty-trained general surgeon who has not been approached by a health system to discuss employment. The majority of physicians find these initial discussions with a hospital administrator daunting at best regardless of whether they are just finishing residency or fellowship training or have had many successful years of private practice under their belt. Just as real estate has the mantra of "location, location, location," I would suggest that physician employment by a health system should have the mantra of "relationship, relationship, relationship." The following tips provide guidance on how to better understand the potential perils, pitfalls, and benefits of specific content sections of a standard template employment agreement between a health system and a physician. Physicians should review, understand, and be ready to engage in dialogue with the hospital administrator before involving attorneys. My experience is that if the dialogue begins with the attorneys representing each party, the opportunity to fully develop a partnership relationship between the parties is either lost or at minimum severely delayed in its development. PMID- 21679631 TI - Thoracic surgery in octogenarians: CVTSA/Inova Fairfax hospital experience, 1990 to 2009. AB - With an increasing proportion of U.S. individuals 80 years of age or older, the authors examined their surgical experience with octogenarians undergoing major, curative-intent thoracic surgery. Between January 1, 1990, and September 1, 2009, 102 octogenarians underwent curative-intent resection for nonsmall cell carcinoma of the lung (NSCCL), esophageal carcinoma (EC), or related surgery for thoracic esophageal perforation (EP). Analysis and reporting followed the guidelines of the Nationwide Inpatient Sample database study (1994 to 2003). Eighty-six patients underwent curative-intent resection for NSCCL, 12 for EC, and four for surgery for EP. Hospital and 30-day mortalities were 0 per cent. Overall 1-, 2-, and 5-year survival rates were: 78, 58, and 32 per cent. Within the NSCCL cohort, minimally invasive exposures (video-assisted thoracic surgery [VATS] and video thoracoscopy [VT]) were associated with fewer and shorter duration of air leaks, leading to shorter length of stay. Since we began using minimally invasive exposure for NSCCL in 2007, the percentage of octogenarians discharged within 5 days of surgery has increased from 35.5 to 66.7 per cent (P = 0.01), and the percentage of patients discharged within 3 days of surgery has increased from 8.1 to 33.3 per cent (P = 0.006). Of 24 patients undergoing surgery for NSCCL since 2007, 18 (75%) underwent minimally invasive (VATS or VT) exposures, of which 15 patients (83.3%) were discharged home within 5 days and eight (44.4%) within 3 days of their procedure. Excellent, short- and longer-term results can be achieved in elderly patients if risks, exposures, and resections are appropriately matched to patient performance. PMID- 21679632 TI - Management of full-thickness duodenal laceration in the damage control era: evolution to primary repair without diversion or decompression. AB - The management of duodenal laceration (DL) is controversial. We sought to determine the influence of damage control (DC) on the use of decompression/diversion/exclusion (DDE) techniques and the risk of duodenal related complications (DRC). We conducted a retrospective review of all patients with full-thickness DL surviving more than 72 hours in the years 1989 to 2009. Forty-one patients with a median duodenal organ injury scale of 3 and a mean abdominal trauma index (ATI) of 45 +/- 24 underwent laparotomy. Twenty-five patients (61%) were treated with DC and 16 (39%) with fascial closure (FC). Although the ATI of the patients treated with DC was greater than the ATI of the patients treated with FC (56 +/- 23 vs 28 +/- 17, P < 0.001), DRCs were equivalent (two vs three, nonsignificant). Twenty-one patients were treated in the first decade and 20 in the second decade. Between the first and second decades, there were trends toward an increased use of DC (52 to 70%, nonsignificant) and a decreased use of DDE (52 to 35%, nonsignificant) with a significant reduction in DRC (5 vs 0, P = 0.04). Among the 18 patients (44%) who underwent DDE procedures there were 2 DRCs (11%) related to DDE. Among the 23 patients who did not have DDE, there were three DRCs (13%), including two obstructions, one partial and one complete. When DC is used after DL, DDE may be unnecessary. Diversion is recommended, however, when the duodenum is at risk for obstruction after primary repair. PMID- 21679633 TI - Defining incidence and outcome of contrast-induced nephropathy among trauma: is it overhyped? AB - Contrast-induced nephropathy (CIN) in trauma patients is uncommon and the incidence is unknown. We studied the incidence of CIN and its outcome. A retrospective chart review of trauma patients 16 years of age and older who were admitted to our Level I trauma center during 2005 was performed. Patients who received the intravenous contrast CT scan and had their serum creatinine (Cr) monitored at admission and at 48 to 72 hours were identified. CIN was defined as a 0.5-mg/dL rise of serum Cr or a 25 per cent increase from the baseline if the baseline Cr was abnormal. We excluded patients transferred from an outside facility, patients without repeated serum Cr measurements, patients who had cardiac arrest or persistent hypotension, and patients who had received N acetylcysteine (Mucomyst) before their CT scan. We compared CIN and non-CIN groups. During 2005, 543 fit our study criteria, of whom 19 (3.5%) had CIN. CIN (vs non-CIN) had a higher baseline serum Cr (1.48 + 0.23 vs 1.06 + 0.02, P < 0.001), a longer intensive care unit stay (17 vs 5 days, P < 0.001), and a longer hospital stay (19 vs 8 days, P < 0.001); the mortality rate was not different (10 vs 4%, P = 0.2). We found elevated baseline serum Cr (OR, 1.92; 95% CI, 1.13 to 3.27; P = 0.016) to be associated with increased risk for CIN. All but two serum Cr levels peaked within 48 hours; all returned to baseline. One patient with an underlying congenital kidney disease required temporary dialysis. CIN incidence in trauma is low and the clinical course is benign. PMID- 21679634 TI - Use of a handheld, semiconductor (cadmium zinc telluride)-based gamma camera in navigation surgery for primary hyperparathyroidism. AB - The recent development of gamma-ray probes makes it possible to perform radioguided surgery for primary hyperparathyroidism (PHPT). There have only been a few reports, however, regarding the use of a handheld gamma camera to detect parathyroid adenoma intraoperatively. The aim of this preliminary study was to assess the efficiency of a semiconductor gamma camera (eZ-SCOPE AN) in navigation surgery for PHPT. The eZ-SCOPE is designed to be used as a handheld, regional diagnostic imaging device. Eleven consecutive patients with documented primary hyperparathyroidism underwent surgery using this compact camera. Scintigraphy images of the neck by eZ-SCOPE were acquired: 1) before skin incision; 2) after adenoma location; 3) after adenoma excision; and 4) ex vivo imaging of the specimen. In scan-positive cases by preoperative Tc-MIBI, the eZ-SCOPE revealed parathyroid adenoma in all cases (100%), whereas ultrasound and CT showed a single adenoma in 63.6 and 72.7 per cent of cases, respectively. Navigation surgery for PHPT using the eZ-SCOPE permitted intraoperative identification and removal of parathyroid adenoma in all cases. Scintigraphy images of the neck by eZ-SCOPE also revealed a single adenoma even before skin incision. Our results suggest that Tc-MIBI scintigraphy with the eZ-SCOPE is useful for navigation surgery for PHPT. The eZ-SCOPE is useful for skin marking and could be easily applied for minimally invasive radioguided parathyroidectomy in scan-positive cases. PMID- 21679635 TI - Reversal of the Hartmann procedure through only a stomal orifice. AB - We performed reversal of the Hartmann procedure only through the stoma site and we did not use either any other incision nor laparoscopic assistance. A total of 8 patients (7 males), ages between 23 and 80 years, were treated by means of a defined technique. The indications of the Hartmann procedure were sigmoid volvulus (4), sigmoid cancer obstruction (2), rectal trauma (1), and Fournier gangrene (one). The duration from the first procedure was a mean of 5 months (range, 2 to 8 months). The length of the rectal stump was at least 5 cm over the pelvic peritoneum and the body mass indices of all patients were less than 30 kg/m2. The diameter of the stoma opening was a mean of 50 mm (range, 40 to 55 mm). Incision extensions from the stomal orifice (accepted as conversion) were needed for two cases as a result of injury on the intestine and inability to identify the distal bowel stump (25%). The mean operative blood loss and duration of operation were 50 mL (range, 30 to 100 mL) and 65 minutes (range, 45 to 80 minutes), respectively. Fecal discharge of all patients was weighed before hospital discharge and the length of postoperative hospital stay was a mean of 5.5 days (range, 4 to 9 days). Neither anastomosis leakage nor surgical site infections were observed in any of the patients and all had an uneventful postoperative course. The described technique can be the least invasive one than the previously described techniques for the reversal of the Hartmann procedure by only using the stoma site, particularly for nonobese patients with a long distal rectal stump. PMID- 21679636 TI - Clinical implication of bile spillage in patients undergoing laparoscopic cholecystectomy for gallbladder cancer. AB - We determined the influence of bile spillage on recurrence and survival during laparoscopic cholecystectomy (LC) for gallbladder (GB) cancer. Among the 136 patients with GB cancer treated at Ajou University Hospital between 1994 and 2007, 28 underwent LC alone. We compared patients without bile spillage (bile spillage [-] group, n = 16) with patients who had bile spillage (bile spillage [+] group, n = 12). There was no statistical difference in stage between the groups. In the bile spillage (-) group, all patients underwent curative resection and there were two patients with locoregional recurrences and three patients with systemic recurrences. In the bile spillage (+) group, five patients underwent R1 resection and one patient underwent R2 resection and all eight recurrent patients had systemic recurrences. The disease-free survival and overall survival were shorter in the bile spillage (+) group (disease-free survival, 71.4 vs 20.9 months; P = 0.028; overall survival, 72.6 vs 25.8 months; P = 0.014). Bile spillage is likely to be an association with an incomplete resection and systemic recurrences. When GB cancer is suspected during LC, conversion to open surgery for preventing bile spillage and achieving curative resection should be considered. PMID- 21679637 TI - Work-related injuries: injury characteristics, survival, and age effect. AB - Work-related injuries impose a significant burden on society. The goal of this study was to delineate the epidemiology and the effect of age on type and mortality after occupational injuries. Patients 16 years of age or older sustaining work-related injuries were identified from the National Trauma Databank 12.0. The study population was stratified into four age groups: 16 to 35, 36 to 55, 56 to 65, and older than 65 years old. The demographic characteristics, type of injury, mechanism of injury, setting of injury, use of alcohol or other illicit drugs, and mortality were analyzed and related to age strata. Overall 67,658 patients were identified. There were 27,125 (40.1%) patients in the age group 16 to 35 years, 30,090 (44.5%) in the group 36 to 55 years, 6,618 (9.8%) in the group 56 to 65 years, and 3,825 (5.7%) older than 65 years. The injury severity increased significantly with age. Elderly patients were significantly more likely to sustain intracranial hemorrhages, spinal, and other skeletal injuries. The overall mortality was 2.9 per cent (1938) with the latter increasing significantly in a stepwise fashion with progressing age, becoming sixfold higher in patients older than 65 years (OR, 6.18; 95% CI, 4.78 to 7.80; P < 0.001). Our examination illustrates the associations between occupational injury and significant mortality that warrant intervention for mortality reduction. There is a stepwise-adjusted increase in mortality with progressing age. PMID- 21679638 TI - The contribution of simulation training in enhancing key components of laparoscopic competence. AB - This study aims to investigate how basic training contributes to the performance of complex laparoscopic tasks performed in a virtual reality (VR) environment. An assessment methodology is proposed based on quantitative error analysis of key components of laparoscopic competence. Twenty-five inexperienced surgeons were trained on four basic tasks. The effect of training was assessed on three independent scenarios (two procedural: adhesiolysis and bowel suturing, and a laparoscopic cholecystectomy [LC]). Several error parameters were post hoc analyzed to yield a quantitative performance index for two fundamental skills: proficiency and safety. Time and instrument path length were also measured and compared. Correlation analysis was performed to study how these indices correlate one another. Significant learning curves were demonstrated during training. For adhesiolysis, all four indices improved significantly (P < 0.05). Time and path length presented plateaus for all basic tasks, whereas proficiency and safety only for two and one task(s), respectively. For bowel suturing, only time and safety errors showed a decrease (P < 0.05). Significant performance enhancement was observed for LC in which errors and path length reduced after training (P < 0.05). Our results revealed also an increased number of correlations after training, especially for proficiency. This study finds it possible to assess key competence skills based on the quantitative analysis of various parameters generated by a VR simulator. The improvement in basic training is transferred to more complex tasks. The proposed methodology is useful for structured evaluation of laparoscopic performance demonstrating fundamental elements of surgical competence. PMID- 21679639 TI - Full-time orthopedic traumatologists enhance rural trauma center pelvic fracture outcomes and financials. AB - We hypothesized that full-time orthopedic traumatologists would increase interfacility transfer patients with pelvic ring injuries at a trauma center seeking American College of Surgeons Level I verification. A trauma registry query identified 790 patients with pelvic ring injuries admitted to a trauma service over 10 years. The study groups included 173 patients 3 years before and 405 patients 3 years after recruitment of two full-time orthopedic traumatologists. Interfacility transfers of patients with pelvic ring injuries requiring operative procedures were increased over 230 per cent (P < 0.01) with full-time orthopedic traumatologists. Financial analysis showed enhanced hospital margin per patient and decreased direct costs (P < 0.01). Complications, mortality rates, and length of stay were decreased (P < 0.01). Full-time orthopedic traumatologists enhance pelvic ring injury patient interfacility transfers, operative procedures, outcomes, and financials at a Level I trauma center in a rural setting. PMID- 21679640 TI - Intraoperative ultrasound can decrease the re-excision lumpectomy rate in patients with palpable breast cancers. AB - Positive margins occur in 15 to 69 per cent of patients undergoing lumpectomy. The current study was performed to evaluate intraoperative ultrasound in patients undergoing lumpectomy for palpable breast cancer. A retrospective chart review was performed of patients with palpable cancer who underwent lumpectomy with intraoperative ultrasound from 2004 to 2009. Each patient was matched with two patients who underwent lumpectomy alone over the same time period. Matching criteria included tumor size, clinical stage, body mass index, age at diagnosis, and lymphovascular invasion or extensive intraductal component. Twenty-two consecutive patients who underwent lumpectomy with intraoperative ultrasound were matched with 44 patients who underwent lumpectomy without intraoperative ultrasound. In addition to matching criteria, the patients were similar with respect to ethnicity, insurance status, weight, predominant histology, estrogen receptor, progesterone receptor, and Her2 status. Patients who underwent lumpectomy with intraoperative ultrasound were significantly less likely to have an involved margin (41 vs 9%, P = 0.01) and less likely to require a re-excision (34 vs 9%, P = 0.04). The lumpectomy volumes in the intraoperative ultrasound group were smaller than the volumes in the lumpectomy alone group. Intraoperative ultrasound can decrease the rate of positive margins and re-excision lumpectomy in patients with palpable breast cancers. PMID- 21679641 TI - Early individual experience with distal venous arterialization as a lower limb salvage procedure. AB - This prospective randomized study reported early results of the treatment of 36 unreconstructable patients with critical lower limb ischemia. The patients were divided into two groups: 12 were treated with distal venous arterialization (DVA) and 24 were conservatively (CT) using antiplatelet drugs. There were seven men and five women with an average age 64.3 +/- 9.9 in DVA and 13 men and 11 women with a average age 67.1 +/- 10.8 in CT groups of patients. The aim of this study was to estimate the validity of DVA as the limb salvage procedure. During the period of monitoring, morbidity and mortality rates were 50 and 0 per cent at DVA versus a mortality rate in the CT group of 33.3 per cent (P < 0.05). The mean follow-up period for DVA was 4.8 +/- 3.9 months (range, 1 to 14 months) versus 4.9 +/- 2.4 months (range, 1 to 9 months) for the CT group (P > 0.05). Graft patency was 83.3 per cent with two early graft thromboses. There were significant differences between the two groups in limb salvage (91.7% DVA vs 12.5% CT, P < 0.001), pain relief (75% DVA vs 8.3% CT, P < 0.001), and wound healing rates (77.8% DVA vs 0% CT, P < 0.001). Lactate level in the blood of deep venous system after repeated measuring was significantly decreased after the multivariate analysis of variance method was applied (F = 7.691, P < 0.01). Hemodynamic parameters such as systolic digital pressure and digitobrachial systolic pressure index were increased after revascularization using Student's t test (P < 0.001). The DVA may improve the outcome of the treatment of the patients for whom the conventional bypass procedure mainly was not possible. PMID- 21679642 TI - Early-onset coronary artery disease after pediatric kidney transplantation: implicating the angiogenesis inhibitor, endostatin. AB - Pediatric kidney transplant recipients have a higher rate of coronary artery disease (CAD) as adults. The angiogenesis inhibitor, endostatin, has been implicated in the development of atherosclerosis. Endostatin levels will vary between adult patients who received a kidney transplant as a child. We conducted a study in young adult patients who had undergone pediatric kidney (n = 12) or liver transplantation (n = 8). Coronary arterial calcification was measured using electron beam CT. Values were compared with age-matched control subjects from an epidemiologic database. Serum endostatin levels were measured using enzyme-linked immunosorbent assay. Risk factors for atherosclerosis were assessed. Kidney transplant recipients had a higher rate of CAD compared with liver transplant recipients (33 vs 0%, P = 0.03). Mean (+/- standard error of mean) serum endostatin levels were higher in kidney transplant recipients compared with liver transplant recipients (26 +/- 7 vs 14 +/- 3 ng/mL, P = 0.04) and control subjects (26 +/- 7 vs 11 +/- 1 ng/mL, P = 0.01). Pediatric kidney transplantation is associated with a higher rate of adult-onset CAD compared with liver transplantation. Endostatin levels were greater in kidney transplant recipients compared with liver transplant recipients and healthy control subjects. Endostatin may play a role in the development of atherosclerosis after kidney transplantation and may serve as a biomarker for atherosclerotic disease. PMID- 21679643 TI - Colonic pseudo-obstruction with distinct transitional zone in adult constipation patients: pathological analysis and results of surgical treatment. AB - There are subsets of chronic constipation patients showing features of colonic pseudo-obstruction (CPO) with distinct transitional zone (TZ). We intended to analyze the clinicopathologic characteristics and surgical outcomes of these patients. Twenty-five consecutive patients who underwent surgery for constipation over the 9-year period were analyzed. TZ (+) group was defined as patients showing symptoms or signs of large bowel obstruction with dilated proximal and collapsed distal colon around the TZ at the time of operation, but without any evidence of mechanical causes of obstruction. Nineteen (76%) patients had features of CPO with TZ. All TZs were located in the left colon. Pathologically, segmental hypoganglionosis was identified at the TZ in all TZ (+) patients. On the other hand, pathologic diagnosis was intestinal neuronal dysplasia type B in the remaining six (24%) patients having a uniform colon diameter without demonstrable dilatations (TZ (-) group). Among TZ (+) patients, 17 (90%) underwent total colectomy with ileorectal anastomosis and two (10%) underwent enterostomy. Long-term follow-up (median 56 months) showed no recurrence of constipation in this group of patients. All six TZ (-) patients underwent total colectomy with ileorectal anastomosis and two (33%) of them had persistent symptoms of constipation on long-term follow-up (median 60 months). In a subset of adult constipation patients presenting with features of CPO with TZ, segmental hypoganglionosis was the final pathologic diagnosis. Constipation patients with features of CPO with distinct TZ in the left colon are expected to benefit from surgical intervention. PMID- 21679644 TI - Mesh repair for midline ventral hernia without lateral fixation of the mesh. AB - The Rives-Stoppa repair is the current standard of care for the open treatment of midline ventral hernia. Transfascial, lateral fixation of the mesh has always been considered an important part of this technique. I reviewed cases of patients with a primary or recurrent midline, ventral hernia who had an open repair using the Rives-Stoppa technique with the exception of mesh fixation. Heavy weight polypropylene mesh was sutured to the midline of the posterior rectus sheath with two to three interrupted stitches. Multiple metal clips were attached to the periphery of the mesh for later identification. Physical exams and CT scans were done on all patients postoperatively to assess the integrity of the repair. From November 2008 to January 2010 13 patients had an open repair using a modified Rives-Stoppa technique. All patients had an intact repair based on physical exam and a contiguous rectus abdominis muscle layer based on CT evaluation. Lateral fixation of heavy weight polypropylene mesh is not necessary when performing a retro-muscular repair using the Rives-Stoppa technique. PMID- 21679645 TI - Breath analysis by mass spectrometry: a new tool for breast cancer detection? AB - Breath analysis has received attention as a noninvasive diagnostic tool with increasing research into its potential usefulness. We are investigating the utility of the analysis of breath volatile organic compounds (VOCs) as an effective modality for breast cancer (BC) detection and monitoring by collecting breath samples with a simple portable device to determine whether BC patients have breath VOCs distinct from those in healthy volunteers. We prospectively enrolled 20 healthy volunteers and 20 newly diagnosed stage II-IV BC patients. The study subjects deeply exhaled into a commercially available Teflon/valved breath sampler equipped with a rapid passive diffusive sampler five times at 5 minute intervals trapping alveolar breath VOCs. The exhaled breath samples were analyzed by thermal desorption/gas chromatography/mass spectrometry monitoring 383 VOCs in the breath of both populations. Our results indicate that aggregate low-dimensional summaries and compound quantities result in specific patterns that can confirm BC. We found a definite clustering of the presence of BC from cancer-free points. Overall sensitivity was 72 per cent and specificity was 64 per cent resulting in a correct classification rate of approximately 77 per cent. Our data show promising evidence that BC patients can be differentiated from healthy volunteers through distinct breath VOCs. PMID- 21679646 TI - Efficacy of short-term antibiotic therapy for consecutive patients with mild appendicitis. AB - Although antibiotic therapy seemed to be a safe treatment option for acute appendicitis, indications of this treatment have not been fully evaluated. We hypothesized that clinical and radiologic mild appendicitis may be a candidate for short-term antibiotic therapy. The purpose of present study was to examine the efficacy and the recurrence rate of short-term antibiotic therapy for consecutive patients with mild appendicitis. A prospective observational study was conducted over 3 years. The mild appendicitis was defined as the intermediate Alvarado score (4-8) and dilated appendix from 6 mm to 10 mm in radiologic study. All patients received initial antibiotics administration with clinical observation during 48 hours. The failure to respond to therapy and the incidence of recurrence were assessed. There were 107 enrolled patients with the mean Alvarado score of 6 +/- 1 and the mean appendiceal diameter of 7.4 +/- 1 mm. Of these, 97 (91%) exhibited improved symptoms and were discharged. The remaining 10 patients underwent surgery because of clinical aggravation, and pathology revealed true appendicitis in six of them. Of the 97 patients in whom the initial treatment was successful, five patients (5%) exhibited recurrent symptoms during a median follow-up period of 18 months. Of these five patients, three were treated with surgery (all true appendicitis), and the remaining two were once again treated with antibiotics. Patients with suspected appendicitis, those in whom mild appendicitis was diagnosed after clinical and radiologic evaluations, were found to benefit from short-term antibiotic therapy. PMID- 21679647 TI - An alternative technique for immediate breast reconstruction. AB - Immediate reconstruction has demonstrated superior cosmesis compared with delayed reconstruction, however, unexpected final pathology may necessitate post mastectomy radiation. We describe an alternative technique for immediate breast reconstruction. Twelve patients underwent 14 skin-sparing mastectomies from July 2006 to December 2009. The skin-sparing mastectomies and sentinel node biopsies were performed through a periareolar incision. At the completion of the operation the incision was closed in a transverse fashion. No simultaneous reconstruction was performed. No drains were placed. After 3 days seroma developed, which maintained the integrity of the skin envelope and appearance of a breast. Nine patients (75%) had a contraindication to breast conservation. All patients were clinically node negative and 67 per cent were clinical stage 0. The majority (75%) experienced an adverse change from clinical stage to final pathologic stage. Four patients (33%) required postmastectomy radiation. The mean time from oncologic procedure to initial reconstruction procedure was 14 days. Two patients (17%) developed postoperative infections. This technique allows immediate reconstruction and avoids the fear of adverse final pathology indicating radiation to the reconstructed breast. In addition, it provides flexibility in scheduling for the surgeons and allows the patient to maintain the appearance of the breast. PMID- 21679648 TI - Transanal endoscopic microsurgery for T1 and T2 rectal cancers: a meta-analysis and meta-regression analysis of outcomes. AB - The objective of this study is to assess transanal endoscopic microsurgery (TEM) as a surgical strategy for stage I rectal cancer. The literature lacks level I and level II evidence of the oncologic competence of TEM. Three randomized controlled, one prospective, and seven retrospective comparative studies were evaluated. End-points included perioperative outcomes, margin involvement, disease-free and overall survival, and recurrence. The number of patients with major (odds ratio (OR) = 0.24, 95% confidence interval (CI) 0.07-0.91) and overall postoperative complications (OR = 0.16, 95% CI 0.06-0.38) were significantly lower in TEM. The disease-free survival was higher in standard resection (SR) group compared with TEM (OR = 0.46, 95% CI 0.24-0.88). The number of patients with positive margins were less in the SR group (OR = 6.49, 95% CI 1.49-24.91), which was associated with lower local recurrence (OR = 4.92, 95% CI 1.81-13.41) and overall recurrence rate (OR = 2.03, 95% CI 1.15-3.57). No survival advantage was observed in favor of either procedure. TEM had lower rate of positive margins and longer disease-free survival when compared with transanal excision (TAE). TEM seems to be superior to SR concerning morbidity whilst less effective in obtaining negative surgical margins, and it is associated with higher local and overall recurrence. No survival advantage was observed in favor of either procedure. Unfavorable tumor preoperative histology does not seem to influence the selection between TEM and SR. TEM is more effective than TAE in obtaining negative surgical margins and shows a greater disease-free survival. PMID- 21679649 TI - Has the use of anti-adhesion barriers affected the national rate of bowel obstruction? AB - In this study, we analyzed temporal trends in anti-adhesion barrier application and admission rates for small bowel obstruction. We used data from the Nationwide Inpatient Sample and identified patients with ICD-9 codes for "application or administration of anti-adhesion barrier substances" from October 2002 through December 2007. Next, we identified cases of bowel obstruction coded from January 1997 through December 2007. We then used Kendall correlation analyses and the Joinpoint regression program to evaluate changes in trends. From October 1, 2002 through December 31, 2007, a total of 28,014 patients had an anti-adhesion barrier substance applied. During the study period, application of anti-adhesion barriers increased from 0.7 applications per 100,000 to 2.6 applications per 100,000 population (Joinpoint and Kendall; P < 0.002). Since 1997 there has been a steady rise in hospitalizations for bowel obstruction, increasing from 18.3 cases per 100,000 to 19.8 cases per 100,000 population (Joinpoint and Kendall; P < 0.002). In conclusion, the application of anti-adhesion barriers has increased significantly since 2002, yet bowel obstructions continue to be a major health problem. PMID- 21679650 TI - Improving mortality predictions in trauma patients undergoing damage control strategies. AB - The increased use of damage control surgery in complex trauma patients requires accurate prognostic indicators. We compared the discriminatory capacity of commonly used trauma and intensive care unit (ICU) scores, including revised trauma score, injury severity scores, trauma score-injury severity scores, acute physiology and chronic health evaluations II, and clinical and laboratory parameters, on 83 consecutive trauma patients admitted to the ICU, undergoing damage control. Logistic regressions were built for mortality prediction within 30 days. Performances of the models were assessed in terms of discrimination and calibration. Areas under the receiver operating characteristic curve from the models were compared. Overall mortality was 38.5 per cent. A "clinical" model was constructed including ICU admission pH and hypothermia (<= 35 C degrees ) and the number of packed red blood cells during the first 24 hours. This model was adjusted for age and demonstrated better discrimination for mortality prediction (areas under the receiver operating characteristic curve = 0.8054) than injury severity score (P value = 0.049), abdominal trauma index (P value = 0.049), and acute physiology and chronic health evaluations II (P value = 0.001). There was no statistically significant difference in discrimination for mortality prediction between the "clinical" model and revised trauma score (P value = 0.4) and trauma score-injury severity score (P value = 0.4). We concluded that the combination of ICU admission pH and hypothermia and blood transfusions during 24 hours provided an excellent discriminatory capacity for mortality prediction in this complex patient population. PMID- 21679651 TI - Assessing the use of venous thromboembolism risk assessment profiles in the trauma population: is it necessary? AB - Deep venous thrombosis (DVT) and the subsequent development of venous thromboembolism (VTE) are a significant cause of mortality, morbidity, and cost of care in trauma patients. This study aims to: 1) validate 5 as a critical threshold for high risk; 2) validate risk factors associated with DVT/VTE development; 3) evaluate exogenous estrogen and smoking as risk factors; and 4) analyze daily risk assessment profile (RAP) score changes. We performed a retrospective chart review of trauma patients admitted from January 2001 through December 2005. Univariate odds ratios were performed to assess potential risk factors for VTE. Of the 110 charts reviewed, 31 patients had confirmed DVT/VTE. Three of 26 patients with an RAP score < 5 suffered a VTE; one resulted in death. Significant risk factors included femoral venous line insertion, operation longer than 2 hours, head abbreviated injury score > 2, and Glasgow Coma Scale score < 8. RAP fluctuations were due to a changing Glasgow Coma Scale score, and whether the patient received more than four transfusions, was in surgery for more than 2 hours, or required a femoral venous catheter or major venous repair. The RAP critical value (5) was not validated. We recommend all trauma patients be treated with prophylactic anticoagulants throughout the hospital stay unless clear contraindications exist. PMID- 21679652 TI - Reactive nodular fibrous pseudotumor presenting as a small bowel obstruction. PMID- 21679653 TI - Sequential Arcanobacterium haemolyticum and Escherichia coli spinal infections after local excision of a rectal polyp. PMID- 21679654 TI - Metastatic cancer of the pancreas from distant disease. PMID- 21679655 TI - Appendiceal sequestration of ingested mercury as a cause of appendicitis. PMID- 21679656 TI - Endoscopic extraction of Trichuris trichiura: an interesting finding. PMID- 21679657 TI - An alternative to the Billroth II technique of gastrojejunostomy after subtotal gastrectomy preserving the duodenal transit. PMID- 21679658 TI - Appearance of retroperitoneal lymphedema on CT scan after penetrating neck injury. PMID- 21679659 TI - George McClellan, M.D.: the man, the surgeon, the founder. PMID- 21679660 TI - Comparison between laparoscopic and open repair of perforated peptic ulcer disease in the elderly. PMID- 21679662 TI - Improved temporal resolution heart rate variability monitoring-pilot results of non-laboratory experiments targeting future assessment of human-computer interaction. AB - This paper outlines the INTERFACE software ergonomic evaluation methodology and presents new validation results. The INTERFACE methodology is based on a simultaneous assessment of heart rate variability, skin conductance, and other data. The results of using this methodology on-site, in a non-laboratory environment indicate that it is potentially capable of identifying quality attributes of elements of software with a temporal resolution of only a few seconds. This paper presents pilot results supporting this hypothesis, showing empirical evidence in spite of the definitely non-laboratory environment: they indicate that the method is robust enough for practical usability tests. Naturally, in the future these pilot results will have to be followed with further laboratory-based verification and refinement. This paper focuses only on some characteristics of this method, not on an actual analysis of human-computer interaction; however, its results can establish a future practical and objective event-related analysis of software use. PMID- 21679661 TI - Aortocolonic fistula: an interesting approach to a rare surgical complication. PMID- 21679663 TI - Event-related assessment of hypermedia-based e-learning materials with an HRV based method that considers individual differences in users. AB - This paper reports results of an assessment of e-learning materials with the INTERFACE software evaluation methodology. On the one hand, this method of analysis allows us to identify ergonomics problems; on the other, to decide to what extent those problems and their severity concern all users in general and to what extent they depend on the users? type and characteristics. This is the first publication to apply the new marking, export, and statistical features of INTERFACE used in a quantitative analysis of heart rate variability (HRV) curves instead of earlier time-based statistics and qualitative methods. It presents correlations between event-related characteristics of human-computer interaction and the currently required mental effort showed with HRV. The paper also discusses correlations between variables and cognitive-style test scores which indicate the role of individual differences in ergonomics. PMID- 21679664 TI - Physical capacity of occupationally active population and capability to perform physical work. AB - The aim of this study was to determine what proportion of occupationally active Poles have working capacity that enables them to tolerate hard and very hard physical work. For this purpose physical capacity of 1188 occupationally active subjects (524 women and 664 men), aged 18-64 years was examined. Their maximal oxygen consumption (VO2max) was determined indirectly on the basis of their heart rate during an incremental exercise test on a bicycle ergometer. It was found that hard occupational physical work was an excessive load for almost 40% of men and women. This paper discusses how this load should be decreased with planned, appropriately long rest breaks. The percentage of persons for whom their hard physical work becomes an excessive load increases with age to such a degree that a new assessment of individual capability for such work is recommended for persons over 40 years old. PMID- 21679665 TI - Measurement consistency among observational job analysis methods during an intervention study. AB - Several observational methods are available for ergonomists to evaluate the exposure to musculoskeletal disorder (MSD) risk factors associated with work. Those methods can be used to evaluate the impact of modifications done at a workstation on the exposure to risk factors. Three methods (QEC, OCRA and 4D Watbak) were used to assess the exposure to MSD risk factors before and after the implementation of changes at a saw and block opening workstation. The results from those 3 methods served to compare the methods and evaluate their consistency. Comparisons among the methods showed positive association between QEC and OCRA indices, and between the QEC back index and 4D Watbak. PMID- 21679666 TI - Evaluation of an incentive-based obesity management program in a workplace. AB - This study is to analyze the effectiveness of an incentive-based obesity management program (the Midas Project aimed to improve good health habits) at an electronics company in 2005. A total of 95 company participants with a high body mass index (BMI) were recruited for a health promotion program for 3 months that awarded gold medals as an incentive for body fat loss. BMI decreased from 28.8 to 27.8 kg/m2 (p = .000), body weight decreased from 87.2 to 83.5 kg (p = .000), and body fat weight decreased from 25.4 to 23.3 kg (p = .000). Systolic and diastolic blood pressure decreased from 130.5 to 125.1 mmHg (p = .002), from 86.4 to 81.7 mmHg (p = .009). The percentage of participants exercising more than 3 times per week increased from 27.3 to 52.3% (p = .000). The percentage who avoided overeating at parties and midnight eating increased from 65.9 to 72.7% (p = .767) and 70.5 to 84.1% (p = .172), respectively. This incentive-based obesity management program was effective in improving not only BMI but also health status. PMID- 21679667 TI - Chinese drivers' risky driving and risk taking in other life situations. AB - The first aim of this study was to investigate Chinese drivers' preferences to risk-taking behaviors encountered in daily life, including safety and health, finance, recreation, social areas, and ethics. The second aim was to evaluate the association between Chinese risky driving and other risk-taking behaviors. A questionnaire survey was conducted with the 324 Chinese drivers who responded. Through a principal component analysis an 8-factor structure was created to interpret different domains of risk-taking behaviors. They were risks in driving, ethics, recreation, gambling, abused health (voluntarily engaging in smoking and binge drinking), investment, ignored health (ignoring personal health, such as eating expired food), and monetary social areas. The result of multiple regression analysis showed that drivers who were likely to engage in driving risks were also likely to take risks in domains of ethics, abused health, gambling, investment, recreation, and ignored health. PMID- 21679668 TI - Prevalence of chronic venous disorders among employees working in prolonged sitting and standing postures. AB - Research was conducted to determine the prevalence and severity of chronic venous disorders (CVD) among people working in prolonged sitting or static standing postures. Clinical examination and duplex Doppler sonography were performed on 126 employees working in a sitting (96 individuals) or a standing posture (30 individuals). Evidence of CVD was found in 59.4% of individuals working in a sitting posture and in 83.4% of those working in a standing posture, and was significantly higher in employees working in a standing posture (p = .015). Incompetent perforating veins and vena saphena magna valves, and bilateral changes were the more frequent signs of CVD. The investigation showed that prolonged standing and sitting at work increases risk of developing CVD. Further, people working in a standing posture are at a significantly greater risk for CVD than those working in a prolonged sitting posture. They should thus be the subject of specific prophylaxis interventions. PMID- 21679670 TI - Asymmetric lifting capabilities for different container dimensions. AB - This study recruited 14 young male participants to examine human 4-h maximum acceptable weight of lifting (MAWL) and maximum weight of lifting (MWL) for different modes of asymmetric lifting and containers. The results showed that asymmetric lifting with trunk rotation decreased MAWL and MWL by 9.1 and 17.3%, respectively, and asymmetric lifting with body turn decreased MAWL and MWL by 6.1%, when compared with the symmetric lifting. The decreasing effects of container width and MAWL and MWL were greater than those of container length. Participants selected MAWL of ~33-37% of their MWL capability. PMID- 21679669 TI - Hand injury from powered wood splitters: machine safety, patterns of use and injury events. AB - INTRODUCTION: The purpose of this study was to describe factors of possible importance for the occurrence of hand injury from powered wood splitters. PATIENTS: Patients were identified by a computerized patient registry. Information was obtained from hospital records, a written questionnaire and a structured telephone interview. RESULTS: Very few splitters were constructed according to European standards. Twenty-one percent of patients injured with wedge splitters thought that having more than one person at the machine was one cause of the accident. Seventy-nine percent of patients injured with screw splitters stated that glove use was one cause of the accident. CONCLUSIONS: The level of safety in wood splitters that cause hand injury is often poor. Having more than one person at the machine during work may contribute to wedge splitter injury. Glove use commonly contributes to screw splitter injury. Prevention should be directed towards unsafe machines and dangerous patterns of use. PMID- 21679671 TI - Neck-upper extremity musculoskeletal disorders among workers in the telecommunications company at Mansoura City. AB - OBJECTIVES: This study was to determine the prevalence and work-related risk factors of neck-upper extremity musculoskeletal disorders (MSDs) among video display terminal (VDT) users. METHODS: A comparative cross-sectional study was conducted; there were 60 VDT users and 35 controls. The participants filled in a structured questionnaire, had electrophysiological tests and an X-ray of the neck. RESULTS: The prevalence of MSDs was higher (28.3%) among VDTs users compared to controls (14.3%) with no statistically significant difference. The prevalence of cervical disorders with or without radiculopathy (18.3%) was the most common disorder followed by carpal tunnel syndrome (6.6%). The mean (SD) age of MSD cases (51 +/- 7.2 years) was statistically significantly higher than of the controls (42.8 +/- 9). Physical exposure to prolonged static posture (OR: 6.9; 95% CI: 0.83-57.9), awkward posture (OR: 5.5; 95% CI: 0.6-46.4) and repetitive movements (OR: 5.5; 95% CI: 0.65-46.4) increased risk of MSDs with a statistically significant difference for static posture only (p < .05). VDT users experienced more job dissatisfaction, work-overload and limited social support from supervisors and colleagues. CONCLUSION: VDT use did not increase the risk of neck-upper extremity MSDs. The risk increased with older age and static posture. PMID- 21679673 TI - 2011 CUA Abstracts. PMID- 21679674 TI - EFSA publishes scientific report on the public health risk of Shiga-toxin producing Escherichia coli (STEC) in fresh vegetables. PMID- 21679672 TI - A survey of work-related skin diseases in different occupations in Poland. AB - Occupational skin disorders, in particular inflammations, dryness and erythema, in 80% of cases affect the skin of hands. The most frequent diagnosis, in over 90% of cases of occupational skin diseases, points to an irritant or allergic contact dermatitis. Our aim was to study the prevalence of self-reported skin symptoms on hands and forearms in different populations. The study was conducted on 581 healthcare workers, 61 hair stylists, 149 beauticians, 90 food services workers, 90 cleaners, 181 metal factory workers and 69 textile workers. Healthcare workers had greatest exposure. Eighty-six percent of dentists, 67% of midwives, 51% of nurses and 41% of physicians reported skin disorders. Problems with latex gloves were declared by 30% of healthcare workers. Thirty-four percent of food services workers, 24% of textile workers, 30% of metal factory workers, 21% of hair stylists and beauticians, and 64% of cleaners reported skin manifestations during the time of employment, which they thought could be work related. PMID- 21679675 TI - Information resources and latest news about the Shiga toxin-producing Escherichia coli (STEC) outbreak in Germany available from ECDC. PMID- 21679676 TI - Pandemic influenza A(H1N1)2009 in Morocco: experience of the Mohammed V Military Teaching Hospital, Rabat, 12 June to 24 December 2009. AB - On 12 June 2009, Morocco was the first country in North Africa to report a laboratory-confirmed case of influenza A(H1N1)2009 virus infection. This study describes the epidemiological and clinical characteristics of 240 laboratory confirmed cases among 594 outpatients with influenza-like illness at the Mohammed V Military Teaching Hospital, Rabat, from 12 June to 24 December 2009. Real-time reverse transcription-PCR was used to confirm the infection. The epidemic peaked in weeks 47 to 49 (16 November to 6 December 2009). The mean age of cases was 23 years (standard deviation: 14 years). Cough was the most common symptom in 200 cases (83%), followed by fever (>=38 degrees C) in 195 (81%). Diarrhoea or vomiting was reported in 12 (5%) patients. None of the cases developed any complications and no deaths occurred during the study period. PMID- 21679677 TI - Genetic characterisation of the emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010. AB - Neisseria meningitidis serogroups B and C have been responsible for the majority of invasive meningococcal disease in Europe. Recently, an increase of N. meningitidis disease due to serogroup Y has been noted in Sweden (in 2010, the proportion was 39%, with an incidence of 0.23 per 100,000 population), as well as in other northern European countries. We aimed to investigate the clonal pattern of the emerging serogroup Y in Sweden during 2000 to 2010. The serogroup Y isolates identified during this time (n=85) were characterised by multilocus sequence typing and sequencing of the fetA, fHbp, penA, porA and porB genes. The most frequent clone (comprising 28 isolates) with identical allele combinations of the investigated genes, was partly responsible for the observed increased number of N. meningitidis serogroup Y isolates. It was sulfadiazine resistant, with genosubtype P1.5-2,10-1,36-2, sequence type 23, clonal complex 23, porB allele 3-36, fetA allele F4-1, fHbp allele 25 and penA allele 22. The first case with disease due to this clone was identified in 2002: there was a further case in 2004, six during 2006 to 2007, eight during 2008 to 2009, with a peak of 12 cases in 2010. An unusual increase of invasive disease in young adults (aged 20 29 years) caused by this clone was shown, but no increase in mortality rate was observed. PMID- 21679678 TI - Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation. AB - A novel influenza A(H1N1)2009 variant with mildly reduced oseltamivir and zanamivir sensitivity has been detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia during the early months of 2011. The variant, which has also been detected in other regions of the Asia-Pacific, contains a S247N neuraminidase mutation. When combined with the H275Y mutation, as detected in an oseltamivir-treated patient, the dual S247N+H275Y mutant had extremely high oseltamivir resistance. PMID- 21679679 TI - Improved treatment of visceral leishmaniasis (kala-azar) by using combination of ketoconazole, miltefosine with an immunomodulator-Picroliv. AB - Visceral leishmaniasis (VL) caused by the parasite Leishmania donovani, is a potentially fatal disease. It is characterized by prolonged fever, enlarged spleen and liver, substantial weight loss and progressive anemia. Available drugs are toxic, costly and require prolonged treatment duration viz; 28 days of oral treatment with miltefosine, 30 days infusion with Amphotericin B and 21 days intramascular with paromomycin sulfate. Drug combination for VL clinically proved to shorten the duration of treatment. The efficacy of drugs is also compromised due to suppression of immune function during the course of infection. To combat this situation leishmanicidal efficacy of already marketed standard antifungal drug, ketoconazole under the approach of 'therapeutic switching' in combination with standard antileishmanial drug, miltefosine and a potent immunomodulator agent, picroliv were evaluated in L. donovani/hamsters model. Animals treated with combination of ketoconazole (50 mg/kg, 5 days, po)+miltefosine (5 mg/kg, 5 days, po) showed augmentation in efficacy against leishmania parasite (72%) in comparison to those treated with ketoconazole (54.67%) and miltefosine (54.77%) separately. Co-administration of picroliv (10 mg/kg, 12 days, po) has further enhanced antileishmanial efficacy from 72% to 82%. Significant generation of ROS, RNS and H(2)O(2) and increased phagocytosis was observed in animals treated with ketoconazole+miltefosine; however, addition of picroliv to this combination did not alter the level of metabolites and phagocytosis due to its antioxidative and nonleishmanicidal characteristics, respectively. Significant rise in cell mediated immunity witnessed in this group reveals the role played by the immunomodulator, picroliv and justifies the significance of enhanced cell mediated immunity in the therapy. These findings suggest a new strategy for leishmanial chemotherapy at reduced cost and toxicity. PMID- 21679680 TI - Importance of worldwide asymptomatic carriers of Leishmania infantum (L. chagasi) in human. AB - Leishmaniasis due to Leishmania infantum (syn. L. chagasi) infection is a zoonotic disease present mainly in Mediterranean basin, central Asia and Brazil. Besides a limited number of human cases of clinical visceral leishmaniasis, a great number of infections remains asymptomatic. In this review, the prevalence of asymptomatic carriers of L. infantum was evaluated worldwide using parasitological methods or indirect testing such as a skin test or serology. The consequences of the presence of asymptomatic carriers on parasite transmission by blood donation or the development of clinical visceral leishmaniasis in immunocompromised individuals and its possible role as reservoir are discussed. PMID- 21679681 TI - Laboratory wash-resistance and field evaluation of deltamethrin incorporated long lasting polyethylene netting (Netprotect((r))) against malaria transmission in Assam, north-east India. AB - North-east India is co-endemic for Plasmodium falciparum and P. vivax malaria, and disease transmission is perennial and persistent. This study reports the results of a field-based village scale trial of deltamethrin incorporated long lasting polyethylene netting (Netprotect((r))) conducted in P. falciparum predominant pocket of Assam, north-east India to assess operational feasibility, acceptability and sustainability against disease vectors and malaria transmission. The study monitored the residual efficacy of the long-lasting net in relation to serial washings in the laboratory and malaria prevalence in experimental villages for the first year of investigations from September 2008 to June 2009. The mosquito vector populations of Anopheles minimus were observed to be highly susceptible to deltamethrin (0.05%), and follow up investigations revealed that the vector mosquito had virtually disappeared in Netprotect((r)) intervention villages. Concurrently, there was consistent decline in malaria cases in Netprotect((r)) villages and transmission reduction was statistically significant compared to untreated net (net without insecticide) and no-net control villages for the corresponding study period. The contact cone-bioassay investigations against malaria transmitting mosquito species revealed that the bioavailability of the insecticide on the net fiber was persistent up to 20th serial wash resulting in >=80% mortality. Community compliance and acceptance were high, and users reported decreased nuisance due to biting mosquitoes. It was concluded that deltamethrin incorporated polyethylene long-lasting netting was safe, wash-resistant, and assessed to be an operationally feasible, community based intervention for sustainable management of disease vectors to prevent malaria transmission. PMID- 21679682 TI - Keeping leeches at bay: field evaluation of plant-derived extracts against terrestrial blood-sucking leeches (Haemadipsidae) in Lao PDR. AB - Terrestrial blood-sucking leeches (Haemadipsidae) are common in the damp forests of the subtropical and tropical Indo-Pacific region. Members of the genus Haemadipsa are abundant in Laos and adjacent countries of Southeast Asia, and discomfort to people and livestock. Plant-derived repellents against arthropods and leeches are common in Lao PDR, and have been used by Lao ethnic groups for generations. Numerous studies have been conducted on the efficacy of traditional plant-derived repellents against mosquitoes but only a few on repellents against terrestrial blood-sucking leeches. Field experiments were conducted to evaluate the leech repellent activities of aqueous extracts of three traditionally used plant species, Sapindus rarak DC., Catunaregam spathulifolia Tirv. and Vernonia elaeagnifolia DC. Stockings impregnated with aqueous extracts exhibited moderate to high leech repellent activity, C. spathulifolia (62.6%), V. elaeagnifolia (63.0%), and S. rarak (82.6%). The corresponding repellencies of deltamethrin and DEET were 73.1% and 88.4%, respectively. An aqueous extract of S. rarak applied on cloth at a concentration of 1.9 mg/cm(2) is an effective and practical prevention method significantly reducing the number of blood-feeding leeches recorded on stockings worn by humans. This plant species is common in Southeast Asia and can be obtained at limited or no cost. PMID- 21679683 TI - ATP synthase superassemblies in animals and plants: two or more are better. AB - ATP synthases are part of the sophisticated cellular metabolic network and therefore multiple interactions have to be considered. As discussed in this review, ATP synthases form various supramolecular structures. These include dimers and homooligomeric species. But also interactions with other proteins, particularly those involved in energy conversion exist. The supramolecular assembly of the ATP synthase affects metabolism, organellar structure, diseases, ageing and vice versa. The most common approaches to isolate supercomplexes from native membranes by use of native electrophoresis or density gradients are introduced. On the one hand, isolated ATP synthase dimers and oligomers are employed for structural studies and elucidation of specific protein-protein interactions. On the other hand, native electrophoresis and other techniques serve as tool to trace changes of the supramolecular organisation depending on metabolic alterations. Upon analysing the structure, dimer-specific subunits can be identified as well as interactions with other proteins, for example, the adenine nucleotide translocator. In the organellar context, ATP synthase dimers and oligomers are involved in the formation of mitochondrial cristae. As a consequence, changes in the amount of such supercomplexes affect mitochondrial structure and function. Alterations in the cellular power plant have a strong impact on energy metabolism and ultimately play a significant role in pathophysiology. In plant systems, dimers of the ATP synthase have been also identified in chloroplasts. Similar to mammals, a correlation between metabolic changes and the amount of the chloroplast ATP synthase dimers exists. Therefore, this review focusses on the interplay between metabolism and supramolecular organisation of ATP synthase in different organisms. PMID- 21679684 TI - Light-induced quinone reduction in photosystem II. AB - The photosystem II core complex is the water:plastoquinone oxidoreductase of oxygenic photosynthesis situated in the thylakoid membrane of cyanobacteria, algae and plants. It catalyzes the light-induced transfer of electrons from water to plastoquinone accompanied by the net transport of protons from the cytoplasm (stroma) to the lumen, the production of molecular oxygen and the release of plastoquinol into the membrane phase. In this review, we outline our present knowledge about the "acceptor side" of the photosystem II core complex covering the reaction center with focus on the primary (Q(A)) and secondary (Q(B)) quinones situated around the non-heme iron with bound (bi)carbonate and a comparison with the reaction center of purple bacteria. Related topics addressed are quinone diffusion channels for plastoquinone/plastoquinol exchange, the newly discovered third quinone Q(C), the relevance of lipids, the interactions of quinones with the still enigmatic cytochrome b559 and the role of Q(A) in photoinhibition and photoprotection mechanisms. This article is part of a Special Issue entitled: Photosystem II. PMID- 21679685 TI - Mutation directional selection sheds light on prion pathogenesis. AB - As mutations in the PRNP gene account for human hereditary prion diseases (PrDs), it is crucial to elucidating how these mutations affect the central pathogenic conformational transition of normal cellular prion protein (PrP(C)) to abnormal scrapie isoform (PrP(Sc)). Many studies proposed that these pathogenic mutations may make PrP more susceptible to conformational change through altering its structure stability. By evaluating the most recent observations regarding pathogenic mutations, it was found that the pathogenic mutations do not exert a uniform effect on the thermodynamic stability of the human PrP's structure. Through analyzing the reported PrDs-related mutations, we found that 25 out of 27 mutations possess strong directional selection, i.e., enhancing hydrophobicity or decreasing negative and increasing positive charge. Based on the triggering role reported by previous studies of facilitating factors in PrP(C) conversion, e.g., lipid and polyanion, we proposed that the mutation-induced changes may strengthen the interaction between PrP and facilitating factors, which will accelerate PrP conversion and cause PrDs. PMID- 21679686 TI - Intact rat superior mesenteric artery endothelium is an electrical syncytium and expresses strong inward rectifier K+ conductance. AB - BACKGROUND AND PURPOSE: Vascular endothelial and smooth muscle cell phenotypes may change dramatically after isolation and in cell cultures. This study was designed to investigate gap junctions coupling in an integrated intact preparation and to test if K(IR) channels modulate resting membrane conductance in "in situ" endothelial cells (EC), and acetylcholine (ACh)-evoked relaxation of the rat superior mesenteric artery. EXPERIMENTAL APPROACH: Whole cell blind patch recordings of ionic currents from in situ EC, dye-coupling experiments, and functional studies were performed in rat superior mesenteric artery. KEY RESULTS: EC were dye-coupled through gap junctions. 18beta-glycyrretinic acid (25 MUM) decreased outward and inward currents, the 80% decay of time and time constant of the capacitative transients, capacitance, and increased input resistance. Barium chloride (30 MUM) decreased resting and ACh-evoked inward currents, the sensitivity of ACh-evoked relaxation, and decreased both the sensitivity and the maximal relaxation to S-nitroso-N-acetyl penicillamine in arteries with, but not in arteries without endothelium. CONCLUSIONS: The present results suggest that the EC layer of this large artery is electrically coupled, and that K(IR) channels regulate resting inward conductance, hence suggesting that they are of importance for resting membrane potential in in situ EC. Moreover, EC K(IR) channels are involved in ACh-evoked relaxation. PMID- 21679687 TI - Innate immune system still works at diapause, a physiological state of dormancy in insects. AB - Diapause is most often observed in insects and is a physiologically dormant state different from other types of dormancy, such as hibernation. It allows insects to survive in harsh environments or extend longevity. In general, larval, pupal, or adult non-diapausing insects possess an innate immune system preventing the invasion of microorganisms into their bodies; however, it is unclear whether this system works under the dormant condition of diapause. We here report the occurrence of innate cellular reactions during diapause using pupae of a giant silkmoth, Samia cynthia pryeri. Scanning electron microscopic analysis demonstrated the presence of two major types of cells in the body fluid isolated from the thoracic region of a pupa. Phagocytosis and encapsulation, characteristics of innate cellular reactions, by these cells were observed when latex beads as foreign targets were microinjected into the internal portion of a pupa. Such behavior by these cells was still observed even when pupae were continuously chilled at 4 degrees C. Our results indicate that innate cellular reactions can work in diapausing insects in a dormant state. PMID- 21679688 TI - Effects of genistein on early-stage cutaneous wound healing. AB - Wound healing occurs in three sequential phases: hemostasis and inflammation, proliferation, and remodeling. Inflammation, the earliest phase, is considered a critical period for wound healing because immune cells remove damaged tissues, foreign debris, and remaining dead tissue. Wound healing would be delayed without inflammation, and this phase is affected by antioxidation capacity. Therefore, we hypothesized that genistein, which has an antioxidant effect, might modulate the wound healing process by altering the inflammatory response. After three days of acclimation, mice were divided into three groups: control, 0.025% genistein, and 0.1% genistein. After two weeks of an experimental diet, skin wounds were induced. Wounded skin areas were imaged, and the healing rate calculated. To measure lipid peroxidation, antioxidant enzyme expression and activity, and pro inflammatory cytokine expression, skin and liver tissues were harvested at 12, 24, 48, and 72 h. Genistein did not affect body weight. The rate of wound closure in mice fed genistein was significantly faster than in the control group during the early stage of wound healing, especially in first three days. Cu, Zn-SOD and Mn-SOD expression in wound skin tissue in the 0.1% genistein group was lower than in the control group. However, CAT expression did not differ among groups. We also found that genistein modulated NF-kappaB and TNF-alpha expression during the early stage of wound healing. The genistein group had significantly lower hepatic lipid peroxidation and higher SOD, CAT, and GPx activities than the control group. These results suggest that genistein supplementation reduces oxidative stress by increasing antioxidant capacity and modulating proinflammatory cytokine expression during the early stage of wound healing. PMID- 21679689 TI - C-reactive protein induces p53-mediated cell cycle arrest in H9c2 cardiac myocytes. AB - C-reactive protein (CRP) is one of the most important biomarker for cardiovascular diseases. Recent studies have shown that CRP affects cell survival, differentiation and apoptosis. However, the effect of CRP on the cell cycle has not been studied yet. We investigated the cell cycle alterations and cellular mechanisms induced by CRP in H9c2 cardiac myocytes. Flow cytometry analysis showed that CRP-treated H9c2 cells displayed cell cycle arrest in G0/G1 phase. CRP treatment resulted in a significant reduction in the levels of CDK4, CDK6 and cyclin D1 in a concentration-dependent manner. Interestingly, CRP caused an increase in the p53 accumulation and its phosphorylation on Ser15, leading to induce p21 upregulation. Treatment with a specific p53 inhibitor, PFT-alpha restored the levels of CDK4 and CDK6. A significant increase of ERK1/2 phosphorylation level was detected in CRP-treated cells. Furthermore, pretreatment of a specific ERK inhibitor resulted in decreased p53 phosphorylation and p21 induction. ERK inhibitor pretreatment induced significant restoration of protein levels of CDK4 and CDK6, leading to re-entry into the cell cycle. In addition, increased phosphorylation of p53 and ERK induced by CRP was considerably reversed by Fc gamma receptor IIIa (FcgammaRIIIa) knock-down using siRNA. FcgammaRIIIa siRNA transfection also restored the levels of cell cycle proteins. Our study has provided the first proposal on the novel insights into how CRP directly affects cell cycle in cells. PMID- 21679690 TI - Antifungal activity of lariciresinol derived from Sambucus williamsii and their membrane-active mechanisms in Candida albicans. AB - Lariciresinol is an enterolignan precursor isolated from the herb Sambucus williamsii, a folk medicinal plant used for its therapeutic properties. In this study, the antifungal properties and mode of action of lariciresinol were investigated. Lariciresinol displays potent antifungal properties against several human pathogenic fungal strains without hemolytic effects on human erythrocytes. To understand the antifungal mechanism of action of lariciresinol, the membrane interactions of lariciresinol were examined. Fluorescence analysis using the membrane probe 3,3'-diethylthio-dicarbocyanine iodide (DiSC(3)-5) and 1,6 diphenyl-1,3,5-hexatriene (DPH), as well as a flow cytometric analysis with propidium iodide (PI), a membrane-impermeable dye, indicated that lariciresinol was associated with lipid bilayers and induced membrane permeabilization. Therefore, the present study suggests that lariciresinol possesses fungicidal activities by disrupting the fungal plasma membrane and therapeutic potential as a novel antifungal agent for the treatment of fungal infectious diseases in humans. PMID- 21679691 TI - A rapid method to improve protein detection by indirect ELISA. AB - The enzyme-linked immunosorbant assay (ELISA) is a rapid, high-throughput, quantitative immunoassay for the selective detection of target antigens. The general principle behind an ELISA is antibody mediated capture and detection of an antigen with a measurable substrate. Numerous incarnations of the ELISA have resulted in its commercialization for sensitive diagnostic applications using a variety of detection platforms. Many of these applications require a pair of antibodies necessary for the capture and detection of a specific antigen (cELISA) in defined substrates. However, the availability of cELISA for target antigens is limited and thus restricts the use of this technique for quantitative measure of antigens during discovery. Alternatively, the indirect ELISA (iELISA) requires only a single antibody directed against a target antigen that has been immobilized to a surface. Unlike the cELISA, which uses an immobilized capture antibody that can bind a native antigen in solution followed by a detector antibody that binds captured antigen, the iELISA uses an antibody the binds directly to an immobilized antigen for detection. Although the iELISA may lack the sensitivity of a cELISA, its requirement of only a single antigen specific antibody makes it a simple technique for evaluating the relative difference in the level of target protein expression between samples. However, many antibodies that work effectively to detect protein antigens in other immunoassays such as Western blotting or immunohistochemistry fail to work in microplate based iELISA. Although these alternate immunoassay methods are useful for qualitative determination of target antigens, they provide limited quantitative information, limiting the assessment of sample specific differences in protein expression. We hypothesized that protein conformation following adsorption on the plastic surface of microplates impedes antibody epitope binding and this restriction could be overcome by a short chemical denaturation step. In this report we define a rapid method to assess the utility of an antibody for iELISA application and demonstrate a significant improvement in both qualitative and quantitative protein detection after chemical denaturation using defined assay conditions. PMID- 21679692 TI - The tight junction protein ZO-2 and Janus kinase 1 mediate intercellular communications in vascular smooth muscle cells. AB - Recent evidence points to a multifunctional role of ZO-2, the tight junction protein of the MAGUK (membrane-associated guanylate kinase-like) family. Though ZO-2 has been found in cell types lacking tight junction structures, such as vascular smooth muscle cells (VSMC), little is known about ZO-2 function in these cells. We provide evidence that ZO-2 mediates specific homotypic cell-to-cell contacts between VSMC. Using mass spectrometry we found that ZO-2 is associated with the non-receptor tyrosine kinase Jak1. By generating specific ZO-2 constructs we further found that the N-terminal fragment of ZO-2 molecule is responsible for this interaction. Adenovirus-based expression of Jak1 inactive mutant demonstrated that Jak1 mediates ZO-2 tyrosine phosphorylation. By means of RNA silencing, expression of Jak1 mutant form and fluorescently labeled ZO-2 fusion protein we further specified that active Jak1, but not Jak1 inactive mutant, mediates ZO-2 localization to the sites of intercellular contacts. We identified the urokinase receptor uPAR as a pre-requisite for these cellular events. Functional requirement of the revealed signaling complex for VSMC network formation was confirmed in experiments using Matrigel and in contraction assay. Our findings imply involvement of the ZO-2 tight junction independent signaling complex containing Jak1 and uPAR in VSMC intercellular communications. This mechanism may contribute to vascular remodeling in occlusive cardiovascular diseases and in arteriogenesis. PMID- 21679693 TI - Zeolites are effective ROS-scavengers in vitro. AB - We report on the use of zeolites to limit the effects of reactive oxygen species (ROS) on human albumin under in vitro conditions. Zeolites of different structure type, channel size, channel polarity, and charge-compensating cation were screened for the elimination of ROS, notably HO(.), resulting from the Fenton reaction. A test based on ischemia-modified albumin (IMA) was used as a marker to monitor the activity of HO(.) after co-exposure of human serum to these zeolites. Two commercial zeolites, faujasite (FAU 13*, channel opening 0.74*0.74 nm with Na(+) as charge-compensating cation) and ferrierite (FER, channel opening 0.54*0.42 nm with H(+) as charge-compensating cation), were found to reduce IMA formation by more than 65% due to removal of HO(.) relative to reference values. It was established that partial ion exchange of the zeolites' respective charge compensating cation vs. Fe(3+) implicated in the Fenton reaction plays a major role in HO(.) deactivation process. Moreover, our results show that no saturation of the respective zeolite active sites occurred. This is possible only when ROS are actively converted to water molecules within the zeolite void system, which generates H(+) ion transport. Because zeolites cannot be administered in blood, their use in medicine should be limited to extra corporeal circuits. Zeolites could be of use during cardiopulmonary bypass or hemodialysis procedures. PMID- 21679694 TI - Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-gamma-dependent activity. AB - Experimental and clinical data support the notion that peroxisome proliferator activated receptor gamma (PPARgamma) activation is associated with anti atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPARgamma agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPARgamma activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPARgamma antagonist), and losartan with no PPARgamma activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NFkappaB) activation and tumor necrosis factor alpha. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPARgamma activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of vascular PPARgamma in db/db mice and this effect of telmisartan was cancelled by the coadministration of GW9662. Our data provided the first evidence indicating that PPARgamma activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. PPARgamma activity of telmisartan was involved in the normalization of vascular PPARgamma downregulation in diabetic mice. Thus, telmisartan seems to exert vascular protective effects in hypertensive patients with diabetes. PMID- 21679695 TI - Delta-6 desaturase from borage converts linoleic acid to gamma-linolenic acid in HEK293 cells. AB - Gamma-linolenic acid (GLA, 18:3 n6) is an essential polyunsaturated fatty acid of the omega-6 family and is found to be effective in prevention and/or treatment of various health problems. In this study, we evaluated the possibility of increasing gamma-linolenic acid contents in mammalian cells using the delta-6 gene from Borago officinalis. The borage Delta6-desaturase gene (sDelta-6) was codon-optimized and introduced into HEK293 cells by lipofectin transfection. Co expression of GFP with sDelta-6 and RT-PCR analysis indicated that sDelta-6 could be expressed in mammalian cells. Subsequently, the heterologous expression of borage Delta6-desaturase was evaluated by fatty acid analysis. Total cellular lipid analysis of transformed cells fed with linoleic acid (LA 18:2 n6) as a substrate showed that the expression of sDelta-6 resulted in an 228-483% (p<0.05) increase of GLA when compared with that in the control cells. The highest conversion efficiency of LA into GLA in sDelta-6(+) cells was 6.9 times higher than that in the control group (11.59% vs. 1.69%; p<0.05). Our present work demonstrated that the sDelta-6 gene from borage could be functionally expressed in mammalian cells, and could convert LA into GLA. Furthermore, this study may pave the way to generate transgenic livestock that can synthesise GLA. PMID- 21679696 TI - H+/myo-inositol transporter genes, hmit-1.1 and hmit-1.2, have roles in the osmoprotective response in Caenorhabditis elegans. AB - Myo-inositol is one of the major organic osmolytes in the brain and the kidney. The accumulation of intracellular organic osmolytes allows cells to regulate intracellular osmolality without altering cytoplasmic ionic strength and to adapt to hyperosmotic conditions. Two types of myo-inositol transporters, sodium/myo inositol transporter and H(+)/myo-inositol transporter (HMIT), have been identified. Sodium/myo-inositol transporters are induced by osmotic stress and might be involved in the intracellular accumulation of myo-inositol in mammals. The role of HMIT, however, remains unknown. In the present study, we characterized three Caenorhabditis elegansHMIT genes, hmit-1.1, hmit-1.2, and hmit-1.3. hmit-1.1 was expressed in the intestine, and hmit-1.2 was expressed in the glia and the excretory canal, which is an osmotic regulatory organ that is functionally analogous to the kidney. hmit-1.3 was expressed in the intestine and the glia. The expression of hmit-1.1 and hmit-1.2 but not hmit-1.3, was markedly induced under hyperosmotic conditions. Animals with mutant hmit-1.1 and hmit-1.2 were hypersensitive to osmotic stress. The defects of hmit-1.1 and hmit-1.2 mutants were rescued by hmit-1.1 and hmit-1.2 transgenes, respectively, and by modified human HMIT. In human cell lines, HMIT expression was induced in hyperosmotic conditions. These findings indicate that the C. elegans HMIT family has a crucial role in the osmoprotective response. PMID- 21679697 TI - Suppression of FAT/CD36 mRNA by human growth hormone in pancreatic beta-cells. AB - Fatty acid-induced damage in pancreatic beta-cells is assumed to play an important role in the development of type 2 diabetes. Lactogens (prolactin, placental lactogen and growth hormone) improve beta-cell survival via STAT5 activation but the molecular targets are incompletely characterized. The aim of this study was to examine the effect of human growth hormone (hGH) on mRNAs of fatty acid transport and binding proteins expressed in pancreatic beta-cells, and to examine this in relation to beta-cell survival after exposure to fatty acids. hGH decreased mRNA levels of FAT/CD36, whereas mRNAs of GPR40, FASN, FABP2, FATP1 and FATP4 were unchanged. RNAi against FAT/CD36 decreased fatty acid-induced apoptosis. Over-expression of constitutively active STAT5 was able to mimic hGH's suppression of FAT/CD36 expression, whereas dominant negative STAT5 was unable to block the effect of hGH indicating that STAT5 did not bind directly to the FAT/CD36 promoter. The hGH-mediated suppression of FAT/CD36 mRNA was associated with a decrease in palmitate uptake and fatty acid-induced basal hyper-secretion of insulin resulting in improved glucose-stimulated insulin secretion. This study suggests that hGH can protect beta-cells against fatty acid-induced damages. PMID- 21679698 TI - Anticancer activity of thymoquinone in breast cancer cells: possible involvement of PPAR-gamma pathway. AB - Thymoquinone (TQ), an active ingredient of Nigella sativa, has been reported to exhibit anti-oxidant, anti-inflammatory and anti-tumor activities through mechanism(s) that is not fully understood. In this study, we report the anticancer effects of TQ on breast cancer cells, and its potential effect on the PPAR-gamma activation pathway. We found that TQ exerted strong anti-proliferative effect in breast cancer cells and, when combined with doxorubicin and 5 fluorouracil, increased cytotoxicity. TQ was found to increase sub-G1 accumulation and annexin-V positive staining, indicating apoptotic induction. In addition, TQ activated caspases 8, 9 and 7 in a dose-dependent manner. Migration and invasive properties of MDA-MB-231 cells were also reduced in the presence of TQ. Interestingly, we report for the first time that TQ was able to increase PPAR gamma activity and down-regulate the expression of the genes for Bcl-2, Bcl-xL and survivin in breast cancer cells. More importantly, the increase in PPAR-gamma activity was prevented in the presence of PPAR-gamma specific inhibitor and PPAR gamma dominant negative plasmid, suggesting that TQ may act as a ligand of PPAR gamma. Also, we observed using molecular docking analysis that TQ indeed formed interactions with 7 polar residues and 6 non-polar residues within the ligand binding pocket of PPAR-gamma that are reported to be critical for its activity. Taken together, our novel observations suggest that TQ may have potential implication in breast cancer prevention and treatment, and show for the first time that the anti-tumor effect of TQ may also be mediated through modulation of the PPAR-gamma activation pathway. PMID- 21679699 TI - Monitoring of 7alpha-hydroxy-4-cholesten-3-one during therapy of cerebrotendinous xanthomatosis: a case report. AB - Cerebrotendinous xanthomatosis (CTX) is a rare, inherited autosomal-recessive lipid-storage disorder caused by 27-hydroxylase deficiency. In this study, we report of a 30-year old man with this disorder who was treated using chenodeoxycholic acid, simvastatin, and low-density lipoprotein (LDL) apheresis. The LDL apheresis was performed weekly for nine months. The first subjective improvement was reported by the patient after his fourth LDL-apheresis. Spasticity, gait disturbances, and his entire psychomotoric test results had improved tremendously. His fine motoric skills have been regained. The efficacy of LDL-apheresis was monitored using quantitative determination of 7alpha-OH-4 cholesten-3-one in plasma based on a LC-MS/MS method. The clearance efficacy of 7alpha-hydroxy-4-cholesten-3-one from the patient's plasma per LDL-apheresis varied between 8% and 53% but returned to the initial high levels after seven days (mean value 241 ng/mL). A slight negative trend in the plasma concentration could be derived over the period of nine months. PMID- 21679700 TI - Bile acid signaling after an oral glucose tolerance test. AB - Monitoring bile acids as signal molecules in combination with a bile acid synthesis marker and the FXR regulator fibroblast growth factor 19 (FGF19), this study addresses significant postprandial changes. The efficacy of the different pathways to regulate bile acid synthesis through short heterodimer partner (SHP) dependent FXR modulation in liver, and SHP independent activation via FGF19 is demonstrated. Characteristic changes of the bile acid profile during an oral glucose tolerance test (oGTT) were investigated in 73 individuals. 15 bile acid species including conjugated and unconjugated forms were quantitatively determined with LC-MS/MS in serum samples collected at three time points during the oGTT. All conjugated bile acid species showed the same time course, a significant increase at 60 min after the glucose intake and an incline at 120 min. In contrast, a consistent decline of all unconjugated bile acids was monitored. 7alpha-Hydroxy-4-cholesten-3-one, an early bile acid synthesis marker, showed an inverse response with a significant decrease at 60 min which proves the efficient and rapid downregulation of CYP7A1 via FXR activation through bile acid signaling. Significantly higher levels of FGF19 were observed 120 min after glucose intake and 60 min after bile acid excursion. PMID- 21679701 TI - Loxin polymorphism is associated with increased resistin levels and with oxidative status. AB - OBJECTIVES: We hypothesized that LOX-1 polymorphism may impact on inflammation and cardiovascular risk by modulating systemic resistin expression. DESIGN AND METHODS: 276 men were randomly selected from a population-based cohort. Metabolic and inflammatory markers were evaluated at baseline and after 6-years follow-up, OLR1 (loxin) IVS4-14 A>G polymorphism was assessed. RESULTS: Mean plasma resistin and nitrotyrosine values were significantly higher, and TAS was significantly lowered in homozygous for the G allele. The G allele was significantly and directly associated with resistin and nitrotyrosine values. CONCLUSION: Enhanced oxidized-LDL uptake by LOX-1 G-allele carriers is associated with increased pro oxidant status and resistin levels, suggesting a major uptake of ox-LDL by macrophages, smooth muscle cells, and monocytes. PMID- 21679702 TI - Effects of cholesterol-loaded cyclodextrins on the quality of frozen-thawed equine epididymal sperm. AB - Equine epididymal sperm are known to be severely sensitive to cryopreservation, in terms of sperm quality and pregnancy rate. The objective of this study was to examine the effects of cholesterol loaded cyclodextrins (CLCs) on the quality of stallion epididymal sperm during cryopreservation. In experiment I, sperm were treated with different concentrations of CLCs: (1) 0mg (control), (2) 1.5mg, (3) 3mg, and (4) 6 mg per 120 * 10(6) sperm. The sperm viability and amount of cholesterol were determined at 15, 30 and 45 min after CLC treatment using viability markers (Ethidium homodimer-1 and Calcein AM) and gas chromatography, respectively. In experiment II, CLC treated sperm (1.5mg CLC per 120 * 10(6) sperm) were fixed and stained with filipin to examine the cholesterol distribution. In experiment III, sperm were treated with CLCs at concentrations of 1.5, 3.0, 6.0 mg per 120 * 10(6) sperm for 15 min, then equilibrated with freezing extender at 4 degrees C for 1h prior to cryopreservation. Epididymal sperm without CLC loading (0mg) were used as the control group. The sperm quality was examined at post-equilibration and 10 min, 2h and 4h after freezing and thawing. The cholesterol was successfully loaded into the plasma membrane of stallion epididymal sperm. The amount of cholesterol was increased in a manner of dose and time dependence, and the filipin-sterol complexes were increasingly labeled over the sperm head. CLCs at 1.5mg/120 * 10(6) sperm significantly improved sperm quality during sperm equilibration and cryopreservation compared to other doses of CLCs and non-CLC control. An increasing concentration and incubation time of CLCs was detrimental to sperm quality. It is concluded that cholesterol loading to the sperm plasma membrane via CLCs decreases chilling sensitivity and also improves epididymal sperm cryopreservability. PMID- 21679703 TI - Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists. AB - Orexin receptor antagonists are being investigated as therapeutic agents for insomnia and addictive disorders. In this study the interactions between the orexin receptors (orexin 1 receptor and orexin 2 receptor), orexin peptides, and small molecule orexin antagonists were explored. To study these phenomena, a variety of mutant orexin receptors was made and tested using receptor binding and functional assays. Domains of the two orexin receptors were exchanged to show the critical ligand binding domains for orexin peptides and representative selective orexin receptor antagonists. Results from domain exchanges between the orexin receptors suggest that transmembrane domain 3 is crucially important for receptor interactions with small molecule antagonists. These data also suggest that the orexin peptides occupy a larger footprint, interacting with transmembrane domain 1, the amino terminus and transmembrane domain 5 as well as transmembrane domain 3. Transmembrane domain 3 has been shown to be an important part of the small molecule binding pocket common to rhodopsin and beta2-adrenergic receptors. Additional orexin receptor 2 point mutations were made based on the common arrangement of receptor transmembrane domains shown in the G-protein coupled receptor crystal structure literature and the impact of orexin 2 receptor residue threonine 135 on the ligand selectivity of the 2 orexin receptors. These data support a model of the orexin receptor binding pocket in which transmembrane domains 3 and 5 are prominent contributors to ligand binding and functional activity. The data also illustrate key contact points for ligand interactions in the consensus small molecule pocket of these receptors. PMID- 21679704 TI - Endothelial cell responses towards low-fouling surfaces bearing RGD in a three dimensional environment. AB - This study reveals that it is possible to obtain a specific cell response towards low-fouling carboxymethyl dextran (CMD) surfaces bearing the RGD adhesive peptide in fibrin. To avoid cell sedimentation on surfaces observed in traditional cell culture systems, CMD surfaces bearing RGD were vertically embedded in fibrin containing human umbilical vein endothelial cells (HUVEC) and their effect over cells was investigated. Compared to the CMD surfaces and to CMD layers bearing the negative control RGE, RGD coatings promoted cell adhesion, induced focal contact formation indicated by co-localization of vinculin and actin fibers, and presented a significant effect over HUVEC net growth during the first 24h of the culture, as revealed by Ki67 staining and cell counting. The intracellular localization of caveolin-1 combined with the expression of beta 1 integrins was investigated and the orientation of HUVEC towards and on the RGD surfaces was studied. When compared to the negative controls, HUVEC responded to the RGD surface in fibrin resulting in acceleration of morphological changes. RGD surfaces supported fibrin degradation by HUVEC as revealed by fluorescent fibrin experiments as well as multi-cellular structure formation, vacuolation and lumen formation. PMID- 21679705 TI - Inhibitor of DNA binding 2 promotes sensory axonal growth after SCI. AB - This study investigated whether neuronal inhibitor of DNA binding 2 (Id2), a regulator of basic helix-loop-helix (bHLH) transcription factors, can activate the intrinsic neuritogenetic mode of dorsal root ganglion (DRG) neurons in adult mice following spinal cord injury (SCI). First, the Id2 developmental expression profile of DRG neurons, along with the correlated activity of Cdh1-anaphase promoting complex (Cdh1-APC), was characterized. Next, a D-box mutant Id2 (Id2DBM) adenoviral vector, resistant to Cdh1-APC degradation, was developed to enhance neuronal Id2 expression. After the vector was introduced into DRG neurons, the effect of Id2 on neurite outgrowth of cultured DRG neurons and sensory axonal regeneration following spinal cord dorsal hemisection was evaluated. The expression of Id2 in DRG neurons was high in the embryonic stage, downregulated after birth, and significantly reduced in the adult. Expression of Cdh1-APC was opposite to Id2, which may be responsible for Id2 degradation during DRG maturation. Overexpression of Id2DBM in DRG neurons enhanced neuritogenesis on both permissive and inhibitory substrates. Following spinal cord dorsal hemisection, overexpression of Id2DBM reduced axon dieback and increased the number and length of regenerative fibers into the lesion gap. Reprogramming the intrinsic growth status of quiescent adult DRG neurons by enhancing Id2 expression results in active neuritogenesis following SCI. Id2 may be a novel target for enhancing sensory axonal regeneration following injuries to the adult spinal cord. PMID- 21679706 TI - Trypanosoma evansi: concentration of 3-nitrotyrosine in the brain of infected rats. AB - Nitric oxide (NO) is involved in many physiological processes, such as blood pressure control, neurotransmission, inhibition of platelet and neutrophil adherence, and the ability to kill tumor cells and parasites. The indirect determination of NO can be made by detection of 3-nitrotyrosine (3-NT) residues. The aim of this study was to measure the concentration of 3-NT in the brain of rats experimentally infected with Trypanosoma evansi. Twenty-four were inoculated intraperitoneally with cryopreserved blood containing 1*10(6) trypomastigotes per animal. Twenty-four animals were used as negative controls and received 0.2 mL of saline by the same route. The experimental groups (group C and T) were established according to the time after infection and the degree of parasitemia as follows: four control subgroups (C3, C5, C10 and C20) with six non-inoculated animals each and four test subgroups (T3, T5, T10 and T20) with six animals infected with T. evansi in each group. The animals were anesthetized with isoflurane and subsequently euthanized at the days 3 (C3, T3), 5 (C5, T5), 10 (C10, T10) and 20 (C20, T20) post-infection (PI). The brain was removed and dissected into cerebellum, cerebral cortex, striatum and hippocampus. Concentration of 3-NT in the brain was determined by Slot blot technique. At the day 3 PI no changes were observed in the concentration of 3-NT among the groups. There was a significant reduction (p<0.05) of 3-NT concentration in the striatum and cerebellum at the days 5 and 10 PI, respectively. At the day 20 PI a significant increase (p<0.05) of 3-NT was observed in the cerebellum, cerebral cortex and hippocampus from the infected animals. Therefore, T. evansi infection caused changes in the concentrations of 3-NT in the central nervous system (CNS), which may be related to clinical signs and infection management. PMID- 21679707 TI - Carbohydrate and amino acid metabolism of Spironucleus vortens. AB - The metabolism of Spironucleus vortens, a parasitic, diplomonad flagellate related to Giardia intestinalis, was investigated using a combination of membrane inlet mass spectrometry, (1)H NMR, (13)C NMR, bioscreen continuous growth monitoring, and ion exchange chromatography. The products of glucose-fuelled and endogenous metabolism were identified by (1)H NMR and (13)C NMR as ethanol, acetate, alanine and lactate. Mass spectrometric monitoring of gas metabolism in buffered cell suspensions showed that glucose and ethanol could be used by S. vortens as energy-generating substrates, but bioscreen automated monitoring of growth in culture medium, as well as NMR analyses, suggested that neither of these compounds are the substrates of choice for this organism. Ion-exchange chromatographic analyses of free amino-acid and amino-acid hydrolysate of growth medium revealed that, despite the availability of large pools of free amino-acids in the medium, S. vortens hydrolysed large amounts of proteins during growth. The organism produced alanine and aspartate, and utilised lysine, arginine, leucine, cysteine and urea. However, mass spectrometric and bioscreen investigations showed that addition of the utilised amino acids to diluted culture medium did not induce any significant increase in metabolic or growth rates. Moreover, as no significant amounts of ornithine were produced, and addition of arginine under aerobic conditions did not generate NO production, there was no evidence of the presence of an energy-generating, arginine dihydrolase pathway in S. vortens under in vitro conditions. PMID- 21679708 TI - HVEM-deficient mice fed a high-fat diet are protected from adipose tissue inflammation and glucose intolerance. AB - HVEM is a member of the TNF receptor superfamily that plays a role in the development of various inflammatory diseases. In this study, we show that HVEM deficiency attenuates adipose tissue inflammatory responses and glucose intolerance in diet-induced obesity. Feeding a high-fat diet (HFD) to HVEM deficient mice elicited a reduction in the number of macrophages and T cells infiltrated into adipose tissue. Proinflammatory cytokine levels in the adipose tissue decreased in HFD-fed HVEM-deficient mice, while levels of the anti inflammatory cytokine IL-10 increased. Moreover, glucose intolerance and insulin sensitivity were markedly improved in the HFD-fed HVEM-deficient mice. These findings indicate that HVEM may be a useful target for combating obesity-induced inflammatory responses and insulin resistance. PMID- 21679709 TI - Distal esophageal spasm in high-resolution esophageal pressure topography: defining clinical phenotypes. AB - BACKGROUND: The manometric diagnosis of distal esophageal spasm (DES) uses "simultaneous contractions" as a defining criterion, ignoring the concept of short latency distal contractions as an important feature. Our aim was to apply standardized metrics of contraction velocity and latency to high-resolution esophageal pressure topography (EPT) studies to refine the diagnosis of DES. METHODS: Two thousand consecutive EPT studies were analyzed for contractile front velocity (CFV) and distal latency to identify patients potentially having DES. Normal limits for CFV and distal latency were established from 75 control subjects. Clinical data of patients with reduced distal latency and/or rapid CFV were reviewed. RESULTS: Of 1070 evaluable patients, 91 (8.5%) had a high CFV and/or low distal latency. Patients with only rapid contractions (n = 186 [17.4%] using conventional manometry criteria; n = 85 [7.9%] using EPT criteria) were heterogeneous in diagnosis and symptoms, with the majority ultimately categorized as weak peristalsis or normal. In contrast, 96% of patients with premature contraction had dysphagia, and all (n = 24; 2.2% overall) were ultimately managed as spastic achalasia or DES. CONCLUSIONS: The current DES diagnostic paradigm focused on "simultaneous contractions" identifies a large heterogeneous set of patients, most of whom do not have a clinical syndrome suggestive of esophageal spasm. Incorporating distal latency into the diagnostic algorithm of EPT studies improves upon this by isolating disorders of homogeneous pathophysiology: DES with short latency and spastic achalasia. We hypothesize that prioritizing measurement of distal latency will refine the management of these disorders, recognizing that outcomes trials are necessary. PMID- 21679710 TI - Wnt-beta-catenin signaling protects against hepatic ischemia and reperfusion injury in mice. AB - BACKGROUND & AIMS: Ischemia and reperfusion injury are common causes of oxidative tissue damage associated with many liver diseases and hepatic surgery. The Wnt beta-catenin signaling pathway is an important regulator of hepatic development, regeneration, and carcinogenesis. However, the role of Wnt signaling in the hepatocellular response to ischemia-reperfusion (I/R) injury has not been determined. METHODS: Hepatic injury following ischemia or I/R was investigated in hepatocyte-specific, beta-catenin-deficient mice, as well as Wnt1-overexpressing and wild-type (control) mice. RESULTS: Wnt-beta-catenin signaling was affected by the cellular redox balance in hepatocytes. Following ischemia or I/R, mice with beta-catenin-deficient hepatocytes were significantly more susceptible to liver injury. Conversely, mice that overexpressed Wnt1 in hepatocytes were resistant to hepatic I/R injury. Hypoxia inducible factor (HIF)-1alpha signaling was reduced in beta-catenin-deficient liver but increased in hepatocytes that overexpressed Wnt1 under hypoxia and following I/R, indicating an interaction between beta catenin and HIF-1alpha signaling in the liver. The mechanism by which Wnt signaling protects against liver injury involves the role of beta-catenin as a transcriptional coactivator of HIF-1alpha signaling, which promotes hepatocyte survival under hypoxic conditions. CONCLUSIONS: Cellular redox balance affects Wnt-beta-catenin signaling, which protects against hypoxia and I/R injury. These findings might be used to develop strategies for protection of hepatocytes, regeneration of liver, and inhibition of carcinogenesis. PMID- 21679711 TI - Antigen-presenting cell production of IL-10 inhibits T-helper 1 and 17 cell responses and suppresses colitis in mice. AB - BACKGROUND & AIMS: Mice that are deficient in interleukin (IL)-10 develop colitis, mediated by T-helper (Th)1 and Th17 cells, and IL-10-producing regulatory T (Treg) cells suppress colitis, implicating IL-10 in maintaining mucosal homeostasis. We assessed the relative importance of immunoregulatory IL 10 derived from T cells or from antigen presenting cells (APCs) in development of intestinal inflammation. METHODS: CD4(+) cells from germ-free (GF) or specific pathogen-free (SPF) IL-10(-/-) or wild-type mice were injected into IL-10(-/-), Rag2(-/-) mice or Rag2(-/-) mice that express IL-10. After 6-8 weeks, we evaluated inflammation, spontaneous secretion of cytokines from colonic tissue, and mRNA levels of the transcription factor T-bet and the immunoregulatory cytokine transforming growth factor (TGF)-beta. CD4(+) T cells were co-cultured with bacterial lysate-pulsed APCs and assayed for cytokine production, FoxP3 expression, and TGF-beta-mediated Smad signaling. RESULTS: CD4(+) cells from GF or SPF IL-10(-/-) or wild-type mice induced more severe colitis and higher levels of inflammatory cytokines in IL-10(-/-), Rag2(-/-) mice than in IL-10-replete, Rag2(-/-) mice. Co-cultures of IL-10(-/-) or wild-type CD4(+) T cells plus bacterial lysate-pulsed APCs from IL-10(-/-) mice contained more interferon (IFN) gamma, IL-12/23p40, and IL-17 than co-cultures of the same T cells plus APCs from wild-type mice. CD11b(+) APCs were required for these effects. Blocking IL-10 receptors increased production of IFN-gamma and IL-12/23p40 whereas exogenous IL 10 suppressed these cytokines. IL-10-producing APCs induced TGF-beta-mediated, retinoic acid-dependent, differentiation of FoxP3(+) Treg cells, whereas blocking the retinoic acid receptor, in vitro and in vivo, reduced proportions of FoxP3(+) Treg cells. CONCLUSIONS: IL-10 produced by APCs regulates homeostatic T-cell responses to commensal bacteria. PMID- 21679713 TI - First evidence for a direct inhibitory effect of kisspeptins on LH expression in the eel, Anguilla anguilla. AB - The kisspeptin system has emerged as one of the main puberty gatekeepers among vertebrates. The European eel (Anguilla anguilla) is a remarkable model due to its phylogenetical position at the basis of teleosts, and its unique life cycle with a blockade of puberty before reproductive migration. We cloned the full length coding sequence of a kisspeptin receptor (Kissr) in the eel. Comparison of Kissr sequences assigned the eel Kissr to a basal position in a clade including most of the known teleost Kissr, in agreement with the eel phylogenetical position. Eel Kissr tissue distribution was analyzed by quantitative real-time PCR. Eel Kissr was highly expressed in the brain, especially in the telencephalon and di-/mes-encephalon, while a very low or undetectable expression was observed in various peripheral organs. A high expression of Kissr was also found in the pituitary indicating a possible direct pituitary role of kisspeptin. Primary cultures of eel pituitary cells were performed to investigate the direct effects of kisspeptin on pituitary hormone expression. Human/lamprey kisspeptin exerted a time- and dose-dependent inhibitory effect on LHbeta expression. All other tested kisspeptins had a similar inhibitory effect on LHbeta expression. The inhibitory effect of kisspeptins was exerted specifically on LHbeta as no change was induced on the expression of other glycoprotein hormone subunits (GPalpha, FSHbeta and TSHbeta) nor of growth hormone. These data provide the first evidence for the existence, in the European eel, of a kisspeptin system, which may play a direct inhibitory role on pituitary LHbeta expression. PMID- 21679712 TI - Durability of radiofrequency ablation in Barrett's esophagus with dysplasia. AB - BACKGROUND & AIMS: Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett's esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE. METHODS: We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included, 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events. RESULTS: After 2 years, 101 of 106 patients had complete eradication of all dysplasia (95%) and 99 of 106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51 of 52 (98%) and intestinal metaplasia was eradicated in 51 of 52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50 of 54 (93%) and intestinal metaplasia was eradicated in 48 of 54 (89%). After 3 years, dysplasia was eradicated in 55 of 56 of subjects (98%) and intestinal metaplasia was eradicated in 51 of 56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4 of 119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1 per 181 patient-years (0.55%/patient-years); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1 per 73 patient-years (1.37%/patient-years). CONCLUSIONS: In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years. PMID- 21679714 TI - From the discovery of the crustacean androgenic gland to the insulin-like hormone in six decades. AB - Over the past six decades, a unique crustacean endocrine organ, the androgenic gland (AG), has occupied the minds of groups researching Crustacea the world over. Unlike male sexual differentiation and maintenance of sexual characteristics in other arthropods, in crustaceans these processes are regulated by the unique male AG. Crustaceans present a particular case in which the gametogenic organ (testis) is clearly separated from the organ regulating sex differentiation (the AG), enabling endocrine manipulations. The AG was first discovered in a decapod species and later investigated in detail not only in decapods but also in amphipods and isopods. The key role of the AG in regulating sex differentiation was subsequently validated in a number of representative species of a wide array of Malacostraca. It was in an isopod species that the AG hormone was first discovered. Later, orthologous genes were found in isopods and decapods, with all these genes sharing the key features of the insulin-like superfamily of peptides. This review unfolds the story of the AG and AG-specific insulin-like factors (IAGs) from a historical perspective, highlighting the main achievements in the field and giving a glimpse of future challenges to be addressed. PMID- 21679715 TI - Compatibility among entomopathogenic hyphocreales and two beneficial insects used to control Trialeurodes vaporariorum (Hemiptera: Aleurodidae) in Mediterranean greenhouses. AB - The effect of the combined use of Encarsia formosa or Macrolophus caliginosus and one of three marketed mycoinsecticides, Mycotal(r) (Leucanicillium muscarium based), Naturalis-LTM (Beauveria bassiana-based) and PreFeRal(r) (Isaria fumosorosea-based), on the control of the whitefly, Trialeurodes vaporariorum, was studied under laboratory and greenhouse conditions. The results of both types of tests, the bioassays and the greenhouse trials, for all combinations of E. Formosa with each of the three mycoinsecticides showed that the total mortality of larval populations of T. vaporariorum was not affected. The mortality of T. vaporariorum larvae treated in the second instar revealed the capacity for both B. bassiana- and L. muscarium-based formulations and E. formosa to kill the host either separately or in association. Because of its higher pathogenic activity (under our test conditions), L. muscarium provoked a large proportion of mycoses in larvae exposed to parasitization. In contrast, the efficacy of parasitization was higher in larvae treated with B. bassiana and exposed to E. formosa because of a lower pathogenic activity of the fungus. Bioassays carried out with third instar larvae of T. vaporariorum showed a low susceptibility to both tested fungi. Consequently, mortalities recorded in larvae subjected to the combined treatments by consecutive exposures or at 2-4 days post-parasitization were mainly caused by the development of the parasitoid. Greenhouse trials showed that fungus-induced mortality of T. vaporariorum in plants treated with L. muscarium, I. fumosorosea, and B. Bassiana was significant compare to control. L. muscarium, B. bassiana and I. fumosorosea killed young whitefly larvae and limited parasitization to 10% or less. Second-instar larvae of M. caliginosus were not susceptible to L. muscarium and B. bassiana formulations with any mode of contamination: direct spraying of larvae, spraying on the foliar substrate or by contaminated T. vaporariorum prey. In greenhouse trials, M. caliginosus populations treated with fungi were not significantly affected compared to controls. PMID- 21679716 TI - Predicting knot and catenane type of products of site-specific recombination on twist knot substrates. AB - Site-specific recombination on supercoiled circular DNA molecules can yield a variety of knots and catenanes. Twist knots are some of the most common conformations of these products, and they can act as substrates for further rounds of site-specific recombination. They are also one of the simplest families of knots and catenanes. Yet, our systematic understanding of their implication in DNA and important cellular processes such as site-specific recombination is very limited. Here, we present a topological model of site-specific recombination characterizing all possible products of this reaction on twist knot substrates, extending the previous work of Buck and Flapan. We illustrate how to use our model to examine previously uncharacterized experimental data. We also show how our model can help determine the sequence of products in multiple rounds of processive recombination and distinguish between products of processive and distributive recombinations. This model studies generic site-specific recombination on arbitrary twist knot substrates, a subject for which there is limited global understanding. We also provide a systematic method of applying our model to a variety of different recombination systems. PMID- 21679718 TI - On following behaviour as a mechanism for collective movement. AB - During collective movement, animals display a wide variety of mechanisms to maintain cohesion. In some species, individuals rely mainly on following their direct predecessor, thereby forming spectacular processions of individuals in single file. Despite being the simplest case of following behaviour, it is largely absent from the theoretical literature on collective migrations. The objective of this study is to quantify the efficiency of following the predecessor, in terms of ensuring cohesion. The situation we consider is a sequence of individuals facing a bifurcation. The choice between left and right is influenced by the choice of the predecessor. First, we model this situation with a two-state Markov chain with a symmetric transition matrix. Cohesion is quantified as the expected number of individuals on either side, and the expected number of consecutive followers. Although cohesion increases with the probability of following, it remains surprisingly low unless the probability is almost equal to one. Furthermore, cohesion decreases with group size regardless of the probability of following. Then, we generalise our model to situations in which individuals have a preference for one of the two choices (asymmetric transition matrix). For some parameter sets, the tendency to follow each other leads a large fraction of the individuals to the non preferred side. Moreover, this fraction increases with the total population size. Finally, we include the possibility to follow N individuals. This provides the link between our model and other collective migration models. If enough individuals are perceived, the results shift from symmetrical (low cohesion) to asymmetrical (high cohesion) distribution of the individuals. All in all, our results suggest that following the direct predecessor must be complemented with other cohesive behaviours (involving the perception of more individuals or a navigation system) to guarantee its efficiency. We discuss our findings in the context of the different following behaviours covered in the literature. PMID- 21679717 TI - ATP-dependent roles of the DEAD-box protein Mss116p in group II intron splicing in vitro and in vivo. AB - The yeast DEAD-box protein Mss116p functions as a general RNA chaperone in splicing mitochondrial group I and group II introns. For most of its functions, Mss116p is thought to use ATP-dependent RNA unwinding to facilitate RNA structural transitions, but it has been suggested to assist in the folding of one group II intron (aI5gamma) primarily by stabilizing a folding intermediate. Here we compare three aI5gamma constructs: one with long exons, one with short exons, and a ribozyme construct lacking exons. The long exons result in slower splicing, suggesting that they misfold and/or stabilize nonnative intronic structures. Nevertheless, Mss116p acceleration of all three constructs depends on ATP and is inhibited by mutations that compromise RNA unwinding, suggesting similar mechanisms. Results of splicing assays and a new two-stage assay that separates ribozyme folding and catalysis indicate that maximal folding of all three constructs by Mss116p requires ATP-dependent RNA unwinding. ATP-independent activation is appreciable for only a subpopulation of the minimal ribozyme construct and not for constructs containing exons. As expected for a general RNA chaperone, Mss116p can also disrupt the native ribozyme, which can refold after Mss116p removal. Finally, using yeast strains with mitochondrial DNA containing only the single intron aI5gamma,? we show that Mss116p mutants promote splicing in vivo to degrees that correlate with their residual ATP-dependent RNA-unwinding activities. Together, our results indicate that, although DEAD-box proteins play multiple roles in RNA folding, the physiological function of Mss116p in aI5gamma splicing includes a requirement for ATP-dependent local unfolding, allowing the conversion of nonfunctional RNA structure into functional RNA structure. PMID- 21679719 TI - The effect of syntax on reading in neglect dyslexia. AB - Individuals with text-based neglect dyslexia omit words on the neglected side of the sentence or text, usually on the left side. This study tested whether the syntactic structure of the target sentence affects reading in this type of neglect dyslexia. Because Hebrew is read from right to left, it enables testing whether the beginning of the sentence and its syntactic properties determine if the final, leftmost, constituent is omitted or not. The participants were 7 Hebrew-speaking individuals with acquired left text-based neglect dyslexia, without syntactic impairments. Each participant read 310 sentences, in which we compared 5 types of minimal pairs of sentences that differed in the obligatoriness of the final (left) constituent. Complements were compared with adjuncts, obligatory pronouns were compared with optional resumptive pronouns, and the object of a past tense verb was compared with the object of a present tense verb, which can also be taken to be an adjective, which does not require an object. Questions that require a verb were compared with questions that can appear without a verb, and clauses that serve as sentential complements of a verb were compared with coordinated clauses, which are not required by the verb. In addition, we compared the reading of noun sequences to the reading of meaningful sentences, and assessed the neglect point in reading 2 texts. The results clearly indicated that the syntactic knowledge of the readers with neglect dyslexia modulated their sentence reading. They tended to keep on reading as long as the syntactic and lexical-syntactic requirements of the sentence had not been met. In 4 of the conditions twice as many omissions occurred when the final constituent was optional than when it was obligatory. Text reading was also guided by a search for a "happy end" that does not violate syntactic or semantic requirements. Thus, the syntactic structure of the target sentence modulates reading and neglect errors in text-based neglect dyslexia, suggesting that the best stimuli to diagnose mild text-based neglect dyslexia are sentences in which the leftmost constituent is optional, and not required by syntax. Another finding of this study is dissociation between neglect dyslexia at the text and at the word levels. Two of the participants had neglect dyslexia at the text level, manifested in omissions of words on the left side of text, without neglect dyslexia at the word level (namely, without omissions, substitutions, or additions of letters on the left side of words). PMID- 21679720 TI - The role of the right parietal cortex in sound localization: a chronometric single pulse transcranial magnetic stimulation study. AB - Auditory spatial functions, including the ability to discriminate between the positions of nearby sound sources, are subserved by a large temporo-parieto frontal network. With the aim of determining whether and when the parietal contribution is critical for auditory spatial discrimination, we applied single pulse transcranial magnetic stimulation on the right parietal cortex 20, 80, 90 and 150 ms post-stimulus onset while participants completed a two-alternative forced choice auditory spatial discrimination task in the left or right hemispace. Our results reveal that transient TMS disruption of right parietal activity impairs spatial discrimination when applied at 20 ms post-stimulus onset for sounds presented in the left (controlateral) hemispace and at 80 ms for sounds presented in the right hemispace. We interpret our finding in terms of a critical role for controlateral temporo-parietal cortices over initial stages of the building-up of auditory spatial representation and for a right hemispheric specialization in integrating the whole auditory space over subsequent, higher order processing stages. PMID- 21679721 TI - An event-related brain potential study of explicit face recognition. AB - To determine the time course of face recognition and its links to face-sensitive event-related potential (ERP) components, ERPs elicited by faces of famous individuals and ERPs to non-famous control faces were compared in a task that required explicit judgements of facial identity. As expected, the face-selective N170 component was unaffected by the difference between famous and non-famous faces. In contrast, the occipito-temporal N250 component was linked to face recognition, as it was selectively triggered by famous faces. Importantly, this component was present for famous faces that were judged to be definitely known relative to famous faces that just appeared familiar, demonstrating that it is associated with the explicit identification of a particular face. The N250 is likely to reflect early perceptual stages of face recognition where long-term memory traces of familiar faces in ventral visual cortex are activated by matching on-line face representations. Famous faces also triggered a broadly distributed longer-latency positivity (P600f) that showed a left-hemisphere bias and was larger for definitely known faces, suggesting links between this component and name generation. These results show that successful face recognition is predicted by ERP components over face-specific visual areas that emerge within 230 ms after stimulus onset. PMID- 21679722 TI - LASSBio 596 per os avoids pulmonary and hepatic inflammation induced by microcystin-LR. AB - Cyanobacterial blooms that generate microcystins (MCYSTs) are increasingly recognized as an important health problem in aquatic ecosystems. We have previously reported the impairment of pulmonary structure and function by microcystin-LR (MCYST-LR) exposure as well as the pulmonary improvement by intraperitoneally injected (i.p.) LASSBio 596. In the present study, we aimed to evaluate the usefulness of LASSBio 596 per os on the treatment of pulmonary and hepatic injuries induced by MCYST-LR. Swiss mice received an intraperitoneal injection of 40 MUl of saline (CTRL) or a sub-lethal dose of MCYST-LR (40 MUg/kg). After 6 h the animals received either saline (TOX and CTRL groups) or LASSBio 596 (50 mg/kg, LASS group) by gavage. Eight hours after the first instillation, lung impedance (static elastance, elastic component of viscoelasticity and resistive, viscoelastic and total pressures) was determined by the end-inflation occlusion method. Left lung and liver were prepared for histology. In lung and hepatic homogenates MCYST-LR, TNF-alpha, IL-1beta and IL-6 were determined by ELISA. LASSBio 596 per os (LASS mice) kept all lung mechanical parameters, polymorphonuclear (PMN) cells, pro-inflammatory mediators, and alveolar collapse similar to control mice (CTRL), whereas in TOX these findings were higher than CTRL. Likewise, liver structural deterioration (hepatocytes inflammation, necrosis and steatosis) and inflammatory process (high levels of pro-inflammatory mediators) were less evident in the LASS than TOX group. LASS and CTRL did not differ in any parameters studied. In conclusion, orally administered LASSBio 596 prevented lung and hepatic inflammation and completely blocked pulmonary functional and morphological changes induced by MCYST-LR. PMID- 21679723 TI - Trends in self-reported health care provider recommendations for colorectal cancer screening by race. AB - OBJECTIVE: To examine whether a racial difference exists in self-reported recommendations for colorectal cancer screening from a health care provider, and whether this difference has changed over time. METHOD: Secondary analysis of the 2002, 2004, 2006, and 2008 Maryland Cancer Surveys, cross-sectional population based random-digit-dial surveys on cancer screening. Participants were 11,368 White and 2495 Black Maryland residents age >= 50 years. RESULTS: For each race, recommendations for colonoscopy/sigmoidoscopy increased over time (67%-83% for Whites, 57%-74% for Blacks; p<0.001 for both), but the race difference remained approximately 10% at each survey. Among respondents without a colonoscopy in the last 10 years (n=5081), recommendations for fecal occult blood test (FOBT) in the past year decreased over time for Whites (37%-24%, p<0.001) and for Blacks (36 28%, p=0.05), with no difference by race in any year. In multivariable analysis, the effect of race on the odds of reporting a provider recommendation did not vary significantly across time for either test (p=0.80 for colonoscopy/sigmoidoscopy, p=0.24 for FOBT for effect modification by year). CONCLUSION: Whites were more likely than Blacks to report ever receiving a provider recommendation for colonoscopy/sigmoidoscopy. Although the proportion of patients receiving recommendations for colonoscopy/sigmoidoscopy increased over time, the gap between races remained unchanged. PMID- 21679724 TI - Parental home smoking policies: the protective effect of having a young child in the household. AB - OBJECTIVE: To examine selected social determinants of a home smoking policy among US households with children and whether these associations vary by the presence of a smoker and children's ages. METHODS: In the 2006/2007 US Tobacco Use Supplement to the Current Population Survey there were 30,874 parents with 0-17 year-olds. RESULTS: 83.9% of parents reported that no one was allowed to smoke inside the home. However, a no smoking policy varied by the presence of a smoker (93.6% of non-smoking households; 55.8% of smoking households) and children's ages (87.1% of parents with any 0-5-year-olds; 82.1% with 6-17-year-olds only; 79.2% with 14-17-year-olds only). In smoking and non-smoking households, parents of 6-17-year-olds were 25%-46% less likely to have a no smoking policy than parents of younger children. Among smoking households, Hispanic and Asian parents were over twice as likely to not allow smoking inside the home as white parents, while Black parents were half as likely. Parents from more disadvantaged circumstances were less likely to have a no smoking policy. CONCLUSIONS: Parents of 6-17-year-olds are less likely to have a no smoking policy than parents of younger children. Parents with children of all ages should enact a smoking policy that promotes a smoke-free home. PMID- 21679726 TI - Surgical treatment for infective endocarditis in elderly patients. AB - OBJECTIVES: We evaluate the clinical, echographic and prognostic characteristics of infective endocarditis (IE) in a large population of elderly patients, and the results of surgical approach. METHODS: Multicentric, prospective, observational cohort study with 961 consecutive left-sided IE: 356 patients aged >=65 years were compared with 605 younger. Indications for cardiac surgery, potential surgical risk, time and outcome, were compared. RESULTS: Hospital-acquired endocarditis, comorbidity, renal failure and septic shock were more frequent in elderly, but embolisms were less. Intracardiac destruction and ventricular failure were similar in both groups, but significantly fewer elderly patients underwent cardiac surgery (36% vs 51%; p < 0.01), and this group showed a worse outcome (43.2% of mortality vs 27% in younger; p < 0.01), resulting age as an independent predictor of mortality (OR: 1.02 CI95%: 1.01-1.03). Compared with medical treatment, surgery showed lower percentages of mortality compared with medical treatment (23.3% vs 31.3%; p = 0.03) in younger group, but a high mortality was observed with both procedures (47.6% vs 40.3%; p = 0.1) in the elderly. CONCLUSIONS: Although similar percentages of heart failure and intracardiac complications, increasing age is associated with higher mortality in IE. Lower rates of surgical treatment and a worse outcome after operation are common features in elderly patients. PMID- 21679725 TI - Serotypes and clones causing invasive pneumococcal disease before the use of new conjugate vaccines in Catalonia, Spain. AB - OBJECTIVES: The objective of this study was to learn the serotype distribution and clonal composition of pneumococci causing invasive pneumococcal disease (IPD) in children and adults in Spain before the introduction of new 10-valent (PCV10) and 13-valent (PCV13) conjugate vaccines. METHODS: This is a 1-year prospective study including all patients with culture-proved IPD admitted to 30 medical centers in Catalonia, Spain, during the year 2009. RESULTS: A total of 614 episodes of IPD occurred in 612 patients. The rates of IPD were highest in children aged <24 months and adults >64 years (64.5 and 44.7 per 100,000 population). The burden of disease was mainly due to pneumonia in all age ranges. 609 of 614 strains were serotyped and 47 different serotypes were found. Among the 609 IPD cases with known serotype, 12.2% were caused by PCV7 serotypes, 51% by PCV10 serotypes, and 71.7% by PCV13 serotypes. 608 of 614 isolates were characterized by MLST. The main clonal types detected were ST306, CC191 and CC230. CONCLUSIONS: PCV13 conjugate vaccine offers good coverage against IPD in Catalonia, Spain. However, the high genetic diversity of pneumococci highlights the importance of molecular surveillance systems for monitoring IPD during the vaccination period. SUMMARY: This study shows that 13-valent conjugate vaccine offers good coverage against invasive pneumococcal disease in children and adults in Spain. However, the high genetic diversity of pneumococci highlights the importance of molecular surveillance systems for monitoring IPD during the vaccination period. PMID- 21679727 TI - Understanding the physical mechanism of transition to epileptic seizures. AB - The mechanisms of generating epileptic seizures are still unknown. To identify the mechanisms that underlie the transition to seizure a combination of features that include firing rate, power spectrum and complexity measures were simultaneously analyzed. Pre-ictal periods are characterized by large fluctuations of firing rate which reflect local dysfunctional regulation of neuronal activity. This local dysfunction in neuronal activity is translated in changes of endogenous electric field within clustered regions with high frequency oscillations (HFO) that act at fundamental level of charge dynamics and lead to chaotic dynamics followed by electrical resonances. Right before the onset of seizures the presence of chaotic behavior becomes persistent and leads all types of cells to fire simultaneously and generate the transition to ictal state. The alteration in neuronal regulation and the nature of physical phenomena involved in this transition supports some models of seizure generation and rules out others. PMID- 21679728 TI - ELISPOT analysis of a new CTL based DNA vaccine for HIV-1 using GM-CSF in DNA prime/peptide boost strategy: GM-CSF induced long-lived memory responses. AB - Genetic adjuvants have potential role in improvement of immune responses against DNA vaccines. GM-CSF as a genetic adjuvant can recruit and augment dendritic cell numbers in the site of immune responses and thereby induce cellular and humoral immune responses. Here we show that co-immunization of a DNA vaccine from HIV 1P24-Nef with GM-CSF in DNA priming and peptide boost strategy increases the immunogenicity of our candidate vaccine. Analysis of immune response shows that co-immunization with GM-CSF boosts cellular immune responses through increasing proliferation activity and CTL function. Results of cytokine profile studies show that both IL-4 and IFN-gamma levels were augmented. Also, co-immunization with GM CSF resulted in a higher level of total IgG, comprising approximately equal levels of both specific IgG1 and IgG2a subtypes. Monitoring of cellular and humoral immune responses for 20 weeks after final immunization revealed the aptitude of GM-CSF for inducing long-lived humoral and cell mediated immune responses. Overall, our results suggest that GM-CSF is able to induce long term memory for the HIV-1 P24-Nef vaccine candidate while the exact mechanisms involved remained to be clarified. PMID- 21679729 TI - Differential effects of maternal immune activation and juvenile stress on anxiety like behaviour and physiology in adult rats: no evidence for the "double-hit hypothesis". AB - Environmental disruptions can influence neurodevelopment during pre- and postnatal periods. Given such a large time window of opportunity for insult, the "double-hit hypothesis" proposes that exposure to an environmental challenge may impact development such that an individual becomes vulnerable to developing a psychopathology, which then manifests upon exposure to a second challenge later in life. The present study in male rats utilized the framework of the "double-hit hypothesis" to investigate potential compounding effects of maternal immune activation (MIA) during pregnancy and exposure of offspring to stress during juvenility on physiological and behavioural indications of anxiety in adulthood. We used an established rat model of MIA via maternal treatment with polyinosinic:polycytidylic acid (poly I:C) on gestation day 15 in combination with a model of juvenile stress (applied ages 27-29 d) in offspring to explore potential interacting/additive effects. First, we confirmed our employment of the MIA model by replicating previous findings that prenatal treatment with poly I:C caused deficits in sensorimotor gating in adult offspring, as measured by prepulse inhibition. Juvenile stress, on the other hand, had no effect on prepulse inhibition. In terms of anxiety-related behaviour and physiology, we found that prenatal poly I:C alone or in combination with juvenile stress had no effects on body weight, adrenal weight, and plasma concentration of corticosterone and cytokines in adult rats. MIA and juvenile stress increased anxiety-related behaviour on the elevated plus maze, but did so independently of each other. In all, our findings do not support an interaction between MIA and juvenile stress in terms of producing marked changes related to anxiety-like behaviour in adulthood. PMID- 21679730 TI - In the eye of the listener: pupil dilation elucidates discourse processing. AB - The current study investigated cognitive resource allocation in discourse processing by means of pupil dilation and behavioral measures. Short question answer dialogs were presented to listeners. Either the context question queried a new information focus in the successive answer, or else the context query was corrected in the answer sentence (correction information). The information foci contained in the answer sentences were either adequately highlighted by prosodic means or not. Participants had to judge the adequacy of the focus prosody with respect to the preceding context question. Prosodic judgment accuracy was higher in the conditions bearing adequate focus prosody than in the conditions with inadequate focus prosody. Latency to peak pupil dilation was longer when new information foci were perceived compared to correction foci. Moreover, for the peak dilation, an interaction of focus type and prosody was found. Post hoc statistical tests revealed that prosodically adequate correction focus positions were processed with smaller peak dilation in comparison to all other dialog conditions. Thus, pupil dilation and results of a principal component analysis suggest an interaction of focus type and focus prosody in discourse processing. PMID- 21679731 TI - A train of electrical pulses applied to the primary auditory cortex evokes a conditioned response in guinea pigs. AB - As a step to develop auditory prosthesis by cortical stimulation, we tested whether a single train of pulses applied to the primary auditory cortex could elicit classically conditioned behavior in guinea pigs. Animals were trained using a tone as the conditioned stimulus and an electrical shock to the right eyelid as the unconditioned stimulus. After conditioning, a train of 11 pulses applied to the left AI induced the conditioned eye-blink response. Cortical stimulation induced no response after extinction. Our results support the feasibility of auditory prosthesis by electrical stimulation of the cortex. PMID- 21679732 TI - SNP genotyping through the melting analysis of unlabelled oligonucleotide applied on dilute PCR amplicon. AB - Adaptation of DNA melting analysis for polymorphic single nucleotides (SNPs) genotyping using an unlabeled oligonucleotide probe for polymorphic DNAs under the presence of fluorescent DNA binding dye necessitates a reaction condition where the probe efficiently associates with a target strand that is PCR amplified. We present experimental evidence that application of an unlabeled probe to a dilute PCR amplicon provides a condition such that the fluorescent signals gained subsequently by probe melting are sufficient to discriminate allelic identities. This approach is best exploited by adapting the multiplexing PCR technique in order to cover multiple SNPs for given samples. 3'-end modification of the probe is unnecessary as the amplicon dilution step provides a way of inactivating the polymerase through divalent cation chelation. With the use of low-cost reagents and ordinary laboratory equipment, this method offers a rapid, simple and cost-efficient way of SNP genotyping. PMID- 21679733 TI - Targeting dendritic cells with nano-particulate PLGA cancer vaccine formulations. AB - Development of safe and effective cancer vaccine formulation is a primary focus in the field of cancer immunotherapy. The recognition of the crucial role of dendritic cells (DCs) in initiating anti-tumor immunity has led to the development of several strategies that target vaccine antigens to DCs as an attempt for developing potent, specific and lasting anti-tumor T cell responses. The main objective of this review is to provide an overview on the application of poly (d,l-lactic-co-glycolic acid) nanoparticles (PLGA-NPs) as cancer vaccine delivery system and highlight their potential in the development of future therapeutic cancer vaccines. PLGA-NPs containing antigens along with immunostimulatory molecules (adjuvants) can not only target antigen actively to DCs, but also provide immune activation and rescue impaired DCs from tumor induced immuosupression. PMID- 21679734 TI - Bilobalide regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. AB - Bilobalide (BB) is a sesquiterpenoid extracted from Ginkgo biloba leaves. An increasing number of studies have demonstrated its neuroprotective effects. The neuroprotective mechanisms may be associated with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Using differentiated SH-SY5Y cells, this study investigated whether BB modulation of intracellular signaling pathways, such as the protein kinase C (PKC) and PI3K pathways, contributes to amyloid precursor protein (APP) metabolism, a key event in the pathogenesis of Alzheimer's disease (AD). We demonstrated in this study that BB enhanced the secretion of alpha-secretase-cleaved soluble amyloid precursor protein (sAPPalpha, a by-product of non-amyloidogenic processing of APP) and decreased the beta amyloid protein (Abeta, a by-product of amyloidogenic processing of APP) via PI3K-dependent pathway. The PI3K pathway mediated the rapid effect of BB on APP processing possibly via regulation of intracellular APP trafficking. After longer time BB incubation (12h), this effect was reinforced by PI3K pathway-mediated up-regulation of disintegrin and metalloproteinase domain containing protein 10 (ADAM10, an alpha-secretase candidate). Given the strong association between APP metabolism and AD pathogenesis, the ability of BB to regulate APP processing suggests its potential use in AD prevention. PMID- 21679735 TI - Ex vivo production of autologous whole inactivated HIV-1 for clinical use in therapeutic vaccines. AB - This study provides a detailed description and characterization of the preparation of individualized lots of autologous heat inactivated HIV-1 virions used as immunogen in a clinical trial designed to test an autologous dendritic cell-based therapeutic HIV-1 vaccine (Clinical Trial DCV-2, NCT00402142). For each participant, ex vivo isolation and expansion of primary virus were performed by co-culturing CD4-enriched PBMCs from the HIV-1-infected patient with PBMC from HIV-seronegative unrelated healthy volunteer donors. The viral supernatants were heat-inactivated and concentrated to obtain 1 mL of autologous immunogen, which was used to load autologous dendritic cells of each patient. High sequence homology was found between the inactivated virus immunogen and the HIV-1 circulating in plasma at the time of HIV-1 isolation. Immunogens contained up to 109 HIV-1 RNA copies/mL showed considerably reduced infectivity after heat inactivation (median of 5.6 log10), and were free of specified adventitious agents. The production of individualized lots of immunogen based on autologous inactivated HIV-1 virus fulfilling clinical-grade good manufacturing practice proved to be feasible, consistent with predetermined specifications, and safe for use in a clinical trial designed to test autologous dendritic cell-based therapeutic HIV-1 vaccine. PMID- 21679736 TI - Enhancing DNA immunization by targeting ASFV antigens to SLA-II bearing cells. AB - One of the main criticisms to DNA vaccines is the poor immunogenicity that they confer on occasions, at least in large animals. Confirming this theory, immunization with plasmid DNA encoding two African swine fever virus genes in frame (pCMV-PQ), failed in inducing detectable immune responses in pigs, while it was successful in mice. Aiming to improve the immune responses induced in swine, a new plasmid was constructed, encoding the viral genes fused in frame with a single chain variable fragment of an antibody specific for a swine leukocyte antigen II (pCMV-APCH1PQ). Our results clearly demonstrate that targeting antigens to antigen professional cells exponentially enhanced the immune response induced in pigs, albeit that the DNA vaccine was not able to confer protection against lethal viral challenge. Indeed, a viremia exacerbation was observed in each of the pigs that received the pCMV-APCH1PQ plasmid, this correlating with the presence of non-neutralizing antibodies and antigen-specific SLA II restricted T-cells. The implications of our discoveries for the development of future vaccines against African swine fever virus and other swine pathogens are discussed. PMID- 21679737 TI - Outer membrane vesicles as an acellular vaccine against Acinetobacter baumannii. AB - Acinetobacter baumannii produces different types of infections including pneumonia, meningitis, and bloodstream infections. The optimal treatment of these infections has been complicated by the global emergence of multidrug resistant strains, requiring the development of novel approaches for treatment and prevention. Outer membrane vesicles are outpouchings of the bacterial outer membrane that are secreted from numerous pathogenic Gram-negative bacteria. In the present study, we describe the isolation of outer membrane vesicles from A. baumannii and their use as a vaccine in a mouse model of disseminated sepsis. Immunization produced a robust antibody response against multiple bacterial antigens which consisted of antigen-specific IgG and IgM. In addition, both IgG1 and IgG2c subtypes were produced by immunization. Immunized mice had lower tissue bacterial loads and lower serum levels of the pro-inflammatory cytokines IL-6 and IL-1beta post-infection compared to control mice. Importantly, vaccination protected mice from challenge with the ATCC 19606 strain and provided protection against two clinical isolates, including a pan-resistant strain. These results indicate that vaccination with outer membrane vesicles may be a viable strategy for preventing A. baumannii infection. PMID- 21679738 TI - State of the art in benefit-risk analysis: introduction. AB - Risk-taking is normal in everyday life if there are associated (perceived) benefits. Benefit-Risk Analysis (BRA) compares the risk of a situation to its related benefits and addresses the acceptability of the risk. Over the past years BRA in relation to food and food ingredients has gained attention. Food, and even the same food ingredient, may confer both beneficial and adverse effects. Measures directed at food safety may lead to suboptimal or insufficient levels of ingredients from a benefit perspective. In BRA, benefits and risks of food (ingredients) are assessed in one go and may conditionally be expressed into one currency. This allows the comparison of adverse and beneficial effects to be qualitative and quantitative. A BRA should help policy-makers to make more informed and balanced benefit-risk management decisions. Not allowing food benefits to occur in order to guarantee food safety is a risk management decision much the same as accepting some risk in order to achieve more benefits. BRA in food and nutrition is making progress, but difficulties remain. The field may benefit from looking across its borders to learn from other research areas. The BEPRARIBEAN project (Best Practices for Risk-Benefit Analysis: experience from out of food into food; http://en.opasnet.org/w/Bepraribean) aims to do so, by working together with Medicines, Food Microbiology, Environmental Health, Economics & Marketing-Finance and Consumer Perception. All perspectives are reviewed and subsequently integrated to identify opportunities for further development of BRA for food and food ingredients. Interesting issues that emerge are the varying degrees of risk that are deemed acceptable within the areas and the trend towards more open and participatory BRA processes. A set of 6 'state of the art' papers covering the above areas and a paper integrating the separate (re)views are published in this volume. PMID- 21679739 TI - State of the art in benefit-risk analysis: food microbiology. AB - Over the past years benefit-risk analysis (BRA) in relation to foods and food ingredients has gained much attention; in Europe and worldwide. BRA relating to food microbiology is however a relatively new field of research. Microbiological risk assessment is well defined but assessment of microbial benefits and the weighing of benefits and risk has not been systematically addressed. In this paper the state of the art in benefit-risk analysis in food microbiology is presented, with a brief overview of microbiological food safety practices. The quality and safety of foods is commonly best preserved by delaying the growth of spoilage bacteria and contamination by bacterial pathogens. However, microorganisms in food can be both harmful and beneficial. Many microorganisms are integral to various food production processes e.g. the production of beer, wine and various dairy products. Moreover, the use of some microorganisms in the production of fermented foods are often claimed to have beneficial effects on food nutrition and consumer health. Furthermore, food safety interventions leading to reduced public exposure to foodborne pathogens can be regarded as benefits. The BRA approach integrates an independent assessment of both risks and benefits and weighs the two using a common currency. Recently, a number of initiatives have been launched in the field of food and nutrition to address the formulation of the benefit-risk assessment approach. BRA has recently been advocated by EFSA for the public health management of food and food ingredients; as beneficial and adverse chemicals can often be found within the same foods and even the same ingredients. These recent developments in the scoping of BRA could be very relevant for food microbiological issues. BRA could become a valuable methodology to support evaluations and decision making regarding microbiological food safety and public health, supplementing other presently available policy making and administrative tools for microbiological food safety management. PMID- 21679740 TI - Antihyperglycemic and antioxidative potential of Psidium guajava fruit in streptozotocin-induced diabetic rats. AB - Psidium guajava Linn. (family Myrtaceae; PG) is a tropical fruit with a blood glucose-lowering effect in diabetic rats, but its mechanism of action is still unknown. We investigated the antihyperglycemic efficacy and mechanisms of action of PG in streptozotocin (STZ)-induced diabetic rats. After 4 weeks of PG supplementation (125 and 250 mg/kg), PG significantly restored the loss of body weight caused by STZ and reduced blood glucose levels in a dose-dependent manner compared with that in diabetic control rats. Mechanistically, PG protected pancreatic tissues, including islet beta-cells, against lipid peroxidation and DNA strand breaks induced by STZ, and thus reduced the loss of insulin-positive beta-cells and insulin secretion. Moreover, PG also markedly inhibited pancreatic nuclear factor-kappa B protein expression induced by STZ and restored the activities of antioxidant enzymes, including superoxide dismutase, catalase, and glutathione peroxidase. We conclude that PG has a significant antihyperglycemic effect, and that this effect is associated with its antioxidative activity. PMID- 21679741 TI - State of the art in benefit-risk analysis: food and nutrition. AB - Benefit-risk assessment in food and nutrition is relatively new. It weighs the beneficial and adverse effects that a food (component) may have, in order to facilitate more informed management decisions regarding public health issues. It is rooted in the recognition that good food and nutrition can improve health and that some risk may be acceptable if benefit is expected to outweigh it. This paper presents an overview of current concepts and practices in benefit-risk analysis for food and nutrition. It aims to facilitate scientists and policy makers in performing, interpreting and evaluating benefit-risk assessments. Historically, the assessments of risks and benefits have been separate processes. Risk assessment is mainly addressed by toxicology, as demanded by regulation. It traditionally assumes that a maximum safe dose can be determined from experimental studies (usually in animals) and that applying appropriate uncertainty factors then defines the 'safe' intake for human populations. There is a minor role for other research traditions in risk assessment, such as epidemiology, which quantifies associations between determinants and health effects in humans. These effects can be both adverse and beneficial. Benefit assessment is newly developing in regulatory terms, but has been the subject of research for a long time within nutrition and epidemiology. The exact scope is yet to be defined. Reductions in risk can be termed benefits, but also states rising above 'the average health' are explored as benefits. In nutrition, current interest is in 'optimal' intake; from a population perspective, but also from a more individualised perspective. In current approaches to combine benefit and risk assessment, benefit assessment mirrors the traditional risk assessment paradigm of hazard identification, hazard characterization, exposure assessment and risk characterization. Benefit-risk comparison can be qualitative and quantitative. In a quantitative comparison, benefits and risks are expressed in a common currency, for which the input may be deterministic or (increasingly more) probabilistic. A tiered approach is advocated, as this allows for transparency, an early stop in the analysis and interim interaction with the decision-maker. A general problem in the disciplines underlying benefit-risk assessment is that good dose-response data, i.e. at relevant intake levels and suitable for the target population, are scarce. It is concluded that, provided it is clearly explained, benefit-risk assessment is a valuable approach to systematically show current knowledge and its gaps and to transparently provide the best possible science-based answer to complicated questions with a large potential impact on public health. PMID- 21679742 TI - High irradiance curing and anomalies of exposure reciprocity law in resin-based materials. AB - OBJECTIVES: The aim of this work was to investigate the effect of high irradiance curing on resultant degree of conversion of 'flowable' resin composites and their counterpart higher viscosity paste materials. METHODS: Five commercial flowable materials (Venus; Heraeus Kulzer, Synergy D6; Coltene, Premise; Kerr, Grandio; Voco and Gradia; GC Corp) and their counterpart higher viscosity restorative versions were tested. Specimens were cured with a halogen Swiss Master Light (EMS, Switzerland) using five different curing protocols with similar radiant exposure (18J/cm(2)): 400mW/cm(2) for 45s, 900mW/cm(2) for 20s, 1500mW/cm(2) for 12s, 2000mW/cm(2) for 9s and 3000mW/cm(2) for 6s. Degree of conversion (DC) was measured in real time by Fourier transform near infrared spectroscopy (FT-NIRS). RESULTS: Three- and subsequent two way ANOVA testing revealed significant differences (p<=0.02) with respect to "composite type" and "cure protocol" for DC for all 5 product comparisons. Supplementary one-way ANOVA also revealed significant differences between curing protocols (p<0.05). The majority of higher viscosity resin composite paste materials exhibited similar DC regardless of curing protocol. However, a significant decrease in DC for specimens cured at 3000mW/cm(2) for 6s compared with 400mW/cm(2) for 45s was observed for the flowable materials, Grandio (41+/-0.36 and 62+/-1.15%, respectively) and Venus (44+/-0.44 and 67+/-0.44%, respectively). Conversely, other flowable materials exhibited little or no significant differences between curing modes. Generally, a higher degree of conversion was observed for flowables compared with their more viscous counterpart, except at high irradiance for those materials where a reciprocal relationship with exposure time was not observed. CONCLUSIONS: The validity of exposure reciprocity law and final degree of conversion depends on several factors, amongst which resin viscosity and filler content were important. Practitioners should be aware of the importance of resin composite constituents and irradiation protocols. Information on material composition and appropriate radiation sources by manufacturers may assist practitioners with the selection of appropriate curing protocols for specific material/light curing unit combinations with the aim of reducing the incidence of under-cured restorations and the clinical impact thereof. PMID- 21679743 TI - Induction of G-quadruplex DNA structure by Zn(II) 5,10,15,20-tetrakis(N-methyl-4 pyridyl)porphyrin. AB - G-quadruplexes (GQ) are formed by the association of guanine-rich stretches of DNA. Certain small molecules can influence kinetics and thermodynamics of this association. Understanding the mechanism of ligand-assisted GQ folding is necessary for the design of more efficient cancer therapeutics. The oligonucleotide d(TAGGG)(2) forms parallel bimolecular GQ in the presence of >=66 mM K(+); GQs are not formed under Na(+), Li(+) or low K(+) conditions. The thermodynamic parameters for GQ folding at 60 MUM oligonucleotide and 100 mM KCl are DeltaH = -35 +/- 2 kcal mol(-1) and DeltaG(310) = -1.4 kcal mol(-1). Quadruplex [d(TAGGG)(2)](2) binds 2-3 K(+) ions with K(d) of 0.5 +/- 0.2 mM. Our work addresses the question of whether metal free 5,10,15,20-tetrakis(N-methyl-4 pyridyl)porphyrin (TMPyP4) and its Zn(II), Cu(II), and Pt(II) derivatives are capable of facilitating GQ folding of d(TAGGG)(2) from single stranded, or binding to preformed GQ, using UV-vis and circular dichroism (CD) spectroscopies. ZnTMPyP4 is unique among other porphyrins in its ability to induce GQ structure of d(TAGGG)(2), which also requires at least a low amount of potassium. ZnTMPyP4 binds with 2:1 stoichiometry possibly in an end-stacking mode with a ~10(6) M(-1) binding constant, determined through UV-vis and ITC titrations. This process is entropically driven and has DeltaG(298) of -8.0 kcal mol(-1). TMPyP4 binds with 3:1 stoichiometry and K(a) of ~10(6) M(-1). ZnTMPyP4 and TMPyP4 are efficient stabilizers of [d(TAGGG)(2)](2) displaying DeltaT(1/2) of 13.5 and 13.8 degrees C, respectively, at 1:2 GQ to porphyrin ratio; CuTMPyP4 shows a much weaker effect (DeltaT(1/2) = 4.7 degrees C) and PtTMPyP4 is weakly destabilizing (DeltaT(1/2) = -2.9 degrees C). The selectivity of ZnTMPyP4 for GQ versus dsDNA is comparable to that of TMPyP4. The ability of ZnTMPyP4 to bind and stabilize GQ, to induce GQ formation, and speed up its folding may suggest an important biological activity for this molecule. PMID- 21679744 TI - Depressive symptoms and attenuated physiological reactivity to laboratory stressors. AB - There is evidence that depressive symptoms are associated with attenuated physiological reactivity to active stressors. However, it is not known whether blunted reactivity in depressed individuals is stressor-specific. We examined cardiovascular and electrodermal reactivity in non-clinical participants with varying levels of depressive symptoms to different active and passive stressors. Depressive symptoms were inversely related to both blood pressure and skin conductance reactivity during a public speaking task and the viewing of the speech video. However, no effects were found during a cold pressor task. Together these findings suggest that depressive symptoms are related to attenuated sympathetic nervous system reactivity in response to self-relevant stressors. PMID- 21679745 TI - Effect of eosinophil cationic protein (ECP) on Hodgkin lymphoma cell lines. AB - OBJECTIVE: In Hodgkin lymphoma (HL), tumor eosinophilia indicates poor prognosis, probably caused by eosinophil-induced stimulation of tumor cells. Our aim was to investigate the effects of eosinophil cationic protein (ECP) on HL tumor cells in vitro. MATERIALS AND METHODS: A fluorometric microculture cytotoxicity assay was used to measure the survival index of cells from the HL cell lines: HDLM-2 (T cell origin, nodular sclerosis histology), KMH2 (B-cell origin, mixed cellularity), and L428 (B-cell origin, nodular sclerosis) after incubation with ECP97arg variants with different glycosylations and with ECP97thr. Flow cytometry monitored the effects of ECP on markers of cell death. RESULTS: For KMH2 and L428, ECP was cytotoxic with a dose-response relationship similar to a previously investigated small-cell lung cancer cell line. HDLM-2 was more sensitive to ECP at low concentrations, but reached a plateau (survival index of 70%) at 0.018 MUM. The IC(50) for KMH2 and L428 were 0.2 and 0.15 MUM, respectively. The IC(50) was never reached for HDLM-2. All tested ECP variants displayed similar activity in HDLM-2, in contrast to KMH2 and L428, which were more sensitive to less glycosylated ECP. Positive DNA staining (propidium iodide) of HDLM-2 cells treated with ECP indicated cell death by necrosis. CONCLUSIONS: ECP is cytotoxic for HL tumor cells even at low concentrations, but heterogeneity between cell lines exists and not all tumor cells are eradicated. Two cell lines of B-cell origin, KMH2 and L428, were sensitive to ECP in a dose-response manner, but for HDLM-2, which is of T-cell origin, the cytotoxicity reached a plateau. PMID- 21679746 TI - Folding small proteins via annealing stochastic approximation Monte Carlo. AB - Recently, the stochastic approximation Monte Carlo algorithm has been proposed by Liang et al. (2007) as a general-purpose stochastic optimization and simulation algorithm. An annealing version of this algorithm was developed for real small protein folding problems. The numerical results indicate that it outperforms simulated annealing and conventional Monte Carlo algorithms as a stochastic optimization algorithm. We also propose one method for the use of secondary structures in protein folding. The predicted protein structures are rather close to the true structures. PMID- 21679747 TI - Model for a population-based microbial oscillator. AB - Genetic oscillators are a major theme of interest in the emerging field of synthetic biology. Until recently, most work has been carried out using intra cellular oscillators, but this approach restricts the broader applicability of such systems. Motivated by a desire to develop large-scale, spatially distributed cell-based computational systems, we present an initial design for a population level oscillator which uses three different bacterial strains. Our system is based on the client-server model familiar to computer science, and uses quorum sensing for communication between nodes. Importantly, it is robust to perturbation and noise. We present the results of extensive in silico simulation tests, which confirm the feasibility of our design. PMID- 21679748 TI - Expression of proliferin-related protein in testis and the biological significance in testosterone production. AB - Proliferin-related protein (PRP) was originally identified as an angiogenesis inhibitor in mouse placentas. Indeed, the tissue expression of PRP has mainly been documented in placentas. We report herein for the first time that PRP is expressed in male rat testes. Immunocytochemical and in situ hybridization results showed positive PRP immunostaining in Leydig cells. Immunofluorescent staining of PRP in the TM3 Leydig cell line indicates that PRP is located within the cytoplasm. The expression pattern of PRP in rat testis exhibited an age related increase. HCG significantly up-regulated the level of expression of PRP in TM3 cells via the PKA pathway. To elucidate the function of PRP, experiments were conducted to examine the consequences of lentiviral-mediated RNA interference (RNAi) of PRP on testosterone production and expression of several genes involved in steroidogenesis. PRP silencing caused a decrease in HCG stimulated testosterone production. In addition, PRP silencing attenuated the increase in PRLR mRNA following HCG stimulation. Moreover, the enhanced effect of PRL on HCG-induced testosterone production was also weakened following PRP silencing, indicating that PRP may be involved in PRL function through an effect on PRL receptor expression in response to stimuli. Taken together, these data suggest that PRP is regulated by HCG and plays roles in male reproduction, such as testosterone production. PMID- 21679749 TI - Accessory olfactory bulb neurons are required for maintenance but not induction of V2R vomeronasal receptor gene expression in vitro. AB - Many mammals detect pheromones by a sensory organ, the vomeronasal organ (VNO). In a previous study using immunoblot and immunocytochemical analyses, we reported that cocultures of VNOs with accessory olfactory bulb (AOB) neurons resulted in the maturation of vomeronasal sensory neurons (VSNs) and a greater expression of V2R family vomeronasal receptors than cultures with VNO alone. To further characterize the V2R expression, we here investigated the time course of the expression of V2R mRNA in the presence or absence of AOB neurons using RT-PCR analysis. The expression of V2R mRNA was already detectable not only in the VNO cocultured with AOB neurons for 3 days in coculture but also in the VNO cultured alone for the same number of days. However, the expression of V2R mRNA in the VNO cultured alone was remarkably decreased during the additional culture period, although that in the cocultured VNO showed sustained expression. Moreover, the application of 2 MUM TTX to the cocultured VNO resulted in a marked decrease in the V2R mRNA expression to a level equal to that in the VNO cultured alone for 14 days in coculture. Our previous working hypothesis was that the expression of V2Rs in VSNs was induced by interacting with AOB neurons. However, the present results suggest that the receptor expression in VSNs is independent of the interaction with AOB neurons in the early developmental stage, but is maintained by the active interaction with AOB neurons. PMID- 21679750 TI - A potential calcium antagonist and its antihypertensive effects. AB - Imperatorin (Imp) as a hypotensive active ingredient, its hypotensive effect was evaluated in the SHRs, its calcium antagonism and affinity to L-type calcium channel was also confirmed. The results showed that the blood pressure was decreased in the SHRs treated with Imp, the aortic ring was relaxed with Imp, L type calcium channel currents and intracellular calcium free ion rise was nearly disappeared when adding Imp. In addition, Imp displayed a chromatographic peak similar to nitrendipine and verapamil by the cell membrane chromatography, same results from protein-drug docking approaches. Hence, Imp target the L-type calcium channel, and may be used as a novel antihypertensive drug. PMID- 21679751 TI - Computational analysis of the fructosyltransferase enzymes in plants, fungi and bacteria. AB - Fructosyltransferases (FTases) are enzymes produced by plants, fungi, and bacteria, which are responsible for the synthesis of fructooligosaccharides. In this study, we conducted a computational analysis of reported sequences for FTase from a diverse source of organisms, such as plants, fungi, and bacteria. Ninety one proteins sequences were obtained; all belonging to the glycoside hydrolase 32 (GH32) and 68 (GH68) families. The sequences were grouped in seven clades, five for plants, one for fungi, and one for bacteria. Our findings suggest that FTases from fungi and bacteria likely evolved from dicotyledonous FTases. The analysis of catalytic domains A, D and E, which contain the amino acids involved in the catalytic binding site, allowed the identification of clade-specific conserved characteristics. The analysis of sequence motifs involved in donor/acceptor molecule affinity showed that additional sequences could be responsible for donor/acceptor molecule affinity. The correlation of this large set of FTases allowed to identify additional features that might be used for the identification and classification of new FTases, and to improve the understanding of these valuable enzymes. PMID- 21679752 TI - Regulation of CD2-associated protein influences podocyte endoplasmic reticulum stress-mediated apoptosis induced by albumin overload. AB - Proteinuria is an exacerbating factor of chronic kidney diseases, leading to glomerulosclerosis. However, the molecular mechanisms mediating protein overload induced podocyte injury are poorly understood. Recent studies have shown that apoptosis mediated by endoplasmic reticulum (ER) stress participated in the progression of a variety of kidney diseases. In the present study, we investigated the role of CD2-associated protein (CD2AP) in protein overload induced ER stress and subsequent podocyte apoptosis. Conditionally immortalized mouse podocytes were cultured in vitro and treated with different concentrations of bovine serum albumin (BSA). In addition, CD2AP eukaryotic expression vector or siRNA was transfected into podocytes before exposed to BSA. Albumin endocytosis and podocyte apoptosis were visualized by confocal microscopy. The subcellular organelles were observed by transmission electron microscopy. The expressions of GRP78, caspase-12 and CD2AP were detected by RT-PCR or Western blot analysis. It was found that albumin was endocytosed by podocytes in a time-dependent manner. Accumulation of albumin in podocytes induced ER stress and apoptosis in a concentration-dependent manner as indicated by upregulation of GRP78 and caspase 12. Meanwhile, the subcellular organelles were disrupted and the expression of CD2AP was downregulated by high concentration of albumin. Transfection of CD2AP eukaryotic expression vector into podocytes increased CD2AP expression, depressed GRP78 and caspase-12 expressions, and inhibited podocyte apoptosis. In contrast, transfection of CD2AP siRNA deteriorated the above changes induced by BSA. It is concluded protein overload induces podocyte apoptosis via ER stress and CD2AP may play a crucial role in albumin overload-induced ER stress and apoptosis in podocytes. PMID- 21679753 TI - Preliminary study on the DNA-binding properties of phage PhiC31 integrase. AB - PhiC31 integrase is a member of the large serine subfamily and is required for the recombination of the phage genome into the host chromosome, either to establish or exit from the lysogenic state. This enzyme can also mediate site specific integration in mammalian cells in a cofactor-independent manner and has been considered as a potentially powerful tool for gene therapy. It has previously been reported that DAXX interacts with PhiC31 integrase and markedly inhibits its integration efficiency, and the 451RFGK454 tetramer of PhiC31 integrase has been identified as the interacting motif. Here, we report that both the deletion of the tetramer or the replacement of Arg with His greatly reduced the recombination activity of the PhiC31 integrase. Electrophoretic mobility shift assays further demonstrated that the DNA-binding ability and binding specificity of the two mutants were dramatically reduced. Bioinformatic analysis indicated a probable helix-turn-helix-like DNA-binding motif between residues 415 525, a region that contains the tetramer motif. However, neither truncated Int(415-525) nor Int(?415-525) alone could bind to the attB target sequence. Results of a circular dichroism spectroscopy assay indicated that Int(415-525) did not fold correctly into a helix-turn-helix-like structure, which may be one of the reasons for its lack of DNA-binding ability. Thus, the identification and confirmation of four key amino acids in the DNA-binding specificity and recombination activity of PhiC31 integrase provide information about the domain structure and function of the large C-terminal region and suggest important implications for the more efficient use of integrase in gene transfer and gene therapy. PMID- 21679754 TI - A combined technique based on prilling and microwave assisted treatments for the production of ketoprofen controlled release dosage forms. AB - In this study the feasibility of joining prilling and microwave (MW) assisted treatments as combined technique to produce controlled release alginate beads was tested. Beads were produced by prilling (laminar jet break-up) using different polymer concentrations and loaded with ketoprofen, a slightly soluble non steroidal anti-inflammatory BCS class II drug characterized by low melting point. MW assisted treatments applied using different irradiating conditions were performed as drying/curing step. The effect of formulation conditions and process variables on drying kinetics, particle micromeritics, shape, surface and inner characteristics of the matrix as well as drug loading and drug release behaviour was studied (USP pH change method). The properties of MW dried particles were compared to those dehydrated by convective methods (room conditions and tray oven 105 degrees C). Results showed that MW dried ketoprofen loaded beads were obtained in a very narrow dimensional range retaining shape and size distribution of the hydrates particles. Compared to the traditional drying methods, MW treatments were able to strongly increase drying rate of the hydrated beads achieving faster and controllable dehydration kinetics. Moreover, different regimes of irradiation affected structural properties of the particles such as matrix porosity as well as the solid state of the loaded drug. DSC, X-ray and FTIR analyses indicated complex chemical interactions between the drug and polymer matrix induced by MW, related with the regime of irradiation, that contributes to the differences in release profiles. In fact, MW treatments under different time and irradiating regimes are able to modulate drug release from alginate beads; high levels of irradiation led to beads suitable for immediate release oral dosage forms whereas the lowest regime of irradiation led to beads that achieved a prolonged/sustained release of the drug till 8h in simulated intestinal medium. This study showed that prilling in combination with microwave treatments is a useful and simple tandem technique to prepare dextran-based dried beads. PMID- 21679755 TI - Preparation and antitumor study of camptothecin nanocrystals. AB - Camptothecin (CPT) is a potent, broad spectrum antitumor agent that inhibits the activity of DNA topoisomerase I. Due to its poor solubility and stability and consequent delivery challenges, its clinical use is nevertheless limited. We aim to use nanocrystal formulation as a way to circumvent the difficult solubilization practice. Specifically, camptothecin nanocrystals were prepared with a sonication-precipitation method without additional stabilizing surfactants. Particle characteristics, cellular cytotoxicity, and animal antitumor effect were examined. CPT nanocrystals were tested to be more potent to MCF-7 cells than CPT solution in vitro. When tested in MCF-7 xenografted BALB/c mice, the CPT nanocrystals exhibited significant suppression of tumor growth. The drug concentration in the tumor was five times more at 24h by using the nanocrystal treatment than by using the drug salt solution. Storage stability study indicated that the nanocrystals were stable for at least six months. Overall, CPT nanocrystals were considered to be potentially feasible to overcome formulation challenges for drug delivery and to be used in clinic. PMID- 21679756 TI - Encapsulation of poorly soluble basic drugs into enteric microparticles: a novel approach to enhance their oral bioavailability. AB - Poorly water soluble basic drugs are very sensitive to pH changes and following dissolution in the acidic stomach environment tend to precipitate upon gastric emptying, which leads to compromised or erratic oral bioavailability. In this work, we show that the oral bioavailability of a model poorly soluble basic drug (cinnarizine) can be improved by drug encapsulation within highly pH-responsive microparticles (Eudragit L). The latter was prepared by emulsion solvent evaporation which yielded discrete spherical microparticles (diameter of 56.4+/ 6.8MUm and a span of 1.2+/-0.3). These Eudragit L (dissolution threshold pH 6.0) microparticles are expected to dissolve and release their drug load at intestinal conditions. Thus, the enteric microparticles inhibited the in vitro release of drug under gastric conditions, despite high cinnarizine solubility in the acidic medium. At intestinal conditions, the particles dissolved rapidly and released the drug which precipitated out in the dissolution vessel. In contrast, cinnarizine powder showed rapid drug dissolution at low pH, followed by precipitation upon pH change. Oral dosing in rats resulted in a greater than double bioavailability of Eudragit L microparticles compared to the drug powder suspension, although C(max) and T(max) were similar. The higher bioavailability with microparticles contradicts the in vitro results. Such an example highlights that although in vitro results are an indispensable tool for formulation development, an early in vivo assessment of formulation behaviour can provide better prediction for oral bioavailability. PMID- 21679757 TI - Differential scanning calorimetry studies on sunscreen loaded solid lipid nanoparticles prepared by the phase inversion temperature method. AB - Solid lipid nanoparticles (SLN) are regarded as interesting carriers to improve sunscreens' safety and effectiveness. In this work, surfactant effects on the physico-chemical properties of SLN loading two of the most widely used UV filters, octylmethoxycinnamate (OMC) and butylmethoxydibenzoylmethane (BMBM), were evaluated and the interactions between SLN components and loaded UV-filters were investigated by differential scanning calorimetry (DSC). All the SLN showed a mean size ranging from 30 to 95 nm, and a single peak in size distribution. The use of isoceth-20 or oleth-20 as primary surfactants did not provide SLN with suitable physico-chemical properties since: (a) OMC loaded SLN proved unstable; (b) BMBM could not be loaded. OMC or BMBM loaded SLN prepared using ceteth-20 as primary surfactant were stable but their loading capacity lowered when both sunscreens were loaded simultaneously. DSC analyses showed that OMC distributed inside the SLN and caused a decrease of the lipid matrix molecules cooperativity while BMBM did not affect SLN calorimetric behaviour. When OMC and BMBM were loaded together into these SLN, an interaction between BMBM and OMC occurred. These results suggest that the interactions between sunscreens and between sunscreens and SLN components deserve further investigation to evaluate their effect on UV-filter-loaded SLN effectiveness. PMID- 21679758 TI - Antitumor effect of laticifer proteins of Himatanthus drasticus (Mart.) Plumel - Apocynaceae. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Himatanthus drasticus (Mart.) Plumel - Apocynaceae is a medicinal plant popularly known as Janaguba. Its bark and latex have been used by the public for cancer treatment, among other medicinal uses. However, there is almost no scientific research report on its medicinal properties. AIM OF THE STUDY: The aim of this study was to investigate the antitumor effects of Himatanthus drasticus latex proteins (HdLP) in experimental models. MATERIALS AND METHODS: The in vitro cytotoxic activity of the HdLP was determined on cultured tumor cells. HdLP was also tested for its ability to induce lysis of mouse erythrocytes. In vivo antitumor activity was assessed in two experimental models, Sarcoma 180 and Walker 256 carcinosarcoma. Additionally, its effects on the immunological system were also investigated. RESULTS: HdLP did not show any significant in vitro cytotoxic effect at experimental exposure levels. When intraperitoneally administered, HdLP was active against both in vivo experimental tumors. However, it was inactive by oral administration. The histopathological analysis indicates that the liver and kidney were only weakly affected by HdLP treatment. It was also demonstrated that HdLP acts as an immunomodulatory agent, increasing the production of OVA-specific antibodies. Additionally, it increased relative spleen weight and the incidence of megakaryocyte colonies. CONCLUSION: In summary, HdLP has some interesting anticancer activity that could be associated with its immunostimulating properties. PMID- 21679759 TI - Pharmacokinetics and tissue distribution of 2,3,5,4'-tetrahydroxystilbene-2-O beta-D-glucoside from traditional Chinese medicine Polygonum multiflorum following oral administration to rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum is an important traditional Chinese medicine used for health promotion and disease treatment. One major bioactive compound in P. multiflorum is a stilbene glycoside (2,3,5,4' tetrahydroxystilbene-2-O-beta-d-glucoside, PM-SG), which possesses antioxidative, anti-inflammatory and endothelial-protective activities. MATERIALS AND METHODS: The purpose of the present study was to investigate in vivo pharmacokinetics and tissue distribution of PM-SG after oral administration of Polygonum multiflorum extract to rats by using a reversed-phase high-performance liquid chromatography coupled with liquid-liquid phase extraction. The pharmacokinetic parameters were determined using both compartmental and non-compartmental analyses. RESULTS: All calibration curves for PM-SG in rat plasma and tissues were linear (all r(2)>0.99) over the range of 0.27-185.00 MUg/ml. The intra- and inter-day variations were less than 3% at concentration range of 8.7-131.2 MUg/ml and good overall recoveries (97.7-101.5%) were obtained at the same range. The maximum concentration (C(max)) and the time to reach this concentration (T(max)) of PM-SG were 31.9 MUg/ml and 40.0 min, respectively. The pharmacokinetic profiles estimated by fitting two-compartment and non-compartment models revealed that PM SG was rapidly absorbed into the body fluids and widely distributed throughout the body, with great efficiency of utility, followed by quick elimination. The highest PM-SG levels were detected in liver and lungs (90.3 +/- 20.8 MUg/g and 86.8 +/- 9.0 MUg/g, respectively) whereas little in brain and testes, indicating PM-SG can hardly penetrate the blood-brain and blood-testicle barriers. CONCLUSIONS: This was the first report on the favorable pharmacokinetic profiles of PM-SG in rat plasma and tissues after oral administration. It may provide a meaningful basis for clinical application of such a bioactive compound of herbal medicines. PMID- 21679760 TI - Anti-inflammatory activities of Chinese herbal medicine sinomenine and Liang Miao San on tumor necrosis factor-alpha-activated human fibroblast-like synoviocytes in rheumatoid arthritis. AB - AIM OF THE STUDY: Sinomenine, an alkaloid isolated from the root of Sinomenium acutum, has been used to alleviate the symptoms of rheumatic diseases. Liang Miao San (LMS), composed of the herbs Rhizoma Atractylodis (Cangzhu) and Cotex Phellodendri (Huangbai), is another traditional Chinese medicine formula for rheumatoid arthritis (RA) treatment. Although numerous studies have demonstrated the potential anti-inflammatory activities of sinomenine and LMS, the underlying intracellular mechanisms regulating the anti-inflammatory activities of sinomenine and LMS on human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects have not been elucidated. MATERIALS AND METHODS: We investigated the in vitro anti-inflammatory activity of sinomenine and LMS on inflammatory cytokine tumor necrosis factor (TNF)-alpha-mediated activation of human normal and RA-FLS. The underlying intracellular signaling molecules were analyzed quantitatively using flow cytometry. RESULTS: Sinomenine was found to significantly inhibit TNF-alpha induced cell surface expression of vascular cell adhesion molecule (VCAM)-1 and release of inflammatory cytokine and chemokine IL-6, CCL2 and CXCL8 from both normal and RA-FLS (all p<0.05). Moreover, the suppression of sinomenine on TNF-alpha induced VCAM-1 expression and IL-6 release of RA-FLS was significantly higher than that of normal FLS (p<0.05). LMS significantly inhibited TNF-alpha-induced inflammatory chemokines CXCL10 and CCL5 release from both normal and RA-FLS, with significantly higher suppression on CXCL10 secretion in RA-FLS than that of normal FLS (all p<0.05). Further investigations showed that sinomenine and LMS could significantly suppress TNF-alpha-induced phosphorylation of inhibitor kappaBalpha and extracellular signal-regulated protein kinase, the central signaling molecules mediating TNF-alpha-induced VCAM-1 expression and chemokine production. CONCLUSION: Our results therefore provide a new insight into the differential anti-inflammatory activities of sinomenine and LMS through the suppression of TNF alpha-activated FLS by modulating distinct intracellular signaling pathways in RA. PMID- 21679761 TI - Practices of traditional birth attendants in Machakos District, kenya. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aim of the study was to document TBAs practices as well as the indigenous herbal remedies they use to manage pre, intra and post partum complications in a rural Kenyan community. MATERIALS AND METHODS: A cross sectional study was conducted on practicing TBAs and their clients living in the study area. Data was collected using structured questionnaires and interviews. Focused group discussions were held with the TBAs to supplement the interviews and questionnaire survey. RESULTS: Two hundred TBAs and 20 clients were interviewed. The majority of the TBAs were females 75% of them having attended to over 200 pregnant women over a period of 5 years and above compared to only 6% of the males. A total of 10 pregnancy related complications and symptoms including threatened abortion, labor complications, post partum hemorrhage and retained after birth were recorded. Fifty five plant species most of them belonging to Euphorbiaceae family were identified for the management of the complications. CONCLUSION: Traditional Birth Attendants still have a role to play in assisting pregnant women in rural communities. Their knowledge on herbal medicines is equally important and should be preserved for posterity. PMID- 21679762 TI - Medicinal plant use in Vanuatu: a comparative ethnobotanical study of three islands. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Our study shows that large parts of Vanuatu's medicinal flora remain unexplored and that a high variability of medicinal plant knowledge between islands exists. AIM OF THE STUDY: The following questions are comparatively analyzed for three islands of Vanuatu: who are the medicinal plant specialists and how important is their knowledge today? Which plants are used to treat common diseases? MATERIALS AND METHODS: On Loh, Ambrym and Aneityum plant related information was collected using semi-structured interviews, transect walks and participant observation. A total of 29 medicinal plant specialists were interviewed. RESULTS: Medicinal plant specialists are either peasants or people with a high rank in the local social system such as members of the chief's family or priests. Their knowledge may be very broad (Loh, Aneityum) or specialized on specific diseases (Ambrym). Medicinal plant knowledge is transmitted family and gender specific (Loh) or gender and family independent (Ambrym and Aneityum). Overall, 133 medicinal plant species were documented of which 117 are new to Vanuatu's ethnopharmacopoeia. Mainly members of the Euphorbiaceae and Fabaceae, followed by Asteraceae, Convolvulaceae, Moraceae and Zingiberaceae are utilized. The majority of documented species are trees (33%), followed by herbs (22%) and shrubs (21%). Leaves accounted for the highest number of use reports (43%). The highest diversity of medicinal plants is found for the most common diseases such as skin, gastrointestinal, respiratory system and urogenital system diseases. Only a small overlap of taxa between the islands was found. CONCLUSIONS: The biocultural diversity of Vanuatu is reflected in the variability of medicinal plant knowledge and differences in the traditional medicinal system between the three islands investigated. Traditional medicine is more vital on remote islands. The better connected the islands are to the main city, the more dominant western medicine becomes and traditional medicine mainly remains to treat illnesses with a magical origin. PMID- 21679763 TI - Alteration of gene expression of IQGAP1 and Rho-family GTPases in the cadmium induced ventral body wall defects in the chick model. AB - Cadmium (Cd) induces ventral body wall defects (VBWD) in the chick embryo, with adherens junctions (AJs) breakdown at 4h post treatment (4H). Signalling by which Cd disrupts AJs in this model remains unclear. IQGAP1 regulates AJs via binding to Cdc42 and Rac1, Rho-family GTPases. Activation of IQGAP1-Cdc42 interaction regulates AJs positively, whereas Rac1 activation inhibits AJs. We hypothesised that IQGAP1 and Cdc42 are downregulated and Rac1 is upregulated during embryogenesis in the Cd chick model. Chick embryos were explanted and treated with saline or Cd after 60 h incubation. Chicks were harvested at 1H, 4H and 8H post treatment and RT-PCR and immunohistochemistry were performed. Gene expression levels of IQGAP1 and Cdc42 were significantly downregulated and Rac1 was upregulated in Cd group compared to controls only at 4H. Immunoreactivity of IQGAP1 and Cdc42 was also markedly decreased, whereas Rac1 was increased in Cd group compared to controls at 4H. Alteration of IQGAP and Rho-family GTPases may cause VBWD in Cd chick model by inducing the dissociation of cadherin-mediated AJs. PMID- 21679764 TI - Trans-resveratrol inhibits phosphorylation of Smad2/3 and represses FSHbeta gene expression by a SirT1-independent pathway in LbetaT2 gonadotrope cells. AB - Resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenol found in red wine, has multiple beneficial activities that are similar to caloric restriction. In this study, we analyzed the effect of resveratrol on the gonadotropin genes, follicle-stimulating hormone (FSHbeta) and luteinizing hormone (LHbeta) in LbetaT2 immortalized mouse gonadotrope cells. Resveratrol specifically inhibited activin-induced FSHbeta mRNA and protein expression, and reduced activin stimulated Smad2/3 phosphorylation. Knockdown of SirT1 gene expression or SirT1 inhibition did not block repression of FSHbeta expression or suppression of Smad2/3 phosphorylation, but did increase p53 acetylation. Taken together, our results suggest that resveratrol down-regulates Smad2/3 phosphorylation and suppresses FSHbeta expression via a SirT1-independent pathway. PMID- 21679765 TI - Neuropsin--a possible modulator of synaptic plasticity. AB - Accumulating evidence has suggested pivotal roles for neural proteases in development, maturation, aging, and cognitive functions. Among such proteases, neuropsin, a kallikrein gene-related (KLK) endoprotease, appears to have a significant plasticity function that has been analyzed primarily in the hippocampal Schaffer-collateral pathway. In this article, after reviewing the general features of neuropsin, its role in Schaffer-collateral synaptic plasticity is discussed in some detail. Enzymatically active neuropsin is necessary to establish the early phase of long-term potentiation (LTP). This type of LTP, which can be elicited by rather weak tetanic stimulation, is significant in synaptic late association between two independent hippocampal synapses. Neuropsin deficiency completely impaired the early phase of LTP, leading to the absence of late associativity. Associations between early and persistent-LTP synapses may be related to mammalian working memory and consequently integration in learning and memory. PMID- 21679766 TI - Introduction to the special issue on translational research involving oxidative stress. PMID- 21679767 TI - Age-related differences in acute neurotoxicity produced by mevinphos, monocrotophos, dicrotophos, and phosphamidon. AB - Age-related differences in the acute neurotoxicity of cholinesterase (ChE) inhibiting pesticides have been well-studied for a few organophosphates, but not for many others. In this study, we directly compared dose-responses using brain and red blood cell (RBC) ChE measurements, along with motor activity, for mevinphos, monocrotophos, dicrotophos, and phosphamidon. Long-Evans hooded male rats were tested as adults and at postnatal day (PND) 17; PND11 pups were also tested with dicrotophos only. All chemicals were administered via oral gavage and tests were conducted at times intended to span peak behavioral and ChE effects. All OPs tested produced a rapid onset and recovery from the behavioral effects. There were age-related differences in the inhibition of brain, but not necessarily RBC, ChE. Mevinphos was clearly more toxic, up to 4-fold, to the young rat. On the other hand, monocrotophos, dicrotophos, and phosphamidon were somewhat more toxic to the young rat, but the magnitude of the differences was < 2-fold lower. Motor activity was consistently decreased in adults for all chemicals tested; however, there was more variability with the pups and clear age related differences were only observed for mevinphos. These data show that three of these four OPs were only moderately more toxic in young rats, and further support findings that age-related differences in pesticide toxicity are chemical specific. PMID- 21679768 TI - Cerebral cortex demyelination and oligodendrocyte precursor response to experimental autoimmune encephalomyelitis. AB - Experimentally induced autoimmune encephalomyelitis (EAE) in mice provides an animal model that shares many features with human demyelinating diseases such as multiple sclerosis (MS). To what extent the cerebral cortex is affected by the process of demyelination and how the corollary response of the oligodendrocyte lineage is explicated are still not completely known aspects of EAE. By performing a detailed in situ analysis of expression of myelin and oligodendrocyte markers we have identified areas of subpial demyelination in the cerebral cortex of animals with conventionally induced EAE conditions. On EAE affected cerebral cortices, the distribution and relative abundance of cells of the oligodendrocyte lineage were assessed and compared with control mouse brains. The analysis demonstrated that A2B5(+) glial restricted progenitors (GRPs) and NG2(+)/PDGFR-alpha(+) oligodendrocyte precursor cells (OPCs) were increased in number during "early" disease, 20 days post MOG immunization, whereas in the "late" disease, 39 days post-immunization, they were strongly diminished, and there was an accompanying reduction in NG2(+)/O4(+) pre-oligodendrocytes and GST pi mature oligodendrocytes. These results, together with the observed steady state amount of NG2(-)/O4(+) pre-myelinating oligodendrocytes, suggested that oligodendroglial precursors attempted to compensate for the progressive loss of myelin, although these cells appeared to fail to complete the last step of their differentiation program. Our findings confirm that this chronic model of EAE reproduces the features of neocortex pathology in progressive MS and suggest that, despite the proliferative response of the oligodendroglial precursors, the failure to accomplish final differentiation may be a key contributing factor to the impaired remyelination that characterizes these demyelinating conditions. PMID- 21679769 TI - Evidence for the interaction of D-amino acid oxidase with pLG72 in a glial cell line. AB - Accumulating genetic evidence indicates that the primate-specific gene locus G72/G30 is related to schizophrenia: it encodes for the protein pLG72, whose function is still the subject of controversy. We recently demonstrated that pLG72 negatively affects the activity of human d-amino acid oxidase (hDAAO, also related to schizophrenia susceptibility), which in neurons and (predominantly) in glia is expected to catabolize the neuromodulator d-serine. The d-serine regulation mechanism relying on hDAAO-pLG72 interaction does not match with the subcellular localizations proposed for hDAAO (peroxisomes) and pLG72 (mitochondria). By using glioblastoma U87 cells transfected with plasmids encoding for hDAAO and/or pLG72 we provide convergent lines of evidence that newly synthesized hDAAO, transitorily present in cytosol before being delivered to the peroxisomes, colocalizes and interacts with pLG72 which we propose to be exposed on the external membrane of mitochondria. We also report that newly synthesized cytosolic hDAAO is catalytically active, and therefore pLG72 binding and ensuing hDAAO inactivation-plays a protective role against d-serine depletion. PMID- 21679770 TI - Impact of mindfulness on the neural responses to emotional pictures in experienced and beginner meditators. AB - There is mounting evidence that mindfulness meditation is beneficial for the treatment of mood and anxiety disorders, yet little is known regarding the neural mechanisms through which mindfulness modulates emotional responses. Thus, a central objective of this functional magnetic resonance imaging study was to investigate the effects of mindfulness on the neural responses to emotionally laden stimuli. Another major goal of this study was to examine the impact of the extent of mindfulness training on the brain mechanisms supporting the processing of emotional stimuli. Twelve experienced (with over 1000 h of practice) and 10 beginner meditators were scanned as they viewed negative, positive, and neutral pictures in a mindful state and a non-mindful state of awareness. Results indicated that the Mindful condition attenuated emotional intensity perceived from pictures, while brain imaging data suggested that this effect was achieved through distinct neural mechanisms for each group of participants. For experienced meditators compared with beginners, mindfulness induced a deactivation of default mode network areas (medial prefrontal and posterior cingulate cortices) across all valence categories and did not influence responses in brain regions involved in emotional reactivity during emotional processing. On the other hand, for beginners relative to experienced meditators, mindfulness induced a down-regulation of the left amygdala during emotional processing. These findings suggest that the long-term practice of mindfulness leads to emotional stability by promoting acceptance of emotional states and enhanced present-moment awareness, rather than by eliciting control over low-level affective cerebral systems from higher-order cortical brain regions. These results have implications for affect-related psychological disorders. PMID- 21679771 TI - Leptin stimulates hepatic activation of thyroid hormones and promotes early posthatch growth in the chicken. AB - Hepatic iodothyronine deiodinases (Ds) are involved in the conversion of thyroid hormones (THs) which interacts with growth hormone (GH) to regulate posthatch growth in the chicken. Previous studies suggest that leptin-like immunoreactive substance deposited in the egg may serve as a maternal signal to program posthatch growth. To test the hypothesis that maternal leptin may affect early posthatch growth through modifying hepatic activation of THs, we injected 5.0MUg of recombinant murine leptin into the albumen of breeder eggs before incubation. Furthermore, chicken embryo hepatocytes (CEHs) were treated with leptin in vitro to reveal the direct effect of leptin on expression and activity of Ds. In ovo leptin administration markedly accelerated early posthatch growth, elevated serum levels of total and free triiodothyronine (tT3 and fT3), while that of total thyroxin (tT4) remained unchanged. Hepatic mRNA expression and activity of D1 which converts T4 to T3 or rT3 to T2, were significantly increased in leptin treated chickens, while those of D3 which converts T3 to T2 or T4 to rT3, were significantly decreased. Moreover, hepatic expression of GHR and IGF-I mRNA was all up-regulated in leptin-treated chickens. Males demonstrated more pronounced responses. A direct effect of leptin on Ds was shown in CEHs cultured in vitro. Expression and activity of D1 were increased, whereas those of D3 were decreased, in leptin-treated cells. These data suggest that in ovo leptin administration improves early posthatch growth, in a gender-specific fashion, probably through improving hepatic activation of THs and up-regulating hepatic expression of GHR and IGF-I. PMID- 21679773 TI - Cytotoxicity measurement in in vitro chromosome aberration test and micronucleus test. PMID- 21679775 TI - Analysis of mammalian fatty acyl-coenzyme A species by mass spectrometry and tandem mass spectrometry. AB - Acyl-CoAs are intermediates of numerous metabolic processes in eukaryotic cells, including beta-oxidation within mitochondria and peroxisomes, and the biosynthesis/remodeling of lipids (e.g. mono-, di-, and triglycerides, phospholipids and sphingolipids). Investigations of lipid metabolism have been advanced by the ability to quantitate acyl-CoA intermediates via liquid chromatography coupled to electrospray ionization-tandem mass spectrometric detection (LC-ESI-MS/MS), which is presently one of the most sensitive and specific analytical methods for both lipids and acyl-CoAs. This review of acyl CoA analysis by mass spectrometry focuses on mammalian samples and long-chain analytes (i.e. palmitoyl-CoA), particularly reports of streamlined methodology, improved recovery, or expansion of the number of acyl chain-lengths amenable to quantitation. PMID- 21679774 TI - DNA repair during in utero development: a review of the current state of knowledge, research needs, and potential application in risk assessment. AB - Exposure to genotoxic chemicals during in utero development may lead to outcomes such as altered gene transcription, mutations, or cell death. Ultimately, such exposures may result in cancer, malformations, or functional deficits. As a mechanism that can limit the impact of genotoxicants in adults, DNA repair may also be an important factor that determines the outcome of the conceptus. This review of the literature examines the current understanding of DNA repair during in utero mammalian development by investigating the importance of maintaining genomic integrity and factors affecting susceptibility, including DNA repair. Most data have been derived from studies in rodent models focusing on DNA repair gene expression, which can vary according to developmental stages, tissues, and DNA repair pathways. Gene expression information is limited for humans but is suggestive that the major repair pathways exist during in utero development. Due to the complexities of DNA repair and its regulation by other pathways, available gene expression data may be limited for clarifying the role of DNA repair as a mechanism controlling the response to in utero exposures to genotoxicants. While not a comprehensive dataset, functional studies assessing in utero DNA repair capacity do demonstrate the variable ability of fetal tissue to remove DNA damage. Data gaps are recognized and recommendations for additional research using stems cells and traditional embryo models are identified. Finally, a brief discussion focuses on how data regarding in utero DNA repair may ultimately be utilized in health risk assessments of genotoxic chemicals. PMID- 21679776 TI - Current strategies in the management of intra-abdominal abscesses in Crohn's disease. AB - Crohn's disease is characterized by inflammation that involves the full thickness of the bowel wall, which can lead to serious complications including intra abdominal and pelvic abscesses. The combination of an intra-abdominal abscess with active Crohn's disease poses a particular dilemma for the treating physician, who must weigh the benefits of using immunosuppressive therapies for the inflammatory bowel disease against the risks of immunosuppression in the presence of serious abdominal infection. Traditionally, Crohn's-related abscesses were managed with early surgery, which often involved external drainage procedures, bowel resection, and the creation of diverting ostomies in acutely ill patients. Today such abscesses often can be managed initially with antibiotics and percutaneous drainage, with evaluation for the need for delayed surgery in selected patients. With delayed surgery performed electively, the surgeon frequently can resect the diseased bowel and create a primary anastomosis, thus avoiding emergency operations and multistage procedures. In highly selected cases, surgery might be avoided entirely. This report reviews the literature on the pathophysiology and management of intra-abdominal abscesses in Crohn's disease (including the roles of percutaneous drainage, immunosuppressive therapy, and surgery), and provides a suggested approach to the management of patients with this difficult problem. PMID- 21679772 TI - Type 2 deiodinase at the crossroads of thyroid hormone action. AB - Thyroid hormone action can be customized on a cell-specific fashion through the controlled action of the deiodinase group of enzymes, which are homodimeric thioredoxin fold containing selenoproteins. Whereas the type II deiodinase (D2) initiates thyroid hormone signaling by activating the pro-hormone thyroxine (T4) to the biologically active T3 molecule, the type III deiodinase (D3) terminates thyroid hormone action by catalyzing the inactivation of both T4 and T3 molecules. Deiodinases play a role in thyroid hormone homeostasis, development, growth and metabolic control by affecting the intracellular levels of T3 and thus gene expression on a cell-specific basis. Whereas both Dio2 and Dio3 are transcriptionally regulated, ubiquitination of D2 is a switch mechanism that controls D2 activity and intracellular T3 production. The hedgehog-inducible WSB 1 and the yeast Doa10 mammalian ortholog TEB4 are two E3 ligases that inactivate D2 via ubiquitination. Inactivation involves disruption of the D2:D2 dimer and can be reversed via two ubiquitin-specific proteases, USP20 and USP33, rescuing catalytic activity and T3 production. The ubiquitin-based switch mechanism that controls D2 activity illustrates how different cell types fine-tune thyroid hormone signaling, making D2 a suitable target for pharmacological intervention. This article reviews the cellular and molecular aspects of D2 regulation and the current models of D2-mediated thyroid hormone signaling. PMID- 21679777 TI - Decreased heat shock protein 27 expression and altered autophagy in human cells harboring A8344G mitochondrial DNA mutation. AB - Mitochondrial DNA (mtDNA) mutations are responsible for human neuromuscular diseases caused by mitochondrial dysfunction. Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a maternally inherited mitochondrial encephalomyopathy with various syndromes involving both muscular and nervous systems. The most common mutation in MERRF syndrome, A8344G mutation in mtDNA, has been associated with severe defects in protein synthesis. This defect impairs assembly of complexes in electron transport chain and results in decreased respiratory function of mitochondria. In this study, we showed a significant decrease of the heat shock protein 27 (Hsp27) in lymphoblastoid cells derived from a MERRF patient and in cybrid cells harboring MERRF A8344G mutation. However, normal cytoplasmic distributions of Hsp27 and normal heat shock responses were observed in both wild type and mutant cybrids. Furthermore, overexpression of wild type Hsp27 in mutant MERRF cybrids significantly decreased cell death under staurosporine (STS) treatment, suggesting a protective function of Hsp27 in cells harboring the A8344G mutation of mtDNA. Meanwhile, reverse transcriptase PCR showed no difference in the mRNA level between normal and mutant cybrids, indicating that alterations may occur at the protein level. Evidenced by the decreased levels of Hsp27 upon treatment with proteasome inhibitor, starvation and rapamycin and the accumulation of Hsp27 upon lysosomal inhibitor treatment; Hsp27 may be degraded by the autophagic pathway. In addition, the increased formation of LC3-II and autophagosomes was found in MERRF cybrids under the basal condition, indicating a constitutively-activated autophagic pathway. It may explain, at least partially, the faster turnover of Hsp27 in MERRF cybrids. This study provides information for us to understand that Hsp27 is degraded through the autophagic pathway and that Hsp27 may have a protective role in MERRF cells. Regulating Hsp27 and the autophagic pathway might help develop therapeutic solutions for treatment of MERRF syndrome in the future. PMID- 21679778 TI - Effects of hemiplegy on pulmonary function and diaphragmatic dome displacement. AB - We evaluated the diaphragmatic excursion, volumetric measurement, maximal inspiratory pressure (PI(max)), lung function tests (forced vital capacity-FVC, forced expiratory volume in the first second-FEV1, mean forced expiratory flow between 25 and 75% of the FVC maneuver-FEF(25-75%), peak expiratory flow-PEF and maximal voluntary ventilation-MVV), displacement of the domes diaphragmatics with ultrasonography and inspiratory capacity, the MAS scale (Motor Assessment Scale) in 20 hemiplegic patients volunteers and eight controls. In right-side hemiplegia, movement was 4.97 +/- 0.78 cm and 4.20 +/- 1.45 cm for the right and left domes of the diaphragm, respectively, whereas these values were 4.42 +/- 0.92 cm and 4.66 +/- 1.17 cm in left-side hemiplegia. PI(max) was -48.75 +/- 27.5 cmH2O in right-side hemiplegic patients and -74.17 +/- 13.57 cmH2O in left-side hemiplegic patients. Right-side hemiplegia exhibited greater impairment of the respiratory muscles than left-side hemiplegia due to the physiologic positioning of the domes of the diaphragm which may be compromised for hemiplegia. PMID- 21679779 TI - Emerging indications for percutaneous cholecystostomy for the management of acute cholecystitis--a retrospective review. AB - Acute cholecystitis is a frequent cause of general surgical admissions with a mortality risk that is related to the age of the patient. Percutaneous cholecystostomy (PC) has been used as a bridging technique while awaiting resolution of sepsis. We evaluated the outcome of our study population following percutaneous cholecystostomy for acute cholecystitis due to benign etiologies. METHODS: Retrospective review of patients undergoing PC from January 1988 to December 2008. Patients were reviewed for demographic features, co-morbidity, resolution of symptoms, hospital stay, outcome, complications and ASA class. RESULTS: 62 patients underwent PC for acute cholecystitis. 49 patients had calculous cholecystitis. 61% (n = 38) were >= 60 years old. 92% had resolution of symptoms within 48 h, and 8% had partial or no resolution. 84% had a decline in total leucocyte counts. The mean hospital stay was 10.6 days and 30-day mortality was 15%. 69% patients had no post-procedure complication. Of the remainder, 1 patient had post-procedure hemorrhage and the remaining developed complications that included pneumonia, hypotension and vasovagal reactions. The duration of drainage ranged from 1 to 3 months. 3 patients underwent emergency cholecystectomy during the same admission, 20 patients underwent interval cholecystectomy. 22 patients had no further intervention and had no recurrent symptoms, of these 73% (n = 16) had calculous cholecystitis. In this sub-group of non-operated patients, 76% were ASA III & IV. CONCLUSIONS: PC is a low risk management option for high risk patients with acute cholecystitis. It can be used as a temporizing measure while awaiting resolution of sepsis and optimization of co-morbidities, or as a definitive therapeutic option for acalculous cholecystitis. We also conclude that it has a good potential to be used as a definitive therapy for high risk (ASAIII & IV) patients with acute calculous cholecystitis. PMID- 21679781 TI - miRNA cassettes in viral vectors: problems and solutions. AB - The discovery of RNA interference (RNAi), an evolutionary conserved gene silencing mechanism that is triggered by double stranded RNA, has led to tremendous efforts to use this technology for basic research and new RNA therapeutics. RNAi can be induced via transfection of synthetic small interfering RNAs (siRNAs), which results in a transient knockdown of the targeted mRNA. For stable gene silencing, short hairpin RNA (shRNA) or microRNA (miRNA) constructs have been developed. In mammals and humans, the natural RNAi pathway is triggered via endogenously expressed miRNAs. The use of modified miRNA expression cassettes to elucidate fundamental biological questions or to develop therapeutic strategies has received much attention. Viral vectors are particularly useful for the delivery of miRNA genes to specific target cells. To date, many viral vectors have been developed, each with distinct characteristics that make one vector more suitable for a certain purpose than others. This review covers the recent progress in miRNA-based gene-silencing approaches that use viral vectors, with a focus on their unique properties, respective limitations and possible solutions. Furthermore, we discuss a related topic that involves the insertion of miRNA target sequences in viral vector systems to restrict their cellular range of gene expression. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. PMID- 21679780 TI - Protein nitrotryptophan: formation, significance and identification. AB - Reactive nitrogen species are formed during a variety of disease states and have been shown to modify several amino acids on proteins. To date, the majority of research in this area has focused on the nitration of tyrosine residues to form 3 nitrotyrosine. However, emerging evidence suggests that another modification, nitration of tryptophan residues, to form nitrotryptophan (NO(2)-Trp), may also play a significant role in the biology of nitrosative stress. This review takes an in-depth look at NO(2)-Trp, presenting the current research about its formation, prevalence and biological significance, as well as the methods used to identify NO(2)-Trp-modified proteins. Although more research is needed to understand the full biological role of NO(2)-Trp, the data presented herein suggest a contribution to nitrosative stress-induced cell dysregulation and perhaps even in physiological cell processes. PMID- 21679782 TI - Comparison and usefulness of cardiac magnetic resonance versus computed tomography in infants six months of age or younger with aortic arch anomalies without deep sedation or anesthesia. AB - The present project investigated whether cardiac magnetic resonance (CMR) of aortic arch anomalies can be performed successfully in infants <6 months of age without the use of cardiac anesthesia or deep sedation. We performed a retrospective review of infants <=6 months old from 2005 to 2009 who underwent either CMR or computed tomography angiography to investigate aortic arch abnormalities. The CMR procedure used a "feed and swaddle" protocol without deep sedation or cardiac anesthesia. Of the 52 infants referred for CMR, 24 underwent the feed and swaddle protocol (aged 2.6 +/- 1.4 months). One patient awoke during the study, and examination of the remaining 23 yielded a definitive diagnosis (success rate 96%). The scanning time was 6.2 +/- 3.1 minutes, with the large airways evaluation accounting for 1/2 the time. Single-shot axial steady-state free precession, in which the definitive diagnosis was made, accounted for 0.59 +/- 0.3 minutes. Fifteen infants were diagnosed with a vascular ring. Of the 8 infants who underwent surgery, the diagnostic accuracy was 100%. During the same period, 19 patients, who had undergone computed tomography angiography (aged 1.67 +/- 1.20 months), were referred for aortic arch evaluation. Of these 19 patients, 6 (32%) underwent sedation or anesthesia. The imaging time was 0.08 +/- 0.06 minutes, significantly different from the CMR times (p <0.01). However, the overall room times (31.3 +/- 22.3 and 35.8 +/- 3.86 minutes, respectively) were not different between the CMR and angiographic groups. The radiation dose was 1.41 +/- 1.03 mSv. In conclusion, CMR evaluation of aortic arch anomalies in children <6 months old can be successfully completed quickly using a feed and swaddle approach with high diagnostic accuracy. This protocol avoids the risks of sedation, as well as the radiation associated with computed tomography angiography. PMID- 21679783 TI - African American race/ethnicity and risk of post-operative atrial fibrillation. PMID- 21679784 TI - Mental models of Boolean concepts. AB - Negation, conjunction, and disjunction are major building blocks in the formation of concepts. This article presents a new model-based theory of these Boolean components. It predicts that individuals simplify the models of instances of concepts. Evidence corroborates the theory and challenges alternative accounts, such as those based on minimal descriptions, algebraic complexity, or structural invariance. A computer program implementing the theory yields more accurate predictions than these rival accounts. Two experiments showed that the numbers of models of a Boolean concept predict the difficulty of formulating a description of it. As mental models may also underlie deductive reasoning, the present theory integrates two hitherto separate areas of investigation. PMID- 21679785 TI - Antibacterial therapy and newer agents. Preface. PMID- 21679786 TI - Pathogens resistant to antibacterial agents. AB - Resistance to antimicrobial drugs is increasing at an alarming rate among both gram-positive and gram-negative bacteria. Traditionally, bacteria resistant to multiple antimicrobial agents have been restricted to the nosocomial environment. A disturbing trend has been the recent emergence and spread of resistant pathogens in nursing homes, in the community, and in the hospital. This article reviews the epidemiology, molecular mechanisms of resistance, and treatment options for pathogens resistant to antimicrobial drugs. PMID- 21679787 TI - Use of antibacterial agents in renal failure. AB - This article provides background information on the pharmacokinetics of antibacterial agents in patients who have normal and impaired renal function. Tables are provided to allow quick determination of appropriate dosages for varying degrees of renal failure. The use of serum levels; newer strategies for cefazolin, vancomycin and aminoglycoside dosing; methods of dialysis and associated antibiotics dosage adjustments, and antibiotic toxicity in renal failure are reviewed. PMID- 21679788 TI - Topical antibacterial agents. AB - Decreased systemic toxicity, ease of application, and increased concentrations at the target site are some of the important advantages topical antibacterial agents offer. This article reviews the literature on selected indications for these agents and provides in-depth examination of specific agents for the prophylaxis and treatment of skin and wound infections. PMID- 21679789 TI - Antibiotics for gram-positive bacterial infection: vancomycin, teicoplanin, quinupristin/dalfopristin, oxazolidinones, daptomycin, telavancin, and ceftaroline. AB - An overview of the mechanism of action, dosing, clinical indications, and toxicities of the glycopeptide vancomycin is provided. The emerging gram-positive bacterial resistance to antimicrobials and its mechanisms are reviewed. Strategies to control this emergence of resistance are expected to be proposed. Newer antimicrobial agents that have activity against vancomycin-resistant organisms are now available and play a critical role in the treatment of life threatening infections. PMID- 21679790 TI - Newer beta-lactam antibiotics: doripenem, ceftobiprole, ceftaroline, and cefepime. AB - This article reviews the new beta-lactam (beta-lactam) antibiotics doripenem, ceftobiprole, and ceftaroline. It covers pharmacokinetic and pharmacodynamic properties, dosing, in vitro activities, safety, and clinical trial results. Doripenem (Doribax) has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal and urinary tract infections. Ceftaroline has received FDA approval for the treatment of skin and soft tissue infections and community acquired pneumonia. Ceftobiprole has not received FDA approval. The article also reviews recent data suggesting increased overall mortality with Cefepime (Maxipime) use compared with other beta-lactam antibiotics and the potential risk for neurotoxicity in the setting of renal failure. PMID- 21679791 TI - Review of macrolides (azithromycin, clarithromycin), ketolids (telithromycin) and glycylcyclines (tigecycline). AB - The advanced macrolides, azithromycin and clarithromycin, and the ketolide, telithromycin, are structural analogs of erythromycin. They have several distinct advantages when compared with erythromycin, including enhanced spectrum of activity, more favorable pharmacokinetics and pharmacodynamics, once-daily administration, and improved tolerability. Clarithromycin and azithromycin are used extensively for the treatment of respiratory tract infections, sexually transmitted diseases, and Helicobacter pylori-associated peptic ulcer disease. Telithromycin is approved for the treatment of community-acquired pneumonia. Severe hepatotoxicity has been reported with the use of telithromycin. PMID- 21679792 TI - The newer fluoroquinolones. AB - Clinicians have enthusiastically used fluoroquinolones owing to their good safety profile and wide range of indications. This article reviews fluoroquinolone pharmacology, pharmacodynamic principles, and fluoroquinolone resistance mechanisms, highlighting recent trends in the epidemiology of fluoroquinolone resistance among gram-negative organisms and Streptococcus pneumonia. Important fluoroquinolone safety concerns are discussed, along with indications for the most commonly used fluoroquinolones--ciprofloxacin, levofloxacin, and moxifloxacin. PMID- 21679793 TI - Current use for old antibacterial agents: polymyxins, rifamycins, and aminoglycosides. AB - This article reviews three classes of antibacterial agents that are uncommonly used in bacterial infections and therefore can be thought of as special-use agents. The polymyxins are reserved for gram-negative bacilli that are resistant to virtually all other classes of drugs. Rifampin is used therapeutically, occasionally as a companion drug in treatment of refractory gram-positive coccal infections, especially those involving foreign bodies. Rifaximin is a new rifamycin that is a strict enteric antibiotic approved for treatment of traveler's diarrhea and is showing promise as a possible agent for refractory Clostridium difficile infections. The aminoglycosides are used mainly as companion drugs for the treatment of resistant gram-negative bacillary infections and for gram-positive coccal endocarditis. PMID- 21679795 TI - Wound management in a patient with rhinophyma and basal cell carcinoma. PMID- 21679796 TI - Photodynamic therapy for the treatment of cutaneous sarcoidosis. PMID- 21679797 TI - ANCA-positive necrotizing vasculitis and thrombotic vasculopathy induced by levamisole-adulterated cocaine: a distinctive clinicopathologic presentation. PMID- 21679798 TI - Metastatic basal cell carcinoma from a small tumor with lymphatic invasion. PMID- 21679799 TI - A novel phenotype with features of basal cell nevus syndrome and basaloid follicular hamartoma syndrome. PMID- 21679800 TI - Grover disease with a contagious twist. PMID- 21679801 TI - Angioedema-type swelling and herpes simplex virus reactivation following hyaluronic acid injection for lip augmentation. PMID- 21679802 TI - Erythema gyratum repens without associated malignancy. PMID- 21679803 TI - Sweet syndrome: adverse drug reaction or novel manifestation of HIV-associated immune reconstitution inflammatory syndrome? PMID- 21679804 TI - An unusual presentation of Buschke-Ollendorff syndrome. PMID- 21679805 TI - Sequential development of eczematous type "multiple drug allergy" to unrelated drugs. PMID- 21679807 TI - Determinants of unfavorable presentation of primary cutaneous melanoma. PMID- 21679808 TI - Papular elastorrhexis and Buschke-Ollendorff syndrome are different entities. PMID- 21679809 TI - Melanoma-associated retinopathy: a presenting sign of metastatic disease. PMID- 21679810 TI - Calcinosis cutis: part I. Diagnostic pathway. AB - Calcinosis cutis is characterized by the deposition of insoluble calcium salts in the skin and subcutaneous tissue. The syndrome is separated into five subtypes: dystrophic calcification, metastatic calcification, idiopathic calcification, iatrogenic calcification, and calciphylaxis. Dystrophic calcification appears as a result of local tissue damage with normal calcium and phosphate levels in serum. Metastatic calcification is characterized by an abnormal calcium and/or phosphate metabolism, leading to the precipitation of calcium in cutaneous and subcutaneous tissue. Idiopathic calcification occurs without any underlying tissue damage or metabolic disorder. Skin calcification in iatrogenic calcinosis cutis is a side effect of therapy. Calciphylaxis presents with small vessel calcification mainly affecting blood vessels of the dermis or subcutaneous fat. Disturbances in calcium and phosphate metabolism and hyperparathyroidism can be observed. PMID- 21679811 TI - Calcinosis cutis: part II. Treatment options. AB - Because calcinosis cutis is a rare syndrome, there is a notable lack of controlled clinical trials on its treatment. The efficacy of calcinosis treatment has only been reported in single cases or small case series. No treatment has been generally accepted as standard therapy, although various treatments have been reported to be beneficial, including warfarin, bisphosphonates, minocycline, ceftriaxone, diltiazem, aluminium hydroxide, probenecid, intralesional corticosteroids, intravenous immunoglobulin, curettage, surgical excision, carbon dioxide laser, and extracorporeal shock wave lithotripsy. PMID- 21679812 TI - Irradiance is an important determinant of pain experienced during topical photodynamic therapy. PMID- 21679813 TI - Proper classification of surgical wounds. PMID- 21679815 TI - Iron deficiency and hair loss--nothing new? PMID- 21679817 TI - Left-sided excess of melanoma occurrence but not of other skin cancers: additional evidence. PMID- 21679818 TI - Left-sided excess of invasive cutaneous melanoma. PMID- 21679820 TI - Is tenderness a reliable predictor for differentiating squamous cell carcinomas from actinic keratoses? PMID- 21679821 TI - Psoralen plus ultraviolet A light may be associated with clearing of peripheral blood disease in advanced cutaneous T-cell lymphoma. PMID- 21679822 TI - Podoconiosis: an experience from Tigray, Northern Ethiopia. PMID- 21679823 TI - Evaluation of the pituitary-adrenal axis function in patients on topical steroid therapy. PMID- 21679824 TI - Childhood bullous pemphigoid: a rare manifestation of chronic renal allograft rejection. PMID- 21679825 TI - Treatment of a giant squamous cell carcinoma on the dominant thumb with intralesional 5-fluorouracil. PMID- 21679826 TI - Squamous cell carcinomas of the lower limbs in African American women. PMID- 21679827 TI - Ectopic facial Hailey-Hailey disease. PMID- 21679828 TI - Imatinib mesylate for aggressive systemic mastocytosis with long bone osteolysis. PMID- 21679829 TI - Newly diagnosed Ehlers-Danlos syndrome in an adult with elastosis perforans serpiginosa. PMID- 21679830 TI - Severe ulcerative panniculitis caused by alpha 1-antitrypsin deficiency: remission induced and maintained with intravenous alpha 1-antitrypsin. PMID- 21679831 TI - Fox-Fordyce disease in monozygotic female twins. PMID- 21679832 TI - Cutaneous lymphoid hyperplasia related to squaric acid dibutyl ester. PMID- 21679833 TI - Evaluation of skin atrophy associated with linear atrophoderma of Moulin by ultrasound imaging. PMID- 21679834 TI - Retiform hemangioendothelioma treated with Mohs micrographic surgery. PMID- 21679835 TI - Disseminated fusarium infection with muscle involvement. PMID- 21679836 TI - Metastatic cutaneous squamous cell carcinoma responding to erlotinib therapy. PMID- 21679837 TI - Hemorrhagic parallel-ridge pattern on dermoscopy in "Playstation fingertip". PMID- 21679838 TI - Crohn's disease and cheilitis granulomatosa: role of silicone fillers. PMID- 21679839 TI - Fatal rhino-orbito-cerebral mucormycosis in a patient with liver disease. PMID- 21679840 TI - Painful generalized erythematous patches: a severe and unusual cutaneous reaction to pemetrexed. PMID- 21679841 TI - Cutaneous Churg-Strauss syndrome: response to dapsone therapy. PMID- 21679842 TI - Severe scombroid fish poisoning: an underrecognized dermatologic emergency. PMID- 21679843 TI - Pigmented mammary Paget disease positive for melanocytic markers. PMID- 21679844 TI - Consequences of systemic absorption of topical glucocorticoids. PMID- 21679845 TI - Introduction: Analysing global health assistance: the reach for ethnographic, institutional and political economic scope. PMID- 21679847 TI - Noncompaction cardiomyopathy and multiple coronary arterioventricular fistulae: 1 or 2 distinct disease entities? PMID- 21679848 TI - Adiposopathy is "sick fat" a cardiovascular disease? AB - Being overweight or obese is a worldwide epidemic. Adiposity can cause fat mass related cardiovascular disease (CVD). Adiposity may also cause adipocyte and adipose tissue anatomic and functional abnormalities, termed adiposopathy (adipose-opathy) or "sick fat," that result in endocrine and immune derangements. Adiposopathy may directly contribute to CVD through pericardiac and perivascular effects on the myocardium and blood vessels. Adiposopathy may also indirectly contribute to CVD through promoting or worsening major CVD risk factors such as type 2 diabetes mellitus, high blood pressure, and dyslipidemia. Despite CVD being the most common cause of mortality among overweight individuals, the pathophysiologic relationship between adiposity and CVD is often thought mysterious, as evidenced by "obesity paradoxes." Underlying this uncertainty are suggestions that excessive body fat does not always increase the risk of CVD and, in some cases, may actually decrease such risks. These paradoxical findings are made less paradoxical when the pathogenic potential of excessive body fat is assessed based on adipose tissue dysfunction rather than simply on increased fat mass alone. This introductory review 1) provides a brief historical perspective of the pathogenic potential of adipose tissue; 2) describes the relationships between adipose tissue (histology, embryology, and adipogenesis) and cardiovascular medicine; 3) outlines the anatomic, functional, endocrine, and immune manifestations of adiposopathy; and 4) describes the importance of cross talk and/or interactions of adipose tissue with other body tissues. Finally, this review describes how "sick fat" helps account for various clinical obesity/cardiovascular paradoxes, supporting adiposopathy as a cardiovascular disease. PMID- 21679849 TI - Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. AB - OBJECTIVES: This study sought to investigate the evolving pattern over time of on clopidogrel platelet reactivity (PR) and its relationship with genotype and clinical outcomes after percutaneous coronary intervention. BACKGROUND: Whether on-clopidogrel PR and role of genotype differ over time is unknown. METHODS: On clopidogrel PR before percutaneous coronary intervention, and 1 and 6 months thereafter via VerifyNow P2Y12 (Accumetrics Inc., San Diego, California), CYP2C19*2, *17, CYP3A5*3, and ABCB1 polymorphisms were evaluated in 300 patients. Death, stroke, myocardial infarction, and bleedings were assessed up to 1 year. RESULTS: On-clopidogrel PR varied significantly over time, being higher at baseline than at 1 and 6 months after. From baseline to 1 month, 83 of 300 patients varied their response status. This was mainly due to baseline poor responders becoming full responders (75 of 83). Genotype justifies roughly 18% of this trend. CYP2C19*2 and *17 influence on PR was consistent over time, whereas that of ABCB1 appeared of greater impact at baseline. On-clopidogrel PR at 1 month independently best predicts ischemic and bleeding events. We found a therapeutic window (86 to 238 P2Y12 reactivity units) with a lower incidence of both ischemic and bleeding complications. A risk score was created by combining genotype (ABCB1 and CYP2C19*2), baseline PR, and creatinine clearance to predict 1-month poor responsiveness and 1-year poor prognosis. CONCLUSIONS: In patients at steady state for clopidogrel undergoing percutaneous coronary intervention, PR decreases from baseline to 1 month. Genotype influences ~18% of this trend. On clopidogrel PR at 1 month is the strongest predictor of adverse outcomes, and this can be predicted by combining genotype to baseline phenotype and clinical variables. PMID- 21679850 TI - Unraveling myths of platelet function and genetic testing the road to making tailored antiplatelet therapy a reality. PMID- 21679851 TI - Clinical strategies and outcomes in advanced heart failure patients older than 70 years of age receiving the HeartMate II left ventricular assist device: a community hospital experience. AB - OBJECTIVES: The primary objective of this study was to determine outcomes in left ventricular assist device (LVAD) patients older than age 70 years. BACKGROUND: Food and Drug Administration approval of the HeartMate II (Thoratec Corporation, Pleasanton, California) LVAD for destination therapy has provided an attractive option for older patients with advanced heart failure. METHODS: Fifty-five patients received the HeartMate II LVAD between October 5, 2005, and January 1, 2010, as part of either the bridge to transplantation or destination therapy trials at a community hospital. Patients were divided into 2 age groups: >= 70 years of age (n = 30) and < 70 years of age (n = 25). Outcome measures including survival, length of hospital stay, adverse events, and quality of life were compared between the 2 groups. RESULTS: Pre-operatively, all patients were in New York Heart Association functional class IV refractory to maximal medical therapy. Kaplan-Meier survival for patients >= 70 years of age (97% at 1 month, 75% at 1 year, and 70% at 2 years) was not statistically different from patients <7 0 years of age (96% 1 month, 72% at 1 year, and 65% at 2 years, p = 0.806). Average length of hospital stay for the >= 70-year age group was 24 +/- 15 days, similar to that of the < 70-year age group (23 +/- 14 days, p = 0.805). There were no differences in the incidence of adverse events between the 2 groups. Quality of life and functional status improved significantly in both groups. CONCLUSIONS: The LVAD patients >= 70 years of age have good functional recovery, survival, and quality of life at 2 years. Advanced age should not be used as an independent contraindication when selecting a patient for LVAD therapy at experienced centers. PMID- 21679852 TI - Imaging of the aortic valve using fluorodeoxyglucose positron emission tomography increased valvular fluorodeoxyglucose uptake in aortic stenosis. AB - OBJECTIVES: Because fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provides a noninvasive index of inflammation, we sought to assess whether FDG uptake in the aortic valve (AV) is increased in aortic stenosis (AS). BACKGROUND: AS is associated with valvular inflammation. METHODS: FDG PET/computed tomography data were retrospectively evaluated in 84 patients (age 73 +/- 9 years, 45% female), 42 patients with AS, and 42 age-matched controls. FDG uptake was determined within the AV while blinded to AS severity. Target-to background ratio (TBR) was calculated as valvular/blood activity. Stenosis severity was established on echocardiography, and presence of AV calcification was independently assessed on computed tomography. RESULTS: The aortic valve PET signal (TBR) was increased in AS compared with controls (median 1.53 [interquartile range (IQR): 1.42 to 1.76] vs. 1.34 [IQR: 1.20 to 1.55]; p < 0.001). Further, compared with controls, TBR was increased in mild (median 1.50 [IQR: 1.36 to 1.75]; p = 0.01) and moderate (median 1.70 [IQR: 1.52 to 1.94]; p < 0.001), but not in severe AS (median 1.49 [IQR: 1.40 to 1.54]; p = 0.08). When subjects were categorized according to AV calcification, valvular FDG uptake was increased in mildly (median 1.50 [IQR: 1.36 to 1.79]; p < 0.01) and moderately (median 1.67 [IQR: 1.50 to 1.85]; p < 0.001), but not severely calcified valves (median 1.51 [IQR: 1.38 to 1.54]; p = 0.15), compared with noncalcified valves (median 1.35 [IQR: 1.20 to 1.52]). CONCLUSIONS: This study supports the hypothesis that AS is an inflammatory condition and suggests that inflammation may be reduced in late-stage disease. This may have important implications in the design of studies assessing the effect of therapeutic agents in modifying progression of AS. PMID- 21679853 TI - Two-dimensional intravascular near-infrared fluorescence molecular imaging of inflammation in atherosclerosis and stent-induced vascular injury. AB - OBJECTIVES: This study sought to develop a 2-dimensional (2D) intravascular near infrared fluorescence (NIRF) imaging strategy for investigation of arterial inflammation in coronary-sized vessels. BACKGROUND: Molecular imaging of arterial inflammation could provide new insights into the pathogenesis of acute myocardial infarction stemming from coronary atheromata and implanted stents. Presently, few high-resolution approaches can image inflammation in coronary-sized arteries in vivo. METHODS: A new 2.9-F rotational, automated pullback 2D imaging catheter was engineered and optimized for 360 degrees viewing intravascular NIRF imaging. In conjunction with the cysteine protease-activatable imaging reporter Prosense VM110 (VisEn Medical, Woburn, Massachusetts), intra-arterial 2D NIRF imaging was performed in rabbit aortas with atherosclerosis (n =10) or implanted coronary bare-metal stents (n = 10, 3.5-mm diameter, day 7 post-implantation). Intravascular ultrasound provided coregistered anatomical images of arteries. After sacrifice, specimens underwent ex vivo NIRF imaging, fluorescence microscopy, and histological and immunohistochemical analyses. RESULTS: Imaging of coronary artery-scaled phantoms demonstrated 8-sector angular resolution and submillimeter axial resolution, nanomolar sensitivity to NIR fluorochromes, and modest NIRF light attenuation through blood. High-resolution NIRF images of vessel wall inflammation with signal-to-noise ratios >10 were obtained in real time through blood, without flushing or occlusion. In atherosclerosis, 2D NIRF, intravascular ultrasound-NIRF fusion, microscopy, and immunoblotting studies provided insight into the spatial distribution of plaque protease activity. In stent-implanted vessels, real-time imaging illuminated an edge-based pattern of stent-induced arterial inflammation. CONCLUSIONS: A new 2D intravascular NIRF imaging strategy provides high-resolution in vivo spatial mapping of arterial inflammation in coronary-sized arteries and reveals increased inflammation regulated cysteine protease activity in atheromata and stent-induced arterial injury. PMID- 21679855 TI - Color doppler flows of corkscrew collaterals in Thromboangiitis obliterans (Buerger's disease) using color duplex ultrasonography. PMID- 21679854 TI - Disruption of platelet-derived growth factor-dependent phosphatidylinositol 3 kinase and phospholipase Cgamma 1 activity abolishes vascular smooth muscle cell proliferation and migration and attenuates neointima formation in vivo. AB - OBJECTIVES: We tested the hypothesis whether selective blunting of platelet derived growth factor (PDGF)-dependent vascular smooth muscle cell (VSMC) proliferation and migration is sufficient to prevent neointima formation after vascular injury. BACKGROUND: To prevent neointima formation and stent thrombosis after coronary interventions, it is essential to inhibit VSMC proliferation and migration without harming endothelial cell function. The role of PDGF-a potent mitogen and chemoattractant for VSMC that does not affect endothelial cells-for neointima formation remains controversial. METHODS: To decipher the signaling pathways that control PDGF beta receptor (betaPDGFR)-driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/betaPDGFR mutants in which the binding sites for betaPDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase Cgamma 1 [PLCgamma]) were individually mutated. Based on in vitro results, the importance of PDGF-initiated signals for neointima formation was investigated in genetically modified mice. RESULTS: Our results indicate that the chemotactic response to PDGF requires the activation of Src, PI3K, and PLCgamma, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLCgamma. These 2 signaling molecules contribute to signal relay of the betaPDGFR by differentially regulating cyclin D1 and p27(kip1). Blunting of betaPDGFR induced PI3K and PLCgamma signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF dependent PI3K and PLCgamma signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury. CONCLUSIONS: Signaling by the activated betaPDGFR, particularly through PI3K and PLCgamma, is crucial for neointima formation after vascular injury. Disruption of these specific signaling pathways is sufficient to attenuate pathogenic processes such as vascular remodeling in vivo. PMID- 21679856 TI - Manuscript revision. PMID- 21679858 TI - Prognostic value of cardiac computed tomography angiography. PMID- 21679857 TI - Elevation of parathyroid hormone levels in atrial fibrillation. PMID- 21679861 TI - Alcohol consumption and risk of atrial fibrillation. PMID- 21679862 TI - Bullous skin diseases. PMID- 21679863 TI - From pemphix to desmogleins. AB - In the not so distant past, the word pemphigus or pemphix was common for describing various diseases characterized by blistering as well as various disorders that do not originate from a blistering pathology. Patients with these conditions were grouped in "other" skin diseases. Step by step, during the past, we were introduced to these severe conditions. First, we learned from sporadic case reports, then new differentiations were reported according to histology, later immunopathology was developed, and now there are discoveries of new molecules. Immense progress with new approaches to therapy has been achieved, but much improvement is still needed. The modern definition of pemphigus undoubtedly represents a group of rare, intraepidermal autoimmune bullous diseases characterized by intraepidermal blisters and circulating autoantibodies desmogleins against the keratinocytes cell surface. PMID- 21679864 TI - Immune functions of the skin. AB - The skin, the body's largest organ, helps to secure the integrity of the host and, at the same time, allows the individual to communicate with the outside world. This finely tuned balance between protection from harmful pathogens (mostly microorganisms) and bidirectional signal exchange is provided by a network of structural, cellular, and molecular elements that are collectively referred to as the skin barrier. This "gateway" has a physical, chemical, and immunologic component. The role of the latter is to elicit a powerful defense reaction in the case of danger and, at the same time, to prevent such a reaction against innocuous substances. Immune responses originating in the skin are mounted and executed by cells and molecules of the innate or the adaptive immune system. Innate reactions are typically rapid, poorly discriminating, and do not exhibit memory. Adaptive responses, in contrast, show a high degree of specificity as well as memory but need a protracted time for their development. As a consequence, innate and adaptive responses are consecutive events influencing each other. In fact, we now know that the type and magnitude of the innate reactions govern and often determine the quality and quantity of adaptive responses. PMID- 21679865 TI - Autoimmune blistering diseases: histologic meaning. AB - The histologic picture of intraepidermal and subepidermal autoimmune bullous dermatoses is presented. Histologic changes are described according to the temporal evolution of lesions, with special reference to crucial elements of the histologic differential diagnosis. The diagnosis of autoimmune bullous dermatoses is complex, mostly requiring additional immunofluorescence assays along with histoclinical correlation to detect the antibodies or target antigen by the methods of molecular biology or immunohistochemistry. Additional tests to reach an accurate diagnosis in various autoimmune bullous dermatoses are briefly described, emphasizing the need of proper integration of all clinical and laboratory data. Although frequently inadequately specific, the histologic finding provides a link between clinical findings and target molecular studies in autoimmune bullous dermatoses. PMID- 21679866 TI - Significance of immunofluorescence in the diagnosis of autoimmune bullous dermatoses. AB - Direct immunofluorescence study remains the diagnostic gold standard in the assessment of patients with bullous disorders, despite novel immunoserologic tests such as enzyme-linked immunosorbent assay and immunoblotting. This contribution provides an update of the classification of autoimmune bullous diseases and diagnostic procedures, with an emphasis on immunofluorescence findings. PMID- 21679867 TI - Molecular organization of the basement membrane zone. AB - The dermal-epidermal basement membrane is a complex assembly of proteins that provide adhesion and regulate many important processes such as development, wound healing, and cancer progression. This contribution focuses on the structure and function of individual components of the basement membrane, how they assemble together, and how they participate in human tissues and diseases, with an emphasis on skin involvement. Understanding the composition and structure of the basement membrane provides insight into the pathophysiology of inherited blistering disorders, such as epidermolysis bullosa, and acquired bullous diseases, such as the pemphigoid group of autoimmune diseases and epidermolysis bullosa acquisita. PMID- 21679868 TI - Ultrastructure and molecular pathogenesis of epidermolysis bullosa. AB - Epidermolysis bullosa (EB) is classified into the three major subtypes depending on the level of skin cleavage within the epidermal keratinocyte or basement membrane zone. Tissue separation occurs within the intraepidermal cytoplasm of the basal keratinocyte, through the lamina lucida, or in sublamina densa regions of the basal lamina (basement membrane) in EB simplex, junctional EB, and dystrophic EB, respectively. Transmission electron microscopy (TEM) is an effective method for determining the level of tissue separation and hemidesmosome (HD) and anchoring fibril morphology if performed by experienced operators, and has proven to be a powerful technique for the diagnosis of new EB patients. Recent advances in genetic and immunofluorescence studies have enabled us to diagnose EB more easily and with greater accuracy. This contribution reviews TEM findings in the EB subtypes and discusses the importance of observations in the molecular morphology of HD and basement membrane associated structures. PMID- 21679869 TI - Molecular genetic assays for inherited epidermolysis bullosa. AB - Epidermolysis bullosa (EB) is a heterogeneous group of genetic disorders, characterized by blistering of skin and mucosal membranes under normal mechanical stress conditions. The clinical phenotype ranges from mild localized to severe generalized disease with secondary extracutaneous symptoms and premature death. The lives of the patients and their families are marked by this disorder, causing severe physical, psychologic, and material burdens. The four major EB types are classified by the level of skin blistering, but more than 30 subtypes can be distinguished, according to clinical and molecular genetic criteria. So far, mutations in 14 genes are known to cause different EB subtypes. The diagnosis of the EB subtype is essential for the prognosis, genetic counseling, and prenatal diagnosis. Because the symptoms are often overlapping or not specific, the diagnosis of the EB type is usually not possible by clinical criteria or routine histologic examination. Immunofluorescence analysis of skin sections with antibodies to proteins of the basement membrane zone is the first diagnostic step to indicate the level of skin split and the missing protein. Mutation analysis indicates the precise cause of the disease, the affected gene, and the inheritance pattern. PMID- 21679870 TI - Adhesion molecules in keratinocytes. AB - Adhesion molecules are proteins on the cell surface that are involved in the interactions between lymphocytes and antigen-presenting cells, especially in inflammatory skin diseases and autoimmune bullous disorders. Adhesion molecules include cadherins (subgroups E, N, P, M), integrins, selectins, and the immunoglobulin gene family. Cadherins E in the epidermis including desmocollin 1 and 2 and desmoglein 1 and 3 are essential transmembrane components of desmosome glycoproteins, which play a major role in bullous diseases, pemphigus in particular. Also important are integrin beta 1 alpha 1 and other integrins, which connect ligands of the collagen, laminin, and fibronectin. Selectins (E, P) are important for leukocyte migration on endothelial cells. Adhesion molecules from the immunoglobulin superfamily (intercellular adhesion molecule-1, 3 [ICAM-1,3]; vascular adhesion molecule-1 [VCAM-1]) have significant roles in the immune and inflammatory mechanisms. PMID- 21679871 TI - Pemphigus group (vulgaris, vegetans, foliaceus, herpetiformis, brasiliensis). AB - Pemphigus is a rare autoimmune bullous disorder involving the skin and mucosa. The disease has a chronic course. It is characterized histologically by an intraepidermal cleavage and the production of pathogenic antibodies directed against different proteins of the desmosomes, which belong to the cadherin family. The diagnosis of the type of pemphigus is made on clinical features, the level of histologic cleavage, and the identification of the antigens recognized by circulating autoantibodies using immunoblot or ELISA analysis of serum. The epidemiology and clinical, histologic, and immunologic findings of pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, and pemphigus herpetiformis are described. PMID- 21679872 TI - IgA pemphigus. AB - Pemphigus is a life-threatening autoimmune blistering disease. Pemphigus is divided into 4 major types; pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, and IgA pemphigus. Among them, IgA pemphigus is characterized by tissue-bound and circulating IgA antibodies targeting desmosomal or nondesmosomal cell surface components in the epidermis. Histopathologically, slight epidermal acantholysis and extensive neutrophilic infiltration in either the upper part or all layers of the epidermis were observed. IgA pemphigus is subdivided into intraepidermal neutrophilic IgA dermatosis-type (IEN-type), whose target antigen is still unknown (probably nondesmosomal cell surface protein), and subcorneal pustular dermatosis-type (SPD-type), whose target antigen is desmocollin 1 (Dsc1). We summarize reported cases of IgA pemphigus and describe current knowledge including epidemiology, clinical manifestations, pathology, laboratory tests, pathophysiology, associated diseases, prognosis and treatment, and future perspectives of IgA pemphigus. PMID- 21679873 TI - Oral involvement in autoimmune bullous diseases. AB - The oral mucosa is frequently involved by autoimmune bullous diseases and often this is the first site of manifestation. In this site the lesions are very similar, making the clinical diagnosis difficult; therefore, the definition of the immunohistopathologic characteristics of each one becomes essential for a differential diagnosis. The authors review the clinical-pathological and therapeutic aspect of these oral injuries in order to help in the diagnosis, treatment and prognosis of the oral conditions of those diseases. PMID- 21679874 TI - Drug-induced pemphigus. AB - Pemphigus is an autoimmune bullous disease that may be influenced by genetic and exogenous factors. Drugs are a leading cause of pemphigus. There is a need for a thorough history taking so as to find the culprit medication. The diagnosis of drug-induced pemphigus is challenging. Patients have often been exposed to multiple drugs, and some drugs may have a prolonged latency period between exposure and onset of the disease. The in vitro interferon-gamma (IFN-gamma) release from lymphocytes test has been shown to be of diagnostic value in drug induced skin reactions. Cessation of the offending drug may alleviate the clinical manifestations and reduce the need for medical treatment. PMID- 21679875 TI - Chocolate and acne: how valid was the original study? PMID- 21679876 TI - Maimonides: part 1--The man and his writings. PMID- 21679877 TI - The sitting statue of Vargas. AB - Medicine and health care in Venezuela have had a roller coaster evolution in parallel with advances and retreats of democracy and of efforts to modernize. The most prominent of the founding fathers of Venezuelan medicine has a sitting statue in the homonymous hospital. After a blossoming of medicine, health care, and research led by dermatology that lasted for nearly four decades, the system went into a tailspin that mirrors what took place in the governmental institutions and in the economy. The statue of Vargas seems to warn Venezuelans that if the decay goes too far, it may become irreversible. PMID- 21679878 TI - Micronutrient supplementation for critically ill adults: a systematic review and meta-analysis. AB - OBJECTIVE: This systematic review assessed the effects of micronutrient supplementation on adults recovering from critical illness. Primary outcomes included clinical endpoints (mortality, infectious complications, length of intensive care unit and of hospital stay). Secondary outcomes included descriptions of practice issues, micronutrient status, morbidity, course of the acute-phase response, and oxidative stress. METHODS: Electronic bibliographic databases, bibliographies of retrieved articles, and personal files were searched and reviewed. Randomized controlled trials (RCTs) of micronutrient supplementation in adult critically ill patients administered enterally and/or parenterally in addition to their routine care were included. Two authors independently extracted data and assessed trial quality. The random-effects model was used to estimate overall relative risk (RR)/mean difference and effect size. P<0.05 was considered statistically significant. RESULTS: Fifteen (n=1714) and 18 (n=1849) RCTs were included for the primary and secondary objectives, respectively. Fourteen trials (n=1468) showed a statistically significant decrease in overall mortality (RR 0.78, 95% confidence interval 0.67-0.90, I2=0%, P=0.0009). Six RCTs (n=1194) indicated a statistically significant decrease in 28 d mortality (RR 0.75, 95% confidence interval 0.63-0.88, I2=0%, P=0.0006). Micronutrient supplementation was not associated with a decrease in infectious complications, length of intensive care unit, or length of hospital stay. In subgroup analyses, a sensitivity analysis of combined micronutrients indicated a significant decrease in mortality (RR 0.69, 95% confidence interval 0.54-0.90, I2=2%, P=0.006). The secondary outcomes confirmed that timing, duration, and dosing appear to be key factors to ensure optimal clinical benefit. CONCLUSION: This review does suggest a potential benefit of micronutrient supplementation in critically ill adults by possibly being associated with a decrease in mortality. PMID- 21679879 TI - The salt debate--more salacious than salubrious. PMID- 21679880 TI - What increased consumption of licorice may reveal in anorexia nervosa. PMID- 21679883 TI - Evolution of the arthropod nervous system. PMID- 21679881 TI - On the move toward evidence-based symptom management guidelines. PMID- 21679884 TI - Morphology of the brain in Hutchinsoniella macracantha (Cephalocarida, Crustacea). AB - External morphological features of Cephalocarida have long been interpreted as plesiomorphic with regard to those of other crustaceans. Based on transmission electron microscopy and light microscopy, however, the brain in the cephalocarid Hutchinsoniella macracantha has been shown to contain a number of structures that are more difficult to interpret in an evolutionary context. These include the multi-lobed complex, a unique cluster of neuropils associated with the olfactory lobes. To establish a well-founded comparison of phylogenetically relevant, neuroanatomical data from Cephalocarida to other arthropods, we investigated the brain in H. macracantha using immunolabeling (acetylated alpha-tubulin, serotonin, RFamide, histamine) and nuclear counter stains of whole mounts and vibratome sections analyzing specimens with confocal laser scanning microscopy and computer-aided 3D-reconstruction. Other 3D-reconstructions were based on serial 1 MUm semi-thin sections. The multi-lobed complex features a pedunculus and shows detailed homologies with the mushroom bodies of certain Insecta and Lithobiomorpha (Chilopoda), suggesting that the hemiellipsoid bodies in Remipedia and Malacostraca have derived from a cephalocarid-like pattern. Like the corresponding tracts in Insecta, the olfactory globular tracts linking the multi lobed complex to the olfactory lobes are ipsilateral, probably constituting the plesiomorphic pattern from which the decussating tracts in Remipedia and Malacostraca have evolved. The olfactory lobes in H. macracantha are uniquely organized into vertical stacks of olfactory glomeruli whose exact shape could not be identified. Similarly to Malacostraca and Insecta, the olfactory glomeruli in H. macracantha are innervated by serotonin-like, RFamide-like, and histamine-like immunoreactive interneurons. This suggests homology of the olfactory lobes across Tetraconata, despite the different morphological organization. Although H. macracantha lacks elongated, unpaired midline neuropils known from the protocerebrum of other Arthropoda, the possible rudiment of a central-body-like neuropil that receives decussating fibers from anterior somata was revealed by the serotonin-like immunoreactive pattern. PMID- 21679885 TI - Infections exotic and ectopic, and everyday practice. PMID- 21679886 TI - Review of vector-borne diseases in Hong Kong. AB - The epidemiology of vector-borne diseases in Hong Kong has changed over the past decade but still poses a significant public health risk. We provided a comprehensive review of the epidemiological information and analysed the trends of major vector-borne diseases, including the vector situation in Hong Kong. The incidence of malaria has dropped dramatically in the past few decades and is now mainly an imported disease acquired from malaria endemic countries. Locally acquired dengue fever occurred in 2002 and 2003, and thereafter all cases were imported, mainly from Southeast Asia areas. Only a few local cases of Japanese encephalitis were reported in the past decade. In contrast, there is a notable increase in scrub typhus and spotted fever cases. The emergence of chikungunya fever in Asia and Indian Ocean countries also resulted in importation of human cases. Given the heavy traffic between this international city and other parts of the world, as well as the presence of vectors in this densely populated area, vigilance should be maintained against these infections. Comprehensive public health measures encompassing disease surveillance, vector surveillance and control measures with support from all sectors of the community are required to combat the old and newly emerging vector-borne diseases in Hong Kong. PMID- 21679887 TI - The viruses of Australia and the risk to tourists. AB - Australia is a climatically diverse country varying from a tropical climate in the north to arid central desert and grassland regions, and to temperate climates in the south. There are many viral infections found in Australia that are common to developed countries worldwide, but this article will focus on those that pose a special risk for travellers to Australia, especially the mosquito-borne viruses. The commonest are the members of the alphavirus genus, particularly Ross River virus and Barmah Forest virus, which cause predominantly arthralgia with or without fever or rash. Less frequent but more serious illness is seen with the encephalitic flaviviruses, Murray Valley encephalitis virus, and the Kunjin strain of West Nile virus. In addition dengue occurs intermittently on the northern part of Queensland, and in recent years Japanese encephalitis virus has been found in the Torres Strait Islands and the tip of far north Queensland. Also of interest, but with a much lower risk, are the bat-borne viruses, Hendra virus and Australian bat lyssavirus, that have caused a small number of human infections. However, it is important to remember that most tourists pass through other countries in the Asia/Pacific region on their way to and from Australia and may therefore have acquired infections prior to or after leaving Australia. PMID- 21679888 TI - Advances in diabetes information. PMID- 21679889 TI - Mitral and tricuspid annular velocities in constrictive pericarditis and restrictive cardiomyopathy: correlation with pericardial thickness on computed tomography. AB - OBJECTIVES: The aims of this study were to: 1) compare early diastolic mitral annular velocity (E') of septal annulus (SE') with E' of lateral mitral annulus (LE') and right lateral tricuspid annulus (RE') in patients with constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM); and 2) assess the relationship between pericardial thickness measured by computed tomography and lateral E' velocity. BACKGROUND: The SE' velocity has been shown to be able to distinguish CP from RCM. However, tissue Doppler parameters of LE' and RE' velocities in patients with CP have not been comprehensively analyzed in comparison with SE'. Moreover, the impact of pericardial thickness on the lateral annulus velocity has not been assessed. METHODS: Thirty-seven patients with CP, 35 patients with RCM, and 70 normal controls were evaluated with echocardiography including SE', LE', and RE'. In CP, the maximal pericardial thicknesses on both left and right ventricle were measured by computed tomography. RESULTS: Mean LE'/SE' (ratio between mitral LE' and SE') was 0.94 +/- 0.17 and RE'/SE' (ratio between tricuspid RE' and mitral SE') was 0.81 +/- 0.26 in patients with CP, which were lower than those in normal controls (LE'/SE' 1.36 +/- 0.24; RE'/SE' 1.30 +/- 0.32; both p<0.001) and patients with RCM (LE'/SE' 1.35 +/- 0.31; RE'/SE' 1.96 +/- 0.71; both p < 0.001). There was a significant inverse correlation between right pericardial thickness and RE' (rho=-0.489; p=0.002) and similar trend between left pericardial thickness and LE' (rho=-0.284; p=0.089). CONCLUSIONS: The ratio between lateral and septal E' was significantly reduced in patients with CP compared with that in normal control patients and patients with RCM so that the reduced ratios of LE'/SE' and RE'/SE' appear to be a useful diagnostic parameter for CP. Moreover, reduced lateral E' was correlated with the pericardial thickness on their respective sides. PMID- 21679890 TI - Annular velocities in constrictive pericarditis: annulus and beyond. PMID- 21679891 TI - Real-time 3D transesophageal echocardiography for the evaluation of rheumatic mitral stenosis. AB - OBJECTIVES: The aims of this study were: 1) to assess the feasibility and reliability of performing mitral valve area (MVA) measurements in patients with rheumatic mitral valve stenosis (RhMS) using real-time 3-dimensional transesophageal echocardiography (3DTEE) planimetry (MVA(3D)); 2) to compare MVA(3D) with conventional techniques: 2-dimensional (2D) planimetry (MVA(2D)), pressure half-time (MVA(PHT)), and continuity equation (MVA(CON)); and 3) to evaluate the degree of mitral commissural fusion. BACKGROUND: 3DTEE is a novel technique that provides excellent image quality of the mitral valve. Real-time 3DTEE is a relatively recent enhancement of this technique. To date, there have been no feasibility studies investigating the utility of real-time 3DTEE in the assessment of RhMS. METHODS: Forty-three consecutive patients referred for echocardiographic evaluation of RhMS and suitability for percutaneous mitral valvuloplasty were assessed using 2D transthoracic echocardiography and real-time 3DTEE. MVA(3D), MVA(2D), MVA(PHT), MVA(CON), and the degree of commissural fusion were evaluated. RESULTS: MVA(3D) assessment was possible in 41 patients (95%). MVA(3D) measurements were significantly lower compared with MVA(2D) (mean difference: -0.16 +/- 0.22; n=25, p<0.005) and MVA(PHT) (mean difference: -0.23 +/- 0.28 cm(2); n=39, p<0.0001) but marginally greater than MVA(CON) (mean difference: 0.05 +/- 0.22 cm(2); n=24, p=0.82). MVA(3D) demonstrated best agreement with MVA(CON) (intraclass correlation coefficient [ICC] 0.83), followed by MVA(2D) (ICC 0.79) and MVA(PHT) (ICC 0.58). Interobserver and intraobserver agreement was excellent for MVA(3D), with ICCs of 0.93 and 0.96, respectively. Excellent commissural evaluation was possible in all patients using 3DTEE. Compared with 3DTEE, underestimation of the degree of commissural fusion using 2D transthoracic echocardiography was observed in 19%, with weak agreement between methods (kappa<0.4). CONCLUSIONS: MVA planimetry is feasible in the majority of patients with RhMS using 3DTEE, with excellent reproducibility, and compares favorably with established methods. Three-dimensional transesophageal echocardiography allows excellent assessment of commissural fusion. PMID- 21679892 TI - Assessment of mitral stenosis: role of real-time 3D TEE. PMID- 21679893 TI - Differences in Fabry cardiomyopathy between female and male patients: consequences for diagnostic assessment. AB - OBJECTIVES: We hypothesized that Fabry cardiomyopathy in female patients might differ substantially from that in male patients and sought to prove this hypothesis in a large cohort consisting of 104 patients with Fabry disease. BACKGROUND: Fabry cardiomyopathy in male patients is characterized by left ventricular (LV) hypertrophy, impaired myocardial function, and subsequent progressive myocardial fibrosis. In contrast, the occurrence of these 3 cardiomyopathic hallmarks in female patients remains unknown. METHODS: In 104 patients (58 females, age 42 +/- 16 years; 46 males, age 42 +/- 13 years) with genetically proven Fabry disease, LV hypertrophy, regional myocardial deformation and myocardial fibrosis were assessed by standard echocardiography, strain rate imaging, and cardiac magnetic resonance (CMR) imaging-guided late enhancement (LE). RESULTS: In men, end-diastolic left ventricular wall thickness (LVWT) ranged from 6 to 19.5 mm (LV mass CMR 55 to 200 g/m(2)), and LE was never seen with LVWT <12 mm (LV mass <99 g/m(2)). In contrast in female patients, LVWT ranged from 5 to 15.5 mm, LV mass ranged from 39 to 146 g/m(2), and LE was already detectable with an LVWT of 9 mm (LV mass 56 g/m(2)). When LV mass was examined in CMR, LE was detected in 23% of the female patients without hypertrophy (n=9), whereas LE was never seen in male patients with normal LV mass. LE was always associated with low systolic strain rate, but the severity of impairment was independent of LVWT in female patients (lateral strain rate in patients with LV hypertrophy with LE -0.7 +/- 0.2 s(-1); patients without LV hypertrophy with LE -0.8 +/- 0.2 s(-1); p=0.45). CONCLUSIONS: In contrast to male patients, the loss of myocardial function and the development of fibrosis do not necessarily require myocardial hypertrophy in female patients with Fabry disease. Thus, in contrast to actual recommendations, initial cardiac staging and monitoring should be based on LV hypertrophy and on replacement fibrosis in female patients with Fabry disease. PMID- 21679894 TI - High-pitch thoracic CT with simultaneous assessment of coronary arteries: effect of heart rate and heart rate variability on image quality and diagnostic accuracy. AB - OBJECTIVES: The aim of this study was to evaluate the mean heart rate and heart rate variability (HRV) required for diagnostic imaging of the coronary arteries simultaneously with thoracic computed tomography for noncardiac purposes, applying a high-pitch spiral image acquisition protocol for computed tomography angiography (CTA) using a dual-source system. BACKGROUND: For the primary prevention of coronary heart disease, screening methods to identify currently asymptomatic people who are at high risk for developing coronary heart disease are essential. Coronary CTA can rule out coronary artery stenoses with high negative predictive value. METHODS: High-pitch thoracic computed tomography was performed in 111 consecutive patients (mean age 60.2 +/- 11.5 years; range 37 to 81 years) using a dual-source system (2 * 128 0.6-mm sections, 38.4-mm collimation width, 0.28-s rotation time). Data acquisition was prospectively electrocardiographically triggered at 60% of the R-R interval using a pitch of 3.2. Image quality was evaluated using a 3-point scale (1=excellent, 2=moderate, 3=poor). RESULTS: Close interobserver agreement for image quality scores of 1,998 evaluated coronary segments was found (kappa=0.93). Image quality was of diagnostic value in 828 of 1,739 segments (47.6%). In 29 of 111 patients (26%), diagnostic image quality was observed for all segments. Average heart rate and HRV were significantly (p<0.001) higher in patients with at least 1 nondiagnostic coronary segment compared with those without. All patients with mean heart rates <64 beats/min and HRV <13 beats/min had diagnostic image quality in all coronary segments. Effective radiation dose for thoracic CTA was 1.9 +/- 0.66 mSv. The mean scan time was 0.9 +/- 0.1 s. CONCLUSIONS: Simultaneous evaluation of coronary arteries in high-pitch dual-source CTA of the thorax for noncardiac purposes is consistently diagnostic in patients with low heart rates and HRV, whereas most patients not receiving beta-blockers had at least 1 segment that was not diagnostic because of heart rate and HRV. Beta blockers are recommended if there are no contraindications and coronary interpretation is anticipated. PMID- 21679895 TI - Peri-infarct zone on early contrast-enhanced CMR imaging in patients with acute myocardial infarction. AB - OBJECTIVES: The aims of this study were to evaluate hyperenhanced regions on contrast-enhanced cardiovascular magnetic resonance (CE-CMR) imaging in patients with acute myocardial infarction (AMI) between early contrast-enhanced cardiovascular magnetic resonance (ECE) (2 min) and late contrast-enhanced cardiovascular magnetic resonance (LCE) (10 to 15 min) after gadolinium administration, and to compare the CE-CMR images with area at risk (AAR) derived from T2-weighted (T2W) CMR. BACKGROUND: Although CE-CMR imaging can demarcate the infarcted myocardium, the value of hyperenhancement in AMI is still in dispute. The size of hyperenhanced regions may vary with time, and overestimation can be often observed with early acquisition. METHODS: Thirty-four patients with successfully reperfused AMI underwent CMR within 4 days after the event. Myocardial regions as percentage of left ventricular (LV) myocardium were quantified on CE and T2W images. Relative peri-infarct zone was calculated as the difference in hyperenhanced regions between ECE and LCE, normalized to the individual infarct size. RESULTS: Both ECE and LCE images revealed hyperenhancement in the territory of the infarct-related artery in all patients. The hyperenhanced region on ECE extended transmurally and was consistently larger than that on LCE (39 +/- 12% vs. 27 +/- 12% of LV myocardium, p<0.001). The relative peri-infarct zone was inversely correlated with the transmurality of infarction (r=-0.59, p<0.001) and the time from symptom to reperfusion (r=-0.46, p<0.01). The hyperenhanced region on ECE was correlated with the T2W CMR-derived AAR (r=0.86, p<0.001) with the average difference of -0.8% and the limits of agreement of +/-11.9%. CONCLUSIONS: ECE depicts ischemically injured but salvaged myocardium, as well as infarcted myocardium in patients with AMI. The myocardium at risk and infarcted myocardium after reperfusion can be retrospectively assessed by the combination of ECE and LCE. PMID- 21679896 TI - Gadolinium can depict area at risk and myocardial infarction: a double-edged sword? PMID- 21679897 TI - Physical activity in older subjects is associated with increased coronary vasodilation: the ADVANCE study. AB - OBJECTIVES: We investigated the association between physical activity and coronary vasodilation to nitroglycerin (NTG) in the ADVANCE (Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology) cohort of older healthy subjects. BACKGROUND: Physical activity may exert its beneficial effects by augmenting coronary responsiveness to nitric oxide. The relationship between physical activity and coronary vasodilatory response to NTG, an exogenous nitric oxide donor, has not been studied in a community-based population with typical activity levels. METHODS: In 212 older adults (ages 60 to 72 years) without cardiovascular disease, we measured the coronary vasodilatory response to NTG using magnetic resonance angiography and physical activity using the Stanford Seven-Day Physical Activity Recall Questionnaire. The primary predictor measure was total physical activity (kcal/kg/day). The primary outcome measure was coronary vasodilatory response (percent increase of cross-sectional area post NTG). RESULTS: Coronary vasodilation was 27.6% in more active subjects (>35 kcal/kg/day, e.g., 1 h of walking per day) compared to 18.9% in less active subjects (p=0.03). Regression analysis showed a significant positive correlation between coronary vasodilation and physical activity (p=0.003), with a slope (beta) of 1.2% per kcal/kg/day. This finding remained significant after adjustment for cardiac risk factors, coronary calcium, the use of vasoactive or statin medications, and analysis of physical activity by quintiles (p < 0.05). Coronary vasodilation was also associated with physical activity intensity (p = 0.03). CONCLUSIONS: In an asymptomatic, community-based cohort of older adults, increased coronary vasodilatory response was independently associated with greater physical activity, supporting the benefits of exercise on the order of 1 h of walking per day. PMID- 21679898 TI - Do imaging studies performed in physician offices increase downstream utilization?: an empiric analysis of cardiac stress testing with imaging. AB - OBJECTIVES: The goal of this study was to compare patterns of downstream testing and procedures after stress testing with imaging performed at physician offices versus at hospital-outpatient facilities BACKGROUND: Stress testing with imaging has grown dramatically in recent years, but whether the location of where the test is performed correlates with different patterns for subsequent cardiac testing and procedures is unknown METHODS: We identified 82,178 adults with private health insurance from 2005 to 2007 who underwent ambulatory myocardial perfusion imaging (MPI) or stress echocardiography (SE). Subsequent MPI, SE, cardiac catheterization or revascularization within 6 months was compared between physician office and hospital outpatient settings. RESULTS: Overall, 85.1% of MPI and 84.9% of SE were performed in physician offices. The proportion of patients who underwent subsequent MPI, SE, or cardiac catheterization was not statistically different between physician office and hospital outpatient settings for MPI (14.2% vs. 13.9%, p=0.44) or SE (7.9% vs. 8.6%, p=0.21). However, patients with physician office imaging had slightly higher rates of repeat MPI within 6 months compared with hospital-outpatient imaging for both index MPI (3.5% vs. 2.0%, p<0.001) and SE (3.4% vs. 2.1%, p<0.001), and slightly lower rates of cardiac catheterization after index MPI (11.4% vs. 12.2%, p=0.04) and SE (4.5% vs. 7.0%, p<0.001). Differences in 6-month utilization were observed across the 5 healthcare markets after index MPI but not after index SE CONCLUSIONS: Physician office imaging is associated with slightly higher repeat MPI and fewer cardiac catheterizations than hospital outpatient imaging, but no overall difference in the proportion of patients undergoing additional further testing or procedures. Although regional variation exists, especially for MPI, the relationship between physician office location of stress testing with imaging and greater downstream resource utilization appears modest. PMID- 21679899 TI - Plaque characteristics of thin-cap fibroatheroma evaluated by OCT and IVUS. AB - OBJECTIVES: The purpose of this study was to assess plaque characteristics of optical coherence tomography (OCT)-derived thin-cap fibroatheroma (TCFA) by integrated backscatter intravascular ultrasound (IB-IVUS). BACKGROUND: Radiofrequency signal-derived IVUS tissue characterization technology has become clinically available and provided objective and quantitative plaque characteristics of the coronary vessel wall. Integrated backscatter IVUS is one of the tissue characterization methods that can possibly provide quantitative plaque characteristics of the OCT-derived TCFA. METHODS: Eighty-one coronary lesions with plaque burden >40% were selected and analyzed with both IB-IVUS and OCT. The OCT-derived TCFA was defined as a presence of thin fibrous cap (<65 MUm) overlying a signal-poor lesion with diffuse border representing a lipid-rich plaque. By conventional gray-scale IVUS, external elastic membrane (EEM) cross sectional area (CSA), lumen CSA, plaque plus media (P+M) CSA, plaque burden and remodeling index were measured. By IB-IVUS, plaque characteristics were further classified as fibrosis, dense fibrosis, calcification, or lipid pool. RESULTS: Optical coherence tomography identified 40 TCFAs (49%) and 41 non-TCFAs. The EEM CSA, P+M CSA, plaque burden, and remodeling index were significantly larger in OCT-derived TCFA than non-TCFA. By IB-IVUS, percentage lipid pool area (= lipid pool area/P+M CSA * 100) was significantly higher (62.4 +/- 12.8% vs. 38.4 +/- 13.1%, p<0.0001) and percentage fibrosis area (= fibrosis area/P+M CSA * 100) was significantly lower (34.6 +/- 11.4% vs. 50.5 +/- 8.7%, p<0.0001) in OCT-derived TCFA than non-TCFA. By receiver-operator characteristic curve analysis, percentage lipid pool area >=55%, percentage fibrosis area <=41%, and remodeling index >=1.0 were predictors of OCT-derived TCFA. CONCLUSIONS: The OCT-derived TCFA had larger plaque burden and positive remodeling with predominant lipid component and less fibrous plaque assessed by IB-IVUS. PMID- 21679900 TI - NIRS and IVUS for characterization of atherosclerosis in patients undergoing coronary angiography. AB - OBJECTIVES: The aim of this study was to compare the findings of near-infrared spectroscopy (NIRS), intravascular ultrasound (IVUS) virtual histology (VH), and grayscale IVUS obtained in matched coronary vessel segments of patients undergoing coronary angiography. BACKGROUND: Intravascular ultrasound VH has been developed to add tissue characterization to the grayscale IVUS assessment of coronary plaques. Near-infrared spectroscopy is a new imaging technique able to identify lipid core-containing coronary plaques (LCP). METHODS: We performed NIRS and IVUS-VH pullbacks in a consecutive series of 31 patients with a common region of interest (ROI) between 2 side branches. For each ROI, we analyzed the chemogram blocks by NIRS, plaque area and plaque burden by grayscale IVUS, and tissue types by IVUS-VH. The chemogram block is a summary metric of a 2-mm vertical slice of the chemogram. The value ranges from 0 to 1 according to the presence of lipids and represents the probability of LCP with a color scale from red (low probability) through orange and tan to yellow (high probability). RESULTS: Plaque area (mm(2)) increases as percentage VH derived-necrotic core (NC) content (4.6 +/- 2.7 vs. 7.4 +/- 3.5 vs. 8.6 +/- 3.4 vs. 7.9 +/- 3.3, grouped in percentage NC quartiles, p<0.001) and chemogram block probability color bin thresholds increase (4.9 +/- 3.8 red, 7.3 +/- 3.6 orange, 8.1 +/- 3.4 tan, and 8.7 +/- 3.4 yellow, p<0.001). The correlation between the block chemogram detection of lipid core and percentage NC content by VH was weak (r=0.149). Correction for the presence of calcium does not improve this correlation. CONCLUSIONS: Larger plaque area by grayscale IVUS was more often associated with either elevated percentage VH-NC or LCP by NIRS; however, the correlation between the detection of LCP by NIRS and necrotic core by VH is weak. PMID- 21679901 TI - Are our tools for the identification of TCFA ready and do we know them? PMID- 21679902 TI - Role of (99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. AB - OBJECTIVES: In a cohort of patients with hereditary transthyretin-related amyloidosis (ATTR), we aimed to assess the role of (99m)Tc-3,3-diphosphono-1,2 propanodicarboxylic acid ((99m)Tc-DPD) in detecting myocardial amyloid infiltration across a wide spectrum of cardiac involvement and in predicting major adverse cardiac events (MACE). BACKGROUND: Hereditary transthyretin-related amyloidosis is a challenging and underdiagnosed condition where both early diagnosis and prognosis remain problematic. METHODS: We evaluated 63 patients with ATTR: 40 with and 23 without echocardiographically diagnosed amyloidotic cardiomyopathy (AC). Myocardial uptake of (99m)Tc-DPD scintigraphy was semiquantitatively and visually assessed at 5 min and 3 h. RESULTS: All patients with AC showed moderate-to-severe myocardial tracer uptake (i.e., visual score >=2). Within the subgroup without AC, only 4 patients (with Ala36Pro, Gly47Ala, Thr49Ala, and Glu89Gln transthyretin mutations) showed myocardial tracer uptake and abnormal heart/whole body retention (H/WB) values: in all these cases endomyocardial biopsies showed amyloidotic infiltration. The H/WB was positively correlated with left ventricular (LV) mean wall thickness (Pearson's r=0.695, p<0.001) and negatively with LV ejection fraction (r=-0.368, p=0.004). The H/WB was an unfavorable predictor of MACE-free survival at Cox univariate analysis and contributed to the multivariate model. Notably, LV wall thickness >12 mm in combination with H/WB >7.5 was associated with the highest event rate. CONCLUSIONS: In ATTR, (99m)Tc-DPD scintigraphy can identify myocardial infiltration across a wide spectrum of morphologic/functional cardiac involvement, allowing an early diagnosis of the disease (even before the appearance of echocardiographic abnormalities). The (99m)Tc-DPD myocardial uptake is a prognostic determinant of "cardiac" outcome in ATTR, either alone or in combination with LV wall thickness. PMID- 21679903 TI - Quantification of myocardial segmental function in acute and chronic ischemic heart disease and implications for cardiovascular cell therapy trials: a review from the NHLBI-Cardiovascular Cell Therapy Research Network. AB - Global left ventricular (LV) ejection fraction (LVEF) has been used as a measure of improvement in LV function following cell therapy. Although the impact of cell therapy on LVEF in short- and long-term follow-up has been generally positive, there is concern that research evaluating regional therapeutics (e.g., cell or gene therapy) may require analysis of regional LV function localized to the site of intervention. Regional LV assessment is traditionally performed with qualitative or quantitative analysis of wall thickening within 16 myocardial segments, but advances in noninvasive imaging permit an increasingly more detailed and accurate evaluation of LV function. Wall-thickness measurements can now include evaluation of over 1,000 myocardial segments. In addition to higher resolution measures of wall thickening, automated assessments of myocardial segment deformation, such as strain imaging, exist. Strain imaging allows for direct evaluation of the mechanical properties that may improve following regional therapeutic intervention. Improvements in regional LV function may also be assessed by determining regional ejection fraction (EF). Regional EF offers the advantage of summarizing the end result of all of the complex deformations in the adjacent myocardial segments. Although regional EF and strain imaging, as compared with wall thickening, enhance detection of improvement in complex measures of regional myocardial function, it remains unclear whether such measures are better able to predict meaningful improvement in clinical outcomes. PMID- 21679904 TI - Contemporary imaging of the pericardium. PMID- 21679905 TI - Arch hypoplasia and aneurysm after aortic coarctation repair: abnormal flow may be the link. PMID- 21679906 TI - ARVC/D task force imaging criteria: it is difficult to get along with the guidelines. PMID- 21679907 TI - Systemic RV in hypoplastic left heart syndrome after surgical palliation. PMID- 21679908 TI - Acquiring multiple parameters from multiple tests: the real principle of multimodality imaging. PMID- 21679909 TI - Interarytenoid osseous bridge after prolonged endotracheal intubation. AB - Posterior glottic stenosis or interarytenoid fibrous adhesion is uncommon and has sometimes been misdiagnosed as cord paralysis. Laryngoscopy and laryngeal electromyography studies are the two main diagnostic aids. We present the case of a 63-year-old man under endotracheal intubation during 10 days after a cardiac procedure who was evaluated in our department for persistent dysphonia. The laryngoscopy showed a granuloma-like lesion in the posterior glottic space. During the microlaryngoscopy procedure, the osseous consistence of the interarytenoid lesion was observed. Laser surgery excision of the lesion was performed with good results. According to our review of the literature, this corresponds to the second case reported. PMID- 21679910 TI - Conditions of directed attention inhibit recognition performance for explicitly presented target-aligned irrelevant stimuli. AB - The fate of irrelevant and overtly presented stimuli that was temporally aligned with an attended target in a separate task was explored. Seitz and Watanabe (2003) demonstrated that if an irrelevant motion stimulus was implicit (i.e., subthreshold), a later facilitation for the same motion direction was observed if the previously presented implicit motion (of the same direction) was temporally aligned with the presence of an attended target. Later research, however, demonstrated that if the motion stimulus aligned with the attended target was explicit (i.e., suprathreshold), a later inhibition was observed (Tsushima, Seitz, & Watanabe, 2008). The current study expands on this by using more salient stimuli (words and pictures) in an inattentional blindness paradigm, and suggests that when attention is depleted, recognition for target-aligned task-irrelevant items is impaired in a subsequent recognition task. Participants were required to respond to either immediate picture, or word, repetitions in a stream of simultaneously presented line drawings and written words, and later given a surprise recognition test that measured recognition for the words or the pictures. When analyzing word recognition performance after attention had been directed to the pictures, words that had appeared simultaneously with a picture repetition in the repetition detection task were recognized at levels significantly below chance. The same inhibition was mirrored when testing for picture recognition after having attended to the words in the repetition detection task. These data suggest an inhibitory mechanism that is exhibited in later recognition tests for salient information that was previously unattended and had been simultaneously being presented with an attended target in a different task. PMID- 21679911 TI - Electro-optic properties of organic nanotubes. AB - In this review article the theoretical and experimental possibilities of applying EO-methods for estimation of the physico-chemical properties of the organic nanotubes (ONTs) are studied. The ONTs are highly organized nanostructures of strongly elongated, anysometric, and hollow cylinders with a size range of 1 nm to 10,000 nm, e.g. in aqueous solutions they could behave as colloid (disperse) particles. They have high interaction ability due to their extremely large curved, rolled-up external surfaces (bilayers of membrane walls) and unique properties because of their specific electric charge distribution and dynamics that make possible the functionalization of their surfaces. Thus they could template guestsubstances such as membrane proteins and protein complexes on the exterior surfaces and in the membrane. We performed our investigations for the case of ONT aqueous colloid suspension. Following our earlier proposition of the general expression for the electro-optic (EO) effect we derived equations for the evaluation of the electric properties of ONT particles such as mechanism of electric polarization and identification of their most important electric Dipole Moments (DM), permanent (pDM) and induced (iDMs). Further we recommend ways for the calculation of their magnitude and direction. Also we evaluated some geometrical properties such as length of the ONT particles and their polydispersity. The knowledge that we provided about the ONT properties may enable us to elucidate and predict their biological activity. Templating biological active ligands (such as membrane proteins and protein complexes) on the inner and outer surfaces as well as in the surface membrane creates their potential usefulness as carrier and deliverer of biopharmaceuticals in bio nanodevices. The theoretical equations were compared with the experimental data for ONTs such as (lipid) LNT, Tobacco Mosaic Virus (TMV) and microtubules (MT). Comparison of EO methods with other methods used till now shows that the EO methods are faster, not invasive and do not alter the studied particles. PMID- 21679913 TI - Should the routine physical examination include squat maneuvers? PMID- 21679914 TI - The morphologic characteristics of corneal nerves in advanced keratoconus as evaluated by acetylcholinesterase technique. AB - PURPOSE: To study the morphologic characteristics of corneal nerves in patients with advanced keratoconus using the acetylcholinesterase technique in corneal whole mounts. DESIGN: Prospective, observational case series. METHODS: Fourteen corneal buttons from 14 keratoconic patients (9 males and 5 females; mean age, 34.3 years) who had undergone keratoplasty for advanced keratoconus and 6 corneal buttons from 6 normal corneas were included. Whole mounts were stained for acetylcholinesterase and were scanned with a novel digital pathology scanning microscope. RESULTS: Seventy-one percent of keratoconic corneas demonstrated central stromal nerve changes, which included thickening, tortuosity, nerve spouting, and overgrowth. The nerve changes ranged from early to extensive and could be separated into 3 different grades. The central stromal nerves were abnormally thicker (18.9 +/- 14.7 MUm) than in controls (8.11 +/- 3.31 MUm; P < .001). The thickness of peripheral stromal nerves (12.6 +/- 3.1 MUm) was similar to that of controls (14.86 +/- 5.60 MUm; P = .072). Subbasal nerves showed changes in the form of loss of radial orientation and increased tortuosity, especially at the cone apex. At the cone base, a concentric arrangement of subbasal nerves was found in 43% of cases. Localized thickenings of subbasal nerves also were observed at their origin from the bulbous terminations of sub Bowman nerves. The terminal bulbs, too, were enlarged. The mean diameter of the subbasal nerves in keratoconus (4.11 +/- 0.60 MUm) did not differ from that of the controls (4.0 +/- 0.61 MUm; P = .422). CONCLUSIONS: This study provides additional histologic evidence of the involvement of corneal nerves in keratoconus and suggests further that they may play a role in the pathophysiologic factors and progression of the disease. PMID- 21679915 TI - Intraocular pressure, central corneal thickness, and glaucoma in chinese adults: the liwan eye study. AB - PURPOSE: To describe the distribution of central corneal thickness (CCT), intraocular pressure (IOP), and their determinants and association with glaucoma in Chinese adults. DESIGN: Population-based cross-sectional study. METHODS: Chinese adults aged 50 years and older were identified using cluster random sampling in Liwan District, Guangzhou. CCT (both optical [OCCT] and ultrasound [UCCT]), intraocular pressure (by Tonopen, IOP), refractive error (by autorefractor, RE), radius of corneal curvature (RCC), axial length (AL), and body mass index (BMI) were measured, and history of hypertension and diabetes (DM) was collected by questionnaire. Right eye data were analyzed. RESULTS: The mean values of OCCT, UCCT, and IOP were 512 +/- 29.0 MUm, 542 +/- 31.4 MUm, and 15.2 +/- 3.1 mm Hg, respectively. In multiple regression models, CCT declined with age (P < .001) and increased with greater RCC (P < .001) and DM (P = .037). IOP was positively associated with greater CCT (P < .001), BMI (P < .001), and hypertension (P < .001). All 25 persons with open-angle glaucoma had IOP <21 mm Hg. CCT did not differ significantly between persons with and without open- or closed-angle glaucoma. Among 65 persons with ocular hypertension (IOP >97.5th percentile), CCT (555 +/- 29 MUm) was significantly (P = .01) higher than for normal persons. CONCLUSIONS: The distributions of CCT and IOP in this study are similar to that for other Chinese populations, though IOP was lower than for European populations, possibly due to lower BMI and blood pressure. Glaucoma with IOP <21 mm Hg is common in this population. We found no association between glaucoma and CCT, though power (0.3) for this analysis was low. PMID- 21679917 TI - Upcoming female preponderance within surgery residents and the association of sex with the surgical career choice in the new millennium: results from a national survey in France. AB - BACKGROUND: Women are increasingly entering the medical studies. We aim to investigate surgical residents' career decision making among surgical residents and to assess the presence of women. METHODS: An "electronic questionnaire" of self-assessment was distributed to the 2,500 current French surgical residents. Items analyzed included population characteristics, demographics, educational experiences, and choice of career. RESULTS: There was a response rate of 31.2% (n = 779). The male/female ratio was 1.1 with 370 women (47.5%). The mean age was 28 +/- 2 years. All surgical specialties were represented. Sex was significantly associated with the choice of surgical specialty (P < .05). Female residents had a shorter working time per week than male residents (P < .001). Sex was significantly linked with future career plans as female residents expected to work in a public hospital (P = .005) and as male residents expected to work in private practice (P = .001). CONCLUSIONS: Female surgical residents are more populous than ever among surgical residents. Sex appears to be linked with where and how the residents expect to work in the future. PMID- 21679916 TI - Risk factors for four-year incidence and progression of age-related macular degeneration: the los angeles latino eye study. AB - PURPOSE: To identify risk factors for 4-year incidence and progression of age related macular degeneration (AMD) in adult Latinos. DESIGN: Population-based prospective cohort study. METHODS: Participants, aged 40 or older, from The Los Angeles Latino Eye Study (LALES) underwent standardized comprehensive ophthalmologic examinations at baseline and at 4 years of follow-up. Age-related macular degeneration was detected by grading 30-degree stereoscopic fundus photographs using the modified Wisconsin Age-Related Maculopathy Grading System. Multivariate stepwise logistic regression was used to examine the independent association of incidence and progression of AMD and baseline sociodemographic, behavioral, clinical, and ocular characteristics. RESULTS: Multivariate analyses revealed that older age (OR per decade of age: 1.52; 95% CI: 1.29, 1.85) and higher pulse pressure (OR per 10 mm Hg: 2.54; 95% CI: 1.36, 4.76) were independently associated with the incidence of any AMD. The same factors were associated with early AMD, soft indistinct drusen, and retinal pigmentary abnormalities. Additionally, presence of clinically diagnosed diabetes mellitus was independently associated with increased retinal pigment (OR: 1.66; 95% CI: 1.01, 2.85), and male gender was associated with retinal pigment epithelial depigmentation (OR 2.50; 95% CI: 1.48, 4.23). Older age (OR per decade of age: 2.20; 95% CI: 1.82, 2.67) and current smoking (OR: 2.85; 95% CI: 1.66, 4.90) were independently associated with progression of AMD. CONCLUSIONS: Several modifiable risk factors were associated with 4-year incidence and progression of AMD in Latinos. The results suggest that interventions aimed at reducing pulse pressure and promoting smoking cessation may reduce incidence and progression of AMD, respectively. PMID- 21679918 TI - Peritoneal fluid: a potential mechanism of systemic neutrophil priming in experimental intra-abdominal sepsis. AB - BACKGROUND: Recent studies suggest that peritoneal fluid (PF) may be an important mediator of inflammation. The aim of this study was to test the hypothesis that PF may drive systemic inflammation in intra-abdominal sepsis by representing a priming agent for neutrophils. METHODS: PF was collected 12 hours after the initiation of intra-abdominal sepsis in swine. Naive human neutrophils were primed with PF before treatment with N-formyl-Met-Leu-Phe or phorbol 12-myristate 13-acetate to elucidate receptor-dependent and receptor-independent mechanisms of neutrophil activation. Flow cytometry was used to quantify neutrophil surface adhesion marker expression of integrins and selectins and superoxide anion production. Additionally, proinflammatory cytokines were quantified in PF. RESULTS: PF primed neutrophils via receptor-dependent and receptor-independent mechanisms. There were significant increases in the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in PF correlating with the development of intra-abdominal sepsis. CONCLUSIONS: PF represents a priming agent for naive polymorphonuclear cells in intra-abdominal sepsis. This may be secondary to increased levels of proinflammatory cytokines. Strategies to reduce the amount of PF may decrease the systemic inflammatory response by reducing a priming agent for neutrophils. PMID- 21679919 TI - Endoscopic ultrasonography is useful for monitoring the tumor response of neoadjuvant chemoradiation therapy in esophageal squamous cell carcinoma. AB - BACKGROUND: Recently, neoadjuvant chemoradiation therapy (CRT) has been introduced for treatment of esophageal squamous cell carcinoma (ESCC). This study was performed to investigate the usefulness of endoscopic ultrasonography (EUS) in comparison with EUS findings before and after CRT, and histologic findings. METHODS: There were 33 patients with potentially resectable ESCC who underwent neoadjuvant CRT. Preoperative EUS and histologic findings were compared. EUS criteria were established on the basis of low and high echoic regions. Resected specimens were examined by hematoxylin-eosin, azan, and cytokeratin immunohistochemical staining. RESULTS: Azan and cytokeratin staining clearly delineated fibrous changes and residual tumor. Low echoic regions corresponded to residual tumor and high echoic spots corresponded to fibrosis. All 12 patients classified as grade 1 on EUS diagnosis had histologic grade 1 tumors. Nineteen of 21 cases that presented with high echo were grade 2 or 3. The prognosis according to EUS diagnosis was similar to the histologic effect. CONCLUSIONS: Preoperative EUS findings reflected the histologic effect after neoadjuvant CRT. EUS is a useful tool to assess the effect for CRT and to predict the prognosis in ESCC patients. PMID- 21679920 TI - Adrenocorticotropic hormone and cortisol response to corticotropin releasing hormone in the critically ill-a novel assessment of the hypothalamic-pituitary adrenal axis. AB - BACKGROUND: The pathophysiology of adrenal insufficiency, common in surgical intensive care units, has not been fully elucidated. METHODS: Patients at risk (age > 55 years, in the surgical intensive care unit >1 week, baseline cortisol < 20 MUg/dL) were enrolled. After measuring cortisol and adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH) was administered. ACTH and cortisol were measured over 120 minutes. Short and long cosyntropin stimulation tests determined adrenal function. Area under the curve (AUC) and mixed linear models were used to compare cortisol and ACTH responses. Patients were grouped according to survival and response to stimulation testing. Chi-square and t tests were performed, and P values < .05 were considered statistically significant. RESULTS: Six of 25 patients responded poorly to cosyntropin, and 5 died compared with 3 after a normal response (P < .01). ACTH (AUC) and ACTH peak were increased in nonsurvivors after CRH administration. Cortisol peak and AUC were not different. CONCLUSIONS: ACTH responsiveness was increased in nonsurvivors and may predict mortality. PMID- 21679921 TI - A randomized controlled trial of emergency treatment of bleeding esophageal varices in cirrhosis for hepatocellular carcinoma. AB - BACKGROUND: Ninety percent of patients with hepatocellular carcinoma (HCC) have cirrhosis. Bleeding esophageal varices (BEV) is a frequent complication of cirrhosis. Detection of HCC in cirrhotic patients with BEV has not been studied. METHODS: Two hundred eleven unselected patients with cirrhosis and BEV were randomized to endoscopic sclerotherapy (n = 106) or emergency portacaval shunt (n = 105). Diagnostic workup and treatment were initiated within 8 hours. Ninety-six percent had >10 years of follow-up. HCC screening involved serum alpha fetoprotein (AFP) every 3 months, ultrasonography every 6 months, and selective computed tomography (CT). RESULTS: HCC occurred in 15 patients, all incurable, a mean of 2.94 years after entry. They died a mean 1.33 years after discovery. Serial AFP and ultrasound examinations were unrevealing over a mean of 2.3 years. The mean model of end-stage liver disease score was 12.7 at entry and 17.4 at HCC diagnosis. CONCLUSIONS: Long-term screening by AFP and ultrasound plus selective CT failed to detect HCC at a curable stage. The detection of HCC in cirrhotic patients with BEV remains a serious, unsolved problem. The use of CT for routine screening warrants consideration despite increased costs. PMID- 21679922 TI - [Usefulness of microalbuminuria in the metabolic syndrome as a predictor of cardiovascular disease. Prospective study about 78 cases]. AB - AIM: Increased urinary albumin-excretion is a cardiovascular risk factor. The metabolic syndrome is associated with an increased risk of chronic kidney disease, cardiovascular disease and mortality. The aim of this prospective study was to explore the combined associations of microalbuminuria and metabolic syndrome with the risk of incident cardiovascular disease. METHODS: The present study involved 78 patients with metabolic syndrome between May 1 and July 30 in 2009 from cardiology clinic of military hospital in Marrakech. They were followed for 1 year. The metabolic syndrome was defined according to the criteria of International Diabetes Federation (IDF). Microalbuminuria was defined as a urinary albumin excretion of 30 to 300mg/d. RESULTS: The mean age was 56 years old. The prevalence of microalbuminuria was 38%. There was a significantly positive correlation between the number of components of the metabolic syndrome and the corresponding prevalence of microalbuminuria. Incidence rates of cardiovascular events were higher in the positive microalbuminuria group than the group without microalbuminuria, the difference was significant for composite criteria but not for each one probably because of the small size of effective and limited duration. CONCLUSIONS: There is a strong relationship between microalbuminuria and the metabolic syndrome. Microalbuminuria accounts for the increased risk of cardiovascular disease in patients with metabolic syndrome. PMID- 21679923 TI - [Disproportionate pulmonary arterial hypertension and lung respiratory diseases: distinctive clinical, hemodynamic and prognosis of patients versus primary pulmonary arterial hypertension]. AB - OBJECTIVES: To characterize and compare patients with disproportionate PH versus patients with primary pulmonary arterial hypertension (PAH). METHODS: All patients referred to our cardiology unit for echocardiography from November 2006 to May 2008 and who have been followed by our pneumologist were screened for severe PH (i.e mean arterial pulmonary pressure>35-40 mmHg at rest). Patients were excluded if a factor that could influence pulmonary hemodynamics was present. We investigated these patients by pulmonary function tests, echocardiography and right heart catheterisation. RESULTS: We reported 16 cases of severe PH in stable patients (n=8, chronic obstructive pulmonary disease emphysema) and 13 patients with PAH. Our findings suggest that the patients with disproportionate PH had right heart dysfunction similar to that observed in PAH. But their outcomes were more severe. It seemed that specific vasodilatator therapy was not efficient. PMID- 21679924 TI - [Study of echocardiographic parameters of type 2 black African diabetics at high cardiovascular risk. A cross-sectional study of 79 cases in Senegal]. AB - INTRODUCTION: The discovery of silent myocardial ischemia in a diabetic placed in a logic of secondary prevention. The objectives of this study were to investigate the echocardiographic parameters of type 2 Senegalese diabetics at high cardiovascular risk and identify those that are predictors of silent myocardial ischemia. PATIENTS AND METHODS: We conducted a cross-sectional study in 79 diabetic patients at high cardiovascular risk. After clinical examination, we conducted laboratory tests (glucose, creatinine, lipid profile, blood count and blood chemistry panel), ECG, standard echocardiography and dobutamine stress echocardiography looking for silent myocardial ischemia. Data were analyzed using SPSS 17 and echocardiographic parameters determining predictors of silent myocardial ischemia using a multivariate analysis. RESULTS: Seventy-nine with type 2 diabetics at high cardiovascular risk were assessed, including 56 women. The mean age was 58.8+/-11.8 years (44-72ans). The abnormalities found in echocardiography were dominated by left atrium dilation (72.2%), increased filling pressures of left ventricle and increased left ventricular mass in 62.02% cases respectively. At stress echocardiography, regional wall motion abnormalities were found in 67.1% of patients. These disorders were significantly more frequent in patients who had a dilated left atrium (P=0.0001), increased filling pressures (P=0.001) and high left ventricular mass (P=0.001). CONCLUSION: In diabetic patients at high cardiovascular risk, the existence of a dilation of the left atrium to left ventricular hypertrophy or increased filling pressures of the left ventricle may indicate a silent myocardial ischemia. PMID- 21679925 TI - Transdiagnostic internet treatment for anxiety and depression: a randomised controlled trial. AB - Disorder-specific cognitive behavioural therapy programs delivered over the internet (iCBT) with clinician guidance are effective at treating specific anxiety disorders and depression. The present study examined the efficacy of a transdiagnostic iCBT protocol to treat three anxiety disorders and/or depression within the same program (the Wellbeing Program). Seventy-seven individuals with a principal diagnosis of major depression, generalised anxiety disorder, panic disorder, and/or social phobia were randomly assigned to a Treatment or Waitlist Control group. Treatment consisted of CBT-based online educational lessons and homework assignments, weekly email or telephone contact from a clinical psychologist, access to a moderated online discussion forum, and automated emails. Eighty one percent of Treatment group participants completed all 8 lessons within the 10 week program. Post-treatment data were collected from 34/37 Treatment group and 35/37 Control group participants, and 3-month follow-up data were collected from 32/37 Treatment group participants. Relative to Controls, Treatment group participants reported significantly reduced symptoms of anxiety and depression as measured by the Depression Anxiety and Stress Scales-21 item, Patient Health Questionnaire-9 item, and Generalised Anxiety Disorder-7 item scales, with corresponding between-groups effect sizes (Cohen's d) at post treatment of.56,.58, and.52, respectively. The clinician spent a mean time of 84.76 min (SD=50.37) per person over the program. Participants rated the procedure as highly acceptable, and gains were sustained at follow-up. These results provide preliminary support for the efficacy of transdiagnostic iCBT in the treatment of anxiety and depressive disorders. PMID- 21679926 TI - Paternal transmission of stress-induced pathologies. AB - BACKGROUND: There has been recent interest in the possibility that epigenetic mechanisms might contribute to the transgenerational transmission of stress induced vulnerability. Here, we focused on possible paternal transmission with the social defeat stress paradigm. METHODS: Adult male mice exposed to chronic social defeat stress or control nondefeated mice were bred with normal female mice, and their offspring were assessed behaviorally for depressive- and anxiety like measures. Plasma levels of corticosterone and vascular endothelial growth factor were also assayed. To directly assess the role of epigenetic mechanisms, we used in vitro fertilization (IVF); behavioral assessments were conducted on offspring of mice from IVF-control and IVF-defeated fathers. RESULTS: We show that both male and female offspring from defeated fathers exhibit increased measures of several depression- and anxiety-like behaviors. The male offspring of defeated fathers also display increased baseline plasma levels of corticosterone and decreased levels of vascular endothelial growth factor. However, most of these behavioral changes were not observed when offspring were generated through IVF. CONCLUSIONS: These results suggest that, although behavioral adaptations that occur after chronic social defeat stress can be transmitted from the father to his male and female F1 progeny, only very subtle changes might be transmitted epigenetically under the conditions tested. PMID- 21679927 TI - Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats. AB - BACKGROUND: Early developmental insults can cause dysfunction within parvalbumin (PVB)-containing interneurons in the prefrontal cortex. The neuropsychiatric disorders associated with such dysfunction might involve neuroinflammatory processes. Cyclooxygenase-2 (COX-2) is a key mediator of inflammation and is therefore a potential target for preventive treatment. Here, we investigated whether the developmental trajectories of PVB expression and COX-2 induction in the prelimbic region of the prefrontal cortex are altered after maternal separation stress in male rats. METHODS: Male rat pups were separated from their mother and littermates for 4 hours/day between postnatal Days 2 and 20. Western blotting and immunohistochemistry were used to analyze PVB and COX-2 expression in the prefrontal cortex and hippocampus. A separate cohort of animals was treated with a COX-2 inhibitor during preadolescence and analyzed for PVB, COX-2, and working memory performance. RESULTS: We demonstrate that maternal separation causes a reduction of PVB and an increase in COX-2 expression in the prefrontal cortex in adolescence, with concurrent working memory deficits. Parvalbumin was not affected earlier in development. Prophylactic COX-2 inhibition preadolescence prevents PVB loss and improves working memory deficits induced by maternal separation. CONCLUSIONS: These data are the first to show a preventive pharmacological intervention for the delayed effects of early life stress on prefrontal cortex interneurons and working memory. Our results suggest a possible mechanism for the relationship between early life stress and interneuron dysfunction in adolescence. PMID- 21679928 TI - FosB is essential for the enhancement of stress tolerance and antagonizes locomotor sensitization by DeltaFosB. AB - BACKGROUND: Molecular mechanisms underlying stress tolerance and vulnerability are incompletely understood. The fosB gene is an attractive candidate for regulating stress responses, because DeltaFosB, an alternative splice product of the fosB gene, accumulates after repeated stress or antidepressant treatments. On the other hand, FosB, the other alternative splice product of the fosB gene, expresses more transiently than DeltaFosB but exerts higher transcriptional activity. However, the functional differences of these two fosB products remain unclear. METHODS: We established various mouse lines carrying three different types of fosB allele, wild-type (fosB(+)), fosB-null (fosB(G)), and fosB(d) allele, which encodes DeltaFosB but not FosB, and analyzed them in stress-related behavioral tests. RESULTS: Because fosB(+/d) mice show enhanced DeltaFosB levels in the presence of FosB and fosB(d/d) mice show more enhanced DeltaFosB levels in the absence of FosB, the function of FosB can be inferred from differences observed between these lines. The fosB(+/d) and fosB(d/d) mice showed increased locomotor activity and elevated Akt phosphorylation, whereas only fosB(+/d) mice showed antidepressive-like behaviors and increased E-cadherin expression in striatum compared with wild-type mice. In contrast, fosB-null mice showed increased depression-like behavior and lower E-cadherin expression. CONCLUSIONS: These findings indicate that FosB is essential for stress tolerance mediated by DeltaFosB. These data suggest that fosB gene products have a potential to regulate mood disorder-related behaviors. PMID- 21679929 TI - Regional expansion of hypometabolism in Alzheimer's disease follows amyloid deposition with temporal delay. AB - BACKGROUND: Cross-sectional imaging studies suggest that patterns of hypometabolism (measured by [(18)F] fluorodeoxyglucose positron emission tomography [FDG-PET]) and amyloid deposition (measured by [(11)C] Pittsburgh Compound B [PiB]- PET) in Alzheimer's disease (AD) show some overlap with each other. This indicates that neuronal dysfunction might spread within the anatomical pattern of amyloid deposition. The aim of this study was to examine longitudinal regional patterns of amyloid deposition and hypometabolism in the same population of mild AD subjects and to establish their regional relationship to each other. METHODS: Twenty patients with mild AD underwent baseline (BL) and follow-up (FU) examination with [(18)F] FDG-PET and [(11)C] PiB-PET. Voxel-by voxel statistical group comparison (SPM5) was performed between patient BL- and FU-PET data as well as between patients and 15 PiB-negative elderly control subjects, who had undergone identical imaging procedures. To obtain objective measures of regional overlap, Dice similarity coefficients (DSC) between the imaging findings were calculated. RESULTS: Compared with elderly control subjects, AD patients showed typical patterns of BL hypometabolism and BL amyloid deposition, with a similarity of 40% (DSC). Amyloid deposition was more extended than hypometabolism at BL and showed only minor changes over time, whereas significant expansion of hypometabolism was observed, almost exclusively within areas already affected by BL amyloid deposition. Thus, increased similarity of FU hypometabolism with BL amyloid deposition was found (DSC: 47%). CONCLUSIONS: Longitudinal regional expansion of cerebral hypometabolism, as a measure of neuronal dysfunction in AD, seems to follow the anatomical pattern of amyloid deposition with temporal delay. This indicates that amyloid-based disruption of neuronal integrity might contribute to the regional expansion of neuronal dysfunction. PMID- 21679930 TI - Effect of inactivation and disinhibition of the oculomotor vermis on saccade adaptation. AB - The ability to adapt a variety of motor acts to compensate for persistent natural or artificially induced errors in movement accuracy requires the cerebellum. For adaptation of the rapid shifts in the direction of gaze called saccades, the oculomotor vermis (OMV) of the cerebellum must be intact. We disrupted the neural circuitry of the OMV by manipulating gamma aminobutyric acid (GABA), the transmitter used by many neurons in the vermis. We injected either muscimol, an agonist of GABA, to inactivate the OMV or bicuculline, an antagonist, to block GABA inhibition. Our previous study showed that muscimol injections cause ipsiversive saccades to fall short of their targets, whereas bicuculline injections cause most ipsiversive saccades to overshoot. Once these dysmetrias had stabilized, we tested the monkey's ability to adapt saccade size to intra saccadic target steps that produced a consistent saccade under-shoot (amplitude increase adaptation required) or overshoot (amplitude decrease adaptation required). Injections of muscimol abolished the amplitude increase adaptation of ipsiversive saccades, but had either no effect, or occasionally facilitated, amplitude decrease adaptation. In contrast, injections of bicuculline impaired amplitude decrease adaptation and usually facilitated amplitude increase adaptation. Neither drug produced consistent effects on the adaptation of contraversive saccades. Taken together, these data suggest that OMV activity is necessary for amplitude increase adaptation, whereas amplitude decrease adaptation may involve the inhibitory circuits within the OMV. PMID- 21679931 TI - Ethanol reduces kainate-evoked glutamate secretion in rat hippocampal astrocytes. AB - In this study we have used rat hippocampal astrocytes in culture to investigate the effect of ethanol on kainate-induced glutamate secretion. Our results show that kainate (10 MUM to 500 MUM) stimulated glutamate release from astrocytes. Preincubation of astrocytes in the presence of ethanol induced a concentration dependent (1mM-50mM) inhibition of glutamate release caused by stimulation of cells with 100 MUM kainate. Inhibition of alcohol-dehydrogenase, by preincubation of astrocytes in the presence of 4-methylpyrazole (1mM), abolished ethanol induced inhibition of glutamate release in response to kainate. On the other hand, preincubation of astrocytes in the presence of the antioxidant cinnamtannin B-1 (10 MUM) also blocked ethanol inhibitory action on glutamate release in response to kainate. Ethanol (50mM) reduced Ca(2+) mobilization in response to kainate, whereas cinnamtannin B-1 reversed the inhibitory action of ethanol on Ca(2+) mobilization by kainate. Our results are consistent with an inhibitory action of ethanol on glutamate secretion from hippocampal astrocytes. The inhibitory effects of ethanol are probably due to its oxidative metabolization, involves reactive oxygen species production, and a lower Ca(2+) mobilization by kainate. Taking into account the pivotal role that astrocytes play within the central nervous system, especially in relation to neurons, the negative effects of ethanol on the release of glutamate might affect neuron-glia communication in the hippocampus, which might lead to functional defects in the brain. PMID- 21679932 TI - Extracellular sodium modulates the excitability of cultured hippocampal pyramidal cells. AB - Recent studies demonstrated a photophobia mechanism with modulation of nociceptive, cortico-thalamic neurons by retinal ganglion cell projections; however, little is known about how their neuronal homeostasis is disrupted. Since we have found that lumbar cerebrospinal fluid (CSF) sodium increases during migraine and that cranial sodium increases in a rat migraine model, the purpose of this study was to examine the effects of extracellular sodium ([Na(+)](o)) on the intrinsic excitability of hippocampal pyramidal neurons. We monitored excitability by whole cell patch using a multiplex micropipette with a common outlet to change artificial CSF (ACSF) [Na(+)](o) at cultured neurons accurately (SD<7 mM) and rapidly (<5s) as determined by a sodium-selective micro-electrode of the same size and at the same location as a neuronal soma. Changing [Na(+)](o) in ACSF from 100 to 160 mM, choline-balanced at 310-320 mOsm, increased the action potential (AP) amplitude, decreased AP width, and augmented firing rate by 28%. These effects were reversed on returning the ACSF [Na(+)](o) to 100mM. Testing up to 180 mM [Na(+)](o) required ACSF with higher osmolarity (345-355 mOsm), at which the firing rate increased by 36% between 100 and 180 mM [Na(+)](o), with higher amplitude and narrower APs. In voltage clamp mode, the sodium and potassium currents increased significantly at higher [Na(+)](o). These results demonstrate that fluctuations in [Na(+)](o) modulate neuronal excitability by a sodium current mechanism and that excessively altered neuronal excitability may contribute to hypersensitivity symptoms. PMID- 21679934 TI - Subitizing reflects visuo-spatial object individuation capacity. AB - Subitizing is the immediate apprehension of the exact number of items in small sets. Despite more than a 100years of research around this phenomenon, its nature and origin are still unknown. One view posits that it reflects a number estimation process common for small and large sets, which precision decreases as the number of items increases, according to Weber's law. Another view proposes that it reflects a non-numerical mechanism of visual indexing of multiple objects in parallel that is limited in capacity. In a previous research we have gathered evidence against the Weberian estimation hypothesis. Here we provide first direct evidence for the alternative object indexing hypothesis, and show that subitizing reflects a domain general mechanism shared with other tasks that require multiple object individuation. PMID- 21679933 TI - Host derived inflammatory phospholipids regulate rahU (PA0122) gene, protein, and biofilm formation in Pseudomonas aeruginosa. AB - This study describes the role of "inflammatory" oxidized (Ox) phospholipids in regulation of rahU (PA0122) expression and biofilm formation in Pseudomonas aeruginosa (383) wild type (rahU(+)) and rahU mutant (rahU(-)) strains. Functional analysis of RahU protein from P. aeruginosa in presence of Ox phospholipids show: (a) LysoPC modulates RahU gene/and protein expression in rahU(+) cells; (b) rahU promoter activity is increased by lysoPC and inhibited by PAPC, Ox-PAPC and arachidonic acid; the latter inhibitory effect can be reversed by lysoPC, which was enzymatically derived from PAPC; (c) biofilm formation increased in rahU(-) cells as compared to rahU(+); and (d) inhibition of rahU promoter activity by PAPC and AA (but not lysoPC) showed significantly augmented biofilm formation in rahU(+) but not in rahU(-) cells. This study shows that host derived Ox-phospholipids affect P. aeruginosa-rahU gene and protein expression, which in turn modulates biofilm formation. The accompanying paper describes the role of RahU protein in eukaryotic-host cells. PMID- 21679935 TI - Brain volumetry: an active contour model-based segmentation followed by SVM-based classification. AB - In this paper a novel automatic approach to identify brain structures in magnetic resonance imaging (MRI) is presented for volumetric measurements. The method is based on the idea of active contour models and support vector machine (SVM) classifiers. The main contributions of the presented method are effective modifications on brain images for active contour model and extracting simple and beneficial features for the SVM classifier. The segmentation process starts with a new generation of active contour models, i.e., vector field convolution (VFC) on modified brain images. VFC results are brain images with the least non-brain regions which are passed on to the SVM classification. The SVM features are selected according to the structure of brain tissues, gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). SVM classifiers are trained for each brain tissue based on the set of extracted features. Although selected features are very simple, they are both sufficient and tissue separately effective. Our method validation is done using the gold standard brain MRI data set. Comparison of the results with the existing algorithms is a good indication of our approach's success. PMID- 21679936 TI - Graphabulation: a graphic form of confabulation. PMID- 21679937 TI - Lead, mercury, cadmium, chromium, and arsenic levels in eggs, feathers, and tissues of Canada geese of the New Jersey Meadowlands. AB - The New Jersey Meadowlands are located within the heavily urbanized New York/New Jersey Harbor Estuary and have been subject to contamination due to effluent and runoff from industry, traffic, and homes along the Hackensack River and nearby waterways. These extensive wetlands, though heavily impacted by development and pollution, support a wide array of bird and other wildlife species. Persistent contaminants may pose threats to birds in these habitats, affecting reproduction, egg hatchability, nestling survival, and neurobehavioral development. Metals of concern in the Meadowlands include arsenic, cadmium, chromium, lead, and mercury. These metals were analyzed in eggs, feathers, muscle, and liver of Canada geese (Branta canadensis) breeding in four wetland sites. We sampled geese collected during control culling (n=26) and collected eggs from goose nests (n=34). Levels of arsenic were below the minimum quantification level (MQL) in most samples, and cadmium and mercury were low in all tissues sampled. Chromium levels were high in feather samples. Mercury levels in eggs of Canada geese, an almost exclusively herbivorous species, were lower (mean +/-SE 4.29+/-0.30MUg/g wet weight) than in eggs of omnivorous mallards (Anas platyrhynchos), and insectivorous red-winged blackbirds (Agelaius phoeniceus) and marsh wrens (Cistothorus palustris) from the Meadowlands, consistent with trophic level differences. However, lead levels were higher in the goose eggs (161+/-36.7ng/g) than in the other species. Geese also had higher levels of lead in feathers (1910+/-386ng/g) than those seen in Meadowlands passerines. By contrast, muscle and liver lead levels were within the range reported in waterfowl elsewhere, possibly a reflection of metal sequestration in eggs and feathers. Elevated lead levels may be the result of sediment ingestion or ingestion of lead shot and sinkers. Finally, lead levels in goose liver (249+/-44.7ng/g) and eggs (161+/-36.7ng/g) may pose a risk if consumed frequently by humans. Mill Creek, the site with the most documented prior contamination, had significantly elevated cadmium, chromium, mercury, and lead in goose tissues. PMID- 21679939 TI - EUS-guided therapy for management of peripancreatic fluid collections after distal pancreatectomy in 20 consecutive patients. PMID- 21679938 TI - Relation between malodor, ambient hydrogen sulfide, and health in a community bordering a landfill. AB - BACKGROUND: Municipal solid waste landfills are sources of air pollution that may affect the health and quality of life of neighboring communities. OBJECTIVES: To investigate health and quality of life concerns of neighbors related to landfill air pollution. METHODS: Landfill neighbors were enrolled and kept twice-daily diaries for 14d about odor intensity, alteration of daily activities, mood states, and irritant and other physical symptoms between January and November 2009. Concurrently, hydrogen sulfide (H(2)S) air measurements were recorded every 15-min. Relationships between H(2)S, odor, and health outcomes were evaluated using conditional fixed effects regression models. RESULTS: Twenty-three participants enrolled and completed 878 twice-daily diary entries. H(2)S measurements were recorded over a period of 80d and 1-h average H(2)S=0.22ppb (SD=0.27; range: 0-2.30ppb). Landfill odor increased 0.63 points (on 5-point Likert-type scale) for every 1ppb increase in hourly average H(2)S when the wind was blowing from the landfill towards the community (95% confidence interval (CI): 0.29, 0.91). Odor was strongly associated with reports of alteration of daily activities (odds ratio (OR)=9.0; 95% CI: 3.5, 23.5), negative mood states (OR=5.2; 95% CI: 2.8, 9.6), mucosal irritation (OR=3.7; 95% CI=2.0, 7.1) and upper respiratory symptoms (OR=3.9; 95% CI: 2.2, 7.0), but not positive mood states (OR=0.6; 95% CI: 0.2, 1.5) and gastrointestinal (GI) symptoms (OR=1.0; 95% CI: 0.4, 2.6). CONCLUSIONS: Results suggest air pollutants from a regional landfill negatively impact the health and quality of life of neighbors. PMID- 21679940 TI - Duodenobronchial fistula presenting with persistent pneumonia: report of a case. PMID- 21679941 TI - Fully endoscopic removal of migrated mesh after laparoscopic fundoplication eroded into the gastroesophageal junction: a case report (with video). PMID- 21679942 TI - Simulating a target lesion for endoscopic submucosal dissection training in an ex vivo pig model. AB - BACKGROUND: Currently, there is no training model that simulates the target lesion encountered during endoscopic submucosal dissection. OBJECTIVE: To develop a novel method simulating a target lesion for endoscopic submucosal dissection. DESIGN: Training program with the use of an ex vivo porcine stomach model. SETTING: Clinical skills training center. INTERVENTION: A pseudopolyp was created by using an esophageal variceal ligation device to simulate a protruding (0-Ip) lesion, and the pseudopolyp was transected with a snare cautery to simulate a depressed (0-IIc) lesion. MAIN OUTCOME MEASUREMENTS: Evaluate the histological depth of the target lesions and resected specimens. RESULTS: Histological findings of the simulated targets showed artificial ulcerative or polypoid lesions involving the muscularis mucosa or superficial submucosa. The resected specimen was limited to the submucosal layer, and no perforation was noted. LIMITATIONS: Pilot study in an ex vivo porcine stomach model. CONCLUSION: The most important advantage of the model is to simulate realistic target lesions like those encountered in clinical practice in endoscopic submucosal dissection training. It allows trainees to practice how to make proper markings, delineate adequate safety margins, and properly manage different subtypes of early gastric cancer. PMID- 21679943 TI - EUS-guided transhepatic antegrade balloon dilation for benign bilioenteric anastomotic strictures in a patient with hepaticojejunostomy. PMID- 21679944 TI - Endoscopic full-thickness resection of a gastric subepithelial tumor by using the submucosal tunnel technique with the patient under conscious sedation (with video). PMID- 21679945 TI - Techniques of image enhancement in EUS (with videos). PMID- 21679946 TI - Miss rate of right-sided colon examination during colonoscopy defined by retroflexion: an observational study. AB - BACKGROUND: Colonoscopy is less effective in the proximal compared with the distal colon. OBJECTIVE: To describe the success rate, yield, and safety of retroflexion of the right side of the colon after a careful forward-viewing examination. DESIGN: Prospective observational study. SETTING: Tertiary-care hospital outpatient endoscopy center and associated ambulatory surgery center. PATIENTS: A total of 1000 consecutive adults undergoing elective screening or surveillance colonoscopy, without previous bowel resection, inflammatory bowel disease, or polyposis syndromes. INTERVENTION: After cecal intubation, a careful examination of the cecum to the hepatic flexure was performed in the forward view with removal of all identified polyps. The colonoscope was then reinserted to the cecum and retroflexed, and examination was performed to the hepatic flexure in retroflexion. MAIN OUTCOME MEASUREMENTS: Success rate, per-polyp and per-patient miss rates, and adverse events rate of retroflexion. RESULTS: Retroflexion was successful in 94.4% of patients. Looping in the insertion tube was the apparent cause of 89% of failed attempts. The forward view identified 634 proximal colon polyps and 497 adenomas, and retroflexion identified an additional 68 polyps and 54 adenomas, representing a per-adenoma miss rate of 9.8% and an intention-to treat, per-patient adenoma miss rate of 4.4%. Older age, male sex, and polyps seen on the forward view predicted polyps seen on retroflexion. There were no adverse events. LIMITATIONS: Single-center, uncontrolled study with only 2 endoscopists. CONCLUSIONS: Right-sided colon retroflexion is generally achievable and safe in our hands. The yield is comparable to that expected from a second examination in the forward view. PMID- 21679947 TI - Benefits of manual vacuum aspiration for abortion. PMID- 21679948 TI - Heterotopic cesarean scar pregnancy associated with a levonorgestrel-releasing intrauterine device. PMID- 21679949 TI - Osteoprotegerin promotes vascular fibrosis via a TGF-beta1 autocrine loop. AB - BACKGROUND: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis. METHODS: Aortic samples were analyzed after in vivo treatment of ApoE(-/-) mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-beta1 (TGF-beta1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-beta1, platelet derived growth factor (PDGF) and angiogensin II (Ang II). RESULTS: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-beta1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-beta1. On the other hand, exposure to recombinant TGF-beta1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC. CONCLUSIONS: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-beta1 and OPG. PMID- 21679951 TI - Low pulse pressure with high pulsatile external left ventricular power: influence of aortic waves. AB - Elevated pulse pressure (pp) is considered to be a risk factor for adverse cardiovascular events since it is directly related to an elevated myocardial workload. Information about both pressure and flow wave must be provided to assess hemodynamic complexity and true level of external left ventricular power (ELVP). pp value as a single feature of aortic waves cannot identify true level of ELVP. However, it is generally presumed that ELVP (and consequently LV workload) is positively correlated with pp. This study examined this positive correlation. The aim of this study was to test the hypothesis that aortic wave dynamics can create destructive hemodynamic conditions that increase the ELVP even though pp appears to be normal. To test this hypothesis, a computational model of the aorta with physiological properties was used. A Finite Element Method with fluid-structure interaction was employed to solve the equations of the solid and fluid. The aortic wall was assumed to be elastic and isotropic. The blood was assumed to be an incompressible Newtonian fluid. Simulations were performed for various heart rates (HR) and different aortic compliances while keeping the shape of the inlet flow and peripheral resistance constant. As expected, in most of the cases studied here, higher pp was associated with higher LV power demand. However, for a given cardiac output, mean pressure, and location of total reflection site, we have found cases where the above-mentioned trend does not hold. Our results suggest that using pp as a single index can result in an underestimation of the LV power demand under certain conditions related to the altered wave dynamics. Hence, in hypertensive patients, a full analysis of aortic wave dynamics is essential for the prevention and management of left ventricular hypertrophy (LVH) and congestive heart failure. PMID- 21679952 TI - Development of a novel intraoral measurement device to determine the biomechanical characteristics of the human periodontal ligament. AB - Periodontal diseases like gingivitis and periodontitis have damaging effects on the periodontium and commonly affect the mechanical properties of the periodontal ligament (PDL), which in the end might lead to loss of teeth. Monitoring tooth mobility and changes of the material properties of the PDL might help in early diagnosis of periodontal diseases and improve their prognosis. It was the aim of this study to develop a novel intraoral device to determine the biomechanical characteristics of the periodontal ligament. This includes the measurement of applied forces and resulting tooth displacement in order to investigate the biomechanical behaviour of the periodontium with varying loading protocols with respect to velocity and tooth displacement. The developed device uses a piezoelectric actuator to apply a displacement to a tooth's crown, and the resulting force is measured by an integrated force sensor. To measure the tooth displacement independently and non-invasively, two magnets are fixed on the teeth. The change in the magnetic field caused by the movement of the magnets is measured by a total of 16 Hall sensors. The displacement of the tooth is calculated from the movement of the magnets. The device was tested in vitro on premolars of four porcine mandibular segments and in vivo on two volunteers. The teeth were loaded with varying activation curves. Comparing the force progression of different activation velocities, the forces decreased with decreasing velocity. Intensive testing demonstrated that the device fulfils all requirements. After acceptance of the ethical committee, further testing in clinical measurements is planned. PMID- 21679950 TI - Carotid artery intima-media thickness in college students: race/ethnicity matters. AB - OBJECTIVE: Racial/ethnic differences in common carotid artery intima-media thickness (CIMT) and in risk factors associated with CIMT have been predominantly observed in middle-aged and older individuals. We aimed to characterize racial/ethnic differences CIMT and other cardiovascular risk factors in a healthy, young-adult population. METHODS: College students were recruited as part of a study to characterize determinants of atherogenesis. Students were eligible if they were lifetime non-smokers, lived in the United States since six months of age, and attended high school in the United States. Blood pressure, heart rate, height, and weight were measured, B-mode carotid ultrasound was performed, questionnaires were administered and a 12-h fasting blood sample was collected. Associations between CIMT and other variables were assessed in 768 students aged 18-25 years using linear regression analysis. RESULTS: In models adjusted for common cardiovascular risk factors, sex exhibited the strongest influence on CIMT, with men having 15.4 MUm larger CIMT compared to women (95%CI 6.6, 24.2). Race/ethnicity was also strongly associated with CIMT. African Americans had 17.3 MUm greater CIMT (95%CI -0.3, 34.8) compared to non Hispanic Whites, whereas Asians and Hispanic Whites had 14.3 (95%CI -24.3, -4.4) and 15.4 (95%CI -26.2, 4.7) MUm smaller CIMT, respectively. BMI and systolic blood pressure were positively associated with CIMT. CONCLUSION: The risk factors associated with atherogenesis later in life are already present and observable in college-aged young adults, so targeted campaigns to reduce life-long cardiovascular disease burden should be initiated earlier in life to improve public health. PMID- 21679953 TI - The role of lubricant entrapment at biological interfaces: reduction of friction and adhesion in articular cartilage. AB - Friction and adhesion of articular cartilage from high- and low-load-bearing regions of bovine knee joints were examined with a tribometer under various loads and equilibration times. The effect of trapped lubricants was investigated by briefly unloading the cartilage sample before friction testing, to allow fluid to reflow into the contact interface and boundary lubricants to rearrange. Friction and adhesion of high-load-bearing joint regions were consistently lower than those of low-load-bearing regions. This investigation is the first to demonstrate the regional variation in the friction and adhesion properties of articular cartilage. Friction coefficient decreased with increasing contact pressure and decreasing equilibration time. Briefly unloading cartilage before the onset of sliding resulted in significantly lower friction and adhesion and a loss of the friction dependence on contact pressure, suggesting an enhancement of the cartilage tribological properties by trapped lubricants. The results of this study reveal significant differences in the friction and adhesion properties between high- and low-load-bearing joint regions and elucidate the role of trapped lubricants in cartilage tribology. PMID- 21679954 TI - Sarcomere overextension reduces stretch-induced tension loss in myofibrils of rabbit psoas. AB - Stretch-induced damage to skeletal muscles results in loss of isometric tension. Although there is no direct evidence, loss of tension has been implicitly assumed to be the consequence of permanent loss of myofilament overlap in some sarcomeres ('sarcomere overextension'). Using isolated myofibrils of rabbit psoas muscle (n=38; 6 control and 32 test specimens) at 12-15 degrees C, we directly tested the idea that loss of tension following stretch is caused by sarcomere overextension. Experimental myofibrils were maximally activated at the edge of the descending limb (sarcomere length ~ 2.9 MUm) of the sarcomere length-tension relationship and then stretched by 1 MUm sarcomere(-1) at a constant speed of 0.1 MUms(-1)sarcomere(-1) to result in an average strain of 33.6 +/- 0.9% (mean +/- 1 SE). Myofibrils were immediately returned to the original lengths and relaxed. Isometric tension measured in a subsequent re-activation 3-5 min later was reduced by 24.6 +/- 1.5% from its original value. In 22 out of the 32 test specimens, all sarcomeres maintained myofilament overlap, while in 10 myofibrils one or two sarcomeres were stretched permanently beyond myofilament overlap (>4.0 MUm), and thus exhibited overextended sarcomeres. Loss of tension following stretch was significantly smaller in myofibrils with overextended sarcomeres compared to myofibrils with no overextended sarcomeres (19.5 +/- 2.3% and 27.1 +/ 1.8%, respectively; p=0.017). Combined, these results suggest that the loss of tension associated with stretch-induced damage can occur in the absence of sarcomere overextension and that sarcomere overextension limits rather than causes stretch-induced tension loss. PMID- 21679956 TI - HILIC at 21: Reflections and perspective. Forward. PMID- 21679955 TI - Optimized ultrasonic assisted extraction-dispersive liquid-liquid microextraction coupled with gas chromatography for determination of essential oil of Oliveria decumbens Vent. AB - Ultrasonic assisted extraction-dispersive liquid-liquid microextraction (UAE DLLME) coupled with gas chromatography (GC) was applied for extraction and determination of essential oil constituents of the plant Oliveria decumbens Vent. Scanning electron microscopy (SEM) was used to see the effect of ultrasonic radiation on the extraction efficiency. By comparison with hydrodistillation, UAE DLLME is fast, low cost, simple, efficient and consuming small amount of plant materials (~1.0 g). The effects of various parameters such as temperature, ultrasonication time, volume of disperser and extraction solvents were investigated by a full factorial design to identify significant variables and their interactions. The results demonstrated that temperature and ultrasonication time had no considerable effect on the results. In the next step, a central composite design (CCD) was performed to obtain the optimum levels of significant parameters. The obtained optimal conditions were: 0.45 mL for disperser solvent (acetonitrile) and 94.84 MUL for extraction solvent (chlorobenzene). The limits of detection (LODs), linear dynamic range and determination coefficients (R(2)) were 0.2-29 ng mL(-1), 1-2100 ng mL(-1) and 0.995-0.998, respectively. The main components of the essential oil were: thymol (47.06%), carvacrol (23.31%), gamma terpinene (18.94%), p-cymene (8.71%), limonene (0.76%) and myristicin (0.63%). PMID- 21679957 TI - Immobilized trypsin on epoxy organic monoliths with modulated hydrophilicity: novel bioreactors useful for protein analysis by liquid chromatography coupled to tandem mass spectrometry. AB - The development of epoxy organic monoliths with modulated hydrophilicity for the preparation of novel trypsin-based microreactors is reported. Porous polymer monoliths have been prepared using methacrylate chemistry triggered by gamma-ray irradiation. In situ polymerization has been optimized and extended to medium and high polymer densities using glycidyl methacrylate (GMA) as reactive monomer as well as to the hydrophilic nature of the co-monomers (glyceryl monomethacrylate, GlyMA and acrylamide, AMD). Enzyme immobilization was smoothly achieved by passing a buffered trypsin solution through the columns kept at room temperature. The activities of the immobilized enzyme were characterized by the apparent Michaelis constant (K(m)) and the apparent maximum velocity (V(max)) of the reaction using a non chromogenic, low-molecular mass substrate N-alpha-benzoyl-l arginine ethyl ester (BAEE). For the kinetic constants determination a new off line chromatographic procedure was developed on purpose. The most efficient IMERs were obtained by immobilizing trypsin on monolithic skeleton prepared with hydrophilic monomers (GlyMA and AMD). One of the most promising bioreactor was applied to the digestion of model proteins with different molecular weight and complexity such as human serum albumin (HSA), beta-casein and ribonuclease B (RNase B), and the produced peptides were analyzed by liquid chromatography-mass spectrometry. Using a digestion time of only 25 min the proteins were recognized by the database with satisfactory sequence coverage, which was 78.22, 49.76 and 80.68% for HSA, beta-casein and RNase B, respectively. PMID- 21679958 TI - Testing the suitability of different high-performance liquid chromatographic methods to determine aflatoxin M1 in a soft fresh Italian cheese. AB - Aflatoxin M1 (AFM1) is a toxic undesirable compound in milk. AFM1 affinity for caseins causes a concentration effect during milk process for dairy transformation. In spite of this, no official method of analysis, nor maximum tolerance level for aflatoxin M1 in cheese have been established. Thus, the aim of this work was to test the suitability of different HPLC methods for the AFM1 quantification in soft cheese samples at three different contamination levels (low, medium and high, at respectively nearly 30, 100 and 250 ng/kg). Nine participants were selected among Italian laboratories accredited by the Italian accreditation body (ACCREDIA) for HPLC toxin analysis. They were asked to analyze samples applying the method routinely used. The different applied methods were compared, and precision and accuracy parameters were evaluated. The main differences among HPLC procedures were registered at the level of extraction step. The use of an enzymatic digestion for the extraction of the toxin from cheese seemed to be particularly advantageous and the use of immunoaffinity columns seemed to be determinant for the improvement of sensitivity at low contamination levels. In general, the applied methods well discriminated the 3 levels of contamination, even though they performed better at the medium and high concentration levels (100 and 250 ng/kg) than at the low one (30 ng/kg). In fact relative standard deviation for reproducibility at low level was higher (60.1%) than the same value at medium and high levels (22.8% and 28.9%, respectively). PMID- 21679959 TI - Photosensitive chitosan to control cell attachment. AB - An approach to control cell adhesion using a photocleavable molecule on chitosan has been developed and studied. Photocleavable 4,5-dimethoxy-2-nitrobenzyl chloroformate (NVOC) was introduced into chitosan to control the surface properties. The two UV illuminations with a photomask controlled the cleavage of NVOC and the presentation of deprotected amines on one chitosan surface spatially and temporally. The following immobilizations of cell repulsive poly(ethylene glycol) after the first illumination and cell adhesive sequence Arg-Gly-Asp-Ser (RGDS) after the second illumination on the surface helped create surface heterogeneity. Fourier transform infrared spectroscopy (FTIR), water contact angle, and UV-visible spectroscopy were used to characterize the surfaces and photoactivation during the process. To study the cell attachment and morphology on our designed surfaces, NIH/3T3 fibroblast cell was used. Cell number and morphology on the surfaces were investigated. The cell study demonstrated the feasibility of the surfaces on the control of cell adhesion and the formation of cell patterns by UV illuminations and the following immobilizations of different biomolecules. PMID- 21679960 TI - Organic-inorganic hybrid of chitosan/organoclay bionanocomposites for hexavalent chromium uptake. AB - Organic-inorganic hybrid of chitosan and nanoclay (Cloisite 10A) was chosen to develop a nanomaterial with combine properties of hydrophilicity of an organic polycation and adsorption capacity of inorganic polyanion. The chitosan/clay nanocomposite (CCN) was prepared by solvent casting method. The material synthesis was found most efficient in adsorbent behavior was studied in detail taking Cr(VI) as representative ion. The chemical, structural and textural characteristics of the material were determined by FTIR, XRD, TEM, SEM and EDAX analysis. XRD and TEM results indicated that an exfoliated structure was formed with addition of small amounts of MMT-Na+(montmorillonite-Na(+)) to the chitosan matrix. These composite material were used for the removal of chromium(VI) from aqueous solution. The conditions for the adsorption by the composite have been optimized and kinetics and thermodynamic studies were performed. Though the adsorption takes place in wide pH range, pH 3 was found most suitable and at this pH the adsorption data were modeled using the Langmuir and Freundlich isotherms at 15 degrees C and 35 degrees C, where the data fitted satisfactorily to Langmuir isotherms, the R(2) values being 0.998 and 0.999 respectively indicating unilayer adsorption. Based on Langmuir model, Q(o) was calculated to be 357.14 mg/g. The adsorption showed pseudo second order kinetics with a rate constant of 8.0763 * 10(-4) g mg(-1) min(-1) at 100 ppm Cr(VI) concentration. PMID- 21679961 TI - Graphene and graphene oxide as effective adsorbents toward anionic and cationic dyes. AB - In the present study, exfoliated graphene oxide (EGO) and reduced graphene oxide (rGO) have been used for the adsorption of various charged dyes such as methylene blue, methyl violet, rhodamine B, and orange G from aqueous solutions. EGO consists of single layer of graphite decorated with oxygen containing functional groups such as carboxyl, epoxy, ketone, and hydroxyl groups in its basal and edge planes. Consequently, the large negative charge density available in aqueous solutions helps in the effective adsorption of cationic dyes on EGO while the adsorption is negligible for anionic dyes. On the other hand, rGO that has high surface area does not possess as high a negative charge and is found to be very good adsorbent for anionic dyes. The adsorption process is followed using UV Visible spectroscopy, while the material before and after adsorption has been characterized using physicochemical and spectroscopic techniques. Various isotherms have been used to fit the data, and kinetic parameters were evaluated. Raman and FT-IR spectroscopic data yield information on the interactions of dyes with the adsorbent. PMID- 21679962 TI - One-step controllable fabrication of superhydrophobic surfaces with special composite structure on zinc substrates. AB - Stable superhydrophobic platinum surfaces have been effectively fabricated on the zinc substrates through one-step replacement deposition process without further modification or any other post-treatment procedures. The fabrication process was controllable, which could be testified by various morphologies and hydrophobic properties of different prepared samples. By conducting SEM and water CA analysis, the effects of reaction conditions on the surface morphology and hydrophobicity of the resulting surfaces were carefully studied. The results show that the optimum condition of superhydrophobic surface fabrication depends largely on the positioning of zinc plate and the concentrations of reactants. When the zinc plate was placed vertically and the concentration of PtCl(4) solution was 5 mmol/L, the zinc substrate would be covered by a novel and interesting composite structure. The structure was composed by microscale hexagonal cavities, densely packed nanoparticles layer and top micro- and nanoscale flower-like structures, which exhibit great surface roughness and porosity contributing to the superhydrophobicity. The maximal CA value of about 171 degrees was obtained under the same reaction condition. The XRD, XPS and EDX results indicate that crystallite pure platinum nanoparticles were aggregated on the zinc substrates in accordance with a free deposition way. PMID- 21679963 TI - Effects of pharmaceutical excipients on cloud points of amphiphilic drugs. AB - The clouding behavior, i.e., formation of phase separation at elevated temperature (the temperature being known as cloud point (CP)), of three amphiphilic drugs, amitriptyline (AMT), clomipramine (CLP) and imipramine (IMP) hydrochlorides in the presence of various additives, like cationic surfactants (conventional and gemini), nonionic surfactants, bile salts, anionic hydrotropes, sodium salts of fatty acids and cyclodextrin has been investigated. These additives are generally used as drug delivery systems. The drugs used are tricyclic antidepressants. All the surfactants increase the CP of mixed micelles formed by cationic (conventional and gemini) and nonionic surfactants. Hydrotropes, bile salts and fatty acid salts, when added in low concentrations, increase the CP, whereas at high concentrations, they decrease it. beta Cyclodextrin behaves as simple sugar and decreases the CP of the drug solutions. PMID- 21679964 TI - Sequential therapy in childhood Helicobacter pylori eradication: emphasis on drug compliance. PMID- 21679967 TI - Truths, associations, and hypotheses. PMID- 21679965 TI - Phenotype severity in the bladder exstrophy-epispadias complex: analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe. AB - OBJECTIVE: To identify genetic and nongenetic risk factors that contribute to the severity of the bladder exstrophy-epispadias complex (BEEC). STUDY DESIGN: Patients with BEEC from North America (n = 167) and Europe (n = 274) were included. The following data were collected: associated anomalies, parental age at conception, mode of conception, periconceptional folic acid supplementation, maternal risk factors during pregnancy, and environmental risk factors. The patients were divided into 3 subgroups according to phenotype severity: (i) mild, epispadias (n = 43); (ii) intermediate, classic bladder exstrophy (n = 366); and (iii) severe, cloacal exstrophy (n = 31). These subgroups then were compared with identify factors that contribute to phenotype severity. RESULTS: Males were overrepresented in all subgroups. A relatively high prevalence of cleft lip, with or without cleft palate, was observed. Maternal smoking and medical radiation during the first trimester were associated with the severe cloacal exstrophy phenotype. Compliance with periconceptional folic acid supplementation was associated with the mildest phenotype (epispadias). CONCLUSIONS: Periconceptional folic acid supplementation appears to prevent the development of the severe phenotype of BEEC. PMID- 21679968 TI - Actigraphic monitoring of activity and rest in schizophrenic patients treated with olanzapine or risperidone. AB - Metabolic disturbances are a growing concern for the treatment of schizophrenia. As decreased activity and poor sleep quality are risk factors for metabolic disturbances, we investigated the activity and sleep patterns of schizophrenic patients using actigraphy. Seventy-three patients with schizophrenia spectrum disorder (mean age 29.2 +/- 10.2 years, 27 females) treated with olanzapine (n = 54) or risperidone (n = 19) and 36 age- and sex-matched healthy controls were examined. Actigraphic recordings were obtained throughout seven consecutive days. The Athens Insomnia Scale (AIS) and Epworth Sleepiness Scale (ESS) were used to assess sleep and daytime sleepiness. Drug side effects were evaluated with the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and Barnes Akathisia Rating Scale (BARS). Mental status was rated with the Positive and Negative Syndrome Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS). The patients had lower mean 24 h-activity (p < 0.001) and mean 10 h daytime-activity (p < 0.001), and longer time in bed (p < 0.001). Higher PANSS scores, especially in the negative symptoms scale, were related to lower activity (r(s) = -0.508, p < 0.001). Higher depressive symptoms were related to lower mean 24 h-activity (r(s) = -0.233, p = 0.049), longer time in bed (r(s) = 0.315, p = 0.007) and higher AIS (r(s) = 0.377, p = 0.001) and ESS scores (r(s) = 0.321, p = 0.006). Healthy females presented higher activity than healthy males (p < 0.001). Similar but not significant gender differences were observed in the patients. These findings show that patients with schizophrenia treated with olanzapine or risperidone exhibit low physical activity and altered sleep pattern which may promote metabolic side effects. These changes are linked to negative and depressive symptoms. PMID- 21679969 TI - Can pupil size and pupil responses during visual scanning contribute to the diagnosis of autism spectrum disorder in children? AB - The purpose of this study was to determine whether baseline pupil size and pupil responses during visual scanning with eye-tracking technology could discriminate children with autism spectrum disorder (ASD) from mental age-matched and chronological age-matched controls. To this end, we used stimuli consisting in still color photographs presented centrally to the participant's midline on a stimulus monitor. Each child was presented with a series of neutral faces, virtual faces (avatars) and different objects, separated by black slides. We recorded the mean pupil size and pupil size changes over time in each of the three categories of stimuli and during exposure to the black slides. Fifty-seven children participated in study (19 ASD, mean age 118 months; 19 mental age matched controls, mean age 87 months; and 19 chronological age-matched controls, mean age 118 months). We compared the baseline pupil size and pupil responses during visual scanning among the three diagnostic groups. During the presentation of slides, the mean pupil size in the ASD group was clearly smaller than in the MA-matched and CA-matched groups. Discriminate analysis of pupil size during the presentation of black slides and slides with visual stimuli successfully predicted group membership in 72% of the participants. Group membership was correctly classified in 89% of the participants in the ASD group, in 63% in the MA-matched group and in 63% in the CA-matched group. These potential biomarkers may contribute to our understanding of the differences in neurological development in the brain in autism and could prove useful as indicators of ASD. PMID- 21679970 TI - No association between APOE epsilon 4 allele and multiple sclerosis susceptibility: a meta-analysis from 5472 cases and 4727 controls. AB - BACKGROUND: Apolipoprotein E (APOE) gene epsilon4, 2 alleles have been reported to be associated with multiple sclerosis (MS), but results were conflicting. In order to derive a more precise estimation of the associations, a meta-analysis was performed. METHODS: The PubMed, EBSCO and BIOSIS databases were searched to identify eligible studies published in English before March, 2011. Data were extracted using standardized forms. The association was assessed by odds ratio (OR) with 95% confidence intervals (CIs). Begg's test was used to measure publication bias. RESULTS: A total of 20 case-control studies, containing 5472 patients/4727 controls for epsilon4 allele and 4636 patients/4047 controls for epsilon2 allele were included. The associations between APOE epsilon4, 2 alleles and MS were not found in overall population (OR(epsilon4)=0.997, 95% CI=0.861 1.156; OR(epsilon2)=1.097, 95% CI=0.940-1.279). Subgroup analysis revealed that APOE epsilon4, 2 alleles were not associated with an increased risk of MS in Caucasian population (OR(c-epsilon4)=0.924, 95% CI=0.819-1.041; OR(c epsilon2)=1.127, 95% CI=0.955-1.331). There was no evidence of publication bias according to Begg's regression test. CONCLUSIONS: This meta-analysis suggests that APOE epsilon4, 2 alleles are not associated with MS susceptibility. However, large sample, representative population-based studies with homogeneous MS patients, and well matched controls are warranted to confirm this finding. PMID- 21679971 TI - Developmental aspects of environmental neurotoxicology: lessons from lead and polychlorinated biphenyls. AB - The particular vulnerability of the developing nervous system for low-level exposure to chemicals is well established. It has been argued that some degree of developmental neurotoxicity was found for a large number of industrial chemicals. However, for only few of these, namely inorganic lead, arsenic, organic mercury and polychlorinated biphenyls (PCBs), human evidence is available to suggest that these may cause neurodevelopmental adversity and may, thus, be involved in contributing to neurodevelopmental disorders like autism, attention-deficit disorder, mental retardation or cerebral palsy. The focus of this overview is on PCBs and inorganic lead as developmental neurotoxicants at environmental levels of exposure. The adverse effects of inorganic lead on the developing brain have long been studied, and much emphasis has been on subtle degrees of mental retardation in terms of intelligence (IQ). The evidence is consistent, but the effect sizes are typically small. Research interest has also been devoted to studying aspects of "attention-deficit hyperactivity disorder" (ADHD) in children in relation to environmental exposure to lead in both cross-sectional and case control studies. More recently, we have also studied core elements of ADHD according to ICD-10 and DSM-IV in relation to environmental exposure to lead, mercury and aluminum in asymptomatic school children in Romania. Both, performance measures (several attention tasks) and questionnaire-based behavior ratings from parents and teachers showed that lead, but not Hg or Al, was consistently and adversely associated with core elements of ADHD. These findings in asymptomatic children nicely fit into the overall pattern of observations and suggest that, apart from genetic influences, low-level exposure to lead contributes to this neurodevelopmental disorder. Polychlorinated biphenyls (PCBs) are persistent organic pollutants with lipophilic properties. Due to their persistence, they are still present in environmental media at potentially harmful concentrations, although production and use of PCBs was already banned in the early 1980s. Several prospective cohort studies-including our Dusseldorf study have demonstrated that pre- and early postnatal exposure to PCBs is associated with deficit or retardation of mental and/or motor development, even after adjusting for maternal intelligence and developmental effects of the quality of the home environment. The pathophysiology is still unclear, although interference with thyroid metabolism during brain development is being discussed. Based on these reviews, three aspects, namely pre- vs. postnatal impact, effect scaling for comparative purposes, and integration of neurobehavioral findings into clinical and neuroscience contexts, are outlined as lessons learned from neurodevelopmental observations in children environmentally exposed to lead or PCBs. PMID- 21679972 TI - Progress in defining the premotor phase of Parkinson's disease. AB - Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinson's disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset. Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD. PMID- 21679973 TI - Thromboembolic complications of intravenous immunoglobulin therapy in patients with neuropathy: a two-year study. AB - BACKGROUND: The incidence and determinants of thromboembolic complications (TEC) of intravenous immunoglobulin (IVIg) therapy in patients with dysimmune neuropathy are uncertain. METHODS: We performed a retrospective study of patients with dysimmune neuropathy seen at our institution and treated with IVIg, over a 24-month period. RESULTS: Sixty-two patients were treated with a total of 616 courses of IVIg. TEC occurred in 7 patients. In 5, these occurred within 14 days after IVIg infusion ("early TEC"). Early TEC were significantly more frequent after courses administered to IVIg-naive patients (3/25 vs. 2/591 courses; p<0.001), but incidences were comparable in newly- vs. previously-treated patients (3/25 vs. 2/44 patients; p=0.34). Early TEC included 2 cases of myocardial infarction, one of acute coronary syndrome, one of deep vein thrombosis (DVT) with pulmonary embolism and one of isolated DVT. Mean dose per course was comparable in affected and unaffected patients (p=0.47), but administration of daily doses >= 35 g correlated significantly with occurrence of early TEC (p=0.028). Previous coronary disease (p=0.037) and immobility at time of treatment (p=0.049) were independent predictors of early TEC. Patients with early TEC had significantly more risk factors (p<0.001), and were significantly more likely to have >= 4 risk factors (p=0.006), than those without early TEC. CONCLUSION: The risk of TEC with IVIg is not negligible in patients with neuropathy. Although higher with a first-ever infusion, the general risk may be comparable in IVIg-naive and previously-treated patients. Administration of daily doses >= 35 g of IVIg may carry a greater risk of early TEC. Coronary disease, immobility at time of treatment, presence of >= 4 risk factors, should lead to caution and consideration of alternative treatments. PMID- 21679974 TI - Ostial left main coronary artery stenosis as an additional risk factor in off pump coronary artery bypass grafting. AB - BACKGROUND: Our aim was to determine whether general left main coronary artery stenosis (LMS) and ostial LMS pose additional risks after off-pump coronary artery bypass grafting (CABG) relative to non-left main coronary artery stenosis. METHODS: From January 1, 2008, to December 31, 2009, 4366 patients underwent primary isolated off-pump CABG at Beijing Anzhen Hospital. Disease was retrospectively classified as non-left main disease (n = 3523), nonostial LMS (n = 765), and ostial LMS (n = 78). Groups were propensity score matched. Kaplan Meier freedoms from major adverse cardiac and cerebrovascular events (MACCEs) were calculated. RESULTS: During the first 30 postoperative days, mortality was significantly higher in the ostial LMS group (6.41%) than in non-left main disease (0.855%, chi(2) = 7.78, P = .005) and nonostial LMS (1.28%, chi(2) = 4.71, P = .03) groups. Incidence of MACCEs was significantly higher in the ostial LMS group (20.5%) than in non-left main disease (5.98%, P = .000) and nonostial LMS (9.62%, P = .002) groups. Odds ratio for early MACCEs of ostial LMS versus non-left main disease was 3.74 (95% confidence interval, 1.72-8.17). At mean follow-up 12.8 +/- 7.5 months and cumulative follow-up 498.5 patient-years, difference among groups in freedom from MACCEs did not reach statistical significance (chi(2) = 2.39, P = .303). CONCLUSIONS: Ostial LMS poses additional early risks of mortality and MACCEs in off-pump CABG. Off-pump CABG for ostial LMS should proceed with greater of intraoperative surveillance and lower threshold for converting to on-pump CABG. PMID- 21679975 TI - Compensation of pulmonary function after upper lobectomy versus lower lobectomy. AB - OBJECTIVE: Major lung resection may induce expansion of the remaining lung, accompanied by some gain in the function of this lung; however, the impact of the site of resection on this compensatory response remains unclear. METHODS: We measured computed tomography-based functional lung volume, representing normal lung attenuation (-600 to -910 Hounsfield units), and spirometry-based lung function (forced expiratory volume in 1 second) preoperatively and 6 months postoperatively in patients with lung cancer and compared them between patients undergoing upper lobectomy (n = 34) and patients undergoing lower lobectomy (n = 26). RESULTS: We removed 17% +/- 4% of the functional lung volume by upper lobectomy and 27% +/- 5% by lower lobectomy (P < .001). Postoperatively, the residual lung expanded by various degrees, accompanied by a proportionate gain in the residual lung function (R = 0.6, P < .001). This anatomic and functional compensation of the residual lung was more remarkable after lower lobectomy than after upper lobectomy (P <.05). Consequently, the percentage loss of the functional lung volume after upper lobectomy (10% +/- 10%) did not differ significantly from that after lower lobectomy (9% +/- 12%, P = .6). Likewise, the percentage loss of lung function after upper lobectomy (12% +/- 16%) did not differ significantly from that after lower lobectomy (14% +/- 17%, P = .6). CONCLUSIONS: Although the lower lobectomy implies greater resection than the upper lobectomy, lung function after lower lobectomy was not inferior to that after upper lobectomy because the compensatory response appeared more robust after lower lobectomy. PMID- 21679976 TI - Penile urethral stricture reconstruction--flap or graft? Graft. PMID- 21679978 TI - Editorial comment. PMID- 21679977 TI - Factors associated with vertebral fractures in men treated with androgen deprivation therapy for prostate cancer. AB - PURPOSE: Androgen deprivation therapy for prostate cancer causes accelerated loss of bone mineral density and is associated with increased fracture risk. We evaluated risk factors associated with vertebral fractures among men enrolled in a fracture prevention trial. MATERIALS AND METHODS: Analysis included men receiving androgen deprivation therapy for prostate cancer and enrolled in a phase III fracture prevention trial. All men were 70 years old or older or had a low bone mineral density (T-score less than -1.5 for the lumbar spine or total hip). We analyzed demographic and laboratory characteristics of men with and those without vertebral fractures at study entry. RESULTS: Of the 1,244 subjects 162 (13.0%) had a vertebral fracture at baseline. The 2 factors significantly associated with vertebral fractures were white race (p=0.028 compared with nonwhite race) and osteoporosis (p=0.002 for osteoporosis at any site, p=0.053 for osteoporosis at the spine, p=0.002 for osteoporosis at the hip). Lower bone mineral density was also significantly associated with vertebral fractures when analyzed as a continuous variable. Factors not associated with vertebral fractures included age, country of residence, androgen deprivation therapy duration at baseline, androgen deprivation therapy mode, body mass index, testosterone, estradiol, C-telopeptide, bone specific alkaline phosphatase and osteocalcin. Results were similar in analyses limited to men 70 years old or older. CONCLUSIONS: White race and low bone mineral density were significantly associated with vertebral fractures in this study of men treated with androgen deprivation for prostate cancer. These observations should inform the assessment and management of fracture risk among such men. PMID- 21679979 TI - Editorial comment. PMID- 21679980 TI - Complications after robotic partial nephrectomy at centers of excellence: multi institutional analysis of 450 cases. AB - PURPOSE: We evaluated the incidence of perioperative complications after robotic partial nephrectomy. MATERIALS AND METHODS: We retrospectively reviewed the records of patients treated with robotic assisted partial nephrectomy across the 4 participating institutions. Demographic, blood loss, warm ischemia time, and intraoperative and postoperative complication data were collected. All complications were graded according to the Clavien classification system. RESULTS: A total of 450 consecutive robotic assisted partial nephrectomies were done between June 2006 and May 2009. Overall 71 patients (15.8%) had a complication, including intraoperative and postoperative complications in 8 (1.8%) and 65 (14.4%), respectively. Hemorrhage developed in 2 patients (0.2%) intraoperatively and in 22 (4.9%) postoperatively. Seven patients (1.6%) had urine leakage. As classified by the Clavien system, complications were grade I-II in 76.1% of cases and grade III-IV in 23.9%. Robotic assisted partial nephrectomy was converted to open or conventional laparoscopic surgery in 3 patients (0.7%) and to radical nephrectomy in 7 (1.6%). There were no deaths. CONCLUSIONS: Current data indicate that robotic assisted partial nephrectomy is safe. Most postoperative complications are Clavien grade I or II, or can be managed conservatively. PMID- 21679981 TI - Clinical predictive factors of poor outcome in patients with stage pT0 disease at radical cystectomy. AB - PURPOSE: We evaluated new pre-cystectomy predictive factors for outcomes in patients with no evidence of residual tumor at cystectomy (pT0). MATERIALS AND METHODS: A total of 1,114 patients underwent radical cystectomy at our institution between August 1978 and June 2002, of whom 141 (12.66%) had stage pT0. We analyzed overall and disease specific survival in relation to pre cystectomy predictive factors, such as clinical stage, grade, size, previous nonmuscle invasive disease, number of previous recurrences, associated carcinoma in situ and lymphovascular invasion in the transurethral resection. Other factors analyzed were lymph node (N+) at cystectomy and induction chemotherapy. RESULTS: Clinical stage was cTa in 10 patients, cT1 in 34, cT2 in 55, cT3 in 30 and cTis in 12. At a median followup of 42.5 months overall survival was 62.53% and disease specific survival was 79.14%. Metastatic disease developed in 17 cases (12.1%). Univariate analysis revealed worse disease specific survival in patients in whom muscle invasive tumor developed after nonmuscle invasive disease (p<0.05), and in those who presented with 5 or more previous recurrences (p<0.05), lymphovascular invasion in the transurethral resection (p<0.05) and N+ at cystectomy (p<0.05). Multivariate analysis confirmed a statistically significant association between disease specific survival and 5 or more previous recurrences (HR 1.5, 95% CI 1.07-2.10, p=0.018), muscle invasive tumor after nonmuscle invasive disease (HR 4.4, 95% CI 1.20-16.5, p=0.026) and lymphovascular invasion in the transurethral resection (HR 1.7, 95% CI 1.12-2.30, p=0.04). CONCLUSIONS: Although clinical outcomes in patients with stage pT0 disease are often excellent, metastatic disease develops in a percentage of them. Muscle invasive tumor after primary nonmuscle invasive disease, 5 or more previous recurrences and lymphovascular invasion in the transurethral resection predict poor survival. PMID- 21679982 TI - Treatment trends for stage I renal cell carcinoma. AB - PURPOSE: Renal cell carcinoma is increasingly diagnosed at stage I, and among stage I cases mean tumor size has been decreasing. Previous reports suggest that nephron sparing surgery is underused for small renal cell carcinomas. We determined updated, population based treatment trends for stage I renal cell carcinoma. MATERIALS AND METHODS: The National Cancer Data Base, which captures approximately 70% of all cancer diagnoses in the United States, was queried for renal cell carcinoma in adults diagnosed between 1993 and 2007. Trends in treatment, including no surgery, total nephrectomy, partial nephrectomy and focal ablation, were analyzed among all stage I tumors and small stage I tumors categorized by size. Logistic regression was used to identify predictors of nephron sparing surgery (partial nephrectomy or focal ablation). RESULTS: During the study period we identified 242,740 renal cell carcinomas, of which 127,691 were stage I. For all stage I tumors partial nephrectomy increased from 6.3% to 32.2% of cases and ablation increased from 1.0% to 6.8%. For tumors less than 2.0, 2.0 to 2.9 and 3.0 to 3.9 cm partial nephrectomy increased from 15.3% to 61.1%, 11.0% to 44.2% and 7.2% to 31.1%, respectively (each p<0.001). Female gender, black race, Hispanic ethnicity, lower income, older age and treatment at community hospitals were associated with lower use of nephron sparing. CONCLUSIONS: While total nephrectomy is still likely overused for small renal cell carcinoma, nephron sparing surgery for stage I renal cell carcinoma has increased substantially in the last 15 years with about 4-fold increases across tumor sizes. These trends appear to be ongoing but sociodemographic disparities exist which must be rectified. PMID- 21679983 TI - Comparison of 11C-choline with 18F-FDG in positron emission tomography/computerized tomography for staging urothelial carcinoma: a prospective study. AB - PURPOSE: 11C-choline was postulated to provide better diagnostic capabilities than other tracers used in positron emission tomography/computerized tomography for staging urothelial carcinoma. We compared the value of using 11C-choline with the well investigated 18F-FDG tracer in this setting. MATERIALS AND METHODS: The study group included 20 consecutive patients with bladder cancer who underwent evaluation for local and metastatic disease using 11C-choline and 18F-FDG positron emission tomography/computerized tomography. Patients were treated with radical cystectomy with lymph node dissection, radiation therapy or chemotherapy independent of positron emission tomography/computerized tomography results. The histopathological findings (when available), followup positron emission tomography and radiological imaging served as the reference standard. Using the paired t test we compared the maximum standardized uptake and lesion-to background ratio of the tracers. The positive predictive values were determined. RESULTS: A total of 51 lesions showed abnormal tracer activity. The positive predictive value for all detected lesions was 84.7% for 11C-choline positron emission tomography/computerized tomography and 90.7% for 18F-FDG positron emission tomography/computerized tomography. The corresponding positive predictive values for extravesical lesions were 79.4% and 88.2%, respectively. Discrepant findings between the tracers were noted at 11 sites. 18F-FDG positron emission tomography/computerized tomography correctly identified 4 extravesical metastases missed by choline positron emission tomography/computerized tomography in the absence of a contrary observation. Mean maximum standardized uptake and lesion-to-background ratio at extravesical sites were significantly higher for FDG. CONCLUSIONS: Within the limitations of a relatively small number of patients and partial histopathological analysis, 11C-choline positron emission tomography/computerized tomography appears to have no advantage compared to 18F FDG positron emission tomography/computerized tomography in the detection of metastatic bladder cancer. 18F-FDG positron emission tomography/computerized tomography has a tendency toward greater accuracy. PMID- 21679984 TI - Characterizing clinically significant prostate cancer using template prostate mapping biopsy. AB - PURPOSE: Definitions of prostate cancer risk are limited since accurate attribution of the cancer grade and burden is not possible due to the random and systematic errors associated with transrectal ultrasound guided biopsy. Transperineal prostate mapping biopsy may have a role in accurate risk stratification. We defined the transperineal prostate mapping biopsy characteristics of clinically significant disease. MATERIALS AND METHODS: A 3 dimensional model of each gland and individual cancer was reconstructed using 107 radical whole mount specimens. We performed 500 transperineal prostate mapping simulations per case by varying needle targeting errors to calculate sensitivity, specificity, and negative and positive predictive value to detect lesions 0.2 ml or greater, or 0.5 ml or greater. Definitions of clinically significant cancer based on a combination of Gleason grade and cancer burden (cancer core length) were derived. RESULTS: Mean+/-SD patient age was 61+/-6.4 years (range 44 to 74) and mean prostate specific antigen was 9.7+/-5.9 ng/ml (range 0.8 to 36.2). We reconstructed 665 foci. The total cancer core length from all positive biopsies for a particular lesion that detected more than 95% of lesions 0.5 ml or greater and 0.2 ml or greater was 10 mm or greater and 6 mm or greater, respectively. The maximum cancer core length that detected more than 95% of lesions 0.5 ml or greater and 0.2 ml or greater was 6 mm or greater and 4 mm or greater, respectively. We combined these cancer burden thresholds with dominant and nondominant Gleason pattern 4 to derive 2 definitions of clinically significant disease. CONCLUSIONS: Transperineal prostate mapping may provide an effective method to risk stratify men with localized prostate cancer. The definitions that we present require prospective validation. PMID- 21679985 TI - Active patient decision making regarding nerve sparing during radical prostatectomy: a novel approach. AB - PURPOSE: The motivation to preserve sexual function can vary widely among patients before prostatectomy. Increasing patient involvement may allow a more personalized experience and may improve satisfaction. We assessed a strategy of surgeon deference to patient choice in regard to nerve sparing to determine to what degree patients are rational actors and capable of active decision making. MATERIALS AND METHODS: A total of 150 patients treated with prostatectomy participated in a standardized preoperative discussion regarding the concept of nerve sparing, extracapsular extension and the potential need for adjuvant radiation in the event of local recurrence. Each patient was given his nomogram predicted risk of extracapsular extension and then elected nerve sparing or nonnerve sparing. The corresponding procedure was performed unless grossly invasive disease was encountered. RESULTS: Of the 150 patients 109 chose nerve sparing (73%) and 41 chose nonnerve sparing (27%). In patients with a nomogram predicted risk of extracapsular extension less than 20%, 20% to 50% and greater than 50%, nerve sparing was elected by 88%, 41% and 25%, respectively. Patients with lower risks of extracapsular extension electing nonnerve sparing were older and had higher rates of erectile dysfunction. CONCLUSIONS: Empowering patients to decide on their nerve sparing status is a reasonable strategy that did not lead to a high rate of patients with a high risk of extracapsular extension electing nerve sparing. With proper counseling informed patients made reasonable decisions, and appeared to be conservative, prioritizing cancer control in the majority of instances where extracapsular extension risk was high. In addition, they may have been overly conservative in electing nonnerve sparing when the risk was low. PMID- 21679987 TI - Assessment of men before androgen deprivation therapy. PMID- 21679988 TI - Impact of postoperative C-reactive protein level on recurrence and prognosis in patients with N0M0 clear cell renal cell carcinoma. AB - PURPOSE: Preoperative C-reactive protein is a strong predictor of recurrence and prognosis in patients with renal cell carcinoma while postoperative C-reactive protein reportedly predicts survival in patients with metastatic renal cell carcinoma. We evaluated the impact of postoperative C-reactive protein on recurrence and prognosis in patients with N0M0 clear cell renal cell carcinoma. MATERIALS AND METHODS: We defined increased preoperative C-reactive protein as 1 mg/dl or greater and postoperative C-reactive protein normalization as at least 1 postoperative measurement of less than 0.3 mg/dl. We reviewed the records of 263 patients with N0M0 clear cell renal cell carcinoma who underwent nephrectomy, and in whom preoperative and postoperative C-reactive protein values were available. We used multivariate analysis to identify independent factors predicting recurrence and prognosis. We also evaluated C-reactive protein at recurrence and its impact on survival. RESULTS: Increased preoperative C-reactive protein and nonnormalization of postoperative C-reactive protein were associated with worse clinicopathological factors. Postoperative C-reactive protein nonnormalization, increased preoperative C-reactive protein, microvascular invasion and histological tumor necrosis were independent predictors for recurrence. Risk stratification using these factors effectively predicted the possibility of recurrence. Anemia, thrombocytosis and postoperative C-reactive protein nonnormalization were independent predictors of overall survival. Postoperative followup revealed recurrence in 50 patients. The 3-year survival rate in patients with C-reactive protein 0.3 mg/dl or greater at recurrence was significantly lower than that in patients with less than 0.3 mg/dl at recurrence (47.3% vs 81.6%). CONCLUSIONS: Nonnormalization of postoperative C-reactive protein is a strong predictor of recurrence and prognosis. Patients with C-reactive protein 0.3 mg/dl or greater at recurrence might not survive as long as those with C reactive protein less than 0.3 mg/dl at recurrence. PMID- 21679989 TI - Penile urethral stricture reconstruction--flap or graft? Flap. PMID- 21679990 TI - Editorial comment. PMID- 21679991 TI - Determination of the cutoff value of the proportion of cystic change for prognostic stratification of clear cell renal cell carcinoma. AB - PURPOSE: Cystic renal cell carcinoma has more favorable biology than noncystic renal cell carcinoma. Recently cystic change detected grossly or by low power microscopy was found to be a good prognostic factor for clear cell renal cell carcinoma. We assessed the optimal cutoff value of the proportion of cystic change with prognostic significance for clear cell renal cell carcinoma. MATERIALS AND METHODS: We identified 223 patients with clear cell renal cell carcinoma who underwent partial or radical nephrectomy between 2001 and 2003. The cystic proportion of the tumor cut surface was calculated objectively and its prognostic significance was evaluated. RESULTS: The ROC curve showed that a cystic percent of between 6% and 10% was appropriate to detect patients with renal cell carcinoma at low risk for cancer mortality and progression. A cutoff of 6% was adopted as a break point of cystic change for patient stratification. We analyzed the records of 87 patients (39.0%) with tumors with a cystic proportion of greater than 5%, that is 6% or greater. They had significantly lower stage and lower Fuhrman nuclear grade than patients with tumors with a cystic change of 5% or less (each p<0.0001). On multivariate analysis a cystic proportion of more than 5% was a good prognostic indicator of cancer specific and progression-free survival (HR 0.221, p=0.044 and HR 0.214, p=0.004, respectively). CONCLUSIONS: In patients with clear cell renal cell carcinoma a cystic change comprising more than 5% of the tumor is a good independent predictor of survival. PMID- 21679992 TI - New N staging system of penile cancer provides a better reflection of prognosis. AB - PURPOSE: We determined whether the new N staging system, which was introduced in 2009, leads to more specific prediction of survival in patients with penile squamous cell carcinoma. MATERIALS AND METHODS: We analyzed the records of 60 patients in whom node positive penile cancer was surgically resected from 1990 to 2008. All cases were staged according the 6th and 7th N staging system after pathological review. Histopathological information on the number of positive lymph nodes, lymph node metastasis laterality, extranodal extension, pelvic lymph node metastasis and lymph node ratio were also recorded. We evaluated the added information on these nodal related prognostic factors to the current N classification. Recurrence-free survival was calculated. Predictive accuracy was assessed by the concordance index. RESULTS: Disease recurred in 27 of the 60 patients (42.4%) at a median of 10 months. In the 33 patients without recurrence at the last visit median followup was 53 months. Using the 6th N classification the 3-year recurrence-free survival rate was 69.8%, 48.2% and 33.3% for the N1, N2 and N3 categories, respectively. Log rank survival analysis failed to show a statistical difference (p=0.054). For the new 7th N categories the 3-year recurrence-free survival rate was 87.5%, 57% and 31.8% in the corresponding N1 to N3 groups. Better survival stratification was observed on analysis (p<0.001). Adding lymph node metastasis laterality or lymph node ratio significantly increased the accuracy of the 7th N category to predict recurrence-free survival. CONCLUSIONS: The new N staging system better reflects the prognosis in patients with penile cancer. PMID- 21679993 TI - Tumor focality does not predict biochemical recurrence after radical prostatectomy in men with clinically localized prostate cancer. AB - PURPOSE: We characterized prostate cancer focality in regard to clinicopathological features, prognostic value and impact on biochemical outcome. MATERIALS AND METHODS: We retrospectively reviewed the records of 1,366 patients in our prospective database who underwent radical prostatectomy between 1999 and 2010 for clinically localized prostate cancer with pathological evaluation using whole mount sectioning techniques and tumor mapping. Unifocal disease was defined as the identification of a solitary cancer focus in the prostate without additional tumor foci or satellite lesions, ie multifocal disease, on histopathological evaluation. Cox regression modeling was used to identify predictors of biochemical progression among groups. RESULTS: A total of 184 patients (13%) fulfilled our unifocal tumor criteria. Unifocal tumors tended to be smaller in volume and in greatest diameter than multifocal tumors (p<0.0001 and <0.005, respectively). Of patients with pathologically insignificant disease the relative proportion with unifocal tumors increased to 28% from 13% in the overall cohort (p<0.0005). Also, tumor focality failed to predict biochemical recurrence in univariate and multivariate models. Accordingly we noted no significant differences in 5-year biochemical recurrence-free survival for unifocal and multifocal tumors (66% and 61%, respectively, p=0.76). Limitations of this study include its retrospective nature. CONCLUSIONS: In this study tumor focality failed to predict patients likely to experience biochemical failure. Tumor characteristics were similar regardless of focality. However, unifocal tumors had smaller volume and were more commonly seen as clinically insignificant compared to multifocal tumors. PMID- 21679994 TI - Assessment of renal oxygenation during partial nephrectomy using hyperspectral imaging. AB - PURPOSE: DLP(r) hyperspectral imaging is a technology that can be used to construct a highly sensitive, noninvasive, real-time tissue hemoglobin saturation map. This almost video rate technology may be a tool to monitor renal perfusion/oxygenation during hilar occlusion and kidney recovery. We describe our initial experience using hyperspectral imaging to assess renal hemoglobin saturation parameters during open partial nephrectomy for renal cortical tumors in humans. MATERIALS AND METHODS: Hyperspectral images were collected intraoperatively during open partial nephrectomy. The kidney was actively illuminated using a hyperspectral imaging camera with visible light consisting of a chemometrically predetermined spectrum (520 to 645 nm) for hemoglobin. Spectroscopic reflectance images were captured by a focal plane array, which were digitally processed to visualize the percent of oxyhemoglobin at each image pixel. RESULTS: Hyperspectral imaging was done in 21 patients with a mean age of 56 years who were undergoing partial nephrectomy. Mean clamp time was 37.0 minutes. Median baseline percent of oxyhemoglobin in all patients was 74.6%. Hyperspectral imaging revealed a median 20.0% decrease from normalized pre occlusion baseline at a median 10.3 minutes of hilar occlusion, where it plateaued for the duration of kidney ischemia. Upon reperfusion the percent of oxyhemoglobin returned to baseline at a median of 5.8 minutes. CONCLUSIONS: Hyperspectral imaging is a real-time noninvasive method to assess renal oxyhemoglobin saturation intraoperatively throughout the kidney. A nadir percent of oxyhemoglobin is attained within 10 minutes of hilar occlusion. This knowledge may allow future surgical or pharmacological interventions that titrate or minimize ischemic injury in real time. PMID- 21679995 TI - Patient preoperative expectations of urinary, bowel, hormonal and sexual functioning do not match actual outcomes 1 year after radical prostatectomy. AB - PURPOSE: We studied patient expectations of post-prostatectomy recovery from urinary incontinence, and urinary irritable, hormonal, bowel and sexual function symptoms after preoperative counseling. MATERIALS AND METHODS: Patients undergoing radical prostatectomy, recruited between June 2007 and November 2008, were extensively counseled preoperatively regarding expected outcomes. They were assessed at baseline and 1 year after surgery using the short form of the Expanded Prostate Index Composite. Their baseline expectations of functional outcomes 1 year after surgery were assessed using the Expanded Prostate Index Composite-Expectations. Pearson's correlation coefficient and a multiple linear regression were used to assess the associations between Expanded Prostate Index Composite-Expectations and Expanded Prostate Index Composite-Short Form at baseline and 1 year. RESULTS: A total of 152 consenting patients completed all questionnaires. Baseline sexual function score predicted significantly expectations of sexual function (p<0.0001) and urinary incontinence (p<0.0001) scores. Expanded Prostate Index Composite-Expectations predicted Expanded Prostate Index Composite-sexual function at 1 year (p<0.0001). Of the patients 36% and 40% expected the same as baseline function at 1 year in urinary incontinence and sexual function, respectively, and 17%, 45%, 39%, 15% and 32% expected worse than baseline function at 1 year in urinary incontinence, urinary irritable symptoms, bowel function, hormonal function and sexual function, respectively. One year after prostatectomy fewer than 22% of patients attained lower than expected urinary irritable symptoms, and bowel and hormonal function. However, 47% and 44% of patients attained lower than expected function for urinary incontinence and sexual function, respectively. Surprisingly 12% and 17% of patients expected better than baseline urinary incontinence and sexual function at 1 year after surgery. CONCLUSIONS: Men have unrealistic expectations of urinary and sexual function after prostatectomy despite preoperative counseling. We hypothesize potentially responsible psychological mechanisms. These data provide a baseline for further preoperative educational interventions. PMID- 21679996 TI - The potential impact of reproducibility of Gleason grading in men with early stage prostate cancer managed by active surveillance: a multi-institutional study. AB - PURPOSE: We evaluated the reproducibility of Gleason grading as relevant to the clinical treatment of men on active surveillance. MATERIALS AND METHODS: Three sets of digital images of prostatic adenocarcinoma in biopsies were reviewed and assigned Gleason scores by a total of 11 pathologists from 7 institutions. Interobserver and intra-observer reproducibility were assessed for assignment of the highest Gleason pattern (3 vs 4 or higher). We also identified 97 consecutive patients on active surveillance. Prostate biopsy glass slides from 82 of the patients were available for re-review and the frequency of carcinoma requiring the distinction of tangentially sectioned Gleason pattern 3 from 4 was determined. RESULTS: Interobserver reproducibility for classic Gleason patterns was substantial (Light's kappa 0.76). Interobserver reproducibility for the histological distinction of tangentially sectioned Gleason pattern 3 from Gleason pattern 4 was only fair (Light's kappa 0.27). Intra-observer reproducibility ranged from 65% to 100% (mean 81.5%). Of the 82 patients on active surveillance 61 had carcinoma and 15 (24.5%) had a set of biopsies with at least 1 focus in which the distinction between tangentially sectioned Gleason pattern 3 and poorly formed pattern 4 glands had to be considered. CONCLUSIONS: The reproducibility of grading classic Gleason patterns is high. However, variability in grading occurred when distinguishing between tangentially sectioned pattern 3 glands and the poorly formed gland subset of pattern 4. Developing universally accepted histological and/or molecular criteria to distinguish these patterns and subsequently characterizing their natural history would be useful when treating patients on active surveillance. PMID- 21679997 TI - Significance of prostate adenocarcinoma perineural invasion on biopsy in patients who are otherwise candidates for active surveillance. AB - PURPOSE: Perineural invasion on biopsy is associated with extraprostatic extension at radical prostatectomy. To our knowledge the significance of perineural invasion on biopsy in patients who otherwise meet the criteria for active surveillance has not been studied. MATERIALS AND METHODS: The biopsy criteria for active surveillance were Gleason score 6 or less, 2 or fewer positive cores and 50% or less involvement any positive core. All cases had at least 12 biopsy cores. A total of 313 cases met the biopsy criteria for active surveillance, and elected to undergo immediate radical prostatectomy at our institution between 1992 and 2008. These cases included 51 with perineural invasion and 262 without perineural invasion. RESULTS: There was no significant difference in patient age and mean serum prostate specific antigen at diagnosis in cases with and those without perineural invasion. Cases with perineural invasion on biopsy had a higher maximum percentage of cancer on biopsy (18.6%) vs those without perineural invasion (15.0%, p=0.02). Cases with perineural invasion also had slightly more with 2 positive cores compared to cases without perineural invasion (56.9% and 39.7%, respectively, p=0.02). Despite a greater extent of cancer on biopsy, cases with and those without perineural invasion on biopsy showed no significant difference in surgical margin involvement (6% vs 7.3%, respectively) or organ confined disease (84.3% vs 91.6%, respectively). CONCLUSIONS: Cases that meet biopsy criteria for active surveillance yet have perineural invasion showed no significant difference from those without perineural invasion in terms of adverse findings at radical prostatectomy. Patients with perineural invasion who meet criteria for active surveillance should not be excluded from this treatment option. PMID- 21679998 TI - Editorial comment. PMID- 21679999 TI - Can we stop prostate specific antigen testing 10 years after radical prostatectomy? AB - PURPOSE: The risk of biochemical recurrence is inversely related to the relapse free interval after radical prostatectomy. We examined predictors of late biochemical recurrence, and the relationship between timing of biochemical recurrence and long-term survival outcomes. MATERIALS AND METHODS: Of 10,609 men treated with radical prostatectomy 1,684 had biochemical recurrence. We examined predictors of late biochemical recurrence (more than 10 years after radical prostatectomy), and calculated metastasis-free and cancer specific survival rates from the time of biochemical recurrence. In the subset of 1,583 men with an undetectable prostate specific antigen at 10 years we calculated actuarial metastasis-free and cancer specific survival estimates at 20 years after radical prostatectomy. RESULTS: Of the biochemical recurrence studied 77.0%, 16.6%, 4.9% and 1.5% occurred at 5 or less, greater than 5 to 10, greater than 10 to 15 and more than 15 years postoperatively. Late recurrence was associated with more favorable pathological features, as well as higher metastasis-free and cancer specific survival rates. For men with an undetectable prostate specific antigen at 10 years the actuarial probability of biochemical recurrence and metastasis at 20 years varied by stage and grade, with no metastases in patients with a prostatectomy Gleason score 6 or less. A single patient with an undetectable prostate specific antigen at 10 years died of prostate cancer within 20 years after radical prostatectomy. CONCLUSIONS: Men with an undetectable prostate specific antigen for more than 10 years have a low risk of subsequent biochemical recurrence, with correspondingly lower rates of metastasis and death. These patients should be counseled that their risk of subsequent cancer related morbidity and mortality is low. Furthermore, these results suggest that annual prostate specific antigen testing may be safely discontinued after 10 years for men with a prostatectomy Gleason score 6 or less and/or limited life expectancy. PMID- 21680000 TI - Editorial comment. PMID- 21680002 TI - COPING with publication ethics. PMID- 21680001 TI - Positive surgical margins after robotic assisted radical prostatectomy: a multi institutional study. AB - PURPOSE: Positive surgical margins are an independent predictive factor for biochemical recurrence after radical prostatectomy. We analyzed the incidence of and associative factors for positive surgical margins in a multi-institutional series of 8,418 robotic assisted radical prostatectomies. MATERIALS AND METHODS: We analyzed the records of 8,418 patients who underwent robotic assisted radical prostatectomy at 7 institutions. Of the patients 323 had missing data on margin status. Positive surgical margins were categorized into 4 groups, including apex, bladder neck, posterolateral and multifocal. The records of 6,169 patients were available for multivariate analysis. The variables entered into the logistic regression models were age, body mass index, preoperative prostate specific antigen, biopsy Gleason score, prostate weight and pathological stage. A second model was built to identify predictive factors for positive surgical margins in the subset of patients with organ confined disease (pT2). RESULTS: The overall positive surgical margin rate was 15.7% (1,272 of 8,095 patients). The positive surgical margin rate for pT2 and pT3 disease was 9.45% and 37.2%, respectively. On multivariate analysis pathological stage (pT2 vs pT3 OR 4.588, p<0.001) and preoperative prostate specific antigen (4 or less vs greater than 10 ng/ml OR 2.918, p<0.001) were the most important independent predictive factors for positive surgical margins after robotic assisted radical prostatectomy. Increasing prostate weight was associated with a lower risk of positive surgical margins after robotic assisted radical prostatectomy (OR 0.984, p<0.001) and a higher body mass index was associated with a higher risk of positive surgical margins (OR 1.032, p<0.001). For organ confined disease preoperative prostate specific antigen was the most important factor that independently correlated with positive surgical margins (4 or less vs greater than 10 ng/ml OR 3.8, p<0.001). CONCLUSIONS: The prostatic apex followed by a posterolateral site was the most common location of positive surgical margins after robotic assisted radical prostatectomy. Factors that correlated with cancer aggressiveness, such as pathological stage and preoperative prostate specific antigen, were the most important factors independently associated with an increased risk of positive surgical margins after robotic assisted radical prostatectomy. PMID- 21680003 TI - A phase I trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of bacillus Calmette-Guerin refractory nonmuscle invasive bladder cancer. AB - PURPOSE: Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin bound paclitaxel (Abraxane(r), ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. MATERIALS AND METHODS: Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. RESULTS: A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. CONCLUSIONS: Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen. PMID- 21680004 TI - Effect of parenchymal volume preservation on kidney function after partial nephrectomy. AB - PURPOSE: The percent of functional volume preservation is a primary determinant of functional outcome after partial nephrectomy. We assessed what is to our knowledge a novel method to estimate the percent of functional volume preservation to assess its effect on functional outcomes. MATERIALS AND METHODS: We studied the glomerular filtration rate outcome based on the modification of diet in renal disease 2 in 39 patients with normal preoperative serum creatinine who underwent open or laparoscopic partial nephrectomy from January 2007 to December 2009. A cylindrical volume ratio method was used to estimate the percent of functional volume preservation on computerized tomography images obtained before and after partial nephrectomy. A model to predict the postoperative estimated glomerular filtration rate was based on multiplying the preoperative glomerular filtration rate by the percent of functional volume preservation, followed by adjustment for the functional contribution of the contralateral kidney. Correlation and multiple regression analysis was done to test the model. RESULTS: The median preoperative, nadir and late estimated glomerular filtration rate in the cohort was 104 (range 53 to 234), 75 (range 21 to 189) and 90 ml per minute/1.73 m2 (range 45 to 228), respectively. The nadir and late estimated glomerular filtration rate was measured at a median of 2 (range 0 to 8) and 358 days (range 13 to 827), respectively. The median percent of functional volume preservation was 88% (range 50% to 100%) for the operated kidney and 94% (range 75% to 105%) when adjusted for total bilateral kidney volume. We noted a 96% correlation between the predicted and the observed late estimated glomerular filtration rate. On multivariate analysis the preoperative glomerular filtration rate (p<0.001) and ischemia time (p=0.02) correlated with the nadir glomerular filtration rate, and the preoperative glomerular filtration rate (p<0.001) and the percent of functional volume preservation (p=0.04) correlated with the late glomerular filtration rate. CONCLUSIONS: These data support the notion that preoperative nephron endowment and the percent of functional volume preservation are the primary determinants of the long-term functional outcome after partial nephrectomy in patients with normal preoperative kidney function who have ischemia time within acceptable limits. PMID- 21680005 TI - Achieving realistic postoperative expectations in the prostatectomy population- is it possible? PMID- 21680006 TI - Increased plastic litter cover affects the foraging activity of the sandy intertidal gastropod Nassarius pullus. AB - This study analyzed the foraging behavior of the gastropod Nassarius pullus on garbage-impacted sandy shores of Talim Bay, Batangas, Philippines. The effect of different levels of plastic garbage cover on foraging efficiency was investigated. Controlled in situ baiting experiments were conducted to quantify aspects of foraging behavior as affected by the levels of plastic litter cover in the foraging area. The results of the study indicated that the gastropod's efficiency in locating and in moving towards a food item generally decreased as the level of plastic cover increased. Prolonged food searching time and increased self-burial in sand were highly correlated with increased plastic cover. The accuracy of orientation towards the actual position of the bait decreased significantly when the amount of plastic cover increased to 50%. These results are consistent with the significant decreases in the abundance of the gastropod observed during periods of deposition of large amounts of plastic and other debris on the shore. PMID- 21680007 TI - Cumulative second-harmonic analysis of ultrasonic Lamb waves for ageing behavior study of modified-HP austenite steel. AB - The cumulative second-harmonic analysis of ultrasonic Lamb wave has been performed to study the precipitation kinetics and microvoid initiation of ferritic Cr-Ni alloy steel during the ageing process. Ageing of ferritic Cr-Ni alloy materials have been done at 1223 K and 1173 K for different degradation time intervals and air cooled. The results show that the normalized acoustic nonlinearity of Lamb wave increases with the formation of fine precipitates at the early stage of ageing till about 1000 h and keeps as a plateau with the precipitates dynamic balance for a long-term ageing, and then decreases gradually at the final holding time with the coarsening of precipitates and initiation of microvoids. The results also show that the variation of nonlinear Lamb wave follows the same trend as that of hardness in materials. Therefore, the cumulative second-harmonic of ultrasonic Lamb waves has been found to be strongly sensitive to the precipitates behavior and microstructure evolution during the thermal ageing of ferritic Cr-Ni alloy steel. PMID- 21680008 TI - Metallothioneins failed to reflect mercury external levels of exposure and bioaccumulation in marine fish--considerations on tissue and species specific responses. AB - The suitability of metallothioneins (MT) in fish as biomarker of exposure to mercury has been questioned. Therefore, this study aimed at investigating the relationship between external levels of exposure, mercury accumulation and MT content, assessing species and tissue specificities. Two ecologically different fish species--Dicentrarchus labrax and Liza aurata--were surveyed in an estuary historically affected by mercury discharges. Total mercury (T-Hg) and MT content were determined in gills, blood, liver, kidney, muscle and brain. All tissues reflected differences in T-Hg accumulation in both species, although D. labrax accumulated higher levels. Regarding MT, D. labrax revealed a depletion in brain MT content and an incapacity to induce MT synthesis in all the other tissues, whereas L. aurata showed the ability to increase MT in liver and muscle. Tissue specificities were exhibited in the MT inducing potential and in the susceptibility to MT decrease. L. aurata results presented muscle as the most responsive tissue. None of the investigated tissues displayed significant correlations between T-Hg and MT levels. Overall, the applicability of MT content in fish tissues as biomarker of exposure to mercury was uncertain, reporting limitations in reflecting the metal exposure levels and the subsequent accumulation extent. PMID- 21680009 TI - Temporal trends of polyfluoroalkyl compounds (PFCs) in liver tissue of grey seals (Halichoerus grypus) from the Baltic Sea, 1974-2008. AB - Temporal trends of polyfluoroalkyl compounds (PFCs) were examined in grey seal (Halichoerus grypus) liver from the Baltic Sea over a period of 35 years (1974 2008). In total, 17 of 43 PFCs were found, including the perfluoroalkyl sulfonates (C(4)-C(10) PFSAs), perfluorooctanesulfinate (PFOSi), long chain perfluoroalkyl carboxylates (C(7)-C(14) PFCAs), and perfluoroalkyl sulfonamides (i.e., perfluorooctane sulfonamide (FOSA) and N-ethyl perfluorooctane sulfonamide (EtFOSA)), whereas saturated and unsaturated fluorotelomer carboxylates, shorter chain PFCAs and perfluoroalkyl phosphonic acids were not detected. Perfluorooctane sulfonate (PFOS) was the predominant compound (9.57-1,444 ng g( 1) wet weight (ww)), followed by perfluorononanoate (PFNA, 0.47-109 ng g(-1) ww). C(6)-C(8) PFSAs, PFOSi and C(7)-C(13) PFCAs showed statistically significant increasing concentrations between 1974 and 1997, with a peak in 1997 and then decreased or levelled off (except for C(12) and C(13) PFCAs). FOSA had a different temporal trend with a maximum in 1989 followed by significant decreasing concentrations until 2008. Toxicological implications for grey seals are limited, but the maximal PFOS concentration found in this study was about 40 times lower than the predicted lowest observed effect concentrations (LOEC). The statistically significant decreasing concentrations or levelling off for several PFCs in the relative closed marine ecosystem of the Baltic Sea indicate a rapidly responding to reduced emissions to the marine environment. However, the high concentrations of PFOS and continuing increasing concentrations of the longer chain PFCAs (C(12)-C(14)) shows that further work on the reduction of environmental emissions of PFCs are necessary. PMID- 21680010 TI - Residual congener pattern of dioxins in human breast milk in southern Vietnam. AB - This study evaluated residual congener patterns of dioxin/furan (=PCDD/DF) related to tactical herbicides aerially sprayed over the regions of southern Vietnam through Operation Ranch Hand. The study focused on Cam Chinh (CC) commune, Quang Tri province (an area sprayed with tactical herbicides), and the Cam Phuc (CP) commune, Ha Tinh province (a non-sprayed area). Breast milk samples for analysis were collected in September 2002 and July 2003 from lactating primiparous and multiparous mothers born after the war (<31 years old). We found the levels of each congener in the CC commune were higher than in the CP commune, and determined specificity in the PCDD/DF congener pattern in CC commune samples by cluster analysis. The congener pattern is characterized by higher (the hexa-, the hepta-, and the octa-) chlorinated PCDD/DFs; this appears to be the same profile as that presented by pentachlorophenol (PCP), rather than 2,4,5 trichlorophenoxy acid (2,4,5-T) contaminated with 2,3,7,8-TCDD. A GC/MS study in the 1970s detected the chlorophenols 2,4-di and 2,4,6-trichlorophenol in some Agent Orange samples, which contained, like PCP, a wide variety of PCDD/DF congeners. In this context, it may be expected that certain tactical herbicides contaminated with various chlorophenol impurities, have a unique congener pattern when compared with pure 2,4,5-T formulations. PMID- 21680011 TI - Photoirradiation of polycyclic aromatic hydrocarbon diones by UVA light leading to lipid peroxidation. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous genotoxic environmental pollutants and potentially pose a health risk to humans. In most if not all cases, PAHs in the environment can be oxidized into their corresponding PAH diones. This process is considered a detoxification pathway with regard to tumorigenicity. Nevertheless, photo-induced toxicological activity of PAH-diones has not been systematically investigated. In this study, we show that 27 potential environmental PAH-diones induced lipid peroxidation, in a dose (light) response manner, when irradiated with UVA at 7 and 21 J cm(-2). Photoirradiation in the presence of sodium azide, deuterated methanol, or superoxide dismutase revealed that lipid peroxidation is mediated by reactive oxygen species. Electron spin resonance (ESR) spin trapping studies supported this observation. These results suggest that UVA photoirradiation of PAH-diones generates reactive oxygen species and induces lipid peroxidation. PMID- 21680012 TI - Chemical and physical characterization of produced waters from conventional and unconventional fossil fuel resources. AB - Characterization of produced waters (PWs) is an initial step for determining potential beneficial uses such as irrigation and surface water discharge at some sites. A meta-analysis of characteristics of five PW sources [i.e. shale gas (SGPWs), conventional natural gas (NGPWs), conventional oil (OPWs), coal-bed methane (CBMPWs), tight gas sands (TGSPWs)] was conducted from peer-reviewed literature, government or industry documents, book chapters, internet sources, analytical records from industry, and analyses of PW samples. This meta-analysis assembled a large dataset to extract information of interest such as differences and similarities in constituent and constituent concentrations across these sources of PWs. The PW data analyzed were comprised of 377 coal-bed methane, 165 oilfield, 137 tight gas sand, 4000 natural gas, and 541 shale gas records. Majority of SGPWs, NGPWs, OPWs, and TGSPWs contain chloride concentrations ranging from saline (>30000 mg L(-1)) to hypersaline (>40000 mg L(-1)), while most CBMPWs were fresh (<5000 mg L(-1)). For inorganic constituents, most SGPW and NGPW iron concentrations exceeded the numeric criterion for irrigation and surface water discharge, while OPW and CBMPW iron concentrations were less than the criterion. Approximately one-fourth of the PW samples in this database are fresh and likely need minimal treatment for metal and metalloid constituents prior to use, while some PWs are brackish (5000-30000 mg Cl(-) L(-1)) to saline containing metals and metalloids that may require considerable treatment. Other PWs are hypersaline and produce a considerable waste stream from reverse osmosis; remediation of these waters may not be feasible. After renovation, fresh to saline PWs may be used for irrigation and replenishing surface waters. PMID- 21680013 TI - Characterisation of dissolved organic matter in karst spring waters using intrinsic fluorescence: relationship with infiltration processes. AB - From analysis of spectrophotometric properties of dissolved organic matter (OM) and the hydrochemical responses of some karst springs under different hydrologic conditions, an assessment of the origin and transfer pathway of OM present in karst spring waters, from soil and epikarst toward the spring, has been conducted for three karst aquifers in southern Spain: Alta Cadena, Sierra de Enmedio and Los Tajos. Intrinsic fluorescence (excitation-emission matrices or EEMs), together with major water chemistry (electrical conductivity, temperature, alkalinity, Cl-, Mg+2) and P(CO2) along with natural hydrochemical tracers (TOC and NO3-, have been monitored in 19 springs which drain the three karst aquifers examined in this study. The spring water EEM spectra indicate that fulvic acid like substances, produced in the soil as a consequence of the decomposition of OM, are the dominant fluorophores, although some of the OM appears to originate from in situ microbiological activity but could be indicative of contamination present in recharge waters from livestock. During each recharge event, TOC and NO3- concentrations increased and variations in fluorescence intensities of peaks attributed to fulvic acid-like compounds were observed. In areas with minimal soil development, spatial and temporal variations in the fluorescence intensity of fulvic acid-like substances and other fluorophores derived from microbiological activity, together with other hydrochemical parameters, provide insights into the hydrogeological functioning of karst aquifers and the infiltration velocity of water from soil and facilitate assessment of contamination vulnerability in these aquifers. PMID- 21680014 TI - Robotic-assisted nephroureterectomy and bladder cuff excision without intraoperative repositioning. AB - OBJECTIVE: To present surgical tips and describe a novel technique for successful performance of robotic nephroureterectomy with bladder cuff excision (RNUBCE). We report a technique of RNUBCE without intraoperative patient repositioning or redocking of the robot. MATERIALS AND METHODS: Nephroureterectomy with bladder cuff excision is the standard management of high-grade or bulky upper tract transitional cell carcinoma. Lymphadenectomy is performed when clinically indicated. Fifteen patients underwent RNUBCE between January 2009 and May 2010. Several key points to this operation contribute to its success. Ports are strategically placed to allow access to the kidney, ureter, and bladder. The ureter is clipped, though not divided, immediately after ligating the renal hilum to minimize the risk of tumor seeding resulting from manipulation of the kidney. In cases of ureteric tumors, wide dissection of the ureter is carried out to avoid a positive margin or entry into the ureter. Bladder stay sutures are placed lateral to the ureterovesical junction to prevent retraction of the bladder once the bladder cuff is excised. If desired, a partial excision of the cuff can be performed with the ureter acting as a bucket handle. RESULTS: All procedures were performed successfully without complications. Mean total operative time was 184 minutes, estimated blood loss was 103 mL, and mean hospital stay was 2.7 days. Short-term oncological outcomes have revealed no recurrences. CONCLUSIONS: RNUBCE, with lymphadenectomy when clinically indicated, provides a viable treatment option for patients with upper tract transitional cell carcinoma. PMID- 21680015 TI - Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes. AB - BACKGROUND: Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development. OBJECTIVE: This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure. METHODS: Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in T(H)1- and T(H)2 relevant genes of CD4(+) T cells. RESULTS: Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-gamma dependent. Furthermore, the IFNG promoter of CD4(+) T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-gamma expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma protective phenotype. Regarding T(H)2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic T(H)2 regulatory region conserved noncoding sequence 1 (CNS1). CONCLUSION: These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection. PMID- 21680016 TI - Network connectivity, mechanical properties and cell adhesion for hyaluronic acid/PEG hydrogels. AB - The study aimed to explore the influence of the network architecture on the mechanical properties and degradability of HA/PEG gels, and to highlight the relationship between Young's modulus and cell colonization with a selected architecture. Three different families of hyaluronic acid (HA)-based photopolymerized PEG diacrylate (PEGDA) hydrogels were compared, using different concentrations and molecular weights (64 and 234 kDa) of HA: semi-IPNs containing native HA in a PEG network (type I gels); co-networks obtained using thiolated HA as chain transfer agent during PEGDA polymerization (type II gels); co-networks obtained from the in situ preparation of a macromonomer derived from the Michael type addition of thiolated HA on PEGDA (type III gels). From a comparative study of rheological properties and enzymatic degradability, type II gels were selected for a further study aiming to link their mechanical properties to cell spreading. Employing RGD-functionalized materials, Young's moduli were measured via AFM nanoindentation while the cell spreading behavior was quantitatively evaluated by monitoring morphology and metabolic activity (MTS assay) of L929 fibroblasts. By revealing a clear relation between increasing modulus and increasing cell spreading/proliferation, the study showed the possibility to fine tune the cell/material interactions with appropriate reactive processing techniques. PMID- 21680017 TI - 5'-Azacitidine for therapy-related myelodysplastic syndromes after non-Hodgkin lymphoma treatment. AB - Therapy-related myelodysplastic syndromes are possible complications in patients treated for previous hematologic malignancies. Therapeutic strategies in these type of disorders are still not well defined: azacitidine has been recently approved for the treatment of higher risk myelodysplastic syndromes, but few data are published relating possible efficacy in therapy-related dysplastic disorders. We reported here 4 patients treated with azacitidine for therapy related dysplasia after chemotherapy for non-Hodgkin lymphoma. PMID- 21680018 TI - Temperature affects cadmium-induced phytotoxicity involved in subcellular cadmium distribution and oxidative stress in wheat roots. AB - In this study, the effect of temperature on Cd toxicity to wheat roots was evaluated in terms of the relative root length and subcellular distribution of Cd as well as the antioxidant enzymatic activities after exposed to Cd for 72 h under different temperatures. The result showed that the EC(50)-values for the relative root length were 9.24, 4.91 and 3.62 MUM Cd at 18, 25 and 30 degrees C, respectively. The Cd concentrations in the cellular metal-sensitive fraction or the potentially toxic fraction (cell debris fraction-Cd) were well correlated with the toxicity of Cd. Interestingly, the superoxide dismutase (SOD) and catalase (CAT) in wheat roots without Cd exposure were increased at 18 degrees C compared to those at 25 degrees C, while decreased at 30 degrees C. The CAT activities decreased with increasing Cd level at 25 and 18 degrees C but did not show the same change at 30 degrees C, which could be explained by the subcellular distribution of Cd. PMID- 21680019 TI - Bioassay technique using seed shrimps for comparative studies regarding the aquatic acute lethality of biodegradable lubricants. AB - To evaluate the environmental load resulting from the spillage of biodegradable lubricants in aquatic systems, a comparative acute lethality test wherein an oil water interfacial area could be examined was considered. In this study, oleic acid was employed as a model biodegradable lubricant. Measurements of the pH value and dissolved oxygen (DO) level of water during the exposure tests indicate that water degradation depends on the oil-water interfacial area, exposure duration, and water temperature. Furthermore, 72 h acute lethality tests were performed using two types of freshwater ostracods (seed shrimps) as test organisms: the large species Stenocypris hislopi and the small species Cypretta seurati. The longevity of the small species, which was physically more active, was strongly affected by water pollution. During the exposure test, the DO in water was significantly consumed by the degradation of the lubricant floating on it. Water exposed to a lubricant containing copper (Cu) demonstrated strong toxicity even after the recovery of the pH value and DO level by aging. The decrease in the DO level of water and increase in the concentration of metal compounds are dominant factors responsible for the mortality of aquatic organisms. PMID- 21680020 TI - Bromoxynil residues and dissipation rates in maize crops and soil. AB - A residue analytical method for the determination of bromoxynil in soil and maize was developed using high performance liquid chromatography with diode-array detector (HPLC-DAD) and high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). The residual level and dissipation rate of bromoxynil in the soil and maize crops were determined using the established method. The mean half-life of bromoxynil in soil was 4.12 days with a dissipation rate of 91.25% over 21 days. The mean half-life in maize seedling was 1.14 days with a dissipation rate of 97.79% over 7 days. The final residues of bromoxynil were undetectable in maize grain, maize stem and soil at the harvest time, suggesting that residual levels of bromoxynil in maize plants are safe to humans and animals as well as to the environment. PMID- 21680021 TI - Detection of Coxiella burnetii, the agent of Q fever, in oviducts and uterine flushing media and in genital tract tissues of the non pregnant goat. AB - The aim of the present study was the detection and quantification of Coxiella burnetii DNA in the flushing media (oviducts and uterine horns) and genital tract tissues of non pregnant goats from 20 goats chosen at random from 86 goats originating from 56 different breeding herds in south-west France. The serological prevalence rate of C. burnetii in the study population was 70.3%. The DNA of C. burnetii was identified using conventional PCR in the flushing media from the oviducts and uterus in 8/20 goats (40%) and in genital tract tissues (oviduct, uterus and ovary) in 5/20 goats (25%). This study clearly shows for the first time that the media used to flush the oviducts or uterine horns, collected using the standard embryo harvesting technique in goats, are susceptible to infection with C. burnetii. The 16 conventional PCR-positive samples were also analyzed using real-time PCR. The bacterial load of the oviduct and uterine flushing media varied from 2.9*10(4) to 7.5*10(6) bacteria per flushing medium, while the bacterial load of the tissue samples varied from 1.0*10(2) to 1.5*10(5) bacteria per mg of tissue. The infection of genital tract flushing media and tissues is a risk factor for the transmission of C. burnetii from donor to recipient during embryo transfer or to the embryo and fetus when gestation is pursued to term. PMID- 21680022 TI - Comparison of latanoprost and timolol in pediatric glaucoma: a phase 3, 12-week, randomized, double-masked multicenter study. AB - OBJECTIVE: To compare the efficacy and safety of latanoprost versus timolol in pediatric patients with glaucoma. DESIGN: Prospective, randomized, double-masked, 12-week, multicenter study. PARTICIPANTS: Individuals aged <=18 years with glaucoma. METHODS: Stratified by age, diagnosis, and intraocular pressure (IOP) level, subjects were randomized (1:1) to latanoprost vehicle at 8 am and latanoprost 0.005% at 8 pm or timolol 0.5% (0.25% for those aged <3 years) twice daily (8 am, 8 pm). At baseline and weeks 1, 4, and 12, IOP and ocular safety were assessed and adverse events were recorded. Therapy was switched to open label latanoprost pm and timolol am and pm for uncontrolled IOP. MAIN OUTCOME MEASURES: Mean IOP reduction from baseline to week 12. Latanoprost was considered noninferior to timolol if the lower limit of the 95% confidence interval (CI) of the difference was >-3 mmHg. A proportion of responders (subjects with >=15% IOP reduction at weeks 4 and 12) were evaluated. Analyses were performed in diagnosis subgroups: primary congenital glaucoma (PCG) and non-PCG. RESULTS: In total, 137 subjects were treated (safety population; 12-18 years, n=48; 3-<12 years, n=55; 0 <3 years, n=34). Mean age was 8.8+/-5.5 years, and mean baseline IOP was 27.7+/ 6.17 mmHg; 125 subjects completed the study, and 107 subjects were in the per protocol population. Mean IOP reductions for latanoprost and timolol at week 12 were 7.2 and 5.7 mmHg, respectively, with a difference of 1.5 mmHg (95% CI, -0.8 to 3.7; P=0.21). Responder rates were 60% for latanoprost and 52% for timolol (P=0.33). Between-treatment differences in mean IOP reduction for PCG and non-PCG subgroups were 0.6 mmHg (95% CI, -2.3 to 3.4) and 2.6 mmHg (95% CI, -0.8 to 6.1), respectively. Responder rates for latanoprost versus timolol were 50% versus 46% for the PCG group and 72% versus 57% for the non-PCG group. Both therapies were well tolerated. CONCLUSIONS: Latanoprost 0.005% is not inferior (i.e., is either more or similarly effective) to timolol and produces clinically relevant IOP reductions across pediatric patients with and without PCG. Both latanoprost and timolol had favorable safety profiles over the duration of this 3-month trial. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21680023 TI - Special requirements for electronic health record systems in ophthalmology. AB - The field of ophthalmology has a number of unique features compared with other medical and surgical specialties regarding clinical workflow and data management. This has important implications for the design of electronic health record (EHR) systems that can be used intuitively and efficiently by ophthalmologists and that can promote improved quality of care. Ophthalmologists often lament the absence of these specialty-specific features in EHRs, particularly in systems that were developed originally for primary care physicians or other medical specialists. The purpose of this article is to summarize the special requirements of EHRs that are important for ophthalmology. The hope is that this will help ophthalmologists to identify important features when searching for EHR systems, to stimulate vendors to recognize and incorporate these functions into systems, and to assist federal agencies to develop future guidelines regarding meaningful use of EHRs. More broadly, the American Academy of Ophthalmology believes that these functions are elements of good system design that will improve access to relevant information at the point of care between the ophthalmologist and the patient, will enhance timely communications between primary care providers and ophthalmologists, will mitigate risk, and ultimately will improve the ability of physicians to deliver the highest-quality medical care. FINANCIAL DISCLOSURE(S): Proprietary or commercial interest disclosure may be found after the references. PMID- 21680024 TI - Risk of relapse in primary acute anterior uveitis. AB - PURPOSE: To evaluate the risk of and risk factors for a second episode (relapse) among patients with remitted primary anterior uveitis. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with primary anterior uveitis presenting to 1 of 4 academic ocular inflammation subspecialty practices achieving remission of the primary episode within 90 days of initial uveitis diagnosis. METHODS: Data were obtained by standardized chart review. MAIN OUTCOME MEASURES: Time to relapse of anterior uveitis and risk factors for relapse. RESULTS: We included 102 patients with a first episode of anterior uveitis who were seen within 90 days of first-ever uveitis onset and followed for 165 person-years after achieving remission of the initial episode. Most patients were female (60%) and white (78%). Forty patients had a recurrence of anterior uveitis. The incidence of relapse was 24% per person-year (95% confidence interval [CI], 17%-33%). At 1.5 years after remission, 61% (95% CI, 48%-71%) were still in remission. Younger adults had significantly higher relapse risk than middle-aged adults (hazard ratio [18- to 35-year-old persons vs. 35- to 55-year-old persons], 2.7; 95% CI, 1.3-6.0). CONCLUSIONS: Our results suggest that many patients with remitted primary anterior uveitis presenting for tertiary uveitis care will relapse. Age in the young adult range was associated with higher risk of relapse. Given the high relapse risk, management of patients with primary anterior uveitis should include an explicit plan for detecting and managing relapses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21680025 TI - Pharmacogenomics of antidepressant induced mania: a review and meta-analysis of the serotonin transporter gene (5HTTLPR) association. AB - BACKGROUND: Antidepressants can trigger a rapid mood switch from depression to mania. Identifying genetic risk factors associated with antidepressant induced mania (AIM) may enable individualized treatment strategies for bipolar depression. This review and meta-analysis evaluates the evidence for association between the serotonin transporter gene promoter polymorphism (5HTTLPR) and AIM. METHODS: Medline up to November 2009 was searched for key words bipolar, antidepressant, serotonin transporter, SLC6A4, switch, and mania. RESULTS: Five studies have evaluated the SLC6A4 promoter polymorphism and AIM in adults (total N=340 AIM+ cases, N=543 AIM- controls). Although a random effects meta-analysis showed weak evidence of association of the S allele with AIM+ status, a test of heterogeneity indicated significant differences in estimated genetic effects between studies. A similar weak association was observed in a meta-analysis based on a subset of three studies that excluded patients on mood stabilizers; however the result was again not statistically significant. LIMITATIONS: Few pharmacogenomic studies of antidepressant treatment of bipolar disorder have been published. The completed studies were underpowered and often lacked important phenotypic information regarding potential confounders such as concurrent use of mood stabilizers or rapid cycling. CONCLUSIONS: There is insufficient published data to confirm an association between 5HTTLPR and antidepressant induced mania. Pharmacogenomic studies of antidepressant induced mania have high potential clinical impact provided future studies are of adequate sample size and include rigorously assessed patient characteristics (e.g. ancestry, rapid cycling, concurrent mood stabilization, and length of antidepressant exposure). PMID- 21680026 TI - Complaints of difficulty to fall asleep increase the risk of depression in later life: the health in men study. AB - OBJECTIVES: To determine if complaints of poor sleep are associated with incident depression in older men. METHODS: Cohort study with an average follow up period of 6 years (range 3 months to 8.5 years). Participants were 5127 community dwelling Western Australian older men aged 70-90 years who provided information about sleep problems. The primary outcome of interest of the study was a recorded diagnosis of depressive episode, recurrent depressive disorder or dysthymia in the Western Australian Data Linkage System. Participants completed a health questionnaire that included questions assessing difficulty falling asleep, remaining awake, as well as early morning awakening. Other measured factors included age, education, country of birth, living arrangements, social support, smoking, body mass index, and prevalent diabetes, hypertension, arthritis, chronic respiratory diseases, coronary artery disease, stroke, and cancer. Biochemical measurement of C-reactive protein, testosterone and plasma homocysteine were available for 3800 men. RESULTS: We found that 60% of men reported at least one sleep problem and that the unadjusted hazard ratio (HR) of depression was higher in men who complained of difficulties to initiate sleep (HR = 2.19, 95% confidence interval--95% CI = 1.47-3.27) or who remained awake most of the night (HR = 1.94, 95% CI = 1.15-3.27). There was no association between early morning awakening and incident depression. The association between incident depression and subjective difficulty falling asleep remained after the analyses were adjusted for other measured factors (HR = 1.83, 95% CI = 1.20-2.79). The association between depression and remaining awake was no longer significant once the analyses were adjusted for confounding (HR = 1.43, 95% CI = 0.81-2.53). A sensitivity analysis confirmed these results. LIMITATIONS: The evaluation of the exposure (sleep disturbance) was limited to self-rating questions that were not externally validated. The diagnosis of depression was based on administrative record linkage rather than structure clinical interviews. The observational nature of the study limits our ability to ascribe a causal relationship between complaints of poor sleep and incident depression. CONCLUSIONS: Complaints of difficulty falling asleep increase the risk of incident depression in older men. Clarifying the mechanisms that underlie this association should become an international research priority, as they may contribute to guide interventions designed to decrease the burden of depression in later life. PMID- 21680027 TI - Influence and interaction of genetic polymorphisms in catecholamine neurotransmitter systems and early life stress on antidepressant drug response. AB - BACKGROUND: Catecholamine neurotransmission plays an important role in major depression. Variation in genes implicated in the synthesis and signal transduction of catecholamines (norepinephrine and dopamine) may interact with environmental factors to affect the outcome of antidepressant treatment. We aimed to determine how a range of polymorphisms in noradrenergic and dopaminergic genes influence this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. METHODS: In a sample of 308 Chinese Han patients with major depressive disorder, 13 single nucleotide polymorphisms (SNPs) in coding regions of six genes (MAOA, SLC6A2, TH, COMT, DRD2, DRD3) with minor allele frequencies >5% were successfully genotyped from an initial series of 35 SNPs in 11 candidate genes associated with catecholamine neurotransmission. The responses to 6 weeks' treatment with antidepressant drugs was determined by changes in the 17-item Hamilton Depression Rating Scale (HAMD-17) score, and previous stressful events were evaluated by the Life Events Scale (LES) and Childhood Trauma Questionnaire-Short Form (CTQ-SF). Single SNP and haplotype associations with treatment response were analysed by UNPHASED 3.0.13, gene-gene interactions were analysed by generalized multifactor dimensionality reduction (GMDR) and gene-environment interactions by logistic regression. RESULTS: A haplotype in MAOA (rs1137070 and rs6323) was significantly associated with antidepressant response in the total group, the nonSSRI subgroup and the female subgroup. Two haplotypes in COMT (involving rs4633, rs4818 and rs769224) were significantly associated with antidepressant response in the nonSSRI subgroup. The SLC6A2 SNPs interacted with childhood trauma to influence antidepressant response. CONCLUSIONS: A haplotype in MAOA and two haplotypes in COMT are found to be associated with antidepressant treatment response in this sample. Stressors in early life may interact with polymorphisms in SLC6A2 to influence response to antidepressant treatment. PMID- 21680028 TI - Alterations of lymphocyte subpopulations in healthy dogs with aging and in dogs with cancer. AB - Changes in an individual's immune status are considered major contributing factors towards the morbidity of cancer and mortality of aging. To evaluate age related changes in the immune status of dogs, the immunophenotypes (CD3, CD4, CD8 and CD21) of peripheral blood lymphocytes were measured in 160 healthy dogs aged from 1 to 17 years, and in 365 dogs with various tumors and at various stages. In healthy dogs, the absolute numbers of white blood cells, lymphocytes, and CD3(+), CD4(+) and CD21(+) lymphocytes decreased significantly with age. The relative percentages of lymphocytes and CD4(+) cells decreased significantly, while CD8(+) cells increased significantly with age. The CD4:CD8 ratio showed a significant age-related decrease. In contrast, dogs with tumors possessed significantly lower absolute numbers and relative percentages of all lymphocyte phenotypes, while the CD4:CD8 ratio was significantly higher than in age-matched controls. The relative percentages of CD3(+) and CD8(+) lymphocytes were significantly lower in dogs with distant metastases compared with dogs without metastases, and the CD4:CD8 ratio increased with advanced stage. These observations illustrate the significant changes in immune status with age and the presence of marked immunological defects in a large-scale study of dogs with advanced tumors. PMID- 21680029 TI - Branchial anomalies in children. AB - BACKGROUND: Branchial cleft anomalies are the second most common head and neck congenital lesions seen in children. Amongst the branchial cleft malformations, second cleft lesions account for 95% of the branchial anomalies. This article analyzes all the cases of branchial cleft anomalies operated on at Great Ormond Street Hospital over the past 10 years. METHODS: All children who underwent surgery for branchial cleft sinus or fistula from January 2000 to December 2010 were included in this study. RESULTS: In this series, we had 80 patients (38 female and 42 male). The age at the time of operation varied from 1 year to 14 years. Amongst this group, 15 patients had first branchial cleft anomaly, 62 had second branchial cleft anomaly and 3 had fourth branchial pouch anomaly. All the first cleft cases were operated on by a superficial parotidectomy approach with facial nerve identification. Complete excision was achieved in all these first cleft cases. In this series of first cleft anomalies, we had one complication (temporary marginal mandibular nerve weakness. In the 62 children with second branchial cleft anomalies, 50 were unilateral and 12 were bilateral. In the vast majority, the tract extended through the carotid bifurcation and extended up to pharyngeal constrictor muscles. Majority of these cases were operated on through an elliptical incision around the external opening. Complete excision was achieved in all second cleft cases except one who required a repeat excision. In this subgroup, we had two complications one patient developed a seroma and one had incomplete excision. The three patients with fourth pouch anomaly were treated with endoscopic assisted monopolar diathermy to the sinus opening with good outcome. CONCLUSION: Branchial anomalies are relatively common in children. There are three distinct types, first cleft, second cleft and fourth pouch anomaly. Correct diagnosis is essential to avoid inadequate surgery and multiple procedures. The surgical approach needs to be tailored to the type of anomaly of origin of the anomaly. Complete excision is essential for good outcomes. PMID- 21680030 TI - Findings from multidisciplinary evaluation of children with permanent hearing loss. AB - OBJECTIVES: To describe clinical findings from a multidisciplinary program for children with permanent hearing loss (PHL). METHODS: Retrospective chart review at a tertiary care children's hospital. PATIENTS: Two hundred patients charts were selected from the population of 260 children with permanent hearing loss presenting between July 2005 and December 2006. MAIN OUTCOME MEASURES: PHL etiology; radiographic findings; clinical findings by genetics, ophthalmology, developmental pediatrics, speech pathology, and aural rehabilitation. RESULTS: Etiology of hearing loss was determined in 60% of subjects. Genetic causes of hearing loss were identified or presumed (positive history of first degree relative with hearing loss) in 27% of the children. Structural ear anomalies were found in 20% of children. Among the 36% of children with CNS imaging, abnormal findings were noted in 32%. There were a high rate of ophthalmological findings (53%) among children seen by ophthalmology (n = 105). Neurodevelopmental evaluations were completed in 58% of subjects and clinically significant findings were noted in 68%. Of the 61% of children who receiving received speech/language evaluations, 77% required intervention. Over half of the 40% of subjects who had an aural rehabilitation evaluation needed therapy. There were not significant differences in rates of findings for children with mild or unilateral hearing loss as compared to children with more severe degrees of hearing loss. CONCLUSIONS: Interdisciplinary medical evaluation of children with PHL allows for the identification and treatment of clinically significant ophthalmologic, neurodevelopmental, genetic, and speech/language disorders. A high rate of CNS and temporal bone abnormalities were identified. These findings provide an understanding of the importance of considering thorough medical and developmental evaluations among children who are deaf/hard of hearing. PMID- 21680032 TI - Assessment of pain-related fear in patients with the thrust plate prosthesis (TPP): due to hip fracture and hip osteoarthritis. AB - The aim of this study is to determine the differences between hip fracture and hip arthrosis groups and to assess pain related fear of injury in patients who were operated using the TPP following hip fracture or hip arthrosis. Fifty-eight patients (mean age = 63.9 +/- 10.3 years) who were operated using the TPP, following hip fracture (hip fracture group; n = 25) or coxarthrosis (coxarthrosis group; n = 33) were recruited. All of the measurements were performed after a follow-up time of at least 2 years. Functional level by Harris Hip Scoring System (HHS), pain related fear by Tampa Scale for Kinesiophobia (TSK) and pain intensity by numerical rating scale (NRS) was evaluated. There were no significant differences between demographic and clinical characteristics of two groups. However, pain intensity was higher in coxarthrosis group than hip fracture group. There was no correlation between the TSK scores and either Harris scores or NRS scores (p > 0.05) in the hip fracture group. No correlation between NRS and TSK was found in coxarthrosis group but there was a significant correlation between TSK and HHS. TSK scores were high in both groups. High TSK scores proved us that the patients with TPP had fear of movement even they had enough physical performance. The coxarthrosis group had higher pain intensity. Rehabilitation clinicians should consider pain-related belief which is more important than pain intensity and functional level in coxarthrosis patients. PMID- 21680033 TI - Measuring and testing for gender discrimination in physician pay: English family doctors. AB - In 2008 the income of female GPs was 70%, and their wages (income per hour) were 89%, of those of male GPs. We estimate Oaxaca decompositions using OLS models of wages and 2SLS models of income and propose a set of new direct tests for within workplace gender discrimination. The direct tests are based on a comparison of the differences in income of female and male GPs in practices with varying proportions of female GPs and with female or male senior partners. These tests provide only weak evidence for discrimination. We also propose a set of indirect tests for discrimination, including a comparison of a GP's actual income with the income they report as an acceptable reward for their job. The indirect tests provide no evidence for gender discrimination within practices. PMID- 21680034 TI - The expanding scope of antimicrobial peptide structures and their modes of action. AB - Antimicrobial peptides (AMPs) are an integral part of the innate immune system that protect a host from invading pathogenic bacteria. To help overcome the problem of antimicrobial resistance, cationic AMPs are currently being considered as potential alternatives for antibiotics. Although extremely variable in length, amino acid composition and secondary structure, all peptides can adopt a distinct membrane-bound amphipathic conformation. Recent studies demonstrate that they achieve their antimicrobial activity by disrupting various key cellular processes. Some peptides can even use multiple mechanisms. Moreover, several intact proteins or protein fragments are now being shown to have inherent antimicrobial activity. A better understanding of the structure-activity relationships of AMPs is required to facilitate the rational design of novel antimicrobial agents. PMID- 21680031 TI - beta-Arrestin-mediated receptor trafficking and signal transduction. AB - beta-Arrestins function as endocytic adaptors and mediate trafficking of a variety of cell-surface receptors, including seven-transmembrane receptors (7TMRs). In the case of 7TMRs, beta-arrestins carry out these tasks while simultaneously inhibiting upstream G-protein-dependent signaling and promoting alternate downstream signaling pathways. The mechanisms by which beta-arrestins interact with a continuously expanding ensemble of protein partners and perform their multiple functions including trafficking and signaling are currently being uncovered. Molecular changes at the level of protein conformation as well as post translational modifications of beta-arrestins probably form the basis for their dynamic interactions during receptor trafficking and signaling. It is becoming increasingly evident that beta-arrestins, originally discovered as 7TMR adaptor proteins, indeed have much broader and more versatile roles in maintaining cellular homeostasis. In this review paper, we assess the traditional and novel functions of beta-arrestins and discuss the molecular attributes that might facilitate multiple interactions in regulating cell signaling and receptor trafficking. PMID- 21680035 TI - Phosphorylation of EGFR measured with in situ proximity ligation assay: relationship to EGFR protein level and gene dosage in cervical cancer. AB - PURPOSE: We have applied the sensitive and specific in situ proximity ligation assay (PLA) to characterize Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR) in cervical cancer in relation to the protein level and gene dosage. MATERIALS AND METHODS: Pretreatment tumor biopsies from 178 patients were analyzed. EGFR protein level was determined by immunohistochemistry, and Tyr1068 phosphorylation was detected with PLA in 97 EGFR positive tumors. EGFR gene dosage was derived from array comparative genomic hybridization of 86 cases. RESULTS: EGFR was expressed in most tumors, whereas phosphorylation was seen in about half of the EGFR positive ones. A correlation was found between the expression of EGFR and phosphorylated EGFR (p=0.016, membrane; p=0.012, cytoplasm). However, tumor regions with high protein level without phosphorylation were occasionally seen and the percentage of EGFR positive cells was higher than the phosphorylated percentage (p<0.001). Moreover, an increase in the phosphorylation in both the membrane (p=0.014) and cytoplasm (p=0.002) was seen in 11 tumors with gain of EGFR. The protein level was not correlated with gene dosage. CONCLUSION: In contrast to gain of the EGFR chromosomal region, high EGFR protein level may not necessarily indicate Tyr1068 phosphorylation and thereby receptor activation in cervical cancer. PMID- 21680036 TI - Increased organ sparing using shape-based treatment plan optimization for intensity modulated radiation therapy of pancreatic adenocarcinoma. AB - PURPOSE: To develop a model to assess the quality of an IMRT treatment plan using data of prior patients with pancreatic adenocarcinoma. METHODS: The dose to an organ at risk (OAR) depends in large part on its orientation and distance to the planning target volume (PTV). A database of 33 previously treated patients with pancreatic cancer was queried to find patients with less favorable PTV-OAR configuration than a new case. The minimal achieved dose among the selected patients should also be achievable for the OAR of the new case. This way the achievable doses to the OARs of 25 randomly selected pancreas cancer patients were predicted. The patients were replanned to verify if the predicted dose could be achieved. The new plans were compared to their original clinical plans. RESULTS: The predicted doses were achieved within 1 and 2 Gy for more than 82% and 94% of the patients, respectively, and were a good approximation of the minimal achievable doses. The improvement after replanning was 1.4 Gy (range 0 4.6 Gy) and 1.7 Gy (range 0-6.3 Gy) for the mean dose to the liver and the kidneys, respectively, without compromising target coverage or increasing radiation dose to the bowel, cord or stomach. CONCLUSIONS: The model could accurately predict the achievable doses, leading to a considerable decrease in dose to the OARs and an increase in treatment planning efficiency. PMID- 21680037 TI - E-Cadherin loss associated with EMT promotes radioresistance in human tumor cells. AB - BACKGROUND AND PURPOSE: Hypoxia is a hallmark of solid cancers and associated with metastases and treatment failure. During tumor progression epithelial cells often acquire mesenchymal features, a phenomenon known as epithelial-to mesenchymal transition (EMT). Intratumoral hypoxia has been linked to EMT induction. We hypothesized that signals from the tumor microenvironment such as growth factors and tumor oxygenation collaborate to promote EMT and thereby contribute to radioresistance. MATERIALS AND METHODS: Gene expression changes under hypoxia were analyzed using microarray and validated by qRT-PCR. Conversion of epithelial phenotype upon hypoxic exposure, TGFbeta addition or oncogene activation was investigated by Western blot and immunofluorescence. Cell survival following ionizing radiation was assayed using clonogenic survival. RESULTS: Upon hypoxia, TGFbeta addition or EGFRvIII expression, MCF7, A549 and NMuMG epithelial cells acquired a spindle shape and lost cell-cell contacts. Expression of epithelial markers such as E-cadherin decreased, whereas mesenchymal markers such as vimentin and N-cadherin increased. Combining hypoxia with TGFbeta or EGFRvIII expression, lead to more rapid and pronounced EMT-like phenotype. Interestingly, E-cadherin expression and the mesenchymal appearance were reversible upon reoxygenation. Mesenchymal conversion and E-cadherin loss were associated with radioresistance. CONCLUSIONS: Our findings describe a mechanism by which the tumor microenvironment may contribute to tumor radioresistance via E-cadherin loss and EMT. PMID- 21680038 TI - ATM-dependent phosphorylation of 53BP1 in response to genomic stress in oxic and hypoxic cells. AB - The ATM kinase is activated by chromatin modification following exogenous and endogenous DSBs or cell stress, including acute anoxia. The p53 binding protein 1 (53BP1) contains multiple ATM-consensus phosphorylation sites in its N- and C termini and may therefore be a distal read-out of ATM function. We have examined the cellular activation of these phosphorylation sites for the first time in situ following anoxic/hypoxic stress and IR-induced exogenous DSBs. We show that multiple residues of 53BP1 are phosphorylated and that these phosphoforms form discrete nuclear foci following IR or during DNA replication as exogenous or endogenous DNA double strand breaks (DSBs), respectively. Novel data pertaining to the phosphorylation of 53BP1(Ser25)in situ supports its dependency on the ATM kinase; but this occurs independently of p53 function. We show that 53BP1(Ser25) is activated specifically in S-phase cells during anoxia in an ATM-dependent manner. Exogenous DSBs form discrete IR-induced foci whereas oxygen stress induced non-localized 53BP1(Ser25) activation. Our in vitro data are supported by irradiated xenograft studies in vivo whereby 53BP1(Ser25) phosphorylation does not occur in sub-regions positive for the hypoxia marker EF5. We propose a model whereby DSBs induce chromatin modification at sites of DNA damage which are tracked by the ATM substrates gamma H2AX and 53BP1(Ser25) in a mechanism distinct from p53-mediated cell cycle arrest. Together this work indicates 53BP1(Ser25), and possibly other 53BP1 phosphoforms, as a bona fide DSB-biomarkers for surveying ongoing DNA-damage related signaling in oxic and hypoxic cells during clinical radiotherapy. PMID- 21680039 TI - Age-, race-, and gender-specific prevalence of diabetes among smokers. AB - A cross-sectional study using the US national 2009 Behavioral-Risk-Factor Surveillance-System data (n=425,846) demonstrates that diabetes prevalence was significantly increased after age 35 in ever smokers, irrespective of gender. Diabetes prevalence was significantly increased in white or Hispanic ever smokers after age 25, and in black ever smokers after age 35. PMID- 21680040 TI - Lower postprandial glucose responses at baseline and after 4 weeks use of a diabetes-specific formula in diabetes type 2 patients. AB - AIMS: To determine whether lower postprandial glucose (PPG) levels after intake of a diabetes-specific formula (DSF) compared with a standard formula were maintained after 4 weeks use. METHODS: Randomized, controlled, double-blind, parallel-group study. Forty-four type 2 diabetes patients on oral anti-diabetes medication consumed 2*200mL/day of a DSF (Diasip((r))) or an isocaloric standard, fiber-containing formula for 4 weeks. PPG responses were assessed at baseline and after 4 weeks by iAUC and (delta) peak glucose concentrations. RESULTS: PPG response was significantly lower in the DSF group after first intake and remained significantly lower after 4 weeks use. Postprandial insulin, fasting glucose, insulin resistance, fructosamine and lipid levels did not differ between groups after 4 weeks. Within the standard group, fasting glucose and HOMA(IR) significantly increased over the intervention period. Changes in body weight between groups were significantly different, with an increase in the standard group. Both products were equally well tolerated. CONCLUSIONS: Superior PPG control by DSF was maintained after 4 weeks use, showing that this formula has added value with respect to PPG control for type 2 diabetes patients compared to a standard, fiber-containing formula. The observed effects on body weight, fasting glucose and HOMA(IR) may further support the use of a DSF. PMID- 21680041 TI - The influence of information and private versus public provision on preferences for screening for prostate cancer: a willingness-to-pay study. AB - This study investigates the influence of information and public versus private provision on preferences for introducing screening (i.e. PSA-test) for prostate cancer in Denmark. The aim is to disclose if preferences (measured as willingness to-pay) are influenced by whether the service is provided by the private or public health care sector, and the extent to which negative information on the PSA-test influences the perceptions of the screening programme. It is also investigated whether the impact of information differs dependent on public private provision. A random sample of the Danish male population (all between 50 and 70 years of age) were invited to fill out a web-based questionnaire. It was found that two thirds of the respondents were willing to participate and willing to pay for a public intervention programme, when provided with all relevant information. In contrast, only approximately one third were so inclined if a prostate cancer screening service was offered by private clinics. Results suggest that public provision framing increases the perceived value of the screening programme, and that the provision of full information regarding the negative characteristics of the programme decreases programme valuation. PMID- 21680042 TI - The importance of patient expectations as a determinant of satisfaction with waiting times for hip and knee replacement surgery. AB - OBJECTIVES: The disconfirmation model hypothesizes that satisfaction is a function of a perceived discrepancy from an initial expectation. Our objectives were: (1) to test the disconfirmation model as it applies to patient satisfaction with waiting time (WT) and (2) to build an explanatory model of the determinants of satisfaction with WT for hip and knee replacement. METHODS: We mailed 1000 questionnaires to 2 random samples: patients waiting or those who had received a joint replacement within the preceding 3-12 months. We used ordinal logistic regression analysis to build an explanatory model of the determinants of satisfaction. RESULTS: Of the 1330 returned surveys, 1240 contained patient satisfaction data. The sample was 57% female; mean age was 70 years (SD 11). Consistent with the disconfirmation model, when their WTs were longer than expected, both waiting (OR 5.77, 95% CI 3.57-9.32) and post-surgery patients (OR 6.57, 95% CI 4.21-10.26) had greater odds of dissatisfaction, adjusting for the other variables in the model. Compared to those who waited 3 months or less, post surgery patients who waited 6 to 12 months (OR 2.59, 95% CI 1.27-5.27) and over 12 months (OR 3.30, 95% CI 1.65-6.58) had greater odds of being dissatisfied with their waiting time. Patients who felt they were treated unfairly had greater odds of being dissatisfied (OR 4.74, 95% CI 2.60-8.62). CONCLUSIONS: In patients on waiting lists and post-surgery for hip and knee replacement, satisfaction with waiting times is related to fulfillment of expectations about waiting, as well as a perception of fairness. Measures to modify expectations and increase perceived fairness, such as informing patients of a realistic WT and communication during the waiting period, may increase satisfaction with WTs. PMID- 21680043 TI - Pharmacy assisted patient self care of minor ailments: a chronological review of UK health policy documents and key events 1997-2010. AB - OBJECTIVES: The aim of this review is to provide a historical perspective of the evolution of UK health policies and key events relevant to pharmacy assisted self care of minor ailments. METHODS: Health policy documents identified from free public web archives of all UK health department(s) published from 1997 to 2010 were reviewed for relevance to pharmacy assisted self care of minor ailments. RESULTS: Substantial focus on pharmacy assisted self care of minor ailments was identified within health policy documents with key drivers being: the need to reduce associated financial burden owing to minor ailments presentation at the General Practices (GPs), increasing patient access to services and aiding pharmacists' professional development through extended role. Two key interventions, directly aimed at shifting this balance of care, were the ongoing legal reclassification of prescription medicines to pharmacy supply and introduction of free minor ailments schemes across the UK. CONCLUSIONS: A shift from GP led to community pharmacy led patient self care of minor ailments has been a focus of many UK health policy documents. The existing burden of minor ailments on GP services requires sustained emphasis on community pharmacy, as well as research to reduce gaps between current policy and practice. PMID- 21680044 TI - Perioperative Systems as a quality model of perioperative medicine and surgical care. AB - OBJECTIVES: There has been a recent widespread international 'paradigm shift' to new Perioperative Systems for surgical patient care. These new systems are based on a multidisciplinary team providing an integrated process of care from the time a decision is made that a patient should have an operation until the patient has recovered from surgery. The objectives of this review were to outline the rationale for new Perioperative Systems, synthesize the evidence supporting these new systems and consider the current state of Perioperative Systems and its future development. METHODS: A systematic review of studies that focus on preoperative management practices to improve patient preparation for surgery and anaesthesia, with restriction to study designs with the highest levels of evidence for the synthesis of evidence. RESULTS: Perioperative Systems are regarded as the standard model of care in Australia, New Zealand, North America and increasingly in Europe. The benefits of Perioperative Systems include: increased surgical volume and flow (20-35%), shorter preoperative length of stay (-0.2 to -1.3 days), fewer cancellations of surgery (absolute reduction 1-8%), relative reduction in the number (23-55%) and cost (40-59%) of preoperative investigations and a lower risk of wound infection (relative risk 0.30, 95% CI 0.12-0.78) compared to the traditional system. The mean reduction in the total cost per patient associated with a Perioperative System was 8-18%. Future developments include offering health promotion activities in the weeks before surgery to improve long term patient outcomes after surgery. CONCLUSION: There is evidence of quality benefits for patients, clinicians and health administrators associated with new Perioperative Systems. Despite this, these systems are yet to be fully developed in many jurisdictions. PMID- 21680045 TI - Biogenesis and function of nuclear bodies. AB - Nuclear bodies including nucleoli, Cajal bodies, nuclear speckles, Polycomb bodies, and paraspeckles are membraneless subnuclear organelles. They are present at steady-state and dynamically respond to basic physiological processes as well as to various forms of stress, altered metabolic conditions and alterations in cellular signaling. The formation of a specific nuclear body has been suggested to follow a stochastic or ordered assembly model. In addition, a seeding mechanism has been proposed to assemble, maintain, and regulate particular nuclear bodies. In coordination with noncoding RNAs, chromatin modifiers and other machineries, various nuclear bodies have been shown to sequester and modify proteins, process RNAs and assemble ribonucleoprotein complexes, as well as epigenetically regulate gene expression. Understanding the functional relationships between the 3D organization of the genome and nuclear bodies is essential to fully uncover the regulation of gene expression and its implications for human disease. PMID- 21680046 TI - Centrosomes and cilia in human disease. AB - Centrioles are microtubule-derived structures that are essential for the formation of centrosomes, cilia and flagella. The centrosome is the major microtubule organiser in animal cells, participating in a variety of processes, from cell polarisation to cell division, whereas cilia and flagella contribute to several mechanisms in eukaryotic cells, from motility to sensing. Although it was suggested more than a century ago that these microtubule-derived structures are involved in human disease, the molecular bases of this association have only recently been discovered. Surprisingly, there is very little overlap between the genes affected in the different diseases, suggesting that there are tissue specific requirements for these microtubule-derived structures. Knowledge of these requirements and disease mechanisms has opened new avenues for therapeutical strategies. Here, we give an overview of recent developments in this field, focusing on cancer, diseases of brain development and ciliopathies. PMID- 21680048 TI - Phase II study of sunitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer. AB - This open-label, phase II study evaluated the antitumor activity and safety of sunitinib monotherapy as maintenance treatment following first-line chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Following treatment with standard doublet chemotherapy (paclitaxel and carboplatin), patients received oral sunitinib (starting dose 50mg/day) in 6-week cycles (Schedule 4/2: 4 weeks on treatment, 2 weeks off treatment) until disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint was probability of survival at 1 year >=55%. Of 84 patients who received first line chemotherapy, 66 (79%) received sunitinib maintenance therapy (median sunitinib cycles started: 2 [range 1-20]). Probability of survival at 1 year was 40.5% (95% confidence interval [CI]: 29.8, 51.0). Median overall survival was 10.4 months (95% CI: 8.0, 12.2). The objective response rate was 27.4% (95% CI: 18.2, 38.2). The most frequently reported all-causality adverse events of any grade during sunitinib maintenance therapy were fatigue/asthenia (55%), diarrhea (36%), and nausea (32%). These data suggest that maintenance therapy may have value in NSCLC, although the primary endpoint of the study was not met. PMID- 21680049 TI - Thinking inside the box: community-level consequences of stage-structured populations. AB - Ecologists have historically represented consumer-resource interactions with boxes and arrows. A key assumption of this conceptualization is that all individuals inside a box are functionally equivalent. Demographic stage structure, however, is a widespread source of heterogeneity inside the boxes. Synthesizing recent studies, we show that stage structure can modify the dynamics of consumer-resource communities owing to stage-related shifts in the nature and strength of interactions that occur within and between populations. As a consequence, stage structure can stabilize consumer-resource dynamics, create possibilities for alternative community states, modify conditions for coexistence of competitors, and alter the strength and direction of trophic cascades. Consideration of stage structure can thus lead to outcomes that are not expected based on unstructured approaches. PMID- 21680047 TI - Constitutive gene expression and the specification of tissue identity in adult planarian biology. AB - Planarians are flatworms that constitutively maintain adult tissues through cell turnover and can regenerate entire organisms from tiny body fragments. In addition to requiring new cells (from neoblasts), these feats require mechanisms that specify tissue identity in the adult. Crucial roles for Wnt and BMP signaling in the regeneration and maintenance of the body axes have been uncovered, among other regulatory factors. Available data indicate that genes involved in positional identity regulation at key embryonic stages in other animals display persisting regionalized expression in adult planarians. These expression patterns suggest that a constitutively active gene expression map exists for the maintenance of the planarian body. Planarians thus present a fertile ground for the identification of factors regulating the regionalization of the metazoan body plan and for the study of the attributes of these factors that can lead to the maintenance and regeneration of adult tissues. PMID- 21680050 TI - Quick-change artists: male plastic behavioural responses to rivals. AB - Behavioural plasticity allows animals to attune their behaviour to rapid environmental changes. Here we focus on plasticity in male mating behaviour in response to socio-sexual conditions. We discuss existing theory, generate predictions to facilitate exploration of the benefits of plastic behaviour, and identify parameters with the highest leverage on fitness. Existing data are synthesised to assess whether plasticity occurs pre- and post-copulation, to determine the direction of changes in behaviour, and to examine if plastic behaviour is fully flexible. We find that plasticity in males is widespread and not dominated by responses that occur pre- or post-copulation. Our synthesis also highlights areas that are underexplored, such as the limited data on the ultimate fitness consequences of such plastic behaviour. PMID- 21680051 TI - Management strategy evaluation: a powerful tool for conservation? AB - The poor management of natural resources has led in many cases to the decline and extirpation of populations. Recent advances in fisheries science could revolutionize management of harvested stocks by evaluating management scenarios in a virtual world by including stakeholders and by assessing its robustness to uncertainty. These advances have been synthesized into a framework, management strategy evaluation (MSE), which has hitherto not been used in terrestrial conservation. We review the potential of MSE to transform terrestrial conservation, emphasizing that the behavior of individual harvesters must be included because harvester compliance with management rules has been a major challenge in conservation. Incorporating resource user decision-making required to make MSEs relevant to terrestrial conservation will also advance fisheries science. PMID- 21680052 TI - KtrB, a member of the superfamily of K+ transporters. AB - KtrB is the K(+)-translocating subunit of the K(+)-uptake system KtrAB from bacteria. It is a member of the superfamily of K(+)transporters (SKT proteins) with other sub-families occurring in archaea, bacteria, fungi, plants and trypanosomes. SKT proteins may have originated from small K(+) channels by at least two gene duplication and two gene fusion events. They contain four covalently linked M(1)PM(2) domains, in which M(1) and M(2) stand for transmembrane stretches, and P for a P-loop, which folds back from the external medium into the membrane. SKT proteins distinguish themselves in two important aspects from K(+) channels: first, with just one conserved glycine residue in their P-loops they contain a much simpler K(+)-selectivity filter sequence than K(+) channels with their conserved Thr-Val-Gly-Tyr-Gly sequence. Secondly, the middle part M(2C2) from the long transmembrane stretch M(2C) of KtrB from the bacterium Vibrio alginolyticus forms a gate inside the membrane, which prevents K(+) permeation to the cytoplasm. Beside the mechanism of K(+) transport via KtrB and other SKT proteins existing hypotheses of how the KtrA protein regulates the K(+)-transport activity of KtrB are discussed. PMID- 21680053 TI - Implications of oligomeric forms of POD-1 and POD-2 proteins isolated from cell walls of the biocontrol agent Pythium oligandrum in relation to their ability to induce defense reactions in tomato. AB - The cell wall protein fraction (CWP) isolated from the biocontrol agent Pythium oligandrum induces defense reactions in tomato. CWP contains two novel elicitin like proteins, POD-1 and POD-2, both with seven cysteines. To determine the essential structure in the defense-eliciting components of CWP, five fractions (F1, F2, F3, F4 and F5) were fractionated from CWP using cation chromatography and their components and disulfide bond compositions were analyzed. The expression levels of three defense-related genes (PR-6, LeCAS and PR-2b) were determined in tomato roots treated with each of the five fractions. Of the five fractions, F4 containing a heterohexamer of POD-1 and POD-2, and F5 containing a homohexamer of POD-1, both with disulfide bonds formed between all cysteine residues, induced the expression of three genes. F4 treatment also induced the accumulation of ethylene in tomato. The predicted three-dimensional structures of POD-1 and POD-2, and the results of SEC and MALDI-TOF MS analyses suggest that F4 consists of three POD-1 and POD-2 disulfide-bonded heterodimers that interleave into a hexameric ring through noncovalent association. These results suggest that this structure, which F5 also appears to form, is essential for stimulating defense responses in tomato. PMID- 21680054 TI - Expression of a GALACTINOL SYNTHASE gene is positively associated with desiccation tolerance of Brassica napus seeds during development. AB - Desiccation tolerance of seeds is positively correlated with raffinose family oligosaccharides (RFOs). However, RFOs' role in desiccation tolerance is still a matter of controversy. The aim of this work was to monitor the accumulation of RFO during acquisition of desiccation tolerance in rapeseed (Brassica napus L.). Rapeseeds become desiccation tolerant at 21-24d after flowering (DAF), and the time was coincident with an accumulation of raffinose and stachyose. A gene encoding galactinol synthase (GolS; EC2.4.1.123), involved in RFO biosynthesis, was cloned and functionally characterized. Enzymatic properties of recombinant galactinol synthase were also determined. Accumulation of BnGOLS-1 mRNA in developing rapeseeds was concomitant with dry weight deposition and the acquisition of desiccation tolerance, and was concurrent with the formation of raffinose and stachyose. The physiological implications of BnGOLS-1 expression patterns in developing seeds are discussed in light of the hypothesized role of RFOs in seed desiccation tolerance. PMID- 21680055 TI - Calciphylaxis and bilateral optic neuropathy. AB - A 51-year-old woman on hemodialysis for chronic renal failure complained of visual loss in her right eye. Right optic disc edema was observed on fundus examination. An arteritic optic neuropathy was suspected. However, a first biopsy did not reveal any inflammatory cells. Two months later, the patient experienced sudden visual loss in her left eye and presented with necrotic cutaneous lesions at the distal phalanges of several fingers of the right hand. Necrotic lesions also appeared on the inner aspect of the thighs. Biopsy of the cutaneous lesions revealed calcification in the wall of a small artery. A new biopsy of the temporal artery showed large calcium deposits in the artery's tunica media. The diagnosis of optic neuropathy secondary to calciphylaxis was made. A temporal artery biopsy should be repeated if the first one is inconclusive. An early diagnosis leading to appropriate treatment may help to prevent an irreversible loss of vision in these patients. PMID- 21680056 TI - [The value of corticosteroids in the treatment of sterile ulcer in rheumatoid arthritis: a case report]. AB - Ocular manifestations of rheumatoid arthritis are mainly dry eye syndrome, scleritis, and keratitis. The occurrence of corneal ulceration in the course of this disease is a rare complication but can lead to ocular perforation. We report the case of a woman followed for rheumatoid arthritis who presented a bilateral sterile paracentral ulcer that responded well to medical treatment. PMID- 21680057 TI - [Granular corneal dystrophy treated with deep anterior lamellar keratoplasty: comparing histological analysis and optical coherence tomography]. AB - Granular corneal dystrophy is a rare autosomal dominant disease. It is characterized by breadcrumb-like granular opacities in the central corneal stroma. The mutation has been localized in the TGFbetaI gene, which codes for keratoepithelin, an adhesion protein found in corneal epithelium and stroma. We report the case of granular corneal dystrophy in a 60-year-old man complaining of reduced visual acuity. Slit-lamp examination revealed multiple opacities in the central stroma of his left eye, and recurrent deposits in his other eye 13 years after penetrating keratoplasty. An anterior segment optical coherence tomography (Visante((r)) OCT) was used to determine the location of deposits, then a deep anterior lamellar keratoplasty was performed in his left eye. The depth of the deposits revealed by Visante((r)) OCT correlated well with the postsurgical histological findings. Visante((r)) OCT can therefore help choose between phototherapeutic keratectomy and lamellar keratoplasty, techniques that are less invasive than penetrating keratoplasty, which is advantageous since this dystrophy is known to recur after surgery. PMID- 21680058 TI - [Serous central chorioretinopathy and tadalafil: a case report]. AB - We report a case of central serous chorioretinopathy in a 46-year-old man with no risk factors except for erectile dysfunction agent use: Tadalafil (Cialis((r))). An association between tadalafil and central serous chorioretinopathy could involve phosphodiesterase type 5 inhibitors and be a risk factor of central serous chorioretinopathy. PMID- 21680059 TI - The utility of high-flow oxygen during emergency department procedural sedation and analgesia with propofol: a randomized, controlled trial. AB - STUDY OBJECTIVE: We determine whether high-flow oxygen reduces the incidence of hypoxia by 20% in adults receiving propofol for emergency department (ED) sedation compared with room air. METHODS: We randomized adults to receive 100% oxygen or compressed air at 15 L/minute by nonrebreather mask for 5 minutes before and during propofol procedural sedation. We administered 1.0 mg/kg of propofol, followed by 0.5 mg/kg boluses until the patient was adequately sedated. Physicians and patients were blinded to the gas used. Hypoxia was defined a priori as an oxygen saturation less than 93%; respiratory depression was defined as an end tidal CO(2) greater than 50 mm Hg, a 10% absolute change from baseline, or loss of waveform. RESULTS: We noted significantly less hypoxia in the 59 patients receiving high-flow oxygen compared with the 58 receiving compressed air (19% versus 41%; P=.007; difference 23%; 95% confidence interval 6% to 38%). Respiratory depression was similar between groups (51% versus 48%; difference 2%; 95% confidence interval -15% to 22%). We observed 2 adverse events in the high flow group (1 hypotension, 1 bradycardia) and 2 in the compressed air group (1 assisted ventilation, 1 hypotension). CONCLUSION: High-flow oxygen reduces the frequency of hypoxia during ED propofol sedation in adults. PMID- 21680060 TI - [Electrical impedance tomography in acute lung injury]. AB - Electrical impedance tomography has been described as a new method of monitoring critically ill patients on mechanical ventilation. It has recently gained special interest because of its applicability for monitoring ventilation and pulmonary perfusion. Its bedside and continuous implementation, and the fact that it is a non-ionizing and non-invasive technique, makes it an extremely attractive measurement tool. Likewise, given its ability to assess the regional characteristics of lung structure, it could be considered an ideal monitoring tool in the heterogeneous lung with acute lung injury. This review explains the physical concept of bioimpedance and its clinical application, and summarizes the scientific evidence published to date with regard to the implementation of electrical impedance tomography as a method for monitoring ventilation and perfusion, mainly in the patient with acute lung injury, and other possible applications of the technique in the critically ill patient. The review also summarizes the limitations of the technique and its potential areas of future development. PMID- 21680061 TI - [Estimation of environmental tobacco smoke exposure: review of questionnaires used in Spain]. AB - INTRODUCTION: In the last few years, health surveys and epidemiological studies on smoking have introduced questions on environmental tobacco smoke (ETS) exposure. However, a standardized questionnaire is lacking. METHODS: Between January and May 2008, we reviewed surveys containing items on ETS exposure carried out in Spain by public administrations, scientific societies and research institutes. The wording of the questions was reviewed and classified according to the study type, target population, geographical setting and place of exposure. RESULTS: We identified 27 surveys that included questions on passive smoking. Most were health surveys (81.5%) and were aimed at the general population (70.4%). The most frequent geographical setting consisted of autonomous regions (48.1%) and the most common place of exposure was the home (88.9%) DISCUSSION: The results show wide variability in the questions used. Questionnaire items on ETS exposure should be homogenized to allow comparison of the results of surveys. PMID- 21680062 TI - Synthesis and biological evaluation of (+/-)-3-(2-(2-fluorobenzyloxy) naphthalen 6-yl)-2-aminopropanoic acid derivatives as novel PTP1B inhibitors. AB - A series of novel nonphosphonate-based pTyr mimetics comprised (+/-)-3-(2-(2 fluorobenzyloxy)naphthalen-6-yl)-2-aminopropanoic acid derivatives were identified as reversible and competitive PTP1B inhibitors via a structure-based design approach. Among the compounds studied, 12h was found to have the best in vitro inhibition activity against PTP1B (IC(50) = 1.25 +/- 0.24 MUM) and the best selectivity (3-fold) between PTP1B and TCPTP. These results should provide suitable druglike lead compounds for the design of inhibitors of PTP1B as well as other PTPs. PMID- 21680064 TI - Design, synthesis and bioevaluation of novel candidate selective estrogen receptor modulators. AB - In an systematic attempt to develop novel Selective Estrogen Receptor Modulators (SERMs), chiral 1-((4-(2-(dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1 yl)methyl)piperidin-4-ols were designed based on an accepted pharmacophore model. Simpler prototypes, viz. racemic 1-((2-hydroxynaphthalen-1 yl)arylmethyl)piperidin-4-ols, were first synthesized to develop kinetic resolution to pure enantiomers. Simultaneously, a series of racemic 1-((4-(2 (dialkylamino)ethoxy)phenyl)(2-hydroxynaphthalen-1-yl)methyl)piperidin-4-ols were evaluated against estrogen-responsive human MCF-7 breast cancer cells, but the compounds were found to be moderately active. The lack of potency could be due to the molecular bulk resulting in inadequate fit at the receptor. Subsequently, the molecular motif was modified to achiral 1-(4-(2 (dialkylamino)ethoxy)benzyl)naphthalen-2-ols by removing the piperidinol moiety. Bioevaluation of this new series of compounds displayed significantly enhanced cytotoxicity against MCF-7 cells. A representative compound for this series showed estrogen receptor alpha binding activity and the action is that of an antagonist. PMID- 21680063 TI - Synthesis and anti-inflammatory effects of a series of novel 7-hydroxycoumarin derivatives. AB - A number of 7-hydroxycoumarins have been synthesised by Pechmann cyclisation using differently substituted resorcinols employing perchloric acid as the condensing agent. All the compounds have been characterised by analytical and spectroscopic methods. The anti-inflammatory properties were tested with LPS induced inflammation in J774 macrophages. Expression of iNOS and COX-2 was determined by Western blot, NO by nitrite assay and IL-6 by ELISA analyses. Fifteen of the tested 7-hydroxycoumarins also inhibited IL-6 production but none of them had any major inhibitory effect on COX-2 expression. PMID- 21680065 TI - Gut derived lactic acid bacteria induce strain specific CD4(+) T cell responses in human PBMC. AB - BACKGROUND & AIMS: Probiotic bacteria are used as food supplement in many different disease settings. The immune modulating capacity of different strains is not always properly tested which might result in a suboptimal choice of strains for clinical use. METHODS: The CD4 T cell responses to 19 different gut derived lactic acid bacteria were tested with different methods to show their diversity in immune modulation and to make a well-founded choice on which strains to use in future clinical trials. After co-culture of PBMC with bacteria, the induction of CD4(+) T cell subsets (regulatory T cells, T helper type (TH)1, TH2 and TH17) was analysed by rtPCR of transcription factor mRNA, intracellular FACS staining of transcription factors and cytokine production. RESULTS: Bacterial strains all have diverse, unique immune modulatory properties. Strains can induce Treg, TH1, TH2 and TH17 cells which can be shown at different levels of T cell activation, and is consistent for most strains tested. For TH1, TH17 and Treg, a positive correlation between the different methods was found. For TH2 cells the correlation was less consistent. CONCLUSIONS: Probiotic bacteria have very different immune modulating capacities. Analysis of transcription factor mRNA is a suitable method for in vitro characterization of strains prior to clinical application. PMID- 21680066 TI - Identifying appearance-related concerns in routine follow-up clinics following treatment for oral and oropharyngeal cancer. AB - Facial disfigurement can be a consequence of treatment for oral or oropharyngeal cancer. Patients' concerns about appearance and the impact this has on quality of life are very important, but are often not recognised in a busy outpatient clinic. We aimed to assess concerns about appearance using the University of Washington Quality of Life questionnaire version 4 (UW-QoL) and the Patient Concerns Inventory (PCI), a self-administered questionnaire that allows patients to choose what they would like to discuss in their consultation. Prospective data were collected from 204 patients who attended routine follow-up clinics from August 2007 to mid-July 2009. Fifty-seven percent were male, 68% had cancer of the oral cavity, 78% had clinical T1-T2 tumours, 19% had node positive tumours, 44% had had radiotherapy since diagnosis, and 48% had had free-flap reconstructive surgery. They all completed the questionnaires using touch-screen computer technology at 454 clinic appointments. Appearance was raised on the inventory at 9% (42/454) of clinics, and at 10% (47/454) it was indicated as a serious problem on the UW-QoL questionnaire. Concerns about appearance were raised on the inventory or were shown to be a serious problem on the UW-QoL in 14% (64/454) of patients. The main factors associated with those who reported concerns about appearance were age (younger patients), sex (female), T stage (III and IV), and site (oropharynx). Patients who choose concerns about appearance for discussion on the UW-QoL questionnaire and not on the PCI risk being missed if only the PCI is completed. Both tools compliment the screening of patients who have problems with facial disfigurement; failure to identify them can have serious clinical and psychosocial implications. PMID- 21680068 TI - Effectiveness of an educational programme in perineal repair for midwives. AB - OBJECTIVE: to evaluate the effectiveness of a work-based module and in-service educational programme in perineal repair for midwives on their perceived level of competency undertaking this skill in clinical practice. DESIGN: a quasi experimental pre-post intervention case study combining a non-equivalent comparison group and evaluation action research. SETTING: six NHS consultant/midwifery led Trusts in South East England between December 2002 and 2006. PARTICIPANTS: 145 midwives from six NHS Trusts. INTERVENTIONS: a post registration work-based module in perineal repair for midwives and alternative two hour in-service perineal repair workshops across five intervention Trusts. MAIN OUTCOME MEASURES: midwives' perceived level of competency and confidence undertaking perineal repair. MAIN FINDINGS: significantly greater numbers of midwives were able to practice perineal repair at higher levels of competency following an educational intervention in five intervention Trusts (P<.006). There was a non-significant difference in the comparison Trust (P<.535). In addition, an educational programme for midwives increased the numbers of senior student midwives who were able to participate in perineal repair confidently under the direct supervision of their mentor when they perceived that their mentor was confident and competent undertaking the procedure. KEY CONCLUSIONS: an educational programme in perineal repair can make a significant difference to the midwives' perceived level of competency and confidence when assessing and managing perineal trauma and repair. IMPLICATIONS FOR PRACTICE: competency and expertise are complex phenomena and the data has provided greater insight into the complex nature of workplace learning alongside the multiple factors influencing clinical decision-making such as staff shortage, time constraints and inadequate numbers of midwives who are able to instruct, supervise and assess competency in perineal repair. Funding for training is fundamental for the sustainability of future practice development. PMID- 21680067 TI - Covering the gold weight with fascia lata graft in paralytic lagophthalmos patients. AB - Loading the eyelid with a gold weight is a popular technique for improving closure of the eyelid in patients with facial palsy. Despite it being both safe and simple, placement of the weight into a submuscular pocket is not always successful. Ulceration of the skin, and extrusion and visibility of the implant, are quite common short or long-term complications. We have developed a technical refinement of lid-loading. After the implant has been sutured in the appropriate place, we cover the implant with a fascia lata graft. We have used this technique in 8 patients who had had excision of an acoustic neuroma. No implant ulcerated or migrated, and none of the patients complained that the implant was visible during follow up of between 3 months and 4 years. Tendinous grafts act as a strong barrier to the gold weight because they are durable and thick. Fascia lata is easily harvested and leaves an inconspicuous scar at the donor site. We therefore recommend the technique to avoid complications. PMID- 21680069 TI - Modular neck for prevention of prosthetic impingement in cases with excessively anteverted femur. AB - BACKGROUND: It is important to adjust stem anteversion in cases of excessive femoral version to avoid prosthetic impingement-related complications in total hip arthroplasty. Although modular necks are considered an effective solution, their application in cases with wide variations in femoral anteversion remains to be elucidated. This study aimed to simulate the effects of different modular necks on prevention of prosthetic impingement due to excessive femoral anteversion. METHODS: We investigated range of motion without prosthetic impingement by collision detection using implant computer-aided design models of the ANCA-Fit system. FINDINGS: Modular necks could provide an adequate range of motion in cases with up to 60 degrees of femoral anteversion. However, few alternative necks were available in cases with excessive femoral anteversion, while many options could be used for femoral offset and version control in cases with average amounts of femoral anteversion without prosthetic impingement. INTERPRETATION: We conclude that modular necks might provide a marginal advantage over other options such as cemented, conical or modular stems for cases with an excessively anteverted femur, although they could help to maintain the femoral offset in some cases with average femoral anteversion. PMID- 21680070 TI - Democracy and growth in divided societies: A health-inequality trap? AB - Despite a tremendous increase in financial resources, many countries are not on track to achieve the child and maternal mortality targets set out in the Millennium Development Goals 4 and 5. It is commonly argued that two main social factors - improved democratic governance and aggregate income - will ultimately lead to progress in reducing child and maternal mortality. However, these two factors alone may be insufficient to achieve progress in settings where there is a high level of social division. To test the effects of growth and democratisation, and their interaction with social inequalities, we regressed data on child and maternal mortality rates for 192 countries against internationally used indexes of income, democracy, and population inequality (including income, ethnic, linguistic, and religious divisions) covering the period 1970-2007. We found that a higher degree of social division, especially ethnic and linguistic fractionalisation, was significantly associated with greater child and maternal mortality rates. We further found that, even in democratic states, greater social division was associated with lower overall population access to healthcare and lesser expansion of health system infrastructure. Perversely, while greater democratisation and aggregate income were associated with reduced maternal and child mortality overall, in regions with high levels of ethnic fragmentation the health benefits of democratisation and rising income were undermined and, at high levels of inequality reversed, so that democracy and growth were adversely related to child and maternal mortality. These findings are consistent with literature suggesting that high degrees of social division in the context of democratisation can strengthen the power of dominant elite and ethnic groups in political decision-making, resulting in health and welfare policies that deprive minority groups (a health-inequality trap). Thus, we show that improving economic growth and democratic governance are insufficient to achieve child and maternal health targets in communities with high levels of persistent social inequality. To reduce child and maternal mortality in highly divided societies, it will be necessary not only to increase growth and promote democratic elections, but also empower disenfranchised communities. PMID- 21680071 TI - Community researchers conducting health disparities research: Ethical and other insights from fieldwork journaling. AB - Lay persons who are trained to conduct research in their own communities form an essential part of many research projects. However, the effects of conducting research in their own communities have not been adequately explored. This paper examines the experiences, perceptions, and challenges faced by a group of community researchers during their involvement in a research project that examined if, and how, the relationships between mothers and their adolescent daughters could be harnessed to develop a daughter-initiated cervical cancer intervention. Seven community researchers interviewed 157 mother-daughter pairs in Cape Town, South Africa. We examine the use of journaling as a tool to document the experiences of community researchers, and we consider how journaling may help the community-based researcher grapple with the research process, and, more broadly, what such journal content illustrates with respect to the nature and challenges of community-engaged health research. An analysis of the content of the journals provides a strong indication of how personal and intimate the research process can be for community researchers by virtue of the background that they bring into the process as well as the additional weight of the research process itself. The complexities of navigating dual and somewhat oppositional roles - the role of impartial scientist or researcher and the role of invested community person - has been both underestimated and insufficiently researched. PMID- 21680072 TI - School-based friendship networks and children's physical activity: A spatial analytical approach. AB - Despite the known health benefits, the majority of children do not meet physical activity guidelines, with past interventions to increase physical activity yielding little success. Social and friendship networks have been shown to influence obesity, smoking and academic achievement, and peer-led interventions have successfully reduced the uptake of adolescent smoking. However, the role of social networks on physical activity is not clear. This paper investigates the extent to which friendship networks influence children's physical activity, and attempts to quantify the association using spatial analytical techniques to account for the social influence. Physical activity data were collected for 986 children, aged 10-11 years old, from 40 schools in Bristol, UK. Data from 559 children were used for analysis. Mean accelerometer counts per minute (CPM) and mean minutes of moderate to vigorous physical activity per day (MVPA) were calculated as objective measures of physical activity. Children nominated up to 4 school-friends, and school-based friendship networks were constructed from these nominations. Networks were tested to assess whether physical activity showed spatial dependence (in terms of social proximity in social space) using Moran's I statistic. Spatial autoregressive modelling was then used to assess the extent of spatial dependence, whilst controlling for other known predictors of physical activity. This model was compared with linear regression models for improvement in goodness-of-fit. Results indicated spatial autocorrelation of both mean MVPA (I = .346) and mean CPM (I = .284) in the data, indicating that children clustered in friendship groups with similar activity levels. Spatial autoregressive modelling of mean MVPA concurred that spatial dependence was present (rho = .26, p < .001), and improved model fit by 31% on the linear regression model. These results demonstrate an association between physical activity levels of children and their school-friends, and indicate that spatial modelling is an informative method for incorporating the influence of school social structure into physical activity analysis. PMID- 21680073 TI - Tissue-engineered polymer-based periosteal bone grafts for maxillary sinus augmentation: five-year clinical results. AB - PURPOSE: Augmentation of the maxillary sinus with allogenic or alloplastic materials, as well as autologous bone grafts, has inherent disadvantages. Therefore, the aim of our study was to evaluate the long-term clinical repair effect of autologous periosteal bone grafts on atrophic maxillary bone. PATIENTS AND METHODS: In the present retrospective cohort study, augmentation of the edentulous atrophic posterior maxilla was performed using autologous tissue engineered periosteal bone grafts based on bioresorbable polymer scaffolds and, in a 1-step procedure, simultaneous insertion of dental implants. The clinical evaluation of 10 patients was performed by radiologic assessment of bone formation, with a follow-up of 5 years. Bone formation was further documented by measuring the bone height and by histologic examination. RESULTS: Excellent clinical and radiologic results were achieved as early as 4 months after transplantation of the periosteal bone grafts. The bone height remained significantly (P < .05) greater (median 14.2 mm) than the preoperative atrophic bone (median 6.9 mm) during the 5-year observation period. Histologically, the bone biopsy specimens of 2 patients obtained after 6 months showed trabecular bone with osteocytes and active osteoblasts. No signs of bone resorption, formation of connective tissue, or necrosis were seen. CONCLUSION: Our results suggest that the transplantation of autologous periosteal bone grafts and implantation of dental implants in a 1-step procedure is a reliable procedure that leads to bone formation in the edentulous posterior maxilla, remaining stable in the long term for a period of at least 5 years. PMID- 21680074 TI - Cutaneous sensibility impairment after mandibular sagittal split osteotomy: a prospective clinical study of the spontaneous recovery. AB - PURPOSE: The aim of this prospective study was to objectively evaluate the inferior alveolar nerve (IAN) sensory disturbances in patients who underwent sagittal split ramus osteotomy (SSRO) and its spontaneous recovery and to define the incidence of sensibility loss, time, and area at which the recovery occurs. PATIENTS AND METHODS: Clinical evaluation of the IAN sensory disturbance was undertaken preoperatively and at the first week, fourth week, 2 months, and 6 months postoperatively in 30 patients who underwent SSRO at the Oral and Maxillofacial Surgery Division of the Araraquara Dental School--Unesp and at the Plastic Surgery Division of the Medical Sciences School--Unicamp. The 30 patients were examined at all periods regarding the IAN functionality by Semmes-Weinstein testing. RESULTS: The mean age of the patients included in this study was 29.36 years old. All patients showed sensibility loss at the 7-day evaluation time. The comparison between sides, gender, and age did not show any significant difference. In most of the examined zone, the data collected at 6 months were statistically similar to the data collected at the preoperative period. All zones presented significant recovery, starting from 30 days after surgery. Twenty patients had total spontaneous recovery at the final period, in all examined zones. CONCLUSIONS: The SSRO presents the disadvantage of temporary paresthesia; however, spontaneous nerve function recovery does occur. The Semmes-Weinstein test is a reliable, inexpensive, and easy-to-apply tool, which can be used for clinical evaluation on a daily basis at offices and hospitals. PMID- 21680075 TI - Role of early diagnosis and multimodal treatment in rhinocerebral mucormycosis: experience of 4 cases. PMID- 21680076 TI - After dentoalveolar surgery, most patients are satisfied with telephone follow up. AB - PURPOSE: To estimate patient satisfaction with telephone follow-up and compare the frequencies of postoperative complications between patients undergoing telephone and those undergoing clinical follow-up after ambulatory office-based dentoalveolar procedures. MATERIALS AND METHODS: Using a retrospective study design, the investigators enrolled a cohort of subjects who had had at least 1 tooth extracted during a 2-year period. The primary study variable was subject self-report of satisfaction with the telephone follow-up. For additional analyses, the predictor variable was follow-up type grouped as telephone versus clinical. The outcome variable was postoperative complications. To measure the relationships between the follow-up type and postoperative complications, bivariate and multiple logistic regression statistics were computed. P <= .05 was considered significant. RESULTS: The sample was composed of 364 subjects, of whom 155 (42.6%) had received telephone follow-up. The sample's mean age was 28.6 +/- 11.7 years, included 220 females (60.4%), and had had an average of 3.4 +/- 2.1 teeth removed. The self-reported patient satisfaction rate with telephone follow up was 95.9%. The subjects who experienced postoperative complications were 90% less likely to be satisfied relative to those without complications (P = .04). The overall complication frequency was 19.2%, with telephone follow-up subjects having a lower complication frequency (12.9%) than the clinical follow-up subjects (23.4%) (P < .01). After adjusting for differences between the 2 samples, no significant difference was found in the complication frequencies according to the method of follow-up (P = .7). CONCLUSION: Patient satisfaction with telephone follow-up was high. The subjects scheduled for telephone follow-up had a complication rate that was similar to that of the clinical follow-up subjects. PMID- 21680077 TI - Centile-based Early Warning Scores derived from statistical distributions of vital signs. PMID- 21680079 TI - Value of HPV-DNA test in women with cytological diagnosis of atypical glandular cells (AGC). AB - OBJECTIVE: This study analyzed whether HPV (human papillomavirus) testing contributes towards defining histological abnormalities in women with atypical glandular cells (AGC) diagnosed at cervical cytology. STUDY DESIGN: One hundred and eight women with conventional cervical cancer screening smears suggestive of AGC not otherwise specified (AGC-NOS) and favor neoplastic (AGC-FN) were consecutively enrolled. All women underwent colposcopic examinations and biopsy was performed according to the cytopathologic and/or colposcopic abnormalities present. All specimens were tested for high risk HPV genotypes by Roche's polymerase chain reaction reverse line blot assay. The chi-square test was used to evaluate the association between HPV findings and a diagnosis of high-grade pre-invasive or invasive disease (CIN 2 or worse) taking negative tests or CIN 1 as a reference. Odds ratios (OR) with their respective 95% confidence intervals (95%CI) were used to evaluate the magnitude of the association between HPV testing and CIN 2 or worse. Sensitivity, specificity and their respective 95% confidence intervals (95%CI), positive predictive values (PPV) and negative predictive values (NPV) were also calculated. RESULTS: Final diagnosis revealed a negative outcome in 80 cases (74%), cervical epithelial neoplasia 1 (CIN 1) in 13 cases (12%), CIN 2 or worse in 12 cases (11%) and glandular neoplasia in 3 (3%) cases. The overall detection rate of HPV was 21% (23/108). Neoplasia was significantly associated with positive HPV-DNA in women with AGC-NOS (OR=15.21; 95%CI: 2.64-87.50); however, there was no significant association between a histological diagnosis of neoplasia and HPV positivity in women with AGC-FN (OR=3.00; 95%CI: 0.36-24.92). The sensitivity, specificity, positive predictive value and negative predictive value of HPV-DNA testing for the detection of CIN 2 or worse in women with AGC-NOS were 71%, 86%, 29% and 97%, respectively. In women with AGC-FN, these values were 50%, 75%, 66% and 60%, respectively. CONCLUSIONS: HPV testing at the time of colposcopy for patients with AGC in whom no colposcopic abnormality is found may be a powerful ancillary tool for identifying women at a high risk of underlying significant cervical lesions. PMID- 21680080 TI - Genomic imprinting in mammals-epigenetic parental memories. AB - Genomic imprinting is an epigenetic phenomenon that brings the difference of expression between paternally or maternally derived alleles and is specific for mammals in vertebrates. This imprint is established in the parental germlines and then inherited to the next generation to regulate expression of imprinted genes that are essential to support proper embryonic development. More than one hundred imprinted genes have been identified in mice and humans. Some are essential for embryonic development, especially placental formation, and others regulate metabolism, behavior and physiological functions. In humans, disruption of genomic imprinting causes several diseases, including cancer. Recently, the molecular mechanisms of genomic imprinting are getting clarified. How do parents regulate gene expression of their children? Why and how is genomic imprinting evolved in mammals? The review offers a handful of recent progress in this area. PMID- 21680081 TI - Degradation and removal methods of antibiotics from aqueous matrices--a review. AB - Over the past few years, antibiotics have been considered emerging pollutants due to their continuous input and persistence in the aquatic ecosystem even at low concentrations. They have been detected worldwide in environmental matrices, indicating their ineffective removal from water and wastewater using conventional treatment methods. To prevent this contamination, several processes to degrade/remove antibiotics have been studied. This review addresses the current state of knowledge concerning the input sources, occurrence and mainly the degradation and removal processes applied to a specific class of micropollutants, the antibiotics. In this paper, different remediation techniques were evaluated and compared, such as conventional techniques (biological processes, filtration, coagulation, flocculation and sedimentation), advanced oxidation processes (AOPs), adsorption, membrane processes and combined methods. In this study, it was found that ozonation, Fenton/photo-Fenton and semiconductor photocatalysis were the most tested methodologies. Combined processes seem to be the best solution for the treatment of effluents containing antibiotics, especially those using renewable energy and by-products materials. PMID- 21680082 TI - Is laparoscopic cryoablation a less invasive and effective procedure to treat small renal masses? PMID- 21680083 TI - Sunitinib prior to planned cytoreductive nephrectomy: is this the new litmus test for metastatic renal cell carcinoma? PMID- 21680084 TI - How well can you actually predict which non-muscle-invasive bladder cancer patients will progress? PMID- 21680085 TI - Undiagnosed depression and its correlates in a predominantly immigrant Hispanic neurology clinic. AB - OBJECTIVE: Previous studies have reported a high incidence of depression in neurology clinics, however areas where there are predominantly underserved immigrants have not been studied. METHODS: Retrospective cohort study in an academic outpatient neurology clinic in Los Angeles, California. Newly referred patients (N=318) were assessed consecutively for depression using a PHQ-9 questionnaire, accompanied by review of the assessment of the depressive disorder. RESULTS: The patient cohort consisted of 190 females (59%) and 130 males (41%), primarily of Hispanic descent (72%), with 8% Asian 11% white, and 5% African-American. Sixty-eight percent (68%) had depression, with 40% exhibiting moderate to severe depression. Patients who had moderate to severe depression (based on PHQ-9) were more likely to be unemployed (75.2% vs. 60.7%, p=0.008), dependent on government income (29.5% vs. 20.4%, p=0.06), and have headache or pain as the reason for referral (42.4% vs. 28.5%, p=0.03). Severity of depression also significantly correlated with current treatment by psychiatrist, current antidepressant use, and less independent living. Patients with moderate to severe depression were more likely to have made ER visits in the last 12 months (0.9 vs. 0.7, p=0.01) and were taking more medications (3.3 vs. 2.5, p=0.03), compared to patient with mild or no depression. CONCLUSION: The presence of moderate to severe depression significantly correlated with socioeconomic status, use of emergency room, and presence of headache/pain. Neurology clinics with predominantly underserved immigrant patients have a disproportionate amount of depression, which may be related to socioeconomic factors resulting in overutilization of scarce healthcare resources. PMID- 21680086 TI - Large middle cerebral artery dissecting aneurysm mimicking hemorrhagic stroke. AB - Dissection of intracranial arteries is a rare cause of cerebrovascular diseases commonly presenting as an ischemic stroke. We report a patient with middle cerebral artery dissection who developed a large middle cerebral artery dissecting aneurysm mimicking a hemorrhagic stroke. PMID- 21680087 TI - Clinical isolated syndrome: a 3-year follow-up study in China. AB - OBJECTIVE: To summarize the characteristics of Chinese clinically isolated syndrome (CIS) patients and their 3-year follow-up results. Investigate the relationship between CIS features and clinical outcomes. METHODS: Forty-nine CIS patients were recruited and 42 of them were able to be followed up for a mean of 38 months (range 26-48 months). We recorded baseline features including patient demographics, site of CIS, presence or absence of cerebrospinal fluid (CSF) oligoclonal bands (OCB) and MRI lesions in brain and spinal cord. The incidence of conversion to clinically definite MS (CDMS) or neuromyelitis optica (NMO) after CIS was calculated, and the relationship between baseline features and CDMS was explored. All data were statistically processed with SPSS for Windows Version 11.5. RESULTS: After a mean follow-up of 38 months, 10/42 patients had converted to CDMS (24%), and one patient had developed definite NMO. The other 31 patients remained in CIS status. A spinal cord syndrome was the initial CIS manifestation in 57% of patients. The conversion rates to MS were 22% (5/23) for patients presenting with a spinal cord syndrome and 27% (3/11) for multi-focal manifestations. The three-year CDMS conversion rates were 70% (7/10) for patients who fulfilled the MRI dissemination in space criteria (2005 revised McDonald) at onset of CIS, while only 9% (3/32) of patients who did not fulfill these criteria converted to CDMS. Females had significantly higher conversion rate than males. CONCLUSION: A spinal cord syndrome was the most common initial presentation of our Chinese CIS group. After a mean follow-up of 38 months, the conversion rate to MS was approximately 25%. The 2005 revised McDonald MRI criteria for dissemination in space is a key prognostic factor for conversion to MS in CIS in Chinese patients. PMID- 21680088 TI - Hydrothermal treatment of municipal solid waste incineration fly ash for dioxin decomposition. AB - Hydrothermal treatment of MSWI fly ash was performed in this paper with a purpose to reduce its dioxin content. First a hydrothermal reactor was set up with a mixture of ferric sulphate and ferrous sulphate serviced as the reactant, then the effects caused by reaction conditions such as reaction temperature, pre treatment by water-washing and reactant dosage were checked; the results showed that as a promising technology, hydrothermal treatment exhibited considerable high efficiencies in decomposition of PCDDs/PCDFs and good stabilization of heavy metals as well. Experimental results also showed that for dioxin destruction, higher reaction temperature is the most important influencing factor followed by Fe addition, and pre-treatment of raw fly ash by water-washing increased the destruction efficiencies of dioxins only very slightly. Finally with help of Gaussian software chemical computational simulation was performed to investigate the mechanism of dioxin decomposition based on quantum chemistry calculation. The calculation results were supported by the experimental data. The leaching toxicities of hydrothermal products were higher than upper limits defined in the latest Chinese standard GB 16889-2008 for sanitary landfill disposal, thus an auxiliary process is suggested after the hydrothermal treatment for heavy metal stabilization. PMID- 21680089 TI - Dye-sensitized TiO2 film with bifunctionalized zones for photocatalytic degradation of 4-cholophenol. AB - A new strategy to photocatalytic degradation of 4-cholophenol (4-CP) under visible light irradiation was described. The TiO(2) film deposited on an ordinary glass sheet was distributed into two zones. One zone was sensitized by N719 dye and fabricated to be a sandwich type cell with a similar structure of dye sensitized solar cells. The other zone was inserted into pollutants solution for degradation. A highly oxidized overvoltage anode was achieved from the dye sensitized zone. The bifunctionalized TiO(2) film and the anode could degrade 4 chlorophenol in two separate reactors with 97% and 96% removal of 4-CP after 5h, respectively. The degradation efficiency could be improved by addition of FeSO(4). The as-prepared bifunctionalized TiO(2) film was comparably stable in the process of degradation. PMID- 21680091 TI - Peripheral inflammation suppresses inward rectifying potassium currents of satellite glial cells in the trigeminal ganglia. AB - Previous studies indicate that silencing Kir4.1, a specific inward rectifying K(+) (Kir) channel subunit, in sensory ganglionic satellite glial cells (SGCs) induces behavioral hyperalgesia. However, the function of Kir4.1 channels in SGCs in vivo under pathophysiological conditions remains to be determined. The aim of the present study was to examine whether peripheral inflammation in anesthetized rats alters the SGC Kir4.1 current using in vivo patch clamp and immunohistochemical techniques. Inflammation was induced by injection of complete Freund's adjuvant into the whisker pad. The threshold of escape from mechanical stimulation applied to the orofacial area in inflamed rats was significantly lower than in naive rats. The mean percentage of small/medium diameter trigeminal ganglion (TRG) neurons encircled by Kir4.1-immunoreactive SGCs in inflamed rats was also significantly lower than in naive rats. In vivo whole-cell recordings were made using SGCs in the trigeminal ganglia (TRGs). Increasing extracellular K(+) concentrations resulted in significantly smaller potentiation of the mean peak amplitude of the Kir current in inflamed compared with naive rats. In addition, the density of the Ba(2+)-sensitive Kir current associated with small diameter TRG neurons was significantly lower in inflamed rats compared with naive rats. Mean membrane potential in inflamed rats was more depolarized than in naive rats. These results suggest that inflammation could suppress Kir4.1 currents of SGCs in the TRGs and that this impairment of glial potassium homeostasis in the TRGs contributes to trigeminal pain. Therefore, the Kir4.1 channel in SGCs may be a new molecular target for the treatment of trigeminal inflammatory pain. PMID- 21680093 TI - Certain doubts and uncertain fears of acupuncture. PMID- 21680092 TI - Targeting temporomandibular disorder pain treatment to hormonal fluctuations: a randomized clinical trial. AB - Mounting evidence supports the importance of hormonal fluctuations in temporomandibular disorder (TMD) pain among women. Stabilizing influential hormones or having a plan and skills for coping with hormonally related increases in TMD pain, therefore, may be beneficial for women with TMD pain. This randomized clinical trial evaluated the short- and long-term efficacy of 3 interventions for women with TMD pain: (1) dental hygienist-delivered pain self management training (SMT; n=59); (2) the same dental hygienist-delivered pain self-management training, but with a focus on menstrual cycle-related changes in pain and other symptoms (targeted SMT, or TSMT; n=55); and (3) continuous oral contraceptive therapy (6-month trial) aimed at stabilizing hormones believed to be influential in TMD pain (COCT; n=57). Study participants completed outcome (pain, activity interference, depression) and process (pain beliefs, catastrophizing, coping effectiveness) measures before randomization, and 6 and 12months later. Intent-to-treat analyses supported the benefits of the SMT and TSMT interventions relative to COCT. Targeting the self-management treatment to menstrual cycle-related symptoms did not increase the treatment's efficacy. The benefits of the self-management interventions relative to COCT for pain and activity interference were statistically significant at 12 months, but not at 6 months, whereas the benefits for the process measures generally were apparent at both time points. COCT was associated with multiple adverse events (none serious). The study provides further support for long-term benefits of a safe, low-intensity (2 in-person sessions and 6 brief telephone contacts), dental hygienist-delivered self-management treatment for TMD pain. PMID- 21680094 TI - Developing vaccines to control protozoan parasites in ruminants: dead or alive? AB - Protozoan parasites are among some of the most successful organisms worldwide, being able to live and multiply within a very wide range of hosts. The diseases caused by these parasites cause significant production losses in the livestock sector involving reproductive failure, impaired weight gain, contaminated meat, reduced milk yields and in severe cases, loss of the animal. In addition, some protozoan parasites affecting livestock such as Toxoplasma gondii and Cryptosporidium parvum may also be transmitted to humans where they can cause serious disease. Data derived from experimental models of infection in ruminant species enables the study of the interactions between parasite and host. How the parasite initiates infection, becomes established and multiplies within the host and the critical pathways that may lead to a disease outcome are all important to enable the rational design of appropriate intervention strategies. Once the parasites invade the hosts they induce both innate and adaptive immune responses and the induction and function of these immune responses are critical in determining the outcome of the infection. Vaccines offer green solutions to control disease as they are sustainable, reducing reliance on pharmacological drugs and pesticides. The use of vaccines has multiple benefits such as improving animal health and welfare by controlling animal infections and infestations; improving public health by controlling zoonoses and food borne pathogens in animals; solving problems associated with resistance to acaricides, antibiotics and anthelmintics; keeping animals and the environment free of chemical residues and maintaining biodiversity. All of these attributes should lead to improved sustainability of animal production and economic benefit. Using different protozoan parasitic diseases as examples this paper will discuss various approaches used to develop vaccines to protect against disease in livestock and discuss the relative merits of using live versus killed vaccine preparations. A range of different vaccination targets and strategies will be discussed to help protect against: acute disease, congenital infection and abortion, persistence of zoonotic pathogens in tissues of food animals and passive transfer of immunity to neonates. PMID- 21680095 TI - Caenorhabditis elegans as a model to screen plant extracts and compounds as natural anthelmintics for veterinary use. AB - The most challenging obstacles to testing products for their anthelmintic activity are: (1) establishing a suitable nematode in vitro assay that can evaluate potential product use against a parasitic nematode of interest and (2) preparation of extracts that can be redissolved in solvents that are miscible in the test medium and are at concentrations well tolerated by the nematode system used for screening. The use of parasitic nematodes as a screening system is hindered by the difficulty of keeping them alive for long periods outside their host and by the need to keep infected animals as sources of eggs or adults when needed. This method uses the free-living soil nematode Caenorhabditis elegans as a system to screen products for their potential anthelmintic effect against small ruminant gastrointestinal nematodes, including Haemonchus contortus. This modified method uses only liquid axenic medium, instead of agar plates inoculated with Escherichia coli, and two selective sieves to obtain adult nematodes. During screening, the use of either balanced salt solution (M-9) or distilled water resulted in averages of 99.7 (+/- 0.73)% and 96.36 (+/- 2.37)% motile adults, respectively. Adult worms tolerated DMSO, ethanol, methanol, and Tween 80 at 1% and 2%, while Labrasol (a bioenhancer with low toxicity to mammals) and Tween 20 were toxic to C. elegans at 1% and were avoided as solvents. The high availability, ease of culture, and rapid proliferation of C. elegans make it a useful screening system to test plant extracts and other phytochemical compounds to investigate their potential anthelmintic activity against parasitic nematodes. PMID- 21680096 TI - Foreword to the 23rd International WAAVP Conference. PMID- 21680097 TI - Vaccination of goats with a glutathione peroxidase DNA vaccine induced partial protection against Haemonchus contortus infection. AB - Due to their critical functions in worm physiology, glutathione peroxidases in Haemonchus contortus are potential candidates for vaccine to control haemonchosis. However, information on the protection potential of these molecules is lacking. In this study, recombinant HC29 antigen was tested for protection against experimental H. contortus infections in goats. Fifteen animals were allocated into three trial groups. The animals of HC29 group was vaccinated with a recombinant HC29 DNA vaccine twice at day 0 and day 14, and then challenged with 5000 infective H. contortus L3 (third larval stage) on the 28th day. An unvaccinated positive control group was challenged with L3 at the same time. An unvaccinated negative control group was not challenged with L3. The results indicated HC29 DNA vaccine was transcribed at local injection sites and expressed in vivo post immunizations, respectively. Following L3 challenge, the mean eggs per gram feces and worm burdens of HC29 group were reduced by 36.1% and 35.6% respectively compared to the positive control group. After immunization with the DNA vaccine, significantly high levels of serum IgG, serum IgA, mucosal IgA and CD4(+) T lymphocytes were detected. These results suggest that recombinant H. contortus HC29 glutathione peroxidase DNA vaccine induced a partial immune response and has protective potentials against caprine haemonchosis. PMID- 21680098 TI - Host-parasite relationship of Ceratomyxa puntazzi n. sp. (Myxozoa: Myxosporea) and sharpsnout seabream Diplodus puntazzo (Walbaum, 1792) from the Mediterranean with first data on ceratomyxid host specificity in sparids. AB - Sparidae are economically important fishes to both, fisheries and aquaculture in the Mediterranean. Species diversification is an important strategy for the development of Mediterranean aquaculture. One of the species recently introduced is the sharpsnout seabream Diplodus puntazzo (Walbaum, 1792). During a parasitological study of fish from the Gulf of Valencia and the Mar Menor (Spain), myxozoan spores belonging to the genus Ceratomyxa were found in the gall bladder of D. puntazzo. A morphological description of the spores, which includes histology and transmission electron microscopy (TEM) as well as molecular (SSU ribosomal DNA) data resulted in the erection of a new species, Ceratomyxa puntazzi n. sp. A histopathological study of C. puntazzi n. sp. infection in D. puntazzo showed that the parasite causes necrosis and loss of epithelial cells in the gall bladder, and provokes a pericholangitis in the liver tissue surrounding the bile ducts. Furthermore, molecular data obtained from C. puntazzi n. sp. and three other ceratomyxids from the closely related fish species Diplodus annularis L. and Sparus aurata L. which share the same habitat suggest that the genus Ceratomyxa is host-specific in sparids, which agrees with data previously obtained from Serranidae, Labridae and Pomacentridae, and that ceratomyxid species from sparids in the Mediterranean originated from a common ancestor. PMID- 21680099 TI - Survey for natural Neospora caninum infection in wild and captive birds. AB - Neospora caninum is a protozoan parasite that presents worldwide distribution and is mainly implicated as responsible for bovine abortion. Although the presence of birds in cattle-raising properties is positively correlated to higher infection rates, very little has been described about the role of these animals in the parasite's life cycle. In that sense, this work aimed to investigate the serological and histological positivity of different avian species sampled in its natural habitat or in captivity. No serological positivity was observed in the 294 tested serum samples. On the other hand, Apicomplexa-like cysts found in muscular tissues of two Psittaciformes were immunostained with N. caninum antisera. These findings indicate that N. caninum may infect a wider range of hosts than described to date, and that further studies should be performed in order to determine the presence of the infection in different avian species. PMID- 21680100 TI - Livestock ectoparasites: integrated management in a changing climate. AB - The prevalence of livestock ectoparasites is the result of a complex interaction of factors such as parasite and host abundance, host susceptibility, climate and, critically, farmer husbandry and intervention strategies, all of which change seasonally in space and time. Given the complexity of the interacting factors, the effects of any climate change on disease incidence are hard to predict, as accordingly are the optimal husbandry responses required to ameliorate any effects. Here cutaneous myiasis in sheep, by the blowfly Lucilia sericata in the United Kingdom, is used to highlight the impact of a range of such issues. Cutaneous myiasis would be expected to be highly sensitive to even small changes in climate and therefore provides a good model to illustrate the problems inherent in attempting to predict the effect of climate change on livestock disease incidence. Both simulation and spatial species distribution models, show that the range of elevated temperatures predicted by current climate change scenarios are likely to result in an elongated blowfly season with earlier spring emergence and a higher cumulative incidence of strike. Strike incidence would be expected to increase, particularly for ewes in early summer. However, under higher IPCC emissions senarios (+3 degrees C), parts of central and southern England may become too hot and dry for strike by L. sericata to persist in mid summer. Under these conditions, it is possible that other, more pathogenic Mediterranean agents of myiasis, such as Wohlfahrtia magnifica could replace L. sericata. Nevertheless, the models suggest that simple changes in some husbandry practices, such as shearing or trap use, could have an important effect in reducing early season ewe strike incidences by L. sericata. The work reviewed here, suggests that climate warming is likely to increase the risk of fly strike incidence, with consequent animal welfare and economic problems. However, practical measures exist which, with modest changes in husbandry practices, should be able to manage expected increases in strike, under the range of climate changes currently predicted. The work demonstrates that attempts to predict the likely impact of climate change on disease incidence must take into account changes in farmer behaviour and animal management practices as well as parasite biology. PMID- 21680101 TI - Nanomedicine: novel approaches in human and veterinary therapeutics. AB - Nanomedicine can be defined as the application of nanotechnology to the prevention and treatment of diseases as well as for diagnosis purposes. In this context, the development of various types of drug-carrier nanodevices offers new strategies for targeted drug delivery, minimising the secondary effects and the toxicity associated to drug widespread to healthy organs or cells. This review is divided in two different parts. The first one summarizes the main types of nanomedicines developed in the past few decades, including drug nanocrystals, polymer therapeutics, lipid-nanosized and polymeric-nanosized drug delivery systems. The second part of our review is devoted, more specifically, to the presentation of polymeric nanoparticles. Here, we discuss various aspects of nanoparticle formulation, characterization, behaviour in the body and some of their potential applications. More particularly we present some approaches for the treatment of cancer, treatment of infectious diseases and the potential of these nanoparticles as adjuvants for vaccination purposes. PMID- 21680102 TI - Dietary salt restriction and chronic fatigue syndrome: a hypothesis. PMID- 21680103 TI - Quality traits and lipid composition of meat from Nellore young bulls fed with different oils either protected or unprotected from rumen degradation. AB - The qualitative characteristics, lipids and chemical composition of the meat of 35 Nellore young bulls were analyzed. These bulls had an average slaughter weight and fat thickness of 532.17+/-30.2 kg, and 7.00 mm, respectively. Significant differences were found only in the meat's water holding capacity (WHC), which was higher for animals fed with fresh linseed oil. More conjugated linoleic acid (CLA) was found in the meat of animals fed with unprotected soybean oil, while better omega-6/omega-3 ratios were noted for those fed unprotected linseed oil. The addition of different vegetable oils to the bulls' diet (soybean or linseed, either protected or not protected from rumen digestion) did not interfere with the qualitative characteristics of their meat while improving the lipid composition of the longissimus muscle. Of the oils examined, unprotected linseed oil most improved the omega-6/omega-3 ratio, thus producing the healthiest meat for human consumption. PMID- 21680104 TI - Association of PPARGC1A and CAPNS1 gene polymorphisms and expression with meat quality traits in pigs. AB - This study aimed to investigate the genes PPARGC1A (peroxisome proliferator activated receptor gamma-coactivator 1A) and CAPNS1 (calpain small subunit 1) as candidate genes affecting meat quality traits in pigs. Four polymorphisms were identified in PPARCG1A and three in CAPNS1. The PPARGC1A polymorphism c.1288T>A was associated with pH and cooking loss in a F2 Duroc*Pietrain experimental cross (DuPi, n=313) and with pH values in Italian Large White (ILW, n=380) and Italian Landrace (ILA, n=158) populations (P<0.05). The CAPNS1 polymorphism c.429A>C was associated with pH and conductivity in DuPi and with meat color in ILA (P<0.05). PPARGC1A mRNA expression associated with drip loss (P<0.01) and the same tendency was found for CAPNS1 (P=0.06). The promoter methylation profiling suggested that methylation is not involved in CAPNS1 expression regulation. In conclusion, porcine PPARGC1A and CAPNS1 genes may affect meat quality traits, with breed specific differences, and they could be used as markers for the improvement of meat quality in pigs. PMID- 21680105 TI - SOX4 expression levels in urothelial bladder carcinoma. AB - High levels of SOX4 gene expression have been reported in a variety of human cancers. The protein may function in the apoptosis pathway, leading to cell death as well as to tumorigenesis. The aim of this study was to investigate the levels of SOX4 expression in bladder cancer. Urinary bladder tumor samples were obtained from 57 bladder cancer and 13 normal bladder biopsies. The levels of SOX4 expression in bladder cancer were determined by immunohistochemistry and real time PCR. SOX4 gene expression was increased 2.2 times in bladder tumors as compared with normal tissue. The presence of protein was confirmed by immunostaining. There were significant differences between immunostaining of bladder tumors and normal bladder tissue (P=0.001). The present data suggest that SOX4 gene may have a role in bladder cancer tumorigenesis. PMID- 21680106 TI - Differential expression of DUSP6 with expression of ERK and Ki-67 in non-small cell lung carcinoma. AB - Dual specificity phosphatase 6 (DUSP6) is a member of the MAP kinase phophatase family. DUSP6 inactivates extracellular signal-regulated kinase (ERK), belonging to the MAP kinase family, and can act in tumor suppressive pathways. The aim of this study was to investigate associations of DUSP6 expression with expression of ERK and Ki-67 and with clinicopathological parameters in lung adenocarcinoma and squamous cell carcinoma. A total of 102 squamous cell carcinomas and 66 adenocarcinomas were studied using immunohistochemistry for DUSP6, ERK1/2, and Ki 67. In 66 adenocarcinomas, high DUSP6 expression was positively correlated with ERK1/2 expression. High DUSP6 expression was correlated with lower histological grade and lower Ki-67 index in the adenocarcinomas. In 102 squamous cell carcinomas, high DUSP6 expression was correlated with lower ERK expression, with greater smoking pack-years, but not with the Ki-67 index. These results indicate that DUSP6 acts as a negative feedback regulator of ERK in adenocarcinoma progression, but that DUSP6 does not play a role in the downregulation of ERK in squamous cell carcinoma. The differential expression of DUSP6 correlated with Ki 67 index, suggesting that DUSP6 plays an important role in cancer resistance in different subtypes of non-small cell lung carcinoma. PMID- 21680107 TI - Sessile serrated lesion and its borderline variant - Variables with impact on recorded data. AB - Sessile serrated lesion (SSL), belonging to non-dysplastic serrated polyps (SP), has lately received much focus. Its role in the serrated neoplasia pathway(s) seems well established. Data on prevalence rate, demography, and some polyp characteristics remain, however, to be firmly established. Nor has its relation to SPs with subtle aberrant features, falling short of definite SSL-histology, been sufficiently addressed. The aim of this study was to highlight variables that may influence recorded data on SSL and to further discuss the appropriate place of SPs that possess histological attributes intermediate between traditional hyperplastic polyp (HP) and SSL, termed borderline SSL (BSSL). Upon review of 8.324 consecutive colorectal polyps signed-out as HP, 219 SSLs and 206 BSSLs were segregated, using strict predetermined criteria. Predominant left sidedness and equal gender distribution characterized the present series, though right-sided SSLs occurred significantly more often in older subjects with a trend toward more females. The lower age of patients with SSL/BSSL in the last part of the study reflects the increased focus on hereditary neoplasm. BSSL differed from SSL only by a smaller polyp size. Discordant SSL-data can be ascribed primarily to diversities in endoscopic procedure, though tissue handling, the criteria used, and study design may contribute. A precursor status of BSSL to SSL is an attractive, though still unsubstantiated thesis. PMID- 21680108 TI - High-dose-rate brachytherapy alone for localized prostate cancer in patients at moderate or high risk of biochemical recurrence. AB - PURPOSE: To evaluate genitourinary (GU) and gastrointestinal (GI) morbidity and biochemical control of disease in patients with localized prostate adenocarcinoma treated with escalating doses per fraction of high-dose rate brachytherapy alone. METHODS AND MATERIALS: A total of 197 patients were treated with 34 Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in three fractions, or 26 Gy in two fractions. Median follow-up times were 60, 54, 36, and 6 months, respectively. RESULTS: Incidence of early Grade >= 3 GU morbidity was 3% to 7%, and Grade 4 was 0% to 4%. During the first 12 weeks, the highest mean International Prostate Symptom Score (IPSS) value was 14, and between 6 months and 5 years it was 8. Grade 3 or 4 early GI morbidity was not observed. The 3-year actuarial rate of Grade 3 GU was 3% to 16%, and was 3% to 7% for strictures requiring surgery (4 year rate). An incidence of 1% Grade 3 GI events was seen at 3 years. Late Grade 4 GU or GI events were not observed. At 3 years, 99% of patients with intermediate-risk and 91% with high-risk disease were free of biochemical relapse (log-rank p = 0.02). CONCLUSIONS: There was no significant difference in urinary and rectal morbidity between schedules. Biochemical control of disease in patients with intermediate and high risk of relapse was good. PMID- 21680109 TI - [Contribution of new MRI sequences in the exploration of the pelvic gynaecological disease]. AB - MRI has emerged for several years as the imaging examination of second-line indications in the majority of female pelvic imaging, after ultrasonography. Recent technical advances have allowed the widespread use of new MRI sequences, allowing a morphological and functional analysis of the pelvic organs. Diffusion weighted-imaging has a definite interest for the detection, characterization and staging of uterine and adnexal lesions. Dynamic contrast-enhanced imaging is an essential tool for characterizing adnexal lesions and to optimize the staging of uterine cancers. The 3D morphological imaging allows multiplanar reconstructions and is particularly useful in mapping fibroids, uterine malformations and in endometriosis. PMID- 21680110 TI - Clinician and service user perceptions of implementing contingency management: a focus group study. AB - BACKGROUND: Contingency management (CM), despite the evidence base for its effectiveness, remains controversial, with sub-optimal implementation. In 2007, UK guidelines recommended the use of CM in publicly funded services, but uptake has also been minimal. Previous surveys of service providers suggest differences in opinions about CM, but to date there has been no published involvement of service users in this debate. METHOD: Focus group methodology was used to explore systematically the attitudes, concerns and opinions of staff and service users about the use of CM, in publicly funded substance misuse services, to identify the key areas that may be influential in terms of implementation and outcome. Data were analysed thematically using the constant comparative method. RESULTS: 70 staff and service users participated in 9 focus groups. 15 themes of discussion around CM were identified, grouped into four categories: how CM was aligned to the philosophy of substance misuse services; the practicalities of implementation; wider ethical concerns; and how participants perceived the evidence for effectiveness. CONCLUSIONS: Robust process evaluation in different treatment systems is needed to define the active components of CM for implementation. Involvement of service users in this process is essential and is likely to provide valuable insights into the mechanism of action of CM and its effectiveness and uptake within complex treatment systems. PMID- 21680111 TI - Cultural competence in outpatient substance abuse treatment: measurement and relationship to wait time and retention. AB - BACKGROUND: Culturally competent practice is broadly acknowledged to be an important strategy to increase the quality of services for racial/ethnic minorities in substance abuse treatment. However, few empirically derived measures of organizational cultural competence exist, and relatively little is known about how these measures affect treatment outcomes. METHOD: Using a nationally representative sample of outpatient substance abuse treatment (OSAT) programs, this study used item response theory to create two measures of cultural competence-organizational practices and managers' culturally sensitive beliefs and examined their relationship to client wait time and retention using Poisson regression modeling. RESULTS: The most common and precisely measured organizational practices reported by OSAT managers included matching providers and clients based on language/dialect; offering cross-cultural training; and fostering connections with community and faith-based organizations connected to racial and ethnic minority groups. The most culturally sensitive belief among OSAT managers was support for language/dialect matching for racial and ethnic minority clients. Results of regression modeling indicate that organizational practices were not related to either outcome. However, managers' culturally sensitive beliefs were negatively associated with average wait time (p<0.05), and positively associated with average retention (p<0.01). CONCLUSIONS: Managers' culturally sensitive beliefs-considered to be influential for effective implementation of culturally competent practices-may be particularly relevant in influencing wait time and retention in OSAT organizations that treat Latinos and African American clients. PMID- 21680112 TI - Investigation of endothelial cells as an in vivo nidus of Anaplasma marginale infection in cattle. AB - Continuous culture of Anaplasma marginale in endothelial cells and the potential implications for vaccine development heightened interest in determining the importance of endothelial cells in the A. marginale life cycle. A. marginale infection trials were performed to determine if endothelial cells are an in vivo host cell in cattle and if A. marginale from in vitro endothelial cells were infective to cattle. Adult, immunocompetent steers were infected by tick-feeding transmission and were euthanized at different points in the parasitemic cycle. Based on quantitative PCR, the tissue distribution of A. marginale DNA during peak and trough parasitemia was variable with higher quantities observed in spleen, lung, hemal nodes, and abomasum. A. marginale was not conclusively identified in tissue endothelial cells from the steers' tick-bitten dermis or post-mortem tissues using three microscopy techniques (dual indirect immunofluorescence, transmission electron microscopy, and in situ DNA target primed rolling-circle amplification of a padlock probe). Intravenous inoculation of spleen-intact or splenectomized calves with endothelial cell culture-derived VA isolate A. marginale did not cause seroconversion or clinical anaplasmosis regardless of whether the endothelial culture-derived bacteria were inoculated as host cell-free organisms or within endothelial cells and regardless of the type of endothelial cell culture used - RF/6A primate endothelial cells or primary bovine testicular vein endothelial cells. Data presented here suggest that endothelial cells are likely not a pivotal component of the A. marginale life cycle in vivo. PMID- 21680113 TI - Dynamics of Torque teno sus virus 1 (TTSuV1) and 2 (TTSuV2) DNA loads in serum of healthy and postweaning multisystemic wasting syndrome (PMWS) affected pigs. AB - Torque teno viruses (TTVs) are vertebrate infecting, small viruses with circular single stranded DNA, classified in the Anelloviridae family. In pigs, two different TTV species have been described so far, Torque teno sus virus 1 (TTSuV1) and 2 (TTSuV2). TTSuVs have lately been linked to postweaning multisystemic wasting syndrome (PMWS). In the present study, TTSuV1 and TTSuV2 prevalence and DNA loads in longitudinally collected serum samples of healthy and PMWS affected pigs from Spanish conventional, multi-site farms were analyzed. Serum samples were taken at 1, 3, 7, 11 and around 15 weeks of age (age of PMWS outbreak) and viral DNA loads determined by quantitative PCR. For both TTSuV species, percentage of viremic pigs increased progressively over time, with the highest prevalence in animals of about 15 weeks of age. TTSuV1 and TTSuV2 viral DNA loads in healthy and TTSuV1 loads in PMWS affected animals increased until 11 weeks of age declining afterwards. On the contrary, TTSuV2 DNA loads in PMWS affected pigs increased throughout the sampling period. It seems that TTSuV species differ in the in vivo infection dynamics in PMWS affected animals. PMID- 21680114 TI - Subunit influenza vaccine candidate based on CD154 fused to HAH5 increases the antibody titers and cellular immune response in chickens. AB - World Health Organization has a great concern about the spreading of avian influenza virus H5N1. To counteract its massive spread, poultry vaccination is highly recommended together with biosecurity measures. In our study, a recombinant vaccine candidate based on the fusion of extracellular segments of hemagglutinin (HA) H5 of avian influenza virus and chicken CD154 (HACD) is tested with the aim of enhancing humoral and cellular immune responses in chickens. Protein expression was carried out by transducing several mammalian cell lines with recombinant adenoviral vectors. HACD purification was assessed by three distinct purification protocols: immunoaffinity chromatography by elution at acidic pH or with a chaotropic agent and size exclusion chromatography. Humoral and cellular immune responses were measured using the hemagglutination inhibition assay and the semiquantitative real time PCR, respectively. The results showed that humoral response against HACD was significantly higher than the obtained with HA alone after booster (P<0.01, P<0.05). From HACD molecules purified by distinct protocols, only the obtained by size exclusion chromatography generated hemagglutinationin-inhibition activity. IFN-gamma levels indicated that cellular immune response was significantly higher with HACD, in its pure or impure form, compared to its counterpart HA (P<0.01). These data demonstrate that HACD is able to significantly enhance humoral and cellular immune responses against HA antigen, which make this fusion protein a promising subunit vaccine candidate against H5N1 virus outbreaks. PMID- 21680115 TI - Serological evidence of West Nile virus circulation in Portugal. AB - The circulation of West Nile virus in Portugal was assessed by serological surveys conducted during 2004-2010 in horses and birds. The detection of WNV antibodies in both species in all the years covered by the study as well as the presence of anti-WNV IgM in symptomatic horses that had not traveled outside the country, support the notion that WNV circulates in Portugal. PMID- 21680116 TI - Genetic and splice variations of Bos taurus CD46 shift cell permissivity to BVDV, the bovine pestivirus. AB - The pestivirus bovine viral diarrhea virus (BVDV) is known to bind to the CD46 molecule, which subsequently promotes entry of the virus. Mapping of the BVD virion-binding site has shown that two peptides, 66EQIV69 and 82GQVLAL87, located on antiparallel beta sheets in the most distal complement control protein module (CCP1), provide the attachment platform. In the present study, we reveal the existence of ten distinct allelic versions of the CCP1 module, varying significantly in frequency among taurine and indicine races. A complex mRNA splicing pattern was also evidenced for bovine CD46, generating three different serine-threonine-proline segments and five different cytoplasmic domains. The four most frequent allelic variants and the six splice variants were then expressed in BVDV-nonpermissive porcine cells and the quantity of progeny virions generated by each cell preparation was measured 48 h post-infection. As expected, ectopic expression of the 10 bovine CD46 isoforms rendered the PK15 cells permissive to BVDV, as attested by the 100,000-fold greater recovery of virions from these cells than from non-transfected cells. This permissivity increase was significantly lower (-33%, P<0.001) when the canonical CCP1 was replaced with the variant most frequent in zebus, suggesting positive or negative selection of this allele in the latter and in the former, respectively. The predicted secondary structure of this variant suggests that the measured loss of function is due to the disappearance of one of the two beta sheets constituting the BVDV attachment platform. On the other hand we showed that for a given CCP1, the titer recovered at 48 hpi also depended on the nature of the CD46 cytoplasmic domain (P<0.001). This result implies that virus binding generates a cytoplasmic-tail-dependent outside-in signal that determines permissivity to BVDV. PMID- 21680117 TI - The Ins and Outs of siderophore mediated iron uptake by extra-intestinal pathogenic Escherichia coli. AB - Extraintestinal pathogenic E. coli (ExPEC) are responsible for many infectious diseases in livestock, such as airsacculitis in poultry, acute mastitis in dairy animals and neonatal septicaemia and urinary tract infections (UTI) in pigs and cattle. In their animal hosts, ExPEC have to cope with low iron availability. By using different strategies, ExPEC strains are able to retrieve iron sequestered by host proteins. One of these strategies is the use of siderophores, which are small secreted molecules with high affinity for iron. ExPEC are known to synthesize up to four different types of siderophores: enterobactin, salmochelins, yersiniabactin and aerobactin. Steps required for iron acquisition by siderophores include (1) siderophore synthesis in the cytoplasm, (2) siderophore secretion, (3) ferri-siderophore reception, (4) ferri-siderophore internalization and (5) iron release in the cytoplasm. Each siderophore has specific properties and may be differentially regulated to provide different advantages, potentially allowing ExPEC to adapt to different environmental conditions or to overcome host innate immunity. Iron acquisition by siderophores plays a significant role in ExPEC virulence and, as it requires outer membrane receptors, it constitutes an interesting target for the development of vaccines that could be used to limit the number of infectious diseases due to ExPEC in livestock. PMID- 21680118 TI - Motor delay in cystic fibrosis infants: an observational study. AB - OBJECTIVE: To verify the prevalence of delay in gross motor development in cystic fibrosis (CF) patients. STUDY DESIGN: This is a cross-sectional observational study. A total of 15 children with CF were included in the analyses. The selection criteria was age between 6 and 42months. Data on demographic, anthropometric, clinical characteristics and severity score (Shwachman) were obtained from patient records. The Bayley Scales of Infant and Toddler Development(r) - III Edition (BSITD-III) was used to assess motor abilities. RESULTS: Motor development delay was observed in 26.7% (n=4) of the children and, in 75% of these, there were statistically significant differences between gross and fine motor scores. Low stature, low weight and periods longer than 60days at hospital showed statistically significant association with motor delay (p=0.025, 0.032, 0.003, respectively). CONCLUSION: The prevalence of motor delay in the studied sample was high, suggesting that biological and ambient conditions of risk present in CF contribute to early motor deficits. Thus, the observation of the motor development in these patients is important for planning an adequate intervention. PMID- 21680119 TI - Perceived control, lifestyle, health, socio-demographic factors and menopause: impact on hot flashes and night sweats. AB - OBJECTIVE: To develop a model to predict the perceived severity of hot flashes (HF) and night sweats (NS) in symptomatic middle-aged women. METHODS: This was a cross-sectional study of a community-based sample of 243 women with vasomotor symptoms. Menopausal status was ascertained using the 'Stages of Reproductive Aging Workshop' criteria. Women's 'perceived control' over their symptoms was measured by a validated Portuguese version of the Perceived Control over Hot Flushes Index. Structural equation modelling was employed to construct a causal model of self-reported severity of both HF and NS, using a set of 20 variables: age, marital status, parity, professional status, educational level, family annual income, recent diseases and psychological problems, medical help-seeking behaviour to manage menopausal symptoms, use of hormone therapy and herbal/soy products, menopause status, intake of alcohol, coffee and hot beverages, smoking, physical exercise, body mass index and perceived control. RESULTS: Significant predictors of perceived severity were the use of hormone therapy for both HF (beta=-.245; p=.022) and NS (beta=-.298; p=.008), coffee intake for both HF (beta=-.234; p=.039) and NS (beta=-.258; p=.029) and perceived control for both HF (beta=-1.0; p<.001) and NS (beta=-1.0; p<.001). The variables explained respectively 67% and 72% of the variability in the perceived severity of HF and NS. Women with high perceived control had a significantly lower frequency (t(235)=2.022; p=.044) and intensity of HF (t(217)=3.582; p<.001); similarly, participants with high perceived control presented a lower frequency (t(235)=3.267; p<.001) and intensity (t(210)=3.376; p<.001) of NS. CONCLUSION: Perceived control was the strongest predictor of the self-reported severity of both HF and NS. Other causal predictors were hormone therapy and caffeine intake. All three were associated with less severe vasomotor symptoms. PMID- 21680120 TI - Quality of life, characteristics and metabolic control in diabetic geriatric patients. AB - OBJECTIVES: To describe the characteristics, metabolic control and health-related quality of life (HRQL) of type 2 diabetes mellitus (T2DM) geriatric patients. STUDY DESIGN: Cross-sectional descriptive study of consecutive patients attended at a geriatric outpatient clinic in a tertiary hospital over three months. Sociodemographic, geriatric assessment variables, HRQL (using the EuroQol instrument) and comorbidity (Charlson and CIRS-G indexes) were measured. The presence of macrovascular and microvascular complications and cardiovascular risk factors were investigated. To assess the degree of metabolic control, the European Union Geriatric Medicine Society (EUGMS) criteria were followed with patients under 80 years old being considered as young elderly and disability as dependence on more than 2 ADLs or need of aid in ambulation. RESULTS: We included 112 patients with an average age of 81.4+/-5.7 years, a Charlson comorbidity index of 4.3+/-1.57 and a CIRS-G index of 9.7+/-3. Seventy four per cent of patients were dependent on none or only one ADL, 38.5% presented cognitive impairment and 40% depression. Appropriate control of basal glucose and glycosylated haemoglobin was seen in 43.2% of the patients. HRQL indicated a high frequency of involvement with a significant relationship with functional dependence, cognitive impairment, and depression but not with metabolic control. CONCLUSIONS: Geriatric patients with T2DM treated on an outpatient basis have a heavy load of comorbidity and an insufficient level of metabolic control even when individually adapted to age and functional state. HRQL is greatly impaired and related to their functional, cognitive and affective derangements. PMID- 21680121 TI - Is mechanical ventilation associated with intraventricular hemorrhage in preterm infants? AB - BACKGROUND: The impact of mechanical ventilation on the incidence of intraventricular hemorrhage (IVH) in very low birth weight (VLBW) infants is unknown, simply because the vast majority of these infants have been routinely intubated and mechanically ventilated. There is a growing interest in the use of early nasal continuous positive airway pressure (ENCPAP) and avoiding mechanical ventilation. OBJECTIVES: To examine the role of mechanical ventilation since delivery room in determining severe IVH in VLBW infants in two neonatal units that follow the same strategy of respiratory management using ENCPAP. METHODS: We collected data on delivery room intubation and mechanical ventilation during the first 3 days of life in VLBW infants. Logistic regression model was constructed to test the relationship between early mechanical ventilation and the diagnosis of severe IVH after controlling for significant confounding variables, such as BW, gender, duration of mechanical ventilation, and partial pressure of CO(2) (PCO(2)). RESULTS: Of the studied 340 VLBW, 35 infants had severe IVH; most of them received mechanical ventilation that started either in the delivery room (n=12) or during the first (n=10) and second (n=3) days of life. Severe IVH was independently associated with lower BW, mechanical ventilation in the delivery room, and the cumulative duration of mechanical ventilation during the first 3 days. The adjusted odds ratio for severe IVH in infants intubated in delivery room was (OR=2.7, CI: 1.1-6.6, P=0.03). Severe IVH was not associated with gender, prenatal steroids, early sepsis, or patent ductus arteriosus. CONCLUSIONS: Mechanical ventilation plays a role in predicting severe IVH. Both the time at which ventilation was initiated and the duration of ventilation are important determinants of severe IVH. Risk for severe IVH in infants who were never intubated in delivery room or during the first 3 days of life is miniscule. PMID- 21680122 TI - Antiretroviral therapy in intensive care. AB - Using antiretroviral therapy (ART) raises numerous issues in intensive care units (ICU): drug administration and kinetics issues in ventilated patients and/or with gastric tube, drug interactions, and risk of immune reconstitution inflammatory syndrome. This is why a lot of ICU physicians stop ART on admission and few initiate it during the ICU stay. However, the literature review suggests that the earlier the ART is started the more effective it is. Furthermore, stopping ART could be hazardous for some patients. The authors present the most frequent issues raised by ART use in an ICU and how to deal with them. PMID- 21680123 TI - Sternal fracture in the emergency department: diagnostic value of multidetector CT with sagittal and coronal reconstruction images. AB - BACKGROUND: Multidetector CT (MDCT) is being increasingly used for patients with traumatic injuries in the emergency room. This is the first study to evaluate the diagnostic performance of MDCT for sternal fracture. PATIENTS AND METHODS: For 87 patients who had motor vehicle accidents, we evaluated the diagnostic performance of MDCT for the sternal fractures. For 31 patients who underwent both MDCT and lateral radiography for the sternum, we compared the diagnostic performance of two examinations for the evaluation of sternal fracture. RESULTS: Thirty-two patients had sternal fractures and all the sternal fractures (sensitivity=100%) were detected on MDCT, especially on the sagittal reconstruction images. However, the axial and coronal images detected 65% and 59% of all sternal fractures, respectively. For 31 patients who underwent both MDCT and lateral radiography for the sternum, MDCT showed superior diagnostic performance compared to that of radiography (accuracy=97% and 77%, respectively, P=.02). For the one case that showed false positivity for sternal fracture on MDCT due to respiratory artifact, the lateral radiography enabled making the correct diagnosis. CONCLUSION: Sternal fracture is frequently seen in patients who have blunt trauma injury secondary to motor vehicle accidents. MDCT, particularly sagittal images detect all of the sternal fractures, is superior to lateral radiography for diagnosis of sternal fracture. In the limited case that CT has severe motion artifact, additional radiography could help the diagnosis of sternal fracture. PMID- 21680124 TI - Volumetric analysis of the mandibular condyle using cone beam computed tomography. AB - OBJECTIVE: The aim was to determine the accuracy of volumetric analysis of the mandibular condyle using cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Five dry mandibles containing 9 condyles were used. CBCT scans of the mandibles and an impression of each condylar area were taken. The physical volumes of the condyles were calculated as the gold standard using the water displacement technique. After isolating, the condylar volume was sectioned in the sagittal plane, and 0.3mm thick sections with 0.9mm intervals were obtained from 3D reconstructions. Using the Cavalieri principle, the volume of each condyle was estimated from the CBCT images by three observers. The accuracy of the CBCT volume measurements and the relation agreements between the results of the three observers were assessed using the Wilcoxon Signed Rank test and Pearson correlation test. The level of statistical significance was set at 0.05. RESULTS: The results of the Pearson correlation showed that there were highly significant positive correlations between the observers' measurements. According to the results of the Wilcoxon Signed Rank test comparing the physical and observers' measurements, there were no statistically significant differences (p>0.05). CONCLUSION: The Cavalieri principle, used in conjunction with a planimetry method, is a valid and effective method for volume estimation of the mandibular condyle on CBCT images. PMID- 21680125 TI - CT-guided percutaneous lung biopsy: comparison of conventional CT fluoroscopy to CT fluoroscopy with electromagnetic navigation system in 60 consecutive patients. AB - PURPOSE: To determine if use of an electromagnetic navigation system (EMN) decreases radiation dose and procedure time of CT fluoroscopy guided lung biopsy in lesions smaller than 2.5 cm. MATERIALS/METHODS: 86 consecutive patients with small lung masses (<2.5 cm) were approached. 60 consented and were randomized to undergo biopsy with CT fluoroscopy (CTF) (34 patients) or EMN (26 patients). Technical failure required conversion to CTF in 8/26 EMN patients; 18 patients completed biopsy with EMN. Numerous biopsy parameters were compared as described below. RESULTS: Average fluoroscopy time using CTF was 28.2s compared to 35.0 s for EMN (p=0.1). Average radiation dose was 117 mGy using CTF and 123 mGy for EMN (p=0.7). Average number of needle repositions was 3.7 for CTF and 4.4 for EMN (p=0.4). Average procedure time was 15 min for CTF and 20 min for EMN (p=0.01). There were 7 pneumothoracesin the CTF group and 6 pneumothoraces in the EMN group (p=0.7). One pneumothorax in the CTF group and 3 pneumothoraces in the EMN group required chest tube placement (p=0.1). One pneumothorax patient in each group required hospital admission. Diagnostic specimens were obtained in 31/34 patients in the CTF group and 22/26 patients in the EMN group (p=0.4). CONCLUSIONS: EMN was not statistically different than CTF for fluoroscopy time, radiation dose, number of needle repositions, incidence of pneumothorax, need for chest tube, or diagnostic yield. Procedure time was increased with EMN. PMID- 21680126 TI - Longitudinal analysis and genotyping of infant dominant bifidobacterial populations. AB - Bifidobacterial population dynamics were investigated by the longitudinal analysis of the dominant population isolated from the feces of young infants. After molecular identification and fingerprinting comparison, clone identity of the consecutive strains belonging to the same species for one individual was performed by pulsed-field gel electrophoresis. The results, obtained from 15 individuals sampled four times over a five-week period suggested a turnover of the dominant bifidobacteria in the population not only at the species but also at its species representative levels. This study provides new insights of the in vivo dynamics of commensal bifidobacteria. It highlights the need to take into consideration the fluctuation of bifidobacterial populations that may occur in one individual in order to investigate reliably the impact of dietary components, such as probiotics or prebiotics, on the intestinal ecosystem. PMID- 21680127 TI - Synthesis, full chemical characterisation and development of validated methods for the quantification of (+/-)-4'-methylmethcathinone (mephedrone): a new "legal high". AB - The recent global increase in the abuse of 4'-methylmethcathinone and related compounds has developed a requirement for full chemical characterisation of these products. In this work we present full synthetic and chemical characterisation data and supplemental information for mephedrone synthesised as both the hydrobromide and hydrochloride salt. Additionally we report the first fully validated chromatographic methods for the detection and quantitative analysis of the substance both in its pure form and in the presence of a number of common adulterants used in illicit drug manufacture. PMID- 21680128 TI - Development and validation of a UPLC-MS/MS method for quantification of SKLB010, an investigational anti-inflammatory compound, and its application to pharmacokinetic studies in beagle dogs. AB - SKLB010 is currently under development as a potential therapeutic agent for the treatment of acute hepatitis and rheumatoid arthritis. The purpose of this paper was to investigate the pre-clinical pharmacokinetics of SKLB010 in beagle dogs. An ultra performance liquid chromatographic tandem mass spectroscopy (UPLC-MS/MS) method was developed and validated for the quantitative determination of SKLB010 in dog plasma, using rosiglitazone as the internal standard (I.S.). Plasma samples were prepared by a simple solid phase extraction (SPE) method. The analyte and internal standard were separated by an Acquity UPLC BEH C18 (2.1 mm * 50 mm) column with a mobile phase of methanol-water (80/20, v/v) over 2 min. Detection was based on the multiple reaction monitoring with the precursor-to product ion transitions m/z 234.10->147.92 (SKLB010) and m/z 356.15->150.00 (I.S.). The method was validated according to FDA guidelines on bio-analytical method validation. The selectivity, sensitivity, linearity, accuracy, precision, extraction recovery, ion suppression and stability were within the acceptable ranges. The method described above was successfully applied to reveal the single- and multi-pharmacokinetic profiles of SKLB010 in beagle dogs and should be extendable to pharmacokinetic studies in other species as well. PMID- 21680129 TI - Analysis of citrate in low-volume seminal fluid samples using a time-gated measurement of europium luminescence. AB - This work aims to develop and validate a rapid analytical method that enables the measurement of citrate in seminal fluid samples. Samples were obtained from men who were within 9 weeks of a vasectomy operation. Two age ranges were examined, between 40-43 and 50-53 years old, with nearly 100 samples in each case. No patient clinical history was available for this anonymous study, simulating a random screening cohort. The concentration of citrate in 0.5 MUL seminal fluid samples was assessed, using a europium emission luminescence method. This involves the ratiometric analysis of two well-separated europium(III) emission bands. Spectral data were obtained using a time-gated spectrometer whose construction and modification is described. Citrate values were confirmed by independent measurements using a citrate lyase enzymatic assay and by 700 MHz 1H NMR analysis of the seminal fluid. Citrate concentrations were not statistically different between age groups and averaged 35.0(+/-14.6) mM for the 40-43 group, and 28.2(+/-12.7) mM for the 50-53 cohort; in each case a polymodal distribution was observed. PMID- 21680130 TI - Unpredicted gender preference of obstetricians and gynecologists by Muslim Israeli-Arab women. AB - OBJECTIVES: To investigate the gender preference of Muslim Israeli-Arab women regarding obstetricians/gynecologists, and identify other features that affect their choice. METHODS: The study included 167 responders to an anonymous questionnaire. RESULTS: Around one-half of the responders had no gender preference regarding family physicians, but most (76.6%) preferred a female gynecologist. Likewise, most responders preferred pelvic examinations (85.6%) and pregnancy follow-up (77.8%) by female gynecologists. Additionally, 61.7% preferred consulting female physicians for major obstetrical and gynecological (OB/GYN) problems. The reasons for female preference were embarrassment (67.7%), feeling comfortable with female gynecologists (80.8%) and the notion that female gynecologists are more gentle (68.3%). The three most important factors which affected actual selection, however, were experience (83.8%), knowledge (70.1%) and ability (50.3%), rather than physician gender (29.3%). Multivariate analysis revealed that other qualities and importance of background variables of the gynecologist were independent predictors of gender preference. CONCLUSIONS: Although Muslim Arab-Israeli women express gender bias regarding their preference for gynecologists/obstetricians, personal and professional skills are considered to be more important factors when it comes to actually making a choice. PRACTICE IMPLICATION: We suggest that the ideal obstetrician/gynecologist for these women would be female, though skilled, knowledgeable, and experienced male would be appropriate. PMID- 21680131 TI - Promoting decision aid use in primary care using a staff member for delivery. AB - OBJECTIVE: To determine the feasibility and effectiveness of in-clinic decision aid distribution using a care assistant. METHODS: We identified potentially eligible patients scheduled for upcoming appointments in our General Internal Medicine Clinic (n=1229). Patients were deemed eligible for two decision aids: prostate cancer screening and/or weight loss surgery. Patients were approached to view the decision aid in-clinic. Our primary measures were the proportion of decision aids distributed to eligible patients, and the proportion of decision aids viewed. RESULTS: Among 913 patients who attended their scheduled appointments, 58% (n=525) were approached and eligibility was assessed by the staff member. Among the 471 who remained eligible, 57% (n=268) viewed at least a portion of the target decision aid. The mean viewing time for patients who watched less than the complete decision aid was 13 min. CONCLUSIONS: In clinic viewing of decision aids may be a feasible and effective distribution method in primary care. PRACTICE IMPLICATIONS: In clinic distribution requires an electronic health information system to identify potentially eligible patients, and a staff member dedicated to DA distribution. Brief decision aids (less than 10 min) are needed so patients can complete their use prior to the visit to facilitate patient-physician decision making. PMID- 21680132 TI - Prognostic factors in stage II/III/IV and stages III/IV endometrioid and serous adenocarcinoma of the endometrium. P. Mhawech-Fauceglia, R.F. Herrmann, J. Kesterson, I. Izevbaye, S. Lele, K. Odunsi. Eur J Surg Oncol 2010 Dec;36(12):1195 201. PMID- 21680133 TI - [Labor epidural analgesia for a woman with a pityriasis versicolor in the lumbar region]. AB - Epidural analgesia is usually contraindicated in case of infection at the site of needle insertion. Tinea versicolor is a benign superficial cutaneous fungal infection caused by the proliferation of a skin commensal yeast of low pathogenicity. We report the case of a pregnant woman with a tinea versicolor in the lumbar region, who benefited from a labor epidural analgesia, realised with reinforced antiseptic measures. No neurological or infectious complication occurred. PMID- 21680134 TI - Povidone iodine: features of critical systemic absorption. AB - Povidone iodine (PI), a skin antiseptic, is sometimes used internally but this procedure exposes to potentially lethal iodine absorption. Indeed, a 41-year-old woman, with no relevant medical history, developed a transient hypotension, anuric renal failure, hemolysis, coagulopathy and uterine infarction after intra uterine injection of PI as a dye to check the fallopian tube patency (hydrotubation). Iodemia peaked at 6929 MUg/dL (normal range 3.4-8.0 MUg/dL), and decreased over the 9 days of renal replacement therapy. Extreme caution should be exercised when PI is in contact with a mucosa, the early recognition of iodine toxicity being of utmost importance to rapidly prompt renal replacement therapy. The main purpose of this report is to highlight the clinical features of PI absorption, whatever the route of administration. PMID- 21680136 TI - How to write a scientific paper - searching and managing biomedical information. PMID- 21680137 TI - The benefits of digital thoracic drainage system for outpatients undergoing pulmonary resection surgery. AB - Since digital thoracic drainage system (DTDS) came onto the market, a number of its advantages have become clear, for example that of eliminating the differences between observers. The withdrawal of thoracic drainage has been found to be comfortable, safe and well tolerated by patients; it helps to reduce or eliminate the cost of hospital stay, because, according to the different series published in recent months, it is possible to withdraw drainage sooner and thus discharge patients earlier. Prospective studies are underway, but as yet nothing has been written about the possible benefits in outpatient surgery programmes. In this report we present our findings of 3 cases of patients undergoing pulmonary resection who were treated with continuous intra-domiciliary DTDS. Pending the results of a prospective study now underway our observation is that with properly selected patients this is a safe method. PMID- 21680138 TI - Comparison of surgical outcomes and implant wear between ceramic-ceramic and ceramic-polyethylene articulations in total hip arthroplasty. AB - The results of a prospective multicenter trial comparing 357 hips randomized to total hip arthroplasty with either ceramic-ceramic or ceramic-polyethylene couplings are presented. No statistically significant difference in clinical outcomes scores between the ceramic-ceramic and ceramic-polyethylene groups was observed at any time interval. The mean linear rate was statistically lower (P < .001) in the ceramic-ceramic group (30.5 MUm/year) when compared with the ceramic polyethylene group (218.2 MUm/year). The rates of ceramic implant fracture (2.6%) and audible component-related noise (3.1%) were statistically higher in the ceramic-ceramic group when compared with the ceramic-polyethylene group (P < .05). Lastly, there was no statistically significant difference in the dislocation or revision rate between the groups at the time of last clinical follow-up. PMID- 21680139 TI - High-flex posterior cruciate-retaining vs posterior cruciate-substituting designs in simultaneous bilateral total knee arthroplasty: a prospective, randomized study. AB - The superiority between the posterior cruciate-retaining and the posterior cruciate-substituting designs still remains controversial. We performed a prospective, randomized control study for evaluation of the superiority of these designs. This study investigated 58 knees in 29 patients with simultaneous bilateral total knee arthroplasty, in which the high-flex CR design was randomly implanted in one knee and the high-flex PS design was implanted in the other knee. The follow-up duration averaged 5.0 years, with a minimum duration of 3 years. Postoperatively, Knee Score and pain points in Knee Score resulted in no significant differences between the 2 designs. However, postoperative arc of range of motion, patient satisfaction, and posterior knee pain at passive flexion in the PS design were significantly superior to that of the CR design. PMID- 21680140 TI - Pain in patients attending a specialist cancer service: prevalence and association with emotional distress. AB - CONTEXT: We know little about how many outpatients of a modern cancer center suffer from clinically significant unrelieved pain and the characteristics of these patients to guide better care. OBJECTIVES: To determine the prevalence of clinically significant pain (CSP) in the outpatients of a regional cancer center and the association with distress and other variables. METHODS: A secondary analysis of cross-sectional, self-reported and clinical data from 2768 patients reattending selected clinics of a regional National Health Service cancer center in the U.K. Pain was measured using the pain severity scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, emotional distress was measured by the Hospital Anxiety and Depression Scale, and demographic and clinical data were taken from medical records. RESULTS: Fifty four percent (95% confidence interval [CI] 52-56) of patients reported pain at least "a little" in the previous week and 18% (95% CI 17-20) at least "quite a bit" (CSP). The strongest independent associations of CSP were active disease (odds ratio [OR] 1.95, 95% CI 1.5-2.5) and emotional distress (OR 4.8, 95% CI 4 6). CONCLUSION: CSP is surprisingly common in outpatients of specialist cancer services, and it is strongly and independently associated with emotional distress. Better symptom management should consider pain and distress together. PMID- 21680141 TI - "I feel uncomfortable 'calling a patient out'": educational needs of palliative medicine fellows in managing opioid misuse. AB - CONTEXT: During the past 10 years, advocates of palliative care have sought to be included earlier in the course of patients' illnesses. Palliative care providers may thus be more likely to care for patients who misuse and abuse opioids. OBJECTIVES: To assess whether hospice and palliative medicine (HPM) fellows see patients at risk for opioid misuse and how competent they perceive themselves to be to treat pain in these patients. METHODS: An electronic survey was distributed to 102 HPM fellows. The survey included questions assessing self-perceived competency in care for patients who misuse opioids. Responses were rated using a Likert scale of one to seven, where one=strongly agree and seven=strongly disagree; any number greater than two was considered to be nonagreement. RESULTS: Fifty-seven (56%) fellows from 34 programs responded to the survey. In the previous two weeks, 77.2% of respondents had seen at least one patient with a substance use disorder (SUD) and 43.9% had treated a patient whom they were concerned was misusing opioids. Half (47.2%) of respondents stated that they have a working knowledge of addiction, 41.4% agreed their training has prepared them to manage opioid misuse, and 36.8% felt they knew how to differentiate pain from addiction. Only 21.1% were satisfied with how they treat symptoms in this population. Fellowship training in opioid misuse was associated with increased satisfaction. CONCLUSION: HPM fellows regularly see patients who are at risk for opioid misuse and feel unprepared to treat pain in these patients. There is a need for more education of fellows in this area. PMID- 21680142 TI - Pulmonary embolism caused by a thrombosed external iliac venous aneurysm. AB - Venous aneurysms (VAs) of the iliac axis are uncommon abnormalities of the vascular system that present as potentially life-threatening events. These aneurysms are occasionally associated with embolism or rupture; therefore, a focused imaging evaluation and prophylactic treatment are important. In this article, we report a thrombosed external iliac venous aneurysm (VA) that led to pulmonary embolism in a 14-year-old girl. The patient was diagnosed using computer tomography pulmonary angiography and computer tomography iliac venography. This case represents the first patient known to have an external iliac VA that progressed to pulmonary embolism. PMID- 21680143 TI - Correlation of intraoperative collateral perfusion pressure during carotid endarterectomy and status of the contralateral carotid artery and collateral cerebral blood flow. AB - BACKGROUND: The optimal method for predicting when carotid shunting is not necessary during carotid endarterectomy (CEA) is controversial. This study will analyze the correlation of collateral perfusion pressure and the status of contralateral carotid/cerebral collaterals and determine whether preoperative duplex ultrasound/cerebral angiography can predict when CEA can be done without shunting. METHODS: Ninety-eight patients were randomized into routine shunting and 102 into selective shunting when the collateral perfusion pressure (systolic carotid stump pressure) was <40 mm Hg during CEA. All patients had preoperative carotid duplex ultrasound and 87 had angiography, the results of which were evaluated for the presence of collateral flow from the contralateral carotid artery or posterior circulation through the anterior and/or posterior communicating arteries. RESULTS: The perioperative stroke rate was 1.5% for the entire group. There was no correlation between preoperative symptoms and the status of the contralateral carotid artery (normal, stenosed, or occluded). The mean collateral perfusion pressure was inversely related to the severity of the contralateral carotid stenosis: 60, 57, 55, 56, and 38 mm Hg for normal, <50% stenosed, 50-69% stenosed, 70-99% stenosed, and occluded arteries, respectively (p = 0.005). There was a direct relation between the number of patients with a collateral perfusion pressure of <40 mm Hg (shunted group) and the severity of the contralateral carotid stenosis: 6 of 62 (10%) for normal carotid, 7 of 43 (16%) for <50% stenosis (OR = 1.82), 12 of 69 (17%) for 50-69% stenosis (OR = 1.97), 3 of 10 (30%) for 70-99% stenosis (OR = 4, CI = 0.81-19.68), and 9 of 13 (70%) for occlusion (OR = 21, CI = 4.98-89.32) (p < 0.0001). None of the patients (0/56) with normal to <70% contralateral carotid stenosis with cross-filling had a collateral perfusion pressure of <40 mm Hg (no shunting was necessary). However, 9 of 17 (47%) patients with <70% contralateral carotid stenosis and no cross-filling had a collateral perfusion pressure of <40 mm Hg (p < 0.0001), whereas 6 of 7 (86%) patients with >=70% contralateral carotid stenosis and cross filling versus 2 of 7 (29%) with >=70% contralateral carotid stenosis and no cross-filling had a collateral perfusion stump pressure of >40 mm Hg (p = 0.1026). Overall, 62 of 63 (98.4%) patients with cross-filling versus 10 of 24 (42%) without cross-filling had a collateral perfusion pressure of >=40 mm Hg (p < 0.0001). CONCLUSIONS: There was an inverse correlation between collateral perfusion pressure and severity of contralateral carotid stenosis, and patients with severe contralateral carotid stenosis/occlusion were more likely to be shunted. The presence of cross-filling with normal to <70% contralateral carotid stenosis was associated with a collateral perfusion stump pressure of >=40 mm Hg in 100% of patients for whom shunting was not carried out in our series. PMID- 21680144 TI - Popliteal artery aneurysm in patient with Klippel--Trenaunay--Weber syndrome. AB - BACKGROUND: The association of Klippel-Trenaunay-Weber syndrome (KTWS) with artery aneurysms is very rare. METHODS AND RESULTS: A 61-year-old man, diagnosed with left lower limb KTWS, presented with a venous ulcer and a popliteal aneurysm measuring 3.5 cm in diameter in the same limb. Endovascular treatment with covered stent was applied with good morphological and clinical results. CONCLUSION: We report a singular case of the association of a popliteal aneurysm with KTWS and its endovascular treatment. This treatment enabled exclusion of the popliteal artery aneurysm with safety and effectiveness and reduced the number of arteriovenous fistulas. PMID- 21680145 TI - Endovascular treatment of a symptomatic mycotic aneurysm of the peroneal artery. AB - A 69-year-old man was referred to our facility owing to the sudden onset of a compression-like pain in the right leg, without limb-threatening acute ischemia. The duplex scan examination, followed by a selective leg angiography, showed the presence of a peroneal artery aneurysm. A diagnosis of mycotic aneurysm was made on the basis of the patient's clinical condition, positive blood cultures, and the unusual location of the lesion. Endovascular repair was performed by using a coil embolization and covered stent release. The patient was discharged in good general condition with complete pain relief. In previously published data, only four cases of peroneal artery aneurysm with a mycotic etiology have been reported. In this case, the endovascular treatment was safe and resolutive. PMID- 21680146 TI - Three extremely rare anatomic variants of the hepatic artery. AB - Numerous, but not all, anatomical variants of the hepatic artery are known presently. New or extremely rare anatomical variations of the hepatic arteries can however be encountered in the current practice. The first case report was documented using computed tomography and refers to a rare variation: retroportal proper hepatic artery anastomosed with the superior mesenteric artery by an arc of Buhler. The second case report presents the results of a dissection study, where a middle hepatic artery (MHA) was found arising in a common gastrohepatic trunk with the right gastric artery, from the stem of the proper hepatic artery; that MHA coursed over the left hepatic artery, hiding it. Moreover, in case report 2, an accessory right hepatic artery was found arising from the superior mesenteric artery. In the third case reported in this article, an arterial loop was found joining the common hepatic artery and gastroduodenal artery and further sending an ascending branch, diagnosed as MHA, and a descending one, considered as a duplicate gastroduodenal artery. We could not find in any previous reports variants such as those found in case reports 2 and 3, thus we consider these to be extremely rare. However, surgeons and radiologists must be aware of such rare morphological possibilities of the hepatic artery. PMID- 21680147 TI - Live case demonstrations: attitudes and ethical implications for practice. AB - BACKGROUND: Live case demonstrations (LCDs) are now prevalent in medical education courses despite ethical concerns including that they may expose patients to undue risk. However, there are limited data regarding many aspects of LCDs to help inform policies and guidelines regarding them. METHODS: We conducted an Internet-based survey of clinicians who have served as faculty or attended the 2009 and 2010 professional meetings sponsored by VIVA (Vascular Interventional Advances). RESULTS: There were 106 VIVA 2009 respondents and 165 VIVA 2010 respondents. Observing an LCD was more valuable than watching a prerecorded video for most (70% in 2009; 82% in 2010) respondents. About one-third of respondents thought that LCD patients are exposed to more risk than non-LCD patients. Respondents who had been operators were more likely to agree that LCD patients are exposed to more risk (p = 0.001 in 2009; p = 0.022 in 2010). Approximately one-third of respondents in 2009 and one-half in 2010 thought that patients experience direct medical benefit in an LCD. The majority (71% in 2009; 76% in 2010) indicated that they would support the decision of a family member or friend to be an LCD patient, few (44% in 2009; 58% in 2010) indicated that they personally would agree to be an LCD patient. CONCLUSIONS: This survey provides new insights into the value and risk of LCDs. Obtaining the perspective of patients would be extremely valuable in helping to ensure that the ethical aspects of LCDs are addressed properly and thoroughly. PMID- 21680148 TI - Regional myocardial dysfunction following Norwood with right ventricle to pulmonary artery conduit in patients with hypoplastic left heart syndrome. AB - BACKGROUND: Improved early survival has led many centers to use the right ventricle-to-pulmonary artery (RVPA) conduit instead of the modified Blalock Taussig shunt for Norwood palliation of hypoplastic left-heart syndrome. However, there is concern regarding the potential deleterious effects of the required right ventriculotomy for placement of the RVPA conduit on global and regional right ventricular (RV) function. The purpose of this study was to investigate global and regional RV wall motion abnormalities after Norwood palliation with RVPA conduit using Velocity Vector Imaging (VVI). METHODS: Thirty consecutive patients with hypoplastic left-heart syndrome who underwent stage 2 palliation between January 2007 and December 2009 were identified from the surgical database. VVI was performed on two-dimensional echocardiographic images obtained before second-stage palliation. Peak systolic circumferential and radial velocity, strain, and strain rate were measured from parasternal short-axis and apical four-chamber views. RV ejection fraction was measured using the biplane modified Simpson's rule. Regional RV systolic deformations were compared between different RV segments. VVI measures were also compared with RV systolic function. In a subgroup (n = 14), VVI was repeated on follow-up after stage 2 palliation to evaluate changes in regional and global RV deformation. RESULTS: A total of 30 patients (20 males) were studied. The median age at the time of interstage echocardiography was 12 weeks (range, 8-18 weeks). In the short axis, average peak systolic circumferential strain values for the anterior, posterior, septal, and RV free wall segments were 3.79 +/- 2.52%, 11.4 +/- 5.2%, 13.3 +/- 6.5%, and 11.1 +/- 5.0%, respectively. From the short-axis view, the anterior RV segment (ventriculotomy site) exhibited significantly reduced circumferential velocity, peak systolic strain, and strain rate (P < .0001). Mean global VVI measurements were correlated with RV ejection fraction. On follow-up after stage 2 palliation, the ventriculotomy region showed persistently reduced velocity, peak systolic strain, and strain rate compared with all other segments. CONCLUSIONS: In patients with hypoplastic left-heart syndrome after Norwood palliation with RVPA conduit, RV myocardial deformation was significantly reduced at the ventriculotomy site, which persisted after stage 2 palliation. VVI-derived measures demonstrating impairment of global systolic myocardial deformation were correlated with RV systolic function. Long-term multicenter studies to evaluate the effects of ventriculotomy scar on single systemic right ventricle are required. PMID- 21680149 TI - Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. AB - Stiff Person Syndrome (SPS) is a rare autoimmune neurological disease attributable to autoantibodies to glutamic acid decarboxylase (anti-GAD) more usually associated with the islet beta cell destruction of autoimmune type 1 diabetes (T1D). SPS is characterized by interference in neurons with the synthesis/activity of the inhibitory neurotransmitter gamma amino butyric acid (GABA) resulting in the prototypic progressive spasmodic muscular rigidity of SPS, or diverse neurological syndromes, cerebellar ataxia, intractable epilepsy, myoclonus and several others. Remarkably, a single autoantibody, anti-GAD, can be common to widely different disease expressions, i.e. T1D and SPS. One explanation for these data is the differences in epitope engagement between the anti-GAD reactivity in SPS and T1D: in both diseases, anti-GAD antibody reactivity is predominantly to a conformational epitope region in the PLP- and C-terminal domains of the 65 kDa isoform but, additionally in SPS, there is reactivity to conformational epitope(s) on GAD67, and short linear epitopes in the C-terminal region and at the N-terminus of GAD65. Another explanation for disease expressions in SPS includes ready access of anti-GAD to antigen sites due to immune responsiveness within the CNS itself according to intrathecal anti-GAD specific B cells and autoantibody. Closer study of the mysterious stiff-person syndrome should enhance the understanding of this disease itself, and autoimmunity in general. PMID- 21680150 TI - SH3BP2-encoding exons involved in cherubism are not associated with central giant cell granuloma. AB - Central giant cell granuloma (CGCG) is a benign lesion with unpredictable biological behaviour ranging from a slow-growing asymptomatic swelling to an aggressive lesion associated with pain, bone and root resorption and also tooth displacement. The aetiology of the disease is unclear with controversies in the literature on whether it is mainly of reactional, inflammatory, infectious, neoplasic or genetic origin. To test the hypothesis that mutations in the SH3BP2 gene, as the principal cause of cherubism, are also responsible for, or at least associated with, giant cell lesions, 30 patients with CGCG were recruited for this study and subjected to analysis of germ line and/or somatic alterations. In the blood samples of nine patients, one codon alteration in exon 4 was found, but this alteration did not lead to changes at the amino acid level. In conclusion, if a primary genetic defect is the cause for CGCG it is either located in SH3BP2 gene exons not yet related to cherubism or in a different gene. PMID- 21680151 TI - Intracranial application of free fasciocutaneous flaps in a novel sandwich technique for skull base reconstruction. AB - Free tissue transfer has been the gold standard of extensive skull base reconstruction, but the onlay of free flaps onto skull base defects carries the risk of cerebrospinal fluid (CSF) leakage. The purpose of this study was the evaluation of a novel technique of a combined sub- and onlay concept with a partially intracranially positioned folded free fasciocutaneous flap in terms of flap applicability, versatility and complication rate. Within 5 years, 7 patients with anterior (n=4), middle (n=2) or posterior (n=1) skull base defects were reconstructed with free extended lateral arm (n=3) or anterolateral thigh (n=4) flaps. The flaps were partially intracranially positioned and fixed with osteo dermal sutures. Both flaps proved to be applicable in terms of sealing efficiency, minimizing intracranial flap volume and folding. No flap loss was observed. Specific complications consisted of one pneumocranium via an accessory frontal sinus and one cerebellar herniation due to lumbar CSF loss. No flap failure or haematoma of the intracranial flap part occurred. This new concept of intracranial positioning of fasciocutaneous flaps in a sandwich technique using osteo-dermal sutures should be considered as a primary treatment for skull base reconstruction rather than merely as a salvage manoeuvre. PMID- 21680152 TI - Post-irradiation "acquired cavernous angiomas" with drug resistant seizures. AB - Cavernomas are well-known congenital vascular lesions with presumably high epileptogenicity. We report two patients who developed cavernomas; both were in remission from childhood acute lymphoblastic leukemia following standard chemo radiotherapy. They developed drug-resistant focal epilepsy secondary to cavernomas and were subjected to surgical/medical management. This report highlights the ictogenesis of radiation-induced "acquired" cavernous angiomatosis in the brain. Appropriate treatment, including resection of these lesions in selected cases, improves the quality of life in such patients. PMID- 21680153 TI - Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures. AB - OBJECTIVE: To evaluate the pharmacokinetics of eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs). METHODS: Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400mg (n=7), 800mg (n=26) or 1200mg (n=18) once-daily. Most patients (n=29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n=34, 66.7%) and valproic acid (n=19, 37.3%). Plasma concentrations of ESL and its metabolites eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry. RESULTS: Similarly to earlier findings in healthy subjects, plasma ESL concentrations were consistently below the lower limit of quantification (50ng/mL). The major compound in plasma was the active metabolite eslicarbazepine, which reached maximum concentrations (C(max)) 2h post-dose; thereafter, its plasma concentrations declined with a mean apparent half-life of 13, 14, and 20h in patients receiving ESL doses of 400, 800, and 1200mg once daily, respectively. Eslicarbazepine C(max) were 9.7, 15.5 and 23.0MUg/mL, and areas under the plasma concentration-time curve over the dosing interval (AUC(0 24)) were 132.5, 205.4 and 336.1MUgh/mL in patients receiving ESL doses of 400, 800 and 1200mg once-daily, respectively. Eslicarbazepine main pharmacokinetic parameters (C(max) and AUC(0-24)) were dose-proportional. R-licarbazepine and OXC were minor metabolites. CONCLUSIONS: Following once-daily oral administration of ESL 400mg, 800mg and 1200mg to epilepsy patients treated concomitantly with one or two other AEDs, ESL was rapidly converted to eslicarbazepine, which was the primary active compound found in plasma. Systemic exposure to eslicarbazepine was dose-proportional. PMID- 21680154 TI - Do shared mechanisms underlying cell cycle regulation and synaptic plasticity underlie the reduced incidence of cancer in schizophrenia? AB - Evidence from epidemiology suggests that the incidence of cancer is reduced in those with schizophrenia. Clues that could explain this finding have recently emerged from neuroscience--genes that were previously thought only to be involved in cell cycle regulation have additional functions in post-mitotic neurons related to neuronal migration and synaptic plasticity. This brief communication provides a concise summary of this evidence. We propose that this convergence between epidemiology and neuroscience will provide a more tractable search space for candidate genes, and provide clues for etiopathogenesis of schizophrenia. PMID- 21680155 TI - 1-(2,4-Dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylpheny)propane inhibits melanin synthesis by dual mechanisms. AB - BACKGROUND: 1-(2,4-Dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylpheny)propane (DP) was reported as a novel tyrosinase inhibitor by Nesterov et al. In previous study, we showed that DP is an antioxidant and accelerates the fading of UVB induced tan in human skin but details of inhibiting mechanism of DP in melanogenesis remain incomplete. OBJECTIVE: To clarify additional mechanisms of DP inhibition of melanogenesis, we studied the effect of DP on tyrosinase processing and degradation. METHODS: Tyrosinase inhibition was assessed using mushroom and human tyrosinase. The effect of DP on mRNA and protein levels as well as glycosylation and degradation of tyrosinase was examined using normal human epidermal melanocytes (NHEM). RESULTS: DP was 200 times more potent than that of kojic acid in inhibiting mushroom tyrosinase activity. In contrast, DP (IC(50)=200MUM) was significantly less effective at inhibiting tyrosinase from NHEM. DP decreased melanin content in cultured NHEM after 7th day (IC(50)=10MUM). The IC(50) for DP against human tyrosinase activity was found to be at least 20 times higher than that of melanin synthesis. At a non-cytotoxic concentration DP did not decrease tyrosinase mRNA however protein level decreased by 46% after 48h treatment. DP did not alter the ratio of mature and immature tyrosinase assayed by endo H cleavage. Tyrosinase degradation assays revealed that DP accelerated tyrosinase degradation in NHEM. CONCLUSIONS: We found that DP acts through dual mechanisms to reduce melanin synthesis; by inhibition of tyrosinase activity via an anti-oxidant effect, and, more importantly, by the acceleration of tyrosinase degradation. PMID- 21680156 TI - Autoimmunity versus autoinflammation from the 2nd JSID-Asia-Oceania-Forum, Wakayama, Japan, 5th December, 2010. PMID- 21680158 TI - A new sulcus-corrected approach for assessing cerebellar volume in spinocerebellar ataxia. AB - Precise volumetry of the cerebellum still remains challenging, due to thin sulci and gyri. We present a new fast and reliable sulcus-corrected approach for quantitative assessment of cerebellar atrophy, evaluated on patients with spinocerebellar ataxia (SCA). Thin-sliced T1-weighted magnetic resonance images (MPRAGE) were acquired in 11 genetically confirmed SCA6 patients and in a group of age-matched control subjects (n=14). Post-processing involves a morphological image segmentation pipeline as a basis for a sulcus-corrected cerebellar volume measurement. Cerebellar volumes and intra-rater, inter-rater and scan-rescan reproducibility were quantified. Reliability of the measurements was validated using an anatomical preparation of the cerebellum. Repeatability coefficients (RC: intra-rater/inter-rater/scan-rescan) of the method were 1.07%/1.11%/1.35%. Absolute cerebellar volumes showed good agreement with the actual volume of the anatomical preparation. The cerebellar volume of the SCA 6 was 96.3+/-12.1ml (mean+/-S.D.), which was significantly lower than the results of the corresponding control groups. The cerebellar volume correlated significantly to clinical dysfunction in SCA6. This is the first study to demonstrate the feasibility of a new sulcus-corrected approach to assess cerebellar volume. In contrast to currently used methods, this new approach may be more sensitive even to small atrophic changes affecting sulcal widening. PMID- 21680159 TI - Quantitative approaches for assessment of white matter hyperintensities in elderly populations. AB - White matter hyperintensities (WMH) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI), including fluid attenuated inverse recovery sequences. Total and regional WMH burden (i.e., volume or severity) has been associated with myriad cognitive, neurological, and psychiatric conditions among older adults. In the current report, we illustrate two approaches to quantify periventricular, deep, and total WMH and examine their reliability and criterion validity among 28 elderly patients enrolled in a depression treatment trial. The first approach, an operator-driven quantitative approach, involves visual inspection of individual MRI scans and manual labeling using a three-step series of procedures. The second approach, a fully automated quantitative approach, uses a processing stream that involves image segmentation, voxel intensity thresholding, and seed growing to label WMH and calculate their volume automatically. There was good agreement in WMH quantification between the two approaches (Cronbach's alpha values from 0.835 to 0.968). Further, severity of WMH was significantly associated with worse depression and increased age, and these associations did not differ significantly between the two quantification approaches. We provide evidence for good reliability and criterion validity for two approaches for WMH volume determination. The operator-driven approach may be better suited for smaller studies with highly trained raters, whereas the fully automated quantitative approach may be more appropriate for larger, high throughput studies. PMID- 21680160 TI - Effects of chemical and physical parameters in the generation of microspheres by hydrodynamic flow focusing. AB - Hydrodynamic flow focusing is a seminal, easy-to-use technology for micro- and nanodroplet generation. It is characterized by the co-axial focusing of two (or more) immiscible liquid streams forced through a small orifice. In this method, the outer continuous phase has a much higher flow velocity than the inner disperse phase. While passing through the orifice, the prevailing pressure drop and shear stress force the inner phase to break up into uniform droplets. Using a biodegradable poly(lactide-co-glycolide) (PLGA) polymer solution as the disperse phase, monodisperse and user-defined polymer micro- and nanospheres can be generated. Here we present a consecutive parameter study of hydrodynamic flow focusing to study the effect of chemical and physical parameters that effect the dispersity of the droplets generated in the 1-5 MUm range. The parameter study shows the applicability and challenges of hydrodynamic flow focusing in the preparation of biodegradable microspheres. Applications for microspheres made with this method can be found in the medical, pharmaceutical and technical fields. PMID- 21680161 TI - Efficient assembly of multi-walled carbon nanotube-CdSe/ZnS quantum dot hybrids with high biocompatibility and fluorescence property. AB - CdSe/ZnS core-shell quantum dots (QDs) were efficiently tethered onto polyamidoamine dendrimer-modified multi-walled carbon nanotubes (MWCNTs) by covalent linkage and mercapto-mediated assembly. The obtained MWCNT-QD hybrids were both photophysically and morphologically characterized. The QDs are well distributed on single nanotube surface in high density and the assembly of QDs onto MWCNTs does not change the fluorescence emission wavelength of QDs but significantly decreases the emission density. Cytotoxicity of MWCNT-QD hybrids to HeLa cells and their fluorescence property in living cell system were evaluated in detail. The hybrids show a little effect on cell viability even at very high concentration (100 MUg mL(-1)). Moreover, they possess intense red fluorescence signal under optical fluorescence microscopy and good fluorescence stability over 72-h exposure in living cell system. PMID- 21680162 TI - Relationship among circulating leukocytes, platelets, and microvascular responses during induction of chronic colitis. AB - The mechanisms by which microvascular alterations contribute to the pathogenesis of the inflammatory bowel diseases (IBDs; Crohn's disease, ulcerative colitis) have not been clearly delineated. The purpose of the current study was to characterize the inflammatory events, microvascular alterations, and blood cell changes that occur in a mouse model of IBD. In this model, CD4(+) T-lymphocytes obtained from interleukin-10-deficient mice were injected intraperitoneally into lymphopenic, recombinase-activating gene-1 deficient (RAG(-/-)) mice. Two groups of control mice were also included: RAG(-/-) mice and C57BL/6 mice that were injected with phosphate-buffered saline but did not receive the T-cells. Four weeks later, the RAG(-/-) mice that had received the T-cell transfer showed significant signs of colonic inflammation, but without significant decreases in either body weight or mean arterial blood pressure. T-cell transfer increased the volume % of circulating platelets, while decreasing the number of circulating red blood cells. Additionally, the T-cell transfer tended to increase the circulating numbers of both lymphocytes and neutrophils when compared to unmanipulated RAG(-/ ) mice. First-order colonic arterioles and venules tended to dilate in the colitic mice; however, the dilation was considerably more substantial with higher numbers of circulating leukocytes. The possibility that circulating inflammatory cells initiate the microvascular alterations in colitis warrants further investigation. PMID- 21680163 TI - [Evaluation of excessive daytime sleepiness in child and adolescent psychopathology]. AB - Childhood and adolescence are characterized by major changes in physiological, social and psychological domains. Some learning, behavior, mood or sleep disorders occurring during these ever-changing periods may lead children and teenagers to search for psychiatric care. It is then crucial to accurately determine which symptoms pertain to sleep and alertness disorders. Otherwise, some sleepy children and adolescents may be incorrectly considered as lazy, hyperactive or depressed. The evaluation of sleepiness requires a thorough physical examination (including the otorhinolaryngologic aspect), the completion of scales and brief questionnaires suited for pediatric patients, a fully completed sleep diary and in some cases biological or electrophysiological exams such as polysomnography (suited for the diagnosis of sleep apnea, narcolepsy, and periodic limb movement disorder). These investigations will help recognize excessive sleepiness, evaluate the often bi-directional links with the associated psychopathology and, should the case arise, diagnose primary sleep disorders (mostly sleep apnea in children and insufficient sleep in adolescents) and guide the adequate treatment. PMID- 21680164 TI - The reproductive system of Hippolyte niezabitowskii (Decapoda, Caridea). AB - Data on the reproductive biology of the genus Hippolyte are available from studies of Hippolyte inermis. These findings support the idea that these species are protandric hermaphrodites, exhibiting sex reversal. However, recent studies of this and other species, such as Hippolyte obliquimanus and Hippolyte williamsi, have not reported sex reversal and suggest a gonochoric condition. In the present study, histological analyses were conducted of the ovaries, testes, oviducts, vasa deferentia and the development of the male appendage. The results of this study show that the Hippolyte niezabitowskii population from southern Spain should also be viewed as a gonochoric species. The study found no evidence of sex reversals. These conclusions are also supported by information on the structure of the population and by the results of studies of the male appendage. The population structure involves different size distributions of males and of females. Size classes 2-14 exhibit substantial overlap. No evidence of sex reversal was obtained from the study of the male appendage. PMID- 21680166 TI - Atrial fibrillation during veno-venous bypass for orthotopic liver transplantation. PMID- 21680165 TI - Tyrosinase activity of Greyia flanaganii (Bolus) constituents. AB - Hyper-pigmentation of the skin is a common problem that is prevalent in middle aged and elderly people. It is caused by over production of melanin. Tyrosinase is known to be the key enzyme in melanin production. Ethanolic extract of Greyia flanaganii leaves showed significant (P<0.05) antityrosinase activity exhibiting the IC50 of 32.62 MUg/ml. The total extract was further investigated for its toxicity and effect on melanin production by melanocytes cells, and showed significant inhibition (P<0.05) (20%) of melanin production at 6.25 MUg/ml and low levels of cytotoxicity (IC50<400 MUg/ml). The amount of antioxidants necessary to decrease the initial DPPH absorbance by 50% (EC50) by the total ethanolic extract was found to be 22.01 MUg/ml. The effect of G. flanaganii against acne causing bacteria, Propionibacterium acnes, was investigated using microdilution assay. The MIC of the extract of G. flanaganii was found to be 250 MUg/ml. Bioassay-guided fractionation led to the isolation of (3S)-4 hydroxyphenethyl 3-hydroxy-5-phenylpentanoate (1), 2',4',6' trihydroxydihydrochalcone (2), 2',6',4-trihydroxy-4'-methoxydihydrochalcone (3), 2',6'-dihydroxy-4'-methoxydihydrochalcone (4), 5,7-dihydroxyflavanone [(2S) pinocembrin] (5), 2',6'-dihydroxy-4',4-dimethoxy dihydrochalcone (6) and (2R,3R) 3,5,7-trihydroxy-3-O-acetylflavanone (7). The isolated compounds were tested for their antioxidant, cytotoxicity, tyrosinase inhibition and antibacterial activities. Compound 2 exhibited significant (P<0.05) antityrosinase activity exhibiting the IC50 of 69.15 MUM. The isolated compounds showed low toxicity of the cells with reduction of melanin content of the cells. All compounds tested showed good radical scavenging activity. These data indicates that G. flanaganii extract and its isolated phenolic constituents could be possible skin lightening agents. PMID- 21680167 TI - Effects of medical and psychological treatment of depression in patients with COPD--a review. AB - Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease characterized by progressive and only partially reversible symptoms and by considerable negative consequences such as reductions in functional status and quality of life. Comorbid depression is highly prevalent in patients with COPD and related to a worse course of the disease. Despite its negative impact, depression often remains unrecognized and untreated in COPD patients. This review summarizes the current state of findings from studies examining the effects of antidepressant treatments in patients with COPD. Reviewed treatment options are antidepressant medical therapy and cognitive-behavioral therapy (CBT). Antidepressant medical trials include treatments with selective serotonin reuptake inhibitors (SSRI) or tricyclic antidepressants (TCA); CBT was applied using various components. Across both treatment types, the majority of studies included patients with a wide range of psychiatric conditions and especially comorbid symptoms of anxiety were often not controlled. Furthermore, greatly varying instruments and methods for assessing depressive symptoms, small sample sizes and rather heterogeneous results were observed. This makes the comparison of treatment options rather difficult and prevents definite conclusions. However, some important implications valuable for further research were obtained. Some limited data suggested that SSRI might show fewer side effects than TCA. A few antidepressants as well as beneficial effects in other outcomes were observed after antidepressant medical treatment. More clearly, CBT showed some potential in terms of improvements in depressive symptoms, and also in other outcome measures. Patient compliance seems more promising for CBT than for antidepressant medical treatment. Overall, the reviewed studies suggest some promising effects for both treatment types and effect sizes in studies with significant antidepressant effects were reasonable. However, future randomized controlled trials comparing antidepressant medical and cognitive-behavioral therapy will be essential to assess distinct and most favorable treatment effects. Because recent data is often limited, sound diagnostic criteria of depression and adequate sample sizes are necessary to draw firm conclusions on the effects of these antidepressant treatment options in patients with COPD and comorbid depression. PMID- 21680169 TI - Feasibility study for thermal treatment of solid tire wastes in Bangladesh by using pyrolysis technology. AB - In this study on the basis of lab data and available resources in Bangladesh, feasibility study has been carried out for pyrolysis process converting solid tire wastes into pyrolysis oils, solid char and gases. The process considered for detailed analysis was fixed-bed fire-tube heating pyrolysis reactor system. The comparative techno-economic assessment was carried out in US$ for three different sizes plants: medium commercial scale (144 tons/day), small commercial scale (36 tons/day), pilot scale (3.6 tons/day). The assessment showed that medium commercial scale plant was economically feasible, with the lowest unit production cost than small commercial and pilot scale plants for the production of crude pyrolysis oil that could be used as boiler fuel oil and for the production of upgraded liquid-products. PMID- 21680168 TI - Reconciling incongruous qualitative and quantitative findings in mixed methods research: exemplars from research with drug using populations. AB - Mixed methods research is increasingly being promoted in the health sciences as a way to gain more comprehensive understandings of how social processes and individual behaviours shape human health. Mixed methods research most commonly combines qualitative and quantitative data collection and analysis strategies. Often, integrating findings from multiple methods is assumed to confirm or validate the findings from one method with the findings from another, seeking convergence or agreement between methods. Cases in which findings from different methods are congruous are generally thought of as ideal, whilst conflicting findings may, at first glance, appear problematic. However, the latter situation provides the opportunity for a process through which apparently discordant results are reconciled, potentially leading to new emergent understandings of complex social phenomena. This paper presents three case studies drawn from the authors' research on HIV risk amongst injection drug users in which mixed methods studies yielded apparently discrepant results. We use these case studies (involving injection drug users [IDUs] using a Needle/Syringe Exchange Program in Los Angeles, CA, USA; IDUs seeking to purchase needle/syringes at pharmacies in Tijuana, Mexico; and young street-based IDUs in San Francisco, CA, USA) to identify challenges associated with integrating findings from mixed methods projects, summarize lessons learned, and make recommendations for how to more successfully anticipate and manage the integration of findings. Despite the challenges inherent in reconciling apparently conflicting findings from qualitative and quantitative approaches, in keeping with others who have argued in favour of integrating mixed methods findings, we contend that such an undertaking has the potential to yield benefits that emerge only through the struggle to reconcile discrepant results and may provide a sum that is greater than the individual qualitative and quantitative parts. PMID- 21680170 TI - Targeted intervention strategies to optimise diversion of BMW in the Dublin, Ireland region. AB - Urgent transformation is required in Ireland to divert biodegradable municipal waste (BMW) from landfill and prevent increases in overall waste generation. When BMW is optimally managed, it becomes a resource with value instead of an unwanted by-product requiring disposal. An analysis of survey responses from commercial and residential sectors for the Dublin region in previous research by the authors proved that attitudes towards and behaviour regarding municipal solid waste is spatially variable. This finding indicates that targeted intervention strategies designed for specific geographic areas should lead to improved diversion rates of BMW from landfill, a requirement of the Landfill Directive 1999/31/EC. In the research described in this paper, survey responses and GIS model predictions from previous research were the basis for goal setting, after which logic modelling and behavioural research were employed to develop site-specific waste management intervention strategies. The main strategies devised include (a) roll out of the Brown Bin (Organics) Collection and Community Workshops in Dun Laoghaire Rathdown, (b) initiation of a Community Composting Project in Dublin City (c) implementation of a Waste Promotion and Motivation Scheme in South Dublin (d) development and distribution of a Waste Booklet to promote waste reduction activities in Fingal (e) region wide distribution of a Waste Booklet to the commercial sector and (f) Greening Irish Pubs Initiative. Each of these strategies was devised after interviews with both the residential and commercial sectors to help make optimal waste management the norm for both sectors. Strategy (b), (e) and (f) are detailed in this paper. By integrating a human element into accepted waste management approaches, these strategies will make optimal waste behaviour easier to achieve. Ultimately this will help divert waste from landfill and improve waste management practice as a whole for the region. This method of devising targeted intervention strategies can be adapted for many other regions. PMID- 21680171 TI - Replacement-free mass-amplified sandwich assay with 180-MHz electrodeless quartz crystal microbalance biosensor. AB - This study describes a sensitivity-amplified detection method in a replacement free electrodeless quartz-crystal microbalance (QCM) biosensor. A sandwich assay is proposed for detecting C-reactive proteins (CRP), where the biotinated second anti-CRP antibody is weighted by streptavidin for sensitivity amplification. Because the first CRP antibody was immobilized nonspecifically on naked quartz surfaces, the sandwich assay was repeated using the same sensor chip, making possible the replacement-free assay. The mass-amplified sandwich assay detected a CRP solution of 0.1 ng/ml. A methodology for determining the molecular mass of the injected protein is also proposed. PMID- 21680172 TI - Biotechnology worldwide and the 'European Biotechnology Thematic Network' Association (EBTNA). AB - The European Biotechnology Congress 2011 held under the auspices of the European Biotechnology Thematic Network Association (EBTNA) in conjunction with the Turkish Medical Genetics Association brings together a broad spectrum of biotechnologists from around the world. The subsequent abstracts indicate the manner in which biotechnology has permeated all aspects of research from the basic sciences through to small and medium enterprises and major industries. The brief statements before the presentation of the abstracts aim to introduce not only Biotechnology in general and its importance around the world, but also the European Biotechnology Thematic Network Association and its aims especially within the framework of education and ethics in biotechnology. PMID- 21680173 TI - Perisomatic inhibition and cortical circuit dysfunction in schizophrenia. AB - Deficits of cognitive control in schizophrenia are associated with altered gamma oscillations in the prefrontal cortex. Paralbumin basket interneurons, which innervate the perisomatic region of pyramidal neurons, appear to play a key role in generating cortical gamma oscillations. In the prefrontal cortex of subjects with schizophrenia, alterations are present in both pre- and post-synaptic markers of the strength of GABA inputs from parvalbumin basket neurons to pyramidal neurons. These alterations may contribute to the neural substrate for impaired gamma oscillations in schizophrenia. PMID- 21680174 TI - RNAi-mediated silencing of VEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the CXCR4, CCR7, VEGFR-2 and VEGFR-3-dependent axes-induced ERK, p38 and AKT signalling pathways. AB - Vascular endothelial growth factor C (VEGF-C) expression is associated with the malignant tumour phenotype making it an attractive therapeutic target. We investigated the biological roles of VEGF-C in tumour growth, migration, invasion and explored the possibility of VEGF-C as a potential therapeutic target for the treatment of non-small cell lung cancer (NSCLC). A lentivirus-mediated RNA interference (RNAi) technology was used to specifically knockdown the expression of VEGF-C in A549 cells. Quantitative reverse transcriptase-polymerase chain reaction, flow cytometry, Western blot, immunohistochemistry, cellular growth, migration, invasion and ELISA assays were used to characterise VEGF-C expression in vitro. A lung cancer xenograft model in nude mice was established to investigate whether knockdown of VEGF-C reduced tumour growth in vivo. Silencing of VEGF-C suppressed tumour cell growth, migration and invasion in vitro; suppressed tumour growth, angiogenesis and lymphangiogenesis by tail vein injection of lentivirus encoded shRNA against VEGF-C in vivo. More importantly, silencing of VEGF-C also trapped the VEGFR-2, VEGFR-3, CXCR4, CCR7-dependent axes, and down-regulated the AKT, ERK and p38 signalling pathways. These results suggest that VEGF-C has a multifaceted role in NSCLC growth, migration and invasion; that VEGF-C-mediated autocrine loops with their cognate receptors and chemokine receptors are significant factors affecting tumour progression; and that RNAi-mediated silencing of VEGF-C represents a powerful therapeutic approach for controlling NSCLC growth and metastasis. PMID- 21680175 TI - Breast cancer in reproductive age. The new plaque or just myth? AB - It is interesting to assess the hitherto knowledge, on breast cancer in reproductive and young females, aged <35. Even if breast cancer is rare in this group, it is, also physically and emotionally devastating. It is characterized by worse prognosis and outcome, in a stage of life, which is delicate for the female patients. This rare subgroup of breast cancer patients is ought to be the center of investigation in future studies. This paper's mail goal is to elucidate this entity, by presenting several aspects of the disease including risk factors, therapy, natural history and major differences between the groups of breast cancer patients and last but not least, the psychosocial features of this clinical entity, by reviewing the current and past medical literature till April 2011. PMID- 21680176 TI - Metabolic engineering of Aeromonas hydrophila 4AK4 for production of copolymers of 3-hydroxybutyrate and medium-chain-length 3-hydroxyalkanoate. AB - A mutant termed Aeromonas hydrophila AKLF was constructed by deleting acetic acid pathway related genes pta and ackA in A. hydrophila 4AK4. Accumulation of poly(3 hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) in A. hydrophila AKLF was increased by 47% from 2.11 to 3.10g/L associated with a reduction on acetic acid formation compared with A. hydrophila 4AK4 when lauric acid was used as carbon resource. A. hydrophila AKLF harboring pVGAB encoding Vitreoscilla hemoglobin, beta-ketothiolase and acetoacetyl-CoA reductase was found to produce 85% more PHBHHx compared to its wild type. Expression of plasmid pD(Ec)L(Pp) harboring genes related to fatty acid metabolism in A. hydrophila AKLF led to 63% more PHBHHx production than A. hydrophila 4AK4. Replacing phaC in A. hydrophila AKLF with a mutant phaC2 from Pseudomonas stutzeri 1317 resulted in enhanced production of copolymers of 3-hydroxybutyrate and medium-chain-length 3 hydroxyalkanoates compared to A. hydrophila 4AK4 harboring the mutant phaC2 in the chromosome as control. PMID- 21680177 TI - Microscopic structure and properties changes of cassava stillage residue pretreated by mechanical activation. AB - This study has focused on the pretreatment of cassava stillage residue (CSR) by mechanical activation (MA) using a self-designed stirring ball mill. The changes in surface morphology, functional groups and crystalline structure of pretreated CSR were examined by using scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) under reasonable conditions. The results showed that MA could significantly damage the crystal structure of CSR, resulting in the variation of surface morphology, the increase of amorphous region ratio and hydrogen bond energy, and the decrease in crystallinity and crystalline size. But no new functional groups generated during milling, and the crystal type of cellulose in CSR still belonged to cellulose I after MA. PMID- 21680178 TI - Overcoming biological constraints to enable the exploitation of microalgae for biofuels. AB - Microalgae have significant potential to form the basis of the next biofuel revolution. They have high growth and solar energy conversion rates. Furthermore, their osmotolerance, metabolic diversity and capacity to produce large amounts of lipids have attracted considerable interest. Although there are a handful of commercially successful examples of the photoautotrophic mass-culture of algae, these have focused on the production of higher value products (pigments, health foods etc.). The technical and commercial challenges to develop an economically viable process for biofuels are considerable and it will require much further R&D. In this paper the biological constraints, with a particular focus on strain selection are discussed. PMID- 21680179 TI - Unsterile and continuous production of polyhydroxybutyrate by Halomonas TD01. AB - An unsterile and continuous fermentation process was developed based on a halophilic bacterium termed Halomonas TD01 isolated from a salt lake in Xinjiang, China. The strain reached 80 g/L cell dry weight containing 80% poly(3 hydroxybutyrate) (PHB) on glucose salt medium during a 56 h fed-batch process. In a 14-day open unsterile and continuous process, the cells grew to an average of 40 g/L cell dry weight containing 60% PHB in the first fermentor with glucose salt medium. Continuous pumping of cultures from the first fermentor to the second fermentor containing the nitrogen-deficient glucose salt medium diluted the cells but allowed them to maintain a PHB level of between 65% and 70% of cell dry weight. Glucose to PHB conversions were between 20% and 30% in the first fermentor and above 50% in the second one. This unsterile and continuous fermentation process opens a new area for reducing the cost in polyhydroxyalkanoates production. PMID- 21680180 TI - Luminostat operation: a tool to maximize microalgae photosynthetic efficiency in photobioreactors during the daily light cycle? AB - The luminostat regime has been proposed as a way to maximize light absorption and thus to increase the microalgae photosynthetic efficiency within photobioreactors. In this study, simulated outdoor light conditions were applied to a lab-scale photobioreactor in order to evaluate the luminostat control under varying light conditions. The photon flux density leaving the reactor (PFD(out)) was varied from 4 to 20 MUmol photons m(-2)s(-1)and the productivity and photosynthetic efficiency of Chlorella sorokiniana were assessed. Maximal volumetric productivity (1.22g kg(-1)d(-1)) and biomass yield on PAR photons (400 700 nm) absorbed (1.27 g mol(-1)) were found when PFD(out) was maintained between 4 and 6 MUmol photons m(-2)s(-1). The resultant photosynthetic efficiency was comparable to that already reported in a chemostat-controlled reactor. A strict luminostat regime could not be maintained under varying light conditions. Further modifications to the luminostat control are required before application under outdoor conditions. PMID- 21680181 TI - The effect of fire retardants on combustion and pyrolysis of sugar-cane bagasse. AB - Experiments were conducted by thermal gravimetric analysis (TGA) and cone calorimetry to measure the affect of three fire retardants (ammonium sulphate, boric acid and borax) on the mass-loss rate and combustion characteristics of sugar-cane bagasse. Compared with untreated bagasse, bagasse impregnated with aqueous solutions of 0.1-0.5M fire retardants exhibited an increase in char mass production from 16% up to 41% when pyrolysed and up to a 41% reduction in total heat release (THR) during combustion. Char mass production was only a weak function of additive concentration over the range of concentrations (0.1-0.5M) used. Combining the additives did not show any synergistic effects for char production or heat release rate (HRR). Treatment of bagasse by these chemicals could be useful to enhance biochar yields in pyrolysis processes or to reduce flammability risk in composites containing bagasse. PMID- 21680182 TI - Design, synthesis and evaluation of monovalent Smac mimetics that bind to the BIR2 domain of the anti-apoptotic protein XIAP. AB - We report the systematic rational design and synthesis of new monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti-apoptotic protein XIAP. Characterization of compounds in vitro (including 9i; ML101) led to the determination of key structural requirements for BIR2 binding affinity. Compounds 9h and 9j sensitized TRAIL-resistant breast cancer cells to apoptotic cell death, highlighting the value of these probe compounds as tools to investigate the biology of XIAP. PMID- 21680183 TI - Pyrazoline based MAO inhibitors: synthesis, biological evaluation and SAR studies. AB - Twenty-two pyrazoline derivatives were synthesized and tested for their human MAO (hMAO) inhibitory activity. Twelve molecules with unsubstituted ring A and substituted ring C (5-16) were found to be potent inhibitors of hMAO-A isoform with SI(MAO-A) in the order 10(3) and 10(4). Ten molecules with unsubstituted ring A and without ring C (21-30), in which eight molecules (21, 23-26, and 28 30) were selective for hMAO-A, one for hMAO-B (22) and the other one non selective (27). Presence of ring C increases potency as well as SI towards hMAO A; however its absence decreases both potency and SI towards hMAO-A and hMAO-B. PMID- 21680184 TI - Changes in nutritional status in ICU patients receiving enteral tube feeding: a prospective descriptive study. AB - OBJECTIVES: This study aimed to assess the changes in nutritional status in Korean ICU patients receiving enteral feeding, and to understand the contribution of baseline nutritional status and energy intake to nutritional changes during the ICU stay. METHODS: This was a prospective study of nutritional changes in 48 ICU patients receiving enteral feeding for 7 days. The Subjective Global Assessment scale was used upon admission. In addition, anthropometric measures (triceps skinfold thickness, mid-arm circumference, mid-arm muscle circumference, body mass index and percent ideal body weight) and biochemical measures (albumin, prealbumin, transferrin, haemoglobin and total lymphocyte count) were evaluated twice, upon admission and 7 days after admission. RESULTS: Seventy-five percent of ICU patients were severely malnourished at admission. Although the nutritional status worsened in both the patients with suspected malnourishment and the patients with severe malnutrition at admission, the nutritional status worsened significantly more in the patients with severe malnutrition than in the patients with suspected malnourishment. Moreover, a number of nutritional measures significantly decreased more in underfed patients than in adequately fed patients. The most significant predicting factor for underfeeding was under prescription. CONCLUSION: The ICU patients in our study were severely malnourished at admission, and their nutritional status worsened during their ICU stay even though enteral nutritional support was provided. The changes in nutritional status during the ICU stay were related to the patients' baseline nutritional status and underfeeding during their ICU stay. This study highlights an urgent need to provide adequate nutritional support for ICU patients. PMID- 21680185 TI - Needs of American relatives of intensive care patients: perceptions of relatives, physicians and nurses. AB - OBJECTIVES: This study investigated differences between the perceptions of American relatives, physicians and nurses concerning the needs of relatives visiting intensive care patients. DESIGN AND PARTICIPANTS: This was a prospective descriptive study. Perceived needs were measured using the 45 item Critical Care Family Needs Inventory (CCFNI) with 101 relatives visiting as well as 28 physicians and 109 nurses working with the same group of patients. SETTING: Data were collected using a convenience sample of patients, their relatives visiting, as well as the physicians and nurses working with the same patients in six adult intensive care units in a large American tertiary acute care medical centre with over a 900 bed capacity. RESULTS AND CONCLUSIONS: There were significant correlations (p<0.05) between the relatives, physicians and nurses on eight of the 45 individual items on the CCFNI. Subscale (Information, Proximity, Assurance, Comfort and Support) scores for the needs perceived by relatives, physicians and nurses were calculated and there were significant differences in the three groups on Information (F=5.90, df=2, p=.0005), Support (F=4.12, df=2, p=.022) and Comfort (F=5.01, df=2, p=.010). Relatives and nurses made multiple comments on the surveys. This is important information for all health care workers to consider in setting visiting policies in adult ICUs and developing approaches such as family centred care. PMID- 21680186 TI - The effectiveness of an evidence-based nursing care program to reduce ventilator associated pneumonia in a Korean ICU. AB - OBJECTIVES: This study has analysed VAP prevention strategies and concentrating on approaches proven to have been effective by previous studies, has developed a general and systematic intervention for preventing VAP. METHOD: The VAP prevention program was composed of short-term interventions and long-term interventions. Using a time series design to verify the program's effectiveness, just before, just after, and 3 months after intervention, 27 convenient selected medical ICU nurses were surveyed for their awareness of VAP prevention and self evaluation of VAP prevention performance as a subjective measure, and their VAP prevention performance was observed as an objective measure. The VAP incidence amongst ICU patients was measured during the 3 months before (n=80) and after (n=75) intervention. RESULTS: That the program would raise nurses' VAP prevention awareness (p=.008) and would increase the nurses' subjective (p=.003) and objective (p<=.001) VAP prevention performance evaluations was supported. That incidences of VAP would decrease from a pre-intervention VAP rate of 17.382 (number of occurances/1000 ventilator days) to a post-intervention rate of 11.044, was not statistically significant (p=.074). CONCLUSION: An intervention VAP prevention program promoted ICU nurses' VAP prevention awareness and performance and could therefore help decrease the VAP rate. PMID- 21680187 TI - Stepping characteristics and Centre of Mass control during stair descent: Effects of age, fall risk and visual factors. AB - Stair edges provide important visual cues for appropriate foot placement on the stair and balance control during stair descent. Previous studies explored age related changes in stepping performance and balance control during stair descent and included fit older adults. The present study investigates both age- and frailty-related changes to stepping parameters and Centre of Mass (COM) control during stair descent and how these measures are affected by visual factors. Older adults were split into two groups containing participants with the lowest (LROA, n=7) and highest (HROA, n=8) combined scores on tests of balance and confidence to negotiate stairs. Data were also collected from younger adult participants (YA, n=8). Kinematic data were collected from participants while they descended stairs under combinations of ambient light (bright and dimmed) and stair edge contrast conditions (high and low). A three (group) * two (illumination)*two (contrast) ANCOVA was performed with average stair walking speed as covariate. HROA cleared the stair edge vertically (p=0.001) and horizontally (p<0.001) with less distance than LROA. Dimmed ambient light resulted in decreased step length in HROA (p=0.006) compared to bright lighting. High stair edge contrast led to reduced vertical COM acceleration variability in HROA (p=0.009) and increased distance between COM and anterior base of support (p=0.017) in LROA. YA increased horizontal foot clearance (p=0.011) when stair edge contrast was high. We conclude that the aforementioned differences in stepping behaviour shown by HROA may contribute towards an increased risk of tripping and that high stair edge contrast has a beneficial effect on balance control in older adults. PMID- 21680188 TI - Spontaneous tension pneumocephalus in a patient with subdural empyema. AB - We report a 45-year old male who developed subdural empyema (SE) with tension pneumocephalus. The patient was admitted unconscious with tonic extensor response to pain. A "gas-forming" organism, Escherichia coli, was detected. Surgical evacuation of the pus and treatment with the appropriate antibiotic did not result in amelioration of his symptoms and the patient died. We identified a rare clinical situation when the SE cavity had a relatively large air loculus that was clearly related to gas-forming bacteria. It appeared that the patient had developed tension pneumocephalus related to the air produced by the pathogen. To our knowledge, this is the first report of a gas-forming organism in an abscess cavity that resulted in tension pneumocephalus and related symptoms. PMID- 21680189 TI - Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains. AB - We designed bidentate ligands to target PDZ domains through two binding sites: site S0, delimited by the GLGF loop, and site S1, a zone situated around loop beta(B)/beta(C). A molecular docking study allowed us to design a generic S0 binder, to which was attached a variable size linker, itself linked to an amino acid aimed to interact with the S1 site of PDZ domains. A series of 15 novel bidentate ligands was prepared in 6-11 steps in good overall yield (24-43%). Some of these ligands showed an inhibitory activity against serotonin 5-HT2A receptor/PSD-95 interaction. This was assessed by pull-down assay using a synthetic decapeptide corresponding to the C-terminal residues of the receptor as a bait. PMID- 21680190 TI - 2-Amino-4-methyl-5-phenylethyl substituted-7-N-benzyl-pyrrolo[2,3-d]pyrimidines as novel antitumor antimitotic agents that also reverse tumor resistance. AB - Gangjee et al. recently reported a novel series of 2-amino-4-methyl-5-phenylethyl substituted-7-benzyl-pyrrolo[2,3-d]pyrimidines, some of which exhibited two digit nanomolar antitumor and antimitotic activity and were not subject to P glycoprotein (Pgp) or multidrug resistance protein 1 (MRP1) mediated tumor resistance (unlike the Vinca alkaloids and taxanes). Some of these compounds, in addition to their antitumor activity, had the ability to reverse the Pgp-mediated resistance to clinically used antimitotic agents. This report consists of an attempt to optimize the various activities of the parent compounds by synthetic variations of the phenyl ring of the 5-phenylethyl side chain. The target compounds were synthesized via a nine-step synthesis involving a Sonogashira reaction. The substituted phenylacetylenes as coupling partners were in turn synthesized from unactivated aryl bromides or iodides. The target compounds exhibited moderate cytotoxicity against MCF-7 tumor cells. However, most of these compounds showed improved cytotoxicity against the resistant NCI/ADR and MCF 7/VP. This study afforded an analog which reversed both Pgp-mediated as well as MRP1-mediated resistance to clinically used antimitotic agents, along with its own antimitotic mediated antitumor activity. In addition, in the NCI-60 cell line panel one of the compounds inhibited the growth of MDA-MD-435 breast cancer cell line at submicromolar concentration. PMID- 21680191 TI - Experimental study of lattice distortion in ellipsoid-like nano-crystallites of copper. AB - The elastic state of embedded inclusions is of considerable importance to the properties of materials. The non-uniform lattice distortion in the inclusions in which the interfaces are shaped with variable curvature cannot be measured by usual experimental methods. In this paper, the lattice distortions in an ellipsoid-like nano-crystallite of copper were measured by means of the peak finding method in the central part of the HRTEM image. The effects of contrast delocalization are studied by HRTEM image simulations, which show that the measured spacings of peaks in the middle part of the crystallite can be considered approximately equal to the true spacings of columns. With the HRTEM method, our measured results show that the nano-crystallite is expanded in the short axis direction and compressed in the long axis direction. The results calculated with the elasticity theory incorporating interface tension consist with the experimental results of HRTEM. PMID- 21680192 TI - Evaluation of neutron sources for ISAGE-in-situ-NAA for a future lunar mission. AB - For a future Moon landing, a concept for an in-situ NAA involving age determination using the (40)Ar-(39)Ar method is developed. A neutron source (252)Cf is chosen for sample irradiation on the Moon. A special sample-in-source irradiation geometry is designed to provide a homogeneous distribution of neutron flux at the irradiation position. Using reflector, the neutron flux is likely to increase by almost 200%. Sample age of 1Ga could be determined. Elemental analysis using INAA is discussed. PMID- 21680193 TI - Importance of evaluating conduction block in radiofrequency ablation for atrial fibrillation. AB - OBJECTIVE: Atrial fibrillation (AF) is the most frequently diagnosed cardiac arrhythmia. Anti-arrhythmic drugs may be used to suppress ectopic foci and interrupt reentry circuits, but are often insufficient to treat recurrent AF and have a number of adverse effects. Alternative therapies, such as catheter and surgical ablation, have been explored. This investigation examines the importance of assessing exit block when performing surgical ablation during beating-heart treatment of AF. METHODS: This was an evaluation of pooled data from multicenter prospective results obtained in AF patients who received ablation with a new, irrigated, vacuum-integrated device that creates linear lesions during beating heart/open-chest or minimally invasive, port-access procedures. Electrocardiogram or Holter data were collected intra-operatively and at 1, 3, 6, and 12 months. Outcomes were also evaluated for patients who were or 'were not' tested for exit block following the ablation procedure. RESULTS: A total of 93 patients were treated (61 open-chest surgeries, 32 port-access procedures). There were no device-related complications and no operative mortality. At 341 days' average follow-up, 71/86 (83%) patients were free from AF, 66/86 (77%) were in sinus rhythm, and 60/86 (70%) were free from AF and off Class I and III anti-arrhythmic drugs (AADs). At 12 months, 23/23 (100%) patients with exit block confirmed were AF free compared with 13/21 (62%) patients with exit block not tested (p<=0.01, Fisher's exact test); 20/23 (87%) were in sinus rhythm compared with 12/21 (57%) patients with exit block not tested (p<=0.05, Fisher's exact test); and 20/23 (87%) were AF free without Class I and III AADs compared with 10/21 (48%) patients with exit block not tested (p<=0.01, Fisher's exact test). Both open chest and port-access procedures yielded decreases in left-atrial size from baseline to 6 months' follow-up. Patients undergoing port-access procedures also observed an increase in left-ventricular ejection fraction, which was also significant at 6 months. CONCLUSION: Patients in whom exit block was confirmed following an ablation procedure were more likely to have successful clinical outcomes. Since testing for exit block must be performed on a beating heart, total epicardial beating-heart ablation may provide an important treatment for AF, providing intra-operative feedback indicative of long-term outcomes. PMID- 21680194 TI - Disseminated lung metastasis of atypical carcinoid tumor of thymic origin? PMID- 21680195 TI - Experience with the autologous pulmonary vein for pulmonary arterioplasty. AB - OBJECTIVE: Lobectomy with pulmonary artery resection and reconstruction is seldom performed in order to avoid pneumonectomy in selected cases. The aim of this study is to determine how safe and effective the graft reconstruction of the pulmonary artery is, using autologous tissue taken from the pulmonary vein. METHODS: Eight patients with diagnosed non-small-cell lung cancer were treated by lobectomy with pulmonary artery reconstruction with curative intent. All patients could have tolerated pneumonectomy. Patch or conduit angioplasty was performed by using a tailored graft, harvested from the autologous pulmonary vein of the resected lobe. Patients were followed up and the clinical records were analyzed retrospectively. Long-term patency of the reconstructed pulmonary artery was investigated by computed tomographic pulmonary angiogram. RESULTS: No procedure related complications and no perioperative mortality were observed. No blood transfusion was required. Follow-up varied from 10 to 64 months. No local recurrences were found next to the angioplasty. Ideal long-term patency of the pulmonary artery was demonstrated in all cases. Two patients are alive with evidence of extrathoracic metastatic disease and four patients are apparently healthy. Two patients died of progressive disease. CONCLUSIONS: The use of pulmonary vein tissue as a graft to repair the pulmonary artery is feasible, reproducible, and seems to be oncologically correct. Pulmonary vein tissue can be easily harvested during surgery and offers a high-quality vascular tissue for pulmonary angioplasty. PMID- 21680196 TI - Circulating tumor cells in prostate cancer: a potential surrogate marker of survival. AB - Prostate-specific antigen (PSA) levels in blood are widely used in prostate cancer (PCa) for the management of this disease at every stage of progression. Currently, PSA levels combined with clinical stage and Gleason score provide the best predictor of survival and the main element to monitor treatment efficiency. However, these areas could be improved by utilizing emerging biomarkers. Recently, circulating tumor cells (CTCs) and disseminating tumor cells (DTCs) have been detected in PCa and may be a new surrogate candidate. Here we provide a systematic review of the literature in order to describe the current evidence of CTC/DTC surrogacy regarding outcome of prostate cancer patients. We also discuss several markers that could be used to increase the sensitivity and specificity of CTC/DTC detection. CTC/DTC detection is performed using a wide variety of techniques. Initially, reverse transcriptase polymerase chain reaction (RT-PCR) based methods were utilized with weak correlation between their positive detection and patients' outcome. More recent immunological techniques have indicated a reproducible correlation with outcome. Such surrogate markers may enable clinicians to provide early detection for inefficient treatments and patients with poor prognosis that are candidates for treatment intensification. Dissecting the micrometastasis phenomenon in CTCs/DTCs is a key point to increase surrogacy of this biomarker. PMID- 21680197 TI - Disseminated and circulating tumor cells in gastrointestinal oncology. AB - Circulating (CTCs) and disseminated tumor cells (DTCs) are two different steps in the metastatic process. Several recent techniques have allowed detection of these cells in patients, and have generated many results using different isolation techniques in small cohorts. Herein, we review the detection results and their clinical consequence in esophageal, gastric, pancreatic, colorectal, and liver carcinomas, and discuss their possible applications as new biomarkers. PMID- 21680198 TI - Molecular and serum markers in hepatocellular carcinoma: predictive tools for prognosis and recurrence. AB - With increased understanding of cancer biology, a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis, including angiogenesis, invasion, and metastasis, has been identified. Lately, they are being aggressively evaluated due to challenges involved in establishing early diagnosis, optimizing therapy for cancer inducing hepatotrophic viruses, minimizing the emergence of new tumors, and preventing recurrence after surgical resection or liver transplantation. This comprehensive review examines and critiques the evidence from published manuscripts reporting various tissue and serum biomarkers involved in hepatocellular carcinoma. These markers not only help in prediction of prognosis or recurrence, but may also assist in deciding appropriate modality of therapy and represent novel targets for potential therapeutic agents. PMID- 21680200 TI - Granulocyte-macrophage colony stimulating factor: Evaluation of biopharmaceutical formulations by stability-indicating RP-LC method and bioassay. AB - The granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine that regulates the proliferation and differentiation of hematopoietic cells and activates granulocytes and macrophages. A reversed-phase liquid chromatography (RP-LC) method was validated for the assessing of the stability of non glycosylated recombinant rhGM-CSF (Molgramostim) in biopharmaceutical formulations. The RP-LC method was carried out on a Jupiter C(4) column (250 mm * 4.6 mm i.d.), maintained at 45 degrees C. The mobile phase A consisted of 0.1% TFA and the mobile phase B was acetonitrile with 0.1% TFA in acetonitrile, run at a flow rate of 1 mL/min, and using photodiode array (PDA) detection at 214 nm. Chromatographic separation was obtained with a retention time of 29.2 min, and was linear over the concentration range of 2-300 MUg/mL (r(2) = 0.9992). Specificity was established in degradation studies. Moreover, the in vitro cytotoxicity test of the degraded products showed significant differences (p < 0.05). The method was applied to the assessment of rhGM-CSF and related proteins in biopharmaceutical dosage forms, and the results were correlated to those of a bioassay. It is concluded that the employment of RP-LC in conjunction with current methods allows a great improvement in monitoring stability, quality control and thereby assures the therapeutic efficacy. PMID- 21680199 TI - New insights into insulin resistance in the diabetic heart. AB - Insulin resistance is a major characteristic of obesity and type 2 diabetes, and develops in multiple organs, including the heart. Compared with its role in other organs, the physiological role of insulin resistance in the heart is not well understood. The heart uses lipid as a primary fuel, but glucose becomes an important source of energy in ischemia. The impaired ability to utilize glucose might contribute to cell death and abnormal function in the diabetic heart. Recent discoveries regarding the role of inflammation, mitochondrial dysfunction and endoplasmic reticulum (ER) stress in obesity have advanced our understanding of how insulin resistance develops in peripheral organs. In this review, we examine these findings in relation to the diabetic heart to provide new insights into the mechanism of cardiac insulin resistance. PMID- 21680201 TI - Use of a retrievable vena cava filter with low-intensity anticoagulation for prevention of pulmonary embolism in patients with cancer: an observational study in 106 cases. AB - PURPOSE: To evaluate a retrievable inferior vena cava (IVC) filter in combination with low-intensity oral anticoagulation for prevention of pulmonary embolism (PE) in patients with malignancy complicated by thromboembolic disease. MATERIALS AND METHODS: From October 2005 to December 2009, 107 Bard G2 filters were placed in 106 patients. Forty-eight patients had deep vein thrombosis (DVT) alone, 53 had PE with DVT, and five had PE with no evidence of DVT. After an initial period of anticoagulation with heparin, low-intensity oral anticoagulant therapy to achieve a target International Normalized Ratio of 1.5-2.0 was instituted. Follow-up computed tomography to evaluate the pulmonary circulation, IVC, and lower limbs was performed at 3 and 6 months. RESULTS: PE recurred in three of 58 patients (5.2%). None of the 48 patients with DVT alone developed PE, nor was there any recurrence of DVT. The filter was removed in 14 patients (13.2%). No complications occurred during the retrieval procedure. A total of 16 complications occurred in seven patients: one migration (0.9%); four cases of vena cava thrombosis (3.7%), three of which were associated with recurrent PE (2.8%); one filter fracture (0.9%); and one IVC penetration (0.9%). Filter tilting greater than 15 degrees occurred in six patients (5.7%) and was associated with other complications in five (4.7%). CONCLUSIONS: In patients with malignancies complicated by venous thromboembolic disease, an IVC filter together with low-intensity anticoagulation may be a possible treatment strategy for PE prophylaxis. Controlled studies are warranted. PMID- 21680202 TI - Comparison of Ponseti versus surgical treatment in congenital talipes equinovarus. AB - In the present study we compared the rate of relapse after conservative Ponseti treatment method with that of a historical cohort who underwent conventional operative treatment. From June 2002 to December 2004, 70 patients presented with 107 clubfeet and started Ponseti treatment. Of these 70 patients, 9 (15 feet) were excluded because of a teratologic deformity. Thus, 50 patients with 75 clubfeet were studied (41 [82%] boys and 9 [18%] girls). Data were compiled from the clinic assessment forms and patient notes. All cases resulting in recasting or additional operative procedures were regarded as failure of conservative treatment. The minimum follow-up period was 2 years or failure of the Ponseti method within this period. These data were then compared with the published data from the same center, regarding relapse after the 2-stage operative method. From 1988 to 1995, 86 patients had presented with 120 clubfeet and undergone operative treatment. Of the 86 patients, 68 (91 clubfeet; 48 boys and 20 girls) underwent the 2-stage operative procedure and were followed up to a mean age of 5.7 (range 2.2 to 9.6) years. The mean age at operative treatment was 8.9 months. The relapse rate of both treatment methods was compared for all feet in all Dimeglio grades. The relapse rate for Ponseti versus surgery was 18.2% versus 0% for grade 2, 36.2% versus 20.4% for grade 3, and 35.3% versus 65.4% for grade 4, respectively. No statistically significant difference was found. The Ponseti method is as valid as the 2-stage operative method for the treatment of clubfoot. The functional outcomes of the 2 treatment methods need to be compared. PMID- 21680203 TI - Choledochoscopic light-guided method for redo biliary reconstruction in patients with biliary stricture after living donor liver transplantation. PMID- 21680204 TI - Risk factors and outcomes of acute versus elective groin hernia surgery. AB - BACKGROUND: Hernia characteristics and patient factors associated with acute compared with elective groin hernia surgery are unknown. STUDY DESIGN: A retrospective study of 1,034 consecutive groin hernia repair cases performed between 2001 and 2009 at a single Veterans Affairs Hospital was conducted. Patient variables, hernia characteristics, time to surgery, and morbidity and mortality outcomes were abstracted and compared between acute and elective hernia repairs. A Kaplan-Meier survival analysis for the two groups was also performed. Logistic regression analysis was conducted to identify associations between type of surgery, patient demographics, and hernia characteristics. RESULTS: Compared with 971 elective repair patients, the 63 acute repair patients had a higher rate of femoral hernias (2.5% vs 7.4%, p = 0.03), a higher rate of scrotal hernias (16.2% vs 32.4%, p = 0.0006), and a higher rate of recurrent hernias (16.7% vs 30.9%, p = 0.0026). Patient age, femoral, scrotal, and recurrent hernias were significantly associated with acute hernia presentation on univariate and multivariable analyses. Complications occurred in 27% and 15.1% of acute and elective repair patients, respectively (p = 0.01). Intraoperative organ resection was required in 7 (11.1%) acute hernia repairs, and in 2 (0.2%) elective repairs (p < 0.0001). Three acute repair patients (4.8%) underwent reoperation within 30 days after surgery, compared with 15 elective repair patients (1.5%), p = 0.05. Age-adjusted Kaplan-Meier survival analysis revealed a shorter time to death among acute repair patients compared with elective repair patients (p < 0.0001). CONCLUSIONS: Age, femoral, scrotal, and recurrent groin hernias are associated with increased risk for acute hernia surgery. Acute hernia repair carries a higher morbidity and lower survival. PMID- 21680205 TI - Value-based insurance design: barriers to implementation in radiology. AB - Expensive and steadily rising health care costs without a concomitant increase in quality have generated a search for solutions to fund health care in the United States. Recent health care reforms and proposals on the agenda have spurred debate about alternative payment plans for health care. Much of the talk centers on imaging, which is a fast-growing and expensive component of health care. Value based insurance design (VBID), a "clinically sensitive" means of sharing the cost of health care, has been proposed as a means to control the runaway costs of health care management including diagnostic testing. A corollary of pay-for performance initiatives in which physician incentives are aligned with evidence based medical practices, VBID seeks to increase patient incentives to comply with evidence-based health care consumption. We previously reviewed the principles of VBID and provided examples of VBID in practice using diabetes management as a model, as well as suggested some areas in diagnostic testing that lend themselves to VBID benefit design. In this article, we summarize the barriers to implementation and outline potential solutions, with particular regard to radiology. PMID- 21680206 TI - Enabling comparative effectiveness research with informatics: show me the data! AB - RATIONALE: Both outcomes researchers and informaticians are concerned with information and data. As such, some of the central challenges to conducting successful comparative effectiveness research can be addressed with informatics solutions. METHODS: Specific informatics solutions which address how data in comparative effectiveness research are enriched, stored, shared, and analyzed are reviewed. RESULTS: Imaging data can be made more quantitative, uniform, and structured for researchers through the use of lexicons and structured reporting. Secure and scalable storage of research data is enabled through data warehouses and cloud services. There are a number of national efforts to help researchers share research data and analysis tools. CONCLUSION: There is a diverse arsenal of informatics tools designed to meet the needs of comparative effective researchers. PMID- 21680207 TI - Construct validity and reliability of structured assessment of endoVascular expertise in a simulated setting. AB - OBJECTIVES: To study the construct validity and reliability of a novel endovascular global rating scale, Structured Assessment of endoVascular Expertise (SAVE). DESIGN: A Clinical, experimental study. MATERIALS: Twenty physicians with endovascular experiences ranging from complete novices to highly experienced operators performed a video-recorded simulated contra-lateral iliac-artery stenting procedure. The virtual-patient case was a novel technically challenging procedure presenting the distal arteries below the knee. METHODS: Three experts assessed the performances blinded to operator identity. Validity was analysed by correlating experience with performance results. Reliability was analysed according to generalisability theory. RESULTS: The mean score on the 29 items of the SAVE scale correlated well with clinical experience (R = 0.84, P < 0.01) and was found discriminative even among the more experienced participants having performed up to 500 endovascular procedures in total. Only the most experienced participants (>5000 procedures) obtained maximum scores. The inter-rater reliability was high (G = 0.94 and G = 0.95). The procedure time (median 69 min, range 32-86) correlated moderately with clinical experience (R = -0.53, P < 0.05), whereas the fluoroscopy time and amount of contrast fluid did not correlate. CONCLUSIONS: The construct validity and reliability of assessment with the SAVE scale was high when applied to performances in a simulation setting with advanced realism. No ceiling effect was present in the assessment situation. PMID- 21680208 TI - Cardiac troponin I and the occurrence of cardiac arrhythmias in horses with experimentally induced endotoxaemia. AB - The aim of this study was to determine whether experimentally-induced endotoxaemia induced elevations in plasma cardiac troponin I (cTnI) concentrations in horses and how this might affect the incidence of cardiac arrhythmias. Eight Standardbred horses received an intravenous continuous rate infusion of endotoxin (total dose 500 ng/kg) for 6 h while being monitored using electrocardiography (ECG). Blood samples were collected before the start of the endotoxin infusion, every 60 min during the infusion, then 1, 2, 3, 8, 10 and 24 h post-infusion, and analysed for cTnI concentrations. One horse was excluded from the study owing to a high initial cTnI concentration. Endotoxin infusion induced an increase in cTnI concentrations in all horses, reaching mean peak concentration of 0.135+/-0.094 MUg/L by 1 h post-infusion. The cTnI concentrations then decreased and were no longer significantly different from pre infusion concentrations at 6, 10 and 24 h post-infusion. The number of ventricular events was generally low during the infusion period, but increased during the first 3 h post-infusion in 6/7 horses. In conclusion, elevated cTnI concentrations could be detected early after an endotoxaemic insult using an ultrasensitive cTnI assay, with peak cTnI concentrations preceding the occurrence of ventricular events on ECG. PMID- 21680209 TI - Aggravation of absence seizure related to levetiracetam. AB - Recent data have reported the effectiveness of levetiracetam (LVT) on generalized seizures. Among them, it seems that LVT can be successfully used to treat absence seizures. Many antiepileptic drugs (AEDs) have been occasionally reported to paradoxically aggravate some seizures. We retrospectively identified patients with aggravation of absence seizures using LVT from the databases of 2 pediatric neurology departments (Robert-Debre, Paris and Amiens; France). We also used the prospective data from an open-label clinical trial performed in a third pediatric neurology department (Necker, Paris; France). We included 6 patients: n = 2 childhood absence epilepsy, n = 3 juvenile absence epilepsy and n = 1 epilepsy with myoclonic absences. All of them have had an aggravation of the absences with a causal and temporal relationship between introduction of the drug and the detrimental effect. The aggravation disappeared when LVT was decreased or was withdrawn. This report highlights that LVT may aggravate epilepsy with absence seizures. PMID- 21680210 TI - Effect of morphine in needle procedures in children with cancer. AB - BACKGROUND: The aim was to investigate whether children experience less fear, distress, and/or pain when they receive oral morphine vs. placebo before a needle is inserted in a subcutaneously implanted intravenous port when combined with topical anesthesia. METHOD: Fifty children 1-18 years of age who were treated in a pediatric oncology and hematology setting were included consecutively when undergoing routine needle insertion into an intravenous port. All children were subjected to one needle insertion following topical anesthetic (EMLA) application in this randomized, triple-blind, placebo-controlled study comparing orally administered morphine (n=26) 0.25 mg/kg body weight with placebo (n=24). The patients' fear, distress, and pain were reported by parents, nurses and the children themselves (if >= 7 years of age) on 0-100 mm Visual Analogue Scales. In addition, observational methods were used to measure distress and procedure pain. RESULTS: No differences between the morphine and the placebo group were found with respect to age, weight, height, physical status, sex, weeks from diagnosis, or weeks from latest needle insertion. According to, parents, nurses, and children, oral morphine at a dose of 0.25 mg/kg body weight did not reduce fear, distress or pain compared with placebo. CONCLUSION: We could not reject the null hypothesis that there is no difference between the oral morphine and placebo groups assuming an effect size of 15 mm on VAS. Therefore it seems that oral morphine at 0.25 mg/kg does not give any additional reduction of fear, distress or pain compared with placebo when combined with topical anesthesia in pediatric patients undergoing subcutaneous port needle insertion, and would not be expected to be of any advantage for similar procedures such as venipuncture and venous cannulation when topical anesthesia is used. PMID- 21680211 TI - Quenching homonuclear couplings in magnetic resonance by trains of non-refocusing pulses. AB - Trains of 2pi or 4pi pulses fail to refocus offsets but can suppress the effects of bilinear interactions such as homonuclear scalar couplings. PMID- 21680212 TI - Trends in surgical correction of strabismus: a 20-year experience, 1990-2009. AB - BACKGROUND: Recent reports and anecdotal observations suggest that strabismus surgery, particularly for infantile esotropia, may be in decline, although a recent population-based study found the incidence to be stable. METHODS: We analyzed the surgical database of 4,494 primary pediatric strabismus procedures from 1990 through 2009 at Children's Medical Center of Dallas. Linear regression models were used to identify the relationship between the year and the proportion of each surgical category (infantile esotropia, all esotropia, exotropia, and other) using the least-squares approach. RESULTS: Surgery for infantile esotropia (mean age, 10 months) was performed on 374 patients (mean, 19; range, 11 27/year). Trend analysis demonstrated no significant change in the annual rate of surgery for infantile esotropia (R(2) = 0.004) during the 20-year study period. Additionally, when compared to the annual number of births in Dallas County, no significant change in the incidence of surgically corrected infantile esotropia was noted during the study period (P = 0.25); however, surgery for both infantile esotropia (P = 0.001) and for any esotropia (P = 0.002) declined, while surgery for exotropia increased (P = 0.002) as a proportion of all primary strabismus surgeries. CONCLUSIONS: The incidence of surgically corrected infantile esotropia has remained stable over a 20-year period. As a proportion of all primary strabismus procedures, surgery for all types of esotropia has decreased and for exotropia has increased. PMID- 21680213 TI - Retinoblastoma with autoinfarction presenting as orbital cellulitis. AB - We describe a case of unilateral retinoblastoma in a 13-month-old boy who presented with signs of orbital cellulitis. Heterochromia, hyphema, and vitreous hemorrhage were observed. Initial computed tomography (CT) imaging failed to reveal the calcified intraocular mass that was later identified on ultrasonography. Histopathology of the enucleated eye revealed diffuse inflammation and tumor necrosis but with absence of malignant retinoblastoma cells. Genetic testing was equivocal. The patient is presumed to have had retinoblastoma that underwent autoinfarction, leading to secondary inflammation. This case highlights the importance of complete ocular evaluation and proper imaging modalities in children presenting with orbital cellulitis. PMID- 21680214 TI - Duane syndrome in association with 48,XXYY karyotype. AB - Duane syndrome is an ocular motility disorder consisting of deficient horizontal eye movements, eyelid retraction, palpebral fissure narrowing, and abnormal vertical eye movements. It occurs in 1%-5% of patients with strabismus and has also been reported in several syndromes and chromosome abnormalities. Although most cases are sporadic, autosomal-dominant inheritance is seen in up to 10% of cases. Recently, Duane syndrome has been reported to occur in the setting of chromosomal duplication. The 48,XXYY syndrome is a rare syndrome involving duplication of the sex chromosomes. Ocular abnormalities are not typical of this condition. We report the first case of Duane syndrome presenting in an 8-month old boy with XXYY syndrome. This case lends further support to the association of chromosomal duplication and Duane syndrome. PMID- 21680215 TI - Computational insights into the different catalytic activities of CYP2A13 and CYP2A6 on NNK. AB - The human cytochrome P450 2A13 (CYP2A13) and P450 2A6 (CYP2A6) are 94% identical in amino acid sequence, but they metabolize many substrates with different efficiencies. Previous experimental results have shown that CYP2A13 exhibited catalytic activity that was more than 300-fold higher than CYP2A6 toward 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogen present in tobacco products. At present, however, the structural determinants accounting for the differential catalytic activities of these two isozymes toward NNK remain unclear. In the present study, molecular docking combined with molecular dynamics simulation and binding free energy calculation was performed to investigate the above issue. The results demonstrate that NNK was able to form a hydrogen bond with Asn297 in either CYP2A13 or CYP2A6. The hydrogen-bond acceptor was the pyridine nitrogen of NNK in the CYP2A13 complex, but it changed to the carbonyl oxygen in the CYP2A6 complex. NNK interacted with the residues in helix I and the K-beta2 loop in CYP2A13, whereas it preferred to contact with the phenylalanine cluster in CYP2A6. The residues in helix I and the K-beta2 loop of CYP2A13 played a vital role in keeping NNK in a more stable binding state. The binding free energies calculated by MM-GBSA were in agreement with the experimental results. PMID- 21680216 TI - Polymorphic locus rs10492972 of the KIF1B gene association with multiple sclerosis in Russia: case control study. AB - Axonal degeneration is responsible for the progression of the irreversible destruction caused by multiple sclerosis (MS) resulting ultimately in permanent disability. The KIF1B protein, a member of the kinesin family, is necessary for axon growth and myelination in vertebrates. In the recent paper, Aulchenko et al. suggested that the rs10492972[C] variant of KIF1B increases susceptibility to MS, but three following replication study didn't confirm this association. We studied the association of the polymorphic locus rs10492972 present in the KIF1B gene with genetic predisposition and its occurrence in clinical presentations of MS patients resident in western Siberia and the Sakha Republic (Yakutia), Russia. rs10492972 has been genotype in 833 samples of MS patient and 689 healthy controls. Distribution of rs10492972 genotypes corresponded with a Hardy-Weinberg distribution in both the MS patient and control groups, with the frequency of the C allele being the same in both groups (33%). Frequencies of occurrence of the genotypes were not shown to be associated with different disease courses or other characteristics of the disease, such as age at onset or duration. A complete meta analysis of all analogous studies published to date showed that the protective effect of the rs10492972[C] allele is statistically significant (OR=0.95, C.I.95% [0.90-0.99], p=0.02). PMID- 21680217 TI - Incidence of hepatitis C virus infection in patients with chronic kidney disease on conservative therapy. AB - Hepatitis C virus (HCV) infection is a never-ending public health problem. Many studies have investigated the incidence of HCV infection among dialysis patients, but there have only been a few epidemiological studies in renal conservative therapy. We studied 320 subjects with pre-dialysis chronic kidney disease living in Sicily, Italy. The incidence of HCV infection was 6.25%. In Europe, incidence ranges from 0.2% to 3.5%. It appears that the incidence of HCV infection is higher in the studied patient population than in the population as a whole. PMID- 21680218 TI - Estimation of renal function in patients with diabetes. AB - Diabetes is the leading cause of chronic kidney disease (CKD), which makes estimation of renal function crucial. Serum creatinine is not an ideal marker of glomerular filtration rate (GFR), which also depends on digestive absorption, and the production of creatinine in muscle and its tubular secretion. Formulas have been devised to estimate GFR from serum creatinine but, given the wide range of GFR, proteinuria, body mass index and specific influence of glycaemia on GFR, the uncertainty of these estimations is a particular concern for patients with diabetes. The most popular recommended formulas are the simple Cockcroft-Gault equation, which is inaccurate and biased, as it calculates clearance of creatinine in proportion to body weight, and the MDRD equation, which is more accurate, but systematically underestimates normal and high GFR, being established by a statistical analysis of results from renal-insufficient patients. This underestimation explains why the MDRD equation is repeatedly found to give a poor estimation of GFR in patients with recently diagnosed diabetes and is a poor tool for reflecting GFR decline when started from normal, as well as the source of unexpected results when applied to epidemiological studies with a 60mL/min/1.73m(2) threshold as the definition of CKD. The more recent creatinine based formula, the Mayo Clinic Quadratic (MCQ) equation, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) improve such underestimation, as both were derived from populations that included subjects with normal renal function. Determination of cystatin C is also promising, but needs standardisation. PMID- 21680219 TI - Number of children and change in markers of metabolic health over 9-years in men and women. Data from the DESIR study. AB - AIM: Parity is associated with an increased risk of coronary heart disease and type 2 diabetes, possibly mediated by long-term modification of metabolic health. Studying associations between the number of children with health and disease in men in addition to women allows for differentiation between the social and lifestyle influences of child-rearing, and the biological influences of childbearing. We sought to determine whether the number of children is associated with the incidence of raised fasting glucose (fasting plasma glucose>=6.1 mmol/L) and changes in glucose, insulin, insulin resistance and beta-cell function over 9 years. METHODS: Analysis of 1798 women and 1737 men from the DESIR study. RESULTS: The number of children was associated with change in fasting glucose for women (P(trend)=0.02) and men (P(trend)=0.03), and increased incidence of raised fasting glucose by 30% (95% CI: 15, 47%) per child for men, but not women (3% [95% CI: -8, 15%]). There was a J-shaped association between number of children and change in insulin (P=0.01) and insulin resistance (P=0.005) for women, and a reduction in beta-cell function in parous women (P=0.07). Men with children had increases in insulin (P=0.02), insulin resistance (P=0.02), and beta-cell function (P=0.07). CONCLUSIONS: The number of children a person has is associated with changes in metabolic health indices long after childbirth for both men and women. The distinct gender differences in deterioration of metabolic health indices emphasize that childbearing and child-rearing are likely to have differential influences on metabolic health. PMID- 21680220 TI - [Solitary fibrous tumors: Case report of a late relapse]. AB - Authors report a case of a woman with a metastasis of a solitary fibrous tumor, 14 years after the diagnosis of a hemangiopericytoma of the soft tissues. This case report allows discussing the pathological features, the therapeutical option and the outcome of these tumors. PMID- 21680221 TI - Evaluating disease activity in rheumatoid arthritis: which composite index is best? A systematic literature analysis of studies comparing the psychometric properties of the DAS, DAS28, SDAI and CDAI. AB - OBJECTIVES: To evaluate and compare four composite indices for assessing the activity of rheumatoid arthritis (RA). METHODS: We conducted a systematic literature review by searching Medline via PubMed and Embase and Cochrane databases for articles published up to March 2009. We selected studies that directly compared at least two of the four composite indices. The DAS (Disease Activity Score), DAS28, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) were evaluated in terms of reproducibility, construct validity, discriminative performance, and sensitivity to change. RESULTS: We included 61 articles. The only study that directly compared the intraobserver reproducibility of the DAS28, SDAI, and CDAI found comparable intraclass correlation coefficients ranging from 0.85 to 0.89. Concordance among indices was good (kappa values of ~0.7), except between the DAS28 and the other indices in definition of remission (kappa 0.48-0.63). The indices had good construct validity by their similar fair-to-good correlations with the Health Assessment Questionnaire (HAQ) score and structural damage. Discriminative performance was comparable and satisfactory for treatment changes or remission according to the American College of Rheumatology (ACR). Two studies evaluated the sensitivity to change of the SDAI and CDAI; both indices detected a difference between responders and non-responders according to ACR definitions. CONCLUSION: The DAS, DAS28, SDAI, and CDAI are valid tools for evaluating the activity of RA. The DAS28 is less conservative in defining remission than are the other three indices. Longitudinal studies of individual patients are needed to confirm these results. PMID- 21680222 TI - Monofocal motor neuropathy with conduction block associated with adalimumab in rheumatoid arthritis. PMID- 21680223 TI - Process optimization and stability of D-limonene-in-water nanoemulsions prepared by ultrasonic emulsification using response surface methodology. AB - D-limonene in water nanoemulsion was prepared by ultrasonic emulsification using mixed surfactants of sorbitane trioleate and polyoxyethylene (20) oleyl ether. Investigation using response surface methodology revealed that 10% d-limonene nanoemulsions formed at S0 ratio (D-limonene concentration to mixed surfactant concentration) 0.6-0.7 and applied power 18 W for 120 s had droplet size below 100 nm. The zeta potential of the nanoemulsion was approximately -20 mV at original pH 6.4, closed to zero around pH 4.0, and around -30 mV at pH 12.0. The main destabilization mechanism of the systems is Ostwald ripening. The ripening rate at 25 degrees C (0.39 m3 s(-1)*10(29)) was lower than that at 4 degrees C (1.44 m3 s(-1)*10(29)), which was in agreement with the Lifshitz-Slezov-Wagner (LSW) theory. Despite of Ostwald ripening, the droplet size of d-limonene nanoemulsion remained stable after 8 weeks of storage. PMID- 21680224 TI - Flow dynamics of a novel counterpulsation device characterized by CFD and PIV modeling. AB - BACKGROUND: Historically, single port valveless pneumatic blood pumps have had a high incidence of thrombus formation due to areas of blood stagnation and hemolysis due to areas of high shear stress. METHODS: To ensure minimal hemolysis and favorable blood washing characteristics, particle image velocimetry (PIV) and computational fluid dynamics (CFD) were used to evaluate the design of a new single port, valveless counterpulsation device (Symphony). The Symphony design was tested in 6-h acute (n=8), 5-day (n=8) and 30-day (n=2) chronic experiments in a calf model (Jersey, 76 kg). Venous blood samples were collected during acute (hourly) and chronic (weekly) time courses to analyze for temporal changes in biochemical markers and quantify plasma free hemoglobin. At the end of the study, animals were euthanized and the Symphony and end-organs (brain, liver, kidney, lungs, heart, and spleen) were examined for thrombus formations. RESULTS: Both the PIV and the CFD showed the development of a strong moving vortex during filling phase and that blood exited the Symphony uniformly from all areas during ejection phase. The laminar shear stresses estimated by CFD remained well below the hemolysis threshold of 400 Pa inside the Symphony throughout filling and ejection phases. No areas of persistent blood stagnation or flow separation were observed. The maximum plasma free hemoglobin (<10mg/dl), average platelet count (pre-implant = 473 +/- 56 K/MUl and post-implant = 331 +/- 62 K/MUl), and average hematocrit (pre-implant = 31 +/- 2% and post-implant = 29 +/- 2%) were normal at all measured time-points for each test animal in acute and chronic experiments. There were no changes in measures of hepatic function (ALP, ALT) or renal function (creatinine) from pre-Symphony implantation values. The necropsy examination showed no signs of thrombus formation in the Symphony or end organs. CONCLUSIONS: These data suggest that the designed Symphony has good washing characteristics without persistent areas of blood stagnation sites during the entire pump cycle, and has a low risk of hemolysis and thrombus formations. PMID- 21680225 TI - Area effects on health inequalities: the impact of neighbouring deprivation on mortality. AB - The exact nature of the association between the context of the local area and local health outcomes is unknown. We investigated whether areas geographically close but divergent in terms of deprivation have greater inequality in health than those where deprivation is similar across neighbouring localities. In order to disaggregate the strong correlation between the deprivation of a target area and that of its surrounding areas, we used principal component analysis to create a measure of relative deprivation. Both deprivation (beta=0.183, p<0.001) and relative deprivation were positively associated with mortality (beta=0.099, p<0.001), and the effect of relative deprivation was shown to be most pronounced in more affluent segments of the population. PMID- 21680226 TI - Clinical conundrums in a case of upper quadrant dysfunction. AB - This case study charts the progress of a 60-year-old angling coach presenting with a complex upper quadrant dysfunction. Following a brief summary of the history and physical examination, the main focus of the paper explores the mechanical and physiological rationale for adopting a neurodynamic approach for a proposed double crush condition. This case further highlights mismatches that arose between the clinical findings and traditional healing timescales, and the importance of considering pathomechanics of the whole quadrant in complex clinical circumstances. PMID- 21680227 TI - Further notes on testosterone as a social hormone. PMID- 21680228 TI - Pattern of cervical lymph node metastasis in tonsil cancer: predictive factor analysis of contralateral and retropharyngeal lymph node metastasis. AB - The purpose of this study was to determine the pattern of cervical lymph node metastasis in tonsil cancer including the retropharyngeal (RPLN) nodal metastasis. Seventy-six tonsillar squamous cell carcinoma patients who underwent surgery-based treatment were retrospectively analyzed. Most patients had advanced stage (stages III and IV: 81.6%) tonsil cancer. Sixteen patients were treated with surgery only. Postoperative radiotherapy was performed to 38 patients, and chemoradiation to 22 patients. Seventy-one therapeutic neck dissections and 27 elective neck dissections were performed. Thirty-four patients underwent RPLN dissection based on the preoperative inclusion criteria. There was a statistically significant metastasis in level I or V nodes, when the ipsilateral multilevel, or contralateral nodes were positive. The rate of contralateral occult cases was 28.6%. T3-4 stages, primary lesions close to the midline, or ipsilateral multilevel involvement were significantly associated with contralateral metastasis. Ipsilateral multilevel involvement was the independent factor with multivariate analysis. RPLN metastasis was confirmed in 9 of the 34 (26.5%) subjects. Disease-specific survival rate was significantly different according to RPLN status (82.1% vs. 55.6%; p=0.021). Positive pre-operative image, posterior pharyngeal wall invasion, more than N2 stage, contralateral node metastasis, or ipsilateral multilevel involvement were correlated with RPLN metastasis. Bilateral neck dissection is mandatory for primary lesions close to the midline and advanced ipsilateral nodal disease. Elective RPLN dissection should be considered for patients with advanced neck and primary tumor, particularly for tumors with posterior pharyngeal wall invasion. PMID- 21680229 TI - Vibrational spectroscopic (FT-IR and FT-Raman), first-order hyperpolarizablity, HOMO, LUMO, NBO, Mulliken charges and structure determination of 2-bromo-4 chlorotoluene. AB - The FT-IR and FT-Raman spectra of 2-bromo-4-chlorotoluene (2B4CT) molecule have been recorded in the region 4000-400 cm(-1) and 3500-50 cm(-1), respectively. Optimized geometrical structures, harmonic vibrational frequencies, intensities, reduced mass, force constants and depolarization ratio have been computed by the B3 based (B3LYP) density functional methods using 6-31+G(d,p) and 6-311++G(d,p) basis sets. The observed FT-IR and FT-Raman vibrational frequencies are analysed and compared with theoretically predicted vibrational frequencies. The geometries and normal modes of vibration obtained from DFT method are in good agreement with the experimental data. The Mulliken charges, the natural bonding orbital (NBO) analysis, the values of electric dipole moment (MU) and the first-order hyperpolarizability (beta) of the investigated molecule were computed using DFT calculations. The calculated HOMO and LUMO energies show that charge transfer occurs within molecule. The influences of bromine atom, chlorine atom and methyl group on the geometry of benzene and its normal modes of vibrations have also been discussed. PMID- 21680230 TI - Surface-enhanced Raman scattering of trans-1,2-bis (4-pyridyl)-ethylene on silver by theory calculations. AB - Surface-enhanced Raman spectra of trans-1,2-bis (4-pyridyl)-ethylene (t-BPE) on silver foil were detected at laser line of 514.5, 633, 785 and 1064 nm, respectively. The structure of Ag-t-BPE, Ag4-t-BPE, Ag6-t-BPE, Ag10-t-BPE and Ag20-t-BPE complexes has been calculated using a local version of the Amsterdam density functional program package. The Raman spectra and electronic polarizability of t-BPE-Ag at 514.5, 633, 785 and 1064 nm excitation lines were calculated. The Raman bands of t-BPE were assigned according to the calculation of potential energy distribution. The experimental and calculated Raman spectra of t-BPE-Ag at 514.5, 633, 785 and 1064 nm were compared. The relative Raman intensities change at different excitation lines were discussed based on the Raman enhanced mechanism and surface selection rules. PMID- 21680231 TI - Spectroscopic studies on interaction and sonodynamic damage of metallochlorophyllin (Chl-M (M=Fe, Zn and Cu)) to protein under ultrasonic irradiation. AB - In this paper, the chlorophyll derivatives, metallochlorophyllin (Chl-M) (M=Fe, Zn and Cu) including chlorophyllin iron (Chl-Fe), chlorophyllin zinc (Chl-Zn) and chlorophyllin copper (Chl-Cu), were adopted as sonosensitizers to combine with ultrasonic irradiation, and the sonodynamic damage of bovine serum albumin (BSA) was investigated. At first, the interaction of Chl-M with BSA was studied by fluorescence spectroscopy. The results show that the quenching mechanism belongs to a static process and among them the affinity of Chl-Fe to BSA is the most obvious. Then, some influence factors on the sonodynamic damage of BSA molecules in the presence of Chl-M under ultrasonic irradiation were also studied. Synchronous fluorescence spectra show that the binding and damage sites of Chl-M to BSA molecule are mainly on the tryptophan (Trp) residues. The generation of ROS in Chl-M sonodynamic process is estimated by the method of Oxidation Extraction Spectrometry (OEP). This paper may offer some valuable references for the study of the sonodynamic activity of Chl-M and the effect of the central metals. Synchronously, it contributes to the application of Chl-M in SDT for tumor treatment. PMID- 21680232 TI - Vibrational spectroscopic study of the mineral tsumebite Pb2Cu(PO4,SO4)(OH). AB - The mineral tsumebite Pb2Cu(PO4)(SO4)(OH), a copper phosphate-sulfate hydroxide of the brackebuschite group has been characterised by Raman and infrared spectroscopy. The brackebuschite mineral group are a series of monoclinic arsenates, phosphates and vanadates of the general formula A2B(XO4)(OH,H2O), where A may be Ba, Ca, Pb, Sr, while B may be Al, Cu2+,Fe2+, Fe3+, Mn2+, Mn3+, Zn and XO4 may be AsO4, PO4, SO4,VO4. Bands are assigned to the stretching and bending modes of PO4(3-) and HOPO3 units. Hydrogen bond distances are calculated based upon the position of the OH stretching vibrations and range from 2.759 A to 3.205 A. This range of hydrogen bonding contributes to the stability of the mineral. PMID- 21680233 TI - Multiple and sequential charge transfer interactions occurring in situ: A redox reaction of thiazolidine-2-thione with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. AB - Interaction of thiazolidine-2-thione (T2T) as an electron donor with 2,3-dichloro 5,6-dicyano-1,4-benzoquinone (DDQ) as an electron pi-acceptor has been studied. Electronic absorption spectra of the system T2T-DDQ in several organic solvents of different polarities have been measured. A charge transfer (CT) complexation has occurred between T2T and DDQ. This CT interaction has led to a redox reaction in which T2T has been oxidized to the corresponding dehydrogenated T2T (T2T-2H), meanwhile DDQ has been fully reduced to the corresponding hydroquinone (DDQH2). However, the two new species, resulting in situ, have been interacted, whereas a CT complex having the formula (T2T-2H.DDQH2) has occurred. IR, 1H NMR and mass spectra were used for ascertaining the structural formula of the synthesized CT complex. Formation constants (KCT), molar absorption coefficients (ECT) and thermodynamic properties of this CT interaction in various organic solvents were determined and discussed. The obtained KCT and ECT values have indicated that T2T 2H is a weak CT donor, whereas the formed CT complex has a low stability and it is classified as a contact-type CT complex. PMID- 21680235 TI - Special issue on Supporting collaboration in healthcare settings: the role of informatics. PMID- 21680234 TI - Synthesis, characterization and anti proliferative effect of [Au(en)2]Cl3 and [Au(N-propyl-en)2]Cl3 on human cancer cell lines. AB - Two Au(III) complexes of the type [Au(en)2]Cl3 (2a) and [Au(N-pr-en)2]Cl3 (3a) were synthesized by reacting Auric acid (HAuCl(4).3H2O) with 2 equiv. ethylenediamine (en) or N-alkyl substituted ethylenediamine ligands. This metallodrug was characterized by various analytical and spectroscopic techniques such as elemental analysis, UV-Vis, Far-IR, 1H NMR and solution 13C as well as solid 13C and 15N NMR. Potentiality of [Au(en)2]Cl3 and [Au(N-pr-en)2]Cl3 as an anti-cancer agent were investigated by measuring some relevant physicochemical and biochemical properties such as stability of Au-N bonds by vibrational stretching from Far IR as well as cytotoxicity and stomach cancer cell inhibiting effect, respectively. The solid-state 15N NMR chemical shift shows that the ligand is strongly bound to gold(III) centre via N atoms. The computational study of 2a shows that the gold coordination sphere adopts distorted square planar geometry with bidentate ethylenediamine ligands acting as a tetradentate chelate. While stable in the solution state, the in vitro biological studies performed with these compounds 2a in solution showed higher activity towards the inhibitory effects of the human cancer cell lines such as prostate cancer (PC-3) and gastric carcinoma (SGC-7901) than that of the N-substituted gold(III) complex (3a). Cytotoxicity of the new compounds has also been estimated in PC-3 and SGC-7901 cells. PMID- 21680236 TI - Analysis and evaluation of the Electronic Health Record standard in China: a comparison with the American national standard ASTM E 1384. AB - OBJECTIVE: To analyze and evaluate the newly issued Electronic Health Record (EHR) Architecture and Data Standard of China (Chinese EHR Standard) and identify areas of improvement for future revisions. DESIGN: We compared the Chinese EHR Standard with the standard of the American Society for Testing and Materials Standard Practice for Content and Structure of Electronic Health Records in the United States (ASTM E 1384 Standard). METHODS: The comparison comprised two steps: (1) comparing the conformance of the two standards to the international standard: Health Informatics-Requirements for an Electronic Health Record Architecture (ISO/TS 18308), and showing how the architectures of the two standards satisfy or deviate from the ISO requirements and (2) comparing the detailed data structures between the two standards. RESULTS: Of the 124 requirement items in ISO/TS 18308, the Chinese EHR Standard and the ASTM E 1384 Standard conformed to 77 (62.1%) and 111 (89.5%), respectively. The Chinese EHR Standard conformed to 34 of 50 Structure requirements (68.0%), 22 of 24 Process requirements (91.7%), and 21 of 50 Other requirements (42.0%). The ASTM E 1384 Standard conformed to 49 of 50 Structure requirements (98.0%), 23 of 24 Process requirements (95.8%), and 39 of 40 Other requirements (78.0%). CONCLUSIONS: Further development of the Chinese EHR Standard should focus on supporting privacy and security mechanism, diverse data types, more generic and extensible lower level data structures, and relational attributes for data elements. PMID- 21680237 TI - Cervical Human Papillomavirus in transplanted Italian women: a long-term prospective follow-up study. AB - BACKGROUND: Human Papillomavirus (HPV) is the leading cause of cervical cancer among women. Immunosuppression is recognized as one of the major risk factors for HPV infection and persistence. OBJECTIVES: Aim of this study was to determine if solid organs (24 kidney and 24 kidney/pancreas) transplanted Italian women undergoing immunosuppressive therapies were at higher risk of HPV genital infection and cervical precancerous lesions in a ten-year follow-up. STUDY DESIGN: Forty-eight women that underwent transplant from 1990 to 2000, receiving multi-drug immunosuppressive therapy, were enrolled prospectively in a long-term follow-up protocol. Patients were cytologically (Pap smear) and virologically (HPV-DNA test) tested each year for 10 years. Incidence of HPV-DNA positivity and of cervical cytological/histological abnormalities was collected. Results were statistically analyzed and compared to a matching control group of 200 healthy women. RESULTS: HPV-DNA positivity and cytological High-Grade (HG-SIL) cervical lesions did not show statistically significant differences in cases compared to controls, while statistical significance was observed in Low-Grade (LG-SIL) cytological diagnoses. No statistically significant difference was observed in histology-proven cervical lesions. CONCLUSIONS: Women receiving immunosuppression therapy following transplant do not seem to require intensive follow-up, and should not be considered a high-risk subgroup, as they do not show a statistically significant higher incidence of HPV infections or high-grade cervical dysplasia compared to healthy immunocompetent matching controls. PMID- 21680238 TI - Blood-borne viruses in health care workers: prevention and management. AB - Three pathogens account for most cases of occupationally acquired blood-borne infection: hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The highest proportion of occupational transmission is due to percutaneous injury (PI) via hollow-bore needles with vascular access. We briefly review prevention and management of blood-borne pathogens in health care workers (HCWs) in developed countries. HCW compliance with standard precautions is necessary for prevention of PI. Safety-engineered devices are now being increasingly promoted as an approach to decreasing the rate of PI. Prevention of HBV transmission requires HCW immunization through vaccination against HBV. In non-vaccinated HCWs (or HCWs with an unknown antibody response to vaccination) exposed to an HbsAg-positive or an untested source patient, post exposure prophylaxis with HBV vaccine, hepatitis B immunoglobulin or both must be started as soon as possible. Although no available prophylaxis exists for HCV, it is crucial to identify HCV exposure and infection in health care settings and to consequently propose early treatment when transmission occurs. Following occupational exposure with potential for HIV transmission, use of antiretroviral post-exposure prophylaxis must be evaluated. Patients need to be protected from blood-borne pathogen-infected HCWs, and especially surgeons performing exposure prone procedures (EPPs) with risk of transmission to the patient. However, HCWs not performing EPPs should be protected from arbitrary administrative decisions that would restrict their practice rights. Finally, it must be emphasized that occupational blood exposure is of great concern in developing countries, with higher risk of exposure to blood-borne viruses because of a higher prevalence of the latter than in developed countries, re-use of needles and syringes and greater risk of sustaining PI, since injection routes are more frequently used for drug administration than in developed countries. PMID- 21680239 TI - Apropos 'The development of a novel serotyping-NS1-ELISA to identify serotypes of dengue virus'. PMID- 21680240 TI - Neurophysiological and clinical responses to rituximab in patients with anti-MAG polyneuropathy. AB - OBJECTIVES: Rituximab treatment has shown clinical improvement in anti-myelin associated glycoprotein (MAG) polyneuropathy. We analyzed scores of clinical scales and the most sensitive electrophysiological parameters before and after immunomodulating treatment with rituximab in a group of patients affected by anti MAG demyelinating polyneuropathy. METHODS: Clinical scores, the percentage of CD20 B-lymphocytes, anti-MAG antibody titers and electrophysiological data in 7 patients with anti-MAG polyneuropathy were analyzed. The patients were examined before a cycle with rituximab, 6, 12 and 24 months after the end of the treatment. Two patients were treated with rituximab additional cycles and re evaluated 48 months after the first treatment. RESULTS: There were no evident correlation between anti-MAG serum antibody titers or clinical scales and electrodiagnostic data. Significant decrease in the proportion of CD20 B lymphocytes was observed. Significant anti-MAG antibodies titers reduction was detected after re-treatment. At follow-up, pinprik sensation and two point discrimination presented a significant improvement compared with the score before treatment. CONCLUSIONS: In our patients, rituximab did not improve any electrophysiological data. No correlation with anti-MAG serum antibodies course was found. With rituximab only pin sensibility improved. SIGNIFICANCE: Rituximab re-treatment significantly reduces anti-MAG serum antibodies titers but improves only small fibers sensibility. PMID- 21680241 TI - A community demand-driven approach toward sustainable water and sanitation infrastructure development. AB - In September 2001, Cooperative Assistance and Relief Everywhere, Peru Country Office (CARE Peru), obtained funding from the United States Agency for International Development (USAID) to implement community-supported, condominial water and sanitation interventions in Manuel Cardozo Davila, a settlement in Iquitos, Peru. With technical support from the Centers for Disease Control and Prevention (CDC), CARE Peru's Urban Environmental Health Models (Modelos Urbanos de Salud Ambiental [MUSA]) project built on previous work from implementing the Protocol for Assessing Community Excellence in Environmental Health in this same community. The project led to the municipal water supply distribution system being extended 1.3 kilometers into the Southern zone of Iquitos, where it connected to the condominial water system. Altogether, 1030 households were connected to the water supply system after the installation of a condominial water and sewerage system in Cardozo. Diarrheal disease decreased by 37% for children less than 5 years of age from 2003 to 2004. This paper illustrates the strategy used by CARE Peru in conjunction with the Cardozo community to assure that the local demand for improved water and sanitation was met. PMID- 21680242 TI - Particulate matter pollution in the megacities of the Pearl River Delta, China - a systematic literature review and health risk assessment. AB - The exposure to ambient particulate matter (PM) pollution is a major threat to public health. Chinese megacities are coined by high levels of PM. Our aims were to examine the concentration levels of PM in megacities (Guangzhou, Hong Kong, and Shenzhen) of the Pearl River Delta (PRD), South China; to compare the results with international and national air quality guidelines; and to assess the health impact in terms of possible reductions in premature deaths due to PM reduction. The Medline((r)) data base was used to identify published studies (systematic literature search). Based on our appraisal criteria 13 studies remained in the analysis. Additionally, publicly available data were extracted from data sources provided by municipal authorities of the cities under study. PM data reported in MUg/m(3) were abstracted from single studies and municipal reports. If possible, the PM data were stratified for season of data collection (summer/winter half year) and simple means were calculated for cities, seasons and months. Based on the abstracted data, a health impact assessment (HIA) was done in order to estimate potential preventable premature deaths due to PM pollution in the cities. Almost all PM data exceeded national and international air quality guidelines. Our HIA showed that in Guangzhou ten thousands of premature deaths could be prevented if the PM burden was reduced to these air quality limit values. We identified no suitable epidemiological study reporting PM according to our study protocol. Further epidemiological studies should be carried out to more precisely determine the spatial distribution of PM-related health risks in PRD. Environmental protection measures and public health interventions are required to reduce burden of PM-related diseases in PRD. PMID- 21680243 TI - Effects of ambient air pollution on pulmonary function among schoolchildren. AB - Literature has shown adverse effects of ambient air pollution exposure on various asthma related outcomes in childhood. However, the associated evidence on pulmonary function effects is still inconsistent. We conducted a population-based study comprised of seventh-grade children in 14 Taiwanese communities. Pulmonary function tests and questionnaires were completed on 3957 subjects. We evaluated the effects of ambient air pollution exposures based on the data collected in 2005-2007 by existing air monitoring stations. Multiple linear mixed effect models were fitted to estimate the relationship between community pollutant levels and pulmonary function indices. After adjustment for individual-level confounders, pulmonary function differed only slightly between communities with different levels of air pollution. We found greater effects of ambient air pollutants on pulmonary function for boys than for girls. Among boys, traffic related pollutants CO, NOx, NO(2), and NO were generally associated with chronic adverse effects on FVC and FEV(1), and subchronic adverse effects mainly on maximal mid-expiratory flow (MMEF) and peak expiratory flow rate. Among girls, only NOx and NO(2) showed subchronic adverse effects on MMEF. Although effect estimates of SO(2), PM(10), and PM(2.5) were generally negative for boys, none achieved statistical significance. Our data suggests that ambient traffic-related pollution had chronic adverse effects on pulmonary function in schoolchildren, especially for boys. PMID- 21680244 TI - Historical review on development of environmental quality standards and guideline values for air pollutants in Japan. AB - Environmental quality standards (EQSs) have been established as desirable levels to be maintained for protection of human health and the conservation of the living environment by Basic Environment Law. EQSs in ambient air had been set for 10 substances (sulfur dioxide (SO(2)), carbon monoxide (CO), suspended particulate matter (SPM), nitrogen dioxide (NO(2)) and photochemical oxidants (Ox), benzene, tetrachloroethylene, trichloroethylene, dioxins and dichloromethane) and guideline values for 7 (acrylonitorile, vinyl chloride monomer, mercury, nickel compounds, 1,3-butadiene, chloroform and 1,2 dichloromethane) in Japan by 2009. EQSs for the classical (or traditional) air pollutants, SO(2), CO, SPM, NO(2) and Ox, were set according to the minimal requirement to protect human health, based on evidence from epidemiological studies conducted before the 1970s. In 1996, the Central Environment Council designated substances which may be hazardous air pollutants and substances requiring priority action, and adopted the concept of risk assessment to set EQSs and guideline values. A life-long risk level (virtually safe dose) of 10(-5) was used to set EQS for benzene, and guideline values for vinyl chloride monomer, nickel compounds, and 1,3-butadiene. EQSs for trichloroethylene, tetrachloroethylene and dichloromethane, and guideline values for acrylonitorile and mercury were set using uncertain factors and lowest observed adverse effect (LOAEL)/no observed adverse effect level (NOAEL). The results of animal experiments were utilized to set guideline values for chloroform and 1,2 dichloroethane. The benchmark approach and human equivalent concentration (HEC) were adopted for 1,2-dichloroethane. The history of setting EQSs and guideline values for hazardous air pollutants is one of adopting new concepts into risk assessment. PMID- 21680245 TI - Host specificity in phylogenetic and geographic space. AB - The measurement of host specificity goes well beyond counting how many host species can successfully be used by a parasite. In particular, specificity can be assessed with respect to how closely related the host species are, or whether a parasite exploits the same or different hosts across its entire geographic range. Recent developments in the measurement of biodiversity offer a new set of analytical tools that can be used to quantify the many aspects of host specificity. We describe here the multifaceted nature of host specificity, summarize the indices available to measure its different facets one at a time or in combination, and discuss their implications for parasite evolution and disease epidemiology. PMID- 21680246 TI - The economy of inflammation: when is less more? AB - In ecology, tolerance of parasites refers to host mitigation of the fitness costs of an infection. This concept of parasite tolerance contrasts with resistance, whereby hosts reduce the intensity of an infection. Anti-inflammatory cells and molecules have been implicated as mechanisms of parasite tolerance, suggesting that a major role of tolerance is in minimizing collateral damage associated with inflammation. A framework is proposed here in which the cost-benefit outcome of an inflammatory host-response is hypothesized to be dependent on host life history, parasite virulence, and the efficacy of a current inflammatory or anti inflammatory response. Testable predictions, both within and among host species, are presented for this hypothesis. PMID- 21680247 TI - Effects of the FSH receptor gene polymorphism p.N680S on cAMP and steroid production in cultured primary human granulosa cells. AB - The study was designed to evaluate in vitro the cellular mechanisms of the single nucleotide polymorphism (SNP) p.N680S of the FSH receptor gene (FSHR) in human granulosa cells (GC) and included patients homozygous for the FSHR SNP (NN/SS) undergoing ovarian stimulation. GC were isolated during oocyte retrieval and cultured for 1-7 days. Basal oestradiol and progesterone concentrations were measured after short-term culture. The kinetics of cAMP, oestradiol and progesterone concentrations in response to various amounts of FSH were analysed in a 6-7 day culture. Basal oestradiol, but not progesterone, concentrations on day 1 of GC culture, were significantly higher in NN compared with SS (P = 0.045), but non-responsive to FSH stimulation. Immunofluorescence microscopy demonstrated the re-appearance of FSHR expression with increasing days in culture. Upon stimulation with FSH, GC cultured for 6-7 days displayed a dose dependent increase of cAMP, oestradiol and progesterone but no difference in the EC50 values between both variants. Primary long-term GC cultures are a suitable system to study the effects of FSH in vitro. However, the experiments suggest that factors down-stream of progesterone production or external to GC might be involved in the clinically observed differences in an FSHR variant-mediated response to FSH. PMID- 21680248 TI - Robert Edwards: the path to IVF. AB - The early influences on Robert Edwards' approach to the scientific research that led to human IVF are described. His interest as a graduate student in the genetics of early mammalian development stimulated him later to investigate whether the origins of human genetic diseases such as Down, Klinefelter and Turner syndromes might be explained by events during egg maturation. This clinical problem provided the most powerful stimulus to achieve both oocyte maturation and fertilization in vitro in humans. Indeed,preimplantation genetic diagnosis was his main goal until he met Patrick Steptoe in 1968. A re-evaluation of his meeting with Steptoe suggests that initially Steptoe's laparoscopic skill was of interest for its potential to solve the sperm capacitation problem. Steptoe'simpact on Edwards was twofold. First, Steptoe's long-held interest in infertility raised this application of IVF higher in Edwards'priorities. Second, Steptoe offered a long-term partnership, in which oocyte collection without in vitro maturation was a possibility.The professional criticism generated by their work together encouraged Edwards to pursue a deliberate programme of public education about the issues raised and to challenge and develop professional bioethical thought and discourse about reproduction. PMID- 21680249 TI - Effectiveness of intervention programs in preventing falls: a systematic review of recent 10 years and meta-analysis. AB - OBJECTIVE: To examine the reported effectiveness of fall-prevention programs for older adults by reviewing randomized controlled trials from 2000 to 2009. DESIGN: Systematic review and meta-analysis of randomized controlled trials. DATA SOURCES: A systematic literature search of articles was conducted using 5 electronic databases (Medline, PubMed, PsycINFO, CINAHL, and RefWorks), including articles describing interventions designed to prevent falls, in English with full text availability, from 2000 through 2009. REVIEW METHODS: Of a potential 227 studies, we identified 17 randomized controlled trials with a duration of intervention of at least 5 months of follow-up. Inclusion and exclusion criteria were used to assess the methodological qualities of the studies. We excluded unidentified study design, quasi-experimental studies, and/or studies that were nonspecific regarding inclusion criteria. DATA EXTRACTION: Primary outcome measures were number of falls and fall rate. Methodological quality assessment included internal and external validity, reporting, and power. Data were extracted independently by 2 investigators and analyzed using a random-effects model. We analyzed the effectiveness of these fall intervention programs using their risk ratios (RR) in 2 single-intervention versus 15 multifactorial intervention trials, 3 nursing homes versus 14 community randomized controlled trials, and 8 Model 1 (initial intervention with subsequent follow up) versus 9 Model II (ongoing intervention throughout the follow-up) studies. RESULTS: The combined RR for the number of falls among 17 studies was 0.855 (z = -2.168; p = .030; 95% CI = 0.742-0.985; Q = 196.204, df = 16, P = .000, I(2) = 91.845), demonstrating that fall-prevention programs across the studies were effective by reducing fall rates by 14%, but with substantial heterogeneity. Subgroup analysis indicated that there was a significant fall reduction of 14% in multifactorial intervention (RR = 0.856, z = -2.039, P = .041) with no variation between multifactorial and single-intervention groups (Q = 0.002, P = .961), 55% in the nursing home setting (RR = 0.453, z = -9.366, P = .000) with significant variation between nursing home and community groups (Q = 62.788, P = .000), and no significant effect was gained by dividing studies into either in Model I or II. Sensitivity analysis found homogeneity (Q = 18.582, df = 12, P = .099, I(2) = 35.423) across studies with a 9% overall fall reduction (RR = 0.906, 95% CI = 0.853-0.963, z = -3.179, P = .001), including a fall-reduction rate of 10% in multifactorial intervention (RR = 0.904, z = -3.036, P = .002), 9% in community (RR = 0.909, z = -3.179, P = .001), and 12% in Model I (RR = 0.876, z = -3.534, P = .000) with no variations among all the groups. Meta regression suggested that the model fit explained 68.6% of the relevant variance. CONCLUSIONS: The meta sensitivity analysis indicates that randomized controlled trials of fall prevention programs conducted within the past 10 years (2000-2009) are effective in overall reduction of fall rates of 9% with a reduction of fall rates of 10% in multifactorial interventions, 9% in community settings, and 12% in Model I interventions (initial intervention efforts and then subsequent follow-up). PMID- 21680251 TI - Reciprocal relationship between pain and depression: a 12-month longitudinal analysis in primary care. AB - Pain and depression are the most prevalent physical and psychological symptom based disorders, respectively, and co-occur 30 to 50% of the time. However, their reciprocal relationship and potentially causative effects on one another have been inadequately studied. Longitudinal data analysis involving 500 primary care patients with persistent back, hip, or knee pain were enrolled in the Stepped Care for Affective Disorders and Musculoskeletal Pain (SCAMP) study. Half of the participants had comorbid depression and were randomized to a stepped care intervention (n = 123) or treatment as usual (n = 127). Another 250 nondepressed patients with similar pain were followed in a parallel cohort. Outcomes were assessed at baseline, 3, 6, and 12 months. Mixed effects model repeated measures (MMRM) multivariable analyses were conducted to determine if change in pain severity predicted subsequent depression severity, and vice versa. Change in pain was a strong predictor of subsequent depression severity (t-value = 6.63, P < .0001). Likewise, change in depression severity was an equally strong predictor of subsequent pain severity (t-value = 7.28, P < .0001). Results from the full cohort were similar in the clinical trial subgroup. In summary, pain and depression have strong and similar effects on one another when assessed longitudinally over 12 months. PERSPECTIVE: This study strengthens the evidence for a bidirectional and potentially causative influence of pain and depression on one another. A change in severity of either symptom predicts subsequent severity of the other symptom. Thus, recognition and management of both conditions may be warranted, particularly when treatment focused on 1 condition is not leading to an optimal response. PMID- 21680252 TI - Elevated pain sensitivity in chronic pain patients at risk for opioid misuse. AB - This study employed quantitative sensory testing (QST) to evaluate pain responses in chronic spinal pain patients at low risk and high risk for opioid misuse, with risk classification based on scores on the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Patients were further subgrouped according to current use of prescription opioids. Of the 276 chronic pain patients tested, approximately 65% were taking opioids; a median split was used to further categorize these patients as being on lower or higher doses of opioids. The high risk group (n = 161) reported higher levels of clinical pain, had lower pressure and thermal pain thresholds at multiple body sites, had lower heat pain tolerance, and rated repetitive mechanical stimuli as more painful relative to the low-risk group (n = 115; P's < .01). In contrast, QST measures did not differ across opioid groups. Multiple linear regression analysis suggested that indices of pain-related distress (ie, anxiety and catastrophizing about pain) were also predictive of hyperalgesia, particularly in patients taking opioids. Collectively, regardless of opioid status, the high-risk group was hyperalgesic relative to the low-risk group; future opioid treatment studies may benefit from the classification of opioid risk, and the examination of pain sensitivity and other factors that differentiate high- and low-risk groups. PERSPECTIVE: This study demonstrates that chronic spinal pain patients at high risk for misuse of prescription opioids are more pain-sensitive than low-risk patients, whether or not they are currently taking opioids. Indices of pain-related distress were important predictors of pain sensitivity, particularly among those patients taking opioids for pain. PMID- 21680253 TI - Experimental muscle pain challenges the postural stability during quiet stance and unexpected posture perturbation. AB - Musculoskeletal pain impairs postural control and stability. Nine subjects stood as quietly as possible on a moveable force platform before, during, and after experimental pain in the right leg muscles. A moveable force platform was used to measure the center of pressure and provided unexpected perturbations. Lower limb muscle activity, joint angles, and foot pressure distributions were measured. Hypertonic saline was used to induce pain in the vastus lateralis, vastus medialis, or biceps femoris muscle of the right leg. Compared to baseline and control sessions, pain in the knee extensor muscles during quiet standing evoked: 1) larger sway area, greater medial-lateral center of pressure displacement and higher speed (P < .05); 2) increased sway displacement in the anterior-posterior direction (P < .05); and 3) increased electromyography (EMG) activity for left tibialis anterior and left erector spinae muscles (P < .05). Pain provoked longer time to return to an equilibrium posture after forward EMG activity for, and pain in vastus medialis muscle decreased the time for the maximum hip flexion during this perturbation (P < .05). These results show that muscle pain impairs postural stability during quiet standing and after unexpected perturbation, which suggest that people suffering from leg muscle pain are more vulnerable to falls. PERSPECTIVE: This article presents the acute responses to leg muscle pain on the postural control. This measure could potentially help clinicians who seek to assess how pain responses may contribute to patient's postural control and stability during quiet standing and after recovering from unexpected perturbations. PMID- 21680255 TI - Topographical pressure and thermal pain sensitivity mapping in patients with unilateral lateral epicondylalgia. AB - Our aim was to quantify spatial differences in pressure and thermal pain sensitivity maps between patients with unilateral lateral epicondylalgia (LE) and age- and sex-matched controls. Pressure (PPT), cold (CPT), and heat (HPT) pain thresholds were assessed over 12 points forming a 3 * 4 matrix (4 points in the superior part, 4 points in the middle, and 4 points in the lower part around the lateral epicondyle) bilaterally in 16 subjects with strictly unilateral LE and 16 age- and sex-matched controls in a blinded design. Topographical pain sensitivity maps to pressure and thermal stimulation over the elbow in patients with LE and healthy controls were calculated. A multilevel 3-way ANCOVA test was applied to detect differences in topographical maps between groups. Subjects with LE showed bilateral lower PPT, higher CPT (pain at higher temperature) and lower HPT (pain at lower temperature) at all the measurement points as compared to controls (all, P < .01). PPT were lower at points over the extensor carpi radialis brevis (ECRB) muscle as compared to points over the extensor digitorum communis muscle (P < .01) and over the extensor carpi ulnaris muscle (P < .001). CPT and HPT were not significantly different between points (P > .05). Topographical pressure and thermal pain sensitivity maps revealed bilateral hyperalgesia in patients with strictly unilateral LE. LE patients exhibited heterogeneously distributed pressure pain hyperalgesia while cold or heat maps were homogenous. The most sensitive localizations for PPT assessment corresponded to the muscle belly of the ECRB. Our results confirm the role of ECRB muscle in LE and argue for evidence of peripheral and central sensitization mechanisms in patients with strictly unilateral symptoms. PERSPECTIVE: Topographical pressure and thermal sensitivity maps revealed bilateral hyperalgesia in patients with strictly unilateral lateral epicondylalgia (LE). LE patients exhibited heterogeneously distributed pressure pain hyperalgesia while cold or heat pain maps were homogenous. The most sensitive localizations for PPT assessment corresponded to the muscle belly of the ECRB. PMID- 21680254 TI - Preservation of acute pain and efferent functions following intrathecal resiniferatoxin-induced analgesia in rats. AB - Resiniferatoxin (RTX) is a potent agonist of TRPV1, which possesses unique properties that can be utilized to treat certain modalities of pain. In the present study, systemic intraperitoneal (i.p.) administration of RTX resulted in a significant decrease in acute thermal pain sensitivity, whereas localized intrathecal (i.t.) administration had no effect on acute thermal pain sensitivity. Both i.p. and i.t. administration of RTX prevented TRPV1-induced nocifensive behavior and inflammatory thermal hypersensitivity. There were no alterations in mechanical sensitivity either by i.p. or i.t. administration of RTX. In spinal dorsal horn (L4-L6), TRPV1 and substance P immunoreactivity were abolished following i.p. and i.t. administration of RTX. In dorsal root ganglia (DRG), TRPV1 immunoreactivity was diminished following i.p. administration, but was unaffected following i.t. administration of RTX. Following i.p. administration, basal and evoked calcitonin gene-related peptide release were reduced both in the spinal cord and peripheral tissues. However, following i.t. administration, basal and evoked calcitonin gene-related peptide release were reduced in spinal cord (L4-L6), but were unaffected in peripheral tissues. Both i.p. and i.t. RTX administration lowered the body temperature acutely, but this effect reversed with time. Targeting TRPV1-expressing nerve terminals at the spinal cord can selectively abolish inflammatory thermal hypersensitivity without affecting acute thermal sensitivity and can preserve the efferent functions of DRG neurons at the peripheral nerve terminals. I.t. administration of RTX can be considered as a strategy for treating certain chronic and debilitating pain conditions. PERSPECTIVE: Localized administration of RTX in spinal cord could be a useful strategy to treat chronic debilitating pain arising from certain conditions such as cancer and at the same time could maintain normal physiological peripheral efferent functions mediated by TRPV1. PMID- 21680256 TI - Involvement of spinal neurotrophin-3 in electroacupuncture analgesia and inhibition of spinal glial activation in rat model of monoarthritis. AB - Although electroacupuncture (EA) has been proven to effectively relieve pain associated with arthritis, the underlying mechanism of EA analgesia requires further investigation. Here, the involvement of spinal neurotrophin-3 (NT-3) in EA's analgesic effects on complete Freund's adjuvant (CFA)-induced inflammatory pain was examined. The present study demonstrated that: 1) repeated EA stimulation of ipsilateral GB30 and GB34 acupoints remarkably suppressed CFA induced hyperalgesia; 2) EA treatment markedly enhanced the upregulation of spinal NT-3 mRNA and protein levels following CFA injection; 3) antisense oligodeoxynucleotides (ODN) specifically against NT-3 intrathecally administered during EA treatment for 7 days significantly attenuated the EA analgesia; and 4) the suppressed expression of spinal GFAP (astrocytic marker), OX-42 (microglial marker) as well as proinflammatory cytokines, interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha by EA treatment was significantly attenuated following NT-3 antisense ODN delivery. These results suggested that endogenous NT 3 may be involved in the analgesic effect of EA on inflammatory pain in rats, mediated through the inhibition of spinal glial activity as well as proinflammatory cytokine production. PERSPECTIVE: The present study may initiate a discussion on the possible roles of NT-3/glia/cytokines in the therapeutic effects of acupuncture and provide insight on the mechanism underlie the analgesic effects of acupuncture on pain associated with arthritis. PMID- 21680257 TI - Prevalence of congenital color vision defects in Saudi females of Arab origin. AB - BACKGROUND: Inherited color vision deficiencies (CVD) vary in prevalence by population and by sex. The most common CVD is X chromosome-linked anomalous trichromacy. Prevalence varies significantly by sex and race. The frequency of color vision defects in Saudi females has not been studied previously. This study surveyed the prevalence of congenital color vision defects in Saudi females of Arab origin. METHODS: Seven thousand four hundred sixty-seven female subjects (N = 7,467) from the Kingdom of Saudi Arabia were screened using both Ishihara pseudoisochromatic plates and the Farnsworth Dichotomous test (D-15). CVD subjects were tested further with the Farnsworth-Munsell 100 Hue test. RESULTS: Of 7,467 female subjects tested, 26 subjects were found to have defective color vision, for a prevalence of 0.35%. Sixteen subjects had a deutan defect, and 10 had a protan defect. Arab females have significantly lower prevalence of CVD when compared with published data from females of other races. Analysis of the 5 regions of Saudi Arabia showed no significant difference between the regions. CONCLUSION: Prevalence of CVD among Saudi females of Arab origin is 0.35% and is among the lowest of all published data. PMID- 21680259 TI - Simultaneous measurement of cyclosporin A and tacrolimus from dried blood spots by ultra high performance liquid chromatography tandem mass spectrometry. AB - Cyclosporin A (CsA) and tacrolimus are immunosuppressant drugs principally used in solid organ transplant recipients. Therapeutic drug monitoring (TDM) of both drugs is essential to avoid toxicity related to overdosage, and transplant rejection from underdosage. This necessitates frequent hospital visits to phlebotomy services. Capillary blood sampling onto dried blood spots (DBS) provides numerous advantages to venous whole blood sampling, including the ability for patients to send DBS to the laboratory by post, significantly reducing the number of unnecessary hospital visits. We have developed a novel, simple and rapid method for the extraction and simultaneous UPLC-MS/MS measurement of both CsA and tacrolimus from DBS. The extraction method involved a simple 30 min hot solvent extraction with ultrasonication. Extract (10 MUL) was injected onto a Waters Acquity UPLC column filter unit security frit, coupled to a Waters Acquity BEH C18 UPLC column, with methanolic mobile phase gradient elution. Eluant was connected to a Waters Quattro Premier XE tandem mass spectrometer operating in ES+ mode. We detected multiple reaction monitoring (MRM) transitions of m/z 1220>1203 and 1231.9>1215.1 for CsA and d12 CsA respectively which co-eluted at 1.30min, and 821.6>768.5 and 809.6>756.5 for tacrolimus and ascomycin respectively which co-eluted at 1.17 min. Ion suppression was negligible. Mean recovery was 95.5% for CsA and 92.8% for tacrolimus. Limit of detection and limit of quantitation were both 8.5 MUg/L for CsA, and 0.5 and 2.3 MUg/L respectively for tacrolimus. The assay was linear up to 1500MUg/L for CsA (r(2)=0.9999), and up to 50 MUg/L for tacrolimus (r(2)=0.9994). Mean intra assay imprecision, inter assay imprecision and bias were all <10% for both CsA and tacrolimus. DBS were stable for at least 14 days at room temperature. Comparison of the DBS UPLC-MS/MS method and the routine venous whole blood LC-MS/MS assay demonstrated good agreement between the two methods for both drugs. We have developed a simple and robust method for the extraction and simultaneous measurement of CsA and tacrolimus from DBS. The method will allow TDM of transplant recipients to proceed at home using capillary blood sampling. PMID- 21680260 TI - Simultaneous analysis of amoxicillin and sulbactam in human plasma by HPLC-DAD for assessment of bioequivalence. AB - A simple and accurate high-performance liquid chromatography with diode array detection-based (HPLC-DAD) method has been developed and validated for simultaneous determination of amoxicillin and sulbactam in human plasma. Sample preparation was involved in protein precipitation with acetonitrile followed by one-step extraction procedure. Chromatographic separation was achieved on a C18 column with an isocratic mobile phase consisting of water (containing 30 mM potassium dihydrogen phosphate, pH 2.8) and acetonitrile. The detection wavelengths of a diode array detector were set at 210 nm for amoxicillin and sulbactam, and 263 nm for the internal standard (cefadroxil). The method was validated for linearity, accuracy, precision, and stability. The calibration curve was linear from 0.163 to 14.7 MUg/mL with correlation coefficient squared of 0.9991 for amoxicillin and 0.250-15.0 MUg/mL with correlation coefficient squared of 0.9988 for sulbactam using 500 MUL plasma samples. The lower limit of quantification was 0.163 and 0.250 MUg/mL for amoxicillin and sulbactam, respectively. The imprecisions of intra- and inter-day validations for amoxicillin and sulbactam were <11% and their accuracies (%) were within the range of 95.4-105.7%. Mean recoveries were 75.9, 72.8, and 70.0% for amoxicillin, sulbactam, and cefadroxil, respectively. The established method was successfully applied to a bioequivalence study of two combination formulations of amoxicillin and sulbactam pivoxil in healthy male volunteers. PMID- 21680258 TI - Premature aging and cancer in nucleotide excision repair-disorders. AB - During the past decades, the major impact of DNA damage on cancer as 'disease of the genes' has become abundantly apparent. In addition to cancer, recent years have also uncovered a very strong association of DNA damage with many features of (premature) aging. The notion that DNA repair systems protect not only against cancer but also equally against to fast aging has become evident from a systematic, integral analysis of a variety of mouse mutants carrying defects in e.g. transcription-coupled repair with or without an additional impairment of global genome nucleotide excision repair and the corresponding segmental premature aging syndromes in human. A striking correlation between the degree of the DNA repair deficiency and the acceleration of specific progeroid symptoms has been discovered for those repair systems that primarily protect from the cytotoxic and cytostatic effects of DNA damage. These observations are explained from the perspective of nucleotide excision repair mouse mutant and human syndromes. However, similar principles likely apply to other DNA repair pathways including interstrand crosslink repair and double strand break repair and genome maintenance systems in general, supporting the notion that DNA damage constitutes an important intermediate in the process of aging. PMID- 21680261 TI - Chromatographic diagnosis of maple syrup urine disease by measuring the L alloisoleucine/L-phenylalanine ratio in dried blood spots. AB - A high-performance ligand-exchange chromatography with ultraviolet detection method for confirmation diagnosis of maple syrup urine disease (MSUD) was developed that relies on the determination of branched-chain amino acids (BCAAs) and Phe levels in blood. The dynamic ranges for the BCAAs and Phe were 50-1000 MUM (r(2)=0.9982-0.9996) and 74-873 MUM (r(2)=0.9992) from a dried blood spot, and the BCAA detection limits (S/N=3) were 0.43-1.91 MUM. The mean recoveries of BCAA for intra- and inter-day assays were 92.1-103.0%. The ranges of alloisoleucine (Allo-Ile)/Phe ratio were ND-0.04 and 1.5-2.4 for PKU and MSUD patient samples, respectively. The lowest ratio (1.5) of the MSUD samples was 37.5 times higher than the highest ratio (0.04) of the PKU samples. Therefore, the Allo-Ile/Phe ratio was very useful biomarker for confirmation diagnosis of MSUD. PMID- 21680262 TI - Quantitative determination of hederagenin in rat plasma and cerebrospinal fluid by ultra fast liquid chromatography-tandem mass spectrometry method. AB - A rapid, sensitive and selective method was developed for the quantitative determination of hederagenin in rat plasma and cerebrospinal fluid (CSF) by ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS). It has been successfully applied in a pharmacokinetic study of hederagenin in the central nervous system (CNS). Sample pretreatment involved a simple protein precipitation with methanol and a one-step extraction with ethyl acetate. Separation was carried out in a Shim-pack XR-ODS II (75 mm * 2.0 mm, i.d., 2.1 MUm) column with gradient elution at a flow rate of 0.35 mL/min. The mobile phase was 5mM ammonium acetate and acetonitrile. Detection was performed in a triple-quadruple tandem mass spectrometer by multiple-reaction-monitoring mode via electrospray ionization. A linear calibration curve for hederagenin was obtained over a concentration range of 0.406 (lower limit of quantification, LLOQ) to 203 ng/mL (r2 > 0.99) for both plasma and CSF. The intra-day and inter-day precision (relative standard deviation, RSD) values were less than 15%. At all quality control (QC) levels, the accuracy (relative error, RE) was within -9.0% and 11.1% for plasma and CSF, respectively. The pharmacokinetics results indicated that hederagenin could pass through the blood-brain barrier. This UFLC-MS/MS method demonstrates higher sensitivity and sample throughput than previous methods. It was also successfully applied to the pharmacokinetic study of hederagenin following oral administration of Fructus akebiae extract in rats. PMID- 21680263 TI - Determination of micafungin and anidulafungin in human plasma: UV- or mass spectrometric quantification? AB - Micafungin and anidulafungin are two newer antifungal drugs from the echinocandine class. They are used as monotherapy or in combination with azole antifungal drugs. The optimized clinical treatment course for the echinocandin drugs with regard to the different infection types and patient subgroups (renal or hepatic impairment, overweight) is still under debate. Therefore, an easy and rugged assay for these two drugs is highly desirable. We here present a method for the quantification of micafungin or anidulafungin in human plasma, applying protein precipitation as sample preparation, reversed phase separation of the analytes and UV-detection and simultaneous tandem mass spectrometry. Anidulafungin served as I.S. for micafungin quantification and vice versa. The method was validated in the calibration ranges from 0.1 MUg/ml to 20 MUg/ml for both substances. Intra-day precision and accuracies recorded with the UV-detector were 1.80% and 2.65% for micafungin and 4.30% and 10.44% for anidulafungin at the 0.1 MUg/ml level. The respective data at the 1 MUg/ml level were 2.25% and -0.83% for micafungin and 4.35% and -1.85% for anidulafungin and at the 20 MUg/ml level 0.97% and -2.98% for micafungin and 1.04% and 4.74% for anidulafungin, respectively. With the mass spectrometer, because of the unique properties of the analyte molecules, no acceptable validation results could be achieved. Therefore, the mass spectrometric chromatograms served only as identity confirmation of the observed UV-peaks. PMID- 21680264 TI - Developing a robust ultrafiltration-LC-MS/MS method for quantitative analysis of unbound vadimezan (ASA404) in human plasma. AB - Ultrafiltration of human plasma in combination with LC-MS/MS has been increasingly used in the quantitative analysis of the free fraction of drug candidates for PK/efficacy assessment. In addition to controlling the pre incubation and centrifugation temperatures, some important factors that must be investigated and addressed include: (1) possible nonspecific binding, (2) possible impact of freeze/thaw cycles of plasma samples and extended storage of plasma samples at room temperature on the analyte recovery prior to ultrafiltration, and (3) identification of the appropriate assay dynamic range to avoid unnecessary dilutions. These factors were explored in the development and validation of a robust LC-MS/MS assay for the quantitative analysis of unbound vadimezan (ASA404) in human plasma. First, to mimic human physiological conditions, all plasma samples were incubated at ~37 degrees C for a minimum of 30 min after thawing and prior to centrifugation to obtain the ultrafiltrate. Second, by passing the calibration standards and QC samples in plasma ultrafiltrate through the ultrafiltration membrane, the observed non-specific binding of the analyte due to the membrane was corrected. Third, the effects of multiple freeze/thaw cycles and/or storage at room temperature for various periods (4, 8, 16 and 24h) were evaluated to determine the impact on analyte concentrations in the ultrafiltrate from the plasma QC samples. Fourth, the appropriate dynamic range was established to accommodate the expected incurred sample free analyte concentrations. The validated assay has a dynamic range of 30.0-30,000 ng/ml for ASA404 in human plasma ultrafiltrate using a sample volume of 30 MUl. Quality control pools containing the analyte were prepared at concentrations of 30.0-22,500 ng/ml to cover the assay calibration range. The intra-assay and inter-assay precision and accuracy were <= 15% (CV) and within +/ 15% (bias) of the nominal values, respectively, for all measured QC concentrations, including the LLOQ. Freeze/thaw for up to three cycles of the plasma samples and/or the extended human plasma sample exposure to room temperature for up to 24h were confirmed to have no impact on the assay results for the free analyte. The validated method was successfully implemented to support clinical studies for the compound. PMID- 21680265 TI - Analyte and internal standard cross signal contributions and their impact on quantitation in LC-MS based bioanalysis. AB - Cross signal contributions between an analyte and its internal standard (IS) are very common due to impurities in reference standards and/or isotopic interferences. Despite the general awareness of this issue, how exactly they affect quantitation in LC-MS based bioanalysis has not been systematically evaluated. In this research, such evaluations were performed first by simulations and then by experiments using a typical bioanalytical method for tiagabine over the concentration range of 1-1000 ng/mL in human EDTA K(3) plasma. The results demonstrate that when an analyte contributes to IS signal, linearity and accuracy can be affected with low IS concentration. Thus, minimum IS concentrations have been obtained for different combinations of concentration range, percentage of cross contribution, and weighting factor. Moreover, while impurity in analyte reference standard is a factor in cross signal contribution, significant systematic errors could exist in the results of unknown samples even though the results of calibration standards and quality controls are acceptable. How these systematic errors would affect stability evaluation, method transfer, and cross validation has also been discussed and measures to reduce their impact are proposed. On the other hand, the signal contribution from an IS to the analyte causes shifting of a calibration curve, i.e. increase of intercept, and theoretically, the accuracy is not affected. The simulation results are well supported by experimental results. For example, good inter-run (between-run) accuracy (bias: -2.70 to 5.35%) and precision (CV: 2.07-10.50%) were obtained when runs were extracted with an IS solution containing 1-fold of the lower limit of quantitation. PMID- 21680266 TI - Screening and quantitation of multiclass drugs of abuse and pharmaceuticals in hair by fast liquid chromatography electrospray time-of-flight mass spectrometry. AB - In this work, an automated screening method for the simultaneous identification and quantitation of 30 representative multiclass drugs (including opiates, cocaine and its main metabolite, cannabinoids, amphetamines and other stimulants in hair samples) has been developed using fast liquid-chromatography time-of flight mass spectrometry (LC-TOFMS). The identification and quantitation of the drugs were carried out by liquid chromatography using a C(18) column (4.6*50 mm) with 1.8 MUm particle size. Accurate mass measurements of ions of interest (typically [M+H](+)) by electrospray time-of-flight mass spectrometry in the positive ionization mode were used for unambiguous confirmation of the targeted species. Three sample preparation methodologies were evaluated: (a) direct methanolic extraction by sonication, (b) acidic extraction, and (c) alkaline digestion. Direct methanolic extraction showed better recoveries and cleaner extracts. The limits of detection obtained in hair matrix were as low as 5 pg mg( 1) for cocaine and cannabidiol, ranging from 5 to 75 pg mg(-1) for the studied species while the LOQ ranged from 15 to 250 pg mg(-1). The method has been applied to six hair samples from drug consumer volunteers, where the presence of at least one drug was confirmed by accurate mass measurements within 2 ppm (mass error) in most cases. The present study demonstrates the usefulness of LC-TOFMS for both screening and quantitation purposes in drug testing in hair. In addition, the possibility of non-target or a posteriori data analysis of samples or the extension of the procedure for testing for additional compounds offers interesting features for forensic analysis. PMID- 21680267 TI - A natural inactivating mutant of human glucagon receptor exhibits multiple abnormalities in processing and signaling. AB - BACKGROUND AND AIM: To elucidate the pathogenetic mechanisms of a mutant P86S glucagon receptor (GCGR) in causing a novel human disease (Mahvash disease). MATERIAL AND METHOD: Enhanced green fluorescent protein (EGFP)-tagged WT and P86S GCGR were expressed in HEK 293 or H1299 cells either transiently or stably. Receptor localization and internalization, and cell apoptosis were studied by fluorescence microscopy, and calcium signaling by Rhod-3 labeling. Gene expression was assayed by RT-PCR or Western blot. Cell fate was determined by live cell imaging. RESULTS: Unlike WT GCGR, P86S was partially localized to the plasma membrane and partially in the cytoplasm as previously reported and did not undergo internalization upon glucagon treatment. P86S did not elicit calcium response after treatment with 1 MUM glucagon. Cells transiently expressing P86S exhibited more apoptosis than those expressing WT GCGR (18.3% vs 2.1%, P<0.05) but the X-box binding protein 1 mRNA cleavage, a marker of endoplasmic reticulum (ER) stress, was not evident, suggesting that the apoptosis did not result from ER stress. Cells stably expressing P86S did not exhibit apoptosis and a quarter of them harbored a novel inclusion body-like circular structure that was marked by P86S and ER residential proteins. These circular ER bodies were not seen in cells expressing WT GCGR or transiently expressing P86S and were not affected by treatment with proteasome inhibitor or microtubule depolymerizer, suggesting that they do not represent aggresome structures. The circular ER bodies could fuse and split to form new bodies. CONCLUSION: The naturally-occurring P86S mutant GCGR exhibits abnormal receptor internalization and calcium mobilization, and causes apoptosis. The novel dynamic circular ER bodies may be adaptive in nature to nullify the toxic effects on P86S. These findings provide further insights into the pathogenetic mechanisms of Mahvash disease. PMID- 21680268 TI - Prevalence and clinical significance of pancreatic cysts associated with cysts in other organs. AB - BACKGROUND AND AIM: Von Hippel-Lindau disease is associated with serous cysts in the pancreas and kidneys. In this study we determined the prevalence of pancreatic cysts occurring concurrently with other abdominal cysts and tested the hypothesis that these patients might represent a forme fruste of Von Hippel Lindau disease and be more likely to be serous cysts. METHODS: A retrospective chart review of patients undergoing endoscopic ultrasound of pancreatic cysts. RESULTS: A total of 156 patients were included in the study. Eighty-five patients (54.8%) had cyst(s) in the pancreas and at least one other intra-abdominal cyst. These cysts included 24 (27.9%) serous cysts, 30 (34.9%), mucinous cysts, 6 (7%) adenocarcinoma and 25 (29.4%) unknowns. Seventy-one patients (45.2%) had isolated pancreatic cysts. These included 17 (23.9%) serous cysts, 28 (39.5%) mucinous cysts, 4 (5.6%) adenocarcinoma and 22 (31%) unknowns. The odds of serous cysts with concurrent extra-pancreatic and pancreatic cysts compared to odds of serous cysts with pancreatic cysts alone were 1.3 (95% CI: 0.6-2.9). CONCLUSIONS: Pancreatic cysts are associated with cysts in other abdominal organs in 54.8% patients. The prevalence of serous cysts was not higher amongst individuals with multiple organ cysts compared to those with only pancreatic cysts. PMID- 21680269 TI - [Pamidronate: a therapeutic alternative in chronic recurrent mutifocal osteomyelitis]. PMID- 21680270 TI - Mitochondrial hepatopathies in the newborn period. AB - Mitochondrial disorders recognized in the neonatal period usually present as a metabolic crisis combined with one or several organ manifestations. Liver disorder in association with a respiratory chain deficiency may be overlooked since liver dysfunction is common in severely sick newborn infants. Lactacidosis, hypoglycemia, elevated serum transaminases and conjugated bilirubin are common signs of mitochondrial hepatopathy. Hepatosplenomegaly may occur in severe cases. A clinical picture with fetal growth restriction, postnatal lactacidosis, hypoglycemia, coagulopathy, and cholestasis, especially in combination with neurological symptoms or renal tubulopathy, should alert the neonatologist to direct investigations on mitochondrial disorder. A normal lactate level does not exclude respiratory chain defects. The most common liver manifestation caused by mutated mitochondrial DNA (deletion) is Pearson syndrome. Recently, mutations in several nuclear DNA genes have been identified that lead to mitochondrial hepatopathy, e.g. mitochondrial depletion syndrome caused by DGUOK, MPV17, SUCLG1, POLG1, or C10ORF2 mutations. A combination of lactacidosis, liver involvement, and Fanconi type renal tubulopathy is common when the complex III assembly factor BCS1L harbors mutations, the most severe disease with consistent genotype-phenotype correlation being the GRACILE syndrome. Mutations in nuclear translation factor genes (TRMU, EFG1, and EFTu) of the respiratory chain enzyme complexes have recently been identified. Diagnostic work-up of neonatal liver disorder should include assessment of function and structure of the complexes as well as mutation screening for known genes. So far, treatment is mainly symptomatic. PMID- 21680272 TI - Eyebrow composite graft for eyelash reconstruction: a case report and review of the literature. AB - Reconstructing the eyelash margin is a challenge for plastic surgeons because eyelashes have specific characteristics. There is still no gold standard procedure for this type of reconstruction, which seeks to protect the eyeball and make the eyelid appear natural. The eyebrow composite graft can be a good option for reconstructing the eyelash margin because it is technically simple and safe, and takes advantage of the structural similarity between the eyelashes and eyebrow. The results presented showed the effectiveness of the technique by providing improved occlusion and a good aesthetic result. PMID- 21680271 TI - Mitochondrial disorders caused by mutations in respiratory chain assembly factors. AB - Mitochondrial diseases involve the dysfunction of the oxidative phosphorylation (OXPHOS) system. This group of diseases presents with heterogeneous clinical symptoms affecting mainly organs with high energy demands. Defects in the multimeric complexes comprising the OXPHOS system have a dual genetic origin, mitochondrial or nuclear DNA. Although many nuclear DNA mutations involve genes coding for subunits of the respiratory complexes, the majority of mutations found to date affect factors that do not form part of the final complexes. These assembly factors or chaperones have multiple functions ranging from cofactor insertion to proper assembly/stability of the complexes. Although significant progress has been made in the last few years in the discovery of new assembly factors, the function of many remains elusive. Here, we describe assembly factors or chaperones that are required for respiratory chain complex assembly and their clinical relevance. PMID- 21680273 TI - MtDNA typing of single-sperm cells isolated by micromanipulation. AB - Some sexual assault crimes constitute a problem for the legal institutions confronted with the DNA analysis of such cases. Often, sperm cells are found in the victim's vaginal tract during medical examination but their successful genotyping is compromised by the huge excess of the victim's epithelial cells as well as by the degradation of genomic DNA present in sperm cells as a consequence of female immune response. Mitochondrial DNA present in the mid-piece of sperm cells might be useful in some specific cases in order to differentiate the donors of a semen sample. The high number of copies per cell and its circular nature that may confer some protection from the action of exonucleases make it more suitable for cases where few cells are available and/or the DNA is degraded. We have developed a novel strategy for typing mtDNA from single-sperm cells. Specific amplification of male mitochondrial DNA is ensured by use of sequence specific primers designed on the basis of mitochondrial single nucleotide polymorphisms existent throughout the control region. The strategy was applied to single-sperm cells isolated by micromanipulation from slides smeared with vaginal swabs taken immediately after sexual intercourse of voluntary couples. After sequencing the PCR products, it was possible to obtain a match between the DNA sequence from the buccal swab and the DNA sequence of the single sperm-cell, for each voluntary man. With this new strategy, the problem of contamination with DNA from the victim observed when using universal primers was completely overtaken. This method will probably allow the resolution of multiple-rapist crimes, where the collected sperm cells can be separately typed. PMID- 21680274 TI - Prevalence and persistence of foreign DNA beneath fingernails. AB - Fingernail scrapings and clippings are routinely examined for the presence of foreign DNA profiles in forensic casework where the case history suggests their evidentiary relevance. In order to better understand the significance of these findings, casework results from the Centre of Forensic Sciences (CFS) were analyzed and several controlled studies were conducted. In an analysis of casework data (n=265), 33% of fingernail samples contained a foreign source of DNA, 63% of which were detected at 5 or more STR loci. In a sampling of fingernails from the general population (n=178), 19% contained a foreign source of DNA, 35% of which were detected at 5 or more STR loci. In a study involving deliberate scratching of another individual (n=30), 33% of individuals had a foreign DNA profile beneath their fingernails from which the person they scratched could not be excluded as the source; however when sampling occurred ~ 6 h after the scratching event, only 7% retained the foreign DNA. This research suggests the incidence of foreign DNA profiles beneath fingernails in the general population is low but, when present, the majority is of limited significance and tends not to persist for an extensive period of time. These data are provided to assist the forensic analyst when providing his or her opinion as to the relevance of foreign DNA present under fingernails. PMID- 21680275 TI - De Quervain's disease treatment using partial resection of the extensor retinaculum: A short-term results survey. AB - BACKGROUND: Several operative methods have been described for de Quervain's disease, but no definite consensus has emerged in the literature. Sometimes simple release of the extensor retinaculum can cause incomplete relief, whereas re-adhesion and excessive excision of the extensor retinaculum can cause volar subluxation of the abductor pollicis longus and extensor pollicis brevis tendons. In this prospective study, we evaluated the early results of operative treatment with one-quarter partial resection of the extensor retinaculum when conservative methods have failed. HYPOTHESIS: We hypothesized that partial removal of the extensor retinaculum may be used as an alternative to solve problems such as incomplete release or re-adhesion and volar subluxation of the tendons. PATIENTS AND METHODS: Thirty-four patients (36 hands; 30 females and four males; mean age: 48.2 years; range: 20 to 75 years) with de Quervain's disease were surgically treated. The surgical procedure was performed under local infiltration anesthesia. One-quarter partial resection of the extensor retinaculum on the dorsal side of the wrist was performed. During the clinical follow-up period, treatment results, a patient-based scoring system and visual analogue scale were used. The mean follow-up duration was 23.7 months (range: 12 to 71 months). RESULTS: Two patients with wound infections were treated with adapted antibiotics. All patients were relieved of their symptoms; no triggering, recurrence or volar subluxation of the tendons of abductor pollicis longus or extensor pollicis brevis occurred. With this partial resection technique and according to a treatment scoring system described by Sawaizumi et al., 23 hands had excellent results, 11 hands had good results, and two hands had fair results; no hand exhibited a poor result. The mean visual analogue scale score was 1.8 (range: 0-6). DISCUSSION: Our results showed that one-quarter partial resection of the extensor retinaculum on the dorsal side of the wrist can be safely used for the operative treatment of de Quervain's disease with satisfactory short-term clinical results and no serious complications. LEVEL OF EVIDENCE: Level IV: low power prospective study. PMID- 21680276 TI - Mini-invasive vaginal hysterectomy with thermo-fusion hemostasis. PMID- 21680277 TI - Helicobacter pylori infection in asymptomatic HBV carriers, alcohol users and normal adult population in Shandong Province, China. AB - OBJECTIVE: The purpose of this study was to investigate the prevalence of Helicobacter pylori (H. pylori) in asymptomatic HBV carriers (ASCs), alcohol users and in the normal adult population in the littoral region of Shandong, China. METHODS: Two hundred and thirty-five ASCs, 573 alcohol users and 1637 nonalcoholic normal adults were recruited from January 2008 to June 2010. The H. pylori infection status of all participants was measured by serum immunoglobulin G antibodies using ELISA and (13)C-urea breath test (UBT). RESULTS: The prevalence of H. pylori infection in ASCs was 38.67%, which was not different than that in the normal adult population (35.94%, P=0.352). H. pylori infection (26.98%) was decreased in alcohol users with normal liver function tests compared to that in the normal adult population (P=0.014). Meanwhile, H. pylori infection was increased to 35.20% in alcohol users with abnormal liver function tests, which was significantly different compared with that of alcohol users with normal liver function tests (P=0.042). CONCLUSION: The epidemiological pattern of H. pylori infection in ASCs is the same as in the normal adult population, and moderate consumption may facilitate elimination of H. pylori infection in alcohol users while H. pylori infection is increased in alcohol users with abnormal liver function tests. PMID- 21680279 TI - Mapping of specific sentinel node locations for skin cancer of the head. AB - In current dermatological practice lymphatic mapping and sentinel lymph node biopsy (SLNB) are frequently used in patients with cutaneous cancers, like malignant melanoma, squamous cell carcinoma and Merkel cell carcinoma. However, those tumors are often located on the head and neck, regions with notoriously variable lymphatic drainage patterns. Consequently, the incidence of successful SLNB in the head and neck is considerably lower compared to the SLNB on the trunk and extremities. Thus, there is a need to improve the hit rate of SLNB in this special area. Therefore, in the current study we analyzed SLNB of 149 patients treated for cutaneous tumors at the Department of Dermatology, University of Tuebingen, Germany. By mapping SLN (sentinel lymph node) locations to their specific tumor sites on the head and neck, we were able to calculate the frequency of SLN distribution to defined tumor locations. Furthermore, our analysis revealed that approximately 7% of tumors on the head and neck drain to contralateral SLN, which is of relevance for the classification in the current cancer TNM system. Thus, our mapping can predict SLN location in patients with cutaneous head and neck tumors and might help to further increase the rate of successful SLNB. PMID- 21680278 TI - Developing a bidirectional academic-community partnership with an Appalachian American community for environmental health research and risk communication. AB - BACKGROUND: Marietta, Ohio, is an Appalachian-American community whose residents have long struggled with understanding their exposure to airborne manganese (Mn). Although community engagement in research is strongly endorsed by the National Institutes of Health and the National Institute of Environmental Health Sciences in particular, little has been documented demonstrating how an academic-community partnership that implements the community-based participatory research (CBPR) principles can be created and mobilized for research. OBJECTIVES: We created a bidirectional, academic-community partnership with an Appalachian-American community to a) identify the community's thoughts and perceptions about local air quality, its effect on health, and the perception of risk communication sources and b) jointly develop and conduct environmental health research. METHODS: We formed a community advisory board (CAB), jointly conducted pilot research studies, and used the results to develop a community-driven research agenda. RESULTS: Persons in the community were "very concerned" to "concerned" about local air quality (91%) and perceived the air quality to have a direct impact on their health and on their children's health (93% and 94%, respectively). The CAB identified the primary research question: "Does Mn affect the cognition and behavior of children?" Although the community members perceived research scientists as the most trusted and knowledgeable regarding risks from industrial emissions, they received very little risk information from research scientists. CONCLUSIONS: Engaging a community in environmental health research from its onset enhanced the quality and relevance of the research investigation. The CBPR principles were a useful framework in building a strong academic-community partnership. Because of the current disconnect between communities and research scientists, academic researchers should consider working collaboratively with community-based risk communication sources. PMID- 21680280 TI - Dermoscopic features in disseminated superficial actinic porokeratosis. PMID- 21680281 TI - Two children with a mild or moderate piebaldism phenotype and a father without leukoderma in a family with the same recurrent missense mutation in the kinase domain of KIT. PMID- 21680282 TI - Stevens-Johnson syndrome triggered by seasonal influenza vaccination and flucloxacillin: a pathogenetic hypothesis. PMID- 21680283 TI - Erythrodermic psoriasis complicated by acute respiratory distress syndrome. PMID- 21680284 TI - Localized pemphigus foliaceus exclusively involving the follicular infundibulum: a novel peau d'orange appearance. AB - Localized pemphigus foliaceus (PF) clinically presents as red plaques with scale and crust due to acantholysis of the epidermis. The follicular infundibulum shows acantholysis, but usually with epidermal acantholysis or at least erosion. Localized PF exclusively involving the follicular infundibulum, which shows a peau d'orange appearance, has never been reported. We describe a patient with a red plaque and peau d'orange appearance on the cheek for 20 years. Dyskeratotic acantholysis in the follicular infundibulum was overlooked when the first biopsy specimen was obtained, and a disseminated lesion developed soon after, which led to the diagnosis. Although a peau d'orange appearance is a rare clinical manifestation of PF, PF should be considered as the differential diagnosis on the basis of this appearance, especially when the lesion persists on the face for long periods. PMID- 21680285 TI - CD4+ CD25+ T-regulatory cells in psoriasis. Correlation between their numbers and biologics-induced clinical improvement. AB - BACKGROUND: Regulatory T-cells (T-reg) play a central role in the immunopathogenesis of psoriasis. T-reg cells are both functionally and numerically impaired in psoriasis and they are up-regulated by drug therapy. OBJECTIVE: To analyse the circulating CD4+CD25 bright FOXP3+ subset in 14 patients with vulgaris/arthropathic psoriasis treated with biological drugs and to investigate their relationship with the clinical response. METHODS: The CD4+ CD25 bright FOXP3+ expression was determined in peripheral blood by flow cytometry at baseline and during treatment. RESULTS: A response was obtained in 10/14 patients with increased CD4+ CD25 bright FOXP3+ (T-reg) in peripheral blood after the first month and then 4 months after therapy with biological drugs. This increase is associated with the achievement of a clinical response and with a reduction in the Psoriasis Activity and Severity Index (PASI) score. 2/14 patients showed a decrease in T-reg after drug therapy and this decrease correlated with a worsening of the clinical skin. CONCLUSION: Biological drugs induce circulating T-reg up-regulation in psoriatic patients; such an increase is an early predictive marker of clinical response. PMID- 21680286 TI - Construction and evaluation of a multidimensional score to assess varicose vein severity - the Homburg Varicose Vein Severity Score (HVVSS). AB - To evaluate a novel score (HVVSS) for varicose vein patients combining subjective symptoms, clinical findings and functional data of venous insufficiency. 91 patients (118 legs) with primary varicose veins of the great, small or accessory anterior saphenous vein were treated with conventional surgery. HVVSS was assessed pre- and 3 months postoperatively. The data were compared with established clinical and disease-related life quality scores (VCSS, AVVQ, CIVIQ). Test responsiveness, validity and reliability were determined using correlations with CEAP stage and venous refilling time as hemodynamic parameter, and inter observer variability was assessed. All scores were highly responsive to varicose vein surgery (p<0.001). HVVSS(0-100) decreased from 34.1 +/- 13.0 to 9.6 +/- 6.9 postoperatively. The relative score change of HVVSS was superior to VCSS (69.5% vs. 58.8%, p=0.005). HVVSS revealed highly significant correlations with the clinical CEAP stage and was exclusively able to differentiate mild from severe disease as defined by venous refilling time (p=0.009). Inter-observer reliability of HVVSS was confirmed by correlation coefficients of 0.977 and 0.950 pre- and postoperatively (p<0.001). HVVSS is a suitable and reliable tool to assess disease severity in varicose vein patients and to quantify therapeutic effects of varicose vein treatment. PMID- 21680287 TI - CD8-positive primary cutaneous anaplastic large cell lymphoma presenting as multiple scrotal nodules and plaques. PMID- 21680288 TI - Increased expression of cellular FLICE/caspase-8 inhibitory protein in condyloma acuminatum. AB - Condyloma acuminatum (CA) is a benign epithelial tumor caused by infection with human papillomaviruses (HPVs) and characterized by abnormal cell proliferation. Cellular caspase-8 (FLICE)-like inhibitory protein (c-FLIP) was originally identified as an inhibitor of death-receptor signaling through competition with caspase-8 for recruitment to FAS-associated via death domain (FADD). More recently, it has been determined that c-FLIP is associated with the survival and proliferation of T cells and keratinocytes. The aim of this work was to study the expression of c-FLIP in CA and its relationship with keratinocyte proliferation. Immunoperoxidase staining methods were applied to analyze the location and expressions of both c-FLIP and proliferating cell nuclear antigens (PCNA) in 34 CA and 16 normal foreskin tissues. Semiquantitative reverse transcriptase polymerase chain reactions (RT-PCR) and western blotting were performed to further identify the expression of c-FLIP in CA. c-FLIP expression at both mRNA and protein level was significantly higher in CA than normal foreskin. c-FLIP expression was highly correlated with the PCNA labeling index (LI) in CA. We concluded that c-FLIP overexpression might take part in keratinocyte proliferation in CA. PMID- 21680289 TI - Aggregation of melanocytic nevi on the paralyzed leg of a patient with poliomyelitis. PMID- 21680290 TI - Absence of the trichodysplasia spinulosa-associated polyomavirus in human pilomatricomas. PMID- 21680291 TI - Oral alitretinoin in chronic refractory hand eczema: a "real life" case-series of 12 patients. PMID- 21680292 TI - Orlistat and obesity: be aware of lichenoid drug eruption. PMID- 21680293 TI - Oxaliplatin, colorectal cancer and predictive factors. PMID- 21680294 TI - The importance of the White Book of Radiation Oncology. PMID- 21680295 TI - microRNAs as novel epigenetic biomarkers for human cancer. AB - MicroRNAs (miRNAs) are regulatory, non-coding RNAs that are approximately 22 nucleotides in length. Nearly 1000 unique miRNAs encoded in the human genome have been identified, shedding new light on the posttranscriptional regulation of more than one-third of human genes. These miRNAs are involved in numerous biological processes, including development, differentiation, apoptosis, homeostasis and stem cell biology. Aberrant miRNA expression patterns also play a substantial role in carcinogenesis. It is believed that genetic and epigenetic regulation is responsible for changes in miRNA expression in cancer development, however the exact mechanisms remain unclear. miRNAs are involved in almost all aspects of cancer biology such as apoptosis, invasion, metastasis and angiogenesis. Thanks to this wide range of biological functions, the analysis of changes in overall miRNA expression occurring within human tumours has helped identify miRNA signatures associated with diagnosis, staging, progression, prognosis and response to treatment. This positions miRNA- targeting therapeutics as a novel and promising tool for cancer treatment. PMID- 21680296 TI - Metformin: a new option in cancer treatment. AB - Metformin is a biguanine, the most widely used antidiabetic drug for the treatment of type 2 diabetes. Some studies suggest that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients. Metformin activates the AMP-activated protein kinase (AMPK) pathway, a major sensor of the energy status of the cell and an inhibitor of mammalian target of rapamycin (mTOR) catalytic activity, inducing a decrease in blood glucose by decreasing hepatic gluconeogenesis and stimulating glucose uptake in the muscle. Some preclinical data supports the inhibition of tumour cancer cell growth associated with mTOR inhibition and a decrease in phosphorylation of S6K, rpS6 and 4E-BP1. Here we have summarised some of the preclinical data and data of many clinical trials that are exploring the true value of metformin for cancer patients, mainly breast and prostate cancer. PMID- 21680298 TI - Current opinion in cervix carcinoma. AB - We review the current status of the conventional therapeutical approaches of cervix carcinoma. Radical hysterectomy remains as the main stone in early stages and play an important role in relapses. Radiotherapy plays an important role in early and advance disease. New techniques and image expand indications and treatment possibilities. Chemotherapy platinum based with radiation therapy goes on being the standard treatment in advanced tumours or non surgical candidates. New systemic strategies are being explored in clinical trials. PMID- 21680297 TI - PET-CT in the staging and treatment of non-small-cell lung cancer. AB - Positron emission tomography with 2-((18)F)-fluoro- 2-deoxy-D-glucose (FDG-PET) is a metabolic imaging technique. FDG-PET is more accurate than CT for the evaluation of mediastinal involvement in patients with nonsmall- cell lung cancer, offering a high negative predictive value. It can detect occult metastases in 11% of patients, although the etiology of the extrathoracic isolated uptakes needs confirmation. Theoretically, FDG-PET can influence the planning volume for radiotherapy, primarily in patients with atelectasis. Quantification of metabolic activity using FDG-PET is influenced by the size of the lesion, glucose levels and the time elapsed since the isotope injection. More clinical trials are required to standardize the methods for performing PET, assess its use as a prognostic factor and for the evaluation of treatment response. PMID- 21680299 TI - The white book of radiation oncology in Spain. AB - The White Book of Radiation Oncology provides a comprehensive overview of the current state of the speciality of radiation oncology in Spain and is intended to be used as a reference for physicians, health care administrators and hospital managers. The present paper summarises the most relevant aspects of the book's 13 chapters in order to bring the message to a wider audience. Among the topics discussed are the epidemiology of cancer in Spain, the role of the radiation oncologist in cancer care, human and material resource needs, new technologies, training of specialists, clinical and cost management, clinical practice, quality control, radiological protection, ethics, relevant legislation, research & development, the history of radiation oncology in Spain and the origins of the Spanish Society of Radiation Oncology (SEOR). PMID- 21680300 TI - The prognostic value of hTERT expression levels in advanced-stage colorectal cancer patients: a comparison between tissue and serum expression. AB - AIM: Telomeres are regions of highly repetitive, non-coding DNA located at the termini of chromosomes whose principal function is to maintain the structural stability of these ends. In 90% of human tumours, telomere length is maintained by the expression and activation of telomerase reverse transcriptase. Various studies have demonstrated an increase in telomerase activity in tumour tissue, which suggests its possible prognostic value. The main objective of our study was to study the prognostic value of the expression level of telomerase catalytic component (hTERT) in patients with colorectal cancer (CRC). METHODS: We analysed the prognostic value of the ratio of telomerase expression in tumour tissue to telomerase expression in the adjacent healthy mucosa and the prognostic value of the expression level of hTERT in the serum of patients diagnosed with CRC. As secondary objectives of the study, we (1) analysed the correlation between telomerase expression in the serum and that in the tumour tissue and (2) analysed the relationship between telomerase expression and different clinical parameters. RESULTS: Peripheral blood and tissue samples taken from 48 patients with CRC were analysed. No significant differences were observed in disease-free survival (DFS) or overall survival time (OST) between the groups of patients categorised based on the ratio of telomerase expression between tumour tissue and healthy tissue. The correlation index (Pearson's coefficient) between telomerase levels in the serum and those in tissue was 0.32. Our study of the relationship between telomerase levels in the serum and different clinical variables, such as tumour size, ganglion affectation, preoperative carcinoembryonic antigen levels and stage, revealed a higher telomerase expression level in patients with stage IV CRC. There was no significant association between telomerase expression in tumour tissue and the clinical parameters analysed. CONCLUSIONS: The results obtained in our study do not allow us to propose that the level of telomerase expression be used as a prognostic factor in colorectal cancer. Thus, we cannot consider telomerase expression in the serum as a surrogate marker of its expression in tumour tissue. PMID- 21680301 TI - The EORTC information questionnaire, EORTC QLQ-INFO25. Validation study for Spanish patients. AB - INTRODUCTION: The EORTC QLQ-INFO25 evaluates the information received by cancer patients. This study assesses the psychometric properties of the QLQ-INFO25 when applied to a sample of Spanish patients. MATERIALS AND METHODS: A total of 169 patients with different cancers and stages of disease completed the EORTC QLQINFO25, the EORTC QLQ-C30 and the information scales of the inpatient satisfaction module EORTC IN-PATSAT32 on two occasions during the patients' treatment and follow- up period. Psychometric evaluation of the structure, reliability, validity and responsiveness to changes was conducted. Patient acceptability was assessed with a debriefing questionnaire. RESULTS: Multi-trait scaling confirmed the 4 multi-item scales (information about disease, medical tests, treatment and other services) and eight single items. All items met the standards for convergent validity and all except one met the standards of item discriminant validity. Internal consistency for all scales (alpha>0.70) and the whole questionnaire (alpha>0.90) was adequate in the three measurements, except information about the disease (0.67) and other services (0.68) in the first measurement, as was test-retest reliability (intraclass correlations >0.70). Correlations with related areas of IN-PATSAT32 (r>0.40) supported convergent validity. Divergent validity was confirmed through low correlations with EORTC QLQ-C30 scales (r<0.30). The EORTC QLQ-INFO-25 discriminated among groups based on gender, age, education, levels of anxiety and depression, treatment line, wish for information and satisfaction. One scale and an item showed changes over time. CONCLUSIONS: The EORTC QLQ-INFO 25 is a reliable and valid instrument when applied to a sample of Spanish cancer patients. These results are in line with those of the EORTC validation study. PMID- 21680302 TI - Phase II clinical trial with gemcitabine and paclitaxel sequential monotherapy as first-line treatment for advanced non-small-cell lung cancer (SLCG 01-04). AB - BACKGROUND: In advanced-stage (IIIB or IV) non-small-cell lung cancer (NSCLC), combination chemotherapy has demonstrated response rates of 20% and a 1-year survival rate of 30%. We conducted a multicentre, open-label, nonrandomised phase II trial to determine the efficacy and tolerability of sequential monotherapy with gemcitabine followed by paclitaxel in chemotherapy-naive patients with advanced NSCLC. MATERIALS AND METHODS: Between December 2002 and July 2004, the Spanish Lung Cancer Group (SLCG) conducted a study in which 34 patients with advanced (stage IIIB or IV) NSCLC received 1200 mg/m(2) of i.v. gemcitabine on days 1, 8 and 15 of each 28-day cycle for a total of 3 cycles followed by 100 mg/m(2) of weekly i.v. paclitaxel for a maximum of 8 weeks. If objective response or stable disease was achieved, 70 mg/m(2) of weekly i.v. paclitaxel was maintained until disease progression was evident or toxic effects were intolerable. Lung Cancer Symptom Scale (LCSS) analysis was performed. Baseline levels of serum VEGF, EGFR, telomerase reverse transcriptase (hTERT) and K-ras mutations were analysed. The primary endpoint was the objective response rate. RESULTS: The median age of the 34 patients who were enrolled was 67 years (range 46-77), but later 8 patients were excluded; 78.8% were men, 81.8% had performance status 1 and also 81.8% had metastatic disease at diagnosis. The objective response rate was 28% (95% CI, 14.2-47.8); the median overall survival was 7.2 months (95% CI, 2.1-12.3) and the median time to progression (TTP) was 3.1 months (95% CI, 2.5-5.3). Grade 3 or 4 drug-related haematological toxicities were observed in 6 patients. Patients with lower baseline serum VEGF levels had significantly longer survival. CONCLUSIONS: Sequential therapy with gemcitabine followed by paclitaxel was well tolerated with a low proportion of grade 3 or 4 adverse events, the absence of unexpected toxicity and with an improvement in quality of life. Unfortunately, the response rate did not meet the minimally required rate of 20% and the study was prematurely closed. VEGF was identified as a poor prognostic factor for TTP and survival. PMID- 21680303 TI - Gene expression signature and response to the use of leucovorin, fluorouracil and oxaliplatin in colorectal cancer patients. AB - PURPOSE: FOLFOX (a combination of leucovorin, fluorouracil and oxaliplatin) has achieved substantial success in the treatment of colorectal cancer (CRC) patients. However, about half of all patients show resistance to this regimen and some develop adverse symptoms such as neurotoxicity. In order to select patients who would benefit most from this therapy, we aimed to build a predictor for the response to FOLFOX using microarray gene expression profiles of primary CRC samples. PATIENTS AND METHODS: Forty patients who underwent surgery for primary lesions were examined. All patients had metastatic or recurrent CRC and received modified FOLFOX6. Responders and nonresponders were determined according to the best observed response at the end of the first-line treatment. Gene-expression profiles of primary CRC were determined using Human Genome GeneChip arrays U133. We identified discriminating genes whose expression differed significantly between responders and nonresponders and then carried out supervised class prediction using the k-nearest-neighbour method. RESULTS: We identified 27 probes that were differentially expressed between responders and nonresponders at significant levels. Based on the expression of these genes, we constructed a FOLFOX response predictor with an overall accuracy of 92.5%. The sensitivity, specificity, positive and negative predictive values were 78.6%, 100%, 100% and 89.7%, respectively. CONCLUSION: The present model suggests the possibility of selecting patients who would benefit from FOLFOX therapy both in the metastatic and the adjuvant setting. To our knowledge, this is the first study to establish a prediction model for the response to FOLFOX chemotherapy based on gene expression by microarray analysis. PMID- 21680305 TI - Duodenal rupture following trauma in a child. AB - We present a case of delayed presentation of a traumatic duodenal rupture in a 15 year-old boy. He presented 12 hours after falling six feet and sustaining blunt trauma to his anterior abdominal wall. On arrival in the Emergency Department he was shocked and peritonitic. After initial resuscitation he was stable and transferred to computed tomography where free retroperitoneal air and duodenal rupture was found. He was transferred to theatre where he underwent laparotomy and successful repair of the rupture. He made an uneventful recovery and was discharged nine days later. Duodenal rupture is a rare but serious complication of blunt abdominal trauma. Diagnosis is difficult but missed diagnosis and delayed presentation is associated with high morbidity and mortality. A high index for suspicion must be kept when dealing with blunt abdominal trauma to ensure this is not missed. PMID- 21680304 TI - Limited impact of palliative chemotherapy on survival in advanced solid tumours in patients with poor performance status. AB - AIM: Oncologists should carefully weigh up the risks and benefits of palliative chemotherapy in patients with advanced solid tumours (AST) and poor general status from the standpoint both of medical and ethical issues and of healthcare resources required. This study is intended to assess the impact on overall survival of palliative chemotherapy in patients with AST and admitted to hospital as a result of their poor ECOG status. MATERIALS AND METHODS: We performed a retrospective analysis of 92 hospitalised patients with AST, ECOG 3-4, who were treated with palliative chemotherapy. Uni- and multivariate statistical analyses were conducted to determine the impact of clinical and disease variables (number of previous chemotherapy lines, presence of comorbidities, presentation of anorexia-cachexia syndrome, delirium, dyspnoea, ascitis, brain metastases, T-cell count, albumin, haemoglobin and LDH) on survival in this patient population. RESULTS: Mean age was 54 years (range 15-80). No chemotherapy had been given for advanced disease in 74%, 13% had received one line, 6% 2 lines and 7% >=3 lines. Median survival, i.e., after initiation of chemotherapy to death, in these patients was 33 days (range 1-1390). The median of chemotherapy cycles was 1. In the multivariate analysis, no previous chemotherapy, and absence of anorexia cachexia syndrome and of comorbidities was associated with significantly improved survival in patients. Forty-nine percent of patients died within 30 days of therapy, 28% died between days 30 and 90, and only 23% of patients lived longer than 90 days. Grade 3-4 toxicities mainly entailed blood disorders, namely anaemia 8%, neutropenia 13% and thrombocytopenia 8%. Six patients (5%) developed sepsis after therapy; of these, 3 died from this toxicity, 1 patient suffered cardiac toxicity, one patient leukoencephalopathy and 1 patient acute pulmonary thromboembolism. CONCLUSION: Palliative chemotherapy given to patients with AST and ECOG 3-4 with short life expectancy provided no benefit for survival. As a result, we may be over-treating these patients and contributing to poor-quality care. PMID- 21680306 TI - A 45-year-old man presenting with anterior compartment syndrome three weeks following conservative treatment of an Achilles tendon rupture. AB - Compartment syndrome complicating a ruptured Achilles tendon has previously been reported in a surgically treated patient. However--to our knowledge--this is the first report of compartment syndrome following conservative treatment. A 45-year old man ruptured his Achilles tendon and elected to have treatment in an equinus cast. Three weeks later, he developed compartment syndrome and despite fasciotomy, required surgical debridement of his anterior compartment. Delay in both diagnosis and subsequent fasciotomy resulted in a poor outcome. Any suspicion of compartment syndrome mandates early compartmental pressure monitoring. The exact aetiology is uncertain but we speculate that the equinus position of his ankle combined with weight-bearing, was a major contributing factor. PMID- 21680307 TI - Type 1 Bland Sutton colonic atresia complicated by fetalis hydrops in a premature neonate. AB - Colonic atresia (CA) is an unusual cause of neonatal intestinal obstruction where a section of the colon has failed to form, leading to blockage or absence. A premature baby was delivered at 32 weeks of gestation via caesarian section following fetal distress. She was grossly oedematous and diagnosed with severe fetalis hydrops secondary to anaemia. She was resuscitated and stabilized. On the sixth day of life, the neonate's abdomen became severely distended with billous vomiting and failure to pass meconium. We suspected intestinal obstruction and performed an omnipaque enema which revealed dilated small bowel loops and a bowel atresia. Exploratory laparotomy confirmed a Type 1 Bland Sutton CA with mucosal web. An end colostomy was successfully performed and uneventful. In our case report, we describe a rare occurrence of postnatally diagnosed CA, complicated by fetalis hydrops and anaemia. PMID- 21680308 TI - Therapeutic hypothermia and frostbite injury: a preventable source. AB - Frostbite injury from cold exposure is not uncommon. The application of ice pack is well known in clinical practice; however, its improper use can pose danger to the patient. We report a case of frostbite injury due to prolonged use of ice packs in a ventilated patient. PMID- 21680309 TI - Primary hepatoid adenocarcinoma of the endometrium with a high alphafetoprotein level. AB - Primary hepatoid adenocarcinoma of the endometrium is a rare tumour that is similar to hepatocellular carcinoma histologically. Here, a patient with primary hepatoid carcinoma of the endometrium with a high alphafetoprotein (AFP) level (90,508 ng/mL) is presented in a 75-year-old woman. The pelvic computed tomography and magnetic resonance imaging suggested a submucosal leiomyoma with degeneration or endometrial hyperplasia. However, the endometrial biopsy revealed a primary hepatoid carcinoma of the endometrium. The patient underwent a staging laparotomy including a total abdominal hysterectomy, bilateral salpingo oophorectomy and lymph node sampling with pelvic cytology. The AFP level can be highly elevated in hepatoid carcinoma of the endometrium. PMID- 21680310 TI - Phylogenetic relationships within Araucariaceae based on rbcL gene sequences. AB - Phylogenetic relationships were determined in the Araucariaceae, which are now found mainly in the Southern Hemisphere. This conifer family was well diversified and widely distributed in both hemispheres during the Mesozoic era. The sequence of 1322 bases of the rbcL gene of cpDNA was determined from 29 species of Araucariaceae, representing almost all the species of the family. Phylogenetic trees determined by the parsimony method indicate that Araucariaceae are well defined by rbcL sequences and also that the monophyly of Agathis or Araucaria is well supported by high bootstrap values. The topology of these trees revealed that Wollemia had derived prior to Agathis and Araucaria. The rbcL phylogeny agrees well with the present recognition of four sections within Araucaria: Araucaria, Bunya, Eutacta, and Intermedia. Morphological characteristics of the number of cotyledons, position of male cone, and cuticular micromorphologies were evaluated as being phylogenetically informative. Section Bunya was found to be derived rather than to be the oldest taxon. Infrageneric relationships of Agathis could not be well elucidated because there are few informative site changes in the rbcL gene, suggesting the more recent differentiation of the species as their fossil records indicate. The New Caledonian Araucaria and Agathis species each formed a monophyletic group with very low differentiation in rbcL sequences among them, indicating rapid adaptive radiation to new edaphic conditions, i.e., ultramafic soils, in the post-Eocene era. PMID- 21680311 TI - Phylogenetic relationships among Lactuca (Asteraceae) species and related genera based on ITS-1 DNA sequences. AB - Internal transcribed spacer (ITS-1) sequences from 97 accessions representing 23 species of Lactuca and related genera were determined and used to evaluate species relationships of Lactuca sensu lato (s.l.). The ITS-1 phylogenies, calculated using PAUP and PHYLIP, correspond better to the classification of Ferakova than to other classifications evaluated, although the inclusion of sect. Lactuca subsect. Cyanicae is not supported. Therefore, exclusion of subsect. Cyanicae from Lactuca sensu Ferakova is proposed. The amended genus contains the entire gene pool (sensu Harlan and De Wet) of cultivated lettuce (Lactuca sativa). The position of the species in the amended classification corresponds to their position in the lettuce gene pool. In the ITS-1 phylogenies, a clade with L. sativa, L. serriola, L. dregeana, L. altaica, and L. aculeata represents the primary gene pool. L. virosa and L. saligna, branching off closest to this clade, encompass the secondary gene pool. L. virosa is possibly of hybrid origin. The primary and secondary gene pool species are classified in sect. Lactuca subsect. Lactuca. The species L. quercina, L. viminea, L. sibirica, and L. tatarica, branching off next, represent the tertiary gene pool. They are classified in Lactuca sect. Lactucopsis, sect. Phaenixopus, and sect. Mulgedium, respectively. L. perennis and L. tenerrima, classified in sect. Lactuca subsect. Cyanicae, form clades with species from related genera and are not part of the lettuce gene pool. PMID- 21680312 TI - Early floral development of Camellioideae (Theaceae). AB - The early floral development of Camellioideae was studied. Two major evolutionary lineages were recognized for this subfamily. The earlier evolved lineage (Camellia, Polyspora, and Pyrenaria) has normally 11-14 perianth members, which are initiated in a continuous spiral and are differentiated into sepals and petals at late floral development, and numerous stamens initiated individually and centrifugally on the whole androecial region. The later derived lineage (Franklinia, Hartia, Schima, and Stewartia) has five sepals and five petals arranged in two whorls, and numerous individual stamens originating centrifugally from the five petal-opposed zones. Hartia-Stewartia and Franklinia-Schima further diverged as two branches - the former is characterized by having androecial fascicles and axile-basal placentation. The androecial fascicle is considered to be derived within this subfamily. The latter exhibits a higher degree of carpellary congenital fusion and axile-central placentaion, and as a whole, is concluded to be the most advanced group in the Camellioideae. A taxonomic treatment of the Camellioideae at the tribal level is also proposed. PMID- 21680313 TI - SSU rDNA phylogeny of cladoniiform lichens. AB - To examine phylogenetic relationships among the "cladoniiform" lichenized fungi, i.e., the families Cladoniaceae, Baeomycetaceae, Icmadophilaceae, Stereocaulaceae, and Siphulaceae, and to provide evidence for the anticipated independent origins of podetia and pseudopodetia, we conducted phylogenetic analyses of SSU (small subunit) rDNA sequences from 39 lichen-forming fungi. These fungi represent all of the major growth forms of lichen associations, fruticose (including "cladoniiform"), foliose, and crustose. Our analysis suggests that lichen-forming fungi with a "cladoniiform" morphology arose multiple times within the ascomycetes. Additionally, each of the other thallus growth forms, crustose, foliose, and fruticose, have originated multiple times. It also seems to be clear that neither all podetiate nor all pseudopodetiate taxa form a monophyletic group. Therefore the term "podetium" should be restricted to homologous structures that are most probably limited to the genera Cladonia, Cladina, Pycnothelia, and allies. The "pseudopodetia" of Stereocaulon (Stereocaulaceae) and Cladia (Cladiaceae) may represent different states of the same homologous character. Our phylogenetic hypothesis supports the monophyletic origin of the order Lecanorales sensu stricto, including representatives of five suborders Cladoniineae, Lecanorineae, Teloschistineae, Agyriineae and Peltigerineae, but excluding representatives of the suborders Acarosporineae (Acarospora schleicheri and Megaspora verrucosa), Pertusariineae (Pertusaria trachythallina), and Umbilicarineae. The suborder Cladoniineae and the family Cladoniaceae both appear to be polyphyletic assemblages. PMID- 21680314 TI - Zygotic embryogenesis in Anthurium (Araceae). AB - Morphological, anatomical, and histochemical aspects of zygotic embryogenesis by Anthurium andraeanum Lind. were investigated from 4 to 24 wk postpollination. Anatomical features were correlated with morphology of the spadix and capacity of embryos to germinate in vitro. Development from a single-cell zygote to fully mature seed takes 24 wk. The suspensor was two ranked and obvious during the early stages of embryogeny. It was apparent by week 8, substantial until week 14, and diminished rapidly until its absence by week 22. Differentiation of the shoot apex, cotyledon, and protoderm occurs at 14 wk. The embryo starts to derive nutrition from the endosperm at this time, and germination of cultured ovules reached 56%. By 20 wk the shoot apex had visible leaf primordia and the root apex was clearly defined. The cotyledon was well developed and surrounded the shoot tip. The storage of protein and starch was at its greatest in the endosperm and embryo. Furthermore, 100% germination of cultured ovules and embryos occurred at 20 wk and thereafter. Fully mature embryos at 24 wk are green and contain protoxylem elements. PMID- 21680315 TI - Independent terrestrial origins of the Halosphaeriales (marine Ascomycota). AB - A phylogenetic study of marine ascomycetes was initiated to test and refine evolutionary hypotheses of marine-terrestrial transitions among ascomycetes. Taxon sampling focused on the Halosphaeriales, the largest order of marine ascomycetes. Approximately 1050 base pairs (bp) of the gene that codes for the nuclear small subunit (SSU) and 600 bp of the gene that codes for the nuclear large subunit (LSU) ribosomal RNAs (rDNA) were sequenced for 15 halosphaerialean taxa and integrated into a data set of homologous sequences from terrestrial ascomycetes. An initial set of phylogenetic analyses of the SSU rDNA from 38 taxa representing 15 major orders of the phylum Ascomycota confirmed a close phylogenetic relationship of the halosphaerialean species with several other orders of perithecial ascomycetes. A second set of analyses, which involved more intensive taxon sampling of perithecial ascomycetes, was performed using the SSU and LSU rDNA data in combined analyses. These second analyses included 15 halosphaerialean taxa, 26 terrestrial perithecial fungi from eight orders, and five outgroup taxa from the Pezizales. In these analyses the Halosphaeriales were polyphyletic and comprised two distinct lineages. One clade of Halosphaeriales comprised 12 taxa from 11 genera and was most closely related to terrestrial fungi of the Microascales. The second clade of halosphaerialean fungi comprised taxa from the genera Lulworthia and Lindra and was an isolated lineage among the perithecial fungi. Both the main clade of Halosphaeriales and the Lulworthia/Lindra clade are supported by the data as being independently derived from terrestrial ancestors. PMID- 21680316 TI - Localization of the genes controlling B chromosome transmission rate in maize (Zea mays ssp. mays, Poaceae). AB - In previous papers we found that the frequency of B chromosomes in native races of maize varies considerably in different populations. Moreover, we found genotypes that control high and low transmission rates (TR) of B chromosomes in the Pisingallo race. In the present work crosses were made to determine whether the genes controlling B-TR are located on the normal chromosome set (As) or on the B chromosomes (Bs). We made female f.0B * male m.2B crosses between and within high (H) and low (L) B-TR groups. The Bs were transmitted on the male side in all cases. The mean B-TR from the progeny of f.0B (H) * m.2B (H) and f.0B (H) * m.2B (L) crosses was significantly higher than that from f.0B (L) * m.2B (L) and f.0B (L) * m.2B (H) crosses. The results show that the B-TR of the crosses corresponds to the H or L B-TR of the 0B female parents irrespective of the Bs of the male parent. This indicates that B-TR is genetically controlled by the 0B female parent and that these genes are located on the A chromosomes. PMID- 21680317 TI - The induction of soluble peroxidase activity in bean leaves by wind-induced mechanical perturbation. AB - The induction of defense-related peroxidase (POD) activity in plants occurs in response to many biotic and abiotic stimuli. This controlled greenhouse study was an attempt to provide insight into the nature of the induction of soluble POD activity by noninjurious wind-induced mechanical perturbation (MP). In a time course study, exposure of common bean (Phaseolus vulgaris) seedlings to daily periods of fan-produced wind induced a significant and sustained increase in soluble POD activity in primary leaves of 7-9-d-old seedlings. In a wind-gradient study, wind-induced MP led to increases in soluble POD activity in leaves that were proportionally related to the wind speed experienced by individual seedlings. Wind-induced MP enhanced soluble POD activity to a degree similar to treatment with 5 mmol/L HgCl(2), a potent oxidizing elicitor of POD activity in plants. However, no further increases in POD activity were induced by HgCl(2) on plants that were preconditioned with wind-induced MP. Finally, short periods of brushing-induced MP enhanced soluble POD activity to the same degree as longer periods of wind-induced MS, suggesting a greater sensitivity to thigmic stimuli than to seismic stimuli in leaves of bean seedlings. This study illustrates the potential importance of wind and other mechanical stimuli as inducers of POD activity and interacting factors in the elicitation of POD activity by other environmental stimuli. PMID- 21680318 TI - Effects of competition and litter on a carnivorous plant, Drosera capillaris (Droseraceae). AB - Although carnivorous plants are widely recognized as being generally restricted to open habitats, tests of the effects of competition on individual performance are extremely rare. In this study, I examined the effects of the removal of herbaceous and shrub canopies on seedling density and growth, survival, and reproduction of phytometers of a small insectivorous plant, Drosera capillaris (pink sundew). I also examined the distribution of this species in relation to the occurrence of woody species in a frequently burned wet savanna in southeastern Mississippi. Killing plants and removing dead biomass increased seedling density in both open areas and shrub thickets. The removal of dead biomass following herbicide application was critical to increasing densities of seedlings. Killing plants with herbicide without also clearing residual litter and standing dead was not sufficient to increase seedling densities in shrub thickets. Although the removal of the groundcover canopy strongly influenced the density of seedlings, it had very little effect on survival, growth, and reproduction of small phytometers during a single growing season. Survival of phytometers was greater in open areas than in shrub thickets, regardless of whether the groundcover canopy was removed. Densities of both seedlings and adults were greater in open areas away from shrub thickets than beneath the woody canopies of thickets and were negatively correlated with the leaf area index of groundcover vegetation. Results of this study show that the establishment of this carnivorous plant species is limited in part by the effects of litter on seedling density in both open areas and shrub thickets. PMID- 21680319 TI - Greater male fitness of a rare invader (Spartina alterniflora, Poaceae) threatens a common native (Spartina foliosa) with hybridization. AB - Hybridization with abundant invaders is a well-known threat to rare native species. Our study addresses mechanisms of hybridization between a rare invader, smooth cordgrass (Spartina alterniflora) and the common native California cordgrass (S. foliosa) in the salt marshes of San Francisco Bay. These species are wind-pollinated and flower in summer. The invader produced 21-fold the viable pollen of the native, and 28% of invader pollen germinated on native stigmas (1.5 fold the rate of the native's own pollen). Invader pollen increased the seed set of native plants almost eightfold over that produced with native pollen, while native pollen failed to increase seed set of the invader. This pollen swamping and superior siring ability by the invader could lead to serial genetic assimilation of a very large native population. Unlike California cordgrass, smooth cordgrass can grow into low intertidal habitats and cover open mud necessary to foraging shorebirds, marine life, navigation, and flood control in channels. To the extent that intertidal range of the hybrids is more similar to the invader than to the native parent, introgression will lead to habitat loss for shore birds and marine life as well to genetic pollution of native California cordgrass. PMID- 21680320 TI - Sex ratios, size distributions, and sexual dimorphism in the dioecious tree Ilex aquifolium (Aquifoliaceae). AB - Sex ratio and sexual dimorphism in physiology and growth were studied in the dioecious tree Ilex aquifolium at two localities in northern Spain. Genet sex ratio was significantly male biased in one locality but not in the other. However, ramet and flowering ramet sex ratios were male biased at both study sites. Males had significantly thicker main trunks than females in one locality and produced more ramets in the other. Growth rate, estimated from mean width of annual rings, did not differ between localities, but males produced wider rings than females at both sites. Mean annual growth rates over the last 10, 20, and 30 yr were significantly higher for males. Measurements of chlorophyll fluorescence indicated that the efficiency of photosynthesis of leaves on nonfruiting branches of females was higher than for leaves on branches of male plants under low-light conditions, though not under saturating-light conditions. Efficiency of photosynthesis was significantly lower on fruiting branches of female plants than on nonfruiting branches. We discuss whether the observed between-sex differences are attributable to the higher cost of reproduction in females and/or to pollen competition. PMID- 21680321 TI - Clonal population structure and genetic variation in sand-shinnery oak,Quercus havardii (Fagaceae). AB - We investigated clonal population structure and genetic variation in Quercus havardii (sand-shinnery oak), a deciduous rhizomatous shrub that dominates vegetation by forming uninterrupted expanses of ground cover over sandy deposits on the plains of western Texas, western Oklahoma, and eastern New Mexico. Isozyme electrophoresis (15 loci coding 11 enzymes) was used to recognize and map clones arrayed in a 2000-m transect (50-m sample intervals) and a 200 * 190 m grid (10-m sample intervals). Ninety-four clones were discovered, 38 in the transect and 56 in the grid, resulting in an estimated density of ~15 clones per hectare. Clones varied greatly in size (~100-7000 m), shape, and degree of fragmentation. The larger clones possessed massive interiors free of intergrowth by other clones, while the smaller clones varied in degree of intergrowth. The population maintained substantial levels of genetic variation (P = 60%, A = 2.5, H(exp) = 0.289) comparable to values obtained for other Quercus spp. and for other long lived perennials. The population was outcrossing as evidenced by conformance of most loci to Hardy-Weinberg expected genotype proportions, although exceptions indicated a limited degree of population substructuring. These data indicate that despite apparent reproduction primarily through vegetative means, Q. havardii possesses conventional attributes of a sexual population. PMID- 21680322 TI - Pollination in Verbascum thapsus (Scrophulariaceae): the advantage of being tall. AB - According to the "effective pollination" hypothesis, tall stature resulting from strong apical dominance attracts greater pollinator visitation, thus allowing larger pollen loads and/or greater outcrossing rates, which in turn produces more vigorous offspring with greater genotypic variability and/or less inbreeding depression. Components of this hypothesis were tested in Verbascum thapsus, which commonly grows unbranched to over 2 m tall with strong apical dominance suppressing all axillary meristems. A natural population survey indicated that plants with visiting pollinators were significantly taller than their nearest neighboring individuals not possessing a visiting pollinator. Plants in natural populations with excluded pollinators produced seeds via a delayed selfing mechanism. However, delayed selfing under pollinator exclusion resulted in only 75% of the seed set obtained with natural pollinators. Under natural pollination, emasculated flowers experienced a 50% reduction in pollen deposition by the time of flower closure but only a 5% reduction in seed set relative to intact flowers. Hence, taller plants attracted more pollinators and maximum seed set could not be achieved without pollinators. Comparison of seed set and seed mass in plants that were artificially selfed and artificially crossed (in both the greenhouse and in natural populations) indicated that plants were fully self-compatible with no evidence of early-acting inbreeding depression. However, this does not exclude the possibility that inbreeding depression is manifested in later life stages. The results suggest that V. thapsus has a mixed mating system with potential for reproductive assurance and various levels of outcrossing depending on variables affecting pollinator availability (e.g., population size). PMID- 21680323 TI - The effect of timing of pollination on the mating system and fitness ofKalmia latifolia (Ericaceae). AB - Plant mating systems are known to vary within species and some immediate ecological factors have been found to be associated with the geographic distribution of selfing. The environmental condition of the maternal plant may influence the production of selfed seed relative to outcrossed seed. This study investigated the effect of late pollination on the mating system of Kalmia latifolia, a long-lived perennial shrub. A 2 * 2 experimental design was used to determine whether reproductive success declines over the course of the flowering season and whether there was an interaction between pollination time (early vs. late in the season) and pollen type (self-fertilized vs. outcrossed). An interaction of this sort would indicate context-dependent fitness of selfed seeds compared to outcrossed seeds and, thus, show an ecological influence over a plant's mating system. Relative fitness was assessed in terms of female reproductive success. Timing of pollination did not affect abortion of outcrossed seeds; however, delay in pollination increased abortion of selfed seeds by 34.7%. Thus, it appears that plants selectively aborted selfed seeds rather than outcrossed seeds and this selection was more intense at the end of the season. An ecological factor such as time of pollination may affect the mating system of K. latifolia. PMID- 21680324 TI - Reproductive biology and population genetic structure of Kandelia candel (Rhizophoraceae), a viviparous mangrove species. AB - The pollination biology, mating system, and population genetic structure of Kandelia candel were investigated. Field observations on its pollination and reproductive biology suggested that this species is pollinator dependent for fruit set, and bee activities can lead to substantial geitonogamous selfing. Quantitative analysis of the mating system parameters was performed using progeny arrays assayed for allozyme markers. Multilocus outcrossing rates (t(m)) were estimated to be 0.697 +/- 0.091 and 0.797 +/- 0.062 in two populations. In comparison to other plant species with mixed-mating system, the level of allozyme variation was very low in the 13 populations sampled along the coastlines of Hong Kong. At the species level, the proportion of polymorphic loci was 20%, number of alleles per locus was 1.2, and heterozygosity was 0.0362. The total gene diversity was primarily distributed within populations (H(S )= 0.0339), and the coefficient of genetic differentiation among populations was low (G(ST )= 0.064). This pattern of population genetic structure suggests that gene flow, primarily in the form of water-dispersed seedlings in viviparous mangrove species, is not as limited as previously thought. However, microgeographic pattern in allele frequency at the marker loci could still be detected between the western and eastern coastal populations. PMID- 21680325 TI - Modeling the growth of individuals in plant populations: local density variation in a strand population of Xanthium strumarium (Asteraceae). AB - We studied the growth of individual Xanthium strumarium plants growing at four naturally occurring local densities on a beach in Maine: (1) isolated plants, (2) pairs of plants <=1 cm apart, (3) four plants within 4 cm of each other, and (4) discrete dense clumps of 10-39 plants. A combination of nondestructive measurements every 2 wk and parallel calibration harvests provided very good estimates of the growth in aboveground biomass of over 400 individual plants over 8 wk and afforded the opportunity to fit explicit growth models to 293 of them. There was large individual variation in growth and resultant size within the population and within all densities. Local crowding played a role in determining plant size within the population: there were significant differences in final size between all densities except pairs and quadruples, which were almost identical. Overall, plants growing at higher densities were more variable in growth and final size than plants growing at lower densities, but this was due to increased variation among groups (greater variation in local density and/or greater environmental heterogeneity), not to increased variation within groups. Thus, there was no evidence of size asymmetric competition in this population. The growth of most plants was close to exponential over the study period, but half the plants were slightly better fit by a sigmoidal (logistic) model. The proportion of plants better fit by the logistic model increased with density and with initial plant size. The use of explicit growth models over several growth intervals to describe stand development can provide more biological content and more statistical power than "growth-size" methods that analyze growth intervals separately. PMID- 21680326 TI - First report of oil cavities in Scrophulariaceae and reinvestigation of air spaces in leaves of Leucophyllum frutescens. AB - Conspicuous air spaces in Leucophyllum (Scrophulariaceae; Leucophylleae) leaves have been suggested to be developmentally transformed secretory cavities. We reinvestigated air space development in Leucophyllum frutescens, using freehand sections of mature fresh leaves and paraffin sections of several leaf stages. Each of the numerous air spaces per leaf forms because greater separation occurs within a local group of spongy mesophyll cells than in the developing spongy mesophyll elsewhere. We found no anatomical evidence of transitory epithelial cells or lysis of cells in developing air spaces, thus the hypothesis that air spaces are transformed secretory cavities is not supported. However, an important finding was that all leaves had one pair of conspicuous true secretory cavities flanking the midvein at the apex, each lined by an epithelium and filled with oil. We also found conspicuous apical cavities in freehand sections of herbarium specimens of this and three other Leucophyllum species. Cavities were not seen in L. revolutum or in the related Eremogeton grandiflorus. This is the first report and description of a true internal secretory cavity in Scrophulariaceae. In the related family Myoporaceae, we found epithelium-lined cavities scattered abundantly in leaves of cleared samples of three genera. PMID- 21680327 TI - Fruit set, nectar reward, and rarity in the Orchidaceae. AB - A review of comparative levels of reproductive success among nectariferous and nectarless orchids worldwide was compiled from a comprehensive survey of fruit set from 117 orchid species in the literature and from our own field studies. It confirms the hypothesis that nectariferous orchids are more successful in setting fruit than are nectarless species. Overall fruit set figures for nectarless and nectariferous orchids were 19.5 and 49.3% for North America, 27.7 and 63.1% for Europe, 41.4 and 74.4% for the temperate southern hemisphere, and 11.5 and 24.9% for the tropics, demonstrating that the dichotomy is consistent across all geographical areas. On average, the provision of nectar doubles the probability of fruit set in both temperate and tropical areas, but tropical orchids are remarkable in that all (whether nectarless or nectariferous, or terrestrial or epiphytic) display low fruit productivity (<50%). Fruiting failure in the tropics may be balanced by higher productivity per capsule, since tropical orchid fruits contain on average 150 times more seeds than temperate ones. Hybridization occurs more frequently among nectarless orchids in Britain and Europe than among nectariferous ones, and there is a significant positive association between orchid rarity and lack of nectar reward in the British Isles. Sexual reproduction in the Orchidaceae is predominantly pollinator dependent, but this can sometimes be successfully circumvented by asexual seed production (agamospermy) or, more frequently, by automatic self-pollination (autogamy). The proportion of highly successful nectarless orchids from all geographic areas is very low and comparable with that of orchids offering rewards other than nectar (~14% of species in each case) emphasizing that high reproductive success is only associated with nectar reward (53% of species). It is suggested that the evolution of nectar production within the family has been the most frequent means of escaping the reproductive limitations of low pollinator visitation frequencies. PMID- 21680328 TI - Cost of reproduction in the pink lady's slipper orchid (Cypripedium acaule, Orchidaceae): an eleven-year experimental study of three populations. AB - An 11-yr experimental study of the cost of reproduction in three wild populations of the perennial orchid Cypripedium acaule contrasted experimental plants that were repeatedly hand-pollinated and often made fruits with control plants that were not hand-pollinated and only rarely made fruits. Repeated flowering without subsequent fruit production resulted in no detectable reduction in either plant size or probability of flowering in subsequent years. A cost of fruit production was evident in experimental plants in all three populations in terms of a reduced probability of flowering and smaller leaf area in subsequent years, but was not evident in terms of mortality rate. Experimental effects of fruit production reached maximum values at 3-7 yr, depending on the population. The probability of remaining dormant below ground in a given year was strongly dependent on plant size in the previous year. Furthermore, the length of the dormancy period (one to several years) was a significant and inverse function of plant size just prior to dormancy. Sample sizes and the consequent ability to detect experimental effects declined over time as more plants died or stopped flowering. Four to seven years appears to be an optimal duration for studies of the cost of reproduction in perennial herbs similar to this species. Studies lasting less than 4 yr may be too brief to reveal experimental effects, whereas those lasting more than 7 yr may fail to reveal new insights. PMID- 21680329 TI - Population-level responses to nutrient heterogeneity and density by Abutilon theophrasti (Malvaceae): an experimental neighborhood approach. AB - An experimental approach was used to examine the effects of spatial nutrient heterogeneity and planting density on the sizes of plants within populations of Abutilon theophrasti. Planting locations were generated using random numbers and replicated among populations growing on two different scales of heterogeneity and homogeneous soils. The same quantity of nutrients (dehydrated cow manure) was added to each population, regardless of the spatial nutrient distribution. The higher density was achieved by adding additional planting locations to those present at the lower density. Plant biomass was compared among ten planting locations present in all populations. Plants in seven locations were smaller at the higher density, but the spatial distribution of nutrients affected plant size in only two locations. At the population level, the higher density reduced mean plant biomass and increased both total biomass and the coefficient of variation in biomass, a measure of size inequality. Only when populations on both scales of heterogeneity were together compared with those on homogeneous soils were population-level measurements found to be significantly affected by soil treatment; heterogeneity resulted in decreased total biomass and an increase in the coefficient of variation, apparently due to an increase in the number of small plants in the population. These results, together with the finding that fine root biomass increased in nutrient-enriched patches, suggest that on heterogeneous soils most plants were able to access nutrient patches. PMID- 21680330 TI - The effects of developmental stage and source leaf position on integration and sectorial patterns of carbohydrate movement in an annual plant, Perilla frutescens (Lamiaceae). AB - A well-integrated plant shows extensive carbohydrate translocation through the plant body. Even in highly integrated plants, however, translocation patterns will be sectorial if vascular tissue restricts carbon movement to sectors along stems. Both integration and sectorial translocation patterns are sensitive to plant architecture and thus may change as a plant develops. These patterns should vary also with the position of the source leaf because leaves at each node are unique in age and vascular relationship to the rest of the plant. I measured the effects of developmental stage and location of the source leaf on integration and sectoriality in an annual plant, Perilla frutescens, by labeling plants with C at one of three leaves and four developmental stages. Stage and source leaf affected both integration and sectoriality. Most notably, integration declined and sectoriality increased during seed fill, when resource demand at each node was high. Furthermore, translocation was least extensive from the leaf supporting the largest number of seeds on its axillary branch. These results suggest that plants are not homogeneous collections of subunits; rather, the role of each leaf in a plant's carbon budget is a function of its age and location on the plant. PMID- 21680331 TI - Organellar genetic diversity in Penstemonhaydenii (Scrophulariaceae): an endangered plantspecies. AB - Genetic variation was analyzed in the endangered prairie forbPenstemon haydenii. Individuals from nine populations weresurveyed for chloroplast DNA (cpDNA) and mitochondrial DNA (mtDNA)variation. No cpDNA polymorphism was found. Analysis of mtDNA revealedvariation within and among populations. A minimum of eight haplotypeswere identified. The distribution of these genotypes suggests that thereis some correlation between geographic and genetic distances, whichreflects the minimal gene flow in thisspecies. PMID- 21680332 TI - Does seed dispersal limit initiation of primary succession in desert playas? AB - To investigate the initiation of primary succession in a cold-desert playa-dune complex, we studied the large-scale (2000 m) seed (diaspore) dispersal patterns at Mono Lake, California. Seeds of seven of the ten species reaching the barren playa had wind-dispersal adaptations. Rates of dispersal (numbers of seeds per square metre per day) were as much as three orders of magnitude lower on the playa than in the diverse dune vegetation. However, seed input appeared sufficient to reach potential safe sites on the playa, with a peak input of 66 +/ 8 total seeds.m.d. The smooth playa surface, the virtual absence of aboveground barriers, and the high windspeed environment promote the long-distance dispersal of seeds (at least 1300 m for Chrysothamnus spp. and at least 700 m for Sarcobatus vermiculatus). The large spatial scale of sampling revealed a relatively high seed input onto the playa by the dominant pioneer species S. vermiculatus, despite the low abundance of parent vegetation in this region. All of these results implicate low rates of seed entrapment as an obstacle to establishment on this desert playa, rather than a lack of seed input. PMID- 21680333 TI - Interspecific variation in plant responses to mycorrhizal colonization in tallgrass prairie. AB - Symbiotic associations between plants and arbuscular mycorrhizal fungi are ubiquitous and ecologically important in many grasslands. Differences in species responses to mycorrhizal colonization can have a significant influence on plant community structure. The growth responses of 36 species of warm- and cool-season tallgrass prairie grasses and 59 tallgrass prairie forbs to arbuscular mycorrhizal (AM) fungal colonization were assessed in greenhouse studies to examine the extent of interspecific variation in host-plant benefit from the symbiosis and patterns of mycorrhizal dependence among host plant life history (e.g., annual, perennial) and taxonomic (e.g., grass, forb, legume, nonlegume) groups and phenological guilds. There was a strong and significant relationship between phenology of prairie grasses and mycorrhizal responsiveness, however this relationship was less apparent in forbs. Perennial warm-season C(4) grasses and forbs generally benefited significantly from the mycorrhizal symbiosis, whereas biomass production of the cool-season C(3) grasses was not affected. The root systems of the cool-season grasses were also less highly colonized by the AM fungi, as compared to the warm-season grasses or forbs. Unlike the native perennials, annuals were generally not responsive to mycorrhizal colonization and were lower in percentage root colonization than the perennial species. Plant growth responsiveness and AM root colonization were positively correlated for the nonleguminous species, with this relationship being strongest for the cool-season grasses. In contrast, root colonization of prairie legumes showed a significant, but negative, relationship to mycorrhizal growth responsiveness. PMID- 21680334 TI - Spatial/temporal variations in shrub thicket soil seed banks on an Atlantic Coast barrier island. AB - Potential species replacement within low-diversity shrub thicket communities was investigated for a Virginia barrier island. Seed bank species composition was quantified in a glasshouse study using soil samples collected beneath closed Myrica cerifera thickets, as well as from thicket gaps. Samples were collected from productive and aging thickets, corresponding to differences in soil age. These data were compared to species presently occurring within the thickets and gaps. Seedbank species composition was not indicative of current community composition for either the intact thickets or the gaps. Seed banks resembled a more pioneer community. Thirteen families, 23 genera, and 25 species were identified from the seed bank beneath the M. cerifera thickets. Four species were woody. The within-gap seed bank included 19 families, 30 genera, and 34 species. Eight species were woody. The current community included 21 families, 33 genera, and 36 species beneath the intact thickets as well as within the thicket gaps. Eighteen species were woody. The species richness of gaps was more than three times that of intact thickets. For low-diversity shrub thickets, gaps enhance species richness. PMID- 21680335 TI - The roles of seedling salt tolerance and resprouting in forest zonation on thewest coast of Florida, USA. AB - To determine whether the zonation of seven coastal tree species in north Florida correlated with the relative abilities of their seedlings to tolerate soil salinity, we subjected seedlings of Sabal palmetto, Juniperus virginiana var. silicicola, Quercus virginiana, Celtis laevigata, Ulmus spp., Acer floridanum, and Liquidambar styraciflua to a range of salinities (~0, 2, 4, 8, 15, and 22 g synthetic sea salt/L; up to 63% full strength seawater salinity) in a 6-mo greenhouse experiment. Pots with shoot-killed plants were flushed with freshwater for >=5 wk to assess recovery. Salt tolerance was assessed as plant survival under saline conditions and as the ability to retain green leaf tissue under saline conditions. Using either criterion, the rank order of seedling salt tolerance correlated significantly (P <= 0.05) with that expected based on species zonation near the coast. Agreement was better, however, using retention of leaf tissue as an index of salt tolerance. Species from forest zones that were frequently exposed to tidal water retained green leaf tissue under saline conditions. Species from zones occasionally subjected to very high tides were shoot killed but resprouted following removal of salt from the root zone. Those restricted to zones exposed only to infrequent storm surges died at salinities >=4 g/L. Thus, differential seedling salt tolerance was consistent with tree zonation and, although the ability of young seedlings to resprout following salt removal did not appear to allow tree establishment at the extreme seaward margin of the forest, it appeared important in intermediate zones. PMID- 21680336 TI - Cladistic biogeography of Gleditsia (Leguminosae) based on ndhF and rpl16 chloroplast gene sequences. AB - We used cladistic analysis of chloroplast gene sequences (ndhF and rpl16) to test biogeographic hypotheses in the woody genus Gleditsia. Previous morphological comparisons suggested the presence of two eastern Asian-eastern North American species pairs among the 13 known species, as well as other intra- and inter continental disjunctions. Results from phylogenetic analyses, interpreted in light of the amount of sequence divergence observed, led to the following conclusions. First, there is a fundamental division of the genus into three clades, only one of which contains both Asian and North American species. Second, the widespread and polymorphic Asian species, G. japonica, is sister to the two North American species, G. triacanthos and G. aquatica, which themselves are closely related inter se, but are both polymorphic and paraphyletic. Third, the lone South American Gleditsia species, G. amorphoides, forms a clade with two eastern Asian species. Gleditsia thus appears to have only one Asian-North American disjunction and no intercontinental species pairs. Low sequence divergence between G. amorphoides and its closest Asian relatives implicates long distance dispersal in the origin of this unusual disjunction. Sequence divergence between Asian and North American Gleditsia is much lower than between Asian and North American species of its closest relative, Gymnocladus. Estimates of Asian North American divergence times for Gymnocladus are in general accordance with fossil data, but estimates for Gleditsia suggest recent divergences that conflict with ages of known North American Gleditsia fossils. PMID- 21680337 TI - Chloroplast DNA restriction site variation and phylogeny of the Berberidaceae. AB - Comparative restriction site mapping of the chloroplast genome was performed to examine phylogenetic relationships among 27 species representing 16 genera of the Berberidaceae and two outgroups. Chloroplast genomes of the species included in this study showed no major structural rearrangements (i.e., they are collinear to tobacco cpDNA) except for the extension of the inverted repeat in species of Berberis and Mahonia. Excluding several regions that exhibited severe length variation, a total of 501 phylogenetically informative sites was mapped for ten restriction enzymes. The strict consensus tree of 14 equally parsimonious trees indicated that some berberidaceous genera (Berberis, Mahonia, Diphylleia) are not monophyletic. To explore phylogenetic utility of different parsimony methods phylogenetic trees were generated using Wagner, Dollo, and weighted parsimony for a reduced data set that included 18 species. One of the most significant results was the recognition of the four chromosomal groups, which were strongly supported regardless of the parsimony method used. The most notable difference among the trees produced by the three parsimony methods was the relationships among the four chromosomal groups. The cpDNA trees also strongly supported a close relationship of several generic pairs (e.g., Berberis-Mahonia, Epimedium Vancouveria, etc.). Maximum likelihood values were computed for the four different tree topologies of the chromosomal groups, two Wagner, one Dollo, and one weighted topology. The results indicate that the weighted tree has the highest likelihood value. The lowest likelihood value was obtained for the Dollo tree, which had the highest bootstrap and decay values. Separate analyses using only the Inverted Repeat (IR) region resulted in a tree that is identical to the weighted tree. Poor resolution and/or support for the relationships among the four chromosomal lineages of the Berberidaceae indicate that they may have radiated from an ancestral stock in a relatively short evolutionary time. PMID- 21680338 TI - Conservation genetics and taxonomic status of the rare Kentucky lady's slipper: Cypripedium kentuckiense (Orchidaceae). AB - Cypripedium kentuckiense is a recently described rare orchid found in Arkansas (predominantly) and in eight other states. Much debate has focused on whether this taxon should be recognized as a distinct species or considered to be an extreme manifestation of the variability present in the widespread taxon Cypripedium parviflorum var. pubescens. In this study, 12 isozyme loci were analyzed for 14 populations of C. parviflorum var. pubescens and eight populations of C. kentuckiense. These data were used to examine the genetic similarity of these taxa, assess whether isozyme data support the continued recognition of C. kentuckiense as a distinct species, and assess whether a newly discovered disjunct Virginia population of C. kentuckiense is genetically isolated from other C. kentuckiense populations. The isozyme data revealed that the two taxa are very closely related with a high interspecific genetic identity. However, C. kentuckiense populations contain a subset of the variation present in C. parviflorum var. pubescens, and they have expected levels of heterozygosity that are one-quarter that of C. parviflorum var. pubescens populations. Cypripedium kentuckiense also possesses one widespread unique allele and a unique multilocus genotype. These data suggest that C. kentuckiense should be recognized as a distinct species, possibly of recent origin from C. parviflorum. Lastly, the isozyme data support the hypothesis that gene flow between the Virginia population and other populations of C. kentuckiense has been restricted. PMID- 21680339 TI - Phylogenetic analysis of Artemisia section Tridentatae (Asteraceae) based on sequences from the internal transcribed spacers (ITS) of nuclear ribosomal DNA. AB - Artemisia sect. Tridentatae is composed of 11 species of xerophytic shrubs, which dominate much of western North America. Sequences of the internal transcribed spacers (ITS) of nuclear ribosomal DNA were used to construct a phylogeny, examine circumscription of the section, resolve interspecific relationships, and test competing hypotheses on the origin of the section. The data support the monophyly of sect. Tridentatae, with the exclusion of A. bigelovii and A. palmeri two historically, anomolous species. However, the ITS data provide insufficient variation to fully resolve interspecific relationships or to support major lineages within the Tridentata clade. Nuclear and chloroplast DNA phylogenies are discordant, which may be a result of interspecific gene flow and subsequent chloroplast capture, particularly related to the placement of A. filifolia and A. californica, in addition to A. bigelovii. Furthermore, the ITS data are in conflict with cpDNA data, providing equivocal evidence for competing hypotheses on the Old World vs. New World origin for the section and do not provide support for definitive subgeneric placement. PMID- 21680340 TI - Estimation of temperature and precipitation from morphological characters of dicotyledonous leaves. AB - The utility of regression and correspondence models for deducing climate from leaf physiognomy was evaluated by the comparative application of different predictive models to the same three leaf assemblages. Mean annual temperature (MAT), mean annual precipitation (MAP), and growing season precipitation (GSP) were estimated from the morphological characteristics of samples of living leaves from two extant forests and an assemblage of fossil leaves. The extant forests are located near Gainesville, Florida, and in the Florida Keys; the fossils were collected from the Eocene Clarno Nut Beds, Oregon. Simple linear regression (SLR), multiple linear regression (MLR), and canonical correspondence analysis (CCA) were used to estimate temperature and precipitation. The SLR models used only the percentage of species having entire leaf margins as a predictor for MAT and leaf size as a predictor for MAP. The MLR models used from two to six leaf characters as predictors, and the CCA used 31 characters. In comparisons between actual and predicted values for the extant forests, errors in prediction of MAT were 0.6 degrees -5.7 degrees C, and errors in prediction of precipitation were 6 89 cm (=6-66%). At the Gainesville site, seven models underestimated MAT and only one overestimated it, whereas at the Keys site, all eight models overestimated MAT. Precipitation was overestimated by all four models at Gainesville, and by three of them at the Keys. The MAT estimates from the Clarno leaf assemblage ranged from 14.3 degrees to 18.8 degrees C, and the precipitation estimates from 227 to 363 cm for MAP and from 195 to 295 cm for GSP. PMID- 21680341 TI - Interpreting recruitment limitation in forests. AB - Studies of tree recruitment are many, but they provide few general insights into the role of recruitment limitation for population dynamics. That role depends on the vital rates (transitions) from seed production to sapling stages and on overall population growth. To determine the state of our understanding of recruitment limitation we examined how well we can estimate parameters corresponding to these vital rates. Our two-part analysis consists of (1) a survey of published literature to determine the spatial and temporal scale of sampling that is basis for parameter estimates, and (2) an analysis of extensive data sets to evaluate sampling intensity found in the literature. We find that published studies focus on fine spatial scales, emphasizing large numbers of small samples within a single stand, and tend not to sample multiple stands or variability across landscapes. Where multiple stands are sampled, sampling is often inconsistent. Sampling of seed rain, seed banks, and seedlings typically span <1 yr and rarely last 5 yr. Most studies of seeding establishment and growth consider effects of a single variable and a single life history stage. By examining how parameter estimates are affected by the spatial and temporal extent of sampling we find that few published studies are sufficiently extensive to capture the variability in recruitment stages. Early recruitment stages are especially variable and require samples across multiple years and multiple stands. Ironically, the longest duration data sets are used to estimate mortality rates, which are less variable (in time) than are early life history stages. Because variables that affect recruitment rates interact, studies of these interactions are needed to assess their full impacts. We conclude that greater attention to spatially extensive and longer duration sampling for early life history stages is needed to assess the role of recruitment limitation in forests. PMID- 21680342 TI - Studies in Neotropical paleobotany. XIII. An Oligo-Miocene palynoflora from Simojovel (Chiapas, Mexico). AB - A plant microfossil assemblage of 24 identified and five unknown pollen and spore types is reported from the early Miocene La Quinta Formation near Simojovel, Chiapas, Mexico. The taxa group into seven paleocommunities representing versions of the modern mangroves (Pelliciera, Rhizophora), swamp and lowland riparian forest (Ceratopteris, Crudia, Pachira), tropical rain forest (Selaginella, cf. Antrophyum, Pteris, Sphaeropteris/Trichipteris, cf. Aguiaria, Crudia, Guarea, Pachira), lower montane rain forest (Alfaroa/Oreomunnea, possibly Eugenia), evergreen cloud forest [Picea, Pinus, Podocarpus, Ericaceae (possibly Cavendishia/Vaccinium)], evergreen seasonal forest (Hymenaea, Ilex, possibly Eugenia), and tropical deciduous forest (Cedrela). Elements of arid and high elevation habitats were absent or few, and northern temperate elements (Picea, Pinus?) were few or rare. Paleoelevations are estimated at 1000-1200 m (present average 2000 m, maximum 3004 m), MAT (mean annual temperature) at least as warm as the present 24 degrees C, and annual rainfall near the present ~2500 mm but more evenly distributed. The La Quinta (Simojovel) and other Tertiary floras from the region reflect a trend toward higher altitudes, more seasonal rainfall, cooling tempertures, increased introduction of cool-temperate elements from the north after ~15 Ma (million years), and increased introduction of tropical elements from the south after completion of the isthmian land bridge ~3.5 Ma ago. PMID- 21680343 TI - The Tertiary history of the northern temperate element in the northern Latin American biota. AB - The time of origin of cool-to-cold-temperate plants of northern affinities in the Latin American biota is unsettled. Two models have been proposed-a Paleogene origin from a once widespread temperate rain forest, and a Neogene origin by introductions from the north which is best supported by new evidence. Fourteen palynofloras of Tertiary age are now available from Mexico and Central America, in addition to numerous others from the southeastern United States and northern South America. Pollen of cool-temperate plants occurs in the Eocene of southeastern United States, but not in northern Mexico, central Panama, or northern South America. In the Miocene this pollen is sparse in deposits from Mexico and Guatemala, rare in Panama, and absent from northern South America. In the Pliocene pollen representing a diverse northern temperate element of ten genera is present in the Pliocene of southeastern Veracruz, Mexico, five in northeastern Guatemala, and two (Myrica, Salix) first appear in northern South America; Alnus and Quercus are added in the Pleistocene. This north-to-south and early-to-late pattern is consistent with the appearance of highlands in southern Central America and northern South America in the Neogene, closure of the isthmian marine portal between 3.5 and 2.5 Ma (million years ago), and the late Cenozoic cooling trend evident in the O/O-based paleotemperature curve. PMID- 21680344 TI - Covariance and decoupling of floral and vegetative traits in nine Neotropical plants: a re-evaluation of Berg's correlation-pleiades concept. AB - Nearly forty years ago R. L. Berg proposed that plants with specialized pollination ecology evolve genetic and developmental systems that decouple floral morphology from phenotypic variation in vegetative traits. These species evolve separate floral and vegetative trait clusters, or as she termed them, "correlation pleiades." The predictions of this hypothesis have been generally supported, but only a small sample of temperate-zone herb and grass species has been tested. To further evaluate this hypothesis, especially its applicability to plants of other growth forms, we examined the patterns of phenotypic variation and covariation of floral and vegetative traits in nine species of Neotropical plants. We recognized seven specific predictions of Berg's hypothesis. Our results supported some predictions but not others. Species with specialized pollination systems usually had floral traits decoupled (weak correlation; Canna and Eichornia) or buffered (relationship with shallow proportional slope; Calathea and Canna) from variation in vegetative traits. However, the same trend was also observed in three species with unspecialized pollination systems (Echinodorus, Muntingia, and Wedelia). One species with unspecialized pollination (Croton) and one wind-pollinated species (Cyperus) showed no decoupling or buffering, as predicted. While species with specialized pollination usually showed lower coefficients of variation for floral traits than vegetative traits (as predicted), the same was also true of species with unspecialized or wind pollination (unlike our prediction). Species with specialized pollination showed less variation in floral traits than did species with unspecialized or wind pollination, as predicted. However, the same was true of the corresponding vegetative traits, which was unexpected. Also in contrast to our prediction, plants with specialized pollination systems did not exhibit tighter phenotypic integration of floral characters than did species with generalized pollination systems. We conclude that the patterns of morphological integration among floral traits and between floral and vegetative traits tend to be species specific, not easily predicted from pollination ecology, and generally more complicated than R. L. Berg envisaged. PMID- 21680345 TI - A new pollination system: dung-beetle pollination discovered in Orchidantha inouei (Lowiaceae, Zingiberales) in Sarawak, Malaysia. AB - Lowiaceae, a family of the Zingiberales, comprise 11 species in the single genus Orchidantha. Here we present the first report on the pollination of Lowiaceae and describe a new system of dung-beetle pollination from Sarawak, Borneo. Orchidantha inouei has a zygomorphic flower located just above the ground. Observations revealed that the plant is visited frequently and is pollinated by scarabaeid dung beetles, mainly members of the genus Onthophagus. All four species of Onthophagus collected on O. inouei have also been caught using traps baited with dung or carrion in Borneo. Onthophagus was presumably attracted to the dung-like odor of the flower. Pollination of O. inouei is different from other examples of beetle pollination in that its flower provides neither reward nor protected space. Dung beetles are excellent at following a particular dung scent. Orchidantha is the only genus that includes species lacking floral nectar. It is interesting that this deception pollination using dung beetles was found in Zingiberales, in which all known species have mutual and specialized relationships with their long-distance, but costly, pollinators-bees, birds, and bats. PMID- 21680346 TI - Beetle pollination of Shorea parvifolia (section Mutica, Dipterocarpaceae) in a general flowering period in Sarawak, Malaysia. AB - Pollination ecology of an emergent tree species, Shorea (section Mutica) parvifolia (Dipterocarpaceae), was studied using the canopy observation system in a lowland dipterocarp forest in Sarawak, Malaysia, during a general flowering period in 1996. Although the species has been reported to be pollinated by thrips in Peninsular Malaysia, our observations of flower visitors and pollination experiments indicated that beetles (Chrysomelidae and Curculionidae, Coleoptera) contributed to pollination of S. parvifolia in Sarawak. Beetles accounted for 74% of the flower visitors collected by net-sweeping, and 30% of the beetles carried pollen, while thrips accounted for 16% of the visitors, and 12% of the thrips carried pollen. The apical parts of the petals and pollen served as a reward for the beetles. Thrips stayed inside the flower almost continuously after arrival, and movements among flowers were rare. Fruit set was significantly increased by introduction of beetles to bagged flowers, but not by introduction of thrips. Hand-pollination experiments and comparison of fruit set in untreated, bagged, and open flowers suggested that S. parvifolia was mainly outbreeding. PMID- 21680347 TI - Phylogenetic relationships among Acanthaceae: evidence from noncoding trnL-trnF chloroplast DNA sequences. AB - We used sequence data from the intron and spacer of the trnL-trnF chloroplast region to study phylogenetic relationships among Acanthaceae. This region is more variable than other chloroplast loci that have been sequenced for members of Acanthaceae (rbcL and ndhF), is more prone to length mutations, and is less homoplasious than these genes. Our results indicate that this region is likely to be useful in addressing phylogenetic questions among but not within genera in these and related plants. In terms of phylogenetic relationships, Elytraria (representing Nelsonioideae) is more distantly related to Acanthaceae sensu stricto (s.s.) than Thunbergia and Mendoncia. These last two genera are strongly supported as sister taxa. Molecular evidence does not support monophyly of Acanthaceae s.s., although there is strong morphological evidence for this relationship. There is strong support for monophyly of four major lineages within Acanthaceae s.s.: the Acanthus, Barleria, Ruellia, and Justicia lineages as here defined. The last three of these comprise a strongly supported monophyletic group, and there is weaker evidence linking the Ruellia and Justicia lineages as closest relatives. Within the Acanthus lineage, our results confirm the existence of monophyletic lineages representing Aphelandreae and Acantheae. Lastly, within the Justicia lineage, we develop initial hypotheses regarding the definition of sublineages; some of these correspond to earlier ideas, whereas others do not. All of these hypotheses need to be tested against more data. PMID- 21680348 TI - Phylogeny of Rubus (rosaceae) based on nuclear ribosomal DNA internal transcribed spacer region sequences. AB - We used nuclear ribosomal DNA internal transcribed spacer region (ITS 1 - 5.8S - ITS 2; ITS) sequences to generate the first phylogeny of Rubus based on a large, molecular data set. We sampled 57 taxa including 20 species of subgenus Rubus (blackberries), one to seven species from each of the remaining 11 subgenera, and the monotypic and closely related Dalibarda. In Rubus, ITS sequences are most informative among subgenera, and variability is low between closely related species. Parsimony analysis indicates that Rubus plus Dalibarda form a strongly supported clade, and D. repens may nest within Rubus. Of the subgenera with more than one species sampled, only subgenus Orobatus appears monophyletic. Three large clades are strongly supported: one contains all sampled species of nine of the 12 subgenera; another includes extreme Southern Hemisphere species of subgenera Comaropsis, Dalibarda, and Lampobatus; and a third clade consists of subgenus Rubus plus R. alpinus of subgenus Lampobatus. Rubus ursinus appears to be a hybrid between a close relative of R. macraei (subgenus Idaeobatus, raspberries) and an unidentified subgenus Rubus species. ITS sequences are generally consistent with biogeography and ploidy, but traditionally important morphological characters, such as stem armature and leaf type, appear to have limited phylogenetic value in Rubus. PMID- 21680349 TI - Molecular systematics of Clerodendrum (Lamiaceae): ITS sequences and total evidence. AB - Thirty-three species of Clerodendrum s.l. and five outgroup genera were included in a sequence analysis of internal transcribed spacers of the nuclear ribosomal DNA. The results of the cladistic analysis were compared to and combined with cpDNA restriction site data from a previous study. All molecular data identified four major clades within Clerodendrum s.l. and showed the genus to be polyphyletic. Clerodendrum s.s., minus Konocalyx and Cyclonema, is monophyletic and the genus should be restricted to this group. Cyclonema and Konocalyx form a clade distinct from Clerodendrum s.s., which has been recognized as Rotheca Raf. PMID- 21680350 TI - Impact of enhanced ultraviolet-B radiation on flower, pollen, and nectar production. AB - Intensified ultraviolet-B radiation or UV-B (wavelengths between 280 and 320 nm) can delay flowering and diminish lifetime flower production in a few plants. Here we studied the effects of enhanced UV-B on floral traits crucial to pollination and pollinator reproduction. We observed simultaneous flowering responses of a new crop plant, Limnanthes alba (Limnathaceae), and a wildflower, Phacelia campanularia (Hydrophyllaceae), to five lifetime UV-B dosages ranging between 2.74 and 15.93 kJ.m.d. Floral traits known to link plant pollination with bee host preference, host fidelity and larval development were measured. Intensified UV-B had no overall effect on nectar and pollen production of L. alba and P. campanularia flowers. A quadratic relationship between UV-B and nectar sugar production occurred in P. campanularia and showed that even subambient UV-B dosages can be deleterious for a floral trait. Other floral responses to UV-B were more dramatic and idiosyncratic. As UV-B dosage increased, L. alba plants were less likely to flower, but suffered no delays in flowering or reductions to lifetime flower production for those that did flower. Conversely, an equal proportion of P. campanularia plants flowered under all UV-B treatments, but these same plants experienced delayed onset to bloom and produced fewer flowers at greater UV-B intensities. Therefore, intensified UV-B elicits idiosyncratic responses in flowering phenology and flower production from these two annual plants. Diurnal patterns in nectar and pollen production strongly coincided with fluctuating humidity and only weakly with UV-B dosage. Overall, our results indicated that intensified UV-B can alter some flowering traits that impinge upon plant competition for pollinator services, as well as plant and pollinator reproductive success. PMID- 21680351 TI - Isozymatic variation and phylogenetic relationships between henequen (Agave fourcroydes) and its wild ancestor A. angustifolia (Agavaceae). AB - Isozymatic variation and phylogenetic relationships among extant henequen (Agave fourcroydes) germplasm and wild populations of its ancestor A. angustifolia in the Yucatan Peninsula in Mexico were analyzed. Analysis of three isozyme systems using starch gel electrophoresis indicated that while A. angustifolia populations have relatively high levels of variation, within each henequen cultivar all individuals were identical. This result corresponds to previous ethnobotanical and morphological analyses, which indicated severe loss of genetic variation of this domesticated plant as a consequence of the promotion by means of asexual propagation of only one cultivar since the middle of the last century. The three extant cultivars of henequen were distinct from each other. Two of them, Sac Ki (SK) and Yaax Ki (YK), could be matched within the progenitor, but Kitam Ki (KK) has a MDH electrophenotype not found in any of the plants growing inside the Yucatan Peninsula, but found in some A. angustifolia plants growing in the Mexican states of Oaxaca and Veracruz. A parsimony analysis of the morphological data indicated two lineages: that of SK and YK, cultivated cordage plants selected for stronger and longer fibers, whose sister group is the Tropical subdeciduous forest ecotype (SF), and that of all the other wild populations, which also included KK, the cultivated textile plants selected for finer fibers and nearly extinct in Yucatan. These results support the hypothesis of the yucatecan origin of SK and YK from the SF ecotype, as well as the hypothesis of a recent introduction of KK to the Yucatan Peninsula in a domestication trend that probably included also Chelem White (its cultivation being abandoned later). PMID- 21680352 TI - Genetic consequences of a single-founder population bottleneck in Trifolium amoenum (Fabaceae). AB - We investigated the genetic consequences of a single-founder bottleneck in a population of showy Indian clover (Trifolium amoenum), a species presumed to be extinct until rediscovered near Occidental, California, in 1993. Electrophoretic variation was evaluated in the bottlenecked population and in a larger population (Dillon Beach) discovered during the course of this study, as well as in populations of two closely related species, T. albopurpureum var. dichotomum and T. macraei. We found a surprisingly high amount of polymorphism in the single founder T. amoenum population from Occidental (15% of loci polymorphic; an average of 1.1 alleles per locus). However, this represents a 53% reduction in number of polymorphic loci and a 20% reduction in average number of alleles per locus compared to three Trifolium populations with putatively similar mating systems (the Dillon Beach T. amoenum population and both populations of T. albopurpureum var. dichotomum). Expanding the genetic base of the Occidental T. amoenum population is a priority due to concerns about loss of evolutionary potential and the possibility of deleterious effects associated with inbreeding. However, using seed from the Dillon Beach T. amoenum population may not be beneficial due to distinct, presumably adaptive differences between plants from the two populations and concerns about outbreeding depression. PMID- 21680353 TI - Inbreeding depression in smooth cordgrass (Spartina alterniflora, Poaceae) invading San Francisco Bay. AB - The magnitude of inbreeding depression in invading plant populations is often presumed to be small and of little consequence. The purpose of this study was to assess the magnitude of inbreeding depression in a pollen-limited, partially self incompatible, invading plant population. The magnitude and timing of inbreeding depression were compared among ten maternal plants sampled from a population of smooth cordgrass (Spartina alterniflora) invading San Francisco Bay. Selfed and outcrossed progeny were compared for embryo abortion, survival of seedlings, and growth/survival at the end of the first growing season in three greenhouse environments. Estimates of inbreeding depression varied among environments, with competitive environment > high-nutrient environment > low-nutrient environment. Population-level estimates of inbreeding depression ranged from 0.61 to 0.81; however, maternal plants varied significantly in their magnitude of inbreeding depression, ranging from 0.1 to 0.97. The 95% confidence interval for inbreeding depression for some maternal plants included zero. There was a significant negative correlation between the overall magnitude of inbreeding depression and self-fertility rate among maternal plants. The few maternal plants with high self fertility carried relatively little genetic load, and their selfed progeny are likely to survive on open mudflats. The noncompetitive, pollen-limited growing conditions associated with invasion may allow self-fertility to spread in this population. PMID- 21680354 TI - Seed provisioning in gynodioeciousSilene acaulis (Caryophyllaceae). AB - In gynodioecious species, which contain females and hermaphrodites, the outcrossed seeds of females have been found to outperform the outcrossed seeds of hermaphrodites, in spite of the fact that their seeds are not larger in mass. Females do not make pollen. Hence the nutrients that hermaphrodites allocate to pollen, such as nitrogen, might be allocated to seeds by the females, such that individual seeds from females are better provisioned than those from hermaphrodites. Alternatively, females might make more seeds, rather than better provisioned seeds. We tested the hypothesis that seeds from females would be better provisioned for the gynodioecious species Silene acaulis, by comparing seed mass, embryo/endosperm mass, nitrogen and phosphorus content, and energy content for outcrossed seeds from females and hermaphrodites produced in a natural population. We also measured the proportion of flowers that set fruit in both morphs. Seeds from the two sexual morphs were not found to differ significantly for any of the measures of seed provisioning, with seeds from females containing either nonsignificantly less or equivalent amounts of each of the measures as compared to hermaphrodites. However, females set a significantly higher proportion of their flowers to fruit, as compared to hermaphrodites. These results indicate that females do not provision individual seeds more than hermaphrodites in S. acaulis, and alternative hypotheses will need to be examined to explain the difference in the performance of the seeds from the two sexual morphs. PMID- 21680355 TI - The cytoplast concept in dividing plant cells: cytoplasmic domains and the evolution of spatially organized cell. AB - The unique cytokinetic apparatus of higher plant cells comprises two cytoskeletal systems: a predictive preprophase band of microtubules (MTs), which defines the future division site, and the phragmoplast, which mediates crosswall formation after mitosis. We review features of plant cell division in an evolutionary context and from the viewpoint that the cell is a domain of cytoplasm (cytoplast) organized around the nucleus by a cytoskeleton consisting of a single "tensegral" unit. The term "tensegrity" is a contraction of "tensional integrity" and the concept proposes that the whole cell is organized by an integrated cytoskeleton of tension elements (e.g., actin fibers) extended over compression-resistant elements (e.g., MTs).During cell division, a primary role of the spindle is seen as generating two cytoplasts from one with separation of chromosomes a later, derived function. The telophase spindle separates the newly forming cytoplasts and the overlap between half spindles (the shared edge of two new domains) dictates the position at which cytokinesis occurs. Wall MTs of higher plant cells, like the MT cytoskeleton in animal and protistan cells, spatially define the interphase cytoplast. Redeployment of actin and MTs into the preprophase band (PPB) is the overt signal that the boundary between two nascent cytoplasts has been delineated. The "actin-depleted zone" that marks the site of the PPB throughout mitosis may be a more persistent manifestation of this delineation of two domains of cortical actin. The growth of the phragmoplast is controlled by these domains, not just by the spindle. These domains play a major role in controlling the path of phragmoplast expansion. Primitive land plants show different morphological changes that reveal that the plane of division, with or without the PPB, has been determined well in advance of mitosis.The green alga Spirogyra suggests how the phragmoplast system might have evolved: cytokinesis starts with cleavage and then actin-related determinants stimulate and positionally control cell-plate formation in a phragmoplast arising from interzonal MTs from the spindle. Actin in the PPB of higher plants may be assembling into a potential furrow, imprinting a cleavage site whose persistent determinants (perhaps actin) align the outgrowing edge of the phragmoplast, as in Spirogyra. Cytochalasin spatially disrupts polarized mitosis and positioning of the phragmoplast. Thus, the tensegral interaction of actin with MTs (at the spindle pole and in the phragmoplast) is critical to morphogenesis, just as they seem to be during division of animal cells. In advanced green plants, intercalary expansion driven by turgor is controlled by MTs, which in conjunction with actin, may act as stress detectors, thereby affecting the plane of division (a response clearly evident after wounding of tissue). The PPB might be one manifestation of this strain detection apparatus. PMID- 21680356 TI - Wind-acclimated thallus morphogenesis in a lichen (Evernia prunastri, Parmeliaceae) probably favored by grazing. AB - How does the morphogenesis of a widespread epiphytic lichen interact with the environment, leading to amazingly polymorphic and wind-tolerant fruticose thalli? A series of photographs showed that the normal branches were basically even and flat with isotomic-dichotomous branchings. Numerous deviations from this basic regular pattern were found and traced back to their origins in the asymmetry of the branches' cross sections. This was observed quantitatively (statistically testable) in the field, while the thalli were growing. This large variability in growth of single branches was a prerequisite for the polymorphism seen in complete thallus growth forms. The structure and distribution of the mentioned important asymmetries in branch cross sections can best be explained by the effect of grazing on cortex and phycobiont layer. Very small-scale growth observations and experimental simulation confirmed this. In thalli with many such small-scale variations in branch growth the overall thallus growth form became wind acclimated as a result of the selective effect of wind exposure on the thallus phenotype: branches growing windwardly grew more slowly. Such thalli were well protected from being dislodged by wind, and they desiccate slowly as demonstrated by a previous study. PMID- 21680357 TI - Destruction of lichen chemical defenses by a fungal. AB - Lichen secondary metabolites are known to inhibit various animal consumers and pathogenic microorganisms. Nevertheless, many obligate fungal pathogens have evolved a tolerance to these inhibitory lichen compounds. We recently discovered a new lichen pathogen in the fungal genus Fusarium that is not only tolerant of lichen compounds but also able to degrade many of these compounds. This organism was discovered in field investigations of a different lichenicolous fungus, Marchandiomyces corallinus, which was found growing on lichens (Lasallia papulosa and L. pensylvanica) that normally inhibit its growth. Subsequent experiments established that M. corallinus is found on Lasallia species only when Fusarium is also present. We hypothesized that Fusarium altered the inhibitory chemistry of Lasallia spp. and permitted colonization by M. corallinus. A laboratory experiment to test this hypothesis demonstrated that sterilized tissues of Lasallia papulosa exposed to Fusarium for 30 d are readily degraded by M. corallinus; control tissues left in sterile water for 30 d continue to inhibit growth of M. corallinus. High performance liquid chromatography (HPLC) established that the lichen compound lecanoric acid, one of several lichen compounds that inhibit growth of M. corallinus, is degraded by extracellular enzymes produced by this newly discovered Fusarium. Taken together, our results demonstrate that enzymatic degradation of lichen compounds permits colonization of lichens by fungi that would otherwise be chemically excluded. PMID- 21680358 TI - Pollination of Picea orientalis (Pinaceae): saccus morphology governs pollen. AB - Sacci of conifer pollen do not function primarily to increase the efficiency of wind pollination as is widely thought. Rather, they are bladders and cause pollen to float upwards in a liquid drop into the ovules. This observation is seemingly unsupported in the case of oriental spruce (Picea orientalis (L.) Link), which has saccate pollen. Ovulate cones are pendant at the time of pollination, which requires that pollen sink into the ovules. Pollen of oriental spruce floats at first but within 1-2 min sinks into the ovule. As sinking does not occur in saccate pollen of other Pinaceae, a variety of techniques was used to determine anatomical differences leading to this uncharacteristic tendency. Light, scanning electron, and confocal microscopy of the pollen surface yielded no significant appearing difference between pollen of oriental spruce and white spruce. However, transmission electron microscopy of freeze-fixed/freeze-substituted hydrated pollen revealed that the ektexine of oriental spruce pollen sacci is porous compared to that of white spruce. Confocal microscopy allowed examination of pollen hydration dynamics. Water enters pollen at the distal pole between sacci, and resulting rapid expansion of the tube cell forces air out of the saccate space. White spruce pollen remains buoyant because of enclosed air pockets in the saccus ektexine. Evolutionary change in pollen wall anatomy with resultant loss of saccus function is correlated with a change in ovulate strobilus orientation at pollination in oriental spruce. A suite of characters interact in the conifer pollination mechanism, and concerted change in these characters may lead to speciation. PMID- 21680359 TI - Ontogenetic differences in mesophyll structure and chlorophyll distribution in Eucalyptus globulus ssp. globulus. AB - Mesophyll structure has been associated with the photosynthetic performance of leaves via the regulation of internal light and CO(2) profiles. Differences in mesophyll structure and chlorophyll distribution within three ontogenetically different leaf types of Eucalyptus globulus ssp. globulus were investigated. Juvenile leaves are blue-grey in color, dorsiventral (adaxial palisade layer only), hypostomatous, and approximately horizontal in orientation. In contrast, adult leaves are dark green in color, isobilateral (adaxial and abaxial palisade), amphistomatous, and nearly vertical in orientation. The transitional leaf type has structural features that appear intermediate between the juvenile and adult leaves. The ratio of mesophyll cell surface area per unit leaf surface area (A(mes)/A) of juvenile leaves was maximum at the base of a single, adaxial palisade layer and declined through the spongy mesophyll. Chlorophyll a + b content showed a coincident pattern, while the chlorophyll a:b ratio declined linearly from the adaxial to abaxial epidermis. In comparison, the mesophyll of adult leaves had a bimodal distribution of A(mes)/A, with maxima occurring beneath both the adaxial and abaxial surfaces within the first layer of multiple palisade layers. The distribution of chlorophyll a + b content had a similar pattern, although the maximum ratio of chlorophyll a:b occurred immediately beneath the adaxial and abaxial epidermis. The matching distributions of A(mes)/A and chlorophyll provide further evidence that mesophyll structure may act to influence photosynthetic performance. These changes in internal leaf structure at different life stages of E. globulus may be an adaptation for increased xeromorphy under increasing light exposure experienced from the seedling to adult tree, similar to the characteristics reported for different species according to sunlight exposure and water availability within their native habitats. PMID- 21680360 TI - A phylogenetic analysis of the Orchidaceae: evidence from rbcL nucleotide. AB - Cladistic parsimony analyses of rbcL nucleotide sequence data from 171 taxa representing nearly all tribes and subtribes of Orchidaceae are presented here. These analyses divide the family into five primary monophyletic clades: apostasioid, cypripedioid, vanilloid, orchidoid, and epidendroid orchids, arranged in that order. These clades, with the exception of the vanilloids, essentially correspond to currently recognized subfamilies. A distinct subfamily, based upon tribe Vanilleae, is supported for Vanilla and its allies. The general tree topology is, for the most part, congruent with previously published hypotheses of intrafamilial relationships; however, there is no evidence supporting the previously recognized subfamilies Spiranthoideae, Neottioideae, or Vandoideae. Subfamily Spiranthoideae is embedded within a single clade containing members of Orchidoideae and sister to tribe Diurideae. Genera representing tribe Tropideae are placed within the epidendroid clade. Most traditional subtribal units are supported within each clade, but few tribes, as currently circumscribed, are monophyletic. Although powerful in assessing monophyly of clades within the family, in this case rbcL fails to provide strong support for the interrelationships of the subfamilies (i.e., along the spine of the tree). The cladograms presented here should serve as a standard to which future morphological and molecular studies can be compared. PMID- 21680361 TI - What does morphology tell us about orchid relationships?--a cladistic. AB - A cladistic analysis of Orchidaceae was undertaken for 98 genera using 71 morphological apomorphies based on a reconsideration of previous character analyses and newly discovered variation. The equally weighted analysis found 60 000 most parsimonious trees with low consistency (CI = 0.29) but high retention (RI = 0.83). The strict consensus reveals a significant amount of structure, and most traditionally recognized subfamilies are supported as monophyletic, including the Apostasioideae, Cypripedioideae, Spiranthoideae, and Epidendroideae. Orchidoideae in the broad sense are paraphyletic, giving rise to spiranthoids. Vanilloids are sister to epidendroids, although exhibiting several states otherwise found only in clearly basal groups, such as Apostasioideae. The nonvandoid epidendroids are poorly resolved, due to a high degree of homoplasy. The vandoids appear to be monophyletic, contrary to recent molecular evidence, possibly due to repeated parallel development of the vandoid character suite. The importance of vegetative characters as evidence putatively independent from floral features is demonstrated in the placement of Tropidia. Implied weighting analysis of these data resulted in similar patterns at high levels, although the Orchidoideae and Spiranthoideae may each be monophyletic and the nonvandoid epidendroids are more resolved. The high degree of structure implied in previous orchid classifications must be reconsidered, given the poor resolution at lower levels in the present trees. PMID- 21680362 TI - Phylogenetic relationships within Korthalsella (Viscaceae) based on nuclear ITS and plastid trnL-F sequence. AB - The nuclear encoded internal transcribed spacer (ITS) region and the plastid encoded trnL-F region were sequenced for 25 populations of Korthalsella, a genus of reduced, monoecious, Old World misletoes. The molecular study confirms the hypothesis that branch shape and cladotaxy (the arrangement of branches with respect to their parent axis) are unreliable indicators of relationship in the genus and demonstrates that many of the taxa previously recognized are not monophyletic. Both gene regions identify three major subgroups within the genus and find lower level relationships within these subgroups highly correlated with geographic distance. An analysis based upon 18S and rbcL sequences identifies Ginalloa as the sister group to Korthalsella, which together with the branching order within the genus, indicates that Korthalsella originated in Papuasia and aids in elucidating evolution of the peculiar inflorescence structure. There are problems associated with species delimitation when evolutionary units are more restricted than morphological lineages, and justification is offered for recognizing only morphologically diagnosable monophyletic lineages as species. Varying substitution rates and differing modes of inheritance in ITS and trnL-F result in complementary utility of the two regions for elucidating infrageneric relationships in Korthalsella. PMID- 21680363 TI - The effects of pollen load size and donor diversity on pollen performance, selective abortion, and progeny vigor in Mirabilis jalapa. AB - The influence of pollen competitive environment on pollen performance (pollen germination, stigmatic penetration, and pollen tube growth rate), the maturation or abortion of initiated fruit, seed size, and seedling vigor was explored by manipulating the size and diversity of stigmatic pollen loads on Mirabilis jalapa. All aspects of pollen performance significantly increased with the number of pollen grains on a stigma or pollen tubes in a style, but was not influenced by the diversity of pollen donors. Plants tended to mature single-ovulate fruits that came from flowers where pollen load size and diversity were greatest and aborted those where these were lowest. No plants from seeds resulting from pollinations with a single pollen grain survived, but other fitness measures were mostly determined by maternal plant. The data suggest that pollen performance is influenced by pollen competitive environment, and both the genetic diversity of the pollen load and number of competing pollen tubes are important determinants of seed/fruit abortion. PMID- 21680364 TI - Pollen competition as a reproductive isolating mechanism between two sympatric Hibiscus species. AB - Differences in pollen tube growth rates (certation) between heterospecific (foreign) and conspecific pollen may strongly influence whether hybrid offspring are produced after mixed pollen loads are delivered to a stigma. For both members of a sympatric species pair, Hibiscus moscheutos and H. laevis, pollination by pure loads of foreign pollen resulted in fruit set that was not significantly different from conspecific pollination, indicating that pure loads of foreign pollen could readily result in hybrid offspring. However, the number of seeds per fruit from pure foreign pollinations was significantly less than that of pure conspecific pollination. Simultaneous mixed pollination resulted in a proportion of hybrid seeds (detected by an electrophoretic marker enzyme) that was significantly lower than expected based upon the capacity of foreign pollen to effect fertilization when applied in pure pollinations. After these 50/50% pollen mixtures were applied to stigmas, 8.0 and 7.4% hybrids were produced when H. moscheutos and H. laevis were the ovule parents, respectively. For these Hibiscus species, pollen competition appears to function as a barrier to hybridization that is of moderate intensity compared with similar barriers occurring between other recently studied sympatric species pairs. PMID- 21680365 TI - Floral morphological changes and reproductive success in deer weed (Lotus scoparius. AB - Pollination-related and time-dependent floral morphological changes occur in a diverse set of angiosperm taxa and appear to be particularly common in species occupying resource-limited environments. In deer weed (Lotus scoparius), such floral modifications include a color change from yellow to orange and a folding of the banner petal down over the keel. These changes are rapidly induced by pollination, but will also occur much more slowly without pollination. Orange flowers typically lack nectar and pollen. We examined the reproductive success of these plants to test the hypothesis that retention of orange flowers increases pollinator visitation rate and fruit set while reducing costs to the pollinators. All of the common species of bee pollinators that visited deer weed easily distinguished between yellow and orange flowers at close range and preferentially probed yellow flowers. Retention of orange flowers by these plants resulted in a higher frequency of pollinator visits and a higher fruit set per flower than plants that lacked orange flowers. The number of flowers visited by each pollinator was lower on plants with a mixture of yellow and orange flowers, suggesting that the presence of orange flowers may reduce selfing. The possible selective pressures involved in the evolution of these mechanisms and their relation to stressful environments are also discussed. PMID- 21680366 TI - Sex allocation and reproductive success in the andromonoecious perennial Solanum carolinense (Solanaceae). I. Female. AB - Relative allocation of resources to growth vs. reproduction has long been known to be an important determinant of reproductive success. The importance of variation in allocation to different structures within reproductive allocation is somewhat less clear. This study was designed to elucidate the importance of allocation to vegetative vs. reproductive functions, and allocation within reproductive functions (sex allocation), to realized female success in an andromonoecious plant, Solanum carolinense. Allocation measurements were taken on plants in experimental arrays exposed to natural pollination conditions. These measurements included total flower number, the proportion of flowers that were male, flower size, and vegetative size. Flower number explained the majority of the variation among individuals in their success-that is, there was strong selection for increased flower production. There was also selection to decrease the proportion of flowers that were male, but neither flower size nor vegetative size (a measure of overall resource availability) were direct determinants of female success. After Bonferroni corrections for multiple comparisons, most phenotypic correlations among the traits measured were nonsignificant. Thus, in this andromonoecious species there is not a strong relationship between resource availability (vegetative size) and female success, and female success is instead determined by the relative production of the two different flower types. PMID- 21680367 TI - The effect of geographic range and dichogamy on genetic variability and population genetic structure in Tricyrtis section Flavae. AB - Populations of each of the four species of Tricyrtis sect. Flavae were sampled using enzyme electrophoresis to examine the effect of geographic range and dichogamy on the genetic diversity of the species. The most widespread species, T. nana, had the lowest level of genetic diversity at both the population and the species level. The depauperate genetic diversity at the population level of T. nana appears to result from the high self-fertilization of the species. The low genetic diversity at the species level of T. nana probably resulted from the bottleneck effect during the speciation process in which this species diverged from the progenitor species, T. flava. Genetic differentiation among populations was high in both adichogamous T. nana and protandrous T. flava. High self fertilization in T. nana and the colonizing nature of T. flava are likely the main factors causing the differentiated population genetic structure. In contrast to a previous study on chloroplast DNA (cpDNA) variation in Tricyrtis sect. Flavae, T. nana was most closely related to T. flava, which corresponds to the morphological resemblance of both species. PMID- 21680368 TI - Levels and patterns of genetic variation in the endangered species Abronia macrocarpa. AB - Genetic variation was evaluated in the federally endangered species Abronia macrocarpa (large-fruited sand-verbena), an herbaceous perennial restricted to deep sandy soils and endemic to three counties of east-central Texas. Seven of the ten known populations were sampled and analyzed using starch gel electrophoresis of eight enzymes coded by 18 interpretable loci. Duplicate gene expression was observed for four loci, suggesting polyploid ancestry for the lineage that includes A. macrocarpa. Values for estimators of genetic polymorphism within populations (ranges: P = 38.9%-61.1%, A = 1.7-2.1, H = 0.122 0.279) exceeded average values for seed plants (P = 34.2%, A = 1.53, H = 0.113). Genotype proportions at most loci in most populations were in Hardy-Weinberg equilibrium, consistent with obligate outcrossing previously documented for this species; exceptions could be attributed to population substructure. Values of F(ST) tended to be high, ranging from 0.021 to 0.481 for individual loci (mean F(ST) = 0.272), indicating substantial divergence and limited gene flow among populations, despite their close geographic proximity. Pairwise values of Nei's genetic identity between populations ranged from 0.799 to 0.975 and tended to be influenced by geographic proximity of population pairs. Collectively, these data suggest a long history of isolation among populations that have not been subjected to bottlenecks. Isolation of A. macrocarpa populations apparently results from the disjunct occurrence of suitable habitat and perhaps has been accentuated by human disturbance. PMID- 21680369 TI - Three groups of species in Petunia sensu Jussieu (Solanaceae) inferred from the intact seed. AB - The intact seed surface morphology in 45 taxa of Petunia sensu Jussieu native to South America (Petunia sensu Wijsman plus Calibrachoa) was compared under scanning electron microscopy. The existence of three groups of species, differentiated in terms of seed morphology, was revealed as follows: (1) all species of Petunia sensu Wijsman, having coarse wavy middle lamellae and anticlinal walls; (2) Calibrachoa parviflora and C. pygmaea, having fine wavy middle lamellae embedded in straight anticlinal walls; and (3) the other species of Calibrachoa, having straight middle lamellae and anticlinal walls. Close relationships between seed morphology and the other characteristics observable in the groups of species are discussed. PMID- 21680370 TI - Integrative approaches to biogeography: patterns and processes on land and in the sea. AB - At the 2002 SICB meeting in Anaheim, we brought together some of the leaders in terrestrial and marine phylogeography for a day-long symposium. This symposium combined presentations from ten scientists whose question-driven research focuses on testing hypotheses about patterns and processes in biogeography in both vertebrate and invertebrate animals and including marine, terrestrial, and freshwater systems. The papers gathered here cover the breadth of the presentations. By explicitly seeking to combine marine and terrestrial workers into a single symposium we hoped that the different patterns and processes that predominate in major biomes and the different assumptions made by the workers in those areas would be highlighted. PMID- 21680371 TI - Phylogeography of four frog species in forest fragments of northeastern Brazil--a preliminary study. AB - I contrast mitochondrial DNA genealogies based on 612 bp of the cytochrome b gene across four co-distributed species of frogs in Northeastern Brazil. They are Hyla albomarginata, Hyla branneri, Proceratophrys boiei, and Scinax nebulosus. Samples were collected from the core or edge of six rainforest remnants in the states of Pernambuco and Alagoas. Three fragments are located within the humid Atlantic Forest morphoclimatic domain (municipalities of Cabo de Santo Agostinho, Ibateguara, and Jaqueira), two are located in the transition zone between the Atlantic Forest domain and the semi-arid Caatinga (Caruaru and Timbauba), and one is found within the Caatinga (Brejo da Madre de Deus). Results show that local patterns and levels of genetic diversity are influenced by taxon-specific habitat requirements. Populations of the montane, closed-canopy species P. boiei show strong geographical structure, reflecting barriers to gene flow that predate human-driven habitat destruction. Species occurring along forest edges, such as H. albomarginata and S. nebulosus, show genetic patterns similar to those of P. boiei, but lower levels of genetic divergence. The more generalist Hyla branneri shows no geographic pattern. The data are in agreement with distribution and fossil data gathered for other groups of organisms, suggesting that mesic forests occupied the currently arid Caatinga in the recent past. PMID- 21680372 TI - Diversification in the tropical pacific: comparisons between marine and terrestrial systems and the importance of founder speciation. AB - Patterns of distribution and processes of differentiation have often been contrasted between terrestrial and marine biotas. The islands of Oceania offer an excellent setting to explore this contrast, because the geographic setting for terrestrial and shallow-water, benthic, marine organisms are the same: the myriad islands strewn across the vast Pacific. The size of species ranges and the geographic distribution of endemism are two biogeographic attributes that are thought to differ markedly between terrestrial and marine biotas in the Pacific. While terrestrial species are frequently confined to single islands or archipelagoes throughout Oceania, marine species tend to have wide to very wide distributions, and are rarely restricted to single island groups except for the most isolated archipelagoes. We explore the conditions under which species can reach an island by dispersal and differentiate. Genetic differentiation can occur either through founder speciation or vicariance; these processes are requisite ends of a continuum. We show that founder speciation is most likely when few propagules enter the dispersal medium and survive well while they travel far. We argue that conditions favorable to founder speciation are common in marine as well as terrestrial systems, and that terrestrial-type, archipelagic-level endemism is likely common in marine taxa. We give examples of marine groups that show archipelagic level endemism on most Pacific island groups as well as of terrestrial species that are widespread. Thus both the patterns and processes of insular diversification are variable, and overlap more between land and sea than previously considered. PMID- 21680373 TI - The geography of evolutionary opportunity: hypothesis and two cases in gastropods. AB - Evolutionary innovations that require or provide increased per-capita energy budgets and competitive performance should appear at times and in places where resources are abundant and accessible and where predators and competitors impose intense selection. By contrast, innovations without functional benefits should become established in productive environments under conditions of weak selection from enemies. I confirmed these predictions in comparative studies of two types of innovation in gastropod shells. The labral tooth, a structure facilitating predation, appeared in 45 Cenozoic clades of marine gastropods, with the highest concentrations originating during the early Miocene, late Miocene, and Pliocene, all times and sites of high planktonic productivity, large expanses of warm shallow water, and diverse predator-rich biotas. Left-handed coiling, a condition with no obvious survival benefits, arose 19 times independently in right-handed clades. Most left-handed clades, including eight arising in regions outside the tropics, evolved in productive regions where the larva and/or the adult is shielded from intense predation. The times and places of origin of new traits in clades thus offer insights into the geography of evolutionary opportunity. PMID- 21680374 TI - The marine indo-west pacific break: contrasting the resolving power of mitochondrial and nuclear genes. AB - Simultaneous studies of both nuclear and mitochondrial markers were undertaken in two widespread Indo-West Pacific (IWP) marine invertebrates to compare and contrast the ability of these markers to resolve genetic structure. In particular, we were interested in the resolution of a genetic break between the Indian and Pacific Oceans due to historical isolation. Sequence variation from the nuclear gene encoding myosin heavy chain (MyHC) and the mitochondrial gene cytochrome oxidase I (COI) were examined for the snapping shrimp Alpheus lottini from wide-ranging populations throughout the Indian and Pacific Oceans. A previously identified genetic break between oceans based on COI sequences appears to have been an artifact caused by the inadvertent inclusion of pseudogene sequences; our new COI data provide evidence only of a break between IWP and East Pacific populations. Distribution of a single nucleotide polymorphism in MyHC, on the other hand, shows evidence of a cline between Indian and Pacific Oceans. New allozyme and mtDNA sequence data were also obtained for the starfish Linckia laevigata. Allozyme data show a clear genetic break between Indian Ocean populations and Pacific (including western Australian) populations, whereas the distribution of mtDNA haplotypes shows a region of overlap in the central IWP. Comparisons of our data for both Alpheus and Linckia with data from other population genetic studies in the IWP suggest that nuclear markers (allozymes, sequence data and morphological characters) may in some instances reveal historical patterns of genetic population structure whereas mtDNA variation better reflects present day patterns of gene flow. PMID- 21680375 TI - Methods in comparative phylogeography, and their application to studying evolution in the north american aridlands. AB - Historical biogeography and comparative phylogeography have much in common. Both seek to discover common historical patterns in the elements of biotas, although typically at different tiers of evolutionary history. Comparative phylogeography is based on phylogeographic analyses of multiple taxa, usually widespread species. By comparing the phylogeographic structures of numerous widespread sympatric species, one can infer whether the current fauna has been historically stable, as evidenced by the relative frequency of geographically congruent reciprocally monophyletic groups. Alternatively, if species distributions are ephemeral over evolutionary time, a mixture of phylogeographic structures is expected. Coalescence analyses contribute information about history irrespective of whether haplotype phylogenies are structured or not. In the aridlands of North America, several isolating events are evident in the phylogeographic patterns of birds, mammals and herps. A mid-peninsular seaway in Baja California, dated at ca. one million years before present, had a pervasive effect, with 13 of 16 assayed species showing a concordant split. Hence, this community appears to have been a stable assemblage of species over the past one million years. In contrast, the avifauna of the Sonoran-Chihuahuan deserts consists of two species with a concordant split and three other species that are undifferentiated across both deserts. Hence, the species in this area have had different histories. The Baja biota appears to resemble its ancestral configuration to a greater degree than the Sonoran-Chihuahuan one. A deeper evolutionary event separated taxa in Baja California from the eastern deserts, showing that the aridlands fauna was affected by events at different times resulting in overlain tiers of history. PMID- 21680376 TI - Dynamics and energetics of animal swimming and flying: introduction. PMID- 21680377 TI - Quantitative flow visualization: toward a comprehensive flow diagnostic tool. AB - Quantitative flow visualization has many roots and has taken several approaches. The advent of digital image processing has made it possible to practically extract useful information from every kind of flow image. In a direct approach, the image intensity or color (wavelength or frequency) can be used as an indication of concentration, density and temperature fields or gradients of these scalar fields in the flow (Merzkirch, 1987). For whole-field velocity measurement, the method of choice by experimental fluid mechanicians has been the technique of Particle Image Velocimetry (DPIV). This paper presents a novel approach to extend the DPIV technique from a planar method to a full three dimensional volume mapping technique useful in both engineering and biological applications. PMID- 21680378 TI - Flow Patterns Around the Carapaces of Rigid-bodied, Multi-propulsor Boxfishes (Teleostei: Ostraciidae). AB - Boxfishes (Teleostei: Ostraciidae) are rigid-body, multi-propulsor swimmers that exhibit unusually small amplitude recoil movements during rectilinear locomotion. Mechanisms producing the smooth swimming trajectories of these fishes are unknown, however. Therefore, we have studied the roles the bony carapaces of these fishes play in generating this dynamic stability. Features of the carapaces of four morphologically distinct species of boxfishes were measured, and anatomically-exact stereolithographic models of the boxfishes were constructed. Flow patterns around each model were investigated using three methods: 1) digital particle image velocimetry (DPIV), 2) pressure distribution measurements, and 3) force balance measurements. Significant differences in both cross-sectional and longitudinal carapace morphology were detected among the four species. However, results from the three interrelated approaches indicate that flow patterns around the various carapaces are remarkably similar. DPIV results revealed that the keels of all boxfishes generate strong longitudinal vortices that vary in strength and position with angle of attack. In areas where attached, concentrated vorticity was detected using DPIV, low pressure also was detected at the carapace surface using pressure sensors. Predictions of the effects of both observed vortical flow patterns and pressure distributions on the carapace were consistent with actual forces and moments measured using the force balance. Most notably, the three complementary experimental approaches consistently indicate that the ventral keels of all boxfishes, and in some species the dorsal keels as well, effectively generate self-correcting forces for pitching motions-a characteristic that is advantageous for the highly variable velocity fields in which these fishes reside. PMID- 21680379 TI - Riding the waves: the role of the body wave in undulatory fish swimming. AB - A continuously swimming mullet modulates its thrust production by changing slip the ratio between its swimming speed U and the speed V with which the body wave travels down its body. This variation in thrust is reflected in the wake of the fish. We obtained 2-dimensional impressions of the wake behind a mullet swimming at a slip of 0.7 equivalent to active swimming, at a slip of 0.9 close to free wheeling, and at a slip of 1.1 when the fish is braking. Independent of the slip, vortices are shed at the tail when the tail tip reaches its maximum lateral excursion. The manner in which the wake changes as it decays depends on the degree of slip: At a slip well below unity, the wake decays without any qualitative changes in shape, the medio-frontal cross section of the mature wake consists of a double row of alternating vortices separated by an undulating jet, and the angle between the jet flow and the mean path of motion is close to 45 degrees ; at a slip above unity, the vortices stretch out laterally and the mature wake resembles a single row of oval vortices with two vortex cores, and the jet between the vortices is almost perpendicular to the mean path of motion; the wake at slip of 0.9 exhibits a pattern intermediate between the wakes at slips 0.7 and 0.9 with slightly elongate vortices and a jet angle of 61 degrees . PMID- 21680380 TI - The scaling and structure of aquatic animal wakes. AB - Animal generated water movements are visualized and quantified using two dimensional particle image velocimetry (PIV). The resulting vector flow fields allow for the study of the distribution of velocity, vorticity and vortices. Structural and temporal aspects of animal-induced flows covering a range of Reynolds (Re) numbers between less than 1 to more than 10(4) are presented.Maps of flow induced by continuous foraging and intermittent escape responses of tethered nauplius and copepodid stages of the marine copepod Temora longicornis offer insight in viscosity-dominated flow regimes. Fast escape responses of the equally sized largest nauplius stage and the smallest copepodid stage are compared. The nauplius moves by generating a viscous flow pattern with high velocities and vorticity; the copepodid moves by using inertial effects to produce a vortex ring with a rearward jet through the center.Larvae and small adult fish (zebra danio) use a burst-and-coast-swimming mode at Re numbers up to 6,000, shedding a vortex ring with the associated jet at the tail during the burst phase. Flow patterns during the coasting phase differ between the small larvae and larger adults due to the changes in importance of viscosity.A 12 cm long mullet swimming in a continuous mode generates a chain of vortex rings with a backward undulating jet through the centers of the rings at Re numbers of 4 * 10(4) in inertia-dominated regimes.Our empirical results provide realistic insight in the scale effects determining the morphology of the interactions between animals and water. PMID- 21680381 TI - Wake dynamics and locomotor function in fishes: interpreting evolutionary patterns in pectoral fin design. AB - The great anatomical diversification of paired fins within the Actinopterygii (ray-finned fishes) can be understood as a suite of evolutionary transformations in design. At a broad taxonomic scale, two clear trends exist in the morphology of the anteriorly situated pectoral fins. In comparing basal to more derived clades, there are general patterns of (i) reorientation of the pectoral fin base from a nearly horizontal to more vertical inclination, and (ii) migration of the pectoral fin from a ventral to mid-dorsal body position. As yet, the functional significance of these historical trends in pectoral fin design remains largely untested by experiment. In this paper we test the proposal that variation in pectoral fin structure has an important influence on the magnitude and orientation of fluid forces generated during maneuvering locomotion. Using digital particle image velocimetry for quantitative wake visualization, we measure swimming forces in ray-finned fishes exhibiting the plesiomorphic and apomorphic pectoral fin anatomy. Our experiments focus on rainbow trout (Oncorhynchus mykiss), a lower teleost with pectoral fins positioned ventrally and with nearly horizontally inclined fin bases, and bluegill sunfish (Lepomis macrochirus), a relatively derived perciform fish with more vertically oriented pectoral fins positioned mid-dorsally on the body. In support of hypotheses arising from our prior wake studies and previously untested models in the literature, we find that the pectoral fins of sunfish generate significantly higher forces for turning and direct braking forces closer to the center of mass of the body than the pectoral fins of trout. These results provide insight into the hydrodynamic importance of major evolutionary transformations in pectoral fin morphology within the Actinopterygii. PMID- 21680382 TI - Experimental Hydrodynamics and Evolution: Function of Median Fins in Ray-finned Fishes. AB - The median fins of fishes consist of the dorsal, anal, and caudal fins and have long been thought to play an important role in generating locomotor force during both steady swimming and maneuvering. But the orientations and magnitudes of these forces, the mechanisms by which they are generated, and how fish modulate median fin forces have remained largely unknown until the recent advent of Digital Particle Image Velocimetry (DPIV) which allows empirical analysis of force magnitude and direction. Experimental hydrodynamic studies of median fin function in fishes are of special utility when conducted in a comparative phylogenetic context, and we have examined fin function in four ray-finned fish clades (sturgeon, trout, sunfish, and mackerel) with the goal of testing classical hypotheses of fin function and evolution. In this paper we summarize two recent technical developments in DPIV methodology, and discuss key recent findings relevant to median fin function. High-resolution DPIV using a recursive local-correlation algorithm allows quantification of small vortices, while stereo DPIV permits simultaneous measurement of x, y, and z flow velocity components within a single planar light sheet. Analyses of median fin wakes reveal that lateral forces are high relative to thrust force, and that mechanical performance of median fins (i.e., thrust as a proportion of total force) averages 0.35, a surprisingly low value. Large lateral forces which could arise as an unavoidable consequence of thrust generation using an undulatory propulsor may also enhance stability and maneuverability. Analysis of hydrodynamic function of the soft dorsal fin in bluegill sunfish shows that a thrust wake is generated that accounts for 12% of total thrust and that the thrust generation by the caudal fin may be enhanced by interception of the dorsal fin wake. Integration of experimental studies of fin wakes, computational approaches, and mechanical models of fin function promise understanding of instantaneous forces on fish fins during the propulsive cycle as well as exploration of a broader locomotor design space and its hydrodynamic consequences. PMID- 21680383 TI - Power requirements of swimming: do new methods resolve old questions? AB - A recurring question in the study of fish biomechanics and energetics is the mechanical power required for tail-swimming at the high speeds seen among aquatic vertebrates. The quest for answers has been driven by conceptual advances in fluid dynamics, starting with ideas on the boundary layer and drag initiated by Prandtl, and in measurement techniques starting with force balances focussing on drag and thrust. Drag (=thrust) from measurements on physical models, carcasses, kinematics as inputs to hydromechanical models, and physiological power sources vary from less than that expected for an equivalent rigid reference to over an order of magnitude greater. Estimates of drag and thrust using recent advances largely made possible by increased computing power have not resolved the discrepancy. Sources of drag and thrust are not separable in axial undulatory self propulsion, are open to interpretation and Froude efficiency is zero. Wakes are not easily interpreted, especially for thrust evaluation. We suggest the best measures of swimming performance are velocity and power consumption for which 2D inviscid simulations can give realistic predictions. Steady swimming power is several times that required for towing an equivalent flat plate at the same speed. PMID- 21680384 TI - Vorticity Control in Fish-like Propulsion and Maneuvering. AB - Vorticity control is employed by marine animals to enhance performance in maneuvering and propulsion. Studies on fish-like robots and experimental apparatus modelling rigid and flexible fins provide some of the basic mechanisms employed for controlling vorticity. PMID- 21680385 TI - Kinematics, dynamics, and energetics of rowing and flapping propulsion in fishes. AB - The shape and motion of the pectoral fins vary considerably among fishes that swim in the labriform mode. Pectoral fin motion in fishes is highly variable, but one conspicuous axis of this variation is the rowing-flapping axis. At one extreme of this axis, paddle-shaped fins row back and forth in a plane that is parallel to fish motion, while at the other extreme, wing-shaped fins flap up and down in a plane that is perpendicular to fish motion. We have used two fish, the threespine stickleback (Gasterosteus aculeatus) and the bird wrasse (Gomphosus varius), that fall near the extremes of the rowing-flapping axis to study the dynamic, energetic, and ecological and evolutionary consequences of this kinematic variation. Our work confirms some traditionally held assumptions about rowing and flapping dynamics and energetics but reject others. A computer simulation experiment of virtual rowing and flapping appendages makes several predictions about differences in maneuvering performance and swimming energetics between rowing and flapping, which, in turn, make predictions about the behavior and ecological distribution of fishes that vary along the rowing-flapping axis. Both laboratory and field studies of labrid swimming ability and distribution support these predictions. PMID- 21680386 TI - Flexible wings and fins: bending by inertial or fluid-dynamic forces? AB - Flapping flight and swimming in many organisms is accompanied by significant bending of flexible wings and fins. The instantaneous shape of wings and fins has, in turn, a profound effect on the fluid dynamic forces they can generate, with non-monotonic relationships between the pattern of deformation waves passing along the wing and the thrust developed. Many of these deformations arise, in part, from the passive mechanics of oscillating a flexible air- or hydrofoil. At the same time, however, their instantaneous shape may well emerge from details of the fluid loading. This issue-the extent to which there is feedback between the instantaneous wing shape and the fluid dynamic loading-is core to understanding flight control. We ask to what extent surface shape of wings and fins is controlled by structural mechanics versus fluid dynamic loading. To address this issue, we use a combination of computational and analytic methods to explore how bending stresses arising from inertial-elastic mechanisms compare to those stresses that arise from fluid pressure forces. Our analyses suggest that for certain combinations of wing stiffness, wing motions, and fluid density, fluid pressure stresses play a relatively minor role in determining wing shape. Nearly all of these combinations correspond to wings moving in air. The exciting feature provided by this analysis is that, for high Reynolds number motions where linear potential flow equations provide reasonable estimates of lift and thrust, we can finally examine how wing structure affects flight performance. Armed with this approach, we then show how modest levels of passive elasticity can affect thrust for a given level of energy input in the form of an inertial oscillation of a compliant foil. PMID- 21680387 TI - Computational biological fluid dynamics: digitizing and visualizing animal swimming and flying. AB - Characterized by complex geometry and complicated dynamic process, biological fluid dynamics in swimming and flying is usually of large scale vortex flows with four-dimensional nature, namely, spatial three-dimensional and one-dimensional in time. Conventional theories for understanding power and energetics in swimming and flying rely exclusively on the consistent potential flow formulation in qualitatively analyzing the physics as well as the observations and measurements in visualizing the flows so as to support the theories. In the present paper we address a new paradigm of the so-called, simulation-based biological fluid dynamics that can digitize and visualize swimming and flying by using computational mechanical modeling of the biological fluid dynamics through faithful reconstruction of morphology and realistic representation of kinematics of an individual object. We demonstrate an integrated computational system as a baseline for the simulation-based biological fluid dynamics, which involves four subsystems of the morphological modeling, the kinematic modeling, the computational fluid dynamic modeling, and the post-processing for visualization. Applications of a realistic model of insect flapping flight and an extensive study on the Micro Air Vehicle are then presented and discussed. PMID- 21680388 TI - The merits and implications of travel by swimming, flight and running for animals of different sizes. AB - Simple models are presented of the energetics of annual migration and of central place foraging, taking account of the speed and energy cost of the journeys. They are applied to insects, fish, birds and mammals of a wide range of sizes, which travel by flapping or soaring flight, by swimming or by running. It is shown that annual migrations of several thousand kilometres are unlikely to be beneficial except for marine mammals and flying birds. Marine mammals and large flying birds are the animals most likely to be able to benefit from foraging over very large distances. Observed migration and foraging ranges generally lie within the limits predicted by the models. PMID- 21680389 TI - Telemetered cephalopod energetics: swimming, soaring, and blimping. AB - Cephalopods are uniquely suited to field energetic studies. Their hollow mantles that pump water for respiration and jetting also can accommodate differential transducer-transmitters. These transmitters indicate pressure-flow power output, which can be calibrated against oxygen consumption by swim-tunnel respirometry. Radio-acoustic positioning telemetry (RAPT) records pressure-flow power and animal movements with meter accuracy in nature. Despite inherent inefficiencies, jetting is the primary mode of locomotion for both primitive nautilus and powerful, migratory oceanic squids. In between, large-finned squid and cuttlefish mix jetting with fin undulation in complex gaits that increase locomotor efficiency. Our studies show that the complex nervous systems cephalopods evolved to control mixed gaits are also sensitive to flow and density fields in nature and that they use these to further reduce locomotion costs. Buoyed up by evacuated shells, nautilus and cuttlefish live in boundary layers and navigate cheaply through them like balloonists. Large-finned, negatively buoyant squid soar like eagles in rising currents, but lose control in currents above one body length per second. Many muscular squids have life histories linked to current systems. Neutrally buoyant ammoniacal cephalopods in the mesopelagic are a limiting case in need of study. The small density differential between seawater and isotonic ammonium chloride trebles their volume, making them blimp-like with very low power densities. Some species live entirely in this restricted habitat, but most become ammoniacal late in ontogeny, as they approach semelparous reproduction. Ammonium retained for buoyancy as carbon is terminally mobilized from muscle protein for gametes and energy, compensates for lost muscle power. PMID- 21680390 TI - Dynamics of dolphin porpoising revisited. AB - Porpoising is the popular name for the high-speed surface piercing motion of dolphins and other species, in which long, ballistic jumps are alternated with sections of swimming close to the surface. The first analysis of this behavior (Au and Weihs, 1980) showed that above a certain "crossover" speed this behavior is energetically advantageous, as the reduction in drag due to movement in the air becomes greater than the added cost of leaping.Since that publication several studies documented porpoising behavior at high speeds. The observations indicated that the behavior was more complex than previously assumed. The leaps were interspersed with relatively long swimming bouts, of about twice the leap length. In the present paper, the possibility of dolphins using a combination of leaping and burst and coast swimming is examined. A three-phase model is proposed, in which the dolphin leaps out of the water at a speed U(f), which is the final speed obtained at the end of the burst phase of burst and coast swimming. The leap is at constant speed and so the animal returns to the water at U(f), goes to a shallow depth and starts horizontal coasting while losing speed, till it reaches U(i). At that point it starts active swimming, accelerating to U(f). It then starts the next leap. Ranges of speeds for which this three-stage swimming is advantageous are calculated as a function of animal and physical parameters.NotationC-Constant defined in equation (12)C(D)-Coasting drag coefficientD-Dragg-Gravitational accelerationH-Height of jumpJ-Energy required for jumpk-Ratio of swim length to jump lengthl-DistanceL-Total distance (eq. 28)m Added massM-Animal massM(1)-Total massr-Coefficient defined in eq. (22)R-Ratio of energies, for three-phase swimmingR(2)-Ratio of energies, for burst and coast swimmingt-TimeT-ThrustU-SpeedV-Body volumeW-Weightalpha-Emergence (=return) anglebeta-Swim / coast drag penalty ratiogamma-Surface effects drag ratiorho Density of seawater and cetacean.Subscriptsa-airav-Averageb-Burst phasec-Coast phasee-Reference (maximal) thrustf-Final, at end of bursti-Initial, at start of burstj-Jump phasen-Nominal reference thrusto-Optimals-Surface swimmingw-Water. PMID- 21680391 TI - Mechanisms of adhesion in geckos. AB - The extraordinary adhesive capabilities of geckos have challenged explanation for millennia, since Aristotle first recorded his observations. We have discovered many of the secrets of gecko adhesion, yet the millions of dry, adhesive setae on the toes of geckos continue to generate puzzling new questions and valuable answers. Each epidermally-derived, keratinous seta ends in hundreds of 200 nm spatular tips, permitting intimate contact with rough and smooth surfaces alike. Prior studies suggested that adhesive force in gecko setae was directly proportional to the water droplet contact angle (theta) , an indicator of the free surface energy of a substrate. In contrast, new theory suggests that adhesion energy between a gecko seta and a surface (W(GS)) is in fact proportional to (1 + costheta), and only for theta > 60 degrees . A reanalysis of prior data, in combination with our recent study, support the van der Waals hypothesis of gecko adhesion, and contradict surface hydrophobicity as a predictor of adhesion force. Previously, we and our collaborators measured the force production of a single seta. Initial efforts to attach a seta failed because of improper 3D orientation. However, by simulating the dynamics of gecko limbs during climbing (based on force plate data) we discovered that, in single setae, a small normal preload, combined with a 5 MUm displacement yielded a very large adhesive force of 200 microNewton (MUN), 10 times that predicted by whole animal measurements. 6.5 million setae of a single tokay gecko attached maximally could generate 130 kg force. This raises the question of how geckos manage to detach their feet in just 15 ms. We discovered that simply increasing the angle that the setal shaft makes with the substrate to 30 degrees causes detachment. Understanding how simultaneous attachment and release of millions of setae are controlled will require an approach that integrates levels ranging from molecules to lizards. PMID- 21680392 TI - Attachment to plant surface waxes by an insect predator. AB - Insects foraging on plant surfaces must attach to the layer of lipophilic materials known as epicuticular waxes (EW) that cover these surfaces. In this paper, we briefly review the evidence that variation in EW morphology can influence the ecology of herbivorous insects directly, by affecting their attachment to plant surfaces, and indirectly by affecting attachment by actively foraging predatory insects to plant surfaces. We then present new data examining how EW micromorphology and chemical composition of Brassica oleracea influence attachment by the predatory beetle, Hippodamia convergens (Coccinellidae). Bioassays with genotypes of B. oleracea differing in wax characteristics, and with EW extracts from these plants applied to glass, show that wax crystals disrupt attachment. In addition, bioassays show that attachment by H. convergens differs among EW extracts prepared to have smooth surfaces without crystals. The differences in attachment under these conditions are evidently due to the chemical composition of the waxes. Bioassays with two pure wax constituents show that wax composition can significantly affect attachment by H. convergens. The study opens the way for using a similar approach to understand attachment by insects to waxy plant surfaces. PMID- 21680393 TI - An integrative study of insect adhesion: mechanics and wet adhesion of pretarsal pads in ants. AB - Many animals that locomote by legs possess adhesive pads. Such organs are rapidly releasable and adhesive forces can be controlled during walking and running. This capacity results from the interaction of adhesive with complex mechanical systems. Here we present an integrative study of the mechanics and adhesion of smooth attachment pads (arolia) in Asian Weaver ants (Oecophylla smaragdina). Arolia can be unfolded and folded back with each step. They are extended either actively by contraction of the claw flexor muscle or passively when legs are pulled toward the body. Regulation of arolium use and surface attachment includes purely mechanical control inherent in the arrangement of the claw flexor system.Predictions derived from a 'wet' adhesion mechanism were tested by measuring attachment forces on a smooth surface using a centrifuge technique. Consistent with the behavior of a viscid secretion, frictional forces per unit contact area linearly increased with sliding velocity and the increment strongly decreased with temperature.We studied the nature and dimensions of the adhesive liquid film using Interference Reflection Microscopy (IRM). Analysis of 'footprint' droplets showed that they are hydrophobic and form low contact angles. In vivo IRM of insect pads in contact with glass, however, revealed that the adhesive liquid film not only consists of a hydrophobic fluid, but also of a volatile, hydrophilic phase. IRM allows estimation of the height of the liquid film and its viscosity. Preliminary data indicate that the adhesive secretion alone is insufficient to explain the observed friction and that rubbery deformation of the pad cuticle is involved. PMID- 21680394 TI - Biomechanics of adhesion in sea cucumber cuvierian tubules (echinodermata, holothuroidea). AB - Several species of sea cucumbers, all belonging to a single family, possess a peculiar and specialized defense system, the Cuvierian tubules. It is mobilized when the animal is mechanically stimulated, resulting in the discharge of a few white filaments, the tubules. In seawater, the expelled tubules lengthen considerably and become sticky upon contact with any object. The adhesiveness of their outer epithelium combined with the tensile strength of their collagenous core make Cuvierian tubules very efficient at entangling and immobilizing most potential predators. We have designed a method to measure the adhesion of holothuroid Cuvierian tubules. Tubule adhesive strength was measured in seven species of sea cucumbers belonging to the genera Bohadschia, Holothuria and Pearsonothuria. The tenacities (force per unit area) varied from 30 to 135 kPa, falling within the range reported for marine organisms using non-permanent adhesion. Two species, H. forskali and H. leucospilota, were selected as model species to study the influence of various factors on Cuvierian tubule adhesive strength. Tubule tenacity varied with substratum, temperature and salinity of the seawater, and time following expulsion. These differences give insight into the molecular mechanisms underlying Cuvierian tubule adhesion. Tenacity differences between substrata of varying surface free energy indicate the importance of polar interactions in adhesion. Variation due to temperature and time after expulsion suggests that an increase of tubule rigidity, presumably under enzymatic control, takes place after tubule elongation and reinforces adhesion by minimizing peeling effects. PMID- 21680395 TI - The influence of surface wettability on the adhesion strength of settled spores of the green alga enteromorpha and the diatom amphora. AB - In this paper we report on the effect of surface wettability on surface selection and adhesion properties of settled (adhered) spores of the biofouling marine alga Enteromorpha and cells of the diatom Amphora, through the use of patterned self assembled monolayers (SAMs). The SAMs were formed from alkanethiols terminated with methyl (CH(3)) or hydroxyl (OH) groups, or mixtures of the two, creating a discontinuous gradient of wettability as measured by advancing water contact angle. In the case of Enteromorpha, primary adhesion, as measured by the transition from a motile spore to a settled, sessile organism, is strongly promoted by the hydrophobic surfaces. On the other hand, adhesion strength of the settled spores, as measured by resistance to detachment in a turbulent flow cell, is greatest on a hydrophilic surface. In the case of Amphora, there is little influence of surface wettability on the primary adhesion of this organism, but motility is inhibited at contact angles >=60 degrees and the cells are more strongly adhered to hydrophobic surfaces. Adhesion strength of Enteromorpha spores is also influenced by group size, spores in groups being more resistant to detachment than single spores. PMID- 21680396 TI - Stickiness--some fundamentals of adhesion. AB - We review some adhesion mechanisms that have been understood in the field of synthetic adhesives, and more precisely for adhesives that adhere instantaneously (a property named tackiness) and whose adhesive strength usually depends on the applied pressure (pressure-sensitive adhesives). The discussion includes effects of surface roughness, elasticity, cavitation, viscous and elastic fingering, substrate flexibility. PMID- 21680397 TI - Structural design and biomechanics of friction-based releasable attachment devices in insects. AB - Design of attachment devices in insects varies enormously in relation to different functional loads. Many systems, located on different parts of the body, involve surfaces with particular frictional properties. Such systems evolved to attach parts of the body to each other, or to attach an insect to the substratum by providing fast and reversible attachment/detachment. Among these systems, there are some that deal with predefined surfaces, and others, in which one surface remains unpredictable. The first type of system occurs, for example, in wing-locking devices and head-arresting systems and is called probabilistic fasteners. The second type is mainly represented by insect attachment pads of two alternative designs: hairy and smooth. The relationship between surface patterns and/or mechanical properties of materials of contact pairs results in two main working principles of the frictional devices: mechanical interlocking, or maximization of the contact area. We give an overview of the functional design of two main groups of friction-based attachment devices in insects: probabilistic fasteners and attachment pads. PMID- 21680398 TI - Mechanics of adhesion through a fibrillar microstructure. AB - Many organisms have evolved a fibrillated interface for contact and adhesion as shown by several of the papers in this issue. For example, in the Gecko, this structure appears to give them the ability to adhere and separate from a variety of surfaces by relying only on weak van der Waals forces. Despite the low intrinsic energy of separating surfaces held together by van der Waals forces, these organisms are able to achieve remarkably strong adhesion. To help understand adhesion in such a case, we consider a simple model of a fibrillar interface. For it, we examine the mechanics of contact and adhesion to a substrate. It appears that this structure allows the organism, at the same time, to achieve good, 'universal' contact and adhesion. Due to buckling, a carpet of fibrils behaves like a plastic solid under compressive loading, allowing intimate contact in the presence of some roughness. As an adhesive, we conjecture that energy in the fibrils is lost upon decohesion and unloading. This mechanism can add considerably to the intrinsic work of fracture, resulting in good adhesion even with only van der Waals forces. Analysis of the mechanics of adhesion through such a fibrillar interface provides rules for the design of the microstructure for desired performance as an adhesive. PMID- 21680399 TI - The structure and adhesive mechanism of octopus suckers. AB - Octopus suckers consist of a tightly packed three-dimensional array of muscle with three major muscle fiber orientations: 1) radial muscles that traverse the wall; 2) circular muscles arranged circumferentially around the sucker; and 3) meridional muscles oriented perpendicular to the circular and radial muscles. The sucker also includes inner and outer fibrous connective tissue layers and an array of crossed connective tissue fibers embedded in the musculature. Adhesion results from reducing the pressure inside the sucker cavity. This can be achieved by the three-dimensional array of muscle functioning as a muscular-hydrostat. Contraction of the radial muscles thins the wall, thereby increasing the enclosed volume of the sucker. If the sucker is sealed to a surface the cohesiveness of water resists this expansion. Thus, the pressure of the enclosed water decreases instead. The meridional and circular muscles antagonize the radial muscles. The crossed connective tissue fibers may store elastic energy, providing an economical mechanism for maintaining attachment for extended periods. Measurements using miniature flush-mounted pressure transducers show that suckers can generate hydrostatic pressures below 0 kPa on wettable surfaces but cannot do so on non-wettable surfaces. Thus, cavitation, the failure of water in tension, may limit the attachment force of suckers. As depth increases, however, cavitation will cease to be limiting because ambient pressure increases with depth while the cavitation threshold is unchanged. Structural differences between suckers will then determine the attachment force. PMID- 21680400 TI - Integrative functional morphology of the gekkotan adhesive system (reptilia: gekkota). AB - Climbing assisted by adhesive subdigital pads in gekkotan lizards has been the subject of intrigue and study for centuries. Many hypotheses have been advanced to explain the mechanism of adhesion, and recently this phenomenon has been investigated at the level of individual setae. The ability to isolate, manipulate and record adhesive forces from individual setae has provided new insights, not only into the mechanism of attachment, but also into the physical orientation of these structures necessary to establish attachment, maximize adhesive force, and effect subsequent release. This, in turn, has enabled a reassessment of the overall morphology and mode of operation of the adhesive system. Digital hyperextension has often been noted as a behavioral characteristic associated with the deployment of the gekkotan adhesive system-this is now understandable in the context of setal attachment and release kinematics, and in the context of the evolution of this pattern of digital movement from the primitive pattern of saurian digital kinematics. The perpendicular and parallel preloads associated with setal attachment are now reconcilable with other morphological aspects of the gekkotan adhesive system-the lateral digital tendon complex and the vascular sinus network, respectively. Future investigations of the integrated adhesive system will help to further elucidate the interdependence of its structural and functional components. PMID- 21680401 TI - The structure and function of adhesive gels from invertebrates. AB - Many marine invertebrates form strong, temporary attachments using viscoelastic gels. To better understand these adhesives, an analysis of what is known of gel structure and function was performed. There are different ways of making gels, ranging from entangling of giant glycoproteins to crosslinking of smaller proteins. The mechanics of the gel depend largely on the size of the polymer, its concentration, and whether it is crosslinked. Compared to gels such as mammalian mucus, the mechanics of adhesive mucous gels often appear to depend more heavily on relatively small proteins than on megadalton-sized glycoproteins. In addition, changes in concentration and the presence of specific proteins have been associated with the change from a non-adhesive to an adhesive form. The attachment strengths produced by different gels at different concentrations were compared with the changes in attachment strength seen in living animals. These data suggest that changes in concentration are not sufficient to account for adhesion. Thus, it is likely that the changes in protein composition may play a large role. PMID- 21680402 TI - Adhesion a la moule. AB - Mussels owe their sessile way of life in the turbulent intertidal zone to adaptive adjustments in the process and biochemistry of permanent attachment. These have understandably attracted scientific interest given that the attachment is rapid, versatile, tough and not subverted by the presence of water. The adhesive pads of mussel byssus contain at least six different proteins all of which possess the peculiar amino acid 3, 4-dihydroxyphenylalanine (DOPA) at concentrations ranging from 0.1 to 30 mol %. Studies of protein distribution in the plaque indicate that proteins with the highest levels of DOPA, such as mefp-3 (20 mol %) and mefp-5 (30 mol %), appear to predominate at or near the interface between the plaque and substratum. Although the presence of DOPA in proteins has traditionally been associated with cross-linking via chelate-mediated or covalent coupling, recent experiments with natural and synthetic DOPA-containing polypeptides suggest that cross-link formation is not the only fate for DOPA. Intact DOPA, particularly near the interface, may be essential for good chemisorption to polar surfaces. Uniformly high DOPA oxidation to cross-links leads to interfacial failure but high cohesive strength, while low DOPA oxidation results in better adhesion at the expense of cohesion. Defining the adaptations involved in balancing these two extremes is crucial to understanding marine adhesion. PMID- 21680403 TI - New perspectives on the origin of metazoan complexity: an introduction to the symposium. PMID- 21680404 TI - The origin of metazoan complexity: porifera as integrated animals. AB - Sponges [Porifera] are the phylogenetically oldest metazoan phylum still extant today; they share the closest relationship with the hypothetical common metazoan ancestor, the Urmetazoa. During the past 8 years cDNAs coding for proteins involved in cell-cell- and cell-tissue interaction have been cloned from sponges, primarily from Suberites domuncula and Geodia cydonium and their functions have been studied in vivo as well as in vitro. Also, characteristic elements of the extracellular matrix have been identified and cloned. Those data confirmed that all metazoan phyla originate from one ancestor, the Urmetazoa. The existence of cell adhesion molecules allowed the emergence of a colonial organism. However, for the next higher stage in evolution, individuation, two further innovations had to be formed: the immune- and the apoptotic system. Major defense pathways/molecules to prevent adverse effects against microbes/parasites have been identified in sponges. Furthermore, key molecules of the apoptotic pathway(s), e.g., the pro-apoptotic molecule comprising two death domains, the executing enzyme caspases, as well as the anti-apoptotic/cell survival proteins belonging to the Bcl-2 family have been identified and cloned from sponges. Based on these results-primarily obtained through a molecular biological approach-it is concluded that cell-cell- and cell-matrix adhesion systems were required for the transition to a colonial stage of organization, while the development of an immune system as well as of apoptotic processes were prerequisites for reaching the integrated stage. As the latter stage already exists in sponges, it is therefore likely that the hypothetical ancestor, the Urmetazoa, was also an "integrated colony." PMID- 21680405 TI - Developmental genes and the reconstruction of metazoan evolution--implications of evolutionary loss, limits on inference of ancestry and type 2 errors. AB - We consider three issues that appear to be important in the interpretation of developmental genetics in an evolutionary context. The three issues under discussion are 1) evolutionary loss as applied to evo-devo data; 2) the limits on our ability to infer ancestry based on tree reconstruction; and 3) "type 2" errors in the assessment of homology of developmental gene expression data. Lack of consideration of any or all of these disparate issues narrows the set of hypotheses under consideration. We examine these issues through examples drawing on new data on POU domain genes as well as through reference to published work on Distal-less, engrailed and Nk2 genes. PMID- 21680406 TI - The significance of syncytial tissues for the position of the hexactinellida in the metazoa. AB - Hexactinellid sponges are metazoans in which the major tissue component is a multinucleated syncytium. The preferred deepwater habitat of these sponges makes collection of hexactinellids in good condition difficult, and has hindered extensive examination of their body plan. Nonetheless, over the last three decades a number of studies have explored their ecology, histology and physiology. It has been shown that hexactinellids are extremely long-lived animals. Their cytoplasm consists of a giant, multinucleated tissue, the trabecular syncytium, which is connected via open and plugged cytoplasmic bridges to cells such as archaeocytes, choanoblasts, and cells with spherical inclusions. Because all of the sponge is cytoplasmically interconnected, electrical signals can propagate through the animal. The effector response is arrest of the feeding current. The perforate plugged junction apparently allows tissues to specialize in different ways while maintaining limited cytoplasmic continuity. Larvae of hexactinellid sponges are already largely syncytial. Although it is not known when the first syncytial tissues are formed or when perforate plugged junctions first appear during embryogenesis, evidence that embryos are cellular until gastrulation suggests that hexactinellid sponges may have evolved from cellular sponges and that syncytial tissues are not a primitive trait of the Metazoa. PMID- 21680407 TI - Bridging morphological transitions to the metazoa. AB - Our inability to answer many questions regarding the development of metazoan complexity may be due in part to the prevailing idea that most eukaryote "phyla" originated within a short period of geologic time from simple unicellular ancestors. This view, however, is contradicted by evidence that larger groups of eukaryotes share characters, suggesting that these assemblages inherited characters from a common ancestor. Because molecular analyses have had limited success in resolving the relationships of higher eukaryote taxa, we have undertaken a phylogenetic analysis based primarily on morphological characters. The analysis emphasizes characters considered to have a high probability of having evolved only once. Transitions between taxa are evaluated for the likelihood of character-state transformations. The analysis indicates that the evolutionary history of the clade containing the Metazoa has been complex, encompassing the gain and loss of a secondary and perhaps a primary photosynthetic endosymbiont with accompanying changes in trophic level. The history also appears to have included a hetero-autotrophic ancestor that possessed a "conoid" feeding apparatus and may have involved a transformation from a flagellate to an amoeboid body form, a trend toward increased intracellular compartmentation, and the development of complex social behavior. Such changes could have been critical for establishing the underlying complexity required for a rapid diversification of cell and tissue types in the early stages of metazoan evolution. PMID- 21680408 TI - The significance of muscle cells for the origin of mesoderm in bilateria. AB - Muscle tissue may have played a central role in the early evolution of mesoderm. The first function of myocytes could have been to control swimming and gliding motion in ciliated vermiform organisms, as it still is in such present-day basal Bilateria as the Nemertodermatida. The only mesodermal cells between epidermis and gastrodermis in Nemertodermatida are myocytes, and conceivably the myocyte was, in fact, the original mesodermal cell type. In Nemertodermatida as well as the Acoela, myocytes are subepithelial fiber-type muscle cells and appear to originate from the gastrodermal epithelium by emigration of single cells. Other mesodermal cells in the acoels are the peripheral parenchyma (connective tissue) and tunica cells of the gonads, and these also arise from the gastrodermis. Musculature in many of the coelomate protostomes and deuterostomes, on the other hand, is in the form of epitheliomuscular (myoepithelial) cells, and this cell type may also have been an early form of the mesodermal myocyte. The mesodermal bands in the small annelid Polygordius and in juvenile enteropneusts have cells intermediate between mesenchymal and epithelial in their histological organization as they develop into myoepithelia. If acoelomates were derived from coelomates by progenesis, then the fiber-type muscles of acoelomates could be products of foreshortened differentiation of such tissue. The precise serial patterning of circular muscle cells along the anterior-posterior axis during embryonic development in the acoel Convoluta pulchra provides a model for early steps in the gradual evolution of segmentation from iterated organ systems. PMID- 21680409 TI - Epithelium--the primary building block for metazoan complexity. AB - In simplest terms, the complexity of the metazoan body arises through various combinations of but two tissue types: epithelium and mesenchyme. Through mutual inductions and interactions, these tissues produce all of the organs of the body. Of the two, epithelium must be considered the default type in the Eumetazoa because it arises first in embryonic development and because mesenchyme arises from it by a switching off of the mechanisms that underly differentiation and maintenance of epithelial cells. In the few model metazoans whose epithelia have been studied by molecular techniques (largely Drosophila, Caenorhabditis, mouse), the molecular mechanisms underlying differentiation of epithelia show remarkable similarity. Extrapolating from these studies and from comparisons of the morphology of epithelia in lower metazoans, I propose how epithelia arose in the stem metazoan. Steps in epithelial differentiation include 1) establishment of cell polarity by molecular markers confined to either apical or basolateral domains in the plasma membrane; 2) aggregation of cells into sheets by localization of cell-adhesion molecules like cadherin to the lateral membrane; 3) formation of a zonula adherens junction from the cadherins by their localization to a discrete belt; 4) cell-to-cell linking of certain transmembrane proteins (primitively in the septate junction) to produce gates that physiologically isolate compartments delimited by the cells; and 5) synthesis of a basal lamina and adaptation of receptors (integrins) to its components. Despite morphological differences in the variety of cell junctions evident in various epithelia, the underlying molecular markers of these junctions are probably universally present in all eumetazoan epithelia. PMID- 21680410 TI - On the reorganization of fitness during evolutionary transitions in individuality. AB - The basic problem in an evolutionary transition is to understand how a group of individuals becomes a new kind of individual, possessing the property of heritable variation in fitness at the new level of organization. During an evolutionary transition, for example, from single cells to multicellular organisms, the new higher-level evolutionary unit (multicellular organism) gains its emergent properties by virtue of the interactions among lower-level units (cells). We see the formation of cooperative interactions among lower-level units as a necessary step in evolutionary transitions; only cooperation transfers fitness from lower levels (costs to group members) to higher levels (benefits to the group). As cooperation creates new levels of fitness, it creates the opportunity for conflict between levels as deleterious mutants arise and spread within the group. Fundamental to the emergence of a new higher-level unit is the mediation of conflict among lower-level units in favor of the higher-level unit. The acquisition of heritable variation in fitness at the new level, via conflict mediation, requires the reorganization of the basic components of fitness (survival and reproduction) and life-properties (such as immortality and totipotency) as well as the co-option of lower-level processes for new functions at the higher level. The way in which the conflicts associated with the transition in individuality have been mediated, and fitness and general life traits have been re-organized, can influence the potential for further evolution (i.e., evolvability) of the newly emerged evolutionary individual. We use the volvocalean green algal group as a model-system to understand evolutionary transitions in individuality and to apply and test the theoretical principles presented above. Lastly, we discuss how the different notions of individuality stem from the basic properties of fitness in a multilevel selection context. PMID- 21680411 TI - Three puzzles in hierarchical evolution. AB - The maximum degree of hierarchical structure of organisms has risen over the history of life, notably in three transitions: the origin of the eukaryotic cell from symbiotic associations of prokaryotes; the emergence of the first multicellular individuals from clones of eukaryotic cells; and the origin of the first individuated colonies from associations of multicellular organisms. The trend is obvious in the fossil record, but documenting it using a high-resolution hierarchy scale reveals three puzzles: 1) the rate of origin of new levels accelerates, at least until the early Phanerozoic; 2) after that, the trend may slow or even stop; and 3) levels may sometimes arise out of order. The three puzzles and their implications are discussed; a possible explanation is offered for the first. PMID- 21680412 TI - Developmental insights into the origin of complex colonial hydrozoans. AB - Colonial hydrozoans represent some of the most diverse and complex body plans within the Metazoa. Complex hydrozoans colonies are more physiologically and structurally integrated than their simple colonial relatives. Colonial integration is commonly associated with the regulation of the general structural plan of the colony, the division of labor, and the physiological integration of the colony. In the hydrozoan Hydractinia, these features are manifested through evolutionary innovations involving the spatial regulation of polyps within the colony, the development of polyp polymorphs, and the acquisition of a stolonal mat. These innovations all involve evolutionary changes in the regulation of polyp and colony-wide patterning systems. In Hydractinia, the ParaHox gene, Cnox 2, is expressed in a spatially restricted manner along the axes of stolons and polyps, suggesting that changes in the regulation of this gene may be in part responsible for the evolutionary innovations important for colonial complexity. PMID- 21680413 TI - Complexity generated by iteration of hierarchical modules in bryozoa. AB - Growth in colonial organisms by iteration of modules inherently provides for an increase in available morpho-ecospace relative to their solitary relatives. Therefore, the interpretation of the functional or evolutionary significance of complexity within groups that exhibit modular growth may need to be considered under criteria modified from those used to interpret complexity in solitary organisms. Primary modules, corresponding to individuals, are the fundamental building blocks of a colonial organism. Groups of primary modules commonly form a second-order modular unit, such as a branch, which may then be iterated to form a more complex colony. Aspects of overall colony form, along with their implications for ecology and evolution, are reflected in second-order modular (structural) units to a far greater degree than by primary modular units (zooids). A colony generated by modular growth can be classified by identifying its second-order modular (structural) unit and then by characterizing the nature and relationships of these iterated units within the colony. This approach to classifying modular growth habits provides a standardized terminology and allows for direct comparison of a suite of functionally analogous character states among taxa with specific parameters of their ecology. PMID- 21680414 TI - Architectures of biological complexity. AB - Three features contribute to the complexity of an entity: number of parts, their order, and their iteration. Many functional biological entities are complex when measured by those attributes, and although they are produced in tree-like architectures, the organizational structures that permit them to function are in the form of hierarchies. Natural hierarchies can be thought of as organizing structures that are emergent properties of complex functional entities, and which are transformed from trees by process networks. For example, hierarchies are observed in the architecture of metazoan bodies (the somatic hierarchy) and in the biotic structure of ecogeographic units (the ecological hierarchy). As the metazoan developmental genome is quite complex and has been evolved through tree like processes, it must harbor at least one hierarchy, which is most clearly indicated in the developmental processes that create the somatic hierarchy. For multicellular organisms, the processes that serve to transform trees of gene expression events into a somatic hierarchy have produced complicated signaling networks whose histories can probably be recovered in general outline. PMID- 21680415 TI - The ediacaran biotas in space and time. AB - The "Ediacaran organisms," which preceded and overlapped the Cambrian radiation of metazoans, include many fossils whose systematic positions remain contentious after over fifty years of study. It might seem that nothing particularly useful can be learned from a biota full of oddballs. However, analyses of the distribution of the Ediacaran organisms in time and space can be carried out without having to guess at the systematic position of the organisms. Combining these results with data on paleotectonics, paleoenvironmental parameters, and the ages of various assemblages sheds light on the origins, ecology, and even the systematic positions of the Ediacaran organisms. Parsimony Analysis of Endemism (PAE) confirms earlier studies in grouping Ediacaran biotas into three major clusters: the Avalon, White Sea, and Nama Assemblages. The available radiometric and stratigraphic data suggest that the Avalon is the oldest, the White Sea is next oldest, and the Nama extends to the base of the Cambrian. The "frondlike" Ediacaran taxa, and to a lesser extent the "medusoids," collectively show significantly longer stratigraphic ranges, broader geographical and paleoenvironmental ranges, and less provinciality than "bilaterian" and tubular taxa. Almost all tubular Ediacarans appear to be confined to equatorial areas, whereas other Ediacaran organisms show weak or no latitudinal diversity gradients. I conclude that the Ediacaran organisms show a diverse range of responses to various environmental parameters. There is no basis for classifying them all as having a single body plan and mode of life, as has often been done in the past. PMID- 21680416 TI - Anatomical information content in the ediacaran fossils and their possible zoological affinities. AB - Various modes of preservation of Ediacaran fossils in different sediments, quartz sand at Zimnie Gory in northern Russia and lime mud at Khorbusuonka in northern Yakutia, show that the sediment was liquid long after formation of the imprints and that its mineralogy did not matter. A laminated 2 mm thick microbial mat is preserved intact at Zimnie Gory. It stabilized the sediment surface allowing formation of imprints on it. The soft body impressions on the under surface of the sand bed and within it developed owing to formation of a less than 1 mm thin "death mask" by precipitation of iron sulfide in the sediment. Fossils of the same species or even parts of the same organism may be preserved differently. Internal organs either collapsed, their cavities being filled with sediment from above, or resisted compression more effectively than the rest of the body. This allows restoration of the original internal anatomy of Ediacaran organisms. At Zimnie Gory numerous series of imprints of Yorgia on the clay bottom surface with the collapsed body at their end represent death tracks. The environment of formation of the Ediacaran fossils was thus inhospitable to most organisms. Those adapted to it, namely the radially organized frondose Petalonamae (of possible ctenophoran affinities), anchored in the mat with their basal bulbs. They evolved towards sessile life possibly in symbiosis with photo- or chemoautotrophic microorganisms. Vagile Ediacaran organisms belong mostly to the Dipleurozoa (somewhat resembling chordates and nemerteans), characterized by a segmented dorsal hydraulic skeleton, intestine with metameric caeca, and serial gonads. Only a fraction of the actual Precambrian faunal diversity is represented in the Ediacaran biota. PMID- 21680417 TI - A fungal analog for newfoundland ediacaran fossils? AB - We propose that some of the more conspicuous Ediacaran fossils from the Avalon Peninsula of Newfoundland, including Aspidella, Charnia, and Charniodiscus, were biologically similar to members of the Kingdom Fungi. These organisms were multicellular or multinuclear, lived below the photic zone, could not move or defoul themselves, did not exhibit taphonomic shrinkage, and were not transported or moved. Aspidella, in particular, appears to exhibit indeterminate growth without a maximum size constraint, and appears to show growth zonations similar to modern mycelia. Other fossils from this deposit exhibit a fractal-like growth pattern. Together, these features falsify algal, lichen, and metazoan interpretations of these fossils, yet reflect characteristics of modern fungal mycelia. We emphasize that although no Mistaken Point fossil appears to be a metazoan, not all of the Mistaken Point taxa, and not all of the Ediacaran organisms in general, can reasonably be interpreted using a fungal analogy. Furthermore, the hypothesis that these fossils were functionally fungus-like need not imply that the organisms were members of the crown-group Fungi. We propose further tests for evaluating both this functional hypothesis and the phylogenetic hypothesis that these organisms were members of the total-group Fungi. PMID- 21680418 TI - The segmented urbilateria: a testable scenario. AB - The idea that the last common ancestor of bilaterian animals (Urbilateria) was segmented has been raised recently on evidence coming from comparative molecular embryology. Leaving aside the complex debate on the value of genetic evidence, the morphological and developmental evidence in favor of a segmented Urbilateria are discussed in the light of the emerging molecular phylogeny of metazoans. Applying a cladistic character optimization procedure to the question of segmentation is vastly complicated by the problem of defining without ambiguity what segmentation is and to what taxa this definition applies. An ancestral segmentation might have undergone many complex derivations in each different phylum, thus rendering the cladistics approaches problematic. Taking the most general definitions of coelom and segmentation however, some remarkably similar patterns are found across the bilaterian tree in the way segments are formed by the posterior addition of mesodermal segments or somites. Postulating that these striking similarities in mesodermal patterns are ancestral, a scenario for the diversification of bilaterians from a metameric ancestor is presented. Several types of evolutionary mechanisms (specialization, tagmosis, progenesis) operating on a segmented ancestral body plan would explain the rapid emergence of body plans during the Cambrian. We finally propose to test this hypothesis by comparing genes involved in mesodermal segmentation. PMID- 21680419 TI - What can DNA Tell us About the Cambrian Explosion? AB - Molecular data is ideal for exploring deep evolutionary history because of its universality, stochasticity and abundance. These features provide a means of exploring the evolutionary history of all organisms (including those that do not tend to leave fossils), independently of morphological evolution, and within a statistical framework that allows testing of evolutionary hypotheses. In particular, molecular data have an important role to play in examining hypotheses concerning the tempo and mode of evolution of animal body plans. Examples are given where molecular phylogenies have led to a re-examination of some fundamental assumptions in metazoan evolution, such as the immutability of early developmental characters, and the evolvability of bauplan characters. Molecular data is also providing a new and controversial timescale for the evolution of animal phyla, pushing the major divisions of the animal kingdom deep into the Precambrian. There have been many reasons to question the accuracy and precision of molecular date estimates, such as the failure to account for lineage-specific rate variation and unreliable estimation of rates of molecular evolution. While these criticisms have been largely countered by recent studies, one problem has remained a challenge: could temporal variation in the rate of molecular evolution, perhaps associated with "explosive" adaptive radiations, cause overestimation of diversification dates? Empirical evidence for an effect of speciation rate, morphological evolution or ecological diversification on rates of molecular evolution is examined, and the potential for rate-variable methods for molecular dating are discussed. PMID- 21680420 TI - The cambrian fossil record and the origin of the phyla. AB - Whilst the "Cambrian Explosion" continues to attract much attention from a wide range of earth and life scientists, the detailed patterns exhibited by the terminal Proterozoic-Early Cambrian biotas remain unclear, for reasons of systematics, biostratigraphy and biogeography. In particular, recent changes in absolute dating of the Cambrian have refined the period of time that the fossil record might be of most help in revealing the dynamics of the undoubted radiation taking place at this time. The famous exceptionally preserved faunas seem to be rather close temporally, and as yet reveal little about the earliest and critical period of evolution, deep in the Cambrian. Nevertheless, the most parsimonious interpretation of the Cambrian fossil record is that it represents a broadly accurate temporal picture of the origins of the bilaterian phyla. PMID- 21680421 TI - Exceptional fossil preservation and the cambrian explosion. AB - Exceptionally preserved, non-biomineralizing fossils contribute importantly to resolving details of the Cambrian explosion, but little to its overall patterns. Six distinct "types" of exceptional preservation are identified for the terminal Proterozoic-Cambrian interval, each of which is dependent on particular taphonomic circumstances, typically restricted both in space and time. Taphonomic pathways yielding exceptional preservation were particularly variable through the Proterozoic-Cambrian transition, at least in part a consequence of contemporaneous evolutionary innovations. Combined with the reasonably continuous record of "Doushantuo-type preservation," and the fundamentally more robust records of shelly fossils, phytoplankton cysts and trace fossils, these taphonomic perturbations contribute to the documentation of major evolutionary and biogeochemical shifts through the terminal Proterozoic and early Cambrian.Appreciation of the relationship between taphonomic pathway and fossil expression serves as a useful tool for interpreting exceptionally preserved, often problematic, early Cambrian fossils. In shale facies, for example, flattened non-biomineralizing structures typically represent the remains of degradation-resistant acellular and extracellular "tissues" such as chaetae and cuticles, whereas three-dimensional preservation represents labile cellular tissues with a propensity for attracting and precipitating early diagenetic minerals. Such distinction helps to identify the acuticular integument of hyolithids, the chaetae-like nature of Wiwaxia sclerites, the chaetognath-like integument of Amiskwia, the midgut glands of various Burgess Shale arthropods, and the misidentification of deposit-feeding arthropods in the Chengjiang biota. By the same reasoning, putative lobopods in the Sirius Passet biota and putative deuterostomes in the Chengiang biota are better interpreted as arthropods. PMID- 21680422 TI - The Ordovician Radiation: A Follow-up to the Cambrian Explosion? AB - There was a major diversification known as the Ordovician Radiation, in the period immediately following the Cambrian. This event is unique in taxonomic, ecologic and biogeographic aspects.While all of the phyla but one were established during the Cambrian explosion, taxonomic increases during the Ordovician were manifest at lower taxonomic levels although ordinal level diversity doubled. Marine family diversity tripled and within clade diversity increases occurred at the genus and species levels. The Ordovician radiation established the Paleozoic Evolutionary Fauna; those taxa which dominated the marine realm for the next 250 million years. Community structure dramatically increased in complexity. New communities were established and there were fundamental shifts in dominance and abundance.Over the past ten years, there has been an effort to examine this radiation at different scales. In comparison with the Cambrian explosion which appears to be more globally mediated, local and regional studies of Ordovician faunas reveal sharp transitions with timing and magnitudes that vary geographically. These transitions suggest a more episodic and complex history than that revealed through synoptic global studies alone.Despite its apparent uniqueness, we cannot exclude the possibility that the Ordovician radiation was an extension of Cambrian diversity dynamics. That is, the Ordovician radiation may have been an event independent of the Cambrian radiation and thus requiring a different set of explanations, or it may have been the inevitable follow-up to the Cambrian radiation. Future studies should focus on resolving this issue. PMID- 21680423 TI - Trilobite tagmosis and body patterning from morphological and developmental perspectives. AB - The Trilobita were characterized by a cephalic region in which the biomineralized exoskeleton showed relatively high morphological differentiation among a taxonomically stable set of well defined segments, and an ontogenetically and taxonomically dynamic trunk region in which both exoskeletal segments and ventral appendages were similar in overall form. Ventral appendages were homonomous biramous limbs throughout both the cephalon and trunk, except for the most anterior appendage pair that was antenniform, preoral, and uniramous, and a posteriormost pair of antenniform cerci, known only in one species. In some clades trunk exoskeletal segments were divided into two batches. In some, but not all, of these clades the boundary between batches coincided with the boundary between the thorax and the adult pygidium. The repeated differentiation of the trunk into two batches of segments from the homonomous trunk condition indicates an evolutionary trend in aspects of body patterning regulation that was achieved independently in several trilobite clades. The phylogenetic placement of trilobites and congruence of broad patterns of tagmosis with those seen among extant arthropods suggest that the expression domains of trilobite cephalic Hox genes may have overlapped in a manner similar to that seen among extant arachnates. This, coupled with the fact that trilobites likely possessed ten Hox genes, presents one alternative to a recent model in which Hox gene distribution in trilobites was equated to eight putative divisions of the trilobite body plan. PMID- 21680424 TI - Unleashing the force of cladistics? Metazoan phylogenetics and hypothesis testing. AB - The accumulation of multiple phylogenetic hypotheses for the Metazoa invites an evaluation of current progress in the field. I discuss three case studies from the recent literature to assess how cladistic analyses of metazoan morphology have contributed to our understanding of animal evolution. The first case study on cleavage cross patterns examines whether a decade of unanimous character scoring across different cladistic studies can be considered a reliable indicator of accumulated wisdom. The two remaining case studies illustrate how the unique strength of cladistic analyses to arbitrate between competing hypotheses can be crippled when insufficient attention is directed towards the construction of the data matrix. The second case study discusses a recent morphological cladistic analysis aimed at providing insight into the evolution of larval ciliary bands (prototrochs) in the Spiralia, and the third case study evaluates how four subsequent morphological cladistic analyses have contributed to our understanding of the phylogenetic placement of a problematicum, the Myzostomida. I conclude that current phylogenetic analyses of the Metazoa have not fully exploited the power of cladistics to test available alternative hypotheses. If our goal is to generate genuine progress in understanding rather than stochastic variation of opinions through time, we have to shift our attention from using cladistics as an easy tool to generate "novel" hypotheses of metazoan relationships, towards employing cladistics more critically as an effective instrument to test the relative merit of available multiple alternative hypotheses. PMID- 21680425 TI - The proterozoic and earliest cambrian trace fossil record; patterns, problems and perspectives. AB - The increase in trace fossil diversity across the Neoproterozoic-Cambrian boundary often is presented in terms of tabulations of ichnogenera. However, a clearer picture of the increase in diversity and complexity can be reached by combining trace fossils into broad groups defined both on morphology and interpretation. This also focuses attention on looking for similarites between Neoproterozoic and Cambrian trace fossils. Siliciclastic sediments of the Neoproterozoic preserve elongate tubular organisms and structures of probable algal origin, many of which are very similar to trace fossils. Such enigmatic structures include Palaeopascichnus and Yelovichnus, previously thought to be trace fossils in the form of tight meanders.A preliminary two or tripartite terminal Neoproterozoic trace fossil zonation can be be recognized. Possibly the earliest trace fossils are short unbranched forms, probably younger than about 560 Ma. Typical Neoproterozoic trace fossils are unbranched and essentially horizontal forms found associated with diverse assemblages of Ediacaran organisms. In sections younger than about 550 Ma a modest increase in trace fossil diversity occurs, including the appearance of rare three-dimensional burrow systems (treptichnids), and traces with a three-lobed lower surfaces. PMID- 21680426 TI - Taking the pulse of the cambrian radiation. AB - The Cambrian radiation is that key episode in the history of life when a large number of animal phyla appeared in the fossil record over a geologically short period of time. Over the last 20 years, scientific understanding of this radiation has increased significantly. Still, fundamental questions remain about the timing of the radiation and also the tempo of evolution. Trilobites are an excellent group to address these questions because of their rich abundance and diversity. Moreover, their complex morphology makes them readily amenable to phylogenetic analysis, and deducing the nature of macroevolutionary processes during the Cambrian radiation requires an understanding of evolutionary patterns. Phylogenetic biogeographic analysis of Early Cambrian olenellid trilobites, based on a modified version of Brooks Parsimony Analysis, revealed the signature of the breakup of Pannotia, a tectonic event that most evidence suggests is constrained to the interval 600 to 550 Ma. As trilobites are derived metazoans, this suggests the phylogenetic proliferation associated with the Cambrian radiation was underway tens of millions of years before the Early Cambrian, although not hundreds of millions of years as some have argued.Phylogenetic information from Early Cambrian olenellid trilobites was also used in a stochastic approach based on two continuous time models to test the hypothesis that rates of speciation were unusually high during the Cambrian radiation. No statistical evidence was found to support this hypothesis. Instead, rates of evolution during the Cambrian radiation, at least those pertaining to speciation, were comparable to those that have occurred during other times of adaptive or taxic radiation throughout the history of life. PMID- 21680427 TI - What is "Integrative Biology"? PMID- 21680428 TI - Switch from Asexual to Sexual Reproduction in the Planarian Dugesia ryukyuensis. AB - Many metazoans convert the reproductive modes presumably depending upon the environmental conditions and/or the phase of life cycle, but the mechanisms underlying the switching from asexual to sexual reproduction, and vice versa, remain unknown. We established an experimental system, using an integrative biology approach, to analyze the mechanism in the planarian, Dugesia ryukyuensis (Kobayashi et al., 1999). Worms of exclusively asexual clone (OH strain) of the species gradually develop ovaries, testes and other sexual organs, then copulate and eventually lay cocoons filled with fertilized eggs, if they are fed with sexually mature worms of Bdellocephala brunnea (an exclusively oviparous species). This suggests the existence of a sexualizing substance(s) in sexually mature worms. Random inbreeding of experimentally sexualized worms (acquired sexuals) produces an F1 population of spontaneous sexuals (innate sexuals) and asexuals in a ratio of approximately 2:1. All regenerants from various portions of innate sexuals become sexuals. In the case of acquired sexuals, head fragments without sexual organs regenerated into asexuals though regenerants from other portions became sexuals. Thus, we conclude that neoblasts, the totipotent stem cells in the planarians, of acquired sexuals remain "asexual" and the worms require external supply of a sexualizing substance for the differentiation of sexual organs and gametes. On the other hand, some, if not all, neoblasts in innate sexuals are somehow "sexual" and do not require external supply of a sexualizing substance for the eventual differentiation of themselves and/or other neoblasts into sexual organs and gametes. It is also shown that sexuality in acquired sexuals is maintained by the putative sexualizing substance(s) of their own. The sexualization is closely coupled with cessation of fission, and the worms seem to have an unknown way of controlling the karyotype. Our integrative approach integrates multiple fields of study, including classic breeding, regeneration, and genetics experiments, as well as karyotyping, and biochemical and molecular biological analyses; none of which would have revealed much about the intricate mechanisms that regulate sex and fission in these animals. PMID- 21680429 TI - Seeking the ultimate and proximate causes of volvox multicellularity and cellular differentiation. AB - Volvox and its relatives provide an exceptional model for integrative studies of the evolution of multicellularity and cellular differentiation. The volvocine algae range in complexity from unicellular Chlamydomonas through several colonial genera with a single cell type, to multicellular Volvox with its germ-soma division of labor. Within the monophyletic family Volvocaceae, several species of Volvox have evolved independently in different lineages, the ultimate cause presumably being the advantage that large size and cellular differentiation provide in competing for limiting resources such as phosphorous. The proximate causes of this type of evolutionary transition are being studied in V. carteri. All volvocine algae except Volvox exhibit biphasic development: cells grow during a motile, biflagellate phase, then they lose motility and divide repeatedly during the reproductive phase. In V. carteri three kinds of genes transform this ancestral biphasic program into a dichotomous one that generates non-motile reproductive cells and biflagellate somatic cells with no reproductive potential: first the gls genes act in early embryos to cause asymmetric division and production of large-small sister-cell pairs; then lag genes act in the large cells to repress the biflagellate half of the ancestral program, while regA acts in the small cells to repress the reproductive half of the program. Molecular genetic analysis of these genes is progressing, as will be illustrated with regA, which encodes a transcription factor that acts in somatic cells to repress nuclear genes encoding chloroplast proteins. Repression of chloroplast biogenesis prevents these obligately photoautotrophic cells from growing, and since they cannot grow, they cannot reproduce. PMID- 21680430 TI - The squid-Vibrio symbioses: from demes to genes. AB - The monospecific light organ association between the Hawaiian sepiolid squid Euprymna scolopes and the marine luminous bacterium Vibrio fischeri has been used as a model for the study of the most common type of coevolved animal-bacterial interaction; i.e., the association of Gram-negative bacteria with the extracellular apical surfaces of polarized epithelia. Analysis of the squid vibrio symbiosis has ranged from characterizations of the harvesting mechanisms by which the host ensures colonization by the appropriate symbiont to identification of bacteria-induced changes in host gene expression that accompany the establishment and maintenance of the relationship. Studies of this model have been enhanced by extensive collaboration with microbiologists, who are able to manipulate the genetics of the bacterial symbiont. The results of our studies have indicated that initiation and persistence of the association requires a complex, reciprocal molecular dialogue between these two phylogenetically distant partners. PMID- 21680431 TI - Toward an integrative historical biogeography. AB - Cladistic biogeographic methods remain susceptible to the confounding effects of "pseudo-congruence" and "pseudo-incongruence" because they were not designed to incorporate information on the absolute timing of the diversification of lineages. Consequently, results from cladistic biogeographic studies are difficult to interpret and cannot be confidently attributed to any particular cause. We illustrate these points with concrete examples, paying special attention to recent work on the biogeography of the Northern Hemisphere, and outline ways in which topological and temporal information might be better integrated. The development of historical biogeography over the last few decades provides general insights into the nature of integration through the life of a discipline. PMID- 21680432 TI - Integrative biology and genetic resources management. AB - Integrative Biology is exemplified by a diversity of recently established collaborations to study the genetic diversity of the European rabbit, Oryctolagus cuniculus. Molecular markers were developed and used to investigate the link between wild population decreases or domestication procedures and possible losses of genetic diversity. Simultaneously, a European programme was launched for the management of genetic resources. The Integrative Biology approach shows that changes in genetic diversity are often buffered by the flexibility of rabbit reproductive systems. It appears, also, that all domestic animals belong to a subset of the wild genetic pool of their species without major loss of diversity despite exposure to severe viral infections. Consequently, management of genetic resources for production purposes and conservation or protection of declining Iberian wild populations require different approaches and measures. PMID- 21680433 TI - The promise of integrative biology: resurrection of the naturalist. PMID- 21680434 TI - Comparative immunology. AB - Comparative immunology, derived from zoology and immunology, examines immune systems during evolution. We now know that invertebrates have molecules that share homology with some of those in vertebrates. Acquired immunity first appeared in the vertebrates, but before then innate immune systems had been successfully defending invertebrates and plants against microbial infections for hundreds of millions of years. The germline-encoded receptors of innate systems are relatively limited in diversity and unable to make fine distinctions between closely related structures. Nevertheless, they can recognize certain chemical features shared by groups of microorganisms (e.g., pattern recognition receptors) but not by the host, such as lipopolysaccharide of Gram-negative bacterial cell walls. This capability enables innate immunity to detect the presence of an infection, if not the precise cause-it is thus a biological rather than a structural distinction. Because of its evolutionary success, innate immunity is no longer considered primarily a stopgap measure, a temporary expedient for host defense. It no longer seems to matter that there is an absence of genetic recombination mechanisms to generate neither specificity nor 'memory', because first and second exposures to a microbial substance elicit similar responses. Comparative immunology has enriched the parent field of immunology. PMID- 21680435 TI - Origin of the metazoan immune system: identification of the molecules and their functions in sponges. AB - During the evolutionary transition to Metazoa, cell-cell- as well as cell-matrix recognition molecules have been formed, which made a further step in evolution possible, the establishment of an immune system. Sponges [Porifera] represent the oldest still extant metazoan phylum and consequently testify to major features of the common metazoan ancestor, the Urmetazoa. Most studies with respect to evolution and phylogeny in sponges have been performed with the marine demosponges Suberites domuncula and Geodia cydonium. These animals possess effective defense systems against microbes and parasites which involve engulfment of bacteria into specific cells, but also signal transduction pathways which actively kill bacteria. Among those is the LPS-mediated pathway, with the stress responsive kinases. In addition, sponges are provided with an interferon-related system, with the (2-5)A synthetase as controlling enzyme. Transplantation studies have been performed on tissue, as well as at the cellular level ("mixed sponge cell reaction assay") which demonstrate the complex molecular strategy by which sponges respond to allogeneic- and/or autogeneic signals. Among the molecules involved in histo(in)compatibility response of sponges, cytokines e.g., the allograft inflammatory factor 1, have been identified which control rejection of allografts. Furthermore, transcription factors, with Tcf-like factor as an example, have been identified which very likely control gene expression during histocompatibility reactions. The immune reactions in sponges can be modulated by FK506, a drug which has been successfully used as immunosuppressant in humans. One further surprising finding is the fact that G. cydonium has several molecules containing polymorphic Ig-like domains of the variable type. It is concluded that the successful evolutionary transition to the Metazoa, with the sponges as the oldest still extant phylum, and the subsequent rapid radiation into the other metazoan phyla, became possible because of the acquisition of modular molecules, involved in cell adhesion and the immune system. PMID- 21680436 TI - Origins and evolutionary relationships between the innate and adaptive arms of immune systems. AB - Long before vertebrates first appeared, protists, plants and animals had evolved diverse, effective systems of innate immunity. Ancestors of the vertebrates utilized components of the complement system, protease-inhibitors, metal-binding proteins, carbohydrate-binding proteins and other plasma-born molecules as humoral agents of defense. In these same animals, immunocytes endowed with a repertoire of defensive behaviors expressed Toll-like receptors. They made NADPH oxidase, superoxide dismutase and other respiratory burst enzymes to produce toxic oxygen radicals, and nitric oxide synthase to produce nitric oxide. Antimicrobial peptides and lytic enzymes were in their armory. Immune responses were orchestrated by cytokines. Furthermore, genes within the immunoglobulin superfamily were expressed to meet a variety of needs possibly including defense. However, recombination activating genes played no role. With the acquisition of one or more transposases and the resulting capacity to generate diverse receptors from immunoglobulin gene fragments, the adaptive (lymphoid) arm of the immune system was born. This may have coincided with the elaboration of the neural crest. Naturally, the role of the adaptive arm was initially subservient to the defensive functions of the pre-existing innate arm. The strong selective advantages that stemmed from having "sharp-shooters" (cells making antigen specific receptors) on the defense team ensured their retention. Refined through evolution, adaptive immunity, even in mammals, remains dependent upon cells of the innate series (e.g., dendritic cells) for signals driving their functional maturation. This paper calls for some fresh thinking leading to a clearer vision of the origins and co-evolution of the two arms of modern immune systems, and suggests a possible neural origin for the adaptive immune system. PMID- 21680437 TI - The role of antimicrobial peptides in innate immunity. AB - Production of antimicrobial peptides and proteins is an important means of host defense in eukaryotes. The larger antimicrobial proteins, containing more than 100 amino acids, are often lytic enzymes, nutrient-binding proteins or contain sites that target specific microbial macromolecules. The smaller antimicrobial peptides act largely by disrupting the structure or function of microbial cell membranes. Hundreds of antimicrobial peptides have been found in the epithelial layers, phagocytic cells and body fluids of multicellular animals, from mollusks to humans. Some antimicrobial peptides are produced constitutively, others are induced in response to infection or inflammation. Studies of the regulation of antimicrobial peptide synthesis in Drosophila have been particularly fruitful, and have provided a new paradigm for the analysis of mammalian host defense responses. It now appears that the general patterns of antimicrobial responses of invertebrates have been preserved in vertebrates ("innate immunity") where they contribute to host defense both independently and in complex interplay with adaptive immunity. PMID- 21680438 TI - Cellular receptors and signal transduction in molluscan hemocytes: connections with the innate immune system of vertebrates. AB - The involvement of circulating hemocytes as the principal cellular effector mediating molluscan immune responses is well established. They participate in a variety of internal defense-related activities including microbial phagocytosis, multicellular encapsulation, and cell-mediated cytotoxicity reactions that are presumed to be initiated through foreign ligand binding to hemocyte receptors and subsequent transduction of the binding signal through the cell resulting in appropriate (or in some cases, inappropriate) hemocyte responses. At present, however, although functional evidence abounds as to the existence of hemocyte "recognition" receptors, few have been characterized at the molecular level. Similarly, signal transduction systems associated with various receptor-mediated hemocyte functions in molluscs are only beginning to be investigated and understood. This review examines what is currently known about the molluscan hemocyte receptors and the putative signal transduction pathways involved in regulating their cellular behaviors/activities. The cumulative data implies the presence of various hemocyte-associated receptors capable of binding specific carbohydrates, extracellular matrix proteins, growth factors, hormones, and cytokines. Moreover, receptor-ligand interactions appear to involve signaling molecules similar to those already recognized in vertebrate immunocyte signal transduction pathways, such as protein kinases A and C, focal adhesion kinase, Src, Ca(2+) and mitogen-activated protein kinase. Overall, the experimental evidence suggests that molluscan immune responses rely on molecules that share homology with those of vertebrate signaling systems. As more information regarding the molecular nature of hemocyte recognition receptors and their associated signaling molecules is accumulated, a clearer picture of how hemocyte immune responses to invading organisms are regulated will begin to emerge. PMID- 21680439 TI - Natural Peptide antibiotics from tunicates: structures, functions and potential uses. AB - Because tunicates rely on innate immunity, their hemocytes are important contributors to host defense. Styela clava, a solitary ascidian, have eight hemocyte subtypes. Extracts of their total hemocyte population contained multiple small (2-4 kDa) antimicrobial peptides. When purified, these fell into two distinct families that were named styelins and clavanins.Styelins A-E are phenylalanine-rich, 32 residue peptides with activity against marine bacteria and human pathogens. They show considerable sequence homology to pleurocidins, antimicrobial peptides of the flounder, Pseudopleuronectes americanus. Styelin D, one of the five styelins identified by peptide isolation and cDNA cloning, was remarkable in containing 12 post-translationally modified residues, including a 6 bromotryptophan, two monohydroxylysines, four 3,4-dihydroxyphenylalanines (DOPA), four dihydroxylysines and one dihydroxyarginine. These modifications enhanced Styelin D's bactericidal ability at acidic pH and high salinity. A novel histochemical stain for DOPA suggested that Styelin D was restricted to granulocytes.Clavanins A-E are histidine-rich, 23 residue peptides that are C terminally amidated and most effective at acidic pH. Clavaspirin is a newly described family member that also has potent cytotoxic properties. By immunocytochemistry, clavanins were identified in the granules of five eosinophilic granulocyte subtypes and in macrophage cytoplasm.Transmission and scanning electron micrographs of methicillin-resistant Staphylococcus aureus (MRSA) and E. coli that had been treated with Styelin D and clavaspirin suggested that both peptides induced osmotic disregulation. Treated bacteria manifested cytoplasmic swelling and extrusion of cytoplasmic contents through their peptidoglycan cell wall. The diverse array of antimicrobial peptides in S. clava hemocytes constitutes an effective host defense mechanism. PMID- 21680440 TI - Diverse lectin repertoires in tunicates mediate broad recognition and effector innate immune responses. AB - It is widely recognized that humoral and phagocyte-associated lectins constitute critical components of innate immunity in vertebrates and invertebrates. Their functions include not only self/non-self recognition but also engaging associated effector mechanisms, such as complement-mediated opsonization and killing of potential pathogens. One of the unresolved questions concerns the diversity in recognition capacity of the lectin repertoire, particularly in those organisms lacking adaptive immunity. In this paper, we discuss evidence suggesting that lectin repertoire in invertebrates and protochordates is highly diversified, and includes most of the lectin classes described so far in vertebrate species, as well as associated effector pathways. PMID- 21680441 TI - Novel Immune-type Receptor Genes and the Origins of Adaptive and Innate Immune Recognition. AB - The prototypic forms of teleost novel immune-type receptors (NITRs) consist of a variable (V) region, a unique V-like C2 (V/C2) domain, a transmembrane region and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibition motifs (ITIMs). NITRs encode diversified V regions in large multigene families but do not undergo somatic rearrangement. Studies in four different bony fish model systems have identified a number of different organizational forms of NITRs. Specifically, NITR genes encode N-terminal ectodomains of the V-type but otherwise vary in the: total number of extracellular immunoglobulin domains, number and location of joining (J) region-like motifs, presence of transmembrane regions, presence of charged residues within transmembrane regions, presence of cytoplasmic tails, and/or distribution of ITIM(s) within the cytoplasmic tails. V region-containing NITRs constitute a far more complex family than recognized originally and currently include individual members that potentially function through inhibitory as well as activating mechanisms. The genomic organization of the NITR gene cluster as well as the structural diversity and overall architecture of the NITR proteins is reminiscent of genes encoded at the mammalian leukocyte receptor cluster (LRC); however, there presently is no functional evidence to support an orthologous relationship between NITR and LRC gene products. Comparisons of the predicted structures of the NITRs have identified several short regions of sequence identity and a novel cloning strategy has been devised that selects for secretory and transmembrane proteins that encode these short motifs. Using this approach, related genes termed immune type receptors (ITRs) have been identified in cartilaginous fish. Taken together, these studies indicate that leukocyte regulatory receptors, including those that mediate natural killer function, might have emerged early in vertebrate evolution and that the NITR/ITR genes represent a new and potentially highly significant link between innate and adaptive immune responses. PMID- 21680442 TI - Did the molecules of adaptive immunity evolve from the innate immune system? AB - The antigen receptors on cells of innate immune systems recognize broadly expressed markers on non-host cells while the receptors on lymphocytes of the adaptive immune system display a higher level of specificity. Adaptive immunity, with its exquisite specificity and immunological memory, has only been found in the jawed vertebrates, which also display innate immunity. Jawless fishes and invertebrates only have innate immunity. In the adaptive immune response, T and B lymphocytes detect foreign agents or antigens using T cell receptors (TCR) or immunoglobulins (Ig), respectively. While Ig can bind free intact antigens, TCR only binds processed antigenic fragments that are presented on molecules encoded in the major histocompatibility complex (MHC). MHC molecules display variation through allelic polymorphism. A diverse repertoire of Ig and TCR molecules is generated by gene rearrangement and junctional diversity, processes carried out by the recombinase activating gene (RAG) products and terminal deoxynucleotidyl transferase (TdT). Thus, the molecules that define adaptive immunity are TCR, Ig, MHC molecules, RAG products and TdT. No direct predecessors of these molecules have been found in the jawless fishes or invertebrates. In contrast, the complement cascade can be activated by either adaptive or innate immune systems and contains examples of molecules that gradually evolved from non-immune functions to being part of the innate and then adaptive immune system. In this paper we examine the molecules of the adaptive immune system and speculate on the existence of direct predecessors that were part of innate immunity. PMID- 21680443 TI - Rapid evolutionary emergence of the combinatorial recognition repertoire. AB - Although the capacity of cells to respond to environmental challenges such as oxidative damage are ancient evolutionary developments that have been carried through to modern higher vertebrates as "innate" immunity, the characteristic immune response of vertebrates is a relatively recent evolutionary development that is present only in jawed vertebrates. The vertebrate "combinatorial" response is defined by the presence of lymphocytes as specific antigen recognition cells and by the complete panel of antibodies, T cell receptors, and major histocompatibility complex molecules all of which are members of the immunoglobulin family. Its emergence in evolution was an extremely rapid event (approximately 10 million years) that was catalyzed by the horizontal transfer of recombinase activator genes (RAG) from microbes to an ancestral jawed vertebrate. RAGs occur in jawed vertebrates, but have not been found in invertebrates and other intermediate species. We propose that antigen recognition capacity contributed by this novel combinatorial mechanism gave jawed vertebrates the ability to recognize the entire range of potential antigenic molecular structures, including self components and molecules of infectious microbes not shared with vertebrates. The contrast within the vertebrates is striking because the most ancient extant jawed vertebrates, sharks and their kin, have the complete panoply of T-cell receptors, antibodies, MHC products and RAG genes, whereas agnathans possess cells resembling lymphocytes but ostensibly lack all of the molecules definitive of combinatorial immunity. Another vertebrate innovation may have been the utilization of nuclear receptor superfamily, in the regulation of lymphocytes and other cells of the immune lineage. Unlike, RAG, however, this superfamily occurs in all metazoans with the exception of sponges. PMID- 21680444 TI - Introduction: the evolution of morphology, performance, and fitness. PMID- 21680445 TI - Performance surfaces and adaptive landscapes. AB - In an earlier characterization of the relationship between morphology, performance and fitness, I focused only on directional selection (Arnold, 1983). The aim of this article is to extend that characterization to include stabilizing and other forms of nonlinear selection. As in the earlier characterization, this more general description of the morphology-performance-fitness relationship splits empirical analysis into two parts: the study of the relationship between morpholgy and performance, and the study of the relationship between performance and fitness. From a conceptual standpoint, my goal is to specify the relationship of performance studies to the adaptive landscape. I begin by reviewing the adaptive landscape concept and its importance in evolutionary biology. A central point emerging from that review is that that key descriptors of the adaptive landscape can be estimated by measuring the impact of selection on the means, variances and covariances of phenotypic traits. Those descriptors can be estimated by making a quadratic (regression) approximation to the selection surface that describes the relationship between the phenotypic traits of individuals and their fitness. Analysis of the effects of morphology on performance follows an analogous procedure: making a quadratic approximation to the individual performance surface and then using that approximation to solve for the descriptors of the performance landscape. I conclude by discussing the evolution of performance and adaptive landscapes. One possibility with biomechanical justification is that the performance landscape evolves along performance lines of least resistance. PMID- 21680446 TI - Body size, performance and fitness in galapagos marine iguanas. AB - Complex organismal traits such as body size are influenced by innumerable selective pressures, making the prediction of evolutionary trajectories for those traits difficult. A potentially powerful way to predict fitness in natural systems is to study the composite response of individuals in terms of performance measures, such as foraging or reproductive performance. Once key performance measures are identified in this top-down approach, we can determine the underlying physiological mechanisms and gain predictive power over long-term evolutionary processes. Here we use marine iguanas as a model system where body size differs by more than one order of magnitude between island populations. We identified foraging efficiency as the main performance measure that constrains body size. Mechanistically, foraging performance is determined by food pasture height and the thermal environment, influencing intake and digestion. Stress hormones may be a flexible way of influencing an individual's response to low food situations that may be caused by high population density, famines, or anthropogenic disturbances like oil spills. Reproductive performance, on the other hand, increases with body size and is mediated by higher survival of larger hatchlings from larger females and increased mating success of larger males. Reproductive performance of males may be adjusted via plastic hormonal feedback mechanisms that allow individuals to assess their social rank annually within the current population size structure. When integrated, these data suggest that reproductive performance favors increased body size (influenced by reproductive hormones), with an overall limit imposed by foraging performance (influenced by stress hormones). Based on our mechanistic understanding of individual performances we predicted an evolutionary increase in maximum body size caused by global warming trends. We support this prediction using specimens collected during 1905. We also show in a common-garden experiment that body size may have a genetic component in iguanids. This 'performance paradigm' allows predictions about adaptive evolution in natural populations. PMID- 21680447 TI - Mutation accumulation, performance, fitness. AB - The morphology-performance-fitness paradigm is usually explored by determining whether natural or "phenotypically engineered" variation among individuals in morphology (physiology) or performance covaries with an index of fitness such as survival. Here we study between-line covariation between performance and fitness for 44 lines of flies that had undergone mutation accumulation (in the absence of natural selection) on the second chromosome for 62 generations, plus 13 control lines. These mutation accumulation (MA) lines were known to have reduced competitive fitness and life history scores, and to have positive between-line covariances among life history traits. We measured several performance traits of larvae and adults (and a life history trait), examined covariances among those trait means, and also examined covariances of traits with competitive fitness. MA lines had significantly lower performances than did control lines in most traits. However, because control lines had been unknowingly contaminated, a conclusion that MA reduces performance must be tentative. Correlations among performance traits were highly variable in sign, suggesting that MA does not negatively affect all traits equivalently. Even so, correlation matrices for MA and for control lines were very similar. In bivariate comparisons, only one performance trait (a "get-a-grip index," which measures the ability of a falling fly to catch itself on baffles) was positively correlated with competitive fitness. Multivariate analyses again suggested the importance primarily of get-a-grip. Two main patterns emerge from this study. First, MA negatively affects diverse aspects of physiological performance, but does so differentially across traits. Second, except for GAG, MA-induced variation in performance is at best weakly correlated with competitive fitness. PMID- 21680448 TI - Measuring performance in nature: implications for studies of fitness within populations. AB - Significant relationships among morphology, behavior, performance and fitness have long served as bona fide evidence for the role of selection in shaping natural populations. Here, I discuss how studies of ecological performance, or how organisms perform in nature, provide an ecological context for such selection studies. Laboratory studies assume that the level of performance expressed under "optimal" conditions accurately reflects the level of performance used in nature, but I show here that this assumption is not always borne out. A review of how various factors affect ecological performance (ontogeny, microhabitat, and macrohabitat) show that animals often express very different levels of movement speed both among different tasks, and when comparing laboratory versus field performance. Thus, a failure to take this variation into account could lead to negative, or even misleading significant fitness-character correlations. While laboratory performance studies should continue to play a key role in studies of selection, recent technological (i.e., portable high-speed cameras) and methodological developments should enable researchers to measure performance in nature to high degrees of accuracy. Thus, I encourage researchers to measure performance both in the laboratory and in the field, and thus expand the traditional paradigm of morphology -> performance -> fitness to morphology -> ecological performance -> fitness. PMID- 21680449 TI - Reciprocal selection at the phenotypic interface of coevolution. AB - Coevolutionary interactions depend upon a phenotypic interface of traits in each species that mediate the outcome of interactions among individuals. These phenotypic interfaces usually involve performance traits, such as locomotion or resistance to toxins, that comprise an integrated suite of physiological, morphological and behavioral traits. The reciprocal selection from species interactions may act directly on performance, but it is ultimately the evolution of these underlying components that shape the patterns of coevolutionary adaptation in performance. Bridging the macroevolutionary patterns of coevolution to the ecological processes that build them therefore requires a way to dissect the phenotypic interface of coevolution and determine how specific components of performance in one species exert selection on complimentary components of performance in a second species. We present an approach for analyzing the strength of selection in a coevolutionary interaction where individuals interact at random, and for identifying which component traits of the phenotypic interface are critical to mediating coevolution. The approach is illustrated with data from a predator-prey arms race between garter snakes and newts that operates through the interface of tetrodotoxin (TTX) and resistance to it. PMID- 21680450 TI - Physiological epistasis, ontogenetic conflict and natural selection on physiology and life history. AB - Ontogenetic conflict arises when optima for alleles governing fitness variation differ between juveniles and adults or between adult sexes. Loci that govern development of alternative phenotypes in the sexes, hereafter termed morph determining loci, mediate development through the endocrine system. Morphotypic selection is defined to be multivariate selection favoring discrete alternative morphotypes (e.g., optima). When the optimal combinations of alleles for alternative morphs differ between the sexes, it generates conflicting selection pressure and thus ontogenetic conflict. Selection on morph alleles promotes ontogenetic conflict because it perturbs physiological epistasis that governs the expression of male versus female traits. Expression of physiological traits arises from homeostasis that maintains trait expression within a normal range. The genetic basis of homeostasis is likely to arise from interactions among several genes (e.g., genetic epistasis) or protein products (e.g., physiological epistasis). For example, endocrine regulation arises from interactions between gondatropins, which are protein hormones produced by the hypothalamic-pituitary glands, and steroid hormones, which are produced by the gonads (e.g., HPG axis). The side-blotched lizard system is discussed with respect to physiological bases of ontogenetic conflict. We also describe a novel molecular marker strategy for uncovering genome-wide physiological epistasis in nature. Finally, ontogenetic conflict exerts selection on females to evolve mate selection or cryptic choice that is reflected in different sires being chosen for son versus daughter production. We describe how side-blotched lizard females ameliorate ontogenetic conflict by cryptic choice of male genotypes to produce sons versus daughters. PMID- 21680451 TI - Multi-trait Selection, Adaptation, and Constraints on the Evolution of Burst Swimming Performance. AB - Whole organism performance represents the integration of numerous physiological, morphological, and behavioral traits. How adaptive changes in performance evolve therefore requires an understanding of how selection acts on multiple integrated traits. Two approaches that lend themselves to studying the evolution of performance in natural populations are the use of quantitative genetics models for estimating the strength of selection acting on multiple quantitative traits and ecological genetic comparisons of populations exhibiting phenotypic differences correlated with environmental variation. In both cases, the ultimate goal is to understand how suites of traits and trade-offs between competing functions respond to natural selection. Here we consider how these two complimentary approaches can be applied to study the adaptive evolution of escape performance in fish. We first present an extension of Arnold's (1983) quantitative genetic approach that explicitly considers how trade-offs between different components of performance interact with the underlying genetics. We propose that such a model can reveal the conditions under which multiple selection pressures will cause adaptive change in traits that influence more than one component of fitness. We then review work on the Atlantic silversides and Trinidadian guppies as two case studies where an ecological genetics approach has been successfully applied to evaluate how the evolution of escape performance trades-off with other components of fitness. We conclude with the general lesson that whole organism performance is embedded in a complex phenotype, and that the net outcome of selection acting on different aspects of the organism will often result in a compromise among competing influences. PMID- 21680452 TI - Evolution of physiological tolerance and performance during freshwater invasions. AB - Invasive species that penetrate habitat boundaries are likely to experience strong selection and rapid evolution. This study documents evolutionary shifts in tolerance and performance following the invasion of fresh water by the predominantly estuarine and salt marsh copepod Eurytemora affinis. Common-garden experiments were performed on freshwater-invading (Lake Michigan) and ancestral saline (St. Lawrence marsh) populations to measure shifts in adult survival (at 0, 5, and 25 PSU), and survival during development and development time (both using full-sib clutches split across 0, 5, 15, and 25 PSU). Results showed clear evidence of heritable shifts in tolerance and performance associated with freshwater invasions. The freshwater population exhibited a gain in low-salinity tolerance and a reduction in high-salinity tolerance relative to the saline population, suggesting tradeoffs. These tradeoffs were supported by negative genetic correlations between survival at fresh (0 PSU) versus higher salinities. Mortality in response to salinity occurred primarily before metamorphosis, suggesting that selection in response to salinity had acted primarily on the early life-history stages. The freshwater population exhibited curious patterns of life-history evolution across salinities, relative to the saline population, of retarded development to metamorphosis but accelerated development from metamorphosis to adulthood. This pattern might reflect tradeoffs between development rate and survival in fresh water at the early life-history stages, but some other selective force acting on later life-history stages. Significant effects of clutch (genotype) and clutch-by-salinity interaction (G * E) on survival and development time in both populations indicated ample genetic variation as substrate for natural selection. Variation for high-salinity tolerance was present in the freshwater population despite negative genetic correlations between high- and low-salinity tolerance. Results implicate the importance of natural selection and document the evolution of reaction norms during freshwater invasions. PMID- 21680453 TI - Integrating development and environment to model reproductive performance in natural populations of an intertidal gastropod. AB - Functional challenges can differ among life-history stages, yet performance at one stage may be linked to the outcome of performance at others. For example, adult performance, in terms of the location or timing of reproduction in response to environmental signals, can set conditions that affect the performance of developmental stages. In marine invertebrates, however, early performance has been studied primarily in the laboratory. I outline an integrative approach to the study of field reproductive performance in a marine gastropod that undergoes development in intertidal habitats. Embryos within gelatinous masses experience high variability in development temperature and frequent exposure to thermal stress. In laboratory experiments, developmental performance was measured as a function of maximum temperature (T(max)) experienced during fluctuations that mimicked field tidal profiles. Performance curves showed declines that coincided with temperature thresholds for heat shock protein (Hsp) expression, a signal of cellular stress. Application of laboratory results to field records of T(max) predicted large variation in the survival of embryos deposited on different days. Timing of field reproduction was non-random with respect to T(max), suggesting that adults could help to buffer embryos from environmental stress. Embryo survival, however, was not predicted to benefit from the non-random pattern of adult reproduction. Adults may be constrained to respond to information that only weakly predicts conditions that embryos will experience. Studies that incorporate linkages between life cycle stages in the field may better reveal how performance capacities and constraints at one stage can influence performance and selection at others. PMID- 21680454 TI - The adaptive evolution of plasticity: phytochrome-mediated shade avoidance responses. AB - Many plants display a characteristic suite of developmental "shade avoidance" responses, such as stem elongation and accelerated reproduction, to the low ratio of red to far-red wavelengths (R:FR) reflected or transmitted from green vegetation. This R:FR cue of crowding and vegetation shade is perceived by the phytochrome family of photoreceptors. Phytochrome-mediated responses provide an ideal system for investigating the adaptive evolution of phenotypic plasticity in natural environments. The molecular and developmental mechanisms underlying shade avoidance responses are well studied, and testable ecological hypotheses exist for their adaptive significance. Experimental manipulation of phenotypes demonstrates that shade avoidance responses may be adaptive, resulting in phenotypes with high relative fitness in the environments that induce those phenotypes. The adaptive value of shade avoidance depends upon the competitive environment, resource availability, and the reliability of the R:FR cue for predicting the selective environment experienced by an induced phenotype. Comparative studies and a reciprocal transplant experiment with Impatiens capensis provide evidence of adaptive divergence in shade avoidance responses between woodland and clearing habitats, which may result from population differences in the frequency of selection on shade avoidance traits, as well as differences in the reliability of the R:FR cue. Recent rapid progress in elucidating phytochrome signaling pathways in the genetic model Arabidopsis thaliana and other species now provides the opportunity for studying how selection on shade avoidance traits in natural environments acts upon the molecular mechanisms underlying natural phenotypic variation. PMID- 21680455 TI - Environmental variation and selection on performance curves. AB - Many aspects of physiological and organismal performance vary with some continuous environmental variable: e.g., photosynthetic rate as a function of light intensity; growth rate or sprint speed as a function of temperature. For such 'performance curves', the environment plays two roles: it affects both the levels of performance expressed, and the relationship between performance and fitness. How does environmental variation within a generation determine natural selection on performance curves? We describe an approach to this question that has three components. First, we quantify natural environmental variation and assess its impact on performance in the field. Second, we develop a simple theoretical model that predicts how fine-grained environmental variation determines selection on performance curves. Third, we describe how directional selection on performance curves may be estimated and compared to theoretical predictions. We illustrate these steps using data on performance curves of short term growth rate as a function of temperature (thermal performance curves) in Pieris caterpillars. We use this approach to explore whether selection acts primarily on growth rate at specific temperatures, or on more integrated aspects of growth. PMID- 21680456 TI - A Comparative View of Alpha Crystallins: The contribution of comparative studies to understanding function. AB - Integration between comparative biology and cellular/molecular biology has helped advance understanding of the structure, function and physiology of the vertebrate small heat shock proteins alphaA- and alphaB-crystallin. These proteins are expressed at high concentration in the eye lens where they contribute to transparency and refractive power. But they also function similarly to molecular chaperones by preventing the aggregation of denatured proteins that can cause opacities, or cataracts. alpha-crystallins also serve a number of other roles in and out of the lens that are still not completely understood. Comparative examination of alpha-crystallins and closely related small heat shock proteins from diverse taxa has helped provide insights into the proteins' three dimensional shape and structure/function relationships. Until recently, no studies had examined the tissue specific expression or chaperone-like activity of alpha-crystallins from a non-mammalian vertebrate. I have been investigating the alpha-crystallins of the zebrafish, Danio rerio, as a first step towards utilizing the bony fishes as a model group for understanding the evolution of alpha-crystallin function. Zebrafish alphaA-crystallin displays similar structure and expression and increased chaperone-like activity compared to its human orthologue. Zebrafish alphaB-crystallin, however, has a truncated C-terminal extension, more limited expression and lower chaperone-like activity than its human orthologue. These data suggest that alphaA-crystallin physiological function may be conserved between zebrafish and mammals, while alphaB-crystallin physiological function has diverged. Understanding zebrafish alpha-crystallin physiology is necessary before this species can be used for developmental and genetic studies, and provides a foundation for further comparative studies. PMID- 21680457 TI - Gene sharing, lens crystallins and speculations on an eye/ear evolutionary relationship. AB - The crystallins comprise 80-90% of the water-soluble proteins of the transparent, cellular, refractive eye lens and are responsible for its optical properties. Comparative studies have established that the crystallins are surprisingly diverse and often differ among species in a taxon-specific fashion. In general, the crystallins are derived from or identical to metabolic enzymes or stress (small heat shock) proteins that are expressed to a lesser extent in other tissues where they have non-refractive roles. We call the phenomenon of having the small heat shock protein or enzyme and lens crystallin encoded in the identical gene "gene sharing"; examples include small heat shock protein/alphaB crystallin, alpha-enolase/tau-crystallin and argininosuccinate lyase/delta2 crystallin. Lens crystallins have evolved by gene sharing in vertebrates (all) and invertebrates (cephalopods, scallops, jellyfish). Similar cis-elements and transcription factors (including Pax6 among others) appear to unify lens expression of crystallin genes in vertebrates and mollusks (especially scallops). Instead of Pax6, cnidarians have a PaxB gene encoding a Pax2 DNA-binding paired domain and octapeptide, and a Pax6 homeodomain; PaxB appears important for ocellus (eye) development and crystallin gene expression in the cubomedusan jellyfish, Tridpedalia cystophora. Finally, we speculate on the basis of our current studies on Tripedalia that eyes and statocysts (associated with mechanoreceptors in many cnidarians and thus possibly ears in vertebrates) are evolutionarily related. Numerous examples indicate that gene sharing is widely used, consistent with changes in gene regulation being an evolutionary driving force for innovation of protein function. PMID- 21680458 TI - Ancestral gene reconstruction and synthesis of ancient rhodopsins in the laboratory. AB - Laboratory synthesis of ancestral proteins offers an intriguing opportunity to study the past directly. The development of Bayesian methods to infer ancestral sequences, combined with advances in models of molecular evolution, and synthetic gene technology make this an increasingly promising approach in evolutionary studies of molecular function. Visual pigments form the first step in the biochemical cascade of events in the retina in all animals known to possess visual capabilities. In vertebrates, the necessity of spanning a dynamic range of light intensities of many orders of magnitude has given rise to two different types of photoreceptors, rods specialized for dim-light conditions, and cones for daylight and color vision. These photoreceptors contain different types of visual pigment genes. Reviewed here are methods of inferring ancestral sequences, chemical synthesis of artificial ancestral genes in the laboratory, and applications to the evolution of vertebrate visual systems and the experimental recreation of an archosaur rod visual pigment. The ancestral archosaurs gave rise to several notable lineages of diapsid reptiles, including the birds and the dinosaurs, and would have existed over 200 MYA. What little is known of their physiology comes from fossil remains, and inference based on the biology of their living descendants. Despite its age, an ancestral archosaur pigment was successfully recreated in the lab, and showed interesting properties of its wavelength sensitivity that may have implications for the visual capabilities of the ancestral archosaurs in dim light. PMID- 21680459 TI - Evolution of insect eye development: first insights from fruit fly, grasshopper and flour beetle. AB - The molecular genetic dissection of Drosophila eye development led to the exciting discovery of a surprisingly large panel of genes and gene activities, which are functionally conserved across phyla. Little effort has yet been made towards pinpointing non-conserved gene functions in the developing Drosophila eye. This neglects the fact that Drosophila visual system development is a highly derived process. The comparative analysis of Drosophila eye development within insects can be expected to enhance resolution and accuracy of between phyla comparisons of eye development, and to reveal molecular developmental changes that facilitated the evolutionary transition from hemimetabolous to holometabolous insect development. Here we review aspects of early Drosophila eye development, which are likely to have diverged from the situation in more primitive insects, as indicated by results from work in the flour beetle Tribolium castaneum and the grasshopper Schistocerca americana. PMID- 21680460 TI - On homology of arthropod compound eyes. AB - Eyes serve as models to understand the evolution of complex traits, with broad implications for the origins of evolutionary novelty. Discussions of eye evolution are relevant at many taxonomic levels, especially within arthropods where compound eye distribution is perplexing. Either compound eyes were lost numerous times or very similar eyes evolved separately in multiple lineages. Arthropod compound eye homology is possible, especially between crustaceans and hexapods, which have very similar eye facets and may be sister taxa. However, judging homology only on similarity requires subjective decisions. Regardless of whether compound eyes were present in a common ancestor of arthropods or crustaceans + hexapods, recent phylogenetic evidence suggests that the compound eyes, today present in myodocopid ostracods (Crustacea), may have been absent in ostracod ancestors. This pattern is inconsistent with phylogenetic homology. Multiple losses of ostracod eyes are an alternative hypothesis that is statistically improbable and without clear cause. One possible evolutionary process to explain the lack of phylogenetic homology of ostracod compound eyes is that eyes may evolve by switchback evolution, where genes for lost structures remain dormant and are re-expressed much later in evolution. PMID- 21680461 TI - To see or not to see: evolution of eye degeneration in mexican blind cavefish. AB - The evolutionary mechanisms responsible for the loss of eyes in cave animals are still unresolved. Hypotheses invoking natural selection or neutral mutation have been advanced to explain eye regression. Here we describe comparative molecular and developmental studies in the teleost Astyanax mexicanus that shed new light on this problem. A. mexicanus is a single species consisting of a sighted surface dwelling form (surface fish) and many blind cave-dwelling forms (cavefish) from different caves. We first review the evolutionary relationships of Astyanax cavefish populations and conclude that eye degeneration may have evolved multiple times. We then compare the mechanisms of eye degeneration in different cavefish populations. We describe the results of experiments showing that programmed cell death of the lens plays a key role in controlling eye degeneration in these cavefish populations. We also show that Pax6 gene expression and fate determination in the optic primordia are modified similarly in different cavefish populations, probably due to hyperactive midline signaling. We discuss the contributions of the comparative developmental approach toward resolving the evolutionary mechanisms of eye degeneration. A new hypothesis is presented in which both natural selection and neutral mutation are proposed to have roles in cavefish eye degeneration. PMID- 21680462 TI - Visual ecology and functional morphology of cubozoa (cnidaria). AB - Jellyfish belong to one of the oldest extant animal phyla, the Cnidaria. The first Cnidaria appear in the fossil record 600 million years ago, preceeding the Cambrian explosion. They are an extremely successful group present in all marine environments and some freshwater environments. In contrast to many animal phyla in which vision is a primary sense Cnidarians do not, generally, employ image forming eyes. One small class stands alone: the Cubozoa. Cubomedusae are commonly known as box jellyfish. They possess image forming eyes (Coates et al., 2001) which certainly evolved independently from other metazoans. Cubomedusae therefore offer a unique perspective on the evolution of image forming eyes. This literature review collects, into one place, what is known about: the multiple eye types of box jellyfish, cubomedusan life history and ecology, and the sensory and neural systems of box jellyfish. Here I discuss how these features set cubomedusae apart from scyphomedusae and hydromedusae. Knowledge in these areas is sparse; the work done to date inspires increased efforts. PMID- 21680463 TI - Polarization vision and its role in biological signaling. AB - Visual pigments, the molecules in photoreceptors that initiate the process of vision, are inherently dichroic, differentially absorbing light according to its axis of polarization. Many animals have taken advantage of this property to build receptor systems capable of analyzing the polarization of incoming light, as polarized light is abundant in natural scenes (commonly being produced by scattering or reflection). Such polarization sensitivity has long been associated with behavioral tasks like orientation or navigation. However, only recently have we become aware that it can be incorporated into a high-level visual perception akin to color vision, permitting segmentation of a viewed scene into regions that differ in their polarization. By analogy to color vision, we call this capacity polarization vision. It is apparently used for tasks like those that color vision specializes in: contrast enhancement, camouflage breaking, object recognition, and signal detection and discrimination. While color is very useful in terrestrial or shallow-water environments, it is an unreliable cue deeper in water due to the spectral modification of light as it travels through water of various depths or of varying optical quality. Here, polarization vision has special utility and consequently has evolved in numerous marine species, as well as at least one terrestrial animal. In this review, we consider recent findings concerning polarization vision and its significance in biological signaling. PMID- 21680464 TI - Effects of Light Adaptation on the Temporal Resolution of Deep-sea Crustaceans. AB - The effects of light adaptation on flicker fusion frequency were examined in the photoreceptors of 13 species of deep-sea crustaceans. Light adaptation produced a significant increase in the maximum critical flicker fusion frequency (CFF(max)) in 7 species-all 6 species of euphausiids in the study, and 1 species of oplophorid (Group 1). This is the first example of an increase in temporal resolution due to light adaptation in a deep-sea species. In the other six species-2 oplophorids, 1 pandalid, 1 pasiphaeid, 1 penaeid and 1 sergestid (Group 2)-light adaptation had no effect, or resulted in a decrease in the flicker fusion frequency. The mean dark-adapted CFF(max) of the Group 1 species was significantly higher, and the mean response latency significantly lower, than those of the Group 2 species. Possible explanations for these differences include the activity and bioluminescence mode of preferred prey items, as well as the retention of larval/juvenile adaptations in adult eyes. PMID- 21680465 TI - Colour vision in diurnal and nocturnal hawkmoths. AB - Diurnal and nocturnal hawkmoths (Sphingidae, Lepidoptera) have three spectral types of receptor sensitive to ultraviolet, blue and green light. As avid flower visitors and pollinators, they use olfactory and visual cues to find and recognise flowers. Moths of the diurnal species Macroglossum stellatarum and the nocturnal species Deilephila elpenor, Hyles lineata and Hyles gallii use and learn the colour of flowers. Nocturnal species can discriminate flowers at starlight intensities when humans and honeybees are colour-blind. M. stellatarum can use achromatic, intensity-related cues if colour cues are absent, and this is probably also true for D. elpenor. Both species can recognise colours even under a changed illumination colour. PMID- 21680466 TI - Lifting the cloak of invisibility: the effects of changing optical conditions on pelagic crypsis. AB - While transparency, cryptic coloration, and counterillumination are all highly successful cryptic strategies for pelagic species, they become less effective when confronted with varying optical conditions. Transparent species are susceptible to detection by reflections from their body surface, particularly at shallow depths. Colored and mirrored species are vulnerable to detection when viewed from certain angles, or at certain times of day. Counterilluminating species must cope with the changes in the angular distribution and spectra of downwelling light at different depths. In all cases the vulnerabilities are more pronounced at shallow depths and essentially negligible at depths greater than 200 m. The results suggest interesting adaptations both for crypsis (e.g., anti reflection coatings, variable coloration, variable filters for photophores) and for visual detection (e.g., circling, crepuscular predation), all of which are potentially fruitful topics for future research. PMID- 21680467 TI - A fourier tool for the analysis of coherent light scattering by bio-optical nanostructures. AB - The fundamental dichotomy between incoherent (phase independent) and coherent (phase dependent) light scattering provides the best criterion for a classification of biological structural color production mechanisms. Incoherent scattering includes Rayleigh, Tyndall, and Mie scattering. Coherent scattering encompasses interference, reinforcement, thin-film reflection, and diffraction. There are three main classes of coherently scattering nanostructures-laminar, crystal-like, and quasi-ordered. Laminar and crystal-like nanostructures commonly produce iridescence, which is absent or less conspicuous in quasi-ordered nanostructures. Laminar and crystal-like arrays have been analyzed with methods from thin-film optics and Bragg's Law, respectively, but no traditional methods were available for the analysis of color production by quasi-ordered arrays. We have developed a tool using two-dimensional (2D) Fourier analysis of transmission electron micrographs (TEMs) that analyzes the spatial variation in refractive index (available from the authors). This Fourier tool can examine whether light scatterers are spatially independent, and test whether light scattering can be characterized as predominantly incoherent or coherent. The tool also provides a coherent scattering prediction of the back scattering reflectance spectrum of a biological nanostructure. Our applications of the Fourier tool have falsified the century old hypothesis that the non-iridescent structural colors of avian feather barbs and skin are produced by incoherent Rayleigh or Tyndall scattering. 2D Fourier analysis of these quasi-ordered arrays in bird feathers and skin demonstrate that these non-iridescent colors are produced by coherent scattering. No other previous examples of biological structural color production by incoherent scattering have been tested critically with either analysis of scatterer spatial independence or spectrophotometry. The Fourier tool is applied here for the first time to coherent scattering by a laminar array from iridescent bird feather barbules (Nectarinia) to demonstrate the efficacy of the technique on thin films. Unlike previous physical methods, the Fourier tool provides a single method for the analysis of coherent scattering by a diversity of nanostructural classes. This advance will facilitate the study of the evolution of nanostructural classes from one another and the evolution of nanostructure itself. The article concludes with comments on the emerging role of photonics in research on biological structural colors, and the future directions in development of the tool. PMID- 21680468 TI - The importance of species: perspectives on expendability and triage. PMID- 21680469 TI - Physiology underlying phenotypic plasticity and polyphenisms: introduction to the symposium. PMID- 21680470 TI - The endocrine regulation of wing polymorphism in insects: state of the art, recent surprises, and future directions. AB - The endocrine mechanisms controlling the development and reproduction of flight capable (long-winged) and flightless (short-winged or wingless) morphs of wing polymorphic insects have been intensively investigated. The "classical model," put forward in the early 1960s, postulates that morph-specific differences in development and reproduction are caused by variation in the titers of juvenile hormone (JH) and/or ecdysone. Despite decades of study, the importance of these hormones in regulating wing polymorphism in aphids and planthoppers remains uncertain. This uncertainly is largely a consequence of technical and size constraints which have severely limited the types of endocrine approaches that can be used in these insects. Recent studies in wing-polymorphic crickets (Gryllus) have provided the first direct evidence that the in vivo blood titers of juvenile hormone and ecdysone, and especially the activity of the JH regulator, juvenile hormone esterase, differ between nascent morphs. Morph differences are largely consistent with the classical model, although some types of data are problematic, and other explanations are possible. Adult morphs differ dramatically in the JH titer but titer differences are more complex than those proposed by the classical model. Detailed endocrine information is thus far available only for a few species of crickets, and the hormonal control of wing polymorphism for insects as a whole remains poorly understood. Future studies should continue to investigate the role of JH and ecdysteroids in morph development and reproduction, and should expand to include studies of morph specific differences in hormone receptors and neurohormones. PMID- 21680471 TI - Genotype to phenotype: physiological control of trait size and scaling in insects. AB - For almost a century, biologists have used trait scaling relationships (bi variate scatter-plots of trait size versus body size) to characterize phenotypic variation within populations, and to compare animal shape across populations or species. Scaling relationships are a popular metric because they have long been thought to reflect underlying patterns of trait growth and development. However, the physiological mechanisms generating animal scaling are not well understood, and it is not yet clear how scaling relationships evolve. Here we review recent advances in developmental biology, genetics, and physiology as they pertain to the control of growth of adult body parts in insects. We summarize four mechanisms known to influence either the rate or the duration of cell proliferation within developing structures, and suggest how mutations in these mechanisms could affect the relative sizes of adult body parts. By reviewing what is known about these four processes, and illustrating how they may contribute to patterns of trait scaling, we reveal genetic mechanisms likely to be involved in the evolution of insect form. PMID- 21680472 TI - Plasticity and canalization in the control of reproduction in the lubber grasshopper. AB - The ability to change reproductive tactics during adult development in response to environmental variation is predicted to enhance fitness. Many organisms show phenotypic plasticity early in non-embryonic development, but later exhibit phases of developmental inflexibility (=canalization). Therefore, we studied reproduction-related hormones and proteins and their relationships to plasticity in the Eastern lubber grasshopper. Diet-switching experiments demonstrated plasticity early in the egg production cycle, but a switch to canalization late in the cycle. We measured developmental titers of 4 hemolymph compounds from single individuals from adult molt until first oviposition. These 4 compounds were the egg-yolk precursor protein vitellogenin, juvenile hormone (the central regulator of insect reproduction), major hemolymph proteins, and ecdysteroids (the arthropod molting hormone that ultimately is stored in the egg). Using diet manipulations, we investigated how these developmental titers relate to the switch from plastic to canalized egg production. All 4 hemolymph compounds reached their peak levels during the canalized phase, about 12 day before oviposition. Diet switches after these peak levels did not affect the timing to oviposition. Therefore, these peak titers were physiological events that occurred after the individual committed to laying. We compared these patterns in reproduction to the development toward adult molt, another major life-history event in insects. We observed an extended canalized phase before the adult molt. This canalized phase always included a peak of ecdysteroids. The similar patterns in the physiology of these life-history events suggested that common limitations may exist in major developmental processes of insects that are directed by hormones. PMID- 21680473 TI - Endocrine mechanisms underlying plasticity in metamorphic timing in spadefoot toads. AB - Amphibian larvae respond to heterogeneous environments by varying their rates of growth and development. Several amphibian species are known to accelerate metamorphosis in response to pond drying or resource restriction. Some of the most extensive studies to date on developmental responses to pond drying have been conducted on species of spadefoot toads (family Pelobatidae). We have found that tadpoles of two species of spadefoot toad accelerate metamorphosis when exposed to water volume reduction in the laboratory (to simulate a drying pond). Furthermore, Western spadefoot toad (Spea hammondii) tadpoles accelerated metamorphosis in response to food restriction, which was intended to simulate a decline in resource availability in the larval habitat. Metamorphic acceleration was accompanied by increased whole body 3,5,3'-triiodothyronine and hindbrain corticotropin-releasing hormone content by 24 hr after transfer of tadpoles from high to low water. Food restriction for 4 day accelerated metamorphosis and elevated whole body thyroid hormone content. Although tadpoles accelerated metamorphosis and activated their thyroid axis in response to the two environmental manipulations, the kinetics of the responses were greater for water volume reduction than for resource restriction. The modulation of hormone secretion and action by environmental factors provides a mechanistic basis for plasticity in the timing of amphibian metamorphosis, and the neuroendocrine stress axis may play a central role in developmental plasticity. PMID- 21680474 TI - Endocrine mediation of vertebrate male alternative reproductive tactics: the next generation of studies. AB - In many species of animals, males may achieve reproductive success via one of several alternative reproductive tactics. Over the past decade or so, there has been a concerted effort to investigate endocrine mechanisms that underlie such discrete behavioral (and often morphological) variation. In vertebrates, the first generation of studies focused on potential organizational or activational effects of steroid hormones (Moore, 1991; Moore et al., 1998). Some of these studies have made it clear that, in addition to circulating hormone levels, one must also consider other aspects of the endocrine system, including hormone receptors, binding globulins and potential interactions among endocrine axes. In this paper, I review recent work on endocrine mechanisms and suggest possibilities for future investigation. I highlight how individual variation in sensitivity to environmental conditions, particularly with respect to various stressors, may account for the existence of alternative male reproductive phenotypes. Along these lines, I briefly explain the logic behind our work with male phenotypes of longear sunfish (Lepomis megalotis) that is aimed at determining the tissue-specific distribution and activity of two enzymes that are common to androgen and glucocorticoid metabolism. A major goal of our work is to examine the potential role of steroidogenic enzymes in the transduction of environmental information to influence the expression of alternative male reproductive phenotypes. PMID- 21680475 TI - How does Behavior Change the Brain? Multiple Methods to Answer Old Questions. AB - Clearly the brain controls behavior but can behavior also "control" the brain? On an evolutionary time scale, selective ecological pressures shape the sensory and motor capacities as well as the body and behavior. Correspondingly, in development, behavior acts in concert with the environment to cause structural changes in the brain lasting a lifetime. Surprisingly, in "real time" social behavior can also cause changes, typically reversible, in the brain in adult animals. Changes caused by behavioral interactions can be dramatic, and in many instances, these interactions are directly related to reproductive behavior. Understanding how behavior sculpts the brain in the course of behavioral interactions is a major challenge. Analyzing such changes requires a model system allowing control of the biological and behavioral environment of many animals simultaneously yet allowing access to physiological, cellular and molecular processes being regulated. The mouthbrooding cichlid Haplochromis (Astatotilapia) burtoni (Gunther) from Lake Tanganyika lends itself to the study of social influences on the brain. It has complex, though easily observable individual and social behaviors regulated by two distinct classes of males, those with territories and those without. Many features of the animals are shaped by social encounters including the maturation of juveniles, the hypothalamic-pituitary gonadal axis, the growth rate, the basal stress level among others. How does social information effect change in the brain and body? Animals must attend to the social scene to identify their chances. Learning how social information is transduced into cellular changes in this species should help understand how this happens in other social animals. PMID- 21680476 TI - Evaluation of sensitivity, performance and reproducibility of microarray technology in neuronal tissue. AB - Microarray technology is a powerful technique that allows the simultaneous study of thousands of gene transcripts. During the past two years there has been an explosion of publications describing experiments utilizing microarray technology that range from original research findings from biological paradigms to mathematically modeled systems. However, neuroscientists using microarray technology face significant challenges due to high tissue complexity, low abundance transcripts, and small magnitude changes in transcript levels that have significant biological impact. This manuscript describes a series of studies designed to address issues regarding microarray sensitivity, ability of microarrays to detect subtle changes, and reproducibility of microarray experiments, all in the context of neuronal tissue. From the presentation of these studies, the authors argue that although microarray technology is limited with regards to sensitivity, the outcome of these experiments, if approached with appropriate skepticism, can be fruitful in the generation of hypotheses and seeding of future experiments. PMID- 21680477 TI - The "ups" and "downs" in Using Subtractive Cloning Techniques to Isolate Regulated Genes in Fish. AB - Over the last decade, subtractive cloning approaches have been used extensively to isolate genes that are up- or down-regulated under various conditions. These techniques have provided the foundation for many subsequent studies concerning gene function and regulation and, as such, have been valuable tools for many biological fields. Over the past 10 years, we have used different subtractive cloning approaches to isolate genes in fish that are regulated in relation to hormonal stimulation or the stage of ovarian maturation. These include conventional cDNA subtraction followed by library screening, differential display PCR, suppression subtraction hybridization, and more recently, iterative PCR subtraction. We continue to use these techniques for the isolation of new genes involved in physiological processes in fish and bivalve molluscs. Examples that illustrate the use of these different subtractive cloning techniques are described, including where possible the advantages and disadvantages of each. In addition, the use of ancillary methods (e.g., "Reverse Northerns") to facilitate the use of these subtractive approaches are discussed. PMID- 21680478 TI - Viewing cell movements in the developing neuroendocrine brain. AB - Many studies suggest that migratory guidance cues within the developing brain are diverse across many regions. To better understand the early development and differentiation of select brain regions, an in vitro method was developed using selected inbred and transgenic strains of embryonic mice. In particular, organotypic slices are used to test factors that influence the movements of neurons during brain development. Thick 250 MUm slices cut on a vibrating microtome are prepared and maintained in vitro for 0-3 days. Nissl stain analyses often show a uniform distribution of cells in the regions of interest on the day of plating (embryonic days 12-15). After 3 days in vitro, cellular aggregation suggesting nuclear formation or the changing position of cells with a defined phenotype show that reasonably normal cell movements occur in several regions. Movements in vitro that mimic changes in vivo suggest that key factors reside locally within the plane of the slices. Video microscopy studies are used to follow the migration of fluorescently labeled cells in brain slices from mice maintained in serum-free media for 1 to 3 days. Transgenic mice with selective promoter driven expression of fluorescent proteins allow us to view specific cell types (e.g., neurons expressing gonadotropin-releasing hormone). The accessibility of an in vitro system that provides for relatively normal brain development over key brief windows of time allows for the testing of important mechanisms. PMID- 21680479 TI - Recent developments in neurobiology: introduction to the symposium. PMID- 21680480 TI - Crustacean phasic and tonic motor neurons. AB - Crustacean motor neurons subserving locomotion are specialized for the type of activity in which they normally participate. Neurons responsible for maintained activity ('tonic' neurons) support moderate to high frequencies of nerve impulses intermittently or continuously during locomotion, while those recruited for short lasting rapid responses ('phasic' neurons) generally fire a few impulses in a rapid burst during rapid locomotion and are otherwise silent. The synaptic responses of the two types, recorded at their respective neuromuscular junctions, differ enormously: phasic neurons exhibit much higher quantal release per synapse and per muscle fibre, along with more rapid synaptic depression and less short term facilitation. We have analyzed the factors that are responsible for the large difference in initial release of neurotransmitter. Several possibilities, including synapse and active zone size differences, entry of calcium at active zones, and immediately releasable vesicle pools, could not account for the large phasic-tonic difference in initial transmitter output. The most likely feature that differentiates synaptic release is the sensitivity of the exocytotic machinery to intracellular calcium. Molecular features of the phasic and tonic presynaptic nerve terminals are currently under investigation. PMID- 21680481 TI - Stress-induced thermoprotection of neuromuscular transmission. AB - Environmental stresses such as high temperature or low levels of oxygen can lead to structural destabilization of cells, disruption of cellular processes, and, in extreme cases, death. Previous experience of sub-lethal stress can lead to protection during a subsequent stress that may otherwise have been lethal. Synapses are particularly vulnerable to extreme environmental conditions and failure of function at this level may be the primary cause of organismal death. Prior heat shock induces enhanced thermotolerance at neuromuscular junctions in the locust extensor tibiae muscle and in abdominal muscles of larval Drosophila. Synaptic thermoprotection is associated with an increase in short-term plasticity at these synapses. Prior anoxic coma in locusts induces synaptic thermotolerance suggesting that the same protective pathways are activated. It is well established that diverse forms of stress induce the upregulation of cellular chaperones (heat shock proteins; HSPs) that mediate acquired protection. The mechanisms underlying HSP-mediated synaptic protection are currently unknown but evidence is accumulating that stabilization of the cytoskeleton may play an important role. PMID- 21680482 TI - Modulation of neural circuit operation by prior environmental stress. AB - Many organisms are exposed to harsh environmental conditions that may impair the operation of vital neuronal circuits and imperil the animal before these conditions directly cause cell and tissue death. Prior exposure to extreme but sub-lethal stress has long-term effects on neural circuit function enabling motor pattern generators to operate under previously non-permissive conditions. Using several model systems we have been investigating the mechanisms underlying stress mediated neuroprotection, particularly thermotolerance imparted by a prior heat shock. Prior anoxia and cold shock also impart thermotolerance of motor pattern generation suggesting that different stressors activate common protective pathways. Synaptic transmission, action potential generation and neuronal potassium conductance are modulated by prior heat shock. Pharmacological block of potassium channels, which increases the duration of action potentials and the amplitude of postsynaptic potentials, mimics the thermoprotective effect of a prior heat shock. A universal consequence of heat shock and other stresses is the increased expression of a suite of heat shock proteins of which HSP70 is most closely linked to organismal thermotolerance. Increased levels of HSP70 are sufficient, but not necessary for synaptic thermoprotection. Accumulating evidence suggests the existence of multiple, overlapping pathways for protection and that these mechanisms may be neuron specific depending on their functional roles. PMID- 21680483 TI - In Search of Food: Exploring the Evolutionary Link Between cGMP-Dependent Protein Kinase (PKG) and Behaviour. AB - Despite an immense amount of variation in organisms throughout the animal kingdom many of their genes show substantial conservation in DNA sequence and protein function. Here we explore the potential for a conserved evolutionary relationship between genes and their behavioural phenotypes. We investigate the evolutionary history of cGMP-dependent protein kinase (PKG) and its possible conserved function in food-related behaviours. First identified for its role in the foraging behaviour of fruit flies, the PKG encoded by the foraging gene has since been associated with the maturation of behaviour (from nurse to forager) in honey bees and the roaming and dwelling food-related locomotion in nematodes. These parallels encouraged us to construct protein phylogenies using 32 PKG sequences that include 19 species. Our analyses suggest five possible evolutionary histories that can explain the apparent conserved link between PKG and behaviour in fruit flies, honey bees and nematodes. Three of these raise the hypothesis that PKG influences the food-related behaviours of a wide variety of animals including vertebrates. Moreover, it appears that the PKG gene was duplicated some time between the evolution of nematodes and a common ancestor of vertebrates and insects whereby current evidence suggests only the for-like PKG might be associated with food-related behaviour. PMID- 21680484 TI - Cellular Mechanisms Underlying Swim Acceleration in the Pteropod Mollusk Clione limacina. AB - The pteropod mollusk Clione limacina swims by dorsal-ventral flapping movements of its wing-like parapodia. Two basic swim speeds are observed-slow and fast. Serotonin enhances swimming speed by increasing the frequency of wing movements. It does this by modulating intrinsic properties of swim interneurons comprising the swim central pattern generator (CPG). Here we examine some of the ionic currents that mediate changes in the intrinsic properties of swim interneurons to increase swimming speed in Clione. Serotonin influences three intrinsic properties of swim interneurons during the transition from slow to fast swimming: baseline depolarization, postinhibitory rebound (PIR), and spike narrowing. Current clamp experiments suggest that neither I(h) nor I(A) exclusively accounts for the serotonin-induced baseline depolarization. However, I(h) and I(A) both have a strong influence on the timing of PIR-blocking I(h) increases the latency to PIR while blocking I(A) decreases the latency to PIR. Finally, apamin a blocker of I(K(Ca)) reverses serotonin-induced spike narrowing. These results suggest that serotonin may simultaneously enhance I(h) and I(K(Ca)) and suppress I(A) to contribute to increases in locomotor speed. PMID- 21680485 TI - Evolutionary divergence in developmental strategies and neuromodulatory control systems of two amphibian locomotor networks. AB - Attempts to understand the neural mechanisms which produce behaviour must consider both prevailing sensory cues and the central cellular and synaptic changes they direct. At each level, neuromodulation can additionally shape the final output. We have investigated neuromodulation in the developing spinal motor networks in hatchling tadpoles of two closely related amphibians, Xenopus laevis and Rana temporaria to examine the subtle differences in their behaviours that could be attributed to their evolutionary divergence.At the point of hatching, both species can swim in response to a mechanosensory stimulus, however Rana embryos often display a more forceful, non-locomotory coiling behaviour. Whilst the synaptic drive that underlies these behaviours appears similar, subtle inter specific differences in neuronal properties shape motor outputs in different ways. For example, Rana neurons express N-methyl-D-aspartate (NMDA)/serotonin (5 HT)-dependent oscillations, not present in hatchling Xenopus and many also exhibit a prominent slow spike after-hyperpolarisation. Such properties may endow the spinal circuitry of Rana with the ability to produce a more flexible range of outputs.Finally, we compare the roles of the neuromodulators 5-HT, noradrenaline (NA) and nitric oxide (NO) in shaping motor outputs. 5-HT increases burst durations during swimming in both Xenopus and Rana, but 5-HT dramatically slows the cycle period in Rana with little effect in Xenopus. Three distinct, but presumably homologous NO-containing brainstem clusters of neurons have been described, yet the effects of NO differ between species. In Xenopus, NO slows and shortens swimming in a manner similar to NA, yet in Rana NO and NA elicit the non rhythmic coiling pattern. PMID- 21680486 TI - Optical and genetic approaches toward understanding neuronal circuits in zebrafish. AB - Optical and genetic tools are beginning to revolutionize the studies of neuronal circuits. Neurons can now be labeled with conventional or genetically encoded indicators that allow their activity to be monitored during behavior in intact animals. Laser ablations and genetic inactivation offer ways to perturb activity of specific cells to test their contributions to behavior. These approaches promise to speed progress in the understanding of vertebrate networks in genetic model systems such as mice and zebrafish. Here we review some of the progress in applying these tools, with an emphasis on our work to develop and apply these approaches in the zebrafish model. PMID- 21680487 TI - Adaptive mechanisms of spinal locomotion in cats. AB - This paper reviews some aspects of locomotor plasticity after spinalisation and after peripheral nerve lesions. Adult cats can recover spontaneous hindlimb locomotion on a treadmill several days or weeks after a complete section of the spinal cord at T13. The kinematics as well as the electromyographic activity are compared in the same animal before and after the spinal section to highlight the resemblance of locomotor characteristics in the two conditions. To study further the mechanisms of spinal plasticity potentially underlying such locomotor recovery, we also summarize the locomotor adaptation of cats submitted to various types of peripheral nerve section of either ankle flexor or extensor muscles or after denervation of the hindpaws' cutaneous inputs. It is argued that, even in the spinal state, cats have the ability to compensate for such lesions of the peripheral nervous system suggesting that the spinal cord has a significant potential for adaptive plasticity that could be used in rehabilitation strategies to restore locomotion after spinal cord injury. PMID- 21680488 TI - Introduction: biology of the canadian arctic: a crucible for change in the 21st century. PMID- 21680489 TI - Seasonal adaptations in arctic insects. AB - Many insect species live in the arctic and show a wide range of adaptations to its extreme severity and seasonality. Long, cold winters are met, for example, by cold hardiness and choice of protected sites. Cold hardiness includes both widespread tolerance to freezing and extreme supercooling ability, as well as unusual responses in a few species, such as lack of typical cryoprotectants. Adaptations to short, cool summers include activity at low temperatures, selection of warm habitats and microhabitats, melanism and hairiness coupled with basking behaviour, and prolonged or abbreviated life cycles. Diapause ensures that many species emerge early in summer, with brief synchronized reproduction that maximizes the time for offspring development before winter returns. Some species overwinter in sites that thaw earliest in spring, even if they are relatively exposed in winter. Other adaptations respond to year-to-year variability: for example, prolonged diapause can provide insurance against unsuitable summers. All of these adaptations are co-ordinated. For example, cold hardiness relies on physiological and biochemical adaptations but also on habitat choice and timing. Because the adaptations are complex, predicted climatic warming probably will have unexpected effects. In particular, an increase in temperature that increases summer cloud when sea ice melts would likely reduce temperatures for insect development and activity, because sunshine provides critical warmth to insects and their microhabitats. Changes in moisture will also be important. Moreover, responses differ among species, depending especially on their microhabitats. The complexity of the responses of insects to arctic conditions reinforces the need for research that is sufficiently detailed. PMID- 21680490 TI - Coping with changing northern environments: the role of the stress axis in birds and mammals. AB - Northern environments present ecological and physiological problems for homeotherms that require adaptations to cope with severe and less predictable physical factors while at the same time continuing to have to cope with the biological ones, such as competition and predation. The stress axis plays a central role in these adaptations and I discuss the range of solutions that birds and mammals have evolved. The stress response in these animals is not static when a challenge occurs, but may be modulated depending on the biological function during the annual cycle (breeding versus nonbreeding), either under-responding to permit reproduction (some song birds) or responding vigorously, yet not having this compromise reproduction (Arctic ground squirrels). Both may trade off survival for reproduction. In contrast, the snowshoe hare shows the expected stress response to chronic high predation risk over 2-3 years: body resources are geared to survival and reproduction is inhibited. Two long term, persistent, and pervasive changes will confront northern birds and mammals in the 21(st) century: global change and persistent organochlorine pollutants (POPs). These may result in either adaptations or shifts in distribution and abundance. For the former, latitudinal variation in the stress axis may help song birds respond rapidly; population variation in the stress axis response is unknown in northern mammals and relatively sedentary mammals may be unable to shift their distribution rapidly to adjust major climate shifts. For the latter, the few POPs studies that have examined the stress axis indicate marked negative effects. PMID- 21680491 TI - "Emerging" parasitic infections in arctic ungulates. AB - Important drivers for emergence of infectious disease in wildlife include changes in the environment, shrinking habitats or concentration of wildlife, and movement of people, animals, pathogens, or vectors. In this paper we present three case studies of emerging parasitic infections and diseases in ungulates in the Canadian north. First we discuss climate warming as an important driver for the emergence of disease associated with Umingmakstrongylus pallikuukensis, a nematode lungworm of muskoxen. Then we examine how Protostrongylus stilesi, the sheep lungworm, emerged (or re-emerged) in muskoxen after re-introduction of this host into its historical range made it sympatric with Dall's sheep. Finally, we consider Teladorsagia boreoarcticus, a newly described and common abomasal nematode of muskoxen that is emerging as a disease-causing parasite and may be an important regulator for muskox populations on Banks Island, Northwest Territories. These and other arctic host-parasite systems are exquisitely tuned and constrained by a harsh and highly seasonal environment. The dynamics of these systems will be impacted by climate change and other ecological disruptions. Baseline knowledge of parasite biodiversity and parasite and host ecology, together with predictive models and long-term monitoring programs, are essential for anticipating and detecting altered patterns of host range, geographic distribution, and the emergence of parasitic infections and diseases. PMID- 21680492 TI - Trophic interactions in a high arctic snow goose colony. AB - We examined the role of trophic interactions in structuring a high arctic tundra community characterized by a large breeding colony of greater snow geese (Chen caerulescens atlantica). According to the exploitation ecosystem hypothesis of Oksanen et al. (1981), food chains are controlled by top-down interactions. However, because the arctic primary productivity is low, herbivore populations are too small to support functional predator populations and these communities should thus be dominated by the plant/ herbivore trophic-level interaction. Since 1990, we have been monitoring annual abundance and productivity of geese, the impact of goose grazing, predator abundance (mostly arctic foxes, Alopex lagopus) and the abundance of lemmings, the other significant herbivore in this community, on Bylot Island, Nunavut, Canada. Goose grazing consistently removed a significant proportion of the standing crop (~40%) in tundra wetlands every year. Grazing changed plant community composition and reduced the production of grasses and sedges to a low-level equilibrium compared to the situation where the presence of geese had been removed. Lemming cyclic fluctuations were strong and affected fox reproduction. Fox predation on goose eggs was severe and generated marked annual variation in goose productivity. Predation intensity on geese was closely related to the lemming cycle, a consequence of an indirect interaction between lemming and geese via shared predators. We conclude that, contrary to the exploitation ecosystem hypothesis, both the plant/herbivore and predator/prey interactions are significant in this arctic community. PMID- 21680493 TI - Agricultural food subsidies, migratory connectivity and large-scale disturbance in arctic coastal systems: a case study. AB - An allochthonous input can modify trophic relationships, by providing an external resource that is normally limiting within a system. The subsidy may not only elicit a growth response of the primary producers via a bottom-up effect, but it also may lead to runaway herbivore growth in the absence of increased predation. If the consumer is migratory and predation is similarly dampened in the alternative system, the increased numbers may produce a top-down cascade of direct and indirect effects on an ecosystem that may be a great distance from the source of the subsidy. In an extreme case, it can lead to a catastrophic shift in ecosystem functioning as a result of biotic exploitation that produces an alternative stable state. The loss of resilience is particularly sensitive to herbivore density which can result in two different outcomes to the vegetation on which the consumer feeds. Over-compensatory growth of above-ground biomass gives way to sward destruction and near irreversible changes in soil properties as density of a herbivore increases. A striking temporal asymmetry exists between a reduction in the consumer population and recovery of damaged vegetation and degraded soils. PMID- 21680494 TI - Keeping pace with fast climate change: can arctic life count on evolution? AB - Adaptations to the cold and to short growing seasons characterize arctic life, but climate in the Arctic is warming at an unprecedented rate. Will plant and animal populations of the Arctic be able to cope with these drastic changes in environmental conditions? Here we explore the potential contribution of evolution by natural selection to the current response of populations to climate change. We focus on the spring phenology of populations because it is highly responsive to climate change and easy to document across a wide range of species. We show that evolution can be fast and can occur at the time scale of a few decades. We present an example of reproductive phenological change associated with climate change (North American red squirrels in the Yukon), where a detailed analysis of quantitative genetic parameters demonstrates contemporary evolution. We answer a series of frequently asked questions that should help biologists less familiar with evolutionary theory and quantitative genetic methods to think about the role of evolution in current responses of ecological systems to climate change. Our conclusion is that evolution by natural selection is a pertinent force to consider even at the time scale of contemporary climate changes. However, all species may not be equal in their capacity to benefit from contemporary evolution. PMID- 21680495 TI - Bioenergetic prediction of climate change impacts on northern mammals. AB - Climate change will likely alter the distribution and abundance of northern mammals through a combination of direct, abiotic effects (e.g., changes in temperature and precipitation) and indirect, biotic effects (e.g., changes in the abundance of resources, competitors, and predators). Bioenergetic approaches are ideally suited to predicting the impacts of climate change because individual energy budgets integrate biotic and abiotic influences, and translate individual function into population and community outcomes. In this review, we illustrate how bioenergetics can be used to predict the regional biodiversity, species range limits, and community trophic organization of mammals under future climate scenarios. Although reliable prediction of climate change impacts for particular species requires better data and theory on the physiological ecology of northern mammals, two robust hypotheses emerge from the bioenergetic approaches presented here. First, the impacts of climate change in northern regions will be shaped by the appearance of new species at least as much as by the disappearance of current species. Second, seasonally inactive mammal species (e.g., hibernators), which are largely absent from the Canadian arctic at present, should undergo substantial increases in abundance and distribution in response to climate change, probably at the expense of continuously active mammals already present in the arctic. PMID- 21680496 TI - Polar bears in a warming climate. AB - Polar bears (Ursus maritimus) live throughout the ice-covered waters of the circumpolar Arctic, particularly in near shore annual ice over the continental shelf where biological productivity is highest. However, to a large degree under scenarios predicted by climate change models, these preferred sea ice habitats will be substantially altered. Spatial and temporal sea ice changes will lead to shifts in trophic interactions involving polar bears through reduced availability and abundance of their main prey: seals. In the short term, climatic warming may improve bear and seal habitats in higher latitudes over continental shelves if currently thick multiyear ice is replaced by annual ice with more leads, making it more suitable for seals. A cascade of impacts beginning with reduced sea ice will be manifested in reduced adipose stores leading to lowered reproductive rates because females will have less fat to invest in cubs during the winter fast. Non-pregnant bears may have to fast on land or offshore on the remaining multiyear ice through progressively longer periods of open water while they await freeze-up and a return to hunting seals. As sea ice thins, and becomes more fractured and labile, it is likely to move more in response to winds and currents so that polar bears will need to walk or swim more and thus use greater amounts of energy to maintain contact with the remaining preferred habitats. The effects of climate change are likely to show large geographic, temporal and even individual differences and be highly variable, making it difficult to develop adequate monitoring and research programs. All ursids show behavioural plasticity but given the rapid pace of ecological change in the Arctic, the long generation time, and the highly specialised nature of polar bears, it is unlikely that polar bears will survive as a species if the sea ice disappears completely as has been predicted by some. PMID- 21680497 TI - Coping mechanisms of alpine and arctic breeding birds: extreme weather and limitations to reproductive resilience. AB - As ground nesting homeotherms, alpine and arctic birds must meet similar physiological requirements for breeding as other birds, but must do so in more extreme conditions. Annual spring snowfall and timing of snow melt can vary by up to 1 month and daily temperatures near the ground surface vary from below freezing to over 45 degrees C in alpine and arctic habitats. Species breeding in these environments have various behavioral, physiological, and morphological adaptations to cope with energetically demanding conditions. We review the ways birds cope with harsh and variable weather, and present data from long term field studies of ptarmigan to examine effects of spring weather on reproduction. In variable but normal spring conditions, timing of breeding was not influenced by snow melt, snow depth or daily temperatures in the alpine, as breeding did not commence until conditions were generally favorable. Arctic ptarmigan tended to vary breeding onset in response to spring conditions. Generally, birds breeding in alpine and arctic habitats suffer a seasonal reproductive disadvantage compared to birds at lower latitudes or elevations because the breeding window is short and in late years, nest failure may be high with little opportunity for renesting. Coping mechanisms may only be effective below a threshold of climactic extremes. Despite strong resilience in fecundity parameters, when snowmelt is extremely delayed breeding success is greatly reduced. Alpine and arctic birds will be further challenged as they attempt to cope with anticipated increases in the frequency and severity of weather events (climate variability), as well as general climate warming. PMID- 21680498 TI - Interannual Variation in Timing of Parturition and Growth of Collared Pikas (Ochotona collaris) in the Southwest Yukon. AB - The length of the snow-free season has a significant influence on reproduction and growth in northern alpine environments, and these life history traits may provide sensitive indicators of the responses of organisms to climate change. We examined growth rates and timing of parturition of collared pikas (Ochotona collaris) from 1995-2002 in the Ruby Range, Yukon Territory, Canada. Growth rates were best described using a Gompertz model, in which the asymptotic mass, determined from the average male and female weights, was 157 g, the growth rate constant (K) was 0.0557, and the age at inflection (I) was 18.12 days, for a birth weight of 10 g. The maximum growth rate for North American pikas (O. collaris and O. princeps) increased with latitude, with maximum growth rates being approximately one-third greater in northern populations where the snow-free season is less than three months long. The mean parturition date varied significantly among years from 3 June to 3 July, and delayed parturition was correlated with indices of high snow accumulation and, to a lesser extent, late spring snowmelt. However, parturition date did not significantly affect the subsequent over-winter survival of juveniles in this population, suggesting that pikas are able to adjust to seasonal uncertainty associated with highly variable spring conditions. PMID- 21680499 TI - Multicellular animals. Peter ax. PMID- 21680500 TI - Identification of deletion mutant respiratory syncytial virus strains lacking most of the G protein in immunocompromised children with pneumonia in South Africa. AB - Respiratory syncytial virus (RSV) G protein deletion mutants replicate effectively in vitro but have not been detected in nature. Subtyping of RSV strains in hospitalized children in South Africa identified G protein PCR amplicons significantly reduced in size in 2 out of 209 clinical specimens screened over 4 years. Sequence analysis revealed subtype B strains lacking nearly the entire G protein ectodomain in one HIV-positive and one HIV-exposed child hospitalized with pneumonia. The association of clinical strains lacking most of the G protein with lower respiratory tract infection in immunocompromised children may have implications for RSV vaccine development. PMID- 21680501 TI - A recombinant vesicular stomatitis virus bearing a lethal mutation in the glycoprotein gene uncovers a second site suppressor that restores fusion. AB - Vesicular stomatitis virus (VSV), a prototype of the Rhabdoviridae family, contains a single surface glycoprotein (G) that is responsible for attachment to cells and mediates membrane fusion. Working with the Indiana serotype of VSV, we employed a reverse genetic approach to produce fully authentic recombinant viral particles bearing lethal mutations in the G gene. By altering the hydrophobicity of the two fusion loops within G, we produced a panel of mutants, W72A, Y73A, Y116A, and A117F, that were nonfusogenic. Propagation of viruses bearing those lethal mutations in G completely depended on complementation by expression of the glycoprotein from the heterologous New Jersey serotype of VSV. The nonfusogenic G proteins oligomerize and are transported normally to the cell surface but fail to mediate acid pH-triggered membrane fusion. The nonfusogenic G proteins also interfered with the ability of wild-type G to mediate fusion, either by formation of mixed trimers or by inhibition of trimer function during fusion. Passage of one recombinant virus, A117F, identified a second site suppressor of the fusion block, E76K. When analyzed in the absence of the A117F substitution, E76K rendered G more sensitive to acid pH-triggered fusion, suggesting that this compensatory mutation is destabilizing. Our work provides a set of authentic recombinant VSV particles bearing lethal mutations in G, confirms that the hydrophobic fusion loops of VSV G protein are critical for membrane fusion, and underscores the importance of the sequence elements surrounding the hydrophobic tips of the fusion loops in driving fusion. This study has implications for understanding dominant targets for inhibition of G-mediated fusion. Moreover, the recombinant viral particles generated here will likely be useful in dissecting the mechanism of G-catalyzed fusion as well as study steps of viral assembly. PMID- 21680502 TI - Analysis of Rab GTPase-activating proteins indicates that Rab1a/b and Rab43 are important for herpes simplex virus 1 secondary envelopment. AB - Assembly of herpes simplex virus 1 (HSV-1) occurs in the cytoplasm, where the capsid and tegument bud into host cell membranes. It is at this point that the viral glycoproteins are incorporated into the virion, as they are located at the assembly site. We investigated the role of the Rab GTPases in coordinating the assembly process by overexpressing 37 human Rab GTPase-activating proteins (GAPs) and assessing infectious titers. Rab GTPases are key cellular regulators of membrane trafficking events that, by their membrane association and binding of effector proteins, ensure the appropriate fusion of membranes. We identified that TBC1D20 and RN-tre and their partner Rabs, Rab1a/b and Rab43, respectively, are important for virion assembly. In the absence of Rab1a/b, the viral glycoproteins are unable to traffic from the endoplasmic reticulum to the assembly compartment, and thus unenveloped particles build up in the cytoplasm. The defect resulting from Rab43 depletion is somewhat more complex, but it appears that the fragmentation and dispersal of the trans-Golgi network and associated membranes render these compartments unable to support secondary envelopment. PMID- 21680503 TI - In vitro whole-virus binding of a norovirus genogroup II genotype 4 strain to cells of the lamina propria and Brunner's glands in the human duodenum. AB - Human norovirus (hNoV) remains refractory to propagation in cell culture systems. We believe that knowing the exact cell type that hNoV targets will provide important insights into culturing the virus. By the use of an in vitro whole virus binding assay, the hNoV genogroup II genotype 4 Sakai variant was found to bind predominantly to cells of the lamina propria and Brunner's glands, but not to those of the luminal epithelial surface, of human duodenum tissue. Our findings, together with accumulating evidence reported elsewhere, suggest that hNoV may display tropism to nonepithelial cells, which is distinct from observations of other human enteric pathogens. PMID- 21680504 TI - Peptidyl-prolyl isomerase Pin1 is a cellular factor required for hepatitis C virus propagation. AB - The life cycle of hepatitis C virus (HCV) is highly dependent on cellular factors. Using small interfering RNA (siRNA) library screening, we identified peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) as a host factor involved in HCV propagation. Here we demonstrated that silencing of Pin1 expression resulted in decreases in HCV replication in both HCV replicon cells and cell culture-grown HCV (HCVcc)-infected cells, whereas overexpression of Pin1 increased HCV replication. Pin1 interacted with both the NS5A and NS5B proteins. However, Pin1 expression was increased only by the NS5B protein. Both the protein binding and isomerase activities of Pin1 were required for HCV replication. Juglone, a natural inhibitor of Pin1, inhibited HCV propagation by inhibiting the interplay between the Pin1 and HCV NS5A/NS5B proteins. These data indicate that Pin1 modulates HCV propagation and may contribute to HCV-induced liver pathogenesis. PMID- 21680505 TI - Analysis of antigenically important residues in human influenza A virus in terms of B-cell epitopes. AB - In this paper we undertake an analysis of the antigenicity of influenza A virus hemagglutinin. We developed a novel computational approach to the identification of antigenically active regions and showed that the amino acid substitutions between successive predominant seasonal strains form clusters that are consistent, in terms of both their location and their size, with the properties of B-cell epitopes in general and with those epitopes that have been identified experimentally in influenza A virus hemagglutinin to date. Such an interpretation provides a biologically plausible framework for an understanding of the location of antigenically important substitutions that is more specific than the canonical "antigenic site" model and provides an effective basis for deriving models that predict antigenic escape in the H3N2 subtype. Our results support recent indications that antibodies binding to the "stalk" region of hemagglutinin are found in the human population and exert evolutionary pressure on the virus. Our computational approach provides a possible method for identifying antigenic escape through evolution in this region, which in some cases will not be identified by the hemagglutinin inhibition assay. PMID- 21680506 TI - The viral nucleoprotein determines Mx sensitivity of influenza A viruses. AB - Host restriction factors play a crucial role in preventing trans-species transmission of viral pathogens. In mammals, the interferon-induced Mx GTPases are powerful antiviral proteins restricting orthomyxoviruses. Hence, the human MxA GTPase may function as an efficient barrier against zoonotic introduction of influenza A viruses into the human population. Successful viruses are likely to acquire adaptive mutations allowing them to evade MxA restriction. We compared the 2009 pandemic influenza A virus [strain A/Hamburg/4/09 (pH1N1)] with a highly pathogenic avian H5N1 isolate [strain A/Thailand/1(KAN-1)/04] for their relative sensitivities to human MxA and murine Mx1. The H5N1 virus was highly sensitive to both Mx GTPases, whereas the pandemic H1N1 virus was almost insensitive. Substitutions of the viral polymerase subunits or the nucleoprotein (NP) in a polymerase reconstitution assay demonstrated that NP was the main determinant of Mx sensitivity. The NP of H5N1 conferred Mx sensitivity to the pandemic H1N1 polymerase, whereas the NP of pandemic H1N1 rendered the H5N1 polymerase insensitive. Reassortant viruses which expressed the NP of H5N1 in a pH1N1 genetic background and vice versa were generated. Congenic Mx1-positive mice survived intranasal infection with these reassortants if the challenge virus contained the avian NP. In contrast, they succumbed to infection if the NP of pH1N1 origin was present. These findings clearly indicate that the origin of NP determines Mx sensitivity and that human influenza viruses acquired adaptive mutations to evade MxA restriction. This also explains our previous observations that human and avian influenza A viruses differ in their sensitivities to Mx. PMID- 21680507 TI - Reassortment between seasonal H1N1 and pandemic (H1N1) 2009 influenza viruses is restricted by limited compatibility among polymerase subunits. AB - Reassortment is important for influenza virus evolution and the generation of novel viruses with pandemic potential; however, the factors influencing reassortment are still poorly understood. Here, using reverse genetics and a replicon assay, we demonstrated that a mixed polymerase complex containing a pandemic (H1N1) 2009 influenza virus PB2 on a seasonal H1N1 virus background has reduced polymerase activity, leading to impaired virus viability. Adaptation of viruses containing the mixed polymerase complex resulted in compensatory mutations in PB1. Taken together, our results identify the cooperation between PB2 and PB1 as an important restricting factor for reassortment of influenza viruses. PMID- 21680508 TI - Conservation of a packaging signal and the viral genome RNA packaging mechanism in alphavirus evolution. AB - Alphaviruses are a group of small, enveloped viruses which are widely distributed on all continents. In infected cells, alphaviruses display remarkable specificity in RNA packaging by encapsidating only their genomic RNA while avoiding packaging of the more abundant viral subgenomic (SG), cellular messenger and transfer RNAs into released virions. In this work, we demonstrate that in spite of evolution in geographically isolated areas and accumulation of considerable diversity in the nonstructural and structural genes, many alphaviruses belonging to different serocomplexes harbor RNA packaging signals (PSs) which contain the same structural and functional elements. Their characteristic features are as follows. (i) Sindbis, eastern, western, and Venezuelan equine encephalitis and most likely many other alphaviruses, except those belonging to the Semliki Forest virus (SFV) clade, have PSs which can be recognized by the capsid proteins of heterologous alphaviruses. (ii) The PS consists of 4 to 6 stem-loop RNA structures bearing conserved GGG sequences located at the base of the loop. These short motifs are integral elements of the PS and can function even in the artificially designed PS. (iii) Mutagenesis of the entire PS or simply the GGG sequences has strong negative effects on viral genome packaging and leads to release of viral particles containing mostly SG RNAs. (iv) Packaging of RNA appears to be determined to some extent by the number of GGG-containing stem-loops, and more than one stem-loop is required for efficient RNA encapsidation. (v) Viruses of the SFV clade are the exception to the general rule. They contain PSs in the nsP2 gene, but their capsid protein retains the ability to use the nsP1-specific PS of other alphaviruses. These new discoveries regarding alphavirus PS structure and function provide an opportunity for the development of virus variants, which are irreversibly attenuated in terms of production of infectious virus but release high levels of genome-free virions. PMID- 21680509 TI - Lack of correlation of central nervous system inflammation and neuropathology with the development of seizures following acute virus infection. AB - Infection of C57BL/6 mice by the intracerebral route with the Daniels (DA) strain of Theiler's murine encephalomyelitis virus (TMEV) resulted in acute behavioral seizures in approximately 50% of the mice. By titration, the viral dose correlated with the percentage of mice developing seizures; however, neuropathological changes were similar over the dose range, and viral clearance from the brains occurred uniformly by day 14 postinfection (p.i.). Other TMEV strains and mutants (GDVII, WW, BeAn 8386 [BeAn], DApBL2M, H101) induced seizures in C57BL/6 mice to various degrees. The BeAn strain and DApBL2M mutant were similar to the DA strain in the percentages of mice developing seizures and neuropathological changes and in the extent of infected cells. The GDVII and WW strains caused 100% mortality by days 5 and 6 p.i., respectively, at which time neuropathological changes and neuronal infection were extensive. The H101 mutant induced seizures and caused 100% mortality by day 7 p.i.; however, only minor neuropathological changes and few infected cells were observed. Thus, in H101 mutant infections, it appears that elevated levels of cytokines, rather than neuronal cell death, play the dominant role in seizure induction. PMID- 21680510 TI - Liposomal nanocontainers as models for viral infection: monitoring viral genomic RNA transfer through lipid membranes. AB - After uptake into target cells, many nonenveloped viruses undergo conformational changes in the low-pH environment of the endocytic compartment. This results in exposure of amphipathic viral peptides and/or hydrophobic protein domains that are inserted into and either disrupt or perforate the vesicular membranes. The viral nucleic acids thereby gain access to the cytosol and initiate replication. We here demonstrate the in vitro transfer of the single-stranded positive-sense RNA genome of human rhinovirus 2 into liposomes decorated with recombinant very low-density lipoprotein receptor fragments. Membrane-attached virions were exposed to pH 5.4, mimicking the in vivo pH environment of late endosomes. This triggered the release of the RNA whose arrival in the liposomal lumen was detected via in situ cDNA synthesis by encapsulated reverse transcriptase. Subsequently, cDNA was PCR amplified. At a low ratio between virions and lipids, RNA transfer was positively correlated with virus concentration. However, membranes became leaky at higher virus concentrations, which resulted in decreased cDNA synthesis. In accordance with earlier in vivo data, the RNA passes through the lipid membrane without causing gross damage to vesicles at physiologically relevant virus concentrations. PMID- 21680511 TI - The cellular RNA helicase UAP56 is required for prevention of double-stranded RNA formation during influenza A virus infection. AB - The cellular DEAD box RNA helicase UAP56 plays a pivotal role in the efficient transcription/replication of influenza A virus. UAP56 is recruited by the nucleoprotein (NP) of influenza A viruses, and recent data revealed that the RNA helicase is required for the nuclear export of a subset of spliced and unspliced viral mRNAs. The fact that influenza viruses do not produce detectable amounts of double-stranded RNA (dsRNA) intermediates during transcription/replication suggests the involvement of cellular RNA helicases. Hence, we examined whether the RNA-unwinding activity of UAP56 or its paralog URH49 plays a role in preventing the accumulation of dsRNA during infection. First, our data showed that not only UAP56 but also its paralog URH49 can interact with NPs of avian and human influenza A viruses. The small interfering RNA (siRNA)-mediated depletion of either RNA helicase reduced the transport of M1 and hemagglutinin (HA) mRNAs and, to a lesser extent, NP and NS1 mRNAs into the cytoplasm. Moreover, we found that virus infection of UAP56-depleted cells leads to the rapid accumulation of dsRNA in the perinuclear region. In parallel, we observed a robust virus-mediated activation of dsRNA-dependent protein kinase R (PKR), indicating that the cellular RNA helicase UAP56 may be recruited by influenza virus to prevent dsRNA formation. The accumulation of dsRNA was blocked when actinomycin D or cycloheximide was used to inhibit viral transcription/replication or translation, respectively. In summary, we demonstrate that UAP56 is utilized by influenza A viruses to prevent the formation of dsRNA and, hence, the activation of the innate immune response. PMID- 21680512 TI - Roles of the fusion and hemagglutinin-neuraminidase proteins in replication, tropism, and pathogenicity of avian paramyxoviruses. AB - Virulent and moderately virulent strains of Newcastle disease virus (NDV), representing avian paramyxovirus serotype 1 (APMV-1), cause respiratory and neurological disease in chickens and other species of birds. In contrast, APMV-2 is avirulent in chickens. We investigated the role of the fusion (F) and hemagglutinin-neuraminidase (HN) envelope glycoproteins in these contrasting phenotypes by designing chimeric viruses in which the F and HN glycoproteins or their ectodomains were exchanged individually or together between the moderately virulent, neurotropic NDV strain Beaudette C (BC) and the avirulent APMV-2 strain Yucaipa. When we attempted to exchange the complete F and HN glycoproteins individually and together between the two viruses, the only construct that could be recovered was recombinant APMV-2 strain Yucaipa (rAPMV-2), containing the NDV F glycoprotein in place of its own. This substitution of NDV F into APMV-2 was sufficient to confer the neurotropic, neuroinvasive, and neurovirulent phenotypes, in spite of all being at reduced levels compared to what was seen for NDV-BC. When the ectodomains of F and HN were exchanged individually and together, two constructs could be recovered: NDV, containing both the F and HN ectodomains of APMV-2; and APMV-2, containing both ectodomains of NDV. This supported the idea that homologous cytoplasmic tails and matched F and HN ectodomains are important for virus replication. Analysis of these viruses for replication in vitro, syncytium formation, mean embryo death time, intracerebral pathogenicity index, and replication and tropism in 1-day-old chicks and 2-week old chickens showed that the two contrasting phenotypes of NDV and APMV-2 could largely be transferred between the two backbones by transfer of homotypic F and HN ectodomains. Further analysis provided evidence that the homologous stalk domain of NDV HN is essential for virus replication, while the globular head domain of NDV HN could be replaced with that of APMV-2 with only a minimal attenuating effect. These results demonstrate that the F and HN ectodomains together determine the cell fusion, tropism, and virulence phenotypes of NDV and APMV-2 and that the regions of HN that are critical to replication and the species-specific phenotypes include the cytoplasmic tail and stalk domain but not the globular head domain. PMID- 21680513 TI - Hepatitis C virus infection causes cell cycle arrest at the level of initiation of mitosis. AB - Chronic infection with the hepatitis C virus (HCV) is associated with increased risk for hepatocellular carcinoma (HCC). Chronic immune-mediated inflammation is likely to be an important factor in the development of HCV-associated HCC, but direct effects of HCV infection on the host cell cycle may also play a role. Although overexpression studies have revealed multiple interactions between HCV encoded proteins and host cell cycle regulators and tumor suppressor proteins, the relevance of these observations to HCV-associated liver disease is not clear. We determined the net effect of these interactions on regulation of the cell cycle in the context of virus infection. Flow cytometry of HCV-infected carboxyfluorescein succinimidyl ester-labeled hepatoma cells indicated a slowdown in proliferation that correlated with abundance of viral antigen. A decrease in the proportions of infected cells in G(1) and S phases with an accumulation of cells in G(2)/M phase was observed, compared to mock-infected controls. Dramatic decreases in markers of mitosis, such as phospho-histone H3, in infected cells suggested a block to mitotic entry. In common with findings described in the published literature, we observed caspase 3 activation, suggesting that cell cycle arrest is associated with apoptosis. Differences were observed in patterns of cell cycle disturbance and levels of apoptosis with different strains of HCV. However, the data suggest that cell cycle arrest at the interface of G(2) and mitosis is a common feature of HCV infection. PMID- 21680514 TI - Nucleolin interacts with the feline calicivirus 3' untranslated region and the protease-polymerase NS6 and NS7 proteins, playing a role in virus replication. AB - Cellular proteins play many important roles during the life cycle of all viruses. Specifically, host cell nucleic acid-binding proteins interact with viral components of positive-stranded RNA viruses and regulate viral translation, as well as RNA replication. Here, we report that nucleolin, a ubiquitous multifunctional nucleolar shuttling phosphoprotein, interacts with the Norwalk virus and feline calicivirus (FCV) genomic 3' untranslated regions (UTRs). Nucleolin can also form a complex in vitro with recombinant Norwalk virus NS6 and -7 (NS6/7) and can be copurified with the analogous protein from feline calicivirus (p76 or NS6/7) from infected feline kidney cells. Nucleolin RNA levels or protein were not modified during FCV infection; however, as a consequence of the infection, nucleolin was seen to relocalize from the nucleoli to the nucleoplasm, as well as to the perinuclear area where it colocalizes with the feline calicivirus NS6/7 protein. In addition, antibodies to nucleolin were able to precipitate viral RNA from feline calicivirus-infected cells, indicating a direct or indirect association of nucleolin with the viral RNA during virus replication. Small interfering RNA (siRNA)-mediated knockdown of nucleolin resulted in a reduction of the cytopathic effect and virus yield in CrFK cells. Taken together, these results demonstrate that nucleolin is a nucleolar component that interacts with viral RNA and NS6/7 and is required for feline calicivirus replication. PMID- 21680515 TI - Construction of a full transcription map of human papillomavirus type 18 during productive viral infection. AB - Human papillomavirus type 18 (HPV18) is the second most common oncogenic HPV genotype, responsible for ~15% of cervical cancers worldwide. In this study, we constructed a full HPV18 transcription map using HPV18-infected raft tissues derived from primary human vaginal or foreskin keratinocytes. By using 5' rapid amplification of cDNA ends (RACE), we mapped two HPV18 transcription start sites (TSS) for early transcripts at nucleotide (nt) 55 and nt 102 and the HPV18 late TSS frequently at nt 811, 765, or 829 within the E7 open reading frame (ORF) of the virus genome. HPV18 polyadenylation cleavage sites for early and late transcripts were mapped to nt 4270 and mainly to nt 7299 or 7307, respectively, by using 3' RACE. Although all early transcripts were cleaved exclusively at a single cleavage site, HPV18 late transcripts displayed the heterogeneity of 3' ends, with multiple minor cleavage sites for late RNA polyadenylation. HPV18 splice sites/splice junctions for both early and late transcripts were identified by 5' RACE and primer walking techniques. Five 5' splice sites (donor sites) and six 3' splice sites (acceptor sites) that are highly conserved in other papillomaviruses were identified in the HPV18 genome. HPV18 L1 mRNA translates a L1 protein of 507 amino acids (aa), smaller than the 568 aa residues previously predicted. Collectively, a full HPV18 transcription map constructed from this report will lead us to further understand HPV18 gene expression and virus oncogenesis. PMID- 21680516 TI - HIV-1 circulating recombinant form in Nepal. PMID- 21680517 TI - E6 and E7 from human papillomavirus type 16 cooperate to target the PDZ protein Na/H exchange regulatory factor 1. AB - Previous studies have shown that the PDZ-binding motif of the E6 oncoprotein from the mucosal high-risk (HR) human papillomavirus (HPV) types plays a key role in HPV-mediated cellular transformation in in vitro and in vivo experimental models. HR HPV E6 oncoproteins have the ability to efficiently degrade members of the PDZ motif-containing membrane-associated guanylate kinase (MAGUK) family; however, it is possible that other PDZ proteins are also targeted by E6. Here, we describe a novel interaction of HPV type 16 (HPV16) E6 with a PDZ protein, Na(+)/H(+) exchange regulatory factor 1 (NHERF-1), which is involved in a number of cellular processes, including signaling and transformation. HPV16 E6 associates with and promotes the degradation of NHERF-1, and this property is dependent on the C terminal PDZ-binding motif of E6. Interestingly, HPV16 E7, via the activation of the cyclin-dependent kinase complexes, promoted the accumulation of a phosphorylated form of NHERF-1, which is preferentially targeted by E6. Thus, both oncoproteins appear to cooperate in targeting NHERF-1. Notably, HPV18 E6 is not able to induce NHERF-1 degradation, indicating that this property is not shared with E6 from all HR HPV types. Downregulation of NHERF-1 protein levels was also observed in HPV16-positive cervical cancer-derived cell lines, such as SiHa and CaSki, as well as HPV16-positive cervical intraepithelial neoplasia (CIN). Finally, our data show that HPV16-mediated NHERF-1 degradation correlates with the activation of the phosphatidylinositol-3'-OH kinase (PI3K)/AKT signaling pathway, which is known to play a key role in carcinogenesis. PMID- 21680518 TI - Nuclear envelope breakdown can substitute for primary envelopment-mediated nuclear egress of herpesviruses. AB - Herpesvirus nucleocapsids assemble in the nucleus but mature to infectious virions in the cytoplasm. To gain access to this cellular compartment, nucleocapsids are translocated to the cytoplasm by primary envelopment at the inner nuclear membrane and subsequent fusion of the primary envelope with the outer nuclear membrane. The conserved viral pUL34 and pUL31 proteins play a crucial role in this process. In their absence, viral replication is strongly impaired but not totally abolished. We used the residual infectivity of a pUL34 deleted mutant of the alphaherpesvirus pseudorabies virus (PrV) for reversion analysis. To this end, PrV-DeltaUL34 was serially passaged in rabbit kidney cells until final titers of the mutant virus PrV-DeltaUL34Pass were comparable to those of wild-type PrV. PrV-DeltaUL34Pass produced infectious progeny independently of the pUL34/pUL31 nuclear egress complex and the pUS3 protein kinase. Ultrastructural analyses demonstrated that this effect was due to virus-induced disintegration of the nuclear envelope, thereby releasing immature and mature capsids into the cytosol for secondary envelopment. Our data indicate that nuclear egress primarily serves to transfer capsids through the intact nuclear envelope. Immature and mature intranuclear capsids are competent for further virion maturation once they reach the cytoplasm. However, nuclear egress exhibits a strong bias for nucleocapsids, thereby also functioning as a quality control checkpoint which is abolished by herpesvirus-induced nuclear envelope breakdown. PMID- 21680519 TI - Phylogeography and evolutionary history of reassortant H9N2 viruses with potential human health implications. AB - Avian influenza viruses of the H9N2 subtype have seriously affected the poultry industry of the Far and Middle East since the mid-1990s and are considered one of the most likely candidates to cause a new influenza pandemic in humans. To understand the genesis and epidemiology of these viruses, we investigated the spatial and evolutionary dynamics of complete genome sequences of H9N2 viruses circulating in nine Middle Eastern and Central Asian countries from 1998 to 2010. We identified four distinct and cocirculating groups (A, B, C, and D), each of which has undergone widespread inter- and intrasubtype reassortments, leading to the generation of viruses with unknown biological properties. Our analysis also suggested that eastern Asia served as the major source for H9N2 gene segments in the Middle East and Central Asia and that in this geographic region within country evolution played a more important role in shaping viral genetic diversity than migration between countries. The genetic variability identified among the H9N2 viruses was associated with specific amino acid substitutions that are believed to result in increased transmissibility in mammals, as well as resistance to antiviral drugs. Our study highlights the need to constantly monitor the evolution of H9N2 viruses in poultry to better understand the potential risk to human health posed by these viruses. PMID- 21680520 TI - Role of TRIM5alpha RING domain E3 ubiquitin ligase activity in capsid disassembly, reverse transcription blockade, and restriction of simian immunodeficiency virus. AB - The mammalian tripartite motif protein, TRIM5alpha, recognizes retroviral capsids entering the cytoplasm and blocks virus infection. Depending on the particular TRIM5alpha protein and retrovirus, complete disruption of the TRIM5alpha RING domain decreases virus-restricting activity to various degrees. TRIM5alpha exhibits RING domain-dependent E3 ubiquitin ligase activity, but the specific role of this activity in viral restriction is unknown. We created a panel of African green monkey TRIM5alpha (TRIM5alpha(AGM)) mutants, many of which are specifically altered in RING domain E3 ubiquitin ligase function, and characterized the phenotypes of these mutants with respect to restriction of simian and human immunodeficiency viruses (SIV(mac) and HIV-1, respectively). TRIM5alpha(AGM) ubiquitin ligase activity was essential for both the accelerated disassembly of SIV(mac) capsids and the disruption of reverse transcription. The levels of SIV(mac) particulate capsids in the cytosol of target cells expressing the TRIM5alpha variants strongly correlated with the levels of viral late reverse transcripts. RING-mediated ubiquitylation and B30.2(SPRY) domain-determined capsid binding independently contributed to the potency of SIV(mac) restriction by TRIM5alpha(AGM). In contrast, TRIM5alpha proteins attenuated in RING ubiquitin ligase function still accelerated HIV-1 capsid disassembly, inhibited reverse transcription, and blocked infection. Replacement of the helix-4/5 loop in the SIV(mac) capsid with the corresponding region of the HIV-1 capsid diminished the dependence of restriction on TRIM5alpha RING function. Thus, ubiquitylation mediated by the RING domain of TRIM5alpha(AGM) is essential for blocking SIV(mac) infection at the stage of capsid uncoating. PMID- 21680521 TI - Expression and functional characterization of the RIG-I-like receptors MDA5 and LGP2 in Rainbow trout (Oncorhynchus mykiss). AB - The retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) comprise three homologues: RIG-I, melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). They activate the host interferon (IFN) system upon recognition of viral RNA pathogen-associated molecular patterns (PAMPs) in the cytoplasm. Bioinformatic analysis of the sequenced vertebrate genomes suggests that the cytosolic surveillance system is conserved in lower vertebrates, and recent functional studies have confirmed that RIG-I is important to fish antiviral immunity. In this study, we have identified MDA5 and LGP2 homologues from rainbow trout Oncorhynchus mykiss and an additional LGP2 variant with an incomplete C-terminal domain of RIG-I. Trout MDA5 and LGP2 were constitutively produced in fibroblast and macrophage cell lines and upregulated by poly(I:C), recombinant IFN, or infection by RNA viruses (viral hemorrhagic septicemia virus and salmon alphavirus) with a single-stranded positive or negative genome. Overexpression of MDA5 and LGP2 but not of the LGP2 variant resulted in significant accumulation of Mx transcripts in cultured cells, which correlated with a marked enhancement of protection against viral infection. These results demonstrate that both MDA5 and LGP2 are important RLRs in host surveillance against infection of both negative and positive viruses and that the LGP2 variant with a deletion of 54 amino acids at the C terminus acts as a negative regulator for LGP2-elicited antiviral signaling by competing for the viral RNA PAMPs. Interestingly, MDA5 expression was not affected by overexpressed LGP2 in transfected cells and vice versa, suggesting that they likely act in parallel as positive regulators for IFN production. PMID- 21680522 TI - Inhibition of p53 by adenovirus type 12 E1B-55K deregulates cell cycle control and sensitizes tumor cells to genotoxic agents. AB - Adenovirus E1B-55K represses p53-mediated transcription. However, the phenotypic consequence of p53 inhibition by E1B-55K for cell cycle regulation and drug sensitivity in tumor cells has not been examined. In HCT116 cells with constitutive E1B-55K expression, the activation of p53 target genes such as the p21, Mdm2, and Puma genes was attenuated, despite markedly elevated p53 protein levels. HCT116 cells with E1B-55K expression displayed a cell cycle profile similar to that of the isogenic HCT116p53(-/-) cells, including unhindered S phase entry despite DNA damage. Surprisingly, E1B-55K-expressing cells were more sensitive to drug treatment than parental cells. Compared to HCT116 cells, HCT116p53(-/-) cells were more susceptible to both doxorubicin and etoposide, and E1B-55K expression had no effects on drug treatment. E1B-55K expression increased the rate of cell proliferation in HCT116 but not in HCT116p53(-/-) cells. Thus, deregulation of p53-mediated cell cycle control by E1B-55K probably underlies sensitization of HCT116 cells to anticancer drugs. Consistently, E1B-55K expression in A549, A172, and HepG2 cells, all containing wild-type (wt) p53, also enhanced etoposide-induced cytotoxicity, whereas in p53-null H1299 cells, E1B-55K had no effects. We generated several E1B-55K mutants with mutations at positions occupied by the conserved Phe/Trp/His residues. Most of these mutants showed no or reduced binding to p53, although some of them could still stabilize p53, suggesting that binding might not be essential for E1B-55K-induced p53 stabilization. Despite heightened p53 protein levels in cells expressing certain E1B-55K mutants, p53 activity was largely suppressed. Furthermore, most of these E1B-55K mutants could sensitize HCT116 cells to etoposide and doxorubicin. These results indicate that E1B-55K might have utility for enhancing chemotherapy. PMID- 21680523 TI - Identification of a phosphorylation site within the P protein important for mRNA transcription and growth of parainfluenza virus 5. AB - The viral RNA-dependent RNA polymerase (vRdRp) of paramyxovirus consists of the large (L) protein and the phosphoprotein (P). P is heavily phosphorylated, and it is thought that the phosphorylation of P plays a role in regulating viral RNA synthesis. However, no phosphorylation site within the P protein in paramyxovirus has been identified as playing a positive role in viral RNA synthesis in virus infection. Using mass spectrometry analysis, the threonine residue at position 286 of P of parainfluenza virus 5 (PIV5) was found phosphorylated. Mutation of T286 to alanine (T286A), aspartic acid (T286D), or glutamic acid (T286E) reduced minigenome activity. Recombinant virus containing a mutation at the T286 position (rPIV5-P-T286A) grew slower than wild-type virus; viral mRNA synthesis and protein expression of rPIV5-P-T286A were delayed. Biochemical studies showed that the binding of NP or L protein with the P mutants or tetramer formation by the mutant P proteins was unaltered from that for wild-type P. While we failed to rescue rPIV5-P-T286E virus, several revertant viruses were obtained. All non-wild type revertants had mutations at T286 and showed defects in both minigenome activity and viral growth. This is the first time that a phosphorylation site within the P protein in paramyxovirus has been found to play a positive role in viral mRNA synthesis and virus growth. PMID- 21680524 TI - The cytoplasmic domain of Marburg virus GP modulates early steps of viral infection. AB - Marburg virus infection is mediated by the only viral surface protein, GP, a trimeric type I transmembrane protein. While its ectodomain mediates receptor binding and fusion of viral and cellular membranes and its transmembrane domain is essential for the recruitment of GP into budding particles by the matrix protein VP40, the role of the short cytoplasmic domain has remained enigmatic. Here we show that a missing cytoplasmic domain did not impair trimerization, intracellular transport, or incorporation of GP into infectious Marburg virus like particles (iVLPs) but altered the glycosylation pattern as well as the recognition of GP by neutralizing antibodies. These results suggest that subtle conformational changes took place in the ectodomain. To investigate the function of the cytoplasmic domain during viral entry, a novel entry assay was established to monitor the uptake of filamentous VLPs by measuring the occurrence of luciferase-labeled viral nucleocapsids in the cytosol of target cells. This quantitative assay showed that the entry process of VLPs incorporating GP missing its cytoplasmic domain (GPDeltaCD) was impaired. Supporting these results, iVLPs incorporating a mutant GP missing its cytoplasmic domain were significantly less infectious than iVLPs containing wild-type GP. Taken together, the data indicate that the absence of the short cytoplasmic domain of Marburg virus GP may induce conformational changes in the ectodomain which impact the filoviral entry process. PMID- 21680525 TI - Multiple CCR5 conformations on the cell surface are used differentially by human immunodeficiency viruses resistant or sensitive to CCR5 inhibitors. AB - Resistance to small-molecule CCR5 inhibitors arises when HIV-1 variants acquire the ability to use inhibitor-bound CCR5 while still recognizing free CCR5. Two isolates, CC101.19 and D1/85.16, became resistant via four substitutions in the gp120 V3 region and three in the gp41 fusion peptide (FP), respectively. The binding characteristics of a panel of monoclonal antibodies (MAbs) imply that several antigenic forms of CCR5 are expressed at different levels on the surfaces of U87-CD4-CCR5 cells and primary CD4(+) T cells, in a cell-type-dependent manner. CCR5 binding and HIV-1 infection inhibition experiments suggest that the two CCR5 inhibitor-resistant viruses altered their interactions with CCR5 in different ways. As a result, both mutants became generally more sensitive to inhibition by CCR5 MAbs, and the FP mutant is specifically sensitive to a MAb that stains discrete cell surface clusters of CCR5 that may correspond to lipid rafts. We conclude that some MAbs detect different antigenic forms of CCR5 and that inhibitor-sensitive and -resistant viruses can use these CCR5 forms differently for entry in the presence or absence of CCR5 inhibitors. PMID- 21680526 TI - Enzyme E2 from Chinese white shrimp inhibits replication of white spot syndrome virus and ubiquitinates its RING domain proteins. AB - Recent studies have shown that the ubiquitin (Ub) proteasome pathway (UPP) is closely related to immune defense. We have identified a ubiquitin-conjugating enzyme, E2, from the Chinese white shrimp, Fenneropenaeus chinensis (FcUbc). Injection of recombinant FcUbc protein (rFcUbc) reduced the mortality of shrimp infected with white spot syndrome virus (WSSV) and inhibited replication of WSSV. rFcUbc, but not a mutant FcUbc (mFcUbc), bound to WSSV RING domains (WRDs) from four potential E3 ligase proteins of WSSV in vitro. Importantly, rFcUbc could ubiquitinate the RING domains (named WRD2 and WRD3) of WSSV277 and WSSV304 proteins in vitro and the two proteins in WSSV-infected Drosophila melanogaster Schneider 2 (S2) cells. Furthermore, overexpression of FcUbc increased ubiquitination of WSSV277 and WSSV304 during WSSV infection. In summary, our study demonstrates that FcUbc from Chinese white shrimp inhibited WSSV replication and could ubiquitinate WSSV RING domain-containing proteins. This is the first report about antiviral function of Ubc E2 in shrimp. PMID- 21680527 TI - Disruption of nuclear organization during the initial phase of African swine fever virus infection. AB - African swine fever virus (ASFV), the causative agent of one of the most devastating swine diseases, has been considered exclusively cytoplasmic, even though some authors have shown evidence of an early stage of nuclear replication. In the present study, an increment of lamin A/C phosphorylation was observed in ASFV-infected cells as early as 4 h postinfection, followed by the disassembling of the lamina network close to the sites where the viral genome starts its replication. At later time points, this and other nuclear envelope markers were found in the cytoplasm of the infected cells. The effect of the infection on the cell nucleus was much more severe than previously expected, since a redistribution of other nuclear proteins, such as RNA polymerase II, the splicing speckle SC-35 marker, and the B-23 nucleolar marker, was observed from 4 h postinfection. All this evidence, together with the redistribution, dephosphorylation, and subsequent degradation of RNA polymerase II after ASFV infection, suggests the existence of sophisticated mechanisms to regulate the nuclear machinery during viral infection. PMID- 21680528 TI - Oncogenic IRFs provide a survival advantage for Epstein-Barr virus- or human T cell leukemia virus type 1-transformed cells through induction of BIC expression. AB - miR-155, processed from the B-cell integration cluster (BIC), is one of the few well-studied microRNAs (miRNAs) and is involved in both innate immunity and tumorigenesis. BIC/miR-155 is induced by distinct signaling pathways, but little is known about the underlying mechanisms. We have identified two conserved potential interferon (IFN) regulatory factor (IRF)-binding/interferon-stimulated response element motifs in the Bic gene promoter. Two oncogenic IRFs, IRF4 and 7, in addition to some other members of the family, bind to and significantly transactivate the Bic promoter. Correspondingly, the endogenous levels of IRF4 and -7 are correlated with that of the BIC transcript in Epstein-Barr virus (EBV) transformed cells. However, RNA interference studies have shown that depletion of IRF4, rather than of IRF7, dramatically decreases the endogenous level of BIC by up to 70% in EBV- or human T-cell leukemia virus type 1 (HTLV1)-transformed cell lines and results in apoptosis and reduction of proliferation rates that are restored by transient expression of miR-155. Moreover, the endogenous levels of the miR-155 target, SHIP1, are consistently elevated in EBV- and HTLV1 transformed cell lines stably expressing shIRF4. In contrast, transient expression of IRF4 decreases the SHIP1 level in EBV-negative B cells. Furthermore, the level of IRF4 mRNA is significantly correlated with that of BIC in adult T-cell lymphoma/leukemia (ATLL) tumors. These results show that IRF4 plays an important role in the regulation of BIC in the context of EBV and HTLV1 infection. Our findings have identified Bic as the first miRNA-encoding gene for IRFs and provide evidence for a novel molecular mechanism underlying the IRF/BIC pathway in viral oncogenesis. PMID- 21680529 TI - Parvovirus B19 infection of human primary erythroid progenitor cells triggers ATR Chk1 signaling, which promotes B19 virus replication. AB - Human parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells of the human bone marrow. Although the mechanism by which the B19V genome replicates in these cells has not been studied in great detail, accumulating evidence has implicated involvement of the cellular DNA damage machinery in this process. Here, we report that, in ex vivo-expanded human erythroid progenitor cells, B19V infection induces a broad range of DNA damage responses by triggering phosphorylation of all the upstream kinases of each of three repair pathways: ATM (ataxia-telangiectasi mutated), ATR (ATM and Rad3 related), and DNA-PKcs (DNA dependent protein kinase catalytic subunit). We found that phosphorylated ATM, ATR, and DNA-PKcs, and also their downstream substrates and components (Chk2, Chk1, and Ku70/Ku80 complex, respectively), localized within the B19V replication center. Notably, inhibition of kinase phosphorylation (through treatment with either kinase-specific inhibitors or kinase-specific shRNAs) revealed requirements for signaling of ATR and DNA-PKcs, but not ATM, in virus replication. Inhibition of the ATR substrate Chk1 led to similar levels of decreased virus replication, indicating that signaling via the ATR-Chk1 pathway is critical to B19V replication. Notably, the cell cycle arrest characteristic of B19V infection was not rescued by interference with the activity of any of the three repair pathway kinases. PMID- 21680530 TI - Charged residues in hepatitis C virus NS4B are critical for multiple NS4B functions in RNA replication. AB - The nonstructural 4B (NS4B) protein of hepatitis C virus (HCV) plays a central role in the formation of the HCV replication complex. To gain insight into the role of charged residues for NS4B function in HCV RNA replication, alanine substitutions were engineered in place of 28 charged residues residing in the N- and C-terminal cytoplasmic domains of the NS4B protein of the HCV genotype 1b strain Con1. Eleven single charged-to-alanine mutants were not viable, while the remaining mutants were replication competent, albeit to differing degrees. By selecting revertants, second-site mutations were identified for one of the lethal NS4B mutations. Second-site mutations mapped to NS4B and partially suppressed the lethal replication phenotype. Further analyses showed that three NS4B mutations disrupted the formation of putative replication complexes, one mutation altered the stability of the NS4B protein, and cleavage at the NS4B/5A junction was significantly delayed by another mutation. Individual charged-to-alanine mutations did not affect interactions between the NS4B and NS3-4A proteins. A triple charged-to-alanine mutation produced a temperature-sensitive replication phenotype with no detectable RNA replication at 39 degrees C, demonstrating that conditional mutations can be obtained by altering the charge characteristics of NS4B. Finally, NS4B mutations dispensable for efficient Con1 RNA replication were tested in the context of the chimeric genotype 2a virus, but significant defects in infectious-virus production were not detected. Taken together, these findings highlight the importance of charged residues for multiple NS4B functions in HCV RNA replication, including the formation of a functional replication complex. PMID- 21680531 TI - Assessment of the genetic susceptibility of sheep to scrapie by protein misfolding cyclic amplification and comparison with experimental scrapie transmission studies. AB - The susceptibility of sheep to scrapie is influenced mainly by the prion protein polymorphisms A136V, R154H, and Q171R/H. Here we analyzed the ability of protein misfolding cyclic amplification (PMCA) to model the genetic susceptibility of sheep to scrapie. For this purpose, we studied the efficiency of brain homogenates from sheep with different PrP genotypes to support PrP(Sc) amplification by PMCA using an ARQ/ARQ scrapie inoculum. The results were then compared with those obtained in vivo using the same sheep breed, genotypes, and scrapie inoculum. Genotypes associated with susceptibility (ARQ/ARQ, ARQ/AHQ, and AHQ/ARH) were able to sustain PrP(Sc) amplification in PMCA reactions, while genotypes associated with resistance to scrapie (ARQ/ARR and ARR/ARR) were unable to support the in vitro conversion. The incubation times of the experimental infection were then compared with the in vitro amplification factors. Linear regression analysis showed that the efficiency of in vitro PrP(Sc) amplification of the different genotypes was indeed inversely proportional to their incubation times. Finally, the rare ARQK176/ARQK176 genotype, for which no in vivo data are available, was studied by PMCA. No amplification was obtained, suggesting ARQK176/ARQK176 as an additional genotype associated with resistance, at least to the isolate tested. Our results indicate a direct correlation between the ability of different PrP genotypes to undergo PrP(C)-to-PrP(Sc) conversion by PMCA and their in vivo susceptibility and point to PMCA as an alternative to transmission studies and a potential tool to test the susceptibility of numerous sheep PrP genotypes to a variety of prion sources. PMID- 21680533 TI - Sunlight exposure-mediated DNA damage in young adults. AB - BACKGROUND: Previous experimental studies showed that single ultraviolet B (UVB) light irradiation increased levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a well-established biomarker of carcinogenesis and oxidative DNA damage, in epithelial cells in animals and humans. We conducted for the first time an epidemiologic study to investigate the correlations among levels of oxidative DNA damage, skin pigmentation, and sunlight exposure in human daily life. METHODS: Digitalized skin pigmentation levels and creatinine-adjusted urinary 8-OHdG levels were examined in 127 healthy young adults aged 20 to 24 years and in hairless mice with normal pigmented skin (HL-mice; n = 20) and hyperpigmented skin (HL-HPS-mice; n = 20). Data obtained by a questionnaire were also analyzed for the 127 subjects. RESULTS: Binary logistic regression analysis showed that increased sunlight intensity, but not sunlight-exposed time or sunlight-exposed skin area, was correlated with elevation in creatinine-adjusted urinary 8-OHdG levels. In contrast, increased skin pigmentation level, but not the use of sunscreen, was correlated with reduction in urinary 8-OHdG level in humans. UVB irradiation corresponding to several minutes of sunlight exposure significantly increased urinary 8-OHdG levels in HL-mice but not in HL-HPS-mice. CONCLUSIONS: We showed that increase in intensity of sunlight in human daily life increased levels of DNA damage. We also showed a protective effect of skin pigmentation on sunlight exposure-mediated DNA damage. IMPACT: We have provided more reliable evidence of routine sunlight exposure-mediated DNA damage in humans through the combination of epidemiologic and experimental studies. PMID- 21680534 TI - Aberrant methylation of RARbeta2 and APC genes in voided urine as molecular markers for early detection of bilharzial and nonbilharzial bladder cancer. AB - BACKGROUND: Bladder cancer cells illustrate major disruptions in their DNA methylation patterns as compared with normal ones. Authors aimed to identify epigenetic molecular markers in urine for early detection of bladder cancer. MATERIALS AND METHODS: We retrospectively analyzed the methylation status of RARbeta(2) and APC genes in urine samples from 210 bladder cancer patients, 61 patients with benign urological diseases, and 49 healthy volunteers by using methylation-specific PCR. RESULTS: Methylated RARbeta(2) and APC were significantly higher in bladder cancer patients (62.8%, 59.5%) than benign (16.4%, 5%) but not detected in healthy volunteers (0%) at (P < 0.0001). Both methylated genes showed no significant difference among clinicopathologic factors; however, they were detected in all grades and stages. Among the 128 patients with bilharzial bladder cancer, 94 (73.4%) showed methylated RARbeta(2) and 86 (67.2%) showed methylated APC. Homoplasmic methylation pattern of both genes were only detected in bilharzial bladder cancer cases. Both sensitivities and specificities of the methylated genes for bladder cancer detection were superior to urine cytology and when altogether combined, the sensitivities improved to (91.8%), (93.5%), (91.9%), and (80.9%) in detection of: bladder cancer, non-muscle invasive bladder cancer, low-grade tumors, and bilharzial associated bladder cancer, respectively. CONCLUSION: Thus, methylated RARbeta(2) and APC genes might be valuable urinary molecular markers for early detection of bilharzial and nonbilharzial bladder cancer. PMID- 21680532 TI - Classical swine fever virus N(pro) limits type I interferon induction in plasmacytoid dendritic cells by interacting with interferon regulatory factor 7. AB - Viruses are detected by different classes of pattern recognition receptors that lead to the activation of interferon regulatory factors (IRF) and consequently to the induction of alpha/beta interferon (IFN-alpha/beta). In turn, efficient viral strategies to escape the type I IFN-induced antiviral mechanisms have evolved. Previous studies established that pestivirus N(pro) antagonizes the early innate immune response by targeting the transcription factor IRF3 for proteasomal degradation. Here, we report that N(pro) of classical swine fever virus (CSFV) interacts also with IRF7, another mediator of type I IFN induction. We demonstrate that the Zn-binding domain of N(pro) is essential for the interaction of N(pro) with IRF7. For IRF3 and IRF7, the DNA-binding domain, the central region, and most of the regulatory domain are required for the interaction with N(pro). Importantly, the induction of IRF7-dependent type I IFN responses in plasmacytoid dendritic cells (pDC) is reduced after wild-type CSFV infection compared with infection with virus mutants unable to interact with IRF7. This is associated with lower levels of IRF7 in pDC. Consequently, wild-type but not N(pro) mutant CSFV-infected pDC show reduced responses to other stimuli. Taken together, the results of this study show that CSFV N(pro) is capable of manipulating the function of IRF7 in pDC and provides the virus with an additional strategy to circumvent the innate defense. PMID- 21680535 TI - ABO genotype and the risk of gastric cancer, atrophic gastritis, and Helicobacter pylori infection. AB - BACKGROUND: Although several studies have investigated the association between ABO blood type and risk of gastric cancer (GC), atrophic gastritis (AG), and Helicobacter pylori (HP) infection, no study has investigated these associations by using ABO genotype. METHODS: We conducted a case-control study in 703 patients with GC and 1,465 noncancer patients. We also conducted a cross-sectional study by using 1,406 of these 1,465 controls, who were examined for pepsinogens and anti-HP IgG antibody levels in serum. ABO genotype was determined from single nucleotide polymorphisms in ABO gene. We used rs8176719 to mark the O allele, and rs8176746 and rs8176747 to mark the B allele. ORs and 95% CIs were calculated by a multivariate logistic model. RESULTS: We observed significant associations between ABO genotype and GC, AG, and HP infection. ORs (95% CIs) of GC were 0.70 (0.50-0.99) for OO and 0.53 (0.36-0.77) for BO relative to AA genotype. An increased risk of GC was observed with addition of the A allele (P(trend) < 0.001), and a decreased risk with that of the B allele (P(trend) = 0.023). An OR of AG was 0.73 (95% CI, 0.53-0.99) for blood type B relative to blood type A, and an OR of HP infection was 0.39 (95% CI, 0.17-0.87) for BB relative to AA genotype. CONCLUSION: This study identified a statistically significant association between ABO genotype and GC risk. In addition, ABO gene locus may influence AG prevalence and HP infection. IMPACT: Further studies are necessary to confirm these findings. PMID- 21680536 TI - Gender disparities in the tumor genetics and clinical outcome of multiple myeloma. AB - BACKGROUND: Several cancer types have differences in incidence and clinical outcome dependent on gender, but these are not well described in myeloma. The aim of this study was to characterize gender disparities in myeloma. METHODS: We investigated the association of gender with the prevalence of tumor genetic lesions and the clinical outcome of 1,960 patients enrolled in the phase III clinical trial MRC Myeloma IX. Genetic lesions were characterized by FISH. RESULTS: Disparities were found in the prevalence of primary genetic lesions with immunoglobulin heavy chain gene (IGH) translocations being more common in women (50% of female patients vs. 38% of male patients, P < 0.001) and hyperdiploidy being more common in men (50% female vs. 62% male, P < 0.001). There were also differences in secondary genetic events with del(13q) (52% female vs. 41% male, P < 0.001) and +1q (43% female vs. 36% male, P = 0.042) being found more frequently in female myeloma patients. Female gender was associated with inferior overall survival (median: 44.8 months female vs. 49.9 months male, P = 0.020). CONCLUSIONS: We found gender-dependent differences in the prevalence of the primary genetic events of myeloma, with IGH translocations being more common in women and hyperdiploidy more common in men. This genetic background may impact subsequent genetic events such as +1q and del(13q), which were both more frequent in women. The higher prevalence of lesions associated with poor prognosis in the female myeloma population, such as t(4;14), t(14;16) and +1q, may adversely affect clinical outcome. IMPACT: These differences suggest that gender influences the primary genetic events of myeloma. PMID- 21680537 TI - Circulating insulin-like growth factor-I in pregnancy and maternal risk of breast cancer. AB - BACKGROUND: Elevated serum concentrations of insulin-like growth factor (IGF)-I have been associated with increased risk of developing breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. This study was conducted to further characterize the association of IGF-I during pregnancy with maternal breast cancer risk. METHODS: A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women younger than 40 years, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched with each case on age and date at blood donation. Serum IGF-I concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate ORs and 95% CIs. RESULTS: No significant associations were observed between serum IGF-I concentrations and breast cancer risk in both the overall analysis (OR, 1.08; 95% CI, 0.80-1.47) and in analyses stratified by histologic subtype, lag time to cancer diagnosis, age at pregnancy, or age at diagnosis. CONCLUSION: There was no association between IGF-I and maternal breast cancer risk during early pregnancy in this large nested case control study. IMPACT: Serum IGF-I concentrations during early pregnancy may not be related to maternal risk of developing breast cancer. PMID- 21680538 TI - Cracking the estrogen receptor's posttranslational code in breast tumors. AB - Estrogen signaling pathways, because of their central role in regulating the growth and survival of breast tumor cells, have been identified as suitable and efficient targets for cancer therapies. Agents blocking estrogen activity are already widely used clinically, and many new molecules have entered clinical trials, but intrinsic or acquired resistance to treatment limits their efficacy. The basic molecular studies underlying estrogen signaling have defined the critical role of estrogen receptors (ER) in many aspects of breast tumorigenesis. However, important knowledge gaps remain about the role of posttranslational modifications (PTM) of ER in initiation and progression of breast carcinogenesis. Whereas major attention has been focused on the phosphorylation of ER, many other PTM (such as acetylation, ubiquitination, sumoylation, methylation, and palmitoylation) have been identified as events modifying ER expression and stability, subcellular localization, and sensitivity to hormonal response. This article will provide an overview of the current and emerging knowledge on ER PTM, with a particular focus on their deregulation in breast cancer. We also discuss their clinical relevance and the functional relationship between PTM. A thorough understanding of the complete picture of these modifications in ER carcinogenesis might not only open new avenues for identifying new markers for prognosis or prediction of response to endocrine therapy but also could promote the development of novel therapeutic strategies. PMID- 21680541 TI - Prostate cancer: score one for validated targets. PMID- 21680539 TI - Emerging roles of protein kinase D1 in cancer. AB - Protein kinase D1 (PKD1) is a serine-threonine kinase that regulates various functions within the cell, including cell proliferation, apoptosis, adhesion, and cell motility. In normal cells, this protein plays key roles in multiple signaling pathways by relaying information from the extracellular environment and/or upstream kinases and converting them into a regulated intracellular response. The aberrant expression of PKD1 is associated with enhanced cancer phenotypes, such as deregulated cell proliferation, survival, motility, and epithelial mesenchymal transition. In this review, we summarize the structural and functional aspects of PKD1 and highlight the pathobiological roles of this kinase in cancer. PMID- 21680542 TI - Translating scientific advancement into clinical benefit for castration-resistant prostate cancer patients. AB - In the past 12 months, three novel therapeutics-sipuleucel-T, cabazitaxel, and abiraterone acetate-were granted Food and Drug Administration regulatory approval for the treatment of metastatic castration-resistant prostate cancer (CRPC) patients based on phase III studies that showed a survival advantage. Other agents, including the novel antiandrogen MDV3100, are at an advanced stage of clinical phase III evaluation. The treatment paradigm for CRPC has now changed significantly, and this has introduced new challenges for physicians, including selecting patients for specific therapies, developing the best sequencing and combination regimens for the several new effective agents that have recently been approved or are in development, and dissecting mechanisms of resistance that will inform the development of a new generation of therapeutics. This Focus issue reviews the results obtained with immunotherapies, taxane cytotoxics, and androgen receptor targeting therapeutics for CRPC, as well as the postulated mechanisms of resistance to these protocols and proposed strategies for improvement. The use of biomarkers for patient selection, monitoring of treatment activity, and acceleration of drug approval will be critical for achieving further improvements in the treatment for CRPC, and is also discussed in detail. PMID- 21680543 TI - Targeting continued androgen receptor signaling in prostate cancer. AB - Prostate cancer is the most common cancer and the second leading cause of death from cancer in males in most Western countries. Prostate cancer has an exquisite sensitivity to androgen deprivation therapy and is the most endocrine-sensitive solid neoplasm, although advanced disease eventually progresses to castration resistant prostate cancer (CRPC). Recent evidence has shown that cancer progression at the CRPC stage is often mediated by androgen receptor signaling, so that subsequent androgen receptor targeting may further contribute to disease control and, eventually, survival improvement. Abiraterone acetate, an androgen biosynthesis inhibitor, was tested in patients with CRPC pretreated with docetaxel in a phase III trial with demonstration of an overall survival benefit, confirming that CRPC remains hormone driven, even in advanced stages of the disease. Several novel agents also targeting androgen receptor signaling are currently being evaluated, including MDV3100 and orteronel (TAK-700). With the availability of newer endocrine treatments and also nonendocrine treatments (e.g., chemotherapy, immunotherapy, and bone-targeting agents), data supporting a more rational use of therapeutic agents are urgently required in patients with CRPC. It is likely that molecular characterization of prostate cancer will lead to the identification of different subsets of prostate cancer disease with a different natural history, sensitivity, and resistance to treatment; efforts to develop, validate, and implement predictive biomarkers in clinical trials and eventually in routine care should now be strongly supported. PMID- 21680544 TI - Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research. AB - A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival-with substantially limited side effects compared with chemotherapy-in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well. PMID- 21680545 TI - Overcoming chemotherapy resistance in prostate cancer. AB - Although treatment for prostate cancer has improved over the past several years, taxanes remain the only form of chemotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). In addition to the promising therapeutic cancer vaccines and newly developed agents targeting androgen receptor signaling, chemotherapy-based treatments will likely continue to play a significant role in patients with mCRPC. Recently published data that showed that a second taxane (cabazitaxel) extends survival after progression on docetaxel was a significant step forward, but also highlighted the need to overcome taxane resistance in prostate cancer. Preliminary evidence suggests that several treatment strategies may improve the activity of taxanes in prostate cancer and perhaps enhance clinical outcomes. PMID- 21680547 TI - KIT pathway alterations in mucosal melanomas of the vulva and other sites. AB - PURPOSE: A significant proportion of mucosal melanomas contain alterations in KIT. The aim of this study was to characterize the pattern of KIT, NRAS, and BRAF mutations in mucosal melanomas at specific sites and to assess activation of the KIT downstream RAF/MEK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in mucosal melanoma specimens. EXPERIMENTAL DESIGN: Seventy-one primary mucosal melanomas from various sites were studied. Mutation analysis was done by DNA sequencing. Expression of KIT, phosphorylated (p)-ERK, and p-AKT was evaluated by immunohistochemistry. RESULTS: KIT mutations were detected in 35% (8 of 23) of vulvar, 9% (2 of 22) of anorectal, 7% (1 of 14) of nasal cavity, and 20% (1 of 5) of penile melanomas. No KIT mutations were found in 7 vaginal melanomas. The difference in KIT mutation frequency between vulvar and nonvulvar cases was statistically significant (P = 0.014). The overall frequencies of NRAS and BRAF mutations were 10% and 6%, respectively. Notably, vaginal melanomas showed a NRAS mutation rate of 43%. KIT gene amplification (>=4 copies), as assessed by quantitative real-time PCR, was observed in 19% of cases. KIT expression was associated with KIT mutation status (P < 0.001) and was more common in vulvar than nonvulvar tumors (P = 0.016). Expression of p-ERK and p-AKT was observed in 42% and 59% of tumors, respectively, and occurred irrespective of KIT/NRAS/BRAF mutation status. NRAS mutation was associated with worse overall survival in univariate analysis. CONCLUSIONS: Results show that KIT mutations are more common in vulvar melanomas than other types of mucosal melanomas and that both the RAF/MEK/ERK and PI3K/AKT pathways are activated in mucosal melanoma specimens. PMID- 21680546 TI - Circulating tumor cells as biomarkers in prostate cancer. AB - Unmet needs in prostate cancer drug development and patient management are the ability to monitor treatment effects and to identify therapeutic targets in a tumor at the time treatment is being considered. This review focuses on establishing analytically valid biomarkers for specific contexts of use in patients with castration-resistant prostate cancer (CRPC), emphasizing a biomarker currently in clinical use, circulating tumor cells (CTC). The FDA Critical Path provides a road map for these investigations, which, if followed, will facilitate the incorporation of these types of assays into clinical decision making. CTC enumeration at baseline and post-treatment is prognostic of survival, with no threshold effect, and the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct from extent of disease. The clinical utility of monitoring CTC changes with treatment, as an efficacy response surrogate biomarker of survival, is currently being tested in large phase III trials, with the novel antiandrogen therapies abiraterone acetate and MDV3100. Molecular determinants can be identified and characterized in CTCs as potential predictive biomarkers of tumor sensitivity to a therapeutic modality. Additionally, we discuss novel technologies to enrich and characterize CTCs from more patients, the potential clinical uses of CTCs in determining prognosis and monitoring treatment effects, and CTCs as a source of tissue to identify predictive markers of drug sensitivity to guide treatment selection. Prospective studies, designed around the biomarker itself and the specific clinical context for which it is applied, are needed to further assess the role of these and novel markers in clinical practice. PMID- 21680549 TI - Left ventricle unloading by percutaneous pigtail during extracorporeal membrane oxygenation. AB - Arterial-venous extracorporeal membrane oxygenation (ECMO) is more and more used as first line mechanical support in acute cardiopulmonary failure. Important pitfall of this technique is the inappropriate unloading of left ventricle (LV) in case of myocardial insufficiency, leading to pulmonary stasis and inadequate myocardial recovery. We report our experience of left side unloading by a 7-F pigtail, introduced in the LV through the aortic valve, connected to the venous drainage. Echographic guidance is sufficient to pigtail positioning and follow-up monitoring avoiding catheterization laboratory transport. With this approach we were able to support three different patients, resolving LV distension and preventing lung congestion, without major complication. PMID- 21680550 TI - Advantages of the L-incision approach comprising a combination of left anterior thoracotomy and upper half-median sternotomy for aortic arch aneurysms. AB - Although surgical outcomes of total arch replacement have improved, the strategy for extended arch aneurysms remains controversial. We have applied the L-incision approach (combination of left anterior thoracotomy and upper half-median sternotomy) for total arch replacement for single-stage repair of extensive arch aneurysms. We retrospectively reviewed the operative outcomes of patients who underwent total arch or extended total arch replacement for degenerative aneurysms from 1999 to 2010. Operations were performed via median sternotomy in 47 patients (M group) and the L-incision approach was used in 38 patients (L group). Through the L-incision approach, we were able to complete distal anastomosis below the pulmonary hilus. The L-incision approach has advantages of reducing selective antegrade cerebral perfusion and lower body circulatory arrest times compared with the M group. Recurrent laryngeal nerve palsy and renal dysfunction were less frequent in the L group than those in the M group. Respiratory dysfunction and wound infection were similar between the groups. Hospital mortalities were 5.3% in the L group and 6.4% in the M group. The L incision approach has similar or better postoperative outcomes compared with the median sternotomy approach. This approach could be useful for single-stage extended total arch replacement with relatively low risk. PMID- 21680551 TI - Intrathoracic chemo-thermotherapy with radiofrequency waves after extrapleural pneumonectomy for malignant pleural mesothelioma. AB - Although multimodal treatment is advocated for malignant pleural mesothelioma (MPM), a standard therapeutic regimen has not been established. This study evaluated the outcome of our aggressive treatment including extrapleural pneumonectomy (EPP) and postoperative intrathoracic chemo-thermotherapy (PICT). Moreover, we assessed the association between the clinical effect and an in vitro chemosensitivity test. Eleven patients with MPM underwent treatment including EPP followed by PICT using 8 MHz radiofrequency waves. In vitro chemosensitivity was examined using the collagen gel droplet embedded culture drug-sensitivity test (CD-DST). Complete resection was performed in nine patients. More than two courses of PICT with sufficient heating were completely performed in seven patients. There was no perioperative mortality. Grade 3 or 4 toxicity was not recognized. The median overall survival was 19 months, and the median local relapse-free survival was 17 months. Local recurrence was recognized in four patients (36.4%). Of these patients, three had received incomplete PICT. Four patients with complete PICT including a CD-DST-sensitive chemoagent did not develop local recurrence. Of three patients who received complete PICT including a CD-DST-resistant chemoagent, one tumor recurred locally. The present multimodal treatment including EPP and PICT is promising in local control for MPM. Furthermore, CD-DST may provide clinically useful information for MPM. PMID- 21680552 TI - Professional parachuting: the risk of acute aortic dissection. AB - Acute aortic dissection is a rare disease, but if it occurs rapid diagnosis and therapy are needed. It is usually seen in elderly patients with long-term persistent arterial hypertension. In younger patients, it is mainly caused by congenital connective tissue disorders, such as Marfan syndrome, or by trauma. We present here a 34-year-old male patient with an acute type A aortic dissection. This patient was a professional parachutist and had carried out a large number of parachute jumps during his lifetime. He was admitted to the emergency department with acute chest pain. The symptoms were not related in time to a parachute jump. During a computed tomography scan, an aortic dissection was diagnosed. The patient was immediately referred to the operating room, and the ascending aorta was replaced by a conduit. After a regular postoperative course, the patient was discharged and recovered completely. Although acute aortic dissection is rare in young patients, it has to be considered in cases of acute chest pain. An immediate diagnosis and adequate therapy are essential to offer the patient a good clinical outcome and long-term survival. PMID- 21680553 TI - Surgery for hemoptysis in various pulmonary tuberculous lesions: a prospective study. AB - Hemoptysis due to pulmonary tuberculous lesions is a common cause of morbidity, and occasionally mortality. The aim of this study is to evaluate the surgical outcome of hemoptysis in patients with various tuberculous pulmonary lesions. A total of 45 cases who underwent surgical procedures for various pulmonary tuberculous lesions with hemoptysis were included in this study. Sixteen patients underwent surgical management within one week of the attack of hemoptysis (group A), the other 29 patients underwent surgery one week after the attack (group B). Hemoptysis was classified into minor, major and massive hemoptysis. Major and massive hemoptysis were the common presentation of group A and tuberculous cavities were the most common lung lesions in both groups (37.7%). Lobectomy was the main surgical procedure performed in both groups (51.1%). Bronchopleural fistula occurred in one case in each group after right pneumonectomy. There was one case (6.2%) of mortality in group A. Tuberculous cavity is the common pulmonary lesion which can result in major and massive hemoptysis, therefore, we recommend early surgical resection of tuberculous cavities to avoid life threatening hemoptysis. Limited resection should be avoided to prevent recurrence. PMID- 21680554 TI - William Ian McDonald: 1933-2006. AB - The life and achievements are described of (William) Ian McDonald, BMedSc MBChB PhD FRACP FRCP FRCOpth FMedSci: neurologist, National Hospital for Neurology and Neurosurgery (1966-98); physician, Moorfields Eye Hospital (1969-96); professor of neurology, Institute of Neurology and Institute of Ophthalmology, University of London (1974-98); Editor of Brain (1991-97); Harveian Librarian, Royal College of Physicians of London (1996-2004); born Wellington, New Zealand, 15 April 1933; died London, 13 December 2006. At his death, Ian McDonald left 33 box files of largely unsorted material relating to his private and professional life. The archive has not been catalogued but this biographical account of his life and work draws on the material contained therein. Where possible the date and provenance of material are identified and cited in the text; his curriculum vitae is provided as a supplementary file with individual papers identified by number within each category. PMID- 21680555 TI - Introduction to the special section: rural health issues in pediatric psychology. PMID- 21680556 TI - Pediatric impact of the H1N1 pandemic in Istanbul. PMID- 21680557 TI - Ccdc66 null mutation causes retinal degeneration and dysfunction. AB - Retinitis pigmentosa (RP) is a group of human retinal disorders, with more than 100 genes involved in retinal degeneration. Canine and murine models are useful for investigating human RP based on known, naturally occurring mutations. In Schapendoes dogs, for example, a mutation in the CCDC66 gene has been shown to cause autosomal recessively inherited, generalized progressive retinal atrophy (gPRA), the canine counterpart to RP. Here, a novel mouse model with a disrupted Ccdc66 gene was investigated to reveal the function of protein CCDC66 and the pathogenesis of this form of gPRA. Homozygous Ccdc66 mutant mice lack retinal Ccdc66 RNA and protein expression. Light and electron microscopy reveal an initial degeneration of photoreceptors already at 13 days of age, followed by a slow, progressive retinal degeneration over months. Retinal dysfunction causes reduced scotopic a-wave amplitudes, declining from 1 to 7 months of age as well as an early reduction of the photopic b-wave at 1 month, improving slightly at 7 months, as evidenced by electroretinography. In the retina of the wild-type (WT) mouse, protein CCDC66 is present at highest levels after birth, followed by a decline until adulthood, suggesting a crucial role in early development. Protein CCDC66 is expressed predominantly in the developing rod outer segments as confirmed by subcellular analyses. These findings illustrate that the lack of protein CCDC66 causes early, slow progressive rod-cone dysplasia in the novel Ccdc66 mutant mouse model, thus providing a sound foundation for the development of therapeutic strategies. PMID- 21680558 TI - Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression. AB - Recent work has led to the identification of several susceptibility genes for autism spectrum disorder (ASD) and an increased appreciation of the importance of rare and de novo mutations. Some of the mutations may be very hard to detect using current strategies, especially if they are located in regulatory regions. We present a new approach to identify functional mutations that exploit the fact that many rare mutations disrupt the expression of genes from a single parental chromosome. The method incorporates measurement of the relative expression of the two copies of a gene across the genome using single nucleotide polymorphism arrays. Allelic expression has been successfully used to study common regulatory polymorphisms; however, it has not been implemented as a screening tool for rare mutation. We tested the potential of this approach by screening for monoallelic expression in lymphoblastoid cell lines derived from a small ASD cohort. After filtering regions shared across multiple samples, we identified genes showing monoallelic expression in specific ASD samples. Validation by quantitative sequencing demonstrated that the genes (or only part of them) are monoallelic expressed. The genes included both previously suspected risk factors for ASD and novel candidates. In one gene, named autism susceptibility candidate 2 (AUTS2), we identified a rare duplication that is likely to be the cause of monoallelic expression. Our results demonstrate the ability to identify rare regulatory mutations using genome-wide allelic expression screens, capabilities that could be expanded to other diseases, especially those with suspected involvement of rare dominantly acting mutations. PMID- 21680559 TI - Retrieval of diagnostic and treatment studies for clinical use through PubMed and PubMed's Clinical Queries filters. AB - OBJECTIVE: Clinical Queries filters were developed to improve the retrieval of high-quality studies in searches on clinical matters. The study objective was to determine the yield of relevant citations and physician satisfaction while searching for diagnostic and treatment studies using the Clinical Queries page of PubMed compared with searching PubMed without these filters. MATERIALS AND METHODS: Forty practicing physicians, presented with standardized treatment and diagnosis questions and one question of their choosing, entered search terms which were processed in a random, blinded fashion through PubMed alone and PubMed Clinical Queries. Participants rated search retrievals for applicability to the question at hand and satisfaction. RESULTS: For treatment, the primary outcome of retrieval of relevant articles was not significantly different between the groups, but a higher proportion of articles from the Clinical Queries searches met methodologic criteria (p=0.049), and more articles were published in core internal medicine journals (p=0.056). For diagnosis, the filtered results returned more relevant articles (p=0.031) and fewer irrelevant articles (overall retrieval less, p=0.023); participants needed to screen fewer articles before arriving at the first relevant citation (p<0.05). Relevance was also influenced by content terms used by participants in searching. Participants varied greatly in their search performance. DISCUSSION: Clinical Queries filtered searches returned more high-quality studies, though the retrieval of relevant articles was only statistically different between the groups for diagnosis questions. CONCLUSION: Retrieving clinically important research studies from Medline is a challenging task for physicians. Methodological search filters can improve search retrieval. PMID- 21680560 TI - Funnel plots for comparing provider performance based on patient-reported outcome measures. AB - BACKGROUND: Patient-reported outcome measures (PROMs) often produce skewed distributions of individual scores after a healthcare intervention. For health performance indicators derived from skewed distributions, funnel plots designed with symmetric control limits may increase the risk of false alarms about poor performance. AIM: To investigate the accuracy of funnel plots with symmetric control limits when comparing provider performance based on PROMs. METHODS: The authors used a database containing condition-specific PROMs for 17,453 hip replacements and 7656 varicose vein procedures performed by providers in the English NHS. The mean postoperative PROM score, adjusted for patient characteristics, was used as the measure of performance. To compare performance, symmetric 99.8% control limits were calculated on funnel plots, 3 SDs away from the overall mean on either side. These were compared to control limits derived directly from percentiles of simulated (bootstrap) distributions of mean scores. RESULTS: The simulated control limits on funnel plots for both procedures were asymmetric. The empirical probability of falling outside the symmetric 99.8% 'poor performance' control limit was inflated from the stipulated rate of 0.1% to 0.2-0.3% for provider sample sizes of up to 150 procedures. The authors observed that, out of 237 providers of hip replacement, eight had adjusted mean scores that exceeded the symmetric 'poor performance' limit compared with only five that exceeded the corresponding simulated limit. In other words, three (1.3%) were differently classified. For varicose vein surgery, five out of 160 providers exceeded the symmetric limit and four exceeded the simulated limit, that is, 1 (0.6%) was differently classified. CONCLUSIONS: When designing funnel plots for comparisons of provider performance based on highly skewed data, the use of simulated control limits should be considered. PMID- 21680561 TI - Indoor air pollution (PM2.5) due to secondhand smoke in selected hospitality and entertainment venues of Karachi, Pakistan. AB - OBJECTIVE: To determine particulate matter smaller than 2.5 MUm (PM(2.5)) levels at various hospitality and entertainment venues of Karachi, Pakistan. METHODS: This was a descriptive cross-sectional study conducted at various locations in Karachi, during July 2009. Sampling was performed at 20 enclosed public places, including hospitality (restaurants and cafes) and entertainment (snooker/billiard clubs and gaming zones) venues. PM(2.5) levels were measured using an aerosol monitor. RESULTS: All entertainment venues had higher indoor PM(2.5) levels as compared to the immediate outdoors. The indoor PM(2.5) levels ranged from 25 to 390 MUg/m(3) and the outdoor PM(2.5) levels ranged from 18 to 96 MUg/m(3). The overall mean indoor PM(2.5) level was 138.8 MUg/m(3) (+/- 112.8). Among the four types of venues, the highest mean indoor PM(2.5) level was reported from snooker/billiard clubs: 264.7 MUg/m(3) (+/- 85.4) and the lowest from restaurants: 66.4 MUg/m(3) (+/- 57.6) while the indoor/outdoor ratio ranged from 0.97 to 10.2, highest being at the snooker/billiard clubs. The smoking density ranged from 0.21 to 0.57, highest being at gaming zones. The indoor PM(2.5) concentration and smoking density were not significantly correlated (Spearman's correlation coefficient = 0.113; p = 0.636). CONCLUSIONS: This study demonstrates unacceptably high levels of PM(2.5) exposure associated with secondhand smoke (SHS) at various entertainment venues of Karachi even after 8 years since the promulgation of smoke-free ordinance (2002) in Pakistan; however, better compliance may be evident at hospitality venues. The results of this study call for effective implementation and enforcement of smoke-free environment at public places in the country. PMID- 21680562 TI - Development assistance for global tobacco control. AB - BACKGROUND: By 2030, the tobacco epidemic will be responsible for over eight million deaths worldwide per year, with 80% of those deaths occurring in low resource countries. Despite the magnitude of the problem, little is known about the funding for global tobacco control. METHODS: To estimate the amount of tobacco control funding, we created an integrated database based on information provided by tobacco control donors. We focus on resources available to low-income and middle-income countries provided as Development Assistance to Control Tobacco (DACT). RESULTS: Global DACT grew from US$1.2 million in 2000 to US$44.2 million in 2009, primarily due to contributions from private philanthropies. Average annual 2000-2009 funding amounted to about US$0.003 per adult (US$0.0003 per adult in 2000 and US$0.011 per adult in 2009). DACT has been supplemented by domestic public funding that reached US$0.009 per adult in 2008. 28% of emerging and developing countries received zero DACT and 15% of those countries reported no funding at all. Out of US$21.8 billion disbursed in 2007 for health-related development assistance, DACT represented only US$0.02 billion, or 0.09%. CONCLUSIONS: Since the funding for both infectious and non-communicable diseases in low-resourced countries is inadequate, the solution for global tobacco control is not to shift resources from other public health priorities, but rather to generate additional tobacco control funding. Several mechanisms to achieve this goal are proposed. PMID- 21680563 TI - Structural equation models in occupational health: an application to exposure modelling. AB - OBJECTIVES: Many occupational hygiene surveys are designed to collect pollutant monitoring data from multiple locations simultaneously to better reflect the reality of work-related exposure. The exposure model must account for the complexity inherent in this study design, as well as be flexible to extrapolating exposures across an occupational cohort for dose-response modelling and risk assessment. This paper explores the structural equation model (SEM) as a tool to analyse pollutant monitoring data from occupational studies with multiple concurrent sampling across exposure locations. METHODS: This study uses exposure data from a comprehensive assessment of diesel exhaust in the US trucking industry to test the strength of SEMs over more standard analytical approaches such as ordinary least squares (OLS). The exposure data consist of concurrent sampling of elemental carbon from multiple co-located monitors on individual workers, work area and background levels at 36 different trucking terminals across the USA. RESULTS: The SEM is compared with two separate OLS specifications one that focuses only on predicting personal exposure and excludes data from the additional monitoring sites, and a second that estimates three separate OLS specifications. When compared with the OLS specifications, the SEM provided a better fit to these layered exposure data. The OLS specifications suffered from bias in the coefficients, including downward bias in the work area and background exposure levels and overstatement of the smoking effect. Additionally, many theoretically valid covariates were significant only in the SEM. CONCLUSIONS: This study provides evidence in favour of more widespread use of SEMs in occupational health. SEMs represent a more robust and realistic framework for modelling multiple exposure pathways and have the potential to reduce exposure misclassification bias and strengthen the linkages between studies of exposure and disease outcomes. PMID- 21680564 TI - Cystic fibrosis, primary ciliary dyskinesia and non-cystic fibrosis bronchiectasis: update 2008-11. AB - A review is presented of key clinical papers published in Thorax and elsewhere between 2008 and April 2011 which have advanced our understanding of cystic fibrosis (CF), primary ciliary dyskinesia and non-CF bronchiectasis. Studies were identified through searches of the Thorax archive and the Medline database. Within the field of CF, the following key themes were studied: diagnosis in equivocal CF, assessment of CF lung disease, novel therapies addressing the basic defect in CF, maintenance pulmonary therapies, management of early Pseudomonas infection, the microbiology of CF lung disease, renal impairment in CF and controversies in lung transplantation in CF. PMID- 21680565 TI - Innate helper cells: a novel cell type essential in the initiation of asthma? AB - The role of the innate immune system in asthma initiation is being increasingly recognised, and several innate epithelial cytokines, such as interleukin 33 (IL 33), IL-25 and thymic stromal lymphopoietin, have been described as important in asthma pathogenesis. However, until now, the mechanism by which these cytokines initiate Th2 responses and form a link with the adaptive immune system was undetermined. The recent discovery of a new group of non-T, non-B innate helper cells, which are induced by epithelial innate cytokines and secrete the Th2 cytokines IL-4 and IL-13, may provide a mechanism by which the innate and adaptive immune systems become activated in asthma. PMID- 21680566 TI - Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis. AB - BACKGROUND: Despite advances in treatment of cystic fibrosis (CF), pulmonary exacerbations remain common. The aim of this study was to determine if frequent pulmonary exacerbations are associated with greater declines in lung function, or an accelerated time to death or lung transplantation in adults with CF. METHODS: A 3-year prospective cohort study was conducted on 446 adult patients with CF from Ontario, Canada who could spontaneously produce sputum. Patients enrolled from 2005 to 2008 and were stratified into groups based upon their exacerbation rates over the 3 year study: <1 exacerbation/year (n=140), 1-2 exacerbations/year (n=160) and >2 exacerbations/year (n=146). Exacerbations were defined as acute/subacute worsening of respiratory symptoms severe enough to warrant oral or intravenous antibiotics. Patient-related factors associated with frequent exacerbations were determined, and clinical outcomes were compared among the three exacerbation groups. RESULTS: Patients with frequent exacerbations were more likely to be female, diabetic and have poorer baseline lung function. Patients with >2 exacerbations/year had an increased risk of experiencing a 5% decline from baseline forced expiratory volume in 1 s (FEV(1)); unadjusted HR 1.47 (95% CI 1.07 to 2.01, p=0.02), adjusted HR 1.55 (95% CI 1.10 to 2.18, p=0.01) compared with patients with <1 exacerbation/year. Patients with >2 exacerbations/year also had an increased risk of lung transplant or death over the 3 year study; unadjusted HR 12.74 (95% CI 3.92 to 41.36, p<0.0001), adjusted HR 4.05 (95% CI 1.15 to 14.28, p=0.03). CONCLUSIONS: Patients with CF with frequent exacerbations appear to experience an accelerated decline in lung function, and they have an increased 3 year risk of death or lung transplant. PMID- 21680567 TI - Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is commonly associated with obesity and can be improved by weight loss. Changes in upper airway size related to regional fat loss may mediate the improvement in OSA. This study aimed to assess changes in upper airway size and regional facial and abdominal fat with weight loss and their association with OSA improvement. METHODS: Middle-aged obese men with moderate-to-severe OSA underwent a 24-week sibutramine-assisted weight loss trial. Polysomnography and CT of the head and neck were performed at baseline and 24 weeks. The upper airway lumen and facial and parapharyngeal fat were measured with image analysis software. RESULTS: Post-intervention there was a significant reduction in weight (-7.8+/-4.2 kg, p<0.001) and apnoea-hypopnoea index (AHI) ( 15.9+/-20.5 events/h, p<0.001). Velopharyngeal airway volume significantly increased from baseline (5.3+/-0.4 to 6.3+/-0.3 cm(3), p<0.01) and facial and paraphayngeal fat volume significantly reduced. A reduction in upper airway length was associated with improvement in AHI (r=0.385, p=0.005). The variance in AHI improvement was best explained by changes in upper airway length and visceral abdominal fat (R(2)=0.31, p=0.004). CONCLUSIONS: Weight loss increases velopharyngeal airway volume, but changes in upper airway length appear to have a greater influence on the reduction in apnoea frequency. Inter-individual variability in the effects of weight loss on OSA severity cannot be explained in terms of changes in upper airway structure and local fat deposition alone. PMID- 21680568 TI - Molecular epidemiology of Mycobacterium tuberculosis in East Lancashire 2001 2009. AB - BACKGROUND: East Lancashire has had high rates of tuberculosis for 40 years. The ethnically diverse population is predominantly of South Asian and white origin. Drug resistance data from 1960 to 1999 indirectly suggest that no significant inter-ethnic transmission has occurred. This study used mycobacterial interspersed repetitive unit variable number tandem repeat (MIRU-VNTR) fingerprinting to assess clustering within and between ethnic groups. METHODS: All isolates of Mycobacterium tuberculosis from January 2001 to July 2009 from East Lancashire postcode areas were MIRU-VNTR fingerprinted. Clusters of strains with indistinguishable profiles were also assessed epidemiologically, and their MIRU-VNTR profiles compared with the UK M tuberculosis Strain Typing Database. RESULTS: 332 strains were typed (63 white patients, and 269 non-white patients). 198 MIRU-VNTR profiles were identified, with 144 profiles occurring only once. The typing clustered 187 strains into 53 clusters indistinguishable at all 12 loci and these were further characterised using the exact tandem repeat loci A, B, and C. The 15 loci clustered 32/63 (50.8%) of white and 110/269 (40.9%) of non white cases and all but nine clusters were of the same ethnicity. The nine inter racial clusters were further assessed from an epidemiological and clinical perspective and fingerprinting using nine additional loci. Isolates within two of the clusters were further discriminated using the additional nine loci. However, the additional loci did not further discriminate the isolates in the other seven inter-racial clusters. CONCLUSIONS: MIRU-VNTR fingerprinting indicates that although there is evidence of a high rate of transmission within the South Asian sub-population, the data suggest that there is little inter-ethnic transmission. PMID- 21680569 TI - In search of the fibrotic epithelial cell: opportunities for a collaborative network. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease of unknown aetiology. It has a very poor prognosis and no effective treatment. There are two major barriers to the development of novel treatments in IPF: an incomplete understanding of its pathogenesis and the fact that current models of the disease are poorly predictive of therapeutic response. Recent studies suggest an important role for the alveolar epithelium in the pathogenesis of IPF. However, practical limitations associated with isolation and culture of primary alveolar epithelial cells have hampered progress towards further elucidating their role in the pathogenesis of the disease or developing disease models that accurately reflect the epithelial contribution. The practical limitations of primary alveolar epithelial cell culture can be divided into technical, logistical and regulatory hurdles that need to be overcome to ensure rapid progress towards improved treatment for patients with IPF. To develop a strategy to facilitate alveolar epithelial cell harvest, retrieval and sharing between IPF research groups and to determine how these cells contribute to IPF, a workshop was organised to discuss the central issues surrounding epithelial cells in IPF (ECIPF). The central themes discussed in the workshop have been compiled as the proceedings of the ECIPF. PMID- 21680570 TI - Pleural infection on the increase but with a better evidence base to inform clinical care. PMID- 21680571 TI - Treatments for macular degeneration: summarising evidence using network meta analysis. PMID- 21680572 TI - Factors associated with occupational stress among Chinese female emergency nurses. AB - BACKGROUND: Nursing is a highly stressful occupation and occupational stress is much greater among nurses who work within emergency departments. However, few studies in China focusing on this problem are available. OBJECTIVE: To explore factors associated with occupational stress among Chinese female emergency nurses. METHODS: A cross-sectional study was conducted during April-May 2008. The study population consisted of 655 female emergency nurses from 16 hospitals in the Liaoning province, China. Occupational stress was measured by questionnaires that included the Chinese version of the Personal Strain Questionnaire, and data were collected on respondents' demographic characteristics, work situations, occupational roles and personal resources. A total of 510 effective respondents comprised our study subjects (response rate 77.9%). A general linear model was applied to analyse the factors associated with occupational stress. RESULTS: The mean Personal Strain Questionnaire score of the emergency nurses was 91.2 and this score was correlated, in descending order of standardised estimate, with role overload, role boundary, role insufficiency, social support, chronic disease and self-care. CONCLUSION: The factors role overload, role boundary and role insufficiency had the highest association with occupational stress. Improving work conditions and providing health education and an occupational training programme might help to reduce occupational stress among Chinese female emergency nurses. PMID- 21680573 TI - Comparison between the Midi Parasep and Midi Parasep Solvent Free (SF) faecal parasite concentrators. AB - AIM: To compare the recovery of parasites in faecal samples using the Midi Parasep with ethyl acetate and Midi Parasep Solvent Free (SF) faecal parasite concentrators. METHODS: 23 preserved and 11 fresh faecal samples were microscopically examined for the presence of parasites using the Midi Parasep concentrator with ethyl acetate centrifuged for 1 and 3 min and the Midi Parasep SF concentrator. RESULTS: The Midi Parasep SF faecal parasite system recovered significantly fewer ova and cysts and resulted in a notably larger deposit than the Midi Parasep concentrator with ethyl acetate. CONCLUSIONS: Parasites present in small numbers that would be detected using the Midi Parasep concentrator with ethyl acetate could be missed using the SF faecal parasite system. PMID- 21680574 TI - Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. AB - BACKGROUND AND AIM: The study of CD44/CD24 and ALDH1 expression is the most accurate method to identify cancer stem cells (CSC) from breast cancer populations. However, the overlap between CD44(+)CD24(-/low) and ALDH1(high) CSC phenotypes in breast cancer seems to be very small, as well as their distribution among intrinsic breast cancer subtypes. Due to this discrepancy, it is imperative to improve the understanding of breast CSC marker distribution. METHODS: 466 invasive breast carcinomas and eight breast cancer cell lines were analysed for the expression of CD44, CD24 and ALDH1, to evaluate their distribution among the distinct molecular subtypes. RESULTS: Basal-like tumours (76.5%) contained the higher percentage of cells with the CSC phenotype CD44(+)CD24(-/low) (p<0.0001). From ALDH1-positive cases, 39.4% were also basal-like tumours (p<0.0001). The analysis of breast cancer cell lines indicated that luminal cell lines are mainly enriched in a CD44(-/low)CD24(+) cell population, basal/mesenchymal breast cancer cell lines are enriched in the CD44(+)CD24(-/low) phenotype, whereas the remaining basal/epithelial cell lines are mainly positive for both markers. ALDH1 activity was mainly found in HER-OE and basal/epithelial breast cancer cell. CONCLUSIONS: CD44(+)CD24(-/low) and ALDH1(+) phenotypes seem to identify CSC with distinct levels of differentiation. It seems that the paramount method and biomarkers that identify breast CSC within the distinct molecular subtypes need to be better explored, because it is pivotal to translate the CSC concept to clinical practice. In the future, the recognition of reliable markers to distinguish the CSC pool in each molecular subtype will be decisive for the development of specific target therapies. PMID- 21680575 TI - Different annual recurrence pattern between lumpectomy and mastectomy: implication for breast cancer surveillance after breast-conserving surgery. AB - PURPOSE: To investigate the recurrence pattern and annual recurrence risk after breast-conserving surgery and compare them with those after mastectomy. METHODS: This retrospective analysis included 6,135 consecutive unilateral breast cancer patients undergoing surgery in 1998-2008, with 847 lumpectomy patients and 5,288 mastectomy patients. Recurrence patterns were scrutinized and annual recurrence rates were calculated. Furthermore, a literature-based review including seven relevant studies was subsequently performed to confirm our single-institution data-based observations. RESULTS: After lumpectomy, 50.9% of recurrences occurred within 3 years and 30.2% of recurrences were detected at 3-5 years; after mastectomy, 64.9% of recurrences occurred within 3 years and 20.4% occurred at 3 5 years. The major locoregional recurrence pattern after lumpectomy was ipsilateral breast tumor recurrence, which mainly (81.3%) occurred <=5 years postsurgery but with a low incidence of 37.5% <=3 years postsurgery. Annual recurrence curves indicated that the relapse peak after mastectomy emerged in the first 2 years; however, recurrence after lumpectomy increased annually with the highest peak near 5 years. By reviewing relevant studies, we confirmed our finding of different annual recurrence patterns for lumpectomy and mastectomy patients. The hazard ratio of dying for those recurring <=5 years postlumpectomy relative to patients relapsing >5 years postlumpectomy was 4.62 (95% confidence interval, 1.05-20.28; p = .042). CONCLUSIONS: Different recurrence patterns between mastectomy and lumpectomy patients imply that scheduling of surveillance visits should be more frequent during the 4-6 years after lumpectomy. Further prospective trials addressing the necessity of frequent and longer surveillance after lumpectomy are warranted. PMID- 21680577 TI - Despite criticism of the FDA review process, new cancer drugs reach patients sooner in the United States than in Europe. AB - The US Food and Drug Administration is often criticized as inefficient compared to its European counterpart, the European Medicines Agency. This criticism is especially common in the field of oncology, where severely ill patients have few therapeutic options. We conducted a direct drug-to-drug comparison of the two regulatory agencies' approvals of new oncology drugs. We found that contrary to public assertions, the median time for approval for new cancer medicines in the United States was just six months--and that these new anticancer medicines are typically available in the United States before they are in Europe. Our findings reinforce the need for strong financial and public support of the Food and Drug Administration, so that such medicines can continue to be made available speedily to patients in need. PMID- 21680576 TI - Nuclear medicine imaging of infection in cancer patients (with emphasis on FDG PET). AB - Infections are a common cause of death and an even more common cause of morbidity in cancer patients. Timely and adequate diagnosis of infection is very important. This article provides clinicians as well as nuclear medicine specialists with a concise summary of the most important and widely available nuclear medicine imaging techniques for infectious and inflammatory diseases in cancer patients with an emphasis on fluorodeoxyglucose positron emission tomography (FDG-PET). 67Ga-citrate has many unfavorable characteristics, and the development of newer radiopharmaceuticals has resulted in the replacement of 67Ga-citrate scintigraphy by scintigraphy with labeled leukocytes or FDG-PET for the majority of conditions. The sensitivity of labeled leukocyte scintigraphy in non-neutropenic cancer patients is comparable with that in patients without malignancy. The specificity, however, is lower because of the uptake of labeled leukocytes in many primary tumors and metastases, most probably as a result of their inflammatory component. In addition, labeled leukocyte scintigraphy cannot be used for febrile neutropenia because of the inability to harvest sufficient peripheral leukocytes for in vitro labeling. FDG-PET has several advantages over these conventional scintigraphic techniques. FDG-PET has shown its usefulness in diagnosing septic thrombophlebitis in cancer patients. It has also been shown that imaging of infectious processes using FDG-PET is possible in patients with severe neutropenia. Although larger prospective studies examining the value of FDG-PET in cancer patients suspected of infection, especially in those with febrile neutropenia, are needed, FDG-PET appears to be the most promising scintigraphic technique for the diagnosis of infection in this patient group. PMID- 21680578 TI - Differences between internists and family practitioners in the diagnosis and management of the same patient with coronary heart disease. AB - It has been suggested that internists and family practitioners have somewhat different "disease" perspectives, which may be generated by use of different explanatory models during medical training (pathophysiological vs. biopsychosocial, respectively). This article explores differences between internists and family practitioners in their suggested diagnoses, level of diagnostic certainty, test and prescription ordering, when encountering exactly the same "patient" with coronary heart disease (CHD). Internists were more certain of a CHD diagnosis than family practitioners and were more likely to act on this diagnosis. Family practitioners were more likely to diagnose (and were more certain of) a mental health condition. While many physicians simultaneously entertain several alternate diagnoses, diagnostic certainty has shown to have an important influence on subsequent clinical actions, such as stress testing and prescription of beta blockers. These results may inform future educational strategies designed to reduce diagnostic uncertainty in the face of life threatening conditions, such as CHD. PMID- 21680579 TI - The 2010 Garrod Lecture: the dimensions of evolution in antibiotic resistance: ex unibus plurum et ex pluribus unum. AB - Antibiotic resistance is not only the result of antibiotic-driven selection, as has been frequently considered, but rather the consequence of extremely complex evolutionary processes. These processes act on bacterial populations, but also on populations of subcellular (as plasmids) or supracellular (species, communities) units of evolution. The consideration of the effects of drift and selection provides a first intuition about the dimensions shaping the evolutionary field. We distinguish two alternative, orthogonal dimensions, respectively pushing evolutionary units towards diversification (ex unibus plurum) or towards unification (ex pluribus unum). Evolution in each one of these dimensions requires alternative evolutionary functional configurations in the evolving unit. These configurations are reached under the influence of evolutionary attractors for diversification or unification, presumably with an oscillatory dynamics. This view illustrates the complexity of possible outcomes in the emergence and evolution of antibiotic-resistant units, and indicates both the absolute need for multilevel epidemiological surveillance of antibiotic resistance, and the necessity of applying new evolutionary synthesis approaches to understand and predict human-driven changes in the microbial world. PMID- 21680581 TI - The antimicrobial resistance pattern of cultured human methanogens reflects the unique phylogenetic position of archaea. AB - OBJECTIVES: Methanogenic archaea are constant members of the human oral and digestive microbiota retrieved, in particular, from periodontitis lesions. The objective of the study was to determine their susceptibility to antimicrobials. METHODS: Using the macrodilution method in Hungate tubes with optical microscope observation combined with monitoring methane production, we determined the antibiotic resistance characteristics of eight methanogenic archaea. RESULTS: Methanobrevibacter smithii strains were resistant to ampicillin, streptomycin, gentamicin, rifampicin, ofloxacin, tetracycline and amphotericin B, with MICs >= 100 mg/L; these strains were also highly resistant to vancomycin (MIC >= 50 mg/L). They were moderately resistant to chloramphenicol (MIC <= 25 mg/L), and were susceptible to bacitracin (MIC <= 4 mg/L), metronidazole, ornidazole and squalamine (MIC <= 1 mg/L). The susceptibility of Methanosphaera stadtmanae was the same as M. smithii, except for chloramphenicol (MIC <= 4 mg/L), and Methanobrevibacter oralis yielded the same data as M. smithii, except for bacitracin (MIC <= 25 mg/L). The antibiotic susceptibility pattern of 'Methanomassiliicoccus luminyensis', which was recently isolated from human faeces, was identical to that of M. smithii. CONCLUSIONS: Human methanogenic archaea are highly resistant to antibiotics, being susceptible only to molecules that are also effective against both bacteria and eukarya. Methanogenic archaea are good candidates to test for antimicrobial activity against members of this unique domain of life. Further studies to develop new molecules specifically targeting archaea as potential causes of infection are warranted. PMID- 21680580 TI - Ageing with HIV: medication use and risk for potential drug-drug interactions. AB - OBJECTIVES: To compare the use of co-medication, the potential drug-drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals according to age, >= 50 years or <50 years. METHODS: All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database. RESULTS: Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age >= 50 and 1020 age <50. Older patients were more likely to receive one or more co medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups. CONCLUSIONS: The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and response. PMID- 21680582 TI - What are school children in Europe being taught about hygiene and antibiotic use? AB - e-Bug is a pan-European antibiotic and hygiene teaching resource that aims to reinforce awareness in school children of microbes, prudent antibiotic use, hygiene and the transmission of infection. Prior to the production of the resource, it was essential to examine the educational structure across each partner country and assess what school children were being taught on these topics. A questionnaire was devised for distribution to each European partner (Belgium, Czech Republic, Denmark, England, France, Greece, Italy, Poland, Portugal and Spain), exploring their educational structure and examining educational resources or campaigns currently available. From the data collected it was evident that the majority of European schools have structured hand hygiene practices in place from a young age. The curricula in all countries cover the topic of human health and hygiene, but limited information is provided on antibiotics and their prudent use. School educational resources that link to the national curriculum and implement National Advice to the Public campaigns in the classroom are limited. The Microbes en question mobile health education campaign in France is an example of a successful children's education campaign and an innovative programme. Evaluation of the impact of school education on attitude and change of behaviour is also limited throughout many European countries. Not enough is currently being done across Europe to educate school children on the importance of appropriate antibiotic use and antibiotic resistance. The data from this research were used to develop e-Bug, a European Union-funded antibiotic and hygiene teaching resource. PMID- 21680583 TI - Development of an educational resource on microbes, hygiene and prudent antibiotic use for junior and senior school children. AB - Health promotion interventions aimed at children and young people have the potential to lay the foundations for healthy lifestyles. One such intervention, e Bug, aims to provide schoolchildren with knowledge of prudent antibiotic use and how to reduce the spread of infection. Many children and schools approach learning in different ways; therefore, it is essential to research school needs and the variety of learning styles when creating any school resources. This article outlines the process involved during the development of a pan-European educational resource, and identifies the final pack layout, based on feedback from teacher focus groups, student questionnaires and European partner discussions. PMID- 21680585 TI - Developing e-Bug web games to teach microbiology. AB - As a complement to the e-Bug teaching pack, two e-Bug games were developed to provide content that aimed to entertain as well as to educate. A set of agreed learning outcomes (LOs) were provided by the scientific partners of the e-Bug Project and the games were developed using user-centred design techniques (the needs, wants and limitations of the potential game players were assessed at each stage of the design process). The e-Bug games were designed for two age groups: Junior (9-12 year olds); and Senior (13-15 year olds). A study using focus groups was done to gain an understanding as to the types of games enjoyed by the target users. According to the preliminary study, the Junior Game was developed as a platform game and the Senior Game was developed as a story-based detective game. The Junior Game consists of five levels, each associated with a set of LOs. Similarly, the Senior Game consists of four missions, each comprising five stages using problem-based learning techniques and LOs. In this paper, the process of development for each game is described in detail and an illustration is provided of how each game level or mission addresses the target LOs. Development of the games used feedback acquired from children in four schools across the UK (Glasgow, London and two in Gloucester). The children were selected according to their willingness to participate. European Partners of the e-Bug Project also provided further support, translation and requests for modifications. The knowledge gained of LOs and further evaluation of the games is continuing, and preliminary results are in press. The final versions of the games, translated into 11 European languages, are available online via www.e-bug.eu. PMID- 21680586 TI - Computer games to teach hygiene: an evaluation of the e-Bug junior game. AB - Handwashing, respiratory hygiene and antibiotic resistance remain major public health concerns. In order to facilitate an effective outcome when teaching the basic principles of hand and respiratory hygiene, educational interventions should first target school children. As computer games are ubiquitous in most children's lives, e-Bug developed computer games targeted at teaching children handwashing, respiratory hygiene and antibiotic resistance. The games were designed for two target audiences: junior school children (9-12 year olds); and senior school children (13-15 year olds). Between May and August 2009, the finalized junior game underwent an evaluation in three UK schools (in Glasgow, Gloucester and London), involving 62 children in the schools and ~ 1700 players accessing the junior game online. The e-Bug junior game consists of a number of levels of play, each of which promotes a set of learning outcomes (LOs). These LOs, complementary to those in the e-Bug packs, are expressed through the game mechanics (the rules of the game) rather than through story or dialogue. Although the junior game's evaluation demonstrated a statistically significant change in the knowledge for only a small number of given LOs, because many children had the required knowledge already before playing the game, this is e-Bug's first statistical study on the junior game and the first comprehensive evaluation of its kind. Future work includes a re-examination of the quiz-style questionnaires utilized in this study and an exploration of the potential knowledge change acquired strictly through engagement. PMID- 21680584 TI - Overview of e-Bug: an antibiotic and hygiene educational resource for schools. AB - Antibiotic resistance is an increasing community problem and is related to antibiotic use. If antibiotic use could be reduced, the tide of increasing resistance could be stemmed. e-Bug is a European project involving 18 European countries, partly funded by The Directorate-General for Health and Consumers (DG SANCO) of the European Commission. It aims to develop and disseminate across Europe a junior and senior school teaching pack and web site (hosting the lesson plans and complementary games) that teach young people about prudent antibiotic use, microbes, transmission of infection, hygiene and vaccines. The aim of e-Bug is to increase young people's understanding, through enjoyable activities, of why it is so important to use antibiotics correctly in order to control antibiotic resistance, and to have good hand and respiratory hygiene to help reduce the spread of infection. Within the senior school pack the sexual transmission of infections has also been included, as the peak age of chlamydial infection is in 16-24 year olds. Teachers, young people and the consortium of 18 countries were closely involved with agreeing learning outcomes and developing the resource activities. Young people helped create the characters and microbe artwork. The resources have been translated, adapted for and disseminated to schools across 10 countries in Europe, and endorsed by the relevant government departments of health and education. The web site has been accessed from >200 countries. The resources will be translated into all European Union languages, and have been used to promote European Antibiotic Awareness Day and better hand and respiratory hygiene during the influenza pandemic in 2009. PMID- 21680587 TI - Evaluating the online activity of users of the e-Bug web site. AB - Web server log analysis is being increasingly used to evaluate the user behaviour on healthcare resource web sites due to the detailed record of activity that they contain. This study aimed to use this information to evaluate the e-Bug web site, a healthcare resource that provides a range of educational resources about microbes, hand and respiratory hygiene, and antibiotics. This evaluation was conducted by analysing the web server logs of the e-Bug web site for the period January 2008 to November 2009, using a proprietary application named Sawmill. The e-Bug web site has had >900,000 page views generated from >88,000 users, with an increase in May 2009 during the swine flu epidemic and a further increase in September 2009 following the official launch of e-Bug. The majority of visitors were from the UK, but visits were recorded from 190 different countries. Word((r)) document resources were downloaded >169,000 times, with the most popular being a swine flu factsheet. PowerPoint((r)) document resources were downloaded >36,000 times, with the most popular relating to the 'chain of infection'. The majority of visitor referrals originated from search engines, with the most popular referral keywords being variations on the e-Bug name. The most common non-search engine referrals were from other healthcare resources and agencies. Use of the site has increased markedly since the official launch of e Bug, with average page views of >200,000 per month, from a range of countries, illustrating the international demand for a teaching resource for microbes, hygiene and antibiotics. PMID- 21680588 TI - Implementation of e-Bug in Belgium. AB - Antimicrobial resistance is an important issue in Belgium. For more than a decade, national projects aiming to promote the prudent use of antimicrobials and to decrease antimicrobial resistance in ambulatory, nursing-home and hospital settings have been launched by the Belgian Antibiotic Policy Coordination Committee (BAPCOC), coordinated by the Federal Public Service of Public Health, Food Chain Safety and Environment. In this paper, we describe the implementation of the e-Bug Project in Belgium by the University of Antwerp in collaboration with BAPCOC and supported by the Ministries of Education, and how e-Bug complemented a new national campaign focusing on antibiotic use in children first started on the European Antibiotic Awareness Day in 2008. We also describe the impact of the organization of education in Belgium on the implementation process, as well as plans for the future of e-Bug in our country. PMID- 21680589 TI - e-Bug implementation in the Czech Republic. AB - The Czech Republic joined the e-Bug Project in 2006, and participated in the evaluation of the e-Bug pilot version together with the United Kingdom and France in 2007. The final version of the educational material was prepared in the UK centre in 2008. These were distributed to all elementary schools in the Czech Republic at the beginning of 2010. This was accompanied by a publicity campaign. The characteristics of the Czech population and its hygiene habits, the Czech system of education, and the development of antibiotic policies are also briefly described. PMID- 21680590 TI - Implementation of e-Bug in Denmark. AB - Bacterial resistance to antimicrobial agents in primary healthcare is low in Denmark compared with most other European countries. Denmark has a vaccination programme for children that recommends immunization against 10 infectious diseases, including a heptavalent pneumococcal conjugate vaccine (PCV7) and a vaccine against human papillomavirus (HPV). Outbreaks in schools due to other infectious illnesses are well recognized and have seasonal variations. A quarter of young people have had a sexually transmitted disease before the age of 25 years. Denmark had a considerable interest in joining the e-Bug project to keep a focus on the low prevalence of bacterial resistance and the prevention of infectious diseases, and to maintain the acceptance of the immunization programme. Furthermore, the Danish Folkeskole, which is the Danish municipal primary and lower secondary school, uses the principle of differentiated teaching, integrating information technology, and there are no recommended textbooks in the curriculum. The teaching is organized so that it both strengthens and develops an individual student's ability to act and care for themselves and for society in general. e-Bug, in its design, was seen as a tool that could be implemented well in the Danish Folkeskole, as it fulfils the goals on teaching methods and output. Two thousand e-Bug packs were printed, 100 local education authorities and 1507 school principals were contacted, and e-Bug was presented to important stakeholders in relevant scientific magazines and at meetings. It has been well accepted. PMID- 21680591 TI - e-Bug implementation in England. AB - e-Bug is an educational resource for schools, covering the topics of microbes and prudent antibiotic use. A coordinated implementation approach with the e-Bug team, the Department of Health, and the Department for Children, Schools and Families resulted in the dissemination of 20,500 Junior and Senior e-Bug packs to all maintained schools in England in 2010. PMID- 21680592 TI - The e-Bug project in France. AB - The high rates of antibiotic prescriptions and antimicrobial resistance in France motivated its participation in the European e-Bug school project concerning microbes, and infection transmission, prevention and treatment. The prospect of raising awareness among children, helping them to adopt suitable attitudes and behaviour towards infection transmission and treatment starting from childhood, generated enthusiastic support from relevant national educational and health institutions throughout the Project. France was actively involved in every stage: background research showed that the subject matter was best suited to the national science curricula of the fourth and fifth forms in junior schools, and the sixth and ninth forms in senior schools; a focus group study with junior and senior teachers elicited teachers' needs concerning teaching resources; and a qualitative and quantitative evaluation, after translation and pack review, enabled further adaptation of the packs. This evaluation showed an overall enthusiastic reception by teachers and their students in France, and reassured teachers on the ease of use of the Project's resources and students' progress. The e-Bug Project was launched through a national institutional implementation plan in September 2009 and orders for e-Bug tools increased rapidly. By the end of October, 57% of all senior science teachers and 16% of all junior school teachers had ordered the pack. France is one of the most frequent users of the e Bug web site. The collaboration with both educational and health partners was particularly helpful to implementing the Project, and this was confirmed by the favourable reception and participation of teachers and students in the field. PMID- 21680593 TI - Implementation of the e-Bug Project in Greece. AB - The e-Bug pack and web site educational material has been translated and adapted to the Greek language and educational background, and implemented throughout Greece as a supplementary educational resource in elementary and junior high schools. Elementary and junior high school teachers in Greece have actively participated in the development of the e-Bug educational resource and supported the implementation of all e-Bug activities. Dissemination to all key national stakeholders has been undertaken, and endorsement has been obtained from educational and medical associations, societies and institutions. Independent evaluation has been carried out, as part of dissertation thesis projects, for postgraduate studies. The e-Bug educational resource provides all the essentials for the dissemination of good health behaviours in hygiene, monitoring the spread of infection and the prudent use of antibiotics, to the youth of this country. Its contribution is expected to be evident in the next adult generation. PMID- 21680594 TI - Pilot implementation of the e-Bug Project in Italy. AB - A pilot of the e-Bug programme has been performed in Italy. Three thousand copies of e-Bug packs have been printed and distributed to primary and first-level secondary schools in three north-eastern regions of the country (Veneto, Trentino Alto Adige and Friuli Venezia Giulia). Following the programme design in the pack, lessons based on the e-Bug resources were delivered for 1 week in a primary school in Verona. This practical approach has been adopted by other schools in these regions, in the cities of Trieste and Udine. Excellent feedback on the e Bug packs has been received from both students and teachers. The National Italian Institute of Health has requested a further 800 primary and 800 secondary e-Bug packs for distribution to different regions. PMID- 21680595 TI - Progress towards implementing the e-Bug Project in Poland. AB - The e-Bug Project provides useful educational tools that can be implemented in primary and secondary schools, and plays important role in reducing the burden of community-acquired infections. Consideration of the Polish education system and educational programmes in schools facilitated the selection of the best age groups for the implementation of e-Bug materials in Poland. The Polish version of the resources has been reviewed by a special group of experts and teachers from pilot schools. The pilot implementation is currently provided by demonstration lessons for educators and recorded as a demonstration material. The e-Bug teaching pack is a valuable resource that is useful for improving knowledge about microorganisms, hygiene and antimicrobial agents, and is aimed at pupils, teachers and parents. PMID- 21680596 TI - Implementation of the e-Bug Project in Portugal. AB - In Portugal, the need for health educational campaigns to reduce antibiotic misuse, and the implementation of handwashing and hygiene measures to reduce cross-transmission have become national priorities. The implementation of the e Bug Project in our country has been conducted by the Directorate-General for Health as the beneficiary entity of the Project, in partnership with the Ministry of Education. The involvement of the operational structures of both ministries in the development of the Project has been guaranteed from the beginning. We have translated and produced 6000 junior and senior e-Bug packs, and started to distribute them to science teachers, health education coordinators and school health teams from all over the country, who were identified as stakeholders and registered as e-Bug users in an e-learning platform from the Ministry of Education. Portugal is deeply interested in the long-term sustainability of the e Bug Project. Portuguese schools and the Portuguese e-Bug team will continue to support this initiative to benefit the health education of Portuguese children. PMID- 21680597 TI - Implementation of the e-Bug Project in Spain. AB - Antibiotic abuse and misuse have been recognized as important factors in the development and spread of antibiotic resistance. To prevent the further dissemination of resistance and to develop effective strategies to foster appropriate antibiotic consumption in all European countries, international cooperation is necessary. In comparison with some European countries, Spain shows high percentages of antibiotic resistance in several community-associated bacterial pathogens. In recent years, the health education of children has become a powerful tool for the promotion of healthy lifestyles. The e-Bug Project is a promising approach to improve the prudent use of antibiotics and hygiene habits, and to prevent disease transmission. It is expected that this project will influence Spanish children and young people, so that the adults of the future may follow healthier lifestyles and misuse antibiotics less. The implementation of the e-Bug Project in Spain is explained in this article, including an additional activity of the Ministry of Education related to the European Antibiotic Awareness Day. PMID- 21680598 TI - Developing capacity and achieving sustainable implementation in healthy 'settings': insights from NHS Health Scotland's Health Promoting Health Service project. AB - Health services continue to be seen as significant settings for health improvement, and developments continue to be made in the nature of such work, means of optimal delivery and outcomes. This paper builds on previous work by reporting on activity in a series of sites within 'NHS Health Scotland's (NHS HS)' Health Promoting Health Service (HPHS) initiative. The objectives of the review were to: describe the achievements of HPHS sites, assess the degree of influence and embedding of the HPHS approach, review the support functions provided by 'NHS HS' and identify the challenges to implementation and sustainability. The review identified a variety of activity associated with HPHS, ranging from a topic focused/behaviour change approach to efforts to re-orientate organizational features. The role that NHS HS played in developing settings capacity was largely endorsed, and there was, despite the existence of some barriers, evidence that HPHS was being successfully embedded within health service organizational policies and procedures. In particular, the role of a national level strategic guidance document to NHS CEOs ['Chief Executive Letter (14)'] is noted as having been significant in creating a conducive context for HPHS. In this context, the paper concludes by reflecting more broadly on the current status of settings-based health improvement and suggests that on the basis of this review there should be optimism in pursuing a relatively expansive vision of health improvement in this particular setting and potentially others. PMID- 21680599 TI - Future predictions of body mass index and overweight prevalence in Australia, 2005-2025. AB - To predict current and future body mass index (BMI) and prevalence of overweight and obesity in Australian children and adults based on sex, age and year of birth (cohort). These predictions are needed for population health planning and evaluation. Data were drawn from 11 cross-sectional national or state population surveys conducted in Australia between 1969 and 2004. These included representative population samples of children (n= 27,635) and adults (n= 43,447) aged 5 years or older with measured height and weight data. Multiple linear regression analyses of measured log-transformed BMI data were conducted to determine the independent effects of age and year of birth (cohort) on ln(BMI) for males and females, respectively. Regression coefficients for cohort obtained from these analyses were applied to the National Nutrition Survey 1995 data set to predict mean BMI and prevalence of overweight (BMI 25-29.99 kg/m(2)) and obesity (BMI >= 30 kg/m(2)) in 2005, 2015 and 2025. Based on past trends, BMI is predicted to continue to increase for both males and females and across the age span. This would result in increases in the prevalence of overweight and obesity of between 0.4 and 0.8% per year, such that by 2025 around one-third of 5-19 year olds will be overweight or obese as will 83% of males and 75% of females aged 20 years and over. The increases in prevalence and mean BMI predicted in this study will have significant impacts on disease burden, healthcare costs and need for prevention and treatment programmes. PMID- 21680600 TI - Influence of the site of measurement on the ability of plethysmographic variability index to predict fluid responsiveness. AB - BACKGROUND: Plethysmographic variability index (PVI) is an accurate predictor of fluid responsiveness in mechanically ventilated patients. However, the site of measurement of the plethysmographic waveform impacts its morphology and its respiratory variation. The goal of this study was to investigate the ability of PVI to predict fluid responsiveness at three sites of measurement (the forehead, ear, and finger) in mechanically ventilated patients under general anaesthesia. METHODS: We studied 28 subjects after induction of general anaesthesia. Subjects were monitored with a pulmonary artery catheter and three pulse oximeter sensors (the finger, ear, and forehead). Pulse pressure variation, central venous pressure, cardiac index (CI), and PVI measured at the forehead, ear, and finger (PVI(forehead), PVI(ear), and PVI(finger)) were recorded before and after fluid loading (FL). Subjects were responders to volume expansion if CI increased >15% after FL. RESULTS: Areas under the receiver-operating curves to predict fluid responsiveness were 0.906, 0.880, and 0.836 for PVI(forehead), PVI(ear), and PVI(finger), respectively (P<0.05). PVI(forehead), PVI(ear), and PVI(finger) had a threshold value to predict fluid responsiveness of 15%, 16%, and 12% with sensitivities of 89%, 74%, and 74% and specificities of 78%, 74%, and 67%, respectively. CONCLUSIONS: PVI can predict fluid responsiveness in anaesthetized and ventilated subjects at all three sites of measurement. However, the threshold values for predicting fluid responsiveness differ with the site of measurement. These results support the use of this plethysmographic dynamic index in the cephalic region when the finger is inaccessible or during states of low peripheral perfusion. PMID- 21680602 TI - Stem cells of the human cornea. AB - INTRODUCTION: Blindness affects 50 million individuals worldwide; a significant proportion of them require a cell or tissue-based repair or replacement strategy to mend their damaged or diseased cornea. This review will focus on the epithelial stem cell (ESC) population of the cornea, where they reside, how they are identified and what alternative cells can be used as functional substitutes. SOURCE OF DATA: Data for this review were collated after performing literature searches by inserting key words (cornea, limbal, stem cells (SCs), epithelium, stroma, and endothelium) into the search engine PubMed. AREAS OF AGREEMENT: The prevailing notion is that corneal ESCs reside in an exclusive niche and their activation is dictated by niche-specific signals. AREAS OF CONTROVERSY: Recent studies refute this hypothesis, as the central cornea of many animal species also possesses similar proliferative and clonogenic activity. The other area of controversy is in relation to the use of autologous and/or allogeneic cell therapies which are mostly contaminated with xenogeneic factors, potentially exposing the recipient to potentially harmful foreign infection. GROWING POINTS: Due to the shortage of donor corneal biomaterial, alternative cellular sources are being sought, discovered and trialed. AREAS TIMELY FOR DEVELOPING RESEARCH: With the exception of conjunctival and oral mucosal epithelium, no other cell type has been successfully used to treat patients with severe corneal epithelial defects. Embryonic and foetal SCs may have the greatest potential of all; however there are moral, legal, religious and scientific hurdles to overcome before they become routinely used in the clinic. PMID- 21680601 TI - Mixed venous oxygen saturation predicts short- and long-term outcome after coronary artery bypass grafting surgery: a retrospective cohort analysis. AB - BACKGROUND: Complications of an inadequate haemodynamic state are a leading cause of morbidity and mortality after cardiac surgery. Unfortunately, commonly used methods to assess haemodynamic status are not well documented with respect to outcome. The aim of this study was to investigate Sv(O2) as a prognostic marker for short- and long-term outcome in a large unselected coronary artery bypass grafting (CABG) cohort and in subgroups with or without treatment for intraoperative heart failure. METHODS: Two thousand seven hundred and fifty-five consecutive CABG patients and subgroups comprising 344 patients with and 2411 patients without intraoperative heart failure, respectively, were investigated. Sv(O2) was routinely measured on admission to the intensive care unit (ICU). The mean (sd) follow-up was 10.2 (1.5) yr. RESULTS: The best cut-off for 30 day mortality related to heart failure based on receiver-operating characteristic analysis was Sv(O2) 60.1%. Patients with Sv(O2) <60% had higher 30 day mortality (5.4% vs 1.0%; P<0.0001) and lower 5 yr survival (81.4% vs 90.5%; P<0.0001). The incidences of perioperative myocardial infarction, renal failure, and stroke were also significantly higher, leading to a longer ICU stay. Similar prognostic information was obtained in the subgroups that were admitted to ICU with or without treatment for intraoperative heart failure. In patients admitted to ICU without treatment for intraoperative heart failure and Sv(O2) >=60%, 30 day mortality was 0.5% and 5 yr survival 92.1%. CONCLUSIONS: Sv(O2) <60% on admission to ICU was related to worse short- and long-term outcome after CABG, regardless of whether the patients were admitted to ICU with or without treatment for intraoperative heart failure. PMID- 21680603 TI - Association of human cytomegalovirus viremia with human leukocyte antigens in liver transplantation recipients. AB - Human cytomegalovirus (HCMV) reactivation is a common complication after liver transplantation (LT). Here, we investigated whether human leukocyte antigen (HLA) matching was related to HCMV infection and subsequent graft failure after LT for hepatitis B virus cirrhosis. This retrospective study reviewed 91 LT recipients. All the patients were grouped according to HLA-A, HLA-B, and HLA-DR locus matching. Clinical data were collected, including complete HLA-typing, HCMV viremia, graft failure, and the time of HCMV viremia. HLA typing was performed using a sequence-specific primer-polymerase chain reaction kit. HCMV was detected by pp65 antigenemia using a commercial kit. The incidence of HCMV infection post-LT was 81.32%. Graft failure was observed in 16 of 91 (17.6%) patients during the 4-year study. The incidence of HCMV viremia was 100% (5/5), 91.4% (32/35), and 72.5% (37/51) in HLA-A two locus, one locus, and zero locus compatibility, respectively. Nevertheless, the degree of the HLA-A, HLA-B, or HLA DR match did not influence the time of HCMV viremia, graft failure, or the time of graft failure after a diagnosis of HCMV viremia (all P > 0.05). An interesting discovery was that the risk of HCMV viremia tended to be higher in patients with better HLA-A compatibility. Graft failure, time of HCMV viremia, and graft failure after a diagnosis of HCMV viremia appear to be independent of HLA allele compatibility. PMID- 21680604 TI - Transfer factor of the radionuclides in food crops from high-background radiation area of south west India. AB - It is necessary to obtain the transfer factor (TF) of long-lived radionuclides because soil type and vegetation can affect TF. We studied the food crops commonly consumed by the general public of Kanyakumari district of south India. The main focus was on rice, fruits, vegetables and tapioca because the consumption of these is high. The soil to rice TF for the radionuclides, (226)Ra, (232)Th, (238)U and (40) K are 8.8*10(-2), 14.2*10(-2), 5.8*10(-2) and 6.3*10( 2), respectively. The TF of tapioca for (226)Ra, (232)Th, (238)U and (40) K are 6.2*10(-2) , 11*10(-2), 1.9*10(-2) and 8.9*10(-2), respectively. For fruits and vegetables, the TFs are low. In the majority of the crops the non-edible parts accumulate more radionuclides than the edible parts. PMID- 21680605 TI - The 'Pounds for Pounds' weight loss financial incentive scheme: an evaluation of a pilot in NHS Eastern and Coastal Kent. PMID- 21680606 TI - Proteomic analysis of high-CO(2)-inducible extracellular proteins in the unicellular green alga, Chlamydomonas reinhardtii. AB - The unicellular green alga Chlamydomonas reinhardtii can acclimate to a wide range of CO(2) concentrations through the regulation of a CO(2)-concentrating mechanism (CCM). By proteomic analysis, here we identified the proteins which were specifically accumulated under high-CO(2) conditions in a cell wall-less strain of C. reinhardtii which release their extracellular matrix into the medium. When the CO(2) concentration was elevated from the ambient air level to 3% during culture, the algal growth rate increased 1.5-fold and the composition of extracellular proteins, but not intracellular soluble and insoluble proteins, clearly changed. Proteomic analysis data showed that the levels of 22 of 129 extracellular proteins increased for 1 and 3 d and such multiple high-CO(2) inducible proteins include gametogenesis-related proteins and hydroxyproline-rich glycoproteins. However, we could not prove the induction of gametogenesis under high-CO(2) conditions, suggesting that the inductive signal might be incomplete, not strong enough or that only high-CO(2) conditions might be not sufficient for the cell stage to proceed to the formation of sexually active gametes. However, these gametogenesis-related proteins and/or hydroxyproline-rich glycoproteins may have novel roles outside the cell under high-CO(2) conditions. PMID- 21680607 TI - AtSAP130/AtSF3b-3 function is required for reproduction in Arabidopsis thaliana. AB - Flowering plants produce multicellular gametophytes through an elaborate regulation of gametogenesis. During female and male gametogenesis in Arabidopsis thaliana, sporogenous cells differentiate and undergo meiosis to produce megaspores and microspores, which in turn go through mitosis to develop into multicellular gametophytes. Here we report that the Arabidopsis spliceosomal protein, SPLICEOSOME-ASSOCIATED PROTEIN 130 (AtSAP130), is required for proper reproduction. AtSAP130 is encoded by two genes, AtSAP130a and AtSAP130b. Plants with reduced expression of the AtSAP130 genes, induced by RNA interference, showed a defect in fertilization. Besides functional impairment observed in the female reproductive organs, analysis focusing on pollen development revealed defects in the transition from the microspore to the bicellular stage. Our results suggest that AtSAP130a and AtSAP130b play an indispensable role in specific spatiotemporal events in reproduction. PMID- 21680608 TI - Review paper: progress in the field of conducting polymers for tissue engineering applications. AB - This review focuses on one of the most exciting applications area of conjugated conducting polymers, which is tissue engineering. Strategies used for the biocompatibility improvement of this class of polymers (including biomolecules' entrapment or covalent grafting) and also the integrated novel technologies for smart scaffolds generation such as micropatterning, electrospinning, self assembling are emphasized. These processing alternatives afford the electroconducting polymers nanostructures, the most appropriate forms of the materials that closely mimic the critical features of the natural extracellular matrix. Due to their capability to electronically control a range of physical and chemical properties, conducting polymers such as polyaniline, polypyrrole, and polythiophene and/or their derivatives and composites provide compatible substrates which promote cell growth, adhesion, and proliferation at the polymer tissue interface through electrical stimulation. The activities of different types of cells on these materials are also presented in detail. Specific cell responses depend on polymers surface characteristics like roughness, surface free energy, topography, chemistry, charge, and other properties as electrical conductivity or mechanical actuation, which depend on the employed synthesis conditions. The biological functions of cells can be dramatically enhanced by biomaterials with controlled organizations at the nanometer scale and in the case of conducting polymers, by the electrical stimulation. The advantages of using biocompatible nanostructures of conducting polymers (nanofibers, nanotubes, nanoparticles, and nanofilaments) in tissue engineering are also highlighted. PMID- 21680609 TI - Development of a pre-vascularized 3D scaffold-hydrogel composite graft using an arterio-venous loop for tissue engineering applications. AB - Hyaluronic acid (HA) and fibrin glue (FG) are effective hydrogels for tissue engineering applications as they support tissue in-growth, retain growth factors, and release them slowly with time. The scaffolds, in combination with a hydrogel, effectuate a successful graft. However, the survival of a graft entirely depends upon a functional vascular supply. Therefore, hydrogels must support the in growing vasculature. To study and compare the vascular patterns, HA and FG hydrogel-containing PLDLLA-TCP-PCL scaffolds were implanted in the groin of male Lewis rats and supplied with a micro-surgically prepared arterio-venous (A-V) loop. The rats were perfused with a vascular contrast media after 4 and 8 weeks and sacrificed for further analysis. The specimens were scanned with micro-CT to find the vascular growth patterns. Corrosion casting of blood vessels followed by SEM demonstrated a high vascular density near the parent blood vessels. Histologically, HA and FG implanted animal groups showed significant angiogenetic activity, especially within the pores of the scaffold. However, formation of new blood vessels was more conspicuously observed at 4 weeks in FG than HA implants. Furthermore, by 8 weeks, the number and pattern of blood vessels were comparable between them. At this time, HA was still present indicating its slow degradation. The finding was confirmed by histomorphometric analysis. This experimental study demonstrates that HA containing composite scaffold systems permit stabile in growth of blood vessels due to sustained degradation over 8 weeks. HA is a potential matrix for a tissue engineered composite graft. PMID- 21680610 TI - Fabrication of oxidized alginate-gelatin-BCP hydrogels and evaluation of the microstructure, material properties and biocompatibility for bone tissue regeneration. AB - Composite hydrogel systems consisting of oxidized alginate, gelatin, and biphasic calcium phosphate were fabricated by the Schiff-base reaction and the effect of oxidation of alginate on the microstructure, material properties, and biocompatibility were evaluated. Alginate was modified by oxidizing the attached OH groups to a -CHO group to facilitate interactions with the -NH2 groups of gelatin. The increased interactions between the functional groups had several effects on the materials properties, physical behaviors, and bio-compatibility. A higher degree of oxidation and thereby a higher extent of crosslinking between the -CHO and -NH2 groups resulted in an increase in water uptake and compressive strength, which was associated with a decrease in porosity, gelation time, bio degradation rate, and to a smaller degree, biocompatibility. The hydrogel structure was highly porous and showed unique channel zed morphology with an extensive branching of the channels. The channels were not continuous and were divided into multiple segments by thin separators that were 5 um thick and branched off of the 10-25 um thick frame. The pores in the hydrogel system were interconnected and the porosity ranged from 44.45 to 67.89% with a pore size ranging from 100 to 300 um. The compressive stress failure of the wet hydrogel was at 12.0 +/- 1.2 MPa when the degree of alginate oxidation was 66.6%. The biocompatibility of the hydrogel system was excellent, although it was slightly lowered by oxidation. These hydrogels are promising biomaterials for bone regeneration with adjustable gelation and bio-degradation time, good mechanical strength, and excellent bio-compatibility. PMID- 21680611 TI - Bupivacaine-enhanced small intestinal submucosa biomaterial as a hernia repair device. AB - Management of post-surgical pain following herniorrhaphy remains a clinical challenge and novel methods to deliver analgesic compounds could be of great benefit. Because there is great interest in the use of natural biomaterials for hernia repair, we investigated the biocompatibility of a natural biomaterial, porcine small intestinal submucosa (SIS), which was impregnated with bupivacaine (SIS-B) via immersion in a solution of poly(lactic-co-glycolic acid) (PLGA). Groups of Sprague Dawley rats underwent surgical creation of a ventral abdominal wall defect with subsequent repair using either SIS or SIS-B. Analysis of serial blood samples showed peak bupivacaine levels (83 ng/mL) were achieved 16 h after implantation of SIS-B. One month after surgery, the rats were euthanized and implant sites harvested for mechanical strength testing and histological analysis. At the time of necropsy, adhesion extent and tenacity was greater in SIS-B rats, with 90% of SIS-B rats have adhesion to the implant site compared to only 75% of SIS rats. Microscopically, SIS implant sites were characterized by small amounts of residual SIS surrounded by mild-to-moderate chronic inflammation. In contrast, rats treated with SIS-B, residual SIS-B was surrounded by a ring of acute inflammatory cells and an outer ring of chronic inflammatory cells, possibly due to bupivacaine or residual PLGA. Mechanical strength testing of the harvested implant sites showed no significant (p <= 0.05) difference between SIS and SIS-B implants. In summary, bupivacaine is readily elaborated from SIS-B; and impregnation of SIS with bupivacaine does not substantially alter the biocompatibility of the biomaterial or its mechanical strength following implantation. PMID- 21680612 TI - Electrospinning of polyvinyl alcohol/gelatin nanofiber composites and cross linking for bone tissue engineering application. AB - A three-dimensional polymer composite system consisting of polyvinyl alcohol/gelatin (PVA/GE) was fabricated via the electrospinning method and physically cross linked by methanol treatment. The effects of cross-linking between PVA/GE blend on physical, mechanical, and biological properties were investigated. After treating with methanol, PVA/GE mats become dense, hard, and aggregative with increased resistance to water dissolution. Osteoblasts like MG 63 cells were seeded on the surfaces of the cross linked PVA/GE mats and were found to attach firmly by expressing philopodial extensions. In addition, MTT assay and Western Blot analysis confirmed that the cells readily proliferated on the cross linked PVA/GE scaffolds. The osteoblast cell-matrix interaction demonstrated that the active biocompatibility of the mats was facilitated by using GE and cross-linking. In conclusion, our results suggest that cross-linked PVA/GE scaffolds hold promise for tissue engineering applications, especially in the field of artificial bone implant. PMID- 21680613 TI - Osteoporosis: yesterday, today and tomorrow. PMID- 21680614 TI - Performance of a semi-automated approach for risk estimation using a common data model for longitudinal healthcare databases. AB - Different structures and coding schemes may limit rapid evaluation of a large pool of potential drug safety signals using multiple longitudinal healthcare databases. To overcome this restriction, a semi-automated approach utilising common data model (CDM) and robust pharmacoepidemiologic methods was developed; however, its performance needed to be evaluated. Twenty-three established drug safety associations from publications were reproduced in a healthcare claims database and four of these were also repeated in electronic health records. Concordance and discrepancy of pairwise estimates were assessed between the results derived from the publication and results from this approach. For all 27 pairs, an observed agreement between the published results and the results from the semi-automated approach was greater than 85% and Kappa coefficient was 0.61, 95% CI: 0.19-1.00. Ln(IRR) differed by less than 50% for 13/27 pairs, and the IRR varied less than 2-fold for 19/27 pairs. Reproducibility based on the intra-class correlation coefficient was 0.54. Most covariates (>90%) in the publications were available for inclusion in the models. Once the study populations and inclusion/exclusion criteria were obtained from the literature, the analysis was able to be completed in 2-8 h. The semi-automated methodology using a CDM produced consistent risk estimates compared to the published findings for most selected drug-outcome associations, regardless of original study designs, databases, medications and outcomes. Further assessment of this approach is useful to understand its roles, strengths and limitations in rapidly evaluating safety signals. PMID- 21680615 TI - From reactive to reflective: evidence for shifts in parents' state of mind during brief under-fives psychoanalytic psychotherapy. AB - This article describes a study that was designed to examine the impact of brief psychoanalytic psychotherapy with children under-five years of age and their families. The work took place in a Child and Adolescent Mental Health Service (CAMHS) in England, to which children are routinely referred with a range of behavioural and emotional problems. The study examined the hypothesis that through formulating the emotional forces that underpin the family's here-and-now experiences and bringing into the frame the child's perspective, a shift in the parents' states of mind from being less reactive and more reflective would be observed. Further, the less reactive parental state would result in the child feeling more contained, and impact positively in relation to symptom presentation. Using clinical description and quantitative data drawn from the videotaped clinical material the hypothesis was tested on seven families. The prediction was borne out, significantly so in relation to the parents being less blaming and more reparative in their comments. Parental reports also highlighted that six of the seven children exhibited a significant reduction / termination of symptoms for which they had been originally referred. The therapeutic process underlying these results is considered. PMID- 21680616 TI - Social networking between cells of the foetal skeleton: the importance of thyroid hormones. AB - In this issue of Journal of Endocrinology, Lanham et al. investigated the effects of hypothyroidism on the developing skeleton of the ovine foetus in utero. Their analyses indicated that, following thyroidectomy, bone growth, structure and mechanical properties were all altered at late gestation or at term. Adrenalectomy, whilst preventing the prepartum rise in triiodothyronine, did not modify skeletal development. The hypothyroid-mediated skeletal defects of the developing foetus described in this study may have clinical implications for bone health in later life. PMID- 21680617 TI - Diabetic nephropathy and long-term treatment effects of rosiglitazone and enalapril in obese ZSF1 rats. AB - Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Yet the pathogenic mechanisms underlying the development of DN are not fully defined, partially due to lack of suitable models that mimic the complex pathogenesis of renal disease in diabetic patients. In this study, we describe early and late renal manifestations of DN and renal responses to long-term treatments with rosiglitazone or high-dose enalapril in ZSF1 rats, a model of metabolic syndrome, diabetes, and chronic renal disease. At 8 weeks of age, obese ZSF1 rats developed metabolic syndrome and diabetes (hyperglycemia, glucosuria, hyperlipidemia, and hypertension) and early signs of renal disease (proteinuria, glomerular collagen IV deposition, tubulointerstitial inflammation, and renal hypertrophy). By 32 weeks of age, animals developed renal histopathology consistent with DN, including mesangial expansion, glomerulosclerosis, tubulointerstitial inflammation and fibrosis, tubular dilation and atrophy, and arteriolar thickening. Rosiglitazone markedly increased body weight but reduced food intake, improved glucose control, and attenuated hyperlipidemia and liver and kidney injury. In contrast, rosiglitazone markedly increased cardiac hypertrophy via a blood pressure-independent mechanism. High-dose enalapril did not improve glucose homeostasis, but normalized blood pressure, and nearly prevented diabetic renal injury. The ZSF1 model thus detects the clinical observations seen with rosiglitazone and enalapril in terms of primary and secondary endpoints of cardiac and renal effects. This and previous reports indicate that the obese ZSF1 rat meets currently accepted criteria for progressive experimental diabetic renal disease in rodents, suggesting that this may be the best available rat model for simulation of human DN. PMID- 21680618 TI - Calcium supplementation reverts central adiposity, leptin, and insulin resistance in adult offspring programed by neonatal nicotine exposure. AB - Obesity is a worldwide epidemic. Calcium influences energy metabolism regulation, causing body weight loss. Because maternal nicotine exposure during lactation programs for obesity, hyperleptinemia, insulin resistance (IR), and hypothyroidism, we decided to evaluate the possible effect of dietary calcium supplementation on these endocrine dysfunctions in this experimental model. Osmotic minipumps containing nicotine solution (N: 6 mg/kg per day for 14 days) or saline (C) were s.c. implanted in lactating rats 2 days after giving birth (P2). At P120, N and C offspring were subdivided into four groups: 1) C - standard diet; 2) C with calcium supplementation (CCa, 10 g calcium carbonate/kg rat chow); 3) N - standard diet; and 4) N with calcium supplementation (NCa). Rats were killed at P180. As expected, N offspring showed higher visceral and total body fat, hyperleptinemia, lower hypothalamus leptin receptor (OB-R) content, hyperinsulinemia, and higher IR index. Also, higher tyrosine hydroxylase (TH) expression (+51%), catecholamine content (+37%), and serum 25-hydroxyvitamin D(3) (+76%) were observed in N offspring. Dietary calcium supplementation reversed adiposity, hyperleptinemia, OB-R underexpression, IR, TH overexpression, and vitamin D. However, this supplementation did not reverse hypothyroidism. In NCa offspring, Sirt1 mRNA was lower in visceral fat (-37%) and higher in liver (+42%). In conclusion, dietary calcium supplementation seems to revert most of the metabolic syndrome parameters observed in adult offspring programed by maternal nicotine exposure during lactation. It is conceivable that the reduction in fat mass per se, induced by calcium therapy, is the main mechanism that leads to the increment of insulin action. PMID- 21680619 TI - Inverse association of plasma level of high-density lipoprotein cholesterol with intracerebral hemorrhage. AB - This study aimed to investigate whether plasma levels of HDL cholesterol (HDL-C) were associated with the risk of intracerebral hemorrhage (ICH). Plasma HDL-C was determined via enzymatic methods, and ICH was ascertained via medical history, physical examination, and brain imaging (computed tomography or magnetic resonance imaging). The multivariable logistic regression model was used to calculate the odds ratios (OR) and 95% confidence intervals (CI) of ICH according to levels of plasma cholesterol. A total of 170 patients with ICH were identified from 6,046 participants. After adjustment for conventional cardiovascular risk factors, the OR was 2.06 (95% CI, 1.25-3.12; P < 0.01) for participants in the first tertile of HDL-C levels (<1.38 mmol/l) and 1.13 (95% CI, 0.72-1.78; P = 0.59) for participants in the second tertile (1.38-1.64 mmol/l), compared with participants in the third tertile (?>=1.65 mmol/l). Subgroup analysis indicated that the detrimental effects of HDL-C were more significant in men and lean participants than in their corresponding controls, independent of hypertension. The results presented herein indicate that low plasma HDL-C (<1.38 mmol/l) may be associated with risk of ICH. PMID- 21680620 TI - Synthetic single-framework antibody library integrated with rapid affinity maturation by VL shuffling. AB - Affinity maturation is often applied to improve the properties of antibodies isolated from universal antibody libraries in vitro. A synthetic human scFv antibody library was constructed in single immunoglobulin framework to enable rapid affinity maturation by updated Kunkel's mutagenesis. The initial diversity was generated predominantly in the V(H) domain combined with only 36 V(L) domain variants yielding 3 * 10(10) unique members in the phage-displayed library. After three rounds of panning the enriched V(H) genes from the primary library selections against lysozyme were incorporated into a ready-made circular single stranded affinity maturation library containing 7 * 10(8) V(L) gene variants. Several unique antibodies with 0.8-10 nM (K(d), dissociation constant) affinities against lysozyme were found after panning from the affinity maturation library, contrasted by only one anti-lysozyme scFv clone with K(d) <20 nM among the clones panned from the primary universal library. The presented single-framework strategy provides a way to convey significant amount of functional V(H) domain diversity to affinity maturation without bimolecular ligation leading to a diverse set of antibodies with binding affinities in the low nanomolar range. PMID- 21680621 TI - Prevention of falls through podiatry care. PMID- 21680623 TI - Support mounts for a social protection guarantee for the world's most vulnerable people. PMID- 21680622 TI - Effectiveness of a multifaceted podiatry intervention to prevent falls in community dwelling older people with disabling foot pain: randomised controlled trial. AB - OBJECTIVE: To determine the effectiveness of a multifaceted podiatry intervention in preventing falls in community dwelling older people with disabling foot pain. DESIGN: Parallel group randomised controlled trial. SETTING: University health sciences clinic in Melbourne, Australia. PARTICIPANTS: 305 community dwelling men and women (mean age 74 (SD 6) years) with disabling foot pain and an increased risk of falling. 153 were allocated to a multifaceted podiatry intervention and 152 to routine podiatry care, with 12 months' follow-up. INTERVENTIONS: Multifaceted podiatry intervention consisting of foot orthoses, advice on footwear, subsidy for footwear ($A100 voucher; L65; ?74), a home based programme of foot and ankle exercises, a falls prevention education booklet, and routine podiatry care for 12 months. The control group received routine podiatry care for 12 months. MAIN OUTCOME MEASURES: Proportion of fallers and multiple fallers, falling rate, and injuries resulting from falls during follow-up. RESULTS: Overall, 264 falls occurred during the study. 296 participants returned all 12 calendars: 147 (96%) in the intervention group and 149 (98%) in the control group. Adherence was good, with 52% of the participants completing 75% or more of the requested three exercise sessions weekly, and 55% of those issued orthoses reporting wearing them most of the time. Participants in the intervention group (n=153) experienced 36% fewer falls than participants in the control group (incidence rate ratio 0.64, 95% confidence interval 0.45 to 0.91, P=0.01). The proportion of fallers and multiple fallers did not differ significantly between the groups (relative risk 0.85, 0.66 to 1.08, P=0.19 and 0.63, 0.38 to 1.04, P=0.07). One fracture occurred in the intervention group and seven in the control group (0.14, 0.02 to 1.15, P=0.07). Significant improvements in the intervention group compared with the control group were found for the domains of strength (ankle eversion), range of motion (ankle dorsiflexion and inversion/eversion), and balance (postural sway on the floor when barefoot and maximum balance range wearing shoes). CONCLUSIONS: A multifaceted podiatry intervention reduced the rate of falls in community dwelling older people with disabling foot pain. The components of the intervention are inexpensive and relatively simple to implement, suggesting that the programme could be incorporated into routine podiatry practice or multidisciplinary falls prevention clinics. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12608000065392. PMID- 21680624 TI - Abolition of strategic health authorities threatens screening of newborns, expert says. PMID- 21680625 TI - UK government's changes to health bill are welcomed by research community. PMID- 21680626 TI - Small voluntary sector groups risk closure, says King's Fund. PMID- 21680627 TI - Judge criticises paediatrician for claiming to know how to assess age of asylum seekers. PMID- 21680628 TI - Health reforms will not succeed without public engagement, say providers. PMID- 21680629 TI - Postural hypotension. PMID- 21680630 TI - Unethical behaviour by the pharmaceutical industry is putting Canadian children's lives at risk, suggests editorial. PMID- 21680631 TI - Public health and preventing violence. PMID- 21680632 TI - Effectiveness of anonymised information sharing and use in health service, police, and local government partnership for preventing violence related injury: experimental study and time series analysis. AB - OBJECTIVE: To evaluate the effectiveness of anonymised information sharing to prevent injury related to violence. DESIGN: Experimental study and time series analysis of a prototype community partnership between the health service, police, and local government partners designed to prevent violence. SETTING: Cardiff, Wales, and 14 comparison cities designated "most similar" by the Home Office in England and Wales. INTERVENTION: After a 33 month development period, anonymised data relevant to violence prevention (precise violence location, time, days, and weapons) from patients attending emergency departments in Cardiff and reporting injury from violence were shared over 51 months with police and local authority partners and used to target resources for violence prevention. MAIN OUTCOME MEASURES: Health service records of hospital admissions related to violence and police records of woundings and less serious assaults in Cardiff and other cities after adjustment for potential confounders. RESULTS: Information sharing and use were associated with a substantial and significant reduction in hospital admissions related to violence. In the intervention city (Cardiff) rates fell from seven to five a month per 100,000 population compared with an increase from five to eight in comparison cities (adjusted incidence rate ratio 0.58, 95% confidence interval 0.49 to 0.69). Average rate of woundings recorded by the police changed from 54 to 82 a month per 100,000 population in Cardiff compared with an increase from 54 to 114 in comparison cities (adjusted incidence rate ratio 0.68, 0.61 to 0.75). There was a significant increase in less serious assaults recorded by the police, from 15 to 20 a month per 100,000 population in Cardiff compared with a decrease from 42 to 33 in comparison cities (adjusted incidence rate ratio 1.38, 1.13 to 1.70). CONCLUSION: An information sharing partnership between health services, police, and local government in Cardiff, Wales, altered policing and other strategies to prevent violence based on information collected from patients treated in emergency departments after injury sustained in violence. This intervention led to a significant reduction in violent injury and was associated with an increase in police recording of minor assaults in Cardiff compared with similar cities in England and Wales where this intervention was not implemented. PMID- 21680633 TI - Recent heavy alcohol consumption at death certified as ischaemic heart disease: correcting mortality data from Kaunas (Lithuania). AB - AIMS: To assess the proportion of deaths assigned to ischaemic heart disease (IHD) which in fact were caused by the toxic effects of alcohol, and how this may affect the official statistics of mortality from IHD in Lithuania. METHODS: Using the IHD register in Kaunas, Lithuania, and verifying underlying causes of death using standard international methodology, 3061 cases were found in Kaunas city who had died from IHD at age 25-64 during 1993-2007. Out-of-hospital sudden deaths accounted for 2467 cases (81%), including 1498 where forensic autopsy was conducted and post-mortem concentration of alcohol in blood and urine was available. RESULTS: In total, 78.4% of all initial IHD diagnoses were verified, while in 8.7% of deaths the underlying cause of death was corrected into an alcohol-related cause and in 12.9% to other diseases. Alcohol was found in about half (50.3%) of out-of-hospital death cases subjected to autopsy. In 18.0% of cases, the alcohol concentration was 3.5% or higher. Alcohol was more likely to be present in winter months and at weekends. CONCLUSION: A significant number of alcohol-attributable deaths in Lithuania were misclassified as coronary deaths, accounting for almost one-tenth of officially registered deaths from IHD in ages 25-64. A high prevalence of positive post-mortem blood or urine alcohol tests suggests that the proportion of alcohol-related deaths among out-of-hospital IHD deaths may be actually even higher. A similar situation may be present in some other countries where high levels of alcohol consumption and binge drinking patterns are observed. PMID- 21680634 TI - A novel FK-506-binding-like protein that lacks peptidyl-prolyl isomerase activity is involved in intracellular infection and in vivo virulence of Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a facultative intracellular bacterial pathogen causing melioidosis, an often fatal infectious disease that is endemic in several tropical and subtropical areas around the world. We previously described a Ptk2 cell-based plaque assay screening system of B. pseudomallei transposon mutants that led to the identification of several novel virulence determinants. Using this approach we identified a mutant with reduced plaque formation in which the BPSL0918 gene was disrupted. BPSL0918 encodes a putative FK-506-binding protein (FKBP) representing a family of proteins that typically possess peptidyl-prolyl isomerase (PPIase) activity. A B. pseudomallei DeltaBPSL0918 mutant showed a severely impaired ability to resist intracellular killing and to replicate within primary macrophages. Complementation of the mutant fully restored its ability to grow intracellularly. Moreover, B. pseudomallei DeltaBPSL0918 was significantly attenuated in a murine model of infection. Structural modelling confirmed a modified FKBP fold of the BPSL0918-encoded protein but unlike virulence associated FKBPs from other pathogenic bacteria, recombinant BPSL0918 protein did not possess PPIase activity in vitro. In accordance with this observation BPSL0918 exhibits several mutations in residues that have been proposed to mediate PPIase activity in other FKBPs. To our knowledge this B. pseudomallei FKBP represents the first example of this protein family which lacks PPIase activity but is important in intracellular infection of a bacterial pathogen. PMID- 21680635 TI - Exclusion of synaptotagmin V at the phagocytic cup by Leishmania donovani lipophosphoglycan results in decreased promastigote internalization. AB - Regulators of membrane fusion play an important role in phagocytosis, as they regulate the focal delivery of endomembrane that is required for optimal internalization of large particles. During internalization of Leishmania promastigotes, the surface glycolipid lipophosphoglycan (LPG) is transferred to the macrophage membrane and modifies its fusogenic properties. In this study, we investigated the impact of LPG on the recruitment of the exocytosis regulator synaptotagmin V (Syt V) at the area of internalization and on the early steps of phagocytosis. Using Leishmania donovani LPG-defective mutants and LPG-coated particles, we established that LPG reduces the phagocytic capacity of macrophages and showed that it causes exclusion of Syt V from the nascent phagosome. Silencing of Syt V inhibited phagocytosis to the same extent as LPG, and these effects were not cumulative, consistent with a Syt V-dependent mechanism for the inhibition of phagocytosis by LPG. Previous work has revealed that LPG-mediated exclusion of Syt V from phagosomes prevents the recruitment of the vacuolar ATPase and acidification. Thus, whereas exclusion of Syt V from phagosomes in the process of formation may be beneficial for the creation of a hospitable intracellular niche, it reduces the phagocytic capacity of macrophages. We propose that the cost associated with a reduced internalization rate may be compensated by increased survival, and could lead to a greater overall parasite fitness. PMID- 21680636 TI - JmjN interacts with JmjC to ensure selective proteolysis of Gis1 by the proteasome. AB - A group of JmjC domain-containing proteins also harbour JmjN domains. Although the JmjC domain is known to possess histone demethylase activity, the function of the JmjN domain remains largely undetermined. Previously, we have demonstrated that the yeast Gis1 transcription factor, bearing both JmjN and JmjC domains at its N terminus, is subject to proteasome-mediated selective proteolysis to downregulate its transcription activation ability. Here, we reveal that the JmjN and JmjC domains interact with each other through two beta-sheets, one in each domain. Removal of either or both beta-strands or the entire JmjN domain leads to complete degradation of Gis1, mediated partially by the proteasome. Mutating the core residues essential for histone demethylase activity demonstrated for other JmjC-containing proteins or deleting both Jumonji domains enhances the transcription activity of Gis1, but has no impact on its selective proteolysis by the proteasome. Together, these data suggest that JmjN and JmjC interact physically to form a structural unit that ensures the stability and appropriate transcription activity of Gis1. PMID- 21680637 TI - Integration host factor alleviates H-NS silencing of the Salmonella enterica serovar Typhimurium master regulator of SPI1, hilA. AB - Coordination of the expression of Salmonella enterica invasion genes on Salmonella pathogenicity island 1 (SPI1) depends on a complex circuit involving several regulators that converge on expression of the hilA gene, which encodes a transcriptional activator (HilA) that modulates expression of the SPI1 virulence genes. Two of the global regulators that influence hilA expression are the nucleoid-associated proteins Hha and H-NS. They interact and form a complex that modulates gene expression. A chromosomal transcriptional fusion was constructed to assess the effects of these modulators on hilA transcription under several environmental conditions as well as at different stages of growth. The results obtained showed that these proteins play a role in silencing hilA expression at both low temperature and low osmolarity, irrespective of the growth phase. H-NS accounts for the main repressor activity. At high temperature and osmolarity, H NS-mediated silencing completely ceases when cells enter the stationary phase, and hilA expression is induced. Mutants lacking IHF did not induce hilA in cells entering the stationary phase, and this lack of induction was dependent on the presence of H-NS. Band-shift assays and in vitro transcription data showed that for hilA induction under certain growth conditions, IHF is required to alleviate H-NS-mediated silencing. PMID- 21680638 TI - Growth-dependent secretome of Candida utilis. AB - Recently, the food yeast Candida utilis has emerged as an excellent host for production of heterologous proteins. Since secretion of the recombinant product is advantageous for its purification, we characterized the secreted proteome of C. utilis. Cells were cultivated to the exponential or stationary growth phase, and the proteins in the medium were identified by MS. In parallel, a draft genome sequence of C. utilis strain DSM 2361 was determined by massively parallel sequencing. Comparisons of protein and coding sequences established that C. utilis is not a member of the CUG clade of Candida species. In total, we identified 37 proteins in the culture solution, 17 of which were exclusively present in the stationary phase, whereas three proteins were specific to the exponential growth phase. Identified proteins represented mostly carbohydrate active enzymes associated with cell wall organization, while no proteolytic enzymes and only a few cytoplasmic proteins were detected. Remarkably, cultivation in xylose-based medium generated a protein pattern that diverged significantly from glucose-grown cells, containing the invertase Inv1 as the major extracellular protein, particularly in its highly glycosylated S-form (slow migrating). Furthermore, cultivation without ammonium sulfate induced the secretion of the asparaginase Asp3. Comparisons of the secretome of C. utilis with those of Kluyveromyces lactis and Pichia pastoris, as well as with those of the human fungal pathogens Candida albicans and Candida glabrata, revealed a conserved set of 10 and six secretory proteins, respectively. PMID- 21680639 TI - Vitamin D deficiency and its association with disease activity in new cases of systemic lupus erythematosus. AB - Evidence has shown a relationship between vitamin D deficiency and systemic lupus erythematosus (SLE). We evaluated the frequency of vitamin D deficiency and its association with disease activity in new cases of SLE. Women with newly diagnosed SLE, based on the American College of Rheumatology (ACR) criteria, were enrolled consecutively. Those receiving vitamin D supplements and postmenopausal women were not included. Disease activity was measured by the BILAG index (2004) and serum concentration of 25-hydroxyvitamin D (25[OH]D) was measured by radioimmunoassay method. Forty SLE patients with mean age of 25.3 +/- 4.2 years were studied. Severe, moderate, and mild vitamin D deficiency, corresponding to serum 25[OH]D concentrations of <12.5, 12.5-24.9, and 25-39.9 nmol/l, were found in 12.5%, 62.5%, and 17.5% of the patients, respectively. Serum 25[OH]D concentration was inversely correlated with the British Isles Lupus Assessment Group (BILAG) index score (r = -0.486, p = 0.001). Those with a more severe vitamin D deficiency had also higher concentrations of liver enzymes (p < 0.05), lower serum albumin and hemoglobin concentrations (p < 0.05), and higher titers of antibodies to double-stranded DNA (ds-DNA) (p < 0.001). This study showed that most of the SLE patients in our society have vitamin D deficiency at the time of diagnosis that is associated with a higher disease activity. Routine screening for vitamin D deficiency and its prompt treatment in patients with newly diagnosed SLE is recommended. PMID- 21680640 TI - Intestinal pseudo-obstruction syndrome in systemic lupus erythematosus. AB - Intestinal pseudo-obstruction (IpsO) occurs in a small subgroup of patients with systemic lupus erythematosus (SLE), and has been under-recognized. The etiology and mechanisms are unclear. Herein, we report two cases. In case 1, IpsO occurred as the complication in a previously diagnosed SLE patient. In case 2, IpsO with an image-evidenced intussusception and a peripheral eosinophilia, was the initial presentation, leading to the diagnosis of SLE. In both cases, IpsO existed concomitantly with ureterohydronephrosis, and evolved into peritonitis, which we called together IpsO syndrome. However, this surgical abdomen-like syndrome had a satisfactory response to glucocorticosteroids instead of antibiotics and surgery. Physician awareness and early diagnosis could positively affect outcomes of this syndrome, avoiding unnecessary surgical intervention. PMID- 21680641 TI - Report of maltreatment as a risk factor for injury death: a prospective birth cohort study. AB - This article presents a population-based study of early childhood injury mortality following a nonfatal allegation of maltreatment. Findings are based on a unique data set constructed by establishing child-level linkages between vital birth records, administrative child protective services records, and vital death records. These linked data reflect over 4.3 million children born in California between 1999 and 2006 and provide a longitudinal record of maltreatment allegations and death. Of interest was whether children reported for nonfatal maltreatment subsequently faced a heightened risk of unintentional and intentional injury mortality during the first 5 years of life. Findings indicate that after adjusting for risk factors at birth, children with a prior allegation of maltreatment died from intentional injuries at a rate that was 5.9 times greater than unreported children (95% CI [4.39, 7.81]) and died from unintentional injuries at twice the rate of unreported children (95% CI [1.71, 2.36]). A prior allegation to CPS proved to be the strongest independent risk factor for injury mortality before the age of five. PMID- 21680642 TI - Proinflammatory and antiinflammatory cytokine levels in complicated and noncomplicated parapneumonic pleural effusions. AB - OBJECTIVES: This study aimed to evaluate a panel of proinflammatory and antiinflammatory cytokines in noncomplicated and complicated parapneumonic pleural effusions and to correlate their levels with pleural fluid biochemical parameters. METHODS: Serum and pleural effusion were collected from 60 patients with noncomplicated (n = 26) or complicated (n = 34) parapneumonic effusions and assayed for cytologic, biochemical, and proinflammatory and antiinflammatory cytokines. Student t test was used to compare serum and pleural fluid values, Spearman correlation to analyze the relationship between pleural fluid cytokines and biochemical parameters, and accuracy of pleural fluid cytokine levels to determine the optimal cutoff value for identification of complicated effusions. Corrections for multiple comparisons were applied and a P value < .05 was accepted as significant. RESULTS: Serum and pleural fluid cytokine levels of IL 8, vascular endothelial growth factor (VEGF), IL-10, and tumor necrosis factor (TNF) soluble receptor (sR) II were similar between groups. In contrast, complicated effusions had higher levels of pleural fluid IL-1beta, IL-1 receptor antagonist (ra), and TNF sRI. Negative correlations were found between pleural fluid glucose with IL-1beta and TNF sRI and positive correlations between lactic dehydrogenate (LDH) with IL-1beta, IL-8, and VEGF. Pleural fluid levels of IL 1beta, IL-1ra, and TNF sRI were more accurate than IL-8, VEGF, IL-10, and TNF sRII in discriminating complicated effusions. CONCLUSIONS: Both proinflammatory and antiinflammatory cytokine levels in pleural fluid are elevated in complicated in comparison with noncomplicated parapneumonic pleural effusions, and they correlate with both pleural fluid glucose and LDH levels. IL-1beta, IL-1ra, and TNF sRI had higher sensitivity and specificity than IL-8, VEGF, IL-10, and TNF sRII in discriminating complicated effusions. PMID- 21680643 TI - Evaluation of pulmonary function and exercise performance by cardiopulmonary exercise testing before and after lung transplantation. AB - BACKGROUND: Detailed description of functional exercise outcomes before and after lung transplantation is lacking. The objective of this study was to describe and compare posttransplant improvement in lung function and peak exercise parameters in patients with advanced lung disease. METHODS: The study included 153 patients who underwent lung transplantation over 7 years who had complete cardiopulmonary exercise testing (CPET) and pulmonary function tests (PFTs) before and after lung transplantation. CPET and PFT within 30 months pretransplant and posttransplant were compared. RESULTS: Pulmonary function markedly improved posttransplant as FVC increased 67%, maximum voluntary ventilation increased 91%, and FEV(1) increased 136%. However, peak oxygen consumption increased only 19%, peak CO(2) production increased 50%, and peak work increased 78%. Although transplant recipients had a 1.5- to 2.0-fold increase in exercise capacity posttransplant, peak exercise capacity remained at 50% of the predicted normal, suggesting a maximal limitation. Subgroup stratification into quartiles based on pretransplant exercise capacity revealed the greatest exercise benefit to be in the lowest functional pretransplant groups. CONCLUSIONS: Lung transplant recipients have an increase in exercise capacity that does not match the improvement in lung function, indicating that poor strength, deconditioning, or other peripheral factors play a significant role in the limitation of exercise benefit posttransplantation. Further elucidation of the mechanisms of exercise limitation may allow for improved exercise outcomes posttransplant. PMID- 21680644 TI - The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. AB - BACKGROUND: In pulmonary arterial hypertension (PAH), survival predictions can be important for optimization of therapeutic strategies. The present study aimed to validate a quantitative algorithm for predicting survival derived from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) and develop a simplified calculator for everyday clinical use. METHODS: Prospectively collected data from patients with newly diagnosed (< 3 months) World Health Organization group I pulmonary hypertension enrolled in the REVEAL Registry were used to validate a predictive algorithm for 1-year survival. Model calibration was evaluated by comparing algorithm-predicted survival with observed Kaplan-Meier estimates for the overall validation cohort and for five risk groups. Similarly, the risk discriminators for the simplified calculator were compared with those of the quantitative algorithm. RESULTS: The validation cohort comprised 504 individuals with mean +/- SD 6-min walk distance 308 +/- 128 m, and 61.5% were functional class III. The proportion of patients surviving 1 year fell within the range predicted by the model (95.1%, 91.5%, 84.6%, 76.3%, and 58.2%, respectively) among patients in the low (predicted survival >= 95%), average (90% to < 95%), moderate (85% to < 90%), high (70% to < 85%), and very high (< 70%) risk strata. Predicted and observed 1-year survival were similar across risk stratum, and the c-index indicated good discrimination for both the full equation (0.726) and the simplified risk calculator (0.724). CONCLUSIONS: The REVEAL Registry predictive algorithm and simplified risk score calculator are well calibrated and demonstrate good discriminatory ability in patients with newly or previously diagnosed PAH. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov. PMID- 21680645 TI - Risk factors for stroke and thromboembolism in relation to age among patients with atrial fibrillation: the Loire Valley Atrial Fibrillation Project. AB - BACKGROUND: According to the latest European guidelines on the management of nonvalvular atrial fibrillation (NVAF), all patients aged >= 65 years should be treated with oral anticoagulation (if not contraindicated). Therefore, stroke risk factors should be investigated exclusively in patients with NVAF aged < 65 years. METHODS: Patients diagnosed with NVAF in a four-hospital institution between 2000 and 2010 were identified. Event rates of stroke/thromboembolism were calculated according to age category (ie, age < 65, 65-74, and >= 75 years). Independent risk factors of stroke and thromboembolism were investigated in univariate and multivariate Cox regression models including patients with NVAF aged < 65 years only. The effect of adding vascular disease to the CHADS(2) (congestive heart failure, hypertension, age >= 75 years, diabetes, previous stroke) score was examined by net reclassification improvement (NRI) and integrated discrimination improvement (IDI) models. RESULTS: Among 6,438 patients with NVAF, 2,002 (31.1%) were aged < 65 years. In patients with no CHADS(2) risk factors who were not treated with anticoagulation (n = 1,035), the stroke/thromboembolic event rate per 100 person-years was 0.23 (95% CI, 0.08 0.72), 2.05 (95% CI, 1.07-3.93), and 3.99 (95% CI, 2.63-6.06) in those aged < 65, 65-74, and >= 75 years, respectively. Heart failure, previous stroke, and vascular disease were significantly associated with increased risk of stroke/thromboembolism in both univariate and multivariate analyses, and vascular disease significantly improved the predictive ability of the CHADS(2) score (NRI, 0.40; IDI, 0.031). CONCLUSIONS: Patients with NVAF aged >= 65 years have event rates that merit oral anticoagulation. In patients with NVAF aged < 65 years, the risk of stroke/thromboembolism is independently increased by the presence of heart failure, previous stroke, or vascular disease. As proposed in the new CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age >= 75 years, diabetes, previous stroke, vascular disease, age 65-74 years, sex category [female]) score, stroke risk stratification by the CHADS(2) score can be improved by the addition of age 65 to 74 years and vascular disease. PMID- 21680646 TI - Adaptive optics for studying visual function: a comprehensive review. AB - Compared to most ophthalmic technologies, adaptive optics, or AO, is relatively young. The first working systems were presented in 1997 and, owing in part to its complexity, the development of AO systems has been relatively slow. Nevertheless, AO for vision science is coming of age and the scope of applications continues to increase. Applications of AO can be broadly split along two lines; for retinal imaging and for testing visual function. This review will focus on the applications of adaptive optics for testing visual function. Since this represents only a subset of the field of AO for ophthalmoscopy, it is possible to cite virtually every paper that has been published in the field to date. As such, this is a comprehensive review whose intent is to get all readers up to speed on the state of the art. More importantly, perhaps, this review will focus on the types of science that can be accomplished with AO with a view to future applications. The reference list alone is informative, since the reader will quickly discover that the community that is using AO for vision science is rather small. Looking at the dates for the cited papers, the reader will also discover that the field is rapidly expanding. PMID- 21680647 TI - Protection against deprivation amblyopia depends on relative not absolute daily binocular exposure. AB - Short daily periods of binocular exposure (BE) can offset longer single daily episodes of monocular exposure (ME) to prevent the development of deprivation amblyopia. To determine whether the outcome depended upon an absolute daily amount of BE or its proportion of the daily visual exposure, daily mixed visual input of 3 different durations (3.5, 7, or 12 h) was imposed on 3 cohorts of kittens. Measurements of the visual acuity of the deprived eye at the end of mixed daily visual input revealed that the acuity of the deprived eye developed to normal values so long as the proportion of the total exposure that was binocular was 30% or more. By contrast, the development of functional ocular dominance domains in V1 revealed by optical imaging suggests that normal domains emerge with a fixed amount of daily binocular exposure. The latter result is consistent with the effects of any daily period of ME, or BE, or both, effectively saturating with a small dose so that the effects of ME of any length can be offset by a short period of BE. The different result for vision may reflect neural events at higher and/or multiple levels in the visual pathway. PMID- 21680648 TI - Podocyte injury can be catching. PMID- 21680649 TI - Sunrise of statins after AURORA and 4D? PMID- 21680650 TI - The fourth dimension: associations of change in albuminuria over time. PMID- 21680651 TI - Induced pluripotent stem cells from human kidney. PMID- 21680652 TI - Pseudotumor cerebri: brief review of clinical syndrome and imaging findings. AB - PTC is a clinical entity of uncertain etiology characterized by intracranial hypertension. The syndrome classically manifests with headaches and visual changes in women with obesity. Traditionally, imaging ruled out secondary causes of elevated CSF pressure but now may reveal findings frequently seen in patients with PTC, including the following: flattening of the globe, an empty sella, an enlarged ONS, protrusion and enhancement of the optic nerve head, and increased tortuosity of the optic nerve. Novel imaging methods, including MR venography, have additionally identified sinovenous stenosis as a potential indicator of PTC. PMID- 21680653 TI - Fully automated atlas-based MR imaging volumetry in Huntington disease, compared with manual volumetry. AB - BACKGROUND AND PURPOSE: The atrophy of the caudate is considered the hallmark of HD-associated neurodegeneration and has high potential as a biomarker in structural MR imaging. This study aimed at comparing automated and manual caudate volumetry. MATERIALS AND METHODS: In this cross-sectional volumetric study in 40 patients with HD and 30 healthy controls, a fully automated caudate measurement by ABV was used for the first time in HD and was directly compared with manual delineation as the generally accepted criterion standard of volumetry. RESULTS: It could be shown that both techniques were able to separate patients and controls to a similar degree. The differences between the 2 volumetric measurements ranged within the limits of agreement; the systematically lower values by manual volumetry were caused by the different assessment of the dorsal caudate tail, which is hard to delineate manually. CONCLUSIONS: ABV may be used instead of manual volumetry to quantify caudate volume loss. Additionally, the ABV technique has the advantage of being much faster, is less laborious, and is free of a subjective region-of interest definition. ABV might serve as a tool in potential future clinical trials of disease-modifying treatments in HD. PMID- 21680654 TI - Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AB - VH and MTS are the neuroimaging hallmarks of JSRD. We aimed to look at the full spectrum of neuroimaging findings in JSRD and reviewed the MR imaging of 75 patients with JSRD, including 13 siblings and 4 patients with OFD VI. All patients had VH and enlargement of the fourth ventricle. The degree of VH and the form of the MTS were variable. In most patients, the cerebellar hemispheres were normal and the PF was enlarged. Brain stem morphology was abnormal in 30% of the patients. Supratentorial findings included hippocampal malrotation, callosal dysgenesis, migration disorders, cephaloceles, and ventriculomegaly. All patients with OFD VI had a similar pattern, including HH in 2 patients. No neuroimaging genotype correlation could be found. The wide neuroimaging spectrum in our patients supports the heterogeneity of JSRD. Neuroimaging differences in siblings represent intrafamilial heterogeneity. Due to the absence of a correlation with genotype, neuroimaging findings are of limited value in classifying patients with JSRD. PMID- 21680655 TI - The topography of brain microstructural damage in amyotrophic lateral sclerosis assessed using diffusion tensor MR imaging. AB - BACKGROUND AND PURPOSE: ALS leads to macrostructural (ie, cortical atrophy and hyperintensities along the corticospinal tract) and microstructural (ie, gray matter intrinsic damage) central nervous system abnormalities. We used a multimodal voxelwise imaging approach to assess microstructural changes independent of macrostructural volume loss in patients with ALS compared with HCs. MATERIALS AND METHODS: Twenty-three patients with ALS and 14 HCs were studied. Conventional imaging and DTI were performed. Images were processed by using SPM5 to assess measures of gray and white matter atrophy as well as microstructural damage (ie, MD and FA). DTI alterations independent of volume loss were investigated. RESULTS: When we accounted for both gray and white matter atrophy, patients with ALS showed increased MD values in several gray and white matter areas mainly located in the orbitofrontal and frontotemporal regions bilaterally, in the right genu of the corpus callosum, and in the right posterior limb of the internal capsule. When we accounted for white matter volume loss, patients with ALS showed decreased FA along the corticospinal tract bilaterally and in the left inferior frontal lobe relative to HCs. The MD of the orbitofrontal regions bilaterally was associated significantly with disease duration. CONCLUSIONS: In patients with ALS, DTI detects microstructural changes independent of brain tissue loss. The affected regions included both motor and extramotor areas. The extent of ALS-related DTI abnormalities was greater than that disclosed by the volumetric analysis. PMID- 21680656 TI - Restoration of spinal alignment and disk mechanics following polyetheretherketone wafer kyphoplasty with StaXx FX. AB - BACKGROUND AND PURPOSE: EPFs sustained during VCFs degrade the disk's ability to develop IDP under load. This inability to develop pressure in combination with residual kyphotic deformity increases the risk for adjacent vertebral fractures. We tested the hypothesis that StaXx FX reduces kyphosis and endplate deformity following vertebral compression fracture, restoring disk mechanics. MATERIALS AND METHODS: Eight thoracolumbar, 5-vertebrae segments were tested. A void was selectively created in the middle vertebra. The specimens were compressed until EPF and to a grade I-II VCF. PEEK wafer kyphoplasty was then performed. The specimens were then tested in flexion-extension (+/-6 Nm) under 400-N preload intact, after EPF, VCF, and kyphoplasty. Endplate deformity, kyphosis, and IDP adjacent to the fractured body were measured. RESULTS: Vertebral body height at the point of maximal endplate deformity decreased after EPF and VCF and was partially corrected after StaXx FX, remaining less than intact (P = .047). Anterior vertebral height decreased after VCF (P = .002) and was partially restored with StaXx FX, remaining less than intact (P = .015). Vertebral kyphosis increased after VCF (P < .001) and reduced after StaXx FX, remaining greater than intact (P = .03). EPF reduced IDP in the affected disk in compression-flexion loading (P < .001), which was restored after StaXx FX (P = 1.0). IDP in the unaffected disk did not change during testing (P > .3). CONCLUSIONS: StaXx FX reduced endplate deformity and kyphosis, and significantly increased anterior height following VCF. Although height and kyphosis were not fully corrected, the disk's ability to pressurize under load was restored. PMID- 21680657 TI - Microembolic signal monitoring after coiling of unruptured cerebral aneurysms: an observational analysis of 123 cases. AB - BACKGROUND AND PURPOSE: Thromboembolic events after aneurysm coiling are common, but the optimal algorithm for emboli prevention remains unclear. MESs correlate with the occurrence of impending ischemic events and may be used for management guidance. This study reports the use of MES monitoring with regard to aneurysm characteristics and coiling technique after a specific anticoagulation protocol. MATERIALS AND METHODS: We analyzed 123 consecutive, elective endovascular procedures. Patients received intraprocedural and continuous heparin if feasible. Demographic data, aneurysm size, type of intervention/complication, medication, imaging, and clinical outcome were analyzed. MES monitoring was performed in all patients both immediately after as well as >12 hours after the procedure. RESULTS: Heparinization within the first 12 hours was associated with lower numbers of MESs early after coiling (3.4 versus 18.8 MESs/hr). When on heparin, larger aneurysm size, stent-assisted procedures, or incomplete occlusion did not lead to a significant increase in MESs. If the initial MES count on heparin was >10 MESs/hr, it was always safe to discontinue heparin. Inability to initiate early, continuous heparinization was associated with new neurologic deficits. Additional administration of antiplatelet agents showed lower MES counts initially, but the difference was not significant. CONCLUSIONS: MES monitoring is a powerful adjunct to monitor efficacy of treatment algorithms for emboli prevention after coiling. In our series, early heparinization was associated with a lower incidence of MESs. This is of particular importance in larger aneurysms, stent-assisted procedures, and incomplete occlusions, in which the thromboembolic risk is greatest early on and antiplatelet treatment alone may not suffice. PMID- 21680658 TI - The two-pore domain potassium channel KCNK5: induction by estrogen receptor alpha and role in proliferation of breast cancer cells. AB - The growth of many human breast tumors requires the proliferative effect of estrogen acting via the estrogen receptor alpha (ERalpha). ERalpha signaling is therefore a clinically important target for breast cancer prevention and therapeutics. Although extensively studied, the mechanism by which ERalpha promotes proliferation remains to be fully established. We observed an up regulation of transcript encoding the pH-sensitive two-pore domain potassium channel KCNK5 in a screen for genes stimulated by 17beta-estradiol (E2) in the ERalpha(+) breast cancer cell lines MCF-7 and T47D. KCNK5 mRNA increased starting 1 h after the onset of E2 treatment, and protein levels followed after 12 h. Estrogen-responsive elements are found in the enhancer region of KCNK5, and chromatin immunoprecipitation assays revealed binding of ERalpha to the KCNK5 enhancer in E2-treated MCF-7 cells. Cells treated with E2 also showed increases in the amplitude of pH-sensitive potassium currents, as assessed by whole-cell recordings. These currents are blocked by clofilium. Although confocal microscopy suggested that most of the channels are located in intracellular compartments, the increase in macroscopic currents suggests that E2 treatment increases the number of active channels at the cell surface. Application of small interfering RNA specific for KCNK5 decreased pH-sensitive potassium currents and also reduced the estrogen-induced proliferation of T47D cells. We conclude that E2 induces the expression of KCNK5 via ERalpha(+) in breast cancer cells, and this channel plays a role in regulating proliferation in these cell lines. KCNK5 may therefore represent a useful target for treatment, for example, of tamoxifen-resistant breast cancer. PMID- 21680659 TI - Dehydroepiandrosterone inhibits glucose flux through the pentose phosphate pathway in human and mouse endometrial stromal cells, preventing decidualization and implantation. AB - Endometrial stromal cells (ESC) must undergo a hormone-driven differentiation to form decidual cells as a requirement of proper embryo implantation. Recent studies from our laboratory have demonstrated that decidualizing cells require glucose transporter 1 expression and an increase in glucose use to complete this step. The present study focuses on the glucose-dependent molecular and metabolic pathways, which are required by ESC for decidualization. Inhibition of glycolysis had no effect on decidualization. However, blockade of the pentose phosphate pathway (PPP) with pharmacologic inhibitors 6-aminonicotinamide or dehydroepiandrosterone (DHEA), and short hairpin RNA-mediated knockdown of glucose-6-phosphate dehydrogenase, the rate-limiting step in the PPP, both led to strong decreases in decidual marker expression in vitro and decreased decidualization in vivo. Additionally, the studies demonstrate that inhibition is due, at least in part, to ribose-5-phosphate depletion, because exogenous nucleoside administration restored decidualization in these cells. The finding that PPP inhibition prevents decidualization of ESC is novel and clinically important, because DHEA is an endogenous hormone produced by the adrenal glands and elevated in a high proportion of women who have polycystic ovary syndrome, the most common endocrinopathy in reproductive age women. Together, this data suggest a mechanistic link between increased DHEA levels, use of glucose via the PPP, and pregnancy loss. PMID- 21680661 TI - European guideline for the management of scabies, 2010. AB - Transmission of the mite Sarcoptes scabiei generally occurs by protracted direct body contact; although in crusted scabies, transmission also occurs via infected clothing or bedding. Diagnosis is usually clinical and topical antiscabietics are the mainstay of treatment. Oral ivermectin is not licensed in most countries, but may have a role in certain patients. Treatment of sexual contacts is indicated. PMID- 21680660 TI - Research resource: New and diverse substrates for the insulin receptor isoform A revealed by quantitative proteomics after stimulation with IGF-II or insulin. AB - The isoform A of the insulin receptor (IR) (IR-A) is a bifunctional receptor, because it binds both insulin and IGF-II. IR-A activation by IGF-II plays a role in development, but its physiological role in adults is unknown. IGF-II signaling through IR-A is deregulated in cancer and favors tumor progression. We hypothesized that IGF-II binding to the IR-A elicits a unique signaling pathway. In order to obtain an unbiased evaluation of IR-A substrates differentially involved after IGF-II and insulin stimulation, we performed quantitative proteomics of IR-A substrates recruited to tyrosine-phosphorylated protein complexes using stable isotope labeling with amino acids in cell culture in combination with antiphosphotyrosine antibody pull down and mass spectrometry. Using cells expressing only the human IR-A and lacking the IGF-I receptor, we identified 38 IR-A substrates. Only 10 were known IR mediators, whereas 28 substrates were not previously related to IR signaling. Eleven substrates were recruited by stimulation with both ligands: two equally recruited by IGF-II and insulin, three more strongly recruited by IGF-II, and six more strongly recruited by insulin. Moreover, 14 substrates were recruited solely by IGF-II and 13 solely by insulin stimulation. Interestingly, discoidin domain receptors, involved in cell migration and tumor metastasis, and ephrin receptor B4, involved in bidirectional signaling upon cell-cell contact, were predominantly activated by IGF-II. These findings indicate that IR-A activation by IGF-II elicits a unique signaling pathway that may play a distinct role in physiology and in disease. PMID- 21680662 TI - European guideline for the management of pediculosis pubis, 2010. AB - Transmission of the crab louse Phthirus pubis generally occurs by close body contact. Diagnosis is usually clinical and screening for other sexually transmitted infections (STIs) is indicated. While most evidence is extrapolated from studies of head lice treatments, topical pediculicides are recommended and treatment of sexual contacts is indicated. PMID- 21680663 TI - Mollaret's meningitis and herpes simplex virus type 2 infections. AB - Benign recurrent aseptic meningitis is a rare disorder described by Mollaret in 1944. When initially described, this form of aseptic meningitis had no identifiable infecting agent. New sophisticated diagnostic tools have now identified herpes simplex type 2 virus as the most commonly isolated agent. Antiviral treatment has been used successfully for prophylaxis and treatment. PMID- 21680664 TI - Field evaluation of five rapid diagnostic tests for screening of HIV-1 infections in rural Rakai, Uganda. AB - The performance characteristics of HIV rapid diagnostic tests (RDTs) vary by test and by population. We assessed five commercial RDTs in Uganda where all but one RDT (Determine; Abbott Laboratories, Germany) performed close to manufacturer's expectations. Determine had low specificity (85.2%, positive predictive value 67.3%) due to false-positive results with weak-positive bands. Properly trained staff, good quality control programmes and validation of RDTs with laboratories having confirmatory testing capacity may be warranted to assure accuracy in each setting. PMID- 21680665 TI - Diagnostic accuracy of ultrasensitive heat-denatured HIV-1 p24 antigen in non-B subtypes in Kampala, Uganda. AB - We evaluated the accuracy of heat-denatured, amplification-boosted ultrasensitive p24 assay (Up24) compared with reverse transcriptase polymerase chain reaction (RT-PCR). We tested 394 samples from Ugandans infected with HIV-1 non-B subtypes. We compared Up24 levels (HIV-1 p24 Core Profile enzyme-linked immunosorbent assay (ELISA), NEN Life Science Products) to RNA viral loads (Amplicor HIV-1 Monitor 1.5, Roche) by linear regression, and calculated sensitivity, specificity, positive and negative predictive values. Median viral load was 4.9 log10 copies/mL (interquartile range [IQR], 2.6-5.5); 114 samples (29%) were undetectable (<400 copies/mL). Sensitivity of the Up24 assay to detect viral load >=400 copies/mL was 69%, specificity was 67%, and positive and negative predictive values were 84% and 47%, respectively. Sensitivity of Up24 was 90%, 80%, 68%, 62% and 45% to detect viral loads of >500,000, 250,000-500,000, 100,000 250,000, 50,000-100,000 and 400-50,000 copies/mL, respectively. In conclusion, when compared with RT-PCR for patients infected with non-B subtypes, the Up24 demonstrated limited sensitivity especially at low viral loads. Moreover, the Up24 was positive in 33% of samples deemed undetectable by RT-PCR, which may limit the use of the Up24 to detect viral suppression. PMID- 21680666 TI - Risk estimates for persistent high-risk human papillomavirus infections as surrogate endpoints of progressive cervical disease critically depend on reference category: analysis of the combined prospective cohort of the New Independent States of the Former Soviet Union and Latin American Screening studies. AB - To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks [RRs]) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease. PMID- 21680667 TI - Non-cirrhotic portal hypertension in HIV-infected individuals. AB - Non-cirrhotic portal hypertension (NCPH) has been associated with didanosine (ddI) exposure. We aimed to determine the number of individuals with NCPH within our cohort and define their characteristics. We identified individuals within our cohort with NCPH and performed a retrospective case note review. Cumulative antiretroviral therapy (ART) use was calculated and a statistical analysis performed to compare exposure to the rest of the clinic cohort for the same time period. Where available, data was collated on FibroScan(r), echocardiography and coagulation profile. Seventeen patients were identified. Upper gastrointestinal bleeding was the most common presenting feature. Liver biopsy showed mild portal or periportal fibrosis in 13 (81%) and four with features of nodular regenerative hyperplasia. There was significantly greater exposure to ddl in this group (59.5 months) compared to the rest of the HIV cohort (21.1 months) P = <0.001. Eleven subjects has a liver elastography performed, six (55%) had a result greater than 9.6 kPa (consistent with greater than F2 disease by Metavir scoring). Echocardiography was performed in seven patients: four met criteria for pulmonary hypertension. This is consistent with other cohorts demonstrating an association between the didanosine exposure and NCPH. Our data also suggest an increased risk of pulmonary hypertension. PMID- 21680668 TI - Low acceptance of HSV-2 testing among high-risk women. AB - We evaluated the acceptability of a community-based herpes simplex virus type 2 (HSV-2) screening programme for at-risk women and assessed factors related to uptake of point of care HSV-2 testing. One hundred recently arrested women (median age 34 years) were recruited from a community court handling lower-level misdemeanour cases in Indianapolis, Indiana. Individuals completed a survey assessing factors related to HSV-2 screening intentions and were offered point of care HSV-2 testing. Rates of HSV-2 infection in this population are high; 61.1% of women tested were positive. The majority (81%) accepted a prescription for suppressive therapy. Women in this sample indicated that HSV-2 screening is an important component of health care but were unwilling to pay the US$10 it cost to be tested. To encourage this and other high-risk populations to be screened for HSV-2, public health resources will be needed to help individuals overcome cost related barriers to care. PMID- 21680669 TI - Is male intent to be vaccinated against HPV a function of the promotion message? AB - We aimed to determine whether the type of outcome expectation, stemming from HPV vaccination, would have any effect on young men's HPV vaccine intent. We recruited young men (18-24 years of age) from two university campuses (n = 150). After answering a series of questions they were randomly assigned to one of three information conditions (all delivered by computer): (1) how women may benefit from men's HPV vaccination, (2) preventing genital warts and (3) preventing head and neck cancers. Intent to be vaccinated against HPV in the next 12 months was assessed before and after receiving the informational session corresponding to the assigned condition. A repeated-measures t-test indicated that a significant increase in young men's intent to be vaccinated after they received the assigned information (t = 9.48, [147], P = 0.0001). However, the increase in intent to be vaccinated did not vary by group assignment as there were no significant differences in mean intent scores between the three groups (F = 0.59, [2/144], P = 0.56). Information that promotes the outcome expectations of protecting women from cervical cancer, preventing genital warts for men and preventing head and neck cancers for men may be equally effective in promoting increased intent for HPV vaccine acceptance among young university men. PMID- 21680670 TI - Different trends for different sexually transmissible infections despite increased testing of men who have sex with men. AB - Australian and New South Wales Sexually Transmissible Infections Strategies recommend sexual health clinics actively target particular populations, including men who have sex with men (MSM), who have increasing rates of sexually transmitted infections (STIs). We describe trends in MSM attendances, STI testing and diagnostic yield from 1996 to 2007 at a Sydney public sexual clinic. Aggregate data were extracted from the clinic database. There was a 76% increase in the number of individual MSM attending, more than three-fold increase in the number of STI tests performed and the proportion of MSM tested. The increase in testing was greatest for rectal infections. The positive yield increased for rectal chlamydia and infectious syphilis; remained stable for pharyngeal gonorrhoea; and decreased for urethral gonorrhoea, rectal gonorrhoea and urethral chlamydia. Our results demonstrate successful service reorientation in response to a local STI epidemic. Differing trends suggest evolving transmission dynamics for different STIs in the context of increased testing of asymptomatic MSM. PMID- 21680671 TI - Is asymptomatic non-chlamydial non-gonococcal urethritis associated with significant clinical consequences in men and their sexual partners: a systematic review. AB - Opinions are divided on whether to screen asymptomatic men for non-chlamydial non gonococcal urethritis (NCNGU). We systematically reviewed the literature to determine whether male asymptomatic NCNGU is associated with significant clinical outcomes for men and/or their sexual partners. We searched electronic databases and reference lists from retrieved articles and reviews. No studies reporting clinical outcomes in men with asymptomatic NCNGU were identified. Two eligible studies report rates of sexually transmitted infections (STIs) in female partners of men with asymptomatic NCNGU; Chlamydia trachomatis was detected in 2.4% and 8.3% of these women. The evidence available is insufficient in quality and breadth to enable us to conclude whether asymptomatic NCNGU is associated with significant health consequences for men or their sexual partners; however, clinical consequences of asymptomatic NCNGU are poorly investigated. Clinicians should be aware of the limitations of the evidence on which current screening guidelines for asymptomatic men are based. PMID- 21680672 TI - Performance of the Euroline Western blot assay in the detection of herpes simplex virus type 2 antibody in Uganda, China and the USA. AB - Herpes simplex virus type 2 (HSV-2) infection is one of the most common sexually transmitted infections (STIs) worldwide. While glycoprotein G-2 enzyme-linked immunosorbent assays are commonly used for the serological detection of HSV-2 antibodies, they have low specificity in developing countries. The Euroline Western blot (WB) is a commercially available assay that is easy to perform; however, little is known about its performance characteristics. This study evaluated Euroline WB for the detection of HSV-2 antibodies compared with University of Washington Western blot in three geographically different regions: Baltimore, MD, USA; Rakai, Uganda; and Kunming, China. Among the 135 American men attending a STI clinic in Baltimore, MD, 72% (n = 97) were HSV-2-positive by Euroline WB, showing a sensitivity of 97.8% and a specificity of 81.8%. Among the 273 commercial sex workers in Kunming, 62.3% were HSV-2-positive by Euroline WB (sensitivity 96.9%, specificity 89.1%). Among the 437 Ugandans in Rakai, 67.3% were HSV-2-positive by Euroline WB (sensitivity 98.7%, specificity 65.4%). The Euroline WB has a consistently high sensitivity, but specificity varied significantly among the different locations. PMID- 21680673 TI - Intimate partner violence and partner notification of sexually transmitted infections among adolescent and young adult family planning clinic patients. AB - Patient-initiated partner notification of sexually transmitted infection (STI), i.e. patients informing their sexual partners of a diagnosis, is a cornerstone of STI prevention. Growing evidence suggests that women exposed to intimate partner violence (IPV) may fear such notification, or face negative consequences in response to STI disclosure. The current study assessed associations of IPV with fear of partner notification, and experiences of partner notification, among adolescent and young adult female family planning clinic patients. Women aged 16 29 years attending five family planning clinics in Northern California, USA (n = 1282) participated in a cross-sectional survey. A history of physical or sexual IPV was associated with fear of partner notification. Moreover, participants exposed to IPV were more likely to have partners say that it was not from them or otherwise accuse them of cheating in response to partner notification. Such partners were less likely to seek indicated STI treatment or testing. Current findings suggest that partner notification for STI may be compromised by IPV. Clinical practices and policies to support effective partner notification should include IPV assessment, and provide mechanisms to address related fears concerning partner notification. PMID- 21680674 TI - Testing the children of HIV-positive mothers. AB - We aimed to establish current practice regarding the testing of children of HIV positive women in two centres in the South Yorkshire HIV Network, UK. Notes were reviewed from 59 women who attended clinic over a three-month period from 01 September 2009 to 30 November 2009. In our sample, only 29 of 52 (56%) children living in the UK who required testing had been HIV tested. Testing rates were high in preschool children (15/15) and fell with age to 2/11 (18%) in the 16-20 years age group. Uptake of testing for children of HIV-positive parents could potentially be improved if testing was incorporated into routine clinic practice as part of the package of care offered to a newly diagnosed individual. PMID- 21680675 TI - Factors associated with a clinician's offer of screening HIV-positive patients for sexually transmitted infections, including syphilis. AB - This retrospective study assessed whether Quality Improvement Scotland national standards for the sexual health care offered to HIV-positive individuals are being met by the Edinburgh genitourinary (GU) medicine clinic; specifically whether HIV-positive patients are offered: (a) sexually transmitted infection (STI) screening annually and (b) syphilis testing six-monthly. The study also reviewed what factors were associated with a clinician's offer of STI screening and syphilis testing. Of the 509 patients seen within the study period, case notes documented that 64% were offered STI screens, and 69% were offered syphilis testing, results consistent with audits of services elsewhere. Sexual orientation (P < 0.0005), relationship status (P = 0.007) and receipt of antiretrovirals (P = 0.001) were independent predictors of clinician offer of STI screening, while gender (P < 0.0005) and receipt of antiretrovirals (P = 0.063) were independent predictors of offer of syphilis testing. Our results suggest that one explanation for clinicians failing to offer STI screens and syphilis serology testing is their (implicit) risk assessment that STI testing is not required in individual patients. PMID- 21680676 TI - Osteomyelitis as the only manifestation of late latent syphilis: case report and literature review. AB - Bone infection, particularly of the skull and the long bones of the legs and arms, despite being a common characteristic of tertiary stage syphilis and congenital syphilis in the past, is seldom encountered clinically due to effective antibiotic therapy. We report a case of a 62-year-old man who presented with one-month acute pain in the left leg. Treponema pallidum particle agglutination test was positive, and radiography showed a pathological fracture of the left tibiofibula. Surgical debridement and biopsy of the bone marrow were performed and a pathological diagnosis of syphilis osteomyelitis was entertained. The patient's symptoms resolved completely after a six-week course of penicillin. We identified 17 previously published cases of bone lesions of syphilis, eight of which had syphilitic osteomyelitis, seven were syphilitic osteitis and two had syphilitic periostitis. We suggest that bone lesions such as osteomyelitis caused by syphilis can be the only manifestation of late latent syphilis. PMID- 21680677 TI - Hereditary angioedema: an unusual cause of genital swelling presenting to a genitourinary medicine clinic. AB - We report a case of a new diagnosis of hereditary angioedema (HAE) presenting with genital swelling to a genitourinary (GU) medicine clinic. There is often a significant delay in diagnosing HAE, but it commonly presents with genital swelling before manifesting as potentially life-threatening visceral attacks. This case highlights the fact that HAE should be considered as an important differential diagnosis of genital oedema, as early recognition may help to prevent more serious future visceral episodes. PMID- 21680678 TI - Raltegravir in pregnancy: a case series presentation. AB - Adequate antiretroviral therapy is essential for HIV-positive pregnant women to prevent mother-to-child transmission. We report a small case series of five women receiving raltegravir as part of their antiretroviral regimen during pregnancy. PMID- 21680679 TI - Can sequential 18F-FDG PET/CT replace WBC imaging in the diabetic foot? AB - White blood cell (WBC) scintigraphy is considered the nuclear medicine imaging gold standard for diagnosing osteomyelitis in the diabetic foot. Recent papers have suggested that the use of (18)F-FDG PET/CT produces similar diagnostic accuracy, but clear interpretation criteria have not yet been established. Our aim was to evaluate the role of sequential (18)F-FDG PET/CT in patients with a high suspicion of osteomyelitis to define objective interpretation criteria to be compared with WBC scintigraphy. METHODS: Thirteen patients whom clinicians considered positive for osteomyelitis (7 with ulcers, 6 with exposed bone) were enrolled. The patients underwent (99m)Tc-exametazime WBC scintigraphy with acquisition times of 30 min, 3 h, and 20 h and sequential (18)F-FDG PET/CT with acquisition times of 10 min, 1 h, and 2 h. A biopsy or tissue culture was performed for final diagnosis. Several interpretation criteria (qualitative and quantitative) were tested. RESULTS: At final biopsy, 7 patients had osteomyelitis, 2 had soft-tissue infection without osteomyelitis, and 4 had no infection. The best interpretation criterion for osteomyelitis with WBC scintigraphy was a target-to-background (T/B) ratio greater than 2.0 at 20 h and increasing with time. A T/B ratio greater than 2.0 at 20 h but stable or decreasing with time was suggestive of soft-tissue infection. A T/B ratio of no more than 2.0 at 20 h excluded an infection. Thus, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for osteomyelitis were 86%, 100%, 100%, 86%, and 92%, respectively. For (18)F-FDG PET/CT, the best interpretation criterion for osteomyelitis was a maximal standardized uptake value (SUVmax) greater than 2.0 at 1 and 2 h and increasing with time. A SUVmax greater than 2.0 after 1 and 2 h but stable or decreasing with time was suggestive of a soft-tissue infection. An SUVmax less than 2.0 excluded an infection. (18)F-FDG PET at 10 min was not useful. Using these criteria, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for osteomyelitis were 43%, 67%, 60%, 50%, and 54%, respectively. Combining visual assessment of PET at 1 h and CT was best for differentiating between osteomyelitis and soft-tissue infection, with a diagnostic accuracy of 62%. CONCLUSION: (18)F-FDG PET/CT, even with sequential imaging, has a low diagnostic accuracy for osteomyelitis and cannot replace WBC scintigraphy in patients with diabetic foot. PMID- 21680680 TI - 177Lu-DOTATATE molecular radiotherapy for childhood neuroblastoma. AB - This study tested the principle that (68)Ga-DOTATATE PET/CT may be used to select children with primary refractory or relapsed high-risk neuroblastoma for treatment with (177)Lu-DOTATATE and evaluated whether this is a viable therapeutic option for those children. METHODS: Between 2008 and 2010, 8 children with relapsed or refractory high-risk neuroblastoma were studied with (68)Ga DOTATATE PET/CT. The criterion of eligibility for (177)Lu-DOTATATE therapy was uptake on the diagnostic scan equal to or higher than that of the liver. RESULTS: Of the 8 children imaged, 6 had abnormally high uptake on the (68)Ga-DOTATATE PET/CT scan and proceeded to treatment. Patients received 2 or 3 administrations of (177)Lu-DOTATATE at a median interval of 9 wk and a median administered activity of 7.3 GBq. Of the 6 children treated, 5 had stable disease by the response evaluation criteria in solid tumors (RECIST). Of these 5 children, 2 had an initial metabolic response and reduction in the size of their lesions, and 1 patient had a persistent partial metabolic response and reduction in size of the lesions on CT, although the disease was stable by RECIST. One had progressive disease. Three children had grade 3 and 1 child had grade 4 thrombocytopenia. No significant renal toxicity has been seen. CONCLUSION: (68)Ga-DOTATATE can be used to image children with neuroblastoma and identify those suitable for molecular radiotherapy with (177)Lu-DOTATATE. We have shown, for what is to our knowledge the first time, that treatment with (177)Lu-DOTATATE is safe and feasible in children with relapsed or primary refractory high-risk neuroblastoma. We plan to evaluate this approach formally in a phase I-II clinical trial. PMID- 21680681 TI - Noninvasive nuclear imaging enables the in vivo quantification of striatal dopamine receptor expression and raclopride affinity in mice. AB - The increasing use of genetically engineered mice as animal models of human disease in biomedical research, latest advances in imaging technologies, and development of novel, highly specific radiolabeled biomarkers provide great potential to study receptor expression and gene function in vivo in mice. (11)C raclopride is a widely used PET tracer to measure striatal D(2) receptor binding and was used to test the feasibility of the multiple-ligand-concentration receptor assay for D(2) receptor quantification. METHODS: Mice underwent a total of 4 scans with decreasing specific activities from 141 to 0.4 GBq/MUmol, corresponding to (11)C-raclopride injected doses of 2.4 to 1,274 nmol/kg, using either a standard bolus injection protocol (n = 12) or a bolus-plus-constant infusion protocol to attain true equilibrium conditions (n = 7). Receptor occupancy was plotted as a function of raclopride dose, and D(2) receptor density and raclopride affinity were calculated using linear and nonlinear regression analysis, respectively. In addition, we used ex vivo autoradiography, a more spatially accurate imaging technology, to validate the in vivo PET measurements, and we performed test-retest experiments to determine the reproducibility and reliability of the PET-derived measures. RESULTS: The receptor occupancy curves showed that an injected tracer dose of 4.5 nmol/kg induces approximately 10% receptor occupancy, whereas 1% receptor occupancy will be achieved at tracer doses of approximately 0.45 nmol/kg. Using the bolus injection protocol and nonlinear regression analysis, we determined that the average D(2) receptor density was 9.6 +/- 1.1 pmol/mL, and the apparent raclopride affinity was 5.0 +/- 0.6 pmol/mL. These values agreed well with those obtained at true equilibrium conditions. In contrast, linear Scatchard analysis did not lead to the expected linear relationship because nonsaturable binding was observed at high raclopride concentrations, and thus, it seems to be unsuitable for quantitative (11)C raclopride analysis in mice. CONCLUSION: Our data showed that the tracer mass, if higher than 4 nmol/kg, can strongly affect binding parameter estimations and must be considered when performing kinetic analysis, specifically in mice. We also demonstrated that the in vivo determination of D(2) receptor density and raclopride affinity is feasible in mice using multiple-injection protocols and nonlinear regression analysis. PMID- 21680682 TI - The need for a low-expense universally acceptable rhTSH protocol. PMID- 21680683 TI - A PET brain reporter gene system based on type 2 cannabinoid receptors. AB - PET of gene expression in the brain may greatly facilitate neuroscience research and potential clinical implementation of gene or cell therapy of central nervous system diseases. To date, no adequate PET reporter system is available for the central nervous system because available tracers either do not cross the intact blood-brain barrier or have high background signals. Here we report the first, to our knowledge, PET reporter system for imaging gene expression in the intact brain. METHODS: We selected the human type 2 cannabinoid receptor (hCB(2)) as a reporter because of its low basal expression in the brain. An inactive mutant (D80N) was chosen so as not to interfere with signal transduction. As a reporter probe we used the (11)C-labeled CB(2) ligand, (11)C-GW405833, which readily crosses the blood-brain barrier. Dual-modality imaging lentiviral and adeno associated viral vectors encoding both hCB(2)(D80N) and firefly luciferase or enhanced green fluorescent protein were engineered and validated in cell culture. Next, hCB(2)(D80N) was locoregionally overexpressed in rat striatum by stereotactic injection of lentiviral and adeno-associated viral vectors. RESULTS: Kinetic PET revealed specific and reversible CB(2) binding of (11)C-GW405833 in the transduced rat striatum. hCB(2) and firefly luciferase expression was followed until 9 mo and showed similar kinetics. Both hCB(2) expression and enhanced green fluorescent protein expression were confirmed by immunohistochemistry. CONCLUSION: Dual-modality imaging viral vectors encoding hCB(2)(D80N) were engineered, and the reporter system was validated in different animal species. The results support the potential future clinical use of CB(2) as a PET reporter in the intact brain. PMID- 21680684 TI - Evaluation of optimal acquisition duration or injected activity for pediatric 18F FDG PET/CT. AB - Pediatric (18)F-FDG dosing and acquisition durations are generally based on coarse extrapolation from adult guidelines. This study sought to determine whether shorter acquisition durations or a lower (18)F-FDG injected activity could be used for pediatric (18)F-FDG PET/CT examinations while maintaining diagnostic utility. Reduction of overall scan time potentially reduces motion artifacts, improves patient comfort, and decreases length of sedation. Alternatively, decreased (18)F-FDG dose minimizes radiation risk. METHODS: Fourteen whole-body (18)F-FDG PET/CT examinations were performed on 13 patients (weight, 13-109 kg; age range, 1-23 y) with a weight-based injected activity (5.3 MBq/kg [0.144 mCi/kg]), fixed acquisition durations (3 min/field of view [FOV] if < 22 kg, 5 min/FOV if > 22 kg), and list-mode acquisition. For each examination, the list-mode data were truncated to form multiple datasets with shorter acquisition durations down to a minimum of 1 min/FOV (i.e., 1, 2, 3, 4, and 5 min/FOV data were formed from single 5 min/FOV acquisition). Fifty-six image volumes were generated, randomized, and reviewed in a masked manner with corresponding CT image volumes by 5 radiologists. Overall, subjective adequacy and objective lesion detection accuracy by body region were evaluated. RESULTS: All examinations with maximum acquisition duration were graded as adequate and were used as the reference standard for detection accuracy. For patients less than 22 kg, 1 of the 3 PET/CT examinations was graded as inadequate for clinical tasks when acquisition duration was reduced to 2 min/FOV, and all examinations were graded as inadequate when reduced to 1 min/FOV. For patients more than 22 kg, all 3-5 min/FOV studies were graded as adequate, and 2 of the 9 studies were graded as inadequate for 2 min/FOV studies. Lesion detection accuracy was perfect for acquisition times between 3 min/FOV and 5 min/FOV for all regions of the body. However, lesion detection became less accurate when imaging acquisition time was reduced more than 40%. CONCLUSION: Evaluation of image volumes generated from simulated shorter acquisition durations suggests that imaging times for larger patients (>22 kg) can be reduced from 5 min/FOV to 3 min/FOV without a loss of diagnostic utility. Using decreased acquisition times as a surrogate for (18)F-FDG dose, (18)F-FDG dose can be reduced by approximately 40% when all patients were scanned for 5 min/FOV. PMID- 21680685 TI - Hepatic blood perfusion measured by 3-minute dynamic 18F-FDG PET in pigs. AB - There is an unmet clinical need for an imaging method for quantification of hepatic blood perfusion. The purpose of the present study was to develop and validate a PET method using blood-to-cell clearance (K(1)) of (18)F-FDG, 3-O (11)C-methylglucose ((11)C-MG), or 2-(18)F-fluoro-2-deoxy-D-galactose ((18)F FDGal) as a measure of hepatic blood perfusion without the need for portal venous blood samples. We aimed to make the method as simple as possible with the prospect of future application to clinical studies. For this purpose, we examined the possibility of using a 3-min data acquisition and a model-derived dual input calculated from measurements of radioactivity concentrations in a peripheral artery. METHODS: Pigs (40 kg) underwent dynamic PET of the liver with (18)F-FDG, (11)C-MG, or (18)F-FDGal with simultaneous measurements of time-activity curves in blood sampled from a femoral artery and the portal vein (PV); blood flow rates were measured in the hepatic artery (HA) and PV by transit-time flow meters. Two input functions were compared: A measured dual input and a model-derived dual input, the latter with the PV time-activity curve estimated from the measured arterial time-activity curve and a previously validated 1-parametric PV model. (K(1)) was estimated for each tracer by fitting compartmental models to the data, comparing 3-min and 60-min data acquisitions and the 2 dual-input time-activity curves. RESULTS: Agreement between (K(1)) estimated using the measured and the model-derived dual input was good for all 3 tracers. For (18)F-FDG and (11)C-MG, (K(1)) (3-min data acquisition, model-derived dual input, and 1-tissue compartmental model) correlated to the measured blood perfusion (P = 0.01 and P = 0.07, respectively). For (18)F-FDGal, the correlation was not significant. CONCLUSION: A simplified method for quantification of hepatic blood perfusion using 3-min dynamic (18)F-FDG PET or (11)C-MG PET with blood sampling from only a peripheral artery was developed. Parametric (K(1)) images were constructed and showed homogeneous blood perfusion in these normal livers. PMID- 21680686 TI - Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study. AB - Formation and progression of atherosclerotic plaque is a dynamic and complex process involving various pathophysiologic steps including inflammation and calcification. The purpose of this study was to compare macrophage activity as determined by (18)F-FDG PET and ongoing mineral deposition as measured by (18)F sodium fluoride PET in atherosclerotic plaque and to correlate these findings with calcified plaque burden as assessed by CT. METHODS: Forty-five patients were examined by whole-body (18)F-FDG PET, (18)F-sodium fluoride PET, and CT. Tracer uptake in various arterial segments was analyzed both qualitatively and semiquantitatively by measuring the blood-pool-corrected standardized uptake value (target-to-background ratio [TBR]). The pattern of tracer uptake in atherosclerotic lesions was compared after color-coded multistudy image fusion of PET and CT studies. The Fisher exact test and the Spearman correlation coefficient r(s) were used for statistical analysis of image-based results and cardiovascular risk factors. Intra- and interrater reproducibility were evaluated using the Cohen kappa. RESULTS: (18)F-sodium fluoride uptake was observed at 105 sites in 27 (60%) of the 45 study patients, and mean TBR was 2.3 +/- 0.7. (18)F FDG uptake was seen at 124 sites in 34 (75.6%) patients, and mean TBR was 1.5 +/- 0.3. Calcified atherosclerotic lesions were observed at 503 sites in 34 (75.6%) patients. Eighty-one (77.1%) of the 105 lesions with marked (18)F-sodium fluoride uptake and only 18 (14.5%) of the 124 lesions with (18)F-FDG accumulation were colocalized with arterial calcification. Coincident uptake of both (18)F-sodium fluoride and (18)F-FDG was observed in only 14 (6.5%) of the 215 arterial lesions with radiotracer accumulation. CONCLUSION: PET/CT with (18)F-FDG and (18)F-sodium fluoride may allow evaluation of distinct pathophysiologic processes in atherosclerotic lesions and might provide information on the complex interactions involved in formation and progression of atherosclerotic plaque. PMID- 21680687 TI - 18F-FDG PET in pregnancy and fetal radiation dose estimates. AB - The purpose of this study was to estimate the fetal radiation exposure resulting from (18)F-FDG PET procedures performed in pregnant patients with malignancies. METHODS: Five pregnant patients with a biopsy-proven diagnosis of malignancy who underwent (18)F-FDG PET studies were retrospectively reviewed. All patients underwent PET-only studies (and not PET/CT studies) with a reduced (18)F-FDG dose (except for 1 patient who had a negative pregnancy test immediately before the (18)F-FDG PET procedure but was confirmed to be pregnant a few weeks later), including vigorous hydration and diuresis to minimize radiation exposure to the fetus. One patient underwent (18)F-FDG PET twice during her pregnancy (in the second and third trimesters). Fetal radiation dose was independently assessed for each patient, and an analysis was made of fetal radiation doses using the measurements of activity in the fetuses at various stages of pregnancy. RESULTS: Six (18)F-FDG PET studies in 5 pregnant patients were analyzed. The (18)F-FDG PET scans were obtained in early pregnancy (n = 1), the second trimester (n = 2), and the third trimester (n = 3). The fetal dose exposure from (18)F-FDG PET studies was estimated to range from 1.1 to 2.43 mGy for various trimesters in pregnancy (except for the patient in the early stage of pregnancy, in whom activity in the whole uterus was considered, and the fetal dose was estimated to be 9.04 mGy). All patients delivered healthy infants with no visible abnormalities at term. CONCLUSION: The fetal radiation dose from (18)F-FDG PET studies is quite low and significantly below the threshold dose for deterministic effects due to radiation exposure to the fetus. The estimated fetal radiation exposure in our cases was slightly lower than existing estimates on fetal dose exposure, and as more data become available, the current fetal dose estimates may have to be modified accordingly. By addressing an important safety issue dealing with performing medically necessary (18)F-FDG PET in pregnant patients, these data are expected to help in the imaging workup of cancer patients during pregnancy. PMID- 21680688 TI - Role of glutamine in cancer: therapeutic and imaging implications. AB - Metabolic imaging has great clinical potential in cancer because perturbations of metabolism are common hallmarks of malignant cellular transformation. Novel imaging strategies focused on glutamine could provide a valuable complement to (18)F-FDG PET, because glutamine complements glucose in the metabolic platforms that support tumor growth at the cellular level. Furthermore, recent work has demonstrated that distinct aspects of glutamine metabolism are under the control of oncogenes and tumor suppressors. It is plausible that imaging glutamine metabolism could predict both the presence of specific transforming mutations in the tumor and the sensitivity to therapeutic agents designed to target glutamine use. Here, we review the essential aspects of glutamine metabolism in cancer cells and discuss opportunities for imaging in cancer patients. PMID- 21680689 TI - SEP-225289 serotonin and dopamine transporter occupancy: a PET study. AB - SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. METHODS: Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP 225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2beta carbomethoxy-3beta-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl 2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. RESULTS: Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% +/- 11% and 2% +/- 13%, respectively, for 8 mg; 44% +/- 4% and 9% +/- 10%, respectively, for 12 mg; and 49% +/- 7% and 14% +/- 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. CONCLUSION: At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about indication, dose, and therapeutic potential. PMID- 21680690 TI - Mapping of lymphatic drainage from the prostate using filtered 99mTc-sulfur nanocolloid and SPECT/CT. AB - We have developed a practice procedure for prostate lymphoscintigraphy using SPECT/CT and filtered (99m)Tc-sulfur nanocolloid, as an alternative to the proprietary product (99m)Tc-Nanocoll, which is not approved in the United States. METHODS: Ten patients were enrolled for this study, and all received radiotracer prepared using a 100-nm membrane filter at a commercial radiopharmacy. Whole-body scans and SPECT/CT studies were performed within 1.5-3 h after the radiotracer had been administered directly into 6 locations of the prostate gland under transrectal ultrasound guidance. The radiation dose was estimated from the first 3 patients. Lymphatic drainage mapping was performed, and lymph nodes were identified. RESULTS: The estimated radiation dose ranged from 3.9 to 5.2 mSv/MBq. The locations of lymph nodes draining the prostate gland were similar to those found using the proprietary product. CONCLUSION: When the proprietary radiolabeled nanocolloid indicated for lymphoscintigraphy is not available, prostate lymph node mapping and identification are still feasible using filtered (99m)Tc-sulfur nanocolloid. PMID- 21680691 TI - 123I-MIP-1072, a small-molecule inhibitor of prostate-specific membrane antigen, is effective at monitoring tumor response to taxane therapy. AB - Because traditional endpoints in oncology trials are not always applicable for metastatic prostate cancer, better ways of following response to treatment are needed. Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in normal human prostate epithelium and is upregulated in prostate cancer. (S)-2-(3-((S)-1-carboxy-5-((4-(123)I iodobenzyl)amino)pentyl)ureido)pentanedioic acid, (123)I-MIP-1072, targets PSMA and was evaluated for monitoring the growth of PSMA-positive LNCaP cells in vitro and as xenografts after paclitaxel therapy. METHODS: LNCaP and 22Rv1 cells were treated with paclitaxel (0-100 nM) for 48 h, after which binding of (123)I-MIP 1072 was examined. Cell number was determined by MTS assay, and PSMA expression was analyzed by Western blotting. LNCaP xenograft-bearing mice were treated with paclitaxel (6.25 mg/kg) for 3.5 cycles of 5 d on and 2 d off. Tissue distribution of (123)I-MIP-1072 was determined on days 2 and 23 from the start of paclitaxel treatment. RESULTS: Paclitaxel (10-100 nM) inhibited LNCaP and 22Rv1 cell growth after 48 h, and binding of (123)I-MIP-1072 was proportional to cell number. Western blot analysis verified there was no paclitaxel-dependent change in PSMA expression. Treatment of LNCaP xenografts with paclitaxel resulted in a decrease in tumor volume (-21%), compared with an increase in the untreated xenografts (+205%) by day 23. Tumor uptake of (123)I-MIP-1072 was proportional to changes in tumor mass: decreased by paclitaxel treatment and increased in untreated mice. CONCLUSION: Treatment of LNCaP cells or xenograft tumors with paclitaxel resulted in growth inhibition, which was detected with (123)I-MIP-1072. The high specificity of (123)I-MIP-1072 for prostate cancer may allow monitoring of tumor progression in patients before, during, and after chemotherapy. PMID- 21680692 TI - Correlation of 18F-FDG uptake with apparent diffusion coefficient ratio measured on standard and high b value diffusion MRI in head and neck cancer. AB - Although the clinical applications of (18)F-FDG PET/CT and diffusion-weighted MRI (DWI) are similar to each other in head and neck cancer, the image acquisition methods in the 2 modalities are significantly different. (18)F-FDG PET/CT traces glucose metabolism, a nonspecific process essential for tumor growth. On the other hand, DWI provides information on Brownian motion of water molecules in tissues, which represents cellularity. The aim of our study was to investigate whether apparent diffusion coefficient (ADC) values at b = 1,000 (ADC(1,000)) and 2,000 (ADC(2,000)) s/mm(2) or whether the change (ADC(ratio)) of ADC values from b = 1,000 to 2,000 s/mm(2) has any significant correlation with the standardized uptake value (SUV) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Our hospital's institutional review board approved this retrospective study. We included 47 patients (32 men and 15 women) with histopathologically proven HNSCC, who underwent both DWI (at both b = 1,000 s/mm(2) and b = 2,000 s/mm(2)) and (18)F-FDG PET/CT in the 2 wk before treatment. ADC(ratio) maps were generated using a pixel-by-pixel computation for which ADC(ratio) is (ADC(2,000)/ADC(1,000)) * 100. The mean ADC(1,000), ADC(2,000), and ADC(ratio) values were evaluated within a manually placed polygonal region of interest within the main tumor on every slice of the ADC(1,000), ADC(2,000), and ADC(ratio) maps, respectively. In addition, the maximal SUV (SUV(max)) and mean SUV (SUV(mean)) were measured for the entire tumor region of interest. Comparisons were made using Pearson correlation analysis, and partial correlation coefficients were derived. RESULTS: No significant correlation was found between the mean ADC(1,000) and SUV(mean) (r = -0.222, P = 0.1325) or the mean ADC(2,000) and SUV(mean) (r = -0.1214, P = 0.4163). However, the ADC(ratio) was significantly and positively correlated to both the SUV(mean) (r = 0.667, P < 0.001) and SUV(max) (r = 0.5855, P < 0.001). CONCLUSION: The ADC(ratio) and SUV were significantly correlated with each other in primary HNSCC patients, possibly because of a higher-cellularity region as a result of relatively increased tumor proliferation. Further studies are warranted to investigate the possible complementary role of DWI and PET/CT in various clinical settings, including staging and treatment response. PMID- 21680693 TI - Significance of oral administration of sodium perchlorate in planning liver directed radioembolization. AB - (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) scanning precedes radioembolization of the liver to detect extrahepatic shunting to the lung or gastrointestinal tract. Despite strict preventive measures in the production of (99m)Tc-MAA and in scanning protocols, the images frequently show a gastric concentration of free (99m)Tc-pertechnetate, hindering accurate evaluation of the gastroduodenal region. Our aim was to evaluate whether oral administration of sodium perchlorate (NaClO(4)) before (99m)Tc-MAA scanning will improve its accuracy by blocking free (99m)Tc-pertechnetate gastric uptake. METHODS: In 144 patients, 171 diagnostic hepatic angiograms combined with a (99m)Tc-MAA scan were performed; 86 angiograms were performed after oral administration of NaClO(4), and 85 were performed without this premedication. Clinical follow-up, esophagogastroduodenoscopy, and angiography served as reference standards. RESULTS: (99m)Tc-MAA studies showed tracer uptake in the gastric region of 25 patients who did not receive NaClO(4). The uptake was interpreted as a free (99m)Tc-pertechnetate concentration in 21 studies and as a (99m)Tc-MAA accumulation in 4 studies. In 5 patients with a free (99m)Tc-pertechnetate concentration, aberrant vessels were detected in angiographic reexamination, and 3 patients developed gastrointestinal ulcer. In 7 studies, gastric findings viewed pretherapeutically as free (99m)Tc-pertechnetate were retrospectively classified as equivocal. Of the patients receiving NaClO(4), 2 showed gastric accumulation of (99m)Tc-MAA but no equivocal or free (99m)Tc pertechnetate. Oral administration of NaClO(4) increased the negative predictive value and accuracy of the test concerning the detection of gastric perfusion from 68% and 69%, respectively, to 93% and 94%, respectively. CONCLUSION: Oral administration of NaClO(4) before the test angiogram with (99m)Tc-MAA resulted in effective avoidance of free (99m)Tc-pertechnetate concentration and, consequently, of equivocal findings in the gastroduodenal region. This technique increased test accuracy and reporter confidence, saved time in reviewing the angiograms, and can improve treatment planning and reduce therapeutic side effects. PMID- 21680694 TI - Metastatic renal cell carcinoma: relationship between initial metastasis hypoxia, change after 1 month's sunitinib, and therapeutic response: an 18F fluoromisonidazole PET/CT study. AB - The aims of this cohort study were to evaluate initial tumor hypoxia in metastatic renal cell carcinoma (mRCC) and its changes after sunitinib treatment, using (18)F-fluoromisonidazole PET/CT, and investigate the possible prognostic value of initial tumor hypoxia or its changes under sunitinib therapy. METHODS: Antiangiogenic-naive patients with mRCC were prospectively enrolled in this cohort study. Before initiation of sunitinib, CT defined up to 10 targets that were assessed at 1 and 6 mo according to the response evaluation criteria in solid tumors (RECIST). Pretreatment target uptake of (18)F-fluoromisonidazole was compared with uptake at 1 mo. Targets were considered hypoxic when their maximal standard uptake value was above mean blood value + 2 SDs. Hypoxic volumes were also computed. Relationships between initial hypoxia status, initial degree of hypoxia, its change at 1 mo, and overall or progression-free survival (OS and PFS, respectively) were assessed by survival analysis. RESULTS: Fifty-three patients were included. Median follow-up was 16.8 mo. (18)F-fluoromisonidazole uptake significantly decreased in initially hypoxic target metastases but did not change in others (-22%, P < 10(-4), vs. +1.5%, P = 0.77; P = 10(-3) between groups). Seventy-five percent of patients with hypoxic metastases were free of progressive disease at 4.8 mo (95% confidence interval, 2.99-11.83), compared with 11.3 mo (95% confidence interval, 3.08-36.9) for other patients (P = 0.02), whereas OS was not significantly different. Changes in tumor hypoxia were not related to PFS or OS. CONCLUSION: Sunitinib reduced hypoxia in initially hypoxic RECIST target metastases but did not induce significant hypoxia in nonhypoxic RECIST target metastases. Patients with initially hypoxic targets have shorter PFS than others. PMID- 21680695 TI - 18F-FDG and diabetic foot infections: the verdict is... PMID- 21680696 TI - Glucagon-like peptide-1 versus somatostatin receptor targeting reveals 2 distinct forms of malignant insulinomas. AB - Glucagon-like peptide-1 (GLP-1) receptor imaging is superior to somatostatin receptor subtype 2 (sst(2)) imaging in localizing benign insulinomas. Here, the role of GLP-1 and sst(2) receptor imaging in the management of malignant insulinoma patients was investigated. METHODS: Eleven patients with malignant insulinoma were prospectively included. (111)In-[Lys(40)(Ahx diethylenetriaminepentaacetic acid [DTPA])NH(2)]-exendin-4 SPECT/CT, (68)Ga- DOTATATE PET/CT, and in vitro receptor autoradiography were performed to assess the receptor status and to evaluate the detection rate. RESULTS: GLP-1 receptor targeting was positive in 4 of 11 patients, and sst(2) receptor expression was positive in 8 of 11. In only 1 patient were both receptors expressed. In 1 patient, GLP-1 receptor imaging was the only method that successfully localized the primary tumor in the pancreas. In 3 patients with sst(2)-expressing tumors, DOTATATE radiotherapy was effectively applied. CONCLUSION: As opposed to benign insulinomas, malignant insulinomas often lack GLP-1 receptors. Conversely, malignant insulinomas often express sst(2), which can be targeted therapeutically. PMID- 21680697 TI - 18F-Fallypride PET of pancreatic islets: in vitro and in vivo rodent studies. AB - Islet cell loss in the pancreas results in diabetes. A noninvasive method that measures islet cell loss and also tracks the fate of transplanted islets would facilitate the development of novel therapeutics and improve the management of diabetes. We describe a novel dopamine D(2)/D(3) receptor (D(2)/D(3)R)-based PET method to study islet cells in the rat pancreas and in islet cell transplantation. METHODS: (18)F-fallypride binding to isolated rat islets and pancreas was evaluated in the absence and presence of the D(2)/D(3)R inhibitor haloperidol. After intravenous (18)F-fallypride (28-37 MBq) administration, normal rats and rats pretreated with haloperidol were imaged in a PET/CT scanner and subsequently studied ex vivo for (18)F-fallypride localization in the pancreas. A streptozotocin-treated diabetic rat model was used to study localization of (18)F-fallypride in the pancreas, in vitro and ex vivo. Rat islet cells were transplanted into the spleen and visualized using (18)F-fallypride PET. RESULTS: (18)F-fallypride bound to isolated islet cells and pancreatic sections with an endocrine or exocrine selectivity of approximately 4; selectivity was reduced by haloperidol, suggesting that binding was D(2)/D(3)R specific. Chemical destruction of islets by streptozotocin decreased (18)F fallypride binding in pancreas by greater than 50%, paralleling the decrease in insulin immunostaining. Uptake of (18)F-fallypride in the pancreas was confirmed by radiochromatography and was 0.05% injected dose/cm(3) as measured by PET/CT. The ratio of (18)F-fallypride uptake in the pancreas to reference tissue (erector spinae muscle) was 5.5. Rat islets transplanted into the spleen were visualized in vivo by (18)F-fallypride and confirmed by immunostaining. The ratio of spleen transplanted islets to erector spinae muscle was greater than 5, compared with a ratio of 2.8 in untransplanted rats. CONCLUSION: These studies demonstrate the potential utility of (18)F-fallypride as a PET agent for islet cells. PMID- 21680698 TI - In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester. AB - Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process. METHODS: To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically. RESULTS: Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages. CONCLUSION: We have identified (11)C ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders. PMID- 21680699 TI - RADAR commentary: Evolution and current status of dosimetry in nuclear medicine. PMID- 21680700 TI - Myocardial perfusion imaging versus CT coronary angiography: when to use which? AB - Both anatomy- and physiology-based approaches to patient management have advantages and limitations. Compared with the latter, the former has a superior ability to exclude disease and does not miss high-risk coronary artery disease (CAD). However, it is limited by a possibility of overestimating the severity of CAD and of potentially failing to determine which posttest therapeutic approach optimizes treatment benefit. On the other hand, although a physiology-based approach could potentially identify optimal therapeutic strategies, the possibility of both false-positive and false-negative findings is a concern. This review incorporates some of the more recent advances in CT coronary angiography and myocardial perfusion imaging (MPI), including PET MPI, into a discussion of anatomic versus physiologic imaging and provides our perspective on how an anatomy-based testing strategy centered in CT coronary angiography versus a physiology-based testing strategy with MPI may be clinically used for the evaluation of known or suspected CAD in symptomatic patients. PMID- 21680701 TI - PET of somatostatin receptor-positive tumors using 64Cu- and 68Ga-somatostatin antagonists: the chelate makes the difference. AB - Somatostatin-based radiolabeled peptides have been successfully introduced into the clinic for targeted imaging and radionuclide therapy of somatostatin receptor (sst)-positive tumors, especially of subtype 2 (sst2). The clinically used peptides are exclusively agonists. Recently, we showed that radiolabeled antagonists may be preferable to agonists because they showed better pharmacokinetics, including higher tumor uptake. Factors determining the performance of radioantagonists have only scarcely been studied. Here, we report on the development and evaluation of four (64)Cu or (68)Ga radioantagonists for PET of sst2-positive tumors. METHODS: The novel antagonist p-Cl-Phe-cyclo(D-Cys Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH(2) (LM3) was coupled to 3 macrocyclic chelators, namely 4,11-bis(carboxymethyl)-1,4,8,11 tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), and DOTA. (64/nat)Cu- and (68/nat)Ga-NODAGA-LM3 were prepared at room temperature, and (64/nat)Cu-CB-TE2A-LM3 and (68/nat)Ga-DOTA LM3 were prepared at 95 degrees C. Binding affinity and antagonistic properties were determined with receptor autoradiography and immunofluorescence microscopy using human embryonic kidney (HEK)-sst2 cells. In vitro internalization and dissociation was evaluated using the same cell line. Biodistribution and small animal PET studies were performed with HEK-sst2 xenografts. RESULTS: All metallopeptides demonstrated antagonistic properties. The affinities depend on chelator and radiometal and vary about 10-fold; (68/nat)Ga-NODAGA-LM3 has the lowest half maximal inhibitory concentration (1.3 +/- 0.3 nmol/L). The biodistribution studies show impressive tumor uptake at 1 h after injection, particularly of (64)Cu- and (68)Ga-NODAGA-LM3 (~40 percentage injected dose per gram of tissue [%ID/g]), which were proven to be specific. Background clearance was fast and the tumor washout relatively slow for (64)Cu-NODAGA-LM3 (~15 %ID/g, 24 h after injection) and almost negligible for (64)Cu-CB-TE2A-LM3 (26.9 +/- 3.3 %ID/g and 21.6 +/- 2.1 %ID/g, 4 and 24 h after injection, respectively). Tumor-to normal-tissue ratios were significantly higher for (64)Cu-NODAGA-LM3 than for (64)Cu-CB-TE2A-LM3 (tumor-to-kidney, 12.8 +/- 3.6 and 1.7 +/- 0.3, respectively; tumor-to-muscle, 1,342 +/- 115 and 75.2 +/- 8.5, respectively, at 24 h, P < 0.001). Small-animal PET shows clear tumor localization and high image contrast, especially for (64)Cu- and (68)Ga-NODAGA-LM3. CONCLUSION: This article demonstrates the strong dependence of the affinity and pharmacokinetics of the somatostatin-based radioantagonists on the chelator and radiometal. (64)Cu- and (68)Ga-NODAGA-LM3 and (64)Cu-CB-TE2A-LM3 are promising candidates for clinical translation because of their favorable pharmacokinetics and the high image contrast on PET scans. PMID- 21680702 TI - Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases--safety, pharmacokinetics, and pharmacodynamics. AB - The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 +/- 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility. PMID- 21680703 TI - Protective effects of prepubertal genistein exposure on mammary tumorigenesis are dependent on BRCA1 expression. AB - This study investigated whether prepubertal dietary exposure to genistein reduces mammary tumorigenesis by upregulating Brca1 expression in mice. Heterozygous Brca1(+/-) mice and their wild-type (WT) littermates were fed control AIN93G diet or 500 ppm genistein-supplemented AIN93G diet from postnatal day (PND) 15 to PND30 and then switched to AIN93G diet. Prepubertal dietary exposure to genistein reduced 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary incidence (P = 0.029) and aggressiveness of the tumors (P < 0.001) in the WT mice and upregulated the expression of Brca1 in their mammary glands (P = 0.04). In contrast, prepubertal genistein diet neither significantly reduced mammary tumorigenesis or tumor aggressivity nor increased Brca1 mRNA expression in the Brca1(+/-) mice. These results may be related to the opposing effects of prepubertal genistein diet on the expression of Rankl and CK5/CK18 ratio (marker of luminal epithelial cell differentiation) in the mammary gland and estrogen receptor (ER-alpha) and progesterone receptor (PgR) protein levels in the mammary tumor: these all were reduced in the WT mice or increased in Brca1(+/-) mice. Both the WT and Brca1(+/-) mice exhibited reduced levels of amphiregulin, CK5, and CK18, delayed ductal elongation and a reduction in terminal end bud number in the normal mammary gland, and reduced HER-2 protein levels in the mammary tumors; however, these effects were not sufficient to significantly reduce mammary tumorigenesis in Brca1(+/-) mice. Our results show that upregulation of Brca1 may be required for prepubertal dietary genistein exposure to reduce later mammary tumorigenesis, perhaps because in the absence of this upregulation, mice do not exhibit genistein-induced downregulation of ER-alpha, PgR, and Rankl. PMID- 21680704 TI - Inactivation of AR/TMPRSS2-ERG/Wnt signaling networks attenuates the aggressive behavior of prostate cancer cells. AB - The development of prostate cancer and its progression to castrate-resistant prostate cancer (CRPC) after antiandrogen ablation therapy are driven by persistent biological activity of androgen receptor (AR) signaling. Moreover, studies have shown that more than 50% of human prostate cancers overexpress ERG (v-ets avian erythroblastosis virus E26 oncogene related gene) due to AR regulated TMPRSS2-ERG fusion gene. However, the reported roles of TMPRSS2-ERG fusion in cancer progression are not clear. In this study, we investigated the signal transduction in the AR/TMPRSS2-ERG/Wnt signaling network for studying the aggressive behavior of prostate cancer cells and further assessed the effects of BR-DIM and CDF [natural agents-derived synthetic formulation and analogue of 3,3' diindolylmethane (DIM) and curcumin, respectively, with improved bioavailability] on the regulation of AR/TMPRSS2-ERG/Wnt signaling. We found that activation of AR resulted in the induction of ERG expression through TMPRSS2-ERG fusion. Moreover, we found that ERG overexpression and nuclear translocation activated the activity of Wnt signaling. Furthermore, forced overexpression of ERG promoted invasive capacity of prostate cancer cells. More important, we found that BR-DIM and CDF inhibited the signal transduction in the AR/TMPRSS2-ERG/Wnt signaling network, leading to the inactivation of Wnt signaling consistent with inhibition of prostate cancer cell invasion. In addition, BR-DIM and CDF inhibited proliferation of prostate cancer cells and induced apoptotic cell death. On the basis of our findings, we conclude that because BR-DIM and CDF downregulate multiple signaling pathways including AR/TMPRSS2-ERG/Wnt signaling, these agents could be useful for designing novel strategies for the prevention and/or treatment of prostate cancer. PMID- 21680705 TI - 17beta-estradiol and tamoxifen prevent gastric cancer by modulating leukocyte recruitment and oncogenic pathways in Helicobacter pylori-infected INS-GAS male mice. AB - Helicobacter pylori infection promotes male predominant gastric adenocarcinoma in humans. Estrogens reduce gastric cancer risk and previous studies showed that prophylactic 17beta-estradiol (E2) in INS-GAS mice decreases H. pylori-induced carcinogenesis. We examined the effect of E2 and tamoxifen (TAM) on H. pylori induced gastric cancer in male and female INS-GAS mice. After confirming robust gastric pathology at 16 weeks postinfection (WPI), mice were implanted with E2, TAM, both E2 and TAM, or placebo pellets for 12 weeks. At 28 WPI, gastric histopathology, gene expression, and immune cell infiltration were evaluated and serum inflammatory cytokines measured. After treatment, no gastric cancer was observed in H. pylori-infected males receiving E2 and/or TAM, whereas 40% of infected untreated males developed gastric cancer. E2, TAM, and their combination significantly reduced gastric precancerous lesions in infected males compared with infected untreated males (P < 0.001, 0.01, and 0.01, respectively). However, TAM did not alter female pathology regardless of infection status. Differentially expressed genes from males treated with E2 or TAM (n = 363 and n = 144, Q < 0.05) associated highly with cancer and cellular movement, indicating overlapping pathways in the reduction of gastric lesions. E2 or TAM deregulated genes associated with metastasis (PLAUR and MMP10) and Wnt inhibition (FZD6 and SFRP2). Compared with controls, E2 decreased gastric mRNA (Q < 0.05) and serum levels (P < 0.05) of CXCL1, a neutrophil chemokine, leading to decreased neutrophil infiltration (P < 0.01). Prevention of H. pylori-induced gastric cancer by E2 and TAM may be mediated by estrogen signaling and is associated with decreased CXCL1, decreased neutrophil counts, and downregulation of oncogenic pathways. PMID- 21680706 TI - Statin use and colorectal cancer risk according to molecular subtypes in two large prospective cohort studies. AB - Use of statins is hypothesized to reduce colorectal cancer risk but the evidence remains inconsistent. This may be partly explained by differential associations according to tumor location or molecular subtypes of colorectal cancer. We examined the association between statin use and colorectal cancer risk according to tumor location, KRAS mutation status, microsatellite instability (MSI) status, PTGS2 (COX-2) expression, or CpG island methylator phenotype (CIMP) status in two large prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study. We applied Cox regression to a competing risks analysis. We identified 1,818 colorectal cancers during 1990 to 2006. Compared with nonusers, current statin use was not associated with colorectal cancer [relative risk (RR) = 0.99, 95% CI = 0.86-1.14] or colon cancer (RR = 1.10, 95% CI = 0.94-1.29) but was inversely associated with rectal cancer (RR = 0.59, 95% CI = 0.41-0.84, P(heterogeneity) < 0.001). When we examined the association within strata of KRAS mutation status, we found no association with KRAS-mutated cancers (RR = 1.20, 95% CI = 0.87-1.67) but did observe a possible inverse association among KRAS wild-type cancers (RR = 0.80, 95% CI = 0.60-1.06, P(heterogeneity) = 0.06). The association did not substantially differ by PTGS2 expression, MSI status, or CIMP status. Current statin use was not associated with risk of overall colorectal cancer. The possibility that statin use may be associated with lower risk of rectal cancer or KRAS wild-type colorectal cancer requires further confirmation. PMID- 21680707 TI - Plasma leptin levels and risk of breast cancer in premenopausal women. AB - Body mass index (BMI) is inversely related to the risk of premenopausal breast cancer, but the underlying biological mechanisms of this association are poorly understood. Leptin, a peptide hormone produced primarily by adipocytes, is a potential mediator of the BMI association because BMI and total body fat are positively associated with circulating leptin levels and leptin and its receptor are overexpressed in breast tumors. We conducted a prospective case-control study nested within the Nurses' Health Study II cohort examining the association between plasma leptin levels in premenopausal women and breast cancer risk. Leptin was measured in blood samples collected between 1996 and 1999. The analysis included 330 incident breast cancer cases diagnosed after blood collection and 636 matched controls. Logistic regression models, controlling for breast cancer risk factors, were used to calculate ORs and 95% CIs. After adjustment for BMI at age 18, weight change since age 18 to blood draw, and other breast cancer risk factors, plasma leptin levels were inversely associated with breast cancer risk (OR for top vs. bottom quartile = 0.55; 95% CI = 0.31-0.99; P(trend) = 0.04). Adjustment for BMI at blood draw attenuated the association (OR = 0.69; 95% CI = 0.38-1.23; P(trend) = 0.26). Our results suggest that leptin may be inversely associated with breast cancer risk, but it is unclear whether any part of this association is independent of BMI. PMID- 21680708 TI - The yeast p24 complex regulates GPI-anchored protein transport and quality control by monitoring anchor remodeling. AB - Glycosylphosphatidylinositol (GPI)-anchored proteins are secretory proteins that are attached to the cell surface of eukaryotic cells by a glycolipid moiety. Once GPI anchoring has occurred in the lumen of the endoplasmic reticulum (ER), the structure of the lipid part on the GPI anchor undergoes a remodeling process prior to ER exit. In this study, we provide evidence suggesting that the yeast p24 complex, through binding specifically to GPI-anchored proteins in an anchor dependent manner, plays a dual role in their selective trafficking. First, the p24 complex promotes efficient ER exit of remodeled GPI-anchored proteins after concentration by connecting them with the COPII coat and thus facilitates their incorporation into vesicles. Second, it retrieves escaped, unremodeled GPI anchored proteins from the Golgi to the ER in COPI vesicles. Therefore the p24 complex, by sensing the status of the GPI anchor, regulates GPI-anchored protein intracellular transport and coordinates this with correct anchor remodeling. PMID- 21680709 TI - Involvement of the Rho-mDia1 pathway in the regulation of Golgi complex architecture and dynamics. AB - In mammalian cells, the Golgi apparatus is a ribbon-like, compact structure composed of multiple membrane stacks connected by tubular bridges. Microtubules are known to be important to Golgi integrity, but the role of the actin cytoskeleton in the maintenance of Golgi architecture remains unclear. Here we show that an increase in Rho activity, either by treatment of cells with lysophosphatidic acid or by expression of constitutively active mutants, resulted in pronounced fragmentation of the Golgi complex into ministacks. Golgi dispersion required the involvement of mDia1 formin, a downstream target of Rho and a potent activator of actin polymerization; moreover, constitutively active mDia1, in and of itself, was sufficient for Golgi dispersion. The dispersion process was accompanied by formation of dynamic F-actin patches in the Golgi area. Experiments with cytoskeletal inhibitors (e.g., latrunculin B, blebbistatin, and Taxol) revealed that actin polymerization, myosin-II-driven contractility, and microtubule-based intracellular movement were all involved in the process of Golgi dispersion induced by Rho-mDia1 activation. Live imaging of Golgi recovery revealed that fusion of the small Golgi stacks into larger compartments was repressed in cells with active mDia1. Furthermore, the formation of Rab6-positive transport vesicles derived from the Golgi complex was enhanced upon activation of the Rho-mDia1 pathway. Transient localization of mDia1 to Rab6 positive vesicles was detected in cells expressing active RhoA. Thus, the Rho mDia1 pathway is involved in regulation of the Golgi structure, affecting remodeling of Golgi membranes. PMID- 21680710 TI - Nab2 functions in the metabolism of RNA driven by polymerases II and III. AB - Gene expression in eukaryotes is an essential process that includes transcription, RNA processing, and export. One important player in this interface is the poly(A)(+)-RNA-binding protein Nab2, which regulates the mRNA poly(A)(+) tail length and export. Here we show that Nab2 has additional roles during mRNA transcription, tRNA metabolism, and ribosomal subunit export. Nab2 is associated with the entire open reading frame of actively transcribed RNA polymerase (RNAP) II and III genes. As a consequence, nab2 mutations confer translation defects that are detected by polysome profiling. Genome-wide analysis of expression of a conditional degron nab2 mutant shows that the role of Nab2 in RNAPII transcription and RNAPIII metabolism is direct. Taken together, our results identify novel functions for Nab2 in transcription and metabolism of most types of RNAs, indicating that Nab2 function is more ubiquitous than previously anticipated, and that it is a central player in the general and coordinated control of gene expression from transcription to translation. PMID- 21680711 TI - Confinement of beta(1)- and beta(2)-adrenergic receptors in the plasma membrane of cardiomyocyte-like H9c2 cells is mediated by selective interactions with PDZ domain and A-kinase anchoring proteins but not caveolae. AB - The sympathetic nervous system regulates cardiac output by activating adrenergic receptors (ARs) in cardiac myocytes. The predominant cardiac ARs, beta(1)- and beta(2)AR, are structurally similar but mediate distinct signaling responses. Scaffold protein-mediated compartmentalization of ARs into discrete, multiprotein complexes has been proposed to dictate differential signaling responses. To test the hypothesis that betaARs integrate into complexes in live cells, we measured receptor diffusion and interactions by single-particle tracking. Unstimulated beta(1)- and beta(2)AR were highly confined in the membrane of H9c2 cardiomyocyte like cells, indicating that receptors are tethered and presumably integrated into protein complexes. Selective disruption of interactions with postsynaptic density protein 95/disks large/zonula occludens-1 (PDZ)-domain proteins and A-kinase anchoring proteins (AKAPs) increased receptor diffusion, indicating that these scaffold proteins participate in receptor confinement. In contrast, modulation of interactions between the putative scaffold caveolae and beta(2)AR did not alter receptor dynamics, suggesting that these membrane domains are not involved in beta(2)AR confinement. For both beta(1)- and beta(2)AR, the receptor carboxy terminus was uniquely responsible for scaffold interactions. Our data formally demonstrate that distinct and stable protein complexes containing beta(1)- or beta(2)AR are formed in the plasma membrane of cardiomyocyte-like cells and that selective PDZ and AKAP interactions are responsible for the integration of receptors into complexes. PMID- 21680712 TI - Histone H2B ubiquitylation and H3 lysine 4 methylation prevent ectopic silencing of euchromatic loci important for the cellular response to heat. AB - In Saccharomyces cerevisiae, ubiquitylation of histone H2B signals methylation of histone H3 at lysine residues 4 (K4) and 79. These modifications occur at active genes but are believed to stabilize silent chromatin by limiting movement of silencing proteins away from heterochromatin domains. In the course of studying atypical phenotypes associated with loss of H2B ubiquitylation/H3K4 methylation, we discovered that these modifications are also required for cell wall integrity at high temperatures. We identified the silencing protein Sir4 as a dosage suppressor of loss of H2B ubiquitylation, and we showed that elevated Sir4 expression suppresses cell wall integrity defects by inhibiting the function of the Sir silencing complex. Using comparative transcriptome analysis, we identified a set of euchromatic genes-enriched in those required for the cellular response to heat-whose expression is attenuated by loss of H2B ubiquitylation but restored by disruption of Sir function. Finally, using DNA adenine methyltransferase identification, we found that Sir3 and Sir4 associate with genes that are silenced in the absence of H3K4 methylation. Our data reveal that H2B ubiquitylation/H3K4 methylation play an important role in limiting ectopic association of silencing proteins with euchromatic genes important for cell wall integrity and the response to heat. PMID- 21680713 TI - Role for casein kinase 1 in the phosphorylation of Claspin on critical residues necessary for the activation of Chk1. AB - The mediator protein Claspin is critical for the activation of the checkpoint kinase Chk1 during checkpoint responses to stalled replication forks. This function involves the Chk1-activating domain (CKAD) of Claspin, which undergoes phosphorylation on multiple conserved sites. These phosphorylations promote binding of Chk1 to Claspin and ensuing activation of Chk1 by ATR. However, despite the importance of this regulatory process, the kinase responsible for these phosphorylations has remained unknown. By using a multifaceted approach, we have found that casein kinase 1 gamma 1 (CK1gamma1) carries out this function. CK1gamma1 phosphorylates the CKAD of Claspin efficiently in vitro, and depletion of CK1gamma1 from human cells by small interfering RNA (siRNA) results in dramatically diminished phosphorylation of Claspin. Consequently, the siRNA treated cells display impaired activation of Chk1 and resultant checkpoint defects. These results indicate that CK1gamma1 is a novel component of checkpoint responses that controls the interaction of a key checkpoint effector kinase with its cognate mediator protein. PMID- 21680714 TI - c-Met recruits ICAM-1 as a coreceptor to compensate for the loss of CD44 in Cd44 null mice. AB - CD44 isoforms act as coreceptors for the receptor tyrosine kinases c-Met and VEGFR-2. However, Cd44 knockout mice do not show overt phenotypes, in contrast to Met and Vegfr-2 knockout mice. We hypothesized that CD44 is being compensated for by another factor in Cd44 null mice. Using RNAi technology and blocking experiments with antibodies, peptides, and purified ectodomains, as well as overexpression studies, we identified intercellular adhesion molecule-1 (ICAM-1) as a new coreceptor for c-Met in CD44-negative tumor cells and in primary hepatocytes obtained from Cd44 null mice. Most strikingly, after partial hepatectomy, CD44v6-specific antibodies inhibited liver cell proliferation and c Met activation in wild-type mice, whereas ICAM-1-specific antibodies interfered with liver cell proliferation and c-Met activation in Cd44 knockout mice. These data show that ICAM-1 compensates for CD44v6 as a coreceptor for c-Met in Cd44 null mice. Compensation of proteins by members of the same family has been widely proposed to explain the lack of phenotype of several knockout mice. Our experiments demonstrate the functional substitution of a protein by a heterologous one in a knockout mouse. PMID- 21680715 TI - Biogenesis of mitochondrial beta-barrel proteins: the POTRA domain is involved in precursor release from the SAM complex. AB - The mitochondrial outer membrane contains proteinaceous machineries for the translocation of precursor proteins. The sorting and assembly machinery (SAM) is required for the insertion of beta-barrel proteins into the outer membrane. Sam50 is the channel-forming core subunit of the SAM complex and belongs to the BamA/Sam50/Toc75 family of proteins that have been conserved from Gram-negative bacteria to mitochondria and chloroplasts. These proteins contain one or more N terminal polypeptide transport-associated (POTRA) domains. POTRA domains can bind precursor proteins, however, different views exist on the role of POTRA domains in the biogenesis of beta-barrel proteins. It has been suggested that the single POTRA domain of mitochondrial Sam50 plays a receptor-like function at the SAM complex. We established a system to monitor the interaction of chemical amounts of beta-barrel precursor proteins with the SAM complex of wild-type and mutant yeast in organello. We report that the SAM complex lacking the POTRA domain of Sam50 efficiently binds beta-barrel precursors, but is impaired in the release of the precursors. These results indicate the POTRA domain of Sam50 is not essential for recognition of beta-barrel precursors but functions in a subsequent step to promote the release of precursor proteins from the SAM complex. PMID- 21680716 TI - Dynamic profiling of mRNA turnover reveals gene-specific and system-wide regulation of mRNA decay. AB - RNA levels are determined by the rates of both transcription and decay, and a mechanistic understanding of the complex networks regulating gene expression requires methods that allow dynamic measurements of transcription and decay in living cells with minimal perturbation. Here, we describe a metabolic pulse-chase labeling protocol using 4-thiouracil combined with large-scale RNA sequencing to determine decay rates of all mRNAs in Saccharomyces cerevisiae. Profiling in various growth and stress conditions reveals that mRNA turnover is highly regulated both for specific groups of transcripts and at the system-wide level. For example, acute glucose starvation induces global mRNA stabilization but increases the degradation of all 132 detected ribosomal protein mRNAs. This effect is transient and can be mimicked by inhibiting the target-of-rapamycin kinase. Half-lives of mRNAs critical for galactose (GAL) metabolism are also highly sensitive to changes in carbon source. The fast reduction of GAL transcripts in glucose requires their dramatically enhanced turnover, highlighting the importance of mRNA decay in the control of gene expression. The approach described here provides a general platform for the global analysis of mRNA turnover and transcription and can be applied to dissect gene expression programs in a wide range of organisms and conditions. PMID- 21680717 TI - Dystroglycan is involved in skin morphogenesis downstream of the Notch signaling pathway. AB - Dystroglycan (Dg) is a transmembrane protein involved both in the assembly and maintenance of basement membrane structures essential for tissue morphogenesis, and the transmission of signals across the plasma membrane. We used a morpholino knockdown approach to investigate the function of Dg during Xenopus laevis skin morphogenesis. The loss of Dg disrupts epidermal differentiation by affecting the intercalation of multiciliated cells, deposition of laminin, and organization of fibronectin in the extracellular matrix (ECM). Depletion of Dg also affects cell cell adhesion, as shown by the reduction of E-cadherin expression at the intercellular contacts, without affecting the distribution of beta(1) integrins. This was associated with a decrease of cell proliferation, a disruption of multiciliated-cell intercalation, and the down-regulation of the transcription factor P63, a marker of differentiated epidermis. In addition, we demonstrated that inhibition or activation of the Notch pathway prevents and promotes transcription of X-dg. Our study showed for the first time in vivo that Dg, in addition to organizing laminin in the ECM, also acts as a key signaling component in the Notch pathway. PMID- 21680718 TI - Cluster analysis of self-monitoring blood glucose assessments in clinical islet cell transplantation for type 1 diabetes. AB - OBJECTIVE: Cluster analysis was performed on the results of self-monitoring of blood glucose (SMBG) to discriminate islet graft function after islet cell transplantation (ICT) in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Eleven islet recipients were included in this study. The patients visited our clinic monthly after ICT and provided blood samples for fasting C peptide (n = 270), which were used to evaluate islet graft function. They also provided their SMBG data through an automatic data collection system. The SMBG data for 3 days immediately before each clinic visit were evaluated using the following assessments: M value, mean amplitude of glycemic excursions, J index, index of glycemic control, average daily risk range, and glycemic risk assessment diabetes equation. The cluster analysis was performed for both SMBG assessments and samples. Multivariate logistic regression analysis was used to evaluate the clusters of SMBG for assessing islet graft function. RESULTS: Analysis for SMBG assessments revealed five types of clusters, which showed similar patterns according to functional or dysfunctional islet graft phase. Two clusters, the euglycemia cluster (P < 0.001) and the hypoglycemia cluster (P = 0.001), were significant factors in the logistic model for islet graft function. The SMBG clusters had significant correlations with clinical graft indexes (P < 0.001). CONCLUSIONS: Cluster analysis of SMBG data as part of an automated data quality system could allow discrimination of islet graft dysfunction after ICT. This approach should be considered for islet recipients. PMID- 21680719 TI - Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study. AB - OBJECTIVE: Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer's disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults. RESEARCH DESIGN AND METHODS: Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998-2001) constituted our study sample (n = 2,439; 1,311 women; age 61 +/- 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-epsilon4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C). RESULTS: We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007). CONCLUSIONS: Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort. PMID- 21680720 TI - Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. AB - OBJECTIVE: The safety of dendritic cells to selectively suppress autoimmunity, especially in type 1 diabetes, has never been ascertained. We investigated the safety of autologous dendritic cells, stabilized into an immunosuppressive state, in established adult type 1 diabetic patients. RESEARCH DESIGN AND METHODS: A randomized, double-blind, phase I study was conducted. A total of 10, otherwise generally healthy, insulin-requiring type 1 diabetic patients between 18 and 60 years of age, without any other known or suspected health conditions, received autologous dendritic cells, unmanipulated or engineered ex vivo toward an immunosuppressive state. Ten million cells were administered intradermally in the abdomen once every 2 weeks for a total of four administrations. The primary end point determined the proportion of patients with adverse events on the basis of the physician's global assessment, hematology, biochemistry, and immune monitoring for a period of 12 months. RESULTS: The dendritic cells were safely tolerated. There were no discernible adverse events in any patient throughout the study. Other than a significant increase in the frequency of peripheral B220+ CD11c- B cells, mainly seen in the recipients of engineered dendritic cells during the dendritic cell administration period, there were no statistically relevant differences in other immune populations or biochemical, hematological, and immune biomarkers compared with baseline. CONCLUSIONS: Treatment with autologous dendritic cells, in a native state or directed ex vivo toward a tolerogenic immunosuppressive state, is safe and well tolerated. Dendritic cells upregulated the frequency of a potentially beneficial B220+ CD11c- B-cell population, at least in type 1 diabetes autoimmunity. PMID- 21680721 TI - Increased risk of myocardial infarction in depressed patients with type 2 diabetes. AB - OBJECTIVE: To investigate major depressive disorder (MDD), which complicates the course of type 2 diabetes and is associated with an increased risk of cardiovascular disease and death. This risk may be due to a greater susceptibility for myocardial infarction (MI) in depressed patients with type 2 diabetes compared with nondepressed patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Veterans Administration electronic medical records were analyzed to identify a cohort free of cardiovascular disease in fiscal years 1999 and 2000, aged 25 to 80 years. ICD-9-CM codes were used to create a four-level risk group indicating 1) neither diabetes nor MDD (n = 214,749), 2) MDD alone (n = 77,568), 3) type 2 diabetes alone (n = 40,953), and 4) comorbid MDD and type 2 diabetes (n = 12,679). Age-adjusted Cox proportional hazards models were computed before and after adjusting for baseline sociodemographic and time-dependent covariates. RESULTS: After adjusting for covariates, patients with type 2 diabetes alone and patients with MDD alone were at ~30% increased risk for MI, and patients with type 2 diabetes and MDD were at 82% increased risk for MI (hazard ratio 1.82 [95% CI 1.69-1.97]) compared with patients without either condition. CONCLUSIONS: Compared with patients with only diabetes or only MDD, individuals with type 2 diabetes and MDD are at increased risk for new-onset MI. Monitoring cardiovascular health in depressed patients with type 2 diabetes may reduce the risk of MI in this especially high-risk group. PMID- 21680722 TI - Deriving ethnic-specific BMI cutoff points for assessing diabetes risk. AB - OBJECTIVE: The definition of obesity (BMI >= 30 kg/m(2)), a key risk factor of diabetes, is widely used in white populations; however, its appropriateness in nonwhite populations has been questioned. We compared the incidence rates of diabetes across white, South Asian, Chinese, and black populations and identified equivalent ethnic-specific BMI cutoff values for assessing diabetes risk. RESEARCH DESIGN AND METHODS: We conducted a multiethnic cohort study of 59,824 nondiabetic adults aged >= 30 years living in Ontario, Canada. Subjects were identified from Statistics Canada's population health surveys and followed for up to 12.8 years for diabetes incidence using record linkages to multiple health administrative databases. RESULTS: The median duration of follow-up was 6 years. After adjusting for age, sex, sociodemographic characteristics, and BMI, the risk of diabetes was significantly higher among South Asian (hazard ratio 3.40, P < 0.001), black (1.99, P < 0.001), and Chinese (1.87, P = 0.002) subjects than among white subjects. The median age at diagnosis was lowest among South Asian (aged 49 years) subjects, followed by Chinese (aged 55 years), black (aged 57 years), and white (aged 58 years) subjects. For the equivalent incidence rate of diabetes at a BMI of 30 kg/m(2) in white subjects, the BMI cutoff value was 24 kg/m(2) in South Asian, 25 kg/m(2) in Chinese, and 26 kg/m(2) in black subjects. CONCLUSIONS: South Asian, Chinese, and black subjects developed diabetes at a higher rate, at an earlier age, and at lower ranges of BMI than their white counterparts. Our findings highlight the need for designing ethnically tailored prevention strategies and for lowering current targets for ideal body weight for nonwhite populations. PMID- 21680723 TI - Effect of computer-generated tailored feedback on glycemic control in people with diabetes in the community: a randomized controlled trial. AB - OBJECTIVE: It is unknown whether computer-generated, patient-tailored feedback leads to improvements in glycemic control in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: We recruited people with type 2 diabetes aged >= 40 years with a glycated hemoglobin (A1C) >= 7%, living in Hamilton, Canada, who were enrolled in a community-based program (Diabetes Hamilton) that provided regular evidence-based information and listings of community resources designed to facilitate diabetes self-management. After completing a questionnaire, participants were randomly allocated to either receive or not receive periodic computer-generated, evidence-based feedback on the basis of their questionnaire responses and designed to facilitate improved glycemic control and diabetes self management. The primary outcome was a change in A1C after 1 year. RESULTS: A total of 465 participants (50% women, mean age 62 years, and mean A1C 7.83%) were randomly assigned, and 12-month A1C values were available in 96% of all participants, at which time the A1C level had decreased by an absolute amount of 0.24 and 0.15% in the intervention and control groups, respectively. The difference in A1C reduction for the intervention versus control group was 0.09% (95% CI -0.08 to 0.26; P = 0.3). No between-group differences in measures of quality of life, diabetes self-management behaviors, or clinical outcomes were observed. CONCLUSIONS: Providing computer-generated tailored feedback to registrants of a generic, community-based program that supports diabetes self management does not lead to lower A1C levels or a better quality of life than participation in the community-based program (augmented by periodic A1C testing) alone. PMID- 21680724 TI - Validation of the Diabetes Prevention Trial-Type 1 Risk Score in the TrialNet Natural History Study. AB - OBJECTIVE: We assessed the accuracy of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS), developed from the Diabetes Prevention Trial-Type 1 (DPT-1), in the TrialNet Natural History Study (TNNHS). RESEARCH DESIGN AND METHODS: Prediction accuracy of the DPTRS was assessed with receiver-operating characteristic curve areas. The type 1 diabetes cumulative incidence within the DPTRS intervals was compared between the TNNHS and DPT-1 cohorts. RESULTS: Receiver-operating characteristic curve areas for the DPTRS were substantial in the TNNHS (P < 0.001 at both 2 and 3 years). The type 1 diabetes cumulative incidence did not differ significantly between the TNNHS and DPT-1 cohorts within DPTRS intervals. In the TNNHS, 2-year and 3-year risks were low for DPTRS intervals <6.50 (<0.10 and <0.20, respectively). Thresholds >=7.50 were indicative of high risk in both cohorts (2-year risks: 0.49 in the TNNHS and 0.51 in DPT-1). CONCLUSIONS: The DPTRS is an accurate and robust predictor of type 1 diabetes in autoantibody-positive populations. PMID- 21680725 TI - Incidence of type 1 diabetes in Sweden among individuals aged 0-34 years, 1983 2007: an analysis of time trends. AB - OBJECTIVE: To clarify whether the increase in childhood type 1 diabetes is mirrored by a decrease in older age-groups, resulting in younger age at diagnosis. RESEARCH DESIGN AND METHODS: We used data from two prospective research registers, the Swedish Childhood Diabetes Register, which included case subjects aged 0-14.9 years at diagnosis, and the Diabetes in Sweden Study, which included case subjects aged 15-34.9 years at diagnosis, covering birth cohorts between 1948 and 2007. The total database included 20,249 individuals with diabetes diagnosed between 1983 and 2007. Incidence rates over time were analyzed using Poisson regression models. RESULTS: The overall yearly incidence rose to a peak of 42.3 per 100,000 person-years in male subjects aged 10-14 years and to a peak of 37.1 per 100,000 person-years in female subjects aged 5-9 years and decreased thereafter. There was a significant increase by calendar year in both sexes in the three age-groups <15 years; however, there were significant decreases in the older age-groups (25- to 29-years and 30- to 34-years age groups). Poisson regression analyses showed that a cohort effect seemed to dominate over a time-period effect. CONCLUSIONS: Twenty-five years of prospective nationwide incidence registration demonstrates a clear shift to younger age at onset rather than a uniform increase in incidence rates across all age-groups. The dominance of cohort effects over period effects suggests that exposures affecting young children may be responsible for the increasing incidence in the younger age-groups. PMID- 21680726 TI - Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and beta-cell function in subjects with long term remission. AB - OBJECTIVE: To examine the effect of intensive glycemic control therapy (IT) on insulin sensitivity and beta-cell function in newly diagnosed type 2 diabetic patients compared with subjects with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Forty-eight newly diagnosed type 2 diabetic patients were randomly assigned to IT for 2 weeks and followed up for 1 year. Intravenous glucose tolerance tests were conducted in NGT, IGT, and diabetic subjects. Blood glucose and insulin were measured before and after IT and at the 1-year follow-up. RESULTS: IT lowered the homeostasis model assessment (HOMA) for insulin resistance (IR) significantly, from 3.12 +/- 1.4 (mean +/- SD) to 1.72 +/- 0.8, a level comparable to the IGT (1.96 +/- 1.1) and NGT (1.37 +/- 0.6) subjects in the remission group; however, no HOMA-IR improvement was observed in nonremission subjects. HOMA-beta in the remission group was improved (mean, interquartile range) from 18.4 (8.3-28.5) to 44.6 (32.1 69.1) and acute insulin response of insulin (AIRins) from 1.50 +/- 0.22 to 1.83 +/- 0.19 MUIU/mL after IT, but was still significantly lower than those in NGT individuals (HOMA-beta: 86.4 [56.7-185.2], P < 0.01; AIRins: 2.54 +/- 0.39 MUIU/mL, P < 0.01). After IT and at 1 year, the hyperbolic relationship between HOMA-beta and HOMA sensitivity of remission subjects shifted close to that of IGT subjects. CONCLUSIONS: IT in newly diagnosed type 2 diabetes not only partially restored beta-cell function but also greatly restored insulin sensitivity. Compared with IGT and NGT subjects, beta-cell function was less restored than insulin sensitivity after IT in the remission subjects. PMID- 21680727 TI - Reflex and tonic autonomic markers for risk stratification in patients with type 2 diabetes surviving acute myocardial infarction. AB - OBJECTIVE: Diabetic postinfarction patients are at increased mortality risk compared with nondiabetic postinfarction patients. In a substantial number of these patients, diabetic cardiac neuropathy already preexists at the time of the infarction. In the current study we investigated if markers of autonomic dysfunction can further discriminate diabetic postinfarction patients into low- and high-risk groups. RESEARCH DESIGN AND METHODS: We prospectively enrolled 481 patients with type 2 diabetes who survived acute myocardial infarction (MI), were aged <= 80 years, and presented in sinus rhythm. Primary end point was total mortality at 5 years of follow-up. Severe autonomic failure (SAF) was defined as coincidence of abnormal autonomic reflex function (assessed by means of heart rate turbulence) and of abnormal autonomic tonic activity (assessed by means of deceleration capacity of heart rate). Multivariable risk analyses considered SAF and standard risk predictors including history of previous MI, arrhythmia on Holter monitoring, insulin treatment, and impaired left ventricular ejection fraction (LVEF) <= 30%. RESULTS: During follow-up, 83 of the 481 patients (17.3%) died. Of these, 24 deaths were sudden cardiac deaths and 21 nonsudden cardiac deaths. SAF identified a high-risk group of 58 patients with a 5-year mortality rate of 64.0% at a sensitivity level of 38.0%. Multivariately, SAF was the strongest predictor of mortality (hazard ratio 4.9 [95% CI 2.4-9.9]), followed by age >=65 years (3.4 [1.9-5.8]), and LVEF <= 30% (2.6 [1.5-4.4]). CONCLUSIONS: Combined abnormalities of autonomic reflex function and autonomic tonic activity identifies diabetic postinfarction patients with very poor prognoses. PMID- 21680728 TI - Developing and validating a risk score for lower-extremity amputation in patients hospitalized for a diabetic foot infection. AB - OBJECTIVE: Diabetic foot infection is the predominant predisposing factor to nontraumatic lower-extremity amputation (LEA), but few studies have investigated which specific risk factors are most associated with LEA. We sought to develop and validate a risk score to aid in the early identification of patients hospitalized for diabetic foot infection who are at highest risk of LEA. RESEARCH DESIGN AND METHODS: Using a large, clinical research database (CareFusion), we identified patients hospitalized at 97 hospitals in the U.S. between 2003 and 2007 for culture-documented diabetic foot infection. Candidate risk factors for LEA included demographic data, clinical presentation, chronic diseases, and recent previous hospitalization. We fit a logistic regression model using 75% of the population and converted the model coefficients to a numeric risk score. We then validated the score using the remaining 25% of patients. RESULTS: Among 3,018 eligible patients, 21.4% underwent an LEA. The risk factors most highly associated with LEA (P < 0.0001) were surgical site infection, vasculopathy, previous LEA, and a white blood cell count >11,000 per mm(3). The model showed good discrimination (c-statistic 0.76) and excellent calibration (Hosmer Lemeshow, P = 0.63). The risk score stratified patients into five groups, demonstrating a graded relation to LEA risk (P < 0.0001). The LEA rates (derivation and validation cohorts) were 0% for patients with a score of 0 and ~50% for those with a score of >=21. CONCLUSIONS: Using a large, hospitalized population, we developed and validated a risk score that seems to accurately stratify the risk of LEA among patients hospitalized for a diabetic foot infection. This score may help to identify high-risk patients upon admission. PMID- 21680729 TI - Leptin and cancer: from cancer stem cells to metastasis. AB - There is growing evidence that obesity is a risk factor of cancer incidence and mortality. Hence, the identification of the mechanistic links between obesity and cancer progression is emerging as a topic of widespread interest. Recently, several groups have addressed the functional roles of leptin, an adipocyte derived adipokine, for mammary tumor progression. In this issue of Endocrine Related Cancer, Zheng et al. study the role of leptin on tumor growth in a xenograft model of MMTV-Wnt1-derived cancer cells. They study growth of these cancer cells in the context of obese animals, such as ob/ob mice (lacking leptin) and db/db mice (lacking functional leptin receptors (LEPR)) and find that leptin triggers LEPR-positive cancer stem cell differentiation, thereby promoting tumor cell survival. These findings highlight the therapeutic potential for leptin and leptin signaling in the context of mammary tumor growth. PMID- 21680730 TI - Structural insights into the down-regulation of overexpressed p185(her2/neu) protein of transformed cells by the antibody chA21. AB - p185(her2/neu) belongs to the ErbB receptor tyrosine kinase family, which has been associated with human breast, ovarian, and lung cancers. Targeted therapies employing ectodomain-specific p185(her2/neu) monoclonal antibodies (mAbs) have demonstrated clinical efficacy for breast cancer. Our previous studies have shown that p185(her2/neu) mAbs are able to disable the kinase activity of homomeric and heteromeric kinase complexes and induce the conversion of the malignant to normal phenotype. We previously developed a chimeric antibody chA21 that specifically inhibits the growth of p185(her2/neu)-overexpressing cancer cells in vitro and in vivo. Herein, we report the crystal structure of the single-chain Fv of chA21 in complex with an N-terminal fragment of p185(her2/neu), which reveals that chA21 binds a region opposite to the dimerization interface, indicating that chA21 does not directly disrupt the dimerization. In contrast, the bivalent chA21 leads to internalization and down-regulation of p185(her2/neu). We propose a structure based model in which chA21 cross-links two p185(her2/neu) molecules on separate homo- or heterodimers to form a large oligomer in the cell membrane. This model reveals a mechanism for mAbs to drive the receptors into the internalization/degradation path from the inactive hypophosphorylated tetramers formed dynamically by active dimers during a "physiologic process." PMID- 21680731 TI - Dipeptidyl peptidases as survival factors in Ewing sarcoma family of tumors: implications for tumor biology and therapy. AB - Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its Y1 and Y5 receptors (Y5Rs). Previously, we have shown that both exogenous NPY and endogenous NPY stimulate ESFT cell death via its Y1 and Y5Rs. Here, we demonstrate that this effect is prevented by dipeptidyl peptidases (DPPs), which cleave NPY to its shorter form, NPY(3-36), not active at Y1Rs. We have shown that NPY-induced cell death can be abolished by overexpression of DPPs and enhanced by their down-regulation. Both NPY treatment and DPP blockade activated the same cell death pathway mediated by poly(ADP-ribose) polymerase (PARP-1) and apoptosis inducing factor (AIF). Moreover, the decrease in cell survival induced by DPP inhibition was blocked by Y1 and Y5R antagonists, confirming its dependence on endogenous NPY. Interestingly, similar levels of NPY-driven cell death were achieved by blocking membrane DPPIV and cytosolic DPP8 and DPP9. Thus, this is the first evidence of these intracellular DPPs cleaving releasable peptides, such as NPY, in live cells. In contrast, another membrane DPP, fibroblast activation protein (FAP), did not affect NPY actions. In conclusion, DPPs act as survival factors for ESFT cells and protect them from cell death induced by endogenous NPY. This is the first demonstration that intracellular DPPs are involved in regulation of ESFT growth and may become potential therapeutic targets for these tumors. PMID- 21680732 TI - Dual processing of FAT1 cadherin protein by human melanoma cells generates distinct protein products. AB - The giant cadherin FAT1 is one of four vertebrate orthologues of the Drosophila tumor suppressor fat. It engages in several functions, including cell polarity and migration, and in Hippo signaling during development. Homozygous deletions in oral cancer suggest that FAT1 may play a tumor suppressor role, although overexpression of FAT1 has been reported in some other cancers. Here we show using Northern blotting that human melanoma cell lines variably but universally express FAT1 and less commonly FAT2, FAT3, and FAT4. Both normal melanocytes and keratinocytes also express comparable FAT1 mRNA relative to melanoma cells. Analysis of the protein processing of FAT1 in keratinocytes revealed that, like Drosophila FAT, human FAT1 is cleaved into a non-covalent heterodimer before achieving cell surface expression. The use of inhibitors also established that such cleavage requires the proprotein convertase furin. However, in melanoma cells, the non-cleaved proform of FAT1 is also expressed at the cell surface together with the furin-cleaved heterodimer. Moreover, furin-independent processing generates a potentially functional proteolytic product in melanoma cells, a persistent 65-kDa membrane-bound cytoplasmic fragment no longer in association with the extracellular fragment. In vitro localization studies of FAT1 showed that melanoma cells display high levels of cytosolic FAT1 protein, whereas keratinocytes, despite comparable FAT1 expression levels, exhibited mainly cell-cell junctional staining. Such differences in protein distribution appear to reconcile with the different protein products generated by dual FAT1 processing. We suggest that the uncleaved FAT1 could promote altered signaling, and the novel products of alternate processing provide a dominant negative function in melanoma. PMID- 21680733 TI - Angiopoietin-2, an angiogenic regulator, promotes initial growth and survival of breast cancer metastases to the lung through the integrin-linked kinase (ILK)-AKT B cell lymphoma 2 (Bcl-2) pathway. AB - The early onsets of breast cancer metastasis involve cell retention, survival, and resistant to apoptosis and subsequent growth at target vascular beds and tissues in distant organs. We previously reported that angiopoietin-2 (Ang2), an angiogenic regulator stimulates MCF-7 breast tumor metastasis from their orthotopic sites to distant organs through the alpha(5)beta(1) integrin/integrin linked kinase (ILK)/Akt pathway. Here, by using an experimental tumor metastasis model and in vitro studies, we further dissect the underlying mechanism by which Ang2 promotes the initial growth and survival of MCF-7 breast cancer metastasis in the lung of animals. We show that Ang2 increases cell survival and suppresses cell apoptosis through ILK-induced phosphorylation of Akt1, Akt2, and up regulation of Bcl-2 in breast cancer cells. Inhibition of ILK, Akt1, and Akt2, and their effector Bcl-2 diminishes Ang2-stimulated breast cancer cell survival and Ang2-attenuated apoptosis in vitro, and initial survival and growth of breast cancer metastasis in the lung of animals. Additionally, siRNA knockdown of endogenous Ang2 in three human metastatic breast cancer cell lines also inhibits phosphorylation of Akt, expression of Bcl-2, and tumor cell survival, migration, and increases cell apoptosis. Since increased expression of Ang2 correlates with elevated potential of human breast cancer metastasis in clinic, our data underscore the importance that up-regulated Ang2 not only stimulates breast cancer growth and metastasis at late stages of the process, but is also critical at the initiating stages of metastases onset, thereby suggesting Ang2 as a promising therapeutic target for treating patients with metastatic breast cancer. PMID- 21680734 TI - Murine diacylglycerol acyltransferase-2 (DGAT2) can catalyze triacylglycerol synthesis and promote lipid droplet formation independent of its localization to the endoplasmic reticulum. AB - Triacylglycerol (TG) is the major form of stored energy in eukaryotic organisms and is synthesized by two distinct acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2. Both DGAT enzymes reside in the endoplasmic reticulum (ER), but DGAT2 also co-localizes with mitochondria and lipid droplets. In this report, we demonstrate that murine DGAT2 is part of a multimeric complex consisting of several DGAT2 subunits. We also identified the region of DGAT2 responsible for its localization to the ER. A DGAT2 mutant lacking both its transmembrane domains, although still associated with membranes, was absent from the ER and instead localized to mitochondria. Unexpectedly, this mutant was still active and capable of interacting with lipid droplets to promote TG storage. Additional experiments indicated that the ER targeting signal was present in the first transmembrane domain (TMD1) of DGAT2. When fused to a fluorescent reporter, TMD1, but not TMD2, was sufficient to target mCherry to the ER. Finally, the interaction of DGAT2 with lipid droplets was dependent on the C terminus of DGAT2. DGAT2 mutants, in which regions of the C terminus were either truncated or specific regions were deleted, failed to co-localize with lipid droplets when cells were oleate loaded to stimulate TG synthesis. Our findings demonstrate that DGAT2 is capable of catalyzing TG synthesis and promote its storage in cytosolic lipid droplets independent of its localization in the ER. PMID- 21680735 TI - Transport activity of the high-affinity monocarboxylate transporter MCT2 is enhanced by extracellular carbonic anhydrase IV but not by intracellular carbonic anhydrase II. AB - The ubiquitous enzyme carbonic anhydrase isoform II (CAII) has been shown to enhance transport activity of the proton-coupled monocarboxylate transporters MCT1 and MCT4 in a non-catalytic manner. In this study, we investigated the role of cytosolic CAII and of the extracellular, membrane-bound CA isoform IV (CAIV) on the lactate transport activity of the high-affinity monocarboxylate transporter MCT2, heterologously expressed in Xenopus oocytes. In contrast to MCT1 and MCT4, transport activity of MCT2 was not altered by CAII. However, coexpression of CAIV with MCT2 resulted in a significant increase in MCT2 transport activity when the transporter was coexpressed with its associated ancillary protein GP70 (embigin). The CAIV-mediated augmentation of MCT2 activity was independent of the catalytic activity of the enzyme, as application of the CA inhibitor ethoxyzolamide or coexpressing the catalytically inactive mutant CAIV V165Y did not suppress CAIV-mediated augmentation of MCT2 transport activity. Furthermore, exchange of His-88, mediating an intramolecular H(+)-shuttle in CAIV, to alanine resulted only in a slight decrease in CAIV-mediated augmentation of MCT2 activity. The data suggest that extracellular membrane-bound CAIV, but not cytosolic CAII, augments transport activity of MCT2 in a non-catalytic manner, possibly by facilitating a proton pathway other than His-88. PMID- 21680736 TI - Sig1R protein regulates hERG channel expression through a post-translational mechanism in leukemic cells. AB - Sig1R (Sigma-1receptor) is a 25-kDa protein structurally unrelated to other mammalian proteins. Sig1R is present in brain, liver, and heart and is overexpressed in cancer cells. Studies using exogenous sigma ligands have shown that Sig1R interacts with a variety of ion channels, but its intrinsic function and mechanism of action remain unclear. The human ether-a-gogo related gene (hERG) encodes a cardiac channel that is also abnormally expressed in many primary human cancers, potentiating tumor progression through the modulation of extracellular matrix adhesive interactions. We show herein that sigma ligands inhibit hERG current density and cell adhesion to fibronectin in K562 myeloid leukemia cells. Heterologous expression in Xenopus oocytes demonstrates that Sig1R potentiates hERG current by stimulating channel subunit biosynthesis. Silencing Sig1R in leukemic K562 cells depresses hERG current density and cell adhesion to fibronectin by reducing hERG membrane expression. In K562 cells, Sig1R silencing does not modify hERG mRNA contents but reduces hERG mature form densities. In HEK cells expressing hERG and Sig1R, both proteins co immunoprecipitate, demonstrating a physical association. Finally, Sig1R expression enhances both channel protein maturation and stability. Altogether, these results demonstrate for the first time that Sig1R controls ion channel expression through the regulation of subunit trafficking activity. PMID- 21680737 TI - Stability screening of arrays of major histocompatibility complexes on combinatorially encoded flow cytometry beads. AB - The binding and stabilization capacity of potential T cell epitopes to class I MHC molecules form the basis for their immunogenicity and provide fundamental insight into factors that dictate cellular immune responses. We have developed a versatile high throughput cell-free method to measure MHC stability by capturing a variety of MHC products on the surface of streptavidin-coated particles followed by flow cytometry analysis. Arrays of peptide-MHC combinations, generated by exchanging conditional ligand-loaded MHC, could be probed in a single experiment, thus combining the molecular precision of biochemically purified MHCs with high content multiparametric flow cytometry-based assays. Semiquantitative determination of the peptide affinity for the restriction element could also be accomplished through competition experiments using this bead-based assay. Furthermore, the generated peptide-MHC reagents could directly be applied to antigen-specific CD8(+) T lymphocyte analysis. The combinatorial labeling of beads allowed straightforward identification by their unique fluorescent signatures and provided a convenient means for extended assay multiplexing. PMID- 21680738 TI - Glucose controls phosphoregulation of hydroxymethylglutaryl coenzyme A reductase through the protein phosphatase 2A-related phosphatase protein, Ppe1, and Insig in fission yeast. AB - HMG-CoA reductase (HMGR) catalyzes a rate-limiting step in sterol biosynthesis and is a key control point in the feedback inhibition that regulates this pathway. Through the action of the membrane protein Insig, HMGR synthesis and degradation are regulated to maintain sterol homeostasis. The fission yeast Schizosaccharomyces pombe encodes homologs of HMGR and Insig called hmg1(+) and ins1(+), respectively. In contrast to the mammalian system, Ins1 regulates Hmg1 by a nondegradative mechanism involving phosphorylation of the Hmg1 active site. Here, we investigate the role of the Ins1-Hmg1 system in coupling glucose sensing to regulation of sterol biosynthesis. We show that Ins1-dependent Hmg1 phosphorylation is strongly induced in response to glucose withdrawal and that HMGR activity is correspondingly reduced. We also find that inability to activate Hmg1 phosphorylation under nutrient limiting conditions results in overaccumulation of sterol pathway intermediates. Furthermore, we show that regulation of Hmg1 phosphorylation requires the protein phosphatase 2A-related phosphatase Ppe1 and its regulator Sds23. These results describe a mechanism by which cells tune the rate of sterol synthesis to match nutrient availability. PMID- 21680739 TI - Alpha-actinin-4 and CLP36 protein deficiencies contribute to podocyte defects in multiple human glomerulopathies. AB - Genetic alterations of alpha-actinin-4 can cause podocyte injury through multiple mechanisms. Although a mechanism involving gain-of-alpha-actinin-4 function was well described and is responsible for a dominantly inherited form of human focal segmental glomerulosclerosis (FSGS), evidence supporting mechanisms involving loss-of-alpha-actinin-4 function in human glomerular diseases remains elusive. Here we show that alpha-actinin-4 deficiency occurs in multiple human primary glomerulopathies including sporadic FSGS, minimal change disease, and IgA nephropathy. Furthermore, we identify a close correlation between the levels of alpha-actinin-4 and CLP36, which form a complex in normal podocytes, in human glomerular diseases. siRNA-mediated depletion of alpha-actinin-4 in human podocytes resulted in a marked reduction of the CLP36 level. Additionally, two FSGS-associated alpha-actinin-4 mutations (R310Q and Q348R) inhibited the complex formation between alpha-actinin-4 and CLP36. Inhibition of the alpha-actinin-4 CLP36 complex, like loss of alpha-actinin-4, markedly reduced the level of CLP36 in podocytes. Finally, reduction of the CLP36 level or disruption of the alpha actinin-4-CLP36 complex significantly inhibited RhoA activity and generation of traction force in podocytes. Our studies reveal a critical role of the alpha actinin-4-CLP36 complex in podocytes and provide an explanation as to how alpha actinin-4 deficiency or mutations found in human patients could contribute to podocyte defects and glomerular failure through a loss-of-function mechanism. PMID- 21680740 TI - Kinesin Kar3Cik1 ATPase pathway for microtubule cross-linking. AB - Kar3Cik1 is a Saccharomyces cerevisiae kinesin-14 that functions to shorten cytoplasmic microtubules (MTs) during yeast mating yet maintains mitotic spindle stability by cross-linking anti-parallel interpolar MTs. Kar3 contains both an ATP- and a MT-binding site, yet there is no evidence of a nucleotide-binding site in Cik1. Presteady-state and steady-state kinetic experiments were pursued to define the regulation of Kar3Cik1 interactions with the MT lattice expected during interpolar MT cross-linking. The results reveal that association of Kar3Cik1 with the MT occurs at 4.9 MUM(-1) s(-1), followed by a 5-s(-1) structural transition that limits ADP release from the Kar3 head. Mant-ATP binding occurred at 2.1 MUM(-1) s(-1), and the pulse-chase experiments revealed an ATP-promoted isomerization at 69 s(-1). ATP hydrolysis was observed as a rapid step at 26 s(-1) and was required for the Kar3Cik1 motor to detach from MT. The conformational change at 5 s(-1) that occurred after Kar3Cik1 MT association and prior to ADP release was hypothesized to be the rate-limiting step for steady state ATP turnover. We propose a model in which Kar3Cik1 interacts with the MT lattice through an alternating cycle of Cik1 MT collision followed by Kar3 MT binding with head-head communication between Kar3 and Cik1 modulated by the Kar3 nucleotide state and intramolecular strain. PMID- 21680741 TI - Stabilization of C4a-hydroperoxyflavin in a two-component flavin-dependent monooxygenase is achieved through interactions at flavin N5 and C4a atoms. AB - p-Hydroxyphenylacetate (HPA) 3-hydroxylase is a two-component flavin-dependent monooxygenase. Based on the crystal structure of the oxygenase component (C(2)), His-396 is 4.5 A from the flavin C4a locus, whereas Ser-171 is 2.9 A from the flavin N5 locus. We investigated the roles of these two residues in the stability of the C4a-hydroperoxy-FMN intermediate. The results indicated that the rate constant for C4a-hydroperoxy-FMN formation decreased ~30-fold in H396N, 100-fold in H396A, and 300-fold in the H396V mutant, compared with the wild-type enzyme. Lesser effects of the mutations were found for the subsequent step of H(2)O(2) elimination. Studies on pH dependence showed that the rate constant of H(2)O(2) elimination in H396N and H396V increased when pH increased with pK(a) >9.6 and >9.7, respectively, similar to the wild-type enzyme (pK(a) >9.4). These data indicated that His-396 is important for the formation of the C4a-hydroperoxy-FMN intermediate but is not involved in H(2)O(2) elimination. Transient kinetics of the Ser-171 mutants with oxygen showed that the rate constants for the H(2)O(2) elimination in S171A and S171T were ~1400-fold and 8-fold greater than the wild type, respectively. Studies on the pH dependence of S171A with oxygen showed that the rate constant of H(2)O(2) elimination increased with pH rise and exhibited an approximate pK(a) of 8.0. These results indicated that the interaction of the hydroxyl group side chain of Ser-171 and flavin N5 is required for the stabilization of C4a-hydroperoxy-FMN. The double mutant S171A/H396V reacted with oxygen to directly form the oxidized flavin without stabilizing the C4a hydroperoxy-FMN intermediate, which confirmed the findings based on the single mutation that His-396 was important for formation and Ser-171 for stabilization of the C4a-hydroperoxy-FMN intermediate in C(2). PMID- 21680742 TI - Two Drosophila myosin transducer mutants with distinct cardiomyopathies have divergent ADP and actin affinities. AB - Two Drosophila myosin II point mutations (D45 and Mhc(5)) generate Drosophila cardiac phenotypes that are similar to dilated or restrictive human cardiomyopathies. Our homology models suggest that the mutations (A261T in D45, G200D in Mhc(5)) could stabilize (D45) or destabilize (Mhc(5)) loop 1 of myosin, a region known to influence ADP release. To gain insight into the molecular mechanism that causes the cardiomyopathic phenotypes to develop, we determined whether the kinetic properties of the mutant molecules have been altered. We used myosin subfragment 1 (S1) carrying either of the two mutations (S1(A261T) and S1(G200D)) from the indirect flight muscles of Drosophila. The kinetic data show that the two point mutations have an opposite effect on the enzymatic activity of S1. S1(A261T) is less active (reduced ATPase, higher ADP affinity for S1 and actomyosin subfragment 1 (actin . S1), and reduced ATP-induced dissociation of actin . S1), whereas S1(G200D) shows increased enzymatic activity (enhanced ATPase, reduced ADP affinity for both S1 and actin . S1). The opposite changes in the myosin properties are consistent with the induced cardiac phenotypes for S1(A261T) (dilated) and S1(G200D) (restrictive). Our results provide novel insights into the molecular mechanisms that cause different cardiomyopathy phenotypes for these mutants. In addition, we report that S1(A261T) weakens the affinity of S1 . ADP for actin, whereas S1(G200D) increases it. This may account for the suppression (A261T) or enhancement (G200D) of the skeletal muscle hypercontraction phenotype induced by the troponin I held-up(2) mutation in Drosophila. PMID- 21680743 TI - Determinants of the higher order association of the restriction factor TRIM5alpha and other tripartite motif (TRIM) proteins. AB - Many tripartite motif (TRIM) proteins self-associate, forming dimers and higher order complexes. For example, dimers of TRIM5alpha, a host factor that restricts retrovirus infection, assemble into higher order arrays on the surface of the viral capsid, resulting in an increase in avidity. Here we show that the higher order association of different TRIM proteins exhibits a wide range of efficiencies. Homologous association (self-association) was more efficient than the heterologous association of different TRIM proteins, indicating that specificity determinants of higher order self-association exist. To investigate the structural determinants of higher order self-association, we studied TRIM mutants and chimeras. These studies revealed the following: 1) the RING domain contributes to the efficiency of higher order self-association, which enhances the binding of TRIM5alpha to the human immunodeficiency virus (HIV-1) capsid; 2) the RING and B-box 2 domains work together as a homologous unit to promote higher order association of dimers; 3) dimerization is probably required for efficient higher order self-association; 4) the Linker 2 region contributes to higher order self-association, independently of effects of Linker 2 changes on TRIM dimerization; and 5) for efficiently self-associating TRIM proteins, the B30.2(SPRY) domain is not required for higher order self-association. These results support a model in which both ends of the core TRIM dimer (RING-B-box 2 at one end and Linker 2 at the other) contribute to the formation of higher order arrays. PMID- 21680744 TI - Evidence of a role for soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery in HIV-1 assembly and release. AB - Retrovirus assembly is a complex process that requires the orchestrated participation of viral components and host-cell factors. The concerted movement of different viral proteins to specific sites in the plasma membrane allows for virus particle assembly and ultimately budding and maturation of infectious virions. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins constitute the minimal machinery that catalyzes the fusion of intracellular vesicles with the plasma membrane, thus regulating protein trafficking. Using siRNA and dominant negative approaches we demonstrate here that generalized disruption of the host SNARE machinery results in a significant reduction in human immunodeficiency virus type 1 (HIV-1) and equine infectious anemia virus particle production. Further analysis of the mechanism involved revealed a defect at the level of HIV-1 Gag localization to the plasma membrane. Our findings demonstrate for the first time a role of SNARE proteins in HIV-1 assembly and release, likely by affecting cellular trafficking pathways required for Gag transport and association with the plasma membrane. PMID- 21680745 TI - Mechanism and specificity of pentachloropseudilin-mediated inhibition of myosin motor activity. AB - Here, we report that the natural compound pentachloropseudilin (PClP) acts as a reversible and allosteric inhibitor of myosin ATPase and motor activity. IC(50) values are in the range from 1 to 5 MUm for mammalian class-1 myosins and greater than 90 MUm for class-2 and class-5 myosins, and no inhibition was observed with class-6 and class-7 myosins. We show that in mammalian cells, PClP selectively inhibits myosin-1c function. To elucidate the structural basis for PClP-induced allosteric coupling and isoform-specific differences in the inhibitory potency of the compound, we used a multifaceted approach combining direct functional, crystallographic, and in silico modeling studies. Our results indicate that allosteric inhibition by PClP is mediated by the combined effects of global changes in protein dynamics and direct communication between the catalytic and allosteric sites via a cascade of small conformational changes along a conserved communication pathway. PMID- 21680747 TI - Histone deacetylase 9 is a negative regulator of adipogenic differentiation. AB - Differentiation of preadipocytes into mature adipocytes capable of efficiently storing lipids is an important regulatory mechanism in obesity. Here, we examined the involvement of histone deacetylases (HDACs) and histone acetyltransferases (HATs) in the regulation of adipogenesis. We find that among the various members of the HDAC and HAT families, only HDAC9 exhibited dramatic down-regulation preceding adipogenic differentiation. Preadipocytes from HDAC9 gene knock-out mice exhibited accelerated adipogenic differentiation, whereas HDAC9 overexpression in 3T3-L1 preadipocytes suppressed adipogenic differentiation, demonstrating its direct role as a negative regulator of adipogenesis. HDAC9 expression was higher in visceral as compared with subcutaneous preadipocytes, negatively correlating with their potential to undergo adipogenic differentiation in vitro. HDAC9 localized in the nucleus, and its negative regulation of adipogenesis segregates with the N-terminal nuclear targeting domain, whereas the C-terminal deacetylase domain is dispensable for this function. HDAC9 co precipitates with USF1 and is recruited with USF1 at the E-box region of the C/EBPalpha gene promoter in preadipocytes. Upon induction of adipogenic differentiation, HDAC9 is down-regulated, leading to its dissociation from the USF1 complex, whereas p300 HAT is up-regulated to allow its association with USF1 and accumulation at the E-box site of the C/EBPalpha promoter in differentiated adipocytes. This reciprocal regulation of HDAC9 and p300 HAT in the USF1 complex is associated with increased C/EBPalpha expression, a master regulator of adipogenic differentiation. These findings provide new insights into mechanisms of adipogenic differentiation and document a critical regulatory role for HDAC9 in adipogenic differentiation through a deacetylase-independent mechanism. PMID- 21680746 TI - Nutritional regulation of bile acid metabolism is associated with improved pathological characteristics of the metabolic syndrome. AB - Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1alpha, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferator-activated receptor beta/delta target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome. PMID- 21680749 TI - Recording patient preferences for end-of-life care as an incentivized quality indicator: what do general practice staff think? AB - INTRODUCTION: Since April 2009, indicators for the UK Quality and Outcomes Framework pilot have been developed and piloted across a nationally representative sample of practices. In October 2009 a single palliative care indicator was piloted for 6 months that looked at, 'the percentage of patients on the palliative care register who have a preferred place to receive end-of-life care documented in the records'. AIM: The aim of this study was to gain the views and experiences of general practice staff on whether the inclusion of a single incentivized indicator to record the preferred place to receive end-of-life care would improve the quality of palliative care. Any issues arising from its implementation in a pay-for-performance scheme were also explored. METHODS: Interviews took place with 57 members of staff in 24 practices: 21 GPs, 16 practice managers, 12 nurses and eight others (mostly information technology experts). RESULTS: The indicator was not deemed appropriate for incentivization due to concerns about incentivizing an isolated, single issue within a multi faceted, multi-disciplinary and complex topic. Palliative care was seen to be too sensitive and patient specific to be amenable to population-level quality measurement. In implementation, the indicator would pose potential harm to patients who may be asked about their end-of-life care at an inappropriate time and by a member of staff who may not be best placed to address this sensitive topic. CONCLUSIONS: The most appropriate time to ask a patient about end-of-life care is subjective and patient specific and therefore does not lend itself to an inflexible single indicator. Focusing on one isolated question simplifies and distracts from a multi-faceted and complex issue and may lead to patient harm. PMID- 21680748 TI - Proton-sensing Ca2+ binding domains regulate the cardiac Na+/Ca2+ exchanger. AB - The cardiac Na(+)/Ca(2+) exchanger (NCX) regulates cellular [Ca(2+)](i) and plays a central role in health and disease, but its molecular regulation is poorly understood. Here we report on how protons affect this electrogenic transporter by modulating two critically important NCX C(2) regulatory domains, Ca(2+) binding domain-1 (CBD1) and CBD2. The NCX transport rate in intact cardiac ventricular myocytes was measured as a membrane current, I(NCX), whereas [H(+)](i) was varied using an ammonium chloride "rebound" method at constant extracellular pH 7.4. At pH(i) = 7.2 and [Ca(2+)](i) < 120 nM, I(NCX) was less than 4% that of its maximally Ca(2+)-activated value. I(NCX) increases steeply at [Ca(2+)](i) between 130-150 nM with a Hill coefficient (n(H)) of 8.0 +/- 0.7 and K(0.5) = 310 +/- 5 nM. At pH(i) = 6.87, the threshold of Ca(2+)-dependent activation of I(NCX) was shifted to much higher [Ca(2+)](i) (600-700 nM), and the relationship was similarly steep (n(H) = 8.0+/-0.8) with K(0.5) = 1042 +/- 15 nM. The V(max) of Ca(2+)-dependent activation of I(NCX) was not significantly altered by low pH(i). The Ca(2+) affinities for CBD1 (0.39 +/- 0.06 MUM) and CBD2 (K(d) = 18.4 +/- 6 MUM) were exquisitely sensitive to [H(+)], decreasing 1.3-2.3-fold as pH(i) decreased from 7.2 to 6.9. This work reveals for the first time that NCX can be switched off by physiologically relevant intracellular acidification and that this depends on the competitive binding of protons to its C(2) regulatory domains CBD1 and CBD2. PMID- 21680750 TI - Access to palliative care services in hospital: a matter of being in the right hospital. Hospital charts study in a Canadian city. AB - Access to palliative care (PC) is a major need worldwide. Using hospital charts of all patients who died over one year (April 2008-March 2009) in two mid-sized hospitals of a large Canadian city, similar in size and function and operated by the same administrative group, this study examined which patients who could benefit from PC services actually received these services and which ones did not, and compared their care characteristics. A significantly lower proportion (29%) of patients dying in hospital 2 (without a PC unit and reliant on a visiting PC team) was referred to PC services as compared to in hospital 1 (with a PC unit; 68%). This lower referral likelihood was found for all patient groups, even among cancer patients, and remained after controlling for patient mix. Referral was strongly associated with having cancer and younger age. Referral to PC thus seems to depend, at least in part, on the coincidence of being admitted to the right hospital. This finding suggests that establishing PC units or a team of committed PC providers in every hospital could increase referral rates and equity of access to PC services. The relatively lower access for older and non-cancer patients and technology use in hospital PC services require further attention. PMID- 21680751 TI - Factors associated with perceived barriers to pediatric palliative care: a survey of pediatricians in Florida and California. AB - PURPOSE: The provision and uptake of pediatric palliative care continues to be plagued by barriers. Several studies have documented these barriers, but none have done so with a diverse sample (most are at a single institution) or specifically about pediatric palliative care. Moreover, none have investigated the factors associated with perceived barriers. Our study has two aims: (1) to describe the barriers to pediatric palliative care as reported by a group of pediatricians practicing in two large States in the US; and (2) to identify factors associated with these perceived barriers. METHODS: Cross-sectional survey data were collected from 303 pediatricians in Florida and California. RESULTS: The two greatest barriers reported by the pediatricians were related to families' reluctance to accept palliative care (95%) and families viewing palliative care as giving up (94%). Only 42% of pediatricians noted that reimbursement was a barrier. Across all the regressions, three factors were consistently associated with barriers to palliative care: race/ethnicity of pediatrician practice setting, and the percentage of low-income patients. CONCLUSIONS: Our findings can be used to develop targeted educational interventions towards providers and families. Understanding the factors that are driving the low uptake in palliative care is the first step in advancing pediatric palliative care overall. PMID- 21680753 TI - The cellular prion protein is expressed in olfactory sensory neurons of adult mice but does not affect the early events of the olfactory transduction pathway. AB - A conformational conversion of the cellular prion protein (PrP(C)) is now recognized as the causal event of fatal neurodegenerative disorders, known as prion diseases. In spite of long-lasting efforts, however, the physiological role of PrP(C) remains unclear. It has been reported that PrP(C) is expressed in various areas of the olfactory system, including the olfactory epithelium, but its precise localization in olfactory sensory neurons (OSNs) is still debated. Here, using immunohistochemistry tools, we have reinvestigated the expression and localization of PrP(C) in the olfactory epithelium of adult congenic mice expressing different PrP(C) amounts, that is, wild-type, PrP-knockout, and transgenic PrP(C)-overexpressing animals. We found that PrP(C) was expressed in OSNs, in which, however, it was unevenly distributed, being detectable at low levels in cell bodies, dendrites and apical layer, and more abundantly in axons. We also studied the involvement of PrP(C) in the response of the olfactory epithelium to odorants, by comparing the electro-olfactograms of the 3 mouse lines subjected to different stimulation protocols. We found no significant difference between the 3 PrP genotypes, supporting previous reports that exclude a direct action of PrP(C) in the early signal transduction activity of the olfactory epithelium. PMID- 21680752 TI - Rationally designed treatment for solid tumors with MAPK pathway activation: a phase I study of paclitaxel and bortezomib using an adaptive dose-finding approach. AB - In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A phase I study was conducted to determine the maximum tolerated dose (MTD) of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting mitogen-activated protein kinase (MAPK) pathway activation were treated weekly with paclitaxel and bortezomib. Starting doses were 40 mg/m(2) for paclitaxel and 0.7 mg/m(2) for bortezomib. A modified continual reassessment method adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m(2) paclitaxel and 1.0 mg/m(2) bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one grade 3 event), fatigue (in 43.75% of patients, one grade 3 event beyond cycle 1), and neuropathy (in 31.25% of patients, one grade 3 event after cycle 1). Of 15 evaluable patients, one non-small-cell lung carcinoma (NSCLC) patient with paclitaxel exposure at the adjuvant setting had a partial response and five patients had stable disease (SD); median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation. PMID- 21680754 TI - Involvement of reperfusion injury salvage kinases in preconditioning depends critically on the preconditioning stimulus. AB - Different preconditioning stimuli can activate divergent signaling pathways. In rats, adenosine-independent pathways (triple 3-min coronary artery occlusion [3CAO3]) and adenosine-dependent pathways (one 15-min coronary artery occlusion [ICAO15]) exist, both ultimately converging at the level of the mitochondrial respiratory chain. Furthermore, while 3CAO3, 1CAO15 and exogenous adenosine (ADO) are equally cardioprotective, only 1CAO15 increases interstitial myocardial adenosine levels. Reperfusion Injury Salvage Kinase (RISK) pathway kinases have been implicated in ischemic preconditioning, but not all preconditioning stimuli activate this pathway. Consequently, we evaluated in anesthetized rats the effects of three distinctly different preconditioning stimuli (3CAO3, 1CAO15 or ADO) on infarct size (IS), signaling pathways with a special emphasis on kinases belonging to the RISK pathway (phosphatidylinositol 3-kinase-Akt-nitric oxide synthase and extracellular signal-related kinase [ERK]) and mitochondrial respiration. All three stimuli increased state-2 respiration (using succinate as complex-II substrate), thereby decreasing the respiratory control index, which was accompanied by a limitation of IS produced by a 60-min coronary artery occlusion (CAO). Nitric oxide synthase inhibition abolished the mitochondrial effects and the cardioprotection by 3CAO3, 1CAO15 or ADO. In contrast, the PI3 kinase inhibitor, wortmannin, blocked protection by 1CAO15, but did not affect protection by 3CAO3 or ADO. Western blotting confirmed that phosphorylation of Akt and ERK were increased by 1CAO15 (which was inhibited by wortmannin), but not by 3CAO3 or ADO. In conclusion, while the three cardioprotective stimuli 3CAO3, 1CAO15 and ADO afford cardioprotection via nitric oxide-mediated modulation of mitochondrial respiration, only the 1CAO15 exerts its protection via activation of kinases belonging to the RISK pathway. PMID- 21680755 TI - Vascular and metabolic dysfunction in Alzheimer's disease: a review. AB - Alzheimer's disease (AD) is thought to start years or decades prior to clinical diagnosis. Overt pathology such as protein misfolding and plaque formation occur at later stages, and factors other than amyloid misfolding contribute to the initiation of the disease. Vascular and metabolic dysfunctions are excellent candidates, as they are well-known features of AD that precede pathology or clinical dementia. While the general notion that vascular and metabolic dysfunctions contribute to the etiology of AD is becoming accepted, recent research suggests novel mechanisms by which these/such processes could possibly contribute to AD pathogenesis. Vascular dysfunction includes reduced cerebrovascular flow and cerebral amyloid angiopathy. Indeed, there appears to be an interaction between amyloid beta (Abeta) and vascular pathology, where Abeta production and vascular pathology both contribute to and are affected by oxidative stress. One major player in the vascular pathology is NAD(P)H oxidase, which generates vasoactive superoxide. Metabolic dysfunction has only recently regained popularity in relation to its potential role in AD. The role of metabolic dysfunction in AD is supported by the increased epidemiological risk of AD associated with several metabolic diseases such as diabetes, dyslipidemia and hypertension, in which there is elevated oxidative damage and insulin resistance. Metabolic dysfunction is further implicated in AD as pharmacological inhibition of metabolism exacerbates pathology, and several metabolic enzymes of the glycolytic, tricarboxylic acid cycle (TCA) and oxidative phosphorylation pathways are damaged in AD. Recent studies have highlighted the role of insulin resistance, in contributing to AD. Thus, vascular and metabolic dysfunctions are key components in the AD pathology throughout the course of disease. The common denominator between vascular and metabolic dysfunction emerging from this review appears to be oxidative stress and Abeta. This review also provides a framework for evaluation of current and future therapeutics for AD. PMID- 21680756 TI - Requirement for N-cadherin-catenin complex in heart development. AB - Cell adhesion, mediated by N-cadherin, is critical for embryogenesis since N cadherin-null embryos die during mid-gestation with multiple developmental defects. To investigate the role of N-cadherin in heart muscle development, N cadherin was specifically deleted from myocardial cells in mice. The structural integrity of the myocardial cell wall was compromised in the N-cadherin mutant embryos, leading to a malformed heart and a delay in embryonic development. In contrast, cardiac-specific deletion of alphaE-catenin, found in adherens junctions, or beta-catenin, did not cause any morphological defects in the embryonic heart, presumably due to compensation by alphaT-catenin that is normally found in intercalated disks and gamma-catenin (plakoglobin), respectively. Embryos lacking beta-catenin in the heart also exhibited a cardiac defect, but only later in development resulting in partial lethality. These genetic studies underscore the importance of the N-cadherin/catenin complex in cardiogenesis. PMID- 21680757 TI - Dermoscopy of pigmented lesions of the mucosa and the mucocutaneous junction: results of a multicenter study by the International Dermoscopy Society (IDS). AB - OBJECTIVE: To better characterize the dermoscopic patterns of mucosal lesions in relation to the histopathologic characteristics. DESIGN: Retrospective and observational study. SETTING: Fourteen referral pigmented lesion clinics in 10 countries. PATIENTS: A total of 140 pigmented mucosal lesions (126 benign lesions, 11 melanomas, 2 Bowen disease lesions, and 1 metastasis) from 92 females (66%) and 48 males (34%) were collected from October 2007 through November 2008. MAIN OUTCOME MEASURES: Scoring the dermoscopic patterns (dots, globules, or clods, circles, lines, or structureless) and colors (brown, black, blue, gray, red, purple, and white) and correlation with the histopathologic characteristics. RESULTS: Based on univariate analysis and 2 diagnostic models, the presence of structureless zones inside the lesions with blue, gray, or white color (the first model) had a 100% sensitivity for melanoma and 92.9% sensitivity for any malignant lesion, and 82.2% and 83.3% specificity for benign lesions in the group with melanoma lesions and the group with malignant lesions, respectively. Based on the colors (blue, gray, or white) only (the second model), the sensitivity for the group with melanoma was 100% and for the group with any malignant lesion was 92.9%, and the specificity was 64.3% and 65.1%, respectively. Patients with malignant lesions were significantly older than patients with benign lesions (mean [SD] ages, 60.1 [22.8] years vs 43.2 [17.3] years, respectively). CONCLUSION: The combination of blue, gray, or white color with structureless zones are the strongest indicators when differentiating between benign and malignant mucosal lesions in dermoscopy. PMID- 21680758 TI - Long-term outcome of Spitz-type melanocytic tumors. AB - OBJECTIVE: Despite recent advances in our molecular understanding of Spitz-type tumors, the clinical behavior of these lesions remains unclear. We thus set out to define the clinical outcome of classic Spitz nevi, atypical Spitz tumors (ASTs), and spitzoid melanomas. DESIGN: From 1987 through 2002, data on all lesions containing the term "Spitz" or "Spitz" [AND] "melanoma" were retrieved from the pathology database at Massachusetts General Hospital, and the cases were followed up for their outcome. SETTING: The study was performed at a university affiliated tertiary health care center in Boston, Massachusetts. PATIENTS: A total of 157 patients with Spitz-type melanocytic lesions and follow-up information were identified. MAIN OUTCOME MEASURES: Sentinel lymph node biopsy results, metastases, or fatality were assessed. RESULTS: There were 68 classic Spitz nevi, 76 ASTs, 10 spitzoid melanomas, and 3 melanomas that arose in Spitz nevi. Spitz nevi were diagnosed at a younger age than ASTs (mean age, 26.4 years vs 33.7 years) (P = .01), though both occurred earlier than melanomas (mean age, 50.4 years, P < .001). Sentinel lymph node biopsy findings were positive in 1 of 6 and 4 of 8 patients with ASTs and spitzoid melanomas, respectively. After a median follow-up of 9.1 years, only 1 patient with an AST, who had a separate intermediate-thickness melanoma, developed distant metastasis. There were 6 documented invasive melanomas among 144 patients with classic Spitz nevi or ASTs (observed/expected ratio, 8.03) (P = .01). CONCLUSIONS: Atypical Spitz tumors are associated with minimal lethal potential, an increased melanoma risk, and a moderate risk of metastasis to regional nodes. It makes clinical sense to minimize aggressive treatment but to offer careful surveillance for rare relapses and subsequent melanomas. PMID- 21680759 TI - Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. AB - BACKGROUND: Interleukin (IL)-23 is involved in the pathogenesis of the chronic inflammatory Crohn disease. Pyoderma gangrenosum (PG) is often associated with and can even be the first manifestation of this disease and has abundant neutrophilic infiltration. Because IL-23 plays a critical role in driving inflammation associated with IL-17 production and especially neutrophil recruitment, we suspect that PG might be driven by a pathogenetic mechanism similar to that of inflammatory bowel diseases or psoriasis. OBSERVATIONS: Tissue sample analysis showed highly elevated expression of IL-23 on both transcriptional and protein level in a recalcitrant PG lesion. On the basis on these data, a treatment targeting the p40 subunit of the heterodimeric IL-23 with the monoclonal antibody ustekinumab was started. Therapy with ustekinumab resulted in a significant decrease of IL-23 expression in PG and healing after 14 weeks of treatment. No relapse occurred in a 6-month follow-up period. CONCLUSIONS: Our data provide evidence of an IL-23-dominated inflammatory infiltrate in PG. This might specify a new concept for PG pathophysiology and suggests a possibility for using ustekinumab as a therapeutic agent in this disease. PMID- 21680760 TI - The impact of pruritus on quality of life: the skin equivalent of pain. AB - OBJECTIVE: To compare the impact of chronic pruritus and chronic pain on quality of life (QoL) using directly elicited health utility scores. DESIGN: Cross sectional study. SETTING: Convenience sample of patients attending the Emory Dermatology Clinic, Emory Spine Center, and Emory Center for Pain Management, Atlanta, Georgia. PARTICIPANTS: Adult men and women (aged >= 18 years) experiencing chronic pain or pruritus for 6 weeks or more. MAIN OUTCOME MEASURES: The mean utility score of patients with chronic pruritus was compared with that of patients with chronic pain. A regression analysis was performed to determine the impact of the primary predictor variable-symptom type-on the primary outcome variable-mean utility score (a metric representing the impact on QoL). RESULTS: The study included 73 patients with chronic pruritus and 138 patients with chronic pain. The mean (SD) utility among patients with pruritus was 0.87 (0.27) compared with 0.77 (0.31) for patients with pain (P < .01). After symptom severity, duration, and demographic factors were controlled for, only symptom severity (0.03 [P < .05]) and single marital status (-0.12 [P = .02]), but not symptom type (P = .43), remained significant predictors of the mean symptom utility score. CONCLUSIONS: Chronic pruritus has a substantial impact on QoL, one that may be comparable to that of pain. The severity of symptoms and the use of support networks are the main factors that determine the degree to which patients are affected by their symptoms. Addressing support networks in addition to developing new therapies may improve the QoL of itchy patients. PMID- 21680761 TI - Reversible posterior leukoencephalopathy syndrome in a patient treated with ustekinumab: case report and review of the literature. AB - BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare, generally reversible neurologic syndrome that is diagnosed based on characteristic clinical and radiologic findings. OBSERVATIONS: We describe the first case of RPLS in a 65-year-old woman who underwent ustekinumab therapy for psoriasis. Approximately 2½ years after the patient began ustekinumab therapy, she experienced an acute onset of confusion, headache, nausea, vomiting, and seizures. Computed tomographic scans and magnetic resonance images of her head revealed characteristic findings, including white matter abnormalities consistent with edema in the absence of infarction. There was no evidence of vasospasm, thrombosis, or infection. Cerebrospinal fluid tests were negative for the JC virus. The patient improved clinically and was discharged 6 days after she presented to the emergency department. She made a full neurologic recovery, with a reversal of the radiologic findings. CONCLUSIONS: Reversible posterior leukoencephalopathy syndrome is an increasingly recognized neurologic disorder that has been reported with the use of systemic and biologic agents to treat moderate to severe psoriasis. Although the relationship between RPLS and ustekinumab therapy remains unclear, this case emphasizes the need for dermatologists to recognize the syndrome's signs and symptoms and to refer patients promptly for evaluation and appropriate treatment if the clinical features of RPLS are suspected. PMID- 21680762 TI - Description and evaluation of a social cognitive model of physical activity behaviour tailored for adolescent girls. AB - The aim of this paper was to describe and test a social cognitive model of physical activity tailored for adolescent girls. Participants were 1518 girls (aged 13.6 +/- 0.02 years) from 24 secondary schools in New South Wales, Australia. Useable accelerometer (>=10 hours day(-1) on at least 3 days) and questionnaire data were obtained from 68% of this sample (N = 1035). Participants completed questionnaires assessing psychological, behavioural, social and environmental correlates of activity. The theoretical model was tested using structural equation modelling in AMOS. The model explaining accelerometer counts per minute was an adequate-to-good fit to the data (Tucker-Lewis Index = 0.89, the comparative fit index = 0.97 and the root mean square of approximation = 0.098; 90% confidence interval = 0.075-0.122) but explained only 5% of the variance in activity. There were significant model pathways from self-efficacy (r = 0.11, P = 0.01), school environment (r = 0.07, P = 0.02) and physical self worth (r = 0.07, P = 0.04) to accelerometer counts. Although the proposed model provided an adequate-to-good fit to the data, it explained a small portion of the variance. Shared method variance may explain the larger portions of variance explained in previous studies. Future studies are encouraged to evaluate theories of physical activity behaviour change using objective measures of physical activity. PMID- 21680763 TI - Interventions to promote physical activity among young and adolescent girls: a systematic review. AB - A narrative systematic review was conducted to describe the available evidence from physical activity (PA) interventions that targeted girls aged 5-18 years and to determine their effectiveness and key characteristics of success. Systematic literature searches were conducted using four databases: PubMed, Web of Science, PsychInfo and SPORTDiscus and by examining the reference lists of included articles and published relevant reviews, to identify studies published in English from 2000 to July 2010. Randomized controlled trials or quasi-experimental designs with pre-test and post-test behavioral outcome data (objective or self report measure) were included. Methodological quality was assessed using a checklist and conclusions were made concerning effectiveness. A total of 29 articles were reviewed, describing the evaluation of 21 interventions. Ten studies reported a favorable intervention effect upon PA outcomes, seven of which were rated as having a high methodological quality. Multi-component school-based interventions that also offer a physical education that address the unique needs of girls seemed to be the most effective. Although family support is revealed as ineffective, peer strategies showed promising evidence. The review finishes highlighting possible intervention strategies and reporting areas where further investigation is required. PMID- 21680764 TI - Differentiation of division I (cfiA-negative) and division II (cfiA-positive) Bacteroides fragilis strains by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is increasingly used in clinical microbiological laboratories to identify bacteria and fungi at a species level and to subtype them. The cfiA gene encoding the unique carbapenemases found in Bacteroides is restricted to division II Bacteroides fragilis strains. The aim of this study was to evaluate whether MALDI-TOF MS is suitable for differentiating B. fragilis strains which harbour the cfiA gene from those that do not. A well-defined collection of 40 B. fragilis isolates with known imipenem MICs (0.062->32 mg l(-1)) were selected for this study. Twelve B. fragilis strains with known cfiA status, including NCTC 9343 (division I) and TAL3636 (division II), were measured by means of microflex LT MALDI-TOF MS and well-defined differences in mass spectra between the cfiA positive and cfiA-negative strains were found in the interval 4000-5500 Da. A further 28 strains were selected for the blind measurements: 9 cfiA-positive clinical isolates with different imipenem MICs ranging between 0.06 and >32 mg l( 1) (different expressions of the metallo-beta-lactamase gene) were clearly separated from the 19 cfiA-negative isolates. The presence or absence of the selected peaks in all tested strains clearly differentiated the strains belonging to B. fragilis division I (cfiA-negative) or division II (cfiA-positive). These results suggest a realistic method for differentiating division II B. fragilis strains (harbouring the cfiA gene) and to determine them at a species level at the same time. Although not all cfiA-positive B. fragilis strains are resistant to carbapenems, they all have the possibility of becoming resistant to this group of antibiotics by acquisition of an appropriate IS element for full expression of the cfiA gene, leading to possible treatment failure. PMID- 21680765 TI - Concurrent diphtheria and infectious mononucleosis: difficulties for management, investigation and control of diphtheria in developing countries. AB - We report a case of concurrent diphtheria and infectious mononucleosis in an 11 year-old Brazilian child. Two days after specific treatment for diphtheria was started the patient was discharged following clinical recovery. This case highlights the difficulties in the clinical diagnosis of diphtheria in partially immunized individuals, and for the management and control of diphtheria in developing countries. PMID- 21680766 TI - Piperine as an inhibitor of the MdeA efflux pump of Staphylococcus aureus. AB - Piperine, a trans-trans-isomer of 1-piperoyl-piperidine, was tested in combination with mupirocin for antimicrobial activity against Staphylococcus aureus strains including meticillin-resistant S. aureus. The combination markedly reduced the MIC of mupirocin and also lowered the mutation frequency. Enhanced accumulation and efflux of ethidium bromide from wild-type and mutant (Mup(r)-1) strains in the presence of piperine indicated that inhibition of efflux could be a possible mechanism of potentiation of mupirocin activity by piperine. The combination of piperine with mupirocin in a dermal infection model of mice showed better in vivo efficacy when compared with the commercially available formulation of 2 % mupirocin. PMID- 21680767 TI - Detection of Aspergillus species in BACTEC blood cultures. AB - Invasive aspergillosis is associated with high morbidity and mortality rates; nevertheless, blood cultures almost invariably yield a negative result. The recovery and detection time of Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus were studied in BACTEC Plus Aerobic/F, Mycosis-IC/F and Myco/F Lytic vials, incubated in the BACTEC 9240 and 9000 MB automated systems. Two different approaches were used for subculture in solid medium: (i) the routine method, using a sterile airway needle/subculture unit, and (ii) a novel procedure, using instead a tuberculin disposable syringe and collecting a larger aliquot (100 ul), following vigorous agitation of the vials. A. fumigatus was detected at inoculum concentrations of >3 conidia per 10 ml after 21-40 h, in both BACTEC Plus Aerobic/F and BACTEC Mycosis-IC/F vials. A few more hours were needed to detect A. flavus and A. terreus. The novel subculture procedure of BACTEC culture vials on solid medium resulted in several positive results that were not detected by the routine sampling procedure. BACTEC Plus Aerobic/F vials show an advantage particularly in patients under antifungal treatment. In cases of polymicrobial bloodstream infections (concurrent bacterial growth), the inoculation of blood samples into a BACTEC Mycosis-IC/F vial achieved the best results. Further multicentre studies are needed to validate this improved automated detection of Aspergillus spp. from blood cultures in clinical laboratories, as this diagnostic procedure allows antifungal susceptibility testing of moulds. PMID- 21680769 TI - Molecular epidemiology of mumps virus strains circulating in south-west China from 2007 to 2009. AB - The genetic characteristics of mumps virus (MuV) strains isolated from sporadic mumps cases between 2007 and 2009 in three provinces of south-west China were investigated. MuV detection was carried out by nested RT-PCR on 117 cases. The small hydrophobic gene of 33 isolated strains was identified, and sequence analysis revealed that all the isolates belonged to the lineage genotype F with slight nucleotide variation. Furthermore, the virus haemagglutinin-neuraminidase and nucleoprotein antigens exhibited a high degree of nucleotide and amino acid similarity (>99 %) within all isolates, whilst the fusion protein appeared to have certain geographical differences. This study on molecular surveillance will help to monitor the circulation of MuV in China. PMID- 21680768 TI - Multilocus sequence typing analysis of Streptococcus mutans strains with the cnm gene encoding collagen-binding adhesin. AB - Streptococcus mutans is one of the oral pathogens associated with infective endocarditis (IE). With respect to bacterial binding ability to the extracellular matrix, the Cnm protein, a cell surface collagen-binding adhesin of S. mutans, is known as one of the possible virulence factors with regard to IE. In this study, we aimed to determine the distribution of the cnm gene, which encodes Cnm, in a large number of clinical isolates of S. mutans from Thai subjects. Then, the cnm positive strains were classified using a multilocus sequence typing (MLST) scheme, which we constructed previously. In addition, the data were analysed together with our previous MLST data of cnm-positive strains from Japan and Finland in order to evaluate the clonal relationship among S. mutans strains harbouring the cnm gene. The cnm gene was detected in 12.4 % of all 750 Thai isolates, and serotype f showed the highest rate of detection (54.5 %). According to the MLST data, two clonal complex groups were revealed as the important clones related to cnm-positive S. mutans from various origins of isolation. Moreover, the collagen-binding properties of S. mutans strains with the cnm gene were significantly greater than those of strains without the gene, although four cnm negative strains classified into two sequence types (STs), ST110 and ST136, showed extremely high collagen-binding rates suggesting the presence of additional genes involved with collagen binding in these STs. Taken together, these results provided information on both epidemiological as well as evolutional aspects of S. mutans possessing the cnm gene. PMID- 21680770 TI - Association of body mass index with self-report and performance-based measures of balance and mobility. AB - BACKGROUND: The incidence of obesity is increasing in older adults, with associated worsening in the burden of disability. Little is known about the impact of body mass index (BMI) on self-report and performance-based balance and mobility measures in older adults. OBJECTIVE: The purposes of this study were (1) to examine the association of BMI with measures of balance and mobility and (2) to explore potential explanatory factors. DESIGN: This was a cross-sectional, observational study. METHODS: Older adults (mean age=77.6 years) who participated in an ongoing observational study (N=120) were classified as normal weight (BMI=18.5-24.9 kg/m(2)), overweight (BMI=25.0-29.9 kg/m(2)), moderately obese (BMI=30.0-34.9 kg/m(2)), or severely obese (BMI >= 35 kg/m(2)). Body mass index data were missing for one individual; thus, data for 119 participants were included in the analysis. Mobility and balance were assessed using self-report and performance-based measures and were compared among weight groups using analysis of variance and chi-square analysis for categorical data. Multiple linear regression analysis was used to examine the association among BMI, mobility, and balance after controlling for potential confounding variables. RESULTS: Compared with participants who were of normal weight or overweight, those with moderate or severe obesity were less likely to report their mobility as very good or excellent (52%, 55%, 39%, and 6%, respectively); however, there was no difference in self-report of balance among weight groups. Participants with severe obesity (n=17) had the lowest levels of mobility on the performance based measures, followed by those who were moderately obese (n=31), overweight (n=42), and of normal weight (n=29). There were no differences on performance based balance measures among weight groups. After controlling for age, sex, minority status, physical activity level, education level, and comorbid conditions, BMI still significantly contributed to mobility (beta=-.02, adjusted R(2)=.41). CONCLUSIONS: Although older adults with severe obesity were most impaired, those with less severe obesity also demonstrated significant decrements in mobility. PMID- 21680771 TI - Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial. AB - BACKGROUND: Fatigue and impaired upright postural control (balance) are the 2 most common findings in people with multiple sclerosis (MS), with treatment approaches varying greatly in effectiveness. OBJECTIVES: The aim of this study was to investigate the benefits of implementing a vestibular rehabilitation program for the purpose of decreasing fatigue and improving balance in patients with MS. DESIGN: The study was a 14-week, single-blinded, stratified blocked randomized controlled trial. SETTING: Measurements were conducted in an outpatient clinical setting, and interventions were performed in a human performance laboratory. PATIENTS: Thirty-eight patients with MS were randomly assigned to an experimental group, an exercise control group, or a wait-listed control group. INTERVENTION: The experimental group underwent vestibular rehabilitation, the exercise control group underwent bicycle endurance and stretching exercises, and the wait-listed control group received usual medical care. MEASUREMENTS: Primary measures were a measure of fatigue (Modified Fatigue Impact Scale), a measure of balance (posturography), and a measure of walking (Six-Minute Walk Test). Secondary measures were a measure of disability due to dizziness or disequilibrium (Dizziness Handicap Inventory) and a measure of depression (Beck Depression Inventory-II). RESULTS: Following intervention, the experimental group had greater improvements in fatigue, balance, and disability due to dizziness or disequilibrium compared with the exercise control group and the wait-listed control group. These results changed minimally at the 4-week follow-up. Limitations The study was limited by the small sample size. Further investigations are needed to determine the underlying mechanisms associated with the changes in the outcome measures due to the vestibular rehabilitation program. CONCLUSION: A 6-week vestibular rehabilitation program demonstrated both statistically significant and clinically relevant change in fatigue, impaired balance, and disability due to dizziness or disequilibrium in patients with MS. PMID- 21680772 TI - Frontal-plane gait mechanics in people with medial knee osteoarthritis are different from those in people with lateral knee osteoarthritis. AB - BACKGROUND: The majority of research on gait mechanics in knee osteoarthritis has focused on people with medial compartment involvement. As a result, little is known about the gait mechanics of people with the less common, lateral compartment disease. OBJECTIVE: The objective of this study was to compare walking mechanics--specifically, differences in frontal-plane lower-extremity kinematics and kinetics--in people with medial knee osteoarthritis, people with lateral knee osteoarthritis, and people who were healthy. DESIGN: A cross sectional design was used. METHODS: Fifteen people with medial knee osteoarthritis, 15 people with lateral knee osteoarthritis, and 15 people who were healthy (control group) were recruited for the study. All participants underwent a gait analysis at an intentional walking speed. The variables of interest for the study were peak frontal-plane moments and angles and angular excursions of the lower extremity during the stance phase of gait. Data were statistically analyzed with a one-way analysis of variance. RESULTS: Participants with lateral knee osteoarthritis exhibited significantly less knee adduction excursion, lower peak knee abduction moment, and lower peak rear-foot eversion compared with the control group and the medial knee osteoarthritis group. LIMITATIONS: Participants in the control group were approximately 10 years younger than participants with knee osteoarthritis. Despite this difference, neither body mass index nor gait speed, each of which is a factor with a stronger influence on gait mechanics, differed among the groups. CONCLUSIONS: Participants with lateral knee osteoarthritis exhibited frontal-plane gait mechanics at the knee and rear foot that were different from those of participants with medial knee osteoarthritis. The results of this study may guide the development of interventions specific to treating people with lateral knee osteoarthritis. PMID- 21680773 TI - Myosin Va plays a key role in nitrergic neurotransmission by transporting nNOSalpha to enteric varicosity membrane. AB - Nitrergic neurotransmission at the smooth muscle neuromuscular junctions requires nitric oxide (NO) release that is dependent on the transport and docking of neuronal NO synthase (nNOS) alpha to the membrane of nerve terminals. However, the mechanism of translocation of nNOSalpha in actin-rich varicosities is unknown. We report here that the processive motor protein myosin Va is necessary for nitrergic neurotransmission. In wild-type mice, nNOSalpha-stained enteric varicosities colocalized with myosin Va and its tail constituent light chain 8 (LC8). In situ proximity ligation assay showed close association among nNOSalpha, myosin Va, and LC8. nNOSalpha was associated with varicosity membrane. Varicosities showed nitric oxide production upon stimulation with KCl. Intracellular microelectrode studies showed nitrergic IJP and smooth muscle hyperpolarizing responses to NO donor diethylenetriamine-NO (DNO). In contrast, enteric varicosities from myosin Va-deficient DBA (for dilute, brown, non-agouti) mice showed near absence of myosin Va but normal nNOSalpha and LC8. Membrane bound nNOSalpha was not detectable, and the varicosities showed reduced NO production. Intracellular recordings in DBA mice showed reduced nitrergic IJPs but normal hyperpolarizing response to DNO. The nitrergic slow IJP was 9.1 +/- 0.7 mV in the wild-type controls and 3.4 +/- 0.3 mV in the DBA mice (P < 0.0001). Deficiency of myosin Va resulted in loss of nitrergic neuromuscular neurotransmission despite normal presence of nNOSalpha in the varicosities. These studies reveal the critical importance of myosin Va in nitrergic neurotransmission by facilitating transport of nNOSalpha to the varicosity membrane. PMID- 21680774 TI - Role of inhibitory kappaB kinase and c-Jun NH2-terminal kinase in the development of hepatic insulin resistance in critical illness diabetes. AB - Hyperglycemia and insulin resistance induced by acute injuries or critical illness are associated with increased mortality and morbidity, as well as later development of type 2 diabetes. The molecular mechanisms underlying the acute onset of insulin resistance following critical illness remain poorly understood. In the present studies, the roles of serine kinases, inhibitory kappaB kinase (IKK) and c-Jun NH(2)-terminal kinase (JNK), in the acute development of hepatic insulin resistance were investigated. In our animal model of critical illness diabetes, activation of hepatic IKK and JNK was observed as early as 15 min, concomitant with the rapid impairment of hepatic insulin signaling and increased serine phosphorylation of insulin receptor substrate 1. Inhibition of IKKalpha or IKKbeta, or both, by adenovirus vector-mediated expression of dominant-negative IKKalpha or IKKbeta in liver partially restored insulin signaling. Similarly, inhibition of JNK1 kinase by expression of dominant-negative JNK1 also resulted in improved hepatic insulin signaling, indicating that IKK and JNK1 kinases contribute to critical illness-induced insulin resistance in liver. PMID- 21680776 TI - Batrachotoxin, pyrethroids, and BTG 502 share overlapping binding sites on insect sodium channels. AB - Batrachotoxin (BTX), a steroidal alkaloid, and pyrethroid insecticides bind to distinct but allosterically coupled receptor sites on voltage-gated sodium channels and cause persistent channel activation. BTX presumably binds in the inner pore, whereas pyrethroids are predicted to bind at the lipid-exposed cavity formed by the short intracellular linker-helix IIS4-S5 and transmembrane helices IIS5 and IIIS6. The alkylamide insecticide (2E,4E)-N-(1,2-dimethylpropyl)-6-(5 bromo-2-naphthalenyl)-2,4-hexadienamide (BTG 502) reduces sodium currents and antagonizes the action of BTX on cockroach sodium channels, suggesting that it also binds inside the pore. However, a pyrethroid-sensing residue, Phe(3i17) in IIIS6, which does not face the pore, is essential for the activity of BTG 502 but not for BTX. In this study, we found that three additional deltamethrin-sensing residues in IIIS6, Ile(3i12), Gly(3i14), and Phe(3i16) (the latter two are also BTX-sensing), and three BTX-sensing residues, Ser(3i15) and Leu(3i19) in IIIS6 and Phe(4i15) in IVS6, are all critical for BTG 502 action on cockroach sodium channels. Using these data as constraints, we constructed a BTG 502 binding model in which BTG 502 wraps around IIIS6, probably making direct contacts with all of the above residues on the opposite faces of the IIIS6 helix, except for the putative gating hinge Gly(3i14). BTG 502 and its inactive analog DAP 1855 antagonize the action of deltamethrin. The antagonism was eliminated by mutations of Ser(3i15), Phe(3i17), Leu(3i19), and Phe(4i15) but not by mutations of Ile(3i12), Gly(3i14), and Phe(3i16). Our analysis revealed a unique mode of action of BTG 502, its receptor site overlapping with those of both BTX and deltamethrin. PMID- 21680777 TI - Functional adaptation of the N-methyl-D-aspartate receptor to inhibition by ethanol is modulated by striatal-enriched protein tyrosine phosphatase and p38 mitogen-activated protein kinase. AB - The hippocampal N-methyl-D-aspartate receptor (NMDAR) activity plays important roles in cognition and is a major substrate for ethanol-induced memory dysfunction. This receptor is a glutamate-gated ion channel, which is composed of NR1 and NR2 subunits in various brain areas. Although homomeric NR1 subunits form an active ion channel that conducts Na+ and Ca2+ currents, the incorporation of NR2 subunits allows this channel to be modulated by the Src family of kinases, phosphatases, and by simple molecules such as ethanol. We have found that short term ethanol application inhibits the NMDAR activity via striatal enriched protein tyrosine phosphatase (STEP)-regulated mechanisms. The genetic deletion of the active form of STEP, STEP61, leads to marked attenuation of ethanol inhibition of NMDAR currents. In addition, STEP61 negatively regulates Fyn and p38 mitogen-activated protein kinase (MAPK), and these proteins are members of the NMDAR super molecular complex. Here we demonstrate, using whole-cell electrophysiological recording, Western blot analysis, and pharmacological manipulations, that neurons exposed to a 3-h, 45 mM ethanol treatment develop an adaptive attenuation of short-term ethanol inhibition of NMDAR currents in brain slices. Our results suggest that this adaptation of NMDAR responses is associated with a partial inactivation of STEP61, an activation of p38 MAPK, and a requirement for NR2B activity. Together, these data indicate that altered STEP61 and p38 MAPK signaling contribute to the modulation of ethanol inhibition of NMDARs in brain neurons. PMID- 21680778 TI - Challenges for diabetic care: rural Africa & type 1 brittle diabetes. PMID- 21680779 TI - Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. AB - Our group and others have determined that immune effector cells from patients with advanced cancers exhibit reduced activation of IFN signaling pathways. We hypothesized that increases in immune regulatory cells termed myeloid-derived suppressor cells (MDSC) could interfere with the host immune response to tumors by inhibiting immune cell responsiveness to IFNs. The C26 murine adenocarcinoma model was employed to study immune function in advanced malignancy. C26-bearing mice had significantly elevated levels of GR1(+)CD11b(+) MDSC as compared with control mice, and splenocytes from tumor-bearing mice exhibited reduced phosphorylation of STAT1 (P-STAT1) on Tyr(701) in response to IFN-alpha or IFN gamma. This inhibition was seen in splenic CD4(+) and CD8(+) T cells as well as natural killer cells. In vitro coculture experiments revealed that MDSC inhibited the IFN responsiveness of splenocytes from normal mice. Treatment of C26-bearing mice with gemcitabine or an anti-GR1 antibody led to depletion of MDSC and restored splenocyte IFN responsiveness. Spleens from C26-bearing animals displayed elevated levels of iNOS protein and nitric oxide. In vitro treatment of splenocytes with a nitric oxide donor led to a decreased STAT1 IFN response. The elevation in nitric oxide in C26-bearing mice was associated with increased levels of nitration on STAT1. Finally, splenocytes from iNOS knockout mice bearing C26 tumors exhibited a significantly elevated IFN response as compared with control C26 tumor-bearing mice. These data suggest that nitric oxide produced by MDSC can lead to reduced IFN responsiveness in immune cells. PMID- 21680781 TI - Effect of quercetin on CYP3A activity in Chinese healthy participants. AB - The aims of this study were to investigate the effect of quercetin on CYP3A activity in vivo. An open, randomized, 2-period crossover experiment was performed in 18 healthy male volunteers. Genotyped data were available from a total of 165 participants. The allelic frequency was 52.5%. Every volunteer ingested orally 500 mg quercetin or placebo once a day for 13 consecutive days. On day 14, a single 7.5-mg midazolam tablet was administrated orally. The plasma concentrations of midazolam and 1-OH-midazolam were determined over 24 hours. The results showed that coadministration of quercetin in CYP3A5*1/*1 and CYP3A5*1/*3 individuals significantly decreased the area under the curve (AUC(0-12 h)) of midazolam (160.88 +/- 45.58 ng.h/mL vs 188.07 +/- 65.75 ng.h/mL, P < .05), significantly decreased the AUC(0-infinity) of midazolam (165.46 +/- 47.15 ng.h/mL vs 211.84 +/- 75.80 ng.h/mL, P < .01), shortened t(1/2) (2.06 +/- 0.51 h vs 2.75 +/- 0.89 h, P < .01), and decreased t(max) significantly (0.48 +/- 0.36 h vs 1.06 +/- 0.69 h, P < .01), respectively. In conclusion, quercetin significantly induced CYP3A activity to substrate midazolam, and the induction was partly related to the CYP3A5 genotype, being more prominent in CYP3A5*1/*1 and CYP3A5*1/*3 individuals. PMID- 21680782 TI - A novel PEGylated interferon beta-1a for multiple sclerosis: safety, pharmacology, and biology. AB - This study clinically evaluated a novel PEGylated form of interferon beta-1a (PEG IFN beta-1a), a potential first-line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single-dose study (n = 60) comparing subcutaneous or intramuscular PEG-IFN beta 1a (63, 125, or 188 ug) with intramuscular unmodified IFN beta-1a 30 ug and a multiple-dose study (n = 69) comparing subcutaneous PEG-IFN beta-1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2',5'-OAS) measures, exploratory immune assessments, safety, and tolerability. A dose-proportional increase in PEG-IFN beta-1a exposure was observed, with a 4-fold greater exposure at 63 ug (6 million international units [MIU]) of PEG-IFN beta-1a than with 30 ug (6 MIU) intramuscular unmodified IFN beta-1a. Increases in neopterin and 2',5'-OAS levels and changes in T helper cell pathway gene expression and lymphocyte subsets were greater and more sustained with PEG-IFN beta-1a than with unmodified IFN beta-1a. PEG-IFN beta-1a was well tolerated, with only transient reductions in absolute neutrophils and some lymphocytes. Flu-like symptoms were a commonly reported adverse event. These data support the continued clinical development of PEG-IFN beta-1a as a potentially effective treatment for patients with relapsing multiple sclerosis. PMID- 21680783 TI - Regucalcin is broadly expressed in male reproductive tissues and is a new androgen-target gene in mammalian testis. AB - Regucalcin (RGN) is a calcium (Ca(2)(+))-binding protein which regulates intracellular Ca(2)(+) homeostasis by modulating the activity of enzymes regulating Ca(2)(+) concentration and enhancing Ca(2)(+)-pumping activity. Several studies have described the pivotal role of proper Ca(2)(+) homeostasis regulation to spermatogenesis and male fertility. Recently, RGN was identified as a sex steroid-regulated gene in prostate and breast; however, a possible role of RGN in spermatogenesis has not been examined. In this study, the expression and localization of RGN in rat and human testis, and other rat reproductive tissues was analyzed. Moreover, we studied whether RGN protein was present in seminiferous tubule fluid (STF). Finally, we examined the effect of 5alpha dihydrotestosterone (DHT) on the expression of Rgn mRNA in rat seminiferous tubules (SeT) cultured ex vivo. The results presented in this study show that RGN is expressed in Leydig and Sertoli cells, as well as in all types of germ cells of both rat and human testis. RGN is also expressed in rat prostate, epididymis, and seminal vesicles. Moreover, RGN protein is present in rat STF. The results also demonstrate that Rgn expression is age dependent in rat testis, and is upregulated by the non-aromatizable androgen DHT in rat SeT cultured ex vivo. Taken together, these findings indicate that Rgn is a novel androgen-target gene in rat testis and that it may have a role in male reproductive function, particularly in the control of spermatogenesis. PMID- 21680780 TI - Medical ultrasound: imaging of soft tissue strain and elasticity. AB - After X-radiography, ultrasound is now the most common of all the medical imaging technologies. For millennia, manual palpation has been used to assist in diagnosis, but it is subjective and restricted to larger and more superficial structures. Following an introduction to the subject of elasticity, the elasticity of biological soft tissues is discussed and published data are presented. The basic physical principles of pulse-echo and Doppler ultrasonic techniques are explained. The history of ultrasonic imaging of soft tissue strain and elasticity is summarized, together with a brief critique of previously published reviews. The relevant techniques-low-frequency vibration, step, freehand and physiological displacement, and radiation force (displacement, impulse, shear wave and acoustic emission)-are described. Tissue-mimicking materials are indispensible for the assessment of these techniques and their characteristics are reported. Emerging clinical applications in breast disease, cardiology, dermatology, gastroenterology, gynaecology, minimally invasive surgery, musculoskeletal studies, radiotherapy, tissue engineering, urology and vascular disease are critically discussed. It is concluded that ultrasonic imaging of soft tissue strain and elasticity is now sufficiently well developed to have clinical utility. The potential for further research is examined and it is anticipated that the technology will become a powerful mainstream investigative tool. PMID- 21680784 TI - Effects of polyunsaturated fatty acid supplementation on ruminal in situ forage degradability, performance, and physiological responses of feeder cattle. AB - Two experiments were conducted to compare ruminal, physiological, and performance responses of forage-fed cattle consuming grain-based supplements without (NF) or with the inclusion (10%; DM basis) of a rumen-protected PUFA (PF) or SFA source (SF). Supplements were offered and consumed at 0.6% of BW/animal daily (DM basis). In Exp. 1, DMI and ruminal in situ forage degradability were evaluated in 3 Angus * Hereford cows fitted with ruminal cannulas and allocated to a 3 * 3 Latin square design. Within each experimental period, hay was offered in amounts to ensure ad libitum access from d 1 to 13, DMI was recorded from d 8 to 13, and cows were limited to receive 90% of their average hay DMI (d 1 to 13) from d 14 to 21. On d 16, polyester bags containing 4 g of ground hay (DM basis) were incubated within the rumen of each cow for 0, 4, 8, 12, 24, 36, 48, 72, and 96 h. Hay and total DMI were reduced (P < 0.05) in cows receiving PF compared with cows receiving SF and NF. No treatment effects were detected (P > 0.48) for ruminal disappearance rate and effective ruminal degradability of hay DM and NDF. In Exp. 2, preconditioning DMI, ADG, carcass traits, and plasma concentrations of cortisol, fatty acids, acute-phase proteins, and proinflammatory cytokines were assessed in 72 Angus * Hereford steers receiving supplement treatments during a 28-d preconditioning period. All steers were transported to a commercial growing lot after preconditioning (d 1) and were later moved to an adjacent commercial finishing yard (d 144), where they remained until slaughter. No treatment effects were detected (P >= 0.52) for preconditioning ADG and G:F, but DMI tended (P = 0.09) to be reduced in steers receiving PF compared with those receiving NF and SF. Plasma PUFA concentrations were greater in steers receiving PF compared with those receiving NF and SF (P = 0.01). After transportation, concentration of tumor necrosis factor-alpha increased for steers receiving NF, did not change for steers receiving SF, but decreased for steers receiving PF (treatment * day interaction, P < 0.01). Steers fed PF had greater (P = 0.02) ADG compared with those fed NF during the growing phase. Carcass yield grade and marbling were greater (P < 0.05) for steers fed PF compared with those fed NF. In conclusion, PUFA supplementation did not affect ruminal forage degradability but did impair DMI in beef cows. Further, PUFA supplementation to steers during preconditioning reduced plasma concentrations of tumor necrosis factor-alpha after transportation, and benefited growing lot ADG and carcass marbling. PMID- 21680785 TI - Genetic associations between feed efficiency measured in a performance test station and performance of growing cattle in commercial beef herds. AB - Interest in selection for improved feed efficiency is increasing, but before any steps are taken toward selecting for feed efficiency, correlations with other economically important traits must first be quantified. The objective of this study was to quantify the genetic associations between feed efficiency measured during performance testing and linear type traits, BW, live animal value, and carcass traits recorded in commercial herds. Feed efficiency data were available on 2,605 bulls from 1 performance test station. There were between 10,384 and 93,442 performance records on type traits, BW, animal value, or carcass traits from 17,225 commercial herds. (Co)variance components were estimated using linear mixed animal models. Genetic correlations between the muscular type traits in commercial animals and feed conversion ratio (-0.33 to -0.25), residual feed intake (RFI; -0.33 to -0.22), and residual BW gain (RG; 0.24 to 0.27) suggest that selection for improved feed efficiency should increase muscling. This is further evidenced by the genetic correlations between carcass conformation of commercial animals and feed conversion ratio (-0.46), RFI (-0.37), and residual BW gain (0.35) measured in performance-tested animals. Furthermore, the genetic correlations between RFI and both ultrasonic fat depth and carcass fat score (0.39 and 0.33, respectively) indicated that selection for improved RFI will result in leaner animals. It can be concluded from the genetic correlations estimated in this study that selection for feed efficiency will have no unfavorable effects on the performance traits measured in this study and will actually lead to an improvement in performance for some traits, such as muscularity, animal price, and carcass conformation. Conversely, this suggests that genetic selection for traits such as carcass quality, muscling traits, and animal value might also be indirectly selecting for more efficient animals. PMID- 21680786 TI - The effects of road transportation on physiological responses and meat quality in sheep differing in age. AB - The aim of this study was to determine the effects of 8 h of road transportation on physiological responses and meat quality traits of sheep at 6, 12, and 24 mo of age. Seventy-two male sheep were equally divided into transported (TRANS) and nontransported (CON) treatments (n = 36), and each treatment was subdivided into 3 groups by age (n = 12). Sheep in CON groups were weighed, blood sampled, and slaughtered, whereas sheep in TRANS groups were weighed, transported, blood sampled, and slaughtered to collect meat samples. The BW of sheep in TRANS groups was reduced significantly (P < 0.001) compared with CON sheep, and older sheep lost more BW than younger animals. However, dressing percentages of TRANS sheep were significantly (P < 0.001) greater than those of CON sheep. Some meat quality variables were affected by transportation, and responses of different ages of sheep varied. Total pigment content and lipid oxidation of LM and gluteus medius of TRANS sheep increased significantly (P < 0.001) compared with CON sheep. Cooking loss of LM and gluteus medius was influenced significantly (P < 0.01) by interaction effect between transportation and age, and the values for 6-mo-old TRANS sheep were less than those of CON sheep. Serum total protein (P = 0.036), globulin (P = 0.026), triglyceride (P < 0.001), and total cholesterol concentrations (P = 0.028) of TRANS sheep decreased compared with CON sheep. Serum NEFA concentration of TRANS sheep increased in relation to CON sheep with a significant interaction (P < 0.001) between transportation and age effect. Numbers of white blood cells were influenced (P = 0.002) by an interaction effect between transportation and age, and values for 6-mo-old sheep were not influenced by transportation. Numbers of platelets were influenced (P = 0.014) by age; they decreased more in 6-mo-old sheep than in older sheep. Transportation and age had no significant effects (P > 0.05) on packed cell volume and lymphocyte number. Serum creatine kinase activities in TRANS sheep were affected (P = 0.01) by an interaction effect between transportation and age. The 2-thiobarbituric acid reactive substances in serum of TRANS sheep increased (P = 0.009) with the greatest change for 6-mo-old compared with older sheep. In conclusion, 8 h of road transportation resulted in greater heme pigment concentrations but improved meat tenderness and induced physiological responses of sheep. However, different ages of sheep showed different responses to the present transportation pattern. PMID- 21680787 TI - Influence of sex and castration on growth performance and carcass quality of crossbred pigs from 2 Large White sire lines. AB - In total, 360 pigs slaughtered at 125 kg of BW and destined for the dry-cured industry were used to study the influence of sex and castration [immunocastrated males (IMC), surgically castrated males (CM), and intact females (IF)] in 2 terminal Large White sire lines [Top York (TY) and Tempo (TE)] on growth performance and carcass and meat quality. The female line was Large White * Landrace. The IMC pigs were immunized against gonadotropin-releasing factor (GnRF) with Improvac at 78 (experimental d 16) and 126 (experimental d 64, 48 d before slaughter) d of age. Each of the 6 treatments was replicated 6 times (10 pigs/pen). Through the day of the first Improvac injection (62 to 78 d of age), IMC and IF grew at a slower rate (P < 0.001) than CM with no differences (P = 0.95) in feed intake. The CM had greater G:F than IF, with IMC being intermediate (P < 0.01). From 78 to 126 d of age (between Improvac injections), the IMC pigs ate less feed (P < 0.001) and grew at a slower rate than CM, with IF being intermediate. The IMC pigs were more feed efficient than IF, and both were more efficient than CM (P < 0.001). However, from 126 to 174 d of age (from the second Improvac injection to slaughter), IMC pigs grew at a faster rate (P < 0.001) and were more efficient (P < 0.001) than IF and CM. Overall, IMC and CM pigs grew at a faster rate (P < 0.01) than IF, and IMC were more efficient than the other sexes (P < 0.001), but had reduced (P < 0.001) carcass yield compared with CM and IF. The IMC and IF pigs also had less (P < 0.001) backfat depth than CM. Intact females had greater (P < 0.01) loin yield but less intramuscular fat than IMC and CM and greater (P < 0.05) fresh and trimmed ham yields than CM, with IMC being intermediate. Crossbreds from TE sires grew at a faster rate (P < 0.001) than crossbreds from TY sires, but no differences (P = 0.23 and 0.14, respectively) were found for feed intake or efficiency. Crossbreds from TY produced greater (P < 0.05) fresh and trimmed ham yield, but less (P < 0.01) loin yield and intramuscular fat content than crossbreds from TE. In conclusion, IMC pigs are more efficient, but have less carcass yield than CM and IF. The intramuscular fat content is least for IF and similar for IMC and CM. Crossbreds from TE sires were larger and had greater intramuscular fat content, but slightly less trimmed ham yield compared with crossbreds from TY sires. Immunocastrated pigs can replace CM for the production of heavy pigs destined for the dry-cured industry. Because of increased carcass weight, crossbreds from TE sires may have an advantage over crossbreds from TY sires. PMID- 21680788 TI - Development of a system for classification of pork loins for tenderness using visible and near-infrared reflectance spectroscopy. AB - Boneless pork loins (n = 901) were evaluated either on the loin boning and trimming line of large-scale commercial plants (n = 465) or at the US Meat Animal Research Center abattoir (n = 436). Exposed LM on the ventral side of boneless loins was evaluated with visible and near-infrared spectroscopy (VISNIR; 450 to 1,000 nm) using a commercial system that was developed for on-line evaluation of beef tenderness. Boneless loin sections were aged (2 degrees C) until 14 d postmortem, and two 2.54-cm-thick chops were obtained from the 11th-rib region. Fresh (never frozen) chops were cooked (71 degrees C) and LM slice shear force (SSF) was measured on each of the 2 chops. Those 2 values were averaged, and that value was used for all analyses. Loins were blocked by plant (n = 3), production day (n = 24), and observed SSF (mean = 13.9 kg; SD = 3.7 kg; CV = 26.8%; range 6.4 to 32.4 kg). One-half of the loins were assigned to a calibration data set, which was used to develop regression equations, and one-half of the loins were assigned to a prediction data set, which was used to validate the regression equations. A partial least-squares regression model was developed, and loins were classified as predicted tender or not predicted tender if their VISNIR-predicted SSF was <14.0 kg or >=14.0 kg, respectively. Analysis of variance was used to determine the effect of VISNIR classification on SSF. The calibration data set and prediction data set had 61.9 and 60.9% of the loins classified as predicted tender, respectively. For both the calibration data set and the prediction data set, mean SSF was less for loins predicted tender than loins not predicted tender (P < 0.001). Relative to loins that were not predicted tender, the percentage of loins with SSF >=20 kg was less for loins predicted tender in the calibration data set (3.6 vs. 8.1%) and prediction data set (1.8 vs. 13.6%). These results clearly indicate that the VISNIR technology could be used to noninvasively classify pork loins on-line for tenderness. PMID- 21680789 TI - Modeling the fate of dietary phosphorus in the digestive tract of growing pigs. AB - Environmental effects of excess P from manure and the soaring price of phosphates are major issues in pig production. To optimize P utilization, it is crucial to improve our capacity to predict the amount of P absorbed, while taking into account the main factors of variation. Mathematical modeling can represent the complexity of the processes and interactions in determining the digestive utilization of P in growing pigs. This paper describes and evaluates a model developed to simulate the fate of the dietary forms of P in the digestive tract of growing pigs, with particular emphasis on the effect of dietary Ca and exogenous phytase on P digestive utilization. The model consists of 3 compartments associated with specific anatomical sections: stomach, proximal small intestine, and distal small intestine. The main metabolic processes occurring in these sections are, respectively, P solubilization/insolubilization and phytate P hydrolysis, and P absorption and P insolubilization. Model parameters governing these flows were derived from in vitro and in vivo literature data. The sensitivity analysis revealed that the model was stable within a large range of model parameter values (+/-1.5 SD). The model was able to predict the efficacy of Aspergillus niger microbial phytase in accordance with literature values, as well as the decreased efficacy of plant phytase compared with microbial phytase. The prediction capabilities of the model were assessed by comparing actual and simulated P and Ca apparent total-tract digestibility (ATTD) based on published pig data not used for model development. Prediction of P digestibility across 66 experiments and 281 observations was adequate [P ATTD observed = 0.24 (SE, 0.943) + 0.98 (SE, 0.0196) * P ATTD predicted; R(2), 0.90; disturbance error (ED), 96.5%], whereas prediction of Ca digestibility across 47 experiments and 193 observations was less accurate (Ca ATTD observed = 11.1 + 0.75 * Ca ATTD predicted; R(2), 0.78; ED, 20.4%). A lack of agreement between experimental and simulated Ca digestibility was found. This model is, therefore, useful in evaluating P digestibility for different feedstuffs and feeding strategies. It can also be used to provide insight for improving dietary P utilization, especially from plant sources, by quantifying the effect of the mean sources of variation affecting P utilization. PMID- 21680790 TI - Alterations in the transcriptome of porcine oocytes derived from prepubertal and cyclic females is associated with developmental potential. AB - The developmental competence of oocytes is progressively attained as females approach puberty. The poor quality of prepubertally derived oocytes suggests that essential processes during cytoplasmic maturation have not been completed. The objective of this experiment was to identify genes in oocytes that are associated with good (cyclic females) and poor (prepubertal females) developmental competence. Development to the blastocyst stage in vitro was significantly decreased in oocytes derived from prepubertal females compared with cyclic females (5.26 and 12.86%, respectively). Approximately 10% of the oocyte transcriptome was differentially expressed between in vitro-matured oocytes derived from cyclic and prepubertal females (P < 0.05); 58% of differentially expressed genes had increased transcript abundance in oocytes derived from cyclic females. Genes involved in the metabolism and regulation of biological processes had increased transcript abundance in oocytes derived from cyclic females, whereas genes involved in translation were increased in prepubertally derived oocytes. Quantitative PCR confirmed differential expression (P < 0.05) for 6 out of 11 selected genes [DPYD (dihydropyrimidine dehydrogenase), RDH11 (retinol dehydrogenase 11), SFRS4 (serine/arginine-rich splicing factor 4), SFRS7 (serine/arginine-rich splicing factor 7), TL4 (transcribed loci 4), and TOP2B (topoisomerase II beta)] that were differentially expressed with greater than a 2 fold change by microarray, although 3 of these genes, DPYD, TL4, and TOP2B, were in opposing directions by the 2 methods. In conclusion, expression of multiple genes involved in metabolism and translation was significantly altered in oocytes from prepubertal females compared with cyclic females, which was associated with reduced in vitro development to the blastocyst stage. These genes may represent important cellular mechanisms that regulate oocyte quality. PMID- 21680791 TI - Warner-Bratzler and slice shear force measurements of 3 beef muscles in response to various aging periods after trenbolone acetate and estradiol implants and zilpaterol hydrochloride supplementation of finishing beef steers. AB - Our objectives were to determine the effects of zilpaterol hydrochloride (ZH) and the release rate of trenbolone acetate and estradiol-17beta on the Warner Bratzler shear force (WBSF) and slice shear force (SSF) of longissimus lumborum (LL) and the WBSF of gluteus medius (GM) and psoas major (PM) in response to various aging periods. British * Continental steers (n = 168) were assigned to treatments in a 3 * 2 factorial. The main effects of treatment were implant (no implant, Revalor-S, Revalor-XS, Intervet/Schering Plough Animal Health, De Soto, KS) and ZH (0 or 8.3 mg/kg of DM for 20 d). Slaughter group was included as a random effect to account for the variation in days on feed (153 or 174 d). Loins (n = 96) were fabricated to obtain strip loin, top sirloin butt, and tenderloin subprimals. Five 2.54-cm steaks were cut from each subprimal and assigned to 1 of 5 aging periods (7, 14, 21, 28, or 35 d postmortem). Feeding ZH increased (P <= 0.01) LL WBSF and SSF values at each aging period compared with controls. Implanting increased (P < 0.05) LL WBSF values at 14 and 21 d, but did not affect LL SSF values (P > 0.05). Only Revalor-S increased (P <= 0.05) WBSF values at 28 and 35 d compared with no implant or Revalor-XS. The percentage of LL steaks with a WBSF value below 4.6 kg did not differ (P > 0.05) between ZH supplementation or implant strategy at any aging period, and by d 28, more than 99% of LL steaks registered WBSF values below 4.6 kg. Feeding ZH increased (P < 0.05) GM WBSF values only on d 21. Implant had no effect (P > 0.05) on GM WBSF values. The percentage of GM steaks with a WBSF value below 4.6 kg did not differ (P > 0.05) between ZH supplementation or implant strategy at any aging period. Neither ZH nor implant strategy affected PM WBSF values (P > 0.05). All PM WBSF values were below 4.6 kg on d 7. The results of this study indicated that feeding ZH increased WBSF and SSF of LL steaks, regardless of the aging period; however, the percentage of steaks with WBSF below 4.6 kg did not differ because of ZH or implant. Implanting increased LL WBSF values, but not SSF values. These results showed that although differences existed between implanting, as well as ZH supplementation of British * Continental steers, 99% of LL steaks were classified as tender based on WBSF values by extending aging to 28 d postmortem. It should be noted that 21.2% of 7-d, 13.8% of 14-d, and 17.3% of 21-d ZH steaks had WBSF values greater than 4.6 kg, but 0% of nonsupplemented steaks were greater than 4.6 kg at these aging periods. However, because ZH and implants can increase retail yield of valuable subprimals, such as the tenderloin, considerable value could be captured through ZH supplementation with anabolic implants because shear force was not affected in PM steaks. PMID- 21680792 TI - Genetic relationships between feed efficiency in growing males and beef cow performance. AB - Most studies on feed efficiency in beef cattle have focused on performance in young animals despite the contribution of the cow herd to overall profitability of beef production systems. The objective of this study was to quantify, using a large data set, the genetic covariances between feed efficiency in growing animals measured in a performance-test station, and beef cow performance including fertility, survival, calving traits, BW, maternal weaning weight, cow price, and cull cow carcass characteristics in commercial herds. Feed efficiency data were available on 2,605 purebred bulls from 1 test station. Records on cow performance were available on up to 94,936 crossbred beef cows. Genetic covariances were estimated using animal and animal-dam linear mixed models. Results showed that selection for feed efficiency, defined as feed conversion ratio (FCR) or residual BW gain (RG), improved maternal weaning weight as evidenced by the respective genetic correlations of -0.61 and 0.57. Despite residual feed intake (RFI) being phenotypically independent of BW, a negative genetic correlation existed between RFI and cow BW (-0.23; although the SE of 0.31 was large). None of the feed efficiency traits were correlated with fertility, calving difficulty, or perinatal mortality. However, genetic correlations estimated between age at first calving and FCR (-0.55 +/- 0.14), Kleiber ratio (0.33 +/- 0.15), RFI (-0.29 +/- 0.14), residual BW gain (0.36 +/- 0.15), and relative growth rate (0.37 +/- 0.15) all suggest that selection for improved efficiency may delay the age at first calving, and we speculate, using information from other studies, that this may be due to a delay in the onset of puberty. Results from this study, based on the estimated genetic correlations, suggest that selection for improved feed efficiency will have no deleterious effect on cow performance traits with the exception of delaying the age at first calving. PMID- 21680793 TI - Rates of treatment discontinuation due to adverse events for echinocandins. PMID- 21680794 TI - Preclinical studies on targeted delivery of multiple IFNalpha2b to HLA-DR in diverse hematologic cancers. AB - The short circulating half-life and side effects of IFNalpha affect its dosing schedule and efficacy. Fusion of IFNalpha to a tumor-targeting mAb (mAb-IFNalpha) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb IFNalpha comprising tetrameric IFNalpha2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFNalpha or a mixture comprising the parental mAb and IFNalpha. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFNalpha and hL243. C2-2b-2b induced more potent and longer-lasting IFNalpha signaling compared with nontargeted IFNalpha. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFNalpha, peginterferonalfa-2a, or a combination of hL243 and IFNalpha, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. PMID- 21680795 TI - Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. AB - We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias, the largest pediatric cancer genome sequencing effort reported to date. Integrated analysis of 179 validated somatic sequence mutations with genome-wide copy number alterations and gene expression profiles revealed a high frequency of recurrent somatic alterations in key signaling pathways, including B-cell development/differentiation (68% of cases), the TP53/RB tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%). Recurrent mutations were also found in ETV6 (6 cases), TBL1XR1 (3), CREBBP (3), MUC4 (2), ASMTL (2), and ADARB2 (2). The frequency of mutations within the 4 major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCR-ABL1 like gene expression profile, 96% had somatic alterations in B-cell development/differentiation, 57% in JAK, and 52% in both pathways, whereas only 9% had Ras pathway mutations. In contrast, 21 cases defined by a distinct gene expression profile coupled with focal ERG deletion rarely had B-cell development/differentiation or JAK kinase alterations but had a high frequency (62%) of Ras signaling pathway mutations. These data extend the range of genes that are recurrently mutated in high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets. PMID- 21680797 TI - Outcome of patients with acute myeloid leukemia with monosomal karyotype who undergo hematopoietic cell transplantation. AB - Monosomal karyotype (MK), defined as >= 2 autosomal monosomies or a single monosomy in the presence of other structural abnormalities, was confirmed by several studies to convey an extremely poor prognosis in patients with acute myeloid leukemia (AML) with a 4-year overall survival after diagnosis of < 4%. A recent investigation by the Southwest Oncology Group found that the only MK(+) patients alive and disease free > 6 years from diagnosis received allogeneic hematopoietic cell transplantation (HCT). To expand this observation, we retrospectively analyzed 432 patients treated with HCT at the Fred Hutchinson Cancer Research Center, 14% of whom were MK(+). The 4-year overall survival of patients after HCT was 25% for MK(+) AML and 56% for MK(-) AML (adjusted hazard ratio = 2.29, P < .0001). Among the MK(+) patients, complex karyotype was associated with a significantly worse outcome than patients with noncomplex karyotype (adjusted hazard ratio = 2.70, P = .03). Thus, although the prognosis of MK(+) patients remains worse than that for MK(-) patients in the transplantation setting, HCT appears to improve the overall outcome of MK(+) patients, especially patients without a complex karyotype. However, the 28% of MK(+) patients > 60 years had only a 6% 4-year survival rate after HCT, stressing the need for new approaches in these patients. PMID- 21680796 TI - IL-7R expression and IL-7 signaling confer a distinct phenotype on developing human B-lineage cells. AB - IL-7 is an important cytokine for lymphocyte differentiation. Similar to what occurs in vivo, human CD19+ cells developing in human/murine xenogeneic cultures show differential expression of the IL-7 receptor alpha (IL-7Ralpha) chain (CD127). We now describe the relationship between CD127 expression/signaling and Ig gene rearrangement. In the present study, < 10% of CD19+CD127+ and CD19+CD127- populations had complete VDJ(H) rearrangements. IGH locus conformation measurements by 3D FISH revealed that CD127+ and CD127- cells were less contracted than pediatric BM pro-B cells that actively rearrange the IGH locus. Complete IGH rearrangements in CD127+ and CD127- cells had smaller CDR3 lengths and fewer N-nucleotide insertions than pediatric BM B-lineage cells. Despite the paucity of VDJ(H) rearrangements, microarray analysis indicated that CD127+ cells resembled large pre-B cells, which is consistent with their low level of Ig light chain rearrangements. Unexpectedly, CD127- cells showed extensive Ig light-chain rearrangements in the absence of IGH rearrangements and resembled small pre-B cells. Neutralization of IL-7 in xenogeneic cultures led to an increase in Ig light-chain rearrangements in CD127+ cells, but no change in complete IGH rearrangements. We conclude that IL-7-mediated suppression of premature Ig light chain rearrangement is the most definitive function yet described for IL-7 in human B-cell development. PMID- 21680798 TI - Angiopoietin-1 promotes endothelial differentiation from embryonic stem cells and induced pluripotent stem cells. AB - Angiopoietin-1 (Ang1) plays a crucial role in vascular and hematopoietic development, mainly through its cognate receptor Tie2. However, little is known about the precise role of Ang1 in embryonic stem cell (ESC) differentiation. In the present study, we used COMP-Ang1 (a soluble and potent variant of Ang1) to explore the effect of Ang1 on endothelial and hematopoietic differentiation of mouse ESCs in an OP9 coculture system and found that Ang1 promoted endothelial cell (EC) differentiation from Flk-1(+) mesodermal precursors. This effect mainly occurred through Tie2 signaling and was altered in the presence of soluble Tie2 Fc. We accounted for this Ang1-induced expansion of ECs as enhanced proliferation and survival. Ang1 also had an effect on CD41(+) cells, transient precursors that can differentiate into both endothelial and hematopoietic lineages. Intriguingly, Ang1 induced the preferential differentiation of CD41(+) cells toward ECs instead of hematopoietic cells. This EC expansion promoted by Ang1 was also recapitulated in induced pluripotent stem cells (iPSCs) and human ESCs. We successfully achieved in vivo neovascularization in mice by transplantation of ECs obtained from Ang1-stimulated ESCs. We conclude that Ang1/Tie2 signaling has a pivotal role in ESC-EC differentiation and that this effect can be exploited to expand EC populations. PMID- 21680799 TI - Monoclonal antibodies detect receptor-induced binding sites in Glu-plasminogen. AB - When Glu-plasminogen binds to cells, its activation to plasmin is markedly enhanced compared with the reaction in solution, suggesting that Glu-plasminogen on cell surfaces adopts a conformation distinct from that in solution. However, direct evidence for such conformational changes has not been obtained. Therefore, we developed anti-plasminogen mAbs to test the hypothesis that Glu-plasminogen undergoes conformational changes on its interaction with cells. Six anti plasminogen mAbs (recognizing 3 distinct epitopes) that preferentially recognized receptor-induced binding sites (RIBS) in Glu-plasminogen were obtained. The mAbs also preferentially recognized Glu-plasminogen bound to the C-terminal peptide of the plasminogen receptor, Plg-R(KT), and to fibrin, plasmin-treated fibrinogen, and Matrigel. We used trypsin proteolysis, immunoaffinity chromatography, and tandem mass spectrometry and identified Glu-plasminogen sequences containing epitopes recognized by the anti-plasminogen-RIBS mAbs: a linear epitope within a domain linking kringles 1 and 2; a nonlinear epitope contained within the kringle 5 domain and the latent protease domain; and a nonlinear epitope contained within the N-terminal peptide of Glu-plasminogen and the latent protease domain. Our results identify neoepitopes latent in soluble Glu-plasminogen that become available when Glu-plasminogen binds to cells and demonstrate that binding of Glu plasminogen to cells induces a conformational change in Glu-plasminogen distinct from that of Lys-Pg. PMID- 21680801 TI - KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib. AB - Systemic mastocytosis (SM) either presents as a malignant neoplasm with short survival or as an indolent disease with normal life expectancy. In both instances, neoplastic mast cells (MCs) harbor D816V-mutated KIT, suggesting that additional oncogenic mechanisms are involved in malignant transformation. We here describe that Lyn and Btk are phosphorylated in a KIT-independent manner in neoplastic MCs in advanced SM and in the MC leukemia cell line HMC-1. Lyn and Btk activation was not only detected in KIT D816V-positive HMC-1.2 cells, but also in the KIT D816V-negative HMC-1.1 subclone. Moreover, KIT D816V did not induce Lyn/Btk activation in Ba/F3 cells, and deactivation of KIT D816V by midostaurin did not alter Lyn/Btk activation. siRNAs against Btk and Lyn were found to block survival in neoplastic MCs and to cooperate with midostaurin in producing growth inhibition. Growth inhibitory effects were also obtained with 2 targeted drugs, dasatinib which blocks KIT, Lyn, and Btk activation in MCs, and bosutinib, a drug that deactivates Lyn and Btk without blocking KIT activity. Together, KIT independent signaling via Lyn/Btk contributes to growth of neoplastic MCs in advanced SM. Dasatinib and bosutinib disrupt Lyn/Btk-driven oncogenic signaling in neoplastic MC, which may have clinical implications and explain synergistic drug interactions. PMID- 21680802 TI - Can low-performing hospitals train high-performing residents? PMID- 21680800 TI - Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. AB - An association between platelets, angiogenesis, and cancer has long been recognized, but the mechanisms linking them remains unclear. Platelets regulate new blood vessel growth through numerous stimulators and inhibitors of angiogenesis by several pathways, including differential exocytosis of angiogenesis regulators. Herein, we investigated the differential release of angiogenesis stimulators and inhibitors from platelets. Activation of human platelets with adenosine diphosphate (ADP) stimulated the release of VEGF, but not endostatin whereas, thromboxane A(2) (TXA(2)) released endostatin but not VEGF. Platelet releasates generated by activation with ADP promoted migration and formation of capillary structures by human umbilical vein endothelial cells (HUV EC-Cs) in in vitro angiogenesis models. Conversely, TXA(2)-stimulated platelet releasate inhibited migration and formation of capillary structures. Because tumor growth beyond 1-2 mm(3) is angiogenesis-dependent, we hypothesized that cancer cells preferentially stimulate platelets to secrete their pro-angiogenic payload. In support of this, the breast cancer cell line MCF-7 stimulated secretion of VEGF and a pro-angiogenic releasate from platelets. Furthermore, the antiplatelet agent aspirin inhibited platelet-mediated angiogenesis after exposure to ADP or MCF-7 cells providing a potential mechanism for how aspirin may impact malignancy. Manipulation of differentially mediated release of angiogenic factors from platelets may provide a new modality for cancer treatment. PMID- 21680803 TI - Ushering in a new era for POEMS. PMID- 21680804 TI - A POTEntial new gene for thrombocytopenia. PMID- 21680805 TI - Chronic GVHD: a new risk score? PMID- 21680806 TI - A path analysis of a randomized promotora de salud cardiovascular disease prevention trial among at-risk Hispanic adults. AB - This study assessed effectiveness of an educational community intervention taught by promotoras de salud in reducing cardiovascular disease (CVD) risk among Hispanics using a structural equation modeling (SEM) approach. Model development was guided by a social ecological framework proposing CVD risk reduction through improvement of protective health behaviors, health beliefs, contextual and social factors. Participants were 328 Hispanic adults with at least one CVD risk factor. SEM analyses assessed direct and indirect effects of intervention participation on CVD risk (Framingham score) and latent variables nutrition intake and health beliefs. The model fit was adequate (root mean square error of approximation = .056 [90% confidence interval = .040, .072], comparative fit index = .967, normed fit index = .938, nonnormed fit index = .947). Intervention participation was associated with improved nutritional consumption, but not lower CVD risk. Stronger health beliefs predicted healthier nutritional habits. This project provided evidence for the adequacy of a conceptual framework that can be used to elicit new pathways toward CVD risk reduction among at-risk Hispanic populations. PMID- 21680807 TI - Physician knowledge and awareness of CA-125 as a screen for ovarian cancer in the asymptomatic, average-risk population. AB - Effective early detection strategies for ovarian cancer do not exist. Current screening guidelines recommend against routine screening using CA-125 alone or in combination with transvaginal ultrasonography (TVS). In this study, the authors used the 2008 DocStyles survey to measure clinician beliefs about the effectiveness of CA-125 and TVS in the asymptomatic, average-risk population in the United States. To assess the need for provider education, the authors used the 2008 HealthStyles survey to examine public awareness of CA-125. Of 1,250 physician respondents, 40.4% said both CA-125 and TVS were effective screens, and 28.3% said neither was an effective ovarian cancer screen in the asymptomatic, average-risk population. Obstetrician/gynecologists [OB/GYNs] more often had responses consistent with current guidelines: 56.5% of OB/GYNs, compared with 34.4% and 29.8% of family/general practitioners and internists, respectively, said neither CA-125 nor TVS was an effective screen. Almost one third of women surveyed reported having heard of CA-125, and about one tenth said they had the CA-125 test. These findings support the need for additional provider education. Educational efforts should include lack of evidence for, as well as the potential harms of, screening for ovarian cancer with CA-125. PMID- 21680809 TI - Daily use of sildenafil improves endothelial function in men with type 2 diabetes. AB - Diminished vascular endothelial function results in decreased vasodilator capacity and is associated with erectile dysfunction (ED) in patients afflicted with type 2 diabetes. The current study was designed to evaluate whether daily use of sildenafil could alter endothelial function and improve penile rigidity in a group of patients with diabetic ED. A double-blind, placebo-controlled, prospective trial was conducted with 24 men with type 2 diabetes who were randomized into 2 groups: one receiving daily sildenafil (50 mg, n = 12) and the other placebo (n = 12) for 10 weeks. Erectile function was captured subjectively using the International Index of Erectile Function (IIEF-5), and endothelial function was objectively monitored via brachial artery flow-mediated dilation. Among the placebo and sildenafil groups, there were no significant differences in average patient age, time from type 2 diabetes diagnosis, duration of ED, or baseline IIEF-5 scores. Past medical histories, including smoking, alcohol consumption, hypertension, and hyperlipidemia, were also similar. At the conclusion of the 10-week trial, patients who received daily sildenafil had significantly improved erectile rigidity as captured by IIEF-5 (P < .001) and increased endothelial function via brachial artery flow-mediated dilation (P < .01). Endothelial function in men with type 2 diabetes was enhanced with daily sildenafil. Improved erectile rigidity and enhanced vascular circulation was noted after 10 weeks of daily sildenafil use. PMID- 21680810 TI - Terraces in phylogenetic tree space. AB - A key step in assembling the tree of life is the construction of species-rich phylogenies from multilocus--but often incomplete--sequence data sets. We describe previously unknown structure in the landscape of solutions to the tree reconstruction problem, comprising sometimes vast "terraces" of trees with identical quality, arranged on islands of phylogenetically similar trees. Phylogenetic ambiguity within a terrace can be characterized efficiently and then ameliorated by new algorithms for obtaining a terrace's maximum-agreement subtree or by identifying the smallest set of new targets for additional sequencing. Algorithms to find optimal trees or estimate Bayesian posterior tree distributions may need to navigate strategically in the neighborhood of large terraces in tree space. PMID- 21680808 TI - Modeling prostate cancer in mice: limitations and opportunities. AB - The complex dynamics of the tumor microenvironment and prostate cancer heterogeneity have confounded efforts to establish suitable preclinical mouse models to represent human cancer progression from early proliferative phenotypes to aggressive, androgen-independent, and invasive metastatic tumors. Current models have been successful in capitulating individual characteristics of the aggressive tumors. However, none of these models comprehensively mimics human cancer progression, establishing the challenge in their exploitation to study human disease. The ability to tailor phenotypic outcomes in mice by compounding mutations to target specific molecular pathways provides a powerful tool toward disruption of signaling pathways contributing to the initiation and progression of castration-resistant prostate cancer. Each model is characterized by unique features contributing to the understanding of prostate tumorigenesis, as well as limitations challenging our knowledge of the mechanisms of cancer development and progression. Emerging strategies utilize genomic manipulation technology to circumvent these limitations toward the formulation of attractive, physiologically relevant models of prostate cancer progression to advanced disease. This review discusses the current value of the widely used and well characterized mouse models of prostate cancer progression to metastasis, as well as the opportunities begging exploitation for the development of new models for testing the antitumor efficacy of therapeutic strategies and identifying new biomarkers of disease progression. PMID- 21680811 TI - An extremely luminous panchromatic outburst from the nucleus of a distant galaxy. AB - Variable x-ray and gamma-ray emission is characteristic of the most extreme physical processes in the universe. We present multiwavelength observations of a unique gamma-ray-selected transient detected by the Swift satellite, accompanied by bright emission across the electromagnetic spectrum, and whose properties are unlike any previously observed source. We pinpoint the event to the center of a small, star-forming galaxy at redshift z = 0.3534. Its high-energy emission has lasted much longer than any gamma-ray burst, whereas its peak luminosity was ~100 times higher than bright active galactic nuclei. The association of the outburst with the center of its host galaxy suggests that this phenomenon has its origin in a rare mechanism involving the massive black hole in the nucleus of that galaxy. PMID- 21680812 TI - A possible relativistic jetted outburst from a massive black hole fed by a tidally disrupted star. AB - Gas accretion onto some massive black holes (MBHs) at the centers of galaxies actively powers luminous emission, but most MBHs are considered dormant. Occasionally, a star passing too near an MBH is torn apart by gravitational forces, leading to a bright tidal disruption flare (TDF). Although the high energy transient Sw 1644+57 initially displayed none of the theoretically anticipated (nor previously observed) TDF characteristics, we show that observations suggest a sudden accretion event onto a central MBH of mass about 10(6) to 10(7) solar masses. There is evidence for a mildly relativistic outflow, jet collimation, and a spectrum characterized by synchrotron and inverse Compton processes; this leads to a natural analogy of Sw 1644+57 to a temporary smaller scale blazar. PMID- 21680813 TI - De-AMPylation of the small GTPase Rab1 by the pathogen Legionella pneumophila. AB - The bacterial pathogen Legionella pneumophila exploits host cell vesicle transport by transiently manipulating the activity of the small guanosine triphosphatase (GTPase) Rab1. The effector protein SidM recruits Rab1 to the Legionella-containing vacuole (LCV), where it activates Rab1 and then AMPylates it by covalently adding adenosine monophosphate (AMP). L. pneumophila GTPase activating protein LepB inactivates Rab1 before its removal from LCVs. Because LepB cannot bind AMPylated Rab1, the molecular events leading to Rab1 inactivation are unknown. We found that the effector protein SidD from L. pneumophila catalyzed AMP release from Rab1, generating de-AMPylated Rab1 accessible for inactivation by LepB. L. pneumophila mutants lacking SidD were defective for Rab1 removal from LCVs, identifying SidD as the missing link connecting the processes of early Rab1 accumulation and subsequent Rab1 removal during infection. PMID- 21680814 TI - Adipose triglyceride lipase contributes to cancer-associated cachexia. AB - Cachexia is a multifactorial wasting syndrome most common in patients with cancer that is characterized by the uncontrolled loss of adipose and muscle mass. We show that the inhibition of lipolysis through genetic ablation of adipose triglyceride lipase (Atgl) or hormone-sensitive lipase (Hsl) ameliorates certain features of cancer-associated cachexia (CAC). In wild-type C57BL/6 mice, the injection of Lewis lung carcinoma or B16 melanoma cells causes tumor growth, loss of white adipose tissue (WAT), and a marked reduction of gastrocnemius muscle. In contrast, Atgl-deficient mice with tumors resisted increased WAT lipolysis, myocyte apoptosis, and proteasomal muscle degradation and maintained normal adipose and gastrocnemius muscle mass. Hsl-deficient mice with tumors were also protected although to a lesser degree. Thus, functional lipolysis is essential in the pathogenesis of CAC. Pharmacological inhibition of metabolic lipases may help prevent cachexia. PMID- 21680815 TI - Making translation work. PMID- 21680820 TI - Japan disaster. Citizens find radiation far from Fukushima. PMID- 21680821 TI - Scientific publishing. Danish sperm counts spark data dispute. PMID- 21680822 TI - Paleoanthropology. Who was Homo habilis--and was it really Homo? PMID- 21680823 TI - Plant biology. Green genomes. PMID- 21680824 TI - Profile: Zhong You. 'Origami engineer' flexes to create stronger, more agile materials. PMID- 21680825 TI - India's education commercialization. PMID- 21680826 TI - Disaster preparation: lessons from Japan. PMID- 21680827 TI - Personality's role in moral action. PMID- 21680828 TI - Infectious disease. Solving the Sisyphean problem of malaria in Zanzibar. PMID- 21680829 TI - Plant science. Innate immunity in plants goes to the PUB. PMID- 21680830 TI - Cell biology. ADaPting to energetic stress. PMID- 21680831 TI - Physics. Detecting intruders on the nanoscale. PMID- 21680832 TI - Geophysics. A tale of two earthquakes. PMID- 21680833 TI - Cell biology. Autophagy's top chef. PMID- 21680834 TI - Plant science. Plants get Hyp to O-glycosylation. PMID- 21680835 TI - EPOXI at comet Hartley 2. AB - Understanding how comets work--what drives their activity--is crucial to the use of comets in studying the early solar system. EPOXI (Extrasolar Planet Observation and Deep Impact Extended Investigation) flew past comet 103P/Hartley 2, one with an unusually small but very active nucleus, taking both images and spectra. Unlike large, relatively inactive nuclei, this nucleus is outgassing primarily because of CO(2), which drags chunks of ice out of the nucleus. It also shows substantial differences in the relative abundance of volatiles from various parts of the nucleus. PMID- 21680836 TI - O-glycosylated cell wall proteins are essential in root hair growth. AB - Root hairs are single cells that develop by tip growth and are specialized in the absorption of nutrients. Their cell walls are composed of polysaccharides and hydroxyproline-rich glycoproteins (HRGPs) that include extensins (EXTs) and arabinogalactan-proteins (AGPs). Proline hydroxylation, an early posttranslational modification of HRGPs that is catalyzed by prolyl 4 hydroxylases (P4Hs), defines the subsequent O-glycosylation sites in EXTs (which are mainly arabinosylated) and AGPs (which are mainly arabinogalactosylated). We explored the biological function of P4Hs, arabinosyltransferases, and EXTs in root hair cell growth. Biochemical inhibition or genetic disruption resulted in the blockage of polarized growth in root hairs and reduced arabinosylation of EXTs. Our results demonstrate that correct O-glycosylation on EXTs is essential for cell-wall self-assembly and, hence, root hair elongation in Arabidopsis thaliana. PMID- 21680837 TI - Long-range topological order in metallic glass. AB - Glass lacks the long-range periodic order that characterizes a crystal. In the Ce(75)Al(25) metallic glass (MG), however, we discovered a long-range topological order corresponding to a single crystal of indefinite length. Structural examinations confirm that the MG is truly amorphous, isotropic, and unstrained, yet under 25 gigapascals hydrostatic pressures, every segment of a centimeter length MG ribbon devitrifies independently into a face-centered cubic (fcc) crystal with the identical orientation. By using molecular dynamics simulations and synchrotron x-ray techniques, we elucidate that the mismatch between the large Ce and small Al atoms frustrates the crystallization and causes amorphization, but a long-range fcc topological order still exists. Pressure induces electronic transition in Ce, which eliminates the mismatch and manifests the topological order by the formation of a single crystal. PMID- 21680838 TI - Three-dimensional plasmon rulers. AB - Plasmon rulers can be used to determine nanoscale distances within chemical or biological species. They are based on the spectral shift of the scattering spectrum when two plasmonic nanoparticles approach one another. However, the one dimensionality of current plasmon rulers hampers the comprehensive understanding of many intriguing processes in soft matter, which take place in three dimensions. We demonstrated a three-dimensional plasmon ruler that is based on coupled plasmonic oligomers in combination with high-resolution plasmon spectroscopy. This enables retrieval of the complete spatial configuration of complex macromolecular and biological processes as well as their dynamic evolution. PMID- 21680839 TI - Direct observation of nodes and twofold symmetry in FeSe superconductor. AB - We investigated the electron-pairing mechanism in an iron-based superconductor, iron selenide (FeSe), using scanning tunneling microscopy and spectroscopy. Tunneling conductance spectra of stoichiometric FeSe crystalline films in their superconducting state revealed evidence for a gap function with nodal lines. Electron pairing with twofold symmetry was demonstrated by direct imaging of quasiparticle excitations in the vicinity of magnetic vortex cores, Fe adatoms, and Se vacancies. The twofold pairing symmetry was further supported by the observation of striped electronic nanostructures in the slightly Se-doped samples. The anisotropy can be explained in terms of the orbital-dependent reconstruction of electronic structure in FeSe. PMID- 21680840 TI - AMPK is a direct adenylate charge-regulated protein kinase. AB - The adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates whole body and cellular energy balance in response to energy demand and supply. AMPK is an alphabetagamma heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations. AMPK activation depends on phosphorylation of the alpha catalytic subunit on threonine-172 (Thr(172)) by kinases LKB1 or CaMKKbeta, and this is promoted by AMP binding to the gamma subunit. AMP sustains activity by inhibiting dephosphorylation of alpha Thr(172), whereas ATP promotes dephosphorylation. Adenosine diphosphate (ADP), like AMP, bound to gamma sites 1 and 3 and stimulated alpha-Thr(172) phosphorylation. However, in contrast to AMP, ADP did not directly activate phosphorylated AMPK. In this way, both ADP/ATP and AMP/ATP ratios contribute to AMPK regulation. PMID- 21680841 TI - A molecular mechanism for circadian clock negative feedback. AB - Circadian rhythms in mammals are generated by a feedback loop in which the three PERIOD (PER) proteins, acting in a large complex, inhibit the transcriptional activity of the CLOCK-BMAL1 dimer, which represses their own expression. Although fundamental, the mechanism of negative feedback in the mammalian clock, or any eukaryotic clock, is unknown. We analyzed protein constituents of PER complexes purified from mouse tissues and identified PSF (polypyrimidine tract-binding protein-associated splicing factor). Our analysis indicates that PSF within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and that the PER complex thereby rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription. These findings provide a function for the PER complex and a molecular mechanism for circadian clock negative feedback. PMID- 21680842 TI - Direct ubiquitination of pattern recognition receptor FLS2 attenuates plant innate immunity. AB - Innate immune responses are triggered by the activation of pattern-recognition receptors (PRRs). The Arabidopsis PRR FLAGELLIN-SENSING 2 (FLS2) senses bacterial flagellin and initiates immune signaling through association with BAK1. The molecular mechanisms underlying the attenuation of FLS2 activation are largely unknown. We report that flagellin induces recruitment of two closely related U box E3 ubiquitin ligases, PUB12 and PUB13, to FLS2 receptor complex in Arabidopsis. BAK1 phosphorylates PUB12 and PUB13 and is required for FLS2 PUB12/13 association. PUB12 and PUB13 polyubiquitinate FLS2 and promote flagellin induced FLS2 degradation, and the pub12 and pub13 mutants displayed elevated immune responses to flagellin treatment. Our study has revealed a unique regulatory circuit of direct ubiquitination and turnover of FLS2 by BAK1-mediated phosphorylation and recruitment of specific E3 ligases for attenuation of immune signaling. PMID- 21680843 TI - SIRT6 promotes DNA repair under stress by activating PARP1. AB - Sirtuin 6 (SIRT6) is a mammalian homolog of the yeast Sir2 deacetylase. Mice deficient for SIRT6 exhibit genome instability. Here, we show that in mammalian cells subjected to oxidative stress SIRT6 is recruited to the sites of DNA double strand breaks (DSBs) and stimulates DSB repair, through both nonhomologous end joining and homologous recombination. Our results indicate that SIRT6 physically associates with poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) and mono-ADP-ribosylates PARP1 on lysine residue 521, thereby stimulating PARP1 poly ADP-ribosylase activity and enhancing DSB repair under oxidative stress. PMID- 21680844 TI - Neurofunctional and behavioral correlates of phonetic and temporal categorization in musically trained and untrained subjects. AB - The perception of rapidly changing verbal and nonverbal auditory patterns is a fundamental prerequisite for speech and music processing. Previously, the left planum temporale (PT) has been consistently shown to support the discrimination of fast changing verbal and nonverbal sounds. Furthermore, it has been repeatedly shown that the functional and structural architecture of this supratemporal brain region differs as a function of musical training. In the present study, we used the functional magnetic resonance imaging technique, in a sample of professional musicians and nonmusicians, in order to examine the functional contribution of the left PT to the categorization of consonant-vowel syllables and their reduced spectrum analogues. In line with our hypothesis, the musicians showed enhanced brain responses in the left PT and superior discrimination abilities in the reduced-spectrum condition. Moreover, we found a positive correlation between the responsiveness of the left PT and the performance in the reduced-spectrum condition across all subjects irrespective of musical expertise. These results have implications for our understanding of musical expertise in relation to segmental speech processing. PMID- 21680845 TI - Valuing one's self: medial prefrontal involvement in epistemic and emotive investments in self-views. AB - Recent neuroimaging research has revealed that the medial prefrontal cortex (MPFC) is consistently engaged when people form mental representations of themselves. However, the precise function of this region in self-representation is not yet fully understood. Here, we investigate whether the MPFC contributes to epistemic and emotive investments in self-views, which are essential components of the self-concept that stabilize self-views and shape how one feels about oneself. Using functional magnetic resonance imaging, we show that the level of activity in the MPFC when people think about their personal traits (by judging trait adjectives for self-descriptiveness) depends on their investments in the particular self-view under consideration, as assessed by postscan rating scales. Furthermore, different forms of investments are associated with partly distinct medial prefrontal areas: a region of the dorsal MPFC is uniquely related to the degree of certainty with which a particular self-view is held (one's epistemic investment), whereas a region of the ventral MPFC responds specifically to the importance attached to this self-view (one's emotive investment). These findings provide new insight into the role of the MPFC in self-representation and suggest that the ventral MPFC confers degrees of value upon the particular conception of the self that people construct at a given moment. PMID- 21680846 TI - Brain potentials dissociate emotional and conceptual cross-modal priming of environmental sounds. AB - The attentional effects triggered by emotional stimuli in humans have been substantially investigated, but little is known about the impact of affective valence on the processing of meaning. Here, we used a cross-modal priming paradigm involving visually presented adjective-noun dyads and environmental sounds of controlled affective valence to test the contributions of conceptual relatedness and emotional congruence to priming. Participants undergoing event related potential recording indicated whether target environmental sounds were related in meaning to adjective-noun dyads presented as primes. We tested spontaneous emotional priming by manipulating the congruence between the affective valence of the adjective in the prime and that of the sound. While the N400 was significantly reduced in amplitude by both conceptual relatedness and emotional congruence, there was no interaction between the 2 factors. The same pattern of results was found when participants judged the emotional congruence between environmental sounds and adjective-noun dyads. These results support the hypothesis that conceptual and emotional processes are functionally independent regardless of the specific cognitive focus of the comprehender. PMID- 21680847 TI - Distractibility during episodic retrieval is exacerbated by perturbation of left ventrolateral prefrontal cortex. AB - The presence of irrelevant external stimuli during the retrieval of long-term memory (LTM) has a negative impact on the fidelity of recollected details. Top down control processes that both guide the selection of internal information relevant to LTM goals and resolve interference on retrieval from irrelevant external information have been associated with the same region in left ventrolateral prefrontal cortex (VLPFC). The current study examined a causal role of the left VLPFC in memory performance when external distraction (i.e., visual stimuli irrelevant to the current task goals) was presented during retrieval of LTM. Immediately after functional perturbation of the left VLPFC with 1-Hz repetitive transcranial magnetic stimulation, participants' memory was tested when their eyes were closed and when their eyes were open and irrelevant visual stimuli were presented. The results showed that visual distraction diminished LTM performance based on an objective measure of recollection and that perturbation of left VLPFC exacerbated the disruptive effect. This is the first evidence of a direct role of the left VLPFC in diminishing the impact of distraction on recollection, elucidating neural mechanisms that are critically involved in how we reconstruct the past while navigating the external environment. PMID- 21680850 TI - Aliskiren combined with losartan in immunoglobulin A nephropathy: an open-labeled pilot study. AB - BACKGROUND: Aliskiren is a relatively new oral direct renin inhibitor (DRI) that has been increasingly used for the treatment of diabetic nephropathy and hypertension. Its potential efficacy in nondiabetic chronic kidney diseases that are driven by renin-angiotensin system activation remains to be explored. METHODS: From a teaching and regional hospital in Hong Kong between July 2009 and March 2010, patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in whom the ratio of protein to creatinine, as measured in early morning urine samples, remained >113 mg/mmol (1000 mg/g), despite receiving the maximum recommended dose of losartan (100 mg daily) were recruited to receive additional DRI treatment. They were followed prospectively for 12 months with changes in proteinuria as the main outcome measure. RESULTS: Twenty-five consecutive patients were enrolled. Treatment with aliskiren for 12 months reduced the mean urinary protein-to-creatinine ratio by 26.3% (95% confidence interval, 20.1-43.6; P = 0.001 versus baseline), with a reduction of >= 50% in 24% of patients. There were significant reductions in plasma renin activity (P < 0.0001) and serum interleukin-6 (P < 0.05) and transforming growth factor-beta (P = 0.01) levels, compared with baseline. Two patients (8%) developed mild allergic reactions and six (24%) had transient hyperkalemia (K >5.5 mmol/L) during the study. CONCLUSION: Aliskiren confers an antiproteinuric effect in IgAN patients with significant residual proteinuria, despite receiving the recommended renoprotective treatment. Further prospective randomized trials are warranted to examine its long-term renoprotective potential. This trial is registered with the ClinicalTrials.gov number NCT00922311. PMID- 21680851 TI - An Indian model for cost-effective CAPD with minimal man power and economic resources. PMID- 21680848 TI - The involvement of the dopaminergic midbrain and cortico-striatal-thalamic circuits in the integration of reward prospect and attentional task demands. AB - Reward has been shown to promote human performance in multiple task domains. However, an important debate has developed about the uniqueness of reward-related neural signatures associated with such facilitation, as similar neural patterns can be triggered by increased attentional focus independent of reward. Here, we used functional magnetic resonance imaging to directly investigate the neural commonalities and interactions between the anticipation of both reward and task difficulty, by independently manipulating these factors in a cued-attention paradigm. In preparation for the target stimulus, both factors increased activity within the midbrain, dorsal striatum, and fronto-parietal areas, while inducing deactivations in default-mode regions. Additionally, reward engaged the ventral striatum, posterior cingulate, and occipital cortex, while difficulty engaged medial and dorsolateral frontal regions. Importantly, a network comprising the midbrain, caudate nucleus, thalamus, and anterior midcingulate cortex exhibited an interaction between reward and difficulty, presumably reflecting additional resource recruitment for demanding tasks with profitable outcome. This notion was consistent with a negative correlation between cue-related midbrain activity and difficulty-induced performance detriments in reward-predictive trials. Together, the data demonstrate that expected value and attentional demands are integrated in cortico-striatal-thalamic circuits in coordination with the dopaminergic midbrain to flexibly modulate resource allocation for an effective pursuit of behavioral goals. PMID- 21680852 TI - Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury. AB - BACKGROUND: Ischemia/reperfusion triggers acute kidney injury (AKI), mainly via aggravating hypoxia, oxidative stress, inflammation and renin-angiotensin system (RAS) activation. We investigated the role of angiotensin-converting enzyme (ACE) inhibition on the progression of AKI in a rat model of ischemia/reperfusion. METHODS: Ninety-nine Sprague-Dawley rats were subjected to 1 h ischemia/reperfusion and/or left unilateral nephrectomy, with concurrent intraperitoneal implantation of Alzet pump. Via this pump, they were continuously infused with captopril 0.5 mg/kg/day, captopril 2 mg/kg/day or saline. The rats were sacrificed following 24, 48 or 168 h. Blood samples, 24-h urine collections and kidneys were allocated, to evaluate renal function, angiotensin-II, nitric oxide (NO), apoptosis, hypoxia, oxidative stress and inflammation. RESULTS: Serum creatinine and cystatin-C significantly increased in ischemic rats, coinciding with histopathologic intrarenal damage, decreased NO, augmented angiotensin-II, interleukin (IL)-6, IL-10, transforming growth factor-beta. At the acute reperfusion stage, captopril prevented excessive angiotensin-II synthesis, ameliorated renal dysfunction, inhibited intrarenal inflammation and improved histopathologic findings. Most of the renoprotective effects of captopril were limited predominantly to acute reperfusion stage. Concurrently, captopril significantly decreased NO availability, exacerbated intrarenal hypoxia and augmented oxidative stress. CONCLUSIONS: At the acute stage of renal ischemia/reperfusion-induced AKI, ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function, inhibiting systemic and intrarenal angiotensin-II, attenuating intrarenal inflammation and preserving renal tissue structure. Later on, at the post-reperfusion stage, most of the beneficial effects of captopril administration on the recuperating post-ischemic kidney were no longer evident. Concurrently, ACE inhibition exacerbated intrarenal hypoxia and accelerated oxidative stress, indicating that renal adaptation to some consequences of ischemia does require bioavailability of RAS components. PMID- 21680853 TI - Ultrasound gel-nerve contact: an experimental animal histologic study. AB - BACKGROUND: Ultrasound (US) regional nerve block requires the use of gel applied over the skin. With subsequent needle insertion, some of the gel may adhere either on the shaft or within the needle lumen and may be carried to the perineural structures or intraneurally. We performed this experimental animal study to investigate the effects of US gel contact on the nerve histologic structure. METHODS: Nine male beagle dogs were studied. Dogs 1 to 3 were the control group and dogs 4 to 9 were the study group. Bilateral posterior tibial nerves were dissected and exposed for the control group. Nerve specimens were obtained for histologic examination immediately for the first dog, at 24 hours for the second dog, and at 48 hours for the third dog followed by wound closure. For the study group, bilateral posterior tibial nerves were exposed, and 2 mL US gel was applied locally directly on the nerve, followed by wound closure. Nerve specimens were excised at 24 hours from one side and at 48 hours from the other side. Nerve specimens were examined by a neuropathologist for evidence of nerve inflammation. RESULTS: The control nerve specimens showed no significant pathology. Nerve specimens of the study group at the end of 24 hours of gel-nerve contact showed mild focal perineural inflammatory changes with clusters of polymorph leukocytes. At 48 hours, perineural moderate inflammatory changes with clusters of lymphocytes and macrophages were demonstrated in 2 animals. Long-term neurologic deficit in the form of limping was observed for all dogs. CONCLUSION: Histologic features after perineural exposure to US gel are rather nonspecific and likely of no clinical significance. However, further studies are needed to determine the effect of US gel injection on intraneural tissues. PMID- 21680854 TI - Nitrous oxide anesthesia and plasma homocysteine in adolescents. AB - BACKGROUND: Nitrous oxide inactivates vitamin B(12), inhibits methionine synthase, and consequently increases plasma total homocysteine (tHcy). Prolonged exposure to nitrous oxide can lead to neuropathy, spinal cord degeneration, and even death in children. We tested the hypothesis that nitrous oxide anesthesia causes a significant increase in plasma tHcy in children. METHODS: Twenty-seven children (aged 10-18 years) undergoing elective major spine surgery were enrolled, and serial plasma samples from 0 to 96 hours after induction were obtained. The anesthetic regimen, including the use of nitrous oxide, was at the discretion of the anesthesiologist. Plasma tHcy was measured using standard enzymatic assays. RESULTS: The median baseline plasma tHcy concentration was 5.1 MUmol/L (3.9-8.0 MUmol/L, interquartile range) and increased in all patients exposed to nitrous oxide (n = 26) by an average of +9.4 MUmol/L (geometric mean; 95% confidence interval, 7.1-12.5 MUmol/L) or +228% (mean; 95% confidence interval, 178%-279%). Plasma tHcy peaked between 6 and 8 hours after induction of anesthesia. One patient who did not receive nitrous oxide had no increase in plasma tHcy. Several patients experienced a severalfold increase in plasma tHcy (maximum +567%). The increase in plasma tHcy was strongly correlated with the duration and average concentration of nitrous oxide anesthesia (r = 0.80; P < 0.001). CONCLUSIONS: Pediatric patients undergoing nitrous oxide anesthesia develop significantly increased plasma tHcy concentrations. The magnitude of this effect seems to be greater compared with adults; however, the clinical relevance is unknown. PMID- 21680856 TI - Ultrasound assessment of the vertebral level of the intercristal line in pregnancy. AB - BACKGROUND: The intercristal line is known to most frequently cross the L4 spinous process or L4-5 interspace; however, it is speculated to be positioned higher during pregnancy because of the exaggerated lumbar lordosis. Clinical estimation of vertebral levels relying on the use of the intercristal line has been shown to often be inaccurate. We hypothesized that the vertebral level of the intercristal line determined by palpation would be higher than the level determined by ultrasound in pregnant women. METHODS: Fifty-one term pregnant patients were recruited. Two experienced anesthesiologists performed estimates of the position of the intercristal line by palpation. Using ultrasound, another anesthesiologist who was blinded to the clinical estimates, determined the position of the superior border of the iliac crest in the transverse and longitudinal planes and then identified the lumbar vertebral levels. The vertebral level at which the clinical estimates of the intercristal line crossed the spine was recorded and compared with the ultrasound-determined level of the superior border of the iliac crest. RESULTS: The clinical estimates of the spinal level of the intercristal line agreed with the ultrasound measurement 14% of the time (14 of 101; 95% confidence interval [CI]: 8%, 22%). The clinical estimates were 1 level higher than the ultrasound measurement 23% of the time (23 of 101; 95% CI: 16%, 32%) and >1 level higher 25% of the time (25 of 101; 1-tailed 95% CI: >18%). The distribution of the clinical estimates found clinicians locating the intercristal line at L3 or L3-4 54% of the time (54 of 101; 95% CI: 44%, 63%) and at L2-3 or higher 27% of the time (27 of 101; 1-tailed 95% CI: >20%). CONCLUSION: The anatomical position of the intercristal line was at L3 or higher in at least 6% of term pregnant patients using ultrasound. Clinical estimates were found to be >=1 vertebral level higher than the anatomical position determined by ultrasound at least 40% of the time. This disparity may contribute to misidentification of lumbar interspaces and increased risk of neurologic injury during neuraxial anesthesia. PMID- 21680855 TI - Evaluation of a new software version of the FloTrac/Vigileo (version 3.02) and a comparison with previous data in cirrhotic patients undergoing liver transplant surgery. AB - BACKGROUND: Reliable cardiac output monitoring is particularly useful in the cirrhotic patient undergoing liver transplant surgery, because cirrhosis of the liver is associated with a vasodilated and high output state, known as cirrhotic cardiomyopathy, that challenges the reliability of pulse contour cardiac output technology. The contractility of the ventricle in cirrhosis is impaired, which is tolerated even though the ejection fraction and cardiac output are elevated because of the low peripheral resistance. However, during surgery the cirrhotic patient can decompensate because of the physiological changes and stress of surgery. Recently, we showed that the FloTrac/VigileoTM failed to perform in cirrhotic patients undergoing transplant surgery. In response, the company upgraded their software. Therefore, we have assessed the accuracy and reliability of this new third-generation (version 3.02) FloTrac/Vigileo algorithm software in the same setting. METHODS: The cardiac index was measured simultaneously by single-bolus thermodilution (CI(TD)), using a pulmonary artery catheter, and pulse contour analysis, using the FloTrac/Vigileo (CI(V)). Readings were made at 10 time points during and after liver transplant surgery in 21 patients. Comparisons with data from our 2009 study, which used second-generation (version 01.10) software, were also made. RESULTS: Our new data show that version 3.02 software significantly reduced the adverse effect on pulse contour cardiac output reading bias in low peripheral resistance states, and thus improves the overall precision and trending ability of the system. Regression analysis between CI(TD) and CI(V) showed that the correlation was moderate (r =0.67, 95% confidence interval, 0.40 to 0.86). The Bland and Altman analysis showed that bias was 0.4 L.min(-1) . m(-2), and the percentage error was 52% (95% confidence interval, 49% to 55%). Trending ability of the new software also was improved but was still well below the current benchmarks. CONCLUSION: The new software (version 3.02) provided substantial improvements over the previous versions with better overall precision and trending ability. Further algorithm refinements will increase this technology's reliability to be extensively used in the highly complex setting of cirrhotic patients undergoing liver transplantation. PMID- 21680857 TI - The making of an anesthesia historian: lessons from a worldwide biographical survey. AB - BACKGROUND: There are few, if any, training opportunities for individuals wishing to pursue a career as an anesthesia historian. We surveyed anesthesia historians to learn about their training and experience, with an emphasis on mentoring, obstacles faced, and opportunities for improvement. METHODS: Questionnaires were sent to 34 anesthesia historians in North America, Europe, Asia, and Australia seeking information about demographics, medical training, training related to history, mentoring, research funding, obstacles faced, and suggestions for improvement. RESULTS: The response rate exceeded 90%. The average age of respondents was 70 years, and 85% of the respondents were male. The majority of respondents resided in North America (68%). The rest were from Europe (21%), Australia (9%), and Asia (3%). Graduate training in history was reported by 6%. Thirty-eight percent considered themselves to be self-trained. Thirty-eight percent were recipients of fellowships from the Wood Library-Museum of Anesthesiology. Research guidance was obtained by 74% of respondents. Guidance came from a department chairman (24%), a member of the Wood Library-Museum staff (33%), or another source (43%). The 3 most common obstacles described were difficulty in obtaining funding for research activities (33%), academic recognition (20%), and availability of training and mentoring (18%). Areas identified as needing improvement were research funding (17%), exposure to anesthesia history during residency training (23%), academic recognition (26%), mentoring (17%), and promotion of anesthesia history (17%). CONCLUSIONS: A study of history does not necessarily produce changes in clinical practice, which may limit the perceived value of historical study. The suggestions by these historians should help preserve the history and heritage of anesthesiology. PMID- 21680858 TI - Reduction of spinal cord ischemia/reperfusion injury with simvastatin in rats. AB - BACKGROUND: Surgery of the thoracic or thoracoabdominal aorta may cause spinal cord ischemia and subsequent paraplegia. However, conventional strategies for preventing paraplegia due to spinal cord ischemia provide insufficient protection and cause additional side effects. We hypothesized that simvastatin, a drug recently shown to be neuroprotective against brain ischemia/reperfusion, would be neuroprotective in a rat spinal cord ischemia/reperfusion model. METHODS: Rats were randomly assigned to simvastatin, vehicle, or sham-surgery (sham) groups (n = 6 per group). Simvastatin (10 mg/kg) or vehicle was administered subcutaneously once daily for 7 days before aortic balloon occlusion, and once at 24 hours after reperfusion. Spinal cord ischemia was induced by balloon inflation of a 2F Fogarty catheter in the thoracic aorta, and the proximal mean arterial blood pressure was maintained at 40 mm Hg for 12 minutes. The sham group received the same operation without inflation of the balloon. Ischemic injury was assessed by hindlimb motor function using the Motor Deficit Index score at 6 to 48 hours after ischemic reperfusion, and histological assessment of the spinal cord was performed 48 hours after reperfusion. RESULTS: The Motor Deficit Index scores at 24 and 48 hours after reperfusion were significantly improved in the simvastatin group compared with the vehicle group (P = 0.021 and P = 0.023, respectively). Furthermore, there were significantly more normal motor neurons in the simvastatin group than in the vehicle group (P = 0.037). The percentage area of white matter vacuolation was significantly smaller in the simvastatin group than in the vehicle group (P = 0.030). CONCLUSIONS: Simvastatin treatment can attenuate hindlimb motor dysfunction and histopathological changes in spinal cord ischemia/reperfusion injury in rats. PMID- 21680859 TI - Learning endotracheal intubation using a novel videolaryngoscope improves intubation skills of medical students. AB - INTRODUCTION: Teaching endotracheal intubation to medical students is a task provided by many academic anesthesia departments. We tested the hypothesis that teaching with a novel videolaryngoscope improves students' intubation skills. METHODS: We prospectively assessed in medical students (2nd clinical year) intubation skills acquired by intubation attempts in adult anesthetized patients during a 60-hour clinical course using, in a randomized fashion, either a conventional Macintosh blade laryngoscope or a videolaryngoscope (C-MAC(r)). The latter permits direct laryngoscopy with a Macintosh blade and provides a color image on a video screen. Skills were measured before and after the course in a standardized fashion (METI Emergency Care Simulator) using a conventional laryngoscope. All 1-semester medical students (n = 93) were enrolled. RESULTS: The students' performance did not significantly differ between groups before the course. After the course, students trained with the videolaryngoscope had an intubation success rate on a manikin 19% higher (95% CI 1.1%-35.3%; P < 0.001) and intubated 11 seconds faster (95% CI 4-18) when compared with those trained using a conventional laryngoscope. The incidence of "difficult (manikin) laryngoscopy" was less frequent in the group trained with the videolaryngoscope (8% vs 34%; P = 0.005). CONCLUSION: Education using a video system mounted into a traditional Macintosh blade improves intubation skills in medical students. PMID- 21680861 TI - An introduction to multilevel modeling for anesthesiologists. AB - In population-based research, subjects are frequently in clusters with shared features or demographic characteristics, such as age range, neighborhood, who they have for a physician, and common comorbidities. Classification into clusters also applies at broader levels. Physicians are classified by physician group or by practice site; hospitals can be characterized by size, location, or demographics. Hierarchical, nested structures pose unique challenges in the conduct of research. Data from nested structures may be interdependent because of similarities among subjects in a cluster, while nesting at multiple levels makes it difficult to know whether findings should be applied to the individual or to the larger group. Statistical tools, known variously as hierarchical linear modeling, multilevel modeling, mixed linear modeling, and other terms, have been developed in the education and social science fields to deal effectively with these issues. Our goal in this article is to review the implications of hierarchical, nested data organization and to provide a step-by-step tutorial of how multilevel modeling could be applied to a problem in anesthesia research using current, commercially available software. PMID- 21680860 TI - The effect of hospital size and surgical service on case cancellation in elective surgery: results from a prospective multicenter study. AB - BACKGROUND: Short-term case cancellation causes frustration for anesthesiologists, surgeons, and patients and leads to suboptimal use of operating room (OR) resources. In many facilities, >10% of all cases are cancelled on the day of surgery, thereby causing major problems for OR management and anesthesia departments. The effect of hospital type and service type on case cancellation rate is unclear. METHODS: In 25 hospitals of different types (university hospitals, large community hospitals, and mid- to small-size community hospitals) we studied all elective surgical cases of the following subspecialties over a period of 2 weeks: general surgery, trauma/orthopedics, urology, and gynecology. Case cancellation was defined as any patient who had been scheduled to be operated on the next day, but cancelled after the finalization of the OR plan on the day before surgery. A list of possible cancellation reasons was provided for standardized documentation. RESULTS: A total of 6009 anesthesia cases of 82 different anesthesia services were recorded during the study period. Services in university hospitals had cancellation rates 2.23 (95% confidence interval [CI] = 1.49 to 3.34) times higher than mid- to small-size community hospitals 12.4% (95% CI = 11.0% to 13.8%) versus 5.0% (95% CI = 4.0% to 6.2%). Of the surgical services, general surgical services had a significantly (1.78, 95% CI = 1.25 to 2.53) higher cancellation rate than did gynecology services-11.0% (95% CI = 9.7% to 12.5%) versus 6.6% (95% CI = 5.1% to 8.4%). CONCLUSIONS: When benchmarking cancellation rates among hospitals, comparisons should control for academic institutions having higher incidences of case cancellation than nonacademic hospitals and general surgery services having higher incidences than other services. PMID- 21680862 TI - The temperature and humidity in a low-flow anesthesia workstation with and without a heat and moisture exchanger. AB - BACKGROUND: The Drager Primus anesthesia workstation has a built-in hotplate to heat the patient's exhaled gas. The fresh gas flow is mixed with the heated exhaled gas as they pass through the soda lime canister. A heat and moisture exchanger (HME) may also be used to further heat and humidify the inhaled gas. In this study we measured the temperature and humidity of the inhaled gas coming from the Drager Primus with or without a HME. METHODS: Thirty female patients were randomly divided into 2 groups and their lungs ventilated by the Primus Drager anesthesia workstation with or without a HME. The humidity and temperature of the inhaled gas were measured 15, 30, 60, 90, and 120 minutes after connecting the patient to the breathing circuit. RESULTS: After 120 minutes of ventilation with a low-flow breathing circuit, the temperatures of inhaled gas were 25 degrees C +/- 1 degrees C and 30 degrees C +/- 2 degrees C without and with HME, respectively, with a statistically significant difference between groups (P < 0.001) with 95% confidence interval (CI) of 3.80 degrees C to 6.40 degrees C; and the absolute humidity values of the inhaled gas were 20.5 +/- 3.6 mgH(2)O . L(-1) and 30 +/- 2 mgH(2)O . L(-1) without and with HME, respectively, with a statistically significant difference between groups (P < 0.001) with 95% CI of 7.37 degrees C to 13.03 degrees C. CONCLUSIONS: The Primus anesthesia workstation partially humidifies the inspired gas when a low fresh gas flow is used. Insertion of an HME increases the humidity in inhaled gas, bringing it close to physiological values. PMID- 21680863 TI - HTS promiscuity analyses for accelerating decision making. AB - Frequent hitters are compounds that are detected as a "hit" in multiple high throughput screening (HTS) assays. Such behavior is specific (e.g., target family related) or unspecific (e.g., reactive compounds) or can result from a combination of such behaviors. Detecting such hits while predicting the underlying reason behind their promiscuous behavior is desirable because it provides valuable information not only about the compounds themselves but also about the assay methodology and target classes at hand. This information can also greatly reduce cost and time during HTS hit profiling. The present study exemplifies how to mine large HTS data repositories, such as the one at Boehringer Ingelheim, to identify frequent hitters, gain further insights into the causes of promiscuous behavior, and generate models for predicting promiscuous compounds. Applications of this approach are demonstrated using two recent large-scale HTS assays. The authors believe this analysis and its concrete applications are valuable tools for streamlining and accelerating decision-making processes during the course of hit discovery. PMID- 21680865 TI - Decoding of temporal visual information from electrically evoked retinal ganglion cell activities in photoreceptor-degenerated retinas. AB - PURPOSE: To restore visual function via the prosthetic stimulation of retina, visual information must be properly represented in the electrically evoked neural activity of retinal ganglion cells (RGCs). In this study, the RGC responses in photoreceptor-degenerated retinas were shown to actually encode temporal information on visual input when they were stimulated by biphasic pulse trains with amplitude modulation. METHODS: Multiple RGC spike trains were recorded from rd1 mouse retinal patches mounted on planar microelectrode arrays while being stimulated by pulse trains with amplitudes modulated by the intensity variation of a natural scene. To reconstruct the time series of pulse train amplitudes from the evoked RGC activity, spike train decoding was performed. The accuracy of decoding-that is, the similarity between the original and decoded pulse amplitudes-was observed, to evaluate the appropriateness of the stimulation. RESULTS: The response strengths of the RGCs could be successfully modulated when the pulse amplitude was varied between 2 and 20 MUA. When the amplitude modulation range and pulse rates were determined elaborately, the temporal profile of the intensity could be successfully decoded from RGC spike trains, although abnormal oscillatory background rhythms (~10 Hz) were consistently present in the rd1 spike activity. CONCLUSIONS: The results extend previous findings on the possibility of visual information encoding by electrical stimulation of normal retinas to stimulate degenerated retinas, in which neural activity is significantly altered. This supports the feasibility of encoding of temporal information by retinal prostheses. PMID- 21680864 TI - Development of a novel high-throughput screen and identification of small molecule inhibitors of the Galpha-RGS17 protein-protein interaction using AlphaScreen. AB - In this study, the authors used AlphaScreen technology to develop a high throughput screening method for interrogating small-molecule libraries for inhibitors of the Galpha(o)-RGS17 interaction. RGS17 is implicated in the growth, proliferation, metastasis, and the migration of prostate and lung cancers. RGS17 is upregulated in lung and prostate tumors up to a 13-fold increase over patient matched normal tissues. Studies show RGS17 knockdown inhibits colony formation and decreases tumorigenesis in nude mice. The screen in this study uses a measurement of the Galpha(o)-RGS17 protein-protein interaction, with an excellent Z score exceeding 0.73, a signal-to-noise ratio >70, and a screening time of 1100 compounds per hour. The authors screened the NCI Diversity Set II and determined 35 initial hits, of which 16 were confirmed after screening against controls. The 16 compounds exhibited IC(50) <10 uM in dose-response experiments. Four exhibited IC(50) values <6 uM while inhibiting the Galpha(o)-RGS17 interaction >50% when compared to a biotinylated glutathione-S-transferase control. This report describes the first high-throughput screen for RGS17 inhibitors, as well as a novel paradigm adaptable to many other RGS proteins, which are emerging as attractive drug targets for modulating G-protein-coupled receptor signaling. PMID- 21680866 TI - Do infants increase the risk of re-emergent infection in households after mass drug administration for trachoma? AB - PURPOSE: Mass treatment with azithromycin for trachoma endemic communities typically excludes infants under age 6 months, whose parents are provided with tubes of tetracycline to administer daily over 4 to 6 weeks. The authors sought to determine whether infants aged <6 months are a source of re-emergent infection in their families after mass treatment in trachoma-endemic communities. METHODS: In a longitudinal study of all children aged less than 10 years in four communities, the authors identified 91 infants aged <6 months living in 86 of 1241 households. All children aged = 10(-2) M. PCs were eliminated by a CaCl(2) concentration >= 5 * 10(-3) M or by lowering pH below 7.20 with HCl and recovered by the addition of iberiotoxin or charybdotoxin, which inhibit large-conductance calcium-activated potassium channels (K(Ca)), or by elevating pH above 7.35 with NaOH. PCs, as well as the spike-and-plateau depolarization, were eliminated by nifedipine, which inhibits L-type voltage-gated calcium channels (Ca(V)). Influx of Ca(2+) through L-type Ca(V), which was opened because closing of K(Ca), secondary to 3,4-DAP-induced closing of K(V), resulted in contraction; the intracellular Ca(2+) increased by this influx opened K(Ca), leading to closure of Ca(V) and consequent cessation of Ca(2+) influx with resultant relaxation. These processes were repeated spontaneously to cause PCs. H(+) and OH(-) were considered to act as the opener and closer of K(Ca), respectively. PMID- 21680888 TI - Pharmacokinetic-pharmacodynamic modeling of biomarker response and tumor growth inhibition to an orally available heat shock protein 90 inhibitor in a human tumor xenograft mouse model. AB - PF04942847 [2-amino-4-{4-chloro-2-[2-(4-fluoro-1H-pyrazol-1-yl)ethoxy]-6 methylphenyl}-N-(2,2-difluoropropyl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6 carboxamide] was identified as an orally available, ATP-competitive, small molecule inhibitor of heat shock protein 90 (HSP90). The objectives of the present study were: 1) to characterize the pharmacokinetic-pharmacodynamic relationship of the plasma concentrations of PF04942847 to the inhibition of HSP90-dependent protein kinase, AKT, as a biomarker and 2) to characterize the relationship of AKT degradation to tumor growth inhibition as a pharmacological response (antitumor efficacy). Athymic mice implanted with MDA-MB-231 human breast cancer cells were treated with PF04942847 once daily at doses selected to encompass ED(50) values. Plasma concentrations of PF04942847 were adequately described by a two-compartment pharmacokinetic model. A time delay (hysteresis) was observed between the plasma concentrations of PF04942847 and AKT degradation; therefore, a link model was used to account for the hysteresis. The model reasonably fit the time courses of AKT degradation with the estimated EC(50) of 18 ng/ml. For tumor growth inhibition, the signal transduction model reasonably fit the inhibition of individual tumor growth curves with the estimated EC(50) of 7.3 ng/ml. Thus, the EC(50) for AKT degradation approximately corresponded to the EC(50) to EC(80) for tumor growth inhibition, suggesting that 50% AKT degradation was required for significant antitumor efficacy (50-80%). The consistent relationship between AKT degradation and antitumor efficacy was also demonstrated by applying an integrated signal transduction model for linking AKT degradation to tumor growth inhibition. The present results will be helpful in determining the appropriate dosing regimen and guiding dose escalation to achieve efficacious systemic exposure in the clinic. PMID- 21680889 TI - The role of the effective population size in compensatory evolution. AB - The impact of the effective population size (Ne) on the efficacy of selection has been the focus of many theoretical and empirical studies over the recent years. Yet, the effect of Ne on evolution under epistatic fitness interactions is not well understood. In this study, we compare selective constraints at independently evolving (unpaired) and coevolving (paired) sites in orthologous transfer RNAs (tRNA molecules for vertebrate and drosophilid species pairs of different Ne. We show that patterns of nucleotide variation for the two classes of sites are explained well by Kimura's one- and two-locus models of sequence evolution under mutational pressure. We find that constraints in orthologous tRNAs increase with increasing Ne of the investigated species pair. Thereby, the effect of Ne on the efficacy of selection is stronger at unpaired sites than at paired sites. Furthermore, we identify a "core" set of tRNAs with high structural similarity to tRNAs from all major kingdoms of life and a "peripheral" set with lower similarity. We observe that tRNAs in the former set are subject to higher constraints and less prone to the effect of Ne, whereas constraints in tRNAs of the latter set show a large influence of Ne. Finally, we are able to demonstrate that constraints are relaxed in X-linked drosophilid tRNAs compared with autosomal tRNAs and suggest that Ne is responsible for this difference. The observed effects of Ne are consistent with the hypothesis that evolution of most tRNAs is governed by slightly to moderately deleterious mutations (i.e., |Nes|<=5). PMID- 21680891 TI - A novel epigenetic regulator associated with the hypervirulent Neisseria meningitidis clonal complex 41/44. AB - Neisseria meningitidis is a major cause of septicemia and meningitis. The hypervirulent clonal complex 41/44 (cc41/44) has emerged as the predominant cause of serogroup B meningococcal disease, having been responsible for recent outbreaks and epidemics worldwide. However, the meningococcal factors that enable transition from asymptomatic carriage to rapidly progressing disease are poorly understood. Here we describe a novel phase-variable DNA methyltransferase, ModD, which was identified in the genome sequence of a New Zealand epidemic isolate. Investigation of the distribution of modD in the wider meningococcal population, by PCR and sequence analysis of genetically diverse N. meningitidis strains, revealed the presence of modD in 20/27 strains in cc41/44, but in only 2/47 strains from other clonal complexes, indicating a significant association of modD with cc41/44 (Fisher's exact P value=3*10(-10)). The modD gene contains 5'-ACCGA 3' repeats that mediate phase variation, leading to reversible on/off switching of modD expression. Microarray analysis of modD-on/off variants revealed that ModD regulates expression of multiple genes involved in colonization, infection, and protection against host defenses, with increased catalase expression in the modD-on variant conferring increased resistance to oxidative stress. The modulation of gene expression via the ModD phase-variable regulon (phasevarion), and its significant association with the cc41/44, suggest a role in the fitness and/or pathogenesis of strains belonging to the cc41/44. PMID- 21680890 TI - Contrasting 5' and 3' evolutionary histories and frequent evolutionary convergence in Meis/hth gene structures. AB - Organisms show striking differences in genome structure; however, the functional implications and fundamental forces that govern these differences remain obscure. The intron-exon organization of nuclear genes is involved in a particularly large variety of structures and functional roles. We performed a 22-species study of Meis/hth genes, intron-rich homeodomain-containing transcription factors involved in a wide range of developmental processes. Our study revealed three surprising results that suggest important and very different functions for Meis intron-exon structures. First, we find unexpected conservation across species of intron positions and lengths along most of the Meis locus. This contrasts with the high degree of structural divergence found in genome-wide studies and may attest to conserved regulatory elements residing within these conserved introns. Second, we find very different evolutionary histories for the 5' and 3' regions of the gene. The 5'-most 10 exons, which encode the highly conserved Meis domain and homeodomain, show striking conservation. By contrast, the 3' of the gene, which encodes several domains implicated in transcriptional activation and response to cell signaling, shows a remarkably active evolutionary history, with diverse isoforms and frequent creation and loss of new exons and splice sites. This region-specific diversity suggests evolutionary "tinkering," with alternative splicing allowing for more subtle regulation of protein function. Third, we find a large number of cases of convergent evolution in the 3' region, including 1) parallel losses of ancestral coding sequence, 2) parallel gains of external and internal splice sites, and 3) recurrent truncation of C-terminal coding regions. These results attest to the importance of locus-specific splicing functions in differences in structural evolution across genes, as well as to commonalities of forces shaping the evolution of individual genes along different lineages. PMID- 21680892 TI - Do RCAN1 proteins link chronic stress with neurodegeneration? AB - It has long been suspected that chronic stress can exacerbate, or even cause, disease. We now propose that the RCAN1 gene, which can generate several RCAN1 protein isoforms, may be at least partially responsible for this phenomenon. We review data showing that RCAN1 proteins can be induced by multiple stresses, and present new data also implicating psychosocial/emotional stress in RCAN1 induction. We further show that transgenic mice overexpressing the RCAN1-1L protein exhibit accumulation of hyperphosphorylated tau protein (AT8 antibody), an early precursor to the formation of neurofibrillary tangles and neurodegeneration of the kind seen in Alzheimer disease. We propose that, although transient induction of the RCAN1 gene might protect cells against acute stress, persistent stress may cause chronic RCAN1 overexpression, resulting in serious side effects. Chronically elevated levels of RCAN1 proteins may promote or exacerbate various diseases, including tauopathies such as Alzheimer disease. We propose that the mechanism by which stress can lead to these diseases involves the inhibition of calcineurin and the induction of GSK-3beta by RCAN1 proteins. Both inhibition of calcineurin and induction of GSK-3beta contribute to accumulation of phosphorylated tau, formation of neurofibrillary tangles, and eventual neurodegeneration. PMID- 21680893 TI - Adenosine monophosphate-activated kinase alpha1 promotes endothelial barrier repair. AB - The vascular endothelium responds to damage through activation of multiple signaling events that restore cell-cell adhesion and vascular integrity. However, the molecular mechanisms that integrate these events are not clearly defined. Herein, we identify a previously unexpected role for adenosine monophosphate activated protein kinase (AMPK) in pulmonary microvascular endothelial cell (PMVEC) repair. PMVECs selectively express the AMPKalpha1 catalytic subunit, pharmacological and short hairpin RNA-mediated inhibition of which attenuates Ca(2+) entry in these cells induced by the inflammatory Ca(2+)-signaling mimetic thapsigargin. We find that AMPKalpha1 activity is required for the formation of PMVEC cell-cell networks in a prorepair environment and for monolayer resealing after wounding. Decreasing AMPKalpha1 expression reduces barrier resistance in PMVEC monolayers, results consistent with a role for AMPKalpha1 in cell-cell adhesion. AMPKalpha1 colocalizes and coimmunoprecipitates with the adherens junction protein N-cadherin and cofractionates with proteins selectively expressed in caveolar membranes. Assessment of permeability, by measuring the filtration coefficient (K(f)) in isolated perfused lungs, confirmed that AMPK activation contributes to barrier repair in vivo. Our findings thus provide novel evidence for AMPKalpha1 in Ca(2+) influx-mediated signaling and wound repair in the endothelium. PMID- 21680894 TI - Peptides derived from the bifunctional kinase/RNase enzyme IRE1alpha modulate IRE1alpha activity and protect cells from endoplasmic reticulum stress. AB - Activation of the bifunctional kinase/RNase enzyme IRE1alpha is part of an adaptive response triggered on accumulation of misfolded proteins in the endoplasmic reticulum (ER). To facilitate recovery of ER homeostasis, IRE1alpha molecules oligomerize, allowing for their transautophosphorylation and endoribonuclease activation. These, in turn, induce the activation of specific transcriptional and post-transcriptional programs. To identify novel and selective modulators of IRE1alpha activity, we investigated IRE1alpha oligomerization properties using IRE1alpha-derived peptides identified through an activity-based in vitro assay. We then used these peptides to probe IRE1alpha activity in vitro and in vivo using both cultured human hepatocellular carcinoma derived HuH7 cells and Caenorhabditis elegans experimental systems. We identified a peptide derived from the kinase domain of human IRE1alpha, which promoted IRE1alpha oligomerization in vitro, enhanced its Xbp1 mRNA cleavage activity in vitro (1.7*) in cell culture (1.8*) and in vivo (1.3*), and attenuated both ER stress-mediated JNK activation and regulated IRE1-dependent mRNA decay (RIDD). This was accompanied by a 2.5-fold increase in survival on tunicamycin-induced ER stress and reduced apoptosis by 1.4-fold in cells expressing this peptide. Hence, targeted and selective activation of the catalytic properties of IRE1alpha may consequently define new strategies to protect cells from deleterious effects of ER stress signaling. PMID- 21680895 TI - Short communication: flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. AB - RATIONALE: Flecainide prevents arrhythmias in catecholaminergic polymorphic ventricular tachycardia, but the antiarrhythmic mechanism remains unresolved. It is possible for flecainide to directly affect the cardiac ryanodine receptor (RyR2); however, an extracellular site of action is suggested because of the hydrophilic nature of flecainide. OBJECTIVE: To investigate the mechanism for the antiarrhythmic action of flecainide in a RyR2(R4496C+/-) knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia. METHODS AND RESULTS: Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2(R4496C+/-) mice. Cellular studies were performed with isolated RyR2(R4496C+/ ) myocytes. Isoproterenol caused the appearance of spontaneous Ca(2+) transients, which were unaffected by flecainide (6 MUmol/L). Flecainide did not affect Ca(2+) transient amplitude, decay, or sarcoplasmic reticulum Ca(2+) content. Moreover, it did not affect the frequency of spontaneous Ca(2+) sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P<0.01), which suggests a primary extracellular antiarrhythmic effect mediated by Na(+) channel blockade. CONCLUSIONS: Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2(R4496C+/-) mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca(2+) homeostasis. Our data suggest that the antiarrhythmic activity of the drug is caused by reduction of Na(+) channel availability and by an increase in the threshold for triggered activity. PMID- 21680896 TI - Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE deficient mice. AB - RATIONALE: The chemokine receptor Ccr6 is a G-protein-coupled receptor expressed on various types of leukocytes identified in mouse atherosclerotic lesions. Recent evidence suggests that both CCR6 and its ligand CCL20 are also present in human atheroma; however, their functional roles in atherogenesis remain undefined. OBJECTIVE: Our objective was to delineate the role of Ccr6 in atherogenesis in the apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis. METHODS AND RESULTS: Both Ccr6 and Ccl20 are expressed in atherosclerotic aorta from ApoE(-/-) mice. Aortic lesion area in Ccr6(-/-)ApoE(-/ ) mice was ~40% and ~30% smaller than in Ccr6(+/+)ApoE(-/-) mice at 16 and 24 weeks of age, respectively. Transplantation of bone marrow from Ccr6(-/-) mice into ApoE(-/-) mice resulted in ~40% less atherosclerotic lesion area than for bone marrow from Ccr6(+/+) mice; lesions in Ccr6(-/-)ApoE(-/-) mice had 44% less macrophage content than lesions in Ccr6(+/+)ApoE(-/-) mice. Ccr6 was expressed on a subset of primary mouse monocytes. Accordingly, Ccl20 induced chemotaxis of primary monocytes from wild-type but not Ccr6(-/-) mice; moreover, Ccl20 induced monocytosis in ApoE(-/-) mice in vivo. Consistent with this, we observed 30% fewer monocytes in circulating blood of Ccr6(-/-)ApoE(-/-) mice, mainly because of fewer CD11b(+)Ly6C(high) inflammatory monocytes. CONCLUSIONS: Ccr6 promotes atherosclerosis in ApoE-deficient mice, which may be due in part to Ccr6 support of normal monocyte levels in blood, as well as direct Ccr6-dependent monocyte migration. PMID- 21680897 TI - Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity. AB - OBJECTIVE: Leukocyte telomere length (LTL), a marker of cellular senescence, is inversely associated with cardiovascular events. However, whether LTL reflects plaque extent or unstable plaques, and the mechanisms underlying any association are unknown. METHODS AND RESULTS: One hundred seventy patients with stable angina or acute coronary syndrome referred for percutaneous coronary intervention underwent 3-vessel virtual histology intravascular ultrasound; 30 372 mm of intravascular ultrasound pullback and 1096 plaques were analyzed. LTL was not associated with plaque volume but was associated with calcified thin-capped fibroatheroma (OR, 1.24; CI, 1.01-1.53; P=0.039) and total fibroatheroma numbers (OR, 1.19; CI, 1.02-1.39; P=0.027). Monocytes from coronary artery disease patients showed increased secretion of proinflammatory cytokines. To mimic leukocyte senescence, we disrupted telomeres and binding and expression of the telomeric protein protection of telomeres protein-1, inducing DNA damage. Telomere disruption increased monocyte secretion of monocyte chemoattractant protein-1, IL-6, and IL-1beta and oxidative burst, similar to that seen in coronary artery disease patients, and lymphocyte secretion of IL-2 and reduced lymphocyte IL-10. CONCLUSIONS: Shorter LTL is associated with high-risk plaque morphology on virtual histology intravascular ultrasound but not total 3-vessel plaque burden. Monocytes with disrupted telomeres show increased proinflammatory activity, which is also seen in coronary artery disease patients, suggesting that telomere shortening promotes high-risk plaque subtypes by increasing proinflammatory activity. PMID- 21680899 TI - Cilostazol promotes vascular smooth muscles cell differentiation through the cAMP response element-binding protein-dependent pathway. AB - OBJECTIVE: Cilostazol, a potent type 3 phosphodiesterase inhibitor, has recently been found to reduce neointimal formation by inhibiting vascular smooth muscle cell (VSMC) proliferation. The aim of this study is to investigate whether cilostazol exerts an action on phenotypic modulation of VSMCs, another important process in the pathogenesis of neointimal formation. METHODS AND RESULTS: Cilostazol may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of smooth muscle cell differentiation marker contractile proteins. The upregulation of contractile proteins by cilostazol involves the cAMP/protein kinase A (PKA) signaling pathway, because the cAMP analog mimicked and specific cAMP/PKA inhibitors opposed the effect of cilostazol. Furthermore, cilostazol-activated cAMP response element (CRE)-binding protein (CREB), including phosphorylation at Ser133 and its nuclear translocation. Deletion and mutational analysis of the contractile protein promoters along with chromatin immunoprecipitation using anti-CREB antibody showed that CRE is essential for cilostazol-induced contractile protein expression. Transfection of dominant negative CREB (mutated Ser133) plasmid in VSMCs blocked cilostazol-stimulated contractile protein expression. In vivo, cilostazol upregulated contractile proteins and induced the activation of CREB in the neointima of balloon-injured arteries. CONCLUSIONS: Cilostazol promotes VSMC differentiation through the cAMP/PKA/CREB signaling cascade. PMID- 21680900 TI - Role of Jagged1 in arterial lesions after vascular injury. AB - OBJECTIVE: Impaired regeneration of endothelial cells (EC) and overactivity of vascular smooth muscle cells (VSMC) are hallmarks of the arterial lesions associated with aging. The occurrence of 2 opposing cellular processes in the same arterial milieu makes pharmaceutical treatment difficult to develop. We previously reported that endothelial expression of a Notch ligand (Jagged1) was reduced in aged animals and that growth of the neointima was enhanced in these animals. METHODS AND RESULTS: Similar to aged animals, Tie2-cre(+) Jagged1(lox/+) mice (with heterologous knockout of Jagged1 in EC) showed exaggerated intimal and medial thickening after carotid artery ligation. Unexpectedly, these mice showed little increase of Jagged1 expression not only in EC but also in VSMC, in contrast to a significant upregulation of Jagged1 in wild-type arteries after ligation. Coculture of VSMC with Jagged1-null EC resulted in the transition of VSMC from the contractile to the synthetic phenotype, along with decreased Jagged1 expression by VSMC. Conversely, overexpression of Jagged1 by EC or VSMC was shown to prevent the unfavorable phenotypic transition of VSMC, under both monoculture and coculture conditions. CONCLUSIONS: These findings suggest a unidirectional effect of Jagged1 on both EC and VSMC that contributes to inhibition of arterial lesions after vascular injury. Our data also indicate that Jagged1 may be a novel therapeutic target for aging-related vascular diseases. PMID- 21680898 TI - Bariatric surgery reduces visceral adipose inflammation and improves endothelial function in type 2 diabetic mice. AB - OBJECTIVE: Bariatric surgery is emerging as an effective method to alleviate a multitude of medical conditions associated with morbid obesity and type 2 diabetes. However, little is known about the effects and mechanisms of bariatric surgery on visceral fat inflammation and endothelial dysfunction in type 2 diabetes. We hypothesize that bariatric surgery ameliorates interferon-gamma mediated adipose tissue inflammation/oxidative stress and improves endothelial function in type 2 diabetic mice. METHODS AND RESULTS: Control mice (m Lepr(db)) and diabetic mice (Lepr(db)) were treated with either sham surgery or improved gastric bypass surgery and then were evaluated at 5, 10, 20, and 30 days to assess postsurgical effects. Surgery reduced body weight, abdominal adiposity, blood glucose level, and food intake in Lepr(db). The surgery-induced decrease in visceral adiposity was accompanied by amelioration of T-lymphocytes and macrophage infiltration, as well as reduction in the expression of interferon gamma and other inflammatory cytokines in the mesenteric adipose tissue (MAT) of Lepr(db) mice. Furthermore, surgery improved endothelium-dependent, but not endothelium-independent, vasorelaxation in small mesenteric arteries (SMA) of Lepr(db) mice. The improvement in endothelial function was largely attenuated by nitric oxide synthase inhibitor (L-NAME) incubation. Interferon-gamma treatment increased the mRNA expression of tumor necrosis factor-alpha in the MAT of control mice and incubation of SMA of control mice with tumor necrosis factor alpha caused impairment of endothelial function. Superoxide production in MAT/SMA and nitrotyrosine protein level in SMA were elevated in diabetic mice. Surgery reduced MAT/SMA oxidative stress in Lepr(db) mice. CONCLUSIONS: The amelioration of adipose tissue inflammation and the improvement of endothelial function may represent important mechanisms that result in cardiovascular benefits after bariatric surgery. PMID- 21680902 TI - Exposure to uremic serum induces a procalcific phenotype in human mesenchymal stem cells. AB - OBJECTIVE: Medial artery calcification in patients with chronic kidney disease proceeds through intramembranous ossification resulting from osteoblast-induced calcification of the collagen extracellular matrix. The current study is based on the hypothesis that mesenchymal stem cells (MSC) constitute critical cells for procalcific extracellular matrix remodeling in patients with chronic kidney disease. METHODS AND RESULTS: Human MSC were cultured in media supplemented with pooled sera from either healthy or uremic patients (20%). Exposure to uremic serum enhanced the proliferation of MSC (cell counting, BrdU incorporation) whereas apoptosis and necrosis were not affected (annexin V and 7-amino actinomycin staining). Uremic serum-exposed MSC recapitulated osteogenesis by matrix calcification and expression of bone-related genes (bone morphogenetic protein [BMP]-2 receptor, alkaline phosphatase, osteopontin, and Runx2) in 35 days. The uremic serum-induced osteogenesis was completely blocked by a BMP-2/4 neutralizing antibody or the natural antagonist NOGGIN. Calcification and matrix remodeling were further analyzed in a collagen-embedded osteogenesis model recapitulating the vascular collagen I/III environment. The uremic serum-induced calcification was shown to occur along collagen fibers as shown by scanning electron microscopy, energy-dispersive X-ray spectroscopy, and von Kossa staining and was accompanied by extensive matrix remodeling. CONCLUSIONS: Uremic serum induced in a BMP-2/4-dependent manner an osteoblast-like phenotype in MSC accompanied by matrix remodeling and calcification. PMID- 21680901 TI - RAGE-dependent activation of the oncoprotein Pim1 plays a critical role in systemic vascular remodeling processes. AB - OBJECTIVE: Vascular remodeling diseases (VRD) are mainly characterized by inflammation and a vascular smooth muscle cells (VSMCs) proproliferative and anti apoptotic phenotype. Recently, the activation of the advanced glycation endproducts receptor (RAGE) has been shown to promote VSMC proliferation and resistance to apoptosis in VRD in a signal transducer and activator of transcription (STAT)3-dependant manner. Interestingly, we previously described in both cancer and VRD that the sustainability of this proproliferative and antiapoptotic phenotype requires activation of the transcription factor NFAT (nuclear factor of activated T-cells). In cancer, NFAT activation is dependent of the oncoprotein provirus integration site for Moloney murine leukemia virus (Pim1), which is regulated by STAT3 and activated in VRD. Therefore, we hypothesized that RAGE/STAT3 activation in VSMC activates Pim1, promoting NFAT and thus VSMC proliferation and resistance to apoptosis. Methods/Results- In vitro, freshly isolated human carotid VSMCs exposed to RAGE activator Nepsilon (carboxymethyl)lysine (CML) for 48 hours had (1) activated STAT3 (increased P STAT3/STAT3 ratio and P-STAT3 nuclear translocation); (2) increased STAT3 dependent Pim1 expression resulting in NFATc1 activation; and (3) increased Pim1/NFAT-dependent VSMC proliferation (PCNA, Ki67) and resistance to mitochondrial-dependent apoptosis (TMRM, Annexin V, TUNEL). Similarly to RAGE inhibition (small interfering RNA [siRNA]), Pim1, STAT3 and NFATc1 inhibition (siRNA) reversed these abnormalities in human carotid VSMC. Moreover, carotid artery VSMCs isolated from Pim1 knockout mice were resistant to CML-induced VSMC proliferation and resistance to apoptosis. In vivo, RAGE inhibition decreases STAT3/Pim1/NFAT activation, reversing vascular remodeling in the rat carotid artery-injured model. CONCLUSIONS: RAGE activation accounts for many features of VRD including VSMC proliferation and resistance to apoptosis by the activation of STAT3/Pim1/NFAT axis. Molecules aimed to inhibit RAGE could be of a great therapeutic interest for the treatment of VRD. PMID- 21680903 TI - Age-related macular degeneration and the risk of stroke: the Rotterdam study. AB - BACKGROUND AND PURPOSE: Age-related macular degeneration (AMD) and stroke are both frequent diseases in the elderly. A link between AMD and stroke has been suggested, because both disorders have many risk factors in common. The aim of this study was to investigate the association between AMD and stroke and the subtypes cerebral infarction and intracerebral hemorrhage in the general elderly population. METHODS: This study was part of the population-based Rotterdam Study and included 6207 participants aged >= 55 years who were stroke-free at baseline (1990 to 1993). Signs of AMD were assessed on fundus photographs at baseline and at regular follow-up examinations and were categorized in 5 stages (0 to 4) representing an increasing severity. Late AMD (Stage 4) was subdivided into dry and wet AMD. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed using time-dependent Cox regression models adjusted for age, sex, and potential confounders. RESULTS: During a median follow-up of 13.6 years, 726 participants developed a stroke (397 cerebral infarction, 59 intracerebral hemorrhage, 270 unspecified). Late AMD was associated with an increased risk of any stroke (hazard ratio, 1.56; 95% CI, 1.08 to 2.26) due to a strong association with intracerebral hemorrhage (hazard ratio, 6.11; 95% CI, 2.34 to 15.98). In contrast, late AMD was not associated with cerebral infarction. Earlier AMD stages were not associated with risk of stroke or any of its subtypes. CONCLUSIONS: We found that late AMD is strongly associated with intracerebral hemorrhage, but not with cerebral infarction, in the general elderly population. PMID- 21680904 TI - Local brain temperature reduction through intranasal cooling with the RhinoChill device: preliminary safety data in brain-injured patients. AB - BACKGROUND AND PURPOSE: Hypothermia is neuroprotectant but currently available cooling methods are laborious, invasive, and require whole-body cooling. There is a need for less invasive cooling of the brain. This study was conducted to assess the safety and efficacy of temperature reduction of the RhinoChill transnasal cooling device. METHODS: We conducted a prospective single-arm safety and feasibility study of intubated patients for whom temperature reduction was indicated. After rhinoscopy, the device was activated for 1 hour. Brain, tympanic, and core temperatures along with vital signs and laboratory studies were recorded. All general and device-related adverse events were collected for the entire hypothermia treatment. RESULTS: A total of 15 patients (mean age, 50.3 +/- 17.1 years) were enrolled. Brain injury was caused by intracerebral hemorrhage, trauma, and ischemic stroke in equal numbers. Hypothermia was induced for fever control in 9 patients and for neuroprotection/intracranial pressure control in 6. Core temperature, brain temperature, and tympanic temperature were reduced an average of 1.1 +/- 0.6 degrees C (range, 0.3 to 2.1 degrees C), 1.4 +/ 0.4 degrees C (range, 0.8 to 5.1 degrees C), and 2.2 +/- 2 degrees C (range, 0.5 to 6.5 degrees C), respectively. Only 2 patients did not achieve the goal of >=1 degrees C decrease in temperature. Brain temperature, tympanic temperature, and core temperature reductions were similar between the afebrile and febrile patients. There were no unanticipated adverse events and only 1 anticipated adverse event: hypertension in 1 subject that led to discontinuation of cooling after 30 minutes. There were no nasal complications. CONCLUSIONS: Intranasal cooling with the RhinoChill device appears safe and effectively lowers brain and core temperatures. Further study is warranted to assess the efficacy of hypothermia through intranasal cooling for brain-injured patients. PMID- 21680905 TI - Simplified modified rankin scale questionnaire: reproducibility over the telephone and validation with quality of life. AB - BACKGROUND AND PURPOSE: The simplified modified Rankin Scale questionnaire (smRSq) enables a reliable and rapid determination of the modified Rankin Scale score after stroke. We test the reliability and validity of a slightly revised smRSq. METHODS: Fifty consecutive outpatients 4.83 +/- 3.00 months after stroke were scored with a slightly revised smRSq by 3 raters selected consecutively from a list of 10: 4 stroke faculty, 3 neurology residents, 2 medial students, and 1 stroke research coordinator. Two ratings were in person within 20 minutes of each other and 1 was by telephone 1 to 3 days later. The telephone rating also included a quality of life scale, the Short-Form-12v2. Each rater was blinded to the other raters' scores. RESULTS: The average estimated time to administer the smRSq was 1.29 minutes (range, 0.50 to 2.25 minutes). The in-person raters agreed 78% (kappa=0.71; CI, 0.57 to 0.86 and weighted kappa [kappa(w)]=0.86; CI, 0.79 to 0.94). The first in-person and telephone raters agreed 82% (kappa=0.76; CI, 0.63 to 0.90 and kappa(w)=0.87; CI, 0.79 to 0.95). The second in-person and telephone rates agreed 82% (kappa=0.77; CI, 0.63 to 0.90 and kappa(w)=0.89; CI, 0.82 to 0.96). The smRSq correlated with the physical (r=-0.50, P=0.005) than the mental (r=-0.36, P=0.048) components of the Short-Form-12v2. CONCLUSIONS: The slightly revised smRSq appears to be useful in clinical stroke; it has excellent reliability in person and by telephone, can usually be administered in <1.5 minutes by a wide variety of raters, and correlates with quality of life. PMID- 21680906 TI - Antibodies preventing the interaction of tissue-type plasminogen activator with N methyl-D-aspartate receptors reduce stroke damages and extend the therapeutic window of thrombolysis. AB - BACKGROUND AND PURPOSE: Tissue-type plasminogen activator (tPA) is the only drug approved for the acute treatment of ischemic stroke but with two faces in the disease: beneficial fibrinolysis in the vasculature and damaging effects on the neurovascular unit and brain parenchyma. To improve this profile, we developed a novel strategy, relying on antibodies targeting the proneurotoxic effects of tPA. METHODS: After production and characterization of antibodies (alphaATD-NR1) that specifically prevent the interaction of tPA with the ATD-NR1 of N-methyl-d aspartate receptors, we have evaluated their efficacy in a model of murine thromboembolic stroke with or without recombinant tPA-induced reperfusion, coupled to MRI, near-infrared fluorescence imaging, and behavior assessments. RESULTS: In vitro, alphaATD-NR1 prevented the proexcitotoxic effect of tPA without altering N-methyl-d-aspartate-induced neurotransmission. In vivo, after a single administration alone or with late recombinant tPA-induced thrombolysis, antibodies dramatically reduced brain injuries and blood-brain barrier leakage, thus improving long-term neurological outcome. CONCLUSIONS: Our strategy limits ischemic damages and extends the therapeutic window of tPA-driven thrombolysis. Thus, the prospect of this immunotherapy is an extension of the range of treatable patients. PMID- 21680908 TI - Acute physiology of stroke score. AB - BACKGROUND AND PURPOSE: The Acute Physiology, Age, Chronic Health Evaluation score for critically ill patients has provided a method of predicting outcome using major physiological variables. We hypothesized that a physiology score for stroke patients (Acute Physiology of Stroke Score [APSS]) when added to a validated clinical prediction model would improve outcome prediction. METHODS: The APSS was developed and validated using multivariable logistic regression. It was added to a previously validated clinical model to assess for increased area under the curve in predicting 3-month outcome. RESULTS: The bootstrap-validated bias-corrected area under the curve for just the APSS predicting alive/dead at discharge was 0.753. The clinical model area under the curve ranged from 0.77 to 0.88 and the addition of the APSS resulted in areas under the curve of 0.77 to 0.89. CONCLUSIONS: These data suggest that the APSS is related to 3-month clinical outcome in patients with ischemic stroke. However, the APSS adds no clinically relevant additional predictive value when added to our previously validated clinical prediction model. PMID- 21680907 TI - Prediction of early stroke risk in transient symptoms with infarction: relevance to the new tissue-based definition. AB - BACKGROUND AND PURPOSE: The risk of stroke shortly after transient ischemic attack with infarction on diffusion-weighted images, also known as transient symptoms with infarction (TSI), is substantially higher than is the risk after imaging-normal transient ischemic attack. We sought to assess the utility of a Web-based recurrence risk estimator (RRE; http://www.nmr.mgh.harvard.edu/RRE/) originally developed for use in patients with ischemic stroke for predicting 7 day risk of stroke in patients with TSI. METHODS: We calculated RRE and ABCD2 scores in a retrospective series of 257 consecutive patients with TSI diagnosed by diffusion-weighted images within 24 hours of symptom onset. We defined subsequent stroke as clinical deterioration associated with new infarction spatially distinct from the index lesion. We assessed the predictive performance of each model by computing the area under receiver-operating characteristics curve. RESULTS: Over 7-day follow-up, 16 patients developed a recurrent stroke (6.2%). The sensitivity and specificity of an RRE score of >= 2 for predicting 7 day stroke risk were 87% and 73%, respectively. The area under the receiver operating characteristics curve was 0.85 (95% CI, 0.78-0.92) for RRE and 0.57 (95% CI, 0.45-0.69) for ABCD2 score (z-test; P<0.001). CONCLUSIONS: The RRE score seems to predict 7-day risk of stroke after a TSI. If further validated in larger data sets, the RRE score could be useful in identifying high-risk patients with TSI who may benefit from early intervention with targeted stroke prevention strategies. PMID- 21680909 TI - Does treatment of ruptured intracranial aneurysms within 24 hours improve clinical outcome? AB - BACKGROUND AND PURPOSE: The purpose of this study was to analyze whether treating ruptured intracranial aneurysms within 24 hours of subarachnoid hemorrhage improves clinical outcome. METHODS: An 11-year database of consecutive ruptured intracranial aneurysms treated with endovascular coiling or craniotomy and clipping was analyzed. Outcome was measured by the modified Rankin Scale at 6 months. Our policy is to treat all cases within 24 hours of subarachnoid hemorrhage. Treatment delays are due to nonclinical logistical factors. RESULTS: Two hundred thirty cases were coiled or clipped within 24 hours of subarachnoid hemorrhage and 229 at >24 hours. No difference in age, gender, smoking, family history of subarachnoid hemorrhage, aneurysm size, or aneurysm location was found between the groups. Poor World Federation of Neurological Surgeons clinical grade patients were overrepresented in the ultra-early group. Increasing age and higher World Federation of Neurological Surgeons clinical grade were predictors of poor outcome. Eight point zero percent (16 of 199) of cases treated within 24 hours of SAH (ultra-early) were dependent or dead at 6 months compared with 14.4% (30 of 209) of those treated at >24 hours post-SAH (delayed; (chi2, P0.044) [corrected]. A total of 3.5% of cases coiled within 24 hours were dependent or dead at 6 months compared with 12.5% of cases coiled at 1 to 3 days, an 82% relative risk reduction and a 10.2% absolute risk reduction (chi2, P=0.040). These groups did not differ in age, World Federation of Neurological Surgeons clinical grade, aneurysm size, or aneurysm location. CONCLUSIONS: Treatment of ruptured aneurysms within 24 hours is associated with improved clinical outcomes compared with treatment at >24 hours. The benefit is more pronounced for coiling than clipping. PMID- 21680911 TI - Understanding cancer incidence in Barrett's esophagus: light at the end of the tunnel. PMID- 21680910 TI - Risk of malignant progression in Barrett's esophagus patients: results from a large population-based study. AB - BACKGROUND: Barrett's esophagus (BE) is a premalignant lesion that predisposes to esophageal adenocarcinoma. However, the reported incidence of esophageal adenocarcinoma in patients with BE varies widely. We examined the risk of malignant progression in patients with BE using data from the Northern Ireland Barrett's esophagus Register (NIBR), one of the largest population-based registries of BE worldwide, which includes every adult diagnosed with BE in Northern Ireland between 1993 and 2005. SUBJECTS AND METHODS: We followed 8522 patients with BE, defined as columnar lined epithelium of the esophagus with or without specialized intestinal metaplasia (SIM), until the end of 2008. Patients with incident adenocarcinomas of the esophagus or gastric cardia or with high grade dysplasia of the esophagus were identified by matching the NIBR with the Northern Ireland Cancer Registry, and deaths were identified by matching with records from the Registrar General's Office. Incidence of cancer outcomes or high grade dysplasia was calculated as events per 100 person-years (% per year) of follow-up, and Cox proportional hazard models were used to determine incidence by age, sex, length of BE segment, presence of SIM, macroscopic BE, or low-grade dysplasia. All P values were from two-sided tests. RESULTS: After a mean of 7.0 years of follow-up, 79 patients were diagnosed with esophageal cancer, 16 with cancer of the gastric cardia, and 36 with high-grade dysplasia. In the entire cohort, incidence of esophageal or gastric cardia cancer or high-grade dysplasia combined was 0.22% per year (95% confidence interval [CI] = 0.19% to 0.26%). SIM was found in 46.0% of patients. In patients with SIM, the combined incidence was 0.38% per year (95% CI = 0.31 to 0.46%). The risk of cancer was statistically significantly elevated in patients with vs without SIM at index biopsy (0.38% per year vs 0.07% per year; hazard ratio [HR] = 3.54, 95% CI = 2.09 to 6.00, P < .001), in men compared with women (0.28% per year vs 0.13% per year; HR = 2.11, 95% CI = 1.41 to 3.16, P < .001), and in patients with low-grade dysplasia compared with no dysplasia (1.40% per year vs 0.17% per year; HR = 5.67, 95% CI = 3.77 to 8.53, P < .001). CONCLUSION: We found the risk of malignant progression among patients with BE to be lower than previously reported, suggesting that currently recommended surveillance strategies may not be cost-effective. PMID- 21680912 TI - Using the tax system to promote physical activity: critical analysis of Canadian initiatives. AB - In Canada, tax incentives have been recently introduced to promote physical activity and reduce rates of obesity. The most prominent of these is the federal government's Children's Fitness Tax Credit, which came into effect in 2007. We critically assess the potential benefits and limitations of using tax measures to promote physical activity. Careful design could make these measures more effective, but any tax-based measures have inherent limitations, and the costs of such programs are substantial. Therefore, it is important to consider whether public funds are better spent on other strategies that could instead provide direct public funding to address environmental and systemic factors. PMID- 21680913 TI - The medicalization of sleeplessness: a public health concern. AB - Sleeplessness, a universal condition with diverse causes, may be increasingly diagnosed and treated (or medicalized) as insomnia. We examined the trend in sleeplessness complaints, diagnoses, and prescriptions of sedative hypnotics in physician office visits from 1993 to 2007. Consistent with the medicalization hypothesis, sleeplessness complaints and insomnia diagnoses increased over time and were far outpaced by prescriptions for sedative hypnotics. Insomnia may be a public health concern, but potential overtreatment with marginally effective, expensive medications with nontrivial side effects raises definite population health concerns. PMID- 21680914 TI - A qualitative assessment of beliefs, attitudes, and behaviors related to diarrhea and water filtration in rural Kenya. AB - OBJECTIVES: We qualitatively assessed beliefs, attitudes, and behaviors related to diarrhea and water filtration in rural Kenya. METHODS: A public health campaign was conducted in rural western Kenya to give community members a comprehensive prevention package of goods and services, including a personal water filter or a household water filter (or both). Two months after the campaign, we conducted qualitative interviews with 34 campaign attendees to assess their beliefs, attitudes, and behaviors related to diarrhea and use of the filtration devices. RESULTS: Participants held generally correct perceptions of diarrhea causation. Participants provided positive reports of their experiences with using filters and of their success with obtaining clean water, reducing disease, and reducing consumption of resources otherwise needed to produce clean water. Several participants offered technical suggestions for device improvements, and most participants were still using the devices at the time of the assessment. CONCLUSIONS: Novel water filtration devices distributed as part of a comprehensive public health campaign rapidly proved acceptable to community members and were consistent with community practices and beliefs. PMID- 21680915 TI - Water stress and water scarcity: a global problem. PMID- 21680916 TI - Health insurance status, medical debt, and their impact on access to care in Arizona. AB - OBJECTIVES: We examined the impact of health insurance status on medical debt among Arizona residents and the impact of both of these factors on access to care. METHODS: We estimated logistic regression models for medical debt (problems paying and currently paying medical bills) and access to care (medical care and medications delayed or missed because of cost or lack of insurance). RESULTS: Insured status did not predict medical debt after control for health status, income, age, and household characteristics. Insured status (adjusted odds ratio [AOR] = 0.32), problems paying medical bills (AOR = 4.96), and currently paying off medical bills (AOR = 3.04) were all independent predictors of delayed medical care, but only problems paying (AOR = 6.16) and currently paying (AOR = 3.68) medical bills predicted delayed medications. Inconsistent coverage, however, was a strong predictor of problems paying bills, and both of these factors led to delays in medical care and medications. CONCLUSIONS: At least in Arizona, health insurance does not protect individuals from medical debt, and medical debt and lack of insurance coverage both predict reduced access to care. These results may represent a troubling message for US health care in general. PMID- 21680917 TI - Leona Baumgartner (1902-1991): leader in domestic and international public health. PMID- 21680918 TI - Mental health promotion in public health: perspectives and strategies from positive psychology. AB - Positive psychology is the study of what is "right" about people-their positive attributes, psychological assets, and strengths. Its aim is to understand and foster the factors that allow individuals, communities, and societies to thrive. Cross-sectional, experimental, and longitudinal research demonstrates that positive emotions are associated with numerous benefits related to health, work, family, and economic status. Growing biomedical research supports the view that positive emotions are not merely the opposite of negative emotions but may be independent dimensions of mental affect. The asset-based paradigms of positive psychology offer new approaches for bolstering psychological resilience and promoting mental health. Ultimately, greater synergy between positive psychology and public health might help promote mental health in innovative ways. PMID- 21680919 TI - The quiet revolution: breastfeeding transformed with the use of breast pumps. AB - A quiet revolution has been taking place in the feeding of US infants in the form of women using electric breast pumps. This revolution in milk expression may be a boon for both mothers and infants if more infants are fed human milk or if they receive human milk for a longer period. Milk expression may also be problematic for mothers, and it may be particularly problematic for infants if they are fed too much, fed milk of an inappropriate composition, or fed milk that is contaminated. As a result, the time has come to determine the prevalence of exclusive and periodic breast milk expression and the consequences of these behaviors for the health of mothers and their infants. PMID- 21680920 TI - Community-based participatory research as worldview or instrumental strategy: is it lost in translation(al) research? PMID- 21680921 TI - A meta-analysis of disparities in childhood sexual abuse, parental physical abuse, and peer victimization among sexual minority and sexual nonminority individuals. AB - OBJECTIVES: We compared the likelihood of childhood sexual abuse (under age 18), parental physical abuse, and peer victimization based on sexual orientation. METHODS: We conducted a meta-analysis of adolescent school-based studies that compared the likelihood of childhood abuse among sexual minorities vs sexual nonminorities. RESULTS: Sexual minority individuals were on average 3.8, 1.2, 1.7, and 2.4 times more likely to experience sexual abuse, parental physical abuse, or assault at school or to miss school through fear, respectively. Moderation analysis showed that disparities between sexual minority and sexual nonminority individuals were larger for (1) males than females for sexual abuse, (2) females than males for assault at school, and (3) bisexual than gay and lesbian for both parental physical abuse and missing school through fear. Disparities did not change between the 1990s and the 2000s. CONCLUSIONS: The higher rates of abuse experienced by sexual minority youths may be one of the driving mechanisms underlying higher rates of mental health problems, substance use, risky sexual behavior, and HIV reported by sexual minority adults. PMID- 21680922 TI - Equitable distribution of PEPFAR-supported HIV/AIDS services in South Africa. PMID- 21680923 TI - Advancing the science of community-level interventions. AB - Community interventions are complex social processes that need to move beyond single interventions and outcomes at individual levels of short-term change. A scientific paradigm is emerging that supports collaborative, multilevel, culturally situated community interventions aimed at creating sustainable community-level impact. This paradigm is rooted in a deep history of ecological and collaborative thinking across public health, psychology, anthropology, and other fields of social science. The new paradigm makes a number of primary assertions that affect conceptualization of health issues, intervention design, and intervention evaluation. To elaborate the paradigm and advance the science of community intervention, we offer suggestions for promoting a scientific agenda, developing collaborations among professionals and communities, and examining the culture of science. PMID- 21680924 TI - The Prevention of Global Chronic Disease: Academic Public Health's New Frontier. AB - A confluence of stimuli is propelling academic public health to embrace the prevention of chronic disease in developing countries as its new frontier. These stimuli are a growing recognition of the epidemic, academia's call to reestablish public health as a mover of societal tectonics rather than a handmaiden to medicine's focus on the individual, and the turmoil in the US health system that makes change permissible. To enable graduating professionals to participate in the assault on chronic diseases, schools of public health must allocate budgets and other resources to this effort. The barriers to chronic disease prevention and risk factor modulation are cultural and political; confronting them will require public health to work with a wide variety of disciplines. Chronic disease will likely become the dominant global public health issue soon. In addressing this issue, academia needs to lead, not follow. PMID- 21680925 TI - Using conditionality as a solution to the problem of low uptake of essential services among disadvantaged communities: a social determinants view. AB - Conditional cash transfer schemes, which use cash to incentivize uptake of basic health and educational services, are well established among social planners inlow and middle-income countries and are now taking hold in high-income countries. We appraised these schemes within a social determinants framework and found some encouraging signs in their first decade of operation. Success, however, has been inconsistent, and it is unclear whether conditional cash transfer schemes can reliably secure meaningful improvements in participants' health and nutritional status or educational attainment. Conditional cash transfer schemes' objectives will not be met unless they are transformed in 3 ways: transferring power as well as resources, emphasizing entitlements alongside conditionality, and avoiding the trap of incoherent or residualized policy. PMID- 21680926 TI - Insurance-related barriers to accessing dental care among African American adults with oral health symptoms in Harlem, New York City. AB - Although ability to pay is associated with dental care utilization, provision of public or private dental insurance has not eliminated dental care disparities between African American and White adults. We examined insurance-related barriers to dental care in interviews with a street-intercept sample of 118 African American adults in Harlem, New York City, with recent oral health symptoms. Although most participants reported having dental insurance (21% private, 50% Medicaid), reported barriers included (1) lack of coverage, (2) insufficient coverage, (3) inability to find a dentist who accepts their insurance, (4) having to wait for coverage to take effect, and (5) perceived poor quality of care for the uninsured or underinsured. These findings provide insights into why disparities persist and suggest strategies to removing these barriers to dental care. PMID- 21680927 TI - Applying the essential medicines concept to US preferred drug lists. AB - OBJECTIVES: We assessed whether state Medicaid preferred drug lists are concordant with the World Health Organization's 2009 16th Essential Medicines List and with each other. We also characterized listed medicines by generic availability and appearance on treatment guidelines. METHODS: We derived generic availability and first-line treatment status from the US Food and Drug Administration's Orange Book and the 2004-2009 National Health Service National Institute for Clinical Excellence guidelines. We report characteristics of Essential Medicines List and preferred drug list (PDL)-only medicines and describe differences between medicines that are frequently and infrequently listed on PDLs. RESULTS: Only 6 of 120 Essential Medicines List medicines appeared on fewer than 50% of PDLs. PDL-only medicines (n = 249) were less likely than were Essential Medicines List medicines (n = 120) to have generic versions available (56% vs 76%) and to be first-line treatments (21% vs 41%). The content of PDLs was variable: 33% of medicines appeared on 80% to 100% of PDLs. CONCLUSIONS: Application of the essential medicines concept to Medicaid PDLs could reduce costs and provide more equitable and evidence-based health care to low-income patients in the United States. PMID- 21680928 TI - Negative aspects of close relationships as a predictor of increased body mass index and waist circumference: the Whitehall II study. AB - OBJECTIVES: We investigated whether exposure to negative aspects of close relationships was associated with subsequent increase in body mass index (BMI) and waist circumference. METHODS: Data came from a prospective cohort study (Whitehall II) of 9425 civil servants aged 35 to 55 years at baseline (phase 1: 1985-1988). We assessed negative aspects of close relationships with the Close Persons Questionnaire (range 0-12) at phases 1 and 2 (1989-1990). We measured BMI and waist circumference at phases 3 (1991-1994) and 5 (1997-1999). Covariates at phase 1 included gender, age, marital status, ethnicity, BMI, employment grade, smoking, physical activity, fruit and vegetable consumption, and common mental disorder. RESULTS: After adjustment for sociodemographic characteristics and health behaviors, participants with higher exposure to negative aspects of close relationships had a higher likelihood of a 10% or greater increase in BMI and waist circumference (odds ratios per 1-unit increase 1.08 [95% confidence interval (CI) =1.02, 1.14; P = .007] and 1.09 [CI = 1.04, 1.14; P <= .001], respectively) as well as a transition from the overweight (25 <= BMI < 30) to the obese (BMI >= 0) category. CONCLUSIONS: Adverse social relationships may contribute to weight gain. PMID- 21680929 TI - US Housing insecurity and the health of very young children. AB - OBJECTIVES: We investigated the association between housing insecurity and the health of very young children. METHODS: Between 1998 and 2007, we interviewed 22,069 low-income caregivers with children younger than 3 years who were seen in 7 US urban medical centers. We assessed food insecurity, child health status, developmental risk, weight, and housing insecurity for each child's household. Our indicators for housing insecurity were crowding (> 2 people/bedroom or>1 family/residence) and multiple moves (>= 2 moves within the previous year). RESULTS: After adjusting for covariates, crowding was associated with household food insecurity compared with the securely housed (adjusted odds ratio [AOR] = 1.30; 95% confidence interval [CI] = 1.18, 1.43), as were multiple moves (AOR = 1.91; 95% CI = 1.59, 2.28). Crowding was also associated with child food insecurity (AOR = 1.47; 95% CI = 1.34, 1.63), and so were multiple moves (AOR = 2.56; 95% CI = 2.13, 3.08). Multiple moves were associated with fair or poor child health (AOR = 1.48; 95% CI =1.25, 1.76), developmental risk (AOR 1.71; 95% CI = 1.33, 2.21), and lower weight-for-age z scores (-0.082 vs -0.013; P= .02). CONCLUSIONS: Housing insecurity is associated with poor health, lower weight, and developmental risk among young children. Policies that decrease housing insecurity can promote the health of young children and should be a priority. PMID- 21680930 TI - Determinants of hearing aid acquisition in older adults. AB - OBJECTIVES: We determined factors associated with hearing aid acquisition in older adults. METHODS: We conducted a population-based, prospective study that used information from 3 examinations performed on study participants as part of the Epidemiology of Hearing Loss Study (1993-2005). We included participants (n = 718; mean age = 70.5 years) who exhibited hearing loss at baseline or the first follow-up and had no prior history of hearing aid use. We defined hearing loss as a pure tone threshold average (PTA) at 0.5, 1, 2, and 4 kilohertz in the better ear of greater than 25 decibels Hearing Level. RESULTS: The 10-year cumulative incidence of hearing aid acquisition was 35.7%. Associated factors included education (college graduate vs all others: hazard ratio [HR] = 2.5; 95% confidence interval [CI] = 1.5, 4.1), self-perception of hearing (poor vs good or better: HR = 2.5; 95% CI = 1.3, 5.0), score on a perceived hearing handicap inventory (+1 difference: HR = 1.1; 95% CI = 1.0, 1.1), and PTA (+ 5 dB difference: HR = 1.4; 95% CI = 1.2, 1.6). CONCLUSIONS: The low rate of hearing aid ownership among older adults is a problem that still needs to be addressed. PMID- 21680931 TI - The influence of social involvement, neighborhood aesthetics, and community garden participation on fruit and vegetable consumption. AB - OBJECTIVES: We considered the relationship between an urban adult population's fruit and vegetable consumption and several selected social and psychological processes, beneficial aesthetic experiences, and garden participation. METHODS: We conducted a population-based survey representing 436 residents across 58 block groups in Denver, Colorado, from 2006 to 2007. We used multilevel statistical models to evaluate the survey data. RESULTS: Neighborhood aesthetics, social involvement, and community garden participation were significantly associated with fruit and vegetable intake. Community gardeners consumed fruits and vegetables 5.7 times per day, compared with home gardeners (4.6 times per day) and nongardeners (3.9 times per day). Moreover, 56% of community gardeners met national recommendations to consume fruits and vegetables at least 5 times per day, compared with 37% of home gardeners and 25% of nongardeners. CONCLUSIONS: Our study results shed light on neighborhood processes that affect food-related behaviors and provides insights about the potential of community gardens to affect these behaviors. The qualities intrinsic to community gardens make them a unique intervention that can narrow the divide between people and the places where food is grown and increase local opportunities to eat better. PMID- 21680933 TI - Estimating the potential health impact and costs of implementing a local policy for food procurement to reduce the consumption of sodium in the county of Los Angeles. AB - OBJECTIVES: We examined approaches to reduce sodium content of food served in settings operated or funded by the government of the County of Los Angeles, California. METHODS: We adapted health impact assessment methods to mathematically simulate various levels of reduction in the sodium content of food served by the County of Los Angeles and to estimate the reductions' potential impacts on mean systolic blood pressure (SBP) among food-service customers. We used data provided by county government food-service vendors to generate these simulations. RESULTS: Our analysis predicted that if the postulated sodium reduction strategies were implemented, adults would consume, on average, 233 fewer milligrams of sodium each day. This would correspond to an average decrease of 0.71 millimeters of mercury in SBP among adult hypertensives, 388 fewer cases of uncontrolled hypertension in the study population, and an annual decrease of $629,724 in direct health care costs. CONCLUSIONS: Our findings suggest that a food-procurement policy can contribute to positive health and economic effects at the local level. Our approach may serve as an example of sodium-reduction analysis for other jurisdictions to follow. PMID- 21680932 TI - Effectiveness of a community health worker intervention among African American and Latino adults with type 2 diabetes: a randomized controlled trial. AB - OBJECTIVES: We tested the effectiveness of a culturally tailored, behavioral theory-based community health worker intervention for improving glycemic control. METHODS: We used a randomized, 6-month delayed control group design among 164 African American and Latino adult participants recruited from 2 health systems in Detroit, Michigan. Our study was guided by the principles of community-based participatory research. Hemoglobin A1c (HbA1c) level was the primary outcome measure. Using an empowerment-based approach, community health workers provided participants with diabetes self-management education and regular home visits, and accompanied them to a clinic visit during the 6-month intervention period. RESULTS: Participants in the intervention group had a mean HbA1c value of 8.6% at baseline, which improved to a value of 7.8% at 6 months, for an adjusted change of -0.8 percentage points (P < .01). There was no change in mean HbA1c among the control group (8.5%). Intervention participants also had significantly greater improvements in self-reported diabetes understanding compared with the control group. CONCLUSIONS: This study contributes to the growing evidence for the effectiveness of community health workers and their role in multidisciplinary teams engaged in culturally appropriate health care delivery. PMID- 21680934 TI - Louis I. Harris (1882-1939): a bold but now little known early twentieth century public health leader. PMID- 21680935 TI - From controlled trial to community adoption: the multisite translational community trial. AB - Methods for translating the findings of controlled trials, such as the Diabetes Prevention Program, into real-world community application have not been clearly defined. A standardized research methodology for making and evaluating such a transition is needed. We introduce the multisite translational community trial (mTCT) as the research analog to the multisite randomized controlled trial. The mTCT is adapted to incorporate the principles and practices of community-based participatory research and the increased relevance and generalizability gained from diverse community settings. The mTCT is a tool designed to bridge the gap between what a clinical trial demonstrates can work in principle and what is needed to make it workable and effective in real-world settings. Its utility could be put to the test, in particular with practice-based research networks such as the Prevention Research Centers. PMID- 21680936 TI - Making ENDS Meet: community networks and health promotion among Blacks in the city of Brotherly Love. AB - This historical inquiry illustrates the power of social networks by examining the Starr Centre and the Whittier Centre, two civic associations that operated in Philadelphia during the early 20th century, a time when Black Americans faced numerous public health threats. Efforts to address those threats included health initiatives forged through collaborative social networks involving civic associations, health professionals, and members of Black communities. Such networks provided access to important resources and served as cornerstones of health promotion activities in many large cities. I trace the origins of these two centers, the development of their programs, their establishment of ties with Black community residents, and the relationship between strong community ties and the development of community health initiatives. Clinicians, researchers, and community health activists can draw on these historical precedents to address contemporary public health concerns by identifying community strengths, leveraging social networks, mobilizing community members, training community leaders, and building partnerships with indigenous community organizations. PMID- 21680937 TI - Estimated deaths attributable to social factors in the United States. AB - OBJECTIVES: We estimated the number of deaths attributable to social factors in the United States. METHODS: We conducted a MEDLINE search for all English language articles published between 1980 and 2007 with estimates of the relation between social factors and adult all-cause mortality. We calculated summary relative risk estimates of mortality, and we obtained and used prevalence estimates for each social factor to calculate the population-attributable fraction for each factor. We then calculated the number of deaths attributable to each social factor in the United States in 2000. RESULTS: Approximately 245,000 deaths in the United States in 2000 were attributable to low education, 176,000 to racial segregation, 162,000 to low social support, 133,000 to individual-level poverty, 119,000 to income inequality, and 39,000 to area-level poverty. CONCLUSIONS: The estimated number of deaths attributable to social factors in the United States is comparable to the number attributed to pathophysiological and behavioral causes. These findings argue for a broader public health conceptualization of the causes of mortality and an expansive policy approach that considers how social factors can be addressed to improve the health of populations. PMID- 21680938 TI - The individual and program impacts of eliminating Medicaid dental benefits in the Oregon Health Plan. AB - OBJECTIVES: We determined how elimination of dental benefits among adult Medicaid beneficiaries in Oregon affected their access to dental care, Medicaid expenditures, and use of medical settings for dental services. METHODS: We used a natural experimental design using Medicaid claims data (n = 22 833) before and after Medicaid dental benefits were eliminated in Oregon in 2003 and survey data for continuously enrolled Oregon Health Plan enrollees (n = 718) covering 3 years after benefit cuts. RESULTS: Claims analysis showed that, compared with enrollees who retained dental benefits, those who lost benefits had large increases in dental-related emergency department use (101.7%; P < .001) and expenditures (98.8%; P < .001) and in all ambulatory medical care use (77.0%; P < .01) and expenditures (114.5%; P < .01). Survey results indicated that enrollees who lost dental benefits had nearly 3 times the odds (odds ratio = 2.863; P = .001) of unmet dental need, and only one third the odds (odds ratio = 0.340; P = .001) of getting annual dental checkups relative to those retaining benefits. CONCLUSIONS: Combined evidence from both analyses suggested that the elimination of dental benefits resulted in significant unmet dental health care needs, which led to increased use of medical settings for dental problems. PMID- 21680939 TI - Competitive foods, discrimination, and participation in the National School Lunch Program. AB - Meals served through the National School Lunch Program (NSLP) must meet rigorous nutritional standards; however, barriers to student participation may limit the program's health and social equity benefits. Unsubsidized meals and food offerings competing with the NSLP offerings in school lunch environments may be lowering qualified student participation either directly or via identification of subsidized low-income students or stigmatization of the NSLP. We document a pilot intervention conducted in San Francisco in 2009 and 2010 that demonstrated gains in NSLP participation after removal of separate competitive a la carte lunch meal offerings. Our observations suggest the need for greater attention to the potential discriminatory effects of competitive foods and to the issue of stigma by school nutrition program administrators, researchers, regulators, and policymakers. PMID- 21680940 TI - Fortification of corn masa flour with folic acid in the United States. AB - Food fortification is an effective public health tool for addressing micronutrient deficiencies. The mandatory fortification of enriched cereal grains (e.g., wheat flour) with folic acid, which began in the United States in 1998, is an example of a successful intervention that significantly reduced the rate of neural tube defects (NTDs). However, despite the drop in NTD rates across all racial/ethnic groups after fortification, Hispanics continue to have the highest rates of this condition. One possible way to reduce this disparity is to fortify corn masa flour to increase the overall intake of folic acid in Hispanic women. We present the available evidence in favor of this approach, address possible safety issues, and outline next steps in the fortification of corn masa flour with folic acid in the United States. PMID- 21680941 TI - Encouraging consumption of water in school and child care settings: access, challenges, and strategies for improvement. AB - Children and adolescents are not consuming enough water, instead opting for sugar sweetened beverages (sodas, sports and energy drinks, milks, coffees, and fruit flavored drinks with added sugars), 100% fruit juice, and other beverages. Drinking sufficient amounts of water can lead to improved weight status, reduced dental caries, and improved cognition among children and adolescents. Because children spend most of their day at school and in child care, ensuring that safe, potable drinking water is available in these settings is a fundamental public health measure. We sought to identify challenges that limit access to drinking water; opportunities, including promising practices, to increase drinking water availability and consumption; and future research, policy efforts, and funding needed in this area. PMID- 21680942 TI - Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. AB - RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. OBJECTIVES: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. METHODS: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. MEASUREMENTS AND MAIN RESULTS: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed "pauciinflammatory." Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1beta, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83-0.95); serum CXCL10, 0.83 (95% CI, 0.70-0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78-0.93), respectively. CONCLUSIONS: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1beta, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation. PMID- 21680944 TI - Noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial. AB - RATIONALE: The use of noninvasive ventilation (NIV) as an early weaning/extubation technique from mechanical ventilation remains controversial. OBJECTIVES: To investigate NIV effectiveness as an early weaning/extubation technique in difficult-to-wean patients with chronic hypercapnic respiratory failure (CHRF). METHODS: In 13 intensive care units, 208 patients with CHRF intubated for acute respiratory failure (ARF) who failed a first spontaneous breathing trial were randomly assigned to three groups: conventional invasive weaning group (n = 69), extubation followed by standard oxygen therapy (n = 70), or NIV (n = 69). NIV was permitted as rescue therapy for both non-NIV groups if postextubation ARF occurred. Primary endpoint was reintubation within 7 days after extubation. Secondary endpoints were: occurrence of postextubation ARF or death within 7 days after extubation, use of rescue postextubation NIV, weaning time, and patient outcomes. MEASUREMENTS AND MAIN RESULTS: Reintubation rates were 30, 37, and 32% for invasive weaning, oxygen-therapy, and NIV groups, respectively (P = 0.654). Weaning failure rates, including postextubation ARF, were 54, 71, and 33%, respectively (P < 0.001). Rescue NIV success rates for invasive and oxygen-therapy groups were 45 and 58%, respectively (P = 0.386). By design, intubation duration was 1.5 days longer for the invasive group than in the two others. Apart from a longer weaning time in NIV than in invasive group (2.5 vs. 1.5 d; P = 0.033), no significant outcome difference was observed between groups. CONCLUSIONS: No difference was found in the reintubation rate between the three weaning strategies. NIV decreases the intubation duration and may improve the weaning results in difficult-to-wean patients with CHRF by reducing the risk of postextubation ARF. The benefit of rescue NIV in these patients deserves confirmation. PMID- 21680945 TI - The inflammatory preatherosclerotic remodeling induced by intermittent hypoxia is attenuated by RANTES/CCL5 inhibition. AB - RATIONALE: The highly prevalent obstructive sleep apnea syndrome (OSA) with its main component intermittent hypoxia (IH) is a risk factor for cardiovascular mortality. The poor knowledge of its pathophysiology has limited the development of specific treatments, whereas the gold standard treatment, continuous positive airway pressure, may not fully reverse the chronic consequences of OSA and has limited acceptance in some patients. OBJECTIVES: To examine the contribution of IH-induced inflammation to the cardiovascular complications of OSA. METHODS: We investigated systemic and vascular inflammatory changes in C57BL6 mice exposed to IH (21-5% Fi(O(2)), 60-s cycle) or normoxia 8 hours per day up to 14 days. Vascular alterations were reassessed in mice treated with a blocking antibody of regulated upon activation, normal T-cell expressed and secreted (RANTES)/CC chemokine ligand 5 (CCL5) signaling pathway, or with the IgG isotype control throughout the IH exposure. MEASUREMENTS AND MAIN RESULTS: IH induced systemic inflammation combining increased splenic lymphocyte proliferation and chemokine expression, with early and predominant RANTES/CCL5 alterations, and enhanced splenocyte migration toward RANTES/CCL5. IH also induced structural and inflammatory vascular alterations. Leukocyte-endothelium adhesive interactions were increased, attested by leukocyte rolling and intercellular adhesion molecule 1 expression in mesenteric vessels. Aortas had increased intima-media thickness with elastic fiber alterations, mucoid depositions, nuclear factor-kappaB-p50 and intercellular adhesion molecule-1 overexpression, hypertrophy of smooth-muscle cells overexpressing RANTES/CCL5, and adventitial-periadventitial T-lymphocyte infiltration. RANTES/CCL5 neutralization prevented both intima-media thickening and inflammatory alterations, independently of the IH-associated proatherogenic dyslipidemia. CONCLUSIONS: Inflammation is a determinant mechanism for IH-induced preatherosclerotic remodeling involving RANTES/CCL5, a key chemokine in atherogenesis. Characterization of the inflammatory response could allow identifying at-risk patients for complications, and its pharmacologic manipulation may represent a potential complementary treatment of sleep apnea consequences. PMID- 21680946 TI - Detection of pulmonary emboli with 99mTc-labeled anti-D-dimer (DI-80B3)Fab' fragments (ThromboView). AB - RATIONALE: We report a new method to diagnose acute pulmonary embolism (PE) by single photon emission computerized tomography (SPECT) after administration of (99m)Tc-labeled anti-D-dimer (DI-80B3) monoclonal antibody Fab' fragments. This novel technique provides an additional approach to diagnosing PE in patients for whom other methods are nondiagnostic or contraindicated. OBJECTIVES: We performed a prospective, multicenter study to investigate the sensitivity and specificity of (99m)Tc-DI-80B3/SPECT in patients with suspected acute PE. METHODS: Subjects with a moderate to high clinical probability of PE or a positive D-dimer test underwent a PE-protocol contrast-enhanced multidetector thoracic computed tomography (CT) scan as well as (99m)Tc-DI-80B3/SPECT (0.5 mg (99m)Tc-DI-80B3 intravenously followed by a thoracic SPECT 2.5 h later). Separate and independent adjudication committees, blinded to clinical data and other test results, interpreted the (99m)Tc-DI-80B3/SPECT scans (PE detected as foci of abnormally increased (99m)Tc uptake) and the thoracic CT scans using Prospective Investigation of Pulmonary Embolism Diagnosis II criteria. MEASUREMENTS AND MAIN RESULTS: Of the 52 patients who were enrolled and completed both tests, 42 had both evaluable SPECT scans and thoracic CT scans. Using the criterion standard (thoracic CT scan) there were 21 patients with PE and 21 without. (99m)Tc-DI 80B3/SPECT had a sensitivity of 76.2% (95% confidence interval, 52.8-91.8%) and a specificity of 90.5% (95% confidence interval, 69.8-98.8%). Treatment-related serious adverse events did not occur. CONCLUSIONS: (99m)Tc-DI-80B3/SPECT was sensitive and specific for acute PE in subjects with moderate to high clinical probability of PE or a positive D-dimer test. (99m)Tc-DI-80B3/SPECT demonstrated an acceptable safety profile and avoids exposure to contrast. PMID- 21680947 TI - Has my patient responded? Interpreting clinical measurements such as the 6-minute walk test. AB - To correctly interpret clinical measurements it is necessary to understand the standard deviation and the standard error; the former reflects the range or variability of individuals within a sample and the latter reflects the precision for which the group parameters have been estimated. When evaluating an individual patient, test measurement properties such as repeatability will assist in concluding whether a repeated test, measured to monitor the response to an intervention, has changed beyond its natural variability. Using the "best" test has an inherent bias and ignores the natural test variation, whereas the average of repeated tests is more representative of the true value, making it more discriminative to change. Serial measurements to follow progress will increase a clinician's confidence in the observed effects of treatment. PMID- 21680948 TI - The emerging field of quantitative blood metabolomics for biomarker discovery in critical illnesses. AB - Metabolomics, a science of systems biology, is the global assessment of endogenous metabolites within a biologic system and represents a "snapshot" reading of gene function, enzyme activity, and the physiological landscape. Metabolite detection, either individual or grouped as a metabolomic profile, is usually performed in cells, tissues, or biofluids by either nuclear magnetic resonance spectroscopy or mass spectrometry followed by sophisticated multivariate data analysis. Because loss of metabolic homeostasis is common in critical illness, the metabolome could have many applications, including biomarker and drug target identification. Metabolomics could also significantly advance our understanding of the complex pathophysiology of acute illnesses, such as sepsis and acute lung injury/acute respiratory distress syndrome. Despite this potential, the clinical community is largely unfamiliar with the field of metabolomics, including the methodologies involved, technical challenges, and, most importantly, clinical uses. Although there is evidence of successful preclinical applications, the clinical usefulness and application of metabolomics in critical illness is just beginning to emerge, the advancement of which hinges on linking metabolite data to known and validated clinically relevant indices. In addition, other important aspects, such as patient selection, sample collection, and processing, as well as the needed multivariate data analysis, have to be taken into consideration before this innovative approach to biomarker discovery can become a reliable tool in the intensive care unit. The purpose of this review is to begin to familiarize clinicians with the field of metabolomics and its application for biomarker discovery in critical illnesses such as sepsis. PMID- 21680949 TI - Systemic steroids in severe sepsis and septic shock. AB - Despite more than 5 decades of study and debate, the role of corticosteroid treatment in patients with severe sepsis and septic shock remains controversial. Data support a beneficial effect on systemic blood pressure in patients with septic shock. However, the ability of corticosteroid therapy to improve mortality in patients with severe sepsis and septic shock remains controversial, with contradictory results from recent large multicenter clinical trials. Although it appears clear that high-dose corticosteroid treatment provides no benefit and possibly harm in septic patients, the experimental design flaws and biases of recent low-dose (physiologic) steroid treatment trials limit their ability to provide adequate answers to the important questions of which septic patients should be treated, how much steroid to give, and the optimum duration of treatment. Unfortunately, the answer to these important questions is not readily evident based on the current evidence or the application of metaanalysis to the available clinical data. This concise evidence-based review highlights the strengths and weaknesses of the current data to inform the practicing clinician as to which patients are likely to derive significant benefit from corticosteroid treatment, while we await more definitive guidance from future multicenter, prospective, randomized, controlled trials designed to better answer these important therapeutic questions. PMID- 21680951 TI - Current controversies and future perspectives in chronic obstructive pulmonary disease. AB - Over the past decade there has been much research and interest in COPD. As a result, the understanding and management of the disease has improved significantly. Yet, there are many uncertainties and controversies that require further work. This review discusses these controversies and anticipates some of the changes that may occur in the near future in the field of COPD. PMID- 21680950 TI - Topographical continuity of bacterial populations in the healthy human respiratory tract. AB - RATIONALE: Defining the biogeography of bacterial populations in human body habitats is a high priority for understanding microbial-host relationships in health and disease. The healthy lung was traditionally considered sterile, but this notion has been challenged by emerging molecular approaches that enable comprehensive examination of microbial communities. However, studies of the lung are challenging due to difficulties in working with low biomass samples. OBJECTIVES: Our goal was to use molecular methods to define the bacterial microbiota present in the lungs of healthy individuals and assess its relationship to upper airway populations. METHODS: We sampled respiratory flora intensively at multiple sites in six healthy individuals. The upper tract was sampled by oral wash and oro-/nasopharyngeal swabs. Two bronchoscopes were used to collect samples up to the glottis, followed by serial bronchoalveolar lavage and lower airway protected brush. Bacterial abundance and composition were analyzed by 16S rDNA Q-PCR and deep sequencing. MEASUREMENTS AND MAIN RESULTS: Bacterial communities from the lung displayed composition indistinguishable from the upper airways, but were 2 to 4 logs lower in biomass. Lung-specific sequences were rare and not shared among individuals. There was no unique lung microbiome. CONCLUSIONS: In contrast to other organ systems, the respiratory tract harbors a homogenous microbiota that decreases in biomass from upper to lower tract. The healthy lung does not contain a consistent distinct microbiome, but instead contains low levels of bacterial sequences largely indistinguishable from upper respiratory flora. These findings establish baseline data for healthy subjects and sampling approaches for sequence-based analysis of diseases. PMID- 21680952 TI - Elevated eosinophil protein X in urine from healthy neonates precedes development of atopy in the first 6 years of life. AB - RATIONALE: Biomarkers predicting development of atopic disease are needed for targeted preventive measures and to study if disease pathology may be active before onset of symptoms. OBJECTIVES: To investigate whether eosinophil protein X, leukotriene-C4/D4/E4, and 11beta-prostaglandin (PG) F2alpha (PGD2 metabolite) assessed in urine from healthy at-risk neonates precede development of atopic disease during the first 6 years of life. METHODS: We measured eosinophil protein X (n = 369), leukotriene-C4/D4/E4 (n = 367), and 11beta-PGF2alpha (n = 366) in urine from 1-month-old children participating in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Clinical data on development of allergic sensitization, allergic rhinitis, nasal eosinophilia, blood eosinophilia, eczema, troublesome lung symptoms (significant cough or wheeze or dyspnea), and asthma were collected prospectively until age 6 years. Associations between urinary biomarkers and development of atopic traits were investigated using general estimating equations, logistic regression, and Cox regression. MEASUREMENTS AND MAIN RESULTS: Eosinophil protein X in the urine of the asymptomatic 1-month-old neonates was significantly associated with development of allergic sensitization (odds ratio, 1.49; 95% confidence interval [CI], 1.08 1.89), nasal eosinophilia (odds ratio, 3.2; 95% CI, 1.2-8.8), and eczema (hazard ratio, 1.4; 95% CI, 1.0-2.0), but not with allergic rhinitis, asthma, or blood eosinophilia. Neither leukotriene-C4/D4/E4 nor 11beta-PGF2alpha was associated with any of the atopic phenotypes. CONCLUSIONS: Eosinophil protein X in urine from asymptomatic neonates is a biomarker significantly associated with later development of allergic sensitization, nasal eosinophilia, and eczema during the first 6 years of life. These findings suggest activation of eosinophil granulocytes early in life before development of atopy-related symptoms. PMID- 21680953 TI - Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. AB - RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial. OBJECTIVES: To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved. METHODS: We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice. CONCLUSIONS: We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis. PMID- 21680955 TI - Lemur tyrosine kinase-3 (LMTK3) in cancer and evolution. PMID- 21680954 TI - Targeting mTOR for the treatment of AML. New agents and new directions. AB - Despite recent advances in the field, the treatment of patients with acute myeloid leukemia (AML) remains challenging and difficult. Although chemotherapeutic agents induce remissions in a large number of patients, many of them eventually relapse and die. A major goal for the development of new approaches for the treatment of AML is to enhance the antileukemic effects of standard chemotherapeutics and to design effective combinations targeting non overlapping cellular pathways. The PI3K/Akt/mTOR signaling pathway plays a critical role in survival and growth of malignant cells and its targeting has been the focus of extensive work and research efforts over the last two decades. It now appears possible that a major limitation of the first generation of mTOR inhibitors can be overcome by a new class of catalytic inhibitors of mTOR. There is emerging evidence that such compounds target both TORC1 and TORC2 and elicit much more potent responses against early leukemic precursors in vitro. In addition, recent studies have shown that combinations of such agents with cytarabine result in enhanced antileukemic responses in vitro, raising the prospect and potential of use of these agents in combination regimens for the treatment of AML. PMID- 21680956 TI - A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. AB - STAT transcription factors transduce signals from the cell surface to the nucleus, where they regulate the expression of genes that control proliferation, survival, self-renewal, and other critical cellular functions. Under normal physiological conditions, the activation of STATs is tightly regulated. In cancer, by contrast, STAT proteins, particularly STAT3 and STAT5, become activated constitutively, thereby driving the malignant phenotype of cancer cells. Since these proteins are largely dispensable in the function of normal adult cells, STATs represent a potentially important target for cancer therapy. Although transcription factors have traditionally been viewed as suboptimal targets for pharmacological inhibition, chemical biology approaches have been particularly fruitful in identifying compounds that can modulate this pathway through a variety of mechanisms. STAT inhibitors have notable anti-cancer effects in many tumor systems, show synergy with other therapeutic modalities, and have the potential to eradicate tumor stem cells. Furthermore, STAT inhibitors identified through the screening of chemical libraries can then be employed in large scale analyses such as gene expression profiling, RNA interference screens, or large-scale tumor cell line profiling. Data derived from these studies can then provide key insights into mechanisms of STAT signal transduction, as well as inform the rational design of targeted therapeutic strategies for cancer patients. PMID- 21680958 TI - Formation and stabilization of single-crystalline metastable AuGe phases in Ge nanowires. AB - We use in situ observations by variable temperature transmission electron microscopy on AuGe alloy drops at the tips of Ge nanowires (NWs) with systematically varying composition to demonstrate the controlled formation of metastable solid phases integrated in NWs. The process, which operates in the regime of vapor-liquid-solid growth, involves a size-dependent depression of the alloy liquidus at the nanoscale that leads to extremely Ge-rich AuGe melts at low temperatures. During slow cooling, these liquid AuGe alloy drops show pronounced departures from equilibrium, i.e., a frustrated phase separation of Ge into the adjacent solid NW, and ultimately crystallize as single-crystalline segments of metastable gamma-AuGe. Our findings demonstrate a general avenue for synthesizing NW heterostructures containing stable and metastable solid phases, applicable to a wide range of materials of which NWs form by the vapor-liquid-solid method. PMID- 21680957 TI - Benefits and drawbacks of zinc in glass ionomer bone cements. AB - Glass polyalkenoate (ionomer) cements (GPCs) based on poly(acrylic acid) and fluoro-alumino-silicate glasses are successfully used in a variety of orthopaedic and dental applications; however, they release small amounts of aluminium, which is a neurotoxin and inhibits bone mineralization in vivo. Therefore there has been significant interest in developing aluminium-free glasses containing zinc for forming GPCs because zinc can play a similar structural role in the glass, allowing for glass degradation and subsequent cement setting, and is reported to have beneficial effects on bone formation. We created zinc-containing GPCs and characterized their mechanical properties and biocompatibility. Zinc-containing cements showed adhesion to bone close to 1 MPa, which was significantly greater than that of zinc-free cements (<0.05 MPa) and other currently approved biological adhesives. However, zinc-containing cements produced significantly lower metabolic activity in mouse osteoblasts exposed to cell culture medium conditioned with the cements than controls. Results show that although low levels of zinc may be beneficial to cells, zinc concentrations of 400 uM Zn(2+) or more resulted in cell death. In summary, we demonstrate that while zinc-containing GPCs possess excellent mechanical properties, they fail basic biocompatibility tests, produce an acute cytotoxic response in vitro, which may preclude their use in vivo. PMID- 21680959 TI - Mass and stiffness calibration of nanowires using thermally driven vibration. AB - Cantilevered or suspended nanowires show promise for force or mass sensing applications due to their small mass, high force sensitivity and high frequency bandwidth. To use these as quantitative sensors, their bending stiffness or mass must be calibrated experimentally, often using thermally driven vibration. However, this can be difficult because nanowires are slightly asymmetric, which results in two spatially orthogonal bending eigenmodes with closely spaced frequencies. This asymmetry presents problems for traditional stiffness calibration methods, which equate the measured thermal vibration spectrum near a resonance to that of a single eigenmode. Moreover, the principal axes may be arbitrarily rotated with respect to the measurement direction. In this work, the authors propose a method for calibrating the bending stiffness and mass of such nanowires' eigenmodes using a single measurement taken at an arbitrary orientation with respect to the principal axes. PMID- 21680960 TI - Effects of pulsed laser radiation on epitaxial self-assembled Ge quantum dots grown on Si substrates. AB - Laser irradiation of Ge quantum dots (QDs) grown on Si(100) substrates by solid source molecular beam epitaxy has been performed using a Nd:YAG laser (532 nm wavelength, 5 ns pulse duration) in a vacuum. The evolution of the Ge QD morphology, strain and composition with the number of laser pulses incident on the same part of the surface, have been studied using atomic force microscopy, scanning electron microscopy and Raman spectroscopy. The observed changes in the topographical and structural properties of the QDs are discussed in terms of Ge Si diffusion processes. Numerical simulations have been developed for the investigation of the temperature evolution of the QDs during laser irradiation. The obtained results indicate that the thermal behaviour and structural variation of the nanostructures differ from conventional thermal annealing treatments and can be controlled by the laser parameters. Moreover, an unusual island motion has been observed under the action of subsequent laser pulses. PMID- 21680961 TI - Structural characterization of InAs quantum dot chains grown by molecular beam epitaxy on nanoimprint lithography patterned GaAs(100). AB - We combine nanoimprint lithography and molecular beam epitaxy for the site controlled growth of InAs quantum dot chains on GaAs(100) substrates. We study the influence of quantum dot growth temperature and regrowth buffer thickness on the formation of the quantum dot chains. In particular, we show that by carefully tuning the growth conditions we can achieve equal quantum dot densities and photoluminescence ground state peak wavelengths for quantum dot chains grown on patterns oriented along the [011], [01 1], [011] and [001] directions. Furthermore, we identify the crystal facets that form the sidewalls of the grooves in the differently oriented patterns after capping and show that the existence of (411)A sidewalls causes reduction of the QD density as well as sidewall roughening. PMID- 21680962 TI - Plasmonic Au islands on polymer nanopillars. AB - The refractive index sensitivity of localized surface plasmon resonance sensors can be improved by placing the plasmonic metal particles on pillars instead of on a planar substrate. In this paper, a simple and versatile colloidal lithography method for the fabrication of plasmonic Au islands on top of polymer nanopillars is described. The pillar height is controlled by varying the thickness of the initial polymer film. An increased pillar height results in a blue shift of the absorption spectrum of the Au islands. This is explained by a decreased effective refractive index around the islands. For pillars higher than approximately 40 nm no further blue shift is observed, in agreement with the decay length of the electromagnetic field around the islands. Pillar-supported Au islands were also fabricated on a flexible foil, demonstrating the potential of the method described here for the fabrication of flexible plasmonic substrates. Benefits and limitations of the method and of using polymers as the pillar material are discussed. PMID- 21680963 TI - Big challenges and nanosolutions. PMID- 21680964 TI - Synthesis of ethanol-soluble few-layer graphene nanosheets for flexible and transparent conducting composite films. AB - We report a facile method of preparing few-layer graphene nanosheets (FLGs), which can be soluble in ethanol. Atomic force microscopy and high-resolution transmission electron microscopy studies reveal that FLGs have average thicknesses in the range of 2.6-2.8 nm, corresponding to 8-9 layers. A graphene/nafion composite film has a sheet resistance of 9.70 kOmega/sq at the transmittance of 74.5% (at 550 nm) while the nafion film on polyethylene terephthalate has a sheet resistance of 128 kOmega/sq at transmittance of 90.0%. For the cycling/bending test, almost no change in resistance was exhibited when the film was bent at an angle up to 140 degrees , and no obvious deviation in resistance could be found after 100 bending cycles was applied. In addition, an FLGs-poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) composite layer was demonstrated as the effective hole transporting layer to improve the hole transporting ability in an organic photovoltaic device, with which the power conversion efficiency was enhanced from 3.10% to 3.70%. The results demonstrated the promising applications of FLGs on graphene-based electronics, such as transparent electrode and flexible conducting film. PMID- 21680965 TI - Electrochemical performance of a graphene-polypyrrole nanocomposite as a supercapacitor electrode. AB - A unique nanoarchitecture has been established involving polypyrrole (PPy) and graphene nanosheets by in situ polymerization. The structural aspect of the nanocomposite has been determined by Raman spectroscopy. Atomic force microscopy reveals that the thickness of the synthesized graphene is ~ 2 nm. The dispersion of the nanometer-sized PPy has been demonstrated through transmission electron microscopy and the electrochemical performance of the nanocomposite has been illustrated by cyclic voltammetry measurements. Graphene nanosheet serves as a support material for the electrochemical utilization of PPy and also provides the path for electron transfer. The specific capacitance value of the nanocomposite has been determined to be 267 F g(-1) at a scan rate of 100 mV s(-1) compared to 137 mV s(-1) for PPy, suggesting the possible use of the nanocomposite as a supercapacitor electrode. After 500 cycles, only 10% decrease in specific capacitance as compared to initial value justifies the improved electrochemical cyclic stability of the nanocomposite. PMID- 21680966 TI - Nanostructured materials for water desalination. AB - Desalination of seawater and brackish water is becoming an increasingly important means to address the scarcity of fresh water resources in the world. Decreasing the energy requirements and infrastructure costs of existing desalination technologies remains a challenge. By enabling the manipulation of matter and control of transport at nanometer length scales, the emergence of nanotechnology offers new opportunities to advance water desalination technologies. This review focuses on nanostructured materials that are directly involved in the separation of water from salt as opposed to mitigating issues such as fouling. We discuss separation mechanisms and novel transport phenomena in materials including zeolites, carbon nanotubes, and graphene with potential applications to reverse osmosis, capacitive deionization, and multi-stage flash, among others. Such nanostructured materials can potentially enable the development of next generation desalination systems with increased efficiency and capacity. PMID- 21680967 TI - Synthesis of erbium oxide nanosheets and up-conversion properties. AB - A novel erbium-based compound as well as Er(2)O(3) nanosheets have been synthesized through a simple hydrothermal route. The nanosheets are of 200 nm width and 10-15 nm thickness. It is suggested that this erbium-based compound has a possible formula of Er(2)O(5)H(4) with a primitive tetragonal structure (cell parameters: a = 8.465(1) and c = 15.117(2) A). Face-centered cubic and body centered cubic structured Er(2)O(3) nanosheets were obtained after calcination of this compound at 623 and 973 K, respectively, both having a paramagnetic behavior. Er(2)O(5)H(4) and Er(2)O(3) nanosheets have similar up-conversion properties with strong blue emission, which is rarely reported in the literature. The existence of absorbed surface contaminations in nanosheets might be the origin for the blue emission enhancement. PMID- 21680972 TI - Misbehaviors of front-line research personnel and the integrity of community based research. AB - There has been little empirical research into misconduct and misbehavior among community research workers who recruit and collect data in vulnerable and marginalized health populations and are also members of those same communities. We conducted qualitative interviews with community research workers and traditional research assistants to understand the context and consequences of misbehaviors that pose a threat to research ethics and data integrity. In our sample, more community research workers acknowledged engaging in research wrongdoing than did traditional research assistants. These behaviors were most prevalent among community research workers who were not well-integrated into the research team. We suggest best practices for investigators to promote an environment that supports research integrity in research projects that employ community research workers. PMID- 21680973 TI - Relationships between community-based processes for research ethics review and institution-based IRBs: a national study. AB - Community groups are implementing research ethics review processes to determine whether and how research is conducted in their communities. We report on a survey of 109 of these community-based review processes about their relationships with institution based research ethics boards (I-REBs). Ninety-two percent reported that studies they review were also reviewed by an I-REB. Over half characterized their relationship with I-REBs positively. Those with positive relationships were significantly more likely to communicate with the involved I-REBs. Challenges when working with I-REBs included delays, communication problems, and lack of I REB understanding of community-based participatory research. Strengthening relationships between community-based review processes and I-REBs could ultimately enhance reviews of community-engaged research. PMID- 21680974 TI - Developing community partner training: regulations and relationships. AB - While funders increasingly support research that partners with communities, community partners still must submit to a regulatory oversight structure that does not reflect their unique research ethics challenges and needs. In recognition of the importance of collaborative research endeavors, the authors engaged in a process of reconnaissance and negotiations with local community partners and research ethics boards (REBs) at the University of Michigan to begin to address the mismatch between regulatory demands and community-based research realities. This preliminary process yielded both changes in the REB oversight structure and training required of community partnered research. While the ultimate impact of these changes remains to be seen, the process itself yielded insights and materials of use to both our local REBs, and hopefully those at other institutions as well. This article will present those insights and provide links to those materials. PMID- 21680975 TI - How do IRB members make decisions? A review and research agenda. AB - Many factors have been found to influence the nature and quality of the human research ethics review process. These are reviewed along with discussion of ways in which normal psychological characteristics and group decision-making processes may affect the decisions of institutional review board (IRB) members when reviewing proposed research activities, and may contribute to the acknowledged variability of IRB responses to identical research proposals. Three salient features of human judgment and decision-making illuminated by the existing psychological research literature are used to illustrate this idea: Research findings related to (a) risk perception and acceptance, (b) the standards people use to make decisions, and (c) some nonrational influences on group decision making suggest how psychological characteristics may affect some outcomes of convened IRB meetings. Recognizing such influences may enable the improvement of IRB decision-making. PMID- 21680976 TI - When a serious adverse event in research occurs, how do other volunteers react? AB - Serious adverse events in research involving healthy volunteers are rare, but their impact on other volunteers is unknown. We conducted semi-structured interviews with 60 healthy volunteers at an institution where a healthy research volunteer died. Most volunteers (85%) had heard of the event, but few said it changed their thoughts about joining research (17%), approach to studies or questions asked (25%), or future participation (4%). Despite knowing few facts, respondents created narratives about the case that served to distance them from the event and justify their continued participation in research. Downward social comparison theory, optimistic bias, and feelings of responsibility and control may help explain these narratives. Findings underscore the importance of communication and understanding of research risks and protections. PMID- 21680977 TI - "If I could in a small way help": motivations for and beliefs about sample donation for genetic research. AB - Human genome research depends upon participants who donate genetic samples, but few studies have explored in depth the motivations of genetic research donors. This mixed methods study examines telephone interviews with 752 sample donors in a U.S. genetic epidemiology study investigating colorectal cancer. Quantitative and qualitative results indicate that most participants wanted to help society, and that many also wanted information about their own health, even though such information was not promised. Qualitative analysis reveals that donors believed their samples contributed to a scientific "common good"; imagined samples as information rather than tissues; and often blurred distinctions between research and diagnostic testing of samples. Differences between African American and White perspectives were distinct from educational and other possible explanatory factors. PMID- 21680978 TI - Computer science security research and human subjects: emerging considerations for research ethics boards. AB - This paper explores the growing concerns with computer science research, and in particular, computer security research and its relationship with the committees that review human subjects research. It offers cases that review boards are likely to confront, and provides a context for appropriate consideration of such research, as issues of bots, clouds, and worms enter the discourse of human subjects review. PMID- 21680979 TI - Ethnographic study of alternative sports by alternative means: list mining as a method of data collection. AB - Increased usage and accessibility of the Internet has led to the rapid growth of cyber communities; typical of groups that have embraced this idea are those who participate in what have been termed alternative or lifestyle sports. Thus far, this online world has received little attention from ethnographers, but the potential for obtaining rich data in this area is huge, most notably through the practice of researching messages sent to Internet-based forums, known as list mining. The inclusion of list mining as a research method, however, is not without its problems and raises new ethical issues when conducting qualitative research. This paper examines in detail the ethical considerations concerning the use of list mining as a method of data collection within the alternative sporting subculture of Ultimate Frisbee. PMID- 21680981 TI - Educational advantage. AB - This issue of JERHRE examines topics relevant to a variety of issues connected with community-engaged research and the relationship of communities with research ethics committees (RECs). It also examines some of the ways in which risk is assessed by subject populations and by RECs. Educational activities are presented that will enable readers to more comprehensively assess the way RECs and communities can work together more easily and effectively, and that will enable RECs to better understand their own functioning, and that of subject populations as these respective groups assess risk. The following assignments are best conducted in small groups. PMID- 21680984 TI - Iatrogenic hypoglycemia in patients with type 2 diabetes: comparison of insulin analog premixes and human insulin premixes. AB - Severe iatrogenic--or therapy-induced--hypoglycemia has been associated with mortality rates as high as 10% in patients with type 2 diabetes mellitus (T2DM), and is therefore one of the most significant barriers to glucose management in this patient population. Therapy with modern insulin analogs has been shown to cause significantly less hypoglycemic episodes than human insulins in basal-bolus regimens. This systematic review examines whether a similar benefit has been observed with the insulin analog premixes (aspart 70/30, lispro 75/25, or lispro 50/50) relative to human insulin premix (human 70/30). Consistent with a prior meta-analysis, the results presented here reconfirm that overall hypoglycemia risk is similar after treatment with either an analog premix or a human premix in many populations of patients with T2DM. However, several studies found a benefit for the analog premixes in a subset of patients who were under more challenging glucometabolic conditions, in particular those later in disease progression or those undergoing post-injection exercise. Pharmacokinetic and pharmacodynamic studies indicate that this may occur because a larger proportion of total analog premix activity is absorbed and utilized during the immediate postprandial period, when it is most acutely needed, compared with human premixes. Consequently, with analog premixes, less insulin activity is available during the inter-meal fasting period, when hypoglycemia is most likely to occur. Given the clinical significance of iatrogenic hypoglycemia, these potential hypoglycemic benefits of analog premixes relative to human premixes in some patients with T2DM may need to be factored into the therapeutic decision-making process. PMID- 21680985 TI - Basal insulin: physiology, pharmacology, and clinical implications. AB - Primary goals in the treatment of type 2 diabetes mellitus (T2DM) include lowering blood glucose levels sufficiently to prevent micro- and macrovascular complications while limiting side effects, such as hypoglycemia and excessive weight gain. Patients with T2DM are typically treated initially with oral antidiabetes agents; however, as the disease progresses, most will require insulin to maintain glycemic control. Often insulin therapy is initiated with basal insulin, and the objective of this article is to present the conceptual aspects of basal insulin therapy and use these concepts to illustrate important clinical aspects. This will be accomplished within a broader contextual discussion of the normal physiologic patterns of insulin secretion, which consist of sustained levels of basal insulin production throughout the day, superimposed with bursts of insulin secretion following a meal (termed bolus or prandial insulin secretion) that slowly decay over 1 to 3 hours. Long-acting basal insulin analogs form a key component of basal-bolus therapy and provide basal support for patients with T2DM. Insulin therapy is often initiated with basal insulin, and newer long-acting analogs, such as insulin glargine and insulin detemir, provide steady, reliable basal insulin coverage in addition to significant advantages over traditional long-acting insulins. This article will integrate conceptual aspects of basal insulin therapy in the context of physiology, molecular pharmacology, and clinical implications of modern basal insulin analogs to provide a foundational understanding of basal insulin biology and physiology. PMID- 21680986 TI - Basal insulin: beyond glycemia. AB - Insulin is a pleiotropic hormone with numerous effects at the cellular, tissue, and organismal levels. Clinicians are familiar with physiological effects of insulin on carbohydrate metabolism, including stimulation of glucose uptake in skeletal muscle and the suppression of glucose production from the liver. Other metabolic effects of insulin include inhibiting the release of free fatty acids from adipose tissue and stimulating the incorporation of amino acids into proteins. Indeed, every organ in the body, including the brain, is a target for insulin action. Insulin resistance, typically defined with respect to glucose metabolism, is a condition in which normal levels of insulin do not trigger the signal for glucose disposition. The effects of insulin resistance and impaired insulin signaling have profound pathophysiologic effects, such as hyperglycemia induced tissue damage, hypertension, dyslipidemia, metabolic syndrome, and cardiovascular and renal disease. An integrated view of insulin action in all of these tissues may yield improved therapeutic insight and possibly even illuminate new therapeutic opportunities. With the increase in the number of patients diagnosed with prediabetes and diabetes, an updated understanding of the disease and the pharmacologic armamentarium used to treat it is needed to improve outcomes. To help expand the clinical care provider's perspective, this article will provide a provocative discussion about the pathophysiology of diabetes, the role of insulin and insulin resistance, and the clinical efficacy potential of insulin. Understanding the cellular and molecular mechanisms underlying the effects of insulin and how these translate into clinical consequences beyond glycemia will assist primary care physicians in the care of their patients with diabetes and metabolic syndrome. PMID- 21680987 TI - A new approach to glucose control in type 2 diabetes: the role of kidney sodium glucose co-transporter 2 inhibition. AB - Hyperglycemia is a defining characteristic of type 2 diabetes mellitus and is a major risk factor associated with the development of many microvascular complications. There are numerous therapies currently available to treat hyperglycemia, but glycemic control rates remain poor. One potential reason is the decline in beta-cell function over time, which decreases the effectiveness of therapies that rely on insulin action. The kidney occupies a central position in the control of glucose homeostasis by its role in gluconeogenesis and by regulating glucose excretion. Under normal conditions, glucose filtered by the kidney is virtually totally reabsorbed in the proximal tubule by the sodium glucose co-transporter 2 (SGLT2). Inhibition of SGLT2 is an attractive, insulin independent target for increasing glucose excretion in the setting of hyperglycemia. A number of SGLT2 inhibitors have been synthesized, and results from preclinical studies have shown that they increase glucose excretion and normalize plasma glucose in diabetic models. Initial clinical data are promising and suggest that SGLT2 inhibitors may be a new therapeutic option for treating type 2 diabetes mellitus. PMID- 21680988 TI - Linagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. AB - Incretin-based therapies constitute a relatively new pharmacological approach to the treatment of type 2 diabetes mellitus. As reflected in the rapidly growing body of literature and the number of glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitor (DPP-4) compounds that are either approved or in development, there is considerable interest in treatments that target the incretin axis. Linagliptin is a recently approved DPP-4 inhibitor with unique pharmacological properties, including very high affinity for the DPP-4 enzyme, postdose DPP-4 inhibition>80% after 24 hours, and a primarily fecal route of elimination. Phase 3 clinical trials on >4000 patients have demonstrated the efficacy of linagliptin as monotherapy or in combination with other antidiabetic agents. Treatment with linagliptin reduced glycated hemoglobin by 0.6% to 0.8%, with a safety profile comparable with placebo. This article provides a review of linagliptin clinical data for primary care physicians treating patients with type 2 diabetes mellitus. PMID- 21680989 TI - Utilizing current diagnostic criteria and treatment algorithms for managing type 2 diabetes mellitus. AB - Within the past 2 years, the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) and the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) have revised their guidelines for the diagnosis and treatment of type 2 diabetes mellitus (T2DM). Both organizations recommend a diagnostic glycated hemoglobin (HbA1c) of >6.5% (based on a new appreciation of the relationship between glycemia and complications) and fasting plasma glucose levels or an oral glucose tolerance test. Findings from major trials of glucose control in patients with T2DM and the approval of novel medications have prompted revised treatment algorithms from both organizations. While both treatment guidelines recommend starting metformin in most patients on diagnosis of T2DM, they differ in terms of the "trigger" for treatment intensification (HbA1c>=7% and >6.5%, respectively) and which agents are preferred as second-line therapies. The ADA/EASD recommends a tiered approach to treatment, starting with well-validated second-line agents, such as sulfonylureas and basal insulin for patients unable to achieve target glucose levels with metformin. The AACE/ACE recommendations are based on the patient's HbA1c level and include a broader range of first- and second-line therapies and combinations. In addition to metformin, the ACCE/ACE treatment algorithm includes dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones, alpha-glucosidase inhibitors, sulfonylureas, and glinides. Both organizations advocate individualizing therapy to meet patient needs. This review highlights recent changes in the guidelines and uses a case based format to illustrate how the current guidelines may be tailored to fit individual patient characteristics and circumstances. PMID- 21680990 TI - Efficacy and safety of saxagliptin combination therapy in US patients with type 2 diabetes. AB - BACKGROUND: The mechanism of action of dipeptidyl peptidase-4 inhibitors, such as saxagliptin, makes them suitable for combination therapy in type 2 diabetes mellitus (T2DM). Genetic, cultural, and environmental differences in individuals from different regions of the world may result in differences in treatment response to oral antidiabetic drugs (OADs). This post-hoc subanalysis assessed the efficacy and safety of saxagliptin as add-on therapy to metformin, glyburide, or a thiazolidinedione in patients with inadequately controlled T2DM in the United States. METHODS: In 3 phase 3 studies of patients with T2DM uncontrolled on monotherapy, 547 adult US patients were randomized to receive saxagliptin (2.5 or 5 mg/d) or placebo as add-on to metformin, glyburide, or a thiazolidinedione (pioglitazone or rosiglitazone). Efficacy was assessed as the change from baseline to week 24 in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial glucose area under the curve (PPG-AUC) and the proportion of patients achieving HbA1c<7.0%. Pooled safety and tolerability data across trials were also analyzed. RESULTS: Reductions from baseline to week 24 in HbA1c were observed in all saxagliptin treatment groups versus placebo: saxagliptin 2.5 or 5 mg plus metformin (mean difference from placebo, -0.87% and -0.89%, respectively), glyburide (-0.51% and -0.52%), or thiazolidinedione (-0.45% and 0.60%). Improvement was also observed in FPG and PPG-AUC. Adverse events for the US cohort were consistent with previously reported data from the 3 trials. The pooled incidence of reported hypoglycemia was 5.3% and 11.4% with saxagliptin 2.5 and 5 mg/d add-on, respectively, versus 6.8% with placebo add-on. CONCLUSIONS: This post-hoc analysis in a cohort of US patients with T2DM uncontrolled on monotherapy suggests that saxagliptin 2.5 or 5 mg as add-on therapy to OADs results in improvement across key glycemic parameters compared with placebo add on and was generally safe and well tolerated. PMID- 21680991 TI - Recognition, prevention, and proactive management of hypoglycemia in patients with type 1 diabetes mellitus. AB - Hypoglycemia is the key barrier that prevents patients from optimizing glycemic control with the use of pharmacotherapeutic interventions. Optimal glycemic control for patients with type 1 diabetes (T1DM) includes methods that provide glucose-regulated physiologic insulin replacement or secretion in association with glucose monitoring methods designed to predict and prevent acute extreme changes in glycemic variability. Patients with T1DM experience an average of 2 episodes of symptomatic hypoglycemia each week and at least 1 episode of severe, disabling hypoglycemia annually. Asymptomatic hypoglycemia is common, as shown in studies using continuous glucose monitoring (CGM). Episodes of hypoglycemia (symptomatic and asymptomatic) impair counterregulatory defenses against subsequent events, resulting in the inability to respond to and recover from serious hypoglycemia. This defective counterregulation is known as hypoglycemic associated autonomic failure. When patients are prescribed a more intensive medication regimen or reinforcing lifestyle interventions, such as medical nutrition therapy and exercise therapy, providers should also assess their ability to proactively identify and manage hypoglycemia. Although self-monitoring of blood glucose regimens, such as pre- and post-meal and periodic middle-of-the night glucose testing, can help predict the risk of developing hypoglycemia, CGM technology allows patients to receive real-time notification of impending events either through preset alarms or simply by looking at the device display. This review explores the utility of initiating CGM within the primary care setting for patients at high risk for developing hypoglycemia. PMID- 21680992 TI - Hypoglycemia in insulin-treated diabetes: a case for increased vigilance. AB - Studies have shown that effective diabetes management can delay or prevent the micro- and macrovascular complications of diabetes. Achieving optimal glycemic control often requires treatment with intensive insulin management. However, with intensive insulin management comes the risk of severe hypoglycemia. Hypoglycemia requiring emergency medical assistance is as common in patients with longstanding insulin-treated type 2 diabetes mellitus as in patients with type 1 diabetes mellitus, and is associated with a significant economic and personal burden; untreated, severe hypoglycemia can result in morbidity and death. Key contributors to severe hypoglycemia are asymptomatic hypoglycemia and nocturnal hypoglycemia; both conditions inhibit patients' ability to recognize hypoglycemia when it is occurring and take appropriate action. As a result, many patients with types 1 and 2 diabetes mellitus are reluctant to follow and/or adjust their insulin regimens as needed because of fear of hypoglycemia, resulting in exposure to chronic hyperglycemia, oxidative stress, and long-term complications. Severe hypoglycemia can be prevented through vigilance in identifying patients at risk, utilizing appropriate medications and medication regimens, and effective glucose monitoring strategies and technologies. The purpose of this article is to review our current understanding of hypoglycemia and its impact on diabetes management, and to provide guidance to health care providers when assisting patients who utilize insulin therapy to do so safely and effectively. PMID- 21680993 TI - Evaluating the OneTouch(r) DelicaTM: a low-pain lancing system for self monitoring of blood glucose. AB - The pain associated with lancing can be a significant barrier to self-monitoring of blood glucose (SMBG). The OneTouch(r) DelicaTM lancing device contains features to reduce lancing pain, including improved lancet control and stability, reduced vibration, and a thinner, 33-gauge lancet. This 2-visit, randomized controlled trial assessed perceived pain of lancing with the OneTouch(r) DelicaTM compared with 4 other common lancing devices: OneTouch(r) ComfortTM, ACCU-CHEK(r) Softclix, ACCU-CHEK(r) Multiclix, and Ascensia(r) MicroletTM2. Two hundred patients with type 1 or type 2 diabetes mellitus were assigned to the OneTouch(r) DelicaTM and also randomized to 1 of the 4 comparator devices (n=50 per device pair). At visit 1, we determined the minimum depth settings required to produce>=1 MUL of fingertip blood for each patient with each device. At visit 2, patients lanced their fingertips with the devices at the predetermined depths and used a 150-mm visual analog scale (VAS) to rate lancing pain relative to their "usual pain" associated with SMBG. The VAS ranged from "much less painful" (0 mm) to "much more painful" (150 mm), with the midpoint (75 mm) labeled as "usual pain." Fingertip pain scores from patients using OneTouch(r) DelicaTM were significantly lower than those obtained using OneTouch(r) ComfortTM, ACCU-CHEK(r) Multiclix, and Ascensia(r) MicroletTM2. Pain scores for OneTouch(r) DelicaTM and ACCU-CHEK(r) Softclix were not significantly different. In conclusion, OneTouch(r) DelicaTM was either less painful or no different than the comparator devices when used for fingertip lancing. Innovative lancing devices that cause less pain may improve compliance and persistence with prescribed SMBG. PMID- 21680994 TI - Effect of case-based training for medical residents on confidence, knowledge, and management of inpatient glycemia. AB - OBJECTIVE: To determine whether a brief, case-based educational intervention improves resident confidence, knowledge, and management of glycemia in hospitalized patients. RESEARCH DESIGN AND METHODS: All 116 medical residents at a large academic medical center were offered a case-based curriculum on the management of inpatient glycemia in fall 2008. Residents on ambulatory and elective rotations were taught in small groups, whereas all others underwent online training. All participants were offered a brief online refresher course in spring 2009. We assessed resident confidence across 9 domains of treating inpatient dysglycemia, knowledge based on 4 questions before the course, a 23 part questionnaire after the intervention, and changes in resident behavior as documented in chart abstractions. RESULTS: One hundred eight (93.1%) residents completed initial training, and 102 (87.9%) completed the refresher course. The share of scores indicating that residents felt "somewhat comfortable" or "completely comfortable" treating inpatient dysglycemia increased from 62.5% before the course to 94.3% (P<0.001) after the initial intervention and 92.8% (P<0.001) after the refresher. Knowledge scores improved from 72.2% correct answers to 88.9% (P<0.001) for the 4 questions asked before and after the course. Across all 23 questions posed after the initial course, residents answered 86.1% correctly and maintained a score of 85.5% after the refresher course. Online trained residents, at 89.7%, outscored their classroom-trained peers (82.3%; P<0.001) after the initial course. Chart abstractions did not show any significant changes in managing glycemia. CONCLUSION: A curriculum on the management of inpatient glycemia was broadly adopted by medical residents at a large academic medical center and led to greater confidence and knowledge among residents. Further expansion to other health care providers and hospitals using a Web-based format and incorporation of updated guidelines is needed to confirm and build on these encouraging results. PMID- 21680995 TI - Clinical interpretation of indices of quality of glycemic control and glycemic variability. AB - The practicing physician is faced with the task of interpreting>2 dozen indices of quality of glycemic control and glycemic variability. It would be desirable to have reference data from relevant patient populations (eg, patients with the same type of diabetes, duration of diabetes, therapeutic regimen, or glycated hemoglobin [HbA1c] levels). The physician can then select the appropriate reference set for interpretation of results for each patient. Institutions and clinics may wish to develop their own reference data. Results can be interpreted as excellent, good, fair, or poor, corresponding with quartiles of their distributions. Each index of glycemic control and variability can be given a numerical score in terms of its percentile within the selected reference population. One can then compute the mean and standard deviation of the percentile scores to obtain an integrated measure of the quality of glycemic control or variability. We calculated quartiles for measures of quality of glycemic control and variability. One can use the percent coefficient of variation (%CV) with criteria that apply irrespective of the HbA1c level as a general rule for interpretation of glycemic variability. For example, a %CV<33.5% can be regarded as excellent, a %CV between 33.5% to 36.8% as good, a %CV between 36.8% to 40.6% as fair, and a %CV>40.6% as poor. A graphical display can be used to make more accurate assessments for narrow HbA1c ranges, as the percentiles of the %CV can change systematically with HbA1c level or with mean glucose level. PMID- 21680996 TI - Diabetic retinopathy in Africa: advantages of screening. AB - OBJECTIVE: To review the epidemiology of diabetic retinopathy (DR) in Africa and discuss the various methods of screening for the disease. METHODS: Review of the peer-reviewed articles in PubMed, Google, and Scirus about DR published from 1985 to 2010. Articles in all languages were considered, provided that the non-English articles included English abstracts. RESULTS: Screening for DR can significantly prevent the loss of vision resulting from long-standing diabetes mellitus. Screening is also financially advantageous for both patients and health care systems. Several screening methods can be employed by primary care providers, who over the past 20 years have become responsible for the treatment and follow-up of patients with diabetes rather than hospitals. An additional concern for screening in African countries is the inefficient referral to ophthalmologists, given their scarce distribution in the African population. Finally, education of both the patient population and caregivers should be included as an essential component of screening programs. CONCLUSION: As of now, African health care systems are not prepared to deal with the increasing burden of diabetes and its complications. With inappropriate glycemic or blood pressure control, most patients will only seek care once micro- or macrovascular complications have already developed. Given the current difficulty in providing costly therapeutic interventions, a well-planned, cost-effective prevention strategy is required. PMID- 21680997 TI - A comparison of the efficacy and safety of irbesartan/hydrochlorothiazide combination therapy with irbesartan monotherapy in the treatment of moderate or severe hypertension in diabetic and obese hypertensive patients: a post-hoc analysis review. AB - Hypertension is difficult to treat in patients with type 2 diabetes mellitus (T2DM) or obesity. Combination therapies are often required to effectively lower blood pressure (BP) and attain BP goals. In this post-hoc analysis of 2 prospective, randomized, controlled studies in patients with uncontrolled or untreated moderate or severe hypertension, the efficacy and safety of treatment with irbesartan/hydrochlorothiazide (HCTZ) and irbesartan was assessed in 2 separate analyses: patients with diabetes (n=143) and by obesity status (n=1125). Patients received irbesartan/HCTZ (150 mg/12.5 mg titrated to 300 mg/25 mg) or irbesartan (150 mg titrated to 300 mg) for 7 (severe hypertension study) or 12 (moderate hypertension study) weeks. Efficacy comparisons between treatment groups were performed using Fisher's exact tests. After 7 to 8 weeks of treatment, systolic BP (SBP)/diastolic BP (DBP) decreased in patients with diabetes by 26.9/17.8 mm Hg and 21.8/15.8 mm Hg after irbesartan/HCTZ and irbesartan treatment, respectively (P [SBP]=0.09, P [DBP]=0.27). In obese patients (n=544), SBP/DBP decreased by 29.4/20.2 mm Hg and 20.1/15.9 mm Hg after irbesartan/HCTZ and irbesartan treatment, respectively (P<0.0001). More patients with T2DM reached the BP goal of <130/80 mm Hg at week 7 to 8 in the irbesartan/HCTZ group than in the irbesartan group (12% vs 5%), although not statistically significant (P=0.22). Significantly more obese patients reached their respective BP goals in the irbesartan/HCTZ group than in the irbesartan group (48% vs 23%; P<0.0001). Treatment-emergent adverse event rates were similar between treatment groups regardless of the presence of diabetes or body mass index (BMI) status. In patients with moderate or severe hypertension and with a BMI >= 30 kg/m(2), initial treatment with irbesartan/HCTZ combination therapy was more effective than irbesartan monotherapy. PMID- 21680998 TI - Control of postprandial glucose levels with insulin in type 2 diabetes. AB - The importance of maintaining effective glycemic control in patients with type 2 diabetes mellitus (T2DM) is well known. It is increasingly recognized that postprandial hyperglycemia is an important component of the overall glycemic burden, though there is as yet a paucity of data showing that lowering of postprandial plasma glucose (PPG) reduces risk of T2DM complications. The contribution of PPG to overall glycemic control is greatest when glycated hemoglobin (HbA1c) is approximately 7% to 8%. Clinical studies show that targeting PPG can improve glycemic control and long-term prognosis in patients with T2DM. Guidelines for T2DM management now include target levels for PPG as treatment goals. One effective approach to PPG control is achieved using mealtime administration of insulin with a rapid onset of effect and a short duration of action, so that PPG excursions are limited without increased risk of hypoglycemia. Basal-bolus and biphasic insulin regimens achieve good PPG control, even in patients unable to reach glycemic targets with other treatments. Although clinical studies are increasingly including PPG as an endpoint, more interventional studies are needed to investigate the effect of different treatment regimens on PPG and the effect of PPG on clinical outcome. This will facilitate future recommendations for the most effective treatment of T2DM. Postprandial glucose is an important glycemic burden in many patients; routine targeting and regular monitoring has potential to ameliorate the cardiovascular complications of T2DM. PMID- 21680999 TI - Clinical outcomes during opioid titration following initiation with or conversion to Remoxy(r), an extended-release formulation of oxycodone. AB - Intra- and interpatient variability in opioid response usually necessitates opioid therapy titration to optimally balance analgesia and side effects, whether initiating therapy or converting from another opioid. Remoxy(r) (King Pharmaceuticals, Inc., Bristol, TN, which was acquired by Pfizer Inc in March 2011) is an extended-release formulation of oxycodone designed to maintain its rate-controlling mechanism following physical and chemical manipulation. A recent phase 3 trial, which required dose titration following initiation or conversion to Remoxy, demonstrated the long-term safety and efficacy of Remoxy in relieving moderate to severe chronic pain. In this study, opioid-naive patients were to be initiated on Remoxy 5 mg twice daily (10 mg total daily oxycodone dose) and opioid-experienced patients were to be converted to Remoxy at a dose equivalent to their previous opioid daily dose, determined from a conversion chart. A post hoc analysis of study data provided clinically relevant information regarding initiation of or conversion to Remoxy. The intent-to-treat population (N=823) consisted of 429 opioid-experienced patients (52%) and 394 opioid-naive patients (48%). A stable Remoxy dose (defined as the first dose administered on 2 consecutive visits, whereby on the first of these visits, further dose titration was deemed unnecessary) was achieved by 325 opioid-experienced patients (76%; mean, 2.2 titration steps), of whom 278 (86%) successfully converted to Remoxy according to the prospectively determined post-hoc definition (<=4 titration steps). Of opioid-naive patients, 300 (76%) reached a stable dose of Remoxy (mean, 2.2 titration steps), 253 (84%) of whom successfully initiated on Remoxy. Pain intensity decreased from baseline to study completion by approximately 35% for both opioid-experienced and opioid-naive patients and adverse events were similar to those typically reported for opioids, with a higher incidence rate reported during titration (pre-stable dose period). These data provide important clinical information when initiating opioid-naive patients on or converting opioid-experienced patients to Remoxy. PMID- 21681000 TI - Sunscreens for non-dermatologists: what you should know when counseling patients. AB - Ultraviolet (UV) radiation is a notorious environmental carcinogen. Acute and chronic UV radiation exposure increase the risk for skin cancer. Protecting oneself from both UVA and UVB radiation with broad-based sunscreen can prevent certain skin cancers, their precursors, and photoaging. Although sun protection factor only measures UVB protection, it is essential to consider protection from UVA radiation when deciding on a particular sunscreen product. Awareness of particular controversies associated with sunscreen, such as vitamin D deficiency and sunscreen toxicity, is necessary to adequately counsel patients with sunscreen concerns. Additionally, all physicians should be familiar with sunscreen composition, proper use, and benefits while encouraging patient compliance. PMID- 21681001 TI - Gastrointestinal tolerability of diclofenac epolamine topical patch 1.3%: a pooled analysis of 14 clinical studies. AB - OBJECTIVE: The purpose of this investigation was to evaluate the gastrointestinal (GI) tolerability profile of diclofenac epolamine topical patch 1.3% (DETP) during short-term treatment in patients with mild-to-moderate pain. DESIGN: Fourteen clinical trials of DETP were examined; 10 placebo-controlled studies were further integrated for analyses. All adverse event (AE) data were coded to the Medical Dictionary for Regulatory Activities. OUTCOME MEASURES: Frequency of GI AEs was summarized by treatment, preferred term, sex, and age group. RESULTS: The percentage of patients reporting GI AEs were similar between patients treated with the DETP and placebo, with only 3 of the 10 placebo-controlled trials reporting events in >2% of patients; there was no significant difference between DETP and placebo for any preferred GI term. The most common GI AE reported for both treatment groups was nausea (1.5% DETP, 1.1% placebo). There was no significant difference between treatment groups and sex in the number of reported events and no noted difference between age groups. CONCLUSION: This study provides evidence that DETP is a topical nonsteroidal anti-inflammatory drug that is a well-tolerated treatment option, demonstrating a low incidence of GI AEs across 14 clinical trials, making it a possible alternative to short-term oral NSAIDs, which are commonly associated with GI complications. PMID- 21681002 TI - Patient characteristics associated with frequent calls to a headache specialty clinic. AB - OBJECTIVE: To identify characteristics of patients who frequently initiate contact with a headache specialty clinic outside of scheduled appointments. MATERIALS AND METHODS: We scanned records of all telephone calls received during 1 calendar year at an academic headache clinic to identify frequent callers. High frequency (HF) callers were defined as established patients who initiated calls on >=20 days during the year. We compared these patients with a cohort of established low-frequency (LF) callers who initiated no telephone calls during the same year. Clinic records were analyzed for demographic characteristics, diagnoses, and medication use. Additionally, we administered a questionnaire to clinic physicians and administrative staff querying their perception of each patient's demands on clinic resources. RESULTS: High-frequency (n=26) and LF (n=18) callers did not differ significantly in marital status, ethnicity, diagnosis, or age. There was a trend toward female gender among HF callers and toward being outside of a body mass index range of 19 to 30 kg/m2. The groups were similar in their use of triptans and botulinum toxin treatments, but HF callers were more likely to be opioid users (96% vs 11.1%) and more likely to be taking multiple opioids in substantially higher potency, dosage, and quantity (154.4 mg vs 1.4 mg morphine equivalents/day). More than 80% of each group were migraineurs, but HF callers were more likely to have comorbid psychiatric disorders (P<0.05). High-frequency callers were also more likely to be rated by administrative staff and physicians as demanding and time-consuming. CONCLUSIONS: In this university-based headache specialty clinic, HF callers were more likely to be opioid users on high morphine-equivalent doses. Compared with LF callers, HF callers placed a greater burden on health care resources as perceived by staff and physicians. PMID- 21681003 TI - Review of the safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. PMID- 21681004 TI - 43rd European Pancreatic Club (EPC) Meeting. PMID- 21681005 TI - Aging and changes in complexity in the neurobehavioral system. AB - The issue of complexity is more and more present in numerous domains of biological research, including aging research. In the present paper, based on a selective review of literature, we propose both a conceptual and a methodological framework to address age-related changes in functional complexity of the neurobehavioral system, presumably resulting from modifications of the coupling between cognitive and sensorimotor processes. In particular, after reviewing pioneering and more recent studies on aging and complexity in the neuromusculoskeletal system, we explore the possibility that an age-induced increase in the coupling between cognitive and sensorimotor domains could be captured by a stronger covariation of high-order variables, common to both cognitive and sensorimotor functioning. Our main assumption is that these variables could behave as neurobehavioral markers of aging in the neuromusculoskeletal system. The present approach markedly differs from other traditional approaches, which focused on process-specific variable correlates of chronological age, domain-by-domain, and task-by-task. It provides a coherent conceptual framework, a terminology, and a method for studying age-related coupling of cognitive and sensorimotor processes with the use of complexity and nonlinear dynamical systems theories. PMID- 21681006 TI - Hospitalized adult patients with 2009 pandemic influenza A (H1N1) in Kaunas, Lithuania. AB - The objective of this study was to identify case characteristics and clinical course of the disease in patients hospitalized with 2009 pandemic influenza A (H1N1) infection during the first wave of the pandemic and to identify risk factors associated with the complicated course of illness. MATERIAL AND METHODS: A retrospective study of adult cases of the laboratory-confirmed 2009 pandemic influenza A (H1N1) virus admitted to three hospitals in Kaunas between November 1, 2009, and March 15, 2010, was carried out. The main outcome measures were clinical characteristics, risk factors for complicated disease, treatment, and clinical course of the disease. RESULTS: The study enrolled 121 of the 125 patients hospitalized due to 2009 pandemic influenza A (H1N1) virus infection. The median age was 31 years (range, 18-83); 5% of the patients were aged more than 65 years. Pregnant and postpartum women comprised 26% of all hospitalized cases. Nearly half (49.5%) of those who underwent chest radiography had findings consistent with pneumonia, which was bilateral in one-third of cases. The risk to have pandemic influenza complicated by pneumonia increased significantly with one day delay from symptom onset to antiviral treatment (OR, 2.241; 95% CI, 1.354 3.710). More than half (57%) of the patients received antiviral treatment. In 45% of the treated patients, antiviral drugs were administered within 48 hours from symptom onset. Intensive care was required in 7.4% of the cases. The overall mortality was 5% (6/121). The median age of the patients who died was 43.5 years (range, 23-62); 4 patients had been previously healthy, 1 patient suffered from chronic lympholeukemia, and 1 patient was a pregnant woman. CONCLUSION: The 2009 pandemic influenza A (H1N1) caused considerable morbidity in a significant proportion of hospitalized adults. The main risk factor associated with the complicated course of illness was delayed antiviral treatment. PMID- 21681007 TI - Giant peptic ulcer hemorrhages: epidemiology, treatment, and outcome in the teaching hospital of Tartu. AB - The aim of the study was to analyze the management and outcome in the case of giant peptic ulcer hemorrhage (GPUH). MATERIAL AND METHODS: We analyzed the data of all 372 cases of 348 patients treated for acute peptic ulcer hemorrhage during 2005-2007. The source and intensity of hemorrhage was assessed endoscopically according to the Forrest classification: class I+II, persistent hemorrhage or signs of recent hemorrhage; and class III, ulcer without signs of recent hemorrhage. Of the 372 cases, 64 (17%) were GPUH (diameter, >=2 cm) (group 1) and the remaining 308 (83%) were peptic ulcer hemorrhages of a standard size (SPUH) (diameter, <2 cm), which formed the control group (group 2). RESULTS: Forrest class I+II hemorrhage occurred significantly more frequently in the group 1 as compared with the group 2 (97% [62/64] vs. 77% [238/308]), as well as endoscopic hemostasis, (80% [51/64] vs. 57% [175/308]), repeat hemostasis procedures (22% [11/51] vs 6.3% [11/175]), and operative treatment (27.6% [16/58] vs 1.7% [5/290]) were needed more frequently in the group 1. No postoperative in-hospital deaths occurred in either group. Five patients died: 2 (3.4% [2/58]) in the group 1 and 3 (1.0% [3/290]) in the group 2. CONCLUSIONS: GPUHs were more intensive as compared with SPUHs and needed more endoscopic hemostasis, including repeat procedures and operative treatment. Endoscopic hemostasis and operative treatment allowed reducing mortality due to GPUH to 3.4%. PMID- 21681008 TI - The influence of CYP2C9 and VKORC1 gene polymorphisms on optimal warfarin doses after heart valve replacement. AB - A clinical effect of warfarin depends on highly polymorphic drug-metabolizing (CYP2C9) and drug-target (VKORC1) enzymes. The objective of this study was to investigate the impact of CYP2C9*2, CYP2C9*3, and VKORC1 (G-1639A) polymorphisms on the variability of warfarin dosage requirements in Lithuanian patients after heart valve replacement. MATERIALS AND METHODS: The study included 83 patients with a mean age of 65.2 years (SD, 13.31) after heart valve replacement with an achieved stable international normalized ratio of 2-3.5. The restriction fragment length polymorphism method was used to identify polymorphisms of VKORC1 and CYP2C9. RESULTS: Daily warfarin dosage significantly correlated with weight (r=0.4087) and height (r=0.3883) of the patients. Patients younger than 60 years required significantly higher daily warfarin dosages than older patients. Two thirds (66.3%) of the patients had the wild-type (WT) CYP2C9*1/*1 genotype; 38.6% and 54.2% of the patients had WT VKORC1 (G/G) and VKORC1 (G/A) genotypes, respectively. WT CYP2C9*1/*1 genotype was associated with a higher daily warfarin dosage (5.84 mg [SD, 2.84]) as compared to other CYP2C9 genotypes. Carriers of WT VKORC1 (G/G) required a higher warfarin dose as compared to (A/A) carriers (6.20+/-2.78 mg and 3.75+/-1.40 mg, respectively; P=0.04). Patients having CYP2C9*1/*1 or 1/*2 in combination with VKORC1 (G/G) or (G/A) genotypes required the highest daily warfarin dosage in comparison to other combinations of genotypes. CONCLUSIONS: The Lithuanian study sample is characterized by high a frequency (92.8%) of VKORC1 G/G and G/A genotypes that determines a higher warfarin-loading dose. Analysis of combined CYP2C9 and VKORC1 gene variants allows the prediction of warfarin dosage. These results can be used to individualize treatment with warfarin in the field of heart surgery in Lithuania. PMID- 21681009 TI - Expression of cytokeratin 7 as a histological marker of cholestasis and stages of primary biliary cirrhosis. AB - The aim of this study was to estimate cytokeratin 7 (CK-7) expression in biopsy specimens of patients with different stages of primary biliary cirrhosis and clinicopathological patterns (cholestatic and hepatitic) and its correlation with some biochemical and pathological parameters and to examine a diagnostic value of CK-7 expression. MATERIAL AND METHODS: A total of 82 biopsy specimens of patients with primary biliary cirrhosis were analyzed. CK-7 expression was graded by 4 grades depending on the extent into parenchymal areas and bile duct epithelium. The correlations of CK-7 expression grade with copper deposition, bile duct/portal tract ratio, bilirubin concentration, and activity of alkaline phosphatase and gamma-glutamyl transpeptidase were studied. CK-7 expression was evaluated as a marker of cholestasis (cholestatic pattern) and inflammation (hepatitic pattern). RESULTS: A positive correlation of CK-7 expression grade with copper-binding protein grade (r=0.698, P<0.0001; OR=6.199, P<0.0001), serum bilirubin level (r=0.375, P=0.001), and alkaline phosphatase activity (r=0.276, p=0.014) was found. CK-7 expression grades correlated positively with histological stages of primary biliary cirrhosis (r=0.639, P<0.000) and negatively with granulomas (r=-0.432, P<0.0001; OR=0.173, P=0.0011). CONCLUSIONS: CK-7 expression is a sensitive marker of bile duct injury, which correlated well with histological stages of primary biliary cirrhosis, copper deposits, and biochemical markers of cholestasis: serum bilirubin level and alkaline phosphatase activity. Evaluation of CK-7 expression may improve the diagnosis of this serious and progressive disease. It is recommended to evaluate copper staining together with cytokeratin 7 expression in liver biopsy specimens for more precise diagnostic evaluation of asymptomatic primary biliary cirrhosis. PMID- 21681010 TI - The effect of heating and cooling on time course of voluntary and electrically induced muscle force variation. AB - The aim of this study was to investigate the effect of heating and cooling on time course of voluntary and electrically induced muscle force variation. MATERIAL AND METHODS: Ten volunteers performed 50 maximal voluntary and electrically induced contractions of the knee extensors at an angle of 120 degrees under the control conditions and after passive lower body heating and cooling in the control, heating, and cooling experiments. Peak torque, torque variation, and half-relaxation time were assessed during the exercise. RESULTS: Passive lower body heating increased muscle and core temperatures, while cooling lowered muscle temperature, but did not affect core temperature. We observed significantly lower muscle fatigue during voluntary contraction compared with electrically induced contractions. Body heating (opposite to cooling) increased involuntarily induced muscle force, but caused greater electrically induced muscle fatigue. In the middle of the exercise, the coefficient of correlation for electrically induced muscle torque decreased significantly as compared with the beginning of the exercise, while during maximal voluntary contractions, this relation for torque remained significant until the end of the exercise. CONCLUSION: It was shown that time course of voluntary contraction was more stable than in electrically induced contractions. PMID- 21681011 TI - The effect of beta-carotene against adriamycin toxicity on the embryo formation. AB - Adriamycin is an anthracycline antibiotic widely used for the treatment of many types of cancer. The cytotoxic effect of Adriamycin occurs by a free radical mediated mechanism. Thus, to prevent or reduce the toxic effect of Adriamycin, it is possible to use it in combination with antioxidants. The aim of this study was to evaluate a potential effect of beta-carotene against Adriamycin-induced toxicity on the embryo formation. MATERIALS AND METHODS: Pregnant rats were treated with Adriamycin, beta-carotene, and their combination during the critical stages of embryogenesis. The first group was control group. Adriamycin was administered on day 9 (group 2a) and day 12 (group 2b) of gestation by a single intraperitoneal injection at a dose of 5 mg/kg. beta-Carotene was given at a dosage of 0.6 mg/(kg.day) from day 6 to 10 or from day 9 (group 3a) to 13 (group 3b) of gestation 5 times per os; in the case of their combination, beta-carotene was given per os 3 times before Adriamycin injection, one time simultaneously with Adriamycin and one time after its injection (groups 4a and 4b). Animals were euthanized on day 21 of gestation. Embryo resorptions and alive fetuses were counted, weighed, and measured. The embryos of each litter were examined macroscopically after the Buen solution fixation for the embryo defects. In order to render the skeleton visible, the soft tissues were macerated using caustic soda, stained with alizarin red, and cleared with glycerin. RESULTS: Adriamycin induced embryotoxicity; the combination of Adriamycin and beta-carotene decreased the number of Adriamycin-induced embryo resorptions about two times. A gavage with Adriamycin alone decreased fetal body weights (P<0.05), while giving it in combination, the fetal body weight was similar to that in the control group. Adriamycin induced the retardation of skeletogenesis and external fetal malformations (microphthalmia, hydrocephaly, anencephaly, and others). After an exposure to beta-carotene, external malformations (diaphragmatic hernia) of embryos were found only occasionally. beta-Carotene in combination with Adriamycin produced no positive effect on Adriamycin-induced skeletodysgenesis or external malformations. CONCLUSIONS: Antioxidant beta-carotene in combination with Adriamycin slightly reduced the Adriamycin-induced embryotoxicity, but produced no positive effect on Adriamycin-induced skeleto-dysgenesis or external malformations. PMID- 21681012 TI - Survival of patients with testicular cancer in Lithuania during 1999-2002. AB - The aim of this study was to evaluate the survival of patients with testicular cancer in Lithuania during 1998-2002 and factors that influenced the survival. MATERIAL AND METHODS: The survival rates of testicular cancer patients were evaluated using the data of the Lithuanian Cancer Registry for 1998-2002. The survival was evaluated using the Kaplan-Meier method and log-rank test in order to compare the survival rates. The observed survival rates were calculated. RESULTS: The 5-year observed survival rate in Lithuania was 71.2% (95% CI, 64.4% 77.5%). The survival of testicular cancer patients depended on age at the time of diagnosis, histology of tumor, stage and extent of disease. CONCLUSIONS: The survival of patients with testicular cancer in Lithuania was substantially lower than in other European countries. The better survival was associated with younger age and lesser extent of metastases. PMID- 21681013 TI - Evaluation of the quality of services in primary health care institutions. AB - The aim of the study was to evaluate patients' satisfaction with the quality of provided services in private primary health care institutions in Kaunas. MATERIAL AND METHODS: A questionnaire-based inquiry of 280 persons registered to family physicians at primary health care settings was performed. The study was carried out using 20-item anonymous questionnaires with questions about the quality of services provided in primary health care settings. RESULTS: More than 50.0% of the respondents stated that they waited for more than 15 minutes at the physician's office, while 17.0% of the respondents stated that the waiting time exceeded 30 minutes. More than 25.0% of the respondents positively evaluated the possibility to consult their family physician by phone. In 67.0% of patients, the family physician determined the cause of the disorder and administered treatment; in 32.0% of patients, the family physician referred them to a specialist, and 1.0% of patients were urgently sent to hospital. More than 90.0% of the respondents were satisfied with the services provided by their family physicians. Those who were dissatisfied with these services indicated that the provided treatment failed to eliminate the disorder, that they wanted to be referred to a specialist, and that they expected more diagnostic tests to be performed for more effective treatment. CONCLUSIONS: A greater part of the patients indicated that the main reason for long waiting at the physician's office was physicians' wish to serve too many patients. More than two-thirds (67.0%) of the patients stated that their family physicians determined the cause of the disorder and prescribed treatment. The overwhelming majority (more than 90.0%) of the patients were satisfied with the services provided by their family physicians. PMID- 21681014 TI - [Early postoperative intraperitoneal chemotherapy for the treatment of advanced gastric cancer]. AB - Surgery remains the main treatment modality for gastric cancer. Adjuvant radiochemotherapy and adjuvant chemotherapy are becoming more and more popular in the treatment of advanced gastric cancer. Early postoperative intraperitoneal chemotherapy as one of the methods of adjuvant chemotherapy is currently being extensively investigated. The aim of the present study was to evaluate the toxicity of early postoperative intraperitoneal chemotherapy and its impact on postoperative complications as well as long-term survival. MATERIAL AND METHODS: A prospective study including 46 patients with gastric cancer who underwent radical resection was carried out during 2004-2005. Fourteen patients who received early postoperative intraperitoneal chemotherapy with 5-FU (EPIC group) were compared with 32 patients not receiving intraperitoneal chemotherapy (control group). All patient, except one patient in the EPIC group, received adjuvant radiochemotherapy or adjuvant chemotherapy. The toxicity of early postoperative intraperitoneal chemotherapy was evaluated using the WHO scale, and survival was estimated by the Kaplan-Meier method. RESULTS: The rate of postoperative complications was similar in both the groups (14.3% in the EPIC group vs. 12.5% in the control group). Four patients (28.6%) in the EPIC group developed grade III toxicity. There was no difference in survival comparing the EPIC group with the control group (median survival, 30 months and 34 months, respectively; P=0.500). CONCLUSIONS: Early postoperative intraperitoneal chemotherapy with 5-fluorouracile demonstrated acceptable toxicity and was relatively simple to perform. No survival benefit was documented combining early postoperative intraperitoneal chemotherapy with adjuvant radiochemotherapy or adjuvant chemotherapy. PMID- 21681015 TI - Genome-wide association studies of asthma. AB - Bronchial asthma is a common inflammatory disease caused by a combination of genetic and environmental factors. To discover the genes and cellular pathways underlying asthma, a large number of genetic studies have been conducted. Genome wide association studies (GWAS), which comprehensively assess genes related to multifactorial diseases and drug reactivity, have enhanced understanding of human diseases. From 2007, GWAS of susceptibility to asthma in Caucasian, Mexican, and African-ancestry populations have been conducted and several susceptible loci were identified. Recently, much larger consortium-based GWAS analyses of collaborative samples with adequate statistical power were performed, and the implicated genes suggested a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Furthermore, GWAS identified candidate loci associated with natural variations in lung function, blood eosinophilia and eosinophilic esophagitis, which is inflammation of the esophagus with abnormal infiltration of eosinophils in an allergic reaction. Comparing GWAS in asthma and these clinical phenotypes might help to clarify the mechanisms underlying asthma. Pharmacogenomics analyses using GWAS regarding genetic factors related to the effectiveness of inhaled corticosteroid (ICS) therapy and inhaled beta(2)- adrenergic agonists are ongoing now. Although a more complete collection of associated genes and pathways is needed, biologic insights revealed by GWAS provide valuable insights into the pathophysiology of asthma and contribute to the development of better treatment and preventive strategies. PMID- 21681016 TI - Pharmacogenetics of beta2-agonists. AB - Short-acting beta2-agonists (SABAs) and long-acting beta2-agonists (LABAs) are both important for treatment of asthma and chronic obstructive pulmonary disease (COPD) because of their bronchodilator and bronchoprotective effects. However, the use of these agonists, at least for asthma, has generated some controversy because of their association with increased mortality. Pharmacogenetics is the study of genetically determined variation in response to medications, which might prove useful for target therapies in highly responsive patients, especially for more expensive therapies or those with increased risk of side effects. Variation in response to both SABAs and LABAs has been observed in patients with polymorphisms in the beta2 adrenoceptor gene (ADRB2). This review summarizes results from various studies on the possible relationship between ADRB2 polymorphisms and the bronchodilator or bronchoprotective effects of inhaled beta2-agonists. By assessing the ADRB2 genotype, the hope is that it will be possible to predict the responsiveness to chronic administration of beta2 agonists. Genetic testing, however, is of limited usefulness at this stage for ADRB2 because the common variants identified thus far account for only a small proportion of the variation observed for given responses. Carefully performed and adequately powered clinical trials continue to be important for achieving the goal of pharmacogenetic approaches to therapy. PMID- 21681017 TI - Addition of leukotriene receptor antagonists to inhaled corticosteroids improved QOL of patients with bronchial asthma surveyed in suburban Tokyo, Japan. AB - BACKGROUND: Bronchial asthma is a chronic inflammatory disease that has a severe impact on health worldwide. METHODS: A survey of 10,771 patients with bronchial asthma in the Tama region, Tokyo was conducted for 5 years to examine treatment and quality of life (QOL). Subjects were patients aged >= 16 years and their physicians who replied to a questionnaire sent in November from 2002 to 2006. Symptoms of bronchial asthma, visits to an emergency room, use of drugs, and severity of asthma were investigated. RESULTS: Asthmatic symptoms improved over the 5 years, with a reduction in the number of emergency room visits. Since inhaled corticosteroids (ICS) were used by >80% of patients in 2002, we suspected that increased use of concomitant leukotriene receptor antagonists (LTRA) and long-acting beta(2) agonists (LABA) might have contributed to these findings. The effects of these drugs were compared between ICS + LTRA (n = 45) and ICS + LABA (n = 54) groups of patients. There was no significant difference in the ICS dose between these groups. In the ICS + LABA group, 18.5% and 22.2% of patients visited an emergency room before and after initiation of combination therapy, respectively, with no statistically significant difference. In contrast, the rate of emergency room visits in the ICS + LTRA group decreased from 24.4% to 6.6% after addition of LTRA. CONCLUSIONS: These results suggest that the frequency of visits to an emergency room was decreased by complementing the anti-inflammatory effect of ICS with further treatment of inflammation, particularly with LTRA. PMID- 21681018 TI - Assessment of bone status in inhaled corticosteroid user asthmatic patients with an ultrasound measurement method. AB - BACKGROUND: The effect of inhaled corticosteroid (ICS) on the bone status of asthmatic patients is still uncertain, because it can differ by race and because there have been few cases in Japan. In this study, the bone status of ICS users with asthma was evaluated in an actual clinical setting in Japan. METHODS: In 7 participating hospitals, ICS users with asthma and control subjects were age- and gender-matched and recruited into this study. To assess bone status, ultrasound measurements of each individual's calcaneus were made using an AOS-100. The ratio of the osteo sono-assessment index (OSI) to the average OSI corrected for age and gender was denoted as %OSI and used for quantitative assessment. The second %OSI measurement was performed 6 months after the first %OSI one. During the study period, individual treatment remained unchanged. RESULTS: There were no significant differences in the 1st and 2nd %OSI between the ICS users and control subjects. However, the 2nd %OSI significantly decreased compared with 1st %OSI in female ICS users, although there were no significant changes in the male and female control subjects and male ICS users. CONCLUSIONS: The 6 month management of asthma in the actual clinical setting, including regular ICS use, might have a harmful influence on the bone status of female asthmatic patients. It may be necessary to manage and treat female patients for potent corticosteroid-induced osteoporosis, although further analyses of bone status in asthma patient ICS users will be required. PMID- 21681019 TI - Increased eosinophilic cationic protein in nasal fluid in hospitalized wheezy infants with RSV infection. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a major respiratory pathogen which causes bronchiolitis with dyspnea and wheezing in children less than 2 years old. RSV bronchiolitis in infancy severe enough to cause hospitalization might be a risk factor for allergic sensitization and bronchial asthma in future. However, the pathophysiology behind this development has not been clearly characterized. To evaluate the existence of airway inflammation and characteristic of RSV bronchiolitis, we analyzed and compared the concentrations of eosinophilic cationic protein (ECP) in nasal fluid and plasma. METHODS: From 69 infants (aged <2 years) hospitalized for possible lower respiratory tract infections including RSV infection, we collected nasal fluid and plasma and determined the ECP concentrations. RESULTS: ECP concentrations in nasal fluid were significantly higher in patients with wheezing and/or bronchial rales than in patients without them (1733 +/- 660 ng/mL vs 680 +/- 450 ng/mL, p = 0.018), and those of the respiratory syncitial virus-infected group were significantly higher than those of the uninfected group (p = 0.04). Meanwhile, there was no significant difference in plasma ECP levels between patients with wheezing and patients without wheezing, and no significant difference between RSV-infected and other pathogen-infected patients. There were significant correlations between nasal fluid ECP concentrations and both neutrophil and eosinophil counts in the peripheral blood. CONCLUSIONS: Nasal fluid ECP concentrations are increased in infants with lower respiratory infections including RSV infection accompanied with wheezing. ECP probably originates from neutrophils as well as eosinophils migrated into airways. The monitoring of ECP concentration in nasal fluid may be useful for evaluating leukocyte (including eosinophils and neutrophils)-mediated airway inflammation during infancy and its severity. PMID- 21681020 TI - Hypersensitivity to fludrocortisone acetate in a recipient of bone marrow transplantation. PMID- 21681021 TI - Deficiency of hepatocystin induces autophagy through an mTOR-dependent pathway. AB - Mutations in the gene encoding hepatocystin/80K-H (PRKCSH) cause autosomal dominant polycystic liver disease (ADPLD). Hepatocystin functions in the processing of nascent glycoproteins as the noncatalytic beta subunit of glucosidase II (Glu II) and regulates calcium release from endoplasmic reticulum (ER) through the inositol 1,4,5-trisphosphate receptor (IP3R). Little is known, however, on how cells respond to a deficiency of hepatocystin. In this study, we demonstrate that knockdown of hepatocystin induces autophagy, the major intracellular degradation pathway essential for cellular health. Ectopic expression of wild-type hepatocystin, but not pathogenic mutants, rescues the siRNA-induced effect. Our data indicate that the induction of autophagy by hepatocystin deficiency is mediated through mammalian target of rapamycin (mTOR). Despite the resulting severe reduction in Glu II activity, the unfolded protein response (UPR) pathway is not disturbed. Furthermore, the inhibition of IP3R mediated transient calcium flux is not required for the induction of autophagy. These results provide new insights into the function of hepatocysin and the regulation of autophagy. PMID- 21681022 TI - BAG3 and friends: co-chaperones in selective autophagy during aging and disease. AB - There is a reciprocal change in the expression of two members of the BAG (Bcl-2 associated athanogen) family, BAG1 and BAG3, during cellular aging and under acute stress ("BAG1-BAG3-switch"). BAG3 was recently described as a mediator of a novel macroautophagy pathway that uses the specificity of heat shock protein 70 (HSP70) to misfolded proteins and also involves other protein partners, such as HSPB8. Also crucial for induction and execution of autophagy are sequestosome 1/p62 (SQSTM1/p62) and LC3, an autophagosome-associated protein. In this novel pathway, BAG3 mediates the targeting and transport of degradation-prone substrates into aggresomes via the microtubule-motor dynein. Interestingly, aggresome-targeting by BAG3 does not depend on substrate ubiquitination and is, therefore, involved in the clearance of misfolded proteins that are not ubiquitinated. PMID- 21681023 TI - Methyl jasmonate signaling and signal crosstalk between methyl jasmonate and abscisic acid in guard cells. AB - Plants tightly control stomatal aperture in response to various environmental changes. A drought-inducible phytohormone, abscisic acid (ABA), triggers stomatal closure and ABA signaling pathway in guard cells has been well studied. Similar to ABA, methyl jasmonate (MeJA) induces stomatal closure in various plant species but MeJA signaling pathway is still far from clear. Recently we found that Arabidopsis calcium dependent protein kinase CPK6 functions as a positive regulator in guard cell MeJA signaling and provided new insights into cytosolic Ca2+-dependent MeJA signaling. Here we discuss the MeJA signaling and also signal crosstalk between MeJA and ABA pathways in guard cells. PMID- 21681054 TI - Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression. AB - OBJECTIVE: LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans. METHODS: Integrase binding domain of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs rs2277191, rs1033056, rs12339417 and rs10283923 referred to as SNP1, SNP2, SNP3 and SNP4, respectively, and one exonic SNP rs61744944 (SNP5, Q472L) were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV_1 IN was measured by AlphaScreen. RESULTS: rs2277191 (SNP1) A was more frequent among seropositives (P = 0.06, Fisher's exact test). Among individuals followed longitudinally SNP1A trended towards association with higher likelihood of HIV-1 acquisition [relative hazard (RH) = 2.21, P = 0.08; Cox model] and it was also associated with rapid disease progression (RH = 5.98, P = 0.04; Cox model) in the recently infected (primary infection) cohort. rs12339417 (SNP3)C was associated with slower decline of CD4(+) T cells (P = 0.02) and lower messenger RNA (mRNA) levels of LEDGF/p75 (P < 0.01). Seroconverters had higher preinfection mRNA levels of LEDGF/p75 (P < 0.01) and these levels decreased after HIV-1 infection (P = 0.02). CONCLUSIONS: Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts. PMID- 21681055 TI - HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons. AB - OBJECTIVE: Experimental studies suggested that HMG-CoA reductase inhibitors ('statins') may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons. DESIGN: A nested case-control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization. METHODS: Cases were incident HIV+ NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanente's electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV + NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT). RESULTS: A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV + NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31-0.95), 0.64 (0.31-1.28), and 0.50 (0.23-1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed. CONCLUSION: Our results suggested an inverse association between statin use and risk of NHL in HIV-positive persons. Potential limitations include the likelihood of residual confounding by indication and limited study power for some statin use subgroups. PMID- 21681056 TI - Ageing with HIV in South Africa. AB - We used an established microsimulation model, quantified to a rural South African setting with a well developed antiretroviral treatment programme, to predict the impact of antiretroviral therapy on the HIV epidemic in the population aged over 50 years. We show that the HIV prevalence in patients aged over 50 years will nearly double in the next 30 years, whereas the fraction of HIV-infected patients aged over 50 years will triple in the same period. This ageing epidemic has important consequences for the South African healthcare system, as older HIV patients require specialized care. PMID- 21681057 TI - Outcomes of antiretroviral treatment in programmes with and without routine viral load monitoring in Southern Africa. AB - OBJECTIVES: To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with those in Malawi and Zambia, where monitoring is based on CD4 cell counts. METHODS: We included 18,706 adult patients starting ART in South Africa and 80,937 patients in Zambia or Malawi. We examined CD4 responses in models for repeated measures and the probability of switching to second-line regimens, mortality and loss to follow-up in multistate models, measuring time from 6 months. RESULTS: In South Africa, 9.8% [95% confidence interval (CI) 9.1-10.5] had switched at 3 years, 1.3% (95% CI 0.9-1.6) remained on failing first-line regimens, 9.2% (95% CI 8.5-9.8) were lost to follow-up and 4.3% (95% CI 3.9-4.8) had died. In Malawi and Zambia, more patients were on a failing first-line regimen [3.7% (95% CI 3.6-3.9], fewer patients had switched [2.1% (95% CI 2.0-2.3)] and more patients were lost to follow-up [15.3% (95% CI 15.0-15.6)] or had died [6.3% (95% CI 6.0-6.5)]. Median CD4 cell counts were lower in South Africa at the start of ART (93 vs. 132 cells/MUl; P < 0.001) but higher after 3 years (425 vs. 383 cells/MUl; P < 0.001). The hazard ratio comparing South Africa with Malawi and Zambia after adjusting for age, sex, first line regimen and CD4 cell count was 0.58 (0.50-0.66) for death and 0.53 (0.48 0.58) for loss to follow-up. CONCLUSION: Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART. PMID- 21681058 TI - Loss of HIV-1-derived cytotoxic T lymphocyte epitopes restricted by protective HLA-B alleles during the HIV-1 epidemic. AB - OBJECTIVE AND DESIGN: HIV-1 is known to adapt to the human immune system, leading to accumulation of escape mutations during the course of infection within an individual. Cross-sectional studies have shown an inverse correlation between the prevalence of human leukocyte antigen (HLA) alleles in a population and the number of cytotoxic T lymphocyte (CTL) escape mutations in epitopes restricted by those HLA alleles. Recently, it was demonstrated that at a population level HIV-1 is adapting to the humoral immune response, which is reflected in an increase in resistance to neutralizing antibodies over time. Here we investigated whether adaptations to cellular immunity have also accumulated during the epidemic. METHODS: We compared the number of CTL epitopes in HIV-1 strains isolated from individuals who seroconverted at the beginning of the HIV-1 epidemic and from individuals who seroconverted in recent calendar time. RESULTS: The number of CTL epitopes in HIV-1 variants restricted by the most common HLA alleles in the population did not change significantly during the epidemic. In contrast, we found a significant loss of CTL epitopes restricted by HLA-B alleles associated with a low relative hazard of HIV-1 disease progression during the epidemic. Such a loss was not observed for CTL epitopes restricted by HLA-A alleles. CONCLUSION: Despite the large degree of HLA polymorphism, HIV-1 has accumulated adaptations to CTL responses within 20 years of the epidemic. The fact that such adaptations are driven by the HLA-B molecules that provide best protection against HIV-1 disease progression has important implications for our understanding of HIV evolution. PMID- 21681059 TI - Assessment of appropriate ankle-foot orthoses models for patients with Charcot Marie-Tooth disease. AB - OBJECTIVE: : The purpose of this study was to demonstrate to what extent ankle foot orthoses improve posture and gait control in patients with Charcot-Marie Tooth disease and to identify the most appropriate characteristics of ankle-foot orthoses for patients regarding their clinical characteristics. DESIGN: : Twenty six Charcot-Marie-Tooth patients were recruited. Clinical data (such as levels of sensory and muscular deficits) and posture and gait capacities were collected in three randomized experimental conditions (wearing ordinary shoes or with plastic and elastic orthoses). Several subgroups of patients, constituted using predictive value analysis, were associated using the probabilities of enhancing posture and gait control while wearing the various models of orthoses. RESULTS: : Compared with ordinary shoes alone, adding plastic ankle-foot orthoses partially improved both gait and posture control, whereas wearing elastic orthoses only partially affected the more dynamic gait control. Furthermore, the choice between the two models can be clarified by taking into account distal lower limb muscle capacity. CONCLUSIONS: : Ankle-foot orthosis prescription appears relevant for improving balance and gait performance in Charcot-Marie-Tooth patients, particularly when the model adequately compensates for specific muscle deficits. This study also provides objective arguments for making adequate bracing. PMID- 21681060 TI - Spinal cord injury and aging: challenges and recommendations for future research. AB - Population aging, caused by reductions in fertility and increasing longevity, varies by country and is anticipated to continue and to reach global proportions during the 21st century. Although the effects of population aging have been well documented for decades, the impact of aging on people with spinal cord injury (SCI) has not received similar attention. It is reasonable to expect that population aging features such as the increasing mean age of the population, share of the population in the oldest age groups, and life expectancy would be reflected in SCI population demographics. Although the mean age and share of the SCI population older than 65 yrs are increasing, data from the National Spinal Cord Injury Statistical Center suggest that life expectancy increases in the SCI population have not kept the same pace as those without SCI in the last 15 yrs. The reasons for this disparity are likely multifactorial and include the changing demographics of the SCI population with more older people being injured; susceptibility of people with SCI to numerous medical conditions that impart a health hazard; risky behaviors leading to a disproportionate percentage of deaths as a result of preventable causes, including septicemia; changes in the delivery of health services during the first year after injury when the greatest resources are available; and other unknown factors. The purposes of this paper are (1) to define and differentiate general population aging and aging in people with SCI, (2) to briefly present the state of the science on health conditions in those aging with SCI, and finally, (3) to present recommendations for future research in the area of aging with SCI. PMID- 21681061 TI - Are abnormalities in sarcoplasmic reticulum calcium cycling properties involved in trapezius myalgia?: case studies on three females. AB - OBJECTIVE: The aim of this study was to demonstrate the feasibility of using samples obtained through muscle biopsy to assess a wide range of cellular properties, some of which may be abnormal in myalgia. Given the recent emphasis on the role of excitation-contraction coupling in health and disease, special emphasis is given to the characterization of the properties involved in this process. DESIGN: Tissue samples were obtained from the upper portion of the descending trapezius muscle in three female patients (PAT) with clinically diagnosed myalgia and assessed for a spectrum of properties related to substrate use, energy production, and excitation-contraction coupling and were compared with samples from three healthy controls. RESULTS: At the level of organization of the metabolic pathways, all PAT generally displayed normal activities of enzymes representing the potential for oxidative phosphorylation, glucose phosphorylation, glycolysis, and lactate oxidation. In contrast, a reduced potential was observed in PAT for both fat oxidation (-20%) and high-energy phosphate transfer (-38%). For excitation-contraction coupling, PAT had a compromised sarcoplasmic reticulum maximal Ca-ATPase activity (-21%), Ca uptake ( 44%), and sarcoplasmic endopleasmic reticulum (SERCA) expression for both SERCA1a (-16%) and SERCA2a (-17%), which were accompanied by a lower phase 2 Ca release ( 45%). The Na-K-ATPase concentration, the enzyme-regulating membrane excitability via active Na and K seemed elevated (+25%) in PAT. CONCLUSIONS: These results demonstrate the feasibility of analyzing tissue samples for a wide range of properties and provide a rationale for studies examining the cellular basis of myalgia with particular emphasis on sarcoplasmic reticulum Ca cycling, given the latter's role in regulating a wide range of cellular functions. PMID- 21681062 TI - Description of a half-day interprofessional fibromyalgia clinic with an evaluation of patient satisfaction. AB - OBJECTIVE: This study aimed to evaluate patient satisfaction of a half-day interprofessional fibromyalgia clinic. DESIGN: A convenience sample of 167 consecutively enrolled patients were evaluated retrospectively for clinical and laboratory findings. After 2 yrs, a patient satisfaction survey and the Fibromyalgia Impact Questionnaire were mailed for follow-up analyses. RESULTS: Sixty-five patients returned the mailed questionnaire (54.2 % response rate). More than 90% of the patients rated their clinic experience and provider visits as very positive or positive. Notably, those patients who reported that their primary care provider regarded fibromyalgia as a valid diagnosis were willing to implement the consultant's recommendations, and those who were prescribed medications were more likely to experience an improvement in symptoms and function. Sleep, fatigue, pain, and work interference were the variables most likely to improve, whereas mood was largely unchanged. Finally, the patients with insulin-like growth factor-1 levels that were within the reference range based on age had a better Fibromyalgia Impact Questionnaire response compared with those with low insulin-like growth factor-1 levels. CONCLUSIONS: A half-day fibromyalgia treatment program is feasible and acceptable to patients. This program was designed to provide an expert interprofessional assessment and treatment recommendations to the referring primary care provider. Overall, the program was positively rated by the participants who, overall, experienced a modest improvement in their fibromyalgia symptoms over a 2-yr period. PMID- 21681063 TI - Measuring height without a stadiometer: empirical investigation of four height estimates among wheelchair users. AB - OBJECTIVE: : This study aimed to compare four methods of measuring or estimating height among wheelchair users, to determine whether these methods result in significantly different estimates, and to determine which method is most accurate. DESIGN: : Height data were obtained for 141 wheelchair users. Height estimates included asking for self-report and measuring recumbent length, knee height, and armspan. All analyses were conducted separately for men and women. A two-group confirmatory factor analysis assessed which measure provided the best estimate of height in this population. It also tested the measurement invariance of the four height estimates between men and women and whether there were significant differences across these estimates within each sex. RESULTS: : Confirmatory factor analysis findings indicated that the four measures yielded significantly different height estimates and body mass index values for both men and women. For both sexes, armspan resulted in the longest estimate, and measured recumbent length resulted in the shortest, with the reverse pattern for body mass index values. The common variance estimates were outstanding for recumbent length (92%) and knee height (>83%) and were very good for self-report (>75%), whereas the common variance for armspan was poor (<42%). CONCLUSIONS: : The measurement method used to estimate height yields significantly different values for both height and body mass index among wheelchair users who cannot stand to be measured using a stadiometer. Recumbent length yields the most accurate height estimate for wheelchair users. However, when logistical and practical considerations pose difficulties for obtaining this measure, height estimates based on knee height and self-report may provide reasonable alternatives. PMID- 21681064 TI - Outcome measures and rehabilitation treatment in patients affected by Charcot Marie-Tooth neuropathy: a pilot study. AB - OBJECTIVE: : We evaluated the sensitivity of various rehabilitation and lung function scales to detect differences between people with Charcot-Marie-Tooth (CMT) disease and healthy controls. We also studied whether these measurements are sensitive to disclose changes in patients with CMT disease after rehabilitative treatment. DESIGN: : Eight patients with different types of CMT participated in the study. Data were gathered at baseline; at the end of the treadmill training, stretching, respiratory, and proprioceptive exercise (TreSPE) treatment period; and after a washout period of 6 mos. The following instruments were used for data collection: Medical Research Council scale for lower limb strength; Tinetti Balance Scale; Physical Performance Battery; ankle angle, oxygen consumption, and lung function tests; peak treadmill velocity and slope; time to walk 6 m; and CMT Neuropathy Score. The participants underwent TreSPE treatment twice every week for 8 wks. RESULTS: : All rehabilitative measures were significantly worse in subjects with CMT disease than in healthy controls. Lung function was always normal except for the maximum expiratory pressure and maximum inspiratory pressure. No dropouts or worsening in any of the different outcome measures were observed after TreSPE. The ankle angle and the time to walk 6 m were the only measures that significantly improved after treatment. CONCLUSIONS: : The rehabilitative outcome measures used in this protocol are useful in detecting clinical impairment in people with CMT disease. Lung function tests were confirmed to be minimally abnormal in patients with CMT disease. The TreSPE treatment, besides being safe and well tolerated, induced some training effects in CMT neuropathy, in the absence of lung function amelioration and effort tolerance. Follow-up showed that CMT patients should be treated at least twice every year because a regression of all outcome measures to the baseline state was found after a 6-mo washout period. PMID- 21681065 TI - Effects of two newly developed spinal orthoses on trunk muscle strength, posture, and quality-of-life in women with postmenopausal osteoporosis: a randomized trial. AB - OBJECTIVES: We conducted a prospective randomized study to evaluate the efficacy of two newly developed spinal orthoses in patients with vertebral fractures. DESIGN: We conducted a prospective, randomized, cross-over study to evaluate the efficacy of two newly developed spinal orthoses in patients with osteoporotic vertebral fractures. Measurements include trunk muscle strength, angle of kyphosis, body height, body sway, and parameters of quality-of-life such as pain, well-being, and limitations of daily living. RESULTS: Wearing the orthosis Spinomed during a 6-mo period (results of Spinomed active are given in parentheses) was associated with a 72% (64%) increase in back extensor strength (P < 0.01), a 44% (56%) increase in abdominal flexor strength (P < 0.01), an 11% (11%) decrease in the angle of kyphosis (P < 0.01), a 23% (20%) decrease in body sway (P = 0.03 and P = 0.02), a 19% (18%) increase in vital capacity (P < 0.01 and P = 0.03), a 41% (47%) decrease in average pain (P < 0.01), an 18% (18%) increase in well-being (P < 0.01), and a 49% (54%) decrease in limitations of daily living (P < 0.01), respectively. The overall tolerability of the orthoses was good; no adverse effects were reported and the dropout rate with 7% was rather low. CONCLUSIONS: The use of an orthosis increases trunk muscle strength and therefore improves posture in patients with vertebral fractures caused by osteoporosis. In addition, a better quality-of-life is achieved by pain reduction, decreased limitations of daily living, and improved well-being. Thereby, the use of an orthosis may represent an efficacious nonpharmacologic treatment option for spinal osteoporosis. PMID- 21681066 TI - The relationship between lumbosacral plexopathy and pelvic fractures. AB - OBJECTIVE: This study aimed to investigate the relationship between lumbosacral (LS) plexopathy and pelvic fracture in patients with pelvic fractures only. DESIGN: This study is a retrospective review of patients with pelvic trauma from 1997 to 2007. All patients underwent radiologic examination. The patients with suspected neurologic deficits underwent electrodiagnostic tests. The pelvic fractures were classified based on anatomic location (anterior, lateral, or posterior) and stability (stable, partially stable, or unstable). LS plexopathy was classified based on anatomic quadrant location (upper anterior, upper posterior, lower anterior, or lower posterior) and severity (mild, moderate, or severe) according to electrodiagnostic findings. RESULTS: A total of 104 patients had pelvic fractures only. Thirty-two of those patients (30.8%) had LS plexopathy (26 unilateral and 6 bilateral patients; 38 limbs with LS plexopathy involvement). The incidence and severity of LS plexopathy were found to increase with the increasing number of involved anatomic fracture locations and with fracture instability. Of the 38 limbs affected by LS plexopathy, 34 (89.5%) involved the lower posterior quadrant. Only four cases (10.5%) involved a solitary quadrant, whereas 12 cases (31.6%) involved all quadrants. There was no correlation between fracture location and LS plexopathy quadrant. CONCLUSIONS: The incidence and severity of LS plexopathy increases with the increasing number of anatomic fracture locations and with increased fracture instability. LS plexopathy does not correlate with fracture location. LS plexopathy may be the result of both simple direct compression by displaced bone and indirect injury. PMID- 21681067 TI - Neuromotor outcomes in children with very low birth weight at 5 yrs of age. AB - OBJECTIVE: : The aim of this study was to assess a cohort of children with very low birth weight (VLBW) with premature history at the age of 5 yrs for the proportion of deficits in growth, motor, cognitive, and adaptive functions and to compare them with children with normal birth weight (>2500 g) in these areas. DESIGN: : This is a descriptive, exploratory study using a convenience sample. A cohort of 160 children with VLBW and 124 children with normal birth weight were examined. Standardized clinical and neuropsychologic assessments were administered. Correlation and multiple comparison procedures were used to analyze the relationships among all continuous outcome variables. RESULTS: : There is a significant difference in overall performance between the VLBW children and children with normal birth weight. Deficits in motor, cognitive, visual perception, visual-motor, and adaptive functions were more prominent when we further examined the VLBW children with motor problems. CONCLUSIONS: : The VLBW children performed more poorly at age 5 yrs than did their counterparts. This validates the need for early screening and regular follow-up of VLBW preterm children, particularly those who have motor problems. PMID- 21681068 TI - Native aortic valve endocarditis caused by Brevibacterium epidermidis in an immunocompetent patient. AB - Although Brevibacterium species used to be considered as nonpathogenic microorganisms until recently, it seems that they can cause a wide variety of clinical diseases by acting mostly as opportunistic pathogens. The present case is the second reported case of infective endocarditis by Brevibacterium species; however, it is the first reported infected native aortic valve in an immunocompetent patient. PMID- 21681069 TI - Pseudallescheria boydii infection of a prosthetic hip joint--an uncommon infection in a rare location. AB - Pseudallescheria boydii infection of the hip joint was diagnosed 2.5 years after implantation of a prosthetic joint in a woman with rheumatoid arthritis. Cure was achieved with a 10-month course of voriconazole coupled with removal of the prosthesis and repeat surgical debridement. Pseudallescheria boydii is an environmental mold that can cause osteoarticular infection, most often not only after local trauma but also after local injections and surgical procedures. Hip involvement was rarely reported, and this is the first description of a prosthetic joint infection with Scedosporium sp. PMID- 21681070 TI - Headache, pituitary lesion and panhypopituitarism in a pregnant woman: tumor, apoplexy or hypophysitis? AB - Pituitary dysfunction during pregnancy and its differential diagnosis and treatment can be challenging, as illustrated by the following case. A 22-year-old woman underwent a C-section at 32 weeks of gestation because of preterm labor. She had headache, vision disturbance, polyuria, polydipsia, hypernatremia, diabetes insipidus and a pituitary lesion with findings compatible with apoplexy. Hormonal testing revealed panhypopituitarism. The peripartum presentation, magnetic resonance imaging findings, autoimmunity and global pituitary dysfunction led to the clinical diagnosis of autoimmune lymphocytic hypophysitis. The patient was begun on appropriate hormone replacement therapy. A follow-up magnetic resonance imaging 6 weeks later showed spontaneous regression of the abnormality and a normal-appearing pituitary gland. Thus, acute presentations of pituitary-based pathology during gestation can include previously unrecognized but enlarging tumors, apoplectic hemorrhage and necrosis, and the entity of lymphocytic hypophysitis. A careful evaluation of the clinical, biochemical and radiological characteristics is imperative for accurate diagnosis and proper management to ensure optimal obstetrical outcome. PMID- 21681071 TI - Gender divergence on the impact of multiple cardiovascular risk factors on the femoral artery intima-media thickness in asymptomatic young adults: the Bogalusa Heart Study. AB - INTRODUCTION: Gender divergence on the impact of multiple cardiovascular risk factors on the femoral artery intima-media thickness (IMT) has not been studied in a biracial (black-white) community-based asymptomatic young adults. METHODS: Femoral IMT was measured by B-mode ultrasonography in 1080 individuals (age, 24 43 years; 71% white; 43% men) enrolled in the Bogalusa Heart Study. RESULTS: Femoral IMT showed a gender difference (men > women; P = 0.001), but no racial difference. In a multivariate model, age, cigarette smoking, systolic blood pressure and total cholesterol to high-density lipoprotein cholesterol ratio related independently, in that order, to IMT in women, and age and low-density lipoprotein cholesterol in men. In women, mean IMT increased with increasing number of risk factors defined as values above the age-, race- and gender specific 75th percentile of systolic blood pressure, waist circumference, total cholesterol to high-density lipoprotein cholesterol ratio and insulin along with positive smoking status (P for trend = 0.001), with respective mean IMT (mm) values of 0.61, 0.65, 0.72 and 0.77, for 0, 1 to 2, 3 and 4 to 5 risk factors. There was no such significant trend in men. CONCLUSIONS: Although men versus women had thicker IMT, the observed increasing trend of femoral IMT with increasing number of risk factors in asymptomatic young women suggests that women may be relatively more susceptible to the burden of multiple risk factors. PMID- 21681072 TI - RETRACTED: Ventricular Ectopic Beats: An Overview of Management Considerations AB - Ventricular ectopic beats are commonly seen in daily clinical practice. Majority of them being asymptomatic, some can cause symptoms. In a normal heart, their occurrence is of no clinical significance. However, in the presence of an underlying heart disease, they signify a susceptibility toward more sinister arrhythmias. In some patients, they are triggered by the same mechanism as ventricular tachycardia and these can be cured by catheter ablation. Recent reports on the use of catheter ablation in cases where focal ventricular ectopics are found to trigger ventricular fibrillation. Clinical evaluation and investigations are important in assessing patients with ventricular ectopic beats so that appropriate treatment can be targeted when necessary. This article discusses the current knowledge and practice in this commonly encountered clinical problem. PMID- 21681073 TI - Correlation of coronary plaque phenotype and carotid atherosclerotic plaque composition. AB - INTRODUCTION: Studies have shown that atherosclerosis in coronary arteries is closely related to that in carotid arteries, but there are few investigations on the correlation between unstable plaques in these 2 vascular beds. The authors aim to investigate the correlation between coronary plaque phenotype and carotid plaque composition. METHODS: Patients (n = 123) with suspected coronary artery disease underwent computed tomography angiography of coronary arteries. Magnetic resonance imaging of bilateral carotid arteries was performed within 2 weeks after computed tomography angiography. The plaque type in each coronary segment was analyzed. Coronary plaques were classified into 3 types: noncalcified, calcified and mixed. The total number of each plaque type was scored. Carotid plaque with calcification, lipid-rich necrotic core (LRNC) or intraplaque hemorrhage (IPH) in either carotid artery was defined as positive. Logistic regression analysis was used to determine the correlation between coronary plaque phenotype and carotid plaque composition. The area under the receiver-operating characteristic curve (AUC) was calculated. RESULTS: There was a significant correlation between the mixed coronary plaque score and carotid IPH (odds ratio = 1.50, P < 0.05). The scores for all 3 types of the coronary plaque were significantly correlated with carotid LRNC and calcification. The mixed coronary plaque score had the highest value in predicting carotid IPH (AUC = 0.74). The calcified coronary plaque score showed the highest value in predicting carotid LRNC (AUC = 0.75) and calcification (AUC = 0.75). CONCLUSION: There was significant correlation between coronary plaque phenotype and carotid plaque composition. A mixed coronary plaque may be suggestive of a high-risk carotid plaque. PMID- 21681074 TI - Primary chest wall abscess caused by Escherichia coli costochondritis. AB - Chest wall abscess may occur as primary infection or secondary to open trauma or thoracic wall surgery. The authors describe an unusual case of Escherichia coli costochondritis occurring 2 months after a blunt chest wall trauma. Primary chest wall abscess due to E coli costochondritis has been previously reported only twice occurring after urinary tract infection. All other very few reports of E coli costochondritis have been reported only after thoracic surgical procedures. An English literature review of primary chest wall abscess showed that 4 pathogens are responsible for the majority of cases: Actinomyces, Staphylococcus aureus, Candida albicans and Salmonella. C albicans costochondritis was most commonly reported among heroin addicts. The appearance of a growing chest wall mass should always prompt a search for an infectious cause, even with little or no systemic signs and symptoms. PMID- 21681075 TI - Influence of linezolid clearance on the induction of thrombocytopenia and reduction of hemoglobin. AB - INTRODUCTION: Although linezolid (LZD) has proven effective for the treatment of infections caused by multidrug-resistant Gram-positive cocci, thrombocytopenia and anemia associated with reduced hemoglobin (Hb) levels are common side effects. To study the association between the development of these adverse effects and blood LZD levels, the authors evaluated the correlation between LZD clearance (LZD-CL), platelet (PLT) counts and Hb levels. METHODS: Sixteen patients with methicillin-resistant Staphylococcus aureus infection were administered LZD over a period of 4 to 41 days, and blood was collected at variable time points beginning on day 4 (n = 31). Blood LZD levels were measured by high-performance liquid chromatography, and LZD-CL was estimated by the population pharmacokinetics mean parameter and Bayesian methods. The relationship between the estimated LZD-CL and reductions in PLT counts and Hb levels was then evaluated by regression analysis. RESULTS: During the LZD treatment period, a weak correlation was identified between the LZD-CL rate and PLT counts (r(2) = 0.31, n = 31). Significantly, the regression analysis between LZD-CL and Hb levels showed a stronger correlation (r(2) = 0.54, n = 31), with Hb levels clearly decreasing with reductions in the LZD-CL rate. CONCLUSIONS: In patients undergoing treatment with LZD, low LZD-CL rates correlated with reductions of both PLT counts and Hb levels, suggesting that increase of blood LZD levels influences hematopoietic function. Because a strong correlation was noted between LZD-CL and Hb levels, closely monitoring changes in Hb levels during treatment with LZD may detect the development of adverse effects such as thrombocytopenia and anemia. PMID- 21681076 TI - A retrospective analysis of clinical presentation of lupus nephritis. AB - INTRODUCTION: Lupus nephritis (LN) is an ominous complication of systemic lupus erythematosus, and the risk factors for the disease progression are not well characterized. METHODS: In a retrospective study, the authors evaluated the mode of presentation and outcomes of 163 consecutive patients with biopsy-proven LN, who presented to the center between January 1999 and September 2008. Using stepwise logistic regression analysis, the authors assessed risk factors independently associated with response to treatment and to progression to end stage renal disease (ESRD) in proliferative LN (PLN). RESULTS: Ninety percent of the patients belonged to minority population. Among 122 patients with class III and IV LN (PLN), 76 patients received intravenous cyclophosphamide and 38 patients received mycophenolate for induction, whereas 34 patients received intravenous cyclophosphamide and 63 patients received mycophenolate for maintenance. Thirty-six (30%) patients with PLN progressed to ESRD, and 3 patients died over a mean follow-up of 37.5 months. In multivariate analysis, chronicity index (CI) (P = 0.0007) and hypertension (P = 0.042) positively correlated with progression to ESRD and death, and CI was associated with increased probability of nonresponse to treatment (P = 0.001). In addition, mycophenolate as maintenance agent was associated with increased likelihood of sustained complete remission and partial remission (P = 0.045). CONCLUSIONS: In patients with LN, hypertension and a high CI are independent risk factors for progression to ESRD or death. Furthermore, a high CI is associated with poor response, and mycophenolate as a maintenance agent may improve the response to treatment. PMID- 21681077 TI - Right ventricular function in patients with different infarction sites after a first acute myocardial infarction. AB - INTRODUCTION: To investigate the effect of different infarction sites on right ventricular (RV) functional changes in patients with a first acute ST-elevation myocardial infarction without concomitant RV infarction. METHODS: Sixty consecutive patients underwent conventional echocardiography and pulsed-wave tissue Doppler imaging for RV function evaluation after successful primary percutaneous coronary intervention. They were divided into 2 groups according to infarct location based on the electrocardiographic findings: group I consisted of 35 patients with anterior (including anteroseptal) wall infarction and group II included 25 patients with inferior (including inferoposterior) wall infarction. Ten healthy individuals served as the control group. RESULTS: The tricuspid annular plane systolic excursion was significantly lower in group I compared with that in the controls (20.3 +/- 3.8 versus 23.9 +/- 2.4 mm, P < 0.05). The ratio of transtricuspid peak early filling velocity to tricuspid annular early diastolic velocity (E/E(m)) was comparable between group I and group II, whereas it was higher in group II than in the controls (6.10 +/- 1.37 versus 4.33 +/- 1.17, P < 0.05). The RV myocardial performance index determined by tissue Doppler imaging was significantly higher in group I than in group II (0.48 +/- 0.25 versus 0.32 +/- 0.10, P < 0.05) and the healthy controls (0.48 +/- 0.25 versus 0.27 +/- 0.08, P < 0.05). CONCLUSIONS: In patients with a first, acute reperfused ST-elevation myocardial infarction without associated RV infarction, RV function may be affected discrepantly depending on the different infarction sites. In patients with inferior infarction without concomitant RV infarction, only regional RV diastolic dysfunction is observed, whereas the alteration of global RV function is more pronounced in patients with anterior wall infarction. PMID- 21681078 TI - Electrocardiographic findings in patients with primary dysmenorrhea. AB - INTRODUCTION: Primary dysmenorrhea (PD), which is characterized by painful menstrual cycles, is one of the common clinical problems in young adult women. The aim of this study was to investigate the risk of cardiac arrhythmias in PD patients by using the electrocardiographic (ECG) parameters. METHODS: Forty patients diagnosed with PD and 30 age-matched normal controls were included in this study. ECGs were performed by using 12-leads with 10 mV amplitude and 25 mm/sec velocity. P and QT waves were manually marked along the isoelectric line. P maximum, P minimum, QT maximum and QT minimum were measured on the surface 12 leads ECG, and the P wave and QT dispersions were calculated. RESULTS: There was not any significant correlation of P wave dispersion and QT dispersion between the age, sex, body mass index, hemoglobin, fasting blood glucose or any other laboratory parameters. P wave dispersion was significantly longer in the PD group than the control group (61.4 +/- 19 msec versus 57 +/- 14 msec, P = 0.01). The P minimum duration was significantly shorter in the PD group compared with the control group (36 +/- 16 msec versus 41 +/- 9 msec, P = 0.03). QT dispersion was significantly higher in the PD group compared with normal controls (76 +/- 23 msec versus 58 +/- 16 msec, P = 0.02). CONCLUSION: These results show that PD can be associated with cardiac arrhythmias, especially atrial fibrillation, by increasing P wave dispersion and ventricular arrhythmia risk because of an increased QT interval. PMID- 21681079 TI - Comparison of aloe vera mouthwash with triamcinolone acetonide 0.1% on oral lichen planus: a randomized double-blinded clinical trial. AB - INTRODUCTION: Corticosteroids are the mainstay for treatment of oral lichen planus (OLP) and have their own side effects. The aim of this study was to compare the therapeutic effects of aloe vera (AV) mouthwash with triamcinolone acetonide 0.1% (TA) on OLP. METHODS: A total of 46 patients with OLP were enrolled in this study. The patients were randomly divided into 2 groups. Each group was treated with received AV mouthwash or TA. The treatment period for both groups was 4 weeks. The basement data were recorded for each patient. Patients were evaluated on days 8, 16 and after completing the course of treatment (visit 1-3). The last follow-up was 2 months after the start of treatment (visit 4). Visual analogue scale was used for evaluating pain and burning sensation and Thongprasom index for clinical improvement and healing. In addition, lesion sizes were measured and recorded at each visit using a grid. RESULTS: Baseline characteristics, including pain and burning sensation score, size and clinical characteristics of the lesions according to Thongprasom index, were not different between the 2 treatment groups. Both AV and TA significantly reduced visual analogue scale score, Thongprasom score and size of the lesions after treatment (P < 0.001) and after 2 months of discontinuation of the treatment (P < 0.001). In the AV group, 74% of patients and in the TA group 78% of patients showed some degrees of healing in the last follow-up. CONCLUSIONS: AV mouthwash is an effective substitute for TA in the treatment of OLP. PMID- 21681080 TI - Diagnostic and prognostic value of thrombocytosis in admitted medical patients. AB - INTRODUCTION: Whether secondary thrombocytosis is a distinguishing clinical biomarker of various diseases, and whether it is an independent predictor of short-term outcome of admitted medical patients is unknown and has never been examined. METHODS: A cohort of all 138 patients with secondary thrombocytosis (platelets count >= 5 x 105/MUL) admitted to the department of medicine during the last 2 years was analyzed. Epidemiological and clinical data, and the final diagnosis and outcome were recorded and compared with a cohort of 684 consecutive admitted patients without thrombocytosis. RESULTS: Thrombocytosis was not a non specific marker of inflammation, because uncomplicated infections and most admission causes were not associated with thrombocytosis, except for inflammatory rheumatic diseases (6% versus 1%), along with anemia (9.4% versus 2.5%) and tumor comorbidity (25% versus 14%). In contrast, thrombocytosis was a distinguishing biomarker for severe pyogenic infections, especially empyema (5% vs. 0%), any abscesses (14% versus 3%), and soft tissue infections (7% versus 3%). Moreover, the thrombocytosis group had significantly more admission days, infections (45% versus 33%), sepsis (21% versus 6%), in-hospital major complications (15% versus 3%) and mortality (19% versus 5%). Finally, thrombocytosis was found to be an independent predictor of mortality, in a multivariate regression analysis. CONCLUSIONS: Thrombocytosis is not a simple marker of inflammation. Its presence warrants thorough investigation for the presence of severe underlying disease, mostly complicated pyogenic infections, inflammatory rheumatic diseases and malignancy. Moreover, thrombocytosis is a marker for major complications and is an independent predictor of mortality in admitted medical patients. PMID- 21681081 TI - A cost-benefit analysis of the ENIGMA trial. AB - BACKGROUND: The ENIGMA trial was a prospective, randomized, multicenter study that evaluated the clinical consequences of including N2O in general anesthesia. Patients who were given a N2O-free anesthetic when undergoing major surgery for which the expected hospital stay was at least 3 days had lower rates of some postoperative complications. This suggests that, despite a higher consumption of potent inhalational agent, there could be a financial benefit when N2O is avoided in such settings. METHODS: A retrospective cost analysis of the 2,050 patients recruited to the ENIGMA trial was performed. We measured costs from the perspective of an implementing hospital. Direct health care costs include the costs for maintaining anesthesia, daily medications, hospitalization, and complications. The primary outcome was the net financial savings from avoiding N2O in major noncardiac surgery. Comparisons between groups were analyzed using Student t test and bootstrap methods. Sensitivity analyses were also performed. RESULTS: Rates of some serious complications were higher in the N2O group. Total costs in the N2O group were $16,203 and in the N2O-free group $13,837, mean difference of $2,366 (95% CI: 841-3,891); P = 0.002. All sensitivity analyses retained a significant difference in favor of the N2O-free group (all P <= 0.005). CONCLUSIONS: Despite N2O reducing the consumption of more expensive potent inhalational agent, there were marked additional costs associated with its use in adult patients undergoing major surgery because of an increased rate of complications. There is no cogent argument to continue using N2O on the basis that it is an inexpensive drug. PMID- 21681082 TI - Overcoming delayed in-vitro response to rFVIIa: effects of rFVIIa and rFVIIa analogue (vatreptacog alfa) concentration escalation in whole blood assays. AB - In a previous pharmacokinetic/pharmacodynamic study in nonbleeding hemophilia patients, variability in laboratory response to recombinant factor VIIa (rFVIIa) 90 MUg/kg was noted, and the patients were described as delayed or rapid laboratory responders based on time to clot formation. The current study determined whether in-vitro experiments could reproduce previous in-vivo findings; whether the delayed laboratory response to rFVIIa 90 MUg/kg is improved by spiking with high-dose rFVIIa or rFVIIa analogue (vatreptacog alfa); whether a dose-response is observed with our method. In-vitro experiments were conducted in our previous patient cohort using rFVIIa 1.28 and 3.84 MUg/ml and vatreptacog alfa 0.28 and 0.56 MUg/ml. Whole blood studies were conducted using the Hemodyne Hemostasis Analysis System (platelet contractile force, clot elastic modulus, force onset time) and rotational thromboelastometry (clotting time, maximum clot firmness). Spiking with rFVIIa 1.28 MUg/ml showed the same distribution of delayed and rapid laboratory response as observed previously. Increasing in-vitro rFVIIa concentrations improved the coagulation parameters; however, there remained delayed and rapid responders. Vatreptacog alfa improved the coagulation parameters at all concentrations tested, and the 0.56 MUg/ml concentration normalized the force onset time, platelet contractile force, clot elastic modulus and clotting time parameters. A dose-response was observed with both assays. There was good agreement between the laboratory responses obtained after intravenous administration of rFVIIa 90 MUg/kg and in-vitro spiking studies. Escalating rFVIIa and vatreptacog alfa concentrations improved coagulation parameters in all patients compared to rFVIIa 1.28 MUg/ml. Vatreptacog alfa produced more pronounced coagulation effects at lower concentrations than rFVIIa; and the 0.56 MUg/ml concentration completely normalized responses in all patients. PMID- 21681083 TI - Venous thrombosis in children: an emerging issue. AB - More and more cases of venous thrombosis are diagnosed in children thanks to newer imaging modalities. Central venous catheters have become commonplace in the care of critically ill children and have contributed to the increased rate of thrombotic events. Lastly, children who develop life-threatening or chronic medical conditions are surviving longer because of advanced medical therapies; these intensive therapies can be complicated by events such as thrombosis. Over the last 10 years, specific guidelines for treating thrombosis in children have become available. Nevertheless, in many situations anticoagulant treatment is specially tailored to each individual patient's needs. Some new antithrombotic drugs which have undergone clinical testing in adults might be beneficial to paediatric patients with thromboembolic disorders; unfortunately, clinical data and reports on the use of these drugs in children, when available, are extremely limited. The aim of this review is to provide physicians with enough background information to be able to manage thrombosis in children. First, by helping them detect a thrombotic event in a child. Upon confirmation of the diagnosis, the physician will request the appropriate tests and will choose the best treatment on the basis of the guidelines and recommendations. Moreover, the paediatrician will have the information he or she needs to identify which children are at highest risk of acute thrombotic events and relevant long-term sequelae and, therefore, to decide on the appropriate prophylactic or pharmacologic strategy. Lastly, we would like to provide the paediatrician with information on future drugs with regard to the treatment and prophylaxis of thrombosis. PMID- 21681084 TI - An online self-help CBT intervention for chronic lower back pain. AB - OBJECTIVES: Research has shown that cognitive and behavioral therapies can effectively improve quality of life in chronic pain patients. Unfortunately, many patients lack access to cognitive and behavioral therapy treatments. We developed a pilot version of an interactive online intervention to teach self-management skills for chronic lower back pain, a leading cause of disability and work absenteeism. The objective of this randomized, controlled trial was to evaluate its efficacy. METHODS: Individuals with chronic lower back pain were recruited over the Internet, screened by phone, and randomly assigned to receive access to the intervention (Wellness Workbook; WW) either immediately (intervention group) or after a 3-week delay (wait-list control). Participants (n=141, 83% female, 23% minority) were asked to complete the WW over 3 weeks. Self-report measures of pain, disability, disabling attitudes and beliefs, self-efficacy for pain control, and mood regulation were completed at baseline, week 3, and week 6. RESULTS: Controlling for baseline individual differences in the outcome measures, multivariate analysis of covariance revealed that, at week 3, the intervention group scored better than the wait-list control group on all outcomes, including pain severity ratings. At week 6, after both groups had been exposed to the WW, there were no differences between groups. DISCUSSION: Use of this pilot intervention seems to have had positive effects on a number of pain-related outcomes, including disability. Future research will evaluate the effectiveness of the completed intervention, with particular attention to quality of life and disability. PMID- 21681085 TI - Volatile compounds in health and disease. AB - PURPOSE OF REVIEW: To summarize the recent progress made in noninvasive monitoring of volatile compounds in exhaled breath and above biological liquids, as they are becoming increasingly important in assessing the nutritional and clinical status and beginning to provide support to conventional clinical diagnostics and therapy. To indicate the potential of these developments in medicine and the specific areas which are currently under investigation. RECENT FINDINGS: The significance of the following breath gases and their concentrations are reported: acetone and the influence of diet; ammonia confirmed as an indicator of dialysis efficacy; hydrogen and the (13)CO(2)/(12)CO(2) ratio (following the ingestion of (13)C-labeled compounds) as related to gastric emptying and bowel transit times; hydrogen cyanide released by Pseudomonas and its detection in breath of children with cystic fibrosis; and multiple trace compounds in breath of patients with specific pathophysiological conditions and 'metabolic profiling'. SUMMARY: Advanced analytical methods, especially exploiting mass spectrometry, are moving breath analysis towards the clinical setting; some trace gas metabolites are already being exploited in diagnosis and therapy. Much effort is being given to the search for biomarkers of tumours in the body. HCN as an indicator of the presence of Pseudomonas in the airways has real potential in therapeutically alleviating the symptoms of cystic fibrosis. PMID- 21681086 TI - Fluids and gastrointestinal function. AB - PURPOSE OF REVIEW: To highlight recent developments relating perioperative fluid therapy to gastrointestinal function by reviewing clinically pertinent English language articles mainly from January 2010 to March 2011. RECENT FINDINGS: The control of fluid and electrolyte balance involves multiple processes in which the gastrointestinal tract plays an integral role. Diseases affecting the gastrointestinal tract commonly cause fluid and electrolyte disturbance. Similarly, intravenous fluid therapy in the perioperative period can affect gastrointestinal function and have a bearing on postoperative outcome. Striking a balance, in terms of both fluid composition and volume, is likely to reduce the morbidity associated with interstitial edema, a frequently observed occurrence with contemporary perioperative fluid regimens. This balance may be best achieved using individualized and goal-directed approaches to fluid therapy, in order to provide fluid when it is needed and in the correct quantities. SUMMARY: In planning strategies of fluid therapy, the possibility of adverse effects on the gastrointestinal tract should be considered, as this is likely to have an impact on fluid and electrolyte balance and postoperative outcome. PMID- 21681087 TI - Gut microbiota interactions with obesity, insulin resistance and type 2 diabetes: did gut microbiote co-evolve with insulin resistance? AB - PURPOSE OF REVIEW: The prevalence of obesity, insulin resistance and type 2 diabetes has steadily increased in the last decades. In addition to the genetic and environmental factors, gut microbiota may play an important role in the modulation of intermediary phenotypes leading to metabolic disease. RECENT FINDINGS: Obesity and type 2 diabetes are associated with specific changes in gut microbiota composition. The mechanisms underlying the association of specific gut microbiota and metabolic disease include increasing energy harvest from the diet, changes in host gene expression, energy expenditure and storage, and alterations in gut permeability leading to metabolic endotoxemia, inflammation and insulin resistance. In some studies, the modifications of gut microbiota induced by antibiotics, prebiotics and probiotics led to improved inflammatory activity in parallel to amelioration of insulin sensitivity and decreased adiposity. However, these effects were mainly observed in animal models. Their extrapolation to humans awaits further studies. SUMMARY: The fascinating role of gut microbiota on metabolic disease opens new avenues in the treatment of obesity, insulin resistance and type 2 diabetes. A co-evolutionary clue for microbiota and insulin resistance is suggested. PMID- 21681088 TI - The gut as a regulator of early inflammation in type 1 diabetes. AB - PURPOSE OF REVIEW: Several studies indicate that factors affecting the gut are capable of modulating the development of autoimmune diabetes. This review discusses the recent research on these mechanisms, which may reveal novel pathogenic pathways and new possibilities for prevention of type 1 diabetes (T1D). RECENT FINDINGS: The role of the gut as a regulator of T1D is mainly based on animal studies in which changes affecting the gut immune system have been shown to modulate the immune-mediated destruction of insulin-producing beta cells. Dietary interventions, alterations in the intestinal microbiota and exposure to enteral pathogens regulate the development of autoimmune diabetes in animal models. In several studies, it has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Also, in humans, increased gut permeability and intestinal inflammation are associated with T1D. A recent report of dietary intervention study in infants at genetic risk of T1D showed that early diet could modulate the development of beta-cell autoimmunity in humans; weaning to hydrolyzed casein formula decreased the risk of beta-cell autoimmunity by age 10. SUMMARY: The gut modulation affecting permeability, inflammation and microbiota is evidently associated with the regulation of the inflammation leading to beta-cell destruction. Although the mechanisms of action are not fully understood, the recent research points out the lines of approach for the prevention of T1D. PMID- 21681089 TI - Is urinary free cortisol of value in the diagnosis of Cushing's syndrome? AB - PURPOSE OF REVIEW: Cushing's syndrome results from prolonged and inappropriately high exposure of tissues to glucocorticoids. Biochemical tests are always needed to confirm the clinical suspicion: these include measurement of excess total endogenous cortisol secretion assessed by 24-h urinary free cortisol (UFC), loss of the normal feedback of the hypothalamo-pituitary-adrenal axis assessed by suppressibility after dexamethasone testing, and disturbance of the normal circadian rhythm of cortisol secretion assessed by midnight serum or salivary cortisol. This review focuses on recent data emerging on the value of UFC as a screening test for Cushing's syndrome. RECENT FINDINGS: Considerable evidence has emerged regarding the utility of UFC in the diagnosis of Cushing's syndrome because of its long-term use in clinical practice. Despite the fact that UFC assesses the active (free) component of cortisol, the methodological difficulties in 24-h urine collection and in assay precision have rendered this screening technique increasingly unpopular. Furthermore, the increased prevalence of mild, preclinical or cyclic Cushing's syndrome along with the fact that cortisol is not uniformly secreted during the day do not support its use as a screening test, although strikingly high levels can be useful. SUMMARY: Since the sensitivity and specificity of UFC are less than ideal when compared with other diagnostic modalities, we suggest the use of other more novel tests as first-step diagnostic tests to screen for hypercortisolaemia. PMID- 21681090 TI - The impact of varicocele and varicocele repair on serum testosterone. AB - PURPOSE OF REVIEW: The increased risk of infertility in men with varicocele is well established. Varicocelectomy has been shown to improve semen parameters and increase pregnancy rates. Yet varicocele pathophysiology is poorly understood and potential implications for testosterone production are less clear. Evidence suggests that varicocele may result in lower serum testosterone levels and that varicocelectomy may, in turn, correct this deficit. RECENT FINDINGS: Several studies published in the past 18 months have assessed the effect of varicocele and varicocelectomy on serum testosterone levels. These include data gathered from two rat models of varicocele induction and outcomes after repair. Of additional interest is a study of serum testosterone levels in men after varicocelectomy, the first of its kind to stratify data by patient age and to address whether varicocele repair is effective in improving testosterone levels in older men. SUMMARY: Definitive statements regarding varicocele, varicocelectomy, and testosterone are difficult to make given the frequent absence of control groups and lack of sample group consistency. Despite this, recent well done animal and human studies suggest an adverse effect of varicocele on testosterone and a potential benefit of varicocele repair. Further controlled studies examining testosterone as a primary data point are required. PMID- 21681091 TI - Cardiovascular disease and ovarian function. AB - PURPOSE OF REVIEW: Coronary heart disease (CHD) is the leading cause of death in the aging female population in the developed world. Ovarian endocrinology plays an important role in modulating a woman's CHD risk. We herein present an overview of our current understanding of CHD risk profile in the context of ovarian physiology and senescence. RECENT FINDINGS: Endogenous ovarian estrogen has long been recognized to offer cardiac benefit and vascular protection against atherosclerosis. Existing data, however, do not allow for an extrapolation of the recognized cardioprotective implications of the reproductive-age endogenous estrogenic milieu to the use of exogenous estrogen in postmenopausal women. Ongoing efforts are targeting the concept that when reintroduced proximate to onset of ovarian senescence, exogenous estrogen may retard the process of atherogenesis. Until this hypothesis is substantiated, cardioprotection must not be an indication for initiating hormone therapy in menopausal women. SUMMARY: Ovarian hormones modulate the processes of atherosclerosis and the mechanisms underlying CHD. The female reproductive hormones offer a cardioprotective milieu that is rapidly attenuated with the cessation of ovarian function (be it following natural menopause or after medical or surgical ovarian extirpation). The role of exogenous hormone therapy, and the nuances of timing and duration of exposure, are still being elucidated. PMID- 21681092 TI - Treatment strategies for Kaposi sarcoma in sub-Saharan Africa: challenges and opportunities. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize recent published literature on treatment of AIDS-associated Kaposi sarcoma, the most common HIV associated malignancy and a leading cancer diagnosis in sub-Saharan Africa (SSA), and to highlight the challenges faced in treating Kaposi sarcoma in this resource limited environment. RECENT FINDINGS: There are few prospective clinical trials for Kaposi sarcoma treatment in SSA, along with a relatively poor cancer treatment infrastructure, leading to late diagnosis and poor access to therapy. The only prospectively randomized trial of chemotherapy compared antiretroviral therapy (HAART) alone to HAART with combination chemotherapy with doxorubicin, bleomycin and vincristine (ABV), and documented a significantly higher rate of tumor regression for the combination along with improvement in quality of life and no adverse effects on HIV control. Other studies suggest that gemcitabine may be an active second-line chemotherapeutic agent after failure of HAART and ABV and suggest that AIDS-associated Kaposi sarcoma in children may respond well to HAART with chemotherapy. There are also (primarily retrospective) data suggesting a beneficial effect of HAART on Kaposi sarcoma, but some evidence for Kaposi sarcoma as a manifestation of immune reconstitution inflammatory syndrome. SUMMARY: Opportunities and need exist for prospective research to establish evidence-based guidelines for the most effective treatments for Kaposi sarcoma in SSA. PMID- 21681093 TI - How we treat elderly patients with Hodgkin lymphoma. AB - PURPOSE OF REVIEW: To review Hodgkin lymphoma in older adults with regard to epidemiology, disease characteristics, prognosis, treatment, and future developments. RECENT FINDINGS: Older Hodgkin lymphoma patients defined by chronological age represent a heterogeneous population in terms of life expectancy, morbidities, and functional status. Twenty-one percent of Swedish Hodgkin lymphoma patients are greater than 65 years (5%, >81 years) at diagnosis. In general, less than 10% of patients included in broad clinical trials are greater than 60 years. The proportion of mixed cellularity histopathology and EBV genome-positive tumors is higher in older adults. Five-year relative survival of Swedish patients 66-80 and greater than 81 years is 0.58 and 0.26, respectively. Older patients have lower remission rates, but relapse-free survival is less impaired. No standard treatment recommendations exist. In older fit patients less than 65-70 years--go for 'young' treatment. Estimate thoroughly the individual patient's frailness/comorbidities in order to properly adjust treatment, thus saving patients from over/undertreatment. The use of early PET should be optimized in clinical practice. Representativeness of large clinical trials including evaluation of functional status and comorbidity remains crucial. SUMMARY: Elderly Hodgkin lymphoma patients still do poorly and improved prognostics, personalized and targeted treatment options associated with fewer side-effects will hopefully advance the clinical Hodgkin lymphoma field. PMID- 21681094 TI - A matter of debate in chronic lymphocytic leukemia: is the occurrence of autoimmune disorders an indicator of chronic lymphocytic leukemia therapy? AB - PURPOSE OF REVIEW: Autoimmune cytopenia is a noninfrequent complication of chronic lymphocytic leukemia (CLL) classified into simple and complex autoimmunity, on the basis of the absence or the concomitance of disease progression. Simple-refractory and complex autoimmunity indicate the need of treatment. Here, we review the epidemiology and the biological mechanisms that account for CLL-associated autoimmune disorders and discuss their prognostic relevance and the indication of treatment. RECENT FINDINGS: Autoimmune disorders can complicate CLL at any stage and even occur in the preleukemic monoclonal B lymphocytosis. CLL cells can act as antigen-presenting cells, possibly inducing the formation of autoreactive T helper cells (through the production of B-cell activator factor and a proliferation-inducing ligand) and nonfunctional T regulatory cells (via CD27-CD70 interaction). Further, nonmalignant lymphocytes may stimulate via CD154-mediated mechanism both tumor growth and the development of autoimmunity, especially after fludarabine-based regimens of therapy. CLL cells tend to produce monoclonal polyreactive autoantibodies suggesting that autoantigen stimulation via B-cell receptor signaling may affect the natural history of CLL. Though the results of multivariate analysis do not allow to separate autoimmune disorders developing in CLL from conventional prognostic factors, the pathogenetic intertwining between autoimmunity and malignant transformation indicates the importance of defining whether the occurrence of autoimmunity in CLL might be considered an autonomous prognostic indicator that influences treatment decisions. SUMMARY: Simple-refractory and complex autoimmunity are independent indicators of therapy for CLL. Further, epidemiological and biological studies will help clarifying the prognostic and possibly also the pathogenetic significance of simple autoimmunity. PMID- 21681095 TI - Which is the better surgical strategy for newly diagnosed epithelial ovarian cancer: primary or interval debulking? AB - PURPOSE OF REVIEW: Surgical debulking is a mainstay of therapy for epithelial ovarian cancer. The traditional timing of this surgery has been prior to chemotherapy, but this view has been challenged over the last decade. This review will focus on the recently completed phase III studies of surgical timing and discuss exceptions to the superior paradigm of neoadjuvant chemotherapy followed by interval debulking. RECENT FINDINGS: The two completed studies have shown that neoadjuvant chemotherapy followed by interval debulking is the superior strategy for stage IIIc and IV ovarian cancer compared to primary surgery followed by chemotherapy. Survival outcomes were the same, but the morbidity for the patient and cost to the system and patient were less with interval debulking. Exceptions to this sequence are potentially stage I or II patients and those stage III patients who can be optimally debulked so as to receive intraperitoneal chemotherapy. SUMMARY: Chemotherapy followed by interval debulking will result in fewer and simpler operations and lesser morbidity for the patients resulting in cost savings for the healthcare system and less inconvenience and toxicity for the patient with equivalent survival outcomes. As such it is the superior strategy. PMID- 21681096 TI - Is durable macrochimerism key to achieving clinical transplantation tolerance? PMID- 21681097 TI - Modifiers of complement activation for prevention of antibody-mediated injury to allografts. AB - PURPOSE OF REVIEW: Improvements in prevention and management of cellular rejection of solid organ transplants, coupled with increasing numbers of sensitized patients, have focused attention on antibody-mediated rejection (AbMR). Complement is a critical component of AbMR, in addition to interfacing between innate and adaptive immunity and the coagulation cascade. This article reviews complement biology and strategies to overcome complement in AbMR, cognisant that antibody can act independently of complement. RECENT FINDINGS: The past decade has witnessed an improvement in the prevention and treatment of AbMR as a result of solid-phase assays to determine antibody specificity, definition of histopathological criteria, and use of plasmapheresis and/or intravenous immunoglobulin (IVIG). Nonetheless, AbMR continues to impact adversely on short- and long-term graft survival. Use of B and/or T-lymphocyte-depleting therapies has not shown measurable benefit, and the need remains for therapies that deplete antibody, or provide better protection from complement-mediated damage. Disordered complement activity in human diseases such as paroxysmal nocturnal haemoglobinuria, has provided additional impetus to pursuing therapeutic complement inhibition. Preliminary data from C5 inhibition with eculizumab in the treatment and prevention of AbMR have shown promise. Trials with recombinant human inhibitors of C1 (effective in angioedema) to prevent or treat AbMR are beginning. SUMMARY: Despite current limitations, 'protection' of the transplant through plasmapheresis and/or IVIG enables many allografts to survive in sensitized recipients. Elucidating the pathways mediating graft acceptance, by constitutive antibody deletion, or 'accommodation' (wherein donor organ remains uninjured despite antibody binding), or other local protective mechanism(s), is an equally important challenge in the quest to overcome AbMR. PMID- 21681098 TI - Computed tomography pulmonary angiography as a single imaging test to rule out pulmonary embolism. AB - PURPOSE OF REVIEW: The aim is to review the evidence on the diagnostic value of computed tomography pulmonary angiography (CTPA) as a single test to rule out acute pulmonary embolism by focussing on the most recent literature and potential alternative and additional imaging modalities or diagnostic strategies. RECENT FINDINGS: Clinical outcome studies have demonstrated that, using algorithms with sequential diagnostic tests, pulmonary embolism can be safely ruled out in patients with a clinical probability indicating pulmonary embolism to be unlikely and a normal D-dimer test result. This obviates the need for additional radiological imaging tests in around one-third of patients. CTPA has been shown to have a high sensitivity and specificity for the diagnosis of pulmonary embolism. Several emerging tests with potential diagnostic or other advantages over CTPA need further validation before they can be implemented in routine clinical care. SUMMARY: CTPA is the imaging test of first choice. The presence or absence of pulmonary embolism can be determined with sufficient certainty without the need for additional imaging tests after a negative CTPA. Compression ultrasonography and ventilation-perfusion scintigraphy is reserved for patients with concomitant symptomatic deep vein thrombosis or a stringent contraindication for CTPA, respectively. Currently, magnetic resonance pulmonary angiography is not a suitable alternative for CTPA. PMID- 21681099 TI - Stem cell therapy in pulmonary fibrosis. AB - PURPOSE OF REVIEW: In the last years, we have witnessed an explosion in preclinical data relating to the isolation, differentiation and application of mesenchymal stem cells (MSCs) as a treatment option in animal models of lung fibrosis and inflammation. The scope of this review is to summarize current knowledge regarding the roles of MSCs in lung tissue repair and regeneration and to highlight future therapeutic perspectives and clinical applications in safety and efficacy trials. RECENT FINDINGS: Although there have been interesting studies of cell therapy for diseases of many systems, there has been a paucity of preclinical and clinical studies regarding pulmonary fibrosis. Today, we have made progress with respect to the understanding of the mechanisms of action and application of MSCs in animal models of lung fibrosis as regulators of tissue remodeling and immune response. There are only a few ongoing clinical trials involving MSCs in chronic lung diseases and extrapolation of these data to underline future therapeutic applications in patients with idiopathic pulmonary fibrosis. SUMMARY: Adult MSCs may prove to be a valuable therapeutic option in lung tissue rescue and repair based on their ready availability, immunomodulatory effects and capacity for cell differentiation. PMID- 21681100 TI - Sarcoidosis and interstitial pulmonary fibrosis; two distinct disorders or two ends of the same spectrum. AB - PURPOSE OF REVIEW: Pulmonary fibrosis is a reparative response characterized by accumulation of extracellular matrix in the lung parenchyma that may be observed in end-stage sarcoidosis. This article will discuss the recent advancements in the understanding of the pathogenesis of pulmonary fibrosis in sarcoidosis in comparison with idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). RECENT FINDINGS: A recent study examined clinical, radiographic, and histopathologic findings of end-stage sarcoidosis patients with lung fibrosis who underwent lung transplantation. The authors found many of the patients to have moderate-to-severe interstitial pneumonitis in some cases with UIP considered to be atypical of end-stage sarcoidosis. Furthermore, these patients had diagnosis of sarcoidosis for a shorter time prior to transplant compared with individuals without interstitial pneumonitis (mean 4.8 years vs. 23.3 years). Another study found a promoter polymorphism in prostaglandin-endoperoxide synthase 2 (PTGS2), 765G>C, to be associated with susceptibility and increased risk for pulmonary fibrosis in sarcoidosis in the white population compared with healthy controls. An altered Sp1/Sp3 binding to the -765 region has been proposed as a possible mechanism for reduced PTGS2 expression. SUMMARY: A subset of patients with sarcoidosis that progresses to pulmonary fibrosis may share some similar mechanistic and morphologic aberrations with IPF/UIP. Future studies are needed to examine the significance of chronic interstitial pneumonitits and UIP pattern in fibrotic sarcoidosis as a potential marker for progressive disease, and the roles of PTGS2 polymorphism in various ethnic groups and Sp1/Sp3 binding in other fibrotic lung diseases. PMID- 21681101 TI - Can a model of graded difficulty in Laerdal SimMan exactly compare performances of direct and indirect laryngoscopes? PMID- 21681102 TI - Entropy decreases post-operative morbidity in patients undergoing major gynaecological laparoscopic surgery. PMID- 21681103 TI - A randomised double-blind crossover trial of the potential analgesic effect of a transdermal nicotine patch in non-smokers based on objective and subjective assessment. AB - OBJECTIVE: The results of studies of the analgesic effect of nicotine in humans are complex because these studies have included smokers with variable smoking histories. We investigated whether the use of a 17.5 mg transdermal nicotine (TDN) patch decreased the magnitude of pressure pain on the hands of healthy non smoking volunteers. DESIGN: This was a randomised double-blind crossover trial. A TDN patch or placebo (drug-free bandage) was applied randomly on the anterior chest of non-smoking volunteers 1 h before the experiments. We measured minimum perceived current and pain threshold on the right hand and then evaluated the magnitude of pressure pain by using the Pain Vision PS-2100 (Nipro Co., Osaka, Japan) which helps in objective quantitative assessment of pain magnitude. After estimating minimum perceived current, pressure pain was produced using a combination of 100-g discs and a rod. The rod and the discs weighing 0 (no disc), 200 (two discs), 400 (four discs), 200 (two discs) and 0 g (no disc) were placed consecutively in this order on the right hand and pain threshold was measured. At the same time, volunteers were asked to rate pain on a numerical rating scale (NRS). Minimum perceived current is the current at which the volunteer perceives the first sensation on applying gradually increasing pulsed current. Pain threshold is the compatible electrode current at which the volunteer feels the intensity of pressure pain. Pain degree is calculated as (pain threshold-minimum perceived current)/minimum perceived current * 100. PARTICIPANTS: Forty non smoking volunteers were enrolled in this study. RESULTS: No significant differences between groups were observed in minimum perceived current, pain threshold, pain degree or NRS. Of the volunteers who received the nicotine patch, four became anorexic and nauseated and two required anti-emetics. CONCLUSION: The nicotine patch had no analgesic effect in non-smoking volunteers. PMID- 21681104 TI - Optimizing Bob Guthrie's legacy--storage and use of residual newborn screening specimens. PMID- 21681105 TI - American College of Medical Genetics recommendations for the design and performance expectations for clinical genomic copy number microarrays intended for use in the postnatal setting for detection of constitutional abnormalities. AB - Genomic copy number microarrays have significantly increased the diagnostic yield over a karyotype for clinically significant imbalances in individuals with developmental delay, intellectual disability, multiple congenital anomalies, and autism, and they are now accepted as a first tier diagnostic test for these indications. As it is not feasible to validate microarray technology that targets the entire genome in the same manner as an assay that targets a specific gene or syndromic region, a new paradigm of validation and regulation is needed to regulate this important diagnostic technology. We suggest that these microarray platforms be evaluated and manufacturers regulated for the ability to accurately measure copy number gains or losses in DNA (analytical validation) and that the subsequent interpretation of the findings and assignment of clinical significance be determined by medical professionals with appropriate training and certification. To this end, the American College of Medical Genetics, as the professional organization of board-certified clinical laboratory geneticists, herein outlines recommendations for the design and performance expectations for clinical genomic copy number microarrays and associated software intended for use in the postnatal setting for detection of constitutional abnormalities. PMID- 21681106 TI - American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. AB - Genomic microarrays used to assess DNA copy number are now recommended as first tier tests for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Application of this technology has resulted in the discovery of widespread copy number variation in the human genome, both polymorphic variation in healthy individuals and novel pathogenic copy number imbalances. To assist clinical laboratories in the evaluation of copy number variants and to promote consistency in interpretation and reporting of genomic microarray results, the American College of Medical Genetics has developed the following professional guidelines for the interpretation and reporting of copy number variation. These guidelines apply primarily to evaluation of constitutional copy number variants detected in the postnatal setting. PMID- 21681107 TI - The safety of electroconvulsive therapy in patients with prolonged QTc intervals on the electrocardiogram. AB - BACKGROUND: Prolonged QTc intervals have been associated with increased cardiac morbidity and mortality. We investigated whether pretreatment prolongation of the QTc interval was associated with increased cardiac-related events (CREs) in electroconvulsive therapy (ECT) treatment of psychiatric disorders. METHODS: The charts of 1437 ECT patients were reviewed for the presence of baseline QTc prolongation. Broadly defined CREs during the course of treatment were abstracted from patient charts. RESULTS: Presence of baseline QTc prolongation was not independent of increased risk of CREs during ECT. IMPLICATIONS: Careful consideration should be given to patients who have QTc prolongation on an electrocardiogram and are undergoing ECT treatment, but this should not definitively exclude patients from receiving ECT treatment. PMID- 21681108 TI - When to switch from unilateral to bilateral electroconvulsive therapy. PMID- 21681109 TI - Value of information in nonfocal colonic biopsies. AB - OBJECTIVES: Pediatric gastrointestinal (GI) biopsies represent a disproportionately large fraction of the mucosal biopsies submitted for pathology evaluation relative to the fraction of pediatric endoscopies performed. We sought to explore the rationale for this large sample volume and identify its diagnostic value. PATIENTS AND METHODS: Conceptual value-of-information analysis of 100 sequential colonoscopies, including 770 total biopsy specimens. The diagnostic value of each biopsy was evaluated based on its order of appearance in the model and overall contribution to the pathological classification of the disease. RESULTS: Current practice standards for pediatric GI biopsies provide no guidance on sampling strategy for nonfocal biopsy of suspected inflammatory diseases, resulting in the collection of a nonstandardized number of individual samples and sampling sites that may vary significantly by clinician and institution. We find that this practice adds little to no diagnostic value over more cost-effective protocols, such as a fewer biopsies overall, or fewer specimens with pooled regional biopsies. CONCLUSIONS: In the absence of clear guidance, pediatric GI clinicians and institutions should explore alternative strategies such as the left-right pooled biopsy protocol (common in adult GI practice), or preferably, a more conservative 4-region protocol covering major anatomical landmarks in the colon for nonfocal pediatric colonic biopsies. This will allow individual practitioners and clinical centers to test the hypothesis, supported by our analysis, that such a reduction in resource utilization will have no measurable impact on the quality of care. PMID- 21681110 TI - Critical role for P-glycoprotein expression in hematopoietic cells in the FVB.Mdr1a(-/-) model of colitis. AB - OBJECTIVE: P-glycoprotein (P-gp), the functional product of the multidrug resistance gene (MDR), is a transmembrane protein that extrudes substrates from the intracellular environment. P-gp is expressed on the apical surface of epithelial cells and on cells from the hematopoietic lineage. Human MDR polymorphisms have been associated with the increased risk of inflammatory bowel disease, and FVB/N animals deficient in mdr1a expression develop spontaneous colitis. Previous studies using adult bone marrow chimeras indicated that colitis development in this animal model was contingent on P-gp deficiency in radiation resistant epithelial cells; however, the use of adult animals may mask the role of hematopoietic immune cells in colitis initiation, due to preexisting epithelial abnormalities. SUBJECTS AND METHODS: To assess the importance of P-gp expression in intestinal epithelial and hematopoietic-derived cells on colitis induction in FVB.mdr1a(-/-) animals, we developed a neonatal model of bone marrow reconstitution. FVB/N and FVB.mdr1a(-/-) adult and neonatal animals were lethally irradiated and reconstituted with bone marrow from FVB/N or FVB.mdr1a(-/-) donors. Animals were observed for 20 weeks. RESULTS: Adult FVB/N animals deficient in P-gp expression in hematopoietically derived immune cells developed colitis similar to adult animals deficient in P-gp expression in radiation resistant epithelial/stromal cells. Neonatal animals deficient in P-gp expression in hematopoietically derived immune cells developed a more histologically significant colitis than those deficient in P-gp expression in epithelial tissue. CONCLUSIONS: The use of a neonatal model of bone marrow reconstitution has revealed a critical role for P-gp expression in hematopoietically derived immune cells in colitis development in the FVB.mdr1a(-/-) model. PMID- 21681111 TI - Novel characterization of drug-associated pancreatitis in children. AB - BACKGROUND AND OBJECTIVES: Medications are a major cause of acute pancreatitis; however, little is known about their influence in children. Our primary aims were to identify common comorbidities and concomitant pancreatitis etiologies in children with drug-associated pancreatitis. Our secondary aims were to identify the most commonly associated drugs in the different age groups, evaluate management practices, and compare drug-associated cases with non-drug-associated cases. PATIENTS AND METHODS: In the present study, we examined children (ages 0 20 years) admitted to Yale-New Haven Children's Hospital with pancreatitis between 1994 and 2007. RESULTS: Of a total of 271 pediatric cases, drugs were associated with pancreatitis in 25.6% (55). The 3 most common comorbidities in children with drug-associated pancreatitis were seizure disorders, acute lymphocytic leukemia, and Crohn disease. One third of drug-associated cases had an additional pancreatitis etiology. The most commonly associated drugs were valproic acid and corticosteroids. Compared with non-drug-associated cases, children with drug-associated cases were more likely to undergo CT scanning (54.5% vs 28.4%; P < 0.001), stay in the hospital longer (10 vs 4 days; P < 0.001), and transition to parenteral nutrition from a nil per os status (37.5% vs 21.2%; P < 0.05). There was a higher frequency of valproic acid-associated cases in children younger than 11 years (29.4% vs 9.5% in the 11- to 20-year-old age group). CONCLUSIONS: Our study underscores the importance of considering drugs as a cause and a contributor to pancreatitis in children, particularly valproic acid in young children. PMID- 21681112 TI - Short-course ondansetron for the prevention of methotrexate-induced nausea in children with Crohn disease. AB - OBJECTIVES: Methotrexate (MTX) is an effective treatment for Crohn disease (CD); however, its application may be limited by the occurrence of nausea. We assessed whether a short course of ondansetron minimized this adverse event. PATIENTS AND METHODS: A retrospective case-control study of patients with CD who received MTX at the Children's Hospital of Eastern Ontario between 2001 and 2009 was conducted. RESULTS: Sixty-four patients received MTX during this time period. The mean age of diagnosis was 12.0 +/- 3.0 years (+/- standard deviation), and the mean age when MTX was initiated was 13.6 +/- 2.6 years. Those receiving only 1 or 2 doses of MTX (N = 4) and stopped for reasons other than development of nausea were not included in the analysis. Fifty patients received ondansetron premedication using a 4- to 8-week tapering schedule with MTX, and only 1 patient (2.0%) developed nausea within the first 3 months of MTX. In contrast, 6 of 10 patients (60.0%, P < 0.001) not premedicated with ondansetron reported nausea following MTX within 3 months. Four of these 6 patients subsequently received ondansetron and had no further complaints. Following ondansetron discontinuation, 5 of 50 (10%) patients developed nausea with subsequent MTX injections, but responded to reinstitution of ondansetron. Some children developed anticipatory nausea (6/60, 10%) and 3 experienced nausea relief after initiating premedication with ondansetron. CONCLUSIONS: Nausea following MTX is a common complaint in patients with CD. For most, this adverse effect may be prevented through the use of a short-course ondansetron as premedication. Ondansetron to treat MTX-induced nausea also can be successfully used but a proactive preventive strategy can be achieved. PMID- 21681113 TI - Medication knowledge: an initial step in self-management for youth with inflammatory bowel disease. AB - OBJECTIVE: Adolescents with chronic illness need to develop skills to independently manage their own health. Knowledge of medication is an early step in this process. We explored which factors affect acquisition of medication knowledge in adolescents with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Consecutive patients with IBD older than 10 years received a confidential survey at an outpatient visit including questions regarding medication name, dose, and adverse effects. Results were compared with the medical record. Demographic characteristics obtained included age, sex, disease duration, and type of IBD. RESULTS: Completed surveys were returned by 294 patients (65% of those approached). Overall, 95% of patients could name their medication and 54% could identify their correct dose. Of 95 patients receiving biologics, 88% could identify the medicine and 50% could report either dose or timing. Of 139 patients on immunomodulator therapy, 94% could name medicine and 68% reported correct dose. Sex, type, or duration of disease did not affect name or dose knowledge. Generally, older patients did not demonstrate better medication or dosage knowledge than younger patients, although there was a significant trend toward improved knowledge of side effects for older patients. However, <32% of all of the patients could report a single major medication side effect. CONCLUSION: Medication knowledge is an early stage of self-management, yet many adolescents cannot report the dose of IBD medications, nor know the side effects of immunosuppression. This finding persists into late adolescence, which has ramifications for patients as they separate from parents for college or work. PMID- 21681114 TI - Thalidomide use and outcomes in pediatric patients with Crohn disease refractory to infliximab and adalimumab. AB - OBJECTIVE: The aim of the study was to evaluate thalidomide as rescue therapy for pediatric patients with severe refractory Crohn disease (CD) who failed to respond to antitumor necrosis factor (TNF) biologic agents. PATIENTS AND METHODS: A computerized database was used to identify children with CD who had failed conventional immunosuppression therapy and received thalidomide rescue therapy. Twelve patients, mean age at diagnosis 10 years, were identified. Eight children had disease localized to the ileum and colon and 4 to the gastroduodenal area and colon. Five cases were complicated by strictures and 7 by fistulae. Previous drug therapy included azathioprine/6-mercaptopurine (11/12), methotrexate (7/12), and anti-TNF biologics (12/12). Outcome measures were Harvey-Bradshaw Index, change in prednisone dose, hospitalizations, bowel resections, and incision and drainage procedures. Laboratory evaluations were calculated before and after 1 to 6 months of thalidomide. RESULTS: Mean Harvey-Bradshaw Index score improved from 11.8 to 3.9 (P = 0.0004), mean prednisone dose decreased from 13.9 to 2.3 mg/day (P = 0.001), mean number of hospitalizations decreased from 6.3 to 1.3 (P = 0.002), and erythrocyte sedimentation rate decreased from 35 to 14 mm/h (P = 0.02). The surgery rate pre-thalidomide was 0.031 and on thalidomide was 0.004. Of the 7 patients with fistulae, 5 had complete fistula closure, 1 had partial closure, and 1 showed no improvement. Adverse reactions that resulted in discontinuation of thalidomide are as follows: 42% peripheral neuropathy, 17% worsening of the CD, 8% dizziness, and 8% allergic reaction. All 5 patients who developed peripheral neuropathy had clinical resolution of the neurologic symptoms within 2 to 3 months after stopping thalidomide. CONCLUSIONS: Thalidomide is a potentially effective rescue therapy for severe refractory CD in children who fail to respond to anti-TNF medications. PMID- 21681115 TI - Evaluation of stool collections to measure efficacy of PERT in subjects with exocrine pancreatic insufficiency. AB - OBJECTIVE: The standard measure of pancreatic enzyme replacement therapy (PERT) efficacy in treating exocrine pancreatic insufficiency (EPI) is the coefficient of fat absorption (CFA). CFA measurement involves 72-hour stool collection, which presents a logistical challenge because, although the test may be performed on an outpatient basis in clinical practice, hospitalization is needed if assurance of complete collection and 100% compliance is required, for example, in controlled situations such as clinical trials. Our aim was to investigate sparse stool sample collection as an alternative to complete 72-hour collection for measurement of stool fat in subjects with EPI. SUBJECTS AND METHODS: Prospective data analysis from a previously published, double-blind, randomized, placebo controlled, 2-period crossover trial in subjects ages 7 to 11 years with EPI caused by cystic fibrosis. Percentage fat (PF) data from sparse stool samples were compared with 72-hour CFA values as a dichotomous variable (<80%, >=80%), with evaluation of sensitivity, specificity, and positive predictive value. Area under the curve values were obtained from receiver operating characteristic plots of sensitivity versus 1-specificity. RESULTS: Twelve subjects provided samples for this analysis. Multiple-sample PF values <=30% were greatly predictive for CFA values >=80%, as shown by positive predictive value, sensitivity, and specificity values >=0.89, with high accuracy (AUCs >=0.93). CONCLUSIONS: Sparse stool sampling for PF analysis appears to be a valid, practical alternative to 72 hour CFA determination and has potential as a screening tool in clinical practice to identify both suboptimal dosing in subjects with EPI receiving PERT and substantial fat malabsorption in subjects not receiving PERT. PMID- 21681116 TI - Next-generation sequencing facilitates the diagnosis in a child with twinkle mutations causing cholestatic liver failure. PMID- 21681117 TI - Erdheim-Chester disease with interatrial septum involvement. AB - Erdheim-Chester disease is an uncommon non-Langerhans cell histiocytosis with systemic manifestations. Most cases discuss radiologic findings once a pathologic diagnosis has already been established. We describe a patient with symptoms and no previously known diagnosis who was imaged with computed tomography, magnetic resonance imaging, and positron emission tomography. This case is unusual in that radiologic imaging demonstrated interatrial septum and diffuse cardiac involvement, in addition to the other characteristic lesions of Erdheim-Chester disease. The importance of this case to the radiologist is the expansion of the differential diagnosis of processes involving the interatrial septum and retroperitoneum. PMID- 21681118 TI - Low-dose gefitinib treatment for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations. AB - INTRODUCTION: Although standard schedule of gefitinib was the administration of 250 mg tablet every day, many patients need dose reduction because of toxicities. However, the efficacy of such low-dose gefitinib for patients with epidermal growth factor receptor-mutated non-small cell lung cancer has rarely been evaluated. METHODS: A post hoc comparison of the efficacy (response rate and survival) in patients treated with gefitinib with or without any dose reduction in NEJ002 study was performed. RESULTS: Among 114 patients treated with first line gefitinib in NEJ002, 61 (54%) continued gefitinib without any dose reduction until their diseases progressed, and 53 (46%) reduced their dose of gefitinib because of some toxicities. There was no significant difference of patient characteristics between the two groups. The progression-free survival of low-dose group tended to be better than that of standard-dose group (median progression free survival, 11.8 versus 9.9 months; p = 0.144), and the overall survival of low-dose group was also better than that of standard-dose group (median survival time, 32.7 versus 25.3 months; p = 0.049). CONCLUSIONS: The results suggest that low-dose gefitinib may be clinically not inferior to standard-dose gefitinib for non-small cell lung cancer with sensitive epidermal growth factor receptor mutations. Prospective study of low-dose gefitinib is warranted especially for frail patients who need less toxic treatment. PMID- 21681119 TI - Epidermal growth factor receptor mutations are associated with docetaxel sensitivity in lung cancer. AB - INTRODUCTION: A recent large randomized controlled trial revealed that patients with lung cancer with epidermal growth factor receptor (EGFR) mutations had better prognoses when treated with the EGFR-tyrosine kinase inhibitor, gefitinib, than with cytotoxic chemotherapeutic agents. Lung cancer with EGFR mutations is highly sensitive to EGFR-tyrosine kinase inhibitors. The previous trial implied that EGFR mutations might be predictive of the response to cytotoxic chemotherapy. METHODS: Forty-six tumor tissue specimens (32 adenocarcinomas and 14 nonadenocarcinomas) were obtained from patients with lung cancer who underwent surgical resection. EGFR mutations were detected using polymerase chain reaction invader assay. A histoculture drug response assay was used as an in vitro drug sensitivity test. The inhibition rates of cisplatin, docetaxel (DOC), vinorelbine, and gemcitabine were measured. RESULTS: Sensitizing EGFR mutations were detected in samples from 14 patients, all with adenocarcinomas. The inhibition rate of cisplatin in tumors with EGFR mutations (group M) was 34.8 +/- 15.5%, which was significantly lower (p = 0.0153) than in wild-type tumors (group W; 46.6 +/- 14.0%). The inhibition rate of DOC in group M (18.8 +/- 13.4%) was also significantly lower (p = 0.0051) than in group W (35.4 +/- 19.1%). There were no significant differences in inhibition rates of gemcitabine and vinorelbine between groups M and W. Inhibition rates of DOC were significantly lower in group M (p = 0.0256) than in group W (32.6 +/- 18.4) in samples from patients with adenocarcinoma. CONCLUSION: The histoculture drug response assay indicated that lung cancers with EGFR mutations were less sensitive to DOC than EGFR wild-type tumors. PMID- 21681120 TI - 2011 Compendium of Physical Activities: a second update of codes and MET values. AB - PURPOSE: The Compendium of Physical Activities was developed to enhance the comparability of results across studies using self-report physical activity (PA) and is used to quantify the energy cost of a wide variety of PA. We provide the second update of the Compendium, called the 2011 Compendium. METHODS: The 2011 Compendium retains the previous coding scheme to identify the major category headings and specific PA by their rate of energy expenditure in MET. Modifications in the 2011 Compendium include cataloging measured MET values and their source references, when available; addition of new codes and specific activities; an update of the Compendium tracking guide that links information in the 1993, 2000, and 2011 compendia versions; and the creation of a Web site to facilitate easy access and downloading of Compendium documents. Measured MET values were obtained from a systematic search of databases using defined key words. RESULTS: The 2011 Compendium contains 821 codes for specific activities. Two hundred seventeen new codes were added, 68% (561/821) of which have measured MET values. Approximately half (317/604) of the codes from the 2000 Compendium were modified to improve the definitions and/or to consolidate specific activities and to update estimated MET values where measured values did not exist. Updated MET values accounted for 73% of all code changes. CONCLUSIONS: The Compendium is used globally to quantify the energy cost of PA in adults for surveillance activities, research studies, and, in clinical settings, to write PA recommendations and to assess energy expenditure in individuals. The 2011 Compendium is an update of a system for quantifying the energy cost of adult human PA and is a living document that is moving in the direction of being 100% evidence based. PMID- 21681121 TI - Community-associated methicillin-resistant Staphylococcus aureus causing orbital cellulitis in Australian children. AB - Community-associated methicillin-resistant Staphylococcus aureus has only emerged recently as a cause of serious ocular infections in several different countries. At a tertiary pediatric hospital in Brisbane, Australia, community-associated methicillin-resistant S. aureus orbital cellulitis was first noted in 2009. Since then, it has caused 4 of 9 such infections. PMID- 21681122 TI - Abdominoplasty with suction undermining and plication of the superficial fascia without drains: a report of 113 consecutive patients. AB - BACKGROUND: Postoperative abdominoplasty seromas are a problem. Although drains are still commonly used during the initial postoperative period, this article has demonstrated that the combination of an extended incision, suction undermining, and progressive tension sutures can produce superior results without the need for suction drains. METHODS: A retrospective review of 113 consecutive abdominoplasty patients operated on between April of 2004 and May of 2010 was carried out and complications were reviewed. RESULTS: There were 109 women and four men, with ages spanning 23 to 76 years (average, 50 years). Complications of the surgery included hematoma (2.7 percent), with one requiring drain placement (0.9 percent) and two treated with needle aspiration (1.8 percent); seroma (8.8 percent), with four requiring closed suction drainage (3.5 percent) and six minimally treated with needle aspiration (5.3 percent); infection (2.7 percent), with one requiring intravenous antibiotics (0.9 percent) and two with minimal local erythema (1.8 percent); and minimal marginal skin necrosis with spontaneous healing (3.5 percent). CONCLUSIONS: The technique of abdominoplasty with the addition of an extended incision, liposuction undermining of the deep fatty tissue between the superficial and abdominal muscle fascia, and the use of progressive tension sutures results in a better abdominal wall and waist contour. This decreases the need for dissection of the abdominal panniculus above the umbilicus except for a small tunnel to allow for the suturing of the rectus abdominis muscles. This allows for preservation of the arterial and lymphatic vessels, improving blood flow to the superior flap and decreasing seroma formation to the point where operative drains are not required. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 21681123 TI - Indocyanine green-enhanced lymphography for upper extremity lymphedema: a novel severity staging system using dermal backflow patterns. AB - BACKGROUND: Management of arm lymphedema following breast cancer treatment is challenging, and emphasis should be put on early diagnosis and prevention of secondary lymphedema. Indocyanine green lymphography is becoming a method of choice for evaluation of lymphedema. METHODS: Twenty patients with secondary arm lymphedema after breast cancer treatment underwent indocyanine green lymphography. Characteristic findings of indocyanine green lymphography were analyzed according to corresponding clinical stages and duration of edema. Based on changes in indocyanine green lymphography findings with progression of lymphedema, a new severity stage, arm dermal backflow stage, was developed and compared with clinical stages. RESULTS: The indocyanine green lymphographic findings were classified into two large groups: linear pattern and dermal backflow patterns. The dermal backflow pattern could be subdivided into splash, stardust, and diffuse patterns. The dermal backflow patterns were found more frequently than the linear pattern in the proximal upper extremity (p=0.001). The dermal backflow patterns also increased significantly in prevalence overall as the duration of lymphedema increased (p=0.032). The arm dermal backflow stage was linearly correlated with clinical stage as described by the line y=1.092x+0.083 (R=0.997; analysis of variance, p<0.001). CONCLUSIONS: Indocyanine green lymphography is a safe and convenient evaluation method for lymphedema that allows qualitative pathophysiologic assessment of lymphedema. The arm dermal backflow stage, based on indocyanine green lymphographic findings, is a simple severity staging system that demonstrates a significant correlation with clinical stage. Indocyanine green lymphography may come to play an important role in early diagnosis of secondary arm lymphedema. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, V. PMID- 21681124 TI - Complex craniosynostosis. AB - BACKGROUND: Complex craniosynostoses (i.e., multisutural, nonsyndromic) are rare and present unique treatment challenges. The authors sought to assess long-term outcomes, including postsurgical growth and development, to develop evidence based treatment algorithms. METHODS: A retrospective review of all patients identified as having multiple sutural synostosis excluding bicoronal and FGFR- and TWIST-associated synostoses was conducted. Data were summarized using descriptive statistics. RESULTS: Over an 18-year period, 858 patients underwent craniosynostosis correction, and 31 patients (3.6 percent) satisfied inclusion criteria. Average number of affected sutures was 2.9 (lambdoid, 36 percent; sagittal, 31 percent; coronal, 18 percent; metopic, 15 percent), and 1.7 procedures were performed per patient (mean follow-up, 3.5 years). Average hospital stay was 2.3 days, 21 percent required blood transfusions, and there were no major complications. For synostosis patterns isolated to one side of the anterior sagittal suture (anterior or posterior skull halves), 93 percent were corrected with a single procedure. When the synostosis pattern crossed both skull halves, 80 percent underwent two procedures (p<0.001). Forty percent developed acquired Chiari deformations; of these, 60 percent required decompression. The incidence of Chiari deformations increased from 7 percent to 70 percent with lambdoid sutural involvement (p<0.002). Anthropometric data revealed postoperative growth impairment. Gross developmental delays were noted in 20 percent (mild, 16 percent; moderate to severe, 4 percent). CONCLUSIONS: Complex craniosynostoses are associated with a higher incidence of acquired Chiari deformations (especially with lambdoid involvement), require multiple operative procedures, and may have more developmental delays than the isolated single sutural synostoses. The authors recommend surgical paradigms based on sutural involvement, compensatory surgical overcorrection, and routine magnetic resonance imaging monitoring for Chiari deformations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 21681125 TI - The ideal split-thickness skin graft donor-site dressing: a clinical comparative trial of a modified polyurethane dressing and aquacel. AB - BACKGROUND: The almost single disadvantage of conventional polyurethane film dressings, uncontrolled leakage, is probably as often described as its numerous advantages for split-thickness skin graft donor sites. This shortcoming can be overcome by perforating the polyurethane dressing, which permits controlled leakage into a secondary absorbent dressing. The study was conducted to compare the polyurethane dressing system and Aquacel, a hydrofiber wound dressing, which also seems to fulfill all criteria of an ideal donor-site dressing. METHODS: This prospective, randomized, double-blind clinical trial included 50 adult patients. Skin graft donor sites were divided equally for the application of Aquacel and polyurethane dressing. The dressings were kept unchanged for 10 days. After removal of the dressing at day 10, the epithelialization rate of both sites was evaluated. Pain scores were assessed according to a 0 to 5 numeric pain scale every postoperative day and during dressing removal. RESULTS: On postoperative day 10, 86.4 percent of the polyurethane dressing donor sites showed complete reepithelialization compared with 54.5 percent of the Aquacel-treated donor sites (p<0.001). Polyurethane dressing was significantly less painful until and during removal of the dressing (p<0.001). There was no significant difference with respect to scar formation. CONCLUSIONS: Overall, polyurethane dressing was superior to Aquacel. Further attributes of the polyurethane dressing such as ease of application, low labor input, high patient comfort, and protection against secondary wound infection qualify this dressing system as an ideal wound covering for donor sites. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 21681126 TI - A 15-year review of midface reconstruction after total and subtotal maxillectomy: part I. Algorithm and outcomes. AB - BACKGROUND: Reconstruction of complex midfacial defects is best approached with a clear algorithm. The goals of reconstruction are functional and aesthetic. METHODS: Over a 15-year period (1992 to 2006), a single surgeon (P.G.C.) performed 100 flaps to reconstruct the following midfacial defects: type I, limited maxillectomy (n = 20); type IIA, subtotal maxillectomy with resection of less than 50 percent of the palate (n = 8); type IIB, subtotal maxillectomy with resection of greater than 50 percent of the palate (n = 8); type IIIA, total maxillectomy with preservation of the orbital contents (n = 22); type IIIB, total maxillectomy with orbital exenteration (n = 23); and type IV, orbitomaxillectomy (n = 19). Free flaps were used in 94 cases (94 percent), and pedicled flaps were used in six (6 percent). RESULTS: One hundred flaps were performed in 96 patients (69 males, 72 percent; 27 females, 28 percent); four patients underwent a second flap reconstruction due to recurrent disease (n = 4, 4 percent). Average patient age was 49.2 years (range, 13 to 81 years). Free-flap survival was 100 percent, with one partial flap loss (1 percent). Five patients suffered systemic complications (5.2 percent), and four died within 30 days of hospitalization (4.2 percent). Over 50 percent of patients returned to normal diet and speech. Almost 60 percent were judged to have an excellent aesthetic result. CONCLUSIONS: Free tissue transfer offers the most effective and reliable form of reconstruction for complex maxillectomy defects. Rectus abdominis and radial forearm free flaps in combination with immediate bone grafting or as osteocutaneous flaps consistently provide the best functional and aesthetic results. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 21681127 TI - A 15-year review of midface reconstruction after total and subtotal maxillectomy: part II. Technical modifications to maximize aesthetic and functional outcomes. AB - BACKGROUND: Midface reconstruction of oncologic defects is one of the most challenging problems in plastic surgery. Over time, the senior author (P.G.C.) has developed modifications in his technique for oncologic midface reconstruction to minimize complications and maximize outcomes. METHODS: Over a 15-year period (1992 to 2006), 100 flaps for midface oncologic reconstruction were performed at Memorial Sloan-Kettering Cancer Center. The first 50 flaps were performed from 1992 to 2000, and the second 50 flaps were performed from 2001 to 2006. Over time, technical improvements were made in the following areas: palate, dental implants and prosthesis, orbital floor, eyelid, nasal sidewall, lips, cranial base and dura, and pedicle anastomosis. Using a prospectively maintained database, the authors compared the functional and aesthetic outcomes of the first 50 flaps and the second 50 flaps. RESULTS: Improvements in palatal reconstruction increased the proportion of patients who achieved normal speech from 38.9 percent in the first half of the series (1992 to 2000) to 50 percent in the second half of the series (2001 to 2006). The percentage of patients who were able to tolerate an unrestricted diet increased from 44.4 to 52 percent. The use of new methods to reconstruct the orbital floor also lowered the ectropion rate from 71.4 to 47.6 percent. The percentage of patients whose aesthetic results were judged as "excellent" increased from 12 to 58.6 percent. CONCLUSIONS: Over the last 15 years, the senior author has refined methods of midface reconstruction that have improved functional and aesthetic outcomes. These technical advancements have made it possible to obtain better and more consistent results. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 21681128 TI - The possibility and potential feasibility of putting an extra functioning free muscle transplant onto a normal limb: experimental rat study. AB - BACKGROUND: Functioning free muscle transplantation is currently and popularly used clinically to restore motor deficit caused by traumatic muscle loss or chronic muscle denervation. However, no one uses functioning free muscle transplantation in a normal subject who has no motor deficit. This study was designed to investigate the possible and potential feasibility of transferring an extra free muscle transplant onto a normal limb. METHODS: A chimeric flap including biceps muscle with its neurovascular pedicles and a skin perforator flap was designed, harvested, and transferred from a Lewis inbred rat to the other rat overlying the original biceps following neurovascular repair where the ulnar nerve was chosen as the neurotizer. Sixteen rats were operated on and evaluated 6 months after surgery. Outcome measurements included arm circumferences, electrophysiologic studies, elbow flexion force, and muscle mass. The contralateral normal biceps was used as the control. RESULTS: All outcome measurements revealed that the extra muscle transfer resulted in significant increases in size and function of the operative limb without interfering with the original biceps function. CONCLUSION: The authors' study demonstrates the possible and potential application of using extra free muscle transplantation for functional and aesthetic augmentation purposes in a normal subject. PMID- 21681129 TI - Closer to an understanding of fate: the role of vascular complications in free flap breast reconstruction. AB - BACKGROUND: Flap loss in autologous breast reconstruction is almost invariably a result of a vascular event; however, not all events portend the same fate. The purpose of this study was to determine whether intraoperative vascular complications predict subsequent postoperative vascular thrombosis and flap loss. METHODS: This was a retrospective review of all free flaps performed between 2005 and 2010 in the University of Pennsylvania Health System for breast reconstruction. Details of all vascular thromboses and intraoperative technical difficulties were recorded. Flaps with a routine intraoperative course were compared with those with an intraoperative complication. RESULTS: Overall, 1173 free flaps were performed in 804 patients. In regression analysis, an intraoperative vascular complication was the only independent predictor of a subsequent delayed vascular complication (odds ratio, 3.11; 95 percent confidence interval, 1.25 to 7.73). In subanalysis, intraoperative arterial thrombosis was not associated with a subsequent delayed arterial thrombosis; however, intraoperative technical difficulties were associated with increased delayed arterial thrombosis (1.0 percent versus 4.2 percent, p=0.05) and partial flap loss (0.6 percent versus 4.2 percent, p=0.02). There was a trend toward increased delayed venous thromboses following intraoperative venous thromboses (1.1 percent versus 16.7 percent, p=0.07). In aggregate, there was a higher rate of complete flap loss following any intraoperative vascular complication (0.9 percent versus 3.5 percent, p=0.04). CONCLUSIONS: In free flap breast reconstruction, an intraoperative vascular problem leads to increased risk of a subsequent postoperative vascular complication and flap loss. Postoperative vascular complications do not appear to be overtly affected by specific surgical intervention or choice of anticoagulation in the setting of a preceding intraoperative problem. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 21681130 TI - Evaluation of the scratch collapse test in peroneal nerve compression. AB - BACKGROUND: The scratch collapse test is a recently described provocative test for diagnosis of peripheral nerve compression. METHODS: The scratch collapse test was studied prospectively in 24 consecutive patients with a diagnosis of common peroneal nerve compression neuropathy. The diagnosis was confirmed by history, physical examination, and electrodiagnostic testing. Provocative testing by the scratch collapse test and Tinel's sign was performed. RESULTS: The scratch collapse test showed a sensitivity of 0.77 and a specificity of 0.99, while the Tinel's sign showed 0.65 and 0.99, respectively. CONCLUSION: The scratch collapse test is a sensitive and specific provocative test that compares favorably to existing clinical tests and aids in the diagnosis of common peroneal neuropathy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 21681131 TI - Microscope sterility during spine surgery. AB - STUDY DESIGN: Prospective study. OBJECTIVE: Assess the contamination rates of sterile microscope drapes after spine surgery. SUMMARY OF BACKGROUND DATA: The use of the operating microscope has become more prevalent in certain spine procedures, providing superior magnification, visualization, and illumination of the operative field. However, it may represent an additional source of bacterial contamination and increase the risk of developing a postoperative infection. METHODS: This study included 25 surgical spine cases performed by a single spine surgeon that required the use of the operative microscope. Sterile culture swabs were used to obtain samples from 7 defined locations on the microscope drape after its use during the operation. The undraped technician's console was sampled in each case as a positive control, and an additional 25 microscope drapes were swabbed immediately after they were applied to the microscope to obtain negative controls. Swab samples were assessed for bacterial growth on 5% sheep blood Columbia agar plates using a semiquantitative technique. RESULTS: No growth was observed on any of the 25 negative control drapes. In contrast, 100% of preoperative and 96% of postoperative positive controls demonstrated obvious contamination. In the postoperative group, all 7 sites of evaluation were found to be contaminated with rates of 12% to 44%. Four of the 7 evaluated locations were found to have significant contamination rates compared with negative controls, including the shafts of the optic eyepieces on the main surgeon side (24%, P = 0.022), "forehead" portion on both the main surgeon (24%, P = 0.022) and assistant sides (28%, P = 0.010), and "overhead" portion of the drape (44%, P = 0.0002). CONCLUSION: Bacterial contamination of the operative microscope was found to be significant after spine surgery. Contamination was more common around the optic eyepieces, likely due to inadvertent touching of unsterile portions. Similarly, all regions above the eyepieces also have a propensity for contamination because of unknown contact with unsterile parts of the surgeon. Therefore, we believe that changing gloves after making adjustments to the optic eyepieces and avoid handling any portion of the drape above the eyepieces may decrease the risks of intraoperative contamination and possibly postoperative infection as well. PMID- 21681132 TI - Different proximal thoracic curve patterns have different relative positions of esophagus to spine in adolescent idiopathic scoliosis: a computed tomography study. AB - STUDY DESIGN: A computed tomography (CT) study. OBJECTIVE: To evaluate the changed relative positions of esophagus in proximal thoracic (PT) curves of adolescent idiopathic scoliosis (AIS) patients and analyze the potential risks of esophageal injuries from thoracic pedicle screw (TPS) insertion. SUMMARY OF BACKGROUND DATA: Translation and rotation of the vertebrae could lead to altered relative positions of surrounding vital structures in AIS patients. The changed positions of aorta and spinal cord in main thoracic (MT) curve have been comprehensively investigated; however, no studies have analyzed the relative position of esophagus in PT curve. METHODS: Twenty patients with complete proximal thoracic (CPT group) curve, 22 patients with fractional proximal thoracic (FPT group) curve, and 14 normal patients with a straight spine (normal group) were included. Axial CT images from T2 to T5 at the midvertebral body level were obtained to evaluate esophagus-vertebral angle (EVA, defined as 0 degrees when the esophagus was located directly lateral to the left, 90 degrees when strictly anterior, and 180 degrees when directly lateral to the right). The percentages of esophagus in the direction of screw passage were calculated to analyze potential risks of esophageal injuries during TPS insertion. RESULTS: EVA in the FPT group was significantly smaller than that in the normal group (P < 0.05), whereas EVA in the CPT group was significantly greater than that in the normal group (P < 0.05) at each level. The esophagus was located approximately anterior to the vertebral body in the normal group but shifted anterolaterally to the right in the CPT group and anterolaterally to the left in the FPT group. The esophagus was at a high risk of injury with right anterior penetrated TPS in the CPT group and was at a high risk of injury with left anterior penetrated TPS in the FPT group. CONCLUSION: Different anatomic patterns of PT curves could cause different altered positions of esophagus relative to spine and result in different potential risks of esophageal injuries during TPS insertion. Spine surgeons should choose appropriate pedicle screw length to avoid anterior cortical perforation in the PT region of AIS patients. PMID- 21681133 TI - Atypical extensive extratemporal hyperpneumatization of the skull base including the cervical spine: case report and review of the literature. AB - STUDY DESIGN: Case report and clinical discussion. OBJECTIVE: To describe a rare case of hyperpneumatization of the skull base including the cervical spine with the atlas bone. SUMMARY OF BACKGROUND DATA: Initial imaging studies of physically traumatized patients consist of conventional radiographs. An atypical radiolucency is often misdiagnosed as a primary malignancy or a secondary osteolytic metastasis. Further imaging studies may reveal an underlying atypical hyperpneumatization as a very rare benign differential diagnosis. Pathophysiologically, embryological developmental anomalies as well as an elevated pressure to the middle and inner ear are discussed. METHODS: We present a symptomatic 40-year-old man with conventional radiographs, after computed tomography and magnetic resonance imaging examinations. RESULTS: Imaging studies reveal an uncommon radiolucency of the skull base including the atlas bone, free air beneath the mastoid bone, stylomastoid foramen, epidural air adjacent to the atlas bone, and surrounding soft-tissue emphysema. CONCLUSION: Atypical radiolucency may represent a very rare benign hyperpneumatization of the skull base, which may include the craniocervical junction. Because of microfractures of the thinned and consecutive, less stable bones, this also can lead to free air and soft-tissue emphysema, which has not been described previously. Special care should be taken to identify epidural free air because of a possible communication of the epidural space with the external environment. Harmful activities and especially high-speed trauma could result in fractures of the cervical spine due to decreased stability of the hyperpneumatized bones. PMID- 21681134 TI - Fixation points within the main thoracic curve: does more instrumentation produce greater curve correction and improved results? AB - STUDY DESIGN: Prospective consecutive multicenter case series. OBJECTIVE: To compare fixation type and amount to curve correction controlled for curve flexibility. SUMMARY OF BACKGROUND DATA: The enhanced spinal purchase from segmental fixation should increase the force implants can exert without failure. This study evaluates whether this translates into correction beyond that expected from preoperative bending radiographs in thoracic curves where maximum correction was feasible (1A, 1B, and nonselective 1C fusions). METHODS: One hundred seventy one Lenke type 1 curves (118 1A, 36 1B, 23 1C) with 2-year follow-up were evaluated for the number and type of fixation points within the main curves compared to the correction obtained on preoperative bend films. SRS scores were compared to the amount of correction. RESULTS: The number of fixation points both within the curve (P = 0.01) and for each vertebral body (P = 0.002) was larger for curves with greater correction compared to the bend films than those with less correction. Overall absolute correction was best for all screw and screw and wire constructs, followed by hook and screw, and least with hooks. However, compared to the bend films, these differences were not significant (P = 0.132). For all groups, the SRS scores significantly improved (P < 0.001), and was slightly more notable for the all screw constructs than other instrumentation patterns (P = 0.023). However, there were no significant difference in this improvement between those correcting more and those correcting less than the bend films (P = 0.578). CONCLUSION: Absolute curve correction improved most with all pedicle screw and screw and wire constructs, but, when compared to bending films, the number of fixation points is more important than fixation type for curve correction. Although SRS scores improved the most in those with all screw constructs, the significance of this improvement is uncertain, and the SRS scores did not relate to whether curve correction was more or less than the bend films. PMID- 21681136 TI - Three-dimensional configuration and morphometric analysis of the lateral atlantoaxial articulation in congenital anomaly with occipitalization of the atlas. AB - STUDY DESIGN: Observational and quantitative study with 3-dimensional (3D) computerized tomographic (CT) analysis. OBJECTIVE: To establish the 3D configuration and morphometric data of obliquity of the lateral atlantoaxial articulations (LAA) in congenital anomaly with occipitalization. SUMMARY OF BACKGROUND DATA: Plane radiographs and normal CT scans cannot clearly demonstrate the configuration of LAA as the hindrance of circumambient bony structures. The morphology of anomalous LAA with occipitalization is underreported. METHODS: A series of 63 cases with occipitalization and 20 control subjects underwent thin slice CT scanning. The 3D configuration of LAA were analyzed and categorized based on the degree of olisthy and inclination orientation of the atlantoaxial articular facets (AAF). The obliquity of the AAF was measured in reconstructed sagittal and coronal planes, respectively. RESULTS: Four types of configuration of LAA with occipitalization were found: type I, characterized by slight anteversion of LAA without olisthy of the inferior and superior facets (16% of 126 sides); type II, characterized by partial olisthy of the 2 facets and evident anteversion of LAA (48%); type III, defined by the separation or complete olisthy of the 2 facets (13%); and type IV, wherein the articular facets sloped dorsally (23%). Forty-eight of 49 cases in the former 3 types wherein AAF sloped ventrally had atlantoaxial dislocation (AAD). All type IV cases wherein AAF sloped dorsally had no AAD. In control subjects, LAA had no evident obliquity of anteversion or retroversion. CONCLUSION: Instability at the C1-C2 junction in congenital anomaly with occipitalization is likely a direct result of the anteversion of LAA and bony malformation of this region, and it aggratates with the increasing obliquity of anteversion of the AAF. Demonstrating 3D morphological changes of LAA may provide a new means to diagnosis instability in congenital anomaly at craniovertebral junction and a basis for rational surgical treatment. PMID- 21681137 TI - Advocating for cost-effective placebos. PMID- 21681138 TI - Convex hemiepiphysiodesis: the limits of vertebral stapling. AB - STUDY DESIGN: We performed a retrospective chart review of patients with nonadolescent idiopathic scoliosis who underwent open vertebral stapling for treatment of spinal deformity. OBJECTIVE: The objective of this study was to determine the efficacy of vertebral stapling in patients with scoliosis. Measurements included initial deformity correction and maintenance of correction. SUMMARY OF BACKGROUND DATA: Growth modulation has become a topic of interest recently in the spinal deformity literature. It refers to the tethering of growth on one side of the spine to allow for compensatory growth on the contralateral side, and, in theory, correction of scoliosis. Recent studies on endoscopic vertebral stapling have shown promising early results in adolescents with idiopathic scoliosis. Little is known about its applicability in patients with more "malignant" types of scoliosis. METHODS: The medical records and radiographs of 11 children who underwent open vertebral stapling between June 2003 and August 2004 were reviewed. Patients with adolescent idiopathic scoliosis (AIS) were excluded. RESULTS.: Diagnoses included myelodysplasia, congenital scoliosis, juvenile, and infantile idiopathic scoliosis, Marfan syndrome, paralytic scoliosis, and neuromuscular scoliosis. The average age at surgery was 6 + 11 year. All patients were skeletally immature. Preoperative curves averaged 68 degrees (22 degrees -105 degrees ). Of the 11, six thoracic curves and five thoracolumbar curves were stapled. Four patients had minor curves, which were not stapled. Initial postoperative radiographs averaged 45 degrees (24 degrees -88 degrees ). Average follow-up was 22 month for our series (16-28 month). At final follow-up, scoliosis averaged 69 degrees (36 degrees -107 degrees ). Five of the 11 patients have subsequently undergone secondary surgical procedures for progression of scoliosis, including growing rod insertion in three, combined anterior/posterior spinal fusion in another, and bilateral vertical expandable prosthetic titanium rib insertion in a patient with myelodysplasia. Three of the remaining six patients are scheduled for secondary surgery. CONCLUSION: More than half of the patients in our series have undergone or are scheduled to undergo further spinal surgery, at an average of 2 year after anterior vertebral stapling. It is unclear if progression may be related to the young age at surgery, the relatively severe average preoperative curve magnitude, the nature of the underlying scoliosis, or a combination of these. PMID- 21681139 TI - Abnormal leptin bioavailability in adolescent idiopathic scoliosis: an important new finding. AB - STUDY DESIGN: This was a cross-sectional study. OBJECTIVE: The present study aimed to explore the differences in leptin bioavailability between adolescent idiopathic scoliosis (AIS) and healthy age-matched girls in a Chinese Han population. SUMMARY OF BACKGROUND DATA: AIS is a common spinal deformity mainly occurring in girls during the peripubertal period. The development of scoliosis is related to relative anterior spinal overgrowth. AIS girls also have associated lower body mass index (BMI) and lower bone mineral status. Leptin, together with soluble leptin receptor (sOB-R), was shown to play an important role in the regulation of bone and energy metabolism in children. It was hypothesized that leptin and sOB-R are abnormal and associated with deranged growth and anthropometric phenotypes in AIS girls. METHODS: Serum leptin and sOB-R were measured together with documentation of anthropometric parameters and clinical data in 95 AIS girls and 46 healthy matched controls (age 11-16 years). Serum leptin and sOB-R concentrations were measured by enzyme-linked immunosorbent assay and correlated with the different measured parameters. RESULTS: AIS girls had significantly lower BMI and longer arm span than healthy controls. AIS girls were found to have significantly higher sOB-R levels and lower free leptin index (FLI) after adjusting for age and body weight in multivariate regression analysis. Significant correlation was found between sOB-R, FLI, and curve severity in AIS girls. CONCLUSION: This is the first study demonstrating the presence of abnormal leptin bioavailability in AIS girls that might play an important role in the etiopathogenesis of AIS. Further investigation is required to provide a better understanding of the underlying mechanisms, with the aim to explore the potential clinical application as a biomarker for predicting curve initiation or progression in AIS. PMID- 21681140 TI - Who should have surgery for an intervertebral disc herniation? Comparative effectiveness evidence from the spine patient outcomes research trial. AB - STUDY DESIGN: Combined prospective randomized controlled trial and observational cohort study of intervertebral disc herniation (IDH), an as-treated analysis. OBJECTIVE: To determine modifiers of the treatment effect (TE) of surgery (the difference between surgical and nonoperative outcomes) for intervertebral disc herniation (IDH) using subgroup analysis. SUMMARY OF BACKGROUND DATA: The Spine Patient Outcomes Research Trial demonstrated a positive surgical TE for IDH at the group level. However, individual characteristics may affect TE. No prior studies have evaluated TE modifiers in IDH. METHODS: IDH patients underwent either discectomy (n = 788) or nonoperative care (n = 404) and were analyzed according to treatment received. Thirty-seven baseline variables were used to define subgroups for calculating the time-weighted average TE for the Oswestry Disability Index (ODI) across 4 years (TE = DeltaODI(surgery) DeltaODI(nonoperative)). Variables with significant subgroup-by-treatment interactions (P < 0.1) were simultaneously entered into a multivariate model to select independent TE predictors. RESULTS: All analyzed subgroups improved significantly more with surgery than with nonoperative treatment (P < 0.05). In minimally adjusted univariate analyses, being married, absence of joint problems, worsening symptom trend at baseline, high school education or less, older age, no worker's compensation, longer duration of symptoms, and an SF-36 mental component score (MCS) less than 35 were associated with greater TEs. Multivariate analysis demonstrated that being married (TE, -15.8 vs. -7.7 single, P < 0.001), absence of joint problems (TE, -14.6 vs. -10.3 joint problems, P = 0.012), and worsening symptoms (TE, -15.9 vs. -11.8 stable symptoms, P = 0.032) were independent TE modifiers. TEs were greatest in married patients with worsening symptoms (-18.3) vs. single patients with stable symptoms (-7.8). CONCLUSION: IDH patients who met strict inclusion criteria improved more with surgery than with nonoperative treatment, regardless of specific characteristics. However, being married, without joint problems, and worsening symptom trend at baseline were associated with a greater TE. PMID- 21681141 TI - The biomechanical effect of transverse connectors use in a pre- and postlaminectomy model of the posterior cervical spine: an in vitro cadaveric study. AB - STUDY DESIGN: An in vitro biomechanical study investigating the effect of transverse connectors on posterior cervical stabilization system in a laminectomy model. OBJECTIVE: To evaluate the optimal design, number, and location of the transverse connectors in stabilizing long segment posterior instrumentation in the cervical spine. SUMMARY OF BACKGROUND DATA: In the cervical spine, lateral mass screw (LMS) fixation is used for providing stability after decompression. Transverse connectors have been used to augment segmental posterior instrumentation. However, in the cervical region the optimal design, number, and the location of transverse connectors is not known. METHODS: Seven fresh human cervicothoracic cadaveric spines (C2-T1) were tested by applying +/-1.5 Nm moments in flexion (F), extension (E), lateral bending (LB), and axial rotation (AR). After testing the intact condition, LMS/rods were placed and then were tested with two different transverse connectors (top-loading connector [TL] and the head-to-head [HH] connector) in multiple levels, pre- and postlaminectomy (PL). RESULTS: LMS significantly reduced segmental motion by 77.2% in F, 75.6% in E, 86.6% in LB, and 86.1% in AR prelaminectomy and by 75.4% in F, 76% in E, 80.6% in LB, and 76.4% in AR postlaminectomy compared to intact (P < 0.05). Only in AR, PL constructs with HH connectors at C3 & C7, TL connectors at C4-C5 & C5-C6, and at C3-C4 & C6-C7 significantly reduced the range of motion by 12.9%, 11.9%, and 11.9%, respectively, compared to PL LMS (P < 0.05). No statistical significance was observed between TL connector and HH connector in all loading directions. CONCLUSION: The biomechanical advantage of transverse connectors is significant in AR, when using two connectors at the proximal and distal ends, compared to one connector. In a clinical setting, this data may guide surgeons on transverse connector configurations to consider during posterior cervical instrumentation. PMID- 21681142 TI - Evaluation of tissue factor bearing microparticles as biomarkers in allogeneic stem-cell transplantation. AB - BACKGROUND: There is compelling evidence that blood-borne tissue factor that is predominantly found on circulating microparticles (MPs) plays an important role in both, cancer biology and organ and stem-cell transplantation (SCT). Therefore, we hypothesized that numbers of tissue factor bearing MPs might be associated with complications and outcome in allogeneic SCT (allo-SCT). MATERIALS AND METHODS: In a prospective study, we enumerated total, platelet, endothelial, and tissue factor bearing MPs in plasma samples obtained from up to 60 patients with hematologic diseases at different time-points during the course of allo-SCT by flow cytometry. Patient- and transplant-related risk factors were included in statistical analysis. RESULTS: Mean follow-up time was 968 days (0-1981 days). Thirty-four (56.7%) patients died, 17 due to transplant-related mortality (28.3%). High numbers of tissue factor positive MPs more than 500/MUL before conditioning were predictive for shorter overall survival (P=0.017, hazard ratio=4.5) in multivariate analysis. This was mainly caused by an increase in transplant-related mortality (P=0.010, hazard ratio=11.0) with cumulative incidences at 1 year of 68.8% compared with patients with lower values (20.1%; P=0.002). CONCLUSIONS: Tissue factor bearing MPs might be useful biomarkers for risk stratification in allo-SCT patients and further studies should investigate their origin, functional properties, and optimal cut-off values. PMID- 21681143 TI - Hepatic steatosis and normothermic perfusion-preliminary experiments in a porcine model. AB - BACKGROUND: Steatotic livers are increasingly common in the donor population. Cold storage of steatotic livers exacerbates ischemia-reperfuson injury and risks primary nonfunction and recipient death. Normothermic preservation avoids prolonged cooling of the organ and may be well suited to the preservation and resuscitation of damaged livers. By ex vivo normothermic perfusion, it may be possible to preserve and improve steatotic livers, so that transplantation is a viable option. METHODS: In a porcine model, streptozotocin was used to induce a hyperglycemic, ketotic state that, together with a high fat diet, resulted in mild hepatic steatosis at 5 weeks. A blood-based oxygenated ex vivo normothermic preservation system was then used to compare extended preservation of normal and mildly steatotic porcine livers at physiological pressures and flows. Serial liver biopsies were stained with Oil Red O, a specialist triglyceride stain, and were analyzed using custom-designed image analysis to quantify the degree of lipid deposition. RESULTS: Steatotic livers were capable of correcting the perfusate base excess and maintaining factor V and bile production and showed markers of liver injury comparable with normal livers. Steatotic livers had a significantly higher urea production and required no glucose support. Preliminary results suggest that prolonged normothermic perfusion results in a reduction in steatosis. CONCLUSIONS: This study suggests that steatotic livers can be successfully preserved using normothermic preservation for prolonged periods and that normothermic preservation facilitates a reduction in hepatic steatosis. Further studies are now needed including transplantation of steatotic livers after normothermic preservation. PMID- 21681145 TI - Psychological problems in children with cancer in the initial period of treatment. AB - BACKGROUND: The increasing survival rate of children with cancer because of more refined treatments makes necessary the investigation of psychological burden for the young patients. OBJECTIVE: The aim of the study was to evaluate the development of psychological problems in children with cancer during the initial 6-month period of intensive treatment. METHODS: This prospective, comparative study was conducted at one of the largest Greek pediatric oncology units in Athens. The sample comprised 132 children with cancer treated during a 30-month period and 100 children with no cancer as control group. Data were collected using the Rutter instruments for parents and teachers. For patients, it was completed by their parents at 1 (T1), 3 (T2), and 6 months (T3) from diagnosis and by teachers at T3. In the control group, the questionnaire was completed by teachers and parents once. RESULTS: The comparison of total Rutter scores for patients at T1, T2, and T3, according to parents' responses, showed statistically significant difference (P < .001). The difference in scores for patients (at T3) and control subjects was also significant according to both parents' (P < .00001) and teachers' (P < .001) responses. Children with leukemia had higher score reduction during treatment (P = .009) compared with the rest. Only age had a marginal impact on score of patients at T1 (R = 0.04). CONCLUSIONS: Based on parental reports, children treated for cancer develop psychological problems during the period of intensive treatment. The development and evolution of these problems depend on their age and type of cancer. IMPLICATIONS FOR PRACTICE: This information can be used for relevant interventions in specific groups. PMID- 21681144 TI - Penile carcinogenesis in a low-incidence area: a clinicopathologic and molecular analysis of 115 invasive carcinomas with special emphasis on chronic inflammatory skin diseases. AB - BACKGROUND: Human papillomavirus (HPV) infections account worldwide for 50% of penile cancers. The role of lichen sclerosus and lichen planus in penile carcinogenesis needs further investigation. MATERIALS AND METHODS: Archival formalin-fixed high-grade penile intraepithelial neoplasias, differentiated penile intraepithelial neoplasias, and invasive carcinomas from a single pathology institution in a low-incidence area for penile cancer were analyzed for 28 HPV low-risk and HPV high-risk genotypes, p16 overexpression, presence of peritumoral lichen sclerosus, lichen planus, precursor lesions, and monoclonal rearrangement of the T-cell receptor gamma locus. RESULTS: A total of 29 penile intraepithelial neoplasias (100%) and 69 of 115 (60%) invasive cancers contained HPV high-risk genotypes with a single HPV high-risk genotype (80% HPV16, 6% HPV33, 2% HPV45 and HPV18, 1% HPV73). Multiple HPV high-risk genotypes were identified in 4% with and in 5% without HPV16/18. p16 overexpression correlated in all but 1 case of HPV high-risk 45 cancer. No p16 overexpression and HPV genotype was found in 6 differentiated penile intraepithelial neoplasias and 46 of 115 (40%) invasive cancers, 30% of which were pT2/pT3 cancers. For 35 cancers, peritumoral tissue was available for analysis. Advanced lichen sclerosus was identified in 26, lichen planus in 9, and differentiated penile intraepithelial neoplasia in 18 carcinomas. Dense T-cell-dominant lymphocytic infiltrates were identified in 22 of 46 carcinomas and in 3 of 6 differentiated penile intraepithelial neoplasias, with 6 of 13 analyzed carcinomas/penile intraepithelial neoplasias showing a monoclonal rearrangement of the T-cell receptor gamma locus. CONCLUSIONS: The prevalence of HPV high-risk in penile cancers from a low-incidence area was slightly higher than the global distribution. HPV-negative carcinomas were associated with advanced lichen sclerosus and lichen planus, differentiated penile intraepithelial neoplasia, and accumulation of T lymphocytes with monoclonal rearrangement of the T-cell receptor gamma locus. PMID- 21681146 TI - Satisfaction with initial screen and compliance with biennial breast screening at centers with and without nurses. AB - BACKGROUND: A woman's experience during her initial breast screen can influence her participation in subsequent screening. OBJECTIVE: The purpose of this study was to determine the association between a woman's satisfaction with her initial screening experience and compliance to biennial screening at centers with and without nurses. METHODS: A stratified random sample of compliers and noncompliers to biennial screening was selected from a cohort of 16 858 eligible women aged 50 to 65 years attending centers with and without nurses for their initial screen at the Ontario Breast Screening Program in 2002. Of these eligible women, 3387 were sent questionnaires, 2640 (77.9%) were contacted, and 1901 (72.0%) were interviewed. The association between satisfaction with initial screen and compliance was estimated separately for centers with and without nurses using logistic regression. RESULTS: Women attending centers with nurses were significantly less likely to comply with their next screen after their clinical breast examination if they were not completely satisfied with the service they received (odds ratio, 0.21; 95% confidence interval, 0.08-0.57) or agreed that the clinical breast examination caused discomfort to their breasts (odds ratio, 0.65; 95% confidence interval, 0.45-0.94). In addition, women attending centers with or without nurses were significantly less likely to comply if they did not understand why they needed to return for screening. CONCLUSIONS: : Nurses at screening centers have an opportunity to significantly impact a woman's compliance to biennial breast screening by providing a positive initial screening experience. IMPLICATIONS FOR PRACTICE: Emphasis should be placed on improving a woman's overall satisfaction with her initial screening experience. PMID- 21681147 TI - Impact of alkylphospholipids on the gene expression profile of HaCaT cells. AB - OBJECTIVE: New alkylphospholipids (APLs) that are structurally derived from the platelet-activating factor (PAF) are promising candidates for anticancer treatment. After incorporation into cell membranes, APLs are able to interfere with a wide variety of key enzymes implicated in cell growth, motility, invasion, and apoptosis. In addition to the prototype 1-O-octadecyl-2-O-methyl-rac-glycero 3-phosphocholine (edelfosine), we presented a novel group of APLs, the glycosidated phospholipids that efficiently inhibit cell proliferation. Two members of this group, Ino-C2-PAF and Glc-PAF, display high efficacy and low cytotoxicity in immortalized nontumorigenic skin keratinocyte cell line, HaCaT. This study investigated the impact of APLs on the transcription of the whole genome. MATERIALS AND METHODS: Using Agilent complementary DNA microarray technology, we compared global gene expression profiles of HaCaT cells treated with edelfosine, Ino-C2-PAF, or Glc-PAF with the profile of control cells. RESULTS: We found that Ino-C2-PAF has the strongest influence on gene expression in comparison with edelfosine and Glc-PAF. Gene Ontology analysis showed that differentially expressed transcripts regulated by the three APLs are mainly implicated in lipid metabolism, lipid biosynthesis, cell differentiation, cell development, and ion homeostasis. Nevertheless, the most remarkable finding is represented by the ability of Ino-C2-PAF to downregulate a broad spectrum of genes associated with the regulation of the innate and acquired immune response and of genes linked to inflammation. CONCLUSION: These results identify Ino-C2 PAF as the most effective APL used in this study. Therefore, Ino-C2-PAF might be a promising compound for further studies that concentrate on the inhibition of inflammatory responses. PMID- 21681148 TI - Anti-migration effects of Gekko sulfated glycopeptide on human hepatoma SMMC-7721 cells. AB - Gekko swinhonis Guenther has been used as an anti-cancer drug in traditional Chinese medicine for hundreds of years. Previous studies showed that the Gekko sulfated polysaccharide-protein complex suppressed the proliferation and migration of hepatoma cells. Gekko sulfated glycopeptide alpha was obtained from Gekko sulfated polysaccharide-protein complex using papain hydrolysis. Gekko sulfated glycopeptide alpha inhibited the proliferation and migration of SMMC 7721 cells. The secretion of IL-8 and the concentration of intracellular calcium were decreased after Gekko sulfated glycopeptide alpha exposure. SMMC-7721 cells in the control group showed abnormal features, with a polygonal shape, whereas this changed to a spindle shape after the treatment with Gekko sulfated glycopeptide alpha. Actin filaments were distributed diffusely along the cell membrane in control cells, whereas those were polymerized and preferentially accumulated in the cytoplasm of treated cells. Microtubules distributed in the cytoplasm of untreated cells were located diffusely whereas those in treated cells were polymerized. Therefore, Gekko sulfated glycopeptide alpha inhibit the migration of hepatoma cells via reducing the secretion of IL-8 and the concentration of intracellular calcium, as well as regulating the reorganization of cytoskeleton. PMID- 21681149 TI - Epitope prediction based on random peptide library screening: benchmark dataset and prediction tools evaluation. AB - Epitope prediction based on random peptide library screening has become a focus as a promising method in immunoinformatics research. Some novel software and web based servers have been proposed in recent years and have succeeded in given test cases. However, since the number of available mimotopes with the relevant structure of template-target complex is limited, a systematic evaluation of these methods is still absent. In this study, a new benchmark dataset was defined. Using this benchmark dataset and a representative dataset, five examples of the most popular epitope prediction software products which are based on random peptide library screening have been evaluated. Using the benchmark dataset, in no method did performance exceed a 0.42 precision and 0.37 sensitivity, and the MCC scores suggest that the epitope prediction results of these software programs are greater than random prediction about 0.09-0.13; while using the representative dataset, most of the values of these performance measures are slightly improved, but the overall performance is still not satisfactory. Many test cases in the benchmark dataset cannot be applied to these pieces of software due to software limitations. Moreover chances are that these software products are overfitted to the small dataset and will fail in other cases. Therefore finding the correlation between mimotopes and genuine epitope residues is still far from resolved and much larger dataset for mimotope-based epitope prediction is desirable. PMID- 21681150 TI - Changes in blood lactate concentrations during different treadmill exercise test protocols. AB - AIM: The purpose of this study was to compare the blood-lactate and heart rate response of three treadmill tests and to define a conversion algorithm. METHODS: Subjects included 19 long-distance runners. The first two tests had increments of 2 km/h every 3 (test3m) or 5 minutes (test5m). The third test (testFm) consisted of four consecutive 2000m-runs. The calculated individual-anaerobic-threshold (IAT) from test3m was defined as speed at the third step of testFm, speed increments between the four steps were 0.25 m/s. RESULTS: Lactate threshold (LT) did not show significant differences. Speed at IAT in test3m (15.09|*plusmn*|2.29 km/h) was significantly higher than in test5m (14.74|*plusmn*|2.22 km/h), heart rates were nearly identical. Speed and heart rate at 2 mmol/L showed no significant differences. At lactate concentrations of 3 and 4 mmol/L, running speeds in test3m were significantly higher than in test5m and testFm. Heart rate were the same in test3m and test5m but significantly higher in testFm. CONCLUSION: Taking test3m as basis for determining endurance-performance, an adjustment of test5m can be made by adding 1.8 mmol/l instead of 1.5 mmol/l to the LT to derive the IAT. TestFm shows similar results as test5m, however, standardization is difficult due to variable increment durations. PMID- 21681151 TI - Relationships between anthropometric and physiological characteristics with throwing velocity and on water jump of female water polo players. AB - AIM: The aim of this study was to examine the relationship between the anthropometric, the physiological, as well as performance related characteristics of elite female water polo players and the two important technical game parameters such as throwing velocity and on water jump. METHODS: Thirty-three female professional water polo players (age:21.7+/-5.4 years, height: 171.5+/-5.8 cm, body mass: 65.5+/-8.0 Kg) members of the top four teams of the Greek A1 women league were assessed for anthropometric and body composition characteristics, for physiological and performance related characteristics as well as technical characteristics. All tests were completed a month prior to an extremely important sport event. RESULTS: The percentage of body fat was 23.6+/-7.0 % and lean body mass was 50.0+/-5.6 kg. VO(2peak) was 47.5+/-5.8 ml?kg(-1) ?min(-1), La (peak) 7.50+/-1.50 mmol?l(-1) and the swimming speed at 25-m sprint test as an indicator of the anaerobic power was 1.76+/-0.1 m?s(-1). The throwing velocity was 15.54+/ 0.71 m s(-1) and vertical jump on water 61.65+/-3.68 cm. External-internal rotator muscles torque showed about a 1:1 ratio. Body lengths, swimming speed, internal-external torque of shoulder muscles as well as VO(2) were significantly correlated with ball throwing velocity (r=0.36 to r=0.70, P<0.05). Body composition and swimming speed were associated with the on-water jump (r=0.34 to r=0.72, P<0.05). CONCLUSION: Knowledge of the physiological and anthropometric features that correlate with the two mainly used techniques in water-polo (throwing velocity and on water jump) can be used by coaches to implement effective training programs. PMID- 21681152 TI - Physiological characteristics of elite sport-dancers. AB - AIM: Dancesport is increasing its popularity and it becomes to be considered as a real sport. Few studies are available about the physiological strain of dancesport competitions: moreover, recent changes in the official rules make it mandatory to revise our knowledge about the specific physiologic demands during competition. The aim of our study was to evaluate physiological parameters in top level dancers. METHODS: Twelve competitive dancesport couples (12 Latin-American and 12 Standard dancers) composed the study population. The first testing session was aimed at determining physical and physiological characteristics of athletes in laboratory; the second, at establishing physiological responses during simulated competition on field, involving the measurement of O(2) uptake (VO(2)), heart rate and blood lactate (BL). RESULTS: Male dancers showed a peak-VO(2) of 60.9+/-6.0 and 59.2+/-7.0 mL/kg/min for Standard and Latin-American dancers, respectively. For females, peak-VO(2) was 53.7+/-5.0 mL/kg/min in Standard and 52.3+/-5.0 mL/kg/min in Latin-American dancers. During simulated competition, male dancers reached the 75.7+/-10.6 and 84.2+/-11.2% of peak-VO(2) (P<0.05) for Standard and Latin-American sequence, respectively. For females, no difference was observed (70.8+/-13.8% in Latin-American and 72.5+/-12.8% in Standard). Peak BL during simulated Standard competition was 6.50+/-2.1 and 6.91+/-2.6 mM in males and females, respectively, and, for Latin-American sequence, 7.95+/-2.1 mM in males and 6.04+/-2.5 mM in females. CONCLUSION: Dancesport can be defined as a sport discipline with an alternate physical activity with medium lasting and high energy-demanding (both aerobic and anaerobic) consecutive phases, separated by short recovery periods. These data must be kept into account while planning specific training programs in sportdancers. PMID- 21681153 TI - Cardiorespiratory fitness and oxidative stress: effect of acute maximal aerobic exercise in children and adolescents. AB - AIM: Evaluate the effects of oxidative stress in saliva in young males, according to their cardiorespiratory fitness and taking acute maximal aerobic exercise into consideration. An incremental exercise test (20 meter shuttle run) was used. METHODS: Seventy healthy male subjects, aged 10 to 14 years, were included in the study and were classified into two groups according to fitness parameters. Subjects were expected to take the 20 meter shuttle run test. RESULTS: Group I had high cardiorespiratory fitness while group II had low cardiorespiratory fitness below the mean for their age. Saliva samples were taken before and immediately after exercise in order to measure levels of reduced glutathione, lipoperoxides, glutathione/lipoperoxides ratio and catalase. The values of reduced glutathione were significantly diminished regardless the subjects' cardiorespiratory fitness. The glutathione/lipoperoxides ratio was significantly diminished in group I. In addition, positive correlations were observed between lipoperoxides values after the 20 meter shuttle run test. CONCLUSION: High cardiorespiratory fitness does not seem to be an essential factor effecting in the oxidative stress values before exercise. However, oxidative stress could be greater with more intensity and duration after and acute maximal physical exercise. PMID- 21681154 TI - The effects of rope or weighted rope jump training on strength, coordination and proprioception in adolescent female volleyball players. AB - AIM: The aim was to assess the effects of a 12-week "rope jumping" and "weighted rope jumping" training programs on functional parameters including multi-joint coordination and proprioception, strength, endurance in adolescent female volleyball players. METHODS: Pretest posttest experimental design. INTERVENTION: Weighted Rope Training group (N.=9; 15+/-1 years), Rope Training group (N.=9; 14.1+/-1.3 years) and Controls (N.=7; 14.4+/-1.3 years). MAIN OUTCOME MEASURES: Motor coordination, proprioception, strength and endurance of the lower extremities with concentric and eccentric performances in closed kinetic chain on multi joint system assessed by the Monitorized Squat system. Absolute average error (cm) and the standard deviation for coordination and proprioception, Peak Force (N), Total Work (Nm), Average Power (Nm/s), Maximal Speed for strength and endurance tests were calculated. Kruskal-Wallis and Mann Whitney U test were utilized. RESULTS: Weighted rope jump group had significant decrease for the deviation results of coordination on the concentric and eccentric phases for both legs (P<0.05). Rope jump and weighted rope jump groups had significantly lower results on non visible second movement deviation (P<0.05). In strength tests, the difference was found for total work that there was difference on the post assessment within groups in favour of Weighted Rope Training group in comparison to controls (P<0.05). Weighted Rope Training and control groups improved in concentric maximal speed (P<0.05). Most significant changes occured on eccentric phaese of the endurance tests that peak force increased in Weighted Rope Training group (P<0.05). CONCLUSIONS: Adding rope jump to training programs improves joint repositioning and coordination. Weighted Rope Training group got greater gains for coordination and eccentric endurance parameters for lower extremities in a closed kinetic chain. PMID- 21681155 TI - Path changes in the movement of English Premier League soccer players. AB - AIM: Traditional time-motion analysis methods have analysed broad locomotive movements and distances covered by players in different speed ranges. It is necessary to consider path changes made during movements in order to understand the agility requirements of soccer. The purpose of the current investigation was to describe the path changes performed in English FA Premier League soccer. METHODS: The Prozone(r) path change identification system identified three different types of path change within accurate timed player co-ordinate data gathered by the Prozone3(r) player tracking system. Data for 90 minute plus performances of 180 different players were included in the current investigation. RESULTS: The players performed 38+/-15 path changes of 45 degrees to 135 degrees to the left, 35.5+/-14.3 path changes of 45o to 135 degrees to the right and 20.2+/-90 path changes of 135o or greater. Positional role had a significant influence on the number of each type of path change performed with midfielders performing more of each path change type than defenders and forwards. There was also a significant difference in the number of each type of path change performed between different 15 minute periods of the match with more of each type being performed in the first 15 minutes and fewer of each type being performed between 60 minutes and 75 minutes than during any other period. CONCLUSION: These results have implications for agility requirements of soccer match play that conditioning coaches should be aware of. PMID- 21681156 TI - Can baseball improve balance in blind subjects? AB - AIM: Baseball, one of the most popular sports in the world, is a fast-moving sport that requires various motor abilities. Baseball is played also by blind subjects that participate in many other sports. In this study, we evaluated the role of the Italian modified version of baseball for blind subjects on balance. METHODS: This modified version of baseball maintains the fast-moving characteristic ensuring the athlete safety. Forty total blind subjects were enrolled: 20 baseball athletes and 20 sedentary participants, as control. The balance was evaluated using the Fukuda Test and Tinetti Test, both in silence and in noise. RESULTS: This baseball game may help to improve the balance ability in blind subjects. The balance was significantly improved in blind athletes as compared with blind sedentary subjects. CONCLUSION: Given the peculiar characteristics of play, this modified version of baseball seems effective in improving various motor skills that, once transferred into daily activities, may significantly ameliorate the quality of life of blind subjects. PMID- 21681157 TI - The effects of low and high glycemic index 24-h recovery diets on cycling time trial performance. AB - AIM: The present study investigated the effects of high and low glycemic index (GI) 24 h recovery meals on the physiological responses and subsequent athletic performance, following a glycogen depleting protocol. METHODS: Ten well trained cyclists (age, 33.6+/-7.4y, height, 175.3+/-7.6 cm, weight 74.5+/-8.2 kg, and VO(2max), 60.5+/-6.0 ml?kg(-1)?min(-1)) participated in two trials in a randomized cross- over design. On day 1, subjects performed a glycogen depleting protocol after which they then consumed either high or low GI recovery diets over the next 24 h, which provided 8 g.kgBW(-1) of carbohydrate. On day 2, the subjects returned to the laboratory, 2- 3 h postprandial, to perform a 40 km time trial (TT) on the Velotron cyclePro(c) ergometer. RESULTS: No difference was observed in TT performance times between the high GI (93. 5+/-9.29 min) trial and the low GI (90.7+/-11.1 min) trial (t=1.1; P=0.35). Additionally, no differences in carbohydrate (F=1.1, P=0.37) fat (F=1.1, P=0.40) oxidation or blood glucose concentration (F=0.9, P=0.5) was observed. DISCUSSION: The results of the present study suggest that the ingestion of a high GI carbohydrate 24 h recovery diet following glycogen depleting exercise, has no greater effect on endurance performance than consuming a low GI carbohydrate 24 h recovery diet. It may be concluded from these results that, provided enough carbohydrate is consumed during a 24 h recovery period, there is no difference in subsequent endurance performance. PMID- 21681158 TI - Effect of mode selection when using contact-electrode bioelectrical impedance analyzers to estimate percent body fat in young adults. AB - AIM: When using bioelectrical impedance analysis (BIA) analyzers to assess body composition, a computer-programmed prediction equation referred to as a mode (i.e., standard STD or athletic ATH) must be selected prior to the assessment. This study examined the effect of mode selection on percent body fat (%BF) determined by leg-to-leg and segmental bioelectrical impedance analysis (LBIA; SBIA) in young adults. METHODS: Ninety-two young adults (52 women; 40 men) had %BF estimated using LBIA (Tanita: TBF-300A) and SBIA (Tanita: BC-418) which was then compared to air displacement plethysmography (ADP). During the BIA assessment, %BF was determined using both the STD and ATH pre-programmed modes. RESULTS: In the women, %BF (mean+/-SD) was significantly (P<0.001) underestimated by the ATH modes of LBIA (23.0+/-6.9%) and SBIA (23.4+/-6.2%) when compared to ADP (25.5+/-7.3%). In the men, the STD mode of LBIA (18.3+/-5%) overestimated %BF when compared to ADP (14.1+/-7%). All standard error of estimate and pure error values (range=3.8% to 6.3%) exceeded the recommended range for accuracy (<3.5%). CONCLUSION: The STD mode produced mean %BF values most similar to ADP in the women, whereas the ATH mode did so in the men; a finding that was consistent for both analyzers. However, large individual prediction errors and wide confidence intervals were observed regardless of the mode selected or analyzer used for the assessment. As such, when precision is critical, the prediction equations programmed in the LBIA and SBIA analyzers examined in this study cannot be recommended to measure %BF on an individual basis. PMID- 21681159 TI - Thermal therapy and delayed onset muscle soreness. AB - AIM: In this study the application of cold water (CW) or warm water (WW) for the recovery delayed onset muscle soreness (DOMS) was investigated in comparison with a control group without the application of water (CO) after eccentric exercise. METHODS: The main study took place in a randomized, controlled study design on 60 healthy, moderately athletic young men (aged 22 years), classified into 3 groups with 20 men per group. The load was equivalent to the 70% of 1 RM, one-repetition maximum at the Deadlift (Bent Leg). Exercise consisted of 10 sets of 10 eccentric contractions of the Hamstrings muscle group after which they were exposed to either CW (20 degrees C), or WW (38 degrees C) or no intervention at all (CO). Blood samples were taken 30min before, after and 1, 2 and 6 hours after performing the exercise. RESULTS: The exercise showed to a clear increase in the muscle stress parameters without significant difference in results between the groups. The application of WW after exercise resulted in a prominent decrease in muscle cell reaction. In addition, a significant decrease was noticed in the skeletal troponin I (sTnI), creatin kinase (CK) and myoglobin (Mb) after ww. CONCLUSION: These results are indicative that the exposure of CW (20 degrees C/30 min) after exercise would lead to an elevated muscle cells stress reaction. On the other hand exposure to WW (38 degrees C/30 min) leads to a decrease in the exercise-induced deflection of muscle cell reaction. PMID- 21681160 TI - No correlation between physicians administered elbow rating systems and patient's satisfaction. AB - AIM: The aim of this study was to assess the functional outcome of patients who had undergone elbow arthroscopy, evaluating the correlation between three elbow scoring systems and the patients' subjective perception of satisfaction METHODS: Fourteen patients who had undergone elbow arthroscopy were retrospective reviewed to evaluate the correlation between three elbow scoring systems and the patients' subjective perception of satisfaction at a mean follow-up time of 24 months (range 12-64 months). Two independent orthopedic surgeons evaluated all patients using three elbow scoring systems, a simple satisfaction question and a visual analogue scale. RESULTS: The three scoring systems showed significant correlation with each other (P<0.05). There was no correlation between the results of the three scoring systems and patients' satisfaction: patients with the same level of satisfaction could perform differently at the scoring systems. CONCLUSION: Although the three scoring systems used to evaluate the patients showed significant correlation with each other, they failed to correlate to patients' satisfaction. In reporting the results of arthroscopic elbow procedures, emphasis should be placed on individual variables, rather than on global elbow ratings. Further studies are needed to develop a single outcome evaluation system which is reliable, valid and sensitive to changes of clinical importance, which takes into account both patients' and physicians perspective, and which is short and practical to use. PMID- 21681161 TI - Endothelial (dys)function: the target of physical exercise for prevention and treatment of cardiovascular disease. AB - AIM: Endothelial dysfunction has been recognized as the early event and the common feature of chronic disorders associated with increased risk for atherosclerotic heart diseases. While the beneficial effects of aerobic, moderate intensity exercise on endothelial function are very well assessed, an intriguing doubt exists about the effects of long-term high-intensity physical activity. The aim of the present study was to compare recent findings of our group concerning homocysteine levels in athletes to available data in literature in order to clarify the meaning of such apparent metabolic paradox. METHODS: The studied population included 185 athletes: 180 healthy age and sex matched subjects served as control group. The assessed variables included homocysteine, folate, vitamin B12, total and HDL cholesterol, LDH, CPK and IL-6. Results were compared to available data in literature. RESULTS: The prevalence of hyperhomocysteinemia (>15 umol/L) in athletes and controls was 55% and 15%, respectively. In the studied population, no correlation was found between homocysteine and all the other investigated variables. CONCLUSION: The present results suggest that intensive physical training could induce a pathological increase of homocysteine levels. With this regard, it has been suggested that the observed increases of cardio-vascular risk factors in athletes could represent an adaptative feature marker of muscle demand but would not actually lead to endothelial damage. This remains, however, a speculative hypothesis and further analysis are needed in order to clarify the clinical significance of those observations in order to better preserve the athletes immediate and future health. PMID- 21681162 TI - Health risk screening in adolescents: a pilot study. AB - AIM: Even if youths are generally perceived to be healthy, adolescent years are associated with significant morbidity. Screening and counselling programmes seem to be cost-effective but adolescents prefer to rely on health care services for the treatment of diagnosed diseases or injuries rather than for preventive actions. Age oriented studies are needed for better understanding the health needs of adolescents in order to provide an adequate offer of preventive opportunities. METHODS: Eight hundred youths ranging from 13 to 18 years of age were recruited. Health status and risks were clustered into the following five categories: clinical assessment, substance use/abuse, nutritional habits, alcohol and tobacco consumption, physical status. Surprisingly, 33% of the youths were suggested to perform further clinical assessment and even more interestingly a significant number of them received a diagnosis of a symptomatic disorder for which he or she did not previously consider a medical visit to be necessary. RESULTS: As expected, alcohol consumption, tobacco smoking, drug use/abuse and sedentary habit represent the risky lifestyles commonly followed by adolescents. CONCLUSION: The present study confirms the importance of screening programs addressed to health issues and behavioural attitudes of adolescents even in light of the fact that they may underestimate even indicative symptoms. PMID- 21681163 TI - Exercise in obesity management. AB - Obesity is considered a global epidemic by the World Health Organization in both developed and developing countries. It is associated with a higher risk of cardiovascular disease, diabetes mellitus, cancer and other clinical conditions. Visceral fat is the major responsible for metabolic complications, such as insulin-resistance, and it acts as an endocrine organ producing adipokines involved in lipidic and glycaemic metabolism. TNF-alpha and IL-6, produced by adipose tissue, increase NADPH oxidase activity activating protein kinase C and NFkappaB leading to an higher oxidative stress. The obesity management includes physical activity: aerobic training improves lipid profile and insulin sensitivity while resistance training increases lean body mass and basal metabolism and has beneficial effects on bone mineral density and glucose tolerance. An exercise program should include 30 to 45 minutes of moderate intensity activity performed 3 to 5 days a week. Weight loss is also associated with lower blood pressure and improved oxidative status, confirmed by reduced oxidative stress markers and increased antioxidant protection. An inverse association between indicators of systemic inflammation and physical activity has been demonstrated, so exercise training may reduce endothelial damage and cardiovascular risk. PMID- 21681164 TI - Dynamic cardiorespiratory changes in obese women. AB - AIM: This study examined the effects of an exercise training program on ventilatory function at rest and the exercise cardiorespiratory pattern in relation to body composition in obese individuals (53.4+/-7.6 years; 158.6+/-6.7 cm). METHODS: After initial tests (exercise testing and anthropometric assessment), ten women participated in a 12-week training program combining strength exercise and aerobic exercise at the ventilatory threshold, three times per week for 90 minutes. RESULTS: The post-training mean ventilatory efficiency (DeltaE/DeltaCO(2)) and cardiac efficiency (DeltaHR/DeltaO(2)) were improved (P<0.05, respectively). Decreased fat mass (-1.2 kg, P<0.01), increased lean body mass (+1 kg, P<0.01), and decreased waist and hip circumferences (-5.5 cm and -5 cm, respectively, P<0.05) were also obtained after training. CONCLUSION: The program significantly improved a number of physiological variables in our obese patients, although not to sedentary healthy levels. The results show that a functional exercise program has the potential to improve physiological variables and dynamic cardiorespiratory response to exercise in obese women. PMID- 21681165 TI - Baseline simple and complex reaction times in female compared to male boxers. AB - AIM: The aim of the study was to compare baseline cognitive performance of female in respect to male amateur boxers. METHODS: Study population included 28 female amateur boxers. Fifty-six male boxers, matched for age, employment and competitive level to female athletes, formed the control group. All boxers had no history of head concussions (except boxing). Each boxer was requested to: 1) fulfill a questionnaire collecting demographic data, level of education, occupational status, boxing record and number of head concussions during boxing; 2) undergo a baseline computerized neuropsychological (NP) test (CogSport) measuring simple and complex reaction times (RT). RESULTS: Female were lighter than male boxers (56+/-7 vs. 73.1+/-9.8 kg, P<0.0001). No significant differences at CogSport scores were observed between groups. Male boxers showed a longer simple-RT at the end of the NP battery than at the beginning (0.247+/-0.007 vs. 0.243+/-0.007 s, P=0.02), however, with a significant lower rate of mistakes (0.7+/-1.6 vs. 2.0+/-3.1%, P=0.005), observed also in the female group (0.5+/-1.1 vs. 2.2+/-3.0%, P=0.005). No boxing activity parameter (record, number of knock outs, etc.) correlated with NP scores. CONCLUSION: Female and male Olympic-style boxers have no (or minimal) differences in baseline cognitive performance. Further research with larger series of female boxers is required to confirm these findings. PMID- 21681166 TI - Cold exposure increases exercise-induced oxidative stress. AB - AIM: We determined the combined effects of cold and exercise on oxidative stress during submaximal exercise. METHODS: Sixteen amateur male cyclists pedaled at a constant speed corresponding to 85% of maximal HR as determined in normal conditions. Eight athletes pedaled indoors at 23 degrees C while 8 athletes pedaled outdoors at a temperature of 4-6 degrees C. We then evaluated the levels of reactive oxygen metabolites and plasma levels of antioxidants after exercise. RESULTS: Performing a physical task in cold conditions increased the free radical production, as demonstrated by the augmented levels of reactive oxygen metabolites and the concomitant decrease of plasma levels of antioxidants in outdoors cyclists as compared to indoors cyclists. The overall ANOVA and the post hoc comparisons revealed a significant exercise and temperature effect. The mean level of reactive oxygen metabolites in athletes who exercised indoors was significantly lower than that of the outdoor athletes. Moreover, the outdoors group presented plasma levels of antioxidants significantly lower than those of the indoors group. CONCLUSION: Since several sports are performed outdoors during the winter season, the increased risk of oxidative stress in cold conditions must be considered in these disciplines. Cyclists, football and rugby players, and runners are all affected by the elevation in oxygen radicals induced by cold and should take appropriate precautions, such as specific antioxidant integration. PMID- 21681167 TI - Oxidative stress and antioxidant defense in plasma after repeated bouts of supramaximal exercise: the effect of coenzyme Q10. AB - AIM: The purpose was to determine the changes of oxidative stress and antioxidant markers in plasma after repeated bouts of supramaximal exercise and the effects of coenzyme Q10 supplementation on these changes. METHODS: This randomized, double blind, crossover study was composed of two 8-week periods of supplementation with either 100 mg.day(-1) CoQ10 or placebo. Fifteen healthy and sedentary men participated in the study. Five Wingate tests with 2 min rest between tests were performed. Blood samples were collected at rest, immediately after, 15 and 60 min after the fifth Wingate test for oxidative stress (malondialdehyde, nitric oxide, xanthine oxidase and adenosine deaminase) and antioxidant (superoxide dismutase, glutathione peroxidase and uric acid) markers. RESULTS: At baseline exercise session, malondialdehyde increased 15 and 60 min after the exercise compared to the rest and immediately after the exercise. Malondialdehyde at rest, immediately after and 60 min after the exercise decreased with coenzyme Q10 supplementation when compared to baseline. At baseline exercise session, uric acid increased 15 and 60 min after the exercise when compared to the rest. In conclusion, lipid peroxidation and antioxidant defense increase after repeated short-term supramaximal exercise. CONCLUSION: Coenzyme Q10 supplementation partially prevents the increase in lipid peroxidation after repeated short-term supramaximal exercise. PMID- 21681168 TI - Variation in heart rate and blood lactate concentration in freestyle kytesurfing. AB - AIM: The aim of this paper was to evaluate the physiological demands of freestyle kitesurfing. METHODS: Ten elite subjects performed an incremental running test on a treadmill and a three 7 min simulated freestyle heats of kitesurfing in MW (Midwind) condition ranging from 15 to 22 knots. Oxygen uptake (VO(2)) was estimated from the heart rate (HR) recorded during the freestyle trial using the individual HR-VO(2) relationship determined during the incremental test. Blood lactate concentration [Lab] was measured at rest and 3 min after the exercise completion. 3 experienced kitesurfers acted as judges to better simulate competition conditions. RESULTS: Linear relationship was demonstrated between scores and % HR(max) on water (r=-0.764, P<0.05), HR(max) on water (r=-0.684, P<0.05) estimated VO(2) on water (r=-0.724, P<0.05), HR on water (r=0.709, P<0.05), % VO(2) on water (r=0.740, P<0.05), final [Lab] (r=-0.884, P<0.05), anaerobic threshold (AT) (r=0.836, P<0.05), HR in AT (r=0.748, P<0.05) and ranking (r=-0,924, P<0.05), mean HR and estimated VO(2) values represented, respectively 85.4+/-3.0% of maximal heart rate and 80.0+/-4.5% of maximal oxygen uptake. Mid values for [Lab] were observed at the end of crossing trial (5.2+/ 0.8 mmol L(-1)). CONCLUSION: This first analysis of freestyle kitesurfing suggests that the energy demand is sustained by both aerobic and anaerobic metabolism during a MW condition and freestyle event of kitesurfing. PMID- 21681169 TI - Acute effect of resistance training volume on hormonal responses in trained men. AB - AIM: The purpose of this study was to investigate the acute hormonal response to resistance training sessions with different volumes in men. METHODS: Ten recreationally trained men (24.5+/-7.6 years; 76.2+/-9.2 kg; 175.6+/-1.5 cm; 24.5+/-5.5 kg/m(-2)) participated in the study. All subjects completed two experimental protocols with different volumes. The first protocol consisted of 3 sets at 80% of 6 RM and the second protocol was 3 sets at 80% of 12 RM with 2 minutes rest between sets and exercises, separated by seven days between them. The exercise order used was: barbell bench press, leg press, machine front lat pull down, leg curl, shoulder abduction and leg extension. The blood variables analyzed were: testosterone, growth hormone (GH), cortisol and testosterone/cortisol ratio (T:C) before (Pre) and immediately after (Post) each exercise session. RESULTS: The intra-groups comparison for testosterone and hGH revealed a significant increase in 80%-6RM and 80%-12RM. Cortisol levels was significantly higher in 80%-12RM and T:C ratio in 80% 6 RM when compared Pre and Post values. Inter-groups comparison showed higher hGH and cortisol levels and lower T:C ratio for 80% 12 RM. There was no statistically significant different between 80%-6RM and 80%-12RM for testosterone. CONCLUSION: The present study confirms that the volume of resistance training can be an important factor in the modulation of acute hormonal responses. PMID- 21681170 TI - Immunoendocrine responses over a three week international rugby union series. AB - AIM: This study evaluated changes in immunoendocrine makers over an international series in professional rugby union players (N.=8). METHODS: Venous bloods were taken on camp-entry, as well as before and after (0, 14 and 38 h) two games spaced over 21-days. Samples were analysed for changes in serum C-reactive protein (CRP), cortisol (C), testosterone (T), blood leukocytes, interleukin 6 (IL-6) and creatine kinase (CK). RESULTS: Significant reductions in CK activity and CRP concentrations were evident on day 5 (pre-game 1) when compared to camp entry (day 1); P<0.05. A large acute-phase response was observed following both games. Differences in the magnitude of this response appeared dependant on the number of collisions players experienced during play. Compared to camp-entry, sharp increases in C (40%) and decreases (37%) in T were evident after both games; P<0.05. A gradual increase in T/C ratio was observed throughout the tournament; values 35% and 45% higher on days 19 and 21 than those observed at camp-entry (P<0.05). CONCLUSION: Current data suggests that improved physiological recovery can be achieved during an international rugby union series. Monitoring of previous club activity is essential to ensure optimal player readiness prior to participation in international rugby union games. PMID- 21681171 TI - Biological and psychological monitoring of training status during an entire season in top kayakers. AB - AIM: The aim of this study was to analyze changes in selected biological and psychological variables in a group of top level kayakers along a 42-week training season. METHODS: Eight top junior sprint kayakers (age=16.8+/-2.1) (5 men and 3 women) with international competitive experience participated in the research. During the 42-wk season the subjects were tested in three occasions: (T1) in the second week of the general training period, (T2) at the beginning of the specific training period, (T3) at the beginning of the competitive training period. Firstly, subjects were asked to complete the Recovery-Stress Questionnaire for Athletes (RESTQ-Sport) and the Profile of Mood States (POMS) questionnaires, and Borg's rate of perceived exertion scale (RPE). Immediately after, blood samples were collected and white blood cells, creatine kinase (CK), C-reactive protein (CRP), myeloperoxidase protein levels (MPO) and glutathione status were determined. ANOVA with repeated measures was used to determine the differences between tests. RESULTS: From the hematological and biochemical measures only total leukocytes changed significantly, increasing at T3 when compared to T1. There were no differences along the entire season in both RESTQ-Sport and POMS scores or indices. Concerning performance, the group improved their maximal strength (+17.4% in bench-press 1RM) and their specific-distance time (+9.8%). The main finding of the present study was that training was well-balanced between stress and recovery because while specific performance increased, signs of overtraining were not found. CONCLUSION: Training monitoring in athletes should be performed in a multilevel approach using measurements of performance as well as biological or psychological parameters. PMID- 21681172 TI - Interactions between adipose, bone, and muscle tissue markers during acute negative energy balance in male rowers. AB - AIM: The purpose of this investigation was to study the influence of prolonged low-intensity single scull rowing exercise on plasma adipocytokine and osteokine concentrations in trained male rowers. Nine single scull rowers (age: 20.1+/-1.6 yrs; height: 184.1+/-4.6 cm; body mass: 81.2+/-5.3 kg; %body fat: 11.1+/-3.9) participated in this study. METHODS: Venous blood samples were obtained before and after a ~2 h constant load on-water sculling training session (distance: 20.6+/-1.5 km; HR: 133+/-4 bpm; intensity: 80.3+/-1.7% of the HR turn-point). RESULTS: The training session created an energy deficit of 1 200-1 500 kcal. Plasma adiponectin increased (+12.2%; P<0.05) while leptin decreased (-23.1%; P<0.05) at 30 min postexercise. Plasma osteocalcin (+23.7%; P<0.05) and type I carboxyterminal telopeptide (ICTP) (+28.6%; P<0.05) were increased on completion of the training session. Plasma IL-6 concentration was increased (P<0.05) about four-fold while insulin concentration was decreased (P<0.05) more than three-fold upon completion of exercise. There were no differences in TNF-alpha, glucose, testosterone and cortisol concentrations over time. Plasma adiponectin (r=0.59) and osteocalcin (r=0.57) concentrations measured immediately after the training session were related (P<0.05) to the distance covered. CONCLUSION: Acute negative energy balance induced by a single endurance rowing training session elicited an inverse metabolic response in adiponectin and osteocalcin concentrations in male rowers. Our results suggest that peripheral markers of negative energy balance, such as adiponectin and osteocalcin, may serve as signals for metabolic reaction to the energy cost of acute exercise in athletes. PMID- 21681173 TI - Physical activity levels of high school students --- United States, 2010. AB - Healthy People 2020 (HP 2020), released in December 2010, outlines numerous public health objectives, including objectives for youth physical activity participation (1). HP 2020 includes three objectives for meeting current federal physical activity guidelines for 1) aerobic physical activity (participation in >=60 minutes of aerobic activity per day, 7 days per week) (PA 3.1); 2) muscle strengthening activity (muscle-strengthening activities on >=3 days per week) (PA 3.2); and 3) aerobic physical activity and muscle-strengthening activity combined (PA 3.3) (1,2). The HP 2020 target for PA 3.1 is 20.2%; targets for PA 3.2 and PA 3.3 are not set because baseline data are not available. To meet the HP 2020 targets for physical activity, promotion of physical activity among female high school students (3), high school students in upper grades (3), and youths with obesity (4) might be warranted, given that these subpopulations are at risk for low levels of physical activity. To determine the proportion of U.S. youths who meet these HP 2020 objectives, CDC analyzed data from the 2010 National Youth Physical Activity and Nutrition Study (NYPANS), a school-based study conducted by CDC that included height and weight measurements and a survey that measured physical activity and dietary behaviors among a nationally representative sample of students in grades 9--12. This report summarizes the results of that analysis, which indicated that among students nationwide in grades 9--12, 15.3% met the aerobic objective, 51.0% met the muscle-strengthening objective, and 12.2% met the objective for both aerobic and muscle-strengthening activities. To improve youth physical activity participation, efforts are needed among CDC, state and local public health agencies, schools, and other public health partners that promote physical activity. PMID- 21681174 TI - Beverage consumption among high school students --- United States, 2010. AB - Milk and 100% fruit juice are a source of water and provide key nutrients such as calcium and vitamin C (1). Other beverages, referred to as sugar drinks or sugar sweetened beverages (SSBs), also are a source of water but have poor nutritional value. SSBs are the largest source of added sugars in the diet of U.S. youths, and the increased caloric intake resulting from these beverages is one factor contributing to the prevalence of obesity among adolescents in the United States (2,3). To determine the extent to which U.S. adolescents consume different types of beverages and variations in consumption by sex and race/ethnicity, CDC analyzed data from the 2010 National Youth Physical Activity and Nutrition Study (NYPANS). NYPANS included a school-based survey conducted by CDC that measured physical activity and dietary behaviors among a nationally representative sample of students in grades 9--12. This analysis indicated that, although water, milk, and 100% fruit juice were the beverages consumed most commonly during the 7 days before the survey, 24.3% of high school students drank a serving (e.g., can, bottle, or glass) of regular soda or pop, 16.1% drank a serving of a sports drink, and 16.9% drank a serving of another SSB one or more times per day during the same period. For all SSBs, male students were more likely than female students, and black students were more likely than white students and Hispanic students to report drinking these beverages one or more times per day. Families, schools, and youth-oriented institutions should limit SSBs among all adolescents while ensuring their access to more healthful beverages. Targeted efforts are especially needed to reduce consumption of SSBs among male and black adolescents. PMID- 21681175 TI - Place of influenza vaccination among adults --- United States, 2010-11 influenza season. AB - The 2010-11 influenza season was the first season after the 2009 influenza A (H1N1) pandemic and the first season that the Advisory Committee on Immunization Practices (ACIP) recommended influenza vaccination for all persons aged >=6 months (1). During the pandemic, many new partnerships between public health agencies and medical and nonmedical vaccination providers were formed, increasing the number of vaccination providers (2). To provide a baseline for places where adults received influenza vaccination since the new ACIP recommendation and to help vaccination providers plan for the 2011-12 influenza season, CDC analyzed information from 46 states and the District of Columbia (DC) on influenza vaccination of adults aged >=18 years for the 2010-11 season, collected during January-March 2011 by the Behavioral Risk Factor Surveillance System (BRFSS). This report summarizes the results of that analysis, which found that, for adults overall, a doctor's office was the most common place (39.8%) for receipt of the 2010-11 influenza vaccine, with stores (e.g., supermarkets or drug stores) (18.4%) and workplaces (17.4%) the next most common. For those aged 18-49 years and 50-64 years, a workplace was the second most common place of vaccination (25.7% and 21.1%, respectively). Persons aged >=65 years who were not vaccinated at a doctor's office were most likely (24.3%) to have been vaccinated at a store. The results indicate that both medical and nonmedical settings are common places for adults to receive influenza vaccinations, that a doctor's office is the most important medical setting, and that workplaces and stores are important nonmedical settings. PMID- 21681176 TI - Notes from the field: hantavirus pulmonary syndrome --- Maine, April 2011. AB - On April 25, 2011, the Maine Center for Disease Control and Prevention was notified of a suspected case of hantavirus pulmonary syndrome (HPS) in a man aged 70 years with no recent out-of-state travel. The Maine resident went to a community hospital in early April with a 5-day history of fatigue, decreased appetite, weakness, chills, myalgias, and progressive shortness of breath. On examination, he was hypoxic and tachypneic. The patient was admitted with laboratory evidence of acute renal insufficiency, leukocytosis and thrombocytopenia, and appearance of diffuse bilateral infiltrates on chest radiograph. Two days later, he was transferred to a tertiary-care facility for management of respiratory failure with hypoxemia and worsening renal insufficiency. The next day, he was intubated and mechanically ventilated. Serum specimens demonstrated high titers of hantavirus reactive immunoglobulin M (1:6,400) and immunoglobulin G (1:1,600) antibodies. Hantavirus RNA was detected in the patient's blood. The patient was discharged to a skilled nursing facility 1 month after admission and is recovering with extensive rehabilitation. PMID- 21681177 TI - Ultrasound for the assessment of bone quality in preterm and term infants. AB - OBJECTIVE: As 80% of intrauterine bone mineralization takes place during the last trimester of pregnancy, preterm infants should be supplemented postnatally with optimal doses of calcium, phosphate and vitamin D. Calcium and phosphate excretion in the urine may be used to monitor individual mineral requirements, but are sometimes difficult to interpret. The objective of this study was to assess the value of quantitative ultrasound (QUS) for the analysis of bone status in neonates. STUDY DESIGN: All admissions to three independent tertiary neonatal intensive care units were studied. In 172 preterm and term infants with a gestational age between 23 and 42 weeks (mean 33.8+/-5.0) and a birth weight from 405 to 5130 g (mean 2132+/-1091 g) bone status was evaluated prospectively by quantitative ultrasound velocity using a standardized protocol. Infants were followed in regular intervals up to their first discharge home. While measurements were conducted in weekly intervals initially (n=55), 2-week intervals were regarded as sufficient thereafter due to limited changes in QUS values within the shorter period. Infants with a birth weight below 1500 g were followed during outpatient visits until up to 17 months of age. RESULT: The intra individual day-to-day reproducibility was 0.62%. QUS-values from the first week of life correlated significantly with gestational age and birth weight (r=0.5 and r=0.6; P<0.001). Small-for-gestational-age infants showed lower values for QUS than appropriate-for-gestational-age infants allowing for their gestational age. Follow-up measurements correlated positively with age and weight during the week of measurement (r=0.2 and r=0.4; P=0.001). Comparing bone quality at 40 weeks of age in infants born at term versus infants born at 24 to 28 weeks, preterm infants showed significantly lower QUS than term infants (P<.0001).There was a significant correlation of QUS with serum alkaline phosphatase (P=0.003), the supplementation with calcium, phosphate and vitamin D (P< 0.001 each), as well as risk factors for a reduced bone mineralization. No correlation was found between QUS and calcium or phosphate concentration in serum or urine. CONCLUSION: QUS is a highly reproducible, easily applicable and radiation-free technique that can be used to monitor bone quality in individual newborns. Further prospective randomized-trials are necessary to evaluate, if therapeutic interventions based on QUS are able to prevent osteopenia of prematurity. PMID- 21681178 TI - Serum mannose-binding lectin (MBL) gene polymorphism and low MBL levels are associated with neonatal sepsis and pneumonia. AB - OBJECTIVE: The aim of this study was to determine the serum mannose-binding lectin (MBL) levels and the frequency of MBL gene polymorphisms in infants with neonatal sepsis. STUDY DESIGN: Between January 2008 and January 2010, a total of 93 infants were included in this study and 53 of them had neonatal sepsis diagnosis as study group and 40 infants who had no sepsis according to clinical and laboratory findings as control group. RESULT: Serum MBL levels were found to be low in 17 of 93 infants. Eleven of them were in the sepsis group and six of them were in the control group. Serum MBL levels were significantly lower in infants with sepsis compared with the control group. Frequencies of genotype AB and BB were also significantly higher in the study group compared with the control group. Most importantly, presence of B allele of MBL exon 1 gene was found to be associated with an increased risk for neonatal sepsis. Additionally, in the study group, the mean serum MBL levels were found to be significantly lower in the premature infants compared with the term infants. Pneumonia, bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) were significantly higher in infants with MBL deficiency compared with infants with normal MBL levels. CONCLUSION: Low MBL levels and presence of B allele of MBL exon 1 gene were found to be important risk factors for development of both neonatal sepsis and pneumonia, especially in premature infants. Low MBL levels and MBL gene polymorphisms might also be associated with inflammation-related neonatal morbidities such as BPD and IVH. PMID- 21681179 TI - Effect of maternal weight on postterm delivery. AB - OBJECTIVE: Examine the effect of prepregnancy weight and maternal gestational weight gain on postterm delivery rates. STUDY DESIGN: This was a retrospective cohort study of term, singleton births (N=375 003). We performed multivariable analyses of the association between postterm pregnancy and both prepregnancy body mass index (BMI) and maternal weight gain. RESULT: Prolonged or postterm delivery (41 or 42 weeks) was increasingly common with increasing prepregnancy weight (P<0.001) and increasing maternal weight gain (P<0.001). Underweight women were 10% less likely to deliver postterm than normal weight women who gain within the recommendations (adjusted odds ratio 0.90 (95% confidence interval 0.83, 0.97)). Overweight women who gain within or above recommendations were also at increased risk of a 41-week delivery. Finally, obese women were at increased risk of a 41 week delivery with increasing risk with increasing weight (below, within and above recommendations adjusted odds ratios 1.19, 1.21, and 1.27, respectively). CONCLUSION: Elevated prepregnancy weight and maternal weight gain both increase the risk of a postterm delivery. Although most women do not receive preconceptional care, restricting weight gain to the within the recommended range can reduce the risk of postterm pregnancy in normal, overweight and obese women. PMID- 21681180 TI - Perinatal morbidity and mortality in late-term and post-term pregnancy. NEOSANO perinatal network's experience in Mexico. AB - OBJECTIVE: The objective of this study is to identify adverse perinatal outcomes associated with pregnancies at or beyond 40 weeks. STUDY DESIGN: Retrospective cohort study conducted in Mexico, with information obtained from the NEOSANO's Perinatal Network Database from April 2006 to April 2009. Multiple births, babies with inaccurate gestational age or babies with congenital malformations were excluded. Logistic regression models were used to analyze perinatal complications associated with pregnancies >= 40 weeks. RESULT: A total of 21 275 babies were analyzed; of these, 4545 (21.3%) were of 40 to 40[frac67] weeks, 3024 (14.2%) 41 to 41[frac67] weeks and 388 (1.8%) 42 to 44 weeks of gestation. Adverse perinatal outcomes associated with 40 to 40[frac67] weeks deliveries were (odds ratio; 95% confidence interval): macrosomia (1.9; 1.5 to 2.6), acute fetal distress (1.4; 1.2 to 1.7), emergency cesarean delivery (1.4; 1.2 to 1.5) and chorioamnionitis (1.4; 1.2 to 1.6). Adverse perinatal outcomes associated with 41 to 41[frac67] weeks were macrosomia (2.5; 1.8 to 3.3), chorioamnionitis (2; 1.7 to 2.3), emergency cesarean delivery (1.8; 1.6 to 2.1) and acute fetal distress (1.4; 1.1 to 1.7). Adverse perinatal outcomes associated with 42 to 44 weeks were macrosomia (7; 4.6 to 10.7), meconium aspiration syndrome (5.6; 2.8 to 11.2), neonatal death (4.8; 1.7 to 13.8), stillbirth (4.3; 1.4 to 13.5), 5' Apgar <4 (4.2; 1.1 to 15.7), chorioamnionitis (2.8; 2.2 to 3.9), admission to neonatal intensive care unit (2.7; 1.5 to 4.8), admission to neonatal intensive care unit or step-down unit (2.4; 1.5 to 3.9), acute fetal distress (1.8; 1.2 to 2.6) and emergency cesarean delivery (1.8; 1.3 to 2.4). CONCLUSION: An increased risk for perinatal and maternal complications were detected as early as 40 weeks' gestation. The risks of stillbirth and neonatal death were significantly higher in the post-term group than the control group. PMID- 21681182 TI - Augmentation index for stratifying progression of chronic kidney disease. PMID- 21681183 TI - Panvascular dysfunction in hypertrophic cardiomyopathy. PMID- 21681184 TI - The role of aortic elastic properties in prognosis of patients with acute heart failure. PMID- 21681185 TI - Emerging benefits of AT1 receptor antagonists with pleiotropic anti-inflammatory activity. PMID- 21681189 TI - Standardization of DNA isolation from low cell numbers for chimerism analysis by PCR of short tandem repeats. AB - Analysis of short tandem repeats (STR) by PCR analysis is routinely used in chimerism diagnostics to monitor donor engraftment and to diagnose relapse. Some applications require chimerism analysis of low cell numbers, but no standardized protocol is available for DNA isolation from 1000 to 30,000 cells. The EU supported EuroChimerism Consortium (project QLRT-2001-01485) selected four different protocols for 'small-scale' DNA isolation, which were tested by six laboratories for their ability to recover reproducible amounts of good quality DNA, suited for PCR-based STR analysis. The protocols included two direct lysis methods with and without detergents and proteinase K, and two commercial column based kits. The direct lysis method using detergents and proteinase K showed the highest DNA recovery and the best performance in the multiplex PowerPlex16 STR assay. DNA isolated with this method also showed the highest sensitivity in chimerism analysis using singleplex PCR reactions of EuroChimerism STR markers. Sensitivity was reached ranging from 1 to 20% of recipient cells in a donor background. In conclusion, the direct lysis method using detergents and proteinase K is a standardized DNA isolation method well suited for chimerism studies on low cell numbers. PMID- 21681188 TI - The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice. AB - The t(10;11)(p13-14;q14-21) translocation, giving rise to the CALM-AF10 fusion gene, is a recurrent chromosomal rearrangement observed in patients with poor prognosis acute myeloid leukemia (AML). Although splicing of the CALM-AF10 fusion transcripts has been described in AML patients, the contribution of different CALM and AF10 domains to in vivo leukemogenesis remains to be defined. We therefore performed detailed structure-function studies of the CALM-AF10 fusion protein. We demonstrate that fusion of the C-terminal 248 amino acids of CALM, which include the clathrin-binding domain, to the octapeptide motif-leucine zipper (OM-LZ) domain of AF10 generated a fusion protein (termed CALM-AF10 minimal fusion (MF)), with strikingly enhanced transformation capabilities in colony assays, providing an efficient system for the expeditious assessment of CALM-AF10-mediated transformation. Leukemias induced by the CALM-AF10 (MF) mutant recapitulated multiple aspects of full-length CALM-AF10-induced leukemia, including aberrant Hoxa cluster upregulation, a characteristic molecular lesion of CALM-AF10 leukemias. In summary, this study indicates that collaboration of the clathrin-binding and the OM-LZ domains of CALM-AF10 is sufficient to induce AML. These findings further suggest that future approaches to antagonize CALM AF10-induced transformation should incorporate strategies, which aim at blocking these key domains. PMID- 21681190 TI - Rare germline variants in regions of loss of heterozygosity may influence clinical course of hematological malignancies. PMID- 21681191 TI - The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories. AB - Massively parallel pyrosequencing allows sensitive deep sequencing to detect molecular aberrations. Thus far, data are limited on the technical performance in a clinical diagnostic setting. Here, we investigated as an international consortium the robustness, precision and reproducibility of amplicon next generation deep sequencing across 10 laboratories in eight countries. In a cohort of 18 chronic myelomonocytic leukemia patients, mutational analyses were performed on TET2, a frequently mutated gene in myeloproliferative neoplasms. Additionally, hotspot regions of CBL and KRAS were investigated. The study was executed using GS FLX sequencing instruments and the small volume 454 Life Sciences Titanium emulsion PCR setup. We report a high concordance in mutation detection across all laboratories, including a robust detection of novel variants, which were undetected by standard Sanger sequencing. The sensitivity to detect low-level variants present with as low as 1-2% frequency, compared with the 20% threshold for Sanger-based sequencing is increased. Together with the output of high-quality long reads and fast run time, we demonstrate the utility of deep sequencing in clinical applications. In conclusion, this multicenter analysis demonstrated that amplicon-based deep sequencing is technically feasible, achieves high concordance across multiple laboratories and allows a broad and in-depth molecular characterization of cancer specimens with high diagnostic sensitivity. PMID- 21681192 TI - Immunophenotype-defined sub-populations are common at diagnosis in childhood B cell precursor acute lymphoblastic leukemia. PMID- 21681194 TI - Cancer research: India meets the West. PMID- 21681193 TI - Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling. AB - Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer. PMID- 21681195 TI - Asthma and allergy: influenza virus and an innate form of asthma. PMID- 21681196 TI - Mucosal immunology: inflammasome shapes the microbiota. PMID- 21681198 TI - Innate immunity: an inducible RNA sensor? IFITs the bill. PMID- 21681197 TI - The light and dark sides of intestinal intraepithelial lymphocytes. AB - The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance. PMID- 21681199 TI - The role of trimerization in the osmoregulated betaine transporter BetP. AB - The osmoregulated betaine transporter BetP is a stable trimer. Structural studies have shown that individual protomers can adopt distinct transport conformations, implying a functional role for the trimeric state in transport, although the role of trimerization in regulation is not yet understood. We designed putative monomeric mutants by molecular-dynamics simulations and in silico alanine scanning mutagenesis. Several mutants including BetP-W101A/T351A were monomeric in detergent as well as in the membrane, as shown by blue native gel electrophoresis, crosslinking and electron microscopy. This monomeric form retains the ability to accumulate betaine, but is no longer regulated by hyperosmotic shock. PMID- 21681200 TI - Prediction of amyloid aggregation in vivo. AB - Many human diseases owe their pathology, to some degree, to the erroneous conversion of proteins from their soluble state into fibrillar, beta-structured aggregates, often referred to as amyloid fibrils. Neurodegenerative diseases, such as Alzheimer and spongiform encephalopathies, as well as type 2 diabetes and both localized and systemic amyloidosis, are among the conditions that are associated with the formation of amyloid fibrils. Several mathematical tools can rationalize and even predict important parameters of amyloid fibril formation. It is not clear, however, whether such algorithms have predictive powers for in vivo systems, in which protein aggregation is affected by the presence of other biological factors. In this review, we briefly describe the existing algorithms and use them to predict the effects of mutations on the aggregation of specific proteins, for which in vivo experimental data are available. The comparison between the theoretical predictions and the experimental data obtained in vivo is shown for each algorithm and experimental data set, and statistically significant correlations are found in most cases. PMID- 21681201 TI - Environmental epigenomics and disease susceptibility. AB - The Keystone symposium on 'Environmental Epigenomics and Disease Susceptibility' was held in late March 2011 at the Grove Park Inn Resort in Asheville, North Carolina, USA. The meeting helped to define the developing field of 'environmental epigenetics' and the research presented established its role in disease aetiology and susceptibility. PMID- 21681202 TI - The brain, the science and the media. The legal, corporate, social and security implications of neuroimaging and the impact of media coverage. PMID- 21681203 TI - A new postal code for dendritic mRNA transport in neurons. PMID- 21681204 TI - Dosage adds new dimension. PMID- 21681205 TI - Disease genetics: converging models for autism. PMID- 21681207 TI - Complex disease: ups and downs at the MHC. PMID- 21681208 TI - Unexpected mismatches, but dogma intact. PMID- 21681209 TI - Beyond DNA: integrating inclusive inheritance into an extended theory of evolution. AB - Many biologists are calling for an 'extended evolutionary synthesis' that would 'modernize the modern synthesis' of evolution. Biological information is typically considered as being transmitted across generations by the DNA sequence alone, but accumulating evidence indicates that both genetic and non-genetic inheritance, and the interactions between them, have important effects on evolutionary outcomes. We review the evidence for such effects of epigenetic, ecological and cultural inheritance and parental effects, and outline methods that quantify the relative contributions of genetic and non-genetic heritability to the transmission of phenotypic variation across generations. These issues have implications for diverse areas, from the question of missing heritability in human complex-trait genetics to the basis of major evolutionary transitions. PMID- 21681210 TI - Towards systematic functional characterization of cancer genomes. AB - Whole-genome approaches to identify genetic and epigenetic alterations in cancer genomes have begun to provide new insights into the range of molecular events that occurs in human tumours. Although in some cases this knowledge immediately illuminates a path towards diagnostic or therapeutic implementation, the bewildering lists of mutations in each tumour make it clear that systematic functional approaches are also necessary to obtain a comprehensive molecular understanding of cancer. Here we review the current range of methods, assays and approaches for genome-scale interrogation of gene function in cancer. We also discuss the integration of functional-genomics approaches with the outputs from cancer genome sequencing efforts. PMID- 21681211 TI - Genome-wide genetic marker discovery and genotyping using next-generation sequencing. AB - The advent of next-generation sequencing (NGS) has revolutionized genomic and transcriptomic approaches to biology. These new sequencing tools are also valuable for the discovery, validation and assessment of genetic markers in populations. Here we review and discuss best practices for several NGS methods for genome-wide genetic marker development and genotyping that use restriction enzyme digestion of target genomes to reduce the complexity of the target. These new methods -- which include reduced-representation sequencing using reduced representation libraries (RRLs) or complexity reduction of polymorphic sequences (CRoPS), restriction-site-associated DNA sequencing (RAD-seq) and low coverage genotyping -- are applicable to both model organisms with high-quality reference genome sequences and, excitingly, to non-model species with no existing genomic data. PMID- 21681212 TI - The additional value of blood culture bottles in the diagnosis of endophthalmitis. AB - PURPOSE: To assess the additional value of blood culture bottles (BCBs) in the diagnosis of endophthalmitis by comparing its culture yield with that of conventional media (CM). DESIGN: Retrospective consecutive case series. METHODS: We included patients who were treated between January 2001 and January 2010 for clinically suspected endophthalmitis of any etiology, and had vitreous specimens cultivated in both BCB and CM. RESULTS: Specimens from 85 eyes from 85 patients were included. The culture yield of BCB was 69%, and that of CM was 72% (difference not significant). Adding the results of BCB improved the yield of CM significantly by 13%, resulting in a combined yield of 81%. The sensitivity of detection of Haemophilus influenzae in BCB seemed lower compared with CM, possibly due to the lack of growth factors in the BCB. There was no difference in yield between specimens obtained by tap or by vitrectomy. CONCLUSION: In contrast with earlier reports, we did not find BCB superior to CM. The combined use of BCB and CM increased the pathogen detection rate significantly and should therefore be considered as the microbiological method of choice in the work-up of endophthalmitis. PMID- 21681213 TI - Recent trends in the rate of trabeculectomy in England. PMID- 21681215 TI - Patients attending eye clinic have poor left right discrimination. PMID- 21681214 TI - Trypan blue dye for anterior segment surgeries. AB - Use of vital dyes in ophthalmic surgery has gained increased importance in the past few years. Trypan blue (TB) has been a popular choice among anterior segment surgeons mainly due to its safety, ease of availability, and remarkable ability to enable an easy surgery in difficult situations mostly related to visibility of the targeted tissue. It is being used in cataract surgery since nearly a decade and its utilization has been extended to other anterior segment surgeries like trabeculectomy and corneal transplantation. This review will discuss the techniques and outcome of TB dye-assisted anterior segment surgeries. PMID- 21681216 TI - Predictive factor and kappa angle analysis for visual satisfactions in patients with multifocal IOL implantation. AB - PURPOSE: To evaluate the visual acuity and quality-related satisfaction of patients implanted with a refractive design multifocal intraocular lens (IOL), and evaluate the factors predicting it including angle kappa. SETTING: Dr Agarwal's Eye Hospital and Eye Research Centre, Chennai. METHODS: In this prospective trial, 50 eyes of 44 consecutive patients were included. All patients underwent phacoemulsification with multifocal IOL implantation (Rezoom IOL, Abbott Medical Optics). The preoperative and postoperative assessment included slit lamp biomicroscopy, uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA) and kappa angle assessment. At 1 year, 37 patients (43 eyes), who finished follow-up, were asked to rate their symptoms on a graded questionnaire (0-5 for five queries). RESULTS: The decimal scores for UCVA and BCVA were 0.38+/ 0.21 and 0.47+/-0.17 (preoperative), and 0.75+/-0.22 and 0.99+/-0.11 (postoperative), respectively. Symptom scores were haloes 0.98+/-1.7, glare 0.69+/-1.48, blurred distance 1.0+/-1.7, intermediate 1.34+/-1.6, near 1.06+/ 1.8. On regression analysis haloes depended on angle kappa and distance UCVA (R (2)=0.26, P=0.029), and glare on angle kappa (R (2)=0.26, P=0.033). Poor satisfactions with distance, intermediate, and near vision were linked with distance UCVA (R (2)=0.17, P=2.3 * 10(-4)), distance UCVA (R (2)=0.1, P=0.04), and near UCVA (R (2)=0.12, P=0.03), respectively. The strongest predictor, however, for overall visual discomfort was distance UCVA (R (2)=0.1, P=0.04). CONCLUSIONS: Our study suggests that there may be a role of misalignment between the visual and pupillary axis (angle kappa) in the occurrence of photic phenomenon after refractive multifocal IOL implantation. PMID- 21681217 TI - A therapeutic challenge in AIDS-associated viral retinitis. PMID- 21681218 TI - Anterior lens capsule has more affinity to trypan blue in patients with pseudoexfoliation. PMID- 21681219 TI - AlphaCor artificial cornea: clinical outcome. AB - PURPOSE: The purpose of this study was to describe the long-term results of AlphaCor implantations, and to evaluate the main complications and risk factors. METHODS: Retrospective analysis of preoperative and follow-up data from 15 AlphaCor implantations. Analysis of outcomes, trends, and associations was performed and compared with data from published clinical trials and a literature review. RESULTS: The survival rate of the device at 1, 2, and 3 years was 87%, 58%, and 42%, respectively. Postoperative visual acuity ranged from hand movement to 0.8. The most significant complications were stromal melt (nine cases), optic deposition (three eyes), and retroprosthetic membrane formation (three eyes). The most common device-unrelated complication was trauma (three patients). All complications were managed without loss of the eye. CONCLUSION: AlphaCor provides a treatment option for patients with corneal blindness in which a donor tissue graft would not succeed. PMID- 21681220 TI - Direct cytotoxicity produced by adenoviral-mediated interferon alpha gene transfer in interferon-resistant cancer cells involves ER stress and caspase 4 activation. AB - Over the past several years we have obtained considerable evidence indicating that adenoviruses-expressing interferon alpha (Ad-IFNalpha) can overcome resistance to the IFNalpha protein itself. Since cancer cells infected with Ad IFNalpha also show high perinuclear cytoplasmic IFNalpha expression, we were interested in whether endoplasmic reticulum (ER) stress and cleavage of caspase 4 could have a major role in Ad-IFNalpha-produced cancer cell death. Indeed, procaspase 4 was upregulated and cleaved as early as 12 h after Ad-IFNalpha infection of the cancer cells, which co-localized with IFNalpha staining and ER tracker. In contrast, immortalized normal human urothelial cells, although exhibiting similar perinuclear IFNalpha staining, showed no cleaved caspase 4. Caspase 4 cleavage was not blocked by the caspase 8 specific inhibitor zIETD, indicating that caspase 4 activation was independent of caspase 8 activation. Blocking caspase 4 also inhibited activation of caspase 3 in Ad-IFNalpha containing cells. Finally, the cleaved form of caspase 4 (p10) was detected in Ad IFNalpha-positive cancer cells from the urine of a patient following intravesical Ad-IFNalpha/Syn3 treatment. Therefore, ER stress and activation of caspase 4 appears to be an important mechanism involved in the direct cancer cell death produced by Ad-IFNalpha and also occurs in the clinical setting. PMID- 21681222 TI - State- and payer-specific estimates of annual medical expenditures attributable to obesity. AB - The goal of this study is to expand prior analyses by presenting current state level estimates of the costs of obesity in total and separately for Medicare and Medicaid. Quantifying current Medicare and Medicaid expenditures attributable to obesity is important because high public sector costs of obesity have been a primary motivation for publicly funded obesity prevention efforts at the state level. We also present estimates of the obesity-attributable fraction (OAF) of total, Medicare, and Medicaid expenditures and the percentage of total obesity costs within each state that is funded by the public sector. We used the 2006 Medical Expenditure Panel Survey, nationally representative data that include information on obesity and medical expenditures, to generate an equation that predicts annual medical expenditures as a function of obesity status. We used the 2006 Behavioral Risk Factor Surveillance System, state representative data, and the equation generated from the national model to predict state (and payer within state) expenditures and the fraction of expenditures attributable to obesity for each state. Across states, annual medical expenditures would be between 6.7 and 10.7% lower in the absence of obesity. Between 22% (Virginia) and 55% (Rhode Island) of the state-level costs of obesity are financed by the public sector via Medicare and Medicaid. The high costs of obesity at the state level emphasize the need to prevent and control obesity as a way to manage state medical costs. PMID- 21681221 TI - Attentional bias to food images associated with elevated weight and future weight gain: an fMRI study. AB - Behavioral studies reveal that obese vs. lean individuals show attentional bias to food stimuli. Yet research has not investigated this relation using objective brain imaging or tested whether attentional bias to food stimuli predicts future weight gain, which are important aims given the prominence of food cues in the environment. We used functional magnetic resonance imaging (fMRI) to examine attentional bias in 35 adolescent girls ranging from lean to obese using an attention network task involving food and neutral stimuli. BMI correlated positively with speed of behavioral response to both appetizing food stimuli and unappetizing food stimuli, but not to neutral stimuli. BMI correlated positively with activation in brain regions related to attention and food reward, including the anterior insula/frontal operculum, lateral orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC), and superior parietal lobe, during initial orientation to food cues. BMI also correlated with greater activation in the anterior insula/frontal operculum during reallocation of attention to appetizing food images and with weaker activation in the medial OFC and ventral pallidum during reallocation of attention to unappetizing food images. Greater lateral OFC activation during initial orientation to appetizing food cues predicted future increases in BMI. Results indicate that overweight is related to greater attentional bias to food cues and that youth who show elevated reward circuitry responsivity during food cue exposure are at increased risk for weight gain. PMID- 21681223 TI - A new BIA equation estimating the body composition of young children. AB - Bioelectric impedance analyses (BIA) provides a valid and reliable measure of body composition in field, clinical, and research settings if standard protocol procedures are followed, and population-specific equations are available and utilized. The objective of this study was to create and cross-validate a new BIA body composition equation with representative healthy weight (HW), overweight (OW), and obese (OB) young children. Participants were 436 children who were 5-11 years of age. Dual-energy absorptiometry fat-free mass (FFM) was used as the criterion measure and a single frequency tetra-polar BIA device was used to create the new BIA equation. The new BIA equation explained 95.2% of the variance in FFM with no statistical shrinkage upon cross-validation. The use of this equation may help to identify effective intervention strategies to prevent or combat childhood obesity, and may assist in additional conditions or treatments where information concerning body composition measures would provide greater accuracy and sensitivity measures for preventing or combating disease. PMID- 21681224 TI - Lifestyle factors and 5-year abdominal fat accumulation in a minority cohort: the IRAS Family Study. AB - The objective of this study was to examine whether lifestyle factors were associated with 5-year change in abdominal fat measured by computed tomography (CT) in the Insulin Resistance and Atherosclerosis (IRAS) Family Study. We obtained abdominal CT scans at baseline and at 5 years, from African Americans (AA) (N = 339) and Hispanic Americans (N = 775), aged 18-81 years. Visceral (VAT) and subcutaneous (SAT) adipose tissue was measured at the L4/L5 vertebral level. Physical activity was documented by self-report of vigorous activity and a 1-year recall instrument. Dietary intake was assessed at follow-up using a semi quantitative food frequency questionnaire referencing the previous year. Generalized linear models, accounting for family structure, were used to assess the associations between percent change in fat accumulation and smoking, physical activity, total calories, polyunsaturated, monounsaturated, protein, and saturated fat intake, percent of calories from sweets, and soluble and insoluble fiber. Soluble fiber intake and participation in vigorous activity were inversely related to change in VAT, independent of change in BMI. For each 10 g increase in soluble fiber, rate of VAT accumulation decreased by 3.7% (P = 0.01). Soluble fiber was not associated with change in SAT (0.2%, P = 0.82). Moderately active participants had a 7.4% decrease in rate of VAT accumulation and a 3.6% decrease in rate of SAT accumulation versus less active participants (P = 0.003 and P = 0.01, respectively). Total energy expenditure was also inversely associated with accumulation of VAT. Soluble fiber intake and increased physical activity were related to decreased VAT accumulation over 5 years. PMID- 21681226 TI - High-volume exercise program in obese bariatric surgery patients: a randomized, controlled trial. AB - Weight regain is a problem among many bariatric surgery patients. Whether a high volume exercise program (HVEP), a strategy to limit weight regain, is feasible in these patients is unknown. The feasibility of an HVEP in obese post-bariatric surgery patients was determined by randomizing 33 Roux-en-Y gastric bypass (RYGB) and gastric banding (GB) surgery patients with a mean BMI of 41 +/- 6 kg/m2 to an HVEP or control group for 12 weeks. The HVEP group was instructed to expend >= 2,000 kcal/week in moderate-intensity exercise. All patients were counseled to limit energy intake. Treatment effect was assessed by repeated measures analysis. During the last 4 weeks of the study, 53% of the HVEP group expended >= 2,000 kcal/week and 82% expended >= 1,500 kcal/week. Step count, reported time spent and energy expended during moderate physical activity, maximal oxygen consumption relative to weight, and incremental area under the postprandial blood glucose curve were significantly improved over 12 weeks in the HVEP group compared to controls (group-by-week effect: P = 0.009-0.03). Both groups reported significant improvement in some quality-of-life scales. Changes in weight, energy and macronutrient intake, resting energy expenditure (REE), fasting lipids and glucose, and fasting and postprandial insulin concentrations were not different between the two groups. HVEP is feasible in about 50% of the patients and enhances physical fitness and reduces postprandial blood glucose in bariatric surgery patients. PMID- 21681225 TI - Role of skeletal muscle mitochondrial density on exercise-stimulated lipid oxidation. AB - Reduced skeletal muscle mitochondrial density is proposed to lead to impaired muscle lipid oxidation and increased lipid accumulation in sedentary individuals. We assessed exercise-stimulated lipid oxidation by imposing a prolonged moderate intensity exercise in men with variable skeletal muscle mitochondrial density as measured by citrate synthase (CS) activity. After a 2-day isoenergetic high-fat diet, lipid oxidation was measured before and during exercise (650 kcal at 50% VO(2)max) in 20 healthy men with either high (HI-CS = 24 +/- 1; mean +/- s.e.) or low (LO-CS = 17 +/- 1 nmol/min/mg protein) muscle CS activity. Vastus lateralis muscle biopsies were obtained before and immediately after exercise. Respiratory exchange data and blood samples were collected at rest and throughout the exercise. HI-CS subjects had higher VO(2)max (50 +/- 1 vs. 44 +/- 2 ml/kg fat free mass/min; P = 0.01), lower fasting respiratory quotient (RQ) (0.81 +/- 0.01 vs. 0.85 +/- 0.01; P = 0.04) and higher ex vivo muscle palmitate oxidation (866 +/- 168 vs. 482 +/- 78 nmol/h/mg muscle; P = 0.05) compared to LO-CS individuals. However, whole-body exercise-stimulated lipid oxidation (20 +/- 2 g vs. 19 +/- 1 g; P = 0.65) and plasma glucose, lactate, insulin, and catecholamine responses were similar between the two groups. In conclusion, in response to the same energy demand during a moderate prolonged exercise bout, reliance on lipid oxidation was similar in individuals with high and low skeletal muscle mitochondrial density. This data suggests that decreased muscle mitochondrial density may not necessarily impair reliance on lipid oxidation over the course of the day since it was normal under a high-lipid oxidative demand condition. Twenty four-hour lipid oxidation and its relationship with mitochondrial density need to be assessed. PMID- 21681228 TI - Birth weight and subsequent adiposity gain in Swedish children and adolescents: a 6-year follow-up study. AB - We examined whether birth weight (BW) predicts changes in body composition over a 6-year period in Swedish children and adolescents. For this purpose, a total of 247 children (55.5% girls) and 162 adolescents (60.5% girls) were included in the study and were followed up 6 years later. BW was obtained from parental records. We measured weight, height, waist circumference, and the bicep, tricep, subscapular, suprailiac, and medial calf skinfolds, and we calculated BMI, fat free mass (FFM), and the sum of five skinfolds. Physical activity was assessed by accelerometry. Changes in pubertal status and baseline anthropometric estimates were used as confounders in all analysis. In the children cohort, we observed that BW was inversely associated with changes in BMI (beta = -0.736, P = 0.002) and the sum of five skinfolds (beta = -6.381, P = 0.009) regardless of confounders and physical activity, only in girls. We did not find any significant association between BW and adiposity gain estimates in the adolescent cohort. These findings give further support to the concept that low BW may have a programming effect of subsequent adiposity gain from childhood to adolescence. We also confirm the sex-related differences in the programming effect of body composition. PMID- 21681229 TI - [Wrong about Kant]. PMID- 21681227 TI - Implantable gastric stimulator does not prevent the increase in plasma ghrelin levels that occurs with weight loss. AB - The SHAPE (Screened Health Assessment and Pacer Evaluation) trial was a 24 month randomized multicenter placebo-controlled study to determine the efficacy of an implantable gastric stimulator (IGS) for weight loss. This report is an investigator-initiated sub-study at one site designed to assess whether IGS affects plasma levels of ghrelin and peptide YY (PYY). The device was implanted in all subjects but was activated in the TREATMENT group (n = 7, BMI = 41.5 +/- 2.0 kg/m2) and remained inactive in the CONTROL (n = 6, BMI = 39.5 +/- 1.7 kg/m2) during the first 12 months. IGS was activated in both groups during months 12-24. Fasting venous blood was drawn at months 0, 12, and 24 and an oral glucose tolerance test (OGTT) was performed at month 12. Although there was no difference in weight loss at 6 months ( CONTROL: -6.6 +/- 1.5% vs. TREATMENT: -6.2 +/- 1.4%), at 24 months the CONTROL group exhibited weight gain from baseline (+2.2 +/- 1.5%) that was significantly different from the weight loss in the TREATMENT group (-1.9 +/- 1.4%; P < 0.05). At 12 months, fasting ghrelin was significantly increased (P < 0.05) in the TREATMENT group (285 +/- 35 to 336 +/- 35 pg/ml; weight change, -4.9 +/- 1.4%), but not in the CONTROL (211 +/- 36 to 208 +/- 35 pg/ml; weight change, -3.4 +/- 1.5%). No significant change was observed in postprandial suppression of plasma ghrelin or in fasting and postprandial PYY levels. In conclusion, IGS does not prevent the increase in fasting plasma ghrelin levels associated with weight loss. Further studies are needed to determine whether changes in technology can improve weight loss and maintenance, perhaps using gut hormones as biomarkers of possible efficacy. PMID- 21681232 TI - The difference between drugs and nutritional supplements. PMID- 21681233 TI - [Fee as antidote]. PMID- 21681234 TI - The working hours of general practitioners 2000-2008. AB - BACKGROUND: There is little reliable information available on the working hours of general practitioners (GPs). The purpose of our study is to describe the development of weekly working hours of Norwegian general practitioners in the period from 2000 to 2008, as well as the length of their patient lists and their perceived workload. MATERIAL AND METHODS: General practitioners in the reference panel of the Research Institute of the Norwegian Medical Association have reported their weekly working hours for 2000, 2002, 2004, 2006 and 2008, and the length of their patient lists for 2002 and 2008. We used non-overlapping 95 per cent confidence intervals for testing inter-group differences in interval variables and proportions. RESULTS: From 227 to 316 general practitioners responded to each survey round. Average weekly working hours constituted 45.1 hours (95 per cent CI: 43.6-46.5 hours) in 2000 and 46.4 hours (95 per cent CI: 45.2-47.6 hours) in 2008. The number of hours increased for women GPs, while the number of hours remained basically unchanged for men from 2000 to 2008. Average length of the patient lists in 2002 and 2008 constituted 1,325 and 1,278 for men, and 1,155 and 1,144 for women GPs respectively. The proportion of GPs who responded that they perceived their workload as unacceptable decreased significantly, from 38.1 per cent in 2000 to 25.5 per cent in 2008. INTERPRETATION: Average weekly working hours for GPs increased by approximately one hour from 2000 to 2008, and this increase is found mainly among women GPs. We believe that the reduction in the proportion reporting to have an unacceptable workload can be explained by the introduction of the list-patient system, which has given the doctors better control of their own workload. PMID- 21681235 TI - [Clinical neurological examination of the geriatric patient]. AB - BACKGROUND: Numerous physiological changes occur in the nervous system with increasing age. On clinical neurological examination, such changes may be misinterpreted as pathology in the nervous system. The objective of this article is to provide a review of the clinical neurological findings that may be caused by normal ageing. MATERIAL AND METHODS: The present manuscript is based on a non systematic search in PubMed as well as on the clinical experience of the authors. RESULTS: Cognitive functions are usually fairly well preserved in old age, apart from executive functioning, psychomotor speed and episodic memory, which are reduced with increasing age. Physiological changes related to increasing age include, in particular, vertical eye movements (upwards), vibration sense, Achilles reflexes, primitive reflexes and motor speed. Muscle power is reduced by 20-40% in healthy individuals aged over 70 years. INTERPRETATION: A correct diagnosis based on findings in the neurological examination cannot be made without knowledge of how ageing affects the physiology of the nervous system. However, the evidence regarding physiological changes in the nervous system is limited, and more research is needed in this field. PMID- 21681236 TI - [ABC transporters' impact on effect and metabolism of drugs]. AB - BACKGROUND: Drugs must be transported to reach the site of action and to be removed from the body. Several proteins within the large family of ABC transporters (ATP-binding domain), are important for pharmacokinetics. In this review article we present, from a clinical point of view, ABC transporters that are known to be important for basic and clinical pharmacology. MATERIAL AND METHOD: This overview is based on literature identified through a non-systematic search in PubMed and on results from our own work. RESULTS: Members of the subfamilies ABCB and ABCC, are most known for contributing to multidrug resistance towards cytostatic and antibiotic drugs. ABCB1 (P-glycoprotein) is shown to form a functional intestinal barrier and the blood-brain barrier by pumping out potentially toxic substances. More recent research indicates that ABC transporters play an important role in absorption, distribution and elimination of many drugs and that their function is dependent on the individual genotype. INTERPRETATION: Individualized therapy may become feasible when more knowledge about ABC transporters is available. PMID- 21681237 TI - [Horse-shoe kidney]. PMID- 21681238 TI - [A 55-year old man with recurrent brain infarction]. PMID- 21681239 TI - [A case report with several possible explanations]. PMID- 21681240 TI - [Clustering of non-contagious disease]. PMID- 21681241 TI - Ability-based notions of health and disease in the Norwegian social security system. PMID- 21681244 TI - High air pollution levels in some takeaway food outlets and barbecue restaurants. Pilot study in Wellington City, New Zealand. PMID- 21681245 TI - How important is urban air pollution as a health hazard? PMID- 21681246 TI - Health equity: a prerequisite for social and economic progress. PMID- 21681247 TI - The disposition and mobility of medical practitioners in New Zealand. PMID- 21681248 TI - Rural practice and retention in New Zealand: an examination of New Zealand trained and foreign-trained doctors. AB - In this paper we examine the problems New Zealand faces with regards the identified shortage and uneven distribution of medical practitioners across urban and rural areas. In particular, we examine the extent to which the origin of training and location of practice affect the mobility of medical practitioners over the period 2000-2008. We find that foreign-trained doctors have a greater propensity to practice in minor urban and rural areas, and in less affluent communities, than New Zealand (domestic)-trained doctors. We also find that mobility among doctors is becoming more pronounced in recent years, with doctors generally being more mobile, with movement out of rural areas and doctors leaving practice in New Zealand being areas of particular concern. PMID- 21681249 TI - A comparison of Maori and non-Maori experiences of general practice. AB - AIM: To compare Maori and non-Maori experiences in relation to access to general practice care. METHODS: A semi-structured personal questionnaire was administered in telephone surveys of random samples of 651 Maori and 400 non-Maori consumers. Differences in these groups of consumers' experiences of accessing general practice care were compared statistically. RESULTS: Compared with the non-Maori, the Maori respondents on average were younger and less advantaged in their socioeconomic and health status. Maori were more likely to report needing their last visit urgently. Most respondents reported seeing a GP when they wanted, but non-Maori were more likely than Maori to have this preference met. Fewer Maori said they were offered a choice of appointment times or were seen on time. CONCLUSIONS: Maori still report high health needs and being less likely to be offered choices at their general practice, to be seen on time, or to be seen within their preferred timeframe. Additional work is needed to align Maori and non-Maori experiences of general practice care. PMID- 21681250 TI - How toxic are fine particles emitted from home fires in Christchurch, New Zealand? AB - AIMS: Fine particles (PM10) in the air in Christchurch have been estimated to be a considerable health hazard, and 9.1% of all deaths have been attributed to them. Concentrations often exceed the national standard. The particles come from wood-burning stoves and hydrocarbon-burning traffic and industry. This study asks whether the particles from these sources are equally toxic, and whether a standard based on concentration of particles is appropriate as a measure for devising regulatory controls to safeguard public health. METHODS: Recorded concentrations of PM10 in Christchurch are much higher in winter than in summer. Published estimates show that 25% of the summer PM10 comes from home fires, and 75% from traffic and industry. It has been estimated that in winter 80% comes from home fires. Other published estimates show that in summer PM10 is 5 to 10 times more toxic than in winter. In this article these estimates are used together to estimate of the relative toxicity of PM10 from home fires compared with PM10 from traffic and industry. RESULTS: The calculations imply that the PM10 from home fires is less toxic than the PM10 from traffic and industry, and despite its predominance as a component in the winter PM10 it may be relatively harmless. An alternative explanation is that toxicity varies seasonally for each kind of PM10. CONCLUSIONS: Reducing total PM10 by reducing the component which comes from home fires may not reduce the incidence of premature deaths from PM10 pollution. PMID- 21681251 TI - A persisting secondhand smoke hazard in urban public places: results from fine particulate (PM2.5) air sampling. AB - AIM: To assess the need for additional smokefree settings, by measuring secondhand smoke (SHS) in a range of public places in an urban setting. METHODS: Measurements were made in Wellington City during the 6-year period after the implementation of legislation that made indoor areas of restaurants and bars/pubs smokefree in December 2004, and up to 20 years after the 1990 legislation making most indoor workplaces smokefree. Fine particulate levels (PM2.5) were measured with a portable real-time airborne particle monitor. We collated data from our previously published work involving random sampling, purposeful sampling and convenience sampling of a wide range of settings (in 2006) and from additional sampling of selected indoor and outdoor areas (in 2007-2008 and 2010). RESULTS: The "outdoor" smoking areas of hospitality venues had the highest particulate levels, with a mean value of 72 mcg/m3 (range of maximum values 51-284 mcg/m3) (n=20 sampling periods). These levels are likely to create health hazards for some workers and patrons (i.e., when considered in relation to the WHO air quality guidelines). National survey data also indicate that these venues are the ones where SHS exposure is most frequently reported by non-smokers. Areas inside bars that were adjacent to "outdoor" smoking areas also had high levels, with a mean of 54 mcg/m3 (range of maximum values: 18-239 mcg/m3, for n=13 measurements). In all other settings mean levels were lower (means: 2-22 mcg/m3). These other settings included inside traditional style pubs/sports bars (n=10), bars (n=18), restaurants (n=9), cafes (n=5), inside public buildings (n=15), inside transportation settings (n=15), and various outdoor street/park settings (n=22). During the data collection in all settings made smokefree by law, there was only one occasion of a person observed smoking. CONCLUSIONS: The results suggest that compliance in pubs/bars and restaurants has remained extremely high in this city in the nearly six years since implementation of the upgraded smokefree legislation. The results also highlight additional potential health gain from extending smokefree policies to reduce SHS exposure in the "outdoor" smoking areas of hospitality venues and to reduce SHS drift from these areas to indoor areas. PMID- 21681252 TI - Maori with aphasia: a people without a voice? AB - AIM: This literature review aimed to investigate whether Maori with aphasia and their whanau are being included in research. A second aim was to identify what, if any, specific outcomes or concerns have been reported. Although the prevalence and incidence of aphasia in the Maori population is unknown, it is likely to be relatively high, given the high rate of stroke among Maori. METHODS: We provide a background to Maori health, stroke, aphasia and rehabilitation. A standard review of the literature was conducted in the online databases PsycINFO, ScienceDirect, PubMed, MEDLINE, CINAHL Plus, and Google Scholar. We searched "Maori" AND "aphasia" and "Maori" AND "dysphasia" as "anywhere in text" and as a keyword with no limits placed on publication dates. CONCLUSIONS: The search revealed no articles that involve Maori with aphasia and none that address aphasia in the Maori population. Four articles involved Maori participants with stroke or a condition linked to communication disorders and specifically addressed either culture or ethnicity in their observations or results. We consider possible explanations for this apparent lack of Maori with aphasia as participants in research, and conclude that the investigation of aphasia in Maori requires an approach that involves Maori with aphasia and their whanau, in a way that is culturally appropriate enabling them to have a voice. PMID- 21681253 TI - Excess winter mortality, wood fires and the uncertainties associated with air pollutants. AB - There is excess mortality in the winter. To minimise this it is important that an adequate indoor temperature is maintained and this is dependent on affordable energy supplies. Standards adopted by the Ministry for the Environment in relation to levels of small particles (PM10) in the air and the Regulations to enforce their implementation are based on inadequate scientific evidence. They are likely to make heating less affordable and have a negative net effect rather than a positive one on general health. Whilst the attainment and maintenance of clean air is laudable, regulations should be based on sound scientific evidence. The costs, benefits, and equity for individuals need careful consideration, as do the implications for energy security. PMID- 21681254 TI - Limitations of the scientific basis for the management of air quality in urban New Zealand. AB - As enumerated by Ministry for the Environment, planned reductions in levels of air pollution in New Zealand sufficient to allow compliance with the National Environmental Standards for Air Quality will save, in a cost-effective manner, numerous lives per year. However, as indicated by careful study of the literature and of the methods employed to perform the relevant calculations, such claims are flawed. Instead of a precise number of deaths avoided, small changes in regional life expectancy are a more likely tangible consequence of compliance and, as such, are better suited to assisting calculation of the associated benefits and costs. Some basic data relevant to communities and regions potentially susceptible to the effects of 'poor quality' or inclement air are provided. These support the view that urban air pollution as officially measured and normally encountered in New Zealand nowadays probably has comparatively small substantive mortality consequences. PMID- 21681255 TI - Hypoglycaemia after treatment with perhexiline maleate: a case report. PMID- 21681256 TI - Medical image. Unusual case of thoracic outlet syndrome. PMID- 21681257 TI - [A comparative study on blood pressure, obesity, smoking and alcohol drinking behavior in Chinese twins reared apart and together]. AB - OBJECTIVE: To test the potential feasibility for studies conducted in twins reared apart and together from the Chinese National Twin Registry (CNTR) and to answer the question whether the rearing environment affects chronic disease risk factors. METHODS: The samples were composed of twins from two sub-registries, which included 503 twin pairs in Lishui and 505 twin pairs in Qingdao. RESULTS: There was a big difference in the rates of twins reared apart in different areas (from 0.6% in Qingdao to 5.4% in Lishui). Only nine pairs of dizygotic twins reared apart in Lishui were recruited. The intraclass correlation coefficients for many indices were not significant. Rearing environment might affect diastolic blood pressure and smoking behavior, but it was hard to interpret its impacts in systolic blood pressure, body mass index, waist-hip ratio and drinking behavior. CONCLUSION: The design of twins reared apart is a valuable study and can be conducted in the CNTR, but the current sample size is still a big issue which requires the registry to recruit more twins to support it. PMID- 21681258 TI - [Chromosomal location of nonsyndromic cleft lip with or without palates for two multiplex families]. AB - OBJECTIVE: To find chromosome region closely linked to nonsyndromic cleft lip with or without palates (NSCL+/-P) by genome-wide scan and linkage analysis for two multiplex families. METHODS: Whole-genome scan and fine genome scan were used to analyse multiplex families members, and parametric, nonparametric and interaction statistical analysis software to determine which chromosomal section was linked to the genetic disease. RESULTS: Both parametric and nonparametric linkage scores increased by a big margin over the initial linkage scores on 1q32.2-41. Although parametric results were not significant, nonparametric linkage gave a strong evidence for a candidate region on chromosome 2p25.1-24.2. The multiplicative model gave the strongest evidence for interaction in 1q32.2-41 and 2p25.1-24.2. CONCLUSION: Parametric and nonparametric linkage analyses for 2 NSCL+/-P multiplex families show that there may be candidate regions on chromosome 1q32.2-41 and 2p25.1-24.2.The two regions of 1q32.2-41 and 2p25.1-24.2 may contribute to NSCL+/-P risks with interaction. PMID- 21681259 TI - [Influence of exogenous 5'-nucleotides on acute alcohol intoxication in rats]. AB - OBJECTIVE: To investigate effects of exogenous 5'-nucleotides on acute alcohol intoxication in SD rats. METHODS: In our study, 24 male SD rats were randomly divided into 4 groups which included a control group treated with normal saline and three experimental groups treated with low, medium and high doses of exogenous 5'-nucleotides (0.2, 0.8, 3.2 g/kg body weight). All the rats were gavaged with 50% ethanol 30 minutes after treatment. Then rotarod test and open field test were taken to assess rats' neurobehavior changes; Tail blood samples were collected to test blood ethanol concentration; Then all the rats were anesthetized and killed to collect blood and liver samples. Contents of serum alanine amino transferase, aspartate amino transferase, triglyceride, total cholesterol, high density lipoprotein cholesterol, total protein and albumin were tested; Their serum superoxide dismutase activity, malondialdehyde content and liver alcohol dehydrogenase activity were measured. RESULTS: Compared with the controls, high dose nucleotides treated rats had lower serum ethanol concentration [(0.56+/-0.18 g/L)vs.(1.11+/-0.44 g/L), P<0.05]. However, exogenous 5'-nucleotides had no impact on neurobehavior and serum biochemical indicators; No difference was found in liver alcohol dehydrogenase activity, serum superoxide dismutase activity and malondialdehyde content were also found no different between the groups. CONCLUSION: Exogenous 5'-nucleotides have no protective properties for acute alcohol intoxication in rats. PMID- 21681260 TI - [The cytotoxicity and expression changes of endoplasmic reticulum related genes induced by MWCNTs with different surface modifications]. AB - OBJECTIVE: To compare the cytotoxicity of RAW264.7 cells induced by two types of multi-walled carbon nanotubes (MWCNTs) with different surface modifications (MWCNTs modified by taurine and MWCNTs treated by acid), and explore the role of endoplasmic reticulum (ER) in MWCNTs-induced apoptosis. METHODS: RAW264.7 cells were exposed to tau-MWCNTs or c-MWCNTs, of which the diameters and impurity contents were the same, at the dose of 0, 1.56, 3.12, 6.25, 12.50, 25.00 MUg/cm(2) for 3, 6, 12 and 24 h, respectively. Then the cytotoxicity of MWCNTs was determined by WST-1 assay, and the percentages of apoptosis were analyzed via flow cytometry with AnnexinV-FITC/PI label. Real-time PCR was used to detect mRNA expression levels of CRT, GRP78 and CHOP genes which were related to ER calcium regulation, stress and apoptosis. RESULTS: Compared with the c-MWCNTs groups, the cytotoxicity of tau-MWCNTs was lower at the same dose and treatment time. Both the two types of MWCNTs could induce cytotoxicity apparently and statistically, when the cells were treated for only 3 h at the doses of more than 12.50 MUg/cm(2) or treated for more than 12 h at the lower dose of 3.12 MUg/cm(2) (P<0.05). The results of flow cytometry showed that the two MWCNTs could induce apoptosis of RAW264.7 cells in the dose- and time-dependently manner. The apoptosis rate of the cells treated for 24 h was higher than that for 12 h. And at each dose, the apoptosis rate induced by c-MWCNTs was also higher than that of the water soluble tau-MWCNTs within our study design. However, in this study, the mRNA expression levels of CRT, GRP78 and CHOP mRNA treated with both types of MWCNTs did not show any significant differences compared with the control groups. CONCLUSION: The cytotoxicity of tau-MWCNTs was much lower than that of c-MWCNTs. Unfortunately, we found the expression of genes related to ER had little effects on the apoptosis of RAW264.7 treated with MWCNTs, indicating that the ER pathway might not be the mechanism of MWCNTs-induced apoptosis. PMID- 21681261 TI - [Effect of equol on breast tumors induced by 7, 12-dimethylbenz (alpha) anthracene in ovariectominzed rats]. AB - OBJECTIVE: To study the effect of equol on the incidence of breast tumors induced by 7, 12-dimethylbenz(alpha) anthracene (DMBA) in ovariectomized rats. METHODS: In the study, 48 female ovariectomized SD rats were randomly divided into 6 groups according to their weights: blank control group, fed on an AIN-93G diet; model group, fed on an AIN-93G diet; estrogen control group, fed on an AIN-93G diet supplemented with 0.25 mg/kg diethylstilbestrol; and low, medium and high doses of equol groups, fed on an AIN-93G diet supplemented with 100, 200 and 400 mg/kg diet of equol, respectively. The animals were palpated to examine the breast tumor, body weight and dietary intake of each rat per week. The data were recorded. At the end of the experiment, the incidence of breast tumor was calculated and the sera were collected for the detection of SOD, MDA and 8-OHdG levels. The expression of Nrf2 in liver was assessed by Western-blotting. RESULTS: Equol decreased the rats' body weights, dietary intakes, breast tumor incidence and MDA levels, but had no effect on the levels of SOD and 8-OHdG in the sera. The expression of Nrf2 was up-regulated dose-dependently in equol groups. CONCLUSION: Supplementation of equol could decrease the incidence of breast tumor in ovariectominzed rats. This effect may result from the reduction of body weight, intake of diet, MDA level in the sera and up-regulation of expression of Nrf2. The effect of equol may be influenced by many factors, such as the structure of equol, which should be further studied. PMID- 21681262 TI - [Systemic oxidative stress induced by intratracheal instilling with PM10 in rats]. AB - OBJECTIVE: To observe the oxidative stress of serum, lung and heart tissues in rats caused by PM10. METHODS: In the study,24 male Wistar rats weighed 320-360 g were randomly divided into four groups, including one saline control group and three PM10 exposed groups. PM10 was administered to the exposed groups by intratracheal instillation at the doses of 3.75, 7.5, 15 mg/kg, respectively. The rats were sacrificed 24 hours after exposure. The levels of MDA and activities of SOD in the serum, lung and heart tissues were measured. In addition, the contents of protein carbonyl in lung and heart tissues were determined. RESULTS: The activities of SOD in the serum, lung and heart tissues decreased markedly in the 7.5 and 15 mg/kg groups. The levels of MDA in the lung tissues significantly increased in the 7.5 and 15 mg/kg groups, while those in the serum and heart tissues significantly increased only in the 15 mg/kg group. The contents of protein carbonyl in the lung tissues markedly increased in the 15 mg/kg group, but no significant change was found in the heart tissues. CONCLUSION: The study showed that PM10 can cause oxidative stress effects in rats. The lipids of cell membrane are more susceptible to oxidative stress than the proteins. PMID- 21681263 TI - [Long-term effects of air pollution on the occurrence of respiratory symptoms in adults of Beijing]. AB - OBJECTIVE: To investigate the long-term effects of air pollution on prevalence of respiratory symptoms in adults, in Beijing. METHODS: A cross-sectional study was conducted in an urban area and a suburban area with different levels of air pollution in October 2008, in Beijing. Respiratory symptoms were investigated by a standard questionnaire from the American Thoracic Society (ATS-DLD-78-A) in 9 052 adults who had lived there for at least two years. The concentrations of air pollutants for recent five years were obtained from Reports on the Quality of the Beijing Environment, Environmental Protection Bureau and Statistics Yearbook. The differences of the prevalence and standardized prevalence of respiratory symptoms in adults between the urban and suburban areas were analyzed by chi(2) test. RESULTS: The standardized prevalences of persistent phlegm and asthma in urban adults were significantly higher than those in suburban adults [(3.06% vs. 2.43%, P<0.05) and (0.65% vs. 0.31%, P<0.01), respectively], but lower than that of the breathless (0.75% vs. 1.12%, P<0.05). CONCLUSION: The study suggested that ambient air pollution had long-term effects on the prevalence of some respiratory symptoms in adults. PMID- 21681264 TI - [Geographic distribution and secular trend of menarche in 9-18 year-old Chinese Han girls]. AB - OBJECTIVE: To analyze the characteristics and secular trend of age at menarche (age at menarche, AAM) in Chinese girls aged 9-18. METHODS: Probit analyses were used to calculate AAMs in various populations of Chinese girls who participated in National Physical Fitness and Health Surveillance in 2005 or 1995. The samples of girls were 92 767 in 2005 and 85 433 in 1995 National Physical Fitness and Health Surveillance, respectively. RESULTS: AAM was 12.76 years in Chinese girls aged 9-18 in China. AAMs were 12.60 and 12.92 years for urban and rural girls, respectively. There was a large variation among different geographic areas, and AAM was earlier in girls living in east of China and later in girls living in northwest of China. AAMs of the top 5 municipalities/provinces were Beijing (12.27 years), Shanghai (12.32 years), Sichuan (12.48 years), Fujian (12.50 years) and Tianjin (12.51 years); and the last 5 provinces/autonomous regions were Qinghai (14.09 years), Hubei (13.33 years), Heilongjiang (13.10 years), Ningxia (13.08 years) and Hunan (12.87 years). AAMs were 0.22 and 0.34 years earlier than those of urban and rural girls in 1995. CONCLUSION: The onset of menarche was generally earlier in urban than in rural girls, and the latest in northwest of China. Significant decline trend of age at menarche could be found in Chinese girls, especially in rural areas. The differences of AAMs among urban and rural areas and in various provinces were with a tendency to shrink in 2005 compared with 1995. PMID- 21681265 TI - [Epidemiology and related factor analysis of visual fatigue in university students of Haidian District of Beijing]. AB - OBJECTIVE: To analyze and explore the epidemiological characteristicss and related factors for visual fatigue among university students in Haidian District of Beijing. METHODS: The investigation with questionnaires was conducted in 2 246 undergraduates and postgraduates from four universities in Haidian District by multi-level stratified cluster sampling. Factor analysis and multivariate Logistic regression model were conducted to explore the related factors for visual fatigue. RESULTS: Among the university students, the total prevalence rate of visual fatigue was 64.9%, and the prevalence rates of males, females, undergraduates and postgraduates were 65.1%, 64.7%, 58.9% and 75.7%, respectively. The result of multivariate logistic regression analysis showed that bad living environment conditions, improper computer use and bad health status were significantly associated with increased risk of visual fatigue, the ORs (95% CI) were 1.185 (1.078, 1.302), 1.490 (1.355, 1.640) and 1.323 (1.182, 1.481), respectively; good sleep and mental status, good psycho-social state, and good factors of habits and diets might be protective against visual fatigue, the ORs (95% CI) were 0.691 (0.628, 0.760), 0.793 (0.720, 0.873) and 0.649 (0.587, 0.717), respectively. CONCLUSION: The university students showed higher prevalence rate of visual fatigue. Psychological state, environment, health status, diets and habits were related to the development of visual fatigue. Health education should be strengthened among university students to prevent the adverse effects of visual fatigue on their health. PMID- 21681266 TI - [An assembly line lighting survey analysis and its optimal illumination range research]. AB - OBJECTIVE: To investigate and analyze present conditions of the assembling line illumination in our country, and to set the recommended values of illuminance standard. METHODS: Questionnaires and field surveys were used in this investigation. A total of 752 workers from seven factories in textile, shoes and electronics industries were selected for the questionnaire survey and site measurement, and corresponding analyses made with SPSS 13.0 statistic software. RESULTS: Uniformity of illumination, definition in working face, general satisfactory degrees, asthenopia were significantly correlated with each other. Assembly line illuminances for five different visual characteristics were recommended in this paper. The illuminances were 500-1 000-1 500 lx, 300-500-1 000 lx, 200-300-750 lx, 100-300-500 lx, 50-100-200 lx, respectively. CONCLUSION: Present conditions of the assembling line illumination are less than satisfactory, uniformity of illumination is on the low side, and there is no assembling line illuminance standard for general satisfactory degrees and asthenopia of workers. The related work should be further improved. PMID- 21681267 TI - [Analysis of syndromic surveillance of 63 325 outpatients in Fever Clinic in Beijing]. AB - OBJECTIVE: To describe findings from syndromic surveillance of Fever Clinic visits and to determine the utility of monitoring Fever Clinic admissions as an indictor of respiratory infectious disease activity in Beijing. METHODS: A census on outpatients in Fever Clinics was conducted in two grade 3 general hospitals in Beijing from April 1, 2009 to March 31, 2010 based on a typical survey, the epidemiological characteristics of outpatients were analyzed and correlation among Fever Clinic visits, acute febrile respiratory illness (ARI) visits, influenza-like illness (ILI) visits and influenza visits determined. RESULTS: The seasonal patterns for Fever Clinic visits, ARI visits and ILI visits were quite similar, but that for influenza visits peaked later than those for ARI and ILI visits. There were high positive relationships between ARI visits, ILI visits or influenza visits and Fever Clinic visits, with a pearson's correlation coefficient of 0.99, 0.99 and 0.48, respectively (P<0.001). CONCLUSION: Syndromic surveillance of Fever Clinic visits is valuable for early warning of respiratory infectious disease outbreaks. The Fever Clinic provides a platform for early diagnosis and treatment of respiratory infectious disease. PMID- 21681268 TI - [Gender-specific differences in relative effects of cardiovascular risk factors among rural population]. AB - OBJECTIVE: To investigate the prevalence and association of cardiovascular disease and its risk factors in Fangshan District, Beijing. METHODS: A total of 7 577 rural residents aged over 40 years were surveyed to estimate the prevalence of cardiovascular disease and its risk factors by questionnaire survey, physical examination and biochemical measures. The prevalence odds ratio (POR) was calculated for the association of stroke / coronary heart disease (CHD) with its risk factors in multiple logistic regression models. RESULTS: Prevalence of CHD, stroke, diabetes, hypertension, dyslipidemia, overweight and obesity was presented as 6.5%, 4.1%, 10.7%, 39.5%, 56.7%, 44.0% and 13.6%, respectively. In the adjusted multiple logistic regression models, hypertension showed stronger association with stroke (POR=2.780, 95%CI: 2.146-3.602), while diabetes had a higher correlation with CHD (POR=2.671, 95%CI: 2.121-3.363). After stratification by gender, significant risk factors for stroke were overweight / obesity (POR=1.652, 95%CI: 1.122-2.433), body mass index (POR=1.048, 95%CI: 1.002- 1.096), systolic blood pressure (POR=1.017, 95%CI: 1.005-1.030) and serum glucose (POR=1.093, 95%CI: 1.048-1.140) in females, whereas dyslipidemia (POR=1.615, 95%CI: 1.124-2.319), total cholesterol (POR=3.932, 95%CI: 1.533-10.086) and high density lipoprotein cholesterol (POR=0.072, 95%CI: 0.022-0.236) were associated with stroke in males. CONCLUSION: Highly prevalent cardiovascular risk factors aggravated the burden brought by stroke and CHD in the rural population, and the various risk factors for stroke and CHD exhibited heterogeneous contributions among the population with different gender. PMID- 21681269 TI - [Psychological resilience features of urban migrant children and rural left behind children in Sichuan province of China]. AB - OBJECTIVE: To explore the characteristics of resilience of urban migrant children and rural left-behind children of Chinese farmer workers and to figure out the discrepancy between them. METHODS: The samples consisted of 1 391 primary students and middle school students from Chengdu, Guangyuan, Yibin, and Mianyang in Sichuan Province. The revised version of the Healthy Kids Resilience Assessment was used for the measurement of resilience. And ANOVA was performed for data analysis. RESULTS: The results of the present study indicated that among all the junior high students, urban migrant children got a significantly lower score of resilience (128.11+/-21.70) than rural left-behind children (135.61+/ 22.77) and the control group (132.87+/-23.22), F(0.05 (2, 884))=8.076, P<0.001. And migrant children got lower scores on three external protective factors of resilience-family, school, community as well as on resilience traits than left behind children and the control group (Family: F(0.05(2, 884))=7.820, P<0.001; School: F(0.05(2, 884))=5.041, P=0.007; Community: F(0.05(2, 884))=9.261, P<0.001; Resilience traits: F(0.05(2, 884))=3.510, P=0.030). No significant difference was noted between left-behind children and control group. Gender difference and grade difference were noted for each group. CONCLUSION: The resilience of migrant children was not so good as non-migrant children. Migrant children were enjoying less intimate interpersonal relationship in their schools, their families as well as their community, and they could get less psychological support from the external environment, so that migrant children could not develop some resilience traits to promote the sound development of themselves. Suggestions for intervention were also discussed. PMID- 21681270 TI - China's process and challenges in achieving the United Nations Millennium. AB - OBJECTIVE: China was categorized as one of the 68 "countdown" countries to achieve the United Nations Millennium Development Goals (MDG) 5. This paper aimed to analyze the situation of maternal survival, and coverage of proven cost effective interventions in China, where specific attention was paid to disparities. METHODS: National maternal and child mortality surveillance data were used to estimate maternal mortality ratio (MMR). Coverage for proven interventions was analyzed based on National Health Services Survey, where experts' consultations were made for complementation. RESULTS: There had been a significant reduction of MMR in China, however great disparities existed, with rural II to IV areas experiencing 2 to 5 times higher maternal mortality risks than urban areas and accounting for over 70% maternal mortality burdens. Postpartum hemorrhage, pregnancy associated hypertension, embolism and sepsis were the leading causes, and over 75% of the maternal mortality was caused by preventable or curable causes. Maternal health services utilization decreased in accordance with region's development level. Socioeconomic factors like financial difficulties were the main obstacles hindering access of care. Even those who made deliveries in hospitals faced different probabilities in receiving qualified care according to their socioeconomic standings. CONCLUSION: China is on track to achieve MDG 5, however great disparities exist. It is necessary to specifically target rural types II to IV areas. Major causes of maternal mortality which can be prevented or averted through the provision of essential obstetrical care. Yet as compared with maternity health needs, insufficient coverage of maternal and child health (MCH) care services and poor service quality are the leading predisposing factors contributing to maternal mortality in China. PMID- 21681271 TI - [Comparative analysis of applying patient experience and satisfaction survey (VPSM) tool in Chinese hospitals]. AB - OBJECTIVE: Patient experience and satisfaction survey has been regarded as an important method of collecting patients' opinions on medical services and improving the quality of management. From 2005 to 2009, Australia Victorian patient satisfaction monitoring, VPSM, was introduced, localized and adopted by over 50 Chinese hospitals. To compare and analyze each localized applications of VPSM and submit suggestions for further applications. METHODS: The paper adopted the way of document research. The researchers collected all of the published and unpublished investigation plans and monitoring reports during these five years, compared the operations and the results of investigations and indicated the advantages and weaknesses. RESULTS: In respect of methods, they were similar but showed some small differences in details such as the questionnaire structure, the reminding letter and the organization of data acquisition and analysis. The localized VPSM was gradually moving towards standardization. The monitoring was able to find the changing of medical services and provided the referential information for management. CONCLUSION: The localization of VPSM is still on its way and it needs improving by means of extending application. PMID- 21681272 TI - [Empirical analysis of relationship between scales and outputs of inpatient services of public comprehensive hospitals in Beijing area]. AB - OBJECTIVE: To analyze the relationship between scale and outputs of inpatient services of public general hospitals. METHODS: Data on hospital scales and outputs were drawn from Beijing Health Statistics Annuals and the Database of Inpatient Record administered by Beijing Health Bureau. The outputs of inpatient services were measured, risk-adjusted by Beijing Diagnosis Related Groups (BJ DRGs). Based on the Cobb-Douglas production function, regression analysis was used to evaluate the contribution of manpower and material resources to the changes in outputs of hospitals on different scales, respectively. RESULTS: Public general hospitals with 200-800 beds were at the stage of economical scale. In the 200-500-bed hospitals, investment of both human and material resources contributed to output changes. In the 501-800-bed hospitals, output changes were positively correlated with manpower input, but not with material resources. CONCLUSION: In the specific environment in Beijing, medium-sized hospitals are appropriate when the government plan to build hospitals mainly focused on inpatient services. The larger the scale of hospitals is, the more important is the manpower imput. The personnel system reform for public hospitals is urgent. PMID- 21681273 TI - [Informational analysis of global health equity studies based on database of Web of Science]. AB - OBJECTIVE: To present the history of global health equity studies and provide reference for the selection of topics of China's health equity study. METHODS: In this article citations on the subject of health equity from Web of Science (WOS) were analyzed and 60 papers concerned which were cited more than 30 times selected. Through the co-citation cluster analysis combined with the content analysis of the highly-cited papers, this article attempted to cluster them into several significant categories. Then we analyzed their strategic importance in the field of health equity by drawing citation strategic diagrams. RESULTS: Six hot topics in health equity studies were as follows: health service equity, the relationship between health service demand and utilization; definitions of health equity; socioeconomic status and mortality, income distribution and health, and the measurement of health inequity. Income distribution and health was the biggest concern and the measurement of health inequity was of the greatest novelty. CONCLUSION: Conducting empirical analyses on the effect of social determinants (including socioeconomic status, social network and psychosocial status etc.) on health by means of health equity measurements marks the development trend of health equity study. PMID- 21681274 TI - [Detection of serum desmoglein antibody level using enzyme-linked immunosorbent assay (ELISA) for monitoring disease activity in patients with pemphigus vulgaris]. AB - OBJECTIVE: Pemphigus is an autoimmune blistering disease of skin and mucous membranes. Pemphigus vulgaris (PV) is a major subtype of pemphigus, which is histologically characterized by suprabasal acantholysis. The major antigen in PV is desmosomal glycoproteins desmoglein (Dsg) 3. The autoantibodies against Dsg3 cause loss of adhesion between keratinocytes. Some PV patients also have circulating anti-Dsg1 autoantibodies. Enzyme-linked immunosorbent assays (ELISAs) with recombinant Dsg3 and Dsg1 are highly sensitive and specific for detecting anti-Dsg3 and anti-Dsg1 autoantibodies in PV patients. To evaluate the role of desmosomal glycoproteins desmoglein (Dsg3) ELISA and Dsg1 ELISA for detecting anti-Dsg3 and anti-Dsg1 autoantibodies in monitoring disease activity in Pemphigus vulgaris patients. METHODS: Twenty PV patients with long-term follow-up were included. We tested their serial sera with modified Dsg3 ELISA (MESACUP Desmoglein TEST "Dsg3", Medical & Biological Laboratories Co. LTD.), Dsg1 ELISA(MESACUP Desmoglein TEST "Dsg1", Medical & Biological Laboratories Co. LTD.) and indirect immunofluorescence (IIF). Then we analyzed the correlation between Dsg3 ELISA index values, Dsg1 ELISA index values, IIF titres and disease activity scores (ABSIS) along the time course. RESULTS: There were significant correlations between Dsg3 ELISA index values, Dsg1 ELISA index values, IIF titres and disease activity scores (both skin scores and oral scores) (P<0.01) along the time course. Significant differences of Dsg3 ELISA index values, Dsg1 ELISA index values and IIF titres between active time-point group and clinical remission time point group were also observed (P<0.01). We found that Dsg3 ELISA index values, Dsg1 ELISA index values and IIF titres fluctuated in parallel with disease activity, and ELISA index values were superior to IIF titres. CONCLUSION: Dsg3 ELISA index values fluctuating in parallel with disease activity are useful to monitor disease activity, predict flares or relapses and plan the schedules for tapering the drugs. PMID- 21681275 TI - [Neurogenin 3 and Paired box gene 4 promote PDX1-induced differentiation of mesenchymal stem cells into pancreatic secretory cells]. AB - OBJECTIVE: To explore the role of neurogenin 3(NGN3) and paired box gene 4(PAX4) in the process of PDX1-driven mesenchymal stem cells (MSCs) to the pancreatic beta-cell differentiation. METHODS: PDX1 gene and NGN3 were constructed with PAX4 genes expression adenovirus vectors, Adxsi-CMV-PDX1 adenovirus infection induced MSCs. One week later, re-Adxsi-CMV-NGN3/CMV-PAX4 adenovirus infection induced MSCs; and detected PDX1, PAX4, NGN3, NK transcription factor related, gene family 2, locus2(NKX2.2), v-maf musculoaponeurotic fibrosarcoma oncogene homolog B(MafB), insulin, glucagon and other pancreatic secretory cell-associated molecule expression. RESULTS: Adxsi-CMV-PDX1 and Adxsi-CMV-NGN3/CMV-PAX4 adenovirus vectors were constructed successfully. Through immuocytochemistry and indirect fluorescence detection, the expressions of PDX1 and NGN3 and PAX4 factors were detected stably in MSCs cellular nuclei which were induced by Adxsi CMV-PDX1 and Adxsi-CMV-NGN3/CMV-PAX4. After transfection for 5 d, the cells formed round, gathered into a mass and showed bright red with dithizone staining. RT-PCR detection showed NruroD1 and NKX2.2 expression after being induced for 1 week and insulin/proinsulin molecules after being induced for 2 week. The induced cells could express some transcription factors such as NKX2.2 and MafB, and also pancreatic-secreting related molecules such as insulin and glucagon, but not the expressions of MafA and C-peptide. CONCLUSION: NGN3 and PAX4 have a favourable role in PDX1 inducing mesenchymal stem cells into pancreatic secretory cells. PMID- 21681276 TI - [Correlation study on different dyslipidemia classification and glucose metabolism in patients with hyperlipidemia]. AB - OBJECTIVE: To detect the impaired glucose metabolism in dyslipidemic patients and explore whether the type of dyslipidemia affects the type of impaired glucose metabolism. METHODS: In our study, 197 patients without diabetes or cardiovascular disease history were divided into 4 groups according to fasting serum lipid levels: hypercholesterolemic group (HCh group, 45 patients); hypertriglyceridemic group (HTG group, 46 patients); combined dyslipidemic group (58 patients) and control group (48 patients). Serum insulin and glucose levels were detected in fasting situation. HOMA-IR was calculated. And then the patients received 75 g oral glucose tolerance test (OGTT) and their GLU120 levels were detected. RESULTS: The GLU120 levels in HTG group [(10.5+/-3.2) mmol/L] and combined dyslipidemic group [(12.0+/-5.4) mmol/L] were significantly higher than those in control group [(8.7+/-3.5) mmol/L, P=0.045 and 0.024, respectively]. HTG group (39.1%) and combined dyslipidemic group (31.0%) also had higher impaired glucose tolerance (IGT) incidence ratios than those in control group (22.9%, P=0.009 and 0.014, respectively). In subgroup study of patients with fasting glucose levels below 6.1 mmol/L, the incidence ratios of IGT in HTG group and combined dyslipidemic group were 51.4% and 43.9%, respectively, which were significantly higher than those in control group (29.7%, P=0.009 and 0.015, respectively). CONCLUSION: There exists a definite ratio of undiscovered impaired glucose metabolism in dyslipidemic patients who have not suffered from cardiovascular disease, especially in hypertriglyceridemic and combined dyslipidemic group. OGTT is suggested to be brought into effect in order that impaired glucose metabolism would be detected in earlier stage. PMID- 21681277 TI - [Characteristic analysis of plasma lipid metabolism level in patients with colorectal adenoma]. AB - OBJECTIVE: To evaluate the relationship between serum lipid level and colorectal adenoma. METHODS: A review analysis was carried out of the patients who underwent colonoscopy in Peking University Third Hospital from May 2009 to February 2010. Subjects with history of colorectal adenocarcinoma before colorectal surgery or of medication which had influenced the serum lipid level were excluded. Adenoma group included the patients who had colorectal adenoma which was evidenced by pathology. The patients with no adenoma were ascribed to control group. The serum total cholesterol, triglyceride, HDL cholesterol and LDL cholesterol levels of the two groups were analyzed. The relation between serum lipid level and location of colorectal adenoma was also summarized. RESULTS: A total of 227 patients were included for final analysis, of whom 124 were in adenoma group (77 males and 47 females; mean age: 56.5+/-10.7 years )and 103 in control group(53 males and 50 females; mean age: 56.8+/-13.6 years). Serum triglyceride level in adenoma group [(1.83+/-1.04) mmol/L] was significantly higher than that of control group[(1.54+/-0.86) mmol/L(P=0.022)] and HDL-C level in adenoma group[(1.05+/ 0.32) mmol / L] was significantly lower than that of control group [(1.26+/-0.46) mmol/L(P=0.000)]. In adenoma group, 73 cases were with HDL-C decreased, which was significantly higher than that of control group (44 cases, P=0.015). In addition, higher incidence of proximal colonic adenomas was observed in elevated triglycerides group and low HDL-C group (39.8%, 37.4%), compared with control group (25.5%), but there was no statistical difference between the two groups(P=0.358). CONCLUSION: The findings of this study suggest that dyslipidemia may affect the incidence of colorectal adenoma, particularly hypertriglyceridemia and low HDL-C levels. In addition, higher triglyceride and lower HDL-C levels seem to be related to higher incidence of proximal colonic adenomas. PMID- 21681278 TI - [Change and significance in the levels of plasma urotensin II and catestatin in children with postural orthostatic tachycardia syndrome]. AB - OBJECTIVE: To explore possible mechanisms by analyzing cardiovascular bioactive peptides levels in children with postural orthostatic tachycardia syndrome (POTS). METHODS: Forty-six children diagnosed as POTS (POTS group, aged 12.1+/ 2.8 years) and 20 healthy children (control group, aged 11.5+/-3.6 years) were enrolled as controls in this clinical controlled study. Two kinds of cardiovascular bioactive peptides named urotensin II (UII) and catestatin (Cs) were measured by using enzyme immunoassay. The comparisons between the two groups were made by independent t test or non-parametric test. Correlation analyses between plasma levels of bioactive peptides and changes in heart rate during standing test or head-up tilt test (HUT) were conducted using bivariate correlations. RESULTS: The plasma UII levels were significantly lower in POTS group as compared with those of controls [0.41 (0.27, 0.85) MUg/L in POTS group vs. 0.46 (0.35, 1.41) MUg/L in control group, P<0.05]. The plasma UII level was negatively correlated with the increase in heart rate during standing test or head-up tilt test (correlation coefficient-0.363, P<0.05). No difference was found in plasma Cs levels between the two groups [ 0.48 (0.20, 1.91) MUg/L in POTS group vs. 0.48 (0.20, 1.91) MUg/L in control group, P>0.05]. CONCLUSION: POTS children had low levels of plasma UII, and disturbance of vascular tone regulation might play a role in POTS of children. PMID- 21681279 TI - [Analysis of current treatment practice and outcomes for in-patients with ST segment elevation acute coronary syndrome in 31 provinces of China]. AB - OBJECTIVE: To evaluate the current clinical practice that has been proven effective by evidence-based medicine on patients with ST segment elevation Acute Coronary Syndrome(ACS)in China. METHODS: A total of 1 307 in-patients with ST segment elevation ACS from 64 hospitals across China were recruited and a standard questionnaire was used to get information about the patients including demographic, treatment and in-hospital outcomes. We analyzed the status of application of reperfusion and aspirin, angiotensin-converting enzyme inhibitors (ACEI), beta-blocker, low molecular weight heparin (LWMH), clopidogrel and cholesterol lowering agents on ST segment elevation ACS patients. RESULTS: (1)30.9%-69.4% of the patients received reperfusion therapies. 1.3%-62.7% received primary PCI, 1.9%-45.8% received thrombolysis, and nearly 46. 2% did not receive any form of reperfusion. Reperfusion therapy was more often used in tertiary hospitals (48.2%) than in secondary hospitals (6.46%). Thrombolysis was more often in secondary hospitals than that in tertiary hospitals (36.8% vs.14.6%).(2) percentages of medications in aspirin were 88.0%-98. 6%; in ACEI 60.5%-84. 4%; in beta-blocker 55.8%-84.4%; in LWMH 54.2%- 94.2%; in clopidogrel 14.3%-88.6%; in cholesterol lowering agents (Statins) 51.9%-90.9%. (3)major in hospital events, death rates and the incidence of combined outcomes were significantly higher in secondary hospitals than in tertiary hospitals, and higher in patients without reperfusion therapy compared with the patients who underwent reperfusion. (4) multivariate logistic regression analysis showed that age>75 years, hypertension , diabetes, reperfusion,aspirin, beta-blocker, and ACEI/ARB inhibitor use were associated independently with in-hospital mortality. CONCLUSION: In most tertiary hospitals in China the application of medications is better than that of the secondary hospitals., but there is a big gap between guidelines and current management of ST segment elevation ACS in China ,and the application status in China could be further improved. PMID- 21681280 TI - [Change in airway anaphylatoxin-complement factors C3a of sputum in patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the possible role of anaphylatoxin(C3a) in chronic obstructive pulmonary disease (COPD). METHODS: Sixty-four elderly patients with COPD (including 51 males, 13 females, 31 with acute exacerbation of COPD and 33 with stable COPD) and 25 healthy controls were recruited in the study. The levels of C3a in the serum of centrifugated induced sputum and cell differential count in sendiment were determined. RESULTS: The level of C3a [44.2 (13.2-48.5) MUg/L] in induced sputum in acute exacerbation of COPD was significantly higher than those in the stable COPD [5.5 (3.6-20.7) MUg/L, Z=-2.974, P=0.003] and the controls [1.7 (0.1-5.9) MUg/L, Z=-3.145, P=0.002]. The level of C3a in the stable COPD was higher than that in the healthy subjects, but the statistical difference was not significant. The C3a levels in smokers and non-smokers of the healthy controls were 1.97 (0.12-6.27) MUg/L and 1.36 (0.09-5.57) MUg/L, respectively, and had no difference (P>0.05). The level of C3a in induced sputum was positively correlated with the number of total leukocytes (r=0.543, P<0.05). CONCLUSION: C3a in induced sputum is significantly increased in COPD, and its high level correlates with the advanced stage of the disease, which suggests a possible role of C3a in the pathogenesis of COPD. PMID- 21681281 TI - [Establishment of a mathematical prediction model to evaluate the probability of malignancy or benign in patients with solitary pulmonary nodules]. AB - OBJECTIVE: To evaluate the clinical factors affecting the definite pathological diagnosis of solitary pulmonary nodules (SPN) with multivariate Logistic regression analysis, and to build the clinical prediction model to estimate the probability of malignancy. METHODS: A retrospective cohort study in our institution included 371 patients (197 males and 174 females) with definite pathological diagnosis of solitary pulmonary nodules from Jan 2000 to Sep 2009 (group A). Clinical data included age, gender, course of disease, symptoms, history and quantity of smoking history, history of tumor, family history of tumor, site, diameter, calcification, speculation, border, lobulation, traction of pleural, vascular convergence sign, and cavity. The independent predictors of malignancy were estimated with multivariate analysis, then the clinical prediction model was built. Other 62 SPN patients (group B) with definite pathological diagnosis in our institute from Oct 2009 to Mar 2010, were used to validate value of this clinical prediction model. RESULTS: 53.1% of the nodules were malignant, and 46.9% were benign in goup A. Logistic regression analysis showed that seven clinical characteristics [age of patient (OR: 1.073), diameter (OR: 1.966), border (OR: 0.245), calcification (OR: 0.199), spiculation (OR: 2.088) and the family history of tumor (OR: 3.550)] were independent predictors of malignancy in patients with SPN (P<0.05). The cut-off value was 0.463. The sensitivity in group B was 92.5%, specificity 81.8%, positive predictive value 90.2%, and negative predictive value 85.7%. The area under the ROC curve for our model was 0.888+/-0.054. CONCLUSION: Age of patient, diameter, border, calcification, spiculation and the family history of tumor are independent predictors of malignancy in patients with SPN. Our prediction model is accurate and sufficient to estimate the malignancy of patients with SPN. PMID- 21681282 TI - [Clinical characteristics and follow-up management of 135 children with myasthenia gravis]. AB - OBJECTIVE: To investigate and analyze the clinical manifestations, classification, therapeutic approaches and follow-up of myasthenia gravis (MG) in children in order to improve its management and prognosis. METHODS: Clinical information of 135 children with MG, who were diagnosed between January 1993 to January 2008, were collected and retrospectively analyzed. And prospective following-up of these patients were conducted. RESULTS: Among the 135 cases, 59 were males and 76 females, giving the ratio of M/F around 1:1.3. Totally, 115 cases (85.2%) were type I MG (ocular type), of which only 4.2% developed to generalized type during the subsequent clinical course. Type II MG (generalized type)was found in 18 cases (13.4%) and type III MG in two cases(1.5%). The onset age ranged from 5 month to 15 years, with 50.3% before three years and 80.7% before seven years. Upper respiratory tract infection was presented in 26.7% (36/135) of the sick children before the onset of MG. Among the 106 children being followed up, recurrence of the disease identified in 50.9% and the number of relapse ranged from 1 to 9. Altogether, 40.19% (43/106) of the cases were positive for anti-acetylcholine receptor antibodies (AchR-Ab) on the initial examination, and the AchR-Ab postitive rate showed no difference among different clinical subtypes and states. However, during the follow-up, 53% (9/17) of the recurrent cases, who were negative at the first onset, turned to be positive, and 37.97% (30/79) were positive for repetitive nerve stimulation in electromyogram test. There were 71 % (45/63) of all the cases showed reduced levels of CD4+ and/or CD3+ and/or CD8+. Thymus proliferation was found in 5.93% (8/135) through CT scan and thymoma in 1.48% (2/135). Steroids and anti-cholinesterase administration were effective in most cases with good prognosis. CONCLUSION: Childhood MG, mainly type I, is relatively common in China, with specific characteristics which are different from western patients or adult MG in morbidity, sex distribution, progress, laboratory examination and treatment. The prevalence of myasthenia gravis crisis and mortality rate in MG children is low, and few are accompanied with thymoma. Most MG cases have a satisfied prognosis and few have neuropsychic sequela. PMID- 21681283 TI - [Correlation analysis of prostate volume with body mass index, blood pressure, blood lipid and glucose in 30-50 year-old men]. AB - OBJECTIVE: To study the correlation between prostate volume and body mass index, blood pressure, blood lipid and glucose in 30-50 year-old males. METHODS: Prostate volume (PV), body mass index (BMI), blood pressure(BP), blood glucose (BG), blood cholesterol (CHOL), triglyceride (TG), low density lipoprotein (LDL) and high density lipoprotein (HDL) were measured in 1 002 30-50 year-old males. The correlation of PV with BMI, BP, BG, CHOL, TG, LDL, and HDL were analyzed with SPSS 13.0 statistical software. RESULTS: The subjects' average age was (43.66 +/- 0.17) years, and their mean prostate volume (14.28+/-0.02) mL. The statistical analyses regarding the age (P=0.000, r=0.62), BMI (P=0.013,r=0.57), BG (P=0.032, r=0.52), CHOL (P=0.040,r=0.51), LDL (P=0.032, r=-0.50), HDL (P=0.017,r=-0.48) were significantly associated with PV. Adjusted for age factors, PV still had a strong correlation with BMI and LDL, P values were 0.029, 0.001, r values were 0.53, -0.49. CONCLUSION: In the 30-50 year-old males, BMI and dyslipidemia could be risk factors in the way of the enlargement of prostate volume. Weight control and therapy of blood lipid abnormalities may delay the increase of prostate volume. PMID- 21681284 TI - [Treatment of hepatolithiasis by multiple operative methods with hepatico subcutaneous stoma]. AB - OBJECTIVE: To evaluate the mid-term and long-term outcomes of patients with hepatolithiasis after receiving multiple operative methods with hepatico subcutaneous stoma. METHODS: A retrospective analysis was performed based on 156 patients with hepatolithiasis who underwent multiple operative methods with hepatico-subcutaneous stoma from Apr. 1993 to Mar. 2010 in Peking University Third Hospital. Thirty-seven of them had stone in the left lobe (23.7%), 22 in the right lobe (14.1%), and 97 in bilateral lobes (62.2%). Ninety-nine patients had hepatolithiasis combined with biliary stricture (63.5%). RESULTS: All of the patients underwent successful operations and recovered well with no death in perioperative period. The rate of operative complications was 35.9%. A total of 146 patients were followed up with a median time of 7 years. The rate of patients with cholangitis, recurrent stone, and biliary stricture newly detected was 13.0% (19/146), 21.9% (32/146) and 8.2% (12/146), respectively. Draining inflammatory bile and taking out recurrent stones by hepatico-subcutaneous stoma were carried out in 35 patients (24.0%). CONCLUSION: Treatment of hepatolithiasis with biliary stricture and its recurrence by multiple operative methods with hepatico subcutaneous stoma is safe, effective, minimally invasive, and easy to perform. PMID- 21681285 TI - [Comparison of dynamic optical breast imaging (DOBI) and mammography in sensitivity, specificity and safety of breast cancer diagnosis: a prospective analysis of 62 patients in two centers]. AB - OBJECTIVE: To assess the sensitivity, specificity and safety of dynamic optical breast imaging (DOBI) and mammography according to the pathological results. METHODS: From June 2005 to January 2006, 62 patients in Peking University People's Hospital and Capital Medical University Affiliated ChaoYang Hospital who received mammography and needed biopsy were enrolled prospectively, signed the consent form and recorded the comfortable level, acceptability and any complications during DOBI examination. Images obtained with DOBI and mammography were evaluated by 3 independent doctors who didn't know the pathological results to calculate the breast cancer diagnostic sensitivity and specificity. RESULTS: In this study the sensitivity and specificity of breast cancer diagnosis by mammography were 0.935 5+/-0.044 1 (95%CI 0.709 2-0.968 2)and 0.451 6+/-0.089 4 (95%CI 0.276 4-0.626 8)respectively. The sensitivity and specificity of DOBI were 0.838 7+/-0.066 1 (95%CI 0.709 2-0.968 2)and 0.612 9+/-0.087 5 (95%CI 0.441 4 0.784 4)respectively. In the DOBI examination there was no adverse reaction. The tolerability of DOBI was good. CONCLUSION: Dynamic optical breast imaging could provide the functional information about angiogenesis on the lesion and improve the breast cancer diagnostic specificity. It is a potential non-invasive breast functional imaging diagnostic tool and needs more large scale clinical trial to determine its indications and diagnostic criteria. PMID- 21681286 TI - Tadalafil alters energy metabolism in C2C12 skeletal muscle cells. AB - Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides, thereby modulating cell functions. Three highly selective PDE5 inhibitors (PDE5i), sildenafil, vardenafil and tadalafil, have been developed for treatment of erectile dysfunction (ED). Experimental evidence showed that chronic treatment with sildenafil PDE5i in a mouse model of diet-induced obesity and insulin resistance improved insulin action and decreased circulating fatty acid levels. It has recently been shown that healthy athletes use PDE5i as performance enhancers, hence in the present study we investigated whether the long-lasting PDE5i tadalafil influences energy metabolism in C2C12 skeletal muscle cells by evaluating lactate production, glucose consumption, and citrate synthase and 3-OH acyl CoA dehydrogenase activities. Our data demonstrate that tadalafil is able to modulate energy homeostasis in mouse skeletal muscle cells, depending on the treatment length and dose. PMID- 21681287 TI - Sequence analysis of human cytomegalovirus US28 gene in low-passage clinical isolates from children and AIDS patients. AB - Human cytomegalovirus (HCMV) is often a dangerous opportunistic pathogen that causes significant morbidity and mortality in newborn children and immunocompromised patients. The different symptoms and tissue tropisms of HCMV infection may result from genetic polymorphism. This study investigated the sequence variability of the HCMV US28 ORF, which shows sequence homology to the G protein-coupled receptor. HCMV isolated from suspected pediatric cases and isolates from AIDS patients were compared in order to examine the possible associations between polymorphisms and pathogenesis. Seventy children with suspected congenital HCMV infection, who suffered from jaundice (47), megacolon (10), and microcephaly (13), and 17 AIDS patients, were studied. Mutation was prevalent among the sequences of US28, with a focus on the two ends of US28. The important functional groups of US28 are highly conserved. An unrooted tree showed that all sequences from suspected congenitally infected infants and AIDS patients were divided into three groups. Comparison showed that most of the sequences (12/17) from pediatric patients were included in the first group (G1), whereas most of the sequences (11/17) from AIDS patients were included in the third group (G3). The specific high mutation sites in US28 from children were located at the C terminus of the protein, whereas those from AIDS patients were located at the N terminus. We demonstrated the existence of polymorphisms among the US28 genes of clinical isolates of HCMV from infants with suspected congenital infection. Comparison of US28 sequences from AIDS patients with those from children showed that both sequences have their own specific high mutation points. PMID- 21681288 TI - Two-photon induced responsive f-f emissive detection of Cyclin A with a europium chelating peptide. AB - Responsive linear and two-photon induced europium emissive probes have been synthesised with a tailor made peptide for the detection of Cyclin A, the hypersensitive Eu emission (Eu-2) gave the real time signalling and also enhanced the two-photon absorption cross section from 12 GM to 68 GM after Cyclin A binding. PMID- 21681289 TI - Surface structure and reactivity of Pd(100) during CO oxidation near ambient pressures. AB - The surface structure of Pd(100) during CO oxidation was measured using a combination of a flow reactor and in situ surface X-ray diffraction coupled to a large-area 2-dimensional detector. The surface structure was measured for P(O(2))/P(CO) ratios between 0.6 and 10 at a fixed total gas pressure of 200 mbar and a fixed CO pressure of 10 +/- 1 mbar. In conjunction with the surface structure the reactivity of the surface was also determined. For all P(O(2))/P(CO) ratios the surface was found to oxidize above a certain temperature. Three different types of oxides were observed: the surface oxide, an epitaxial layer of bulk-like PdO, and a non-epitaxial layer of bulk-like PdO. As soon as an oxide was present the reactivity of the surface was found to be mass transfer limited by the flux of CO molecules reaching the surface. PMID- 21681290 TI - Enhanced photocatalytic and adsorptive degradation of organic dyes by mesoporous Cu/Al2O3-MCM-41: intra-particle mesoporosity, electron transfer and OH radical generation under visible light. AB - Mesoporous Cu/Al(2)O(3)-MCM-41 composite was synthesized by two step processes; in situ incorporation of high surface area mesoporous Al(2)O(3) (MA) into the framework of MCM-41 (in situ method) followed by impregnation of Cu(II) by incipient wetness method. The interesting thing is that starch was used for the first time as template for the preparation of high surface area MA. To evaluate the structural and electronic properties, these catalysts were characterized by low angle X-ray diffraction (LXRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), UV-vis DRS, FTIR and photoluminescent (PL) spectra. The various cationic dye such as methylene blue (MB), methyl violet (MV), malachite green (MG) and rhodamine 6G (Rd 6G) of high concentration 500 mg L(-1) were degraded and adsorbed very efficiently (100%) using the 5 Cu/Al(2)O(3) MCM-41 composite within 30 and 60 min, respectively. The high and quick removal of such concerted cationic organic dyes and also mixed dyes (MB+MV+MG+Rd 6G) by means of photocatalysis/adsorption is basically due to the combined effect three characteristics of synthesized mesoporous 5 Cu/Al(2)O(3)-MCM-41 composite. These characteristics are intra-particle mesoporosity, electron transfer and OH radical generation under solar light. PMID- 21681291 TI - A series of novel rare-earth bismuth tungstate compounds LnBiW2O9 (Ln=Ce, Sm, Eu, Er): synthesis, crystal structure, optical and electronic properties. AB - The structural, optical, and electronic properties of four rare-earth bismuth tungstate compounds, LnBiW(2)O(9) (Ln = Ce, Sm, Eu, Er), have been investigated by means of single-crystal X-ray diffraction, elemental analyses, and spectral measurements. For some of the compounds, the calculations of energy band structures and density of states have also been made by the density functional theory. The structure of CeBiW(2)O(9) features a three-dimensional (BiW(2)O(9))(3 ) anionic framework with interesting channels where Ce atoms are located. The framework is constructed by one-dimensional BiO(9) polyhedra chains and one dimensional zigzag W(2)O(9) chains via edge- and face-sharing. LnBiW(2)O(9) (Ln = Sm, Eu, Er) are isostructural and their structures feature a three-dimensional network based on alternating (BiO(2))(-) layers and (Ln(2)W(2)O(12))(6-) layers connected by corner-linked chains of WO(6) octahedra. Results of spectral measurements indicate that EuBiW(2)O(9) exhibit the characteristic yellow-red light emission under excitation at 395 nm, and it will be a red phosphor in designing white light-emitting diode device. The calculated results of band structures by using the density functional theory (DFT) show that the solid-state compound CeBiW(2)O(9) and SmBiW(2)O(9) are indirect band gap materials. PMID- 21681292 TI - Enhancement of dye-sensitized photocurrents by gold nanoparticles: effects of dye particle spacing. AB - Photocurrents of a ruthenium dye-TiO(2) system are enhanced by gold nanoparticles (100 or 40 nm diameter) embedded in TiO(2). As dye-particle spacing decreases to 10 nm, enhancement factor and intensity of localized electric fields at the TiO(2) surface increase. A further decrease in the spacing suppresses the enhancement. PMID- 21681293 TI - The two spin states of an end-on copper(II)-superoxide mimic. AB - The reaction of nitrosobenzene with copper(I) complexes of a tetradentate ligand led to two novel species that are best described as copper(II) complexes of an O bonded nitrosobenzyl radical anion, in either the singlet or the triplet spin state. Both states were characterized by crystal structures, magnetic measurements and DFT calculations. PMID- 21681294 TI - Synthesis, characterization, and photovoltaic properties of a low-bandgap copolymer based on 2,1,3-benzooxadiazole. AB - PBDTBO, a conjugated polymer comprising benzo[1,2-b:4,5-b']dithiophene (BDT) and 5,6-bis(octyloxy)benzo[c][1,2,5]oxadiazole (BO) units, exhibits a deep HOMO energy level of -5.27 eV and excellent solubility. A device incorporating PBDTBO and [6,6]-phenyl-C(61)-butyric acid methyl ester (1:1, w/w) exhibited a power conversion efficiency of 5.7%. PMID- 21681295 TI - Direct, copper-catalyzed oxidation of aromatic C-H bonds with hydrogen peroxide under acid-free conditions. AB - The direct oxidation of benzene into phenol using hydrogen peroxide has been achieved in the absence of any acid with Tp(x)Cu(NCMe) complexes as the catalysts. In the case of anthracenes as the substrates, valuable anthraquinones have been quantitatively obtained in the same manner. PMID- 21681301 TI - An advanced model framework for solid electrolyte intercalation batteries. AB - Recent developments of solid electrolytes, especially lithium ion conductors, led to all solid state batteries for various applications. In addition, mathematical models sprout for different electrode materials and battery types, but are missing for solid electrolyte cells. We present a mathematical model for ion flux in solid electrolytes, based on non-equilibrium thermodynamics and functional derivatives. Intercalated ion diffusion within the electrodes is further considered, allowing the computation of the ion concentration at the electrode/electrolyte interface. A generalized Frumkin-Butler-Volmer equation describes the kinetics of (de-)intercalation reactions and is here extended to non-blocking electrodes. Using this approach, numerical simulations were carried out to investigate the space charge region at the interface. Finally, discharge simulations were performed to study different limitations of an all solid state battery cell. PMID- 21681302 TI - Highly sensitive phototransistor with crystalline microribbons from new pi extended pyrene derivative via solution-phase self-assembly. AB - A new pyrene-cored pi-conjugated molecule has been synthesized through Sonogashira coupling reaction. The single-crystalline microribbon-based FET exhibited the highest mobility of 0.7 cm(2) V(-1) s(-1) (I(on)/I(off) > 10(6)). Single-crystalline microribbons were employed to operate in an organic phototransistor (OPT) under very low light intensity (I = 5.6 MUW cm(-2)). PMID- 21681303 TI - Signal-on electrochemiluminescent biosensor for ATP based on the recombination of aptamer chip. AB - A novel signal-on electrochemiluminescent (ECL) biosensor based on adenosine triphosphate (ATP)-induced recombination of split aptamer chips is presented. PMID- 21681304 TI - Studies on the reactivity of group 15 Zintl ions with carbodiimides: synthesis and characterization of a heptaphosphaguanidine dianion. AB - Reaction of the hydrogenheptaphosphide dianion, [HP(7)](2-), with one equivalent of bis(2,6-diisopropylphenyl)carbodiimide yielded the exo-functionalized cluster [P(7)C(NDipp)(NHDipp)](2-) (Dipp = 2,6-diisopropylphenyl). This species was characterized by single crystal X-ray diffraction, multielement NMR spectroscopy and electrospray mass-spectrometry. DFT calculations on the dianion were also conducted. PMID- 21681305 TI - alpha-Fe2O3 nanotubes with superior lithium storage capability. AB - Polycrystalline alpha-Fe(2)O(3) nanotubes with thin walls have been synthesized by one-step template-engaged precipitation of Fe(OH)(x) followed by thermal annealing. In virtue of the unique structural features, these alpha-Fe(2)O(3) nanotubes exhibit superior lithium storage capabilities with exceptional high rate capacity retention as a potential anode material for lithium-ion batteries. PMID- 21681306 TI - Bacterial formation of extracellular U(VI) nanowires. AB - Shewanella oneidensis MR-1 rapidly accumulates long, extracellular, U(VI) nanowires composed of polycrystalline chains of discrete meta-schoepite (UO(3).2H(2)O) nanocrystallites. The production of uranium(VI) nanowires could provide a novel strategy for remediation of uranium contamination in sediments and aquifers, as well as the recovery of uranium in manufacturing processes. PMID- 21681307 TI - In vivo cell death mediated by synthetic ion channels. AB - Synthetic ion channel hydraphiles, which are known to infiltrate membranes and disrupt ion homeostasis, were tested as direct injection toxins in live mice as potential schlerotic agents. The study uses a near-IR dye to image and evaluate the success of the approach. PMID- 21681309 TI - Luminescence properties of 4-hydroxy-5-phenylpyrido[3,2,1-jk]carbazol-6-one: solvatochromism and sensitivity to amine solution. AB - A detailed photophysical analysis of 4-hydroxy-5-phenylpyrido[3,2,1-jk]carbazol-6 one (HPPCO) is presented. When exposed to UV light, the compound produced deep blue to green luminescence, depending on the solvent. The luminescence peak shifts with the Gutmann donor number (DN) of the solvent and the proton substitution affects luminescence; a correlation between quantum yield and decay time indicated that proton transfer plays a key role in the observed solvatochromism. The ground-state deprotonation of HPPCO was apparently evidenced from the absorption and/or the excitation spectra in the solvents with large DN values. DFT and ZINDO calculations on the structural and optical properties have shown that deprotonation increases the contribution of oxygen atoms to the HOMO, thereby lowering the transition energy from the HOMO to the LUMO. Because the luminescence properties of HPPCO depend on proton transfer, it may be used to detect and quantitate amines in solution. The sensitivity of the luminescence to various amines was ~10(5) M(-1) and was more effective in ethanol than in methanol. PMID- 21681308 TI - Differential transition metal uptake and fluorescent probe localization in hippocampal slices. AB - Metals are taken up by the combined action of metal transporters and ion channels. In this communication we have measured the uptake of the biologically important transition metals Mn, Fe, Co, Ni, Cu, Zn and Cd by rat and mouse hippocampal slices using the fluorescent probes FluoZin-3 (FZ3) and Newport Green (NPG), introduced by acetoxymethyl ester (AM) loading. The combination of metals and probes is also used to attempt to localize cellular sites into which metals translocate. We show that FZ3 and NPG partition into different cellular compartments; FZ3 into neuropil, whereas NPG localizes in neuropil and compartments within the cell bodies of neurons. Ni, Zn and Cd pass across the plasma membrane and then accumulate in intracellular vesicles and within intracellular membranes of cell bodies. The latter accumulate Cd, while synaptic vesicles take up Co. The passage of Mn, Cu and Fe into cells can be detected but there is some uncertainty about their disposition within the cell. All of our experiments are consistent with metals accumulating in intracellular compartments rather than the cytoplasm. Whether and to what extent there are transient elevations of free zinc levels in the cytoplasm remains unclear. PMID- 21681310 TI - Metallothionein-inspired prototype of molecular pincer. AB - Study of Zn and Pb release from complexes with natural and synthetic amidothiol motifs inspired the design of a "molecular pincer" that scavenges quantitatively metals from liquid environment and releases them, on-demand, under very mild oxidative conditions. PMID- 21681311 TI - Multiple photosynthetic reaction centres composed of supramolecular assemblies of zinc porphyrin dendrimers with a fullerene acceptor. AB - Multiple photosynthetic reaction centres have successfully been constructed using supramolecular complexes of zinc porphyrin dendrimers [D(ZnP)(n): n = 4, 8, 16] with fulleropyrrolidine bearing a pyridine ligand (C(60)py). Efficient energy migration occurs completely between the ZnP units of dendrimers prior to the electron transfer with increasing the generation of dendrimers to attain an extremely long charge-separation lifetime. PMID- 21681312 TI - Top-down shaping of metal nanoparticles in solution: partially etched Au@Pt nanoparticles with unique morphology. AB - Metallic nanoparticles with a unique morphology were produced by combining bottom up nucleation/growth and top-down etching for Au core-Pt shell nanoparticles. Interesting optical and electrocatalytic properties were observed for the newly formed shapes. PMID- 21681313 TI - Organosilica nanotubes: large-scale synthesis and encapsulation of metal nanoparticles. AB - In this communication we have demonstrated the synthesis of organosilica nanotubes with inner diameter of ~6 nm and their carbonization to form carbon/silica composite nanotubes. Pd nanoparticles. encapsulated in the organosilica and carbon/silica nanotubes show different catalytic activities in the hydrogenation of cyclohexene. PMID- 21681314 TI - 2-step plasma-enhanced CVD for low-temperature fabrication of silica membranes with high gas-separation performance. AB - Amorphous SiO(2) membranes were prepared via a 2-step plasma-enhanced CVD (PECVD) technique at room temperature on porous TiO(2)/Al(2)O(3) substrates. SiO(2) membranes showed molecular sieving properties with a high separation factor for He/N(2) and He/H(2), and high thermal stability, indicating the successful preparation of high-performance membranes at low temperatures. PMID- 21681315 TI - Reversible pressure-induced amorphization of a zeolitic imidazolate framework (ZIF-4). AB - We report the reversible pressure-induced amorphization of a zeolitic imidazolate framework (ZIF-4, [Zn(Im)(2)]). This occurs irrespective of pore occupancy and takes place via a novel high pressure phase (ZIF-4-I) when solvent molecules are present in the pores. A significant reduction in bulk modulus upon framework evacuation is also observed for both ZIF-4 and ZIF-4-I. PMID- 21681316 TI - Selective cage boron/carbon extrusion reaction of 13-vertex carborane MU-1,2 (CH2)3-1,2-C2B11H11: formation of nido-CB10, closo-CB10, and closo-C2B10 species. AB - The nature of nucleophiles greatly influences the reactivity patterns of 13 vertex carboranes. MU-1,2-(CH(2))(3)-1,2-C(2)B(11)H(11) reacts with Et(3)N/MeOH, pyridine or bipyridine to give cage-boron and -carbon extrusion products nido CB(10) or closo-CB(10), or a cage-boron extrusion compound closo-C(2)B(10) while the cage-carbon extrusion species closo-CB(11) monoanions are produced by treatment with MeOH or Ph(3)P. PMID- 21681317 TI - Confined PFSA-zeolite composite membrane for self-humidifying fuel cell. AB - Perfluorosulfonic acid (PFSA) polyelectrolyte confined in subnanoliter volume within zeolite cladded walls exhibits higher glass transition temperature and excellent tolerance to high-temperature fuel cell operation under dry conditions, generating an order of magnitude higher power density than standard PEMFC. PMID- 21681318 TI - A versatile palladium catalyst system for Suzuki-Miyaura coupling of alkenyl tosylates and mesylates. AB - A general and effective palladium system for Suzuki-Miyaura coupling of alkenyl electrophiles under mild reaction conditions is reported. With the Pd(OAc)(2)/CM phos system, a variety of alkenyl tosylates are coupled well with ArB(OH)(2). Moreover, the first successful examples of using alkenyl mesylates in alkenylation are also described. PMID- 21681319 TI - Polybenzimidazole block sulfonated poly(arylene ether sulfone) ionomers. AB - Novel ionomers based on polybenzimidazole block sulfonated poly(arylene ether sulfone) show excellent thermal properties. The ionic aggregation of sulfonic acid groups leads to well-developed phase separated morphology and thus high proton conductivity at wide humidity range, up to 65 mS cm(-1) at 90% relative humidity. PMID- 21681320 TI - Control of electron-transfer reduction by protonation of zinc octabutoxyphthalocyanine assisted by intramolecular hydrogen bonding. AB - Facile protonation of alpha-octabutoxyphthalocyaninato zinc(II) (Zn(OBu)(8)Pc) occurs to afford up to tetra-protonated species stabilized by intramolecular hydrogen bonding, resulting in positive shifts of the reduction potentials of Zn(OBu)(8)PcH(n)(n+) (n = 1-4) with increasing the number of protons attached to facilitate electron-transfer reduction. PMID- 21681321 TI - The phytoalexins from cultivated and wild crucifers: chemistry and biology. AB - Phytoalexins are antimicrobial secondary metabolites produced de novo by plants in response to stress, including microbial attack. In general, phytoalexins are important components of plant defenses against fungal and bacterial pathogens. The phytoalexins of crucifers are indole alkaloids derived from (S)-tryptophan, most of which contain a sulfur atom derived from cysteine. Beside their antimicrobial activity against different plant pathogenic species, cruciferous phytoalexins have shown anticarcinogenic effects on various human cell lines. This review focuses on the phytoalexins produced by cruciferous plants reported to date, with particular emphasis on their chemical synthesis, biosynthesis, metabolism by plant fungal pathogens and biological activities. A summary table containing all phytoalexins, their cultivated and wild cruciferous sources, their synthetic starting materials, biotransformation products and biological activities is provided. PMID- 21681322 TI - A stable molecular nickel catalyst for the homogeneous photogeneration of hydrogen in aqueous solution. AB - Light-driven H(2) production is catalyzed by [Ni(P(2)(Ph)N(2)(Ph))(2)](BF(4))(2) when irradiated with visible light in water/acetonitrile mixed solvent in the presence of a photosensitizer (PS) and ascorbate. The catalyst gives over 2700 turnovers over 150 h, and does not degrade despite photodecomposition of the PS. PMID- 21681323 TI - Reversibility of electrochemical reactions of sulfur supported on inverse opal carbon in glyme-Li salt molten complex electrolytes. AB - Electrochemical reactions of sulfur supported on three-dimensionally ordered macroporous carbon in glyme-Li salt molten complex electrolytes exhibit good reversibility and large capacity based on the mass of sulfur, which suggests that glyme-Li salt molten complexes are suitable electrolytes for Li-S batteries. PMID- 21681324 TI - Viscoelastic nanocomposite composed of titania nanosheets: multiple conductometric sensitivities. AB - Graft polymerization of trimethoxysilyl-containing ammonium cations on negatively charged titania nanosheets gives a photoluminescent viscoelastic nanocomposite. Proton conduction network comprised of adsorbed water molecules near the titania slabs leads to the multiple conductometric sensitivities to temperature, humidity, and photo-irradiation. PMID- 21681325 TI - Cu(I) and Pb(II) complexes containing new tris(7-naphthyridyl)methane derivatives: synthesis, structures, spectroscopy and geometric conversion. AB - Two novel facial-capping tris-naphthyridyl compounds, 2-chloro-5-methyl-7-((2,4 dimethyl-1,8-naphthyridin-7(1H)-ylidene)(2,4-dimethyl-1,8-naphthyridin-7 yl))methyl-1,8-naphthyridine (L(1)) and 2-chloro-7-((2-methyl-1,8-naphthyridin 7(1H)-ylidene)(2-methyl-1,8-naphthyridin-7-yl))methyl-1,8-naphthyridine (L(2)), as well as their Cu(i) and Pb(ii) complexes, [CuL(a)(PPh(3))]BF(4) (1) (PPh(3) = triphenylphosphine, L(a) = bis(2,4-dimethyl-1,8-naphthyridin-7-yl)(2-chloro-5 methyl-1,8-naphthyridin-7-yl)methane), [CuL(b)(PPh(3))]BF(4) (2) (L(b) = bis(2 methyl-1,8-naphthyridin-7-yl)(2-chloro-1,8-naphthyridin-7-yl)methane), [Pb(OL(a))(NO(3))(2)] (3) (OL(a) = bis(2,4-dimethyl-1,8-naphthyridin-7-yl)(2 chloro-5-methyl-1,8-naphthyridin-7-yl)methanol) and [Pb(L(b))(2)][Pb(CH(3)OH)(NO(3))(4)] (4), have been synthesized and characterized by X-ray diffraction analysis, MS, NMR and elemental analysis. The structural investigations revealed that the transfer of the H-atom at the central carbon to an adjacent naphthyridine-N atom affords L(1) and L(2) possessing large conjugated architectures, and the central carbon atoms adopt the sp(2) hybridized bonding mode. The reversible hydrogen transfer and a geometric configuration conversion from sp(2) to sp(3) of the central carbon atom were observed when Pb(II) and Cu(I) were coordinated to L(1) or L(2). The molecular energy changes accompanying the hydrogen migration and titration of H(+) to different receptor-N at L(1) were calculated by density functional theory (DFT) at the SCRF-B3LYP/6 311++G(d,p) level in a CH(2)Cl(2) solution, and the observed lowest-energy absorption and emission for L(1) and L(2) can be tentatively assigned to an intramolecular charge transfer (ICT) transition in nature. PMID- 21681326 TI - Neodymium(III) complexation by amino-carbohydrates via a ligand-controlled hydrolysis mechanism. AB - Chelation of Nd(3+) by D-glucosamine (DGA) and chitosan was investigated in solution at near-physiological pH and ionic strength. This research demonstrates the first example of the lanthanide ion heteroleptic hydroxo-carbohydrate complex in solution. Amino-carbohydrates DGA and chitosan suppressed formation of polynuclear Nd(3+) species at elevated pH. PMID- 21681327 TI - High performance of phosphonate-functionalized mesoporous silica for U(VI) sorption from aqueous solution. AB - The renaissance of nuclear energy promotes increasing basic research on the separation and enrichment of nuclear fuel associated radionuclides. Herein, we report the first study for developing mesoporous silica functionalized with phosphonate (NP10) as a sorbent for U(VI) sorption from aqueous solution. The mesoporous silica was synthesized by co-condensation of diethylphosphatoethyltriethoxysilane (DPTS) and tetraethoxysilane (TEOS), using cationic surfactant cetyltrimethylammonium bromide (CTAB) as the template. The synthesized silica nanoparticles were observed to possess a mesoporous structure with a uniform pore diameter of 2.7 nm, and to have good stability and high efficiency for U(VI) sorption from aqueous solution. A maximum sorption capacity of 303 mg g(-1) and fast equilibrium time of 30 min were achieved under near neutral conditions at room temperature. The adsorbed U(VI) can be easily desorbed by using 0.1 mol L(-1) HNO(3), and the reclaimed mesoporous silica can be reused with no decrease of sorption capacity. In addition, the preconcentration of U(VI) from a 100 mL aqueous solution using the functionalized mesoporous silica was also studied. The preconcentration factor was found to be as high as 100, suggesting the vast opportunities of this kind of mesoporous silica for the solid phase extraction and enrichment of U(VI). PMID- 21681328 TI - DFT/TDDFT study on the electronic structures and optoelectronic properties of several red-emitting osmium(II) complexes with different P^P ancillary ligands. AB - The ground and excited state geometries of several red-emitting phosphors (N^N)(2)Os(P^P) [where N^N = 5-(1-isoquinolyl)-1,2,4-triazoles, P^P = bis(dimethylphosphino)methylene(dmpm) (1); P^P = cis-1,2-bis (dimethylphosphino)ethene(dmpe) (2); P^P = 1,2 bis(dimethylphosphino)benzene(dmpb) (3); P^P = 1,2 bis(dimethylphosphino)naphthalene(dmpn) (4); P^P = 1,2-bis(dimethylphosphino)-4 cyano-benzene(dmpcb) (5)] have been investigated by using the density functional theory (DFT) methods. The calculated results indicate that, for the studied complexes, the electron-transporting performance is better than the hole transporting performance. The alteration of cis-P^P ancillary ligands with different conjugation lengths and substituents has an impact on the optoelectronic properties of these complexes, especially the electron-withdrawing group -CN in 5. The calculated energy gaps are nearly the same for complexes 1 to 4 (3.34 eV), while for 5, the HOMO and LUMO energies are lowered and the energy gap increases (3.42 eV). The absorption of 1 is red shifted, while that of 5 is blue shifted compared with the absorptions of 2, 3, and 4, which have similar absorptions. Complexes 2, 3, and 4 have almost identical emission wavelength 699 nm, while 1 (715 nm) and 5 (735 nm) are red shifted. The calculated electron affinities and reorganization energies indicate that complex 5 is the easiest for electron injection and has the best electron-transporting performance. PMID- 21681329 TI - Facile synthesis of LiMnPO4 olivines with a plate-like morphology from a dittmarite-type KMnPO4.H2O precursor. AB - Dittmarite-type compound KMnPO(4).H(2)O was used as a new precursor for the synthesis of nanostructured LiMnPO(4) phospho-olivines with a plate-like morphology at low temperature (about 200 degrees C) and a short reaction time (90-180 min). The dehydration of KMnPO(4).H(2)O was studied by DTA and TG analysis. Structural and morphological characterization of both KMnPO(4).H(2)O and LiMnPO(4) was performed by powder XRD, SEM and TEM analyses. The formation of nanostructured LiMnPO(4) was examined by electron paramagnetic resonance spectroscopy and TEM. It was found that the reaction between KMnPO(4).H(2)O with the LiCl-LiNO(3) mixture includes a fast ionic exchange of K(+) with Li(+) in the framework of the dittmarite structure, followed by H(2)O release and the formation of the olivine-type structure. The morphology and texture of the dittmarite-type precursor results in a plate-like morphology of LiMnPO(4) with a preferred orientation along the [100] direction. The plate-like morphology of LiMnPO(4) is stable after annealing at 500 degrees C. The plates are composed of nanocrystallites, with various sizes in the range 10-20 nm. The EPR signal of LiMnPO(4) is due to the exchange-coupled Mn(2+) ions. It was demonstrated that the EPR line-width correlates with the Scherrer crystallite size. PMID- 21681330 TI - Monofunctional platinum complexes containing a 4-nitrobenzo-2-oxa-1,3-diazole fluorophore: distribution in tumour cells. AB - Two monofunctional platinum(II) complexes, cis-[PtL(NH(3))(2)Cl]NO(3) (1) and cis [PtL'(NH(3))(2)Cl]NO(3) (2) {L = N-methyl-7-nitro-N-(2-(pyridin-2 yl)ethyl)benzo[c][1,2,5]-oxadiazol-4-amine, L' = 7-nitro-N-(2-(pyridin-2 yl)ethyl)benzo[c][1,2,5] oxadiazol-4-amine}, have been synthesized and characterized. The X-ray single crystal structure of complex 1 shows that platinum(II) is coordinated in a square-planar geometry with a [PtN(3)Cl] setting. Fluorescence profiles of the complexes show that complex 1 is more suitable for cellular imaging than complex 2. The cellular uptake and distribution of complex 1 in the human cervical cancer HeLa cells were studied using confocal microscopy. Complex 1 enters the cells slowly, induces cytoplasmic vacuolations, and accumulates in the nucleoli. These results suggest that monofunctional platinum(II) complexes can stimulate tumour cells to undergo a nonapoptotic death process, which is distinct from the apoptosis induced by cisplatin. PMID- 21681331 TI - Palladium-assisted multicomponent cyclization of aromatic aldehydes, arylamines and terminal olefins under molecular oxygen: an assembly of 1,4-dihydropyridines. AB - The palladium-assisted one-pot three-component reactions of aldehydes, amines and olefins proceeded smoothly to give 2,6-unsubstituted 1,4-dihydropyridines (1,4 DHPs) using molecular oxygen as a sole oxidant. It also provides efficient Pd catalyzed aerobic oxidation access to the anti-Markovnikov oxidative amination products of olefins from primary aromatic amines and alkenes. The method is atom efficient, using cheap and easily available starting materials and an environmentally benign oxidant. PMID- 21681332 TI - Unsymmetrical diimine chelation to M(II) (M=Zn, Cd, Pd): atropisomerism, pi-pi stacking and photoluminescence. AB - Three types of atropisomeric unsymmetrical diimine complexes, tetrahedral (L(R)(Phi))MX(2) (M = Zn, Cd; X = Cl, Br; R = Me, CMe(3), OH, OMe, Cl; 1a-k, type I), tetrahedral (L(Me2)(Phi))ZnBr(2) (2, type-II) and square planar (L(OH)(phi))PdCl(2) (3, type-III) with different photoluminescence properties, have been reported (L(R)(Phi) = (E)-4-R-N-(pyridine-2-ylmethylene)aniline; Phi = dihedral angle between the diimine unit including the pyridine ring and the phenyl ring planes). In crystals, Phi = 0 degrees for type-I, 90 degrees for type-II and 63 degrees for type-III atropisomers have been confirmed by single crystal X-ray structure determinations of 1c, 1e, 2 and 3.H(2)O isomers. Optimizations of geometries in methanol have established Phi = 28-32 degrees for type-I, 90.83 degrees for type-II and 43.44 degrees for type-III isomers. In solids, type-I atropisomers with Phi = 0, behave as conjugated 14pie systems facilitating pi-pi stacking and are brightly luminescent at room temperature while type-II and type-III isomers in solid and type-I isomers in solutions are more like non-conjugated 8pie + 6pie systems and non-emissive. Frozen glasses of acetonitrile, methanol and dichloromethane-toluene mixture at 77 K of type-I isomers are emissive and display structured excitation and emission spectra for R = Me, CMe(3), OMe species. Excitation and emission maxima of frozen glasses (lambda(ex) = 320-380 nm; lambda(em) = 440-485 nm) are red shifted in the solid (lambda(ex) = 390-455 nm; lambda(em) = 470-550 nm). TD-DFT calculations on 1b, 1d, 1f and stacked (1b)(2) isomers and luminescence lifetime measurements have elucidated that an excited (1)ILCT state has been the origin of emission of the type-I isomers and delocalizations of the photoactive pi(diimine) and pi(diimine)(*) orbitals of the L(R)(Phi) over the stacked layers shift the lambda(ext) and lambda(em) of solids to lower energies than those in frozen glasses. The trends of diimine ligand based electron transfer events of the complexes in DMF have been investigated by cyclic voltammetry at 298 K. PMID- 21681334 TI - A rapid and convergent synthesis of the integrastatin core. AB - The tetracyclic core of the integrastatin natural products has been prepared in a convergent and rapid manner. Our strategy relies upon a palladium(II)-catalyzed oxidative cyclization to form the central [3.3.1]-dioxabicycle of the natural product core. Overall, the core has been completed in only 4 linear steps from known compounds. PMID- 21681333 TI - A highly selective space-folded photo-induced electron transfer fluorescent probe for carbonic anhydrase isozymes IX and its applications for biological imaging. AB - The first highly selective and sensitive fluorescent probe Z1 for detection of carbonic anhydrase IX (CA IX) over isoforms CA I and CA II was developed. As demonstrated, Z1 worked effectively in both enzymatic systems and living hypoxia cells. PMID- 21681335 TI - [Cardioprotection by the inhibitory effect of nitric oxide]. AB - Endothelial and neuronal nitric oxide synthases (eNOS and nNOS) are constitutively expressed in cardiomyocytes under the physiological condition, while inducible nitric oxide synthase (iNOS) is only expressed in cell stress. Nitric oxide (NO) derived from the constitutive isoforms of eNOS and nNOS plays four kinds of inhibitory effects on the myocardium: reducing the contractile frequency of cardiomyocyte, slightly attenuating cardiac contractility, accelerating relaxation and increasing distensibility of cardiomyocyte, and slightly inhibiting mitochondrial respiration and improving the efficiency of myocardial oxygen consumption. In conditions of enhanced cardiac reserve and cardiac hypertrophy, NO derived from eNOS, which forms a complex with a certain kind of receptor on the sarcolemma, modulates receptor-mediated signaling and generates an "accentuated antagonism" by moderate inhibition of cardiac contractility. NO derived from the complex of nNOS-ryanodine receptor (RyR) stabilizes RyR calcium release and increases the efficiency of Ca(2+) cycling in sarcoplasmic reticulum by the inhibitory effects. However, besides the above mentioned inhibitions of NO derived from eNOS and nNOS, NO derived from iNOS generally prevents mitochondrial permeability transition pore opening by inhibiting mitochondrial respiration under the conditions of the myocardial ischemia-reperfusion injury and heart failure. Therefore, both in the physiological condition and in the pathological condition, NO exhibits a moderate inhibition in cardiac function, and eventually produces cardioprotection. PMID- 21681336 TI - [c-SRC knockdown decreases phosphorylated STAT3 expression and viability of HeLa cells]. AB - The present study was to determine the effect of c-SRC on the viability of human cervical cancer HeLa cells and the expression of phosphorylated signal transducer and activator of transcription-3 (p-STAT3) of the cell. Post-transfection of c SRC RNA interference vector, RT-PCR and Western blot were utilized to observe the contents of c-SRC mRNA and protein, respectively, in HeLa cells. The MTT was used to observe the viability of the cells. Cell cycle was observed by flow cytometry. The content of p-STAT3 in the cells was also investigated after knockdown of c SRC. Knockdown of c-SRC significantly decreased the contents of c-SRC mRNA and protein in the cells. The viability of the cells decreased by 23.1%, 29.3%, 38.6% and 45.0% (all P < 0.05), respectively, after the cells were transfected with c SRC RNA interference vector for 24, 48, 72, and 96 h. The number of S-phase cells decreased by 5.6%, 10.0%, 15.2% and 19.9% (all P < 0.05), respectively, after transfection of c-SRC RNA interference vector for 24, 48, 72, and 96 h. The content of p-STAT3 also decreased when c-SRC was knockdowned. Compared with the control group, after treatment of HeLa cells with STAT3 inhibitor Piceatannol for 24, 48, 72, and 96 h, the cell viability decreased by 23.8%, 29.7%, 37.3% and 45.4% (all P < 0.05), respectively, while increase of c-SRC content could not reverse the inhibitory effect. These results suggest that the inhibited viability of HeLa cells caused by knockdown of c-SRC is associated with the decreased content of p-STAT3 protein. PMID- 21681337 TI - [Effect of chronic intermittent hypobaric hypoxia on contractile activity of arteries in rats]. AB - The present study is aimed to investigate the effect of chronic intermittent hypobaric hypoxia (CIHH) on contractile activities in isolated thoracic aorta and pulmonary artery rings and the underlying mechanism in rats. Sprague-Dawley (SD) rats were randomly divided into 4 groups: control group (CON), 14 days CIHH treatment group (CIHH14), 28 days CIHH treatment group (CIHH28) and 42 days CIHH treatment group (CIHH42). CIHH rats were exposed to hypoxia in a hypobaric chamber simulating 5 000 m altitude, 6 h daily for 14, 28 and 42 d, respectively. After artery rings were prepared from pulmonary artery and thoracic aorta, the contractile activity of the artery rings was recorded using organ bath technique. Results are shown as follows. (1) There were no significant differences of noradrenaline (NA)- and KCl-induced contractions in thoracic aorta and pulmonary artery rings among CIHH and CON rats. (2) Angiotensin II (ANGII)-induced contraction in thoracic aorta rings, not in pulmonary artery rings, of CIHH rats was decreased compared with that in CON rats. There was no significant difference of ANGII-induced contraction in thoracic aorta rings among CIHH rats. (3) Inhibitory effect of CIHH on ANGII-induced contraction in thoracic aorta rings was endothelium-independent, and was reversed by glibenclamide (Gli), an ATP sensitive potassium channels (K(ATP)) blocker, and L-NAME, a NO synthase inhibitor, but not by indomethacin (Indo), a cyclooxygenase inhibitor. These results suggest that CIHH attenuates the contraction induced by ANGII in thoracic aorta rings of rat, which is related to the opening of K(ATP) channel and the increased production of NO. PMID- 21681338 TI - [Dynamin-mediated endocytic process contributes to neuronal nitric oxide synthase mediated regulation of cardiac contraction]. AB - Nitric oxide synthases (NOSs) play complex roles in the regulation of cardiac excitation contraction coupling under basal and stressed conditions. Herein, using the recording approach for intracellular calcium transient and synchronous myocyte contraction, the potential mechanism for NOSs-mediated cardiomyocyte contraction was explored. We found that selective inhibition of neuronal NOS (nNOS) with 100 umol/L spermidine markedly enhanced the cardiomyocyte twitch [control: (10.5 +/- 0.21)%; nNOS inhibition: (12.4 +/- 0.18)%] and calcium transient [control: (0.27 +/- 0.03)%; nNOS inhibition: (0.42 +/- 0.01)%], but slowed the relengthening of twitch [control: (25.2 +/- 1.3) ms; nNOS inhibition: (53 +/- 2.8) ms] and the calcium transient decay [control: (129 +/- 4.3) ms; nNOS inhibition: (176 +/- 7.1) ms], which was similar to that by dynamin inhibition with 30 umol/L dynasore. The nNOS inhibition- or dynasore-mediated effects could be rescued by an NO donor, S-Nitroso-N-acetylpenicillamine (SNAP). Our data suggest that the selective nNOS-mediated regulation of cardiac contractile activity may partly involve the dynamin-mediated endocytic mechanism. PMID- 21681339 TI - [Effects of ethanol on action potential of rat myocardium and human Kv1.5 channel]. AB - The purpose of the present study was to investigate the effects of different concentrations of ethanol on action potential (AP) in the isolated rat myocardium and the possible mechanism of electric-physiological changes. Standard microelectrode technique was used to record AP in isolated rat myocardium, and whole cell patch clamp technique was used to record the human Kv1.5 (hKv1.5) channel currents in HEK293 cells. The effects of different concentrations of ethanol (6.25, 12.5, 25.0, 50.0, 100.0 and 200.0 mmol/L) on AP parameters in rat atrium and papillary and Kv1.5 channel currents in HEK293 cells were analyzed. The results showed that in isolated atrium, action potential amplitude (APA), action potential duration (APD), action potential duration of 50% repolarization (APD(50)) and action potential duration of 90% repolarization (APD(90)) were not affected by 6.25 and 12.5 mmol/L ethanol, while APD, APD(50) and APD(90) were prolonged significantly by 25.0-200.0 mmol/L ethanol (P < 0.05 or P < 0.01), and APA was reduced with 100.0 and 200.0 mmol/L ethanol (P < 0.05 or P < 0.01). In isolated papillary, APA, APD, APD(50) and APD(90) were not affected by 6.25-25.0 mmol/L ethanol, while APD, APD(50) and APD(90) were prolonged significantly with 50.0-200.0 mmol/L ethanol (P < 0.05 or P < 0.01), and APA was reduced with 200.0 mmol/L ethanol (P < 0.05). The Kv1.5 channel currents were inhibited by ethanol in a concentration dependent manner in HEK293 cells. These findings suggest that 6.25 and 12.5 mmol/L ethanol produce no effects on AP parameters, and 50.0-200.0 mmol/L ethanol prolong APD significantly in isolated rat atrium and papillary. The prolonged effect on APD in isolated myocardium may be due to the inhibition of the Kv1.5 channel currents. PMID- 21681340 TI - [Chronic effects of oligomeric Abeta(1-42) on hippocampal synaptic plasticity in vivo]. AB - Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), is widely considered as one of the major mechanisms underlying learning and memory. This study explored hippocampal synaptic plasticity and spatial memory formation of an Alzheimer's disease (AD) rat model established by intrahippocampal injection of oligomeric Abeta(1-42). Twenty four Sprague-Dawley rats at 2.5 months of age were randomly divided into AD and control groups, and were bilaterally injected with 5 MUg oligomeric Abeta(1-42) or normal saline into dentate gyrus (DG) of hippocampus. Morris water maze test was used to observe the capability of learning and memory of two groups, 30 d after injection. To investigate the variations of paired-pulse facilitation (PPF) and range of synaptic plasticity, field potentials were recorded in the DG of the dorsal hippocampus by stimulating the perforant path (PP). The results showed that oligomeric Abeta(1-42) obviously impaired spatial memory formation in rats (P < 0.05). Furthermore, oligomeric Abeta(1-42) reduced the PPF ratio (P < 0.05) and hippocampal LTP formation (P < 0.05), while facilitated the hippocampal LTD formation (P < 0.05). These data suggest that chronic Abeta aggregation impairs synaptic plasticity of hippocampal PP-DG pathway, which may be involved in the spatial memory deficit in AD rats. PMID- 21681341 TI - [Involvement of cAMP-PKA pathway in group II metabotropic glutamate receptors mediated regulation of respiratory rhythm from neonatal rat brainstem slice]. AB - The study aims to identify the role of cAMP-PKA pathway in the group II metabotropic glutamate receptors (mGluRs)-mediated regulation of respiratory rhythm from the brainstem slice. Neonatal (aged 0-3 d) Sprague-Dawley rats of either sex were used. The brainstem slice containing the medial region of the nucleus retrofacialis (mNRF) and the hypoglossal nerve rootlets was prepared, and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous carbogen (95% O2 and 5% CO2) bubbling, and ended in 3 min. Respiratory rhythmical discharge activity (RRDA) of the hypoglossal nerve rootlets was recorded by suction electrode. Eighteen brainstem slice preparations were divided into 3 groups. In group 1, group II mGluRs specific antagonist (2S)-alpha ethylglutamic acid (EGLU) was added into the perfusion solution for 10 min. In group 2, after application of Forskolin for 10 min, washout with MKS, the slice was perfused with Rp-cyclic 3', 5'-hydrogen phosphorothioate adenosine triethylammonium salt (Rp-cAMPS) alone for another 10 min. In group 3, after application of Rp-cAMPS for 10 min, additional EGLU was added into the perfusion for another 10 min. The results showed EGLU shortened respiratory cycle (RC), but the changes of integral amplitude (IA) and inspiratory time (TI) were not statistically significant. Forskolin induced significant decreases in RC, and increased TI, IA. Rp-cAMPS could make the opposite effect compared with the changes of RRDA with Forskolin. The effect of EGLU on the RRDA was inhibited after blocking the cAMP-PKA pathway. Taken together, cAMP-PKA pathway may play an important role in the group II mGluRs-mediated regulation of RRDA in the brainstem slice of neonatal rats. PMID- 21681342 TI - [Inhibition of Beclin 1 enhances apoptosis by H2O2 in glioma U251 cells]. AB - Oxidative stress could induce apoptosis and autophagy process simultaneously, but the role of autophagy is still not clear. Beclin 1, a key gene regulating the preautophagosome formation, is involved in the injury induced by oxidative stress. To observe the role of autophagy in H2O2-induced injury of U251 cells, the recombinant plasmid Psilencer3.1-siRNA-Beclin 1 was transfected into U251 cells by eukaryotic cell transfection technique. Plasmid vector and cell culture medium were used as negative and control groups respectively. The cells were collected 24 h later, and the cell total protein was extracted to detect Beclin 1, Bcl-2 and Bax protein expressions by Western blot. After the Beclin 1-siRNA cells were treated with 1 mmol/L H2O2, the autophagic vacuoles in the cells were stained with monodansylcadaverine (MDC), and the cell apoptotic ratio was determined with PI/Annexin V-FITC staining by flow cytometry analysis. The results showed that the synthetic siRNA decreased the expression of Beclin 1 protein significantly, but had no obvious effect on the levels of Bcl-2 and Bax protein expressions. Compared with those in the control group, the autophagic vacuoles, the level of LC3-II protein expression and the percentage of apoptotic cells increased (P < 0.05) in 1 mmol/L H2O2 group. In Beclin 1-siRNA + H2O2 group, autophagic vacuoles and the levels of LC3-II protein expression decreased obviously, the percentage of apoptotic cells increased significantly compared with that in 1 mmol/L H2O2 group (P < 0.05). H2O2 and autophagy inhibitor 3 methyladenine (3-MA) combination also increased the percentage of apoptotic cells obviously (P < 0.05). These results revealed that the transfection of Psilencer3.1-siRNA-Beclin 1 effectively inhibited the expression of Beclin 1 protein expression, degraded the autophagy level and increased the apoptotic rate in U251 cells under oxidative stress, which was coincident with the effect of autophagy inhibitor 3-MA. This study suggests that autophagy is a cell protective role in oxidative stress process, and the inhibition of autophagy may enhance apoptosis. PMID- 21681343 TI - Chronic administration of Liu Wei Dihuang protects rat's brain against D galactose-induced impairment of cholinergic system. AB - This study was aimed to investigate the protective effect of Liu Wei Dihuang (LWDH) against D-galactose (D-gal)-induced brain injury in rats and the existence of sex-dependent differences in LWDH protection. Sixty-four rats evenly composed of males and females were randomly assigned into 4 groups (n = 8): normal saline (NS) + NS (N + N), NS + LWDH (N + L), D-gal + NS (D + N) and D-gal + LWDH (D + L) groups. Rats in D + N and D + L groups received daily injection of D-gal (100 mg/kg, s.c.) for six weeks to establish the aging model, while rats in N + N and N + L groups were injected with the same volume of NS. From the third week, rats in N + L and D + L groups were orally administered with a decoction of LWDH for subsequent six weeks. Rats in N + N and D + N groups were orally administered just with the same volume of NS simultaneously. Morris water maze test was employed to evaluate the ability of learning and memory of the rats in all the groups. Acetylcholine (ACh) content, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in visual cortex were assayed. Hematoxylin and eosin (HE) staining were used to observe the morphologic injury in hippocampus and visual cortex, and immunohistochemistry was performed to evaluate ChAT and AChE expression levels in the visual cortex. The results showed that the rats in D + N groups exhibited a longer escape latency to platform, lower swimming speed, less percent of target quadrant search time and platform crossings, compared with N + N groups, suggesting the establishment of aging model, while LWDH improved these indexes in D-gal-treated rats. Compared with D + N groups, LWDH increased ACh content and ChAT activity, and decreased AChE activity in visual cortex. Remarkable loss of neurons was found in hippocampus and visual cortex of aging rats, and the injury was significantly attenuated by LWDH. Immunohistochemistry showed D-gal-induced decreases of ChAT and AChE expressions were restored by LWDH. Furthermore, under the neural protection of LWDH, the improvement on platform crossings in male aging rats was better than that in female ones, while in ChAT expression and neuron density in visual cortex, female aging rats obtained more amelioration. These results suggest LWDH can markedly reverse the D-gal-induced cognitive impairments and neuronal damage in both hippocampus and visual cortex, which are achieved at least partly through restoring cholinergic system in central nervous system. Moreover, there is some sex difference in protective effects of LWDH against D-gal-induced impairment. PMID- 21681344 TI - [Tumor conditioned medium regulates the proliferation, adhesion and migration of human umbilical vein endothelial cells]. AB - The aim of the present study was to investigate the effects of tumor conditioned medium (TCM) on the proliferation, adhesion and migration of human umbilical vein endothelial cell (HUVEC). Cells were divided into control group, TCM stock solution group, TCM monodilution group and TCM didilution group (n = 6), and MTT assay was used to determine endothelial cells proliferation level after being stimulated with TCM for 24 h. Coating culture dishes with Fn was used to detect the adhesion ability of endothelial cells to basement membrane in control group and TCM stock solution group (n = 6). Wound closure model was used to test the migration ability of endothelial cells in control group and TCM stock solution group at 12 h and 24 h (n = 6). The results showed that TCM at different concentrations influenced proliferation of endothelial cells in distinct degree. Compared to the control group (absorbance value: 0.58 +/- 0.04), the stock solution had no effect on proliferation of endothelial cells (absorbance value: 0.55 +/- 0.01). However, the TCM monodilution and TCM didilution enhanced the proliferation of endothelial cells significantly (absorbance value: 0.66 +/- 0.03, P < 0.01 and 0.70 +/- 0.02, P < 0.001 separately). TCM downregulated the adhesion of endothelial cells to basement membrane. Moreover, compared to the migration distance of control group at 12 h and 24 h [(14.05 +/- 6.25) um and (48.75 +/- 16.37) um separately], TCM upregulated the basement membrane migration [(68.25 +/- 26.20) um and (119.70 +/- 34.90) um at 12 h and 24 h, both P < 0.05 separately]. These results suggest that TCM downregulates the adhesion ability of endothelial cells and upregulates their migration ability, and thus facilitates tumor metastasis. PMID- 21681345 TI - [Anti-sense nucleic acid of CyclinD1 induces apoptosis of lung adenocarcinoma cancer cell A549]. AB - To explore the potential of the anti-sense nucleic acid of CyclinD1 in lung cancer therapy, the expression vector containing the anti-sense nucleic acid of CyclinD1 was constructed and named pcDNA3.1-CyclinD1. The A549 cells were transfected with pcDNA3.1-CyclinD1 vectors. After being screened by G418, the stable expression positive clones were obtained. MTT method and flow cytometry technique were used to detect cell proliferation and apoptosis, respectively. The results showed the transfected cells exhibited significantly increased apoptosis and inhibited cell growth, compared with negative control and empty vector groups. To investigate the mechanism for anti-sense nucleic acid of CyclinD1 inducing A549 cells apoptosis, the expression levels of retinoblastoma protein (pRb), adenovirus E2 factor-1 (E2F-1), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and MMP-9 were detected by Western blot, and the results showed the expressions of these proteins were all decreased significantly in anti-sense nucleic acid of CyclinD transfected group, compared with those in negative control and empty vector groups. In a word, anti-sense nucleic acid of CyclinD1 induces the apoptosis of lung adenocarcinoma cancer cells, and the depressions of pRb, E2F-1, VEGF, MMP-2 and MMP-9 expressions may be the possible mechanism. PMID- 21681346 TI - [Inhibitory effects of soluble endoglin on invasive ability of cultured cytotrophoblasts of first trimester of pregnancy]. AB - The present study aims to investigate the effects of soluble endoglin (sEng) on invasive ability of cultured cytotrophoblasts of first trimester of pregnancy. Cytotrophoblasts of normal 6 to 8-week pregnancy were cultured by trypsin digestion method, and were incubated with cell culture medium without (control group) and with 10 MUg/L sEng (sEng group), respectively for 24 h. The invasive ability was determined by transwell invasion assay, and expressions of MMP-2, MMP 9 mRNA and protein were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, respectively. The results showed that the invasive ability of cytotrophoblasts in sEng group was lower than that in control group (P < 0.05). Compared with control group, the expressions of MMP-2 and MMP-9 mRNA and protein of cytotrophoblasts were significantly lower (P < 0.05). In conclusion, sEng may participate in the genesis of preeclampsia by affecting the invasive ability of cytotrophoblasts through regulation of the expression of MMP 2 and MMP-9. PMID- 21681347 TI - Chuanxiongzine-astragaloside IV decreases IL-1beta and Caspase-3 gene expressions in rat brain damaged by cerebral ischemia/reperfusion: a study of real-time quantitative PCR assay. AB - The purpose of this study was to establish an absolute quantitative method to detect IL-1beta and Caspase-3 gene expressions in rat brain after cerebral ischemia-reperfusion (I/R) using real-time PCR. Rats were randomized into the following groups: sham operation group, model group (cerebral I/R group), astragaloside IV (AST IV) group, chuanxiongzine-AST IV group and nimodipine group (n = 10 in each group). The rats in all the groups except sham operation group were subjected to cerebral I/R treatment. Sham operation and model groups were treated by normal saline (5 mL/kg). AST IV, chuanxiongzine-AST IV and nimodipine groups received 20 mg/kg AST IV, 10 mg/kg chuanxiongzine plus 20 mg/kg AST IV, and 10 mg/kg nimodipine treatments, respectively. The administrations of drugs were performed with intraperitoneal injections at 0 and 12 h, 1 d, 2 d, 3 d, till to 7 d after I/R. A real-time quantitative PCR assay was developed for absolute quantification of the expressions of IL-1beta and Caspase-3 genes. The absolute quantification approach relies on the construction of an accurate standard curve. Thus, two plasmids which contained rat IL-1beta and Caspase-3 genes respectively were constructed. The cloned circular plasmids were then quantified using a spectrophotometer and used as standards. Standard curves were generated, and the copy numbers of IL-1beta and Caspase-3 mRNA isolated from I/R-damaged brain tissue were also calculated by SYBR Green I dye method using specific primers. The results showed that melting curves exhibited sharp peaks, and PCR product also generated prominent band with expected size in agarose gel electrophoresis, which validated the optimization of the selected primer sets of IL-1beta and Caspase-3 genes. The optimal annealing temperatures of IL-1beta and Caspase-3 genes were 59 degrees C and 61.2 degrees C, respectively. Real-time PCR results showed that the expression of IL-1beta and Caspase-3 genes in the model group was significantly elevated compared to that in the sham operation group. However, compared to those in the model group, IL-1beta and Caspase-3 gene expressions were obviously decreased in AST IV, chuanxiongzine-AST IV and nimodipine groups. Especially in chuanxiongzine-AST IV group, those two genes showed the most significant expression down-regulation. These results suggest the absolute quantitative method established in the present study is capable of detecting the changes of IL-1beta and Caspase-3 gene expressions in rat brain damaged by I/R. PMID- 21681348 TI - [Electrophysiological characteristics of the isolated muscle spindle in rats]. AB - The aim of this study was to observe the electrophysiological characteristics of the isolated rat muscle spindle. The muscle spindle was isolated from rat soleus and the afferent discharge of the isolated muscle spindle was recorded by air-gap technique. In the basic physiological salt solution, the spontaneous impulses of muscle spindle were at a lower level with irregular intervals. The mean frequency of afferents was (51.78 +/- 25.63) impulses/1 000 s (n = 13). The muscle spindle afferents were significantly increased and maintained over time by the addition of certain amino acids during the observation. The number of the action potential recorded per 1 000 s was 200-1 000 [mean: (687.62 +/- 312.56) impulses/1 000 s, n = 17]. In addition to the typical propagated action potential, a large number of abortive spikes were observed. The results indicate that the activities of isolated muscle spindles in rats can be well maintained by the addition of certain amino acids. The results initially establish and provide the possibility for further research conducted in isolated rat muscle spindles. PMID- 21681349 TI - Allergic nickel dermatitis caused by shaving: case report and assessment of nickel release from an electric shaver. PMID- 21681350 TI - Atopic dermatitis-like pre-Sezary syndrome: role of immunosuppression. AB - We describe here 4 patients with Sezary syndrome masquerading as adult-onset atopic dermatitis. The patients presented with a clinical picture compatible with wide-spread atopic dermatitis and did not fulfil the criteria for Sezary syndrome (lack of lymphoadenopathy and blood involvement, skin histology without presence of atypical cells). In our patients, overt Sezary syndrome developed after immunosuppressive treatment (including cyclosporine). These cases support the validity of the concept of pre-Sezary syndrome, which is a long-lasting, pre malignant condition, and which may develop to true malignancy in a state of immunosuppression. PMID- 21681351 TI - High-dose intravenous immunoglobulin monotherapy for drug-induced hypersensitivity syndrome. PMID- 21681352 TI - Pustular penile pyoderma gangrenosum successfully treated with topical tacrolimus ointment. PMID- 21681353 TI - A brownish-grey plaque with ulceration on the nasolabial area: a quiz. Microcystic adnexal carcinoma. PMID- 21681354 TI - Photoallergic erythroderma due to doxycycline therapy of erythema chronicum migrans. PMID- 21681355 TI - Disseminated erosive pustular dermatosis also involving the mucosa: successful treatment with oral dapsone. PMID- 21681356 TI - Patient-doctor interaction, psychobehavioural characteristics and mental disorders in patients with suspected allergies: do they predict "medically unexplained symptoms"? AB - In approximately 20% of patients with suspected allergies, no organic symptom explanation can be found. Limited knowledge about patients with "medically unexplained symptoms (MUS)" contributes to them being perceived as "difficult" and being treated inadequately. This study examined the psychobehavioural characteristics of patients presenting for a diagnostic allergy work-up. Patients were interviewed and completed various self-rating questionnaires. Patient-Doctor interaction was evaluated, and the organic explicability of the patients' symptoms was rated by allergists. Patients with vs. those without MUS differed in several respects. Mental comorbidity, female sex, dissatisfaction with care, and a problematic countertransference (the interviewer's feelings towards the patient) independently predicted MUS. Patients whose symptoms could be explained organically reported more psychobehavioural problems than a control group of immuno-therapy patients. There were no differences in patient-doctor interaction. In patients with suspected allergies, recognition of psychological burden and concurrent mental disorders is important. Mental comorbidity and a difficult patient-doctor interaction may predict MUS. PMID- 21681357 TI - A case of systemic sclerosis with sarcoidosis. PMID- 21681358 TI - New approach in combined therapy of perifolliculitis capitis abscedens et suffodiens. PMID- 21681359 TI - Multiple follicular pustules as an atypical cutaneous manifestation of drug induced hypersensitivity syndrome. PMID- 21681360 TI - 5-year recurrence rates of Mohs micrographic surgery for aggressive and recurrent facial basal cell carcinoma. AB - Mohs micrographic surgery allows for complete microscopic examination of the surgical margin when treating aggressive and recurrent facial basal cell carcinomas. This leads to the highest cure rates and maximal preservation of healthy tissue. The 5-year recurrence rates of 587 aggressive and/or recurrent facial basal cell carcinomas treated during 1993 to 2003 at our centre were studied retrospectively. The resulting 5-year recurrence rates using Kaplan-Meier survival analysis were 2.1% for primary (previously untreated) tumours, 5.2% for recurrent basal cell carcinomas and 3.3% overall. In total, 87.9% of the tumours required at least two stages of Mohs micrographic surgery. The surgical defect's size after complete excision was, on average, approximately twice the size of the defect after excision of the clinically visible tumour with a 2-3 mm margin. Mohs micro-graphic surgery is underused in Scandinavia despite being the treatment of choice for aggressive and recurrent facial basal cell carcinomas. PMID- 21681361 TI - Experimentally confirmed induction of Sweet's syndrome by phototesting. PMID- 21681362 TI - Immunohistochemical features of Merkel cell carcinoma in correlation with presence of Merkel cell polyomavirus DNA. PMID- 21681363 TI - Cerebriform plantar hyperplasia: the clinico-pathological hallmark of Proteus syndrome. PMID- 21681364 TI - Pre-treatment evaluation of basal cell carcinoma for photodynamic therapy: comparative measurement of tumour thickness in punch biopsy and excision specimens. AB - Tumour thickness affects the outcome of photodynamic therapy in basal cell carcinoma (BCC). The aim of this study was to evaluate whether punch biopsy provides reliable information on BCC tumour thickness, by comparing corresponding measurements in biopsy and excision specimens for 48 lesions in 43 patients. BCC tumours were between 0.2 and 6.1 mm thick. The mean depth of the excisions were 0.14 mm greater than that of the biopsies. Bland-Altman 95% limits of agreement were (-1.3, 1.6) mm, but the difference between measurements increased with tumour thickness. A punch biopsy tumour thickness of 1.0 mm yielded an upper 95% predicted limit for excision depth within 2.0 mm. In conclusion, there was reasonable overall agreement between corresponding measurements. A biopsy thickness of 1.0 mm suggests that the tumour will most likely be within the current accepted limits for photodynamic therapy. With increasing tumour thickness, however, individual tumour measurements may differ considerably. PMID- 21681365 TI - Publications of physical and rehabilitation medicine physicians concerning musculoskeletal ultrasonography: an overview. AB - OBJECTIVE: Interest in the use of musculoskeletal ultrasonography in the field of Physical Medicine and Rehabilitation has increased significantly over recent years. In order to determine to what extent this growing interest among Physical and Rehabilitation Medicine physicians is resulting in publications, we reviewed the trend in publications by physiatrists on musculoskeletal ultrasonography. METHODS: We searched retrospectively for all papers indexed in Science Citation Index-Expanded and Index Medicus in which "rehabilitation medicine" was addressed as at least one of the authors' affiliations (up to 2011). All papers were examined individually for the authors' affiliations, document types, publication years, countries, and journal categories. RESULTS: A total of 171 papers was included in the study. After 2004, there appears to be a significant amount of increase in the number of publications. USA, Turkey, Taiwan and South Korea were the leading countries in which physiatrists carry out research and publish papers on musculoskeletal ultrasonography. The top 5 journal categories in which these papers were published were: Rehabilitation (44.3%), Orthopaedics (14.1%), Radiology (10.7%), Neurology (8.1%) and Rheumatology (6.7%). CONCLUSION: The number of scientific publications by physiatrists about musculoskeletal ultrasonography is increasing in parallel with the interest regarding its routine use in Physical Medicine and Rehabilitation clinics. PMID- 21681366 TI - [Quantification of fluorescein angiography in patients with non-arteritic anterior ischemic optic neuropathy]. AB - PURPOSE: The aim of this study was to evaluate the retinal hemodynamics and optic disc leakage by fluorescein angiography in patients with non-arteritic anterior ischemic optic neuropathy (NAION) and to correlate fluorescein angiography findings with the extent and topography of visual field loss. METHODS: A total of 26 patients with acute NAION were included in the study. Fluorescein angiograms were performed by means of a scanning laser ophthalmoscope. The extent of early phase optic disc leakage was assessed using a semiquantitative approach (focal versus diffuse type of leakage). Retinal arteriovenous passage (AVP) times were measured using dye dilution curves and digital image analysis for each hemisphere. The number of defective visual field points (StatPac: p<0.5%, uncorrected deviation plot) were evaluated (30/2 SITA, Humphrey-Zeiss) for the hemifields and different sectors. RESULTS: In this study of patients with NAION the mean AVP was 1.79 s+/-0.43 which was not significantly correlated to the number of defective points. Furthermore, AVP was not significantly different in focal versus diffuse optic disc leakage. The number of defective points were not significantly different in focal versus diffuse leakage of the optic disc (p=0.57). CONCLUSION: Retinal perfusion is not linked to the type and topography of disc leakage or the extent and topography of visual field damage in NAION. A global circulatory disorder e.g. due to a compartment syndrome of the optic nerve might account for these results. PMID- 21681367 TI - Microscopic polyangiitis presenting with peripheral and central neurological manifestations. AB - Although peripheral neuropathy is a common complication of microscopic angiitis, manifestations involving the muscle and the central nervous system have been rarely reported. We describe a 48-year-old man who rapidly developed a clinical picture of mononeuritis multiplex. A month after the appearance of the primary symptoms, he became comatose and had left hemiplegia in relation with a massive cerebral haematoma. Laboratory data revealed signs of inflammation, glomerular dysfunction with microhaematuria, and positive myeloperoxidase-antineutrophil cytoplasmic antibodies. The neuromuscular biopsy disclosed a small-vessel vasculitis, consisting with microscopic angiitis, associated with myositis and extensive axonal loss. The patient had surgical evacuation of the haematoma and received immunosuppressive therapy with good outcome. Thus, microscopic angiitis should be considered as a differential diagnosis in cases of myositis and intracerebral haemorrhage. PMID- 21681368 TI - Basilar artery occlusion in migraine-like headache: a possible triggering effect of sumatriptan. AB - Headache is a common symptom at the onset of acute ischemic cerebrovascular disease. Simultaneous development of migraine-like headache and stroke in the same patient makes it difficult to differentiate between migraine-induced stroke and migraine-like headache attributed to ischemic stroke. We report a case of a 34-year-old woman with no previous migraine history who presented with migraine like headache, thought to be a first attack of migraine, and who developed brainstem infarction shortly after triptan administration. Magnetic resonance imaging revealed an acute pontine infarction, and CT angiography revealed occlusion of the basilar artery. A detailed etiological evaluation revealed no risk factor for ischemic stroke. We believe that the migraine-like headache was the first symptom of cerebral ischemia and that sumatriptan accelerated the development of the infarction. This case report emphasizes the importance of accurate diagnosis of migraine before using triptans. Secondary causes of migraine-like headache should be excluded, especially in patients with migraine like headache for the first time. PMID- 21681369 TI - Prostaglandin E(2) (PGE (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4. AB - The COX-2 product prostaglandin E(2) (PGE(2)) contributes to the high metastatic capacity of breast tumors. Our published data indicate that inhibiting either PGE(2) production or PGE(2)-mediated signaling through the PGE(2) receptor EP4 reduces metastasis by a mechanism that requires natural killer (NK) cells. It is known that NK cell function is compromised by PGE(2), but very little is known about the mechanism by which PGE(2) affects NK effector activity. We now report the direct effects of PGE(2) on the NK cell. Endogenous murine splenic NK cells express all four PGE(2) receptors (EP1-4). We examined the role of EP receptors in three NK cell functions: migration, cytotoxicity, and cytokine release. Like PGE(2), the EP4 agonist PGE(1)-OH blocked NK cell migration to FBS and to four chemokines (ITAC, MIP-1alpha, SDF-1alpha, and CCL21). The EP2 agonist, Butaprost, inhibited migration to specific chemokines but not in response to FBS. In contrast to the inhibitory actions of PGE(2), the EP1/EP3 agonist Sulprostone increased migration. Unlike the opposing effects of EP4 vs. EP1/EP3 on migration, agonists of each EP receptor were uniformly inhibiting to NK-mediated cytotoxicity. The EP4 agonist, PGE(1)-OH, inhibited IFNgamma production from NK cells. Agonists for EP1, EP2, and EP3 were not as effective at inhibiting IFNgamma. Agonists of EP1, EP2, and EP4 all inhibited TNFalpha; EP4 agonists were the most potent. Thus, the EP4 receptor consistently contributed to loss of function. These results, taken together, support a mechanism whereby inhibiting PGE(2) production or preventing signaling through the EP4 receptor may prevent suppression of NK functions that are critical to the control of breast cancer metastasis. PMID- 21681370 TI - Therapeutic effects of metformin in breast cancer: involvement of the immune system? AB - Breast cancer and associated diabetes mellitus have gained raising interest as an elevated risk of breast cancer prognosis resulting in increased mortality in diabetic patients. In this context, the long-acting insulin analog glargine and other antidiabetics have been discussed to promote tumorigenesis. In contrast, the biguanide class oral antidiabetic metformin has been shown capable of enhancing cell cycle arrest and inducing apoptosis as well as reducing growth factor signaling. Consequently, several studies are underway to evaluate a possible role of metformin in breast cancer treatment. Although mechanisms involved are not definitely clear yet, here, we discuss metformin's anticancer effects including the potential impact of the immune system. PMID- 21681371 TI - Vaccination of patients with cutaneous melanoma with telomerase-specific peptides. AB - PURPOSE: A phase I study was conducted to investigate the safety, tolerability, and immunological responses to vaccination with a combination of telomerase derived peptides GV1001 (hTERT: 611-626) and p540 (hTERT: 540-548) using granulocyte-macrophage colony-stimulating factor (GM-CSF) or tuberculin as adjuvant in patients with cutaneous melanoma. EXPERIMENTAL DESIGN: Ten patients with melanoma stages UICC IIb-IV were vaccinated 8 times intradermally with either 60 or 300 nmole of GV1001 and p540 peptide using GM-CSF as adjuvant. A second group of patients received only 300 nmole GV1001 in combination with tuberculin PPD23 injections. HLA typing was not used as an inclusion criterion. Peptide-specific immune responses were measured by delayed-type hypersensitivity (DTH) reactions, in vitro T cell proliferation assays, and cytotoxicity (51 Chromium release) assays for a selected number of clones subsequently generated. RESULTS: Vaccination was well tolerated in all patients. Peptide-specific immune response measured by DTH reactions and in vitro response could be induced in a dose-dependent fashion in 7 of 10 patients. Cloned T cells from the vaccinated patients showed proliferative responses against both vaccine peptides GV1001 and p540. Furthermore, T cell clones were able to specifically lyse p540-pulsed T2 target cells and various pulsed and unpulsed tumor cell lines. CONCLUSION: These results demonstrate that immunity to hTERT can be generated safely and effectively in patients with advanced melanoma and therefore encourage further trials. PMID- 21681372 TI - Dendritic cells combining with cytokine-induced killer cells synergize chemotherapy in patients with late-stage non-small cell lung cancer. AB - BACKGROUND: Lung cancer is the leading cause for cancer-related mortality and morbidity, and the survival of late-stage non-small cell lung cancer (NSCLC) remains poor. We hereby evaluate conventional chemotherapy followed by immunotherapy using dendritic cells and cytokine-induced killer cells in the treatment for late stage of NSCLC. METHODS: Twenty-eight untreated patients suffered from IIIB to IV NSCLC were enrolled in the study between August 2004 and October 2005, and all received four courses of vinorelbine-platinum (NP) chemotherapy. Fourteen of them received conventional NP chemotherapy followed by vaccinated with CEA (605-613) peptide-pulsed autologous dendritic cells and CIK cells. Vaccination was repeated at 30-day intervals for 4 cycles. The adverse effects, time to progression (TTP), and overall survival (OS) in each group were evaluated. RESULTS: The adverse effect as a result of chemoimmunotherapy was mild and tolerable. Rash, acne, and pruritus were more frequent in the chemoimmunotherapy group than in the chemotherapy group (64.2% vs. 7.1%, P = 0.004). Non-infectious fever was more frequent in the chemoimmunotherapy group than in the chemotherapy group (71.4% vs. 21.4% P = 0.02). Less grade 3/4 fatigue was observed in patients receiving chemoimmunotherapy: 7.1% versus 57.1% in chemotherapy group, P = 0.01. Compared with patients in chemotherapy group, time to progression in chemoimmunotherapy significantly prolonged, with the median improved from 5.2 months (95% CI: 3.3-6.0) to 6.9 months (95% CI: 5.0-8.8) (P = 0.03). The 1-, 2-, and 5-year survival rates were 64.3, 49, and 21.0%, respectively in chemoimmunotherapy group. Overall survival rate showed no statistically difference between two groups (P = 0.18). CONCLUSIONS: Chemoimmunotherapy could alleviate adverse effects of conventional chemotherapy and prolong survival for patients with late-stage NSCLC. PMID- 21681373 TI - Increased prevalence of regulatory T cells in the lung cancer microenvironment: a role of thymic stromal lymphopoietin. AB - Expansion of CD4+CD25+ regulatory T cells (Tregs) in tumor microenvironment was one of the mechanisms by which cancer cells escaped host defense. Thymic stromal lymphopoietin (TSLP) contributes to the generation of natural Tregs in thymus. Therefore, the purpose of this report was to investigate the role of TSLP in the increasing prevalence of Tregs in lung cancer microenvironment. The expression ratio of TSLP protein in tumor tissues was significantly increased compared with that in benign lesion and non-cancer lung tissue. The prevalence of Tregs in tumor microenvironment was correlated with the expression of TSLP in lung cancer. Dendritic cells (DCs) were induced from peripheral blood mononuclear cells (PBMCs) collected from lung cancer patients and left unstimulated (imDCs) or exposed to hTSLP (TSLP-DCs) or LPS (LPS-DCs). TSLP-DCs expressed intermediate levels of CD83 and high levels of CD86, CD11C, and HLA-DR, which showed a characteristic of less mature DCs. TSLP-DCs secreted low levels of IL-6, IL-12, IL-10, TNF-alpha and IFN-gamma, and high levels of TGF-beta and MDC. The percentage of Tregs in CD4+CD25- T cells cocultured with TSLP-DCs group was statistically higher than that of LPS-DCs and imDCs. Transwell assays showed that TSLP-DCs exhibited increased ability to attract the migration of CD4+CD25- Tregs, when compared with imDCs. These results indicated that TSLP proteins were expressed in lung tumor tissue and correlated with the prevalence of Tregs. TSLP DCs could induce CD4+CD25- T cells to differentiate into CD4+CD25+foxp3+ T cells and the migration of CD4+CD25+ T cells. PMID- 21681374 TI - Polyfunctionality of a DKK1 self-antigen-specific CD8(+) T lymphocyte clone in lung cancer. AB - Polyfunctionality is the capacity of a T-cell to execute a variety of effector functions mainly mediated by production of cytokines, chemokines, and cytolytic enzymes. Studies in anti-viral immunity have acknowledged the importance of polyfunctionality in the clearance of infections and maintenance of protection. Although accepted in the field, this concept has not been as well characterized in cancer immunology. Here, we report the polyfunctionality profile analysis of a CD8(+) T-cell clone isolated from a lung cancer patient and directed against Dickkopf-1, a potentially new tumor-associated antigen (TAA). The clone showed Tc1/Th1 effector tendencies confirmed by secretion of cytokines such as IFN gamma, IP-10, MIP-1beta, MIP-1alpha, IL-2, GM-CSF, and expression of cytolytic enzyme granzyme B. This secretion profile is of particular interest in the context of an anti-tumor response. Although secretion of IL-5 and IL-13 was also detected, absence of IL-4 and IL-10 opposes the idea of cytokine-dependent Th1 inhibition. Establishing a comprehensive cytokine secretion profile may help predict T cells' specific response against a novel TAA in a peptide vaccination context. It may further help in selecting clones with an optimal functional profile from the peripheral blood of cancer patients for expansion and adoptive cell transfer therapy. PMID- 21681375 TI - Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide. AB - Dendritic cell (DC) vaccine has been used to treat patients with advanced colorectal cancer (CRC). The results of vaccine-induced clinical responses have not always been satisfactory partially because of DC incompetence. In order to evaluate the feasibility of novel mature DCs for therapeutic adjuvants against CRC, we conducted clinical trials with carcinoembryonic antigen (CEA) peptide loaded DC quickly generated with a combination of OK432 (Streptococcuspyogenes preparation), prostanoid, and interferon-alpha (OPA-DC). In the ten patients enrolled in this study, the OPA-DC vaccine was well tolerated and administered four times every 2 weeks except for two patients, who were switched to other treatments due to disease progression. Among the eight evaluable patients, one displayed stable disease (SD), while the remaining seven showed progressive disease (PD). In the SD patient, natural killer (NK) cell frequency and cytolytic activity were increased. In the same patient, the frequency of CEA-specific cytotoxic T cells (CTLs) increased stepwise with repetitive vaccinations; however, most of the CTLs exhibited central memory phenotype. In those with PD, NK cells proliferated well regardless of failure of response, whereas CTLs failed to do so. We concluded that the OPA-DC vaccine is well tolerated and has immune stimulatory capacity in patients with CRC. Additional modulation is needed to attain significant clinical impact. PMID- 21681377 TI - Evidence expands total gastrectomy decision for asymptomatic patients with CDH1 inherited mutations. PMID- 21681376 TI - Priming with very low-affinity peptide ligands gives rise to CD8(+) T-cell effectors with enhanced function but with greater susceptibility to transforming growth factor (TGF)beta-mediated suppression. AB - While the effects of TCR affinity and TGFbeta on CD8(+) T-cell function have been studied individually, the manner in which TCR affinity dictates susceptibility to TGFbeta-mediated suppression remains unknown. To address this issue, we utilized OVA altered peptide ligands (APLs) of different affinities in the OT-I model. We demonstrate that while decreased TCR ligand affinity initially results in weakened responses, such interactions prime the resultant effector cells to respond more strongly to cognate antigen upon secondary exposure. Despite this, responses by CD8(+) T cells primed with lower-affinity TCR ligands are more effectively regulated by TGFbeta. Susceptibility to TGFbeta-mediated suppression is associated with downregulation of RGS3, a recently recognized negative regulator of TGFbeta signaling, but not expression of TGFbeta receptors I/II. These results suggest a novel tolerance mechanism whereby CD8(+) T cells are discriminately regulated by TGFbeta according to the affinity of the ligand on which they were initially primed. In addition, because of the major role played by TGFbeta in tumor-induced immune suppression, these results identify the affinity of the priming ligand as a primary concern in CD8(+) T-cell-mediated cancer immunotherapeutic strategies. PMID- 21681378 TI - The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection. AB - BACKGROUND: The extracellular matrix metalloproteases MMP-9 and MMP-2 are critical for the invasive potential of tumors. However, it is not clear which of the two plays the predominant role in tumor invasion and progression. In the present study, we compared the clinical efficacy of MMP-9 and MMP-2 overexpression for predicting tumor recurrence and survival after surgical resection in HCC patients. MATERIALS AND METHODS: MMP-9 and MMP-2 expression in HCC cell lines and in vitro HCC invasion model were detected by quantitative RT PCR and immunofluorescence. The expression levels of MMP-9 and MMP-2 were assessed by immunohistochemistry in HCC tissue microarrays from HCC patients (study set) who underwent curative resection. The clinicopathological data were retrospectively analyzed. The results were further verified in an independent cohort of 92 HCC patients (validation set). RESULTS: Univariate analysis demonstrated that high expression of MMP-9 was associated with both time to recurrence (TTR, P = .015) and overall survival (OS, P = .024), whereas high expression of MMP-2 was only correlated with TTR (P = .041). Multivariate analysis confirmed that MMP-9 expression was an independent predictor of TTR and OS. The coindex of MMP-9 and preoperative serum AFP levels was significantly correlated with TTR and OS (P = .036 and P = .040), but the coindex of MMP-2 and AFP did not show prognostic significance for either TTR or OS (P = .067 and P = .053). The prognostic value of MMP-9 overexpression was validated in the independent data set. CONCLUSION: MMP-9 is superior to MMP-2 for the prediction of tumor recurrence and survival in HCC patients after surgical resection. PMID- 21681379 TI - Impact of routine unilateral central neck dissection on preablative and postablative stimulated thyroglobulin levels after total thyroidectomy in papillary thyroid carcinoma. AB - BACKGROUND: Prophylactic central neck dissection (CND) remains controversial in papillary thyroid carcinoma (PTC). Because postsurgical stimulated thyroglobulin (sTg) level is a good surrogate for recurrence, the study aimed to evaluate the impact of prophylactic CND on preablative and postablative sTg levels after total thyroidectomy. METHODS: Of the 185 patients retrospectively analyzed, 82 (44.3%) underwent a total thyroidectomy and prophylactic CND (CND-positive group) while 103 (55.7%) underwent total thyroidectomy only (CND-negative group). All patients had no preoperative or intraoperative evidence of lymph node metastases. Clinicopathological characteristics, postoperative outcomes, and preablative and postablative sTg levels were compared between the two groups. Preablative sTg level was taken at the time of radioiodine ablation, while postablative sTg level was taken 6 months after ablation. A multivariable analysis was conducted to identify factors for preablative athyroglobulinemia (sTg<0.5 MUg/L). RESULTS: Relative to the CND-negative group, the CND-positive group had larger tumors (15 mm vs. 10 mm, P < 0.005), more extrathyroidal extension (26.8% vs. 14.6%, P<0.003), more tumor, node, metastasis system stage III disease (32.9% vs. 9.7%, P < 0.001), and more temporary hypoparathyroidism (18.3% vs. 8.7%, P=0.017). Fourteen patients (17.1%) in the CND-positive group were upstaged from stages I/II to III as a result of prophylactic CND. The CND-positive group experienced lower median preablative sTg (<0.5 MUg/L vs. 6.7 MUg/L, P < 0.001) and a higher rate of preablative athyroglobulinemia (51.2% vs. 22.3%, P = 0.024), but these differences were not observed 6 months after ablation. Prophylactic CND was the only independent factor for preablative athyroglobulinemia. CONCLUSIONS: Although performing prophylactic CND in total thyroidectomy may offer a more complete initial tumor resection than total thyroidectomy alone by minimizing any residual microscopic disease, such a difference becomes less noticeable 6 months after ablation. PMID- 21681380 TI - Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. AB - BACKGROUND: Management of patients with neuroendocrine liver metastasis (NELM) remains controversial. We sought to examine the relative efficacy of surgical management versus intra-arterial therapy (IAT) for NELM and determine factors predictive of survival. METHODS: A total of 753 patients who had surgery (n = 339) or IAT (n = 414) for NELM from 1985 to 2010 were identified from nine hepatobiliary centers. Clinicopathologic data were assessed with regression modeling and propensity score matching. RESULTS: Most patients had a pancreatic (32%) or a small bowel (27%) primary tumor; 47% had a hormonally active tumor. There were statistically significant differences in characteristics between surgery versus IAT groups (hormonally active tumors: 28 vs. 48%; hepatic tumor burden >25%: 52% vs. 76%) (all P < 0.001). Among surgical patients, most underwent hepatic resection alone without ablation (78%). The median number of IAT treatments was 1 (range, 1-4). Median and 5-year survival of patients treated with surgery was 123 months and 74% vs. 34 months and 30% for IAT (P < 0.001). In the propensity-adjusted multivariate Cox model, asymptomatic disease (hazard ratio 2.6) was strongly associated with worse outcome (P = 0.001). Although surgical management provided a survival benefit over IAT among symptomatic patients with >25% hepatic tumor involvement, there was no difference in long term outcome after surgery versus IAT among asymptomatic patients (P = 0.78). CONCLUSIONS: Asymptomatic patients with a large (>25%) burden of liver disease benefited least from surgical management and IAT may be a more appropriate treatment strategy. Surgical management of NELM should be reserved for patients with low-volume disease or for those patients with symptomatic high-volume disease. PMID- 21681381 TI - Prognostic significance of TWEAK expression in colorectal cancer and effect of its inhibition on invasion. AB - BACKGROUND: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in tumor development and progression. The aim of this study was to investigate the role of TWEAK in colorectal cancer (CRC) progression. METHODS: To investigate the involvement of TWEAK in the progression of human CRC, normal, and tumor specimens from 174 patients were analyzed immunohistochemically for the expression of TWEAK. TWEAK recombinant protein treatment, transfection of expression plasmids, and small interfering RNA to knockdown TWEAK expression were performed to test invasive ability with a Boyden chamber. The mRNA expression profile in recombinant TWEAK treatment was compared to a control group by microarray analysis. To identify downstream effectors, Raf kinase inhibitor (RKIP) and its correlation with TWEAK in vitro and in vivo were examined by quantitative real-time polymerase chain reaction and invasion assays. RESULTS: CRC patients whose tumors displayed high TWEAK expression had a statistically significantly higher overall survival and a disease-free advantage over those with a low TWEAK expression. In in vitro invasion assays, alterations in TWEAK expression in CRC cell lines inversely modulated their invasive ability. By means of integrated genomics, we identified RKIP as a downstream effector in TWEAK mediated invasion inhibition. Knockout of RKIP expression in HCT116 cells by short hairpin RNA (shRKIP) resulted in increased invasiveness. Clinically, RKIP and TWEAK mRNA expression showed strong positive correlations in CRC patient samples. CONCLUSIONS: Our results implicate TWEAK as a key regulator of CRC invasion, and it appears to be a useful prognostic factor for patients with CRC. PMID- 21681382 TI - Features associated with successful recruitment of diverse patients onto cancer clinical trials: report from the American College of Surgeons Oncology Group. AB - BACKGROUND: The clinical trials mechanism of standardized treatment and follow-up for cancer patients with similar stages and patterns of disease is the most powerful approach available for evaluating the efficacy of novel therapies, and clinical trial participation should protect against delivery of care variations associated with racial/ethnic identity and/or socioeconomic status. Unfortunately, disparities in clinical trial accrual persist, with African Americans (AA) and Hispanic/Latino Americans (HA) underrepresented in most studies. STUDY DESIGN: We evaluated the accrual patterns for 10 clinical trials conducted by the American College of Surgeons Oncology Group (ACOSOG) 1999-2009, and analyzed results by race/ethnicity as well as by study design. RESULTS: Eight of 10 protocols were successful in recruiting AA and/or HA participants; three of four randomized trials were successful. Features that were present among all of the successfully recruiting protocols were: (1) studies designed to recruit patients with regional or advanced-stage disease (2 of 2 protocols); and (2) studies that involved some investigational systemic therapy (3 of 3 protocols). DISCUSSION: AA and HA cancer patients can be successfully accrued onto randomized clinical trials, but study design affects recruitment patterns. Increased socioeconomic disadvantages observed within minority-ethnicity communities results in barriers to screening and more advanced cancer stage distribution. Improving cancer early detection is critical in the effort to eliminate outcome disparities but existing differences in disease burden results in diminished eligibility for early-stage cancer clinical trials among minority-ethnicity patients. PMID- 21681383 TI - Population-wide dietary sodium restriction: a cautious view. AB - "What I tell you three times is true"-Lewis Carroll. How many times have we been told that reducing dietary sodium intake will improve the health of whole populations? But is there adequate evidence to support this idea? Some recent studies have indicated that caution is needed. Targeting those most likely to benefit should prevent inadvertent harm and free the rest of the population from yet another nagging plea to alter their lifestyle. PMID- 21681384 TI - Update on pathophysiology and treatment of hypertension in the elderly. AB - Hypertension is common in the elderly, and its prevalence increases with aging. The vascular system is a prototypical aging tissue, and arterial stiffness plays a major role in hypertension as the individual ages. Some unique aging changes in the nitric oxide and angiotensin II pathways are particularly important for vascular aging. Studies focusing on direct measures of vascular stiffness have increased understanding of the pathophysiology behind increased arterial stiffness. Goal blood pressure in the elderly is debated, but based on current outcome data, a goal blood pressure of 150/80-90 mm Hg is reasonable in at least the very elderly. This review discusses in detail the various landmark hypertension studies in the elderly. We recommend use of thiazide diuretics, long acting calcium channel blockers, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers as either monotherapy or in combination, with beta-blockers reserved for patients with specific indications. PMID- 21681385 TI - Psychometric properties of the Oral Mucositis Daily Questionnaire for child self report and importance of mucositis in children treated with chemotherapy. AB - PURPOSE: The objectives of this study were to examine the psychometric properties of the self-report Oral Mucositis Daily Questionnaire (OMDQ) and to measure the importance of mucositis in children receiving intensive chemotherapy. METHODS: Children >= 12 years of age receiving intensive chemotherapy for leukemia/lymphoma or undergoing stem cell transplantation were asked to complete the OMDQ daily for 21 days after chemotherapy. Other measures of mucositis obtained concurrently with OMDQ included the World Health Organization (WHO) mucositis scale, the pain visual analog scale (VAS), and the Functional Assessment of Cancer Therapy Esophageal Cancer Sub-scale (FACT-ECS). The importance of mucositis was estimated using a VAS, time trade-off technique, and willingness to pay to avoid mucositis. RESULTS: Fifteen children participated. Test-retest reliability demonstrated at least moderate correlation for all questions within the OMDQ. Assessment of construct validity of the OMDQ revealed at least moderate correlation with WHO, VAS, and FACT-ECS for questions regarding pain, swallowing, drinking, and eating. Effect on sleeping and talking had lower correlations than that expected a priori. The diarrhea question of the OMDQ did not correlate with other measures of mucositis. Severe mucositis is important to children, while mild mucositis is less important to them. Children were willing to pay moderate amounts of money to prevent mucositis. CONCLUSIONS: The OMDQ exhibits test-retest reliability, and most questions show construct validity with the exceptions of the sleep, talking, and diarrhea questions. Therefore, the OMDQ should not be used unmodified as a self-report instrument in children with cancer. Severe mucositis is of importance to these children. PMID- 21681386 TI - The development and impact of a new Psychosocial Oncology Program. AB - Cancer patients and their families face multiple psychosocial challenges when coping with illness, including emotional distress. The inability to detect and respond appropriately to these needs lead to greater suffering. Consistent with the philosophy of comprehensive care, innovative psychosocial oncology programs need to be created in meeting these complex needs. The purpose of this short communication is to share the experience of developing a new Psychosocial Oncology Program at the McGill University Health Centre in Montreal, Canada. Various challenges and lessons have been learned in the process and are described in this report. PMID- 21681387 TI - Metal-ceramic crowns cemented with two luting agents: short-term results of a prospective clinical study. AB - A prospective, randomized, controlled, split-mouth trial was performed to evaluate the cementation modes for metal-ceramic crowns. A total of 40 fully veneered metal-ceramic crowns were delivered in the posterior jaw segments of 20 patients using either a self-adhesive resin cement (RelyX Unicem Aplicap, 3M ESPE; n = 20) or a zinc oxide phosphate cement (Hoffmann's Cement, Hoffmann; n = 20). Thirteen parameters related to the abutment teeth and their periodontal status were evaluated. A visual analog scale was used to assess the sensitivity of the abutment teeth by patient-based outcomes. Data were statistically analyzed by a single-classification ANOVA (alpha = 0.05) and logistic regression analysis. The results presented were obtained after a mean observation period of 1.8 years. The dropout rate was 0%. None of the abutment teeth exhibited secondary caries at the restoration margins. No significant differences were demonstrated between the luting agents based on visual analog scale (p > 0.05), hypersensitivity (OR = 1.31), abutment mobility (p > 0.05), or probing depths (p > 0.05). Based on the sulcus fluid flow rates, a significantly greater mean difference was obtained with zinc oxide phosphate cement than with self-adhesive resin cement (9.2 units; p = 0.0006). Significant differences between the baseline examination and the follow-up examinations for sulcus bleeding index (p = 0.0013) and plaque index (p < 0.0001) were observed regardless of the luting agent used. The two cement types showed scarcely any differences between the parameters investigated. The outcomes of cementing fully veneered metal-ceramic crowns were equally good with self adhesive resin cement as with the clinically proven zinc oxide phosphate cement. PMID- 21681388 TI - Saliva-based creatine kinase MB measurement as a potential point-of-care testing for detection of myocardial infarction. AB - Myocardial infarction (MI) is the main cause of death all over the world. Biomarkers of cardiac necrosis are of great importance in the diagnosis of MI. The aim of this study was to determine probable changes of creatine kinase MB isoform (CK-MB) levels in saliva of patients with acute MI. A case-control study was carried out on 30 patients with acute MI who were hospitalized in Kamkar Arabnia Hospital of Qom City and 30 healthy control subjects. CK-MB levels were measured by immunoinhibition assay in saliva and serum of patients and healthy individuals. Statistical analysis of the Student's t test and Pearson correlation coefficient was used. CK-MB levels showed a significant elevation in saliva and serum of patients with acute MI compared to healthy controls. Furthermore, there was a strong correlation between salivary levels of CK-MB and its serum values. Subsequent to an acute MI, there is a rise in salivary levels of CK-MB just as what occurs in the serum. Moreover, salivary levels of CK-MB reflect well its serum values. It seems that cardiac biomarker CK-MB is measurable in the saliva of patients with acute MI. Salivary CK-MB may serve as an easy-to-use diagnostic tool for point-of-care testing of acute MI. PMID- 21681389 TI - Glycan-binding specificities of Streptococcus mutans and Streptococcus sobrinus lectin-like adhesins. AB - Since the adhesion of bacteria to the tooth surface is a prerequisite for dental plaque and subsequent caries development, a promising caries preventive strategy could be to block the lectin-glycan-mediated adherence of cariogenic bacteria. The aim of the study was to evaluate potential differences in glycan-binding specificities of two Streptococcus mutans strains (DSM 20523 and DSM 6178) and Streptococcus sobrinus (DSM 20381). A competitive enzyme-linked lectin-binding assay was used to identify the binding specificities of isolated bacterial surface lectins. Blotting of the microbial proteins on neoglycoprotein-coated PVP membranes enabled a qualitative protein analysis of all specific bacterial lectins. Different glycan-binding sites could be identified for the S. mutans strains in comparison to S. sobrinus. An earlier reported glycan-binding specificity for terminal galactose residues could be confirmed for the S. mutans strains. For the S. sobrinus strain, more than one glycan-binding specificity could be found (oligomannose and terminal sialyl residues). Each of the tested strains showed more than one surface lectin responsible for the specific lectin binding with varying molecular weight (S. mutans, 90/155 kDa and S. sobrinus, 35/45 kDa). The established experimental setup could be used as future standard procedure for the identification of bacterial lectin-derived binding specificities. The findings from this study might serve as basis for the design of an individual 'glycan cocktail' for the competitive inhibition of lectin mediated adhesion of mutans streptococci to oral surfaces. PMID- 21681390 TI - Acquired severe aplastic anemia after H1N1 influenza virus vaccination successfully treated with allogeneic bone marrow transplantation. PMID- 21681391 TI - Interpretive conundrum on the exclusion criterion of "transplantation with xenografts" for tissue and cell donation. AB - In the context of the EU Directives for human tissues and cells (2004/23/EC, 2006/17/EC and 2006/86/EC) further interest has arisen on the practical application of a few clauses. One such aspect, for the evaluation phase of a potential donor, is the interpretation of the exclusion criterion "transplantation with xenografts." This article outlines the consensus viewpoints regarding the earlier evaluation of the risks related to xenotransplantation and describes the current status of the terminology and recommendations/laws in several healthcare sectors. The application of uniform terminology is encouraged within the healthcare sectors at the international level. PMID- 21681392 TI - The effects of different preservation processes on the total protein and growth factor content in a new biological product developed from human amniotic membrane. AB - The aim of this work is to quantify the total protein and growth factors content in a tissue-suspension obtained from processed human amniotic membrane (hAM). hAM was collected, frozen, freeze dried, powdered and sterilized by gamma irradiation. At each step of the process, samples were characterized for the total protein amounts by a Bradford protein assay and for the growth factor concentrations by ELISA test of the tissue suspensions. Frozen-hAM samples show higher release of total proteins and specific growth factors in the tissue suspension in comparison with freeze-dried hAM. We observed that even if the protein extraction is hindered once the tissue is dried, the powdering process allows a greater release in the tissue suspension of total proteins and growth factors after tissue re-solubilization in comparison with only the freeze-drying process (+91 +/- 13% for EGF, +16 +/- 4% for HGF, +11 +/- 5% for FGF, +16 +/- 9% for TGF-beta1), and a greater release of EGF (85 +/- 10%) in comparison with only the freezing process, because proteins become much readily solubilized in the solution. According with these results, we describe a protocol to obtain a new sterile biological product from hAM tissue, with well-known effects of thermal, mechanical and physical processes on the total protein and grow factors contents. PMID- 21681393 TI - Prevalence of contraindications and conditions for precaution for prasugrel administration in a real world acute coronary syndrome population. AB - The prevalence of prasugrel contraindications and specific conditions requiring precaution for its use in a real world acute coronary syndrome (ACS) population is not known. We performed a prospective descriptive study in 1016 consecutive moderate to high risk ACS patients. In 646 patients (63.6%) subjected to percutaneous coronary intervention, analysis of absolute contraindications (history of stroke/transient ischemic attack or active bleeding), relative contraindications and specific conditions (age >= 75 years and/or weight < 60 kg) for prasugrel theoretical administration was performed. In 242 (37.5%) patients there was at least one absolute or relative contraindication or specific condition requiring attention for its use. Overall, 23.1% of patients in our cohort had a prior stroke/transient ischemic attack and/or specific condition to be considered for prasugrel administration. Specifically, the prevalence of stroke/TIA was 3.6%, the prevalence of patients >=75 years 20% and the prevalence of patients weighing <60 kg 2.2%. Among patients >=75 years old, 63 (9.8%) had diabetes mellitus or previous myocardial infarction, consisting a high risk subgroup that might benefit from prasugrel administration. In a real world ACS population a relatively high proportion of patients have a potential contraindication for prasugrel administration or necessitate special attention for its use. PMID- 21681394 TI - Congenital FVII deficiency and thrombotic events after replacement therapy. AB - Thrombosis has been occasionally described in congenital FVII deficiency. This report deals with patients with FVII deficiency who presented thrombotic events after substitution therapy. At least 12 patients are reported in the literature. In all but two cases thrombosis occurred after prothrombin complex concentrates or plasma derived FVII concentrates. In two instances pulmonary embolism occurred after the administration of large amounts of whole blood. Concomitant prothrombotic risk factors were present in most of these cases (surgery, immobilization, old age, etc.). Personal files allowed us to add another patient who developed bilateral pulmonary embolism after two vials of an aFVII concentrate. In this case also, concomitant risk factors were present, namely surgery for hysterectomy, immobilization. The pulmonary embolism occurred in spite of the congenital FVII deficiency indicating that no sure antithrombotic protection is assured by this defect. The actual needs of substitution therapy in patients with some variants of FVII deficiency is discussed, together with comments on the therapeutic management of the thrombotic events in these patients. PMID- 21681395 TI - Fluoride contamination and fluorosis in rural community in the vicinity of a phosphate fertilizer factory in India. AB - We studied chronic fluoride intoxication in 10 villages of Udaipur receiving F emissions from phosphate fertilizer factories. Although fluoride remained below permissible limit in most of the drinking water samples, the incidence of fluorosis in adults as well as in children was surprisingly high. Khemli appeared to be the most affected village (with >48% cases) where, about 93% of 2 h air samples contained fluoride above 2.0 MUg m(-3) and crops and vegetable F ranged from 27.5 to 143.4 MUg g(-1). Concentrations of fluoride and inorganic P in urine showed asynchrony and were well linked with prevalence of fluorosis. The study indicated that air-borne fluoride was the major factor for higher prevalence of fluorosis in these rural areas. PMID- 21681396 TI - Concentrations, sources and risk assessment of polycyclic aromatic hydrocarbons (PAHs) in soils of Liaohe estuarine wetland. AB - Concentration, source, and risk of PAHs were investigated in 31 sites from surface soils of Liaohe estuarine wetland. Total PAHs concentrations ranged from 293.4 to 1735.9 ng/g with a mean of 675.4 ng/g. The 3- and 4-ring PAHs were the dominant species. The ratios of high-molecular weight PAHs to low-molecular weight PAHs and anthracene/(anthracene+phenanthrene) were calculated to apportion sources of PAHs. It was found that both pyrogenic and petrogenic PAHs sources were important. Effect range low and effect range median showed that the PAHs would occasionally cause adverse effects. The nemerow composite index revealed that about 41.9% soil sampling sites were safety; about 58.1% sites had different grades of PAHs pollution. PMID- 21681397 TI - Ultraviolet radiation increases sensitivity to pesticides: synergistic effects on population growth rate of Daphnia magna at low concentrations. AB - In the present study we aimed to investigate whether UV-B radiation can exacerbate effects of pesticides fenoxycarb, pirimicarb, and tebufenpyrad on the survival, reproduction, and population growth rate of the standard test species Daphnia magna. We applied sublethal pesticides' concentrations and UV doses and observed no effects on survival. However, we observed synergistic effects of UV and pesticides on both cumulative reproduction and population growth rate (21 days) for fenoxycarb (100 MUg/L) and pirimicarb (10 MUg/L), but a less-than additive effect for tebufenpyrad (5-10 MUg/L). In the series exposed to UV and fenoxycarb or pirimicarb, the population growth rate dropped down to 0.1, while in the control series it was around 0.3. The results indicate that concentrations of some toxicants that are nontoxic in standard tests can cause harmful population-level effects when combined with UV. PMID- 21681398 TI - Monitoring of organochlorine pesticide residue levels in adipose tissue of Veracruz, Mexico inhabitants. AB - The objective of the present study was to monitor the levels of organochlorine pesticides HCB, alpha-beta-gamma-HCH, pp'DDE, op'DDT and pp'DDT in 150 adipose tissue samples of Veracruz, Mexico inhabitants. In analyzed samples, the following pesticides were detected: p,p'-DDE in 100% of the samples at mean 1.643 mg/kg; p,p'-DDT in 99.3.% of the samples at mean 0.227 mg/kg; beta-HCH in 97.3% of the samples at mean 0.063 mg/kg; and op'DDT in 93.3% of the samples at mean 0.022 mg/kg. Comparing mean, median and geometric mean concentrations of organochlorine pesticides shows a decrease in values from mean to median and to geometric mean which points out a prevalence of lower concentrations among the total samples and the existence of occasional cases of extreme exposure expressed in range values. The pooled samples divided according to sex, showed only significant differences of pp'DDE median concentrations between sexes. The other organochlorine pesticides indicated no statistical differences between sexes, including the pp'DDE/pp'DDT ratio. The samples grouped according to age, showed that the third tertile was more contaminated for both sexes, indicating age as a positively associated factor with organochlorine pesticide levels in adipose tissue of Veracruz inhabitants. Comparing organochlorine pesticide levels between 2008 and 2010 years, a decreased tendency for beta-HCH, pp'DDE, Sigma-DDT and pp'DDE/pp'DDT ratio levels was observed. PMID- 21681399 TI - Time- and dose-dependent induction of HSP70 in Lemna minor exposed to different environmental stressors. AB - The objective of this study was to examine the influence of different stressors, including cadmium (heavy metal), anthracene (polycyclic aromatic hydrocarbon-PAH) and chloridazon (herbicide), on population growth and biosynthesis of cytoplasmic HSP70 in Lemna minor (duckweed) in short (4 h)- and long (7 days)-term tests. A heat shock response was confirmed in Lemna exposed to high temperature: 35, 37.5, 40, or 42.5 degrees C in short-term (4 h) treatments. The chemicals tested stimulated the biosynthesis of the cytoplasmic HSP70 protein in a concentration dependent way (0.5-5 MUM), higher in fronds exposed to lower doses of stressors. Additionally, production of HSP70 was greater after 4 h of incubation than after 7 days. The results suggest that HSP70 could be applied as a non-specific and sensitive detector of stress induced by different chemicals at concentrations below those that produce the type of response observed in classical cytotoxicity tests, such as growth inhibition. PMID- 21681400 TI - Groundwater from infiltration galleries used for small public water supply systems: contamination with pesticides and endocrine disruptors. AB - Infiltration galleries are among the oldest known means used for small public water fountains. Owing to its ancestral origin they are usually associated with high quality water. Thirty-one compounds, including pesticides and estrogens from different chemical families, were analysed in waters from infiltration galleries collected in Alto Douro Demarcated Wine region (North of Portugal). A total of twelve compounds were detected in the water samples. Nine of these compounds are described as presenting evidence or potential evidence of interfering with the hormone system of humans and wildlife. Although concentrations of the target analytes were relatively low, many of them below their limit of quantification, four compounds were above quantification limit and two of them even above the legal limit of 0.1 MUg/L: dimethoate (30.38 ng/L), folpet (64.35 ng/L), terbuthylazine-desethyl (22.28 to 292.36 ng/L) and terbuthylazine (22.49 to 369.33 ng/L). PMID- 21681401 TI - Effect of light and pH on persistence of flubendiamide. AB - Persistence of flubendiamide in soil as affected by UV and sunlight exposure and in water as affected by pH was studied. At field capacity moisture regime, soil was treated with flubendiamide and exposed to UV and sunlight. Dissipation for the pesticide followed mono-phasic first order kinetics. Residues of flubendiamide, as thin film on petri-plates and soil thin film, dissipated with half-lives of 7.0 and 9.1 days under UV light and 12.0 and 19.1 days under sunlight, respectively. Residues of flubendiamide dissipated faster under UV light as compared to sunlight. Persistence study in aqueous medium under different pH condition indicated that flubendiamide residues persisted in water beyond 250 days with half-lives ranging from 250.8 to 301.0 days. Dissipation in water was faster at pH 4.0 (T(1/2) 250.8 days), followed by pH 9.2 (T(1/2) 273.6 days) and 7.0 (T(1/2) 301.0 days). PMID- 21681402 TI - Energy dispersive X-ray fluorescence analysis of mine waters from the Migori Gold Mining Belt in Southern Nyanza, Kenya. AB - Analyses of water samples from Mikei, Osiri, Masara and Macalder (Makalda) gold mines of the Migori gold mining belt of Southwestern Kenya were done to determine the level of heavy metals using the Energy Dispersive X-ray Fluorescence technique. The concentrations of the heavy metals were; copper (29.34 +/- 5.01 14,975.59 +/- 616.14 MUg/L); zinc (33.69 +/- 4.29-683.15 +/- 32.93 MUg/L); arsenic (958.16 +/- 60.14-18,047.52 +/- 175.00 MUg/L) and lead (19.51 +/- 5.5 214.53 +/- 6.29 MUg/L). High levels of arsenic and lead were noted. These heavy metals are not only dangerous to the lives of miners and the local inhabitants; they are also a threat to aquatic life since these waters finally find their way into Lake Victoria. PMID- 21681403 TI - The viability to a wall shear stress and propagation of Bifidobacterium longum in the intensive membrane bioreactor. AB - Bifidobacterium longum grew at 65 L pilot scale of the membrane bioreactor (MBR), externally fitted with ceramic membrane (0.7 m2). Cell mass at the MBR reached 22.18 g L(-1) as dry cell weight in 12 h, which is 8.44 times higher than cell mass attained at the vial culture. The growth rate in the vial culture was MU = 0.385 h- and at the batch culture was MU = 1.13 h- in the exponential period and MU = 0.31 h(-1) in the stationary period. In the fed-batch mode was MU = 1.102 h( 1) for 6 h with inoculation and declined to MU = 0.456 h(-1) with feeding of feed medium. The growth rate at the MBR was MU = 0.134 h(-1). The number of viable cells was 6.01 * 10(12) cfu L(-1) at the batch culture, but increased to 1.15 * 10(14) cfu L(-1) at the MBR culture. The specific growth rate of viable cell number (colony-forming units per liter, per hour) improved by 6.01 times from the batch to the MBR culture. The wall shear stress mainly generated by the pump, and the membrane incorporated into the MBR was controlled during the cultivation at the MBR. The viability of B. longum declined to under 10% in the first 2 weeks of the 4-week stability test (40 degrees C) as B. longum was exposed to over wall shear stress 713 Pa, but the viability improved to 30-40% in wall shear stress of 260 Pa or STR culture. The loss in the cell viability can be saved by managing with wall shear stress during the cultivation at the MBR. PMID- 21681404 TI - Small bowel wall thickening: MDCT evaluation in the emergency room. AB - Small bowel wall thickening detected on computed tomography is a frequent finding in patients referring to emergency room with acute abdominal pain. In this pictorial review, we aim to discuss patterns of small bowel wall thickening and to explain hints for differential diagnosis with imaging findings. PMID- 21681405 TI - Physical activity among adult survivors of childhood lower-extremity sarcoma. AB - INTRODUCTION: Adult survivors of childhood lower-extremity sarcoma are largely physically inactive, a behavior which potentially compounds their health burden. Altering this behavior requires understanding those factors that contribute to their physical inactivity. Therefore, this investigation sought to identify factors associated with inactivity in this subpopulation of cancer survivors. METHODS: Demographic, personal, treatment, and physical activity information from adult survivors of childhood lower-extremity sarcomas was obtained from the Childhood Cancer Survivor Study (CCSS) cohort. Generalized linear models were used to identify variables that best identified those individuals who were physically inactive. RESULTS: Only 41% of survivors met Center for Disease Control (CDC) activity guidelines. Survivors were 1.20 (95% confidence intervals (CI) 1.11-1.30) more likely compared to CCSS sibling cohort and 1.12 (95% CI 1.10 1.15) times more likely than the general population to fail to meet CDC guidelines. Significant predictors of physical inactivity included female sex, hemipelvectomy surgery, and platinum and vinca alkaloid chemotherapy. CONCLUSIONS: The primary findings of this study are that survivors of childhood onset lower-extremity sarcoma are (1) highly likely to be physically inactive and (2) less likely than their siblings or the general population to regularly exercise. This study has identified treatment-related risk factors associated with inactivity that will help health and wellness practitioners develop successful exercise interventions to help these survivors achieve recommended levels of physical activity for health. IMPLICATIONS FOR CANCER SURVIVORS: These results suggest that physical activity interventions for adult survivors of childhood lower-extremity sarcomas should be sex specific and responsive to unique physical late effects experienced by these survivors. PMID- 21681407 TI - Infarcted papillary thyroid cancer after fine needle aspiration biopsy. PMID- 21681406 TI - Social welfare and legal constraints associated with work among breast and prostate cancer survivors: experiences from Ireland. AB - INTRODUCTION: Around 40% of cancer survivors are of working age. We investigated employment outcomes among survivors in Ireland where sick leave and sick pay are at the employers' discretion and the law affords no protection against dismissal following extended absence. METHODS: A questionnaire was mailed to 1,373 survivors, identified from the National Cancer Registry, 6-24 months post diagnosis. The analysis included breast and prostate cancer respondents who were working at diagnosis. Factors associated with work continuation post-diagnosis and work resumption after cancer-related absence were identified using logistic regression. RESULTS: The response rate was 54%. Three hundred forty-six respondents were working at diagnosis (breast cancer = 246; prostate cancer = 100). Sixty-two (18%) continued working post-diagnosis. Factors significantly associated with work continuation were: self-employment, prostate cancer, lower pre-diagnosis household income, and not having surgery. Two hundred eighty-four took time off work post-diagnosis; of these, 51 (18%) had left the workforce, 187 (66%) had resumed working, and 46 (16%) planned to resume working. Factors significantly associated with work resumption were: tertiary education, not having chemotherapy, receiving sick pay, and not having a medical card (which provides free access to public health services). Among those who resumed working, the median absence was 30.1 weeks (inter-quartile range = 12.9-51.6). The length of absence varied significantly by socio-demographic, financial, medical, and job and social welfare-related factors. Median working hours pre- and post-diagnosis differed significantly (pre-diagnosis = 38/week; post-diagnosis = 30/week; p<0.001). CONCLUSIONS: The high level of workforce departure and associations between self-employment, sick pay and medical cards, and employment outcomes suggest that social welfare and legal provisions are important determinants of the survivors' workforce participation. IMPLICATIONS FOR SURVIVORS: In formulating strategies to optimise survivors' employment outcomes, it is important that policy- and decision-makers are aware of the influence of social welfare and legal provisions. PMID- 21681408 TI - Prioritizing prevention: culture, context, and cervical cancer screening among Vietnamese American women. AB - Few studies have investigated what Vietnamese American women believe about the Pap smear or how those beliefs might influence behavior. Thirty-one Vietnamese American women recruited through snowball sampling were interviewed about their beliefs regarding the Pap smear. Interviews were qualitatively analyzed using a theoretically informed, inductive approach. The women interviewed emphasized the importance of primary prevention of disease through culturally-informed personal health regimens. They were also largely unfamiliar with the Pap smear, but believed that gynecological exams in general were effective and necessary for disease detection. Finally, when access to gynecological care was difficult, women's faith in their own preventive behaviors helped alleviate their concerns over lack of care. While culturally associated beliefs do not simply "cause" Vietnamese American women to seek or avoid Pap smears, they do influence screening behaviors to a greater or lesser degree, depending on other contextual variables. PMID- 21681409 TI - Daily granulocyte and monocyte adsorptive apheresis in patients with active ulcerative colitis: a prospective safety and feasibility study. AB - BACKGROUND: This prospective study was to assess the safety and feasibility of daily granulocyte and monocyte adsorptive apheresis (GMA) therapy in patients with active ulcerative colitis (UC). METHODS: Thirty consecutive patients with moderately or severely active UC received daily GMA treatment (5 sessions over 5 consecutive days) with the Adacolumn. Adverse events (AE), patient tolerability, and clinical symptoms were monitored daily. RESULTS: Sixteen patients (53%) experienced AE during at least one GMA session. The most frequent AE was mild headache followed by fatigue and fever. None of the AE was serious, and all patients completed the 5 consecutive GMA sessions. Clinical symptoms (stool frequency and/or rectal bleeding) were improved in 21 patients (70%) during the course of GMA therapy. Clinical remission defined as normal stool frequency and no rectal bleeding was achieved in 7 patients (23%) after 5 GMA sessions. Seven of 20 patients (35%) with moderately active disease achieved clinical remission, whereas none of the 10 patients with severely active disease achieved clinical remission. Total and differential leukocyte counts, platelet count, and hemoglobin level did not significantly change, but C-reactive protein level significantly decreased during the course of GMA therapy. CONCLUSIONS: This is the first report on daily GMA in the treatment of patients with UC. Daily GMA was safe and well tolerated without serious AE. Furthermore, daily GMA was associated with rapid improvement of clinical symptoms in patients with moderately active UC. However, controlled trials are warranted to assess a definite efficacy for daily GMA therapy. PMID- 21681410 TI - Pretreatment prediction of anemia progression by pegylated interferon alpha-2b plus ribavirin combination therapy in chronic hepatitis C infection: decision tree analysis. AB - BACKGROUND: This study aimed to develop a model to predict the development of severe anemia during pegylated interferon alpha-2b plus ribavirin combination therapy. METHODS: Data were collected from 1081 genotype 1b chronic hepatitis C patients who were treated at 6 hospitals in Japan. These patients were randomly assigned to a model-building group (n = 691) or an internal validation group (n = 390). Factors predictive of severe anemia (hemoglobin, Hb < 8.5 g/dl) were explored using data-mining analysis. RESULTS: Hb values at baseline, creatinine clearance (Ccr), and an Hb concentration decline by 2 g/dl at week 2 were used to build a decision-tree model, in which the patients were divided into 5 subgroups based on variable rates of severe anemia ranging from 0.4 to 11.8%. The reproducibility of the model was confirmed by the internal validation group (r2 = 0.96). The probability of severe anemia was high in patients whose Hb value was <14 g/dl before treatment (6.5%), especially (a) in those whose Ccr was <80 ml/min (11.8%) and (b) those whose Ccr was >= 80 ml/min but whose Hb concentration decline at week 2 was >= 2 g/dl (11.5%). The probability of severe anemia was low in the other patients (0.4-2.5%). CONCLUSIONS: The decision-tree model that included Hb values at baseline, Ccr, and an Hb concentration decline by 2 g/dl at week 2 was useful for predicting the probability of severe anemia, and has the potential to support clinical decisions regarding early dose reduction of ribavirin. PMID- 21681413 TI - Novel PPARgamma partial agonists with weak activity and no cytotoxicity; identified by a simple PPARgamma ligand screening system. AB - Peroxisome proliferator-activated receptors (PPARs) are the transcriptional factor that regulate glucose and lipid homeostasis and widely well-known as molecular targets for improvement of metabolic disorder. Because major transcriptional activity of PPARs depends on their proper ligands, the studies for PPAR ligands have been continuously developed. We previously reported the simple enzyme-linked immunosorbent assay (ELISA) systems to screen PPAR ligands and a chemical library including flavonoid derivatives have applied to these systems. In this study, we introduce two compounds (KU16476 and KU28843) identified as PPARgamma partial agonists by a screening ELISA for PPARgamma ligand. KU16476 and KU28843 significantly increased binding between PPARgamma and SRC-1 in a simple ELISA system. Co-activator recruiting-induced abilities of two compounds were less than that of indomethacin, a well-known PPARgamma agonist. To determine whether these compounds would be PPARgamma partial agonists, each candidate with indomethacin were applied to a simple ELISA based on binding between PPARgamma and SRC-1. Cotreatment with indomethacin significantly increased binding between PPARgamma and SRC-1 than treatment of indomethacin or candidate alone. Two compounds had no considerable cytotoxicities, induced partial adipogenesis, and accumulated lipid droplets in 3T3-L1 fibroblast. Also, these two compounds enhanced expression of PPARgamma-mediated genes such as aP2 and UCP-2. By docking study, we confirmed that two compounds bound well to the active site of PPARgamma with hydrophobic interactions. We suggest that two compounds identified by a simple ELISA system can be PPARgamma partial agonists. These PPARgamma partial agonists and these studies to find out novel PPARgamma agonists may contribute to drug development against metabolic disorders. PMID- 21681412 TI - Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome in nonobese adults. AB - PURPOSE: The relationship between obstructive sleep apnea (OSA) syndrome and metabolic syndrome is far from conclusion for obesity as a confounding factor. The aim of the present study was to investigate the association between OSA and some components of metabolic abnormality in nonobese patients. METHODS: We consecutively recruited nonobese subjects who underwent polysomnography and analyzed some components of metabolic abnormality in subjects with and without OSA. Multiple linear regression was used to evaluate the independent risk factor of some components of metabolic abnormality. RESULTS: A total of 154 subjects were enrolled and were divided to control group (45 subjects) and OSA group (113 subjects). Body mass index was no different between groups. Systolic blood pressure, triglycerides, and insulin concentration were significantly higher among OSA group compared with control group (p = 0.000, 0.043, and 0.006, respectively), and the prevalences of dyslipidemia, hypertension, and at least two of the metabolic abnormalities were significantly greater in OSA group (p = 0.003, 0.031, and 0.000, respectively). After adjusting for confounding factors, lowest O(2) saturation was the major contributing factor for elevated systolic blood pressure (p = 0.001), and independent associations were found between apnea hypopnea index and the following parameters of metabolic abnormality: triglycerides and homeostasis model assessment of insulin resistance (all p = 0.000). CONCLUSIONS: Our finding was consistent with previous studies that OSA was independently associated with dyslipidemia, hypertension, and at least two of metabolic abnormalities in nonobese patients. PMID- 21681411 TI - The power and richness of modelling tauopathies in Drosophila. AB - Tauopathies are a group of neurodegenerative disorders characterised by altered levels of phosphorylation or mutations in the neuronal microtubule protein Tau. The heterogeneous pathology of tauopathies suggests differential susceptibility of different neuronal types to wild-type and mutant Tau. The genetic power and facility of the Drosophila model has been instrumental in exploring the molecular aetiologies of tauopathies, identifying additional proteins likely contributing to neuronal dysfunction and toxicity and novel Tau phosphorylations mediating them. Importantly, recent results indicate tissue- and temporal-specific effects on dysfunction and toxicity coupled with differential effects of distinct Tau isoforms within them. Therefore, they reveal an unexpected richness of the Drosophila model that, coupled with its molecular genetic power, will likely play a significant role in our understanding of multiple tauopathies potentially leading to their differential treatment. PMID- 21681414 TI - Isomer-specific effects of conjugated linoleic acid on proliferative activity of cultured neural progenitor cells. AB - Conjugated linoleic acid (CLA) has been shown to have a variety of biological activities. However, the effects of CLA on the proliferation of neural progenitor cells (NPCs) are not clear. The objective of this study was to determine the effects of cis-9 trans-11 CLA and trans-10 cis-12 CLA, the predominant individual isomers, on the proliferative activity of NPCs in vitro. Cell counts showed that treatment of NPCs with cis-9 trans-11 CLA increased the cell number in a dose- and time- dependent manner while significant inhibition effect of trans-10 cis-12 CLA was observed. Western blot analysis revealed the elevated expression of cyclin D1 induced by cis-9 trans-11 CLA treatment and the decreased expression of cyclin D1 by trans-10 cis-12 CLA treatment in NPCs. Cyclin D1-siRNA transfection significantly inhibited the promotion of cell proliferation by cis-9 trans-11 CLA. In addition, trans-10 cis-12 CLA inhibited the phosphorylation of protein kinase B (PKB/Akt), while cis-9 trans-11 CLA had no effect on phospho Akt levels. Furthermore, immunofluorescence assay showed that after CLA treatment, the cells retained their functional characteristics of neural progenitors. These results indicated that cis-9 trans-11 CLA can effectively enhance the proliferation of hADSCs. The effect of cis-9 trans-11 CLA may be associated with the up-regulation of cyclin D1 expression. PMID- 21681415 TI - Acute and chronic effects of endosulfan on the haemato-immunological and histopathological responses of a threatened freshwater fish, spotted murrel, Channa punctatus. AB - Two experiments, one short-term and one long-term, were conducted to elucidate the acute and chronic effects, respectively, of endosulfan exposure on the haemato-immunological and histopathological responses of Channa puncatatus. In the short-term study, fish were exposed to sublethal endosulfan (8.1 MUg l(-1)) for 12, 24, 36, 48, 72 and 96 h. In the long-term study, fish were fed with normal diet and simultaneously either exposed to endosulfan (1.2 MUg l(-1)) for 90 days or not. Results showed that the ascorbic acid levels in both the liver and the muscle decreased significantly (P < 0.05) by acute and chronic endosulfan exposure. The haemoglobin (Hb) level reduced significantly (P < 0.05) by 15.5% within 12 h of acute endosulfan exposure, further decreased by 25.8% after 24 h of exposure, however, thereafter the values increased and at the end of 72 h returned to normal levels. Almost similar trend was observed for the erythrocyte (RBC) count. The WBC count and the nitroblue tetrazolium (NBT) value showed a general increasing trend with increase in the duration of acute endosulfan exposure. The chronic exposure of C. punctatus to endosulfan significantly (P < 0.05) lowered the Hb level, RBC and WBC counts, NBT reduction value and the plasma parameters such as plasma protein, albumin (A) and globulin (G) compared with that of the control (except for A/G ratio). Endosulfan exposure also severely altered the liver histological structure. Overall results indicated that both short-term acute and long-term chronic endosulfan exposure had a significant impact on the haemato-immunological parameters and tissue histopathology of C. punctatus. PMID- 21681416 TI - Health of farmed fish: its relation to fish welfare and its utility as welfare indicator. AB - This brief review focuses on health and biological function as cornerstones of fish welfare. From the function-based point of view, good welfare is reflected in the ability of the animal to cope with infectious and non-infectious stressors, thereby maintaining homeostasis and good health, whereas stressful husbandry conditions and protracted suffering will lead to the loss of the coping ability and, thus, to impaired health. In the first part of the review, the physiological processes through which stressful husbandry conditions modulate health of farmed fish are examined. If fish are subjected to unfavourable husbandry conditions, the resulting disruption of internal homeostasis necessitates energy-demanding physiological adjustments (allostasis/acclimation). The ensuing energy drain leads to trade-offs with other energy-demanding processes such as the functioning of the primary epithelial barriers (gut, skin, gills) and the immune system. Understanding of the relation between husbandry conditions, allostatic responses and fish health provides the basis for the second theme developed in this review, the potential use of biological function and health parameters as operational welfare indicators (OWIs). Advantages of function- and health-related parameters are that they are relatively straightforward to recognize and to measure and are routinely monitored in most aquaculture units, thereby providing feasible tools to assess fish welfare under practical farming conditions. As the efforts to improve fish welfare and environmental sustainability lead to increasingly diverse solutions, in particular integrated production, it is imperative that we have objective OWIs to compare with other production forms, such as high-density aquaculture. However, to receive the necessary acceptance for legislation, more robust scientific backing of the health- and function-related OWIs is urgently needed. PMID- 21681417 TI - Effects of brimonidine timolol fixed combination therapy on anterior ocular segment configuration. AB - PURPOSE: To assess the effects of brimonidine and of brimonidine and timolol fixed combination (BTFC) therapy on the pupil and angle structures in both normal subjects and in open angle glaucoma patients. METHODS: For the first study, 60 healthy normal subjects were divided into 2 groups. In group 1, brimonidine was administered to the right eye and timolol to the left eye. In group 2, a BTFC was administered to the right eye and pilocarpine 2% to the left eye. All subjects had a full ophthalmic examination including IOL master, ORB II scan and three times of Visante OCT both before and after instillation of the eyedrops. After testing, we analyzed the pupil size, anterior chamber depth and anterior chamber angle parameters including angle opening distance, trabecular-iris space area, angle recess area and trabecular-iris angle. In the second study, we evaluated the effects of BTFC therapy on the anterior chamber over time through reviewing ORB scan data of glaucoma patients who had instilled BTFC for at least 6 months (n = 126). RESULTS: Brimonidine and BTFC therapy caused miosis and widening of most of the anterior chamber angle parameters without changing the anterior chamber depth. The effects of BTFC on the angle were likely to be greater than those resulting from the use of pilocarpine. The miotic effects remained during instillation of BTFC. CONCLUSION: Brimonidine and BTFC cause passive miosis with angle widening; these results could be applied in the treatment of various types of glaucoma. PMID- 21681418 TI - Differential sensitivity to amphetamine's effect on open field behavior of psychosocially stressed male rats. AB - RATIONALE: Studies of socially housed rodents have provided significant information regarding the mechanisms of stress and of stress-related disorders. OBJECTIVE: Since psychosocial stress is known to alter the functional activity of dopaminergic system, we employed amphetamine (AMP) to evaluate the involvement dopamine in mediating the behavioral consequences of psychosocial stress. METHODS: Male rats housed two per cage were designated as dominant (DOM) or subdominant (Sdom) based on initial evaluations of agonistic behaviors and body weight changes. Diad-housed rats and a group of single-housed (SiH) rats were tested in an open field after injections of saline or amphetamine (0.9 or 2.7 mg/kg IP) prior to and again while diad-housing. RESULTS: Compared to future DOM rats, saline-injected future Sdom rats entered the open field center less frequently, spent less time in rearing behavior and groomed less. At the pre-diad test AMP treatment elevated locomotor activity of all rats, while stimulation of center entries was more marked in future DOM rats. At the diad test, AMP's locomotor stimulant effect was evident in all experimental groups with DOM rats showing higher effects compared to Sdom and SiH rats. Amphetamine's stimulation of center entries in DOM rats was similar to the pre-diad test, but it was diminished in Sdom rats, while stimulation of rearing behavior was most evident in diad-housed rats. CONCLUSION: The dopaminergic system modulates the psychosocial stress-induced differences in explorative and emotional behaviors. Furthermore, behavioral traits like frequency of grooming behavior and of center entries were predictive of future hierarchical status. PMID- 21681419 TI - Temperature and parasitism by Asobara tabida (Hymenoptera: Braconidae) influence larval pupation behaviour in two Drosophila species. AB - In holometabolous insects, pupation site selection behaviour has large consequences for survival. Here, we investigated the combined effects of temperature and parasitism by the parasitoid Asobara tabida on larval pupation behaviour in two of its main Drosophila sp. hosts differing in their climate origin. We found that larvae of Drosophila melanogaster--a species with a (sub)tropical origin--placed at 25 degrees C pupated higher in rearing jars than those placed at 15 degrees C. The opposite pattern was observed for Drosophila subobscura larvae--a species from temperate regions--which pupated lower, i.e. on or near the substrate at 25 degrees C, than those placed at 15 degrees C. When placed at 25 degrees C, parasitized larvae of both species pupated closer to the substrate than unparasitized ones. Moreover, the Drosophila larvae that had been exposed and probably stung by A. tabida, but were not parasitized, pupated lower than the control unparasitized larvae. These results provide new insights of host behaviour manipulation by A. tabida larvae. PMID- 21681420 TI - Transgenic mice with overexpression of mutated human optineurin(E50K) in the retina. AB - In the present work, Site-directed mutagenesis to insert the Glu50Lys amino acid substitution was achieved by PCR using plasmid pBluescript-OPTN. Mutated human OPTN(E50K) gene-driven mouse c-kit promoter was constructed and confirmed by endonuclease digestion and sequence analysis. Transgenic mice were generated via the microinjection method. PCR and DNA dot blot were used to screen the positive transgenic mice. RT-PCR analyzed the RNA level and location of mutated human OPTN(E50K) mRNA expression in transgenic mice. Western blot and immunohistochemistry were used to detect the level and location of mutated human OPTN(E50K) expression in transgenic mice. A transgenic mouse model with overexpression of mutated human OPTN(E50K) in retina was successfully established. The transgene was integrated and transmitted into the chromosome of transgenic mice. Mutated human OPTN(E50K) gene was controlled by c-kit promoter and expressed in the retina in mice. Mutated human OPTN(E50K) in transgenic mice was higher than that of wild type C57BL/6J mice. Our studies had provided a new transgenic model for investigating the molecular properties of mutated human OPTN(E50K). PMID- 21681421 TI - Selection of 29 highly informative InDel markers for human identification and paternity analysis in Chinese Han population by the SNPlex genotyping system. AB - The interest of forensic researchers in single nucleotide polymorphism (SNP) has been attracted because of its potential advantages, such as low mutation rates, amenable to high-throughput automated platform and the improved application in the analysis of degraded samples. In this paper, 29 highly informative insertion/deletion (InDel, a special kind of SNP) markers were selected from the dbSNP ( http://www.ncbi.nlm.nih.gov/SNP/ ) according to the given criteria. 109 unrelated Chinese Han subjects were genotyped for the 29 InDels with SNPlex genotyping system. The allele frequency data revealed that the combined power of discrimination for the 29 InDel markers was 0.999999999990867 and the combined probability of paternity exclusion (PE) was 0.9930. Sensitivity studies were performed to evaluate the flexibility of the SNPlex genotyping system on the set of 29 InDels. Highly reproducible results could be obtained with 40-100 ng genomic DNA and the proportion of total allele drop-in was significantly increased when the amount of DNA added to PCR was lower than 35 ng. These results suggested that the set of 29 InDels was useful in paternity analysis or human identification in the future. PMID- 21681422 TI - N-acetyl cysteine suppresses the foam cell formation that is induced by oxidized low density lipoprotein via regulation of gene expression. AB - Foam cells derived from macrophages have been implicated as markers of early stage atherosclerosis development. In this study, we found that N-acetyl cysteine (NAC), a well-known inhibitor of reactive oxygen species (ROS), decreased the generation of ROS and suppressed foam cell formation in the presence of oxidized low density lipoprotein through down-regulation of cluster of differentiation 36 expression. We investigated gene expression profiles in order to determine the effects of NAC on foam cell formation using a microarray analysis. The level of apolipoprotein E, which is involved in lipid efflux, was increased and the levels of the antioxidant genes glutathione peroxidase 1 and 3 were also increased. The expression levels of the oxidative stress response and the DNA repair genes were decreased. These results were confirmed using quantitative real-time PCR. Our results indicate that oxidative stress plays an important role in foam cell formation, and that regulation of oxidation using antioxidants is a potential therapeutic method for blocking atherosclerosis development. PMID- 21681423 TI - Generation and analysis of expressed sequence tags from the bone marrow of Chinese Sika deer. AB - Sika deer is one of the best-known and highly valued animals of China. Despite its economic, cultural, and biological importance, there has not been a large scale sequencing project for Sika deer to date. With the ultimate goal of sequencing the complete genome of this organism, we first established a bone marrow cDNA library for Sika deer and generated a total of 2,025 reads. After processing the sequences, 2,017 high-quality expressed sequence tags (ESTs) were obtained. These ESTs were assembled into 1,157 unigenes, including 238 contigs and 919 singletons. Comparative analyses indicated that 888 (76.75%) of the unigenes had significant matches to sequences in the non-redundant protein database, In addition to highly expressed genes, such as stearoyl-CoA desaturase, cytochrome c oxidase, adipocyte-type fatty acid-binding protein, adiponectin and thymosin beta-4, we also obtained vascular endothelial growth factor-A and heparin-binding growth-associated molecule, both of which are of great importance for angiogenesis research. There were 244 (21.09%) unigenes with no significant match to any sequence in current protein or nucleotide databases, and these sequences may represent genes with unknown function in Sika deer. Open reading frame analysis of the sequences was performed using the getorf program. In addition, the sequences were functionally classified using the gene ontology hierarchy, clusters of orthologous groups of proteins and Kyoto encyclopedia of genes and genomes databases. Analysis of ESTs described in this paper provides an important resource for the transcriptome exploration of Sika deer, and will also facilitate further studies on functional genomics, gene discovery and genome annotation of Sika deer. PMID- 21681424 TI - Expression and characterization of a cold-active and xylose-stimulated beta glucosidase from Marinomonas MWYL1 in Escherichia coli. AB - The gene encoding a cold-active and xylose-stimulated beta-glucosidase of Marinomonas MWYL1 was synthesized and expressed in Escherichia coli. The recombinant enzyme (reBglM1) was purified and characterized. The molecular mass of the purified reBglM1 determined by SDS-PAGE agree with the calculated values (50.6 Da). Optima of temperature and pH for enzyme activity were 40 degrees C and 7.0, respectively. The enzyme exhibited about 20% activity at 5 degrees C and was stable over the range of pH 5.5-10.0. The presence of xylose significantly enhanced enzyme activity even at higher concentrations up to 600 mM, with maximal stimulatory effect (about 1.45-fold) around 300 mM. The enzyme is active with both glucosides and galactosides and showed high catalytic efficiency (k (cat) = 500.5 s(-1)) for oNPGlc. These characterizations enable the enzyme to be a promising candidate for industrial applications. PMID- 21681425 TI - Polymorphisms of STAT5A gene and their association with milk production traits in Holstein cows. AB - The STAT5A gene was studied as a candidate gene for five milk production traits (milk yield at 305 days, protein percentage, fat percentage, lactose percentage and dry matter percentage) in Holstein cows. According to the sequence of bovine STAT5A gene, two pairs of primers (P1 and P2) were designed to detect polymorphisms of STAT5A gene in 401 Holstein cows by PCR-RFLP and PCR-SSCP. The results showed that the products amplified by primers P1 and P2 displayed polymorphisms. For P1, three genotypes (AA, AG, and GG) were detected, and the frequency of AA/AG/GG was 0.252/0.486/0.262, respectively. Sequence analysis revealed a single nucleotide substitution A-G at 14217 bp (GenBank NC_007317) of bovine STAT5A gene while compared GG genotype with AA genotype. The differences of the least squares means for the four milk production traits (milk yield at 305 days, fat percentage, lactose percentage and dry matter percentage) between AA, AG and GG were not significant (P > 0.05). Least squares mean of protein percentage for AG or GG was significantly higher than that for AA (P < 0.05); the difference of the least squares mean for protein percentage was not significant between AG and GG (P > 0.05). For P2, three genotypes (CC, CT, and TT) were detected in Holstein cows, and the frequency of CC/CT/TT was 0.751/0.234/0.015, respectively. Sequencing revealed an insertion CCT at 17266 (NC_007317) of bovine STAT5A gene while compared CC genotype with TT genotype. The differences of the least squares means for the three milk production traits (protein percentage, lactose percentage and dry matter percentage) between CC, CT and TT were not significant (P > 0.05). Least squares mean of milk yield at 305 days for TT or CT was significantly higher than that for CC (P < 0.05); the difference of the least squares mean for milk yield at 305 days was not significant between TT and CT (P > 0.05). Least squares mean of fat percentage for CC or CT was significantly higher than that for TT (P < 0.05); the difference of the least squares mean for fat percentage was not significant between CC and CT (P > 0.05). The results preliminarily indicated that allele G of A14217G polymorphic site of STAT5A gene is a potential DNA marker for improving protein percentage in dairy cattle, 17266indelCCT polymorphic site of STAT5A gene is a potential DNA marker for improving milk yield at 305 days and fat percentage in dairy cattle. PMID- 21681426 TI - Isolation and functional characterization of a Medicago sativa L. gene, MsLEA3-1. AB - A full-length cDNA of 1,728 nt, called MsLEA3-1, was cloned from alfalfa by rapid amplification of cDNA ends from an expressed sequence tag homologous to soybean pGmPM10 (accession No. AAA91965.1). MsLEA3-1, encodes a deduced protein of 436 amino acids, a calculated molecular weight of 47.0 kDa, a theoretical isoelectric point of 5.18, and closest homology with late embryogenesis abundant proteins in soybean. Sequence homology suggested a signal peptide in the N terminus, and subcellular localization with GFP revealed that MsLEA3-1 was localized preferentially to the nucleolus. The transcript titre of MsLEA3-1 was strongly enriched in leaves compared with roots and stems of mature alfalfa plants. Gene expression of MsLEA3-1 was strongly induced when seedlings were treated with NaCl and ABA. Expression of the MsLEA3-1 transgenic was detected in transgenic tobacco. Malondialdehyde content and, electrical conductivity content were reduced and electrical conductivity and proline content were increased in transgenic tobacco compared with non-transgenic tobacco under salt stress. The results showed that accumulation of the MsLEA3-1 protein in the vegetative tissues of transgenic plants enhanced their tolerance to salt stress. These results demonstrate a role for the MsLEA3-1 protein in stress protection and suggest the potential of the MsLEA3-1 gene for genetic engineering of salt tolerance. PMID- 21681428 TI - The specific binding of chlorogenic acid to human serum albumin. AB - Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in human diet. It is also an active component in traditional Chinese medicines which are used to treat various diseases. In this study, fluorescence spectroscopy in combination with UV-Vis absorption spectroscopy was employed to investigate the specific binding of CGA to human serum albumin (HSA) under the physiological conditions. In the mechanism discussion, it was proved that the fluorescence quenching of HSA by CGA is a result of the formation of CGA-HSA complex. Binding parameters calculating from Stern-Volmer method and Scatchard method showed that CGA bind to HSA with the binding affinities of the order 10(4) l mol(-1). The thermodynamic parameters studies revealed that the binding was characterized by negative enthalpy and positive entropy changes and the electrostatic interactions play a major role for CGA-HSA association. Site marker competitive displacement experiments demonstrated that CGA specific bind to site I (subdomain IIA) of HSA. The binding distance r (3.10 nm) between donor (Trp-214) and acceptor (CGA) was obtained according to fluorescence resonance energy transfer. Furthermore, the effect of metal ions on CGA-HSA system was studied. PMID- 21681427 TI - -251 T/A polymorphism of the interleukin-8 gene and cancer risk: a HuGE review and meta-analysis based on 42 case-control studies. AB - The -251T/A (rs4073), a single nucleotide polymorphism, has been identified in the promoter region of the interleukin-8 (IL-8) gene. It's presence could influence the production of IL-8 protein by regulating the transcriptional activity of the gene. A large number of studies have been performed to evaluate the role of -251T/A polymorphism on various cancers, with inconsistent results being reported. In this paper, we summarized 13,189 cases and 16,828 controls from 42 case-control studies and attempted to assess the susceptibility of 251T/A polymorphism to cancers by a comprehensive meta-analysis. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analysis were also performed. Results showed that the carriers of the -251A allele had about a 12-21% increased risk for the reviewed cancer, in total. The carriers of -251A had an elevated risk to breast cancer, gastric cancer and nasopharyngeal cancer and a reduced risk to prostate cancer, but no evidence was found to indicate that the -251A allele predisposed its carriers to colorectal and lung cancers. When stratified separately by 'racial descent' and 'study design', it was found that the carriers of the -251A allele among the African group, Asian group and hospital-based case control study group were at a higher risk for cancer, but not in European group and population-based case-control study. These results show that -251A allele is susceptible in the development of low-penetrance cancers. PMID- 21681429 TI - The complete mitochondrial genome of two recently derived species of the fish genus Nannoperca (Perciformes, Percichthyidae). AB - Here we report the complete sequence of mitochondrial genomes for two sister taxa of freshwater teleosts, the recently derived Yarra pigmy perch Nannoperca obscura and the southern pigmy perch Nannoperca australis. These represent the first complete mitochondrial genomes for Percichthyidae (Perciformes), a family mostly distributed in Australia. The de novo genome assembly of 316,430 pyrosequencing reads from 454 libraries has produced the entire mitochondria for N. obscura and a nearly complete version for N. australis. The mtDNA genome from the latter was completed through the design of one primer set and standard Sanger sequencing for genome finishing, followed by the hybrid assembly of reads with MIRA software using N. obscura sequence as reference genome. The complete mitogenomes of N. obscura and N. australis are 16,496 and 16,494 bp in size, respectively. Both genomes contain 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes and a control region. Several characteristics of mitochondria typically found in teleost fishes were detected, such as: (i) most genes found in the heavy strand, with the exception of ND6 and eight tRNA genes; (ii) avoidance of G as the third base of codons; (iii) presence of gene overlapping; (iv) percentage of bases usage. We found only eight indels and 197 nucleotide substitutions between these Nannoperca mitogenomes, consistent with a previous hypothesis of recent speciation. The data reported here provide a resource for comparative analysis of recent evolution of mitochondrial genomes. PMID- 21681430 TI - Synergism between paraoxonase Arg 192 and the angiotensin converting enzyme D allele is associated with severity of coronary artery disease. AB - We have previously shown that angiotensin-converting enzyme (ACE) gene D allele is an independent risk factor for early onset coronary artery disease (CAD). Little is known about the concomitant presence of the ACE gene D allele and paraoxonase (PON1) codon 192 arginine (Arg) on the severity of CAD. Regarding the high rate of CAD among Iranians the aim of present study was to examine the hypothesis of synergistic effects between ACE-D and PON1-Arg alleles on predisposition and the severity of CAD in our population. The PON1 192 and ACE insertion/deletion (I/D) genotypes were detected by PCR-RFLP and PCR, respectively in 414 individuals undergoing their first coronary angiography. Patients were placed into one of two groups: CAD and control without CAD or diabetes. We mentioned the synergistic effects of both genes and not ACE gene alone is a risk factor for CAD. We found that PON1 Arg 192 and ACE D allele act synergistically to increase the risk of CAD (OR 1.3, P = 0.044). Our results showed a significant correlation between the possession of both PON1 192 Arg and the ACE D allele and the extent of CAD in CAD patients and CAD subjects without diabetes, represented by the increased frequency of three-vessel disease with OR 2.7, P = 0.046; chi(2) = 4, P = 0.046 and OR 2.4, P = 0.051; chi(2) = 3.8, P = 0.051, respectively. We found that PON1 Arg 192 and ACE D alleles act synergistically to increase the risk of CAD in CAD patients and CAD subjects without diabetes from west of Iran, who have high frequency of three-vessel disease. Our data suggest that PON1 192 Arg and the ACE D allele in combination with each other can be important independent risk factor for severity of CAD in patients carrying both PON1 192 Arg and the ACE D allele in a west population of Iran. PMID- 21681431 TI - Expression of Nogo-66 receptor in human astrocytoma is correlated with tumor malignancy. AB - Nogo-A is a myelin-associated neuronal growth inhibitory molecule in central nervous system after trauma. However, the physiological functions of Nogo-A in neural development and in healthy oligodendrocytes are largely unknown. In this study, we investigated the expression of Nogo-66 receptor (NgR) protein in 60 cases of human astrocytoma by Western blot RT-PCR and immunohistochemistry. The correlation between the expression of NgR and pathologic grades of astrocyoma was further analyzed. The results showed that the expression of NgR protein and NgR mRNA immunoreactivity score, were decreased markedly with the increasing pathological grades. Double immunostaining results showed that Nogo-A and NgR were colocalized at the interface of astrocytoma cells and extracellular matrix. Our results indicated that NgR may have inhibitory effects on tumor activity and Nogo-A may restrict migration of tumor cells via NgR. PMID- 21681432 TI - Association between methylation in mismatch repair genes, V600E BRAF mutation and microsatellite instability in colorectal cancer patients. AB - Colorectal cancer (CRC) corresponds to the third most prevalent type of cancer. Its origins can either be sporadic or inherited, being Lynch syndrome the most common form of hereditary CRC. The activation of BRAF oncogene, inactivation of mismatch repair genes by methylation of CpG islands, and microsatellite instability (MSI) have been reported to be involved in CRC development. The goal of the study was to characterize CRC tumors using clinical and molecular criteria through association and cluster analysis. Amsterdam II and Bethesda guidelines and molecular variables were analyzed in 77 patients from Brazil. The replication error (RER) status, based in microsatellite instability, showed association with metachronous tumor, MLH1 gene methylation and inverse association with left-sided and synchronous tumors. The PMS2 gene was considered the best predictor for differentiating levels of methylation and the mononucleotide were considered the best markers to evaluate RER status. The cluster 1 was characterized of individuals over 60 years of age, female, right-sided tumor, high microsatellite instability, and metachronous or synchronous tumors. The individuals in cluster 2 were younger than 45 years of age, male and showed left sided or rectum tumors, and microsatellite stability. Even though it was not observed a significant association, a higher number of individuals with family history of cancer and tumors without promoter methylation were found in cluster 2. The V600E mutation did not show association with clinical or molecular characteristics. Evaluation of MSI and methylation of MLH1 and PMS2 genes should be considered in order to assist with clinical diagnosis. PMID- 21681433 TI - Time-course analyses of abscisic acid level and the expression of genes involved in abscisic acid biosynthesis in the leaves of Betula platyphylla. AB - Abscisic acid (ABA) is a plant hormone regulating the essential physiological processes of plants and plant responses to various environmental stresses. Recent studies revealed that the key enzymes involved in ABA biosynthesis were zeaxanthin epoxidase (ZEP), 9-cis-epoxycarotenoid dioxygenases (NCED), short chain dehydrogenase/reductase (SDR), and ABA-aldehyde oxidase (AAO). In this study, we cloned 12 unique genes potentially involved in ABA synthesis, including 5 of BpNCEDs, 1 of BpAAO, and 6 of BpZEPs from birch leaves. We analyzed the time course expression of these 12 genes during the phase from May to August by real time reverse transcriptase-polymerase chain reaction (RT-PCR). Further, we determined birch endogenous ABA content during this period by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results indicated that ABA level significantly (P < 0.05) increased during the early stages of development and ABA was present in birch leaves throughout the studied period, suggesting that endogenous ABA is necessary for the normal growth and development of plants. The correlation between the expression of above-mentioned genes and ABA levels was analyzed by Pearson correlation analysis. The results revealed that the expression of three genes, namely, BpNCED4, BpNCED5 and BpZE6 significantly (P < 0.05) correlated with the ABA level. Therefore, these three genes may play important roles in ABA biosynthesis. PMID- 21681434 TI - Career development needs assessment in cancer prevention and control: focus on research in minority and international settings. AB - This study was conducted as a needs assessment to inform the development of an educational program designed to provide mentorship and skills supporting careers in cancer research, with a focus on domestic minority populations and international settings. The objectives were to determine: (1) the level of interest among trainees in careers in cancer research and (2) preferences and constraints constituted by potential components, features, and duration of the proposed extramural training program. The target populations were participants and directors of federal training programs in cancer research, specifically (1) trainees in the NCI-K01, K07, and K08 programs, as well as the Department of Defense (DoD) Breast and Prostate Control Programs and (2) PIs of NCI R25 training programs and federally designated Comprehensive Cancer Centers. We developed, piloted, and administered electronically a survey to elicit perspectives of trainees' career development needs and preferences. Response rates from each training group exceeded 65%, with the exception of the K08 trainees (49%). The proportion of cancer research trainees who are interested in careers that include research on US minority groups was 70% of K01 trainees, 72% of K07 trainees, 45% of K08 trainees, and 75% of DoD trainees. A substantial percent of these trainees indicated their plans also include cancer research in international settings: 60% of K01s; 50% of K07s, 42% of K08s, and 87% of DoD trainees. Trainees identified substantial interest in a program that would provide the following: mentoring, manuscript writing skills, collaborative research in special populations, financial support, and focused modular courses. This study offers encouraging evidence of interest which focused in extramural education to augment skills facilitating cancer-related research in special populations. PMID- 21681435 TI - What a difference one person can make: a tribute to Mary P. Lovato. PMID- 21681436 TI - Monocanalicular versus bicanalicular intubation in the treatment of congenital nasolacrimal duct obstruction. AB - BACKGROUND: To compare the success rate of monocanalicular intubation (MCI) compared with bicanalicular silicone intubation (BCI) in congenital nasolacrimal duct obstruction (CNLDO) in infants and toddlers. METHODS: In a prospective, nonrandomized, comparative study, MCI (n = 35 eyes) through the inferior canaliculus or BCI (n = 35 eyes) were performed under general anaesthesia in children aged 10 to 36 months with CNLDO. The tubes were removed 3-4 months after tube placement, and the children were followed up for 6 months after the removal of tubes. Therapeutic success was defined as the fluorescein dye disappearance test grade 0-1, corresponding with a complete resolution of previous symptoms. Partial success was defined as improvement with some residual symptoms. RESULTS: Complete and partial improvement was achieved in 31/35 (88.57%) in the BCI group and 34/35 (97.14%) in the MCI group. The difference between the two groups was not significant (p = 0.584). Complications occurred in both groups. Dislodgement of the tube and premature removal was observed in four BCI cases, and loss of the tube was observed twice in the MCI group. Canalicular slitting was observed in five eyes in the BCI group. Granuloma pyogenicum observed in 2 cases with MCI revealed a few weeks after the tube removal. Corneal erosion in the inferior medial quadrant was observed in one MCI eye and revealed in a few days after the local treatment without tube removal. CONCLUSIONS: Both MCI and the BCI are effective methods for treating CNLDO. MCI has the advantage of a lower incidence of canalicular slit and easy placement. PMID- 21681437 TI - S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice. AB - PURPOSE: To study the protective effects and underlying molecular mechanisms of SAMC on carbon tetrachloride (CCl4)-induced acute hepatotoxicity in the mouse model. METHODS: Mice were intraperitoneally injected with CCl4 (50 MUl/kg; single dose) to induce acute hepatotoxicity with or without a 2-h pre-treatment of SAMC intraperitoneal injection (200 mg/kg; single dose). After 8 h, the blood serum and liver samples of mice were collected and subjected to measurements of histological and molecular parameters of hepatotoxicity. RESULTS: SAMC reduced CCl4-triggered cellular necrosis and inflammation in the liver under histological analysis. Since co-treatment of SAMC and CCl4 enhanced the expressions of antioxidant enzymes, reduced the nitric oxide (NO)-dependent oxidative stress, and inhibited lipid peroxidation induced by CCl4. SAMC played an essential antioxidative role during CCl4-induced hepatotoxicity. Administration of SAMC also ameliorated hepatic inflammation induced by CCl4 via inhibiting the activity of NF-kappaB subunits p50 and p65, thus reducing the expressions of pro inflammatory cytokines, mediators, and chemokines, as well as promoting pro regenerative factors at both transcriptional and translational levels. CONCLUSIONS: Our results indicate that SAMC mitigates cellular damage, oxidative stress, and inflammation in CCl4-induced acute hepatotoxicity mouse model through regulation of NF-kappaB. Garlic or garlic derivatives may therefore be a potential food supplement in the prevention of liver damage. PMID- 21681438 TI - Triacylglycerol-rich lipoproteins derived from healthy donors fed different olive oils modulate cytokine secretion and cyclooxygenase-2 expression in macrophages: the potential role of oleanolic acid. AB - PURPOSE: Current evidence suggests that consumption of virgin olive oil (VOO) helps to protect against the development of atherosclerosis and that minor components such as oleanolic acid contribute to this effect. In this study, the effects of triacylglycerol-rich lipoproteins (TRLs) derived from olive oil on inflammatory processes in macrophages and how they are modulated by oleanolic acid was investigated. METHODS: TRLs isolated from healthy volunteers 2 and 4 h after a test meal containing VOO, pomace olive oil (POO) (the second pressing of olive oil, enriched in minor components) or POO enriched with oleanolic acid (OPOO) were incubated with macrophages derived from the human monocyte cell line, THP-1. RESULTS: All types of TRLs caused a decrease of about 50% in the secretion of monocyte chemoattractant protein-1 (MCP-1) by the cells. Interleukin (IL)-6 secretion was also significantly decreased by 2 and 4 h VOO TRLs and by 4 h OPOO TRLs. In contrast, increased IL-1beta secretion was observed with all 2 h TRL types, and increased tumour necrosis factor-alpha (TNF-alpha) production with 2 h VOO and POO, but not OPOO, TRLs. TRLs isolated after 4 h, however, had no significant effects on TNF-alpha secretion and increased IL-1beta secretion only when they were derived from VOO. Cyclooxygenase-2 (COX-2) mRNA expression was strongly down-regulated by all types of TRLs, but protein expression was significantly depressed only by 4 h OPOO TRLs. CONCLUSION: These findings demonstrate that TRLs derived from olive oil influence inflammatory processes in macrophages and suggest that oleanolic acid may have beneficial effects. PMID- 21681439 TI - Major dietary patterns and cardiovascular risk factors among young Brazilian adults. AB - PURPOSE: Diet is one of the most important modifiable risk factors for cardiovascular diseases. The scientific literature has consistently shown the effects of certain diets on health; however, given the variety of cultures and dietary habits across the world, it is likely that much remains to be learned about dietary patterns and health outcomes. We assessed the associations between main dietary patterns and cardiovascular risk factors among 4,202 young Brazilian adults in a cross-sectional analysis. METHODS: In a principle components analysis, two main dietary patterns were identified: common Brazilian and processed food. As outcomes, we examined body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol, HDL cholesterol (HDL-c), and LDL cholesterol (LDL-c). Means, crude, and adjusted beta coefficients and 95% CIs were estimated according to quintiles of dietary patterns. RESULTS: Common Brazilian scores were inversely associated with BMI, WC, LDL-c, HDL-c, and total cholesterol values among men. Among women, inverse association trends were observed with SBP, DBP, LDL-c, HDL c, and total cholesterol. The processed food pattern was positively associated with LDL-c, HDL-c, total cholesterol, BMI, and WC values among the men. Among the women, the processed food pattern was not significantly associated with cardiovascular risk factors. CONCLUSIONS: In conclusion, our findings confirm that diet has an important role on health during early adulthood. The common Brazilian pattern showed generally healthier trends regarding CVD risk factors, but the ultimate effects on risk of risk of disease are unclear because of the inverse relation with HDL-c levels. PMID- 21681440 TI - Risk factors for hyperbilirubinemia in breastfed term neonates. AB - Increased breastfeeding was suggested as a contributing factor to significant hyperbilirubinemia. The aim of this study was to identify the risk factors associated with jaundice in exclusively breastfed term neonates. We retrospectively reviewed all consecutively live-born neonates from August 2009 to July 2010 who had complete outpatient department (OPD) follow-up at <=14 days old. Hyperbilirubinemia was defined as a transcutaneous bilirubin (TcB) value of >=15 mg/dl. During the study period, there were 718 deliveries, of which 152 neonates were transferred to the special care nursery or neonatal intensive care unit; 566 neonates were discharged from the nursery, and 243 neonates were excluded: 83 did not return to the OPD, 46 were older than 14 days at OPD follow up, 44 were <37 weeks of gestational age, and 70 had been fed formula. In total, 323 neonates were enrolled and classified into the hyperbilirubinemic (114 neonates) and non-hyperbilirubinemic groups (209 neonates). The gender, gestational age, Apgar score, age at nursery discharge, birth weight, and body weight at nursery discharge and at OPD were comparable between the two groups. TcB values at nursery discharge were positively correlated with TcB values in the OPD. Infants with hyperbilirubinemia exhibited significantly greater body weight loss from birth to the OPD follow-up and significantly less body weight gain from nursery discharge to OPD follow-up. CONCLUSION: High TcB values at nursery discharge and a smaller body weight gain are associated with hyperbilirubinemia in term neonates who are exclusively breastfed. PMID- 21681441 TI - Pressure-induced phase transition in wurtzite ZnTe: an ab initio study. AB - A constant pressure ab initio MD technique and density functional theory with a generalized gradient approximation (GGA) was used to study the pressure-induced phase transition in wurtzite ZnTe. A first-order phase transition from the wurtzite structure to a Cmcm structure was successfully observed in a constant pressure molecular dynamics simulation. This phase transformation was also analyzed using enthalpy calculations. We also investigated the stability of wurtzite (WZ) and zinc-blende (ZB) phases from energy-volume calculations, and found that both structures show quite similar equations of state and transform into a Cmcm structure at 16 GPa using enthalpy calculations, in agreement with experimental observations. The transition phase, lattice parameters and bulk properties we obtained are comparable with experimental and theoretical data. PMID- 21681442 TI - Insight into the binding interactions of CYP450 aromatase inhibitors with their target enzyme: a combined molecular docking and molecular dynamics study. AB - CYP450 aromatase catalyzes the terminal and rate-determining step in estrogen synthesis, the aromatization of androgens, and its inhibition is an efficient approach to treating estrogen-dependent breast cancer. Insight into the molecular basis of the interaction at the catalytic site between CYP450 aromatase inhibitors and the enzyme itself is required in order to design new and more active compounds. Hence, a combined molecular docking-molecular dynamics study was carried out to obtain the structure of the lowest energy association complexes of aromatase with some third-generation aromatase inhibitors (AIs) and with other novel synthesized letrozole-derived compounds which showed high in vitro activity. The results obtained clearly demonstrate the role of the pharmacophore groups present in the azaheterocyclic inhibitors (NSAIs)-namely the triazolic ring and highly functionalized aromatic moieties carrying H-bond donor or acceptor groups. In particular, it was pointed out that all of them can contribute to inhibition activity by interacting with residues of the catalytic cleft, but the amino acids involved are different for each compound, even if they belong to the same class. Furthermore, the azaheterocyclic group strongly coordinates with the Fe(II) of heme cysteinate in the most active NSAI complexes, while it prefers to adopt another orientation in less active ones. PMID- 21681443 TI - Analysis of surface cavity in serpin family reveals potential binding sites for chemical chaperone to reduce polymerization. AB - Serpin constitute about 10% of blood protein and are associated with mutations that results in aberrant intermolecular linkages which leads to polymer formation. Studies with short peptides have shown promise in depolymerization of serpins however a reactive center loop based peptide also makes the serpin inactive. A chemical chaperone based approach is a better option in terms of maintaining activity and retarding polymerization but not much is known about its binding and mechanism. Specific target for chemical chaperones and its effectiveness across many serpin is not known. We did an analysis of serpin cavity using CASTp and show that cavities are distributed throughout the molecule where the largest cavities are generally present in areas of major conformational change like shutter region, helix D and helix F. An analysis of different conformational states of serpins showed that this large cavity undergoes increase in size in latent and cleaved states as compared to native state. We targeted serpins with a variety of carbohydrate, methylamine and amino acid based chemical chaperones and selected those that have highest binding energy across different serpins to assess their ability to bind large cavities. The results show that carbohydrate based chemical chaperone like sorbitol, sucrose, arabitol and trehalose and amino acid based chaperones like dopamine, phenylalanine, arginine and glutamic acid are the most effective in binding serpins. Most of these chemical chaperone interacted with residues in the shutter region and the helix D arm at the C-terminal which are part of the largest cavities. We selected the carbohydrate based chemical chaperone with best binding energies and did experimental study under the condition that induce polymerization and show that indeed they were able to retard polymer formation with moderate effect on inhibition rates. However a fluorometric study with native antithrombin showed that chemical chaperone may effect the conformation of the proteins. Our study shows that chemical chaperones have the best binding affinities for the cavities around shutter region and helix D and that a cavity targeting based approach seems to be a better option for retarding polymerization in serpins, but a thorough analysis of its effect on folding, inhibition and cofactor binding is required. PMID- 21681444 TI - Novel biomarkers in acute heart failure. AB - Heart failure goes beyond mechanical dysfunction and involves an interplay of multiple pathophysiologic mechanisms, including inflammation, tissue remodeling, neurohormonal and endocrine signaling, and interactions with the renal and nervous systems. This article highlights some novel biomarkers that may aid in diagnosis, treatment, and prognosis of acute heart failure, specifically focusing on ST2, endoglin, galectin-3, cystatin C, neutrophil gelatinase-associated lipocalin, midregional pro-adrenomedullin, chromogranin A, adiponectin, resistin, and leptin and their emerging clinical roles. PMID- 21681445 TI - Associations among baseline variables, treatment-related factors and health related quality of life 2 years after breast cancer surgery. AB - Provision of social support and rehabilitation for patients with physical, mental, and functional problems after cancer treatment is important for long-term health-related quality of life (HRQOL). Effective use of human and financial healthcare resources requires identification of patients requiring rehabilitation. The objectives of the current study were to clarify the patterns of physical and psychosocial recovery over time, to evaluate the associations among baseline variables, treatment-related factors and HRQOL at 6 months, 1, and 2 years after breast cancer surgery, and to identify the significant factors predicting HRQOL at each point. A multicenter longitudinal study was performed to evaluate physical conditions, anxiety, depression, and HRQOL at 1 month (baseline), 6 months, 1, and 2 years after surgery in 196 patients (mean age: 53.3 years old) with early breast cancer and no postoperative recurrence. Physical conditions were evaluated using a patient-reported symptom checklist. HRQOL was rated using the functional assessment of cancer treatment scale-general (FACT-G) and the breast cancer subscale (FACT-B). Anxiety and depression were rated using the hospital anxiety and depression scale (HADS). More than 50% of patients had local problems of "tightness", "arm weakness." and "arm lymphedema", and systemic problems of "reduced energy, fatigue, and general weakness" postoperatively. The HRQOL score significantly improved 1 year after surgery, and scores for physical, emotional and functional well-being also increased with time, whereas the score for social well-being was the highest at baseline and decreased with time. Depression and anxiety significantly improved with time. Concomitant disease, marital status, and the presence of a partner, anxiety and depression at baseline, pathological lymph node involvement, and adjuvant intravenous chemotherapy were significant factors predicting FACT-G scores at 6 months, 1, and 2 years after surgery. Depression at baseline was a strong predictor of HRQOL up to 2 years after surgery. These results suggest that physical rehabilitation is required for tightness and lymphedema to improve long term postoperative physical function. A further study of psychosocial interventions is required to improve depression and social well-being after breast cancer surgery. PMID- 21681446 TI - Gene expression profile testing for breast cancer and the use of chemotherapy, serious adverse effects, and costs of care. AB - As gene expression profile (GEP) testing for breast cancer may provide additional prognostic information to guide the use of adjuvant chemotherapy, we examined the association between GEP testing and use of chemotherapy, serious chemotherapy related adverse effects, and total charges during the 12 months following diagnosis. Medical record review was conducted for women age 30-64 years, with incident, non-metastatic, invasive breast cancer diagnosed 2006-2008 in a large, national health plan. Of 534 patients, 25.8% received GEP testing, 68.2% received chemotherapy, and 10.5% experienced a serious chemotherapy-related adverse effect. GEP testing was most commonly used in women at moderate clinical risk of recurrence (52.0 vs. 25.0% of low-risk women and 5.5% of high-risk). Controlling for the propensity to receive GEP testing, women who had GEP were less likely to receive chemotherapy (propensity adjusted odds ratio, 95% confidence interval 0.62, 0.39-0.99). Use of GEP was associated with more chemotherapy use among women at low risk based on clinical characteristics (OR = 42.19; CI 2.50-711.82), but less use among women with a high risk based on clinical characteristics (OR = 0.12; CI 0.03-0.47). Use of GEP was not associated with chemotherapy for the moderate risk group. There was no significant relationship between GEP use and either serious chemotherapy-associated adverse effects or total charges. While GEP testing was associated with an overall decrease in adjuvant chemotherapy, we did not find differences in serious chemotherapy-associated adverse events or charges during the 12 months following diagnosis. PMID- 21681447 TI - Clinical application of shear wave elastography (SWE) in the diagnosis of benign and malignant breast diseases. AB - Shear wave elastography (SWE) is an emerging technique which can obtain quantitative elasticity values in breast disease. We therefore evaluated the diagnostic performance of SWE for the differentiation of breast masses compared with conventional ultrasound (US). Conventional US and SWE were performed by three experienced radiologists for 158 consecutive women who had been scheduled for US-guided core biopsy or surgical excision in 182 breast masses (89 malignancies and 93 benign; mean size, 1.76 cm). For each lesion, quantitative elasticity was measured in terms of the Young's modulus (in kilopascals, kPa) with SWE, and BI-RADS final categories were assessed with conventional US. The mean elasticity values were significantly higher in malignant masses (153.3 kPa +/- 58.1) than in benign masses (46.1 kPa +/- 42.9), (P < 0.0001). The average mean elasticity values of invasive ductal (157.5 +/- 57.07) or invasive lobular (169.5 +/- 61.06) carcinomas were higher than those of ductal carcinoma in situ (117.8 kPa +/- 54.72). The average mean value was 49.58 +/- 43.51 for fibroadenoma, 35.3 +/- 31.2 for fibrocystic changes, 69.5 +/- 63.2 for intraductal papilloma, and 149.5 +/- 132.4 for adenosis or stromal fibrosis. The optimal cut-off value, yielding the maximal sum of sensitivity and specificity, was 80.17 kPa, and the sensitivity and specificity of SWE were 88.8% (79 of 89) and 84.9% (79 of 93). The area under the ROC curve (Az value) was 0.898 for conventional US, 0.932 for SWE, and 0.982 for combined data. In conclusion, there were significant differences in the elasticity values of benign and malignant masses as well as invasive and intraductal cancers with SWE. Our results suggest that SWE has the potential to aid in the differentiation of benign and malignant breast lesions. PMID- 21681448 TI - Metabotropic glutamate receptor-1: a potential therapeutic target for the treatment of breast cancer. AB - Metabotropic glutamate receptors are G-protein-coupled receptors normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release. However, recent data suggest that these receptors are also expressed and functional in some cancers, most notably melanoma. We detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in triple negative breast cancer cells and evaluated its role in regulating the pro proliferative phenotype of these cells. mGluR1 inhibitors (Riluzole or BAY36 7620) inhibited the proliferation of triple negative breast cancer cells in a time- and dose-dependent manner and this inhibition correlated with increased apoptosis as demonstrated by increase in PARP cleavage products and Annexin V staining. mGluR1 knockdown using Lentiviral constructs expressing shRNA targeting GRM1 also inhibited proliferation compared to non-silencing controls. In addition, treatment of mice bearing MDA-MB-231 xenografts with Riluzole or BAY36 7620, by intraperitoneal injection, resulted in a significant reduction in tumor volume of up to 80%. Moreover, Riluzole was effective against triple negative breast cancer xenografts in mice at doses equivalent to those currently being used in humans for the treatment of amyotrophic lateral sclerosis. Our observations implicate mGluR1 and glutamate signaling as a promising new molecular target for the treatment of breast cancer. Even more promising, Riluzole, because it is an oral drug that can be administered with low toxicity, represents a promising approach in the treatment of triple negative breast cancer. PMID- 21681449 TI - Lessons from a Canadian province: examining collaborations between the mental health and justice sectors. AB - OBJECTIVE: The objective of this paper was to identify the factors that program developers perceived as important to the successful collaboration between the mental health and justice sectors in seven Ontario, Canada, post-booking programs. METHODS: Semi-structured telephone interviews with developers of the programs in each region were conducted. Key informants were identified using a snowball technique. All transcripts were analyzed using a modified grounded theory approach. RESULTS: The primary themes identified involved partnership development, adjustment to broader mandates and addressing ongoing challenges. Conclusions were validated through member checking. CONCLUSIONS: The findings highlight important considerations for cross-ministerial enterprises. If partnerships are constructed within the existing parameters of systems, the system with the most flexibility will be required to work around its partner's constraints. The role of the adapter could be acknowledged by having the funding flow through the adapter's system. Program development will involve a significant time investment including activities to become part of both systems' culture through education, establishing a presence and identifying boundary spanners. Long-run implications for both systems should also be considered. PMID- 21681450 TI - Son preference and sex-selective abortion in China: informing policy options. AB - OBJECTIVES: There is growing evidence in China that son preference is on the decline, but the sex ratio at birth is still the highest in the world at around 120 male births to 100 females. The aim of the study was to explore attitudes towards gender preference among people of reproductive age, to determine the reasons why the sex ratio is persistently high, and to inform policy options. METHODS: We conducted in-depth interviews with 212 individuals who aged from 18 to 39 in rural and urban areas of three provinces: Yunnan, Guizhou and Zhejiang. RESULTS: We show that while son preference has weakened considerably, it has not disappeared. The sex ratio remains high, because of this small minority of individuals, who still choose sex-selective abortion to ensure male offsprings. CONCLUSIONS: Intensive local policy interventions have been successful in reducing the sex ratio in some areas and these should be disseminated widely. In addition, the law forbidding sex selection should be actively enforced, and the One Child Policy should be relaxed in some areas, to reduce the disproportionately high sex ratio in the second order births. PMID- 21681451 TI - Prostate-specific antigen testing in Tyrol, Austria: prostate cancer mortality reduction was supported by an update with mortality data up to 2008. AB - OBJECTIVES: The objective of this study was to update an in-depth analysis of the time trend for prostate cancer (PCA) mortality in the population of Tyrol by 5 years, namely to 2008. In Tyrol, prostate-specific antigen (PSA) tests were introduced in 1988/89; more than three-quarters of all men in the age group 45-74 had at least one PSA test in the past decade. METHODS: We applied the same model as in a previous publication, i.e., an age-period-cohort model using Poisson regression, to the mortality data covering more than three decades from 1970 to 2008. RESULTS: For Tyrol from 2004 to 2008 in the age group 60+ period terms show a significant reduction in prostate cancer mortality with a risk ratio of 0.70 (95% confidence interval 0.57, 0.87) for Tyrol, and for Austria excluding Tyrol a moderate reduction with a risk ratio of 0.92 (95% confidence interval 0.87, 0.97), each compared to the mortality rate in the period 1989-1993. CONCLUSIONS: This update strengthens our previously published results, namely that PSA testing offered to a population at no charge can reduce prostate cancer mortality. The extent of mortality reduction is in line with that reported in the other recent publications. However, our data do not permit us to fully assess the harms associated with PCA screening, and no recommendation for PSA screening can be made without a careful evaluation of overdiagnosis and overtreatment. PMID- 21681452 TI - Inequality in self-rated health among immigrants, their descendants and ethnic Danes: examining the role of socioeconomic position. AB - OBJECTIVES: We investigated inequalities in self-rated health between immigrants, their descendants, and ethnic Danes and explored mediation by socioeconomic position and interactions between country of origin and socioeconomic position. METHODS: Cross-sectional survey data on self-rated health from 4,985 individuals aged 18-66 years including immigrants from seven non-Western countries, their descendants, and ethnic Danes was linked to registry-based data on education, employment status, and income as indicators of socioeconomic position. Using multiple logistic regression analysis, we estimated the association between country of origin and self-rated health. RESULTS: Immigrants reported poorer health compared with ethnic Danes [age-adjusted odds ratio (OR) = 2.0-7.3 for men; 2.1-10.5 for women, dependent on country of origin] as well as their descendants (OR = 1.6-3.8 for men; 1.5-2.0 for women). Adjustment for socioeconomic position attenuated this association. Stratified analysis indicated that the effect of socioeconomic position on self-rated health varied across the groups. CONCLUSION: Policies addressing inequalities in health between immigrants, their descendants, and ethnic Danes should target underlying socioeconomic inequalities. Further research of the effects of socioeconomic position on health among immigrants and descendants is needed. PMID- 21681453 TI - Weekly lottery sales volume and suicide numbers: a time series analysis on national data from Taiwan. AB - OBJECTIVE: To investigate the association between weekly lottery sales and number of suicide deaths in Taiwan. METHODS: All suicides aged 15+ years during 2004 2006 in Taiwan were included. Poisson autoregression time series models investigated associations of weekly numbers with contemporaneous and recent sales from two national lotteries in operation. Adjustments were made for seasonal fluctuation, temperature, monthly unemployment and autocorrelation. RESULTS: In fully adjusted models, suicide deaths were negatively correlated with sales of tickets for a low-prize, low-cost lottery system. However, they were correlated positively with recent sales for a higher-cost, larger-prize system. Both correlations were stronger for male than female suicide numbers but differed in terms of age groups most strongly implicated. CONCLUSIONS: Associations between lottery sales and suicide numbers differed according to the nature of the lottery. A low-prize, low-publicity system appeared to be more benign than a high prize, high-publicity one. PMID- 21681454 TI - Poor mental health influences risk and duration of unemployment: a prospective study. AB - PURPOSE: The current paper aims to investigate the role of mental health in determining future employment status. Much of the previous longitudinal and prospective research has focused on how unemployment adversely influences mental health, while the reverse causal direction has received much less attention. METHODS: This study uses five waves of data from 5,846 respondents in the HILDA survey, a nationally representative household panel survey conducted annually since 2001. Prospective analyses followed a group of respondents who were not unemployed at baseline across four subsequent years and investigated whether baseline mental health was associated with subsequent unemployment. RESULTS: Baseline mental health status was a significant predictor of overall time spent unemployed for both men and women. Decomposing this overall effect identified sex differences. For women but not men, baseline mental health was associated with risk of experiencing any subsequent unemployment whereas for men but not women mental health was associated with the duration of unemployment amongst those who experienced unemployment. CONCLUSIONS: By following a group of respondents who were not unemployed over time, we showed that poor mental health predicted subsequent unemployment. On average, men and women who experienced symptoms of common mental disorders spent greater time over the next 4 years unemployed than those with better mental health but there were sex differences in the nature of this effect. These findings highlight the importance of mental health in the design and delivery of employment and welfare policy. PMID- 21681455 TI - Rescuers at risk: a systematic review and meta-regression analysis of the worldwide current prevalence and correlates of PTSD in rescue workers. AB - PURPOSE: We sought to estimate the pooled current prevalence of posttraumatic stress disorder (PTSD) among rescue workers and to determine the variables implicated in the heterogeneity observed among the prevalences of individual studies. METHODS: A systematic review covering studies reporting on the PTSD prevalence in rescue teams was conducted following four sequential steps: (1) research in specialized online databases, (2) review of abstracts and selection of studies, (3) review of reference list, and (4) contact with authors and experts. Prevalence data from all studies were pooled using random effects model. Multivariate meta-regression models were fitted to identify variables related to the prevalences heterogeneity. RESULTS: A total of 28 studies, reporting on 40 samples with 20,424 rescuers, were selected. The worldwide pooled current prevalence was 10%. Meta-regression modeling in studies carried out in the Asian continent had, on average, higher estimated prevalences than those from Europe, but not higher than the North American estimates. Studies of ambulance personnel also showed higher estimated PTSD prevalence than studies with firefighters and police officers. CONCLUSIONS: Rescue workers in general have a pooled current prevalence of PTSD that is much higher than that of the general population. Ambulance personnel and rescuers from Asia may be more susceptible to PTSD. These results indicate the need for improving pre-employment strategies to select the most resilient individuals for rescue work, to implement continuous preventive measures for personnel, and to promote educational campaigns about PTSD and its therapeutic possibilities. PMID- 21681456 TI - [Anticholinergic agents for overactive bladder syndrome: current head-to-head comparison]. AB - Overactive-bladder syndrome is characterized by the symptoms pollakisuria, nocturia and urgency with and without urge incontinence. The primary diagnostic procedure includes noninvasive or minimally invasive techniques. Antimuscarinic drugs lead within the therapeutic cascade. Only after unsuccessful use of several antimuscarinics should further treatment options such as electromotive drug administration or infiltration of the detrusor muscle with botulinum toxin A be discussed. The presented review article tries to give an overview by including the existing head-to-head-studies in this field. PMID- 21681457 TI - Suicide assessment and prevention during and after emergency commitment. AB - The purpose of this study was to address two primary issues within the context of emergency commitment: (a) the suicide-prevention measures implemented at receiving facilities where emergency commitments occur and (b) the perceptions of key stakeholders about access to community services post-discharge. One hundred seventy-eight respondents who worked in receiving facilities, where emergency commitments occur, responded to an online survey or were interviewed. Respondents indicated the use of suicide-prevention measures such as suicide assessment tools used at intake and discharge and strategies utilized to maintain client safety when the issue of suicidality had been determined at intake. Almost half of respondents (46.6%) described the availability of community mental health treatment at discharge from emergency commitment as being "less than adequate." Emerging themes about community service availability are discussed and include long waiting periods and funding issues. PMID- 21681458 TI - Relative importance of various measures of HIV-related stigma in predicting psychological outcomes among children affected by HIV. AB - To assess the relative importance of four different measures of HIV-related stigma in predicting psychological problems among children affected by HIV in rural China. Cross-sectional data were collected from 755 orphans (i.e., children who lost one or both of their parents to HIV), 466 vulnerable children (children who were living with HIV-infected parents), and 404 comparison children who were from the same community and did not have HIV-related illness or death in their families. Four HIV-related stigma measures include perceived public stigma against people living with HIV/AIDS (PLWHA), perceived public stigma against children affected by HIV (orphans and vulnerable children), personal stigmatizing attitudes against PLWHA, and enacted stigma among children affected by HIV. Psychological problems included depression and adjustment problems. Various measures of HIV-related stigma independently and differentially contribute to children's psychological problems. Enacted stigma and children's perceived public stigma against PLWHA or children affected by HIV are generally stronger predictors of psychological problems than their own feelings or attitudes towards PLWHA. Various aspects of HIV-related stigma are important for us to understand the perception, attitudes, and experience of children affected by HIV, including both children experiencing HIV-related parental illness and death in their own family and children who were living in the communities hardly hit by HIV. Future health promotion and psychological care efforts for children affected by HIV need to consider the effect of various forms of HIV-related stigma on these children's psychosocial well-being and mobilize the community resources to mitigate the negative effect of HIV-related stigma on PLWHA and their children. PMID- 21681459 TI - The effects of working alliance and client-clinician ethnic match on recovery status. AB - Sixty-seven clients with severe and persistent mental illnesses (SPMI) recruited from community mental health centers were interviewed to assess their subjective quality of life, self-efficacy, importance of ethnic matching and level of working alliance (WA) with their clinicians. Results revealed that clients in the ethnically matched group reported significantly higher WA compared to the non matched group. Clients who reported a higher level of WA also reported better recovery status. Results suggest that, in a multicultural community, ethnic matching may help augment WA and address potential barriers to treatment engagement, and identifying strategies to promote WA may enhance treatment effectiveness in programs for SPMI. PMID- 21681460 TI - Psychological distress and subjective burden of caregivers of people with mental illness: the role of affiliate stigma and face concern. AB - The present study tested the mediating role of affiliate stigma on the relationships between face concern with psychological distress and subjective burden among caregivers of people with severe mental illnesses. One hundred and eight Chinese caregivers in Hong Kong were surveyed. Based on Baron and Kenny's (J Pers Soc Psychol 51:1173-1182, 1986) approach, affiliate stigma was found to serve as a partial mediator between face concern and caregiver distress and a full mediator between face concern and subjective burden. Cultural linkage of stigma and caregiver outcomes was identified, suggesting that researchers and practitioners should use a culturally sensitive approach to understand caregivers' experience and alleviate their stigma. PMID- 21681461 TI - Prognostic value of loss of wall enhancement for bowel infarction. PMID- 21681462 TI - Modulation of exogenous glutathione in ultrastructure and photosynthetic performance against Cd stress in the two barley genotypes differing in Cd tolerance. AB - Greenhouse hydroponic experiments were conducted using Cd-sensitive (Dong 17) and tolerant (Weisuobuzhi) barley genotypes to evaluate genotypic differences in response of photosynthesis and ultrastructure to Cd toxicity in the presence of exogenous glutathione (GSH). Addition of 20 mg L(-1) GSH in 5 MUM Cd culture medium (Cd + GSH) significantly alleviated Cd-induced growth inhibition and reduced Cd concentration in leaves and roots especially in the sensitive genotype Dong 17. Exogenous GSH greatly ameliorated Cd-induced damages on leaf/root ultrastructure, e.g., compared with Cd alone treatment, chloroplasts in plants treated with Cd + GSH become better or in relatively normal shape with well structured thylakoid membranes and parallel pattern of lamellae and unfolded more starch grains but less osmiophilic plastoglobuli; nuclei of root cells were better formed and chromatin distributed more uniformly in both genotypes, and number of plastids and mitochondria cristae in Dong 17 resumed to control level. The examination of photosynthetic performance revealed GSH dramatically increased net photosynthetic rate (P(n)), stomatal conductance (G(s)), and transpiration rate (T(r)) in the both genotypes and strongly stimulated Cd-induced decrease in the maximal photochemical efficiency (F(v)/F(m)) especially in the sensitive genotype. PMID- 21681464 TI - Cr(VI) induces lipid peroxidation, protein oxidation and alters the activities of antioxidant enzymes in human erythrocytes. AB - The effect of potassium dichromate (K(2)Cr(2)O(7)), a hexavalent chromium compound, on human erythrocytes was studied under in vitro conditions. Incubation of erythrocytes with different concentrations of K(2)Cr(2)O(7) resulted in marked hemolysis in a concentration-dependent manner. K(2)Cr(2)O(7) treatment also caused significant increase in protein oxidation, lipid peroxidation and decrease in total sulfhydryl content, indicating that it causes oxidative stress in human erythrocytes. However, there was no concomitant nitrosative stress as the nitric oxide levels in hemolysates from K(2)Cr(2)O(7)-treated erythrocytes were lower than in control. Exposure of erythrocytes to K(2)Cr(2)O(7) decreased the activities of catalase, glutathione peroxidase, thioredoxin reductase, glucose-6 phosphate dehydrogenase, and glutathione reductase, whereas the activities of Cu Zn superoxide dismutase and glutathione S-transferase were increased. These results show that K(2)Cr(2)O(7) induces oxidative stress and alters the antioxidant defense mechanism of human erythrocytes. PMID- 21681466 TI - Copper excess impairs mobilization of storage proteins in bean cotyledons. AB - Germination represents a limiting stage of plant life cycle. One of the underlying metabolic activities following imbibition of seed is the reserve mobilization. Seeds of bean (Phaseolus vulgaris L. var. soisson nain hatif) were germinated by soaking in distilled water or 200 MUM CuCl(2). Storage proteins breakdown and amino acids freeing from reserve tissues were investigated. Compared to the control, Cu caused a reduction in germination rate, embryo growth, and in mobilization of cotyledonary biomass. The failure in albumin and globulin hydrolysis after the exposure to the pollutant was argued by (1) higher contents of remaining proteins than control ones, (2) persistence of some polypeptide bands resolved by polyacrylamide gel electrophoresis of albumin and globulin-rich fractions, and (3) decrease in the availability of amino acids. Nitrogen starvation in embryonic axis should be associated with the Cu-imposed delay in growth. PMID- 21681465 TI - Influence of exogenous silicon addition on aluminium tolerance in rice seedlings. AB - For better understanding of silicon (Si)-mediated increase in metal tolerance in plants, the alterations in growth, mineral elements and anatomical features were investigated in rice seedlings exposed to Si (10 MUM) and aluminium (Al; 50 MUM). Al decreased seedling growth which was accompanied by an increase in Al accumulation. In contrast, addition of Si alleviated toxic effects of Al and led to the decrease in Al accumulation. Magnesium (Mg) and zinc (Zn) contents were decreased by Al; however, Si addition prevented decrease in Mg and Zn contents. Manganese (Mn) content was increased by Al while Si addition did not have a significant effect on Mn content under Al treatment. Al exposure decreased frequency of stomata and root hairs, length of root hairs and leaf epidermal cells, and distorted the structure and integrity of mesophyll cells and phloem; however, addition of Si reduced these abnormalities. Results showed that Si addition protected rice seedlings against Al toxicity by decreasing Al accumulation and by maintaining level of some mineral elements, and the key structures of leaf and root. PMID- 21681467 TI - Responses of growing Japanese quails that received selenium from selenium enriched kale sprout (Brassica oleracea var. alboglabra L.). AB - The objectives of this study were to determine the effect of selenium (Se) from Se-enriched kale sprout (Brassica oleracea var. alboglabra L.) on the performance and Se concentrations in tissues of growing Japanese quails. Two hundred quails were divided into five treatments. Each treatment consisted of four replicates and each replicate contained ten quails in a completely randomize design. The experiment was conducted for 5 weeks. The treatments were T1, control diet; T2, control diet plus 0.2 mg Se/kg from sodium selenite; T3, T4, and T5, control diet plus 0.2, 0.5, and 1.0 mg Se/kg from Se-enriched kale sprout. The results revealed that Se supplementation had no impact on feed intake, performance, and carcass characteristics of quails (p > 0.05). However, Se supplementation from both sodium selenite and Se-enriched kale sprout increased (p < 0.05) Se concentrations in the heart and breast meat of quails. Se concentrations in the liver and breast meat of quails increased (p < 0.05) with increasing Se concentration from Se-enriched kale sprout. The results indicate that Se from Se enriched kale sprout offers no advantage over Se from sodium selenite on tissue Se concentration. PMID- 21681468 TI - Effects of selenium sources and levels on reproductive performance and selenium retention in broiler breeder, egg, developing embryo, and 1-day-old chick. AB - An 8-week experiment was conducted using 540 48-week-old Lingnan Yellow broiler breeders to evaluate the effect of the sources and levels of selenium (Se) on reproduction and Se retention. After receiving basal diet for 8 weeks, breeders were randomly assigned to six dietary treatments and fed corn-soy-based diets supplemented with 0.15 or 0.30 mg/kg of Se from sodium selenite (SS) or from Se enriched yeast (SY) or from selenomethionine (SM). The Se concentration of basal diet was 0.04 mg/kg of Se. With the increase of dietary Se level, hatchability decreased (P < 0.05), but the Se concentrations were elevated in liver, kidney, pancreas, and breast muscle of breeders, yolk and albumen, liver and breast muscle of developing embryos, and tissues (liver, kidney, pancreas, and breast muscle) of 1-day-old chicks (P < 0.01). Irrespective of the Se level, the Se concentrations in liver, kidney, pancreas, and breast muscle were greater (P < 0.01) in breeders fed SY or SM compared with breeders fed SS, and kidney from breeders fed SM had greater Se concentration than that from breeders fed SY (P < 0.01). Yolk and albumen from SM treatments also had the greatest Se concentrations (P < 0.01). The embryonic liver and breast muscle from SM treatments had higher (P < 0.01) Se concentrations than those of SS treatments. The Se concentrations in liver, kidney, and breast muscle of 1-day-old chicks were greater (P < 0.01) in SY or SM treatments compared with SS treatments, and there was a more significant increase in Se concentrations in kidney and breast muscle of 1-day-old chicks from SM treatments than those from SY treatments (P < 0.01). The results suggest that the Se retention efficiency of SM is higher than that of SY, which, in turn, is higher than that of SS for broiler breeders and their offspring. PMID- 21681469 TI - [Ectomesenchymal chondromyxoid tumor of the anterior tongue]. AB - Ectomesenchymal chondromyxoid tumor of the anterior tongue is a rare entity. To date, 37 cases have been reported in the literature. We present the case of a 52 year-old male patient with an ectomesenchymal chondromyxoid tumor at the typical location with a characteristic lobular proliferation of ovoid and fusiform uniform tumor cells on a chondromyxoid background and showing expression of typical immunohistochemical markers GFAP and S-100. Despite its rarity, this special tumor should be considered in the differential diagnosis when dealing with localized swellings of the anterior tongue. PMID- 21681470 TI - [Anal cancer: diagnostic and differential diagnostic issues]. AB - Tumors of the anal canal are mostly epithelial in origin. The transition of gland forming rectal mucosa via specialized urothelium-like cells at the dentate line to anal non-keratinized and finally perianal keratinized squamous epithelium implies a broad spectrum of tumor types, with most cancers exhibiting a mixture of different histological features. Moreover, secondary neoplasias extending into or metastasizing to the anal region need to be considered. Based on epithelial metaplasia at the transformation zone, poorly differentiated squamous anal carcinomas may show co-expression of both the squamous (CK5/6) and glandular type keratins (CK7). Since HPV infection of high-risk types (often 16 and 18) is etiologically associated with anal cancer, p16(INK4a) is highly sensitive and specific in the detection of high-grade anal squamous intraepithelial neoplasias (ASIN) and corresponding invasive squamous carcinomas. Diagnosis of secondary malignancies, including pagetoid extension into the anogenital region, requires the application of specific immunohistochemical marker panels. PMID- 21681472 TI - Evidence of two genetic clusters of manatees with low genetic diversity in Mexico and implications for their conservation. AB - The Antillean manatee (Trichechus manatus manatus) occupies the tropical coastal waters of the Greater Antilles and Caribbean, extending from Mexico along Central and South America to Brazil. Historically, manatees were abundant in Mexico, but hunting during the pre-Columbian period, the Spanish colonization and throughout the history of Mexico, has resulted in the significantly reduced population occupying Mexico today. The genetic structure, using microsatellites, shows the presence of two populations in Mexico: the Gulf of Mexico (GMx) and Chetumal Bay (ChB) on the Caribbean coast, with a zone of admixture in between. Both populations show low genetic diversity (GMx: N(A) = 2.69; H(E) = 0.41 and ChB: N(A) = 3.0; H(E) = 0.46). The lower genetic diversity found in the GMx, the largest manatee population in Mexico, is probably due to a combination of a founder effect, as this is the northern range of the sub-species of T. m. manatus, and a bottleneck event. The greater genetic diversity observed along the Caribbean coast, which also has the smallest estimated number of individuals, is possibly due to manatees that come from the GMx and Belize. There is evidence to support limited or unidirectional gene flow between these two important areas. The analyses presented here also suggest minimal evidence of a handful of individual migrants possibly between Florida and Mexico. To address management issues we suggest considering two distinct genetic populations in Mexico, one along the Caribbean coast and one in the riverine systems connected to the GMx. PMID- 21681471 TI - [Steatohepatitis after chemotherapy for colorectal liver metastases (CASH)]. AB - Neoadjuvant chemotherapy provides an important treatment option for patients who, as a consequence of colorectal cancer, have developed liver metastases. Regression of metastases prior to surgery may substantially improve prognosis. However, chemotherapeutics may harm non-tumorous liver tissue, particularly if this is already impaired prior to chemotherapy. The present article discusses the risks of chemotherapeutics for liver tissue-including sinusoidal obstruction syndrome, nodular regenerative hyperplasia, and chemotherapy-associated steatohepatitis, amongst others-which should be borne in mind when selecting therapy. PMID- 21681473 TI - Epigenetic repressor-like genes are differentially regulated during grapevine (Vitis vinifera L.) development. AB - Grapevine sexual reproduction involves a seasonal separation between inflorescence primordia (flowering induction) and flower development. We hypothesized that a repression mechanism implicating epigenetic changes could play a role in the seasonal separation of these two developmental processes in grapevine. Therefore, the expression of five grapevine genes with homology to the Arabidopsis epigenetic repressor genes FERTILIZATION INDEPENDENT ENDOSPERM (FIE), EMBRYONIC FLOWER 2 (EMF2), CURLY LEAF (CLF), MULTICOPY SUPPRESSOR OF IRA 1 (MSI1) and SWINGER (SWN) was analyzed during the development of buds and vegetative and reproductive organs. During bud development, the putative grapevine epigenetic repressor genes VvCLF, VvEMF2, VvMSI1, VvSWN and VvFIE are mainly expressed in latent buds at the flowering induction period, but also detected during bud burst and inflorescence/flower development. The overlapping expression patterns of grapevine PcG-like genes in buds suggest that chromatin remodeling mechanisms could be operating during grapevine bud development for controlling processes such as seasonal flowering, dormancy and bud burst. Furthermore, the expression of grapevine PcG-like genes was also detected in fruits and vegetative organs, suggesting that epigenetic changes could be at the basis of the regulation of various proliferation-differentiation cell transitions that occur during grapevine development. PMID- 21681474 TI - [Electrolyte disorders]. AB - Disorders of electrolyte balance are frequent and pathophysiologically complex. Sodium is responsible for a large part of the osmolarity of extracellular fluids. Therefore, pathological concentrations of serum sodium reflect the relation between sodium and water in the extracellular compartment rather than the total body sodium content. The causes of hypo- or hypernatremia can only be deduced if total body volume status is considered. Patients with hyponatremia and volume deficit should receive sodium chloride solution while patients with this disorder in the presence of volume overload need strict water restriction. In certain cases additional specific pharmacotherapy directed at the effects of antidiuretic hormone may be considered. Potassium and calcium are extracellular regulatory ions; their concentrations do not relevantly contribute to osmolarity and water distribution but to electrophysiologically relevant transmembrane potentials. These ions are influenced by active membrane transporters and regulated by several hormones. The rather small extracellular pools are overfilled or depleted by alterations of intake and excretion. In addition, several inborn or acquired defects of transmembrane transporters may severely alter their extracellular concentrations. Therapy needs to consider the specific mechanisms that led to the electrolyte disorder including modification of intake, excretion or extra intracellular distribution. PMID- 21681476 TI - Do Clark's nutcrackers demonstrate what-where-when memory on a cache-recovery task? AB - What-where-when (WWW) memory during cache recovery was investigated in six Clark's nutcrackers. During caching, both red- and blue-colored pine seeds were cached by the birds in holes filled with sand. Either a short (3 day) retention interval (RI) or a long (9 day) RI was followed by a recovery session during which caches were replaced with either a single seed or wooden bead depending upon the color of the cache and length of the retention interval. Knowledge of what was in the cache (seed or bead), where it was located, and when the cache had been made (3 or 9 days ago) were the three WWW memory components under investigation. Birds recovered items (bead or seed) at above chance levels, demonstrating accurate spatial memory. They also recovered seeds more than beads after the long RI, but not after the short RI, when they recovered seeds and beads equally often. The differential recovery after the long RI demonstrates that nutcrackers may have the capacity for WWW memory during this task, but it is not clear why it was influenced by RI duration. PMID- 21681475 TI - Capuchin monkeys (Cebus apella) use positive, but not negative, auditory cues to infer food location. AB - Nonhuman primates appear to capitalize more effectively on visual cues than corresponding auditory versions. For example, studies of inferential reasoning have shown that monkeys and apes readily respond to seeing that food is present ("positive" cuing) or absent ("negative" cuing). Performance is markedly less effective with auditory cues, with many subjects failing to use this input. Extending recent work, we tested eight captive tufted capuchins (Cebus apella) in locating food using positive and negative cues in visual and auditory domains. The monkeys chose between two opaque cups to receive food contained in one of them. Cup contents were either shown or shaken, providing location cues from both cups, positive cues only from the baited cup, or negative cues from the empty cup. As in previous work, subjects readily used both positive and negative visual cues to secure reward. However, auditory outcomes were both similar to and different from those of earlier studies. Specifically, all subjects came to exploit positive auditory cues, but none responded to negative versions. The animals were also clearly different in visual versus auditory performance. Results indicate that a significant proportion of capuchins may be able to use positive auditory cues, with experience and learning likely playing a critical role. These findings raise the possibility that experience may be significant in visually based performance in this task as well, and highlight that coming to grips with evident differences between visual versus auditory processing may be important for understanding primate cognition more generally. PMID- 21681477 TI - Large-billed crows (Corvus macrorhynchos) have retrospective but not prospective metamemory. AB - Evidence of metamemory, the ability to monitor one's own memory, has been obtained in some primates, but it appears to be weaker in other species. In this study, we examined whether crows flexibly modulate their behavior by monitoring the strength of memory trace in a delayed matching-to-sample task using two paradigms. First, crows performing a memory test were given an escape option to decline taking the test (prospective metamemory). Second, crows were given the escape option as a "not confident" report after completing the test (retrospective metamemory). Accurate memory performance yielded a reward with a higher probability, whereas inaccurate memory performance resulted in no such recompense. The escape option yielded a reward with a lower probability. In the prospective metamemory test, crows escaped the memory test more frequently with longer delay intervals than they did with shorter delay intervals but no more frequently in the sample-omission than the sample-present trials, indicating that the crows decided to take the test or decline it by using the delay interval as a cue. In contrast, in the retrospective metamemory test, the crows escaped the memory test more frequently when their memory-test response was incorrect than correct and more frequently in the sample-omission than the sample-present trials, indicating that the crows recognized confidence regarding their choice in the memory test and utilized the escape option to maximize reward probability. Although these results suggest that crows retrospectively monitor the strength of memory trace, their prospective metamemory ability has not yet been confirmed in the present paradigm. PMID- 21681479 TI - Validation of the Sensewear Armband during recreational in-line skating. AB - Multi-sensor body monitors that combine accelerometry with other physiological data are designed to overcome drawbacks of accelerometers in assessing activities with little or no vertical movement. One of such devices is the Sensewear Armband (SWA) which has been extensively validated during various activities. However, very few of the validation studies included activities other than walking and running. The aim of this investigation was to assess the validity of the SWA during recreational in-line skating. Nineteen participants (11 females and 8 males), 28 (+/-6) years of age, performed in-line skating exercise on a circular track at a self-selected pace. Energy expenditure was measured with the SWA and the Cosmed K4b(2) breath-by-breath portable metabolic unit. The mean (SD) energy expenditure during in-line skating estimated by the SWA [25.5 (5.8) kJ/min] was significantly lower compared with indirect calorimetry [44.2 (9.7) kJ/min, P < 0.001]. Similarly, the mean (SD) MET values recorded by the SWA were also lower compared with IC [5.3 (1.0) METs vs. 9.1 (1.6) METs, P < 0.001]. The ratio limits of agreement suggest that in 95% of cases the SWA will underestimate the energy expenditure and MET values during in-line skating by as much as 24-56% compared with indirect calorimetry. In conclusion, the results of the present study indicate that the SWA is not able to overcome the drawbacks of accelerometry in assessing activities with limited vertical movement. PMID- 21681478 TI - Modulation of catecholamine-synthesizing enzymes in adrenal medulla and stellate ganglia by treadmill exercise of stressed rats. AB - The sympatho-adrenal system represents one of the main systems involved in the response to stressful events because its stress-induced activation results in an increased release of catecholamines. Exercise training acts as an important modulator of sympatho-adrenal system, adrenal medulla and stellate ganglia being two components of this system. This study aimed at investigating physical exercise-related changes in gene expression of catecholamine biosynthetic enzymes tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase in the adrenal medulla and stellate ganglia of chronically psychosocially stressed adult rats exposed daily to 20-min treadmill exercise for 12 weeks, using TaqMan RT-PCR assay. Chronic psychosocial stress decreased gene expression of the examined enzymes in the adrenal medulla and treadmill exercise did not lead to further modulation of the corresponding gene expression. On the other hand, chronic psychosocial stress produced a significant increase of TH (about 51%) and DBH (about 103%) gene expression in stellate ganglia, while treadmill exercise decreased gene expression of these enzymes to control levels in psychosocially stressed rats. Our data indicate that treadmill exercise leads to a decreased gene transcription of catecholamine biosynthetic enzymes in stellate ganglia and attenuation of cardiac noradrenaline production in stressful situations. Reduction of catecholamine synthesis in stellate ganglia may be linked to the beneficial effects of treadmill exercise on cardiovascular system in stressed animals. PMID- 21681480 TI - Effects of mild-exercise training cessation in human skeletal muscle. AB - Stoppage of endurance exercise training leads to complete loss of maximal oxygen uptake ([Formula: see text]) gain but not submaximal exercise blood lactate concentrations. However, the detailed mechanisms are still unknown. Thus, we investigated the effects of exercise-training cessation at lactate threshold (LT) intensity on physiological adaptations and global mRNA expressions in human skeletal muscle. The [Formula: see text], muscle capillaries density and global gene expression were measured after 12 weeks of LT training, and after 12 weeks of detraining. Twelve weeks of detraining reversed the effect of 12 weeks LT training on [Formula: see text] and [Formula: see text] at LT intensity, although the later value was higher than the pre-training level. Moreover, the training cessation did not affect the number of capillaries around type I fiber, which was increased by training. The training modulated 243 characterized transcripts, in which 77% showed a significant reversible effect by detraining. However, the transcripts most-induced by the training were still elevated after the same period of detraining. The pathway and network analysis revealed that these genes were related to oxidative phosphorylation (OxPhos), calcium signalling and tissue development. Therefore, these physiological and transcriptional changes suggest improved oxygen supply and OxPhos in the skeletal muscle, which may contribute to the incomplete loss of absolute [Formula: see text] at LT intensity after training cessation. The present study does not only demonstrate, for the first time, sustained effects of training after detraining at the transcriptional level, but also indicates the possible signalling pathways. PMID- 21681481 TI - Physiological responses during linear periodized training in rats. AB - This study was undertaken to characterize the effects of the linear periodized training in rats on aerobic and anaerobic performance, glycogen concentration in soleus, gastrocnemius and liver, hormones concentrations (testosterone and corticosterone), enzymes and metabolites (creatine kinase, lactate dehydrogenase, creatinine, uric acid and urea) as well as antioxidant system (catalase, superoxide dismutase and sulfhydryl groups) after basic, specific and taper periods. Seventy male Wistar rats were randomly separated in two groups: control/sedentary (CT, n = 40) and linear periodized training (LPT, n = 30). The LPT was carried out during a period of 12 weeks (w) with frequency of 6 days/week. The training period was subdivided in three mesocycles: basic (6 weeks), specific (4.5 weeks) and taper (1.5 weeks). The real volume of the training obtained in LPT reduced 7% in relation to the estimated volume. The anaerobic index in LPT after basic and taper was higher than CT in respective period but unchanged intra-group during mesocycles. The aerobic performance in LPT was higher than CT after basic, specific and taper. The creatine kinase and catalase reduced after the taper period in relation to CT and baseline. The glycogen stores in soleus increased after basic in relation to CT. The liver glycogen concentration increased after taper in relation to basic and specific period as well in comparison to CT. In conclusion, the stress biomarkers reduced in taper period in order to increase the aerobic and anaerobic performance in relation to CT. PMID- 21681482 TI - Assessment of time to pregnancy and spontaneous abortion status following occupational exposure to organic solvents mixture. AB - PURPOSE: Due to increasing usage of chemicals in various industries, occupational exposure of women with these materials is unavoidable. Nowadays, some studies indicate adverse effects of exposure to these chemicals, especially organic solvents on the reproductive system of females. This study aimed to assess the relationship between spontaneous abortion and occupational exposure to organic solvents mixture in pharmaceutical industry. METHODS: This study was carried out in a pharmaceutical factory located in the suburb of Tehran in 2010. During the study, married women who were working in the factory laboratory units and had exposure to mixed organic solvents were compared with married women who were working in the packing units of the factory without occupational exposure to organic solvents in terms of spontaneous abortion frequency and duration of pregnancy using statistical methods. RESULTS: In this study, the frequency of spontaneous abortion in employees with and without exposure to organic solvents mixture was 10.7 and 2.9% respectively. This study showed that even after adjustment for confounding factors, there was a significant correlation between spontaneous abortion and occupational exposure to organic solvents mixture and this correlation increased with increasing levels of exposure to organic solvents. Also, a significant correlation was observed between occupational exposure to mixed organic solvents and waiting time to become pregnant (TTP). Furthermore, this study showed that even after adjustment for confounding variables, shift workers were significantly more affected by spontaneous abortion compared to daytime workers (P < 0.001). Also, in our study, synergistic effect between shift working and occupational exposure to organic solvents mixture on spontaneous abortion was seen. CONCLUSIONS: According to the results of this study, since there is probability of spontaneous abortion resulting from occupational exposure to various chemicals including organic solvents, recommendation to review the status of occupational exposure of workers can be helpful in improving fertility consultations and reproductive health. PMID- 21681483 TI - Impact of gene stacking on gene flow: the case of maize. AB - To respect the European labelling threshold for the adventitious presence of genetically modified organisms (GMOs) in food and feed, stakeholders mainly rely on real-time PCR analysis, which provides a measurement expressed as a percentage of GM-DNA. However, this measurement veils the complexity of gene flow, especially in the case of gene stacking. We have investigated the impact of gene stacking on adventitious GM presence due to pollen flow and seed admixture as well as its translation in terms of the percentage of GM-DNA in a non-GM maize harvest. In the case of varieties bearing one to four stacked events, we established a set of relationships between the percentage of GM kernels and the percentage of GM-DNA in a non-GM harvest as well as a set of relationships between the rate of seed admixture and the percentages of GM material in a non-GM harvest. Thanks to these relationships, and based on simulations with a gene flow model, we have been able to demonstrate that the number of events and the stacking structure of the emitting fields impact the ability of a non-GM maize producer to comply with given GM kernel or GM-DNA thresholds. We also show that a great variability in the rates of GM kernels, embryos and DNA results from seed admixture. Finally, the choice of a unit of measurement for a GM threshold in seed lots can have opposite effects on the ability of farmers to comply with a given threshold depending on whether they are crop or seed producers. PMID- 21681484 TI - Purification and properties of phenolic acid decarboxylase from Candida guilliermondii. AB - A heat-labile phenolic acid decarboxylase from Candida guilliermondii (an anamorph of Pichia guilliermondii) was purified to homogeneity by simple successive column chromatography within 3 days. The molecular mass was 20 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 36 kDa by gel filtration chromatography, suggesting that the purified enzyme is a homodimer. The optimal pH and temperature were approximately 6.0 and 25 degrees C. Characteristically, more than 50% of the optimal activity was observed at 0 degrees C, suggesting that this enzyme is cold-adapted. The enzyme converted p coumaric acid, ferulic acid, and caffeic acid to corresponding products with high specific activities of approximately 600, 530, and 46 U/mg, respectively. The activity was stimulated by Mg(2+) ions, whereas it was completely inhibited by Fe(2+), Ni(2+), Cu(2+), Hg(2+), 4-chloromericuribenzoate, N-bromosuccinimide, and diethyl pyrocarbonate. The enzyme was inducible and expressed inside the cells moderately by ferulic acid and p-coumaric acid and significantly by non metabolizable 6-hydroxy-2-naphthoic acid. PMID- 21681485 TI - Isolation and characterization of an arsenate-reducing bacterium and its application for arsenic extraction from contaminated soil. AB - A Gram-negative anaerobic bacterium, Citrobacter sp. NC-1, was isolated from soil contaminated with arsenic at levels as high as 5,000 mg As kg(-1). Strain NC-1 completely reduced 20 mM arsenate within 24 h and exhibited arsenate-reducing activity at concentrations as high as 60 mM. These results indicate that strain NC-1 is superior to other dissimilatory arsenate-reducing bacteria with respect to arsenate reduction, particularly at high concentrations. Strain NC-1 was also able to effectively extract arsenic from contaminated soils via the reduction of solid-phase arsenate to arsenite, which is much less adsorptive than arsenate. To characterize the reductase systems in strain NC-1, arsenate and nitrate reduction activities were investigated using washed-cell suspensions and crude cell extracts from cells grown on arsenate or nitrate. These reductase activities were induced individually by the two electron acceptors. This may be advantageous during bioremediation processes in which both contaminants are present. PMID- 21681486 TI - Experimental evidence for a novel mechanism driving variation in habitat quality in a food-caching bird. AB - Variation in habitat quality can have important consequences for fitness and population dynamics. For food-caching species, a critical determinant of habitat quality is normally the density of storable food, but it is also possible that quality is driven by the ability of habitats to preserve food items. The food caching gray jay (Perisoreus canadensis) occupies year-round territories in the coniferous boreal and subalpine forests of North America, but does not use conifer seed crops as a source of food. Over the last 33 years, we found that the occupancy rate of territories in Algonquin Park (ON, Canada) has declined at a higher rate in territories with a lower proportion of conifers compared to those with a higher proportion. Individuals occupying territories with a low proportion of conifers were also less likely to successfully fledge young. Using chambers to simulate food caches, we conducted an experiment to examine the hypothesis that coniferous trees are better able to preserve the perishable food items stored in summer and fall than deciduous trees due to their antibacterial and antifungal properties. Over a 1-4 month exposure period, we found that mealworms, blueberries, and raisins all lost less weight when stored on spruce and pine trees compared to deciduous and other coniferous trees. Our results indicate a novel mechanism to explain how habitat quality may influence the fitness and population dynamics of food-caching animals, and has important implications for understanding range limits for boreal breeding animals. PMID- 21681487 TI - Linkage analysis in unconventional mating designs in line crosses. AB - Linkage estimation and genetic map construction with genotyped DNA markers in plants preferentially employ a few maximally informative early-generation or recombinant-inbred mating designs. Fitting their recombination models to unconventional designs adapted to cultivar development (series of backcrossing, selfing, haploid-doubling, random-intercrossing, and sib-mating steps) distorts single- and multipoint linkage estimates even with dense marker coverage. Two methods are provided for correct linkage estimation in unconventional designs: fitting a correct multigeneration model, or correcting the estimates produced by fitting a one-generation model with any conventional software. These methods also support calculation of multilocus genotype frequencies and QTL-genotype distributions and are available in software. PMID- 21681488 TI - Development and application of a set of breeder-friendly SNP markers for genetic analyses and molecular breeding of rice (Oryza sativa L.). AB - Single nucleotide polymorphisms (SNPs) are the most abundant DNA markers in plant genomes. In this study, based on 54,465 SNPs between the genomes of two Indica varieties, Minghui 63 (MH63) and Zhenshan 97 (ZS97) and additional 20,705 SNPs between the MH63 and Nipponbare genomes, we identified and confirmed 1,633 well distributed SNPs by PCR and Sanger sequencing. From these, a set of 372 SNPs were further selected to analyze the patterns of genetic diversity in 300 representative rice inbred lines from 22 rice growing countries worldwide. Using this set of SNPs, we were able to uncover the well-known Indica-Japonica subspecific differentiation and geographic differentiations within Indica and Japonica. Furthermore, our SNP results revealed some common and contrasting patterns of the haplotype diversity along different rice chromosomes in the Indica and Japonica accessions, which suggest different evolutionary forces possibly acting in specific regions of the rice genome during domestication and evolution of rice. Our results demonstrated that this set of SNPs can be used as anchor SNPs for large scale genotyping in rice molecular breeding research involving Indica-Japonica and Indica-Indica crosses. PMID- 21681489 TI - Association mapping in an elite maize breeding population. AB - Association mapping (AM) is a powerful approach to dissect the genetic architecture of quantitative traits. The main goal of our study was to empirically compare several statistical methods of AM using data of an elite maize breeding program with respect to QTL detection power and possibility to correct for population stratification. These models were based on the inclusion of cofactors (Model A), cofactors and population effect (Model B), and SNP effects nested within populations (Model C). A total of 930 testcross progenies of an elite maize breeding population were field-evaluated for grain yield and grain moisture in multi-location trials and fingerprinted with 425 SNP markers. For grain yield, population stratification was effectively controlled by Model A. For grain moisture with a high ratio of variance among versus within populations, Model B should be applied in order to avoid potential false positives. Model C revealed large differences among allele substitution effects for trait-associated SNPs across multiple plant breeding populations. This heterogeneous SNP allele substitution effects have a severe impact for genomic selection studies, where SNP effects are often assumed to be independent of the genetic background. PMID- 21681490 TI - Evaluation of near-isogenic lines for drought resistance QTL and fine mapping of a locus affecting flag leaf width, spikelet number, and root volume in rice. AB - Drought stress is a major limiting factor for crop production and breeding for drought resistance is very challenging due to the complex nature of this trait. Previous studies in rice suggest that the upland japonica variety IRAT109 shows better drought resistance than the lowland indica variety Zhenshan 97. Numerous quantitative trait loci (QTL) have been previously mapped using a recombinant inbred line population derived from these two genotypes. In this study, near isogenic lines (NILs) for 17 drought resistance-related QTL were constructed and phenotypic variations of these NILs were investigated under drought and normal conditions. Fourteen of these NILs showed significant phenotypic differences relative to the recurrent parent under at least one of the conditions and nine NILs showed significant differences under both conditions. After eliminating the effect of heading date on drought resistance, only four NILs carrying seven QTL (four for the same grain yield-related traits and three for the same or similar root traits QTL) showed differences consistent with the original QTL mapping results. One of these lines (N19) contains qFSR4, a QTL on chromosome 4 controlling root volume per tiller and co-segregating with flag leaf width and spikelet number per panicle. Using a population derived from N19, qFSR4 was mapped to a 38-kb region containing three open reading frames including the previously characterized NARROW LEAF 1 (NAL1) gene. NAL1, which controls leaf width and also affects vein patterning and polar auxin transport, is the most promising candidate genes for qFSR4. Our results underscore the importance of the development of NILs to confirm the identification of QTL affecting complex traits such as drought resistance. PMID- 21681491 TI - A novel FAD2-1 A allele in a soybean plant introduction offers an alternate means to produce soybean seed oil with 85% oleic acid content. AB - The alteration of fatty acid profiles in soybean to improve soybean oil quality has been a long-time goal of soybean researchers. Soybean oil with elevated oleic acid is desirable because this monounsaturated fatty acid improves the nutrition and oxidative stability of soybean oil compared to other oils. In the lipid biosynthetic pathway, the enzyme fatty acid desaturase 2 (FAD2) is responsible for the conversion of oleic acid precursors to linoleic acid precursors in developing soybean seeds. Two genes encoding FAD2-1A and FAD2-1B were identified to be expressed specifically in seeds during embryogenesis and have been considered to hold an important role in controlling the seed oleic acid content. A total of 22 soybean plant introduction (PI) lines identified to have an elevated oleic acid content were characterized for sequence mutations in the FAD 2-1A and FAD2-1B genes. PI 603452 was found to contain a deletion of a nucleotide in the second exon of FAD2-1A. These important SNPs were used in developing molecular marker genotyping assays. The assays appear to be a reliable and accurate tool to identify the FAD 2-1A and FAD2-1B genotype of wild-type and mutant plants. PI 603452 was subsequently crossed with PI 283327, a soybean line that has a mutation in FAD2-1B. Interestingly, soybean lines carrying both homozygous insertion/deletion mutation (indel) FAD2-1A alleles and mutant FAD2-1B alleles have an average of 82-86% oleic acid content, compared to 20% in conventional soybean, and low levels of linoleic and linolenic acids. The newly identified indel mutation in the FAD2-1A gene offers a simple method for the development of high oleic acid commercial soybean varieties. PMID- 21681492 TI - Arterial therapies of colorectal cancer metastases to the liver. AB - Intra-arterial therapies directed to the liver take advantage that liver tumors are fed by the hepatic artery while the liver vascularization is 30% arterial. Most common techniques of intra-arterial therapies for colorectal cancer liver metastases (CRLM) include intra-arterial hepatic chemotherapy (IAHC), transarterial chemoembolization (TACE), and radioembolization. Such treatments are used as salvage therapies because they provide response when systemic therapies are inefficient. They are also used as a first line therapy to produce maximal response in order to convert the patient from non-surgical to surgical. IAHC with FUDR or oxaliplatinum allow 90% response rate and conversion to surgery of 40% to 50% of initially inoperable patients. TACE is used in CRLM with promising response rate, namely due to the use of drug eluting beads that can be loaded with irinotecan which can elute the drug they contain after embolization in liver tumor. Radioembolization is a unique way of delivering a high tumoricidal dose of radiation (>100 Gy) to liver tumor without harming the healthy liver, and provided interesting results in salvage therapy, enough to be evaluated today in a randomized control trial in first line therapy where FOLFOX is proposed with and without additional radioembolization. PMID- 21681493 TI - The peroral pneumocolon revisited: a valuable fluoroscopic and CT technique for ileocecal evaluation. AB - The peroral pneumocolon represents a time-honored but somewhat forgotten and underutilized technique for improved ileocecal evaluation at small bowel fluoroscopy. The peroral pneumocolon entails fluoroscopically guided gaseous insufflation per rectum following the arrival of barium at the cecum at conventional small bowel follow-through examination. In most cases, high-quality double contrast evaluation of the terminal ileum can be achieved, often superior to enteroclysis examination for this critical location. The peroral pneumocolon improves diagnostic confidence, including assessment of disease activity, and may result in a reversal of the diagnostic impression. This simple procedure will be discussed and a spectrum of fluoroscopic findings with CT and endoscopic correlation will be provided to demonstrate the added yield of this technique in the evaluation of known or suspected Crohn's disease. Application of the pneumocolon technique to CT for combined small and large bowel evaluation ("CT coloenterography") will also be discussed, which represents an attractive new option for investigating inflammatory bowel disease and other bowel-related conditions. Through the use of automated low-pressure carbon dioxide delivery per rectum, supplemented by IV glucagon for relaxation of the ileocecal valve, a CT based pneumocolon examination may prove to be a useful hybrid technique for bowel evaluation in the future. PMID- 21681494 TI - Portal biliopathy: a multitechnique imaging approach. AB - Portal biliopathy (PB) is a disorder characterized by biliary ductal and gallbladder wall abnormalities seen in patients with extrahepatic portal vein obstruction. These abnormalities consist mainly of bile duct compression and tethering, stenoses, fibrotic strictures and dilatation of both extrahepatic and intrahepatic bile ducts, as well as gallbladder varices. In this pictorial essay, we describe the imaging findings of PB, which allow differentiation of this entity from other diseases that may have similar imaging findings including cholangiocarcinoma, extrinsic compression of the bile duct caused by metastatic adenopathy or sclerosing cholangitis. PMID- 21681496 TI - Nanosurgical interventions in the practice of human ARTs. PMID- 21681495 TI - Localization of sporadic neuroendocrine tumors by gene expression analysis of their metastases. AB - A characteristic of human gastroenteropancreatic neuroendocrine tumors (GEP-NET) is a minute unobtrusive primary tumor which often cannot be detected by common physical examinations. It therefore remains unidentified until the tumor has spread and space-occupying metastases cause clinical symptoms leading to diagnosis. Cases in which the primary cannot be located are referred to as NET with CUP-syndrome (cancer of unknown primary syndrome). With the help of array CGH (comparative genomic hybridization, Agilent 105K) and gene expression analysis (Agilent 44K), microdissected primaries and their metastases were compared to identify up- and down-regulated genes which can be used as a marker for tumor progression. In a next analysis step, a hierarchical clustering of 41.078 genes revealed three genes [C-type lectin domain family 13 member A (CD302), peptidylprolyl isomerase containing WD40 repeat (PPWD1) and abhydrolase domain containing 14B (ABHD14B)] which expression levels can categorize the metastases into three groups depending on the localization of their primary. Because cancer therapy is dependent on the localization of the primary, the gene expression level of these three genes are promising markers to unravel the CUP syndrome in NET. PMID- 21681497 TI - The follicular stigma--a window for better understanding of ovulation. PMID- 21681498 TI - Effects of retinoic acid on maturation of immature mouse oocytes in the presence and absence of a granulosa cell co-culture system. AB - PURPOSE: Evaluation of the all-trans retinoic acid (t-RA) effects on in vitro maturation (IVM) and in vitro fertilization (IVF) of immature mouse oocytes in the presence and absence of granulosa cell monolayer. METHODS: Denuded oocytes isolated from mice ovaries and matured in IVM medium alone (Control I), IVM medium in the presence of granulosa cells (Control II), IVM medium with t-RA (Experimental I) and IVM medium simultaneously with t-RA and granulosa cells (Experimental II). After 24 h, matured oocytes were fertilized in T6 medium and their development was followed until the blastocyst stage. Metaphase II oocytes ploidy were evaluated by chromosome counting. RESULTS: The t-RA group compared to the control groups showed no obvious abnormalities. Additionally maturation and embryo development rates significantly increased in the t-RA treated granulosa cell co-culture system. CONCLUSIONS: In conclusion, association of t-RA with granulosa cell co-culture during in vitro maturation increases meiosis resumption, formation of metaphase II oocytes, as well as 2-cell and blastocyst stage embryos. PMID- 21681499 TI - Retrospective study on the effect of tight glucose control in postoperative sepsis patients using an artificial pancreas. AB - Tight glucose control (TGC) using a sliding scale based on intermittent blood glucose measurements occasionally can have a fatal outcome as a result of insulin induced hypoglycemia. The present study was undertaken to examine whether the use of an artificial pancreas to achieve TGC would be possible in postoperative patients with sepsis. The retrospective study was carried out as an exploratory study, focusing on the possibility of precise evaluation of the significance of TGC as a beneficial intervention by serological monitoring of various mediators. TGC was accomplished using an artificial pancreas (STG-22; (Nikkiso, Tokyo, Japan). The patients were divided into two groups: the TGC group (6 patients with sepsis in whom the target blood glucose level set at <150 mg/dl was attempted using the artificial pancreas), and the glucose control (GC) group (6 patients with sepsis in whom glucose control was attempted using a sliding scale; target blood glucose level was set at 200 mg/dl or lower). The mean blood glucose level was 129.7 +/- 9.7 mg/dl in the TGC group and 200.9 +/- 14.7 mg/dl in the GC group (P < 0.01, ANOVA). No hypoglycemia associated with the artificial pancreas was seen in any of the patients. The serum levels of S100A12 and HMGB-1 tended to decrease, and those of sRAGE tended to increase, in the TGC group. Further data collection from a larger number of cases would be expected to allow a precise assessment of TGC as a potentially beneficial intervention in sepsis patients. PMID- 21681500 TI - Clinical implications of interleukin-18 levels in pediatric patients with Mycoplasma pneumoniae pneumonia. AB - The immunological pathogenesis of Mycoplasma pneumoniae pneumonia is known to involve several cytokines. The serum levels of interleukin-18 (IL-18) were examined using enzyme-linked immunosorbent assay in 23 pediatric patients (median age 6 years; range 4-13 years; 14 girls and 9 boys) with M. pneumoniae pneumonia admitted to our hospital. Serum levels of IL-18 ranged from 22 to 1808 pg/ml with a mean of 543 pg/ml. We started steroid therapy in two cases with IL-18 values greater than 1000 pg/ml without being aware of IL-18 levels. Examination of associations between IL-18 levels determined by enzyme-linked immunosorbent assay and a routine laboratory test showed that levels of lactate dehydrogenase (LDH) and IL-18 were significantly correlated. To determine the appropriateness of steroid administration in M. pneumoniae pneumonia patients, serum LDH should be examined. Patients with elevated levels of LDH are likely to have significantly elevated IL-18 values (>=1000 pg/ml) and thus can be candidates for steroid therapy. PMID- 21681501 TI - Guillain-barre syndrome following influenza vaccination: causal or coincidental? AB - In 1976, the emergence of a new swine-origin influenza virus prompted concerns about an impending influenza pandemic. Although the outbreak never materialized, the epidemiological link between Guillain-Barre syndrome, a potentially severe peripheral nerve disorder, and the influenza vaccines developed against this virus caught public health officials, clinicians, and the public by surprise. Subsequently, a great deal of scrutiny has been placed on the possible risk of other formulations of influenza vaccine causing this adverse event. Several epidemiologic and biological assessments have been performed in subsequent years to assess this risk, yet considerable uncertainty remains among health care providers about the possible association. The development and rapid implementation of vaccines against the pandemic 2009 A(H1N1) influenza virus once again highlighted this issue. This article reviews the evidence for and against the association of the 1976 influenza vaccines and subsequent seasonal influenza vaccines with the development of Guillain-Barre syndrome. PMID- 21681502 TI - [Dynamic instrumentation of the lumbar spine. Clinical and biomechanical analysis of success factors]. AB - Total disc replacement and posterior dynamic stabilization represent alternatives to lumbar spinal fusion which should reduce the risk of adjacent segment degeneration. Disc replacement is indicated for pure discopathy without facet joint degeneration. Spinopelvic balance influences the implant's biomechanics. Therefore pelvic incidence, sacral slope, segmental lordosis and the mean axis of rotation need to be considered. Dynamic stabilization is indicated in moderate discopathy and facet joint degeneration, in degenerative spondylolisthesis grade I with a hypermobile segment and in dynamic lumbar stenosis. The combination of caudal fusion and cranial dynamic stabilization allows a better maintenance of lordosis with multiple level instrumentation and prevents adjacent segment degeneration. If pelvic incidence and sacral slope are high, L5-S1 should be fused because of elevated shear forces. PMID- 21681503 TI - [Utilization rates of lower extremity prostheses in Germany and Switzerland: A comparison of the years 2005-2008]. AB - BACKGROUND: In the United States the use of total hip arthroplasty (THA) has substantially increased over the last decade. It is not known, however, if this trend can be applied to other countries as well. The aim of the current study was therefore a detailed comparison of hip, knee, and ankle arthroplasty utilization rates in Germany and Switzerland in the years 2005-2008 and a secondary comparison with the United States. PATIENTS AND METHODS: Based on datasets from the national statistical offices the number of inhabitants, gender and age distributions and the number of primary and revision surgeries were determined. These figures served for calculating primary, revision and overall surgical volumes, revision burden, primary and revision rates per 100,000 inhabitants, gender and age-specific primary and revision rates. A comparably smaller dataset was provided for the respective US analyses. RESULTS: In Germany, Switzerland and the US the number of implanted total and partial hip arthroplasties per 100,000 inhabitants rose from 235.8, 238.2 and 116.8 in 2005 to 254.7, 262.7 and 127.3 in 2008, respectively. For total and partial knee arthroplasty the rates were 156.3, 140.1 and 178.2 implantations in 2005 and 188.3, 176.8 and 213.6 in 2008, respectively. With 13.6% the revision burden in Germany was 3.6% higher than in Switzerland and accounted for 11.2% in the US. In 2008 it was 15.1% in Germany, was hence 4.6% higher than in Switzerland and remained stable at 11.2% in the US. For knee replacements the 2005 German revision burden was 11.1% which was 3.5% higher than in Switzerland and was 7.4% in the US. In 2008 it was 12.8% in Germany and 4.2% lower in Switzerland and in the US it accounted for 8.9%. In all three countries the revision burden for knee arthroplasty was constantly lower than for hip arthroplasty. CONCLUSION: In all three countries the primary rates for hip and knee replacements rose over the years but those for knee arthroplasty to a higher extent. The 2008 revision burden was highest in Germany for both types of arthroplasty. In Switzerland there was a transient revision burden decrease with a new increase from the year 2007 onwards. The US hip replacement utilization rates per 100,000 inhabitants were considerably lower than those in Germany and Switzerland and for knee replacements they were slightly higher. PMID- 21681504 TI - In silico analysis of IRES RNAs of foot-and-mouth disease virus and related picornaviruses. AB - Foot-and-mouth disease virus (FMDV) uses an internal ribosome entry site (IRES), a highly structured segment of its genomic RNA, to hijack the translational apparatus of an infected host. Computational analysis of 162 type II picornavirus IRES RNA sequences yielded secondary structures that included only base pairs supported by comparative or experimental evidence. The deduced helical sections provided the foundation for a hypothetical three-dimensional model of FMDV IRES RNA. The model was further constrained by incorporation of data derived from chemical modification and enzymatic probing of IRES RNAs as well as high resolution information about IRES RNA-bound proteins. PMID- 21681505 TI - Efficacy of intravenous glycyrrhizin in the early stage of acute onset autoimmune hepatitis. AB - BACKGROUND: Acute onset autoimmune hepatitis (AIH) shows acute presentation like acute hepatitis and does not have typical clinicopathological features of AIH. There is no gold standard for making the diagnosis. Therefore, losing the timing of starting immunosuppressive therapy, some of the cases develop into severe or fulminant form and have poor prognosis. AIMS: Our aim was to elucidate the efficacy of intravenous glycyrrhizin in decreasing alanine aminotransferase (ALT) level in the early stage of acute onset AIH. METHODS: Thirty-one patients were defined as acute onset AIH based on our uniform criteria, and were enrolled in this study. We prospectively treated 17 patients with sufficient doses (100 ml/day) of intravenous glycyrrhizin (SNMC) at an early stage (SNMC group), and treated 14 patients of severe disease with intravenous glycyrrhizin and corticosteroids (CS) (SNMC + CS group). We examined their clinical and biochemical features and treatment responses. RESULTS: The ALT level could be controlled at an early stage using SNMC with no significant difference compared with SNMC + CS, and responsiveness to the therapy was determined by the disease severity at the time of starting therapy rather than the time duration from onset to therapy. Recovery rate was higher in the SNMC group than in the SNMC + CS group (P = 0.035). CONCLUSIONS: The early introduction of sufficient doses of SNMC might prevent disease progression in patients with acute onset AIH. SNMC can be used safely and be useful for patients with difficult-to-diagnose acute liver disease as an 'initial' treatment tool to improve liver inflammation before starting disease-specific treatments. PMID- 21681506 TI - Predictors of colorectal cancer following a negative colonoscopy in the Medicare population. AB - BACKGROUND: The incidence of colorectal cancer following a normal colonoscopy in the Medicare population is not known. METHODS: A 5% national sample of Medicare enrollees from 1996 to 2005 was used to identify patients undergoing complete colonoscopy. A colonoscopy not associated with any procedure (e.g., biopsy, polypectomy or fulguration) was defined as a negative colonoscopy. Patients with history of inflammatory bowel disease, colorectal cancer or death within 12 months of colonoscopy were excluded. A multivariable model was constructed to evaluate the factors associated with a new diagnosis of colorectal cancer in the period from 12 to 120 months following the negative colonoscopy. RESULTS: Among 200,857 patients (mean age 74 years, 61% female, 92% White) with a negative colonoscopy, the incidence of colorectal cancer was 1.8 per 1,000 person-years. The incidence rate for matched follow-up periods decreased from 2.0/1,000 person years for patients undergoing colonoscopy during 1996-2000 to 1.2/1,000 person years during 2001-2005. Multivariate analysis revealed a significant regional variation in the incidence of colorectal cancer following a negative colonoscopy. The incidence was higher in patients >85 years, males and patients who underwent a negative colonoscopy by a non-gastroenterologist or endoscopist in the lowest volume quartile. On stratified analyses, endoscopist volume was a significant predictor for non-gastroenterologists only. CONCLUSIONS: The specialty and experience of the endoscopist are significant predictors of the incidence rate of colorectal cancer in Medicare patients with a negative colonoscopy. PMID- 21681507 TI - Postoperative infliximab is not associated with an increase in adverse events in Crohn's disease. AB - BACKGROUND: Infliximab is effective treatment for Crohn's disease and has been associated with rare, but serious infectious complications. Emerging data suggest a benefit of infliximab in preventing postoperative Crohn's disease recurrence. It is not known whether administration of infliximab shortly after resective surgery for Crohn's disease increases postoperative complications. AIMS: To evaluate the risk of developing postoperative complications among Crohn's disease patients receiving infliximab within 4 weeks of intestinal resection. METHODS: As part of a randomized placebo-controlled infliximab postoperative prevention study, adverse events were prospectively monitored. Crohn's disease patients undergoing intestinal resection were randomized to placebo or infliximab 2-4 weeks after surgery. Study infusions were administered at 0, 2, and 6 weeks then every 8 weeks for 1 year. To evaluate whether infliximab increased postoperative complications, we analyzed all adverse events for 1 year after surgery. RESULTS: Twenty-four patients were randomized to infliximab or placebo after intestinal resection for Crohn's disease. Mean time to first postoperative infusion was 20 days (range 14-25 days). Over the course of 1 year, there were 22 total adverse events, but no difference between infliximab and placebo patients (12 versus 10, respectively, P = 1.0). In the immediate postoperative period, within 8 weeks of surgery, the number of adverse events was also similar between the two groups (3 infliximab and 5 placebo patients, P = 0.68). There were no serious adverse events and no complications related to wound healing or infection. CONCLUSIONS: Initiation of infliximab within 4 weeks of intestinal resection was not associated with postoperative complications. PMID- 21681508 TI - Make the right choice on primary treatments for salvage liver transplantation strategy. PMID- 21681509 TI - Multiparametric assessment of vascular function and atherosclerosis in patients with autoimmune gastritis: a comparative study. AB - BACKGROUND/AIMS: Patients with autoimmune gastritis might have accelerated atherosclerosis due to autoimmunity and chronic inflammation. Endothelial dysfunction often precedes manifest atherosclerosis. The aim of the present study was to evaluate the risk factors of early atherosclerosis by using several different techniques. METHODS: A total of 99 patients with autoimmune gastritis were compared to 42 healthy age sex-matched subjects. Patients with a known risk factor for atherosclerosis were excluded. Intima-media thickness of the common carotid artery, pulse wave velocity and flow-mediated dilation of brachial artery were measured. Clinical data and laboratory parameters (serum gastrin, antiparietal cell antibody, anti-Hp IgG, serum vitamin B(12) and lipid profile) were also determined. RESULTS: Intima-media thickness (mm) of the carotid artery was significantly higher in autoimmune gastritis (0.062 +/- 0.031 vs. 0.042 +/- 0.007, P < 0.001) than in healthy individuals. Flow-mediated dilation was significantly lower in patients with autoimmune gastritis compared to control group (13.91 +/- 6.68% vs. 20.37 +/- 7.80%, P = 0.021) and there was a significant increase in pulse wave velocity (m/s) in autoimmune gastritis patients compared to controls (9.25 +/- 3.42 vs. 6.40 +/- 0.91, P = 0.001). Antiparietal cell antibody positivity (P = 0.05), low vitamin B(12) level (P = 0.05), and age (P = 0.002) were the predictors of high pulse wave velocity (>14 m/s). CONCLUSION: Patients with autoimmune gastritis may have an increased risk for the development of early atherosclerosis. As early preventive treatment for accelerated atherosclerosis is available, it is important to detect those patients with autoimmune gastritis who would benefit from such treatment. PMID- 21681510 TI - Mechanical characteristics of distension-evoked peristaltic contractions in the esophagus of systemic sclerosis patients. AB - BACKGROUND: Systemic sclerosis (SS) patients with severe esophageal affection have impaired peristalsis. However, motor function evaluated in vivo by manometry and fluoroscopy does not provide detailed information about the individual contraction cycles. AIMS: To apply, for the first time in gastrointestinal (GI) patients, a method and principles modified from cardiac research to study esophageal muscle behavior in SS patients. METHODS: Muscle contraction cycles were analyzed using pressure-cross-sectional area (P-CSA) loops during distension pressure up to 5 kPa. The probe with bag and electrodes for CSA measurements was positioned 7 and 15 cm above the lower esophageal sphincter (LES) in eleven healthy volunteers and eleven SS patients. The P-CSA, the wall tension, Deltatension (afterload tension - preload tension), contraction velocity, work output (area of the tension-CSA loops), and power output (preload tension * CSA rate) were analyzed. RESULTS: The P-CSA loops consisted of phases with relaxation and contraction behavior. The tension-stretch ratio loops in patients were shifted to the left at both distension sites, indicative of a stiffer wall in patients. Lower contraction amplitudes and smaller P-CSA loops were observed for the SS patients. The work output, power output, Deltatension, and contraction velocity were lower in patients (P < 0.001). Association was found between disease duration and the work output, Deltatension, and velocity at pressure steps higher than 3 kPa (P < 0.05). CONCLUSIONS: Distension-evoked esophageal contraction can be studied in vivo and analyzed with advanced methods. Increased esophageal stiffness and impaired muscle function that depended on disease duration were observed for SS patients. The analysis may be useful for characterization of other diseases affecting GI function. PMID- 21681511 TI - A mobile agent approach for secure integrated medical information systems. AB - Different patient-related information in medical organizations is the primary reference for medical personnel diagnosing, treating, and caring patients. With the rapid development of information technology, paper-based medical records have gradually been changed to electronic forms. However, different medical organizations present individual system specifications and data-saving formats so that the medical information of the same patient cannot be exchanged, shared, and securely accessed. In order not to largely change the present medical information systems as well as not to increase abundant costs, Virtual Integrated Medical information Systems (VIMS) is proposed to assist various hospitals in information exchange. Furthermore, with Mobile Agent, the dispersed medical information can be securely integrated. It presents confidentiality, non-repudiation, source authentication, and integrity in network transmission. Virtual Integrated Medical information Systems (VIMS) is a virtual electronic integration system combined with Mobile Agent technology. With the features of independence, adaptability, mobility, objectives, and autonomy, Mobile Agent is applied to overcome the problems from heterogeneous systems. With the features, the over-dispersed medical records can be integrated. Moreover, Mobile Agent can ensure the instantaneity and usability of medical records from which doctors can make the most appropriate evaluation and diagnoses. It will avoid the waste of medical resources, such as repetition medication, as well as become the reference of further consultation or health check. Not only can it improve the medical care quality, but it can be provided for medical research. PMID- 21681512 TI - Classification of juvenile myoclonic epilepsy data acquired through scanning electromyography with machine learning algorithms. AB - In this paper, classification of Juvenile Myoclonic Epilepsy (JME) patients and healthy volunteers included into Normal Control (NC) groups was established using Feed-Forward Neural Networks (NN), Support Vector Machines (SVM), Decision Trees (DT), and Naive Bayes (NB) methods by utilizing the data obtained through the scanning EMG method used in a clinical study. An experimental setup was built for this purpose. 105 motor units were measured. 44 of them belonged to JME group consisting of 9 patients and 61 of them belonged to NC group comprising ten healthy volunteers. k-fold cross validation was applied to train and test the models. ROC curves were drawn for k values of 4, 6, 8 and 10. 100% of detection sensitivity was obtained for DT, NN, and NB classification methods. The lowest FP number, which was obtained by NN, was 5. PMID- 21681513 TI - Formal verification of medical monitoring software using Z language: a representative sample. AB - Medical monitoring systems are useful aids assisting physicians in keeping patients under constant surveillance; however, taking sound decision by the systems is a physician concern. As a result, verification of the systems behavior in monitoring patients is a matter of significant. The patient monitoring is undertaken by software in modern medical systems; so, software verification of modern medial systems have been noticed. Such verification can be achieved by the Formal Languages having mathematical foundations. Among others, the Z language is a suitable formal language has been used to formal verification of systems. This study aims to present a constructive method to verify a representative sample of a medical system by which the system is visually specified and formally verified against patient constraints stated in Z Language. Exploiting our past experience in formal modeling Continuous Infusion Insulin Pump (CIIP), we think of the CIIP system as a representative sample of medical systems in proposing our present study. The system is responsible for monitoring diabetic's blood sugar. PMID- 21681514 TI - Enabling fast brain-computer interaction by single-trial extraction of visual evoked potentials. AB - This paper investigates the challenging issue of enabling fast brain-computer interaction to construct a mental speller. Exploiting visual evoked potentials as communication carriers, an online paradigm called "imitating-human-natural reading" is realized. In this online paradigm, single-trial estimation with the intrinsically real-time feature should be used instead of grand average that is traditionally used in the cognitive or clinical experiments. By the use of several montages of component features from four channels with parameter optimization, we explored the support vector machines-based single-trial estimation of evoked potentials. The results on a human-subject show the advantages of the inducing paradigm used in our mental speller with a high classification rate. PMID- 21681515 TI - Evaluation of cervical conization as a definitive treatment for microinvasive cervical carcinoma and cervical intraepithelial neoplasia grade 3. AB - PURPOSE: The aim of the study was to evaluate disease persistence after conization of CIN3 and microinvasive cervical carcinoma. METHODS: Medical records from a total of 231 patients were reviewed. The prevalence of CIN3 and cervical carcinoma diagnosed by means of conization were analyzed. All conizations were performed under lumbar anesthesia using a laser technique. RESULTS: Of the 231 patients, 25 had margin involvement with CIN3 or microinvasive carcinoma. Among these 25 patients, 10 underwent hysterectomy. Two of these 10 patients had CIN3 and eight had microinvasive carcinoma. Residual disease was observed in hysterectomy specimens from 9 of the 10 patients. Of the eight patients diagnosed with microinvasion from post-cone hysterectomy specimens, four had CIN3 and three had microinvasive carcinoma. The three patients with microinvasion were found to have a larger area of residual disease as compared with other patients with margin involvement. CONCLUSIONS: Conization alone seems to be a reasonable treatment for patients with CIN1, 2, 3, and microinvasive carcinoma. For adenocarcinoma, in situ treatment with conization alone is possible but requires careful follow-up. Hysterectomy appears to be a safe treatment option for microinvasive adenocarcinoma, although follow-up by cytology is sometimes possible in cases with negative surgical margins. PMID- 21681516 TI - Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. AB - PURPOSE: To investigate the efficacy and safety of dienogest as a long-term treatment in endometriosis, with follow-up after treatment discontinuation. The study included women with endometriosis, who had previously completed a 12-week, placebo-controlled study of dienogest, who participated in an open-label extension study for up to 53 weeks. Thereafter, a patient subgroup was evaluated in a 24-week follow-up after treatment discontinuation. METHODS: A multicenter study performed in Germany, Italy and Ukraine. Women with endometriosis were enrolled at completion of the placebo-controlled study (n = 168). All women received dienogest (2 mg once daily, orally) and changes in pelvic pain (on a visual analog scale), bleeding pattern, adverse events and laboratory parameters were evaluated during and after treatment. RESULTS: The completion rate among women who entered the open-label extension study was 90.5% (n = 152). A significant decrease in pelvic pain was shown during continued dienogest treatment (P < 0.001). The mean frequency and intensity of bleeding progressively decreased. Adverse events, rated generally mild or moderate, led to withdrawal in four patients (2.4%). No clinically relevant changes in laboratory parameters were observed. During treatment-free follow-up (n = 34), the reduction in pelvic pain persisted, while bleeding frequency and intensity returned to normal patterns. CONCLUSIONS: Long-term dienogest showed a favorable efficacy and safety profile, with progressive decreases in pain and bleeding irregularities during continued treatment; the decrease of pelvic pain persisted for at least 24 weeks after treatment cessation. PMID- 21681517 TI - [Diagnosis of multiple sclerosis 2010 revision of the McDonald criteria]. PMID- 21681518 TI - Air-liquid interface cultures enhance the oxygen supply and trigger the structural and functional differentiation of intestinal porcine epithelial cells (IPEC). AB - The specific function of the epithelium as critical barrier between the intestinal lumen and the organism's internal microenvironment is reflected by permanent maintenance of intercellular junctions and cellular polarity. The intestinal epithelial cells are responsible for absorption of nutritional components, facing mechanical stress and a changing oxygen supplementation via blood stream. Oxygen itself can regulate the barrier and the absorptive function of the epithelium. Therefore, we compared the dish cell culture, the transwell like membrane culture and the oxygen enriched air-liquid interface (ALI) culture. We demonstrated strong influence of the different culture conditions on morphology and function of intestinal porcine epithelial cell lines in vitro. ALI culture resulted in a significant increase in cell number, epithelial cell layer thickness and expression as well as apical localisation of the microvilli associated protein villin. Remarkable similarities regarding the morphological parameters were observed between ALI cultures and intestinal epithelial cells in vivo. Furthermore, the functional analysis of protein uptake and degradation by the epithelial cells demonstrated the necessity of sufficient oxygen supply as achieved in ALI cultures. Our study is the first report providing marked evidence that optimised oxygen supply using ALI cultures directly affects the morphological differentiation and functional properties of intestinal epithelial cells in vitro. PMID- 21681519 TI - Isolation and characterization of Microbulbifer species 6532A degrading seaweed thalli to single cell detritus particles. AB - To reduce the volume of seaweed wastes and extract polysaccharides, seaweed degrading bacteria were isolated from drifting macroalgae harvested along the coast of Toyama Bay, Japan. Sixty-four bacterial isolates were capable of degrading "Wakame" (Undaria pinnatifida) thallus fragments into single cell detritus (SCD) particles. Amongst these, strain 6532A was the most active degrader of thallus fragments, and was capable of degrading thallus fragments to SCD particles within a day. Although the sequence similarity of the 16S rRNA gene of strain 6532A was 100% similar to that of Microbulbifer elongatus JAMB-A7, several distinct differences were observed between strains, including motility, morphology, and utilization of D: -arabinose and gelatin. Consequently, strain 6532A was classified as a new Microbulbifer strain, and was designated Microbulbifer sp. 6532A. Strain 6532A was capable of degrading both alginate and cellulose in the culture medium, zymogram analysis of which revealed the presence of multiple alginate lyases and cellulases. To the best of our knowledge, this is the first study to directly demonstrate the existence of these enzymes in Microbulbifer species. Shotgun cloning and sequencing of the alginate lyase gene in 6532A revealed a 1,074-bp open reading frame, which was designated algMsp. The reading frame encoded a PL family seven enzyme composed of 358 amino acids (38,181 Da). With a similarity of 74.2%, the deduced amino acid sequence was most similar to a Saccharophagus enzyme (alg 7C). These findings suggest that algMsp in strain 6532A is a novel alginate lyase gene. PMID- 21681520 TI - Kinetics of biodegradation of diethylketone by Arthrobacter viscosus. AB - The performance of an Arthrobacter viscosus culture to remove diethylketone from aqueous solutions was evaluated. The effect of initial concentration of diethylketone on the growth of the bacteria was evaluated for the range of concentration between 0 and 4.8 g/l, aiming to evaluate a possible toxicological effect. The maximum specific growth rate achieved is 0.221 h(-1) at 1.6 g/l of initial diethylketone concentration, suggesting that for higher concentrations an inhibitory effect on the growth occurs. The removal percentages obtained were approximately 88%, for all the initial concentrations tested. The kinetic parameters were estimated using four growth kinetic models for biodegradation of organic compounds available in the literature. The experimental data found is well fitted by the Haldane model (R (2) = 1) as compared to Monod model (R (2) = 0.99), Powell (R (2) = 0.82) and Loung model (R (2) = 0.95). The biodegradation of diethylketone using concentrated biomass was studied for an initial diethylketone concentration ranging from 0.8-3.9 g/l in a batch with recirculation mode of operation. The biodegradation rate found followed the pseudo-second order kinetics and the resulting kinetic parameters are reported. The removal percentages obtained were approximately 100%, for all the initial concentrations tested, suggesting that the increment on the biomass concentration allows better results in terms of removal of diethylketone. This study showed that these bacteria are very effective for the removal of diethylketone from aqueous solutions. PMID- 21681521 TI - The spinal muscular atrophy mouse model, SMADelta7, displays altered axonal transport without global neurofilament alterations. AB - Spinal muscular atrophy (SMA) is a neurodegenerative disease resulting from decreased levels of survival motor neuron 1 (SMN1) protein. Reduced SMN1 levels are linked to pathology at neuromuscular junctions (NMJs), which includes decreased vesicle density and organization, decreased quantal release, increased endplate potential duration, and neurofilament (NF) accumulations. This work presents a first study towards defining molecular alterations that may lead to the development of NMJ pathology in SMA. Fast, anterograde transport of synaptic vesicle 2 (SV2-c) and synaptotagmin (Syt1) proteins was reduced 2 days prior to the observed decrease in synaptic vesicle density. Moreover, reduced accumulation of SV2-c or Syt1 was not due to reduced protein expression or reduced kinesin activity. Dynein levels were reduced at times that are consistent with NF accumulations at NMJs. Furthermore, NF distribution, from cell body to sciatic nerve, appeared normal in SMA?7 mice. Taken together, these results suggest that reduced axonal transport may provide a mechanistic explanation for reduced synaptic vesicle density and concomitant synaptic transmission defects, while providing evidence that suggests NF accumulations result from local NMJ alterations to NFs. PMID- 21681522 TI - Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. AB - Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct. PMID- 21681523 TI - Antegrade pressure measurement as a diagnostic tool in modern pediatric urology. AB - INTRODUCTION: The antegrade pressure measurement (APM) or perfusion pressure-flow test (Whitaker test) is a method of antegrade measurement of pressure in the upper urinary tract. In this study, we present the long-term follow-up results of APMs performed in our institution in the late 1980s and early 1990s to see whether the diagnostic decisions that were based on the outcomes of the test prove to be correct in the long term. MATERIALS AND METHODS: We conducted a retrospective study by searching our hospital's electronic database. We found a total of 16 APMs performed between 1987 and 1995 (10 boys, six girls; mean age 61 months). RESULTS: In nine cases, action was undertaken immediately after the APM had been performed; in seven cases, this was a surgical procedure (re implantation/re-calibration or pyeloplasty) after obstruction was demonstrated. In two cases (both postoperative after previous pyeloplasty), absence of obstruction was demonstrated and nephrostomy tubes were subsequently closed. In one case, this resulted in hydronephrosis that had to be treated with a new JJ stent. In all the seven cases in which no action was deemed necessary as a result of the outcome of the APM, long-term follow-up showed that intervention had indeed not been necessary. CONCLUSION: Although not often used anymore, the APM seems to be a safe and valuable diagnostic tool in the work up for possible urinary tract obstruction in children, especially in cases in which there is serious doubt concerning conservative watchful waiting. PMID- 21681524 TI - Periarterial papaverine improves early postoperative renal function after retroperitoneoscopic partial nephrectomy. AB - OBJECTIVE: To study the impact of periarterial papaverine application on the postoperative glomerular filtration rate (GFR) after retroperitoneoscopic partial nephrectomy (PN). MATERIALS AND METHODS: A consecutive series of patients underwent retroperitoneoscopic PN with intraoperative, periarterial application of 50 mg of papaverine. These patients were compared with a group of patients who underwent retroperitoneoscopic PN at this institution prior to this protocol. Patients were matched for preoperative GFR, tumor size, ischemia time, and operative time. RESULTS: In total, 37 patients who received periarterial papaverine (P) and 37 patients without periarterial papaverine, who served as controls (C), were included in this analysis and matched according to preoperative GFR (P: 98.2, C: 97.8 ml/min/1.72 m(2)), tumor size (P: 2.5 cm, C: 2.5 cm), ischemia time (P: 22 min, C: 23 min), and operative time (P: 86 min, C: 85 min). Postoperative GFR was 86.4 ml/min/1.72 m(2) in controls (C) and 91.8 ml/min/1.72 m(2) in the papaverine group. The pre- to postoperative decrease in GFR was reduced by 56.9% in the papaverine group compared with controls (relative decrease in GFR: P: 5.3% vs. C: 12.5%; P = 0.02). Intra- and postoperative complications were pneumothorax (P: n = 2, C: n = 3), urinary fistula (P: n = 0, C: n = 2), and one suture-fixed drainage (P: n = 1, C: n = 0). No papaverine related side effects were observed, and the surgical procedure was not hampered by the periarterial application of papaverine. CONCLUSION: As with laparoscopic donor nephrectomy, periarterial papaverine seems to improve postoperative renal function after retroperitoneoscopic partial nephrectomy. This nephroprotective effect might be particularly advantageous for patients with an impaired renal function preoperatively. PMID- 21681525 TI - Predictive factors of recurrence and survival of upper tract urothelial carcinomas. AB - OBJECTIVE: UTUCC is a rare tumor, and most reports on prognostic factors come from small single-center series. The objective of this article was to provide an updated overview of current clinical, pathological and biological prognostic factors of UTUC. METHODS: PubMed was searched for records from 2002 to 2010 using the terms "prognostic factors", "recurrence", "survival", and "upper tract urothelial carcinoma". Among identified citations, papers were selected based on their clinical relevance. RESULTS: Classical clinical factors that influence UTUC prognosis include age, presence of symptoms, hydronephrosis, and interval from diagnosis. Many biomarkers have shown promises to better appraise the natural course of UTUC although none is currently used in clinical practice. Stage, grade, lymph node metastases, lymphovascular invasion, tumor necrosis, and tumor architecture are strong pathological parameters. RNU is the standard treatment of localized UTUC. Both laparoscopic and open approaches seem to offer similar cancer control. Lymph node dissection increases staging accuracy and might confer a survival benefit. CONCLUSION: RNU is the standard treatment for most patients with UTUC. Recent multicenter studies confirmed the prognostic value of classical prognostic parameters. Better survival prediction might be obtained with prognostic systems including clinical data and new biomarkers. PMID- 21681526 TI - The alleles at the E1 locus impact the expression pattern of two soybean FT-like genes shown to induce flowering in Arabidopsis. AB - A small gene family of phosphatidyl ethanolamine-binding proteins (PEBP) has been shown to function as key regulators in flowering; in Arabidopsis thaliana the FT protein promotes flowering whilst the closely related TFL1 protein represses flowering. Control of flowering time in soybean [Glycine max (L.) Merrill] is important for geographic adaptation and maximizing yield. Soybean breeders have identified a series of loci, the E-genes, that control photoperiod-mediated flowering time, yet how these loci control flowering is poorly understood. The objectives of this study were to evaluate the expression of GmFT-like genes in the E1 near-isogenic line (NIL) background. Of the 20 closely related PEBP proteins in the soybean genome, ten are similar to the Arabidopsis FT protein. Expression analysis of these ten GmFT-like genes confirmed that only two are detectable in the conditions tested. Further analysis of these two genes in the E1 NILs grown under short-day (SD) and long-day (LD) conditions showed a diurnal expression and tissue specificity expression commensurate with soybean flowering time under SD and LD conditions, suggesting that these were good candidates for flowering induction in soybean. Arabidopsis ft mutant lines flowered early when transformed with the two soybean genes, suggesting that the soybean genes can complement the Arabidopsis FT function. Flowering time in E1 NILs is consistent with the differential expression of the two GmFT-like genes under SD and LD conditions, suggesting that the E1 locus, at least in part, impacts time to flowering through the regulation of soybean FT expression. PMID- 21681527 TI - Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening. AB - BACKGROUND: Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. METHODS: An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability. RESULTS: Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models. CONCLUSIONS: This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses. PMID- 21681528 TI - The success of structural genomics. AB - The International Conference on Structural Genomics (ICSG 2011, http://sgc.utoronto.ca/ICSG2011/index.php ) [corrected], held in Toronto Canada May 10-14, 2011 was a rich and exciting demonstration of how far structural genomics has come. Structural genomics has now matured into a field that includes both structure and the biology that structure enables. This has allowed targeting based on systematic approaches and on known biological importance and allows biochemical studies to be closely tied to structure determination. The wealth of purified proteins, clones, and chemical probes produced by structural genomics groups will enable a vast amount of follow-on research. The technologies, the structures, and the biology that were described at the meeting were at the cutting edge of science. Structural genomics has become a success. PMID- 21681529 TI - On labels and issues: the lysenko controversy and the cold war. PMID- 21681530 TI - Defending Scientific Freedom and Democracy: The Genetics Society of America's Response to Lysenko. AB - In the late 1940s and early 1950s, the leaders of the Genetics Society of America (GSA) struggled to find an appropriate group response to Trofim Lysenko's scientific claims and the Soviet treatment of geneticists. Although some of the leaders of the GSA favored a swift, critical response, procedural and ideological obstacles prevented them from following this path. Concerned about establishing scientific orthodoxy on one hand and politicizing the content of their science on the other, these American geneticists drew on democratic language and concepts as they engaged in this political issue. The relatively weak statements that did emerge from the GSA attracted little attention in the scientific or popular press. The intensely politicized atmosphere of American science complicated the GSA's task, as domestic concerns about protecting democracy were beginning to constrain academic freedom. In the context of American Cold War culture, Lysenko became just one example of the dangers the Cold War world presented to scientific freedom. PMID- 21681531 TI - [Headaches from an ophthalmological perspective]. AB - Headaches are a common and widespread complaint. Differential diagnostics are crucial for successful therapy and often require an interdisciplinary approach. General practitioners tend to refer patients with extraordinary types of headaches to physicians specialized in neurology, ophthalmology and otolaryngology. This article offers an overview about the range of headache disorders particularly associated with the ophthalmologic anatomy and function. PMID- 21681532 TI - Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus. AB - PURPOSE: Our intent was to identify whether cerebrovascular CO(2) reactivity in diabetic patients is a risk factor for postoperative cognitive dysfunction after coronary artery bypass graft (CABG) surgery. METHODS: One hundred twenty-four diabetic patients undergoing elective CABG were studied and analyzed. Diabetic patients were divided into three groups: normal CO(2) reactivity group (above 5%/mmHg), medium CO(2) reactivity group (between 5 and 3%/mmHg), or impaired CO(2) reactivity group (below 3%/mmHg). After the induction of anesthesia and before the start of surgery, cerebrovascular CO(2) reactivity was measured for all patients. Hemodynamic parameters (arterial and jugular venous blood gas values) were measured during cardiopulmonary bypass. All patients underwent a battery of neurological and neuropsychological tests the day before surgery, 7 days after surgery, and 6 months after surgery. RESULTS: At 7 days, the rate of cognitive dysfunction in the impaired CO(2) group was higher than in the other three groups (normal, 30%; medium, 25%; impaired, 57%; *P < 0.01 compared with the other groups). In contrast, at 6 months postoperatively, no significant difference in the rate of cognitive dysfunction was found among the three groups. Age, hypertension, CO(2) reactivity, the duration for which jugular venous oxygen saturation (SjvO(2)) was less than 50%, ascending aorta atherosclerosis, diabetic retinopathy, and insulin therapy were independent predictors of short-term cognitive dysfunction in diabetic patients, and HbA1c, diabetic retinopathy, and insulin therapy were independent predictors of long-term cognitive dysfunction in diabetic patients. CONCLUSIONS: We found that impaired cerebrovascular CO(2) reactivity was associated with postoperative short-term cognitive dysfunction in diabetic patients. PMID- 21681533 TI - Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. AB - PURPOSE: To identify the effects of adding two different doses of dexamethasone on the duration and quality of interscalene block in patients undergoing shoulder surgery in ambulatory surgery settings. METHODS: The study design was reviewed and approved by the University at Buffalo Institutional Review Board for Human Subjects. After obtaining informed consent, a total of 90 patients undergoing shoulder surgery using interscalene block with 0.5% bupivacaine (40 mL) were assigned randomly to one of three groups: control patients, "Group C," who received no additive; low dose, "Group L," who received additional dexamethasone 4 mg; and high dose, "Group H," who received dexamethasone 8 mg in addition to 0.5% bupivacaine. Postoperative analgesia was assessed using the numeric rating scores of pain and the postoperative consumption of acetaminophen 325 mg + hydrocodone 7.5 mg tablets. Analysis was by intention to treat. Statistical significance was tested using a two-way analysis of variance and a nonparametric analysis of variance for consumption of analgesics. RESULTS: Four patients were excluded from the study due to either a failed block or inadequate follow-up. The duration of analgesia was significantly prolonged in both Group L (21.6 +/- 2.4 h) and Group H (25.2 +/- 1.9 h) compared with Group C (13.3 +/- 1.0 h) (p < 0.05). Similarly, the duration of motor block was longer in both Group L (36.7 +/ 4.1 h), and Group H (39.2 +/- 3.9 h) compared to Group C (24.6 +/- 3.3 h) (p < 0.05). Postoperative analgesic consumption for the first 48 h was significantly lower in Group L (6.5 [4-8] tabs) and in Group H (5.5 [4-7] tabs) vs. 9.5 [8-12] tabs in Group C (p < 0.01). There were no adverse events related to dexamethasone during the 4-week follow-up period. CONCLUSION: The addition of dexamethasone to bupivacaine significantly prolonged the duration of the motor block and improved the quality of analgesia following interscalene block. There was no difference in the duration of analgesia and motor block between low-dose and high-dose dexamethasone. PMID- 21681534 TI - Determinants of lead exposure in children on the outskirts of Salvador, Brazil. AB - Lead (Pb) is a toxic heavy metal that is widely distributed throughout the environment. Pb is an important neurotoxic metal and children are more susceptible to its effect due to their higher absorption rate and greater susceptibility of the developing nervous system. In this work, we evaluated the lead exposure levels in children living near a metallurgical plant and identified risk factors associated with its internal dose. All children, aged 1-10 years and 11 months, living near a metallurgical plant in the great Salvador area, Brazil were evaluated in this cross-sectional study and compared with children from a non exposed area. Occipital hair and blood were used to assess exposure. Air lead levels in the respirable fraction (PM(2.5)) were also measured in both areas. Blood lead levels (BLL), hair lead levels (PbH) and air lead were determined by graphite furnace atomic absorption spectrometry. Spearman correlations analysis was used to evaluate correlations between BLL, PbH and descriptors. Significant risk factors were modeled using multivariate linear regression analysis. Air lead levels were approximately ten-folds lower than EPA reference concentration (0.15 MUg/m(3)). Median BLL and PbH were 1.65 +/- 1.45 MUg/dL and 1.26 +/- 3.70 MUg/g, respectively, in exposed children. In the referents, medians were BLL 1.20 +/- 1.20 MUg/dL; PbH 2.09 +/- 2.06 MUg/g. No significant difference was observed in biomarkers levels between boys and girls. It was observed a positive weak correlation (Spearman rho = 0.197, p = 0.033) between BLL and PbH. Our data show that children's lead body burden measured as BLL or PbH are low when compared with the recommended reference values. Despite that, we were able to identify four risk factors associated with increased biological lead levels: age, living near industrial site, environmental tobacco smoking and, above all, domestic waste burning. In order to prevent such avoidable exposure, environmental education and proper waste management should be implemented, especially in developing countries. PMID- 21681535 TI - Assessment of the effects of municipal sewage, immersed idols and boating on the heavy metal and other elemental pollution of surface water of the eutrophic Hussainsagar Lake (Hyderabad, India). AB - The surface water qualities of Hussainsagar, an eutrophic urban lake in the midst of twin cities of Hyderabad and Secunderabad (India) receiving large quantities of external inputs--both untreated municipal sewage containing industrial effluents, and treated sewage, a large number of annually immersed idols of God and Goddess, and intense boating activities were assessed in relation to the concentration of elements including heavy metals of the water along the necklace road of the lake. Elemental analyses of water using ICP-MS revealed 26 elements including heavy metals--As, Cd, Cr, Ni, Pb, Cu, Fe, Mn, Se, Ba, Zn, Mo, V, Co, Ag, Sr, Rb, Mg, K, Ca, Al, Si, Sb, Na, Li, and B, in the surface water of the lake. Of these, the first 15 elements were found in elevated concentrations in the water at the outfall point of the untreated municipal sewage (site 3), which was the main dominating source of contamination of the lake water while Cu and Sb were recorded in higher concentrations at the outfall of treated effluent from Sewage Treatment Plant, and three elements (Ba, Si, and B) were in higher concentration at the sites of outfall of sewage flowing from an oxygenated pond (site 4), Ca, Zn, and Sr, at the site immersed with idols (site 1), and Pb, Ag, and Al at the center of the lake (site 5) with intense boating activities. Concentrations of most of these elements exceeded the maximum permissible limits of national (Indian Council Medical Research) standards for drinking water. The concentrations of most of the elemental contaminants showed significant positive correlations between them. PMID- 21681536 TI - Meningioangiomatosis-associated meningioma misdiagnosed as glioma by radiologic and intraoperative histological examinations. AB - As an extremely rare condition, meningioma may occur together with meningioangiomatosis. We report here a case of meningioangiomatosis-associated meningioma misdiagnosed as glioma by preoperative radiologic and intraoperative histological examinations. A 50-year-old woman presented with a 1-year history of headache and dizziness. Magnetic resonance imaging revealed a round left temporal mass located cortically with hypointensity on T(1)-weighted images and hyperintensity on T(2)-weighted images. In the intraoperative histological examination, a diagnosis of glioma was made based on high cellularity and large tumor cells with nuclear atypia. However, postoperative histological diagnosis of the lesion was meningioangiomatosis-associated meningioma corresponding to World Health Organization (WHO) grade I. A part of the cortical lesion showed the histological features of meningioangiomatosis. Neoplastic cells in the meningioma portion were a transitional variant with immunoreactivity to epithelial membrane antigen and low MIB-1 index, up to 1%. The patient has been followed up for 6 months without adjuvant radiotherapy or chemotherapy. No tumor recurrence was found during this period. Meningioangiomatosis-associated meningioma might be erroneously interpreted as tumor invasion by those who were not familiar with this condition. Therefore, removal of sufficient tissue from different portions of the lesion is essential for the neuropathologist to make a precise diagnosis in the intraoperative histological examination. PMID- 21681538 TI - Successful deployment of an iliac limb graft to repair acute aortic rupture after balloon aortoplasty of recoarctation in a child with Turner syndrome. AB - Aortic rupture is a rare but potentially catastrophic complication following a balloon aortoplasty for recoarctation. The treatment of aortic ruptures remains challenging. We present here a 9-year-old girl with Turner syndrome who experienced a life-threatening rupture in her aorta after a balloon aortoplasty for recoarctation. She was successfully rescued by the antegrade deployment of a commercially available iliac limb extension stent-graft via an ascending aortic conduit. Prudent balloon aortoplasty for recoarctation in patients with Turner syndrome is important due to their inherent aortopathy and previous surgical repairs. Possible reasons for an aortic rupture are oversized ballooning and the choice of balloon diameter based only on an angiographic measurement. In agreement with earlier reports, our case also confirms the importance of keeping a commercially available stent graft available to treat this complication that has potentially fatal consequences. PMID- 21681539 TI - Noninvasive assessment of left ventricular contractility in pediatric patients using the maximum rate of pressure rise in peripheral arteries. AB - The maximum rate of left ventricular pressure rise (LV dp/dt(max)) is a good indicator of ventricular contractility. However, its measurement requires invasive cardiac catheterization. By applying the relationship between the ratio of aorta (Ao) dp/dt(max) to LV dp/dt(max) and the mean artery pressure (MAP), we tested the possible noninvasive estimation of LV dp/dt(max) by the maximum rate of pressure rise in peripheral arteries, as measured by tonometry. The study subjects were 31 children with cardiovascular disease. The LV and Ao pressures were measured during cardiac catheterization, with simultaneous recording of the brachial (BrA) or radial (RaA) artery pressure. The relationships between BrA dp/dt(max) and Ao dp/dt(max) and between RaA dp/dt(max) and Ao dp/dt(max) were determined (Ao dp/dt(max) = 0.299 * BrA dp/dt(max) + 210.6, n = 17, r = 0.78, SEE = 74.0, P = 0.0002, and Ao dp/dt(max) = 1.442 * RaA dp/dt(max) + 165.9, n = 14, r = 0.87, SEE = 66.1, P = 0.0001). Using these relationships and the equation Ao dp/dt(max)/LV dp/dt(max) = 0.694 - 4.00 * 10(-3) * MAP, LV dp/dt(max) was estimated from BrA dp/dt(max) or RaA dp/dt(max). The estimated LV dp/dt(max) correlated well with the measured LV dp/dt(max) independent of the site of measurement (y = 0.912 * x + 112.9, r = 0.91, P < 0.0001). Furthermore, there was excellent correlation between the measured and estimated LV dp/dt(max) after changes in contractility with dobutamine in 10 randomly selected patients (y = 0.86 * x + 34.2, r = 0.77, P = 0.01). It is possible to estimate LV dp/dt(max) noninvasively in children using tonometry. This procedure can be useful for bedside assessment of LV contractility and the clinical management of patients with cardiovascular disease. PMID- 21681540 TI - [Symmetrically enlarging pigmented lesion in an adolescent]. AB - A 16-year-old boy with multiple nevi presented with an enlarging pigmented lesion on his right chest. Previously excised nevi were all benign. Dermoscopy of the symmetrical lesion revealed a trizonal globular-homogeneous pattern. A peripheral rim of brown globules was followed by a zone with homogeneous pigmentation. The centre of the lesion showed black dots and globules. Histopathology confirmed a dysplastic compound nevus and found no diagnostic aspects of pigmented spindle cell nevus (Reed). PMID- 21681541 TI - [Giant papillomas of the tongue and pharynx in focal dermal hypoplasia: a case report]. AB - Focal dermal hypoplasia is a rare congenital syndrome with dominant X-linked mode of inheritance characterized by a wide range of meso-ectodermal anomalies. The clinical variation is great, as explained by the Lyon hypothesis and mosaicism. Findings include skin atrophy along the lines of Blaschko and papillomas. Our case is striking with rapidly-growing giant pharyngeal papillomas which caused dysphagia and required resection. PMID- 21681542 TI - [Molecular etiology of skin aging. How important is the genetic make-up?]. AB - Although the fundamental mechanisms in the pathogenesis of skin aging are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways. Recent data obtained by expression profiling studies and studies upon progeroid syndromes illustrate that among the most important biological processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, extracellular matrix, lipid synthesis, ubiquitin-induced proteolysis and cellular metabolism. One of the major factors which have been proposed to play an exquisite role in the initiation of aging is the physiological decline of hormones occurring with age. However, hormones at age-specific levels may not only regulate age associated mechanisms but also modulate tumor suppressor pathways that influence carcinogenesis. In conclusion, understanding the molecular mechanisms of ageing may open new strategies to deal with the various diseases accompanying advanced age including cancer. PMID- 21681543 TI - [Role of the extracellular matrix in extrinsic skin aging]. AB - Photoaged skin is clinically characterized by wrinkling, laxity and a leather like appearance. These symptoms of actinic aging are causally connected to histological and ultrastructural changes of the connective tissue of the dermis. Changes include both enzymatic degradation and reduced de novo synthesis of collagen which cause premature wrinkling of the skin. Changes in the hyaluronan and proteoglycan matrix lead to reduced water content and thereby increased laxity of the skin. Furthermore, the UV-induced remodeling of the extracellular matrix strongly affects the cellular phenotypes such as the regenerative capacity of dermal fibroblasts. In recent years considerable progress has been made towards the understanding of molecular and cellular mechanisms underlying the UV induced changes of the extracellular matrix. Current findings in this field reveal interesting insights in the dermal aging and provide new targets and strategies for the treatment of photoaging. PMID- 21681544 TI - [Diabetic foot syndrome]. AB - Diabetic foot syndrome is a major complication for patients with diabetes mellitus. About 25% of the 6 million patients with diabetes in Germany will suffer from diabetic foot syndrome at some point during the course of disease. Diabetic neuropathy and peripheral vascular disease are the main causative factors in the pathogenesis of diabetic foot ulcers. The mortality rate of these patients is more than twice as high as that of the average population. 25% of costs incurred by patients with diabetes are spent on diabetic foot ulcers, and 50% of hospital days are attributed to the treatment of the diabetic foot syndrome. This syndrome is also the most common cause of non-traumatic amputations. Both the risk of amputation and mortality are much increased in case of peripheral vascular disease. Hence, the aim is to lower the still high number of amputations in Germany by appropriate preventive measures as well as by multidisciplinary diagnostics and therapy. PMID- 21681545 TI - [Calciphylaxis. Pathogenesis and therapy]. AB - Calciphylaxis is a rare disease associated with thrombotic cutaneous ischemia and necrosis. Lesions are usually located on the lower extremities, buttocks and the abdomen. Calciphylaxis is recognized by medial calcification, inflammation and subintimal fibrosis of cutaneous arterioles. Calcification, thrombus formation and occlusion occur sequential before tissue necrosis. The disease is usually observed in patients with end-stage renal disease and hyperparathyroidism. In end stage renal disease, an elevated parathyroid hormone level, hypercalcemia and hyperphosphatemia direct to vascular mineralization. Calciphylaxis affects about 4% of hemodialysis patients. The clinical syndrome is characterized by a high mortality rate. The most important measure is an active multidisciplinary management approach, with intention to wound care and prevention of sepsis. PMID- 21681546 TI - Obesity but not overweight is associated with increased mortality risk. AB - The association between body mass index (BMI) and survival has been described in various populations. However, the results remain controversial and information from low-prevalence Western countries is sparse. Our aim was to examine this association and its public health impact in Switzerland, a country with internationally low mortality rate and obesity prevalence. We included 9,853 men and women aged 25-74 years who participated in the Swiss MONICA (MONItoring of trends and determinants in CArdiovscular disease) study (1983-1992) and could be followed up for survival until 2008 by using anonymous record linkage. Cox regression models were used to calculate mortality hazard ratios (HRs) and to estimate excess deaths. Independent variables were age, sex, survey wave, diet, physical activity, smoking, educational class. After adjustment for age and sex the association between BMI and all-cause mortality was J shaped (non-smokers) or U shaped (smokers). Compared to BMI 18.5-24.9, among those with BMI >= 30 (obesity) HR for all-cause mortality was 1.41 (95% confidence interval: 1.23 1.62), for cardiovascular disease (CVD) 2.05 (1.60-2.62), for cancer 1.29 (1.04 1.60). Further adjustment attenuated the obesity-mortality relationship but the associations remained statistically significant. No significant increase was found for overweight (BMI 25-29.9). Between 4 and 6.5% of all deaths, 8.8-13.7% of CVD deaths and 2.4-3.9% of cancer deaths could be attributed to obesity. Obesity, but not overweight was associated with excess mortality, mainly because of an increased risk of death from CVD and cancer. Public health interventions should focus on preventing normal- and overweight persons from becoming obese. PMID- 21681547 TI - Fetal growth, early life circumstances, and risk of suicide in late adulthood. AB - Recent studies in Sweden and Scotland have found early life conditions to be associated with increased risk of attempted and completed suicide in adolescence and young adulthood. It is not known, however, whether early life conditions affect suicide risk throughout the life course, from adulthood into old age. We examined the effects of early life conditions, including markers of fetal growth, and social and economic characteristics in adulthood, on risk of suicide by violent and non-violent methods in women and men aged 31-87 years using Cox regression. 11,650 women and men born at the Uppsala University Hospital in Sweden between 1915 and 1929 were followed from 1960 until 2002 using linked records from obstetric archives, Census, population and mortality registries. During 435,039 person-years of follow-up 161 completed suicides (104 in males, 57 in females) were observed. An inverse association was found between lower birthweight-for-gestational age and risk of violent suicide in females, although the association did not reach the conventional level of statistical significance (minimally adjusted HR 2.02, 95% CI (0.88-4.63); Table 4). Being male, unmarried, and in the "other or unknown" social class category in adulthood were independently associated with increased rates of suicide. There was a weak association between higher maternal parity and suicide rates. Our findings suggest differences in effects of fetal growth patterns and perinatal circumstances on suicide risk later in life, and suggest that suicide in adults and in the elderly may be influenced by a different combination of factors than those that influence suicide in adolescence and young adulthood. PMID- 21681550 TI - Coll2-1, Coll2-1NO2 and myeloperoxidase concentrations in the synovial fluid of equine tarsocrural joints affected with osteochondrosis. AB - The measurement of biomarkers that reflect cartilage breakdown is a powerful tool for investigating joint damage caused by disease or injury. Particularly in cases of osteochondrosis, synovial concentrations of these biomarkers may reveal the presence of osteoarthritic changes. Coll2-1, Coll2-1 NO2 and myeloperoxidase have recently been introduced in equine osteoarticular research but comparison between the concentrations of these markers in OCD affected and healthy joints has not been made. Therefore, this study aimed at reporting the synovial concentrations of these biomarkers in joints affected with osteochondral fragments in the tarsocrural joint compared to unaffected joints. Myeloperoxidase and Coll2-1NO2 revealed to have similar levels between affected joints and controls. However, in contrast to previous studies using C2C the present study demonstrated that synovial levels of Coll2-1 were significantly elevated in tarsocrural joints affected with osteochondrosis. Thus, Coll2-1 may be an earlier marker of cartilage degeneration than other cartilage degradation markers that have been previously used in equine medicine. PMID- 21681549 TI - Selection of suitable reference genes for quantitative real-time PCR in apoptosis induced MCF-7 breast cancer cells. AB - Apoptosis is induced in MCF-7 breast cancer cells following treatment with salicylic acid (20 mM), either in the presence or absence of a heat shock (42 degrees C for 30 min). In order to study the alterations of apoptotic genes with quantitative real-time PCR (qPCR), suitable genes with unchanged expression following the treatments is required for normalizing the gene expression levels. In this study, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin (ACTB), Histone H2A (HIST), constitutively expressed heat shock protein 70 (HSC70) and tyrosine 3-monooxygenase/trytophan 5 monooxygenase activation protein, 14-3-3 (YWHAZ) were evaluated as appropriate reference genes. Analysis of gene expression data with one-way ANOVA, geNorm and NormFinder identified HIST and YWHAZ as the least affected during the induction of apoptosis by the different treatments, and is the most suitable gene-pair for normalization during qPCR analysis in MCF-7 breast cancer cells undergoing apoptosis following treatment with SA and/or HS. PMID- 21681551 TI - The identification and management of hereditary diffuse gastric cancer in a large Jordanian family. AB - The management of families with hereditary diffuse gastric cancer is challenging as screening for cancer in CDH1 mutation carriers is insufficiently sensitive and the commonly recommended option, prophylactic total gastrectomy, is associated with certain morbidity and even potential mortality. We describe the particular challenges associated with the diagnosis and management of a large Jordanian family with hereditary diffuse gastric cancer. A preliminary pedigree enabled DNA testing for CDH1 mutation, denoted as c.1137G -> A, on 4 family members; all were identified as mutation carriers. A family information service was then conducted in Amman, Jordan, where 40 family members gathered and we provided education and counseling. Signed permission enabled DNA collection for CDH1 germline mutation studies. Non-attendees were contacted and provided detailed information. Twenty three family members have been tested for CDH1; 13 were positive and 10 were negative. The proband, a CDH1 mutation carrier, has undergone successful prophylactic total gastrectomy. We are hopeful that this model can be repeated throughout Jordan as well as other emerging countries where knowledge and action about hereditary cancer is lacking. PMID- 21681552 TI - Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals. AB - Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron-exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations. PMID- 21681553 TI - Communication of BRCA1 and BRCA2 genetic test results to health care providers following genetic testing at a tertiary care center. AB - Individuals at high risk for hereditary cancers often receive genetic counseling and testing at tertiary care centers; however, they may receive care for long term management of their cancer risk in community settings. Communication of genetic test results to health care providers outside of tertiary care settings can facilitate the long-term management of high risk individuals. This study assessed women's communication of BRCA1/BRCA2 genetic test results to health care providers outside of tertiary care settings (termed "outside" health care providers, or OHCPs) and women's perceptions regarding communication of results. Women (n = 312) who underwent BRCA1/BRCA2 genetic counseling and testing completed a questionnaire assessing whether or not they shared test results with OHCPs and perceptions regarding the communication of test results to OHCPs. Most (72%) shared genetic test results with OHCPs. Women with no personal history of cancer were more likely to have shared results compared to women with a personal history of cancer. Mutation status did not significantly predict sharing of genetic information. Most reported positive perceptions regarding the disclosure of genetic test results to OHCPs. The majority did not report any concerns about potential insurance discrimination (88%) and indicated that OHCPs were able to appropriately address their questions (81%). Although most women shared their genetic test results with OHCPs, those with a personal history of cancer may need further encouragement to share this information. Tertiary care centers should facilitate outreach and education with OHCPs in order to assure appropriate long term cancer risk management for high risk populations. PMID- 21681555 TI - PET imaging for prediction of response to therapy and outcome in oesophageal carcinoma. PMID- 21681554 TI - Application of shape-based and pharmacophore-based in silico screens for identification of Type II protein kinase inhibitors. AB - The identification of new, potent and selective inhibitors of important protein kinase targets is a major goal of drug discovery. Here we analyze the crystal structures of 55 protein kinase complexes with Type II inhibitors and find they adopt a conserved twisted V-shape, with an angle of 121 +/- 8 degrees and twist of 78 +/- 8 degrees . The tightly conserved twist appears important in ensuring ligands curve around the protein backbone and towards the deep pocket. From this, we develop predictive pharmacophore- and shape-based screens to identify Type II inhibitors from a database which also contains Type I inhibitors as decoys. Both approaches exhibit a good level of discrimination for Type II molecules. The most effective pharmacophore model requires six features and three excluded volume regions. Shape-based screening using ROCS generally performs at least as well as pharmacophore approaches. There is only a moderate dependence of shape-based or pharmacophore-based screens on the underlying conformer generator (MOE, Macromodel, Omega and SPE), as well as on ligand linkage chemistry (amide and urea). Finally, we apply our approach to retrieval of Type II inhibitors from a modified version of the DUD database, containing over 104,000 compounds. We observe good enrichment, providing further evidence that the in silico screens developed here will constitute useful guides for identification of small molecule inhibitors targetting protein kinases in their inactive conformational state. PMID- 21681556 TI - Production of gamma-linolenic acid using a novel heterologous expression system in the oleaginous yeast Lipomyces kononenkoae. AB - A novel expression system was established in the oleaginous yeast, Lipomyces kononenkoae. The expression vector pLK-rhPHG of L. kononenkoae was constructed and using the hygromycin phosphotransferase gene and green fluorescent protein gene as reporter genes. A delta 6-fatty acid desaturase gene (D6DM) from Cunninghamella echinulata MIAN6 was then expressed in this strain. The recombinant strain accumulated about 1.2% gamma-linolenic acid in the total fatty acids. PMID- 21681557 TI - Alterations in serotonin receptors and transporter immunoreactivities in the hippocampus in the rat unilateral hypoxic-induced epilepsy model. AB - Unilateral hypoxic-ischemia results in the frequent occurrence of interictal spikes, and occasionally sustained ictal discharges accompanied by a reduction in paired-pulse inhibition within the non-lesioned dentate gyrus. To elucidate the roles of serotonin (5-hydroxytryptamine [5-HT]) in an epileptogenic insult, we investigated the changes in 5-HT receptors and serotonin transporter (5-HTT) immunoreactivities within the lesioned and contralateral hippocampus following unilateral hypoxic-ischemia. During epileptogenic periods following hypoxic ischemia, both 5-HT(1A) and 5HT(1B) receptor immunoreactivities were decreased within the lesioned and the non-lesioned hippocampus. However, 5-HTT immunoreactivity was transiently increased within the hippocampus bilaterally. These findings indicate that alteration of the 5-HT system results in a "diaschisis" pattern, and may contribute to neuronal death and the development of emotional disorders in epileptic patients accompanied by psychological stress. PMID- 21681558 TI - Adenoviral astrocyte-specific expression of BDNF in the striata of mice transgenic for Huntington's disease delays the onset of the motor phenotype. AB - Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. The most characteristic structural feature of this disease is neurodegeneration accompanied by gliosis in the striatum. BDNF has been proposed to protect striatal neurons from degeneration, because it is an important survival factor for these neurons from development to adulthood. Considering the extensive gliosis and the survival effects of BDNF, we constructed an adenovirus to express a BDNF cDNA in astrocyte cells using a promoter of the glial fibrillary acidic protein gene. Cells stably transfected in vitro with a BDNF cDNA driven by this promoter expressed BDNF and responded to external stimuli increasing BDNF production. When the vector was applied into the striata of mice transgenic for HD, long-term expression of the transgene was observed, associated with a delay of onset of the motor phenotype of the R6/2 HD transgenic mice. The present data indicate that the striatal expression of BDNF is a potential adjuvant for the treatment of HD. PMID- 21681559 TI - A role for hypothalamic AMP-activated protein kinase in the mediation of hyperphagia and weight gain induced by chronic treatment with olanzapine in female rats. AB - Olanzapine is known to be advantageous with respect to outcome and drug compliance in patients with schizophrenia. However, olanzapine has adverse effects, including a higher incidence of weight gain and metabolic disturbances, when compared with those of other antipsychotic agents. The mechanisms underlying these adverse events remain obscure. Female rats were orally administered olanzapine (2 mg/kg) or vehicle once a day for 2 weeks to ascertain if hypothalamic AMP-activated protein kinase (AMPK) mediates olanzapine-induced weight gain and hyperphagia. Body weight and food intake in each rat were evaluated every day and every two days, respectively. After the termination of drug treatment, we measured the protein levels of AMPK and phosphorylated AMPK in the hypothalamus using western blot analyses. Olanzapine significantly increased body weight and food intake. The phosphorylation levels of AMPK were significantly elevated by olanzapine. These results suggest that activation of hypothalamic AMPK may mediate hyperphagia and weight gain induced by chronic treatment with olanzapine. PMID- 21681560 TI - Fatty acid status determination by cheek cell sampling combined with methanol based ultrasound extraction of glycerophospholipids. AB - Tissue and blood fatty acid compositions are used as biological markers of fatty acid intakes to improve dietary assessments. These approaches are invasive and not well accepted, particularly in infants and young children. We developed a sensitive method for the analysis of fatty acids in cheek cell glycerophospholipids, which includes significant improvements of cell sampling, non-chromatographic isolation of glycerophospholipids and base-catalyzed synthesis of fatty acid methyl esters. Sphingophospholipids are not detected by this method. This enables a highly accurate determination of cheek cell glycerophospholipid fatty acids, even if cell numbers are limited. Coefficients of variation for fatty acids contributing more than 0.3% to total glycerophospholipid fatty acids are below 10% in samples with more than 10(5) cells. Good correlations were shown between docosahexaenoic and eicosapentaenoic acid percentages in cheek cell and plasma glycerophospholipids (r = 0.83 and 0.64, respectively; P < 0.001) with a linear relationship over the whole concentration range observed in adult study participants (n = 29). Cheek cell sampling is non-invasive and can easily be applied in infants. The accuracy and reliability of this new method is comparable to conventional invasive methods for the determination of the n-3 fatty acid status in humans, and it is well applicable in interventional or epidemiological studies. PMID- 21681561 TI - Global mental health as a component of psychiatric residency training. AB - This study seeks to assess the educational value of an international psychiatry elective using a cross section of psychiatric residents. In 2010, a 10-item semi structured questionnaire was administered to Mount Sinai psychiatric residents who have participated in the Global Health Residency Track of the Mount Sinai School of Medicine. Authors reviewed the qualitative data and arrived at a consensus regarding trends and deviations regarding residents' experiences of their international field work. Six residents participated in this study. Common themes included exposure to sicker, treatment-naive patients in resource scarce conditions, enhancement of cross-cultural communications skills, renewed appreciation for psychiatry, empowerment as teachers, and greater awareness of health-care systems. Knowing that an international elective existed would be a significant factor in their choice of residency. Respondents had concerns for the sustainability. Participants felt that the elective was a place to consolidate skills already learned during residency and resulted in increased professional confidence although it did not necessarily alter career paths. International electives can enrich psychiatric residency training in terms of understanding of mental health care systems, cross cultural psychiatry, sharpening diagnostic skills, building professional confidence and communication skills, and reaffirming motivation to practice psychiatry. PMID- 21681562 TI - A protective effect of circumcision among receptive male sex partners of Indian men who have sex with men. AB - The role of circumcision in the transmission of human immunodeficiency virus (HIV) among men who have sex with men (MSM) in resource restricted regions is poorly understood. This study explored the association of circumcision with HIV seroprevalence, in conjunction with other risk factors such as marriage and sex position, for a population of MSM in India. Participants (n = 387) were recruited from six drop-in centers in a large city in southern India. The overall HIV prevalence in this sample was high, at 18.6%. Bivariate and multivariable analyses revealed a concentration of risk among receptive only, married, and uncircumcised MSM, with HIV prevalence in this group reaching nearly 50%. The adjusted odds of HIV infection amongst circumcised men was less than one fifth that of uncircumcised men [adjusted odds ratio (AOR) 0.17; 95% CI 0.07-0.46; P < 0.001]. Within the group of receptive only MSM, infection was found to be lower among circumcised individuals (AOR, 0.30, 95% CI 0.12-0.76; P < 0.05) in the context of circumcised MSM engaging in more UAI, having a more recent same sex encounter and less lubricant use when compared to uncircumcised receptive men. To further explain these results, future studies should focus on epidemiologic analyses of risk, augmented by social and sexual network analyses of MSM mixing. PMID- 21681563 TI - A comparison of the efficacy of two interventions to reduce HIV risk behaviors among drug users. AB - Numerous interventions have been developed and implemented to decrease risk behaviors which lead to HIV infection and transmission. These interventions have been differentially successful in reducing high risk behaviors in various populations. Testing and evaluation of the interventions have been subject to various degrees of rigor. The CDC recommends the use of interventions which have been rigorously tested and meet the standards for evidence based intervention rather than the continuation of the development of new interventions. Project RESPECT is an evidence based intervention that proved efficacious in increasing condom use among patients of STD clinics. We tested the efficacy of the RESPECT intervention against the NIDA standard intervention to determine if the RESPECT intervention was more effective in reducing high risk behaviors among drug users. Both interventions showed changes from baseline to follow-up; RESPECT was more effective than the NIDA standard intervention in reducing high risk sex behaviors. PMID- 21681564 TI - Measuring engagement at work: validation of the Chinese version of the Utrecht Work Engagement Scale. AB - BACKGROUND: Work engagement is a positive work-related state of fulfillment characterized by vigor, dedication, and absorption. Previous studies have operationalized the construct through development of the Utrecht Work Engagement Scale. Apart from the original three-factor 17-item version of the instrument (UWES-17), there exists a nine-item shortened revised version (UWES-9). PURPOSE: The current study explored the psychometric properties of the Chinese version of the Utrecht Work Engagement Scale in terms of factorial validity, scale reliability, descriptive statistics, and construct validity. METHOD: A cross sectional questionnaire survey was conducted in 2009 among 992 workers from over 30 elderly service units in Hong Kong. RESULTS: Confirmatory factor analyses revealed a better fit for the three-factor model of the UWES-9 than the UWES-17 and the one-factor model of the UWES-9. The three factors showed acceptable internal consistency and strong correlations with factors in the original versions. Engagement was negatively associated with perceived stress and burnout while positively with age and holistic care climate. CONCLUSION: The UWES-9 demonstrates adequate psychometric properties, supporting its use in future research in the Chinese context. PMID- 21681565 TI - Kinetics of circulating Th17 cytokines and adipokines in psoriasis patients. AB - Psoriasis is associated with an increase of Th17 cytokines, such as IL-17, IL-22, IL-21, and TNF-alpha, which are produced by Th17 cells. Adipokines are peptide hormones or cytokines secreted from adipose tissues and involved in the pathogenesis of metabolic syndrome (MS). Psoriasis patients have a high prevalence of the MS. In this study, we investigated the statistics of circulating Th17-related cytokines and adipokines in psoriasis patients. Our study identified the significant elevation of serum IL-6, IL-21, IL-22, and resistin levels in psoriasis patients. Increased serum levels of IL-22 and adiponectin were positively correlated with Psoriasis Area and Severity Index (PASI). In contrast, serum high molecular weight adiponectin levels were decreased in psoriasis and negatively correlated with PASI. PMID- 21681566 TI - Evolution of dispersal distance. AB - The problem of how often to disperse in a randomly fluctuating environment has long been investigated, primarily using patch models with uniform dispersal. Here, we consider the problem of choice of seed size for plants in a stable environment when there is a trade off between survivability and dispersal range. Ezoe (J Theor Biol 190:287-293, 1998) and Levin and Muller-Landau (Evol Ecol Res 2:409-435, 2000) approached this problem using models that were essentially deterministic, and used calculus to find optimal dispersal parameters. Here we follow Hiebeler (Theor Pop Biol 66:205-218, 2004) and use a stochastic spatial model to study the competition of different dispersal strategies. Most work on such systems is done by simulation or nonrigorous methods such as pair approximation. Here, we use machinery developed by Cox et al. (Voter model perturbations and reaction diffusion equations 2011) to rigorously and explicitly compute evolutionarily stable strategies. PMID- 21681567 TI - Protective effect of soy protein on collagen-induced arthritis in rat. AB - To evaluate preventive and therapeutic effects of soy protein on collagen-induced arthritis rats. Sprague-Dawley rats immunized with bovine type II collagen emulsified in adjuvant and treated with soy protein (7 g/kg), dexamethasone (1 mg/kg), and casein (in control groups) by daily gavages feedings for 30 days. Score of arthritis recorded every day for each paws of animal. Tumor necrosis factor-alpha, interleukin6, leptin, and adiponectin were measured in serums. Treatment with soy protein resulted in significant delay in time to onset of arthritis as well as significantly decreased arthritis incidence, clinical arthritis severity score, histopathological arthritis severity score, and in vivo cell-mediated immunity to collagen (P < 0.05). Administration of soy protein significantly suppressed the progression of collagen II-induced arthritis and inhibited the production of tumor necrosis factor-alpha, interleukin6, leptin, and adiponectin. Soy protein appeared to be a potent immunomodulatory inhibitor of collagen II-induced arthritis in rats. It could delay onset of RA and reduced cartilage erosion and synovitis inflammation. Therefore, it may be a useful protein in the prevention and treatment of rheumatoid arthritis patient. PMID- 21681568 TI - The effects of NSAIDs on types I, II, and III collagen metabolism in a rat osteoarthritis model. AB - The effects of long-term use of celecoxib, ibuprofen, and indomethacin on types I, II, and III collagen metabolism were evaluated in rat osteoarthritis (OA) model. One hundred and thirty wistar rats were randomly divided into 4 groups: the celecoxib group, the ibuprofen group, the indomethacin group, and the normal saline group. The osteoarthritis was induced by the excision of the left Achilles tendon. In the 3rd, 6th, and 9th month of treatment after surgically induced osteoarthritis, the articular cartilage was observed with microscope using HE staining. The expression of proteoglycans was semiquantified using toluidine blue staining. And, the expressions of types I, II, and III collagen in chondrocytes were examined using immunohistochemistry. The results suggested that celecoxib had no remarkable effects on the expression of types I, II, and III collagen. Ibuprofen upgraded the expression of types I, II, and III collagen and increased the synthesis of collagen. Indomethacin suppressed the expression of type II collagen and enhanced the expression of types I and III collagen. Therefore, during the long-term use of NSAIDs in osteoarthritis, celecoxib may have no remarkable influences on collagen metabolism of the articular cartilage and may be the ideal choice in the treatment of chronic destructive joint disease when anti-inflammatory drugs need to be used for a prolonged period. Ibuprofen may be unfavorable, and indomethacin may be harmful to collagen metabolism in OA treatment. PMID- 21681569 TI - The evolving management of laryngeal neuroendocrine carcinomas. PMID- 21681570 TI - Vestibular function in Lermoyez syndrome at attack. AB - Lermoyez syndrome (LS) has been regarded as a variant of Meniere's disease (MD), but so far there have been very few cases of LS reported in the literature, so such a conclusion is debatable. Specifying the pattern of auditory and vestibular changes at attack using objective quantitative measures is important for understanding the mechanism responsible for MD and LS. Here we report the first objective measures of dynamic otolith function and dynamic semicircular canal function in an LS patient at the time of the attack as well as at quiescence, documenting the fluctuation in otolith and semicircular canal function in the patient. The very rapid changes in dynamic vestibular function at the time of the LS attack appear to complement some of the rapid changes in auditory and vestibular function at the attack in Meniere's disease, supporting the contention that LS is a variant of MD. PMID- 21681571 TI - Myringotomy and ventilation tube insertion with minims tetracaine drops. AB - We present a novel and safe technique for insertion of ventilation tubes under local anaesthetic which we feel improves the patient's experience and shortens the overall procedural time. PMID- 21681572 TI - Montelukast attenuates side effects of cisplatin including testicular, spermatological, and hormonal damage in male rats. AB - In the current study, the protective effect of montelukast (ML) on cisplatin induced reproductive toxicity in rats was investigated. Twenty-eight rats were equally divided into four groups; first group was kept as control. In the second group, ML was orally administered at the dose of 10 mg/kg/day for 10 days. In the third group, CP was intraperitoneally administered at the dose of 7 mg/kg a single injection, and in fourth group, CP and ML were given together at the same doses. Although CP induced oxidative stress via significant increase in the formation of TBARS, it caused a significant decline in the levels of GSH, CAT, GPx, and SOD in rats. In contrast, ML prevents these effects of CP through cause an increase in GSH, CAT, GPx, and SOD levels and a decrease in formation of TBARS. In addition, sperm motility and serum testosterone levels significantly decrease and histopathological damage increases with CP treatment. However, the effects of CP on sperm motility, serum testosterone level, oxidative and histopathological changes are eliminated by ML treatment. In conclusion, the current study demonstrated that the reproductive toxicity caused by CP may be prevented by ML treatment. Thus, it was judged that co-administration of ML with CP may be useful to attenuate the negative effects of CP on male reproductive system. PMID- 21681573 TI - Efficacy of increased-dose erlotinib for central nervous system metastases in non small cell lung cancer patients with epidermal growth factor receptor mutation. AB - PURPOSE: Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. We describe a Japanese woman with NSCLC and CNS metastases who was resistant to 75 mg daily erlotinib, but the metastases were improved by 150 mg daily erlotinib. We investigated the plasma and CSF concentrations of erlotinib at each dose as well as the correlation between the plasma and CSF concentrations of erlotinib. METHODS: Including this patient, we administered 150 mg erlotinib daily to nine NSCLC patients with CNS metastases and measured the plasma and CSF concentrations just before administration on day 8. The concentrations were determined using high-performance liquid chromatography with ultraviolet detection. RESULTS: The plasma and CSF concentrations of erlotinib at a dose of 75 mg were 433 and 14 nM, respectively. The plasma and CSF concentrations of erlotinib at a dose of 150 mg were increased to 1,117 and 44 nM, respectively. The mean +/- standard deviation of CSF concentrations and penetration rates were 106 +/- 59 nM and 4.5 +/- 1.5%, respectively. There was a good correlation (R(2) = 0.84) between plasma and CSF concentrations (P = 0.0005). CONCLUSIONS: This study indicates that CSF concentrations of erlotinib depend on its plasma concentration. As seen in this patient, high CSF concentrations of erlotinib can be achieved by high-dose administration, and this finding suggests the efficacy of high-dose administration, especially to refractory CNS metastases of NSCLC patients. PMID- 21681574 TI - Percutaneous local ablation of unifocal subclinical breast cancer: clinical experience and preliminary results of cryotherapy. AB - OBJECTIVES: To assess the ablative effectiveness, the oncological and cosmetic efficacy of image-guided percutaneous cryoablation in the treatment of single breast nodules with subclinical dimensions after identification with ultrasonography (US), mammography, magnetic resonance (MRI) and characterization by vacuum assisted biopsy. MATERIALS: Fifteen women with a mean age of 73 +/- 5 years (range 64-82 years) and lesion diameter of 8 +/- 4 mm were undergoing cryotherapy technology with a single probe under US-guidance associated with intra-procedural lymph-node mapping and excision of the sentinel node. All the patients underwent surgical resection (lumpectomy) from 30 to 45 days after the percutaneous ablation. RESULTS: The iceball size generated by the cryoprobe during the procedure at minus 40 degrees C was 16 * 41 mm. In 14 of the 15 patients was observed a complete necrosis of the cryo-ablated lesion both in post procedural MRI follow-up and anatomo-pathological evaluation after surgical resection. In one case there was a residual disease in post-procedural MRI and postoperative histological examination, probably justified by an incorrect positioning of the probe. CONCLUSION: The percutaneous cryoablation as a "minimally invasive" technique can provide excellent oncological and cosmetic results on selected cases handled by experienced operators by using the tested devices. PMID- 21681575 TI - Comment on Cho et al.: Usefulness of FDG PET/CT in determining benign from malignant endobronchial obstruction. PMID- 21681576 TI - Genetic structure of Indian valerian (Valeriana jatamansi) populations in western Himalaya revealed by AFLP. AB - Valeriana jatamansi Jones is a natural tetraploid species indigenous to the Indian Himalaya. To assess its genetic diversity and population structure, we analyzed six natural populations from the western Himalayan region using amplified fragment length polymorphism. An analysis of molecular variance found that 93% of the genetic variation of V. jatamansi was within populations and 7% among populations. The correlation between genetic and geographic distances (r = 0.14) was not significant. Though the populations are well separated, the lack of distinct genetic variation between populations may be due to either recent rapid fragmentation from a wide and continuous area resulting in genetically similar populations or wide dispersal of seed by wind, since the follicles are feathery. Polyploidy may be the reason for the lack of genetic impoverishment due to fragmentation. PMID- 21681577 TI - FAD2 gene mutations significantly alter fatty acid profiles in cultivated peanuts (Arachis hypogaea). AB - A panel of 55 peanut lines was analyzed for fatty acid composition with gas chromatography and also genotyped with SNP markers from the FAD2 genes by real time PCR. Significant variation in fatty acid composition was identified, and the ratio of oleic acid to linoleic acid (O/L) ranged from 1.23 to 56.45. In terms of the FAD2 gene mutation, the assayed lines were classified into four genotypes: wild type (Ol(1)Ol(1)Ol(2)Ol(2)), single functional homozygous mutation on the A genome (ol(1)ol(1)Ol(2)Ol(2)), single functional homozygous mutation on the B genome (Ol(1)Ol(1)ol(2)ol(2)), and a double mutation on both A and B genomes (ol(1)ol(1)ol(2)ol(2)). Each genotype has a significantly different fatty acid profile. Both FAD2A and FAD2B are involved in the conversion of oleic acid to linoleic acid in peanuts. Overall, these results demonstrate the combined power of genetic analysis with biochemical analysis on peanut fatty acid research. PMID- 21681578 TI - An efficient DNA extraction method for desert Calligonum species. AB - Genetic conservation programs in arid environments rely on molecular methods for diversity assessments. DNA-based molecular profiling will aid in conservation and protection of species from genetic erosion. Obtaining intact genomic DNA from Calligonum species, of sufficiently high-quality that is readily amplifiable using PCR, is challenging because of the presence of the exceptionally large amount of oxidized polyphenolic compounds, polysaccharides, and other secondary metabolites. The present method involves a modification of the available CTAB method employing higher concentrations of NaCl and CTAB, and incorporating PEG 6000 (1%) and glucose. The yield of DNA was 60-670 MUg g(-1) of fresh tissue. The protocol has been tested with two species from the arid region. The DNA isolated was successfully amplified by two ITS primer pairs. PCR-RFLP analysis of the ITS1 5.8S-ITS2 region among and within Calligonum species followed by sequencing is under way. PMID- 21681579 TI - Remodeling of inward rectifying K(+) currents in rat atrial myocytes by overexpression of A(1)-adenosine receptors. AB - In rat atrial myocytes GIRK (Kir3) channels can be activated by acetylcholine and adenosine via M(2) and A(1) receptors coupled to Pertussis-toxin-sensitive G proteins, such as M(2)R or A(1)R. Owing to the lower density of A(1)R, the amplitude of current activated by a saturating concentration (10 MUM) of Ado (I(K(Ado))) amounts to about 40% of maximum I(K(ACh)). Adenovirus-driven overexpression of A(1)R results in an increase in I(K(Ado)). In a fraction of A(1)R-overexpressing cells, both ACh and Ado failed to activate GIRK channels. These cells had a large constitutive Ba(2+)-sensitive inward rectifying background K(+) current, which was insensitive to the GIRK channel inhibitor tertiapin (200 nM), suggesting this current component to be carried by I(K1) (Kir) channels. This effect of A(1)R overexpression was reduced by treatment (48 h) with the A(1)R antagonist DPCPX. siRNA-mediated knockdown of Kir2.1, simultaneously with A(1)R overexpression, substantially reduced I(K1). The mechanisms underlying the upregulation of functional I(K1) channels involve activation of the phosphatidylinositol 3-kinase (Pi3K)/Akt (protein kinase B) pathway. Kir2.1 transcripts are not increased in myocytes overexpressing A(1)R. These data demonstrate that manipulation of the expression level of a G protein coupled receptor has unpredictable effects on functional expression of proteins that are supposed to be unrelated to the pathway controlled by that GPCR. PMID- 21681580 TI - The activation of NMDA receptor-ERK pathway in the central amygdala is required for the expression of morphine-conditioned place preference in the rat. AB - Reinforcing effects of addictive drugs can be evaluated with the conditioned place preference (CPP) test which involves both the action of drugs and environmental cues. However, the encoded neural circuits and underlying signaling mechanism are not fully understood. In this study, we have used morphine-CPP model in the rat and characterized the role of N-methyl-D: -aspartate (NMDA) receptor and the phosphorylation of extracellular signal-regulated kinase (ERK) in the central nuclei of amygdala (CeA) in the expression of morphine-induced CPP. We have found that morphine repeated pairing treatment causes a significant preference for compartment paired with morphine after 1 day or 7 days post training, which is associated with increased ERK1/2 phosphorylation (p-ERK1/2, a measure of ERK activity) in the CeA. More than 80% of the positive p-ERK1/2 neurons express NMDA receptor subunit NR1 by double immunofluorescence studies. The infusion of either MEK inhibitor U0126 or NMDA receptor antagonist MK-801 in the CeA not only suppresses the activation of ERK1/2 in the CeA but also abolishes the expression of CPP. These results suggest that the activation of the NMDA receptor-ERK signaling pathway in the CeA is required for the expression of morphine-induced place preference in the rat. PMID- 21681581 TI - Intraoperative bronchoscopy for bronchial carcinoid parenchymal-sparing resection: a pediatric case report. AB - Bronchial carcinoid tumors are the most common primary pulmonary neoplasm in the pediatric population. The widely accepted treatment for carcinoid tumors is surgical, specifically aiming at being as much as conservative on lung parenchyma, while the entire tumor is resected. A brief case is described, highlighting the importance and advantages of a surgical and endoscopic combined approach. PMID- 21681582 TI - An 18 years' review of exomphalos highlighting the association with malrotation. AB - INTRODUCTION: This was a retrospective 18 years' review of infants with exomphalos with particular attention to its association with malrotation. MATERIALS AND METHODS: We reviewed all exomphalos cases presenting to our neonatal surgery unit, from October 1991 to September 2009. Data were presented as median and range values. Categorical data were analyzed using Fisher's exact tests and P value of <=0.05 was considered as significant. RESULTS: Forty-two infants with exomphalos (E. major 23, E. minor 19) were treated during this period. The incidence of surgically confirmed malrotation was 45% in E. major and 31% in E. minor. CONCLUSION: The association of malrotation in exomphalos major and exomphalos minor infants is alarmingly high and supports the need to actively exclude this abnormality, either operatively or radiologically. PMID- 21681583 TI - The familial context of adolescent language brokering within immigrant Chinese families in Canada. AB - Language brokering, whereby children of immigrants provide informal translation and interpretation for others, is considered commonplace. However, the research evidence remains inconsistent concerning how language brokering relates to the psychological health of child language brokers and their relationships with their parents. Furthermore, few studies have examined the familial context as an explanation source. This study evaluated the moderating effects of adolescents' support of family obligation values and their perceptions of parental psychological control on relationships between language brokering frequency and both adolescent psychological health and parent-child relationship quality. Adolescents from 182 immigrant Chinese families residing in Canada (average age 15 years, 52% females) reported the frequency with which they translated or interpreted various materials for their parents. More frequent language brokering was associated with poorer psychological health for adolescents who held strong family obligation values or who perceived parents as highly psychologically controlling. More frequent language brokering was also associated with more parent-child conflict. Contrary to some past findings, language brokering frequency was not significantly positively associated with self-esteem or with parent-child congruence (i.e., levels of understanding and satisfaction with parent-child relationships). The findings are discussed in relation to their support for theories of parent-child role reversals or independent-interdependent scripts in language brokering. PMID- 21681584 TI - Yeast communities associated with artisanal mezcal fermentations from Agave salmiana. AB - The aims of this work were to characterize the fermentation process of mezcal from San Luis Potosi, Mexico and identify the yeasts present in the fermentation using molecular culture-dependent methods (RFLP of the 5.8S-ITS and sequencing of the D1/D2 domain) and also by using a culture-independent method (DGGE). The alcoholic fermentations of two separate musts obtained from Agave salmiana were analyzed. Sugar, ethanol and major volatile compounds concentrations were higher in the first fermentation, which shows the importance of having a quality standard for raw materials, particularly in the concentration of fructans, in order to produce fermented Agave salmiana must with similar characteristics. One hundred ninety-two (192) different yeast colonies were identified, from those present on WL agar plates, by RFLP analysis of the ITS1-5.8S- ITS2 from the rRNA gene, with restriction endonucleases, HhaI, HaeIII and HinfI. The identified yeasts were: Saccharomyces cerevisiae, Kluyveromyces marxianus, Pichia kluyveri, Zygosaccharomyces bailii, Clavispora lusitaniae, Torulaspora delbrueckii, Candida ethanolica and Saccharomyces exiguus. These identifications were confirmed by sequencing the D1-D2 region of the 26S rRNA gene. With the PCR-DGGE method, bands corresponding to S. cerevisiae, K. marxianus and T. delbrueckii were clearly detected, confirming the results obtained with classic techniques. PMID- 21681585 TI - The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the prostaglandin E2 human model of headache. AB - Using a human Prostaglandin E(2) (PGE(2)) model of headache, we examined whether a novel potent and selective EP(4) receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healthy volunteers were randomly allocated to receive 200 and 400 mg BGC20-1531 and placebo, followed by a 25-min infusion of PGE(2). We recorded headache intensity on a verbal rating scale, MCA blood flow velocity and STA diameter. There was no difference in headache response or prevention of the dilation of the MCA or the STA (P > 0.05) with either dose of BGC20-1531 relative to placebo, although putative therapeutic exposures were not reached in all volunteers. In conclusion, these data suggest that the other EP receptors may be involved in PGE(2) induced headache and dilatation in normal subjects. PMID- 21681586 TI - Characterisation of Mhc class I and class II DRB polymorphism in red-bellied tamarins (Saguinus labiatus). AB - The infection of red-bellied tamarins (Saguinus labiatus) with GB virus B (GBV-B) is an important surrogate model of hepatitis C virus infection in man. To fully exploit the value of this model, we have characterised MHC class I G and class II DRB alleles in eight tamarins representing a cross-section of a UK breeding colony. The results indicated a high degree of classes I and II DRB allele sharing. Each animal transcribed three to four putative surface-expressed class I alleles and two to four class II DRB alleles. Most animals also transcribed at least one class I allele predicted to result in a C-terminal truncated protein. These results represent the first description of MHC polymorphism in this species and provide a foundation for characterisation of MHC diversity in breeding populations of red-bellied tamarins. The data will facilitate the identification of associations between MHC polymorphism and control of viral infections, and detailed dissection of cellular immune responses against GBV-B. PMID- 21681587 TI - Therapeutic sesamol attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats by inhibiting matrix metalloproteinase-9. AB - We investigated the therapeutic effect of sesamol against monocrotaline-induced sinusoidal obstruction syndrome (SOS) in rats. Male Sprague-Dawley rats were gavaged with a single dose of monocrotaline (90 mg/kg) to induce SOS. Sesamol (5, 10, 20, and 40 mg/kg) was subcutaneously injected 24 h after monocrotaline treatment. Control rats were given saline only. Aspartate transaminase, alanine transaminase, mast cells, CD 68(+) Kupffer cells, neutrophils, myeloperoxidase, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), laminin, and collagen were assessed 48 h after monocrotaline treatment. All tested parameters, except for TIMP-1, laminin, and collagen, were significantly higher in monocrotaline-treated rats than in control rats, and, except for TIMP-1, laminin, and collagen, significantly lower in sesamol-treated rats than in monocrotaline-treated rats. In addition, liver pathology revealed that sesamol offered significant protection against SOS. We conclude that a single dose of sesamol therapeutically attenuated SOS by decreasing the recruitment of inflammatory cells, downregulating MMP-9, and upregulating TIMP-1 expression. PMID- 21681588 TI - Cellulase and xylanase activity in relation to biofilm formation by two intertidal filamentous fungi in a novel polymethylmethacrylate conico-cylindrical flask. AB - A polymethylmethacrylate (PMMA) conico-cylindrical flask (CCF) with an inner arrangement consisting of eight equidistantly spaced rectangular strips mounted radially on a circular disk to provide additional surface area for fungal attachment was employed for production of cellulase by Chaetomium crispatum and xylanase by Gliocladium viride. The design allowed comparison of production between CCFs with hydrophobic surface (PMMA-CCF), hydrophilic glass surface (GS CCF) and 500-ml Erlenmeyer flask (EF). Compared with the EF, endo-beta-1,4 glucanase and FPase (filter paper degradation) activities increased from 0.044 to 0.156 and from 0.008 to 0.021 IU/ml, respectively, in the PMMA-CCF, while growth of C. crispatum was higher by at most 1.38-fold compared with the other vessels. Xylanase production in the EF was at most 5.08-fold higher and growth of G. viride was at most 1.52-fold higher compared with the other vessels. Temporal pattern of biofilm development based on two-channel fluorescence detection of extracellular polymeric substances (EPSs) and whole cells in a confocal laser scanning microscope demonstrated increase by 100% in biovolume, 25% in thickness and 62.5% both in substratum coverage and total spreading of C. crispatum biofilm in PMMA-CCF over 6 days. Biovolume of G. viride biofilm in GS-CCF increased by 150% over 4 days while that in PMMA-CCF enhanced by 200% over 2 days. Biofilm thickness in PMMA-CCF was 44% higher compared with GS-CCF and increased by 175% over 2 days. Substratum coverage was 38% higher in GS-CCF compared with PMMA-CCF. Thus, reactor surface area and property, shear forces and biofilm formation influenced enzyme production. PMID- 21681589 TI - Angiogenesis in unknown primary tumors. PMID- 21681590 TI - Are autism spectrum conditions more prevalent in an information-technology region? A school-based study of three regions in the Netherlands. AB - We tested for differences in the prevalence of autism spectrum conditions (ASC) in school-aged children in three geographical regions in the Netherlands. Schools were asked to provide the number of children enrolled, the number having a clinical diagnosis of ASC and/or two control neurodevelopmental conditions. Prevalence was evaluated by negative binomial regression and adjustments were made for non-response and size of the schools. The prevalence estimates of ASC in Eindhoven was 229 per 10,000, significantly higher than in Haarlem (84 per 10,000) and Utrecht (57 per 10,000), whilst the prevalence for the control conditions were similar in all regions. Phase two is planned to validate school reported cases using standardized diagnostic methods and to explore the possible causes for these differences. PMID- 21681591 TI - Parental perspectives of communication about sexuality in families of children with autism spectrum disorders. AB - To explore the content of communication about sexuality between parents and children with autism spectrum disorders, semi-structured interviews were conducted with 18 parents of children ages 6-13. Content analysis and ethnographic summary were used to interpret the data. Findings suggest that parent's perceptions of a child's behaviors and comprehension are associated with the likelihood that communication occurs. However, parents recognize the risks their children experience, with the greatest fears being sexual victimization and misperceptions related to the intent of their child's behaviors. This study provides information on the nature of communication about sexuality in families of children with autism spectrum disorders and can help tailor interventions aimed at assisting parents to communicate sexuality information effectively. PMID- 21681592 TI - Has bedside teaching had its day? AB - Though a diverse array of teaching methods is now available, bedside teaching is arguably the most favoured. Students like it because it is patient-centred, and it includes a high proportion of relevant skills. It is on the decline, coinciding with declining clinical skills of junior doctors. Several factors might account for this: busier hospitals, broader roles of clinicians, competing teaching modalities, and the limited training of clinicians as medical educators. However, bedside teaching offers unique benefits. Students gain first-hand experience of the doctor patient relationship. They see the process of interacting with patients, investigative yet sensitive, demystified. Certain clinical skills, like the recognition of the tactile sensation of hepatosplenomegaly cannot be simulated elsewhere. We advocate the preservation of bedside learning experience. Teaching guidelines should be written to minimise disruption to ward work, and to ensure the preservation of patient autonomy. Greater emphasis should be placed on bedside skills in the undergraduate curriculum. For teachers, training in teaching methodology should begin at undergraduate level, with subsequent protected teaching time in job plans. This would increase not just the quantity, but also the quality of bedside teaching. PMID- 21681593 TI - Universal screening for alcohol and drug use and racial disparities in child protective services reporting. AB - This study examines racial disparities in Child Protective Services (CPS) reporting at delivery in a county with universal screening for alcohol/drug use in prenatal care. It also explores two mechanisms through which universal screening could reduce reporting disparities: Equitable Surveillance and Effective Treatment. Equitable Surveillance is premised on the assumptions that identification of drug use through screening in prenatal care leads to CPS reporting at delivery and that Black women are screened more than White women, which leads to disproportionate reporting of Black newborns. Universal screening would correct this by ensuring that prenatal providers screen and therefore also report White women to CPS, thereby reducing disparities. Effective Treatment is premised on the idea that identification of drug use through screening in prenatal care leads women to receive treatment during pregnancy, which thereby reduces CPS reporting at delivery. Universal screening would lead to prenatal providers screening more Black women and thereby to more Black women receiving treatment prenatally. The increase in treatment receipt during pregnancy would then decrease the number of Black newborns reported to CPS at delivery, thereby reducing disparities. County data were used to compare the racial/ethnic distribution of women and newborns in three points in the system (identification in prenatal care, treatment entry during pregnancy, and reporting to CPS at delivery related to maternal alcohol/drug use) and explore pathways to treatment. Despite Black women having alcohol/drug use identified by prenatal care providers at similar rates to White women and entering treatment more than expected, Black newborns were four times more likely than White newborns to be reported to CPS at delivery. This contradicts the premise of Effective Treatment. By default, findings were more consistent with Equitable Surveillance than Effective Treatment. Providers and policy makers should not assume that universal screening in prenatal care reduces CPS reporting disparities. PMID- 21681594 TI - Drainage efficiency with dual versus single catheters in severe intraventricular hemorrhage. AB - BACKGROUND: Little is known about the efficacy of single versus dual extraventricular drain (EVD) use in intraventricular hemorrhage (IVH), with and without thrombolytic therapy. METHODS: Post-hoc analysis of seven patients with dual bilateral EVDs from two multicenter trials involving 100 patients with IVH, and spontaneous intracerebral hemorrhage (ICH) volume <30 ml requiring emergency external ventricular drainage. Seven "control" patients with single catheters were matched by IVH volume and distribution and treatment assignment. Head CT scans were obtained daily during intraventricular injections for quantitative determination of IVH volume. RESULTS: Median [min-max] age of the 14 subjects was 56 [40-73] years. Median duration of EVD was 7.9 days (single catheter group) versus 12.2 days (dual catheter group) (P = 0.34). Baseline median IVH volume was not significantly different between groups (75.4 ml [22.4-105.1]--single EVD vs. 84.5 ml [42.0-132.0]--dual EVD; P = 0.28). Comparing the change in IVH volume on time-matched CT scans during dual EVD use, the median decrease in IVH volume in dual catheter patients was significantly larger (52.1 [31.7-81.1] ml) versus single catheter patients (34.5 [13.1-73.9] ml) (P = 0.004). There was a trend to greater decrease in IVH volume during dual EVD use in both rt-PA (P = 0.9) and placebo-treated (P = 0.11) subgroups. CONCLUSION: The decision to place dual EVDs is generally reserved for large IVH (>40 ml) with casting and mass effect. The use of dual simultaneous catheters may increase clot resolution with or without adjunctive thrombolytic therapy. PMID- 21681595 TI - Surgical management of mesh-related complications after prior pelvic floor reconstructive surgery with mesh. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study is to evaluate the complications and anatomical and functional outcomes of the surgical treatment of mesh-related complications. METHODS: A retrospective cohort study of patients who underwent complete or partial mesh excision to treat complications after prior mesh-augmented pelvic floor reconstructive surgery was conducted. RESULTS: Seventy-three patients underwent 30 complete and 51 partial mesh excisions. Intraoperative complications occurred in 4 cases, postoperative complications in 13. Symptom relief was achieved in 92% of patients. Recurrence of pelvic organ prolapse (POP) occurred in 29% of complete and 5% of partial excisions of mesh used in POP surgery. De novo stress urinary incontinence (SUI) occurred in 36% of patients who underwent excision of a suburethral sling. CONCLUSIONS: Mesh excision relieves mesh-related complications effectively, although with a substantial risk of serious complications and recurrence of POP or SUI. More complex excisions should be performed in skilled centers. PMID- 21681596 TI - Uterosacral ligament vaginal vault suspension using delayed absorbable monofilament suture. AB - INTRODUCTION AND HYPOTHESIS: We investigated the incidence of suture complications and recurrent prolapse following uterosacral ligament suspension (USLS) using delayed absorbable polyglyconate monofilament suture (Maxon). METHODS: We reviewed the medical records of subjects who underwent vaginal USLS using polyglyconate suture. Primary outcomes were suture complications and anatomic failures defined as recurrent apical prolapse stage 1 or greater. Secondary outcomes were subjective failures and reoperation rate for apical prolapse. RESULTS: Fifty-seven out of 68 subjects who underwent USLS with polyglyconate suture over the study period were included in analysis. At median follow-up of 12 months, 3.5% had suture complications. The anatomic and symptomatic failure rate was 7%. One subject underwent repeat surgery for prolapse. CONCLUSIONS: Suture complications are uncommon using polyglyconate suture for USLS, and failure rates are low. This is in comparison to a 44.6% suture erosion rate with permanent suture reported by our institution using the same surgical technique. PMID- 21681597 TI - Religiosity and adolescents' involvement with both drugs and sex. AB - Previous research has shown that religion reduces adolescents' risk of substance use, while having little impact on sexual risk-taking. However, few studies have examined how religion might mitigate adolescents' involvement with both drugs and sex. Using the Child Development Supplement (CDS) in combination with the Panel Study of Income Dynamics (PSID), we fill this gap by determining how adolescents' involvement with both drugs and sex is related to religiosity. We find the statistically significant relationship between religiosity and adolescents' involvement in both risk behaviors is accounted for by school attachment, but the relationship between religiosity and drugs is robust. PMID- 21681598 TI - Medicine and spiritual healing within a region of Canada: preliminary findings concerning Christian Scientists' healthcare practices. AB - Christian Science is the largest and most recognized of various spiritual healing groups that encourage members to forgo or overcome the need for medicine. Even so, it appears that some Scientists occasionally use medicine. In this study, I argue that Scientists in one region of Canada respond to influences on their healthcare practices differently and follow a variety of healthcare practices. These practices range from refusing medically necessary treatment (which could potentially harm individuals' health) to making full use of the medical system. I base my findings primarily on interviews with eleven current members and one former Christian Scientist. PMID- 21681599 TI - Repair of osteochondral lesions in the knee by chondrocyte implantation using the MACI(r) technique. AB - PURPOSE: Matrix-associated autologous chondrocyte implantation (MACI((r))) is an innovative therapeutic option for the treatment of chondral and osteochondral lesions of the knee. METHODS: Fifty-three patients (54 knees) with MRI-documented osteochondral lesions were treated with MACI((r)). A clinical assessment was performed using VAS score, Lysholm score, and Tegner activity level after an average follow-up of 27 months (SD: 2.3). MRI scans were performed 12 and 24 months after surgery. Seventeen patients were reevaluated after an average time of 59 months (SD: 6.7) after surgery. RESULTS: Two years after transplantation, Lysholm score increased from a preoperative mean value of 70 (SD: 13.4) to 95 (SD: 6.4); the average VAS score decreased from a preoperative value of 5.2 (SD: 2.9) to 1.9 (SD: 2.1). The difference with respect to Tegner activity level did not prove to be significant. At 1 year, MRI scans documented a completely repaired defect with slight subchondral bone abnormality in 38 cases (70%). Satisfying outcomes were confirmed on 17 patients who were reevaluated 5 years after surgery. At 60 months, MRI scans showed complete integration with the surrounding native cartilage without any sign of detachment or bone marrow edema in 15 cases (88%). CONCLUSION: The MACI((r)) technique is a safe and clinically effective procedure, which has been proven to be valuable in treating osteochondral defects even over the long term. LEVEL OF EVIDENCE: Therapeutic study, Level III-2 (retrospective cohort study). PMID- 21681600 TI - CD10 expression in epithelial and stromal cells of non-small cell lung carcinoma (NSCLC): a clinic and pathologic correlation. AB - CD10 is a zinc dependent metallopeptidase, and its expression in stromal and/or epithelial cells of many carcinomas has been suggested to have prognostic value. This study investigates CD10 expression in epithelial and stromal cells of non small cell lung carcinoma (NSCLC), and evaluates its prognostic value for this tumor and its histologic subtypes. Sixty-six cases of NSCLC [35 cases of nonsquamous cell carcinoma (NSCC) and 31 cases of squamous cell carcinoma (SCC)] were analyzed immuno-histochemically for CD10 antibody. Fisher's exact test and univariate survival analyses were performed. Comparison of clinicopathologic characteristics for NSCLC showed that only stromal CD10 expression had worse prognostic impact, associated with the presence of recurrence (p = 0.001), death (p = 0.006) and disease positivity (p = 0.001). For SCC, CD10 was found to be expressed mainly in the stromal cells, and was associated with a decreased survival (p = 0.000) and disease free survival (p = 0.000). CD10 expression was restricted to the epithelial cells in NSCC and associated with an increased disease free survival (p = 0.036). Stromal CD10 expression apppears to be a worse prognostic factor in NSCLCs. CD10 which is expressed in different cell components of SCC and NSCC appears to have opposing effects on the behaviour of these histologic types. PMID- 21681601 TI - Tumour topoisomerase II alpha protein expression and outcome after adjuvant dose dense anthracycline-based chemotherapy. AB - There is a need for the selection of those breast cancers where benefit may be attained from the addition of an anthracycline to the adjuvant chemotherapy. The expression of topoisomerase II alpha (TOP2A) protein in 3 cohorts of breast cancers treated with adjuvant dose-dense anthracycline-based chemotherapy was determined retrospectively. The TOP2A status was analysed in relation with the other standard tumour features and the outcome. TOP2A IHC results were assessable in 106 patients: with a cut-off value of 15%, 48% of the tumours were classified as TOP2A-positive. The expression of TOP2A correlated with that of Ki67 (R = 0.532, p < 0.001) and a high grade (p = 0.04), but did not correlate with the proportion of ER- or PR-positive cells in the tumour. More tumors were TOP2A negative among the ER- or PR-positive cancers than among the ER/PR-negative cancers (p = 0.021 and p = 0.002, respectively). After a median follow-up time of 64.5 months, 31 relapses (23.5%) and 23 deaths (17.4%) had occurred in 131 patients. The overall survival was longer in the TOP2A-positive cases than in the TOP2A-negative cases. The recurrence-free survival and the overall survival were significantly more favourable in the ER/PR-negative and TOP2A-positive tumours than in other subgroups. In a Cox proportional hazards model, the grade and TOP2A remained significant determinants in the ER/PR-negative subgroup. TOP2A positivity and grade 3 indicated a decrease in the risk of death with HR = 0.211 (95% CI: 0.042-1.05, p = 0.056) and HR = 0.216 (95% CI: 0.047-0.990, p = 0.048), respectively. A higher sensitivity to anthracycline-containing regimens is suggested in ER/PR-negative and TOP2A-positive cancers. PMID- 21681602 TI - Correlation analysis of JAK-STAT pathway components on prognosis of patients with prostate cancer. AB - Janus kinases (JAK)/signal transducers and activator of transcription (STAT) pathway is activated constitutively in prostate cancer (PCa). Despite previous reports implying a role of this pathway in the development of clinical hormone refractory PCa, the correlation of pathway members with the clinicopathologic features and prognosis of patients with PCa has not been elucidated. To address this problem, pJAK-1(Tyr1022/1023) and pSTAT-3(Tyr705) were evaluated by immunostaining in needle biopsies of the prostate from 202 PCa patients treated by definitive therapy (105 cases) or hormonal therapy (97 cases). The correlation of two protein expression with the clinicopathologic features and the prognosis of PCa were subsequently assessed. The expression levels of pJAK-1(Tyr1022/1023) and pSTAT-3(Tyr705) were both positively correlated with Gleason score and clinical stage of patients with PCa. Their expression was also significantly higher in patients with biochemical (prostate-specific antigen, PSA) failure than that in those with no PSA failure (both P < 0.001). In all patients, the recurrence-free survival (RFS) rates were significantly higher in those with low pJAK-1(Tyr1022/1023) and pSTAT-3(Tyr705) expression than that in those with high expression (both P < 0.001). Moreover, for patients treated by definitive or hormonal therapy, the RFS rates in those with lower pJAK-1(Tyr1022/1023) (P < 0.001 and 0.012, respectively) and pSTAT-3(Tyr705) expression (P < 0.001 and 0.015, respectively) were significantly higher than in those with higher expression. Cox multivariate analysis showed that the expression levels of pJAK 1(Tyr1022/1023) (P = 0.002) and pSTAT-3(Tyr705) (P = 0.005) were prognostic factors for PCa in addition to extraprostatic extension (P = 0.026) and Gleason score (P = 0.018). The results of pJAK-1(Tyr1022/1023) and pSTAT-3(Tyr705) immunostainings in needle-biopsy specimens are prognostic factors for PCa. PMID- 21681603 TI - Lack of prognostic significance of survivin in pediatric medulloblastoma. AB - Medulloblastoma (MDB) is the most common malignant cerebellar tumor in children. Because of the significant rate of mortality and treatment-related morbidity, the identification of prognostic factors could lead to a more accurate selection of patients who can benefit from a less aggressive therapy and improve risk stratification. Survivin is an inhibitor of apoptosis protein (IAP), the expression of which has been associated with worse prognosis in MDB. However, both of its subcellular localizations may contribute to tumor progression, and ultimately, survivin subcellular localization prognostic value depends on tumor type biological features. The goal of this study was to analyze these survivin features in the pediatric MDB tumor samples and its impact on clinical outcome. Survivin expression and subcellular localization were accessed by immunohistochemistry in a series of 41 tumor samples. Kaplan-Meier survival curves were compared using the log-rank test. Survivin expression ranged from completely absent to fully present in a notably higher pattern of nuclear localization than cytoplasmic (19 of 41 versus 4 of 41, respectively). However, survivin expression and subcellular localization were not associated with five year overall survival or metastasis status at diagnosis, which was the only statistically significant prognostic factor in our series (p = 0.008). Taken together, our results suggest that survivin expression should be further studied in large, multicenter series to determine its accurate impact on prognosis and pathobiology of pediatric MDB. PMID- 21681604 TI - Cellular and molecular mechanisms in the two major forms of inflammatory bowel disease. AB - The factors involved in the pathogenesis of Crohn's disease and ulcerative colitis, the two major types of inflammatory bowel disease (IBD) are summarized. Intestinal antigens composed of bacterial flora along with antigen presentation and impaired mucosal barrier have an important role in the initiation of IBD. The bacterial community may be modified by the use of antibiotics and probiotics. The dentritic cells recognize the antigens by cell surface Toll like receptor and the cytoplasmic CARD/NOD system. The balance between Th1/Th2/Th17 cell populations being the source of a variety of cytokines regulates the inflammatory mechanisms and the clearance of microbes. The intracellular killing and digestion, including autophagy, are important in the protection against microbes and their toxins. The homing process determines the location and distribution of the immune cells along the gut. All these players are potential targets of pharmacological manipulation of disease status. PMID- 21681605 TI - Evaluation of multitype mathematical models for CFSE-labeling experiment data. AB - Carboxy-fluorescein diacetate succinimidyl ester (CFSE) labeling is an important experimental tool for measuring cell responses to extracellular signals in biomedical research. However, changes of the cell cycle (e.g., time to division) corresponding to different stimulations cannot be directly characterized from data collected in CFSE-labeling experiments. A number of independent studies have developed mathematical models as well as parameter estimation methods to better understand cell cycle kinetics based on CFSE data. However, when applying different models to the same data set, notable discrepancies in parameter estimates based on different models has become an issue of great concern. It is therefore important to compare existing models and make recommendations for practical use. For this purpose, we derived the analytic form of an age-dependent multitype branching process model. We then compared the performance of different models, namely branching process, cyton, Smith-Martin, and a linear birth-death ordinary differential equation (ODE) model via simulation studies. For fairness of model comparison, simulated data sets were generated using an agent-based simulation tool which is independent of the four models that are compared. The simulation study results suggest that the branching process model significantly outperforms the other three models over a wide range of parameter values. This model was then employed to understand the proliferation pattern of CD4+ and CD8+ T cells under polyclonal stimulation. PMID- 21681606 TI - Metabolism and tissue distribution of sulforaphane in Nrf2 knockout and wild-type mice. AB - PURPOSE: To determine the metabolism and tissue distribution of the dietary chemoprotective agent sulforaphane following oral administration to wild-type and Nrf2 knockout (Nrf2(-/-)) mice. METHODS: Male and female wild-type and Nrf2(-/-) mice were given sulforaphane (5 or 20 MUmoles) by oral gavage; plasma, liver, kidney, small intestine, colon, lung, brain and prostate were collected at 2, 6 and 24 h (h). The five major metabolites of sulforaphane were measured in tissues by high performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Sulforaphane metabolites were detected in all tissues at 2 and 6 h post gavage, with the highest concentrations in the small intestine, prostate, kidney and lung. A dose-dependent increase in sulforaphane concentrations was observed in all tissues except prostate. At 5 MUmole, Nrf2(-/-) genotype had no effect on sulforaphane metabolism. Only Nrf2(-/-) females given 20 MUmoles sulforaphane for 6 h exhibited a marked increase in tissue sulforaphane metabolite concentrations. The relative abundance of each metabolite was not strikingly different between genders and genotypes. CONCLUSIONS: Sulforaphane is metabolized and reaches target tissues in wild-type and Nrf2(-/-) mice. These data provide further evidence that sulforaphane is bioavailable and may be an effective dietary chemoprevention agent for several tissue sites. PMID- 21681608 TI - Abstracts of the 2011 CIS (Clinical Immunology Society) Annual Meeting. Chicago, Illinois, USA. May 19-22, 2011. PMID- 21681610 TI - Effects of vitamin K intake on gamma-carboxylated proteins, bone fractures, and vascular calcifications. PMID- 21681607 TI - Modeling sleep data for a new drug in development using markov mixed-effects models. AB - PURPOSE: To characterize the time-course of sleep in insomnia patients as well as placebo and concentration-effect relationships of two hypnotic compounds, PD 0200390 and zolpidem, using an accelerated model-building strategy based on mixed effects Markov models. METHODS: Data were obtained in a phase II study with the drugs. Sleep stages were recorded during eight hours of sleep for two nights per treatment for the five treatments. First-order Markov models were developed for one transition at a time in a sequential manner; first a baseline model, followed by placebo and lastly the drug models. To accelerate the process, predefined models were selected based on a priori knowledge of sleep, including inter subject and inter-occasion variability. RESULTS: Baseline sleep was described using piece-wise linear models, depending on time of night and duration of sleep stage. Placebo affected light sleep stages; drugs also affected slow-wave sleep. Administering PD 0200390 30 min earlier than standard dosing was shown through simulations to reduce latency to persistent sleep by 40%. CONCLUSION: The proposed accelerated model-building strategy resulted in a model well describing sleep patterns of insomnia patients with and without treatments. PMID- 21681611 TI - Osteoid osteoma is an osteocalcinoma affecting glucose metabolism. AB - Osteocalcin is a hormone secreted by osteoblasts, which regulates energy metabolism by increasing beta-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. This has been demonstrated in mice, but to date, the evidence implicating osteocalcin in the regulation of energy metabolism in humans are indirect. To address this question more directly, we asked whether a benign osteoblastic tumor, such as osteoma osteoid in young adults, may secrete osteocalcin. The study was designed to assess the effect of surgical resection of osteoid osteoma on osteocalcin and blood glucose levels in comparison with patients undergoing knee surgery and healthy volunteers. Blood collections were performed the day of surgery and the following morning after overnight fasting. Patients and controls were recruited in the orthopedic surgery department of New York Presbiterian Hospital, NY-USA and Hospices Civils de Lyon, France. Seven young males were included in the study: two had osteoid osteoma, two underwent knee surgery, and three were healthy volunteers. After resection of the osteoid osteomas, we observed a decrease of osteocalcin by 62% and 30% from the initial levels. Simultaneously, blood glucose increased respectively by 32% and 15%. Bone turnover markers were not affected. This case study shows for the first time that osteocalcin in humans affects blood glucose level. This study also suggests that ostoid osteoma may be considered, at least in part, as an osteocalcinoma. PMID- 21681612 TI - Inactivation of endothelial proprotein convertase 5/6 decreases collagen deposition in the cardiovascular system: role of fibroblast autophagy. AB - Proprotein convertase (PC) 5/6 belongs to a family of secretory proteases involved in proprotein proteolysis. Several studies suggest a role for PC5/6 in cardiovascular disease. Because lethality at birth of mice lacking PC5/6 precluded elucidation of its function in the adult, we generated mice in which the gene of PC5/6 (pcsk5) is specifically inactivated in endothelial cells (ecKO), which are viable and do not exhibit overt abnormalities. In order to uncover the function of PC5/6 in the cardiovascular system, the effect of ecKO was studied in aging mice. In 16 to 18-month-old ecKO mice, the left ventricle (LV) mass, media cross-sectional area of aorta and coronary arteries, and media to-lumen ratio of mesenteric arteries were decreased. The LV presented decreased diastolic function, and mesenteric arteries showed decreased stiffness. Collagen was decreased in the LV myocardial interstitium and perivascularly in coronary arteries and aorta. Cardiovascular hypotrophy likely develops with aging, since no significant changes were observed in 2-month-old ecKO mice. Fibroblasts, as a source of collagen in myocardium and vasculature, may play a role in the decrease in collagen deposition. Fibroblasts co-cultured with ecKO endothelial cells showed decreased collagen production, decreased insulin-like growth factor (IGF) 1/Akt/mTOR signaling, and enhanced autophagic activation. PC5/6 inactivation in endothelial cells results in cardiovascular hypotrophy associated with decreased collagen deposition, decreased LV diastolic function, and vascular stiffness, suggesting a trophic role of endothelial PC5/6 in the cardiovascular system, likely mediated by IGF-1/Akt/mTOR signaling and control of autophagy. PMID- 21681613 TI - Biodegradability and ecotoxicitiy of tramadol, ranitidine, and their photoderivatives in the aquatic environment. AB - PURPOSE: This study was designed to assess the fate and the overall potential impacts of the widely prescribed drugs ranitidine and tramadol after their introduction into the aquatic environment. METHODS: The probability to detect these two drugs in the aquatic environment was studied by analyzing their abiotic and biotic degradation properties. For this purpose, samples were irradiated with different light sources, and three widely used biodegradability tests from the OECD series, the closed bottle test (OECD 301 D), the manometric respirometry test (OECD 301 F) and the Zahn-Wellens test (OECD 302 B), were conducted. The ecotoxicity of the photolytically formed transformation products was assessed by performing the bacterial growth inhibition test (EN ISO 10712). Furthermore, quantitative structure-activity relationship analysis and a risk analysis based on the calculation of the predicted environmental concentrations have also been conducted to assess the environmental risk potential of the transformation products. The possible formation of stable products by microbial or photolytical transformation has been investigated with DOC and LC-MS analytics. RESULTS: In the present study, neither ranitidine, nor tramadol, nor their photoderivatives were found to be readily or inherently biodegradable according to test guidelines. The photolytic transformation was faster under a UV lamp compared to the reaction under an Xe lamp with a spectrum that mimics sunlight. No chronic toxicity against bacteria was found for ranitidine or its photolytic decomposition products, but a low toxicity was detected for the resulting mixture of the photolytic transformation products of tramadol. CONCLUSIONS: The study demonstrates that transformation products may have a higher environmental risk potential than the respective parent compounds. PMID- 21681614 TI - Lower dose and shorter acquisition: pushing the boundaries of myocardial perfusion SPECT. PMID- 21681615 TI - The nuclear cardiology report: problems, predictors, and improvement. A report from the ICANL database. AB - BACKGROUND: The quality of nuclear cardiology reports is essential for the effective communication of results of cardiac radionuclide imaging and has never been evaluated for compliance with the ICANL standards. This retrospective study was designed to evaluate required reporting elements and site characteristics to determine differences in the compliance of applicant nuclear cardiology laboratories with The ICANL Standards, and identify potential mechanisms for improvement. METHODS AND RESULTS: Site characteristics and the 18 elements of the ICANL nuclear cardiology reporting standard ranked by level of importance were evaluated in 1,301 labs applying for accreditation from 1/1/08 to 1/1/09. A majority of labs were non-compliant (57.2%) with >=1 of the 18 elements, mean number of errors 2.13 +/- 2.58. There were significant differences among applications with different accreditation decisions, first application and repeat applications, and region of the United States. Laboratories with multiple re accreditations had significantly increased compliance. These findings were confirmed following analysis of the ranked importance of the non-compliant elements. CONCLUSIONS: Nuclear cardiology reports have a high degree of non compliance with the current ICANL standards. There were identifiable characteristics defining labs more likely to be non-compliant. Feedback from prior applications improves compliance with reporting standards on subsequent applications. PMID- 21681616 TI - Neuro-developmental outcome at 18 months in premature infants with diffuse excessive high signal intensity on MR imaging of the brain. AB - BACKGROUND: Diffuse excessive high signal intensity (DEHSI) may represent damage to the white matter in preterm infants, but may be best studied alongside quantitative markers. Limited published data exists on its neuro-developmental implications. OBJECTIVE: The purpose of this study was to assess whether preterm children with DEHSI at term-corrected age have abnormal neuro-developmental outcome. MATERIALS AND METHODS: This was a prospective observational study of 67 preterm infants with MRI of the brain around term-equivalent age, including diffusion-weighted imaging (DWI). Images were reported as being normal, overtly abnormal or to show DEHSI. A single observer placed six regions of interest in the periventricular white matter and calculated the apparent diffusion coefficients (ADC). DEHSI was defined as (1) high signal on T2-weighted images alone, (2) high signal with raised ADC values or (3) raised ADC values independent of visual appearances. The neuro-development was assessed around 18 months' corrected age using the Bayley Scales of Infant and Toddler Development (3rd Edition). Standard t tests compared outcome scores between imaging groups. RESULTS: No statistically significant difference in neuro-developmental outcome scores was seen between participants with normal MRI and DEHSI, regardless of which definition was used. CONCLUSION: Preterm children with DEHSI have similar neuro-developmental outcome to those with normal brain MRI, even if the definition includes objective markers alongside visual appearances. PMID- 21681617 TI - A well-documented multimodality imaging approach to fetus in fetu: pre- and postnatal imaging features. PMID- 21681618 TI - Cytotoxicity, permeability, and inflammation of metal oxide nanoparticles in human cardiac microvascular endothelial cells: cytotoxicity, permeability, and inflammation of metal oxide nanoparticles. AB - Wide applications and extreme potential of metal oxide nanoparticles (NPs) increase occupational and public exposure and may yield extraordinary hazards for human health. Exposure to NPs has a risk for dysfunction of the vascular endothelial cells. The objective of this study was to assess the cytotoxicity of six metal oxide NPs to human cardiac microvascular endothelial cells (HCMECs) in vitro. Metal oxide NPs used in this study included zinc oxide (ZnO), iron(III) oxide (Fe(2)O(3)), iron(II,III) oxide (Fe(3)O(4)), magnesium oxide (MgO), aluminum oxide (Al(2)O(3)), and copper(II) oxide (CuO). The cell viability, membrane leakage of lactate dehydrogenase, intracellular reactive oxygen species, permeability of plasma membrane, and expression of inflammatory markers vascular cell adhesion molecule-1, intercellular adhesion molecule-1, macrophage cationic peptide-1, and interleukin-8 in HCMECs were assessed under controlled and exposed conditions (12-24 h and 0.001-100 MUg/ml of exposure). The results indicated that Fe(2)O(3), Fe(3)O(4), and Al(2)O(3) NPs did not have significant effects on cytotoxicity, permeability, and inflammation response in HCMECs at any of the concentrations tested. ZnO, CuO, and MgO NPs produced the cytotoxicity at the concentration-dependent and time-dependent manner, and elicited the permeability and inflammation response in HCMECs. These results demonstrated that cytotoxicity, permeability, and inflammation in vascular endothelial cells following exposure to metal oxide nanoparticles depended on particle composition, concentration, and exposure time. PMID- 21681619 TI - Maladaptive hypertrophy after acute myocardial infarction positive effect of bone marrow-derived stem cell therapy on regional remodeling measured by cardiac MRI. AB - OBJECTIVE: In the aftermath of myocardial infarction, increased loading conditions will trigger hypertrophy of viable myocardium. This in turn causes deterioration of regional contractility. Cardiac magnetic resonance imaging (cMRI) allows the exact differentiation of viable and infarcted myocardium and therefore the measurement of regional wall thickness and function. Bone marrow derived stem cell (BMC) transfer has been shown to improve global function and remodeling. The present study examines the effect of BMC transfer on regional remodeling and function after myocardial infarction by cMRI. DESIGN: Fifty-four patients of the MR substudy of the REPAIR-AMI trial have been studied at baseline and 12-month follow-up. Enddiastolic wall thickness (EDWT) and wall thickening (WT%) have been measured on SSFP cine sequences. RESULTS: Enddiastolic wall thickness decreased in both placebo and BMC groups in viable as well as infarcted segments. The effect was largest in the pre-specified subgroup of patients below the median EF of 48.9% (infarcted segments -1.14 mm Placebo vs. -1.91 mm BMC, p for interaction 0.01, remote segments -0.19 mm Placebo vs. -0.94 mm BMC, p for interaction 0.00001). Corrected for baseline values BMC therapy yielded smaller EDWT at 12 months in infarcted and remote segments (infarcted 7.58 mm Placebo vs. 6.13 mm BMC p = 0.0001, remote 8.76 mm Placebo vs. 7.32 mm BMC, p = 0.0001). This was associated with better contractility within the infarcted segments among BMC patients (WT% 24.17% Placebo vs. 49.31% BMC, p = 0.0001). The WT% was inversely correlated with EDWT (r = -0.37, p = 0.0001). CONCLUSION: Bone marrow-derived stem cell therapy yields smaller EDWT when compared with placebo patients suggesting a positive effect on maladaptive hypertrophy of viable myocardium. This notion is supported by the enhanced regional contractility within the BMC group which is inversely correlated with EDWT. PMID- 21681620 TI - Influence of weather conditions on hiking behavior. AB - This study determines the major weather factors affecting hiking activity and builds a prediction model to estimate participation. An empirical assessment of hiking participation using weather factors was demonstrated for trails on Kuanyin Mountain, Taiwan. By adapting the concepts of the range of tolerance and the eclectic model, a nonlinear function was used to explain hiking participation with weather factors. Stepwise multiple-regression analysis was carried out to determine the major weather factors affecting hiking participation. The results indicate that not only did participation vary with the season but hiking behavior was affected by different weather factors in each season. The explanation rates for the seasons exceeded 90% except that for spring. PMID- 21681621 TI - Complications in laparoscopic adrenalectomy: the value of experience. AB - BACKGROUND: With the increased diffusion of laparoscopic adrenalectomy (LA), surgeons from nonreferral surgical departments are beginning to approach this procedure, even if they are less experienced than surgeons from centers with a larger workflow. This study was designed to establish the real incidence of perioperative complications, in LA, in both major and minor surgical departments. METHODS: Patients were prospectively recorded into the Italian Registry of Endoscopic Surgery-Adrenalectomy (IRES-A) database since January 2000. Surgical Centers were divided in to referral centers (RC) with >30 adrenalectomies and nonreferral centers (NRC) with <30 adrenalectomies performed. Peri- and postoperative complications were evaluated. RESULTS: Of the 833 patients included in the IRES-A, 66 patients (7.9%) had complications (33 females; mean age 48 +/- 8 years). Mean age and body mass index were significantly lower in noncomplicated patients. Pheochromocytoma histotype and large mass dimension were associated with a higher complication rate. The whole number of complications, conversion rate, and nonsurgery-related complications were statistically lower in the RC groups than the NRC groups. CONCLUSIONS: The main risk factors for the occurrence of complications during laparoscopic adrenalectomy appear to be surgical inexperience, age, and body mass index of the patient, the dimension of the mass, and pheochromocytoma. Therefore, laparoscopic adrenalectomy, especially for tumors that are potentially more complicated, should only be undertaken in high volume specialist centers by surgeons with the appropriate training and experience. PMID- 21681622 TI - Laparoscopic repair of perforated peptic ulcer. PMID- 21681623 TI - Laparoscopic splenectomy is an effective and safe intervention for hypersplenism secondary to liver cirrhosis. AB - BACKGROUND: Laparoscopic splenectomy has become the standard procedure for the normal to moderately enlarged spleens. We performed this study to investigate the safety, feasibility, and effectiveness of laparoscopic splenectomy for hypersplenism secondary to liver cirrhosis. METHODS: We performed a retrospective chart review of 24 cases of laparoscopic splenectomy (group 1), 24 cases of open splenectomy (group 2) for hypersplenism secondary to liver cirrhosis, and 68 cases of laparoscopic splenectomy for immune thrombocytopenic purpura (group 3). We performed comparisons between groups 1 and 2 and groups 1 and 3 in terms of demographic, intraoperative, postoperative variables, and changes in blood counts and liver function. RESULTS: Patients in groups 1 and 2 had comparable demographic characteristics, but those in group 1 had less estimated blood loss, fewer complications, and shorter duration of oral intake, and they required less analgesia and shorter post-hospital stays. In both groups, leukocyte and platelet counts increased significantly and transaminase and total bilirubin decreased postoperatively, but not significantly, and there was no significant difference between the two groups. Compared with group 3, patients in group 1 were older, had lower preoperative hemoglobin levels and leukocyte counts, poorer Child-Pugh class, required more operation time, and suffered more estimated blood loss; however, there were no statistically significant differences in terms of conversion rates, transfusion rates, complication rates, and postoperative course. CONCLUSIONS: Laparoscopic splenectomy is a safe, feasible, and effective procedure for hypersplenism secondary to liver cirrhosis. PMID- 21681624 TI - Technique, risks, and true impact of routine preoperative endoscopic evaluation of morbidly obese patients undergoing bariatric surgery. PMID- 21681625 TI - A new skin excision pattern to correct protruding earlobe deformity in prominent ears. PMID- 21681626 TI - Advice-taking as an unobtrusive measure of prejudice. AB - A new unobtrusive measure of prejudice is proposed based on an advice-taking task. The computer-based task requires participants to find a token hidden behind one of two boxes. Prior to making their choice, however, someone (depicted by a name or a face) provides advice as to the token's location. An unobtrusive measure of prejudice is derived by manipulating the advice-giver's social group (e.g., male or female, Asian or White) and comparing the proportions of advice taken from each group. In Experiment 1, although the participants were not aware of it, they took more advice from males than from females. In Experiment 2, the relative proportion of advice taken from Asian versus White advice-givers correlated with responses to a news story pertaining to Asians. In Experiment 3, the relative proportion of advice taken from Asian versus White advice-givers correlated with scores on the Implicit Association Test (IAT) and predicted discriminatory behaviour, as indexed by the lost e-mail technique, better than other measures. In Experiment 4, scores on the advice task were uncontaminated by social desirability concerns and reactance and reflected the relative amounts of trust that people placed in different social groups. Taken together, these findings suggest that the advice task may be a useful tool for researchers seeking an unobtrusive measure of prejudice with predictive validity. PMID- 21681627 TI - Imageability and body-object interaction ratings for 599 multisyllabic nouns. AB - We collected imageability and body-object interaction (BOI) ratings for 599 multisyllabic nouns. We then examined the effects of these variables on a subset of these items in picture-naming, word-naming, lexical decision, and semantic categorization. Picture-naming latencies were taken from the International Picture-Naming Project database (Szekely, Jacobsen, D'Amico, Devescovi, Andonova, Herron, et al. Journal of Memory and Language, 51, 247-250, 2004), word-naming and lexical decision latencies were taken from the English Lexicon Project database (Balota, Yap, Cortese, Hutchison, Kessler, Loftis, et al. Behavior Research Methods, 39, 445-459, 2007), and we collected semantic categorization latencies. Results from hierarchical multiple regression analyses showed that imageability and BOI separately accounted for unique latency variability in each task, even with several other predictor variables (e.g., print frequency, number of syllables and morphemes, age of acquisition) entered first in the analyses. These ratings should be useful to researchers interested in manipulating or controlling for the effects of imageability and BOI for multisyllabic stimuli in lexical and semantic tasks. PMID- 21681628 TI - MD CT angiography and MR angiography of nonatherosclerotic renal artery disease. AB - We reviewed the computed tomographic and magnetic resonance angiographic appearances of the various nonatherosclerotic renal artery pathologies. Rapid progress in cross-sectional techniques has allowed computed tomography and magnetic resonance angiography to replace digital subtraction angiography in most circumstances. When state-of-the-art equipment and optimized protocols are used, diagnosing a wide range of nonatherosclerotic pathologies is possible. PMID- 21681629 TI - Is a vertebrate a better host for a parasite than an invertebrate host? Fecundity of Proctoeces cf lintoni (Digenea: Fellodistomidae), a parasite of fish and gastropods in northern Chile. AB - The fecundity, the relationship between fecundity and worm size, as well as abundance of the adult worm Proctoeces cf. lintoni (Digenea: Fellodistomidae) in four gastropod hosts (keyhole limpets of the genus Fissurella) and one vertebrate host, the clingfish Sicyases sanguineus from northern Chile, were compared. Worms obtained from Fissurella latimarginata were smaller than those from Fissurella maxima, Fissurella limbata, and S. sanguineus. The mean fecundity of parasites from Fissurella crassa was significantly lower than those from F. limbata, F. maxima and S. sanguineus. For all invertebrate hosts, there were significant, positive relationships between worm size and fecundity, and the slopes of the regression did not differ significantly for the invertebrate hosts. Parasites of the keyhole limpet F. limbata and the clingfish showed the highest intensity, prevalence, and mean fecundity, and these species must be considered to be the hosts in which P. cf lintoni shows the best fitness. PMID- 21681630 TI - Prevalence of community-associated meticillin-resistant Staphylococcus aureus and Panton-Valentine leucocidin-positive S. aureus in general practice patients with skin and soft tissue infections in the northern and southern regions of The Netherlands. AB - The purpose of this investigation was to determine the prevalence of community associated meticillin-resistant Staphylococcus aureus (CA-MRSA) and Panton Valentine leucocidin (PVL)-positive S. aureus in general practice (GP) patients with skin and soft tissue infections (SSTI) in the northern (Groningen and Drenthe) and southern (Limburg) regions of The Netherlands. Secondary objectives were to assess the possible risk factors for patients with SSTI caused by S. aureus and PVL-positive S. aureus using a questionnaire-based survey. From 2007 to 2008, wound and nose cultures were obtained from patients with SSTI in general practice. These swabs were analysed for the presence of S. aureus and the antibiotic susceptibility was determined. The presence of the PVL toxin gene was determined by polymerase chain reaction (PCR) and the genetic background with the use of spa typing. A survey was performed to detect risk factors for S. aureus infection and for the presence of PVL toxin.S. aureus was isolated from 219 out of 314 (70%) patients with SSTI, of which two (0.9%) patients were MRSA-positive. In 25 (11%) patients, the PVL toxin gene was found. A higher prevalence of PVL positive S. aureus of patients with SSTI was found in the northern region compared to the south (p < 0.05). Regional differences were found in the spa types of PVL-positive S. aureus isolates, and for PVL-negative S. aureus isolates, the genetic background was similar in both regions. The prevalence of CA-MRSA in GP patients with SSTI in The Netherlands is low. Regional differences were found in the prevalence of PVL-positive S. aureus isolates from GP patients with SSTI. Household contacts having similar symptoms were found to be a risk factor for SSTI with S. aureus. PMID- 21681631 TI - Initial experience with the use of an expandable titanium cage as a vertebral body replacement in patients with tumors of the spinal column: a report of 95 patients. AB - OBJECTIVE: Vertebral body resection to treat spine tumors necessitates reconstruction to maintain spinal stability. The durability of reconstruction may be a challenge in cancer patients as treatment with chemotherapy and/or radiation coupled with poor nutritional status may compromise bone quality. We present a series of patients who underwent implantation of an expandable titanium cage (ETC) for reconstruction after vertebral body resection for primary or metastatic spine tumors. We report the functional outcome, assess the durability of reconstruction, and describe complications associated with this procedure. METHODS: A retrospective review of patients undergoing placement of ETC after vertebrectomy for spinal tumor at our institution was performed. RESULTS: From September 2001 to August 2006, 95 patients underwent implantation of an ETC for reconstruction of the anterior spinal column following vertebrectomy for tumor (75 one-level, 19 two-level, 1 three-level). All patients underwent spinal stabilization as well. The median survival after surgery was 13.7 months; 23 patients had primary spinal tumors and 72 had metastatic tumors. Numerical pain scores were significantly improved postoperatively indicating a palliative benefit. No new neurological deficits were noted postoperatively, except when intentional neurological sacrifice was performed for oncologic reasons. Median height correction of 14% (range 0-118%) and median improvement in sagittal alignment of 6 degrees (range 0-28 degrees ) were demonstrated on immediate postoperative imaging. Three patients experienced hardware related complications, one of which had posterior migration of the ETC. On postoperative imaging, 12 patients demonstrated subsidence of greater than 1 mm, but none required operative revision. CONCLUSION: Use of an ETC for spinal reconstruction in patients with spinal tumors is safe, decreases pain associated with pathologic fracture, protects neurologic function, and is durable. We found a very low incidence of cage-related construct failures and no significant problems with subsidence. PMID- 21681632 TI - Takotsubo cardiomyopathy following ischemic stroke: a cause of troponin elevation. PMID- 21681633 TI - Japanese encephalitis (JE) part II: 14 years' follow-up of survivors. AB - Japanese encephalitis, the commonest Arbovirus encephalitis, has been endemic in many parts of Asia, the Pacific Islands, and India; also, there have been many epidemics. Most of the post JE cases have been associated with neurological and neuropsychiatric deficits but have not been properly classified and followed. Practically all the previous studies were in children or young adults. The aim of this study, involving only adult cases, the largest ever being reported, has been to follow the 688/1,199 survivors of JE patients out of 1,282 of acute cases admitted during four epidemics for a period of 14 years after properly classifying the sequelae. This prospective study was conducted in B.R.D. Medical College Gorakhpur (India), involving 665/688 post JE cases with neuropsychiatric deficits from four epidemics of 1978, 1980, 1988 and 1989 which were properly classified in nine groups. While the first epidemic of 1978 was being studied, more disastrous episodes flared up and the patients were subsequently added. Hence, the total duration of this prospective study was from November 1978 to December 2003. There were 14 defaulted initially from 688 followed (23/688 without sequelae and 665/688 with neuropsychiatric deficits), and later 130 were lost from time to time at various stages of follow up. Four out of 23/688 discharged without any deficit had to be readmitted for bizarre movements, assaultative behaviour and euphoria without fever and altered sensorium. All of them improved by symptomatic treatment. Progressive improvement occurred in all the parameters consisting of psychological disturbances, higher cerebral dysfunction, speech disorders (dysphonia, dysarthria, dysphasias, apraxia and agnosia), extra pyramidal, pyramidal features, and hypothalamic disturbances, cranial nerves including pupils and fundi and seizures. Maximum cases improved between 6 months (55%) to 1 year (78%). Only some features improved between 5 to 14 years. Four patients of hemiplegia remained bed ridden. Some non disabling features like dysarthria and corticospinal features without paralysis persisted in 5% (95% improved) and 74% (26% improved) respectively. One patient with bizarre movement and nine with marked tremors could not regain normalcy. A large number of patients of JE are left with several minor or gross residual neuropsychiatric and neurological features after the acute phase. In this series also the discharged patients with neurological deficits who were quite disabled initially and needed constant care by family members and also those who required some help intermittently improved with passage of time and eventually returned to normal life. Some of them were left with non-disabling residual neurological signs even after 14 years. Fourteen of 544 (3%) could not return to their livelihood. PMID- 21681634 TI - Subjective assessment of right ventricle enlargement from computed tomography pulmonary angiography images. PMID- 21681635 TI - Nitrogen fixation in Asaia sp. (family Acetobacteraceae). AB - The genus Asaia (family Acetobacteraceae) was first introduced with a single species-Asaia bogorensis and later six more species were described namely A. siamensis, A. krungthepensis, A. lannaensis, A. platycodi, A. prunellae, and A. astilbes. Acetobacteraceae family has been divided into ten genera but, only three of them include nitrogen fixing species: Gluconacetobacter, Acetobacter, and Swaminathania. This article originated from our study primarily aimed to isolate new endosymbiotic nitrogen fixer among Acetobacteraceae during which we have isolated, for the first time in India, four different strains of Asaia sp. from three different sources: Michalia champaca flower, Anopheles mosquito, and ant Tetraponera rufonigra. All the endosymbiotic strains isolated possess the ability to fix nitrogen. Evidence for both nitrogenase activity and the presence of nifH gene in isolated Asaia sp. is presented. Asaia bogorensis (MTCC 4041(T)) and A. siamensis (MTCC 4042(T)), two of the validated type strains available from the repository, were tested positive for the presence of functional nitrogenase. The nifH gene sequences from these type strains were also confirmed and compared with other nitrogen fixing members of the family Acetobacteraceae. Our result corroborate with the previous reports that Asaia sp. are indeed widely distributed in nature but this is the first time demonstration of their functional nitrogenase activity. This study shows Asaia sp. as fourth genera of nitrogen fixing bacteria in the family Acetobacteraceae. PMID- 21681636 TI - Do patient characteristics, prenatal care setting, and method of payment matter when it comes to provider-patient conversations on perinatal mood? AB - To examine factors associated with provider-patient conversations regarding prenatal and postpartum depressed mood. This study included 3,597 White, African American, Hispanic, and Asian/Pacific Islander NYC resident women who completed the Pregnancy Risk Assessment Monitoring System (PRAMS) survey from 2004-2007, a population-based assessment of patient and health care characteristics. Social determinants including race, nativity, maternal age, prenatal health care setting, and payment type were associated with patient report of having had a conversation about perinatal mood with their provider. Compared to Whites, Asian/Pacific Islanders were less likely to have this conversation (OR = 0.7, CI = 0.5-0.9). Older (OR = 0.6, CI = 0.4-0.9), non-US born (OR = 0.6, CI = 0.5-0.8), and women receiving care from a private doctor or HMO clinic (OR = 0.7, CI = 0.6 0.9) were less likely to have this conversation compared to their respective counterparts. Those who paid for their prenatal care primarily through personal income or through an expanded Medicaid program for prenatal care compared to those who did not were more likely to have had a conversation about mood with their providers. Health care providers and public health advocates should be aware that non-US born women were less likely to have conversations about mood than US born women. However, young mothers shown to be at risk for perinatal depression were more likely to have these conversations compared to older women. Protocols for assessing and educating patients about perinatal mood should be evaluated to improve conversation rates for those receiving care through private doctors and managed care organizations. Income and prenatal care assistance funds may play separate and important roles in provider-patient conversations. PMID- 21681637 TI - Resectable VX-2 rabbit brain tumor model for development of intraoperative local administration of drugs. PMID- 21681638 TI - Bypass of the maxillary to proximal middle cerebral artery or proximal posterior cerebral artery with radial artery graft. AB - The authors report three cases of radial artery (RA) graft bypass from the maxillary artery (MA) to either the middle cerebral artery (MCA) or the posterior cerebral artery (PCA). The first two cases presented with the features of basal ganglion ischemia, and magnetic resonance imaging (MRI) revealed left and right basal ganglion ischemia respectively, whereas angiogram showed MCA occlusion. Computed tomography angiography (CTA) of the third case, who presented with headache and dysphasia, showed a giant basilar artery aneurysm with an absence of the left posterior communicating artery (PComA). The first two cases underwent MA MCA graft bypass and the third case underwent MA-posterior cerebral artery (PCA) RA graft bypass, followed by clipping of the left dominance vertebral artery and a sub-occipital decompressive craniotomy. Postoperative angiogram disclosed patent RA graft and refilling of the ischemic segment. Follow-up at 7-9 months showed marked clinical improvement in all cases. To our knowledge, MA bypass has not been performed clinically till the date and this method may be a safe, effective and new surgical technique for the extracranial-intracranial (EC-IC) bypass surgery. PMID- 21681639 TI - Frame stability and anatomical QA in radiosurgery. AB - OBJECTIVES: The aim of the study was to analyze whether the fixation of the stereotactic frame is stable and whether the location of the treated target coincides with its anatomical location during Gamma Knife((r)) surgery (GKS). MATERIALS AND METHODS: Stereotactic MR examinations using the same high resolution MRI protocol were performed before and after GKS in 18 consecutive patients. The stereotactic (x,y,z) coordinates for three different anatomical landmarks were independently defined three times in each study for each landmark of the images taken before and after GKS by two of the authors, resulting in a total of 648 coordinate definitions. RESULTS: The uncertainty in the readings of the coordinates for the anatomical landmarks was of the same magnitude as the difference in the coordinates before and after GKS in all but one patient. The differences in this one case were due to MR distortion and not to repositioning of the frame. The difference in the coordinates before and after treatment was not affected by the removal of one of the frontal fixation screws in one of the patients. CONCLUSIONS: The stereotactic frame position is stable and does not move. PMID- 21681640 TI - Hypolipidemic activity of Symplocos cochinchinensis S. Moore leaves in hyperlipidemic rats. AB - The hypolipidemic activity of Symplocos cochinchinensis S. Moore leaves was studied in Triton WR-1339- and high fat diet-induced hyperlipidemic rats. In Triton WR-1339-induced hyperlipidemic rats, the hexane extract (250 and 500 mg/kg) exerted a significant (P < 0.01) lipid-lowering effect compared to ethyl acetate and methanol extracts, as assessed by the reversal of the plasma levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). In high fat diet-fed hyperlipidemic rats, the hexane extract (250 and 500 mg/kg) caused the lowering of lipid levels in the plasma and liver. The hypolipidemic activity of S. cochinchinensis leaves was compared with fenofibrate, a known lipid-lowering drug, in both models. PMID- 21681641 TI - Successful treatment of progressive renal injury due to granulomatous tubulointerstitial nephritis with uveitis. AB - Acute tubulointerstitial nephritis and bilateral uveitis (TINU) syndrome is a rare disease usually occurring in young women. We report the exceptional case of a 48-year-old man with TINU syndrome who had a 10-month history of interstitial nephritis before the onset of uveitis. Findings from the renal biopsy specimen indicated tubular atrophy, dense infiltration of lymphocytes, granulomatous infiltration with multinucleated giant cells, and disruption of the vessel wall. The patient was initially diagnosed to have chronic kidney disease; interstitial nephritis could not be diagnosed until blurred vision occurred. However, he was successfully treated with steroid pulse and oral maintenance therapy. Steroid therapy may be effective to treat TINU syndrome irrespective of the onset of the disease. PMID- 21681642 TI - High recurrence risk and use of adjuvant trastuzumab in patients with small, HER2 positive, node-negative breast cancers. AB - BACKGROUND: Five randomized trials of adjuvant trastuzumab have reported significant improvements in recurrence-free survival (RFS) and overall survival. However, patients with node-negative tumors 1 cm or smaller were excluded from these trials. We assessed the recurrence risk and benefit of adjuvant therapy in such patients with small tumors. METHODS: We identified patients with node negative breast tumors 1 cm or smaller between April 2003 and December 2007. Patients were categorized according to HER2 status and pathological tumor size (pT <5 mm vs. 5-10 mm), hormone receptor (HR) status and adjuvant chemotherapy. The primary endpoint was RFS. RESULTS: Of 267 patients included in the analysis, 42 had HER2-positive tumors. The median follow-up was 4.3 years. RFS was worse in patients with HER2-positive tumors than HER2-negative tumors (90.5 vs. 97.7% at 5 years; P = 0.031). In the group with HER2-positive tumors, there were no recurrences in patients with pT<5 mm, but 4 recurrences in those with pT 5-10 mm. RFS was worse in patients with pT 5-10 mm than pT <5 mm (79.0 vs. 100%, P = 0.025). Furthermore 3 recurrences occurred in patients without adjuvant trastuzumab, and 1 recurrence occurred as soon as adjuvant trastuzumab was finished. Our results appear to establish the efficacy of adjuvant trastuzumab therapy. HR status and use of adjuvant chemotherapy were not significantly associated with RFS. CONCLUSIONS: Patients with HER2-positive, node-negative breast tumors 1 cm or smaller (especially 0.5-1.0 cm) have a significant recurrence risk and the decision to employ adjuvant trastuzumab therapy should be discussed with patients based on our results and those of other studies. PMID- 21681643 TI - Catheter-related bloodstream infection with removal of catheter in pediatric oncology patients: a 10-year experience in Taiwan. AB - BACKGROUND: Long-term central venous catheter (CVC) implantation has become more affordable in Taiwan since 1995. Surgical removal of the catheter may be the essential treatment for catheter-related bloodstream infections (CRBSI). The aim of this study was to evaluate the clinical features and microbial isolates in pediatric cancer patients with removal of CVC for CRBSI. PROCEDURE: The records of positive blood culture from hospitalized pediatric oncology patients between 1995 and 2004 were reviewed. One hundred and forty-three patients implanted with a long-term CVC were further identified. RESULTS: Seventeen catheters in 16 patients developed catheter-related bacteremia that needed catheter removal. The rate of catheter removal was 11.9%. The median device life was 7.7 months. Six catheters were removed within 3 months of insertion. Nine of the 17 catheters were removed from patient younger than 2 years. Eight infections occurred during severe neutropenia, and 6 patients had refractory or relapsed underlying disease. The cultural isolates were Gram-negative bacilli in 7, Gram-positive in 5, fungi in 5, and atypical mycobacterium in 1. The frequency of catheter removal for infection control was significantly higher in the first 5 years (1994-1999) compared to the last 5 years (2000-2004) (30.9 vs. 4.0%, p = 2.3 * 10(-4)). CONCLUSIONS: Factors such as microbiological isolates, age of infection, the status of malignancy, and neutropenia are related to catheter outcome. The reduction in patients with positive cultures needing removal of the catheters can be related to improved nursing care and more aggressive antibiotic therapy. PMID- 21681644 TI - Congenital aorta right atrial fistula: successful transcatheter closure with the Amplatzer occluder. PMID- 21681645 TI - Emerging role of IL-23 in rheumatoid arthritis. PMID- 21681646 TI - Recombinant cell bioassays for the detection of (gluco)corticosteroids and endocrine-disrupting potencies of several environmental PCB contaminants. AB - Sensitive and robust bioassays for glucocorticoids are very useful for the pharmaceutical industry, environmental scientists and veterinary control. Here, a recombinant yeast cell was constructed that expresses the human glucocorticoid receptor alpha and a green fluorescent reporter protein in response to glucocorticoids. Both the receptor construct and the reporter construct were stably integrated into the yeast genome. The correct and specific functioning of this yeast glucocorticoid bioassay was studied by exposures to cortisol and other related compounds and critically compared to a GR-CALUX bioassay based on a human bone cell. Although less sensitive, the new yeast glucocorticoid bioassay showed sensitivity towards all (gluco)corticoids tested, with the following order in relative potencies: budesonide >> corticosterone > dexamethasone > cortisol = betamethasone > prednisolone > aldosterone. Hormone representatives for other hormone nuclear receptors, like 17beta-estradiol for the oestrogen receptor, 5alpha-dihydrotestosterone for the androgen receptor and progesterone for the progesterone receptor, showed no clear agonistic responses, whilst some polychlorinated biphenyls were clearly able to interfere with the GR activity. PMID- 21681647 TI - The composition of some Roman medicines: evidence for Pliny's Punic wax? AB - Residues from medicine containers in the collections of the British Museum have been investigated as part of a wider programme of scientific work on Roman surgical instruments. The cylindrical bronze containers are often described as instrument cases, but some contain materia medica, ranging from extensive extant remains of ancient preparations to possible minor deposits on the interior surfaces of the containers. Samples from seven residues have been analysed by gas chromatography-mass spectrometry (GC-MS) to identify lipid, resin and carbohydrate components and by X-ray fluorescence and Raman spectroscopy to characterise inorganic materials. The results have provided evidence for ointments and powders or pills consistent with a medical purpose. The ingredients identified include beeswax, fat, conifer resin and gum-derived sugars, plus elemental carbon and lead and zinc salts. Particularly significant were the varied compositions of residues from four sections of a multi-compartment container. In one of these compartments, the beeswax seems to have been prepared as the 'Punic wax' described by Pliny. Experimental preparation of Punic wax following Pliny's method was undertaken in the laboratory and the product analysed to compare with the ointment residues. This paper discusses the GC-MS results of both the experimental material and the archaeological residues and their significance for the interpretation of the past intended applications of the medicines and the use of the containers. PMID- 21681648 TI - Diagnostic ability of MDCT to assess right hepatic artery invasion by perihilar cholangiocarcinoma with left-sided predominance. AB - BACKGROUND/PURPOSE: There have been few reports on the diagnostic ability of multidetector-row computed tomography (MDCT) to assess invasion of the hepatic artery. The aim of this study was to assess the diagnostic ability of MDCT for right hepatic artery (RHA) invasion. METHODS: From August 2006 to October 2010, 103 consecutive patients with left-sided predominance perihilar cholangiocarcinoma underwent left-sided hepatectomy; all patients received MDCT as a preoperative workup. Three-dimensional volume-rendered and multiplanar reformation (MPR) images were retrospectively examined for evidence of RHA invasion, and the agreement between intraoperative macroscopic and histologic findings was assessed. RESULTS: No macroscopic evidence of RHA invasion was found in any of the 50 patients presenting visible low-density planes on MPR images between the RHA and adjacent tumor. Of the remaining 53 patients without visible low-density planes, 38 patients presented macroscopic evidence of RHA invasion and underwent combined RHA resection; the other 15 patients did not exhibit RHA invasion. The RHA contact length, as measured on MDCT images by curved planar reformations, was significantly longer in the former 38 patients than in the latter 15 patients (24.3 +/- 16.9 vs. 8.6 +/- 3.0 mm, respectively, P = 0.001). Histologic cancer infiltration of the resected RHA was found in 18 (47.4%) of the 38 patients who underwent RHA resection. Diagnosis of macroscopic RHA invasion based on the presence or absence of a low-density plane had an accuracy of 85.4%. CONCLUSIONS: We conclude that MDCT is useful for assessing RHA invasion by perihilar cholangiocarcinoma. PMID- 21681649 TI - Endoscopic bilateral metallic stenting for malignant hilar obstruction using newly designed stents. AB - BACKGROUND/PURPOSE: Whether unilateral or bilateral drainage should be performed for malignant hilar biliary obstruction is controversial. Moreover, endoscopic placement of bilateral metallic stents is difficult and complicated. METHODS: New metallic stents, such as the Niti-S Y-type stent (Y-stent), BONASTENT M-Hilar, and Niti-S large cell D-type stent (LCD), have recently been developed for bilateral stent-in-stent procedures to facilitate contralateral stent deployment through the interstices of the first metallic stent. We review the features and efficacy of these metallic stents designed for bilateral drainage in patients with hilar biliary obstruction. RESULTS: The newly designed stents examined exhibited high technical success rates, low stent-related complications, and good stent patency. Endoscopic reinterventions for occluded stents could be performed easily, particularly in patients with bilateral LCD placement. CONCLUSION: Endoscopic bilateral stenting using newly designed metallic stents is feasible, safe, and effective in patients with unresectable malignant hilar biliary obstruction. PMID- 21681651 TI - Acute management of sick infants with suspected inborn errors of metabolism. AB - Diagnosis of inborn errors of metabolism (IEM) such as an organic acidemia or urea cycle defects requires high index of suspicion in a critically ill infant as these conditions mimic common pediatric illnesses. Prompt initiation of the treatment is mandatory even if a definitive diagnosis is not established immediately. Initial screening investigations may give clues and help to classify these disorders in broad categories. It is of utmost importance to preserve samples for testing. PMID- 21681650 TI - Quantifying millisecond time-scale exchange in proteins by CPMG relaxation dispersion NMR spectroscopy of side-chain carbonyl groups. AB - A new pulse sequence is presented for the measurement of relaxation dispersion profiles quantifying millisecond time-scale exchange dynamics of side-chain carbonyl groups in uniformly (13)C labeled proteins. The methodology has been tested using the 87-residue colicin E7 immunity protein, Im7, which is known to fold via a partially structured low populated intermediate that interconverts with the folded, ground state on the millisecond time-scale. Comparison of exchange parameters extracted for this folding 'reaction' using the present methodology with those obtained from more 'traditional' (15)N and backbone carbonyl probes establishes the utility of the approach. The extracted excited state side-chain carbonyl chemical shifts indicate that the Asx/Glx side-chains are predominantly unstructured in the Im7 folding intermediate. However, several crucial salt-bridges that exist in the native structure appear to be already formed in the excited state, either in part or in full. This information, in concert with that obtained from existing backbone and side-chain methyl relaxation dispersion experiments, will ultimately facilitate a detailed description of the structure of the Im7 folding intermediate. PMID- 21681653 TI - Subcutaneous immunoglobulin replacement therapy with Hizentra, the first 20% SCIG preparation: a practical approach. AB - To reduce the risk of infection in adults and children with primary immunodeficiencies, replacement therapy with IgG, which can be administered to patients intravenously or subcutaneously, is required. Although intravenous administration of IgG (IVIG) has been the therapy of choice in the US and widely used in Europe for many years, subcutaneous administration of IgG (SCIG) has recently gained considerable acceptance among patients and doctors. SCIG therapy achieves high and stable serum IgG levels, is well tolerated, and can be self administered. Hizentra (IgPro20; CSL Behring, Berne, Switzerland) is the first, ready-to-use 20% liquid preparation of human IgG specifically formulated for subcutaneous infusions. The high concentration (20%) might allow shorter infusion times due to smaller infusion volumes, with potential improvement in the convenience of SCIG therapy. Hizentra is well tolerated and has been shown to protect adult and pediatric primary immunodeficiency patients against serious bacterial infections. In addition, it is easy to handle and can be stored at a temperature up to 25 degrees C. In summary, Hizentra is an advance in the field of immunoglobulin replacement therapy, which might offer benefits for home therapy patients. PMID- 21681652 TI - Microbiological efficacy of a new ophthalmic formulation of moxifloxacin dosed twice-daily for bacterial conjunctivitis. AB - INTRODUCTION: An alternative formulation of 0.5% moxifloxacin ophthalmic solution (Moxeza, MOXI-AF, Alcon Laboratories, Inc., Fort Worth, TX, USA) containing xanthan gum to prolong retention on the eye has been developed. MOXI-AF was designed to optimize the treatment regimen for bacterial conjunctivitis for the convenience of the patient with twice-daily dosing. METHODS: A safety and efficacy clinical study was conducted as a multicenter, vehiclecontrolled, randomized, double-masked, parallel group study in clinically diagnosed bacterial conjunctivitis patients aged >28 days. MOXI-AF or its vehicle was dosed one drop twice-daily for 3 days. Microbiological specimens were obtained from affected eyes on day 1, prior to the initial dose, and on day 4 after 3 days of dosing, and processed using routine clinical microbiology laboratory methods. All recovered bacteria were identified to the species level. RESULTS: This paper reports on the microbiological success rate, a secondary efficacy variable in the trial. All patients (1180) were randomized to treatment. Patient age ranged from 30 days to 92 years. The microbiological success rate for patients treated topically with MOXI-AF twice-daily for 3 days was 74.5%, compared with 56.0% of patients treated with its vehicle control (P<0.0001). MOXI-AF was also statistically more effective than vehicle in eradicating the three principle conjunctivitis pathogens, Haemophilus influenzae (98.5% vs. 59.6%, respectively), Streptococcus pneumoniae (86.4% vs. 50.0%, respectively), and Staphylococcus aureus (94.1% vs. 80.0%, respectively) (P<0.001). CONCLUSION: The xanthan gum based 0.5% moxifloxacin ophthalmic formulation, MOXI-AF, provides effective eradication of the three principle causative pathogens of bacterial conjunctivitis across all age groups when dosed twice-daily for 3 days. PMID- 21681654 TI - LvBMP-2 gene-modified BMSCs combined with calcium phosphate cement scaffolds for the repair of calvarial defects in rats. AB - The study aims to evaluate the effect of bone marrow stromal cells (BMSCs) expressing bone morphogenic protein-2 (BMP-2) mediated by lentiviral (Lv) gene transduction combined with calcium phosphate cement (CPC) scaffolds for the repair of critical size calvarial defects in rats. BMSCs derived from Fisher 344 rats were transduced with LvBMP-2 or lentivirus encoding enhanced green fluorescent protein (LvEGFP) in vitro. Obvious osteogenic differentiation of BMSCs in the LvBMP-2 group was demonstrated by alkaline phosphatase staining and alizarin red staining. Enzyme-linked immunosorbent assay results show that LvBMP 2 gene expression in vitro can last for at least 8 weeks. Gene-transduced or untransduced BMSCs were seeded onto CPC scaffolds to repair rat calvarial defects with a diameter of 5 mm. Scanning electron microscope analysis indicated that porous CPC scaffolds facilitated initial adhesion and spreading of BMSCs onto its surface. Calvarial defects were successfully repaired with LvBMP-2-transduced BMSCs/CPC constructs 8 weeks postoperatively. The percentage of new bone formation in the LvBMP-2 group was significantly higher than in other control groups. Lentiviral mediated BMP-2 gene therapy together with CPC scaffolds can be used successfully in calvarial repair and bone regeneration. PMID- 21681655 TI - Analysis of the cytotoxicity of differentially sized titanium dioxide nanoparticles in murine MC3T3-E1 preosteoblasts. AB - There is an increased use of nanophase titanium dioxide (TiO(2)) in bone implants and scaffolds. However, nano-debris is generated at the bone-biomaterial interface. Therefore, TiO(2) nanoparticles (NPs) of many sizes were investigated for cytotoxic effects on murine MC3T3-E1 preosteoblasts. These TiO(2) NPs induced a time- and dose-dependent decrease in cell viability. There was a significant increase in lactate dehydrogenase (LDH) release, apoptosis and mitochondrial membrane permeability following short-term exposure of the cells to TiO(2) NPs. These NPs also increased granulocyte-macrophage colony stimulating factor (GM CSF) and granulocyte colony-stimulating factor (G-CSF) gene expression. Compared with the 32 nm TiO(2) NPs, 5 nm TiO(2) NPs were more toxic, induced more apoptosis, increased mitochondrial membrane permeability and stimulated more GM CSF expression at a high concentration (>=100 MUg/ml). The results implied that the differential toxicity was associated with variations in size, so more attention should be given to the toxicity of small NPs for the design of future materials for implantation. PMID- 21681656 TI - Poly(lactide-co-glycolide)/hydroxyapatite nanofibrous scaffolds fabricated by electrospinning for bone tissue engineering. AB - Poly(lactide-co-glycolide) (PLGA) nanofibrous composite scaffolds having nano hydroxyapatite particles (HAp) in the fibers were prepared by electrospinning of PLGA and HAp with an average diameter of 266.6 +/- 7.3 nm. Microscopy and spectroscopy characterizations confirmed integration of the crystalline HAp in the scaffolds. Agglomerates gradually appeared and increased on the fiber surface along with increase of the HAp concentration. In vitro mineralization in a 5 * simulated body fluid (SBF) revealed that the PLGA/HAp nanofibrous scaffolds had a stronger biomineralization ability than the control PLGA scaffolds. Biological performance of the nanofibrous scaffolds of the control PLGA and PLGA with 5 wt% HAp (PLGA/5HAp) was assessed by in vitro culture of neonatal mouse calvaria derived MC3T3-E1 osteoblasts. Both types of the scaffolds could support cell proliferation and showed sharp increase of viability until 7 days, but the cells cultured on the PLGA/5HAp nanofibers showed a more spreading morphology. Despite the similar level of the cell viability and cell number at each time interval, the alkaline phosphatase secretion was significantly enhanced on the PLGA/5HAp scaffolds, indicating the higher bioactivity of the as-prepared nano-HAp and the success of the present method for preparing biomimetic scaffold for bone regeneration. PMID- 21681658 TI - Fabrication of silver nanocomposite films impregnated with curcumin for superior antibacterial applications. AB - Silver nanocomposite films are found to be very effective material for anti bacterial application. In the present work, sodium carboxylmethyl cellulose silver nanocomposite films (SCMC SNCF) were tried for antibacterial applications. To enhance their applicability novel film-silver nanoparticle-curcumin composites have been developed. SCMC SNCF are developed from sodium carboxylmethyl cellulose (SCMC), N,N(1)-methylenebisacrylamide (MBA) and silver nitrate solution. These films were characterized by FTIR, UV-visible, XRD, TGA, DSC and TEM techniques. The formed silver nanoparticles have an average particle size of ~15 nm as observed by transmission electron microscopy (TEM). Curcumin loading into SCMC SNCF is achieved by diffusion mechanism. The UV-Visible analysis indicated that higher encapsulation of curcumin in the films with higher SCMC content. Further, it was observed that the presence of silver nanoparticles in the films enhanced the encapsulation of curcumin indicating an interaction between them. Moreover, the antibacterial activity showed that the SCMC films generated with silver nanoparticles have a synergistic effect in the antimicrobial activity against Escherichia coli (E. coli). In order improve the healing efficacy as antibacterial agents, curcumin loaded with SCMC SNCFs were developed which showed significant inhibition of E. coli growth than the silver nanoparticles and curcumin alone film. Therefore, the present study clearly provides novel antimicrobial films which are potentially useful in preventing/treating infections. PMID- 21681659 TI - Health-related quality of life and adaptive behaviors of adolescents with sickle cell disease: stress processing moderators. AB - The objective of this study was to examine resilience among adolescents with sickle cell disease (SCD), focusing on the interaction of health-related quality of life with stress processing to explain adaptive behavior. Forty-four adolescents with SCD completed paper-and-pencil measures of health-related quality of life, appraisals (hope), pain coping strategies (e.g. adherence), and adaptive behavior. Self-reported health-related quality of life was significantly associated with adaptive behavior, as was adherence. Findings for moderation were mixed. Pain coping strategies moderated the association of health-related quality of life with adaptive behavior such that at lower levels of Coping Strategies Questionnaire (CSQ) Adherence, better quality of life was associated with higher adaptive behavior. Similarly, at higher levels of hope, better quality of life was associated with higher adaptive behavior, and poorer quality of life was associated with lower adaptive behavior. Adolescents with SCD showed resilience, particularly in terms of personal adjustment, that may be explained by their appraisals and stress processing strategies. Interventions to support an optimistic or hopeful outlook and improve adherence to recommendations for medical management of sickle cell pain may result in improved resilience/adaptive behavior. PMID- 21681660 TI - Perceptual recovery from consonant-cluster simplification in Korean using language-specific phonological knowledge. AB - Two experiments examined whether perceptual recovery from Korean consonant cluster simplification is based on language-specific phonological knowledge. In tri-consonantal C1C2C3 sequences such as /lkt/ and /lpt/ in Seoul Korean, either C1 or C2 can be completely deleted. Seoul Koreans monitored for C2 targets (/p/ or / k/, deleted or preserved) in the second word of a two-word phrase with an underlying /l/-C2-/t/ sequence. In Experiment 1 the target-bearing words had contextual lexical-semantic support. Listeners recovered deleted targets as fast and as accurately as preserved targets with both Word and Intonational Phrase (IP) boundaries between the two words. In Experiment 2, contexts were low-pass filtered. Listeners were still able to recover deleted targets as well as preserved targets in IP-boundary contexts, but better with physically-present targets than with deleted targets in Word-boundary contexts. This suggests that the benefit of having target acoustic-phonetic information emerges only when higher-order (contextual and phrase-boundary) information is not available. The strikingly efficient recovery of deleted phonemes with neither acoustic-phonetic cues nor contextual support demonstrates that language-specific phonological knowledge, rather than language-universal perceptual processes which rely on fine grained phonetic details, is employed when the listener perceives the results of a continuous-speech process in which reduction is phonetically complete. PMID- 21681661 TI - Oral elastofibromatous lesions: a review and case series. AB - Elastofibromas of the oral cavity are rare, with only 5 cases reported. In this paper, we present a series of five new cases of oral elastofibromatous lesions, occurring in 4 males and 1 female, with ages ranging from 33 to 76 years. The clinical differential diagnosis includes fibroepithelial polyp or fibroma, among other connective tissue tumours. Elastofibromas probably develop as reactive lesions, for which surgical treatment is definitive. PMID- 21681663 TI - An unexpected finding of a bronchogenic cyst presenting as a thyroid mass. AB - Herein we present a case of a bronchogenic cyst masquerading as a thyroid mass. Bronchogenic cysts are rare congenital malformations that result from an abnormal development of the ventral foregut during organogenesis. They are commonly asymptomatic lesions rarely found in the neck. In our case, a young male presented with complaints of neck discomfort over a long period presumed to be secondary to a thyroid mass based on imaging studies. Fine needle aspiration was inconclusive. Post-operative pathological sectioning revealed evidence of a bronchogenic cyst. These lesions have a low incidence of malignancy, and complete surgical excision has been recommended. PMID- 21681662 TI - Salivary oncocytic cystadenoma with intraluminal crystalloids: a case report with review of the literature. AB - Oncocytic cystadenoma is a rare benign tumor of major salivary glands that in rare occasions may present histologically with intraluminal crystalloids. We report a case of 53-year-old man with a progressively enlarging lump in the left submandibular region. Ultrasound examination revealed a cystic mass with an intraluminal fluid collection. The tumor was surgically removed. Histologic examination yielded a diagnosis of oncocytic cystadenoma with a high concentration of intraluminal crystalloids. The microscopic features of the crystalloids were compatible with nontyrosine (alpha-amylase) crystalloids. When compared with previously published cases in the literature, this is the first report of oncocytic cystadenoma with intraluminal crystalloids arising in the submandibular gland, and the second reported case of the nontyrosine type of crystalloids occurring in association with this tumor. The nontyrosine crystalloids may be highly characteristic to salivary gland tumors with oncocytic differentiation. PMID- 21681664 TI - Signal honesty through differential quantity in the female-produced sex pheromone of the moth Heliothis virescens. AB - Over the last 50 years, female-produced sex pheromones of moths have been subjected to intensive study. Most work has focused on their role in mate recognition, and little on any role they may have in mate assessment. This is largely because it has been assumed that female, rather than male, moths are "choosy", and invest larger amounts of carbon in eggs than in pheromone. Recently, we found that pheromone production in the moth Heliothis virescens depended on hemolymph trehalose concentration, and that sugar-stressed females produced less pheromone than unstressed ones. In this paper, we demonstrate, for the first time in moths, that a female-produced pheromone signal can allow H. virescens males to assess sugar resources (quality) of a female. This signal honesty is based on quantitative, rather than qualitative (component ratio), differences in pheromone, produced and released by sugar-stressed and unstressed females. Increasing marginal cost of pheromone production, as sugar resources are depleted, may ensure signal honesty. PMID- 21681665 TI - Undifferentiated sarcoma of the sellar region. AB - Malignancies lacking specific features of cellular maturation are termed "undifferentiated" and represent 5-10% of all human tumors. They are encountered at a variety of sites but do not, as a rule, arise in the sellar region. A 39 year-old male with a history of testicular seminoma and an unsuccessful biopsy of a third ventricular neoplasm, presented with visual disturbances and memory loss. Light microscopically, the tumor consisted entirely of undifferentiated spindle cells. No germ cell component was noted. An exhaustive immunohistochemical study found immunoreactivity for vimentin and desmin, but for no other myoid markers. Polymerase chain reaction showed no X;18 translocation. Based upon these studies, a diagnosis of "undifferentiated sarcoma" was made. Our case, being highly unusual among reported sellar neoplasms, underscores the difficulties inherent in the differential diagnosis of undifferentiated neoplasms. PMID- 21681667 TI - A special issue on nanotoxicology. PMID- 21681666 TI - TDP-43 autoregulation: implications for disease. AB - TDP-43 is a nuclear protein that has been shown to play a central role in RNA metabolism. In recent years, this protein has become very important in the study of neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration (FTLD). These diseases share, as common feature, the presence of abnormally aggregated, posttranslationally modified, and mislocalized TDP-43 in the cell cytoplasm of both neurons and glial cells. A major question in TDP-43 research is represented by the investigation of the mechanism(s) that trigger this process and its potential consequences. Regarding the first issue, it is likely that relative protein expression levels might play an important role as has been demonstrated for many protein aggregation processes. In fact, the eventual misregulation of TDP-43 expression leading to enhanced protein production might well correlate with enhanced aggregation, and thus results in increasingly harmful gain- or loss-of-function effects on cellular metabolism. For this reason, it is important to determine the mechanisms that act to regulate TDP-43 levels within the cell. In normal conditions, it is now clear that TDP-43 can modulate its own protein levels through a negative feedback loop triggered by binding to its own RNA in the 3'UTR region leading to mRNA degradation. This work discusses how an eventual disruption of this mechanism might affect TDP-43 pathology, focusing in particular on its association with stress granules and intrinsic aggregation properties. PMID- 21681668 TI - Partial liver transplantation. AB - Partial liver transplantation, including reducedsize liver transplantation, split liver transplantation, and living donor liver transplantation, has been developed with several innovative techniques because of donor shortage. Reduced-size liver transplantation is based on Couinaud's anatomical classification, benefiting children and small adult recipients but failing to relieve the overall donor shortage. Split liver transplantation provides chances to two or even more recipients when only one liver graft is available. The splitting technique must follow stricter anatomical and physiological criteria either ex situ or in situ to ensure long-term quality. The first and most important issue involving living donor liver transplantation is donor safety. Before surgery, a series of donor evaluations-including anatomical, liver volume, and liver function evaluations-is indispensable, followed by ethnic agreement. At different recipient conditions, auxiliary liver transplantation and auxiliary partial orthotopic liver transplantation, which employ piggyback techniques, are good alternatives. Partial liver transplantation enriches the practice and knowledge of the transplant society. PMID- 21681669 TI - The influence of brain death on donor liver and the potential mechanisms of protective intervention. AB - Brain-dead donors have become one of the main sources of organs for transplantation in Western countries. The quality of donor organs is closely related to the outcome of the transplantation. Experimental studies have confirmed the inferior graft survival of livers from brain-dead donors compared with those from living donors. Studies conducted in the past 10 years have shown that brain death is associated with effects on the decreased donor organ quality. However, whether the decrease in the viability of donor organs is caused by brain death or by the events before and after brain death remains uncertain. The purpose of this review is to introduce the advances and controversies regarding the influence of brain death on the viability of donor livers and to summarize the mechanisms of the different protective interventions for donor livers. PMID- 21681670 TI - Integrated management of cardiac failure: the cardiac failure clinic. AB - The prevalence of the risk factors and the risk of cardiac failure are both increasing in China. This might be the consequence of the changes of the life conditions (emigration to the urban areas, changes in the diet and life style, lack of physical exercise, etc.). The wide range of clinical presentations of cardiac failure (acute or chronic) and of therapeutic approaches (medical or surgical) makes necessary the integration within the same structure of the various experts involved in the diagnosis and the treatment of cardiac diseases. Technologic and human resources required to offer all the options represent a multifaceted commitment which should be focused optimally in dedicated centers. In these centers, collaboration should replace competition between the medical and the surgical cardiac specialists. Development of team work should permit to optimize the cost efficacy of the treatments. Most of all, such a structure will facilitate the translation of innovative therapies between the research centers and clinical facilities. PMID- 21681671 TI - Therapeutic potential of stem cell in liver regeneration. AB - Liver transplantation is the only life-saving procedure for patients with end stage liver disease. However, its potential benefits are hampered by many disadvantages, such as the relative shortage of donors, operative risks, and high costs. These issues have prompted the search for new alternative therapies for irreversible liver disease. Stem cell therapy, with the ability for self-renewal and potential for multilineage differentiation, is a promising alternative approach. Several studies have demonstrated that transplantation of hepatic stem/progenitor cells or hepatocyte-like cells derived from multipotent stem cells leads to donor cell-mediated repopulation of the liver and improved survival rates in experimental models of liver disease. However, a registered clinical application based on stem cell technology will take at least an additional 5 to 10 years because of some limitations; e.g. the lack of suitable cell sources and risk of teratoma formation. This review summarizes the general understanding of the therapeutic potentials of stem cells in liver disease, including the sources, mechanisms, and delivery methods of hepatic stem cells in liver regeneration, and discusses some challenges for their therapeutic application. PMID- 21681672 TI - Regulatory factors of mesenchymal stem cell migration into injured tissues and their signal transduction mechanisms. AB - Adult stem cells hold great promise for wound healing and tissue regeneration. Mesenchymal stem cells (MSCs), for example, have been shown to play a role in tissue repair. Research has shown that endogenous bone marrow MSCs or exogenously delivered MSCs migrate to the sites of injury and participate in the repair process. The precise mechanisms underlying migration of MSCs into the injured tissue are still not fully understood, although multiple signaling pathways and molecules were reported, including both chemoattractive factors and endogenous electric fields at wounds. This review will briefly summarize the regulatory facors and signaling transduction pathways involved in migration of MSCs. A better understanding of the molecular mechanisms involved in the migration of MSCs will help us to develop new stem cell-based therapeutic strategies in regenerative medicine. PMID- 21681673 TI - Stem cell niches and endogenous electric fields in tissue repair. AB - Adult stem cells are responsible for homeostasis and repair of many tissues. Endogenous adult stem cells reside in certain regions of organs, known as the stem cell niche, which is recognized to have an important role in regulating tissue maintenance and repair. In wound healing and tissue repair, stem cells are mobilized and recruited to the site of wound, and participate in the repair process. Many regulatory factors are involved in the stem cell-based repair process, including stem cell niches and endogenous wound electric fields, which are present at wound tissues and proved to be important in guiding wound healing. Here we briefly review the role of stem cell niches and endogenous electric fields in tissue repair, and hypothesize that endogenous electric fields become part of stem cell niche in the wound site. PMID- 21681674 TI - Arsenic in the treatment of newly diagnosed acute promyelocytic leukemia: current status and future research direction. AB - Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia. In past decades, intensive studies on the biology and treatment of this disease have resulted in a remarkably thorough understanding of its pathogenesis and improvement of treatment outcomes. In particular, the introduction of all-trans retinoic acid to conventional chemotherapy improved dramatically the remission and survival rates of APL patients and consequently became the major treatment modality for it. In the last decade, the groundbreaking development of arsenic further improved the survival rate of APL patients. As the most active agent in APL, arsenic directly degrades the PML-RARalpha fusion transcript, leading to the differentiation and apoptosis of leukemia cells and the potential eradication of APL leukemiainitiating cells (LICs), thus making the disease a potentially curable type of leukemia. More notably, the recent development of oral arsenic compounds may further enhance not only clinical outcomes but also the convenience of patients, which may dramatically change the APL clinical scenario in the near future. PMID- 21681675 TI - Lobectomy by video-assisted thoracoscopic surgery (VATS) for early stage of non small cell lung cancer. AB - Video-assisted thoracoscopic surgery (VATS) provides a new approach for treating early-stage lung cancer. Lobectomy by VATS has many advantages over conventional thoracotomy, such as shorter recovery time, less postoperative pain, and faster resumption of a normal lifestyle. However, there is still much debate on the role of VATS in lobectomy for the treatment of lung cancer. Concerns regarding safety, the extent of mediastinal lymph node dissection, and long-term survival have made some surgeons apprehensive of its validity for lung cancer. In this paper, we review the development of thoracoscopy, the present status of VATS for early stage of non-small cell lung cancer (NSCLC), and comparison between VATS and open thoracotomy in the management of NSCLC. PMID- 21681676 TI - Tissue engineering of cartilage, tendon and bone. AB - Tissue engineering aims to produce a functional tissue replacement to repair defects. Tissue reconstruction is an essential step toward the clinical application of engineered tissues. Significant progress has recently been achieved in this field. In our laboratory, we focus on construction of cartilage, tendon and bone. The purpose of this review was to summarize the advances in the engineering of these three tissues, particularly focusing on tissue regeneration and defect repair in our laboratory. In cartilage engineering, articular cartilage was reconstructed and defects were repaired in animal models. More sophisticated tissues, such as cartilage in the ear and trachea, were reconstructed both in vitro and in vivo with specific shapes and sizes. Engineered tendon was generated in vitro and in vivo in many animal models with tenocytes or dermal fibroblasts in combination with appropriate mechanical loading. Cranial and limb bone defects were also successfully regenerated and repaired in large animals. Based on sophisticated animal studies, several clinical trials of engineered bone have been launched with promising preliminary results, displaying the high potential for clinical application. PMID- 21681677 TI - The role of protein kinase C epsilon in neural signal transduction and neurogenic diseases. AB - Protein kinase C epsilon (PKC E) is one of major isoforms in novel PKC family. Although it has been extensively characterized in the past decade, the role of PKC E in neuron is still not well understood. Advances in molecular biology have now removed significant barriers to the direct investigation of PKC E functions in vivo, and PKC E has been increasingly implicated in the neural biological functions and associated neurogenic diseases. Recent studies have provided important insights into the influence of PKC E on cortical processing at both the single cell level and network level. These studies provide compelling evidence that PKC E could regulate distinct aspects of neural signal transduction and suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of PKC E signal pathway in the developing brain. PMID- 21681678 TI - Self-etching adhesives: possible new pulp capping agents to vital pulp therapy. AB - Pulp capping is one of the solving for keeping vital pulp in the case of dentin caries, reversible pulpitis or traumatic pulp exposure. The presence of bacteria on the cavity walls or in the pulp was the major factor that leads to the failure of pulp capping. Traditional pulp capping agent, calcium hydroxide, may not prevent microleakage. Selfetching system is a newly developed adhesive system, which could provide less microleakage and would not break down or dissolve, preventing the oral fluids and bacteria from the pulp along the cavity wall. This may reduce such clinical problems as postoperative sensitivity, secondary caries and marginal discoloration. Researches showed that some kinds of self-etching adhesives induced the mild to moderate inflammatory pulp response, with negative bacterial staining. Inclusion of antibacterial components into self-etching system, such as 12-methacryloyloxydodecylpyridinium bromide (MDPB) may inhibit bacteria and provide better clinical effects. It is speculated that using the self-etching adhesive system containing the antibacterial agent, such as MDPB, to the dental pulp directly or indirectly, may inhibit bacteria after the placement of restoration as well as residual bacteria in the cavity. PMID- 21681679 TI - Successful kidney transplantation in highly sensitized patients. AB - Highly sensitized patients experience an increased number of rejection episodes and have poorer graft survival rates; hence, sensitization is a significant barrier to both access to and the success of organ transplantation. This study reports our experience in kidney transplantation in highly sensitized patients. Fourteen patients with sensitization or high levels of panelreactive antibodies (PRA) were studied. All patients were desensitized with pre-transplant intravenous immunoglobulin (IVIG)/plasmapheresis (PP) with or without rituximab and thymoglobulin induction therapy, combined with a Prograf/MMF/Pred immunosuppressive regimen. Of 14 patients, 10 showed good graft functions without acute rejection (AR) episodes. Acute cellular rejection in two patients was reversed by methylprednisolone. Two patients underwent antibody-mediated rejection; one was treated with PP/IVIG successfully, whereas the other lost graft functions due to the de novo production of donor-specific antibodies (DSA). Graft functions were stable, and there were no AR episodes in other patients. Conclusively, desensitization using PP/IVIG with or without rituximab increases the likelihood of successful live-donor kidney transplantation in sensitized recipients. PMID- 21681680 TI - Overexpression of netrin-1 improves neurological outcomes in mice following transient middle cerebral artery occlusion. AB - Netrin-1 (NT-1) is one of the axon-guiding molecules that are critical for neuronal development. Because of its structural homology to the endothelial mitogens, NT-1 may have similar effects on vascular network formation. NT-1 was shown to be able to stimulate the proliferation and migration of human cerebral endothelial cells in vitro and also promote focal neovascularization in adult brain in vivo. In the present study, we reported the delivery of NT-1 using an adeno-associated virus (AAV) vector (AAV-NT-1) into mouse brain followed by transient middle cerebral artery occlusion (tMCAO). We found that AAV vectors did not elicit a detectable inflammatory response, cell loss or neuronal damage after brain transduction. The level of NT-1 was increased in the AAV-NT-1-transduced tMCAO mice compared with the control mice. Furthermore, the neurobehavioral outcomes were significantly improved in AAV-NT-1-transduced mice compared with the control animals (P<0.05) 7 days after tMCAO. Our data suggests that NT-1 plays a neuronal function recovery role in ischemic brain and that NT-1 gene transfer might present a valuable approach to treat brain ischemic disorders. PMID- 21681681 TI - Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. AB - Mesenchymal stem cells (MSC) have been used in clinical trials for severe diabetes, a chronic disease with high morbidity and mortality. Bone marrow is the traditional source of human MSC, but human term placenta appears to be an alternative and more readily available source. Here, the therapeutic effect of human placenta-derived MSC (PD-MSC) was studied in type 2 diabetes patients with longer duration, islet cell dysfunction, high insulin doses as well as poor glycemic control in order to evaluate the safety, efficacy and feasibility of PDMSC treatment in type 2 diabetes (T2D). Ten patients with T2D received three intravenous infusions of PDSC, with one month interval of infusion. The total number of PDSC for each patient was (1.22-1.51) * 10(6)/kg, with an average of 1.35 * 10(6)/kg. All of the patients were followed up after therapy for at least 3 months. A daily mean dose of insulin used in 10 patients was decreased from 63.7+/-18.7 to 34.7+/-13.4 IU (P<0.01), and the C-peptide level was increased from 4.1 +/-3.7 ng/mL to 5.6 +/-3.8 ng/mL (P<0.05) respectively after therapy. In 4 of 10 responders their insulin doses reduced more than 50% after infusion. The mean levels of insulin and C-peptide at each time point in a total of 10 patients was higher after treatment (P<0.05). No fever, chills, liver damage and other side effects were reported. The renal function and cardiac function were improved after infusion. The results obtained from this pilot clinical trial indicate that transplantation of PD-MSC represents a simple, safe and effective therapeutic approach for T2D patients with islet cell dysfunction. Further large-scale, randomized and well-controlled clinical studies will be required to substantiate these observations. PMID- 21681682 TI - Downregulation effects of beta-elemene on the levels of plasma endotoxin, serum TNF-alpha, and hepatic CD14 expression in rats with liver fibrosis. AB - It has been demonstrated that beta-elemene could protect against carbon tetrachloride (CCl(4))-induced liver fibrosis in our laboratory work, and the aim of this paper is to reveal the protective mechanisms of beta-elemene. The hepatic fibrosis experimental model was induced by the hypodermical injection of CCl(4) in Wistar male rats. beta-elemene was intraperitoneally administered into rats for 8 weeks (0.1 mL/100 g bodyweight per day), and plasma endotoxin content was assayed by biochemistry. The serum TNF-alpha level was detected using radioactive immunity. CD14 expression in rat livers was measured by immunohistochemistry and Western blot. The results showed that beta-elemene can downregulate the levels of plasma endotoxins, serum TNF-alpha, and hepatic CD14 expression in rats with liver fibrosis. beta-elemene plays an important role in downregulating the lipopolysaccharide signal transduction pathway, a significant pathway in hepatic fibrosis development. PMID- 21681683 TI - A better way to do small-for-size liver transplantation in rats. AB - Establishing a model for small-for-size liver transplantation is the basis for this study of partial and living donor graft liver transplantation. This study aims to explore a simpler and more effective way of establishing a 30% small-for size liver transplantation in rats. Sprague-Dawley rats were selected as the donors and recipients. Small-for-size orthotopic liver transplantation was performed using Kamada's two-cuff method. The donor's liver was flushed via the abdominal aorta and hepatectomy was performed in situ. The animals were divided into three groups depending on the graft selected, with 40 pairs of rats in each group. In group I, the median lobe of the liver was used as graft; in group II, the right half of the median lobe and the right lobe were used as graft; and in group III, the median and right lobes were used as graft. In groups I and II, the bodyweights of donors were the same as those of recipients; however, in group III the bodyweights of donors were 100-120 g less than those of the recipients. The duration needed for transplantation, the 7-day survival rates, and the technical complication rates were compared among these three groups. The time required for hepatectomy was shorter in group III compared with groups I and II (8.8+/-0.7 min vs. 11.5+/-1.1 min and 10.1+/-1.0 min, P = 0.001). The cold ischemia time for the grafts, the anhepatic times, and the transplantation times for the recipients were not significantly different among the three groups. Compared with groups I and II, the incidence of bleeding, bile leakage, and inferior vena caval strictures were significantly decreased in group III (P<0.05). No significant differences between the three groups were found based on other complications after the operation (P>0.05). Group III had better 7-day survival rates and longer median survival times but the differences were not statistically significant. The method of small for donor bodyweight using the median and right lobes for grafting may be a more effective and simpler way of establishing a 30% small-for-size liver transplantation in rats, as shown by the shorter hepatectomy time and the occurrence of fewer complications after the operation. PMID- 21681684 TI - Passive immunization with allergen-specific antibodies. AB - The induction of allergen-specific IgG antibodies has been identified as a major mechanism responsible for the reduction of allergic inflammation in allergic patients treated by allergen-specific immunotherapy. Several studies suggest that allergen-specific IgG antibodies induced by vaccination with allergens block mast cell and basophil degranulation, IgE-facilitated allergen presentation to T cells and IgE production. The availability of recombinant allergens and technologies for the production of recombinant human antibodies allows engineering of allergen specific antibodies which can be used for passive immunization (i.e., therapy) and eventually for the prevention of allergy (i.e., prophylaxis). This chapter summarizes data supporting the possible use of allergen-specific antibodies for treatment and prophylaxis. Finally, concrete approaches for the treatment and prevention of allergy based on blocking antibodies are envisioned. PMID- 21681686 TI - Erratum. AB - PMID- 21681685 TI - The dermis as a portal for dendritic cell-targeted immunotherapy of cutaneous melanoma. AB - Complete surgical excision at an early stage remains the only curative treatment for cutaneous melanoma with few available adjuvant therapy options. Nevertheless, melanoma is a relatively immunogenic tumor type and particularly amenable to immunotherapeutic approaches. A dense network of cutaneous dendritic cells (DC) may account for the reported efficacy of vaccination through the skin and provide an attractive target for the immunotherapy of melanoma. Several phenotypically distinct DC subsets are discernable in the skin, among others, epidermal Langerhans cells and dermal DC. Upon appropriate activation both subsets can efficiently migrate to melanoma-draining lymph nodes (LN) to prime T cell mediated responses. Unfortunately, from an early stage, melanoma development is characterized by strong immune suppression, facilitating unchecked tumor growth and spread. Particularly the primary tumor site and the first-line tumor-draining LN, the so-called sentinel LN, bear the brunt of this melanoma-induced immune suppression-and these are exactly the sites where anti-melanoma effector T cell responses should be primed by DC in order to prevent early metastasis. Through local immunopotentiation or through DC-targeted vaccination, the dermis may be utilized as a portal to activate DC and kick-start or boost effective T cell mediated anti-melanoma immunity, even in the face of this immune suppression. PMID- 21681687 TI - Spontaneous in vitro IL-6 production in various intestinal segments in patients with inflammatory bowel disease. AB - Interleukin-6 (IL-6) plays an important role in regulation of intestinal inflammatory processes in inflammatory bowel disease (IBD). The levels of IL-6 in media from cultured biopsy samples were determined by ELISA in 14 Crohn's disease (CD) patients, 17 patients with ulcerative colitis (UC), and 24 healthy controls in terminal ileum, cecum, and rectum. Results were confirmed by measuring mRNA expression in selected patients. In CD patients, there were increased levels of IL-6 (expressed in picograms per milligram of biopsy tissue mass) in terminal ileum compared with controls (median, 617 vs. 90.4; p < 0.001). High IL-6 levels were found in the rectum of CD patients with active disease but normal endoscopic findings (791 vs. 131; p < 0.05). This result was confirmed by mRNA expression. There was a substantial increase of IL-6 levels in cultured cecal (median, 327 vs. 94.0; p < 0.001) and rectal mucosa (median, 282 vs.131; p < 0.05) but not in ileal mucosa of UC patients. In conclusion, IL-6 production was higher in IBD patients than in controls; it correlated with disease activity and varied among different intestinal segments. In clinically active CD patients without rectal involvement, high IL-6 levels in cultured rectal mucosa suggest immune stimulation even in the absence of macroscopic inflammation. PMID- 21681688 TI - Neuroradiological response criteria for high-grade gliomas. AB - The recently introduced new response criteria of the response assessment in neuro oncology (RANO) working group and its clinical implications are the topic of this article. Establishing this working group as a work-in-progress platform and its first report, the RANO criteria represent an important step forward in the accurate assessment of response to therapy in patients with malignant gliomas not only in clinical trials but also in daily practice. Anti-angiogenic therapy and other new treatment modalities have increased the incidence and awareness of novel imaging phenomena, such as pseudoprogression and pseudoresponse not only within clinical trials. The new RANO criteria also take clinical parameters, such as steroid medication and neurological symptoms into account. Neuroradiologists and neuro-oncologists need to be aware of and experienced in applying these new criteria to correctly assess the response to treatment in patients with malignant gliomas. Further research is needed to study new imaging techniques, such as perfusion and diffusion-weighted imaging and to investigate and incorporate these for routine tumor response criteria. PMID- 21681689 TI - Combination of ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, and cisplatin enhances the inhibition of growth of human ovarian cancers. AB - PURPOSE: We have recently reported that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands produce antitumor effects against human ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis via regulating prostaglandin (PG) E(2) level. In this study, we investigated the effects of combination of ciglitazone, a PPARgamma ligand, and cisplatin, a cytotoxic anti-cancer drug, on growth of ovarian cancer. METHODS: Tumor growth and survival were examined in female nu/nu mice xenografted with subcutaneous OVCAR-3 tumors or with intraperitoneal DISS tumors and treated with cisplatin alone (5 mg/kg intraperitoneally once on day 1), ciglitazone alone (15 mg/kg intraperitoneally once a week), or the combination. RESULTS: Ciglitazone alone, cisplatin alone, or their combination significantly suppressed the growth of OVCAR-3 tumors xenotransplated subcutaneously and prolonged the survival of mice with malignant ascites derived from DISS cells as compared with the control. Furthermore, the combination produced a significantly greater antitumor effect than cisplatin or ciglitazone alone and also significantly prolonged the survival time as compared with cisplatin or ciglitazone alone. The combination significantly decreased PGE(2) concentration in serum as well as in ascites, reduced vascular endothelial growth factor as well as microvessel density, and induced apoptosis in solid OVCAR-3 tumor as compared with cisplatin or ciglitazone alone. The combination remarkably decreased the expression of cyclooxygenase-2 (COX-2), microsomal PG E synthase (mPGES), and PG receptor 3 (EP3) in tumors. In vitro experiment showed that ciglitazone enhances the cytotoxicity of cisplatin against ovarian cancer cells. CONCLUSION: In conclusion, the combination inhibited the growth of ovarian cancer in conjunction with reduction in angiogenesis and induction of apoptosis resulting from suppression of PGE(2) activation through decreasing the expression of COX-2, mPGES, and EP3. The inhibitory effect of this combination treatment on growth of ovarian cancer suggests a potential to lead a novel therapeutic strategy against ovarian cancer. PMID- 21681691 TI - Continuity in sex-typed behavior from preschool to adolescence: a longitudinal population study of boys and girls aged 3-13 years. AB - Sex-typed behavior was assessed at age 3 using the Pre-School Activities Inventory, and at age 13 using the Multidimensional Gender Identity Scale, in 54 masculine boys, 57 masculine girls, 75 feminine boys, 65 feminine girls, 61 control boys, and 65 control girls. At age 13, girls who had been masculine at age 3 felt less similar to other girls, were less content being a girl, and had greater self-efficacy for male-typed activities than control girls, and girls who had been feminine at age 3 had greater self-efficacy for female-typed activities. Boys who had been feminine at age 3 felt less similar to other boys and had lower self-efficacy for male-typed activities than control boys at age 13, and boys who had been masculine at age 3 felt more competent in agentic roles. Thus, sex-typed behavior at age 3 predicted sex-typed behavior at age 13. It was concluded that the degree of sex-typed behavior shown by preschool children is a good indicator of their degree of sex-typed behavior following the transition to adolescence. PMID- 21681692 TI - Doing more good than harm? The effects of participation in sex research on young people in the Netherlands. AB - Ethical guidelines for research with human participants stress the importance of minimizing risks and maximizing benefits. In order to assist Institutional Review Boards (IRBs) and researchers to make more informed risk/benefit analyses with regard to sex research among adolescents, the current study examined the effects of participation in sex research among 899 young people (15-25 years old). Participants completed three questionnaires on a wide range of sexuality-related measures. They also completed scales measuring their levels of distress, need for help, and positive feelings due to their research participation. In general, negative effects of research participation seemed limited, while benefits of participation appeared substantial. Several differences with regard to sociodemographic characteristics were found (e.g., females experienced more distress then males and younger or lower educated participants experienced more positive feelings). In addition, victims of sexual coercion reported more distress and need for help due to their participation, but also experienced more positive feelings. No significant differences were found in relation to experience with sexual risk behaviors (e.g., experience with one-night-stands). Several limitations of the study were discussed, as were implications for future research. Overall, the findings caution IRBs and researchers against being overly protective regarding the inclusion of young people in sex research. PMID- 21681693 TI - Audiogenic seizure proneness requires the contribution of two susceptibility loci in mice. AB - Juvenile mice of the DBA/2J strain undergo generalised seizures when exposed to a high-intensity auditory stimulus. Genetic analysis identified three different loci underlying this audiogenic seizure proneness (ASP)-Asp1, Asp2 and Asp3 on chromosomes 12, 4 and 7, respectively. Asp1 is thought to have the strongest influence, and mice with only Asp1 derived from the DBA/2J strain are reported to exhibit ASP. The aim of this study was to characterise more accurately the contributions of the Asp1 and Asp3 loci in ASP using congenic strains. Each congenic strain contains a DBA/2J-derived interval encompassing either Asp1 or Asp3 on a C57BL/6J genetic background. A double congenic C57BL/6J strain containing both Asp loci derived from DBA/2J was also generated. Here, we report that DBA/2J alleles at both of these Asp loci are required to confer ASP because congenic C57BL/6 mice harbouring DBA/2J alleles at only Asp1 or Asp3 do not exhibit ASP, whereas DBA/2J alleles at both loci resulted in increased susceptibility for audiogenic seizure in double congenic C57BL/6 mice. PMID- 21681690 TI - Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance. AB - BACKGROUND: Circulating tumor cells (CTCs) have long been considered a reflection of tumor aggressiveness. Hematogenous spreading of CTCs from a primary tumor is a crucial step in the metastasis cascade, which leads ultimately to the formation of overt metastases. However, owing to the rarity of CTCs in peripheral blood, detecting these cells requires methods combined with high sensitivity and specificity, which sets tremendous challenges for the implementation of these assays into clinical routine. METHODS: Generally, CTCs detection methods are composed of the following two steps: enrichment (isolation) process (morphological and immunological techniques) and detection (identification) process (cytometric and nucleic acid techniques), which may or may not be separate from enrichment. Genetic and molecular characterization of CTCs carried out by fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH), PCR-based techniques, and biomarker immunofluorescent staining extract more information about malignant profile, metastatic potential of CTCs, and the extent to which CTCs are genetically identical to the primary tumor. RESULTS: Recent technical advances made it possible to detect CTCs. The efficacy of circulating tumor cell (CTC) detection among patients with solid malignancy has been investigated, which shows great potential to become a tool for real-time parameter of prognosis and serve as an early marker to assess the therapeutic response in overt cancers. Improvements in detection and characterization of CTCs will hopefully lead to refinement of clinical management of cancer patients. CONCLUSION: This review addresses the majority of assays that have been published thus far, including the enrichment and detection steps and the markers used in these assays, accompanied by some biological issues of CTC and the results of clinical application harvested. PMID- 21681694 TI - Oncogene-induced senescence and its role in tumor suppression. AB - While senescence has been known for some time as an inevitable result of repeated DNA replication, oncogene-induced senescence (OIS) represents a relatively new phenomenon. OIS, like apoptosis, has emerged to represent a putative barrier to tumorigenesis in many tissues, including the breast. Here we discuss signals that initiate OIS, evidence for its role in tumor suppression, and mechanisms for its evasion in tumorigenesis. PMID- 21681695 TI - Periconceptional intake of folic acid and food folate and risks of preterm delivery. AB - We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N = 487) were preterm (<37 weeks). Compared with women who began intake of supplements with folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery. PMID- 21681697 TI - Effects of combined intralesional 5-Fluorouracil and topical silicone in prevention of keloids: a double blind randomized clinical trial study. AB - Keloids are aesthetically disfiguring and severely disabling. The optimal treatment remains undefined. This clinical study, evaluate the efficacy and side effects of combined topical silicone and 5-Fluorouracil on the prevention of keloids. In this double blind randomized clinical trial, fifty patients with keloids were randomly allocated in two groups. The control group were treated by perilesional surgical excision of keloids combined with topical silicone and the trial group were treated with adjuvant treatment of intralesional 5-Fluorouracil. All patients were examined and assessment was done by an independent observer. the data collected were analyzed by SPSS statistical software with using tables and chi square tests. 75% of the cases in the trial group were keloid free 21% have keloid partially improvement and 4% have keloid recurrence, compared to patients in the control group respectively: 43%, 35% and 22%, findings suggest that efficacy of 5-Fluorouracil combined with topical silicone used for the prevention of keloid is comparable to other modality. The lack of any serious side effects and the evidence of recurrence at one year of follow-up make this an effective tool for the prevention of keloids. PMID- 21681696 TI - [Emergencies in vascular surgery--a major challenge for the local infrastructure]. AB - INTRODUCTION: Emergencies in vascular surgery are often life-threatening and require a timely and prompt treatment. Little information is available in the literature about which demands must be made for this on the personnel and infrastructural resources of a hospital. METHODS: All vascular surgical emergency operations of the Surgical University Hospital of Munich - Grosshadern over a period of 2 years were evaluated concerning the emergency category, the leading clinical symptomatology, the genesis, the affected stream area, the intervention time, as well as the need for postoperative intensive medical care. RESULTS: The prevailing procedures were arterial operations (76 %). Ischaemia with 37 % and bleeding with 29 % were the leading clinical symptomatology. Thrombotic events (34 %) showed the most frequent genesis followed by embolism (13 %), stenosis (11 %), aneurysms (10 %) and iatrogenic impairments (10 %). 68 % of the emergencies were treated outside of the daytime working hours. A total of 77 % of the patients needed intensive care treatment or observation after surgery. CONCLUSION: The spectrum and the frequency of emergencies in vascular surgery make high demands on local infrastructure of the hospital and require a fair number of intensive care beds and an adequate and highly trained staff. Only under these conditions can a high quality of treatment be guaranteed for the sometimes life-threatened patients. PMID- 21681698 TI - Prevention of adhesion after endoscopic sinus surgery: role of mitomycin C. AB - Adhesions after endoscopic sinus surgery (ESS) are a potential cause of surgical failure. Mitomycin-C (MMC) is recently proposed as a solution for these adhesions. This study was performed to investigate the effect of Mitomycin C in reducing scar formation and adhesion in the nasal mucosa after endoscopic nasal surgery. This double blind randomized clinical trial study was performed on 37 patients with bilateral chronic rhinosinusitis. At the end of ESS, randomly impregnated mesh with MMC was placed in one side and another mesh impregnated with saline in the opposite side for 5 minutes. Patients were followed at least for three months, and the results of diagnostic endoscopy were recorded. Post operative adhesion occurred in 12 (32.4%) patients (2 bilateral/10 unilateral). Among total of 14 adhesions, 4 (10.8%) were in the MMC side and 10 (27%) in the control side. This differences was close to statistically significant (P=0.058). MMC may reduce adhesions after ESS, but further studies with different doses, sample size and frequent use of topical MMC is recommended. PMID- 21681699 TI - Comparison of leishmanin skin test and direct smear for the diagnosis of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis (CL) is an endemic disease in some parts of Iran and it has high morbidity in some areas of the country. The disease is detected by parasitological examinations including direct microscopic and culture tests. This comparative study aimed to evaluate the relationship between positivity of the leishmanin skin test (LST), microscopically examination and clinical forms of CL for the diagnosis of human cutaneous leishmaniasis. This study was performed on 66 patients suspected to cutaneous leishmaniasis. CL cases evaluated by both microscopical examination and leishmanin skin test. In this study, 1 ml of leishmanin fluid (lot no 121/1, produced in Pasteur institute of Iran) was injected intradermally in forearms of all patients and indurations were measured after 72 hours. Induration of 5 mm and higher was considered as positive results. The collected data were statistically analyzed using the SPSS version 13.5. From 66 CL patients who were evaluated in this study, 30 (45.5%) of them had positive microscopically results while 28(42/4%) of them had showed positive leishmanin skin test (>= 5 mm diameter). From 36 (54.5%) patients who had negative microscopical examination, only 6(16/6%) of them had positive leishmanin skin test. The agreement between two tests was 87.9 % by kappa analysis (p< 0.01). In attention to the results of this study, it seems the LST would be used as an alternative diagnosis method when there is a strong clinical doubt to cutaneous leishmaniasis even there is no parasite in direct smear. PMID- 21681700 TI - Detection of Duchenne/Becker muscular dystrophy carriers in a group of Iranian families by linkage analysis. AB - This study determines the value of linkage analysis using six RFLP markers for carrier detection and prenatal diagnosis in familial DMD/BMD cases and their family members for the first time in the Iranian population. We studied the dystrophin gene in 33 unrelated patients with clinical diagnosis of DMD or BMD. Subsequently, we determined the rate of heterozygosity for six intragenic RFLP markers in the mothers of patients with dystrophin gene deletions. Finally, we studied the efficiency of linkage analysis by using RFLP markers for carrier status detection of DMD/BMD. In 63.6% of the patients we found one or more deletions. The most common heterozygous RFLP marker with 57.1% heterozygosity was pERT87.15Taq1. More than 80% of mothers in two groups of familial or non-familial cases had at least two heterozygous markers. Family linkage analysis was informative in more than 80% of the cases, allowing for accurate carrier detection. We found that linkage analysis using these six RFLP markers for carrier detection and prenatal diagnosis is a rapid, easy, reliable, and inexpensive method, suitable for most routine diagnostic services. The heterozygosity frequency of these markers is high enough in the Iranian population to allow carrier detection and prenatal diagnosis of DMD/BMD in more than 80% of familial cases in Iran. PMID- 21681701 TI - Serum C-reactive protein level as a biomarker for differentiation of ischemic from hemorrhagic stroke. AB - Cerebrovascular accidents rank first in the frequency and importance among all neurological disease. Although a number of studies had shown increased level of the high sensitive C-reactive protein (hs-CRP) in patients with ischemic stroke, the association of increased hs-CRP with various type of stroke especially the assessment hs-CRP level in ischemic and hemorrhagic stroke have not been investigated. In the present study, we assessed the concentration of hs-CRP in patients with documented ischemic and hemorrhagic stroke in the first 24 hours of the onset of symptoms. Thirty-two patients with Ischemic and hemorrhagic stroke were evaluated at neurology department of Poursina Hospital. The presence of baseline vascular risk factors, including hypertension, diabetes mellitus, hypercholesterolemia, obesity, and smoking, was determined. The blood samples were then collected and routine hematology and biochemistry tests were done. hs CRP levels were determined using a highly sensitive immunonephelometric method. In this cross sectional study, the age of patient varied from 45-85 years (Mean 70.9 +/- 9.4). Serum level of hs-CRP in Ischemic patients were 18.92 +/- 11.28 and in hemorrhagic group was 2.65 +/- 1.7. This relationship was statistically significant (P<0.0001). It might be concluded that hs-CRP might be considered as a usefully adjunct method for the initial diagnosis of the type of stroke. PMID- 21681702 TI - The effect of literacy level on health related-quality of life, self-efficacy and self-management behaviors in diabetic patients. AB - Illiteracy in studies on quality of life (QOL) and self-efficacy (SE) of diabetic patients has been ignored. Illiteracy and diabetes have high rates in developing countries. The aim of this study was to identify the effect of literacy level on health outcomes. To achieve this, we studied health outcomes such as SE, self management behaviors and Health-Related Quality of Life (HRQOL) in diabetic patients. A cross-sectional study was carried out in an Iranian urban federally funded diabetes clinic (with 1400 diabetes patients) in Bandar Abbas, a city located in south of Iran. 256 Non Insulin Dependent Diabetic Mellitus patients were chosen during June, July and August 2007. Patients were grouped as illiterates, low-literates and literates. SE and QOL were measured by standard questionnaires. HbA1C was measured by calorimetric method. Data was collected with interview. Data analysis was carried out with one way ANOVA Post Hoc, and bivariate analysis method. Literacy level among the three groups from the view points of age, physical domain, psychological domain, environmental domain and SE were significant. There was no significant difference for the level of HbA1C among three groups. Literacy level does not have any effects on glycemic control. There is a strong relationship between self-efficacy and QOL domains. PMID- 21681703 TI - Relationship between oral poor hygiene and broken teeth with oral tongue squamous cell carcinoma. AB - Previous studies on etiology of squamous cell carcinoma (SCC) of the tongue have reported results with respect to long term exposure to cigarette smoking and alcohol abuse. The aim of this study was to investigate risk factors for SCC of the tongue in a set of patients with minimum exposure to cigarette smoking and alcohol. Sixty four cases with diagnosis of oral tongue SCC were reviewed in this study. The patients underwent surgical management at the educational and therapeutic centers, Imam and Buali Hospitals (Hamedan, Iran) between the dates of January 1990 and December 2006. Eighty five percent of patients were older than 40 years of age. Most of patients had poor oral hygiene, dental decay and halitosis. It appears that poor oral hygiene and nutritional deficiency can be considered as risk factors for the SCC of the tongue in west of Iran. PMID- 21681704 TI - Pattern of animal-related injuries in Iran. AB - Animal related injuries as most common causes of human morbidity have different pattern by geographical zones. We aimed to explore the main descriptive epidemiology of animal-related injuries in both rural and urban areas in Iran. Between 2000 and 2004, we collected the data of all the cases of animal related trauma hospitalized for more than 24 hours in eight cities (Tehran, Mashhad, Ahwaz, Shiraz, Tabriz, Qom, Kermanshah, and Babol). Further evaluations were conducted on 17753 eligible subjects. Of 17753 traumatic patients, 40 subjects (0.2%), had animal-related injuries. The highest rate was seen in Tabriz with 11 cases. Upper and lower extremities were the most frequent sites of trauma and they were injured in 13 and 11 cases respectively. Dog bite and cow-related injuries were responsible for 40% and 32.5% of injuries respectively. Amputation of the phalanx was done in 2 cases due to dog bite and bull gore occurred. One thoracotomy, one laparatomy and one craniotomy were done. One patient needed fasciatomy due to snake bite. Educating the patients could decrease the incidence of morbidity of these injuries. PMID- 21681705 TI - Patellofemoral pain syndrome in Iranian female athletes. AB - Patellofemoral pain syndrome (PFPS) is the most common overuse syndrome in athletes. It is one of the causes of anterior knee pain in athletic population who come to the sports medicine clinic. Patellofemoral pain is more common among female athletes especially adolescents and young adults. Symptoms include: persistent pain behind the patella or peripatella. Pain increases on ascending and descending stairs and squatting and prolonged sitting. The aim of this study was to evaluate the prevalence of PFPS in Iranian female athletes. 418 female athletes aged 15-35 years were examined in five sports: Soccer (190), volleyball (103), running (42), fencing (45) and rock climbing (38). The athletes who had non- traumatic onset anterior knee pain of at least 3 months that increased in descending and ascending stairs and squatting, had no other causes of anterior knee pain such as ligament instability, bursitis, meniscal injury, tendonitis and arthritis and no history of knee surgery during the one past year were diagnosed as PFPS. 26/190 (13.68 %) soccer players, 21/103(20.38 %) volleyball players, 7/42 (16.66 %) runners, 6/45(13.33 %) fencers and 10/38 (26.31%) rock climbers had patellofemoral pain. Among the 418 female athletes who were evaluated 70 had PFPS. Rock climbers were the most common athletes with PFPS followed by volleyball players and runners. PMID- 21681706 TI - Determination of the actual height predictors in Iranian healthy children. AB - Height measurement is an important part of nutritional assessment especially in children. However, in such cases as hospitalized or certain kinds of malformations or disabilities, height cannot be measured accurately. We aimed to determine appropriate height predictors in Iranian healthy children for further use in disabled and/or hospitalized children. A total of 730 apparently healthy children aged 7-11 years old from both sexes from Tehran, Meshed and Rasht were enrolled in a cross sectional study. Height, demispan (DS), halfspan (HS), arm length (AL) and tibia length (TL) were all measured using a measuring tape. Linear regression models were established between height, DS, HS, AL and TL. For boys AL (R2=0.783) and TL (R2=0.837) and for girls AL (R2=0.720), TL (R2=0.765), HS (R2=0.771) and age (R2=0.775), respectively, entered the linear regression model. When height predictors were evaluated individually for each city, only in Tehran DS also entered the regression model. Concordance of different percentiles of height estimates based on AL with those of actual height proposed this measure as a reliable height proxy for this age group in clinical as well as field practice. PMID- 21681707 TI - Subconjunctival bevacizumab injection in treatment of pterygium. AB - This study determined the clinical effect of subconjunctival administration of bevacizumab in patients with primary and recurrent pterygium. The study was an off-label, single-dosing, interventional case series involving 22 patients with primary and recurrent pterygium. They received subconjunctival bevacizumab (0.2 cc). Pterygium vascularity and thickness was graded. The size of the pterygium (measured by surface area in cm2) was recorded from baseline to 12 weeks, after injection. Treatment-related complications and adverse events were reported. The main outcome of measurements was the change in size, vascularity, thickness, color intensity. There were 15 males (68.2%) and 7 females (31.8%) of 22 patients with a mean age of 45.5 years (SD 11.68 years). One cases didn't cooperate, and excluded. There was a significant difference in the mean surface area of pterygium at different intervals (P < 0.05) and the size of pterygium was reduced. On comparison of the mean pterygium size, there was no significant difference between men and women (P >0.05). There was a significant reduction in the mean pterygium size of patients younger than 45 years in comparison to those older than 45 years after three month (P =0.037), but after 6 months, this difference was not significant (P = 0.338). Average changes in pterygium size for both eyes were not different. The reduction of color intensity in both eyes was significant (P =0.031). Subconjuctival bevacizumab injection is useful in management of patients with primary and recurrent pterygium without significant local or systemic adverse effects. PMID- 21681708 TI - Prevalence, risk factors and severity of asthma symptoms in children of Kermanshah, IRAN: ISAAC phase I, II. AB - Asthma is the most common chronic disorder of school-age children and youth, with rising prevalence in all over the world. By attention to the geographic area there is considerable difference in the prevalence of asthma. The International Study of Asthma and Allergies in Childhood (ISAAC), was founded to maximize the value of epidemiological research into asthma and allergic disease by establishing a standardized methodology and facilitating international collaboration. To determine the prevalence of asthma and related symptoms in Kermanshah (a city in west of IRAN) schoolchildren and also identifying the related variables that increased asthma risk using the ISAAC protocols. This descriptive analytic study was done by the ISAAC written questionnaire and additional questions about family number, demographic and socio-economic characteristics of two groups of first and second grade of primary and guidance schools (6-7 y, 13-14 y). Suggested sample size were applied and selected randomly. Results were analyzed by SPSS soft ware by 95% confidence interval. The ISAAC-written questionnaire was completed by a total of 6236 (48.7% were 6-7 and 51/3% were 13-14 years old) schoolchildren. 50.4% of students were girls and 49/6% were boys. The prevalence of diseases and symptoms were as follows: 20.6% had ever wheezing (27.4% in 13-14 years old and 13.4% in 6-7 years old children and it was 21.6% in girls and 19.5% in boys). Among which the estimated mean national 12-month prevalence of wheeze (current wheeze), speech limiting wheeze , exercise wheeze, night cough and physician diagnosed asthma (ever asthma) were respectively 30.1%, 5.4%, 9.4%, 7.3% and 3.3% for the 6-7 year age group and 44.2%, 13.5%, 28.9% , 17.4% and 2.1% for the 13-14 year age group. Current wheeze was higher in Childs and adolescents with family history of smoking and in higher family number. Comparing with regional study the results of this epidemiological survey of asthma in Kermanshah indicate that asthma is more common here, more prevalent in girls than boys and is higher in 13-14 years old than 6-7 years old but sever asthma is much less common. The results may be due to better diagnosis and better control of disease. PMID- 21681709 TI - Retinoblastoma and retinal astrocytoma: unusual double tumor in one eye. AB - Retinoblastoma is the most common intraocular neoplasm in children. Glial tumor of the retina and optic nerve head are considered to be congenital and are therefore classified as hamartomas. Concurrent occurrence of these tumors in one eye is uncommon and by reviewing the studies, a few cases have been reported. We report a 9 years old boy with eye enucleation and concurrent occurrence of retinoblastoma and astrocytoma in one eye as two separate and different masses. Although retinoblastoma and astrocytoma are two distinct tumors and their concurrent occurrence in one eye is rare, concurrent occurrence of these tumors may suggest differentiation of these two tumors from a neuroectodermal primary cell. PMID- 21681710 TI - A case report of unusual vasculitic reaction after Methocarbamol injection. AB - Descriptive case report of a 42-year old woman with coetaneous vasculitis, and severe abdominal pain, which was led to diagnostic laparotomy. These presentations are probably as a side effect of Methocarbamol injection. This is the first report according to our literature search (PubMed, google scholar, ISI web of knowledge, ProQuest, MD consult, Science Direct, SCOPUS) about Methocarbamol related vasculitis from 1966 since now. Vasculitis is not a known side effect of Methocarbamol. This case indicates, likely the potential for development of vasculitis with this medication. PMID- 21681711 TI - [Bisphosphonates: indications in bone diseases other than osteoporosis]. AB - AIM: Report of bisphosphonates indications for osseous diseases other than osteoporosis. METHODS: Narrative review of the literature. RESULTS: Bisphosphonates represent a new medication which is increasingly used. Besides osteoporosis, it is indicated as first choice in different bone diseases such as Paget's disease and the prevention of bone complications in tumoral osteolysis. Bisphosphonates' efficiency has been proven in other pathologies: the fibrous dysplasia and the osteogenesis imperfecta. More over, many studies are driven having for goal to show the efficiency of bisphosphonates in the algoneurodystrophy, non corticosteroid-treated osteoporosis in chronic inflammatory rheumatism and aseptic osteonecrosis. CONCLUSION: Bisphosphonates are a powerful inhibition of osseous resoption frestable indicated for osteoporosis. Their indications were retended to paget's disease, malignant hypercalcemia, and osseous complications of malignant osterlysis. PMID- 21681712 TI - [Management of failure of infliximab in inflammatory bowel disease]. AB - BACKGROUND: Infliximab is a chimeric monoclonal anti TNFa whose effectiveness during IBD has been demonstrated especially in Crohn's disease and more recently in the course of ulcerative colitis. However, a significant number of patients estimated to be between 20 to 30% of patients with crohn's disease and 30 to 40% with ulcerative colitis, not responding to treatment with infliximab, thus the failure of infliximab is a real problem which the clinician should resolve quickly. This review aimed to describe predictif factors and mecanique of infliximab failure during MICI treatment and to precise differents therapeutique options. METHODS: Literature review RESULTS: The definition of failure of infliximab during inflammatory bowel disease is not consensual; it is very varied from one study to another. However, we define two types of non response to infliximab as either primary or secondary. Factors predisposing to failure of infliximab have been reported. Some alternative therapies may be recommended. The sequential treatment comparing to the episodic treatment by infliximab is better in obtaining an endoscopic and clinical response of patients with inflammatory bowel disease. The injection of infliximab should be preceded by the taking of immunosuppressive and concomitant use of these during treatment significantly improves the clinical response of patients. Also, the increased time of exposure to infliximab, either by increasing doses or shorter intervals of infusion therapy is a considerable therapy alternative. Moreover, thanks to the advent of new molecular anti TNFa, a relay by adalinumab or certolizumab may be proposed. CONCLUSION: The failure of infliximab is a common situation but not so easily solved by the clinician. The alternative therapies are aimed at strengthening; improve the action of infliximab or to change the therapeutic molecule. The efficacy of infliximab, being dependent on the rate of infliximab antibody, a therapeutic strategy based on the serum concentration of infliximab is proposed. If the serum concentration is low or undetectable suggesting a high rate of antibody, a change of molecule should be promoted. As if against the serum concentration is high or intermediate, increased time of exposure to infliximab or the addition of immunosuppressive can be proposed. PMID- 21681714 TI - [Cardio respiratory arrest out of the hospital at the eldest]. AB - BACKGROUND: The management of the older constituted a problematic that will be more attractive in the future because of the population's advanced age. AIM: To evaluate the management of the older more than 75 years that presented an arrest chest. METHODS: Retrospective study during 12 months (from the first January 2004 to 31 December 2004) and interested 15 regulation's documents; we studied demographic parameters, the cause and the time of called the evolution after cardio-respiratory resuscitation. RESULTS: We had 9276 called cases: 320 concerned patients more than 75 years (3, 45%) among 15 (4, 68%) had a chest arrest, the ratio sex was 0, 5 and the middle age: 78, 4 years. In the most cases; the called arrived by night (40%). The principal symptomatology was respiratory troubles (33, 33%); the outcome was fatal in all cases. CONCLUSION: The older over than 75 years had many pathologies that is why the prognostic of the chest arrest was very bad (mortality 100%), the gravity of the chest arrest was seen on this study so we must take seriously all the pathology presented by the older, multiplied the medical consultations to detect the complications earlier and to improve the life's quality. PMID- 21681713 TI - [Idiopathic steroid-resistant nephrotic syndrome in child : study of 20 cases]. AB - BACKGROUND: Idiopathic steroid-resistant nephrotic syndrome (ISRNS) is rare and represents a significant therapeutic dilemma for paediatricians and paediatric nephrologists. AIM: To analyze characteristics of the ISRNS in the child. METHODS: Retrospective study of 20 cases of ISRNS enrolled in paediatric department of nephrology in Sahloul hospital (Tunisia) between June 1993 and December 2007 (14 years period). RESULTS: There were eight girls and 12 boys (mean age: 5.8+/- 3.7 years) originating from the center or the south of Tunisia. Eight of them had a minimal-change disease (MCD), 11 a focal and segmental glomerulosclerosis (FSGS) and one a mesangioproliferative glomerulonephritis (MePGN). In this group, no family form could be identified. All patients were treated by cyclosporine associated with low dose of steroid. We noted a complete remission (CR) in nine cases, partial remission (PR) in three cases and no response to cyclosporine in eight cases. Among patients with CR, six presented MCD and three a FSGS. In this group, we observed relapse of nephrotic syndrome in six cases. End stage renal disease (ESRD) was noted in 10 patients of which five not responded to cyclosporine, two initially having presented a RC and three having since the beginning a PR. Among them, two only could be grafted; one relapses on transplant was observed with a single patient initially presenting a secondarily transformed MePGN in FSGS. CONCLUSION: Our study confirms the clinical, histological and evolutive heterogeneity of idiopathic steroid resistant nephrotic syndrome. Although there is any therapeutic consensus in this domain, cyclosporine remains indicated in first intention in sporadic forms of ISRNS. On the other hand, renal transplantation constitutes the only therapeutic alternate in genetic forms that constantly evolve at ESRD. PMID- 21681715 TI - [Intracranial complications of sinusitis]. AB - BACKGROUND: Intracranial complications of sinusitis are always a subject of actuality. They present diagnostic and therapeutic problems. AIM: To study the clinical characteristics and treatment modalities for intracranial complications of sinusitis while insisting on their severity. METHODS: Retrospective study concerning 7 patients who had intracranial complications secondary to sinusitis. RESULTS: Our study was about 3 men and 4 women. The mean age of patients was 24 years. Neurologic signs were the most common symptoms. The diagnosis was confirmed by CT scan and lumbar puncture. The different complications were empyema in 5 cases and meningitis in 2 cases. Treatment included parenteral antibiotic therapy and surgery. The neurosurgical management has been achieved in 3 cases. Control was obtained in 4 cases, the mean receding was 18 months. CONCLUSION: Intracranial complications of sinusitis must be evoked, especially in cases of febrile headache or facial oedema. CT scan must be realized in slightest doubt. The treatment must be started precociously allowing a cure without after effects. PMID- 21681716 TI - [Palliative chemotherapy of non small lung cancer in Tunisia. Prospective study of the cost and impact on the quality of life]. AB - BACKGROUND: Bronchopulmonary cancer is actually the first cancer in the world. In Tunisia, recent statistics are alarmous. The most bronchopulmonary cancer in tunisian series are diagnosis at metastatic states. AIM: To evaluate the cost of the global treatment by chemotherapy in patients with metastatic non small lung cancer and its impact over the quality of life in Tunisia. METHODS: It's a prospective study lead between January 2006 and Juin 2007 to evaluate the quality of life for patients hading metastatic non small lung cancer treated by palliative chemotherapy in Ibn Nafiss department in Abderrahmen Mami hospital.The evaluation of the quality of life is inspired by the questionnaire of EORTC: QLQC30 version 3 translated in en Arab language, filled before chemotherapy, after the le 3rd cycle, and at the end of the first ligne. The study of the cost is effected for the 2 protocols whose the most used in first ligne : Cisplatin Vinorelbine (P-V) and Cisplatin- Gemcitabine (P-G) RESULTS: 30 patients had benefit from palliative chemotherapy based on P-V (18 cases) or P-G (12 cases). All patients had responded for the questionnaire in the opportunity moments. After 3 cycles of chemotherapy, we note an improve of the symptomatic, physical, activity, emotional and global health scales. In opposition, we note a deterioration of cognitive and social scales without any supplementary improvement(no significant difference) if we add other cycles in the twice protocols. At the same level of the benefit in term of quality of life and survival without supplementary toxicity, the choice is made by the less cost's protocol in other words P-V. CONCLUSION: Our results confirm the benefit from chemotherapy in term of survival and quality of life in our context, however, the important cost of the chemotherapy necessitate to rationalize the indications and the le choice of the treatments in this palliative indication. PMID- 21681717 TI - [Profile of biochemical markers in cystic fibrosis. Prospective study about 13 cases]. AB - BACKGROUND: To study the disturbances of biochemical parameters which make it possible to evaluate the nutritional state during the cystic fibrosis. METHODS: Prospective study about 13 cases hospitalized over a 7 months period, whose age varies between 2 months and 12 years and addressed for a suspicion of cystic fibrosis. For all the patients we made a clinical collection of the data and a biochemical study. RESULTS: Hypoprotidemia (protidemia < 60 g/l) was noted in 6 cases. Three cases presented a hypocalcaemia (calcemia < 2.20 mmol/l). A hypomagnesaemia (magnesemia < 0.70 mmol/L) was observed in 2 cases. The totality of the patients presented zinc concentrations lower than the normal value. Iron concentrations lower than the normal (11- 24 mmol/l) was noted in 5 cases. Four patients (4/13) presented a concentration of iron between 11.2 and 20 mmol/l, whereas a high concentration (32.3 mmol/l) was noted in only one case (7.7%). CONCLUSION: The study of the biochemical parameters allowed to evaluate the variation of some trace elements in cystic fibrosis and their consequence on the nutritional state of the patients, which constitutes an essential element for the assessment of these patients. PMID- 21681718 TI - [Iron overload in sickle cell anemia : a study of 94 patients]. AB - BACKGROUND: Sickle cell disease is an autosomal, recessive hemoglobinopathy characterized by hemolytic anemia. Red blood cell transfusions are uncommon therapeutic mainstay in sickle cell disease and repeated transfusions can result in iron overload. The predicted risks of iron overload and organ failure increase with both the duration of disease requiring transfusion therapy and the number of transfusions. AIM: To assess the state of iron overload in patients with sickle ce anemia according to their number of transfusions. METHODS: The medical records of 94 patients with sickle cell anemia (46 had homozygous sickle cell disease, 41 had sickle-beta thalassemia, 7 had compound heterozygous hemoglobin: 4 SC and 3 SOArab) were retrospectively reviewed for the following: clinical exam, serum ferritin level, liver function tests, abdominal ultrasound exam and heart Doppler. RESULTS: 61% of our patients are from the Northern- west of the country. The average age is 18.29 years (2 to 62 years) and the sexratio is 0.62. In addition to parental consanguinity which is found in 28.72% of the cases. The average level of ferritin is 660.35 ng/ml. 41.5% of the patients have a high status of ferritin witch ranged from 521.4 to 3360 ng/ml. There is not a significant difference of ferritin level according to age, sex and a phenotype of sickle cell anemia. However, it is higher among the transfused patients with a same phenotype (p<0.05). We found a correlation between serum ferritin levels and the number of transfusions (r =+0.74). Splenectomy has a preventive role because it allowed stopping the transfusion in 65% of the cases. The evaluation of organ dysfunction has found a hepatomegaly in 29% of the cases, half of witch were have a high status of serumferritin (> 1000 ng/ml). Left ventricular hypertrophy associated to valvulopathy was classified in 10 % of the cases. CONCLUSION: Iron overload in sickle cell anemia, though relying on transfusion, remains moderate. The repetitive assessment of serum ferritin level is considered as the best test though it does not evaluate an organic dysfunction. To evaluate them better, other tests are requiring: magnetic resonance imaging and Tc-Squid biosusceptometers. PMID- 21681719 TI - Maternal and fetal outcomes of large fetus delivery: a comparative study. AB - AIM: To review the deliveries of macrosomic babies, weighing over than 4000g and their obstetrical and neonatal outcomes. METHODS: Retrospective study involving a total of 209 deliveries at term of macrosomic babies between Marsh 2006 and February 2007 in the Maternity Hospital of Mahmoud ELMATRI, Tunis. The study concerned risk factors, mode of delivery and the incidence of maternal and perinatal complications.We compared data in the study group to a control group of normal weight infants delivered at the same period. RESULTS: Macrosomia occurred in 9.2% of all deliveries. The main risk factors of macrosomia were maternal age over 30 years (p=0,017), multiparty (p<0.001), diabetes mellitus (p=0.012) and prolonged term of delivery (p=0.02). These risk factors were statistically significant compared to control group. Caesarian delivery was achieved in 24.4% in macrosomy group and in 13.7% in control group (p=0,003) the major part occurred during labor. Among vaginal deliveries in macrosomia group, shoulder dystocia was noted in 1,9%, fetal respiratory failure and admission in intensive care unit was noted in 4,8% of the cases and hypoglycemia complicated 15,8% of deliveries. Maternal complications were dominated by post partum hemorrhage documented in 1.2% of the cases and perineal tears noted in 8,2% of vaginal deliveries. CONCLUSION: Vaginal delivery is the most frequent mode of delivery for a fetus weighing in excess of 4 kg and vaginal delivery should be attempted in the absence of contraindications and there is no need for elective systematic caesarian. However, shoulder dystocia remains the main complication of vaginal delivery for macrosomic fetuses and requires experienced obstetricians to manage these deliveries. PMID- 21681720 TI - [Prevalence of extra-hepatic manifestations in infection with hepatitis C virus: study of 140 cases]. AB - AIM: To determine the extrahepatic manifestations (EHM) in chronic hepatitis C and to correlate signs with age, sex, degree of fibrosis and genotype of hepatitis C virus. METHODS: One hundred forty cases of chronic infection by hepatitis C virus were investigated in a period of 10 years. By interrogation, clinical examination and laboratory tests, the EHM were determined. Correlations with age, sex, viral genotype and degree of fibrosis were determined by the chi2 test. RESULTS: Mean age of our patients was 59 years (16-85 years). 74% were women. The genotype 1b was found in 75% of cases. The clinical EHM were found in 62% of cases: buccal dryness in 17.1% of cases, arthralgias in 33% of cases and fatigue in 65% of cases. 25% of patients had at least one biological EHM associated with chronic hepatitis C: proteinuria in 3 cases, cryoglobulinemia in 4 cases, dysthyroidism in 8 cases and more frequently a positive immunologie test. During the follow-up, we found one case of breast cancer, one case of rectal cancer, 2 cases of MALT lymphoma and one case pf splenic lymphoma. A positive correlation was found between the prevalence of EHM in chronic hepatitis C and the female sex. A degree of fibrosis 3 2 in METAVIR classification was significantly associated with more important frequency of EHM. CONCLUSION: EHM should be screened systematically in chronic infection with HCV. Pathogenic mechanisms in a B lymph node proliferation or diabetes and outcome of these abnormalities under antiviral therapy should be further investigated. PMID- 21681721 TI - [Results of surgical treatment of intracardiac total anomalous pulmonary venous return]. AB - BACKGROUND: Total anomalous pulmonary venous return (TAPVR) has a rather low incidence (1-3%) of all congenital heart disease. Intracardiac TAPVR represent 25 30% of all TAPVR. AIM: To report our results and long-term follow-up of surgical management of intracardiac TAPVR. METHODS: Retrospective study of 7 patients with intra cardiac TAPVR treated surgically between Mai 1992 and July 2007. RESULTS: The surgical technique has been an intra atrial procedure in all cases. We didn't report any early post-operative death. Early postoperative complications were principally pulmonary infections. We report one death at three months of follow up caused by laryngeal stenosis. Late follow-up was good for all patients. CONCLUSION: Good result of surgical treatment of intracardiac TAPVR depends on early diagnosis and adequate surgical technique. PMID- 21681722 TI - C677t polymorphism of MTHFR and G80A polymorphism of RFC genes and their relation with homocysteine levels in obese Tunisian children. AB - AIMS: To investigate the frequencies of C677T polymorphism in MTHFR gene and G80A polymorphism in RFC gene in obese and no obese Tunisian children and to assess their relation with homocysteine (tHcy), folate and vitamin B12 levels. METHODS: We have studied 31 obese compared to 22 no obese children. tHcy was assessed by fluorescence-immunoassay ; folate and vitamin B12 by radioimmunoassay. C677T and G80A mutations were detected using pyrosequencing. RESULTS: There were no differences in tHcy levels between obese and no obese, (10,34 +/- 4,86MUmoll/l vs11,00 +/- 4,26MUmoll/l). We found no difference for the allelic frequencies of the C677T polymorphism (29.03 % vs 30.95 %) and of the G80A polymorphism (64.52 % vs 59.52 %). Mean levels of tHcy, folic acid and vitamin B12 were not significantly different according to MTHFR and RFC genotypes. CONCLUSION: We demonstrated no difference in tHcy, folates, vitamin B12 levels and allelic frequencies of C677T and G80A polymorphisms in MTHFR and RFC genes between obese and no obese Tunisian children. These two polymorphisms don't seem to have any impact on homocysteine, folate and vitamin B12 status in the two populations. PMID- 21681723 TI - Giant trichoblastoma of the scalp. AB - BACKGROUND: Trichoblastoma is a rare and benign adnexial tumor with characteristic histological features. It occurs on any hair folliclebearing location, and usually presents as a solitary lesion most often less than 2 cm in size. Giant trichoblastoma has been rarely reported in the literature. AIM: To report a new case of giant trichoblastoma, misleading for malignancy. CASE REPORT: A 57-year-old woman presented with a 5 cm-solitary asymptomatic nodular lesion of the scalp, of 28 years. It had been previously excised with recurrence and progressive regrowth. On examination, it was a dome-shaped, erythematous, firm, papillomatous, non infiltrated nodule. Full body work up revealed no metastases. Cutaneous biopsy concluded to trichoblastoma but failed to eliminate malignancy. After excision with secondary skin graft, histological examination confirmed the benignity with clear margins. There was no evidence of recurrence after a 5 year-follow-up period. CONCLUSION: This case illustrates a rare clinical variant of trichoblastoma with an unusual important size. This can be misleading for malignancy, but the slowly progressive course of the tumour in our patient, together with histological benignity led to the correct diagnosis. This tumour is considered as a distinct entity by some authors. PMID- 21681724 TI - Erosive arthritis in a patient with Behcet's disease. PMID- 21681725 TI - [Remitting septic arthritis due to albicans candida in an immunocompetent subject]. PMID- 21681726 TI - [Salpingocolonic fistula complicating diverticulitis during pregnancy]. PMID- 21681727 TI - [Retroperitoneal schwanoma associated to renal oncocytoma]. PMID- 21681728 TI - [Postpartum-urinary retention]. PMID- 21681729 TI - [Difficult etiological diagnosis of unilateral hyperlucent lung]. PMID- 21681730 TI - Acute pancreatitis due to hereditary angioedema. PMID- 21681731 TI - Jaw malignancies: signs that should alert the dentist. PMID- 21681732 TI - [Colorectal endocrine tumors]. PMID- 21681733 TI - [Digestive incarceration post celioscopy]. PMID- 21681734 TI - Pixantrone dimaleate in combination with fludarabine, dexamethasone, and rituximab in patients with relapsed or refractory indolent non-Hodgkin lymphoma: phase 1 study with a dose-expansion cohort. AB - BACKGROUND: Pixantrone dimaleate (pixantrone) has been shown to have antitumor activity in leukemia and lymphoma in vitro models and to lack delayed cardiotoxicity associated with mitoxantrone in animal models. FND-R, a combination regimen of fludarabine, mitoxantrone, dexamethasone, and rituximab, has been shown to be an effective regimen for low-grade lymphomas. METHODS: This dose-escalation study, with an expansion cohort, was conducted to evaluate the safety and preliminary efficacy of FPD-R, in which pixantrone was substituted for mitoxantrone in the FND-R regimen, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL). Escalated doses of pixantrone were administered to newly enrolled patients on day 2 of each 28-day cycle of FPD-R. RESULTS: Twenty-eight of 29 enrolled patients received at least 1 cycle of FPD-R (median, 5 cycles). Pixantrone 120 mg/m(2) was identified as the recommended dose in this regimen. Grade 3-4 adverse events were primarily hematologic; grade 3-4 lymphopenia occurred in 89% of patients and leukopenia in 79%. No patients developed congestive heart failure or grade 3-4 cardiac adverse events. Left ventricular ejection fraction decreases occurred in 8 (29%) patients, and most were grade 1 or 2, transient, and asymptomatic. The overall response rate was 89%. Estimated survival was 96% after 1 year and 92% after 3 years. CONCLUSIONS: The FPD-R regimen was well-tolerated and highly active in patients with relapsed or refractory indolent NHL. PMID- 21681735 TI - Adjuvant trastuzumab with chemotherapy is effective in women with small, node negative, HER2-positive breast cancer. AB - BACKGROUND: Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted. METHODS: Women with <= 2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization >= 2) breast cancer were identified through an institutional database. A "no-trastuzumab" cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a "trastuzumab" cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods. RESULTS: The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the "no trastuzumab" and "trastuzumab" cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the "no trastuzumab" cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the "trastuzumab" cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the "no trastuzumab" and "trastuzumab" cohorts, respectively. CONCLUSIONS: Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. PMID- 21681736 TI - Physician over-recommendation of mammography for terminally ill women. AB - BACKGROUND: There has been recent, sometimes intense, debate about when to begin screening and how often to screen women for breast cancer with mammography. However, there should be no controversy regarding screening women who are unlikely to benefit from the procedure, such as those with a serious, life limiting illness who would not live long enough to benefit from the potential detection and treatment of breast cancer. Identifying characteristics of physicians who recommend mammography for terminally ill women can help guide efforts to minimize patient risks and make better use of health care resources. METHODS: The authors used data from a nationally representative survey of primary care physicians (PCPs) (N = 1196; response rate, 67.5%) conducted in 2006 and 2007 to examine PCPs' breast cancer screening recommendations for hypothetical patients ages 50 years, 65 years, and 80 years who were healthy, had a moderate comorbidity, or had a terminal comorbidity. RESULTS: Many PCPs (47.7%) reported that they would recommend mammography to a woman aged 50 years, 65 years, or 80 years with terminal lung cancer, indicating over-recommendation. Physician characteristics associated with over-recommending mammography included obstetrician/gynecologist (odds ratio [OR], 1.69) or internal medicine (OR, 0.45) specialty, being a woman (OR, 1.40), being a racial/ethnic minority (OR, 1.72), and working in a smaller practice (OR, 1.41). CONCLUSIONS: The current results indicated that physician over-recommendation of screening mammography among terminally ill women is common. Certain physician and practice characteristics, including specialty, were associated with over-recommending mammography. The authors concluded that an informed and shared mammography decision-making process for terminally ill women may eliminate unnecessary patient risks and health care expenditures. PMID- 21681737 TI - IQGAP1 involvement in MTOC and granule polarization in NK-cell cytotoxicity. AB - Natural killer (NK) cells form a region of tight contact called the NK immunological synapse (NKIS) with their target cells. This is a dynamic region serving as a platform for targeted signaling and exocytotic events. We previously identified IQGAP1 as a cytoskeletal component of the NK-like cell line YTS. The present study was undertaken to determine the role of IQGAP1 in the function of NK cells. Silencing of IQGAP1 expression resulted in almost complete loss of the cytotoxic activity of YTS cells. Loss of IQGAP1 did not prevent conjugate formation with target cells but it did result in a failure to reorient the microtubule organizing centre to the immune synapse. Significantly, IQGAP1 expression was required for the perigranular accumulation of an F-actin network. IQGAP1 was shown to undergo marked rearrangements during synapse maturation in effector target conjugates of YTS or primary NK cells. These results suggest previously undescribed role(s) for IQGAP1 in regulating multiple aspects of cytoskeletal organization and granule polarization in NK cells. PMID- 21681738 TI - The inflammasome drives protective Th1 and Th17 cellular responses in disseminated candidiasis. AB - The Nlrp3 inflammasome has been proposed to play an important role in antifungal host defense. However, studies exploring the role of the inflammasome in antifungal host defense have been limited to the direct effects on IL-1beta processing. Although IL-1beta has important direct effects on the innate immune response, important effects of the caspase-1-dependent cytokines IL-1beta and IL 18 are exerted on the initiation of the adaptive Th1 and Th17 cellular responses. No studies have been employed to assess the impact of the inflammasome on the Th1/Th17 defense mechanisms in vivo during candidiasis. In the present study, we demonstrate an essential role for caspase-1 and ASC (apoptosis-associated speck like protein containing a caspase recruitment domain) in disseminated candidiasis through regulating antifungal Th1 and Th17 responses. Caspase-1(-/-) and ASC(-/-) mice display diminished Th1/Th17 responses, followed by increased fungal outgrowth and lower survival. These observations identify a critical role for the inflammasome in controlling protective adaptive immune responses during invasive fungal infection. PMID- 21681740 TI - CD4+ T-cell immunity in the female genital tract is critically dependent on local mucosal immunization. AB - Immunizations via the i.n. and intravaginal (ivag) routes effectively generate strong genital tract antibody-mediated immunity. To what extent the same is true for T-cell responses is incompletely known. Therefore, we set out to investigate optimal conditions for stimulation of genital tract CD4(+) T-cell responses, using adoptive transfer of mouse DO11.10 TCR transgenic T cells specific for OVA and OVA conjugated to cholera toxin (CT) as an immunogen. We observed that progesterone was required for a T-cell response following ivag immunization, whereas estradiol prevented a response. Although i.n. immunization stimulated OVA specific CD4(+) T-cell responses in the draining LNs, it was substantially less effective compared to ivag. More importantly, an ivag booster immunization was absolutely required to attract T cells to the genital tract mucosa itself. While clinical use of CT is precluded because of its toxicity, we developed a combined adjuvant vector based on a non-toxic derivative of CT and immune-stimulating complexes. The CTA1-DD/immune-stimulating complexes (ISCOMs) adjuvant together with major outer membrane protein was effective at stimulating genital tract CD4(+) T-cell immunity and protection against a live chlamydial infection, which holds promise for the development of mucosal vaccines against sexually transmitted infections. PMID- 21681739 TI - Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors. AB - Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE(2) and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE(2) and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxin-induced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE(2) and the EP4 agonist prevented the activation and cell-surface clustering of beta2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-alpha-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE(2) from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin- and TNF-alpha-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE(2) -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration. PMID- 21681741 TI - Helicobacter pylori infection and the risks of Barrett's oesophagus: a population based case-control study. AB - Infection with Helicobacter pylori is associated with significantly reduced risks of oesophageal adenocarcinoma; however, few studies have examined the association between H. pylori and Barrett's oesophagus (BO), the precursor lesion. We explored the relationship between H. pylori infection and BO and sought to identify potential modifiers. We compared the prevalence of positive H. pylori serology among 217 adults with simple BO (without dysplasia), 95 with dysplastic BO and 398 population controls sourced from the metropolitan Brisbane area. We determined H. pylori serostatus using enzyme-linked immunosorbent assay. To estimate relative risks, we calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable logistic regression in the entire sample and stratified by factors known to cause BO. The prevalence of H. pylori seropositivity was 12%, 3%, and 18%, respectively, among patients with simple BO, dysplastic BO and population controls. BO patients were significantly less likely to have antibodies for H. pylori (Simple BO: OR = 0.51, 95% CI: 0.30-0.86; Dysplastic BO: OR = 0.10, 95% CI: 0.03-0.33) than population controls. For simple BO, the association was diminished after adjustment for frequency of gastro oesophageal reflux (GOR) symptoms. Adjustment for frequency of GOR symptoms did not substantially alter the observed effect for dysplastic BO. Although there was some variation in the magnitude of risk estimates across strata of age, sex, GOR symptoms and use of proton pump inhibitors or H2-receptor antagonists, the differences were uniformly nonsignificant. Helicobacter pylori infection is inversely associated with BO, and our findings suggest that decreased acid load is not the only mechanism underlying the H. pylori protective effect. PMID- 21681742 TI - Prostate stem-cell antigen gene is associated with diffuse and intestinal gastric cancer in Caucasians: results from the EPIC-EURGAST study. AB - A genome-wide study performed in a Japanese population identified a strong association between SNP rs2294008 (Met1Thr) in the Prostate Stem Cell Antigen gene (PSCA) and diffuse-type gastric cancer (GC). This association was validated in different Asian populations, and, very recently, a study has been published in Caucasians. In this study, we analyzed the association between PSCA variation and GC risk in Caucasians from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Six tagSNPs covering the PSCA gene region were genotyped in 411 incident gastric adenocarcinoma cases and 1530 matched controls from a nested case-control study in the EPIC cohort. Associations were analyzed by unconditional logistic regression, adjusting for age, sex and country. The T allele of rs2294008 in PSCA was found to be a highly significant risk factor for GC (per allele OR = 1.42, 95% CI: 1.23-1.66, p-value = 6.5 * 10(-6) ), particularly of the noncardia-type (per allele OR = 1.47, 95% CI: 1.19-1.81, p value = 3 * 10(-4) ). At contrast with previous studies, no significant differences were observed between the diffuse (per allele OR = 1.54, 95% CI: 1.20 1.96, p-value = 5 * 10(-4) ) and the intestinal (per allele OR = 1.52, 95% CI: 1.20-1.93, p-value = 5 * 10(-4) ) GC histological subtypes. Although rs12155758 and rs9297976 were also found associated with GC, this association appeared to be due to linkage disequilibrium with rs2294008. Haplotype analysis did not provide additional information. These results confirm the association between variation in the promoter region of PSCA and GC risk in Caucasians and also indicate that the rs2294008 variant is a similar risk factor for both the diffuse and intestinal-types of GC. PMID- 21681743 TI - The association of circulating adiponectin levels with pancreatic cancer risk: a study within the prospective EPIC cohort. AB - Excess body weight and type 2 diabetes mellitus, risk factors of pancreatic cancer, are characterized by decreased levels of adiponectin. In addition to anti inflammatory and anti-proliferative actions, adiponectin has an important role in regulating glucose metabolism, i.e., decreasing circulating blood glucose levels. Prospectively, hyperglycemia has been associated with risk of pancreatic cancer. The aim of this study was to investigate the association of pre-diagnostic adiponectin levels with pancreatic cancer risk. We conducted a case-control study nested within European Prospective Investigation into Cancer and Nutrition. Blood samples of 452 pancreatic cancer cases and 452 individually matched controls were analyzed by immunoassays. Multivariate conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Overall, adiponectin showed no association with pancreas cancer risk; however, among never smokers, higher circulating levels of adiponectin were associated with a reduction in pancreatic cancer risk (OR = 0.44 [95% CI 0.23-0.82] for highest vs. lowest quartile), whereas among current smokers there was no significant association (OR = 1.59 [95% CI 0.67-3.76] for highest vs. lowest quartile; p trend = 0.530; p-interaction = 0.309). In our study, lower adiponectin concentrations may be associated with the development of pancreatic cancer among never smokers, whereas the only other prospective study being conducted so far showed a decrease in risk among male smokers. Therefore, further studies are needed to clarify the role of adiponectin in pancreatic cancer development. PMID- 21681744 TI - Calpain-6 is an endothelin-1 signaling dependent protective factor in chemoresistant osteosarcoma. AB - Bone tumors strongly influence normal tissues and stimulate bone cells for the production of cytokines supporting proliferation and abnormal survival in cancer cells. We previously reported that the proteoglycan syndecan-2 controls the activity of various cytokines and growth factors and also modulates apoptosis and response to cytotoxic agents in osteosarcoma cell lines. Here, we show that syndecan-2 has a stronger tumor suppressor activity in vivo. We identify calpain 6 as a target gene downregulated by syndecan-2 in cells and in vivo. We demonstrate that calpain-6 expression in osteosarcoma cells depends on endothelin 1, a mediator of the tumor progression in bone. Syndecan-2 overexpression alters ERK1/2, PI3K/AKT and NFkappaB pathways that are calpain-6-promoting signals downstream of endothelin-1. Immunohistochemical analysis shows that calpain-6 is expressed in human bone tumors and metastases. A high expression of calpain-6 was specially found in recurrent osteosarcoma. Moreover, calpain-6 levels in primary tumors were inversely related to the response to chemotherapy. Consistently, calpain-6 was increased by doxorubicin and was found to be expressed at higher levels in doxorubicin-resistant U2OS osteosarcoma-derived cells as compared to responsive cells. Inhibition of calpain-6 with shRNA resulted in decreased proliferation, increased spontaneous apoptosis and increased sensitivity to doxorubicin and also methotrexate in responsive and resistant osteosarcoma cells. Taken together, our data show that syndecan-2 exerts its pro-apoptotic function through modulation of the endothelin-1/NFkappaB signaling and through downregulation of calpain-6, a protective factor that contributes to abnormal cell survival. Thus, this study identifies calpain-6 as a new possible therapeutic target in chemoresistant osteosarcoma. PMID- 21681745 TI - Lessons learned from a long-term psychoanalysis on the telephone. AB - This article describes my 30+ years of psychoanalysis, the bulk of which has occurred on the telephone. I am publishing the article anonymously so that I can speak freely, without family or professional repercussions, about these vital topics. Of the myriad issues that have been addressed in the treatment, I have elected to focus in this article on separation-individuation challenges, adult life trauma, career dynamics, silences in analysis, and the value of consultations and adjunctive treatments. The article focuses on the applicability of these themes to my personal life and their relevance to me as a clinician and clinical supervisor. PMID- 21681746 TI - Delayed synapse elimination in mouse levator palpebrae superioris muscle. AB - At birth, synaptic sites in developing rodent muscles are innervated by numerous motor axons. During subsequent weeks, this multiple innervation disappears as one terminal strengthens, and all the others are eliminated. Experimental perturbations that alter neuromuscular activity affect the rate of synaptic refinement, with more activity accelerating the time to single innervation and neuromuscular blockade retarding it. However, it remains unclear whether patterns of muscle use (driven by endogenous neuronal activity) contribute to the rate of synapse elimination. For this reason we examined the timing of supernumerary nerve terminal elimination at synapses in extraocular muscles (EOMs), a specialized set of muscles controlling eye movements. On the basis of their exceptionally high patterns of activity, we hypothesized that synaptic refinement would be greatly accelerated at these synapses. We found, however, that rates of synaptic refinement were only modestly accelerated in rectus and oblique EOMs compared with synapses in somite-derived skeletal muscle. In contrast to these results, we observed a dramatic delay in the elimination of supernumerary nerve terminals from synapses in the levator palpebrae superioris (LPS) muscle, a specialized EOM that initiates and maintains eyelid elevation. In mice, natural eye opening occurs at the end of the second postnatal week of development. Thus, although synapse elimination is occurring in most EOMs and somite-derived skeletal muscles, it appears to be dramatically delayed in a set of specialized eyelid muscles that remain immobile during early postnatal development. PMID- 21681747 TI - Blueprint of an ancestral neurosensory organ revealed in glial networks in human dental pulp. AB - Sensory function of human dental pulp has long been known. A composite role has been suggested for odontoblasts as sensory cells in addition to the synthesis of dentinal matrix. However, the neural basis for such a composite sensory activity remains enigmatic. Here, we aimed to probe the question by pursuing an evolutionary logic; if dental pulp is a vestigial sensory organ co-opted to a function of synthesis of mineralized matrix, essential elements of neurosensory organs may persist in dental pulp. Through structural analysis by confocal laser scanning microscopy, three distinct cell populations adjacent to odontoblasts, glial fibrillary acidic protein (GFAP)(+) seracytes, S100(+) telacytes, and HLA II(+) alacytes were identified in peripheral human dental pulp. Subsequent molecular fingerprinting by quantitative reverse transcriptase-polymerase chain reaction established these cells as analogous to radial glia (GFAP(+) cells), astrocytes (S100(+) cells), and microglia (HLA-II(+) cells) of central nervous system organs. In the cell-rich zone of the pulp, S100(+) cells formed a network, ensheathed unmyelinated axons, and extended end-feet around the capillaries. The microcirculation adjacent to the glial cells in the cell-rich zone possessed ultrastructural features and a gene expression profile typical of the blood-brain barrier system. These novel findings support a new paradigm for understanding sensory functionality of dental pulp by the demonstration of a sophisticated neural structure in the human dental pulp that is analogous to other central sensory organs. Further, the structure that is revealed informs the concept of the evolutionary origin of the dental pulp, suggesting that a neurosensory organ was the precursor structure of teeth. PMID- 21681748 TI - Selective localization of collybistin at a subset of inhibitory synapses in brain circuits. AB - Collybistin is a brain-specific guanine nucleotide exchange factor (GEF) that is crucial for the postsynaptic accumulation of gephyrin and gamma-aminobutyric acid A receptors (GABA(A) Rs) at a specific subset of inhibitory synapses. Our understanding of the in vivo function of collybistin has been hampered by lack of information about the synaptic localization of this protein in brain circuits. Here we describe the subcellular localization of endogenous collybistin by using antibodies raised against distinct molecular domains that should recognize the majority of endogenous collybistin isoforms. We show that collybistin co-clusters with gephyrin and GABA(A) Rs in synaptic puncta and is recruited to postsynaptic specializations early during synapse development. Notably, collybistin is present in only a subset of gephyrin-positive synapses, with variable co-localization values in different brain regions. Moreover, collybistin co-localizes with GABA(A) Rs containing the alpha1, alpha2, or alpha3 subunits, arguing against a selective association with specific GABA(A) R subtypes. Surprisingly, we found that collybistin is expressed only transiently in Purkinje cells, suggesting that in these cerebellar neurons collybistin plays a selective role during the initial assembly of postsynaptic specializations. These data reveal a remarkable heterogeneity in the organization of GABAergic synapses and provide an anatomical basis for interpreting the variable effects caused by disruption of the collybistin gene in human X-linked intellectual disability and mouse knockout models. PMID- 21681750 TI - Visual system scaling in teleost fish. AB - Teleost fish grow continuously throughout their lifespan, and this growth includes visual system components: eyes, optic nerves, and brain. As fish grow, the optic nerve lengthens and neural signals must travel increasing distances from the eye to the optic tectum along thousands of retinal ganglion cell (RGC) axons. Larger fish have better vision that enhances their ability to capture prey, but they are faced with the potential computational problem of changes in the relative timing of visual information arriving at the brain. Optic nerve conduction delays depend on RGC axon conduction velocities, and velocity is primarily determined by axon diameters. If axon diameters do not increase in proportion to body length, then absolute and relative conduction delays will vary with fish size. We have measured optic nerve lengths and axon diameter distributions in different sized zebrafish (Danio rerio) and goldfish (Carassius auratus) and find that, as both species of fish grow, axon diameters increase to reduce average conduction delays by about half and to keep relative delays constant. This invariance of relative conduction delays simplifies computational problems faced by the optic tectum. PMID- 21681751 TI - Expression analysis of the regenerating gene (Reg) family members Reg-IIIbeta and Reg-IIIgamma in the mouse during development. AB - The regenerating gene/regenerating islet-derived (Reg) family is a group of small secretory proteins. Within this family, Reg type-III (Reg-III) consists of: Reg IIIalpha, -beta, -gamma, and -delta. To elucidate the physiological relevance of Reg-III, we examined the localization and ontogeny of Reg-IIIbeta and Reg IIIgamma in mice at different time points spanning from embryonic day 13.5 to 7 weeks old, using in situ hybridization and immunohistochemistry. Our results showed that Reg-IIIbeta was expressed in specific subsets of primary sensory neurons and motor neurons, and that expression was transient during the embryonic and perinatal periods. Reg-IIIbeta expression was also observed in absorptive epithelial cells of the intestine. In contrast, Reg-IIIgamma expression was mainly observed in epithelial cells of the airways and intestine, but not in the nervous system, and expression levels showed a gradually increasing pattern along with development. In the airways Reg-IIIgamma was expressed in goblet and Clara like cells, whereas in the intestine Reg-IIIgamma was expressed in the absorptive epithelial cells and Paneth cells, and was found to be expressed in development before these organs had been exposed to the outside world. The present findings imply that Reg-IIIbeta and Reg-IIIgamma expression is regulated along divergent pathways. Furthermore, we also suggest that expression of Reg-IIIgamma in the airway and intestinal epithelia may occur to protect these organs from exposure to antigens or other factors (e.g., microbes) in the outer world, whereas the transient expression of Reg-IIIbeta in the nervous system may be associated with the development of the peripheral nervous system including such processes as myelination. PMID- 21681749 TI - Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degeneration. AB - Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photoreceptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies. PMID- 21681752 TI - Physical stability and recrystallization kinetics of amorphous ibipinabant drug product by fourier transform raman spectroscopy. AB - The solid-state physical stability and recrystallization kinetics during storage stability are described for an amorphous solid dispersed drug substance, ibipinabant, at a low concentration (1.0%, w/w) in a solid oral dosage form (tablet). The recrystallization behavior of the amorphous ibipinabant polyvinylpyrrolidone solid dispersion in the tablet product was characterized by Fourier transform (FT) Raman spectroscopy. A partial least-square analysis used for multivariate calibration based on Raman spectra was developed and validated to detect less than 5% (w/w) of the crystalline form (equivalent to less than 0.05% of the total mass of the tablet). The method provided reliable and highly accurate predictive crystallinity assessments after exposure to a variety of stability storage conditions. It was determined that exposure to moisture had a significant impact on the crystallinity of amorphous ibipinabant. The information provided by the method has potential utility for predictive physical stability assessments. Dissolution testing demonstrated that the predicted crystallinity had a direct correlation with this physical property of the drug product. Recrystallization kinetics was measured using FT Raman spectroscopy for the solid dispersion from the tablet product stored at controlled temperature and relative humidity. The measurements were evaluated by application of the Johnson-Mehl Avrami (JMA) kinetic model to determine recrystallization rate constants and Avrami exponent (n = 2). The analysis showed that the JMA equation could describe the process very well, and indicated that the recrystallization kinetics observed was a two-step process with an induction period (nucleation) followed by rod-like crystal growth. PMID- 21681753 TI - Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus,TM simulations to predict absorption. AB - Dogs are one of the most commonly used non-rodent species in toxicology studies and are known to have basal stomach pH ranging from 2 to 7 in the fasted state. Thus absorption and resulting plasma exposure of weakly basic compounds administered as crystalline suspensions to dogs are often variable. LY2157299 is a potent and selective transforming growth factor (TGF)-beta receptor type 1 kinase (TGF-betaRI) inhibitor that displayed variable absorption in early dog studies. This molecule is a weakly basic Biopharmaceutics Classification System (BCS)Class II compound, and depends on the rate and extent of dissolution to drive oral absorption. An artificial stomach and duodenum (ASD) dissolution model was utilized to evaluate potential effect of gastric pH on the absorption of suspension and buffered solution formulations. GastroPlusTM was also employed to predict the magnitude of gastric pH changes on LY2157299 absorption. The ASD experiments demonstrated that administration of a buffered acidic solution could improve the potential for absorption by normalizing gastric pH and enabling supersaturation in the duodenum. GastroPlusTM modeling suggested that direct modulation of gastric pH could lead to marked changes in bioavailability. Pharmacokinetic experiments were conducted in dogs to evaluate the effect of gastric pH modification on plasma exposure. The data were qualitatively consistent with the predictions. PMID- 21681755 TI - Fuel from plant cell walls: recent developments in second generation bioethanol research. AB - As bioethanol from sugarcane and wheat falls out of favour due to concerns about food security, research is ongoing into genetically engineering model plants and microorganisms to find the optimum cell wall structure for the ultimate second generation bioethanol crop. Charis Cook and Alessandra Devoto highlight here the progress made to tailor the plant cell wall to improve the accessibility of cellulose by acting on the regulation, the structure or the relative composition of other cell wall components to ultimately improve saccharification efficiency. They also consider possible side effects of cell wall modification and focus on the latest advances made to improve the efficiency of digestion of lignocellulosic materials by cell wall degrading microorganisms. PMID- 21681754 TI - Potent enhancement of GFP uptake into HT-29 cells and rat skin permeation by coincubation with tat peptide. AB - The delivery enhancements of green fluorescent protein (GFP), a model reporter protein into/transepithelial colon adenocarcinoma (HT-29) cells and excised rat skin by coincubation, by simple mixing or as fusion protein with HIV1-trans activating transcriptional (Tat), a cell-penetrating peptide, have been described. By simple mixing, Tat/GFP mixture could increase the cellular uptake of GFP into HT-29 cells by 4.25-fold and 1.79-fold of GFP and Tat-GFP fusion protein, respectively. The incubation time showed no effect on the cellular uptake of Tat/GFP and Tat-GFP. In transepithelial study, Tat-GFP demonstrated the highest ability to penetrate through the HT-29 cells of about 1.3-fold and 1.2 fold of GFP and Tat/GFP, respectively. Only Tat/GFP gave lower cytotoxicity than Tat or GFP alone. In transdermal delivery study, Tat/GFP showed better transdermal delivery profile with higher cumulative amount than Tat-GFP in stratum corneum (SC), viable epidermis and dermis, and the receiver compartment of the diffusion cell with the highest fluxes of 7.42 and 35.6; 8.87-fold and 5.57-fold of GFP and Tat-GFP in SC and receiver compartment, respectively. This study demonstrated an efficient enhancement of GFP uptake into cells and through excised rat skin by simple mixing with Tat peptide, which can be further applied for the development of protein drug delivery systems. PMID- 21681756 TI - Response surface optimisation of extraction of antioxidants from strawberry fruit, and lipid peroxidation inhibitory potential of the fruit extract in cooked chicken patties. AB - BACKGROUND: Strawberries contain high levels of antioxidants and have beneficial effects against oxidative stress-mediated diseases, such as cancer. They contain multiple phenolic compounds, which contribute to their biological properties. Hence, a study was carried out to optimise the extraction of antioxidants and evaluate the antioxidant potential of strawberry fruit extract (SE) in cooked chicken patties during refrigerated storage. The activity of SE was compared with that of butylhydroxytoluene (BHT). RESULTS: The effect of solvent type (MeOH and EtOH), concentration (0-70%) of EtOH in the system, temperature (30-60 degrees C), and time (30-150 min) on DPPH*-scavenging activity of SE was investigated. Response surface methodology was used to estimate the optimum extraction conditions for each parameter. The maximum predicted DPPH* scavenging under the optimised conditions (100% MeOH, 30 degrees C, 150 min) was 43% at 1 mg SE mL-1. Freshly prepared chicken patties were treated with 5% and 10% SE and 2% BHT, and stored aerobically at 4 degrees C for 6 days. SE had no influence (P < 0.05) on any of the sensory attributes of the patties. The values of thiobarbituric acid reactive substances reduced significantly (P < 0.05) from 2.47 mg in control patties to 0.312 mg and 0.432 mg malonaldehyde kg-1 sample in 5-SE and 10-SE patties, respectively, on the day 6 of storage. CONCLUSION: The optimised model depicted MeOH at 30 degrees C with an extended time of 150 min as the optimum settings for extraction of compounds from strawberry that had the scavenging activity. The study shows that the extraction of natural antioxidants from strawberry can be improved by optimising several key extraction parameters. SE also acted as an effective antioxidant and suppressed lipid peroxidation in cooked chicken patties. PMID- 21681757 TI - How to prevent ripening blockage in 1-MCP-treated 'Conference' pears. AB - BACKGROUND: Some European pear varieties treated with 1-methylcyclopropene (1 MCP) often remain 'evergreen', meaning that their ripening process is blocked and does not resume after removal from cold storage. In this work this was confirmed also to be the case in 'Conference' pears. To reverse the blockage of ripening 1 MCP treatments combined with external exogenous ethylene were tested. RESULTS: 1 MCP treatment of 'Conference' pears is very effective in delaying ripening and, more specifically, softening. The same 1-MCP concentration in different experimental years caused a different response. The higher dose of 1-MCP (600 nL L-1) always resulted in irreversible blockage of ripening, whereas the behaviour of fruit receiving a lower dose (300 nL L-1) depended on the year, and this did not depend on maturity at harvest or on storage conditions. Simultaneous exposure to 1-MCP and exogenous ethylene significantly affected fruit ripening, allowing significant softening to occur but at a lower rate compared with control fruit. CONCLUSION: The application of exogenous ethylene and 1-MCP simultaneously after harvest permitted restoration of the ripening process after storage in 'Conference' pears, extending the possibility of marketing and consumption. PMID- 21681758 TI - Limonoid content of sour orange varieties. AB - BACKGROUND: Modern Citrus cultivars are thought to have arisen from three parents: the pummelo, the mandarin, and citron. Taxological and genetic data support that sweet and sour oranges share a common parentage. However, as their name suggests, the organoleptic properties of the fruit from these two families is distinctly different. Analysis of the limonoid content of sour orange varieties has been limited. RESULTS: Juice samples prepared from a selection of sour orange cultivars were evaluated for their limonoid A-ring lactone, aglycone, and glucoside contents. Limonoate A-ring lactone concentrations ranged from 11.1 to 44. 9 mg L-1, whereas nomilinoate A-ring lactone levels were found not to exceed 1.2 mg L-1. Total limonoid aglycone and total limonoid glucoside concentrations varied from 2.4 to 18.4 mg L-1 and from 149.0 to 612.3 mg L-1, respectively. Limonoid glucoside profiling by liquid chromatography-mass spectrometry suggest that the sour oranges are distinctly different from sweet oranges and other citrus species. CONCLUSION: Limonoid aglycone and A-ring contents across sweet and sour oranges are similar, whereas limonoid glucoside profiles are distinctly different. Juice prepared from Citrus maderaspatana had the highest limonoid concentrations among the samples tested and could potentially be used for the isolation of limonoid A-ring lactones and glucosides. PMID- 21681759 TI - Effects of exogenous nitric oxide on contents of soluble sugars and related enzyme activities in 'Feicheng' peach fruit. AB - BACKGROUND: Sugar content is one of the main characteristics related to the quality of fruit. Research confirms that nitric oxide (NO) involves a physiological process and prolongs the storage life of fruit. However, little attention has been paid to the effects of NO on sugar metabolism in fruit during storage. In this study, the effect of different concentrations (0, 10, 30 umol L 1) of exogenous NO treatment on sugar content and related enzyme activities in 'Feicheng' peach fruit was investigated during storage (0-12 days after harvest) at room temperature (25 degrees C). RESULTS: Results showed that the decrease of firmness and accumulation of sugar and acid:sugar ratio in peach fruit during storage were significantly inhibited by treatment with 10 umol L-1 NO. Treatment with 10 umol L-1 NO could promote fructose and glucose metabolism during the first 4 days of storage, and increase the content of sucrose and the activities of sorbitol dehydrogenase, sorbitol oxidase and sucrose phosphate synthase in peach fruit during storage. However, acid invertase activity from 8 to 12 days of storage and neutral invertase activity during the first 4 days of storage were inhibited by treatment with 10 umol L-1 NO. At the same time, treatment with 10 umol L-1 NO inhibited sucrose synthase (SS) activity in decomposition during storage and SS activity in synthesis from 8 to 12 days of storage. CONCLUSION: Treatment with 10 umol L-1 NO had a significant impact on content of soluble sugars and related enzyme activities in 'Feicheng' peach fruit during storage (0 12 days) at room temperature (25 degrees C). PMID- 21681760 TI - Aroma volatiles recovered in the water phase of cashew apple (Anacardium occidentale L.) juice during concentration. AB - BACKGROUND: There is a considerable loss of volatile compounds during the thermal concentration of cashew apple juice, damaging product quality, and as yet there is little research on the subject. Thus the purpose of this research was to identify the aroma volatiles evaporated off from cashew apple juice and recovered in the water phase during concentration of this beverage in an industrial plant. Water phase volatiles were extracted using dichloromethane, concentrated under a nitrogen flow, separated by gas chromatography (GC) and identified by GC-mass spectrometry. In order to determine the contribution of each volatile to the cashew aroma, five trained judges evaluated the GC effluents using the Osme GC olfactometry technique. RESULTS: 71 volatiles were identified; of these, 47 were odour active. Alcohols were preferentially recovered in the cashew water phase, notably heptanol, trans-3-hexen-1-ol and 3-methyl-1-butanol, representing 42% of the total chromatogram area and imparting green grass and fruity aroma notes to the water phase. Esters represented 21% of the total chromatogram area, especially ethyl 2-hydroxyhexanoate, ethyl trans-2-butenoate and ethyl 2 methylbutanoate, and were responsible for the fruity/cashew-like aroma of the water phase. On the other hand, 3-methylbutanoic and 2-methylbutanoic acids were the volatiles that presented the greatest odour impact in the GC effluents of the water phase. CONCLUSION: Overall, the results of the present study strongly indicated that further concentration of the esters recovered in the water phase, either by partial distillation or by alternative technologies such as pervaporation, could generate a higher-quality natural cashew apple essence. PMID- 21681761 TI - Dietary plant materials reduce acrylamide formation in cookie and starch-based model systems. AB - BACKGROUND: Dietary plant materials have attracted much attention because of their health benefits to humans. Acrylamide is found in various heated carbohydrate-rich foods. Our previous results showed that crude aqueous extracts from diverse dietary plants and some phenolic compounds could mitigate acrylamide formation in an asparagine-glucose model system. Based on our previous study, several plant materials were selected to further investigate their inhibitory effects on acrylamide formation in cookies and starch-based model systems. RESULTS: Addition of raw powders from selected dietary plants and their crude aqueous extracts could considerably reduce acrylamide formation in both cookie and potato starch-based models. Aqueous extracts of clove at 4% caused the largest reduction (50.9%) of acrylamide in cookies, whereas addition of 2% proanthocyanidins from grape seeds gave the greatest acrylamide reduction (62.2%) in a starch-based model system. CONCLUSION: It may be feasible to use some of the tested dietary plant materials to reduce acrylamide formation in cookies and other starchy foods. PMID- 21681762 TI - Degradation of beta-carotene in amorphous polymer matrices. Effect of water sorption properties and physical state. AB - BACKGROUND: The use of encapsulation in amorphous matrices of carbohydrate and/or polymer formed during dehydration processes to enhance the stability and retention of labile compounds is increasing in the food and pharmaceutical industries. Efforts to improve encapsulating properties have been made using mixtures of carbohydrates with proteins or gums in different proportions. The objective of the present work was to study the stability of encapsulated beta carotene and its degradation kinetics in maltodextrin/gum arabic and maltodextrin/gelatin matrices in relation to the physical properties and state of the dehydrated matrix. RESULTS: The degradation of beta-carotene followed a first order kinetic model of fractional retention for all encapsulating matrices. The Guggenheim-Anderson-de Boer (GAB) model was adequate to describe the sorption isotherms of the studied systems. beta-Carotene losses were observed mainly at relative humidities (RHs) above the glass transition temperatures (T(g) ) of the corresponding systems, where the matrices were fully plasticised and collapsed (75 and 92% RH). At these high RHs the best beta-carotene retention was obtained in the system containing gum arabic. CONCLUSION: The results showed that pigment degradation was determined by the physical state of the matrix, related to the degree of collapse. They represent a contribution to the knowledge of physical factors that affect the retention kinetics of labile biomolecules encapsulated in dehydrated matrices. PMID- 21681763 TI - Modifying glucose release from high carbohydrate foods with natural polymers extracted from cereals. AB - BACKGROUND: Sustained elevated blood glucose and insulin levels are linked to many health problems that may be prevented or better managed by controlling glucose availability for uptake. Glucose release from consumed starch may be altered by the processing conditions, particle size and structural features of the food, and by the addition of dietary fibres. Many approaches to lower glucose release are not suitable for all high carbohydrate foods, especially bakery products. Methods to modulate the starch digestion without compromising product quality are required. This study describes an approach to protect the granules and alter the particle size of the starch component using an extract from barley (BE). Wheat starch was suspended in the BE at different ratios and cast dried, milled to 2-3 mm particles, or finely ground to produce different particle sizes. RESULTS: The BE treatments resulted in the formation of clusters of starch granules embedded in a matrix of fibres and protein. The rate of in vitro starch digestion was decreased, and further reduction occurred when the particle size of the starch material increased. CONCLUSION: The extract provided a physical barrier that limited the starch exposure to the digestion enzymes and water that led to reduction in starch digestion and the release of glucose. PMID- 21681764 TI - Effects of mouldy core and core rot on physiological and biochemical responses of apple fruit. AB - BACKGROUND: Apple mouldy core (MC) and core rot (CR) are pathogenic disorders associated with the core region of fruits of susceptible varieties that have open calyx tubes. MC is not economically important because its symptoms are restricted to within the seed cavities, but CR is an important postharvest disease because its symptoms penetrate the fruit flesh and bring about economic losses. Recently, most studies have focused on causal agents and control of apple MC and CR. However, there is little information on the physiological and biochemical responses of apple fruits with MC and CR. RESULTS: The results indicated that MC and CR have different effects on the physiological and biochemical indices of apple fruits. Higher polyphenol oxidase (PPO) activity and total phenolic content were found in MC, dry CR (DCR) and asymptomatic tissue of wet CR (asympWCR) fruits than in healthy fruits, as well as significantly higher catalase and peroxidase activities in DCR and symptomatic tissue of WCR (sympWCR) fruits respectively, while asympWCR fruits showed a marked increase in malondialdehyde content, membrane permeability and superoxide production and a significant decrease in superoxide dismutase activity. CONCLUSION: The findings suggest that PPO and phenolic compounds may play a key role in the defence system of apple fruits against MC and CR. PMID- 21681765 TI - Essential oils and fatty acids composition of Tunisian and Indian cumin (Cuminum cyminum L.) seeds: a comparative study. AB - BACKGROUND: Cumin (Cuminum cyminum L.) seeds of two geographic origins, Tunisia (TCS) and India (ICS), were studied regarding their fatty acid and essential oil composition. RESULTS: Oil yields were 17.77 and 15.40% for TCS and ICS respectively. Petroselinic acid (C18:1n-12) was the major fatty acid in both varieties, with a higher proportion being found in TCS (55.90% of total fatty acids (TFA)) than in ICS (41.42% TFA). Moreover, the most predominant fatty acids were palmitic, petroselenic and linoleic acids, accounting for more than 91% TFA in both varieties. The unsaturated fatty acid content was high: 70.95% TFA in TCS and 62.17% TFA in ICS. Essential oil yields differed significantly (P < 0.05) between the two varieties: 1.21 and 1.62% for ICS and TCS respectively. A total of 40 compounds were identified, 34 of which were present in both essential oils. The two varieties displayed different chemotypes: gamma-terpinene/1-phenyl-1,2 ethanediol for TCS and cuminaldheyde/gamma-terpinene for ICS. CONCLUSION: The study revealed that the biochemical composition of cumin seeds is origin dependent and that cumin seeds are rich in an unusual fatty acid, petroselinic acid. Besides, cumin essential oil is a rich source of many compounds, including cuminaldehyde and gamma-terpinene. The overall results suggest the exploitation of cumin seeds as a low-cost renewable source for industrial processing in the fields of cosmetics, perfumes and pharmaceuticals. PMID- 21681770 TI - Speed, democracy, free accessibility... and quality? Social media, quo vaditis? PMID- 21681767 TI - Targeting COPD: advances on low-molecular-weight inhibitors of human neutrophil elastase. AB - Chronic obstructive pulmonary disease (COPD) is a major increasing health problem and the World Health Organization (WHO) reports COPD as the fifth leading cause of death worldwide. COPD refers to a condition of inflammation and progressive weakening of the structure of the lung as well as irreversible narrowing of the airways. Current treatment is only palliative and no available drug halts the progression of the disease. Human neutrophil elastase (HNE) is a serine protease, which plays a major role in the COPD inflammatory process. The protease/anti protease imbalance leads to an excess of extracellular HNE hydrolyzing elastin, the structural protein that confers elasticity to the lung tissue. Although HNE was identified as a therapeutic target for COPD more than 30 years ago, only Sivelestat (ONO-5046), an HNE inhibitor from Ono Pharmaceutical, has been approved for clinical use. Nevertheless, Sivelestat is only approved in Japan and its development in the USA was terminated in 2003. Other inhibitors in pre clinical or phase I trials were discontinued for various reasons. Hence, there is an urgent need for low-molecular-weight synthetic elastase inhibitors and the present review discusses the recent advances on this field covering acylating agents, transition-state inhibitors, mechanism-based inhibitors, relevant natural products, and major patent disclosures. PMID- 21681773 TI - beta-Cell evolution: How the pancreas borrowed from the brain: The shared toolbox of genes expressed by neural and pancreatic endocrine cells may reflect their evolutionary relationship. PMID- 21681774 TI - It takes guts to grow a brain: Increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood. AB - A new study entitled "Normal gut microbiota modulates brain development and behavior", published in the Proceedings of the National Academy of Sciences, requires that we reconsider the notion that the brain is an immune-privileged site. The authors demonstrate that intestinal microbiota must be present within a set time-frame for normal synaptogenesis to occur in the brain. In the absence of intestinal microbiota, histopathological and behavioral abnormalities arise. These observations necessitate a new look at the many interconnections of the immune system and the brain, suggesting new frontiers for research and new therapeutic strategies for neurodevelopmental diseases. PMID- 21681775 TI - Aberrant expression of katanin p60 in prostate cancer bone metastasis. AB - BACKGROUND: Katanin p60 is a microtubule-severing protein and is involved in microtubule cytoskeleton organization in both mitotic and non-mitotic processes. Its role in cancer metastasis is unknown. METHODS: Differential protein profiles of bone marrow aspirates were analyzed by chromatography, electrophoresis, and mass spectrometry. Expression of katanin p60 in primary and metastatic prostate cancer was examined by immunohistochemistry. Cellular function of katanin p60 was further examined in prostate cell lines. RESULTS: In a proteomic profiling of bone marrow aspirates from men with prostate cancer, we found that katanin p60 was one of the proteins differentially expressed in bone metastasis samples. Immunohistochemical staining showed that katanin p60 was expressed in the basal cells in normal human prostate glands. In prostatic adenocarcinomas, in which the basal cells were absent, katanin p60 was expressed in the prostate cancer cells. In the specimens from bone metastasis, katanin p60 was detectable in the metastatic cancer cells. Strikingly, some of the metastatic cancer cells also co expressed basal cell biomarkers including the tumor suppressor p53-homologous protein p63 and the high molecular weight cytokeratins, suggesting that the metastatic prostate cancer cells may have a basal cell-like phenotype. Moreover, overexpression of katanin p60 inhibited prostate cancer cell proliferation but enhanced cell migration activity. CONCLUSIONS: Katanin p60 was aberrantly expressed during prostate cancer progression. Its expression in the metastatic cells in bone was associated with the re-emergence of a basal cell-like phenotype. The elevated katanin p60 expression may contribute to cancer cell metastasis via a stimulatory effect on cell motility. PMID- 21681776 TI - Acute bacterial inflammation of the mouse prostate. AB - BACKGROUND: Prostatic inflammation is gaining increasing attention as a potential etiologic factor in prostate cancer, benign prostatic hyperplasia, lower urinary tract symptoms, and CPPS. This study was performed to address the need for a well characterized model of acute prostatic inflammation that may be used to study the effect of acute inflammation on epithelial and stromal cell proliferation, voiding behavior, and neurovascular physiology. METHODS: Uropathogenic E. coli 1677 was instilled transurethrally into adult C57BL/6J male mice. Prostates were analyzed at 1, 2, 3, 5, 7, or 14 days post-instillation and compared to saline instilled and naive controls. Time course and severity of inflammation were characterized by the quantity and type of inflammatory infiltrate present, hemorrhage, proliferation, and reactive hyperplasia. RT-PCR was performed to characterize inflammatory mediators including IL-1alpha, IL-1beta, IL-1RA, IL-18, IL-6, IL-10, IL-8, TNFalpha, and COX-2. RESULTS: Inflammation was evident in all lobes of the prostate with the DLP most severely affected. Infection consistently led to a significant increase in neutrophils and macrophages in the early stages of prostate infection, followed by lymphocytic inflammation at the later time points. Inflammation was accompanied by induction of several inflammatory genes, including IL-1 family members, IL-6, and COX-2, and induced a significant increase in epithelial proliferation and reactive hyperplasia in all three prostate lobes. CONCLUSIONS: Transurethral inoculation of uropathogenic E. coli 1677 reliably infects the mouse prostate, produces a significant inflammatory response, and induces quantifiable epithelial proliferation and reactive hyperplasia. PMID- 21681777 TI - Does absolute neutrophil count predict high tumor grade in African-American men with prostate cancer? AB - BACKGROUND: African-Americans (AA) are at risk for benign ethnic neutropenia (BEN), which has been implicated as a potential source of disparity in cancer outcomes among AAs. Since AAs with prostate cancer (PCa) are more likely to have aggressive pathological features, this investigation sought to determine if absolute neutrophil count (ANC) is associated with adverse pathologic findings at radical prostatectomy (RP) within a cohort of AA men. METHODS: A single institution, retrospective review was conducted of all AA patients undergoing RP who had a pre-operative CBC with differential and known RP pathology. Neutropenia was defined as ANC <=1.5 * 10(9) /L (1.5). Clinical and pathologic variables were characterized for the study cohort, and Cox regression and Kaplan-Meier analyses performed to evaluate the association between ANC and adverse pathology. RESULTS: A total of 336 patients were included, and 18 patients (5.4%) had ANC <=1.5. Mean age was 59.8 +/- 7.5 years; mean follow-up time 47.4 +/- 43.3 months. Neutropenic patients had significantly higher clinical stages and pathologic Gleason scores (P < 0.05). On multivariable analysis, ANC <=1.5 was significantly predictive of high tumor grade (HR 1.22, CI 1.01-1.48). CONCLUSIONS: Neutropenia in AAs predicts high tumor grade at prostatectomy. Further studies are necessary to further characterize the importance of these findings with regard to the pathogenesis of PCa, particularly as it relates to the AA population. PMID- 21681778 TI - RhoGDIalpha suppresses growth and survival of prostate cancer cells. AB - BACKGROUND: Treatment for primary prostate cancer (CaP) is the withdrawal of androgens. However, CaP eventually progresses to grow in a castration-resistant state. The mechanisms involved in the development and progression of castration resistant prostate cancer (CRPC) remain unknown. We have previously generated LNCaP-IL6+ cells by treating LNCaP cells chronically with interleukin-6 (IL-6), which have acquired the ability to grow in androgen-deprived conditions. METHODS: We compared the protein expression profile of LNCaP and LNCaP-IL6+ cells using two-dimensional gel electrophoresis. The gels were then silver stained in order to visualize proteins and the differentially expressed spots were identified and characterized by micro sequencing using MALDI-PMF mass spectrometry. RESULTS: In this study, we have identified RhoGDIalpha (GDIalpha) as a suppressor of CaP growth. Expression of GDIalpha was reduced in LNCaP-IL6+ cells and was down regulated in more aggressive CaP cells compared to LNCaP cells. Over expression of GDIalpha inhibited the growth of CaP cells and caused LNCaP-IL6+ cells reversal to androgen-sensitive state, while down-regulation of GDIalpha enhanced growth of androgen-sensitive LNCaP CaP cells in androgen-deprived conditions. In addition, GDIalpha suppressed the tumorigenic ability of prostate tumor xenografts in vivo. CONCLUSIONS: These results demonstrate that loss of GDIalpha expression promotes the development and progression of prostate cancer. PMID- 21681780 TI - Bayesian analysis of non-linear differential equation models with application to a gut microbial ecosystem. AB - Process models specified by non-linear dynamic differential equations contain many parameters, which often must be inferred from a limited amount of data. We discuss a hierarchical Bayesian approach combining data from multiple related experiments in a meaningful way, which permits more powerful inference than treating each experiment as independent. The approach is illustrated with a simulation study and example data from experiments replicating the aspects of the human gut microbial ecosystem. A predictive model is obtained that contains prediction uncertainty caused by uncertainty in the parameters, and we extend the model to capture situations of interest that cannot easily be studied experimentally. PMID- 21681779 TI - GPRC6A regulates prostate cancer progression. AB - BACKGROUND: GPRC6A is a nutrient sensing GPCR that is activated in vitro by a variety of ligands, including amino acids, calcium, zinc, osteocalcin (OC), and testosterone. The association between nutritional factors and risk of prostate cancer, the finding of increased expression of OC in prostate cancer cells, and the association between GPRC6A and risk of prostate cancer in Japanese men implicates a role of GPRC6A in prostate cancer. METHODS: We examined if GPRC6A is expressed in human prostate cancer cell lines and used siRNA-mediated knockdown GPRC6A expression in prostate cancer cells to explore the function of GPRC6A in vitro. To assess the role of GPRC6A in prostate cancer progression in vivo, we intercrossed Gprc6a(-/-) mice onto the TRAMP mouse prostate cancer model. RESULTS: GPRC6A transcripts were markedly increased in prostate cancer cell lines 22Rv1, PC-3, and LNCaP, compared to the normal prostate RWPE-1 cell line. In addition, a panel of GPRC6A ligands, including calcium, OC, and arginine, exhibited in prostate cancer cell lines a dose-dependent stimulation of ERK activity, cell proliferation, chemotaxis, and prostate specific antigen and Runx2 gene expression. These responses were inhibited by siRNA-mediated knockdown of GPRC6A. Finally, transfer of Gprc6a deficiency onto a TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival of compound Gprc6a(-/-) /TRAMP mice. CONCLUSIONS: GPRC6A is a novel molecular target for regulating prostate growth and cancer progression. Increments in GPRC6A may augment the ability of prostate cancer cells to proliferate in response to dietary and bone derived ligands. PMID- 21681781 TI - The role of 18F-FDG PET/CT imaging in Waldenstrom macroglobulinemia. AB - Disease assessment in WM is dependent on the quantification of the IgM monoclonal protein and percent involvement of the bone marrow. There is a need for imaging studies that objectively measure tumor load in these patients. In this study, we sought to examine the role of combined FDG-PET/CT imaging in the detection of tumor load and in the assessment of response to therapy. Thirty-five patients were enrolled on a prospective study using bortezomib and rituximab therapy and were included in this study because they completed a pre- and post-treatment FDG PET/CT imaging at one facility (12 newly diagnosed and 23 relapsed/refractory). The use of combined FDG-PET/CT imaging showed positive findings in 83% of patients with WM, unlike prior studies using conventional imaging that indicate that only 20% of patients have lymphadenopathy or hepatosplenomegaly. Moreover, 43% of patients had abnormal bone marrow uptake on FDG-PET imaging that can potentially help in the assessment of their tumor load, especially with heterogenous sampling of the bone marrow. There was no statistical correlation between EORTC response criteria for FDG-PET/CT and response by monoclonal protein. This is the first study to examine the role of FDG-PET/CT imaging in WM. Future studies should examine the role of FDG-PET/CT in conjunction with monoclonal protein response in the assessment of progression-free survival in patients with WM. PMID- 21681783 TI - POEMS syndrome: 2011 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and typically little to no peripheral neuropathy but has several of the minor diagnostic criteria for POEMS syndrome. DIAGNOSIS: The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyradiculoneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. RISK STRATIFICATION: Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the plasma cell disorder is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. RISK-ADAPTED THERAPY: For those patients with a dominant sclerotic plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement and for those who have progression of their disease 3 to 6 months after completing radiation therapy should receive systemic therapy. Corticosteroids are temporizing, but alkylators are the mainstay of treatment, either in the form of low dose conventional therapy or high dose with stem cell transplantation. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes. PMID- 21681782 TI - Nf1 mutant mice with p19ARF gene loss develop accelerated hematopoietic disease resembling acute leukemia with a variable phenotype. AB - Juvenile Myelomonocytic Leukemia (JMML) is a relentlessly progressive myeloproliferative/myelodysplastic (MPD/MDS) hematopoietic disorder more common in patients with any one of at least three distinct genetic lesions, specifically NF1 gene loss and PTPN11 and NRAS mutations. NF1 and PTPN11 are molecular lesions associated with Neurofibromatosis Syndrome Type I (NF1 Syndrome) and Noonan's Syndrome, respectively. The occurrence of JMML is rare; even among those predisposed with these syndromes to development of disease, and secondary genetic events likely contribute to the development and progression of disease. In NF1 syndrome, loss of p53 function is a common event in solid tumors, but uncommon in JMML, suggesting that the p53 pathway may be modified by other events in this hematopoietic disorder. The work presented here investigates the possible role of the p19(Arf) (p19) tumor suppressor in development of MPD associated with Nf1 gene loss in mice. We find that Nf1 mutant hematopoietic cells with loss of p19 develop accelerated hematopoietic disease similar to acute leukemia with a variable phenotype. This suggests that p19 may play a role in development of JMML and evaluation of the human p19 homolog (p14(ARF)) in JMML may be informative. PMID- 21681784 TI - Chills and limb pain following administration of low-molecular-weight heparin for treatment of acute venous thromboembolism. PMID- 21681785 TI - Eosinophilic myocarditis in hypereosinophilic syndrome. PMID- 21681786 TI - Proportions of bone marrow lymphocyte subsets at diagnosis may predict survival in patients with newly diagnosed diffuse large B-cell lymphoma independently of the international prognostic index. PMID- 21681787 TI - Comparison of autologous stem cell transplantation versus consolidation chemotherapy for patients with cytogenetically normal acute myeloid leukemia (CN AML) and FLT3ITD. PMID- 21681788 TI - John W. "Jack" Griffin, MD. PMID- 21681789 TI - Japan's neurological community contends with triple disaster. PMID- 21681790 TI - Who controls the price of pharmaceuticals? PMID- 21681792 TI - Training the next generation of child neurologists - a neuroscience based approach. PMID- 21681793 TI - Uncovering the genetic architecture of white matter disease. PMID- 21681794 TI - Getting to value in neurological care: a roadmap for academic neurology. AB - Academic neurology is undergoing transformational changes. The public investment in biomedical research and clinical care is enormous and there is a growing perception that the return on this huge investment is insufficient. Hospitals, departments, and individual neurologists should expect more scrutiny as information about their quality of care and financial relationships with industry are increasingly reported to the public. There are unprecedented changes occurring in the financing and delivery of health care and research that will have profound impact on the mission and operation of academic departments of neurology. With the passage of the Patient Protection and Affordable Care Act (PPACA) there will be increasing emphasis on research that demonstrates value and includes the patient's perspective. Here we review neurological investigations of our clinical and research enterprises that focus on quality of care and comparative effectiveness, including cost-effectiveness. By highlighting progress made and the challenges that lie ahead, we hope to create a clinical, educational, and research roadmap for academic departments of neurology to thrive in today's increasingly regulated environment. PMID- 21681795 TI - Therapies for dopaminergic-induced dyskinesias in Parkinson disease. AB - Existing and emerging strategies for managing L-dopa-induced dyskinesias (LIDs) in patients with Parkinson disease have involved either delaying the introduction of L-dopa therapy, treatment with an antidyskinetic agent, using a therapy or delivery system that can provide continuous dopaminergic stimulation, or using novel agents that target receptors implicated in the mechanisms underlying LIDs. Treatment with dopamine agonists such as pramipexole or ropinirole allows levodopa to be delayed, but once levodopa is added to the drug regimen the usual course of onset of dyskinesias is observed. Amantadine, an N-methyl-D-aspartate antagonist, is so far the only approved compound with evidence of providing a sustained antidyskinetic benefit in the absence of unacceptable side effects. These findings support the hypothesis of glutamate overactivity in the development of dyskinesias. More continuous delivery of dopaminergic medication, such as through intraintestinal or subcutaneous routes, is promising but invasive and associated with injection site reactions. As a result of molecular research and elucidation of the role of a variety of neurotransmitters in the mechanism of LIDs, new compounds have been identified, including those that modulate the direct and indirect striatal output pathways; some of these new agents are in the early stages of development or undergoing proof-of-concept evaluation as antidyskinetic agents. PMID- 21681797 TI - Anatomy of disturbed sleep in pallido-ponto-nigral degeneration. AB - OBJECTIVE: Pallido-ponto-nigral degeneration (PPND), caused by an N279K mutation of the MAPT gene, is 1 of a family of disorders collectively referred to as frontotemporal dementia and parkinsonism linked to chromosome 17. This study aims to characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Pathological findings are also provided. METHODS: Ten subjects were recruited from the PPND kindred; 5 affected and 5 unaffected. The subjects underwent clinical assessment, polysomnography, and wrist actigraphy. Available sleep-relevant areas (pedunculopontine/laterodorsal tegmentum, nucleus basalis of Meynert, thalamus, and locus ceruleus) of affected subjects were analyzed postmortem. RESULTS: The affected group's total sleep time was an average of 130.8 minutes compared to 403.6 minutes in the control group (p < 0.01). Initial sleep latency was significantly longer in affected subjects (range, 58-260 minutes vs 3-34 minutes). Affected subjects also had an increase in stage I sleep (8.5% vs 1%), and less stage III/IV sleep (8.5% vs 17%). At the time of autopsy, all cases had severe neuronal tau pathology in wake-promoting nuclei, as well as decreases in thalamic cholinergic innervations. There was no difference in orexinergic fiber density in nucleus basalis of Meynert or locus ceruleus compared to controls. INTERPRETATION: The PPND kindred showed severe sleep disturbance. Sleep abnormalities are common in neurodegenerative illnesses, but this is the first study of sleep disorders in PPND. Unlike most neurodegenerative conditions, PPND is characterized by decreased total sleep time, increased sleep latency, and decreased sleep efficiency, without daytime hypersomnolence. PMID- 21681796 TI - Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. AB - OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. RESULTS: We identified 6 novel risk associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 * 10(-9) ; p(replication) = 1.3 * 10(-7) ; p(combined) = 4.0 * 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 * 10(-9) ), rs11869977 (p = 5.7 * 10(-9) ), rs936393 (p = 6.8 * 10(-9) ), rs3744017 (p = 7.3 * 10(-9) ), and rs1055129 (p = 4.1 * 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample). INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH. PMID- 21681799 TI - A neurology resident's reflections on an elective in hyderabad. PMID- 21681798 TI - Alternative processing of gamma-secretase substrates in common forms of mild cognitive impairment and Alzheimer's disease: evidence for gamma-secretase dysfunction. AB - OBJECTIVE: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by gamma-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor gamma-secretase reaction product (Abeta42) to that of the major reaction product (Abeta40). Although no PS1 mutations are present, altered Abeta42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Abeta42 as amyloid. METHODS: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP alpha secretases and gamma-secretases, yielding a fragment that we have named p3 Alc(alpha) because of the parallel genesis of p3-Alc(alpha) peptides and the p3 fragment of APP. As with Abeta, both major and minor p3-Alc(alpha) s are generated. We studied the alternative processing of p3-Alc(alpha) in various clinical populations. RESULTS: We previously reported that changes in the Abeta42/40 ratio showed covariance in a linear relationship with the levels of p3 Alc(alpha) [minor/major] ratio in media conditioned by cells expressing FAD linked PS1 mutants. Here we studied the speciation of p3-Alc(alpha) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(alpha) variant, p3-Alc(alpha) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts. INTERPRETATION: These results suggest that some SAD may involve alternative processing of multiple gamma-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve gamma-secretase dysfunction. PMID- 21681801 TI - Comment on "no evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset". PMID- 21681804 TI - The neurofilament light chain is not stable in vitro. PMID- 21681806 TI - Vitamin B12, folate and hyperhomocysteinemia in patients with epilepsy. PMID- 21681808 TI - Licofelone-nitric oxide donors as anticancer agents. AB - Five licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H pyrrolizin-5-yl]acetic acid) nitric oxide donor conjugates were developed by a parallel synthesis approach. The biological screening revealed that compounds with a propyl (6b), butyl (6c), or octyl (6d) chain between licofelone and the nitric oxide donor exhibited high antiproliferative potency at MCF-7 and MDA-MB 231 breast cancer as well as at HT-29 colon cancer cells. Moreover, 6b-d possessed at least 2-fold higher cytotoxicity at MDA-MB-231 cells than the parent compound licofelone although they showed less inhibitory activity at COX-1 and COX-2. A correlation between COX inhibition and growth inhibitory properties is not visible. However, the high levels of nitric oxide production of the compounds may result in their high cytotoxic activity. PMID- 21681809 TI - Synthesis, anti-inflammatory and analgesic evaluation of certain new 3a,4,9,9a tetrahydro-4,9-benzenobenz[f]isoindole-1,3-diones. AB - In an effort to establish new candidates with improved analgesic and anti inflammatory activities, we reported here the synthesis and in-vivo analgesic and anti-inflammatory evaluation of various series of 2-substituted-3a,4,9,9a tetrahydro-4,9-benzeno-benz[f]isoindole-1,3-diones: [4-Bromobutoxy] 6, 5 bromopentoxy 7, [4-(4-phenylpiperazin-1-yl)butoxy] 9, [5-(4-phenylpiperazin-1 yl)pentoxy] 10, 2-(2(4)-(4-phenylpiperazin-1-yl)-2-oxoethyl/4-oxobutyl 17, 19, [2(4)-(4-methylpiperazin-1-yl]-2-oxoethyl/4-oxobutyl 20, 22, [2(4)-morpholino-2 oxoethyl/4-oxobutyl] 23, 25, and 2(4)-(piperidin-1-yl)2-oxoethyl/4-oxobutyl) 26 and 28. The newly synthesized compounds were characterized by (IR, (1)H-, (13)C NMR, and mass spectra). The representative compounds were evaluated as analgesic and anti-inflammatory activities. Compounds 9, 19, 22, 25, and 28 exhibited activities higher than the reference drug. PMID- 21681810 TI - Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates. AB - The synthesis and antitumor activity screening of novel isatin based conjugates with thiazolidine and pyrazoline moieties were performed. Reaction of 3,5-diaryl 4,5-dihydropyrazoles with chloroacetyl chloride yielded starting 2-chloro-1-(3,5 diaryl-4,5-dihydropyrazol-1-yl)-ethanones which were utilized in alkylation of isatin and 5-bromoisatin. Thus, corresponding 1-[2-(3,5-diaryl-4,5-dihydropyrazol 1-yl)-2-oxoethyl]-1H-indole-2,3-diones (1a-1d) have been obtained. The compounds 1a-1d have been used in Knoevenagel condensation with 4-thiazolidinones for obtaining a series of 5-ylidenederivatives 2a-2f and 3a-3d. The synthesized compounds were tested for their anticancer activity in NCI60 cell lines. Among the tested compounds, 5-bromo-1-{2-[5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5 dihydropyrazol-1-yl]-2-oxoethyl}-1H-indole-2,3-dione (1d) was found to be the most active candidate with selective influence on leukemia subpanel tumor cell lines with GI(50) values range of 0.69-3.35 uM. PMID- 21681811 TI - Design, synthesis, and preliminary activity evaluation of novel peptidomimetics as aminopeptidase N/CD13 inhibitors. AB - The synthesis of a series of novel N-alpha-galloylated isoglutamic acid gamma amide peptidomimetics is described. Their enzymatic inhibition against aminopeptidase N (APN/CD13) and matrix metalloproteinase-2 (MMP-2) was tested. The preliminary activity assay revealed that most of the compounds displayed selective inhibition against APN as compared with MMP-2, with IC(50) values in a micromolar range. Within this series, compound 4 (IC(50) = 10.2 +/- 0.9 uM) demonstrated comparable APN inhibition as compared with the positive control bestatin (IC(50) = 13.1 +/- 0.7 uM), which might be a promising lead for further molecular optimizations. PMID- 21681812 TI - Influence of dissolved organic carbon on toxicity of copper to a unionid mussel (Villosa iris) and a cladoceran (Ceriodaphnia dubia) in acute and chronic water exposures. AB - Acute and chronic toxicity of copper (Cu) to a unionid mussel (Villosa iris) and a cladoceran (Ceriodaphnia dubia) were determined in water exposures at four concentrations of dissolved organic carbon (DOC; nominally 0.5, 2.5, 5, and 10 mg/L as carbon [C]). Test waters with DOC concentrations of 2.5 to 10 mg C/L were prepared by mixing a concentrate of natural organic matter (Suwannee River, GA, USA) in diluted well water (hardness 100 mg/L as CaCO(3) , pH 8.3, DOC 0.5 mg C/L). Acute median effect concentrations (EC50s) for dissolved Cu increased approximately fivefold (15-72 ug Cu/L) for mussel survival in 4-d exposures and increased about 11-fold (25-267 ug Cu/L) for cladoceran survival in 2-d exposures across DOC concentrations from 0.5 to 10 mg C/L. Similarly, chronic 20% effect concentrations (EC20s) for the mussel in 28-d exposures increased about fivefold (13-61 ug Cu/L for survival; 8.8-38 ug Cu/L for biomass), and the EC20s for the cladoceran in 7-d exposures increased approximately 17-fold (13-215 ug Cu/L) for survival or approximately fourfold (12-42 ug Cu/L) for reproduction across DOC concentrations from 0.5 to 10 mg C/L. The acute and chronic values for the mussel were less than or approximately equal to the values for the cladoceran. Predictions from the biotic ligand model (BLM) used to derive the U.S. Environmental Protection Agency's ambient water quality criteria (AWQC) for Cu explained more than 90% of the variation in the acute and chronic endpoints for the two species, with the exception of the EC20 for cladoceran reproduction (only 46% of variation explained). The BLM-normalized acute EC50s and chronic EC20s for the mussel and BLM-normalized chronic EC20s for the cladoceran in waters with DOC concentrations of 2.5 to 10 mg C/L were equal to or less than the final acute value and final chronic value in the BLM-based AWQC for Cu, respectively, indicating that the Cu AWQC might not adequately protect the mussel from acute and chronic exposure, and the cladoceran from chronic exposure. PMID- 21681813 TI - Smad6 is essential to limit BMP signaling during cartilage development. AB - Bone morphogenetic protein (BMP) signaling pathways regulate multiple aspects of endochondral bone formation. The importance of extracellular antagonists as regulators of BMP signaling has been defined. In vitro studies reveal that the intracellular regulators, inhibitory Smads 6 and 7, can regulate BMP-mediated effects on chondrocytes. Although in vivo studies in which inhibitory Smads were overexpressed in cartilage have shown that inhibitory Smads have the potential to limit BMP signaling in vivo, the physiological relevance of inhibitory Smad activity in skeletal tissues is unknown. In this study, we have determined the role of Smad6 in endochondral bone formation. Loss of Smad6 in mice leads to defects in both axial and appendicular skeletal development. Specifically, Smad6 /- mice exhibit a posterior transformation of the seventh cervical vertebra, bilateral ossification centers in lumbar vertebrae, and bifid sternebrae due to incomplete sternal band fusion. Histological analysis of appendicular bones revealed delayed onset of hypertrophic differentiation and mineralization at midgestation in Smad6-/- mice. By late gestation, however, an expanded hypertrophic zone, associated with an increased pool of proliferating cells undergoing hypertrophy, was evident in Smad6 mutant growth plates. The mutant phenotype is attributed, at least in part, to increased BMP responsiveness in Smad6-deficient chondrocytes. Overall, our results show that Smad6 is required to limit BMP signaling during endochondral bone formation. PMID- 21681814 TI - Estrogen inhibits Dlk1/FA1 production: a potential mechanism for estrogen effects on bone turnover. AB - We have recently identified delta-like 1/fetal antigen 1 (Dlk1/FA1) as a novel regulator of bone mass that functions to mediate bone loss under estrogen deficiency in mice. In this report, we investigated the effects of estrogen (E) deficiency and E replacement on serum (s) levels of Dlk1/FA1 (s-Dlk1FA1) and its correlation with bone turnover markers. s-Dlk1/FA1 and bone turnover markers (serum cross-linked C-telopeptide [s-CTX] and serum osteocalcin) were measured in two cohorts: a group of pre- and postmenopausal women (n = 100) and a group of postmenopausal women, where half had received estrogen-replacement therapy (ERT, n = 166). s-Dlk1/FA1 and s-CTX were elevated in postmenopausal E-deficient women compared with premenopausal E-replete women (both p < 0.001). s-Dlk1/FA1 was correlated with s-CTX (r = 0.30, p < 0.01). ERT in postmenopausal women decreased s-Dlk1/FA1, as well as s-CTX and s-osteoclacin (all p < .0001). Changes in s-Dlk1 were significantly correlated with those observed in s-CTX (r = 0.18, p < 0.05) and s-osteocalcin (r = 0.28, p < 0.001). In conclusion, s-Dlk1/FA1 is influenced by E-deficiency and is correlated with bone turnover. Increased levels of s Dlk1/FA1 in postmenopausal women may be a mechanism mediating the effects of estrogen deficiency on bone turnover. PMID- 21681815 TI - Clinical and functional outcomes in patients with major depressive disorder and painful physical symptoms switched to treatment with duloxetine. AB - OBJECTIVE: This post hoc analysis of a multicenter, single-arm, open-label trial (the Attributes of Response in Depressed Patients Switched to Treatment with Duloxetine [ARDENT] study) assessed the relationship between functional improvement in the Sheehan Disability Scale (SDS) and clinical outcomes of mood, pain, and anxiety over 8 weeks after switching treatment to duloxetine in patients with major depressive disorder. METHODS: Analyses included all 195 patients who completed the study. Pearson's correlation and multivariate regression analyses were used to evaluate the relationship between change from baseline in SDS total score and 17-item Hamilton Rating Scale for Depression (HAMD(17)) Maier score (mood), Brief Pain Inventory-Short Form average pain score (pain), and Hamilton Anxiety Rating Scale total score (anxiety) at week 8. RESULTS: At week 8, change in SDS total score was positively correlated with change in mood (r = 0.49), anxiety (r = 0.44), and pain (r = 0.40). Multivariate linear regression coefficients for mood and pain were estimated at 1.21 (standard error [SE] = 0.184) and 1.16 (SE = 0.180), respectively (both p < 0.0001) compared with 0.02 (SE = 0.097; p = 0.82) for anxiety. Overall, 43% of patients achieved both HAMD(17) and SDS total remission. CONCLUSIONS: Functional improvement at 8 weeks was positively correlated with mood, pain, and anxiety in patients with major depressive disorder switched to duloxetine. Change in mood and pain exerted a relatively stronger joint effect on functioning than did anxiety in this patient population. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21681816 TI - 6-Sulfatoxymelatonin as a predictor of clinical outcome in depressive patients. AB - OBJECTIVES: This study established the value of the 6-sulfatoxymelatonin (aMT6s) urine concentration as a predictor of the therapeutic response to noradrenaline reuptake inhibitors in depressive patients. METHODS: Twenty-two women aged 18-60 years were selected. Depressive symptoms were assessed by using the Hamilton Depression Scale. Urine samples were collected at 0600-1200 h, 1200-1800 h, 1800 2400 h, and 2400-0600 h intervals, 1 day before and 1 day after starting on the nortriptyline treatment. Urine aMT6s concentration was analyzed by a one-way analysis of variance/Bonferroni test. Spearman's rank correlation coefficient was used to analyze the correlation between depressive symptoms after 2 weeks of antidepressant treatment and the increase in aMT6s urine concentration. RESULTS: Higher and lower size effect groups were compared by independent Student's t tests. At baseline, the 2400- to 0600-h interval differed from all other intervals presenting a significantly higher aMT6s urine concentration. A significant difference in aMT6s urine concentrations was found 1 day after treatment in all four intervals. Higher size effect group had lower levels of depressive symptoms 2 weeks after the treatment. A positive correlation between depressive symptoms and the delta of aMT6s in the 2400-0600 h interval was observed. CONCLUSION: Our results reinforce the hypothesis that aMT6s excretion is a predictor of clinical outcome in depression, especially in regard to noradrenaline reuptake inhibitors. PMID- 21681818 TI - Evaluation of a virtual reality-based memory training programme for Hong Kong Chinese older adults with questionable dementia: a pilot study. AB - BACKGROUND: Older adults with questionable dementia are at risk of progressing to dementia, and early intervention is considered important. The present study investigated the effectiveness of a virtual reality (VR)-based memory training for older adults with questionable dementia. METHODS: A pre-test and post-test design was adopted. Twenty and 24 older adults with questionable dementia were randomly assigned to a VR-based and a therapist-led memory training group, respectively. Primary outcome measures included the Multifactorial Memory Questionnaire and Fuld Object Memory Evaluation. RESULTS: Both groups demonstrated positive training effects, with the VR group showing greater improvement in objective memory performance and the non-VR group showing better subjective memory subtest results in the Multifactorial Memory Questionnaire. CONCLUSION: The use of VR seems to be acceptable for older adults with questionable dementia. Further study on the effect of educational background and memory training modality (visual, auditory) is warranted. PMID- 21681817 TI - Treatment-related alteration of cortisol predicts change in neuropsychological function during acute treatment of late-life anxiety disorder. AB - OBJECTIVE: Older adults with anxiety disorders are burdened by impairment in neurocognition, which may be mediated by elevated circulating cortisol levels. In a randomized controlled trial of acute serotonin-reuptake inhibitor treatment for late-life anxiety disorder, we examined whether change in salivary cortisol concentrations during treatment predicted improvements in measures of memory and executive function. METHODS: We examined 60 adults aged 60 years and older, who took part in a 12-week trial of escitalopram versus placebo for generalized anxiety disorder. All subjects had pre-treatment and post-treatment assessments that included monitoring of peak and total daily cortisol and a comprehensive neuropsychological evaluation. RESULTS: Salivary cortisol changes during treatment showed significant associations with changes in immediate and delayed memory but no association with executive tasks (measures of working memory and set shifting). Analyses suggested that a decrease in cortisol due to serotonin reuptake inhibitor treatment was responsible for the memory changes: memory improvement was seen with cortisol reduction among patients receiving escitalopram but not among patients receiving placebo. CONCLUSION: Serotonin reuptake inhibitor-induced alteration in circulating cortisol during treatment of generalized anxiety disorder predicted changes in immediate and delayed memory. This finding suggests a novel treatment strategy in late-life anxiety disorders: targeting hypothalamic-pituitary- adrenal axis dysfunction to improve memory. PMID- 21681819 TI - The metabolism and toxicity of hemin in astrocytes. AB - Hemin is cytotoxic, and contributes to the brain damage that accompanies hemorrhagic stroke. In order to better understand the basis of hemin toxicity in astrocytes, the present study quantified hemin metabolism and compared it to the pattern of cell death. Heme oxygenase-1 (HO-1) expression was first evident after 2 h incubation with hemin, with maximal expression being observed by 24 h. Despite the induction of HO-1, it was found that the proportion of hemin metabolized by astrocytes remained fairly constant throughout the 24 h period, with 70-80% of intracellular hemin remaining intact. A period of cell loss began after 2 h exposure to hemin, which gradually increased in severity to reach a maximum by 24 h. This cell loss could not be attenuated by the iron chelator, 1,10-phenanthroline, or by several antioxidant compounds (Trolox, N-acetyl-L cysteine and N-tert-butyl-alpha-phenylnitrone), indicating that the mechanism of hemin toxicity does not involve iron. While these results make it unlikely that hemin toxicity is due to interactions with endogenous H(2)O(2), hemin toxicity was increased in the presence of supraphysiological levels of H(2)O(2) and this increase was ameliorated by PHEN, indicating that the iron released from hemin can be toxic under some pathological conditions. However, when H(2)O(2) is present at physiological levels, the toxicity of hemin appears to be caused by other mechanisms that may involve bilirubin and carbon monoxide in this model system. PMID- 21681820 TI - High-performance liquid chromatographic enantioseparation of Betti base analogs on a newly developed isopropyl carbamate-cyclofructan6-based chiral stationary phase. AB - The direct separation of the enantiomers of 1-(alpha-aminoarylmethyl)-2-naphthol, 1-(alpha-aminoalkyl)-2-naphthol, 2-(alpha-aminoarylmethyl)-1-naphthol analogs, and 2-(1-amino-2-methylpropyl)-1-naphthol) was performed on a newly developed chiral stationary phase containing isopropyl carbamate-cyclofructan6 as chiral selector, with n-heptane/alcohol/trifluoroacetic acid as mobile phase. The effects of the mobile-phase composition, the nature and concentration of the alcoholic and acidic modifiers, and the structures of the analytes on the retention and resolution were investigated. In some cases, separations were carried out at constant mobile-phase compositions in the temperature range 5-40 degrees C. Thermodynamic parameters and T(iso) values were calculated from plots of ln k' or ln alpha versus 1/T. -Delta(DeltaH degrees ) ranged from 2.8 to 3.2 kJ mol(-1) , -Delta(DeltaS degrees ) from 7.7 to 10.1 J mol(-1) K(-1) , and Delta(DeltaG degrees ) from 0.2 to 0.5 kJ mol(-1) . It was found that the enantioseparations were enthalpy driven. The sequence of elution of the stereoisomers determined in some cases was (R) < (S). PMID- 21681821 TI - Liver-specific overexpression of matrix metalloproteinase 9 (MMP-9) in transgenic mice accelerates development of hepatocellular carcinoma. AB - Matrix metalloproteinase-9 (MMP-9) plays a central role in tumor invasion and development of metastases. Expression of MMP-9 had been shown in human hepatocellular carcinomas (HCCs). However, it remained unclear whether MMP-9 could influence development of HCC. In order to address this issue, we generated transgenic mice overexpressing MMP-9 in the liver. In order to avoid embryonic lethality a Cre-lox system was utilized for conditional overexpression of MMP-9 under control of an albumin enhancer and promoter. Induction of MMP-9 overexpression in transgenic mice was achieved by i.v. injection of an adenovirus coding for the Cre recombinase. Initiation of liver carcinogenesis was achieved by injection of diethylnitrosamine (DEN) followed by Phenobarbital administration in drinking water. Transgene expression was induced at the age of 6 wk. Four and six months later mice were sacrificed and examined macroscopically and microscopically in a blinded manner. Alb/Cre/MMP-9-transgenic mice showed liver specific overexpression of MMP-9-mRNA and protein after induction. At the age of 6 months livers of transgenic mice showed 15.7 +/- 11.6 tumors (mean +/- SD) in contrast to wildtype mice with only 7.9 +/- 11.0 tumors (P < 0.03). By histopathology examination of the livers HCCs were identified in 42% of the transgenic mouse livers but only 8% in wildtype animals. In summary, we established a novel MMP-9 transgenic mouse model, and report on a significantly increased susceptibility of MMP-9 transgenic mice to chemically induced carcinogenesis. This is the first in vivo proof that MMP-9 overexpression promotes liver tumor development. PMID- 21681822 TI - Transcriptional down-regulation of Brca1 and E-cadherin by CtBP1 in breast cancer. AB - Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. Immunohistochemistry staining using human breast cancer tissue arrays revealed that 92% of invasive ductal breast cancer cases have CtBP1 positive staining compared to 4% CtBP1-positive in normal breast tissue. To explore the functional impact of CtBP1 in breast cancer, we examined CtBP1's transcriptional regulation of known tumor suppressors, breast cancer susceptibility gene 1 (Brca1), and E-cadherin. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. Concomitantly, Brca1 loss was detected in 57% and E-cadherin loss was detected in 76% of human invasive ductal breast cancers, and correlated with CtBP1 nuclear staining in these lesions. Importantly, siRNA knock down of CtBP1 restored Brca1 and E-cadherin expression in breast cancer cell lines, implying CtBP1 down regulates Brca1 and E-cadherin genes in human breast cancer. This study provides evidence that although genetic loss of Brca1 and E-cadherin are infrequent in breast cancer, they are down-regulated at the transcriptional level by CtBP1 expression. Thus, CtBP1 activation could be a potential biomarker for breast cancer development. PMID- 21681823 TI - Role of GSTT1 and M1 null genotypes as risk factors for B-cell lymphoma: influence of geographical factors and occupational exposure. AB - The interrelationship between genetic susceptibility and carcinogenic exposure is important in the development of haematopoietic malignancies. Both factors need to be considered to enable assessment of disease risk associated with a given individual under certain environmental conditions. GSTT1 and GSTM1 are two genes whose proteins are involved in the detoxification of potential carcinogens. We have studied the prevalence of GSTT1 and GSTM1 null polymorphisms using a novel PCR multiplex protocol in a group of 158 patients with B-cell lymphoma (BCL, 138 with non-Hodgkin lymphoma and 20 with Hodgkin lymphoma) and 214 healthy controls. A questionnaire regarding occupational exposure and lifestyle factors was also completed by both groups. GSTM1 null genotype showed no significant differences between patients and controls (46.9% and 55.6%, respectively). In contrast, GSTT1 null genotype was observed in 25.3% of patients and 15.4% of controls (P=0.013; OR=1.85; CI (95%):1.11-3.09), suggesting a role for the GSTT1 null genotype in the development of BCL. This effect was even more evident in females (27.5% vs. 14%: P=0.014). No significant association was observed between GST genotypes and disease risk in relation to smoking or occupational exposure. PMID- 21681824 TI - DNA mismatch repair network gene polymorphism as a susceptibility factor for pancreatic cancer. AB - DNA repair plays a critical role in human cancers. We hypothesized that DNA mismatch repair gene variants are associated with risk of pancreatic cancer. We retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 mismatch repair related genes in 706 patients with pancreatic cancer and 706 cancer-free controls using the mass spectroscopy-based MassArray method. Association of genotype with pancreatic cancer risk was tested by multivariate logistic regression models. A significance level of P <= 0.0015 was set at the false discovery rate (FDR) <1% using the Beta-Uniform Mixture method. We found 28 SNPs related to altered pancreatic cancer risk (P < 0.05). Adjusting for multiple comparisons, MGMT I143V AG/GG, PMS2 IVS1-1121C > T TC/TT, and PMS2L3 Ex1 + 118C > T CT/TT genotypes showed significant main effects on pancreatic cancer risk at FDR <1% with OR (95% CI) of 0.60 (0.46-0.80), 1.44 (1.14-1.81), and 5.54 (2.10 14.61), respectively (P <= 0.0015). To demonstrate genotype-phenotype association, we measured O(6)-ethylguanosine (O(6)-EtGua) adduct levels in vitro by immunoslot blot assay in lymphocytes treated with N-ethyl-N-nitrosourea (ENU) in 297 case/control subjects. MGMT I143V GG, MGMT K178R GG, MSH6 G39E AG/AA, PMS2L3 IVS3 + 9A > G GA and TP73 IVS1-7449G > C CG/CC genotypes correlated with a higher level of ENU-induced DNA adducts. Haplotypes of MGMT, MSH6, PMS2, PMS2L3, and TP73 were significantly associated with pancreatic cancer risk (P <= 0.0015). Our findings suggest that mismatch repair gene variants may affect susceptibility to pancreatic cancer. PMID- 21681827 TI - From molecules to materials: the cluster of excellence "engineering of advanced materials" at Friedrich-Alexander University of Erlangen-Nuremberg. PMID- 21681825 TI - Loss of Desmocollin 3 in skin tumor development and progression. AB - Desmocollin 3 (DSC3) is a desmosomal cadherin that is required for maintaining cell adhesion in the epidermis as demonstrated by the intra-epidermal blistering observed in Dsc3 null skin. Recently, it has been suggested that deregulated expression of DSC3 occurs in certain human tumor types. It is not clear whether DSC3 plays a role in the development or progression of cancers arising in stratified epithelia such as the epidermis. To address this issue, we generated a mouse model in which Dsc3 expression is ablated in K-Ras oncogene-induced skin tumors. Our results demonstrate that loss of Dsc3 leads to an increase in K-Ras induced skin tumors. We hypothesize that acantholysis-induced epidermal hyperplasia in the Dsc3 null epidermis facilitates Ras-induced tumor development. Further, we demonstrate that spontaneous loss of DSC3 expression is a common occurrence during human and mouse skin tumor progression. This loss occurs in tumor cells invading the dermis. Interestingly, other desmosomal proteins are still expressed in tumor cells that lack DSC3, suggesting a specific function of DSC3 loss in tumor progression. While loss of DSC3 on the skin surface leads to epidermal blistering, it does not appear to induce loss of cell-cell adhesion in tumor cells invading the dermis, most likely due to a protection of these cells within the dermis from mechanical stress. We thus hypothesize that DSC3 can contribute to the progression of tumors both by cell adhesion-dependent (skin surface) and likely by cell adhesion-independent (invading tumor cells) mechanisms. PMID- 21681830 TI - Minkowski tensor shape analysis of cellular, granular and porous structures. AB - Predicting physical properties of materials with spatially complex structures is one of the most challenging problems in material science. One key to a better understanding of such materials is the geometric characterization of their spatial structure. Minkowski tensors are tensorial shape indices that allow quantitative characterization of the anisotropy of complex materials and are particularly well suited for developing structure-property relationships for tensor-valued or orientation-dependent physical properties. They are fundamental shape indices, in some sense being the simplest generalization of the concepts of volume, surface and integral curvatures to tensor-valued quantities. Minkowski tensors are based on a solid mathematical foundation provided by integral and stochastic geometry, and are endowed with strong robustness and completeness theorems. The versatile definition of Minkowski tensors applies widely to different types of morphologies, including ordered and disordered structures. Fast linear-time algorithms are available for their computation. This article provides a practical overview of the different uses of Minkowski tensors to extract quantitative physically-relevant spatial structure information from experimental and simulated data, both in 2D and 3D. Applications are presented that quantify (a) alignment of co-polymer films by an electric field imaged by surface force microscopy; (b) local cell anisotropy of spherical bead pack models for granular matter and of closed-cell liquid foam models; (c) surface orientation in open-cell solid foams studied by X-ray tomography; and (d) defect densities and locations in molecular dynamics simulations of crystalline copper. PMID- 21681832 TI - Morphology and linear-elastic moduli of random network solids. AB - The effective linear-elastic moduli of disordered network solids are analyzed by voxel-based finite element calculations. We analyze network solids given by Poisson-Voronoi processes and by the structure of collagen fiber networks imaged by confocal microscopy. The solid volume fraction phi is varied by adjusting the fiber radius, while keeping the structural mesh or pore size of the underlying network fixed. For intermediate phi, the bulk and shear modulus are approximated by empirical power-laws K(phi)proptophin and G(phi)proptophim with n~1.4 and m~1.7. The exponents for the collagen and the Poisson-Voronoi network solids are similar, and are close to the values n=1.22 and m=2.11 found in a previous voxel based finite element study of Poisson-Voronoi systems with different boundary conditions. However, the exponents of these empirical power-laws are at odds with the analytic values of n=1 and m=2, valid for low-density cellular structures in the limit of thin beams. We propose a functional form for K(phi) that models the cross-over from a power-law at low densities to a porous solid at high densities; a fit of the data to this functional form yields the asymptotic exponent n~1.00, as expected. Further, both the intensity of the Poisson-Voronoi process and the collagen concentration in the samples, both of which alter the typical pore or mesh size, affect the effective moduli only by the resulting change of the solid volume fraction. These findings suggest that a network solid with the structure of the collagen networks can be modeled in quantitative agreement by a Poisson Voronoi process. PMID- 21681836 TI - meso-Aryl phenanthroporphyrins: synthesis and spectroscopic properties. AB - The successful synthesis of tetraphenyltetraphenanthroporphyrin (TPTPhenP; 5a) in 2006 under modified Rothemund-Lindsey conditions yielded a tetraphenyl porphyrinoid with a B band redshifted to an unprecedented 576 nm. Radially symmetric fused-ring expansion of tetraphenylporphyrin with phenanthrene moieties results in very deep saddling due to steric crowding and very marked redshifts of the Q and B (or Soret) porphyrinoid absorption bands. The extent to which the TPTPhenP structure can be further modified is explored, and the optical properties of TPTPhenPs are analyzed based on a perimeter model approach that makes use of time-dependent DFT calculations and magnetic circular dichroism spectroscopy and also based on a detailed analysis of the fluorescence emission. Attempts to introduce substituents at the ortho and meta positions of the meso phenyl groups and to insert a central metal proved unsuccessful. The synthesis of a series of TPTPhenPs with strong electron-withdrawing (-CN, -NO(2)) and donating (-CH(3), -N(CH(3))(2)) substituents at the para positions of the meso phenyl rings is reported. Marked redshifts of the main spectral bands were consistently observed. The most pronounced spectral changes were observed with N(CH(3))(2) groups (5i) due to a marked destabilization of the HOMO, which has large MO coefficients on the meso-carbon atoms. Protonation of 5i at both the ligand core and at the -N(CH(3))(2) groups resulted in unprecedented Q(00) band absorption at wavelengths greater than 1200 nm. PMID- 21681837 TI - Detection of single nucleotide polymorphisms by a gold nanowire-on-film SERS sensor coupled with S1 nuclease treatment. AB - Single nucleotide polymorphisms (SNPs) can serve as important biomarkers for genetic diseases, for which accurate detection of SNPs is essential for early diagnosis. We have developed a novel SNP sensor by combining a Au nanowire-on film surface-enhanced Raman scattering (SERS) platform with S1 nuclease reaction. The combined sensor system provides reproducible SERS signals only in the presence of perfectly matched target DNAs, to probe DNAs as a result of single stranded DNA-specific degradation by S1 nuclease. Furthermore, point mutations in DNA causing Wilson disease and Avellino corneal dystrophy were successfully identified by this sensor, thereby indicating its practical ability to diagnose genetic diseases. PMID- 21681838 TI - Tunable emission of static excimer in a pyrene-modified polyamidoamine dendrimer aggregate through positive solvatochromism. AB - Significant aggregation is observed in pyrene-modified zero- and first-generation polyamidoamine (PAMAM) dendrimers above their critical aggregation concentration (CAC, >10(-6) M). The pyrene units are attached to the dendrimer skeleton through imine bonds, which play a pivotal role in enhancing the aggregation propensity of the PAMAM dendrimers. Scanning electron microscopy studies suggest that pyrene modified PAMAM dendrimers aggregate into doughnut-shaped assemblies. As a result of aggregation, the pyrene chromophores are pre-arranged in a face-to-face geometry in the ground state, and readily generate pyrene "static excimer" on photoexcitation. The static pyrene excimer emits with an unprecedented quantum yield of 0.62 +/- 0.01 in dichloromethane, and also exhibits remarkable positive solvatochromism from 498 to 638 nm, which leads to the highest bathochromic shift for pyrene excimer emission in solution reported so far. Lippert-Mataga analysis of the system suggests that general and specific solvent effects play a crucial role in the positive solvatochromism exhibited by the system. Luminescence quenching studies on both monomer and aggregate systems were carried out in the presence of various metal ions, and the results imply that pyrene-modified PAMAM dendrimer can be utilized for selective detection of Hg ions in the presence of a wide variety of transition, alkali, and alkaline earth metal ions. This report presents the first dendrimer-based chromophoric system exhibiting positive solvatochromism over a range of 140 nm, and shows that pyrene-modified PAMAM dendrimers can be effectively utilized to generate wavelength-tunable emitting systems displaying bluish green, greenish yellow, and orange-red colors at room temperatures. PMID- 21681840 TI - Spectroscopic investigation of heterogeneous Ziegler-Natta catalysts: Ti and Mg chloride tetrahydrofuranates, their interaction compound, and the role of the activator. AB - X-ray powder diffraction (XRPD), Infrared, Raman, and UV/Vis spectroscopy have been used to investigate the structural, vibrational, and optical properties of Ti and Mg chloride tetrahydrofuranates as precursors of heterogeneous Ziegler Natta catalysts for polyethylene production; as well as their interaction compound (pro-catalyst) and the final catalyst obtained after interaction with the AlR(3) activator. Although the structure of the precursors and of the pro catalyst were well known, that of the catalyst (obtained by reaction of the pro catalyst with AlR(3)) was not easily obtainable from XRPD data. IR and Raman spectroscopy provided important information on tetrahydrofuran (thf) coordination and on the nu(M-Cl) region; whereas UV/Vis spectroscopy gave the direct proof on both the formal oxidation state and the coordination environment of the active Ti sites. Those presented herein are among the first direct experimental data on the structure of the active Ti sites in Ziegler-Natta catalysts, and can be used to validate the many computational studies that have been increasing exponentially in the last few decades. PMID- 21681839 TI - Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation. AB - Platinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-Pt(IV) carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug-protein interactions between EA-CPT and GST P1-1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA-CPT preferentially docks at the dimer interface at GST P1-1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H-sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex. PMID- 21681841 TI - The first total synthesis of cytopiloyne, an anti-diabetic, polyacetylenic glucoside. AB - The first total synthesis of cytopiloyne 1, a novel bioactive polyacetylenic glucoside isolated from the extract of Bidens pilosa, is described. The structure of cytopiloyne was determined to be 2-beta-D-glucopyranosyloxy-1-hydroxytrideca 5,7,9,11-tetrayne by using various spectroscopic methods, but the chirality of the polyyne moiety was unknown. Herein, the convergent synthesis of two diastereomers of cytopiloyne by starting from commercially available 4-(2 hydroxyethyl)-2,2-dimethyl-1,3-diozolane is described. The synthetic sequence involved two key steps: stereoselective glycosylation of the glucosyl trichloroacetimidate with 1-[(4-methoxybenzyl)oxy]hex-5-yn-2-ol to give the desired beta-glycoside and the construction of the glucosyl tetrayne skeleton by using a palladium/silver-catalyzed cross-coupling reaction to form the alkyne alkyne bond, the first such use of this reaction. Comparison between the observed and published characterization data showed the 2R isomer to be the natural product cytopiloyne. PMID- 21681842 TI - Click-dendronized poly(amide-triazole)s--effect of dendron size and polymer backbone symmetry on self-assembling and gelation properties. AB - Nine dendronized poly(amide-triazole)s 2-Gm Gn (m=1-3, n=1-3), were prepared by the 1:1 copolymerization between AA-type dendritic diazides 4-Gm (m=1-3) and BB type dendritic diacetylenes 5-Gn (n=1-3) under the copper(I)-mediated click coupling conditions. The degree of polymerization value of the polymers was found to range from 15-50, and decreased with increasing size of the dendron, suggesting steric hindrance had a retardation role on the copolymerization efficiency. Based on FT-IR and (1)H NMR studies, it was found that significantly strong, interchain hydrogen bonding between the amide units was present in the solution state after copolymerization, whereas the monomers 4-Gm and 5-Gn were devoid of any intermolecular hydrogen-bonding interaction. Hence a positive allosteric hydrogen-bonding effect was observed after polymerization, and could be rationalized by the zip effect. The strength of the interchain association in polymers 2-Gm Gn was found to decrease with increasing size of the dendron (i.e., 2-G1 G1>2-G1 G2>2-G2 G1~2-G2 G2>2-G1 G3~2-G3 G1>2-G2 G3~2-G3 G2>2-G3 G3). Among the nine polymers, only 2-G1 G2 and 2-G2 G1 were good organogelators for aromatic solvents, while the 2-G2 G2 polymer, bearing the closest structural resemblance to the previously reported organogelator 1-G2 prepared from the polymerization of AB-type monomers, was devoid of gelating power. Careful analysis of structures of the present polymer series 2-Gm Gn and the previously reported series 1-Gn suggested that the polymer backbone symmetry played a subtle role in controlling their self-assembling and gelating properties. PMID- 21681844 TI - Modulation of autophagy influences development and apoptosis in mouse embryos developing in vitro. AB - Autophagyis, the bulk degradation of proteins and organelles, is essential for cellular maintenance, cell viability, and development, and is often involved in type II programmed cell death in mammals. This study investigated the expression levels of autophagy-related genes and the effect of 3-methyladenine (3-MA, an autophagy inhibitor) or rapamycin (an autophagy inducer) on the in vitro development and apoptosis of mouse embryos. LC3, which is essential for the formation of autophagosomes, was widely expressed in mouse embryos, and high levels of transcript were present from 1 to 4 cells but gradually decreased through the morula and blastocyst stages. 3-MA-treated embryos exhibited significantly reduced developmental rates and total cell numbers, but increased rates of apoptosis. Furthermore, both the expression of Lc3, Gabarap, Atg4A, and Atg4B, and the synthesis of LC3 were significantly reduced at the blastocyst stage. Although rapamycin treatment did not affect developmental rates, cell numbers decreased, and the apoptosis rate increased. Expression of Lc3, Gabarap, Atg4A, and Atg4B, and synthesis of LC3 increased as well. Modulation of Lc3 mRNA and LC3 protein levels using 3-MA or rapamycin significantly increased apoptotic cell death through the disruption of mitochondrial morphology and reduction of mtDNA copy number at the blastocyst stage. Interestingly, the inner cell mass, detected by immunostaining with POU5F1 (OCT3/4) after 3-MA or rapamycin treatment of embryos, was significantly increased compared to controls. These results suggest that autophagy influences developmental patterning and apoptosis, and may play a role in early mouse embryogenesis. PMID- 21681845 TI - Insulin receptor-related (Irr) is expressed in pre-implantation embryos: a possible relationship to "growth factor Y" and sex determination. PMID- 21681843 TI - Protein tyrosine kinase signaling during oocyte maturation and fertilization. AB - The oocyte is a highly specialized cell capable of accumulating and storing energy supplies as well as maternal transcripts and pre-positioned signal transduction components needed for zygotic development, undergoing meiosis under control of paracrine signals from the follicle, fusing with a single sperm during fertilization, and zygotic development. The oocyte accomplishes this diverse series of events by establishing an array of signal transduction pathway components that include a select collection of protein tyrosine kinases (PTKs) that are expressed at levels significantly higher than most other cell types. This array of PTKs includes cytosolic kinases such as SRC-family PTKs (FYN and YES), and FAK kinases, as well as FER. These kinases typically exhibit distinct patterns of localization and in some cases are translocated from one subcellular compartment to another during meiosis. Significant differences exist in the extent to which PTK-mediated pathways are used by oocytes from species that fertilize externally versus internally. The PTK activation profiles as well as calcium signaling pattern seems to correlate with the extent to which a rapid block to polyspermy is required by the biology of each species. Suppression of each of the SRC-family PTKs as well as FER kinase results in failure of meiotic maturation or zygote development, indicating that these PTKs are important for oocyte quality and developmental potential. Future studies will hopefully reveal the extent to which these factors impact clinical assisted reproductive techniques in domestic animals and humans. PMID- 21681846 TI - Transient cultural influences on infant mortality: Fire-Horse daughters in Japan. AB - OBJECTIVES: Parental investment theory suggests that the quality and quantity of parental care depends, in part, on assessments of whether offspring will survive and yield grandchildren. Consistent with this theory, we hypothesize that parental perception that a birth cohort will have low reproductive success coincides with higher than expected infant mortality in the cohort. We test this hypothesis in industrialized Japan in 1966 when cultural aversion to females born in the astrological year of the Fire-Horse may have jeopardized the life of female infants. METHODS: We applied time-series methods to cohort infant mortality data for Japan, from 1947 to 1976, to test whether female infant mortality in 1966 rose above levels expected from history, male infant mortality, and fertility. Methods control for the secular decline in infant mortality as well as other temporal patterns that could induce spurious associations. RESULTS: Findings support the hypothesis in that female infant mortality rises by 1.1 deaths per 1,000 live births above expected levels (coefficient = 0.0011; standard error = 0.0005; P = 0.03). The result indicates an excess of 721 female infant deaths statistically attributable to the Fire-Horse year. Findings remain robust to control for male infant mortality and the secular decline in mortality over the test period. CONCLUSIONS: The discovery of a predictable, acute increase in female infant mortality during the Fire-Horse year supports the relevance of parental investment theory to developed countries. Results should encourage further research on the health sequelae of abrupt, population-level shifts in culture. PMID- 21681847 TI - Nutritional vulnerability in Mbya-Guarani adolescents and adults from Misiones, Argentina. AB - OBJECTIVES: The aim of this study was to evaluate the nutritional status and body composition in Mbya-Guarani adolescents and adults from three communities in the Province of Misiones, in northern Argentina. METHODS: Anthropometric parameters were analyzed in 45 individuals (aged 14-60). Data were transformed to z-scores using NHANES I and II. RESULTS: Ninety-three percent of the sample showed some kind of malnutrition (undernutrition and/or excess of weight). Stunting and overweight reached the highest prevalences (85.0 and 10.0%, respectively). The most Mbya people were found to have low arm muscle and fat areas. They also tended to have shorter than normal lower limbs. Centralized obesity was evident in both sexes and in all the age intervals. CONCLUSIONS: Extreme poverty, together with changes in life habits and diet composition, resulted in decrease of body size and changes in body proportions and composition. Although these changes could be considered as an adaptive response to the chronic exposure of these populations to adverse environmental conditions, they would favor the co occurrence of malnutrition and overweight in a single scenario, and consequently increase the risk of infectious and nontransmissible diseases. PMID- 21681848 TI - A meta-analysis of fat intake, reproduction, and breast cancer risk: an evolutionary perspective. AB - OBJECTIVES: This study is a systematic review of literature published up to May of 2010 aimed to identify relationships between dietary fat, and fat subtypes, with risk of breast cancer in women. METHODS: Descriptive data, estimates of relative risk and associated 95% confidence interval (CI) were extracted from relative studies and analyzed using the random effects model of DerSimonian and Laird. RESULTS: Cohort study results indicated significant summary relative risks between polyunsaturated fat and breast cancer (1.091, 95% CI: 1.001; 1.184). In case-control studies no association between fat and breast cancer was observed. Post-menopausal women indicated a significant association between total fat (1.042, 95%CI: 1.013; 1.073), PUFA intake (1.22, 95% CI: 1.08; 1.381), and breast cancer. A non-significant inverse relation between intake of all fat types and breast cancer was identified in premenopausal women. CONCLUSIONS: These results support the idea that possible elevations in serum estrogen levels by an adult exposure to a high-fat diet would increase breast cancer risk. Furthermore, menopausal status was observed to affect women's risk of breast cancer. Higher risks of breast cancer were found in post-menopausal women consuming diets high in total fat and polyunsaturated fats. Conversely, dietary fat appears to have preventative effects in pre-menopausal women. This study takes a transformative approach combining epidemiological, biomedical, and evolutionary theory to evaluate how biocultural variations in risk factors (i.e., diet and reproduction) affect the evolution of breast cancers. PMID- 21681849 TI - Does sitting height ratio affect estimates of obesity prevalence among Canadian Inuit? Results from the 2007-2008 Inuit Health Survey. AB - OBJECTIVES: High sitting height ratio (SHR) is a characteristic commonly associated with Inuit morphology. Inuit are described as having short leg lengths and high trunk-to-stature proportions such that cutoffs for obesity derived from European populations may not adequately describe thresholds of disease risk. Further, high SHR may help explain the reduced impact of BMI on metabolic risk factors among Inuit relative to comparison populations. This study investigates the relationship between SHR and body mass index (BMI) in Inuit. METHODS: Subjects are 2,168 individuals (837 males and 1,331 females) from 36 Inuit communities in the Canadian Arctic. Mean age is 42.63 +/- 14.86 years in males and 41.71 +/- 14.83 years in females. We use linear regression to examine the association between age, sex, height, sitting height, SHR, waist circumference (WC), and BMI. We then evaluate the efficacy of the relative sitting height adjustment as a method of correcting observed BMI to a population-standardized SHR. RESULTS: Mean BMI is significantly higher than among non-Inuit Canadians. Obesity prevalence is high, particularly among Inuit women. In the regression, only age and WC are significant predictors of BMI. While SHR is significantly greater than that of the US population, there is substantial agreement between overweight and obesity prevalence using observed and corrected BMI. CONCLUSIONS: We find no consistent relationship between SHR and BMI and suggest the unique anthropometric and metabolic profile observed in Inuit arise from factors not yet delineated. More complex anthropometric and imaging studies in Inuit are needed. PMID- 21681850 TI - Utilisation of transdermal fentanyl in Germany from 2004 to 2006. AB - PURPOSE: Oral morphine is the first-choice opioid for moderate to severe cancer pain. Transdermal fentanyl is an alternative in patients with stable requirements of high-potency opioids (HPO) or if drugs cannot be taken orally. Drug regulatory authorities have issued several alerts to use transdermal fentanyl only for chronic pain and in HPO-tolerant patients to minimise the risk of severe opioid side effects. The aim of this study was to characterise utilisation of transdermal fentanyl in Germany. METHODS: The analysis was based on data from four German statutory health insurances from the years 2004-2006. Descriptive analyses were performed in new users of transdermal fentanyl to assess HPO naivety, potential difficulties with the oral route in HPO-naive patients and the number of transdermal fentanyl dispensations. The initial dose in new users was assessed in 2005-2006 after marketing of transdermal fentanyl 12.5 ug/hour. RESULTS: Of 35 262 patients with new use of transdermal fentanyl, 29 793 (84.5%) were assessed as HPO-naive. Of those, 21 596 (72.5%) did not have diagnoses indicating difficulties with the oral route. For 71.2% of the HPO-naive new users of transdermal fentanyl, the first dose exceeded the recommended dose of 12.5 ug/hour, and 49.3% of them received only one prescription of the drug. CONCLUSIONS: Transdermal fentanyl was used as a first-choice opioid, which may increase the risk of serious opioid side effects, in a substantial number of HPO naive patients. Inappropriate prescribing included also high initial doses in HPO naive patients and possible prescription for acute pain in a considerable proportion of patients. PMID- 21681851 TI - Starting the conversation. PMID- 21681852 TI - Single base-pair substitutions at the translation initiation sites of human genes as a cause of inherited disease. AB - A total of 405 unique single base-pair substitutions, located within the ATG translation initiation codons (TICs) of 255 different genes, and reported to cause human genetic disease, were retrieved from the Human Gene Mutation Database (HGMD). Although these lesions comprised only 0.7% of coding sequence mutations in HGMD, they nevertheless were 3.4-fold overrepresented as compared to other missense mutations. The distance between a TIC and the next downstream in-frame ATG codon was significantly greater for genes harboring TIC mutations than for the remainder of genes in HGMD (control genes). This suggests that the absence of an alternative ATG codon in the vicinity of a TIC increases the likelihood that a given TIC mutation will come to clinical attention. An additional 42 single base pair substitutions in 37 different genes were identified in the vicinity of TICs (positions -6 to +4, comprising the so-called "Kozak consensus sequence"). These substitutions were not evenly distributed, being significantly more abundant at position +4. Finally, contrary to our initial expectation, the match between the original TIC and the Kozak consensus sequence was significantly better (rather than worse) for genes harboring TIC mutations than for the HGMD control genes. PMID- 21681853 TI - Mutations in NOTCH2 in families with Hajdu-Cheney syndrome. AB - Hajdu-Cheney syndrome (HCS) is a rare genetic disorder whose hallmark is acro osteolysis, shortening of terminal phalanges, and generalized osteoporosis. We assembled a cohort of seven families with the condition and performed whole exome resequencing on a selected set of affected patients. One protein-coding gene, NOTCH2, carried heterozygous truncating variants in all patients and their affected family members. Our results replicate recently published studies of HCS and further support this as the causal gene for the disorder. In total, we identified five novel and one previously reported mutation, all clustered near the carboxyl terminus of the gene, suggesting an allele specific genotype phenotype effect since other mutations in NOTCH2 have been reported to cause a form of Alagille syndrome. Notch-mediated signaling is known to play a role in bone metabolism. Our results support a potential therapeutic role for Notch pathways in treatment of osteoporosis. PMID- 21681854 TI - The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations. AB - Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder that can be inherited autosomal dominantly (DDEB) or recessively (RDEB) and covers a group of several distinctive phenotypes. A large number of unique COL7A1 mutations have been shown to underlie DEB. Although general genotype-phenotype correlation rules have emerged, many exceptions to these rules exist, compromising disease diagnosing and genetic counseling. We therefore constructed the International DEB Patient Registry (http://www.deb-central.org), aimed at worldwide collection and sharing of phenotypic and genotypic information on DEB. As of May 2011, this MOLGENIS-based registry contains detailed information on 508 published and 71 unpublished patients and their 388 unique COL7A1 mutations, and includes all combinations of mutations. The current registry RDEB versus DDEB ratio of 4:1, if compared to prevalence figures, suggests underreporting of DDEB in the literature. Thirty-eight percent of mutations stored introduce a premature termination codon (PTC) and 43% an amino acid change. Submission wizards allow users to quickly and easily share novel information. This registry will be of great help in disease diagnosing and genetic counseling and will lead to novel insights, especially in the rare phenotypes of which there is often lack of understanding. Altogether, this registry will greatly benefit the DEB patients. PMID- 21681855 TI - A novel GJA3 mutation associated with congenital nuclear pulverulent and posterior polar cataract in a Chinese family. AB - Congenital cataract (CC) is the leading cause of visual disability in children. To date, mutations in many genes have been linked to CC. In a four-generation Chinese family with congenital nuclear pulverulent and posterior polar cataracts, we detected a heterozygous c.5G>A transition in the second exon of GJA3, resulting in the substitution of a highly conserved glycine with aspartic acid (p.G2D) at the N-terminus of the connexin46 (Cx46) protein. Wild type (wt) and mutant Cx46 plasmids were transfected into HeLa cells to examine the molecular basis of cataract formation. Unlike wt Cx46, Cx46G2D mutant formed gap junction plaques inefficiently, changed hemichannel permeability, and caused apoptosis. These results suggest that the glycine residue at the second position of the N terminus is important for gap junction plaque formation and hemichannel function. PMID- 21681856 TI - Separating brain processing of pain from that of stimulus intensity. AB - Regions of the brain network activated by painful stimuli are also activated by nonpainful and even nonsomatosensory stimuli. We therefore analyzed where the qualitative change from nonpainful to painful perception at the pain thresholds is coded. Noxious stimuli of gaseous carbon dioxide (n = 50) were applied to the nasal mucosa of 24 healthy volunteers at various concentrations from 10% below to 10% above the individual pain threshold. Functional magnetic resonance images showed that these trigeminal stimuli activated brain regions regarded as the "pain matrix." However, most of these activations, including the posterior insula, the primary and secondary somatosensory cortex, the amygdala, and the middle cingulate cortex, were associated with quantitative changes in stimulus intensity and did not exclusively reflect the qualitative change from nonpainful to pain. After subtracting brain activations associated with quantitative changes in the stimuli, the qualitative change, reflecting pain-exclusive activations, could be localized mainly in the posterior insular cortex. This shows that cerebral processing of noxious stimuli focuses predominately on the quantitative properties of stimulus intensity in both their sensory and affective dimensions, whereas the integration of this information into the perception of pain is restricted to a small part of the pain matrix. PMID- 21681857 TI - N-carbamylglutamate enhancement of ureagenesis leads to discovery of a novel deleterious mutation in a newly defined enhancer of the NAGS gene and to effective therapy. AB - N-acetylglutamate synthase (NAGS) catalyzes the conversion of glutamate and acetyl-CoA to NAG, the essential allosteric activator of carbamyl phosphate synthetase I, the first urea cycle enzyme in mammals. A 17-year-old female with recurrent hyperammonemia attacks, the cause of which remained undiagnosed for 8 years in spite of multiple molecular and biochemical investigations, showed markedly enhanced ureagenesis (measured by isotope incorporation) in response to N-carbamylglutamate (NCG). This led to sequencing of the regulatory regions of the NAGS gene and identification of a deleterious single-base substitution in the upstream enhancer. The homozygous mutation (c.-3064C>A), affecting a highly conserved nucleotide within the hepatic nuclear factor 1 (HNF-1) binding site, was not found in single nucleotide polymorphism databases and in a screen of 1,086 alleles from a diverse population. Functional assays demonstrated that this mutation decreases transcription and binding of HNF-1 to the NAGS gene, while a consensus HNF-1 binding sequence enhances binding to HNF-1 and increases transcription. Oral daily NCG therapy restored ureagenesis in this patient, normalizing her biochemical markers, and allowing discontinuation of alternate pathway therapy and normalization of her diet with no recurrence of hyperammonemia. Inc. PMID- 21681858 TI - Complete meiosis from human induced pluripotent stem cells. AB - Gamete failure-derived infertility affects millions of people worldwide; for many patients, gamete donation by unrelated donors is the only available treatment. Embryonic stem cells (ESCs) can differentiate in vitro into germ-like cells, but they are genetically unrelated to the patient. Using an in vitro protocol that aims at recapitulating development, we have achieved, for the first time, complete differentiation of human induced pluripotent stem cells (hiPSCs) to postmeiotic cells. Unlike previous reports using human ESCs, postmeiotic cells arose without the over-expression of germline related transcription factors. Moreover, we consistently obtained haploid cells from hiPSCs of different origin (keratinocytes and cord blood), produced with a different number of transcription factors, and of both genetic sexes, suggesting the independence of our approach from the epigenetic memory of the reprogrammed somatic cells. Our work brings us closer to the production of personalized human gametes in vitro. PMID- 21681859 TI - CC chemokine ligand 2 and leukemia inhibitory factor cooperatively promote pluripotency in mouse induced pluripotent cells. AB - The pluripotency of mouse embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can be maintained by feeder cells, which secrete leukemia inhibitory factor (LIF). We found that feeder cells provide a relatively low concentration (25 unit/ml) of LIF, which is insufficient to maintain the ESCs/iPSCs pluripotency in feeder free conditions. To identify additional factors involved in the maintenance of pluripotency, we carried out a global transcript expression profiling of mouse iPSCs cultured on feeder cells and in feeder-free (LIF-treated) conditions. This identified 17 significantly differentially expressed genes (adjusted p value <0.05) including seven chemokines overexpressed in iPSCs grown on feeder cells. Ectopic expression of these chemokines in iPSCs revealed that CC chemokine ligand 2 (Ccl2) induced the key transcription factor genes for pluripotency, Klf4, Nanog, Sox2, and Tbx3. Furthermore, addition of recombinant Ccl2 protein drastically increased the number of Nanog-green fluorescent protein-positive iPSCs grown in low-LIF feeder free conditions. We further revealed that pluripotency promotion by Ccl2 is mediated by activating the Stat3-pathway followed by Klf4 upregulation. We demonstrated that Ccl2 mediated increased pluripotency is independent of phosphoinositide 3-kinase and mitogen-activated protein kinase pathways and that Tbx3 may be upregulated by Klf4. Overall, Ccl2 cooperatively activates the Stat3-pathway with LIF in feeder free conditions to maintain pluripotency for ESCs/iPSCs. PMID- 21681860 TI - Geminin regulates cortical progenitor proliferation and differentiation. AB - During cortical development, coordination of proliferation and differentiation ensures the timely generation of different neural progenitor lineages that will give rise to mature neurons and glia. Geminin is an inhibitor of DNA replication and it has been proposed to regulate cell proliferation and fate determination during neurogenesis via interactions with transcription factors and chromatin remodeling complexes. To investigate the in vivo role of Geminin in the maintenance and differentiation of cortical neural progenitors, we have generated mice that lack Geminin expression in the developing cortex. Our results show that loss of Geminin leads to the expansion of neural progenitor cells located at the ventricular and subventricular zones of the developing cortex. Early cortical progenitors lacking Geminin exhibit a longer S-phase and a reduced ability to generate early born neurons, consistent with a preference on self-renewing divisions. Overexpression of Geminin in progenitor cells of the cortex reduces the number of neural progenitor cells, promotes cell cycle exit and subsequent neuronal differentiation. Our study suggests that Geminin has an important role during cortical development in regulating progenitor number and ultimately neuron generation. PMID- 21681862 TI - Testing the dimensionality of posttraumatic stress responses in young Chinese adult earthquake survivors: further evidence for "dysphoric arousal" as a unique PTSD construct. AB - BACKGROUND: This study investigated an alternative five-factor diagnostic model for posttraumatic stress disorder (PTSD) symptoms, and tested external convergent and discriminant validity of the model in a young Chinese sample of earthquake survivors. METHODS: A total of 938 participants (456 women, 482 men) aged 15-20 years were recruited from a vocational school originally located in Beichuan County Town which was almost completely destroyed by the "Wenchuan Earthquake." The participants were administrated with the PTSD Checklist and the Hopkins Symptoms Checklist-25 12 months after the earthquake. RESULTS: The results of confirmatory factor analysis showed that the five-factor intercorrelated model (intrusion, avoidance, numbing, dysphoric arousal, and anxious arousal) fit the data significantly better than the four-factor numbing model proposed by King et al. (1998: Psychol Assess 10:90-96) and the four-factor dysphoria model proposed by Simms et al. (2002: J Abnorm Psychol 111:637-647). Further analyses indicated that four out of five PTSD factors yielded significantly different correlations with external measures of anxiety versus depression. CONCLUSIONS: The findings provide further empirical evidence in favor of the five-factor diagnostic model of PTSD, and carry implications for the upcoming DSM-5. PMID- 21681861 TI - Genetically encoding unnatural amino acids in neural stem cells and optically reporting voltage-sensitive domain changes in differentiated neurons. AB - Although unnatural amino acids (Uaas) have been genetically encoded in bacterial, fungal, and mammalian cells using orthogonal transfer RNA (tRNA)/aminoacyl-tRNA synthetase pairs, applications of this method to a wider range of specialized cell types, such as stem cells, still face challenges. While relatively straightforward in stem cells, transient expression lacks sufficient temporal resolution to afford reasonable levels of Uaa incorporation and to allow for the study of the longer term differentiation process of stem cells. Moreover, Uaa incorporation may perturb differentiation. Here, we describe a lentiviral-based gene delivery method to stably incorporate Uaas into proteins expressed in neural stem cells, specifically HCN-A94 cells. The transduced cells differentiated into neural progenies in the same manner as the wild-type cells. By genetically incorporating a fluorescent Uaa into a voltage-dependent membrane lipid phosphatase, we show that this Uaa optically reports the conformational change of the voltage-sensitive domain in response to membrane depolarization. The method described here should be generally applicable to other stem cells and membrane proteins. PMID- 21681863 TI - Cognitive-behavioral treatment of persistent functional somatic complaints and pediatric anxiety: an initial controlled trial. AB - BACKGROUND: Children and adolescents who seek medical treatment for persistent physical distress often suffer from co-occurring anxiety disorders. Treatment options for this impaired population are limited. This study tests the feasibility and potential efficacy of a cognitive-behavioral intervention targeting pain and anxiety for youth with impairing functional physical symptoms and anxiety disorders presenting to pediatricians for medical care. METHODS: Children and adolescents (aged 8-16) experiencing somatic complaints, without an explanatory medical disorder (i.e., functional), were recruited from primary care and specialty (gastroenterologists and cardiologists) pediatricians. Forty children, primarily with gastrointestinal symptoms, who met criteria for a co occurring anxiety disorder, were randomly assigned to a cognitive-behavioral treatment addressing pain and anxiety, Treatment of Anxiety and Physical Symptoms (TAPS), or to a waiting list control. RESULTS: TAPS was found to be an acceptable treatment for this population and was superior to the waiting list condition. Eighty percent of children in TAPS were rated as treatment responders by independent evaluators compared with none of the controls. Overall, self- and parent ratings indicated reductions in children's somatic discomfort and anxiety following intervention. TAPS participants maintained clinical gains 3 months following treatment. CONCLUSIONS: The study supports the feasibility and preliminary efficacy of a cognitive-behavioral intervention targeting co occurring physical distress and anxiety in youth presenting for medical treatment. Such an approach has the potential to exert broad impact on children's dysfunction and to minimize exposure to invasive, ineffective, and costly medical procedures and treatments. PMID- 21681865 TI - The association between affect amplification and urgency. AB - BACKGROUND: Individuals lacking effective coping skills to manage aversive affective states are more likely to behave impulsively despite harmful long-term consequences. Urgency or the propensity to act rashly in response to negative affect is associated with a host of maladaptive behaviors. However, relatively little research has evaluated the impact of affective variables--such as emotion regulation--on urgency. Moreover, the role of urgency has not been examined in populations with mood and anxiety disorders, a group for whom maladaptive coping and avoidance behaviors are common responses to heightened affect. This study evaluated the association between urgency and three variables associated with the amplification of affect (anxiety sensitivity (AS), access to emotion regulation strategies, and distress intolerance). METHODS: Data were collected from an unselected community sample (n = 297) and a clinical sample with a mood and/or anxiety disorder (n = 99). RESULTS: Results from a linear regression indicated significant associations between both distress intolerance and emotion regulation strategies and urgency. AS was significantly associated with urgency when considered alone, but did not remain significant when considered in the context of an alternative measure of distress intolerance and emotion regulation. CONCLUSIONS: These findings suggest that intolerance of distressing states and lack access to a repertoire of emotion regulation strategies are strongly associated with acting impulsively in response to negative affect. Treatment implications and future research directions are discussed. PMID- 21681864 TI - Synthesis of the psychometric properties of the PTSD checklist (PCL) military, civilian, and specific versions. AB - The posttraumatic stress disorder checklist is a commonly used measure, with military (PCL-M), civilian (PCL-C), and specific trauma (PCL-S) versions. This synthesis of the psychometric properties of all three versions found the PCL to be a well-validated measure. The PCL shows good temporal stability, internal consistency, test-retest reliability, and convergent validity. The majority of structural validity studies support four factor models. Little is available on discriminant validity and sensitivity to change. Strengths, limitations, and future research directions are discussed. Understanding the PCL's psychometric properties, strengths (e.g., items map on to DSM-IV diagnostic criteria), and limitations (e.g., may overestimate PTSD prevalence) will help clinicians and researchers make educated decisions regarding the appropriate use of this measure in their particular setting. PMID- 21681866 TI - Relationships between vascular dysfunction, circulating endothelial progenitor cells, and psychological status in healthy subjects. AB - BACKGROUND: Although the mechanisms remain unclear, depression and mental stress are associated with endothelial dysfunction and increases risk of cardiovascular disease (CVD). Recent studies suggest that circulating endothelial progenitor cells (EPC) play an important role in endothelial repair and correlate with endothelial function. METHODS: We studied the relationship between the level of circulating CD34/KDR(+) EPCs and CD133/KDR(+) EPCs, brachial artery flow-mediated dilation (FMD), Depression Anxiety Stress Scales in 129 normal individuals (54 +/ 10 years, 54 men) without prior CVD or diabetes. RESULTS: Their median depression score (DS) and stress score (SS) was 4 (range 0-34) and 6 (range 0 32), respectively. As defined by the >=75th percentile, 41 subjects (32%) had high DS (>=8) and 31 (24%) had high SS (>=14). Subjects with high DS had significantly lower FMD (5.4 +/- 2.7 versus 8.0 +/- 4.0%, P<0.001) and percentage of CD34/KDR(+) EPC (1.2 +/- 1.3 versus 2.0 +/- 2.4%, P = 0.037), but not CD133/KDR(+) EPC (0.56 +/- 0.42 versus 0.68 +/- 0.76%, P = 0.44), than those with normal DS. In contrast, there were no significant difference in FMD (6.8 +/- 3.5 versus 7.3 +/- 3.9%, P = 0.46), percentages of circulating CD34/KDR(+) EPC (1.20 +/- 1.28 versus 1.95 +/- 2.34%, P = 0.052) and CD133/KDR(+) EPC (0.55 +/- 0.41 versus 0.67 +/- 0.73%, P = 0.52) between subjects with high and normal SS. Multivariate regression analysis revealed that high DS (OR 1.08, 95% CI: 1.02 1.15, P = 0.010) and old age (OR 1.05, 95% CI: 1.01-1.10, P = 0.019), but not SS or percentage of circulating EPC, were independent predictors for decreased FMD. CONCLUSIONS: Our results demonstrated that, in subjects without significant CVD, a high DS was associated with impaired brachial FMD and depletion of circulating EPC. However, only DS, but not SS or EPC count, was an independent predictor for impaired brachial FMD. PMID- 21681867 TI - Serotonin transporter gene and childhood trauma--a G * E effect on anxiety sensitivity. AB - BACKGROUND: Genetic factors and environmental factors are assumed to interactively influence the pathogenesis of anxiety disorders. Thus, a gene environment interaction (G * E) study was conducted with respect to anxiety sensitivity (AS) as a promising intermediate phenotype of anxiety disorders. METHOD: Healthy subjects (N = 363) were assessed for AS, childhood maltreatment (Childhood Trauma Questionnaire), and genotyped for functional serotonin transporter gene variants (5-HTTLPR/5-HTT rs25531). The influence of genetic and environmental variables on AS and its subdimensions was determined by a step-wise hierarchical regression and a multiple indicator multiple cause (MIMIC) model. RESULTS: A significant G * E effect of the more active 5-HTT genotypes and childhood maltreatment on AS was observed. Furthermore, genotype (LL)-childhood trauma interaction particularly influenced somatic AS subdimensions, whereas cognitive subdimensions were affected by childhood maltreatment only. CONCLUSIONS: Results indicate a G * E effect of the more active 5-HTT genotypes and childhood maltreatment on AS, with particular impact on its somatic subcomponent. PMID- 21681868 TI - Functional impairment in adults with past posttraumatic stress disorder: findings from primary care. AB - BACKGROUND: Although many patients with posttraumatic stress disorder (PTSD) experience a reduction in posttraumatic symptoms over time, little is currently known about the extent of their residual functional impairment. This study examines functional impairment in primary care patients with a history of PTSD as compared to patients with current PTSD, and those who never developed PTSD following exposure to trauma. METHODS: The sample consisted of 321 trauma-exposed low-income, predominantly Hispanic adults attending a large urban primary care practice. PTSD was assessed with the Lifetime Composite International Diagnostic Interview and other psychiatric disorders with the SCID-I. Physical and mental health-related quality of life was assessed with the Medical Outcome Health Survey (SF-12), and functional impairment with items from the Sheehan Disability Scale and Social Adjustment Scale Self-Report. RESULTS: Logistic regression analyses controlling for gender, psychiatric comorbidity, and interpersonal traumas showed that although patients with past PTSD function significantly better than patients with current PTSD, they experience persisting deficits in mental health-related quality of life compared to trauma-exposed patients who never developed PTSD. Overall, results revealed a continuum of severity in psychiatric comorbidity, functioning, and quality of life, with current PTSD associated with the most impairment, never having met criteria for PTSD with the least impairment, and history of PTSD falling in between. CONCLUSIONS: In this primary care sample, adults with a history of past PTSD but no current PTSD continued to report enduring functional deficits, suggesting a need for ongoing clinical attention. PMID- 21681869 TI - Further evidence for the efficacy of association splitting as a self-help technique for reducing obsessive thoughts. AB - BACKGROUND: Despite improved treatment options, many people with obsessive compulsive disorder (OCD) do not seek or even actively avoid therapy due to shame or fear of stigmatization. Self-help treatment is increasingly acknowledged as a means to "treat the untreated" and to motivate patients for face-to-face psychotherapy. Our group has gathered preliminary evidence for the efficacy of a novel self-help approach entitled association splitting (AS) aimed at the reduction of obsessions. METHODS: For this study, a total of 46 participants with a likely diagnosis of OCD were randomly allocated to either AS or a waitlist control (WL). Treatment consisted of the self-study of a manual sent via e-mail. At baseline and four weeks later symptoms were assessed online using the self report version of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Obsessive-Compulsive Inventory-Revised (OCI-R), and the Beck Depression Inventory (BDI). RESULTS: A total of 74% of the initial sample took part in the re assessment. Results were in accordance with prior uncontrolled data indicating that AS is a feasible approach leading to a symptom decline of approximately 25% on the Y-BOCS. The technique also exerted a positive effect on depression (BDI) and the OCI-R subscale obsessive thoughts. CONCLUSIONS: The study confirms the feasibility and efficacy of AS for a subgroup of patients with OCD. Ongoing studies explore whether short-term effects are maintained over time and whether therapist-guided therapy may enhance the efficacy of AS. PMID- 21681870 TI - Classification of trauma and stressor-related disorders in DSM-5. AB - This review examines the question of whether there should be a cluster of disorders, including the adjustment disorders (ADs), acute stress disorder (ASD), posttraumatic stress disorder (PTSD), and the dissociative disorders (DDs), in a section devoted to abnormal responses to stress and trauma in the DSM-5. Environmental risk factors, including the individual's developmental experience, would thus become a major diagnostic consideration. The relationship of these disorders to one another is examined and also their relationship to other anxiety disorders to determine whether they are better grouped with anxiety disorders or a new specific grouping of trauma and stressor-related disorders. First how stress responses have been classified since DSM-III is reviewed. The major focus is on PTSD because it has received the most attention, regarding its proper placement among the psychiatric diagnoses. It is discussed whether PTSD should be considered an anxiety disorder, a stress-induced fear circuitry disorder, an internalizing disorder, or a trauma and stressor-related disorder. Then, ASD, AD, and DD are considered from a similar perspective. Evidence is examined pro and con, and a conclsion is offered recommending inclusion of this cluster of disorders in a section entitled "Trauma and Stressor-Related Disorders." The recommendation to shift ASD and PTSD out of the anxiety disorders section reflects increased recognition of trauma as a precipitant, emphasizing common etiology over common phenomenology. Similar considerations are addressed with regard to AD and DD. PMID- 21681871 TI - Decision making for depression treatment during pregnancy and the postpartum period. AB - BACKGROUND: To explore women's perspectives about the treatment decision-making process for depression during pregnancy and after birth. METHOD: One hundred pregnant and postpartum women completed an anonymous web-based surveys regarding treatment decision making for depression. RESULTS: Survey data reveal that most women in this sample prefer an active collaborative role in treatment decision making for depression. Sixty-five percent of the sample made a decision for treatment of their major depressive disorder, including a decision for no treatment, and 34% reported not having made a decision or feeling unsure about their decision. More than half of the sample preferred combination treatment with medications and counseling (55%) followed by counseling (22%), no treatment (8%), and medications (8%). Overall, respondents in this sample had low levels of decisional conflict (uncertainty) with younger women in the sample reporting higher levels of decisional conflict. CONCLUSIONS: Treatment decision making for depression during the perinatal period is complex. Asking women about their preferences for participation in decision making, their treatment preferences and their decision making needs during the clinical encounter may lead to improved communication, decision making and quality of care. PMID- 21681873 TI - Distress tolerance and obsessions: an integrative analysis. AB - BACKGROUND: Recent research implicates a potential relationship between poor distress tolerance (DT) and obsessive-compulsive disorder (OCD) and obsessions in particular, though this evidence has been largely indirect. We sought to examine the incremental and specific associations between DT and obsessions using multiple methodologies. METHODS: We conducted three separate studies using independent nonclinical samples (total N=558) that involved cross-sectional (Study 1) and prospective self-report designs (Study 2), as well as the use of an in vivo neutralization task (Study 3). RESULTS: Poor DT was specifically associated with obsessing but not other OCD symptoms, even when covarying for several theoretically relevant constructs. Further, poor DT was predictive of residual change in obsessing symptoms 1-month later. Poor DT was also associated with neutralization in response to an OCD-like intrusion and postneutralization period anxiety. CONCLUSIONS: These consistent findings provide support for an important relationship between DT and obsessions and suggest that interventions targeting DT may have special benefit for the treatment of obsessions. PMID- 21681872 TI - Are consumers of Internet health information "cyberchondriacs"? Characteristics of 24,965 users of a depression screening site. AB - BACKGROUND: The number of individuals looking for health information on the Internet continues to expand. The purpose of this study was to understand the prevalence of major depression among English-speaking individuals worldwide looking for information on depression online. METHODS: An automated online Mood Screener website was created and advertised via Google AdWords, for 1 year. Participants (N = 24,965) completed a depression screening measure and received feedback based on their results. Participants were then invited to participate in a longitudinal mood screening study. RESULTS: Of the 24,965 who completed the screening, 66.6% screened positive for current major depression, 44.4% indicated current suicidality, and 7.8% reported a recent (past 2 weeks) suicide attempt. Of those consenting to participate in the longitudinal study (n = 1,327 from 86 countries), 77.4% screened positive for past depression, 64.6% reported past suicidality, and 17.5% past suicide attempt. Yet, only 25% of those screening positive for current depression, and only 37.2% of those reporting a recent suicide attempt are in treatment. CONCLUSION: Many of the consumers of Internet health information may genuinely need treatment and are not "cyberchondriacs." Online screening, treatment, and prevention efforts may have the potential to serve many currently untreated clinically depressed and suicidal individuals. PMID- 21681874 TI - Graphene oxide-peptide conjugate as an intracellular protease sensor for caspase 3 activation imaging in live cells. PMID- 21681875 TI - Reaction of frustrated Lewis pairs with conjugated ynones-selective hydrogenation of the carbon-carbon triple bond. PMID- 21681877 TI - Synthesis of gem-difluorinated cyclopropanes and cyclopropenes: trifluoromethyltrimethylsilane as a difluorocarbene source. PMID- 21681876 TI - Noninvasive photoacoustic microscopy of living cells in two and three dimensions through enhancement by a metabolite dye. PMID- 21681878 TI - Unexpected bonding mode of the diboran(4)yl ligand: combining the boryl motif with a dative Pt-B interaction. PMID- 21681879 TI - Total synthesis of synechoxanthin through iterative cross-coupling. PMID- 21681880 TI - N-methylation of the amide bond by methyltransferase asm10 in ansamitocin biosynthesis. AB - Ansamitocins are potent antitumor agents produced by Actinosynnema pretiosum. As deduced from their structures, an N-methylation on the amide bond is required among the various modifications. The protein encoded by asm10 belongs to the SAM dependent methyltransferase family. Through gene inactivation and complementation, asm10 was proved to be responsible for the N-methylation of ansamitocins. Asm10 is a 33.0 kDa monomer, as determined by gel filtration. By using N-desmethyl-ansamitocin P-3 as substrate, the optimal temperature and pH for Asm10 catalysis were determined to be 32 degrees C and 10.0, respectively. Asm10 also showed broad substrate flexibility toward other N-desmethyl-ansamycins and synthetic indolin-2-ones. Through site-directed mutagenesis, Asp154 and Leu155 of Asm10 were confirmed to be essential for its catalysis, possibly through the binding of SAM. The characterization of this unique N methyltransferase has enriched the toolbox for engineering N-methylated derivatives from both natural and synthetic compounds; this will allow known potential drugs to be modified. PMID- 21681881 TI - Efficient suppression of gene expression by targeting 5'-UTR-based RNA quadruplexes with bisquinolinium compounds. PMID- 21681883 TI - T1, T2 state energies and electron affinities of small alpha,omega diphenylpolyenes investigated by anion photodetachment photoelectron spectroscopy and excited-state theory. AB - Photodetachment photoelectron spectroscopy (PD-PES) on molecular radical anions provides electron affinities and direct spectroscopic access to the lowest triplet states T(1) and T(2) of the corresponding neutral molecules. Herein, we apply this method to investigate trans-stilbene (SB), all-trans-1,4-diphenyl-1,3 butadiene (DPB), and all-trans-1,6-diphenyl-1,3,5-hexatriene (DPH). Our gas-phase T(1) energies agree with previous measurements on condensed crystals. The T(2) state energies are determined in this work for the first time. Experimental electron affinities, neutral excited-state transition energies and intensities are compared to theoretical data calculated by using DFT (ground states) or DFT/MRCI (excited states) methods. We give an explanation why intersystem crossing is of minor importance in all three compounds although the T(2) states are situated close below the S1 states. PMID- 21681882 TI - Subcellular protein localization by using a genetically encoded fluorescent amino acid. PMID- 21681884 TI - Tuning of photocatalytic hydrogen production and photoinduced intramolecular electron transfer rates by regioselective bridging ligand substitution. AB - Artificial photosynthesis based on supramolecular photocatalysts offers the unique possibility to study the molecular processes underlying catalytic conversion of photons into chemical fuels in great detail and to tune the properties of the photocatalyst by alterations of the molecular framework. Herein we focus on both possibilities in studying the photocatalytic reduction of protons by derivatives of the well-known photocatalyst [(tbbpy)(2)Ru(tpphz)PdCl(2)](PF(6))(2) [4,4'-di-tert-butyl-2,2'-bipyridine (tbbpy), tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]phenazine (tpphz)]. We report on a modified photocatalyst where the crucial bridging ligand tpphz is substituted by bromine and investigate the effect of the structural variation on the catalytic properties of the complex and its ultrafast intramolecular charge transfer behavior. It is found that structural modification stabilizes the phenanthroline-centered metal-to-ligand charge-transfer state on the tpphz moiety, thereby reducing the electron transfer gradient across the entire electron-relaying bridging ligand and at the same time accelerating nanosecond ground-state recovery. The same structural modifications cause an overall reduction of the catalytic activity of the complex. Thus, the results highlight the potential of small structural variations in the molecular framework of supramolecular catalysts in understanding the photoinduced charge-transfer processes and optimizing their catalytic performance. PMID- 21681887 TI - Testing the strength of biodegradable stents. PMID- 21681888 TI - A randomized comparison of manual versus mechanical thrombus removal in primary percutaneous coronary intervention in the treatment of ST-segment elevation myocardial infarction (TREAT-MI). AB - OBJECTIVES: The objective of this study was to compare the efficacy and long-term clinical outcome of manual thrombus aspiration with the Export catheter (Medtronic, Minneapolis, MN) versus mechanical thrombus cutting/aspiration with the X-sizer system (eV3, White Bear Lake, MN) in primary percutaneous coronary intervention (PPCI). BACKGROUND: In PPCI for acute ST-segment elevation myocardial infarction (STEMI), markers of myocardial reperfusion are improved with adjunctive thrombectomy. Previous studies of different devices showed a variability in performance, suitability, and short-term clinical outcome. In current literature, no direct comparison is available. METHODS: We prospectively randomized 201 patients admitted for PPCI for STEMI to either the Export catheter or the X-sizer prior to stent deployment. Technical success in advancing to and across the lesion, improvement of flow, reduction of thrombus, and the effect on ST-segment resolution were examined. The primary endpoint of the follow-up study was the combined endpoint of cardiac death, recurrent myocardial infarction (MI), or target-vessel revascularization (TVR) at 3 years. RESULTS: Although the Export catheter was more successfully deployed, other procedural parameters were similar with a trend toward better ST-segment resolution (56.6% vs. 44%; P = 0.06) as compared to the X-sizer system. The occurrence of the primary clinical endpoint at 3 years was 22.2% and 18.6%, respectively (HR 1.20; 95% CI 0.65-2.22; P = 0.35). CONCLUSION: Despite shorter procedural times, better lesion crossing, and fewer complications, both surrogate endpoints as well as 3-year clinical follow up were similar with the use of the Export catheter as compared to the X-sizer system. PMID- 21681889 TI - Comparison between thrombus removal devices: aspirations meet reality. PMID- 21681890 TI - What can we do for patients undergoing saphenous vein graft interventions? PMID- 21681891 TI - I am left handed but work on the right: most of the time now. PMID- 21681892 TI - Optimizing femoral access outcomes: how far can we go? PMID- 21681893 TI - Radials are not small femorals: perforations should be minor events. PMID- 21681894 TI - Saphenous vein graft recanalization without embolic protection: impossible is nothing. PMID- 21681895 TI - "Once upon a time there was ... intracoronary thrombolysis". PMID- 21681896 TI - Approaching the aortic valve: still some legwork to do! PMID- 21681897 TI - Hybrid approach for treating recoarctation in infants and small children after Norwood procedure. PMID- 21681899 TI - Closing in on large hole closure. PMID- 21681898 TI - Comparison of closure strategies after balloon aortic valvuloplasty: suture mediated versus collagen based versus manual. AB - OBJECTIVES: To compare complication rates of a collagen-mediated closure device, suture-mediated closure technique and manual compression for access site management following balloon aortic valvuloplasty (BAV). BACKGROUND: Vascular complications, including perforation, limb ischemia, ateriovenous fistulas, and pseudoaneurysm, are a common source of morbidity in patients undergoing BAV with large bore femoral artery access. The available options for closure of the access site include manual compression, suture-mediated closure devices, and recently reported collagen-based closure devices. METHODS: The study cohort consisted of 333 patients with severe aortic stenosis undergoing BAV. Patients were divided into four groups according to access closure method: (1) Manual compression in 64 (19.2%); (2) Proglide 6 Fr in 162 (48.6%); (3) Angio-Seal 8 Fr in 89 (26.75%); and (4) Prostar 10 Fr in 18 (5.4%). RESULTS: There were no significant differences in baseline characteristics among the groups; although the Prostar group was had more males and the Angio-Seal group reported a lower incidence of renal failure and peripheral vascular disease. The Angio-Seal group had shorter procedural duration times compared with the other groups. In the Angio-Seal group (n = 47, 52.8%), a 10 Fr sheath size was primarily used to access the femoral artery, as compared with the manual compression and Proglide groups, which used a 12 Fr sheath in 29 (45.3%) and 66 patients (40.7%), respectively. A 13 Fr sheath was used in the Prostar group (n = 11, 61.1%), P < 0.001. The device failure rate was significantly higher in the Proglide group (n = 20, 12.3%) as compared with Angio-Seal (n = 3, 3.3%) and Prostar groups (n = 1, 5.5%), P = 0.03. Serious vascular complications requiring intervention were significantly higher in the manual compression group (n = 11, 17.1%) compared with the Proglide (n = 11, 6.7%), Angio-Seal (n = 5, 5.6%), and Prostar groups (n = 5, 1%), P < 0.001. The requirement for blood transfusion in the Angio-Seal group was significantly lower (n = 7, 7.8%) as compared with the manual compression (n = 20, 31.2%), Proglide (n = 35, 21.6%), and Prostar groups (n = 5, 27.7%), P < 0.001. CONCLUSION: In our case series, collagen-based closure devices and suture-mediated closure devices had fewer vascular complications than manual compression for hemostasis following BAV. Patient selection for collagen-based versus suture-mediated closure requires further study. PMID- 21681900 TI - Transaortic flow velocity from dual-source MDCT for the diagnosis of aortic stenosis severity. AB - OBJECTIVES: To describe a method for the estimation of transaortic flow from multidetector computer tomography (MDCT). BACKGROUND: Cardiac MDCT may not allow instantaneous flow measurement yet the components of flow, namely, volume change over time and lumenal area are recorded. METHODS: In 36 patients, the transaortic flow velocity was determined on transthoracic echocardiography and also with cardiac MDCT as follows: On MDCT an axial orientation through the aortic root was obtained so that the nadir of all three aortic leaflets could be seen simultaneously in one axial image. Aortic valve area (AVA) was determined by planimetry and left ventricular volumes by endocardial border mapping at every 5% increment of the RR intervals. Flow velocity was then calculated as the incremental ejection volume / duration of the increment / AVA. RESULTS: The transthoracic echocardiography (TTE) peak velocity and MDCT peak velocity were highly correlated (r = 0.75, P < 0.01). Transaortic peak velocity was higher when measured by MDCT as compared to TTE, with respectively a median [IQ-range] of 4.5 [2.9-5.3] and 4.0 [3.0-4.6], P < 0.01. For the diagnosis of severe aortic stenosis greater concordance with TTE peak velocity was seen with MDCT peak velocity (sensitivity 100%, specificity 76%) than with MDCT AVA (sensitivity 74%, specificity 76%). CONCLUSIONS: We show for the first time that transaortic flow velocity can be estimated by dual-source MDCT and has a better sensitivity for the detection of severe aortic stenosis than AVA planimetry when compared to the gold standard of TTE peak flow velocity. PMID- 21681901 TI - Use of a dose-dependent follow-up protocol and mechanisms to reduce patients and staff radiation exposure in congenital and structural interventions. AB - BACKGROUND: Increasingly complex structural/congenital cardiac interventions require efforts at reducing patient/staff radiation exposure. Standard follow-up protocols are often inadequate in detecting all patients that may have sustained radiation burns. METHODS: Single-center retrospective chart review divided into four intervals. Phase 1 (07/07-06/08, 413 procedures (proc)): follow-up based on fluoroscopy time only; frame rate for digital acquisition (DA) 30 fps, and fluoroscopy (FL) 30 fps. Dose-based follow-up was used for phase 2-4. Phase 2 (07/08-08/09, 458 proc): DA: 30 fps, FL: 15 fps. Phase 3 (09/09-06/10, 350 proc): DA: 15-30 fps, FL: 15 fps, use of added radiation protection drape. Phase 4 (07/10-10/10, 89 proc): DA: 15-30 fps, FL: 15 fps, superior noise reduction filter (SNRF) with high-quality fluoro-record capabilities. RESULTS: There was a significant reduction in the median cumulative air kerma between the four study periods (710 mGy vs. 566 mGy vs. 498 mGy vs. 241 mGy, P < 0.001), even though the overall fluoroscopy times remained very similar (25 min vs. 26 min vs. 26 min vs. 23 min, P = 0.957). There was a trend towards lower physician radiation exposure over the four study periods (137 mrem vs. 126 mrem vs. 108 mrem vs. 59 mrem, P = 0.15). Fifteen patients with radiation burns were identified during the study period. When changing to a dose-based follow-up protocol (phase 1 vs. phase 2), there was a significant increase in the incidence of detected radiation burns (0.5% vs. 2%, P = 0.04). CONCLUSIONS: Dose-based follow-up protocols are superior in detecting radiation burns when compared to fluoroscopy time-based protocols. Frame rate reduction of fluoroscopy and cine acquisition and use of modified imaging equipment can achieve a significant reduction to patient/staff exposure. PMID- 21681902 TI - Radiation dose: it is more than just "time". PMID- 21681903 TI - Two-stage percutaneous closure of mitral periprosthetic valvular leak. AB - Periprosthetic valve leak can develop as a complication of valve replacement surgery and may manifest as symptomatic valvular regurgitation, heart failure, or haemolysis. We report a case of severe mitral periprosthetic valve leak requiring a two-stage percutaneous closure technique with multiple Amplatzer(r) III vascular plugs. PMID- 21681904 TI - Technique of temporary subcutaneous "Figure-of-Eight" sutures to achieve hemostasis after removal of large-caliber femoral venous sheaths. AB - Over the last decade, significant advances have been made in percutaneous treatment of structural heart diseases. Many of these interventions require insertion of large caliber sheaths in the femoral veins. Manual compression, compression devices, and various closure devices have been used for removal of large-sized venous sheaths. Here, we describe the use of a temporary subcutaneous "Figure-of-Eight" suture technique for venous access site closure after removal of large-caliber sheaths. PMID- 21681905 TI - Prognostic role of preprocedural glucose levels on short- and long-term outcome in patients undergoing percutaneous coronary revascularization. AB - OBJECTIVES: We investigated the prognostic role of preprocedural blood glucose levels (BGLs) on short- and long-term outcome in patients undergoing elective percutaneous coronary intervention (PCI). BACKGROUND: Hyperglycemia and hypoglycemia, with or without pre-existing diabetes mellitus, are associated with adverse outcome in patients with coronary artery disease. Moreover, neointimal hyperplasia after coronary stent implantation is increased in presence of suboptimal glycemic control. METHODS: Preprocedural BGLs were prospectively measured in 572 patients and predefined groups were considered: hypoglycemia <= 80 mg/dl; euglycemia 81-109 mg/dl; mild hyperglycemia 110-125 mg/dl; hyperglycemia >= 126 mg/dl. Primary end point was represented by the incidence of peri-procedural myocardial infarction (MI) and secondary end point was the occurrence of major adverse cardiac events (MACE) at follow-up. RESULTS: Hypoglycemia was associated with an increased risk of peri-procedural MI (51% vs 30%, 29%, and 37% in euglycemia, mild hyperglycemia and hyperglycemia groups, respectively; P for trend 0.025). After a mean follow-up of 15 +/- 8 months, the occurrence of MACE was 38% in the hypoglycemia group, 12% in the euglycemia group, 14% in the mild hyperglycemia and 22% in the hyperglycemia group (P < 0.001). The incidence of in-stent restenosis and target vessel revascularization was also higher in patients with abnormal pre-procedural BGLs (P for trend 0.007 and <0.001, respectively). Multivariate analysis confirmed hypoglycemia as a predictor of early and long-term unfavorable cardiac prognosis (OR = 2.53, 95% CI 1.09-5.81, P = 0.029 for peri-procedural MI; OR = 2.91, 95% CI 1.26-6.69, P = 0.012 for MACE occurrence). CONCLUSIONS: We observed a significant association between preprocedural BGLs and adverse short-and long-term outcome in patients undergoing elective PCI. Thus, a careful glycemic monitoring should be recommended in all patients undergoing coronary stenting, irrespective of the diabetic status. PMID- 21681906 TI - Then and now--a 25-year perspective of the journal Luminescence. PMID- 21681907 TI - The role of UV-irradiation pretreatment on the degradation of 2,4 dichlorophenoxyacetic acid in water. AB - The degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) in water by the combination process of UV-irradiation, humic acids and activated sludge treatment has been studied. The photoreaction rate of all irradiated samples was lowest for the sample irradiated at 308 nm (the XeCl excilamp) in the absence and in the presence of humic acids, and highest for the sample irradiated at 222 nm (the KrCl excilamp). Photolysis of 2,4-D has been shown to enhance the subsequent microbial degradation. PMID- 21681908 TI - The relationship between exhaled carbon monoxide and human neutrophil function in the Japanese general population. AB - We have evaluated the relationship between exhaled carbon monoxide (CO) level and neutrophil-related functions such as reactive oxygen species (ROS) production capability, phagocytic activity and serum opsonic activity in the general population. Serum opsonic activity was determined by measuring the effects of serum on neutrophil ROS production capability using lucigenin- and luminol dependent chemiluminescence (LgCL, LmCL). LgCL is associated with the detection of O(2)(-) , whereas LmCL mainly detects H(2)O(2) and HOCl, which are higher reactive oxygen radicals. In females, exhaled CO level was found to have positive associations with ROS production capability and LgCL. However, the opposite tendency was seen between exhaled CO level and LmCL in both genders. This result suggests that neutrophil ROS production in females may have contributed to oxidative stress, which led to the increases in intrinsic CO and exhaled CO consequently. Such changes then may have inhibited the process of changing reactive oxygen radicals into higher oxidizing potential levels. PMID- 21681909 TI - Practical application of bioluminescence enzyme immunoassay using enhancer for firefly luciferin-luciferase bioluminescence. AB - Firefly luciferin-luciferase bioluminescence is known for its high quantum yield (41.0 +/- 7.4%). Given this high quantum yield, application of this bioluminescence is expected to be useful in the field of clinical diagnostics. The kinetic profile of this bioluminescence exhibits an instant rise (<1 s) and a rapid decay in light emission (decreased to 42% after 5 s). In this study, we applied four enhancers including coenzyme A, inosine5'-triphosphate sodium salt, sodium tripolyphosphate and potassium pyrophosphate to prolong light emission. When these enhancers were used, luminescence was only decreased to 89, 83, 87 and 82% after 5 s, respectively. These materials modified the kinetic profile of bioluminescence so that the luminescence is more suitable for clinical application. It becomes more suitable because they enable highly sensitive integration and simplification of a device by separating luminescence measurements from dispensing of reagents. Using these enhancers, we then developed a bioluminescent enzyme immunoassay (BLEIA) for hepatitis B virus surface antigen (HBsAg) that employed firefly luciferase as a labeling enzyme. We compared the results obtained from the HBsAg BLEIA method with the conventional chemiluminescent enzyme immunoassay method, and found a satisfactory correlation (r=0.984, n=118). PMID- 21681910 TI - Radical scavenging ability of some compounds isolated from Piper cubeba towards free radicals. AB - The purpose of this study was to identify the antioxidant activity of 16 compounds isolated from Piper cubeba (CNCs) through the extent of their capacities to scavenge free radicals, hydroxyl radical (HO(*)), superoxide anion radical O*(2)(-) and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH(*)), in different systems. Electron paramagnetic resonance (EPR) and 5,5-dimethyl-1 pyrroline-N-oxide, DMPO, as the spin trap, and chemiluminescence techniques were applied. Using the Fenton-like reaction [Fe(II) + H(2)O(2)], CNCs were found to inhibit DMPO-OH radical formation ranging from 5 to 57% at 1.25 mmol L(-1) concentration. The examined CNCs also showed a high DPPH antiradical activity (ranging from 15 to 99% at 5 mmol L(-1) concentration). Furthermore, the results indicated that seven of the 16 tested compounds may catalyse the conversion of superoxide radicals generated in the potassium superoxide/18-crown-6 ether system, thus showing superoxide dismutase-like activity. The data obtained suggest that radical scavenging properties of CNCs might have potential application in many plant medicines. PMID- 21681911 TI - Reduced-oxidized difference spectral analysis and chemiluminescence-based Scatchard analysis demonstrate selective binding of myeloperoxidase to microbes. AB - Myeloperoxidase (MPO), a microbicidal haloperoxidase of neutrophil leukocytes, was observed to selectively bind to bacteria. Binding was quantified by dithionite-reduced minus oxidized (R-O) difference spectral analysis. Escherichia coli and Pseudomonas aeruginosa showed large MPO binding by R-O difference spectral analysis, whereas Streptococcus sanguinis did not. For increased sensitivity, free and microbe-bound MPO and chloroperoxidase (CPO) activities were quantified by acid-optimum haloperoxidase-dependent chemiluminescence (CL) measurements, and these data were used for Scatchard analysis. The MPO bound/free (B/F) CL ratio was 49.5 for P. aeruginosa, 14.6 for Staphylococcus aureus, 2.8 for E. coli, 0.7 for Candida albicans and 0.4 for S. sanguinis. By comparison, the CPO B/F CL ratio was 0.03 for P. aeruginosa, 0.09 for S. aureus, 0.31 for E. coli, 0.18 for C. albicans and 0.16 for S. sanguinis. As a member of the lactic acid family of bacteria and a viridans streptococcus, S. sanguinis does not synthesize cytochromes and is catalase-negative. The metabolic products of S. sanguinis, i.e. lactic acid and hydrogen peroxide, provide optimal acidity and substrate for MPO oxidation of chloride to hypochlorite. Hypochlorite can react with organic substrates to yield dehydrogenated or chlorinated products, but when peroxide is not limiting, hypochlorite reacts with peroxide yielding singlet oxygen. The reactivity of hypochlorite is dependent on substrate availability. The microsecond half-life of electronically excited singlet oxygen restricts reactivity to within a radius of <0.25 um; i.e. the reactivity of singlet oxygen is both substrate and half-life dependent. Poor MPO binding provides protection and possibly competitive advantage to viridans streptococci. PMID- 21681912 TI - Zinc(II)-selective ratiometric fluorescent probe based on perylene bisimide derivative. AB - A fluorescent probe of N,N'-biscyclohexyl-1,7-di(3-pyridoxy)-perylene-3,4:9,10 tetracarboxylic acid diimide has been synthesized, and exhibited excellent selectivity and sensitivity for Zn(2+) over other competing biological cations. The Zn(2+) -selective fluorescence blue-shift and enhancing property in conjunction with a visible colorimetric change from orange to green could be observed. With favorable photophysical properties in the visible region, the perylene bisimide derivatives remarkably improved the performance of the probe. PMID- 21681913 TI - Synthesis, characterization and luminescent properties of lanthanide complexes with an unsymmetrical tripodal ligand. AB - Solid complexes of lanthanide nitrates with an novel unsymmetrical tripodal ligand, butyl-N,N-bis[((2'-benzylaminofomyl)phenoxyl)ethyl]-amine (L) have been synthesized and characterized by elemental analysis, infrared spectra and molar conductivity measurements. At the same time, the luminescent properties of the Sm(III), Eu(III), Tb(III) and Dy(III) nitrate complexes in solid state were also investigated. Under the excitation of UV light, these complexes exhibited characteristic emission of central metal ions. PMID- 21681914 TI - Spectrofluorimetric determination of nomifensine in human plasma and urine by derivatization with fluorescamine. AB - A sensitive, simple and rapid spectrofluorimetric method was developed for the determination of nomifensine in human plasma and urine. The present method was based on the derivatization by fluorescamine in phosphate buffer at pH 4.0 to produce a highly fluorescent product which was measured at 488 nm (excitation at 339 nm). The method was validated according to the ICH guidelines with respect to linearity, limit of detection, limit of quantification, accuracy, precision, recovery and robustness. The assay was linear over the concentration ranges 100 2,000 and 50-2,000 ng/mL for plasma and urine, respectively. The limits of detection were calculated to be 13.9 and 7.5 ng/mL for plasma and urine, respectively. The method was successfully applied to the analysis of the drug in human plasma and urine.